CN102603861A

CN102603861A - Tanshinone derivatives, medicine compositions thereof, and purposes thereof in medicine

Info

Publication number: CN102603861A
Application number: CN2012100441999A
Authority: CN
Inventors: 赵勤实; 冷颖; 邓旭; 赵昱; 沈瑜; 罗晓星
Original assignee: Kunming Institute of Botany of CAS
Current assignee: Kunming Institute of Botany of CAS
Priority date: 2012-02-25
Filing date: 2012-02-25
Publication date: 2012-07-25

Abstract

The invention relates to tanshinone derivatives represented by a general formula (I), wherein the tanshinone derivatives are substituted by different groups on A ring, B ring, C ring, and D ring. The invention also relates to medicine compositions with the derivatives as active components, preparation methods of the medicines, and applications thereof in preparing a 1-type 11beta-hydroxysteroid dehydrogenase (11beta-HSD1) inhibiting agent. The invention also provides applications of the compounds represented by the general formula (I) in preparations of medicines used for treating diabetes and related metabolic diseases (such as hypertension, obesity, senile dementia, and the like).

Description

Tanshinone derivative and pharmaceutical composition thereof and its purposes in medicine

Technical field:

The invention belongs to medical compounds and technical field of pharmaceuticals; Be specifically related to the class I tanshinone compound; This compounds is the pharmaceutical composition of activeconstituents, its preparation method and this compounds and its pharmaceutical composition preparation 1 type 11-beta-hydroxysteroid dehydrogenase (in the selective depressant of 11 β-HSD1) with the medicine of anti-diabetic and correlated metabolism (hypertension, obesity, senile dementia etc.) disease in application.

Background technology:

The metabolic disease (comprising obesity, blood lipid dysbolism, hypertension and cardiovascular complication etc.) that mellitus and glucocorticosteroid are relevant has become puzzlement modern's main health problem (Rosenstock, J.et.Diabetes Care 2010,33,1516.).Show that according to The World Health Organization's incomplete statistics the whole world has 1,600,000,000 body weight for humans overweight approximately, wherein has 400,000,000 people to show clinical diabetic symptom (Wamil; M.et.Drug Discovery Today 2007; 12,504), and situation also among further worsening.Therefore, severe situation has been given the mission that medical worker is duty-bound---and the mellitus matter hormone of seeking new and effective low spinoff is one type of important steroid hormone.It participates in regulating some and coercing relevant physiological process, like glyconeogenesis, and inflammatory reaction, brain function, immunne response etc.The glucocorticosteroid that two kinds of forms are arranged in the human body, that is: the KE of the HYDROCORTISONE INJECTIONS of activity form and inactive form.

11 beta-hydroxysteroid dehydrogenases (the pivotal player of 11 β-HSD) in the glucocorticosteroid horizontal adjustment, play the part of.Since 11 β-HSD in 1988 comes to light (Lakshmi, V.et.Endocrinology 1988,123, and 2390.), the researchist is lasting to the research enthusiasm of 11 β-HSD, and is also more and more deep to 11 β-HSD understanding.11 beta-hydroxysteroid dehydrogenases that two kinds of hypotypes are arranged in the organism, and 11 beta-hydroxysteroid dehydrogenases, 1 type enzyme (11 β-HSD1) and 2 type enzymes (11 β-HSD2).11 β-HSD1 and 11 β-HSD2 is to be cofactors with nicotinamide-adenine (NADPH), and all is positioned on the endocytoplasmic reticulum film, and their fellowships are regulated the level of biological activity in vivo glucocorticosteroid and nonactive glucocorticosteroid.11 β-HSD1 has oxidation and the effect of reductive dual catalytic, is distributed widely in the target organ of glucocorticosteroid, is one and has tissue-specific glucocorticoid modulators (Tomlinson, J.W.et.Endocr.Rev.2004,25,831.).It is generally acknowledged now; 11 β-HSD1 (in body) under the complete situation of cell is mainly reductase enzyme, in the presence of coenzyme NADP 11, the intravital target site of people is regenerated as active HYDROCORTISONE INJECTIONS with inactive KE---and the most obvious with performance in liver, fatty tissue and the cerebral tissue; Thereby amplified the activation (Tomlinson of GR in local organization; J.W.et.Drug Discovery Today.:Therapeutic Strategies2005,2,93).And 11 β-HSD2 mainly shows as oxydase, and the above-mentioned reversed reaction of catalysis (Staab, C.A.et.J.Steroid Biochem.Mol.Biol.2010,119,56) mainly at kidney, is expressed in large intestine and the saliva.Under the normal circumstances in the human body, generally have only 5% HYDROCORTISONE INJECTIONS to be free on blood plasma.The HYDROCORTISONE INJECTIONS of the overwhelming majority and high affine sphaeroprotein or low affine albumin bound, in case receive environment-stress, its content rises rapidly and reaches mM level (Stewart, P.M.et.Vitam.Horm.1999,57,249).After active glucocorticosteroid freely is diffused into blood plasma; Form mixture with glucocorticosteroid (some the is organized as mineralocorticoid) receptors bind in the blood plasma; Mixture is transported in the nucleus, directly or with the common regulate gene expression of other transcription factor interaction (Staab, C.A.et.J.Steroid Biochem.Mol.Biol.2010; 119,56) (figure-1).

Research shows, 11 β-HSD1 is at the evolution of the control of insulin sensitivity and insulin resistance play an important role (Tomlinson, J.W.et.Drug Discovery Today:Therapeutic Strategies 2005,2,93).The transgenic mice experimental result has also confirmed this inference: the mouse of overexpression 11 β-HSD1 just shows insulin resistant in several weeks, and the heart is hungry fat, symptoms such as hypertension; And the mouse of 11 β-HSD1 gene knockout does not show these symptoms (Boyle, C.D.Curr.Opin.Drug.Discov.Devel.2008,11,495; Wamil, M.et.Drug Discovery Today 2007,12,504).In addition, after the patient who suffers from Cushing ' s syndromes took sugared cortisol receptor antagonist, illness can significantly be alleviated.The result of study of chewing tooth class animal and a small amount of human experimentation also confirms: the activity that suppresses 11 β-HSD1 is effective way (Odermatt, A.Curr.Enzyme Inhib.2005,1,107 of treatment metabolic syndrome; Ge, R.et.Curr.Med.Chem.2010,17,412; Staab, C.A.et.J.Steroid Biochem.Mol.Biol.2010,119,56).

Still non-selectivity 11 beta-HSD 1 inhibitors clinically at present.11 β of early development-HSD suppressor factor mainly is an Enoxolone derivative.Carbenoxolone (CBX) be first by 11 β of broad research-HSD suppressor factor, it is the monomester succinate of glycyrrhetinic acid (GA).After thin metabolic syndrome patient takes CBX; Insulin sensitivity and blood fat total content have obviously improved, and after fat metabolic syndrome patient took CBX, insulin sensitivity and blood fat total content did not improve; This possibly be because CBX can not enter into the interior (Staab of the fatty tissue of obese individuals; C.A.et.J.Steroid Biochem.Mol.Biol.2010,119,56).In view of CBX is nonselective 11 beta-HSD 1 inhibitors, it can suppress 11 β-HSD1 and 11 β-HSD2 simultaneously, and its clinical value receives great restriction.Therefore, research and development a new generation has height 11 β-HSD1 narrow spectrum suppressor factor and has important practical significance.

Tanshinone II A and VSZ3505 are for separating two fat-soluble cpdss that obtain from the ethanol extraction of the dry root and rhizome of China's traditional Chinese medicine red sage root (Salvia miltiorrhiza Bge.).Tanshinone compound often has wide biological activity---and like platelet aggregation-against, reducing blood-fat, antitumor, E.C. 3.1.1.7 inhibition etc., existing at present red sage root sodium sulfonate is used to treat cardiovascular disordeies such as coronary heart disease, Stroke, atherosclerosis clinically.Patent about tanshinone compound mainly concentrates on its extraction and separation method (as: Yao Yudong, Jin Bo, Hu Yaochang, Mo Qiwu, Liu Hancha, a kind of method of extracting and refining tanshinone IIA by supercritical CO 2, publication number CN1369485 at present; Chu Zhide, Meng Xianling, a kind of process for extracting of Tanshinone II A, publication number CN1923846; Weiping YIN, Wang Zhongdong, horse military camp, Wu Yunji, Wang Xiaowei, Duan Wenlu, Zhang Yanping, Lv Benlian, pharmaceutical intermediate Tanshinone I I A extraction process, publication number CN1935799; Zheng Zhigang, Yang Yuewu, Wang Shuanming, Lu Wenliang, a kind of process for extracting of TANSHINONES, publication number CN1670019; Tian Guilian, Zhang Tianyou, a kind of method of separation and purification TANSHINONES, publication number CN1394870 etc.), the preparation method of preparation (like Chu Maoquan, Gu Hongchen, Liu Guojie, tanshinone solid disperser and preparation method thereof, publication number CN1277840; Chu Maoquan, Gu Hongchen; , Liu Guojie, spherical lipid powder of tanshinone precursor and preparation method thereof, publication number CN1298697; Chu Maoquan, Gu Hongchen, Liu Guojie, TANSHINONES micro mist preparation and microwave aided co-grinding process for preparing thereof, publication number CN1286083; Liu Li, Tanshinone II A sulfonic acid or Danshinone II A sodium sulphonate freeze dried powder injection agent preparation and preparation method thereof, publication number CN1623538; Lv Weifeng, Xi Tao, appoint quick, Tanshinone II A dripping pill, publication number CN1698597; Military spring breeze, Tanshinone II A infusion solution and preparation method thereof, publication number CN1732915; Mao Shengjun; Jin Hui, beam is attained, Wu Yu; A kind of tanshinone emulsion and preparation method thereof; Publication number CN1839818 etc.), the application in treatment cardiovascular disorder, antitumor, anti-senile dementia disease of TANSHINONES and TANSHINONES sodium sulfonate (like Zou Qiaogen, the application of Tanshinone I sodium sulfonate in field of medicaments, publication number CN1857250; Shao Pengzhu, He Zhiyun, Feng Guopei, Wen Zhichang, TANSHINONES is as the application of acetylcholinesterase depressant in the treatment relative disease, publication number CN1764447; Yuan Shulan, the sheep descendants are bright, the gold-tinted fine jade, Zhou Qinghua, Liu Ting, Wang Xiujie, Huang Ren is quick, Zhou Hongyuan, the application of TANSHINONES in preparation medicine for treating tumor thing, publication number CN1264580 etc.).Yet the synthetic preparation patent about tanshinone derivative less (as: Qin Yinlin, Yan Peiling, He Longqi, the Tanshinone II A application in pharmacy, publication number CN 1631364; Qin Yinlin, Tanshinone I verivate and the application in pharmacy thereof, publication number CN 1837200; Du Zhiyun opens Kun, Fang Yanxiong, the ancient power of practicing, Huang Baohua, Zhao Suqing, Zhou Lihua, Zheng Jie, tanshinone derivative and the application in the preparation aldose reduction enzyme inhibitor pharmaceutical, publication number CN 101012270; The ancient power of practicing, Liu Peiqing, Li Guihua, Tanshinone II A are used for the preparation prevention and treat atherosclerotic medicine, publication number CN 1426782 etc.), and aspect active, mainly still concentrate on traditional cardiovascular and tumor area.At present; As yet relevant for the synthetic of tanshinone derivative and report, there is not its report in the prior art as selectivity 11-beta-HSD 1 inhibitors and the application in preparation treatment mellitus and relevant metabolic disease (hypertension, obesity, senile dementia etc.) medicine thereof yet.

