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

Abstract

The present invention provides tanshinone derivatives substituted by different groups on ring A, ring B, ring C and ring D represented by general formula (I), pharmaceutical compositions using them as active ingredients, their preparation methods, and preparation methods. Use of type 1 11β-hydroxysteroid dehydrogenase (11β-HSD1) inhibitors. Also provided is the application of the compound of general formula (I) in the preparation of medicines for treating diabetes and related metabolic diseases (hypertension, obesity, senile dementia, etc.).

Description

Tanshinone derivatives and their pharmaceutical compositions and their use in medicine

Technical field:

The invention belongs to the technical field of pharmaceutical compounds and medicines, and in particular relates to a class of tanshinone compounds, which are pharmaceutical compositions of active ingredients, their preparation methods and the preparation of type 1 11-β-hydroxylation compounds and their pharmaceutical compositions. Steroid dehydrogenase (11β-HSD1) selective inhibitors neutralize the application of anti-diabetic and related metabolic (hypertension, obesity, senile dementia, etc.) drugs.

Background technique:

Diabetes and glucocorticoid-related metabolic diseases (including obesity, dyslipidemia, hypertension and cardiovascular complications, etc.) have become major health problems that plague modern people (Rosenstock, J.et.Diabetes Care 2010, 33, 1516 .). According to incomplete statistics from the World Health Organization (WHO), there are about 1.6 billion overweight people in the world, of which 400 million people show clinical symptoms of diabetes (Wamil, M.et.Drug Discovery Today 2007, 12, 504), and The situation is still deteriorating. Therefore, the grim situation entrusts medical workers with an inescapable mission—to find new high-efficiency and low-side-effect diabetic hormones, which is an important class of steroid hormones. It participates in the regulation of some stress-related physiological processes, such as gluconeogenesis, inflammatory response, brain function, immune response, etc. There are two forms of glucocorticoids in the body, the active form hydrocortisone and the inactive form cortisone.

11β-Hydroxysteroid dehydrogenase (11β-HSD) plays a key role in the regulation of glucocorticoid levels. Since 11β-HSD was discovered in 1988 (Lakshmi, V. et. Endocrinology 1988, 123, 2390.), researchers have been enthusiastic about 11β-HSD for a long time, and their understanding of 11β-HSD has become more and more in-depth. There are two subtypes of 11β-hydroxysteroid dehydrogenase in organisms, 11β-hydroxysteroid dehydrogenase type 1 enzyme (11β-HSD1) and type 2 enzyme (11β-HSD2). Both 11β-HSD1 and 11β-HSD2 use nicotinamide adenine (NADPH) as a coenzyme factor, and both are located on the endoplasmic reticulum membrane of cells. 11β-HSD1 has dual catalytic functions of oxidation and reduction, is widely distributed in the target organs of glucocorticoids, and is a tissue-specific glucocorticoid regulator (Tomlinson, J.W.et.Endocr.Rev.2004, 25, 831. ). It is now generally believed that 11β-HSD1 is mainly a reductase when the cells are intact (in vivo), and in the presence of the coenzyme NADPH, it regenerates the inactive cortisone into active hydrocortisone at the target site in the human body—— It is most obvious in liver, adipose tissue and brain tissue, thereby amplifying the activation of glucocorticoid receptors in local tissues (Tomlinson, J.W.et. Drug Discovery Today.: Therapeutic Strategies 2005, 2, 93). 11β-HSD2 is mainly expressed as an oxidase, which catalyzes the above reverse reaction (Staab, C.A.et.J. Steroid Biochem. Mol. Biol. 2010, 119, 56), and is mainly expressed in the kidney, large intestine and saliva. Under normal circumstances, only 5% of hydrocortisone is dissociated in the plasma in the human body. The vast majority of hydrocortisone binds to high-affinity globulin or low-affinity albumin, once subjected to environmental stress, its content rises rapidly to reach the mM level (Stewart, P.M.et.Vitam.Horm.1999, 57, 249) . After the active glucocorticoid freely diffuses into the plasma, it binds to the glucocorticoid (mineralocorticoid in some tissues) receptors in the plasma to form a complex, and the complex is transported into the nucleus, where it interacts directly or with other transcription factors Regulation of gene expression (Staab, C.A.et.J. Steroid Biochem. Mol. Biol. 2010, 119, 56) (Figure-1).

Studies have shown that 11β-HSD1 plays an important role in the control of insulin sensitivity and the development of insulin resistance (Tomlinson, J.W.et. Drug Discovery Today: Therapeutic Strategies 2005, 2, 93). The results of transgenic mice experiments also confirmed this inference: mice overexpressing 11β-HSD1 showed symptoms of insulin resistance, hunger, obesity, and hypertension within a few weeks; while mice knocked out of 11β-HSD1 did 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, patients with Cushing's syndrome can be significantly relieved after taking glucocortisol receptor antagonists. The results of research on rodents and a small number of human experiments also confirm that inhibiting the activity of 11β-HSD1 is an effective way to treat metabolic syndrome (Odermatt, A.Curr.Enzyme Inhib.2005, 1, 107; Ge, R.et. Curr. Med. Chem. 2010, 17, 412; Staab, C.A. et. J. Steroid Biochem. Mol. Biol. 2010, 119, 56).

Currently, there is no selective 11β-HSD1 inhibitor clinically. The early developed 11β-HSD inhibitors were mainly glycyrrhetinic acid derivatives. The first widely-studied 11β-HSD inhibitor was carbophenone (CBX), which is a succinic monoester of glycyrrhetinic acid (GA). After taking CBX, lean patients with metabolic syndrome significantly improved insulin sensitivity and total blood lipid content, while obese patients with metabolic syndrome did not improve insulin sensitivity and total blood lipid content after taking CBX, which may be due to the inability of CBX to enter into the adipose tissue of obese individuals (Staab, C.A.et.J. Steroid Biochem. Mol. Biol. 2010, 119, 56). Since CBX is a non-selective 11β-HSD1 inhibitor, it can simultaneously inhibit 11β-HSD1 and 11β-HSD2, and its clinical application value is greatly limited. Therefore, it is of great practical significance to research and develop a new generation of highly specific 11β-HSD1 inhibitors.

