WO2007095851A1 - Unsaturated 5-member heterocycle compounds, uses and preparation methods theirof - Google Patents

Abstract

The present invention has disclosed a set of pentac unsaturated heterocycle compounds which can up accommodate the expression activity of Osteogenesis protein BMP-2 to increase the bone density, and inhibit cholesterol biosynthesis to reduce blood fats. The present invention has disclosed the synthesis of a set of pentac unsaturated heterocycle compounds and has measured their upper opsonization of Osteogenesis protein BMP-2 and inhibiting effect on key fat metabolism enzyme HMG-CoA. It lays the foundation of treatment of diseases relating to bone metabolic disorders or blood fat metabolic disorders of mentioned compounds.

Description

 Use of five-membered unsaturated heterocyclic compound, compound and preparation method thereof

 The present invention relates to the use of a group of five-membered unsaturated heterocyclic compounds for promoting bone morphology forming protein BMP-2 expression, increasing bone density, inhibiting cholesterol biosynthesis, and lowering blood fat. The five-membered unsaturated heterocyclic compound of the present invention has an anti-osteoporosis effect while resisting lipid metabolism and disorder; the present invention also relates to the novel compound having the above use, a preparation method thereof, and a pharmaceutical composition containing the same .

Background technique

 Normal metabolism of bone is a dynamic balance of bone deposition and osteolysis coordinated by osteoblasts and osteoclasts. Metabolic disorders of the bone (osteoporosis) are mainly due to a decrease in bone mass due to osteolysis greater than bone deposition. The main strategy for osteoporosis treatment today is to reduce bone dissolution, which is to reduce bone mass. By increasing the expression of bone morphogenetic protein BMP-2, it promotes osteoblast differentiation, increases bone stratification, reaches new bone mass dynamic balance, and treats osteoporosis by increasing the orderly deposition of bone.

 Disorders of dyslipidemia, mainly disorders of cholesterol metabolism. The so-called hypolipidemic, mainly to reduce cholesterol (ie LDL-C) carried by plasma low-density lipoprotein. Cholesterol biosynthesis inhibitors such as statins have been shown to be effective. Lipid-lowering drugs are based on the activity of HMGCoA reductase, a key enzyme that inhibits cell cholesterol biosynthesis, reducing the amount of cholesterol and stimulating cell surface receptors. The expression of LDL receptor increases the uptake of plasma LDL by peripheral tissues, thereby reducing blood fat.

 Cholesterol biosynthesis inhibitors, especially HMG-CoA reductase inhibitors, reduce the degree of prenylation required for modification and activation of small G proteins that negatively regulate osteoblast differentiation, thereby increasing BMP-2 Etc. transcription and expression. Increased differentiation of osteoblasts ultimately increases bone density and bone level, thereby simultaneously treating osteoporosis.

 Statins are widely used as a hypolipidemic drug in clinical practice. · Clinical practice observations show that after taking long-term statin drugs, the patient's bone quality is also clearly improved while treating hyperlipidemia. Mundy et al. (Mundy et al: Science 1999; 286: 1946-1948) confirmed that statins, in addition to inhibiting 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA), also contributed to Osteoblast differentiation.

Shi Shuyi, etc., Institute of Pharmaceutical Biotechnology, Chinese Academy of Medical Sciences (Yang Wei, Si Shuyi and Zhang Yueqin, etc.: Proceedings of the 10th National Antibiotics Conference P128-130; Shijiazhuang, August 2005) Established BMP for bone formation The -2 promoter is an anti-osteoporosis drug screening model for drug targets and is used for high-throughput screening. Through extensive screening, the compound 2-acetylbenzothiophene was found to have a significant up-regulation of BMP-2 activity. Previously, there was no report on the biological activity of 2-acetylbenzothiophene. The present invention first discovered 2-acetylbenzothiophene and its structural analogs. The role in promoting bone formation. As described above, bone metabolism shares a common pathway with fat metabolism. Therefore, the present inventors have also studied the action of such a structure on the key enzyme of lipoprotein metabolism HMG-CoA, and as a result, it has been confirmed that the molecule has a 2-acyl substituted five-membered unsaturated In addition to regulating the activity of bone-forming egg S, the compound of the ring structure also has a significant inhibitory effect on the key enzyme of fat metabolism, HMG-CoA reductase. The above findings are the first report of the present invention. In particular, the molecular structure of 2-acetylbenzothiophene is very simple, and has no similarity with the structures of the currently used anti-osteoporosis drugs and hypolipidemic drugs, and is a novel lead structure. Based on the above studies, the present invention synthesized and studied the 2-acyl substituted aromatic thiophene or 2-acyl substituted aromatic pyrrole compounds and their up-regulation of BMP-2 protein and inhibition of HMG-CoA for the first time. It lays the foundation for the treatment of osteoporosis or the development and application of drugs for the treatment of dyslipidemia. '

Summary of the invention

 The object of the present invention is to find a new use of a five-membered unsaturated heterocyclic compound, that is, to promote bone bone formation protein BMP-2 expression, increase bone density and inhibit cholesterol biosynthesis and lower blood fat, and also to bone The use of protein BMP-2 expression has a significant up-regulation activity, can be used for anti-bone metabolism disorders and dyslipidemia, and adds a new family of compounds to the medical field for treating and preventing osteoporosis symptoms.

 The object of the present invention is also to synthesize and screen out a novel small molecule bone-promoting compound by using a structure-activity relationship study on a five-membered unsaturated heterocyclic compound, which has a small molecular weight, a simple structure, and is easy to prepare. advantage. The in vitro activity results show that the five-membered unsaturated heterocyclic compound of the present invention, especially the novel compound of the present invention, 2-acetylbenzothiophene and its derivatives, and a part of 3-substituted 2-acetylbenzofuran, anthracene Significant activity of lowering blood fat and increasing bone density, as well as significant up-regulation activity of bone morphogenetic protein BMP-2, laid the foundation for further research and anti-osteoporosis of the compound.

 The present invention provides a novel use of a five-membered unsaturated heterocyclic compound having the structural formula of Formula I, which promotes bone morphogenetic protein BMP-2 expression, increases bone density, and inhibits cholesterol biosynthesis to lower blood fat.

Where: X is 0 or S or NR _5;

3⁄4 represents a group: H, a hydrocarbon group, 'hydrocarbyl group containing a halogen, an amino group, a nitro group, a hydroxyl group, a hydrocarbyloxy group, a carboxyl group, a sulfonic acid group, a nitrile group or a phosphoric acid group, the hydrocarbon group having 1 to 18 carbons , for example, methyl, halo (including F, Cl, Br or I) methyl, ethyl, propenyl, phenylpropenyl, etc., or a salt thereof; R ₂ may be the same or different from ^, and represents the following groups: anthracene, phenyl, nitro group, amino group, carboxyl group, sulfonic acid group, nitrile group, acyl group, hydrocarbyl group, halogenated hydrocarbon group, carbonyl hydrocarbon group, hydroxyhydrocarbyl group, An aminohydrocarbyl group, a hydrocarbyloxy group or the like, or a salt thereof; and Κ _{4 are} selected from the group consisting of the same or different: hydrazine, halogen, nitro group, amine group, carboxyl group, sulfonic acid group, nitrile group, lower alkyl group, halogenated group a hydrocarbyl group, a carbonyl hydrocarbyl group, a hydroxy group, an amino group, a hydrocarbyl group, a substituted vinyl group, or a salt thereof, or R ₃ , bonded together by carbon, oxygen, or nitrogen to form a 5-7 membered aromatic ring structure;

 Selected from H, a hydrocarbyl group, a halogenated hydrocarbyl group, a carbonyl hydrocarbyl group, a hydroxyhydrocarbyl group, an aminohydrocarbyl group or a hydrocarbyloxy group;

 The above hydrocarbon group and alkoxy group each contain 1 to 18 carbons.

 The present invention also provides a five-membered unsaturated heterocyclic compound having the above formula I, which is capable of reducing blood fat by inhibiting cholesterol biosynthesis, and increasing bone growth by inhibiting cholesterol biosynthesis to promote expression of bone morphogenetic protein BMP-2. The application of density in medicine.

 The present invention finds that the compound of the group, especially the thiophene and the benzothiophene derivative, exhibits a significant up-regulation activity on the expression of the bone morphogenetic protein BMP-2 by studying the structure-activity relationship of the five-membered unsaturated heterocyclic compound. The anti-osteoporosis effect laid the theoretical foundation.

In the anti-bone metabolism disorder and the disorder of blood lipid metabolism according to the present invention, the structure of the compound is preferably wherein Rt R _{2 is} independently selected from the group consisting of H, acetyl, haloacetyl, propionyl, halopropionyl, Or a salt thereof; R ₃ and R ₄ are bonded together by carbon, oxygen and nitrogen to form a 5-7 membered aromatic ring structure.

 Based on the above studies, the present invention synthesizes a series of substituted five-membered unsaturated heterocyclic compounds, and determines the expression of the synthesized compound BMP-2 and inhibits the activity of the key enzyme HMG-CoA, in order to screen for a new therapeutic bone. Metabolic disorders and disorders of dyslipidemia.

 The present invention also provides a five-membered unsaturated heterocyclic compound which is a five-membered unsaturated having an effect of inhibiting cholesterol biosynthesis and increasing bone density by inhibiting cholesterol biosynthesis to promote expression of bone morphogenetic protein BMP-2. Heterocyclic compound, having the structural formula of formula I -

Where: X is 0 or S or NR _5;

 Represents the following groups: H, containing 1-18 carbon lower hydrocarbon groups, halogen (amino, nitro, hydroxy, alkoxy, carboxyl, sulfonate, nitrile, phosphate) substituted hydrocarbyl, or a salt thereof;

It may be the same as or different from R, and represents the following groups: H, halogen, nitro, amine, carboxyl, sulfonate, a nitrile group, an acyl group, a lower hydrocarbon group, a halogenated hydrocarbon group, a carbonyl hydrocarbon group, a hydroxyhydrocarbyl group, an aminoalkyl group, a hydrocarbyloxy group, or the like; or a salt thereof;

R ₃ , through a carbon, oxygen, nitrogen linkage to form a 5- 7-membered aromatic ring structure, the aromatic ring structure may have a substituent R _6; selected from H, lower hydrocarbon group, halogenated hydrocarbon group, carbonyl hydrocarbon group, hydroxy hydrocarbon group, amine group Hydrocarbyl or hydrocarbyloxy.

 R^H, , nitro, amino group, carboxyl group, sulfonic acid group, nitrile group, containing 1-18 carbon lower hydrocarbon groups, hydrocarbyl group, carbonyl hydrocarbyl group, hydroxyhydrocarbyl group, aminohydrocarbyl group or hydrocarbyloxy group.

 The "hydrocarbon" described in the above lower hydrocarbon group, hydrocarbon group or alkoxy group each contains 1 to 18 carbons.

When the X is 0, the compound is a furan compound; when X is S, it is a thiophene compound; and when X is NR ₅ , it is a pyrrole compound.

The above five-membered unsaturated heterocyclic compound of the present invention preferably has a methyl group, an ethyl group, a propenyl group or a phenylpropenyl group; R^H, a halogen, a methyl group, an ethyl group, a halogenated methyl group or a 1- a lower hydrocarbon group of 18 carbons, R ₃ and R ₄ are a benzo structure or a substituted benzo structure formed by a carbon linkage; R _e may be H, a halogen, a nitro group, an amine group, a carboxyl group, a sulfonic acid group, a nitrile group, a lower hydrocarbon group having 1 to 18 carbons, a halogenated hydrocarbon group, a carbonyl hydrocarbon group, a hydroxyalkyl group, an aminoalkyl group or an oxy group; more preferably an acetyl group, R^H, fluorine, methyl group, trifluoromethyl group, R ₃ is a benzo structure formed by carbon bonding.

