CN105198786B

CN105198786B - Amides compound of aryl substitution and preparation method thereof, the pharmaceutical composition comprising it and its application

Info

Publication number: CN105198786B
Application number: CN201410270006.0A
Authority: CN
Inventors: 司书毅; 李永臻; 许艳妮; 冯婷婷; 刘畅; 王潇; 刘鹏; 巫晔翔; 贺晓波; 李东升; 陈明华; 刘伟
Original assignee: Institute of Medicinal Biotechnology of CAMS
Current assignee: Institute of Medicinal Biotechnology of CAMS
Priority date: 2014-06-17
Filing date: 2014-06-17
Publication date: 2018-06-29
Anticipated expiration: 2034-06-17
Also published as: CN105198786A

Abstract

Amides compound and preparation method thereof for replacing the present invention relates to the aryl of formula (I) includes its pharmaceutical composition and their applications in pharmacy, wherein Ar_l、L₁、M₁、M₂、_L2And Ar₂As defined herein.The amides compound of the aryl substitution of the present invention can excitement TRPV1, exciting nuclear receptor (LXRs, PPARs, RXR), the expression for adjusting cholesterol efflux GAP-associated protein GAP ABCA1/G1, the expression of SR BI, adjusting inflammation related proteins TNF α etc., so as to play promote row outside cholesterol and lipid, hypoglycemic, adjust blood fat, it is anti-inflammatory, reduce blood pressure the effects that, for treating and/or preventing and/or alleviate cardiovascular and cerebrovascular disease, the diseases such as adjusting blood fat, antiatherosclerosis, diabetes, anti-inflammatory, pain and anti-hypertension.

Description

Amides compound of aryl substitution and preparation method thereof includes its pharmaceutical composition Object and its application

Technical field

The present invention relates to the amides compound of aryl substitution or its pharmaceutical salts, preparation method, include its medicine group Close object and its application.

Background technology

Atherosclerosis (Atherosclerosis, AS) is that coronary heart disease, myocardial infarction, cerebral apoplexy, hypertension etc. are a variety of The common pathophysiological basis of cardiovascular and cerebrovascular disease.The death toll as caused by the disease accounts for the 1/ of global total toll every year 3。

The pathogenesis of AS is more complicated, closely related with lipid infiltration, blood vessel endothelium injury, inflammation etc..Macrophage is thin Born of the same parents unlimitedly absorb lipid, cholesterol and the low-density lipoprotein of denaturation (m- by SR-A the and CD36 receptors on its surface LDL the foamed of macrophage) is formed.A large amount of lipids (mainly cholesterol and cholesteryl ester) film foamed cell in the blood vessels Interior accumulation forms atherosclerotic plaque, and with the aggravation of inflammatory reaction, the dissolving of fibrous cap, eventually leads to Atherosclerosis Change the formation with thrombus etc., and further develop into the angiocardiopathies such as coronary heart disease, heart infarction.

At present, the fat-reducing medicament of clinical practice mainly has the drugs such as niacin, fibrates, cholic acid chelating agent and Statins.Cigarette The mechanism of action of acid is the effect for enhancing lipoprotein lipase, free fatty acid levels is reduced, but its adverse reaction is more, so seldom It uses.The mechanism of action of fibrates fat regulation medicine is exciting alpha types peroxisome activated form proliferation receptor (PPAR α), is enhanced The effect of lipoprotein lipase, the lethal danger of non-cardiovascular disease of such drug is higher, therefore limits answering for such drug With.Cholic acid chelating agent class drug by congugated bile acids, increase its excretion, so as to accelerate conversion of the cholesterol to bile acid.Courage There are the shortcomings of taking dose is big, gastrointestinal reaction is apparent, patient tolerability is poor for acid sequestering agent class drug.Statins is that treatment is high The first-line drug of blood lipid disorder, mechanism of action are to inhibit internal HMG-CoA reductase activity, reduce low density lipoprotein Albumen (LDL) is horizontal, but long-term use can lead to rhabdomyolysis, gastrointestinal dysfunction syndrome, fash and hepar damnification Wait serious adverse reactions.It is therefore, clinical that there is an urgent need to it is found that and drug of the development with anti-AS new target drones.People are finding Extensive work is made in terms of anti-AS drugs of the research and development with other mechanism of action.

In recent years, it as people deepen continuously to the understanding of atherogenesis mechanism, finds to promote cholesterol Counter transport (Reverse cholesterol transport, RCT) process can slow down generation and the hair of atherosclerosis Exhibition, and the atherosclerosis to having been formed has reverse effect, fundamentally reduces the heart as caused by atherosclerosis The generation of cranial vascular disease.Reverse cholesterol transport is high-density lipoprotein (HDL) by the cholesterol transport in peripheral tissues to liver Dirty metabolism again or the process drained in the form of cholic acid, are the effective means for preventing and treating AS, and mediation macrophage courage is consolidated The main molecules of alcohol outflow include ATP binding cassette transporter protein family (ATP binding cassette Transporter, ABC) in ABCA1, ABCG1, the SR-BI (Scavenger of HDL receptor family Receptor type B class I)/CLA-1, peroxisome proliferation-activated receptors (Peroxisome Proliferator-Activated Receptor, PPARs), liver X receptor (liver X receptor, LXRs) etc. (A.R.Tall.Cholesterol efflux pathways and other potential mechanisms involved in the athero-protective effect of high density lipoproteins.J Intern Med.2008,263 (3)：256-73.).And the critical function of HDL includes anti-inflammatory, antithrombotic, vascular protection, promotees cholesterol stream Go out, is anti-oxidant, increasing (Navab M, Reddy ST, Van Lenten BJ, the Fogelman AM.HDL and such as NO generations cardiovasculardisease：atherogenic and atheroprotective mechanisms.Nat Rev Cardiol.2011,8 (4)：222-32.).Research finds these associated receptors, transmembrane protein and related nuclear receptor, is not orphan It on the spot works, actually exists the mutually coordinated and Cell Signal Transduction Network regulation mechanism between each receptor.

ABCA1 can mediate cholesterol and phosphatide to flow to poor fat or apolipoprotein A-1 without fat from peripheral cells (apolipoprotein A-I, apoA-I) has important work to the occurrence and development of lipid-metabolism, cholesterol metabolic, AS, inflammation With.The transgenic mice of ABCA1 high expression can increase the level of blood plasma HDL, apoA-I, and make in Macrophage cholesterol Outflow is apparent to be increased, so as to reduce the danger of AS.ABCG1 can promote cholesterol to be flowed out from macrophage, and HDL consolidates for its courage The acceptor of alcohol, so as to which cholesterol be promoted to be discharged from liver, small intestine.SR-BI not only promotes cholesterol to be flowed from macrophage Go out, promote the selectivity intake of cholesteryl ester in liver.In addition, the expression of ABCA1, ABCG1, SR-BI are also surpassed by nuclear receptor Family's (including LXRs, retinoic acid X receptors (RXR), farnesol X receptors (FXR) and Thyroid Hormone Receptors), PPARs, transcription The regulation and control such as the factor (such as AP-1, AP-2, NF- κ B and Sp1 etc.).LXR direct regulations and controls participate in many keys in cholesterol metabolic approach The expression of target gene (including ABCA1, ABCG1 etc.) is the receptor of body inner cholesterol metabolism, for maintaining body cholesterol Homeostasis plays the role of vital.The effect of PPARs is very extensive, is metabolized, in vivo except lipid and lipoprotein is participated in Sugared balance external further relates to the differentiation of the various kinds of cell such as adipocyte, monokaryon/macrophage, inhibits inflammatory factor generation and inflammatory reaction, It adjusts blood vessel to relax/contract and influence atherogenesis etc., PPARs agonists are for lipid-metabolism, glycometabolism, inflammation phase Related disorders (such as angiocardiopathy, inflammation, atherosclerosis, diabetes) play an important role and application prospect (Timothy M.Willson, Millard H.Lambert, and Steven A.Kliewer.Peroxisome proliferator- Activated receptor.Annu.Rev.Biochem.2001,70：341-67).Therefore, it adjusts and (increases or exciting) The activity on treatment AS of ABCA1, ABCG1, SR-BI, LXRs, PPARs, HDL etc. is beneficial.It is beneficial to treat angiocardiopathy, inflammation The diseases such as disease, atherosclerosis, diabetes.

TRPV1 is (the Transient Receptor Potentialca-tion of transient receptor potential vanillic aldehyde subfamily 1 Channel subfamily V member1, TRPV1).TRPV1 is mainly expressed in periphery nerve cell, can by high temperature, proton, The inside and outside source property substance activating such as capsaicine, lipid metaboli product, causes with Ca²⁺Based on transmembrane ion flowing, make intracellular Ca²⁺ Concentration changes, and then activates a series of Intracellular signals, is functionally mainly shown as and participates in the processes (Rong such as nociception Xia, Kim Dekermendiian, Elke Lullau, and Niek Dekker.TRPV1：a therapy target that Attracts the pharmaceutical interests.Adv Exp Med Biol.2011,704：637-65.).Excitement TRPV1 can promote the release of calcitonin gene-related peptide (calcitonin gene-related peptide, CGRP), so as to Play its cardiovascular protection (such as hypertension, endothelial dysfunction, apoplexy), anti-hypertension, analgesia pharmacological activity.Excitement The cardiovascular protective effect that TRPV1 is generated is also related to ABCA1, ABCG1, PPARs, LXRs.TRPV1 excitement also with inflammation Occur related to inhibition.The excitement of TRPV1 has the expression for inhibiting inflammatory factor and activation, while plays the prevention to AS Effect.

The diseases such as the cardiovascular and cerebrovascular diseases such as atherosclerosis, diabetes, inflammation, hypertension, pain, inflammation seriously affect The health of the mankind, in clinical and pharmaceutical field, there is an urgent need to find and develop the novel compounds for the treatment of and/or the above-mentioned disease of prevention Object.

Invention content

For this purpose, the object of the present invention is to provide the amides compound of a kind of novel aryl substitution or its pharmaceutical salts, its Preparation method includes its pharmaceutical composition and their purposes.The new compound of the present invention is directed to the difference of above-mentioned disease Target, can excitement TRPV1, exciting nuclear receptor (LXRs, PPARs, RXR), adjusting cholesterol efflux related membrane protein ABCA1/G1, The expression of SR-BI, the expression for adjusting inflammation related proteins TNF-α etc., so as to play the outer row for promoting the lipids such as cholesterol, drop Sugar adjusts blood fat, is anti-inflammatory, the effects that reducing blood pressure, for treating or preventing atherosclerosis, cardiovascular and cerebrovascular disease, high in fat Mass formed by blood stasis, diabetes, inflammation, hypertension or pain.

On the one hand, the present invention provides a kind of compound of formula (I)：

Wherein,

Ar₁Represent indoles -2- bases, indol-3-yl or phenyl, the indoles -2- bases, indol-3-yl or phenyl optionally quilt Substituent group substitution in the group being made of the following terms：Hydrogen, halogen, hydroxyl ,-CHO, C₁-C₆Alkanoyl, C₁-C₆Alkyl or C₁-C₆Alkoxy；

L₁Represent C₁-C₆Alkylidene is not present；

M₁And M₂It expression-CO- or is not present differently from one another；

L₂Represent C₁-C₆Alkylidene, C₁-C₆Alkylene oxide group ,-O-, C₁-C₆Alkylenethio ,-S- are not present；And

Ar₂It representsWherein R₁Represent hydrogen, hydroxyl, amino, halogen Element, C₁-C₆Alkyl, halogenated C₁-C₆Alkyl, C₁-C₆Alkylamino radical, two (C₁-C₆Alkyl) amido, amino C₁-C₆Alkyl, amino C₁-C₆ Alkanoyl, C₁-C₆Alkyl amide, two (C₁-C₆Alkanoyl) amido, halogenated C₁-C₆Alkyl amide, carboxyl or-COO (C₁-C₆) alkane Base；R₂Represent hydrogen, amino, hydroxyl, C₁-C₆Alkyl or C₁-C₆Alkanoyl；R₃Represent hydrogen, halogen, C₁-C₆Alkyl, C₁-C₆Alkyl halide Base or C₁-C₆Alkanoyl；

Or its pharmaceutical salts.

In a preferred embodiment, in the Formulas I：

Ar₁Represent indoles -2- bases, indol-3-yl or phenyl, the indoles -2- bases, indol-3-yl or phenyl optionally quilt Substituent group in the group being made of the following terms：Hydrogen ,-CHO, C₁-C₄Alkanoyl or C₁-C₄Alkoxy；

L₁Represent C₁-C₂Alkylidene is not present；

L₂Represent C₁-C₄Alkylidene, C₁-C₄Alkylene oxide group ,-O- are not present；And

Ar₂It representsWherein R₁Represent optionally selected freely following The phenyl of substituent group substitution in the group of items composition：Hydrogen, hydroxyl, amino, C₁-C₄Alkyl, C₁-C₄Alkylamino, two (C₁-C₄Alkane Base) amino, amino C₁-C₄Alkanoyl, C₁-C₄Alkyl amido, two (C₁-C₄Alkanoyl) amino, halogenated C₁-C₄Alkyl amido, carboxyl Or-COO (C₁-C₃) alkyl；R₂Represent hydrogen, amino, hydroxyl, C₁-C₄Alkyl or C₁-C₄Alkanoyl；R₃Represent hydrogen, C₁-C₄Alkyl or C₁-C₄Alkanoyl.

