CN104844617B

CN104844617B - Brusatol derivative and its purposes in inflammation and immunologic function disorder disease

Info

Publication number: CN104844617B
Application number: CN201410054069.2A
Authority: CN
Inventors: 庾石山; 侯琦; 汤伟彬; 袁绍鹏; 徐嵩; 吕海宁; 屈晶; 马双刚; 白金叶
Original assignee: Institute of Materia Medica of CAMS
Current assignee: Institute of Materia Medica of CAMS
Priority date: 2014-02-18
Filing date: 2014-02-18
Publication date: 2019-01-01
Anticipated expiration: 2034-02-18
Also published as: CN104844617A

Abstract

The invention discloses a kind of Brusatol derivative and its purposes in inflammation and immunologic function disorder disease.More particularly to a kind of nitric oxide donors Brusatol derivative or its medically acceptable salt, the Pharmaceutical composition containing these derivatives and they preparing the application in anti-inflammatory and immunosuppressive drug.Application in preparation inflammation and/or immunologic derangement related disease drug.

Description

Brusatol derivative and its purposes in inflammation and immunologic function disorder disease

Technical field

The present invention relates to biomedicine fields, and in particular to a kind of nitric oxide donors Brusatol derivative or its medicine Upper acceptable salt, the Pharmaceutical composition containing these derivatives and they prepare it is anti-inflammatory with answering in immunosuppressive drug With.

Background technique

Guassin is a kind of natural products with extensive pharmacological activity, and activity includes antitumor, anti-malarial, anti-inflammatory, is killed Worm etc., but it generally has very strong toxicity.Crow gallbladder pavilion was once used as anti-tumor drug to enter clinical research in guassin, however One of the reason of internal serious toxicity is its failure.While how improving or keep activity, reducing toxicity is by quassia Chlorins compound is for clinical key.According to the literature (I.H.Hall, K.H.Lee and etc, J.Pharm.Sci, 1983;72:1282), quassinoids natural products Brusatol can stablize lysosome membrane, reduce the release of hydrolase, to drop The low damage to surrounding tissue.In rat body on inflammatory model, Brusatol (brusatol) shows very strong anti-inflammatory work Property, activity is much better than Indomethacin.However, Brusatol has very strong toxicity, limit its application.

NO is endogenous compound, with extensive physiological action.Studies have shown that continuing in vivo low in cellular level NO (either endogenic or exogenous) apoptosis capable of inhibiting cell of concentration has protection to cell and promotes the work of growth With.In immunological diseases research, most scholars, which tend to endogenous NO, may participate in the occurrence and development process of autoimmunity disease, have Immunoregulatory activity, adjustable leucocyte and endothelial cell adhesion inhibit the aggregation of blood platelet, leucocyte, and T cell is inhibited to increase It grows, improves the effect of NK cell activity etc..Currently, according to existing research shows that NO donor (possesses point of release NO ability Son or group) the nitric oxide donors non-steroid anti-inflammatory drug (NO-NSAID) of generation is coupled with NSAID, it is keeping or is increasing While NSAID curative effect (such as anti-platelet activity increase), adverse reaction (such as gastrointestinal tract and the heart of NSAID can be substantially reduced Blood vessel adverse reaction).However NO also has double action, on the one hand appropriate endogenous NO plays the role of inhibiting inflammation in vivo;Separately INOS(iNOS in one side inflammatory process) activation, inflammation can be further aggravated again by synthesizing excessive NO.

Therefore, NO donor and Brusatol are coupled, obtain nitric oxide donor type derivant, it is artificial it is controllable in vivo Inflammation initial stage generates a small amount of NO, plays similar endothelium-derived NO and acts on, to inhibit inflammation, so that iNOS be inhibited to over-express. Persistently the NO of low concentration can also improve survival rate of the cell under the toxic effect of Brusatol simultaneously, play the work for reducing toxicity With.

Currently, had no in the prior art about to NO donator type Brusatol derivative or its medically acceptable salt, For treating the report of the diseases such as inflammation and immunologic function disorder.

Summary of the invention:

The present invention be in order to overcome disadvantage of the existing technology to propose, it is solved the technical issues of be to provide one kind Active high and small toxic side effect Brusatol analog derivative.

For this purpose, the invention discloses a kind of noval chemical compounds, that is, the nitric oxide donator type Brusatol as shown in general formula I Derivative:

Wherein, R₁、R₂、R₄It is independent selected from H,Substituted furazan ring,

Wherein, substituted furazan ring is selected fromOr

Wherein, L₁Selected from R₆Or-R₆-X₁-Y₁, wherein Y₁It is connect with O in primer, R₆Selected from C_2-6Alkyl, C_2-4OC_2-4 Alkyl, C_2-6Alkenyl, C_2-6Alkynyl, substituted or unsubstituted phenyl, wherein the substituent group of the phenyl be selected from C_1-6Alkyl, X₁Choosing From O or NH, Y₁Selected from succinyl base or phthalyl；

L₂Selected from R₇、-R₇-X₂-Y₂-、Y₂, wherein Y₂It is connect with O in primer, R₇Selected from substituted or unsubstituted phenyl, Wherein the substituent group of the phenyl is selected from C_1-6Alkyl, X₂Selected from O or NH, Y₂Selected from succinyl base or phthalyl；

R₃Selected from OH, OCH₃, replace furazan ring,

The furazan ring wherein replaced is selected fromOr

Wherein R₉Selected from C_2-6Alkyl, C_2-4OC_2-4Alkyl, C_2-6Alkenyl, C_2-6Alkynyl, substituted or unsubstituted phenyl, wherein The substituent group of the phenyl is selected from C_1-6Alkyl；

L₃Selected from-O-R₁₀- O- or O, wherein R₁₀Selected from substituted or unsubstituted phenoxy group, wherein CH on oxygen and furazan ring₂ It is connected, wherein the substituent group of the phenoxy group is selected from C_1-6Alkyl；

, according to the invention it is preferred to logical formula (I) compound represented including but not limited to chemical combination shown in general formula (Ia) Object:

Wherein, R₃Selected from OH, OCH₃, L₁Selected from-R₆-X₁-Y₁, wherein Y₁It is connect with O in primer, R₆Selected from C_2-6Alkane Base, C_2-4OC_2-4Alkyl, C_2-6Alkynyl ,-o-Ph- (CH₂)_n, wherein n=0,1,2,3,4 ,-m-Ph- (CH₂)_n, wherein n=0,1, 2,3,4 ,-p-Ph- (CH₂)_n, wherein n=0,1,2,3,4；X₁Selected from O, Y₁Selected from succinyl base or phthalyl.

, according to the invention it is preferred to logical formula (I) compound represented including but not limited to chemical combination shown in general formula (Ib) Object:

Wherein, R₃Selected from OH, OCH₃, L₂Selected from R₇、-R₇-X₂-Y₂-、Y₂, wherein Y₂It is connect with O in primer, R₇Selected from- o-Ph-(CH₂)_n, wherein n=0,1,2,3,4 ,-m-Ph- (CH₂)_n, wherein n=0,1,2,3,4 ,-p-Ph- (CH₂)_n, wherein n= 0,1,2,3,4；X₂Selected from O, Y₂Selected from succinyl base or phthalyl.

, according to the invention it is preferred to logical formula (I) compound represented including but not limited to chemical combination shown in general formula (Ic) Object:

Wherein, L₁Selected from-Y₁-X₁-R₆, wherein Y₁It is connect with O in primer, R₆Selected from C_2-6Alkyl, C_2-4OC_2-4Alkyl, C_2-6Alkynyl ,-(CH₂)_n- o-Ph-, wherein n=0,1,2,3,4 ,-(CH₂)_n- m-Ph-, wherein n=0,1,2,3,4 ,-(CH₂)_n-p- Ph-, wherein n=0,1,2,3,4, wherein the connected CH of phenyl₂And X₁It is connected；X₁Selected from O, Y₁Selected from succinyl base or adjacent benzene two Formoxyl.

, according to the invention it is preferred to logical formula (I) compound represented including but not limited to chemical combination shown in general formula (Id) Object:

Wherein, L₂Selected from-Y₂-X₂-R₇, wherein Y₂It is connect with O in primer, R₇Selected from-(CH₂)_n- o-Ph-, wherein n= 0,1,2,3,4 ,-(CH₂)_n- m-Ph-, wherein n=0,1,2,3,4 ,-(CH₂)_n- p-Ph-, wherein n=0,1,2,3,4, wherein benzene The connected CH of base₂And X₂It is connected；X₂Selected from O, Y₂Selected from succinyl base or phthalyl.

, according to the invention it is preferred to logical formula (I) compound represented including but not limited to chemical combination shown in general formula (Ie) Object:

Wherein, R₉Selected from C_2-6Alkyl, C_2-4OC_2-4Alkyl, C_2-6Alkynyl ,-(CH₂)_n- o-Ph-, wherein n=0,1,2,3,4 ,- (CH₂)_n- m-Ph-, wherein n=0,1,2,3,4 ,-(CH₂)_n- p-Ph-, wherein n=0,1,2,3,4, wherein the connected CH of phenyl₂It is logical O is crossed to be connected with primer.

, according to the invention it is preferred to logical formula (I) compound represented including but not limited to chemical combination shown in general formula (If) Object:

Wherein, L₃Selected from-O-R₁₀- O- or O,

Wherein, R₁₀Selected from-(CH₂)_n- o-Ph-, wherein n=0,1,2,3,4 ,-(CH₂)_n- m-Ph-, wherein n=0,1,2,3, 4 ,-(CH₂)_n- p-Ph-, wherein n=0,1,2,3,4, wherein the connected CH of phenyl₂It is connected by O with primer.

, according to the invention it is preferred to logical formula (I) compound represented including but not limited to chemical combination shown in general formula (Ig) Object:

Wherein, R₁Selected from H,L₁Selected from-R₆-X₁-Y₁, wherein Y₁It is connected with O in primer, R₆ Selected from C_2-6Alkyl, C_2-4OC_2-4Alkyl, C_2-6Alkynyl ,-o-Ph- (CH₂)_n, wherein n=0,1,2,3,4 ,-m-Ph- (CH₂)_n, its Middle n=0,1,2,3,4 ,-p-Ph- (CH₂)_n, wherein n=0,1,2,3,4, wherein the connected CH of phenyl₂And X₁It is connected；X₁Selected from O, Y₁Selected from succinyl base or phthalyl.

, according to the invention it is preferred to logical formula (I) compound represented including but not limited to chemical combination shown in general formula (Ii) Object:

Wherein, R₁Selected from H,L₂Selected from-R₇-X₂-Y₂-、Y₂, wherein Y₂It is connected with O in primer, R₇Selected from-o-Ph- (CH₂)_n, wherein n=0,1,2,3,4 ,-m-Ph- (CH₂)_n, wherein n=0,1,2,3,4 ,-p-Ph- (CH₂)_n, wherein n=0,1,2,3,4, wherein the connected CH of phenyl₂And X₂It is connected；X₂Selected from O;Y₂Selected from succinyl base or adjacent benzene Diformyl.

Specifically, nitric oxide donator type Brusatol derivative shown in general formula I preferably is selected from but is not limited only to following Compound (compound numbers correspond to the compound numbers in embodiment):

Compound	R₆	X₁	Y₁
				1	(CH₂)₃	O	CO(CH₂)₂CO
2	(CH₂)₄	O	CO(CH₂)₂CO
				3	(CH₂)₂CH(CH₃)	O	CO(CH₂)₂CO
4	(CH₂)₅	O	CO(CH₂)₂CO
				5	(CH₂)₂O(CH₂)₂	O	CO(CH₂)₂CO
6	CH₂C≡CCH₂	O	CO(CH₂)₂CO
				7	p-PhCH₂	O	CO(CH₂)₂CO
8	m-PhCH₂,	O	CO(CH₂)₂CO
				9	(CH₂)₄	O	CO-o-PhCO

Compound

R₇

X₂

Y₂

10	p-Ph-CH₂	O	CO(CH₂)₂CO
				11	m-Ph-CH₂	O	CO(CH₂)₂CO
12	o-Ph-CH₂	O	CO(CH₂)₂CO
				13	-	O	CO(CH₂)₂CO
14	-	O	CO-o-PhCO
				15	p-Ph-CH₂	-	-

Compound	R₆	X₁	Y₁
				16	(CH₂)₃	O	CO(CH₂)₂CO
17	(CH₂)₄	O	CO(CH₂)₂CO
				18	(CH₂)₂CH(CH₃)	O	CO(CH₂)₂CO
19	(CH₂)₅	O	CO(CH₂)₂CO
				20	(CH₂)₂O(CH₂)₂	O	CO(CH₂)₂CO
21	CH₂C≡CCH₂	O	CO(CH₂)₂CO
				22	CH₂-p-Ph	O	CO(CH₂)₂CO
23	CH₂-m-Ph	O	CO(CH₂)₂CO
				24	(CH₂)₄	O	CO-o-PhCO

Compound	R₇	X₂	Y₂
				25	CH₂-p-Ph	O	CO(CH₂)₂CO
26	CH₂-m-Ph	O	CO(CH₂)₂CO
				27	CH₂-o-Ph	O	CO(CH₂)₂CO
28	-	O	CO(CH₂)₂CO
				29	-	O	CO-o-PhCO

Compound	R₉
		30	CH₂CH₂CH₂
31	CH₂CH₂CH₂CH₂
		32	CH₂-p-Ph
33	CH₂-m-Ph

Compound	L₃
		34	OCH₂-p-PhO
35	OCH₂-m-PhO
		36	OCH₂-o-PhO
37	O

The invention further relates to a kind of containing medicine effective dose the compound as described in each situation of general formula I and pharmaceutically may be used The pharmaceutical composition of the carrier of receiving.

According to the present invention, the compounds of this invention can exist in the form of isomers, and usually described " of the present inventionization Conjunction object " includes the isomers of the compound.

According to an embodiment of the invention, the compounds of this invention further includes acceptable salt, salt in its pharmacodynamics Hydrate or pro-drug.

The invention further relates to containing as the compounds of this invention and customary pharmaceutical excipients of active ingredient or the medicine of adjuvant Compositions.Usual pharmaceutical composition of the present invention contains the compounds of this invention of 0.1~95% weight.This hair in unit dosage form The bright general content of compound is 0.1~100mg, and preferred unit dosage form contains 4~50mg.

The pharmaceutical composition of the compounds of this invention can be prepared according to method well known in the art.When for this purpose, if It needs, can be by the compounds of this invention in conjunction with one or more solids or liquid pharmaceutical excipients and/or adjuvant, being made can be used as The administration form or dosage form appropriate that people's medicine or veterinary drug use.

The compounds of this invention can be administered in a unit containing its pharmaceutical composition, and administration route can be enteron aisle Or non-bowel, such as oral, muscle, subcutaneous, nasal cavity, oral mucosa, skin, peritonaeum or rectum.The compounds of this invention contains The administration route of its pharmaceutical composition can be drug administration by injection.Injection includes intravenous injection, intramuscular injection, subcutaneous injection, intradermal Injection and acupoint injection therapy etc..

Form of administration can be liquid dosage form, solid dosage forms.As liquid dosage form can be true solution class, colloidal type, particle Dosage form, emulsion dosage form, mixed suspension form.Other dosage forms such as tablet, dripping pill, aerosol, pill, pulvis, solution, mixes capsule Suspension, emulsion, granule, suppository, freeze drying powder injection etc..

The compounds of this invention can be made ordinary preparation, be also possible to sustained release preparation, controlled release preparation, targeting preparation and various Particulate delivery system.

Such as in order to which tablet is made in unit dosage forms for administration, various carriers well known in the art can be widely used.About The example of carrier is, such as diluent and absorbent, such as starch, dextrin, calcium sulfate, lactose, mannitol, sucrose, sodium chloride, Portugal Grape sugar, urea, calcium carbonate, white bole, microcrystalline cellulose, alumina silicate etc.；Wetting agent and adhesive, such as water, glycerol, poly- second two Alcohol, ethyl alcohol, propyl alcohol, starch slurry, dextrin, syrup, honey, glucose solution, mucialga of arabic gummy, gelatine size, carboxymethyl cellulose Sodium, lac, methylcellulose, potassium phosphate, polyvinylpyrrolidone etc.；Disintegrating agent, such as dry starch, alginate, agar Powder, laminaran, sodium bicarbonate and citric acid, calcium carbonate, polyoxyethylene sorbitol aliphatic ester, dodecyl sodium sulfate, Methylcellulose, ethyl cellulose etc.；Disintegration inhibitor, such as sucrose, glyceryl tristearate, cocoa butter, hydrogenated oil and fat etc.；It inhales Receive promotor, such as quaternary ammonium salt, lauryl sodium sulfate etc.；Lubricant, such as talcum powder, silica, cornstarch, tristearin Hydrochlorate, boric acid, atoleine, polyethylene glycol etc..Tablet can also be further made to coating tablet, such as sugar coated tablet, film Coating tablet, enteric coated tablets or double-layer tablets and multilayer tablet.

Such as in order to which pill is made in administration unit, various carriers well known in the art can be widely used.About carrier Example be such as diluent and absorbent, such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, polyvinylpyrrolidine Ketone, single stearic acid glycerine lipoprotein, kaolin, talcum powder etc.；Adhesive, such as Arabic gum, bassora gum, gelatin, ethyl alcohol, honey, liquid Sugar, rice paste or batter etc.；Disintegrating agent, such as agar powder, dry starch, alginate, dodecyl sodium sulfate, methylcellulose, Ethyl cellulose etc..

Such as in order to which capsule is made in administration unit, effective component the compounds of this invention and above-mentioned various carriers are mixed It closes, and thus obtained mixture is placed in hard gelatine capsule or soft capsule.It can also be by effective component the compounds of this invention Microcapsules is made, is suspended in aqueous medium and forms suspension, also can be fitted into hard capsule or be made injection application.

For example, injection preparation is made in the compounds of this invention, such as solution, suspension solution, emulsion, freeze-dried powder Agent, this preparation can be aqueous or non-aqueous, can contain acceptable carrier in a kind of and/or a variety of pharmacodynamics, diluent, viscous Mixture, lubricant, preservative, surfactant or dispersing agent.As diluent can be selected from water, ethyl alcohol, polyethylene glycol, 1,3- the third two Alcohol, the isooctadecanol of ethoxylation, polyoxygenated isooctadecanol, polyoxyethylene sorbitol rouge, fat acid esters etc..In addition, in order to make Standby isotonic injection, can add suitable sodium chloride, glucose or glycerol, further, it is also possible to add into injection preparation Conventional cosolvent, buffer, pH adjusting agent etc..These auxiliary materials are commonly used in the art.

In addition, if desired, can also be added into pharmaceutical preparation colorant, preservative, fragrance, corrigent, sweetener or Other materials.

To reach medication purpose, enhance therapeutic effect, drug of the invention or pharmaceutical composition well known can be given with any The administration of prescription method.

The dosage of the compounds of this invention pharmaceutical composition depends on many factors, such as to be prevented or be treated disease Property and severity, gender, age, weight, personality and the individual reaction of patient or animal, administration route, administration number of times, Therapeutic purposes, therefore therapeutic dose of the invention can have large-scale variation.In general, Chinese pharmacology ingredient of the present invention makes It is well known to those skilled in the art with dosage.It can be according to the present invention contained in preparation last in compound composition Actual drug quantity is subject to adjustment appropriate, to reach the requirement of its therapeutically effective amount, completes prevention or treatment mesh of the invention 's.The daily Suitable dosage ranges of the compounds of this invention: the dosage of the compound of the present invention is 0.001~100mg/Kg body Weight, preferably 0.1~60mg/Kg weight, more preferably 1~30mg/Kg weight, most preferably 2~15mg/Kg weight.It is adult The compounds of this invention that patient takes is 10~500mg daily, preferably 20~100mg, can once take or divide 2~3 clothes With；The dosage of children taking is according to 5~30mg of every kg weight, preferably 10~20mg/kg weight.Above-mentioned dosage can be single dose Amount form is divided into several, such as two, three or four dosage forms for administration, this is limited to the clinical experience of administration doctor and controls The dosage regimen for the treatment of means.The compound of the present invention or composition can individually be taken, or with other treatment drug or symptomatic drugs Merge and uses.

Another object of the present invention, which is to provide a kind of nitric oxide donator type Brusatol derivative or its, can medically connect The hydrate or pro-drug of the salt, salt received are preparing anti-inflammatory and immunosupress or immunologic function disorder and its related disease drug Middle application.

The related diseases such as the inflammation and immunologic function disorder include rheumatoid arthritis, osteoarthritis, rheumatic Arthritis, urarthritis, lupus erythematosus syndrome, bronchitis, bursal synovitis, tenosynovitis, psoriasis, eczema, burn, skin Inflammation, inflammatory bowel disease, Ke Laoen disease, gastritis, irritable bowel syndrome, ulcerative colitis, multiple sclerosis, autoimmune Encephalomyelitis, colorectal cancer, arteritis nodosa, thyroiditis, rheumatic fever, gingivitis, periodontitis canker sore, ephritis, The swelling, myocardial ischemia, various infectious pneumonias, physics and chemistry pneumonia and the allergy pneumonia that occur after damage, chronic resistance Plug property tuberculosis, asthma, proctalgia fugax and rectum split, liver and gallbladder capsulitis, cholangitis sclerosing cholangitis, primary biliary liver Cirrhosis and cholecystitis etc..The universals of this kind of disease on a cellular level show themselves in that macrophage overactivity, generate excessive NO；Lymphocyte transformation is abnormal, leads to immunologic function disorder.

It is small to the experiment and compounds affect that inhibit the macrophage stimulated through LPS generation NO that the present invention has carried out compound Mouse splenic lymphocyte proliferation, transformation experiment illustrate that the Brusatol derivative of invention has from cellular level and inhibit macrophage It is the activity of T cell and B cell that cell, which generates excessive NO and inhibits lymphocyte transformation,.Pass through the compound of research invention simultaneously Influence to chmice acute otitis and allergic dermatitis, further demonstrate that the Brusatol derivative of invention in vivo experiment according to So there is good anti-inflammatory and immunosuppressive activity.In addition, also pass through two pathological models of asthma and chronic obstructive pneumonia, into One step proves that the compounds of this invention also has good therapeutic effect to immunologic function disorder related disease.

It is good anti-inflammatory and immune to show that Brusatol derivative of the invention has from inside and outside the pharmacological results Inhibitory activity, and can be used to treat inflammation and/or immunologic function disorder related disease, it is a kind of active high poison Small side effects Compound has good Development volue.

Detailed description of the invention

Mouse body weight increase situation in Fig. 1 asthmatic model

Influence of the Fig. 2 to asthmatic mouse pathological change

Elisa measurement result of the Fig. 3 to mouse asthma SERUM IgE

The influence that Fig. 4 converts mouse asthma spleen lymphocyte proliferation

Arneth's count result in Fig. 5 mouse asthma bronchoalveolar lavage fluid

Elisa measurement result of the Fig. 6 to inflammatory factor in mouse asthma bronchoalveolar lavage fluid

Arneth's count result in Fig. 7 chronic obstructive pulmonary disease mouse bronchoalveolar lavage fluid

Fig. 8 mouse bronchoalveolar lavage fluid inflammatory factor secretes situation

Specific embodiment:

In order to which the present invention is furture elucidated, a series of embodiments are given below, these embodiments be entirely it is illustrative, it Only be used to the present invention specifically describe, be not construed as limitation of the present invention.

