CN108191662A - A kind of mangosteen 01 derivatives and application - Google Patents

A kind of mangosteen 01 derivatives and application Download PDF

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Publication number
CN108191662A
CN108191662A CN201810045807.5A CN201810045807A CN108191662A CN 108191662 A CN108191662 A CN 108191662A CN 201810045807 A CN201810045807 A CN 201810045807A CN 108191662 A CN108191662 A CN 108191662A
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mangosteen
derivatives
formula
compound
yield
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CN108191662B (en
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张宝华
史兰香
刘斯婕
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Jiangxi Sungold Pharmaceutical Co ltd
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Shijiazhuang University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/02—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen
    • C07C69/12—Acetic acid esters
    • C07C69/18—Acetic acid esters of trihydroxylic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
    • C07C49/82—Ketones containing a keto group bound to a six-membered aromatic ring containing hydroxy groups
    • C07C49/83—Ketones containing a keto group bound to a six-membered aromatic ring containing hydroxy groups polycyclic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
    • C07C49/84—Ketones containing a keto group bound to a six-membered aromatic ring containing ether groups, groups, groups, or groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/02—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen
    • C07C69/12—Acetic acid esters
    • C07C69/21—Acetic acid esters of hydroxy compounds with more than three hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Abstract

The invention discloses a kind of mangosteen 01 derivatives or its pharmaceutically acceptable salt（I）, including its stereoisomer or tautomer.Preparation method the present invention relates to such compound and the purposes in preventing and managing cardiac insufficiency drug.