 The novel five-membered unsaturated heterocyclic compound provided by the invention comprises 3-fluoromethyl-2-acetylbenzothiophene, 3-methyl-2-acetylbenzothiophene, 3-trifluoromethyl-2-acetyl Benzothiophene, 2-phenylacryloylbenzothiophene, 3-fluoro-2-acetylbenzofuran, 3-methyl-2-acetylbenzofuran, 3-trifluoromethyl-2-acetylbenzofuran, 2-Phenylacryloylbenzofuran, 3-acetylindole.

 The present invention also provides a method for synthesizing the above aromatic and five-membered unsaturated heterocyclic compound, which comprises: o-halogen (expressed by M, including chlorine, bromine or iodine) substituted aromatic acetyl compound II under basic conditions and tetrabutyl In the presence of ammonium bromide, the reaction is stirred with an alcohol, a thiol or an amine under reflux, and after the refluxing reaction of the obtained product with the halomethyl ketone is completed, the target is isolated, that is, R3 and R4 in the five-membered unsaturated heterocyclic compound are passed. A benzo structural compound formed by carbon bonding.

In a preferred embodiment of the present invention, the method for synthesizing the five-membered unsaturated heterocyclic compound is as follows: wherein, in the five-membered unsaturated heterocyclic compound, R ₃ is a benzo structure formed by carbon bonding, 2 - The method for synthesizing the acyl substituted benzo five-membered unsaturated heterocyclic compound III comprises: adding an aromatic acetyl compound II with an alcohol or a thiol or an amine to an aqueous solution of a strong alkali, stirring, adding a substituted o-halophenyl ketone II and tetrabutyl Ammonium bromide, reflux reaction, the product obtained is refluxed with a halomethyl ketone for 2 to 5 hours to obtain the target III. The synthetic route is:

II III Wherein, X, R ₂ , R ₅ , the same as above; M represents halogen, including Cl, Br or I; R ₆ is H, halogen, nitro, amine, carboxyl, sulfonic acid group, nitrile group, lower hydrocarbon group (1 18 carbons), a halogenated hydrocarbon group, a carbonyl hydrocarbon group, a hydroxyhydrocarbyl group, an aminohydrocarbyl group or a hydrocarbyloxy group, the hydrocarbyl group having 1 to 18 carbons.

 When the 2- or 3-position of the five-membered unsaturated heterocyclic ring is a compound VI and/or n substituted with an acryloyl group, the synthesis method comprises the step of adding a proton to the aqueous solution of the low-base (50 Å to -50 ° C) a solvent, wherein the protic solvent is a solvent containing a hydroxyl group, and the five-membered unsaturated heterocyclic compound and the aryl formaldehyde are added at a low temperature, and the five-membered unsaturated heterocyclic compound is a 2-acylated derivative having an IV structural formula. Or a 3-acylated derivative having a V structural formula, which is isolated after room temperature reaction to obtain a target VI or VII, and the synthesis route is:

其中， X、 Rt、 R₂、 R₃、 同上； R₇、 R_s独立地选自 H， 卤素， 硝基， 羧基， 腈基、 低级 烃基，卤代烃基， 羟基烃基， '胺基烃基， 烃氧基， 或其盐； 所述烃基具有 1一 18个碳。

Wherein, X, Rt, R ₂ , R ₃ , i.sup.; R ₇ , R _{s are} independently selected from H, halogen, nitro, carboxy, nitrile, lower hydrocarbyl, halohydrocarbyl, hydroxyhydrocarbyl, 'aminohydrocarbyl, a hydrocarbyloxy group, or a salt thereof; the hydrocarbyl group having from 1 to 18 carbons.

 When the compound VIII or IX of the 5- or 3-hydroxycarbonyl group of the 5-membered unsaturated heterocyclic ring, the synthetic method comprises, the acylated derivative of the 5- or 3-position of the 5-membered unsaturated heterocyclic compound IV or V is in the absence of water. In ether, low temperature (50 ° C to - 50 Ό) and base catalysis, with different carboxylic acid esters f W ^. The reaction yields the target, i.e., the compound VIII or IX which gives a 2- or 3-position carbonyl acetyl group, and the synthetic route is:

其中， X、 R₂、 R₃、 同上； R₇、 R₉独立地选.自 H， 卤素， 硝基， 羧基， 腈基、 低级 烃基，卤代烃基， 羟基烃基， 胺基烃基， 烃氧基， 或其盐； 。为含 1-12个碳的低级烷基;所述 烃基含有 1一 18个碳。

Wherein, X, R ₂ , R ₃ , the same as above; R ₇ and R _{9 are} independently selected from H, halogen, nitro, carboxyl, nitrile, lower hydrocarbyl, halohydrocarbyl, hydroxyhydrocarbyl, aminohydrocarbyl, hydrocarbyl Base, or its salt; It is a lower alkyl group having 1 to 12 carbons; the hydrocarbon group contains 1 to 18 carbons.

 a synthetic method in which a carbonyl group is substituted by a hydroxy group at the 2-position or the '3-position acyl group of the 5-membered unsaturated heterocyclic ring, wherein the carbonyl group in the 2-position or 3-position acyl group of the five-membered unsaturated heterocyclic ring is replaced by a hydroxy group, The unsaturated heterocyclic compound is the compound X or XI, and the synthesis method comprises: reacting the compound of the formula IV or V in tetrahydrofuran and water under the action of sodium borohydride to obtain the target X or XI, and the synthesis route is:

其中， X、 R„ R₂、 R₃、 同上; R₇、 R_u独立地选自 H， 卤素， 硝基， 羧基， 腈基、 烃基, 卤代烃基， 羟基烃基， 胺基烃基， 烃氧基， 或其盐； 所述烃基含有 0-18个碳。

Wherein X, R „ R ₂ , R ₃ , supra; R ₇ and R _{u are} independently selected from the group consisting of H, halogen, nitro, carboxy, nitrile, hydrocarbyl, halohydrocarbyl, hydroxyhydrocarbyl, aminohydrocarbyl, hydrocarbyl a base, or a salt thereof; the hydrocarbon group contains 0-18 carbons.

When the 5-membered unsaturated heterocyclic compound is H, ^ is a substituted vinyl compound 2-acyl-4-substituted ethylene derivative vi or 2-hydroxyalkyl 4-substituted styrene derivative viii, the five-membered unsaturated The method for synthesizing a cyclic compound comprises: the 3-methyl five-membered unsaturated heterocyclic compound i is preferably irradiated with chlorine gas under a 500 W mercury lamp to obtain a 3-chloromethyl five-membered unsaturated heterocyclic compound ii; ii is heated with acetic anhydride. Refluxing to give 2-acetyl 3-chloromethyl 5-membered unsaturated heterocyclic compound iii; iii condensing with a diol under basic conditions to obtain a ketal compound iv, and reacting with triphenylphosphine under a strong base to obtain a quaternary phosphonium salt V, and then reacted with a substituted benzaldehyde under a strong base to obtain a target, that is, a 2-acyl-4-substituted ethylene derivative vi; and then vi is deprotected under acidic conditions, from -10'C to 100 °C, 7j, The obtained compound vii and sodium borohydride are reacted in tetrahydrofuran and water to obtain a target, that is, a 2-hydroxyalkyl 4-substituted styrene derivative viii. The specific synthetic route is:

其中， X 、 R_t、 R₂、 R₃、 R₄和 R₉同上； R₁₂选自 H, 烃基，卤代烃基， 羟基烃基， 胺基烃基 或 C烃氧基， 所述烃基含有 1一 18个碳。

Wherein X, R _t , R ₂ , R ₃ , R ₄ and R _{9 are the} same as above; R _{12 is} selected from H, a hydrocarbyl group, a halogenated hydrocarbyl group, a hydroxyhydrocarbyl group, an aminohydrocarbyl group or a C alkoxy group, and the hydrocarbyl group contains 1 18 carbons.

When the five-membered unsaturated heterocyclic compound is hydrogen and R ₃ is a lower hydrocarbon group (containing 1 to 18 carbons) of a substituted thiophene compound or a derivative thereof xi or xii, the synthesis method comprises a 2-acyl five-membered unsaturated heterocyclic ring. The compound is condensed with a diol under basic conditions to obtain a ketal compound ix, ix is refluxed with a hydrocarbyl magnesium bromide in an anhydrous ether solvent to obtain a compound X, and a deketal protecting group is obtained under acidic conditions to obtain a 2-acyl compound xi, xi And reacting sodium borohydride in tetrahydrofuran and water to obtain a target, that is, a 2-substituted hydroxymethyl 4-substituted five-membered unsaturated heterocyclic derivative xii, and the anhydrous ether solvent may be, for example, diethyl ether, tetrahydrofuran, or Oxycyclohexane, ethylene glycol dimethyl ether, polyethylene glycol, diphenyl ether, synthetic route inclusion,

Wherein, and the same as above; R _{13 is} selected from H, a hydrocarbon group having 1 to 18 carbons (lower hydrocarbon group), (^ _-18 aromatic hydrocarbon group, 0, S, N d- ₁₈ hydrocarbon group; n = 1-8).

According to the above route and method, the compound of the present invention can be synthesized stably and reproducibly. The present invention also provides a composition which can contain a therapeutically effective amount of the above five-membered unsaturated heterocyclic compound as an active ingredient The component, and one or more pharmaceutically acceptable excipients (carriers), preferably comprising a weight ratio of 0.1% to 99.5% of a five-membered unsaturated heterocyclic compound, more preferably a five-membered unsaturated heterocyclic ring. 5%之间。 The weight ratio of the compound is 0. 5% - 99 · 5 ° / ₀ .

 The present invention investigates the up-regulation of bone morphogenetic protein BMP-2 expression activity, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) inhibitory activity and anti-osteoporosis activity in rats in the formula (1). It provides a basis for the treatment of bone metabolic disorders and dyslipidemia. .

 The compound of the present invention and the composition containing the same have an effect of promoting bone morphology-forming protein BMP-2 expression, increasing bone density, and inhibiting cholesterol biosynthesis to lower blood fat.

 The compounds of the invention and compositions containing the compounds are useful for the treatment and/or prevention of osteoporosis.

 The compounds of the invention and compositions containing the compounds are also useful in the treatment of disorders of dyslipidemia.

 The various dosage forms of the pharmaceutical compositions of the present invention can be prepared according to conventional methods of manufacture in the pharmaceutical art, for example, by mixing the active ingredient with one or more carriers, which are then employed in such compositions. Pharmacodynamic test

 Using the partial compounds prepared by the present invention, the inventors have provided the following biological activity and pharmacological test results, which are intended to illustrate the medicinal effects of the compounds of the present invention.