The synthetic route of compound 1-9 in embodiment: (intermediate a₁-a₈Middle R₆、X₁Respectively with R in compound 1-8₆、X₁One It causes, b₁-b₉Middle R₆、X₁、Y₁Respectively with R in compound 1-9₆、X₁、Y₁Unanimously)

The final product (compound numbers correspond to the compound numbers in embodiment) of synthesis:

Compound numbers	R₆	X₁	Y₁
				1	(CH₂)₃	O	CO(CH₂)₂CO
2	(CH₂)₄	O	CO(CH₂)₂CO
				3	(CH₂)₂CH(CH₃)	O	CO(CH₂)₂CO
4	(CH₂)₅	O	CO(CH₂)₂CO
				5	(CH₂)₂O(CH₂)₂	O	CO(CH₂)₂CO
6	CH₂C≡CCH₂	O	CO(CH₂)₂CO
				7	p-PhCH₂	O	CO(CH₂)₂CO
8	m-PhCH₂,	O	CO(CH₂)₂CO
				9	(CH₂)₄	O	CO-o-PhCO

Embodiment 1:

Step 1:3- (3- benzenesulfonyl -1,2,5- oxadiazoles -2- oxide -4-) oxygen propyl alcohol (a₁) preparation

2.5g (32mmol) 1,3-PD is dissolved in 15mlTHF, 10% NaOH solution 6ml is added to it, in ice water It is added dropwise under the conditions of bath and contains 2.2g(6mmol) 2- oxygen -3,4- dibenzenesulfonyl -1,2, the 30ml THF solution of 5- oxadiazoles (A).Drop Finish, changes so that reaction is stirred at room temperature.After 2h, reaction solution is poured into 200ml water, with ethyl acetate (3 × 200ml) extraction.It is organic It is laminated simultaneously, saturated common salt water washing, then dry with anhydrous sodium sulfate.After drying, filtering, filtrate concentration.Silica gel column chromatography separation, With ethyl acetate: petroleum ether (60~90 DEG C)=1:3~1:1 (V:V) gradient elution obtains white powdery solids 1.0g, to change Close object a₁, yield 55.5%.

Step 2:4- [3- (2- oxygen -3- benzenesulfonyl -1,2,5- oxadiazoles -4- oxygen)-propoxyl group] -4- ketobutyric acid (b₁) Preparation

Take a₁280mg(0.93mmol), succinic anhydride 200mg(2mmol), DMAP about 30mg(0.25mmol) with anhydrous two Chloromethanes 40ml dissolution, 40 DEG C of return stirring reactions are for 24 hours.After reaction, respectively with hot water, saturated common salt water washing.It is organic Layer is dry with anhydrous sodium sulfate.After drying, filtering, filtrate concentration, silica gel column chromatography separation, with methylene chloride: methanol=50:0~ 50:1 gradient elution obtains white powdery solids 330mg, is compound b₁, yield 88.4%.

Step 3:3-O- { 4- [3- (2- oxygen -3- benzenesulfonyl -1,2,5- oxadiazoles -4- oxygen)-propoxyl group] -4- oxo fourth Acyl group }-Brusatol (1) preparation

By EDCI86mg(0.44mmol), intermediate b₁140mg(0.35mmol) be placed in a reaction flask, in ice-water bath, Anhydrous methylene chloride dissolution is added, after ten minutes, Brusatol 90mg(0.17mmol is added in stirring) and DMAP23mg (0.19mmol), continuation are stirred to react 3h under ice bath, then change to react at room temperature 48h.Reaction solution is dilute respectively with dilute HCl NaHCO₃Solution, saturated common salt water washing, organic layer are dry with anhydrous sodium sulfate.After drying, filtering, filtrate concentration, silicagel column Chromatographic isolation, with methylene chloride: methanol=60:1 elution obtains white powdery solids about 50mg, is compound 1, yield 32.0%. The physical and chemical parameter of compound 1 is as follows:

¹H NMR(600MHz,CD₃COCD₃) δ 8.07 (2H, br d, J=7.8Hz, ArH), 7.87 (1H, t, J=7.8Hz, ArH),7.75(2H,t,J=7.8Hz,ArH),6.12(1H,br s,H-15),5.63(1H,s,H-2’),4.98(1H,s,H- 7),4.73(1H,d,J=7.8Hz,H_a- 20), 4.55 (2H, t, J=6.0Hz, OCH₂), 4.29 (2H, t, J=6.0Hz, OCH₂), 4.26 (2H, overlap, H-11, H-12), 4.13 (2H, t, J=6.5Hz, OCH₂),3.78(1H,d,J=7.8Hz,H_b-20), 3.70(3H,s,CH₃O-21),3.33(1H,br s,H-14),3.24(1H,d,J=12.6Hz,H-5),2.85(2H,m, COCH₂),2.81(1H,d,J=16.0Hz,H_β-1),2.79(1H,d,J=16.0Hz,H_α-1),2.71(2H,t,J=6.0Hz, COCH₂),2.39(1H,br s,H-9),2.29(1H,dt,J=15.0,2.4Hz,H_α-6),2.22(2H,m,CH₂),2.14(3H, H-5’),1.98(1H,ddd,J=15.0,12.6,2.4Hz,H_β-6),1.91(3H,s,H-4’),1.82(3H,s,H-18), 1.49(3H,s,H-19);

¹³C NMR(150MHz,CD₃COCD₃)δ189.9(C-2),172.5(C=O),171.7(C-21),170.8(C=O), 167.6(C-16),164.9(C-1’),160.0(C-3’),159.0(C=N),146.8(C-3),142.7(C-4),139.0 (ArC),136.7(ArC),130.7(ArC×2),129.4(ArC×2),115.8(C-2’),111.5(C=N),83.2(C- 7),82.3(C-13),76.4(C-12),74.0(C-20),72.7(C-11),69.0(OCH₂),67.6(C-15),61.3 (OCH₂),52.7(C-21),51.2(C-14),50.4(C-1),46.1(C-8),43.2(C-5),41.6(C-9),41.5(C- 10),29.6(COCH₂),29.4(COCH₂),29.1(C-6),28.6(CH₂),27.2(C-4’),20.2(C-5’),15.8(C- 19),14.5(C-18)；HRESIMS m/z903.2476[M+H]⁺(calcd for C₄₁H₄₇N₂O₁₉S,903.2488).

Embodiment 2:

3-O- { 4- [4- (2- oxygen -3- benzenesulfonyl -1,2,5- oxadiazoles -4- oxygen)-butoxy] -4- oxobutanoyl } - Brusatol (2)

Step 1: referring to step 1 in embodiment 1,1,3-PD and 2- oxygen -3,4- hexichol sulphur being replaced with 1,4-butanediol Acyl group -1,2,5- oxadiazoles reaction, obtains 4- (3- benzenesulfonyl -1,2,5- oxadiazoles -2- oxide -4-) oxygen butanol (a₂)。

Step 2: referring to step 2 in embodiment 1, with a₂Instead of a₁, react to obtain intermediate 4- [4- (2- with succinic anhydride Oxygen -3- benzenesulfonyl -1,2,5- oxadiazoles -4- oxygen)-butoxy] -4- ketobutyric acid (b₂).

Step 3: referring to step 3 in embodiment 1, with b₂Instead of b₁, under the action of excessive EDCI and DMAP, with crow gallbladder Picrol, which reacts, is made white powdery solids, is compound 2, yield 65.5%.

The physical and chemical parameter of compound 2 is as follows:

¹H NMR(400MHz,CDCl₃) δ 8.05 (2H, br d, J=7.6Hz, ArH), 7.76 (1H, t, J=7.6Hz, ArH), 7.62(2H,t,J=7.6Hz,ArH),6.24(1H,br s,H-15),5.62(1H,s,H-2’),4.79(1H,s,H-7),4.72 (1H,d,J=7.6Hz,H_a- 20), 4.44 (2H, t, J=6.0Hz, OCH₂),4.24(1H,d,J=2.8Hz,H-11),4.20(2H, T, J=6.0Hz, OCH₂),4.19(1H,s,H-12),3.79(1H,d,J=7.6Hz,H_b-20),3.78(3H,s,CH₃O-21), 3.14(1H,br s,H-14),3.04(1H,d,J=12.4Hz,H-5),2.95(1H,d,J=16.0Hz,H_β-1),2.88(2H, t,J=6.8Hz,COCH₂),2.72(2H,m,COCH₂),2.39(1H,d,J=16.0Hz,H_α-1),2.36(1H,d,J=14.0Hz, H_α-6),2.19(3H,s,H-5’),2.09(1H,br s,H-9),1.97(2H,m,CH₂),1.93(3H,s,H-4’),1.84 (2H,m,CH₂),1.84(1H,overlap,H_β-6),1.81(3H,s,H-18),1.47(3H,s,H-19);

¹³C NMR(100MHz,CDCl₃)δ188.9(C-2),172.0(C=O),171.9(C-21),170.2(C=O), 166.9(C-16),164.4(C-1’),161.0(C-3’),158.9(C=N),145.6(C-3),142.1(C-4),138.0 (ArC),135.6(ArC),129.7(ArC×2),128.6(ArC×2),114.0(C-2’),110.5(C=N),82.1(C- 7),81.2(C-13),75.8(C-12),73.9(C-20),71.0(OCH₂),70.8(C-11),65.7(C-15),63.9 (OCH₂),53.0(OCH₃),51.6(C-14),50.1(C-1),45.3(C-8),42.8(C-5),41.7(C-9),40.7(C- 10),29.0(C-6),28.8(COCH₂),28.5(COCH₂),27.7(C-4’),25.1(CH₂),25.0(CH₂),20.6(C- 5'),15.4(C-19),14.5(C-18)；

HRESIMS m/z939.2450[M+Na]⁺(calcd for C₄₂H₄₈N₂N_aO₁₉S,939.2464).

Embodiment 3:

(±) -3-O- { 4- [(2- oxygen -3- benzenesulfonyl -1,2,5- oxadiazoles -4- oxygen) -3- butoxy] -4- oxo butyryl Base }-Brusatol (3)

Step 1: referring to step 1 in embodiment 1,1,3-PD and 2- oxygen -3,4- hexichol sulphur being replaced with 1,3-BDO Acyl group -1,2,5- oxadiazoles reaction, obtains (3- benzenesulfonyl -1,2,5- oxadiazoles -2- oxide -4-) oxygen -3- butanol (a₃)。

Step 2: referring to step 2 in embodiment 1, with a₃Instead of a₁, react to obtain intermediate 4- [(2- oxygen-with succinic anhydride 3- benzenesulfonyl -1,2,5- oxadiazoles -4- oxygen) -3- butoxy] -4- ketobutyric acid (b₃).

Step 3: referring to step 3 in embodiment 1, with b₃Instead of b₁, under the action of excessive EDCI and DMAP, with crow gallbladder Picrol, which reacts, is made white powdery solids, is compound 3, yield 50.0%.

The physical and chemical parameter of compound 3 is as follows:

¹H NMR(600MHz,CD₃COCD₃) (for raceme, part hydrogen shows the peak m, therefore peak shape is not indicated) δ 8.06 (2H, ArH),7.87(1H,ArH),7.75(2H,ArH),6.11(1H,H-15),5.63(1H,H-2’),5.17(1H,OCH),4.97 (1H,H-7),4.73(1H,H_a-20),4.51(2H,OCH₂),4.26(2H,H-11,H-12),3.78(1H,H_b-20),3.69 (3H,CH₃O-21),3.32(1H,H-14),3.23(1H,H-5),2.85(2H,COCH₂),2.78(1H,H_β-1),2.72(1H, H_α-1),2.69(2H,COCH₂),2.39(1H,H-9),2.28(1H,H_α-6),2.15(2H,CH₂),2.14(3H,H-5’), 1.96(1H,H_β-6),1.91(3H,H-4’),1.79(3H,H-18),1.48(3H,H-19),1.32(3H,CH₃);

¹³C NMR(150MHz,CD₃COCD₃)δ189.9(C-2),172.2(C=O),171.7(C-21),170.8(C=O), 167.6(C-16),164.9(C-1’),160.0(C-3’),159.0(C=N),146.8(C-3),142.7(C-4),139.0 (ArC),136.7ArC),130.7(ArC×2),129.4(ArC×2),115.8(C-2’),111.5(C=N),83.2(C-7), 82.3(C-13),76.4(C-12),74.0(C-20),72.7(C-11),71.7(OCH),68.8(OCH₂),68.4(OCH₂), 67.7(C-15),52.7(C-21),51.3(C-14),50.4(C-1),46.1(C-8),43.2(C-5),41.6(C-9),41.5 (C-10),35.4(CH₃),29.9(COCH₂),29.1(C-6),27.2(C-4’),20.2(C-5’),15.7(C-19),14.5 (C-18)；

HRESIMS m/z939.2475[M+Na]⁺(calcd for C₄₂H₄₈N₂N_aO₁₉S,939.2464).

Embodiment 4:

3-O- { 4- [5- (2- oxygen -3- benzenesulfonyl -1,2,5- oxadiazoles -4- oxygen)-amoxy] -4- oxobutanoyl } - Brusatol (4)

Step 1: referring to step 1 in embodiment 1,1,5-PD being replaced into 1,3-PD and 2- oxygen -3,4- hexichol sulphur Acyl group -1,2,5- oxadiazoles reaction, obtains 5- (3- benzenesulfonyl -1,2,5- oxadiazoles -2- oxide -4-) oxygen-amylalcohol (a₄)。

Step 2: referring to step 2 in embodiment 1, with a₄Instead of a₁, react to obtain intermediate 4- [5- (2- with succinic anhydride Oxygen -3- benzenesulfonyl -1,2,5- oxadiazoles -4- oxygen)-amoxy] -4- ketobutyric acid (b₄).

Step 3: referring to step 3 in embodiment 1, with b₄Instead of b₁, then under the action of excessive EDCI and DMAP, with crow Gallbladder picrol, which reacts, is made white powdery solids, is compound 4, yield 56.5%.

The physical and chemical parameter of compound 4 is as follows:

¹H NMR(500MHz,CD₃COCD₃)δ8.06(2H,dd,J=8.0,1.0Hz,ArH),7.88(1H,t,J=8.0Hz, ArH),7.75(2H,dd,J=8.0,8.0Hz,ArH),6.10(1H,br s,H-15),5.63(1H,s,H-2’),4.98(1H, s,H-7),4.73(1H,d,J=7.5Hz,H_a-20),4.46(2H,t,J=6.5Hz,OCH₂),4.27(1H,overlap,H-11), 4.26(1H,d,J=4.5Hz,H-12),4.13(2H,t,J=6.5Hz,OCH₂),3.78(1H,d,J=7.5Hz,H_b-20),3.69 (3H,s,CH₃O-21),3.32(1H,br s,H-14),3.25(1H,d,J=12.5Hz,H-5),2.85(2H,m,COCH₂), 2.81(1H,d,J=16.0Hz,H_β-1),2.72(1H,d,J=16.0Hz,H_α-1),2.69(2H,t,J=6.5Hz,COCH₂), 2.40(1H,br s,H-9),2.29(1H,dt,J=14.0,2.5Hz,H_α-6),2.13(3H,s,H-5’),2.01(1H,ddd,J =14.0,12.5,2.5Hz,H_β-6),1.91(3H,s,H-4’),1.89(2H,m,CH₂),1.83(3H,s,H-18),1.73(2H, m,CH₂),1.55(2H,m,CH₂),1.50(3H,s,H-19);

¹³C NMR(125MHz,CD₃COCD₃)δ189.9(C-2),172.5(C=O),171.7(C-21),170.8(C=O), 167.6(C-16),165.0(C-1’),160.1(C-3’),159.0(C=N),146.8(C-3),142.7(C-4),139.1 (ArC),136.7(ArC),130.7(ArC×2),129.3(ArC×2),115.8(C-2’),111.4(C=N),83.2(C- 7),82.3(C-13),76.4(C-12),74.0(C-20),72.6(C-11),72.1(OCH₂),67.5(C-15),64.8 (OCH₂),52.7(C-21),51.1(C-14),50.4(C-1),46.1(C-8),43.2(C-5),41.6(C-9),41.5(C- 10),29.6(COCH₂),29.4(COCH₂),29.1(C-6),28.8(CH₂),28.7(CH₂),27.2(C-4’),22.8(CH₂), 20.2(C-5'),15.7(C-19),14.5(C-18)；

HRESIMS m/z953.2610[M+Na]⁺(calcd for C₄₃H₅₀N₂N_aO₁₉S,953.2621).

Embodiment 5:

3-O- { 4- { 2- { 2- [(2- oxygen 3- benzenesulfonyl -1,2,5- oxadiazoles -4- oxygen) ethyoxyl] }-ethyoxyl } -4- oxygen For bytyry }-Brusatol (5)

Step 1: referring to step 1 in embodiment 1,1,3-PD and 2- oxygen -3,4- hexichol being replaced with diglycol Sulfonyl -1,2,5- oxadiazoles reaction, obtains 2- { 2- [(3- benzenesulfonyl -1,2,5- oxadiazoles -2- oxide -4-) oxygen ethoxy Base] }-ethyl alcohol (a₅)。

Step 2: referring to step 2 in embodiment 1, with a₅Instead of a₁, react to obtain intermediate 4- { 2- { 2- with succinic anhydride [(2- oxygen 3- benzenesulfonyl -1,2,5- oxadiazoles -4- oxygen) ethyoxyl] }-ethyoxyl } -4- ketobutyric acid (b₅).

Step 3: referring to step 3 in embodiment 1, with b₅Instead of b₁, under the action of excessive EDCI and DMAP, with crow gallbladder Picrol, which reacts, is made white powdery solids, is compound 5, yield 47.2%.

The physical and chemical parameter of compound 5 is as follows:

¹H NMR(500MHz,CDCl₃) δ 8.06 (2H, dd, J=7.5,1.0Hz, ArH), 7.75 (1H, t, J=7.5Hz, ArH),7.62(2H,t,J=7.5Hz,ArH),6.24(1H,br s,H-15),5.62(1H,s,H-2’),4.79(1H,s,H- 7),4.72(1H,d,J=8.0Hz,H_a- 20), 4.56 (2H, m, OCH₂), 4.30 (2H, m, OCH₂),4.25(1H,s,H-11), 4.19 (1H, s, H-12), 3.91 (2H, m, OCH₂),3.79(1H,overlap,H_b- 20), 3.79 (2H, m, OCH₂),3.78 (3H,s,CH₃O-21),3.15(1H,br s,H-14),3.04(1H,d,J=12.5Hz,H-5),2.95(1H,d,J=16.0Hz, H_β-1),2.88(2H,t,J=6.8Hz,COCH₂),2.74(2H,m,COCH₂),2.39(1H,d,J=16.0Hz,H_α-1),2.38 (1H,dt,J=14.0Hz,2.5Hz,H_α-6),2.19(3H,d,J=1.0Hz,H-5’),2.09(1H,br s,H-9),1.93 (3H,d,J=1.0Hz,H-4’),1.82(1H,ddd,J=14.0,12.5,2.5Hz,H_β- 6), 1.80 (3H, d, J=1.0Hz, H- 18),1.47(3H,s,H-19);

¹³C NMR(125MHz,CDCl₃)δ188.9(C-2),172.0(C=O),171.9(C-21),170.2(C=O), 166.9(C-16),164.4(C-1’),161.0(C-3’),158.9(C=N),145.7(C-3),142.1(C-4),138.0 (ArC),135.6(ArC),129.7(ArC×2),128.5(ArC×2),114.0(C-2’),110.5(C=N),82.1(C- 7),81.2(C-13),75.8(C-12),73.9(C-20),70.8(C-11),70.5(OCH₂),69.3(OCH₂),68.4 (OCH₂),65.7(C-15),63.8(OCH₂),53.0(OCH₃),51.6(C-14),50.1(C-1),45.3(C-8),42.8(C- 5),41.7(C-9),40.7(C-10),28.9(C-6),28.8(COCH₂),28.4(COCH₂),27.6(C-4’),20.6(C- 5'),15.4(C-19),14.4(C-18)；

HRESIMS m/z955.2418[M+Na]⁺(calcd for C₄₂H₄₈N₂N_aO₂₀S,955.2413).

Embodiment 6:

3-O- { 4- [4- (2- oxygen -3- benzenesulfonyl -1,2,5- oxadiazoles -4- oxygen) -2- alkynes-butoxy] -4- oxo butyryl Base }-Brusatol (6)

Step 1: referring to step 1 in embodiment 1,1,3-PD and 2- oxygen -3,4- hexichol sulphur being replaced with Isosorbide-5-Nitrae butynediols Acyl group -1,2,5- oxadiazoles reaction, obtains 4- (3- benzenesulfonyl -1,2,5- oxadiazoles -2- oxide -4-) oxygen -2- alkynes-butanol (a₆)。

Step 2: referring to step 2 in embodiment 1, with a₆Instead of a₁, react to obtain intermediate 4- [4- (2- with succinic anhydride Oxygen -3- benzenesulfonyl -1,2,5- oxadiazoles -4- oxygen) -2- alkynes-butoxy] -4- ketobutyric acid (b₆).

Step 3: referring to step 3 in embodiment 1, with b₆Instead of b₁, under the action of excessive EDCI and DMAP, with crow gallbladder Picrol, which reacts, is made white powdery solids, is compound 6, yield 45.0%.

The physical and chemical parameter of compound 6 is as follows:

¹H NMR(500MHz,CD₃COCD₃) δ 8.07 (2H, dd, J=8.0,1.0Hz, ArH), 7.89 (1H, t, J=7.5Hz, ArH), 7.76 (2H, dd, J=8.0,7.5Hz, ArH), 6.12 (1H, br s, H-15), 5.63 (1H, s, H-2 '), 5.23 (2H, s,OCH₂),4.98(1H,s,H-7),4.83(2H,s,OCH₂),4.73(1H,d,J=7.5Hz,H_a-20),4.26(2H, overlap,H-11,H-12),3.78(1H,d,J=7.5Hz,H_b-20),3.69(3H,s,CH₃O-21),3.32(1H,br s,H- 14),3.26(1H,d,J=12.5Hz,H-5),2.86(2H,m,COCH₂),2.82(1H,d,J=16.5Hz,H_β-1),2.74(2H, t,J=6.5Hz,COCH₂),2.73(1H,overlap,H_α-1),2.41(1H,br s,H-9),2.30(1H,dt,J=15.0, 2.5Hz,H_α-6),2.14(3H,s,H-5’),1.99(1H,ddd,J=14.0,12.5,2.5Hz,H_β-6),1.91(3H,s,H- 4’),1.84(3H,d,J=1.0Hz,H-18),1.50(3H,s,H-19);

¹³C NMR(125MHz,CD₃COCD₃)δ189.9(C-2),171.9(C=O),171.7(C-21),170.6(C=O), 167.6(C-16),164.9(C-1’),159.2(C-3’),159.0(C=N),146.9(C-3),142.7(C-4),138.9 (ArC),136.8(ArC),130.7(ArC×2),129.4(ArC×2),115.8(C-2’),111.6(C=N),84.6(C≡ C,1C),83.2(C-7),82.3(C-13),79.8(C≡C,1C),76.4(C-12),74.0(C-20),72.7(C-11), 67.6(C-15),59.5(CH₂),52.7(C-21),52.6(CH₂)50.9(C-14),50.4(C-1),46.1(C-8),43.3 (C-5),41.7(C-9),41.5(C-10),29.5(COCH₂),29.4(COCH₂),29.0(C-6),27.2(C-4’),20.2 (C-5'),15.8(C-19),14.5(C-18)；

HRESIMS m/z935.2165[M+Na]⁺(calcd for C₄₂H₄₄N₂N_aO₁₉S,935.2151).

