CN110105344B

CN110105344B - Compound and synthesis method and application thereof

Info

Publication number: CN110105344B
Application number: CN201910455532.7A
Authority: CN
Inventors: 雷晓光; 吴凡; 岳宗伟; 郭富生
Original assignee: Peking University
Current assignee: Peking University
Priority date: 2019-05-29
Filing date: 2019-05-29
Publication date: 2021-07-09
Anticipated expiration: 2039-05-29
Also published as: CN110105344A

Abstract

The invention relates to a compound, a synthesis method and application thereof, wherein the compound has a structure shown in a general formula I, shows good inhibitory activity to different tumor cell lines under the condition of illumination, and has ideal anti-tumor and anti-skin disease treatment effects. The invention also relates to a synthetic method of the compound, which adopts a chemical total synthesis route, and the convergent synthetic route can be applied to the chemical synthesis of compounds with similar structures and related derivatives, thereby opening up a wide development space for novel anti-tumor and anti-skin disease drugs.

Description

Compound and synthesis method and application thereof

Technical Field

The invention relates to the field of pharmaceutical chemistry, in particular to a light-operated anti-tumor and anti-skin disease compound, and also relates to a chemical synthesis method of the compound and application of the compound in preparation of medicines.

Background

Malignant tumors are one of the most major worldwide lethal factors, with millions or even tens of millions of people dying from the disease each year. Prevention, control and treatment of malignant tumors are medical problems that are urgently needed to be solved. When a gene controlling processes such as cell proliferation and cell cycle is mutated, abnormal cell proliferation is caused, and finally malignant tumor is formed. Tumor cells differ in their energy metabolism compared to normal cells by their higher uptake of glucose. In order to obtain higher nutrients, the tumor tissue can continue to form new blood vessels during the formation process and can spread and metastasize to other parts of the body in the later stages. The immune system often accompanies inflammatory responses when attempting to eliminate tumor cells. The establishment of a tumor growth microenvironment can be promoted by inflammatory reaction and angiogenesis, and in the microenvironment, the tumor cells can be rapidly and autonomously proliferated by the abnormally expressed growth factors, growth factor receptors and downstream signal molecules of the signal pathways of the growth factors and the growth factors, so that the growth of the tumor cells is completely separated from control.

The therapeutic means for malignant tumor include surgical treatment, chemical drug therapy and physical radiation therapy. Traditional chemotherapy not only kills tumor cells, but also has dose-dependent toxicity to normal cells, and the main problem of traditional chemotherapy is that 'killing one thousand and eight hundred self-damage' is caused. In addition, due to different tumor-producing reasons, malignant tumors can acquire different drug resistance in the medication process, so that the drug treatment means is ineffective. In order to solve the problems of toxic and side effects and drug resistance of the antitumor drugs, some novel antitumor drugs need to be developed, such as light-operated therapeutic drugs, molecular drugs targeting key proteins and nucleic acid molecules in the tumor generation process, and the like.

Psoriasis is commonly called as psoriasis, is a chronic inflammatory skin disease, has long course of disease and easy recurrence tendency, and some cases are not cured almost for the whole life. The disease is mainly developed in young and old years, and has great influence on the physical health and mental conditions of patients. Although there are many drugs on the market for treating the disease at present, many drugs, especially topical drugs, have the disadvantages of poor effect or significant side effects in clinical use.

Natural products are a rich source of drugs and are also considered to be an important choice for the search for new anti-tumor drugs. Many of the drugs available on the market today are of natural product origin, both with the active ingredient being directly a natural product and from an altered analogue of a natural product. Statistically, 41% of anticancer drugs and 65% of antibacterial drugs are natural products or similar derivatives. Examples of natural products found and used as medicaments are well known, such as morphine, an opioid analgesic, penicillin, a beta-lactam antibiotic, artemisinin, an antimalarial drug and the like. The natural product provides a wide compound library for drug screening by using the unique structural characteristics and the skeleton diversity of the natural product. Hert et al reported that 83% of the core backbone of the natural product was not present in commercially available compounds and screening libraries.

Gilvocarcin V is the major metabolite of Streptomyces griseoflavus and of various other types of Streptomyces, which is often produced with a small number of its homologues gilvacicin M and gilvacicin E, which differ by the side chain at the C-8 position. These natural products, extracted from different streptomyces species organisms, are collectively referred to as gilvacrcin-type compounds. These compounds are polyketides of the benzo [ d ] naphtho [1,2-b ] pyran-6-one type, but differ in the part of the sugar that is glycosylated. The natural products of the family have strong antitumor activity, unique action mechanism and low toxicity. In early studies on natural products of the gilvacrcin family, it was discovered that it could exert an anti-tumor effect by inhibiting the catalytic activity of human topoisomerase II. In human leukemia cells, its median inhibitory concentration (IC50s) was below 1mM, and significant DNA damage and apoptosis could be observed.

Disclosure of Invention

The first purpose of the invention is to provide a novel compound or a pharmaceutically acceptable salt thereof, which shows good inhibitory activity on tumor cells under the condition of light and has ideal anti-tumor and anti-skin disease treatment effects.

Specifically, the present invention provides a compound as described above or a pharmaceutically acceptable salt thereof:

in the general formula I:

R₁、R₂、R₆independently of one another, represents hydrogen, alkyl or phosphate;

R₃、R₄、R₅independently of one another, represents glucose, galactose, mannose, N-acetylglucose, glucuronic acid, 6-deoxy-glucose, 2, 6-dideoxy-glucose, N-acetylgalactosamine, sialic acid, fucose, xylose, rhamnose, maltose, lactose, a polysaccharide, hydrogen, an aromatic ring, an amide group, a formaldehyde group, a carboxyl group (COOH), a halogen atom, a nitro group (NO), a carboxyl group (COOH)₂) Hydroxyl (OH), amino (NH)₂) A cyano group;

R₇represents a vinyl group.

In any of the configurations described herein (i.e., may correspond to any of the related concepts, any ranges, etc., mentioned herein below):

the alkyl group means a straight or branched chain saturated hydrocarbon group including 1 to 18 carbon atoms, for example, 1 to 12 carbon atoms, and further for example, 1 to 6 carbon atoms. Examples of alkyl groups may be selected from methyl, ethyl, 1-propyl or n-propyl ("n-Pr"), 2-propyl or isopropyl ("i-Pr"), 1-butyl or n-butyl ("n-Bu"), 2-methyl-1-propyl or isobutyl ("i-Bu"), 1-methylpropyl or sec-butyl ("s-Bu"), 1-dimethylethyl or tert-butyl ("t-Bu").

The amido refers to substituted amino (or amine) group, and the substituent of the amino (or amine) group includes but is not limited to alkyl, alkynyl, heterocyclic radical; wherein alkynyl means propargyl; heterocyclyl means a 4 to 12 membered monocyclic, bicyclic or tricyclic saturated or unsaturated ring group comprising at least one carbon atom other than at least one heteroatom selected from N, O or S; the number of heteroatoms is from 1 to 4, preferably from 1 to 3, more preferably 1 or 2 heteroatoms; monocyclic rings are preferred, such as piperidine, morpholine, tetrahydropyrrole, 4-piperidylpiperidine, 2-hydroxyethylpyrrole, homopiperazine, piperazine and tetrahydropyran.

Preferably, the amide group refers to an amide group in which the substituent of the amino (or amine) group is an alkyl group of 1 to 6 carbon atoms, a propargyl group, a piperidine, a morpholine, a tetrahydropyrrole, a 4-piperidyl piperidine.

The halogen atom is one of F, Cl, Br and I.

The aromatic ring is selected from optionally substituted aromatic hydrocarbon groups with 6 to 20 carbon atoms, preferably optionally substituted monocyclic aromatic hydrocarbon, bicyclic aromatic hydrocarbon or polycyclic aromatic hydrocarbon; more preferably, the aromatic ring is a substituted benzene ring; the substituted benzene ring is characterized in that at least one hydrogen on the benzene ring is substituted by an isotope, a cyano group, a nitro group, a carboxyl group, an ester group, a phenoxy group, a methylthio group which is unsubstituted or substituted by 1-3 fluorine atoms, and an alkyl or alkoxy group with 1-8 carbon atoms, wherein one or more hydrogen in the alkyl or alkoxy group can be optionally substituted by halogen; particularly preferably, the substituted phenyl ring comprises at least one hydrogen on the phenyl ring substituted with deuterium, tritium, cyano, trifluoromethyl, difluoromethyl, methoxy, trifluoromethoxy, phenoxy, nitro, acetyl, carboxy, benzoate, methylthio or trifluoromethylthio.

The fucose includes fucofuranose and fucopyranose.

In any of the structures described herein, preferably R₁、R₂、R₆Independently of one another, represents hydrogen or alkyl, or R₁And R₆Represents a methyl group; r₂Represents hydrogen, alkyl or phosphate, preferably the alkyl is C₁-C₃More preferably methyl;

further, in the general formula I, R is preferably₁、R₂、R₆In which at least two represent methyl, and/or R₆Is methyl (i.e. at least R)₆Is methyl).

In any of the structures described herein, preferably R₃、R₄、R₅Independently of one another, represents hydrogen, an amide group, a carboxaldehyde group, a carboxyl group,Glucose, galactose, mannose, N-acetylglucose, glucuronic acid, 6-deoxy-glucose, 2, 6-dideoxy-glucose, N-acetylgalactosamine, sialic acid, fucose (including fucofuranose and fucopyranose), xylose, rhamnose, maltose, lactose, a polysaccharide, a benzene ring, a substituted benzene ring, a pyridine ring or a salt thereof; the substituted benzene ring is characterized in that at least one hydrogen on the benzene ring is substituted by an isotope thereof, a cyano group, a nitro group, a carboxyl group, an ester group, a phenoxy group, a methylthio group which is unsubstituted or substituted by 1-3 fluorine atoms, and an alkyl or alkoxy group with 1-8 carbon atoms, wherein one or more hydrogen in the alkyl or alkoxy group is optionally substituted by halogen;

preferably, the substituted phenyl ring comprises at least one hydrogen on the phenyl ring substituted with deuterium, tritium, cyano, trifluoromethyl, difluoromethyl, methoxy, trifluoromethoxy, phenoxy, nitro, acetyl, carboxyl, an ester group (such as benzoate), methylthio or trifluoromethylthio.

In any of the structures described herein, preferably R₃、R₄、R₅At least two of which represent hydrogen; more preferably, R₃、R₄Represents hydrogen, R₅Represents glucose, galactose, mannose, N-acetylglucose, glucuronic acid, 6-deoxy-glucose, 2, 6-dideoxy-glucose, N-acetylgalactosamine, sialic acid, fucose (including fucose and fucopyranose), xylose, rhamnose, maltose, lactose, polysaccharide or amide groups.

As a side-by-side scheme (hereinafter may also be referred to as side-by-side structure 1), among the above compounds:

R₄is hydrogen; r₃、R₅Independently of one another, represents glucose, galactose, mannose, N-acetylglucose, glucuronic acid, N-acetylgalactosamine, sialic acid, fucose, fucopyranose, xylose, rhamnose, 6-deoxy-glucose, 2, 6-dideoxy-glucose, amide groups, formaldehyde groups, carboxyl groups, aromatic rings, maltose, lactose, polysaccharidesHydrogen, a halogen atom, a nitro group, a hydroxyl group, an amino group, or a cyano group;

preferably, R₃、R₅Any one of them represents hydrogen, and the other one represents glucose, galactose, mannose, N-acetylglucose, glucuronic acid, N-acetylgalactosamine, sialic acid, fucofuranose, fucopyranose, xylose, rhamnose, maltose, lactose, polysaccharide, 6-deoxy-glucose, 2, 6-dideoxy-glucose, amide, formaldehyde, carboxyl, aromatic ring (which are specifically referred to above);

more preferably, R₃、R₅Any one of which represents hydrogen and the other represents rhamnose, fucose;

R₇represents a vinyl group;

as another parallel embodiment of the present invention (hereinafter may also be referred to as parallel structure 2), among the above compounds:

R₃、R₄、R₅independently of one another, represents glucose, galactose, mannose, N-acetylglucose, glucuronic acid, 6-deoxy-glucose, 2, 6-dideoxy-glucose, N-acetylgalactosamine, sialic acid, fucose (including fucofuranose and fucopyranose), xylose, rhamnose, maltose, lactose, polysaccharides, hydrogen, aromatic rings (which are specifically referred to above), amide groups, formyl groups, carboxyl groups (COOH), halogen atoms (F, Cl, Br, I), nitro groups (NO), or₂) Hydroxy (OH), amino (NH)₂) Cyano, group; and R is₄Is not hydrogen;

R₇represents a vinyl group.

In the formula I, R is preferably selected₇Represents vinyl, R₃、R₅Independently of one another, represents hydrogen, fucose, fucopyranose, xylose, rhamnose, maltose, lactose, a polysaccharide, 6-deoxy-glucose, 2, 6-dideoxy-glucose, an amide group, a formaldehyde group, a carboxyl group, an aromatic ring (which are specifically indicated above); in this case, R₁、R₂、R₄、R₆Any of the selection ranges as described above may be selected.

