CN115246802A - Vitis vinifera derivatives, preparation method thereof, pharmaceutical composition and application thereof - Google Patents

Vitis vinifera derivatives, preparation method thereof, pharmaceutical composition and application thereof Download PDF

Info

Publication number
CN115246802A
CN115246802A CN202110452611.XA CN202110452611A CN115246802A CN 115246802 A CN115246802 A CN 115246802A CN 202110452611 A CN202110452611 A CN 202110452611A CN 115246802 A CN115246802 A CN 115246802A
Authority
CN
China
Prior art keywords
group
unsubstituted
substituted
glu
acyl
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.)
Granted
Application number
CN202110452611.XA
Other languages
Chinese (zh)
Other versions
CN115246802B (en
Inventor
姚春所
林明宝
侯琦
范旖瑶
苏福宝
陈英
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Institute of Materia Medica of CAMS
Original Assignee
Institute of Materia Medica of CAMS
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Institute of Materia Medica of CAMS filed Critical Institute of Materia Medica of CAMS
Priority to CN202110452611.XA priority Critical patent/CN115246802B/en
Publication of CN115246802A publication Critical patent/CN115246802A/en
Application granted granted Critical
Publication of CN115246802B publication Critical patent/CN115246802B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/80—Radicals substituted by oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Immunology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Rheumatology (AREA)
  • Pain & Pain Management (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Saccharide Compounds (AREA)

Abstract

The invention belongs to the field of biological medicines, and discloses a class of viniferin derivatives, and a preparation method, a pharmaceutical composition and application thereof. In particular to 2,3-diaryl-5-styrylbenzofuran type grape derivatives shown in a general formula (I) and pharmaceutically acceptable salts thereof, a pharmaceutical composition of the compounds and application of the compounds in preparation of medicines for preventing or treating or assisting in treating inflammation and immunity related diseases.