Embodiment 7:

3-O- { 4- [4- (2- oxygen -3- benzenesulfonyl -1,2, -4 oxygen of 5- oxadiazoles)-benzyloxy] -4- oxobutanoyl } - Brusatol (7)

Step 1: referring to step 1 in embodiment 1,1,3-PD and 2- oxygen -3,4- hexichol being replaced with p-Hydroxybenzylalcohol Sulfonyl -1,2,5- oxadiazoles reaction, obtains 4- (3- benzenesulfonyl -1,2,5 oxadiazoles -2- oxide -4-) methoxybenzyl (a₇)。

Step 2: referring to step 2 in embodiment 1, with a₇Instead of a₁, react to obtain intermediate 4- [4- (2- with succinic anhydride Oxygen -3- benzenesulfonyl -1,2, -4 oxygen of 5- oxadiazoles)-benzyloxy] -4- ketobutyric acid (b₇).

Step 3: referring to step 3 in embodiment 1, with b₇Instead of b₁, under the action of excessive EDCI and DMAP, with crow gallbladder Picrol, which reacts, is made white powdery solids, is compound 7, yield 47.4%.

The physical and chemical parameter of compound 7 is as follows:

¹H NMR(500MHz,CD₃COCD₃) δ 8.08 (2H, dd, J=7.5,1.0Hz, ArH), 7.90 (1H, t, J=7.5Hz, ArH),7.75(2H,dd,J=7.5,7.5Hz,ArH),7.53(2H,d,J=8.5Hz,ArH),7.42(2H,d,J=8.5Hz, ArH),6.10(1H,br s,H-15),5.63(1H,s,H-2’),5.19(2H,t,J=13.0Hz,OCH₂),4.97(1H,s,H- 7),4.74(1H,d,J=7.5Hz,H_a-20),4.26(2H,overlap,H-11,H-12),3.78(1H,d,J=7.5Hz,H_b- 20),3.69(3H,s,CH₃O-21),3.33(1H,br s,H-14),3.25(1H,d,J=13.0Hz,H-5),2.86(2H,m, COCH₂),2.81(1H,overlap,H_β-1),2.76(2H,t,J=6.5Hz,COCH₂),2.73(1H,d,J=16.5Hz,H_α- 1),2.41(1H,br s,H-9),2.29(1H,dt,J=14.5,2.5Hz,H_α-6),2.14(3H,s,H-5’),2.01(1H, ddd,J=2.5,13.0,14.0Hz,H_β-6),1.91(3H,s,H-4’),1.78(3H,d,J=1.0Hz,H-18),1.50(3H, s,H-19);

¹³C NMR(125MHz,CD₃COCD₃)δ189.9(C-2),172.4(C=O),171.7(C-21),170.7(C=O), 167.6(C-16),165.0(C-1’),159.6(C-3’),159.0(C=N),153.7(ArC),146.9(C-3),142.7(C- 4),138.8(ArC),136.8(ArC),135.9(ArC),130.7(ArC×2),130.7(ArC×2),129.5(ArC× 2),120.6(ArC×2),115.9(C-2’),112.1(C=N),83.2(C-7),82.3(C-13),76.5(C-12),74.0 (C-20),72.7(C-11),67.6(C-15),65.9(OCH₂),52.7(C-21),51.1(C-14),50.5(C-1),46.1 (C-8),43.3(C-5),41.7(C-9),41.6(C-10),30.2(COCH₂),30.0(COCH₂),29.1(C-6),27.2(C- 4'),20.2(C-5'),15.8(C-19),14.5(C-18)；

HRESIMS m/z973.2310[M+Na]⁺(calcd for C₄₅H₄₆N₂N_aO₁₉S,973.2308).

Embodiment 8:

3-O- { 4- [3- (2- oxygen -3- benzenesulfonyl -1,2, -4 oxygen of 5- oxadiazoles)-benzyloxy] -4- oxobutanoyl } - Brusatol (8)

Step 1: referring to step 1 in embodiment 1,1,3-PD and 2- oxygen -3,4- hexichol being replaced with salicylic alcohol Sulfonyl -1,2,5- oxadiazoles reaction, obtains 3- (3- benzenesulfonyl -1,2,5 oxadiazoles -2- oxide -4-) methoxybenzyl (a₈)。

Step 2: referring to step 2 in embodiment 1, with a₈Instead of a₁, react to obtain intermediate 4- [3- (2- with succinic anhydride Oxygen -3- benzenesulfonyl -1,2, -4 oxygen of 5- oxadiazoles)-benzyloxy] -4- ketobutyric acid (b₈).

Step 3: referring to step 3 in embodiment 1, with b₈Instead of b₁, under the action of excessive EDCI and DMAP, with crow gallbladder Picrol, which reacts, is made white powdery solids, is compound 8, yield 46.2%.

The physical and chemical parameter of compound 8 is as follows:

¹H NMR(500MHz,CD₃COCD₃) δ 8.07 (2H, dd, J=7.5,1.5Hz, ArH), 7.90 (1H, t, J=7.5Hz, ArH),7.75(2H,dd,J=7.5,7.5Hz,ArH),7.50(1H,t,J=7.5Hz,ArH),7.45(1H,s,ArH),7.40 (2H,m,ArH),6.10(1H,br s,H-15),5.63(1H,s,H-2’),5.19(2H,s,OCH₂),4.97(1H,s,H-7), 4.74(1H,d,J=7.5Hz,H_a-20),4.27(2H,overlap,H-11,H-12),3.78(1H,d,J=7.5Hz,H_b-20), 3.70(3H,s,CH₃O-21),3.33(1H,br s,H-14),3.24(1H,d,J=13.0Hz,H-5),2.87(2H,m, COCH₂),2.80(1H,overlap,H_β-1),2.77(2H,t,J=6.5Hz,COCH₂),2.70(1H,d,J=16.0Hz,H_α- 1),2.40(1H,br s,H-9),2.29(1H,dt,J=15.0,2.5Hz,H_α-6),2.14(3H,s,H-5’),1.98(1H, ddd,J=15.0,13.0,2.5Hz,H_β-6),1.91(3H,s,H-4’),1.78(3H,d,J=1.0Hz,H-18),1.49(3H, s,H-19);

¹³C NMR(125MHz,CD₃COCD₃)δ189.9(C-2),172.3(C=O),171.7(C-21),170.7(C=O), 167.6(C-16),165.0(C-1’),159.6(C-3’),159.0(C=N),154.1(ArC),146.9(C-3),142.7(C- 4),140.0(ArC),138.8(ArC),136.8(ArC),131.0(ArC),130.7(ArC×2),129.5(ArC×2), 126.7(ArC),120.1(ArC),119.9(ArC),115.8(C-2’),112.1(C=N),83.2(C-7),82.3(C-13), 76.5(C-12),74.0(C-20),72.7(C-11),67.5(C-15),65.8(OCH₂),52.7(C-21),50.9(C-14), 50.4(C-1),46.1(C-8),43.2(C-5),41.7(C-9),41.5(C-10),30.2(COCH₂),30.1(COCH₂), 29.1(C-6),27.2(C-4'),20.2(C-5'),15.8(C-19),14.5(C-18)；

HRESIMS m/z951.2490[M+H]⁺(calcd for C₄₅H₄₇N₂O₁₉S,951.2488).

Embodiment 9:

3-O- { 2- [4- (2- oxygen -3- benzenesulfonyl -1,2,5- oxadiazoles -4- oxygen)-butoxy carbonyl]-benzoyl } - Brusatol (9)

Step 2: referring to step 2 in embodiment 1, with a₂Instead of a₁, succinic anhydride is replaced with phthalic anhydride, is reacted To intermediate 2- [4- (2- oxygen -3- benzenesulfonyl -1,2,5- oxadiazoles -4- oxygen)-butoxy carbonyl]-benzoic acid (b₉).

Step 3: referring to step 3 in embodiment 1, with b₉Instead of b₁, under the action of excessive EDCI and DMAP, with crow gallbladder Picrol, which reacts, is made white powdery solids, is compound 9, yield 25.0%.

The physical and chemical parameter of compound 9 is as follows:

¹H NMR(500MHz,CD₃COCD₃)δ8.07(2H,br d,J=7.5Hz,ArH),8.06(1H,overla_p, ArH), 7.84 (1H, t, J=7.5Hz, ArH), 7.81 (1H, m, ArH), 7.71 (4H, m, ArH), 6.12 (1H, br s, H-15), 5.64(1H,s,H-2’),4.99(1H,s,H-7),4.75(1H,d,J=7.5Hz,H_a- 20), 4.51 (2H, t, J=6.0Hz, OCH₂), 4.39 (2H, m, OCH₂),4.27(2H,overlap,H-11,H-12),3.79(1H,d,J=7.5Hz,H_b-20),3.70 (3H,s,CH₃O-21),3.33(1H,overlap,H-14),3.33(1H,d,J=12.5Hz,H-5),2.88(1H,d,J= 16.0Hz,H_β-1),2.81(1H,d,J=16.0Hz,H_α-1),2.44(1H,br s,H-9),2.34(1H,dt,J=14.5, 2.5Hz,H_α-6),2.14(3H,s,H-5’),2.04(1H,overlap,H_β-6),2.00(2H,m,CH₂),1.98(3H,s,H- 4’),1.94(2H,m,CH₂),1.91(3H,s,H-18),1.57(3H,s,H-19);

¹³C NMR(125MHz,CD₃COCD₃)δ189.9(C-2),171.7(C-21),167.8(C=O),167.7(C- 16),165.5(C=O),165.0(C-1’),160.1(C-3’),159.0(C=N),147.8(C-3),142.7(C-4),139.1 (ArC),136.7(ArC),133.6(ArC),132.7(ArC),132.1(ArC),131.8(ArC),130.7(ArC×2), 130.5(ArC),129.7(ArC),129.3(ArC×2),115.8(C-2’),111.5(C=N),83.2(C-7),82.3(C- 13),76.4(C-12),74.0(C-20),72.7(C-11),71.9(OCH₂),67.5(C-15),65.6(OCH₂),52.7(C- 21),50.9(C-14),50.5(C-1),46.1(C-8),43.4(C-5),41.7(C-9),41.5(C-10),29.1(C-6), 27.2(C-4’),25.9(CH₂),25.6(CH₂),20.2(C-5'),15.9(C-19),14.8(C-18)；

HRESIMS m/z987.2477[M+Na]⁺(calcd for C₄₆H₄₈N₂N_aO₁₉S,987.2464).

The synthetic route of compound 10-14 in embodiment: (intermediate c₁-c₃Middle R₇、X₂Respectively with R in compound 10-12₇、 X₂Unanimously, d₁-d₅Middle R₇、X₂、Y₂Respectively with R in compound 10-14₇、X₂、Y₂Unanimously)

Compound numbers	R₇	X₂	Y₂
				10	p-Ph-CH₂	O	CO(CH₂)₂CO
11	m-Ph-CH₂	O	CO(CH₂)₂CO
				12	o-Ph-CH₂	O	CO(CH₂)₂CO
13	-	O	CO(CH₂)₂CO

14

-

O

CO-o-PhCO

Embodiment 10:

Step 1:2- oxygen -3- methylol -4- phenyl -1,2, the preparation of 5- oxadiazoles (B)

Will 2.00g (15mmol) cinnamyl alcohol be added 3mL glacial acetic acid in, be stirred at room temperature to its dissolution, under condition of ice bath to It is added dropwise in reaction solution and contains 3.00g (72mmol) NaNO₂Saturated aqueous solution, rear room temperature is added dropwise and is stirred to react 5h.Reaction knot 20ml water is added into reaction solution by Shu Hou, with ethyl acetate (3 × 50ml) extraction, merges organic layer, then successively molten with 5%NaOH Liquid (3 × 15mL), saturated sodium chloride solution (3 × 20ml) washing, anhydrous sodium sulfate are dry.After drying, filtering, filtrate concentration, Silica gel column chromatography separation, with dichloromethane eluent, obtains orange/yellow solid 1.2g, is compound B, yield 46.2%.

Step 2:4- (4- phenyl -1,2,5- oxadiazoles -2- oxide -3) methoxy benzyl alcohol (c₁) preparation

B0.33g (1.72mmo1) is dissolved in methylene chloride l5mL, is added anhydrous pyridine 0.32mL (4mmol).In ice bath After middle cooling, instills thionyl chloride 0.35ml (5.95mmol), be stirred overnight at room temperature.Reaction solution is washed with ice water (2 × 25ml) It washs, is then washed till neutrality with saturated sodium bicarbonate aqueous solution, then washed with saturated salt solution 25ml.Organic layer concentration, obtains orange Color grease.The grease is dissolved in 20ml acetonitrile, is added p-Hydroxybenzylalcohol 647mg (5.2mmol), Anhydrous potassium carbonate 97mg (0.703mmol) and potassium iodide 0.114g (0.687mmol), reacts 20h at room temperature.It after reaction stops, filtering, filtrate is dense Contracting, then with ether dissolution, insoluble matter is filtered off, with 5% sodium hydroxide solution (3 × 30mL) washing, organic layer is dry with anhydrous magnesium sulfate It is dry.Filtering, filtrate concentration, silica gel column chromatography separation, with ethyl acetate: petroleum ether (60~90 DEG C)=1:4~1:3 (V:V) ladder Degree elution, obtains faint yellow solid 0.32g, is compound c₁, yield 62.5%.

Step 3:4- [4- (2- oxygen -4- phenyl -1,2, -3 methoxyl group of 5- oxadiazoles)-benzyloxy] -4- ketobutyric acid (d₁) preparation

Take c₁310mg(1.04mmol), succinic anhydride 200mg(2mmol), DMAP about 30mg(0.25mmol) with anhydrous two Chloromethanes 40ml dissolution, 40 DEG C of return stirring reactions are for 24 hours.After reaction, respectively with hot water (2 × 20mL), saturated salt solution (1 × 20ml) washing.Organic layer is dry with anhydrous sodium sulfate.After drying, filtering, organic layer concentration, silica gel column chromatography separation, with Methylene chloride: methanol=50:0~50:1 gradient elution obtains pale yellow powder shape solid 400mg, is compound d₁, yield 96.7%。

Step 4:3-O- { 4- [4- (2- oxygen -4- phenyl -1,2, -3 methoxyl group of 5- oxadiazoles)-benzyloxy] -4- oxo fourth Acyl group }-Brusatol (10) preparation

By EDCI120mg(0.62mmol), intermediate d₁220mg(0.55mmol) be placed in a reaction flask, in ice-water bath, 30ml anhydrous methylene chloride is added, after ten minutes, Brusatol 160mg(0.31mmol is added in stirring) and DMAP70mg (0.57mmol), continuation are stirred to react 3h under ice bath, then change to react at room temperature 48h.Reaction solution is dilute respectively with dilute HCl NaHCO₃Solution, saturated common salt water washing, organic layer are dry with anhydrous sodium sulfate.After drying, filtering, filtrate concentration, silicagel column Chromatographic isolation, with methylene chloride: methanol=60:1 elution obtains white powdery solids about 85mg, is compound 10, yield 30.7%。

The physical and chemical parameter of compound 10 is as follows:

¹H NMR(500MHz,CD₃COCD₃) δ 7.88 (2H, dd, J=8.5,1.5Hz, ArH), 7.61 (3H, m, ArH), 7.36(2H,d,J=8.5Hz,ArH),7.03(2H,d,J=8.5Hz,ArH),6.10(1H,br s,H-15),5.63(1H,s,H- 2’),5.27(2H,s,OCH₂),5.08(2H,t,J=13.0Hz,OCH₂),4.96(1H,s,H-7),4.73(1H,d,J=7.5Hz, H_a-20),4.26(2H,overlap,H-11,H-12),3.78(1H,d,J=7.5Hz,H_b-20),3.70(3H,s,CH₃O-21), 3.32(1H,br s,H-14),3.24(1H,d,J=12.5Hz,H-5),2.84(2H,m,COCH₂),2.81(1H,d,J= 15.5Hz,H_β-1),2.72(2H,t,J=6.0Hz,COCH₂),2.70(1H,overlap,H_α-1),2.40(1H,br s,H-9), 2.27(1H,dt,J=14.5,2.0Hz,H_α-6),2.13(3H,s,H-5’),1.97(1H,ddd,J=14.0,12.5,2.0Hz, H_β-6),1.91(3H,s,H-4’),1.77(3H,d,J=1.0Hz,H-18),1.50(3H,s,H-19);

¹³C NMR(125MHz,CD₃COCD₃)δ189.9(C-2),172.4(C=O),171.8(C-21),170.7(C=O), 167.6(C-16),164.9(C-1’),159.0(C=N),158.3(ArC),158.1(C-3’),146.8(C-3),142.7(C- 4),132.2(ArC),131.1(ArC),130.8(ArC×2),130.2(ArC×2),128.6(ArC×2),127.3 (ArC),115.8(C-2’),115.8(ArC×2),113.1(C=N),83.2(C-7),82.3(C-13),76.4(C-12), 74.0(C-20),72.7(C-11),67.7(C-15),66.3(OCH₂),59.6(OCH₂),52.7(C-21),51.0(C-14), 50.4(C-1),46.1(C-8),43.2(C-5),41.6(C-9),41.5(C-10),29.5(COCH₂,overlapped withCD3COCD3),29.4(COCH₂),29.1(C-6),27.2(C-4’),20.2(C-5’),15.8(C-19),14.5(C- 18)；

HRESIMS m/z923.2844[M+Na]⁺(calcd for C₄₆H₄₈N₂N_aO₁₇,923.2845).

Embodiment 11:

3-O- { 4- [3- (2- oxygen -4- phenyl -1,2, -3 methoxyl group of 5- oxadiazoles)-benzyloxy] -4- oxobutanoyl } - Brusatol (11)

Step 1: being replaced with salicylic alcohol to hydroxyl referring to step 2 in embodiment 10 by B first with thionyl chloride chloro Base benzyl alcohol reacts to obtain 3- (4- phenyl -1,2,5- oxadiazoles -2- oxide -3) methoxy benzyl alcohol (c₂).

Step 2: referring to step 3 in embodiment 10, with c₂Instead of c₁, react to obtain intermediate 4- [3- (2- with succinic anhydride Oxygen -4- phenyl -1,2, -3 methoxyl group of 5- oxadiazoles)-benzyl] -4- ketobutyric acid (d₂).

Step 3: referring to step 4 in embodiment 10, with d₂Instead of d₁, under the action of excessive EDCI and DMAP, with crow gallbladder Picrol, which reacts, is made white powdery solids, is compound 11, yield 70.0%.

The physical and chemical parameter of compound 11 is as follows:

¹H NMR(500MHz,CD₃COCD₃) δ 7.88 (2H, dd, J=8.0,1.5Hz, ArH), 7.61 (3H, m, ArH), 7.31(1H,t,J=8.0Hz,ArH),7.06(2H,m,ArH),7.00(1H,dd,J=8.0,1.5Hz,ArH),6.11(1H,br s,H-15),5.63(1H,s,H-2’),5.27(2H,s,OCH₂),5.11(2H,t,J=13.0Hz,OCH₂),4.98(1H,s,H- 7),4.73(1H,d,J=8.0Hz,H_a-20),4.26(2H,overlap,H-11,H-12),3.78(1H,d,J=8.0Hz,H_b- 20),3.70(3H,s,CH₃O-21),3.33(1H,br s,H-14),3.23(1H,d,J=13.0Hz,H-5),2.86(2H,m, COCH₂),2.77(1H,overlap,H_β-1),2.76(2H,t,J=6.0Hz,COCH₂),2.69(1H,J=16.0Hz,H_α-1), 2.39(1H,br s,H-9),2.27(1H,dt,J=14.5,2.0Hz,H_α-6),2.14(3H,s,H-5’),1.96(1H,ddd,J =14.0,13.0,2.0Hz,H_β-6),1.91(3H,s,H-4’),1.76(3H,s,H-18),1.48(3H,s,H-19);

¹³C NMR(125MHz,CD₃COCD₃)δ189.9(C-2),172.4(C=O),171.7(C-21),170.7(C=O), 167.6(C-16),165.1(C-1’),159.0(C=N),158.4(ArC),158.3(C-3’),146.8(C-3),142.7(C- 4),139.4(ArC),132.2(ArC),130.7(ArC),130.2(ArC×2),128.6(ArC×2),127.3(ArC), 122.4(ArC),115.8(C-2’),115.4(ArC),115.2(ArC),113.1(C=N),83.2(C-7),82.3(C-13), 76.5(C-12),74.0(C-20),72.7(C-11),67.6(C-15),66.3(OCH₂),59.6(OCH₂),52.7(C-21), 51.0(C-14),50.4(C-1),46.1(C-8),43.2(C-5),41.6(C-9),41.5(C-10),29.5(COCH₂, overlap-ped withCD₃COCD₃),29.4(COCH₂),29.1(C-6),27.2(C-4’),20.2(C-5’),15.8(C- 19),14.4(C-18)；

HRESIMS m/z923.2824[M+Na]⁺(calcd for C₄₆H₄₈N₂N_aO₁₇,923.2845).

Embodiment 12:

3-O- { 4- [2- (2- oxygen -4- phenyl -1,2, -3 methoxyl group of 5- oxadiazoles)-benzyloxy] -4- oxobutanoyl } - Brusatol (12)

Step 1: referring to step 2 in embodiment 10, by B first with thionyl chloride chloro, then with diathesin replacement pair Salicylic alcohol reacts to obtain 2- (4- phenyl -1,2,5- oxadiazoles -2- oxide -3) methoxy benzyl alcohol (c₃).

Step 2: referring to step 3 in embodiment 10, with c₃Instead of c₁, react to obtain intermediate 4- [2- (2- with succinic anhydride Oxygen -4- phenyl -1,2, -3 methoxyl group of 5- oxadiazoles)-benzyl] -4- ketobutyric acid (d₃).

Step 3: referring to step 4 in embodiment 10, with d₃Instead of d₁, under the action of excessive EDCI and DMAP, with crow gallbladder Picrol, which reacts, is made white powdery solids, is compound 12, yield 51.0%.

