WO1995035277A1 - Composes d'azetidinone substitues utilises comme agent hypercholesterolemiant - Google Patents

Composes d'azetidinone substitues utilises comme agent hypercholesterolemiant Download PDF

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WO1995035277A1
WO1995035277A1 PCT/US1995/007117 US9507117W WO9535277A1 WO 1995035277 A1 WO1995035277 A1 WO 1995035277A1 US 9507117 W US9507117 W US 9507117W WO 9535277 A1 WO9535277 A1 WO 9535277A1
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phenyl
oxo
trans
aryl
azetidinyl
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PCT/US1995/007117
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English (en)
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Wayne Vaccaro
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Schering Corporation
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Priority to AU29430/95A priority Critical patent/AU2943095A/en
Priority to EP95925237A priority patent/EP0766667A1/fr
Priority to JP8502289A priority patent/JPH10501811A/ja
Priority to MX9606319A priority patent/MX9606319A/es
Publication of WO1995035277A1 publication Critical patent/WO1995035277A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
    • C07D205/085—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams with a nitrogen atom directly attached in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/10—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/0803—Compounds with Si-C or Si-Si linkages
    • C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
    • C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages

Definitions

  • the present invention relates to substituted azetidinones useful as hypochoiesterolemic agents in the treatment and prevention of atherosclerosis, and to the combination of a substituted azetidinone of this invention and a cholesterol biosynthesis inhibitor for the treatment and prevention of atherosclerosis.
  • Atherosclerotic coronary heart disease represents the major cause for death and cardiovascular morbidity in the western world. Risk factors for atherosclerotic coronary heart disease include
  • a total cholesterol level in excess of 225- 250 mg/dl is associated with significant elevation of risk of CHD.
  • Cholesteryl esters are a major component of atherosclerotic lesions and the major storage form of cholesterol in arterial wall cells. Formation of cholesteryl esters is also a key step in the intestinal absorption of dietary cholesterol. Thus, inhibition of cholesteryl ester formation and reduction of serum cholesterol is likely to inhibit the progression of atherosclerotic lesion formation, decrease the
  • U.S. 4,983,597 discloses N-sulfonyl-2-azetidinones as anticholesterolemic agents and Ram, et al., in Indian J. Chem., Sect. B, 29B, 12 (1990), p. 1134-7, disclose ethyl 4-(2- oxoazetidin-4-yl)phenoxy-alkanoates as hypolipidemic agents.
  • European Patent Publication 264,231 discloses 1-substituted-4-phenyl-3-(2-oxo- alkylidene)-2-azetidinones as blood platelet aggregation inhibitors.
  • European Patent 199,630 and European Patent Application 337,549 disclose elastase inhibitory substituted azetidinones said to be useful in treating inflammatory conditions resulting in tissue destruction which are associated with various disease states, e.g. atherosclerosis.
  • WO93/02048 published February 4, 1993, discloses substituted ⁇ -lactams useful as hypocholesterolemic agents.
  • the regulation of whole-body cholesterol homeostasis in humans and animals involves the regulation of dietary cholesterol and modulation of cholesterol biosynthesis, bile acid biosynthesis and the catabolism of the cholesterol-containing plasma lipoproteins.
  • the liver is the major organ responsible for cholesterol biosynthesis and catabolism and for this reason, it is a prime determinant of plasma cholesterol levels.
  • the liver is the site of synthesis and secretion of very low density lipoproteins (VLDL) which are subsequently metabolized to low density lipoproteins (LDL) in the circulation.
  • VLDL very low density lipoproteins
  • LDL low density lipoproteins
  • LDL low density lipoproteins
  • VLDL hepatic lipoprotein