Summary of the invention:

The object of the present invention is to provide the class I tanshinone verivate; With it is the pharmaceutical composition of activeconstituents; Their compound method; And the application of this compounds in preparation selectivity 11 beta-HSD 1 inhibitors medicines, the application of this compounds in preparation treatment mellitus and correlated metabolism diseases (hypertension, obesity, senile dementia etc.) medicine also is provided simultaneously.

Above-mentioned purpose of the present invention is to realize through following technical scheme:

Tanshinone derivative shown in the general formula (I)

R ₁, R ₂, R ₃, R ₄, R ₅, R ₆Independently be selected from hydrogen respectively; Halogen; Hydroxyl; The ketone carbonyl; Lower alkoxy; Cycloalkyloxy; The substituted carbon acyloxy of low alkyl group; The carbon acyloxy of cycloalkyl substituted; The substituted carbon acyloxy of aryl or heterocyclic aryl; The substituted carbonyl of low alkyl group; The carbonyl of cycloalkyl substituted; The substituted carbonyl of aryl or heterocyclic aryl; Amino; Cyanic acid; Nitrine; The substituted amido of low alkyl group; The amido of cycloalkyl substituted; The substituted amido of aryl or heterocyclic aryl; The substituted carboxamido-group of low alkyl group; The carboxamido-group of cycloalkyl substituted; The substituted carboxamido-group of aryl or heterocyclic aryl; The substituted sulfoamido of low alkyl group; The sulfoamido of cycloalkyl substituted; The substituted sulfoamido of aryl or heterocyclic aryl; The substituted alkylsulfonyl of low alkyl group; The alkylsulfonyl of cycloalkyl substituted; The substituted alkylsulfonyl of aryl or heterocyclic aryl; OC (=O) N (R ₁₃) ₂, O (CH ₂) mN (R ₁₃) ₂, OC (=O) (CH ₂) mCOOR ₁₃, m=1-5 wherein, R ₁₃Be hydrogen or low alkyl group;

R ₇Independently be selected from hydrogen respectively; Halogen; Aryl or heterocyclic aryl; The substituted carbonyl of low alkyl group; The carbonyl of cycloalkyl substituted; The substituted carbonyl of aryl or heterocyclic aryl; Nitro; Amino; The substituted amido of low alkyl group; The amido of cycloalkyl substituted; The substituted amido of aryl or heterocyclic aryl; The substituted carboxamido-group of low alkyl group; The carboxamido-group of cycloalkyl substituted; The substituted carboxamido-group of aryl or heterocyclic aryl; The substituted sulfoamido of low alkyl group; The sulfoamido of cycloalkyl substituted; The substituted sulfoamido of aryl or heterocyclic aryl; The substituted alkylsulfonyl of low alkyl group; The alkylsulfonyl of cycloalkyl substituted; The substituted alkylsulfonyl of aryl or heterocyclic aryl;

R ₈, R ₉Independently be selected from hydrogen respectively; Carboxyl; Methyl; The hydroxyl methylene radical; The lower alkoxy methylene radical; The cycloalkyloxy methylene radical; The substituted phosphinylidyne oxygen of low alkyl group methylene; The phosphinylidyne oxygen methylene of cycloalkyl substituted; The substituted phosphinylidyne oxygen of aryl or heterocyclic aryl methylene; The substituted amido methylene radical of low alkyl group; The substituted amido methylene radical of aryl; The substituted carboxamido-group methylene radical of low alkyl group; The substituted carboxamido-group methylene radical of aryl; The fluoro methylene radical; The substituted sulfoamido methylene radical of low alkyl group; The sulfoamido methylene radical of cycloalkyl substituted; The substituted sulfoamido methylene radical of aryl or heterocyclic aryl;

R ₁₀, R ₁₁Independently be selected from hydrogen respectively; Halogen; Carboxyl; Aryl or heterocyclic aryl; The hydroxyl methylene radical; The lower alkoxy methylene radical; The cycloalkyloxy methylene radical; The substituted phosphinylidyne oxygen of low alkyl group methylene; The phosphinylidyne oxygen methylene of cycloalkyl substituted; The substituted phosphinylidyne oxygen of aryl or heterocyclic aryl methylene; The substituted amido methylene radical of low alkyl group; The substituted amido methylene radical of aryl; The substituted carboxamido-group methylene radical of low alkyl group; The substituted carboxamido-group methylene radical of aryl; The fluoro methylene radical; The substituted sulfoamido methylene radical of low alkyl group; The sulfoamido methylene radical of cycloalkyl substituted; The substituted sulfoamido methylene radical of aryl or heterocyclic aryl; The substituted carbonyl of low alkyl group; The carbonyl of cycloalkyl substituted; The substituted carbonyl of aryl or heterocyclic aryl; Nitro; Amino; The substituted amido of low alkyl group; The amido of cycloalkyl substituted; The substituted amido of aryl or heterocyclic aryl; The substituted carboxamido-group of low alkyl group; The carboxamido-group of cycloalkyl substituted; The substituted carboxamido-group of aryl or heterocyclic aryl; The substituted sulfoamido of low alkyl group; The sulfoamido of cycloalkyl substituted; The substituted sulfoamido of aryl or heterocyclic aryl;

R ₁₂Independently be selected from the substituted carbonyl of carbonyl, aryl or heterocyclic aryl, the substituted alkylsulfonyl of low alkyl group of hydrogen, alkyl, naphthenic base, aryl or heterocyclic aryl, the substituted carbonyl of low alkyl group, cycloalkyl substituted, the substituted alkylsulfonyl of alkylsulfonyl, aryl or heterocyclic aryl of cycloalkyl substituted respectively;

Or R ₁, R ₃Form covalent linkage;

Or R ₂, R ₄Form covalent linkage;

Or R ₈, R ₁₀Form covalent linkage;

Or R ₉, R ₁₁Form covalent linkage;

Or R ₅, R ₆Formation=X ₆, X wherein ₆Be selected from C, O, S, NH etc.;

X ₁, X ₂, X ₃, X ₄Independently be selected from the alkyl of acyloxy, alkoxyl group, hydroxyl, β-carbonyl substituted etc. respectively;

Or X ₁, X ₃Form covalent linkage;

Or X ₂, X ₄Form covalent linkage;

Or X ₁, X ₂Formation=X ₆, X wherein ₆Be selected from C, O, S, NH etc.;

Or X ₁, X ₂, X ₃, X ₄Form 2-substituted imidazole ring, the substituted thiazole ring of 2-, 2,3-Qu Dai De oxazole, 2,3 substituted piperazine rings etc.;

Or X ₁, X ₂, X ₃, X ₄Form C (=O) OC (=O), C (=O) NR ₁₄C (=O), R wherein ₁₄Be selected from hydrogen or low alkyl group;

X ₃Be selected from carbon, nitrogen, oxygen, sulphur atom etc.;

" alkyl " mentioned in the literary composition is meant the hydrocarbon functional group of the straight or branched that contains 1-10 carbon atom; For example methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, n-pentyl, isopentyl, neo-pentyl, n-hexyl, isohexyl, 3-methyl hexyl, 2; 2-dimethyl-amyl group, 2; 3-dimethyl-amyl group, n-heptyl, n-octyl, n-nonyl, positive decyl etc., but not only for as listed above.

" low alkyl group " mentioned in the literary composition is meant the hydrocarbon functional group of the straight or branched that contains 1-4 carbon atom, for example methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl etc., but not only for as listed above.