In another preferred embodiment, in the Formulas I：

Ar₁Represent that phenyl, indoles -2- bases, indol-3-yl, 2- by C₁-C₄Alkanoyl substitution indol-3-yl, 2- By the indol-3-yl of-CHO substitutions or 5- by C₁-C₄The indol-3-yl of alkoxy substitution；

L₁Represent C₁-C₂Alkylidene is not present；

Ar₂It representsWherein R₁Represent optionally selected freely following The phenyl of substituent group substitution in the group of items composition：Hydrogen, hydroxyl, amino, C₁-C₄Alkyl, C₁-C₄Alkylamino, two (C₁-C₄Alkane Base) amino, amino C₁-C₄Alkanoyl, C₁-C₄Alkyl amido, two (C₁-C₄Alkanoyl) amino, halogenated C₁-C₄Alkyl amido, carboxyl Or-COO (C₁-C₃) alkyl；R₂Represent hydrogen, amino, hydroxyl or C₁-C₄Alkyl；R₃Represent hydrogen or C₁-C₄Alkyl.

In another preferred embodiment, in the Formulas I：

Ar₁Represent phenyl, optionally by the indol-3-yl of methoxy substitution or optionally by the indoles of methoxy substitution- 2- bases；

L₁It represents methylene, ethylidene or is not present；

L₂It represents methylene or is not present；And

Ar₂Represent phenyl, 2-aminopyridine -3- bases, pyridin-3-yl, quinoline -3- bases, by amino, hydroxyl, carbamyl, Trifluoroacetyl group, propiono, carboxyl or methyl substituted phenyl.

On the other hand, the invention further relates to a kind of method for being used to prepare above compound, the method includes：Foundation Following reaction scheme (i) or (ii), in anhydrous inert organic solvent, with the amine and formula (a) of formula (b) or (c) or the carboxylic acid of (d) Or acyl chlorides is raw material, is reacted in the presence of condensing agent and basic catalyst,

Reaction scheme (i)：

Reaction scheme (ii)：

Wherein Ar1, L1, M1, M2, L2 and Ar2 be as defined above.

On the other hand, the present invention provides a kind of pharmaceutical composition, described pharmaceutical composition include above compound or its Pharmaceutical salts and pharmaceutical carrier.

On the other hand, the present invention provides above compound and is preparing the drug for treating and/or preventing following disease In application：Atherosclerosis, cardiovascular and cerebrovascular disease, hyperlipidemia, diabetes, inflammation, hypertension or pain.

On the other hand, the present invention provides aforementioned pharmaceutical compositions and is preparing for treating and/or prevent following disease Application in drug：Atherosclerosis, cardiovascular and cerebrovascular disease, hyperlipidemia, diabetes, inflammation, hypertension or pain.

The amides compound of aryl substitution provided by the invention has can significantly excitement TRPV1, exciting nuclear receptor (LXRs, PPARs, RXR), the expression for adjusting cholesterol efflux related membrane protein ABCA1/G1, HDL receptor SR-BI/CLA-1 are adjusted The expression of inflammation related proteins tumor necrosis factor α (Mouse tumor necrosis factor α, TNF-α) etc. is saved, so as to The effects that playing the outer row for promoting the lipids such as cholesterol, hypoglycemic, adjusting blood fat, is anti-inflammatory, reducing blood pressure, can be used for treatment or pre- Anti- atherosclerosis, cardiovascular and cerebrovascular disease, dyslipidemia, diabetes, inflammation, hypertension or pains and other diseases.

Description of the drawings

Fig. 1 shows agonist activity effect of the compound according to the present invention to TRPV1；

Fig. 2 shows the influences that compound according to the present invention expresses ABCA1, SR-BI/CLA-1, ABCG1；

Fig. 3 shows that compound according to the present invention promotes the diagram of Cholesterol Efflux；

Fig. 4 shows that compound according to the present invention inhibits the result of macrophage foam cell formation；

Fig. 5 shows influence of the compound according to the present invention to aorta overall length atherosclerotic plaque；

Fig. 6 shows the influence of compounds on cardiac efferent tract atherosclerotic plaque according to the present invention；

Fig. 7 shows influence of the compound according to the present invention to T-CHOL in liver；

Fig. 8 shows the influence of the compound on inflammation factor according to the present invention；

Fig. 9 shows influence of the compound according to the present invention to mouse blood pressure；

Figure 10 shows influence of the compound according to the present invention to blood glucose.

Specific embodiment

The present invention relates to the compounds of formula (I) a kind of：

Wherein,

L₁Represent C₁-C₆Alkylidene is not present；

M₁And M₂It expression-CO- or is not present differently from one another；

Ar₂It representsWherein R₁Represent hydrogen, hydroxyl, amino, halogen Element, C₁-C₆Alkyl, halogenated C₁-C₆Alkyl, C₁-C₆Alkylamino radical, two (C₁-C₆Alkyl) amido, amino C₁-C₆Alkyl, amino C₁-C₆ Alkanoyl, C₁-C₆Alkyl amide, two (C₁-C₆Alkanoyl) amido, halogenated C₁-C₆Alkyl amide, carboxyl or-COO (C₁-C₆) alkane Base；R₂Represent hydrogen, amino, hydroxyl, C₁-C₆Alkyl or C₁-C₆Alkanoyl；R₃Represent hydrogen, halogen, C₁-C₆Alkyl, C₁-C₆Alkyl halide Base or C₁-C₆Alkanoyl.

Derivative, its isomers, raceme or optical isomer, its pharmaceutical salts the invention further relates to above compound or Its solvate.

Terms used herein " alkyl " include straight chain and branched alkyl, prefix such as " C₁-C₆" represent amount of carbon atom It is 1-6；Term " alkylidene " represents divalent alkyl；Term " alkanoyl " represents alkyl-CO-；Term " alkoxy " represents alkane Base-O-；Term " alkylene oxide group " represents alkylidene-O-；Term " alkylamino " represents alkyl-NH-；Term " alkylthio group " represents alkane Base-S-；Term " alkylenethio " represents alkylidene-S-；Term " aminoalkanoyl radical " represents NH₂Alkanoyl；Term " alkane acyl ammonia Base " represents alkanoyl-NH-；Term " halogen " refers to F, Cl, Br or I.Terms used herein " aryl " represent aromatics, quilt (being mono or poly substituted) or the unsubstituted group of substitution, including containing the heteroatomic heteroaryls of one or more N. In addition, in the present context, term " amides compound " represents the compound containing-N (H)-CO- groups, covers Lactam analog compound.

In a kind of compound of preferred Formulas I：

L₁Represent C₁-C₂Alkylidene is not present；

In the compound of another preferred Formulas I：

L₁Represent C₁-C₂Alkylidene is not present；

In the compound of another preferred Formulas I：

L₁It represents methylene, ethylidene or is not present；

L₂It represents methylene or is not present；And

Those and its pharmaceutical salts that the particularly preferred compound of the present invention is including but not limited to described in detail in table 1 below：

Table 1：Particularly preferred compound of formula I

The invention further relates to the preparation method of logical formula (I) compound represented, for example, the compounds of formula I of the present invention It can prepare as follows：

Work as M₁In the presence of and for CO, M₂In the absence of, logical formula (I) part of compounds (I-1) is obtained by following reaction scheme (i)；

Reaction scheme (i)：

Work as M₂For CO, M₁For in the absence of, logical formula (I) part of compounds (I-2) is obtained by reaction scheme (ii),

Reaction scheme (ii)：

Wherein Ar₁、L₁、M₁、M₂、L₂And Ar₂As defined above.

Above-mentioned reaction belongs to the popular response of the synthesizing amide of this field, wherein in anhydrous inert organic solvent (such as dichloro Methane or n,N-Dimethylformamide) in, with corresponding amine (b) or (c) and carboxylic acid or acyl chlorides (a) or (d) for raw material, it is being condensed Agent (such as dicyclohexylcarbodiimide, 1- ethyls-(3- dimethylamino-propyls) carbodiimide hydrochloride) and basic catalyst (such as three Ethamine or 4-dimethylaminopyridine) in the presence of, in room temperature to the temperature of 120 DEG C (when such as using n,N-Dimethylformamide as solvent) Lower reaction 2-24h, eventually passes through such as column chromatography separating purification and obtains target product.

Biological experiment result of study shows institute's test target compound of the present invention, cellular level can excitement TRPV1, Exciting nuclear receptor (LXRs, PPARs, RXR), the table for adjusting cholesterol efflux related membrane protein ABCA1/G1, HDL receptor SR-BI The expression that reach, adjusts inflammation related proteins TNF-α etc. promotes lipid, cholesterol efflux, can adjust in vivo blood fat, reduce it is dynamic Arteries and veins patch inhibits inflammatory Cytokines Expression, reduces blood glucose, reduces blood pressure, for prepare clinical effective treatment and/or prevention and/or Alleviate cardiovascular and cerebrovascular disease, hyperlipemia, atherosclerosis, diabetes, inflammation, pain and high blood pressure disease drug to carry Preferable potential applicability in clinical practice is supplied.

The amides compound of the aryl substitution of the present invention can be given with itself administration or in the form of pharmaceutical composition Medicine.

The compounds of the invention or their medicinal salts of the Pharmaceutical composition including therapeutically effective amount of the present invention as active ingredient, And one or more pharmaceutical carriers, excipient or diluent.

The pharmaceutical composition of the present invention can be prepared in the usual way, use one or more physiologically acceptable loads Body, excipient and auxiliary agent are conducive to reactive compound being processed into pharmaceutical preparations.Appropriate preparation depends on selected give Medicine approach can be prepared according to method well known in the art.

Suitable carrier, excipient or diluent can be selected for expected mode of administration and standard practices.Properly The example of carrier include：Lactose, starch, glucose, methylcellulose, magnesium stearate, mannitol, sorbierite etc..

Therapeutically effective amount is 0.1% to 99.9%w/w any amount, such as 0.1-50%w/w or 50-99.9%w/w, Such as 1-95%w/w or 5-90%w/w or 10-80%w/w.

The composition of the present invention can be discharged by various administration routes or mode to patient.Suitable administration route packet It includes but is not limited to sucking, transdermal, oral, rectum, transmucosal, enteral and parenteral administration, parenteral administration includes intramuscular, subcutaneous And intravenous injection.

Compounds for oral administration be suitably formulated as compressed tablets, tablet, capsule, gel capsule, powder, Solution, disperse system, suspension, drops etc..These forms can be produced according to known method, and can be included arbitrary Suitable adhesive, lubricant, suspending agent, coating agent or solubilizer or combination thereof.

The composition applied by means of injecting suitably is formulated as sterile solution or breast from suitable solution or powder Agent.Alternatively, composition can be suppository, pessary, suspension, emulsion, lotion, cream, ointment, skin patch, gel, Colloidal sol, spray, the form of solution or face powder.

The daily dose of instruction is about 1mg to about 1000mg (such as 2mg-750mg or 3mg-650mg or 5mg-500mg). Usually every dose of the composition provided with dosage form is containing about 0.25mg to about 250mg (such as 0.5mg-200mg or 0.75mg- 150mg or 1mg-100mg) active constituent.

Composition can include one or more additional active constituents or can with comprising identical or different for treating The composition of other active constituents of illness is applied together.Co-administration can be simultaneously, consistently or sequentially.

Compound defined above can be free form, i.e., usually as alkali or any appropriate salt or ester-formin. In a usual manner, the compound of free form can be converted to salt or ester-formin, and vice versa.

Suitable salt includes：Hydrochloride, dihydrochloride, hydrogen formates, amide, succinate, hemisuccinic acid salt, maleic acid Salt, acetate, trifluoroacetate, fumarate, phthalate, four phthalates (tetraphthalate), benzene Formates, sulfonate, sulfate, phosphate, oxalates, malonate, bimalonate, ascorbate, glycollate, breast Hydrochlorate, malate, tartrate, citrate, aspartate or glutamate and their variant.Suitable for forming acid The acid of addition salts include corresponding acid, i.e., hydrochloric acid, formic acid, amino acid, succinic acid, maleic acid, acetic acid, trifluoroacetic acid, fumaric acid, Phthalandione, four phthalandiones, benzoic acid, sulfonic acid, sulfuric acid, phosphoric acid, oxalic acid, malonic acid, ascorbic acid, oxyacetic acid, lactic acid, malic acid, wine Stone acid, citric acid, asparatate or glutamic acid etc..

The present invention will be further illustrated by the examples that follow, but not had to the present invention restricted.