 I. Determination of the activity of bone morphogenetic protein-2 expression in vitro

The activity of the patented compound was evaluated by the established bone morphogenetic protein-2 (BMP-2) screening model (Chinese Patent Application No. 03104750. 5). The specific process was as follows: 100 μί / hole of the appropriate concentration of MC3T3E1 The cells were cultured in a 96-well sterile plastic culture plate for 8 h, and the appropriate amount of PYJ plasmid DNA was diluted in a sterile centrifuge tube with 25 μίίί serum-free, double-antibody DMEM medium, and 25 μL in another sterile centrifuge tube. /well serum-free no-anti-DMEM medium dilution 0. 5 μ 1 / well LF2000 Reagent, within 5 min, the above two tubes were combined and mixed, and then incubated for 20 min at room temperature, the mixed transfection suspension was added Into the above 96-well plate, · 50 IL per well, mix well, place 96-well plate in a 37 ° C carbon dioxide incubator, culture for a certain period of time and then add appropriate concentration of drug-acting cells before fluorescence detection; The procedure is as follows: · Discard the medium in the 96-well plate, gently rinse the cells with 200 L/?L PBS (pH 7.0), completely discard the PBS, add 1 XPLB in 25 μ!7 well, room temperature Shake for 15 min, completely lyse the cells, and completely aspirate the lysate to the fluorescein. For the light analysis, the corresponding white hole of the 96-well white plate was added to the analytical whiteboard after adding 70 μL/well of the analytical reagent LAR II. Immediately (within 5 minutes), the analytical whiteboard was placed in a Galaxy spectrophotometer; the detection conditions were: No excitation light. Wavelength, emitted light wavelength is empty, Positioning delay is 1. 0, Number of intervals is 1, Interval time is 1. 0s, Set the instrument reading before shaking mode, Shake diameter is 1 mm, use setting The positive control, blank control, and related data and calculation formulas are used to calculate the up-regulation rate of the sample. See Table 1 and Table 2 for the experimental results. Table 1. Structure of thiophene and furan derivatives and their up-regulation rate of bone morphogenetic protein-2

. Structure of benzothiophene, benzofuran and anthracene derivatives and their up-regulation rate of bone morphogenetic protein-2

 The results of multiple activity assays demonstrated that the compounds of the invention both upregulate bone morphogenetic protein-2. Among them, the activities of the compounds 3, 27, 29, 37, 39, 92, 93 were stronger than those of the control drugs, and the activity of most of the compounds was comparable to that of the control drug. 2. In vitro inhibition of HMG-CoA activity assay

 The activity of the inventive compound in inhibiting 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) was determined in vitro using the growth-dependent characteristics of C. sphaeroides (S04). The cell membrane of S. militaris is composed of sterol. Its growth and reproduction depend on the synthesis ability of cholesterol and its analogues. HMG-CoA is a key enzyme in lipid metabolism. The activity of HMG-CoA is inhibited, and yeast growth and reproduction Blocked or even caused death. Moreover, this inhibition can be offset by the 3-hydroxy 3-methylpentanoic acid, a catalytic product of HMG-CoA reductase.

Based on the above principle, the inhibitory activity of the inventive compound against S. grisea was determined. The minimum inhibitory concentration (MIC) of each compound is shown in Table 3, and the inhibitory activity can be offset by 3-light-based 3-methylvaleric acid. Table 3. Inhibitory activity of the inventive compounds on HMG-CoA

 Third, the activity of anti-osteoporosis in vivo

In vivo anti-osteoporosis activity was performed using an ovariectomized rat osteoporosis model, and a sham-operated control group was set up. After ovariectomy rats were fed for three months, the test sample was orally administered (dose of compound 39 and 3 was 10mg k _g, lovastatin dose is 5mg / kg), once a day for 3 Months.

 The proximal tibia of the rat was taken 1/3 to remove soft tissue. Dehydrated step by step with ethanol, xylene is transparent, twice each time, 24h each time. Preparation of the infiltration solution: Liquid I: methyl methacrylate (Beijing Yili Fine Chemicals Co., Ltd., batch number: 20050317) 75ml, dibutyl phthalate (Beijing Chemical Reagent Co., Ltd., batch number: 040401) 25mh II solution. · Add benzoyl peroxide to the liquid I (Beijing Jinlong Chemical Reagent Co., Ltd., batch number: 20000420) lg; III liquid: Add 2.5 g of benzoyl peroxide to the liquid I. Mix the above three liquids thoroughly with a magnetic stirrer. Specimens were soaked in I, II, and III fluids for 36 h. Inject about 5ml of sputum into the penicillin vial, put the specimen into the bottle in the same direction, then put it in a 40-inch oven for 3~4 days. After it becomes a colorless and transparent hard-embedded block, smash the vial. Remove the embedded block. After the trimming, on the Reicheit-Jung 2040 microtome (Germany), longitudinal non-decalcified bone sections of 5 μπι and ΙΟμιη were cut with a tungsten steel knife. 5 μ πι slices After dissolving the resin in xylene, the gradient ethanol was added to water and toluidine blue staining; Ιθ μ πι sections were directly used for fluorescence observation.

 According to the method of Zhang Mingfang et al., the Leica Qwin image analysis system was used for bone tissue morphometry. Bone level The main indication of trabecular bone volume as a percentage of the total volume of the bone marrow cavity measured (TBV%) is shown in Table 4 and Figure 1-5.

 Table 4. Percentration of trabecular bone volume in each experimental group (TBV%)

In vivo studies in animals showed that experimental compounds 39 and 3 significantly improved rat bone mass compared with the model group. Among them, compound 39 was more active than the control drug lovastatin, compound 3 and Lova The statin is quite. The experimental rat tibial section is shown in Figure 1 -5.

 Fourth, acute toxicity test in mice

 Compound 39 was selected for acute toxicity experiments.

Acute toxicity test of mice by intragastric administration: 20 mice, male and female, fasted for 12 hours, administered with 5000mg/kg gavage (0.8ml/20g) and continued feeding for 14 days, no There are animals that die. That is, LD _{5Q for} intragastric administration is greater than

Acute toxicity test by intraperitoneal injection: 60 mice were randomly divided into 6 groups. The mice in the group were half male and half fasted for 12 hours. After the intraperitoneal injection, the rats were fed for 14 days. The LD ₅₀ of the mouse death was calculated to be 1581 _mg / kg. See Table 5 for the results of acute toxicity experiments.

附图说明 图 1 : 假手术组 （正常对照组）大鼠胫骨切片图; Table 5. Acute toxicity of compound 39

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 : A sacral slice of a sham operation group (normal control group);

 Figure 2: Diagram of the tibia slice of the model control group; '

 Figure 3: Diagram of the tibia slice in the lofestatin group;

Figure 4 _: Figure of the tibia slice of the sample group 39;

 Figure 5: Diagram of the tibia slices of the No. 3 sample group. detailed description

The following examples are intended to provide a more complete understanding of the invention, and are not intended to limit the invention in any way. The structure of all compounds was determined by ¹ H R.

Example 1: Preparation of 2-acetyl(4-fluoro)benzothiophene (40)

Mix 30.45 g (0.49 mol) of ethanethiol, 19,6 g (0.49 mol) of sodium hydroxide and 47 ml of 7j, stir for 1 h, add 6-fluoro-2-chlorobenzaldehyde 50 g (0.36 mol) and tetrabutyl 1.25 _{g of} ammonium bromide, refluxed for 4 h, cooled, extracted with dichloromethane (150 ml×2), dried over anhydrous magnesium sulfate, and dried to give a yellow oil 6-fluoro-2-mercaptobenzaldehyde 79.44 g. The next step is the reaction.

The crude 6-fluoro-2-mercaptobenzaldehyde 10.0 g (0.06 mol) obtained in the previous step, 8.46 g (0.09 mol) of chloroacetone and 0.85 g of calcium oxide were mixed, heated under reflux for 3 h, cooled, and added with 50 ml of cyclohexane. Consider, dry, to give a pale yellow solid, 2-acetyl (4-fluoro)benzothiophene, 9.74g, (92%) ₀ ¹ HNM (CDC1 ₃ ) δ , (ppm): 2.673 (3H ₃ s CH ₃ CO ), 7.049-7.263 (2H,m, 5H,6H of benzothiophene ring), 7.547 (ΙΗ, ηα, 7H of benzothiophene ring), 7.860 (1H, s, 3H of benzothiophene ring). Example 2: Preparation of 2-acetyl(4-methyl)benzothiophene (41)

2-Acetyl(7-methyl)benzothiophene was synthesized in a similar manner to Example 1. ¹ H NMR (CDCls) δ, (ppm): 2.357 (3H, s, a CH ₃ ), 2.615 (3H, s, -CH ₃ C0), 7.147-7.326 (2H, ra, 5H, 6H of benzothiophene ring ), 7.628 (1H, m, 7H of the benzothiophene ring), 7.90K1H, s, 3H of the benzothiophene ring.

Example 3: Preparation of 2-acetyl(5-methoxy)benzothiophene (42)

2-Acetyl(5-methoxy)benzothiophene was synthesized in a similar manner to Example 1. NMR (CDC1 ₃ ) δ , (ppm): 2.590 (3H, s, - C3⁄4C0> , 3.804 (3H, s, -0CH ₃ ), 6.880-6.867 (lH, m, 6H of benzothiophene ring), 7.315- 7.331 (1H, m, 4H of the benzothiophene ring), 7.705-7.892 (1H, m, 7H of the benzothiophene ring), 8.021 (1H, s, 3H of the benzothiophene ring).

Example 4: Preparation of 2-benzothiophene styrene (24)

After dissolving sodium hydroxide (0.063 g, 1.57 mmol) in 0.52 ml of water, cooling in an ice bath, adding 0.26 g of ethanol, and adding 2-acetylbenzothiophene (0.20 g, 1.14 mmol) with stirring, and then continuing to add benzene. Formaldehyde (0.13 g, 1.23 mmol), EtOAc m. ^l HNMR (CDC1 ₃ ) δ , (ppm) : 7.439-7.705 (8Η, ra, 5 hydrogens on the phenyl ring, styrene 1H and 4H' 7H of the benzothiophene ring), 7.881-7.947 (3H, m, Benzothiophene ring 5H, 6H and styrene 2H), 8.123 (1H, s, 3H of benzothiophene ring). Example 5: Preparation of 2-(4-fluoro)benzothiophene ketene (79)

2-(4-Fluoro)benzophenanthrene styrene was synthesized in a similar manner to Example 4. 'HNMR (CDC1 ₃ ) δ , (ppm) : 7.103-7.326 (7H, m, 5 hydrogens on the phenyl ring, 7H of styrene 1H and benzothiophene ring), 7.820-7.901 (3H, m, benzo Thiophene ring 5H, 6H and styrene 2H), 8.109 (1H, s, 3H of benzothiophene ring).

Example 6: Preparation of 2-(4-methyl)benzothiophene styrene (80)

2-(4-Methyl)benzothiophenestyrene was synthesized in a similar manner to Example 4. ^l H simply R (CDCls) δ, (ppm): 2.359 (3H, s, CH ₃ ), 7.206-7.458 (6H, m, 5 hydrogens on the phenyl ring, styrene 1H), 7.592-7.629 (m, 1H, 7H) of benzothiophene ring, 7.796-7.872 (3H, m, benzothiophene ring 5H, 6H and styrene 2H), 8.209 (1H, s, 3H of benzothiophene ring).

