CN109956952A - α-mangostin derivative and the preparation method and application thereof - Google Patents

α-mangostin derivative and the preparation method and application thereof Download PDF

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CN109956952A
CN109956952A CN201711336313.4A CN201711336313A CN109956952A CN 109956952 A CN109956952 A CN 109956952A CN 201711336313 A CN201711336313 A CN 201711336313A CN 109956952 A CN109956952 A CN 109956952A
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mangostin
added
group
hzam
derivative
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CN109956952B (en
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占扎君
单伟光
陈艳
舒仁欢
王建伟
马列峰
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Shanghai Ruling Biomedical Co ltd
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Zhejiang University of Technology ZJUT
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/78—Ring systems having three or more relevant rings
    • C07D311/80—Dibenzopyrans; Hydrogenated dibenzopyrans
    • C07D311/82—Xanthenes
    • C07D311/84—Xanthenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 9
    • C07D311/86—Oxygen atoms, e.g. xanthones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems

Abstract

Application the invention discloses a kind of α-mangostin derivative with logical structure shown in formula I and preparation method thereof and in preparation in the brain injury disease therapeuticing medicine as caused by ischemic, such as vascular dementia and cerebral infarction；The vascular dementia is it is characterized in that learning memory disorder or hippocampal dentate area cell loss to cause after vascular lesion, cerebral ischemia.

Description

α-mangostin derivative and the preparation method and application thereof
Technical field
The present invention relates to α-mangostin derivative and α-mangostin derivative preparation method and α-mangostin derivatives The application in ischemic brain damage therapeutic agent is being prepared, pharmaceutical technology field invention is belonged to.
Background technique
The brain diseases as caused by vascular lesions, it has also become a kind of disease for seriously endangering health, especially as China Elderly population it is increasing, this problem more looms large.Cerebral infarction refers to since brain blood supplies obstacle, ischemic, anoxic The clinical common type of the ischemic necrosis or cerebromalacia of caused limitation brain tissue, cerebral infarction has cerebral thrombosis, lacuna Property infarct and cerebral embolism etc., cerebral infarction account for the 80% of whole cerebral apoplexies.Vascular dementia (vascular dementia, VD) is Chronic brain syndrome caused by brain tissue damage is led to as cerebrovascular factor, morbidity accounts for about the 20% of the old cognitive disorder cause of disease, is At present after Alzheimer's disease, clinical incidence comes deputy cognitive disorder disease, seriously affects the life of patient Deposit quality.The cause of disease of vascular dementia is unknown so far, scientific investigations showed that causing the risk factor of vascular dementia numerous, causes a disease Factor is complicated, includes mainly global cerebral ischemia caused by sudden cardiac arrest, cerebral arterial thrombosis further includes hypertension, hyperlipidemia, glycosuria The chronic diseases factor such as disease.Cognitive disorder pathomechanism caused by vascular dementia may with common cognitive disorder, other are silly Cognitive disorder mechanism caused by staying is similar, but also has its particularity.In general, the pathomechanism of vascular dementia includes Vascular lesion, white matter lesions and hereditation etc., wherein vascular lesion is its pathogenic basis.
The therapeutic agent of cerebral infarction mainly has Edaravone and butylphenyl phthaleine, and there are also some drugs for prevention for remaining, such as Thrombolysis class drug.The therapeutic effect of Edaravone is simultaneously bad, and side effect is bigger, and main function is by anti-oxidant Effect.Butylphenyl phthaleine is pretty good to cerebral infarction therapeutic effect, and main function is to be worked by anti-inflammatory, but do not have to vascular dementia There is apparent therapeutic effect.The treatment to vascular dementia clinical at present, mainly to control based on the precautionary measures such as risk factor, Therapeutic agent (such as anticholinesterase) only alleviates symptom, is not directed to the specific aim medicine of vascular dementia in marketed drug Object, therefore urgent need finds the new protective agents of one kind and copes with this disease.
The compound of the present invention not only can treat the effect of cerebral infarction, but also also have good treatment to vascular dementia Effect.Mechanism Study the compound of the present invention has anti-inflammatory, anti-oxidant, neuroprotection, and the multiple actions such as Neural Differentiation have both The advantages of Edaravone and butylphenyl phthaleine.There are larger correlations with vascular lesion for the cause of disease based on cerebral infarction and vascular dementia, and Non- single factors cause neural cell injury, therefore carry out treatment for single factors and be extremely difficult to preferable therapeutic effect, than As some compounds have neuroprotection or anti-oxidant, but the effect for the treatment of cerebral infarction or vascular dementia is not had.Just It is there is multiple action due to compound of the present invention, and institute of the present invention is found by the evaluation of a large amount of animal experimental model The compound stated has good therapeutic effect to cerebral infarction and vascular dementia, so that compound of the present invention is clinically It can be used for the treatment of cerebral infarction and vascular dementia.In addition the compound described in this has good safety, therefore has huge Prospect in medicine.
Summary of the invention
In order to achieve the above objectives, the present invention provides a kind of α-mangostin derivatives and α-mangostin derivative preparation side Method and α-mangostin derivative are preparing the application in ischemic brain damage therapeutic agent.
α of the present invention-mangostin derivative, the derivative are such as general formula I compound represented.
Wherein, R1For H, C1-C6Linear or branched alkyl group；R2For C5-C6Cyclic hydrocarbon group, C1-C8Chain or branched alkane Base, phenyl, pyridyl group or substituted-phenyl, the substituent group of the substituted-phenyl are methyl, ethyl, chlorine, bromine, fluorine, methoxyl group, ammonia Base or nitro；Or R1、R2With N cyclization, the ring is containing N or simultaneously containing the six-membered cyclic heterocycle of N and O.
Further, the R1Preferably methyl or ethyl.
Further, the R2Preferably phenyl or aminomethyl phenyl.
Further, the R1、R2With N cyclization, the ring is morpholinyl, piperazinyl, N- substituted piperazinyl or piperidines Base.
Further, α shown in Formulas I of the present invention-mangostin derivative is one of following:
Further, α shown in Formulas I of the present invention-mangostin derivative preparation method, it is characterised in that: described α-mangostin derivative be prepared as follows:
(1) triphosgene is dissolved in the dichloromethane solution that methylene chloride is made into the triphosgene that concentration is 0.1~0.5mol/L, Under ice bath, the methylene chloride of nitrogenous compound shown in the formula III that concentration is 0.1~0.5mol/L is added dropwise in triphosgene solution After solution and triethylamine, 4~6h is stirred at room temperature, obtains reaction mixture A；Nitrogenous chemical combination shown in the triphosgene and formula III The ratio between amount of substance of object, triethylamine is 1:0.67~1.5:1.33~3；
(2) under ice bath, chemical combination shown in the formula II that concentration is 0.05~0.25mol/L is added dropwise into reaction mixture A The dichloromethane solution of object continues 4~6h of stirring, after reaction, the post-treated α-for obtaining Formulas I of gained reaction mixture B Mangostin derivative；The mass ratio of the material of II compound represented of formula and the triphosgene is 1:2.0~3.0.
Wherein, R1For H, C1-C6Linear or branched alkyl group, R2For C5-C6Cyclic hydrocarbon group, C1-C8Chain or branched alkane Base, phenyl, pyridyl group or substituted-phenyl, the substituent group of the substituted-phenyl are methyl, ethyl, chlorine, bromine, fluorine, methoxyl group, ammonia Base or nitro；Or R1、R2With N cyclization, the ring is containing N or simultaneously containing the six-membered cyclic heterocycle of N and O.
Further, the post-processing approach of the reaction mixture B are as follows: 3~6 times are added into gained reaction mixture B The distilled water of reaction mixture B volume, then be extracted with ethyl acetate 3-5 times, merge organic layer, to be saturated NaCl solution washing, It is dry with anhydrous Na 2SO4, it filters, the crude product of yellow oily is concentrated to give, then by crude product through petroleum ether: ethyl acetate body The mixed solvent that product ratio is 20:1 elutes, thin layer detection, collects the aobvious strong ultraviolet and polarity at 254nm and is less than accordingly such as formula II Compound eluent, merge eluent, decompression boil off product that eluting solvent obtains it is dry after up to α-shown in formula I Mangostin derivative.
Further, the compound of formula II of the present invention is prepared as follows:
α-mangostin is dissolved in toluene and is made into the toluene solution that concentration is 0.1~0.5mol/L, at room temperature, above-mentioned molten In liquid plus 2~3 times of equivalents 2,3- bis- chloro- 5,6 dicyanobenzoquinones (DDQ), it is to be dissolved it is complete after, 40 DEG C react 5~8 hours, it is thin Layer detection, vacuum distillation removes toluene, silica gel column chromatography separating purification, with petroleum ether: ethyl acetate volume ratio after reaction It is eluted for the mixed solvent of 10:1, thin layer detection, collects the aobvious strong ultraviolet and polarity at 254nm and be less than α-mangostin compound Eluent, merge eluent, decompression boil off product that eluting solvent obtains it is dry after up to the compound such as formula II；The α- Mangostin: the mass ratio of the material of DDQ is 1:2.0~3.0.
Further, α of the present invention-mangostin derivative treats the brain injury disease as caused by ischemic in preparation Application in the drug of disease, wherein brain injury disease is preferably vascular dementia and cerebral infarction.
Further, its learning memory disorder for causing for vascular lesion, after cerebral ischemia of the vascular dementia or sea Horse dentate fascia area cell loss.
More specifically, the present invention makes focal brain ischemia-reperfusion injury in rats model using Longa line brush, with This investigates α of the present invention-therapeutic effect of the mangostin derivative to models of cerebral ischemia-reperfusion injury rat.Experiment knot Fruit show the present invention the α-mangostin derivative can significantly reduce the brain infarction area of rat and reduce brain tissue and contain Water, illustrate the present invention the α-mangostin derivative have good therapeutic effect to cerebral infarction.The present invention uses MCAO line Bolt method causes cerebral ischemic simulated blood vessel dull-witted, by Morris water maze laboratory and spacious field experimental evaluation drug to vascular The effect of the Spatial memory ability of dementia rats, and cellular morphology variation in Hippocampal CA 1 is observed by Nissl's staining, it probes into α of the present invention-therapeutic effect of the mangostin derivative to the treatment of vascular dementia.Experimental result, which is shown, gives different doses The rat that α of the present invention-mangostin derivative of amount can be shortened ischemic induction finds platform preclinical time, spacious field Middle exploratory behaviour restores obvious, and can reverse the damage of Hippocampal CA 1 cell.Illustrate the present invention the α-mangostin spread out Biology has good therapeutic effect to vascular dementia.