" naphthenic base " mentioned in the literary composition is meant the ring-type functional group that contains 3-8 atom; For example Trimetylene base, tetramethylene base, pentamethylene base, cyclohexyl, suberane base, cyclooctane base or pyrrolidyl, morphine quinoline base, piperidyl etc., but not only for as listed above.

" aryl " mentioned in the literary composition is meant the aromatic ring functional group that contains 5-10 atom, like phenyl, naphthyl, furyl, thiazolyl, thienyl, imidazolyl, oxazolyl, quinolyl, indyl etc., but not only for as listed above.

" halogen " mentioned in the literary composition is meant fluorine, chlorine, bromine, iodine.

The salt of allowing on general formula (I) tanshinone derivative or its pharmacology is preferably compound T4, T6, T7, T8, T9, T14, T21, T24, T25, T28, T31, T38, T39, T43, the T51 shown in the following structural formula.

Pharmaceutical composition wherein contains claim 1 general formula (I) tanshinone compound and the pharmaceutically acceptable carrier of treating significant quantity.

The preparation method of general formula (I) tanshinone derivative comprises the acid catalyzed Fridiel-Craft reaction of the synthetic imidazoles of three component reaction, catalytic hydrogenation, the oxidation of benzyl position, aromatic ring halo, Suzuki cross-coupling reaction, the catalytic dihydroxylation reaction of potassium osmate, Bransted, the synthetic pyrroles's reaction of diketone of nitrated, the adjacent dicarbapentaborane participation of elimination reaction, allylic oxidation, hydroxyl fluoro, phenyl ring of free radical mediated.

The preparation method of aforesaid general formula (I) tanshinone derivative comprises the elimination reaction synthetic compound T4 by free radical mediated, by SeO ₂The allylic oxidation synthetic compound T7 and the T8 that participate in are by SeO ₂The benzyl position oxidation synthetic compound T43 that participates in, the catalytic Suzuki linked reaction of Pd (0) synthetic compound T29, T30, T31, T32, T33, T34.

The salt of allowing on general formula (I) tanshinone derivative or its pharmacology is the application of effective constituent in preparation 11 β-HSD1 selective depressant medicine.

The salt of allowing on general formula (I) tanshinone derivative or its pharmacology is that effective constituent reaches the application in relevant metabolic disease (hypertension, obesity, the senile dementia etc.) medicine in preparation treatment mellitus.

The salt of allowing on its pharmacology of tanshinone derivative of the present invention for example can be enumerated and mineral acids such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, Hydrogen bromide, perhaps toxilic acid, fumaric acid, tartrate, lactic acid, Hydrocerol A, acetate, methylsulfonic acid, tosic acid; Hexanodioic acid, palmitinic acid, organic acids such as Weibull; Lithium; Basic metal such as sodium, potassium, earth alkali metal such as calcium, magnesium, the salt that basic aminoacidss such as Methionin become.

When The compounds of this invention is used as medicine, can directly use, perhaps use with the form of pharmaceutical composition.This pharmaceutical composition contains 0.1-99%, is preferably the The compounds of this invention of 0.5-90%, and all the other are acceptable on the pharmacology, nontoxic and inert pharmaceutically acceptable carrier to humans and animals.

Described pharmaceutically acceptable carrier is one or more solids, semisolid and liquid diluent, filler and pharmaceutical preparation auxiliary material.Pharmaceutical composition of the present invention uses with the form of per weight dose.Using the adoptable formulation of medicine of the present invention is the lid human relations form of administration of habitually practising, for example: ointment, tablet, pill, suppository emulsion, input liquid and injection liquid etc.These formulations use traditional additive and excipient to make according to well-known method.The medicine that makes thus as required can be by part, non-enteron aisle, administration such as oral.

The amount of application of The compounds of this invention can be according to variations such as the type of route of administration, patient's age, body weight, the disease of being treated and severity, and its per daily dose can be the 0.01-10mg/kg body weight, preferred 0.1-5mg/kg body weight.Can use by one or many.

Characteristics of the present invention and superiority are; Reported one type of novel tanshinone derivative; Their preparation method, and, in the metabolic disease medicine for preparing the treatment mellitus and be correlated with, good application prospects is arranged as one type of new and high-efficiency, highly selective 11 beta-HSD 1 inhibitors.

Description of drawings:

Fig. 1 is the effect (draw from J.Steroid Biochem.Mol.Biol.2010,119,56) of 11 β-HSD in glucocorticosteroid is regulated;

Fig. 2 is the reacting flow chart to Tanshinone II A and VSZ3505 A ring and B ring derived compounds;

Fig. 3 is the reacting flow chart to Tanshinone II A and VSZ3505 C ring derived compounds;

Fig. 4 is the reacting flow chart to Tanshinone II A and VSZ3505 D ring derived compounds.

Embodiment:

Essence for a better understanding of the present invention; The preparation method and the pharmacological action result of the tanshinone derivative shown in the general formula of the present invention (I) will be described with Test Example of the present invention, embodiment and FORMULATION EXAMPLE below; But technical scheme of the present invention is not limited thereto; The similar technical scheme of the present invention of any employing, the scheme that does not need those of ordinary skills' creative work to make are all thought and are belonged to technical scheme category of the present invention.

Embodiment 1:

Concrete experimental technique of the present invention is: to separate the Tanshinone II A and the VSZ3505 that obtain in the traditional Chinese medicine red sage root is starting raw material, the tanshinone derivative shown in the synthetic general formula (I).Specifically, Tanshinone II A and VSZ3505 are the starting raw materials that is used to prepare this compounds, and Tanshinone II A (T1) can separate from the ethanol extract of the traditional Chinese medicine red sage root with VSZ3505 (T2) and obtains.

The structural formula of Tanshinone II A and VSZ3505 is:

Tanshinone compound shown in the general formula (I) can obtain (seeing reacting flow chart, Fig. 2,3,4) by Tanshinone II A and VSZ3505 through 1-4 step reaction through the reaction process among the embodiment 1.

Fig. 2 is the reacting flow chart to Tanshinone II A and VSZ3505 A ring and B ring derived compounds; Reagent and reaction conditions are: a) NBS, AIBN, CCl ₄, reflux; B) NaOAc, TBAI, DMF, RT; C) K ₂OsO ₄, NMO, 2,6-lutidine, t-BuOH/H ₂O, RT; D) NBS, AIBN, CCl ₄, reflux; E) SeO ₂, 1,4-dioxane, reflux; F) DAST, DCM ,-78 ℃; G) succinic anhydride, Et ₃N, DMAP, DCM, RT; H) H ₂, Pd/C, HCOOH, MeOH, RT; I) HNO ₃, H ₂8O ₄, 0 ℃;

Fig. 3 is the reacting flow chart to Tanshinone II A and VSZ3505 C ring derived compounds; Reagent and reaction conditions are: a) Lewesson ' s reagent, THF, RT; B) PhCHO, AcONH ₄, EtOH, reflux; C) PtO ₂, H ₂, Pyridine, Ac ₂O, RT; D) m-CPBA, NaHCO ₃, DCM, RT; E) diethyl amine, acetone ,-40 ℃;

Fig. 4 is the reacting flow chart to Tanshinone II A and VSZ3505 D ring derived compounds; Reagent and reaction conditions are: a) NaOH (2N), THF/H ₂O, ultrasound; B) NH ₃H ₂O, EtOH, RT; C) RCOCl, Et ₃N, DCM, RT; D) RSO ₂Cl, DMAP, Pyridine, 78 ℃-RT; E) IBX, DMSO, RT; Then, NH ₄OAc (or PhNH ₂), HOAc, 60 ℃; F) SeO ₂, HOAc, reflux; G) MsCl, Et ₃N, DMAP, THF, RT; Then, PhNH ₂, TBAI, THF, reflux; H) TBAI, nucleaphilic reagent, DMF, 50 ℃; J) DAST, DCM ,-78 ℃; K) succinic anhydride, Et ₃N, DMAP, DCM, RT; 1) IBX, DMSO, RT; Then, NaClO ₂, iso-pentene, KH ₂PO ₄, acetone/H ₂O, RT; N) NIS, TFA, DCM, RT; O) ArB (OH) ₂, Pd (PPh ₃) ₄, PPh ₃, K ₂CO ₃, DMF/H ₂O, 80 ℃; P) HCHO, HCl (con.), H ₂O, reflux;

Following method is used in the preparation of TANSHINONES and VSZ3505 (compound T1, T2):

Radix Salviae Miltiorrhizae extract (process for extracting referring to: Pharmacopoeia of People's Republic of China 2010 editions); Use acetone, dissolve with ethanol successively; The elimination insolubles, filtrating silica gel mixed sample column chromatography, sherwood oil/acetone gradient elution; Recycle method purifying such as positive, reversed phase column chromatography and sherwood oil/acetone recrystallization then and obtain TANSHINONES (sherwood oil: ETHYLE ACETATE=10: 1, R _f=0.4), VSZ3505 (sherwood oil: ETHYLE ACETATE=5: 1, R _f=0.3) monomer.