Description

Vitis vinifera derivatives, preparation method thereof, pharmaceutical composition and application thereof
Technical Field
The invention relates to the field of biological medicines, in particular to 2,3-diaryl-5-styrylbenzofuran type grape pigment derivatives or medically acceptable salts thereof, a pharmaceutical composition containing the derivatives and application of the derivatives in preparation of medicines for preventing or treating inflammatory immune related diseases.
Background
The research and development of new drugs based on active natural products is one of the important ways of modern drug research and development. The natural product has the characteristics of wide source, low toxicity, small side effect and the like. A natural lead compound with obvious activity is found from traditional Chinese herbal medicines, and a safe and efficient candidate compound is searched from the natural lead compound as a clinically useful prototype medicine by structural modification, in-vivo and in-vitro activity test of a system and comprehensive evaluation of patent medicine property, so that the natural lead compound is an important direction for research and development of medicines. The oligomeric stilbene compounds are natural products which are polymerized by stilbene monomers in different modes and have complex structures and various bioactivities, and are mainly distributed in plants of grapes, gnetum, dipterocarpaceae, leguminosae, cyperaceae, paeoniaceae and the like. The stilbene monomers with different structures have different polymerization modes and polymerization degrees, and the formed oligomeric stilbene natural products have various structural types, so that the oligomeric stilbene compounds discovered at present also have various biological activities, including activities in the aspects of oxidation resistance, inflammation resistance, bacteria resistance, tumor resistance, virus resistance, senile dementia resistance and the like. In recent 10 years, due to the continuous development of separation and structure identification technology, more and more oligomeric stilbene compounds with complex structures and remarkable biological activities are separated and identified, so that the research of the oligomeric stilbene compounds is greatly developed in the aspects of structure and activity. Particularly in the aspect of biological activity research, not only more compounds with different activities and complex structures are found, but also the compounds are found to show remarkable biological activities in more aspects, such as beta-secretase inhibition activity, anti-influenza virus activity, anti-herpes virus (HSV) activity and the like. The continuously discovered new activity shows that the compounds have great potential in the aspect of drug development and utilization, so that the oligomeric stilbene compounds have more extensive attention, and have developed into one of the hot spots of natural product research. Especially, the activity of the dimer compound is generally stronger than that of a monomer stilbene compound, the molecular weight is between 400 and 600, and the dimer compound has great potential for developing medicaments. In recent years, the total synthesis of stilbene dimer compounds has been one of the hot points of research, and has made great progress, and the total synthesis research of main dimer structural frameworks, including benzofuran structures, indene structures and diaryl [3.2.1] octane structures, has made breakthrough progress, and provides guarantee for the research and development of the dimer compounds. However, besides the natural products obtained by separation and identification, the research on the structural modification and structure-activity relationship of the active oligomer compounds (especially dimers) is still a new research field, and so far, the related research reports in the literature are few. The dibenzofuran type and benzodihydrofuran type diphenyl ethylene dimer derivatives are the most natural products in the dimer type compounds, and are the compounds with the most remarkable activity. The grape pigment derivative (dehydo-delta-viniferin) with 2,3-diaryl-5-styrylbenzofuran structure is a natural product analogue synthesized by dehydrogenation of a natural product delta-viniferin, and thus, the inflammation inhibitory activity thereof has not been studied so far. The research carries out systematic derivatization research, anti-inflammatory activity test and structure-activity relationship research on 2,3-diaryl-5-styrylbenzofuran type grape pigment (dehydro-delta-viniferin), obtains a series of new-structure grape pigment derivatives with obvious inhibitory activity to inflammatory factor NO, and the inflammatory inhibitory activity of the synthesized compound is not reported in documents so far. The invention has important significance for developing and utilizing the compounds.
Disclosure of Invention
The invention aims to solve the technical problem of providing 2,3-diaryl-5-styryl benzofuran type grape pip derivatives with a novel structure, a preparation method, a pharmaceutical composition and application thereof.
The first aspect of the technical scheme of the invention provides a 2,3-diaryl-5-styrylbenzofuran type compound and derivatives thereof, which are shown as general formulas (I), (II) (IIA), (IIAa), (IIAb), (IIAc), (IIAd), (IIB), (IIBa), (III), (IIIA), (IIIAa), (IIIAb), (IIIB), (IIIBa), (IV) and (IVA).
Specifically, the invention relates to 2,3-diaryl-5-styrylbenzofuran type grape derivatives and pharmaceutically acceptable salts thereof shown as a general formula (I):
Figure BDA0003039367360000021
wherein R is 1 、R 2 、R 3 、R 4 、R 5 Each independently selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Acyl, substituted or unsubstituted C 2-6 Unsaturated hydrocarbon group, substituted or unsubstituted C 3-6 Cycloalkyl, glu, SO 3 H、PO 3 H 2 (ii) a The substituent is selected from hydrogen, hydroxyl, nitro, cyano, amino, carboxyl, methylamino, dimethylamino and C 1-6 Alkyl of (C) 1-6 Alkoxy group of (1), C 1-6 Acyl group of (1), C 1-6 Acyloxy group of (2) and (C) 1-6 Alkoxyacyl group, C 2-6 Unsaturated hydrocarbon group of (C) 3-6 Cycloalkyl of, C 1-6 Alkylthio, F, cl, br, I, glu, SO 3 H、PO 3 H 2 ；
Glu represents beta-D glucopyranosyl; SO 3 H represents a sulfonyl group; PO (PO) 3 H 2 Represents a phosphoryl group.
According to the present invention, preferred vitin derivatives represented by the general formula (I) include, but are not limited to, compounds represented by the general formula (II), and pharmaceutically acceptable salts thereof, wherein the compounds are represented by the general formula (II):
Figure BDA0003039367360000031
wherein R is 2 、R 3 、R 4 、R 5 Each independently selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Acyl, substituted or unsubstituted C 2-6 Unsaturated hydrocarbon group, substituted or unsubstituted C 3-6 Cycloalkyl, glu, SO 3 H、PO 3 H 2 (ii) a The substituent is selected from hydrogen, hydroxyl, nitro, cyano, amino, carboxyl, methylamino, dimethylamino and C 1-6 Alkyl of (C) 1-6 Alkoxy group of (C) 1-6 Acyl group of (1), C 1-6 Acyloxy group of (2) and (C) 1-6 Alkoxy radicalAcyl radical, C 2-6 Unsaturated hydrocarbon group of (C) 3-6 Cycloalkyl of, C 1-6 Alkylthio, F, cl, br, I, glu, SO 3 H、PO 3 H 2 ；
Glu represents beta-D glucopyranosyl; SO (SO) 3 H represents a sulfonyl group; PO 3 H 2 Represents a phosphoryl group.
According to the present invention, preferred vitin derivatives represented by the general formula (II) include, but are not limited to, compounds represented by the general formula (IIA), and pharmaceutically acceptable salts thereof, wherein the compounds are represented by the general formula (IIA):
Figure BDA0003039367360000032
wherein R is 3 、R 4 、R 5 Each independently selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Acyl, substituted or unsubstituted C 2-6 Unsaturated hydrocarbon group, substituted or unsubstituted C 3-6 Cycloalkyl, glu, SO 3 H、PO 3 H 2 (ii) a The substituent is selected from hydrogen, hydroxyl, nitro, cyano, amino, carboxyl, methylamino, dimethylamino and C 1-6 Alkyl of (C) 1-6 Alkoxy group of (C) 1-6 Acyl group of (1), C 1-6 Acyloxy group of (2) and (C) 1-6 Alkoxyacyl group, C 2-6 Unsaturated hydrocarbon group of (C) 3-6 Cycloalkyl of, C 1-6 Alkylthio, F, cl, br, I, glu, SO 3 H、PO 3 H 2 ；
Glu represents beta-D glucopyranosyl; SO 3 H represents a sulfonyl group; PO 3 H 2 Represents a phosphoryl group.
Preferred viniferin derivatives of formula (IIA) according to the present invention include, but are not limited to, compounds of formula (IIAa), and pharmaceutically acceptable salts thereof, wherein said compounds are represented by formula (IIAa):
Figure BDA0003039367360000041
wherein R is 4 、R 5 Each independently selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Acyl, substituted or unsubstituted C 2-6 Unsaturated hydrocarbon group, substituted or unsubstituted C 3-6 Cycloalkyl, glu, SO 3 H、PO 3 H 2 (ii) a The substituent is selected from hydrogen, hydroxyl, nitro, cyano, amino, carboxyl, methylamino, dimethylamino and C 1-6 Alkyl of (C) 1-6 Alkoxy group of (1), C 1-6 Acyl group of (1), C 1-6 Acyloxy group of (2) and (C) 1-6 Alcoxyl acyl radical, C 2-6 Unsaturated hydrocarbon group of (C) 3-6 Cycloalkyl of, C 1-6 Alkylthio, F, cl, br, I, glu, SO 3 H、PO 3 H 2 ；
Glu represents beta-D glucopyranosyl; SO (SO) 3 H represents a sulfonyl group; PO (PO) 3 H 2 Represents a phosphoryl group.
Preferred viniferin derivatives of formula (IIA) according to the present invention include, but are not limited to, compounds of formula (IIAb), and pharmaceutically acceptable salts thereof, wherein the compounds are represented by formula (IIAb):
Figure BDA0003039367360000042
wherein R is 5 Selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Acyl, substituted or unsubstituted C 2-6 Unsaturated hydrocarbon group, substituted or unsubstituted C 3-6 Cycloalkyl, glu, SO 3 H、PO 3 H 2 (ii) a The substituent is selected from hydrogen, hydroxyl, nitro, cyano, amino, carboxyl, methylamino, dimethylamino and C 1-6 Alkyl of (C) 1-6 Alkoxy group of (C) 1-6 Acyl group of (1), C 1-6 Acyloxy group of (2), C 1-6 Alkoxyacyl group, C 2-6 Unsaturated hydrocarbon group of (C) 3-6 Cycloalkyl of, C 1-6 Alkylthio, F, cl, br, I, glu, SO 3 H、PO 3 H 2 ；
Glu represents beta-D glucopyranosyl; SO 3 H represents a sulfonyl group; PO (PO) 3 H 2 Represents a phosphoryl group.
Preferred viniferin derivatives of formula (IIA) according to the present invention include, but are not limited to, compounds of formula (IIAc), and pharmaceutically acceptable salts thereof, wherein the compounds are represented by formula (IIAc):
Figure BDA0003039367360000043
wherein R is 3 、R 5 Independently selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Acyl, substituted or unsubstituted C 2-6 Unsaturated hydrocarbon group, substituted or unsubstituted C 3-6 Cycloalkyl, glu, SO 3 H、PO 3 H 2 (ii) a The substituent is selected from hydrogen, hydroxyl, nitro, cyano, amino, carboxyl, methylamino, dimethylamino and C 1-6 Alkyl of (C) 1-6 Alkoxy group of (C) 1-6 Acyl group of (1), C 1-6 Acyloxy group of (2) and (C) 1-6 Alkoxyacyl group, C 2-6 Unsaturated hydrocarbon group of (C) 3-6 Cycloalkyl of, C 1-6 Alkylthio, F, cl, br, I, glu, SO 3 H、PO 3 H 2 。
Glu represents beta-D glucopyranosyl; SO (SO) 3 H represents a sulfonyl group; PO (PO) 3 H 2 Represents a phosphoryl group;
preferred derivatives of viniferin of formula (IIA) according to the present invention include, but are not limited to, compounds of formula (IIAd), and pharmaceutically acceptable salts thereof, wherein said compounds are represented by formula (IIAd):
