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CN101200443B - Azetidinone derivatives, processes for their preparation and pharmaceutical combinations containing them - Google Patents

Azetidinone derivatives, processes for their preparation and pharmaceutical combinations containing them Download PDF

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Publication number
CN101200443B
CN101200443B CN200710133305XA CN200710133305A CN101200443B CN 101200443 B CN101200443 B CN 101200443B CN 200710133305X A CN200710133305X A CN 200710133305XA CN 200710133305 A CN200710133305 A CN 200710133305A CN 101200443 B CN101200443 B CN 101200443B
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phenyl
azetidinone
hydroxypropyl
instead
methoxy
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CN101200443A (en
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黄文龙
张惠斌
王玉斌
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China Pharmaceutical University
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China Pharmaceutical University
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Abstract

本发明涉及在治疗和预防动脉粥样硬化中用作降低血浆胆固醇药物的取代氮杂环丁酮，它们的合成方法，含有它们的药物组合，其中R1、Ar1、Ar2的定义见说明书。 The present invention relates to substituted azetidinones used as plasma cholesterol-lowering drugs in the treatment and prevention of atherosclerosis, their synthesis methods, and drug combinations containing them, wherein the definitions of R 1 , Ar 1 , and Ar 2 are described in the instructions .

Description

Aza cyclo-butanone derivatives, its preparation method and contain their drug regimen
Technical field
The present invention relates to be used as in atherosis at treatment and prevention of arterial the substituted azetidinone of reduction plasma cholesterol medicine, their synthetic method contains their drug regimen.
Background technology
By the hyperlipidaemia due to the abnormalities of sugar/lipid metabolism one of Hazard Factor that cause atherosclerosis and other cardiovascular and cerebrovascular diseases.The clinical treatment medicine of hyperlipidaemia mainly contains statins, fibrate and nicotinic acid derivates, but these Side effects of pharmaceutical drugs are also clearly.Particularly the Cerivastatin in the statins is because the side effect of rhabdomyolysis causes many cases clinically dead case.(3R, 4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)-2-azetidinone (ezetimibe, Ezetimibe, Zetia TM) be the novel cholesterol absorption inhibitor of Merck/Schering-Plough company development, to go on the market in Germany in November, 2002, go on the market in the U.S. same period.This medicine can reach the purpose that reduces cholesterol in the blood plasma by the absorption that optionally suppresses small intestine place cholesterol, the effect of performance reducing blood-fat.Only ezetimibe listing in the cholesterol absorption inhibitor at present, but and ezetimibe reflectivity ground cause the increase of liver synthesis cholesterol, thereby slacken the effect that it falls plasma cholesterol.Therefore it is strong to seek cholesterol-lowering activity, and the low cholesterol absorption inhibitor of side effect becomes the technological difficulties of this research direction most critical.
Summary of the invention
The object of the present invention is to provide the novel cholesterol absorption inhibitor of a class, it is stronger that it falls the plasma cholesterol activity, and security is higher.
The present invention also aims to provide a kind of preparation method of synthesizing new cholesterol absorption inhibitor.
Another object of the present invention also is to provide a kind of pharmaceutical preparation that contains cholesterol absorption inhibitor.
Summary of the invention is as follows in detail:
The present invention has synthesized a series of general formulas (I) compound:
Figure DEST_PATH_G200710133305X20080130D000011
Wherein:
Ar 1Represent R 2The aryl of-replacement; Ar 2Represent R 3The aryl of-replacement;
R 1Represent R 4The aryl of-replacement or benzyl, low alkyl group;
R 2-, R 3-and R 4-represent 1-5 substituting group, they independently are selected from and comprise :-OR 5,-O (CO) R 5,-O (CO) OR 5,-O (CH 2) 1-5OR 5,-O (CH 2) 1-2O-,-O (CO) NR 5R 6,-NR 5R 6,-NR 5(CO) R 6,-NR 5(CO) OR 6,-NR 5(CO) NR 6R 7,-NR 5SO 2-low alkyl group ,-NR 5SO 2-aryl ,-CONR 5R 6,-COR 5,-SO 2NR 5R 6, S (O) 0-2-alkyl, S (O) 0-2-aryl ,-O (CH 2) 1-10-COOR 5,-O (CH 2) 1-10CONR 5R 6, hydrogen, neighbour-halo ,-halo, right-halo, neighbour-low alkyl group ,-low alkyl group, right-low alkyl group, aryl ,-NO 2, CF 3,-(low-grade alkylidene)-COOR 5With-CH=CH-COOR 5
R 5, R 6And R 7Independently be selected from: hydrogen, low alkyl group, aryl, the low alkyl group that aryl replaces.
