CN102190632B - 2,4,5-tri-replaces selenazoles compounds and preparation method thereof, composition and purposes - Google Patents

Abstract

The present invention relates to 2,4,5-tri-and replace selenazoles compounds and preparation method thereof, composition and purposes.Particularly, the present invention relates to compounds of Formula I:

Description

2,4,5-tri-replaces selenazoles compounds and preparation method thereof, composition and purposes

Technical field

The present invention relates to 2 as phospholipid transfer protein (Phospholipidtransferprotein (PLTP)) inhibitor and/or cholesteryl ester transfer protein (Cholesterylestertransferprotein (CETP)) inhibitor, 4, 5-tri-replaces selenazoles compounds, and their preparation method and the purposes at medical field, particularly treat and raise to blood plasma PLTP activity relevant with preventing and/or raise the purposes of relevant various diseases with plasma C ETP activity, described disease comprises atherosclerosis, cardiovascular disorder and peripheral vascular disease etc.

Background technology

The disease that atherosclerosis causes is the primary cause of death of developed country.In China, along with the aging of socioeconomic development and population, cardiovascular and cerebrovascular disease incidence and mortality also significantly increases in recent years.Atheromatosis because of, pathology complicated, to illustrate not yet completely at present, but known closely related with following factors: hyperlipemia, hypertension, diabetes, obesity, smoking etc.Hyperlipemia to the most important induction factor of atherogenesis in factors.Hyperlipemia main manifestations is that LDL-C level raises and HDL cholesterol levels declines.

Phospholipid transfer protein (PLTP) was called lipid transfer proteins II in the past, be the glycoprotein be present in blood plasma, net transfer and the exchange of phosphatide and can be mediated between phospholipid capsule bubble and high-density lipoprotein (HDL) (high-densitylipoprotein (HDL)) between main lipoprotein.PLTP containing 476 amino-acid residues, be distributed in a organized way in, high expression level in placenta, pancreas, fatty tissue and lung, low expression in liver, kidney and heart, biosynthesizing mainly completes in liver and fatty tissue.There are two kinds of PLTP in blood plasma, a kind of high activity form (being combined with apoE), a kind of low activity form (being combined with apoA-I), high activity form accounts for 46% (Tol, A.V.2002 in blood plasma; JanisM.T., SigginsS., TahvanainenE., etal.J.Lipid.Res.2004; 45 (12): 2303-2309).The metabolism of PLTP to lipoprotein has very important effect.

The Main Function of PLTP in lipoprotein metabolism has three: one to be phosphatide transfer activity, namely shift phosphatide from the residual grain in surface of the chylomicron steatolysis, vldl (verylow-densitylipoprotein (VLDL)) and low-density lipoprotein (low-densitylipoprotein (LDL)) to HDL, HDL particle is increased; Two is reinvent HDL, namely regulate HDL granular size and subclass composition, the fusion of mediation two HDL3 particles, produces macrobead HDL2 and pre-β-HDL, and phosphatide transfer is the prerequisite reinventing HDL, pre-β-HDL is effective receptor of cholesterol in reverse cholesterol transport process; Three is regulate hepatocytes secrete apolipoprotein B (apoB), and increase the content of VLDL in blood, PLTP lacks the minimizing that VLDL can be caused to secrete.Participate in vitamin-E in addition from lipoprotein to the transfer of cytolemma, can make during active reduction to increase containing the VE content in apoB lipoprotein (VLDL and LDL), the antioxygenation of lipoprotein strengthens; PLTP also has the activity of transfer lipopolysaccharides, and enhancing body is to reaction (HuuskonenJ., OlkkonenV.M., JauhiainenM., EhnholmC.Atherosclerosis2001,155, the 269-281 of inflammation; AlbersJ.J., CheungM.C.CurrentOpinioninLipidology2004,15,255-260; HuuskonenJ., OlkkonenV.M., EhnholmC.etal.Biochemistry2000,39,16092-16098).

PLTP and CETP belongs to fat transfer/lipopolysaccharide binding protein family, this protein family has four members, and other member is sterilization permeability-increasing protein (bactericidalpermeabilityincreasingprotein (BPI)) and lipopolysaccharide binding protein (lipopolysaccharidebindingprotein (LBP)).The neutral fats such as CETP was called lipid transfer proteins I in the past, mediation cholesteryl ester are from HDL to the transfer of LDL, and result makes HDL particle reduce.Finder's loss of heterozygosity CETP causes HDL level significantly to raise, the moderate decline of LDL level, has caused the research and development (BrownM.L., InazuA., HeslerC.B.etal.Nature1989,342,448-451) of CETP inhibitor.Clinical study shows that CETP inhibitor can raise HDL, for atherosclerotic prevention and therapy, CETP inhibitor Torcetrapib (BrousseauM.E., SchaeferE.J., WolfeM.L.etal.N.Engl.J.Med.2004, 350, 1505-1515) with JTT-705 (deGroothG.J., KuivenhovenJ.A., StalenhoefA.F.etal.Circulation2002, 105, 2159-2165) be in three phases and the second stage of clinical study respectively, Torcetrapib combines with atorvastatin (Atorvastatin) and treats for atherosclerosis and hyperlipemia in the clinical study of three phases.

In these four members, the BPI of people is only had to report X ray diffractive crystal structure.The crystalline structure of BPI shows it for boomerang shape, is made up of, presents false symmetrical structure Liang Ge subunit.Have two nonpolar pockets respectively at two concave faces of boomerang, each pocket is in conjunction with the lecithin molecules of, and acyl chain that is main and phosphatide interacts, and infers that BPI combines with the acyl chain of lipopolysaccharides in physiological process.Can be inferred the mechanism of this fat transfer protein family fat transfer by the structure of BPI, two nonpolar pockets are its main functional structure (BeamerL.J., CarrollS.F., EisenbergD.Science1997,276,1861-1864).The people such as the Huuskonen structure of PLTP that taken BPI as template protein Blast search, amino acid positional mutation research shows that the N port bag of PLTP is most important to phosphatide transfer activity, C port bag major function is combined (HuuskonenJ. with HDL, WohlfahrtG., JauhiainenM.etal.J.lipidRes.1999,40,1123-1130; PonsinG., QuS.J., FanH.Z.etal.Biochemistry2003,42,4444-4451).

Epidemiological study result shows, in patients with coronary artery disease blood plasma, the content of PLTP is significantly higher than control group (25.5 couples of 22.4pmol/ μ L/h; P < 0.0001).The probability that 1/5th crowds that 1/5th crowds that in blood plasma, the content of PLTP is the highest are minimum than content suffer from coronary artery disease exceeds 1.9 times.Multivariate regression analysis shows: after correcting the factors such as age, blood plasma fat, smoking, diabetes, hypertension, and PLTP activity is the independent effect factor of coronary heart disease prediction.In blood plasma, the rising of phospholipid transfer protein level is Hazard Factor (SchlittA., BickelC., ThummaP.etal.ArteriosclerThromb.Vasc.Biol.2003,23 (10), 1857-62.) to coronary artery disease.Blood plasma PLTP activity is raise (Tol, A.V.2002) in I phase and II phase diabetes, obesity and insulin resistance patient.The transgenic mice blood plasma PLTP activity level of overexpression people PLTP raises 2.5 ~ 4.5 times, cause the reduction by 30 ~ 40% compared with wild type animal of plasma HDL cholesterol level, enhance the Forming ability (VanHaperenR. of pro-β-HDL simultaneously, vanTolA.VermeulenP.etal.ArteriosclerThrombVascBiol.2000,20,1082-1088).Overexpression PLTP in the hybrid mice body of ldl receptor disappearance, PLTP activity is caused to improve 1.3 ~ 2 times, dose-dependently increase atherosclerotic lesions (YangX.P., YanD., QiaoC.etal.ArteriosclerThromb.Vasc.Biol.2003,23,1601-1607).

In PLTP knock out mice liver, apolipoprotein b secretion reduces, cause VLDL to secrete to reduce, lipoprotein resistance of oxidation strengthens, improve the anti-inflammatory action of HDL, make it be subject to atherosclerotic damage and significantly reduce (JiangX.C., ZhouH.W.Curr.Opin.Lipidol.2006,17,302-308; JiangX.C., QinS., QiaoC.etal.Nat.Med.2001,7,847-852.).Feeding food rich in fat to PLTP depleted mice does not cause plasma lipoprotein abnormal, but hinders all major plasma phosphatide from VLDL to the transfer of HDL, significantly reduces level (Jiang, the X.C. of HDL; Bruce, C.; Mar, J.etal.J.Clin.Invest.1999,103,907-914.).The mouse liver secretion VLDL of PLTP overexpression increases by 48%, demonstrates from negative side the keying action (LieJ., deCromR., vanG.T.etal.J.LipidRes.2002,43 (11), 1875-80) that PLTP secretes VLDL.The reason of PLTP deficiency state enhancing plasma lipoprotein resistance of oxidation is the increase in the accumulation of vitamin-E, add the bioavailability (JiangX.C. of vitamin-E in atherogenic lipoprotein (LDL and VLDL), TallA.R., QinS.etal.J.Biol.Chem.2002,277 (35), 31850-56).The mouse body anti-inflammatory power that the people such as Schlitt report disappearance PLTP strengthens (SchlittA., LiuJ., YanD.etal.BiochimBiophysActa.2005,1733 (2-3), 187-91).

In sum, reduce blood plasma PLTP activity and have study of anti-atherogenic effect, its mechanism of action has following three at least: the secretion reducing liver apolipoprotein B, makes VLDL secretion level decline; Strengthen the antioxygenation of LDL, alleviate and that cause atherogenesis oxidized due to LDL; Enhancing body anti-inflammatory power, alleviates the atherosclerotic lesions brought out due to inflammation.So PLTP inhibitor is the atherosclerotic novel drug target of prevention and therapy.

PLTP and CETP is all fat transfer/lipopolysaccharide binding protein family member, research shows that both do not intersect in physiological function, reduce the secretion that PLTP activity can reduce VLDL, and reduce CETP activity can raises HDL cholesterol level, these two aspects is all favourable to atherosclerosis prevention and therapy, so it is treatment of atherosclerosis target (JiangX.C., a TallA.R.PCTInt.Appl.WO2002068450 likely that the people such as Jiang propose PLTP and CETP double inhibitor; JiangX.C., ZhouH.W.Curr.Opin.Lipidol.2006,17,302-308).N-{2-[2-(2,2-dimethvl-propionamide)-phenyl disulfide group]-phenyl }-2,2-dimethvl-propionamide is the unique PLTP inhibitor reported in current document, and be PLTP and CETP double inhibitor, 15 μMs and 13 μMs (WO2002068450) are respectively to the Ki value that both suppress.

Research shows, PLTP selective depressant, PLTP with CETP double inhibitor and CETP selective depressant all can be used for treat with prevention Mammals (including but not limited to people) suffer to blood plasma PLTP and/or plasma C ETP activity raise relevant various diseases: as atherosclerosis, peripheral vascular disease, dyslipidemia, hyperlipidaemia, hypercholesterolemia, hypertriglyceridemia, familial hypercholesterolemia, cardiovascular disorder, stenocardia, local asphyxia, heart ischemia, apoplexy, myocardial infarction, reperfusion injury, hypertension, diabetic vascular complications, obesity or endotoxemia etc.

This area still needs new phospholipid transfer protein inhibitor and/or cholestery ester transfer protein inhibitors.

Summary of the invention

The object of the invention is to find and develop phospholipid transfer protein inhibitor and/or cholestery ester transfer protein inhibitors, by suppressing phospholipid transfer protein activity and/or suppressing cetp activity, regulate the metabolism of associated lipoprotein, treat and prevent various to raise to Plasma phospholipid transfer protein activity and/or plasma cholesterol transesterify protein-active raises relevant disease.