Embodiment 2:

The preparation of compound T3, T4, T5:

To compound T1 (29mg, CCl 0.1mmol) ₄(5mL) in the solution, add successively NBS (27mg, 0.15mmol) and Benzoyl Peroxide (36mg, 0.15mmol).After adding, substitute gas (N ₂), room temperature condition reacted 3 hours down then.After reaction finishes, add the DCM dilution, use saturated Na then ₂SO ₃The aqueous solution is washed, and water merges organic phase with three times (5mL * 3) of DCM extraction, washes with saturated sodium-chloride water solution, and anhydrous sodium sulfate drying concentrates back column chromatography (sherwood oil: ETHYLE ACETATE=15: 1), get compound T3 (15mg, 50%).The structural analysis data of compound T3 are following:

ESI-MS measures on shimadzu LCMS-2010EV mass spectrograph; 1D and 2D NMR measure on BrukerAM-300 and DRX-500 NMR, and used deuterated reagent is produced for Sigma Aldrich, and TMS is as interior mark, and δ unit is ppm, and J unit is Hz.Mix appearance and use silica gel to be the 100-200 order, silica gel for chromatography is that 300-400 order and preparation thin layer plate (thickness 0.4-0.5mm) are the production of river, Yantai friend's silica gel development corporation, Ltd.; The analytical pure solvent all is Tianjin chemical industry ltd products.

Compound T3: red solid, ¹H-NMR (400MHz, CDCl ₃) δ 7.62 (s, 1H), 6.77 (s, 1H), 2.38 (t, J=12Hz, 12Hz, 2H), 2.15 (m, 5H), 1.61 (d, J=12Hz, 2H), 1.38 (s, 3H), 1.18 (s, 3H);

Compound T4: red solid, red solid, ¹H-NMR (400MHz, CDCl ₃) δ 7.86 (d, J=12Hz, 1H), 7.57 (s, 2H), 7.23 (s, 1H), 6.33 (dt, J=8Hz, 4Hz, 4Hz, 1H), 2.28 (m, 2H), 2.27 (s, 3H), 1.61 (s, 3H), 1.30 (s, 6H);

Embodiment 3:

The preparation of compound T6:

To compound T3 (18mg, in DMF 0.05mmol) (1.0mL) solution, add successively NaOAc (16mg, 0.2mmol) and TBAI (3mg).After adding, room temperature condition reacted 12 hours down.After reaction finishes, add water (10mL) dilution, then with three times (8mL * 3) of EtOAc extraction; Merge organic phase, water and saturated sodium-chloride water solution are washed successively, anhydrous sodium sulfate drying; Concentrate back column chromatography (sherwood oil: ETHYLE ACETATE=6: 1), get compound T6 (12mg, 70%).

Compound T6:: red solid, ¹H-NMR (500MHz, CDCl ₃) δ 7.73 (d, J=10Hz, 1H), 7.72 (s, 1H), 6.41 (s, 1H), 2.21 (s, 3H), 2.02 (s, 3H), 1.90-1.98 (m, 2H), 1.60 (m, 4H), 1.40 (s, 3H), 1.28 (s, 3H);

Embodiment 4:

The preparation of compound T7, T8:

At N ₂Under the atmosphere,, in 4-dioxane (1.0mL) solution, add SeO to 1 of compound T4 (15mg) ₂(22mg), be heated to back flow reaction 1.5 hours.After the TLC detection reaction finished, thin up with EtOAc extraction three times, merged organic phase then; Wash with saturated sodium-chloride water solution, anhydrous sodium sulfate drying concentrates back column chromatography (sherwood oil: ETHYLE ACETATE=5: 1 → 2: 1); Get compound T7 (10mg, 67%) and T8 (3mg, 20%).

Compound T7: red solid, ¹H-NMR (500MHz, CDCl ₃) δ 8.92 (d, J=10Hz, 1H), 7.72 (d, J=10Hz, 1H), 7.65 (d, J=5Hz, 1H), 7.23 (s, 1H), 6.34 (d, J=10Hz, 1H), 2.22 (s, 3H), 1.44 (s, 6H).

Compound T8: red solid, ¹H-NMR (500MHz, CDCl ₃) δ 8.98 (d, J=10Hz, 1H), 7.79 (d, J=5Hz, 1H), 7.71 (d, J=10Hz, 1H), 7.29 (s, 1H), 6.41 (d, J=10Hz, 1H), 2.28 (s, 3H), 1.59 (s, 2H), 1.50 (s, 6H).

Embodiment 5:

The preparation of compound T9

At N ₂Under the atmosphere, to the t-BuOH/H of compound T4 (15mg) ₂In 0 (0.8mL/0.2mL) solution, add 2 successively, 6-lutidine (10mg) and Russia's acid potassium (4mg), stirring at room once added sodium periodate (42mg) after 15 minutes, and room temperature reaction 4 hours after the TLC detection reaction finishes, adds saturated Na ₂S ₂O ₃Cancellation is reacted, and behind the thin up, with EtOAc extraction three times, merges organic phase, washes with saturated sodium-chloride water solution, and anhydrous sodium sulfate drying concentrates back column chromatography (sherwood oil: ETHYLE ACETATE=1.5: 1), get compound T9 (11mg, 68%).

Compound T9: red solid, ¹H-NMR (400MHz, CDCl ₃) δ 7.70 (s, 1H), 7.26 (s, 1H), 5.00 (d, J=4Hz, 1H), 3.93 (dt, J=12Hz, 4Hz, 4Hz, 1H), 2.26 (s, 3H), 2.09 (t, J=12Hz, 12Hz, 1H), 1.76 (dd, J=12Hz, 4Hz, 1H), 1.39 (s, 3H), 1.32 (s, 1H).

Embodiment 6:

The preparation of compound T10, T11

In the MeOH/HCOOH of compound T7 (15mg) (8.0mL/1.0mL) solution, add Pd/C (3mg), substitute gas (H ₂), room temperature reaction 2.5 hours.After the TLC detection reaction finished, thin up with EtOAc extraction three times, merged organic phase then; Wash with saturated sodium-chloride water solution, anhydrous sodium sulfate drying concentrates back column chromatography (chloroform: acetone=3: 1); Get compound T10 (8mg, 54%) and T11 (5mg, 33%).

Compound T10: red solid, ¹H-NMR (400MHz, CDCl ₃) δ 7.66 (d, J=8Hz, 1H), 7.60 (d, J=8Hz, 1H), 7.24 (s, 1H), 3.78 (d; J=12Hz, 1H), 3.40 (dt, J=20Hz, 4Hz, 4Hz, 1H), 3.27 (dt, J=16Hz; 4Hz, 4Hz, 1H), 1.94-2.04 (m, 4H), 1.35 (s, 3H), 1.34 (s, 3H);

Compound T11: red solid, ¹H-NMR (400MHz, CDCl ₃) δ 7.67 (d, J=12Hz, 1H), 7.65 (d, J=8Hz, 1H), 4.90 (t, J=8Hz, 8Hz; 1H), 4.38 (t, J=8Hz, 4Hz, 1H), 3.79 (d, J=8Hz, 1H), 3.62 (dd; J=8Hz, 4Hz, 1H), 3.42-3.49 (m, 1H), 3.26-3.31 (m, 1H), 2.04-2.07 (m, 1H); 1.89-1.98 (m, 1H), 1.55-1.62 (m, 2H), 1.37 (d, J=12Hz, 3H), 1.25 (s, 6H);

Embodiment 7:

The preparation of compound T12, T42, T48 (with the example that is prepared as of compound T48)

At N ₂Under atmosphere ,-78 ℃ of conditions, in the DCM of compound T43 (12mg) (1.0mL) solution, dropwise add DAST (20mg), reaction is 15 minutes under this temperature; After the LC detection reaction finished, thin up was then with EtOAc extraction three times; Merge organic phase, wash anhydrous sodium sulfate drying with saturated sodium-chloride water solution; Concentrate back column chromatography (sherwood oil: ETHYLE ACETATE=10: 1), get compound T48 (8mg, 68%).Compound T48: red solid, ¹H-NMR (400MHz, CDCl ₃) δ 7.70 (d, J=8Hz, 1H), 7.64 (m, 2H), 7.57 (d, J=24Hz, 1H), 6.28 (d, J=8Hz, 1H), 5.64 (t, J=8Hz, 8Hz, 1H), 3.22 (m, 2H), 1.81 (m, 2H), 1.67 (m, 2H), 1.32 (s, 6H).

Embodiment 8:

The preparation of compound T13, T49 (with the example that synthesizes of compound T49)

Under the ice-water bath condition, in the DCM of compound T43 (16mg) (1.0mL) solution, add DMAP (4mg) and Succinic anhydried (10mg) successively, again to wherein dropwise adding Et ₃N (20mg) rose to room temperature reaction 3 hours, after the TLC detection reaction finishes, and thin up; With EtOAc extraction three times, merge organic phase then, wash anhydrous sodium sulfate drying with saturated sodium-chloride water solution; Concentrate the back column chromatography (chloroform: methyl alcohol=30: 1), compound T49 (mg, %).

Compound T49: yellow solid, ¹H-NMR (400MHz, CDCl ₃) δ 7.65 (d, J=8Hz, 1H), 7.57 (d, J=8Hz, 1H), 7.48 (s, 1H), 5.26 (s, 1H); 3.17 (t, J=8Hz, 8Hz, 1H), 2.64-2.69 (M, 4H), 1.79 (d, J=4Hz, 2H); 1.66 (d, J=8Hz, 2H), 1.58-1.63 (m, 2H), 1.31 (s, 3H), 1.25 (s, 3H);

Embodiment 9:

The preparation of compound T14

Under the ice-water bath condition, in the reaction flask of compound T1 (16mg), dropwise add the vitriol oil (0.25mL); The vitriol oil (0.15mL) solution that in above-mentioned solution, dropwise adds concentrated nitric acid (0.1mL) then, reaction is 15 minutes under this temperature, after the TLC detection reaction finishes; With the frozen water dilution, with EtOAc extraction three times, merge organic phase then; Wash with saturated sodium bicarbonate solution, water, saturated sodium-chloride water solution successively, anhydrous sodium sulfate drying concentrates back column chromatography (sherwood oil: ETHYLE ACETATE=3: 1); Get compound T14 (3mg, 15%).