Figure BDA0003039367360000051
wherein R is 3 Selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Acyl, substituted or unsubstituted C 2-6 Unsaturated hydrocarbon group, substituted or unsubstituted C 3-6 Cycloalkyl, glu, SO 3 H、PO 3 H 2 (ii) a The substituent is selected from hydrogen, hydroxyl, nitro, cyano, amino, carboxyl, methylamino, dimethylamino and C 1-6 Alkyl of (C) 1-6 Alkoxy group of (1), C 1-6 Acyl group of (1), C 1-6 Acyloxy group of (2) and (C) 1-6 Alcoxyl acyl radical, C 2-6 Unsaturated hydrocarbon group of (C) 3-6 Cycloalkyl of, C 1-6 Alkylthio, F, cl, br, I, glu, SO 3 H、PO 3 H 2 ；
Glu represents beta-D glucopyranosyl; SO 3 H represents a sulfonyl group; PO 3 H 2 Represents a phosphoryl group.
Preferred vitin derivatives represented by the general formula (II) according to the present invention include, but are not limited to, compounds represented by the general formula (IIB), and pharmaceutically acceptable salts thereof, wherein the compounds are represented by the general formula (IIB):
Figure BDA0003039367360000052
wherein R is 2 、R 3 、R 5 Each independently selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Acyl, substituted or unsubstituted C 2-6 Unsaturated hydrocarbon group, substituted or unsubstituted C 3-6 Cycloalkyl, glu, SO 3 H、PO 3 H 2 (ii) a The substituent is selected from hydrogen, hydroxyl, nitro, cyano, amino, carboxyl, methylamino, dimethylamino and C 1-6 Alkyl of (C) 1-6 Alkoxy group of (C) 1-6 Acyl group of (1), C 1-6 Acyloxy group of (2), C 1-6 Alcoxyl acyl radical, C 2-6 Unsaturated hydrocarbon group of (C) 3-6 Cycloalkyl of, C 1-6 Alkylthio, F, cl, br, I,Glu、SO 3 H、PO 3 H 2 ；
Glu represents beta-D glucopyranosyl; SO (SO) 3 H represents a sulfonyl group; PO (PO) 3 H 2 Represents a phosphoryl group.
Preferred viniferin derivatives of formula (IIB) according to the present invention include, but are not limited to, compounds of formula (IIBa), and pharmaceutically acceptable salts thereof, wherein the compounds are represented by formula (IIBa):
Figure BDA0003039367360000061
wherein R is 2 、R 3 Each independently selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Acyl, substituted or unsubstituted C 2-6 Unsaturated hydrocarbon group, substituted or unsubstituted C 3-6 Cycloalkyl, glu, SO 3 H、PO 3 H 2 (ii) a The substituent is selected from hydrogen, hydroxyl, nitro, cyano, amino, carboxyl, methylamino, dimethylamino and C 1-6 Alkyl of (C) 1-6 Alkoxy group of (1), C 1-6 Acyl group of (1), C 1-6 Acyloxy group of (2) and (C) 1-6 Alcoxyl acyl radical, C 2-6 Unsaturated hydrocarbon group of (C) 3-6 Cycloalkyl of, C 1-6 Alkylthio, F, cl, br, I, glu, SO 3 H、PO 3 H 2 ；
Glu represents beta-D glucopyranosyl; SO 3 H represents a sulfonyl group; PO (PO) 3 H 2 Represents a phosphoryl group.
According to the present invention, preferred derivatives of the viniferin of formula (I) include, but are not limited to, compounds of formula (III) and pharmaceutically acceptable salts thereof, wherein the compounds are represented by formula (III):
Figure BDA0003039367360000062
wherein R is 1 、R 3 、R 4 、R 5 Each independently selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Acyl, substituted or unsubstituted C 2-6 Unsaturated hydrocarbon group, substituted or unsubstituted C 3-6 Cycloalkyl, glu, SO 3 H、PO 3 H 2 (ii) a The substituent is selected from hydrogen, hydroxyl, nitro, cyano, amino, carboxyl, methylamino, dimethylamino and C 1-6 Alkyl of (C) 1-6 Alkoxy group of (C) 1-6 Acyl group of (1), C 1-6 Acyloxy group of (2), C 1-6 Alcoxyl acyl radical, C 2-6 Unsaturated hydrocarbon group of (C) 3-6 Cycloalkyl of, C 1-6 Alkylthio, F, cl, br, I, glu, SO 3 H、PO 3 H 2 ；
Glu represents beta-D glucopyranosyl; SO (SO) 3 H represents a sulfonyl group; PO (PO) 3 H 2 Represents a phosphoryl group.
According to the present invention, preferred derivatives of the viniferin of formula (III) include, but are not limited to, compounds of formula (IIIA) and pharmaceutically acceptable salts thereof, wherein the compounds are represented by formula (IIIA):
Figure BDA0003039367360000071
wherein R is 1 、R 4 、R 5 Each independently selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Acyl, substituted or unsubstituted C 2-6 Unsaturated hydrocarbon group, substituted or unsubstituted C 3-6 Cycloalkyl, glu, SO 3 H、PO 3 H 2 (ii) a The substituent is selected from hydrogen, hydroxyl, nitro, cyano, amino, carboxyl, methylamino, dimethylamino and C 1-6 Alkyl of (C) 1-6 Alkoxy group of (C) 1-6 Acyl group of (1), C 1-6 Acyloxy group of (2) and (C) 1-6 Alcoxyl acyl radical, C 2-6 Unsaturated hydrocarbon group of (C) 3-6 Cycloalkyl of (C) 1-6 Alkylthio, F, cl, br, I, gl ofu、SO 3 H、PO 3 H 2 ；
Glu represents beta-D glucopyranosyl; SO (SO) 3 H represents a sulfonyl group; PO (PO) 3 H 2 Represents a phosphoryl group.
According to the present invention, preferred derivatives of the viniferin of formula (IIIA) include, but are not limited to, compounds of formula (IIIAa), and pharmaceutically acceptable salts thereof, wherein the compounds are represented by formula (IIIAa):
Figure BDA0003039367360000072
wherein R is 1 、R 5 Each independently selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Acyl, substituted or unsubstituted C 2-6 Unsaturated hydrocarbon group, substituted or unsubstituted C 3-6 Cycloalkyl, glu, SO 3 H、PO 3 H 2 (ii) a The substituent is selected from hydrogen, hydroxyl, nitro, cyano, amino, carboxyl, methylamino, dimethylamino and C 1-6 Alkyl of (C) 1-6 Alkoxy group of (1), C 1-6 Acyl group of (1), C 1-6 Acyloxy group of (2) and (C) 1-6 Alcoxyl acyl radical, C 2-6 Unsaturated hydrocarbon group of (C) 3-6 Cycloalkyl of (C) 1-6 Alkylthio, F, cl, br, I, glu, SO 3 H、PO 3 H 2 ；
Glu represents beta-D glucopyranosyl; SO 3 H represents a sulfonyl group; PO (PO) 3 H 2 Represents a phosphoryl group.
According to the present invention, preferred viniferin derivatives of formula (IIIA) include, but are not limited to, compounds of formula (IIIAb), and pharmaceutically acceptable salts thereof, wherein the compounds are represented by formula (IIIAb):
Figure BDA0003039367360000073
wherein R is 1 Selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Acyl, substituted or unsubstituted C 2-6 Unsaturated hydrocarbon group, substituted or unsubstituted C 3-6 Cycloalkyl, glu, SO 3 H、PO 3 H 2 (ii) a The substituent is selected from hydrogen, hydroxyl, nitro, cyano, amino, carboxyl, methylamino, dimethylamino and C 1-6 Alkyl of (C) 1-6 Alkoxy group of (C) 1-6 Acyl group of (1), C 1-6 Acyloxy group of (2) and (C) 1-6 Alcoxyl acyl radical, C 2-6 Unsaturated hydrocarbon group of (C) 3-6 Cycloalkyl of, C 1-6 Alkylthio, F, cl, br, I, glu, SO 3 H、PO 3 H 2 ；
Glu represents beta-D glucopyranosyl; SO 3 H represents a sulfonyl group; PO (PO) 3 H 2 Represents a phosphoryl group.
According to the present invention, preferred derivatives of the viniferin of formula (III) include, but are not limited to, compounds of formula (IIIB) and pharmaceutically acceptable salts thereof, wherein the compounds are represented by formula (IIIB):
Figure BDA0003039367360000081
wherein R is 1 、R 3 、R 5 Each independently selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Acyl, substituted or unsubstituted C 2-6 Unsaturated hydrocarbon group, substituted or unsubstituted C 3-6 Cycloalkyl, glu, SO 3 H、PO 3 H 2 (ii) a The substituent is selected from hydrogen, hydroxyl, nitro, cyano, amino, carboxyl, methylamino, dimethylamino and C 1-6 Alkyl of (C) 1-6 Alkoxy group of (C) 1-6 Acyl group of (1), C 1-6 Acyloxy group of (2) and (C) 1-6 Alkoxyacyl group, C 2-6 Unsaturated hydrocarbon group of (C) 3-6 Cycloalkyl of, C 1-6 Alkylthio, F, cl, br, I, glu, SO 3 H、PO 3 H 2 ；
Glu represents beta-D glucopyranosyl; SO (SO) 3 H represents a sulfonyl group; PO (PO) 3 H 2 Represents a phosphoryl group.
According to the present invention, preferred derivatives of the viniferin of formula (IIIB) include, but are not limited to, compounds of formula (IIIBa), and pharmaceutically acceptable salts thereof, wherein the compounds are represented by formula (IIIBa):
Figure BDA0003039367360000082
wherein R is 1 、R 3 Each independently selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Acyl, substituted or unsubstituted C 2-6 Unsaturated hydrocarbon group, substituted or unsubstituted C 3-6 Cycloalkyl, glu, SO 3 H、PO 3 H 2 (ii) a The substituent is selected from hydrogen, hydroxyl, nitro, cyano, amino, carboxyl, methylamino, dimethylamino and C 1-6 Alkyl of (C) 1-6 Alkoxy group of (C) 1-6 Acyl group of (1), C 1-6 Acyloxy group of (2) and (C) 1-6 Alcoxyl acyl radical, C 2-6 Unsaturated hydrocarbon group of (C) 3-6 Cycloalkyl of (C) 1-6 Alkylthio, F, cl, br, I, glu, SO 3 H、PO 3 H 2 ；
Glu represents beta-D glucopyranosyl; SO (SO) 3 H represents a sulfonyl group; PO (PO) 3 H 2 Represents a phosphoryl group.
According to the present invention, preferred vitin derivatives represented by the general formula (I) include, but are not limited to, compounds represented by the general formula (IV), and pharmaceutically acceptable salts thereof, wherein the compounds are represented by the general formula (IV):
Figure BDA0003039367360000091
wherein R is 1 、R 2 、R 3 、R 5 Each independently of the otherIs selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Acyl, substituted or unsubstituted C 2-6 Unsaturated hydrocarbon group, substituted or unsubstituted C 3-6 Cycloalkyl, glu, SO 3 H、PO 3 H 2 (ii) a The substituent is selected from hydrogen, hydroxyl, nitro, cyano, amino, carboxyl, methylamino, dimethylamino and C 1-6 Alkyl of (C) 1-6 Alkoxy group of (C) 1-6 Acyl group of (1), C 1-6 Acyloxy group of (2) and (C) 1-6 Alkoxyacyl group, C 2-6 Unsaturated hydrocarbon group of (C) 3-6 Cycloalkyl of (C) 1-6 Alkylthio, F, cl, br, I, glu, SO 3 H、PO 3 H 2 ；
Glu represents beta-D glucopyranosyl; SO (SO) 3 H represents a sulfonyl group; PO (PO) 3 H 2 Represents a phosphoryl group.
Preferred vitin derivatives of formula (IV) according to the present invention include, but are not limited to, compounds of formula (IVA), and pharmaceutically acceptable salts thereof, wherein the compounds are represented by formula (IVA):
Figure BDA0003039367360000092
wherein R is 1 、R 2 、R 3 Each independently selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Acyl, substituted or unsubstituted C 2-6 Unsaturated hydrocarbon group, substituted or unsubstituted C 3-6 Cycloalkyl, glu, SO 3 H、PO 3 H 2 (ii) a The substituent is selected from hydrogen, hydroxyl, nitro, cyano, amino, carboxyl, methylamino, dimethylamino and C 1-6 Alkyl of (C) 1-6 Alkoxy group of (1), C 1-6 Acyl group of (1), C 1-6 Acyloxy group of (2) and (C) 1-6 Alkoxyacyl group, C 2-6 Unsaturated hydrocarbon group of (C) 3-6 Cycloalkyl of, C 1-6 Alkylthio, F, cl, br, I, glu, SO 3 H、PO 3 H 2 ；
Glu represents beta-D glucopyranosyl; SO 3 H represents a sulfonyl group; PO (PO) 3 H 2 Represents a phosphoryl group.
The present invention provides a novel one of the following compounds, wherein the compound is a novel compound represented by the general formula (I) 1-6 The alkyl group of (1) includes methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, tert-pentyl, cyclopentyl, n-hexyl, cyclohexyl, cyclopentylmethyl; c 1-6 The acyl group of (a) includes formyl, acetyl, propionyl, isopropylacyl, butyryl, tert-butylacyl, n-pentylacyl, isopentylacyl, n-hexylacyl, cyclohexylacyl, cyclopentylmethyl acyl; c 2-6 The unsaturated hydrocarbon group of (1) includes vinyl, ethynyl, propenyl, isopropenyl, propynyl, isopropynyl, butenyl, isopropenyl, 1,3-butadienyl, pentenyl, isopentenyl, isoprenyl, cyclopentenyl, cyclopentadienyl, hexenyl, cyclohexenyl, cyclohexadienyl, phenyl; c 3-6 The cycloalkyl group of (1) includes a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group.