The present inventor finds through research, formula I provided by the invention has the effective activity suppressing phospholipid transfer protein and/or suppress cholesteryl ester transfer protein, thus the secretion of liver VLDL and/or the level of raises HDL cholesterol can be reduced, and then may be used for that treatment and prevention and phospholipid transfer protein are active to be raised and/or cetp activity raises relevant various diseases.The present invention is based on above-mentioned discovery and be accomplished.

Summary of the invention

First aspect present invention provides formula I:

Or its all possible isomer, prodrug, pharmacologically acceptable salt, solvate or hydrate, wherein:

R1 is selected from phenyl, phenyl-C1-C6 alkyl-, C1-C22 alkyl, C3-C10 cycloalkyl-C1-C6 alkyl-, with C3-C10 cycloalkyl, wherein said phenyl is not substituted or by 1-3 (such as 1-2, 1, 2, or 3) replace independently selected from following substituting group: halogen, nitro, hydroxyl, amino, cyano group, C1-C6 alkyl, C1-C6 alkoxyl group, with C1-C6 haloalkyl, and wherein said alkyl and cycloalkyl can optionally by hydroxyls,-O-(C1-C4)-alkyl, oxo, amino,-NH-(C1-C4)-alkyl, or-N-[(C1-C6)-alkyl] 2 replaced, or described alkyl and cycloalkyl are optionally by-O-,-S-,-NH-,-COO-, or-CONH-institute interval,

R2 is selected from phenyl and C1-C6 alkyl, and wherein said phenyl is not substituted or is replaced independently selected from following substituting group by 1-3 (such as 1-2,1,2 or 3): hydroxyl, methoxyl group, nitro, amino, cyano group, C1-C6 alkyl, C1-C6 alkoxyl group,

C1-C6 haloalkyl; Or

The definition of R2 is identical with the definition of R1;

R3 is selected from the group with following structure:

Wherein:

R4 be selected from hydrogen, C1-C6 alkyl, C1-C6 alkyl acyl-, benzoyl and benzenesulfonyl, the phenyl wherein in benzoyl and benzenesulfonyl is optionally independently selected from following substituting group by one or two and replaces: hydroxyl, halogen, nitro, amino, cyano group, C1-C6 alkyl, C1-C6 alkoxyl group or C1-C6 haloalkyl;

R5 is selected from C1-C8 alkyl and phenyl, and wherein said phenyl is not substituted or is replaced independently selected from following substituting group by 1-3 (such as 1-2,1,2 or 3): hydroxyl, methoxyl group, C1-C6 alkoxyl group, halogen, nitro, amino, cyano group; Or

The definition of R2 is identical with the definition of R1;

X is selected from-and (C=O)-or-(SO2)-.

The formula I of any one according to a first aspect of the present invention, wherein: R1 is selected from phenyl, phenyl-C1-C6 alkyl-, C1-C22 alkyl, wherein said phenyl is not substituted or by 1-3 (such as 1-2, 1, 2, or 3) replace independently selected from following substituting group: halogen, nitro, hydroxyl, amino, cyano group, C1-C6 alkyl, C1-C6 alkoxyl group, with C1-C6 haloalkyl, and wherein said alkyl is optionally by hydroxyl,-O-(C1-C4)-alkyl, oxo, amino,-NH-(C1-C4)-alkyl, or-N-[(C1-C6)-alkyl] 2 replaced, or described alkyl is optionally by-O-,-S-,-NH-,-COO-, or-CONH-institute interval.In one embodiment, R1 be selected from phenyl, phenyl-C1-C4 alkyl-, C1-C6 alkyl, wherein said phenyl is not substituted or is replaced independently selected from following substituting group by 1-3 (such as 1-2,1,2 or 3): halogen, nitro, hydroxyl, amino, cyano group, C1-C6 alkyl, C1-C6 alkoxyl group and C1-C6 haloalkyl, and wherein said alkyl optionally by hydroxyl ,-O-(C1-C4)-alkyl, oxo, amino ,-NH-(C1-C4)-alkyl or-N-[(C1-C6)-alkyl] 2 replace.In one embodiment, R1 be selected from phenyl, phenyl-C1-C4 alkyl-, C1-C6 alkyl, wherein said phenyl is not substituted or is replaced independently selected from following substituting group by 1-3 (such as 1-2,1,2 or 3): halogen, nitro, hydroxyl, amino, cyano group, C1-C4 alkyl, C1-C4 alkoxyl group and C1-4 haloalkyl.

The formula I of any one according to a first aspect of the present invention, wherein: R2 is selected from phenyl and C1-C6 alkyl, wherein said phenyl is not substituted or is replaced independently selected from following substituting group by 1-3 (such as 1-2,1,2 or 3): hydroxyl, methoxyl group, nitro, amino, cyano group, C1-C4 alkyl, C1-C4 alkoxyl group, C1-C4 haloalkyl.In one embodiment, R2 is selected from phenyl and C1-C6 alkyl, and wherein said phenyl is not substituted or is replaced independently selected from following substituting group by 1-3 (such as 1-2,1,2 or 3): hydroxyl, methoxyl group, C1-C4 alkyl, C1-C4 alkoxyl group.

The formula I of any one according to a first aspect of the present invention, wherein: R4 be selected from hydrogen, C1-C6 alkyl, C1-C6 alkyl acyl-.In one embodiment, R4 be selected from hydrogen, C1-C4 alkyl, C1-C4 alkyl acyl-.In one embodiment, R4 is selected from hydrogen.

The formula I of any one according to a first aspect of the present invention, wherein: R5 is selected from C1-C8 alkyl and phenyl, wherein said phenyl is not substituted or is replaced independently selected from following substituting group by 1-3 (such as 1-2,1,2 or 3): hydroxyl, methoxyl group, C1-C6 alkoxyl group, halogen, nitro, amino, cyano group.In one embodiment, R5 is selected from C1-C6 alkyl and phenyl, and wherein said phenyl is not substituted or is replaced independently selected from following substituting group by 1-3 (such as 1-2,1,2 or 3): hydroxyl, methoxyl group, C1-C4 alkoxyl group, halogen, nitro, amino.

The formula I of any one according to a first aspect of the present invention; wherein: R5 be selected from hydrogen, C1-C6 alkyl, C1-C6 alkyl acyl-, benzoyl and benzenesulfonyl, the phenyl wherein in benzoyl and benzenesulfonyl is optionally independently selected from following substituting group by one or two and replaces: hydroxyl, halogen, nitro, amino, cyano group, C1-C6 alkyl, C1-C6 alkoxyl group or C1-C6 haloalkyl.

The formula I of any one according to a first aspect of the present invention, wherein: X is-(C=O)-.

The formula I of any one according to a first aspect of the present invention, it is with following formula Ia compound:

Or its all possible isomer, prodrug, pharmacologically acceptable salt, solvate or hydrate, wherein:

R1 be selected from phenyl, phenyl-C1-C4 alkyl-, C1-C6 alkyl, wherein said phenyl is not substituted or is replaced independently selected from following substituting group by 1-3 (such as 1-2,1,2 or 3): halogen, nitro, hydroxyl, amino, cyano group, C1-C6 alkyl, C1-C6 alkoxyl group and C1-C6 haloalkyl;

R2 is selected from phenyl and C1-C6 alkyl, and wherein said phenyl is not substituted or is replaced independently selected from following substituting group by 1-3 (such as 1-2,1,2 or 3): hydroxyl, methoxyl group, nitro, amino, cyano group, C1-C4 alkyl, C1-C4 alkoxyl group, C1-C4 haloalkyl;

R4 is selected from hydrogen, C1-C4 alkyl;

R5 is selected from C1-C6 alkyl and phenyl, and wherein said phenyl is not substituted or is replaced independently selected from following substituting group by 1-3 (such as 1-2,1,2 or 3): hydroxyl, methoxyl group, C1-C4 alkoxyl group, halogen, nitro, amino, cyano group;

X is-(C=O)-.

The formula I of any one according to a first aspect of the present invention, it is selected from:

(1) N-[5-benzyl-4-(4-methoxyl group-phenyl)-1,3-selenazoles-2-base]-3,4-dimethoxybenzarnide;

(2) N-[5-benzyl-4-(4-methoxyl group-phenyl)-1,3-selenazoles-2-base]-3,4,5-trimethoxy-benzamides;

(3) N-[5-benzyl-4-(4-methoxyl group-phenyl)-1,3-selenazoles-2-base]-4-benzamide;

(4) N-[5-benzyl-4-(4-methoxyl group-phenyl)-1,3-selenazoles-2-base]-3,4,5-benzamide trifluoroacetates;

(5) N-[5-benzyl-4-(4-methoxyl group-phenyl)-1,3-selenazoles-2-base]-4-nitrobenzamide;

(6) N-[5-benzyl-4-(4-hydroxy-pheny)-1,3-selenazoles-2-base]-3,4-dihydroxy benzoyl amines;

(7) N-[5-benzyl-4-(4-hydroxy-pheny)-1,3-selenazoles-2-base]-gallamide;

(8) N-[5-benzyl-4-(4-hydroxy-pheny)-1,3-selenazoles-2-base]-hexanamide;

(9) N-[5-ethyl-4-(4-methoxyl group-phenyl)-1,3-selenazoles-2-base]-3,4-dimethoxybenzarnide;

(10) N-[5-ethyl-4-(4-methoxyl group-phenyl)-1,3-selenazoles-2-base]-3,4,5-trimethoxy-benzamides;

(11) N-[5-ethyl-4-(4-methoxyl group-phenyl)-1,3-selenazoles-2-base]-4-chlorobenzamide;

(12) N-[5-ethyl-4-(4-hydroxy-pheny)-1,3-selenazoles-2-base]-gallamide;

(13) N-[5-ethyl-4-(4-hydroxy-pheny)-1,3-selenazoles-2-base]-4-chlorobenzamide;

(14) N-[5-butyl-4-(4-methoxyl group-phenyl)-1,3-selenazoles-2-base]-3,4-dimethoxybenzarnide;

(15) N-[5-butyl-4-(4-methoxyl group-phenyl)-1,3-selenazoles-2-base]-4-benzamide;

(16) N-[5-butyl-4-(4-methoxyl group-phenyl)-1,3-selenazoles-2-base]-4-chlorobenzamide;

(17) N-[5-butyl-4-(4-methoxyl group-phenyl)-1,3-selenazoles-2-base]-3,4,5-trimethoxy-benzamides;

(18) N-[5-butyl-4-(4-hydroxy-pheny)-1,3-selenazoles-2-base]-3,4,5-trihydroxybenzene acid amides;

(19) N-[5-butyl-4-(4-hydroxy-pheny)-1,3-selenazoles-2-base]-ethanamide;

(20) N-[5-butyl-4-(4-hydroxy-pheny)-1,3-selenazoles-2-base]-4-chlorobenzamide;

(21) N-[4,5-phenylbenzene-1,3-selenazoles-2-base]-3,4,5-trimethoxy-benzamides;

(22) N-[4,5-phenylbenzene-1,3-selenazoles-2-base]-benzamide;

(23) N-[4,5-phenylbenzene-1,3-selenazoles-2-base]-3,4,5-benzamide trifluoroacetates;

(24) N-[4,5-phenylbenzene-1,3-selenazoles-2-base]-gallamide; With

(25) N-[4,5-phenylbenzene-1,3-selenazoles-2-base]-3,4-dihydroxy benzoyl amines,

Or its all possible isomer, prodrug, pharmacologically acceptable salt, solvate or hydrate.

Second aspect present invention relates to the method for the formula I of any one of preparation first aspect present invention, and it comprises the following steps:

I () such as, such as, such as, under high temperature (such as 50-120 DEG C, 60-100 DEG C, 70-90 DEG C, about 75-85 DEG C), under carrier exists, makes C1-C6 alkanoic acid ammonium and Potassium Selenocyanate and formula the compound reaction represented, obtains formula the amino selenazoles compound of the 2-represented;

(ii) under carbonyl activation agent and acid binding agent exist, in inert solvent, by formula the amino selenazoles compound of 2-and the carboxylic acid that represents of formula R5-X-OH or sulfonic acid react, obtain formula the compound represented; With optional

(iii) end product of step (ii) is made to carry out the process such as purifying, salify, formation solvate, separation,

Wherein, the definition of each symbol is with described in any one of first aspect present invention formula I.