The physical and chemical parameter of compound 12 is as follows:

¹H NMR(500MHz,CD₃COCD₃)δ7.89(2H,dd,J=7.5,1.5Hz,ArH),7.61(3H,m,ArH), 7.35 (2H, m, ArH), 7.17 (1H, d, J=7.5Hz, ArH), 7.03 (1H, t, J=7.5Hz, ArH), 6.11 (1H, br s, H- 15), 5.63 (1H, s, H-2 '), 5.32 (2H, s, OCH₂), 5.04 (2H, dd, J=12.5Hz, OCH₂),4.97(1H,s,H-7), 4.73(1H,d,J=7.5Hz,H_a-20),4.26(2H,overlap,H-11,H-12),3.78(1H,d,J=7.5Hz,H_b-20), 3.70(3H,s,CH₃O-21),3.33(1H,br s,H-14),3.22(1H,d,J=13.0Hz,H-5),2.82(2H,m, COCH₂),2.78(1H,overlap,H_β-1),2.69(1H,overlap,H_α-1),2.65(2H,t,J=6.5Hz,COCH₂), 2.39(1H,br s,H-9),2.27(1H,dt,J=14.5,2.5Hz,H_α-6),2.14(3H,s,H-5’),1.96(1H,ddd,J =14.0,12.5,2.5Hz,H_β-6),1.91(3H,s,H-4’),1.75(3H,d,J=1.0Hz,H-18),1.49(3H,s,H- 19);

¹³C NMR(125MHz,CD₃COCD₃)δ189.9(C-2),172.3(C=O),171.7(C-21),170.6(C=O), 167.6(C-16),165.0(C-1’),159.0(C=N),158.2(C-3’),156.1(ArC),146.8(C-3),142.7(C- 4),132.3(ArC),130.9(ArC),130.6(ArC),130.3(ArC×2),128.5(ArC×2),127.2(ArC), 126.1(ArC),122.8(ArC),115.8(C-2’),113.1(C=N,ArC),83.2(C-7),82.3(C-13),76.5(C- 12),74.0(C-20),72.7(C-11),67.6(C-15),61.9(OCH₂),59.8(OCH₂),52.7(C-21),51.1(C- 14),50.4(C-1),46.1(C-8),43.2(C-5),41.6(C-9),41.5(C-10),29.5(COCH₂),29.4 (COCH₂),29.1(C-6),27.2(C-4'),20.2(C-5'),15.8(C-19),14.4(C-18)；

HRESIMS m/z901.3027[M+H]⁺(calcd for C₄₆H₄₉N₂O₁₇,901.3026).

Embodiment 13:

3-O- [4-(2- oxygen -4- phenyl -1,2, -3 methoxyl group of 5- oxadiazoles) -4- oxobutanoyl]-Brusatol (13)

Step 1: referring to step 3 in embodiment 10, B being replaced into c₁, directly react to obtain intermediate 4-(4- with succinic anhydride Phenyl -1,2,5- oxadiazoles -2- oxide -3) methoxyl group -4- ketobutyric acid (d₄).

Step 2: referring to step 4 in embodiment 10, with d₄Instead of d₁, under the action of excessive EDCI and DMAP, with crow gallbladder Picrol, which reacts, is made white powdery solids, is compound 13, yield 41.8%.

The physical and chemical parameter of compound 13 is as follows:

¹H NMR(500MHz,CD₃COCD₃) δ 7.81 (2H, dd, J=8.0,1.5Hz, ArH), 7.61 (3H, m, ArH), 6.10(1H,br s,H-15),5.63(1H,s,H-2’),5.25(2H,t,J=14.0Hz,OCH₂),4.98(1H,s,H-7), 4.74(1H,d,J=7.5Hz,H_a-20),4.26(2H,s,H-11,H-12),3.78(1H,d,J=7.5Hz,H_b-20),3.70 (3H,s,CH₃O-21),3.33(1H,br s,H-14),3.25(1H,d,J=12.5Hz,H-5),2.84(2H,m,COCH₂), 2.81(1H,d,J=15.5Hz,H_β-1),2.68(1H,overlap,H_α-1),2.65(2H,t,J=6.5Hz,COCH₂),2.39 (1H,br s,H-9),2.27(1H,dt,J=14.5,2.0Hz,H_α-6),2.14(3H,s,H-5’),1.96(1H,ddd,J= 14.0,12.5,2.0Hz,H_β-6),1.91(3H,s,H-4’),1.75(3H,s,H-18),1.49(3H,s,H-19);

¹³C NMR(125MHz,CD₃COCD₃)δ189.9(C-2),172.0(C=O),171.7(C-21),170.6(C=O), 167.6(C-16),165.0(C-1’),159.0(C=N),158.1(C-3’),146.9(C-3),142.7(C-4),132.1 (ArC),130.2(ArC×2),128.6(ArC×2),127.2(ArC),115.8(C-2’),112.5(C=N),83.2(C- 7),82.3(C-13),76.4(C-12),74.0(C-20),72.7(C-11),67.6(C-15),55.3(OCH₂),52.7(C- 21),51.0(C-14),50.4(C-1),46.1(C-8),43.2(C-5),41.6(C-9),41.5(C-10),29.4 (COCH₂),29.3(COCH₂),29.0(C-6),27.2(C-4'),20.2(C-5'),15.8(C-19),14.4(C-18)； HRESIMS m/z817.2428[M+Na]⁺(calcd for C₃₉H₄₂N₂N_aO₁₆,817.2427).

Embodiment 14:

3-O- [2-(2- oxygen -4- phenyl -1,2, -3 methoxyl group of 5- oxadiazoles) carbonyl benzoyl base]-Brusatol (14)

Step 1: referring to step 3 in embodiment 10, B being replaced into c₁, directly intermediate [2- is obtained with phthalic acid anhydride reactant (2- oxygen -4- phenyl -1,2, -3 methoxyl group of 5- oxadiazoles)-carbonyl] benzoic acid (d₅).

Step 2: referring to step 4 in embodiment 10, with d₅Instead of d₁, under the action of excessive EDCI and DMAP, with crow gallbladder Picrol, which reacts, is made white powdery solids, is compound 14, yield 30.5%.

The physical and chemical parameter of compound 14 is as follows:

¹H NMR(500MHz,CD₃COCD₃)δ8.06(1H,m,ArH),7.81(2H,d,J=7.0Hz,ArH),7.72(3H, m,ArH),7.61(3H,m,ArH),6.14(1H,br s,H-15),5.64(1H,s,H-2’),5.52,5.41(each1H,d,J =13.5Hz,OCH₂),5.01(1H,s,H-7),4.76(1H,d,J=7.5Hz,H_a-20),4.28(2H,overlap,H-11,H- 12),3.81(1H,d,J=7.5Hz,H_b-20),3.71(3H,s,CH₃O-21),3.35(1H,br s,H-14),3.27(1H,d,J =13.0Hz,H-5),2.85(1H,d,J=16.0Hz,H_β-1),2.73(1H,d,J=16.0Hz,H_α-1),2.42(1H,br s,H- 9),2.30(1H,d,J=14.5Hz,H_α-6),2.15(3H,s,H-5’),1.99(1H,ddd,J=14.0,13.0,1.5Hz,H_β- 6),1.92(3H,s,H-4’),1.82(3H,s,H-18),1.53(3H,s,H-19);

¹³C NMR(125MHz,CD₃COCD₃)δ189.7(C-2),171.7(C-21),167.7(C-16),167.5(C= O),165.0(C=O,C-1’),159.0(C=N),158.0(C-3’),147.7(C-3),142.6(C-4),133.1(ArC), 132.7(ArC),132.5(ArC),132.2(ArC),131.1(ArC),130.8(ArC),130.2(ArC×2),129.8 (ArC),128.6(ArC×2),127.2(ArC),115.8(C-2’),112.3(C=N),83.2(C-7),82.3(C-13), 76.5(C-12),74.0(C-20),72.7(C-11),67.5(C-15),56.2(OCH₂),52.7(C-21),51.2(C-14), 50.4(C-1),46.1(C-8),43.4(C-5),41.7(C-9),41.6(C-10),29.4(C-6),27.2(C-4’),20.3 (C-5'),15.9(C-19),14.5(C-18)；

HRESIMS m/z843.2590[M+H]⁺(calcd for C₄₃H₄₃N₂O₁₆,843.2607).

Embodiment 15:

Synthetic route:

Step 1:4- (4- phenyl -1,2,5- oxadiazoles -2- oxide -3)-methoxybenzyl bromine (e₁) preparation

Take c₁About 140mg(0.47mmol) it is placed in a reaction flask, with the dissolution of 20ml anhydrous methylene chloride.In ice-water bath condition Under, excess PBr is added₃, continue to react in ice-water bath.After 2h, change to be stirred at room temperature and react 2h again.After reaction, to anti- Dropwise addition 1ml water in liquid is answered, 10min is stirred.For reaction solution with water (2 × 20ml) washing, organic layer is dry with anhydrous sodium sulfate.It is dry Afterwards, it filters, filtrate concentration, silica gel column chromatography separation, with ethyl acetate: petroleum ether (60~90 DEG C)=1:8 (V:V) elution obtains Faint yellow solid 140mg is compound e₁, yield 82.8%.

Step 2:3-O- [4- (2- oxygen -4- phenyl -1,2,5- oxadiazoles -3)-methoxy-benzyl]-Brusatol (15) Preparation

By e₁About 150mg(0.42mmol), Brusatol about 120mg(0.23mmol), Anhydrous potassium carbonate 70mg (0.51mmol) is placed in a reaction flask, and anhydrous acetonitrile 20ml, 80 DEG C of return stirring 20h is added.Reaction solution is cooling, filtering, filtrate Concentration, with methylene chloride 30ml dissolution.Again with water (3 × 30ml) washing.Water layer merges, and with 30ml methylene chloride extraction 1 time, closes And all organic layers, it is dry with anhydrous sodium sulfate.After drying, filtering, organic layer concentration, silica gel column chromatography separation, with dichloromethane Alkane: methanol=50:1 (V:V) elution obtains white powdery solids about 100mg, is compound 15, yield 54.2%.

The physical and chemical parameter of compound 15 is as follows:

¹H NMR(500MHz,CD₃COCD₃)δ7.88(2H,dd,J=8.0,1.5Hz,ArH),7.60(3H,m,ArH), 7.38(2H,d,J=8.5Hz,ArH),7.01(2H,d,J=8.5Hz,ArH),6.10(1H,br s,H-15),5.63(1H,s,H- 2’),5.27(2H,s,OCH₂),4.93(1H,s,H-7),4.84,4.78(each1H,d,J=11.0Hz,OCH₂),4.71(1H, d,J=7.5Hz,H_a-20),4.26(2H,overlap,H-11,H-12),3.75(1H,d,J=7.5Hz,H_b-20),3.70(3H, s,CH₃O-21),3.30(1H,br s,H-14),3.09(1H,d,J=12.5Hz,H-5),2.78(1H,d,J=16.0Hz,H_β- 1),2.63(1H,d,J=16.0Hz,H_α-1),2.31(1H,br s,H-9),2.22(1H,dt,J=14.5,2.0Hz,H_α-6), 2.13(3H,s,H-5’),1.91(3H,s,H-4’),1.84(1H,ddd,J=14.5,12.5,2.0Hz,H_β-6),1.76(3H, d,J=1.5Hz,H-18),1.32(3H,s,H-19);

¹³C NMR(125MHz,CD₃COCD₃)δ193.4(C-2),171.7(C-21),167.6(C-16),165.0(C- 1’),159.0(C-3’),158.2(C=N),158.0(ArC),146.1(C-3),144.9(C-4),132.7(ArC),132.2 (ArC),131.2(ArC×2),130.2(ArC×2),128.5(ArC×2),127.2(ArC),115.8(C-2’),115.7 (ArC×2),113.1(C=N),83.4(C-7),82.3(C-13),76.4(C-12),74.1(C-20),73.3(OCH₂), 72.6(C-11),67.6(C-15),59.6(OCH₂),52.7(C-21),51.6(C-1),51.2(C-14),46.1(C-8), 43.2(C-5),41.8(C-10),41.2(C-9),29.5(C-6,overlapped with CD3COCD3),27.2(C-4’), 20.2(C-5'),15.7(C-19),14.4(C-18)；

HRESIMS m/z801.2867[M+H]⁺(calcd for C₄₂H₄₅N₂O₁₄,801.2865).

The synthetic route of compound 16-29 in embodiment:

Embodiment 16:

Step 1:3-O-(dimethyl tertiary butyl silicon substrate)-Brusatol (C)

By Brusatol 110mg(0.21mmol), imidazoles 60mg(0.88mmol), DMAP is a small amount of, tert-butyldimethylsilyl chloride Silane 50mg(0.33mmol), with anhydrous DMF 1.5ml dissolution, it is stirred to react at 45 DEG C.After 3h, it is added into reaction solution 20ml methylene chloride, with water (2 × 30ml) washing.Water layer is extracted 1 time again with 20ml methylene chloride, merges all organic layers, with Anhydrous sodium sulfate is dry.After drying, filtering, filtrate concentration, silica gel column chromatography separation, with methylene chloride: methanol=50:0~50:1 (V:V) it elutes, obtains faint yellow solid 120mg, be compound C, yield 89.6%.

Step 2:3-O-(dimethyl tertiary butyl silicon substrate)-bruceolide (D)

Take C110mg(0.17mmol) with the dissolution of 3ml methanol, the methanol that 1mol/L KOMe is added under the conditions of ice-water bath is molten Liquid 20ml, continues in ice-water bath and is stirred to react.After 8h, Dowex50W-X2H is added into reaction solution⁺Ion exchange resin is adjusted It saves to PH=7.Filtering, filtrate concentration, is changed and is dissolved with chloroform.Organic layer is respectively with saturated sodium bicarbonate solution (1 × 30ml), water (1 × 30ml), saturated salt solution (1 × 30ml) washing.Organic layer is dry with anhydrous sodium sulfate, and after dry, concentration is obtained white solid Body about 49mg is compound D, yield 51.2%.

Step 3:15-O- { 4- [3- (2- oxygen -3- benzenesulfonyl -1,2,5- oxadiazoles -4- oxygen)-propoxyl group] -4- oxo fourth Acyl group }-bruceolide (16)

By D about 170mg(0.31mmol), EDCI110mg(0.57mmol), intermediate b₁220mg(0.55mmol), DMAP120mg(1mmol it) is placed in a reaction flask, anhydrous methylene chloride dissolution is added in ice-water bath and changes after stirring 3h with room temperature React 48h.Reaction solution concentration, is diluted with tetrahydrofuran, a small amount of glacial acetic acid is added, the tetrahydrofuran of 1mol/LTBAF is added portionwise Solution is until desiliconization ether protecting group is complete.Reaction stops, and 30ml methylene chloride is added in reaction solution, then respectively with dilute HCl(1 × 30ml), it is saturated NaHCO₃Solution (1 × 30ml), saturated salt solution (1 × 30ml) washing, organic layer are dry with anhydrous sodium sulfate. After drying, filtering, filtrate concentration, silica gel column chromatography separation, with methylene chloride: methanol=50:1 elution obtains white powdery solids About 98mg is compound 16.It is calculated by raw material of compound D, two step total recoverys 38.9%.

The physical and chemical parameter of compound 16 is as follows:

¹H NMR(500MHz,CD₃COCD₃) δ 8.07 (2H, dd, J=8.0,1.0Hz, ArH), 7.87 (1H, t, J= 7.5Hz), 7.41 (2H, t, J=7.5Hz, ArH), 6.81 (1H, s, 3-OH), 6.14 (1H, br s, H-15), 4.93 (1H, s, H- 7),4.73(1H,d,J=8.0Hz,H_a- 20), 4.55 (2H, t, J=6.0Hz, OCH₂), 4.28 (2H, t, J=6.0Hz, OCH₂), 4.26(2H,overlap,H-11,H-12),3,79(3H,s,CH₃O-21),3.79(1H,overlap,H_b-20),3.26(1H, d,J=12.0Hz,H-14),3.06(1H,d,J=13.0Hz,H-5),2.82(1H,J=16.0Hz,H_β-1),2.69(1H,J= 16.0Hz,H_α-1),2.62(4H,s,COCH₂CH₂CO),2.36(1H,br s,H-9),2.24(1H,overlap,H_α-6), 2.22(2H,m,CH₂),1.89(1H,ddd,J=14.0,13.0,2.0Hz,H_β-6),1.82(3H,d,J=1.5Hz,H-18), 1.39(3H,s,H-19);

¹³C NMR(125MHz,CD₃COCD₃)d193.1(C-2),172.4(C=O),171.9(C=O),171.1(C-21), 167.4(C-16),160.1(C=N),145.0(C-3),139.0(ArC),136.7(ArC),130.6(ArC×2),129.4 (ArC×2),128.2(C-4),111.5(C=N),83.7(C-7),82.3(C-13),76.5(C-12),74.1(C-20), 72.5(C-11),68.9(OCH₂),68.4(C-15),61.3(OCH₂),52.9(OCH₃),51.0(C-14),49.3(C-1), 46.3(C-8),42.2(C-9),41.9(C-5),41.8(C-10),29.5(C-6),29.4(COCH₂),29.3(COCH₂), 28.6(CH₂),15.6(C-19),13.3(C-18);

HRESIMS m/z843.1888[M+Na]⁺(calcd for C₃₆H₄₀N₂NaO₁₈S,843.1889).

Embodiment 17:

15-O- { 4- [4- (2- oxygen -3- benzenesulfonyl -1,2,5- oxadiazoles -4- oxygen)-butoxy] -4- oxobutanoyl } - Bruceolide (17)

Referring to step 3 in embodiment 16, with b₂Instead of b₁, under the action of excessive EDCI and DMAP, first reacted with D, then With TBAF desiliconization ether protecting group, white powdery solids are made, are compound 17, two step total recoverys 58.0%.

The physical and chemical parameter of compound 17 is as follows:

¹H NMR(300MHz,CDCl₃) δ 8.06 (2H, br d, J=7.8Hz, ArH), 7.77 (1H, t, J=7.5Hz, ArH), 7.63 (2H, t, J=7.5Hz, ArH), 6.38 (1H, d, J=12.9Hz, H-15), 6.08 (1H, s, 3-OH), 4.73 (1H, s, H- 7),4.73(1H,d,J=7.5Hz,H_a- 20), 4.46 (2H, t, J=6.0Hz, OCH₂),4.25(1H,m,H-11),4.22(1H,s, H-12),4.19(2H,overlap,OCH₂),3.88(3H,s,CH₃O-21),3.81(1H,d,J=7.5Hz,H_b-20),3.06 (1H,d,J=13.2Hz,H-14),2.98(1H,J=16.2Hz,H_β-1),2.93(1H,d,J=12.9Hz,H-5),2.68(4H, m,COCH₂CH₂CO),2.40(1H,J=16.5Hz,H_α-1),2.35(1H,d,J=14.7Hz,H_α-6),2.18(1H,d,J= 3.3Hz,H-9),1.95(2H,m,CH₂),1.84(2H,m,CH₂),1.84(3H,s,H-18),1.77(1H,ddd,J=14.7, 12.9,2.4Hz,H_β-6),1.39(3H,s,H-19);

¹³C NMR(75MHz,CDCl₃)δ192.1(C-2),172.3(C=O),171.8(C=O),170.6(C-21), 166.7(C-16),158.9(C=N),144.0(C-3),137.9(ArC),135.6(ArC),129.6(ArC×2),128.5 (ArC×2),127.8(C-4),110.4(C=N),82.8(C-7),81.4(C-13),75.5(C-12),73.9(C-20), 70.9(C-11,OCH₂),66.9(C-15),64.1(OCH₂),53.1(OCH₃),51.5(C-14),48.4(C-1),45.6(C- 8),41.9(C-9),41.8(C-5),41.0(C-10),.28.9(C-6),28.7(COCH₂),28.3(COCH₂),25.1 (CH₂),24.8(CH₂),15.3(C-19),13.2(C-18);

HRESIMS m/z857.2050[M+Na]⁺(calcd for C₃₇H₄₂N₂NaO₁₈S,857.2046).

Embodiment 18:

(±) -15-O- { 4- [(2- oxygen -3- benzenesulfonyl -1,2,5- oxadiazoles -4- oxygen) -3- butoxy] -4- oxo fourth Acyl group] -4- oxobutanoyl }-bruceolide (18)

Referring to step 3 in embodiment 16, with b₃Instead of b₁, under the action of excessive EDCI and DMAP, first reacted with D, then With TBAF desiliconization ether protecting group, white powdery solids are made, are compound 18, two step total recoverys 47.8%.

The physical and chemical parameter of compound 18 is as follows:

¹H NMR(500MHz,CDCl₃) (for raceme, part hydrogen shows the peak m, therefore peak shape is not indicated) δ 8.05 (2H, ArH),7.75(1H,ArH),7.62(2H,ArH),6.31(1H,H-15),6.11(1H,3-OH),5.16(1H,OCH),4.71 (1H,H-7),4.73(1H,H_a- 20), 4.45(2H, OCH₂), 4.24(1H, H-11), 4.20 (1H, s, H-12), 4.10,3.78 (each1H, OCH₂), 3.84 (3H, s, CH₃O-21),3,46(1H,H_b-20),3.03(1H,H-14),2.96(1H,H_β-1), 2.91(1H,H-5),2.60(4H,COCH₂CH₂CO),2.42(1H,H_α-1),2.35(1H,H_α-6),2.17(1H,H-9),2.10 (2H,CH₂),1.83(3H,H-18),1.75(1H,H_β-6),1.37(3H,H-19),1.32(3H,CH₃)

¹³C NMR(125MHz,CDCl₃)δ192.1(C-2),171.8(C=O),171.7(C=O),170.6(C-21), 166.7(C-16),158.9(C=N),144.0(C-3),137.9(ArC),135.6(ArC),129.6(ArC×2),128.6 (ArC×2),127.7(C-4),110.6(C=N),82.8(C-7),81.4(C-13),75.5(C-12),74.0(C-20), 70.9(C-11),68.1(OCH),67.7(OCH₂),66.9(C-15),53.1(OCH₃),51.7(C-14),48.5(C-1), 45.7(C-8),41.9(C-9),41.8(C-5),41.0(C-10),34.7(CH₂),29.0(C-6),29.0(COCH₂),28.4 (COCH₂),20.1(CH₃),15.4(C-19),13.3(C-18);

HRESIMS m/z857.2058[M+Na]⁺(calcd for C₃₇H₄₂N₂NaO₁₈S,857.2046).

Embodiment 19:

15-O- { 4- [5- (2- oxygen -3- benzenesulfonyl -1,2,5- oxadiazoles -4- oxygen)-amoxy] -4- oxobutanoyl } - Bruceolide (19)

Referring to step 3 in embodiment 16, with b₄Instead of b₁, under the action of excessive EDCI and DMAP, first reacted with D, then With TBAF desiliconization ether protecting group, white powdery solids are made, are compound 19, two step total recoverys 38.6%.

The physical and chemical parameter of compound 19 is as follows:

¹H NMR(500MHz,CDCl₃) δ 8.04 (2H, br d, J=7.5Hz, ArH), 7.76 (1H, t, J=7.5Hz, ArH), 7.62 (2H, t, J=7.5Hz, ArH), 6.38 (1H, d, J=12.0Hz, H-15), 6.09 (1H, s, 3-OH), 4.73 (1H, s, H- 7),4.72(1H,d,J=8.0Hz,H_a- 20), 4.42 (2H, t, J=6.0Hz, OCH₂), 4.24 (1H, br s, H-11), 4.22 (1H, s, H-12), 4.19(2H, m, OCH₂), 3.86 (3H, s, CH₃O-21),3.79(1H,d,J=8.0Hz,H_b-20),3.06 (1H,d,J=13.0Hz,H-14),2.96(1H,J=16.5Hz,H_β-1),2.92(1H,d,J=13.5Hz,H-5),2.66(4H, m,COCH₂CH₂CO),2.40(1H,J=16.5Hz,H_α-1),2.35(1H,dt,J=14.5,2.0Hz,H_α-6),2.18(1H,br s,H-9),1.90(2H,m,CH₂),1.83(3H,s,H-18),1.76(1H,ddd,J=14.5,13.5,2.0Hz,H_β-6),1.72 (2H,m,CH₂),1.54(2H,m,CH₂),1.38(3H,s,H-19);

¹³C NMR(125MHz,CDCl₃)δ192.0(C-2),172.5(C=O),171.6(C=O),170.6(C-21), 166.7(C-16),159.0(C=N),144.0(C-3),138.0(ArC),135.6(ArC),129.6(ArC×2),128.5 (ArC×2),127.5(C-4),110.5(C=N),82.8(C-7),81.5(C-13),75.6(C-12),74.1(C-20), 71.2(OCH₂),71.0(C-11,),66.8(C-15),64.6(OCH₂),53.2(OCH₃),51.7(C-14),48.5(C-1), 45.8(C-8),42.2(C-9),41.9(C-5),41.1(C-10),.29.0(C-6),28.7(COCH₂),28.4(COCH₂), 28.0(CH₂×2),22.1(CH₂),15.4(C-19),13.3(C-18);

HRESIMS m/z849.2383[M+H]⁺(calcd for C₃₈H₄₅N₂O₁₈S,849.2383).

Embodiment 20:

15-O- { 4- { 2- { 2- [(2- oxygen 3- benzenesulfonyl -1,2,5- oxadiazoles -4- oxygen) ethyoxyl] }-ethyoxyl } -4- Oxobutanoyl }-bruceolide (20)

Referring to step 3 in embodiment 16, with b₅Instead of b₁, under the action of excessive EDCI and DMAP, first reacted with D, then With TBAF desiliconization ether protecting group, white powdery solids are made, are compound 20,

Two step total recoverys 48.7%.

The physical and chemical parameter of compound 20 is as follows:

¹H NMR(300MHz,CDCl₃) δ 8.05 (2H, br d, J=7.5Hz, ArH), 7.75 (1H, t, J=7.5Hz, ArH), 7.61 (2H, t, J=7.5Hz, ArH), 6.34 (1H, d, J=13.2Hz, H-15), 6.10 (1H, s, 3-OH), 4.73 (1H, s, H- 7),4.71(1H,d,J=8.1Hz,H_a-20),4.56(2H,t,J=3.9Hz,OCH₂),4.29(2H,m,OCH₂), 4.23 (1H, d, J=3.3Hz H-11), 4.20 (1H, s, H-12), 3.90 (2H, t, J=4.2Hz, OCH₂),3.84(3H,s,CH₃O-21),3.79 (1H,overlap,H_b- 20), 3.79 (2H, t, J=4.2Hz, OCH₂),3.06(1H,d,J=13.2Hz,H-14),2.95(1H,J= 15.9Hz,H_β-1),2.92(1H,d,J=12.6Hz,H-5),2.68(4H,m,COCH₂CH₂CO),2.40(1H,J=15.9Hz, H_α-1),2.35(1H,d,J=14.4Hz,H_α-6),2.18(1H,br s,H-9),1.82(3H,s,H-18),1.75(1H,ddd,J =14.4,12.6,2.4Hz,H_β-6),1.37(3H,s,H-19);

¹³C NMR(75MHz,CDCl₃)δ192.0(C-2),172.3(C=O),171.6(C=O),170.5(C-21), 166.7(C-16),158.9(C=N),144.0(C-3),137.9(ArC),135.6(ArC),129.6(ArC×2),128.5 (ArC×2),127.6(C-4),110.5(C=N),82.8(C-7),81.5(C-13),75.5(C-12),74.0(C-20), 71.0 (C-11), 70.5(OCH₂), 69.2(OCH₂), 68.3(OCH₂), 66.8 (C-15), 63.8 (OCH₂),53.1(OCH₃), 51.6(C-14),48.4(C-1),45.7(C-8),42.1(C-9),41.9(C-5),41.0(C-10),29.0(C-6),28.7 (COCH₂),28.3(COCH₂),15.3(C-19),13.3(C-18);

HRESIMS m/z873.2000[M+Na]⁺(calcd for C₃₇H₄₂N₂NaO₁₉S,873.1995).

Embodiment 21:

15-O- { 4- [4- (2- oxygen -3- benzenesulfonyl -1,2,5- oxadiazoles -4- oxygen) -2- alkynes-butoxy] -4- oxo fourth Acyl group }-bruceolide (21)

Referring to step 3 in embodiment 16, with b₆Instead of b₁, under the action of excessive EDCI and DMAP, first reacted with D, then With TBAF desiliconization ether protecting group, white powdery solids are made, are compound 21, two step total recoverys 33.7%.

The physical and chemical parameter of compound 21 is as follows:

¹H NMR(500MHz,CDCl₃) δ 8.06 (2H, br d, J=7.5Hz, ArH), 7.76 (1H, t, J=7.5Hz), 7.63 (2H, t, J=7.5Hz, ArH), 6.36 (1H, d, J=11.0Hz, H-15), 6.10(1H, s, 3-OH), 5.10(2H, s, OCH₂), 4.77(1H,s,H-7),4.76(2H,overlap,OCH₂),4.73(1H,d,J=8.0Hz,H_a20), -4.25(1H, d, J= 3.5Hz, H-11), 4.22 (1H, s, H-12), 3.86 (3H, s, CH₃O-21),3.79(1H,d,J=8.0Hz,H_b-20),3.06 (1H,d,J=13.0Hz,H-14),2.96(1H,J=16.0Hz,H_β-1),2.93(1H,d,J=12.5Hz,H-5),2.70(4H, m,COCH₂CH₂CO),2.41(1H,J=16.0Hz,H_α-1),2.36(1H,dt,J=15.0,2.5Hz,H_α-6),2.19(1H,d,J =3.0Hz,H-9),1.83(3H,d,J=1.5Hz,H-18),1.76(1H,ddd,J=14.0,12.5,2.5Hz,H_β-6),1.38 (3H,s,H-19);

¹³C NMR(125MHz,CDCl₃)δ192.1(C-2),171.7(C=O),171.5(C=O),170.4(C-21), 166.7(C-16),157.9(C=N),144.0(C-3),137.7(ArC),135.7(ArC),129.7(ArC×2),128.6 (ArC×2),127.7(C-4),110.6(C=N),83.6(C≡C,1C),82.8(C-7),81.4(C-13),78.8(C≡C, 1C),75.6(C-12),74.0(C-20),71.0(C-11),66.9(C-15),58.6(OCH₂),53.2(OCH₃),52.3 (OCH₂),51.6(C-14),48.5(C-1),45.7(C-8),42.1(C-9),41.9(C-5),41.0(C-10),29.0(C- 6),28.5(COCH₂),28.3(COCH₂),15.4(C-19),13.3(C-18);

HRESIMS m/z853.1750[M+Na]⁺(calcd for C₃₇H₃₈N₂NaO₁₈S,853.1733).

Embodiment 22:

15-O- { 4- [4- (2- oxygen -3- benzenesulfonyl -1,2, -4 oxygen of 5- oxadiazoles)-benzyloxy] -4- oxo butyryl Base } -- bruceolide (22)

Referring to step 3 in embodiment 16, with b₇Instead of b₁, under the action of excessive EDCI and DMAP, first reacted with D, then With TBAF desiliconization ether protecting group, white powdery solids are made, are compound 22,

Two step total recoverys 35.3%.

The physical and chemical parameter of compound 22 is as follows:

¹H NMR(500MHz,CD₃COCD₃) δ 8.08 (2H, br d, J=7.5Hz, ArH), 7.90 (1H, t, J=7.5Hz, ArH),7.76(2H,t,J=7.5Hz,ArH),7.54(2H,d,J=8.5Hz,ArH),7.43(2H,d,J=8.5Hz,ArH), 6.83(1H, s, 3-OH), 6.16 (1H, br s, H-15), 5.19 (each1H, d, J=13.0Hz, OCH₂),4.96(1H,s,H- 7),4.73(1H,d,J=8.0Hz,H_a-20),4.26(2H,overlap,H-11,H-12),3.78(1H,overlap,H_b-20), 3.77(3H,s,CH₃O-21),3.27(1H,d,J=12.5Hz,H-14),3.12(1H,d,J=13.0Hz,H-5),2.83(1H,J =16.0Hz,H_β-1),2.71(1H,J=16.0Hz,H_α-1),2.65(4H,m,COCH₂CH₂CO),2.40(1H,br s,H-9), 2.26(1H,dt,J=15.0,2.5Hz,H_α-6),1.90(1H,ddd,J=14.5,13.0,2.5Hz,H_β-6),1.82(3H,d,J= 1.5Hz,H-18),1.39(3H,s,H-19);

¹³C NMR(125MHz,CD₃COCD₃)δ193.2(C-2),172.3(C=O),171.9(C=O),171.1(C-21), 167.4 (C-16), 159.6 (C=N), 153.6(ArC) 145.1 (C-3), 138.8 (ArC), 136.8 (ArC), 135.9 (ArC), 130.7(ArC×2),130.7(ArC×2),129.5(ArC×2),128.1(C-4),120.6(ArC×2),112.1(C= N),83.7(C-7),82.4(C-13),76.5(C-12),74.1(C-20),72.6(C-11),68.5(C-15),65.9 (OCH₂),52.9(OCH₃),51.2(C-14),49.3(C-1),46.4(C-8),42.3(C-9),41.9(C-5),41.9(C- 10),29.7(C-6).29.5(COCH₂), 29.5(COCH₂,overlapped with CD₃COCD₃), 15.6 (C-19), 13.3 (C-18);

HRESIMS m/z891.1902[M+Na]⁺(calcd for C₄₀H₄₀N₂NaO₁₈S,891.1889).

Embodiment 23:

15-O- { 4- [3- (2- oxygen -3- benzenesulfonyl -1,2, -4 oxygen of 5- oxadiazoles)-benzyloxy] -4- oxo butyryl Base }-bruceolide (23)

Referring to step 3 in embodiment 16, with b₈Instead of b₁, under the action of excessive EDCI and DMAP, first reacted with D, then With TBAF desiliconization ether protecting group, white powdery solids are made, are compound 23,

Two step total recoverys 29.7%.

The physical and chemical parameter of compound 23 is as follows:

¹H NMR(500MHz,CD₃COCD₃) δ 8.08 (2H, dd, J=8.5,1.5Hz, ArH), 7.90 (1H, t, J=7.5Hz, ArH),7.75(2H,t,J=8.0Hz,ArH),7.50(1H,t,J=8.0Hz,ArH),7.46(1H,t,J=1.5Hz,ArH), 7.39 (2H, m, ArH), 6.84(1H, s, 3-OH), 6.16 (1H, br s, H-15), 5.17 (2H, s, OCH₂),4.96(1H,t,J =2.5Hz,H-7),4.73(1H,d,J=7.5Hz,H_a-20),4.25(2H,overlap,H-11,H-12),3.78(1H, overlap,H_b-20),3.77(3H,s,CH3O-21),3.27(1H,d,J=12.5Hz,H-14),3.10(1H,d,J= 13.0Hz,H-5),2.83(1H,J=16.5Hz,H_β-1),2.71(1H,overlap,H_α-1),2.66(4H,m, COCH₂CH₂CO),2.39(1H,br s,H-9),2.25(1H,dt,J=15.0,2.5Hz,H_α-6),1.89(1H,ddd,J= 14.0,13.0,2.5Hz,H_β-6),1.82(3H,d,J=1.5Hz,H-18),1.39(3H,s,H-19);

¹³C NMR(125MHz,CD₃COCD₃)δ193.2(C-2),172.2(C=O),171.9(C=O),171.0(C-21), 167.5(C-16),159.6(C=N),154.1(ArC),145.0(C-3),139.9(ArC),138.8(ArC),136.8 (ArC),131.0(ArC),130.7(ArC×2),129.5(ArC×2),128.2(C-4),126.7(ArC),120.1 (ArC),119.8(ArC),112.1(C=N),83.7(C-7),82.4(C-13),76.5(C-12),74.1(C-20),72.5 (C-11),68.5(C-15),65.8(OCH₂),52.9(OCH₃),51.1(C-14),49.3(C-1),46.3(C-8),42.2(C- 9),41.9(C-5),41.9(C-10),29.6(C-6,overlapped with CD₃COCD₃).29.5(COCH₂),29.5 (COCH₂,overlapped with CD₃COCD₃), 15.6 (C-19), 13.3 (C-18);

HRESIMS m/z891.1898[M+Na]⁺(calcd for C₄₀H₄₀N₂NaO₁₈S,891.1889).

Embodiment 24:

15-O- { 2- [4- (2- oxygen -3- benzenesulfonyl -1,2,5- oxadiazoles -4- oxygen)-butoxy carbonyl]-benzoyl } - Bruceolide (24)

Referring to step 3 in embodiment 16, with b₉Instead of b₁, under the action of excessive EDCI and DMAP, first reacted with D, then With TBAF desiliconization ether protecting group, white powdery solids are made, are compound 24, two step total recoverys 27.8%.

The physical and chemical parameter of compound 24 is as follows:

¹H NMR(500MHz,CDCl₃) δ 8.04 (2H, br d, J=7.8Hz, ArH), 7.74 (3H, m, ArH), 7.58 (4H, M, ArH), 6.62 (1H, d, J=11.0Hz, H-15), 6.10(1H, s, 3-OH), 4.77 (1H, s, H-7), 4.73 (1H, d, J= 8.0Hz, Ha-20), 4.48(2H, t, J=6.0Hz, OCH₂), 4.43 (2H, m, OCH₂),4.30(1H,d,J=4.0Hz,H-11), 4.26(1H,s,H-12),3.80(1H,d,J=7.5Hz,H_b-20),3.43(3H,s,CH₃O-21),3.18(1H,d,J= 13.5Hz,H-14),2.99(1H,J=16.0Hz,H_β-1),2.96(1H,overlap,H-5),2.43(1H,J=16.0Hz,H_α- 1),2.40(1H,overlap,H_α-6),2.26(1H,d,J=3.3Hz,H-9),2.00(4H,m,CH₂),1.84(3H,s,H- 18),1.78(1H,ddd,J=14.5,13.0,2.5Hz,H_β-6),1.39(3H,s,H-19);

¹³C NMR(125MHz,CDCl₃)δ192.3(C-2),171.2(C-21),167.3(C-16),166.8(C=O), 165.5(C=O),159.2(C=N),144.3(C-3),138.2(ArC),135.9(ArC),131.7(ArC×2),129.9 (ArC×2),129.2(ArC×2),129.1(ArC×2)128.8(ArC×2),127.8(C-4),110.7(C=N),83.2 (C-7),81.9(C-13),75.6(C-12),74.4(C-20),71.3(C-11),71.2(OCH₂), 67.9 (C-15), 65.5 (OCH₂),53.0(OCH₃),52.0(C-14),48.7(C-1),46.2(C-8),42.4(C-9),42.2(C-5),41.3(C- 10),29.3(C-6),25.5(CH₂),25.1(CH₂),15.6(C-19),13.6(C-18);

HRESIMS m/z905.2057[M+Na]⁺(calcd for C₄₁H₄₂N₂NaO₁₈S,905.2046).

Embodiment 25:

15-O- { 4- [4- (2- oxygen -4- phenyl -1,2, -3 methoxyl group of 5- oxadiazoles)-benzyloxy] -4- oxo butyryl Base }-bruceolide (25)

Referring to step 3 in embodiment 16, with d₁Instead of b₁, under the action of excessive EDCI and DMAP, first reacted with D, then With TBAF desiliconization ether protecting group, white powdery solids are made, are compound 25, two step total recoverys 56.4%.

The physical and chemical parameter of compound 25 is as follows:

¹H NMR(300MHz,CDCl₃) δ 7.83 (2H, dd, J=7.5,1.2Hz, ArH), 7.53 (3H, m, ArH), 7.31 (2H, d, J=7.8Hz, ArH), 6.97 (2H, d, J=7.8Hz, ArH), 6.36 (1H, d, J=12.9Hz, H-15), 6.12 (1H, s, 3-OH),5.09(2H,s,OCH₂),5.07(2H,s,OCH₂),4.74(1H,s,H-7),4.73(1H,d,J=8.1Hz,H_a-20), 4.25(1H, d, J=3.9Hz, H-11), 4.22 (1H, s, H-12), 3.84 (3H, s, CH₃O-21),3.79(1H,d,J=8.1Hz, H_b-20),3.06(1H,d,J=13.2Hz,H-14),2.96(1H,J=16.2Hz,H_β-1),2.91(1H,overlap,H-5), 2.67(4H,m,COCH₂CH₂CO),2.41(1H,J=16.2Hz,H_α-1),2.35(1H,d,J=14.1Hz,H_α-6),2.18(1H, d,J=3.0Hz,H-9),1.83(3H,s,H-18),1.76(1H,ddd,J=14.1,13.2,1.5Hz,H_β-6),1.38(3H,s, H-19);

¹³C NMR(75MHz,CDCl₃)δ192.1(C-2),172.2(C=O),171.6(C=O),170.6(C-21), 166.8(C-16),157.0(C=N),156.9(ArC),144.0(C-3),131.4(ArC),130.3(ArC×2),129.5 (ArC),129.3(ArC×2),127.7(C-4),127.6(ArC×2),126.0(ArC),114.9(ArC×2),112.0(C =N),82.8(C-7),81.4(C-13),75.5(C-12),74.0(C-20),70.9(C-11),66.9(C-15),66.3 (OCH₂),58.3(OCH₂),53.1(OCH₃),51.6(C-14),48.4(C-1),45.7(C-8),42.0(C-9),41.9(C- 5),41.0(C-10),29.0(C-6),28.8(COCH₂),28.3(COCH₂),15.3(C-19),13.3(C-18)

HRESIMS m/z841.2436[M+Na]⁺(calcd for C₄₁H₄₂N₂NaO₁₆,841.2427).

Embodiment 26:

15-O- { 4- [3- (2- oxygen -4- phenyl -1,2, -3 methoxyl group of 5- oxadiazoles)-benzyloxy] -4- oxo butyryl Base }-bruceolide (26)

Referring to step 3 in embodiment 16, with d₂Instead of b₁, under the action of excessive EDCI and DMAP, first reacted with D, then With TBAF desiliconization ether protecting group, white powdery solids are made, are compound 26, two step total recoverys 31.5%.

The physical and chemical parameter of compound 26 is as follows:

¹H NMR(300MHz,CDCl₃)δ7.83(2H,dd,J=7.8,1.8Hz,ArH),7.53(3H,m,ArH),7.29 (1H, t, J=8.1Hz, ArH), 6.96 (3H, m, ArH), 6.39 (1H, d, J=13.2Hz, H-15), 6.10 (1H, s, 3-OH), 5.16,5.11(each1H,d,J=12.3Hz,OCH₂),5.15,5.09(each1H,d,J=12.3Hz,OCH₂),4.72(1H,s, H-7),4.72(1H,d,J=7.8Hz,Ha-20),4.24(1H,br s,H-11),4.20(1H,s,H-12),3.84(3H,s, CH₃O-21),3.79(1H,d,J=7.8Hz,H_b-20),3.05(1H,d,J=13.2Hz,H-14),2.96(1H,J=16.2Hz, H_β-1),2.96(1H,overlap,H-5),2.73(4H,m,COCH₂CH₂CO),2.41(1H,J=16.2Hz,H_α-1),2.36 (1H,dt,J=14.1,2.1Hz,H_α-6),2.18(1H,d,J=3.6Hz,H-9),1.84(3H,s,H-18),1.76(1H,ddd, J=14.1,12.9,2.1Hz,H_β-6),1.38(3H,s,H-19);

¹³C NMR(75MHz,CDCl₃)δ192.0(C-2),172.2(C=O),171.7(C=O),170.6(C-21), 166.7(C-16),157.2(ArC),157.1(C=N),144.0(C-3),137.7(ArC),131.4(ArC),129.9 (ArC),129.3(ArC×2),127.7(ArC×2),127.5(C-4),126.1(ArC),121.7(ArC),115.1 (ArC),113.8(ArC),112.2(C=N),82.8(C-7),81.5(C-13),75.6(C-12),74.1(C-20),71.0 (C-11),66.9(C-15),66.2(OCH₂),58.4(OCH₂),53.2(OCH₃),51.8(C-14),48.4(C-1),45.7 (C-8),42.0(C-9),41.8(C-5),41.0(C-10),29.0(C-6),28.8(COCH₂),28.4(COCH₂),15.4(C- 19),13.3(C-18)

HRESIMS m/z841.2435[M+Na]⁺(calcd for C₄₁H₄₂N₂NaO₁₆,841.2427).

Embodiment 27:

15-O- { 4- [2- (2- oxygen -4- phenyl -1,2, -3 methoxyl group of 5- oxadiazoles)-benzyloxy] -4- oxo butyryl Base }-bruceolide (27)

Referring to step 3 in embodiment 16, with d₃Instead of b₁, under the action of excessive EDCI and DMAP, first reacted with D, then With TBAF desiliconization ether protecting group, white powdery solids are made, are compound 27, two step total recoverys 70.2%.

The physical and chemical parameter of compound 27 is as follows:

¹H NMR(300MHz,CDCl₃)δ7.83(2H,d,J=7.8Hz,ArH),7.53(3H,m,ArH),7.32(2H,m, ArH), 7.02 (2H, t, J=8.7Hz, ArH), 6.33 (1H, d, J=12.9Hz, H-15), 6.12(1H, s, 3-OH), 5.13 (2H, s,OCH₂),5.05(2H,s,OCH₂),4.72(1H,s,H-7),4.72(1H,overlap,H_a- 20), 4.23(1H, br s, H- 11), 4.19 (1H, s, H-12), 3.81 (3H, s, CH₃O-21),3.79(1H,overlap,H_b-20),3.05(1H,d,J= 13.2Hz,H-14),2.95(1H,J=15.9Hz,H_β-1),2.91(1H,overlap,H-5),2.60(4H,m, COCH₂CH₂CO),2.41(1H,J=15.9Hz,H_α-1),2.36(1H,d,J=14.1Hz,H_α-6),2.18(1H,br s,H-9), 1.82(3H,s,H-18),1.75(1H,ddd,J=14.1,12.9,2.4Hz,H_β-6),1.38(3H,s,H-19);

¹³C NMR(75MHz,CDCl₃)δ192.2(C-2),172.1(C=O),171.5(C=O),170.5(C-21), 166.8(C-16),157.0(C=N),155.0(ArC),144.0(C-3),131.4(ArC),130.6(ArC),130.1 (ArC),129.4(ArC×2),127.8(C-4),127.6(ArC×2),126.0(ArC),124.5(ArC),122.2 (ArC),112.0(C=N),111.9(ArC),82.7(C-7),81.4(C-13),75.5(C-12),73.9(C-20),70.9 (C-11),66.8(C-15),61.9(OCH₂),58.6(OCH₂),53.1(OCH₃),51.6(C-14),48.4(C-1),45.7 (C-8),42.0(C-9),41.8(C-5),41.0(C-10),29.0(C-6),28.6(COCH₂),28.3(COCH₂),15.3(C- 19),13.3(C-18)

HRESIMS m/z857.2162[M+K]⁺(calcd for C₄₁H₄₂KN₂O₁₆,857.2166).

Embodiment 28:

15-O- [4- (2- oxygen -4- phenyl -1,2, -3 oxygen of 5- oxadiazoles) -4- oxobutanoyl]-bruceolide (28)

Referring to step 3 in embodiment 16, with d₄Instead of b₁, under the action of excessive EDCI and DMAP, first reacted with D, then With TBAF desiliconization ether protecting group, white powdery solids are made, are compound 28, two step total recoverys 24.0%.

The physical and chemical parameter of compound 28 is as follows:

¹H NMR(500MHz,CD₃COCD₃) δ 7.83 (2H, m, ArH), 7.62 (3H, m, ArH), 6.82 (1H, s, 3-OH), 6.14(1H,br s,H-15),5.26,5.24(each1H,d,J=14.0Hz,OCH₂),4.94(1H,s,H-7),4.72(1H, d,J=7.5Hz,H_a-20),4.25(2H,overlap,H-11,H-12),3.76(1H,overlap,Hb-20),3.75(3H,s, CH₃O-21),3.27(1H,d,J=12.5Hz,H-14),3.11(1H,d,J=13.0Hz,H-5),2.83(1H,J=16.0Hz,H_β- 1),2.71(1H,J=16.0Hz,H_α-1),2.61(4H,m,COCH₂CH₂CO),2.38(1H,br s,H-9),2.25(1H,dt,J =14.7,2.5Hz,H_α-6),1.90(1H,ddd,J=14.5,12.5,2.5Hz,H_β-6),1.82(3H,s,H-18),1.39(3H, s,H-19);

¹³C NMR(125MHz,CD₃COCD₃)δ193.2(C-2),172.0(C=O),171.9(C=O),171.0(C-21), 167.4(C-16),158.1(C=N),145.1(C-3),132.1(ArC),130.2(ArC×2),128.7(ArC×2), 128.1(C-4),127.2(ArC),112.6(C=N),83.7(C-7),82.4(C-13),76.5(C-12),74.1(C-20), 72.6(C-11),68.6(C-15),55.2(OCH₂),52.9(OCH₃),51.1(C-14),49.3(C-1),46.3(C-8), 42.3 (C-9), 41.9 (C-5), 41.9 (C-10), 29.7(C-6), 29.2 (COCH₂),29.2(COCH₂),15.6(C-19), 13.3(C-18)

HRESIMS m/z713.2172[M+H]⁺(calcd for C₃₄H₃₇N₂O₁₅,713.2188).

Embodiment 29:

15-O- [2-(2- oxygen -4- phenyl -1,2, -3 methoxyl group of 5- oxadiazoles) carbonyl benzoyl base]-bruceolide (29)

Referring to step 3 in embodiment 16, with d₅Instead of b₁, under the action of excessive EDCI and DMAP, first reacted with D, then With TBAF desiliconization ether protecting group, white powdery solids are made, are compound 29, two step total recoverys 17.8%.

The physical and chemical parameter of compound 29 is as follows:

¹H NMR(500MHz,CDCl₃)δ7.80(1H,dd,J=7.5,0.5Hz,ArH),7.76(2H,dd,J=7.5, 0.5Hz,ArH),7.71(1H,dd,J=7.5,0.5Hz,ArH),7.59(5H,m,ArH),6.59(1H,d,J=13.2Hz,H- 15), 6.09 (1H, s, 3-OH), 5.49,5.38 (each1H, d, J=13.0Hz, OCH₂),4.79(1H,s,H-7),4.74(1H, d,J=8.0Hz,H_a- 20), 4.30 (1H, m, H-11), 4.24 (1H, s, H-12), 3.84 (1H, d, J=7.8Hz, H_b-20),3.42 (3H,s,CH₃O-21),3.18(1H,d,J=12.5Hz,H-14),3.01(1H,J=16.5Hz,H_β-1),2.96(1H,d,J= 13.0Hz,H-5),2.42(1H,J=16.0Hz,H_α-1),2.42(1H,overlap,H_α-6),2.23(1H,br s,H-9), 1.87(3H,s,H-18),1.79(1H,ddd,J=14.0,13.0,2.5Hz,H_β-6),1.42(3H,s,H-19);

¹³C NMR(125MHz,CDCl₃)δ191.9(C-2),171.1(C-21),168.1(C-16),166.4(C=O), 165.0(C=O),156.8(C=N),144.1(C-3),132.1(ArC×2),131.7(ArC×2),131.5(ArC),129.5 (ArC×2),129.3(ArC×2),127.7(ArC×2),127.3(C-4),125.9(ArC),111.3(C=N),82.9(C- 7),81.6(C-13),75.4(C-12),74.1(C-20),71.1(C-11),67.8(C-15),55.4(OCH₂),52.8 (OCH₃),51.7(C-14),48.5(C-1),45.9(C-8),42.3(C-9),42.0(C-5),41.1(C-10),29.1(C- 6),15.4(C-19),13.3(C-18)

HRESIMS m/z783.2014[M+Na]⁺(calcd for C₃₈H₃₆N₂NaO₁₅,783.2008).

Embodiment 30:

Synthetic route:

Step 1:3- (2- oxygen -3- benzenesulfonyl -1,2,5- oxadiazoles -4-) oxygen iodopropane (g₁)

Take a₁85mg(0.28mmol), triphenylphosphine about 90mg(0.34mmol), imidazoles 40mg(0.61mmol) with anhydrous Methylene chloride 40ml dissolution.After dissolution, I is added₂About 90mg(0.35mmol), room temperature, which is protected from light, to be stirred to react.After 5h, reaction solution point Not with dilute NaHCO₃Solution, 10%Na₂S₂O₃Solution washing, organic layer are dry with anhydrous sodium sulfate.It after drying, filters, filtrate is dense Contracting, silica gel column chromatography separation, with ethyl acetate: petroleum ether (60~90 DEG C)=1:4 (V:V) elution obtains white fluffy solid 100mg is compound g₁, yield 86.2%.

Step 2:3-O-(dimethyl tertiary butyl silicon substrate) -21-O- demethyl Brusatol (E)

Take C about 18g(0.028mol), lithium iodide 18g(0.13mol) with the dissolution of 35ml anhydrous pyridine, under nitrogen protection, 13h is stirred to react at 100 DEG C.After reaction, vacuum distillation removes most of pyridine, and concentrate is dilute with 200ml ethyl acetate It releases.Organic layer is washed with dilute hydrochloric acid, and pickling solution merges all organic phases, with ethyl acetate (1 × 100ml) extraction with anhydrous sulphur Sour sodium is dry.After drying, filtering, filtrate concentration obtains orange red crude product about 17.5g.Take crude product about 500mg through preparing HPLC(YMC ODS column, acetonitrile: water containing 0.03%TFA=60:40) separation, sterling about 325mg is obtained, is compound E, yield 65.5%.Step 3: 21-O- [3- (2- oxygen -3- benzenesulfonyl -1,2,5- oxadiazoles -4- oxygen)-propoxyl group] -21-O- demethyl Brusatol (30)

Take E45mg(0.073mmol), g₁50mg(0.12mmol), it is dissolved with 5mlDMF, adds K₂CO₃50mg (0.36mmol) is stirred to react 12h under argon gas protection with 40 DEG C.After reaction, vacuum distillation removes solvent, changes with two Chloromethanes dissolution, with dilute hydrochloric acid, the washing of saturated common salt aqueous solution, organic layer is dry with anhydrous sodium sulfate.It after drying, filters, filter Liquid concentration, is diluted with tetrahydrofuran, a small amount of glacial acetic acid is added, and the tetrahydrofuran solution of 1mol/LTBAF is added portionwise until desiliconization Ether protecting group is complete.Reaction stops, and 30ml methylene chloride is added in reaction solution, then respectively with dilute HCl(1 × 30ml), saturation NaHCO₃Solution (1 × 30ml), saturated salt solution (1 × 30ml) washing, organic layer are dry with anhydrous sodium sulfate.After drying, mistake Filter, filtrate concentration, to prepare the separation of thin layer silica gel plate, methylene chloride: methanol=30:1 is solvent, obtains white powdery solids About 10mg is compound 30, two step total recoverys 17.5%.

The physical and chemical parameter of compound 30 is as follows:

¹H NMR(400MHz,CDCl₃)δ8.05(2H,br d,J=7.6Hz,Ar-H),7.77(1H,t,J=7.6Hz,Ar- H),7.63(2H,t,J=7.6Hz,Ar-H),6.32(1H,d,J=11.6Hz H-15),6.08(1H,s,OH-3),5.64(1H, s,H-2’),4.80(1H,s,H-7),4.71(1H,d,J=7.6Hz,H_a- 20), 4.55(2H, t, J=6.0Hz, OCH₂), 4.49, 4.33(each1H,m,OCH₂),4.25(1H,d,J=2.8Hz,H-11),4.22(1H,s,H-12),3.78(1H,d,J= 7.6Hz,H_b-20),3.14(1H,d,J=11.6Hz,H-14),2.98(1H,d,J=16.0Hz,H_β-1),2.95(1H, overlap,H-5),2.39(1H,d,J=16.0Hz,H_α-1),2.39(1H,overlap,H_α-6),2.30(2H,m,CH₂), 2.19(3H,s,H-5’),2.12(1H,br s,H-9),1.93(3H,s,H-4’),1.84(3H,d,J=1.2Hz,H-18), 1.76(1H,ddd,J=14.0,12.8,2.0Hz,H_β-6),1.40(3H,s,H-19);

¹³C NMR(100MHz,CDCl₃)δ191.9(C-2),171.7(C-21),167.0(C-16),164.4(C-1’), 161.4 (C-3 '), 158.8 (C=N), 144.0 (C-3), 137.7 (ArC), 135.8 (ArC), 129.7 (ArC × 2), 128.6 (ArC × 2), 127.6 (C-4), 113.9 (C-2 '), 110.5 (C=N), 82.3 (C-7), 81.3 (C-13), 75.8 (C-12), 74.1(C-20),71.0(C-11),68.0(OCH₂),65.7(C-15),62.6(OCH₂),51.7(C-14),48.6(C-1), 45.5(C-8),42.0(C-9),41.8(C-5),41.1(C-10),29.1(C-6),27.7(CH₂),27.7(C-4’),20.7 (C-5’),15.4(C-19),13.3(C-18);

HRESIMS m/z811.1979[M+Na]⁺(calcd for C₃₆H₄₀N₂NaO₁₆S,811.1991).

Embodiment 31:

Synthetic route:

Step 1:21-O- demethyl Brusatol (F)

E crude product 17g and 100ml tetrahydrofuran obtained in embodiment 30 is placed in a reaction flask, is added portionwise The tetrahydrofuran solution of 40ml1mol/LTBAF, is stirred overnight.Reaction solution is concentrated, and standby post separation is suppressed in reverse phase ODS column, with first Alcohol: water containing 0.03%TFA=10:90~15:85~20:80~25:75 (V:V) gradient elution obtains white powdery solids about 7.1g.The yield of compound F is calculated using compound C in embodiment 32 as raw material, is compound F, and two step total recoverys are 49.5%.

Step 2:21-O- [4- (2- oxygen -3- benzenesulfonyl -1,2,5- oxadiazoles -4- oxygen)-butoxy] -21-O- demethyl Brusatol (31)

Take F24mg(0.047mmol), b₂30mg(0.096mmol), EDCI18mg(0.094mmol), DMAP40mg (0.33mmol) is added anhydrous methylene chloride dissolution and changes after stirring 5h to be stirred overnight at room temperature in ice-water bath.Reaction stops Only, reaction solution is with water, and dilute HCl, saturated common salt water washing, organic layer is with anhydrous sodium sulfate drying.After drying, filtering, organic layer Concentration, to prepare HPLC(YMC ODS column, acetonitrile: water containing 0.03%TFA=60:40) separation, white powdery solids are obtained, about 9mg is compound 31, yield 23.7%.

The physical and chemical parameter of compound 31 is as follows:

¹H NMR(400MHz,CDCl₃)δ8.05(2H,br d,J=7.6Hz,Ar-H),7.77(1H,t,J=7.6Hz,Ar- H),7.63(2H,t,J=7.6Hz,Ar-H),6.28(1H,d,J=11.6Hz H-15),6.08(1H,s,OH-3),5.62(1H, s,H-2’),4.80(1H,s,H-7),4.69(1H,d,J=8.0Hz,H_a-20),4.49(2H,t,J=4.8Hz,OCH₂),4.36, 4.24(each1H,m,OCH₂),4.24(1H,br s,H-11),4.22(1H,s,H-12),3.78(1H,d,J=8.0Hz,H_b- 20),3.14(1H,d,J=11.6Hz,H-14),2.98(1H,d,J=16.0Hz,H_β-1),2.94(1H,overlap,H-5), 2.38(1H,d,J=16.0Hz,H_α-1),2.39(1H,d,J=14.4,H_α-6),2.19(3H,s,H-5’),2.11(1H,br s, H-9),2.00(2H,m,CH₂),1.93(2H,m,CH₂),1.92(3H,s,H-4’),1.84(3H,s,H-18),1.76(1H, ddd,J=14.4,12.8,2.0Hz,H_β-6),1.39(3H,s,H-19);

¹³C NMR(100MHz,CDCl₃)δ192.0(C-2),171.6(C-21),167.0(C-16),164.4(C-1’), 161.1 (C-3 '), 159.0 (C=N), 144.0 (C-3), 137.8 (ArC), 135.7 (ArC), 129.7 (ArC × 2), 128.6 (ArC × 2), 127.7 (C-4), 114.0 (C-2 '), 110.6 (C=N), 82.3 (C-7), 81.2 (C-13), 75.8 (C-12), 74.0(C-20),71.0(C-11),70.8(OCH₂),65.8(C-15),65.7(OCH₂),51.6(C-14),48.6(C-1), 45.5(C-8),41.9(C-9),41.8(C-5),41.1(C-10),29.1(C-6),27.7(C-4’),25.4(CH₂),24.8 (CH₂),20.7(C-5’),15.4(C-19),13.3(C-18);

HRESIMS m/z803.2337[M+H]⁺(calcd for C₃₇H₄₃N₂O₁₆S,803.2328).

The synthetic route of compound 32,33 in embodiment: (intermediate a₇, a₈Middle R₆, intermediate h₁、h₂Middle R₆Respectively with change Close R in object 32,33₉Unanimously)

Compound	R₉
		32	CH₂-p-Ph
33	CH₂-m-Ph

Embodiment 32:

Step 1:4- (3- benzenesulfonyl -1,2,5 oxadiazoles -2- oxide -4-) oxygen benzyl bromine (h₁)

Take a₇330mg(0.95mmol) be placed in a reaction flask, with the dissolution of 20ml anhydrous methylene chloride.In ice-water bath condition Under, excess PBr is added₃, continue to react in ice-water bath.After 3h, change to be stirred overnight at room temperature.After reaction, to reaction solution In be slowly added to 20ml water, stir 10min.Organic layer is taken, with water (2 × 20ml) washing.Water layer is with methylene chloride extraction 1 time. Merge all organic layers, to be saturated NaHCO₃Solution is washed again to neutrality, and organic layer is dry with anhydrous sodium sulfate.After drying, Filtering, filtrate concentration, obtains white solid 356mg, is compound h₁, yield 91.8%.

Step 2:21-O- [4- (2- oxygen -3- benzenesulfonyl -1,2,5- oxadiazoles -4- oxygen)-benzyloxy] -21-O- goes first Base Brusatol (32)

Take E70mg(0.11mmol), h₁70mg(0.17mmol), K₂CO₃135mg(0.98mol), molten with 5ml anhydrous acetonitrile Solution, under argon gas protection, 50 DEG C are stirred to react 5h.After reaction stops, reaction solution filtering, filtrate concentration changes with 20ml dichloromethane Alkane dissolution, with dilute HCl(1 × 20ml), saturated salt solution (1 × 20ml) washing, organic layer is with anhydrous sodium sulfate drying.It is dry Afterwards, filter, organic layer concentration, with the isolated 3-O-(dimethyl tertiary butyl silicon substrate of silica gel column chromatography) -21-O- [4- (2- oxygen - 3- benzenesulfonyl -1,2,5- oxadiazoles -4- oxygen)-benzyloxy] -21-O- demethyl Brusatol crude product.Gained crude product is with two Chloromethanes 5ml dissolution, adds 5ml tetrahydrofuran and a small amount of glacial acetic acid, the tetrahydrofuran solution of 1mol/LTBAF is added portionwise Until desiliconization ether protecting group is complete.Reaction stops, and 20ml methylene chloride is added in reaction solution, then respectively with dilute HCl(1 × 20ml), It is saturated NaHCO₃(1 × 20ml) solution, saturated salt solution (1 × 20ml) washing, organic layer are dry with anhydrous sodium sulfate.It is dry Afterwards, it filters, organic layer concentration.To prepare HPLC(YMC ODS column, acetonitrile: water=56:44) separation, obtain white powdery solids 50mg is compound 32, two step total recoverys 53.0%.

The physical and chemical parameter of compound 32 is as follows:

¹H NMR(400MHz,CDCl₃)δ8.10(2H,br d,J=8.0Hz,Ar-H),7.80(1H,t,J=8.0Hz,Ar- H),7.66(2H,t,J=8.0Hz,Ar-H),7.43(2H,d,J=8.4Hz,Ar-H),7.34(2H,d,J=8.4Hz,Ar-H), 6.29(1H,d,J=11.6Hz,H-15),6.09(1H,s,OH-3),5.52(1H,s,H-2’),5.23,5.16(each1H,d,J =12.8Hz,OCH₂),4.80(1H,s,H-7),4.71(1H,d,J=7.6Hz,H_a-20),4.25(1H,d,J=3.6Hz,H-11), 4.23(1H,s,H-12),3.79(1H,d,J=7.6Hz,H_b-20),3.17(1H,d,J=10.4Hz,H-14),2.96(1H,d,J =16.0Hz,H_β-1),2.95(1H,overlap,H-5),2.38(1H,d,J=16.0Hz,H_α-1),2.38(1H,overlap, H_α-6),2.15(3H,s,H-5’),2.15(1H,overlap,H-9),1.89(3H,s,H-4’),1.83(3H,s,H-18), 1.75(1H,ddd,J=14.4,12.8,2.4Hz,H_β-6),1.38(3H,s,H-19);

¹³C NMR(100MHz,CDCl₃)δ192.1(C-2),171.3(C-21),167.0(C-16),164.4(C-1’), 161.2(C-3’),158.2(C=N),152.6(ArC),144.0(C-3),137.8(ArC),135.9(ArC),133.3 (ArC), 129.8 (ArC × 2), 129.8 (ArC × 2), 128.6 (ArC × 2), 127.9 (C-4), 120.2 (ArC × 2), 113.9(C-2’),110.7(C=N),82.3(C-7),81.3(C-13),75.8(C-12),74.0(C-20),71.0(C-11), 66.8(OCH₂)65.8(C-15),51.5(C-14),48.5(C-1),45.5(C-8),41.8(C-9),41.8(C-5),41.1 (C-10),29.0(C-6),27.7(C-4’),20.6(C-5’),15.4(C-19),13.3(C-18);

HRESIMS m/z859.2008[M+Na]⁺(calcd for C₄₀H₄₀N₂NaO₁₆S,859.1991).

Embodiment 33:

21-O- [3- (2- oxygen -3- benzenesulfonyl -1,2,5- oxadiazoles -4- oxygen)-benzyloxy] -21-O- demethyl crow gallbladder Picrol (33)

Step 1: referring to step 1 in embodiment 32, with a₈Instead of a₇With PBr₃Reaction obtain 3- (3- benzenesulfonyl -1,2,5 Oxadiazoles -2- oxide -4-) oxygen benzyl bromine (h₂)。

Step 2: referring to step 2 in embodiment 32, with h₂Instead of h₁, in K₂CO₃Under the action of, it is reacted with E, passes through silica gel Column chromatography obtains 3-O-(dimethyl tertiary butyl silicon substrate) -21-O- [4- (2- oxygen -3- benzenesulfonyl -1,2,5- oxadiazoles -4- oxygen) - Benzyloxy] -21-O- demethyl Brusatol crude product.Gained crude product sloughs silicon ether protecting group again with TBAF, through preparing HPLC (YMC ODS column, acetonitrile: water=56:44) separation, obtains white powdery solids, is compound 33, two step total recoverys 30.9%.

The physical and chemical parameter of compound 33 is as follows:

¹H NMR(400MHz,CDCl₃)δ8.10(2H,dd,J=8.0,1.2Hz,Ar-H),7.80(1H,t,J=8.0Hz, Ar-H),7.66(2H,t,J=8.0Hz,Ar-H),7.48(1H,t,J=8.0Hz,Ar-H),7.39(1H,br s,Ar-H),7.30 (1H,dd,J=8.0,2.0Hz,Ar-H),7.29(1H,d,J=8.0,Ar-H),6.31(1H,d,J=11.6Hz,H-15),6.07 (1H,s,OH-3),5.50(1H,s,H-2’),5.25,5.20(each1H,d,J=12.8Hz,OCH₂),4.80(1H,s,H-7), 4.72(1H,d,J=8.0Hz,H_a-20),4.26(1H,br s,H-11),4.23(1H,s,H-12),3.81(1H,d,J= 8.0Hz,H_b-20),3.17(1H,d,J=11.6Hz,H-14),2.98(1H,d,J=16.0Hz,H_β-1),2.95(1H,d,J= 12.0Hz,H-5),2.39(1H,d,J=16.0Hz,H_α-1),2.39(1H,overlap,H_α-6),2.15(3H,s,H-5’), 2.12(1H,overlap,H-9),1.89(3H,s,H-4’),1.85(3H,d,J=1.6Hz,H-18),1.73(1H,ddd,J= 13.6,12.0,2.4Hz,H_β-6),1.36(3H,s,H-19);

¹³C NMR(100MHz,CDCl₃)δ192.0(C-2),171.2(C-21),167.0(C-16),164.4(C-1’), 161.2(C-3’),158.1(C=N),152.9(ArC),144.0(C-3),137.6(ArC),137.1(ArC),135.9 (ArC),130.4(ArC),129.8(ArC×2),128.7(ArC×2),127.8(C-4),125.8(ArC),119.8 (ArC),119.0(ArC),113.9(C-2’),110.7(C=N),82.2(C-7),81.4(C-13),75.8(C-12),74.0 (C-20),71.0(C-11),66.5(OCH₂),65.7(C-15),51.6(C-14),48.6(C-1),45.5(C-8),41.8 (C-9),41.8(C-5),41.1(C-10),29.0(C-6),27.7(C-4’),20.6(C-5’),15.4(C-19),13.3(C- 18);

HRESIMS m/z837.2204[M+H]⁺(calcd for C₄₀H₄₁N₂O₁₆S,837.2212).

The synthetic route of compound 34-36 in embodiment: (intermediate c₁-c₃Middle R₇, intermediate e₁-e₃Middle R₇Respectively with change Close R in object 34-36₁₀Unanimously)

The compound of synthesis:

Compound	R₁₀
		34	CH₂-p-Ph
35	CH₂-m-Ph
		36	CH₂-o-Ph

Embodiment 34:

21-O- [4- (2- oxygen -4- phenyl -1,2, -3 methoxyl group of 5- oxadiazoles)-benzyloxy] -21-O- demethyl crow gallbladder Picrol (34)

Referring to step 2 in embodiment 32, with gained e in step 1 in embodiment 15₁Instead of h₁, in K₂CO₃Under the action of, with E reaction, obtaining 3-O- (dimethyl tertiary butyl silicon substrate) -21-O- by silica gel column chromatography, [(2- oxygen -4- phenyl -1,2,5- are disliked 4- - 3 methoxyl group of diazole)-benzyloxy] -21-O- demethyl Brusatol crude product.Gained crude product sloughs the protection of silicon ether again with TBAF Base, through preparing HPLC(YMC ODS column, acetonitrile: water=56:44) separation, white powdery solids are obtained, are compound 34, two steps Total recovery 60.9%.

The physical and chemical parameter of compound 34 is as follows:

¹H NMR(400MHz,CDCl₃)δ7.86(2H,dd,J=8.0,1.2Hz,Ar-H),7.56(3H,m,Ar-H),7.32 (2H,d,J=8.4Hz,Ar-H),7.02(2H,d,J=8.4Hz,Ar-H),6.32(1H,d,J=11.6Hz,H-15),6.07(1H, s,OH-3),5.54(1H,s,H-2’),5.16,5.11(each1H,d,J=12.4Hz,OCH₂), 5.13 (2H, s, OCH₂),4.78 (1H,s,H-7),4.70(1H,d,J=8.0Hz,H_a-20),4.25(1H,d,J=3.2Hz,H-11),4.20(1H,s,H-12), 3.79(1H,d,J=8.0Hz,H_b-20),3.10(1H,d,J=12.8Hz,H-14),2.98(1H,d,J=16.0Hz,H_β-1), 2.96(1H,d,J=12.8Hz,H-5),2.39(1H,d,J=16.0Hz,H_α-1),2.39(1H,overlap,H_α-6),2.17 (3H,s,H-5’),2.13(1H,br s,H-9),1.91(3H,s,H-4’),1.85(3H,d,J=1.2Hz,H-18),1.76 (1H,ddd,J=14.0,12.8,1.2Hz,H_β-6),1.40(3H,s,H-19);

¹³C NMR(100MHz,CDCl₃)δ192.1(C-2),171.4(C-21),167.1(C-16),164.4(C-1’), 161.1(C-3’),157.2(ArC),157.0(C=N),144.0(C-3),131.5(ArC),130.2(ArC×2),129.4 (ArC×2),128.5(ArC),128.0(C-4),127.6(ArC×2),126.0(ArC),115.1(ArC×2),114.0 (C-2’),112.0(C=N),82.3(C-7),81.3(C-13),75.8(C-12),73.9(C-20),71.0(C-11),67.4 (OCH₂),65.7(C-15),58.4(OCH₂),51.5(C-14),48.5(C-1),45.5(C-8),41.8(C-9),41.8(C- 5),41.1(C-10),29.0(C-6),27.7(C-4’),20.6(C-5’),15.4(C-19),13.3(C-18);

HRESIMS m/z787.2714[M+H]⁺(calcd for C₄₁H₄₃N₂O₁₄,787.2709).

Embodiment 35:

21-O- [3- (2- oxygen -4- phenyl -1,2, -3 methoxyl group of 5- oxadiazoles)-benzyloxy] -21-O- demethyl crow gallbladder Picrol (35)

Step 1: referring to step 1 in embodiment 15, with c₂Instead of c₁, with PBr₃Reaction obtains 3-, and (4- phenyl -1,2,5- are disliked Diazole -2- oxide -3) methoxybenzyl bromine (e₂)。

Step 2: referring to step 2 in embodiment 32, with e₂Instead of h₁, in K₂CO₃Under the action of, it is reacted with E, passes through silica gel Column chromatography obtains 3-O-(dimethyl tertiary butyl silicon substrate) -21-O- [3- (2- oxygen -4- phenyl -1,2, -3 methoxyl group of 5- oxadiazoles) - Benzyloxy] -21-O- demethyl Brusatol crude product.Gained crude product sloughs silicon ether protecting group again with TBAF, through preparing HPLC (YMC ODS column, acetonitrile: water=56:44) separation, obtains white powdery solids, is compound 35, two step total recoverys 60.3%. The physical and chemical parameter of compound 35 is as follows:

¹H NMR(400MHz,CDCl₃)δ7.90(2H,dd,J=8.0,1.2Hz,Ar-H),7.57(3H,m,Ar-H),7.31 (1H,t,J=8.4Hz,Ar-H),7.14(1H,br s,Ar-H),6.98(2H,m,Ar-H),6.32(1H,brs,H-15),6.08 (1H,s,OH-3),5.30,5.14(each1H,d,J=12.8Hz,OCH₂),5.25(1H,s,H-2’),5.22,5.14 (each1H,d,J=13.2Hz,OCH₂),5.13(2H,s,OCH₂),4.91(1H,s,H-7),4.73(1H,d,J=7.6Hz,H_a- 20),4.26(1H,br s,H-11),4.24(1H,s,H-12),3.94(1H,d,J=7.6Hz,H_b-20),3.39(1H,d,J= 13.2Hz,H-14),3.00(1H,d,J=16.4Hz,H_β-1),2.96(1H,d,J=12.0Hz,H-5),2.40(1H,d,J= 16.4Hz,H_α-1),2.39(1H,overlap,H_α-6),2.18(1H,brs,H-9),2.11(3H,s,H-5’),1.85(3H,d, J=1.2Hz,H-18),1.80(3H,s,H-4’),1.76(1H,overlap,H_β-6),1.42(3H,s,H-19);

¹³C NMR(100MHz,CDCl₃)δ192.2(C-2),171.4(C-21),167.5(C-16),164.3(C-1’), 161.0(C-3’),157.2(ArC),157.1(C=N),144.0(C-3),137.0(ArC),131.5(ArC),130.1 (ArC),129.4(ArC×2),128.0(C-4),127.7(ArC×2),126.0(ArC),121.4(ArC),116.1 (ArC),113.8(C-2’),113.2(ArC),112.6(C=N),82.3(C-7),81.4(C-13),75.7(C-12),74.0 (C-20),71.1(C-11),67.0(OCH₂),65.8(C-15),58.4(OCH₂),51.2(C-14),48.5(C-1),45.6 (C-8),41.9(C-9),41.9(C-5),41.1(C-10),29.0(C-6),27.6(C-4’),20.6(C-5’),15.4(C- 19),13.3(C-18);

HRESIMS m/z787.2720[M+H]⁺(calcd for C₄₁H₄₃N₂O₁₄,787.2709).

Embodiment 36:

21-O- [2- (2- oxygen -4- phenyl -1,2, -3 methoxyl group of 5- oxadiazoles)-benzyloxy] -21-O- demethyl crow gallbladder Picrol (36)

Step 1: referring to step 1 in embodiment 15, with c₃Instead of c₁With PBr₃Reaction obtains 3-, and (4- phenyl -1,2,5- dislike two Azoles -2- oxide -3) methoxybenzyl bromine (e₃)。

Step 2: referring to step 2 in embodiment 32, with e₃Instead of h₁, in K₂CO₃Under the action of, it is reacted with E, passes through silica gel Column chromatography obtains 3-O-(dimethyl tertiary butyl silicon substrate) -21-O- [2- (2- oxygen -4- phenyl -1,2, -3 methoxyl group of 5- oxadiazoles) - Benzyloxy] -21-O- demethyl Brusatol crude product.Gained crude product sloughs silicon ether protecting group again with TBAF, through preparing HPLC (YMC ODS column, acetonitrile: water=56:44) separation, obtains white powdery solids, is compound 36, two step total recoverys 53.3%.

The physical and chemical parameter of compound 36 is as follows:

¹H NMR(400MHz,CDCl₃)δ7.80(2H,br d,J=7.6Hz,Ar-H),7.55(3H,m,Ar-H),7.38 (2H,m,Ar-H),7.06(2H,m,Ar-H),6.31(1H,br s,H-15),6.07(1H,s,OH-3),5.33(1H,s,H- 2’),5.21,5.17(each1H,d,J=12.0Hz,OCH₂),5.13(2H,s,OCH₂),4.76(1H,s,H-7),4.62(1H, d,J=8.0Hz,H_a-20),4.19(1H,br s,H-11),4.10(1H,s,H-12),3.71(1H,d,J=8.0Hz,H_b-20), 3.08(1H,d,J=11.6Hz,H-14),2.94(1H,d,J=16.0Hz,H_β-1),2.92(1H,overlap,H-5),2.36 (1H,overlap,H_α-6),2.33(1H,d,J=16.0Hz,H_α-1),2.11(3H,s,H-5’),2.09(1H,br s,H-9), 1.83(3H,s,H-4’),1.79(3H,s,H-18),1.76(1H,ddd,J=13.6,12.8,1.2Hz,Hb-6),1.37(3H, s,H-19);

¹³C NMR(100MHz,CDCl₃)δ192.0(C-2),171.5(C-21),167.0(C-16),164.3(C-1’), 160.7(C-3’),156.9(C=N),155.5(ArC),144.0(C-3),131.6(ArC),130.9(ArC),130.6 (ArC),129.5(ArC×2),127.7(C-4),127.6(ArC×2),126.0(ArC),123.7(ArC),122.4 (ArC),113.9(C-2’),112.1(ArC),111.9(C=N),82.0(C-7),81.3(C-13),75.8(C-12),73.9 (C-20),70.9(C-11),65.5(C-15),63.4(C-1’’),58.6(OCH₂),51.4(C-14),48.6(C-1),45.4 (C-8),41.9(C-9),41.8(C-5),41.1(C-10),29.0(C-6),27.5(C-4’),20.6(C-5’),15.4(C- 19),13.3(C-18);

HRESIMS m/z787.2707[M+H]⁺(calcd for C₄₁H₄₃N₂O₁₄,787.2709).

Embodiment 37:

Synthetic route:

21-O- [(4- phenyl -1,2,5- oxadiazoles -2- oxide -3) methoxyl group] -21-O- demethyl Brusatol (37)

Step 1: referring to step 1 in embodiment 15, c being replaced with B₁With PBr₃Reaction obtains 2- oxygen -3- bromomethyl -4- phenyl - 1,2,5- oxadiazoles (e₄)。

Step 2: referring to step 2 in embodiment 32, with e₄Instead of h₁, then in K₂CO₃Under the action of, it is reacted with E, passes through silicon Rubber column gel column chromatography obtains 3-O-(dimethyl tertiary butyl silicon substrate) -21-O- [(4- phenyl -1,2,5- oxadiazoles -2- oxide -3) methoxy Base] -21-O- demethyl Brusatol crude product.Gained crude product sloughs silicon ether protecting group again with TBAF, through preparing HPLC(YMC ODS Column, acetonitrile: water=52:48) separation, white powdery solids are obtained, are compound 37, two step total recoverys 48.0%.

The physical and chemical parameter of compound 37 is as follows:

¹H NMR(400MHz,CDCl₃)δ7.75(2H,dd,J=7.6,1.2Hz,Ar-H),7.57(3H,m,Ar-H),6.26 (1H,d,J=11.6Hz H-15),6.07(1H,s,OH-3),5.46(1H,s,H-2’),5.31,5.23(each1H,d,J= 13.6Hz,OCH₂),4.66(1H,d,J=8.0Hz,H_a-20),4.62(1H,s,H-7),4.23(1H,d,J=3.2Hz,H-11), 4.17(1H,s,H-12),3.59(1H,d,J=8.0Hz,H_b-20),3.23(1H,br s,H-14),2.94(1H,d,J= 16.0Hz,H_β-1),2.92(1H,d,J=12.0Hz,H-5),2.38(1H,d,J=16.0Hz,H_α-1),2.36(1H,d,J= 14.8Hz,H_α-6),2.15(3H,s,H-5’),2.12(1H,br s,H-9),1.88(3H,s,H-4’),1.83(3H,s,H- 18),1.76(1H,ddd,J=14.0,12.0,1.2Hz,H_β-6),1.36(3H,s,H-19);

¹³C NMR(100MHz,CDCl₃)δ192.0(C-2),170.7(C-21),166.9(C-16),164.3(C-1’), 162.0(C-3’),156.5(C=N),144.0(C-3),131.5(ArC),129.5(ArC×2),127.9(C-4),127.8 (ArC×2),125.9(ArC),113.4(C-2’),110.6(C=N),82.1(C-7),81.4(C-13),75.6(C-12), 74.1(C-20),71.1(C-11),65.4(C-15),55.7(OCH₂),51.6(C-14),48.5(C-1),45.4(C-8), 41.8(C-9),41.8(C-5),41.0(C-10),29.0(C-6),27.6(C-4’),20.7(C-5’),15.4(C-19), 13.3(C-18);

HRESIMS m/z703.2108[M+Na]⁺(calcd for C₃₄H₃₆N₂NaO₁₃,703.2110).

The synthetic route of compound 38-40 in embodiment:

Change F and b₂Feed ratio, the 38,39,40 of available different proportion

Embodiment 38:

12-O- { 4- [4- (2- oxygen -3- benzenesulfonyl -1,2,5- oxadiazoles -4- oxygen)-butoxy] -4- oxobutanoyl } - 21-O- demethyl Brusatol (38)

By F28mg (0.055mmol), b₂35mg (0.085mmol), EDCI20mg(0.10mmol), DMAP50mg (0.41mmol) is placed in a reaction flask, under the conditions of ice-water bath, be added anhydrous methylene chloride dissolution, after being stirred to react 5h, change with Reaction is stirred at room temperature overnight.Reaction solution is respectively with dilute HCl, dilute NaHCO₃Solution, saturated common salt water washing.Dilute NaHCO₃Washing lotion with Dilute HCl tune pH to 4, then with methylene chloride extraction 1 time.Merge all organic layers, it is dry with anhydrous sodium sulfate.After drying, filtering, Filtrate concentration, through preparing HPLC(YMC ODS column, acetonitrile: water containing 0.03%TFA=50:50) separation, it is solid to obtain white powder Body, about 17mg are compound 38, yield 34.1%.(embodiment can also obtain minority specioz 43,44)

The physical and chemical parameter of compound 38 is as follows:

¹H NMR(500MHz,CDCl₃)δ8.05(2H,br d,J=8.0Hz,Ar-H),7.77(1H,t,J=8.0Hz,Ar- H),7.63(2H,t,J=8.0Hz,Ar-H),6.08(1H,d,J=11.6Hz,H-15),6.08(1H,overlap,OH-3), 5.68(1H,s,H-2’),5.26(1H,s,H-12),4.82(1H,s,H-7),4.78(1H,d,J=6.5Hz,H_a-20),4.45 (2H,t,J=6.0Hz,OCH₂),4.19(1H,br s,H-11),4.15(2H,m,OCH₂),3.80(1H,d,J=6.0Hz,H_b- 20),3.25(1H,br s,H-14),2.97(1H,d,J=13.0Hz,H-5),2.92(1H,d,J=17.0Hz,H_β-1),2.67 (1H,d,J=17.0Hz,H_α-1),2.62(1H,overlap,H_α-6),2.52(4H,m,COCH₂CH₂CO),2.16(3H,s,H- 5’),2.16(1H,overlap,H-9),1.95(2H,m,CH₂),1.90(3H,s,H-4’),1.84(3H,s,H-18),1.81 (2H,m,CH₂),1.78(1H,overlap,H_β-6),1.37(3H,s,H-19);

¹³C NMR(125MHz,CDCl₃)δ192.3(C-2),172.4(C=O),171.5(C-21),170.9(C=O), 167.1(C-16),164.7(C-1’),160.8(C-3’),158.9(C=N),144.0(C-3),137.9(ArC),135.7 (ArC), 129.7 (ArC × 2), 128.6 (ArC × 2), 128.4 (C-4), 114.2 (C-2 '), 110.5 (C=N), 82.6 (C- 7),80.1(C-13),74.7(C-12),74.0(C-20),71.0(OCH₂),68.9(C-11),65.5(C-15),64.3 (OCH₂),51.3(C-14),48.4(C-1),45.2(C-8),42.0(C-9),41.8(C-5),41.0(C-10),29.3(C- 6),29.0(COCH₂),28.8(COCH₂),27.6(C-4’),25.2(CH₂),24.9(CH₂),20.5(C-5’),15.5(C- 19),13.4(C-18);

HRESIMS m/z925.2316[M+Na]⁺(calcd for C₄₁H₄₆N₂NaO₁₉S,925.2308).

Embodiment 39:

3,12-O- bis- { 4- [4- (2- oxygen -3- benzenesulfonyl -1,2,5- oxadiazoles -4- oxygen)-butoxy] -4- oxo butyryl Base } -21-O- demethyl Brusatol (39)

By b₂6.3g (15.2mmol), EDCI2.96g(15.4mmol), DMAP7g(57.3mmol) it is placed in a reaction flask, Under the conditions of ice-water bath, anhydrous methylene chloride dissolution is added, after stirring 3h, F3.85g(7.61mmol is added), continue in ice water It is stirred to react 2h under bath, then changes to react at room temperature.After 12h, b is added₂1.1g(2.7mmol),EDCI0.55g (2.87mmol), DMAP0.5g(4.1mmol), continue that reaction is stirred at room temperature for 24 hours.After reaction, reaction solution is concentrated, Sephadex LH-20 gel column chromatography separation, with methylene chloride: methanol=1:1(V:V) elute to obtain crude product 5.2g.Crude product is in Standby ODS pillar layer separation is suppressed, with methanol: water=65:35 (V:V) elution obtains white powdery solids 3.3g, is compound 39, yield 33.4%.The physical and chemical parameter of compound 39 is as follows:

¹H NMR(500MHz,CDCl₃)δ8.04(4H,br d,J=7.5Hz,Ar-H),7.75(2H,t,J=7.5Hz,Ar- H),7.63(4H,t,J=7.5Hz,Ar-H),6.08(1H,br s,H-15),5.67(1H,s,H-2’),5.25(1H,s,H- 12),4.83(1H,s,H-7),4.76(1H,d,J=7.5Hz,H_a-20),4.45(4H,m,OCH₂×2),4.19(1H, overlap,H-11),4.19(2H,t,J=6.5Hz,OCH₂),4.14(2H,m,OCH₂),3.79(1H,d,J=7.5Hz,H_b- 20),3.26(1H,br s,H-14),3.06(1H,d,J=13.0Hz,H-5),2.89(1H,d,J=17.5Hz,H_β-1),2.87 (2H,t,J=6.5Hz,COCH₂),2.71(2H,m,COCH₂),2.66(1H,overlap,H_α-6),2.65(1H,overlap, H_α-1),2.53(4H,m,COCH₂CH₂CO),2.15(3H,s,H-5’),2.15(1H,overlap,H-9),1.94(4H,m,CH₂ ×2),1.90(3H,s,H-4’),1.82(4H,m,CH₂×2),1.80(3H,s,H-18),1.78(1H,overlap,H_β-6), 1.44(3H,s,H-19);

¹³C NMR(125MHz,CDCl₃)δ189.3(C-2),172.5(C=O),172.0(C=O),171.4(C-21), 170.5(C=O),170.3(C=O),167.1(C-16),164.7(C-1’),160.9(C-3’),158.9(C=N×2),146.2 (C-3),142.0(C-4),138.0(ArC×2),135.7(ArC×2),129.7(ArC×4),128.5(ArC×4), 114.2(C-2’),110.5(C=N×2),82.3(C-7),80.1(C-13),74.6(C-12),73.7(C-20),71.0 (OCH₂×2),68.8(C-11),65.5(C-15),64.3(OCH₂),64.0(OCH₂),51.2(C-14),49.8(C-1), 45.0(C-8),42.8(C-5),41.9(C-9),40.7(C-10),29.3(C-6),29.0(COCH₂),28.8(COCH₂×2), 28.5(COCH₂),27.6(C-4’),25.1(CH₂×2),24.9(CH₂),24.9(CH₂),20.6(C-5’),15.5(C-19), 14.5(C-18);

HRESIMS m/z1297.2962[M-H]^-(calcd for C57H61N4O27S2,1297.2970).

Embodiment 40:

3-O- { 4- [4- (2- oxygen -3- benzenesulfonyl -1,2,5- oxadiazoles -4- oxygen)-butoxy] -4- oxobutanoyl } - 21-O- demethyl Brusatol (40)

By the operation of embodiment 39, when with Sephadex LH-20 gel chromatography separation 39, in addition to obtaining 38, obtain another One white powdery solids about 520mg is compound 40, yield 7.6%.(embodiment can also obtain minority specioz 38)

The physical and chemical parameter of compound 40 is as follows:

¹H NMR(500MHz,CDCl₃) δ 8.04 (2H, br d, J=7.5Hz, ArH), 7.76 (1H, t, J=7.5Hz, ArH), 7.62(2H,t,J=7.5Hz,ArH),6.30(1H,br s,H-15),5.66(1H,s,H-2’),4.82(1H,s,H-7),4.69 (1H,br s,H_a- 20), 4.44 (2H, t, J=6.0Hz, OCH₂), 4.19 (2H, t, J=6.0Hz, OCH₂),4.19(1H, overlap,H-11),4.11(1H,s,H-12),3.77(1H,br s,Hb-20),3.07(1H,d,J=10.5Hz,H-14), 3.07(1H,overlap,H-5),2.91(1H,overlap,H_β-1),2.88(2H,t,J=6.0Hz,COCH₂),2.71(2H,t, J=6.0Hz,COCH₂),2.49(1H,d,J=14.0Hz,H_α-1),2.34(1H,d,J=12.0Hz,H_α-6),2.19(1H,br s, H-9),2.12(3H,s,H-5’),1.94(2H,m,CH₂),1.88(3H,s,H-4’),1.82(2H,m,CH₂),1.80(1H, overlap,H_β-6),1.80(3H,s,H-18),1.41(3H,s,H-19);

¹³CNMR(125MHz,CDCl₃)δ190.2(C-2),172.7(C-21),172.2(C=O),170.6(C=O), 167.3(C-16),165.0(C-1’),161.0(C-3’),158.9(C=N),147.3(C-3),141.9(C-4),137.9 (ArC),135.7(ArC),129.7(ArC×2),128.5(ArC×2),114.2(C-2’),110.5(C=N),82.3(C- 7),80.9(C-13),75.7(C-12),73.7(C-20),71.0(C-11),70.7(OCH₂),65.8(C-15),64.2 (OCH₂),51.2(C-14),49.7(C-1),45.3(C-8),42.8(C-5),41.2(C-9),40.7(C-10),29.0(C- 6),28.7(COCH₂),28.5(COCH₂),27.6(C-4’),25.2(CH₂),24.9(CH₂),20.7(C-5’),15.5(C- 19),14.6(C-18)；

HRESIMS m/z925.2266[M+Na]⁺(calcd for C₄₁H₄₆N₂NaO₁₉S,925.2308).

Following (the pharmacological evaluation part of anti-inflammatory and immunosuppressive activity the pharmacological experimental method and result of the compounds of this invention Compound numbers correspond to embodiment in compound numbers):

Experimental example 1, compounds towards macrophages NO generate inhibitory activity

Macrophage executes body non-specific immune function, can produce the inflammation such as NO under the induction such as bacteria lipopolysaccharide LPS Sex factor participates in simultaneously inducing inflammatory reaction, has higher water during inflammation immunologic process initial stage and pathological development It is flat.By detecting the mouse macrophage NO production quantity of originally culture, can be used as external preliminary observation and screening have it is certain anti-inflammatory The index and model of active component or compound.

Experimental method:

1), experiment is divided into blank control group 1 (cell liquid is only added), blank control group 2 (cell liquid and sample is added), mould Type group, administration group, positive control drug group.

2), the sodium thioglycollate of C57BL6/J mouse peritoneal injection 4% drains blood by mouse sacrificed by decapitation after 4 days. PBS physiological buffer is injected intraperitoneally, liquid in abdominal cavity is sucked out, centrifugation discards supernatant liquid, and cell is resuspended with RPMI1640, counts thin Cell concentration is adjusted to 1 × 10 by born of the same parents⁶cell·mL^-1。

3), inoculating cell is in 48 porocyte culture plates.37 DEG C, 5%CO₂Adhere-wall culture keeps cell adherent.Incline and cultivates Base is rinsed twice with PBS physiological buffer, removes non-attached cell, it is stand-by that 500 hole μ l/ of RPMI1640 culture medium is added in every hole.

4), culture medium is only added in blank control group, and model group adds LPS (final concentration of 1 μ g/ml), and administration group is removed plus and mould Outside type group equivalent LPS, drug to be measured is additionally incorporated, final concentration of 10^-5M, 37 DEG C of 5%CO₂Continue culture 24 hours.

5), take 100 μ l supernatants and equivalent Griess reagent in mixing on micro oscillator, microplate reader measures 570nm and reads Number, according to NO₂ ^-Standard curve calculates NO₂ ^-Content, later sample absorbance value is converted into NO according to this standard curve₂ ^- Content.

6), during aforesaid operations, positive control drug is also tested using conventional mtt assay and drug to be measured is thin to macrophage The growth inhibition ratio of born of the same parents

Note: with the detection of blank group 2, discovery combound itself can discharge micro NO, but all pierce well below model group LPS The NO that macrophage generates after swashing, avoids the appearance of false negative result.

Experimental result:

Table 1

Note: F is 21-O- demethyl Brusatol

From table 1 it follows that compared with lead compound Brusatol, compound or toxicity drop through structure of modification Low or increased activity, and index is selected to be above lead compound Brusatol.Especially compound 15,38,39,40, not only With significantly inhibitory activity is generated to macrophage NO, also there is the selection for being apparently higher than lead compound Brusatol to refer to Number.

The immunosuppressive activity that experimental example 2, compound are proliferated mouse spleen lymphocyte, convert

Experimental method:

1), experiment is divided into blank control group (only be added cell liquid), Con A group, LPS group, and administration A group is (only plus medicine to be measured Object), it is administered B group (adding Con A and drug to be measured), is administered C group (adding LPS and drug to be measured).2) it is ground after, taking out mice spleen Broken, sieving is rinsed 3 times with RPMI1640 culture solution.

3), with erythrocyte cracked liquid splitting erythrocyte, 1000 turns/min centrifugation 5min.PBS is resuspended after centrifugation, counts thin Born of the same parents.

4), inoculating cell is into 96 porocyte culture plates, and 1 × 10⁶Cells/well.

5) 100 μ l of culture medium is only added in, blank control group, Con A group, LPS group.Administration A, B, C group is then added containing dense Degree is the 100 μ l of RPMI1640 culture solution of 10 μM of test-compounds.It is (final concentration of that ConA is added in Con A group and administration B group after 1h 5 μ g/ml), it is converted for inducing T cell, LPS (final concentration of 10 μ g/ml) is added in LPS group and administration C group, for inducing B thin Dysuria with lower abdominal colic sets 5%CO₂, 37 DEG C of culture 72h.

6), the 4h before terminating culture, is added MTT (final concentration of 5mg/ml) to each group, 100 μ lDMSO is added after 4h, OD value is read at microplate reader 570nm.It is thin to calculate separately splenocyte growth inhibition ratio, B according to relevant control experiment for administration group Dysuria with lower abdominal colic inhibiting rate, T cell convert inhibiting rate.

Experimental result:

Table 2

Note: Dex is positive control drug dexamethasone sodium phosphate

By result in table 2 as it can be seen that at 10 μM of administration concentration, 10,15 pairs of splenocyte growth inhibition ratios of compound are significantly lower than Positive control drug (DEX) and Brusatol (Brusatol), show that toxicity is lower.Meanwhile compound 10,15 is all with higher B cell converts inhibiting rate and T cell converts inhibiting rate, shows that compound can inhibit B cell, T cell conversion has apparent Immunosuppressive activity.

Experimental example 3, part of compounds cause the active influence of otitis to mouse knoting oil

Experimental method:

Swelling model is promoted using mouse ear croton oil, observation test medicine adjusts inhibitory activity to acute inflammation.

Male KM mouse is selected, is randomly divided into Normal group, model group, administration group, every group 10, gastric infusion connects Continuous administration 5 days.Administration group gives test-compound, and model group is only filled with distilled water.Subcutaneous administrations, dosage 10mg/kg, 1 After hour, 2% croton oil 50ul is smeared on mouse right ear two sides, puts to death animal after 4 hours.Left and right auricle is cut, with diameter 8mm's Punch removes auricle, weighing, indicates ear thickness with the difference of L-R auricle weight.Using stomach-filling distilled water group as sky White control group calculates compound to the inhibiting rate of mouse ear swelling.

Experimental result:

Table 3

Compound number	Dosage (mg/kg)	Inhibiting rate (%)
			Brusatol	10mg/kg is subcutaneously × 1	37***
2	10mg/kg is subcutaneously × 1	54***
			8	10mg/kg is subcutaneously × 1	53.2***

Note: compared with model group, * * p ﹤ 0.01；* * p ﹤ 0.001

By result in table 3 as it can be seen that subcutaneous administration 1 time, when concentration 10mg/kg, inhibition of the compound 2,8 pair mouse ear swelling Rate is apparently higher than primer Brusatol.

Experimental example 4, part of compounds cause the inhibitory activity of mouse allergic dermatitis to 2,4-dinitrofluorobenzene (DNFB).

Dinitrofluorobenzene is a kind of haptens, is applied to after skin of abdomen and is combined into comlete antigen with skin protein and makes Sensitization of skin is reinforced once afterwards for 24 hours, is applied to ear again within sensitization the 5th day, causes delayed allergy.Experiment purpose It is to observe inhibiting effect of the compound to mouse allergic dermatitis, its immunosuppressive activity of preliminary assessment.

Experimental method:

ICR mouse is selected, is randomly divided into Normal group, model control group, administration group, every group 10.Test-compound Daily administration.Abdomen depilation, is evenly coated in abdomen sensitization for 1%DNFB, and rear same procedure is reinforced primary for 24 hours, sensitization the 5th day, will 1%DNFB is uniformly applied to mouse right ear and is attacked, and puts to death mouse afterwards for 24 hours, cuts left and right ear, and ear is made with diameter 8mm blunderbuss Piece, weighing indicate swelling with left and right auricle weight difference, calculate swelling inhibiting rate (%)；Mouse thymus and spleen are taken, is weighed, The ratio of organ wet weight and weight indicates organ index, calculates organ index inhibiting rate (%), for evaluating compound to immune function The influence of energy.Organ index inhibiting rate is higher, shows that immunosuppression capability is stronger, but excessively high inhibiting rate also prompts compound pair The toxicity of internal organs is too strong.

Experimental result:

Table 4.

Note: compared with model group, * p ﹤ 0.05；* * p ﹤ 0.001

In table 4 the results show that with 1mg/kg dosage, subcutaneous administrations, successive administration 6 days, compound 10 was to mouse ear Swelling inhibitory activity is significantly stronger than primer Brusatol, while being substantially less than first to the inhibiting rate of thymus index and index and spleen index Object Brusatol is led, systemic immunity is prompted to inhibit reaction smaller, Brusatol is lower than to the toxicity of internal organs.

Table 5

Note: compared with model group, * p ﹤ 0.05；* p ﹤ 0.01；* * p ﹤ 0.001

In table 5 the results show that with 2mg/kg dosage, oral administration gavage administration, successive administration 6 days, compound 2 was swollen to mouse ear Swollen inhibitory activity is better than primer Brusatol, while being substantially less than primer Brusatol prompt to the inhibiting rate of thymus index Brusatol is lower than to the toxicity of thymus gland, but index and spleen index inhibiting rate has no significant difference.

Table 6

Note: compared with model group, * p ﹤ 0.05；* p ﹤ 0.01；* * p ﹤ 0.001

In table 6 the results show that with 2mg/kg dosage, oral administration gavage administration, successive administration 6 days, 34,39 pairs of mouse of compound Ear swelling inhibitory activity is better than primer Brusatol, is substantially less than primer to the inhibiting rate of thymus index and index and spleen index Brusatol prompts systemic immunity to inhibit reaction smaller, is lower than Brusatol to the toxicity of internal organs.

Inhibitory activity of 5. part of compounds of experimental example to OVA inducing mouse inflammation of asthma

Experimental method:

I. group and dosage are arranged:

Blank control group: isometric solvent；

Model group: isometric solvent；

Dexamethasone sodium phosphate (516.41): 1 μm of ol/Kg (0.516mg/Kg)；

Brusatol (520): 4 μm ol/Kg (2.08mg/Kg)；

Compound 2 (916): 4 μm of ol/Kg (3.664mg/Kg).

Compound 10 (900): 4 μm of ol/Kg (3.6mg/Kg)；

Ii. the foundation of model:

Animal is randomly divided into 7 groups, every 20, weighs；It is other each in addition to blank control group gives isometric physiological saline 50 μ L(20 μ g of OVA solution is injected intraperitoneally in group animal) sensitization is carried out with the mixed liquor of 50 μ L of gel aluminum hydroxide；For the first time after sensitization 7th, 14 day, in addition to blank control group gives isometric physiological saline, sensitization same dose was injected intraperitoneally in groups of animals respectively OVA and gel aluminum hydroxide carry out immune strengthening；1 hour after the 14th day immune strengthening, animal is arranged by group and dosage Shown gastric infusion, once a day, continuous 14 days；In the 26th day, anesthetized mice, the OVA solution of tracheal instillation 1.60mg/ml 50 μ L are attacked, once a day, for three days on end；After last attack for 24 hours, animal is put to death, materials carry out Indexs measure.

Iii. Testing index and method:

Bronchoalveolar lavage fluid Arneth's count:

Animal is put to death after being anaesthetized with amobarbital intraperitoneal injection, dissects neck, exposure tracheae, with No. 4 half syringe needles Head promoting the circulation of qi cannula, is pre-chilled normal saline flushing 3 times with 0.8ml, and every all over rinsing 3 times back and forth, (rate of recovery reaches recycling irrigating solution 80%) it, is centrifuged 10min in 4 DEG C of 1500rpm/min, collects supernatant, -20 DEG C freeze, and are used for cytokines measurement；Contained with 0.5ml Have 1%BSA PBS be resuspended cell precipitation, in five classification blood cell count instrument on carry out Arneth's count.

The ELISA measurement of relevant inflammatory factors in bronchoalveolar lavage fluid:

It takes -20 DEG C to freeze irrigating solution, thaws on ice, strictly carried out referring to the ELISA kit specification of the corresponding factor Operation.

The ELISA measurement of IgE level in serum:

Animal socket of the eye venous blood collection, 3000rpm/min are centrifuged 15min, separate serum, are placed in -70 DEG C of low temperature refrigerators and save, survey Timing is strictly operated referring to ELISA kit specification.

The measurement of the proliferation conversion capability of splenic lymphocytes:

After mouse is put to death, 5min is impregnated in 75% ethyl alcohol, in the super quiet sterile taking-up spleen of workbench, shreds, is ground with pintle The serum-free medium of mill, pre-cooling rinses, and excessively unicellular mesh screen prepares spleen single cell suspension, adjusts to suitable cell density, connect Kind is in 96 orifice plates, 5x10⁵/ hole, every group sets 4 multiple holes；In addition to blank control group gives isometric solvent, each group is separately added into 10 μ g/ml or ConA final concentration of LPS final concentration, 5 μ g/ml, in 37 DEG C, 5%CO₂Under the conditions of cultivate 48h；Terminate preceding 4h in culture, WST-8 solution 20ul is added in every hole, continues after cultivating 4h, and oscillation mixes, and measures absorbance (A) at microplate reader 450nm, calculates Lymphocytic proliferation rate (%).

Pathologic state colony inspection:

Zootomy chest cuts open, and the middle lobe of right lung is taken to organize, and after 10% formalin is fixed, carries out paraffin embedding, slice, HE dye Color makes Histopathology and changes inspection.

Experimental result

I. to the influence of the weight of animals variation

As shown in Figure 1, the weight of animals growth is significantly inhibited after Brusatol and positive drug DEX administration compared with model group, And influence unknown significance difference of other each compounds to body weight increase.

Ii. to the influence of asthmatic mouse pathological change

It, can after Brusatol, compound 2 and positive control drug DEX administration compared with model group as shown in Fig. 2 result The significant pathologics such as inflammatory cell infiltration, alveolar structure destruction that mitigate change, and prompt that there is significant anti-inflammation of asthma to damage Wound effect；And compound 10 changes then unknown significance to pathologic and improves.Iii. to the influence of mice serum IgE secretion

As shown in Fig. 3 result, compared with model group, heavy breathing can be significantly inhibited after compound 2 and positive control drug DEX administration The serum IgE level of asthma mouse increases, and prompts have significant anti-asthma effect.

Iv. to the influence of mice spleen lymphocytic hyperplasia situation

As shown in Fig. 4 A result, compared with model group, it can be significantly inhibited after compound 10 and positive control drug DEX administration The cellular immunity of LPS induction；As shown in Fig. 4 B result, compared with model group, Brusatol, compound 2, compound 10 and The humoral immunity that ConA induction can be significantly inhibited after DEX administration prompts to have the function of mitigating mouse asthma antibody tormation.

V. to the influence of bronchoalveolar lavage fluid Lymphocyte subset

It, can after Brusatol, compound 2 and positive control drug DEX administration compared with model group as shown in Fig. 5 result Substantially reduce the total white blood cells and neutrophil leucocyte number in irrigating solution；And compound 2 can substantially reduce it is thermophilic in irrigating solution Eosinophil；As a result prompt compound 2 can significantly mitigate mouse asthmatic inflammation.

Vi. to the influence of mouse asthma bronchoalveolar lavage fluid inflammatory factor secretion situation

It, can after Brusatol, compound 2 and positive control drug DEX administration compared with model group as shown in Fig. 6 result The secretion of inflammatory factor IL-1 β, IL-6 and TNF-α is significantly inhibited, and Brusatol remarkably promotes point of anti-inflammatory factors IL-10 It secretes, compound 2 has the trend for promoting IL-10 secretion, but there was no significant difference, and Brusatol and compound 2 is as a result prompted to have There is anti-inflammation of asthma.

Inhibitory activity of 6. part of compounds of experimental example to murine chronic obstructive pneumonia

Experimental method:

I. group and dosage are arranged:

Blank control group: isometric solvent；

Model group: isometric solvent；

Dexamethasone sodium phosphate (516.41): 1 μm of ol/Kg；

Brusatol (520): 2 μm ol/kg；

Compound 2 (916): 2 μm of ol/kg.

Compound 39 (1298): 2 μm of ol/kg；

Ii. the foundation of model:

Animal is randomly divided into 7 groups, every group 20, weighs；It is other in addition to blank control group gives isometric physiological saline Each group gives the drug dose as shown in group and dosage setting, and gastric infusion, (dexamethasone administration time section is 26- 1 time a day 35 days, other time gave isometric physiological saline)；In the 1st, 14 day administration 1 hour after, after Animal Anesthesia tracheae instill 30 μ/ L contains the normal saline solution of 20 μ g LPS, and blank control group gives isometric physiological saline；Respectively at 2-13 days, 15- 1 hour after administration in 35 days, mouse, which is placed in smoking apparatus, carries out fumigation, every time 8 mouse, every time half root cigarette, and 5min/ times, often It is 2 times；In last dose for 24 hours after, put to death animal, materials carry out Indexs measure.

Iii. Testing index and method:

Bronchoalveolar lavage fluid Arneth's count:

Experimental result

I. to the influence of bronchoalveolar lavage fluid Lymphocyte subset

As shown in Fig. 7 result, compared with model group, after Brusatol, compound 2,39 and positive control drug DEX administration Total white blood cells, neutrophil leucocyte number and the eosinophil in irrigating solution can be substantially reduced, shows as significantly resisting small Mouse COPD inflammatory effect.

Ii. to the influence of mouse bronchoalveolar lavage fluid inflammatory factor secretion situation

As shown in Fig. 8 result, compared with model group, after Brusatol, compound 2,39 and positive control drug DEX administration The secretion of inflammatory factor IL-1 β in bronchoalveolar lavage fluid, IL-6, TNF-α and IL-17 can be significantly inhibited, prompts to have significant anti- The pulmonary inflammatory effect of COPD.

Claims

1. such as general formula (Ia) compound represented:

Wherein, R₃Selected from OH, OCH₃, L₁Selected from-R₆-X₁-Y₁, wherein Y₁It is connect with O on the parent nucleus of Fourth Ring, R₆Selected from C_2-6Alkyl, C_2-4OC_2-4Alkyl, C_2-6Alkynyl ,-o-Ph- (CH₂)_n, wherein n=0,1,2,3,4 ,-m-Ph- (CH₂)_n, wherein n=0,1,2, 3,4 ,-p-Ph- (CH₂)_n, wherein n=0,1,2,3,4；X₁Selected from O, Y₁Selected from succinyl base.

2. such as general formula (Ib) compound represented:

Wherein, R₃Selected from OH, OCH₃, L₂Selected from R₇、-R₇-X₂-Y₂-、Y₂, wherein Y₂It is connect with O on the parent nucleus of Fourth Ring, R₇Selected from-o- Ph-(CH₂)_n, wherein n=0,1,2,3,4 ,-m-Ph- (CH₂)_n, wherein n=0,1,2,3,4 ,-p-Ph- (CH₂)_n, wherein n =0,1,2,3,4；X₂Selected from O, Y₂Selected from succinyl base.

3. such as general formula (Ic) compound represented:

Wherein, L₁Selected from-Y₁-X₁-R₆, wherein Y₁It is connect with O on the parent nucleus of Fourth Ring, R₆Selected from C_2-6Alkyl, C_2-4OC_2-4Alkyl, C_2-6Alkynyl；X₁Selected from O, Y₁Selected from succinyl base.

4. such as general formula (Id) compound represented:

Wherein, L₂Selected from-Y₂-X₂-R₇, wherein Y₂It is connect with O on the parent nucleus of Fourth Ring, R₇Selected from-(CH₂)_n- o-Ph-, wherein n=0, 1,2,3,4 ,-(CH₂)_n- m-Ph-, wherein n=0,1,2,3,4 ,-(CH₂)_n- p-Ph-, wherein n=0,1,2,3,4, wherein benzene The connected CH of base₂And X₂It is connected；X₂Selected from O, Y₂Selected from succinyl base.

5. such as general formula (Ie) compound represented:

Wherein, R₉Selected from C_2-6Alkyl, C_2-4OC_2-4Alkyl, C_2-6Alkynyl.

6. such as general formula (If) compound represented:

Wherein, L₃Selected from-O-R₁₀- O-,

Wherein, R₁₀Selected from-(CH₂)_n- o-Ph-, wherein n=0,1,2,3,4 ,-(CH₂)_n- m-Ph-, wherein n=0,1,2,3,4 ,- (CH₂)_n- p-Ph-, wherein n=0,1,2,3,4, wherein the connected CH of phenyl₂It is connected by O with Fourth Ring parent nucleus.

7. such as general formula (Ig) compound represented:

Wherein, R₁Selected from H,L₁Selected from-R₆-X₁-Y₁, wherein Y₁It is connected with O on the parent nucleus of Fourth Ring, R₆It is selected from C_2-6Alkyl, C_2-4OC_2-4Alkyl, C_2-6Alkynyl；X₁Selected from O, Y₁Selected from succinyl base.

8. compound is selected from:

Compound R₆ X₁ Y₁ 1 (CH₂)₃ O CO(CH₂)₂CO 2 (CH₂)₄ O CO(CH₂)₂CO 3 (CH₂)₂CH(CH₃) O CO(CH₂)₂CO 4 (CH₂)₅ O CO(CH₂)₂CO 5 (CH₂)₂O(CH₂)₂ O CO(CH₂)₂CO 6 CH₂C≡CCH₂ O CO(CH₂)₂CO 7 p-PhCH₂ O CO(CH₂)₂CO 8 m-PhCH₂, O CO(CH₂)₂CO

Compound R₇ X₂ Y₂ 10 p-Ph-CH₂ O CO(CH₂)₂CO 11 m-Ph-CH₂ O CO(CH₂)₂CO 12 o-Ph-CH₂ O CO(CH₂)₂CO 13 - O CO(CH₂)₂CO 15 p-Ph-CH₂ - -

Compound R₇ X₂ Y₂ 25 CH₂-p-Ph O CO(CH₂)₂CO 26 CH₂-m-Ph O CO(CH₂)₂CO 27 CH₂-o-Ph O CO(CH₂)₂CO

Compound R₉ 30 CH₂CH₂CH₂ 31 CH₂CH₂CH₂CH₂

。

9. a kind of pharmaceutical composition, by the described in any item compounds of claim 1-8 of effective dose or its can medically connect Salt and pharmaceutically acceptable carrier or the auxiliary material composition received.

10. pharmaceutical composition according to claim 9, which is characterized in that the pharmaceutical composition is selected from tablet, capsule, ball Agent, injection.

11. pharmaceutical composition according to claim 9, which is characterized in that the pharmaceutical composition is selected from sustained release preparation, controlled release Preparation and particulate delivery system.

12. the described in any item compounds of claim 1-8 or its medically acceptable salt in preparation inflammation and/or are immunized disorderly Application in random disease medicament, wherein inflammation and immunologic derangement disease include: psoriasis, eczema, dermatitis, infectious pneumonia, reason The property changed pneumonia and allergy pneumonia, chronic obstructive pulmonary disease, asthma.