Compound T14: red solid, ¹H-NMR (400MHz, CDCl ₃) δ 7.52 (s, 2H), 4.80 (t, J=8Hz, 8Hz, 1H), 4.29 (dd, J=8Hz, 8Hz, 1H); 3.49-3.55 (m, 1H), 3.16 (t, J=8Hz, 4Hz, 1H), 1.75 (d, J=4Hz, 2H); 1.61-1.63 (m, 2H), 1.56 (s, 4H), 1.30 (d, J=8Hz, 3H), 1.26 (s, 6H);

Embodiment 10:

The preparation of compound T15

To compound T2 (29mg, Ac 0.1mmol) ₂In O (5mL) solution, add PtO successively ₂(5mg) and pyridine (0.2mL).After adding, substitute gas (H ₂), room temperature condition reacted 4 hours down.Elimination insolubles after reaction finishes, filtrate decompression is concentrated into dried, thick product column chromatography (sherwood oil: ETHYLE ACETATE=7: 1), get compound T15 (31mg, 81%).

Compound T15: red solid, ¹H-NMR (400MHz, CDCl ₃) δ 7.74 (d, J=8Hz, 1H), 7.42 (d, J=8Hz, 1H), 4.86 (t, J=8Hz, 8Hz, 1H), 4.30 (dd, J=8Hz, 8Hz, 1H), 2.37 (s, 3H), 2.34 (s, 3H), 1.80 (m, 2H), 1.66 (m, 2H), 1.32 (s, 6H).

Embodiment 11:

The preparation of compound T16

At N ₂Under atmosphere ,-40 ℃ of conditions, in the THF of compound T2 (29mg) (1.0mL) solution, drip anhydrous propanone (290mg) and diethylamine (73mg) successively; After 4 hours, add the entry dilution in reaction under this temperature, water is with three times (5mL * 3) of EtOAc extraction; Merge organic phase, water, saturated sodium-chloride water solution are washed successively, and anhydrous sodium sulfate drying concentrates back column chromatography (sherwood oil: ETHYLE ACETATE=5: 1); (12mg, 72%brsm), other reclaims raw material (15mg) to get compound T16.

Compound T16: yellow solid, ¹H-NMR (400MHz, CDCl ₃) δ 7.70 (d, J=4Hz, 1H), 7.49 (d, J=4Hz, 1H), 4.60 (s, 1H), 4.53 (s, 1H); 4.29 (s, 1H), 4.24 (m, 1H), 4.02 (d, J=8Hz, 1H), 3.85 (s, 2H), 3.06-3.10 (m; 3H), 2.93 (d, J=16Hz, 2H), 2.83 (d, J=12Hz, 1H), 2.67 (d, J=12Hz, 1H); 2.31 (s, 3H), 2.20 (s, 2H), 2.15 (s, 3H), 1.96 (s, 3H), 1.79-1.81 (m, 2H); 1.49-1.55 (m, 4H), 1.24 (d, J=4Hz, 3H), 1.21 (s, 3H), 1.18 (s, 3H);

Embodiment 12:

The preparation of compound T17

In toluene (1.5mL) solution of compound T2 (29mg), add Lawesson reagent (80mg) and NaHCO successively ₃(27mg), be warming up to 50 ℃ of reactions 3 hours, after the TLC detection reaction finishes, the filtration insolubles, filtrating concentrates directly column chromatography (sherwood oil: ETHYLE ACETATE=20: 1), get compound T17 (10mg, 32%) of back

Compound T17: ¹H NMR (400MHz, CDCl ₃) δ 7.65 (d, J=8Hz, 1H), 7.59 (d, J=8Hz, 1H), 7.23 (s, 1H), 3.19 (t, J=8Hz, 4Hz, 2H), 2.27 (s, 3H), 1.78-1.81 (m, 2H), 1.43 (dd, J=16Hz, 8Hz, 2H), 1.31 (s, 6H).

Embodiment 13:

The preparation of compound T18

At N ₂Under the atmosphere, in ethanol (1.5mL) solution of compound T1 (29mg), add 4-hydroxy benzaldehyde (30mg) and ammonium acetate (15mg); Be heated to back flow reaction after 4 hours, the TLC detection reaction finishes, and adds the entry dilution; Water merges organic phase with three times (5mL * 3) of EtOAc extraction, and water, saturated sodium-chloride water solution are washed successively; Anhydrous sodium sulfate drying concentrates back column chromatography (sherwood oil: ETHYLE ACETATE=3: 1), get compound T18 (19mg, 44%).

Compound T18: ¹H-NMR (500MHz, D-pyr) δ 8.62 (d, J=8Hz, 2H), 8.52 (d, J=8Hz, 1H), 7.80 (s, 1H), 7.73 (d, J=8Hz, 1H), 7.31 (d, J=4Hz, 1H), 2.67 (s, 3H), 2.02 (s, 2H), 1.76 (s, 2H), 1.40 (s, 6H);

Embodiment 14:

The preparation of compound T19

At ambient temperature, in the DCM of compound T1 (29mg) (1.5mL) solution, add CaSO ₄(5mg), stir after 15 minutes, add m-CPBA (27mg) again, add the back room temperature reaction after 10 hours, the elimination insolubles, (sherwood oil: ETHYLE ACETATE=8: 1), (15mg, 75%brsm), other reclaims raw material (10mg) to get compound T19 to concentrate the direct column chromatography in back.

Compound T19: colourless jelly, ¹H-NMR (400MHz, CDCl ₃) δ 7.66 (d, J=8Hz, 1H), 7.63 (d, J=8Hz, 1H), 7.33 (s, 1H), 2.89 (t, J=8Hz, 4Hz, 2H), 2.28 (s, 3H), 1.85 (m, 2H), 1.71 (m, 2H), 1.33 (s, 6H).

Embodiment 15:

The preparation of compound T2 '

At N ₂Under atmosphere ,-40 ℃ of conditions, in the THF of compound T1 (29mg) (1.5mL) solution, drip Et successively ₃SiH (120mg) and BF ₃Et ₂O (28mg) after adding, makes it rise to room temperature reaction naturally, after the TLC detection reaction finishes, adds saturated NaHCO ₃Aqueous solution cancellation is reacted, and water merges organic phase with three times (5mL * 3) of EtOAc extraction, and water, saturated sodium-chloride water solution are washed successively, and anhydrous sodium sulfate drying concentrates back column chromatography (sherwood oil: ETHYLE ACETATE=5: 1), get compound T2 ' (21mg, 75%).

Compound T2 ': red solid, ¹H-NMR (400MHz, CDCl ₃) ¹H NMR (400MHz, CDCl ₃) δ 7.64 (d, J=8Hz, 1H), 7.49 (d, J=8Hz, 1H), 4.89 (t, J=8Hz, 8Hz, 1H); 4.37 (dd, J=4Hz, 8Hz, 1H), 3.60 (m, 1H), 3.21 (t, J=8Hz, 8Hz, 1H); 1.79 (m, 2H), 1.66 (m, 2H), 1.36 (d, J=8Hz, 3H), 1.31 (s, 6H);

Embodiment 16:

The preparation of compound T20

To compound T2 (29mg, in THF 0.1mmol) (1.5mL) solution, be added dropwise to NaOH the aqueous solution (2N, 0.5mL).After adding, ultrasonic reaction is 4 hours under the room temperature condition.Pressure reducing and steaming THF after reaction finishes, thin up is then with three times (5mL * 3) of EtOAc extraction; Merge organic phase, wash with saturated sodium-chloride water solution, anhydrous sodium sulfate drying concentrates back column chromatography (sherwood oil: ETHYLE ACETATE=2: 1); Get compound T20 (32mg, 100%).

Compound T20: weak yellow foam shape thing, ¹H-NMR (500MHz, CDCl ₃) δ 7.98 (d, J=10Hz, 1H), 7.73 (d, J=10Hz, 1H), 3.93 (dd, J=10Hz; 10Hz, 1H), 3.83 (dd, J=10Hz, 5Hz, 1H), 3.44 (dd, J=5Hz; 5Hz, 1H), 3.23 (t, J=5Hz, 5Hz, 2H), 1.81 (m, 2H); 1.66 (m, 2H), 1.30 (s, 6H), 1.26 (d, J=10Hz, 3H).

Embodiment 17:

The preparation of compound T21

To compound T2 (29mg, in EtOH 0.1mmol) (0.5mL) solution, be added dropwise to ammoniacal liquor (33%, 1mL).After adding, ultrasonic reaction is after 6 hours under the room temperature condition, and TLC finds that reaction finishes; Pressure reducing and steaming EtOH, thin up is then with three times (8mL * 3) of EtOAc extraction; Merge organic phase, wash with saturated sodium-chloride water solution, anhydrous sodium sulfate drying concentrates back column chromatography (chloroform: methyl alcohol=6: 1); Get compound T21 (15mg, 50%).

