CN105198786A

CN105198786A - Aryl-substituted amide compound, preparing method thereof, medicine composition comprising same, and application thereof

Info

Publication number: CN105198786A
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: 2015-12-30
Anticipated expiration: 2034-06-17
Also published as: CN105198786B

Abstract

The invention relates to an aryl-substituted amide compound in the formula (I), a preparing method thereof, a medicine composition comprising the same, and application of the amide compound and the medicine composition to pharmacy, wherein Arl, L1, M1, M2, L2 and Ar2 are defined as in the text. The aryl-substituted amide compound can excite TRPV1 and nuclear receptors (LXRs, PPARs and RXR), adjust expression of cholesterol excretion gap-associated protein ABCA1/G1, SR-BI, adjust expression of inflammation gap-associated protein TNF-alpha and the like, and play roles in promoting excretion of cholesterol and lipid, reducing sugar, adjusting blood lipid, resisting inflammation and reducing blood pressure, and can be used for treating and/or preventing and/or relieving cardiovascular and cerebrovascular diseases, adjusting blood lipid, and resisting atherosclerosis, diabetes mellitus, inflammation, pain and hypertension.

Description

Amides and preparation method thereof that aryl replaces, comprise its pharmaceutical composition and application thereof

Technical field

The present invention relates to amides or its pharmaceutical salts, its preparation method, the pharmaceutical composition comprising it and the application thereof of aryl replacement.

Background technology

Atherosclerosis (Atherosclerosis, AS) is the common pathophysiological basis of the multiple cardiovascular and cerebrovascular diseases such as coronary heart disease, myocardial infarction, cerebral apoplexy, hypertension.The annual death toll caused by this disease accounts for 1/3 of global total toll.

The pathogenesis more complicated of AS, itself and lipid infiltrate, blood vessel endothelium injury, inflammation etc. are closely related.Scavenger cell is by SR-A and the CD36 acceptor on its surface unrestrictedly absorbs lipid, the low-density lipoprotein (m-LDL) of cholesterol and sex change forms scavenger cell foamed.A large amount of lipid (mainly cholesterol and cholesteryl ester) forms atherosclerotic plaque in the intracellular accumulation of tunica intima foamed, and along with the aggravation of inflammatory reaction, the dissolving of fibrous cap, finally cause the formation of atherosclerosis and thrombus etc., and develop into the cardiovascular disorder such as coronary heart disease, heart stalk further.

At present, the fat-reducing medicament of clinical application mainly contains the medicine such as nicotinic acid, shellfish special class, cholic acid chelating agent and Statins.The mechanism of action of nicotinic acid is the effect strengthening lipoprotein lipase, reduce free fatty acid levels, but its untoward reaction is more, so seldom use.The mechanism of action of the special class fat regulation medicine of shellfish is exciting alpha type peroxisome activated form propagation acceptor (PPAR α), strengthen the effect of lipoprotein lipase, the lethal danger of non-cardiovascular disease of such medicine is higher, because which limit the application of this type of medicine.Cholic acid chelating agent class medicine by conjugated bile acid, increase its excretion, thus accelerate cholesterol to the conversion of bile acide.There is the shortcomings such as taking dose is large, gastrointestinal reaction is obvious, patient tolerability is poor in cholic acid chelating agent class medicine.Statins is the first-line drug for the treatment of hyperlipidaemic conditions, its mechanism of action suppresses HMG-CoA reductase in body active, reduce low-density lipoprotein (LDL) level, but long-term taking can cause the serious adverse reactions such as rhabdomyolysis, gastrointestinal dysfunction syndromes, fash and hepar damnification.Therefore, clinical in it is found that and developing the medicine with anti-AS new target drone.People have made extensive work finding in the anti-AS medicine that research and development have other mechanism of action.

In recent years, along with people deepen continuously to the understanding of atherogenesis mechanism, find the counter transport (Reversecholesteroltransport promoting cholesterol, RCT) process can slow down atherosclerotic generation and development, and to the atherosclerosis formed, there is reverse effect, fundamentally reduce the generation of the cardiovascular and cerebrovascular diseases caused by atherosclerosis.Reverse cholesterol transport is high-density lipoprotein (HDL) (HDL) by the cholesterol transport in peripheral tissues to liver metabolism or the process of draining with the form of cholic acid again, it is the effective means of prevention and therapy AS, the main molecules that mediation Macrophage cholesterol flows out comprises ATP binding cassette transporter protein family (ATPbindingcassettetransporter, ABC) ABCA1 in, ABCG1, SR-BI (the ScavengerreceptortypeBclassI)/CLA-1 of high-density lipoprotein (HDL) receptor family, peroxisome proliferation-activated receptors (PeroxisomeProliferator-ActivatedReceptor, PPARs), liver X receptor (liverXreceptor, (the A.R.Tall.Cholesteroleffluxpathwaysandotherpotentialmecha nismsinvolvedintheathero-protectiveeffectofhighdensityli poproteins.JInternMed.2008 such as LXRs), 263 (3): 256-73.).And the critical function of HDL comprise anti-inflammatory, antithrombotic, vascular protection, short Cholesterol Efflux, anti-oxidant, increase (the NavabM such as NO generation; ReddyST; VanLentenBJ; FogelmanAM.HDLandcardiovasculardisease:atherogenicandath eroprotectivemechanisms.NatRevCardiol.2011,8 (4): 222-32.).Research finds these associated receptors, transmembrane protein and relevant nuclear receptor, is not work isolatedly, is actually and there is mutual coordination between each acceptor and Cell Signal Transduction Network regulation mechanism.

ABCA1 can mediate cholesterol and phosphatide flows to poor fat or the apolipoprotein A-1 (apolipoproteinA-I, apoA-I) without fat from peripheral cells, has vital role to the generation development of lipid metabolism, cholesterol metabolic, AS, inflammation.The transgenic mice of ABCA1 high expression level can the level of elevate plasma HDL, apoA-I, and makes to flow out in Macrophage cholesterol obviously to increase, thus reduces the danger of AS.ABCG1 can promote that cholesterol flows out from scavenger cell, and HDL is the receptor of its cholesterol, thus promotes that cholesterol is discharged from liver, small intestine.SR-BI not only promotes that cholesterol flows out from scavenger cell, promotes that the selectivity of cholesteryl ester is absorbed in liver.In addition, the expression of ABCA1, ABCG1, SR-BI is also subject to nuclear receptor superfamily (comprising LXRs, vitamin A acid X acceptor (RXR), farnesol X acceptor (FXR) and Thyroid Hormone Receptors), PPARs, transcription factor (as AP-1, AP-2, NF-κ B and Sp1 etc.) etc. regulation and control.LXR direct regulation and control participates in the expression of many crucial target genes (comprising ABCA1, ABCG1 etc.) in cholesterol metabolic approach, is the susceptor of body inner cholesterol metabolism, plays vital effect for maintenance body cholesterol homeostasis.The effect of PPARs widely, except participating in lipid and lipoprotein metabolism, sugared balance external in body, also relate to adipocyte, monokaryon/huge such as to bite at the differentiation of various kinds of cell, the inflammation-inhibiting factor produces and inflammatory reaction, blood vessel is regulated to relax/contract and affect atherogenesis etc., PPARs agonist is for lipid metabolism, carbohydrate metabolism, inflammation related disease is (as cardiovascular disorder, inflammation, atherosclerosis, diabetes etc.) play an important role and application prospect (TimothyM.Willson, MillardH.Lambert, andStevenA.Kliewer.Peroxisomeproliferator-activatedrecep tor.Annu.Rev.Biochem.2001, 70:341-67).Therefore, the activity on treatment AS of adjustment (increasing or excitement) ABCA1, ABCG1, SR-BI, LXRs, PPARs, HDL etc. are useful.Be of value to the diseases such as Cardiovarscular, inflammation, atherosclerosis, diabetes.

TRPV1 is transient receptor potential Vanillin subfamily 1 (TransientReceptorPotentialca-tionchannelsubfamilyVmember 1, TRPV1).TRPV1 mainly expresses at periphery neurocyte, by inside and outside source property substance activatings such as high temperature, proton, capsaicine, lipid metabolism products, can cause with Ca ²⁺be main transmembrane ion flowing, make Ca in cell ²⁺concentration changes, and then activate a series of Intracellular signals, functionally main manifestations is for participating in the process (RongXia such as nociception, KimDekermendiian, ElkeLullau, andNiekDekker.TRPV1:atherapytargetthatattractsthepharmac euticalinterests.AdvExpMedBiol.2011,704:637-65.).Exciting TRPV1 can promote calcitonin-gene-related peptide (calcitoningene-relatedpeptide; CGRP) release, thus play the pharmacologically actives such as its cardiovascular protection (as hypertension, endothelial function disturbance, apoplexy), hypertension, analgesia.The cardiovascular protective effect that exciting TRPV1 produces is also relevant to ABCA1, ABCG1, PPARs, LXRs.The excitement of TRPV1 is also relevant with suppression to the generation of inflammation.The excitement of TRPV1 has expression and the activation of the inflammation-inhibiting factor, plays the preventive and therapeutic effect to AS simultaneously.

The diseases such as the cardiovascular and cerebrovascular diseases such as atherosclerosis, diabetes, inflammation, hypertension, pain, inflammation have a strong impact on the health of the mankind, treat and/or prevent the novel cpd of above-mentioned disease at clinical and pharmacy field in the urgent need to discovery and development.

Summary of the invention

For this reason, the object of this invention is to provide amides or its pharmaceutical salts, its preparation method of the novel aryl replacement of a class, comprise its pharmaceutical composition and their purposes.Novel cpd of the present invention is for the different targets of above-mentioned disease, the exciting TRPV1 of energy, exciting nuclear receptor (LXRs, PPARs, RXR), cholesterol regulating are arranged the expression of related membrane protein ABCA1/G1, SR-BI outward, are regulated the expression of inflammation related proteins TNF-α etc., thus play effects such as promoting outer row, hypoglycemic, adjusting blood lipid, the anti-inflammatory of the lipids such as cholesterol, reduce blood pressure, to be used for the treatment of or prevention of arterial is atherosis, cardiovascular and cerebrovascular diseases, hyperlipidaemia, diabetes, inflammation, hypertension or pain.

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

Wherein,

Ar ₁represent indoles-2-base, indol-3-yl or phenyl, the substituting group that described indoles-2-base, indol-3-yl or phenyl are optionally selected from the group be made up of the following replaces: hydrogen, halogen, hydroxyl ,-CHO, C ₁-C ₆alkyloyl, C ₁-C ₆alkyl or C ₁-C ₆alkoxyl group;

L ₁represent C ₁-C ₆alkylidene group or do not exist;

M ₁and M ₂represent-CO-differently from one another or do not exist;

L ₂represent C ₁-C ₆alkylidene group, C ₁-C ₆alkylene oxide group ,-O-, C ₁-C ₆alkylenethio ,-S-or do not exist; And

Ar ₂represent wherein R ₁represent hydrogen, hydroxyl, amino, halogen, C ₁-C ₆alkyl, halo C ₁-C ₆alkyl, C ₁-C ₆alkylamino radical, two (C ₁-C ₆alkyl) amido, amino C ₁-C ₆alkyl, amino C ₁-C ₆alkyloyl, C ₁-C ₆alkyl amide, two (C ₁-C ₆alkyloyl) amido, halo C ₁-C ₆alkyl amide, carboxyl or-COO (C ₁-C ₆) alkyl; R ₂represent hydrogen, amino, hydroxyl, C ₁-C ₆alkyl or C ₁-C ₆alkyloyl; R ₃represent hydrogen, halogen, C ₁-C ₆alkyl, C ₁-C ₆haloalkyl or C ₁-C ₆alkyloyl;

Or its pharmaceutical salts.