The method of any one according to a second aspect of the present invention, wherein said carrier is selected from Al2O3, SiO2 or its combination.

The method of any one according to a second aspect of the present invention, wherein said C1-C6 alkanoic acid ammonium is ammonium acetate.

The method of any one according to a second aspect of the present invention, wherein said C1-C6 alkanoic acid ammonium uses Al2O3 as carrier.

The method of any one according to a second aspect of the present invention, wherein said Potassium Selenocyanate uses SiO2 as carrier.

The method of any one according to a second aspect of the present invention, wherein said carbonyl activation agent is N, N-Dimethylamino-pyridine.

The method of any one according to a second aspect of the present invention, wherein said acid binding agent is triethylamine.

The method of any one according to a second aspect of the present invention, wherein said inert solvent is selected from tetrahydrofuran (THF), ethyl acetate, methylene dichloride or its combination.

A third aspect of the present invention provides a kind of pharmaceutical composition, and it comprises the formula I described in any one of at least one first aspect present invention and one or more optional pharmaceutically acceptable carriers or vehicle that treat and/or prevent significant quantity.Pharmaceutical composition of the present invention can be solution, tablet, capsule or injection; These pharmaceutical compositions can pass through injection administration or oral administration.

The pharmaceutical composition of any one according to a third aspect of the present invention, wherein also comprises at least one other medicines.In one embodiment, described other medicines are different from formula I.In one embodiment, described other medicines be can produce with formula I act synergistically, synergism or reduce the drugs with function of formula I untoward reaction.In one embodiment, described other medicines be can produce with formula I act synergistically, synergism or reduce the drugs with function of formula I untoward reaction, and they are combined in may be used for treating and/or preventing and raise to phospholipid transfer protein activity and/or cetp activity raises purposes in the medicine of relevant disease or illness.In one embodiment, describedly to raise to phospholipid transfer protein activity and/or cetp activity raises relevant disease or illness includes but not limited to: atherosclerosis, peripheral vascular disease, dyslipidemia, hyperlipidaemia, hypercholesterolemia, hypertriglyceridemia, familial hypercholesterolemia, cardiovascular disorder, stenocardia, local asphyxia, heart ischemia, apoplexy, myocardial infarction, reperfusion injury, hypertension, diabetic vascular complications, obesity or endotoxemia etc.In one embodiment, above-mentioned other medicines also can the form with medicine box together with formula I provide, and namely above-mentioned other medicines can be present in different preparation unit respectively from formula I.

Fourth aspect present invention provides pharmaceutical composition described in formula I described in any one of first aspect present invention or any one of third aspect present invention and to raise to phospholipid transfer protein activity and/or cetp activity raises purposes in the medicine of relevant disease or illness for the preparation for the treatment of and/or preventing.

The purposes of any one according to a fourth aspect of the present invention, it to raise to Plasma phospholipid transfer protein activity and/or plasma cholesterol transesterify protein-active raises purposes in the medicine of relevant disease or illness for the preparation for the treatment of and/or preventing for pharmaceutical composition described in the formula I described in any one of first aspect present invention or any one of third aspect present invention.

The purposes of any one according to a fourth aspect of the present invention, wherein said to raise to phospholipid transfer protein activity and/or cetp activity raises relevant disease or illness includes but not limited to: atherosclerosis, peripheral vascular disease, dyslipidemia, hyperlipidaemia, hypercholesterolemia, hypertriglyceridemia, familial hypercholesterolemia, cardiovascular disorder, stenocardia, local asphyxia, heart ischemia, apoplexy, myocardial infarction, reperfusion injury, hypertension, diabetic vascular complications, obesity or endotoxemia etc.

Fifth aspect present invention provides a kind for the treatment of and/or preventing in Mammals in need and to raise and/or cetp activity raises relevant disease or the method for illness to phospholipid transfer protein activity, the method comprise treat and/or prevent significant quantity to administration in need the formula I described in any one of at least one first aspect present invention or any one of third aspect present invention described in pharmaceutical composition.In one embodiment, the present invention relates to and suppress the method that Mammals PLTP is active and/or CETP is active (such as blood plasma PLTP is active and/or plasma C ETP is active), this method comprises needing to suppress PLTP is active and/or CETP is active (such as blood plasma PLTP is active and/or plasma C ETP is active) administration to treat and/or prevent pharmaceutical composition described in formula I described in any one of at least one first aspect present invention of significant quantity or any one of third aspect present invention.

The method of any one according to a fifth aspect of the present invention, it to raise and/or plasma cholesterol transesterify protein-active raises relevant disease or the method for illness to Plasma phospholipid transfer protein activity for a kind for the treatment of and/or preventing in Mammals in need, the method comprise treat and/or prevent significant quantity to administration in need the formula I described in any one of at least one first aspect present invention or any one of third aspect present invention described in pharmaceutical composition.

The method of any one according to a fifth aspect of the present invention, wherein said to raise to phospholipid transfer protein activity and/or cetp activity raises relevant disease or illness includes but not limited to: atherosclerosis, peripheral vascular disease, dyslipidemia, hyperlipidaemia, hypercholesterolemia, hypertriglyceridemia, familial hypercholesterolemia, cardiovascular disorder, stenocardia, local asphyxia, heart ischemia, apoplexy, myocardial infarction, reperfusion injury, hypertension, diabetic vascular complications, obesity or endotoxemia etc.

Sixth aspect present invention provides and is used for the treatment of and/or prevents and pharmaceutical composition described in the formula I described in any one of first aspect present invention that phospholipid transfer protein activity raises and/or cetp activity raises relevant disease or illness or any one of third aspect present invention

The formula I of any one or pharmaceutical composition according to a sixth aspect of the present invention, it is for being used for the treatment of and/or preventing to raise to Plasma phospholipid transfer protein activity and/or pharmaceutical composition described in formula I described in any one of first aspect present invention that plasma cholesterol transesterify protein-active raises relevant disease or illness or any one of third aspect present invention.

The formula I of any one or pharmaceutical composition according to a sixth aspect of the present invention, wherein said to raise to phospholipid transfer protein activity and/or cetp activity raises relevant disease or illness includes but not limited to: atherosclerosis, peripheral vascular disease, dyslipidemia, hyperlipidaemia, hypercholesterolemia, hypertriglyceridemia, familial hypercholesterolemia, cardiovascular disorder, stenocardia, local asphyxia, heart ischemia, apoplexy, myocardial infarction, reperfusion injury, hypertension, diabetic vascular complications, obesity or endotoxemia etc.

Should be appreciated that the feature of either side of the present invention is equally applicable to other either side.

detailed Description Of The Invention:

All documents that the present invention quotes from, their full content is incorporated to herein by reference, and if the implication expressed by these documents and the present invention inconsistent time, be as the criterion with statement of the present invention.In addition, the various term that the present invention uses and phrase have and well known to a person skilled in the art general sense, nonetheless, the present invention still wishes to be described in more detail at this these terms and phrase and to explain, the term mentioned and phrase, if any inconsistent with common art-recognized meanings, are as the criterion with the implication that the present invention states.

Term " halogen ", " halogen ", " Hal " or " halo " refer to fluorine (fluoro), chlorine (chloro), bromine (bromo) or iodine (iodo) ".

Term used herein " C1-C6 alkyl ", be no matter himself or as other more macoradical as a part for C1-C6 alkoxyl group, all refer to the atomic group containing 1-6 carbon atom of straight or branched, include but are not limited to: methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl, isobutyl-and the tertiary butyl etc.In addition, term " C1-C6 alkyl " also comprises its subgroup, and such as it can be C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl; Similar, " C1-C8 alkyl " also comprises its subgroup, and such as it can be C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl; Similar, " C1-C22 alkyl " also comprises its subgroup, and such as it can be C1-C18 alkyl, C1-C15 alkyl, C1-C10 alkyl, C1-C8 alkyl, C1-C6 alkyl, C1-C5 alkyl.In this manual, described alkyl can be all the alkyl of straight or branched.

Term used herein " C1-C6-alkoxyl group " refers to " C1-C6-alkyl-O-", and the example of alkoxyl group includes but not limited to methoxyl group, oxyethyl group, isopropoxy etc.

Term used herein " C1-C6 haloalkyl " refers to the C1-C6 alkyl that wherein one or more hydrogen are replaced by halogen atom needs to should be mentioned that trifluoromethyl (-CF3) here especially.

Term used herein " C3-C10 cycloalkyl " refers to the cyclic alkyl radical comprising 3-10 carbon atom, also optionally comprises the ring hetero atom that 1-3 is selected from nitrogen, oxygen and sulphur in this cyclic alkyl radical.In one embodiment, " C3-C10 cycloalkyl " should also comprise its subgroup, such as it can be C3-C8 cycloalkyl, C3-C7 cycloalkyl, C3-C6 cycloalkyl, C3-C5 cycloalkyl.

Term used herein " (C1-C4)-alkyl ", though its Individual existence or with other moiety combinations, its implication is identical with " C1-C4 alkyl "; Similar " (C1-C6)-alkyl " implication is identical with " C1-C6 alkyl ".

Phrase used herein " to raise and/or cetp activity raises relevant disease or illness to phospholipid transfer protein activity " and refers to animal (such as Mammals, such as people) one or more diseases of suffering from or illness, amount and/or the activity change of described disease or illness and phospholipid transfer protein in this animal body are relevant, particularly disease or illness and phospholipid transfer protein in this animal body amount and/or active raise relevant; And/or amount and/or the activity change of described disease or illness and this animal body inner cholesterol transesterify albumen are relevant, particularly disease or illness and this animal body inner cholesterol transesterify albumen amount and/or active raise relevant.In one embodiment, formula I can be used for treating and/or preventing and mammiferously raises relevant to blood plasma PLTP activity and/or raise the disease of being correlated with plasma C ETP is active, and described disease is including, but not limited to atherosclerosis, peripheral vascular disease, dyslipidemia, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, familial hypercholesterolemia, cardiovascular disorder, stenocardia, local asphyxia, apoplexy, myocardial infarction, reperfusion injury, hypertension, diabetic vascular complications, obesity or toxin mass formed by blood stasis etc.

Term used herein " PLTP selective depressant " refers to a compound, and it can suppress PLTP active, and does not have restraining effect to CETP activity.Term used herein " PLTP and CETP double inhibitor " refers to a compound, and it can suppress PLTP active, and CETP can be suppressed again active.Term used herein " CETP selective depressant " refers to a compound, and it can suppress CETP active, and does not have restraining effect to PLTP activity.

Term used herein " composition " means to comprise the product of each appointment composition comprising specified amount, and any product directly or indirectly produced from the combination of each appointment composition of specified amount.In one embodiment, described " composition " is " pharmaceutical composition ".

The present invention relates to suitable pharmaceutically useful salt, solvate or the hydrate of compound as shown in general formula I, but wherein pharmaceutically useful salt comprise be not limited to salt formed by compound of Formula I and mineral acid example hydrochloric acid, sulfuric acid, phosphoric acid, phosphorous acid, Hydrogen bromide and nitric acid and with various organic acid, salt as formed in toxilic acid, oxysuccinic acid, fumaric acid, succsinic acid, tartrate, citric acid, acetic acid, lactic acid, methylsulfonic acid, tosic acid, palmitinic acid etc.Some compounds in the present invention with water or various organic solvent crystallization or recrystallization, in this case, may may form all kinds of SOLVENTS compound.The present invention includes those stoichiometric solvates, comprise hydrate, be also included within the compound comprising variable water gaging formed when preparing with lyophylization.

