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

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

A kind of grapefruit derivative, its preparation method, pharmaceutical composition and use

Technical Field

The present invention relates to the field of biomedicine, and in particular to a class of 2,3-diaryl-5-phenylvinylbenzofuran-type viniferin derivatives or their medically acceptable salts, pharmaceutical compositions containing these derivatives, and applications thereof in the preparation of drugs for preventing or treating inflammatory immune-related diseases.

Background Art

Developing new drugs based on active natural products is one of the important ways of modern drug development. Natural products have the characteristics of wide sources, low toxicity and small side effects. Discovering natural lead compounds with significant activity from traditional Chinese herbal medicines, and finding safe and efficient candidate compounds as clinically useful prototype drugs through structural modification, combined with systematic in vitro and in vivo activity tests and comprehensive evaluation of drugability is an important direction of drug research and development. Oligostilbene compounds are a class of natural products with complex structures and multiple biological activities formed by the polymerization of diphenylethylene monomers in different ways. They are mainly distributed in plants such as grapes, Gnetaceae, Dipterocarpaceae, Leguminosae, Cyperaceae, and Paeoniaceae. Different structures of diphenylethylene monomers have different polymerization modes and polymerization degrees, and the resulting oligostilbene natural products show rich and diverse structural types. Correspondingly, the oligostilbene compounds discovered so far also show a variety of biological activities, including antioxidant, anti-inflammatory, antibacterial, anti-tumor, antiviral and anti-Alzheimer's activities. In the past 10 years, due to the continuous development of separation and structure identification technology, more and more complex oligostilbene compounds with significant biological activity have been separated and identified, making the research on oligostilbene compounds have made great progress in both structure and activity. Especially in the study of biological activity, not only more complex compounds with different activities have been discovered, but also such compounds have been found to exhibit significant biological activity in more aspects, such as β-secretase inhibitory activity, anti-influenza virus activity, anti-herpes virus (HSV) activity, etc. The continuous discovery of new activities shows that such compounds have great potential in drug development and utilization, which has led to more widespread attention on oligostilbene compounds, and has now developed into one of the hot spots in natural product research. In particular, the dimer compounds are generally more active than the monomeric stilbene compounds, with a molecular weight between 400-600, and have great potential for development into drugs. In recent years, the total synthesis of stilbene dimer compounds has been one of the hot topics of research, and great progress has been made. The total synthesis of the main dimer structure skeletons, including benzofuran structure, indene structure and diaryl[3.2.1]octane structure, has made breakthrough progress, providing a guarantee for the research and development of dimer compounds. However, in addition to the separation and identification of natural products, the systematic structural modification and structure-activity relationship research of active oligomer compounds (especially dimers) is still a new research field. So far, there are few related research reports in the literature. Benzofuran and dihydrobenzofuran stilbene dimer derivatives are the most numerous natural products among dimer compounds, and they are also the most active class of compounds. Viniferin derivatives (dehydro-δ-viniferin) with 2,3-diaryl-5-styrylbenzofuran structure are natural product analogs synthesized by dehydrogenation of natural product δ-viniferin. So far, there are few studies on its anti-inflammatory activity. This study systematically studied the derivatization, anti-inflammatory activity test and structure-activity relationship of 2,3-diaryl-5-phenylvinylbenzofuran-type viniferin (dehydro-δ-viniferin), and obtained a series of new-structure viniferin derivatives with significant inhibitory activity against the inflammatory factor NO. The inflammatory inhibitory activity of the synthesized compounds has not been reported in the literature so far. The present invention is of great significance for the development and utilization of such compounds.

Summary of the invention

The technical problem to be solved by the present invention is to provide a class of 2,3-diaryl-5-phenylvinylbenzofuran-type viniferin derivatives with a new structure, and a preparation method, a pharmaceutical composition and use thereof.

The first aspect of the technical solution of the present invention provides a 2,3-diaryl-5-phenylvinylbenzofuran type compound and its derivatives as shown in the general formula (I), (II) (IIA), (IIAa), (IIAb), (IIAc), (IIAd), (IIB), (IIBa), (III), (IIIA), (IIIAa), (IIIAb), (IIIB), (IIIBa), (IV) and (IVA).

Specifically, the present invention relates to 2,3-diaryl-5-phenylvinylbenzofuran-type viniferin derivatives and pharmaceutically acceptable salts thereof as shown in the general formula (I):

wherein R ₁ , R ₂ , R ₃ , R ₄ , and R ₅ are 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, and PO ₃ H ₂ ; and the substituent is selected from hydrogen, hydroxy, nitro, cyano, amino, carboxyl, methylamino, dimethylamino, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 acyl, C _1-6 acyloxy, C _1-6 alkoxyacyl, C _2-6 unsaturated hydrocarbon group, C _3-6 cycloalkyl, C _1-6 alkylthio, F, Cl, Br, I, Glu, SO ₃ H, and PO ₃ H ₂ ;

Glu represents β-D-pyranoglucopyranosyl; SO ₃ H represents sulfonyl; and PO ₃ H ₂ represents phosphoryl.

According to the present invention, preferred grapefruit derivatives represented by general formula (I) include, but are not limited to, compounds represented by general formula (II), and pharmaceutically acceptable salts thereof, characterized in that the compounds are represented by general formula (II):

wherein R ₂ , R ₃ , R ₄ , and R ₅ are 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, and PO ₃ H ₂ ; and the substituent is selected from hydrogen, hydroxy, nitro, cyano, amino, carboxyl, methylamino, dimethylamino, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 acyl, C _1-6 acyloxy, C _1-6 alkoxyacyl, C _2-6 unsaturated hydrocarbon group, C _3-6 cycloalkyl, C _1-6 alkylthio, F, Cl, Br, I, Glu, SO ₃ H, and PO ₃ H ₂ ;

Glu represents β-D-pyranoglucopyranosyl; SO ₃ H represents sulfonyl; and PO ₃ H ₂ represents phosphoryl.