In a preferred embodiment, in described formula I:

Ar ₁represent indoles-2-base, indol-3-yl or phenyl, described indoles-2-base, indol-3-yl or phenyl are optionally selected from the substituting group in the group be made up of the following: hydrogen ,-CHO, C ₁-C ₄alkyloyl or C ₁-C ₄alkoxyl group;

L ₁represent C ₁-C ₂alkylidene group or do not exist;

L ₂represent C ₁-C ₄alkylidene group, C ₁-C ₄alkylene oxide group ,-O-or do not exist; And

Ar ₂represent wherein R ₁represent the phenyl that the substituting group be optionally selected from the group be made up of the following replaces: hydrogen, hydroxyl, amino, C ₁-C ₄alkyl, C ₁-C ₄alkylamino, two (C ₁-C ₄alkyl) amino, amino C ₁-C ₄alkyloyl, C ₁-C ₄alkyl amido, two (C ₁-C ₄alkyloyl) amino, halo C ₁-C ₄alkyl amido, carboxyl or-COO (C ₁-C ₃) alkyl; R ₂represent hydrogen, amino, hydroxyl, C ₁-C ₄alkyl or C ₁-C ₄alkyloyl; R ₃represent hydrogen, C ₁-C ₄alkyl or C ₁-C ₄alkyloyl.

In another preferred embodiment, in described formula I:

Ar ₁represent that phenyl, indoles-2-base, indol-3-yl, 2-position are by C ₁-C ₄the indol-3-yl that the indol-3-yl that alkyloyl replaces, 2-position quilt-CHO replace or 5-position are by C ₁-C ₄the indol-3-yl that alkoxyl group replaces;

L ₁represent C ₁-C ₂alkylidene group or do not exist;

Ar ₂represent wherein R ₁represent the phenyl that the substituting group be optionally selected from the group be made up of the following replaces: hydrogen, hydroxyl, amino, C ₁-C ₄alkyl, C ₁-C ₄alkylamino, two (C ₁-C ₄alkyl) amino, amino C ₁-C ₄alkyloyl, C ₁-C ₄alkyl amido, two (C ₁-C ₄alkyloyl) amino, halo C ₁-C ₄alkyl amido, carboxyl or-COO (C ₁-C ₃) alkyl; R ₂represent hydrogen, amino, hydroxyl or C ₁-C ₄alkyl; R ₃represent hydrogen or C ₁-C ₄alkyl.

In another preferred embodiment, in described formula I:

Ar ₁represent phenyl, optionally by the indol-3-yl of methoxy substitution or optionally by the indoles-2-base of methoxy substitution;

L ₁represent methylene radical, ethylidene or do not exist;

L ₂represent methylene radical or do not exist; And

Ar ₂represent phenyl, PA-3-base, pyridin-3-yl, quinoline-3-base, by amino, hydroxyl, carbamyl, trifluoroacetyl group, propionyl, carboxyl or methyl substituted phenyl.

On the other hand, the invention still further relates to a kind of method for the preparation of above-claimed cpd, described method comprises: according to following reaction scheme (i) or (ii), in anhydrous inert organic solvent, with formula (b) or the amine of (c) and the carboxylic acid of formula (a) or (d) or acyl chlorides for raw material, reaction under condensing agent and basic catalyst exist

Reaction scheme (i):

Reaction scheme (ii):

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

On the other hand, the invention provides a kind of pharmaceutical composition, described pharmaceutical composition comprises above-claimed cpd or its pharmaceutical salts, and pharmaceutical carrier.

On the other hand, the invention provides above-claimed cpd for the preparation of the application treated and/or prevented in the medicine of following disease: atherosclerosis, cardiovascular and cerebrovascular diseases, hyperlipidaemia, diabetes, inflammation, hypertension or pain.

On the other hand, the invention provides aforementioned pharmaceutical compositions for the preparation of the application treated and/or prevented in the medicine of following disease: atherosclerosis, cardiovascular and cerebrovascular diseases, hyperlipidaemia, diabetes, inflammation, hypertension or pain.

The amides that aryl provided by the invention replaces has can remarkable exciting TRPV1, exciting nuclear receptor (LXRs, PPARs, RXR), cholesterol regulating arranges related membrane protein ABCA1/G1 outward, the expression of HDL acceptor SR-BI/CLA-1, regulate inflammation related proteins tumor necrosis factor alpha (Mousetumornecrosisfactor α, TNF-α) etc. expression, thus play the outer row promoting the lipids such as cholesterol, hypoglycemic, adjusting blood lipid, anti-inflammatory, the effect such as reduce blood pressure, may be used for treatment or prevention of arterial atherosis, cardiovascular and cerebrovascular diseases, hyperlipemia, diabetes, inflammation, hypertension or pains and other diseases.

Accompanying drawing explanation

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

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

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

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

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

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

Fig. 7 shows compound according to the present invention to the impact of total cholesterol in liver;

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

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

Figure 10 shows compound according to the present invention to the impact of blood sugar.

Embodiment

The invention provides the compound relating to a kind of formula (I):

Wherein,

L ₁represent C ₁-C ₆alkylidene group or do not exist;

M ₁and M ₂represent-CO-differently from one another or do not exist;

Ar ₂represent wherein R ₁represent hydrogen, hydroxyl, amino, halogen, C ₁-C ₆alkyl, halo C ₁-C ₆alkyl, C ₁-C ₆alkylamino radical, two (C ₁-C ₆alkyl) amido, amino C ₁-C ₆alkyl, amino C ₁-C ₆alkyloyl, C ₁-C ₆alkyl amide, two (C ₁-C ₆alkyloyl) amido, halo C ₁-C ₆alkyl amide, carboxyl or-COO (C ₁-C ₆) alkyl; R ₂represent hydrogen, amino, hydroxyl, C ₁-C ₆alkyl or C ₁-C ₆alkyloyl; R ₃represent hydrogen, halogen, C ₁-C ₆alkyl, C ₁-C ₆haloalkyl or C ₁-C ₆alkyloyl.

The invention still further relates to the derivative of above-claimed cpd, its isomer, raceme or optical isomer, its pharmaceutical salts or its solvate.

Term used herein " alkyl " comprises straight chain and branched-chain alkyl, its prefix such as " C ₁-C ₆" represent that amount of carbon atom is 1-6; Term " alkylidene group " represents divalent alkyl; Term " alkyloyl " represents alkyl-CO-; Term " alkoxyl group " represents alkyl-O-; Term " alkylene oxide group " represents alkylidene group-O-; Term " alkylamino " represents alkyl-NH-; Term " alkylthio " represents alkyl-S-; Term " alkylenethio " represents alkylidene group-S-; Term " aminoalkanoyl radical " represents NH ₂-alkyloyl; Term " alkyl amido " represents alkyloyl-NH-; Term " halogen " refers to F, Cl, Br or I.That term used herein " aryl " represents aromatics, that be substituted (mono-substituted or polysubstituted) or unsubstituted group, comprise containing the heteroatomic heteroaryl of one or more N.In addition, in the present context, term " amides " represents the compound containing-N (H)-CO-group, and it contains lactam analog compound.

In the compound of a kind of preferred formula I:

L ₁represent C ₁-C ₂alkylidene group or do not exist;

In the compound of another preferred formula I:

L ₁represent C ₁-C ₂alkylidene group or do not exist;

In the compound of another preferred formula I:

L ₁represent methylene radical, ethylidene or do not exist;

L ₂represent methylene radical or do not exist; And

Particularly preferred compound of the present invention include but not limited to describe in detail in table 1 below those, and pharmaceutical salts:

Table 1: particularly preferred formula I

The invention still further relates to the preparation method of the compound shown in general formula (I), such as, the compound of general formula I of the present invention can be prepared as follows:

Work as M ₁exist and be CO, M ₂when not existing, general formula (I) part of compounds (I-1) is obtained by following reaction scheme (i);

Reaction scheme (i):

Work as M ₂for CO, M ₁during for not existing, general formula (I) part of compounds (I-2) is obtained by reaction scheme (ii),

Reaction scheme (ii):

Wherein Ar ₁, L ₁, M ₁, M ₂, L ₂and Ar ₂as defined above.

Above-mentioned reaction belongs to the popular response of the synthesizing amide of this area, wherein at anhydrous inert organic solvent (as methylene dichloride or N, dinethylformamide) in, with corresponding amine (b) or (c) and carboxylic acid or acyl chlorides (a) or (d) for raw material, at condensing agent (as dicyclohexylcarbodiimide, 1-ethyl-(3-dimethylamino-propyl) carbodiimide hydrochloride) and basic catalyst (as triethylamine or DMAP) exist under, in room temperature to 120 DEG C (as with N, when dinethylformamide is solvent) temperature under react 2-24h, eventually pass through such as column chromatography separating purification and obtain target product.

Biological experiment result of study shows, institute of the present invention test target compound, at the exciting TRPV1 of cell levels energy, exciting nuclear receptor (LXRs, PPARs, RXR), cholesterol regulating arranges related membrane protein ABCA1/G1 outward, the expression of HDL acceptor SR-BI, regulate the expression of inflammation related proteins TNF-α etc., promote lipid, cholesterol efflux, in vivo can adjusting blood lipid, reduce artery plaque, inflammation-inhibiting factor expression, reduce blood sugar, reduce blood pressure, clinically effectively treat and/or prevent for preparing and/or alleviate cardiovascular and cerebrovascular diseases, hyperlipidemia, atherosclerosis, diabetes, inflammation, pain and high blood pressure disease medicine provide good potential applicability in clinical practice.

The amides that aryl of the present invention replaces can itself administration, or with the form administration of pharmaceutical composition.

Medicinal compositions of the present invention comprises the treatment the compounds of this invention of significant quantity or its pharmaceutical salts as effective constituent, and one or more pharmaceutical carriers, vehicle or thinner.

Pharmaceutical composition of the present invention can be prepared in the usual way, uses acceptable carrier, vehicle and auxiliary agent on one or more physiology, is conducive to active compound to be processed into pharmaceutical preparations.Suitable preparation depends on selected route of administration, can be prepared according to method well known in the art.

Suitable carrier, vehicle or thinner can be selected for the mode of administration of expection and standard practices.The example of suitable carrier comprises: lactose, starch, glucose, methylcellulose gum, Magnesium Stearate, N.F,USP MANNITOL, sorbyl alcohol etc.

Treatment significant quantity is any amount of 0.1% to 99.9%w/w, 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.

Composition of the present invention can be released into patient by various route of administration or mode.The route of administration be applicable to includes but not limited to suction, transdermal, oral, rectum, in mucous membrane, intestines and administered parenterally, administered parenterally comprises intramuscular, subcutaneous and intravenous injection.

Composition for oral administration is suitably formulated as compressed tablets, tablet, capsule, gel capsule, powder, solution, dispersed system, suspension, drops etc.These forms can be produced according to known method, and can comprise the tackiness agent of any appropriate, lubricant, suspending agent, Drug coating or solubilizing agent or their combination.

By means of injecting the composition used, be suitably formulated as sterile solution or emulsion from suitable solution or powder.Or composition can be the form of suppository, hysterophore, suspension, emulsion, lotion, ointment, ointment, skin patch, gel, colloidal sol, sprays, solution or face powder.

The per daily dose of instruction is about 1mg to about 1000mg (such as 2mg-750mg or 3mg-650mg or 5mg-500mg).The usual every agent of the composition provided with dosage form is containing 0.25mg extremely about 250mg (such as 0.5mg-200mg or 0.75mg-150mg or 1mg-100mg) activeconstituents of having an appointment.

Composition can comprise one or more extra activeconstituentss, or can use together with comprising the composition of other activeconstituents being used for the treatment of identical or different illness.Jointly using can be side by side, consistently or sequentially.

Compound defined above can be free form, namely usually used as alkali, or the salt of any appropriate or ester-formin.In a usual manner, the compound of free form can transform salify or ester-formin, and vice versa.

Suitable salt comprises: hydrochloride, dihydrochloride, hydrogen formate, acid amides, succinate, hemisuccinic acid salt, maleate, acetate, trifluoroacetate, fumarate, phthalate, four phthalates (tetraphthalate), benzoate, sulfonate, vitriol, phosphoric acid salt, oxalate, malonate, bimalonate, ascorbate salt, glycollate, lactic acid salt, malate, tartrate, Citrate trianion, aspartate or glutaminate and their variant.The acid being applicable to be formed acid salt comprises corresponding acid, i.e. hydrochloric acid, formic acid, amino acid, succsinic acid, toxilic acid, acetic acid, trifluoroacetic acid, fumaric acid, phthalandione, four phthalandiones, phenylformic acid, sulfonic acid, sulfuric acid, phosphoric acid, oxalic acid, propanedioic acid, xitix, hydroxyethanoic acid, lactic acid, oxysuccinic acid, tartrate, citric acid, aspartic acid or L-glutamic acid etc.

