Aloe-emodin nitrogen heterocyclic derivative and preparation method and application thereof

文档序号：1282259 发布日期：2020-08-28 浏览：23次中文

阅读说明：本技术 一种芦荟大黄素氮杂环衍生物及其制备方法和用途 (Aloe-emodin nitrogen heterocyclic derivative and preparation method and application thereof ) 是由黎勇于 2020-05-29 设计创作，主要内容包括：本发明提供了一种芦荟大黄素氮杂环衍生物及其制备方法和用途,属于化学医药领域。该一种芦荟大黄素氮杂环衍生物是式I所示的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前药、或其代谢产物。本发明化合物可有效抑制巨噬细胞产生NO和炎性因子,还可有效抑制iNOS和COX-2的表达,进而抑制NF-κB信号通路的激活,减轻炎症反应或抑制炎症反应的发生；同时,本发明化合物对于结肠炎,特别是急性溃疡性结肠炎有良好的治疗效果；其中,本发明化合物5r的生物活性显著优于芦荟大黄素。此外,本发明化合物安全性良好,代谢稳定,对抗炎药物的研发具有重要的应用价值。<Image he="381" wi="700" file="DDA0002516759580000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The invention provides an aloe-emodin azacyclic derivative and a preparation method and application thereof, belonging to the field of chemical medicine. The aloe-emodin azacyclic derivative is a compound shown in a formula I, or a salt, a stereoisomer, a solvate, a prodrug or a metabolite thereof. The compound can effectively inhibit macrophage from generating NO and inflammatory factors, and also can effectively inhibit the expression of iNOS and COX-2, so as to inhibit the activation of NF-kB signal channel, reduce inflammatory reaction or inhibit the generation of inflammatory reaction; meanwhile, the compound has good treatment effect on colitis, particularly acute ulcerative colitis; wherein, the biological activity of the compound 5r of the invention is obviously better than that of aloe-emodin. In addition, the compound has good safety and stable metabolism, and has important application value in the research and development of anti-inflammatory drugs.)

1. A compound represented by formula I, or a salt thereof, or a stereoisomer thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof:

wherein the content of the first and second substances,

R₁、R₂are respectively and independently selected from hydrogen and C₁～C₆Alkyl radical, C₁～C₆An alkoxy group;

the ring A is a 3-8-membered saturated heterocyclic group, the number of heteroatoms of the saturated heterocyclic group is 1-3, the heteroatoms of the saturated heterocyclic group are N, O or S, and at least one heteroatom in the saturated heterocyclic group is N;

n R on the A ring₃Substitution;

n is an integer of 0 to 6;

R₃each independently selected from halogen, substituted or unsubstituted C₁～C₆Alkyl radical, C₂～C₆Alkenyl, substituted or unsubstituted C₁～C₆Alkoxy, hydroxy, cyano, ester, -N (H) C (O) OR₄、-C(O)R₅The heterocyclic ring comprises a substituted or unsubstituted 3-8-membered unsaturated cycloalkyl group and a 3-8-membered unsaturated heterocyclic group, wherein the number of heteroatoms of the unsaturated heterocyclic group is 1-3, and the heteroatoms of the unsaturated heterocyclic group are N, O or S;

or two R on two adjacent carbon atoms₃Forming a 3-to 8-membered saturated cycloalkyl group, a substituted or unsubstituted 3-to 8-membered unsaturated cycloalkyl group;

or two R on the same carbon atom₃A 3-to 8-membered substituted or unsubstituted saturated heterocyclic group having a double bond and connected to an O atom, and a hetero atom of the saturated heterocyclic groupThe number of the saturated heterocyclic groups is 1-3, and the heteroatom of the saturated heterocyclic group is N, O or S;

the substituent of the alkyl is-N (H) C (O) OR₄Hydroxy, substituted or unsubstituted C₁～C₆Alkoxy, substituted or unsubstituted 3-to 8-membered unsaturated cycloalkyl;

the substituent of the unsaturated cycloalkyl is halogen and C₁～C₆An alkoxy group;

two substituents on the same carbon atom of the saturated heterocyclic group form a double bond and are connected to an O atom;

the substituent of the alkoxy is hydroxyl;

R₄、R₅are each independently selected from C₁～C₆An alkyl group.