Compound T21: red solid, ¹H-NMR (400MHz, CD ₃OD) δ 7.72 (d, J=8Hz, 1H), 7.69 (d, J=8Hz, 1H), 3.87 (dd, J=4Hz, 8Hz; 1H), 3.74 (dd, J=4Hz, 8Hz, 1H), 3.27 (s, 2H), 3.14 (t, J=4Hz; 4Hz, 1H), 3.07 (dd, J=4Hz, 8Hz, 2H), 1.71 (d, J=4Hz, 1H); 1.61 (t, J=8Hz, 8Hz, 1H), 1.26 (s, 6H), 1.21 (d, J=4Hz, 3H);

Embodiment 18:

The preparation of compound T22, T23 (with the example that synthesizes of compound T22)

At N ₂Under atmosphere ,-40 ℃ of conditions, in the DCM (1.5mL) of compound T21 (15mg) and DMAP (4mg) solution, drip Et successively ₃N (15mg) and Benzoyl chloride 99min. (12mg) make its natural temperature reaction after 1.5 hours after adding, TLC finds that reaction finishes; Add the shrend reaction of going out, with three times (8mL * 3) of EtOAc extraction, merge organic phase then; Wash with saturated sodium-chloride water solution; Anhydrous sodium sulfate drying concentrates back column chromatography (chloroform: methyl alcohol=30: 1), get compound T23 (13mg, 56%).

Compound T23: red solid, red solid, ¹H-NMR (400MHz, CDCl ₃) δ 8.11 (d, J=8Hz, 1H), 8.01 (d, J=8Hz, 1H), 7.39-7.64 (m, 5H), 5.99 (s, 1H); 4.64 (dd, J=8Hz, 4Hz, 1H), 4.52 (t, J=8Hz, 8Hz, 1H), 3.25 (m; 1H), 3.18 (t, J=8Hz, 8Hz, 1H), 2.03 (s, 2H), 1.75-1.80 (m, 2H); 1.63-1.67 (m, 4H), 1.47 (d, J=4Hz, 3H), 1.29 (s, 3H), 1.25 (s, 3H);

Embodiment 19:

The preparation of compound T24, T25 (with the example that synthesizes of compound T25)

At N ₂Under atmosphere ,-40 ℃ of conditions, in the DCM (1.0mL) of compound T21 (15mg) and DMAP (3mg) solution, drip DIPEA (38mg) and MsCl (17mg) successively; Make it be warming up to room temperature reaction naturally after 3.5 hours after adding, TLC finds that reaction finishes, and adds the shrend reaction of going out; With three times (8mL * 3) of EtOAc extraction, merge organic phase then, wash with saturated sodium-chloride water solution; Anhydrous sodium sulfate drying concentrates back column chromatography (sherwood oil: ETHYLE ACETATE=3: 1), get compound T24 (11mg, 62%).

Compound T24: red solid, ¹H-NMR (500MHz, CDCl ₃) δ 8.21 (d, J=4Hz, 2H), 7.72 (d, J=4Hz, 2H), 4.62 (dd, J=16Hz, 4Hz; 1H), 4.02 (d, J=16Hz 1H), 3.56 (s, 3H), 3.31 (dd, J=12Hz, 4Hz, 2H); 1.80 (dt, J=12Hz, 4Hz, 4Hz, 2H), 1.67 (t, J=8Hz, 8Hz; 2H), 1.42 ((d, J=8Hz, 3H), 1.34 (s, 3H), 1.32 (s, 3H).

Compound T25: ¹H-NMR (500MHz, CDCl ₃) δ 7.72 (m, 2H), 7.64 (d, J=5Hz, 1H), 7.55 (m, 2H), 7.22 (s, 1H), 4.30 (t; J=10Hz, 5Hz, 2H), 4.09 (d, J=5Hz, 1H), 3.18 (t, J=10Hz, 5Hz, 1H); 2.26 (s, 3H), 1.79 (m, 2H), 1.64 (m, 2H), 1.31 (s, 6H), 1.25 (s, 3H);

Embodiment 20:

The preparation of compound T26, T27 (with the example that synthesizes of compound T26)

Step1: take by weighing compound T20 (31mg) and be dissolved among the DMSO (1mL), then in two batches after wherein adding IBX (28mg/ criticizes), reacting 3 hours at ambient temperature; TLC finds that reaction finishes, and thin up in reaction system is then with EtOAc extraction three times; Merge organic phase, water, saturated sodium-chloride water solution are washed successively, anhydrous sodium sulfate drying; Concentrate back column chromatography (sherwood oil: ETHYLE ACETATE=3: 1), get C-16 position hydroxyl oxidize product (20mg, 65%).

Step 2: take by weighing the oxidation products (16mg) that obtains among the Step 1 and be dissolved in the 0.5mL Glacial acetic acid min. 99.5, then once to wherein adding ammonium acetate (38mg), be heated to 60 ℃ of reactions after 1 hour; TLC detect to find that reaction finishes, and in reaction solution, adds the shrend reaction of going out, and extracts three times with EtOAc again; Merge organic phase, with saturated common salt washing, anhydrous sodium sulfate drying; Concentrate back column chromatography (sherwood oil: ETHYLE ACETATE=4: 1), get compound T26 (12mg, 79%)

Compound T26: yellow solid, ¹H-NMR (400MHz, CDCl ₃) δ 9.39 (s, 1H), 8.09 (d, J=8Hz, 1H), 7.70 (d, J=8Hz, 1H), 6.82 (s, 1H), 3.37 (t, J=8Hz, 4Hz, 2H), 2.42 (s, 2H), 1.82 (m, 2H), 1.67 (m, 2H), 1.62 (s, 3H), 1.34 (s, 6H);

Compound T27: ¹H-NMR (400MHz, CDCl ₃) δ 7.54 (m, 3H), 7.39 (m, 2H), 7.13 (d, J=8Hz, 1H), 6.48 (s, 1H), 6.43 (d, J=8Hz, 2H), 3.11 (t, J=8Hz, 4Hz, 2H), 2.35 (s, 2H), 1.72 (m, 2H), 1.25 (s, 3H), 1.19 (s, 6H);

Embodiment 21:

The preparation of compound T28

Under N2 atmosphere ,-40 ℃ of conditions, in the DCM of compound T1 (29mg) (1mL) solution, add NIS (34mg), in system, drip TFA (11mg) after five minutes again; After reacting 3 hours under this temperature, the TLC detection reaction finishes, and in system, adds saturated sodium sulfite aqueous solution cancellation reaction; Behind the thin up,, merge organic phase with EtOAc extraction three times; With the saturated common salt washing, anhydrous sodium sulfate drying concentrates back column chromatography (sherwood oil: ETHYLE ACETATE=15: 1); Get compound T28 (38mg, 92%) compound T28: red solid ¹H-NMR (500MHz, CDCl ₃) δ 7.63 (d, J=10Hz, 1H), 7.55 (d, J=5Hz, 1H), 3.17 (t, J=5Hz, 5Hz, 2H), 2.22 (s, 2H), 1.80 (m, 2H), 1.66 (m, 2H), 1.31 (s, 6H), 1.25 (s, 3H);

Embodiment 22:

The preparation of compound T29, T30, T31, T32, T33, T34, T35 (with the example that synthesizes of compound T29)

At N ₂Under the atmosphere, to compound T28 (21mg), phenylo boric acid (10mg) and K ₂CO ₃DMF/H ₂Add Pd (PPh among the O (1mL/0.2mL) ₃) ₄(5mg), be heated to 80 ℃ of reactions then after 3 hours, the TLC detection reaction finishes; Be cooled to room temperature, behind the thin up, with EtOAc extraction three times; Merge organic phase, with saturated common salt washing, anhydrous sodium sulfate drying; Concentrate back column chromatography (sherwood oil: ETHYLE ACETATE=8: 1), get compound T29 (18mg, 98%).

Compound T29: red solid, ¹H-NMR (400MHz, CDCl ₃) δ 7.63 (d, J=8Hz, 2H), 7.57 (s, 2H), 7.43,7.41 (t, J=8Hz, 8Hz, 2H), 7.31 (t, J=8Hz, 8Hz, 1H), 3.12 (t, J=8Hz, 8Hz, 2H), 2.45 (s, 3H), 1.73 (m, 2H), 1.60 (m, 2H), 1.25 (s, 6H).

Compound T30: ¹H-NMR (500MHz, CDCl ₃) δ 7.67 (m, 2H), 7.64 (m, 2H), 7.18 (t, J=10Hz, 10Hz, 2H), 3.19 (t, J=5Hz, 5Hz, 2H), 2.50 (s, 3H), 1.79 (m, 2H), 1.66 (m, 2H), 1.32 (s, 6H).

Compound T31: red solid, ¹H-NMR (400MHz, CDCl ₃) δ 9.20 (s, 1H), 9.08 (s, 1H), 7.69 (m, 3H), 7.56,7.54 (t, J=8Hz, 8Hz, 1H), 7.47 (m, 2H), 3.19 (t, J=8Hz, 4Hz, 1H), 2.57 (s, 2H), 1.81 (m, 2H), 1.67 (m, 1H), 1.33 (s, 3H), 1.25 (s, 6H).