According to the present invention, preferred grapefruit derivatives represented by general formula (II) include, but are not limited to, compounds represented by general formula (IIA), and pharmaceutically acceptable salts thereof, characterized in that the compounds are represented by general formula (IIA):

wherein R ₃ , R ₄ , and R ₅ are 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, and PO ₃ H ₂ ; and the substituent is selected from hydrogen, hydroxy, nitro, cyano, amino, carboxyl, methylamino, dimethylamino, C _1-6 alkyl, C _{1-6 alkoxy, C 1-6} acyl, _{C 1-6} acyloxy, C _1-6 alkoxyacyl, C _2-6 unsaturated hydrocarbon group, C _3-6 cycloalkyl, C _1-6 alkylthio, F, Cl, Br, I, Glu, SO ₃ H, and PO ₃ H ₂ ;

Glu represents β-D-pyranoglucopyranosyl; SO ₃ H represents sulfonyl; and PO ₃ H ₂ represents phosphoryl.

According to the present invention, preferred vinblastine derivatives represented by general formula (IIA) include, but are not limited to, compounds represented by general formula (IIAa), and pharmaceutically acceptable salts thereof, characterized in that the compounds are represented by general formula (IIAa):

wherein R ₄ and R ₅ are 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 ; the substituent is selected from hydrogen, hydroxyl, nitro, cyano, amino, carboxyl, methylamino, dimethylamino, C _1-6 alkyl, C _1-6 alkoxy, C 1-6 acyl, C _1-6 acyloxy, C _1-6 alkoxyacyl, C _2-6 unsaturated hydrocarbon group, C _3-6 cycloalkyl, C _1-6 alkylthio, F, Cl, Br, I, _Glu , SO ₃ H, PO ₃ H ₂ ;

Glu represents β-D-pyranoglucopyranosyl; SO ₃ H represents sulfonyl; and PO ₃ H ₂ represents phosphoryl.

According to the present invention, preferred vinblastine derivatives represented by general formula (IIA) include, but are not limited to, compounds represented by general formula (IIAb), and pharmaceutically acceptable salts thereof, characterized in that the compounds are represented by general formula (IIAb):

wherein R ₅ is 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, substituted or unsubstituted C _3-6 cycloalkyl, Glu, SO ₃ H, PO ₃ H ₂ ; the substituent is selected from hydrogen, hydroxy, nitro, cyano, amino, carboxyl, methylamino, dimethylamino, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 acyl, C _{1-6 acyloxy, C 1-6 alkoxyacyl} , C _2-6 unsaturated hydrocarbon, C _3-6 cycloalkyl, C _1-6 alkylthio, F, Cl, Br, I, Glu, SO ₃ H, PO ₃ H ₂ ;

Glu represents β-D-pyranoglucopyranosyl; SO ₃ H represents sulfonyl; and PO ₃ H ₂ represents phosphoryl.

According to the present invention, preferred vinblastine derivatives represented by general formula (IIA) include, but are not limited to, compounds represented by general formula (IIAc), and pharmaceutically acceptable salts thereof, characterized in that the compounds are represented by general formula (IIAc):

Wherein, R ₃ and R ₅ are 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 ; the substituent is selected from hydrogen, hydroxyl, nitro, cyano, amino, carboxyl, methylamino, dimethylamino, C _1-6 alkyl, C _1-6 alkoxy, C 1-6 acyl, C _1-6 acyloxy, C _1-6 alkoxyacyl, C _2-6 unsaturated hydrocarbon group, C _3-6 cycloalkyl, _{C 1-6 alkylthio} , F, Cl, Br, I, Glu, SO ₃ H, PO ₃ H ₂ .

Glu represents β-D-pyranose glucopyranosyl; SO ₃ H represents sulfonyl; PO ₃ H ₂ represents phosphoryl;

According to the present invention, preferred vinblastine derivatives represented by general formula (IIA) include, but are not limited to, compounds represented by general formula (IIAd), and pharmaceutically acceptable salts thereof, characterized in that the compounds are represented by general formula (IIAd):

wherein R ₃ is 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, substituted or unsubstituted C _3-6 cycloalkyl, Glu, SO ₃ H, PO ₃ H ₂ ; the substituent is selected from hydrogen, hydroxy, nitro, cyano, amino, carboxyl, methylamino, dimethylamino, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 acyl, C _{1-6 acyloxy, C 1-6 alkoxyacyl} , C _2-6 unsaturated hydrocarbon, C _3-6 cycloalkyl, C _1-6 alkylthio, F, Cl, Br, I, Glu, SO ₃ H, PO ₃ H ₂ ;

Glu represents β-D-pyranoglucopyranosyl; SO ₃ H represents sulfonyl; and PO ₃ H ₂ represents phosphoryl.

According to the present invention, preferred grapefruit derivatives represented by general formula (II) include, but are not limited to, compounds represented by general formula (IIB), and pharmaceutically acceptable salts thereof, characterized in that the compounds are represented by general formula (IIB):

wherein R ₂ , R ₃ , and R ₅ are 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, and PO ₃ H ₂ ; and the substituent is selected from hydrogen, hydroxy, nitro, cyano, amino, carboxyl, methylamino, dimethylamino, C _1-6 alkyl, C _{1-6 alkoxy, C 1-6} acyl, _{C 1-6} acyloxy, C _1-6 alkoxyacyl, C _2-6 unsaturated hydrocarbon group, C _3-6 cycloalkyl, C _1-6 alkylthio, F, Cl, Br, I, Glu, SO ₃ H, and PO ₃ H ₂ ;

Glu represents β-D-pyranoglucopyranosyl; SO ₃ H represents sulfonyl; and PO ₃ H ₂ represents phosphoryl.