Embodiment 1：The synthesis of representative compound

(1) N- (2- (1H- indol-3-yls) ethyl) -2- aminobenzamides (CD1)

Tryptamines (purchased from this company of Adama, purity ＞ 99%) (0.80g, 5mmol) is added in 50mL round-bottomed flasks, adds Enter 25mLN, dinethylformamide sequentially adds 2- aminobenzoic acids (0.68g, 5mmol), 1- ethyls-(3- dimethylaminos third Base) carbodiimide (EDCI) hydrochloride (being purchased from Beijing coupling Science and Technology Ltd., purity ＞ 98%) (0.96g, 5mmol), Room temperature reaction is overnight.Decompression steams most of solvent, is extracted with ethyl acetate after adding 30mL water and is dried with anhydrous sodium sulfate.Second With ethyl acetate after the concentration of acetoacetic ester extract liquor: petroleum ether=1: 3 obtain CD1 sterlings 1.14g (productions for eluant, eluent through silicagel column elution Rate 82%), white solid, mp159-160 DEG C (156-157 DEG C of literature value).MS(ESIm/z)280.28(M+H)⁺, HRMS (ESI m/z)[M+H]⁺Theoretical molecular formula C₁₇H₁₈N₃O, theoretical molecular weight 280.1444, actual molecular weight 280.1444.¹H NMR (400MHz, CD₃COCD₃) the δ 9.99 (- NH of s, 1H, 1 '), the 7.65 (- H of d, J=8.0Hz, 1H, 4 '), 7.60 (brs, 1H, CONH), 7.45 (d, J=8.0Hz, 1H, 6-H), the 7.37 (- H of d, J=8.0Hz, 1H, 7 '), the 7.20 (- H of s, 1H, 2 '), 7.13-7.07 (m, 2H, 5 ' 6 ' -2H), 7.01 (t, J=8.0Hz, 1H, 5-H), 6.73 (d, J=8.0Hz, 1H, 3-H), 6.49 (t, J=8.0Hz, 1H, 4-H), 6.24 (brs, 2H, NH₂), 3.66 (q, J=6.8Hz, 2H, CH₂NH), 3.05 (t, J=6.8Hz, 2H, CH₂)。

(2) N- (2- (5- acetyl group -1H- indol-3-yls) ethyl) -2- aminobenzamides (CD2)

By the method for synthesis (CD1), with 5- acetyl group tryptamines (purchased from this company of Adama, purity ＞ 99%) (1.0g, It is 5mmol) raw material, synthesis obtains CD2 sterlings 1.21g (yield 76%), MS (ESIm/z) 322.26 (M+H)⁺。¹H NMR (400MHz, CD₃COCD₃) the δ 9.85 (- NH of s, 1H, 1 '), the 7.72 (- H of d, J=2.0Hz, 1H, 4 '), 7.62 (brs, 1H, CONH), 7.48 (d, J=8.0Hz, 1H, 6-H), the 7.37 (- H of d, J=8.0Hz, 1H, 7 '), the 7.20 (- H of s, 1H, 2 '), 7.13-7.07 (- the H of dd, J=2.0,8.0Hz, 1H, 6 '), 7.01 (t, J=8.0Hz, 1H, 5-H), 6.73 (d, J=8.0Hz, 1H, 3-H), 6.49 (t, J=8.0Hz, 1H, 4-H), 6.24 (brs, 2H, NH₂), 3.66 (q, J=6.8Hz, 2H, CH₂NH), 3.38 (s, 3H, CH₃) 3.05 (t, J=6.8Hz, 2H, CH₂)。

(3) N- (2- (5- acetyl group -1H- indol-3-yls) ethyl) -3- Aminomethyl benzamides (CD3)

By the method for synthesis (CD1), Beijing (is purchased from 5- acetyl group tryptamines (1.0g, 5mmol) and 3- amino-methyl benzoic acids It is coupled Science and Technology Ltd., purity ＞ 98%) (0.76g, 5mmol) reaction, it synthesizes and obtains CD3 sterlings 1.27g (yield 86%), MS(ESIm/z)294.16(M+H)⁺。¹H NMR (400MHz, CD₃COCD₃) the δ 9.85 (- NH of s, 1H, 1 '), 7.72 (d, J= - the H of 2.0Hz, 1H, 4 '), 7.62 (brs, 1H, CONH), 7.48 (d, J=8.0Hz, 1H, 6-H), 7.37 (d, J=8.0Hz, 1H, 7 '-H), the 7.20 (- H of s, 1H, 2 '), the 7.13-7.07 (- H of dd, J=2.0,8.0Hz, 1H, 6 '), 7.01 (m, 2H, 4,5-2H), 6.73 (s, 1H, 2-H), 5.54 (brs, 1H, NH), 3.66 (q, J=6.8Hz, 2H, CH₂NH), 3.43 (s, 2H, CH₂), 3.38 (s, 3H, CH₃) 3.05 (t, J=6.8Hz, 2H, CH₂)。

(4) N- (2- (1H- indol-3-yls) ethyl) -3- chlorobenzamides (CD4)

It is (limited purchased from Beijing coupling science and technology with 3- chlorobenzoic acids with tryptamines (1.0g, 5mmol) by the method for synthesis (CD1) Company, purity ＞ 98%) (0.78g, 5mmol) reaction, it synthesizes and obtains CD04 sterlings 1.18g (yield 78%), MS (ESIm/z) 299.23(M+H)⁺。¹H NMR (400MHz, DMSO-d6) δ 10.80 (- NH of brs, 1H, 1 '), 8.34 (t, J=5.6Hz, 1H, CONH), the 7.58 (- H of d, J=8.0Hz, 1H, 4 '), the 7.34 (- H of d, J=8.0Hz, 1H, 7 '), 7.17 (d, J=2.4Hz, 1H, 2 '-H), 7.09-7.04 (m, 3H, 5 ', 6 ' -2H and2-H), 6.99 (td, J=1.2,7.6Hz, 1H, 5-H), 6.96 (d, J= 7.6Hz, 1H, 6-H), 6.68 (dd, J=1.2,7.6Hz, 1H, 4-H), 3.50 (q, J=7.2Hz, 2H, CH₂NH), 2.93 (t, J =7.2Hz, 2H, CH₂)。

(5) N- (2- (5- methoxyl group -1H- indol-3-yls) ethyl) -2- aminobenzamides (CD6)

By the method for synthesis (CD1), with 5- methoxytryptamines (purchased from this company of Adama, purity ＞ 98%) (0.95g, 5mmol) CD6 sterlings 0.57g (yield 37%) is obtained for reactant, white solid, mp105-107 DEG C.MS(ESIm/z) 310.18(M+H)⁺, 332.17 (M+Na)⁺, HRMS (ESIm/z) [M+H]⁺Theoretical molecular formula C₁₈H₂₀N₃O₂, theoretical molecular weight 310.1550 actual molecular weight 310.1549.¹H NMR (500MHz, DMSO-d6) δ 10.65 (- NH of s, 1H, 1 '), 8.31 (t, J =5.5Hz, 1H, CONH), 7.46 (d, J=8.0Hz, 1H, 6-H), 7.23 (d, J=8.0Hz, 1H, 3-H), 7.17-7.10 (m, 2H, 4 ', 7 ' -2H), the 7.07 (- H of d, J=2.5Hz, 1H, 2 '), 6.75-6.67 (m, 2H, 4,5-2H), 6.50 (t, J=7.5Hz, 1H, 6 '-H), 6.42 (brs, 2H, NH₂), 3.75 (s, 3H, CH₃O), 3.49 (q, J=7.0Hz, 2H, CH₂NH), 2.91 (t, J= 7.0Hz, 2H, CH₂)。

(6) N- (2- (the chloro- 1H- indol-3-yls of 5-) ethyl) -2- propionamido-s benzamide (CD8)

It is (pure purchased from uncommon love (Shanghai) the chemical conversion industry Development Co., Ltd of ladder with 5- chlorine tryptamines by the method for synthesis (CD1) Degree ＞ 98%) (0.97g, 5mmol) first obtain intermediate N (2- (the chloro- 1H- indol-3-yls of 5-) ethyl) -2- amino for raw material Benzamide, then this intermediate is dissolved in dry dichloromethane, it adds in triethylamine and (is purchased from Chinese medicines group chemical reagent Beijing Co., Ltd) 0.5mL, propionyl chloride (self-control) is added dropwise into above-mentioned solution, reacts at room temperature 4h, isolates and purifies to obtain CD8 sterlings 1.25g (yield 68%), MS (ESIm/z) 370.22 [M+H]⁺。¹H NMR (400MHz, DMSO-d6) δ 11.30 (s, 1H, 1 '- NH), 10.82 (s, 1H, CONH), 8.85 (t, J=5.75Hz, 1H, CH₂NH), 8.42 (dd, J=1.17,8.50Hz, 1H, 6- H), 7.69 (dd, J=1.52,8.02Hz, 1H, 3-H), the 7.58 (- H of d, J=7.79Hz, 1H, 4 '), 7.47 (td, J=1.46, 8.60Hz, 1H, 5-H), the 7.34 (- H of d, J=8.07Hz, 1H, 7 '), the 7.20 (- H of d, J=2.27Hz, 1H, 2 '), 7.16-6.94 (- the H of m, 2H, 6 ' and 4-H), 3.56 (q, J=7.44,2H, CH₂NH), 2.98 (t, J=7.43Hz, 2H, CH₂), 2.36 (q, J= 7.52Hz, 2H, CH₂), 1.12 (t, J=7.52Hz, 3H, CH₃)。

(7) N- (2- (1H- indoles -3-) ethyl) -2-N, TMSDMA N dimethylamine yl-benzamide (CD11)

By tryptamines (0.32g, 2mmol) and 2- (N, TMSDMA N dimethylamine base) benzoic acid (be coupled Science and Technology Ltd. purchased from Beijing, Purity ＞ 98%) (0.35g, 2mmol) be added to 30mL drying DCM in, add in EDCI hydrochlorides (0.42g, 2mmol), room Temperature reaction is overnight.Mixture is after washing and being dried with anhydrous sodium sulfate, with ethyl acetate: petroleum ether system is through silicagel column elution Obtain CD11 sterlings 88mg (yield 14%), white solid, mp132-134 DEG C.MS(ESIm/z)308.21(M+H)⁺, 330.17 (M+Na)⁺, HRMS (ESI m/z) [M+H]⁺Theoretical molecular formula C₁₉H₂₂ON₃, theoretical molecular weight 308.1757, actual molecular weight 308.1760。¹H NMR (500MHz, d6-dMSO) δ 10.87 (- NH of s, 1H, 1 '), 9.14 (t, J=5.41Hz, 1H, CONH), 7.67 (m, 1H, 6-H), the 7.61 (- H of d, J=8.0Hz, 1H, 4 '), 7.39-7.36 (m, 2H, 5-H and 7 '-H), 7.24 (d, J= - the H of 2.42Hz, 1H, 2 '), 7.13 (d, J=8.0Hz, 1H, 3-H), 7.09 (t, J=7.5Hz, 1H, 4-H), 7.05 (t, J= - the H of 7.5Hz, 1H, 6 '), the 6.99 (- H of t, J=7.5Hz, 1H, 5 '), 3.75-3.61 (m, 2H, CH₂), 2.98 (t, J=7.11Hz, 2H, CH₂), 2.48 (s, 6H, 2 × CH₃)。

(8) N- (2- (1H- indol-3-yls) ethyl) benzamide (CD12)

Tryptamines (0.48g, 3mmol) is added to 50mL flasks and is dissolved in the dichloromethane of 20mL dryings, chlorobenzoyl chloride (from System) (0.35mL, 3mmol) is added drop-wise in above-mentioned solution, crude product is obtained by the reaction.Using ethyl acetate/petroleum ether as eluant, eluent, warp The isolated product crude product of silica gel chromatographic column, then obtain CD18 sterlings 0.65g (yield 82%), mp141- through re-crystallizing in ethyl acetate 143℃。MS(ESI m/z)265.25(M+H)⁺, 287.19 (M+Na)⁺, HRMS (ESIm/z) [M+H]⁺Theoretical molecular formula C₁₇H₁₇N₂O, theoretical molecular weight 265.1335, actual molecular weight 265.1336.¹HNMR (400MHz, DMSO-d6) δ 10.79 (s, 1H, 1 '-H), 8.59 (t, J=5.6Hz, 1H, CONH), 7.84-7.82 (m, 2H, 2,6-2H), 7.58 (d, J=8.0Hz, 1H, 4 '-H), 7.49-7.43 (m, 3H, 3,4,5-3H), the 7.33 (- H of d, J=8.0Hz, 1H, 7 '), 7.17 (d, J=2.0Hz, 1H, 2 '-H), the 7.06 (- H of td, J=0.8,7.6Hz, 1H, 6 '), the 6.97 (- H of t, J=0.8,7.6Hz, 1H, 5 '), 3.56-3.51 (m, 2H, CH₂NH), 2.94 (t, J=7.6Hz, 2H, CH₂)。

(9) N- (2- (1H- indol-3-yls) ethyl) -2-Hydroxylbenzamide (CD13)

By the method for synthesis (CD12), crude product is obtained by the reaction for raw material with bigcatkin willow acyl chlorides (self-control) (1.5g, 10mmol), with Dichloromethane is eluant, eluent through the isolated Main Components of silicagel column, then with ether: petroleum ether crystallizes to obtain CD13 sterlings 1.63g (yield 58%), white solid, mp136-138 DEG C.MS(ESIm/z)281.19(M+H)⁺, 303.15 (M+Na)⁺, HRMS (ESIm/z)[M+H]⁺Theoretical molecular formula C₁₇H₁₇N₂O₂, theoretical molecular weight 281.1284, actual molecular weight 281.1284.¹HNMR (400MHz, CD₃OD) δ 7.64 (d, J=8.0Hz, 1H, 6-H), the 7.54 (- H of d, J=8.0Hz, 1H, 4 '), 7.31-7.26 (m, 2H, 2 ' 7 ' -2H), 7.04-7.00 (m, 2H, 5 ', 6 ' -2H), 6.93 (t, J=7.2Hz, 1H, 5-H), 6.83-6.78 (m, 2H, 3,4-2H), 3.62 (t, J=7.2Hz, 2H, CH₂NH), 3.00 (t, J=7.2Hz, 2H, CH₂)。