Compared with prior art, the beneficial effects of the present invention are:
While α of the present invention-mangostin derivative remains α-mangostin active constituent, compound is reduced Toxicity.α of the present invention-mangostin derivative has good therapeutic effect to vascular dementia, and activity is better than sun The property more naphthalene piperazines of medicine are neat.α of the present invention-mangostin derivative has good therapeutic effect to cerebral infarction, and activity is obvious strong It is suitable with butylphenyl phthaleine in Edaravone；Edaravone and butylphenyl phthaleine are substantially better than to the improvement of brain water content.This illustrates this Invention α-mangostin the derivative to the combined therapy effect of cerebral infarction be better than the market frontline similar drugs Edaravone and Butylphenyl phthaleine.In addition α of the present invention-mangostin derivative has high safety, under 2g/Kg intraperitoneal injection dosage, Experimental animal does not show any ill symptoms, and parent compound α-mangostin median lethal dose is 200mg/Kg.Therefore α of the present invention-mangostin derivative has wide answer in the brain injury disease treatment as caused by ischemic in preparation Use prospect.
Detailed description of the invention
The influence tested vascular dementia rats Morris water maze is administered in Fig. 1 HZAM-1 of the present invention.
Fig. 2 HZAM-1 of the present invention administration is to crossing over grid number in vascular dementia rats spacious field space exploration behavior Influence.
Fig. 3 HZAM-1 administration of the present invention lifts forearm in vascular dementia rats spacious field space exploration behavior secondary Several influences.
Fig. 4 HZAM-1 administration of the present invention stops center lattice in vascular dementia rats spacious field space exploration behavior The influence of time.
Fig. 5 Nissl's staining sham-operation group Hippocampal CA 1 figure.
Fig. 6 Nissl's staining model group Hippocampal CA 1 figure.
Fig. 7 Nissl's staining HZAM-1 administration group Hippocampal CA 1 figure.
Specific embodiment
The present invention is further described in conjunction with the accompanying drawings and embodiments, but does not therefore limit the present invention to the reality Within the scope of applying.
The synthesis of embodiment 1: α-mangostin derivative HZAM-1 (synthetic route chart is as shown in Figure 1)
Take α-mangostin (40mg, 0.1mmol) in toluene solution, stirring is to dissolving, and solution is in yellow at this time, adds 2,3- Two chloro- 5,6 dicyanobenzoquinones (DDQ, 45mg, 0.2mmol), 40 DEG C are reacted, and are detected in reaction process with TLC, and knot is reacted after 5 hours Beam, vacuum distillation remove toluene, and silica gel column chromatography separating purification obtains yellow solid compound HZA, yield 85%.
BTC (60mg, 0.202mmol) is weighed in 25mL two-mouth bottle, is added 5mL anhydrous methylene chloride, magnetic agitation, It is added equivalent methylphenylamine, triethylamine (0.25mmol) and 5mL methylene chloride in 25mL constant pressure funnel, under ice bath, It is slowly added dropwise, completion of dropwise addition recession deicing salt bath stirs 4h at room temperature.
HZA (40mg, 0.1mmol) is added in 10ml single port bottle, trace DMAP, 5mL methylene chloride is added, at room temperature magnetic Power is stirred to being completely dissolved.Solution is slowly dropped in upper step reaction solution under ice salt bath, completion of dropwise addition removes ice salt bath, room temperature Lower stirring.After the reaction was completed, the distilled water of 3~6 times of reaction solution volumes is added in above-mentioned reaction solution, then is extracted with ethyl acetate 3-5 times, merge organic layer, to be saturated NaCl solution washing, uses anhydrous Na2SO4It is dry, it filters, is concentrated to give the thick production of yellow oily Object, then by crude product through petroleum ether: the mixed solvent that ethyl acetate volume ratio is 20:1 elutes, and thin layer detection is collected The eluent that strong ultraviolet and polarity is less than HZA is shown under 254nm, merges eluent, it is dry that decompression boils off the product that eluting solvent obtains Up to HZAM-1, yield 90% after dry.
HZAM-1:ESI-MS m/z:540([M-H]-,C32H31NO7)；1H-NMR(CDCl3)δ:13.55(1H,s,5-OH), 7.46-7.40 (5H, m, Ar-H), 7.26 (1H, s, H-10), 6.74 (1H, d, J=10.2Hz, H-4), 6.26 (1H, s, H- 12), 5.59 (1H, d, J=10.1Hz, H-3), 5.20 (1H, s, H-14), 4.12 (1H, s, H-13), 4.11 (1H, s, H-13), 3.46(3H,s,8-OCH3),3.39(3H,s,N-CH3),1.83(3H,s,17-CH3),1.68(3H,s,16-CH3),1.48 (6H,s,18,19-CH3)；13C-NMRδ:182.2,160.3,158.0,156.4,153.8,152.4,149.5,146.7, 142.5,138.5,131.9,130.9,129.6,129.3,128.9,127.2,127.2,123.1,116.3,115.6, 110.4,104.5,104.0,94.2,78.1,61.6,38.6,28.4,28.4,26.3,25.8,19.2.
The synthesis of embodiment 2: α-mangostin derivative HZAM-2 (synthetic route chart is as shown in Figure 1)
The synthetic method of compound HZA is same as above.
BTC (58mg, 0.2mmol) is weighed in 25mL two-mouth bottle, 5mL anhydrous methylene chloride, magnetic agitation, 25mL is added It is added equivalent N-ethylaniline, triethylamine (0.25mmol) and 5mL methylene chloride in constant pressure funnel, under ice bath, slowly It is added dropwise, completion of dropwise addition recession deicing salt bath stirs 4h at room temperature.
HZA (40mg, 0.1mmol) is added in 10ml single port bottle, trace DMAP, 5mL methylene chloride is added, at room temperature magnetic Power is stirred to being completely dissolved.Solution is slowly dropped in upper step reaction solution under ice salt bath, completion of dropwise addition removes ice salt bath, room temperature Lower stirring.After the reaction was completed, the distilled water of 3~6 times of reaction solution volumes is added in above-mentioned reaction solution, then is extracted with ethyl acetate 3-5 times, merge organic layer, to be saturated NaCl solution washing, uses anhydrous Na2SO4It is dry, it filters, is concentrated to give the thick production of yellow oily Object, then by crude product through petroleum ether: the mixed solvent that ethyl acetate volume ratio is 20:1 elutes, and thin layer detection is collected The eluent that strong ultraviolet and polarity is less than HZA is shown under 254nm, merges eluent, it is dry that decompression boils off the product that eluting solvent obtains Up to HZAM-2, yield 94% after dry.
HZAM-2:ESI-MS m/z (%): 556 ([M+H]+,C33H33NO7)；1H-NMR(CDCl3)δ:13.55(1H,s,5- ), OH 7.45-7.36 (5H, m, Ar-H), 7.28 (1H, s, H-10), 6.74 (1H, d, J=10.1Hz, H-4), 6.25 (1H, s, ), H-12 5.58 (1H, d, J=10.1Hz, H-3), 5.19 (1H, s, H-14), 4.11 (1H, s, H-13), 4.10 (1H, s, H- 13),3.86(3H,s,8-OCH3),3.70(2H,m,N-CH2),1.83(3H,s,17-CH3),1.68(3H,s,16-CH3), 1.48(6H,s,18,19-CH3),1.28(3H,m,N-CH3)；13C-NMRδ:182.3,160.3,158.1,156.5,153.9, 152.1,149.6,146.8,141.1,138.4,131.8,129.3,129.0,128.5,127.7,127.5,127.4, 127.2,123.2,116.2,115.7,110.4,104.6,104.1,94.2,78.0,61.5,52.7,46.2,28.4,28.4, 26.4,25.6,18.2.
The synthesis of embodiment 3: α-mangostin derivative HZAM-3 (synthetic route chart is as shown in Figure 1)
The synthetic method of compound HZA is same as above.
BTC (58mg, 0.2mmol) is weighed in 25mL two-mouth bottle, 5mL anhydrous methylene chloride, magnetic agitation, 25mL is added Equivalent N- methyl o-toluidine, triethylamine (0.25mmol) and 5mL methylene chloride, ice bath are added in constant pressure funnel Under, it is slowly added dropwise, completion of dropwise addition recession deicing salt bath stirs 4h at room temperature.
HZA (40mg, 0.1mmol) is added in 10ml single port bottle, trace DMAP, 5mL methylene chloride is added, at room temperature magnetic Power is stirred to being completely dissolved.Solution is slowly dropped in upper step reaction solution under ice salt bath, completion of dropwise addition removes ice salt bath, room temperature Lower stirring.After the reaction was completed, the distilled water of 3~6 times of reaction solution volumes is added in above-mentioned reaction solution, then is extracted with ethyl acetate 3-5 times, merge organic layer, to be saturated NaCl solution washing, uses anhydrous Na2SO4It is dry, it filters, is concentrated to give the thick production of yellow oily Object, then by crude product through petroleum ether: the mixed solvent that ethyl acetate volume ratio is 20:1 elutes, and thin layer detection is collected The eluent that strong ultraviolet and polarity is less than HZA is shown under 254nm, merges eluent, it is dry that decompression boils off the product that eluting solvent obtains Up to HZAM-3, yield 89% after dry.
HZAM-3:ESI-MS m/z (%): 554 ([M-H]-,C33H33NO7)；1H-NMR(CDCl3)δ:13.55(1H,s,5- ), OH 7.32-7.26 (4H, m, Ar-H), 7.26 (1H, s, H-10), 6.74 (1H, d, J=10.0Hz, H-4), 6.26 (1H, s, ), H-12 5.58 (1H, d, J=10.0Hz, H-3), 5.17 (1H, s, H-14), 4.09 (1H, s, H-13), 4.08 (1H, s, H- 13),3.37(3H,s,8-OCH3),3.35(3H,s,N-CH3),2.40(3H,s,Ar-CH3),1.81(3H,s,17-CH3), 1.66(3H,s,16-CH3),1.48(6H,s,18,19-CH3)；13C-NMRδ:182.2,160.2,158.0,156.4,153.7, 152.5,149.6,146.6,141.0,138.4,135.6,131.8,131.1,128.3,127.4,127.2,126.4, 123.1,123.0,116.1,115.6,110.1,104.5,104.0,94.1,78.1,61.3,38.8,28.4,28.4,26.3, 25.8,18.2,17.4.
The synthesis of embodiment 4: α-mangostin derivative HZAM-4 (synthetic route chart is as shown in Figure 1)
The synthetic method of compound HZA is same as above.
BTC (58mg, 0.2mmol) is weighed in 25mL two-mouth bottle, 5mL anhydrous methylene chloride, magnetic agitation, 25mL is added Equivalent N- methyl m-toluidine, triethylamine (0.25mmol) and 5mL methylene chloride, ice bath are added in constant pressure funnel Under, it is slowly added dropwise, completion of dropwise addition recession deicing salt bath stirs 4h at room temperature.
HZA (40mg, 0.1mmol) is added in 10ml single port bottle, trace DMAP, 5mL methylene chloride is added, at room temperature magnetic Power is stirred to being completely dissolved.Solution is slowly dropped in upper step reaction solution under ice salt bath, completion of dropwise addition removes ice salt bath, room temperature Lower stirring.After the reaction was completed, the distilled water of 3~6 times of reaction solution volumes is added in above-mentioned reaction solution, then is extracted with ethyl acetate 3-5 times, merge organic layer, to be saturated NaCl solution washing, uses anhydrous Na2SO4It is dry, it filters, is concentrated to give the thick production of yellow oily Object, then by crude product through petroleum ether: the mixed solvent that ethyl acetate volume ratio is 20:1 elutes, and thin layer detection is collected The eluent that strong ultraviolet and polarity is less than HZA is shown under 254nm, merges eluent, it is dry that decompression boils off the product that eluting solvent obtains Up to HZAM-4, yield 92% after dry.