Tanshinone IIA and cryptotanshinone are two fat-soluble compounds isolated from the ethanol extracts of the dried roots and rhizomes of the traditional Chinese medicine Salvia miltiorrhiza Bge. Tanshinone compounds often have a wide range of biological activities - such as anti-platelet aggregation, lowering blood lipids, anti-tumor, acetylcholinesterase inhibition, etc. At present, salvia sulfonate has been clinically used in the treatment of coronary heart disease, stroke, atherosclerosis Cardiovascular diseases such as sclerosis. At present, the patents on tanshinone compounds mainly focus on their extraction and separation methods (such as: Yao Yudong, Jin Bo, Hu Yaochang, Mo Qiwu, Liu Hancha, a method for refining tanshinone IIA by supercritical carbon dioxide extraction, publication number CN1369485; Chu Zhide, Meng Xianling , a method for extracting tanshinone IIA, publication number CN1923846; Yin Weiping, Wang Zhongdong, Ma Junying, Wu Yunji, Wang Xiaowei, Duan Wenlu, Zhang Yanping, Lu Benlian, extraction process of drug intermediate tanshinone II A, publication number CN1935799; Zheng Zhigang, Yang Yuewu, Wang Shuangming, Lu Wen Liang, a method for extracting tanshinone, publication number CN1670019; Tian Guilian, Zhang Tianyou, a method for separating and purifying tanshinone, publication number CN1394870, etc.), preparation methods of preparations (such as Chu Maoquan, Gu Hongchen, Liu Guojie, Tanshinone solid dispersion Chu Maoquan, Gu Hongchen; Liu Guojie, tanshinone proliposome spherical powder preparation and its preparation method, publication number CN1298697; Chu Maoquan, Gu Hongchen, Liu Guojie, tanshinone micropowder preparation Its microwave-assisted co-grinding preparation method, publication number CN1286083; Liu Li, Tanshinone IIA sulfonic acid or sodium tanshinone IIA sulfonate freeze-dried powder preparation and its preparation method, publication number CN1623538; Lu Weifeng, Xi Tao, Ren Min, Tanshinone IIA Dropping pills and its preparation method and application, publication number CN1698597; Wu Chunfeng, Tanshinone IIA infusion and its preparation method, publication number CN1732915; Mao Shengjun, Jin Hui, Liang Zhen, Wu Yu, a tanshinone emulsion and its preparation method, publication No. CN1839818, etc.), tanshinone and tanshinone sodium sulfonate in the treatment of cardiovascular disease, anti-tumor, anti-senile dementia diseases (such as Zou Qiaogen, application of tanshinone I sulfonate sodium in the field of medicine, publication number CN1857250; Shao Pengzhu, He Zhiyun, Feng Guopei, Wen Zhichang, Application of Tanshinone as an Acetylcholinesterase Inhibitor in the Treatment of Related Diseases, Publication No. CN1764447; Yuan Shulan, Yang Yiming, Huang Guangqi, Zhou Qinghua, Liu Ting, Wang Xiujie, Huang Renmin, Zhou Hongyuan, Tanshinone in Application in the preparation of drugs for treating tumors, publication number CN1264580, etc.). However, there are fewer patents about the synthesis and preparation of tanshinone derivatives (such as: Qin Yinlin, Yan Peiling, He Longqi, the application of tanshinone IIA in pharmacy, publication number CN 1631364; Qin Yinlin, Tanshinone I derivatives and their application in pharmacy Application of tanshinone derivatives, publication number CN 1837200; Du Zhiyun, Zhang Kun, Fang Yanxiong, Gu Lianquan, Huang Baohua, Zhao Suqing, Zhou Lihua, Zheng Jie, Tanshinone derivatives and their application in the preparation of aldose reductase inhibitor drugs, publication number CN 101012270; Gu Lianquan, Liu Peiqing, Li Guihua, Tanshinone IIA is used to prepare drugs for the prevention and treatment of atherosclerosis, publication number CN 1426782, etc.), and its activity is mainly concentrated in the traditional cardiovascular and tumor fields. At present, there is no synthesis and report about tanshinone derivatives in the prior art, nor does it serve as a selective 11-beta-HSD1 inhibitor and its use in the preparation and treatment of diabetes and related metabolic diseases (hypertension, obesity, senile dementia) etc.) reports on the application in medicine.

Invention content:

The object of the present invention is to provide a class of tanshinone derivatives, pharmaceutical compositions using them as active ingredients, their synthesis methods, and the application of such compounds in the preparation of selective 11β-HSD1 inhibitor drugs, and also provide the tanshinone derivatives Application of the compound in the preparation of medicines for treating diabetes and related metabolic diseases (hypertension, obesity, senile dementia, etc.).

Above-mentioned purpose of the present invention is achieved by following technical scheme:

Tanshinone derivatives shown in general formula (I)

R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , and R ₆ are independently selected from hydrogen, halogen, hydroxyl, ketocarbonyl, lower alkoxy, cycloalkoxy, carbonyloxy substituted by lower alkyl, Cycloalkyl substituted carbonyloxy, aryl or heterocyclic aryl substituted carbonyloxy, lower alkyl substituted carbonyl, cycloalkyl substituted carbonyl, aryl or heterocyclic aryl substituted carbonyl, amino , cyano, azide, lower alkyl substituted amine, cycloalkyl substituted amine, aryl or heterocyclic aryl substituted amine, lower alkyl substituted amide, cycloalkyl substituted amide , aryl or heterocyclic aryl substituted amido, lower alkyl substituted sulfonamide, cycloalkyl substituted sulfonamide, aryl or heterocyclic aryl substituted sulfonamide, lower alkyl substituted sulfonyl Acyl, cycloalkyl substituted sulfonyl, aryl or heterocyclic aryl substituted sulfonyl, OC(=O)N(R ₁₃ ) ₂ , O(CH ₂ )mN(R ₁₃ ) ₂ , OC(=O )(CH ₂ )mCOOR ₁₃ , wherein m=1-5, R ₁₃ is hydrogen or lower alkyl;

_R7 are independently selected from hydrogen, halogen, aryl or heterocyclic aryl, lower alkyl substituted carbonyl, cycloalkyl substituted carbonyl, aryl or heterocyclic aryl substituted carbonyl, nitro, amino, lower alkane substituted amino group, cycloalkyl substituted amino group, aryl or heterocyclic aryl substituted amino group, lower alkyl substituted amido group, cycloalkyl substituted amido group, aryl or heterocyclic aryl substituted Amide, lower alkyl substituted sulfonyl, cycloalkyl substituted sulfonyl, aryl or heterocyclic aryl substituted sulfonyl, lower alkyl substituted sulfonyl, cycloalkyl substituted sulfonyl , sulfonyl substituted by aryl or heterocyclic aryl;

R ₈ and R ₉ are independently selected from hydrogen, carboxyl, methyl, hydroxymethylene, lower alkoxymethylene, cycloalkoxymethylene, lower alkyl substituted carbonyloxymethylene, Cycloalkyl substituted carbonyloxymethylene, aryl or heterocyclic aryl substituted carbonyloxymethylene, lower alkyl substituted aminomethylene, aryl substituted aminomethylene , lower alkyl substituted amido methylene, aryl substituted amido methylene, fluoromethylene, lower alkyl substituted sulfonamido methylene, cycloalkyl substituted sulfonamido methylene Sulfonamidomethylene substituted with radical, aryl or heterocyclic aryl;

