CN1191244C - Baicalein 8-position substituted methylamine like derivative and its preparation method - Google Patents
Baicalein 8-position substituted methylamine like derivative and its preparation method Download PDFInfo
- Publication number
- CN1191244C CN1191244C CN 02111185 CN02111185A CN1191244C CN 1191244 C CN1191244 C CN 1191244C CN 02111185 CN02111185 CN 02111185 CN 02111185 A CN02111185 A CN 02111185A CN 1191244 C CN1191244 C CN 1191244C
- Authority
- CN
- China
- Prior art keywords
- methylamine
- derivative
- reaction
- scutellarin
- baicalein
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention belongs to the pharmacy field, particularly to a methylamine type derivative of baicalein of a Chinese herbal medicine and a preparation method thereof. The present invention adopts baicalein as a raw material; Mannich reaction is carried out with formalin, or paraformaldehyde, and amine or amine salts in polar solvent, and a baicalein 8-position substituted methylamine type derivative with a structural formula (I) is prepared. The present invention ideally introduces various kinds of substituted methylamino in the baicalein structure, and particularly, aromatic amine substituent groups are conveniently and directly introduced. The present invention has the advantages of moderate reaction condition, easy refining and purification of products and simple preparation steps, and yield is more than 80%. The methylamine type derivative of baicalein of the present invention has strong action on suppressing the activity of protein kinase C (PKC) and acquired immunodeficiency syndrome viruses HIV/IIIB, and the methylamine type derivative can be used for preparing a medicine for resisting cancer and the acquired immunodeficiency syndrome.
Description
Technical field
The invention belongs to pharmacy field, be specifically related to methylamine like derivative of herbal medicine root of large-flowered skullcap element and preparation method thereof.
Background technology
One of the effective constituent of baikal skullcap root baicalin can obtain aglycon-scutellarin through hydrolysis, and scutellarin belongs to and contains polyhydric flavonoid compound. (Chin.Pharm.J, 2001,36 (11), 728-731.J.Nat.Prod, 1994,57:42-49 according to the literature; Biochem.Biophy.Res, Commun1989,160:982; J.Med.Chem, 1995,38:890-897; Antivira-1 Research, 1990,14:279; Acta.Pharmaceutica Sinica, 1997,32 (2): 140-143; Acta.Pharmaceutica Sinica, 1998,33 (1): 22-27) baicalin or scutellarin have resisiting influenza virus, anti-murine leukemia virus (MLV), anti-HIV-1 virus and cytotoxic effect thereof.Known flavonoid compound structure activity relationship is: the existence of hydroxyl is that physiologically active exists institute necessary on the A ring, and to keep the plane of its structure also be the active key that exists, when the two keys on the prosposition when saturated, molecule will lose the plane, cause active decline; If when having amino, substituted-amino or nitro to replace on the carbon of A ring 8-position, then cytotoxicity strengthens.Other has bibliographical information (Jerry March., Advanced Organic ChemistryReactions, Mechanisms And Structure. (published by McGraw-Hill, Znc.) Second Edition, 1977,820-823; " drug synthetic reaction " Chemical Industry Press, 1990,6. second edition .204-210 ", Man Nixi (Mannich) reaction mainly is applicable to the compound with reactive hydrogen, but is used for ketone compounds more.Therefore the class byproduct of reaction is many, and yield is not ideal enough, and when especially introducing aromatic amine, a little less than alkalescence, difficulty is carried out the Mannich reaction, so normal employing is carried out permutoid reaction with the Mannich alkali of aromatic primary amine or secondary amine and aliphatic amide indirectly.
Summary of the invention
The objective of the invention is to carry out the Mannich reaction, in molecule, introduce the substituted methylamine base, be prepared into the methylamine like derivative that scutellarin 8-position replaces with scutellarin.Another object of the present invention provides the method for preparing the scutellarin methylamine like derivative.