According to the present invention, preferred grapefruit derivatives represented by general formula (IIB) include, but are not limited to, compounds represented by general formula (IIBa), and pharmaceutically acceptable salts thereof, characterized in that the compounds are represented by general formula (IIBa):

wherein R ₂ and R ₃ are 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 ; the substituent is selected from hydrogen, hydroxyl, nitro, cyano, amino, carboxyl, methylamino, dimethylamino, C _1-6 alkyl, C _1-6 alkoxy, C 1-6 acyl, C _1-6 acyloxy, C _1-6 alkoxyacyl, C _2-6 unsaturated hydrocarbon group, C _3-6 cycloalkyl, C _1-6 alkylthio, F, Cl, Br, I, _Glu , SO ₃ H, PO ₃ H ₂ ;

Glu represents β-D-pyranoglucopyranosyl; SO ₃ H represents sulfonyl; and PO ₃ H ₂ represents phosphoryl.

According to the present invention, preferred grapefruit derivatives represented by general formula (I) include, but are not limited to, compounds represented by general formula (III), and pharmaceutically acceptable salts thereof, characterized in that the compounds are represented by general formula (III):

wherein R ₁ , R ₃ , R ₄ , and R ₅ are 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, substituted or unsubstituted C _3-6 cycloalkyl, Glu, SO ₃ H, and PO ₃ H ₂ ; and the substituent is selected from hydrogen, hydroxy, nitro, cyano, amino, carboxyl, methylamino, dimethylamino, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 acyl, C _1-6 acyloxy, C 1-6 alkoxyacyl, C _2-6 unsaturated hydrocarbon, C _3-6 cycloalkyl, C _1-6 alkylthio, F, Cl, Br, I, _Glu , SO ₃ H, and PO ₃ H ₂ ;

Glu represents β-D-pyranoglucopyranosyl; SO ₃ H represents sulfonyl; and PO ₃ H ₂ represents phosphoryl.

According to the present invention, preferred grapefruit derivatives represented by general formula (III) include, but are not limited to, compounds represented by general formula (IIIA), and pharmaceutically acceptable salts thereof, characterized in that the compounds are represented by general formula (IIIA):

wherein R ₁ , R ₄ , and R ₅ are 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, substituted or unsubstituted C _3-6 cycloalkyl, Glu, SO ₃ H, and PO ₃ H ₂ ; and the substituent is selected from hydrogen, hydroxy, nitro, cyano, amino, carboxyl, methylamino, dimethylamino, C _1-6 alkyl, _C 1-6 alkoxy, C _1-6 acyl, C _1-6 acyloxy, C _1-6 alkoxyacyl, C _2-6 unsaturated hydrocarbon, C _3-6 cycloalkyl, C _1-6 alkylthio, F, Cl, Br, I, Glu, SO ₃ H, and PO ₃ H ₂ ;

Glu represents β-D-pyranoglucopyranosyl; SO ₃ H represents sulfonyl; and PO ₃ H ₂ represents phosphoryl.

According to the present invention, preferred grapefruit derivatives represented by general formula (IIIA) include, but are not limited to, compounds represented by general formula (IIIAa), and pharmaceutically acceptable salts thereof, characterized in that the compounds are represented by general formula (IIIAa):

wherein R ₁ and R ₅ are 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 ; the substituent is selected from hydrogen, hydroxyl, nitro, cyano, amino, carboxyl, methylamino, dimethylamino, C _1-6 alkyl, C _1-6 alkoxy, C 1-6 acyl, C _1-6 acyloxy, C _1-6 alkoxyacyl, C _2-6 unsaturated hydrocarbon group, C _3-6 cycloalkyl, C _1-6 alkylthio, F, Cl, Br, I, _Glu , SO ₃ H, PO ₃ H ₂ ;

Glu represents β-D-pyranoglucopyranosyl; SO ₃ H represents sulfonyl; and PO ₃ H ₂ represents phosphoryl.

According to the present invention, preferred vinblastine derivatives represented by general formula (IIIA) include, but are not limited to, compounds represented by general formula (IIIAb), and pharmaceutically acceptable salts thereof, characterized in that the compounds are represented by general formula (IIIAb):

wherein R ₁ is 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, substituted or unsubstituted C _3-6 cycloalkyl, Glu, SO ₃ H, PO ₃ H ₂ ; the substituent is selected from hydrogen, hydroxy, nitro, cyano, amino, carboxyl, methylamino, dimethylamino, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 acyl, C _{1-6 acyloxy, C 1-6 alkoxyacyl} , C _2-6 unsaturated hydrocarbon, C _3-6 cycloalkyl, C _1-6 alkylthio, F, Cl, Br, I, Glu, SO ₃ H, PO ₃ H ₂ ;

Glu represents β-D-pyranoglucopyranosyl; SO ₃ H represents sulfonyl; and PO ₃ H ₂ represents phosphoryl.