In particular to a viniferin derivative shown in general formulas (I), (II) (IIA), (IIAa), (IIAb), (IIAc), (IIAd), (IIB), (IIBa), (III), (IIIA), (IIIAa), (IIIAb), (IIIB), (IIIBa), (IV) and (IVA) and a pharmaceutically acceptable salt thereof, and is characterized in that the compound is selected from the following groups:
Figure BDA0003039367360000101
Figure BDA0003039367360000111
the second aspect of the technical scheme of the invention provides a pharmaceutical composition, which comprises at least one 2,3-diaryl-5-styrylbenzofuran type grape derivative shown as general formulas (I), (II) (IIA), (IIAa), (IIAb), (IIAc), (IIAd), (IIB), (IIBa), (III), (IIIA), (IIIAa), (IIIAb), (IIIB), (IIIBa), (IV) and (IVA), and pharmaceutically acceptable salts and carriers commonly used in the pharmaceutical field.
The invention also relates to pharmaceutical compositions containing a compound of the invention as active ingredient and conventional pharmaceutical excipients or auxiliaries. Typically, the pharmaceutical compositions of the present invention contain 0.1 to 95% by weight of a compound of the present invention. The compounds of the invention are generally present in an amount of 0.1 to 100mg in a unit dosage form, with a preferred unit dosage form containing 4 to 50mg.
Pharmaceutical compositions of the compounds of the invention may be prepared according to methods well known in the art. For this purpose, the compounds of the invention can, if desired, be combined with one or more solid or liquid pharmaceutical excipients and/or adjuvants and brought into a suitable administration form or dosage form for use as human or veterinary medicine.
The compound of the present invention or the pharmaceutical composition containing it can be administered in unit dosage form, and the administration route can be intestinal or parenteral, such as oral, intramuscular, subcutaneous, nasal, oral mucosa, skin, peritoneum or rectum. The route of administration of the compounds of the invention or the pharmaceutical compositions containing them may be by injection. The injection includes intravenous injection, intramuscular injection, subcutaneous injection, intradermal injection, acupoint injection, etc.
The administration dosage form can be liquid dosage form or solid dosage form. For example, the liquid dosage form can be true solution, colloid, microparticle, emulsion, or suspension. Other dosage forms such as tablet, capsule, dripping pill, aerosol, pill, powder, solution, suspension, emulsion, granule, suppository, lyophilized powder for injection, etc.
The compound can be prepared into common preparations, sustained release preparations, controlled release preparations, targeting preparations and various particle drug delivery systems.
For example, to form a unit dosage form into a tablet, a wide variety of carriers known in the art can be used. As examples of the carrier, diluents and absorbents such as starch, dextrin, calcium sulfate, lactose, mannitol, sucrose, sodium chloride, glucose, urea, calcium carbonate, kaolin, microcrystalline cellulose, aluminum silicate and the like; wetting agents and binders such as water, glycerin, polyethylene glycol, ethanol, propanol, starch slurry, dextrin, syrup, honey, glucose solution, acacia slurry, gelatin slurry, sodium carboxymethylcellulose, shellac, methyl cellulose, potassium phosphate, polyvinylpyrrolidone and the like; disintegrating agents such as dry starch, alginate, agar powder, brown algae starch, sodium bicarbonate and citric acid, calcium carbonate, polyoxyethylene sorbitol fatty acid ester, sodium dodecylsulfate, methyl cellulose, ethyl cellulose, etc.; disintegration inhibitors such as sucrose, glyceryl tristearate, cacao butter, hydrogenated oil and the like; absorption accelerators such as quaternary ammonium salts, sodium lauryl sulfate and the like; lubricants, for example, talc, silica, corn starch, stearate, boric acid, liquid paraffin, polyethylene glycol, and the like. The tablets may be further formulated as coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layered and multi-layered tablets.
For example, to form the administration units into pills, carriers well known in the art are widely used. Examples of the carrier are, for example, diluents and absorbents such as glucose, lactose, starch, cacao butter, hydrogenated vegetable oil, polyvinylpyrrolidone, glycerin monostearate, kaolin, talc or the like; binders such as acacia, tragacanth, gelatin, ethanol, honey, liquid sugar, rice paste or batter, etc.; disintegrating agents, such as agar powder, dried starch, alginate, sodium dodecylsulfate, methylcellulose, ethylcellulose, etc.
For example, to encapsulate a dosage unit, the compounds of the present invention are mixed with the various carriers described above, and the resulting mixture is placed in a hard gelatin or soft gelatin capsule. The effective component of the compound can also be prepared into microcapsules, and the microcapsules can be suspended in an aqueous medium to form a suspension, and can also be filled into hard capsules or prepared into injections for application.
For example, the compounds of the present invention may be formulated as injectable preparations, such as solutions, suspensions, emulsions, lyophilized powders, which may be aqueous or non-aqueous, and may contain one or more pharmaceutically acceptable carriers, diluents, binders, lubricants, preservatives, surfactants or dispersants. For example, the diluent may be selected from water, ethanol, polyethylene glycol, 1,3-propanediol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitol ester, fatty acids, and the like. In addition, for the preparation of isotonic injection, sodium chloride, glucose or glycerol may be added in an appropriate amount to the preparation for injection, and conventional cosolvents, buffers, pH adjusters and the like may also be added. These adjuvants are commonly used in the art.
In addition, colorants, preservatives, flavors, flavorings, sweeteners or other materials may also be added to the pharmaceutical preparation, if desired.
For administration purposes, to enhance the therapeutic effect, the medicaments or pharmaceutical compositions of the invention may be administered by any known method of administration.
The dosage of the pharmaceutical composition of the compound of the present invention to be administered depends on many factors, such as the nature and severity of the disease to be prevented or treated, the sex, age, body weight, character and individual response of the patient or animal, the administration route, the number of administrations and the therapeutic purpose, and thus the therapeutic dosage of the present invention can be widely varied. Generally, the dosages of the ingredients of the invention to be used are well known to those skilled in the art. The prophylactic or therapeutic objectives of the present invention can be accomplished by appropriate adjustment of the actual amount of drug contained in the final formulation of the compound composition of the present invention to achieve the desired therapeutically effective amount. Suitable daily dosage ranges for the compounds of the invention: the compounds of the invention are used in an amount of 0.001 to 100mg/kg body weight, preferably 0.1 to 60mg/kg body weight, more preferably 1 to 30mg/kg body weight, most preferably 2 to 15mg/kg body weight. The compound of the invention is taken by adult patients at a daily dose of 10-500 mg, preferably 10-100 mg, and can be taken once or in 2-3 times; the dose administered to children is 5 to 30mg per kg body weight, preferably 10 to 20mg per kg body weight. The above-mentioned dosage may be administered in a single dosage form or divided into several, e.g., two, three or four dosage forms, which is limited by the clinical experience of the administering physician and the dosage regimen of the therapeutic means. The compounds or compositions of the present invention may be administered alone or in combination with other therapeutic or symptomatic agents.
The third aspect of the technical scheme of the invention provides 2,3-diaryl-5-styrylbenzofuran type glucose derivatives and pharmaceutically acceptable salts thereof shown as general formulas (I), (II) (IIA), (IIAa), (IIAb), (IIAc), (IIAd), (IIBa), (III), (IIIA), (IIIAa), (IIIAb), (IIIB), (IIIBa), (IV) and (IVA), and application of the derivatives and the pharmaceutically acceptable salts thereof in preparing medicaments for treating, preventing and assisting in treating various inflammations and diseases related to inflammatory immunity.
The various inflammatory and inflammatory immune-related diseases include: rheumatoid arthritis, osteoarthritis, rheumatoid arthritis, gouty arthritis, lupus erythematosus syndrome, bronchitis, bursitis, tenosynovitis, psoriasis, eczema, burns, dermatitis, inflammatory bowel disease, crohn's disease, gastritis, irritable bowel syndrome, ulcerative colitis, multiple sclerosis, autoimmune encephalomyelitis, colorectal cancer, nodular arteritis, thyroiditis, wind-heat-dampness, gingivitis, periodontitis, oral ulcers, nephritis, swelling following insult, myocardial ischemia, various infectious pneumonia, physicochemical and allergic pneumonia, chronic obstructive pulmonary disease, asthma, spastic anal pain and rectal fissure, hepatocystitis, cholangitis, primary biliary cirrhosis and cholecystitis. The compounds of the present invention include derivatives and pharmaceutically acceptable salts thereof.
The common features of inflammatory immune diseases at the cellular level are represented by: macrophages are over activated and produce excess NO. Therefore, the invention performs an inhibition experiment of the compound on LPS-induced macrophage NO generation in the abdominal cavity of primary mice, and shows that the 2,3-diaryl-5-styryl benzofuran type compound has the activity of inhibiting excessive generation of macrophage NO on a cellular level.
In a fourth aspect of the present invention, there is provided a process for producing the derivative according to the first aspect.
The synthesis method of the target derivative in the invention comprises the following steps (the required raw material resveratrol can be obtained by commercial purchase):
Figure BDA0003039367360000141
the method comprises the following steps: resveratrol dimerization reaction is carried out to synthesize a 2,3-diaryl-5-styryl benzodihydrofuran structure resveratrol dimer derivative delta-viniferin (A).
Extracting resveratrol with Ag in anhydrous acetone 2 And O is taken as an oxidant to carry out oxidative coupling reaction, and the reaction liquid is filtered, decompressed and concentrated to be dry to obtain a crude product. The crude product is separated and purified by chromatography to obtain a target product 2,3-diaryl-5-styryl dihydrobenzofuran resveratrol dimer delta-viniferin (A).
Step two: and (3) performing phenolic hydroxyl acetylation on the product obtained in the step one to synthesize a 2,3-diaryl-5-styryl benzodihydrofuran type intermediate derivative (B) subjected to phenolic hydroxyl acetylation.
And (3) performing acetylation reaction on the product A obtained in the step one and acetic anhydride in dry pyridine, removing the pyridine from the reaction solution, and performing reduced pressure concentration to obtain the benzodihydrofuran type resveratrol dimer derivative (B) with the phenolic hydroxyl group acetylated.