Preferred compound is:
Instead-1-(4-chloro-phenyl-)-3-(3,3-phenylbenzene-3-hydroxypropyl)-4-(4-p-methoxy-phenyl)-2-azetidinone (I1);
Instead-1-(4-chloro-phenyl-)-3-(3,3-phenylbenzene-3-hydroxypropyl)-4-(3,4-dioxy methylene radical phenyl)-2-azetidinone (I2);
Instead-1-(4-aminomethyl phenyl)-3-(3,3-phenylbenzene-3-hydroxypropyl)-4-(4-p-methoxy-phenyl)-2-azetidinone (I3);
Instead-1-(4-aminomethyl phenyl)-3-(3,3-phenylbenzene-3-hydroxypropyl)-4-(3,4-dioxy methylene radical phenyl)-2-azetidinone (I4);
Instead-1-phenyl-3-(3,3-phenylbenzene-3-hydroxypropyl)-4-(4-p-methoxy-phenyl)-2-azetidinone (I5);
Instead-1-(4-p-methoxy-phenyl)-3-(3,3-phenylbenzene-3-hydroxypropyl)-4-(3,4-dioxy methylene radical phenyl)-2-azetidinone (I6);
Instead-1-phenyl-3-(3,3-phenylbenzene-3-hydroxypropyl)-4-(3,4-dioxy methylene radical phenyl)-2-azetidinone (I7);
Instead-1-(2-aminomethyl phenyl)-3-(3,3-phenylbenzene-3-hydroxypropyl)-4-(4-p-methoxy-phenyl)-2-azetidinone (I8);
Instead-1-(2-aminomethyl phenyl)-3-(3,3-phenylbenzene-3-hydroxypropyl)-4-(3,4-dioxy methylene radical phenyl)-2-azetidinone (I9);
Instead-1-(4-fluorophenyl)-3-(3,3-phenylbenzene-3-hydroxypropyl)-4-(4-p-methoxy-phenyl)-2-azetidinone (I10);
Instead-and 1-(2-aminomethyl phenyl)-3-[3,3-two (4-fluorophenyl)-3-hydroxypropyl]-preparation (I11) of 4-(3,4-dioxy methylene radical phenyl)-2-azetidinone;
Instead-and 1-(4-p-methoxy-phenyl)-3-[3,3-two (4-fluorophenyl)-3-hydroxypropyl]-preparation (I12) of 4-(4-p-methoxy-phenyl)-2-azetidinone;
Instead-and 1-(4-chloro-phenyl-)-3-[3,3-two (4-fluorophenyl)-3-hydroxypropyl]-preparation (I13) of 4-(4-p-methoxy-phenyl)-2-azetidinone;
Instead-and 1-(4-aminomethyl phenyl)-3-[3,3-two (4-fluorophenyl)-3-hydroxypropyl]-preparation (I14) of 4-(3,4-dioxy methylene radical phenyl)-2-azetidinone;
Instead-and 1-(4-fluorophenyl)-3-[3,3-two (4-fluorophenyl)-3-hydroxypropyl]-preparation (I15) of 4-(4-p-methoxy-phenyl)-2-azetidinone;
Instead-and 1-(4-ethoxyl phenenyl)-3-[3,3-two (4-fluorophenyl)-3-hydroxypropyl]-preparation (I16) of 4-(4-p-methoxy-phenyl)-2-azetidinone;
Instead-and 1-(4-bromophenyl)-3-[3,3-two (4-fluorophenyl)-3-hydroxypropyl]-preparation (I17) of 4-(4-p-methoxy-phenyl)-2-azetidinone;
Instead-and 1-(4-chloro-phenyl-)-3-[3,3-dibenzyl-3-hydroxypropyl]-4-(3,4-dioxy methylene radical phenyl)-2-azetidinone (I18);
Instead-and 1-(4-p-methoxy-phenyl)-3-[3,3-two (4-fluorophenyl)-3-hydroxypropyl]-4-(3,4-dioxy methylene radical-6-bromophenyl)-2-azetidinone (I19).
The structural formula that it is corresponding:
Figure S200710133305XD00031
R 1 Ar 1 Ar 2
I1 -Ph?
Figure S200710133305XD00032
I2 -Ph?
I3 -Ph?
I4 -Ph?
Figure S200710133305XD00035
I5 -Ph?
Figure S200710133305XD00036
I6 -Ph?
Figure S200710133305XD00037
I7 -Ph?
Figure S200710133305XD00038
I8 -Ph?
Figure S200710133305XD00039
I9 -Ph?
Figure S200710133305XD000310
I10 -Ph?
Figure S200710133305XD000311
I11?
Figure S200710133305XD000312
I12?
Figure S200710133305XD000313
I13?
Figure S200710133305XD000314
I14?
Figure S200710133305XD000315
I15?
Figure S200710133305XD000316
I16?
Figure S200710133305XD00041
I17?
Figure S200710133305XD00042
I18?
Figure S200710133305XD00043
I19?
