CN1944448B - Puerarin derivative and its medicinal use - Google Patents
Puerarin derivative and its medicinal use Download PDFInfo
- Publication number
- CN1944448B CN1944448B CN2006100008140A CN200610000814A CN1944448B CN 1944448 B CN1944448 B CN 1944448B CN 2006100008140 A CN2006100008140 A CN 2006100008140A CN 200610000814 A CN200610000814 A CN 200610000814A CN 1944448 B CN1944448 B CN 1944448B
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- Prior art keywords
- puerarin
- substituted
- unsubstituted
- group
- hydrogen
- Prior art date
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- HKEAFJYKMMKDOR-VPRICQMDSA-N puerarin Chemical class O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1C1=C(O)C=CC(C2=O)=C1OC=C2C1=CC=C(O)C=C1 HKEAFJYKMMKDOR-VPRICQMDSA-N 0.000 title claims abstract description 65
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 7
- 201000010099 disease Diseases 0.000 claims abstract description 6
- 239000003814 drug Substances 0.000 claims abstract description 6
- 238000002360 preparation method Methods 0.000 claims abstract description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 24
- 239000001257 hydrogen Substances 0.000 claims description 24
- -1 pivaloyloxymethylene Chemical group 0.000 claims description 24
- 150000001875 compounds Chemical class 0.000 claims description 21
- 150000002431 hydrogen Chemical class 0.000 claims description 18
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 10
- 229910052757 nitrogen Inorganic materials 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 5
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 claims description 4
- 125000002252 acyl group Chemical group 0.000 claims description 4
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 4
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
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- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 4
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- 150000001555 benzenes Chemical group 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- HRQGCQVOJVTVLU-UHFFFAOYSA-N bis(chloromethyl) ether Chemical compound ClCOCCl HRQGCQVOJVTVLU-UHFFFAOYSA-N 0.000 description 1
- 230000008499 blood brain barrier function Effects 0.000 description 1
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- 125000004432 carbon atom Chemical group C* 0.000 description 1
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- 125000000664 diazo group Chemical group [N-]=[N+]=[*] 0.000 description 1
- 238000006193 diazotization reaction Methods 0.000 description 1
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
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- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
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- 239000008103 glucose Substances 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 1
- 125000005113 hydroxyalkoxy group Chemical group 0.000 description 1
- 125000005191 hydroxyalkylamino group Chemical group 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 208000012947 ischemia reperfusion injury Diseases 0.000 description 1
- GOMNOOKGLZYEJT-UHFFFAOYSA-N isoflavone Chemical compound C=1OC2=CC=CC=C2C(=O)C=1C1=CC=CC=C1 GOMNOOKGLZYEJT-UHFFFAOYSA-N 0.000 description 1
- CJWQYWQDLBZGPD-UHFFFAOYSA-N isoflavone Natural products C1=C(OC)C(OC)=CC(OC)=C1C1=COC2=C(C=CC(C)(C)O3)C3=C(OC)C=C2C1=O CJWQYWQDLBZGPD-UHFFFAOYSA-N 0.000 description 1
- 235000008696 isoflavones Nutrition 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 239000008297 liquid dosage form Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 1
- 229910052753 mercury Inorganic materials 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 1
- LRMHVVPPGGOAJQ-UHFFFAOYSA-N methyl nitrate Chemical compound CO[N+]([O-])=O LRMHVVPPGGOAJQ-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000008065 myocardial cell damage Effects 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 239000000709 neurohypophysis hormone Substances 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- JCZMXVGQBBATMY-UHFFFAOYSA-N nitro acetate Chemical compound CC(=O)O[N+]([O-])=O JCZMXVGQBBATMY-UHFFFAOYSA-N 0.000 description 1
- JBCXQJHXIYZCNI-UHFFFAOYSA-N nitro benzoate Chemical compound [O-][N+](=O)OC(=O)C1=CC=CC=C1 JBCXQJHXIYZCNI-UHFFFAOYSA-N 0.000 description 1
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- 229910052760 oxygen Inorganic materials 0.000 description 1
- 125000005489 p-toluenesulfonic acid group Chemical class 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 239000006201 parenteral dosage form Substances 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- 230000001817 pituitary effect Effects 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229940068189 posterior pituitary hormone Drugs 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 125000005420 sulfonamido group Chemical group S(=O)(=O)(N*)* 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention discloses the puerarin derivatives, and their preparation process, medicine compositions and application in preparing medicine for treating cardiac and cerebral vascular diseases, obstruction of retinal artery and vein, sudden hearing loss and other diseases, improving memory and lowering blood sugar.
Description
Technical Field
The invention relates to a novel puerarin derivative shown in a general formula (I), a preparation method thereof, a pharmaceutical composition containing one or more compounds, and application of the compounds in preparing medicaments for treating diseases related to heart and brain circulation, diseases such as retinal artery and vein occlusion, sudden deafness and the like, improving memory, and reducing blood sugar.
Background
Puerarin (puerarin) is isoflavone glucosylcarbenoside extracted and separated from dried roots of Pueraria lobata (Willd.) Ohwi and Pueraria thomsonii Benth which are leguminous plants, has a chemical name of 74' -dihydroxy-8-beta-D-glucosylisoflavone, is one of main active ingredients in the traditional Chinese medicine radix puerariae, and has wide pharmacological action. Research shows that puerarin has an expansion effect on coronary artery, can protect whole-heart ischemic myocardium and myocardial ischemia reperfusion injury, reduce acute myocardial infarction area, reduce myocardial oxygen consumption, and prevent platelet adhesion, aggregation and thrombosis; has the function of dredging retinal embolism; and has obvious protective effect on acute cerebral ischemia; and has effects of improving memory and reducing blood sugar.
Clinical puerarin is mainly used for treating coronary heart disease, angina pectoris, myocardial infarction, ischemic cerebrovascular disease, retinal occlusion and other diseases. However, the polyhydroxy chemical structure of puerarin determines the defects of poor fat solubility and low bioavailability, and the puerarin is mainly administered in an injection form at present, so that long-term injection on chronic cardiovascular and cerebrovascular diseases with long treatment course brings inconvenience to patients, even causes local tissue necrosis or infection, and increases the pain of the patients. Although some tablets, capsules and granules appear, the oral administration of puerarin has poor absorption in gastrointestinal tract and low bioavailability. Moreover, the polyhydroxy structure of puerarin is not conducive to crossing blood brain barrier, affecting the therapeutic effect on cerebrovascular diseases. To fundamentally increase the lipid solubility of puerarin, improve the bioavailability of puerarin and improve the drug effect, the puerarin needs to be structurally modified and reformed. To date, some work has been done at the university of pharmaceutical sciences in China on structural modification of puerarin molecules, limited to modification of the hydroxyl group at the 7-position, 4' -position, and the hydroxymethyl group at the 11-position of the molecule (Yang Ruolin, Lina et al, proceedings of the university of pharmaceutical sciences in China, 1999, 30 (2): 81-85), where Shaanxi Zhen pharmaceutical factories applied for a patent on hydroxyethylpuerarin as a new drug for treating cerebrovascular diseases (CN 1394603A). The invention respectively modifies and reforms according to different hydroxyl groups with different reaction activities in puerarin molecules and different reaction sites on benzene rings.