According to the present invention, preferred grapefruit derivatives represented by general formula (III) include, but are not limited to, compounds represented by general formula (IIIB), and pharmaceutically acceptable salts thereof, characterized in that the compounds are represented by general formula (IIIB):

wherein R ₁ , R ₃ , and R ₅ are 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, substituted or unsubstituted C _3-6 cycloalkyl, Glu, SO ₃ H, and PO ₃ H ₂ ; and the substituent is selected from hydrogen, hydroxy, nitro, cyano, amino, carboxyl, methylamino, dimethylamino, C _1-6 alkyl, _C 1-6 alkoxy, C _1-6 acyl, C _1-6 acyloxy, C _1-6 alkoxyacyl, C _2-6 unsaturated hydrocarbon, C _3-6 cycloalkyl, C _1-6 alkylthio, F, Cl, Br, I, Glu, SO ₃ H, and PO ₃ H ₂ ;

Glu represents β-D-pyranoglucopyranosyl; SO ₃ H represents sulfonyl; and PO ₃ H ₂ represents phosphoryl.

According to the present invention, preferred grapefruit derivatives represented by general formula (IIIB) include, but are not limited to, compounds represented by general formula (IIIBa), and pharmaceutically acceptable salts thereof, characterized in that the compounds are represented by general formula (IIIBa):

wherein R ₁ and R ₃ are 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 ; the substituent is selected from hydrogen, hydroxyl, nitro, cyano, amino, carboxyl, methylamino, dimethylamino, C _1-6 alkyl, C _1-6 alkoxy, C 1-6 acyl, C _1-6 acyloxy, C _1-6 alkoxyacyl, C _2-6 unsaturated hydrocarbon group, C _3-6 cycloalkyl, C _1-6 alkylthio, F, Cl, Br, I, _Glu , SO ₃ H, PO ₃ H ₂ ;

Glu represents β-D-pyranoglucopyranosyl; SO ₃ H represents sulfonyl; and PO ₃ H ₂ represents phosphoryl.

According to the present invention, preferred grapefruit derivatives represented by general formula (I) include, but are not limited to, compounds represented by general formula (IV), and pharmaceutically acceptable salts thereof, characterized in that the compounds are represented by general formula (IV):

wherein R ₁ , R ₂ , R ₃ , and R ₅ are 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, substituted or unsubstituted C _3-6 cycloalkyl, Glu, SO ₃ H, and PO ₃ H ₂ ; and the substituent is selected from hydrogen, hydroxy, nitro, cyano, amino, carboxyl, methylamino, dimethylamino, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 acyl, C _1-6 acyloxy, C 1-6 alkoxyacyl, C _2-6 unsaturated hydrocarbon, C _3-6 cycloalkyl, C _1-6 alkylthio, F, Cl, Br, I, _Glu , SO ₃ H, and PO ₃ H ₂ ;

Glu represents β-D-pyranoglucopyranosyl; SO ₃ H represents sulfonyl; and PO ₃ H ₂ represents phosphoryl.

According to the present invention, preferred grapefruit derivatives represented by general formula (IV) include, but are not limited to, compounds represented by general formula (IVA), and pharmaceutically acceptable salts thereof, characterized in that the compounds are as represented by general formula (IVA):

wherein R ₁ , R ₂ , and R ₃ are 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, substituted or unsubstituted C _3-6 cycloalkyl, Glu, SO ₃ H, and PO ₃ H ₂ ; and the substituent is selected from hydrogen, hydroxy, nitro, cyano, amino, carboxyl, methylamino, dimethylamino, C _1-6 alkyl, _C 1-6 alkoxy, C _1-6 acyl, C _1-6 acyloxy, C _1-6 alkoxyacyl, C _2-6 unsaturated hydrocarbon, C _3-6 cycloalkyl, C _1-6 alkylthio, F, Cl, Br, I, Glu, SO ₃ H, and PO ₃ H ₂ ;

Glu represents β-D-pyranoglucopyranosyl; SO ₃ H represents sulfonyl; and PO ₃ H ₂ represents phosphoryl.

The grapefruit derivatives and pharmaceutically acceptable salts thereof in all the above-mentioned general formulas of the present invention are characterized in that the _C1-6 alkyl group includes methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, tert-pentyl, cyclopentyl, n-hexyl, cyclohexyl, and cyclopentylmethyl; the _C1-6 acyl group includes formyl, acetyl, propionyl, isopropyl acyl, butyryl, tert-butyl acyl, n-pentyl acyl, isopentyl acyl, n-hexyl acyl, cyclohexyl acyl, and cyclopentylmethyl acyl; the _C2-6 unsaturated hydrocarbon group includes vinyl, ethynyl, propenyl, isopropenyl, propynyl, isopropynyl, butenyl, isopropenyl, 1,3-butadienyl, pentenyl, isopentenyl, isopentenyl, cyclopentenyl, cyclopentadienyl, hexenyl, cyclohexenyl, cyclohexadienyl, and phenyl; The cycloalkyl groups of _{3 to 6} include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

Specifically, the grape sugar derivatives represented by general formula (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 compound is selected from the following group:

A second aspect of the technical solution of the present invention provides a pharmaceutical composition, comprising at least one 2,3-diaryl-5-phenylvinylbenzofuranose derivative as represented by general formula (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 a carrier commonly used in the pharmaceutical field.

The present invention also relates to a pharmaceutical composition containing the compound of the present invention as an active ingredient and conventional pharmaceutical excipients or adjuvants. Usually the pharmaceutical composition of the present invention contains 0.1 to 95% by weight of the compound of the present invention. The compound of the present invention generally contains 0.1 to 100 mg in a unit dosage form, and a preferred unit dosage form contains 4 to 50 mg.

The pharmaceutical composition of the compounds of this invention can be prepared according to methods well known in the art. When used for this purpose, if necessary, the compounds of this invention can be combined with one or more solid or liquid pharmaceutical excipients and/or adjuvants to prepare suitable application forms or dosage forms that can be used as human medicine or veterinary medicine.