Description

A kind of mangosteen 01 derivatives and application
Technical field
The present invention relates to mangosteen 01 derivatives and preparation method thereof with as prevent and management cardiac insufficiency drug should With.
Background technology
Mangosteen alcohol is a kind of polyisopreneyl benzophenone derivates, is extracted from the dry fruit skin of Garcinia indica A kind of yellow crystals compound come, chemical constitution seemingly, have carcinoma of mouth apparent chemistry in advance with antioxidant curcumin Anti- effect is one to prevention and management role that cardiac insufficiency caused by chemotherapy, drug, disease or life style etc. has had A up-and-coming native chemical prophylactic agent, but it is undesirable to viscous permeability of the membrane, bioavilability, up for further It improves.
Fluorine atom passes through the effects that hydrogen bond, the conformation to molecule, the combination with receptor, to the physiological activity of compound It produces bigger effect.Fluorine atom and hydrogen atom van der Waals radius are very close, after fluorine atom replaces the hydrogen atom in molecule so that Former compound molecule volume change is little, and the metabolism of organism can be successfully entered instead of non-fluorine parent.CF3The introducing of group The fat-soluble of parent molecule, metabolic stability, bioactivity can be significantly changed.The present invention is by introducing fluoro-containing group to mangosteen alcohol It is chemically modified, to improve its absorption and permeability, improves its bioavilability, develop more effective, less toxic change Learn prophylactic agent.
Invention content
The purpose of the present invention is to provide a kind of mangosteen 01 derivatives, with good prevention and management cardiac insufficiency Activity, and toxicity is relatively low.
Another object of the present invention is to provide the preparation method of above-mentioned mangosteen 01 derivatives.
It is still another object of the present invention to provide the purposes of above-mentioned mangosteen 01 derivatives.
The present invention will be described in detail below.
The present invention provides below general formula（I）Mangosteen 01 derivatives or its pharmaceutically acceptable salt.Structure is shown below：
In formula, R1Respectively stand alone as F, CF3;R2,R3,R4Respectively stand alone as H, OH, OCH3, OAc and other alkoxies.
General formula of the present invention（I）Compound includes its stereoisomer and tautomer.
The formula（I）The specific example of compound includes：
The present invention also provides above-mentioned general formulas（I）The preparation method of compound, step include the following steps：
In formula, R1Respectively stand alone as F, CF3;R2,R3,R4Respectively stand alone as H, OH, OCH3, OAc and other alkoxies.
The mangosteen 01 derivatives of the present invention have good prevention and management cardiac insufficiency activity, and toxicity is relatively low.
The present invention is further illustrated by following embodiment, but should be noted that the scope of the present invention is not implemented by these Any restrictions of example.
Specific embodiment
Embodiment 1
The 1 of 56g (0.5mol) is taken, hydroresorcinol is dissolved in the water of 100ml, is cooled to DEG C, is slowly added to 71.5g (0.5mol) Triisopropylamine, then slowly plus 82g (0.55mol) 3,3- dimethallyl bromides, be stirred overnight at room temperature.It is added in reaction solution 2NNaOH solution 725mL, layering, water phase are extracted with 300ml ethyl acetate, and water phase is acidified to pH3-4 with glacial acetic acid, are filtered, and are done It is dry, it does not need to purify.Obtain intermediate（II）, yield 60%.ESI-MSm/z:181.0[M+H].
Take 35.3g（0.196mol）Intermediate（II）It is dissolved in 300ml acetone, adds in 116.6g（0.686mol）Isopropyl Iodine and 64g（0.784mol) potassium carbonate.Reaction is overnight.Decompression boils off acetone, and 400ml water and 400ml trichlorines are added in into residue First is burnt, dissolving.Layering, water phase are extracted with dichloromethane（2x300ml), it is dry.Concentration, silica gel column chromatography purifying（V acetic acid second Ester):V petroleum acids)=1：6）, obtain intermediate（Ⅲ）, yield 93%.ESI-MSm/z: 223.0[M+H].
Take 22.3g（0.1mol）Intermediate（Ⅲ）It is dissolved in the THF of 150ml, adds in 32.6g（0.1mol）Cs2CO3, cooling To -10 DEG C, 34.7g is added in（0.11mol）NFSI, reaction overnight, are filtered, concentration, and silica gel column chromatography purifying obtains 3- isopropyl oxygen Base -2- (3- methyl-2-butenes base) -6- fluorine hexamethylene -2- ketenes（IVa）, yield 59%.ESI-MSm/z: 241.1[M+H].
Take 24g (0.1mol) intermediate（IVa）, 250mlTHF is added in, is cooled to 0 DEG C, is slowly added to 85mL lithium methides (1.3M Diethyl ether solution), 30min is stirred at room temperature, reaction solution is cooled to 0 DEG C, with dilute hydrochloric acid adjust pH6, be stirred for 30min.It is layered dense Contracting, water phase are extracted with ethyl acetate (3x200ml).Washing, it is dry.Concentration, silica gel column chromatography purify to obtain intermediate（Va）, production Rate 72%.