The invention aims to improve the pharmacokinetic property of puerarin molecules by carrying out structural modification and reconstruction on the puerarin molecules, improve the oral bioavailability and obtain puerarin derivatives and analogues with excellent performance.
Disclosure of Invention
Another object of the present invention is to provide a method for preparing a novel puerarin derivative;
it is a further object of the present invention to provide a pharmaceutical composition comprising one or more of such compounds;
the invention also aims to provide the application of the novel puerarin derivatives in medicaments for treating cardiovascular and cerebrovascular related diseases.
In order to achieve the purpose of the invention, the invention adopts the following technical scheme:
the present invention relates to novel puerarin derivatives having the general formula I:
wherein,
R1and R2Are independently selected from hydrogen, substituted or unsubstituted C1-18Alkyl, substituted or unsubstituted C3-9Cycloalkyl, substituted or unsubstituted aromatic ring, substituted or unsubstituted aromatic heterocycle, substituted or unsubstituted C1-18Alkanoyl, substituted or unsubstituted C1-18Alkoxyacyl (substituent selected from halogen, nitro, hydroxyl, sulfhydryl, carboxyl, ester, amino, amido, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkylthio radical, C1-6Alkanoyl radical, C1-6Alkanoyloxy, methanesulfonyl, aminomethanesulfonyl);
more preferred R1And R2Is alkanoyloxymethylene, alkoxyacyl, amino lower alkyl, hydroxy lower alkyl, carboxy lower alkyl, -C (═ O) (CH)2)nCOOH n＝2，3，4，
R3And R4Are respectively selected from hydrogen; halogen; a nitro group; substituted or unsubstituted amino (substituents are selected from substituted or unsubstituted C1-18Alkyl, substituted or unsubstituted C3-9Cycloalkyl radicals or containingCycloalkyl having one or two hetero atoms, substituted or unsubstituted aromatic ring, substituted or unsubstituted aromatic heterocycle, substituted or unsubstituted C1-18Alkanoyl, substituted or unsubstituted C3-9Cycloalkanes or cycloalkanoyl groups containing one or two hetero atoms, substituted or unsubstituted aroyl groups, substituted or unsubstituted heterocyclic aroyl groups, substituted or unsubstituted C3-9Cycloalkane or cycloalkanoyloxy group containing one or two hetero atoms, substituted or unsubstituted aroyloxy group, substituted or unsubstituted heterocyclic aroyloxy group, substituted or unsubstituted C1-18Alkoxyacyl, substituted or unsubstituted C1-18Alkylsulfonyl, substituted or unsubstituted C3-9Cycloalkanes or cycloalkylsulfonyl containing one or two heteroatoms, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted heterocyclic arylsulfonyl (substituents selected from halogen, nitro, hydroxy, mercapto, carboxy, ester, amino, amido, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkylthio radical, C1-6Alkanoyl radical, C1-6Alkanoyloxy, methanesulfonyl, aminomethanesulfonyl), sulfonyl,); substituted or unsubstituted hydroxyl (substituent is selected from substituted or unsubstituted C1-18Alkyl, substituted or unsubstituted C3-9Cycloalkyl or cycloalkyl containing one or two hetero atoms, substituted or unsubstituted aromatic rings, substituted or unsubstituted aromatic heterocycles, substituted or unsubstituted C1-18Alkanoyl, substituted or unsubstituted C3-9Cycloalkanes or cycloalkanoyl groups containing one or two hetero atoms, substituted or unsubstituted aroyl groups, substituted or unsubstituted heterocyclic aroyl groups, substituted or unsubstituted C3-9Cycloalkane or cycloalkanoyloxy group containing one or two hetero atoms, substituted or unsubstituted aroyloxy group, substituted or unsubstituted heterocyclic aroyloxy group, substituted or unsubstituted C1-18Alkoxyacyl, substituted or unsubstituted C1-18Alkylsulfonyl, substituted or unsubstituted C3-9Cycloalkanes or cycloalkylsulfonyl containing one or two heteroatoms, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted heterocyclic arylsulfonyl (substituents selected from halogen, nitro, hydroxy, mercapto, carboxy, ester, nitro,Amino, amido, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkylthio radical, C1-6Alkanoyl radical, C1-6Alkanoyloxy, methanesulfonyl, aminomethanesulfonyl)); -OSO3H；-OC(＝O)(CH2)nCOOH n＝2，3，4；-OP(＝O)(OH)2。
More preferred R3And R4Is hydrogen, nitro, amino, N-alkylamino, N, N-dialkylamino, alkanoylamino, sulfonamido, alkylsulfonylamino, hydroxyalkylamino, carboxyalkylamino, halogen, hydroxyl, alkoxy, alkanoyloxy, alkoxyacyloxy, aminoalkoxy, hydroxyalkoxy, carboxyalkoxy, alkanoyloxymethylenoxy, carbamoylalkoxy, -OSO3H，-OC(＝O)(CH2)nCOOH n＝2，3，4，-OP(＝O)(OH)2。
R5Selected from hydrogen, substituted or unsubstituted C1-18Alkyl, substituted or unsubstituted C3-9Cycloalkyl or cycloalkyl containing one or two hetero atoms, substituted or unsubstituted aralkyl, substituted or unsubstituted aromatic heterocycle, substituted or unsubstituted C1-18Alkanoyl, substituted or unsubstituted C3-9Cycloalkanes or cycloalkanoyl groups containing one or two hetero atoms, substituted or unsubstituted aroyl groups, substituted or unsubstituted heterocyclic aroyl groups, substituted or unsubstituted C3-9Cycloalkane or cycloalkanoyloxy group containing one or two hetero atoms, substituted or unsubstituted aroyloxy group, substituted or unsubstituted heterocyclic aroyloxy group, substituted or unsubstituted C1-18Alkoxyacyl, substituted or unsubstituted C1 -18Alkylsulfonyl, substituted or unsubstituted C3-9Cycloalkanes or cycloalkylsulfonyl containing one or two heteroatoms, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted heterocyclic arylsulfonyl (substituents selected from halogen, nitro, hydroxy, mercapto, carboxy, ester, amino, amido, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkylthio radical, C1-6Alkanoyl radical, C1-6Alkanoyloxy, methanesulfonyl, aminomethanesulfonyl)); -OSO3H；-OC(＝O)(CH2)nCOOHn＝2，3，4；-OP(＝O)(OH)2。
