- METHOD OF PREPARING EZETIMIBE AND INTERMEDIATE THEREOF
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Disclosed is a method of preparing ezetimibe, including cross-metathesis using a Grubbs 2nd catalyst and deprotection using a Pearlman's catalyst, and an intermediate thereof. The method of preparing ezetimibe is useful as an efficient ezetimibe synthesis technique in pharmaceutical fields using ezetimibe as a raw material.
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Paragraph 0074-0076
(2019/08/30)
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- Preparation method of ezetimibe for treating hyperlipidemia
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The invention discloses a preparation method of ezetimibe for treating hyperlipidemia, and belongs to the field of drug synthesizing. The method is characterized in that a compound 2 is treated as theraw material and subjected to four synthesizing steps to prepare ezetimibe 1, wherein the four steps include the step of protection for carbonyl group, cyclizing, carbonyl reduction and hydrogenationdeprotection. Compared with methods in existing documents, the preparation method has the advantages that the use of polluting titanium agents is avoided; the synthesizing steps are decreased; the technology stability is improved; massive production can be performed.
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- Preparation method of ezetimibe intermediate
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The invention provides a preparation method of an ezetimibe intermediate I. The preparation method includes: (1), in an inert solvent and at the presence of alkali, enabling a compound shown as a formula III to react with fluoroacetophenone to obtain a compound shown as a formula II; (2), providing a mixed solution A of hexamethyl disilicon sodium amide and an organic solvent; (3), enabling the compound shown as the formula II to react with the mixed solution A to obtain a compound shown as a formula I. The method can be completed at room temperature, reaction yield is increased to about 90% from 70% of the prior art, reactant purity is improved greatly, and a condition is provided for realizing industrial production of ezetimibe.
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Paragraph 0043; 0046; 0050; 0054
(2018/07/30)
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- METHOD FOR PRODUCING DIPHENYL AZETIDINE DERIVATIVE
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PROBLEM TO BE SOLVED: To provide a highly efficient industrial production method of a diphenyl azetidine derivative which is a production raw material of a β-lactam derivative useful for the treatment and prevention of hypercholesterolemia such as arteriosclerosis. SOLUTION: There is provided a method for producing a compound represented by the general formula (III) [wherein, R is the same as the case of the general formula (I)] by reacting a compound represented by the general formula (I) [wherein, R represents a lower alkyl group which may be branched, an ally group, a lower alkyl group including a lower alkoxy group, a lower alkyl group including a lower thioalkyl group, a tetrahydropyranyl group, a triphenylmethyl group, a silyl group having a substituent, a phenyl group which may have a substituent and a benzyl group which may have a substituent.] and a compound represented by the general formula (II) [wherein, M represents MgCl, MgBr, MgI or Li) in a toluene solvent. SELECTED DRAWING: None COPYRIGHT: (C)2018,JPOandINPIT
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Paragraph 0028; 0030
(2018/07/31)
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- Ezetimibe intermediate, synthesis method of intermediate and synthesis method of ezetimibe
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The invention provides an ezetimibe intermediate, a synthesis method of the intermediate and a synthesis method of ezetimibe. The method is short in synthetic route. The method includes the steps of making fluorobenzene as the initial raw material sequentially have acylation reaction with glutaric anhydride and 4(S)-4-phenyl oxazolidinone to generate a compound II, protecting carbonyl through 2,2-bis-substituted-1,3-propylene glycol to obtain a compound III, generating a compound V through the compound III and a compound IV under the catalysis of titanium tetrachloride, cyclizing the compound V to generate a compound VI, hydrolyzing the compound VI to obtain a compound VII, and reducing the compound VII through a borane chiral reducing agent and removing a benzyl protecting group in a hydrogenated mode to obtain the ezetimibe. The method is high in yield, little in side reaction and suitable for industrial mass production.