R ₁₀ and R ₁₁ are independently selected from hydrogen, halogen, carboxyl, aryl or heterocyclic aryl, hydroxymethylene, lower alkoxymethylene, cycloalkoxymethylene, lower alkyl substituted carbon Acyloxymethylene, cycloalkyl substituted carbonyloxymethylene, aryl or heterocyclic aryl substituted carbonyloxymethylene, lower alkyl substituted aminomethylene, aryl Substituted aminomethylene, lower alkyl-substituted amidomethylene, aryl-substituted amidomethylene, fluoromethylene, lower alkyl-substituted sulfonamidomethylene, cycloalkyl Substituted sulfonamidomethylene, aryl or heteroaryl substituted sulfonamidomethylene, lower alkyl substituted carbonyl, cycloalkyl substituted carbonyl, aryl or heteroaryl substituted carbonyl, Nitro, amino, lower alkyl substituted amino, cycloalkyl substituted amino, aryl or heterocyclic aryl substituted amino, lower alkyl substituted amido, cycloalkyl substituted amido, aryl Amino group substituted by radical or heterocyclic aryl group, sulfonamide group substituted by lower alkyl group, sulfonamide group substituted by cycloalkyl group, sulfonamide group substituted by aryl group or heterocyclic aryl group;

R ₁₂ are independently selected from hydrogen, alkyl, cycloalkyl, aryl or heterocyclic aryl, carbonyl substituted by lower alkyl, carbonyl substituted by cycloalkyl, carbonyl substituted by aryl or heteroaryl, lower alkane A sulfonyl group substituted with a radical, a sulfonyl group substituted with a cycloalkyl group, a sulfonyl group substituted with an aryl group or a heterocyclic aryl group;

Or R ₁ and R ₃ form a covalent bond;

Or R ₂ and R ₄ form a covalent bond;

Or R ₈ , R ₁₀ form a covalent bond;

Or R ₉ and R ₁₁ form a covalent bond;

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

X ₁ , X ₂ , X ₃ , and X ₄ are independently selected from acyloxy, alkoxy, hydroxyl, β-carbonyl substituted alkyl, etc.;

Or X ₁ and X ₃ form a covalent bond;

Or X ₂ and X ₄ form a covalent bond;

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

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

Or X ₁ , X ₂ , X ₃ , X ₄ form 2-substituted imidazole ring, 2-substituted thiazole ring, 2,3-substituted oxazole, 2,3-substituted piperazine ring, etc.;

Or X ₁ , X ₂ , X ₃ , X ₄ form C(=O)OC(=O), C(=O)NR ₁₄ C(=O), wherein R ₁₄ is selected from hydrogen or lower alkyl;

_X3 is selected from carbon, nitrogen, oxygen, sulfur atoms, etc.;

The "alkyl" mentioned herein refers to a straight chain or branched chain hydrocarbon functional group containing 1-10 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl group, n-octyl group, n-nonyl group, n-decyl group, etc., but not limited to those listed above.

The "lower alkyl" mentioned herein refers to a straight chain or branched chain hydrocarbon functional group containing 1-4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl , tert-butyl, etc., but not limited to those listed above.

The "cycloalkyl" mentioned in the text refers to a cyclic functional group containing 3-8 atoms, such as cyclopropyl, cyclobutanyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctane or pyrrolidinyl, morpholinyl, piperidinyl, etc., but not limited to those listed above.

The "aryl" mentioned in the text refers to an aromatic ring functional group containing 5-10 atoms, such as phenyl, naphthyl, furyl, thiazolyl, thienyl, imidazolyl, oxazolyl, quinolinyl, indole Basic class, but not limited to those listed above.

The "halogen" mentioned herein refers to fluorine, chlorine, bromine and iodine.

General formula (I) tanshinone derivatives or pharmacologically acceptable salts thereof are preferably compounds T4, T6, T7, T8, T9, T14, T21, T24, T25, T28, T31, T38, T39, T43, T51.

A pharmaceutical composition, which contains a therapeutically effective amount of the tanshinone compound of the general formula (I) of claim 1 and a pharmaceutically acceptable carrier.

The preparation method of the tanshinone derivatives of the general formula (I), including free radical-mediated elimination reaction, allyl position oxidation, hydroxyl fluorination, benzene ring nitration, three-component reaction synthesis of imidazole with the participation of o-dicarbonyl, catalytic hydrogenation, benzyl Oxidation, aromatic ring halogenation, Suzuki cross-coupling reaction, dihydroxylation reaction catalyzed by potassium osmate, Fridiel-Craft reaction catalyzed by Bransted acid, synthesis of pyrrole from diketone.

The preparation method of general formula (I) tanshinone derivative as mentioned above comprises the elimination reaction synthesis compound T4 by free radical mediated, by _SeO Participating allylic oxidation compound T7 and T8, by SeO Participating _benzyl Compound T43 was synthesized by site oxidation, and compounds T29, T30, T31, T32, T33, and T34 were synthesized by Suzuki coupling reaction catalyzed by Pd(0).

The tanshinone derivatives of the general formula (I) or their pharmacologically acceptable salts are used as active ingredients in the preparation of 11β-HSD1 selective inhibitor drugs.

The tanshinone derivatives of the general formula (I) or their pharmacologically acceptable salts are used as active ingredients in the preparation of drugs for treating diabetes and related metabolic diseases (hypertension, obesity, senile dementia, etc.).

The pharmacologically acceptable salts of the tanshinone derivatives of the present invention include, for example, inorganic acids such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, and hydrobromic acid, or maleic acid, fumaric acid, tartaric acid, lactic acid, and citric acid. , acetic acid, methanesulfonic acid, p-toluenesulfonic acid, adipic acid, palmitic acid, tannic acid and other organic acids, alkali metals such as lithium, sodium and potassium, alkaline earth metals such as calcium and magnesium, and basic amino acids such as lysine of salt.

When the compound of the present invention is used as a medicine, it can be used directly or in the form of a pharmaceutical composition. The pharmaceutical composition contains 0.1-99%, preferably 0.5-90%, of the compound of the present invention, and the rest is a pharmaceutically acceptable, non-toxic and inert pharmaceutical carrier to humans and animals.

The pharmaceutically acceptable carrier is one or more solid, semi-solid and liquid diluents, fillers and auxiliary materials for pharmaceutical products. The pharmaceutical composition of the present invention is used in the form of dosage per body weight. The dosage form that can be adopted for applying the medicine of the present invention is the customary galenic administration dosage form, for example: ointment, tablet, pill, suppository emulsion, infusion solution and injection solution and the like. These dosage forms are prepared according to well-known methods, using conventional additives and excipients. The medicine thus prepared can be administered locally, parenterally, orally, etc. as required.

The administration amount of the compound of the present invention can vary according to the administration route, patient's age, body weight, type and severity of the disease to be treated, etc. The daily dose can be 0.01-10 mg/kg body weight, preferably 0.1-5 mg/kg body weight. Administration can be one or more times.