More preferably, R₃、R₄At least one of them represents hydrogen; further preferably, R₃Represents hydrogen, R₄Represents acylamino, fucose pyranose, xylose, rhamnose, maltose, lactose, polysaccharide, 6-deoxy-glucose, 2, 6-dideoxy-glucose, formaldehyde group, carboxyl group, aromatic ring. In this case, R₁、R₂、R₅、R₆、R₇Can be selected from any of the selection ranges described above; preferably R₇Represents vinyl, R₅Represents hydrogen, fucose, fucopyranose, xylose, rhamnose, maltose, lactose, polysaccharide, 6-deoxy-glucose, 2, 6-dideoxy-glucose, amide, formaldehyde, carboxyl, aromatic ring.

As a preferred embodiment, the compound comprises a structure according to formula II:

wherein R is₂Is hydrogen, alkyl or phosphate.

R₃Is selected from glucose, galactose, mannose, N-acetylglucose, glucuronic acid, 6-deoxy-glucose, 2, 6-dideoxy-glucose, N-acetylgalactosamine, sialic acid, fucose, xylose, rhamnose, maltose, lactose, polysaccharide, and hydrogen;

R₄is a substituted benzene ring or hydrogen; the substituted benzene ring is characterized in that at least one hydrogen on the benzene ring is substituted by an isotope thereof, a cyano group, a nitro group, a carboxyl group, an ester group, a phenoxy group, a methylthio group which is unsubstituted or substituted by 1-3 fluorine atoms, and an alkyl or alkoxy group with 1-8 carbon atoms, wherein one or more hydrogen in the alkyl or alkoxy group is optionally substituted by halogen;

preferably, the substituted phenyl ring comprises at least one hydrogen on the phenyl ring substituted with deuterium, tritium, cyano, trifluoromethyl, difluoromethyl, methoxy, trifluoromethoxy, phenoxy, nitro, acetyl, carboxyl, ester, methylthio or trifluoromethylthio; especially methoxy or trifluoromethyl;

R₅is an amide group, which refers to a substituted amino (or amine) group, wherein the substituents of the amino (or amine) group include, but are not limited to, alkyl, alkynyl, heterocyclic; alkyl means a straight or branched chain saturated hydrocarbon group comprising 1 to 18 carbon atoms, such as 1 to 12 carbon atoms, further such as 1 to 6 carbon atoms; alkynyl refers to propargyl; heterocyclyl means a 4 to 12 membered monocyclic, bicyclic or tricyclic saturated or unsaturated ring group comprising at least one carbon atom other than at least one heteroatom selected from N, O or S; the number of heteroatoms is from 1 to 4, preferably from 1 to 3, more preferably 1 or 2 heteroatoms; preferably a monocyclic ring, more preferably such as piperidine, morpholine, tetrahydropyrrole, 4-piperidylpiperidine, 2-hydroxyethylpyrrole, homopiperazine, piperazine and tetrahydropyran;

preferably, in the above formula II, R₂、R₃、R₄Is hydrogen, R₅The substituent of the amino (or amine) group is an amide group of an alkyl group, an alkynyl group or a heterocyclic group; more preferably R₂、R₃、R₄Is hydrogen, R₅The substituent group which is an amino (or amine) group is an alkyl group having 1 to 6 carbon atoms, a propargyl group, a piperidine, a morpholine, a tetrahydropyrrole, an amido group of a 4-piperidyl piperidine.

In particular, as a preferred embodiment of the present invention, the compound may be selected from compounds of the following structures:

the invention also provides pharmaceutically acceptable salts of the compounds, wherein the pharmaceutically acceptable salts include, but are not limited to, inorganic acid salts selected from, for example, hydrochloride, phosphate, hydrobromide, sulfate; also included are organic salts selected from, for example, malate, maleate, fumarate, tartrate, succinate, citrate, lactate, methanesulfonate, p-toluenesulfonate, benzoate, salicylate, stearate, alkanoates such as acetate and salts of HOOC- (CH2) n-COOH, where n is selected from 0 to 4. Similarly, examples of pharmaceutically acceptable cations include, but are not limited to, sodium, potassium, calcium, aluminum, lithium, and ammonium.

In addition, if the compounds described herein are obtained in the form of their conventional salts, those skilled in the art will recognize a variety of synthetic methods which may be employed without undue experimentation in preparing non-toxic pharmaceutically acceptable addition salts.

As defined herein, "pharmaceutically acceptable salts" include salts of the compounds, as well as salts of stereoisomers of the compounds, such as salts of enantiomers, and/or salts of diastereomers.

The invention also provides, inter alia, preferred derivatives of the above compounds which are their phosphates, especially when R is₂Is phosphate radical, R₁、 R₆Is methyl, R₇Is vinyl, R₃、R₄Is hydrogen, R₅Is an amide group, such as compound I-22.

The second purpose of the invention is to provide a synthesis method of the compound.

The compound has a structure shown as general formula I:

in the general formula I, R₁～R₇The references are as defined above for any of the compounds (applicable in different preferred cases).

In this case, the synthetic route of the compound is:

the synthesis method comprises the following steps: compound I is prepared from lactone compound 7 (of known structure, where Bn means benzyl and I-PrO means isopropyl) by at least one deprotection reaction and/or at least one addition reaction.

The sequence of the deprotection reaction and the addition reaction is not limited, and can be adjusted according to the structure of a specific target compound.

In the above synthesis method, different synthetic routes are selected according to different selection ranges of the substituents:

when R is₁Represents methyl, R₂Represents hydrogen, R₇Represents vinyl, R₆When the substituent represents methyl (the choice range of other undefined substituent is the same as any one of the limitations on the structure of the general formula I), the synthesis method specifically comprises the following steps:

the compound 7 is subjected to palladium/hydrocarbon hydrolysis to remove benzyl, triflate is added in a one-pot method, and the obtained product and vinyl potassium trifluoroborate undergo Suzuki coupling reaction to obtain an aromatic ring compound; and (3) carrying out carbon-glycosylation reaction on the aromatic ring compound, and removing all acetyl protection of the obtained product to obtain the product.

Particularly preferably, the invention provides a synthesis method of amide derivatives, wherein the amide derivatives refer to R in the general formula I₅A compound selected from the group consisting of amides, and more particularly, a method for synthesizing a compound having another preferred structure,

the compounds contain a structure as shown in formula II:

wherein R is₂Is hydrogen, alkyl or phosphate;

R₄to substituteBenzene ring or hydrogen of (a); the substituted benzene ring is characterized in that at least one hydrogen on the benzene ring is substituted by an isotope thereof, a cyano group, a nitro group, a carboxyl group, an ester group, a phenoxy group, a formamide, a methylthio group which is unsubstituted or substituted by 1-3 fluorine atoms, and an alkyl or alkoxy group with 1-8 carbon atoms, wherein one or more hydrogen in the alkyl or alkoxy group is optionally substituted by halogen;

preferably, the substituted phenyl ring comprises at least one hydrogen on the phenyl ring substituted with deuterium, tritium, cyano, trifluoromethyl, difluoromethyl, methoxy, trifluoromethoxy, phenoxy, nitro, acetyl, carboxyl, an ester group (such as benzoate), formamide, methylthio, or trifluoromethylthio.

R₅Is an amide group, which refers to a substituted amino (or amine) group, wherein the substituents of the amino (or amine) group include, but are not limited to, alkyl, alkynyl, heterocyclic; "alkyl" refers to a straight or branched chain saturated hydrocarbon group comprising 1 to 18 carbon atoms, such as 1 to 12 carbon atoms, further such as 1 to 6 carbon atoms; alkynyl refers to propargyl; heterocyclyl means a 4 to 12 membered monocyclic, bicyclic or tricyclic saturated or unsaturated ring group comprising at least one carbon atom other than at least one heteroatom selected from N, O or S; the number of heteroatoms is from 1 to 4, preferably from 1 to 3, more preferably 1 or 2 heteroatoms; preferably a monocyclic ring, such as piperidine, morpholine, tetrahydropyrrole, 4-piperidylpiperidine, 2-hydroxyethylpyrrole, homopiperazine, piperazine and tetrahydropyran;

Specifically, when R is₃、R₄Is hydrogen, R₂Is hydrogen, alkyl or phosphate radical, R₅In the case of amide group, the synthetic route is as follows:

the method comprises the following steps:

(i) performing formylation (such as Vilsmeier reaction under phosphorus oxychloride condition) on the compound 8 to obtain a compound 9;

(ii) the compound 9 is oxidized (preferably by Pinnic oxidation) to obtain a compound 10;

(iii) and amidating the compound 10 to obtain the amide compound shown in the formula II.

Preferably, the amidation is a condensation reaction under the conditions of condensing agents HBTU and HOBt.

Compound 8 can be synthesized, among others, according to the procedures (i) to (vi) described below for the synthesis of polycardin V.

Or: when the compound has a structure as shown in formula III:

wherein R is₂Is hydrogen, alkyl or phosphate.

R₃Is methylene substituted by aldehyde group, carboxyl, amido or amino.

R₅Is glucose, galactose, mannose, N-acetylglucose, glucuronic acid, N-acetylgalactosamine, sialic acid, fucose, fucopyranose, xylose, rhamnose, 6-deoxy-glucose, 2, 6-dideoxy-glucose or an amide group.

In this case, the synthetic route of the compound is:

the method comprises the following steps:

(i) carrying out a formaldehyde reaction on the compound 8 to obtain a compound 29;

(ii) said compound 29 is subjected to at least one reductive amination and/or oxidation followed by a condensation reaction to produce compound III;

or: when the compound has a structure as shown in formula IV:

wherein R is₂Is hydrogen, alkyl or phosphate;

R₄is a carboxamide substituted benzene ring group;

in this case, the synthetic route of the compound is:

the method comprises the following specific steps: the isopropyl of the compound 7 is removed by aluminum trichloride, a guide group is arranged, and the obtained product is subjected to C-H functional group reaction to obtain a compound 13; the compound 13 undergoes palladium/hydrocarbon hydrolysis to remove benzyl and a guide group, triflate is added in a one-pot method, and the obtained product and vinyl potassium trifluoroborate undergo Suzuki coupling reaction to obtain a compound 14; and (3) removing tert-butyl group and carrying out condensation reaction by using the compound 14 under an acidic condition to obtain a compound IV.

By way of example, synthetic routes to several preferred structures are provided below, for example:

according to the above method, a known antitumor compound polycarrin V (polycarrin V) can be synthesized from a specific compound having a corresponding group as a starting material.

Specifically, the polycardin V can be synthesized by the following method:

the method comprises the following specific steps:

(i) the compound 1 is protected by isopropyl on 2-iodopropane to obtain a compound 2;

(ii) the compound 2 is subjected to carbon-hydroboration reaction catalyzed by iridium to obtain a borate compound 3;

(iii) the borate compound 3 is selectively reduced to remove bromine atoms to obtain a compound 4;

(iv) the compound 4 and the compound 5 are subjected to Suzuki coupling reaction and methyl ester is hydrolyzed to obtain a compound 6;

(v) the compound 6 undergoes a carbon-hydrogen lactonization reaction catalyzed by silver to obtain a lactonization compound 7;

(vi) the lactone compound 7 undergoes palladium/hydrocarbon hydrolysis to remove benzyl, triflate is added in a one-pot method, and the obtained product and vinyl potassium trifluoroborate undergo Suzuki coupling reaction to obtain an aromatic ring compound 8;

(vii) the compound 8 and glycosyl donor compound 16 are subjected to carbon-glycosylation reaction under the action of a molecular sieve and stannic chloride, and all acetyl protection of the obtained product 17 is removed under the conditions of sulfuric acid and methanol to obtain polycarbin V.

The compound I-2 can be synthesized by the following method:

compound 8 was synthesized according to steps (i) - (vi) described for polycardin V synthesis;

(vii) the compound 8 and glycosyl donor compound 18 are subjected to carbon-glycosylation reaction under the action of a molecular sieve and stannic chloride, the obtained product 19 is subjected to isopropyl removal under the conditions of boron trichloride and dichloromethane, and then all acetyl protection is removed under the conditions of sulfuric acid and methanol to obtain a compound I-2.

The compound I-3 can be synthesized by the following method:

(vii) the compound 8 and glycosyl donor compound 20 are subjected to carbon-glycosylation reaction under the action of a molecular sieve and stannic chloride, and all acetyl protection of the obtained product 21 is removed under the conditions of sulfuric acid and methanol to obtain a compound I-3.

The compound I-4 can be synthesized by the following method:

(viii) the compound 8 and the glycosyl donor compound 22 are subjected to glycosylation reaction under the promotion of tin tetrachloride, and all protecting groups of the obtained product 23 are removed under the condition of boron trichloride to obtain a compound I-4.

The compound I-5 can be synthesized by the following method:

(ix) the compound 8 and the glycosyl donor compound 24 are subjected to glycosylation reaction under the promotion of tin tetrachloride, and all protecting groups of the obtained product 25 are removed under the condition of methanol solution of sodium methoxide to obtain a compound I-5.