2. The compound according to claim 1, or a salt thereof, or a stereoisomer thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof, wherein:

R₁、R₂are respectively and independently selected from hydrogen and C₁～C₃An alkyl group;

the A ring is a 4-6-membered saturated heterocyclic group, the number of heteroatoms of the saturated heterocyclic group is 1-2, the heteroatoms of the saturated heterocyclic group are N or O, and at least one heteroatom in the saturated heterocyclic group is N;

n R on the A ring₃Substitution;

n is an integer of 0 to 4;

R₃each independently selected from halogen, substituted or unsubstituted C₁～C₃Alkyl radical, C₂～C₃Alkenyl, substituted or unsubstituted C₁～C₃Alkoxy, hydroxy, cyano, carbomethoxy, -N (H) C (O) OR₄、-C(O)R₅The heterocyclic ring is a substituted or unsubstituted phenyl group, and a 5-6-membered unsaturated heterocyclic group, wherein the number of heteroatoms of the unsaturated heterocyclic group is 1-2, and the heteroatoms of the unsaturated heterocyclic group are N or O;

or two R on two adjacent carbon atoms₃Form 5-6 yuan fullAnd cycloalkyl, substituted or unsubstituted phenyl;

or two R on the same carbon atom₃Forming a double bond and connecting an O atom and a substituted or unsubstituted 5-6-membered saturated heterocyclic group, wherein the number of heteroatoms of the saturated heterocyclic group is 1-2, and the heteroatoms of the saturated heterocyclic group are N or O;

the substituent of the alkyl is-N (H) C (O) OR₄Hydroxy, substituted C₁～C₃Alkoxy, substituted or unsubstituted phenyl;

the substituent of the phenyl is halogen and C₁～C₃An alkoxy group;

two substituents on the same carbon atom of the saturated heterocyclic group form a double bond and are connected to an O atom;

the substituent of the alkoxy is hydroxyl;

R₄、R₅are each independently selected from C₁～C₄An alkyl group.

3. The compound according to claim 1, or a salt thereof, or a stereoisomer thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof, wherein: the compound is represented by formula II:

wherein the content of the first and second substances,

R₁、R₂are respectively and independently selected from hydrogen and C₁～C₃An alkyl group;

n is an integer of 0 to 1; when N is 0, N is hydrogen;

R₃each independently selected from halogen, substituted or unsubstituted C₁～C₃Alkyl radical, C₂～C₃Alkenyl, substituted or unsubstituted C₁～C₃Alkoxy, hydroxy, cyano, carbomethoxy, -N (H) C (O) OR₄、-C(O)R₅Substituted or unsubstituted phenyl, 5-to 6-membered unsaturated heterocyclic group, hetero atom of the unsaturated heterocyclic groupThe number of the sub-groups is 1-2, and the heteroatom of the unsaturated heterocyclic group is N or O;

the substituent of the alkyl is-N (H) C (O) OR₄Hydroxy, substituted C₁～C₃Alkoxy, substituted or unsubstituted phenyl;

the substituent of the phenyl is halogen and C₁～C₃An alkoxy group;

the substituent of the alkoxy is hydroxyl;

R₄、R₅are each independently selected from C₁～C₄An alkyl group;

preferably, the first and second electrodes are formed of a metal,

R₁、R₂are respectively and independently selected from hydrogen and C₁～C₃An alkyl group;

n is an integer of 0 to 1; when N is 0, N is hydrogen;

the substituent of the alkyl is-N (H) C (O) OR₄Hydroxy, substituted C₁～C₃Alkoxy, substituted or unsubstituted phenyl;

the substituent of the phenyl is halogen and C₁～C₃An alkoxy group;

the substituent of the alkoxy is hydroxyl;

R₄、R₅are each independently selected from C₁～C₄An alkyl group.