The characteristics and excellence of the present invention are that it reports a class of novel tanshinone derivatives, their preparation methods, and as a class of novel highly efficient and highly selective 11β-HSD1 inhibitors, which are useful in the preparation and treatment of diabetes and related metabolic diseases. It has a good application prospect in disease medicine.

Description of drawings:

Figure 1 is the role of 11β-HSD in the regulation of glucocorticoids (quoted from J.Steroid Biochem.Mol.Biol.2010, 119, 56);

Figure 2 is a reaction flow diagram for compounds derived from tanshinone IIA and cryptotanshinone A ring and B ring;

Figure 3 is a reaction flow diagram for compounds derived from tanshinone IIA and cryptotanshinone C ring;

Figure 4 is a reaction scheme for compounds derived from the D ring of tanshinone IIA and cryptotanshinone.

Detailed ways:

In order to better understand the essence of the present invention, the preparation method and pharmacological action results of the tanshinone derivatives shown in the general formula (I) of the present invention will be described below with the test examples, examples and preparation examples of the present invention, but The technical solution of the present invention is not limited thereto, and any solution that can be made by using a technical solution similar to the present invention without the need for creative work by those of ordinary skill in the art is considered to belong to the category of the technical solution of the present invention.

Example 1:

The specific experimental method of the present invention is as follows: using tanshinone IIA and cryptotanshinone separated from traditional Chinese medicine Danshen as starting materials, synthesizing tanshinone derivatives represented by general formula (I). Specifically, tanshinone IIA and cryptotanshinone are starting materials for the preparation of such compounds, and tanshinone IIA (T1) and cryptotanshinone (T2) can be isolated from the ethanol extract of traditional Chinese medicine Danshen.

The structural formulas of tanshinone IIA and cryptotanshinone are:

Tanshinone compounds represented by the general formula (I) can be obtained from tanshinone IIA and cryptotanshinone through 1-4 steps of the reaction scheme in Example 1 (see the reaction scheme, Figures 2, 3 and 4).

Figure 2 is a reaction flow diagram for compounds derived from tanshinone IIA and cryptotanshinone ring A and ring B; the reagents and reaction conditions are: a) NBS, AIBN, CCl ₄ , reflux; b) NaOAc, TBAI, DMF, RT; c ) K ₂ OsO ₄ , NMO, 2,6-lutidine, t-BuOH/H ₂ O, RT; d) NBS, AIBN, CCl ₄ , reflux; e) SeO ₂ , 1,4-dioxane, reflux; f) DAST, DCM, -78°C; g) succinic anhydride, Et ₃ N, DMAP, DCM, RT; h) H ₂ , Pd/C, HCOOH, MeOH, RT; i) HNO ₃ , H ₂ 8O ₄ , 0°C ;

Figure 3 is a reaction flow diagram for compounds derived from tanshinone IIA and cryptotanshinone C ring; the reagents and reaction conditions are: a) Lewesson's reagent, THF, RT; b) PhCHO, AcONH ₄ , EtOH, reflux; c) PtO ₂ , H ₂ , Pyridine, Ac ₂ O, RT; d) m-CPBA, NaHCO ₃ , DCM, RT; e) diethyl amine, acetone, -40°C;

Figure 4 is a reaction flow diagram for compounds derived from tanshinone IIA and cryptotanshinone D ring; the reagents and reaction conditions are: a) NaOH (2N), THF/H ₂ O, ultrasound; b) NH ₃ ·H ₂ O, EtOH , RT; c) RCOCl, Et ₃ N, DCM, RT; d) RSO ₂ Cl, DMAP, Pyridine, 78°C-RT; e) IBX, DMSO, RT; Then, NH ₄ OAc (or PhNH ₂ ), HOAc , 60°C; f) SeO ₂ , HOAc, reflux; g) MsCl, Et ₃ N, DMAP, THF, RT; then, PhNH ₂ , TBAI, THF, reflux; h) TBAI, nuclear reagent, DMF, 50°C; j) DAST, DCM, -78°C; k) succinic anhydride, Et ₃ N, DMAP, DCM, RT; 1) IBX, DMSO, RT; Then, NaClO ₂ , iso-pentene, KH ₂ PO ₄ , acetone/H ₂ O, RT; n) NIS, TFA, DCM, RT; o) ArB(OH) ₂ , Pd(PPh ₃ ) ₄ , PPh ₃ , K ₂ CO ₃ , DMF/H ₂ O, 80°C; p) HCHO , HCl (con.), H ₂ O, reflux;

The preparation of tanshinone and cryptotanshinone (compound T1, T2) uses the following method:

Salvia miltiorrhiza extract (see: Pharmacopoeia of the People's Republic of China 2010 Edition) was dissolved in acetone and ethanol in sequence, and the insolubles were filtered off. Reverse-phase column chromatography and petroleum ether/acetone recrystallization were purified to obtain tanshinone (petroleum ether:ethyl acetate=10:1, R _f =0.4), cryptotanshinone (petroleum ether:ethyl acetate=5:1, R _f =0.3) Monomer.

Example 2:

Preparation of compounds T3, T4, T5:

To a solution of compound T1 (29 mg, 0.1 mmol) in CCl ₄ (5 mL), NBS (27 mg, 0.15 mmol) and benzoyl peroxide (36 mg, 0.15 mmol) were added sequentially. After the addition, the gas was purged (N ₂ ), and then reacted at room temperature for 3 hours. After the reaction was completed, add DCM to dilute, then wash with saturated _Na2SO3 aqueous solution, extract the aqueous phase with DCM three _times (5mL×3), combine the organic phases, wash with saturated aqueous sodium chloride solution, dry over anhydrous sodium sulfate and concentrate Chromatography (petroleum ether: ethyl acetate = 15:1) gave compound T3 (15 mg, 50%). The structural analysis data of compound T3 are as follows:

ESI-MS was measured on a shimadzu LCMS-2010EV mass spectrometer; 1D and 2D NMR were measured on a BrukerAM-300 and DRX-500 nuclear magnetic resonance instrument, the deuterated reagent used was produced by Sigma Aldrich, TMS was used as an internal standard, and the unit of δ was ppm, The unit of J is Hz. The silica gel used for mixing samples is 100-200 mesh, the silica gel used for chromatography is 300-400 mesh and the thin-layer plate (thickness 0.4-0.5mm) is produced by Yantai Jiangyou Silica Gel Development Co., Ltd. Ltd. products.

Compound T3: red solid, ¹ H-NMR (400MHz, CDCl ₃ ) δ7.62(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, ¹ H-NMR (400MHz, CDCl ₃ ) δ7.86(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);

Example 3:

Preparation of compound T6:

To a solution of compound T3 (18 mg, 0.05 mmol) in DMF (1.0 mL), NaOAc (16 mg, 0.2 mmol) and TBAI (3 mg) were added sequentially. After the addition, the reaction was carried out at room temperature for 12 hours. After completion of the reaction, dilute with water (10 mL), then extract three times with EtOAc (8 mL × 3), combine the organic phases, wash with water and saturated aqueous sodium chloride successively, dry over anhydrous sodium sulfate, concentrate and column chromatography (petroleum ether: Ethyl acetate=6:1) to obtain compound T6 (12 mg, 70%).