The compounds I-6 and I-7 of the invention can be synthesized by the following methods:

compound 7 was synthesized according to steps (i) - (V) described for the synthesis of polycardin V;

(x) Removing isopropyl from the compound 7 under the condition of aluminum trichloride, and adding a guide group under the condition of cesium carbonate to obtain a compound 12;

(xi) The compound 12 is subjected to C-H functional group reaction to obtain a compound 13;

(xii) The compound 13 undergoes palladium hydroxide/hydrocarbon hydrolysis to remove benzyl, triflate is added in a one-pot method, and the obtained product and vinyl potassium trifluoroborate undergo Suzuki coupling reaction to obtain a compound 14;

(xiii) The compound 14 undergoes trifluoroacetic acid to remove tert-butyl, and then undergoes condensation reaction under condensing agent HBTU and HOBt conditions to obtain a compound 15;

(xiv) The compound 15 is subjected to click reaction to obtain compounds I-6 and I-7.

The compound I-21 of the invention can be synthesized by the following method:

compound 11 is synthesized according to the steps described in the synthesis of I-8;

(xix) And carrying out condensation reaction on the compound 11 under the conditions of condensing agents HBTU and HOBt to obtain a compound 28.

(xx) Carrying out methylation reaction on the compound 28 to obtain a compound I-21;

another preferred structure described in connection with the present invention, namely R₂The representative phosphate radical can be prepared by carrying out phosphorylation reaction on a structure corresponding to the general formula I, for example, phosphorus oxychloride is used as a raw material, and the phosphorylation reaction is carried out in the presence of triethylamine, wherein specific conditions are known to those skilled in the art, and a synthetic route is provided by taking the compound I-22 as an example:

the compound I-22 can be synthesized by the following method:

compound I-18 is obtained according to the synthesis steps described in the synthesis of I-18;

(xxi) And carrying out phosphorylation reaction on the compound I-18 under the conditions of phosphorus oxychloride and triethylamine to obtain a compound I-22.

The compound I-23 can be synthesized by the following method:

compound 17 was synthesized according to the procedure described for synthesis 17;

(xxii) The compound 17 is subjected to a formaldehyde reaction under the reflux conditions of urotropine, p-toluenesulfonic acid and acetic acid to obtain a compound 29.

(xxiii) The compound 29 is subjected to reductive amination reaction under the conditions of propargylamin, acetic acid and sodium cyanoborohydride to obtain a compound 30.

(xxiv) The compound 30 is subjected to acetyl protection removal under the conditions of sulfuric acid and methanol to obtain I-23.

The above synthesis method, the reaction in each step can be carried out by using known conventional conditions unless otherwise specified, and the present invention is not particularly limited thereto.

The method of the invention provides a synthetic route for the antitumor compound, and the antitumor compound comprises polycrcin V and derivatives thereof. The highly convergent synthetic route can be applied to the chemical synthesis of compounds with similar structures and related derivatives, and opens up a wide development space for novel antitumor drugs.

The third purpose of the invention is to protect the application of the compound, the derivative and the pharmaceutically acceptable salt thereof in preparing anti-tumor and dermatological drugs.

Preferably, the tumor comprises a cavity tumor, a cavity tumor and a body surface tumor; the skin diseases comprise yinqiao disease and vitiligo; more preferably, the cavity tumor is mainly gastric cancer, colorectal cancer, skin lymphoma, etc.

The compound, the derivative thereof and the pharmaceutically acceptable salt thereof generally show ideal application effects when being used for treating and relieving tumors and skin diseases.

The invention also provides a method for treating tumors, which comprises the following steps: administering to a patient an effective amount of the above compounds and derivatives, pharmaceutically acceptable salts thereof.

The invention also provides a method for treating skin diseases, which comprises the following steps: an effective amount of the above compound and its derivatives, pharmaceutically acceptable salts are administered to a patient.

When used to treat tumors, it is particularly preferred that the compounds have the following structure:

wherein R is₁、R₆Represents methyl, R₂、R₃、R₄Represents hydrogen, R₇Represents vinyl, R₅Represents rhamnose, 6-deoxy-glucose, 2, 6-dideoxy-glucose or an amide group, and further preferably the following specific compounds I-1, I-18 and I-21;

when used to treat skin disorders, it is particularly preferred that the compounds have the following structure:

wherein R is₁、R₆Represents methyl, R₂、R₃、R₄Represents hydrogen, R₇Represents vinyl, R₅Represents rhamnose, 6-deoxy-glucose, 2, 6-dideoxy-glucose or an amide group, and is more preferably the following specific compounds I-1, I-18 and I-21.

When the compound and its derivative or pharmaceutically acceptable salt are used, an effective amount of the compound and its derivative or pharmaceutically acceptable salt is administered to a patient to treat, alleviate or prevent the above diseases, and the specific form can adopt various known means, which is not particularly limited in the present invention.

Herein, "treating" or "alleviating" refers to administering at least one compound disclosed herein and/or at least one derivative and/or at least one pharmaceutically acceptable salt thereof to a subject in need thereof identified, e.g., the subject has a tumor.

Herein "effective amount" refers to an amount of at least one compound and/or at least one derivative thereof, and/or at least one pharmaceutically acceptable salt thereof disclosed herein that is effective to "treat" (as defined above) a disease or disorder in a subject.

The compound, the derivative or the pharmaceutically acceptable salt thereof provided by the invention shows good inhibitory activity to different tumor cell lines under the illumination condition, wherein the 'illumination condition' refers to 365-450nm ultraviolet light or visible light irradiation, which shows that the compound has ideal inhibitory activity to melanoma and cutaneous lymphoma, and can be used as a novel anti-tumor medicament or a novel anti-skin disease medicament.

Drawings

FIG. 1 is a schematic representation of the effect of polycacin V on the expression level of apoptosis-related proteins;

FIG. 2 is a schematic diagram of the skin on the back of a mouse in a function verification experiment of the protection and repair of IMQ-induced warp-like lesions by Polycardin V (PV) compounds;

FIG. 3 is a schematic diagram of a scale score curve in a function verification experiment of protection and repair of IMQ-induced warp-like lesions by Polycardin V (PV) compounds;

FIG. 4 is a graphical representation of the swelling-induced erythema score curves in IMQ-induced protection and repair function verification experiments for psoriasis-like lesions using Polycarcin V (PV) compounds;

FIG. 5 is a schematic diagram showing HE staining results of skin tissue sections in an experiment for verifying the protection and repair functions of Polycardin V (PV) compounds on IMQ-induced warp-like lesions;

FIG. 6 shows the quantitative results of the functional verification experiment of the protection and repair of IMQ-induced warp-like lesions by Polycardin V (PV) compounds.

FIG. 7 shows the dorsal skin psoriatic disease phenotype of different groups of mice treated with I-1 plus a blue light source.

FIG. 8 is a plot of dorsal skin scale scores for different groups of mice treated with I-1 plus a blue light source.

FIG. 9 is a graph showing the skin rash score of the back of different groups of mice treated with I-1 and blue light source.

FIG. 10 is a structural diagram showing H & E section staining structure of back skin of different groups of mice after I-1 plus blue light source treatment.

FIG. 11 is a diagram showing the results of quantifying the thickness of the dorsal skin acanthosphere layer of different groups of mice treated with I-1 and blue light source.

FIG. 12 shows the dorsal skin psoriasis phenotype of different groups of mice treated with I-1 and analogs with a blue light source.

FIG. 13 is a plot of dorsal skin scaling scores for different groups of mice treated with I-1 and its analogs with a blue light source.

FIG. 14 is a graph of the skin rash score of the back of different groups of mice treated with I-1 and its analogs with a blue light source.

FIG. 15 is a structural diagram showing the staining structure of H & E sections of the back skin of different groups of mice after treatment of I-1 and the like with a blue light source.

FIG. 16 is a graph showing the results of quantifying the thickness of the dorsal skin acanthosphere layer of different groups of mice treated with I-1 and its analogs with blue light source.

Detailed Description

The compounds disclosed herein, or pharmaceutically acceptable salts thereof, can be synthesized from commercially available starting materials along with the disclosure herein. The following schemes describe some of the methods for the preparation of the compounds disclosed herein. The following examples and preparations are provided to enable those skilled in the art to more clearly understand and practice the present invention. They should not be considered as limiting the scope of the invention, but merely as being illustrative and representative thereof.

Example 1: polycardin V and its synthesis

Polycarbin V was synthesized as follows:

(1) synthesis of Compound 2:

compound 1(2.34g,9.24mmol) was dissolved in 72mL of anhydrous N, N-dimethylformamide at room temperature. The solution was then cooled to 0 ℃ by an ice-water bath and sodium hydride (60% dispersion in mineral oil, 665mg,16.63mmol) was slowly added carefully. The resulting mixture was stirred for 30 minutes, then isopropyl iodide (1.88mL,18.48mmol) was added via syringe. The reaction was heated to 70 ℃ and stirred overnight, then cooled to room temperature. The reaction solution was quenched by pouring into ice-cold water and extracted with dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. Purification by silica gel column chromatography (petroleum ether/ethyl acetate 97/3) gave compound 2 (2.54g, 93%) as a white solid. The characterization information is specifically as follows:

¹H NMR(400MHz,CDCl₃)δ7.83(d,J＝8.3Hz,1H),7.66(d,J＝8.3Hz,1H),7.46(t,J＝8.2Hz,1H), 6.90(d,J＝7.8Hz,1H),6.79(d,J＝8.3Hz,1H),4.53(sept,J＝6.1Hz,1H),3.95(s,3H),1.40(d,J＝6.1Hz, 6H)；

(2) synthesis of Compound 3:

putting a sealed tube containing magneton into glove box, and sequentially adding [ Ir (cod) OMe]₂(60mg,0.09mmol) and 4,4 '-di-tert-butyl-2, 2' -bipyridine (47mg,0.18mmol), and then the stopper of the closed vessel was screwed and taken out of the glove box. Under an argon atmosphere, add raw material 2(1.643 g,5.57mmol), n-hexane (22mL), pinacolborane (2.2mL,14.71mmol) successively at room temperature. The resulting reaction mixture was heated to 80 ℃ and stirred at this temperature for 60 hours. Subsequently, the reaction solution was cooled to room temperature, and directly applied to a silica gel column for separation and purification (petroleum ether/ethyl acetate 97/3). Borate 3(1.78g, 76%, 87% brsm) was obtained as a white foam and 207mg of starting material 2 was recovered. The characterization information is specifically as follows:

¹H NMR(400MHz,CDCl₃)δ8.30(s,1H),7.65(d,J＝8.3Hz,1H),7.23(s,1H),6.83(d,J＝8.3Hz,1H), 4.49(sept,J＝6.1Hz,1H),3.99(s,3H),1.40-1.37(m,18H)；

(3) synthesis of Compound 4:

a round-bottom flask was charged with starting material 3(1.78g,4.23mmol), palladium acetate (47mg,0.2mmol) and dry, anhydrous tetrahydrofuran (21 mL), and argon was passed through the flask. Potassium fluoride (0.49g,8.4mmol) dissolved in 8.2mL of water was added via syringe during the introduction of argon. Then, the reaction flask was plugged with an argon ball for protection, and polymethylhydrosiloxane (1.0mL,16.9mmol) was slowly added dropwise using a syringe. The reaction solution was stirred at room temperature for 7 hours, and then diluted with ether. After separation, the ether phase was filtered through celite (eluting with ethyl acetate), and the filtrate was concentrated under reduced pressure and dried by spin-drying, followed by separation and purification by silica gel column chromatography (petroleum ether to petroleum ether/ethyl acetate 95/5) to obtain boronic acid ester 4(1.28g, 89%) as a white foam. The characterization information is specifically as follows:

¹H NMR(400MHz,CDCl₃)δ7.93(s,1H),7.49(d,J＝7.6Hz,1H),7.34(t,J＝7.6Hz,1H),7.16(s,1H), 6.99(d,J＝7.6Hz,1H),4.52(sept,J＝6.1Hz,1H),4.00(s,3H),1.41-1.37(m,18H)；

(4) synthesis of Compound 6:

compound 5(1.09g,3.1mmol) and compound 4(1.38g,4.0mmol) were dissolved in methyl t-butyl ether (45.9mL) and water (4.9mL) at room temperature. Under the protection of argon, adding [ Pd (dppf) Cl into the solution successively₂]·CH₂Cl₂(77.5mg,0.093mmol) and potassium hydroxide (1.02g, 15.5 mmol). The resulting mixture was heated to 80 ℃ and stirred at this temperature for 23 hours, followed by addition of 40% aqueous sodium hydroxide (12.4 mL). The mixture was stirred at 80 ℃ for a further 20 hours, then cooled to room temperature, acidified with 1M aqueous hydrochloric acid and subsequently extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate 85/15) to give carboxylic acid 6(1.30g, 88%) as a pale yellow foam. The characterization information is specifically as follows:

¹H NMR(400MHz,CDCl₃)δ7.48-7.27(m,7H),7.24(s,1H),7.08(d,J＝2.2Hz,1H),6.89(d,J＝7.4Hz, 1H),6.76(d,J＝2.2Hz,1H),6.72(s,1H),5.10(s,2H),4.55(sept,J＝6.1Hz,1H),3.87(s,3H),3.67(s,3H), 1.41(d,J＝6.0Hz,6H)；