4. The compound according to claim 3, or a salt thereof, or a stereoisomer thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof, wherein: the compound is shown as a formula II-A:

wherein the content of the first and second substances,

n is an integer of 0 to 1; when N is 0, N is hydrogen;

the substituent of the alkyl is-N (H) C (O) OR₄Hydroxy, substituted C₁～C₃Alkoxy, substituted or unsubstituted phenyl;

the substituent of the phenyl is halogen and C₁～C₃An alkoxy group;

the substituent of the alkoxy is hydroxyl;

R₄、R₅are each independently selected from C₁～C₄An alkyl group.

5. The compound according to claim 3, or a salt thereof, or a stereoisomer thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof, wherein: the compound is shown as a formula II-B:

wherein the content of the first and second substances,

n is an integer of 0 to 1; when N is 0, N is hydrogen;

the substituent of the alkyl is-N (H) C (O) OR₄Hydroxy, substituted C₁～C₃Alkoxy, substituted or unsubstituted phenyl;

the substituent of the phenyl is halogen and C₁～C₃An alkoxy group;

the substituent of the alkoxy is hydroxyl;

R₄、R₅are each independently selected from C₁～C₄An alkyl group.

6. The compound according to claim 1, or a salt thereof, or a stereoisomer thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof, wherein: the compound is shown as formula III:

wherein the content of the first and second substances,

n R on the A ring₃Substitution;

n is an integer of 0 to 4;

or two R on two adjacent carbon atoms₃Forming a 5-to 6-membered saturated cycloalkyl group, a substituted or unsubstituted phenyl group;

the substituent of the alkyl is-N (H) C (O) OR₄Hydroxy, substituted C₁～C₃Alkoxy, substituted or unsubstituted phenyl;

the substituent of the phenyl is halogen and C₁～C₃An alkoxy group;

two substituents on the same carbon atom of the saturated heterocyclic group form a double bond and are connected to an O atom;

the substituent of the alkoxy is hydroxyl;

R₄、R₅are each independently selected from C₁～C₄An alkyl group.

7. The compound according to any one of claims 1 to 6, or a salt thereof, or a stereoisomer thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof, wherein: the compound is one of the following compounds:

8. a process for preparing a compound of claim 4 or 6, wherein: it comprises the following steps:

step a: dissolving the compound 1 in an organic solvent, and reacting with dimethyl sulfate and potassium carbonate to obtain a compound 2;

step b: reacting the thionyl chloride with the compound 2 to obtain a compound 3;

step c: a compound 3,Dissolving potassium carbonate in a solvent, and reacting under the action of a catalytic amount of a catalyst to obtain a compound 4;

wherein, A ring, R₃And n is the same as in claim 4 or 6;

preferably, the first and second electrodes are formed of a metal,

in the step a, the organic solvent is acetone;

and/or in step a, the molar ratio of the compound 1, dimethyl sulfate and potassium carbonate is 1:2.5: 4;

and/or in the step a, refluxing for 10-12 h at the temperature of 60-100 ℃;

and/or in the step b, the volume mass ratio of the thionyl chloride to the compound 2 is 10 mL: 1mmol of the active component;

and/or in the step b, refluxing for 8-10 h at 90-100 ℃;

and/or, in step c, compound 3,The molar ratio of the potassium carbonate to the potassium carbonate is 1:1: 2;

and/or, in step c, the catalyst is potassium iodide;

and/or, in the step c, the solvent is a mixed solution of DMF and MeCN, and the volume ratio of the DMF to the MeCN is 1: 4;

and/or in the step c, heating for 8-10 h at 70-100 ℃;

more preferably still, the first and second liquid crystal compositions are,

step a, purifying the compound 2, wherein the purification method comprises the steps of cooling the mixture to room temperature after the reaction is finished, filtering, washing residues with water and drying in the air;