The present invention relates to the various isomer of compound of Formula I.In the present invention, part of compounds may exist with the form of optical isomer or tautomer, the present invention includes the form of its all existence forms, particularly pure isomer.Different isomeric forms with the isomer separation of the means of various routine and other form or can split, or certain isomer can the synthetic method of various routine or three-dimensional method that is single-minded or asymmetric synthesis obtain.Such as, since compound of Formula I for the purpose of medicinal, is appreciated that they preferably provide in a pure form, the purity of at least 60%, more suitably 75%, better 85%, the preferably purity (% refers to weight percent) of at least 98%.The preparation method of pure compound not can be used for form purer in medicinal compositions.At least containing 1%, be more suitable for 5% in these products pure not, better at least 10% the compound as shown in general formula I or its pharmaceutically useful derivative.

In the method for synthetic compound of formula i of the present invention, the various starting material reacting used are that those skilled in the art can prepare according to existing knowledge, or can be obtained by the known method of document, or can be buied by business.Intermediate used in above reaction scheme, starting material, reagent, reaction conditions etc. all can have knowledge according to those skilled in the art can make appropriate change.Or those skilled in the art also method can synthesize other not specifically enumerated formula I of the present invention according to a second aspect of the present invention.

The present invention relates to the synthetic method of preparation compound of Formula I.The compound of general formula I can with known or commercially available compound for raw material, prepared by the method through synthetic.If raw material can not be buied, then provide their preparation method here, or they can be prepared by the method for bibliographical information.

In a specific embodiment, the invention provides the method preparing compound of Formula I or its pharmacologically acceptable salt, solvate or hydrate, it comprises following concrete steps:

The synthesis of intermediate: at 80 DEG C, with Al2O3, SiO2 for carrier, Ammoniom-Acetate, Potassium Selenocyanate and alpha-brominated reactive ketone obtain the amino selenazoles of 2-, and wherein aluminum oxide is activated alumina.

At carbonyl activation agent if N, N-Dimethylamino-pyridine and acid binding agent are as under the existence of triethylamine, at inert solvent as in tetrahydrofuran (THF), ethyl acetate or methylene dichloride etc., amino for 2-selenazoles and carboxylic acid or sulfonic acid are obtained by reacting following general formula compound:

Each symbol in above formula as first aspect present invention define.

Functional group conversions can be carried out according to methods known in the art to the substituting group in compound, such as compound phenyl ring being connected with methoxyl group, can in methylene dichloride, in the temperature range of-78 ~ 50 DEG C, it is used boron tribromide process, remove methyl and obtain the compound of corresponding hydroxyl, for have on multiple phenyl ring with on methoxyl group or phenyl ring with the mole number of the corresponding increase boron tribromide of the compound of multiple methoxyl group.

Compound of Formula I can use the single synthesis of ordinary method, also the method for available combination chemistry mixed-point method or parallel projects with storehouse (at least containing two in each storehouse, or 5-1000, preferably 10-100 compound) be unit synthesis, namely can synthesize in the liquid phase and also can use solid phase synthesis process.

The data more detailed about preparation compound of Formula I is shown in embodiment.

In one aspect, the present invention relates to the compound of general formula I, its all possible isomer, prodrug, pharmacologically acceptable salt, solvate or hydrate for the production of the purposes of medicine, described medicine is used for the treatment of and mammiferously raises relevant to blood plasma PLTP activity with preventing and/or raise the disease of being correlated with plasma C ETP is active.Described disease is including, but not limited to following disease: atherosclerosis, peripheral vascular disease, dyslipidemia, hyperlipidaemia, hypercholesterolemia, hypertriglyceridemia, familial hypercholesterolemia, cardiovascular disorder, stenocardia, local asphyxia, heart ischemia, apoplexy, myocardial infarction, reperfusion injury, hypertension, diabetic vascular complications, obesity or endotoxemia etc.

The invention still further relates to treatment, mammiferous activity raises relevant and/or active with the plasma C ETP method raising the disease of being correlated with to blood plasma PLTP, and the method comprises compound, its all possible isomer, prodrug, pharmacologically acceptable salt, solvate or hydrate of the general formula I by suitable mode, the Mammals that needs are treated being given to effective dose.The invention also discloses needing the mammiferous administering mode for the treatment of, the effective dose of compound of Formula I or its suitable pharmacologically acceptable salt or hydrate.

In one aspect, the present invention relates to the compound of general formula I, its all possible isomer, prodrug, pharmacologically acceptable salt, solvate or hydrate for the production of the purposes of medicine that can suppress the active and/or plasma C ETP activity of mammalian plasma PLTP.

The invention still further relates to the method suppressing mammalian plasma PLTP activity and/or plasma C ETP activity, this method comprises compound of Formula I, its all possible isomer, prodrug, pharmacologically acceptable salt, solvate or hydrate to needing the suppression blood plasma PLTP suitable mode of Mammals that is active and/or plasma C ETP activity to give effective dose.

In one aspect, invention relates to the compound of general formula I, its all possible isomer, prodrug, pharmacologically acceptable salt, solvate or hydrate for the production of the purposes of the medicine for suppressing the active and/or plasma C ETP activity of mammalian plasma PLTP.

In one aspect; the compound of general formula I of the present invention or its pharmaceutically useful salt can be used alone; or use with the form of pharmaceutical composition together with pharmaceutically useful carrier or vehicle; when using with the form of pharmaceutical composition; usually the compound of Formula I of the present invention of effective dose or its pharmacologically acceptable salt or hydrate and one or more pharmaceutically acceptable carrier or thinner are combined and make suitable administration form or dosage form, this program comprise by suitable mode, component is mixed, granulation, compression or dissolve.Therefore, the invention provides pharmaceutical composition, it comprises the compound of general formula I, its all possible isomer, prodrug, pharmacologically acceptable salt, solvate or hydrate and the pharmaceutically useful carrier of at least one.

The pharmaceutical composition of the compounds of this invention, can the any-mode of following aspect grant: oral, spraying suction, rectal administration, intranasal administration, vagina administration, topical, parenterai administration are as in subcutaneous, vein, intramuscular, intraperitoneal, sheath, in ventricle, in breastbone or intracranial injection or input, or by a kind of reservoir medication of outer planting, wherein preferred oral, intramuscular injection, intraperitoneal or intravenous administration mode.

The compounds of this invention or the pharmaceutical composition containing it can administrations in a unit.Form of administration can be liquid dosage form, solid dosage.Liquid dosage form can be true solution class, colloidal type, particulate formulations, emulsion dosage form, mixed suspension form.Other formulations are tablet, capsule, dripping pill, aerosol, pill, pulvis, solution, suspensoid, emulsion, granule, suppository, lyophilized injectable powder, inclusion compound, implants, patch, liniment etc. such as.

Can also containing conventional carrier in pharmaceutical composition of the present invention, pharmaceutically acceptable carrier described here is including, but not limited to ion-exchanger, aluminum oxide, aluminum stearate, Yelkin TTS, serum protein is as human serum protein, buffer substance is as phosphoric acid salt, glycerine, Sorbic Acid, potassium sorbate, the partial glyceride mixtures of saturated vegetable fatty acid, water, salt or ionogen, as protamine sulfate, Sodium phosphate dibasic, potassium hydrogen phosphate, sodium-chlor, zinc salt, colloided silica, Magnesium Trisilicate, polyvinylpyrrolidone, cellulosic material, polyoxyethylene glycol, Xylo-Mucine, polyacrylic ester, beeswax, wool grease etc.The content of carrier in pharmaceutical composition can be 1 % by weight-98 % by weight, usually accounts for greatly 80 % by weight.For simplicity, local anesthetic, sanitas, buffer reagent etc. can directly be dissolved in carrier.

Oral tablet and capsule can contain vehicle as tackiness agent, as syrup, and gum arabic, sorbyl alcohol, tragacanth, or polyvinylpyrrolidone, weighting agent, as lactose, sucrose, W-Gum, calcium phosphate, sorbyl alcohol, Padil, lubricant, as Magnesium Stearate, talcum, polyoxyethylene glycol, tripoli, disintegrating agent, as yam starch, or acceptable dibutyl phthalate, as bay sodium alkoxide vitriol.Tablet can with method dressing known in pharmacopedics.

Oral liquid can make the suspension of water and oil, and solution, emulsion, syrup or elixir, also can make dry product, with front make up water or other suitable medium.This liquid preparation can comprise conventional additive, as suspension agent, and sorbyl alcohol, Walsroder MC 20000S, dextrose syrup, gel, Natvosol, carboxymethyl cellulose, aluminium stearate gel, the food oils of hydrogenation, emulsifying agent, as Yelkin TTS, sorb gathers candy list oleate, Sudan Gum-arabic; Or nonaqueous carrier (may edible oil be comprised), as Prunus amygdalus oil, grease as glycerine, ethylene glycol, or ethanol; Sanitas, as methyl p-hydroxybenzoate or propyl ester, Sorbic Acid.As needs can add seasonings or tinting material.

Suppository can comprise conventional suppository base, as cocoa butter or other glyceryl ester.

For parenteral, liquid forms is made up of the carrier of compound and a kind of sterilization usually.The first-selected water of carrier.According to the difference of selected carrier and drug level, compound had both dissolved in carrier and also can be made into aaerosol solution, first that compound is soluble in water when making injection solution, loaded in sealed bottle or ampoule after filter-sterilized.

When topical application, the compounds of this invention can make suitable ointment, lotion, or the form of creme, and wherein activeconstituents suspends or is dissolved in one or more carrier.Wherein the operable carrier of ointment formulation is including, but not limited to mineral oil, Albolene, white vaseline, propylene glycol, polyoxyethylene, polyoxytrimethylene, emulsifying wax and water; Lotion and the spendable carrier of creme include but not limited to: mineral oil, sorbitan monostearate, polysorbate60, cetyl ester wax, and cetene is fragrant and mellow, 2-Standamul G, benzyl alcohol and water.

Must recognize, the best dosage of compound of Formula I and interval are determined by external conditionss such as the form of compound property and such as administration, path and position and the specific Mammalss treated, and this best dosage can be determined by the technology of routine.Also must recognize, the best course for the treatment of, i.e. the dosage of compound of Formula I every day within the specified time, available method well known in the art is determined simultaneously.

Formula I also comprises its isomer, raceme, enantiomorph, diastereomer, enantiomorph enriched substance, solvate and ester, formula I and its isomer, raceme, enantiomorph, diastereomer, enantiomorph enriched substance, solvate and ester can also form solvate, such as hydrate, alcohol adduct etc.Above-claimed cpd can also be prodrug or the form that can discharge described activeconstituents in vivo after metabotic change.Selecting and preparing suitable prodrug derivant is technology as well known to those skilled in the art.In general, for object of the present invention, as suitable with non solvate form in the solvate form thereof of water, ethanol etc. with the acceptable solvent of pharmacy.

The active compound amount of gained the actual dose level of each activeconstituents in pharmaceutical composition of the present invention can be changed, so that effectively can obtain required therapeutic response for concrete patient, composition and administering mode.Dosage level must according to the activity of particular compound, route of administration, treat the severity of the patient's condition and the patient's condition of patient to be treated and medical history and select.But the way of this area is, the dosage of compound, from lower than for obtaining level that required result for the treatment of requires, increases dosage, gradually until obtain required effect.

When for above-mentioned treat and/or prevent or other treatment and/or prevention time, a kind of the compounds of this invention treating and/or preventing significant quantity can be applied in a pure form, or with the acceptable ester of pharmacy or prodrug forms (when there are these forms) application.Or described compound can accept the pharmaceutical composition administration of vehicle containing this object compound and one or more medicines.The compounds of this invention that word " treats and/or prevents significant quantity " refers to the compound of the q.s of the reasonable effect/Hazard ratio treatment obstacle being applicable to any therapeutic treatment and/or prevention.But it should be understood that total daily dosage portion of the compounds of this invention and composition must be maked decision within the scope of reliable medical judgment by attending physician.For any concrete patient, concrete treatment effective dose level must be determined according to many factors, and described factor comprises treated obstacle and the severity of this obstacle; The activity of the particular compound adopted; The concrete composition adopted; Age of patient, body weight, general health situation, sex and diet; The administration time of the particular compound adopted, route of administration and excretion rate; The treatment time length; The medicine combinationally using with adopted particular compound or use simultaneously; And the known similar factor of medical field.Such as, the way of this area is, the dosage of compound, from lower than for obtaining level that required result for the treatment of requires, increases dosage, gradually until obtain required effect.In general, formula I is used for the dosage of Mammals particularly people can between 0.001 ~ 1000mg/kg body weight/day, such as, between 0.01 ~ 100

Mg/kg body weight/day, such as, between 0.01 ~ 10mg/kg body weight/day.