HZAM-4:ESI-MS m/z (%): 556 ([M+H]+,C33H33NO7)；1H-NMR(CDCl3)δ:13.55(1H,s,5- ), OH 7.33-7.19 (4H, m, Ar-H), 7.26 (1H, s, H-10), 6.74 (1H, d, J=10.0Hz, H-4), 6.26 (1H, s, ), H-12 5.59 (1H, d, J=10.1Hz, H-3), 5.20 (1H, s, H-14), 4.13 (1H, s, H-13), 4.12 (1H, s, H- 13),3.45(3H,s,8-OCH3),3.37(3H,s,N-CH3),2.40(3H,s,Ar-CH3),1.83(3H,s,17-CH3), 1.68(3H,s,16-CH3),1.48(6H,s,18,19-CH3)；13C-NMRδ:182.2,160.3,158.0,156.4,153.8, 152.4,149.5,146.7,142.4,139.2,138.4,131.9,129.3,129.0,127.2,123.2,123.2, 116.2,115.6,115.6,110.4,104.5,104.0,94.2,78.1,61.6,38.6,28.4,28.4,26.3,25.8, 21.3,18.2.
The synthesis of embodiment 5: α-mangostin derivative HZAM-5 (synthetic route chart is as shown in Figure 1)
The synthetic method of compound HZA is same as above.
BTC (58mg, 0.2mmol) is weighed in 25mL two-mouth bottle, 5mL anhydrous methylene chloride, magnetic agitation, 25mL is added Equivalent N- methyl open-chain crown ether, triethylamine (0.25mmol) and 5mL methylene chloride, ice bath are added in constant pressure funnel Under, it is slowly added dropwise, completion of dropwise addition recession deicing salt bath stirs 4h at room temperature.
HZA (40mg, 0.1mmol) is added in 10ml single port bottle, trace DMAP, 5mL methylene chloride is added, at room temperature magnetic Power is stirred to being completely dissolved.Solution is slowly dropped in upper step reaction solution under ice salt bath, completion of dropwise addition removes ice salt bath, room temperature Lower stirring.After the reaction was completed, the distilled water of 3~6 times of reaction solution volumes is added in above-mentioned reaction solution, then is extracted with ethyl acetate 3-5 times, merge organic layer, to be saturated NaCl solution washing, uses anhydrous Na2SO4It is dry, it filters, is concentrated to give the thick production of yellow oily Object, then by crude product through petroleum ether: the mixed solvent that ethyl acetate volume ratio is 20:1 elutes, and thin layer detection is collected The eluent that strong ultraviolet and polarity is less than HZA is shown under 254nm, merges eluent, it is dry that decompression boils off the product that eluting solvent obtains Up to HZAM-5, yield 91% after dry.
HZAM-5:ESI-MS m/z (%): 556 ([M+H]+,C33H33NO7)；1H-NMR(500MHz)δ:13.55(1H,s, 5-OH), 7.29-7.23 (4H, m, Ar-H), 7.26 (1H, s, H-10), 6.74 (1H, d, J=10.0Hz, H-4), 6.26 (1H, S, H-12), 5.58 (1H, d, J=10.0Hz, H-3), 5.20 (1H, s, H-14), 4.12 (1H, s, H-13), 4.11 (1H, s, H- 13),3.49(3H,s,8-OCH3),3.41(3H,s,N-CH3),2.38(3H,s,Ar-CH3),1.83(3H,s,17-CH3), 1.68(3H,s,16-CH3),1.48(6H,s,18,19-CH3)；13C-NMRδ:182.2,160.2,158.0,156.4,153.8, 152.6,149.6,146.8,142.6,138.4,131.9,129.9,127.2,127.2,126.3,123.0,123.0, 116.3,115.7,115.7,110.5,104.5,104.0,94.2,78.1,61.6,38.6,28.4,28.4,26.3,25.8, 21.0,18.2.
The synthesis of embodiment 6: α-mangostin derivative HZAM-6 (synthetic route chart is as shown in Figure 1)
The synthetic method of compound HZA is same as above.
BTC (58mg, 0.2mmol) is weighed in 25mL two-mouth bottle, 5mL anhydrous methylene chloride, magnetic agitation, 25mL is added Equivalent N- methyl o-aminoanisole, triethylamine (0.25mmol) and 5mL methylene chloride, ice bath are added in constant pressure funnel Under, it is slowly added dropwise, completion of dropwise addition recession deicing salt bath stirs 4h at room temperature.
HZA (40mg, 0.1mmol) is added in 10ml single port bottle, trace DMAP, 5mL methylene chloride is added, at room temperature magnetic Power is stirred to being completely dissolved.Solution is slowly dropped in upper step reaction solution under ice salt bath, completion of dropwise addition removes ice salt bath, room temperature Lower stirring.After the reaction was completed, the distilled water of 3~6 times of reaction solution volumes is added in above-mentioned reaction solution, then is extracted with ethyl acetate 3-5 times, merge organic layer, to be saturated NaCl solution washing, uses anhydrous Na2SO4It is dry, it filters, is concentrated to give the thick production of yellow oily Object, then by crude product through petroleum ether: the mixed solvent that ethyl acetate volume ratio is 20:1 elutes, and thin layer detection is collected The eluent that strong ultraviolet and polarity is less than HZA is shown under 254nm, merges eluent, it is dry that decompression boils off the product that eluting solvent obtains Up to HZAM-6, yield 88% after dry.
HZAM-6:ESI-MS m/z (%): 572 ([M+H]+,C33H33NO8)；1H-NMR(CDCl3)δ:13.57(1H,s,5- ), OH 7.34-7.30 (4H, m, Ar-H), 7.26 (1H, s, H-10), 6.74 (1H, d, J=10.0Hz, H-4), 6.25 (1H, s, ), H-12 5.58 (1H, d, J=10.0Hz, H-3), 5.18 (1H, s, H-14), 4.10 (1H, s, H-13), 4.08 (1H, s, H- 13),3.90(3H,s,Ar-OCH3),3.43(3H,s,8-OCH3),3.32(3H,s,N-CH3),1.81(3H,s,17-CH3), 1.66(3H,s,16-CH3),1.48(6H,s,18,19-CH3)；13C-NMRδ:182.3,160.2,158.0,156.4,155.1, 153.2,153.0,149.8,146.6,138.2,131.8,131.0,129.2,128.8,127.1,123.0,120.8, 115.9,115.6,111.8,110.1,104.5,104.0,94.1,78.0,61.2,55.6,37.7,28.4,28.4,26.3, 25.8,18.1.
The synthesis of embodiment 7: α-mangostin derivative HZAM-7 (synthetic route chart is as shown in Figure 1)
The synthetic method of compound HZA is same as above.
BTC (58mg, 0.2mmol) is weighed in 25mL two-mouth bottle, 5mL anhydrous methylene chloride, magnetic agitation, 25mL is added Equivalent N- methyl m-anisidine, triethylamine (0.25mmol) and 5mL methylene chloride, ice bath are added in constant pressure funnel Under, it is slowly added dropwise, completion of dropwise addition recession deicing salt bath stirs 4h at room temperature.
HZA (40mg, 0.1mmol) is added in 10ml single port bottle, trace DMAP, 5mL methylene chloride is added, at room temperature magnetic Power is stirred to being completely dissolved.Solution is slowly dropped in upper step reaction solution under ice salt bath, completion of dropwise addition removes ice salt bath, room temperature Lower stirring.After the reaction was completed, the distilled water of 3~6 times of reaction solution volumes is added in above-mentioned reaction solution, then is extracted with ethyl acetate 3-5 times, merge organic layer, to be saturated NaCl solution washing, uses anhydrous Na2SO4It is dry, it filters, is concentrated to give the thick production of yellow oily Object, then by crude product through petroleum ether: the mixed solvent that ethyl acetate volume ratio is 20:1 elutes, and thin layer detection is collected The eluent that strong ultraviolet and polarity is less than HZA is shown under 254nm, merges eluent, it is dry that decompression boils off the product that eluting solvent obtains Up to HZAM-7, yield 91% after dry.
HZAM-7:ESI-MS m/z (%): 572 ([M+H]+,C33H33NO8)；1H-NMR(CDCl3)δ:13.55(1H,s,5- ), OH 7.35-7.32 (4H, m, Ar-H), 7.26 (1H, s, H-10), 6.74 (1H, d, J=10.0Hz, H-4), 6.25 (1H, s, ), H-12 5.59 (1H, d, J=10.0Hz, H-3), 5.20 (1H, s, H-14), 4.13 (1H, s, H-13), 4.12 (1H, s, H- 13),3.84(3H,s,Ar-OCH3),3.5(3H,s,8-OCH3),3.34(3H,s,N-CH3),1.83(3H,s,17-CH3), 1.68(3H,s,16-CH3),1.48(6H,s,18,19-CH3)；13C-NMRδ:182.2,160.3,160.2,158.0,156.4, 153.8,152.4,149.5,146.7,143.6,138.5,131.9,129.9,127.2,127.2,123.1,123.1, 116.3,115.6,112.6,110.5,104.5,104.0,94.2,78.1,61.2,55.5,38.6,28.4,28.4,26.4, 25.8,18.2.
The synthesis of embodiment 8: α-mangostin derivative HZAM-8 (synthetic route chart is as shown in Figure 1)
The synthetic method of compound HZA is same as above.
BTC (58mg, 0.2mmol) is weighed in 25mL two-mouth bottle, 5mL anhydrous methylene chloride, magnetic agitation, 25mL is added Equivalent N- methyl P-nethoxyaniline, triethylamine (0.25mmol) and 5mL methylene chloride, ice bath are added in constant pressure funnel Under, it is slowly added dropwise, completion of dropwise addition recession deicing salt bath stirs 4h at room temperature.
HZA (40mg, 0.1mmol) is added in 10ml single port bottle, trace DMAP, 5mL methylene chloride is added, at room temperature magnetic Power is stirred to being completely dissolved.Solution is slowly dropped in upper step reaction solution under ice salt bath, completion of dropwise addition removes ice salt bath, room temperature Lower stirring.After the reaction was completed, the distilled water of 3~6 times of reaction solution volumes is added in above-mentioned reaction solution, then is extracted with ethyl acetate 3-5 times, merge organic layer, to be saturated NaCl solution washing, uses anhydrous Na2SO4It is dry, it filters, is concentrated to give the thick production of yellow oily Object, then by crude product through petroleum ether: the mixed solvent that ethyl acetate volume ratio is 20:1 elutes, and thin layer detection is collected The eluent that strong ultraviolet and polarity is less than HZA is shown under 254nm, merges eluent, it is dry that decompression boils off the product that eluting solvent obtains Up to HZAM-8, yield 90% after dry.