  • HMG CoA 3-hydroxy-3- methylglutaryl coenzyme A reductase
  • Novel hypocholesterolemic compounds of the present invention are represented by the formula I
  • Ar 1 is aryl or R 3 -substituted aryl
  • Ar 2 is aryl or R 4 -substituted aryl
  • R 1 is selected from the group consisting of
  • V is C 3 -C 6 cycloalkylene, f is 1-5 and g is 0-5, provided that the sum of f and g is 1-6;
  • R 3 and R 4 are independently selected from the group consisting of 1-3 substituents independently selected from the group consisting of lower alkyl, -OR 6 , -O(CO)R 6 , -O(CO)OR 9 , -O(CH 2 ) 1-5 OR 6 , -O(CO)NR 6 R 7 , -NR 6 R 7 , -NR 6 (CO)R 7 , -NR 6 (CO)OR 9 , -NR 6 (CO)NR 7 R 8 , -NR 6 SO 2 R 9 , -COOR 6 , -CONR 6 R 7 , -COR 6 , -SO 2 NR 6 R 7 , S(O) 0-2 R 9 ,
  • R 5 is -OR or -NRR 12 , wherein R and R 12 are independently selected from the group consisting of hydrogen, lower alkyl, aryl and aryl- substituted lower alkyl;
  • R 6 , R 7 and R 8 are independently selected from the group consisting of hydrogen, lower alkyl, aryl and aryl-substituted lower alkyl;
  • R 9 is lower alkyl, aryl or aryl-substituted lower alkyl
  • R 10 is hydrogen, lower alkyl, aryl lower alkyl or -C(O)R 6 .
  • R 3 when present, is preferably a halogen.
  • R 4 when present, is preferably halogen or -OR 6 , wherein R 6 is lower alkyl or hydrogen.
  • Ar 2 is 4- fluorophenyl.
  • R 1 is preferably -(CH 2 ) q - or -(CH 2 ) e -Z-(CH 2 ) r -, wherein referred values for q are 2 and 3; Z is preferably -O-; e is preferably 0; and r is preferably 2.
  • R 2 is preferably in the para-position.
  • the lower alkylene portion is preferably methylene or ethylene.
  • R 5 is preferably lower alkyl, especially methyl, or hydrogen.
  • Ar 1 is phenyl or R 3 -substituted phenyl, especially (4-R 3 )-substituted phenyl
  • Ar 2 is phenyl or R 4 -substituted phenyl, especially (4-R 4 )-substituted phenyl
  • R 1 is -(CH 2 ) q - or -(CH 2 ) e -Z-(CH 2 ) r - , wherein Z is -O-.
  • This invention also relates to a method of lowering the serum cholesterol level in a mammal in need of such treatment comprising administering an effective amount of a compound of formula I. That is, the use of a compound of the present invention as an hypocholesterolemic agent is also claimed.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a serum cholesterol-lowering effective amount of a compound of formula I in a pharmaceutically acceptable carrier.
  • the present invention also relates to a method of reducing plasma cholesterol levels, and to a method of treating or preventing atherosclerosis, comprising administering to a mammal in need of such treatment an effective amount of a combination of a substituted
  • the present invention relates to the use of a substituted azetidinone cholesterol absorption inhibitor of formula I for combined use with a cholesterol biosynthesis inhibitor (and, similarly, use of a cholesterol biosynthesis inhibitor for combined use with a substituted azetidinone cholesterol absorption inhibitor of formula I) to treat or prevent atherosclerosis or to reduce plasma cholesterol levels.
  • the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising an effective amount of a substituted azetidinone cholesterol absorption inhibitor of formula I, a cholesterol biosynthesis inhibitor, and a pharmaceutically acceptable carrier.
  • the invention relates to a kit comprising in one container an effective amount of a substituted azetidinone cholesterol absorption inhibitor of formula I in a pharmaceutically acceptable carrier, and in a separate container, an effective amount of a cholesterol biosynthesis inhibitor in a pharmaceutically acceptable carrier.
  • lower alkyl means straight or branched alkyl chains of 1 to 6 carbon atoms.
  • lower alkylene means a divalent alkyl chain, straight or branched, of 1 to 6 carbon atoms
  • cycloalkylene means a divalent cycloalkyl group.
  • Aryl means phenyl, naphthyl, indenyl, tetrahydronaphthyl or indanyl.
  • Phenylene means a divalent phenyl group.
  • Halogeno refers to fluorine, chlorine, bromine or iodine atoms.
  • Compounds of the invention have at least one asymmetric carbon atom and therefore all isomers, including enantiomers and diastereomers are contemplated as being part of this invention.
