CN115246802B - Grape extract derivative, its preparation method, pharmaceutical composition and use - Google Patents

Grape extract derivative, its preparation method, pharmaceutical composition and use Download PDF

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CN115246802B
CN115246802B CN202110452611.XA CN202110452611A CN115246802B CN 115246802 B CN115246802 B CN 115246802B CN 202110452611 A CN202110452611 A CN 202110452611A CN 115246802 B CN115246802 B CN 115246802B
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CN115246802A (en
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姚春所
林明宝
侯琦
范旖瑶
苏福宝
陈英
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    • 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

Abstract

The invention belongs to the field of biological medicine, and discloses a grape extract derivative, a preparation method, a pharmaceutical composition and application thereof. In particular to a 2, 3-diaryl-5-styryl benzofuran type grape derivative shown in a general formula (I) and a pharmaceutically acceptable salt thereof, a pharmaceutical composition of the compound and application of the compound in preparing a medicament for preventing or treating or assisting in treating inflammatory immune related diseases.

Description

Grape extract derivative, its preparation method, pharmaceutical composition and use
Technical Field
The invention relates to the field of biological medicine, in particular to 2, 3-diaryl-5-styryl benzofuran derivatives or pharmaceutically 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 development of new drugs based on active natural products is one of the important ways of modern drug development. The natural product has the characteristics of wide sources, low toxicity, small side effect and the like. The natural lead compound with obvious activity is found from traditional Chinese herbal medicines, and through structural modification, in-vivo and in-vitro activity test and comprehensive evaluation of the pharmacy of a combination system, a safe and efficient candidate compound is searched from the natural lead compound to serve as a clinically useful proto-drug, so that the natural lead compound is an important direction of drug research and development. The oligomeric stilbene compounds are natural products which are polymerized by stilbene monomers in different modes, have complex structures and various biological activities, and are mainly distributed in plants of grape, gnetaceae, borneol-aromataceae, leguminous, sedge, paeoniaceae and the like. The polymerization modes and polymerization degrees of the stilbene monomers with different structures are different, the formed oligomeric stilbene natural products are rich and various in structure types, and the oligomeric stilbene natural products are suitable for the various structure types, and the oligomeric stilbene compounds which are discovered at present also show various biological activities including activities in aspects of antioxidation, anti-inflammatory, antibacterial, anti-tumor, antiviral, anti-Alzheimer disease 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 activity are separated and identified, so that the research of the oligomeric stilbene compounds has been greatly developed in the aspects of structure and activity. Especially in the aspect of biological activity research, more complex compounds with different activities are found, and 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 discovered new activity shows that the compounds have great potential in the aspect of drug development and utilization, so that the oligomeric stilbene compounds are more widely concerned, and the oligomeric stilbene compounds are developed into one of the hot spots of natural product research at present. Particularly, the dimer compound has activity generally stronger than that of the monomer stilbene compound, has molecular weight between 400 and 600, and has great potential for developing medicaments. In recent years, the total synthesis of the stilbene dimer compound is one of the hot points of research, and has greatly progressed, and the main dimer structure skeleton, including the coumarone structure, the indene structure and the diaryl [3.2.1] octane structure, has all progressed in a breakthrough manner, so that the research and development of the dimer compound are guaranteed. However, in addition to isolation and identification of natural products, systematic structural modification and structure-activity relationship studies on active oligomeric compounds (especially dimers) remain a completely new field of research, and so far, few related studies have been reported in the literature. Benzofuran-type and benzodihydrofuran-type stilbene dimer derivatives are the most abundant natural products of dimer-type compounds, and are also the most active ones. The grape extract derivative (dehydo-delta-viniferin) having the 2, 3-diaryl-5-styrylbenzofuran structure is a natural product analogue synthesized by dehydrogenation of the natural product delta-viniferin, and so far, there has been little research on its inflammation-inhibiting activity. The research carries out systematic derivatization research, anti-inflammatory activity test and structure-activity relation research on 2, 3-diaryl-5-styryl benzofuran type grape essence (dehydro-delta-viniferin), a series of new structure grape essence derivatives with obvious inhibiting activity on inflammatory factor NO are obtained, and the inflammation inhibiting activity of the synthesized compound is not reported in the literature 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 a 2, 3-diaryl-5-styryl benzofuran type grape extract derivative with a novel structure, and a preparation method, a pharmaceutical composition and application thereof.
The first aspect of the present invention provides a 2, 3-diaryl-5-styrylbenzofuran type compound and its derivative represented by general formulae (I), (II) (IIA), (IIAa), (IIAb), (IIAc), (IIAd), (IIB), (IIBa), (III), (IIIA), (IIIAa), (IIIAb), (IIIB), (IIIBa), (IV) and (IVA).
Specifically, the invention relates to a 2, 3-diaryl-5-styryl benzofuran type grape derivative shown in a general formula (I) and pharmaceutically acceptable salts thereof:
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 of (C) 3 H、PO 3 H 2 The method comprises the steps of carrying out a first treatment on the surface of the The substituents are selected from hydrogen, hydroxy, nitro, cyano, amino, carboxyl, methylamino, dimethylamino, C 1-6 Alkyl, C of (2) 1-6 Alkoxy, C 1-6 Acyl group, C 1-6 Acyl group C of (2) 1-6 Alkoxyacyl, C 2-6 Unsaturated hydrocarbon group, C 3-6 Cycloalkyl, C 1-6 Alkylthio of F, cl, br, I, glu, SO) 3 H、PO 3 H 2 ；
Glu represents a beta-D glucopyranosyl group; SO (SO) 3 H represents a sulfonyl group; PO (Positive oxide) 3 H 2 Represents a phosphoryl group.