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- MANUFACTURING METHOD OF (3R,4S)-1-(4-FLUOROPHENYL)-[3(S)-HYDROXY-3-(4-FLUOROPHENYL)PROPYL]-[4-(PHENYLMETHOXY)PHENYL]-2-AZETIDINONE
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PROBLEM TO BE SOLVED: To provide a method for effectively manufacturing high purity (3R,4S)-1-(4-fluorophenyl)-[3(S)-hydroxy-3-(4-fluorophenyl)propyl]-[4-(phenylmethoxy)phenyl]-2-azetidinone with reduced contents of specific impurities and enantiomers. SOLUTION: When a benzyl protective body is manufactured by reacting a benzyl protective keto body and borane in presence of a CBS catalyst, the benzyl protective keto body is injected under a condition with co-existing a part of borane of needed amount in a reaction system in advance and remaining borane is added later to conduct the reaction. SELECTED DRAWING: None COPYRIGHT: (C)2017,JPOandINPIT
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- Synthesis method of ezetimibe
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The invention discloses a synthesis method of ezetimibe, which comprises the following steps: under the protection of inert gas, adding N,O-dimethylhydroxylamine hydrochloride and EZE-5 into a solvent, and dropwisely adding a DEAC toluene solution to react, thereby obtaining EZE-15; adding magnesium chips and THF (tetrahydrofuran), and dropwisely adding a 4-fluorobromobenzene THF solution to obtain oily EZE-8; adding ethyl benzene, and stirring; dropwisely adding a prepared triethylamine-formic acid mixed reagent, and adding a catalyst to react, thereby obtaining EZE-9; adding THF and EtOH, stirring, adding 5% Pd/C, replacing air in a reaction bulb with high-purity nitrogen, introducing high-purity hydrogen, and carrying out LC until the reaction is complete, thereby obtaining a crude product EZE-10; and refining the crude product with isopropanol and water to obtain the white crystalline powder high-purity EZE-10. The method has the advantages of high synthesized ezetimibe purity, simple used equipment, simplified steps and low production cost, and is suitable for industrial production.
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Paragraph 0025-0039
(2016/10/31)
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- Preparation method of azetidinone derivatives
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The invention discloses a preparation method of azetidinone derivatives. The preparation method comprises that a compound I undergoes a benzoylation reaction to produce an intermediate A, the intermediate A is hydrolyzed to form an intermediate B and the intermediate B undergoes a decarboxylic reaction to produce an azetidinone derivative. The preparation method has a simple synthesis route, utilizes cheap and easily available industrial products as raw materials, has simple reaction processes and simple treatment processes, can produce ezetimibe in a short production period, directly utilizes intermediate crude products for the next reaction process, has a high technology serialization degree and greatly improves a total yield.
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Paragraph 0058; 0059; 0060
(2016/12/01)
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- PROCESS FOR SYNTHESIS OF EZETIMIBE AND INTERMEDIATES USED IN SAID PROCESS
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A process for the production of ezetimibe and intermediates used in said process are disclosed. A kind of Morita-Baylis-Hillman adduct can be altered to chiral carboxylic acid derivatives of β-arylamino α-methylene with high activity and selectivity by means of ally lamination reaction, and the above carboxylic acid derivatives of β-arylamino α-methylene can be altered to the chiral intermediates of ezetimibe by means of simple conversion and further synthesized into the chiral drug ezetimibe. The synthesis route introduces chirality through the use of a chiral catalysis method, thereby avoiding the use of the chiral auxiliary oxazolidinone; and the route is economical and eco-friendly.
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- PROCESS FOR SYNTHESIS OF EZETIMIBE AND INTERMEDIATES USED IN SAID PROCESS
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A process for the production of ezetimibe and intermediates used in said process are disclosed. A kind of Morita-Baylis-Hillman adduct can be altered to chiral carboxylic acid derivatives of β-arylamino α-methylene with high activity and selectivity by means of ally lamination reaction, and the above carboxylic acid derivatives of β-arylamino α-methylene can be altered to the chiral intermediates of ezetimibe by means of simple conversion and further synthesized into the chiral drug ezetimibe. The synthesis route introduces chirality through the use of a chiral catalysis method, thereby avoiding the use of the chiral auxiliary oxazolidinone; and the route is economical and eco-friendly.
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Paragraph 0177; 0178
(2015/06/24)
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- PROCESS FOR THE PREPARATION OF INTERMEDIATE COMPOUNDS USEFUL IN THE PREPARATION OF EZETIMIBE
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The present invention provides an improved process for preparing (3R, 4S)-4-(4- (benzyloxy)phenyl)-1-(4-fluorophenyl)-3-(3-(4-fluorophenyl)-3-oxopropyl)azetidin-2-one, which is a key intermediate for the preparation of Ezetimibe, and involves the use of new intermediate compounds.
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- INTERMEDIATES IN THE PREPARATION OF 1,4-DIPHENYL AZETIDINONE
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The process of the present invention relates to a method for the synthesis of a 1,4-diphenylazetidinone of formula (VIII) by using novel oxime intermediates.
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Page/Page column 13-14
(2010/11/03)
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- A PROCESS FOR THE PREPARATION OF AN ALDEHYDE BETA-LACTAM COMPOUND
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The invention relates to a process for the preparation of an aldehyde beta-lactam compound of formula (I), wherein P1 is H or a protecting group, useful in the preparation of ezetimibe, from a nitrone compound of formula (II). The nitrone compound Il is prepared by reacting 4-fluorophenylhydroxyloamine with OH- protected 4-hydroxybenzaldehyde. The nitrone compound of formula (II) is reacted with an acetylene compound of formula (III) to form a compound of formula (IV), and the compound of formula (IV), after optional deprotection, is oxidized to obtain an aldehyde of formula (V), which undergoes isomerisation to the compound of formula (I). The subject of the invention are also novel compounds of formulas (II) and (IV).
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Page/Page column 32-33
(2010/09/17)
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- Process for the synthesis of ezetimibe and intermediates useful therefor
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The present invention discloses novel and useful intermediates for the synthesis of ezetimibe (EZT), which intermediates share a characteristic Z-isomeric structure. Based on Z-5-(4-fluorophenyl)-pent-4-enoic acid, and proceeding the synthesis through further Z-intermediates, a total synthesis is presented to obtained final ezetimibe in high yields.
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Page/Page column 13-14
(2010/03/02)
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- (Z)-5-(4-fluorophenyl)pent-4-enoic acid: A precursor for convenient and efficient synthesis of the antihypercholesterolemia agent ezetimibe
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A convenient and efficient total synthesis of ezetimibe, an intestinal cholesterol absorption inhibitor and useful anticholesteremic agent, is described. Based on (Z)-5-(4-fluorophenyl)pent-4-enoic acid as a starting compound, and taking the synthesis through further Z-configured intermediates, the total yield is remarkably increased, compared with the use of the corresponding E-configured starting substances or intermediates. Georg Thieme Verlag Stuttgart.
- Sova, Matej,Mravljak, Janez,Kovac, Andreja,Pecar, Slavko,Casar, Zdenko,Gobec, Stanislav
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experimental part
p. 3433 - 3438
(2010/11/21)
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- PROCESSES FOR PREPARING INTERMEDIATE COMPOUNDS USEFUL FOR THE PREPARATION OF EZETIMIBE
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The invention relates, in general, to an improved process for the preparation of the compounds (3R,4S)-4-(4-(benzyloxy)phenyl)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl]azetidin-2-one and (3R,4S)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl]-4-(4-hydroxyphenyl)-azetidin-2-one, which are key intermediates for the synthesis of ezetimibe, as well as the use of these intermediates for the preparation of ezetimibe.
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Page/Page column 17
(2009/09/26)
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- An improved and scalable process for the synthesis of ezetimibe: An antihypercholesterolemia drug
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An efficient, cost-effective and large-scale synthesis of ezetimibe 1, an antihypercholesterolemia drug, is described. Chiral oxazolidinone chemistry was used to fix the required stereochemistry of the β-lactam ring, and the chiral oxazaborolidine chemistry was used to fix the hydroxyl group stereochemistry. The synthesis significantly lowers the cost and provides easy access to ezetimibe on large scale.