More preferably R5Selected from the group consisting of hydrogen, alkyl, aralkyl, alkanoyl, alkoxyformyl, alkanoyloxymethylene, -SO3H，-C(＝O)(CH2)nCOOH n＝2，3，4，-P(＝O)(OH)2。
R6，R7And R8Are independently selected from hydrogen, substituted or unsubstituted C1-18Alkyl, substituted or unsubstituted C3-9Cycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aromatic heterocycle, substituted or unsubstituted C1-18Alkanoyl, substituted or unsubstituted C1-18Alkoxyacyl (substituent selected from halogen, nitro, hydroxyl, sulfhydryl, carboxyl, ester, amino, amido, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkylthio radical, C1-6Alkanoyl radical, C1-6Alkanoyloxy, methanesulfonyl, aminomethanesulfonyl); -SO3H，-C(＝O)(CH2)nCOOH n＝2，3，4，-P(＝O)(OH)2。
More preferably R6，R7And R8Are independently selected from hydrogen, alkyl, aralkyl, alkanoyl, alkoxyacyl, alkanoyloxymethylene, -SO3H，-C(＝O)(CH2)nCOOH n＝2，3，4，-P(＝O)(OH)2。
Most preferred is
R1And R2Selected from hydrogen, acetyl, pivaloyl, benzoyl, methoxycarbonyl, pivaloyloxymethylene;
R3and R4Selected from hydrogen, 3 '-nitro, 3' -amino, N-dimethylamino;
R5、R6、R7and R8Selected from hydrogen, acetyl, pivaloyl, benzoyl, methoxycarbonyl, pivaloyloxymethylene, benzylidene and propylidene.
But instead of the other end of the tube
R1、R2、R3、R4、R5、R6，、R7And R8Cannot be simultaneously hydrogen and cannot be simultaneously acetyl.
R3、R4、R5、R6，、R7And R8While being hydrogen, R1And R2Cannot be simultaneously hydroxyethyl.
R1、R2、R3、R4、R6、R7And R8While being hydrogen, R5And cannot be trityl and benzoyl.
"alkyl" groups in the context of the present invention generally include straight-chain or branched-chain or cyclic aliphatic alkyl groups, which may contain one or two heteroatoms (N, O, S, N), halogen substituted or unsubstituted; also includes substituted or unsubstituted aromatic alkanes (aromatic rings or aromatic heterocycles), wherein the substituent (mono-or polysubstituted) can be halogen, nitro, alkoxy, ester group, acylamino, alkyl, methylsulfonyl or aminomethylsulfonyl).
The lower alkyl group in the invention generally refers to substituted or unsubstituted straight-chain alkyl group with 1-5 carbon atoms, and the substituent can be aliphatic alkyl or aromatic alkane.
R of the invention3May be mono-substituted in the 3 'or 5' position, wherein R3Can be reacted with R1Combined into a substituent; r3It may also be a double substitution of the 3 'and 5' positions, or of the 3 'and 6' positions, or of the 5 'and 2' positions. R4However, the substitution at the 6-position may be a single substitution or a double substitution at the 5-position and the 6-position.
R of the invention5，R2，R6，R7，R8Two of them can be combined into a substituent, such as 12-O, 15-O-propylidene puerarin, 12-O, 15-O-phenmethyl puerarin.
To prepare the compounds of formula I of the present invention, the process of the present invention comprises:
selectively acylating or alkylating phenolic hydroxyl in an alkaline medium, and respectively acylating and alkylating the 7-position phenolic hydroxyl and the 4' -position phenolic hydroxyl of puerarin molecules by selecting proper reaction conditions according to the difference of steric hindrance and reaction performance of the two phenolic hydroxyl. Alternative inorganic bases include: anhydrous sodium carbonate, anhydrous potassium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium hydride, and the like; the optional organic base comprises amines, nitrogen-containing heterocycles, weak acid and strong base salts, basic ion exchange resin and the like. Alternative solvents include polar protic and polar aprotic solvents such as acetone, N-dimethylformamide, dimethyl sulfoxide, hexamethylphosphoramide, isopropanol, ethanol, tert-butanol, tetrahydrofuran, pyridine, triethylamine and the like.
In an acidic environment, the alcoholic hydroxyl group can be selectively acylated or alkylated, and the primary alcoholic hydroxyl group and the secondary alcoholic hydroxyl group in the puerarin molecule are respectively acylated or alkylated by selecting proper reaction conditions according to different reaction activities of the primary alcoholic hydroxyl group and the secondary alcoholic hydroxyl group. Alternative inorganic acids include: lewis acids such as boron trifluoride, aluminum trichloride, zinc dichloride and the like, protonic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, oxalic acid and the like, strong acids such as ammonium chloride and weak base salts and acid salts; alternative organic acids include: carboxylic acids such as formic acid, acetic acid and benzoic acid, sulfonic acids such as methanesulfonic acid and p-toluenesulfonic acid, phenols, organic alkali strong acid salts and acidic ion exchange resins. Alternative solvents include polar protic and polar aprotic solvents such as acetone, N-dimethylformamide, dimethyl sulfoxide, hexamethylphosphoramide, isopropanol, ethanol, tert-butanol, tetrahydrofuran, ethyl acetate, chloroform and the like.
The phenolic hydroxyl and the alcoholic hydroxyl of the puerarin molecule can be respectively acylated or alkylated through protection and deprotection strategies. For example, the phenolic hydroxyl group can be protected by using chloromethyl ether under alkaline environment, then the acylation of the alcoholic hydroxyl group is carried out, and then the methyl ether protecting group is removed under acidic condition.
Or completely acylating or alkylating the phenolic hydroxyl and the alcoholic hydroxyl of the puerarin firstly, and then selecting proper reaction conditions for selective removal, thereby obtaining the required structure modified product.