Such as, according to the difference of administering mode, in component, can weight ratio 0.1% be contained, or the active ingredient of more suitably weight ratio 10-60%.But when comprising unitary dose in component, each unit preferably comprises 5-500 milligram activeconstituents.Such as, in one embodiment, the difference of foundation route of administration and administration frequency, the suitable therapeutic doses for being grown up is 100-3000 milligram every day, as every day 1500 milligrams.This dose corresponds to 1.5-50 mg/kg/day, and suitable dosage is 5-20 mg/kg/day.

The present inventor is surprised to find, formula I provided by the invention has the effective activity suppressing phospholipid transfer protein and/or suppress cholesteryl ester transfer protein, thus the secretion of liver VLDL and/or the level of raises HDL cholesterol can be reduced, and then may be used for that treatment and prevention and phospholipid transfer protein are active to be raised and/or cetp activity raises relevant various diseases.

Embodiment

Can be conducted further description the present invention by the following examples, but scope of the present invention is not limited to following embodiment.One of skill in the art can understand, and under the prerequisite not deviating from the spirit and scope of the present invention, can carry out various change and modification to the present invention.

The present invention carries out generality and/or concrete description to the material used in test and test method.Although for realizing many materials that the object of the invention uses and working method is well known in the art, the present invention still describes in detail as far as possible at this.

The fusing point of compound is measured by RY-1 melting point apparatus, and thermometer is without calibration.Mass spectrum is measured by MicromassZabSpec high resolution mass spectrometer (resolving power 1000).1H-NMR is measured by JNM-ECA-400 SUPERCONDUCTING NMR instrument, operating frequency 1H-NMR400MHz.

the preparation of embodiment 1N-[5-benzyl-4-(4-methoxyl group-phenyl)-1,3-selenazoles-2-base]-3,4-dimethoxybenzarnide (compound 1)

the preparation of step 13-phenylpropionyl chloride

20.0g (133.2mmol) 3-phenylpropionic acid and 24.5g (205.9mmol) thionyl chloride is added in 100mL eggplant type flask, reflux condensing tube with calcium chloride tube and sodium hydroxide acid gas absorption plant is installed, magnetic agitation refluxes 1 hour, underpressure distillation removes excessive thionyl chloride, obtain 3-phenylpropionyl chloride crude product, for light yellow oil, be not purifiedly directly used in the next step.

the preparation of step 21-(4-methoxyl group-phenyl)-3-phenyl-propan-1-ketone

In the 500mL three-necked bottle being furnished with mechanical stirrer and thermometer, add theoretical amount prepared by step 1 is the solution that the 3-phenylpropionyl chloride of 22.4g (133.2mmol) is dissolved in 100mL methylene dichloride, 14.4g (205.9mmol) methyl-phenoxide and 150mL methylene dichloride, cryosel bath is cooled to less than-5 DEG C, in keeping, temperature is at-5 ~-10 DEG C, add 17.8g (133.2mmol) anhydrous AlCl3 in batches, 1 hour is stirred at such a temperature after adding, stirred at ambient temperature 1 hour, by reaction solution under agitation impouring 100g ice, in the mixture of 100g water and 40mL concentrated hydrochloric acid, separate organic layer, water layer dichloromethane extraction 2 times × 20mL, merge organic layer, wash with saturated brine, saturated sodium bicarbonate aqueous solution washs, extremely neutral with saturated brine washing again, anhydrous magnesium sulfate drying, filter also concentrating under reduced pressure and obtain crude product, with sherwood oil and ethyl acetate (2: 1) recrystallization, obtain product 23.5g, after mother liquor concentrations, recrystallization obtains product 3.3g again, add up to yield 83.7%, mp:96-97 DEG C.1H-NMR(CDCl3，400MHz)δ：3.05(t，2H)，3.25(t，2H)，3.86(s，3H)，6.92(d，2H)，7.18-7.32(m，5H)，7.94(d，2H)；m/z：240.1。

the preparation of the bromo-1-of step 32-(4-methoxyl group-phenyl)-3-phenyl-propan-1-ketone

1-(4-methoxyl group-phenyl)-3-phenyl-propan-1-ketone 23.0g (95.7mmol) prepared by step 2 is added in the 500mL three-necked bottle being equipped with thermometer, 0.30g (2.25mmol) anhydrous AlCl3 and 150mL chloroform, stirring and dissolving, ice-water bath controls to maintain the temperature at 5 ~ 10 DEG C of droppings and is dissolved in bromine in 30mL chloroform, controlling to drip speed makes the color of bromine decorporate very soon, stirring at room temperature 30 minutes after adding, proceed in separating funnel, water washing, saturated sodium bicarbonate aqueous solution washs, water washing again, anhydrous sodium sulfate drying, filter also concentrating under reduced pressure and obtain crude product, through silica gel column chromatography, petrol ether/ethyl acetate (13: 1) washing obtains product 28.7g, colourless liquid, white solid is obtained with dehydrated alcohol recrystallization, yield 93.9%, mp:57-58 DEG C.1H-NMR(CDCl3，400MHz)δ：3.34(dd，1H)，3.66(dd，1H)，3.13(s，3H)，5.29(t，1H)，6.91(d，2H)，7.18～7.32(m，5H)，7.94(d，2H)；m/z+1：320.8。

the preparation of step 45-benzyl-4-(4-methoxyl group-phenyl)-selenazoles-2-base amine

The bromo-1-of 2-(4-methoxyl group-phenyl)-3-phenyl-propan-1-ketone 2.88g (9mmol) and the 15mL toluene of step 3 preparation is added in 100mL eggplant type flask, 3.7g (15mmol) KSeCN/SiO2 and 18g (18mmol) CH3COONH4/Al2O3 is added under stirring, react at 80 DEG C, the CH3COONH4/Al2O3 that doubles is mended after 12h, continue reaction 12h, be cooled to room temperature, filter, by toluene wash, be spin-dried for obtain viscous brown thing, column chromatography purification, sherwood oil: ethyl acetate (3: 1) washing obtains brown liquid 0.52g, yield 16.8%.1H-NMR(DMSO-d6，400MHz)δ：7.473(m，2H)，7.451(t，2H)，7.208(m，3H)，6.948(d，2H)，6.809(s，2H)，4.060(d，2H)，3.759(s，3H)。m/z：344(M+)。

the preparation of step 5N-[5-benzyl-4-(4-methoxyl group-phenyl)-1,3-selenazoles-2-base]-3,4-dimethoxybenzarnide

3,4-dimethoxybenzoic acid 0.11g (0.61mmol) is dissolved in 5ml dry DMF, add DIEA0.31g (2.44mmol), HOBT0.16g (1.22mmol), and 5-benzyl-4-(4-methoxyl group-phenyl)-selenazoles-2-base amine 0.21g (0.61mmol) prepared by step 4, stirring at room temperature 15 minutes, add EDC0.18g (0.00092mol), DMAP0.1g, room temperature reaction spends the night.Add the water of triplication, separate out earthy solid, solid is dissolved in acetone again, column chromatography, sherwood oil: ethyl acetate (4: 1) purifying obtains light yellow solid 55mg, yield 20%, mp:66-68 DEG C.1H-NMR(DMSO，400MHz)δ：12.717(s，1H)，7.745(d，2H)，7.556(d，2H)，7.322(m，5H)，7.025(t，3H)，4.240(s，2H)，3.837(d，9H).m/z+1：509。

the preparation of embodiment 2N-[5-benzyl-4-(4-methoxyl group-phenyl)-1,3-selenazoles-2-base]-3,4,5-trimethoxy-benzamides (compound 2)

Adopt method preparation similar to Example 1, with 5-benzyl-4-(4-methoxyl group-phenyl)-selenazoles-2-base amine 0.99g (0.0029mol) and 3 of embodiment 1 step 4 preparation, 4,5-trimethoxybenzoic acid 0.06g (0.0029mol) is raw material, the method of embodiment 1 step 5 is adopted to prepare light yellow solid 160mg, yield 50%, mp:162-163 DEG C.1H-NMR(DMSO，400MHz)δ：12.837(s，1H)，7.487(d，2H)，7.341(s，2H)，7.324(t，2H)，7.273(t，3H)，7.500(t，2H)，4.254(s，2H)，3.864(s，6H)，3.793(s，3H)，3.734(s，3H).m/z+1：539。

the preparation of embodiment 3N-[5-benzyl-4-(4-methoxyl group-phenyl)-1,3-selenazoles-2-base]-4-benzamide (compound 3)

Adopt method preparation similar to Example 1,5-benzyl-4-(4-methoxyl group-phenyl)-selenazoles-2-base amine 0.73g (0.00212mol) prepared with embodiment 1 step 4 and phenylformic acid 0.26g (0.00212mol) are for raw material, the method of embodiment 1 step 5 is adopted to prepare faint yellow solid 80mg, yield 80%, mp:144-146 DEG C.1H-NMR(DMSO，400MHz)δ：12.816(s，1H)，8.106(d，2H)，7.55(m，5H)，7.271(m，5H)，7.030(d，2H)，4.242(s，2H)，3.798(s，3H)。m/z：448。

the preparation of embodiment 4N-[4-benzyl-5-(4-methoxyl group-phenyl)-1,3-selenazoles-2-base]-3,4,5-benzamide trifluoroacetates (compound 4)

Adopt method preparation similar to Example 1,5-benzyl-4-(4-methoxyl group-phenyl)-selenazoles-2-base amine 0.25g (0.00073mol) prepared with embodiment 1 step 4 and phenylformic acid 0.13g (0.00073mol) are for raw material, the method of embodiment 1 step 5 is adopted to prepare faint yellow solid 60mg, yield 80%, mp:184-186 DEG C.1H-NMR(DMSO，400MHz)δ：12.838(s，1H)，7.551-7.264(m，9H)，7.031(d，2H)，4.235(s，2H)，3.796(s，3H).m/z：502.1。

the preparation of embodiment 5N-[5-benzyl-4-(4-methoxyl group-phenyl)-1,3-selenazoles-2-base]-4-nitrobenzamide (compound 5)

Adopt method preparation similar to Example 1,5-benzyl-4-(4-methoxyl group-phenyl)-selenazoles-2-base amine 0.25g (0.00073mol) prepared with embodiment 1 step 4 and phenylformic acid 0.13g (0.00073mol) are for raw material, the method of embodiment 1 step 5 is adopted to prepare yellow solid 60mg, yield 30.6%, mp:180-184 DEG C.1H-NMR(DMSO，400MHz)δ：13.207(s，1H)，8.344(m，4H)，7.339(d，2H)，7.322(m，5H)，7.253(d，2H)，4.239(s，2H)，3.806(s，3H).m/z-1：492.3。

the preparation of embodiment 6N-[5-benzyl-4-(4-hydroxy-pheny)-1,3-selenazoles-2-base]-3,4-dihydroxy benzoyl amines (compound 6)

Adopt the N-[5-benzyl-4-(4-methoxyl group-phenyl)-1 that embodiment 1 is obtained, 3-selenazoles-2-base]-3,4-dimethoxybenzarnide 103mg (0.203mg) is dissolved in 5mlCH2Cl2, be cooled to 0 DEG C, drip the boron tribromide 0.1ml being dissolved in 5mlCH2Cl2, react 1h at 0 DEG C, room temperature reaction 1h, add borneol stopped reaction, separate out solid, filter, solid is dissolved in methyl alcohol, crosses post, sherwood oil: ethyl acetate (2: 1) wash-out, obtain white solid 40mg, yield: 36%, mp:244-246 DEG C.1H-NMR(DMSO，400MHz)δ：12.441(s，1H)，9.819(s，1H)，9.570(s，1H)，9.337(s，1H)，7.441(d，1H)，7.420(m，3H)，7.331(t，2H)，7.261(d，3H)，6.830(t，3H)，4.207(s，2H)，.m/z+1：467.