Preferred grape derivatives of formula (I) according to the present invention include, but are not limited to, compounds of formula (II), and pharmaceutically acceptable salts thereof, wherein the compounds are represented by formula (II):
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 of (C) 3 H、PO 3 H 2 The method comprises the steps of carrying out a first treatment on the surface of the The substituents are selected from hydrogen, hydroxy, nitro, cyano, amino, carboxyl, methylamino, dimethylamino, C 1-6 Alkyl, C of (2) 1-6 Alkoxy, C 1-6 Acyl group, C 1-6 Acyl group C of (2) 1-6 Alkoxyacyl, C 2-6 Unsaturated hydrocarbon group, C 3-6 Cycloalkyl, C 1-6 Alkylthio of F, cl, br, I, glu, SO) 3 H、PO 3 H 2 ；
Glu represents a beta-D glucopyranosyl group; SO (SO) 3 H represents a sulfonyl group; PO (Positive oxide) 3 H 2 Represents a phosphoryl group.
Preferred grape derivatives of formula (II) according to the present invention include, but are not limited to, compounds of formula (IIA), and pharmaceutically acceptable salts thereof, wherein the compounds are represented by formula (IIA):
wherein,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 of (C) 3 H、PO 3 H 2 The method comprises the steps of carrying out a first treatment on the surface of the The substituents are selected from hydrogen, hydroxy, nitro, cyano, amino, carboxyl, methylamino, dimethylamino, C 1-6 Alkyl, C of (2) 1-6 Alkoxy, C 1-6 Acyl group, C 1-6 Acyl group C of (2) 1-6 Alkoxyacyl, C 2-6 Unsaturated hydrocarbon group, C 3-6 Cycloalkyl, C 1-6 Alkylthio of F, cl, br, I, glu, SO) 3 H、PO 3 H 2 ；
Glu represents a beta-D glucopyranosyl group; SO (SO) 3 H represents a sulfonyl group; PO (Positive oxide) 3 H 2 Represents a phosphoryl group.
Preferred grape 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 the compounds are represented by formula (IIAa):
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 of (C) 3 H、PO 3 H 2 The method comprises the steps of carrying out a first treatment on the surface of the The substituents are selected from hydrogen, hydroxy, nitro, cyano, amino, carboxyl, methylamino, dimethylamino, C 1-6 Alkyl, C of (2) 1-6 Alkoxy, C 1-6 Acyl group, C 1-6 Acyl group C of (2) 1-6 Alkoxyacyl, C 2-6 Unsaturated hydrocarbon group, C 3-6 Cycloalkyl, C 1-6 Alkylthio of F, cl, br, I, glu, SO) 3 H、PO 3 H 2 ；
Glu represents a beta-D glucopyranosyl group; SO (SO) 3 H represents a sulfonyl group; PO (Positive oxide) 3 H 2 Represents a phosphoryl group.
Preferred grape 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):
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 of (C) 3 H、PO 3 H 2 The method comprises the steps of carrying out a first treatment on the surface of the The substituents are selected from hydrogen, hydroxy, nitro, cyano, amino, carboxyl, methylamino, dimethylamino, C 1-6 Alkyl, C of (2) 1-6 Alkoxy, C 1-6 Acyl group, C 1-6 Acyl group C of (2) 1-6 Alkoxyacyl, C 2-6 Unsaturated hydrocarbon group, C 3-6 Cycloalkyl, C 1-6 Alkylthio of F, cl, br, I, glu, SO) 3 H、PO 3 H 2 ；
Glu represents a beta-D glucopyranosyl group; SO (SO) 3 H represents a sulfonyl group; PO (Positive oxide) 3 H 2 Represents a phosphoryl group.
Preferred grape 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):
wherein R is 3 、R 5 Independently selected from hydrogen, substituted or unsubstitutedSubstituted 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 of (C) 3 H、PO 3 H 2 The method comprises the steps of carrying out a first treatment on the surface of the The substituents are selected from hydrogen, hydroxy, nitro, cyano, amino, carboxyl, methylamino, dimethylamino, C 1-6 Alkyl, C of (2) 1-6 Alkoxy, C 1-6 Acyl group, C 1-6 Acyl group C of (2) 1-6 Alkoxyacyl, C 2-6 Unsaturated hydrocarbon group, C 3-6 Cycloalkyl, C 1-6 Alkylthio of F, cl, br, I, glu, SO) 3 H、PO 3 H 2 。
Glu represents a beta-D glucopyranosyl group; SO (SO) 3 H represents a sulfonyl group; PO (Positive oxide) 3 H 2 Represents a phosphoryl group;
preferred grape derivatives of formula (IIA) according to the present invention include, but are not limited to, compounds of formula (IIAd), and pharmaceutically acceptable salts thereof, wherein the compounds are represented by formula (IIAd):
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 of (C) 3 H、PO 3 H 2 The method comprises the steps of carrying out a first treatment on the surface of the The substituents are selected from hydrogen, hydroxy, nitro, cyano, amino, carboxyl, methylamino, dimethylamino, C 1-6 Alkyl, C of (2) 1-6 Alkoxy, C 1-6 Acyl group, C 1-6 Acyl group C of (2) 1-6 Alkoxyacyl, C 2-6 Unsaturated hydrocarbon group, C 3-6 Cycloalkyl, C 1-6 Alkylthio of F, cl, br, I, glu, SO) 3 H、PO 3 H 2 ；
Glu represents a beta-D glucopyranosyl group; SO (SO) 3 H represents a sulfonyl group; PO (Positive oxide) 3 H 2 Represents a phosphoryl group.