Compound T6:: red solid, ¹ H-NMR (500MHz, CDCl ₃ ) δ7.73(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);

Example 4:

Preparation of compounds T7 and T8:

Under N ₂ atmosphere, SeO ₂ (22 mg) was added to a solution of compound T4 (15 mg) in 1,4-dioxane (1.0 mL), and heated to reflux for 1.5 hours. After the completion of the TLC detection reaction, dilute with water, then extract three times with EtOAc, combine the organic phases, wash with saturated aqueous sodium chloride, dry over anhydrous sodium sulfate, concentrate and then column chromatography (petroleum ether: ethyl acetate=5: 1→ 2:1), to obtain compounds T7 (10 mg, 67%) and T8 (3 mg, 20%).

Compound T7: red solid, ¹ H-NMR (500MHz, CDCl ₃ ) δ8.92 (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, ¹ H-NMR (500MHz, CDCl ₃ ) δ8.98 (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).

Example 5:

Preparation of compound T9

To a solution of compound T4 (15 mg) in t-BuOH/H ₂ 0 (0.8 mL/0.2 mL) under N ₂ atmosphere, 2,6-lutidine (10 mg) and potassium oxalate (4 mg) were sequentially added , after stirring at room temperature for 15 minutes, sodium periodate (42 mg) was added once, and the reaction was carried out at room temperature for 4 hours. After the reaction was detected by TLC, saturated Na ₂ S ₂ O ₃ was added to quench the reaction, diluted with water, extracted three times with EtOAc, and combined The organic phase was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, concentrated and then column chromatographed (petroleum ether: ethyl acetate = 1.5:1) to obtain compound T9 (11 mg, 68%).

Compound T9: red solid, ¹ H-NMR (400MHz, CDCl ₃ ) δ7.70(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:

Preparation of compounds T10 and T11

To compound T7 (15 mg) in MeOH/HCOOH (8.0 mL/1.0 mL), Pd/C (3 mg) was added, gas exchanged (H ₂ ), and react at room temperature for 2.5 hours. After the TLC detection reaction was completed, it was diluted with water, then extracted three times with EtOAc, the organic phases were combined, washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, concentrated and then column chromatographed (chloroform: acetone = 3: 1) to obtain the compound T10 (8 mg, 54%) and T11 (5 mg, 33%).

Compound T10: red solid, ¹ H-NMR (400MHz, CDCl ₃ ) δ7.66(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, ¹ H-NMR (400MHz, CDCl ₃ ) δ7.67(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:

Preparation of compounds T12, T42, T48 (taking the preparation of compound T48 as an example)

Under the condition of _N2 atmosphere and -78℃, DAST (20mg) was added dropwise to the solution of compound T43 (12mg) in DCM (1.0mL), reacted at this temperature for 15 minutes, after the reaction was detected by LC, diluted with water , and then extracted three times with EtOAc, the organic phases were combined, washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, concentrated and then column chromatographed (petroleum ether: ethyl acetate = 10: 1) to obtain compound T48 (8 mg, 68 %). Compound T48: red solid, ¹ H-NMR (400MHz, CDCl ₃ ) δ7.70(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:

Preparation of compounds T13 and T49 (taking the synthesis of compound T49 as an example)

Under the condition of ice-water bath, to compound T43 (16mg) in DCM (1.0mL), DMAP (4mg) and succinic anhydride (10mg) were added successively, then Et ₃ N (20mg) was added dropwise thereto, warmed to room temperature Reacted for 3 hours, after the reaction was detected by TLC, it was diluted with water, then extracted three times with EtOAc, the organic phases were combined, washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, concentrated and then column chromatographed (chloroform:methanol=30:1 ) to obtain compound T49 (mg, %).

Compound T49: yellow solid, ¹ H-NMR (400MHz, CDCl ₃ ) δ7.65(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:

Preparation of Compound T14

Under ice-water bath conditions, in the reaction flask of compound T1 (16mg), add concentrated sulfuric acid (0.25mL) dropwise, then add concentrated nitric acid (0.1mL) to the solution of concentrated sulfuric acid (0.15mL) dropwise in the above solution, in React at this temperature for 15 minutes. After the reaction is detected by TLC, dilute with ice water, then extract three times with EtOAc, combine the organic phases, wash with saturated sodium bicarbonate solution, water, and saturated aqueous sodium chloride solution successively, and dry over anhydrous sodium sulfate. , after concentration, column chromatography (petroleum ether: ethyl acetate = 3:1) gave compound T14 (3 mg, 15%).

Compound T14: red solid, ¹ H-NMR (400MHz, CDCl ₃ ) δ7.52(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);

Example 10:

Preparation of compound T15

To a solution of compound T2 (29 mg, 0.1 mmol) in Ac ₂ O (5 mL), PtO ₂ (5 mg) and pyridine (0.2 mL) were added sequentially. After the addition, the gas was purged (H ₂ ), and the reaction was carried out at room temperature for 4 hours. After the reaction was completed, the insoluble matter was filtered off, the filtrate was concentrated to dryness under reduced pressure, and the crude product was subjected to column chromatography (petroleum ether: ethyl acetate = 7:1) to obtain compound T15 (31 mg, 81%).

Compound T15: red solid, ¹ H-NMR (400MHz, CDCl ₃ ) δ7.74(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) .

Example 11:

Preparation of Compound T16

Under the condition of _N2 atmosphere and -40°C, to the solution of compound T2 (29 mg) in THF (1.0 mL), add anhydrous acetone (290 mg) and diethylamine (73 mg) dropwise successively, and react at this temperature for 4 hours Afterwards, adding water for dilution, the aqueous phase was extracted three times with EtOAc (5mL×3), the organic phases were combined, washed with water and saturated aqueous sodium chloride successively, dried over anhydrous sodium sulfate and concentrated, followed by column chromatography (petroleum ether: ethyl acetate = 5:1), compound T16 (12 mg, 72% brsm) was obtained, and the raw material (15 mg) was recovered.

Compound T16: yellow solid, ¹ H-NMR (400MHz, CDCl ₃ ) δ7.70(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);

Example 12:

Preparation of compound T17

To the toluene (1.5mL) solution of compound T2 (29mg), add Lawesson reagent (80mg) and NaHCO ₃ (27mg) successively, raise the temperature to 50°C and react for 3 hours. Direct column chromatography (petroleum ether: ethyl acetate = 20:1) gave compound T17 (10mg, 32%)

Compound T17: ¹ H NMR (400MHz, CDCl ₃ ) δ7.65(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).