The modification of two benzene rings in puerarin molecule can be carried out by selecting proper nitrating agent and controlling proper reaction condition to carry out selective nitration, further reduce into amino, carry out alkylation or acylation on amino, further carry out nitration on benzene ring, and further carry out diazotization on amino, thereby carrying out diazo substitution reaction and obtaining a series of benzene ring substitution products. The nitrating agent may be selected from: HNO3/AcOH，HNO3/Ac2O，HNO3/BF3，CH3ONO2/BF3，NH4NO3/HNO3/Ac2O, benzoyl nitrate, acetyl nitrate, and the like.
The invention also relates to a pharmaceutical composition containing a pharmaceutically effective dose of the compound shown in the general formula I and a pharmaceutically acceptable carrier.
In the compounds of the general formula I of the invention, when R is1、R2、R5、R6、R7、R8When the acyl group or part of the acyl group is the acyl group and the rest is hydrogen, the compounds are prodrugs of puerarin, and the puerarin is easily hydrolyzed and converted into original puerarin under the action of esterase or phosphatase in a biological medium, and the lipid solubility and the bioavailability of the esterified compounds are greatly improved. And the uses of these esterified compounds should include those presently known and later discovered.
In the compounds of the general formula I according to the invention, R1、R2、R5、R6、R7、R8When is alkyl or part of alkyl and the remainder is hydrogen, and R3、R4When the puerarin derivatives are not hydrogen or partially not hydrogen, the biological activity of the puerarin derivatives as the new active ingredients is better than or equal to that of puerarin in certain aspects. Pharmacological research shows that partial compounds of the puerarin derivatives show equivalent or superior activity to puerarin in reducing myocardial tissue ischemia injury in an action model of isolated rat heart reperfusion injury and pituitrin-induced rat myocardial ischemia.
The compound of the general formula I has the effects of expanding coronary arteries, protecting global ischemic myocardium and myocardial ischemia reperfusion injury, reducing the area of acute myocardial infarction, reducing the oxygen consumption of myocardium, preventing platelet adhesion, aggregation and thrombosis, dredging retinal embolism, obviously protecting acute cerebral ischemia, and improving memory and reducing blood glucose. Clinically, it can be used for treating coronary heart disease, angina pectoris, myocardial infarction, ischemic cerebrovascular disease, and retinal occlusion.
The compounds of the invention may be administered orally or parenterally. The oral preparation can be tablet, granule, capsule, and soft capsule; parenteral dosage forms include injections and suppositories. These formulations are prepared according to methods well known to those skilled in the art. The adjuvants used for preparing tablet, granule, capsule, and soft capsule are conventional adjuvants, such as starch, lactose, gelatin, syrup, glycerol, beeswax, acacia, silica gel micropowder, pulvis Talci, and polyethylene glycol. Solvents used in liquid dosage forms are, for example, water, ethanol, propylene glycol, vegetable oils such as corn oil, peanut oil, olive oil and the like. The formulations containing the compounds of the present invention may also contain other adjuvants such as surfactants, lubricants, antioxidants, disintegrants, preservatives, flavoring agents, coloring agents, and the like.
The dosage of a compound of formula I according to the invention in tablets, granules, capsules, soft capsules, injections or suppositories is calculated as the amount of compound present in the unit dosage form. The compound of formula I of the present invention is generally present in an amount of from 10 to 50mg in a unit dosage form, with a preferred unit dosage form containing from 20 to 100 mg.
Detailed Description
The present invention will be further illustrated with reference to the following examples, but the scope of the present invention is not limited thereto.
The measuring instrument: melting points were measured using a Yanaco micro melting point apparatus and NMR spectroscopy using a Vaarian Mercury 300 NMR spectrometer. Mass spectra were obtained on ZAD-2F and VG300 mass spectrometers.
Example 1.7-O-pivaloyl Puerarin
Dissolving 0.416 g (1 mmol) of puerarin in 50 ml of acetone, adding 0.414 g (3 mmol) of anhydrous potassium carbonate, dropwise adding 1 mmol of pivaloyl chloride in batches under stirring at room temperature, tracking the reaction by TLC, stirring at room temperature until the raw material point disappears, removing most of solvent by spinning, adding ethyl acetate for extraction, washing with water, drying with anhydrous sodium sulfate, removing the solvent by spinning, and performing column chromatography (ethyl acetate: methanol is 10: 1) to obtain 0.345 g of a white solid product, wherein the melting point is: 216 ℃ and 218 ℃ in 69%.
1H NMR(300MHZ，CD3OD)，δ：8.261(S，3/7H，H2)，8.246(S，4/7H，H2)，8.17(d，1H，H5)，7.35(d，2H，H2′6′)，7.165(d，3/7H，H6)，7.095(d，4/7H，H6)，6.80(d，2H，H3′5′)，1.37(S，9H，-CH3)，5.05(d，4/7H，H9)，4.66(d，3/7H，H9)，4.16(t，3/7H，H14)，3.94(t，4/7H，H14)，3.83(d，1H，H15)，3.64(dd，3/7H，H15)，3.54(dd，4/7H，H15)，3.22-3.52(m，3H，H11，H12，H13)。
MS(FAB)：M+1＝501。
Example 2.7-O-AcetylPuerarin
Dissolving 0.416 g (1 mmol) of puerarin in 50 ml of acetone, adding 0.414 g (3 mmol) of anhydrous potassium carbonate, dropwise adding 1 mmol of acetyl chloride while stirring at room temperature, tracking the reaction by TLC, stirring at room temperature until the raw material point disappears, removing most of the solvent by rotation, adding ethyl acetate for extraction, washing with water, drying with anhydrous sodium sulfate, removing the solvent by rotation, and performing column chromatography (ethyl acetate: methanol is 10: 1) to obtain 0.289 g of a white solid product. Melting point: 194 ℃ and 196 ℃ in 63 percent yield.