Preferred grape derivatives of formula (II) according to the present invention include, but are not limited to, compounds of formula (IIB), and pharmaceutically acceptable salts thereof, wherein the compounds are represented by formula (IIB):
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 of (C) 3 H、PO 3 H 2 The method comprises the steps of carrying out a first treatment on the surface of the The substituents are selected from hydrogen, hydroxy, nitro, cyano, amino, carboxyl, methylamino, dimethylamino, C 1-6 Alkyl, C of (2) 1-6 Alkoxy, C 1-6 Acyl group, C 1-6 Acyl group C of (2) 1-6 Alkoxyacyl, C 2-6 Unsaturated hydrocarbon group, C 3-6 Cycloalkyl, C 1-6 Alkylthio of F, cl, br, I, glu, SO) 3 H、PO 3 H 2 ；
Glu represents a beta-D glucopyranosyl group; SO (SO) 3 H represents a sulfonyl group; PO (Positive oxide) 3 H 2 Represents a phosphoryl group.
Preferred grape 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):
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 of (C) 3 H、PO 3 H 2 The method comprises the steps of carrying out a first treatment on the surface of the The substituents are selected from hydrogen, hydroxy, nitro, cyano, amino, carboxyl, methylamino, dimethylamino, C 1-6 Alkyl, C of (2) 1-6 Alkoxy, C 1-6 Acyl group, C 1-6 Acyl group C of (2) 1-6 Alkoxyacyl, C 2-6 Unsaturated hydrocarbon group, C 3-6 Cycloalkyl, C 1-6 Alkylthio of F, cl, br, I, glu, SO) 3 H、PO 3 H 2 ；
Glu represents a beta-D glucopyranosyl group; SO (SO) 3 H represents a sulfonyl group; PO (Positive oxide) 3 H 2 Represents a phosphoryl group.
Preferred grape derivatives of formula (I) according to the present invention include, but are not limited to, compounds of formula (III), and pharmaceutically acceptable salts thereof, wherein the compounds are represented by formula (III):
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 of (C) 3 H、PO 3 H 2 The method comprises the steps of carrying out a first treatment on the surface of the The substituents are selected from hydrogen, hydroxy, nitro, cyano, amino, carboxyl, methylamino, dimethylamino, C 1-6 Alkyl, C of (2) 1-6 Alkoxy, C 1-6 Acyl group, C 1-6 Acyl group C of (2) 1-6 Alkoxyacyl, C 2-6 Unsaturated hydrocarbon group, C 3-6 Cycloalkyl, C 1-6 Alkylthio of F, cl, br, I, glu, SO) 3 H、PO 3 H 2 ；
Glu represents a beta-D glucopyranosyl group; SO (SO) 3 H represents a sulfonyl group; PO (Positive oxide) 3 H 2 Represents a phosphoryl group.
Preferred grape derivatives of formula (III) according to the present invention include, but are not limited to, compounds of formula (IIIA), and pharmaceutically acceptable salts thereof, wherein the compounds are represented by formula (IIIA):
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 of (C) 3 H、PO 3 H 2 The method comprises the steps of carrying out a first treatment on the surface of the The substituents are selected from hydrogen, hydroxy, nitro, cyano, amino, carboxyl, methylamino, dimethylamino, C 1-6 Alkyl, C of (2) 1-6 Alkoxy, C 1-6 Acyl group, C 1-6 Acyl group C of (2) 1-6 Alkoxyacyl, C 2-6 Unsaturated hydrocarbon group, C 3-6 Cycloalkyl, C 1-6 Alkylthio of F, cl, br, I, glu, SO) 3 H、PO 3 H 2 ；
Glu represents a beta-D glucopyranosyl group; SO (SO) 3 H represents a sulfonyl group; PO (Positive oxide) 3 H 2 Represents a phosphoryl group.
Preferred grape derivatives of formula (IIIA) according to the present invention include, but are not limited to, compounds of formula (IIIAa), and pharmaceutically acceptable salts thereof, wherein the compounds are represented by formula (IIIAa):
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 of (C) 3 H、PO 3 H 2 The method comprises the steps of carrying out a first treatment on the surface of the The substituents are selected from hydrogen, hydroxy, nitro, cyano, amino, carboxyl, methylamino, dimethylamino, C 1-6 Alkyl, C of (2) 1-6 Alkoxy, C 1-6 Acyl group, C 1-6 Acyl group C of (2) 1-6 Alkoxyacyl, C 2-6 Unsaturated hydrocarbon group, C 3-6 Cycloalkyl, C 1-6 Alkylthio of F, cl, br, I, glu, SO) 3 H、PO 3 H 2 ；
Glu represents a beta-D glucopyranosyl group; SO (SO) 3 H represents a sulfonyl group; PO (Positive oxide) 3 H 2 Represents a phosphoryl group.