Compound T32: red solid, ¹H-NMR (400MHz, CDCl ₃) δ 8.75 (d, J=4Hz, 1H), 7.83 (d, J=4Hz, 1H), 7.73 (s, 1H), 7.67 (m, 2H); 7.55 (t, J=8Hz, 8Hz, 1H), 7.46 (dt, J=8Hz, 8Hz, 4Hz, 2H), 3.21 (t; J=8Hz, 8Hz), 2.69 (s, 3H), 1.82 (m, 2H), 1.68 (m, 2H), 1.34 (s, 6H);

Compound T33: ¹H-NMR (500MHz, CDCl ₃) δ 7.62 (dd, J=20Hz, 15Hz, 2H), 7.57 (m, 1H), 7.46 (m, 2H), 3.18 (t, J=5Hz, 5Hz, 2H), 2.48 (s, 3H), 1.80 (m, 2H), 1.67 (m, 2H), 1.32 (s, 6H);

Compound T34: red solid, ¹H-NMR (400MHz, CDCl ₃) δ 9.34 (s, 1H), 8.65 (s, 1H), 8.10 (d, J=8Hz, 1H), 8.00 (d, J=8Hz; 1H), 7.79 (t, J=8Hz, 8Hz, 1H), 7.71 (t, J=8Hz, 8Hz, 1H); 7.64 (dd, J=16Hz, 8Hz, 2H), 3.23 (t, J=4Hz, 4Hz, 2H), 2.36 (s; 3H), 1.82 (m, 2H), 1.69 (m, 2H), 1.32 (s, 6H), 1.25 (s, 3H)

Compound T35: ¹H-NMR (400MHz, CDCl ₃) δ 7.64 (d, J=8Hz, 1H), 7.56 (d, J=8Hz, 1H), 7.23 (s, 1H), 3.19 (t, J=8Hz, 8Hz, 2H), 2.27 (s, 3H), 1.80 (m, 2H), 1.66 (m, 2H), 1.56 (s, 2H), 1.31 (s, 3H), 1.26 (s, 3H);

Embodiment 23:

The preparation of compound T38, T39

N ₂Under the condition, to 1 of compound T1 (29mg), add in 4-dioxane (0.5mL) solution formalin (38%, 0.5mL); After wherein adding a concentrated hydrochloric acid, be heated to back flow reaction after 2 hours again, the TLC detection reaction finishes, and is cooled to room temperature; Behind the thin up,, merge organic phase, wash with saturated common salt with EtOAc extraction three times; Anhydrous sodium sulfate drying concentrates back column chromatography (sherwood oil: ETHYLE ACETATE=3: 1 → 1: 1), get compound T38 and T39 (20mg, 63%).

Compound T38: red solid, ¹H-NMR (400MHz, CDCl ₃) δ 7.60 (d, J=8Hz, 1H), 7.52 (d, J=8Hz, 1H), 4.66 (s, 2H), 3.16 (t, J=8Hz, 4Hz, 2H), 2.27 (s, 3H), 1.79 (m, 2H), 1.65 (m, 2H), 1.30 (s, 6H);

Compound T39: ¹H-NMR (400MHz, CDCl ₃) δ 7.56 (d, J=8Hz, 1H), 7.42 (d, J=8Hz, 1H), 4.62 (s, 2H), 3.89 (t, J=4Hz, 4Hz, 2H), 3.09 (t, J=8Hz, 4Hz, 2H), 2.95 (t, J=8Hz, 4Hz, 2H), 1.78 (m, 2H), 1.65 (m, 2H), 1.31 (s, 6H)

Embodiment 24:

The preparation of compound T40, T46 (with the example that is prepared as of compound T40)

Step1: under the room temperature condition, in the DMSO of compound T38 (16mg) (0.8mL) solution, once add IBX (28mg), room temperature reaction is after 4 hours; The TLC detection reaction finishes, behind the thin up, with EtOAc extraction three times; Merge organic phase, with saturated common salt washing, anhydrous sodium sulfate drying; Concentrate back column chromatography (sherwood oil: ETHYLE ACETATE=4: 1), get oxidation products (12mg, 72%).

Step2: at N ₂Under the atmosphere, to NaClO ₂(9mg) and NaH ₂PO ₄In water (8mg) (0.15mL) solution, acetone (0.3mL) solution of step oxidation products (5mg) in the dropping is then to wherein adding isopentene (7mg).After mixed solution reacts 1 hour at ambient temperature, after the TLC detection reaction finishes, add a small amount of saturated sodium sulfite aqueous solution cancellation reaction; Behind the thin up,, merge organic phase with EtOAc extraction three times; With the saturated common salt washing, anhydrous sodium sulfate drying concentrates back column chromatography (chloroform: methyl alcohol=10: 1); Get oxidation products (4mg, 82%).

Compound T40: ¹H-NMR (400MHz, CDCl ₃) δ 9.88 (s, 1H), 7.97 (d, J=8Hz, 1H), 7.68 (d, J=8Hz, 1H), 2.94 (t, J=8Hz, 8Hz, 2H), 2.66 (s, 3H), 2.09 (t, J=8Hz, 8Hz, 2H), 1.81 (m, 2H), 1.36 (s, 6H).

Embodiment 25:

The preparation of compound T43

In Glacial acetic acid min. 99.5 (1mL) solution of compound T1 (147mg), once add SeO ₂(55mg).After adding, substitute gas (Ar2), be heated to 130 ℃ of reactions 15 minutes.After the TLC detection reaction finished, thin up extracted three times with EtOAc, merges organic phase, water, saturated common salt washing successively, and anhydrous sodium sulfate drying concentrates back column chromatography (sherwood oil: ETHYLE ACETATE=2: 1), get compound T43 (127mg, 82%).Compound T43: red solid, ¹H-NMR (400MHz, CDCl ₃) ¹H NMR (400MHz, CDCl ₃) δ 7.66 (d, J=8Hz, 1H), 7.58 (d, J=8Hz, 1H), 7.39 (s, 1H), 4.66 (s, 2H), 3.18 (t, J=4Hz, 4Hz, 2H), 1.79 (m, 2H), 1.65 (m, 2H), 1.60 (m, 2H), 1.31 (s, 6H);

Embodiment 26:

The preparation of compound T45

At N ₂Under atmosphere, the ice-water bath condition, in the THF (1mL) of compound T43 (9mg) and DMAP (2mg) solution, drip Et successively ₃N (12mg) and MsCl (7mg).After adding, rise to room temperature reaction naturally 2 hours, in reaction solution, add TBAI (2mg) and Et again ₃N (6mg) added the back stirring at room 10 minutes, dripped aniline (8mg) then, continued reaction after 2.5 hours; The TLC detection reaction finishes, and thin up is with EtOAc extraction three times; Merge organic phase, water, saturated common salt washing successively, anhydrous sodium sulfate drying; Concentrate back column chromatography (sherwood oil: ETHYLE ACETATE=1: 1), get compound T45 (5mg, 34%).

Compound T45: red solid, ¹H-NMR (400MHz, CDCl ₃) δ 7.63 (d, J=8Hz, 1H), 7.53 (d, J=8Hz, 1H), 7.40 (s, 1H), 7.16 (m, 2H), 6.70 (t; J=8Hz, 8Hz, 1H), 6.66 (d, J=8Hz, 2H), 4.39 (s, 2H), 3.18 (t, J=4Hz; 4Hz, 1H), 1.79 (m, 2H), 1.65 (m, 2H), 1.30 (s, 6H), 1.25 (s, 2H);

Embodiment 27:

The preparation of compound T51, T52 (with the example that synthesizes of compound T51)

In the THF of compound T5 (7.5mg) (1mL) solution, add Et successively ₃N (8mg), TBAI (2mg), t-BuNH ₂(5mg).Room temperature reaction 4 hours, after the TLC detection reaction finished, thin up was with EtOAc extraction three times; Merge organic phase, water, saturated common salt washing successively, anhydrous sodium sulfate drying; Concentrate back column chromatography (chloroform: methyl alcohol=20: 1), get compound T51 (4.5mg, 61%).

Compound T51: red solid, ¹H-NMR (400MHz, CDCl ₃) δ 7.73 (d, J=12Hz, 1H), 7.70 (s, 1H), 7.49 (s, 2H), 6.24-6.27 (m, 1H), 3.95 (s, 3H), 3.22 (s, 4H), 2.18 (m, 2H), 1.30 (s, 9H), 1.18 (s, 3H), 1.11 (s, 3H).

Below come further to illustrate the pharmacological action of tanshinone derivative of the present invention through Test Example:

Test Example 1:

1 external mouse or people source 11 β-HSD1 suppress experimental technique:

Adopt molecular biology method; To be cloned into the PcDNA3-VSVtag carrier for expression of eukaryon available from mouse or the people 11 β-HSD1 gene order of NIH Mammalian Gene Collection (NIH MGC); Transfection obtains the cell mixing clone of stable transfection in the HEK293 cell after G418 (0.75g/L) screening after restriction enzyme digestion and dna sequencing checking.The trysinization cell mixing is cloned and with unicellular inoculation 96 well culture plates, is given conditionality cell culture fluid (HEK293 cell culture supernatant) simultaneously, after 14-20 days, obtains unicellular propagation clone.Amplification back trysinization collecting cell, centrifugal after the ultrasonication (4 ℃, 1500rpm, 10min), supernatant once more ultracentrifugation (4 ℃, 100000g, 1h), phosphate buffered saline buffer (40mM Na ₂HPO ₄, 1mMEDTA, 5%glycerol) mouse or the people 11 β-HSD1 purifying enzyme of resuspended post precipitation acquisition ,-80 ℃ are frozen subsequent use.

Adopting SPA (Scintillation proximity assay) is that liquid dodges near determination techniques, measures compound to little and restraining effect people 11-β-HSD1, calculates inhibiting rate and IC50 value.All verivate T4-T52 that obtain from embodiment 1-27 have been carried out mouse and the inhibiting primary dcreening operation of people 11-β-HSD1; Select 1 μ M as primary dcreening operation concentration (The selection result is seen table 1); Part primary dcreening operation inhibiting rate surpassed 50% verivate and further carry out dose-effect relationship research, calculating IC50 (The selection result is seen table 2).