The compound of the present invention or the pharmaceutical composition containing it can be administered in a unit dosage form, and the administration route can be enteral or parenteral, such as oral, intramuscular, subcutaneous, nasal, oral mucosa, skin, peritoneum or rectum. The compound of the present invention or the pharmaceutical composition containing it can be administered by injection. Injection includes intravenous injection, intramuscular injection, subcutaneous injection, intradermal injection and acupoint injection.

The dosage form for administration can be a liquid dosage form or a solid dosage form. For example, the liquid dosage form can be a true solution, a colloid, a microparticle dosage form, an emulsion dosage form, or a suspension dosage form. Other dosage forms include tablets, capsules, dripping pills, aerosols, pills, powders, solutions, suspensions, emulsions, granules, suppositories, freeze-dried powder injections, and the like.

The compound of the present invention can be made into common preparations, or can be made into sustained-release preparations, controlled-release preparations, targeted preparations and various microparticle drug delivery systems.

For example, in order to prepare a unit dosage form into tablets, various carriers well 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, etc.; wetting agents and binders, such as water, glycerol, polyethylene glycol, ethanol, propanol, starch slurry, dextrin, syrup, honey, glucose solution, acacia slurry, gelatin slurry, sodium carboxymethyl cellulose, shellac, methylcellulose, potassium phosphate, polyvinyl pyrrolidone, etc.; disintegrants, such as dry starch, alginate, agar powder, brown seaweed starch, sodium bicarbonate and citric acid, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, methylcellulose, ethyl cellulose, etc.; disintegration inhibitors, such as sucrose, tristearin, cocoa butter, hydrogenated oil, etc.; absorption promoters, such as quaternary ammonium salts, sodium lauryl sulfate, etc.; lubricants, such as talc, silicon dioxide, corn starch, stearate, boric acid, liquid paraffin, polyethylene glycol, etc. The tablets can be further made into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer tablets and multi-layer tablets.

For example, in order to make the dosing unit into a pill, carriers known in the art can be widely used. Examples of carriers include diluents and absorbents, such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, polyvinyl pyrrolidone, glyceryl monostearate, kaolin, talc, etc.; binders, such as gum arabic, tragacanth gum, gelatin, ethanol, honey, liquid sugar, rice paste or flour paste, etc.; disintegrants, such as agar powder, dry starch, alginate, sodium dodecyl sulfate, methyl cellulose, ethyl cellulose, etc.

For example, in order to prepare the dosing unit into a capsule, the compound of the present invention is mixed with the above-mentioned various carriers, and the resulting mixture is placed in a hard gelatin capsule or a soft capsule. The active ingredient compound of the present invention can also be prepared into a microcapsule, suspended in an aqueous medium to form a suspension, or loaded into a hard capsule or prepared as an injection for use.

For example, the compound of the present invention is made into an injection preparation, such as a solution, a suspension solution, an emulsion, or a freeze-dried powder injection. This preparation may be aqueous or non-aqueous, and may contain one and/or more pharmacodynamically acceptable carriers, diluents, adhesives, lubricants, preservatives, surfactants, or dispersants. For example, the diluent may be selected from water, ethanol, polyethylene glycol, 1,3-propylene glycol, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol esters, fatty acids, and the like. In addition, in order to prepare an isotonic injection, an appropriate amount of sodium chloride, glucose, or glycerol may be added to the injection preparation. In addition, conventional cosolvents, buffers, pH regulators, and the like may also be added. These excipients are commonly used in the art.

In addition, if necessary, colorants, preservatives, perfumes, flavoring agents, sweeteners or other materials may be added to the pharmaceutical preparations.

To achieve the purpose of medication and enhance the therapeutic effect, the drug or pharmaceutical composition of the present invention can be administered by any known administration method.

The dosage of the pharmaceutical composition of the compound 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, personality and individual response of the patient or animal, the route of administration, the number of administrations, and the purpose of treatment. Therefore, the therapeutic dose of the present invention can vary widely. Generally speaking, the dosage of the ingredients in the present invention is well known to those skilled in the art. It can be appropriately adjusted according to the actual amount of the drug contained in the final preparation of the compound composition of the present invention to achieve the requirements of its therapeutically effective amount and complete the prevention or treatment purpose of the present invention. The daily suitable dosage range of the compound of the present invention: the dosage of the compound of the present invention is 0.001-100 mg/kg body weight, preferably 0.1-60 mg/kg body weight, more preferably 1-30 mg/kg body weight, and most preferably 2-15 mg/kg body weight. The daily dosage of the compound of the present invention taken by adult patients is 10-500 mg, preferably 10-100 mg, which can be taken once or in 2-3 times; the dosage for children is 5-30 mg per kg body weight, preferably 10-20 mg/kg body weight. The above dosage can be administered in a single dosage form or divided into several, such as two, three or four dosage forms, which is limited by the clinical experience of the administering physician and the dosing regimen of the treatment. The compound or composition of the present invention can be taken alone or in combination with other therapeutic drugs or symptomatic drugs.

The third aspect of the technical solution of the present invention provides 2,3-diaryl-5-phenylvinylbenzofuranose derivatives and pharmaceutically acceptable salts thereof as shown in general formula (I), (II) (IIA), (IIAa), (IIAb), (IIAc), (IIAd), (IIB), (IIBa), (III), (IIIA), (IIIAa), (IIIAb), (IIIB), (IIIBa), (IV) and (IVA), and their use in the preparation of drugs for the treatment, prevention and adjuvant treatment of various inflammations and inflammatory immune-related diseases.