1H NMR(300MHz，CD3OD)，δ：8.278(S，2/5H，H2)，8.246(S，3/5H，H2)，8.18(d，1H，H5)，7.36(d，2H，H2′6′)，7.175(d，2/5H，H6)，7.15(d，3/5H，H6)，6.80(d，2H，H3′5′)，1.37(S，9H，-CH3)，5.05(d，3/5H，H9)，4.67(d，2/5H，H9)，4.15(t，2/5H，H14)，3.93(t，3/5H，H14)，3.83(d，1H，H15)，3.64(dd，2/5H，H15)，3.54(dd，3/5H，H15)，3.3-3.5(m，3H，H11，H12，H13)。
MS(FAB)：M+1＝459.3。
Example 3.7-O, 4' -O-Dipivaloyl Puerarin
Dissolving 0.416 g (1 mmol) of puerarin in 50 ml of acetone, adding 0.414 g (3 mmol) of anhydrous potassium carbonate, dropwise adding two mmol of pivaloyl chloride while stirring at room temperature, tracking the reaction by TLC, stirring at room temperature until the raw material point disappears, removing most of solvent by spinning, adding ethyl acetate for extraction, washing with water, drying with anhydrous sodium sulfate, removing the solvent by spinning, and performing column chromatography (ethyl acetate: methanol is 10: 1) to obtain 0.42 g of a white solid product. Melting point: 163 ℃ and 165 ℃ in a yield of 71%.
1H NMR(300MHz，CDCl3)，δ：8.01(S，2/3H，H2)，7.99(S，1/3H，H2)，8.31(d，1H，H5)，7.41(d，2/3H，H2′6′)，7.39(d，4/3H，H2′6′)，7.11(d，1/3H，H6)，7.02(d，2/3H，H6)，6.85(d，2H，H3′5′)，5.28(d，2/3H，H9)，4.83(d，1/3H，H9)，5.62(dd，1/3H，H14)，5.39(dd，2/3H，H14)，3.40-4.20(m，5H，H11，H12，H13，H15).0.80-1.50(m，18H，CH3)。
MS(FAB)：M+1＝585.2。
Example 4.7-O, 4' -O, 15-O-Tripivaloyl Puerarin
Dissolving 0.416 g (1 mmol) of puerarin in 50 ml of acetone, adding 0.414 g (3 mmol) of anhydrous potassium carbonate, dropwise adding 3 mmol of pivaloyl chloride while stirring at room temperature, tracking the reaction by TLC, stirring at room temperature until the raw material point disappears, removing most of solvent by spinning, adding ethyl acetate for extraction, washing with water, drying with anhydrous sodium sulfate, removing the solvent by spinning, and performing column chromatography (ethyl acetate: methanol is 10: 1) to obtain 0.32 g of white solid product. Melting point: 142 ℃ and 144 ℃ and the yield is 47 percent.
1H NMR(300MHz，CDCl3)，δ：8.10(S，4/9H，H2)，8.09(S，5/9H，H2)，8.27(d，5/9H，H5)，8.21(dd，4/9H，H5)，7.55(d，10/9H，H2′6′)，7.51(dd，8/9H，H2′6′)，7.05(dd，4/9H，H6)，7.00(d，5/9H，H6)，7.12(d，10/9H，H3′5′)，7.07(dd，8/9H，H3′5′)，5.18(d，4/9H，H9)，4.77(d，5/9H，J＝9.9Hz，H9)，5.64(dd，4/9H，H14)，5.44(dd，5/9H，H14)，3.38-3.93(m，5H，H11，H12，H13，H15)，0.82-1.42(m，27H，CH3)。
MS(FAB)：M+1＝669.2。
Example 5.7-O, 4' -O-dibenzoylpuerarin
Dissolving 0.416 g (1 mmol) of puerarin in 50 ml of acetone, adding 0.414 g (3 mmol) of anhydrous potassium carbonate, dropwise adding two mmol of benzoyl chloride while stirring at room temperature, tracking the reaction by TLC, stirring at room temperature until the raw material point disappears, removing most of solvent by spinning, adding ethyl acetate for extraction, washing with water, drying with anhydrous sodium sulfate, removing the solvent by spinning, and performing column chromatography (ethyl acetate: methanol is 10: 1) to obtain 0.18 g of a white solid product. Melting point: 169 ℃ and 171 ℃, and the yield is 29 percent.
1H NMR(300MHZ，CD3COCD3)，δ：8.52(S，1H，H2)，8.17(d，1H，H5)，7.81(d，2H，H2′6′)，7.65(d，2H，H3′5′)，6.90(d，1H，H6)，8.31(m，2H，ArH)，7.3-7.9(m，8H，ArH)，5.87(dd，1H，H14)，5.43(d，1H，H9)，3.0-5.0(m，5H，H15，H11，H12，H13)。
MS(FAB)：M+1＝625.1。
Example 6.12-O, 13-O, 14-O-triacetyl puerarin
Dissolving 0.416 g (1 mmol) of puerarin in 50 ml of acetone, dropwise adding 0.2 ml of boron trifluoride diethyl etherate and 5 mmol of acetic anhydride acylating agent in an ice-water bath, tracking the reaction by TLC, stirring at room temperature until the raw material point disappears, adding 5 ml of ethanol, stirring for 1 hour, dropwise adding saturated sodium bicarbonate solution to terminate the reaction, removing most of solvent by rotation, extracting by ethyl acetate, washing by saturated sodium bicarbonate solution, drying by anhydrous sodium sulfate, removing the solvent by rotation, and then carrying out column chromatography (ethyl acetate: methanol is 10: 1) to obtain 0.17 g of yellow solid, wherein the melting point is as follows: 141 ℃ and 143 ℃ in 31 percent yield.
1H NMR(300MHz，CD3OD)，δ：8.24(S，1H，H2)，7.98(d，1H，H5)，7.34(d，2H)，6.90(d，1H，H6)，6.79(d，2H，H3′5′)，5.81(w，1H，H9)，5.28(w，1H，H14)，5.22(dd，1H，H13)，3.97(dd，1H，H12)，3.84(m，2H，H15)，3.54(m，1H，H11)，1.96(S，3H，COCH3)，1，49(S，3H，COCH3)，1.32(S，3H，COCH3)。
MS(FAB)：M+1＝541。
Example 7.12-O, 13-O, 14-O, 4' -O-tetraacetyl Puerarin
Dissolving 0.416 g (1 mmol) of puerarin in 50 ml of acetone, dropwise adding 0.2 ml of boron trifluoride diethyl etherate and 5 mmol of acetic anhydride acylating agent in an ice-water bath, tracking the reaction by TLC, stirring at room temperature until the raw material point disappears, adding 5 ml of ethanol, stirring for 1 hour, dropwise adding saturated sodium bicarbonate solution to terminate the reaction, removing most of solvent by rotation, extracting by ethyl acetate, washing by saturated sodium bicarbonate solution, drying by anhydrous sodium sulfate, removing the solvent by rotation, and then carrying out column chromatography (ethyl acetate: methanol is 10: 1) to obtain 0.26 g of yellow solid. Melting point: 126 ℃ and 128 ℃ with a yield of 45 percent.