the preparation of embodiment 7N-[5-benzyl-4-(4-hydroxy-pheny)-1,3-selenazoles-2-base]-gallamide (compound 7)

Adopt method preparation similar to Example 6, with the N-[5-benzyl-4-(4-methoxyl group-phenyl)-1 that embodiment 1 is obtained, 3-selenazoles-2-base]-3,4,5-trimethoxy-benzamide 0.2g (0.00037mol) are raw material, obtained N-[5-benzyl-4-(4-hydroxy-pheny)-1,3-selenazoles-2-base]-gallamide 70mg, yield 39%, mp:156-158 DEG C.1H-NMR(DMSO，400MHz)δ：7.413(d，2H)，7.327(t，2H)，7.255(d，3H)，7.077(s，2H)，6.831(d，2H)，4.193(s，2H).m/z+1：483。

the preparation of embodiment 8N-[5-benzyl-4-(4-hydroxy-pheny)-1,3-selenazoles-2-base]-hexanamide (compound 8)

The method similar with embodiment 1 step 5 is adopted to prepare, 5-benzyl-4-(4-methoxyl group-phenyl)-selenazoles-2-base amine 0.64g (0.00186mol) prepared with embodiment 1 step 4 and n-caproic acid 0.22g (0.00186mol) are for raw material, obtained N-[5-benzyl-4-(4-methoxyl group-phenyl)-1,3-selenazoles-2-base]-hexanamide 230mg, yield 28%.With N-[5-benzyl-4-(4-methoxyl group-phenyl)-1,3-selenazoles-2-base]-hexanamide 230mg (0.00052mol) is raw material, adopt the method for embodiment 7, obtained N-[5-benzyl-4-(4-hydroxy-pheny)-1,3-selenazoles-2-base]-hexanamide 180mg, yield 81.8%, mp:130-132 DEG C.1H-NMR(DMSO，400MHz)δ：12.241(s，1H)，9.564(s，1H)，7.404(d，2H)，7.318(t，2H)，7.215(t，3H)，6.791(d，2H)，4.191(s，2H)，2.502(t，2H)，1.567(m，2H)，1.236(m，4H)，0.851(t，3H)。m/z+1：429.1。

the preparation of embodiment 9N-[5-ethyl-4-(4-methoxyl group-phenyl)-1,3-selenazoles-2-base]-3,4-dimethoxybenzarnide (compound 9)

the preparation of step 1 butyryl chloride

Adopt the method similar with embodiment 1 step 1, with butyric acid 19.72g (0.17mol) for raw material, preparation 1-(4-methoxyl group-phenyl)-butyryl chloride, not purified, directly carry out next step reaction.

the preparation of step 21-(4-methoxyl group-phenyl)-butanone

Adopt the method similar with embodiment 1 step 2 to prepare, the butyryl chloride prepared with step 1 and methyl-phenoxide 18.36g (0.17mol), for raw material, obtain 1-(4-methoxyl group-phenyl)-butanone 29.0g, clear yellow viscous liquid, yield 82.9%.

the preparation of step 32-bromo-1-(4-methoxyl group-phenyl)-butanone

The method similar with embodiment 1 step 3 is adopted to prepare, 1-(4-methoxyl group-phenyl)-butanone 29g (0.14mol) prepared with step 2 and bromine 24.78g (0.14mol) are for raw material, obtained 2-bromo-1-(4-methoxyl group-phenyl)-butanone 29.5g, faint yellow viscous fluid, obtain through column chromatography for separation, yield 73.9%.

step 4 prepares the preparation of N-4-(4-methoxyl group-phenyl)-5-ethyl-selenazoles-2-base amine

The method preparation adopting embodiment 1 step 4 similar, with the 2-bromo-1-(4-methoxyl group-phenyl) of embodiment 9 step 3 preparation-butanone 2.304g (0.009mol), KSeCN/SiO23.70g (0.015mol), CH3COONH4/AlCl39g (0.018mol) for raw material, obtained N-4-(4-methoxyl group-phenyl)-5-ethyl-selenazoles-2-base amine 0.64g, field gray solid, yield 25%.

1H-NMR(DMSO，400MHz)δ：7.388(d，2H)，7.024(s，1H)，6.934(d，2H)，3.763(s，3H)，2.726(f，2H)，1.185(t，3H)，m/z+1：282。

step 5 prepares 5-ethyl-4-(4-methoxyl group-phenyl)-1,3-selenazoles-2-base] preparation of-3,4-dimethoxybenzarnide

The method preparation adopting embodiment 1 step 5 similar, with N-4-(4-methoxyl group-phenyl)-5-ethyl-selenazoles-2-base amine 0.22g (0.00083mol) and 3 of embodiment 9 step 4 preparation, 4-dimethoxybenzoic acid 0.15g (0.00083mol) is raw material, obtained 5-ethyl-4-(4-methoxyl group-phenyl)-1,3-selenazoles-2-base]-3,4-dimethoxybenzarnide 60mg, light yellow solid, yield 16.2%, mp:157-160 DEG C.1H-NMR(DMSO，400MHz)δ：12.664(s，1H)，7.771(d，2H)，7.497(t，2H)，7.096(m，3H)，3.845(d，9H)，2.898(t，2H)，1.280(t，3H)，.m/z+1：447.1.

the preparation of embodiment 10N-[5-ethyl-4-(4-methoxyl group-phenyl)-1,3-selenazoles-2-base]-3,4,5-trimethoxy-benzamides (compound 10)

The method preparation adopting embodiment 1 step 5 similar, with N-4-(4-methoxyl group-phenyl)-5-ethyl-selenazoles-2-base amine 0.17g (0.00064mol) and 3 of embodiment 9 step 4 preparation, 4,5-trimethoxybenzoic acid 0.14g (0.00064mol) is raw material, obtained N-[5-ethyl-4-(4-methoxyl group-phenyl)-1,3-selenazoles-2-base]-3,4,5-trimethoxy-benzamide 80mg, light yellow solid, yield 26.7%, mp:118-120 DEG C.1H-NMR(DMSO，400MHz)δ：12.788(s，1H)，7.518(d，4H)，7.019(d，2H)，3.879(s，6H)，3.796(s，3H)，3.743(s，3H)，2.509(m，2H)，1.282(t，3H).m/z：476.1。

the preparation of embodiment 11N-[5-ethyl-4-(4-methoxyl group-phenyl)-1,3-selenazoles-2-base]-4-chlorobenzamide (compound 11)

The method preparation adopting embodiment 1 step 5 similar, N-4-(4-methoxyl group-phenyl)-5-ethyl-selenazoles-2-base amine 0.3g (0.0011mol) prepared with embodiment 9 step 4 and Chlorodracylic acid 0.17g (0.00011mol) are for raw material, obtained N-[5-ethyl-4-(4-methoxyl group-phenyl)-1,3-selenazoles-2-base]-4-chlorobenzamide 170mg, light yellow solid, yield 37%, mp:201-202 DEG C.

1H-NMR(DMSO，400MHz)δ：12.824(s，1H)，8.127(d，2H)，7.604(d，2H)，7.482(d，2H)，7.002(d，2H)，3.799(s，3H)，2.887(m，2H)，1.271(t，3H).m/z：420.1.

the preparation of embodiment 12N-[5-ethyl-4-(4-hydroxy-pheny)-1,3-selenazoles-2-base]-gallamide (compound 12)

The method preparation adopting embodiment 6 similar, with N-[5-ethyl-4-(4-methoxyl group-phenyl)-1,3-selenazoles-2-base]-3,4 prepared by embodiment 10,5-trimethoxy-benzamide 0.11g (0.00021mol) is raw material, obtained N-[5-ethyl-4-(4-hydroxy-pheny)-1,3-selenazoles-2-base]-3,4,5-trihydroxybenzene methane amide 60mg, grey block, yield 34.9%, mp:181-184 DEG C.1H-NMR(DMSO，400MHz)δ：12.299(s，1H)，9.496(s，1H)，9.188(s，2H)，8.963(s，1H)，7.372(d，2H)，7.103(t，2H)，6.824(d，2H)，2.864(m，2H)，1.258(t，3H).m/z+1：421.0.

the preparation of embodiment 13N-[5-ethyl-4-(4-hydroxy-pheny)-1,3-selenazoles-2-base]-4-chlorobenzamide (compound 13)

The method preparation adopting embodiment 6 similar, with N-[5-ethyl-4-(4-methoxyl group-phenyl)-1 prepared by embodiment 11,3-selenazoles-2-base]-4-chlorobenzamide 0.12g (0.000285mol) is raw material, obtained N-[5-ethyl-4-(4-hydroxy-pheny)-1,3-selenazoles-2-base]-4-chlorobenzamide 60mg, white crystal, yield 94.8%, mp:198-202 DEG C.1H-NMR(DMSO，400MHz)δ：9.596(s，1H)，8.146(d，2H)，7.605(d，2H)，7.354(d，2H)，6.817(d，2H)，2.863(m，2H)，1.263(t，3H)。m/z+1：407.0。

the preparation of embodiment 14N-[5-butyl-4-(4-methoxyl group-phenyl)-1,3-selenazoles-2-base]-3,4-dimethoxybenzarnide (compound 14)

the preparation of step 1 caproyl chloride

The method preparation adopting embodiment 1 step 1 similar, with caproic acid 19.72g (0.17mol) for raw material, prepares caproyl chloride, not purified, is directly used in next step reaction.

the preparation of step 21-(4-methoxyl group-phenyl) hexanone

The method preparation adopting embodiment 1 step 2 similar, with caproyl chloride, methyl-phenoxide 18.36g (0.17mol) for raw material, obtained 1-(4-methoxyl group-phenyl) hexanone 29g, colourless viscous liquid, yield: 82.9%.

the preparation of step 32-bromo-1-(4-methoxyl group-phenyl) hexanone

The method preparation adopting embodiment 1 step 3 similar, 1-(4-methoxyl group-phenyl) the hexanone 29g (0.14mol) obtained with step 2 and bromine 24.78g (0.14mol) is for raw material, obtained 2-bromo-1-(4-methoxyl group-phenyl) hexanone 19.89g, yield is 50.0%.

the preparation of step 4N-4-(4-methoxyl group-phenyl)-5-butyl-selenazoles-2-base amine

The method preparation adopting embodiment 1 step 4 similar, 2-bromo-1-(4-methoxyl group-phenyl) the hexanone 1.77g (0.0086mol) prepared with step 3 and KSeCN/SiO23.53g (0.014mol), CH3COONH4/AlCl317.2g (0.017mol) are for raw material, obtained N-4-(4-methoxyl group-phenyl)-5-butyl-selenazoles-2-base amine 0.52g, yield 19.5%.1H-NMR(DMSO，400MHz)δ：7.380(d，2H)，6.988(s，2H)，6.932(d，2H)，3.763(s，3H)，2.694(t，2H)，1.523(m，2H)，1.33(m，2H)，0.839(t，3H)。m/z：474。

the preparation of step 5N-[5-butyl-4-(4-methoxyl group-phenyl)-1,3-selenazoles-2-base]-3,4-dimethoxybenzarnide