The present invention utilizes the Mannich prepared in reaction to become 8-substituted methylamine analog derivative on scutellarin molecule C-8.And the methylamine like derivative that scutellarin 8-position replaces carried out arrestin kinase c (PKC) and suppressed the biological activity test of HIV (human immunodeficiency virus) (HIV/IIIB), the result shows that the methylamine like derivative that scutellarin 8-position replaces has the activity that suppresses PKC and HIV/IIIB, can be used for the medicine of anticancer disease and AIDS resisting in medical treatment.
It is raw material that the present invention adopts the scutellarin of structural formula (II), in methyl alcohol or ethanol or polar solvent, with formalin or Paraformaldehyde 96 and amine or the direct condensation single step reaction of amine salt, be prepared into the methylamine like derivative of the scutellarin 8-position replacement of structural formula (I).The present invention has introduced the methylamino of various replacements more satisfactoryly in the scutellarin structure, directly introduced the aromatic amine substituting group especially easily, and yield reaches more than 80% all.
Reaction conditions gentleness of the present invention, product is single, easily refining purifying, preparation process is simple, is beneficial to industrial production.Reaction formula is expressed as follows:
Reaction formula of the present invention, wherein R
1R
2N represents the amine general formula; R
1, R
2Can be identical or inequality, each represents hydrogen, C
1-C
4Alkyl, phenyl, phenyl-C
1-C
4Alkyl or R
1, R
2With coupled nitrogen-atoms common form contain be selected from nitrogen, oxygen and sulphur atom 5 Yuans or 6 element heterocycles of heterocycle.
In the reaction method of the present invention, can not add acid or alkali as a catalyst, the alkalescence of reactant amine itself has been controlled the pH value of Mannich reaction, and reaction also can be carried out under slightly acidic or weak basic condition.The big I of reactant amine alkalescence itself influences the yield of structural formula (I), and is wherein better with the derivative yield of aromatic amine replacement.
In the method involved in the present invention, use polar solvent, as alcohols (lower aliphatic alcohols such as methyl alcohol, ethanol), the reaction after product can obtain purer structural formula (I) with the alcohol washing.
In the method involved in the present invention, temperature of reaction can be carried out in 20 ℃~80 ℃ scopes, and the reaction times is excellent with 1h wherein at 15min~2h.
The salifiable routinely method of structural formula of the present invention (I) is prepared into the hydrochloride of structural formula (I) in solvent with hydrochloric acid.
Embodiment
The following example explanation the present invention.But the present invention is not limited by embodiment, temperature with degree centigrade (℃) expression.The fusing point test capillary tube technique.
Embodiment 1:
8-(N, N-dimethyl)-methylamino-5,6, the preparation of 7-trihydroxy--2-phenyl-4H-1-chromene-4-ketone
The 100mg scutellarin adds 7.0mL methyl alcohol and 0.11mL formalin, is heated to 60~70 ℃ of reaction solutions and becomes clarification, adds the 0.15g dimethylamine hydrochloride, stirring at room reaction 6h, the pressure reducing and steaming solvent is oily matter, add anhydrous diethyl ether and ethanol, end, filter to there being solid to separate out.Use the dehydrated alcohol recrystallization, drying, yellow solid product, 76.3mg, mp:286~288 ℃.HRESIMS:328.1145[M+1]
+,C
18O
5H
17N?requires328.1185。
Embodiment 2:
8-(N-propyl group)-methylamino-5,6, the preparation of 7-trihydroxy--2-phenyl-4H-1-chromene-4-ketone
100mg scutellarin, 8mL methyl alcohol and 0.055mL formalin drip the 0.08mL propylamine, resolution of precipitate, room temperature reaction 20 minutes in reaction flask, there is yellow mercury oxide to separate out, filters, get yellow solid, wash repeatedly 3 times with methyl alcohol, drying, product 107.1mg, mp:206~208 ℃.HRESIMS:m/z?342.1343[M+1]
+,C
19O
5H
19N?requires?342.1341。
Embodiment 3:
8-(N-benzyl)-methylamino-5,6, the preparation of 7-trihydroxy--2-phenyl-4H-1-chromene-4-ketone
The 50mg scutellarin adds 4mL methyl alcohol, 0.0275mL formalin, reaction solution are muddy shape, dropwise add the 0.041mL benzylamine again, reaction becomes clarification, room temperature reaction 2h has yellow solid to separate out, and filters, solid is washed 3 times repeatedly with methyl alcohol, product 65.91mg, mp:184~186 ℃, HRESIMS:m/z 390.1341[M+1]
+, C
23O
5H
19Nrequires 390.1341.