Example 7: Preparation of 2-(5-methoxy)benzothiophene styrene (81)

2-(5-Methoxy)benzothiophenestyrene was synthesized in a similar manner to Example 4. 'HNMR (CDC1 ₃ ) δ, (ppm): 3.824 (3H, s, 0C3⁄4), 7.219-7.521 (7H, m, 5 hydrogens on the phenyl ring, styrene 1H and benzothiophene ring 6H) 7.558-7.809 (3H, m, 4H, 7H and styrene 2H of the benzothiophene ring), 8.028 (1H, s, 3H of the benzothiophene ring). Example 8: Preparation of 3-benzothiophenylidene ketone (25)

3-benzothiophenylidene ketone was synthesized in a similar manner to Example 4. 3⁄4N R (CDCI3) δ, (ppm): 7.422-7.554 (6H, ra, 5 hydrogens on the phenyl ring, styrene 1H), 7. 646-7. 679 (2H, m, benzothiophene ring 5H, 6H), 7. 862-7. 914 (2H, m , benzothiophene ring 4H, 7H), 8. 383 (1H, s, 2H of benzothiophene ring), 8. 775-8. 801 (1H, d, J = 7. 8 Hz styrene 2H). Example 9: Preparation of 2-benzofuranstyrene (27)

2-Benzofuranyl styrene was synthesized in a similar manner to the examples. 3⁄4 NMR (CDC1 ₃ ) δ , (ppm) : 7. 314-7. 762 (12H, m, 5 hydrogens on the phenyl ring, 2 H of styrene and 5 H of benzofuran), 7. 941- 7. 995 (1H, d, J = 16.2 Hz styrene 2H).

Example 10: Preparation of 3-indolyl styrene (33)

A 3-indolyl styrene was synthesized in a similar manner to Example 4. ¹ Sa R (CDC1 ₃ ) δ , (ppm) : 7. 280-7. 463 (7H, m, 5 hydrogens on the phenyl ring, styrene 1H and oxime 5H), 7. 641-7. 667 (2H, m, 66H and 7H), 7. 811-7. 862 ( 1H, d, J=15. 3, styrene 2H ) , 8. 023-8. 031 (1H, d, J= 5, 4, 2 2H), 8. 514-8. 546 (1H, m, 4 4H), 8. 647 (1H, s, NH) ₀

Example 11: Preparation of 3-acetylstilbene styrene (32)

3-Acetylstyreneamine was synthesized in a similar manner to Example 4. 'HNMR (CD ₃ 0D) δ , (ppm) : 3. 051-3. 360 (2H, m, -CH ₃ C0, 5. 522-5. 266 (1H, m, styrene IH) , 7. 141 -7. 196 (4H, m, 4 hydrogens on the benzene ring), 7. 240-7. 289 (2H, m, 5H and 6H), 7. 353-7. 404 (3H, m, , styrene 2H, argon 7H and 1 hydrogen on the benzene ring), 8. 039 (lH, s, 2 2H), 8. 193-8. 224 (IH, m, 吲哚 4H Example 12: Preparation of 2-benzothiophene o-chlorostyrylone (23)

2-Benzothiphenyl-o-chlorostyrene ketone was synthesized in a similar manner to Example 4. With R (CDC1 ₃ ) δ , (ppm): 7. 338-7. 542 (6H, m, 4 hydrogens on the phenyl ring, styrene IH and benzothiophene 6H), 7. 778-7. 809 ( IH, m, benzothiophene ring 5H), 7. 891- 7. 943 (2H, m, benzothiophene ring 4H, 7H), 8. 111 (1H, s, 3H of benzothiophene ring), 8. 254-8. 306 (IH, d, J=15. 3 Hz styrene 2H).

Example 13: Preparation of 3-benzothiophene o-chlorostyrylone (26)

3-Benzothiophene o-chlorostyrene ketone was synthesized in a similar manner to Example 4. 'HNMR (CDC1 ₃ ) δ, (ppm): 7. 323-7. 558 (6H, ra, 4 hydrogens on the phenyl ring, styrene 1H and benzothiophene 6H), 7. 749-7. 778 ( IH, m, benzothiophene ring 5H), 7. 888-7. 917 (IH, d, J=8. 7 Hz, benzothiophene ring 4H), 8. 181-8. 232 (IH, d, J =15. 3 Hz, styrene 2H), 8. 383 (lH, s, 2H of benzothiophene ring), 8. 779-8. 808 (IH, d, J=8. 7Hz benzothiophene ring 7H) . Example 14: Preparation of 2-benzothiophene o-methylstyrene ketone (82)

2-Benzothiophene o-methylstyrene ketone was synthesized in a similar manner to Example 4. 3⁄4 NMR (CDCI3) δ , (ppm) : 2. 401 ( 3H, s, CH ₃ ) , 7. 109-7. 461 (6H, m, 4 hydrogens on the phenyl ring, styrene 1H and benzothiophene 6H ), 7. 552-7. 607 (IH, ra, benzothiophene ring 5H), 7' 854-7. 961 (2H, m, 'benzothiophene ring H, 7H), 8. 024 (IH, s , 3H) of the benzothiophene ring, 8. 154-8. 205 (1H, d, J=15. 3Hz styrene 2H) ₀

Example 15: Preparation of 2-benzothiophene p-methoxystyrene ketone (83)

2-Benzothiophene p-methoxystyrene ketone was synthesized in a similar manner to Example 4. NMR (CDCla) δ, (ppm): 3. 815 (3H, s, 0CH ₃ ) , 6. 892-7. 324 (6H, m, 4 hydrogens on the phenyl ring, styrene 1H and benzothiophene 6H ), 7. 607 - 7. 861 (3H, m, benzothiophene ring 5H, 4H and 7H), 8. 119 (1Η, s, benzothiophene ring. 3H), 8. 149-8. 207 ( 1H, d, J = 17. 4 Hz styrene 2H).

Example 16: Preparation of 2-benzofuran o-chlorostyrylone (28)

 2-benzofuran o-chlorostyrene ketone was synthesized in a similar manner to Example 4.

3⁄4 NMR (CDC1 ₃ ) δ, (ppm): 7. 317-7. 651 (7H, m, 4 hydrogens on the phenyl ring, styrene 1H and benzofuran 6H, 7H), 7. 674 (1H, s , benzofuran ring 3H), 7. 736-7. 762 (1H, ra, benzofuran ring 7H), 7. 816-7. 850 (1H, ra, benzofuran ring 4H), 8. 329- 8. 383 (1H, d, J = 16. 2 Hz styrene 2H).

Example 17: Preparation of 3-oxiranolyl chlorostyrene (34)

 3-oxo-chlorostyrylone was synthesized in a similar manner to Example 4. NMR (CDCL) δ , (ppm): 7. 297-7. 463 (7H, m, 4 hydrogens on the phenyl ring, styrene 1H and oxime 5H, 6H), 7. 732-7. 763 ( 1H, m, Η7Η), 8. 009-8. 017C 1H, m, Η 2Η), 8. 158- 8. 209 (1Η, d, J=15. 3, styrene 2H), 8. 514- 8. 543 (1H, m, 4H of 吲哚), 8. 636 (IH, s, NH).

Example 18: Preparation of 3-acetyl sulfonium chlorostyrylamine (35)

3-Acetyl-o-chlorostyrylamine was synthesized in a similar manner to Example 4. 'Η兰R (CD ₃ 0D) δ, (ppm): 3. 095-3. 250 (2H, m, - CH ₃ C0> , 5. 659-5. 701 (IH, m, styrene IH), 7. 144-7. 216 (4H, m, 4 hydrogens on the benzene ring), 7. 269-7. 316 (2H, m, 5H and 6H of 吲哚), 7. 366-7. 395 (IH , m, 7 7H), 7. 658-7684 ( lH, d, J=7. 8 Hz, styrene 2H), 8. 072 (IH, m, 2 2H), 8. 218-8 249 (1H, m, 4H of hydrazine). Example 19: Preparation of thiophene styrene (29)

Thiophene styrene was synthesized in a similar manner to Example 4. 'HNMR (CDC1 ₃ ) δ, (ppm) 7. 182-7. 210 (IH, m, thiophene 4H), 7. 405-7. 699 (7Η, ra, 5 hydrogens on the phenyl ring, styrene 1H And thiophene 4H), 7. 838-7. 888 (2H, m, styrene 2H and thiophene 5H).

Example 20: Preparation of thiophene o-chlorostyrene ketone (30)

Thiophene-o-chlorostyrene was synthesized in a similar manner to Example 4. ^l HNMR (CDC1 ₃ ) δ , ( _ppm ) 7. 181-7. 470 (5Η, m, 4 hydrogens on the phenyl ring, styrene 1H), 7. 697-7. 712 (IH, d, J= 4. 5 Hz, thiophene 3H), 7. 730-7. 763 (IH, m, thiophene 4H), 7. 866-7. 877 (IH, d, J = 3. 3 Hz, thiophene 5 Η), 8. 203- 8. 258 (IH, d, J = 16.5 Hz, styrene 2H). Example 21: Preparation of furanstyrene (38) Furan styrene ketone was synthesized in a similar manner to Example 4. R (CDC1 ₃ ) δ, (ppm) 6.592-6.610 (1H, ro, furan 4H), 7.332-7.345 (lH, d, J = 4.5 Hz, furan 3H), 7.397- 7.672 (7H, m, benzene ring 5 hydrogens, stupid ethylene 1H and furan 5H), 7.860-7.912 (1H, d, J = 15.6 Hz, styrene 2H).

Example 22: Preparation of furan o-chlorostyrene ketone (31)

 Furan o-chlorostyrene ketone was synthesized by the method of Example 4. 3⁄4!3⁄4R (CDCla) δ , (ppm)

 6.600-6.618 (1H, m, furan 4H), 7.314-7.457 (5H, m, 4 hydrogens on the phenyl ring and styrene 1H), 7.66 (1H, s, furan 3H), 7.752-7.783 (1H, m , furan 5H), 8.243-8.298 (1H, d, J = 16.5 Hz, styrene 2H), Example 23: Preparation of 2-benzothiophene acetyl ketone (13)

2-Acetylbenzothiophene (0.20 g, 1.14 of 1) and ethyl acetate (0.273 g, 1,23 ol) were added to 2 ml of anhydrous diethyl ether, and 60% sodium hydride (0.075 g) was added to the ice bath. After the reaction was completed, the mixture was reacted for 2 hr. 3⁄4 NMR (CDC1 ₃ ) δ, (ppm) 2.189 (3H, s, - C C0) , 4.132 (1H, s, olefin H), 6.148 (1H, s, olefin H), 7.376-7.471 (2H, m, benzene And thiophene ring 5H, 6H), 7.856-7.947 (2H, m, benzothiophene ring 4H, 7H), 7.991 (1 Η, s, benzothiophene ring 3H), 15.608 (1H, s, 0H).

Example 24: Preparation of 3-benzothiophene acetyl ketone (14)

Synthesis was carried out in a similar manner to Example 23 to give 3-benzothiophene acetyl ketone. ^l HNMR (CDC1 ₃ ) δ , (p _pm ) 2.180 (3H, s, - CH ₃ C0) , 4.114 (1H, s, olefin H), 6.115 (1H, s, olefin H), 7.391-7.541 (2H, m, benzothiophene ring 5H, 6H), 7.863- 7.889 (lH, d, J = 7.8 Hz, benzothiophene ring 4H), 8.114 (lH, s, benzothiophene ring 2H) 8.576-8.605 (ΙΗ'd , J = 8.7 Hz, benzothiophene ring 7H), 15.997 (ΙΗ' s, 0Η).