The method preparation adopting embodiment 1 step 5 similar, with N-4-(4-methoxyl group-phenyl)-5-butyl-selenazoles-2-base amine 0.40g (0.00135mol) and 3 prepared by step 4,4-dimethoxybenzoic acid 0.25g (0.00135mol) is raw material, preparation N-[5-butyl-4-(4-methoxyl group-phenyl)-1,3-selenazoles-2-base]-3,4-dimethoxybenzarnide 240mg, yield 37.5%, mp:184-185 DEG C.1H-NMR(DMSO，400MHz)δ：12.673(s，1H)，7.762(d，2H)，7.484(d，2H)，7.018(d，1H)，6.995(d，2H)，3.795(d，9H)，2.881(t，2H)，1.606(m，2H)，1.325(m，2H)，0.852(t，3H)。m/z：474.1。

the preparation of embodiment 15N-[5-butyl-4-(4-methoxyl group-phenyl)-1,3-selenazoles-2-base]-4-benzamide (compound 15)

The method preparation adopting embodiment 1 step 5 similar, N-4-(4-methoxyl group-phenyl)-5-butyl-selenazoles-2-base amine 0.14g (0.00047mol) prepared with embodiment 14 step 4 and phenylformic acid 0.06g (0.00047mol) are for raw material, obtained N-[5-butyl-4-(4-methoxyl group-phenyl)-1,3-selenazoles-2-base]-4-benzamide 60mg, yield 31.6%, mp:149-150 DEG C.1H-NMR(DMSO，400MHz)δ：8.114(d，2H)，7.501(m，5H)，7.000(d，2H)，3.799(s，3H)，2.885(t，2H)，1.610(m，2H)，1.364(m，2H)，0.870(t，3H)。m/z：414.1。

the preparation of embodiment 16N-[5-butyl-4-(4-methoxyl group-phenyl)-1,3-selenazoles-2-base]-4-chlorobenzamide (compound 16)

The method preparation adopting embodiment 1 step 5 similar, N-4-(4-methoxyl group-phenyl)-5-butyl-selenazoles-2-base amine 0.37g (0.00125mol) prepared with embodiment 14 step 4 and Chlorodracylic acid 0.20g (0.00125mol) are for raw material, obtained N-[5-butyl-4-(4-methoxyl group-phenyl)-1,3-selenazoles-2-base]-4-chlorobenzamide 0.28g, white foam solid, yield: 51%, mp:152-154 DEG C.1H-NMR(DMSO，400MHz)δ：8.143(d，2H)，7.619(d，2H)，7.358(d，2H)，6.837(d，2H)，2.844(t，2H)，1.606(m，2H)，1.331(m，2H)，0.860(t，3H)。m/z：448.1。

the preparation of embodiment 17N-[5-butyl-4-(4-methoxyl group-phenyl)-1,3-selenazoles-2-base]-3,4,5-trimethoxy-benzamides (compound 17)

The method preparation adopting embodiment 1 step 5 similar, with N-4-(4-methoxyl group-phenyl)-5-butyl-selenazoles-2-base amine 0.46g (0.0016mol) and 3 of embodiment 14 step 4 preparation, 4,5-trimethoxybenzoic acid 0.33g (0.0016mol) is raw material, obtained N-[5-butyl-4-(4-methoxyl group-phenyl)-1,3-selenazoles-2-base]-4-benzamide 60mg, yield 37.5%, mp:184-186 DEG C.

1H-NMR(DMSO，400MHz)δ：12.746(s，1H)，7.483(d，4H)，6.994(d，2H)，3.875(s，6H)，3.796(s，3H)，3.744(s，3H)，2.885(m，2H)，1.605(m，2H)，1.363(m，2H)，0.870(t，3H).m/z：504.2。

the preparation of embodiment 18N-[5-butyl-4-(4-hydroxy-pheny)-1,3-selenazoles-2-base]-3,4,5-trihydroxybenzene acid amides (compound 18)

The method preparation adopting embodiment 6 similar, with N-[5-butyl-4-(4-methoxyl group-phenyl)-1,3-selenazoles-2-base]-3,4 prepared by embodiment 17,5-trimethoxy-benzamide 0.18g (0.00037mol) is raw material, obtained N-[4-butyl-5-(4-hydroxy-pheny)-1,3-selenazoles-2-base]-3,4,5-trihydroxybenzene acid amides 50mg, gray solid, yield: 30%, mp:149-152 DEG C.

1H-NMR(DMSO，400MHz)δ：12.339(s，1H)，9.522(s，1H)，9.235(s，2H)，9.016(s，1H)，7.361(d，2H)，7.092(s，2H)，6.797(d，2H)，2.512(t，2H)，1.604(m，2H)，1.335(m，2H)，0.864(t，3H)。m/z+1：449.0。

the preparation of embodiment 19N-[5-butyl-4-(4-hydroxy-pheny)-1,3-selenazoles-2-base]-ethanamide (compound 19)

Another product N-[5-butyl-4-(4-methoxyl group-phenyl)-1 is obtained in the preparation process of embodiment 17,3-selenazoles-2-base]-ethanamide 0.14g (0.00021mol), with this compound for raw material, the method preparation adopting embodiment 6 similar, obtain N-[5-butyl-4-(4-hydroxy-pheny)-1,3-selenazoles-2-base]-ethanamide 70mg, yield: 50%, mp:173-175 DEG C.1H-NMR(DMSO，400MHz)δ：12.190(s，1H)，7.321(d，2H)，6.800(d，2H)，2.835(t，2H)，2.129(s，3H)，1.561(m，2H)，1.337(m，2H)，0.851(t，3H).m/z+1：339.2。

the preparation of embodiment 20N-[5-butyl-4-(4-hydroxy-pheny)-1,3-selenazoles-2-base]-4-chlorobenzamide (compound 20)

The method preparation adopting embodiment 6 similar, with N-[5-butyl-4-(4-methoxyl group-phenyl)-1 prepared by embodiment 16,3-selenazoles-2-base]-4-chlorobenzamide 0.21g (0.00048mol) is raw material, obtained N-[5-butyl-4-(4-hydroxy-pheny)-1,3-selenazoles-2-base]-4-chlorobenzamide 90mg, white solid, yield 45%, mp:221-224 DEG C.1H-NMR(DMSO，400MHz)δ：7.361(d，2H)，7.092(d，4H)，6.818(d，2H)，2.852(t，2H)，1.604(m，2H)，1.335(m，2H)，0.864(t，3H).m/z：434.1。

the preparation of embodiment 21N-[4,5-phenylbenzene-1,3-selenazoles-2-base]-3,4,5-trimethoxy-benzamides (compound 21)

the preparation of step 1N-4-phenyl-5-phenyl-selenazoles-2-base amine

The method preparation adopting embodiment 1 step 4 similar, with 2-bromo-1,2-diphenylethan 1.24g (0.0045mol) and KSeCN/SiO21.85g (0.0075mol), CH3COONH4/AlCl39g (0.009mol) are raw material, obtained N-4-phenyl-5-phenyl-selenazoles-2-base amine 0.38g, yield 28%.1H-NMR(DMSO，400MHz)δ：7.397(s，2H)，7.226(m，2H)，7.208(m，6H)，7.152(d，2H)。m/z：300。

the preparation of step 2N-[4,5-phenylbenzene-1,3-selenazoles-2-base]-3,4,5-trimethoxy-benzamides

The method preparation adopting embodiment 1 step 5 similar, N-4-phenyl-5-phenyl-selenazoles-2-base amine 0.38g (0.00118mol) prepared with step 1 and 3,4,5-trimethoxybenzoic acid 0.26g (0.00118mol) are for raw material, obtained N-[4,5-phenylbenzene-1,3-selenazoles-2-base]-3,4,5-trimethoxy-benzamide 440mg, white solid, yield 73.0%, mp:130-132 DEG C.1H-NMR(DMSO，400MHz)δ：13.048(s，1H)，7.560(s，2H)，7.303(d，2H)，7.295(m，8H)，3.893(s，6H)，3.759(s，3H).m/z+1：495.2。

the preparation of embodiment 22N-[4,5-phenylbenzene-1,3-selenazoles-2-base]-benzamide (compound 22)

The method preparation adopting embodiment 1 step 5 similar, N-4-phenyl-5-phenyl-selenazoles-2-base amine 0.1g (0.00033mol) prepared with embodiment 19 step 1 and phenylformic acid 0.04g (0.00033mol) are for raw material, obtained N-[4,5-phenylbenzene-1,3-selenazoles-2-base]-benzamide 80mg, gray solid, yield 61.5%, mp:160-162 DEG C.1H-NMR(DMSO，400MHz)δ：13.079(s，1H)，8.172(d，2H)，7.571(t，1H)，7.435(t，2H)，7.431(d，2H)，7.315(m，8H).m/z：404。

the preparation of embodiment 23N-[4,5-phenylbenzene-1,3-selenazoles-2-base]-3,4,5-benzamide trifluoroacetates (compound 23)

The method preparation adopting embodiment 1 step 5 similar, N-4-phenyl-5-phenyl-selenazoles-2-base amine 0.11g (0.00037mol) prepared with embodiment 19 step 1 and 3,4,5-trifluoro-benzoic acid 0.06g (0.00037mol) are for raw material, obtained N-[4,5-phenylbenzene-1,3-selenazoles-2-base]-3,4,5-benzamide trifluoroacetate 90mg, white solid, yield 52.9%, mp:164-165 DEG C.1H-NMR(DMSO，400MHz)δ：13.200(s，1H)，7.408(s，1H)，7.335(m，1H)，7.329(d，2H)，7.313(m，8H).m/z+1：459.2。

the preparation of embodiment 24N-[4,5-phenylbenzene-1,3-selenazoles-2-base]-gallamide (compound 24)

The method preparation adopting embodiment 6 similar, N-[4, the 5-phenylbenzene-1 prepared with embodiment 20,3-selenazoles-2-base]-3,4,5-trimethoxy-benzamide 0.43g (0.00087mol) are raw material, obtained N-[4,5-phenylbenzene-1,3-selenazoles-2-base]-3,4,5-trihydroxybenzene methane amide 90mg, gray solid, yield: 24%, mp:276-278 DEG C.1H-NMR(DMSO，400MHz)δ：12.677(s，1H)，9.291(s，2H)，9.095(s，1H)，7.319(s，1H)，7.302(m，9H)，7.148(s，2H).m/z-1：451.3。

the preparation of embodiment 25N-[4,5-phenylbenzene-1,3-selenazoles-2-base]-3,4-dihydroxy benzoyl amines (compound 25)

the preparation of step 1N-[4,5-phenylbenzene-1,3-selenazoles-2-base]-3,4-dimethoxybenzarnide

The method preparation adopting embodiment 1 step 5 similar, with N-4-phenyl-5-phenyl-selenazoles-2-base amine 0.22g (0.00074mol) and 3 of embodiment 19 step 1 preparation, 4-dimethoxybenzoic acid 0.13g (0.00073mol) is raw material, obtained N-[4,5-phenylbenzene-1,3-selenazoles-2-base]-3,4-dimethoxybenzarnide, not purified, directly carry out next step reaction.

the preparation of step 2N-[4,5-phenylbenzene-1,3-selenazoles-2-base]-3,4-dihydroxy benzoyl amines

The method preparation adopting embodiment 6 similar, with N-[4,5-phenylbenzene-1,3-selenazoles-2-base]-3 prepared by step 1,4-dimethoxybenzarnide 0.11g (0.00024mol) is raw material, obtained N-[4,5-phenylbenzene-1,3-selenazoles-2-base]-3,4-dihydroxy benzoyl amine 45mg, white solid, yield: 40.2%, mp:198-196 DEG C.1H-NMR(DMSO，400MHz)δ：12.762(s，1H)，7.542(d，1H)，7.423(s，1H)，7.419(d，2H)，7.303(m，8H)，6.828(d，1H)。m/z+1：437.1。

biological test example

The PLTP inhibit activities of the compound that the present invention relates to can detect with in method exemplary as follows:

biological test example 1, PLTP inhibit activities measuring method

By 30 μ l phospholipid liposomes (about 1,000cpm/ μ l), 30 μ lHDL (6.0g albumen/μ l), 337 μ lTSE and the mixing of 3 μ l blood plasma, in 37 DEG C of water-baths, temperature incubates 1 hour.Then 300 μ l sedimentation solution (500ml solution preparations: 5.36ml5NNaCl are added, 9.075ml2MMnCl2 with 46mg Vitrum AB, add water to 50ml), at room temperature by this solution left standstill 10 minutes, then high speed rotating 10 minutes (for removing phospholipid liposome), gets 500 μ l supernatant liquor countings.PLTP activity (cpm/h/3 μ l)=sample cpm-background cpm.The PLTP inhibit activities measurement result of the exemplary partial compound of formula I is in table 1.