  • the invention includes d and I isomers in both pure form and in admixture, including racemic mixtures.
  • Isomers can be prepared using conventional techniques, either by reacting chiral starting materials or by separating isomers of a compound of formula I. Isomers may also include geometric isomers, e.g. when a double bond is present. All such geometric isomers are contemplated for this invention.
  • Compounds of the invention with an amino group can form pharmaceutically acceptable salts with organic and inorganic acids.
  • Suitable acids for salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic and other mineral and carboxylic acids well known to those in the art.
  • the salt is prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt.
  • the free base form may be regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous sodium
  • the free base form differs from its respective salt form somewhat in certain physical properties, such as solubility in polar solvents, but the salt is otherwise equivalent to its respective free base form for purposes of the invention.
  • Certain compounds of the invention are acidic (e.g., those compounds which possess a carboxyl group). These compounds form pharmaceutically acceptable salts with inorganic and organic bases. Examples of such salts are the sodium, potassium, calcium, aluminum, gold and silver salts. Also included are salts formed with pharmaceutically acceptable amines such as ammonia, alkyl amines, hydroxyalkylamines, N-methylglucamine and the like.
  • Cholesterol biosynthesis inhibitors for use in the combination of the present invention include HMG CoA reductase inhibitors such as lovastatin, pravastatin, fluvastatin, simvastatin, and CI-981 ; HMG CoA synthetase inhibitors, for example L-659,699 ((E,E)-11-[3'R-(hydroxymethyl)-4'-oxo-2'R-oxetanyl]-3,5,7R-trimethyl-2,4-undecadienoic acid); squalene synthesis inhibitors, for example squalestatin 1 ; and squalene epoxidase inhibitors, for example, NB-598 ((E)-N-ethyl-N-(6,6-dimethyl-2- hepten-4-ynyl)-3-[(3,3'-bithiophen-5-yl)methoxy]benzene-methanamine hydrochloride) and other cholesterol biosynthesis inhibitor
  • Reactive groups not involved in the above processes can be protected during the reactions with conventional protecting groups which can be removed by standard procedures after the reaction.
  • Table 1 shows some typical protecting groups:
  • compounds of this invention lower serum lipid levels, in particular serum cholesterol levels.
  • Compounds of this invention have been found to inhibit the intestinal absorption of cholesterol and to significantly reduce the formation of liver cholesteryl esters in animal models.
  • compounds of this invention are hypocholesterolemic agents by virtue of their ability to inhibit the intestinal absorption and/or esterification of cholesterol; they are, therefore, useful in the treatment and prevention of atherosclerosis in mammals, in particular in humans.
  • the in vivo activity of the compounds of formula I can be determined by the following procedure: In Vivo Assay of Hypolipidemic A ⁇ ents Using the Hyperiipidemic Hamster
  • Hamsters are separated into groups of six and given a controlled cholesterol diet (Purina Chow #5001 containing 0.5% cholesterol) for seven days. Diet consumption is monitored to determine dietary cholesterol exposure in the face of test compounds. The animals are dosed with the test compound once daily beginning with the initiation of diet. Dosing is by oral gavage of 0.2 mL of corn oil alone (control group) or solution (or suspension) of test compound in corn oil. All animals moribund or in poor physical condition are euthanized. After seven days, the animals are anesthetized by intramuscular (IM) injection of ketamine and sacrificed by decapitation. Blood is collected into vacutainer tubes containing EDTA for plasma lipid analysis and the liver excised for tissue lipid analysis.
  • IM intramuscular
  • Lipid analysis is conducted as per published procedures (Schnitzer-Polokoff, R., et al, Comp. Biochem. Physiol., 99A, 4 (1991 ), p. 665-670) and data is reported as percent reduction of lipid versus control.