Example 13:

Preparation of Compound T18

Under _N2 atmosphere, in the ethanol (1.5mL) solution of compound T1 (29mg), add 4-hydroxybenzaldehyde (30mg) and ammonium acetate (15mg), after heating to reflux reaction for 4 hours, TLC detects that the reaction is complete, Diluted by adding water, the aqueous phase was extracted three times with EtOAc (5mL×3), the organic phases were combined, washed with water and saturated aqueous sodium chloride successively, dried over anhydrous sodium sulfate and concentrated, followed by column chromatography (petroleum ether: ethyl acetate=3: 1) to obtain compound T18 (19 mg, 44%).

Compound T18: ¹ H-NMR (500MHz, D-pyr) δ8.62(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);

Example 14:

Preparation of Compound T19

At room temperature, CaSO ₄ (5 mg) was added to a solution of compound T1 (29 mg) in DCM (1.5 mL). After stirring for 15 minutes, m-CPBA (27 mg) was added. The insoluble matter was filtered off, concentrated and then directly chromatographed (petroleum ether: ethyl acetate = 8:1) to obtain compound T19 (15 mg, 75% brsm), and another raw material (10 mg) was recovered.

Compound T19: Colorless gum, ¹ H-NMR (400MHz, CDCl ₃ ) δ7.66(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).

Example 15:

Preparation of Compound T2'

Under the condition of N ₂ atmosphere and -40°C, Et ₃ SiH (120 mg) and BF ₃ ·Et ₂ O (28 mg) were sequentially added dropwise to compound T1 (29 mg) in THF (1.5 mL). After the addition was complete, Allow it to naturally rise to room temperature and react. After TLC detects that the reaction is complete, add saturated NaHCO ₃ aqueous solution to quench the reaction. The aqueous phase is extracted three times with EtOAc (5mL×3). The combined organic phases are washed with water and saturated aqueous sodium chloride successively. After drying over sodium sulfate and concentrating, column chromatography (petroleum ether: ethyl acetate = 5:1) gave compound T2' (21 mg, 75%).

Compound T2': red solid, ¹ H-NMR (400MHz, CDCl ₃ ) ¹ H NMR (400MHz, CDCl ₃ ) δ7.64 (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);

Example 16:

Preparation of Compound T20

To a solution of compound T2 (29 mg, 0.1 mmol) in THF (1.5 mL) was added dropwise an aqueous solution of NaOH (2N, 0.5 mL). After the addition, ultrasonic reaction was carried out at room temperature for 4 hours. After the reaction was completed, THF was distilled off under reduced pressure, diluted with water, and then extracted three times with EtOAc (5mL×3). Ethyl ester=2:1) to obtain compound T20 (32 mg, 100%).

Compound T20: Pale yellow foam, ¹ H-NMR (500MHz, CDCl ₃ ) δ7.98(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).

Example 17:

Preparation of compound T21

To a solution of compound T2 (29 mg, 0.1 mmol) in EtOH (0.5 mL), aqueous ammonia (33%, 1 mL) was added dropwise. After the addition was completed, after ultrasonic reaction at room temperature for 6 hours, TLC found that the reaction was complete. EtOH was evaporated under reduced pressure, diluted with water, and then extracted three times with EtOAc (8mL×3). The organic phases were combined and washed with saturated aqueous sodium chloride solution. After drying and concentrating over anhydrous sodium sulfate, column chromatography (chloroform:methanol=6:1) gave compound T21 (15 mg, 50%).

Compound T21: red solid, ¹ H-NMR (400MHz, CD ₃ OD) δ7.72 (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);

Example 18:

Preparation of compounds T22 and T23 (taking the synthesis of compound T22 as an example)

Under the condition of N ₂ atmosphere and -40°C, to the DCM (1.5 mL) solution of compound T21 (15 mg) and DMAP (4 mg), Et ₃ N (15 mg) and benzoyl chloride (12 mg) were successively added dropwise, and the addition was completed. After allowing it to naturally heat up and react for 1.5 hours, TLC found that the reaction was complete, adding water to quench the reaction, and then extracting three times with EtOAc (8mL×3), combining the organic phases, washing with saturated aqueous sodium chloride, drying and concentrating over anhydrous sodium sulfate Column chromatography (chloroform:methanol=30:1) gave compound T23 (13 mg, 56%).

Compound T23: red solid, red solid, ¹ H-NMR (400MHz, CDCl ₃ ) δ8.11(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);

Example 19:

Preparation of compounds T24 and T25 (taking the synthesis of compound T25 as an example)

Under the condition of N ₂ atmosphere and -40°C, to the DCM (1.0 mL) solution of compound T21 (15 mg) and DMAP (3 mg), DIPEA (38 mg) and MsCl (17 mg) were sequentially added dropwise, and allowed to naturally After warming up to room temperature and reacting for 3.5 hours, TLC found that the reaction was complete, adding water to quench the reaction, then extracting three times with EtOAc (8mL×3), combining the organic phases, washing with saturated aqueous sodium chloride, drying and concentrating the column layer with anhydrous sodium sulfate Analysis (petroleum ether: ethyl acetate = 3:1) gave compound T24 (11 mg, 62%).

Compound T24: red solid, ¹ H-NMR (500MHz, CDCl ₃ ) δ8.21(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: ¹ H-NMR (500MHz, CDCl ₃ ) δ7.72(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);

Example 20:

Preparation of compounds T26 and T27 (taking the synthesis of compound T26 as an example)

Step1: Weigh compound T20 (31mg) and dissolve it in DMSO (1mL), then add IBX (28mg/batch) to it in two batches, react at room temperature for 3 hours, TLC finds that the reaction is complete, add water to the reaction system Dilute, then extract three times with EtOAc, combine the organic phases, wash with water and saturated aqueous sodium chloride successively, dry over anhydrous sodium sulfate, concentrate and column chromatography (petroleum ether: ethyl acetate = 3: 1), to obtain C-16 Hydroxyoxidation product (20 mg, 65%).