Preferred grape derivatives of formula (IIIA) according to the present invention include, but are not limited to, compounds of formula (IIIAb), and pharmaceutically acceptable salts thereof, wherein the compounds are represented by formula (IIIAb):
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 of (C) 3 H、PO 3 H 2 The method comprises the steps of carrying out a first treatment on the surface of the The substituents are selected from hydrogen, hydroxy, nitro, cyano, amino, carboxyl, methylamino, dimethylamino, C 1-6 Alkyl, C of (2) 1-6 Alkoxy, C 1-6 Acyl group, C 1-6 Acyl group C of (2) 1-6 Alkoxyacyl, C 2-6 Unsaturated hydrocarbon group, C 3-6 Cycloalkyl, C 1-6 Alkylthio of F, cl, br, I, glu, SO) 3 H、PO 3 H 2 ；
Glu represents a beta-D glucopyranosyl group; SO (SO) 3 H represents a sulfonyl group; PO (Positive oxide) 3 H 2 Representation ofA phosphoryl group.
Preferred grape derivatives of formula (III) according to the present invention include, but are not limited to, compounds of formula (IIIB), and pharmaceutically acceptable salts thereof, wherein the compounds are represented by formula (IIIB):
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 of (C) 3 H、PO 3 H 2 The method comprises the steps of carrying out a first treatment on the surface of the The substituents are selected from hydrogen, hydroxy, nitro, cyano, amino, carboxyl, methylamino, dimethylamino, C 1-6 Alkyl, C of (2) 1-6 Alkoxy, C 1-6 Acyl group, C 1-6 Acyl group C of (2) 1-6 Alkoxyacyl, C 2-6 Unsaturated hydrocarbon group, C 3-6 Cycloalkyl, C 1-6 Alkylthio of F, cl, br, I, glu, SO) 3 H、PO 3 H 2 ；
Glu represents a beta-D glucopyranosyl group; SO (SO) 3 H represents a sulfonyl group; PO (Positive oxide) 3 H 2 Represents a phosphoryl group.
Preferred grape derivatives of formula (IIIB) according to the present invention include, but are not limited to, compounds of formula (IIIBa), and pharmaceutically acceptable salts thereof, wherein the compounds are represented by formula (IIIBa):
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 of (C) 3 H、PO 3 H 2 The method comprises the steps of carrying out a first treatment on the surface of the The substituents are selected from hydrogen, hydroxy, nitro, cyano, amino, carboxyl, methylamino, dimethylamino, C 1-6 Alkyl, C of (2) 1-6 Alkoxy, C 1-6 Acyl group, C 1-6 Acyl group C of (2) 1-6 Alkoxyacyl, C 2-6 Unsaturated hydrocarbon group, C 3-6 Cycloalkyl, C 1-6 Alkylthio of F, cl, br, I, glu, SO) 3 H、PO 3 H 2 ；
Glu represents a beta-D glucopyranosyl group; SO (SO) 3 H represents a sulfonyl group; PO (Positive oxide) 3 H 2 Represents a phosphoryl group.
Preferred grape derivatives of formula (I) according to the present invention include, but are not limited to, compounds of formula (IV), and pharmaceutically acceptable salts thereof, wherein the compounds are represented by formula (IV):
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 of (C) 3 H、PO 3 H 2 The method comprises the steps of carrying out a first treatment on the surface of the The substituents are selected from hydrogen, hydroxy, nitro, cyano, amino, carboxyl, methylamino, dimethylamino, C 1-6 Alkyl, C of (2) 1-6 Alkoxy, C 1-6 Acyl group, C 1-6 Acyl group C of (2) 1-6 Alkoxyacyl, C 2-6 Unsaturated hydrocarbon group, C 3-6 Cycloalkyl, C 1-6 Alkylthio of F, cl, br, I, glu, SO) 3 H、PO 3 H 2 ；
Glu represents a beta-D glucopyranosyl group; SO (SO) 3 H represents a sulfonyl group; PO (Positive oxide) 3 H 2 Represents phosphorusAn acyl group.
Preferred grape 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):
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 of (C) 3 H、PO 3 H 2 The method comprises the steps of carrying out a first treatment on the surface of the The substituents are selected from hydrogen, hydroxy, nitro, cyano, amino, carboxyl, methylamino, dimethylamino, C 1-6 Alkyl, C of (2) 1-6 Alkoxy, C 1-6 Acyl group, C 1-6 Acyl group C of (2) 1-6 Alkoxyacyl, C 2-6 Unsaturated hydrocarbon group, C 3-6 Cycloalkyl, C 1-6 Alkylthio of F, cl, br, I, glu, SO) 3 H、PO 3 H 2 ；
Glu represents a beta-D glucopyranosyl group; SO (SO) 3 H represents a sulfonyl group; PO (Positive oxide) 3 H 2 Represents a phosphoryl group.
The glucagons derivative and the pharmaceutically acceptable salt thereof in all the above general formulas are characterized by C 1-6 Alkyl groups of (a) include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, tert-pentyl, cyclopentyl, n-hexyl, cyclohexyl, cyclopentylmethyl; c (C) 1-6 Acyl groups of (a) include formyl, acetyl, propionyl, isopropylacyl, butyryl, t-butylacyl, n-pentyroyl, isopentyl, n-hexylacyl, cyclohexylacyl, cyclopentylmethyl acyl; c (C) 2-6 Unsaturated hydrocarbon groups of (2) include vinyl, ethynyl, propenyl, isopropenyl, propynyl, isopropenyl, butenyl, and isopropanylAlkenyl, 1, 3-butadienyl, pentenyl, isopentenyl, prenyl, cyclopentenyl, cyclopentadienyl, hexenyl, cyclohexenyl, cyclohexadienyl, phenyl; c (C) 3-6 Cycloalkyl groups of (2) include cyclopropane, cyclobutane, cyclopentane, and cyclohexane.