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula I and a pharmaceutically acceptable carrier.
  • the compounds of formula I can be administered in any conventional dosage form, preferably an oral dosage form such as a capsule, tablet, powder, cachet, suspension or solution.
  • the formulations and pharmaceutical compositions can be prepared using conventional pharmaceutically acceptable excipients and additives and conventional techniques.
  • Such pharmaceutically acceptable excipients and additives include non-toxic compatible fillers, binders, disinteg rants, buffers, preservatives, anti-oxidants, lubricants, flavorings, thickeners, coloring agents, emulsifiers and the like.
  • the daily hypocholesteremic dose of a compound of formula I is about 0.1 to about 30 mg/kg of body weight per day, preferably about 0.1 to about 15 mg/kg.
  • the dosage level is therefore from about 5 mg to about 1000 mg of drug per day, given in a single dose or 2-4 divided doses .
  • the exact dose is determined by the attending clinician and is dependent on the potency of the compound administered, the age, weight, condition and response of the patient.
  • the typical daily dose of the cholesterol biosynthesis inhibitor is 0.1 to 80 mg/kg of mammalian weight per day administered in single or divided dosages, usually once or twice a day: for example, for HMG CoA reductase inhibitors, about 10 to about 40 mg per dose is given 1 to 2 times a day, giving a total daily dose of about 10 to 80 mg per day, and for the other cholesterol biosynthesis inhibitors, about 1 to 1000 mg per dose is given 1 to 2 times a day, giving a total daily dose of about 1 mg to about 2000 mg per day.
  • the exact dose of any component of the combination to be administered is determined by the attending clinician and is dependent on the potency of the compound administered, the age, weight, condition and response of the patient.
  • the number of doses of each component given per day may not necessarily be the same, e.g. where one component may have a greater duration of activity, and will therefore need to be administered less frequently.
  • the present invention relates to the reduction of plasma cholesterol levels by treatment with a combination of active ingredients wherein said active ingredients may be administered separately, the invention also relates to combining separate
  • kits are contemplated wherein two separate units are combined: a cholesterol biosynthesis inhibitor pharmaceutical composition and a substituted azetidinone cholesterol absorption inhibitor pharmaceutical composition.
  • the kit will preferably include directions for the administration of the separate components.
  • the kit form is particularly advantageous when the separate components must be administered in different dosage forms (e.g. oral and parenteral) or are administered at different dosage intervals.
  • Example 2 Disslove the product of Example 2 (0.35 g, 0.77 mmol) in EtOAc (6 mL) and purge with N 2 . Add 10% Pd/C (0.082 g), purge the resulting suspension with H2 and stir under a balloon of H 2 for 3 h. Filter the mixture through celite, wash the filter cake with EtOAc and concentrate the filtrate to obtain 0.35 g (100%) of the title compound as a clear oil.
  • Step 1 (5S)-1-(5-Phenyl-1-oxo-pentanyl)-5-phenyloxalozidinone:
  • Step 1 as an amber oil, 24.2g (-100%).
  • Step 3 Trans (3R,4S)- 1-(-methoxyphenyl)-3-(3-phenylpropyl)-4-(4- benxyloxyphenyl)-2-azetidinone:
  • Step 4 Trans (3R,4S)- 1 -(-methoxyphenyl)-3-(3-phenylpropyl)-4-(4- hydroxyphenyl)-2-azetidinone:
  • Step 5 Trans (3R,4S)- 1-(-methoxyphenyl)-3-(3-phenylpropyl)-4-(4- trifluoromethanesulfonyl)phenyl)-2-azetidinone:
  • Step 6 Trans (3R,4S)-1-(4-Methoxyphenyl)- 3-(3-phenylpropyl)-4-(4- vinylphenyl)-2-azetidinone: Dissolve the product of Step 5 (1.22g, 2.35 mmol) in dioxane (30 mL), add LiCI (0.30 g, 7.04 mmol) and palladium tetrakistriphenyl- phosphine (Pd(Ph 3 P) 4 ) (0.28 g, 0.24 mmol). Add vinyltributyltin (0.83 ml, 2.82 mmol) and heat the mixture to 90 °C, monitoring the reaction by TLC (25% EtOAc/hexanes).