Figure S200710133305XD00044
General formula (I) compounds process for production thereof is as follows: substituted aroma aldehyde and substituted aromatic amine reaction, generate intermediate (II), carry out the Staudinger cycloaddition with the chloroformyl methyl-butyrate again, generate intermediate (III), last and corresponding Grignard reagent reaction obtains target compound (I).Route is as follows:
Figure S200710133305XD00045
Wherein the preparation of key intermediate chloroformyl methyl-butyrate is by the Pyroglutaric acid alcoholysis, and chloride obtains again.Concrete reaction scheme is as follows:
Figure S200710133305XD00046
Below be the pharmacological experiment data of invention part of compounds:
1, animal, reagent and instrument
1.1 animal
Male SD rat, 180-220g, the The 2nd Army Medical College Experimental Animal Center provides, and credit number is: SCXK (Shanghai) 2002-0006
1.2 reagent
Cholesterol provides for the emerging chemical reagent in Shanghai institute, and lot number is 020628
Total cholesterol (TC) is measured test kit and is provided for Shanghai Rongsheng Bioisystech Co., Ltd, and lot number is that 20070205 high-density lipoprotein (HDL) (HDL) mensuration test kit provides for Tianjin, Wenzhou agate bio tech ltd, and lot number is: 2007040213
1.3 the preparation of test-compound and positive drug
Test-compound and positive drug faced with preceding the grinding with 0.05%CMC-Na solution be mixed with suspension.
1.4 instrument
T6 new millennium ultraviolet-visible pectrophotometer: Beijing Puxi General Instrument Co., Ltd
2, method
Healthy male SD rat is divided into blank group, model group, positive drug group and is subjected to the reagent group, 8 every group; Each treated animal is irritated stomach to high-fat emulsion once equal every day, each 2ml, and gastric infusion again after two hours, continuous 7 days, got blood and put to death half an hour after administration the last day, measures plasma total cholesterol levels and hdl concentration.
The preparation of high-fat emulsion: get lard 25g, be placed in the 200ml beaker, magnetic agitation is heated to 100 ℃, adds the 10g cholesterol, dissolves, and it is excellent to add 1g third match again, fully stirs evenly, and adds the 25ml tween 80, makes oil phase; Get another beaker and add 30ml distilled water and 1,2-propylene glycol 20ml is placed on and is heated to 60 ℃ on the electric furnace, adds the 2g Sodium desoxycholate then, fully stirs up to dissolving fully, makes water; Water is added oil phase, abundant mixing, high-fat emulsion.
3, experimental result
Table 1, compound are to the inhibition activity of rat cholesterol absorption
(?
Figure S200710133305XD00051
n＝8)
Sequence number Test-compound Dosage (mg/kg) TC content (mmol/L) HDL content (mmol/L)
1 2 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 Blank group model group ezetimibe I 1 I 2 I 3 I 4 I 5 I 6 I 7 I 8 I 9 I 10 I 11 I 12 I 13 I 14 I 15 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 10.73±0.99 13.26±1.59 11.01±1.27 11.00±1.32 11.67±0.94 12.35±0.91 10.64±0.55 11.66±1.11 12.70±1.96 13.44±1.92 11.78±1.86 13.13±1.60 13.27±0.80 13.21±0.60 11.94±2.20 13.24±1.24 13.27±1.17 13.16±0.30 4.00±0.47 2.80±0.15 3.44±0.52 2.99±0.26 2.94±0.37 2.92±0.35 3.26±0.41 3.02±0.56 3.49±0.14 3.26±0.13 2.95±0.32 3.46±0.33 3.77±0.54 3.40±0.29 3.06±0.44 3.10±0.19 2.91±0.37 3.04±0.21
[0078]?
20 21 22 23 I 16 I 17 I 18 I 19 50 50 50 50 11.12±1.81 13.21±1.06 13.24±0.69 13.31±0.40 2.40±0.29 3.61±0.39 3.31±0.39 3.59±0.16
Above pharmacology data shows, the reduction plasma cholesterol effect that general formula of the present invention (I) compound tool is stronger.
The present invention also comprises pharmaceutical preparation, and said preparation comprises general formula (I) compound and the pharmaceutically acceptable carrier as promoting agent.Pharmaceutically acceptable carrier is meant one or more inert, atoxic solid or liquid filler material, thinner, auxiliary agent etc., and their not reverse and active compounds or patient have an effect.
But common formulations on the pharmaceuticies such as the formulation tablet of the present composition, capsule, pill, suppository, soft capsule, oral liquid, suspensoid, injection liquid.
Tablet for oral use and capsule contain traditional vehicle such as weighting material, thinner, lubricant, dispersion agent and tackiness agent.Can be prepared according to the method for knowing in this area.
The dosage of above active compound will be different because of prescription.
Usually, prove favourable amount for reaching required result, the total amount of per 24 hours administration general formulas (I) of every kg body weight compound is about 0.01-100mg, the preferred about 0.1-50mg of total amount.If necessary, with the form administration of single dose several times.Yet, if necessary, also can depart from above-mentioned consumption, promptly this depends on experimenter's to be treated type and body weight, individual behavior to medicine, the character of disease and type and the administration time or the interval of seriousness, preparation and administration.
By the following examples the present invention is done into description.
Embodiment:
Embodiment 1
The preparation of chloroformyl methyl-butyrate
50g (0.439mol) Pyroglutaric acid is dissolved in the 30ml anhydrous methanol, and behind the reflux 1h, unreacted methanol is removed in underpressure distillation; Reaction solution is cooled to room temperature, slowly adds 100ml thionyl chloride and 3 DMF, behind the reflux 2h, the water pump underpressure distillation, remove remaining thionyl chloride after, use the oil pump underpressure distillation again, collect the cut of 96-98 ℃/10mmHg, get weak yellow liquid 62.1g, yield: 86.1%.