HZAM-8:ESI-MS m/z (%): 570 ([M-H]-,C33H33NO8)；1H-NMR(CDCl3)δ:13.55(1H,s,5- ), OH 7.32-6.94 (4H, m, Ar-H), 7.26 (1H, s, H-10), 6.74 (1H, d, J=10.0Hz, H-4), 6.25 (1H, s, ), H-12 5.58 (1H, d, J=10.0Hz, H-3), 5.18 (1H, s, H-14), 4.11 (1H, s, H-13), 4.10 (1H, s, H- 13),3.84(3H,s,Ar-OCH3),3.5(3H,s,8-OCH3),3.34(3H,s,N-CH3),1.83(3H,s,17-CH3), 1.68(3H,s,16-CH3),1.48(6H,s,18,19-CH3)；13C-NMRδ:182.2,160.2,158.0,156.4,153.8, 152.7,149.5,146.7,142.5,138.4,131.9,129.9,127.7,127.2,127.2,123.1,123.1, 116.2,115.6,114.5,114.5 110.5,104.5,104.0,94.1,78.1,61.6,55.5,38.9,28.4,28.4, 26.3,25.8,18.2.
The synthesis of embodiment 9: α-mangostin derivative HZAM-9 (synthetic route chart is as shown in Figure 1)
The synthetic method of compound HZA is same as above.
BTC (58mg, 0.2mmol) is weighed in 25mL two-mouth bottle, 5mL anhydrous methylene chloride, magnetic agitation, 25mL is added Equivalent N- methyl o ethyl aniline, triethylamine (0.25mmol) and 5mL methylene chloride, ice bath are added in constant pressure funnel Under, it is slowly added dropwise, completion of dropwise addition recession deicing salt bath stirs 4h at room temperature.
HZA (40mg, 0.1mmol) is added in 10ml single port bottle, trace DMAP, 5mL methylene chloride is added, at room temperature magnetic Power is stirred to being completely dissolved.Solution is slowly dropped in upper step reaction solution under ice salt bath, completion of dropwise addition removes ice salt bath, room temperature Lower stirring.After the reaction was completed, the distilled water of 3~6 times of reaction solution volumes is added in above-mentioned reaction solution, then is extracted with ethyl acetate 3-5 times, merge organic layer, to be saturated NaCl solution washing, uses anhydrous Na2SO4It is dry, it filters, is concentrated to give the thick production of yellow oily Object, then by crude product through petroleum ether: the mixed solvent that ethyl acetate volume ratio is 20:1 elutes, and thin layer detection is collected The eluent that strong ultraviolet and polarity is less than HZA is shown under 254nm, merges eluent, it is dry that decompression boils off the product that eluting solvent obtains Up to HZAM-9, yield 89% after dry.
HZAM-9:ESI-MS m/z (%): 568 ([M+H]+,C34H35NO7)；1H-NMR(CDCl3)13.55(1H,s,5- ), OH 7.36-7.28 (4H, m, Ar-H), 7.25 (1H, s, H-10), 6.74 (1H, d, J=10.1Hz, H-4), 6.25 (1H, s, ), H-12 5.58 (1H, d, J=10.1Hz, H-3), 5.17 (1H, s, H-14), 4.08 (2H, s, H-13), 3.35 (3H, s, 8- OCH3),3.34(3H,s,N-CH3),2.75(2H,m,Ar-CH2),1.80(3H,s,17-CH3),1.66(3H,s,16-CH3), 1.48(6H,s,18,19-CH3),1.33(3H,m,Ar-CH3)；13C-NMRδ:182.2,160.3,158.0,156.4,153.8, 152.7,149.6,146.6,141.3,140.6,138.4,131.9,129.4,128.5,127.6,127.2,127.1, 123.1,116.1,115.7,110.4,104.6,104.0,94.2,78.1,61.3,38.4,28.4,28.4,26.4,25.8, 23.7,18.2,14.5.
The synthesis of embodiment 10: α-mangostin derivative HZAM-10 (synthetic route chart is as shown in Figure 1)
The synthetic method of compound HZA is same as above.
BTC (58mg, 0.2mmol) is weighed in 25mL two-mouth bottle, 5mL anhydrous methylene chloride, magnetic agitation, 25mL is added Equivalent N- methyl m-ethyl aniline, triethylamine (0.25mmol) and 5mL methylene chloride, ice bath are added in constant pressure funnel Under, it is slowly added dropwise, completion of dropwise addition recession deicing salt bath stirs 4h at room temperature.
HZA (40mg, 0.1mmol) is added in 10ml single port bottle, trace DMAP, 5mL methylene chloride is added, at room temperature magnetic Power is stirred to being completely dissolved.Solution is slowly dropped in upper step reaction solution under ice salt bath, completion of dropwise addition removes ice salt bath, room temperature Lower stirring.After the reaction was completed, the distilled water of 3~6 times of reaction solution volumes is added in above-mentioned reaction solution, then is extracted with ethyl acetate 3-5 times, merge organic layer, to be saturated NaCl solution washing, uses anhydrous Na2SO4It is dry, it filters, is concentrated to give the thick production of yellow oily Object, then by crude product through petroleum ether: the mixed solvent that ethyl acetate volume ratio is 20:1 elutes, and thin layer detection is collected The eluent that strong ultraviolet and polarity is less than HZA is shown under 254nm, merges eluent, it is dry that decompression boils off the product that eluting solvent obtains Up to HZAM-10, yield 92% after dry.
HZAM-10:ESI-MS m/z (%): 568 ([M+H]+,C34H35NO7)；1H-NMR(CDCl3)13.55(1H,s,5- ), OH 7.35-7.32 (4H, m, Ar-H), 7.26 (1H, s, H-10), 6.73 (1H, d, J=10.1Hz, H-4), 6.25 (1H, s, ), H-12 5.58 (1H, d, J=10.1Hz, H-3), 5.20 (1H, s, H-14), 4.11 (2H, s, H-13), 3.43 (3H, s, 8- OCH3),3.43(3H,s,N-CH3),2.70(2H,m,Ar-CH2),1.82(3H,s,17-CH3),1.67(3H,s,16-CH3), 1.47(6H,s,18,19-CH3),1.26(3H,m,Ar-CH3)；13C-NMRδ:182.3,160.3,158.0,156.4,153.8, 152.6,149.6,145.6,142.5,138.5,131.9,129.1,127.2,127.2,123.0,123.0,116.2, 115.6,115.6,110.4,104.5,104.0,94.2,78.1,61.6,38.4,30.9,28.4,28.4,26.4,25.8, 18.2,15.4.
The synthesis of embodiment 11: α-mangostin derivative HZAM-11 (synthetic route chart is as shown in Figure 1)
The synthetic method of compound HZA is same as above.
BTC (58mg, 0.2mmol) is weighed in 25mL two-mouth bottle, 5mL anhydrous methylene chloride, magnetic agitation, 25mL is added Equivalent N- methyl is added in constant pressure funnel to ethyl aniline, triethylamine (0.25mmol) and 5mL methylene chloride, ice bath Under, it is slowly added dropwise, completion of dropwise addition recession deicing salt bath stirs 4h at room temperature.
HZA (40mg, 0.1mmol) is added in 10ml single port bottle, trace DMAP, 5mL methylene chloride is added, at room temperature magnetic Power is stirred to being completely dissolved.Solution is slowly dropped in upper step reaction solution under ice salt bath, completion of dropwise addition removes ice salt bath, room temperature Lower stirring.After the reaction was completed, the distilled water of 3~6 times of reaction solution volumes is added in above-mentioned reaction solution, then is extracted with ethyl acetate 3-5 times, merge organic layer, to be saturated NaCl solution washing, uses anhydrous Na2SO4It is dry, it filters, is concentrated to give the thick production of yellow oily Object, then by crude product through petroleum ether: the mixed solvent that ethyl acetate volume ratio is 20:1 elutes, and thin layer detection is collected The eluent that strong ultraviolet and polarity is less than HZA is shown under 254nm, merges eluent, it is dry that decompression boils off the product that eluting solvent obtains Up to HZAM-11, yield 94% after dry.
HZAM-11:ESI-MS m/z (%): 568 ([M+H]+,C34H35NO7)；1H-NMR(CDCl3)13.55(1H,s,5- ), OH 7.31-7.26 (4H, m, Ar-H), 7.25 (1H, s, H-10), 6.74 (1H, d, J=10.1Hz, H-4), 6.26 (1H, s, ), H-12 5.58 (1H, d, J=10.1Hz, H-3), 5.19 (1H, s, H-14), 4.11 (2H, s, H-13), 3.47 (3H, s, 8- OCH3),3.41(3H,s,N-CH3),2.67(2H,m,Ar-CH2),1.83(3H,s,17-CH3),1.66(3H,s,16-CH3), 1.48(6H,s,18,19-CH3),1.26(3H,m,Ar-CH3)；13C-NMRδ:182.3,160.3,158.0,156.4,153.8, 152.6,146.7,140.1,138.5,131.9,128.7,128.7,127.2,127.2,126.4,123.1,123.1, 116.1,115.7,115.7,110.5,104.5,104.0,94.2,78.1,61.6,38.4,30.9,28.4,28.4,26.4, 25.8,18.2,15.5.
The synthesis of embodiment 12: α-mangostin derivative HZAM-12 (synthetic route chart is as shown in Figure 1)
The synthetic method of compound HZA is same as above.
BTC (58mg, 0.2mmol) is weighed in 25mL two-mouth bottle, 5mL anhydrous methylene chloride, magnetic agitation, 25mL is added It is added equivalent N- methyl o-chloraniline, triethylamine (0.25mmol) and 5mL methylene chloride in constant pressure funnel, under ice bath, It is slowly added dropwise, completion of dropwise addition recession deicing salt bath stirs 4h at room temperature.
HZA (40mg, 0.1mmol) is added in 10ml single port bottle, trace DMAP, 5mL methylene chloride is added, at room temperature magnetic Power is stirred to being completely dissolved.Solution is slowly dropped in upper step reaction solution under ice salt bath, completion of dropwise addition removes ice salt bath, room temperature Lower stirring.After the reaction was completed, the distilled water of 3~6 times of reaction solution volumes is added in above-mentioned reaction solution, then is extracted with ethyl acetate 3-5 times, merge organic layer, to be saturated NaCl solution washing, uses anhydrous Na2SO4It is dry, it filters, is concentrated to give the thick production of yellow oily Object, then by crude product through petroleum ether: the mixed solvent that ethyl acetate volume ratio is 20:1 elutes, and thin layer detection is collected The eluent that strong ultraviolet and polarity is less than HZA is shown under 254nm, merges eluent, it is dry that decompression boils off the product that eluting solvent obtains Up to HZAM-12, yield 88% after dry.