The present invention will be further illustrated by following examples, but not have restricted to the present invention.

Embodiment 1: the synthesis of representative compound

(1) N-(2-(1H-indol-3-yl) ethyl)-2-aminobenzamide (CD1)

Tryptamines is (purchased from this company of Adama, purity > 99%) (0.80g, 5mmol) join in 50mL round-bottomed flask, add 25mLN, dinethylformamide, add 2-benzaminic acid (0.68g successively, 5mmol), 1-ethyl-(3-dimethylamino-propyl) carbodiimide (EDCI) hydrochloride is (all purchased from Beijing coupling Science and Technology Ltd., purity > 98%) (0.96g, 5mmol), room temperature reaction spends the night.Decompression steams most of solvent, is extracted with ethyl acetate and uses anhydrous sodium sulfate drying after adding 30mL water.With ethyl acetate after acetic acid ethyl acetate extract is concentrated: sherwood oil=1: 3 obtain CD1 sterling 1.14g (productive rate 82%) for eluent through silicagel column elution, white solid, mp159-160 DEG C (literature value 156-157 DEG C).MS (ESIm/z) 280.28 (M+H) ⁺, HRMS (ESIm/z) [M+H] ⁺theoretical molecular formula C ₁₇h ₁₈n ₃o, theoretical molecular 280.1444, actual molecular weight 280.1444. ¹HNMR(400MHz，CD ₃COCD ₃)δ9.99(s，1H，1’-NH)，7.65(d，J＝8.0Hz，1H，4’-H)，7.60(brs，1H，CONH)，7.45(d，J＝8.0Hz，1H，6-H)，7.37(d，J＝8.0Hz，1H，7’-H)，7.20(s，1H，2’-H)，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，NH ₂)，3.66(q，J＝6.8Hz，2H，CH ₂NH)，3.05(t，J＝6.8Hz，2H，CH ₂)。

(2) N-(2-(5-ethanoyl-1H-indol-3-yl) ethyl)-2-aminobenzamide (CD2)

By the method for synthesis (CD1); with 5-ethanoyl tryptamines (purchased from this company of Adama; purity > 99%) (1.0g; 5mmol) be raw material; synthesis obtains CD2 sterling 1.21g (productive rate 76%), MS (ESIm/z) 322.26 (M+H) ⁺. ¹HNMR(400MHz，CD ₃COCD ₃)δ9.85(s，1H，1’-NH)，7.72(d，J＝2.0Hz，1H，4’-H)，7.62(brs，1H，CONH)，7.48(d，J＝8.0Hz，1H，6-H)，7.37(d，J＝8.0Hz，1H，7’-H)，7.20(s，1H，2’-H)，7.13-7.07(dd，J＝2.0，8.0Hz，1H，6’-H)，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，NH ₂)，3.66(q，J＝6.8Hz，2H，CH ₂NH)，3.38(s，3H，CH ₃)3.05(t，J＝6.8Hz，2H，CH ₂)。

(3) N-(2-(5-ethanoyl-1H-indol-3-yl) ethyl)-3-Aminomethyl benzamide (CD3)

By the method for synthesis (CD1); with 5-ethanoyl tryptamines (1.0g; 5mmol) with 3-amino-methyl benzoic acid (purchased from Beijing coupling Science and Technology Ltd.; purity > 98%) (0.76g; 5mmol) react; synthesis obtains CD3 sterling 1.27g (productive rate 86%), MS (ESIm/z) 294.16 (M+H) ⁺. ¹HNMR(400MHz，CD ₃COCD ₃)δ9.85(s，1H，1’-NH)，7.72(d，J＝2.0Hz，1H，4’-H)，7.62(brs，1H，CONH)，7.48(d，J＝8.0Hz，1H，6-H)，7.37(d，J＝8.0Hz，1H，7’-H)，7.20(s，1H，2’-H)，7.13-7.07(dd，J＝2.0，8.0Hz，1H，6’-H)，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，CH ₂NH)，3.43(s，2H，CH ₂)，3.38(s，3H，CH ₃)3.05(t，J＝6.8Hz，2H，CH ₂)。

(4) N-(2-(1H-indol-3-yl) ethyl)-3-chlorobenzamide (CD4)

By the method for synthesis (CD1), with tryptamines (1.0g, 5mmol) with 3-chloro-benzoic acid (purchased from Beijing coupling Science and Technology Ltd., purity > 98%) (0.78g, 5mmol) react, synthesis obtains CD04 sterling 1.18g (productive rate 78%), MS (ESIm/z) 299.23 (M+H) ⁺. ¹HNMR(400MHz，DMSO-d6)δ10.80(brs，1H，1’-NH)，8.34(t，J＝5.6Hz，1H，CONH)，7.58(d，J＝8.0Hz，1H，4’-H)，7.34(d，J＝8.0Hz，1H，7’-H)，7.17(d，J＝2.4Hz，1H，2’-H)，7.09-7.04(m，3H，5’，6’-2Hand2-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，CH ₂NH)，2.93(t，J＝7.2Hz，2H，CH ₂)。

(5) N-(2-(5-methoxyl group-1H-indol-3-yl) ethyl)-2-aminobenzamide (CD6)

By the method for synthesis (CD1), with 5-methoxytryptamine (purchased from this company of Adama, purity > 98%) (0.95g, 5mmol) for reactant obtains CD6 sterling 0.57g (productive rate 37%), 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 C ₁₈h ₂₀n ₃o ₂, theoretical molecular 310.1550, actual molecular weight 310.1549. ¹HNMR(500MHz，DMSO-d6)δ10.65(s，1H，1’-NH)，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)，7.07(d，J＝2.5Hz，1H，2’-H)，6.75-6.67(m，2H，4，5-2H)，6.50(t，J＝7.5Hz，1H，6’-H)，6.42(brs，2H，NH ₂)，3.75(s，3H，CH ₃O)，3.49(q，J＝7.0Hz，2H，CH ₂NH)，2.91(t，J＝7.0Hz，2H，CH ₂)。

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

By the method for synthesis (CD1), (like that (Shanghai) changes into industrial development company limited purchased from ladder is uncommon with 5-chlorine tryptamines, purity > 98%) (0.97g, 5mmol) for raw material first obtains intermediate N (2-(the chloro-1H-indol-3-yl of 5-) ethyl)-2-aminobenzamide, again this intermediate is dissolved in dry methylene dichloride, add triethylamine (purchased from traditional Chinese medicines group chemical reagent Beijing company limited) 0.5mL, propionyl chloride (self-control) is dripped in above-mentioned solution, room temperature reaction 4h, separation and purification obtains CD8 sterling 1.25g (productive rate 68%), MS (ESIm/z) 370.22 [M+H] ⁺. ¹hNMR (400MHz, DMSO-d6) δ 11.30 (s, 1H, 1 '-NH), 10.82 (s, 1H, CONH), 8.85 (t, J=5.75Hz, 1H, CH ₂nH), 8.42 (dd, J=1.17,8.50Hz, 1H, 6-H), 7.69 (dd, J=1.52,8.02Hz, 1H, 3-H), 7.58 (d, J=7.79Hz, 1H, 4 '-H), 7.47 (td, J=1.46,8.60Hz, 1H, 5-H), 7.34 (d, J=8.07Hz, 1H, 7 '-H), 7.20 (d, J=2.27Hz, 1H, 2 '-H), 7.16-6.94 (m, 2H, 6 '-H and 4-H), 3.56 (q, J=7.44,2H, CH ₂nH), 2.98 (t, J=7.43Hz, 2H, CH ₂), 2.36 (q, J=7.52Hz, 2H, CH ₂), 1.12 (t, J=7.52Hz, 3H, CH ₃).

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

By tryptamines (0.32g, 2mmol) with 2-(N, N dimethylamine base) phenylformic acid is (purchased from Beijing coupling Science and Technology Ltd., purity > 98%) (0.35g, 2mmol) join in the DCM of 30mL drying, add EDCI hydrochloride (0.42g, 2mmol), room temperature reaction spends the night.Mixture through washing and with after anhydrous sodium sulfate drying, with ethyl acetate: petroleum ether system obtains CD11 sterling 88mg (productive rate 14%) through silicagel column elution, white solid, mp132-134 DEG C.MS (ESIm/z) 308.21 (M+H) ⁺, 330.17 (M+Na) ⁺, HRMS (ESIm/z) [M+H] ⁺theoretical molecular formula C ₁₉h ₂₂oN ₃, theoretical molecular 308.1757, actual molecular weight 308.1760. ¹hNMR (500MHz, d6-dMSO) δ 10.87 (s, 1H, 1 '-NH), 9.14 (t, J=5.41Hz, 1H, CONH), 7.67 (m, 1H, 6-H), 7.61 (d, J=8.0Hz, 1H, 4 '-H), 7.39-7.36 (m, 2H, 5-H and 7 '-H), 7.24 (d, J=2.42Hz, 1H, 2 '-H), 7.13 (d, J=8.0Hz, 1H, 3-H), 7.09 (t, J=7.5Hz, 1H, 4-H), 7.05 (t, J=7.5Hz, 1H, 6 '-H), 6.99 (t, J=7.5Hz, 1H, 5 '-H), 3.75-3.61 (m, 2H, CH ₂), 2.98 (t, J=7.11Hz, 2H, CH ₂), 2.48 (s, 6H, 2 × CH ₃).

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

Tryptamines (0.48g, 3mmol) joins 50mL flask and is dissolved in the methylene dichloride of 20mL drying, and Benzoyl chloride (self-control) (0.35mL, 3mmol) is added drop-wise in above-mentioned solution, is obtained by reacting crude product.Take ethyl acetate/petroleum ether as eluent, be separated through silica gel chromatographic column and obtain product crude product, then obtain CD18 sterling 0.65g (productive rate 82%) through re-crystallizing in ethyl acetate, mp141-143 DEG C.MS (ESIm/z) 265.25 (M+H) ⁺, 287.19 (M+Na) ⁺, HRMS (ESIm/z) [M+H] ⁺theoretical molecular formula C ₁₇h ₁₇n ₂o, theoretical molecular 265.1335, actual molecular weight 265.1336. ¹HNMR(400MHz，DMSO-d6)δ10.79(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)，7.33(d，J＝8.0Hz，1H，7’-H)，7.17(d，J＝2.0Hz，1H，2’-H)，7.06(td，J＝0.8，7.6Hz，1H，6’-H)，6.97(t，J＝0.8，7.6Hz，1H，5’-H)，3.56-3.51(m，2H，CH ₂NH)，2.94(t，J＝7.6Hz，2H，CH ₂)。

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

By the method for synthesis (CD12), with bigcatkin willow acyl chlorides (self-control) (1.5g, 10mmol) for raw material reaction obtains crude product, be that eluent obtains Main Components through silicagel column separation with methylene dichloride, use ether again: sherwood oil crystallization obtains CD13 sterling 1.63g (productive rate 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 C ₁₇h ₁₇n ₂o ₂, theoretical molecular 281.1284, actual molecular weight 281.1284. ¹HNMR(400MHz，CD ₃OD)δ7.64(d，J＝8.0Hz，1H，6-H)，7.54(d，J＝8.0Hz，1H，4’-H)，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，CH ₂NH)，3.00(t，J＝7.2Hz，2H，CH ₂)。

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

2-indolecarboxylic acid is (purchased from Beijing coupling Science and Technology Ltd., purity > 98%) (0.80g, 5mmol) join in 50mL round-bottomed flask, add dry methylene dichloride (30mL), continue to add EDCI hydrochloride (1.04g, 5.4mmol), 2-aminobenzamide (0.68g is added after stir about 30min, 5mmol), room temperature reaction 20h, filters, washing dry crude product.Filtrate dichloromethane extraction with anhydrous sodium sulfate drying.With ethyl acetate after organic layer is concentrated: sherwood oil=1: 3 are separated to obtain CD15 sterling 0.86g (productive rate 62%) for eluent through silica gel chromatographic column, white solid, mp258-260 DEG C.MS(ESIm/z)278(M-H) ^-， ¹HNMR(400MHz，DMSO-d6)δ13.05(s，1H，1’-H)，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)，7.86(s，1H，3’-H)，7.70(d，J＝8.0Hz，1H，4’-H)，7.57(td，J＝1.2，8.0Hz，1H，5-H)，7.46(d，J＝8.0Hz，1H，7’-H)，7.23(t，J＝7.6Hz，1H，6’-H)，7.16(t，J＝7.6Hz，1H，5’-H)，7.08(m，2H，NH ₂)。

(11) N-benzyl-2-(1H-indol-3-yl) ethanamide (CD16)

30mL methylene dichloride is added in 50mL flask, and add indole-3-acetic acid (0.35g successively, 2mmol) with benzylamine (0.22mL, 2mmol) for reactant is (all purchased from Beijing coupling Science and Technology Ltd., purity > 98%), add EDCI hydrochloride (0.4g, 2mmol) again to react and be separated and obtain CD16 sterling 0.28g (productive rate 35.4%), mp149-151 DEG C.MS (ESIm/z) 265 [M+H] ⁺, HRMS (ESIm/z) [M+H] ⁺theoretical molecular formula C ₁₇h ₁₇n ₂o, theoretical molecular 265.1335, actual molecular weight 265.1335. ¹hNMR (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, CH ₂nH), 3.58 (s, 2H, CH ₂).