The various inflammations and inflammation-immune-related diseases include: rheumatoid arthritis, osteoarthritis, rheumatic 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 after damage, myocardial ischemia, various infectious pneumonias, physical and chemical pneumonia and allergic pneumonia, chronic obstructive pulmonary disease, asthma, spastic anal pain and rectal fissure, hepatobiliary cystitis, cholangitis, primary biliary cirrhosis and cholecystitis. The compounds of the present invention include derivatives and pharmacodynamically acceptable salts thereof.

The common characteristics of inflammatory immune diseases at the cellular level are: over-activation of macrophages and excessive production of NO. Therefore, the present invention conducted an experiment to inhibit the production of NO in primary mouse peritoneal macrophages induced by LPS, and demonstrated that 2,3-diaryl-5-phenylvinylbenzofuran compounds have the activity of inhibiting the excessive production of NO in macrophages at the cellular level.

The fourth aspect of the technical solution of the present invention is to provide a method for preparing the derivative described in the first aspect.

The synthesis method of the target derivative in the present invention comprises the following steps (the required raw material resveratrol can be obtained through commercial purchase):

Step 1: Resveratrol dimerization reaction is used to synthesize the resveratrol dimer derivative δ-viniferin (A) with a 2,3-diaryl-5-phenylbenzodihydrofuran structure.

Resveratrol is subjected to oxidative coupling reaction in anhydrous acetone with Ag ₂ O as an oxidant, and the reaction solution is filtered and concentrated to dryness 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-phenylvinylbenzodihydrofuran resveratrol dimer δ-viniferin (A).

Step 2: The product obtained in step 1 is subjected to phenolic hydroxyl acetylation reaction to synthesize a phenolic hydroxyl acetylated 2,3-diaryl-5-phenylvinylbenzodihydrofuran type intermediate derivative (B).

The product A obtained in step 1 is subjected to acetylation reaction with acetic anhydride in dry pyridine. After removing pyridine from the reaction solution, it is concentrated under reduced pressure to obtain a phenolic hydroxyl acetylated benzodihydrofuran-type resveratrol dimer derivative (B).

Step 3: The product obtained in step 2 is subjected to a dehydrogenation reaction to synthesize a fully acetylated 2,3-diaryl-5-phenylvinylbenzofuran derivative (C).

The product B obtained in step 2 is subjected to oxidation reaction with DDQ in dioxane. After the reaction mixture is filtered to remove DDQ, the fully acetylated benzofuran-type resveratrol dimer derivative (C) is separated by chromatography.

Step 4: The product obtained in step 3 is subjected to a deacetylating reaction to synthesize a 2,3-diaryl-5-phenylvinylbenzofuran-type resveratrol dimer derivative dehydro-δ-viniferin (D).

The fully acetylated product obtained in step 3 is subjected to a deacetylation reaction with NH ₄ OAc in a mixed solution of dichloromethane and methanol. After removing NH ₄ OAc from the reaction mixture, it is concentrated under reduced pressure to obtain the target product, 2,3-diaryl-5-phenylvinylbenzofuran-type resveratrol dimer dehydro-δ-viniferin (D).

Step 5: The product D obtained in step 4 is subjected to an incomplete methylation reaction to synthesize 2,3-diaryl-5-phenylvinylbenzofuran-type resveratrol dimer derivatives with different methoxy substitutions.

Beneficial technical effects

The inventors of the present invention found that the semi-synthetic derivative of the natural product viniferin (δ-viniferin) isolated from wild grapes, a natural product analogue dehydro-δ-viniferin with a 2,3-diaryl-5-phenylphenylbenzofuran structure, had strong antioxidant and anti-inflammatory activities in animal models. On this basis, the compound was structurally derivatized to obtain a series of viniferin derivatives with a 2,3-diaryl-5-phenylphenylbenzofuran structure, and the obtained derivatives were evaluated for inflammation inhibition activity, confirming the anti-inflammatory activity of the compounds. The compounds have significant inhibitory activity on LPS-induced NO production in primary mouse peritoneal macrophages, and have potential value for further research and development.

At present, there is no literature report on the activity and structure-activity relationship of 2,3-diaryl-5-phenylvinylbenzofuran-type viniferin derivatives substituted with different substituents. There is no report in the existing literature and technology on 2,3-diaryl-5-phenylvinylbenzofuran-type viniferin derivatives substituted with different substituents or their medically acceptable salts, and the use of such compounds in the treatment of inflammatory diseases.

Detailed description of the invention:

The various terms and phrases used in the present invention have the general meanings known to those skilled in the art. Even so, the present invention still hopes to provide a more detailed description and explanation of these terms and phrases. If the terms and phrases mentioned are inconsistent with the known meanings, the meanings expressed in the present invention shall prevail. The following are the definitions of various terms used in the present invention, which apply to the terms used in the entire specification of this application, unless otherwise specified in specific circumstances.

The following provides definitions of various groups in the compounds of the present invention, which are used uniformly in the specification and claims unless otherwise defined.

The term "alkyl" mentioned in the present invention refers to an alkyl group having a specified number of carbon atoms, which may be a straight chain or branched alkyl group. For example, the " _C3-6 cycloalkyl group" mentioned refers to a substituted or unsubstituted cycloalkyl group having 3 _{, 4} , 5 or 6 carbon atoms, and may include sub-ranges represented by C3-5 cycloalkyl, _C3-4 cycloalkyl, _C4-6 cycloalkyl, _C4-5 cycloalkyl, _C5-6 cycloalkyl, etc., as well as preferred specific groups, such as cyclopropyl, cyclopentyl and cyclohexyl.