(5) synthesis of compound 7:

to the round bottom flask was added carboxylic acid 6(1.85g,3.92mmol), potassium persulfate (3.01g,11.76mmol), silver nitrate (67 mg,0.39mmol), acetonitrile (88mL) and water (88mL) at room temperature. During the feeding process, the round-bottom flask is always in an open state, and a plug is plugged after the feeding is finished. The reaction mixture was stirred at 50 ℃ for 17 hours and then cooled to room temperature. The reaction was quenched with saturated aqueous sodium bicarbonate and extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered and spin-dried under reduced pressure. The residue was separated and purified by silica gel column (petroleum ether/ethyl acetate/dichloromethane 7/2/1) to give lactone compound 7(1.55g, 84%) as a yellow solid. The characterization information is specifically as follows:

¹H NMR(400MHz,CDCl₃)δ8.37(s,1H),8.24(dd,J＝8.5,0.8Hz,1H),7.70(d,J＝2.5Hz,1H),7.53-7.34 (m,6H),7.06(d,J＝7.3Hz,1H),7.01(d,J＝2.5Hz,1H),5.21(s,2H),4.60(sept,J＝6.1Hz,1H),4.06(s,3H), 4.01(s,3H),1.44(d,J＝6.1Hz,6H)；

(6) synthesis of compound 8:

to a mixture of starting material 7(1.35g,2.87mmol) and 5% Pd/C (270mg) was added 75mL of methanol. The resulting mixture was degassed at-78 ℃ and then filled 3 times with hydrogen, and finally the flask stopper was plugged with a hydrogen balloon. The reaction was stirred at room temperature for 13 hours, followed by concentration under reduced pressure to remove the solvent. The residue was dissolved in 54mL of dichloromethane. To this solution was added triethylamine (2.3mL,16.8mmol) at room temperature. The resulting solution was cooled to-78 deg.C and trifluoromethanesulfonic anhydride (0.73mL,4.34mmol) was slowly added dropwise. After the reaction solution was stirred at this temperature for 1 hour, it was quenched with a saturated sodium bicarbonate solution and warmed to room temperature. The mixture was extracted with dichloromethane and the organic phases were combined and dried over anhydrous sodium sulfate. Filtering, and concentrating under reduced pressure to obtain crude product.

To the crude product (1.0g,1.95mmol), potassium vinyltrifluoroborate (533mg,3.90mmol) and [ Pd (dppf) Cl under an argon atmosphere₂]·CH₂Cl₂(48.8mg,0.0585mmol) to a mixture was added n-propanol (48mL) and triethylamine (0.43mL, 3.12mmol) in that order. The resulting reaction mixture was heated under reflux for 4 hours, and then the reaction solution was cooled to room temperature and diluted with water. The mixture was extracted with dichloromethane, the organic phases were combined and dried over anhydrous sodium sulfate, filtered and dried under reduced pressure to give a crude solid product. Purification by silica gel column chromatography (petroleum ether/dichloromethane ═ 1/1 to 1/2) afforded compound 8 as a yellow solid. The characterization information is specifically as follows:

¹H NMR(400MHz,CDCl₃)δ8.30(s,1H),8.20(d,J＝8.5Hz,1H),8.08(s,1H),7.47(t,J＝8.1Hz,1H), 7.27(s,1H),7.05(d,J＝8.0Hz,1H),6.75(dd,J＝17.5,10.8Hz,1H),5.90(d,J＝17.5Hz,1H),5.40(d,J＝10.8 Hz,1H),4.58(sept,J＝6.0Hz,1H),4.05(s,3H),3.97(s,3H),1.44(d,J＝6.0Hz,6H)；

(7) synthesis of Compound 17 and polycardin V:

under the protection of argon, a solution containing 16(10mg,0.03mmol) of a sugar donor, 8(35.2mg,0.09mmol) of an aromatic ring,

Molecular sieves (300 mg) and Magnetitum were charged in a round bottom flask with 1.75mL of dry, anhydrous dichloroethane. The resulting mixture was stirred at room temperature for 2 hours, then cooled to 0 ℃ and SnCl was slowly added dropwise thereto₄(1.0M dichloromethane solution, 90. mu.L, 0.09 mmol). After the reaction mixture was stirred at 0 ℃ for 30 minutes, it was warmed to room temperature and stirred for another 35 hours. The reaction was quenched with saturated sodium bicarbonate solution and extracted with dichloromethane. After the organic phases were combined, dried over anhydrous sodium sulfate, filtered and the solvent was spin-dried under reduced pressure. Purification by silica gel column separation (petroleum ether/dichloromethane/ethyl acetate. cndot. 0/100/0 to 75/10/15 to 65/20/15) gave compounds 17(5.3mg, 29%) and 17' (3.4mg, 17%) both as yellow solids.

The characterization information of compound 17 is specifically:

¹H NMR(400MHz,CDCl₃)δ9.77(s,1H),8.44(s,1H),8.20(d,J＝1.5Hz,1H),7.87(d,J＝8.4Hz,1H), 7.36(d,J＝1.4Hz,1H),6.99(d,J＝8.4Hz,1H),6.80(dd,J＝17.6,10.9Hz,1H),6.32(s,1H),5.94(d,J＝17.6 Hz,1H),5.93(d,J＝3.2Hz,1H),5.71(dd,J＝9.9,3.4Hz,1H),5.46(d,J＝10.9Hz,1H),5.22(t,J＝9.8Hz,1H), 4.11(s,3H),4.11(s,3H),3.91(dd,J＝9.6,6.1Hz,1H),2.10(s,3H),1.95(s,3H),1.88(s,3H),1.38(d,J＝6.1 Hz,3H).

the characterization information for compound 17' is specifically:

¹H NMR(400MHz,CDCl₃)δ8.48(s,1H),8.20(d,J＝1.5Hz,1H),7.87(d,J＝8.4Hz,1H),7.37(d,J＝1.5 Hz,1H),7.04(d,J＝8.5Hz,1H),6.81(dd,J＝17.6,10.9Hz,1H),6.36(s,1H),5.97(d,J＝2.8Hz,1H),5.95(d, J＝17.2Hz,1H),5.73(dd,J＝9.9,3.4Hz,1H),5.44(d,J＝10.9Hz,1H),5.22(t,J＝9.8Hz,1H),4.57(sept,J＝ 6.0Hz,1H),4.11(s,3H),3.98(s,3H),3.92(dd,J＝9.8,6.3Hz,1H),2.10(s,3H),1.95(s,3H),1.86(s,3H),1.42 (d,J＝6.0Hz,3H),1.39(d,J＝6.0Hz,3H),1.37(d,J＝5.1Hz,3H).

(2) synthesis of the compound polycardin V (I-1):

to a mixture of 17(5.3mg,0.0085mmol) and methanol (0.8mL) at room temperature was added a solution of sulfuric acid in methanol (3.0M, 0.8 mL). The resulting mixture was heated to 70 ℃ and stirred for 5.5 hours, followed by cooling to room temperature. The reaction solution was diluted with water and then extracted with chloroform/isopropanol (3/1). The organic phases were combined and washed with saturated sodium bicarbonate solution and then dried over anhydrous sodium sulfate. Purification by flash column chromatography on silica gel (dichloromethane/methanol-9/1) after filtration and spin-drying under reduced pressure afforded the compound polycarbin V (2.6mg, 62%) as a yellow solid. The spectrum of the synthesized polycarcin V was consistent with that reported in the literature (Li, y.et al. org.biomol. chem.2008,6,3601). The characterization information of the compound polycrcin V (I-1) is specifically as follows:

¹H NMR(500MHz,DMSO-d6)δ9.73(s,1H),8.45(s,1H),7.97(d,J＝1.2Hz,1H),7.81(d,J＝8.4Hz, 1H),7.73(d,J＝1.2Hz,1H),6.96(d,J＝8.5Hz,1H),6.94(dd,J＝17.6,11.0Hz,1H),6.14(d,J＝17.6Hz,1H), 5.84(s,1H),5.50(d,J＝11.0Hz,1H),4.81(d,J＝5.1Hz,1H),4.47(d,J＝5.3Hz,1H),4.16(s,3H),4.11(s,3H), 4.07(dd,J＝5.6,3.1Hz,1H),4.01(m,1H),3.78(m,1H),3.36(m,1H)3.31(m,1H),1.29(d,J＝5.9Hz,3H).

this example also synthesizes compounds I-2 and I-3, the specific procedures and reaction conditions being identical to those of the synthesis of I-1 described above, except that instead of the corresponding glycosyl donor starting material, in particular: the synthesis of compound I-2 uses the glycosyl donor starting material 18, while the synthesis of compound I-3 uses the glycosyl donor starting material 20, the following are the characterization information for compounds I-2 and I-3:

the characterization information of the compound I-2 is specifically as follows:

¹H NMR(400MHz,CDCl₃)δ9.74(s,1H),8.49(s,1H),8.13(s,1H),7.93(d,J＝8.4Hz,1H),7.41(s,1H), 7.04(d,J＝8.4Hz,1H),6.84(dd,J＝17.6,10.8Hz,1H),5.97(d,J＝17.6Hz,1H),5.92(s,1H),5.47(d,J＝10.8 Hz,1H),5.39-5.32(m,3H),4.16(s,3H),4.14(s,3H),2.05-1.97(m,2H)1.43(d,J＝5.6Hz,3H).

the characterization information of the compound I-3 is specifically as follows:

¹H NMR(400MHz,CDCl₃)δ9.84(s,1H),8.50(s,1H),8.12(s,1H),7.84(d,J＝8.4Hz,1H),7.41(s,1H), 7.01(d,J＝8.4Hz,1H),6.83(dd,J＝17.6,11.0Hz,1H),6.00-5.95(m,1H),5.97(d,J＝17.6Hz,1H), 5.50-5.37(m,1H),5.49(d,J＝10.8Hz,1H),5.00(t,J＝9.6Hz,1H),4.61-4.52(m,1H),4.35-4.26(m,1H),4.03(s, 3H),4.00(s,3H),1.22(d,J＝6.0Hz,3H).

example 2: compound I-4 and synthesis thereof

Derivative I-4 was synthesized according to the following procedure:

(1) synthesis of compound 23:

to a solution of the aromatic ring 8(43.7mg,0.125mmol) and the sugar donor 22(49.8mg,0.105mmol) in dry dichloroethane (0.6mL) at room temperature was added

Molecular sieves (1.00g), tin tetrachloride (1.0M dichloroethane solution, 0.31mL,0.305 mmol). The reaction mixture was stirred at room temperature for 18 hours, then dichloromethane and saturated sodium bicarbonate solution were added. The organic phase was separated, washed with water and then concentrated under reduced pressure. The residue was purified by preparative thin layer Chromatography (CH)₂Cl₂EtOAc ═ 98/2) gave compound 8(29.7mg, 37%) as a yellow solid. The characterization information is specifically as follows:

¹H NMR(400MHz,CDCl3)δ9.71(s,1H),8.22(s,1H),8.11–8.01(m,2H),7.75(d,J＝8.8Hz,1H),7.47 (d,J＝7.2Hz,2H),7.42(d,J＝7.3Hz,2H),7.34(ddd,J＝17.0,9.4,4.2Hz,7H),7.03(t,J＝7.3Hz,1H),6.96(t, J＝7.3Hz,2H),6.84(d,J＝7.1Hz,2H),6.76(dd,J＝17.5,11.0Hz,1H),5.93(d,J＝17.5Hz,1H),5.44(d,J＝ 10.8Hz,1H),5.12(d,J＝11.8Hz,1H),5.04(d,J＝9.5Hz,1H),4.87(d,J＝11.8Hz,1H),4.82(d,J＝4.9Hz, 1H),4.79(d,J＝4.9Hz,1H),4.55(d,J＝10.7Hz,1H),4.14(t,J＝9.5Hz,1H),4.09(s,3H),4.05–4.01(m,1H), 3.99(s,3H),3.83(dd,J＝9.5,2.6Hz,1H),3.77–3.72(m,2H),1.28(d,J＝6.3Hz,3H).