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

With 3,4-dihydro-β-carboline (self-control) (0.26g, 1.5mmol) be raw material, be suspended in the methylene dichloride of 20mL drying, add Benzoyl chloride (0.4mL, 3.4mmol), add triethylamine (0.4mL, 3mmol) again, room temperature reaction 3h, the 30mL adjust ph that adds water is to neutral, and dichloromethane extraction also uses anhydrous sodium sulfate drying.Crude product ethyl acetate: sherwood oil=1: 1 obtains CD17 sterling 0.82g (productive rate 82%) through silica gel chromatographic column wash-out, mp275-277 DEG C.MS(ESIm/z)293.22(M+H) ⁺，315.21(M+Na) ⁺。 ¹HNMR(400MHz，CDCl ₃)δ10.01(s，1H，2’-CHO)，8.83(s，1H，1’-NH)，7.81(d，J＝8.0Hz，1H，4’-H)，7.66(dd，J＝1.2，7.2Hz，2H，5’，7’-2H)，7.50-7.38(m，5H，Ph-H)，7.20-7.15(m，1H，5’-H)，6.25(s，1H，CONH)，3.83(q，J＝6.8Hz，2H，CH ₂NH)，3.47(t，J＝6.8Hz，2H，CH ₂)。

(13) N-(2-(1H-indol-3-yl) ethyl)-2-methyl benzamide (CD18)

By the method for synthesis (CD12), with 2-methyl benzoyl chloride (self-control) (0.34g, 2.2mmol) for raw material obtains product crude product.Crude product is with ethyl acetate: sherwood oil is eluent, is separated obtains CD18 sterling 0.32g (productive rate 58%), white solid, mp159-161 DEG C through silicagel column.MS (ESIm/z) 301.18 (M+Na) ⁺, HRMS (ESIm/z) [M+H] ⁺theoretical molecular formula C ₁₈h ₁₉n ₂o, theoretical molecular 279.1492, actual molecular weight 279.1493. ¹hNMR (400MHz, CD ₃cOCD ₃) δ 9.99 (s, 1H, 1 '-NH), 7.65 (d, J=8.0Hz, 1H, 4 '-H), 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), 7.09 (td, J=0.8,7.6Hz, 1H, 6 '-H), 7.01 (td, J=0.8,7.6Hz, 1H, 5 '-H), 3.69 (q, J=7.2Hz, 2H, CH ₂nH), 3.08 (t, J=7.2Hz, 2H, CH ₂), 2.37 (s, 3H, CH ₃).

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

Nicotinic acid is (purchased from Beijing coupling Science and Technology Ltd., purity > 98%) (0.85g, 7mmol) be dissolved in 30mLN, in dinethylformamide solution, add EDCI hydrochloride (1.41g, 7mmol) and tryptamines (1.12g, 7mmol), 60 DEG C of reaction 20h, finally obtain CD19 sterling 1.34g (productive rate 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 C ₁₆h ₁₆n ₃o, theoretical molecular 266.1288, actual molecular weight 266.1287. ¹HNMR(500MHz，DMSO-d6)δ10.85(s，1H，1’-H)，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)，7.59(d，J＝8.0Hz，1H，4’-H)，7.36(d，J＝8.0Hz，1H，7’-H)，7.21(d，J＝2.0Hz，1H，2’-H)，7.08(t，J＝7.5Hz，1H，6’-H)，6.99(t，J＝7.5Hz，1H，5’-H)，3.59(td，J＝5.5，7.5Hz，2H，CH ₂NH)，2.99(t，J＝7.5Hz，2H，CH ₂)。

(15) N-(2-(2-ethanoyl-1H-indol-3-yl) ethyl) niacinamide (CD21)

1-methyl-3,4-dihydro-β-carboline (self-control) (0.74g, 4mmol) be dissolved in 30mL pyridine, add nicotinoyl chloride hydrochloride (1.41g, 8mmol), 60 DEG C of reaction 5h, with about 25% ammoniacal liquor adjust ph to 10, dichloromethane extraction and wash, the saturated common salt aqueous solution washes, concentrated after organic over anhydrous dried over sodium sulfate, crude product obtains jelly through ethyl acetate (triethylamine) wash-out, obtains CD20 sterling 0.25g (productive rate 21%), mp155-156 DEG C after methylene dichloride process.MS(ESIm/z)294.08(M+H) ⁺， ¹HNMR(400MHz，CD ₃COCD ₃)δ10.06(s，1H，2’-CHO)，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)，7.51(d，1H，J＝8.0Hz，7’-H)，7.42(m，1H，5-H)，7.35(td，1H，J＝0.8，8.0Hz，6’-H)，7.11(td，1H，J＝0.8，8.0Hz，5’-H)，3.76(q，2H，J＝6.8Hz，CH ₂NH)，3.48(t，2H，J＝6.8Hz，CH ₂)。

(16) 4-(N-(2-(1H-indol-3-yl) ethyl)-3-aminopyridine methane amide (CD22)

By the method for synthesis (CD1), with 3-amino-Isonicotinic acid (purchased from this company of Adama, purity > 99%) (0.28g, 2mmol) for reactant obtains crude product, and be eluent with ethyl acetate, CD22 sterling 0.15g (productive rate 28%), mp104-105 DEG C, MS (ESIm/z) 281.13 [M+H] is separated to obtain through silicagel column ⁺. ¹HNMR(400MHz，DMSO-d6)10.87(s，1H，1’-H)，8.84(m，1H，CONH)，8.18(s，1H，2-H)，7.84(d，J＝5.6Hz，1H，5-H)，7.58(d，J＝7.6Hz，1H，4’-H)，7.53(d，J＝5.6Hz，1H，6-H)，7.36-7.33(m，1H，7’-H)，7.19(d，J＝2.4Hz，1H，2’-H)，7.07(td，J＝1.2，7.2Hz，1H，6’-H)，6.98(td，J＝1.2，7.2Hz，1H，5’-H)，6.72(brs，2H，NH ₂)，3.39-3.37(m，2H，CH ₂NH)，3.09-3.03(m，2H，CH ₂)。

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

Tryptamines (0.8g, 5mmol) be dissolved in 50mL dehydrated alcohol, add Tetra hydro Phthalic anhydride (purchased from traditional Chinese medicines group chemical reagent Beijing company limited, purity > 98%) (0.75g, 5mmol) back flow reaction 1h, crystallisation by cooling obtains solid, and recrystallizing methanol obtains CD25 sterling 1.7g (productive rate 90%), mp163-164 DEG C.MS(ESIm/z)308.75(M+H) ⁺，330.68(M+Na) ⁺。 ¹HNMR(500MHz，DMSO-d6)δ10.83(s，1H，1’-NH)，7.89-7.83(m，4H，Ph-H)，7.56(d，J＝8.0Hz，1H，4’-H)，7.34(d，J＝8.0Hz，1H，7’-H)，7.19(d，J＝2.0Hz，1H，2’-H)，7.07(td，J＝1.0，7.5Hz，1H，6’-H)，6.98(td，J＝1.0，7.5Hz，1H，5’-H)，3.86(t，J＝7.5Hz，2H，CH ₂NH)，3.04(t，J＝7.5Hz，2H，CH ₂)。

(18) N-(2-(1H-indol-3-yl) ethyl)-2-phenoxy-acetamide (CD27)

Phenoxy acetic acid is (purchased from Beijing coupling Science and Technology Ltd., purity > 98%) (0.31g, 2mmol) be dissolved in DMF (15mL), add EDCI hydrochloride (0.4g, after 2mmol) reacting about 30min, add tryptamines (0.32g, 2mmol) again and react 6h, decompression steams solvent, add water extraction into ethyl acetate after 30mL, organic over anhydrous dried over sodium sulfate.After organic layer is concentrated, the process of crude product methylene dichloride obtains CD27 sterling 0.42g (productive rate 71%), mp137-139 DEG C.MS (ESIm/z) 295.29 [M+H] ⁺, 317.29 [M+Na] ⁺, HRMS (ESIm/z) [M+H] ⁺theoretical molecular formula C ₁₈h ₁₉n ₂o ₂, theoretical molecular 295.1441, actual molecular weight 295.1440. ¹hNMR (400MHz, DMSO-d6) δ 10.82 (s, 1H, 1 '-NH), 8.17 (t, J=5.6Hz, 1H, CONH), 7.56 (d, J=8.0Hz, 1H, 4 '-H), 7.34 (d, J=8.0Hz, 1H, 7 '-H), 7.31 (dt, J=8.0Hz, 2H, Ph-2H), 7.14 (d, J=2.0Hz, 1H, 2 '-H), 7.07 (dt, J=8.0Hz, 1H, 6 '-H), 7.00-6.94 (m, 4H, 5 '-H and Ph-3H), 4.47 (s, 2H, CH ₂o), 3.43 (q, J=7.2Hz, 2H, CH ₂nH), 2.87 (t, J=8.0Hz, 2H, CH ₂).

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

By the method for synthesis (CD12), with phenyl chloroformate (purchased from Beijing coupling Science and Technology Ltd., purity > 98%) (0.26mL, 2mmol) for reactant obtains crude product, crude product is with ethyl acetate: sherwood oil is eluent, be separated through silicagel column and obtain Main Components, then obtain CD28 sterling 174mg (productive rate 31%) with ether/sherwood oil crystallization, mp63-65 DEG C.HRMS (ESIm/z) [M+H] ⁺theoretical molecular formula C ₁₇h ₁₇n ₂o ₂, theoretical molecular 281.1284, actual molecular weight found281.1284. ¹hNMR (400MHz, DMSO-d6) δ 10.84 (brs, 1H, 1 '-NH), 7.86 (t, J=5.6Hz, 1H, CONH), 7.56 (d, J=7.6Hz, 1H, 4 '-H), 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 (m, 3H, 6 '-H and 3,5-2H), 6.99 (t, J=7.2Hz, 1H, 5 '-H), 3.38-3.33 (m, 2H, CH ₂nH), 2.91 (t, J=7.2Hz, 2H, CH ₂).