- Sasikala,Padi, Pratap Reddy,Sunkara, Vishnuvardhan,Ramayya, Pattabhi,Dubey,Uppala, Venkata Bhaskar Rao,Praveen, Cherukupally
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experimental part
p. 907 - 910
(2010/04/22)
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- PROCESS FOR PREPARING HIGHLY PURE EZETIMIBE USING NOVEL INTERMEDIATES
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The present invention relates to an industrially advantageous process for the preparation of ezetimibe of formula (I) in high yields by using novel benzyl ester intermediates. The present invention further provides a process for the purification of ezetimibe of formula (I).
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Page/Page column 19-20
(2008/12/08)
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- Process for the preparation of ezetimibe and derivatives thereof
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The present invention relates to the method of preparing of ezetimibe and in particular to novel intermediates for its synthesis and an improved process for preparing such intermediates. Said intermediates may be obtained in high yields and purity in a fast and cost efficient manner. The present invention relates to a novel crystalline form of ezetimibe as well.
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Page/Page column 16
(2008/12/07)
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- Processes for the purification of (3R,4S)-4-(4-hydroxy-protected-phenyl)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl]azetidin-2-one
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Provided are processes for purifying (3R,4S)-4-(4-hydroxyprotected-phenyl)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl]azetidin-2-one having the following formula II wherein X and Y are hydrogen or a substituted or unsubstituted C1-8 alkyl; n is an integer between 0 and 3; and P is a hydroxyl protecting group. The Compound of formula II may be converted to an azetidinone compound, which is useful, for example, in reducing cholesterol in mammals.
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Page/Page column 8; 11
(2008/06/13)
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- IMPROVED PROCESS FOR THE PREPARATION OF EZETIMIBE AND ITS INTERMEDIATES
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The present invention provides an improved process for the preparation of ezetimibe through novel organic amine salt compounds of general formula (1). The present invention also relates to a highly pure ezetimibe and 3-((3R,4S)-1-(4-fluorophenyl)-2-oxo-4-(4-(benzyloxy)phenyl) azetidin-3-yl)propionic acid compound.
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Page/Page column 16; 20
(2008/06/13)
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- A PROCESS FOR THE PREPARATION OF EZETIMIBE VIA A NOVEL INTERMEDIATE
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The present invention relates to a process for the preparation of Ezetimibe via a novel intermediate. Trans-3(R)-(3-[2-oxo-4(S)-(4-benzyloxyphenyl)-1-(4-fluorophenyl)-azetidinyl]propanoic acid is converted to trans-N-methoxy-N-methyl-3(R)-3-[2-oxo-4(S)-(4-benzyloxyphenyl)-1-(4-fluorophenyl)-azetidinyl]propanamide and the resultant intermediate is subjected to Grignard reaction to obtain trans-1-(4-fluorophenyl)-3(R)-[3-oxo-3-(4-fluorophenyl)propyl]-4(S)-(4-benzyloxyphenyl)-2-azetidinone. Reduction of trans-1-(4-JGiuorophenyl)-3(R)-[3-oxo-3-(4-fluorophenyl) propyl]-4(S)-(4-benzyloxyphenyl)-2-azetidinone, followed by debenzylation provides Ezetimibe. The invention also relates to the preparation of the intermediate occurring in the above process.
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Page/Page column 8-9
(2010/11/28)
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- PROCESSES FOR THE SYNTHESIS OF AZETIDINONE
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Provided are intermediates useful for the synthesis of hydroxyl-alkyl substituted azetidinones, processes of their preparation, and processes for the synthesis of certain hydroxyl-alkyl substituted azetidinones. Also provided are processes for the synthesis ofl-(4-fluorophenyl)-3(R)-[3-(4-fluorophenyl)-3(S)- hydroxypropyl]-4(S)-(4-hydroxyphenyl)-2-azetidinone, or ezetimibe.