Example 25: Preparation of 2-benzofuran acetyl ketone (10)

2-Benzofuranone was synthesized in a similar manner to Example 23. ^ι Η R (CDC1 ₃ ) δ , (p _pra ) 2.229 ( 3H, s, -CH ₃ C0 ) , 6.300 (lH, s, olefin H), 7.273 (1H, s, olefin H), 7.299-7.322 ( 1H, m, benzofuran 6H), 7.408-7.459 (1H, m, benzofuran ring 5H), 7.475 (1 Η, s, benzofuran ring 3H), 7.529-7.558 (1H, d, J = 8.7 Hz , benzofuran ring 7H)

7.692-7.716 (lH,d, J=7.2 Hz, benzofuran ring 4H).

Example 26: Preparation of 2-thiophene acetyl ketone (11)

2-thiopheneacetyl ketone was synthesized in a similar manner to Example 23. ^l HNMR (CDC1 ₃ ) δ , ( _ppm ) 2.128 C3H, s, -CH3CO) , 4.017 (1H, s, olefinic H), 6.01 coffee, s, olefin H), 7.105-7.156 (lH,m, thiophene ring 4H ), 7.581-7.596 (lH, m, thiophene ring 5H), 7.674-7.708 (1H, m, thiophene ring 3H), 15.651 (1H, s, 0H). Example 27: Preparation of 2-furan ketone (12) 2-furan ketone was synthesized in a similar manner to Example 23. NMR (GDC1 ₃ ) δ , (ppm) 2.143 (3H, s, -C3⁄4C0) , 3.952 (lH, s, olefin H), 6.069 (1H, s, olefin H), 6.538-6.572 (lH, m, furan ring 4H), 7.141-7.154 (IH'ra, furan ring 5H), 7.563-7.609 (IH, m, furan ring 3H), 15.495 (1H, s, 0H). Example 28: Preparation of 2-(4-methyl)benzothiophene acetyl ketone (73)

2-(4-Methyl)benzothiophene acetyl ketone was synthesized in a similar manner as in Example .23. _3⁄4 MR (CDC1 ₃ > δ , ( _ppm )

2.189 (3Η, s, -C3⁄4C0), 2.408 (3H, s, C3⁄4), 4.207 (IH, s, alkene H), 6.159 (1H, s, alkene H), 7.198-7.273 (2H, m, stupid and thiophene Ring 5H, 6H), 7.721- 7.814 (lH, m, benzophene ring 7H), 8.013 (1H, s, benzothiophene ring 3H), 15.590 (IH, s, 0H) _o . Example 29: 2- Preparation of (4-fluoro)benzothiophene acetyl ketone (72)

2-(4-Fluoro)benzothiopheneacetyl ketone was synthesized in a similar manner to Example 23. NMR (CDC1 ₃ ) δ , (ppm) 2.146

(3H, s, - CH ₃ C0) , 4.189 (IH, s, olefin H), 6.165 (IH, s, olefin H), 7.172-7.193 (2H, m, benzothiophene ring 5H, 6H ) , 7.869- 7.807 (IH, m, benzothiophene ring 7H), 8.052 (IH, s, benzothiophene ring 3H), 16.028 (1H, s, 0H).

Example 30: Preparation of 2-(5-methoxy)benzothiophene acetyl ketone (74)

2-(5-Methoxy)benzothiophene acetyl ketone was synthesized in a similar manner to Example 23. NMR (CDC1 ₃ ) δ , (ppm)

2.153 (3Η, s, - C C0) , 3.736 (3H, s, 0C3⁄4) , 4.192 (IH, s, alkene H), 6.175 (IH, s, alkene H), 7.164- 7.181 ( 1H, m, benzo Thiophene ring 6H), 7.786-7.805 (2H, m, benzothiophene ring 4H and 7H), 8.128 (IH, s, benzothiophene ring 3H), 16.067 (lH, s, OH).

Example 31: Preparation of 2-chloroacetobenzothiophene (15) and 2-dichloroacetobenzothiophene (16)

 Dichlorosulfoxide (0.168 g, 1.25 awake ol) was dissolved in 0.1 ml of carbon tetrachloride, and 2-acetylbenzothiophene was added dropwise with stirring.

(0.20 g, 1.14 emo) in lml of carbon tetrachloride solution, reacted at room temperature for 2 h. After spin-drying the solution, it was separated by silica gel column chromatography to yield white solid 2-chloroacetophenthiophene 0.09 g (37.6%) and white solid 2-dichloroacetylbenzothiophene 0.17 g (60.8%).

2-Chloroacetylbenzothiophene: 3⁄4 NMR (CDC1 ₃ ) δ , (ppm) 4.704 (2Η, s, C3⁄4) , 7.419-7.538 (2H, m, 5H and 6H of benzothiophene ring), 7.886-7.942 (2H , m, 4H and 7H of the benzothiophene ring, 8.055 (lH, s, 3H of the benzothiophene ring;).

 2-Dichloroacetobenzothiophene: 3⁄4 NMR (CDCI3) δ , (ppm) 6.580 (IH, s, CH), 7.434-7.561 (2H, m, 5H and 6H of benzothiophene ring), 7.897-7.973 (2H , m, 4H and 7H of the benzothiophene ring, 8.290 (IH, s, 3H of the benzothiophene ring). Example 32: Preparation of 2-chloroacetobenzofuran (17) and 2-dichloroacetobenzofuran (18)

 2-Chloroacetylbenzofuran and 2-dichloroacetobenzofuran were synthesized in a similar manner to Example 31.

2-chloroacetobenzofuran: ¹ Sa R (CDC1 ₃ ) δ , (ppm) 4.718 (2H, s, C3⁄4) , 7.326-7.377 (IH, m, 5H of benzofuran ring), 7.501-7.586 (2H , m, 6H and 7H of the benzofuran ring, 7.665 (1H, s, 3H of the benzofuran ring), 7. 733-7. 758 (1H, d, J=7.5, 4H of the benzofuran ring).

2-Chloroacetylbenzofuran: 'HNMR (CDC1 ₃ ) δ, ( _PP m) 6. 707 (1H, s, CH) , 7. 349-7. 400 (1H, m, 6H of stupid and furan ring ), 7. 535-7. 640 (2H, ra, 5H and 7H of the benzofuran ring), 7. 756-7. 784 (1H, d, J=7.5, 4H of the benzofuran ring), 7. 852 (1H, s, 3H of the benzofuran ring).

Example 33: Preparation of 2-chloroacetylthiophene (21) and 2-dichloroacetylthiophene (22)

 2-Chloroacetylthiophene and 2-dichloroacetylthiophene were synthesized in a similar manner to Example 31.

2-chloroacetylthiophene: 'Ranth R (CDC1 ₃ ) δ, (ppm) 4. 603 (2H, s, CH ₂ ) , 7. 165-7. 193 (1H, m, 4H of the thiophene ring), 7. 727-7. 744 (1H, d, J=5. 1Hz, 5H of thiophene ring), 7. 792-7. 804 (IH, d, J=3, 6Hz, 3H of thiophene ring;).

2-Dichloroacetylthiophene: 'HNMR (CDC1 ₃ ) δ , (ppm) 6. 81 (IH, s, CH), 7. 199-7. 227 (IH, m, 4H of the thiophene ring), 7. 798 -7. 812 (1H, d, J = 4. 2 Hz, 5H of the thiophene ring), 8. 007- 8. 021 (IH, d, J = 4. 2 Hz, 3H of the thiophene ring). Example 34: Preparation of 2-chloroacetylfuran (19) and 2-dichloroacetylfuran (20)

₂ -Chloroacetylfuran and 2-dichloroacetylfuran were synthesized in a similar manner to Example 31.

2-Chloroacetylfuran: 'HNMR (CDC1 ₃ ) δ , (ppm) 4. 567 (2H, s, CH ₂ ) , 6. 590-6. 607 (IH, m, 4H of furan ring), 7. 328 -7. 342 (IH; d, J=4.2 Hz, 3H of 'furan ring), 7. 633 (IH, s, 5H of furan ring)

2 -Dichloroacetylfuran: ¹ Wake up R (CDC1 ₃ ) δ , (ppm) 6. 580 (IH, s, CH) , 6. 651-6. 659 (IH, m, 4H of furan ring), 7. 507-7. 518 (IH, d, J = 3. 3 Hz, 3H of furan ring), 7. 710 (1H, s, 5H of furan ring).

Example 35: Preparation of 2-chloroacetyl(4-fluoro)benzothiophene (75) and 2-dichloroacetyl(4-fluoro)benzothiophene (76) 2-chloroacetyl was synthesized in a similar manner to Example 31. (4-Fluoro)benzothiophene and 2-dichloroacetyl(4-fluoro)benzothiophene. 2-Chloroacetyl(4-fluoro)benzothiophene: ¹ draws R (CDC1 ₃ ) δ, (ppm) 4. 814 (2H, s, CH ₂ ), 7. 408-7. 561 (2H, ra, stupid 5H and 6H) of the thiophene ring, 7. 792-7. 869 (IH, m, 7H of the benzothiophene ring), 7. 981 (IH, s, 3H of the benzothiophene ring).

2-Dichloroacetyl(4-fluoro)benzothiophene: ^l HNMR (CDC1 ₃ ) δ , (ppm) 6. 492 (1H, s, CH) ,

7. 309-7. 535 (2H, m, 5H and 6H of benzothiophene ring), 7. 882-7. 957 (lH, m, benzothiophene ring 7H),

8. 108 (IH, s, 3H of the benzothiophene ring).

Example 36: Preparation of 2-chloroacetyl(5-methoxy)benzothiophene (77) and 2-dichloroacetyl(5-methoxy)benzothiophene (78) were synthesized in a similar manner as in Example 31. Chloroacetyl (5-methoxy)benzothiophene and 2-dichloroacetyl (5-methoxy)benzothiophene.

2-Chloroacetyl(5-methoxy)benzothiophene: 'HNMR (CDC1 ₃ ) δ, (ppm) 3. 751 ( 3H, s, 0CH ₃ ) , 5. 026 (2H, s, C3⁄4), 6. 985-7. 018 (lH, m, 6H), 7. 364-7. 751 (2H, m, 4H and 7H of benzothiophene ring), 7. 892 (IH, s, 3H of benzothiophene ring) .

2-dichloroacetyl(5-methoxy)benzothiophene: NMR (CDCL) δ , (ppm) 3. 852 C 3H, s, 0C3⁄4 ) , 6. 393 (lH, s, CH), 7. 208- 7. 317 (lH, m, 6H of benzothiophene ring), 7. 529-7. 801 (1H, m, benzothiophene ring 4H and 7H ), 7. 968 (1H, s, 3H of the benzothiophene ring).

Example 37: Preparation of 2-hydroxyethylbenzothiophene (6)

2, 043g, sodium borohydride (0. 043g, slowly added to a mixture of tetrahydrofuran (2ml) and water (2ml). 1. 14mmol), reaction 0. 5h, filtration, the filtrate was added with a small amount of anhydrous ether, and the organic layer was combined, dried over anhydrous magnesium sulfate, dried over silica gel. Benzothiophene 0. 136 _g (67° / 3⁄4 NMR (CDCL) δ , (ppm) 1. 652-1. 672 (33⁄4 d, J=6. ΟΗζ, CH ₃ ) , 2. 045 (1Η, s, OH) , 5. 174-5. 239 (1H, ra, CH) , 7. 193 (1H, s, 3H of benzothiophene ring), 7. 278-7. 366 (2Η, m, benzothiophene ring 5H and 6H), 7. 703-7. 734 (1H, m, 7H of benzothiophene ring), 7. 806-7. 829 (1H, d, J = 6.9 Hz, 4H of benzothiophene ring ).