  • Step 7 Trans Methyl 4-[1-(4-Methoxyphenyl)-4-oxo-3(R)-(3-phenyl- propyl)-2(S)-azetidinyl]phenyl-2-ethanol:
  • Step 8 Trans Methyl 2-[4-[1-(4-Methoxyphenyl)-4-oxo-3(R)-(3- phenylpropyl)-2(S)-azetidinyl]phenyi]-acetic acid:
  • Example 8 Dissolve the product of Example 6 (0.066g, 0.14 mmol) in THF (3 mL), add LiOH (0.04 g, 0.86 mmol) and stir the mixture at room temperature overnight. Acidify the solution to pH 3 with 1 M HCl, dilute with EtOAc, wash with water and brine, dry over Na 2 SO 4 and concentrate to give 0.061 g, (91%) of the title compound as an oil.
  • HRMS calc'd for C 27 H 26 NO 4 F: M+H 448.1924; found 448.1911. (FAB): 444 (M +1 , 100).
  • Step 1 Prepare trans 1-phenyl-3-(3-phenylpropyl)-4-(3-benzyl- oxyphenyl)-2-azetidinone in a manner similar to that described in
  • Step 2 Using the procedure of Example 4, Step 4, treat the product of Step 1 to obtain trans 1-phenyl-3-(3-phenylpropyl)-4-(3-hydroxyphenyl)-2- azetidinone.
  • Step 3 Using the procedure of Example 4, Step 5, treat the product of Step 2 to obtain trans 1-phenyl-3-(3-phenylpropyl)-4-((3-trifluoromethyl- sulfonyl))phenyl)-2-azetidinone.
  • Step 4 Using the procedure of Example 5, treat the product of Step 3 to obtain compound 8-1 , trans methyl 3-[3-[1 -phenyl-4-oxo-3-(3- phenylpropyl)-2-azetidinyl]phenyl]-2-propenoate.
  • Step 5 Using the procedure of Example 3, treat the product of Step 4 to obtain the title compound (8-2). HRMS calc'd for C 28 H 29 NO 3 : M+H 428.2226; found 428.2235. MS (Cl): 428 (M +1 ,100).
  • Step 1 Hydrolyze the product of Example 2 according to the procedure described in Example 7 to obtain trans 3-[4-[1-(4-methoxyphenyl)-4-oxo-3- (3-phenylpropyl)-2-azetidinyl]phenyl]-2-propenoic acid (compound 11-1 ).
  • Step 2 Hydrogenate the product of Step 1 according to the procedure described in Example 3 to obtain the title compound (11-2).
  • HRMS calc'd for C 28 H 31 NO 4 : M+H 444.2175; found 444.2165. (FAB): 444(M +1 , 100).
  • Step 1 Trans (3R, 4S)-1-(4-fluorophenyl)-4-(4-((trimethylsilyl)acetylenyl)- phenyl)-3-(3-phenylpropyl)-2-azetidinone:
  • Extract with EtOAc combine the extracts, wash with water and brine, dry over anhydrous Na 2 SO 4 and concentrate onto enough silica that a free flowing powder is obtained.
  • Step 3 Using a procedure similar to that of Example 4, step 9, treat the product of step 3 to obtain the title compound, 0.023 g (25%).
  • HRMS calc'd for C28H29NO3F: (M+H) 446.2131 ; found 446.2150.
  • Step 1 Trans (3R, 4S)-1-(4-fluorophenyl)-4-(4-(3-hydroxy-1-propynyl)- phenyl)-3-(3-phenylpropyl)-2-azetidinone:
  • Step 2 Trans (3R, 4S)-1-(4-fluorophenyl)-4-(4-(3-hydroxy-1-propyl)- phenyl)-3-(3-phenylpropyl)-2-azetidinone:
  • Step 4 Using a procedure similar to that of Example 4, step 9, but using THF, treat the product of step 3 to obtain the title compound, 0.54 g (57%). HRMS calc'd for C28H29NO3F: (M+H) 446.2131 ; found 446.2150.
  • Step 1 Trans methyl (3R, 2S)-3-[4-[1-(4-fluorophenyl)-4-oxo-3-(3-phenyl- propyl)-2-azetidinyl]phenyl]-E-2-propenoate:
  • Step 2 Treat the product of step 1 as described in Example 7, purifying by chromatography on a column prepacked with silica and 0.5% HOAc/2.5% EtOH/97% CH 2 CI 2 , eluting with the same eluant to obtain the title compound.
  • HRMS calc'd for C 27 H 25 NO 3 F: (M+H) 430.1818; found 430.1810.
  • compositions comprising a cholesterol biosynthesis inhibitor are well known in the art. It is contemplated that where the two active ingredients are administered as a single
  • composition the dosage forms disclosed above for substituted
  • azetidinone compounds may readily be modified using the knowledge of one skilled in the art. Using the test procedures described above, the following in vivo data were obtained for representative compounds of formula I.
  • racemic compounds of formula I or active diastereomers or enantiomers of compounds of formula I compounds administered at dosages of 1-50 mg/kg show a range of -97 to -12% reduction in cholesterol esters, and a -49 to 0% reduction in serum cholesterol.
  • the reduction in cholesterol esters is the more important measure of activity, and active compounds preferably show a range of -30 to -97% reduction in cholesterol esters.