Specifically, the glucinol derivatives represented by the general formulae (I), (II) (IIA), (IIAa), (IIAb), (IIAc), (IIAd), (IIB), (IIBa), (III), (IIIA), (IIIAa), (IIIAb), (IIIB), (IIIBa), (IV) and (IVA) and pharmaceutically acceptable salts thereof are characterized in that the compounds are selected from the group consisting of:
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 in general formulas (I), (II) (IIA), (IIaa), (IIAb), (IIAc), (IIAd), (IIB), (IIBa), (III), (IIIA), (IIIaa), (IIIAb), (IIIB), (IIIBa), (IV) and (IVA), pharmaceutically acceptable salts thereof and carriers commonly used in the pharmaceutical field.
The invention also relates to pharmaceutical compositions containing as active ingredient a compound according to the invention and conventional pharmaceutical excipients or auxiliaries. Typically, the pharmaceutical compositions of the present invention contain 0.1 to 95% by weight of the compound of the present invention. The compounds of the invention are generally present in unit dosage forms in amounts of from 0.1 to 100mg, with preferred unit dosage forms containing from 4 to 50mg.
Pharmaceutical compositions of the compounds of the present invention may be prepared according to methods well known in the art. For this purpose, the compounds of the invention may, if desired, be combined with one or more solid or liquid pharmaceutical excipients and/or auxiliaries, in suitable administration forms or dosage forms which can be used as human or veterinary medicine.
The compounds of the present invention or pharmaceutical compositions containing them may be administered in unit dosage form by the enteral or parenteral route, such as oral, intramuscular, subcutaneous, nasal, oral, dermal, peritoneal or rectal, etc. The route of administration of the compounds of the invention or 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 may be liquid dosage form or solid dosage form. For example, the liquid dosage form may 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 of the invention can be prepared into common preparations, and can also be sustained release preparations, controlled release preparations, targeted preparations and various microparticle administration systems.
For example, in order to prepare a unit dosage form into a tablet, various carriers known in the art can be widely used. Examples of carriers include 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; humectants and binders such as water, glycerin, polyethylene glycol, ethanol, propanol, starch slurry, dextrin, syrup, honey, dextrose solution, acacia slurry, gelatin slurry, sodium carboxymethyl cellulose, shellac, methyl cellulose, potassium phosphate, polyvinylpyrrolidone, and the like; disintegrants such as dry starch, alginate, agar powder, brown algae starch, sodium bicarbonate and citric acid, calcium carbonate, polyoxyethylene sorbitol fatty acid ester, sodium dodecyl sulfonate, methylcellulose, ethylcellulose, and the like; disintegration inhibitors such as sucrose, glyceryl tristearate, cocoa butter, hydrogenated oils and the like; absorption promoters such as quaternary ammonium salts, sodium lauryl sulfate, and the like; lubricants such as talc, silica, corn starch, stearate, boric acid, liquid paraffin, polyethylene glycol, and the like. The tablets may be further formulated into coated tablets, such as sugar coated tablets, film coated tablets, enteric coated tablets, or bilayer and multilayer tablets.
For example, carriers well known in the art may be widely used for the purpose of making the dosage unit into a pill. Examples of carriers are, for example, diluents and absorbents such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oils, polyvinylpyrrolidone, glycerol monostearate, kaolin, talc and the like; binders such as acacia, tragacanth, gelatin, ethanol, honey, liquid sugar, rice paste or batter, and the like; disintegrants such as agar powder, dry starch, alginate, sodium dodecyl sulfate, methylcellulose, ethylcellulose, etc.
For example, in order to capsule the administration unit, the compounds of the invention are mixed with the various carriers described above, and the mixture thus obtained is placed in a hard gelatin capsule or a soft capsule. The active ingredient of the compound can be prepared into microcapsules, and the microcapsules can be suspended in an aqueous medium to form a suspension, or can be filled into hard capsules or prepared into injection for application.
For example, the compounds of the present invention may be formulated as injectable formulations, such as solutions, suspension solutions, emulsions, lyophilized powder for injection, 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, polyoxyl isostearyl alcohol, polyoxyethylene sorbitol ester, fatty acids, and the like. In addition, in order to prepare an isotonic injection, an appropriate amount of sodium chloride, glucose or glycerin may be added to the preparation for injection, and further, a conventional cosolvent, a buffer, a pH adjuster, and the like may be added. These adjuvants are commonly used in the art.
In addition, colorants, preservatives, flavors, flavoring agents, sweeteners, or other materials may also be added to the pharmaceutical formulation, if desired.
For the purpose of administration, the drug or the pharmaceutical composition of the present invention can be administered by any known administration method to enhance the therapeutic effect.
The dosage of the pharmaceutical composition of the present invention depends on many factors such as the nature and severity of the disease to be prevented or treated, the sex, age, weight, character and individual response of the patient or animal, the route of administration, the number of times of administration, the purpose of treatment, and thus the therapeutic dosage of the present invention may vary widely. Generally, the dosages of the ingredients to be used in the present invention are well known to those skilled in the art. The amount of the actual drug contained in the final formulation of the compound composition of the present invention may be appropriately adjusted to achieve the therapeutically effective amount thereof, thereby achieving the preventive or therapeutic object of the present invention. Daily suitable dosage range of the compounds of the invention: the amount of the compound of the present invention is 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 2-3 times; the dose taken by children is 5-30 mg, preferably 10-20 mg/kg body weight per kg body weight. The above-mentioned dosages may be administered in a single dosage form or in divided dosage forms, for example, two, three or four dosage forms, which are limited by the clinical experience of the administering physician and the administration 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 application of 2, 3-diaryl-5-styrylbenzofuran type grape derivatives shown in general formulas (I), (II) (IIA), (IIAa), (IIAb), (IIAc), (IIAd), (IIB), (IIBa), (III), (IIIA), (IIIAa), (IIIAb), (IIIB), (IIIBa), (IV) and (IVA) and pharmaceutically acceptable salts thereof in preparing medicaments for treating, preventing and assisting in treating various inflammations and inflammatory immune related diseases.