(10) N- (2-benzamide base) (1H) indole 2-carboxamides (CD15)

2- indolecarboxylic acids (being coupled Science and Technology Ltd., purity ＞ 98% purchased from Beijing) (0.80g, 5mmol) are added to In 50mL round-bottomed flasks, dry dichloromethane (30mL) is added in, EDCI hydrochlorides (1.04g, 5.4mmol) is continuously added, stirs It mixes and 2- aminobenzamides (0.68g, 5mmol) is added in after about 30min, react at room temperature 20h, filtering, washing and dry crude product. Filtrate is extracted with dichloromethane and is dried with anhydrous sodium sulfate.With ethyl acetate after organic layer concentration: petroleum ether=1: 3 be elution Agent obtains CD15 sterlings 0.86g (yield 62%) through silica gel chromatograph post separation, white solid, mp258-260 DEG C.MS(ESIm/z) 278(M-H)^-,¹H NMR (400MHz, DMSO-d6) δ 13.05 (- H of s, 1H, 1 '), 11.88 (s, 1H, CONH), 8.68 (d, J= 8.0Hz, 1H, 6-H), 8.43 (s, 1H, 4-H), 7.90 (dd, J=1.2,8.0Hz, 1H, 3-H), the 7.86 (- H of s, 1H, 3 '), The 7.70 (- H of d, J=8.0Hz, 1H, 4 '), 7.57 (td, J=1.2,8.0Hz, 1H, 5-H), 7.46 (d, J=8.0Hz, 1H, 7 '- H), the 7.23 (- H of t, J=7.6Hz, 1H, 6 '), the 7.16 (- H of t, J=7.6Hz, 1H, 5 '), 7.08 (m, 2H, NH₂)。

(11) N- benzyls -2- (1H- indol-3-yls) acetamide (CD16)

30mL dichloromethane is added in 50mL flasks, and sequentially adds indole-3-acetic acid (0.35g, 2mmol) and benzylamine (0.22mL, 2mmol) (is purchased from Beijing and is coupled Science and Technology Ltd., purity ＞ 98%) for reactant, adds EDCI hydrochloric acid Salt (0.4g, 2mmol) reacts and isolated CD16 sterlings 0.28g (yield 35.4%), mp149-151 DEG C.MS(ESIm/z) 265[M+H]⁺, HRMS (ESIm/z) [M+H]⁺Theoretical molecular formula C₁₇H₁₇N₂O, theoretical molecular weight 265.1335, actual molecular weight 265.1335。¹H NMR (400MHz, DMSO-d6) δ 10.87 (brs, 1H, 1-NH), 8.38 (brs, 1H, CONH), 7.55 (d, J =8.0Hz, 1H, 4-H), 7.34 (d, J=8.0Hz, 1H, 7-H), 7.29 (m, 2H, 2 ', 6 ' -2H), 7.24-7.20 (m, 4H, 2- H and 3 ', 4 ', 5 ' -3H), 7.07 (t, J=7.2Hz, 1H, 6-H), 6.97 (t, J=7.2Hz, 1H, 5-H), 4.27 (d, J= 6.0Hz, 2H, CH₂NH), 3.58 (s, 2H, CH₂)。

(12) N- (2- (2- carboxaldehyde radicals -1H- indol-3-yls) ethyl)-benzamide (CD17)

With 3,4- dihydros-B-carboline (self-control) (0.26g, 1.5mmol) for raw material, it is suspended in the dichloro of 20mL dryings In methane, chlorobenzoyl chloride (0.4mL, 3.4mmol) is added in, adds triethylamine (0.4mL, 3mmol), 3h is reacted at room temperature, adds water 30mL adjusts pH value to neutrality, and dichloromethane is extracted and dried with anhydrous sodium sulfate.Crude product ethyl acetate: petroleum ether=1: 1 warp Silica gel chromatographic column affords CD17 sterlings 0.82g (yield 82%), mp275-277 DEG C.MS(ESIm/z)293.22(M+H)⁺, 315.21(M+Na)⁺。¹H NMR (400MHz, CDCl₃) the δ 10.01 (- CHO of s, 1H, 2 '), the 8.83 (- NH of s, 1H, 1 '), 7.81 (d, - the H of J=8.0Hz, 1H, 4 '), 7.66 (dd, J=1.2,7.2Hz, 2H, 5 ', 7 ' -2H), 7.50-7.38 (m, 5H, Ph-H), The 7.20-7.15 (- H of m, 1H, 5 '), 6.25 (s, 1H, CONH), 3.83 (q, J=6.8Hz, 2H, CH₂NH), 3.47 (t, J= 6.8Hz, 2H, CH₂)。

(13) N- (2- (1H- indol-3-yls) ethyl) -2- methyl benzamides (CD18)

By the method for synthesis (CD12), produced with 2- methyl benzoyl chlorides (self-control) (0.34g, 2.2mmol) for raw material Object crude product.Crude product is using ethyl acetate: petroleum ether is eluant, eluent, through the isolated CD18 sterlings 0.32g (yield 58%) of silicagel column, White solid, mp159-161 DEG C.MS(ESIm/z)301.18(M+Na)⁺, HRMS (ESIm/z) [M+H]⁺Theoretical molecular formula C₁₈H₁₉N₂O, theoretical molecular weight 279.1492, actual molecular weight 279.1493.¹H NMR (400MHz, CD₃COCD₃) δ 9.99 (s, 1H, 1 '-NH), the 7.65 (- H of d, J=8.0Hz, 1H, 4 '), 7.37 (d, J=8.0Hz, 1H, 6-H), 7.32 (d, J=7.2Hz, 1H, 7 '-H), 7.28-7.12 (m, 4H, 3,4,5-3H and 7 '-H), the 7.09 (- H of td, J=0.8,7.6Hz, 1H, 6 '), 7.01 (- the H of td, J=0.8,7.6Hz, 1H, 5 '), 3.69 (q, J=7.2Hz, 2H, CH₂NH), 3.08 (t, J=7.2Hz, 2H, CH₂), 2.37 (s, 3H, CH₃)。

(14) N- (2- (1H- indol-3-yls) ethyl) niacinamide (CD19)

Niacin (being coupled Science and Technology Ltd., purity ＞ 98% purchased from Beijing) (0.85g, 7mmol) is dissolved in 30mLN, N- bis- In methylformamide solution, EDCI hydrochlorides (1.41g, 7mmol) and tryptamines (1.12g, 7mmol) are added in, 60 DEG C are reacted 20h, Finally obtain CD19 sterlings 1.34g (yield 84.3%), mp104-105 DEG C.MS(ESIm/z)266.73(M+H)⁺, 388.46 (M +Na)⁺, HRMS (ESIm/z) [M+H]⁺Theoretical molecular formula C₁₆H₁₆N₃O, theoretical molecular weight 266.1288, actual molecular weight 266.1287。¹H NMR (500MHz, DMSO-d6) δ 10.85 (- H of s, 1H, 1 '), 9.13 (d, J=1.5Hz, 1H, 2-H), 9.04 (t, J=5.5Hz, 1H, CONH), 8.85 (d, J=5.0Hz, 1H, 6-H), 8.50 (d, J=8.0Hz, 1H, 4-H), 7.79 (dd, J=5.0,8.0Hz, 1H, 5-H), the 7.59 (- H of d, J=8.0Hz, 1H, 4 '), the 7.36 (- H of d, J=8.0Hz, 1H, 7 '), 7.21 (- the H of d, J=2.0Hz, 1H, 2 '), the 7.08 (- H of t, J=7.5Hz, 1H, 6 '), the 6.99 (- H of t, J=7.5Hz, 1H, 5 '), 3.59 (td, J=5.5,7.5Hz, 2H, CH₂NH), 2.99 (t, J=7.5Hz, 2H, CH₂)。

(15) N- (2- (2- acetyl group -1H- indol-3-yls) ethyl) niacinamide (CD21)

1- methyl -3,4- dihydro-B-carboline (self-control) (0.74g, 4mmol) is dissolved in 30mL pyridines, adds in nicotinoyl villaumite Hydrochlorate (1.41g, 8mmol), 60 DEG C of reaction 5h adjust pH value to 10 or so with 25% ammonium hydroxide, and dichloromethane extracts and washes, satisfies It is washed with common salt aqueous solution, organic layer concentrates after being dried with anhydrous sodium sulfate, and crude product elutes gluey through ethyl acetate (triethylamine) Object obtains CD20 sterlings 0.25g (yield 21%) after dichloromethane processing, mp155-156 DEG C.MS(ESIm/z)294.08(M+ H)⁺,¹H NMR (400MHz, CD₃COCD₃) the δ 10.06 (- CHO of s, 1H, 2 '), 8.97 (d, 1H, J=1.6Hz, 2-H), 8.66 (dd, 1H, J=1.6,4.8Hz, 4-H), 8.13 (td, 2H, J=2.0,8.0Hz, 6-H), 7.86 (d, 1H, J=8.0Hz, 4 '- H), the 7.51 (- H of d, 1H, J=8.0Hz, 7 '), 7.42 (m, 1H, 5-H), the 7.35 (- H of td, 1H, J=0.8,8.0Hz, 6 '), 7.11 (- the H of td, 1H, J=0.8,8.0Hz, 5 '), 3.76 (q, 2H, J=6.8Hz, CH₂NH), 3.48 (t, 2H, J=6.8Hz, CH₂)。

(16) 4- (N- (2- (1H- indol-3-yls) ethyl) -3- aminopyridines formamides (CD22)

By the method for synthesis (CD1), with 3- amino-Isonicotinic acid (purchased from this company of Adama, purity ＞ 99%) (0.28g, 2mmol) obtains crude product, and using ethyl acetate as eluant, eluent for reactant, and CD22 sterlings are obtained through silica gel post separation 0.15g (yield 28%), mp104-105 DEG C, MS (ESI m/z) 281.13 [M+H]⁺。¹H NMR (400MHz, DMSO-d6) The 10.87 (- H of s, 1H, 1 '), 8.84 (m, 1H, CONH), 8.18 (s, 1H, 2-H), 7.84 (d, J=5.6Hz, 1H, 5-H), 7.58 (- the H of d, J=7.6Hz, 1H, 4 '), 7.53 (d, J=5.6Hz, 1H, 6-H), the 7.36-7.33 (- H of m, 1H, 7 '), 7.19 (d, J= - the H of 2.4Hz, 1H, 2 '), the 7.07 (- H of td, J=1.2,7.2Hz, 1H, 6 '), the 6.98 (- H of td, J=1.2,7.2Hz, 1H, 5 '), 6.72 (brs, 2H, NH₂), 3.39-3.37 (m, 2H, CH₂NH), 3.09-3.03 (m, 2H, CH₂)。

(17) 2- (N- (2- (1H- indoles -3-) ethyl) carbamyl) benzoic acid (CD25)

Tryptamines (0.8g, 5mmol) is dissolved in 50mL absolute ethyl alcohols, adds in phthalic anhydride (purchased from Chinese medicines group chemistry Reagent Beijing Co., Ltd, purity ＞ 98%) (0.75g, 5mmol) back flow reaction 1h, crystallisation by cooling obtains solid, recrystallizing methanol CD25 sterlings 1.7g (yield 90%), mp163-164 DEG C.MS(ESIm/z)308.75(M+H)⁺, 330.68 (M+Na)⁺。¹H NMR (500MHz, DMSO-d6) δ 10.83 (- NH of s, 1H, 1 '), 7.89-7.83 (m, 4H, Ph-H), 7.56 (d, J=8.0Hz, 1H, 4 '-H), the 7.34 (- H of d, J=8.0Hz, 1H, 7 '), the 7.19 (- H of d, J=2.0Hz, 1H, 2 '), 7.07 (td, J=1.0, - the H of 7.5Hz, 1H, 6 '), the 6.98 (- H of td, J=1.0,7.5Hz, 1H, 5 '), 3.86 (t, J=7.5Hz, 2H, CH₂NH), 3.04 (t, J=7.5Hz, 2H, CH₂)。

(18) N- (2- (1H- indol-3-yls) ethyl) -2- phenoxy-acetamides (CD27)