and/or, in the step b, further purifying the compound 3, wherein the purification method comprises the steps of spin-drying the solvent after the reaction, quenching the residue with ice water, extracting with ethyl acetate, combining organic phases, washing, drying, and purifying by silica gel column chromatography; further preferably, the silica gel column chromatography is eluted with a gradient of 95:5 by volume of DCM and MeOH;

and/or, in the step c, purifying the compound 4, wherein the purification method comprises the steps of diluting with ethyl acetate after the reaction is finished, adding water for extraction, washing an organic phase, drying, and purifying by using a column chromatography; it is further preferred that the column chromatography is eluted with a gradient of DCM and MeOH at a volume ratio of 97: 3.

9. A process for preparing the compound of claim 5, wherein: it comprises the following steps:

step A: dissolving the compound 1 in an organic solvent, adding thionyl chloride, and reacting to obtain a compound 6;

and B: the compound 6,Dissolving potassium carbonate in a solvent, and reacting under the action of a catalytic amount of a catalyst to obtain a compound 7;

wherein R is₃And n is the same as in claim 5;

preferably, the first and second electrodes are formed of a metal,

in the step A, the organic solvent is DMF;

and/or, in the step A, the molar volume ratio of the compound 1 to the thionyl chloride is 1 mmol: 2 mL;

and/or in the step A, the reaction is carried out at room temperature;

and/or, in step B, the compound 6,The molar ratio of the potassium carbonate is 1:1: 2;

and/or, in the step B, the catalyst is potassium iodide;

and/or in the step B, the solvent is a mixed solution of DMF and MeCN, and the volume ratio of the DMF to the MeCN is 1: 4;

and/or in the step B, heating for 8-10 h at 70-100 ℃;

more preferably still, the first and second liquid crystal compositions are,

step A, purifying the compound 6, wherein the purification method comprises the steps of adding ice water and stirring after the reaction is finished to obtain orange precipitate, and filtering, washing and drying the precipitate;

and/or, in the step B, purifying the compound 7, wherein the purification method comprises the steps of diluting with ethyl acetate after the reaction is finished, adding water for extraction, washing an organic phase, drying, and purifying by using a column chromatography; it is further preferred that the column chromatography is eluted with a gradient of DCM and MeOH at a volume ratio of 97: 3.

10. Use of a compound according to any one of claims 1 to 7, or a salt thereof, or a stereoisomer thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof, for the manufacture of an anti-inflammatory agent;

preferably, the medicament is a medicament for treating colitis;

more preferably, the medicament is a medicament for treating ulcerative colitis;

further preferably, the medicament is a medicament for treating acute ulcerative colitis.

11. Use of a compound according to any one of claims 1 to 7, or a salt thereof, or a stereoisomer thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof, for the preparation of an NO inhibitor, an IL-1 β inhibitor, a TNF- α inhibitor, a PGE2 inhibitor, an iNOS inhibitor, a COX-2 inhibitor, or an NF- κ B inhibitor.

12. A medicament, characterized by: the compound or the salt thereof, the stereoisomer thereof, the solvate thereof, the prodrug thereof, or the metabolite thereof according to any one of claims 1 to 7 is used as an active ingredient, and is added with pharmaceutically acceptable auxiliary materials to prepare the preparation.

Technical Field

The invention belongs to the field of chemical medicine, and particularly relates to an aloe-emodin nitrogen heterocyclic derivative, and a preparation method and application thereof.

Background

Inflammation is a fundamental pathological process in which a defense response is mainly generated by the stimulation of living tissues having a vascular system to various injury factors. The typical symptoms of acute inflammation include redness, swelling, heat, pain, dysfunction, etc., and are accompanied by systemic reactions such as fever, peripheral blood leukocyte changes, etc. During the development of inflammation, the NF- κ B signaling pathway plays an important role, and in dormant cells, local cytoplasm of NF- κ B and inhibitors are combined into I κ B. Proinflammatory cytokines, such as IL-1 and TNF- α, can trigger NF- κ B signaling pathway activation, leading to phosphorylation and subsequent proteasome-mediated degradation. Once degenerated, inhibitors and NF-. kappa.B are no longer bound as I.kappa.B, free entry of NF-. kappa.B into the nucleus induces expression of a variety of genes, including those encoding cytokines (e.g., IL-1, 2 and 6), TNF-. alpha.and other proteins, that stimulate the inflammatory response.