Example 38: Preparation of 3-ethylbenzothiophene (55)

3-Lightethylbenzothiophene was synthesized in a similar manner to Example 37. 3⁄4 NMR (CDCla) δ , (ppm) 1. 619 (1H, s, OH) , 1. 667-L 690 (3H, d, J=6. 9Hz, CH ₃ ) , 5. 267-5. 332 (1H , m, CH) , 7. 335- 7. 422 (3H, m, 2H, 5H and 6H of benzothiophene ring), 7. 857- 7. 928 (2H, m, 4H and 7H of benzothiophene ring) ).

Example 39: Preparation of 2-hydroxyethylbenzofuran (8)

2-Hydroxyethylbenzofuran was synthesized in a similar manner to Example 37. 'HNMR (CDC1 ₃ ) δ , (ppm) 1. 633-1. 657 (3Η, d, J=7. 2Hz, CH ₃ ) , 2. 024 (1H, s, OH) , 4. 995-5. 060 (1H, m, CH), 6. 616 (1H, s, 3H of the benzofuran ring), 7. 193-7. 299 (2H, m, 5H and 6H of the benzofuran ring), 7. 452 -7. 477 (1H, d, J = 7. 5 Hz, 7H of the benzofuran ring), 7. 534-7. 558 (1H, d, J = 7. 2 Hz, 4H of the benzofuran ring).

Example 40: Preparation of 2-light ethylthiophene (7)

 2-Hydroxyethylthiophene was synthesized by a similar method as in Example 37. 3⁄4 NMR (CDCI3) δ , (ppm) 1. 592-1. 613 (33⁄4 d, J=6. 3Hz, C3⁄4) , 2. 08 (1H, s, OH) , 5. 099-5. 161 (1H, m, CH), 6. 949-6. 975 (211, 111, thiophene ring 311 and ^), 7. 229- 7. 250 (1 111, thiophene ring 5).

Example 41: Preparation of 2-light ethylfuran (9)

 2-Hydroxyethylfuran was synthesized by a similar method as in Example 37. 'HNMR (CDCL) δ , (ppm)

1. 538-1. 558 (3H, d, J=6. OHz, C3⁄4), l. 885 (1H, s, OH), 4. 856-4. 923 (1H, ra, CH), 6. 227 -6. 238 (1H, m, 4H of furan ring), 6. 328 (1H, s, 3H of furan ring), 7. 400 (1H, s, 5H of furan ring).

Example 42: Preparation of 2-hydroxyethyl(4-methyl)benzothiophene (69)

2-Light ethyl (4-methyl)benzothiophene was synthesized in a similar manner to Example 37. NMR (CDC1 ₃ ) δ , ( _ppm ) 1. 526-1. 542 (3H, d, J=6. 3Hz, CH0HC3⁄4) , 2. 064 (1H, s, OH) , 2. 364- 2· 380 ( 3H, s, CH ₃ ) , 4. 921- 5.027 (IH, m, CH), 6.992-7, 281 (3H, m, 3H, 5H, and 6H of the benzothiophene ring), 7.637-7.904 (IH, m, 7H of the benzothiophene ring).

 Example 43: Preparation of 2-ethyl (4-fluoro)benzothiophene (70)

2-Hydroxyethyl(4-fluoro)benzothiophene was synthesized in a similar manner to Example 37. 'HNMR (CDC1 ₃ ) δ, (ppm) 1.517-1.539 (3H, d, J=6.3Hz, CH'0i3⁄4), 2.079 (IH, s, OH), 4.673-4.908 (IH, m, CH) , 7.085 - 7.624 (3H, m, 3H, 5H and 6H of the benzothiophene ring), 7.657-7.849 (IH, ra, 7H of the benzothiophene ring).

 Example 44: Preparation of 2-hydroxyethyl (5-methoxy)benzothiophene (71)

2-Hydroxyethyl(5-methoxy)benzothiophene was synthesized in a similar manner to Example 37. 'HNMR (CDC1 ₃ ) δ, (ppm)

1.592—1.613 (3H, d, J=6.3Hz, C3⁄4), 2.048 (IH, s, OH), 3.752 (3H, s, 0C3⁄4), 5.099-5.161 (IH, m, CH), 6.949- 6.957 (2H , m, 3H and 6H of the benzothiophene ring, 7.340-7.806 (2H, m, 4H and 7H of the benzothiophene ring). Example 45: Preparation of 2-acetyl-4-(4,-methyl-phenyl)thiophene (43)

Magnesium turnings (6.07 g, 0.25 mol) and 16.2 ml of anhydrous diethyl ether were added to the reaction flask. Then, a solution of p-methyl 'benzyl chloride (64.62 g, 0.25 mol) dissolved in 46.2 ml of anhydrous diethyl ether was added dropwise with stirring, and stirring was continued for 30 min. Then 37.5 ml of freshly purified dioxane was added and the mixture was stirred for 30 min. Then, 2-acetylthiophene (35.2 _g) 0.2 mol) was added dropwise to the suspension, and the mixture was stirred and refluxed for 24 h. After the heat preservation, the reaction liquid was cooled with an ice bath, and 20% of ice-cold ammonia water droplets were added to the reaction liquid to decompose the unreacted Grignard complex. The mixture was extracted with diethyl ether, dried over anhydrous magnesium sulfate, and then purified by column chromatography to give the product 2-acetyl-4-(4'-methyl-phenyl)thiophene (11.2 g, 20%). ¹ awake R (CDC1 ₃ ) δ ( Ppm) 2.189 (3Η, s, - C ) ,

2.539 (3H, s, -C0CH ₃ ) , 3.796 (2H, s, methylene group between thiophene and benzene ring), 6.882-6.931 (4H, m, 4 hydrogens on the phenyl ring), 7.025 (lH, s , thiophene 5H), 7.298 (IH, s, thiophene 3H).

Example 46: Preparation of 2-acetyl-4-(3,-chloro-phenylethyl)thiophene (44)

2-Acetyl-4-(3,-chlorophenethyl)thiophene was synthesized in a similar manner to Example 45. ^l HNMR (CDC1 ₃ ) δ (ppm) 2.531 (3H, s, -COCH3) _x 2.797-2.872 (4H, m, 2 methylene groups between thiophene and benzene ring), 7.025-7.368 (6H, m, benzene 4 hydrogens on the ring and 2 hydrogens of thiophene).

Example 47: Preparation of 2-acetyl-4-(3'-methoxy-phenylene)thiophene (45)

 To a three-necked reaction flask equipped with a reflux condenser and a dropping funnel, 3-methylthiophene (19.6 g, 0.2 mol) and 50 ml of carbon tetrachloride were added, and the reaction mixture was heated and boiled, and irradiated under a 500 W mercury lamp. Add bromine (32.8 g, dried over concentrated sulfuric acid)

0.2 mol), the reaction mixture was cooled with ice water, washed with ice-cooled sodium hydrogen carbonate solution, washed with ice water, dried over anhydrous magnesium sulfate, and separated by column chromatography to give 3-bromomethylthiophene (24.7 g, 70%).

3-bromomethylthiophene (20 g, 0.11 mol), acetic anhydride (21.79 g, 0.21 mol) and iodine (0.049 g, 0.31 mraol) were added to the reaction flask, and the mixture was heated under reflux for 1.5 h. After cooling, the reaction mixture was poured. 18ml in water. Extracted with chloroform The mixture was washed twice with aqueous sodium carbonate and dried over anhydrous sodium sulfate. After separation by column chromatography, 4-bromomethyl-2-acetylthiophene (17.5 g, 70%) was obtained.

 A solution of 4-bromomethyl-2-acetylthiophene (17.5 g, 0.079 mol) in 20 liter benzene was added dropwise to the stirred triphenylphosphorate (21.78 g, 0.083 mol) in a 75 rn dry benzene solution. After stirring overnight, the quaternary phosphonium salt was filtered off and washed with petroleum ether and benzene. The solid quaternary phosphonium bromide 4-methyl-2-acetylthiophene triphenylphosphine (32, 45 g, 85%) was obtained by vacuum drying. ;

M-methoxybenzaldehyde (9. llg, 0. 067 mol), 4-methyl-2-acetylthiophenetriphenylphosphonium bromide (32.45 g, 0. 067 mol) and dichloromethane 33.5 ml, in vigorous 5毫升的水溶液水溶液的水溶液。 3, 3 ml of 50% aqueous sodium hydroxide solution was added dropwise. Stirring was continued for 30 minutes and the reaction was completed. The organic phase was separated, washed with water and dried over anhydrous magnesium sulfate. 'HNMR (CDC1 ₃ ) δ (ppm) 2. 548 (3Η, s, - C0C ), 3. 691 (33⁄4 s, -OCHa) , 6. 701-7. 096 (6H, m, between thiophene and benzene ring 2 olefinic hydrogens and 4 hydrogens on the benzene ring), 7. 234-7. 401 (2H, m, 2 hydrogens of thiophene).

Example 48: Preparation of 2-acetyl-4-(3,5,-dimethoxy-styrene)thiophene (46)

2-Acetyl-4-(3,5,1-dimethoxystyrene)thiophene was synthesized in a similar manner to Example 47. 'HNMR (CDC1 ₃ ) δ (ppm) 2. 471 (3H, s- C0CH ₃ ), 3. 782 (6H, s, - 0C3⁄4), 6. 217-6· 702 (5H, m, thiophene and benzene ring 2 olefins and 3 hydrogens on the benzene ring), 7. 504-7. 610 (2H, m, 2 hydrogens of thiophene).

Example 49: Preparation of 2-acetyl-4-(4,-fluorenyl-phenyl)furan (47)

2-Acetyl-4-(4'-aminophenyl)furan was synthesized in a similar manner to Example 45. 'HNMR (CDC1 ₃ ) δ (ppm) 2. 534 (3H, s, -C0CH ₃ ) , 5. 859 (1H, s, NH ₂ ) , 6. 702-7. 431 (6H, tn, on benzene ring 4 hydrogens and 2 hydrogens on the furan ring). Example 50 _: Preparation of 2-acetyl-4-(3,-fluoro-benzyl)furan (48)

2-Acetyl-4-(3,-fluorobenzyl)furan was synthesized in a similar manner to Example 45. NMR (CDC1 ₃ ) δ (ppm)

2. 514 (3H, s, - C0CH ₃ ), 3. 806-3. 827 (2H, m, methylene group between furan and benzene ring), 6. 802-7. 120 (6H, m, benzene ring) 4 hydrogens on the upper and 2 hydrogens on the furan ring).

Example 51: Preparation of 2-acetyl-4-(4,-methyl-phenylethyl)furan (49)

2-Acetyl-4-(4'-methyl-phenethyl)furan was synthesized in a similar manner to Example 45. ^l HNMR (CDC1 ₃ ) δ (ppm) 2. 186 (3H, s, - C3⁄4), 2. 502 (3H, s, - C0C), 2. 762-2. 817 (4H, m, furan and benzene ring 2 methylene groups), 6. 972-7. 086 (6H, m, 4 hydrogens on the phenyl ring and 2 hydrogens of the furan ring).