The various inflammation and inflammation 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, canker sore, nephritis, swelling occurring after damage, myocardial ischemia, various infectious pneumonia, physicochemical pneumonia and allergic pneumonia, chronic obstructive pulmonary disease, asthma, spasmodic anal pain and rectal laceration, hepatobiliary bursitis, cholangitis, primary biliary cirrhosis and cholecystitis. The compounds of the present invention include derivatives and pharmaceutically acceptable salts thereof.
The general features of inflammatory immune diseases at the cellular level are represented by: macrophages are overactivated and produce excess NO. Therefore, the invention performs an experiment of inhibiting the generation of macrophage NO in the abdominal cavity of a primary mouse induced by LPS by the compound, and shows that the 2, 3-diaryl-5-styrylbenzofuran type compound has the activity of inhibiting excessive generation of macrophage NO at the cellular level.
According to a fourth aspect of the present invention there is provided a process for the preparation of the derivative of the first aspect.
The synthesis method of the target derivative comprises the following steps (the resveratrol as a required raw material is commercially available):
step one: resveratrol dimer derivative delta-viniferin (A) with 2, 3-diaryl-5-styryl benzodihydrofuran structure is synthesized by resveratrol dimerization reaction.
Resveratrol in anhydrous acetone with Ag 2 O is used as oxidant for oxidation coupling reaction, and the reaction liquid is filtered and concentrated to be dry under reduced pressure to obtain a crude product. The crude product is separated and purified by chromatography to obtain the target product 2, 3-diaryl-5-styryl benzodihydrofuran resveratrol dimer delta-viniferin (A).
Step two: and (3) synthesizing the phenolic hydroxyl acetylated 2, 3-diaryl-5-styryl benzodihydrofuran intermediate derivative (B) by the phenolic hydroxyl acetylation reaction of the product obtained in the step (I).
And (3) carrying out an acetylation reaction on the product A obtained in the step (A) and acetic anhydride in dry pyridine, removing pyridine from a reaction solution, and concentrating under reduced pressure to obtain the phenolic hydroxyl acetyl benzodihydrofuran type resveratrol dimer derivative (B).
Step three: and (3) carrying out dehydrogenation reaction on the product obtained in the step two to synthesize the peracetylated 2, 3-diaryl-5-styrylbenzofuran derivative (C).
And (3) oxidizing the product B obtained in the step (II) in dioxane by using DDQ, filtering a reaction mixture to remove the DDQ, and separating by chromatography to obtain the fully-acetylated benzofuran resveratrol dimer derivative (C).
Step four: and (3) performing acetyl removal reaction on the product obtained in the step (III) to synthesize the 2, 3-diaryl-5-styrylbenzofuran resveratrol dimer derivative dehydro-delta-viniferin (D).
The total acetylation product obtained in the step three is prepared in a mixed solution of dichloromethane and methanol by NH 4 OAc is subjected to acetyl removal reaction, and the reaction mixture is subjected to NH removal 4 After OAc, the target product 2, 3-diaryl-5-styryl benzofuran type resveratrol dimer dehydro-delta-viniferin (D) is obtained through decompression concentration.
Step five: and D, synthesizing different methoxy substituted 2, 3-diaryl-5-styrylbenzofuran type resveratrol dimer derivatives by incomplete methylation reaction.
Beneficial technical effects
The inventor of the invention finds that the compound has stronger antioxidant and anti-inflammatory activity on an animal model in the activity research process of a natural product analogue dehydro-delta-viniferin with a 2, 3-diaryl-5-styrylbenzofuran structure, which is a semisynthetic derivative of natural product grape extract (delta-viniferin) separated from amur grape. On the basis, the compound is structurally derivatized to obtain a series of grape derivatives with 2, 3-diaryl-5-styryl benzofuran structures, and the obtained derivatives are subjected to inflammation inhibition activity evaluation to confirm the anti-inflammatory activity of the compound. The compound has remarkable inhibitory activity on generation of macrophage NO in abdominal cavity of primary mice induced by LPS, and has potential value of further research and development.
At present, the research on the activity and structure-activity relationship of 2, 3-diaryl-5-styryl benzofuran type grape derivatives substituted by different substituents is not reported in the literature. There are no reports in the prior literature and technology about 2, 3-diaryl-5-styryl benzofuran type grape derivatives substituted by different substituents or pharmaceutically acceptable salts thereof, and the compounds are used for treating inflammatory diseases.
Detailed description of the invention:
various terms and phrases used herein have the ordinary and customary meaning as understood by those skilled in the art, and even though they are still intended to be more fully described and explained herein, the terms and phrases used herein are to be understood and to have a meaning inconsistent with the ordinary and customary meaning as set forth herein. The following are definitions of various terms used in the present invention, which are applicable to terms used throughout the specification of the present application, unless otherwise specified in the specific context.