(2) synthesis of Compound I-4:

to a mixture of 23(5.0mg,0.00654mmol) and dry dichloromethane (0.8mL) was slowly added boron trichloride (1.0M in dichloromethane, 39.0. mu.L, 0.0392mmol) dropwise at-78 ℃. The resulting reaction solution was stirred at this temperature for 2 hours and then quenched with water. The mixture was extracted with dichloromethane, and the organic phases were combined and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, purification by flash silica gel column (dichloromethane) gave I-4(2.8mg, 87%) as a yellow solid. The characterization information is specifically as follows:

¹H NMR(600MHz,DMSO)δ9.75(s,1H),8.40(d,J＝5.7Hz,1H),8.02(s,1H),7.86(d,J＝8.7Hz,1H), 7.74(s,1H),7.67(d,J＝8.8Hz,1H),6.94(dd,J＝17.6,11.0Hz,1H),6.16(d,J＝17.6Hz,1H),5.50(d,J＝11.0 Hz,1H),4.68(d,J＝3.4Hz,1H),4.67(s,1H),4.53(d,J＝5.4Hz,1H),4.47(d,J＝5.2Hz,1H),4.17(s,3H), 4.13(s,3H),3.76(td,J＝9.3,5.3Hz,1H),3.68(q,J＝6.3Hz,1H),3.59–3.56(t,1H),3.49(m,J＝9.1,5.8,3.4 Hz,1H),1.15(d,J＝6.4Hz,3H).

example 3: compound I-5 and synthesis thereof

Derivative I-5 was synthesized according to the following procedure:

(1) synthesis of compound 25:

to a solution of the aromatic ring 8(400mg,1.204mmol) and the sugar donor 24(105.0mg,0.301mmol) in dry dichloroethane (17.7 mL) was added tin tetrachloride (1.0M solution in dichloroethane, 2.7mL,2.709mmol) at room temperature. The reaction mixture was stirred at room temperature for 46 hours, then dichloromethane and saturated sodium bicarbonate solution were added.The organic phase was separated, washed with water and then concentrated under reduced pressure. The residue was purified by preparative thin layer Chromatography (CH)₂Cl₂EtOAc ═ 98/2) gave compound 25(15.1mg, 8%) as a yellow solid. The characterization information is specifically as follows:

¹H NMR(400MHz,CDCl3)δ9.52(s,1H),8.01–7.95(m,3H),7.68(d,J＝8.8Hz,1H),7.15(s,1H),6.68 (dd,J＝17.5,10.9Hz,1H),5.88(d,J＝17.5Hz,1H),5.70(d,J＝2.5Hz,1H),5.40(d,J＝10.8Hz,1H),5.33(dd, J＝10.1,3.2Hz,1H),5.23(d,J＝7.1Hz,2H),3.98(s,3H),3.93(s,3H),3.80(dd,J＝9.3,6.2Hz,1H),2.11(s, 3H),1.99(s,3H),1.87(s,3H),1.41(d,J＝6.1Hz,3H).

(2) synthesis of Compound I-5:

to a mixture of 25(9.5mg,0.0153mmol) and methanol (0.5mL) was added sodium methoxide in methanol (1.0M, 34. mu.L) at room temperature. The resulting mixture was stirred at room temperature for 3 hours, the reaction was quenched with acetic acid, and the crude product was purified by preparative thin layer chromatography (dichloromethane/methanol-90/10) to give compound I-5 as a yellow solid (5.1mg, 67%). The characterization information is specifically as follows:

¹H NMR(500MHz,DMSO)δ9.73(s,1H),8.30(s,1H),7.97(d,J＝1.4Hz,1H),7.81(d,J＝8.7Hz,1H), 7.71(d,J＝8.7Hz,1H),7.67(d,J＝1.3Hz,1H),6.90(dd,J＝17.6,11.0Hz,1H),6.13(d,J＝17.6Hz,1H),5.48 (d,J＝11.0Hz,1H),4.87(s,1H),4.83(br,1H),4.68(br,1H),4.27(d,J＝4.9Hz,1H),4.13(s,3H),4.09(s,3H), 3.96(br,1H),3.45(br,1H),1.30(d,J＝5.4Hz,3H).

example 4: compounds I-6, I-7 and synthesis thereof

The derivatives I-6, I-7 were synthesized according to the following procedure:

(1) synthesis of compound 12:

to anhydrous dichloroethane (35mL) charged with compound 7(110mg,0.318mmol) was added aluminum trichloride at 0 deg.C. The resulting mixture was stirred at 0 ℃ for 15 minutes and quenched with waterThe reaction was quenched and extracted with dichloromethane. After the organic phases were combined, dried over anhydrous sodium sulfate, filtered and the solvent was spin-dried under reduced pressure. The crude product obtained is dissolved in anhydrous DMF and cesium carbonate (606mg,1.86mmol), compound 26(158mg,1.12mmol) are added successively at 0 ℃ and the resulting mixture is stirred at room temperature for 8 hours, after which the reaction mixture is diluted with ethyl acetate and saturated NaHCO₃The solution was washed twice and once with saturated brine, and after the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was spin-dried under reduced pressure. Purification by flash column chromatography (dichloromethane/methanol-200/1) afforded compound 12(91.4mg, 46%) as a yellow solid.

The characterization information of compound 12 is specifically:

¹H NMR(400MHz,CDCl3)δ8.47(d,J＝4.2Hz,1H),8.32(s,1H),8.20(d,J＝8.4Hz,1H),7.66(d,J＝2.0 Hz,1H),7.56(d,J＝7.5Hz,1H),7.43(ddd,J＝30.7,16.4,7.3Hz,6H),7.25–7.14(m,2H),6.97(d,J＝1.9Hz, 1H),5.40(s,2H),5.18(s,2H),4.02(s,3H),3.90(s,3H),2.55(s,3H).

(2) synthesis of compound 13:

under argon protection, compound 12(90mg,0.169mmol), Ar-I (205mg,0.676mmol), Pd (OAc)₂(7.6mg,20 mol%), L1(7.5mg,20 mol%), AgOAc (112.0mg,0.676mmol), NBE-COOMe (51. mu.L, 0.34mmol) in chloroform (5 ml). The resulting mixture was stirred at 100 ℃ for 18 hours, and then the reaction mixture was cooled to room temperature, filtered through celite (eluting with ethyl acetate), the filtrate was concentrated under reduced pressure and dried by spin-drying, and then separated and purified by silica gel column chromatography (dichloromethane/methanol ═ 200/1) to obtain compound 13(89mg, 74%) as a yellow solid. The characterization information is specifically as follows:

the characterization information is specifically as follows:

¹H NMR(400MHz,CDCl3)δ9.35(s,1H),8.29(s,1H),8.12(s,1H),8.06(s,1H),7.84(d,J＝7.6Hz,1H), 7.49(qd,J＝14.8,7.2Hz,3H),7.31(s,1H),7.02(s,1H),6.77(dd,J＝17.5,10.9Hz,1H),5.93(d,J＝17.5Hz, 1H),5.44(d,J＝10.8Hz,1H),4.11(s,3H),4.10(s,3H),1.30(s,9H).

(3) synthesis of compound 14:

to a mixture of compound 13((33mg,0.047mmol) and 10% Pd/C (66mg) were added 4mL of methanol and 4mL of tetrahydrofuran, the resulting mixture was charged in an autoclave with 30bar of hydrogen, the reaction was stirred at room temperature for 12 hours, then the solvent was removed by concentration under reduced pressure, the residue was dissolved in 10mL of dichloromethane, at room temperature, triethylamine (32. mu.L, 0.225mmol) and PhNTf2(18mg,0.05mmol) were added to the solution, after stirring at that temperature for 24 hours, the reaction solution was quenched with a saturated ammonium chloride solution, warmed to room temperature, the mixture was extracted with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product, under argon shield, to the crude product, potassium vinyltrifluoroborate (9.3 mg, 0.070), [ Pd (dppf) Cl₂]·CH₂Cl₂(2.3mg,0.0028mmol) to a mixture was added n-propanol (2mL) and triethylammine (12. mu.L, 0.084mmol) in that order. The resulting reaction mixture was heated under reflux for 4 hours, and then the reaction solution was cooled to room temperature and diluted with water. The mixture was extracted with dichloromethane, the organic phases were combined and dried over anhydrous sodium sulfate, filtered and dried under reduced pressure to give a crude solid product. Purification by silica gel column chromatography (petroleum ether/ethyl acetate/dichloromethane ═ 5/1/1) gave compound 14(15mg, 61% for 3steps) as a yellow solid. The characterization information is specifically as follows:

¹H NMR(400MHz,CDCl3)δ9.35(s,1H),8.29(s,1H),8.09(d,J＝24.2Hz,2H),7.84(d,J＝7.6Hz,1H), 7.49(qd,J＝14.8,7.2Hz,3H),7.31(s,1H),7.02(s,1H),6.77(dd,J＝17.5,10.9Hz,1H),5.93(d,J＝17.5Hz, 1H),5.44(d,J＝10.8Hz,1H),4.10(d,J＝6.9Hz,6H),1.30(s,9H).

(4) synthesis of compound 15:

to an anhydrous dichloroethane (6mL) charged with compound 14(12.0mg,0.023mmol) was added 0.45mL of trifluoroacetic acid at 0 deg.C. The resulting mixture was slowly warmed to room temperature and stirred at room temperature for 6 hours, and the solvent was spin-dried under reduced pressure. To the resulting crude product were added HOBt (3.1mg, 0.023mmol) and HBTU (10.6mg,0.028mmol), dissolved in 2ml of anhydrous DMF, followed by addition of the resulting mixture of propargylamines (7.5. mu.L, 0.115mmol), DIPEA (19.5. mu.L, 0.115mmol) in that order, stirring at room temperature for 12 hours, then diluting the reaction solution with ethyl acetate,with saturated NaHCO₃The solution was washed twice and once with saturated brine, and after the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was spin-dried under reduced pressure. Purification by flash column chromatography (dichloromethane/methanol-200/1) afforded compound 15(6.8mg, 50%) as a yellow solid.

The characterization information of compound 15 is specifically:

¹H NMR(400MHz,CDCl3)δ8.30(s,1H),8.20(d,J＝8.5Hz,1H),8.08(s,1H),7.47(t,J＝8.1Hz,1H), 7.27(s,1H),7.05(d,J＝8.0Hz,1H),6.75(dd,J＝17.5,10.8Hz,1H),5.90(d,J＝17.5Hz,1H),5.40(d,J＝10.8 Hz,1H),4.58(sept,J＝6.0Hz,1H),4.05(s,3H),3.97(s,3H),1.44(d,J＝6.0Hz,6H)；

(5) synthesis of Compound I-6:

compound 15(2.0eq.) and CuSO4(2.0mg,0.0125mmol) were dissolved in 200. mu.l of water, and to the phase mixture was added sodium ascorbate (12.3mg,0.0623mmol), TBTA (5mg,0.089mmol), DMF (200. mu.l), t-BuOH (200. mu.l). Compound 27 (4.2mg,0.0083mmol) was then added and the reaction stirred at room temperature for 3 hours, then the reaction was lyophilized to give the crude product, which was purified by preparative HPLC to give compound I-6(3.6mg, 64%) as a yellow solid.

The characterization information of the compound I-6 is specifically as follows:

¹H NMR(600MHz,DMSO)δ9.61(s,1H),8.92(t,J＝5.5Hz,1H),8.43(s,1H),8.04(s,1H),7.93(s,1H), 7.78(d,J＝15.1Hz,2H),7.57(s,2H),7.54–7.47(m,2H),7.04(s,1H),6.94(dd,J＝17.5,11.0Hz,1H),6.17(d,J ＝17.6Hz,1H),5.50(d,J＝10.9Hz,1H),5.23(d,J＝9.1Hz,1H),5.14(d,J＝5.6Hz,1H),4.96(d,J＝4.8Hz, 1H),4.70(d,J＝5.2Hz,1H),4.43–4.36(m,2H),4.19(s,3H),4.14(s,3H),4.03–3.98(m,1H),3.77(dd,J＝ 12.5,6.1Hz,1H),3.54–3.47(m,2H),1.08(d,J＝6.6Hz,3H).

this example also synthesizes Compound I-7, the specific procedures and reaction conditions being identical to those described above for the synthesis of I-18, except that the corresponding glycosyl donor starting material was replaced,

the characterization information of the compound I-7 is specifically as follows:

¹H NMR(400MHz,DMSO)δ9.61(s,1H),8.94(s,1H),8.44(s,1H),8.04(s,1H),7.94(s,1H),7.83(s,1H), 7.77(s,1H),7.58–7.49(m,4H),7.04(s,1H),6.95(dd,J＝17.2,10.8Hz,1H),6.17(d,J＝17.6Hz,1H),5.51(d, J＝11.1Hz,1H),5.33(d,J＝5.7Hz,4H),5.24(d,J＝4.6Hz,1H),5.13(d,J＝5.2Hz,1H),4.61(s,1H),4.40(d, J＝5.6Hz,2H),4.19(s,3H),4.14(s,3H),3.76(d,J＝6.4Hz,1H),3.61(d,J＝4.6Hz,1H),3.40(s,1H),3.21(d, J＝5.0Hz,1H).

example 5: compounds I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-15, I-16, I-17, I-18, I-19, I-20 and syntheses thereof

(1) Synthesis of compound 9:

to the tube was added a solution of starting material 8(150mg,0.384mmol) in dichloromethane (7.5mL) under argon followed by DMF (0.6mL) and phosphorus oxychloride (0.7mL) in that order at 0 deg.C, the tube was sealed and the reaction was stirred at 70 deg.C for 6 hours. The reaction solution was then cooled to 0 ℃, diluted with dichloromethane, and then 1N aqueous sodium hydroxide solution was slowly added until the liquid phase became basic, and the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the solvent was spin-dried under reduced pressure. Separation and purification with a silica gel column (petroleum ether/ethyl acetate 20/80) gave compound 9(160.6mg, quant) having the following characteristic information:

¹H NMR(400MHz,CDCl3)δ11.16(s,1H),8.48(s,1H),8.12(d,J＝1.5Hz,1H),8.09(d,J＝8.4Hz,1H), 7.36(d,J＝1.5Hz,1H),7.00(d,J＝8.4Hz,1H),6.79(dd,J＝17.5,10.9Hz,1H),5.96(d,J＝17.6Hz,1H),5.46 (d,J＝10.9Hz,1H),4.81–4.73(m,1H),4.13(s,3H),4.00(s,3H),1.49(d,J＝6.0Hz,6H).