(20) N-(2-(1H-indol-3-yl) ethyl) quinoline-3-methane amide (CD31)

Quinoline-3-carboxylic acid is (purchased from Beijing coupling Science and Technology Ltd., purity > 98%) (0.35g, 2mmol) be dissolved in DMF (15mL), add EDCI hydrochloride (0.45g, after 2.3mmol) reacting 30min, add tryptamines (0.32g, 2mmol), spend the night 100 DEG C of reactions, steam solvent, DCM extraction after adding water, then through ethyl acetate: sherwood oil is crossed after post is separated and is obtained CD31 sterling 0.41g (productive rate 65%), mp107-109 DEG C.MS(ESIm/z)316.15[M+H] ⁺。 ¹HNMR(400MHz，DMSO-d6)δ10.87(s，1H，1’-H)，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)，7.58(d，J＝8.0Hz，1H，4’-H)，7.35(d，J＝8.0Hz，1H，7’-H)，7.21(d，J＝2.0Hz，1H，2’-H)，7.07(td，J＝1.2，8.0Hz，1H，6’-H)，6.98(td，J＝0.8，8.0Hz，1H，5’-H)，3.59(q，J＝7.2Hz，2H，CH ₂NH)，2.99(t，J＝7.2Hz，2H，CH ₂)。

(21) 5-ethanoyl-N-(2-(1H-indol-3-yl) ethyl) quinoline-3-methane amide (CD33)

By the method for synthesis (CD31); with 5-acetylquinoline-3-carboxylic acid (purchased from this company of Adama; purity > 98%) (0.43g; 2mmol) be raw material; target product CD33 sterling 0.56g (productive rate 79%) is obtained by reacting, MS (ESIm/z) 358.19 [M+H] with equimolar tryptamines ⁺. ¹HNMR(400MHz，DMSO-d6)δ10.87(s，1H，1’-H)，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)，7.58(d，J＝8.0Hz，1H，4’-H)，7.35(d，J＝8.0Hz，1H，7’-H)，7.21(d，J＝2.0Hz，1H，2’-H)，7.07(td，J＝1.2，8.0Hz，1H，6’-H)，6.98(td，J＝0.8，8.0Hz，1H，5’-H)，3.59(q，J＝7.2Hz，2H，CH ₂NH)，3.25(s，3H，CH ₃)，2.99(t，J＝7.2Hz，2H，CH ₂)。

(22) 7-methyl-N-(2-(1H-indol-3-yl) ethyl) quinoline-3-methane amide (CD35)

By the method for synthesis (CD31), with 7-toluquinoline-3-carboxylic acid (purchased from Beijing coupling Science and Technology Ltd., purity > 98%) (0.37g, 2mmol) be raw material, target product CD35 sterling 0.50g (productive rate 76%) is obtained by reacting, MS (ESIm/z) 330.21 [M+H] with equimolar tryptamines ⁺. ¹HNMR(400MHz，DMSO-d6)δ10.87(s，1H，1’-H)，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)，7.58(d，J＝8.0Hz，1H，4’-H)，7.35(d，J＝8.0Hz，1H，7’-H)，7.21(d，J＝2.0Hz，1H，2’-H)，7.07(td，J＝1.2，8.0Hz，1H，6’-H)，6.98(td，J＝0.8，8.0Hz，1H，5’-H)，3.59(q，J＝7.2Hz，2H，CH ₂NH)，2.99(t，J＝7.2Hz，2H，CH ₂)，1.23(s，3H，CH ₃)。

(23) N-(2-(1H-indol-3-yl) ethyl)-2-(2-bromine propionamido-) benzamide (CD36)

CD1 (0.28g, 1mmol) is dissolved in methylene dichloride (20mL), under ice-water bath, drips the dichloromethane solution of equimolar 2-bromo propionyl chloro (self-control), finish, room temperature reaction 4h, add water and use saturated NaHCO ₃solution adjust pH is to weakly alkaline (7-8), and extraction also with anhydrous sodium sulfate drying, obtains CD36 sterling 0.15g (productive rate 36.6%), mp165-166 DEG C after silica gel column chromatography is separated.MS(ESIm/z)414.09[M+H] ⁺，436.06[M+Na] ⁺。 ¹HNMR(500MHz，DMSO-d6)δ11.95(s，1H，1-NH)，11.81(d，J＝5.0Hz，1H，CONH)，10.83(s，1H，CONH)，8.92(t，J＝5.5Hz，1H，CH ₂NH)，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)，7.36(d，J＝8.0Hz，1H，7’-H)，7.22-7.18(m，2H，2’，4-H)，7.08(t，J＝7.5Hz，1H，6’-H)，6.99(t，J＝7.5Hz，1H，5’-H)，4.84-4.79(m，1H，CH-Br)，3.57(q，J＝7.5Hz，2H，CH ₂)，2.99(t，J＝7.5Hz，2H，CH ₂)1.80(d，J＝6.7Hz，1.5H)，1.7(d，J＝6.7Hz，1.5H)。

(24) N-(2-(1H-indol-3-yl) ethyl)-2-chlor(o)acetamide yl-benzamide (CD38)

By the synthetic method of (CD36), with equimolar chloroacetyl chloride (purchased from Beijing coupling Science and Technology Ltd., purity > 98%) and CD1 (0.28g, 1mmol) react to obtain crude product, CD38 sterling 143mg (productive rate 40%) is obtained, mp158-159 DEG C after silica gel column chromatography is separated.MS(ESIm/z)356.15[M+H] ⁺，378.21[M+Na] ⁺。 ¹HNMR(400MHz，DMSO-d6)δ11.94(s，1H，1’-NH)，10.83(s，1H，2-NH)，8.91(s，1H，NH-CH ₂)，8.42(d，J＝8.0Hz，1H，6-H)，7.73(d，J＝8.0Hz，1H，3-H)，7.59(d，J＝8.0Hz，1H，4’-H)，7.53(t，J＝8.0Hz，1H，4-H)，7.35(d，J＝8.0Hz，1H，7’-H)，7.19(m，2H，2’，5-2H)，7.07(t，J＝7.2Hz，1H，6’-H)，6.98(t，J＝7.2Hz，1H，5’-H)，4.41(s，2H，CH ₂-Cl)，3.57(q，J＝6.4Hz，2H，CH ₂-NH)，2.99(t，J＝6.8Hz，2H，CH ₂)。

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

By the synthetic method of (CD36), with CD1 (0.28g, 1mmol) be obtained by reacting product crude product with waiting mole propionyl chloride (self-control), sterling CD40 sterling 0.10g (productive rate 30%) is obtained after silica gel column chromatography is separated, mp123-124 DEG C, MS (ESIm/z) 336.22 [M+H] ⁺, 358.19 [M+Na] ⁺.HRMS (ESIm/z) [M+H] ⁺theoretical molecular formula C ₂₀h ₂₂n ₃o ₂, theoretical molecular 336.1706, actual molecular weight 336.1706. ¹hNMR (400MHz, DMSO-d6) δ 11.30 (s, 1H, 1 '-NH), 10.82 (s, 1H, CONH), 8.85 (t, J=5.75Hz, 1H, CH ₂nH), 8.42 (dd, J=1.17,8.50Hz, 1H, 6-H), 7.69 (dd, J=1.52,8.02Hz, 1H, 3-H), 7.58 (d, J=7.79Hz, 1H, 4 '-H), 7.47 (td, J=1.46,8.60Hz, 1H, 5-H), 7.34 (d, J=8.07Hz, 1H, 7 '-H), 7.20 (d, J=2.27Hz, 1H, 2 '-H), 7.16-6.94 (m, 3H, 5 ' 6 '-2H and 4-H), 3.56 (q, J=7.44,2H, CH ₂nH), 2.98 (t, J=7.43Hz, 2H, CH ₂), 2.36 (q, J=7.52Hz, 2H, CH ₂), 1.12 (t, J=7.52Hz, 3H, CH ₃).

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

By the synthetic method of (CD27), with trifluoroacetic acid (purchased from Sigma-Aldrich, purity > 99%) 0.1mL and CD1 (0.31g, 1.1mmol) for reactant synthesis obtains crude product, CD43 sterling 0.13g (productive rate 32%) is obtained through silica gel chromatography column purification, mp160-161 DEG C, MS (ESIm/z) 376.20 (M+H) ⁺, 398.22 (M+Na) ⁺, HRMS (ESIm/z) [M+H] ⁺theoretical molecular formula C ₁₉h ₁₇n ₃o ₂f ₃, theoretical molecular 376.1267, actual molecular weight 376.1266. ¹HNMR(400MHz，CD ₃COCD ₃)δ13.47(brs，1H，1’-NH)，10.02(brs，1H，CONH)，8.55(d，J＝8.0Hz，1H，6-H)，8.39(s，1H，CH ₂NH)，7.86(d，J＝8.0Hz，1H，3-H)，7.62(d，J＝8.0Hz，1H，4’-H)，7.60(t，J＝8.0Hz，1H，5-H)，7.38(d，J＝8.0Hz，1H，7’-H)，7.25(t，J＝8.0Hz，1H，4-H)，7.22(d，J＝1.6Hz，1H，2’-H)，7.09(t，J＝7.6Hz，1H，6’-H)，7.00(t，J＝7.6Hz，1H，5’-H)，3.75(q，J＝6.8Hz，2H，CH ₂NH)，3.11(t，J＝6.8Hz，2H，CH ₂)。

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

2-aminoethyl phenol is (purchased from Beijing coupling Science and Technology Ltd., purity > 98%) (0.68g, 5mmol) join 30mLN, in dinethylformamide with 2-benzaminic acid (0.68g, 5mmol), add EDCI hydrochloride (1.02g again, 5mmol), room temperature reaction 24h, decompression steams solvent, the solid that added water is separated out, and filters and dry intermediate.Intermediate is dissolved in the methylene dichloride of 30mL drying, add triethylamine 0.5mL, drip propionyl chloride to above-mentioned solution, and room temperature reaction 4h aftertreatment obtains BCD1 sterling 1.1g (productive rate 71%), MS (ESIm/z) 313.23 (M+H) ⁺. ¹HNMR(400MHz，CD ₃COCD ₃)δ10.52(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，CH ₂NH)，3.38(q，J＝7.5Hz，2H，CH ₂-CH ₃)，2.91(t，J＝7.2Hz，2H，CH ₂)，1.67(t，J＝7.2Hz，3H，CH ₃)。

(28) N-(2-phenylethyl)-2-aminobenzamide (BCD3)

At EDCI hydrochloride (1.02g, under 5mmol) existing, by phenylethylamine (purchased from Beijing coupling Science and Technology Ltd., purity > 98%) (0.61g, 5mmol) react in methylene dichloride with equimolar 2-benzaminic acid, BCD1 sterling 0.90g (productive rate 75%) is obtained, white solid, mp92-94 DEG C after process.MS (ESIm/z) 241.53 (M+H) ⁺, 263.39 (M+Na) ⁺, HRMS (ESIm/z) [M+H] ⁺theoretical molecular formula C ₁₅h ₁₇n ₂o, theoretical molecular 241.1335, actual molecular weight 241.1334. ¹HNMR(400MHz，CD ₃COCD ₃)δ7.56(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-NH ₂)，3.59(q，J＝7.2Hz，2H，CH ₂NH)，2.91(t，J＝7.2Hz，2H，CH ₂)。

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

Phenylethylamine (1.2mL, 10mol) and o-hydroxy formyl chloride (self-control) (1.5g, 10mmol) are dissolved in methylene dichloride (40mL), and add triethylamine 2mL, room temperature reaction spends the night, stopped reaction.Dichloromethane extraction with after anhydrous sodium sulfate drying, crude product methylene dichloride through silicagel column elution winner component, then obtains BCD2 sterling 1.58g (productive rate 66%) with ether/sherwood oil crystallization, white solid, mp90-92 DEG C.MS (ESIm/z) 242.20 (M+H) ⁺, 264.17 (M+Na) ⁺, HRMS (ESI) [M+H] ⁺theoretical molecular formula C ₁₅h ₁₆nO ₂, theoretical molecular 242.1176, actual molecular weight 242.1175. ¹HNMR(400MHz，CD ₃OD)δ7.64(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，CH ₂NH)，2.86(t，J＝7.2Hz，2H，CH ₂)。

(30) N-(2-(3-acetylphenyl) ethyl)-2-propionamido-benzamide (BCD5)

By the method for synthesis (BCD1), with 3-amino-ethyl methyl phenyl ketone (purchased from Beijing coupling Science and Technology Ltd., purity > 98%) (0.81g, 5mmol) be raw material reaction, BCD5 sterling 1.3g (productive rate 76%) is finally obtained, MS (ESIm/z) 339.23 (M+H) through separation and purification ⁺, ¹hNMR (400MHz, CD ₃cOCD ₃) 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, CH ₂nH), 3.45 (q, J=7.5Hz, 2H, CH ₂-CH ₃), 2.91 (t, J=7.2Hz, 2H, CH ₂), 1.25 (t, J=7.2Hz, 3H, CH ₃).

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

ABCA1p-LUCHepG2 cell is available from country of Inst. of Medicinal Biological Technology, Chinese Academy of Medical Sciences new drug (microorganism) laboratory.Can see the article IdentificationofUp-regulatorsofHumanATP-bindingCassetteT ransporterAlviaHigh-throughputScreeningofSyntheticandNat uralCompoundLibrary of the people such as such as JieGao (coming finder ABCA1 adjusts by high flux screening synthesis and natural product storehouse) .JBiomolScreen.2008 to the treating processes of this cell, 13 (7): 648-656, and noble and unsullied Ph D dissertation " taking ABCA1 as the study on its developing research of the novel Antiatherosclerosis medicine screening model of target spot ".