Step 2: Weigh the oxidation product (16mg) obtained in Step 1 and dissolve it in 0.5mL glacial acetic acid, then add ammonium acetate (38mg) to it at one time, heat to 60°C and react for 1 hour, TLC detects that the reaction is complete, and add Water was added to the reaction solution to quench the reaction, and then extracted three times with EtOAc, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and column chromatographed (petroleum ether: ethyl acetate = 4: 1) to obtain the compound T26 (12mg, 79%)

Compound T26: yellow solid, ¹ H-NMR (400MHz, CDCl ₃ ) δ9.39(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: ¹ H-NMR (400MHz, CDCl ₃ ) δ7.54(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);

Example 21:

Preparation of Compound T28

Add NIS (34 mg) to a solution of compound T1 (29 mg) in DCM (1 mL) under N2 atmosphere at -40°C, and then add TFA (11 mg) dropwise to the system after five minutes, and react at this temperature for 3 hours Afterwards, TLC detects that the reaction is complete, adding saturated aqueous sodium sulfite solution to the system to quench the reaction, diluting with water, extracting three times with EtOAc, combining the organic phases, washing with saturated brine, drying over anhydrous sodium sulfate, and column chromatography (petroleum ether) after concentration : ethyl acetate=15:1), to obtain compound T28 (38 mg, 92%) Compound T28: red solid, ¹ H-NMR (500MHz, CDCl ₃ ) δ7.63 (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);

Example 22:

Preparation of compounds T29, T30, T31, T32, T33, T34, T35 (taking the synthesis of compound T29 as an example)

Under N ₂ atmosphere, to compound T28 (21 mg), phenylboronic acid (10 mg) and K ₂ CO ₃ in DMF/H ₂ O (1 mL/0.2 mL) was added Pd(PPh ₃ ) ₄ (5 mg), then heated to After reacting at 80°C for 3 hours, TLC detected that the reaction was complete, cooled to room temperature, diluted with water, extracted three times with EtOAc, combined the organic phases, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and column chromatography (petroleum ether: acetic acid Ethyl ester=8:1) to obtain compound T29 (18 mg, 98%).

Compound T29: red solid, ¹ H-NMR (400MHz, CDCl ₃ ) δ7.63(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: ¹ H-NMR (500MHz, CDCl ₃ ) δ7.67(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, ¹ H-NMR (400MHz, CDCl ₃ ) δ9.20(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, ¹ H-NMR (400MHz, CDCl ₃ ) δ8.75(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: ¹ H-NMR (500MHz, CDCl ₃ ) δ7.62(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, ¹ H-NMR (400MHz, CDCl ₃ ) δ9.34(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: ¹ H-NMR (400MHz, CDCl ₃ ) δ7.64(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);

Example 23:

Preparation of compounds T38 and T39

Under _N2 conditions, add formaldehyde aqueous solution (38%, 0.5mL) to the solution of compound T1 (29mg) in 1,4-dioxane (0.5mL), then add a drop of concentrated hydrochloric acid therein, and heat to reflux reaction After 2 hours, TLC detected that the reaction was complete, cooled to room temperature, diluted with water, extracted three times with EtOAc, combined organic phases, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and column chromatography (petroleum ether: ethyl acetate = 3:1→1:1), to obtain compounds T38 and T39 (20 mg, 63%).

Compound T38: red solid, ¹ H-NMR (400MHz, CDCl ₃ ) δ7.60(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: ¹ H-NMR (400MHz, CDCl ₃ ) δ7.56(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)

Example 24:

Preparation of compounds T40 and T46 (taking the preparation of compound T40 as an example)

Step1: At room temperature, add IBX (28 mg) to compound T38 (16 mg) in DMSO (0.8 mL) once, and react at room temperature for 4 hours. TLC detects that the reaction is complete, dilute with water, extract three times with EtOAc, and combine organic phase, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and then column chromatographed (petroleum ether: ethyl acetate = 4:1) to obtain the oxidized product (12 mg, 72%).

Step2: Under N ₂ atmosphere, in the water (0.15mL) solution of NaClO ₂ (9mg) and NaH ₂ PO ₄ (8mg), add the acetone (0.3mL) solution of step oxidation product (5mg) dropwise, then to To this was added isopentene (7 mg). After the mixture was reacted at room temperature for 1 hour, TLC detected that the reaction was complete, and then quenched the reaction by adding a small amount of saturated aqueous sodium sulfite solution, diluted with water, extracted three times with EtOAc, combined the organic phases, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, column chromatography (chloroform:methanol=10:1) gave the oxidized product (4mg, 82%).

Compound T40: ¹ H-NMR (400MHz, CDCl ₃ ) δ9.88(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).

Example 25:

Preparation of compound T43

To a solution of compound T1 (147 mg) in glacial acetic acid (1 mL) was added _SeO2 (55 mg) in one portion. After the addition was completed, the gas was purged (Ar2), and heated to 130° C. for 15 minutes to react. After the reaction was detected by TLC, it was diluted with water, extracted three times with EtOAc, the organic phases were combined, washed with water and saturated brine successively, dried over anhydrous sodium sulfate, concentrated and then column chromatographed (petroleum ether: ethyl acetate = 2: 1) to obtain Compound T43 (127 mg, 82%). Compound T43: red solid, ¹ H-NMR (400MHz, CDCl ₃ ) ¹ H NMR (400MHz, CDCl ₃ ) δ7.66 (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);

Example 26:

Preparation of Compound T45

To a THF (1 mL) solution of compound T43 (9 mg) and DMAP (2 mg) was added dropwise Et ₃ N (12 mg) and MsCl (7 mg) sequentially under N ₂ atmosphere and ice-water bath. After the addition, it was naturally raised to room temperature and reacted for 2 hours, then TBAI (2 mg) and Et ₃ N (6 mg) were added to the reaction solution, stirred at room temperature for 10 minutes after the addition, then aniline (8 mg) was added dropwise, and the reaction was continued for 2.5 hours Afterwards, TLC detected that the reaction was complete, diluted with water, extracted three times with EtOAc, combined the organic phases, washed with water and saturated brine successively, dried over anhydrous sodium sulfate, concentrated and then column chromatographed (petroleum ether: ethyl acetate=1:1), Compound T45 (5 mg, 34%) was obtained.

Compound T45: red solid, ¹ H-NMR (400MHz, CDCl ₃ ) δ7.63(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);

Example 27:

Preparation of compounds T51 and T52 (taking the synthesis of compound T51 as an example)

To a solution of compound T5 (7.5 mg) in THF (1 mL), Et ₃ N (8 mg), TBAI (2 mg), t-BuNH ₂ (5 mg) were added sequentially. React at room temperature for 4 hours. After the reaction was detected by TLC, dilute with water, extract three times with EtOAc, combine the organic phases, wash with water and saturated brine successively, dry over anhydrous sodium sulfate, concentrate and column chromatography (chloroform:methanol=20:1) , to obtain compound T51 (4.5 mg, 61%).

Compound T51: red solid, ¹ H-NMR (400MHz, CDCl ₃ ) δ7.73(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).

Further illustrate the pharmacological action of tanshinone derivatives of the present invention by test example below:

Test example 1:

1 In vitro mouse or human 11β-HSD1 inhibition test method:

Using molecular biology methods, the mouse or human 11β-HSD1 gene sequence purchased from NIH Mammalian Gene Collection (NIH MGC) was cloned into the PcDNA3-VSVtag eukaryotic expression vector, and then transfected in HEK293 cells were screened with G418 (0.75g/L) to obtain stable transfected mixed cell clones. Mixed cell clones were trypsinized and inoculated into 96-well culture plates with single cells, and conditioned cell culture medium (HEK293 cell culture supernatant) was given at the same time, and single cell proliferation clones were obtained after 14-20 days. After amplification, the cells were collected by trypsinization, sonicated and centrifuged (4°C, 1500rpm, 10min), the supernatant was ultracentrifuged again (4°C, 100000g, 1h), phosphate buffer (40mM Na ₂ HPO ₄ , 1mM EDTA, 5% glycerol) to resuspend the mouse or human 11β-HSD1 purified enzyme, and freeze at -80°C for future use.