1H NMR(300MHz，CD3OD)，δ：8.34(S，1H，H2)，7.99(d，1H，H5)，7.55(d，2H，H2′6′)，6.92(d，1H，H6)，7.12(d，2H，H3′5′)，5.80(w，1H，H9)，5.31(w，1H，H14)，5.25(t，1H，H13)，3.98(t，1H，H12)，3.84(m，2H，H15)，3.54(m，1H，H11)，2.23(S，3H，COCH3)，1.96(S，3H，COCH3)，1，49(S，3H，COCH3)，1.32(S，3H，COCH3)。
MS(FAB)：M+1＝583。
Example 8.14-O-MethyoylPuerarin
Dissolving 0.416 g (1 mmol) of puerarin in 50 ml of acetone, adding 0.414 g (3 mmol) of anhydrous potassium carbonate, dropwise adding two mmol of methoxy formyl chloride while stirring at room temperature, tracking the reaction by TLC, stirring at room temperature until the raw material point disappears, removing most of solvent by spinning, adding ethyl acetate for extraction, washing with water, drying with anhydrous sodium sulfate, removing the solvent by spinning, and performing column chromatography (ethyl acetate: methanol is 10: 1) to obtain 0.25 g of a white solid product. Melting point: 180 ℃ and 182 ℃, 59 percent.
1H NMR(300MHz，CD3OD)，δ：8.16(S，1H，H2)，7.98(d，1H，H5)，7.33(d，2H，H2′6′)，6.89(d，1H，H6)，6.78(d，2H，H3′5′)，5.38(dd，1H，H14)，5.15(d，H，H9)，3.85(dd，1H，H15)，3.67(dd，1H，H15)，3.63(dd，1H，H13)，3.52(t，1H，H12)，3.42(dd，1H，H11)，3.39(S，3H，-OCH3)。
MS(FAB)：M+1＝475.1
Example 9.7-O, 4' -O, 12-O, 14-O-tetraacetylpuerarin
Dissolving 0.416 g (1 mmol) of puerarin in 50 ml of acetone, dropwise adding 0.2 ml of boron trifluoride diethyl etherate and 5 mmol of acetic anhydride acylating agent in an ice-water bath, tracking the reaction by TLC, stirring at room temperature until the raw material point disappears, adding 5 ml of ethanol, stirring for 1 hour, dropwise adding saturated sodium bicarbonate solution to terminate the reaction, removing most of solvent by spinning, extracting by ethyl acetate, washing by saturated sodium bicarbonate solution, drying by anhydrous sodium sulfate, removing the solvent by spinning, and then performing column chromatography (ethyl acetate: methanol is 10: 1) to obtain 0.12 g of yellow solid, wherein the melting point is as follows: 134 ℃ and 136 ℃ in a yield of 21 percent.
1H NMR(300MHz，CD3OD)，δ：8.35(S，1H，H2)，8.14(d，1H，H5)，7.57(d，2H，H2′6′)，7.07(d，1H，H6)，7.15(d，2H，H3′5′)，4.81(d，1H，H9)，4.39(dd，1H，H14)，5.11(dd，1H，H12)，3.85(dd，1H，H15)，3.63(m，3H，H11，H13，H15)，2.24(S，3H，COCH3)，2.10(S，3H，COCH3)，1.54(S，3H，COCH3).1.20(S，3H，COCH3)。
MS(FAB)：M+1＝585
Example 10.12-O, 15-O-benzylidene puerarin
Dissolving 0.416 g (1 mmol) of puerarin in 50 ml of acetone, adding two p-toluenesulfonic acids, dropwise adding 1.2 mmol of benzaldehyde under ice-water bath, tracking the reaction by TLC, stirring at room temperature until the raw material point disappears, adding a few drops of saturated sodium carbonate solution to terminate the reaction, removing most of solvent by rotation, extracting with ethyl acetate, washing with water, washing with saturated sodium bicarbonate solution, drying with anhydrous sodium sulfate, removing the solvent by rotation, and separating by column chromatography (ethyl acetate: methanol is 10: 1) to obtain 0.24 g of white solid product. Melting point: 199 ℃ and 201 ℃, and the yield is 48 percent.
1H NMR(300MHZ，CD3OD)，δ：8.16(S，1H，H2)，8.00(d，1H，H5)，7.48(m，2H，H17)，7.31(d，2H，H2′6′)，6.95(d，1H，H6)，7.29(m，3H，H18)，6.79(d，2H，H3′5′)，5.59(S，1H，H16)，4.32(dd，1H，H14)，5.15(d，1H，H9)，4.22(dd，1H，H15)，3.76(dd，1H，H15)，3.69(dd，1H，H13)，3.63(dd，1H，H12)，3.57(m，1H，H11)。
MS(FAB)：M+1＝505。
Example 11.12-O, 15-O-propylidene Puerarin
Dissolving 0.416 g (1 mmol) of puerarin in 50 ml of acetone, adding two pieces of p-toluenesulfonic acid, dropwise adding 1.2 mmol of 2-methoxypropene under an ice-water bath, tracking the reaction by TLC, stirring until the raw material point disappears, adding a few drops of saturated sodium carbonate solution to terminate the reaction, removing most of the solvent by rotation, extracting with ethyl acetate, washing with water, washing with saturated sodium bicarbonate solution, drying with anhydrous sodium sulfate, removing the solvent by rotation, and separating by column chromatography (ethyl acetate: methanol is 10: 1) to obtain 0.27 g of a white solid product. Melting point: 230 ℃ and 232 ℃ with a yield of 59 percent.
1H NMR(300MHZ，CD3OD)，δ：8.16(S，1H，H2)，8.01(d，1H，H5)，7.33(d，2H，H2′6′)，6.94(d，1H，H6)，6.79(d，2H，H3′5′)，4.26(t，1H，H14)，5.06(d，1H，H9)，3.80(m，2H，H15)，3.69(dd，1H，H13)，3.54(dd，1H，H12)，3.39(m，1H，H11)，1.51(S，3H，CH3)，1.36(S，3H，CH3)。
MS(FAB)，M+1＝457。
Example 12.7-O-pivaloyloxymethylene Puerarin
Pivaloyloxymethylene chloride (6.8 mmol) and anhydrous sodium iodide (1.02 g, 6.8 mmol) were dissolved in 15 ml of anhydrous acetone and sealed overnight, then added to 150 ml of acetone solution of anhydrous potassium carbonate (1.9 g, 13.6 mmol) and puerarin (1.4 g, 6.8 mmol) and stirred, followed by TLC to complete the reaction, after removal of most of the solvent, 150 ml of ethyl acetate was added for dilution, filtered, concentrated under reduced pressure and subjected to column chromatography to obtain 0.19 g of white solid, melting point: 183 ℃ and 185 ℃, and the yield is 37 percent.