By ABCA1-LUCHepG2 cell, with 5 × 10 ⁴individual/hole is inoculated in 96 porocyte culture plates, and about 6h is after cell attachment, is replaced by the serum-free RPMI-1640 substratum (Hyclone) (200 μ l/ hole) of the compounds of this invention containing a series of weaker concn respectively.The hole of final concentration 0.1%DMSO substratum is as blank.Continue at 37 DEG C, after cultivating 18-24h under 5%CO2 condition, PBS (200 μ l/ hole) washes plate 2 times, abandons PBS.Add cell pyrolysis liquid (CCLR, Promega) (20 μ l/ hole), after 15-30min, after basis of microscopic observation lysis completely, add luciferase (Promega) (60 μ l/ hole), measure uciferase activity (microplate reader immediately, EnVision, PerkinElmer) reading), the dose-effect relationship between analytic sample concentration and the rate of change of uciferase activity, calculates EC50.

With following Equation for Calculating testing sample to the rate of change of uciferase activity:

Regulation rate (%)=A/B × 100

Wherein, A is cell fluorescence element enzymic activity (RLU) measured after adding testing sample, cell fluorescence element enzymic activity (RLU) that B measures afterwards for adding blank control sample (DMSO).Regulation rate >=150% of testing sample be namely considered as the positive, and observe the impact of positive on cell state.

Utilize GraphPadPrim5 computed in software EC50, result is as following table 2.As can be seen from Table 2, in ABCA1p-LUCHepG2 cell, compound of the present invention has the activity of rise ABCA1 in various degree.This also illustrates that compound of the present invention can increase the expression of ABCA1, and ABCA1 high expression level just can promote the lipids such as cholesterol to arrange outward, is conducive to treating and/or preventing the cardiovascular and cerebrovascular diseases such as hyperlipidaemia and atherosclerosis.

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

CLAp-LUCHepG2 is available from country of Inst. of Medicinal Biological Technology, Chinese Academy of Medical Sciences new drug (microorganism) laboratory.Can see the article IdentificationofNovelHumanHigh-DensityLipoproteinRecepto rUp-regulatorsUsingaCell-BasedHigh-ThroughputScreeningAs say of the people such as such as YuanYang (utilize and find high-density lipoprotein (HDL) receptor is adjusted based on the experiment of cell high flux screening) .JBiomolScreen2007 to the treating processes of this cell, 12 (2): 211-219, and the Ph D dissertation of Yang Yuan " screening that microbe-derived high-density lipoprotein (HDL) receptor is adjusted, discovery and related activity research ".

By CLAp-LUCHepG2 cell, with 5 × 10 ⁴individual cells/well is inoculated in 96 porocyte culture plates, until cell attachment after about 6 hours, is changed to the serum-free MEM-EBSS substratum (200 μ l/ hole) of the compounds of this invention containing a series of weaker concn respectively.Keep the final concentration of DMSO in each hole to be 0.1%, separately set final concentration as the hole of 0.1%DMSO substratum is as blank.Continue at 37 DEG C, cultivate after 18 hours under 5%CO2 condition, PBS (200 μ l/ hole) washes plate 2 times, abandons PBS.Add cell pyrolysis liquid (20 μ l/ hole) (Promega), after 15-30min, basis of microscopic observation cell splits completely, add luciferase (60 μ l/ hole), measure uciferase activity (microplate reader reading) immediately, dose-effect relationship between analytic sample concentration and the rate of change of uciferase activity, calculates EC50.

Regulation rate (%)=A/B × 100

Utilize GraphPadPrim5 computed in software EC50, result is as following table 2.As can be seen from Table 2, compound of the present invention has the activity raising SR-BI/CLA-1 in various degree.This illustrates that described compound has good rise effect to SR-BI/CLA-1, the expression of SR-BI/CLA-1 will be increased, and SR-BI/CLA-1 high expression level can promote the lipids such as cholesterol to arrange outward, be conducive to treating and/or preventing the cardiovascular and cerebrovascular diseases such as hyperlipidaemia and 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 comprises PPAR γ, PPAR α, LXRs comprise LXR α, LXR β.PPARs, LXRs have two main structural domains: ligand binding domains (LBD) and DNA binding domains (DBD), they have independently function separately.

The PPAR gamma agonist model utilizing this room to build, is built into fusion expression vector pBIND-PPAR γ-LBD by the ligand binding domains (LBD) of PPAR γ and the DNA binding domains (DBD) of yeast cell transcription factor GAL4.The respective element of synthetic 5 × GAL4, inserts reporter gene upstream and builds reporter plasmid pG5-promotor-GAL4 (being called for short GAL4).In like manner, pBIND-PPAR α-LBD, pBIND-LXR α-LBD, pBIND-LXR β-LBD is constructed.

PBIND-PPAR γ-LBD, PPAR α-LBD, pBIND-LXR α-LBD, pBIND-LXR β-LBD, GAL4 plasmid, and PPAR γ, PPAR α, LXR α, LXR beta-agonists model is all available from country of Inst. of Medicinal Biological Technology, Chinese Academy of Medical Sciences new drug (microorganism) laboratory, wherein the treating processes of plasmid construction process and cell can see Zheng Zhihui, Li Ni Ph D dissertation, such as Zheng Zhihui Ph D dissertation " be correlated with nuclear receptor drug screening by metabolic disease, the foundation of appraisement system and the pharmaceutical research of active compound ", Li Ni Ph D dissertation " discovery of the novel Antiatherosclerosis medicine primer of target liver X receptor and molecular pharmacology research ".

GAL4 reporter plasmid is respectively with the recombinant plasmid pBIND-PPAR γ-LBD, the pBIND-PPAR α-LBD that build, pBIND-LXR α-LBD, pBIND-LXR β-LBD be through Lipofectamine ^tM2000 (Invitrogen) mediate cotransfection HepG2 cell, and 5 × 10 ⁴individual cells/well (96 orifice plate), 200ng plasmid DNA (ratio of reporter plasmid GAL4 and expression plasmid pBIND-PPAR γ-LBD etc. is 10: 1), 0.5 μ l liposome/hole, the serum-free MEM substratum (200 μ l/ hole) of the compounds of this invention containing a series of weaker concn is changed to after transfection 6h, continue to hatch 18h, blank adds containing the MEM substratum with testing sample same concentrations DMSO.Measure uciferase activity in the HepG2 cell of transient transfection.The determinand that testing sample adds in cell the indirect reaction of uciferase activity rate of change to the transcriptional activation activity of PPAR γ, PPAR α, LXR α, LXR β, with following Equation for Calculating testing sample to the rate of change of the uciferase activity of cell:

Regulation rate (%)=A/B × 100

Wherein, A is cell fluorescence element enzymic activity (RLU) measured after adding testing sample, cell fluorescence element enzymic activity (RLU) that B measures afterwards for adding blank control sample (DMSO).

The agonist activity of described compound to PPARs the results are shown in Table 3.As can be seen from Table 3, compound of the present invention can exciting PPARs, and exciting PPARs will have vital role to lipid and cholesterol efflux, and meanwhile, exciting PPARs will reduce sugar level.The agonist activity of described compound to LXRs the results are shown in Table 4.As can be seen from Table 4, compound of the present invention can exciting LXRs, and exciting LXRs will have vital role to lipid and cholesterol efflux.Therefore, compound of the present invention can be applied to treating and/or preventing of the cardiovascular and cerebrovascular diseases such as hyperlipidaemia, atherosclerosis.

Table 3: amount of activated compound is to PPARs agonist activity

Table 4: amount of activated compound is to LXRs agonist activity

Embodiment 5: compound is to the agonist activity of TRPV1

Plasmid PCMV6-hTRPV1 is available from ORIGENE company, and this plasmid is the multiple clone site ORF district of people TRPV1 (altogether 2520bp) being inserted PCMV6 expression plasmid.Utilize Lipo2000 (Invitrogen) by PCMV6-hTRPV1 plasmid transfection Chinese hamster ovary cancer Chinese hamster ovary celI (national new drug (microorganism) screening experiment room), 100 μ g/mlG418 (Sigma) select the mono-clonal of high expression level people TRPV1, Liquid nitrogen storage, called after CHO-hTRPV1 (country of Inst. of Medicinal Biological Technology, Chinese Academy of Medical Sciences new drug (microorganism) laboratory), thus successfully build the stable cell line of high expression level people TRPV1.

Fluo4-AM (Invitrogen) is a kind of acetoxymethyl ester derivative of Fluo4, by cultivating, can enter in cell easily.After Fluo4-AM enters cell can be hydrolyzed by born of the same parents' lactonase, the Fluo4 of generation subsequently can with calcium ion (Ca ²⁺) combine and send fluorescence.

If the exciting TRPV1 of compound energy, then can cause Ca ²⁺interior stream, the Ca namely in cell ²⁺increase, the Ca that Fluo4 combines ²⁺also can increase, then can show strong fluorescence values, according to the enhancing of fluorescence values thus filter out can the compound of exciting TRPV1.

Concrete steps: by stable cell line CHO-hTRPV1 with 5 × 10 ⁴individual/hole is inoculated in 96 porocyte culture plates, 37 DEG C, and 5%CO2 cultivates, and treat after 6H that substratum siphons away by cell attachment, HBSS (100 μ l/ hole) washes plate 3 times, abandons HBSS.Add 2 μMs of Fluo4-AM (50 μ l/ hole) (Invitrogen), 37 DEG C hatch 30min after, HBSS (100 μ l/ hole) washes plate 2 times, add HBSS (100 μ l/ hole) 37 DEG C and hatch 30min (entering after cell abundant by the hydrolysis of born of the same parents' lactonase until Fluo4-AM), add the compound (0.5 μ l/ hole) of a series of DMSO weaker concn, measuring exciting light is immediately 495nm, utilizing emitted light is the fluorescence values (microplate reader reading) at 518nm place, the every 2s of numerical value reads once, the fluorescence values change in monitoring 2-6min.

The agonist activity of multiple compounds to TRPV1 the results are shown in Figure 1.As can be seen from Figure 1, the compounds of this invention can exciting TRPV1, and exciting TRPV1 will have vital role to anti-inflammatory and analgesia, meanwhile, now there are some researches show that exciting TRPV1 also has important effect to cardiovascular disorder.Therefore, compound of the present invention can be applied to the cardiovascular and cerebrovascular diseases such as atherosclerosis, inflammation, the treating and/or preventing of pain.

Embodiment 6: compound is on the impact of the protein expression level of ABCA1, SR-BI/CLA-1, ABCG1 in RAW264.7 cell and HepG2 cell

1) preparation of protein sample: compd B CD1 (0.01,0.1,1,10 μM) effect HepG2 cell or RAW264.7 cell 18-24h, Compound C D1 (0.01,0.1,1,10 μM) are acted on HepG2 cell or RAW264.7 cell 18-24h; Digestion centrifugal collecting cell, PBS washes once.Utilize RIPA (Beijing Puli comes company), each orifice plate adds the lysate (adding PMSF, the leupeptin of 1 μ g/ml and the Aprotinin of 1 μ g/ml that final concentration is 100 μ g/ml in every 1ml lysate) of 70 μ l respectively, in lysing cell 30min on ice.Collect each group of cell pyrolysis liquid, in 4 DEG C, the centrifugal 15min of 12000 × g.Collect supernatant, with BCA test kit (BCA ^tMproteinAssayKit, Pierce) carry out quantitatively to albumen, with cell pyrolysis liquid, each histone sample is adjusted to same concentration quantitatively.

2) protein electrophoresis (SDS-PAGE): the separation gel of preparation 8%, albumen sample 15 μ l, pre-dyed albumen Marker (10kDa, 15kDa on every duct, 27kDa, 35kDa, 55kDa, 70kDa, 100kDa, 130kDa, 250kDa), Fermentas Products.