The term "C _1-6 alkyl" mentioned in the present invention refers to a straight chain or branched alkyl group with 1, ₂ , 3, 4, 5, or 6 carbon atoms, and may include sub-range groups represented by C 1-5 alkyl, C _1-4 alkyl, C _2-5 alkyl, C _2-4 alkyl, C _2-3 alkyl, C _3-5 alkyl, etc., as well as preferred specific groups, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, etc.

The term " _C1-6 alkoxy" mentioned in the present invention refers to an alkoxy group having _{1, 2} , 3, 4, 5, or 6 carbon atoms, including sub-range groups represented by C1-5 alkoxy, _C1-2 alkoxy, _C2-4 alkoxy, _C2-3 alkoxy, _C3-4 alkoxy, etc., as well as preferred specific groups such as methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, sec-butyloxy, tert-butyloxy, etc.

The term " _C2-6 unsaturated hydrocarbon group" mentioned in the present invention refers to an unsaturated hydrocarbon group with 2, ₃ , 4, 5, or 6 carbon atoms, and may include sub-range groups represented by _C2-5 unsaturated hydrocarbon groups, C2-4 unsaturated hydrocarbon groups, _C2-5 unsaturated hydrocarbon groups, _C2-4 unsaturated hydrocarbon groups, etc., as well as preferred specific groups, such as vinyl, ethynyl, isopropenyl, isopropynyl, isobutenyl, isopentenyl, 1,3-dibutenyl, etc.

The term "C _1-6 acyl" mentioned in the present invention refers to acyl with 1, 2, 3, 4, 5, 6 carbon atoms, and may include sub-range groups represented by C _1-5 acyl, C _1-3 acyl, C _2-5 acyl, C _2-3 acyl, C _3-4 acyl, etc., as well as preferred specific groups, such as formyl, acetyl, propionyl, etc.

The "C _1-6 acyloxy group" mentioned in the present invention refers to a straight chain or branched acyloxy group with 1 _{, 2} , 3, 4, 5, or 6 carbon atoms, and may include sub-range groups represented by C 1-5 acyloxy, C _1-3 acyloxy, C _2-5 acyloxy, C _2-3 acyloxy, C _3-4 acyloxy, etc., as well as preferred specific groups, such as formyloxy, acetoxy, propionyloxy, etc.

The "C _1-6 alkoxyacyl" mentioned in the present invention refers to alkoxyacyl with 1, 2, 3, 4, 5, and 6 carbon atoms, and may include sub-ranges represented by C _1-5 alkoxyacyl, C _1-3 alkoxyacyl, C _2-5 alkoxyacyl, C _2-3 alkoxyacyl, C _3-4 alkoxyacyl, etc., as well as preferred specific groups, such as methoxyacyl, ethoxyacyl, etc.

The term " _C1-6 alkylthio" mentioned in the present invention refers to a straight chain or branched alkylthio group having 1 _{, 2} , 3, _4, 5, or 6 carbon atoms, and may include sub-range groups represented by C1-5 alkylthio, C1-3 alkylthio, _C2-5 alkylthio, _C2-3 alkylthio, _C3-4 alkylthio, etc., as well as preferred specific groups, such as methylthio, ethylthio, etc.

DETAILED DESCRIPTION

In order to further illustrate the present invention, a series of embodiments are given below. These embodiments are purely illustrative and are only used to specifically describe the present invention, and should not be understood as limiting the present invention.

Example 1: The method for synthesizing the target derivative of the present invention comprises the following steps (the synthetic raw material resveratrol can be obtained commercially):

Example 1

Step 1: Resveratrol dimerization reaction is used to synthesize a resveratrol dimer derivative (A) with a 2,3-diaryl-5-phenylbenzodihydrofuran structure.

60g of resveratrol (263.158mmol) was dissolved in 1500ml of anhydrous acetone, and 67.8g of Ag ₂ O solid was added. The mixture was heated under reflux for 3d to stop the reaction. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated to dryness under reduced pressure to obtain a crude product. The crude product was separated by silica gel (200-300 mesh) column chromatography with petroleum ether: acetone = 3:2 (v/v) to obtain 6.7g of yellow solid A (14.758mmol), with a yield of 11.2%, mp 154-156°C.

Step 2: The product obtained in step 1 is subjected to phenolic hydroxyl acetylation reaction to synthesize a phenolic hydroxyl acetylated 2,3-diaryl-5-phenylvinylbenzodihydrofuran type intermediate derivative (B).

1.28g of compound A (2.81mmol) was dissolved in 15ml of dry pyridine, and 6.64ml of acetic anhydride (70.25mmol) was added, and stirred at room temperature overnight. After the reaction was complete, ice water was slowly dripped in an ice bath, and after it stopped heating, it was transferred to a separatory funnel, and 3 times the volume of water was added to dilute it, and ethyl acetate was extracted three times. The organic phases were combined, washed with saturated CuSO ₄ solution, saturated brine, and water in turn, and dried with anhydrous Na ₂ SO _4. After the obtained organic phase was evaporated to dryness under reduced pressure, the crude product was separated by silica gel (200-300 mesh) column chromatography with petroleum ether: acetone = 3: 1 to obtain 1.79g (2.70mmol) of white solid B, with a yield of 95.7%, mp 182-183°C

Step 3: The product obtained in step 2 is subjected to a dehydrogenation reaction to synthesize a fully acetylated 2,3-diaryl-5-phenylvinylbenzofuran derivative (C).

1.79 g of compound B (2.70 mmol) was dissolved in 25 ml of dry dioxane, and 0.854 g of DDQ (4.05 mmol) was added. The reaction was stopped after heating under reflux for 48 h. The reaction solution was evaporated under reduced pressure. The reaction mixture was dissolved in a small amount of dichloromethane and wet loaded. The mixture was separated by silica gel (200-300 mesh) column chromatography using dichloromethane as eluent to obtain 1.45 g (2.19 mmol) of light white solid C with a yield of 81.1%, m.p.173-174 ° C.