SPA (Scintillation proximity assay) was used to measure the inhibitory effect of compounds on Xiaohe human 11-β-HSD1, and the inhibitory rate and IC50 value were calculated. All the derivatives T4-T52 obtained from Examples 1-27 were screened for the inhibition of mouse and human 11-beta-HSD1, and 1 μM was selected as the primary screening concentration (screening results are shown in Table 1). The derivatives whose sieve inhibition rate exceeds 50% are further studied on the dose-effect relationship, and the IC50 is calculated (the screening results are shown in Table 2).

2. Experimental results: The results of the activity test showed that, 1) the introduction of hydroxyl or alkoxy groups at the C-1 and C-2 positions of the A ring decreased the activity of 11β-HSD1 of human and mouse origin compared with the parent compound. The decrease of human 11β-HSD1 was particularly obvious; after the alkenyl group was introduced, the activity of mouse 11β-HSD1 was improved to some extent, but the activity of human 11β-HSD1 was decreased. After introducing a carbonyl group at the C-3 position, the activity against human 11β-HSD1 is doubled, but the activity against mouse 11β-HSD1 is significantly decreased; and the substitution of hydroxyl and fluorine atoms at this position is effective against human and mouse 11β-HSD1 activity is unfavorable. Therefore, it can be concluded that the polar functional group of the A ring is detrimental to the activity.

2) The nitro substitution of the B ring decreased the activity of both human and mouse 11β-HSD1, and the decrease of human 11β-HSD1 was particularly obvious.

3) All the remodeling activities for the o-bisbiscarbonyl group of the C ring were greatly reduced, or even completely disappeared, so it was believed that the o-bisbiscarbonyl group was the key pharmacophore of this type of compound.

4) The effect of the D ring on the activity of human and mouse 11β-HSD1 is not consistent. When the D ring is opened (under the premise that the o-dicarbonyl structure remains unchanged), the activity of mouse 11β-HSD1 does not decrease, but has increased; while the human 11β-HSD1 decreased significantly. The introduction of a hydroxyl group at the C-17 position almost completely retains the 11β-HSD1 inhibitory activity against human and mouse sources, and the water solubility of this compound is greatly improved, and the drug-like property is significantly enhanced, which is a relatively interesting modification; The activity of polar F atoms almost disappears. The introduction of the aryl functional group at the C-15 position can not only improve the inhibitory activity of murine 11β-HSD1, but also enhance the drug-like properties of the molecule. When the furan ring of ring D was changed to pyrrole ring, the activity of 11β-HSD1 from both sources decreased significantly.

5) For tanshinone compounds, human 11β-HSD1 is more sensitive to various introduced functional groups, while mouse 11β-HSD1 has better functional group tolerance.

Table 1 Results of preliminary screening of tanshinone derivatives

Table 2 Rescreening results of some tanshinone derivatives

Table 3 List of abbreviations involved in the text

Ac acetyl

AIBN Azobisisobutylcyanide

t-Bu tert-butyl

DAST Diethylaminosulfur trifluoride

DBU 1,8-diazabicyclo-bicyclo(5,4,0)-7-undecene

DCM dichloromethane

DMAP 4-N, N-dimethylaminopyridine

DMF N,N-Dimethylformamide

DMP Dess-Martin oxidizer

DMSO Dimethyl Sulfoxide

IBX 2-iodoxybenzoic acid

Ms methanesulfonyl

m-CPBA m-chloroperoxybenzoic acid

NBS N-Bromosuccinimide

NIS N-iodosuccinimide

NMO N-methylmorpholine-N-oxide

PE Petroleum ether

PTSA p-toluenesulfonic acid

TBAI Tetrabutylammonium iodide

TFA Trifluoroacetic acid

THF Tetrahydrofuran

Ts p-toluenesulfonyl

Formulation Example 1:

According to the method of Example 1-27, first obtain tanshinone derivatives T3-T52, and utilize organic acids (tartaric acid, citric acid, formic acid, oxalic acid, etc.) or inorganic acids (hydrochloric acid, sulfuric acid, phosphoric acid, etc.) to make salts, Add water for injection according to routine, fine filter, potting and sterilizing to make injection solution.

Preparation Example 2:

According to the method of Example 1-27, first obtain tanshinone derivatives T3-T52, and utilize organic acids (tartaric acid, citric acid, formic acid, oxalic acid, etc.) or inorganic acids (hydrochloric acid, sulfuric acid, phosphoric acid, etc.) to make salts, Dissolve it in sterile water for injection, stir to dissolve, filter with a sterile suction filter funnel, then filter aseptically, divide it into 2 ampoules, freeze-dry at low temperature, and aseptically melt seal to obtain a powder injection.

Preparation Example 3:

Tanshinone derivatives T3-T52 obtained in Examples 1-27, and salts made from organic acids (tartaric acid, citric acid, formic acid, oxalic acid, etc.) or inorganic acids (hydrochloric acid, sulfuric acid, phosphoric acid, etc.), and The weight ratio of excipients is 9:1 by adding excipients to make powder.

Formulation Example 4:

Tanshinone derivatives T3-T52 obtained in Examples 1-27, and salts made from organic acids (tartaric acid, citric acid, formic acid, oxalic acid, etc.) or inorganic acids (hydrochloric acid, sulfuric acid, phosphoric acid, etc.), according to The weight ratio of the excipient to the excipient is 1:5-1:10, and the excipient is added, granulated and pressed into tablets.

Formulation Example 5:

Tanshinone derivatives T3-T52 obtained in Examples 1-27, and salts made from organic acids (tartaric acid, citric acid, formic acid, oxalic acid, etc.) or inorganic acids (hydrochloric acid, sulfuric acid, phosphoric acid, etc.), according to Conventional oral liquid preparation method is made into oral liquid.

Formulation Example 6:

Tanshinone derivatives T3-T52 obtained in Examples 1-27, and salts made from organic acids (tartaric acid, citric acid, formic acid, oxalic acid, etc.) or inorganic acids (hydrochloric acid, sulfuric acid, phosphoric acid, etc.), according to It is added to the excipient at a weight ratio of 5:1 to prepare capsules, granules or granules.

Formulation Example 7:

Tanshinone derivatives T3-T52 obtained in Examples 1-27, and salts made from organic acids (tartaric acid, citric acid, formic acid, oxalic acid, etc.) or inorganic acids (hydrochloric acid, sulfuric acid, phosphoric acid, etc.), according to It is added to the excipient at a weight ratio of 3:1 to prepare capsules, granules or granules.

Claims (9)

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

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;

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 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;

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.

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.

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