3) Westernblot analyzes: after SDS-PAGE electrophoresis, adopts semidrying or wet method by the protein delivery on separation gel on pvdf membrane.Electric current is set according to 0.8mA/cm2, constant current transferring film 2.5h.After transferring film terminates, TBS (W/V) rocked at room temperature be placed in by pvdf membrane containing 5% skim-milk closes 1-2h.Close and terminate, wash pvdf membrane three times with 1 × TBS, each 10min.Dilute corresponding primary antibodie with the TBST (W/V) containing 5% skim-milk, be placed in hybridization bag, 4 DEG C of overnight incubation.From hybridization bag, take out pvdf membrane, wash three times with 1 × TBST, each 10min.Anti-ly hybridization bag is placed in, incubated at room 2h with dilute containing the TBST (W/V) of 5% skim-milk that horseradish peroxidase (HRP) marks two.From hybridization bag, take out pvdf membrane, wash three times with 1 × TBST, each 10min.

4) develop the color: in the front of film, namely turn the mixed solution (matching while using) having the one side of albumen to add appropriate enhanced chemical luminescent solution A, B liquid, be placed in gel imaging instrument immediately and develop the color.

Result is see Fig. 2.As can be seen from Figure 2, compd B CD1 (0.01,0.1,1,10 μM) significantly can increase the expression of ABCA1, SR-BI/CLA-1, ABCG1 in HepG2 cell and RAW264.7 cell.Compound C D1 significantly can increase the expression of ABCA1, SR-BI, ABCG1 in RAW264.7 cell.

ABCA1, SR-BI/CLA-1, ABCG1 are the key proteins promoting Cholesterol Efflux in RCT, compound of the present invention can increase the expression of these albumen, just can promote that the lipids such as cholesterol are arranged outward, be conducive to treating and/or preventing the cardiovascular and cerebrovascular diseases such as hyperlipidaemia, atherosclerosis.

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

1) the DMEM-high glucose medium (500 μ l/ hole) of mouse monokaryon-scavenger cell RAW264.7 containing 10%FBS, with 2 × 10 ⁵individual/hole, is inoculated on 24 porocyte culture plates, in 37 DEG C, and incubated overnight under 5%CO2 condition.

2) abandon enchylema, be changed to the DMEM-high glucose medium (500 μ l/ hole) containing 0.2% (w/v) BSA, add 1,2-[3H] cholesterol and make its final concentration be 1 μ Ci/ml, 37 DEG C, under 5%CO2 condition, hatching 24h.

3) cell is washed 2 times with PBS (1ml/ hole), (DMEM adds 0.2%BSA to the mensuration substratum adding containing Compound C D1, CD10, BCD1 (concentration is respectively 0.1,1 μM), 0.1%DMSO, 25mMHEPES, pH7.4), 18-24h is hatched for 37 DEG C.

4) wash cell 2 times with PBS (1ml/ hole), add substratum (DMEM adds 0.2%BSA, 0.1%DMSO, 25mMHEPES, pH7.4), have or without the apoA-I of 10 μ g/ml, hatch 4h.

5) collect substratum, the centrifugal 5min of 10000 × g, gets supernatant to be measured.

6) with 0.1MNaOH0.5ml lysis at room temperature cell 30min, lysate is collected to be measured.

7) measure: testing sample is transferred to respectively on 3MM filter paper, 75 DEG C of oven dry, the scraps of paper being placed on liquid dodges in cup, (mass concentration is 0.5%PPO (2 to add 10ml liquid sudden strain of a muscle liquid, 5-diphenyloxazole) and 0.05%POPOP (Isosorbide-5-Nitrae-bis--2-15-oxazolyl phenyl benzene) and volume fraction be that the solvent of 55% dimethylbenzene and 45% glycol dimethyl ether is prepared, be placed in brown container and put, to spend the night use), liquid scintillation counter counts.Whole experimental cell is divided into control group (not adding cholesterol still to add apoA-I, add cholesterol) and application of sample group (simultaneously adding cholesterol, apoA-I and certain density testing sample [15,20]).

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

=nutrient solution cpm value/(nutrient solution cpm value+cell cpm value) × 100%.

Result is see Fig. 3.As can be seen from Figure 3, compared with the control, the compounds of this invention CD1, CD10, BCD1, when 0.1 and 1 μM of two dosage, can significantly promote that intracellular cholesteryl flows out.And promote that Cholesterol Efflux is the key for the treatment of and the/cardiovascular and cerebrovascular diseases such as preventing hyperlipidemia and atherosclerosis, the above-mentioned disease for the treatment of is of great significance.

Embodiment 8: macrophage foam cell formationization is tested

The DMEM-high sugared nutrient solution adherent culture of monocytes/macrophages RAW264.7 containing 10%FBS of mouse.Cell is with 6 × 10 ⁴individual/hole is inoculated on 96 porocyte culture plates, in 37 DEG C, and 5%CO ₂under condition after incubated overnight, be changed to serum-free DMEM-high glucose medium (100 μ l/ hole).Cell is divided into control group, foam cell group and application of sample group, add final concentration be the Ox-LDL of 80mg/L to foam cell group and application of sample group, application of sample group will add certain density testing sample simultaneously.37 DEG C, 5%CO ₂after cultivating 24h under condition, carry out oil red O stain.

By 96 orifice plates from CO ₂take out in incubator, 4% paraformaldehyde is fixed (15 μ l/ hole) 10min, abandon solution, distilled water washes twice, then adds 60% Virahol (150 μ l/ hole), places 5min, discards solution.Liquid is used to add in each hole oil red O, 150 μ l/ holes, dyeing 1h.Discard solution, with 60% Virahol (150 μ l/ hole) hole flushing, then use distilled water (150 μ l/ hole) to wash twice, last every hole adds 150 μ l distilled waters and is placed in basis of microscopic observation, takes pictures.Result see Fig. 4, wherein a: blank; B:ox-LDL (80 μ g/ml); C:ox-LDL+CD1 (10 μMs); D:ox-LDL+CD2 (10 μMs); E:ox-LDL+BCD1 (10 μMs); F:ox-LDL+BCD2 (10 μMs).As can be seen from Figure 4, it is more only to add ox-LDL (80 μ g/ml) (Fig. 4 .b) lipid within endothelial cells, and oil red color is obvious, does not almost have redness in blank group (not adding ox-LDL) (Fig. 4 .a) cell.With only add compared with ox-LDL (Fig. 4 .b), Compound C D1, CD2, BCD1, BCD2 (10 μMs) significantly can reduce scavenger cell picked-up ox-LDL, reduce lipid and cholesterol is built up in cell.And promote and lipids cholesterol to arrange outward be the key treating and/or preventing the cardiovascular and cerebrovascular diseases such as hyperlipidaemia and atherosclerosis, be of great significance treating above-mentioned disease.

Embodiment 9: compound is at apoE ^-/-pharmacodynamic evaluation in Mice Body

A) apoE ^-/-the structure of rat aorta is atherosis model

ApoE ^-/-mouse (Beijing Vital River Experimental Animals Technology Co., Ltd.), in 7 week age, normal diet is fed one week;

By apoE ^-/-mouse is weighed, random packet, is divided into 4 groups (model group, CD1 group, CDl0 group, negative control group), only often organizes 6-8;

From 8 week age, model group and administration group fed high lipid food (Chinese military medicine academy of sciences, formula: 80% mouse mash feed, 20% lard, 1.5% cholesterol), and negative control group continues to feed normal diet;

Administration: CD1 (20mg/kg), CD10 (20mg/kg), intraperitoneal injection; Negative control group and model group to carboxymethylcellulose sodium solution, gastric infusion, administration 4 weeks;

By the administration apoE of 4 weeks ^-/-mouse fasting 6h; Pluck eyeball and get blood, collect blood with the EP pipe of heparin rinse, turn upside down, be placed on ice, 4000rpm/min, 4 DEG C of centrifugal 3min, supernatant liquor is transferred in new EP pipe and (divides two parts), be placed in-20 DEG C of preservations.

Fixing mouse, cuts off skin until belly with operating scissors along the median line of neck, cuts off abdominal cavity, first leave and take fresh liver organization, puts into EP pipe (dividing three parts), puts into liquid nitrogen immediately, stay and do RNA and Protein Assav;

After having got liver, cut off thoracic cavity, cut off breastbone, expose heart, carry out cardiac perfusion immediately, first pour into about 1ml with the paraformaldehyde of 4%, then change PBS into and pour into about 4ml, stop after liver bleaches;

Take out liver and small intestine successively; Be separated from aorta to the artery total length of the total branch of ilium, take out heart and artery.After dissection, liver, heart and aorta are put into the paraformaldehyde of 4%, 37 DEG C of fixing 2h, then put into the sucrose solution of 20%, and 4 DEG C are spent the night.

B) blood lipid level detects

By administration or the carboxymethyl cellulose apoE of 8 weeks ^-/-mouse fasting 6h; Pluck eyeball and get blood, blood is collected with the EP pipe of heparin rinse, turn upside down, be placed on ice, 4000rpm/min, 4 DEG C of centrifugal 3min, measure the content of serum total cholesterol (TC), triglyceride level (TG), high density lipoprotein cholesterol (HDL-C) and low density lipoprotein cholesterol (LDL-C) according to the world and explanation by the serum be separated.Above detection kit is Beijing Zhong Shengbei and controls clinical reagent Products.

Table 5: compound is to apoE ^-/-the impact (mg/dL) of lipid of mice level

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

Result is see table 5.As can be seen from Table 5, compared with model group, in administration CD1 group and CD10 group, TC, TG, LDL-C level significantly reduces, and HDL-C level raises.TC, TG, LDL-C level illustrates that the compounds of this invention well can reduce the blood fat disorder diseases such as hyperlipidaemia, and HDL-C raises, and is conducive to the metabolism such as body inner cholesterol, be conducive to playing anti-inflammatory, antithrombotic, the effect such as anti-oxidant.In a word, table 5 result illustrates the compounds of this invention energy well adjusting blood lipid, may be used for the treatment treating and/or preventing the cardiovascular and cerebrovascular diseases such as hyperlipidaemia, inflammation and atherosclerosis.

C) making method of frozen section

1.5mlEP pipe is cut off from middle part, leaves part with cover, lid is covered, carry out mark;

OCT embedding medium is added in EP pipe, notes not having bubble;

The tissue soaked in 20% sucrose is put in OCT, during heart embedding, stays about 1/3 heart, cut flat, slowly put into OCT by apex of the heart part upward; During liver embedding, when keeping tangent plane to put into OCT in one plane;

Organized for bag EP pipe is slowly put in liquid nitrogen;

Wrap the EP pipe freezed immediately with tinfoil ,-20 DEG C keep in Dark Place, and long-term preservation is placed on-80 DEG C.

D) aorta oil red O stain

Taken out from 20% sucrose by aorta, PBS washes once;

Under dissecting microscope, aorta is longitudinally cut open;

The aorta cut off is distilled washing 3 times;

60% Virahol soaks 10min, carries out synchronization;

Good for synchronization is put into the oil red working fluid (oil red storage liquid configures, and filters in 1-2h and uses) newly prepared, 30min;

Put into 60% Virahol color separation 1min;

Distilled water washes 3 times;

Aorta solution cut open is laid on black wax, and photographic camera is taken a picture immediately.

Result is see Fig. 5.As can be seen from Figure 5, high fat diet is after 2 months, and in model group aorta total length, patch is obvious; Compared with model group, in administration CD1 group and CD10 group aorta total length, plaque area obviously reduces.The above results illustrates, the compounds of this invention CD1 and CD10 can prevent and/or treat atherosclerosis effectively, and useful to preventing and/or treating of the cardiovascular and cerebrovascular diseases based on atherosclerosis.

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

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

Section is put into 4% paraformaldehyde, fixing 10min;

Abandon paraformaldehyde solution, add distilled water, wash 3 times, each 3min;

60% Virahol soaks section 3min, carries out synchronization;

Then the section that synchronization is good is put into the oil red working fluid (oil red storage liquid configures, and filters in 1-2h and uses) newly prepared, 30min;

Section is put into 60% Virahol color separation, examine under a microscope at any time;

Distilled water washes 3 times;

Phenodin dye 2-3min, redyes nucleus;

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

Water-based mountant mounting (9 parts of medical glycerines+1 part of distilled water);

The slice, thin piece surrounding sealed is coated with nail varnish, and drying in the shade in shady and cool place, takes a picture immediately.