The definitions of the various groups of the compounds of the invention are provided below and are used throughout the specification and claims unless otherwise indicated.
The term "alkyl" as referred to herein means an alkyl group having the indicated number of carbon atoms, which may be a straight or branched chain alkyl group, e.g. "C" as referred to 3-6 Cycloalkyl "of (C) refers to a substituted or unsubstituted cycloalkyl group having 3, 4, 5, 6 carbon atoms, and may include C 3-5 Cycloalkyl, C 3-4 Cycloalkyl, C 4-6 Cycloalkyl, C 4-5 Cycloalkyl, C 5-6 Cycloalkyl, etc., and preferred specific groups such as cyclopropane, cyclopentane, and cyclohexane.
The term "C" as referred to in the present invention 1-6 The "alkyl" of (C) refers to a straight or branched alkyl group having 1, 2,3, 4, 5, 6 carbon atoms, and may include C 1-5 Alkyl, C 1-4 Alkyl, C 2-5 Alkyl, C 2-4 Alkyl, C 2-3 Alkyl, C 3-5 Alkyl groups and the like, and preferablySpecific groups are, for example, 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, C 1-2 Alkoxy, C 2-4 Alkoxy, C 2-3 Alkoxy, C 3-4 Alkoxy, and the like, and preferred specific groups are 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, C 2-4 Unsaturated hydrocarbon group, C 2-5 Unsaturated hydrocarbon group, C 2-4 And the like, and preferred specific groups such as 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" refers to an acyl group having 1, 2,3, 4, 5, and 6 carbon atoms, and may include C 1-5 Acyl, C 1-3 Acyl, C 2-5 Acyl, C 2-3 Acyl, C 3-4 Acyl, etc., and preferred specific groups, such as formyl, acetyl, propionyl, etc.
Reference to "C" in the present invention 1-6 The "acyloxy group" of (C) refers to a straight-chain or branched acyloxy group having 1, 2,3, 4, 5, 6 carbon atoms and may include C 1-5 Acyloxy radicals, C 1-3 Acyloxy radicals, C 2-5 Acyloxy radicals, C 2-3 Acyloxy radicals, C 3-4 Acyl groups, etc., and preferred specific groups, such as formyl, acetyl, propionyloxy, etc.
Reference to "C" in the present invention 1-6 Alkoxyacyl "of (C) is an alkanoyl group having 1, 2,3, 4, 5, 6 carbon atoms and may include C 1-5 Alkoxyacyl, C 1-3 Alkoxyacyl, C 2-5 Alkoxyacyl, C 2-3 Alkoxyacyl, C 3-4 Alkoxyacyl and the like, and preferred specific groups such as methoxyacyl, ethoxyacyl and the like.
The term "C" as referred to in the present invention 1-6 Alkylthio "of (C) refers to straight-chain or branched alkylthio of 1, 2,3, 4, 5, 6 carbon atoms, and may include C 1-5 Alkylthio, C 1-3 Alkylthio, C 2-5 Alkylthio, C 2-3 Alkylthio, C 3-4 Alkylthio groups and the like, and preferred specific groups, such as methylthio, ethylthio and the like.
Detailed Description
In order to further illustrate the invention, the following examples are given purely by way of illustration and are not to be construed as limiting the invention.
Example 1: the synthesis method of the target derivative comprises the following steps (resveratrol as a synthesis raw material is commercially available):
example 1
Step one: resveratrol dimer derivative (A) with 2, 3-diaryl-5-styryl benzodihydrofuran structure is synthesized by resveratrol dimerization reaction.
60g resveratrol (263.158 mmol) was dissolved in 1500ml anhydrous acetone and 67.8g Ag was added 2 The O solid was heated to reflux for 3d, and the reaction was stopped. 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 column chromatography on silica gel (200-300 mesh) with petroleum ether: acetone=3:2 (v/v) to give 6.7g of yellow solid a (14.758 mmol) in 11.2% yield, m.p.154-156 ℃.
Step two: and (3) synthesizing the phenolic hydroxyl acetylated 2, 3-diaryl-5-styryl benzodihydrofuran intermediate derivative (B) by the phenolic hydroxyl acetylation reaction of the product obtained in the step (I).
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 overnight at room temperature. After the reaction is completed, slowly dripping ice water under ice bath, transferring into a separating funnel after the ice water does not generate heat, adding 3 times of water for dilution, extracting with ethyl acetate for three times, combining organic phases, and sequentially using saturated CuSO 4 Solution, saturated saline, water washing, anhydrous Na 2 SO 4 After drying, the resulting organic phase was evaporated to dryness under reduced pressure, the crude product was purified by petroleum ether: acetone=3: 1 to obtain white solid B1.79 g (2.70 mmol) with a yield of 95.7% and m.p.182-183℃ by silica gel (200-300 mesh) column chromatography
Step three: and (3) carrying out dehydrogenation reaction on the product obtained in the step two to synthesize the peracetylated 2, 3-diaryl-5-styrylbenzofuran 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 48h, the reaction mixture was dissolved in a small amount of dichloromethane and then wet-loaded, and silica gel (200-300 mesh) column chromatography was carried out with dichloromethane as eluent to obtain pale white solid C1.45g (2.19 mmol) with a yield of 81.1% and m.p.173-174 ℃.
Step four: and (3) performing acetyl removal reaction on the product obtained in the step (III) to synthesize the 2, 3-diaryl-5-styrylbenzofuran type resveratrol dimer derivative (D).