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Page/Page column 64-65
(2008/06/13)
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- PREPARATION OF EZETIMIBE
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A process for preparing ezetimibe.
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Page/Page column 10
(2010/11/26)
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- IMPROVED PROCESS FOR THE PREPARATION OF EZETIMIBE
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The present invention relates to a cost effective and industrially advantageous process for the preparation of (3R,4S)-l-(4-Fluorophenyl)-3-[3(S)-3-(4-fluorophenyl)-3 - hydroxypropyl)]-4-(4-hydroxyρhenyl)-2-azetidinone, referred to here as Ezetimibe, it is represented as formula (1).
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Page/Page column 13
(2008/06/13)
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- Combinations of lipid modulating agents and substituted azetidinones and treatments for vascular conditions
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The present invention provides compositions, therapeutic combinations and methods including: (a) at least one lipid modulating agent; and (b) at least one substituted azetidinone or substituted β-lactam sterol absorption inhibitor which can be useful for treating vascular conditions, diabetes, obesity and lowering plasma levels of sterols or 5α-stanols.
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Page/Page column 23-24
(2008/06/13)
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- A novel one-step diastereo- and enantioselective formation of trans- azetidinones and its application to the total synthesis of cholesterol absorption inhibitors
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An efficient and practical asymmetric process was developed for the synthesis of azetidinone-based cholesterol absorption inhibitors. Key to this synthesis was the discovery of a novel one-step diastereo- and enantioselective formation of trans β-lactams starting from commercially available 3(S)-hydroxy-γ-lactone. Various trans β-lactams can be prepared in good yields and with better than 95:5 enantio- and diastereoselctivity. A Lewis acid-catalyzed aldol condensation and a highly enantioselective oxazaborolidine-catalyzed chiral reduction completes the side chain.
- Wu,Wong,Chen,Ding
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p. 3714 - 3718
(2007/10/03)
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- Discovery of 1-(4-fluorophenyl)-(3R)-[3-(4-fluorophenyl)-(3S)- hydroxypropyl]-(4S)-(4-hydroxyphenyl)-2-azetidinone (SCH 58235): A designed, potent, orally active inhibitor of cholesterol absorption
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(3R)-(3-Phenylpropyl)-1,(4S)-bis(4-methoxyphenyl)-2-azetidinone (2, SCH 48461), a novel inhibitor of intestinal cholesterol absorption, has recently been described by Burnett et al. and has been demonstrated to lower total plasma cholesterol in man. The potential sites of metabolism of 2 were considered, and the most probable metabolites were prepared. The oral cholesterol-lowering efficacy of the putative metabolites was evaluated in a 7-day cholesterol-fed hamster model for the reduction of serum total cholesterol and liver cholesteryl esters versus control. On the basis of our analysis of the putative metabolite structure-activity relationship (SAR), SCH 58235 (1, 1-4-fluorophenyl)-(3R)-[3-(4-fluorophenyl)-(3S)-hydroxypropyl]- (4S)-(4-hydroxyphenyl)-2-azetidinone) was designed to exploit activity enhancing oxidation and to block sites of potential detrimental metabolic oxidation. Additionally, a series of congeners of 2 were prepared incorporating strategically placed hydroxyl groups and fluorine atoms to further probe the SAR of 2-azetidinone cholesterol absorption inhibitors. Through the SAR analysis of a series of putative metabolites of 2, compound 1 was targeted and found to exhibit remarkable efficacy with an ED50 of 0.04 mg/kg/day for the reduction of liver cholesteryl esters in a 7-day cholesterol-fed hamster model.
- Rosenblum, Stuart B.,Huynh, Tram,Afonso, Adriano,Davis Jr., Harry R.,Yumibe, Nathan,Clader, John W.,Burnett, Duane A.
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p. 973 - 980
(2007/10/03)
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