Result is see Fig. 6.As can be seen from Figure 6, high fat diet is after 2 months, and in model group heart efferent tract, patch is obvious; Compared with model group, in administration CD1 group and CD10 group heart efferent tract, plaque area obviously reduces.The above results illustrates, Compound C D1 and CD10 can prevent and/or treat atherosclerosis effectively, and useful to preventing and/or treating of the cardiovascular and cerebrovascular diseases based on atherosclerosis.

F) on the impact of cholesterol in liver

The liver of every mouse is got 50mg, according to organizing total cholesterol enzymic measuring reagent box step (E1505, Beijing Puli's Lay company) measure total cholesterol level in each sample, utilize the protein concentration (with determination of protein concentration in embodiment 6) of protein quantification kit measurement sample, then calculate the total cholesterol level of every mouse liver.Total cholesterol level (μm ol/g)=total cholesterol concentration/protein concentration.

Result is see Fig. 7.As can be seen from Figure 7, high fat diet is after 2 months, and in model group liver, total cholesterol level significantly increases than blank group; Compared with model group, administration CD1 group and CD10 total cholesterol significantly reduce.The above results illustrates, Compound C D1 of the present invention and CD10 can prevent and/or treat atherosclerosis effectively, and it is useful Atherosclerosis to be turned to preventing and/or treating of the cardiovascular and cerebrovascular diseases of pathologic basis.

G) on the impact of blood pressure

Administration is after 2 months, and utilize blood pressure instrument (SoftronBP-98A, Japan) rating model group and administration respectively to organize the blood pressure of mouse, record systolic pressure SBP numerical value, every only detection three times, averages.

Result is see Fig. 8.As can be seen from Figure 8, high fat diet is after 2 months, and compared with model group, administration CD1 group and CD10 group blood pressure SBP reduce.The above results illustrate, Compound C D1 and CD10 can reduce blood pressure, and hypertensive prevent and/or treat useful.

H) on the impact of inflammatory factor

Utilize tumor necrosis factor alpha (Mousetumornecrosisfactor α, TNF-α), MCP 1 (Mousemonocytechemotacticprotein1/monocytechemotacticanda ctivatingfacto, MCP-1/MCAF) test kit (CUSABIO) measures the level such as inflammatory factor TNF-α, MCP-1/MCAF in serum.

Result is see Fig. 9.As can be seen from Figure 9, compared with model group, in administration CD1 group and CD10 group serum, TNF-α, MCP-1/MCAF reduce.The above results illustrates, Compound C D1 and CD10 has anti-inflammatory action, useful to preventing and/or treating of inflammation.

Embodiment 10: the pharmacodynamic evaluation of compound in diabetic mice

1) structure of db/db diabetes mice model:

8 week age, BKS.Cg-Dock7 ^m+ /+Lepr ^ab/ J mouse (Beijing Vital River Experimental Animals Technology Co., Ltd.), high fat diet (filling a prescription the same) 8-12 week, before grouping, detect fasting plasma glucose and weigh, select fasting plasma glucose>=11.1mmol/L and the close mouse random packet (negative control group of body weight, positive drug group, administration group), only often organize 6-8.

2) administration: use the CMC-Na solution of 0.5% that compound is prepared into uniform suspension.Gavage, every day 1 time, continuous 2 weeks.Dosage 50mg/kg.

3) fasting plasma glucose is detected:

Detection time: first 1 time of medicine, administration 2 weeks latter 1 time.

Detection method: the equal fasting 6h (freely drinking water) of animal before getting blood, tail point gets blood, measures with blood glucose meter and supporting test paper.

Result is see Figure 10.As can be seen from Figure 10, compared with the control, blood glucose value significantly reduces for CD1, CD2, BCD1, BCD2.The above results illustrates, Compound C D1, CD2, BCD1, BCD2 can reduce blood sugar, useful to preventing and/or treating of diabetes.

Embodiment 11: compound is on the impact of pain

Female Wistar rats 15, in 4 ~ 6 week age, body weight (180) g, is provided by Beijing Vital River Experimental Animals Technology Co., Ltd..Main agents: complete Freund's adjuvant (CFA, Sigma Products).

Animal adaptability is divided into 3 groups after raising 3d at random, often organizes the 5: 1st group and is left intact; As model group, get 0.1mlCFA and be injected in the subcutaneous induced arthritis generation of the left back toes of rat for 2nd group; 3rd group, get 0.1mlCFA and be injected in the subcutaneous induced arthritis generation of the left back toes of rat, and in rat left back toes subcutaneous injection BCD110mg/kg; 4th group, get 0.1mlCFA and be injected in the subcutaneous induced arthritis generation of the left back toes of rat, and in rat left back toes subcutaneous injection CD1310mg/kg; 5th group 5 only in rat left back toes subcutaneous injection 0.01mol/L Glacial acetic acid 0.1ml, to get rid of the sensitizing effect of solvent in CFA.

Result show, administration BCD1, CD13 group rat redness degree obviously weak than model group, illustrate that the compounds of this invention has good effect to inflammation and alleviating pain, therefore the compounds of this invention to inflammation, pain prevent and/or treat useful.

Although some embodiments of general plotting of the present invention have been shown and explanation, those skilled in the art will appreciate that, when not deviating from principle and the spirit of general plotting of the present invention, can make a change these embodiments, scope of the present invention is with claim and their equivalents.

Claims

1. the compound of a formula (I):

Wherein,

L ₁represent C ₁-C ₆alkylidene group or do not exist;

M ₁and M ₂represent-CO-differently from one another or do not exist;

Ar ₂represent wherein R ₁represent hydrogen, hydroxyl, amino, halogen, C ₁-C ₆alkyl, halo C ₁-C ₆alkyl, C ₁-C ₆alkylamino radical, two (C ₁-C ₆alkyl) amido, amino C ₁-C ₆alkyl, amino C ₁-C ₆alkyloyl, C ₁-C ₆alkyl amide, two (C ₁-C ₆alkyloyl) amido, halo C ₁-C ₆alkyl amide, carboxyl or-COO (C ₁-C ₆) alkyl; R2 represents hydrogen, amino, hydroxyl, C ₁-C ₆alkyl or C ₁-C ₆alkyloyl; R ₃represent hydrogen, halogen, C ₁-C ₆alkyl, C ₁-C ₆haloalkyl or C ₁-C ₆alkyloyl;

Or its pharmaceutical salts.

2. compound according to claim 1, is characterized in that,

L ₁represent C ₁-C ₂alkylidene group or do not exist;

Ar ₂represent wherein R ₁represent the phenyl that the substituting group be optionally selected from the group be made up of the following replaces: hydrogen, hydroxyl, amino, C ₁-C ₄alkyl, C ₁-C ₄alkylamino, two (C ₁-C ₄alkyl) amino, amino C ₁-C ₄alkyloyl, C ₁-C ₄alkyl amido, two (C ₁-C ₄alkyloyl) amino, halo C ₁-C ₄alkyl amido, carboxyl or-COO (C ₁-C ₃) alkyl; R ₂represent hydrogen, amino, hydroxyl, C ₁-C ₄alkyl or C ₁-C ₄alkyloyl; R ₃represent hydrogen, C ₁-C ₄alkyl or C ₁-C ₄alkyloyl;

Or its pharmaceutical salts.

3. compound according to claim 1, is characterized in that,

L ₁represent C ₁-C ₂alkylidene group or do not exist;

Ar ₂represent wherein R ₁represent the phenyl that the substituting group be optionally selected from the group be made up of the following replaces: hydrogen, hydroxyl, amino, C ₁-C ₄alkyl, C ₁-C ₄alkylamino, two (C ₁-C ₄alkyl) amino, amino C ₁-C ₄alkyloyl, C ₁-C ₄alkyl amido, two (C ₁-C ₄alkyloyl) amino, halo C ₁-C ₄alkyl amido, carboxyl or-COO (C ₁-C ₃) alkyl; R ₂represent hydrogen, amino, hydroxyl or C ₁-C ₄alkyl; R ₃represent hydrogen or C ₁-C ₄alkyl;

Or its pharmaceutical salts.

4. compound according to claim 1, is characterized in that,

L ₁represent methylene radical, ethylidene or do not exist;

L ₂represent methylene radical or do not exist; And

Ar ₂represent phenyl, PA-3-base, pyridin-3-yl, quinoline-3-base, by amino, hydroxyl, carbamyl, trifluoroacetyl group, propionyl, carboxyl or methyl substituted phenyl,

Or its pharmaceutical salts.

5. compound according to claim 1, is characterized in that, described compound is selected from the group be made up of the following:

N-(2-(1H-indol-3-yl) ethyl)-2-aminobenzamide (CD1),

N-(2-(5-ethanoyl-1H-indol-3-yl) ethyl)-2-aminobenzamide (CD2),

N-(2-(5-ethanoyl-1H-indol-3-yl) ethyl)-3-Aminomethyl benzamide (CD3),

N-(2-(1H-indol-3-yl) ethyl)-3-chlorobenzamide (CD4),

N-(2-(5-methoxyl group-1H-indol-3-yl) ethyl)-2-aminobenzamide (CD6),

N-(2-(the chloro-1H-indol-3-yl of 5-) ethyl)-2-propionamido-benzamide (CD8),

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

N-(2-(1H-indol-3-yl) ethyl) benzamide (CD12),

N-(2-(1H-indol-3-yl) ethyl)-2-Hydroxylbenzamide (CD13),

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

N-benzyl-2-(1H-indol-3-yl) ethanamide (CD16),

N-(2-(2-carboxaldehyde radicals-1H-indol-3-yl) ethyl)-benzamide (CD17),

N-(2-(1H-indol-3-yl) ethyl)-2-methyl benzamide (CD18),

N-(2-(1H-indol-3-yl) ethyl) niacinamide (CD19),

N-(2-(2-ethanoyl-1H-indol-3-yl) ethyl) niacinamide (CD21),

4-(N-(2-(1H-indol-3-yl) ethyl)-3-aminopyridine methane amide (CD22),

2-(N-(2-(1H-indoles-3-) ethyl) carbamyl) phenylformic acid (CD25),

N-(2-(1H-indol-3-yl) ethyl)-2-phenoxy-acetamide (CD27),

2-(1H-indol-3-yl) ethylamino-phenyl formate (CD28),

N-(2-(1H-indol-3-yl) ethyl) quinoline-3-methane amide (CD31),

5-ethanoyl-N-(2-(1H-indol-3-yl) ethyl) quinoline-3-methane amide (CD33),

7-methyl-N-(2-(1H-indol-3-yl) ethyl) quinoline-3-methane amide (CD35),

N-(2-(1H-indol-3-yl) ethyl)-2-(2-bromine propionamido-) benzamide (CD36),

N-(2-(1H-indol-3-yl) ethyl)-2-chlor(o)acetamide yl-benzamide (CD38),

N-(2-(1H-indol-3-yl) ethyl)-2-propionamido-benzamide (CD40),

N-(2-(1H-indol-3-yl) ethyl)-2-trifluoroacetamide yl-benzamide (CD43),

N-(2-(3-hydroxy phenyl) ethyl)-2-propionamido-benzamide (BCD1),

N-(2-phenylethyl)-2-aminobenzamide (BCD3),

N-(2-phenylethyl)-2-Hydroxylbenzamide (BCD4),

N-(2-(3-acetylphenyl) ethyl)-2-propionamido-benzamide (BCD5),

Or its pharmaceutical salts.

6. the method for the preparation of compound according to claim 1, described method comprises according to following reaction scheme (i) or (ii), in anhydrous inert organic solvent, with formula (b) or the amine of (c) and the carboxylic acid of formula (a) or (d) or acyl chlorides for raw material, reaction under condensing agent and basic catalyst exist

Reaction scheme (i):

Wherein Ar ₁, L ₁, M ₁, M ₂, L ₂and Ar ₂as claim 1 define.

7. a pharmaceutical composition, described pharmaceutical composition comprises compound or pharmaceutically acceptable salt thereof according to any one of claim 1-5 and pharmaceutical carrier.

8. the compound according to any one of claim 1-5 is for the preparation of the application treated and/or prevented in the medicine of following disease: atherosclerosis, cardiovascular and cerebrovascular diseases, hyperlipidaemia, diabetes, inflammation, hypertension or pain.

9. pharmaceutical composition according to claim 7 is for the preparation of the application treated and/or prevented in the medicine of following disease: atherosclerosis, cardiovascular and cerebrovascular diseases, hyperlipidaemia, diabetes, inflammation, hypertension or pain.