Excessive inflammatory responses can trigger a variety of diseases, including inflammatory bowel disease, rheumatoid arthritis, alzheimer's disease, and the like. Among them, ulcerative colitis is an autoimmune inflammatory disease affecting millions of people worldwide and is characterized by uncontrolled chronic inflammation of the intestinal mucosa. There is currently no complete cure, the main therapeutic goal being to reduce relapse and improve the quality of life of the patient. Aminosalicylic acid and glucocorticoid drugs are the current first choice for the treatment of ulcerative colitis, however, these drugs may also cause severe side effects including diarrhea, cramps, abdominal pain with fever, and, with continued use, risk of developing hypertension.

Natural animals and plants have been a treasure house for the discovery of bioactive components. In recent years, there have been increasing numbers of researchers developing new anti-inflammatory drugs from natural active ingredients. Aloe-emodin is an anthraquinone bioactive substance extracted from radix et rhizoma Rhei and Aloe. Recent research shows that aloe-emodin has anticancer, antiviral, antiphlogistic, antibacterial and other pharmacological effects. However, aloe-emodin has the characteristics of poor intestinal absorption, short half-life period, low bioavailability and the like, and clinical development and application of aloe-emodin are limited, so that modification of aloe-emodin structure, namely retention of biological activity, and overcoming of the existing problems are necessary.

Disclosure of Invention

The invention aims to provide an aloe-emodin nitrogen heterocyclic derivative and a preparation method and application thereof.

The present invention provides a compound represented by formula I, or a salt thereof, or a stereoisomer thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof:

wherein the content of the first and second substances,

R₁、R₂are respectively and independently selected from hydrogen and C₁～C₆Alkyl radical, C₁～C₆An alkoxy group;

n R on the A ring₃Substitution;

n is an integer of 0 to 6;

or two R on two adjacent carbon atoms₃Forming a 3-to 8-membered saturated cycloalkyl group, a substituted or unsubstituted 3-to 8-membered unsaturated cycloalkyl group;

or two R on the same carbon atom₃Forming a double bond and connecting an O atom and a substituted or unsubstituted 3-to 8-membered saturated heterocyclic group, wherein the number of heteroatoms of the saturated heterocyclic group is 1 to 3, and the heteroatom of the saturated heterocyclic group is N, O or S;

the substituent of the alkyl is-N (H) C (O) OR₄Hydroxy, substituted or unsubstituted C₁～C₆Alkoxy, substituted or unsubstituted 3-to 8-membered unsaturated cycloalkyl;

the substituent of the unsaturated cycloalkyl is halogen and C₁～C₆An alkoxy group;

two substituents on the same carbon atom of the saturated heterocyclic group form a double bond and are connected to an O atom;

the substituent of the alkoxy is hydroxyl;

R₄、R₅are each independently selected from C₁～C₆An alkyl group.

Further, the air conditioner is provided with a fan,

R₁、R₂are respectively and independently selected from hydrogen and C₁～C₃An alkyl group;

n R on the A ring₃Substitution;

n is an integer of 0 to 4;

or two R on two adjacent carbon atoms₃Forming a 5-to 6-membered saturated cycloalkyl group, a substituted or unsubstituted phenyl group;

the substituent of the alkyl is-N (H) C (O) OR₄Hydroxy, substituted C₁～C₃Alkoxy, substituted or unsubstituted phenyl;

the substituent of the phenyl is halogen and C₁～C₃An alkoxy group;

two substituents on the same carbon atom of the saturated heterocyclic group form a double bond and are connected to an O atom;

the substituent of the alkoxy is hydroxyl;

R₄、R₅are each independently selected from C₁～C₄An alkyl group.

Further, the compound is represented by formula II:

wherein the content of the first and second substances,

R₁、R₂are respectively and independently selected from hydrogen and C₁～C₃An alkyl group;

n is an integer of 0 to 1; when N is 0, N is hydrogen;

the substituent of the alkyl is-N (H) C (O) OR₄Hydroxy, substituted C₁～C₃Alkoxy, substituted or unsubstituted phenyl;

the substituent of the phenyl is halogen and C₁～C₃An alkoxy group;

the substituent of the alkoxy is hydroxyl;

R₄、R₅are each independently selected from C₁～C₄An alkyl group;

preferably, the first and second electrodes are formed of a metal,

R₁、R₂are respectively and independently selected from hydrogen and C₁～C₃An alkyl group;

n is an integer of 0 to 1; when N is 0, N is hydrogen;

R₃each independently selected from halogen, substituted or unsubstituted C₁～C₃Alkyl radical, C₂～C₃Alkenyl, substituted or unsubstituted C₁～C₃Alkoxy, hydroxy, cyano, methyl formate, ethyl formate, acetic acidCarbethoxy, -N (H) C (O) OR₄、-C(O)R₅Substituted or unsubstituted phenyl, pyridyl, pyrimidinyl;

the substituent of the alkyl is-N (H) C (O) OR₄Hydroxy, substituted C₁～C₃Alkoxy, substituted or unsubstituted phenyl;

the substituent of the phenyl is halogen and C₁～C₃An alkoxy group;

the substituent of the alkoxy is hydroxyl;

R₄、R₅are each independently selected from C₁～C₄An alkyl group.

Further, the compound is represented by formula II-A:

wherein the content of the first and second substances,

n is an integer of 0 to 1; when N is 0, N is hydrogen;

the substituent of the alkyl is-N (H) C (O) OR₄Hydroxy, substituted C₁～C₃Alkoxy, substituted or unsubstituted phenyl;

the substituent of the phenyl is halogen and C₁～C₃An alkoxy group;

the substituent of the alkoxy is hydroxyl;

R₄、R₅are each independently selected from C₁～C₄An alkyl group.

Further, the compound is represented by formula II-B:

wherein the content of the first and second substances,

n is an integer of 0 to 1; when N is 0, N is hydrogen;

the substituent of the alkyl is-N (H) C (O) OR₄Hydroxy, substituted C₁～C₃Alkoxy, substituted or unsubstituted phenyl;

the substituent of the phenyl is halogen and C₁～C₃An alkoxy group;

the substituent of the alkoxy is hydroxyl;

R₄、R₅are each independently selected from C₁～C₄An alkyl group.

Further, the compound is represented by formula III:

wherein the content of the first and second substances,

n R on the A ring₃Substitution;

n is an integer of 0 to 4;

or two R on two adjacent carbon atoms₃Forming a 5-to 6-membered saturated cycloalkyl group, a substituted or unsubstituted phenyl group;

the substituent of the alkyl is-N (H) C (O) OR₄Hydroxy, substituted C₁～C₃Alkoxy, substituted or unsubstituted phenyl;

the substituent of the phenyl is halogen and C₁～C₃An alkoxy group;

two substituents on the same carbon atom of the saturated heterocyclic group form a double bond and are connected to an O atom;

the substituent of the alkoxy is hydroxyl;

R₄、R₅are each independently selected from C₁～C₄An alkyl group.

Further, the compound is one of the following compounds:

the present invention also provides a process for preparing the aforementioned compound, comprising the steps of:

step a: dissolving the compound 1 in an organic solvent, and reacting with dimethyl sulfate and potassium carbonate to obtain a compound 2;

step b: reacting the thionyl chloride with the compound 2 to obtain a compound 3;

step c: a compound 3,Dissolving potassium carbonate in a solvent, and reacting under the action of a catalytic amount of a catalyst to obtain a compound 4;

wherein, A ring, R₃And n is the same as previously;

preferably, the first and second electrodes are formed of a metal,

in the step a, the organic solvent is acetone;

and/or in step a, the molar ratio of the compound 1, dimethyl sulfate and potassium carbonate is 1:2.5: 4;

and/or in the step a, refluxing for 10-12 h at the temperature of 60-100 ℃;

and/or in the step b, the volume mass ratio of the thionyl chloride to the compound 2 is 10 mL: 1mmol of the active component;

and/or in the step b, refluxing for 8-10 h at 90-100 ℃;

and/or, in step c, compound 3,The molar ratio of the potassium carbonate to the potassium carbonate is 1:1: 2;

and/or, in step c, the catalyst is potassium iodide;

and/or, in the step c, the solvent is a mixed solution of DMF and MeCN, and the volume ratio of the DMF to the MeCN is 1: 4;

and/or in the step c, heating for 8-10 h at 70-100 ℃;

more preferably still, the first and second liquid crystal compositions are,

The present invention also provides a process for preparing the aforementioned compound, comprising the steps of:

step A: dissolving the compound 1 in an organic solvent, adding thionyl chloride, and reacting to obtain a compound 6;

and B: the compound 6,Dissolving potassium carbonate in a solvent, and reacting under the action of a catalytic amount of a catalyst to obtain a compound 7;

wherein R is₃And n is the same as previously;

preferably, the first and second electrodes are formed of a metal,

in the step A, the organic solvent is DMF;

and/or, in the step A, the molar volume ratio of the compound 1 to the thionyl chloride is 1 mmol: 2 mL;

and/or in the step A, the reaction is carried out at room temperature;

and/or, in step B, the compound 6,Mols of potassium carbonateThe ratio is 1:1: 2;

and/or, in the step B, the catalyst is potassium iodide;

and/or in the step B, the solvent is a mixed solution of DMF and MeCN, and the volume ratio of the DMF to the MeCN is 1: 4;

and/or in the step B, heating for 8-10 h at 70-100 ℃;

more preferably still, the first and second liquid crystal compositions are,

The invention also provides the application of the compound or the salt thereof, or the stereoisomer thereof, or the solvate thereof, or the prodrug thereof, or the metabolite thereof in preparing anti-inflammatory drugs;

preferably, the medicament is a medicament for treating colitis;

more preferably, the medicament is a medicament for treating ulcerative colitis;

further preferably, the medicament is a medicament for treating acute ulcerative colitis.

The invention also provides application of the compound or the salt thereof, or the stereoisomer thereof, or the solvate thereof, or the prodrug thereof, or the metabolite thereof in preparing NO inhibitors, IL-1 beta inhibitors, TNF-alpha inhibitors, PGE2 inhibitors, iNOS inhibitors, COX-2 inhibitors or NF-kB inhibitors.

The invention also provides a medicament which is a preparation prepared by taking the compound, or the salt, the stereoisomer, the solvate, the prodrug or the metabolite thereof as an active ingredient and adding pharmaceutically acceptable auxiliary materials.

The room temperature in the invention is 25 +/-5 ℃; the overnight refers to 12. + -. 2 h.

The compounds and derivatives provided in the present invention may be named according to the IUPAC (international union of pure and applied chemistry) or CAS (chemical abstracts service, Columbus, OH) naming system.

Definitions of terms used in connection with the present invention: the initial definitions provided herein for a group or term apply to that group or term throughout the specification unless otherwise indicated; for terms not specifically defined herein, the meanings that would be given to them by a person skilled in the art are to be given in light of the disclosure and the context.

"substituted" means that a hydrogen atom in a molecule is replaced by a different atom or molecule.

The structures of the compounds in the invention are all structures capable of stably existing.