Example 52: Preparation of 2-acetyl-4-styrene furan (50)

2-Acetyl-4-styrene furan was synthesized in a similar manner to Example 47. ^l HNMR (CDC1 ₃ ) δ (ppm) 2. 97 (3H, s, - C0CH ₃ ) , 6. 867-6. 982 (2H, ra, 2 olefinic hydrogen between the furan ring and the benzene ring), 7. 198-7. 406 (7H, m, 2 hydrogens of the furan ring and 5 hydrogens of the benzene ring). Example 53: Preparation of 2-acetyl-4-(4'-methoxy-benzyl)furan (51)

2-Acetyl-4-(4,-methoxy-benzyl)furan was synthesized in a similar manner to Example 45. ^l HNMR (CDC1 ₃ ) δ (ppm) 2. 503 (3H, s, -C0C3⁄4) , 3. 719 (3H, s, - 0CH ₃ ) , 3. 798-3. 812 (2H, m, furan and benzene Methylene group between rings, 6. 718-7. 094 (6H, m, 4 hydrogens on the phenyl ring and 2 hydrogens on the furan ring).

Example 54: Preparation of 2-acetyl-4-(3'-chloro-phenethyl)furan (52)

2-Acetyl-4-(3,-chloro-phenethyl)furan was synthesized in a similar manner to Example 45. 3⁄4 NMR (CDC1 ₃ ) δ (ppm) 2. 528 (3H, s, - C0C3⁄4), 2. 769-2. 827 (4H, m, 2 methylene groups between furan and benzene ring), 6. 948- 7. 304 (6H, m, 4 hydrogens on the phenyl ring and 2 hydrogens on the furan ring).

Example 55: Preparation of 2-acetyl-4-(3'-methoxy-styrene) furan (53)

2-Acetyl-4-(3'-methoxy-styrene)furan was synthesized in a similar manner to Example 47. Should R (CDC1 ₃ ) δ

(ppm) 2. 539 (3H, s, - C0CH ₃ ), 3. 726 (3H, s, -0C3⁄4), 6. 721-7. 109 (6H, m, 2 olefins between furan and benzene ring And 4 hydrogens on the benzene ring), 7. 112-7. 208 (2H, m, 2 hydrogens of furan).

Example 56: Preparation of 2-acetyl-4-(3,5'-dimethoxy-styrene) furan (54)

2-Acetyl-4-(3,5'-dimethoxy-styrene) furan was synthesized in a similar manner to Example 47. NMR (CDCla) δ (ppm) 2. 527 (3H, s-C0CH ₃ ) , 3. 758 (6H, s, -0CH ₃ ) , 6. 224-6. 713 (3H, m, 3 on the benzene ring Hydrogen), 6. 897-6. 923 (2H, m, 2 olefinic hydrogens between furan and benzene ring), 7. 108- 7. 213 (2H, m, 2 hydrogens of furan). Example 57: Preparation of 2-hydroxyethyl-4-(2'-methyl-benzyl)thiophene (56)

 2-Acetyl-4-(2'-methyl-benzyl)thiophene was synthesized in a similar manner to Example 45.

2-Acetyl-4-(2,-methyl-benzyl)thiophene (0.5 g, 2. 17ramol) was added to a mixed solution of tetrahydrofuran (4 ml) and water (1⁄21), and the mixture was slowly cooled in a water bath. The sodium borohydride (0. 082 g, 2.17 mmol) was added in portions, and the mixture was evaporated to dryness. After that, a yellowish solid 2-hydroxyethyl-4-(2,-methyl-benzyl)thiophene 0. 327 g (65%) was obtained. 3⁄4 NMR (CDC1 ₃ ) δ (ppm) 1. 435-1. 460 (3H, m, -C3⁄4CH0H), 2. 132 (3H, s, - C3⁄4), 3. 796 (2H, s, between thiophene and benzene ring Methylene), . 601-4. 672 (IH, m, -CH ₃ CH0H), 5. 010 (IH, s, OH), 6. 381 (IH, s, thiophene 3H), 6. 468 ( IH, s, thiophene 5H), 6. 992-7. 102 (4H, ra, 4 hydrogens on the phenyl ring). '

Example 58: Preparation of 2-ethyl-4-(3'-chloro-phenylethyl)thiophene (57)

2-Hydroxyethyl-4-(3'-chlorophenethyl)thiophene was synthesized in a similar manner to Example 57. NMR (CDC1 ₃ ) δ (ppm) 1. 472-1. 484 (3H, m, -C3⁄4CH0H), 2. 614-2. 780 (4H, m, 2 methylene groups between thiophene and benzene ring), 4. 517-4. 602 (IH, m, -CH ₃ CH0H) , 5. 307 ( ΙΗ' s, OH), 6. 376 (IH, s, thiophene 3H), 6. 467 (IH, s, thiophene 5H) , 7. 005-7. 123 (4H, m, 4 hydrogens on the phenyl ring). Example 59: Preparation of 2-hydroxyethyl-4-(3'-methoxy-styrene)thiophene C5S)

 2-Acetyl-4-(3,-methoxy-phenethyl)thiophene was synthesized in a similar manner to Example 47.

 Reduction of 2-acetyl-4-(3'-methoxy-styrene)thiophene to a 2-hydroxyethyl group by a similar method as in Example 57

- 4-(3,-methoxy-styrene) thiophene NMR (CDCla) δ (ppm) 1. 482-1. 496 (3H, ra, -CHjCHOH) , 3. 726 (3H, s, -OCH3) , 4. 621-4. 659 (IH, ra, -CH ₃ CH0H) , 5. 420 (1H, s, . ' OH) , 6. 527-6, 543 (2H, m, thiophene

2 hydrogens), 6. 687-7. 095 (6H, m, 2 olefinic hydrogens between the thiophene and the benzene ring and 4 hydrogens on the phenyl ring).

Example 60: Preparation of 2-ethyl-4-(3',5'-dimethoxy-styrene)thiophene (59)

 2-Hydroxyethyl-4-(3',5'-dimethoxystyrene)thiophene was synthesized in a similar manner to Example 58. Jane 1?

(CDC1 ₃ ) δ (ppm) 1. 473-1. 486 (3H, m, -C3⁄4CH0H) , 3. 792 (6H, s, -0CH ₃ ) , 4. 597-4. 615 (IH, ra, - C CHOH) , 5. 581 (IH, s, OH) , 6. 230-6. 921 (5H, ra, 2 olefinic hydrogens between thiophene and benzene ring and 3 hydrogens on benzene ring), 7. 012 -7. 215 (2H, m, 2 hydrogens of thiophene).

Example 61: Preparation of 2-ethyl-4-(3,-amino-phenyl)furan (60)

2-Hydroxyethyl-4-(3'-amino-benzene)furan was synthesized in a similar manner to Example 57. 'HNMR (CDC1 ₃ ) δ

(ppm) 1. 479-1. 490 (3H, m, -C3⁄4CH0H), 4. 792-4. 912 (IH, m, -CH ₃ CH0H) , 5. 021 (IH, s, OH), 6. 023 (IH, s, NH ₂ ) , 6. 317-7. 253 (6H, jn , 4 hydrogens on the phenyl ring and 2 hydrogens on the furan ring).

Example 62: Preparation of 2-ethyl-4-(4,-chloro-benzyl)furan (61)

2-Hydroxyethyl-4-(4'-chloro-benzyl)furan was synthesized in a similar manner to Example 57. 'H陋R (CDC1 ₃ ) δ

(ppm) 1. 482-1. 495 (3H, m, -C3⁄4CH0H), 3. 795-3. 816 (2H, s, methylene group between benzene ring and furan ring),

4. 891-4. 927 (IH, m, -CH ₃ CH0H) , 5. 172 (1H, s, OH), 6. 023 (IH, s, 3H of furan ring), 7. 017-7. 126 (5H, m, 4 hydrogens on the phenyl ring and 5H on the furan ring).

Example 63: Preparation of 2-ethylethyl-4-phenylethylfuran (62)

2-Hydroxyethyl-4-phenethylfuran was synthesized in a similar manner to Example 57. ¹ side R (CDC1 ₃ ) δ (ppm)

1. 478-1. 485 (3H, m, -CH3CHOH), 2. 817-2. 885 (4H, m, 2 methylene groups between furan and benzene ring),

4. 898-4. 932 (IH, ra, -C3⁄4CH0H), 5. 167 (IH, s, OH), 6. 036 (IH, s, 3H of furan ring), 7. 017-7. 126 (5H , ra, 4 hydrogens on the phenyl ring and 5H on the furan ring).

Example 64: Preparation of 2-ethyl-4-(4,-methyl-styrene)furan (63)

2-Hydroxyethyl-4-(4,-methyl-styrene)furan was synthesized in a similar manner to Example 58. 'Draw R (CDC1 ₃ ) δ (ppm) 1. 485-1. 496 (3H, m, -C3⁄4CH0H) , 2· 419 (3H, s, -CH ₃ ) , 4. 735-4. 894 (IH, m, -CH ₃ CH0H) ,

5. 169 (1H, s, OH), 6. 317 (IH, s, 3H of the furan ring), 6. 927-6. 996 (2H, ra, 2 olefinic hydrogens between the furan ring and the benzene ring), 7. 175-7. 364 (6H, m, 2 hydrogens of the furan ring and 4 hydrogens of the benzene ring). Example 65: Preparation of 2-light ethyl 4-(4'-chlorophenyl)furan (64)

2-Hydroxyethyl-4-(4'-chlorophenyl)furan was synthesized in a similar manner to Example 57. ^I HNMR (CDC1 ₃ ) δ (ppm) 1. 68-1. 482 (3H, m, -C3⁄4CH0H) , 4. 821-4. 920 (1H, , -CH ₃ CH0H) , 5. 035 (IH, s , OH), 6. 318 (IH, s, 3H of the furan ring), 7. 334-7. 765 (5H, m, 4 hydrogens on the phenyl ring and 1 hydrogen on the furan ring).

Example 66: Preparation of 2-hydroxyethyl-4-(2,-methoxy-benzyl)furan. (65)

2-Hydroxyethyl-4-(2'-methoxy-benzyl)furan was synthesized in a similar manner to Example 57. ^l HNMR (CDC1 ₃ ) δ (ppm) 1. 479-1. 498 (3H, ra, -C3⁄4CH0H), 3. 701-3. 729 (3H, s, - 0CH ₃ ) , 3. 802-3. 825 (2H, s, methylene group between benzene ring and furan ring), .769-4. 915 (IH, ra, -C3⁄4CH0H), 5. 178 (IH, s, OH), 6. 134 (1H, s, 3H of the furan ring, 6. 758-7. 024 (5H, 4 hydrogens on the phenyl ring and 5H on the furan ring).

Example 67: Preparation of 2-hydroxyethyl-4-(3,-chloro-phenylethyl)furan (66)

2-Hydroxyethyl-4-(3,-chloro-phenethyl)furan was synthesized in a similar manner to Example 57. Wake up R (CDC1 ₃ ) δ (ppm) 1. 485-1. 498 (3H, m, -C3⁄4CH0H), 2. 836-2. 897 (4H, m, furan and stupid 2 methylene groups) ,

4. 792-4. 927 (IH, m, -CH ₃ CH0H) , 5. 179 (IH, s, OH) , 6. 038 (IH, s, 3H of furan ring), 7. 009-7. 324 (5 Η, ra, 4 hydrogens on the phenyl ring and 5H on the furan ring).