Step three: and (3) dehydrogenating the product obtained in the second step to synthesize the fully acetylated 2,3-diaryl-5-styrylbenzofuran type derivative (C).
And (3) carrying out oxidation reaction on the product B obtained in the step (II) in dioxane by using DDQ, filtering the reaction mixture to remove the DDQ, and carrying out chromatographic separation to obtain the fully acetylated benzofuran resveratrol dimer derivative (C).
Step four: and performing acetyl removal reaction on the product obtained in the step three to synthesize 2,3-diaryl-5-styrylbenzofuran type resveratrol dimer derivative hydro-delta-viniferin (D).
Putting the fully acetylated product obtained in the third step in a mixed solution of dichloromethane and methanol to obtain NH 4 Subjecting OAc to acetyl removal reaction, removing NH from reaction mixture 4 After OAc, the target product 2,3-diaryl-5-styrylbenzofuran type resveratrol dimer dehydro-delta-viniferin (D) is obtained by decompression and concentration.
Step five: and (3) synthesizing different methoxyl-substituted 2,3-diaryl-5-styryl benzofuran type resveratrol dimer derivatives from the product D obtained in the fourth step through incomplete methylation reaction.
Advantageous technical effects
In the activity research process of a natural product analogue dehydride-delta-viniferin with a 2,3-diaryl-5-styrylbenzofuran structure, namely a semisynthetic derivative of a natural product of a grape element (delta-viniferin) separated from vitis amurensis, the inventor finds that the compound has strong antioxidant and anti-inflammatory activities on an animal model. On the basis, the compound is subjected to structural derivatization to obtain a series of viniferin derivatives with 2,3-diaryl-5-styrylbenzofuran structures, and the obtained derivatives are subjected to inflammation inhibition activity evaluation to confirm the anti-inflammatory activity of the compound. The compound has obvious inhibition activity on the generation of LPS-induced primary mouse abdominal cavity macrophage NO, and has potential value of further research and development.
At present, the study on the activity and structure-activity relationship of 2,3-diaryl-5-styrylbenzofuran type grapevine derivatives substituted by different substituents has not been reported in the literature. No report on 2,3-diaryl-5-styrylbenzofuran type vitin derivatives substituted by different substituents or medically acceptable salts thereof and the application of the compounds in treating inflammatory diseases is found in the prior literatures and the prior art.
Detailed description of the invention:
although the terms and phrases used herein have a general meaning known to those skilled in the art, it is to be understood that the invention is not limited to the exact construction and operation as illustrated and described, and that other terms and phrases may be substituted and substituted if desired. The following are definitions of various terms used herein, which apply to the terms used throughout the specification of the present application unless otherwise specified in specific instances.
Definitions for various groups of the compounds of the invention are provided below and, unless otherwise defined, are used uniformly throughout the specification and claims.
The term "alkyl" as referred to herein isRefers to an alkyl group having the specified number of carbon atoms, which may be straight or branched, e.g. as mentioned for "C 3-6 The "cycloalkyl group" refers to a substituted or unsubstituted cycloalkyl group having 3, 4, 5, 6 carbon atoms and may include C 3-5 Cycloalkyl radical, C 3-4 Cycloalkyl radical, C 4-6 Cycloalkyl radical, C 4-5 Cycloalkyl radical, C 5-6 Cycloalkyl, and the like, and preferably specific groups such as cyclopropyl, cyclopentyl, and cyclohexyl.
The term "C" as referred to herein 1-6 The "alkyl group" of (A) means a straight-chain or branched alkyl group having 1, 2,3, 4, 5, 6 carbon atoms and may include C 1-5 Alkyl radical, C 1-4 Alkyl radical, C 2-5 Alkyl radical, C 2-4 Alkyl radical, C 2-3 Alkyl radical, C 3-5 Alkyl, etc., and preferred specific groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, etc.
The term "C" as referred to in the present invention 1-6 Alkoxy "refers to an alkoxy group having 1, 2,3, 4, 5, 6 carbon atoms, including C 1-5 Alkoxy radical, C 1-2 Alkoxy radical, C 2-4 Alkoxy radical, C 2-3 Alkoxy radical, C 3-4 Alkoxy, and the like, and preferred specific groups include methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, sec-butyloxy, tert-butyloxy, and the like.
The term "C" as referred to in the present invention 2-6 The unsaturated hydrocarbon group "means an unsaturated hydrocarbon group having 2,3, 4, 5, 6 carbon atoms and may include C 2-5 Unsaturated hydrocarbon group of (C) 2-4 Unsaturated hydrocarbon group of (C) 2-5 Unsaturated hydrocarbon group of (C) 2-4 And the like, and preferred specific groups, for example, vinyl, ethynyl, isopropenyl, isobutenyl, isopentenyl, 1,3-dibutenyl, and the like.
The term "C" as referred to in the present invention 1-6 The "acyl group" refers to an acyl group having 1, 2,3, 4, 5, 6 carbon atoms and may include C 1-5 Acyl radical, C 1-3 Acyl radical, C 2-5 Acyl radical, C 2-3 Acyl radical, C 3-4 Acyl, and the like, and preferred specific groups, such as formyl, acetyl, propionyl, and the like.
"C" as referred to in the invention 1-6 The "acyloxy group" of (a) means a straight or branched acyloxy group having 1, 2,3, 4, 5 or 6 carbon atoms and may include C 1-5 Acyloxy, C 1-3 Acyloxy, C 2-5 Acyloxy, C 2-3 Acyloxy, C 3-4 Acyloxy, and the like, as well as preferred specific groups such as formyloxy, acetoxy, propionyloxy, and the like.
"C" as referred to in the invention 1-6 The "alkoxyacyl group" is an alkoxyacyl group having 1, 2,3, 4, 5 or 6 carbon atoms and may include C 1-5 Alcoxyl acyl radical, C 1-3 Alcoxyl acyl radical, C 2-5 Alkoxyacyl group, C 2-3 Alcoxyl acyl radical, C 3-4 Alkoxyacyl groups and the like, and preferred specific groups such as methoxyacyl group, ethoxyacyl group and the like.
The term "C" as referred to in the present invention 1-6 The "alkylthio group" of (A) means a straight-chain or branched alkylthio group having 1, 2,3, 4, 5 or 6 carbon atoms and may include C 1-5 Alkylthio radical, C 1-3 Alkylthio radical, C 2-5 Alkylthio radical, C 2-3 Alkylthio radical, C 3-4 Alkylthio, and the like, as well as preferred specific groups, such as methylthio, ethylthio, and the like.
Detailed Description
To further illustrate the present invention, a series of examples are given below, which are purely illustrative and are intended to be a detailed description of the invention only and should not be understood as limiting the invention.
Example 1: the synthesis method of the target derivative in the invention comprises the following steps (the synthesis raw material resveratrol can be obtained by commercial purchase):
Figure BDA0003039367360000171
example 1
The method comprises the following steps: and (3) performing dimerization reaction on the resveratrol to synthesize a resveratrol dimer derivative (A) with a 2,3-diaryl-5-styryl dihydrobenzofuran structure.
60g resveratrol (263.158 mmol) was dissolved in 1500ml anhydrous acetone, and 67.8g Ag was added 2 And heating and refluxing the solid O for 3d to stop the reaction. The reaction solution was filtered through celite, and the filtrate was concentrated to dryness under reduced pressure to give a crude product. The crude product was isolated by silica gel (200-300 mesh) column chromatography using petroleum ether acetone =3:2 (v/v) to give 6.7g of a yellow solid a (14.758 mmol) in 11.2% yield m.p.154-156 ℃.
Step two: and (3) performing phenolic hydroxyl acetylation on the product obtained in the step one to synthesize a 2,3-diaryl-5-styryl benzodihydrofuran type intermediate derivative (B) subjected to phenolic hydroxyl acetylation.
1.28g of Compound A (2.81 mmol) was dissolved in 15ml of dry pyridine, 6.64ml of acetic anhydride (70.25 mmol) was added and stirred at room temperature overnight. After the reaction is completed, slowly dripping ice water in ice bath, transferring the ice water into a separating funnel after the ice water does not generate heat, adding 3 times of water for dilution, extracting the ice water with ethyl acetate for three times, combining organic phases, and sequentially adding saturated CuSO 4 Washing with water, saturated salt solution, and anhydrous Na 2 SO 4 Drying, evaporating the organic phase to dryness under reduced pressure, and mixing the crude product with petroleum ether: acetone =3:1, performing silica gel (200-300 mesh) column chromatography to obtain white solid B1.79 g (2.70 mmol), yield 95.7%, m.p.182-183 deg.C
Step three: and (3) carrying out dehydrogenation reaction on the product obtained in the step two to synthesize the fully acetylated 2,3-diaryl-5-styryl benzofuran type derivative (C).
1.79g of Compound B (2.70 mmol) was dissolved in 25ml of dry dioxane, 0.854g of DDQ (4.05 mmol) was added, the reaction was stopped after heating and refluxing for 48 hours, the reaction solution was distilled off under reduced pressure, the reaction mixture was dissolved in a small amount of methylene chloride and then wet-loaded, and column chromatography on silica gel (200-300 mesh) was carried out using methylene chloride as an eluent to give C1.45g (2.19 mmol) as a pale white solid in a yield of 81.1% m.p.173-174 ℃.
Step four: and performing acetyl removal reaction on the product obtained in the third step to synthesize 2,3-diaryl-5-styrylbenzofuran type resveratrol dimer derivative (D).
1.45g of Compound C (2.19 mmol) are dissolved in 15ml of dichloromethane, 15ml of methanol are added and 25.36g of NH are added 4 OAc (329 mmol), stirred at room temperature for 2d. Diluting the reaction solution with water, extracting with ethyl acetate, combining organic phases, and adding anhydrous Na 2 SO 4 Drying, vacuum filtering, and evaporating solvent to dryness under reduced pressure to obtain yellow solid D0.98 g (2.17 mmol), with yield of 98.9%, m.p.97-99 deg.C.
Step five: the intermediate D is synthesized by incomplete methylation reaction to obtain a mixture of the compounds 1-13, and the mixture is separated to prepare pure products of each compound. Their reaction processes and spectral identification data are as follows:
0.98g of Compound D (2.17 mmol) are dissolved in 15ml of anhydrous acetone and added portionwise with stirring 1.5g K 2 CO 3 Solid (10.85 mmol), stirred for 30min, and then 0.675ml CH was slowly added dropwise 3 I (10.85 mmol), stirring at room temperature for 12h, adding a small amount of water into the reaction system to stop the reaction, and filtering. The reaction solution was diluted with ethyl acetate, washed with water and saturated brine in this order, and the organic phase was concentrated under reduced pressure to give a crude product. The reaction mixture is separated by 200-300 mesh silica gel column chromatography, and nine components I-IX are obtained by petroleum ether: acetone 15, 1-1:1 (v/v) gradient elution. Component I (15.2 mg) was separated by HPLC using 95% methanol in water as the mobile phase through a C18 semi-preparative column (ODS, 5 μm, YMC, 250X 10mm, the same applies hereinafter) to give compound 13 (3.0 mg); separating component II (71.3 mg) with 85% methanol water as mobile phase by HPLC using C18 semi-preparative column to obtain compound 11 (3.6 mg) and 12 (2.5 mg); fraction IV (82.8 mg) was separated by HPLC using 90% methanol in water as the mobile phase through C18 semi-preparative column to give compounds 8 (9.0 mg), 9 (2.0 mg) and 10 (2.0 mg); separating component V (131.7 mg) with 85% methanol water as mobile phase on HPLC by C18 semi-preparative column to obtain compound 6 (7.0 mg) and component V-A (21.5 mg); component V-A (21.5 mg) is further separated by C18 semi-preparative column using 70% methanol water as mobile phase to obtain compound 7 (13.2 mg); fraction VI (224.6 mg) was separated by HPLC using 75% methanol in water as the mobile phase on a C18 semi-preparative column to give compound 5 (4.0 mg) and VI-C (85.0 mg); VI-C (85.0 mg) further 50%Acetonitrile water was separated on a C18 semi-preparative column to give compounds 3 (2.0 mg) and 4 (6.0 mg); fraction VIII (290.7 mg) was separated by HPLC using 70% methanol in water as the mobile phase over a C18 semi-preparative column to give compounds 1 (8.1 mg) and 2 (2.0 mg).