Embodiment 2
The preparation of N-(3,4-dioxy methylene-benzene methylene radical)-4-monomethylaniline (II4)
Add the 7.5g piperonylaldehyde in 500ml two neck bottles, 5.36g is to monomethylaniline, the catalytic amount tosic acid, and 250ml toluene, oil bath is heated to backflow, induction stirring, fraction water device water-dividing reacted 12 hours, and TLC follows the tracks of reaction process.Reaction is finished, suction filtration while hot, filter cake discards, filtrate be spin-dried for crude product 10.9g, yield: 85.0%.
Embodiment 3
Instead-and 3-[2-oxo-4-(3,4-dioxy methylene radical phenyl)-1-(4-aminomethyl phenyl)-2-azelidinyl] preparation of methyl propionate (III4)
Add 9.2g (0.038mol) N-(3 in the 250ml three-necked flask, 4-dioxy methylene radical phenyl)-the 4-monomethylaniline, 130ml toluene, 27.4ml (0.114mol) tri-n-butylamine, after the reflux, slowly splash into the solution of 12.7g (0.076mol) chloroformyl methyl-butyrate and 10ml toluene, reaction solution is the faint yellow redness that becomes rapidly, and the dropping process needs 0.5h approximately, continues reflux 8h, cooling, add the rare HCl 40ml of 1mol/L, behind the stirring at room 15min, with EtOAc extraction (50ml*3), organic phase is used the rare HCl of 1mol/L (50ml*3), saturated NaHCO successively 3(50ml*3), saturated aqueous common salt (50ml*3) is washed, and anhydrous sodium sulfate drying filters, concentrate, and system sand, column chromatography purification gets white needle-like crystals 9.2g, productive rate: 65.1%.
Embodiment 4
Instead-preparation of 1-(4-aminomethyl phenyl)-3-(3,3-phenylbenzene-3-hydroxypropyl)-4-(3,4-dioxy methylene radical phenyl)-2-azetidinone (I4)
In the 100ml three-necked bottle, add 1.3g (III4), it is dissolved in 50 anhydrous diethyl ethers then, slowly be added drop-wise among the 7.5mmol Grignard reagent PhMgBr, keep refluxing, have a large amount of white solids to generate.Drip and finish the 40min that refluxes again, stopped reaction, remove oil bath, add ice-water bath, in reaction flask, pour the mixture termination reaction of 1mol/LHCl and trash ice then into, extracted with diethyl ether, washing, drying, concentrate faint yellow oily thing 1.1g, with the THF dissolving, add the capacity LiOH aqueous solution, stirring at room 6h, use ethyl acetate extraction, saturated NaCl washes twice, anhydrous MgSO 4Drying is filtered, and filtrate concentrates, column chromatography for separation (ethyl acetate: sherwood oil=1: 5), get white solid 0.60g, yield: 34.5%; Mp:169-170 ℃. 1H-NMR(CDCl 3，300Hz)δ：1.90(2H，m，-CH 2-)，2.26(3H，s，Ar-CH 3)，2.42(2H，m，-CH 2-)，3.15(1H，d，-CH-)，4.46(1H，d，-NCH-)，5.95(2H，d，-OCH 2O-)，6.77~7.29(17H，m，Ar-H)；
MS(ESI+，m/z)：514.3[M+Na +]。
Embodiment 5
Instead-preparation of 1-(4-chloro-phenyl-)-3-(3,3-phenylbenzene-3-hydroxypropyl)-4-(4-p-methoxy-phenyl)-2-azetidinone (I1)
With reference to the preparation method of I4, be starting raw material with aubepine and p-Chlorobenzoic acid amide, get white solid 0.58g, yield: 35.2%; Mp:64-67 ℃.
1H-NMR(CDCl 3，300Hz)δ：1.64(1H，m，-OH)，1.93(2H，m，-CH 2-)，2.42(2H，m，-CH 2-)，3.15(1H，d，-CH-)，3.80(3H，s，-OCH 3)，4.51(1H，d，-NCH-)，6.88~7.42(18H，m，Ar-H)；MS(ESI+，m/z)：520.2[M+Na +]。
Embodiment 6
Instead-preparation of 1-(4-chloro-phenyl-)-3-(3,3-phenylbenzene-3-hydroxypropyl)-4-(3,4-dioxy methylene radical phenyl)-2-azetidinone (I2)
With reference to the preparation method of I4, with 3,4-dioxy methylene-benzene formaldehyde and p-Chlorobenzoic acid amide are starting raw material, get white solid 0.71g, yield: 33.7%; Mp:147-150 ℃.