Phenoxy acetic acid (being coupled Science and Technology Ltd., purity ＞ 98% purchased from Beijing) (0.31g, 2mmol) is dissolved in N, N- bis- In methylformamide (15mL), add in EDCI hydrochlorides (0.4g, 2mmol) react about 30min after, add tryptamines (0.32g, 6h 2mmol) is reacted, decompression steams solvent, and ethyl acetate extracts after adding water 30mL, and organic layer is dried with anhydrous sodium sulfate.It is organic Crude product handles to obtain CD27 sterlings 0.42g (yield 71%) with dichloromethane after layer concentration, mp137-139 DEG C.MS(ESI m/z) 295.29[M+H]⁺, 317.29 [M+Na]⁺, HRMS (ESI m/z) [M+H]⁺Theoretical molecular formula C₁₈H₁₉N₂O₂, theoretical molecular weight 295.1441 actual molecular weight 295.1440.¹H NMR (400MHz, DMSO-d6) δ 10.82 (- NH of s, 1H, 1 '), 8.17 (t, J =5.6Hz, 1H, CONH), the 7.56 (- H of d, J=8.0Hz, 1H, 4 '), the 7.34 (- H of d, J=8.0Hz, 1H, 7 '), 7.31 (dt, J =8.0Hz, 2H, Ph-2H), the 7.14 (- H of d, J=2.0Hz, 1H, 2 '), the 7.07 (- H of dt, J=8.0Hz, 1H, 6 '), 7.00- The 6.94 (- H of m, 4H, 5 ' and Ph-3H), 4.47 (s, 2H, CH₂O), 3.43 (q, J=7.2Hz, 2H, CH₂NH), 2.87 (t, J= 8.0Hz, 2H, CH₂)。

(19) (2- (1H- indol-3-yls) ethyl) phenyl carbamate (CD28)

By the method for synthesis (CD12), with phenyl chloroformate (being coupled Science and Technology Ltd., purity ＞ 98% purchased from Beijing) (0.26mL, 2mmol) obtains crude product for reactant, and crude product is using ethyl acetate: petroleum ether is isolated through silicagel column as eluant, eluent Main Components, then crystallize to obtain CD28 sterlings 174mg (yield 31%) with ether/petroleum ether, mp63-65 DEG C.HRMS(ESIm/z) [M+H]⁺Theoretical molecular formula C₁₇H₁₇N₂O₂, theoretical molecular weight 281.1284, actual molecular weight found 281.1284.¹H NMR (400MHz, DMSO-d6) δ 10.84 (- NH of brs, 1H, 1 '), 7.86 (t, J=5.6Hz, 1H, CONH), 7.56 (d, J= - the H of 7.6Hz, 1H, 4 '), 7.40-7.34 (m, 3H, 2,6-2H and 7 '-H), 7.22-7.14 (m, 2H, 2 ', 4-2H), 7.10-7.06 (- the H of m, 3H, 6 ' and 3,5-2H), the 6.99 (- H of t, J=7.2Hz, 1H, 5 '), 3.38-3.33 (m, 2H, CH₂NH), 2.91 (t, J= 7.2Hz, 2H, CH₂)。

(20) N- (2- (1H- indol-3-yls) ethyl) quinoline -3- formamides (CD31)

Quinoline-3-carboxylic acid (being coupled Science and Technology Ltd., purity ＞ 98% purchased from Beijing) (0.35g, 2mmol) is dissolved in DMF (15mL) after adding in EDCI hydrochlorides (0.45g, 2.3mmol) reaction 30min, adds in tryptamines (0.32g, 2mmol), at 100 DEG C Reaction overnight, steams solvent, and DCM is extracted, then through ethyl acetate after adding water: petroleum ether obtains CD31 sterlings after crossing post separation 0.41g (yield 65%), mp107-109 DEG C.MS(ESIm/z)316.15[M+H]⁺。¹H NMR (400MHz, DMSO-d6) δ The 10.87 (- H of s, 1H, 1 '), 9.16 (d, J=4.0Hz, 1H, CONH), 9.11 (s, 1H, 2-H), 8.88 (d, J=5.2Hz, 2H, 5,6-2H), 8.57 (s, 1H, 4-H), 7.85 (d, J=4.8Hz, 2H, 7,8-2H), the 7.58 (- H of d, J=8.0Hz, 1H, 4 '), The 7.35 (- H of d, J=8.0Hz, 1H, 7 '), the 7.21 (- H of d, J=2.0Hz, 1H, 2 '), 7.07 (td, J=1.2,8.0Hz, 1H, 6 '- H), the 6.98 (- H of td, J=0.8,8.0Hz, 1H, 5 '), 3.59 (q, J=7.2Hz, 2H, CH₂NH), 2.99 (t, J=7.2Hz, 2H, CH₂)。

(21) 5- acetyl group-N- (2- (1H- indol-3-yls) ethyl) quinoline -3- formamides (CD33)

By the method for synthesis (CD31), with 5- acetylquinoline -3- carboxylic acids (purchased from this company of Adama, purity ＞ 98%) (0.43g, 2mmol) is raw material, and target product CD33 sterlings 0.56g (yield 79%), MS is obtained by the reaction with equimolar tryptamines (ESIm/z)358.19[M+H]⁺。¹H NMR (400MHz, DMSO-d6) δ 10.87 (- H of s, 1H, 1 '), 9.16 (d, J=4.0Hz, 1H, CONH), 9.11 (s, 1H, 2-H), 8.88 (d, J=5.2Hz, 1H, 6-H), 8.57 (s, 1H, 4-H), 7.85 (d, J= 4.8Hz, 2H, 7,8-2H), the 7.58 (- H of d, J=8.0Hz, 1H, 4 '), the 7.35 (- H of d, J=8.0Hz, 1H, 7 '), 7.21 (d, J= - the H of 2.0Hz, 1H, 2 '), the 7.07 (- H of td, J=1.2,8.0Hz, 1H, 6 '), the 6.98 (- H of td, J=0.8,8.0Hz, 1H, 5 '), 3.59 (q, J=7.2Hz, 2H, CH₂NH), 3.25 (s, 3H, CH₃), 2.99 (t, J=7.2Hz, 2H, CH₂)。

(22) 7- methyl-N- (2- (1H- indol-3-yls) ethyl) quinoline -3- formamides (CD35)

By the method for synthesis (CD31), Science and Technology Ltd., purity (are coupled purchased from Beijing with 7- methylquinoline -3- carboxylic acids ＞ 98%) (0.37g, 2mmol) be raw material, target product CD35 sterling 0.50g (yields are obtained by the reaction with equimolar tryptamines 76%), MS (ESIm/z) 330.21 [M+H]⁺。¹H NMR (400MHz, DMSO-d6) δ 10.87 (- H of s, 1H, 1 '), 9.16 (d, J =4.0Hz, 1H, CONH), 9.11 (s, 1H, 2-H), 8.88 (d, J=5.2Hz, 2H, 5,6-2H), 8.57 (s, 1H, 4-H), 7.85 (d, J=4.8Hz, 1H, 8-H), the 7.58 (- H of d, J=8.0Hz, 1H, 4 '), the 7.35 (- H of d, J=8.0Hz, 1H, 7 '), The 7.21 (- H of d, J=2.0Hz, 1H, 2 '), the 7.07 (- H of td, J=1.2,8.0Hz, 1H, 6 '), 6.98 (td, J=0.8,8.0Hz, 1H, 5 '-H), 3.59 (q, J=7.2Hz, 2H, CH₂NH), 2.99 (t, J=7.2Hz, 2H, CH₂), 1.23 (s, 3H, CH₃)。

(23) N- (2- (1H- indol-3-yls) ethyl) -2- (2- bromines propionamido-) benzamide (CD36)

CD1 (0.28g, 1mmol) is dissolved in dichloromethane (20mL), under ice-water bath, equimolar 2- bromines third are added dropwise The dichloromethane solution of acyl chlorides (self-control), finishes, and reacts at room temperature 4h, adds water and with saturation NaHCO₃Solution tune pH value is to alkalescent (7-8) is extracted and is dried with anhydrous sodium sulfate, CD36 sterlings 0.15g (yield 36.6%) is obtained after silica gel column chromatography detaches, mp165-166℃。MS(ESIm/z)414.09[M+H]⁺, 436.06 [M+Na]⁺。¹H NMR (500MHz, DMSO-d6) δ 11.95 (s, 1H, 1-NH), 11.81 (d, J=5.0Hz, 1H, CONH), 10.83 (s, 1H, CONH), 8.92 (t, J=5.5Hz, 1H, CH₂NH), 8.38 (dd, 1H, J=8.5Hz, 6-H), 7.74 (d, J=7.5Hz, 1H, 3-H), 7.59 (d, J=8.0Hz, 1H, 4 '-H), 7.53 (t, J=7.5Hz, 1H, 5-H), the 7.36 (- H of d, J=8.0Hz, 1H, 7 '), 7.22-7.18 (m, 2H, 2 ', 4- H), the 7.08 (- H of t, J=7.5Hz, 1H, 6 '), the 6.99 (- H of t, J=7.5Hz, 1H, 5 '), 4.84-4.79 (m, 1H, CH-Br), 3.57 (q, J=7.5Hz, 2H, CH₂), 2.99 (t, J=7.5Hz, 2H, CH₂) 1.80 (d, J=6.7Hz, 1.5H), 1.7 (d, J= 6.7Hz, 1.5H).

(24) N- (2- (1H- indol-3-yls) ethyl) -2- chloroacetamides yl-benzamide (CD38)

By the synthetic method of (CD36), Science and Technology Ltd., purity ＞ (are coupled purchased from Beijing with equimolar chloracetyl chloride 98%) crude product is reacted to obtain with CD1 (0.28g, 1mmol), CD38 sterling 143mg (yields is obtained after silica gel column chromatography detaches 40%), mp158-159 DEG C.MS(ESIm/z)356.15[M+H]⁺, 378.21 [M+Na]⁺。¹H NMR (400MHz, DMSO-d6) δ The 11.94 (- NH of s, 1H, 1 '), 10.83 (s, 1H, 2-NH), 8.91 (s, 1H, NH-CH₂), 8.42 (d, J=8.0Hz, 1H, 6-H), 7.73 (d, J=8.0Hz, 1H, 3-H), the 7.59 (- H of d, J=8.0Hz, 1H, 4 '), 7.53 (t, J=8.0Hz, 1H, 4-H), 7.35 (- the H of d, J=8.0Hz, 1H, 7 '), 7.19 (m, 2H, 2 ', 5-2H), the 7.07 (- H of t, J=7.2Hz, 1H, 6 '), 6.98 (t, J= - the H of 7.2Hz, 1H, 5 '), 4.41 (s, 2H, CH₂- Cl), 3.57 (q, J=6.4Hz, 2H, CH₂- NH), 2.99 (t, J=6.8Hz, 2H, CH₂)。

(25) N- (2- (1H- indol-3-yls) ethyl) -2- propionamido-s benzamide (CD40)

By the synthetic method of (CD36), product is obtained by the reaction with CD1 (0.28g, 1mmol) and equimolar propionyl chloride (self-control) Crude product, obtains sterling CD40 sterlings 0.10g (yield 30%) after silica gel column chromatography detaches, mp123-124 DEG C, MS (ESIm/z) 336.22[M+H]⁺, 358.19 [M+Na]⁺.HRMS(ESIm/z)[M+H]⁺Theoretical molecular formula C₂₀H₂₂N₃O₂, theoretical molecular weight 336.1706 actual molecular weight 336.1706.¹H NMR (400MHz, DMSO-d6) δ 11.30 (- NH of s, 1H, 1 '), 10.82 (s, 1H, CONH), 8.85 (t, J=5.75Hz, 1H, CH₂NH), 8.42 (dd, J=1.17,8.50Hz, 1H, 6-H), 7.69 (dd, J =1.52,8.02Hz, 1H, 3-H), the 7.58 (- H of d, J=7.79Hz, 1H, 4 '), 7.47 (td, J=1.46,8.60Hz, 1H, 5- H), the 7.34 (- H of d, J=8.07Hz, 1H, 7 '), the 7.20 (- H of d, J=2.27Hz, 1H, 2 '), 7.16-6.94 (the 6 ' -2H of m, 3H, 5 ' And 4-H), 3.56 (q, J=7.44,2H, CH₂NH), 2.98 (t, J=7.43Hz, 2H, CH₂), 2.36 (q, J=7.52Hz, 2H, CH₂), 1.12 (t, J=7.52Hz, 3H, CH₃)。

(26) N- (2- (1H- indol-3-yls) ethyl) -2- trifluoroacetamides yl-benzamide (CD43)

By the synthetic method of (CD27), with trifluoroacetic acid (purchased from Sigma-Aldrich, purity ＞ 99%) 0.1mL It synthesizes to obtain crude product for reactant with CD1 (0.31g, 1.1mmol), CD43 sterlings 0.13g (productions is obtained through silica gel chromatograph column purification Rate 32%), mp160-161 DEG C, MS (ESI m/z) 376.20 (M+H)⁺, 398.22 (M+Na)⁺, HRMS (ESI m/z) [M+H]⁺ Theoretical molecular formula C₁₉H₁₇N₃O₂F₃, theoretical molecular weight 376.1267, actual molecular weight 376.1266.¹HNMR (400MHz, CD₃COCD₃) the δ 13.47 (- NH of brs, 1H, 1 '), 10.02 (brs, 1H, CONH), 8.55 (d, J=8.0Hz, 1H, 6-H), 8.39 (s, 1H, CH₂NH), 7.86 (d, J=8.0Hz, 1H, 3-H), the 7.62 (- H of d, J=8.0Hz, 1H, 4 '), 7.60 (t, J= 8.0Hz, 1H, 5-H), the 7.38 (- H of d, J=8.0Hz, 1H, 7 '), 7.25 (t, J=8.0Hz, 1H, 4-H), 7.22 (d, J= - the H of 1.6Hz, 1H, 2 '), the 7.09 (- H of t, J=7.6Hz, 1H, 6 '), the 7.00 (- H of t, J=7.6Hz, 1H, 5 '), 3.75 (q, J= 6.8Hz, 2H, CH₂NH), 3.11 (t, J=6.8Hz, 2H, CH₂)。