(2) synthesis of compound 10:

adding compound 10(200mg,0.478mmol), NaH₂PO₄(745.7mg,4.78mmol), and 2-methyl-2-butene (1.52ml, 14.34mmol) were dissolved in a mixed solution of tetrahydrofuran, t-butanol, and water (4:4:1) (0.04M). To the mixture was added sodium chlorite (432.3mg,4.78mmol) at room temperature. The reaction solution was stirred at room temperature12 hours, then saturated Na₂CO₃The solution was quenched, extracted with ethyl acetate, the organic phases combined, dried over anhydrous sodium sulfate, filtered, and the solvent was spin dried under reduced pressure. Compound 10 was obtained as a yellow solid and used directly in the next reaction.

To an anhydrous dichloroethane (35mL) charged with compound 10(110mg,0.318mmol) was added aluminum trichloride at 0 ℃. The resulting mixture was stirred at 0 ℃ for 15 minutes, quenched with water, and extracted with dichloromethane. After the organic phases were combined, dried over anhydrous sodium sulfate, filtered and the solvent was spin-dried under reduced pressure. Separation and purification on a silica gel column (dichloromethane/methanol-90/10) gave compound 11(160.6mg, quant).

(3) Synthesis of Compound I-8:

to compound 11(30.3mg,0.077mmol) were added HOBt (10.0mg,0.077mmol) and HBTU (35.0mg,0.093 mmol), dissolved in 2ml of anhydrous DMF followed by the sequential addition of propargylamines (25. mu.L, 0.387mmol) and DIPEA (64. mu.L, 0.387mmol) resulting mixture at room temperature for 12 hours, after which the reaction was diluted with ethyl acetate, and saturated NaHCO was used₃The solution was washed twice, then once with saturated brine, the organic phases were combined, dried over anhydrous sodium sulfate, filtered and the solvent was spin-dried under reduced pressure. Purification on flash silica gel (dichloromethane/methanol-200/1) afforded compound 5(23.7mg, 72%) as a yellow solid.

The characterization information of the compound I-8 is specifically as follows:

¹H NMR(400MHz,CDCl₃)δ9.64(s,1H),8.28(s,1H),7.99(s,1H),7.45(d,J＝7.8,1H),7.24(s,1H),6.91(d,J ＝8.0Hz,1H),6.73(dd,J＝17.5,10.9Hz,1H),6.02(t,J＝4.6Hz,1H),5.91(d,J＝17.5Hz,1H),5.44(d,J＝10.9Hz, 1H),4.51(dt,J＝4.6,2.5Hz,2H),4.09(s,3H),4.05(s,3H),2.29(t,J＝2.5Hz,1H).

this example also synthesizes compound I-9, the specific procedures and reaction conditions are the same as those for the synthesis of I-8 above, except that the corresponding amine is replaced, specifically: methylamine was used for the synthesis of compound I-9, and the following is the characterization information for compound I-9:

the characterization information of the compound I-9 is specifically as follows:

¹H NMR(400MHz,CDCl₃)δ9.66(s,1H),8.41(s,1H),8.07(s,1H),7.45(d,J＝7.9Hz,1H),7.34(s,1H),6.94 (d,J＝7.9Hz,1H),6.78(dd,J＝17.6,11.0Hz,2H),5.94(d,J＝17.5Hz,2H),5.45(d,J＝10.8Hz,1H),4.14(s,3H), 4.11(s,3H),3.20(d,J＝4.8Hz,3H).

this example also synthesizes compound I-10, the specific procedures and reaction conditions being the same as those for the synthesis of I-8 above, except that the corresponding amine was replaced, specifically: synthesis of Compound I-10 was performed using dimethylamine, which is characteristic information of Compound I-10 as follows:

the characterization information of the compound I-10 is specifically as follows:

¹H NMR(400MHz,CD₃OD)δ8.47(s,1H),7.98(s,1H),7.54(s,1H),7.35(d,J＝7.6Hz,1H),7.00(d,J＝7.6Hz, 1H),6.83(dd,J＝17.5,10.9Hz,1H),6.01(d,J＝17.5Hz,1H),5.43(d,J＝10.9Hz,1H),4.12(s,6H),3.35(s,6H).

this example also synthesizes Compound I-11, the specific procedure and reaction conditions are the same as those for the synthesis of I-8 above, except that the corresponding amine is replaced, specifically: ethylamine was used for the synthesis of the compound I-11, and the following is characteristic information of the compound I-11:

the characterization information of the compound I-11 is specifically as follows:

¹H NMR(400MHz,CDCl₃)δ9.68(s,1H),8.43(s,1H),8.10(s,1H),7.46(d,J＝8.0Hz,1H),7.33(s,1H),6.95(d, J＝7.9Hz,1H),6.78(dd,J＝17.6,11.0Hz,1H),5.94(d,J＝17.5Hz,1H),5.45(d,J＝10.8Hz,1H),4.14(s,3H),4.11 (s,3H),3.71(dq,J＝11.9,7.3Hz,1H),1.36(t,J＝7.3Hz,3H).

this example also synthesizes Compound I-12, the specific procedures and reaction conditions being the same as those for the synthesis of I-8 above, except that the corresponding amine was replaced, specifically: synthesis of Compound I-12 was performed using n-propylamine, the following characterizing information for Compound I-12:

the characterization information of the compound I-12 is specifically as follows:

¹H NMR(400MHz,CDCl₃)δ9.65(s,1H),8.34(s,1H),8.03(d,J＝1.6Hz,1H),7.44(d,J＝8，0Hz,1H),7.28(d, J＝1.6Hz,1H),6.92(d,J＝8.0Hz,1H),6.74(dd,J＝17.6,10.9Hz,1H),5.91(d,J＝17.5Hz,1H),5.43(d,J＝10.9 Hz,2H),4.10(s,3H),4.07(s,3H),3.66–3.59(m,2H),1.76(dq,J＝14.7,7.3Hz,2H),1.04(t,J＝7.4Hz,3H).

this example also synthesizes compound I-13, the specific procedures and reaction conditions being the same as those for the synthesis of I-8 above, except that the corresponding amine was replaced, specifically: the synthesis of compound I-13 uses isopropylamine, and the following is the characterization information of compound I-13:

the characterization information of the compound I-13 is specifically as follows:

¹H NMR(400MHz,CDCl₃)δ9.69(s,1H),8.39(s,1H),8.08(s,1H),7.44(d,J＝7.9Hz,1H),7.30(s,1H),6.93 (C),6.76(dd,J＝17.5,10.8Hz,1H),5.93(d,J＝17.6Hz,1H),5.44(d,J＝10.8Hz,1H),4.53(sept,J＝6.8Hz,1H), 4.12(s,3H),4.09(s,3H),1.38(d,J＝6.8Hz,6H).

this example also synthesizes Compound I-14, the exact procedure and reaction conditions are the same as those described above for the synthesis of I-8, except that the corresponding amine is replaced, specifically: n-butylamine was used for the synthesis of compound I-14, and the following is information characterizing compound I-14:

the characterization information of the compound I-14 is specifically:

¹H NMR(400MHz,CDCl₃)δ9.68(s,1H),8.41(s,1H),8.08(s,1H),7.45(d,J＝7.9Hz,1H),7.32(s,1H),6.94 (d,J＝7.9Hz,1H),6.77(dd,J＝17.5,10.9Hz,1H),5.93(d,J＝17.5Hz,1H),5.44(d,J＝10.9Hz,1H),4.13(s,3H), 4.10(s,3H),3.66(t,J＝7.3Hz,2H),1.75-1.67(m,2H),1.52–1.42(m,2H),0.99(t,J＝7.4Hz,3H).

this example also synthesizes compound I-15, the specific procedures and reaction conditions being the same as those for the synthesis of I-8 above, except that the corresponding amine was replaced, specifically: n-pentylamine was used for the synthesis of compound I-15, and the following is the characterization information for compound I-15:

the characterization information of the compound I-15 is specifically as follows:

¹H NMR(400MHz,CDCl₃)δ9.68(s,1H),8.41(s,1H),8.22(s,1H),7.93(d,J＝8.0Hz,1H),7.32(s,1H),6.97 (d,J＝8.0Hz,1H),6.80(dd,J＝17.5,10.9Hz,1H),5.95(d,J＝17.5Hz,1H),5.46(d,J＝10.9Hz,1H),4.14(s,3H), 4.10(s,3H),3.66(t,J＝7.3Hz,2H),1.75-1.71(m,2H),1.52-1.59(m,2H),1.46-1.39(m,2H)，0.95-0.90(m,3H).

this example also synthesizes Compound I-16, the specific procedures and reaction conditions being the same as those for the synthesis of I-8 above, except that the corresponding amine was replaced, specifically: the synthesis of compound I-16 used n-hexylamine, and the following is the characterization information of compound I-16:

the characterization information of the compound I-16 is specifically as follows:

¹H NMR(400MHz,CDCl₃)δ9.68(s,1H),8.41(s,1H),8.20(s,1H),7.91(d,J＝8.0Hz,1H),7.30(s,1H),6.97 (d,J＝8.0Hz,1H),6.79(dd,J＝17.5,10.9Hz,1H),5.93(d,J＝17.5Hz,1H),5.45(d,J＝10.9Hz,1H),4.12(s,3H), 4.11(s,3H),3.71(t,J＝7.2Hz,2H),1.61-1.30(m,8H)，0.89(d,J＝6.0Hz,1H).

this example also synthesizes compound I-17, the specific procedures and reaction conditions being the same as those for the synthesis of I-8 above, except that the corresponding amine was replaced, specifically: piperidine was used for the synthesis of compound I-17, and the following is characteristic information of compound I-17:

the characterization information of the compound I-17 is specifically:

¹H NMR(400MHz,CDCl₃)δ8.46(s,1H),8.10(s,1H),7.41(d,J＝7.9Hz,1H),7.32(s,1H),7.47(d,J＝8.0Hz, 1H),6.80(dd,J＝17.5,10.9Hz,1H),5.96(d,J＝17.5Hz,1H),5.46(d,J＝10.9Hz,1H),4.16(s,3H),4.13(s,3H), 3.97-3.92(m,2H),3.73-3.62(m,2H),2.08-1.98(m,6H),1.67–1.56(m,3H).

this example also synthesizes Compound I-18, the specific procedures and reaction conditions being the same as those for the synthesis of I-8 above, except that the corresponding amine was replaced, specifically: the synthesis of compound I-18 was performed using morpholine, and the following characterization information for compound I-18:

the characterization information of the compound I-18 is specifically:

¹H NMR(400MHz,CDCl₃)δ8.42(s,1H),8.10(s,1H),7.36(d,J＝8.0Hz,1H),7.34(s,1H),7.01(d,J＝8.0Hz, 1H),6.77(dd,J＝17.5,10.9Hz,1H),5.94(d,J＝17.5Hz,1H),5.46(d,J＝10.9Hz,1H),4.23-3.98(m,3H),4.13(s, 3H),4.10(s,3H),3.85-3.76(m,1H),3.66-3.60(m,1H),3.58-3.50(m,1H),3.31-3.25(m,2H).

this example also synthesizes compound I-19, the specific procedures and reaction conditions being the same as those for the synthesis of I-8 above, except that the corresponding amine was replaced, specifically: pyrrolidine was used for the synthesis of compound I-19, and the following is the characterization information for compound I-19:

the characterization information of the compound I-19 is specifically:

¹H NMR(400MHz,CDCl₃)δ9.63(s,1H),8.35(s,1H),8.04(s,1H),7.39(d,J＝8.0Hz,1H),7.31(s,1H),7.00 (d,J＝8.0Hz,1H),6.74(dd,J＝17.5,10.9Hz,1H),5.92(d,J＝17.5Hz,1H),5.43(d,J＝10.9Hz,1H),4.11(s,3H), 4.10(s,3H),3.75-3.67(m,1H),3.19-2.99(m,2H),2.14-1.77(m,5H).

this example also synthesizes compound I-20, the specific steps and reaction conditions being the same as those for the synthesis of I-8 above, except that the corresponding amine was replaced, specifically: synthesis of Compound I-20 was performed using 4-piperidylpiperidine, the following characterizing information for Compound I-20:

the characterization information of the compound I-20 is specifically as follows:

¹H NMR(400MHz,CDCl₃)δ9.72(s,1H),8.49(s,1H),8.00(s,1H),7.41(s,1H),7.28(d,J＝8.0Hz,1H),7.00 (d,J＝8.0Hz,1H),6.81(dd,J＝17.5,10.9Hz,1H),5.95(d,J＝17.5Hz,1H),5.47(d,J＝10.9Hz,1H),4.18(s,3H), 4.15(s,3H),4.17-4.11(m,2H),3.64-3.12(m,7H),2.10-1.78(m,7H),1.47-1.21(m,3H).

example 6: compound I-21 and synthesis thereof

(1) Synthesis of compound 28:

to compound 11(30.0mg,0.077mmol) were added HOBt (10.0mg,0.077mmol) and HBTU (35.0mg,0.093 mmol), dissolved in 2ml of anhydrous DMF, followed by the sequential addition of a mixture of N, N-dimethyl-1, 3-diaminopropane (49. mu.L, 0.389mmol), DIPEA (64. mu.L, 0.387mmol)After stirring at room temperature for 12 hours, the reaction was diluted with ethyl acetate and saturated NaHCO₃The solution was washed twice and once with saturated brine, and after the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was spin-dried under reduced pressure. Purification by flash column chromatography on silica gel (dichloromethane/methanol-100/1) afforded compound 5(24.6mg, 67%) as a yellow solid.