It weighs 0.512g (2.5mmol) cuprous bromide dimethyl sulphide and is cooled to -78 DEG C, be slowly added to 83.3mI （0.25mmol）Methyl-magnesium-bromide (the diethyl ether solution of 3M）, 17.92g (100mmol) hexamethyl neighbour's acyl triamine is slow added into, instead 20min is answered, is slowly added to the 50mlTHF containing 12.0g (50mmol) intermediate Va and 10.86g (100mmol) methylchlorosilane Solution, insulation reaction 2 hours.1N dilute hydrochloric acid is slowly added in, adjusts pH5, then react 30min, is warmed to room temperature reaction 10min, Reaction liquid layer, decompression boil off THF, and water phase is extracted with ethyl acetate（3x200ml).It is dry, concentration, silica gel column chromatography purifying, Obtain intermediate VIa, yield 87%.
25.4g (100mmol) intermediates VIa is taken to add in 100mL dichloromethane, is cooled to 0 DEG C, adds in 3.0g (300mmol) triethylamine, 0 DEG C of reaction 15min, is slow added into 26.6g (120mmol) Trimethylsilyl trifluoromethanesulfonate, instead It should stay overnight, add in 300ml petroleum ethers, be layered, dry, concentration obtains VIIa.
The VIIa of 15.98g is taken, is dissolved in 200ml ether, leads to nitrogen, is cooled to -20 DEG C, is slowly added to 6.7g (47mmol) malonyl chloride, insulation reaction is overnight, adds the aqueous solution of 10.53g potassium hydroxide and 70ml water, adds 500mg tetrabutylammonium chlorides.React at room temperature 5h.200ml water and 200ml petroleum ethers are added in, sodium hydroxide solution is added in and adjusts PH11, layering, water layer are cooled to 0 DEG C, are acidified with dilute hydrochloric acid with petroleum ether extraction (3x250ml), water phase, will adjust pH2, dichloromethane Alkane extracts (3x300ml), dry, and silica gel column chromatography purifying obtains compound VIIIa, yield 19%.
280mg (1mmol) compounds VIIIa is taken to be dissolved in the anhydrous THF of 20ml, is slowly added to 101mg under nitrogen protection (1mmol) triethylamine, adds the THF solution of the 5ml of 3, the 4- diacetoxy benzoyl nitriles of 296mg (1.2mmol), and temperature is stirred The ammonium chloride solution for adding in 20ml saturations overnight is mixed, decompression boils off THF, and ethyl acetate extraction (3x20ml) is dry.Concentration, silicon Plastic column chromatography detaches, and obtains compound（1）, yield 70%.ESI-MS m/z: 499.1[M-H].
Embodiment 2
Take 22.3g（0.1mol）Intermediate（Ⅲ）It is dissolved in the CHCl of 100ml3In, add in 7.6g（0.004mol）CuI and 11.7g （0.11mol）Cs2CO3, -10 DEG C are cooled to, adds in 34.8g（0.11mol）Togni reagent II, reaction for 24 hours, are filtered, concentration, Silica gel column chromatography purifies, and obtains 3- isopropoxies -2- (3- methyl-2-butenes base) -6- trifluoromethyl hexamethylene -2- ketenes（IVb）, production Rate 67%.ESI-MSm/z: 291.1[M+H].
By 24g (0.1mol) intermediate（IVa）It is changed to 29g (0.1mol) intermediate（IVb）, it is other to operate with embodiment 1, Obtain intermediate（Vb）, yield 71%.
12.0g (50mmol) intermediates Va is changed to 14.5g (50mmol) intermediates Vb, other operations are obtained with embodiment 1 To intermediate VIb, yield 84%.
25.4g (100mmol) intermediates VIa is changed to 26.2g (100mmol) intermediates VIb, other same embodiments of operation 1, obtain compound VIIIb, yield 20%.
280mg (1mmol) compounds VIIIa is changed to 330mg (1mmol) compound VIIIb, by 296mg (1.2mmol) 3,4- diacetoxy benzoyl nitriles are changed to 201mg (1.2mmol) 3,4- dihydroxybenzoyl nitriles, other to operate with embodiment 1, Obtain compound（2）, yield 73%.ESI-MS m/z: 465.2[M-H].
Embodiment 3
296mg (1.2mmol) 3,4- diacetoxy benzoyl nitriles are changed to 212mg (1.2mmol) 3- methoxyl group -4- hydroxy benzenes Formyl nitrile, other operations obtain compound with embodiment 2（3）, yield 75%.ESI-MS m/z: 479.2[M-H].
Embodiment 4
296mg (1.2mmol) 3,4- diacetoxy benzoyl nitriles are changed to 366mg (1.2mmol) 3,4,5- triacetyl benzene Formyl nitrile, other operations obtain compound with embodiment 2（4）, yield 75%.ESI-MS m/z: 607.2[M-H].
Embodiment 5
Take 608mg (1.0mmol) compound（4）, 15mL methanol is added in, the NaOH solution of 15mL2N is added, 5h is stirred at room temperature, Compound is made in dilute hydrochloric acid tune pH3, concentration, column chromatography purifying（5）, yield 87%.ESI-MS m/z: 481.1[M-H].
Embodiment 6
296mg (1.2mmol) 3,4- diacetoxy benzoyl nitriles are changed to 265mg (1.2mmol) 3,4,5- trimethoxy-benzenes Formyl nitrile, other operations obtain compound with embodiment 2（6）, yield 79%.ESI-MS m/z: 523.2[M-H].
Embodiment 7
Take 500mg (1.0mmol) compound（1）Hydrolysis, operates same embodiment 5, and compound is made（7）, yield 89%.ESI-MS m/z: 415.1[M-H]。
Embodiment 8
Mangosteen 01 derivatives test the cardiac insufficiency caused by the administration of long-term adriamycin and cardioprotection.
With 20mg/Kg（It is oral）The mangosteen 01 derivatives pretreatment male Wistar rat of dosage 30 days.The 1,7th, 14 and 28 days, by adriamycin with 2mg/Kg dosage intravenously administrables.At the 30th day, animal is put to death, histopathology is carried out to heart It checks.The results show that after being pre-processed with mangosteen 01 derivatives, extend QT intervals, ST intervals and QTc intervals that adriamycin is led to Significant normalization, and can prevent heart rate from declining（Table 1）.