Table 1 external PLTP inhibit activities measurement result

Compound	IC50(μM)
		1	80μM
5	85μM
		6	35μM
7	32μM
		8	60μM
9	100μM
		12	32μM
13	60μM
		14	80μM
17	150μM
		18	10μM
19	60μM
		20	60μM
24	25μM
		25	8μM

It will be apparent to those skilled in the art that for suppression PLTP active, it is useful for having the material that IC50 is less than 500 μMs, and the IC50 of preferred compound is less than 400 μMs, and preferred IC50 is less than 200 μMs.

biological test example 2, PLTP activity in vivo measuring method

Select wild mouse (C57BL/6 system), drug level is 20uM, pass through mouse tail vein injection, injected dose is (dosage: 5ul compound solution+195ulPBS, amount to 200ul/ mouse), measure the activity of PLTP and the impact on cholesterol, triglyceride level and phosphatide after mouse vivo medicine-feeding after administration 5h, the results are shown in Table 2.

Table 2 compound is to the evaluation of effect result of PLTP in Mice Body

^＊P＜0.05， ^＊＊P＜0.01.N＝5

Significantly can suppress the activity of PLTP after compound 18 and 25 administration 5h, significantly reduce the level of Mice Body inner cholesterol and phosphoric acid, compound 18 significantly can reduce the content of triglyceride level in Mice Body.

biological test example 3, PLTP selectivity activity in vivo measuring method

Select the mouse that PLTP knocks out, administration and measuring method are with biological test example 2.The results are shown in Table 3.

Table 3 compound is to the evaluation of effect result of PLTP in PLTP knock-out mice body

^＊P＜0.05， ^＊＊P＜0.01.N＝5

Compound 18 and 25 does not affect mouse phosphatide (Phospholipid) level that PLTP knocks out, and proves that compound 18 and 25 is PLTP inhibitor of highly selective.

The present inventor also finds, the compound of other compound of the present invention unlisted in above each table particularly in embodiment, have equally gratifying, with above respectively show in the similar beneficial outcomes of compound results.The present inventor also finds, the compound of the compounds of this invention particularly in embodiment, also has gratifying, to suppress cetp activity beneficial outcomes.

Claims (19)

1. formula I:

Or its pharmacologically acceptable salt, wherein:

R1 be selected from phenyl, phenyl-C1-C6 alkyl-, C1-C10 alkyl, wherein said phenyl is not substituted or is replaced independently selected from following substituting group by 1-3: halogen, hydroxyl, amino, cyano group, C1-C6 alkyl, C1-C6 alkoxyl group and C1-C6 haloalkyl;

R2 is selected from phenyl, and wherein said phenyl is not substituted or is replaced independently selected from following substituting group by 1-3: hydroxyl, methoxyl group, amino, cyano group, C1-C6 alkyl, C1-C6 alkoxyl group, C1-C6 haloalkyl;

R3 is selected from the group with following structure:

Wherein:

R4 is selected from hydrogen, C1-C6 alkyl;

R5 is selected from C1-C8 alkyl and phenyl, and wherein said phenyl is replaced independently selected from following substituting group by 1-3: hydroxyl, methoxyl group, C1-C6 alkoxyl group, halogen, nitro, amino, cyano group;

X is selected from-and (C=O)-or-(SO2)-;

Further, described compound does not comprise:

N-[4,5-phenylbenzene-1,3-selenazoles-2-base]-ethanamide, and

N-[4,5-phenylbenzene-1,3-selenazoles-2-base]-benzamide.

2. formula I according to claim 1, wherein R2 is selected from phenyl, and wherein said phenyl is not substituted or is replaced independently selected from following substituting group by 1-3: hydroxyl, methoxyl group, amino, cyano group, C1-C4 alkyl, C1-C4 alkoxyl group, C1-C4 haloalkyl.

3. formula I according to claim 1, wherein X be-(C=O)-.

4. formula I according to claim 1, it is with following formula Ia compound:

Or its pharmacologically acceptable salt, wherein:

R1 be selected from phenyl, phenyl-C1-C4 alkyl-, C1-C6 alkyl, wherein said phenyl is not substituted or is replaced independently selected from following substituting group by 1-3: halogen, hydroxyl, amino, cyano group, C1-C6 alkyl, C1-C6 alkoxyl group and C1-C6 haloalkyl;

R2 is selected from phenyl, and wherein said phenyl is not substituted or is replaced independently selected from following substituting group by 1-3: hydroxyl, methoxyl group, amino, cyano group, C1-C4 alkyl, C1-C4 alkoxyl group, C1-C4 haloalkyl;

R4 is selected from hydrogen, C1-C4 alkyl;

R5 is selected from C1-C6 alkyl and phenyl, and wherein said phenyl is replaced independently selected from following substituting group by 1-3: hydroxyl, methoxyl group, C1-C4 alkoxyl group, halogen, nitro, amino, cyano group;

X is-(C=O)-;

Further, described compound does not comprise:

N-[4,5-phenylbenzene-1,3-selenazoles-2-base]-ethanamide, and

N-[4,5-phenylbenzene-1,3-selenazoles-2-base]-benzamide.

5., according to the formula I of any one of Claims 1-4, the substituting group number of wherein said phenyl is 1-2 independently of one another.

6., according to the formula I of any one of Claims 1-4, the substituting group number of wherein said phenyl is 1,2 or 3 independently of one another.

7., according to the formula I of any one of Claims 1-4, it is selected from:

(1) N-[5-benzyl-4-(4-methoxyl group-phenyl)-1,3-selenazoles-2-base]-3,4-dimethoxybenzarnide;

(2) N-[5-benzyl-4-(4-methoxyl group-phenyl)-1,3-selenazoles-2-base]-3,4,5-trimethoxy-benzamides;

(3) N-[5-benzyl-4-(4-methoxyl group-phenyl)-1,3-selenazoles-2-base]-4-benzamide;

(4) N-[5-benzyl-4-(4-methoxyl group-phenyl)-1,3-selenazoles-2-base]-3,4,5-benzamide trifluoroacetates;

(5) N-[5-benzyl-4-(4-methoxyl group-phenyl)-1,3-selenazoles-2-base]-4-nitrobenzamide;

(6) N-[5-benzyl-4-(4-hydroxy-pheny)-1,3-selenazoles-2-base]-3,4-dihydroxy benzoyl amines;

(7) N-[5-benzyl-4-(4-hydroxy-pheny)-1,3-selenazoles-2-base]-gallamide;

(8) N-[5-benzyl-4-(4-hydroxy-pheny)-1,3-selenazoles-2-base]-hexanamide;

(9) N-[5-ethyl-4-(4-methoxyl group-phenyl)-1,3-selenazoles-2-base]-3,4-dimethoxybenzarnide;

(10) N-[5-ethyl-4-(4-methoxyl group-phenyl)-1,3-selenazoles-2-base]-3,4,5-trimethoxy-benzamides;

(11) N-[5-ethyl-4-(4-methoxyl group-phenyl)-1,3-selenazoles-2-base]-4-chlorobenzamide;

(12) N-[5-ethyl-4-(4-hydroxy-pheny)-1,3-selenazoles-2-base]-gallamide;

(13) N-[5-ethyl-4-(4-hydroxy-pheny)-1,3-selenazoles-2-base]-4-chlorobenzamide;

(14) N-[5-butyl-4-(4-methoxyl group-phenyl)-1,3-selenazoles-2-base]-3,4-dimethoxybenzarnide;

(15) N-[5-butyl-4-(4-methoxyl group-phenyl)-1,3-selenazoles-2-base]-4-benzamide;

(16) N-[5-butyl-4-(4-methoxyl group-phenyl)-1,3-selenazoles-2-base]-4-chlorobenzamide;

(17) N-[5-butyl-4-(4-methoxyl group-phenyl)-1,3-selenazoles-2-base]-3,4,5-trimethoxy-benzamides;

(18) N-[5-butyl-4-(4-hydroxy-pheny)-1,3-selenazoles-2-base]-3,4,5-trihydroxybenzene acid amides;

(19) N-[5-butyl-4-(4-hydroxy-pheny)-1,3-selenazoles-2-base]-ethanamide;

(20) N-[5-butyl-4-(4-hydroxy-pheny)-1,3-selenazoles-2-base]-4-chlorobenzamide;

(21) N-[4,5-phenylbenzene-1,3-selenazoles-2-base]-3,4,5-trimethoxy-benzamides;

(23) N-[4,5-phenylbenzene-1,3-selenazoles-2-base]-3,4,5-benzamide trifluoroacetates;

(24) N-[4,5-phenylbenzene-1,3-selenazoles-2-base]-gallamide; With

(25) N-[4,5-phenylbenzene-1,3-selenazoles-2-base]-3,4-dihydroxy benzoyl amines,

Or its pharmacologically acceptable salt.

8. prepare the method for the formula I of claim 1, it comprises the following steps:

I () at high temperature, under carrier exists, makes C1-C6 alkanoic acid ammonium and Potassium Selenocyanate and formula the compound reaction represented, obtains formula the amino selenazoles compound of the 2-represented, described high temperature refers to 50-120 DEG C;

(ii) under carbonyl activation agent and acid binding agent exist, in inert solvent, by formula the amino selenazoles compound of 2-and the carboxylic acid that represents of formula R5-X-OH or sulfonic acid react, obtain formula the compound represented, described carbonyl activation agent is N, N-Dimethylamino-pyridine; With optional

(iii) end product of step (ii) is made to carry out purifying, salify or separating treatment,

Wherein, the definition of each symbol is with described in claim 1.

9. the method for claim 8, the high temperature wherein described in step (i) refers to 60-100 DEG C.

10. the method for claim 8, the high temperature wherein described in step (i) refers to 70-90 DEG C.

The method of 11. claims 8, the high temperature wherein described in step (i) refers to 75-85 DEG C.

12. any one of claim 8-11 method, it is characterized in that following a) to any one of d), f) and g) or multinomial:

A) carrier described in is selected from Al2O3, SiO2 or its combination;

B) the C1-C6 alkanoic acid ammonium described in is ammonium acetate;

C) the C1-C6 alkanoic acid ammonium described in uses Al2O3 as carrier;

D) Potassium Selenocyanate described in uses SiO2 as carrier;

F) acid binding agent described in is triethylamine;

G) inert solvent described in is selected from tetrahydrofuran (THF), ethyl acetate, methylene dichloride or its combination.

13. a pharmaceutical composition, it comprises the formula I described in any one of at least one claim 1-7 and one or more pharmaceutically acceptable carriers or vehicle that treat and/or prevent significant quantity.

Pharmaceutical composition described in formula I described in 14. any one of claim 1-7 or claim 13 to raise to phospholipid transfer protein activity and/or cetp activity raises purposes in the medicine of relevant disease or illness for the preparation for the treatment of and/or preventing.

The purposes of 15. claims 14, wherein said to raise to phospholipid transfer protein activity and/or cetp activity raises relevant disease or illness is selected from: atherosclerosis, peripheral vascular disease, dyslipidemia, cardiovascular disorder, stenocardia, local asphyxia, apoplexy, myocardial infarction, reperfusion injury, hypertension, diabetic vascular complications, obesity or endotoxemia.

The purposes of 16. claims 15, wherein said dyslipidemia is hyperlipidaemia.

The purposes of 17. claims 16, wherein said hyperlipidaemia is selected from hypercholesterolemia and hypertriglyceridemia.

The purposes of 18. claims 17, wherein said hypercholesterolemia is familial hypercholesterolemia.

The purposes of 19. claims 15, wherein said local asphyxia is heart ischemia.