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Abstract

Agent hypercholestérolémiant d'azétidinone substitué de formule (I) ou d'un sel pharmaceutiquement acceptable où : Ar1 représente aryle ou R3-aryle; Ar2 représente aryl ou R4-aryle; R1 est sélectionné dans le groupe composé de -(CH¿2?)q-, où q est compris entre 2-6; -(CH2)e-Z-(CH2)r-, où Z représente -O-, -C(O)-, phénylène, -NR?10¿- ou -S(O)¿0-2?-, e est compris entre 0-5 et r est compris entre 0-5, à condition que la somme de e et de r soit comprise entre 1-6; -(C2-C6 alcénylène)-; et -(CH2)f-V-(CH2)g-, où V représente C3-C6 cycloalkylène, f est compris entre 1-5 et g est compris entre 0-5, à condition que la somme de f et g soit comprise entre 1-6; R?2¿ représente -(alkylène inférieur)-COR5 ou -(CH=CH)-COR?5; R3 et R4¿ représentent séparément des substituants en position 1-3 sélectionnés à partir d'alkyle inférieur, -OR6, -O(CO)R6, -O(CO)OR9, -O(CH¿2?)1-5OR?6¿, -O(CO)NR?6R7, -NR6R7, -NR6(CO)R7, -NR6(CO)OR9, -NR6(CO)NR7R8, -NR6SO¿2R?9, -COOR6, -CONR6R7, -COR6, -SO¿2NR6R7, S(O)¿0-2R?9, -O(CH¿2?)1-10-COOR?6¿, -O(CH¿2?)1-10CONR?6R7¿, -(alkylène inférieur)-COOR6, -CH=CH-COOR6, -CF3, -CN, -NO2 et halogène; R5 représente -OR ou -NRR?12; R, R6, R7, R8 et R12¿ sont sélectionnés séparément à partir d'hydrogène, alkyle inférieur, et alkyle inférieur à substitution aryle; R9 représente alkyle inférieur, ou alkyle inférieur à substitution aryle; et R10 représente alkyle inférieur, alkyle inférieur aryle ou -C(O)R6; l'invention concerne également une méthode permettant d'abaisser le taux de cholestérol sérique en appliquant un composé, seul ou en combinaison avec un inhibiteur de biosynthèse du cholestérol, ainsi que les compositions pharmaceutiques les contenant.
PCT/US1995/007117 1994-06-20 1995-06-15 Composes d'azetidinone substitues utilises comme agent hypercholesterolemiant WO1995035277A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
AU29430/95A AU2943095A (en) 1994-06-20 1995-06-15 Substituted azetidinone compounds useful as hypocholesterolemic agents
EP95925237A EP0766667A1 (fr) 1994-06-20 1995-06-15 Composes d'azetidinone substitues utilises comme agent hypercholesterolemiant
JP8502289A JPH10501811A (ja) 1994-06-20 1995-06-15 低コレステロール化剤として有用な置換アゼチジノン化合物
MX9606319A MX9606319A (es) 1994-06-20 1995-06-15 Compuestos de acetidinonas sustituidas utiles como agentes hipocolesterolemicos.

Applications Claiming Priority (2)

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US26178594A 1994-06-20 1994-06-20
US08/261,785 1994-06-20

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WO1995035277A1 true WO1995035277A1 (fr) 1995-12-28

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JP (1) JPH10501811A (fr)
AU (1) AU2943095A (fr)
CA (1) CA2191455A1 (fr)
MX (1) MX9606319A (fr)
WO (1) WO1995035277A1 (fr)