Claims (4)

1. a kind of mangosteen 01 derivatives or its pharmaceutically acceptable salt（I）, it is special including its stereoisomer or tautomer Sign is that it has below formula：
In formula, R1Respectively stand alone as F, CF3;R2,R3,R4Respectively stand alone as H, OH, OCH3, OAc and other alkoxies.
2. according to the formula described in right 1（I）Mangosteen 01 derivatives or its pharmaceutically acceptable salt, it is characterised in that：The formula （I）The specific example of compound includes：
。
3. formula（I）Compound preparation method, this method includes the following steps：
In formula, R1Respectively stand alone as F, CF3;R2,R3,R4Respectively stand alone as H, OH, OCH3, OAc and other alkoxies.
4. according to the formula described in right 1（I）Mangosteen 01 derivatives prepare prevention and management cardiac insufficiency drug in should With.
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH08259493A (en) * 1995-03-20 1996-10-08 Sugimoto Masami Anti-mrsa active substance
CN102911058A (en) * 2012-11-19 2013-02-06 江苏扬农化工股份有限公司 Synthetic method of plant growth regulator trinexapac-ethyl intermediate 3-carbethoxy-5-oxo-cyclohexane-1-enol cyclopropanecarboxylate
CN103459362A (en) * 2010-12-09 2013-12-18 英德斯生物科技私人有限公司 A complex of garcinol, cyclodextrin and method thereof
WO2016063296A1 (en) * 2014-10-21 2016-04-28 Council Of Scientific & Industrial Research Polyprenylated phloroglucinol compounds as potent p-glycoprotein inducers
US20160309711A1 (en) * 2015-04-24 2016-10-27 Research Foundation Of The City University Of New York Method of inhibiting biofilm formation

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH08259493A (en) * 1995-03-20 1996-10-08 Sugimoto Masami Anti-mrsa active substance
CN103459362A (en) * 2010-12-09 2013-12-18 英德斯生物科技私人有限公司 A complex of garcinol, cyclodextrin and method thereof
CN102911058A (en) * 2012-11-19 2013-02-06 江苏扬农化工股份有限公司 Synthetic method of plant growth regulator trinexapac-ethyl intermediate 3-carbethoxy-5-oxo-cyclohexane-1-enol cyclopropanecarboxylate
WO2016063296A1 (en) * 2014-10-21 2016-04-28 Council Of Scientific & Industrial Research Polyprenylated phloroglucinol compounds as potent p-glycoprotein inducers
US20160309711A1 (en) * 2015-04-24 2016-10-27 Research Foundation Of The City University Of New York Method of inhibiting biofilm formation

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Title
P. NUHANT ET AL.，: ""α,α’-Annulation of 2,6-Prenyl-Substituted Cyclohexanone Derivatives with Malonyl Chloride:Application to a Short Synthesis of (±)-Clusianone. Formation and", 《ORG.LETT.》 *
X.Y. ZHOU ET AL.，: ""The C8 side chain is one of the key functional group of Garcinol for its anti-cancer effects"", 《BIOORGANIC CHEMISTRY》 *
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韩超明: ""天然产物山竹醇的衍生物的合成及其生物活性研究"", 《中国优秀硕士学位论文全文数据库工程科技Ⅰ辑》 *

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