Synthesis of the final product (compound code number corresponds to the compound code number in the examples):
Figure BDA0003039367360000191
Figure BDA0003039367360000201
compound 1: 1 H NMR(500MHz,acetone-D 6 ),δ:7.66[2H,d,J＝8.5Hz,H-2(6)a],7.64(1H,br s,H-2b),7.61(1H,d,J＝8.5Hz,H-6b),7.55(1H,d,J＝8.5Hz,H-5b),7.23(1H,d,J＝16.5Hz,H-7b),7.06(1H,d,J＝16.5Hz,H-8b),6.97[2H,d,J＝8.5Hz,H-3(5)a],6.60[2H,br s,H-10(14)b],6.51[2H,br s,H-10(14)a],6.46(1H,br s,H-12a),6.29(1H,br s,H-12b),3.84(3H,s,-OCH 3 ). 13 C NMR(400MHz,acetone-D 6 ),δ:160.20(C-4a),159.31[C-11(13)a],158.79[C-11(13)b],130.81(C-7b),128.46[C-2(6)a],127.96(C-8b),114.04[C-3(5)a],108.04[C-10(14)a],105.08[C-10(14)b],102.33(C-12a),102.16(C-12b),54.85(-OCH 3 ).(+)-HRESIMS m/z:467.1481[M+H] + ,(cald for C 29 H 23 O 6 :467.1489).
compound 2: 1 H NMR(400MHz,acetone-D 6 ),δ:7.64(1H,br s,H-2b),7.61(1H,dd,J＝8.4Hz,H-6b),7.58-7.53[3H,m,H-2(6)a,5b],7.23(1H,d,J＝16.4Hz,H-7b),7.05(1H,d,J＝16.4Hz,H-8b),6.87[2H,d,J＝8.8Hz,H-3(5)a],6.60-6.59[4H,m,H-10(14)b,10(14)a],6.50(1H,t,J＝2.4Hz,H-12a),6.29(1H,t,J＝2.0Hz,H-12b),3.79(3H,s,-OCH 3 ). 13 C NMR(400MHz,acetone-D 6 ),δ:161.62(C-11a),159.14(C-13a),158.71[C-11(13)b],158.13(C-4a),130.71(C-7b),128.58[C-2(6)a],127.87(C-8b),115.41[C-3(5)a],109.04(C-14a),106.36(C-10a),104.98[C-10(14)b],102.06(C-12b),100.90(C-12a),54.70(-OCH 3 ).(+)-HRESIMS m/z:467.1481[M+H] + ,(cald for C 29 H 23 O 6 :467.1489).
compound 3: 1 H NMR(400MHz,acetone-D 6 ),δ:7.66[2H,d,J＝8.8Hz,H-2(6)a],7.64-7.61(2H,m,H-6b,2b),7.55(1H,d,J＝9.2Hz,H-5b),7.31(1H,d,J＝16.4Hz,H-7b),7.10(1H,d,J＝16.4Hz,H-8b),6.97[2H,d,J＝8.8Hz,H-3(5)a],6.72(1H,t,J＝2.0Hz,H-10b),6.69(1H,t,J＝2.0Hz,H-14b),6.50[2H,d,J＝2.0Hz,H-10(14)a],6.46(1H,t,J＝2.0Hz,H-12a),6.33(1H,t,J＝2.0Hz,H-12b),3.84(3H,s,-OCH 3 ),3.78(3H,s,-OCH 3 ). 13 C NMR(600MHz,acetone-D 6 ),δ:161.24(C-11b),160.11(C-4a),159.27[C-11(13)a],158.70(C-13b),130.71(C-7b),128.32[C-2(6)a],127.71(C-8b),113.95[C-3(5)a],107.93[C-10(14)a],106.16(C-10b),103.02(C-14b),102.26(C-12a),100.87(C-12b),54.76(-OCH 3 ),54.56(-OCH 3 ).(+)-HRESIMS m/z:481.1644[M+H] + ,(cald for C 30 H 25 O 6 :481.1646).
compound 4: 1 H NMR(500MHz,acetone-D 6 ),δ:7.65-7.62[4H,m,H-2(6)a,2b,6b],7.56(1H,d,J＝8.5Hz,H-5b),7.24(1H,d,J＝16.5Hz,H-7b),7.06(1H,d,J＝16.5Hz,H-8b),6.97[2H,d,J＝9.0Hz,H-3(5)a],6.60-6.59[4H,m,H-10(14)b,H-10(14)a],6.51(1H,br s,H-12a),6.29(1H,br s,H-12b),3.84(3H,s,-OCH 3 ),3.79(3H,s,-OCH 3 ). 13 C NMR(400MHz,acetone-D 6 ),δ:161.74(C-11a),160.26(C-4a),159.26(C-13a),158.80[C-11(13)b],130.75(C-7b),128.47[C-2(6)a],128.00(C-8b),114.05[C-3(5)a],109.13(C-14a),106.47(C-10a),105.09[C-10(14)b],102.17(C-12b),101.04(C-12a),54.85(-OCH 3 ),54.79(-OCH 3 ).(+)-HRESIMS m/z:481.1645[M+H] + ,(cald for C 30 H 25 O 6 :481.1646).
compound 5: 1 H NMR(400MHz,acetone-D 6 ),δ:7.64(1H,d,J＝1.6Hz,H-2b),7.62(1H,dd,J＝1.6Hz,8.8Hz,H-6b),7.56[2H,d,J＝8.8Hz,H-2(6)a],7.55(1H,d,J＝8.8Hz,H-5b),7.23(1H,d,J＝16.4Hz,H-7b),7.05(1H,d,J＝16.4Hz,H-8b),6.87[2H,d,J＝8.8Hz,H-3(5)a],6.68[2H,d,J＝2.0Hz,H-10(14)a],6.59[2H,d,J＝2.0Hz,H-10(14)b],6.58(1H,t,J＝2.0Hz,H-12a),6.29(1H,t,J＝2.0Hz,H-12b),3.82(6H,s,-OCH 3 ). 13 C NMR(400MHz,acetone-D 6 ),δ:161.53[C-11(13)a],158.72[C-11(13)b],158.20(C-4a),130.66(C-7b),128.59[C-2(6)a],127.90(C-8b),115.43[C-3(5)a],107.44[C-10(14)a],105.00[C-10(14)b],102.07(C-12b),99.79(C-12a),54.85(-OCH 3 ).(+)-HRESIMS m/z:481.1646[M+H] + ,(cald for C 30 H 25 O 6 :481.1646).
compound 6: 1 H NMR(400MHz,acetone-D 6 ),δ:7.63(1H,br s,H-2b),7.63-7.61(1H,dd,H-6b),7.57[2H,d,J＝8.8Hz,H-2(6)a],7.55(1H,d,J＝9.2Hz,H-5b),7.31(1H,d,J＝16.4Hz,H-7b),7.10(1H,d,J＝16.4Hz,H-8b),6.87[2H,d,J＝8.8Hz,H-3(5)a],6.72(1H,t,J＝2.4Hz,H-14b),6.69(1H,t,J＝2.4Hz,H-10b),6.60(1H,dd,J＝2.4Hz,H-14a),6.59(1H,dd,J＝2.4Hz,H-10a),6.51(1H,t,J＝2.4Hz,H-12a),6.33(1H,t,J＝2.4Hz,H-12b),3.79(3H,s,-OCH 3 ),3.78(3H,s,-OCH 3 ). 13 C NMR(400MHz,acetone-D 6 ),δ:161.63(C-11a),161.26(C-11b),159.17(C-13a),158.68(C-13b),158.15(C-4a),130.76(C-7b),128.56[C-2(6)a],127.70(C-8b),115.43[C-3(5)a],109.06(C-14a),106.40(C-10a),106.17(C-10b),103.08(C-14b),100.86(C-12b),100.86(C-12a),54.71(-OCH 3 ),54.59(-OCH 3 ).(+)-HRESIMS m/z:481.1646[M+H] + ,(cald for C 30 H 25 O 6 :481.1646).
compound 7: 1 H NMR(400MHz,acetone-D 6 ),δ:7.61-7.58[4H,m,H-2b,6b,2(6)a],7.52(1H,d,J＝8.0Hz,H-5b),7.20(1H,d,J＝16.4Hz,H-7b),7.02(1H,d,J＝16.4Hz,H-8b),6.93[2H,d,J＝8.8Hz,H-3(5)a],6.64[2H,d,J＝2.0Hz,H-10(14)a],6.56[2H,d,J＝2.0Hz,H-10(14)b],6.55(1H,t,J＝2.0Hz,H-12a),6.26(1H,t,J＝2.0Hz,H-12b),3.80(3H,s,-OCH 3 ),3.78(6H,s,-OCH 3 ). 13 C NMR(400MHz,acetone-D 6 ),δ:161.64[C-11(13)a],160.30(C-4a),158.78[C-11(13)b],130.71(C-7b),128.48[C-2(6)a],128.03(C-8b),114.05[C-3(5)a],107.54[C-10(14)a],105.12[C-10(14)b],102.15(C-12b),99.92(C-12a),54.93(-OCH 3 ),54.85(-OCH 3 ).(+)-HRESIMS m/z:495.1800[M+H] + ,(cald for C 31 H 27 O 6 :495.1802).
compound 8: 1 H NMR(400MHz,acetone-D 6 ),δ:7.67-7.63[4H,m,H-2b,6b,2(6)a],7.57(1H,d,J＝8.8Hz,H-5b),7.32(1H,d,J＝16.4Hz,H-7b),7.11(1H,d,J＝16.4Hz,H-8b),6.98[2H,d,J＝9.2Hz,H-3(5)a],6.73(1H,t,J＝2.0Hz,H-14b),6.69(1H,t,J＝2.0Hz,H-10b),6.61-6.59[2H,m,H-(10)14a],6.53(1H,t,J＝2.0Hz,H-12a),6.34(1H,t,J＝2.0Hz,H-12b),3.85(3H,s,-OCH 3 ),3.80(3H,s,-OCH 3 ),3.79(3H,s,-OCH 3 ). 13 C NMR(400MHz,acetone-D 6 ),δ:161.67(C-11a),161.26(C-11b),160.18(C-4a),159.18(C-13a),158.65(C-13b),130.72(C-7b),128.38[C-2(6)a],127.75(C-8b),113.98[C-3(5)a],109.04(C-14a),106.44(C-10a),106.19(C-10b),103.09(C-14b),100.94(C-12a),100.86(C-12b),54.78(-OCH 3 ),54.72(-OCH 3 ),54.58(-OCH 3 ).(+)-HRESIMS m/z:495.1802[M+H] + ,(cald for C 31 H 27 O 6 :495.1802).
compound 9: 1 H NMR(500MHz,acetone-D 6 ),δ:7.64-7.54[5H,m,H-2(6)a,2b,6b,5b],7.31(1H,d,J＝16.5Hz,H-7b),7.10(1H,d,J＝16.5Hz,H-8b),6.87[2H,d,J＝8.5Hz,H-3(5)a],6.71(1H,br s,H-10b),6.68(1H,br s,H-14b),6.67[2H,d,J＝2.0Hz,H-10(14)a],6.58(1H,br s,H-12a),6.33(1H,br s,H-12b),3.82(6H,s,-OCH 3 ),3.78(3H,s,-OCH 3 ). 13 C NMR(600MHz,acetone-D 6 ),δ:161.52[C-11(13)a],161.22(C-11b),158.72(C-13b),158.25(C-4a),130.69(C-7b),128.53[C-2(6)a],127.72(C-8b),115.42[C-3(5)a],107.46[C-10(14)a],106.14(C-10b),103.08(C-14b),100.81(C-12b),99.72(C-12a),54.83(-OCH 3 ),54.56(-OCH 3 ).(+)-HRESIMS m/z:495.1801[M+H] + ,(cald for C 31 H 27 O 6 :495.1802).
compound 10: 1 H NMR(500MHz,acetone-D 6 ),δ:7.65-7.62[2H,m,H-2b,6b],7.57-7.55[3H,m,H-2(6)a,5b],7.40(1H,d,J＝16.5Hz,H-7b),7.16(1H,d,J＝16.5Hz,H-8b),6.87[2H,d,J＝8.0Hz,H-3(5)a],6.81[2H,br s,H-10(14)b],6.59(1H,br s,H-14a),6.57(1H,br s,H-10a),6.51(1H,br s,H-12a),6.39(1H,br s,H-12b),3.81(6H,s,-OCH 3 ),3.79(3H,s,-OCH 3 ). 13 C NMR(600MHz,acetone-D 6 ),δ:161.18[C-11(13)b],158.18(C-4a),130.79(C-7b),128.50[C-2(6)a],127.52(C-8b),115.41[C-3(5)a],109.05(C-14a),106.40(C-10a),104.26[C-10(14)b],100.85(C-12a),99.66(C-12b),54.70(-OCH 3 ),54.68(-OCH 3 ).(+)-HRESIMS m/z:495.1799[M+H] + ,(cald for C 31 H 27 O 6 :495.1802).
compound 11: 1 H NMR(400MHz,acetone-D 6 ),δ:7.66-7.63[4H,m,H-2(6)a,2b,6b],7.57(1H,d,J＝9.2Hz,H-5b),7.31(1H,d,J＝16.4Hz,H-7b),7.10(1H,d,J＝16.4Hz,H-8b),6.97[2H,d,J＝8.8Hz,H-3(5)a],6.71(1H,t,J＝2.0Hz,H-10b),6.68(1H,t,J＝2.0Hz,H-14b),6.67[2H,d,J＝2.0Hz,H-10(14)a],6.60(1H,t,J＝2.0Hz,H-12a),6.33(1H,t,J＝2.0Hz,H-12b),3.84(3H,s,-OCH 3 ),3.82(6H,s,-OCH 3 ),3.78(3H,s,-OCH 3 ). 13 C NMR(400MHz,acetone-D 6 ),δ:161.57[C-11(13)a],161.26(C-11b),160.23(C-4a),158.67(C-13b),130.68(C-7b),128.37[C-2(6)a],127.78(C-8b),113.98[C-3(5)a],107.48[C-10(14)a],106.19(C-10b),103.13(C-14b),100.84(C-12b),99.80(C-12a),54.86(-OCH 3 ),54.78(-OCH 3 ),54.58(-OCH 3 ).(+)-HRESIMS m/z:509.1955[M+H] + ,(cald for C 32 H 29 O 6 :509.1959).
compound 12: 1 H NMR(400MHz,acetone-D 6 ),δ:7.66-7.63[4H,m,H-2(6)a,2b,6b],7.57(1H,d,J＝8.0Hz,H-5b),7.40(1H,d,J＝16.4Hz,H-7b),7.16(1H,d,J＝16.4Hz,H-8b),6.97[2H,d,J＝8.8Hz,H-3(5)a],6.81[2H,d,J＝2.4Hz,H-10(14)b],6.60(1H,m,H-14a),6.58(1H,m,H-10a),6.53(1H,t,J＝2.4Hz,H-12a),6.39(1H,t,J＝2.0Hz,H-12b),3.84(3H,s,-OCH 3 ),3.81(6H,s,-OCH 3 ),3.79(3H,s,-OCH 3 ). 13 CNMR(600MHz,acetone-D 6 ),δ:161.65(C-11a),161.18[C-11(13)b],160.16(C-4a),159.21(C-13a),130.76(C-7b),128.33[C-2(6)a],127.58(C-8b),113.96[C-3(5)a],109.04(C-14a),106.43(C-10a),104.27[C-10(14)b],100.91(C-12a),99.67(C-12b),54.77(-OCH 3 ),54.70(-OCH 3 ).(+)-HRESIMS m/z:509.1953[M+H] + ,(cald for C 32 H 29 O 6 :509.1959).
compound 13: 1 H NMR(300MHz,CDCl 3 ),δ:7.62[2H,d,J＝8.4Hz,H-2(6)a]7.57(1H,br s,H-2b),7.49(2H,br s,H-5b,6b),7.16(1H,d,J＝16.2Hz,H-7b),6.98(1H,d,J＝16.2Hz,H-8b),6.86[2H,d,J＝8.4Hz,H-3(5)a],6.66[4H,br s,H-10(14)a,10(14)b],6.53(1H,br s,H-12a),6.37(1H,br s,H-12b),3.82(9H,br s,-OCH 3 ),3.79(6H,br s,-OCH 3 ). 13 C NMR(400MHz,CDCl 3 ),δ:161.28[C-11(13)a],160.98[C-11(13)b],159.83(C-4a),130.86(C-7b),128.49[C-2(6)a],127.55(C-8b),113.93[C-3(5)a],107.75[C-10(14)a],104.36[C-10(14)b],99.91(C-12b),99.91(C-12a),55.50(-OCH 3 ),55.40(-OCH 3 ),55.32(-OCH 3 ).(+)-HRESIMS m/z:523.2113[M+H] + ,(cald for C 33 H 31 O 6 :523.2115).
pharmacological experiments
The pharmacological test methods and results of the anti-inflammatory activity of the compounds of the present invention are as follows (the compound numbers of the pharmacological test section correspond to the compound numbers in the examples):
experimental example 1: the inhibitory activity of the grape extract on the generation of LPS-induced primary mouse abdominal cavity macrophage NO.
Macrophages perform the nonspecific immune function of an organism, can generate inflammatory factors such as NO and the like under the induction of bacterial Lipopolysaccharide (LPS), participate and mediate inflammatory reaction, and have higher levels in the initial stage of various inflammatory immune processes and the pathological development process. By detecting the generation amount of macrophage NO of primarily cultured mice, the method can be used as an index for preliminarily observing and screening components or compounds with certain anti-inflammatory activity in vitro.
The experimental method comprises the following steps:
inoculating primary mouse abdominal cavity macrophage in 96-well plate, adding different compounds to be tested (10) -5 M) and a positive control drug dexamethasone (Dex) for 1h; then, 1. Mu.g/ml LPS was added at 37 ℃ and 5% CO 2 After 24h of incubation in an incubator, the supernatant was collectedLiquid, the content of NO is determined by Griess method
Figure BDA0003039367360000241
Figure BDA0003039367360000242
Meanwhile, the cell proliferation inhibition rate was measured by the MTT method.
The experimental results are as follows:
as shown in table 1, compared with the lead compound dehydro- δ -viniferin (DRs-1), the structurally modified viniferin derivatives have significantly reduced toxicity of compounds 6, 8 and 9 while maintaining activity. Among them, compounds 1, 2, 4, 5, 6, 7, 8 and 9 had significant NO production inhibitory activity.
TABLE 1 Effect of the derivatives of Vitis vinifera on LPS-induced NO production by macrophages in the peritoneal cavity of primary mice. *
Figure BDA0003039367360000243
Figure BDA0003039367360000251
* Concentration: 10 -5 M; the treatment direction is as follows: anti-inflammatory. # The compound numbers correspond to the compound numbers in the examples.