Embodiment 4:
The methylamine like derivative that scutellarin and scutellarin 8-position thereof replace has all shown inhibition PKC active function in various degree, wherein the scutellarin methylamine like derivative of aniline, morphine quinoline, the replacement of sulfo-morphine quinoline obviously is better than scutellarin and saturated scutellarin straight chained alkyl substituted methylamine analog derivative, still demonstrating the inhibiting rate more than 80% under the concentration of 12.5 μ M, is stronger pkc inhibitor.Table 1 is that the PKC of scutellarin and methylamine like derivative thereof suppresses active.
Table 1
Embodiment 5:
The inhibiting mensuration of AIDS resisting virus, sample is solvent with DMSO, be made into 5~10 μ g/ml concentration, according to the cytotoxicity experiment result, carry out antivirus test, HIV (human immunodeficiency virus) is HIV/IIIB, with AZT, the positive contrast of Dextran Sulfate and Melanin found that the therapeutic index of the scutellarin methylamine derivative that 8-position benzylamine replaces is higher than scutellarin.Table 2 is inhibition activity of the anti-HIV of scutellarin and methylamine like derivative thereof.
Table 2
Claims (9)
1. the methylamine like derivative that replaces of a scutellarin 8-position, it is characterized in that the having formula structure of (I)
Described reaction formula, R
1, R
2Can be identical or inequality, each represents hydrogen, C
1-C
4Alkyl, phenyl, phenyl-C
1-C
4Alkyl or R
1, R
2With coupled nitrogen-atoms common form contain be selected from nitrogen, oxygen and sulphur atom 5 Yuans or 6 element heterocycles of heterocycle.
2. press the preparation method of the methylamine like derivative of the described scutellarin 8-of claim 1 position replacement, it is characterized in that the compound with formula (II) is a raw material
In polar solvent, carry out the Mannich reaction with formalin or Paraformaldehyde 96 and amine or amine salt, generate the methylamine like derivative that scutellarin 8-position replaces.
3. by the described preparation method of claim 2, wherein said polar solvent is a lower aliphatic alcohols.
4. by the described preparation method of claim 2, wherein said polar solvent is methyl alcohol or ethanol.
5. by the described preparation method of claim 2, in the wherein said reaction method, can not add acid or alkali as a catalyst.
6. by the described preparation method of claim 2, in the wherein said reaction method, temperature of reaction is 20 ℃~80 ℃, and the reaction times is 15min~2h.
7. by the described preparation method of claim 5, the wherein said reaction times is 1h.
8. the application of the methylamine like derivative of scutellarin 8-position replacement in the preparation cancer therapy drug.
9. the application of the methylamine like derivative of scutellarin 8-position replacement in the preparation AIDS drug.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN 02111185 CN1191244C (en) | 2002-03-28 | 2002-03-28 | Baicalein 8-position substituted methylamine like derivative and its preparation method |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN 02111185 CN1191244C (en) | 2002-03-28 | 2002-03-28 | Baicalein 8-position substituted methylamine like derivative and its preparation method |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1427003A CN1427003A (en) | 2003-07-02 |
CN1191244C true CN1191244C (en) | 2005-03-02 |
Family
ID=4741440
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN 02111185 Expired - Fee Related CN1191244C (en) | 2002-03-28 | 2002-03-28 | Baicalein 8-position substituted methylamine like derivative and its preparation method |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN1191244C (en) |
Families Citing this family (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101333205A (en) * | 2008-07-10 | 2008-12-31 | 大连理工大学 | Baicalin piperazine of cyclin-dependent kinases and preparation method thereof |
CN101633652B (en) * | 2009-07-01 | 2011-05-04 | 西安医学院 | Baicalein-8-sodium sulfonate and preparation method thereof and pharmaceutical use thereof |
CN101797246B (en) * | 2009-10-30 | 2012-11-07 | 曲敬来 | Application of radix scutellariae and flavonoid against sub-type infection of influenza virus A (H1N1) |
CN104004037B (en) * | 2014-06-12 | 2016-10-19 | 宜春学院 | 8-position methylamine like derivative of baicalin and ester thereof and preparation method thereof |
CN105884735B (en) * | 2016-04-21 | 2017-03-15 | 吉林省中医药科学院 | Chrysin derivative and its preparation and its application in treatment hyperuricemia |
CN106117189B (en) * | 2016-06-15 | 2019-02-01 | 张帆 | Acetyl group Chrysin Mannich base derivative and application thereof |
CN108864024B (en) * | 2018-08-10 | 2020-09-08 | 沈阳药科大学 | Scutellarin aglycone nitrogen mustard derivative and preparation method and application thereof |
CN113109473B (en) * | 2021-04-13 | 2022-01-14 | 长沙晨辰医药科技有限公司 | Formaldehyde derivatization test method |
-
2002
- 2002-03-28 CN CN 02111185 patent/CN1191244C/en not_active Expired - Fee Related
Also Published As
Publication number | Publication date |
---|---|
CN1427003A (en) | 2003-07-02 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US7998937B2 (en) | Flavonoid compound having an antiviral activity | |
NO327812B1 (en) | Dimeric compounds, such compounds as pharmaceutical agents, pharmaceutical compositions containing them, use thereof for the manufacture of medicaments for the treatment of disease, and an in vitro method for the detection of influenza viruses | |
CN1191244C (en) | Baicalein 8-position substituted methylamine like derivative and its preparation method | |
BR9912969A (en) | Compound, pharmaceutical composition, method for the treatment of neurological disorders associated with the production of b-amyloid, method for the treatment of alzheimer's disease associated with the production of b-amyloid, method for the treatment of neurological disorders associated with the production of b-amyloid and method to inhibit y-secretase activity | |
US20210060042A1 (en) | Patentiflorin A Analogs as Antiviral Agents | |
EP2128125A1 (en) | Caffeoyl quinic acid derivatives containing nitrogen, and preparation method, pharmaceutically composition and usage thereof | |
DE69624813T2 (en) | ROBUSTAFLAVON AND ITS DERIVATIVES AS AN ANTIVIRAL AGENT | |
CN112707901B (en) | Preparation method of compound A | |
CN105367558B (en) | Andrographolidume derivative and its preparation method and application | |
KR20090127071A (en) | Diaryl hepatonoid for viral inhibitor | |
WO2019030643A1 (en) | Compositions of eugenol derivatives for treatment of visceral leishmaniasis | |
CN109053798B (en) | Rhein ester derivative and preparation method and application thereof | |
CN113398125B (en) | Tezonite pharmaceutical composition and medical application thereof | |
CN106496219B (en) | The method of high-purity technical metaplasia production Tizanidine | |
CN111303087B (en) | Furanone compound and preparation method and application thereof | |
RU2810504C1 (en) | Method of increasing solubility of triazavirin | |
CN114907346B (en) | Alkaloid compound, extract and application thereof in preparation of products with respiratory syncytial virus resisting effect | |
CN112891329B (en) | Application of terpenoid in preparation of anti-influenza virus medicine | |
RU2791806C1 (en) | Use of 5'-o-(3-phenylpropionyl)-n4-hydroxycytidine to inhibit influenza virus replication in vitro and in vivo | |
KR102049140B1 (en) | Isoquinolinone derivatives, preparation method thereof and pharmaceutical composition for treating influenza virus containing the same | |
WO2022135136A1 (en) | Tuberculatin analogs as antiviral agents | |
CN108084044B (en) | Senecio scandens derivative and application thereof in medicine | |
CN114085259A (en) | N4-hydroxycytidine monohydrate, crystal form B thereof, preparation method and application | |
JP2003246792A (en) | Anti-influenza-viral compound | |
CN116265447A (en) | Preparation and application of anti-influenza A virus compound |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
C17 | Cessation of patent right | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20050302 Termination date: 20140328 |