1H NMR(300MHZ，CD3OD)，δ：8.17(S，1H，H2)，8.21(d，1H，H5)，7.34(d，2H，H2′6′)，5.90(dd，2H，-OCH2O-)，7.34(d，1H，H6)，6.80(d，2H，H3’5’)，1.16(S，9H，-CH3)，5.02(d，2/5H，H9)，4.96(d，3/5H，H9)，4.17(t，1H，H14)，3.82(dd，1H，H15)，3.64(dd，1H，H15)，3.25-3.45(m，3H，H11，H12，H13)。
MS(FAB)：M+1＝531
Example 13.7-O, 4' -O-Dipivaloyloxymethylene Puerarin
Pivaloyloxymethylene chloride 2.04 g (13.6 mmol) and anhydrous sodium iodide 2.04 g (13.6 mmol) were dissolved in 30 ml of anhydrous acetone and sealed overnight, then added to 150 ml of acetone solution of anhydrous potassium carbonate 1.9 g (13.6 mmol) and puerarin 1.4 g (6.8 mmol) and stirred, TLC followed the reaction until complete, after most of the solvent was removed, 150 ml of ethyl acetate was added for dilution, filtered, concentrated under reduced pressure and column chromatography (ethyl acetate: methanol 10: 1) was performed to obtain 0.37 g of white solid. Melting point: 176 ℃ and 178 ℃ in 58% yield.
1H NMR(300MHZ，CD3OD)，δ：8.19(S，1H，H2)，8.21(d，1H，H5)，7.36(d，2H，H2′6′)，6.01(S，2H，-OCH2O-)，7.38(d，1H，H6)，5.90(dd，2H，-OCH2O-)，6.80(d，2H，H3′5′)，1.10(S，9H，-CH3)，1.16(S，9H，-CH3)，5.02(d，2/5H，H9)，4.96(d，3/5H，H9)，4.17(t，1H，H14)，3.82(dd，1H，H15)，3.64(dd，1H，H15)，3.25-3.45(m，3H，H11，H12，H13)。
MS(FAB)：M+1＝645
Example 14.3' -Nitro Puerarin
Dissolving 3 g of puerarin in a mixed solution of 30 ml of water and 30 ml of acetic acid, slowly dropwise adding a mixed solution of 36 ml of acetic acid and 24 ml of concentrated nitric acid in an ice-water bath, tracking and reacting by TLC, stirring until the raw material point disappears, filtering, washing with water, and drying to obtain 2.18 g of a product yellow solid, wherein the melting point is 237-.
1H NMR(300MHz，CD3OD)，δ：8.33(S，1H，H2)，8.02(d，1H，H5)，8.31(d，1H，H6′)，7.78(dd，1H，H2′)，6.96(d，1H，H6)，7.17(d，1H，H3′)，5.04(d，1H，H9)，4.06(t，1H，H14)，3.84(dd，1H，H15)，3.69(dd，1H，H15)，3.45(m，3H，H11，H13，H12)。
MS(FAB)：M+1＝462
Example 15.3' -Aminopuerarin
Dissolving 0.5 g of the nitro compound obtained above in 20 ml of solvent, adding Raney-Ni0.05 g, hydrogenating under normal pressure until the raw material point disappears, filtering out Raney-Ni, spin-drying the filtrate, recrystallizing with ethanol to obtain 0.5 g of white solid, carbonizing at 260 ℃, and obtaining the yield of 95%.
1H NMR(300MHz，CD3OD)，δ：8.08(S，1H，H2)，7.99(d，1H，H5)，8.31(d，1H，H6′)，6.70(S，2H，H2′，H6′)，6.92(d，1H，H6)，6.88(S，1H，H3′)，5.03(d，1H，H9)，4.05(w，1H，H14)，3.83(dd，1H，H15)，3.69(dd，1H，H15)，3.39-3.50(m，3H，H11，H13，H12)。
MS(FAB)：M+1＝432.2
Example 16.3' -N, N-Dimethylaminopuerarin
Dissolving 0.5 g of the nitro compound obtained above and 0.07 ml of 36% formaldehyde aqueous solution in 50 ml of solvent, adding 0.05 g of Raney-Ni, hydrogenating under normal pressure until the raw material point disappears, filtering out the Raney-Ni, spin-drying the filtrate, and recrystallizing with ethanol to obtain 0.51 g of the product. Melting point: 180 ℃ and 182 ℃ with a yield of 95 percent.
1H NMR(300MHz，CD3COCD3)，δ：8.19(S，1H，H2)，8.03(d，1H，J＝9，H5)，7.41(S，1H，H2’)，7.11(d，H，J＝7.8，H6’)6.94(d，1H，J＝9，H6)，6.85(d，1H，J＝7.8，H5’)，5.18(d，1H，J＝9.9，H9)，3.89(w，1H，H14)，3.81(dd，1H，H15)，3.69(dd，1H，H15)，3.39-3.50(m，3H，H11，H13，H12)，2.69(S，6H，2N-CH3).
MS(FAB)：M+1＝460.2.
Example 17.7-O, 4 '-O, 12-O, 13-O, 14-O, 15-O-hexaacetyl-3' -N, N-dimethylamino-puerarin
Placing 0.23 g (0.5 mmol) of 3' -N, N-dimethylamino puerarin in a 30 ml round-bottom flask, adding 2 ml of acetic anhydride and 2 ml of pyridine, stirring for 2 hours at room temperature, pouring into 20 ml of water, extracting with ethyl acetate, washing for 3 times, drying with anhydrous sodium sulfate, removing the solvent under reduced pressure to obtain 0.35 g of white solid, melting point 78-80 ℃ and yield 98%.
1H NMR(300MHz，CD3COCD3)，δ：8.66(S，1H，H2)，8.24(d，1H，J＝9，H5)，7.38(S，1H，H2’)，7.28(d，H，J＝8.1，H6’)，7.28(d，1H，J＝9，H6)，7.07(d，1H，J＝8.1，H5’)，5.8～4.0(m，7H，H9，H11，H13，H12，2H15，H14)，2.79(S，6H，2N-CH3)，1，68～2.44(6S，18H，COCH3).