Claims (25)

1.2,3-diaryl-5-styrylbenzofuran type of a vitin derivative represented by the general formula (I):
Figure FDA0003039367350000011
wherein R is 1 、R 2 、R 3 、R 4 、R 5 Each independently selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Acyl, substituted orUnsubstituted C 2-6 Unsaturated hydrocarbon group, substituted or unsubstituted C 3-6 Cycloalkyl, glu, SO 3 H、PO 3 H 2 (ii) a The substituent is selected from hydrogen, hydroxyl, nitro, cyano, amino, carboxyl, methylamino, dimethylamino and C 1-6 Alkyl of (C) 1-6 Alkoxy group of (C) 1-6 Acyl group of (1), C 1-6 Acyloxy group of (2) and (C) 1-6 Alkoxyacyl group, C 2-6 Unsaturated hydrocarbon group of (C) 3-6 Cycloalkyl of, C 1-6 Alkylthio, F, cl, br, I, glu, SO 3 H、PO 3 H 2 ；
Glu represents beta-D glucopyranosyl; SO 3 H represents a sulfonyl group; PO (PO) 3 H 2 Represents a phosphoryl group.
2. The viniferin derivative and the pharmaceutically acceptable salts thereof according to claim 1, wherein the compound is represented by the following general formula (II):
Figure FDA0003039367350000012
wherein R is 2 、R 3 、R 4 、R 5 Each independently selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Acyl, substituted or unsubstituted C 2-6 Unsaturated hydrocarbon group, substituted or unsubstituted C 3-6 Cycloalkyl, glu, SO 3 H、PO 3 H 2 (ii) a The substituent is selected from hydrogen, hydroxyl, nitro, cyano, amino, carboxyl, methylamino, dimethylamino and C 1-6 Alkyl of (C) 1-6 Alkoxy group of (1), C 1-6 Acyl group of (1), C 1-6 Acyloxy group of (2) and (C) 1-6 Alcoxyl acyl radical, C 2-6 Unsaturated hydrocarbon group of (C) 3-6 Cycloalkyl of, C 1-6 Alkylthio, F, cl, br, I, glu, SO 3 H、PO 3 H 2 ；
Glu represents beta-D glucopyranosyl; SO (SO) 3 H represents a sulfonyl group; PO (PO) 3 H 2 Represents a phosphoryl group.
3. The viniferin derivative and pharmaceutically acceptable salts thereof as claimed in claim 2, wherein said compound is represented by formula (IIA):
Figure FDA0003039367350000021
wherein R is 3 、R 4 、R 5 Each independently selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Acyl, substituted or unsubstituted C 2-6 Unsaturated hydrocarbon group, substituted or unsubstituted C 3-6 Cycloalkyl, glu, SO 3 H、PO 3 H 2 (ii) a The substituent is selected from hydrogen, hydroxyl, nitro, cyano, amino, carboxyl, methylamino, dimethylamino and C 1-6 Alkyl of (C) 1-6 Alkoxy group of (C) 1-6 Acyl group of (1), C 1-6 Acyloxy group of (2) and (C) 1-6 Alcoxyl acyl radical, C 2-6 Unsaturated hydrocarbon group of (C) 3-6 Cycloalkyl of, C 1-6 Alkylthio, F, cl, br, I, glu, SO 3 H、PO 3 H 2 ；
Glu represents beta-D glucopyranosyl; SO (SO) 3 H represents a sulfonyl group; PO 3 H 2 Represents a phosphoryl group.
4. The derivative of Vitis vinifera as claimed in claim 3, wherein the compound is represented by the general formula (IIAa):
Figure FDA0003039367350000022
wherein R is 4 、R 5 Each independently selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Acyl, substituted or unsubstituted C 2-6 Unsaturated hydrocarbon group, substitutedOr unsubstituted C 3-6 Cycloalkyl, glu, SO 3 H、PO 3 H 2 (ii) a The substituent is selected from hydrogen, hydroxyl, nitro, cyano, amino, carboxyl, methylamino, dimethylamino and C 1-6 Alkyl of (C) 1-6 Alkoxy group of (C) 1-6 Acyl group of (1), C 1-6 Acyloxy group of (2) and (C) 1-6 Alcoxyl acyl radical, C 2-6 Unsaturated hydrocarbon group of (C) 3-6 Cycloalkyl of, C 1-6 Alkylthio, F, cl, br, I, glu, SO 3 H、PO 3 H 2 ；
Glu represents beta-D glucopyranosyl; SO (SO) 3 H represents a sulfonyl group; PO (PO) 3 H 2 Represents a phosphoryl group.
5. The derivative of Vitis vinifera as claimed in claim 3, wherein the compound is represented by the general formula (IIAb):
Figure FDA0003039367350000023
wherein R is 5 Selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Acyl, substituted or unsubstituted C 2-6 Unsaturated hydrocarbon group, substituted or unsubstituted C 3-6 Cycloalkyl, glu, SO 3 H、PO 3 H 2 (ii) a The substituent is selected from hydrogen, hydroxyl, nitro, cyano, amino, carboxyl, methylamino, dimethylamino and C 1-6 Alkyl of (C) 1-6 Alkoxy group of (C) 1-6 Acyl group of (1), C 1-6 Acyloxy group of (2) and (C) 1-6 Alcoxyl acyl radical, C 2-6 Unsaturated hydrocarbon group of (C) 3-6 Cycloalkyl of, C 1-6 Alkylthio, F, cl, br, I, glu, SO 3 H、PO 3 H 2 ；
Glu represents beta-D glucopyranosyl; SO (SO) 3 H represents a sulfonyl group; PO (PO) 3 H 2 Represents a phosphoryl group.
6. The viniferin derivative and pharmaceutically acceptable salts thereof as claimed in claim 3, wherein said compound is represented by the general formula (IIAc):
Figure FDA0003039367350000031
wherein R is 3 、R 5 Independently selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Acyl, substituted or unsubstituted C 2-6 Unsaturated hydrocarbon group, substituted or unsubstituted C 3-6 Cycloalkyl, glu, SO 3 H、PO 3 H 2 (ii) a The substituent is selected from hydrogen, hydroxyl, nitro, cyano, amino, carboxyl, methylamino, dimethylamino and C 1-6 Alkyl of (C) 1-6 Alkoxy group of (1), C 1-6 Acyl group of (1), C 1-6 Acyloxy group of (2) and (C) 1-6 Alcoxyl acyl radical, C 2-6 Unsaturated hydrocarbon group of (C) 3-6 Cycloalkyl of (C) 1-6 Alkylthio, F, cl, br, I, glu, SO 3 H、PO 3 H 2 ；
Glu represents beta-D glucopyranosyl; SO 3 H represents a sulfonyl group; PO (PO) 3 H 2 Represents a phosphoryl group.
7. The derivative of Vitis vinifera as claimed in claim 3, wherein the compound is represented by the general formula (IIAd):
Figure FDA0003039367350000032
wherein R is 3 Selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Acyl, substituted or unsubstituted C 2-6 Unsaturated hydrocarbon group, substituted or unsubstituted C 3-6 Cycloalkyl, glu, SO 3 H、PO 3 H 2 (ii) a The substituent is selected from hydrogen, hydroxyl, nitro, cyano, amino, carboxyl and methylAmino, dimethylamino, C 1-6 Alkyl of (C) 1-6 Alkoxy group of (1), C 1-6 Acyl group of (1), C 1-6 Acyloxy group of (2) and (C) 1-6 Alcoxyl acyl radical, C 2-6 Unsaturated hydrocarbon group of (C) 3-6 Cycloalkyl of, C 1-6 Alkylthio, F, cl, br, I, glu, SO 3 H、PO 3 H 2 ；
Glu represents beta-D glucopyranosyl; SO (SO) 3 H represents a sulfonyl group; PO (PO) 3 H 2 Represents a phosphoryl group.
8. The viniferin derivative and pharmaceutically acceptable salts thereof as claimed in claim 2, wherein said compound is represented by the general formula (IIB):
Figure FDA0003039367350000041
wherein R is 2 、R 3 、R 5 Each independently selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Acyl, substituted or unsubstituted C 2-6 Unsaturated hydrocarbon group, substituted or unsubstituted C 3-6 Cycloalkyl, glu, SO 3 H、PO 3 H 2 (ii) a The substituent is selected from hydrogen, hydroxyl, nitro, cyano, amino, carboxyl, methylamino, dimethylamino and C 1-6 Alkyl of (C) 1-6 Alkoxy group of (C) 1-6 Acyl group of (1), C 1-6 Acyloxy group of (2) and (C) 1-6 Alcoxyl acyl radical, C 2-6 Unsaturated hydrocarbon group of (C) 3-6 Cycloalkyl of, C 1-6 Alkylthio, F, cl, br, I, glu, SO 3 H、PO 3 H 2 ；
Glu represents beta-D glucopyranosyl; SO (SO) 3 H represents a sulfonyl group; PO (PO) 3 H 2 Represents a phosphoryl group.
9. The derivative of Vitis vinifera as claimed in claim 2, wherein the compound is represented by the general formula (IIBa):
Figure FDA0003039367350000042
wherein R is 2 、R 3 Each independently selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Acyl, substituted or unsubstituted C 2-6 Unsaturated hydrocarbon group, substituted or unsubstituted C 3-6 Cycloalkyl, glu, SO 3 H、PO 3 H 2 (ii) a The substituent is selected from hydrogen, hydroxyl, nitro, cyano, amino, carboxyl, methylamino, dimethylamino and C 1-6 Alkyl of (C) 1-6 Alkoxy group of (C) 1-6 Acyl group of (1), C 1-6 Acyloxy group of (2) and (C) 1-6 Alcoxyl acyl radical, C 2-6 Unsaturated hydrocarbon group of (C) 3-6 Cycloalkyl of (C) 1-6 Alkylthio, F, cl, br, I, glu, SO 3 H、PO 3 H 2 ；
Glu represents beta-D glucopyranosyl; SO 3 H represents a sulfonyl group; PO (PO) 3 H 2 Represents a phosphoryl group.
10. The viniferin derivative and pharmaceutically acceptable salts thereof as claimed in claim 1, wherein said compound is represented by the general formula (III):
Figure FDA0003039367350000043
wherein R is 1 、R 3 、R 4 、R 5 Each independently selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Acyl, substituted or unsubstituted C 2-6 Unsaturated hydrocarbon group, substituted or unsubstituted C 3-6 Cycloalkyl, glu, SO 3 H、PO 3 H 2 (ii) a The substituent is selected from hydrogen, hydroxyl, nitro, cyano, amino, carboxyl, methylamino, dimethylamino and C 1-6 Alkyl group of (A) or (B),C 1-6 Alkoxy group of (C) 1-6 Acyl group of (1), C 1-6 Acyloxy group of (2) and (C) 1-6 Alcoxyl acyl radical, C 2-6 Unsaturated hydrocarbon group of (C) 3-6 Cycloalkyl of, C 1-6 Alkylthio, F, cl, br, I, glu, SO 3 H、PO 3 H 2 ；
Glu represents beta-D glucopyranosyl; SO (SO) 3 H represents a sulfonyl group; PO (PO) 3 H 2 Represents a phosphoryl group.
11. The viniferin derivative and pharmaceutically acceptable salts thereof as claimed in claim 10, wherein said compound is represented by the general formula (IIIA):
Figure FDA0003039367350000051
wherein R is 1 、R 4 、R 5 Each independently selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Acyl, substituted or unsubstituted C 2-6 Unsaturated hydrocarbon group, substituted or unsubstituted C 3-6 Cycloalkyl, glu, SO 3 H、PO 3 H 2 (ii) a The substituent is selected from hydrogen, hydroxyl, nitro, cyano, amino, carboxyl, methylamino, dimethylamino and C 1-6 Alkyl of (C) 1-6 Alkoxy group of (C) 1-6 Acyl group of (1), C 1-6 Acyloxy group of (2), C 1-6 Alcoxyl acyl radical, C 2-6 Unsaturated hydrocarbon group of (C) 3-6 Cycloalkyl of, C 1-6 Alkylthio, F, cl, br, I, glu, SO 3 H、PO 3 H 2 ；
Glu represents beta-D glucopyranosyl; SO (SO) 3 H represents a sulfonyl group; PO (PO) 3 H 2 Represents a phosphoryl group.
12. The viniferin derivative and pharmaceutically acceptable salts thereof as claimed in claim 11, wherein said compound is represented by the general formula (IIIAa):
Figure FDA0003039367350000052
wherein R is 1 、R 5 Each independently selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Acyl, substituted or unsubstituted C 2-6 Unsaturated hydrocarbon group, substituted or unsubstituted C 3-6 Cycloalkyl, glu, SO 3 H、PO 3 H 2 (ii) a The substituent is selected from hydrogen, hydroxyl, nitro, cyano, amino, carboxyl, methylamino, dimethylamino and C 1-6 Alkyl of (C) 1-6 Alkoxy group of (C) 1-6 Acyl group of (1), C 1-6 Acyloxy group of (2) and (C) 1-6 Alcoxyl acyl radical, C 2-6 Unsaturated hydrocarbon group of (C) 3-6 Cycloalkyl of, C 1-6 Alkylthio, F, cl, br, I, glu, SO 3 H、PO 3 H 2 ；
Glu represents beta-D glucopyranosyl; SO (SO) 3 H represents a sulfonyl group; PO (PO) 3 H 2 Represents a phosphoryl group.
13. The viniferin derivative and pharmaceutically acceptable salts thereof as claimed in claim 11, wherein the compound is represented by the following general formula (IIIAb):
Figure FDA0003039367350000061
wherein R is 1 Selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Acyl, substituted or unsubstituted C 2-6 Unsaturated hydrocarbon group, substituted or unsubstituted C 3-6 Cycloalkyl, glu, SO 3 H、PO 3 H 2 (ii) a The substituent is selected from hydrogen, hydroxyl, nitro, cyano, amino, carboxyl, methylamino, dimethylamino and C 1-6 Alkyl of (C) 1-6 Alkoxy group of (C) 1-6 Acyl group of (1), C 1-6 Acyloxy group of (2) and (C) 1-6 Alcoxyl acyl radical, C 2-6 Unsaturated hydrocarbon group of (C) 3-6 Cycloalkyl of, C 1-6 Alkylthio, F, cl, br, I, glu, SO 3 H、PO 3 H 2 ；
Glu represents beta-D glucopyranosyl; SO (SO) 3 H represents a sulfonyl group; PO 3 H 2 Represents a phosphoryl group.
14. The viniferin derivative and pharmaceutically acceptable salts thereof according to claim 10, wherein the compound is represented by formula (IIIB):
Figure FDA0003039367350000062
wherein R is 1 、R 3 、R 5 Each independently selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Acyl, substituted or unsubstituted C 2-6 Unsaturated hydrocarbon group, substituted or unsubstituted C 3-6 Cycloalkyl, glu, SO 3 H、PO 3 H 2 (ii) a The substituent is selected from hydrogen, hydroxyl, nitro, cyano, amino, carboxyl, methylamino, dimethylamino and C 1-6 Alkyl of (C) 1-6 Alkoxy group of (C) 1-6 Acyl group of (1), C 1-6 Acyloxy group of (2) and (C) 1-6 Alcoxyl acyl radical, C 2-6 Unsaturated hydrocarbon group of (C) 3-6 Cycloalkyl of, C 1-6 Alkylthio, F, cl, br, I, glu, SO 3 H、PO 3 H 2 ；
Glu represents beta-D glucopyranosyl; SO (SO) 3 H represents a sulfonyl group; PO (PO) 3 H 2 Represents a phosphoryl group.
15. The viniferin derivative and pharmaceutically acceptable salts thereof as claimed in claim 14, wherein said compound is represented by the general formula (IIIBa):
Figure FDA0003039367350000063
wherein R is 1 、R 3 Each independently selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Acyl, substituted or unsubstituted C 2-6 Unsaturated hydrocarbon group, substituted or unsubstituted C 3-6 Cycloalkyl, glu, SO 3 H、PO 3 H 2 (ii) a The substituent is selected from hydrogen, hydroxyl, nitro, cyano, amino, carboxyl, methylamino, dimethylamino and C 1-6 Alkyl of (C) 1-6 Alkoxy group of (C) 1-6 Acyl group of (1), C 1-6 Acyloxy group of (2) and (C) 1-6 Alcoxyl acyl radical, C 2-6 Unsaturated hydrocarbon group of (C) 3-6 Cycloalkyl of, C 1-6 Alkylthio, F, cl, br, I, glu, SO 3 H、PO 3 H 2 ；
Glu represents beta-D glucopyranosyl; SO (SO) 3 H represents a sulfonyl group; PO 3 H 2 Represents a phosphoryl group.
16. The viniferin derivative and pharmaceutically acceptable salts thereof as claimed in claim 1, wherein said compound is represented by the general formula (IV):
Figure FDA0003039367350000071
wherein R is 1 、R 2 、R 3 、R 5 Each independently selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Acyl, substituted or unsubstituted C 2-6 Unsaturated hydrocarbon group, substituted or unsubstituted C 3-6 Cycloalkyl, glu, SO 3 H、PO 3 H 2 (ii) a The substituent is selected from hydrogen, hydroxyl, nitro, cyano, amino, carboxyl, methylamino, dimethylamino and C 1-6 Alkyl of (C) 1-6 Alkoxy group of (1), C 1-6 Acyl group of (1), C 1-6 Acyloxy group of (2) and (C) 1-6 Alkoxyacyl group, C 2-6 Of unsaturated hydrocarbon group、C 3-6 Cycloalkyl of, C 1-6 Alkylthio, F, cl, br, I, glu, SO 3 H、PO 3 H 2 ；
Glu represents beta-D glucopyranosyl; SO (SO) 3 H represents a sulfonyl group; PO (PO) 3 H 2 Represents a phosphoryl group.
17. The viniferin derivative and pharmaceutically acceptable salts thereof as claimed in claim 16, wherein said compound is represented by the general formula (IVA):
Figure FDA0003039367350000072
wherein R is 1 、R 2 、R 3 Each independently selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Acyl, substituted or unsubstituted C 2-6 Unsaturated hydrocarbon group, substituted or unsubstituted C 3-6 Cycloalkyl, glu, SO 3 H、PO 3 H 2 (ii) a The substituent is selected from hydrogen, hydroxyl, nitro, cyano, amino, carboxyl, methylamino, dimethylamino and C 1-6 Alkyl of (C) 1-6 Alkoxy group of (1), C 1-6 Acyl group of (1), C 1-6 Acyloxy group of (2) and (C) 1-6 Alcoxyl acyl radical, C 2-6 Unsaturated hydrocarbon group of (C) 3-6 Cycloalkyl of, C 1-6 Alkylthio, F, cl, br, I, glu, SO 3 H、PO 3 H 2 ；
Glu represents beta-D glucopyranosyl; SO (SO) 3 H represents a sulfonyl group; PO 3 H 2 Represents a phosphoryl group.
18. The viniferin derivative according to any one of claims 1 to 17, wherein C is C, and pharmaceutically acceptable salts thereof 1-6 The alkyl group of (1) includes methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, tert-pentyl, cyclopentyl, n-hexyl, cyclohexyl, cyclopentylmethyl; c 1-6 Acyl package ofIncluding formyl, acetyl, propionyl, isopropylacyl, butyryl, tert-butylacyl, n-pentylacyl, isopentyloyl, n-hexylacyl, cyclohexylacyl, cyclopentylmethyl acyl; c 2-6 The unsaturated hydrocarbon group of (a) includes vinyl, ethynyl, propenyl, isopropenyl, propynyl, isopropynyl, butenyl, isopropenyl, 1,3-butadienyl, pentenyl, isopentenyl, isoprenyl, cyclopentenyl, cyclopentadienyl, hexenyl, cyclohexenyl, cyclohexadienyl, phenyl; c 3-6 The cycloalkyl group of (2) includes a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group.
19. The viniferin derivative and pharmaceutically acceptable salts thereof as claimed in claim 1, wherein said compound is selected from the group consisting of:
Figure FDA0003039367350000081
Figure FDA0003039367350000091
20. a pharmaceutical composition comprising an effective amount of a viniferin derivative and a pharmaceutically acceptable salt thereof according to any one of claims 1-19 and a pharmaceutically acceptable carrier or excipient.
21. The pharmaceutical composition of claim 20, wherein said pharmaceutical composition is selected from the group consisting of tablets, capsules, pills, and injections.
22. The pharmaceutical composition of claim 20, wherein said pharmaceutical composition is selected from the group consisting of a sustained release formulation, a controlled release formulation, and a variety of microparticle delivery systems.
23. Use of a vitin derivative as claimed in any one of claims 1 to 19 and pharmaceutically acceptable salts thereof in the manufacture of an NO generation inhibitor.
24. Use of the viniferin derivative of any one of claims 1 to 19 and pharmaceutically acceptable salts thereof for the manufacture of a medicament for the treatment, prevention or co-treatment of various inflammatory and immune-related diseases.
25. The use according to claim 24, wherein the inflammation and inflammatory immune-related disorders comprise: rheumatoid arthritis, osteoarthritis, rheumatoid arthritis, gouty arthritis, lupus erythematosus syndrome, bronchitis, bursitis, tenosynovitis, psoriasis, eczema, burns, dermatitis, inflammatory bowel disease, crohn's disease, gastritis, irritable bowel syndrome, ulcerative colitis, multiple sclerosis, autoimmune encephalomyelitis, colorectal cancer, nodular arteritis, thyroiditis, wind-heat-dampness, gingivitis, periodontitis, oral ulcers, nephritis, swelling following insult, myocardial ischemia, various infectious pneumonia, physicochemical and allergic pneumonia, chronic obstructive pulmonary disease, asthma, spastic anal pain and rectal fissure, hepatocystitis, cholangitis, primary biliary cirrhosis and cholecystitis.
CN202110452611.XA 2021-04-26 2021-04-26 Grape extract derivative, its preparation method, pharmaceutical composition and use Active CN115246802B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202110452611.XA CN115246802B (en) 2021-04-26 2021-04-26 Grape extract derivative, its preparation method, pharmaceutical composition and use