1H-NMR(CDCl 3，300Hz)δ：1.90(2H，m，-CH 2-)，2.45(2H，m，-CH 2-)，3.10(1H，d，-CH-)，4.46(1H，d，-NCH-)，5.97(2H，d，-OCH 2O-)，6.75~7.42(17H，m，Ar-H)；
MS(ESI+，m/z)：534.3([M+Na +])。
Embodiment 7
Instead-preparation of 1-(4-aminomethyl phenyl)-3-(3,3-phenylbenzene-3-hydroxypropyl)-4-(4-p-methoxy-phenyl)-2-azetidinone (I3)
With reference to the preparation method of I4, be starting raw material with aubepine with to monomethylaniline, get pure product 0.65g, yield: 39.2%; Mp:130-131 ℃.
1H-NMR(CDCl 3，300Hz)δ：1.64(1H，m，-OH)，1.86(2H，m，-CH 2-)，2.25(3H，s，-ArCh 3)，2.42(2H，m，-CH 2-)，2.48(1H，s，-OH)，3.05(1H，d，-CH-)，3.80(3H，s，-OCH 3)，4.51(1H，d，-NCH-)，6.87~7.42(18H，m，Ar-H)；
MS(ESI+，m/z)：500.3([M+Na +])。
Embodiment 8
Instead-preparation of 1-phenyl-3-(3,3-phenylbenzene-3-hydroxypropyl)-4-(4-p-methoxy-phenyl)-2-azetidinone (I5)
With reference to the preparation method of I4, be starting raw material with aubepine and aniline, get pure product 0.80g, yield: 37.4%; Mp:128-131 ℃.
1H-NMR(CDCl 3，300Hz)δ：1.64(1H，m，-OH)，1.85(2H，m，-CH 2-)，2.44(2H，m，-CH 2-)，3.09(1H，d，-CH-)，3.80(3H，s，-OCH 3)，4.53(1H，d，-NCH-)，6.88~7.43(19H，m，Ar-H)；
MS(ESI+，m/z)：486.3([M+Na +])。
Embodiment 9
Instead-preparation of 1-(4-p-methoxy-phenyl)-3-(3,3-phenylbenzene-3-hydroxypropyl)-4-(3,4-dioxy methylene radical phenyl)-2-azetidinone (I6)
With reference to the preparation method of I4, with 3,4-dioxy methylene-benzene formaldehyde and P-nethoxyaniline are starting raw material, get pure product 0.67g, yield: 36.7%; Mp:154-156 ℃.
1H-NMR(CDCl 3，300Hz)δ：1.88(2H，m，-CH 2-)，2.42(2H，m，-CH 2-)，3.09(1H，d，-CH-)，3.74(3H，s，-OCH 3)，4.45(1H，d，-NCH-)，5.95(2H，d，-OCH 2O-)，6.76~7.43(17H，m，Ar-H)；
MS(ESI+，m/z)：530.1([M+Na +])。
Embodiment 10
Instead-preparation of 1-phenyl-3-(3,3-phenylbenzene-3-hydroxypropyl)-4-(3,4-dioxy methylene radical phenyl)-2-azetidinone (I7)
With reference to the preparation method of I4, with 3,4-dioxy methylene-benzene formaldehyde and aniline are starting raw material, must get pure product 0.55g, yield: 34.7%; Mp:132-135 ℃.
1H-NMR(CDCl 3，300Hz)δ：1.88(2H，m，-CH 2-)，2.42(2H，m，-CH 2-)，3.08(1H，d，-CH-)，4.48(1H，d，-NCH-)，5.95(2H，d，-OCH 2O-)，6.79~7.43(17H，m，Ar-H)；
MS(ESI+，m/z)：500.1([M+Na +])。
Embodiment 11
Instead-preparation of 1-(2-aminomethyl phenyl)-3-(3,3-phenylbenzene-3-hydroxypropyl)-4-(4-p-methoxy-phenyl)-2-azetidinone (I8)
With reference to the preparation method of I4, be starting raw material with aubepine and Ortho Toluidine, get pure product 0.60g, yield: 35.0%;
1H-NMR(CDCl 3，300Hz)δ：1.94(2H，m，-CH 2-)，2.36(3H，s，-ArCH 3)，2.47(2H，m，-CH 2-)，3.18(1H，d，-CH-)，4.68(1H，d，-NCH-)，3.76(3H，s，-OCH 3)，6.83~7.96(18H，m，Ar-H)；
MS(ESI+，m/z)：500.2([M+Na +])。
Embodiment 12
Instead-preparation of 1-(2-aminomethyl phenyl)-3-(3,3-phenylbenzene-3-hydroxypropyl)-4-(3,4-dioxy methylene radical phenyl)-2-azetidinone (I9)
With reference to the preparation method of I4, with 3,4-dioxy methylene-benzene formaldehyde and Ortho Toluidine are starting raw material, get pure product 0.73g, yield: 36.4%.