2, experimental result: active testing is the result show, 1) introduce hydroxyl or alkoxyl group in C-1, the C-2 position of A ring the 11 β-HSD1 activity in people source and mouse source is all descended than parent compound to some extent, descend especially obvious with people source 11 β-HSD1; And behind the introducing thiazolinyl, the 11 β-HSD1 activity in mouse source is improved, but descend to people source 11 β-HSD1 is active.Behind the carbonylate of C-3 position, people source 11 β-HSD1 activity is doubled, but obviously descend mouse source 11 β-HSD1 is active; And the hydroxyl of this position and fluorine atom replace all unfavorable to the 11 β-HSD1 activity in people source and mouse source.Therefore, can reach a conclusion: the polar functional group of A ring is unfavorable to activity.

2) nitro of B ring replaces, and the 11 β-HSD1 activity in people source and mouse source is all descended, and wherein people source 11 β-HSD1 descends especially obvious.

3) all the transformation activity to the adjacent two pairs of carbonyls of C ring all decline to a great extent, even completely dissolve, therefore think adjacent two pairs of crucial pharmacophores that carbonyl is this compounds.

4) D ring is to the active influence of 11 β-HSD1 in people source and mouse source and inconsistent, and during the open loop of D ring (adjacent two pairs of carbonyl structures constant prerequisite under), mouse source 11 β-HSD1 activity does not descend, on the contrary rising to some extent; 11 β-HSD1 to the people source then declines to a great extent.Introduce hydroxyl in the C-17 position, the 11 β-HSD1 that almost completely keeps people source and mouse source suppresses active, and the water-soluble significantly raising of this compound, and quasi-medicated property obviously strengthens, and is more significant transformation; Introduce in this position nonpolar F atom then activity almost disappear.The C-15 position is introduced aryl functional group and is suppressed the quasi-medicated property that the active while also can strengthen molecule at raising mouse source 11 β-HSD1.When the furan nucleus of D ring becomes pyrrole ring, the 11 β-HSD1 activity in two kinds of sources is all declined to a great extent.

5) as far as tanshinone compound, 11 β in people source-HSD1 is relatively more responsive to the functional group of multiple introducing, and functional group's tolerance of 11 β in mouse source-HSD1 is then better.

Table 1 tanshinone derivative primary dcreening operation result

Table 2 part tanshinone derivative sieves the result again

The abbreviation language table look-up that relates in table 3 literary composition

The Ac ethanoyl

The AIBN azo-bis-isobutyl cyanide

The t-Bu tertiary butyl

The DAST diethylaminosulfurtrifluoride

DBU 1,8-diazabicylo-dicyclo (5,4,0)-7-hendecene

The DCM methylene dichloride

DMAP 4-N, N-two Dimethylamino pyridines

DMF N, dinethylformamide

DMP Dess-Martin oxygenant

The DMSO DMSO 99.8MIN.

IBX 2-iodoxy phenylformic acid

The Ms methylsulfonyl

The m-CPBA metachloroperbenzoic acid

NBS N-bromo-succinimide

NIS N-iodo succimide

NMO N-methylmorpholine-N-oxide compound

The PE sherwood oil

The PTSA tosic acid

The TBAI tetrabutylammonium iodide

The TFA trifluoroacetic acid

The THF THF

The Ts p-toluenesulfonyl

FORMULATION EXAMPLE 1:

Method by embodiment 1-27 makes tanshinone derivative T3-T52 earlier, and utilizes organic acid (tartrate, Hydrocerol A, formic acid; Oxalic acid etc.) or the salt processed of mineral acid (hydrochloric acid, sulfuric acid, phosphoric acid etc.); Add the injection water by routine, smart filter, injection liquid is processed in the embedding sterilization.

FORMULATION EXAMPLE 2:

Method by embodiment 1-27 makes tanshinone derivative T3-T52 earlier, and utilizes organic acid (tartrate, Hydrocerol A, formic acid; Oxalic acid etc.) or the salt processed of mineral acid (hydrochloric acid, sulfuric acid, phosphoric acid etc.); It is dissolved in the sterile water for injection, and stirring makes molten, filters with aseptic suction funnel; Aseptic more smart filter is sub-packed in 2 ampoules, and aseptic sealing by fusing gets powder injection behind the frozen drying.

FORMULATION EXAMPLE 3:

With the resulting tanshinone derivative T3-T52 of embodiment 1-27, and utilize organic acid (tartrate, Hydrocerol A; Formic acid, oxalic acid etc.) or mineral acid (hydrochloric acid, sulfuric acid; Phosphoric acid etc.) salt of processing, with the vehicle weight ratio be that 9: 1 ratio adds vehicle, process pulvis.

FORMULATION EXAMPLE 4:

With the resulting tanshinone derivative T3-T52 of embodiment 1-27, and utilize organic acid (tartrate, Hydrocerol A; Formic acid, oxalic acid etc.) or mineral acid (hydrochloric acid, sulfuric acid; Phosphoric acid etc.) salt of processing is 1 in itself and vehicle weight ratio: 5-1: 10 ratio adds vehicle, pelletizing press sheet.

FORMULATION EXAMPLE 5:

With the resulting tanshinone derivative T3-T52 of embodiment 1-27, and the salt that utilizes organic acid (tartrate, Hydrocerol A, formic acid, oxalic acid etc.) or mineral acid (hydrochloric acid, sulfuric acid, phosphoric acid etc.) to process, oral liquid processed by conventional oral liquid method for making.

FORMULATION EXAMPLE 6:

With the resulting tanshinone derivative T3-T52 of embodiment 1-27, and utilize organic acid (tartrate, Hydrocerol A; Formic acid; Oxalic acid etc.) or the salt processed of mineral acid (hydrochloric acid, sulfuric acid, phosphoric acid etc.); In itself and vehicle weight ratio is that 5: 1 ratio adds vehicle, processes capsule or granule or electuary.

FORMULATION EXAMPLE 7:

With the resulting tanshinone derivative T3-T52 of embodiment 1-27, and utilize organic acid (tartrate, Hydrocerol A; Formic acid; Oxalic acid etc.) or the salt processed of mineral acid (hydrochloric acid, sulfuric acid, phosphoric acid etc.); In itself and vehicle weight ratio is that 3: 1 ratio adds vehicle, processes capsule or granule or electuary.

Claims

1. the salt of allowing on the tanshinone derivative shown in the general formula (I) or its pharmacology,

Or R ₁, R ₃Form covalent linkage;

Or R ₂, R ₄Form covalent linkage;

Or R ₈, R ₁₀Form covalent linkage;

Or R ₉, R ₁₁Form covalent linkage;

Or R ₅, R ₆Formation=X ₆, X wherein ₆Be selected from C, O, S, NH;

X ₁, X ₂, X ₃, X ₄Independently be selected from the alkyl of acyloxy, alkoxyl group, hydroxyl, β-carbonyl substituted respectively;

Or X ₁, X ₃Form covalent linkage;

Or X ₂, X ₄Form covalent linkage;

Or X ₁, X ₂Formation=X ₆, X wherein ₆Be selected from C, O, S, NH;

Or X ₁, X ₂, X ₃, X ₄Form 2-substituted imidazole ring, the substituted thiazole ring of 2-, 2,3-Qu Dai De oxazole, 2,3 piperazine ring;

X ₃Be selected from carbon, nitrogen, oxygen, sulphur atom.

2. the salt of allowing on (I) tanshinone derivative of the general formula shown in claim 1 or its pharmacology is compound T4, T6, T7, T8, T9, T14, T21, T24, T25, T28, T31, T38, T39, T43, the T51 shown in the following structural formula,

3. the salt of allowing on the pharmacology like claim 1 or 2 each described tanshinone derivatives comprises and mineral acid hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, Hydrogen bromide; Perhaps organic acid toxilic acid, fumaric acid, tartrate, lactic acid, Hydrocerol A, acetate, methylsulfonic acid, tosic acid, hexanodioic acid, palmitinic acid, Weibull; Perhaps alkali metal lithium, sodium, potassium; Alkaline earth metals calcium, magnesium; The salt that the Methionin basic aminoacids becomes.

4. pharmaceutical composition wherein contains the salt and the pharmaceutically acceptable carrier of allowing on claim 1 general formula (I) tanshinone compound of treating significant quantity or its pharmacology.

5. the preparation method of the general formula shown in the claim 1 (I) tanshinone derivative comprises the acid catalyzed Fridiel-Craft reaction of the synthetic imidazoles of three component reaction, catalytic hydrogenation, the oxidation of benzyl position, aromatic ring halo, Suzuki cross-coupling reaction, the catalytic dihydroxylation reaction of potassium osmate, Bransted, the synthetic pyrroles's reaction of diketone of nitrated, the adjacent dicarbapentaborane participation of elimination reaction, allylic oxidation, hydroxyl fluoro, phenyl ring of free radical mediated.

6. the preparation method of the general formula shown in claim 5 (I) tanshinone derivative is characterized in that the elimination reaction synthetic compound T4 by free radical mediated, by SeO ₂The allylic oxidation synthetic compound T7 and the T8 that participate in are by SeO ₂The benzyl position oxidation synthetic compound T43 that participates in, the catalytic Suzuki linked reaction of Pd (0) synthetic compound T29, T30, T31, T32, T33, T34.

7. the application of the salt of allowing on (I) tanshinone derivative of the general formula shown in the claim 1 or its pharmacology in preparation 11 β-HSD1 selective depressant medicine.

8. the application of the salt of allowing on (I) tanshinone derivative of the general formula shown in the claim 1 or its pharmacology in the medicine of preparation treatment mellitus.

9. the application of the salt of allowing on (I) tanshinone derivative of the general formula shown in the claim 1 or its pharmacology in the medicine of preparation treatment hypertension, obesity, senile dementia.