(27) N- (2- (3- hydroxy phenyls) ethyl) -2- propionamido-s benzamide (BCD1)

2- aminoethyl phenols (being coupled Science and Technology Ltd., purity ＞ 98% purchased from Beijing) (0.68g, 5mmol) and 2- Aminobenzoic acid (0.68g, 5mmol) is added to 30mLN, in dinethylformamide, add EDCI hydrochlorides (1.02g, 5mmol), for 24 hours, decompression steams solvent for room temperature reaction, and water is added to have a solid precipitation, filters and dry intermediate.Intermediate is molten In the dichloromethane of 30mL dryings, triethylamine 0.5mL is added in, propionyl chloride is added dropwise to above-mentioned solution, and after reacting at room temperature 4h Reason obtains BCD1 sterlings 1.1g (yield 71%), MS (ESI m/z) 313.23 (M+H)⁺。¹HNMR (400MHz, CD₃COCD₃)δ 10.52 (brs, 1H, CONH), 8.65 (s, 1H, OH), 7.56 (brs, 1H, CONH), 7.42 (dd, J=1.6,8.0Hz, 1H, 6- H), 7.42-7.13 (m, 4H, Ph-4H), 7.11 (td, J=1.6,8.0Hz, 1H, 5-H), 6.73 (d, 1H, J=8.0Hz, 3- H), 6.49 (t, J=8.0Hz, 1H, 4-H), 3.59 (q, J=7.2Hz, 2H, CH₂NH), 3.38 (q, J=7.5Hz, 2H, CH₂- CH₃), 2.91 (t, J=7.2Hz, 2H, CH₂), 1.67 (t, J=7.2Hz, 3H, CH₃)。

(28) N- (2- phenylethyls) -2- aminobenzamides (BCD3)

It is in the presence of EDCI hydrochlorides (1.02g, 5mmol), phenyl ethylamine is (pure purchased from Beijing coupling Science and Technology Ltd. Degree ＞ 98%) (0.61g, 5mmol) react in methylene chloride with equimolar 2- aminobenzoic acids, BCD1 sterlings are obtained after processing 0.90g (yield 75%), white solid, mp92-94 DEG C.MS(ESIm/z)241.53(M+H)⁺, 263.39 (M+Na)⁺, HRMS (ESI m/z)[M+H]⁺Theoretical molecular formula C₁₅H₁₇N₂O, theoretical molecular weight 241.1335, actual molecular weight 241.1334.¹H NMR (400MHz, CD₃COCD₃) δ 7.56 (brs, 1H, CONH), 7.42 (dd, J=1.6,8.0Hz, 1H, 6-H), 7.42-7.13 (m, 5H, Ph-5H), 7.11 (td, J=1.6,8.0Hz, 1H, 5-H), 6.73 (d, 1H, J=8.0Hz, 3-H), 6.49 (t, J= 8.0Hz, 1H, 4-H), 6.20 (brs, 2H, 2-NH₂), 3.59 (q, J=7.2Hz, 2H, CH₂NH), 2.91 (t, J=7.2Hz, 2H, CH₂)。

(29) N- (2- phenylethyls) -2-Hydroxylbenzamide (BCD4)

Phenyl ethylamine (1.2mL, 10mol) and o-hydroxy formyl chloride (self-control) (1.5g, 10mmol) are dissolved in dichloromethane In (40mL), triethylamine 2mL is added in, room temperature reaction overnight, stops reaction.Dichloromethane is extracted and is dried with anhydrous sodium sulfate Afterwards, crude product dichloromethane crystallizes to obtain BCD2 sterling 1.58g (yields through silicagel column elution winner component, then with ether/petroleum ether 66%), white solid, mp90-92 DEG C.MS(ESIm/z)242.20(M+H)⁺, 264.17 (M+Na)⁺, HRMS (ESI) [M+H]⁺ Theoretical molecular formula C₁₅H₁₆NO₂, theoretical molecular weight 242.1176, actual molecular weight 242.1175.¹H NMR (400MHz, CD₃OD)δ 7.64 (d, J=8.0Hz, 1H, 6-H), 7.30 (t, J=8.0Hz, 1H, 5-H), 7.32-7.12 (m, 4H, Ph-5H), 6.81 (m, 2H, 3,4-2H), 3.55 (t, J=7.2Hz, 2H, CH₂NH), 2.86 (t, J=7.2Hz, 2H, CH₂)。

(30) N- (2- (3- acetylphenyls) ethyl) -2- propionamido-s benzamide (BCD5)

By the method for synthesis (BCD1), Science and Technology Ltd., purity ＞ (are coupled purchased from Beijing with 3- amino-ethyls acetophenone 98%) (0.81g, 5mmol) is reacted for raw material, and BCD5 sterlings 1.3g (yield 76%), MS (ESI are finally obtained through isolating and purifying m/z)339.23(M+H)⁺,¹H NMR (400MHz, CD₃COCD₃) δ 10.52 (brs, 1H, CONH), 7.56 (brs, 1H, CONH), 7.42 (dd, J=1.6,8.0Hz, 1H, 6-H), 7.42-7.13 (m, 4H, Ph-4H), 7.11 (td, J=1.6,8.0Hz, 1H, 5- H), 6.73 (d, 1H, J=8.0Hz, 3-H), 6.49 (t, J=8.0Hz, 1H, 4-H), 3.59 (q, J=7.2Hz, 2H, CH₂NH), 3.45 (q, J=7.5Hz, 2H, CH₂-CH₃), 2.91 (t, J=7.2Hz, 2H, CH₂), 1.25 (t, J=7.2Hz, 3H, CH₃)。

Embodiment 2：Compound is to the activity of adjustment screening model on ABCA1

ABCA1p-LUC HepG2 cells are obtained from new drug (the micro- life of country of Inst. of Medicinal Biological Technology, Chinese Academy of Medical Sciences Object) laboratory.It can be found in the article Identification of Up- of such as Jie Gao et al. to the processing procedure of the cell regulators of Human ATP-binding Cassette Transporter Al via High-throughput Screening of Synthetic and Natural Compound Library are (by high flux screening synthesis and naturally Product library is come on finder ABCA1 to adjust) .J Biomol Screen.2008,13 (7)：648-656 and noble and unsullied doctor Paper " structure and application study using ABCA1 as the novel Antiatherosclerosis medicine screening model of target spot ".

By ABCA1-LUC HepG2 cells, with 5 × 10⁴A/hole is inoculated in 96 porocyte culture plates, and about 6h treats cell After adherent, it is changed to a series of serum-free RPMI-1640 culture mediums of the compounds of this invention containing diluted concentrations respectively (Hyclone) (200 μ l/ holes).The hole of final concentration 0.1%DMSO culture mediums is as blank control.37 DEG C are continued at, 5%CO2 items After cultivating 18-24h under part, PBS (200 μ l/ holes) board-washing 2 times abandons PBS.Add in cell pyrolysis liquid (CCLR, Promega) (20 μ L/ holes), after 15-30min, after micro- Microscopic observation cell cracking is complete, luciferase (Promega) (60 μ l/ holes) is added in, is stood Measure uciferase activity (microplate reader, EnVision, PerkinElmer) reading), analysis sample concentration and fluorescein enzyme activity Property rate of change between dose-effect relationship, calculate EC50.

Rate of change of the sample to be tested to uciferase activity is calculated with equation below：

Regulation rate (%)=A/B × 100

Wherein, A is to add in the cell fluorescence element enzymatic activity (RLU) measured after sample to be tested, and B is adds in blank control sample (DMSO) the cell fluorescence element enzymatic activity (RLU) measured afterwards.Regulation rate >=150% of sample to be tested is considered as the positive, and see Examine influence of the positive to cell state.

EC50 is calculated using GraphPad Prim5 softwares, as a result such as the following table 2.From Table 2, it can be seen that in ABCA1p- In LUC HepG2 cells, the compound of the present invention has the activity of different degrees of up-regulation ABCA1.This also illustrates the present invention's Compound can increase the expression of ABCA1, and ABCA1 high expression can just promote to arrange outside the lipids such as cholesterol, be conducive to treatment and/or Prevent the cardiovascular and cerebrovascular diseases such as hyperlipidemia and atherosclerosis.

Embodiment 3：Compound is to the activity of adjustment screening model on SR-BI/CLA1

It is real that CLAp-LUC HepG2 are obtained from country of Inst. of Medicinal Biological Technology, Chinese Academy of Medical Sciences new drug (microorganism) Test room.It can be found in the article Identification of Novel of such as Yuan Yang et al. to the processing procedure of the cell Human High-Density Lipoprotein Receptor Up-regulators Using a Cell-Based High-Throughput Screening Assay (using based on cell high flux screening experiment find high-density lipoprotein by Adjusted on body) .J Biomol Screen2007,12 (2)：The doctoral thesis of 211-219 and Yang Yuan is " microbe-derived highly dense Screening, discovery and the related activity research adjusted on degree lipoprotein receptor ".

By CLAp-LUC HepG2 cells, with 5 × 10⁴A cells/well is inoculated in 96 porocyte culture plates, treats that cell pastes After wall about 6 hours, it is changed to a series of serum-free MEM-EBSS culture mediums (200 μ of the compounds of this invention containing diluted concentrations respectively L/ holes).Final concentration of 0.1% of DMSO in each hole is kept, separately sets the hole of final concentration of 0.1%DMSO culture mediums as blank pair According to.37 DEG C are continued at, after being cultivated 18 hours under the conditions of 5%CO2, PBS (200 μ l/ holes) board-washing 2 times abandons PBS.Cell is added in split Liquid (20 μ l/ holes) (Promega) is solved, after 15-30min, after micro- Microscopic observation cell is split completely, adds in luciferase (60 μ l/ Hole), uciferase activity (microplate reader reading) is measured immediately, is analyzed between sample concentration and the rate of change of uciferase activity Dose-effect relationship calculates EC50.

Regulation rate (%)=A/B × 100

EC50 is calculated using GraphPad Prim5 softwares, as a result such as the following table 2.From Table 2, it can be seen that the change of the present invention Closing object has the activity of up-regulation SR-BI/CLA-1 in various degree.It is good that this illustrates that the compound has SR-BI/CLA-1 Up-regulation acts on, it will increase the expression of SR-BI/CLA-1, and SR-BI/CLA-1 high expression can promote to arrange outside the lipids such as cholesterol, Be conducive to treat and/or prevent hyperlipidemia and the cardiovascular and cerebrovascular diseases such as atherosclerosis.

Table 2：Compound is to the Activity Results of adjustment model on ABCA1 and SR-BI/CLA-1

Embodiment 4：Compound is to the agonist activity of PPARs, LXRs

PPARs includes PPAR γ, PPAR α, and LXRs includes LXR α, LXR β.There are two main structural domains by PPARs, LXRs： Ligand binding domains (LBD) and DNA binding structural domains (DBD), each has the function of independent.

The PPAR gamma agonist models built using this room are thin by the ligand binding domains (LBD) and yeast of PPAR γ The DNA binding structural domains (DBD) of born of the same parents' transcription factor GAL4 are built into fusion expression vector pBIND-PPAR γ-LBD.It is artificial synthesized The respective element of 5 × GAL4 is inserted into reporter gene upstream structure reporter plasmid pG5-promotor-GAL4 (abbreviation GAL4).Together Reason, constructs pBIND-PPAR α-LBD, pBIND-LXR α-LBD, pBIND-LXR β-LBD.

PBIND-PPAR γ-LBD, PPAR α-LBD, pBIND-LXR α-LBD, pBIND-LXR β-LBD, GAL4 plasmids, with And PPAR γ, PPAR α, LXR α, LXR beta-agonists models are all obtained from country of Inst. of Medicinal Biological Technology, Chinese Academy of Medical Sciences New drug (microorganism) laboratory, wherein plasmid construction process and the processing procedure of cell can be found in Zheng Zhihui, Li Ni doctor opinion Text, such as Zheng Zhihui doctoral thesis " drug screening of metabolic disease correlation nuclear receptor, the foundation of appraisement system and reactive compound Pharmaceutical research ", Li Ni doctoral thesis " targeting liver X receptor novel Antiatherosclerosis medicine primer discovery with Molecular pharmacology research ".

GAL4 reporter plasmids respectively with the recombinant plasmid pBIND-PPAR γ-LBD of structure, pBIND-PPAR α-LBD, PBIND-LXR α-LBD, pBIND-LXR β-LBD are through Lipofectamine^TM2000 (Invitrogen) mediation cotransfections HepG2 Cell, 5 × 10⁴A cells/well (96 orifice plate), 200ng Plasmid DNA (reporter plasmid GAL4 and expression plasmid pBIND-PPAR γ- The ratio of LBD etc. is 10: 1), 0.5 μ l liposomes/hole are changed to a series of the compounds of this invention containing diluted concentrations after transfecting 6h Serum-free MEM culture mediums (200 μ l/ holes), continue be incubated 18h, blank control add in contain and sample to be tested same concentrations DMSO MEM culture mediums.Measure uciferase activity in the HepG2 cells transiently transfected.Sample to be tested changes uciferase activity The determinand added in rate indirect reaction cell to PPAR γ, PPAR α, LXR α, LXR β transcriptional activation activity, with as follows Equation calculation sample to be tested is to the rate of change of the uciferase activity of cell：

Regulation rate (%)=A/B × 100

Wherein, A is to add in the cell fluorescence element enzymatic activity (RLU) measured after sample to be tested, and B is adds in blank control sample (DMSO) the cell fluorescence element enzymatic activity (RLU) measured afterwards.