1H-NMR(CDCl 3，300Hz)δ：1.90(2H，m，-CH 2-)，2.37(3H，s，-ArCH 3)，2.43(2H，m，-CH 2-)，3.13(1H，d，-CH-)，4.65(1H，d，-NCH-)，5.93(2H，d，-OCH 2O-)，6.74~7.45(17H，m，Ar-H)；
MS(ESI+，m/z)：514.1([M+Na +])。
Embodiment 13
Instead-preparation of 1-(4-fluorophenyl)-3-(3,3-phenylbenzene-3-hydroxypropyl)-4-(4-p-methoxy-phenyl)-2-azetidinone (I10)
With reference to the preparation method of I4, be starting raw material with aubepine and para-fluoroaniline, get pure product 0.84g, yield: 36.4%.
1H-NMR(CDCl 3，300Hz)δ：1.89(2H，m，-CH 2-)，2.43(2H，m，-CH 2-)，3.07(1H，d，-CH-)，3.80(3H，s，-OCH 3)，4.50(1H，d，-NCH-)，6.88~7.43(18H，m，Ar-H)
MS(ESI+，m/z)：504.1([M+Na +])。
Embodiment 14
Instead-and 1-(2-aminomethyl phenyl)-3-[3,3-two (4-fluorophenyl)-3-hydroxypropyl]-preparation of the preparation (I11) of 4-(3,4-dioxy methylene radical phenyl)-2-azetidinone
With reference to the preparation method of I4, with 3,4-dioxy methylene-benzene formaldehyde and Ortho Toluidine are starting raw material, white solid 0.8g, productive rate: 21.4%, mp:89.0～91.0 ℃.
1H-NMR(CDCl 3，300Hz)δ：1.90(2H，m，-CH 2-)，2.37(3H，s，Ar-CH 3)，2.41(1H，m，-OH)，2.72(2H，m，-CH 2-)，3.15(1H，d，-CH-)，4.64(1H，d，-NCH-)，5.93(2H，m，-OCH 2O-)，6.74~7.40(15H，m，Ar-H)；
MS(ESI+，m/z)：[M+Na] +550.2。
Embodiment 15
Instead-and 1-(4-p-methoxy-phenyl)-3-[3,3-two (4-fluorophenyl)-3-hydroxypropyl]-preparation of the preparation (I12) of 4-(4-p-methoxy-phenyl)-2-azetidinone
With reference to the preparation method of I4, be starting raw material with aubepine and P-nethoxyaniline, get white solid 0.9g, productive rate: 24.6%; Mp:130.0～131.0 ℃.
1H-NMR(CDCl 3，300Hz)δ：1.85(2H，m，-CH 2-)，2.37(1H，m，-OH)，2.63(2H，m，-CH 2-)，3.08(1H，d，-CH-)，3.73(3H，s，-OCH 3)，3.80(3H，s，-OCH 3)，4.48(1H，d，-NCH-)，6.75~7.38(16H，m，Ar-H)；
MS(ESI+，m/z)：[M+Na] +552.2。
Embodiment 16
Instead-and 1-(4-chloro-phenyl-)-3-[3,3-two (4-fluorophenyl)-3-hydroxypropyl]-preparation of the preparation (I13) of 4-(4-p-methoxy-phenyl)-2-azetidinone
With reference to the preparation method of I4, be starting raw material with aubepine and p-Chlorobenzoic acid amide, white solid 1.1g, productive rate: 26.0%, mp:91.0～93.0 ℃.
1H-NMR(CDCl 3，300Hz)δ：1.86(2H，m，-CH 2-)，2.40(1H，m，-OH)，2.48(2H，m，-CH 2-)，3.10(1H，d，-CH-)，3.81(3H，s，-OCH 3)，4.50(1H，d，-NCH-)，6.88~7.38(16H，m，Ar-H)；MS(ESI+，m/z)：[M+Na] +556.2。
Embodiment 17
Instead-and 1-(4-aminomethyl phenyl)-3-[3,3-two (4-fluorophenyl)-3-hydroxypropyl]-preparation of the preparation (I14) of 4-(3,4-dioxy methylene radical phenyl)-2-azetidinone
With reference to the preparation method of I4, with 3,4-dioxy methylene-benzene formaldehyde and para-totuidine are starting raw material, white solid 1.9g, productive rate: 31.5%, mp:121.0～123.0 ℃.
1H-NMR(CDCl 3，300Hz)δ：1.86(2H，m，-CH 2-)，2.26(3H，s，Ar-CH 3)，2.37(1H，m，-OH)，2.54(2H，m，-CH 2-)，3.06(1H，d，-CH-)，4.45(1H，d，-NCH-)，5.95(2H，m，-OCH 2O-)，6.77~7.38(15H，m，Ar-H)；
MS(ESI+，m/z)：[M+Na] +550.2。
Embodiment 18
Instead-and 1-(4-fluorophenyl)-3-[3,3-two (4-fluorophenyl)-3-hydroxypropyl]-preparation of the preparation (I15) of 4-(4-p-methoxy-phenyl)-2-azetidinone
With reference to the preparation method of I4, be starting raw material with aubepine and para-fluoroaniline, white solid 1.9g, productive rate: 29.2%, mp:100.0～103.0 ℃.