The minimum and maximum carbon atom contents of the hydrocarbon groups in the present invention are indicated by prefixes, e.g. prefix (C)_a～C_b) Alkyl means any alkyl group containing from "a" to "b" carbon atoms. Thus, for example, C₁～C₆The alkyl refers to a straight chain or branched chain alkyl containing 1-6 carbon atoms; c₂～C₆The alkenyl group means an alkenyl group having 2 to 6 carbon atoms; c₁～C₆The alkoxy group means an alkoxy group having 1 to 6 carbon atoms.

In the invention, the 3-8 membered saturated cycloalkyl refers to monocyclic cycloalkyl consisting of 3-8 carbon atoms, wherein the cycloalkyl has no double bond; the 3-8-membered unsaturated cycloalkyl refers to monocyclic cycloalkyl consisting of 3-8 carbon atoms, wherein the cycloalkyl contains one or more double bonds; the 3-8 membered saturated heterocyclic group refers to a monocyclic heterocyclic group having no double bond, wherein at least one heteroatom in the heterocyclic group is O, S or N, and the remaining ring atoms are carbon; the 3-8 membered unsaturated heterocyclic group is a monocyclic heterocyclic group containing at least one double bond, wherein the heterocyclic group has at least one heteroatom selected from O, S or N, and the remaining ring atoms are carbon.

In the present invention, halogen is fluorine, chlorine, bromine or iodine.

Substitution of the inventionThe radicals "-N (H) C (O) OR₄The structural formula isSubstituent groups of the invention "-C (O) R₅The structural formula is

In the present invention, the "two substituents on the same carbon atom form a double bond and are bonded to an O atom" forms a structure

The compounds of the invention have the following beneficial effects:

(1) the compound has an inhibiting effect on macrophage NO generation, wherein the inhibiting effect of the compounds 5r, 7a, 7b and 7c is obvious and is obviously superior to that of aloe-emodin, and the compound can be used for preparing NO inhibitors; among them, compound 5r has the best cell compatibility;

(2) the compounds of the present invention may also inhibit the production of cytokines L-1 β, TNF- α and PGE2 by macrophages; and inhibiting the expression of iNOS and COX-2, and inhibiting the activation of NF-kB and the expression of relevant proinflammatory factors to a certain extent; thereby reducing inflammatory reaction; the compound can be used for preparing NO inhibitors, IL-1 beta inhibitors, TNF-alpha inhibitors, PGE2 inhibitors, iNOS inhibitors, COX-2 inhibitors or NF-kappa B inhibitors.

(3) The compound can effectively improve the pathological changes and the inflammatory cell number of the acute ulcerative colitis, and prevent and treat the colon length shortening; can be used for treating acute ulcerative colitis, and can be used for preparing medicine for treating acute ulcerative colitis.

In a word, the compound can effectively inhibit macrophage from generating NO and inflammatory factors, and also can effectively inhibit the expression of iNOS and COX-2, so as to inhibit the activation of NF-kB signal channel, relieve inflammatory reaction or inhibit the generation of inflammatory reaction; meanwhile, the compound has good treatment effect on colitis, particularly acute ulcerative colitis; wherein, the biological activity of the compound 5r of the invention is obviously better than that of aloe-emodin. In addition, the compound has good safety and stable metabolism, and has important application value in the research and development of anti-inflammatory drugs.

Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.

The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.

Drawings

FIG. 1 shows the results of cytotoxicity evaluation of compounds 5r, 7a, 7b and 7 c.

FIG. 2 shows the inhibitory activity of compound 5r on the production of cytokines TNF- α, IL-1 β, IL-6, PGE 2.

FIG. 3 is a graph showing the effect of compound 5r on NF- κ B signaling pathway and related proinflammatory factors.

Figure 4 is the anti-inflammatory activity of compound 5r on a DSS-induced mouse colitis model.

Figure 5 is a picture of the pathological changes of compound 5r on the DSS-induced mouse colitis model.

Detailed Description

The raw materials and equipment used in the embodiment of the present invention are known products and obtained by purchasing commercially available products.

The synthetic routes for compounds 4a-4t and compounds 5a-5r are as follows:

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Aloe-emodin nitrogen heterocyclic derivative and preparation method and application thereof

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