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202110452611.XA CN115246802B (en) 2021-04-26 2021-04-26 Grape extract derivative, its preparation method, pharmaceutical composition and use

Publications (2)

Publication Number Publication Date
CN115246802A true CN115246802A (en) 2022-10-28
CN115246802B CN115246802B (en) 2024-03-26

Family

ID=83695969

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202110452611.XA Active CN115246802B (en) 2021-04-26 2021-04-26 Grape extract derivative, its preparation method, pharmaceutical composition and use

Country Status (1)

Country Link
CN (1) CN115246802B (en)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1566054A (en) * 2003-06-27 2005-01-19 中国医学科学院药物研究所 Resveratrol oligo cattail compounds, its manufacturing process, pharmaceutical combination and uses thereof
CN102180846A (en) * 2010-06-22 2011-09-14 上海交通大学 Resveratrol dimer derivative and preparation and application methods thereof
CN109893522A (en) * 2017-12-08 2019-06-18 中国医学科学院药物研究所 Amurensin H derivative is treating and preventing the application in Chronic Obstructive Pulmonary Disease
CN110433153A (en) * 2018-05-03 2019-11-12 中国医学科学院药物研究所 A kind of Amurensin H derivative is treating and preventing the application in liver related disease
CN110433152A (en) * 2018-05-03 2019-11-12 中国医学科学院药物研究所 Application of the plain derivative of a kind of grapevine penta in preparation treatment liver related disease drug

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1566054A (en) * 2003-06-27 2005-01-19 中国医学科学院药物研究所 Resveratrol oligo cattail compounds, its manufacturing process, pharmaceutical combination and uses thereof
CN102180846A (en) * 2010-06-22 2011-09-14 上海交通大学 Resveratrol dimer derivative and preparation and application methods thereof
CN109893522A (en) * 2017-12-08 2019-06-18 中国医学科学院药物研究所 Amurensin H derivative is treating and preventing the application in Chronic Obstructive Pulmonary Disease
CN110433153A (en) * 2018-05-03 2019-11-12 中国医学科学院药物研究所 A kind of Amurensin H derivative is treating and preventing the application in liver related disease
CN110433152A (en) * 2018-05-03 2019-11-12 中国医学科学院药物研究所 Application of the plain derivative of a kind of grapevine penta in preparation treatment liver related disease drug

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
BIN-HAO TENG等: "Total synthesis of the active resveratrol dimer dehydro-δ-viniferin", JOURNAL OF ASIAN NATURAL PRODUCTS RESEARCH, vol. 22, pages 947 - 955 *

Also Published As

Publication number Publication date
CN115246802B (en) 2024-03-26

Similar Documents

Publication Publication Date Title
CN109897021B (en) Grapevine pentalin derivative, preparation method thereof, pharmaceutical composition and application
CN109134586B (en) Tripterine derivative and application thereof
TWI648257B (en) Compounds from antrodia camphorata, method for preparing the same and use thereof
CN112876495A (en) Parthenolide derivative, pharmaceutical composition thereof, preparation method and application thereof
CN113336765B (en) Curcumenol esterified product, preparation method and application of curcumenol esterified product in medicine for treating colorectal cancer
CN103627772A (en) Preparation method of triptolide derivatives and products and application of triptolide derivatives
CN115246802B (en) Grape extract derivative, its preparation method, pharmaceutical composition and use
CN105130884B (en) 5 methyl 2 (1H) Pyridione derivatives and its production and use
CN114075102B (en) 2, 3-diaryl indene derivative, preparation method, pharmaceutical composition and application thereof
JP2015523349A (en) Acylated derivatives of porphyrin I, methods for their preparation and use
CN112745288B (en) Beta-alkoxy alcohol dibenzoxanthene compound and application thereof
CN113061124B (en) Sesquiterpene dimer compound, and preparation method, application and pharmaceutical composition thereof
CN110563688B (en) Benzopyran compounds with anti-complement activity and application thereof
CN113979851B (en) 2' -halogenated chalcone derivative, preparation method, pharmaceutical composition and application thereof
CN109232710B (en) Preparation method of special iso-steroid alkaloid and derivatives thereof
Liu et al. Dihydromyricetin from Ampelopsis grossedentata and its derivatives: Structural characterization and anti-hepatocellular carcinoma activity
CN110498755B (en) Dihydrophenanthrene derivative and preparation method and application thereof
CN106822088B (en) Application of diene iridoid compound in preparation of anti-cancer drugs
CN101590035B (en) Application of dehydrogenated silybin in preparing anti-lung-cancer medicament
CN107281180B (en) Application of 8-alkyl berberine salt in preparing medicine for preventing and treating lung cancer
KR101554562B1 (en) Novel macrosphelide derivatives, preparation method thereof and pharmaceutical composition for the prevention or treatment of cancer disease containing the same as an active ingredient
CN104334571B (en) The acylated derivatives of Rhizoma Paridis saponin I, and its preparation method and application
CN114874135B (en) Small molecular compound for resisting breast cancer and preparation method thereof
CN114426538B (en) Berberine canagliflozin derivative and preparation method and application thereof
CN117105763A (en) Halogenated chalcone heterocyclic derivative, preparation method, pharmaceutical composition and application thereof

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant