CN103622954A

CN103622954A - Applications of sesquiterpene lactone compound and derivative of sesquiterpene lactone compound in treatment of diabetes

Info

Publication number: CN103622954A
Application number: CN201210300440.XA
Authority: CN
Inventors: 龙海波
Original assignee: Individual
Current assignee: Individual
Priority date: 2012-08-22
Filing date: 2012-08-22
Publication date: 2014-03-12

Abstract

The invention relates to applications of a sesquiterpene lactone compound and a derivative of the sesquiterpene lactone compound in treatment of diabetes, belongs to the technical field of medicine, and specifically relates to applications of a compound represented by formula (I) in prevention, therapy or adjuvant therapy of diabetes and diabetic chronic complications, and in preparation of medicines used for prevention, therapy or adjuvant therapy of the diabetes and diabetic chronic complications.

Description

The application in diabetes of sesquiterpene lactones compounds and derivant thereof

Technical field

The invention belongs to technical field of pharmaceuticals, specifically, relate to the application in prevention, treatment or adjuvant therapy of diabetes, chronic complicating diseases of diabetes of sesquiterpene lactones compounds and derivant thereof, and take it as the application in the medicine of preparation prevention, treatment or adjuvant therapy of diabetes, chronic complicating diseases of diabetes of effective ingredient or pharmaceutical composition.

Background technology

Along with the change of growth in the living standard, the aging of population, life style, the prevalence of diabetes (diabetes mellitus, DM) increases sharply, and has become developed country's the third-largest noninfectious after cardiovascular diseases and tumor.China DM sickness rate is also rising year by year, according to statistics, and calendar year 2001 whole nation DM patient sum approximately 3,000 ten thousand; Within 2008, the Chinese DM prevalence of discovery is investigated up to 9.7% by diabetes mellitus in China association and organization, estimates national DM patient approximately 9,240 ten thousand.The WHO statistics of 2011 shows, the DM patient in the whole world has reached 3.66 hundred million.DM becomes the worldwide public health problem of serious harm human health.

Discovery and extensive use along with insulin and oral antidiabetic drug, the acute complications of DM significantly declines as the death toll that ketoacidosis, Hyperosmolar hyperglycemic state cause, various chronic complicating diseases become the principal element that affects DM patients ' life quality and prognosis as diabetes cardiovascular and cerebrovascular disease, diabetic nephropathy (diabetic nephropathy, DN), diabetic peripheral neuropathy, diabetic renal papillary necrosis, diabetic foot.Diabetes cardiovascular and cerebrovascular disease is the lethal one of the main reasons disabling of DM patient.It is Clinical symptoms that DN be take albuminuria and progressivity renal insufficiency, is one of chronic complicating diseases that DM patient is common, the most serious, is also the main cause of death of end stagerenaldisease (end stage renal disease, ESRD) in global range.According to statistics, the 1 type DM patient up to 40% and about 20%～50% 2 type DM patients finally will there will be kidney damage, and the 5 years survival rates of ESRD patient due to DN are lower than 20%.Diabetic renal papillary necrosis has become the first cause of adult's blinding in developed country, the danger of China DM patient blinding is higher 25 times than non-DM patient.Diabetic foot not only causes DM patient's quality of life to decline, and causes huge economy and burden on society, and about 5%～10% patient needs row amputation, and in atraumatic amputation, DM patient accounts for more than 50%.Therefore the various chronic complicating diseases that, how effectively to prevent, treat DM have become the common problem of paying close attention to of medical circle.

At present the treatment of DM and various chronic complicating diseases thereof is mainly comprised: diet and exercise therapy, control hyperglycemia (oral antidiabetic thing, insulinize), hypertension and blood fat disorder, blocking-up renin-angiotensin system (RAS), strictly controls urine protein and Chinese medicine etc.Yet, even strict blood glucose, blood pressure and blood fat are controlled, also only can partly play the effect that the various DM chronic complicating diseases of prevention occur.Although RAS blocker angiotensin converting enzyme inhibitor (ACEI), angiotensin ii receptor antagonist (ARB) are to be acknowledged as the first-line drug with direct Renoprotective Effect, while using the various DM chronic complicating diseases such as ACEI and ARB treatment DN, do not obtain gratifying effect.Other medicine, as Thiazolidinediones, PKC-beta inhibitor, endothelin antagonist etc. also all can reduce DM patient's urine protein, delay the development of DN, but these medicines only limits to laboratory research or small sample clinical research.Chinese traditional treatment DM and various chronic complicating diseases thereof also have certain curative effect, but its preparation process, quality standard, Clinical design and mechanism research still exist many problems.Therefore, although existing multi-medicament may slow down generation and the development of the various DM chronic complicating diseases such as DN at present, but the equal limited of clinical efficacy, the new drug tool of actively researching and developing treatment DM evident in efficacy, toxic and side effects is little, quality controllable and easy to use and various chronic complicating diseases thereof is of great significance.

Have no at present the report in prevention, treatment or adjuvant therapy of diabetes, chronic complicating diseases of diabetes and the application in the medicine of preparation prevention, treatment or adjuvant therapy of diabetes, chronic complicating diseases of diabetes thereof about formula (I) compound or its pharmaceutical composition.

Summary of the invention

The invention provides formula (I) compound at preparation treatment diabetes, chronic complicating diseases of diabetes or prepare as the purposes in adjuvant therapy of diabetes, chronic complicating diseases of diabetes medicine.

R wherein ₁, R ₂the two keys of common formation or R ₁for hydrogen or deuterium, R ₂for

and with the pharmaceutically acceptable salt that mineral acid or organic acid form, comprise and R ₅the quaternary ammonium salt of Z-shaped one-tenth, wherein R ₃and R ₄can be identical or different, be respectively hydrogen, alkyl, cycloalkyl, hydroxyl substituted alkyl, thiazolinyl, alkynyl, aryl, alkylaryl, aryl alkyl, aryl alkenyl, aromatic yl polysulfide yl, heterocyclic radical, trifluoromethyl, polyfluoro substituted alkyl, itrile group, itrile group methyl, acyl group, carbamoyl, sulfonyl, sulfoamido or aryloxyalkyl group, R ₃, R ₄form circulus with N atom, ring is preferably 3-9 ring, in circulus, can be replaced by one or more substituent groups, comprise hydrogen, alkyl, cycloalkyl, thiazolinyl, alkynyl, aryl, alkylaryl, aryl alkyl, aryl alkenyl, aromatic yl polysulfide yl or heterocyclic radical, Z is fluorine, chlorine, bromine, iodine, p-methyl benzenesulfonic acid ester group, methanesulfonic acid ester group, benzenesulfonic acid ester group or trifluoromethane sulfonic acid ester group, R ₅for alkyl, cycloalkyl, hydroxyl substituted alkyl, thiazolinyl, alkynyl, aryl, heterocyclic radical, aryl substituted alkyl, aryl alkenyl, aromatic yl polysulfide yl, cyano group substituent methyl, alkoxyl substituted alkyl or fragrant oxygen substituted alkyl, mineral acid or organic acid are Fluohydric acid., hydrochloric acid, hydrobromic acid, hydroiodic acid, sulphuric acid, nitric acid, phosphoric acid, carbonic acid, boric acid, Monohydrated selenium dioxide, phosphomolybdic acid, phosphorous acid, sulfurous acid, citric acid, maleic acid, D-malic acid, L MALIC ACID, DL-malic acid, Pfansteihl, D-ALPHA-Hydroxypropionic acid, DL-LACTIC ACID, oxalic acid, methanesulfonic acid, valeric acid, oleic acid, lauric acid, p-methyl benzenesulfonic acid, 1-naphthalene sulfonic aicd, 2-LOMAR PWA EINECS 246-676-2, phthalandione, tartaric acid, malonic acid, succinic acid, fumaric acid, glycolic, thiolic acid, glycine, sarcosine, sulfonic acid, nicotinic acid, picolinic acid, .gamma.-pyridinecarboxylic acid, dichloroacetic acid, benzoic acid or substituted benzoic acid.R ₂or be

wherein X=oxygen or sulfur, R ₆for hydrogen, alkyl, cycloalkyl, hydroxyl substituted alkyl, thiazolinyl, alkynyl, aryl, alkylaryl, aryl alkyl, aryl alkenyl, aromatic yl polysulfide yl, heterocyclic radical, trifluoromethyl, polyfluoro substituted alkyl, itrile group, itrile group methyl, acyl group, carbamoyl, sulfonyl, sulfoamido or aryloxyalkyl group.

R ₇with R ₈between---when-key does not exist, R ₇with R ₈the two keys of common formation, or R ₇for methyl, R ₈for hydroxyl or OCOR ₉, R wherein ₉for alkyl, substituted alkyl, rare base, replace rare base, aryl, substituted aryl, heterocyclic radical, substituted heterocyclic radical.

R ₇with R ₈between---when-key is singly-bound, R ₇=R ₈=methylene.

R ₁₀for hydrogen, or R ₁₀with R ₈become singly-bound.

R ₁₁for hydrogen, or R ₁₁with R ₁₃become singly-bound or epoxy bond.

R ₁₂with R ₁₃between---when-key does not exist, R ₁₂with R ₁₃the two keys of common formation, or R ₁₂for hydroxyl or OR ₁₄, R wherein ₁₄for alkyl, substituted alkyl, rare base, replace rare base, aryl, substituted aryl, heterocyclic radical, substituted heterocyclic radical, R ₁₃for methyl.

R ₁₂with R ₁₃between---during-key mapping singly-bound, R ₁₂=R ₁₃=methylene.

Structural formula (I) is preferably:

The purposes of above-claimed cpd in prevention, treatment or adjuvant therapy of diabetes, chronic complicating diseases of diabetes medicine.

The purposes of above-claimed cpd in preparation prevention, treatment or adjuvant therapy of diabetes, chronic complicating diseases of diabetes medicine.

The present invention also provides a kind of pharmaceutical composition, contains the compound as the compound of the arbitrary claim of at least one claim 1 to 2 of active component and pharmaceutically acceptable carrier or other preventions, treatment or adjuvant therapy of diabetes, chronic complicating diseases of diabetes.

When the compounds of this invention is used as medicine, can directly use, or use with the form of pharmaceutical composition.This pharmaceutical composition contains 0.1%～99%, be preferably 0.5%～90% the compounds of this invention, all the other are acceptable on materia medica, pharmaceutically suitable carrier of and inertia nontoxic to humans and animals and/or excipient or with the medication combined medication of other preventions, treatment or adjuvant therapy of diabetes, chronic complicating diseases of diabetes.Compositions of the present invention can be prepared into injection, Tablet and Capsula etc.

Described pharmaceutical carrier or excipient are one or more solids, semisolid and liquid diluent, filler and pharmaceutical preparation adjuvant.Pharmaceutical composition of the present invention is used with the form of per weight dose.Medicine of the present invention can be through injection and oral two kinds of form administrations, and injection is as intravenous injection and intramuscular injection, and oral dosage form can be Tablet and Capsula agent.

The specific embodiment

In order to understand the present invention, with embodiment, further illustrate the present invention below, but be not meant to, limit the scope of the invention.

Embodiment 1: the preparation method of compound 1-50

The preparation of compound 1:

Parthenolide (50mg, 0.2mmol) is dissolved in 2.5mL dichloromethane, adds p-methyl benzenesulfonic acid (5mg, 0.026mmol).Reaction system is positioned over room temperature, and stirring is spent the night.Forward reactant liquor to NaHCO ₃(10mL) in saturated solution, collect organic facies, a small amount of dichloromethane extraction for water, is combined together organic facies, uses Na ₂sO ₄dry, filter, then use Rotary Evaporators distilling under reduced pressure organic solvent, silicagel column purification, obtains compound 1 (45mg, yield 90%). ¹H NMR(CDCl ₃，400MHz)δ6.20(d，J＝3.2Hz，1H)5.49(d，J＝3.2Hz，1H)3.81(t，J＝10.4Hz，1H)，2.70(d，J＝10.4Hz，1H)，2.65-2.62(m，2H)，2.40-2.34(m，1H)，2.07-2.26(m，4H)，1.73-1.86(m，2H)，1.68(s，3H)，1.36-1.28(m，4H)； ¹³C NMR(CDCl ₃，100MHz)δ169.8，138.7，131.7，130.8，119.5，84.1，80.2，58.5，49.5，38.2，34.8，30.0，25.7，23.9，23.6。

The synthetic logical method of compound 2-20:

Under nitrogen protection; under ice-water bath; acyl chlorides (RCl) is added drop-wise to compound 1 (24.8mg; 0.1mmol) and DMAP (1.25mg; 0.01mmol) and in the mixed liquor of triethylamine (0.12mL, 1.2mmol), drip and finish recession deicing and bathe; stirring at normal temperature, until the reaction of TLC detecting reactant is complete.Reactant mixture is poured in frozen water, with ethyl acetate (5mL * 3) extraction, organic layer agriculture time citric acid solution (20mL), saturated NaHCO ₃(10mL), saturated aqueous common salt (10mL) washing, organic facies anhydrous sodium sulfate drying, concentrating under reduced pressure obtains crude product, and silica gel column chromatography is separated, obtains sterling.

Compound 2, productive rate is 62.8%. ¹H NMR(400MHz，CDCl ₃)δ6.13(1H，d，J＝3.1Hz)，5.40(1H，d，J＝2.8Hz)，3.72(1H，t，J＝10.2Hz)，3.08(1H，d，J＝10.1Hz)，2.65～2.59(1H，m)，2.41～2.35(2H，m)，2.21～2.13(4H，m)，2.04～2.00(1H，m)，1.97(3H，s)，1.91～1.83(1H，m)，1.65(3H，s)，1.48(3H，s)； ¹³C NMR(100MHz，CDCl ₃)δ169.6，169.3，138.4，130.6，129.4，117.8，87.7，82.0，55.6，49.1，35.4，33.9，29.4，24.9，23.2，21.5，17.8。

Compound 3, productive rate is 70.0%, ¹h NMR (400MHz, CDCl3) δ 6.20 (1H, d, J=3.1Hz), 5.47 (1H, d, J=2.8Hz), 3.79 (1H, t, J=10.1Hz), 3.13 (1H, d, J=10.2Hz), 2.71～2.66 (1H, m), 2.49～2.42 (2H, m), 2.38～2.30 (2H, m), 2.28～2.26 (4H, m), 2.11～2.08 (1H, dd, J=13.8,1.8Hz), 1.97～1.89 (1H, m), 1.72 (3H, s), 1.57 (6H, d, J=9.0Hz); ¹³c NMR (100MHz, CDCl3) δ 173.8,170.2,139.5,131.5,130.4,118.6,88.4,83.0,56.6,50.1,36.5,34.9,30.4,28.7,25.9,24.1,18.8,9.1.

Compound 4, productive rate is 30.0%, ¹h NMR (400MHz, CDCl3) δ 6.22 (1H, d, J=2.7Hz), 5.49 (1H, d, J=2.1Hz), 3.81 (1H, t, J=10.1Hz), 3.16 (1H, d, J=10.3Hz), 2.52～2.44 (2H, m), 2.36～2.23 (6H, m), 2.13～2.10 (1H, m), 1.99～1.91 (1H, m), 1.74 (3H, s), 1.70～1.68 (1H, m), 1.65 (3H, s), 1.57 (2H, s), 0.98 (3H, t, J=7.3Hz); ¹³cNMR (100MHz, CDCl3) δ 173.2,170.3,139.5,131.6,130.5,118.7,88.5,83.0,56.8,50.2,37.4,36.6,35.0,30.5,25.9,24.2,18.8,18.5,13.6.

Compound 5, productive rate is 37.6%, ¹h NMR (400MHz, CDCl3) δ 6.19 (1H, d, J=3.1Hz), 5.47 (1H, d, J=2.9Hz), 3.78 (1H, t, J=10.1Hz), 3.13 (1H, d, J=10.0Hz), 2.7～2.66 (1H, m), 2.49～2.42 (2H, m), 2.37～2.31 (1H, m), 2.30～2.26 (4H, m), 2.12～2.08 (1H, dd, J=13.7,2.2Hz), 1.97～1.88 (1H, m), 1.75 (3H, s), 1.64～1.56 (2H, m), 1.55 (3H, s), 1.40～1.31 (3H, m), 0.92 (3H, t, J=7.3Hz); ¹³c NMR (100MHz, CDCl3) δ 173.4,170.2,139.5,131.6,130.4,118.7,88.5,83.0,56.8,50.2,36.5,35.2,34.9,30.5,27.1,25.9,24.1,22.2,18.8,13.8.

Compound 6, productive rate is 26.8%, ¹h NMR (400MHz, CDCl3) δ 6.21 (1H, d, J=3.0Hz), 5.48 (1H, d, J=2.8Hz), 3.81 (1H, t, J=0.1Hz), 3.15 (1H, d, J=10.3Hz), 2.74～2.68 (1H, m), 2.57～2.44 (3H, m), 2.30～2.29 (3H, m), 2.14～2.10 (1H, dd, J=13.7,2.1Hz), 1.98～1.90 (1H, m), 1.74 (3H, s), 1.66 (1H, s), 1.56 (3H, s), 1.21～1.17 (6H, m); ¹³cNMR (100MHz, CDCl3) δ 176.6,170.2,139.6,131.5,130.4,118.6,88.2,83.0,56.8,50.1,36.5,35.0,34.7,30.5,26.0,24.2,19.0,18.9,18.7.

Compound 7, productive rate is 47.8%, ¹hNMR (400MHz, CDCl3) δ 6.19 (1H, d, J=3.2Hz), 5.46 (1H, d, J=.9Hz), 3.78 (1H, t, J=10.1Hz), 3.13 (1H, d, J=10.1Hz), 2.71～2.66 (1H, m), 2.50～2.42 (2H, m), 2.28～2.26 (3H, m), 2.20～2.07 (4H, m), 1.97～1.89 (1H, m), 1.72～1.69 (4H, m), 1.56 (3H, s), 0.97 (6H, d, J=5.9Hz); ¹³c NMR (100MHz, CDCl3) δ 172.7,170.2,139.5,131.6,130.5,118.7,88.5,83.0,56.8,50.2,44.6,36.6,35.0,30.5,25.9,25.8,24.2,22.4,22.3,18.8.

Compound 8, productive rate is 13.9%, ¹h NMR (400MHz, CDCl3) δ 6.20 (1H, d, J=2.9Hz), 5.47 (1H, d, J=2.4), 4.07～3.95 (2H, q, J=16.4Hz), 3.79 (1H, t, J=10.1Hz), 3.47 (3H, s), 3.19 (1H, d, J=10.1Hz), 2.71～2.66 (1H, m), 2.51～2.44 (2H, m), 2.27 (3H, s), 2.11～2.08 (1H, dd, J=12.5,0.7Hz), 2.04～1.95 (1H, m), 1.72 (3H, s) 1.63 (1H, s), 1.58 (3H, s); ¹³c NMR (100MHz, CDCl3) δ 170.2,169.7,139.3,131.9,130.0,118.9,89.6,82.9,70.3,59.3,56.4,50.0,36.4,35.0,30.4,25.9,24.2,18.9.

Compound 9, productive rate is 56.2%, ¹hNMR (400MHz, CDCl3) δ 6.23 (1H, d, J=3.3Hz), 5.50 (1H, d, J=3.1Hz), 4.1～4.05 (2H, m), 3.81 (1H, t, J=10.1Hz), 3.20 (1H, d, J=10.0Hz), 2.74～2.68 (1H, m), 2.54～2.47 (2H, m), 2.30～2.29 (3H, m), 2.15～2.11 (1H, dd, J=13.8,2.3Hz), 2.07～1.97 (1H, m), 1.75 (3H, s), 1.62 (4H, s); ¹³cNMR (100MHz, CDCl3) δ 170.1,166.4,139.2,132.1,129.8,119.0,90.8,82.8,56.4,50.1,42.0,36.3,35.0,30.3,25.9,24.2,18.8.

Compound 10, productive rate is 20.7%, ¹h NMR (400MHz, CDCl3) δ 6.23 (1H, d, J=3.3Hz), 5.96 (1H, s), 5.51 (1H, d, J=3.0Hz), 3.81 (1H, t, J=10.1Hz), 3.21 (1H, d, J=10.1Hz), 2.76～2.70 (1H, m), 2.56～2.48 (2H, m), 2.30 (3H, s), 2.15～2.11 (1H, dd, J=13.8,2.3Hz), 2.07～1.99 (1H, m), 1.75 (3H, s), 1.66 (4H, s); ¹³c NMR (100MHz, CDCl3) δ 169.9,163.4,139.2,132.4,129.5,119.0,92.3,82.5,65.2,56.5,50.1,36.0,34.9,30.2,25.9,24.1,18.6.

Compound 11, productive rate is 46.5%, ¹h NMR (400MHz, CDCl3) δ 6.22 (1H, d, J=3.3Hz), 5.49 (1H, d, J=3.0Hz), 3.86 (2H, s), 3.80 (1H, t, J=10.1Hz), 3.18 (1H, d, J=9.9Hz), 2.74～2.68 (1H, m), 2.53～2.46 (2H, m), 2.30～2.29 (3H, m), 2.14～2.10 (1H, dd, J=13.8,2.3Hz), 2.06～1.94 (1H, m), 1.74 (3H, s), 1.71 (1H, s), 1.60 (3H, s); ¹³c NMR (100MHz, CDCl3) δ 170.1,166.3,139.3,132.1,129.9,118.9,90.8,82.8,56.5,50.1,36.2,34.9,30.3,27.7,25.9,24.2,18.7.

Compound 12, productive rate is 25.8%, ¹h NMR (400MHz, CDCl3) δ 6.22 (1H, d, J=3.2Hz), 5.49 (1H, d, J=21.8Hz), 3.81 (1H, t, J=10.2Hz), 3.47 (2H, t, J=6.5Hz), 3.15 (1H, d, J=10.0Hz), 2.73～2.68 (1H, m), 2.51～2.44 (2H, m), 2.40～2.32 (2H, m), 2.30 (2H, d, J=6.4Hz), 2.14.10 (1H, dd, J=13.7,1.9Hz), 1.99～1.91 (3H, m), 1.83～1.78 (2H, m), 1.74 (3H, s), 1.60 (3H, s), 1.57 (2H, s); ¹³c NMR (100MHz, CDCl3) δ 172.5,170.2,139.4,131.7,130.2,118.8,88.75,83.0,56.7,50.1,36.5,35.0,34.5,33.5,32.0,30.5,25.9,24.2,23.6,18.8.

Compound 13, productive rate is 47.6%, ¹h NMR (400MHz, CDCl3) δ 6.22 (1H, d, J=3.3Hz), 5.49 (1H, d, J=3.0Hz), 3.81 (1H, t, J=10.2Hz), 3.37～3.33 (2H, m), 3.16 (1H, d, J=10.1Hz), 2.74～2.68 (1H, m), 2.51～2.45 (2H, m), 2.41～2.33 (2H, m), 2.31～2.29 (3H, m), 2.14～2.10 (1H, dd, J=13.7,2.2Hz), 2.00～1.92 (1H, m), 1.74 (3H, s), 1.73～1.66 (4H, m), 1.62 (1H, s), 1.57 (3H, s); ¹³c NMR (100MHz, CDCl3) δ 171.5,169.2,138.4,130.7,129.2,117,7,87.7,82.0,55.7,50.1,49.1,35.5,34.0,33.9,29.4,27.2,24.9,23.1,21.2,17.8.

Compound 14, productive rate is 78.2%, ¹h NMR (400MHz, CDCl3) δ 6.47～6.37 (1H, dd, J=17.3,1.3Hz), 6.21 (1H, d, J=3.3Hz), 6.13～6.06 (1H, m), 5.80～5.77 (1H, dd, J=10.3,1.3Hz), 5.48 (1H, d, J=3.1Hz), 3.82 (1H, t, J=0.1Hz), 3.15 (1H, d, J=10.1Hz), 2.73～2.67 (1H, m), 2.58～2.44 (2H, m), 2.29～2.27 (3H, m), 2.12～2.08 (1H, dd, J=13.7,2.3Hz), 2.00～1.92 (1H, m), 1.73 (3H, s), 1.59 (4H, s); ¹³c NMR (100MHz, CDCl3) δ 170.3,165.5,139.4,131.7,130.2,130.1,130.0,118.8,88.8,83.0,57.1,50.1,36.5,35.0,30.5,25.9,24.2,18.6.

Compound 15, productive rate is 13.5%, ¹h NMR (400MHz, CDCl3) δ 6.22 (1H, d, J=3.3Hz), 5.49 (1H, d, J=3.0Hz), 5.20 (1H, d, J=5.0Hz), 5.16 (1H, s), 3.81 (1H, t, J=10.1Hz), 3.16 (1H, d, J=8.8Hz), 3.12～3.09 (2H, m), 2.74～2.68 (1H, m), 2.51～2.44 (2H, m), 2.30～2.28 (4H, m), 2.14～2.10 (1H, dd, J=13.7, 2.1Hz), 2.00～1.92 (1H, m), 1.88～1.86 (1H, dd, J=6.9, 1.3Hz), 1.74 (3H, s), 1.59 (1H, s), 1.58 (3H, s), ¹³c NMR (100MHz, CDCl3) δ 171.0,170.2,139.5,131.7,130.7,130.3,118.7,118.2,89.0,83.0,56.7,50.1,40.2,36.5,35.0,30.5,25.9,24.2,18.8.

Compound 16, productive rate is 26.6%, ¹h NMR (400MHz, CDCl3) δ 6.20 (1H, d, J=3.2Hz), 5.68 (1H, s), 5.47 (1H, d, J=2.8Hz), 3.81 (1H, t, J=10.2Hz), 3.15 (1H, d, J=10.0Hz), 2.73～2.67 (1H, m), 2.57～2.43 (2H, m), 2.28～2.27 (3H, m), 2.15 (3H, s), 2.12～2.08 (1H, dd, J=13.9,2.1Hz), 2.00～1.92 (2H, m), 1.87 (3H, s), 1.73 (3H, s), 1.59 (3H, s); ¹³c NMR (100MHz, CDCl3) δ 170.3,166.2,155.4,139.5,131.5,130.6,118.7,117.7,88.2,83.1,57.0,50.3,36.8,34.9,30.6,27.4,25.9,24.2,20.1,18.9.

Compound 17, productive rate is 23.3%, ¹h NMR (400MHz, CDCl3) δ 7.76 (1H, d, J=16.0Hz), 7.59～7.57 (2H, m), 7.39 (3H, d, J=5.0Hz), 6.45 (1H, d, J=16.0Hz), 6.24 (1H, d, J=3.1Hz), 5.51 (1H, d, J=2.7Hz), 3.88 (1H, t, J=10.2Hz), 3.20 (1H, d, J=10.0Hz), 2.78～2.73 (1H, m), 2.65～2.61 (1H, m), 2.55～2.48 (1H, m), 2.31 (3H, s), 2.16 (1H, d, J=13.5Hz), 2.07～1.98 (1H, q), 1.75 (3H, s), 1.63 (4H, s); ¹³cNMR (100MHz, CDCl3) δ 170.4,166.4,144.5,139.5,134.7,131.6,130.0,129.9,128.8,128.2,119.7,118.8,88.7,83.1,57.3,50.0,36.7,35.0,30.6,26.0,24.2,18.6.

Compound 18, productive rate is 53.3%, ¹h NMR (400MHz, CDCl3) δ 6.18 (1H, d, J=3.2Hz), 5.87～5.80 (1H, m), 5.46 (1H, d, J=3.0Hz), 5.09 (1H, d, J=16.9Hz), 5.00 (1H, d, J=9.6Hz), 3.80～3.74 (1H, m), 3.12 (1H, d, J=7.4Hz), 2.68 (1H, s), 2.45～2.40 (3H, m), 2.37 (4H, s), 2.25 (3H, s), 2.11～2.07 (1H, m), 1,95～1.89 (1H, m), 1.71 (3H, s), 1.54 (3H, d, J=3.8Hz); ¹³c NMR (100MHz, CDCl3) δ 172.4,170.2,139.5,136.9,131.6,130.3,118.7,115.3,88.7,82.9,56.7,50.1,36.5,35.0,34.6,30.4,29.0,25.9,24.2,18.8.

Compound 19, productive rate is 65.2%, ¹h NMR (400MHz, CDCl3) δ 6.21 (1H, d, J=3.1Hz), 5.49 (1H, d, J=2.7Hz), 3.82 (1H, t, J=10.0Hz), 3.15 (1H, d, J=9.3Hz), 2.91～2.82 (3H, m), 2.14～2.10 (1H, m), 2.04～2.01 (3H, m), 1.97～1.87 (8H, m), 1.83～1.75 (6H, m), 1.63 (1H, s); ¹³c NMR (100MHz, CDCl3) δ 172.4,170.2,139.4,131.7,130.2,118.8,88.8,83.6,83.0,69.0,56.7,50.1,36.5,34.9,34.1,30.5,25.9,24.2,23.7,18.8,17.8.

Compound 20, productive rate is 24.0%, ¹h NMR (400MHz, CDCl3) δ 7.32～7.18 (5H, m), 6.22 (1H, d, J=3.3Hz), 5.49 (1H, d, J=3.0Hz), 3.80 (1H, t, J=10.1Hz), 3.12 (1H, d, J=10.1Hz), 2.99 (2H, t, J=7.9Hz), 2.73～2.59 (3H, m), 2.49～2.43 (2H, m), 2.30～2.28 (3H, m), 2.14～2.10 (1H, dd, J=13.8,2.3Hz), 1.96～1.87 (1H, m), 1.74 (3H, s), 1.65 (1H, s), 1.56 (3H, s); ¹³c NMR (100MHz, CDCl3) δ 172.3,170.2,140.8,139.5,131.6,130.4,128.4,126.0,118.7,88.8,83.0,56.7,50.1,36.8,36.5,35.0,31.0,30.5,26.0,24.2,18.8.

Synthesizing of compound 21:

In the 10mL of dried and clean reaction bulb, add 5-acetylenic acid and compound 19 (200mg, 0.584mmol), 6-nitrine-1-hexanol (125.43mg, 0.876mmol), hydrated copper sulfate (145.80mg, 0.584mmol) and sodium ascorbate (462.78mg, 2.336mmol), add distilled water and the tert-butyl alcohol (1: 2) mixed solution (3mL) to be dissolved into homogeneous phase, stirring at normal temperature 2 hours.With Rotary Evaporators, partial solvent is screwed out, residue reaction mixture is extracted with ethyl acetate, and collects organic facies and uses anhydrous sodium sulfate drying, decompress filter.With Rotary Evaporators, organic facies is spin-dried for, silica gel column chromatography is separated, obtains compound 21 (120.0mg), and productive rate is 61.3%. ¹H NMR(400MHz，CDCl3)δ7.52(1H，s)，6.20(1H，d，J＝3.3Hz)，5.49(1H，d，J＝3.0Hz)，4.34(2H，t，J＝7.1Hz)，3.81(1H，t，J＝10.2Hz)，3.63(2H，t，J＝6.4Hz)，3.14(1H，d，J＝10.1Hz)，2.81～2.76(2H，m)，2.74～2.67(1H，m)，2.51～2.43(2H，m)，2.39～2.31(2H，m)，2.29～2.27(4H，m)，2.13～2.09(1H，dd，J＝13.8，2.3Hz)，2.05～2.00(3H，m)，1.97～1.88(5H，m)，1.72(4H，s)，1.60～1.53(6H，m)； ¹³C NMR(100MHz，CDCl3)δ172.6，170.2，147.1，139.4，131.7，130.0，121.3，118.8，88.6，83.1，62.2，56.7，50.0，49.9，36.4，34.9，34.7，32.3，30.4，30.1，26.1，25.8，25.1，24.8，24.7，24.1，18.8。

The preparation of compound 22:

By dimethyl amine hydrochlorate (1.5g, 18mmol) and K ₂cO ₃(5.0g, 36mmol) mixing adds in 100ml dichloromethane stirs 15min, and then pressure filtration, directly joins in compound 5 (300mg, 1.2mmol), at room temperature stirs 3h.Removal of solvent under reduced pressure, then dissolve with a small amount of dichloro, water is washed three times fast, Na ₂sO ₄dry, filter, dichloromethane is removed in decompression, the crude product dimethyl amine intermediate obtaining is dissolved in a small amount of dichloromethane again, add while stirring dilute hydrochloric acid solution (with dimethyl amine intermediate equivalent), during stirring, to measure the pH value of aqueous solution, when pH value of water solution is 4-5, stop dripping aqueous hydrochloric acid solution.Collect water, lyophilizing, obtains compound 22.

Dimethyl amine intermediate: ¹h NMR (CDCl ₃, 400MHz) δ 3.76 (t, J=10.0Hz, 1H), 2.96 (s, 1H), 2.49-2.67 (m, 3H), 2.28-2.34 (m, 1H), 2.30-2.34 (m, 2H), 2.18 (s, 6H), 2.09 (br s, 2H), 1.96 (d, J=11.2Hz, 1H) 1.67-1.73 (m, 2H), 1.60 (s, 3H), 1.22 (br s, 3H), 1.18 (br s, 2H); 13C NMR (CDCl3,300MHz) δ 177.0,131.8,131.3,84.0,80.2,58.3,58.1,50.9,46.0,44.6,38.4,35.3,30.0,27.2,23.7,22.8.

Compound 22:[α] _d ²⁰=-42.0 (c=10, H ₂o); IR (KBr): 3334,2927,2856,1767,1467,992,967,874,831,719,669,626,504cm-1; ¹h NMR (D ₂o, 400MHz) δ 4.14 (t, J=10.3Hz, 1H), 3.51 (q, J=12.6Hz, 1H), 3.40 (dd, J=13.3,2.9Hz, 1H), 3.18-3.04 (m, 1H), 2.96 (d, J=10.6Hz, 6H), 2.67 (d, J=10.2Hz, 1H), 2.37 (dd, J=16.2,8.1Hz, 1H), 2.27-2.05 (m, 4H), 1.87 (d, J=12.9Hz, 1H), 1.73 (dd, J=19.5,11.7Hz, 2H), 1.66 (s, 3H), 1.46-1.31 (m, 2H), 1.26 (s, 3H); ¹³c NMR (CDCl ₃, 100MHz) δ 178.4,132.6,131.4,85.1,80.7,56.9,55.6,49.9,45.1,42.3,41.5,39.2,34.4,29.5,25.9,23.2,21.4.HRMS calcd for C ₁₇h ₂₇nO ₃[M ⁺h] ⁺294.1991 found 294.2069.

The preparation of compound 23:

By dimethyl amine hydrochlorate (1.5g, 18mmol) and K ₂cO ₃(5.0g, 36mmol) mixing adds in 100ml dichloromethane stirs 15min, and then pressure filtration, directly joins in compound 5 (300mg, 1.2mmol), at room temperature stirs 3h.Removal of solvent under reduced pressure, then dissolve with a small amount of dichloro, water is washed three times fast, Na ₂sO ₄dry, to filter, dichloromethane is removed in decompression, and the crude product dimethyl amine intermediate obtaining is dissolved in a small amount of dichloromethane again, adds while stirring fumaric acid (with dimethyl amine intermediate equivalent), and concentrate drying obtains compound 23. ¹H NMR(DMSO，400MHz)δ6.58(s，2H)，3.80(t，J＝10.3Hz，1H)，2.64(s，3H)，2.49-2.53(m，3H)，2.26-2.27(m，1H)，2.23(s，6H)，1.96-2.10(m，6H)，1.60(s，3H)，1.57-1.59(m，2H)，1.23-1.25(m，1H)，1.15(s，3H)； ¹³C NMR(CDCl ₃，100MHz)δ177.8，167.6，135.2，133.7，131.4，83.4，80.31，58.0，57.1，51.7，45.2，43.6，41.0，35.3，30.2，27.0，24.2，23.2.

The preparation of compound 24:

Compound 1 (628mg, 12.5mmol) is dissolved in 35ml dichloromethane, then adds m-CPBA (680mg, 4.0mmol).Reaction system is positioned over stirring at room, and reacts with TCL monitoring.Raw material is poured over 5%NaHCO by reaction mixture after disappearing ₃(60mL) in, organic facies washes (20ml) again with water, collects organic facies, and uses Na ₂sO ₄dry, filter, vacuum rotary steam, obtains thick product and purifies and obtain compound 24 with silicagel column. ¹H NMR(CDCl3，400MHz)δ6.17(d，J＝3.2Hz，1H)，5.47(d，J＝2.8Hz，1H)，4.04(t，J＝10.8Hz，1H)，2.36-2.20(m，4H)，2.03-1.08(m，4H)，1.68-1.62(m，1H)，1.46(s，3H)，1.46(d，J＝12.8Hz，1H)，1.29(s，3H)； ¹³C NMR(CDCl3，100MHz)δ169.5，137.9，119.5，81.7，79.5，69.7，62.1，55.3，49.2，37.2，33.2，29.3，23.1，23.0，21.8。

The preparation of compound 25:

According to document Yin Hong power, Qi Xiulan, Hua Huiming, Pei Yuehu, Saussurea lappa Clarke chemical constitution study, Chinese pharmaceutical chemistry magazine, 15 4 phases of volume in 2005,217-220.From Saussurea lappa Clarke, separation and purification obtains.

Compound 26 and 30 preparation:

Compound 25 (150mg, 0.65mmol), the methanol solution of Feldalat NM (20mg, 0.37mmol) stirs 10 hours at 30 ℃.After TLC has detected, reactant liquor is poured in frozen water, be extracted with ethyl acetate four times, combined ethyl acetate layer, uses 5% hydrochloric acid, saturated sodium bicarbonate aqueous solution successively, saturated common salt water washing, anhydrous magnesium sulfate drying, concentrated column purification and obtained methoxylation product (136mg, 80%) after filtration.

¹H-NMR(400MHz，CDCl ₃)δ5.19(d，J＝1.6Hz，1H)，5.03(d，J＝1.6Hz，1H)，4.87(s，1H)，4.76(s，1H)，3.93(t，J＝9.2Hz，1H)，3.70(dd，J＝4.4，9.8Hz，1H)，3.63(dd，J＝3.2，9.8Hz，1H)，3.37(s，3H)，2.90(m，1H)，2.83(m，1H)，2.51(m，2H)，2.49(m，1H)，2.44(m，1H)，2.38(m，1H)，2.19(m，1H)，2.07(m，1H)，1.95(m，1H)，1.86(m，1H)，1.32(m，1H)； ¹³C-NMR(100MHz，CDCl ₃)δ175.7，151.8，149.9，111.5，108.8，85.3，68.9，59.0，51.7，47.7，46.9，43.9，37.7，32.5，32.4，30.1.

In the two-mouth bottle that connects condensing tube and drying tube, add Zn-Cu neat (812mg) and absolute ether (4mL), add a granule iodine, stir until the color of iodine disappears.Ether (2mL) solution that adds methoxylation product (262mg, 1mmol) and diiodomethane (0.8mL.10mmol), refluxes 72 hours.After TLC demonstration reacts completely, incline and diethyl ether solution, twice of ether washing (3mL) for residual solid, combined ether layer, uses respectively saturated aqueous ammonium chloride, water (10mL) washed twice, with anhydrous sodium sulfate drying, filtering and concentrating, it is a white solid compound 30 (206mg, 71%) that mistake column purification obtains product. ¹H-NMR(400MHz，CDCl ₃)δ4.20(m，1H)，3.65(dd，J＝3.9，9.9Hz，1H)，3.59(dd，J＝3.0，9.9Hz，1H)，3.34(s，1H)，2.30-2.40(m，3H)，1.92-2.07(m，2H)，1.15-1.70(m，7H)，0.85(m，1H)，0.70(m，1H)，0.50(m，1H)，0.40(m，1H)，0.16-0.36(m，4H)； ¹³C-NMR(100MHz，CDCl ₃)δ176.4，83.9，69.2，59.2，51.5，47.9，47.3，44.3，36.2，35.9，29.0，27.3，26.7，18.5，12.5，10.4，10.0，8.8；ESI-HRMS m/z：291.1964[M+H]。

Compound 30 (0.023g, 0.080mmol) is dissolved in acetonitrile (0.52mL), adds 4MNaOH aqueous solution (0.11mL), refluxes 5 hours, and TLC detects completely, is cooled to room temperature, slowly add 10% hydrochloric acid to pH be 3.Add ethyl acetate (20mL), wash with water twice (2 * 20mL), water is extracted with ethyl acetate (2 * 20mL) again twice, merge organic layer, anhydrous sodium sulfate drying, filters, concentrating post, to obtain product be a white solid 26 (0.019g, 94%).

Molecular formula: C ₁₇h ₂₂o ₂

Molecular weight: 258

Character: white unformed powder

Spectral data:

¹H-NMR(400MHz，CDCl ₃)δ6.17(d，J＝3.2Hz，1H)，5.45(d，J＝3.2Hz，1H)，4.24(dd，J＝8.8，10.8Hz，1H)，2.87(m，1H)，2.20(m，1H)，2.07(m，1H)，1.95(dd，J＝8.8，10.4Hz，1H)，1.71(m，2H)，1.37-1.61(m，5H)，0.98(m，1H)，0.64(m，1H)，0.49(m，1H)，0.43(m，1H)，0.27-0.37(m，4H)； ¹³C NMR(100MHz，CDCl ₃)δ169.4，139.4，118.5，82.5，51.6，47.4，44.2，34.2，32.8，26.4，26.2，25.3，17.4，11.1，10.7，10.5，7.8；ESI-HRMS m/z：259.1692[M+H]。

The preparation of compound 27:

Dimethylamine hydrochloride (245mg) is suspended in 11mL dichloromethane solution, add potassium carbonate (380mg) to stir half an hour, add compound 26 (42mg), reflux 4 hours, silica gel column chromatography (petroleum ether: ethyl acetate :=70: 30), obtain oily compound 27, yield: 78%.

Molecular formula: C ₁₉h ₂₉nO ₂

Molecular weight: 303

Character: oily liquids

Spectral data:

¹H-NMR(400MHz，CDCl ₃)δ4.19(dd，J＝9.5，10.2Hz，1H)，2.66(dd，J＝12.8，4.8Hz，1H)，2.49(dd，J＝12.8，6.8Hz，1H)，2.25-2.38(m，2H)，2.21(s，6H)，1.98-2.12(m，2H)，1.80-1.84(m，1H)，1.68(m，1H)，1.27-1.48(m，5H)，1.11(m，1H)，1.01(m，1H)，0.69(m，1H)，0.46(m，1H)，0.18-1.37(m，4H)，0.11(m，2H)； ¹³C NMR(100MHz，CDCl ₃)δ181.3，82.8，58.0，50.8，46.4，46.0，45.0，44.6，35.2，34.9，28.2，26.3，25.7，17.5，11.5，9.6，9.2，7.9；ESI-HRMS m/z：304.2273[M+H]。

The synthetic method of compound 28:

Compound 27 (38mg) is dissolved in 2mL dichloromethane, slowly adds 0.05M dilute hydrochloric acid until pH is 4 under stirring, separate water by washed with dichloromethane once, water lyophilization obtains compound 28 (31mg), yield: 73%.

Molecular formula: C ₁₉h ₃₀nO ₂cl

Molecular weight: 339

Character: white solid

Spectral data:

¹H-NMR(400MHz，D ₂O)δ4.42(m，1H)，3.31-3.37(m，1H)，3.21-3.25(m，1H)，2.92(m，1H)，2.82(s，3H)，2.80(s，3H)，2.11-2.26(m，2H)，1.94(m，1H)，1.79(m，1H)，1.39-1.58(m，5H)，1.23(m，1H)，1.13(m，1H)，0.69(m，1H)，0.46(m，1H)，0.18-1.33(m，4H)，0.11(m，2H)； ¹³C NMR(100MHz，D ₂O)δ178.2，85.8，56.0，51.0，47.2，45.9，44.8，42.5，42.2，35.7，35.2，27.5，27.2，26.6，18.3，12.2，10.3，9.8，8.6；ESI-HRMS m/z：304.2271[M+H]

Synthesizing of compound 29:

In reaction bulb, add 20mg compound 26, with 1mL THF, dissolve, add subsequently ethyl prolinate hydrochlorate 86mg, DBU 0.2mL, stirs 24 hours, crosses column purification and obtains compound 29 (12mg). yield: 39%.

Molecular formula: C ₂₄h ₃₅nO ₄

Molecular weight: 401

Character: colorless oil compound

Spectral data:

¹H NMR(400MHz，CDCl ₃)：δ4.10-4.22(m，3H)，3.31(dd，J＝8.8，5.2Hz，1H)，3.05(dd，J＝13.2，5.2Hz，1H)，2.91-2.96(m，1H)，2.86(dd，J＝13.2，3.6Hz，1H)，2.37-2.49(m，3H)，2.23-2.29(m，1H)，1.96-2.11(m，3H)，1.73-1.94(m，3H)，1.57-1.69(m，3H)，1.40-1.47(m，1H)，1.17-1.36(m，6H)，0.83-0.89(m，1H)，0.70-0.75(m，1H)，0.48-0.53(m，1H)，0.40-0.45(m，1H)，0.26-0.36(m，2H)，0.17-0.24(m，2H)； ¹³C NMR(100MHz，CDCl ₃)：δ178.3，174.4，84.3，66.6，60.6，53.9，51.9，51.7，47.5，47.2，44.7，36.6，36.2，29.3，29.1，27.6，27.0，24.0，18.8，14.5，12.8，10.6，10.1，9.1；ESI-HRMS m/z：402.2644[M+H]。

The synthetic method of compound 31:

Get compound 26 (51.6mg), dimethylamino naphthyridine (4mg) is dissolved in 2mL dichloromethane, adds 66mg phenylmercaptan., stirs 12 hours, is spin-dried for, and purification by silica gel column chromatography obtains compound 31 (68mg). ¹H NMR(400MHz，CDCl ₃)δ7.44-7.34(m，2H)，7.30(dd，J＝10.3，4.8Hz，2H)，7.20(t，J＝7.3Hz，1H)，4.24-4.14(m，1H)，3.47(dd，J＝13.8，4.0Hz，1H)，3.11(dd，J＝13.8，7.0Hz，1H)，2.52(ddd，J＝11.2，7.0，4.1Hz，1H)，2.30(ddd，J＝20.7，10.6，4.2Hz，1H)，2.21(dd，J＝18.2，8.9Hz，1H)，2.13-2.03(m，1H)，1.96-1.86(m，1H)，1.73-1.63(m，1H)，1.61-1.47(m，2H)，1.43(ddd，J＝12.3，8.5，3.5Hz，1H)，1.39-1.25(m，3H)，0.89(dt，J＝9.8，4.8Hz，1H)，0.65(ddd，J＝9.2，5.4，3.8Hz，1H)，0.42(tt，J＝13.4，4.6Hz，2H)，0.36-0.30(m，1H)，0.29-0.21(m，2H)，0.18-0.08(m，1H)； ¹³C NMR(100MHz，CDCl ₃)δ177.1，136.3，130.0，129.6，127.0，84.2，77.92，52.6，48.3，47.4，47.1，35.9，35.4，33.8，29.7，27.7，27.0，18.8，12.8，11.4，9.3。The synthetic method of compound 32:

Compound 26 (51.6mg), 1,8-diazabicylo [5.4.0], 11 carbon-7-alkene (15.2mg) is dissolved in 0.5mL acetonitrile, adds 37.3mg benzyl mercaptan, stirs 24 hours, is spin-dried for, and purification by silica gel column chromatography obtains compound 32 (75mg). ¹H NMR(400MHz，CDCl ₃)δ7.30-7.23(m，4H)，7.22-7.17(m，1H)，4.13(t，J＝9.9Hz，1H)，3.77-3.63(m，2H)，2.80-2.66(m，2H)，2.35(dt，J＝10.5，5.1Hz，1H)，2.28-2.14(m，2H)，1.89(ddd，J＝14.0，10.1，5.2Hz，2H)，1.67-1.49(m，2H)，1.48-1.38(m，2H)，1.38-1.30(m，1H)，1.30-1.17(m，2H)，0.83(dt，J＝9.7，4.9Hz，1H)，0.63(ddd，J＝9.4，5.4，4.0Hz，1H)，0.48-0.40(m，1H)，0.36(dt，J＝8.9，4.5Hz，1H)，0.33-0.25(m，1H)，0.24-0.13(m，3H)； ¹³C NMR(100MHz，CDCl ₃)δ177.4，138.6，129.5，129.0，127.6，84.3，52.2，48.0，47.7，46.8，38.1，36.1，36.0，30.7，29.6，27.8，27.1，18.9，13.0，11.2，11.0，9.3。

The synthetic method of compound 33:

Get compound 26 (51.6mg) and be dissolved in 1mL methanol, add 321mg benzylamine, stir 24 hours, be spin-dried for, purification by silica gel column chromatography obtains intermediate (76mg), is dissolved in 5mL methanol, add 21mg pyrovinic acid, stir after ten minutes and be spin-dried for and obtain compound 33 (97mg). ¹H NMR(400MHz，MeOD)δ7.47(d，J＝38.9Hz，5H)，4.41(t，J＝9.9Hz，1H)，4.27(q，J＝13.1Hz，2H)，3.26(s，1H)，2.93-2.79(m，1H)，2.67(s，3H)，2.39-2.28(m，1H)，2.17(t，J＝16.3Hz，1H)，2.04(t，J＝9.7Hz，1H)，1.86(d，J＝8.2Hz，1H)，1.60(dd，J＝17.1，7.0Hz，2H)，1.45(d，J＝35.5Hz，3H)，1.30(dt，J＝28.7，13.8Hz，3H)，0.83(d，J＝4.0Hz，1H)，0.62(s，1H)，0.48(d，J＝3.8Hz，1H)，0.41(d，J＝3.9Hz，1H)，0.30(d，J＝4.0Hz，2H)，0.21(s，2H)； ¹³C NMR(100MHz，MeOD)δ178.38，132.13，131.14，130.72，130.28，86.43，52.59，52.52，48.62，46.81，46.39，44.39，39.60，36.78，36.68，29.12，28.21，27.69，19.31，13.06，11.09，10.81，9.44。

The synthetic method of compound 34:

Compound 26 (103mg) is dissolved in methanol 2mL, adds 366mg ethylaminoethanol, stirs 24 hours, purification by silica gel column chromatography obtains amine addition intermediate radical 118mg, be dissolved in 5mL methanol, add pyrovinic acid 35.6mg, stir after ten minutes and be spin-dried for and obtain compound 34 (153mg). ¹H NMR(400MHz，D ₂O)δ4.60(t，J＝10.1Hz，1H)，3.85(t，J＝5.0Hz，2H)，3.41-3.31(m，2H)，3.29-3.18(m，2H)，2.97-2.84(m，1H)，2.78(s，3H)，2.33(q，J＝8.8Hz，2H)，2.03(t，J＝9.8Hz，1H)，1.96-1.86(m，1H)，1.67(dd，J＝11.8，7.7Hz，1H)，1.59-1.37(m，5H)，1.35-1.23(m，1H)，0.83-0.74(m，1H)，0.55-0.38(m，3H)，0.38-0.25(m，3H)，0.24-0.19(m，1H)； ¹³C NMR(100MHz，D ₂O)δ178.39，85.67，56.28，50.62，49.68，46.96，45.74，45.67，43.11，38.58，35.95，35.62，27.66，27.22，26.69，18.27，12.28，10.14，9.49，8.72。

The synthetic method of compound 35:

Get compound 26 (103mg), dimethylamine hydrochloride (489mg) is dissolved in 20mL dichloromethane, add 1.66g potassium carbonate, reflux 6 hours, filter, be spin-dried for, silica gel column chromatography obtains compound 27 (110mg), gets 49mg compound 27 and is dissolved in 1mL methanol, adds 20.9mg dichloroacetic acid, stir 10 minutes, be spin-dried for to obtain compound 35 (69mg). ¹H NMR(400MHz，MeOD)δ5.91(s，1H)，4.41(t，J＝10.1Hz，1H)，3.37(dd，J＝13.3，9.2Hz，1H)，3.22(dd，J＝13.3，4.0Hz，1H)，2.98-2.91(m，1H)，2.85(s，6H)，2.35(dd，J＝17.4，9.1Hz，1H)，2.25-2.14(m，1H)，2.08-2.00(m，1H)，1.98-1.88(m，1H)，1.69-1.56(m，2H)，1.56-1.44(m，3H)，1.40-1.22(m，2H)，0.85(dt，J＝9.6，4.8Hz，1H)，0.63(ddd，J＝9.3，5.4，3.9Hz，1H)，0.52-0.46(m，1H)，0.45-0.39(m，1H)，0.35-0.29(m，2H)，0.21(td，J＝9.5，5.2Hz，2H)； ¹³C NMR(100MHz，MeOD)δ178.45，170.46，86.32，70.47，57.60，52.72，48.77，47.52，44.52，43.69，36.93，36.85，29.11，28.36，27.85，19.45，13.22，11.23，10.93，9.58。

The synthetic method of compound 36:

Get compound 26 (50.0mg), be dissolved in 1mL absolute methanol, add 0.27mL piperidines, reaction is spent the night, concentrated, purification by silica gel column chromatography obtains amine addition intermediate radical compound 50mg, is dissolved in 10mL methanol, by equivalent, add methanesulfonic acid, be spin-dried for, obtain compound 36 (63mg). ¹H NMR(CD ₃OD，400MHz)δ0.13-0.18(m，2H)，0.24-0.30(m，2H)，0.33-0.38(m，1H)，0.41-0.45(m，1H)，0.55-0.59(m，1H)，0.76-0.81(m，1H)，0.92(d，J＝6.5Hz，3H)，1.19-1.66(m，9H)，1.81-1.92(m，3H)，1.96-2.01(m，1H)，2.12-2.18(m，1H)，2.26-2.31(m，1H)，2.61(s，3H)，2.92-3.02(m，3H)，3.18-3.36(m，3H)，3.53(t，J＝13.6Hz，2H)，4.37(t，J＝10.1Hz，1H)； ¹³C NMR(CD ₃OD，100MHz)δ9.4，10.8，11.1，13.1，19.3，21.4，27.7，28.2，28.9，29.5，32.4，32.4，36.7，36.8，39.7，43.1，47.7，52.4，54.2，55.4，56.6，86.0，178。

The synthetic method of compound 37:

Get compound 26 (50.0mg), be dissolved in 1mL absolute methanol, add 0.30mL piperazine, reaction is spent the night, concentrated, purification by silica gel column chromatography obtains amine addition intermediate radical compound 51mg, is dissolved in 10mL methanol, by equivalent, add fumaric acid, be spin-dried for, obtain compound 37 (62mg). ¹H NMR(CD ₃OD，400MHz)δ0.07-0.13(m，2H)，0.17-0.22(m，2H)，0.28-0.32(m，1H)，0.36-0.40(m，1H)，0.49-0.53(m，1H)，0.72-0.76(m，1H)，1.09-1.58(m，7H)，1.84-1.95(m，2H)，2.06-2.12(m，1H)，2.18-2.25(m，1H)，2.37-2.43(m，1H)，2.52-2.69(m，6H)，2.69(s，3H)，3.10(brs，3H)，3.16-3.17(m，1H)，4.19(t，J＝10.0Hz，1H)，6.56(s，2H)； ¹³C NMR(CD ₃OD，100MHz)δ9.5，11.1，11.2，13.0，19.4，27.7，28.3，29.7，36.8，36.8，43.4，46.4，47.9，48.9，51.6，53.1，54.5，57.2，85.6，136，170.6，179.9。

The synthetic method of compound 38:

Compound 26 (100mg, 0.39mmol) is dissolved in to absolute methanol (20mL), adds morpholine (508mg, 5.85mmol), stirred overnight at room temperature.Silica gel column chromatography separation and purification obtains product (100mg, 0.29mmol), and product is dissolved in to absolute methanol (5mL), adds pyrovinic acid (27.8mg, 0.29mmol), and methanol is spin-dried for to obtain to compound 38 (127.8mg). ¹H NMR(400MHz，D ₂O)δ4.56(t，J＝10.1Hz，1H)，4.10(s，2H)，3.92(m，J＝17.5，12.5Hz，2H)，3.67-3.46(m，3H)，3.39(dd，J＝13.8，3.3Hz，1H)，3.35-3.25(m，2H)，3.12-3.01(m，1H)，2.77(s，3H)，2.34(dt，J＝15.8，7.9Hz，2H)，2.05(t，J＝9.9Hz，1H)，1.93(s，1H)，1.76-1.44(m，5H)，1.43-1.33(m，1H)，1.34-1.22(m，1H)，0.88-0.74(m，1H)，0.65-0.52(m，1H)，0.52-0.18(m，6H)； ¹³C NMR(100MHz，D ₂O)δ178.38，85.98，63.53，55.30，50.93，48.80，47.00，45.84，41.70，38.45，35.16，34.68，27.34，26.77，26.31，17.94，11.76，9.99，9.71，8.11。

The synthetic method of compound 39:

Compound 26 (50mg, 0.195mmol) is dissolved in to absolute methanol (5mL), adds pyrrolidine (208mg, 2.93mmol), stirred overnight at room temperature.Silica gel column chromatography separation and purification obtains product (52mg, 0.16mmol), and product is dissolved in to absolute methanol (5mL), adds pyrovinic acid (15.2mg, 0.16mmol), and methanol is spin-dried for to obtain to compound 39 (57.2mg). ¹H NMR(400MHz，D ₂O)δ4.44(t，J＝10.0Hz，1H)，3.79-3.58(m，2H)，3.50(dd，J＝13.4，9.5Hz，1H)，3.35(dd，J＝13.5，3.6Hz，1H)，3.21-3.03(m，2H)，2.90(dd，J＝5.9，3.2Hz，1H)，2.73(s，3H)，2.33(d，J＝8.5Hz，1H)，2.24-2.08(m，3H)，2.06-1.95(m，3H)，1.92(s，1H)，1.52(dt，J＝24.8，8.8Hz，5H)，1.33-1.15(m，2H)，0.87-0.71(m，1H)，0.65-0.53(m，1H)，0.46-0.08(m，6H)； ¹³C NMR(100MHz，D ₂O)δ178.08，85.50，55.92，54.06，52.97，50.74，46.95，45.81，43.22，38.44，35.58，35.18，27.47，26.99，26.50，22.66，22.54，18.10，12.03，10.04，9.54，8.43。

The synthetic method of compound 40:

Compound 26 (100mg, 0.39mmol) is dissolved in to absolute methanol (2mL), adds N-methylethanolamine (438mg, 5.85mmol), stirred overnight at room temperature.Silica gel column chromatography separation and purification obtains product (100mg, 0.30mmol), and product is dissolved in to dichloromethane (5mL), adds pyrovinic acid (28.8mg, 0.30mmol), and dichloromethane is spin-dried for to obtain to compound 40 (128.8mg). ¹H NMR(400MHz，CDCl ₃)δ4.36(t，J＝9.9Hz，1H)，3.92(s，2H)，3.65-3.43(m，2H)，3.34(s，2H)，3.01(s，3H)，2.98-2.83(m，1H)，2.71(s，J＝2.8Hz，3H)，2.37-2.22(m，1H)，2.19-2.10(m，2H)，2.05-1.88(m，2H)，1.57(m，J＝29.9，18.2Hz，5H)，1.31(d，J＝10.9Hz，1H)，1.21(s，1H)，0.78(m，1H)，0.59(m，1H)，0.54-0.06(m，6H)。

The synthetic method of compound 41:

Compound 26 (50mg, 0.195mmol) is dissolved in to absolute methanol (2mL), adds N-methylbutylamine (254mg, 2.93mmol), stirred overnight at room temperature.Silica gel column chromatography separation and purification obtains amine addition intermediate radical (50mg, 0.14mmol), is dissolved in dichloromethane (5mL), adds pyrovinic acid (13.9mg, 0.14mmol), and dichloromethane is spin-dried for to obtain to compound 41 (63.9mg). ¹H NMR(400MHz，D ₂O)δ4.60(s，1H)，3.59-3.07(m，4H)，3.06-2.96(m，1H)，2.90(s，3H)，2.77(s，3H)，2.32(dd，J＝18.0，8.9Hz，2H)，2.07-1.97(m，1H)，1.94-1.81(m，1H)，1.76-1.62(m，3H)，1.61-1.51(m，2H)，1.48(d，J＝8.1Hz，1H)，1.45-1.24(m，5H)，0.91(t，J＝7.4Hz，3H)，0.83-0.76(m，1H)，0.57-0.49(m，1H)，0.45(ddd，J＝17.8，8.7，4.7Hz，2H)，0.38-0.24(m，3H)，0.23-0.17(m，1H)。

The synthetic method of compound 42-45:

In 50mL round-bottomed flask, add Azide trimethyl silane (575mg, 5.0mmol) and acetic acid (300mg, 5.0mmol), after stirring at room 20 minutes, in this reactant liquor, add compound 26 (258mg, 1.0mmol) with catalytic amount triethylamine (20.2mg, 0.2mmol), be warming up to 60 ℃ and stir until react completely (TLC detection).In the appropriate frozen water of reaction mixture impouring, with ethyl acetate (50mL * 3) extraction, then use successively saturated sodium bicarbonate solution (20mL * 3) and saturated aqueous common salt (20mL * 3) to wash respectively, anhydrous sodium sulfate drying.After sucking filtration is concentrated, obtain Azide intermediate.

Get Azide intermediate (0.25mmol), sodium ascorbate (10mg, 0.05mmol), copper sulphate pentahydrate (12mg, 0.05mmol) in pre-dry reaction bulb, evacuation, inflated with nitrogen and sealing.Add again mixed solvent (tert-butyl alcohol: water=1: 1) 5mL, 5-hexin-1-alcohol (49mg, 0.5mmol), stirring at room is until raw material reaction completely (TLC detection).In the appropriate frozen water of reaction mixture impouring, with ethyl acetate (10mL * 3) extraction, then with saturated common salt water washing three times, anhydrous sodium sulfate drying, concentrating under reduced pressure, purification by silica gel column chromatography obtains compound 42 (71mg).

¹H NMR(400MHz，CDCl ₃)δ7.40(s，1H)，4.73-4.58(m，2H)，4.23(t，J＝10.0Hz，1H)，3.65(t，J＝6.3Hz，2H)，2.73(t，J＝7.4Hz，2H)，2.63(dt，J＝11.7，4.2Hz，1H)，2.21(dd，J＝18.0，9.0Hz，1H)，1.96-1.89(m，1H)，1.88-1.80(m，2H)，1.79-1.69(m，3H)，1.59(dt，J＝16.7，7.6Hz，4H)，1.52-1.44(m，2H)，1.38-1.29(m，2H)，1.27-1.19(m，1H)，0.81(dd，J＝9.2，4.8Hz，1H)，0.65-0.54(m，1H)，0.47-0.40(m，1H)，0.40-0.35(m，1H)，0.34-0.27(m，1H)，0.23(m，3H)； ¹³C NMR(CDCl ₃，100MHz)：176.1，149.0，122.3，84.9，62.4，52.0，48.6，47.9，47.5，44.6，36.0，35.5，32.4，28.6，27.6，27.0，25.9，25.6，18.6，12.8，11.1，10.9，9.1。

As above method, is prepared into compound 43 (70mg).

¹H NMR(400MHz，CDCl ₃)δ7.90(s，1H)，7.81(d，J＝7.6Hz，2H)，7.39(t，J＝7.4Hz，2H)，7.29(dd，J＝14.9，7.7Hz，1H)，4.79-4.65(m，2H)，4.20(t，J＝9.9Hz，1H)，2.68(dt，J＝8.7，4.1Hz，1H)，2.17(dd，J＝17.9，8.9Hz，1H)，2.07-1.92(m，1H)，1.84(d，J＝6.1Hz，1H)，1.74(t，J＝9.8Hz，1H)，1.63-1.49(m，2H)，1.42(dd，J＝13.1，7.5Hz，2H)，1.30(dt，J＝20.0，9.9Hz，2H)，1.24-1.15(m，1H)，0.79(dd，J＝17.1，12.5Hz，1H)，0.61-0.51(m，1H)，0.37(dd，J＝20.4，4.1Hz，2H)，0.29-0.13(m，4H)； ¹³C NMR(100MHz，CDCl ₃)δ175.54，148.13，130.37，128.88，128.29，125.73，120.84，84.53，51.46，48.24，47.47，47.20，44.21，35.62，35.21，28.27，27.24，26.61，18.29，12.51，10.69，10.42，8.70。

As above method obtains compound 44 (63mg).

¹H NMR(400MHz，CDCl ₃)δ8.21(s，1H)，4.81-4.68(m，2H)，4.28(dd，J＝19.8，9.6Hz，1H)，3.95(s，3H)，2.76-2.65(m，1H)，2.20(q，J＝9.1Hz，1H)，2.04-1.85(m，2H)，1.74(t，J＝9.9Hz，1H)，1.65(dd，J＝19.0，10.4Hz，1H)，1.60-1.43(m，3H)，1.42-1.32(m，2H)，1.32-1.19(m，1H)，0.81(dt，J＝9.5，4.7Hz，1H)，0.59(dt，J＝9.2，4.5Hz，1H)，0.49-0.36(m，2H)，0.36-0.29(m，1H)，0.30-0.20(m，3H)； ¹³C NMR(100MHz，CDCl ₃)δ175.09，160.87，140.15，128.87，84.49，52.19，51.58，48.00，47.55，47.51，44.20，35.51，34.96，28.18，27.18，26.54，18.23，12.42，10.76，10.53，8.64。

As above method is prepared into compound 45 (65mg).

¹H NMR(400MHz，CDCl ₃)δ7.58(d，J＝33.3Hz，1H)，5.07(d，J＝4.9Hz，1H)，4.78-4.60(m，2H)，4.26(t，J＝10.0Hz，1H)，2.68(dt，J＝9.5，4.4Hz，1H)，2.23(dd，J＝17.7，8.7Hz，1H)，2.03-1.92(m，1H)，1.89-1.73(m，2H)，1.69-1.62(m，1H)，1.62-1.54(m，4H)，1.47(t，J＝12.5Hz，2H)，1.35(dd，J＝20.3，10.3Hz，2H)，1.30-1.18(m，2H)，0.87-0.77(m，1H)，0.67-0.57(m，1H)，0.49-0.36(m，2H)，0.36-0.29(m，1H)，0.25(m，3H)。

The synthetic method of compound 46:

Get compound 26 (167mg), deuterated dimethylamine hydrochloride (530mg) is dissolved in 15mL dichloromethane, adds 1.8g potassium carbonate, stirs 24 hours, filter, be spin-dried for, cross post and obtain dimethylamino intermediate (150mg), get 49mg intermediate, be dissolved in 10mL methanol, add 18.7mg fumaric acid, stir 10 minutes, be spin-dried for to obtain compound 46 (67mg). ¹H NMR(400MHz，MeOD)δ6.70(s，2H)，4.46(dd，J＝18.9，8.7Hz，1H)，3.46(dd，J＝13.4，6.3Hz，1H)，3.35-3.28(m，1H)，2.95(d，J＝14.0Hz，6H)，2.38(dd，J＝17.4，9.1Hz，1H)，2.27-2.19(m，1H)，2.11-2.03(m，1H)，2.01-1.92(m，1H)，1.67(ddd，J＝18.7，11.2，5.0Hz，2H)，1.60-1.48(m，3H)，1.45-1.27(m，2H)，0.88(dt，J＝9.6，4.8Hz，1H)，0.66(ddd，J＝9.3，5.4，3.8Hz，1H)，0.56-0.50(m，1H)，0.45(dt，J＝9.3，4.7Hz，1H)，0.36(dt，J＝11.9，4.7Hz，2H)，0.29-0.20(m，2H)； ¹³C NMR(101MHz，MeOD)δ178.3I，171.09，136.26，86.31，57.22，52.69，48.74，47.41，44.23，36.90，36.82，30.84，29.03，28.35，27.83，19.43，13.21，11.20，10.90，9.56。

The synthetic method of compound 47:

Parthenolide (566.2mg, 1.99mmol) is dissolved in to methanol, adds p-methyl benzenesulfonic acid (687.5mg, 4.0mmol).Reaction system is positioned over room temperature, and stirring is spent the night.Reaction mixture Na ₂hPO ₄(568mg, 4.0mmol) neutralization, then uses dichloromethane extraction, collected organic layer, and use Na ₂sO ₄dry, filter, then use Rotary Evaporators distilling under reduced pressure organic solvent, remaining product is purified with silicagel column, obtains compound 47. ¹H NMR(CDCl ₃，400MHz)δ6.12(d，J＝2.8Hz，1H)，5.44(s，1H)，4.13(t，J＝9.6Hz，1H)，3.12(d，J＝2.8Hz，3H)，2.79(t，J＝11.8Hz，2H)，2.26(t，J＝9.6Hz，1H)，2.11-2.08(m，1H)，1.98-1.62(m，6H)，1.52-1.45(m，1H)，1.31-1.37(m，4H)，1.09(s，3H)； ¹³C NMR(CDCl ₃，100MHz)δ169.5，138.9，119.8，82.5，80.3，77.9，55.3，48.1，46.4，45.7，35.3，38.7，25.2，24.1，22.5，14.0。

Compound 48 and 49 synthetic method:

By parthenolide (1.03g, 4.1mmol) solution and acetone: in water (95: 5) solution, add amberlyst 15 (12.88g), reaction system is placed under room temperature reacts, with TLC monitoring reaction until raw material disappear.After question response is complete, revolves to steam and remove solvent, remaining material is dissolved in dichloromethane, and uses Na ₂sO ₄dry.Filter, revolve to steam and remove solvent, recycle silicon glue column purification obtains product 48,49.

Compound 48: ¹h NMR (CDCl ₃, 400MHz) δ 6.12 (d, J=3.2Hz, 1H), 5.44 (d, J=3.2Hz, 1H), 4.92 (s, 1H), 4.88 (s, 1H), 4.03-3.94 (m, 1H), 2.93 (dd, J=11.6,8.8Hz, 1H), 2.71-2.65 (m, 1H), 2.61-2.56 (m, 1H), 2.29 (t, J=12Hz, 1H), 2.22-2.16 (m, 1H), 1.85-1.74 (m, 3H), 1.72-1.69 (m, 3H), 1.34-1.26 (m, 3H), 1.23 (s, 3H); ¹³c NMR (CDCl ₃, 100MHz) δ 169.6,147.8, and 138.5,120.5,112.4,83.8,79.5,55.4,47.0,43.7,40.0,38.9,31.2,25.9,23.6.

Compound 49: ¹h NMR (CDCl ₃, 400MHz) δ 6.24 (d, J=3.6Hz, 1H), 5.56 (d, J=3.2Hz, 1H), 4.26 (dd, J=9.6,2.0Hz, 1H), 2.75-2.62 (m, 2H), 2.40 (t, J=12.4Hz, 1H), 2.20-2.14 (m, 1H), 2.08 (s, 1H), 2.03-1.96 (m, 2H), 1.91-1.79 (m, 2H), 1.76-1.60 (m, 2H), 1.52-1.45 (m, 1H), 1.36 (s, 3H), 1.28 (s, 1H), 1.25 (s, 3H); ¹³cNMR (CDCl ₃, 400MHz) δ 169.6,138.4, and 120.4,82.7,80.0,74.7,55.2,49.6,47.1,39.3,25.2,24.9,24.1,23.4,20.6.

The preparation method of compound 50:

Martin ' s sulfurane (382mg, 0.57mmol) is dissolved in 2mL dichloromethane, in the condition of Ar protection, slowly drips the 4mL dichloromethane solution of compound 24.It is yellow that reaction mixture gradually becomes, and stirs 24h, and after reaction raw materials disappears completely, vacuum rotary steam, except desolventizing, obtains yellow oily material, and thick product obtains compound 50 after purifying with silicagel column. ¹H NMR(CDCl ₃，400MHz)δ6.14(d，J＝3.2Hz，1H)，5.57(s，1H)，5.41(d，J＝3.2Hz，1H)，4.00(t，J＝10.4Hz，1H)，2.93(br.d，J＝10.8Hz，1H)，2.77(br.d，J＝17.6Hz，1H)，2.27-2.12(m，3H)，2.03(m，1H)，1.97(br s，3H)，1.84(br.d，J＝14.0Hz，1H)，1.48(m，1H)，1.35(s，3H)； ¹³C NMR(CDCl ₃，400MHz)δ170.6，140.7，139.2，125.0，118.4，83.0，72.6，62.8，52.9，51.2，39.8，33.6，22.9，21.6，18.4。

Embodiment 2: the anti-diabetic of compound 1-50, chronic complicating diseases of diabetes active testing

Chronic complicating diseases of diabetes is that DM is disabled, lethal main cause, its pathogenesis relates to polyhydric alcohol bypass, Protein kinase C, hexosamine activates and the generation of advanced glycosylation end products, it is possible common ground that the mitochondrion reactive oxidants product of discovered in recent years hyperglycemia induction generates increase, the oxidasic activation of nicotinamide adenine dinucleotide reduced be more and more considered to high sugared induced oxidation stress key link, high sugar is by causing that protein uncoupling causes the overexpression of mitochondrion peroxide, cause oxidative stress, finally cause DNA damage.Simultaneously, from external model test and pathological examination to epidemiological study, many evidences show that inflammatory reaction is also one of main pathogeny of chronic complicating diseases of diabetes, relate to complicated molecular network and path: chemotactic factor is as monocyte chemoattractant protein (monocyte chemoattractant protein, MCP)-1 etc.; Adhesion molecule is as endothelial adhesion molecule 1, vascular cell adhesion albumen 1, and endotheliocyte selective attachment molecule, selects plain E, and α-actinin 4; Transcription factor is as nuclear factor (nuclear factor, NF)-κ B; And inflammatory cytokine is as IL-1, IL-6, IL-18 and tumor necrosis factor.Wherein NF-κ B has central role in the expression that regulates inflammation related gene, and the MCP-1 of mesangial cell secretion has brought into play pivotal role in inflammatory cell recruitment and interaction process.Therefore, chronic complicating diseases of diabetes is a kind of inflammatory episode in essence, inflammatory reaction is that oxidative stress damage, organizational structure change and a main mechanism of dysfunction, and inflammation and pro-inflammatory cytokine play decisive role in the developing of chronic complicating diseases of diabetes.

In vitro normal rat mesangial cell is exposed to the RPMI-1640 culture fluid 24h containing the high sugar of 30mmol/L, the gene expression dose of NF-κ B, MCP-1 and malonaldehyde (malondialdehyde in supernatant, MDA) content all obviously increases, the compound 1-50 that the inventive method obtains all can significantly suppress these under 10 μ mol/L concentration to be changed, and experimental data is as follows:

NF-κ B gene expression dose (x ± s) in table 1 mesangial cell culture supernatant

Group	NF-κB
		Normal control	0.092±0.013
High sugar	0.83±0.19
		Compound 1	0.33±0.026
Compound 2	0.25±0.012
		Compound 3	0.21±0.015
Compound 4	0.26±0.014
		Compound 5	0.29±0.016
Compound 6	0.31±0.012
		Compound 7	0.23±0.009
Compound 8	0.38±0.013
		Compound 9	0.30±0.015

Compound 10	0.24±0.008
		Compound 11	0.39±0.016
Compound 12	0.36±0.017
		Compound 13	0.32±0.016
Compound 14	0.28±0.007
		Compound 15	0.34±0.018
Compound 16	0.27±0.007
		Compound 17	0.46±0.027
Compound 18	0.35±0.012
		Compound 19	0.22±0.006
Compound 20	0.18±0.005
		Compound 21	0.36±0.014
Compound 22	0.41±0.022
		Compound 23	0.43±0.013
Compound 24	0.34±0.017
		Compound 25	0.37±0.016
Compound 26	0.39±0.011
		Compound 27	0.27±0.006
Compound 28	0.37±0.015
		Compound 29	0.36±0.016
Compound 30	0.45±0.017
		Compound 31	0.22±0.006
Compound 32	0.38±0.014
		Compound 33	0.33±0.014
Compound 34	0.44±0.019
		Compound 35	0.27±0.007
Compound 36	0.26±0.005
		Compound 37	0.19±0.005
Compound 38	0.47±0.015
		Compound 39	0.32±0.016
Compound 40	0.48±0.018
		Compound 41	0.45±0.016
Compound 42	0.38±0.015
		Compound 43	0.35±0.015
Compound 44	0.34±0.011
		Compound 45	0.36±0.015
Compound 46	0.29±0.017
		Compound 47	0.33±0.012
Compound 48	0.36±0.053

Compound 49	0.29±0.009
		Compound 50	0.37±0.011

The content (x ± s, pg/mL) of MCP-1 in table 2 mesangial cell culture supernatant

Group	MCP-1
		Normal control	30.28±6.86
High sugar	220.99±30.16
		Compound 1	40.36±10.33
Compound 2	50.18±12.09
		Compound 3	43.39±11.66
Compound 4	60.78±15.01
		Compound 5	55.66±9.32
Compound 6	70.58±20.42
		Compound 7	60.12±14.88
Compound 8	55.41±10.51
		Compound 9	43.45±8.74
Compound 10	66.52±19.59
		Compound 11	57.39±13.81
Compound 12	77.38±21.69
		Compound 13	46.37±8.62
Compound 14	56.36±14.54
		Compound 15	67.41±17.35
Compound 16	52.24±13.39
		Compound 17	49.87±14.65
Compound 18	57.59±14.29
		Compound 19	61.42±18.91
Compound 20	59.34±16.56
		Compound 21	70.16±20.70
Compound 22	52.43±17.83
		Compound 23	58.36±13.32
Compound 24	47.37±10.15
		Compound 25	44.19±9.76
Compound 26	61.42±15.52
		Compound 27	80.77±25.74
Compound 28	50.31±11.76
		Compound 29	56.43±12.89
Compound 30	54.38±14.96
		Compound 31	74.39±19.51

Compound 32	76.37±17.47
		Compound 33	65.41±16.25
Compound 34	68.35±17.22
		Compound 35	51.41±9.66
Compound 36	55.29±10.37
		Compound 37	54.31±14.75
Compound 38	58.35±13.26
		Compound 39	65.34±15.55
Compound 40	66.31±18.16
		Compound 41	67.41±17.54
Compound 42	47.36±11.59
		Compound 43	52.43±13.62
Compound 44	62.35±18.39
		Compound 45	65.18±14.33
Compound 46	63.76±19.06
		Compound 47	51.84±12.05
Compound 48	56.58±15.04
		Compound 49	66.19±17.55
Compound 50	68.38±12.16

The content (x ± s, nmol/L) of MDA in table 3 mesangial cell culture supernatant

Group	MDA
		Normal control	0.36±0.09
High sugar	2.55±0.63
		Compound 1	0.73±0.17
Compound 2	0.59±0.18
		Compound 3	0.90±0.29
Compound 4	0.47±0.16
		Compound 5	0.66±0.23
Compound 6	0.73±0.22
		Compound 7	0.86±0.27
Compound 8	0.62±0.21
		Compound 9	0.72±0.26
Compound 10	0.67±0.12
		Compound 11	0.68±0.15
Compound 12	0.59±0.17
		Compound 13	0.61±0.18
Compound 14	0.74±0.26

Compound 15	0.79±0.38
		Compound 16	0.61±0.21
Compound 17	0.65±0.24
		Compound 18	0.62±0.20
Compound 19	0.75±0.25
		Compound 20	0.78±0.19
Compound 21	0.59±0.15
		Compound 22	0.69±0.19
Compound 23	0.71±0.12
		Compound 24	0.63±0.13
Compound 25	0.88±0.27
		Compound 26	0.61±0.14
Compound 27	0.75±0.16
		Compound 28	0.95±0.28
Compound 29	0.64±0.17
		Compound 30	0.73±0.21
Compound 31	0.71±0.15
		Compound 32	0.75±0.25
Compound 33	0.64±0.23
		Compound 34	0.61±0.24
Compound 35	0.54±0.12
		Compound 36	0.64±0.14
Compound 37	0.94±0.30
		Compound 38	0.67±0.19
Compound 39	0.55±0.15
		Compound 40	0.74±0.24
Compound 41	0.63±0.13
		Compound 42	0.58±0.09
Compound 43	0.69±0.18
		Compound 44	0.64±0.25
Compound 45	0.76±0.29
		Compound 46	0.74±0.14
Compound 47	0.55±0.17
		Compound 48	0.65±0.20
Compound 49	0.77±0.26
		Compound 50	0.73±0.18

The present invention has observed compound 1-50 to normal rat mesangial cell secretion NF-κ B, the MCP-1 of high sugar cultivation and the impact of MDA, result shows, compound 1-50 all can significantly lower the expression of NF-κ B and MCP-1, reduce the generation of MDA, thereby inflammation-inhibiting reacts, alleviates oxidative stress damage, the effect of performance treatment diabetes, chronic complicating diseases of diabetes.

Embodiment 3: injection

The prepared compound 1-50 of embodiment 1 injects water after dissolving with a small amount of DMSO routinely, fine straining, and injection is made in embedding sterilizing.

Embodiment 4: tablet

The ratio that the prepared compound 1-50 of embodiment 1 and excipient are 5: 1 according to weight ratio adds excipient, and pelletizing press sheet, obtains tablet.

Embodiment 5: capsule

The ratio that the prepared compound 1-50 of embodiment 1 and excipient are 5: 1 according to weight ratio adds excipient, makes capsule.

Compound of the present invention, purposes and method are described by specific embodiment.Those skilled in the art can use for reference the links such as content appropriate change raw material of the present invention, process conditions and realize corresponding other object, its relevant change does not all depart from content of the present invention, within all similar replacements and change will become apparent to those skilled in the art that and be all deemed to be included in scope of the present invention.

Claims

1. formula (I) compound is in prevention, treatment or adjuvant therapy of diabetes, chronic complicating diseases of diabetes and the application in the medicine of preparation prevention, treatment or adjuvant therapy of diabetes, chronic complicating diseases of diabetes thereof.

R ₇with R ₈between---when-key is singly-bound, R ₇=R ₈=methylene.

R ₁₀for hydrogen, or R ₁₀with R ₈become singly-bound.

2. in claim 1, structural formula (I) is preferably:

3. the application of the compound of the arbitrary claim of claim 1 to 2 in prevention, treatment or adjuvant therapy of diabetes, chronic complicating diseases of diabetes medicine.

4. the application of the compound of the arbitrary claim of claim 1 to 2 in preparation prevention, treatment or adjuvant therapy of diabetes, chronic complicating diseases of diabetes medicine.

5. a pharmaceutical composition for prevention, treatment or adjuvant therapy of diabetes, chronic complicating diseases of diabetes, described pharmaceutical composition contains the compound as the compound of the arbitrary claim of at least one claim 1 to 2 of active component and pharmaceutically acceptable carrier or other preventions, treatment or adjuvant therapy of diabetes, chronic complicating diseases of diabetes.