The characterization information for compound 28 is specifically:

¹H NMR(400MHz,CD₃CN)δ8.41(s,1H),7.89(s,1H),7.52(s,1H),7.38(d,J＝8.0Hz,1H),7.23(s,1H),6.88 –6.79(m,2H),6.03(d,J＝17.5Hz,1H),5.47(d,J＝10.8Hz,1H),4.12(s,6H),3.50(d,J＝5.6Hz,2H),3.26(s,2H), 2.85(s,6H),2.14-2.06(m,2H).

(2) synthesis of Compound I-21:

under argon, charge 28(10,0mg,0.0210mmol), dimethyl sulfate (39.8. mu.l, 0.42mmol) and acetonitrile (0.5ml) sequentially into the tube. The stopper of the sealed tube was screwed and the reaction was stirred at 100 ℃ for 8 hours. The reaction was then spin dried. The crude product was purified by preparative thin layer chromatography (dichloromethane/methanol-90/10) to give compound I-21 as a yellow solid (4.9mg, 48%). The characterization information is specifically as follows:

¹H NMR(400MHz,CD₃OD)δ8.37(s,1H),7.81(s,1H),7.43(s,1H),7.28(d,J＝8.0Hz,1H),7.13(s,1H),6.91 –6.83(m,2H),5.93(d,J＝17.5Hz,1H),5.36(d,J＝10.8Hz,1H),4.08(s,6H),3.44(d,J＝5.6Hz,2H),3.31(s, 9H),3.18(s,2H),2.11-2.00(m,2H).

example 7: compound I-22 and synthesis thereof

(1) Synthesis of Compound I-22:

compound I-21(4.6mg,0.0099mmol) was dissolved in 1ml of anhydrous dichloromethane, and the resulting mixture of phosphorus oxychloride (18.6. mu.L, 0.2mmol) and triethylamine (27.8. mu.L, 0.2mmol) was added successively, stirred at room temperature for 4 hours, then added with 2ml of water to react for 1 hour, then extracted with dichloromethane solution, after the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was dried under reduced pressure. Preparative high performance liquid chromatography (hydroalkane/methanol-80/20-10/90) afforded compound 5(2.1mg, 38%) as a yellow solid.

The characterization information of the compound I-22 is specifically as follows:

¹H NMR(400MHz,CD₃OD)δ8.68(s,1H),8.11(s,1H),7.69(s,1H),7.53(d,J＝8.0Hz,1H),7.46(d,J＝8.0 Hz,1H),6.92(dd,J＝17.5,10.9Hz,1H)，6.08(d,J＝17.5Hz,1H),5.49(d,J＝10.8Hz,1H),4.21(s,3H),4.08(s, 3H),3.95(s,4H),3.80(d,J＝2.0Hz,1H).

example 8: compound I-23 and synthesis thereof

(1) Synthesis of compound 29:

compound 17(61.2mg,0.0986mmol) was dissolved in 3ml of acetic acid, followed by addition of the resulting mixture of HMTA (15mg,0.0986mmol) and p-toluenesulfonic acid (15mg,0.0789mmol) in that order, stirring at 118 ℃ for 5 hours, and then addition of Na₂CO₃The reaction was quenched, extracted with dichloromethane solution, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was spin dried under reduced pressure. Purification by flash column chromatography (dichloromethane/methanol-100/1) afforded compound 29(15.9mg, 25%) as a yellow solid. The characterization information of compound 29 is specifically:

¹H NMR(400MHz,CDCl₃)δ10.53(s,1H),8.54(s,1H),8.23(s,1H),8.19(d,J＝1.6Hz,1H),7.37(d,J＝1.5 Hz,1H),6.80(dd,J＝17.5,10.9Hz,1H),6.24(s,1H),5.97(d,J＝17.5Hz,1H),5.89(d,J＝3.3Hz,1H),5.68(dd,J＝ 10.0,3.3Hz,1H),5.49(d,J＝10.9Hz,1H),5.23(ddd,J＝13.3,10.0,7.6Hz,2H),4.15(s,3H),4.12(s,3H),2.11(d,J ＝3.3Hz,3H),1.95(s,3H),1.86(s,3H),1.40(d,J＝6.1Hz,3H).

(2) synthesis of compound 30:

compound 29(9mg,0.0139mmol) was dissolved in a mixed solution of 1Ml methanol and 1Ml dichloromethane, followed by the sequential addition of propargylamide (2. mu.L)0.0278mmol), acetic acid (0.8. mu.L, 0.0139mmol) was stirred at room temperature for 6 hours, then NaBH was added₃CN is reacted for 2 hours, then 3Ml of water is added to quench the reaction, the dichloromethane solution is used for extraction, after organic phases are combined, the anhydrous sodium sulfate is used for drying, the filtration is carried out, and the solvent is dried by spinning under reduced pressure. Purification by flash silica gel column separation (dichloromethane/methanol-100/1) afforded compound 30 as a yellow solid which was used directly in the next reaction.

(3) Synthesis of Compound I-23:

to a mixture of 30(10mg,0.0140mmol) and methanol (1.5mL) was added a solution of sulfuric acid in methanol (3.0M, 1.5mL) at room temperature. The resulting mixture was heated to 70 ℃ and stirred for 7 hours, followed by cooling to room temperature. The reaction solution was diluted with water and then extracted with chloroform/isopropanol (3/1). The organic phases were combined and washed with saturated sodium bicarbonate solution and then dried over anhydrous sodium sulfate. Filtration and spin-drying under reduced pressure followed by purification on flash silica gel (dichloromethane/methanol-9/1) gave compound I-23 as a yellow solid (4.9mg, 63% over 2 steps).

¹H NMR(400MHz,MeOD)δ8.24(s,1H),7.82(s,1H),7.69(s,1H),7.25(s,1H),6.78(dd,J＝17.5,10.9Hz, 1H),5.97(d,J＝17.6Hz,1H),5.74(s,1H),5.47(d,J＝10.9Hz,1H),4.16(d,J＝6.7Hz,1H),4.14(s,3H),4.04(dd,J ＝11.2,3.1Hz,2H),4.00(s,3H),3.83(t,J＝2.5Hz,2H),3.47(t,J＝9.3Hz,2H),3.08(t,J＝2.4Hz,1H),1.53(t,J＝ 6.0Hz,3H).

Experimental example I: detecting antitumor activity of compound

DMEM complete medium: 500mL of DMEM liquid medium (Gibco), 55mL of fetal bovine serum (Gibco) and 5mL of streptomycin were thoroughly mixed, and then filtered through a sterile filter with a pore size of 0.22. mu.m and sterilized.

Tumor cell culture

1. Resuscitated different tumor cells were inoculated into 10mL DMEM complete medium in 5% CO₂Cultured in an incubator at 37 ℃.

2. When the cell density reaches 80-90%, using pancreatin to digest, and carrying out cell passage.

Second, antitumor Activity test

1. Inoculating the cultured tumor cells to a 96-well plate, wherein the density is 10000 cells/well, 90 mu L of DMEM complete culture medium is used for each well, and culturing for 12h to allow the cells to grow in an adherent manner;

2. the compound was prepared as a 10mM stock solution in sterile DMSO, and then sequentially diluted with 10% DMSO in DMEM complete medium to give concentrations of 1mM, 100. mu.M, 10. mu.M, 1. mu.M, …, 10. mu.M^-7mu.M, 0. mu.M dilution. The following compounds were used respectively: compounds I-1, I-2, …, I-23.

Adding compounds with different concentrations into a 96-well plate according to a one-tenth ratio under a dark condition, then uniformly mixing, and incubating for 30min at 37 ℃;

3. irradiating the cells for 30min under 365nm light, and then putting the cells into an incubator for culturing for 48 h;

4. finally, cell viability was measured with CellTiter-Glo kit: add 100. mu.L CellTiter-Glo reagent to each well, then place the plate on the shaker gently to shake, incubate for 15min at room temperature, make it produce stable luminescent signal. Recording luminescence signal, preparing curve, determining IC of compound₅₀The values and results are shown in tables 1 and 2.

IC₅₀The value, i.e., the concentration of a certain compound that induces apoptosis of tumor cells by 50%, is referred to as the 50% inhibitory concentration.

Table 1: results of Activity assay (IC) of Polycarcin V (I-1) on different tumor cell lines₅₀Value, μ M)

Table 2: detection of antitumor Activity of different Compounds on HeLa cells (IC)₅₀Value, μ M)

Compound (I)	Illumination (IC)₅₀)	Compound (I)	Illumination (IC)₅₀)
				I-1	1x10^-8	I-13	6x10^-8
I-2	5x10^-8	I-14	4x10^-7
				I-3	4x10^-4	I-15	7x10^-4
I-4	1x10^-7	I-16	1x10^-6
				I-5	8x10^-6	I-17	0.1
I-6	40	I-18	1x10^-6
				I-7	49	I-19	0.3
I-8	1x10^-8	I-20	2x10^-6
				I-9	1x10^-7	I-21	3x10^-7
I-10	6x10^-6	I-22	0.06
				I-11	5x10^-7	I-23	1x10^-7
I-12	1x10^-7

As can be seen from Table 1, the compounds provided by the invention have very strong killing effect on different tumor cell lines under the illumination condition; in dark conditions, the cells showed relatively little toxicity. Therefore, the compounds belong to light-operated anti-tumor compounds.

As can be seen from Table 2, different derivatives of Polycarcin V (I-1) also showed strong antitumor activity against tumor cell lines.

Experimental example II: antitumor mechanisms of Compounds

1.20 mg calf thymus DNA was dissolved in 20mL Tris buffer (10mM Tris,1mM Na, EDTA, pH 8.0), and the polycardin V compound was dissolved in DMSO to a final concentration of 1 mg/mL.

2.1 mL of the compound was mixed with 20mL of calf thymus DNA, incubated in the dark for 30min, and then irradiated under 365nm light for 30 min.

3. Ethanol precipitation of DNA: 70mL of precooled ethanol, 3mL of saturated NaCl was added and left at-20 ℃ for 1 h. 10000rpm, 4 ℃ for 30min, and discarding the supernatant.

4. The DNA precipitate was dissolved in 10mL of 0.1N HCl and then reacted at 100 ℃ for 2h to acid-cleave the DNA into single bases.

5. LC-MS detects and separates the base addition product of the compound to DNA and finally characterizes the addition product by NMR as a [2+2] cycloaddition product of polycardin V with T base.

From this fact, it is known that the compound polycacin V covalently binds to the T base of DNA under light irradiation, and further affects many biological processes such as DNA replication and transcription, thereby exhibiting antitumor activity.

The mechanism of covalent binding of polycacin V to DNA is the [2+2] cycloaddition reaction of the vinyl group of the compound with the T base in DNA, and all other compounds have the key group-vinyl group associated with this activity, and thus are similar to the antitumor mechanism of polycacin V.

Experimental example III: compound induced apoptosis

Western-blot assay to analyze the expression of apoptosis-related proteins (cl-Caspase3, cl-PARP, BCL2, BAX):

caspase3, one of the half-light aspartase family members, is a key performer of apoptosis; activation of Caspase3, detection of clear Caspase3, is a common biological marker for apoptosis studies. PARP as a substrate of Caspase3 can be cut by activated Caspase3, so that cleared PARP is also considered as an important index of apoptosis; bcl2 family proteins play an important role in guiding apoptosis, and one class of proteins can resist apoptosis, such as Bcl 2; another class can promote the development of apoptosis, such as BAX.

The experimental steps are as follows:

1. treating HeLa cells with polycardin V (I-1) of different concentrations, incubating for 30min, irradiating with 365nm light for 30min, and culturing in a carbon dioxide incubator at 37 deg.C for 24 h;

2. washing the cells with PBS buffer, then extracting the cell lysate with RIPA (weak) lysis buffer; carrying out SDS-PAGE electrophoresis after protein quantification;

3. film transfer: transferring the protein to a PVDF membrane; blocking the membrane for 1h by using BSA blocking solution; c, reacting cl-Caspase3, cl-PARP, BCL2, BAX and GAPDH antibodies for 1-2 h at room temperature, washing the membrane for 3 times by using a washing solution, and reacting the membrane with an HRP-labeled secondary antibody for 1h at room temperature; finally, the membrane is washed for 3 times by using the washing liquid, and then chemiluminescence color development is carried out.