The compound the results are shown in Table 3 to the agonist activity of PPARs.From table 3 it is observed that the compound of the present invention can With exciting PPARs, and excitement PPARs will play an important roll lipid and cholesterol efflux, meanwhile, exciting PPARs will drop Low sugar is horizontal.The compound the results are shown in Table 4 to the agonist activity of LXRs.As can be seen from Table 4, the compound of the present invention can With exciting LXRs, and excitement LXRs will play an important roll lipid and cholesterol efflux.Therefore, the compound of the present invention can To be applied to the treatment of the cardiovascular and cerebrovascular diseases such as hyperlipidemia, atherosclerosis and/or prevention.

Table 3：Amount of activated compound is to PPARs agonist activities

Table 4：Amount of activated compound is to LXRs agonist activities

Embodiment 5：Compound is to the agonist activity of TRPV1

Plasmid PCMV6-hTRPV1 is obtained from ORIGENE companies, which is to insert the ORF areas (common 2520bp) of people TRPV1 Enter the multiple cloning sites of PCMV6 expression plasmids.It will be in PCMV6-hTRPV1 plasmid transfections using Lipo2000 (Invitrogen) State's Hamster Qvary cancer Chinese hamster ovary celI (national new drug (microorganism) screening experiment room), 100 μ g/ml G418 (Sigma) select high table The monoclonal of intelligent TRPV1, Liquid nitrogen storage are named as CHO-hTRPV1 (Inst. of Medicinal Biological Technology, Chinese Academy of Medical Sciences National new drug (microorganism) laboratory), so as to which successfully structure height expresses the stable cell line of people TRPV1.

Fluo4-AM (Invitrogen) is a kind of acetoxymethyl ester derivative of Fluo4, by culture, can be entered easily In cell.Fluo4-AM can be hydrolyzed after entering cell by intracellular esterase, and the Fluo4 of generation then can be with calcium ion (Ca²⁺) knot Merging sends out fluorescence.

If compound energy excitement TRPV1, can lead to Ca²⁺Ca in interior stream, i.e. cell²⁺Increase, the Ca that Fluo4 is combined²⁺ Also can increase, then can show strong fluorescence values, according to the enhancing of fluorescence values so as to filter out can excitement TRPV1 change Close object.

Specific steps：By stable cell line CHO-hTRPV1 with 5 × 10⁴A/hole is inoculated in 96 porocyte culture plates, and 37 DEG C, 5%CO2 cultures, 6H treats that cell is adherent later and siphons away culture medium that HBSS (100 μ l/ holes) board-washing 3 times abandons HBSS.Add in 2 μM Fluo4-AM (50 μ l/ holes) (Invitrogen), after 37 DEG C are incubated 30min, HBSS (100 μ l/ holes) board-washing 2 times adds in 37 DEG C of HBSS (100 μ l/ holes) is incubated 30min (abundant by intracellular esterase hydrolyzed after Fluo4-AM enters cell), adds in a system The compound (0.5 μ l/ holes) of row DMSO diluted concentrations, it is 495nm to measure exciting light immediately, and transmitting light is glimmering at 518nm Light numerical value (microplate reader reading), numerical value read primary, the fluorescence values variation in monitoring 2-6min per 2s.

Multiple compounds are to the agonist activity the result is shown in Figure 1 of TRPV1.From figure 1 it appears that the compounds of this invention can be with Exciting TRPV1, and excitement TRPV1 will play an important roll anti-inflammatory and analgesia, meanwhile, it is existing research shows that exciting TRPV1 Angiocardiopathy is also played an important role.Therefore, the compound of the present invention can be applied to the heart and brain such as atherosclerosis The treatment and/or prevention of vascular diseases, inflammation, pain.

Embodiment 6：Compound is to the egg of ABCA1, SR-BI/CLA-1, ABCG1 in RAW264.7 cells and HepG2 cells The influence of white expression

1) preparation of protein sample：By (0.01,0.1,1,10 μM) effect HepG2 cell of compound BCD1 or RAW264.7 (0.01,0.1,1,10 μM) effect HepG2 cell of cell 18-24h, compound CD1 or RAW264.7 cells 18-24h；Digest from The heart collects cell, and PBS is washed once.Using RIPA (Beijing Puli is come company), the lysate that each orifice plate is separately added into 70 μ l is (every The Aprotinin of the PMSF of final concentration of 100 μ g/ml, the leupeptin of 1 μ g/ml and 1 μ g/ml are added in 1ml lysates), In lytic cell 30min on ice.Each group cell pyrolysis liquid is collected, in 4 DEG C, 12000 × g centrifuges 15min.Supernatant is collected, uses BCA Kit (BCA^TMProtein Assay Kit, Pierce) albumen is quantified, it is quantitative after with cell pyrolysis liquid by each group Protein sample is adjusted to same concentration.

2) protein electrophoresis (SDS-PAGE)：8% separation gel is prepared, often 15 μ l of albumen sample on duct, pre-dyed albumen Marker (10kDa, 15kDa, 27kDa, 35k Da, 55kDa, 70kDa, 100kDa, 130kDa, 250kDa), Fermentas are public Take charge of product.

3) Western blot are analyzed：After SDS-PAGE electrophoresis, using semidry method or wet method by the albumen on separation gel It is transferred on pvdf membrane.According to 0.8mA/cm2, electric current, constant current transferring film 2.5h are set.After transferring film, pvdf membrane is placed in and is contained Rocked at room temperature closes 1-2h in the TBS (W/V) of 5% skimmed milk power.Closing terminates, and washes pvdf membrane three times with 1 × TBS, every time 10min.Corresponding primary antibody is diluted with the TBST (W/V) containing 5% skimmed milk power, is placed in hybridization bag, 4 DEG C of overnight incubations.From miscellaneous It hands in bag and takes out pvdf membrane, washed three times with 1 × TBST, each 10min.Horseradish is diluted with the TBST (W/V) containing 5% skimmed milk power The secondary antibody of peroxidase (HRP) label is placed in hybridization bag, is incubated at room temperature 2h.Pvdf membrane is taken out from hybridization bag, with 1 × TBST is washed three times, each 10min.

4) it develops the color：In the front of film, that is, the one side for turning to have albumen adds in the mixing of appropriate enhanced chemical luminescent solution A, B liquid Liquid (matching while using), is immediately placed in gel imager and develops the color.

As a result referring to Fig. 2.From figure 2 it can be seen that compound BCD1 (0.01,0.1,1,10 μM) can be dramatically increased The expression of ABCA1, SR-BI/CLA-1, ABCG1 in HepG2 cells and RAW264.7 cells.Compound CD1 can be dramatically increased The expression of ABCA1, SR-BI, ABCG1 in RAW264.7 cells.

ABCA1, SR-BI/CLA-1, ABCG1 be in RCT promote Cholesterol Efflux key protein, the compound of the present invention The expression of these albumen can be increased, with regard to that can promote to arrange outside the lipids such as cholesterol, be conducive to treat and/or prevent hyperlipidemia, is dynamic The cardiovascular and cerebrovascular diseases such as pulse atherosclerosis.

Embodiment 7：1,2- [³H] Cholesterol Efflux experiment

1) DMEM- high glucose mediums (500 μ l/ hole) of the mouse monokaryon-macrophage RAW264.7 containing 10%FBS, with 2 ×10⁵A/hole is inoculated in 24 porocyte culture plates, in 37 DEG C, is incubated overnight under the conditions of 5%CO2.

2) cell liquid is abandoned, is changed to the DMEM- high glucose mediums (500 μ l/ holes) containing 0.2% (w/v) BSA, adds in 1,2- [3H] cholesterol simultaneously makes its final concentration of 1 μ Ci/ml, 37 DEG C, is incubated for 24 hours under the conditions of 5%CO2.

3) it washes cell 2 times with PBS (1ml/ holes), adds in CD1 containing compound, CD10, BCD1 (concentration is respectively 0.1,1 μM) Measure culture medium (DMEM add in 0.2%BSA, 0.1%DMSO, 25mM HEPES, pH7.4), 37 DEG C of incubation 18-24h.

4) cell is washed 2 times with PBS (1ml/ holes), adding in culture medium, (DMEM adds in 0.2%BSA, 0.1%DMSO, 25mM HEPES, pH7.4), with or without the apoA-I of 10 μ g/ml, it is incubated 4h.

5) culture medium is collected, 10000 × g centrifugation 5min take supernatant to be measured.

6) with 0.1M NaOH0.5ml lysis at room temperature cell 30min, it is to be measured to collect lysate.

7) it measures：Sample to be tested is transferred to respectively on 3MM filter paper, 75 DEG C of drying, the scraps of paper are placed on liquid dodges in cup, adds in 10ml liquid dodges liquid, and (mass concentration for 0.5%PPO (2,5- diphenyloxazole) and 0.05%POPOP, (dislike by Isosorbide-5-Nitrae-bis- -2-15- phenyl Azoles benzene) with solvent mixed preparing of the volume fraction for 55% dimethylbenzene and 45% glycol dimethyl ether, be placed in brown container memory Put, use overnight), liquid scintillation counter counts.Entire experimental cell is divided into control group and (is not added with cholesterol but adds apoA-I, add Cholesterol) and sample-adding group (while adding in cholesterol, apoA-I and certain density sample to be tested [15,20]).

Cholesterol Efflux rate %=culture solution cpm values/total cpm value × 100%

=culture solution cpm values/(culture solution cpm values+cell cpm values) × 100%.

As a result referring to Fig. 3.From figure 3, it can be seen that compared with the control, the compounds of this invention CD1, CD10, BCD1 are in 0.1 and During 1 μM of two dosage, intracellular cholesteryl outflow can be remarkably promoted.And it is treatment and/prevention hyperlipemia to promote Cholesterol Efflux The key of the cardiovascular and cerebrovascular diseases such as disease and atherosclerosis is of great significance to treating above-mentioned disease.

Embodiment 8：Macrophage foam cell formationization is tested

The monocytes/macrophages RAW264.7 of the mouse sugared culture solution adhere-wall cultures of the DMEM- high containing 10%FBS.Cell With 6 × 10⁴A/hole is inoculated in 96 porocyte culture plates, in 37 DEG C, 5%CO₂Under the conditions of be incubated overnight after, be changed to serum-free DMEM- high glucose mediums (100 μ l/ holes).Cell is divided into control group, foam cells group and sample-adding group, is added in final concentration of For the Ox-LDL of 80mg/L to foam cells group and sample-adding group, sample-adding group will add in certain density sample to be tested simultaneously.37 DEG C, 5%CO₂Under the conditions of cultivate for 24 hours after, carry out oil red O stain.

By 96 orifice plates from CO₂It is taken out in incubator, 4% paraformaldehyde fixes (15 μ l/ holes) 10min, abandons solution, distilled water is washed Twice, 60% isopropanol (150 μ l/ holes) is added, 5min is placed, discards solution.Oil red O is added in using liquid in each hole, 150 1h is dyed in μ l/ holes.Solution is discarded, with 60% isopropanol (150 μ l/ holes) hole flushing, then washes two with distilled water (150 μ l/ holes) It is secondary, it is last 150 μ l distilled waters to be added to be placed in micro- Microscopic observation, take pictures per hole.As a result referring to Fig. 4, wherein a：Blank control；b： ox-LDL(80μg/ml)；c：ox-LDL+CD1(10μM)；d：ox-LDL+CD2(10μM)；e：ox-LDL+BCD1(10μM)；f： ox-LDL+BCD2(10μM).From fig. 4, it can be seen that only addition ox-LDL (80 μ g/ml) (Fig. 4 .b) lipid within endothelial cells are more, oil Red color is apparent, and blank control group (not adding in ox-LDL) (Fig. 4 .a) is into the cell almost without red.With only adding in ox-LDL (Fig. 4 .b) is compared, and compound CD1, CD2, BCD1, BCD2 (10 μM) can substantially reduce macrophage intake ox-LDL, reduce fat Matter and cholesterol are built up in the cell.And it is treatment and/or prevention hyperlipidemia and artery congee to be arranged outside promotion and lipids cholesterol The key of the cardiovascular and cerebrovascular diseases such as sample hardening is of great significance to treating above-mentioned disease.