MS(FAB)：M+1＝712.2
Example 18.7-O, 4 '-O-dipivaloyl-3' -N, N-dimethylamino-puerarin,
dissolving 0.23 g (0.5 mmol) of 3' -N, N-dimethylamino puerarin in 60 ml of acetone, adding 0.414 g (3 mmol) of anhydrous potassium carbonate, dropwise adding two mmol of pivaloyl chloride in batches under stirring at room temperature, stirring at room temperature until the raw material point disappears, removing most of solvent by rotation, adding ethyl acetate for extraction, washing with water, drying with anhydrous sodium sulfate, removing the solvent by rotation, and performing column chromatography to obtain 0.21 g of a white solid product. Melting point: 136-138 ℃ and the yield is 66%.
1H NMR(300MHz，CD3COCD3)，δ：8.49(S，2/3H，H2)，8.39(S，1/3H，H2)，8.26(d，2/3H，J＝9，H5)，8.24(d，1/3H，J＝9，H5)，7.25～7.44(m，3H，H2′H6′H6)，7.16(d，2/3H，J＝8.1，H5′)，6.90(d，1/3H，J＝8.1，H5′)，5.20～5.38(m，1H，H9)，2.80(S，6H，2N-CH3)，2.0～4.0(6S，18H，CH3)，3.4～3.9(m，5H，H14，H11，H12，H13，H15).
MS(FAB)：M+1＝628.2.
Activity evaluation test
Experimental example 1 Effect of Puerarin derivatives on isolated rat Heart reperfusion injury model
Model preparation SD rats were used to prepare Langendorff isolated hearts. The experiment was divided into model group, blank control group and administration group. The observation was a measure of LDH activity in perfused heart effluent. The statistical method is to compare each administration group with the model group respectively and carry out significance test by using student test. The results are shown in the following table:
TABLE 1 Effect of Puerarin derivatives on in vitro rat Heart reperfusion injury model
*P＜0.05，**P < 0.01vs ischemia model. Positive control-puerarin
The results show that: the tested samples, example 1 and example 15, can significantly reduce the ratio of post-reperfusion/pre-ischemia LDH activity of Langendorff isolated heart ischemia reperfusion injury model, and significantly reduce myocardial cell injury.
Experimental example 2 Effect of Puerarin derivative Pituitrin on inducing myocardial ischemia model in SD rat
The model was prepared using SD rats, which were anesthetized beforehand, the normal electrocardiogram II leads of the rats were recorded, followed by intravenous injection of posterior pituitary and continuous recording of the electrocardiogram of the rats for 5 minutes. The change of ST segment of electrocardiogram of rat is observed. The rats in the test sample group were previously administered with 20mg/kg and 40mg/kg of test samples subcutaneously once a day for 7 consecutive days, respectively, and were induced to develop a myocardial ischemia model by intravenous injection of 0.5U/kg of posterior pituitary hormone 30 minutes after the last administration. The observation index is a measure of elevation of the ST wave of the electrocardiogram. The results of the experiment are shown in the following table:
TABLE 2 Effect of puerarin derivatives (20mg/kg subcutaneously injected for 7 days) on postpituitary-induced cardiac ischemia in SD rats in electrocardiogram ST segment
*P＜0.05，**P < 0.01VS blank control group
TABLE 3 Effect of Puerarin derivatives (40mg/kg subcutaneously injected for 7 days) on the postpituitary-induced cardiac ischemia in SD rats in electrocardiogram ST segment
*P＜0.05，**P < 0.01VS blank control group
The results show that: the ST segment elevation of the ECG after the injection of pituitrin in rats in the test samples of example 1, example 12 and example 15, both in the 20mg/kg dose group and the 40mg/kg dose group, was significantly reduced compared to the model group, indicating that the test samples can significantly reduce the ischemic damage of myocardial tissues.
Claims (5)
1. A puerarin derivative represented by the general formula (I):
wherein,
R1and R2Selected from hydrogen, C1-5Alkanoyloxymethylene, C1-5Alkoxyacyl group, C1-5An alkanoyl group;
R3and R4Is selected from the group consisting of hydrogen,nitro, amino, N-C1-5Alkylamino, N, N-di-C1-5An alkylamino group;
R5、R6，R7and R8Are respectively selected from hydrogen and C1-5Alkyl, phenyl substituted C1-5Alkyl radical, C1-5Alkanoyl radical, C1-5Alkoxyacyl group, C1-5An alkanoyloxymethylene group;
but instead of the other end of the tube
R1、R2、R3、R4、R5、R6，、R7And R8Cannot be simultaneously hydrogen; and does not include the following compounds:
2. a puerarin derivative represented by the general formula (I):
wherein,
R1and R2Selected from hydrogen, acetyl, pivaloyl, benzoyl, methoxycarbonyl, pivaloyloxymethylene;
R3and R4Selected from hydrogen, 3 '-nitro, 3' -amino, N-dimethylamino;
R5、R6、R7and R8Selected from hydrogen, acetyl, pivaloyl, methoxycarbonyl, pivaloyloxymethylene, benzylidene and propylidene.
3. A compound selected from the group consisting of:
4. a pharmaceutical composition comprising a compound according to any one of claims 1 to 3 and a pharmaceutically acceptable carrier.
5. Use of a compound according to any one of claims 1 to 3 for the preparation of a medicament for the treatment of a disease associated with cardio-cerebral circulatory disorders.
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|---|---|---|---|---|
| CN1511840A (en) * | 2002-12-31 | 2004-07-14 | 中国人民解放军军事医学科学院放射医 | Puerarin compound containing water soluble group and its preparation and use |
-
2006
- 2006-01-11 CN CN2006100008140A patent/CN1944448B/en not_active Expired - Fee Related
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1511840A (en) * | 2002-12-31 | 2004-07-14 | 中国人民解放军军事医学科学院放射医 | Puerarin compound containing water soluble group and its preparation and use |
Non-Patent Citations (4)
| Title |
|---|
| 杨若林 等.葛根素衍生物的制备及其活性.中 国 药 科 大 学 学 报30 2.1999,30(2),81-85页. |
| 杨若林 等.葛根素衍生物的制备及其活性.中 国 药 科 大 学 学 报30 2.1999,30(2),81-85页. * |
| 王 靖 等.葛根素研究进展.药 学 进 展27 2.2003,27(2),70-73. |
| 王 靖 等.葛根素研究进展.药 学 进 展27 2.2003,27(2),70-73. * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1944448A (en) | 2007-04-11 |
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