HZAM-12:ESI-MS m/z (%): 574 ([M-H]-,C32H30ClNO7)；1H-NMR(CDCl3)δ:13.55(1H, S, 5-OH), 7.52-7.34 (4H, m, Ar-H), 7.24 (1H, s, H-10), 6.74 (1H, d, J=10.0Hz, H-4), 6.26 (1H, s, H-12), 5.58 (1H, d, J=10.1Hz, H-3), 5.17 (1H, s, H-14), 4.10 (1H, s, H-13), 3.90 (1H, s,H-13),3.45(3H,s,8-OCH3),3.37(3H,s,N-CH3),1.81(3H,s,17-CH3),1.66(3H,s,16- CH3),1.48(6H,s,18,19-CH3)；13C-NMRδ:182.2,160.2,158.0,156.4,153.8,152.4,149.4, 146.7,142.5,138.5,135.7,130.4,129.4,128.7,128.0,127.2,123.1,120.3,116.3, 115.6,110.3,104.5,104.0,94.2,78.1,61.5,38.6,28.4,28.4,26.4,25.8,18.2.
The synthesis of embodiment 13: α-mangostin derivative HZAM-13 (synthetic route chart is as shown in Figure 1)
The synthetic method of compound HZA is same as above.
BTC (58mg, 0.2mmol) is weighed in 25mL two-mouth bottle, 5mL anhydrous methylene chloride, magnetic agitation, 25mL is added It is added equivalent N- methyl m-chloroaniline, triethylamine (0.25mmol) and 5mL methylene chloride in constant pressure funnel, under ice bath, It is slowly added dropwise, completion of dropwise addition recession deicing salt bath stirs 4h at room temperature.
HZA (40mg, 0.1mmol) is added in 10ml single port bottle, trace DMAP, 5mL methylene chloride is added, at room temperature magnetic Power is stirred to being completely dissolved.Solution is slowly dropped in upper step reaction solution under ice salt bath, completion of dropwise addition removes ice salt bath, room temperature Lower stirring.After the reaction was completed, the distilled water of 3~6 times of reaction solution volumes is added in above-mentioned reaction solution, then is extracted with ethyl acetate 3-5 times, merge organic layer, to be saturated NaCl solution washing, uses anhydrous Na2SO4It is dry, it filters, is concentrated to give the thick production of yellow oily Object, then by crude product through petroleum ether: the mixed solvent that ethyl acetate volume ratio is 20:1 elutes, and thin layer detection is collected The eluent that strong ultraviolet and polarity is less than HZA is shown under 254nm, merges eluent, it is dry that decompression boils off the product that eluting solvent obtains Up to HZAM-13, yield 92% after dry.
HZAM-13:ESI-MS m/z (%): 574 ([M-H]-,C32H30ClNO7)；1H-NMR(CDCl3)δ:13.55(1H, S, 5-OH), 7.32 (2H, m, Ar-H), 7.25 (1H, s, H-10), 6.98 (2H, m, Ar-H), 6.74 (1H, d, J=10.0Hz, ), H-4 6.26 (1H, s, H-12), 5.58 (1H, d, J=10.1Hz, H-3), 5.20 (1H, s, H-14), 4.12 (1H, s, H- 13),4.11(1H,s,H-13),3.57(3H,s,8-OCH3),3.46(3H,s,N-CH3),1.83(3H,s,17-CH3),1.68 (3H,s,16-CH3),1.48(6H,s,18,19-CH3)；13C-NMRδ:182.2,160.3,158.0,156.4,153.8, 152.4,149.2,146.7,143.6,138.7,134.7,134.7,132.1,130.2,130.2,127.3,123.0, 123.0,116.5,115.6,115.6,110.5,104.5,104.0,94.2,78.1,61.7,38.4,28.4,28.4,26.3, 25.8,18.2.
The synthesis of embodiment 14: α-mangostin derivative HZAM-14 (synthetic route chart is as shown in Figure 1)
The synthetic method of compound HZA is same as above.
BTC (58mg, 0.2mmol) is weighed in 25mL two-mouth bottle, 5mL anhydrous methylene chloride, magnetic agitation, 25mL is added It is added equivalent N- methyl parachloroanilinum, triethylamine (0.25mmol) and 5mL methylene chloride in constant pressure funnel, under ice bath, It is slowly added dropwise, completion of dropwise addition recession deicing salt bath stirs 4h at room temperature.
HZA (40mg, 0.1mmol) is added in 10ml single port bottle, trace DMAP, 5mL methylene chloride is added, at room temperature magnetic Power is stirred to being completely dissolved.Solution is slowly dropped in upper step reaction solution under ice salt bath, completion of dropwise addition removes ice salt bath, room temperature Lower stirring.After the reaction was completed, the distilled water of 3~6 times of reaction solution volumes is added in above-mentioned reaction solution, then is extracted with ethyl acetate 3-5 times, merge organic layer, to be saturated NaCl solution washing, uses anhydrous Na2SO4It is dry, it filters, is concentrated to give the thick production of yellow oily Object, then by crude product through petroleum ether: the mixed solvent that ethyl acetate volume ratio is 20:1 elutes, and thin layer detection is collected The eluent that strong ultraviolet and polarity is less than HZA is shown under 254nm, merges eluent, it is dry that decompression boils off the product that eluting solvent obtains Up to HZAM-14, yield 92% after dry.
HZAM-14:ESI-MS m/z (%): 576 ([M+H]+,C32H30ClNO7)；1H-NMR(CDCl3)δ:13.52(1H, S, 5-OH), 7.42-7.34 (4H, m, Ar-H), 7.29 (1H, s, H-10), 6.74 (1H, d, J=10.0Hz, H-4), 6.25 (1H, s, H-12), 5.58 (1H, d, J=10.1Hz, H-3), 5.18 (1H, s, H-14), 4.10 (1H, s, H-13), 4.12 (1H, s,H-13),3.44(3H,s,8-OCH3),3.36(3H,s,N-CH3),1.81(3H,s,17-CH3),1.66(3H,s,16- CH3),1.47(6H,s,18,19-CH3)；13C-NMRδ:182.2,160.2,158.0,156.4,153.7,152.1,149.3, 146.6,141.2,138.4,133.6,131.9,129.7,129.4,128.7,127.2,123.1,123.0,116.2, 115.6,110.5,104.8,104.1,94.2,78.1,61.4,37.4,28.4,28.4,26.3,25.8,18.2.
The synthesis of embodiment 15: α-mangostin derivative HZAM-15 (synthetic route chart is as shown in Figure 1)
The synthetic method of compound HZA is same as above.
BTC (58mg, 0.2mmol) is weighed in 25mL two-mouth bottle, 5mL anhydrous methylene chloride, magnetic agitation, 25mL is added It is added equivalent N- methyl o-bromoaniline, triethylamine (0.25mmol) and 5mL methylene chloride in constant pressure funnel, under ice bath, It is slowly added dropwise, completion of dropwise addition recession deicing salt bath stirs 4h at room temperature.
HZA (40mg, 0.1mmol) is added in 10ml single port bottle, trace DMAP, 5mL methylene chloride is added, at room temperature magnetic Power is stirred to being completely dissolved.Solution is slowly dropped in upper step reaction solution under ice salt bath, completion of dropwise addition removes ice salt bath, room temperature Lower stirring.After the reaction was completed, the distilled water of 3~6 times of reaction solution volumes is added in above-mentioned reaction solution, then is extracted with ethyl acetate 3-5 times, merge organic layer, to be saturated NaCl solution washing, uses anhydrous Na2SO4It is dry, it filters, is concentrated to give the thick production of yellow oily Object, then by crude product through petroleum ether: the mixed solvent that ethyl acetate volume ratio is 20:1 elutes, and thin layer detection is collected The eluent that strong ultraviolet and polarity is less than HZA is shown under 254nm, merges eluent, it is dry that decompression boils off the product that eluting solvent obtains Up to HZAM-15, yield 90% after dry.
HZAM-15:ESI-MS m/z (%): 620 ([M+H]+,C32H30BrNO7)；1H-NMR(CDCl3)δ:13.54(1H, S, 5-OH), 7.48-7.40 (4H, m, Ar-H), 7.24 (1H, s, H-10), 6.74 (1H, d, J=10.0Hz, H-4), 6.26 (1H, s, H-12), 5.58 (1H, d, J=10.1Hz, H-3), 5.17 (1H, s, H-14), 4.10 (1H, s, H-13), 4.09 (1H, s,H-13),3.45(3H,s,8-OCH3),3.37(3H,s,N-CH3),1.81(3H,s,17-CH3),1.66(3H,s,16- CH3),1.48(6H,s,18,19-CH3)；13C-NMRδ:182.2,160.2,158.0,156.4,153.7,152.1,149.3, 146.6,141.2,138.4,133.6,131.9,129.7,129.4,128.7,128.0,127.2,123.1,116.3, 115.6,110.3,104.5,104.0,94.2,78.1,61.5,38.6,28.4,28.4,26.4,25.8,18.2.
The synthesis of embodiment 16: α-mangostin derivative HZAM-16 (synthetic route chart is as shown in Figure 1)
The synthetic method of compound HZA is same as above.
BTC (58mg, 0.2mmol) is weighed in 25mL two-mouth bottle, 5mL anhydrous methylene chloride, magnetic agitation, 25mL is added It is added equivalent N- methyl m-bromoaniline, triethylamine (0.25mmol) and 5mL methylene chloride in constant pressure funnel, under ice bath, It is slowly added dropwise, completion of dropwise addition recession deicing salt bath stirs 4h at room temperature.
HZA (40mg, 0.1mmol) is added in 10ml single port bottle, trace DMAP, 5mL methylene chloride is added, at room temperature magnetic Power is stirred to being completely dissolved.Solution is slowly dropped in upper step reaction solution under ice salt bath, completion of dropwise addition removes ice salt bath, room temperature Lower stirring.After the reaction was completed, the distilled water of 3~6 times of reaction solution volumes is added in above-mentioned reaction solution, then is extracted with ethyl acetate 3-5 times, merge organic layer, to be saturated NaCl solution washing, uses anhydrous Na2SO4It is dry, it filters, is concentrated to give the thick production of yellow oily Object, then by crude product through petroleum ether: the mixed solvent that ethyl acetate volume ratio is 20:1 elutes, and thin layer detection is collected The eluent that strong ultraviolet and polarity is less than HZA is shown under 254nm, merges eluent, it is dry that decompression boils off the product that eluting solvent obtains Up to HZAM-16, yield 91% after dry.
HZAM-16:ESI-MS m/z (%): 620 ([M+H]+,C32H30BrNO7)；1H-NMR(CDCl3)δ:13.52(1H, S, 5-OH), 7.46-7.29 (4H, m, Ar-H), 7.24 (1H, s, H-10), 6.74 (1H, d, J=10.0Hz, H-4), 6.26 (1H, s, H-12), 5.59 (1H, d, J=10.1Hz, H-3), 5.20 (1H, s, H-14), 4.13 (1H, s, H-13), 4.12 (1H, s,H-13),3.49(3H,s,8-OCH3),3.45(3H,s,N-CH3),1.83(3H,s,17-CH3),1.68(3H,s,16- CH3),1.47(6H,s,18,19-CH3)；13C-NMRδ:182.3,160.3,158.0,156.4,153.8,152.2,149.2, 146.7,143.7,138.6,132.0,130.5,127.2,127.2,123.0,123.0,122.5,116.3,115.6, 115.6,110.5,104.6,104.0,94.2,78.1,61.7,38.4,28.4,28.4,26.4,25.8,18.2
The synthesis of embodiment 17: α-mangostin derivative HZAM-17 (synthetic route chart is as shown in Figure 1)
The synthetic method of compound HZA is same as above.
BTC (58mg, 0.2mmol) is weighed in 25mL two-mouth bottle, 5mL anhydrous methylene chloride, magnetic agitation, 25mL is added It is added equivalent N- methyl para-bromoaniline, triethylamine (0.25mmol) and 5mL methylene chloride in constant pressure funnel, under ice bath, It is slowly added dropwise, completion of dropwise addition recession deicing salt bath stirs 4h at room temperature.
HZA (40mg, 0.1mmol) is added in 10ml single port bottle, trace DMAP, 5mL methylene chloride is added, at room temperature magnetic Power is stirred to being completely dissolved.Solution is slowly dropped in upper step reaction solution under ice salt bath, completion of dropwise addition removes ice salt bath, room temperature Lower stirring.After the reaction was completed, the distilled water of 3~6 times of reaction solution volumes is added in above-mentioned reaction solution, then is extracted with ethyl acetate 3-5 times, merge organic layer, to be saturated NaCl solution washing, uses anhydrous Na2SO4It is dry, it filters, is concentrated to give the thick production of yellow oily Object, then by crude product through petroleum ether: the mixed solvent that ethyl acetate volume ratio is 20:1 elutes, and thin layer detection is collected The eluent that strong ultraviolet and polarity is less than HZA is shown under 254nm, merges eluent, it is dry that decompression boils off the product that eluting solvent obtains Up to HZAM-17, yield 93% after dry.
HZAM-17:ESI-MS m/z (%): 618 ([M-H]-,C32H30BrNO7)；1H-NMR(CDCl3)δ:13.52(1H, S, 5-OH), 7.57-7.29 (4H, m, Ar-H), 7.23 (1H, s, H-10), 6.74 (1H, d, J=10.0Hz, H-4), 6.26 (1H, s, H-12), 5.59 (1H, d, J=10.1Hz, H-3), 5.19 (1H, s, H-14), 4.12 (1H, s, H-13), 4.11 (1H, s,H-13),3.49(3H,s,8-OCH3),3.43(3H,s,N-CH3),1.83(3H,s,17-CH3),1.68(3H,s,16- CH3),1.48(6H,s,18,19-CH3)；13C-NMRδ:182.1,160.3,158.0,156.4,153.8,152.2,149.2, 146.7,141.5,138.6,132.4,132.4,132.0,127.2,127.2,123.0,123.0,116.3,115.6, 115.6,110.5,104.6,104.0,94.2,78.1,61.7,38.4,28.4,28.4,26.4,25.8,18.2.
The synthesis of embodiment 18: α-mangostin derivative HZAM-18 (synthetic route chart is as shown in Figure 1)
The synthetic method of compound HZA is same as above.
BTC (58mg, 0.2mmol) is weighed in 25mL two-mouth bottle, 5mL anhydrous methylene chloride, magnetic agitation, 25mL is added Equivalent N- methyl is added in constant pressure funnel to n-butyl aniline, triethylamine (0.25mmol) and 5mL methylene chloride, ice bath Under, it is slowly added dropwise, completion of dropwise addition recession deicing salt bath stirs 4h at room temperature.
HZA (40mg, 0.1mmol) is added in 10ml single port bottle, trace DMAP, 5mL methylene chloride is added, at room temperature magnetic Power is stirred to being completely dissolved.Solution is slowly dropped in upper step reaction solution under ice salt bath, completion of dropwise addition removes ice salt bath, room temperature Lower stirring.After the reaction was completed, the distilled water of 3~6 times of reaction solution volumes is added in above-mentioned reaction solution, then is extracted with ethyl acetate 3-5 times, merge organic layer, to be saturated NaCl solution washing, uses anhydrous Na2SO4It is dry, it filters, is concentrated to give the thick production of yellow oily Object, then by crude product through petroleum ether: the mixed solvent that ethyl acetate volume ratio is 20:1 elutes, and thin layer detection is collected The eluent that strong ultraviolet and polarity is less than HZA is shown under 254nm, merges eluent, it is dry that decompression boils off the product that eluting solvent obtains Up to HZAM-18, yield 90% after dry.
HZAM-18:ESI-MS m/z (%): 596 ([M-H]-,C36H39NO7)；1H-NMR(CDCl3)13.55(1H,s,5- ), OH 7.31-7.28 (4H, m, Ar-H), 7.24 (1H, s, H-10), 6.74 (1H, d, J=10.1Hz, H-4), 6.26 (1H, s, ), H-12 5.58 (1H, d, J=10.1Hz, H-3), 5.19 (1H, s, H-14), 4.11 (2H, s, H-13), 3.46 (3H, s, 8- OCH3),3.42(3H,s,N-CH3),2.64(2H,m,Ar-CH2),1.83(3H,s,17-CH3),1.68(3H,s,16-CH3), 1.60(2H,m,Ar-CH2),1.48(6H,s,18,19-CH3),1.37(2H,m,Ar-CH2),1.27(2H,m,Ar-CH2), 0.94(3H,m,Ar-CH3)；13C-NMRδ:182.3,160.3,158.0,156.4,153.8,152.6,149.6,146.7, 140.1,138.4,131.9,129.2,129.2,127.2,127.2,126.4,123.1,123.1,116.1,115.7, 110.4,104.5,104.0,94.2,78.1,61.6,38.6,35.2,33.5,28.4,28.4,26.3,25.8,22.3, 18.2,13.9.
The synthesis of embodiment 19: α-mangostin derivative HZAM-19 (synthetic route chart is as shown in Figure 1)
The synthetic method of compound HZA is same as above.
BTC (58mg, 0.2mmol) is weighed in 25mL two-mouth bottle, 5mL anhydrous methylene chloride, magnetic agitation, 25mL is added Equivalent N- methyl O-ethoxyl amine, triethylamine (0.25mmol) and 5mL methylene chloride, ice bath are added in constant pressure funnel Under, it is slowly added dropwise, completion of dropwise addition recession deicing salt bath stirs 4h at room temperature.
HZA (40mg, 0.1mmol) is added in 10ml single port bottle, trace DMAP, 5mL methylene chloride is added, at room temperature magnetic Power is stirred to being completely dissolved.Solution is slowly dropped in upper step reaction solution under ice salt bath, completion of dropwise addition removes ice salt bath, room temperature Lower stirring.After the reaction was completed, the distilled water of 3~6 times of reaction solution volumes is added in above-mentioned reaction solution, then is extracted with ethyl acetate 3-5 times, merge organic layer, to be saturated NaCl solution washing, uses anhydrous Na2SO4It is dry, it filters, is concentrated to give the thick production of yellow oily Object, then by crude product through petroleum ether: the mixed solvent that ethyl acetate volume ratio is 20:1 elutes, and thin layer detection is collected The eluent that strong ultraviolet and polarity is less than HZA is shown under 254nm, merges eluent, it is dry that decompression boils off the product that eluting solvent obtains Up to HZAM-19, yield 93% after dry.
HZAM-19:ESI-MS m/z (%): 584 ([M-H]-,C35H34NO8)；1H-NMR(CDCl3)13.55(1H,s,5- ), OH 7.31-7.28 (4H, m, Ar-H), 7.24 (1H, s, H-10), 6.74 (1H, d, J=10.1Hz, H-4), 6.26 (1H, s, ), H-12 5.58 (1H, d, J=10.1Hz, H-3), 5.19 (1H, s, H-14), 4.12 (1H, s, H-13), 4.11 (1H, s, H- 13),4.06(2H,m,Ar-OCH2),3.49(3H,s,8-OCH3),3.44(3H,s,N-CH3),1.83(3H,s,17-CH3), 1.68(3H,s,16-CH3),1.48(6H,s,18,19-CH3),1.26(3H,m,Ar-CH3)；13C-NMRδ:182.3,160.2, 158.0,156.4,153.8,152.4,149.5,146.7,143.8,138.4,131.9,129.8,127.2,127.2, 123.0,123.0,116.3,115.6,113.2,110.4,104.5,104.0,94.2,78.1,61.6,58.4,38.6, 28.4,28.4,26.3,25.8,18.2,14.7.
The synthesis of embodiment 20: α-mangostin derivative HZAM-20 (synthetic route chart is as shown in Figure 1)
The synthetic method of compound HZA is same as above.
BTC (58mg, 0.2mmol) is weighed in 25mL two-mouth bottle, 5mL anhydrous methylene chloride, magnetic agitation, 25mL is added It is added 0.8 equivalent pyrrolidines, triethylamine (0.25mmol) and 5mL methylene chloride in constant pressure funnel, under ice bath, slow drop Add, completion of dropwise addition recession deicing salt bath stirs 4h at room temperature.
HZA (40mg, 0.1mmol) is added in 10ml single port bottle, trace DMAP, 5mL methylene chloride is added, at room temperature magnetic Power is stirred to being completely dissolved.Solution is slowly dropped in upper step reaction solution under ice salt bath, completion of dropwise addition removes ice salt bath, room temperature Lower stirring.After the reaction was completed, the distilled water of 3~6 times of reaction solution volumes is added in above-mentioned reaction solution, then is extracted with ethyl acetate 3-5 times, merge organic layer, to be saturated NaCl solution washing, uses anhydrous Na2SO4It is dry, it filters, is concentrated to give the thick production of yellow oily Object, then by crude product through petroleum ether: the mixed solvent that ethyl acetate volume ratio is 20:1 elutes, and thin layer detection is collected The eluent that strong ultraviolet and polarity is less than HZA is shown under 254nm, merges eluent, it is dry that decompression boils off the product that eluting solvent obtains Up to HZAM-20, yield 91% after dry.
HZAM-20:ESI-MS m/z (%): 506 ([M+H]+,C29H31NO7)；1H-NMR(CDCl3)13.55(1H,s,5- ), OH 7.22 (1H, s, H-10), 6.74 (1H, d, J=10.1Hz, H-4), 6.26 (1H, s, H-12), 5.59 (1H, d, J= 10.1Hz,H-3),5.23(1H,s,H-14),4.16(1H,s,H-13),4.15(1H,s,H-13),3.79(3H,s,8- OCH3),3.52(2H,m,Py-CH2),3.44(2H,m,Py-CH2),1.83(3H,s,17-CH3),1.70(3H,s,16-CH3), 1.48(6H,s,18,19-CH3),1.25(4H,m,Py-CH2)；13C-NMRδ:182.3,160.2,158.0,156.4,153.9, 151.6,149.6,138.4,131.9,127.2,123.1,116.1,115.7,110.6,104.5,104.0,94.2,78.1, 61.6,46.7,46.6,28.4,28.4,26.4,25.8,25.0,25.0,18.2.
The synthesis of embodiment 21: α-mangostin derivative HZAM-21 (synthetic route chart is as shown in Figure 1)
The synthetic method of compound HZA is same as above.
BTC (58mg, 0.2mmol) is weighed in 25mL two-mouth bottle, 5mL anhydrous methylene chloride, magnetic agitation, 25mL is added It is added 0.8 equivalent cyclohexyl amine, triethylamine (0.25mmol) and 5mL methylene chloride in constant pressure funnel, under ice bath, slow drop Add, completion of dropwise addition recession deicing salt bath stirs 4h at room temperature.
HZA (40mg, 0.1mmol) is added in 10ml single port bottle, trace DMAP, 5mL methylene chloride is added, at room temperature magnetic Power is stirred to being completely dissolved.Solution is slowly dropped in upper step reaction solution under ice salt bath, completion of dropwise addition removes ice salt bath, room temperature Lower stirring.After the reaction was completed, the distilled water of 3~6 times of reaction solution volumes is added in above-mentioned reaction solution, then is extracted with ethyl acetate 3-5 times, merge organic layer, to be saturated NaCl solution washing, uses anhydrous Na2SO4It is dry, it filters, is concentrated to give the thick production of yellow oily Object, then by crude product through petroleum ether: the mixed solvent that ethyl acetate volume ratio is 20:1 elutes, and thin layer detection is collected The eluent that strong ultraviolet and polarity is less than HZA is shown under 254nm, merges eluent, it is dry that decompression boils off the product that eluting solvent obtains Up to HZAM-21, yield 94% after dry.
HZAM-21:ESI-MS m/z (%): 530 ([M+Na]+,C29H33NO7)；1H-NMR(CDCl3500MHz)13.56 (1H, s, 5-OH), 7.19 (1H, s, H-10), 6.73 (1H, d, J=10.1Hz, H-4), 6.25 (1H, s, H-12), 5.58 (1H, D, J=10.1Hz, H-3), 5.27 (1H, m, N-H), 5.24 (1H, s, H-14), 4.15 (1H, s, H-13), 4.14 (1H, s, H- 13),3.78(3H,s,8-OCH3),3.32(2H,m,Bu-CH2),1.85(3H,s,17-CH3),1.70(3H,s,16-CH3), 1.48(6H,s,18,19-CH3),1.60(2H,m,Ar-CH2),1.41(2H,m,Bu-CH2),1.26(2H,m,Bu-CH2), 0.99(3H,m,Bu-CH3)；13C-NMRδ:182.3,160.3,158.0,156.4,153.9,146.8,138.5,132.0, 127.2,123.0,116.2,115.6,110.4,104.5,104.0,94.2,78.1,61.6,41.2,31.8,28.4,28.4, 26.4,25.8,19.9,18.2,13.7.
The synthesis of embodiment 22: α-mangostin derivative HZAM-22 (synthetic route chart is as shown in Figure 1)
The synthetic method of compound HZA is same as above.
BTC (58mg, 0.2mmol) is weighed in 25mL two-mouth bottle, 5mL anhydrous methylene chloride, magnetic agitation, 25mL is added It is added equivalent n-butylamine, triethylamine (0.25mmol) and 5mL methylene chloride in constant pressure funnel, under ice bath, slow drop Add, completion of dropwise addition recession deicing salt bath stirs 4h at room temperature.
HZA (40mg, 0.1mmol) is added in 10ml single port bottle, trace DMAP, 5mL methylene chloride is added, at room temperature magnetic Power is stirred to being completely dissolved.Solution is slowly dropped in upper step reaction solution under ice salt bath, completion of dropwise addition removes ice salt bath, room temperature Lower stirring.After the reaction was completed, the distilled water of 3~6 times of reaction solution volumes is added in above-mentioned reaction solution, then is extracted with ethyl acetate 3-5 times, merge organic layer, to be saturated NaCl solution washing, uses anhydrous Na2SO4It is dry, it filters, is concentrated to give the thick production of yellow oily Object, then by crude product through petroleum ether: the mixed solvent that ethyl acetate volume ratio is 20:1 elutes, and thin layer detection is collected The eluent that strong ultraviolet and polarity is less than HZA is shown under 254nm, merges eluent, it is dry that decompression boils off the product that eluting solvent obtains Up to HZAM-22, yield 94% after dry.
HZAM-22:ESI-MS m/z (%): 556 ([M+Na]+,C31H35NO7)；1H-NMR(CDCl3)13.57(1H,s,5- ), OH 7.20 (1H, s, H-10), 6.74 (1H, d, J=10.1Hz, H-4), 6.26 (1H, s, H-12), 5.59 (1H, d, J= 10.1Hz,H-3),5.22(1H,s,H-14),5.14(1H,m,N-H),4.15(1H,s,H-13),4.14(1H,s,H-13), 3.78(3H,s,8-OCH3),3.54(1H,m,He-CH),2.01(2H,m,He-CH2),1.93(2H,m,He-CH2),1.85 (3H,s,17-CH3),1.70(3H,s,16-CH3),1.48(6H,s,18,19-CH3),1.42(2H,m,He-CH2),1.39 (2H,m,He-CH2)；13C-NMRδ:182.3,160.3,158.0,156.4,153.9,152.1,146.8,138.5,132.0, 127.2,123.0,116.2,115.6,110.4,104.5,104.0,94.2,78.1,61.6,50.5,33.2,,28.4, 28.4,26.4,25.9,24.9,24.7,18.2.
Therapeutic effect of the embodiment 23:HZAM-1 to vascular dementia
The production of vascular dementia rats model: male SD rat (10-12 weeks, 220-250g, every group 10), random point Group, experiment adapt to MCAO mould be made according to Zea Longa etc. and the methods of Nagasawa reforming Longa method in environment 7 days before starting Type.After (1g/kg) anesthesia is injected intraperitoneally in 10% chloraldurate of rat, fixation of being lain on the back.Separate right common carotid artery (CCA), neck Simultaneously hanging wire is spare for interior artery (ICA) and external carotid artery (ECA), ligatures ECA and CCA, fast after closing ICA distal end with artery clamp folder Speed makees a kerf in ECA and ICA crotch, from incision insertion heating one end at smooth, spherical nylon wire bolt.Line is inserted into ICA Afterwards, nylon wire and inlet ICA sections are ligatured slightly in inlet, then unclamp the artery clamp that folder closes ICA, continue into nylon wire It is slightly withdrawn after to slightly resistance, until line insertion depth is (18.5 ± 0.5) mm or so, realizes that middle cerebral artery occlusion causes brain to lack Blood.Inlet is ligatured again, and about 1cm, skin suture are stayed outside nylon wire.Stayed the end of a thread is gently lifted after 45min to there is resistance, in fact Existing arteria cerebri media fills again, then modeling is completed.Sham-operation group only ligatures ECA and ICA.The successful standard of animal model is (according to Zea It is 2-3 points of animal that 5 grades of point systems of Longa, which take scoring): there is the tired song of opposite side forelimb after ischemic 45min in animal or walking turns It encloses or walks and fall sign to opposite side and be then judged as model success, animal will be considered as mould without this sign or in postoperative still not awake person Type is unsuccessful and superseded.CON group is sham-operation group, i.e. blank control；VD is model group.The HZAM-1 of purity 99% is dissolved in note It penetrates and uses isopropyl myristate, animal is through intraperitoneal injection, dosage are as follows: 5mg/kg, 10mg/kg, 20mg/kg, CON group and mould The physiological saline of the type group intraperitoneal injection isopropyl myristate of injection containing equivalent.Daily 19:00 administration, successive administration 20d.
The influence tested vascular dementia rats Morris water maze is administered in HZAM-1: water maze is by a diameter 150cm, high 50cm, the pond that 20 DEG C of water temperature, camera and analysis system composition.Pond depth of water 30cm, the round water surface are passed through The imaginary vertical line of two of the center of circle is divided into 4 quadrants.It is straight from putting one at water surface 1.5cm among the wherein waters of a quadrant Diameter 10cm's flees from platform.Platform is made into for transparent material, observes directly platform to avoid experimental rat.At random by rat from The 1 of pond, into the water, rat can escape water environment to 2,3,4 four quadrants as possible, stay in after finding platform on platform, With the latent time of automatic tracking system record rat discovery platform, it is then denoted as 90s more than 90s, calculates daily mean latency Phase.Experimental result shows that model group rats escape latency was considerably longer than sham-operation group (P < 0.05) at test 1 to 4 day, Administration group 5mg/kg group substantially reduced escape latency (P < 0.05) at the 1st, 2,3,4 day；Administration group 10mg/kg group the 1st, 2, escape latency (P < 0.05) is substantially reduced within 4 days；It is latent that administration group 20mg/kg group substantially reduced escape at the 1st, 2,3,4 day Phase (P < 0.05), mouse swimming rate is without significant change in 4 days.As shown in Fig. 1.The result shows that HZAM-1 is remarkably improved The low problem of learning and memory caused by vascular dementia, can significantly improve the ability of learning and memory of mammal.
The influence to vascular dementia rats spacious field space exploration performance testing is administered in HZAM-1: spacious field experimental provision is by spacious Field experimental box and ANY-maze video recording tracking system composition.Thorough cleaning spacious field experimental box, confirms that its cleaning is tasteless before testing.It is real The person of testing records the number of rat in operating software, holds and is put into one jiao of experimental box towards tank wall at rat tails 1/3, experimenter Start record system rapidly and evacuate to the invisible place of experimental rat, the experimental record time is 3 minutes.It will after experiment Rat is put back in cage, cleans experimental box and with 75% alcohol wipe, is tested next time again after air-drying.Rat is among spacious field The exploratory behaviour that can be considered rat in foreign environment is lifted in shuttle, forearm, and every rat is placed in spacious field 120s, and record passes through lattice Number, the forearm of son lift number, center lattice residence time.Experimental result shows, model group rats overstate lattice number test 1 to Considerably less than sham-operation group (P < 0.05), administration group 5mg/kg group dramatically increased at the 1st, 2,3 day and overstates lattice number (P < within 3 days 0.05)；Administration group 10mg/kg group dramatically increased at the 1st, 2,3 day and overstates lattice number (P < 0.05)；Administration group 20mg/kg group is 1, it dramatically increases within 2,3 days and overstates lattice number (P < 0.05).Model group rats forearm lift number test 1 to 3 day considerably less than Sham-operation group (P < 0.05), administration group 5mg/kg group dramatically increased forearm at the 1st, 2,3 day and lift number (P < 0.05)；Administration Group 10mg/kg group dramatically increased forearm at the 1st, 2,3 day and lifts number (P < 0.05)；Administration group 20mg/kg group is in the 1st, 2,3 It dramatically increases forearm and lifts number (P < 0.05).The model group rats center lattice residence time is significant few at test 1 to 3 day In sham-operation group (P < 0.05), administration group 5mg/kg group dramatically increased center lattice residence time (P < 0.05) at the 1st, 2,3 day； Administration group 10mg/kg group dramatically increased center lattice residence time (P < 0.05) at the 1st, 2,3 day；Administration group 20mg/kg group is 1, it dramatically increases within 2,3 days center lattice residence time (P < 0.05).As shown in attached drawing 2, Fig. 3, Fig. 4.The result shows that HZAM-1 can Vascular dementia animal is significantly improved to the adaptability of strange environment, helps the exploratory behaviour for restoring its study.
The result to the area vascular dementia rats hippocampal dentate CA1 Pathologic Observation is administered in HZAM-1: rat is hydrated After chloralization, brain tissue is separated after 4% paraformaldehyde (0.1M phosphate buffer, PH=7.4) perfusion, immerses 4% In paraformaldehyde, 4 DEG C are kept in dark place for 24 hours, then immerse 30% sucrose solution 3 days, freezing microtome slice.After frozen section dries Instill absolute alcohol 5-10min, 75% alcohol 3min instills dye liquor, 95% alcohol twice, dimethylbenzene each 5min twice, finally With neutral gum mounting, naturally dry, mottled bluish violet dyeing is presented in cell, and microscope is taken pictures.Experimental result is shown, is done evil through another person Art group cell arrangement is close, and shape is intact, as shown in Fig. 5.There is obvious Cells Depletion in VD model group, and cell arrangement is at random, As shown in Fig. 6.Administration group has larger improvement compared to model group, and cell arrangement is more neat, as shown in Fig. 7.Hippocampal dentate The area CA1, which takes on, causes the position Apoptosis and missing about memory and sterically defined effect, vascular dementia.As a result Show that HZAM-1 can improve the memory of vascular dementia animal by reversing the ultrastructure of the area hippocampal dentate CA1 damage The state of power decline and direction unconsciousness.
Therapeutic effect of the embodiment 24:HZAM-1 to cerebral infarction
90 rats are randomly divided into 6 groups, respectively sham-operation group, model group, Edaravone group (3mg/kg, 0.02mmol), butylphenyl phthaleine group (20mg/kg, 0.1mmol), HZAM-1 group (60mg/kg, 0.1mmol), every group 15.Using Longa line brush makes focal brain ischemia-reperfusion injury in rats model, realizes that middle cerebral artery occlusion leads to cerebral ischemia.2h Realize that arteria cerebri media fills again afterwards, then modeling is completed.Sham-operation group only separates CCA, ICA and ECA, without any processing.To big Enter subsequent experimental according to the model for dividing standard screen processed to select 2 points or 3 points of Zea longa 5 after mouse revival.After ischemic 2h respectively 0h, 6h, 12h are respectively administered once after blood reperfusion, and the drug of corresponding dosage in corresponding group is injected intraperitoneally.Sham-operation group Isopropyl myristate solvent is injected intraperitoneally with model group, Edaravone, the butylbenzene of corresponding dosage is injected intraperitoneally in Edaravone group Phthalein and HZAM-1.Each group administered volume is 1ml/100g.Anesthetized rat, left ventricle PBS perfusion are rushed again after Reperfu- sion 22h Brain tissue is taken to carry out rat cerebral tissue's water content and brain infarction area detection after net blood, as a result as 1 table 2 of table is shown.With ELISA method detects serum Tumor Necrosis Factor α (TNF-α), the content of interleukin-1 beta (IL-1 β), is tried using biochemistry Calcium surveys content (Ca in agent box Indexs measure each group rat brain2+) and nitric oxide (NO) assay.As a result as shown in Table 3. In terms of cerebral infarction area, compared with sham-operation group, model group rats brain infarction area dramatically increases (P < 0.01)；With model group It compares, butylphenyl phthaleine group and HZAM-1 group rat cerebral infarction area are substantially reduced (P < 0.01), and Edaravone is not imitated significantly Fruit.For HZAM-1 compared with Edaravone, effect is substantially better than Edaravone, is not significantly different with butylphenyl phthaleine.In rat brain group In terms of knitting water content, with sham-operation group ratio, model group rats brain water content significantly increases (P < 0.01)；With model group phase Than Edaravone group, HZAM-1 group rat cerebral tissue water content significantly reduce (P < 0.01).And butylphenyl phthaleine is not obviously imitated Fruit.For HZAM-1 compared with butylphenyl phthaleine, effect is substantially better than butylphenyl phthaleine, is not significantly different with Edaravone.The experimental results showed that HZAM-1 has significant effect to the improvement of brain infarction area and rat cerebral tissue's water content, and butylphenyl phthaleine and Edaravone are only It is effective to the improvement of brain infarction area or rat cerebral tissue's water content.This illustrates that HZAM-1 ischemic brain damage has multiple effect Fruit, implying has clinical therapeutic efficacy more better than butylphenyl phthaleine and Edaravone.Index of correlation, discovery are detected using kit HZAM-1 is to TNF-α, IL-1 β, Ca2+, MDA all have good effect, and butylphenyl phthaleine and Edaravone only have part index number Effect.This is also to match with animal integral experiment result, illustrates HZAM-1 to brain infarction area and rat brain well The improvement of tissue water content has the reason of significant effect.It also illustrates simultaneously, caused by ischemic brain damage is multifactor A kind of disease, it is only single to be directed to a certain therapy target, it is extremely difficult to good therapeutic effect.In conclusion HZAM-1 is to causing The multiple target spots of ischemic brain damage all have good effect, have good potential applicability in clinical practice.
Influence of the table 1 to rat cerebral infarction area
Group Infarct size percentage (%)
Sham-operation group 0.00±0.00
Model group 15.91±9.06a
Edaravone group 6.44±5.15
Butylphenyl phthaleine group 1.64±1.03b
HZAM-1 group 1.78±0.91bc
aThe P < 0.01 compared with sham-operation group；bThe P < 0.01 compared with model group；cThe P > 0.1 compared with fourth this phthalein group；
Influence of the table 2 to rat cerebral tissue's water content
Group Water content (%)
Sham-operation group 77.89±0.48
Model group 83.17±2.40a
Edaravone group 80.33±1.29b
Butylphenyl phthaleine group 81.20±3.26
HZAM-1 group 77.41±0.64bc
aThe P < 0.01 compared with sham-operation group；bThe P < 0.01 compared with model group；cThe P > 0.1 compared with Edaravone
Table 3 is to TNF-α, IL-1 β, Ca in rat tissue2+, MDA content
aThe P < 0.01 compared with sham-operation group；bThe P < 0.01 compared with model group；cThe P > 0.1 compared with model group；dWith mould Type group compares P < 0.0.

Claims (10)

1. a kind of α shown in Formulas I-mangostin derivative,
Wherein, R1For H, C1-C6Linear or branched alkyl group, R2For C5-C6Cyclic hydrocarbon group, C1-C8Chain or branched alkyl, benzene Base, pyridyl group or substituted-phenyl, the substituent group of the substituted-phenyl be methyl, ethyl, chlorine, bromine, fluorine, methoxyl group, amino or Nitro；Or R1、R2With N cyclization, the ring is containing N or simultaneously containing the six-membered cyclic heterocycle of N and O.
2. α as described in claim 1-mangostin derivative, it is characterised in that: the R1For methyl or ethyl, the R2 For phenyl or aminomethyl phenyl.
3. α as described in claim 1-mangostin derivative, it is characterised in that: the ring is morpholinyl, piperazinyl, N- take For piperazinyl or piperidyl.
4. α as described in claim 1-mangostin derivative, it is characterised in that: the α-mangostin derivative be it is following it One:
5. a kind of α shown in Formulas I as described in one of Claims 1 to 4-mangostin derivative preparation method, feature exist In: the α-mangostin derivative is prepared as follows:
(1) triphosgene is dissolved in the dichloromethane solution that methylene chloride is made into the triphosgene that concentration is 0.1~0.5mol/L, ice bath Under, the dichloromethane solution of nitrogenous compound shown in the formula III that concentration is 0.1~0.5mol/L is added dropwise in triphosgene solution After triethylamine, 4~6h is stirred at room temperature, obtains reaction mixture A；Nitrogenous compound, three shown in the triphosgene and formula III The ratio between amount of substance of ethamine is 1:0.67~1.5:1.33~3；
(2) under ice bath, II compound represented of formula that concentration is 0.05~0.25mol/L is added dropwise into reaction mixture A Dichloromethane solution continues 4~6h of stirring, after reaction, post-treated α-chinaberry for obtaining Formulas I of gained reaction mixture B Plain derivative；The mass ratio of the material of II compound represented of formula and the triphosgene is 1:2.0~3.0.
Wherein, R1For H, C1-C6Linear or branched alkyl group, R2For C5-C6Cyclic hydrocarbon group, C1-C8Chain or branched alkyl, benzene Base, pyridyl group or substituted-phenyl, the substituent group of the substituted-phenyl be methyl, ethyl, chlorine, bromine, fluorine, methoxyl group, amino or Nitro；Or R1、R2With N cyclization, the ring is containing N or simultaneously containing the six-membered cyclic heterocycle of N and O.
6. method as claimed in claim 5, it is characterised in that: the post-processing approach of the reaction mixture B are as follows: to gained The distilled water of 3~6 times of reaction mixture B volumes is added in reaction mixture B, then is extracted with ethyl acetate 3-5 times, merges organic Layer uses anhydrous Na to be saturated NaCl solution washing2SO4It is dry, it filters, is concentrated to give the crude product of yellow oily, then will slightly produce Object is through petroleum ether: the mixed solvent that ethyl acetate volume ratio is 20:1 elutes, thin layer detection, collects and shows strong ultraviolet at 254nm And polarity is less than accordingly such as the eluent of the compound of formula II, merges eluent, decompression boils off the product that eluting solvent obtains Up to α shown in formula I-mangostin derivative after drying.
7. method as claimed in claim 5, it is characterised in that: II compound represented of formula is specifically made as follows It is standby:
α-mangostin is dissolved in toluene and is made into α-mangostin toluene solution that concentration is 0.1~0.5mol/L, at room temperature, in institute In the α stated-mangostin toluene solution plus 2, the 3- bis- chloro- 5 of 2~3 times of equivalents, 6 dicyanobenzoquinones, it is to be dissolved it is complete after, it is anti-at 40 DEG C It answers 5~8 hours, after reaction, gained reaction mixture C is evaporated under reduced pressure and removes toluene, silica gel column chromatography separating purification is used Petroleum ether: the mixed solvent that ethyl acetate volume ratio is 10:1 elutes, and thin layer detection collects and shows strong ultraviolet and pole at 254nm Property be less than the eluent of α-mangostin compound, merge eluent, decompression boil off product that eluting solvent obtains it is dry after i.e. Obtain the compound such as formula II；The mass ratio of the material of the α-mangostin and chloro- 5,6 dicyanobenzoquinone of 2,3- bis- is 1:2.0~3.0.
8. α as described in claim 1-mangostin derivative is in the medicine of preparation treatment brain injury disease as caused by ischemic Application in object.
9. application as claimed in claim 8, the brain injury disease is cerebral infarction and vascular dementia.
10. application as claimed in claim 9, it is characterised in that: the vascular dementia is vascular lesion, draws after cerebral ischemia The learning memory disorder or hippocampal dentate area cell loss of hair.
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