Embodiment 9：Compound is in apoE^-/-Pharmacodynamic evaluation in Mice Body

A)apoE^-/-The structure of mouse atherosclerosis model

apoE^-/-Mouse (Beijing Vital River Experimental Animals Technology Co., Ltd.), 7 week old, normal diet are fed one week；

By apoE^-/-Mouse is weighed, random to be grouped, and is divided into 4 groups of (model group, CD1 groups, CDl0 groups, negative controls Group), every group of 6-8 is only；

Since 8 week old, model group and administration group feed high lipid food (the Chinese military medicine academy of sciences, formula：80% is small Mouse mash feed, 20% lard, 1.5% cholesterol), negative control group continues to feed normal diet；

Administration：CD1 (20mg/kg), CD10 (20mg/kg), intraperitoneal injection；Negative control group and model group give carboxylic first Base sodium cellulosate solution, gastric infusion are administered 4 weeks；

The apoE of 4 weeks will be administered^-/-Mouse fasting 6h；It plucks eyeball and takes blood, collect blood with the EP pipes of heparin rinse, up and down It is reverse, it is placed on ice, 4000rpm/min, supernatant is transferred in new EP pipes and (is divided to two parts) by 4 DEG C of centrifugation 3min, be placed in- 20 DEG C of preservations.

Fixed mouse cuts off skin until abdomen, cuts off abdominal cavity, first leave and take fresh with operating scissors along the median line of neck Liver organization, be put into EP pipes (point three parts), be immediately placed in liquid nitrogen, stay and be RNA and Protein Assav；

After having taken liver, cut off thoracic cavity, cut off breastbone, exposure heart carries out cardiac perfusion immediately, first with 4% poly Formaldehyde pours into about 1ml, then changes PBS into and pours into about 4ml, stops after liver bleaches；

Liver and small intestine are taken out successively；Aorta is isolated to the artery overall length of the total branch of ilium, takes out heart and artery. After dissection, liver, heart and aorta are put into 4% paraformaldehyde, 37 DEG C of fixed 2h, be then placed in 20% sucrose it is molten In liquid, 4 DEG C overnight.

B) blood lipid level detects

By administration or the carboxymethyl cellulose apoE of 8 weeks^-/-Mouse fasting 6h；It plucks eyeball and takes blood, with heparin rinse EP pipes collect blood, turn upside down, are placed on ice, 4000rpm/min, and 4 DEG C of centrifugation 3min according to the world and say the serum of separation Bright measure serum total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein courage The content of sterol (LDL-C).More than detection kit is Beijing Zhong Shengbei control clinical reagent Products.

Table 5：Compound is to apoE^-/-The influence (mg/dL) of lipid of mice level

# represents that model group the #P ＜ 0.05 compared with blank group, * represent administration group * P ＜ 0.05 compared with model group

As a result referring to table 5.As can be seen from Table 5, compared with model group, TC, TG, LDL-C in CD1 groups and CD10 groups is administered Level significantly reduces, and HDL-C levels increase.It is high in fat that TC, TG, LDL-C level illustrate that the compounds of this invention can reduce well The blood fat disorders disease such as mass formed by blood stasis, and HDL-C is increased, and is conducive to the metabolism such as internal cholesterol, is conducive to play anti-inflammatory, anti-blood Bolt, it is anti-oxidant the effects that.In short, 5 result of table illustrates that the compounds of this invention can adjust blood fat well, can be used for treatment and/ Or the treatment of the cardiovascular and cerebrovascular diseases such as prevention hyperlipidemia, inflammation and atherosclerosis.

C) the production method of frozen section

1.5ml EP pipes from middle part are cut off, part with cover is left, lid is covered, mark；

OCT embedding mediums are added in EP pipes, have been careful not to bubble；

The tissue impregnated in 20% sucrose is put into OCT, when heart embeds, about 1/3 heart is stayed, cuts flat with, by the heart Nose part upward, is slowly put into OCT；When liver embeds, when holding section is put into OCT in one plane；

Organized EP pipes will be wrapped slowly to be put into liquid nitrogen；

Wrap the EP pipes freezed immediately with tinfoil, -20 DEG C are kept in dark place, and long-term preserve is placed on -80 DEG C.

D) aorta oil red O stain

Aorta is taken out from 20% sucrose, PBS is washed once；

Under a dissecting microscope, aorta is longitudinally splitted；

By the aorta cut off distillation washing 3 times；

60% isopropanol impregnates 10min, synchronizing；

(oil red storing liquid is configured, and is used in filtering 1-2h) is put into the oil red working solution newly prepared by what is synchronized, 30min；

It is put into 60% isopropanol color separation 1min；

Distilled water is washed 3 times；

The aorta that solution is splitted is laid on black wax, camera is taken a picture immediately.

As a result referring to Fig. 5.From figure 5 it can be seen that after high fat diet 2 months, patch is bright in model group aorta overall length It is aobvious；Compared with model group, plaque area in CD1 groups and CD10 group aorta overall lengths is administered and significantly reduces.The above results explanation, this Invention compound CD1 and CD10 can effectively prevent and/or treat atherosclerosis, and turn to base to Atherosclerosis The prevention and/or treatment of the cardiovascular and cerebrovascular disease of plinth are beneficial.

E) frozen section oil red O stain (heart efferent tract and liver organization)

Slice is placed into 30min at room temperature, dries up frozen section；

Slice is put into 4% paraformaldehyde, fixed 10min；

Paraformaldehyde solution is abandoned, distilled water is added in, washes 3 times, each 3min；

60% isopropanol impregnates slice 3min, synchronizing；

Then the slice synchronized is put into the oil red working solution newly prepared (configuration of oil red storing liquid, filtering 1-2h Interior use), 30min；

Slice is put into 60% isopropanol color separation, is observed under the microscope at any time；

Distilled water is washed 3 times；

Hematoxylin contaminates 2-3min, redyes nucleus；

After distilled water washes 3 times, slice is placed in distilled water；

Aqueous mountant mounting (+1 part of distilled water of 9 parts of medical glycerines)；

The slice, thin piece surrounding sealed is applied into nail polish, shady place dries in the shade, takes a picture immediately.

As a result referring to Fig. 6.From fig. 6 it can be seen that after high fat diet 2 months, patch is bright in model group heart efferent tract It is aobvious；Compared with model group, plaque area in CD1 groups and CD10 group heart efferent tracts is administered and significantly reduces.The above results illustrate, change Atherosclerosis can effectively be prevented and/or treat, and to the heart and brain based on atherosclerosis by closing object CD1 and CD10 The prevention and/or treatment of vascular diseases are beneficial.

F) to the influence of cholesterol in liver

The liver of every mouse is taken into 50mg, according to tissue T-CHOL enzymic measuring reagent box step (E1505, Beijing Puli's Lay company) total cholesterol level in each sample is measured, it is (same using the protein concentration of protein quantification kit measurement sample Determination of protein concentration in embodiment 6), then calculate the total cholesterol level of every mouse liver.Total cholesterol level (μm ol/ G)=total cholesterol concentration/protein concentration.

As a result referring to Fig. 7.It can be seen from figure 7 that after high fat diet 2 months, total cholesterol level in model group liver It is dramatically increased than blank group；Compared with model group, CD1 groups are administered and CD10 T-CHOLs substantially reduce.The above results explanation, this The compound CD1 and CD10 of invention can effectively prevent and/or treat atherosclerosis, and turn to disease to Atherosclerosis Prevention and/or the treatment for managing the cardiovascular and cerebrovascular disease on basis are beneficial.

G) to the influence of blood pressure

After administration 2 months, using blood pressure instrument (Softron BP-98A, Japan) rating model group and each group mouse is administered Blood pressure, records systolic pressure SBP numerical value, and every detection three times, is averaged.

As a result referring to Fig. 8.As can be seen from Figure 8, after high fat diet 2 months, compared with model group, administration CD1 groups with CD10 group blood pressures SBP is reduced.The above results illustrate that compound CD1 and CD10 can reduce blood pressure, and the prevention of hypertension and/ Or treatment is beneficial.

H) to the influence of inflammatory factor

Utilize tumor necrosis factor α (Mouse tumor necrosis factor α, TNF-α), monocyte chemotactic egg White 1 (Mouse monocyte chemotactic protein 1/monocyte chemotactic and activating Facto, MCP-1/MCAF) kit (CUSABIO) measures the levels such as inflammatory factor TNF-α, MCP-1/MCAF in serum.

As a result referring to Fig. 9.It can be seen in figure 9 that compared with model group, TNF- in CD1 groups and CD10 group serum is administered α, MCP-1/MCAF are reduced.The above results illustrate, compound CD1 and CD10 have an anti-inflammatory effect, prevention to inflammation and/or control It treats beneficial.

Embodiment 10：Pharmacodynamic evaluation of the compound in diabetic mice body

1) structure of db/db diabetes mices model：

8 week old, BKS.Cg-Dock7^m+/+Lepr^ab/ J mouse (Beijing Vital River Experimental Animals Technology Co., Ltd.), High fat diet (formula is same as above) 8-12 weeks detects fasting blood-glucose and is weighed before grouping, selects fasting blood-glucose >=11.1mmol/L And mouse similar in weight is grouped (negative control group, positive drug group, administration group) at random, every group of 6-8 is only.

2) it is administered：Compound is prepared into uniform suspension using 0.5% CMC-Na solution.Gavage, 1 time a day, Continuous 2 weeks.Dosage 50mg/kg.

3) fasting blood-glucose is detected：

Detection time：1 time before medicine, administration 2 weeks after 1 time.

Detection method：The equal fasting 6h (free water) of animal before blood is taken, tail point takes blood, is carried out with blood glucose meter and mating test paper It measures.

As a result referring to Figure 10.It can be seen from fig. 10 that CD1, CD2, BCD1, BCD2 are compared with the control, blood glucose value is notable It reduces.The above results illustrate that compound CD1, CD2, BCD1, BCD2 can reduce blood glucose, have to the prevention and/or treatment of diabetes Benefit.

Embodiment 11：Influence of the compound to pain

Female Wistar rats 15,4~6 week old, weight (180) g are limited by Beijing dimension tonneau China experimental animal technology Company provides.Main agents：Complete Freund's adjuvant (CFA, Sigma Products).

After Animal adaptability raising 3d, it is randomly divided into 3 groups, every group 5：1st group without any processing；2nd group is used as mould Type group takes 0.1ml CFA to be injected in the subcutaneous induced arthritis of the left back toes of rat and occurs；3rd group, 0.1ml CFA is taken to be injected in The subcutaneous induced arthritis of the left back toes of rat occurs, and BCD110mg/kg is subcutaneously injected in the left back toes of rat；It 4th group, takes 0.1mlCFA is injected in the subcutaneous induced arthritis of the left back toes of rat and occurs, and is subcutaneously injected in the left back toes of rat CD1310mg/kg；0.01mol/L glacial acetic acid 0.1ml only are subcutaneously injected in the left back toes of rat for 5th group 5, it is molten in CFA to exclude The sensitizing effect of agent.

The results show that administration BCD1, CD13 group rat redness degree is significantly weaker than model group, illustrate the compounds of this invention pair Inflammation and preferable effect is relieved pain, therefore the compounds of this invention is beneficial to the prevention and/or treatment of inflammation, pain.

Although some embodiments of present general inventive concept have been shown and have illustrated, those of ordinary skill in the art will manage Solution in the case of without departing substantially from the principle of present general inventive concept and spirit, can make a change these embodiments, of the invention Range is limited with claim and their equivalent.

Claims

1. a kind of compound, which is characterized in that the compound is selected from the group being made of the following terms：

N- (2- (5- acetyl group -1H- indol-3-yls) ethyl) -2- aminobenzamides,

N- (2- (5- acetyl group -1H- indol-3-yls) ethyl) -3- Aminomethyl benzamides,

N- (2- (the chloro- 1H- indol-3-yls of 5-) ethyl) -2- propionamido- benzamides,

5- acetyl group-N- (2- (1H- indol-3-yls) ethyl) quinoline -3- formamides,

N- (2- (1H- indol-3-yls) ethyl) -2- (2- bromines propionamido-) benzamide,

N- (2- (1H- indol-3-yls) ethyl) -2- chloroacetamide yl-benzamides,

N- (2- (1H- indol-3-yls) ethyl) -2- trifluoroacetamide yl-benzamides,

N- (2- (5- methoxyl group -1H- indol-3-yls) ethyl) -2- (2- bromines propionamido-) benzamide,

N- (2- (1H- indol-3-yls) ethyl) -3- chloroacetamide yl-benzamides,

N- (2- (1H- indol-3-yls) ethyl) -3- trifluoroacetamide yl-benzamides,

N- (2- (1H- indol-3-yls) ethyl) -4- trifluoroacetamide yl-benzamides,

N- (2- (3- hydroxy phenyls) ethyl) -2- propionamido- benzamides,

N- (2- (3- acetylphenyls) ethyl) -2- propionamido- benzamides,

Or its pharmaceutical salts.

2. a kind of pharmaceutical composition, described pharmaceutical composition include compound or pharmaceutically acceptable salt thereof according to claim 1 with And pharmaceutical carrier.

3. application of the compound according to claim 1 in the drug for treating and/or preventing following disease is prepared： Atherosclerosis, hyperlipidemia, diabetes, inflammation, hypertension or pain.

4. compound according to claim 1 is being prepared for treating and/or prevent in the drug of cardiovascular and cerebrovascular disease Using.

5. pharmaceutical composition according to claim 2 is in the drug for treating and/or preventing following disease is prepared Using：Atherosclerosis, hyperlipidemia, diabetes, inflammation, hypertension or pain.

6. pharmaceutical composition according to claim 2 is preparing the drug for treating and/or preventing cardiovascular and cerebrovascular disease In application.