1.45g of Compound C (2.19 mmol) were dissolved in 15ml of dichloromethane and 15ml of methanol were added thereto, followed by 25.36g of NH 4 OAc (329 mmol), stirring at room temperature for 2d. The reaction solution was diluted with water, extracted with ethyl acetate, the organic phases combined, and anhydrous Na 2 SO 4 Drying, suction filtration and evaporation of the solvent under reduced pressure gave 0.98g (2.17 mmol) of a yellow solid D in 98.9% yield, m.p.97-99 ℃.
Step five: intermediate D is synthesized through incomplete methylation reaction to obtain a mixture of compounds 1-13, and the mixture is separated to prepare pure products of the compounds. Their reaction process and spectroscopic identification data are as follows:
0.98g of Compound D (2.17 mmol) was dissolved in 15ml of anhydrous acetoneAdd 1.5. 1.5g K in portions with stirring 2 CO 3 After stirring the solid (10.85 mmol) for 30min, 0.675ml of CH was slowly added dropwise 3 I (10.85 mmol), stirring at room temperature for 12h, adding a small amount of water to the reaction system to stop the reaction, and suction 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 was separated by 200-300 mesh silica gel column chromatography, and the nine components I-IX were obtained by gradient elution of petroleum ether: acetone 15:1-1:1 (v/v). Component I (15.2 mg) was separated on HPLC using 95% methanol water as a mobile phase by a C18 semi-preparative column (ODS, 5 μm, YMC, 250X 10mm, the same applies below) to give compound 13 (3.0 mg); component II (71.3 mg) was separated on HPLC using 85% methanol water as the mobile phase by C18 semi-preparative column to give compounds 11 (3.6 mg) and 12 (2.5 mg); component IV (82.8 mg) was separated on HPLC using 90% methanol water as the mobile phase via a C18 semi-preparative column to give compounds 8 (9.0 mg), 9 (2.0 mg) and 10 (2.0 mg); component V (131.7 mg) was separated on HPLC using 85% methanol water as the mobile phase by Sup>A C18 semi-preparative column to give compound 6 (7.0 mg) and component V-A (21.5 mg); component V-A (21.5 mg) was further separated by C18 semi-preparative column using 70% methanol water as mobile phase to give compound 7 (13.2 mg); component VI (224.6 mg) was separated on HPLC using 75% methanol in water as the mobile phase by a C18 semi-preparative column to give Compound 5 (4.0 mg) and VI-C (85.0 mg); VI-C (85.0 mg) further separated in 50% acetonitrile water on a C18 semi-preparative column to give compounds 3 (2.0 mg) and 4 (6.0 mg); component VIII (290.7 mg) was separated on HPLC using 70% methanol in water as the mobile phase via a C18 semi-preparative column to give compounds 1 (8.1 mg) and 2 (2.0 mg).
Synthetic end products (compound codes correspond to those in the examples):
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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 method and results of the anti-inflammatory activity of the compounds of the present invention are as follows (the compound codes of the pharmacological test section correspond to those of the examples):
experimental example 1: inhibitory Activity of the Vitin derivative on LPS-induced primary mouse peritoneal macrophage NO production.
Macrophages, which perform the nonspecific immune function of the organism, can produce inflammatory factors such as NO and the like under the induction of bacterial lipopolysaccharide LPS, participate in and mediate inflammatory reactions, and have higher levels in the early stages of various inflammatory immune processes and in the pathological development process. The NO production of the primary cultured mouse macrophage can be detected to be used as an index for initially observing and screening components or compounds with certain anti-inflammatory activity in vitro.
The experimental method comprises the following steps:
taking primary mouse abdominal cavity macrophages to inoculate in a 96-well plate, adding different compounds to be detected (10) -5 M) and a positive control drug dexamethasone (Dex) were pre-protected for 1h; then, 1. Mu.g/ml LPS was added at 37℃with 5% CO 2 Culturing in incubator for 24 hr, collecting supernatant, and determining NO content by Griess method Meanwhile, the inhibition rate of cell proliferation was measured by MTT method.
Experimental results:
the results are shown in Table 1, where the toxicity of compounds 6, 8, 9 is significantly reduced while maintaining activity compared to the precursor compound dehydo-delta-viniferin (DRs-1). Among them, compounds 1, 2, 4, 5, 6, 7, 8, 9 have remarkable NO generation inhibitory activity.
Table 1. Effect of Vitin derivatives on LPS-induced generation of NO by macrophages in the abdominal cavity of primary mice. *
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* Concentration: 10 -5 M; the treatment direction is as follows: anti-inflammatory. # The compound numbers correspond to the compound numbers in the examples.

Claims (4)

1. A glucagons derivative and pharmaceutically acceptable salts thereof as shown below:
2. use of a glucagons derivative according to claim 1, and a pharmaceutically acceptable salt thereof, for the preparation of an inhibitor of NO production.
3. The use of a glucagons derivative according to claim 1 and a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment, prevention or adjuvant treatment of various inflammations and inflammatory immune-related diseases.
4. Use according to claim 3, wherein the inflammation and inflammatory immune related disorder comprises: 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, canker sore, nephritis, swelling occurring after damage, myocardial ischemia, various infectious pneumonia, physicochemical pneumonia and allergic pneumonia, chronic obstructive pulmonary disease, asthma, spasmodic anal pain and rectal laceration, hepatobiliary bursitis, cholangitis, primary biliary cirrhosis and cholecystitis.
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