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WO2002050068A1 (fr) * 2000-12-21 2002-06-27 Aventis Pharma Deutschland Gmbh Derives de diphenylazetidinone, procede permettant de les produire, medicaments contenant lesdits composes et leur utilisation
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WO2002058685A2 (fr) * 2001-01-26 2002-08-01 Schering Corporation Combinaisons d'acide nicotinique et de derives de ce dernier, inhibiteur(s) d'absorption de sterols et traitements de conditions vasculaires
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EP1864680A2 (fr) * 2001-01-26 2007-12-12 Schering Corporation Combinaisons d'activateur(s) du récepteur activé de la prolifération des peroxysomes (PPAR) et inhibiteur(s) d'absorption de stérol, et traitements pour les indications vasculaires
AU2007201970B2 (en) * 2001-01-26 2008-04-17 Organon Llc Combinations of peroxisome proliferator-activated receptor (PPAR) activator(s) and sterol absorption inhibitor(s) and treatments for vascular indications
AU2006203175B2 (en) * 2001-01-26 2008-07-24 Organon Llc Combinations of peroxisome proliferator-activated receptor (PPAR) activators(s) and sterol absorption inhibitors(s) and treatments for vascular indications
WO2008108486A1 (fr) 2007-03-06 2008-09-12 Teijin Pharma Limited Dérivés de 1-biarylazétidinone
AU2008201609B2 (en) * 2001-01-26 2008-12-11 Organon Llc Combinations of peroxisome proliferator-activated receptor (ppar) activator(s) and sterol absorption inhibitors(s) and treatments for vascular indications
US7470678B2 (en) 2002-07-05 2008-12-30 Astrazeneca Ab Diphenylazetidinone derivatives for treating disorders of the lipid metabolism
WO2010100255A1 (fr) 2009-03-06 2010-09-10 Lipideon Biotechnology Ag Compositions pharmaceutiques hypocholestérolémiques
US7842684B2 (en) 2006-04-27 2010-11-30 Astrazeneca Ab Diphenylazetidinone derivatives possessing cholesterol absorption inhibitor activity
CN1915429B (zh) * 2001-01-26 2010-12-15 先灵公司 过氧化物酶体增殖物激活受体(ppar)活化剂和甾醇吸收抑制剂的组合药
US7871998B2 (en) 2003-12-23 2011-01-18 Astrazeneca Ab Diphenylazetidinone derivatives possessing cholesterol absorption inhibitory activity
WO2011017907A1 (fr) 2009-08-11 2011-02-17 浙江海正药业股份有限公司 Composés azétidinone et leur utilisation médicale
US7893048B2 (en) 2005-06-22 2011-02-22 Astrazeneca Ab 2-azetidinone derivatives as cholesterol absorption inhibitors for the treatment of hyperlipidaemic conditions
EP1911462A3 (fr) * 2001-01-26 2011-11-30 Schering Corporation Combinaisons comprenant un inhibiteur d'absorption de stérol
WO2015092448A1 (fr) * 2013-12-18 2015-06-25 Rudjer Boskovic Institute Inhibiteurs de l'absorption du cholestérol de type bêta-lactamines
EP2965752A1 (fr) 2007-12-10 2016-01-13 ratiopharm GmbH Composition pharmaceutique comprenant l'ezetimibe

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US6498156B2 (en) 2000-12-21 2002-12-24 Aventis Pharma Deutschland Gmbh Diphenylazetidinone derivatives, process for their preparation, medicaments comprising these compounds and their use
WO2002050068A1 (fr) * 2000-12-21 2002-06-27 Aventis Pharma Deutschland Gmbh Derives de diphenylazetidinone, procede permettant de les produire, medicaments contenant lesdits composes et leur utilisation
WO2002050060A1 (fr) * 2000-12-21 2002-06-27 Avantis Pharma Deutschland Gmbh Derives de diphenylazetinone, procede permettant de les produire, medicaments contenant lesdits composes et leur utilisation
US6703386B2 (en) 2000-12-21 2004-03-09 Aventis Pharma Deutschland Gmbh Diphenylazetidinone derivatives, process for their preparation, medicaments comprising these compounds and their use
EP1810693A2 (fr) * 2001-01-26 2007-07-25 Shering Corporation Combinaisons des inhibiteurs d'absorption de stérol avec des modificateurs de sang pour des indications vasculaires
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CA2191455A1 (fr) 1995-12-28
MX9606319A (es) 1997-05-31
AU2943095A (en) 1996-01-15
JPH10501811A (ja) 1998-02-17
EP0766667A1 (fr) 1997-04-09

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