Step 4: The product obtained in step 3 is subjected to a deacetylating reaction to synthesize a 2,3-diaryl-5-phenylvinylbenzofuran-type resveratrol dimer derivative (D).

1.45g of compound C (2.19mmol) was dissolved in 15ml of dichloromethane, and then 15ml of methanol was added, followed by 25.36g _{of NH4OAc} (329mmol), and stirred at room temperature for 2d. The reaction solution was diluted with water, extracted with ethyl acetate, the organic phases were combined, dried over anhydrous _{Na2SO4 ,} filtered, and the solvent was evaporated under reduced pressure to obtain 0.98g (2.17mmol) of yellow solid D, with a yield of 98.9%, mp 97-99°C.

Step 5: Intermediate D is synthesized by incomplete methylation reaction to obtain a mixture of compounds 1-13, and the mixture is separated to obtain pure products of each compound. Their reaction process and spectral identification data are as follows:

0.98g of compound D (2.17mmol) was dissolved in 15ml of anhydrous acetone, and 1.5g of K ₂ CO ₃ solid (10.85mmol) was added in batches under stirring. After stirring for 30min, 0.675ml of CH ₃ I (10.85mmol) was slowly added dropwise, and stirred at room temperature for 12h. A small amount of water was added to the reaction system to stop the reaction, and the reaction was filtered. The reaction solution was diluted with ethyl acetate, washed with water and saturated brine in turn, and the organic phase was concentrated under reduced pressure to obtain a crude product. The reaction mixture was separated by 200-300 mesh silica gel column chromatography, and nine components I-IX were obtained by gradient elution with petroleum ether: acetone 15:1-1:1 (v/v). Component I (15.2 mg) was separated on HPLC with 95% methanol water as the mobile phase via a C18 semi-preparative column (ODS, 5 μm, YMC, 250×10 mm, the same below) to obtain compound 13 (3.0 mg); component II (71.3 mg) was separated on HPLC with 85% methanol water as the mobile phase via a C18 semi-preparative column to obtain compounds 11 (3.6 mg) and 12 (2.5 mg); component IV (82.8 mg) was separated on HPLC with 90% methanol water as the mobile phase via a C18 semi-preparative column to obtain compounds 8 (9.0 mg), 9 (2.0 mg) and 10 (2.0 mg); component V (131.7 mg) was separated on HPLC with 85% methanol water as the mobile phase via a C18 semi-preparative column to obtain compound 6 (7.0 mg) and component VA (21.5 mg); component VA (21.5 mg) was further separated on a C18 semi-preparative column with 70% methanol water as the mobile phase to obtain compound 7 (13.2 mg); component VI (224.6 mg) was separated on a C18 semi-preparative column with 75% methanol water as the mobile phase to obtain compounds 5 (4.0 mg) and VI-C (85.0 mg); VI-C (85.0 mg) was further separated on a C18 semi-preparative column with 50% acetonitrile water to obtain compounds 3 (2.0 mg) and 4 (6.0 mg); component VIII (290.7 mg) was separated on a C18 semi-preparative column with 70% methanol water as the mobile phase to obtain compounds 1 (8.1 mg) and 2 (2.0 mg).

Synthetic final product (compound code corresponds to the compound code in the example):

Compound 1: ¹ H NMR (500MHz, acetone-D ₆ ), δ: 7.66 [2H, d, J = 8.5 Hz, 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＝8.8 Hz,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],10 9.04(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 = 8.8 Hz, 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 (400 MHz, 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 forC 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 = 8.4 Hz, H-2(6)a] 7.57 (1H, brs, 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＝8.4 Hz,H-3(5)a],6.66[4H,br s,H-10(14)a,10(14)b],6.53(1H,brs,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 codes in the pharmacological test section correspond to the compound codes in the examples):

Experimental Example 1: Inhibitory activity of vinblastine derivatives on LPS-induced NO production in primary mouse peritoneal macrophages.

Macrophages perform nonspecific immune functions of the body. They can produce inflammatory factors such as NO under the induction of bacterial lipopolysaccharide LPS, participate in and mediate inflammatory responses, and have high levels in the early stages of various inflammatory immune processes and during the development of pathology. By detecting the NO production of primary cultured mouse macrophages, it can be used as an indicator for preliminary in vitro observation and screening of components or compounds with certain anti-inflammatory activity.

Experimental methods:

Primary mouse peritoneal macrophages were inoculated in 96-well plates, and different test compounds (10 ^-5 M) and positive control drug dexamethasone (Dex) were added for pre-protection for 1 hour; then, 1 μg/ml LPS was added and cultured in a 37°C, 5% CO ₂ incubator for 24 hours, and the supernatant was collected and the NO content was determined by the Griess method. At the same time, the cell proliferation inhibition rate was determined by MTT method.

Experimental results:

The results are shown in Table 1. Compared with the lead compound dehydro-δ-viniferin (DRs-1), the structurally modified viniferin derivatives, while maintaining their activity, have significantly reduced toxicity of compounds 6, 8, and 9. Among them, compounds 1, 2, 4, 5, 6, 7, 8, and 9 have significant NO generation inhibitory activity.

Table 1. Effects of vinblastine derivatives on LPS-induced NO production in primary mouse peritoneal macrophages. ^*

* Concentration: 10 ^-5 M; Therapeutic direction: anti-inflammatory. ^# Compound codes correspond to the compound codes 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.