Example 68: Preparation of 2-hydroxyethyl-4-(3,-methoxy-styrene) furan (67)

2-Hydroxyethyl-4-(3,-methoxy-styrene) furan was synthesized in a similar manner to Example 59. 'HNMR (CDC1 ₃ ) δ (ppm) 1. 485-1. 499 (3H, ra, -C3⁄4CH0H) , 3. 734 (3H, s, - 0CH ₃ ) , 4. 782-4. 896 (IH, m , -C3⁄4CH0H) ,

5. 208 (IH, s, OH), 6. 709-7. 213 (8H, m, 2 hydrogens of furan, 2 olefinic hydrogens between furan and benzene ring and 4 hydrogens on benzene ring). Example 69: Preparation of 2-hydroxyethyl-4-(3,5'-dimethoxy-styrene) furan (68)

 2-Hydroxyethyl-4-(3',5'-dimethoxystyrene) furan was synthesized in a similar manner to Example 59. NMR

(CDCla) δ (ppm) 1. 489-1. 507 (3H, m, -C3⁄4CH0H), 3. 783 (6H, s, - 0CH ₃ ), 4. 824-4. 912 (IH, m, - C

CHOH) , 5. 283 (IH, s, OH), 6. 243-7. 028 (7H, m, 2 olefinic hydrogens between furan and benzene ring, 3 hydrogens on benzene ring and 2 hydrogens of furan) ).

 The compound obtained by the above synthetic method was subjected to an activity measurement in an anti-osteoporosis experiment in vivo, and a bone tissue morphometry was performed using a Leica Qwin image analysis system, and the trabecular bone volume mainly marked by the bone mass level accounted for the total volume of the bone marrow cavity to be measured. Percentage (TBW.), see Figure 1-5 for the results. Figure 1 is a tibiofibular slice of the sham-operated group (normal control group); Figure 2 is a tibia slice of the model control group; Figure 3 is a tibia slice of the lofestatin group; Figure 4 is a sample of the 39th sample. Rat tibia slice diagram; Figure 5 is a tibia slice diagram of the No. 3 sample group. In vivo studies in animals showed that the compounds of the present invention, particularly samples Nos. 39 and 3, had a significant effect on improving bone quality in rats compared to the model group.

Claims

Rights request  1. Use of a five-membered unsaturated heterocyclic compound having the formula I of the formula I for the preparation of a drug which promotes the expression of a bone morphogenetic protein BMP-2 to increase bone density and inhibit cholesterol biosynthesis thereby lowering blood fat,

among them: X is 0, S or NR ₅ ;  ^ represents a group: H, a hydrocarbon group, a hydrocarbon group containing a halogen, an amino group, a nitro group, a hydroxyl group, a hydrocarbyloxy group, a carboxyl group, a sulfonic acid group, a nitrile group or a phosphoric acid group, or a salt thereof;  Same as, or different from, the following groups: H, halogen, nitro, amino, carboxyl, sulfonic acid, nitrile, acyl, hydrocarbyl, halohydrocarbyl, carbonyl hydrocarbyl, hydroxyhydrocarbyl, aminohydrocarbyl , alkoxy, or a salt thereof; R ₃ , selected from the same or different groups: H, halogen, nitro, amine, carboxyl, sulfonic acid group, nitrile group, lower hydrocarbyl group, halogenated hydrocarbyl group, carbonyl hydrocarbyl group, hydroxyhydrocarbyl group, amino hydrocarbyl group, hydrocarbon An oxy group, a substituted vinyl group, or a salt thereof, or a combination of carbon, oxygen, or nitrogen to form a 5-7 membered aromatic ring structure;  Selected from H, a hydrocarbyl group, a halogenated hydrocarbyl group, a carbonyl hydrocarbyl group, a hydroxyhydrocarbyl group, an aminohydrocarbyl group or a hydrocarbyloxy group;  The above hydrocarbon groups each contain from 1 to 18 carbons.  2. A five-membered unsaturated heterocyclic compound having a structure of formula I, which promotes the expression of bone morphogenetic protein BMP-2 to increase bone density and inhibit cholesterol biosynthesis and thereby lower blood fat.

Wherein X, R„ R _{2 is the} same as claim 1; R ₃ , connected by carbon, oxygen, nitrogen to form a 5-7 membered aromatic ring structure, and the aromatic ring structure may have a substituent; RH, halogen, nitro, amine, carboxyl, sulfonic acid group, nitrile group, hydrocarbyl group, hydrocarbyl group, carbonyl hydrocarbyl group, hydroxyhydrocarbyl group, aminohydrocarbyl group or hydrocarbyloxy group, said hydrocarbyl group containing 1 to 18 carbons. The five-membered unsaturated heterocyclic compound according to claim 2, wherein ^ is a methyl group, an ethyl group, a propylene group or a phenylpropenyl group; and is a methyl group, a halogenated methyl group, and contains 1 to 18 carbons. The hydrocarbon group, R ₃ and R _{4 ,} is a benzo structure formed by carbon bonding.  4. The five-membered unsaturated heterocyclic compound according to claim 2, which comprises 3-fluoromethyl-2-acetylbenzothiophene, 3-methyl-2-acetylbenzothiophene, 3-trifluoromethyl- 2-acetylbenzothiophene, 2-phenylacryloylbenzothiophene, 3-fluoro2-acetylbenzofuran, 3-methyl-2-acetylbenzofuran, 3-trifluoromethyl-2-acetylbenzofuran, 2-phenylacryloylbenzofuran, 3-acetylhydrazine . A method for synthesizing a five-membered unsaturated heterocyclic compound according to claim 2, which comprises: R ₆ is an ortho-halogen M-substituted aromatic acetyl compound II under basic conditions and in the presence of tetrabutylammonium bromide, with an alcohol The reaction is stirred under reflux with a thiol or an amine. After the reaction of the obtained product with a halomethyl ketone is refluxed, the target is isolated, and the synthesis route is:

The method for synthesizing a five-membered unsaturated heterocyclic compound according to claim 5, wherein when the 2- or 3-position of the five-membered unsaturated heterocyclic ring is a compound VI and/or n substituted with an acryloyl group, the synthesis method comprises Adding a protic solvent to an aqueous solution of a strong base at 50 ° C to -50 ° C, the protic solvent being a solvent containing a hydroxyl group, and maintaining the 50 ° C to -50 Torr to add a five-membered unsaturated heterocyclic compound And an aryl formaldehyde, the 5-ary unsaturated heterocyclic compound is a 2-acylated derivative having an IV structural formula or a 3-acylated derivative having a V structural formula, and is subjected to a reaction at room temperature to obtain a target VI or VII, and the synthesis route is :

Wherein R ₇ and R _{8 are} independently selected from the group consisting of H, halogen, nitro, carboxy, nitrile, hydrocarbyl, halohydrocarbyl, hydroxyhydrocarbon a group, an aminohydrocarbyl group, a hydrocarbyloxy group, or a salt thereof; the hydrocarbyl group contains 1 to 18 carbons. The method for synthesizing a five-membered unsaturated heterocyclic compound according to claim 5, wherein, when the compound VIII or IX of the 5- or 3-position carbonylacetyl group of the 5-membered unsaturated heterocyclic ring, the synthesis method comprises, The 2- or 3-position acylated derivative IV or V of the unsaturated heterocyclic compound is in an anhydrous diethyl ether, 50 to -5 CTC and a base catalyzed with a carboxylic acid ester ∞ ₂ 1 . The reaction is carried out to obtain the target compound VIII or IX which is a 2- or 3-position carbonyl acetyl group. The synthetic route is:

Wherein R ₇ and R _{9 are} independently selected from the group consisting of H, halogen, nitro, carboxyl, nitrile group, hydrocarbon group having 1 to 18 carbons, halogenated hydrocarbon group, hydroxyalkyl group, aminoalkyl group, alkoxy group, or a salt thereof ; It is H or an alkyl group having 1 to 12 carbons.  The method for synthesizing a five-membered unsaturated heterocyclic compound according to claim 5, wherein, when the carbonyl group at the 2- or 3-position acyl group of the five-membered unsaturated heterocyclic ring is replaced by a hydroxy group, the five-membered unsaturated heterocyclic compound is Compound X or XI, the synthesis method comprises: reacting a compound of the formula IV or V in tetrahydrofuran and water under the action of sodium borohydride to obtain the target X or XI, and the synthesis route is:

Wherein R ₇ and Ru are independently selected from the group consisting of H, halogen, nitro, carboxy, nitrile, hydrocarbyl, halohydrocarbyl, hydroxyhydrocarbyl, aminohydrocarbyl, alkoxy, or a salt thereof; Carbon. The method for synthesizing a five-membered unsaturated heterocyclic compound according to claim 5, wherein, when the five-membered unsaturated is hetero a compound in the ring compound wherein H, R ₃ is a substituted vinyl group 2-acyl 4-substituted ethylene derivative vi or 2-hydroxyalkyl 4-substituted styrene derivative viii, the synthesis method comprises 3-methyl five-membered The unsaturated heterocyclic compound i is reacted with chlorine gas to obtain a 3-chloromethyl five-membered unsaturated heterocyclic compound ii; ii is heated under reflux with acetic anhydride to obtain a 2-acetyl 3-chloromethyl five-membered unsaturated heterocyclic compound iii; Condensation with a diol under basic conditions to obtain a ketal compound iv, which is then reacted with triphenylphosphine under a strong base to obtain a quaternary phosphonium salt V, which is then reacted with a substituted benzaldehyde under a strong base to obtain a target, ie, a 2-acyl group. - 4 - Substituting the ethylene derivative vi; further hydrolyzing the deprotecting group under acidic conditions from -10 Torr to 100 Torr, and the obtained compound vii and sodium borohydride are reacted in tetrahydrofuran and water to obtain a target substance, that is, 2-hydroxyhydrocarbyl group 4 - Instead of the styrene derivative viii, the synthetic route is:

Wherein R _{12 is} selected from the group consisting of H, a hydrocarbyl group, a halogenated hydrocarbyl group, a hydroxyhydrocarbyl group, an aminohydrocarbyl group or a hydrocarbyloxy group, and the hydrocarbyl group contains 1 to 18 carbons. The method for synthesizing a five-membered unsaturated heterocyclic compound according to claim 5, wherein, when the five-membered unsaturated heterocyclic compound is hydrogen, R ₃ is a hydrocarbyl-substituted thiophene compound having 0 to 18 carbons or a derivative xi or xii, the synthesis method comprising: condensing a 2-acyl five-membered unsaturated heterocyclic compound with a diol under basic conditions to obtain a ketal compound ix, ix refluxing with a hydrocarbyl magnesium bromide in an anhydrous ether solvent The compound x, X is subjected to a deketal protecting group under acidic conditions to obtain a 2-acyl compound xi, xi and sodium borohydride in tetrahydrofuran and water to obtain a target, that is, a 2-substituted hydroxymethyl 4-substituted octahydrate The ring derivative xii, the synthetic route is:

Wherein R _{13 is} selected from the group consisting of H, a hydrocarbyl group, an aromatic hydrocarbon group, a hydrocarbyl group containing 0, S, N; the hydrocarbyl group contains 1 to 18 carbons; n = 1 - 8.  A composition comprising a therapeutically effective amount of the five-membered unsaturated heterocyclic compound of claim 2 and a pharmaceutically acceptable adjuvant.  01。 The composition of claim 11, comprising a weight ratio of 0.1% - 99. 5% of a five-membered unsaturated heterocyclic compound.  13. Use of the composition of claim 11 in the manufacture of a medicament for promoting bone morphogenetic protein BMP-2 expression to increase bone density and inhibit cholesterol biosynthesis thereby lowering blood lipids.  14. The use of claim 13 wherein said medicament comprises an anti-bone metabolism disorder drug.  15. The use of claim 13 wherein said medicament comprises an anti-osteoporosis drug.  16. The use of claim 13 wherein said medicament comprises an anti-dyslipidemia drug.