1H-NMR(CDCl 3，300Hz)δ：1.88(2H，m，-CH 2-)，2.38(1H，m，-OH)，2.50(2H，m，-CH 2-)，3.10(1H，d，-CH-)，3.81(3H，s，-OCH 3)，4.50(1H，d，-NCH-)，6.89~7.38(16H，m，Ar-H)；
MS(ESI+，m/z)：[M+Na] +540.3。
Embodiment 9
Instead-and 1-(4-ethoxyl phenenyl)-3-[3,3-two (4-fluorophenyl)-3-hydroxypropyl]-preparation of the preparation (I16) of 4-(4-p-methoxy-phenyl)-2-azetidinone
With reference to the preparation method of I4, be starting raw material with aubepine and p-ethoxyaniline, white solid 1.3g, productive rate: 30.0%, mp:137.0～139.0 ℃.
1H-NMR(CDCl 3，300Hz)δ：1.36(3H，m，-CH 3)，1.85(2H，m，-CH 2-)，2.38(1H，m，-OH)，2.56(2H，m，-CH 2-)，3.08(1H，d，-CH-)，3.80(3H，s，-CH 3)，3.93(2H，m，-CH 2-)，4.48(1H，d，-NCH-)，6.74~7.39(16H，m，Ar-H)；
MS(ESI+，m/z)：[M+Na] +566.3。
Embodiment 20
Instead-and 1-(4-bromophenyl)-3-[3,3-two (4-fluorophenyl)-3-hydroxypropyl]-preparation of the preparation (I17) of 4-(4-p-methoxy-phenyl)-2-azetidinone
With reference to the preparation method of I4, be starting raw material with aubepine and para-bromoaniline, get white solid 1.1g, productive rate: 19.9%; Mp:122.0～124.0 ℃, 1H-NMR (CDCl 3, 300Hz) δ: 1.86 (2H, m ,-CH 2-), 2.30 (1H, m ,-OH), 2.47 (2H, m ,-CH 2-), 3.10 (1H, m ,-CH-), 3.81 (3H, s ,-OCH 3), 4.50 (1H, d ,-NCH-), 6.88 ~ 7.38 (16H, m, Ar-H);
MS(ESI+，m/z)：[M+Na] +601.0
Embodiment 21
Instead-and 1-(4-chloro-phenyl-)-3-[3,3-dibenzyl-3-hydroxypropyl]-preparation of 4-(3,4-dioxy methylene radical phenyl)-2-azetidinone (I18)
With reference to the preparation method of I4, with 3,4-dioxy methylene-benzene formaldehyde and p-Chlorobenzoic acid amide are starting raw material, get faint yellow solid 0.7g, productive rate: 19.5%;
1H-NMR(CDCl 3，300Hz)δ：1.57(2H，m，-CH 2-)，1.97(2H，m，-CH 2-)，2.75(2H，s，PhCH 2-)，?2.80(2H，d，PhCH 2-)，2.97(1H，d，-CH-)，4.26(1H，d，-NCH-)，5.92(2H，m，-OCH 2O-)，6.52~7.35(17H，m，Ar-H)；
MS(ESI+，m/z)：[M+Na] +562.3
Embodiment 22
Instead-and 1-(4-p-methoxy-phenyl)-3-[3,3-two (4-fluorophenyl)-3-hydroxypropyl]-preparation of 4-(3,4-dioxy methylene radical-6-bromophenyl)-2-azetidinone (I19)
With reference to the preparation method of I4, with 3,4-dioxy methylene radical-6-bromobenzaldehyde and P-nethoxyaniline are starting raw material, get faint yellow solid 0.6g, productive rate: 21.5%;
1H-NMR(CDCl 3，300Hz)δ：1.93(2H，m，-CH 2-)，2.47(2H，m，-CH 2-)，3.02(1H，d，-CH-)，3.76(3H，s，-OCH 3)，5.00(1H，d，-NCH-)，5.95(2H，m，-OCH 2O-)，6.68~7.49(14H，m，Ar-H)；
MS(ESI+，m/z)：[M+Na] +644.2。
Embodiment 23
The tablet that contains promoting agent I4:
Every contains (mg)
I4 50mg
Lactose 100mg
W-Gum 40mg
Magnesium Stearate 1.5mg
Ethanol is an amount of
According to a conventional method supplementary material is mixed, granulate drying, compressing tablet.

Claims (3)

1. following arbitrary compound and pharmacologically acceptable salt thereof:
Instead-1-(4-chloro-phenyl-)-3-(3,3-phenylbenzene-3-hydroxypropyl)-4-(4-p-methoxy-phenyl)-2-azetidinone;
Instead-1-(4-chloro-phenyl-)-3-(3,3-phenylbenzene-3-hydroxypropyl)-4-(3,4-dioxy methylene radical phenyl)-2-azetidinone;
Instead-1-(4-aminomethyl phenyl)-3-(3,3-phenylbenzene-3-hydroxypropyl)-4-(4-p-methoxy-phenyl)-2-azetidinone;
Instead-1-(4-aminomethyl phenyl)-3-(3,3-phenylbenzene-3-hydroxypropyl)-4-(3,4-dioxy methylene radical phenyl)-2-azetidinone;
Instead-1-phenyl-3-(3,3-phenylbenzene-3-hydroxypropyl)-4-(4-p-methoxy-phenyl)-2-azetidinone;
Instead-1-(4-p-methoxy-phenyl)-3-(3,3-phenylbenzene-3-hydroxypropyl)-4-(3,4-dioxy methylene radical phenyl)-2-azetidinone;
Instead-1-phenyl-3-(3,3-phenylbenzene-3-hydroxypropyl)-4-(3,4-dioxy methylene radical phenyl)-2-azetidinone;
Instead-1-(2-aminomethyl phenyl)-3-(3,3-phenylbenzene-3-hydroxypropyl)-4-(4-p-methoxy-phenyl)-2-azetidinone;
Instead-1-(2-aminomethyl phenyl)-3-(3,3-phenylbenzene-3-hydroxypropyl)-4-(3,4-dioxy methylene radical phenyl)-2-azetidinone;
Instead-1-(4-fluorophenyl)-3-(3,3-phenylbenzene-3-hydroxypropyl)-4-(4-p-methoxy-phenyl)-2-azetidinone;
Instead-and 1-(2-aminomethyl phenyl)-3-[3,3-two (4-fluorophenyl)-3-hydroxypropyl]-4-(3,4-dioxy methylene radical phenyl)-2-azetidinone;
Instead-and 1-(4-p-methoxy-phenyl)-3-[3,3-two (4-fluorophenyl)-3-hydroxypropyl]-4-(4-p-methoxy-phenyl)-2-azetidinone;
Instead-and 1-(4-chloro-phenyl-)-3-[3,3-two (4-fluorophenyl)-3-hydroxypropyl]-4-(4-p-methoxy-phenyl)-2-azetidinone;
Instead-and 1-(4-aminomethyl phenyl)-3-[3,3-two (4-fluorophenyl)-3-hydroxypropyl]-4-(3,4-dioxy methylene radical phenyl)-2-azetidinone;
Instead-and 1-(4-fluorophenyl)-3-[3,3-two (4-fluorophenyl)-3-hydroxypropyl]-4-(4-p-methoxy-phenyl)-2-azetidinone;
Instead-and 1-(4-ethoxyl phenenyl)-3-[3,3-two (4-fluorophenyl)-3-hydroxypropyl]-4-(4-p-methoxy-phenyl)-2-azetidinone;
Instead-and 1-(4-bromophenyl)-3-[3,3-two (4-fluorophenyl)-3-hydroxypropyl]-4-(4-p-methoxy-phenyl)-2-azetidinone;
Instead-and 1-(4-chloro-phenyl-)-3-[3,3-dibenzyl-3-hydroxypropyl]-4-(3,4-dioxy methylene radical phenyl)-2-azetidinone;
Instead-and 1-(4-p-methoxy-phenyl)-3-[3,3-two (4-fluorophenyl)-3-hydroxypropyl]-4-(3,4-dioxy methylene radical-6-bromophenyl)-2-azetidinone.
2. each described compound or pharmaceutically acceptable salt thereof is used to prepare treatment or prevention of arterial is atherosis or reduce the purposes of the medicine of blood plasma cholesterol level in the claim 1.
3. a pharmaceutical composition wherein contains each the described compound or pharmaceutically acceptable salt thereof of claim 1 and the pharmaceutically acceptable carrier for the treatment of significant quantity.
CN200710133305XA 2007-10-17 2007-10-17 Azetidinone derivatives, processes for their preparation and pharmaceutical combinations containing them Expired - Fee Related CN101200443B (en)

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US20040082561A1 (en) * 2002-06-19 2004-04-29 Gerhard Jaehne Ring -substituted diphenylazetidinones, process for their preparation, medicaments comprising these compounds, and their use
CN1662495A (en) * 2002-06-19 2005-08-31 安万特医药德国有限公司 Acid-group-substituted diphenylazetidinones, process for their preparation, medicaments comprising these compounds, and their use
WO2006116499A1 (en) * 2005-04-26 2006-11-02 Microbia, Inc. 4-biarylyl-1-phenylazetidin-2-one glucuronide derivatives for hypercholesterolemia
CN1898203A (en) * 2003-12-23 2007-01-17 阿斯利康(瑞典)有限公司 Diphenylazetidinone derivates possessing cholesterol absorption inhibitory activity

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CN1144522A (en) * 1994-03-25 1997-03-05 先灵公司 Substituted azetidinone compounds useful as hypocholesterolemic agents
US20040082561A1 (en) * 2002-06-19 2004-04-29 Gerhard Jaehne Ring -substituted diphenylazetidinones, process for their preparation, medicaments comprising these compounds, and their use
CN1662495A (en) * 2002-06-19 2005-08-31 安万特医药德国有限公司 Acid-group-substituted diphenylazetidinones, process for their preparation, medicaments comprising these compounds, and their use
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WO2006116499A1 (en) * 2005-04-26 2006-11-02 Microbia, Inc. 4-biarylyl-1-phenylazetidin-2-one glucuronide derivatives for hypercholesterolemia

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