The results show (see fig. 1) that polycacin V can activate the function of Caspase3, initiate the cleavage of PARP, inhibit the expression of the anti-apoptotic protein Bcl2, and promote the expression of the pro-apoptotic protein BAX. The changes in the expression levels of these apoptosis-related protein markers are a good indication that the compound polycacin V can induce the apoptotic process in tumor cells. All other compounds also have a similar mechanism for inducing apoptosis.

Example IV: protection and repair of compound on Yinqiao-like skin lesion formed by IMQ induction

The test method comprises the following steps: the yinqiao disease is a hereditary dermatitis type disease, is commonly regulated by innate immunity and acquired immunity, and is mainly characterized by excessive vascular proliferation, abnormal differentiation of stratum corneum cells, active infiltration of immune cells, generation of skin scales, thickening of acanthosis spinosa and the like in clinical characteristics. The mouse psoriasis-like skin lesion induced by Imiquimod (IMQ) is one of the most commonly used mouse models for researching the psoriasis pathology and pharmacology at present, the characteristics of the psoriasis can be reflected from multiple aspects, the pathological changes on the skin are mainly manifested by erythema swelling and scale generation, and the acanthosis layer is obviously thickened when the section is dyed. In this example, the model was used to test the protection and repair functions of I-1 and its analogues I-18 and I-21 compounds described in the above section on IMQ-induced warp-like lesions under light activation, and 8-methoxy-furocoumarin (8-Methoxypsoralen,8-Mop) (pharmaceutical name methoxsalen) was used as a positive control. Female BALB/c wild type mice 8-10 weeks old were fed on regular diet with free drinking water in SPF-rated animal houses at the center of Experimental animals, Beijing university. 8-Mop, I-1, I-18 and I-21 are configured into corresponding working required concentrations by 60% ethanol, so that 200uL of smearing administration can meet the administration requirements, namely the configured concentrations of the drugs are 5ug/mL, 25ug/mL and 100ug/mL when 1 ug/day/mouse, 5 ug/day/mouse and 20 ug/day/mouse are administered. The mice are adapted to the environment for a week in advance, the hair on the same part of the back is removed by using the mouse depilatory cream one day before administration, and the mice are randomly grouped into groups of 6-8 mice each. Each experiment set up a negative control group, a model group, a single light group and several compound-light treated groups. At 9 am every morning, 200 muL of 60% ethanol is smeared on the back hair-shedding positions of a negative control group, a model group and a single illumination group; the compound-light treatment group was coated with 200uL of a previously prepared drug working solution according to the dosing schedule. After 15 minutes, the back of mice in the individual light groups and all compound-light treated groups were given 1 minute of light using a 365nm wavelength light source or a blue light source. After the total time is 2 hours from the application of the medicine, 62.5mg of vaseline is applied to the back of the mice in the negative control group; the model group, the light-alone group and all the compound-light-treated groups were coated with 62.5mg of IMQ (sichuan mingxin pharmaceuticals, imiquimod cream). The above procedure was carried out continuously for 7 days, observed before each administration, recorded photographically, and scored for erythema and scaling of 0-4 points on lesions of each mouse according to the clinical pasi (clinical psychiatric areas Area and sensitivity index) scoring criteria. PASI scoring criteria are as follows: 0, none; 1, light; 2, moderate; 3, severe; 4, very severe. The scores of the mice in each group are averaged, and then lesion curves are drawn to compare the differences. And after the last day of photographing and recording, euthanizing the mice, flattening the skin tissues of the back part of the same part on tin foil paper, fixing the skin tissues by using 10% formaldehyde solution, embedding the skin tissues in paraffin, slicing, carrying out H & E staining, and observing the skin pathological changes of all groups of mice. Freezing part of skin with liquid nitrogen, collecting blood, centrifuging, and collecting serum at-80 deg.C.

Test results 1: the compounds I-1(5 mu g/day/mouse) and 8-Mop (5 mu g/day/mouse) have relieving effect on IMQ-induced psoriasis-like skin damage under 365nm light source irradiation, and the effect is equivalent under the condition of the same dosage. The photographing result of the skin on the back of the mouse (figure 2) shows that the negative control group is the normal skin of the normal mouse, is smooth and ruddy, has no erythema and swelling, and has no scales; severe erythema swelling and scaling of the back skin was seen in the model group and the single-light group; the I-1 and 8-Mop treated groups showed some improvement in scaling and erythema swelling compared to the model group. The daily photographs of the skin on the back of the mice were averaged by PASI (0-4) and plotted as a score curve. The scale score curve (fig. 3) shows that the negative control group was normal skin of normal mice, no scale, and a score of 0; the back skin white scales of the model group and the single illumination group are higher in score; compared with the model group, the I-1 and 8-Mop treatment groups have reduced scale scores, which indicates that the scale lesions are improved, and the scoring result is consistent with the digital photographing result. The erythema swelling score curve (fig. 4) shows that the negative control group is normal skin of normal mice, no erythema swelling, and score 0; the back skin erythema swelling scores of the model group and the single illumination group are higher; compared with the model group, the I-1 and 8-Mop treatment groups have reduced erythema swelling scores, which show that the erythema lesion is improved, and the scoring result is consistent with the digital photographing result. The results of HE staining (figure 5) of the skin tissue section and quantification of the thickness of the acanthoderma layer, which is an important indicator of the psoriasis, according to an H & E staining chart (figure 6) show that the acanthoderma layer of the skin of a mouse in a model group is obviously thickened and is consistent with the clinical lesion phenotype of the skin lesion of the psoriasis, the thickness of the acanthoderma layer is not obviously different in a single illumination group compared with the model group, and the thickness of the acanthoderma layer of the skin can be obviously reduced by I-1 and 8-Mop treatment. The data show that the I-1 and 8-Mop can relieve the psoriasis-like lesion diseases under 365nm illumination, and the treatment effect is from the I-1 and 8-Mop compounds and is not from the effect of independent illumination.

Test results 2: the compound I-1 has a relieving effect on the psoriasis-like skin lesion induced by IMQ under the irradiation of a blue light source, and is superior to a positive control 8-Mop under the condition of the same dosage. After cell level tests, the activity of the 1-1 compound can be activated at high intensity under the condition that blue light is the same as 365nm light, so that the same mouse disease model is utilized by the people to detect whether the compound 1-1 has a relieving effect on psoriasis-like skin damage under the activation of the blue light. I-1 dose was set at three concentrations of 1. mu.g/day/mouse, 5. mu.g/day/mouse and 20. mu.g/day/mouse, respectively, and 8-Mop (20. mu.g/day/mouse) was used as a positive control. The photographing result of the skin on the back of the mouse (figure 7), the scale scoring curve (figure 8) and the erythema swelling scoring curve (figure 9) show that the skin of the negative control group mouse is smooth and ruddy without scales and red swelling; the scales of the model group mice are accumulated, and the red swelling is obvious; the single light illumination group and the model group have no difference; the 8-Mop and the I-1 can reduce redness and swelling and reduce the generation of scales under the help of blue light. The skin tissue section HE staining result (figure 10) and the quantitative result (figure 11) of the thickness of the acanthosis layer, which is an important indicator of the yinqiao disease, according to the H & E staining chart show that the acanthosis layer of the mouse in the model group is obviously thickened; the single-light illumination group is not different from the model group; 8-Mop and I-1 can obviously reduce the thickness of the acanthosphere layer of the skin epidermis with the help of blue light. It is worth pointing out that I-1 has certain drug concentration dependence on the relieving effect of psoriasis-like lesion, and the relieving effect is better than that of the positive control 8-Mop.

Test results 3: the compounds I-1, I-18 and I-21 have relieving effect on IMQ-induced psoriasis-like skin lesion under the irradiation of blue light source. The test results show that the compound I-1 has a relieving effect on the psoriasis-like lesions under 365nm and blue light irradiation, and in order to investigate whether the analogues I-18 and I-21 also have the relieving effect on the psoriasis-like lesions, the same mouse disease model is used for detecting whether the compounds 1-18 and I-21 also have the relieving effect on the psoriasis-like lesions under the blue light activation. The amounts of I-1, I-18 and I-21 administered were all 5. mu.g/day/mouse. The photographing result of the skin on the back of the mouse (figure 12), the scale scoring curve (figure 13) and the erythema swelling scoring curve (figure 14) show that the skin of the negative control group mouse is smooth and ruddy, and has no scales and red swelling; the scales of the model group mice are accumulated, and the red swelling is obvious; the single-light illumination group is not different from the model group; the I-1, I-18 and I-21 can reduce red swelling and reduce the generation of scales under the irradiation of blue light. The results of HE staining of skin tissue sections (figure 15) and quantification of the thickness of the acanthosphere, which is an important indicator of the yinqiao disease, according to the H & E staining chart (figure 16) indicate that the acanthosphere of the mouse in the model group is obviously thickened; the single-light illumination group is not different from the model group; the thickness of the skin epidermal acanthosphere layer can be obviously reduced by the irradiation of the blue light by the I-1, the I-18 and the I-21. The above results indicate that compounds I-18 and I-21 also have a soothing effect on IMQ-induced psoriatic lesions.

And (4) test conclusion: this example shows that compounds I-1, I-18 and I-21 and their potential analogs have excellent protective and reparative effects in the alleviation and treatment of skin disorders such as psoriasis under the excitation of ultraviolet and blue light.

Although the protection and repair function against the yinqiao disease has been described in detail in the above description by the general description, the specific embodiments and the experiments, it will be apparent to those skilled in the art that some modifications or improvements may be made on the basis of the present invention. Accordingly, such modifications and improvements are intended to be within the scope of this invention as claimed.

Claims

1. An application of a compound with a structure shown in a general formula I or a pharmaceutically acceptable salt thereof in preparing a medicament for treating skin diseases,

in the general formula I, R₁、R₂、R₆Independently of one another, represents hydrogen or an alkyl group, said alkyl group being a straight-chain or branched saturated hydrocarbon group having from 1 to 18 carbon atoms;

R₃、R₄is hydrogen; r₅Represents glucose, galactose, mannose, N-acetylglucose, glucuronic acid, 6-deoxy-glucose, 2, 6-dideoxy-glucose, N-acetylgalactosamine, sialic acid, fucose, xylose, rhamnose, maltose, lactose;

R₇represents a vinyl group.

2. The use according to claim 1,

the alkyl group means a straight or branched chain saturated hydrocarbon group of 1 to 12 carbon atoms;

the fucose includes fucofuranose and fucopyranose.

3. Use according to claim 2, characterized in that said alkyl group is a saturated hydrocarbon group, straight or branched, of 1 to 6 carbon atoms.

4. Use according to any one of claims 1 to 3, characterized in that, in the general formula I, R₁、R₂、R₆Independently of one another, represents hydrogen or alkyl, or R₁And R₆Represents methyl, R₂Represents hydrogen or alkyl, said alkyl being C₁-C₃Alkyl group of (1).

5. Use of a compound or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a dermatological disorder, wherein the compound is selected from the structures:

6. use according to any one of claims 1 to 3, 5, wherein: the skin diseases include psoriasis and vitiligo.

7. Use according to claim 4, characterized in that: the skin diseases include psoriasis and vitiligo.

8. A compound or a pharmaceutically acceptable salt thereof, wherein the compound comprises a structure according to formula II:

wherein:

R₂、R₃、R₄is hydrogen, R₅The substituent of the amino group is an amido group of an alkyl group of 1 to 6 carbon atoms.

9. A compound, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the structures:

10. a synthetic method of a compound with a structure shown in a general formula III or pharmaceutically acceptable salt thereof is characterized in that,

compound III is prepared from lactone compound 7 by at least one deprotection reaction and/or at least one addition reaction;

wherein R is₁～R₇As defined in any one of claims 8 or 9, Bn is benzyl and i-Pr is isopropyl.

11. The method of claim 10, wherein: when the compound has a structure shown in a general formula IV, the synthetic route of the compound comprises the following steps:

the method comprises the following steps:

(i) performing formaldehyde alkylation on the compound 8 to obtain a compound 9;

(ii) oxidizing the compound 9 to obtain a compound 10;

(iii) amidating the compound 10 to obtain a compound shown in a formula IV;

wherein R is₂Is hydrogen or phosphate radical, R₅As defined in any one of claims 8 or 9.

12. Use of a compound according to any one of claims 8 or 9 or a pharmaceutically acceptable salt thereof, or a compound prepared by a method according to any one of claims 10 to 11 or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of tumours and dermatological disorders.

13. The use of claim 12, wherein the tumor comprises a luminal, a luminal or a superficial tumor.

14. The use of claim 13, wherein the body surface tumor comprises: cutaneous lymphoma, melanoma; and endoscopically-illuminable tumors include: gastric cancer, colorectal cancer, esophageal cancer, nasopharyngeal carcinoma.

15. The use according to claim 12, wherein said skin disorders comprise psoriasis and vitiligo.