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WO1994026738A1 - Derives d'uree n'-heterocyclyl-n-benzofuranyle et leurs analogues, utilises comme inhibiteurs de l'acat - Google Patents

Derives d'uree n'-heterocyclyl-n-benzofuranyle et leurs analogues, utilises comme inhibiteurs de l'acat Download PDF

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Publication number
WO1994026738A1
WO1994026738A1 PCT/JP1994/000785 JP9400785W WO9426738A1 WO 1994026738 A1 WO1994026738 A1 WO 1994026738A1 JP 9400785 W JP9400785 W JP 9400785W WO 9426738 A1 WO9426738 A1 WO 9426738A1
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WIPO (PCT)
Prior art keywords
substituted
compound
alkyl
nmr
aryl
Prior art date
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PCT/JP1994/000785
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English (en)
Inventor
Yoshikuni Itoh
Kazuhiko Ohne
Hirokazu Tanaka
Shunsuke Goto
Shigeru Ieda
Original Assignee
Fujisawa Pharmaceutical Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Priority claimed from GB939310320A external-priority patent/GB9310320D0/en
Priority claimed from GB939323890A external-priority patent/GB9323890D0/en
Priority claimed from GB9403187A external-priority patent/GB9403187D0/en
Application filed by Fujisawa Pharmaceutical Co., Ltd. filed Critical Fujisawa Pharmaceutical Co., Ltd.
Priority to AU66911/94A priority Critical patent/AU6691194A/en
Priority to JP6525244A priority patent/JPH08510233A/ja
Publication of WO1994026738A1 publication Critical patent/WO1994026738A1/fr

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    • 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
    • C07D405/12—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 chain containing hetero atoms as chain links
    • 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
    • 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
    • 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
    • C07D405/14—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 three or more hetero 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
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • This invention relates to new urea derivatives and pharmaceutically acceptable salts thereof which are useful as a medicament.
  • acyl-CoA cholesterol acyltransferase enzyme (hereinafter, ACAT) inhibitors, for example, in U.S.Patent Nos. 4,473,579 and 4,623,662, EP Patent Application Publication Nos. 0354994, 0399422 and 0512570 and PCT International Publication Nos. WO 91/13871 and WO 93/24458.
  • ACAT cholesterol acyltransferase enzyme
  • This invention relates to new urea derivatives and pharmaceutically acceptable salts thereof.
  • urea derivatives and pharmaceutically acceptable salts thereof which have an inhibitory activity against ACAT and an advantage of good absorption into blood on oral administration, to processes for the preparation thereof, to a pharmaceutical composition comprising the same and to a method for the prevention and/or treatment of hypercholesterolemia, hyperlipidemia, atherosclerosis or diseases caused thereby.
  • One object of this invention is to provide new and useful urea derivatives and pharmaceutically acceptable salts which possess an inhibitory activity against ACAT.
  • Another object of this invention is to provide processes for preparation of said urea derivatives and salts thereof.
  • a further object of this invention is to provide a pharmaceutical composition comprising, as an active ingredient, said urea derivatives and pharmaceutically acceptable salts thereof.
  • Still further object of this invention is to provide a therapeutic method for the prevention and/or treatment of hypercholesterolemia, hyperlipidemia, atherosclerosis or diseases caused thereby in human beings or animals, using said urea derivatives and pharmaceutically acceptable salts thereof.
  • ACAT inhibitors are useful for the prevention and/or treatment of hypercholesterolemia, hyperlipidemia, atherosclerosis of diseases caused thereby such as cardiac insufficiency (e.g. angina pectoris, myocardial infarction, etc.), cerebrovascular disturbance (e.g. cerebral infarction, cerebral apoplexy, etc.), arterial aneurism, peripheral vascular disease, xanthomas, restenosis after percutaneous transluminal coronary angioplasty, or the like.
  • cardiac insufficiency e.g. angina pectoris, myocardial infarction, etc.
  • cerebrovascular disturbance e.g. cerebral infarction, cerebral apoplexy, etc.
  • arterial aneurism e.g. cerebral infarction, cerebral apoplexy, etc.
  • R ⁇ is a heterocyclic group which may be substituted with substituent(s) selected from the group consisting of lower alkyl, lower alkylthio, halogen, nitro, a ino, lower alkylamino, lower alkoxy and acylamino
  • R 2 is hydrogen; alkyl; lower alkenyl; cycloalkyl; or lower alkyl which is substituted with halogen, lower alkoxy, lower alkylthio, cyclo(lower)alkyl, cyclo(lower)alkenyl, a heterocyclic group or aryl optionally substituted with substituent(s) selected from the group consisting of halogen, hydroxy, lower alkoxy, ar(lower)alkoxy and lower alkylamino;
  • R 3 is hydrogen, lower alkyl or aryl which may be substituted with halogen, nitro, amino or lower alkylamino
  • R ⁇ is hydrogen, halogen, lower alkyl, lower alkoxy or aryl which may be substituted with halogen
  • R 5 is hydrogen, halogen, lower alkyl or aryl
  • A is a single bond or lower alkylene
  • X is 0, S or NH, provided that at least one of unsubstituted or substituted aryl for R 3 , R ⁇ and R ⁇ is aryl except phenyl or substituted aryl, and pharmaceutically acceptable salts thereof.
  • the object compound (I) or its salt can be prepared by processes as illustrated in the following reaction schemes.
  • Process 1 The object compound (I) or its salt can be prepared by processes as illustrated in the following reaction schemes.
  • R , R 2 , R3, R4 5 , A an( j ⁇ are eac h as defined above,
  • is lower alkyl which is substituted with aryl substituted with lower alkoxy, and is lower alkyl which is substituted with aryl substituted with hydroxy.
  • lower alkenyl and “lower alkenylene” are intended to mean a group having 2 to 6 carbon atoms.
  • the lower moiety in the term “cyclo(lower)alkyl” is intended to mean a group having 3 to 6 carbon atoms.
  • cyclo(lower)alkenyl is intended to mean a group having 3 to 6 carbon atoms.
  • alkyl may include lower alkyl and higher alkyl.
  • cycloalkyl may include cyclo(lower)alkyl and eyelo(higher)alkyl.
  • Suitable "lower alkyl” and lower alkyl moiety in the terms “lower alkylthio”, “lower alkylamino” and “ar(lower)alkyl” may be a straight or branched one such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert- butyl, pentyl, isopentyl, hexyl or the like, in which preferable one is one having 1 to 5 carbon atom(s) such as methyl, ethyl, propyl, isopropyl, isobutyl, pentyl or isopentyl.
  • Preferable one in alkyl for R 2 is alkyl having 3 to 7 carbon atoms, in which more preferable one is isopentyl.
  • Suitable "cyclo(lower)alkyl” may be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • Suitable “lower alkenyl” may be a straight or branched one such as ethenyl, propenyl, pentenyl (e.g. 2- pentenyl, 3-pentenyl or 4-pentenyl), isopropenyl, butenyl (e.g. 2-butenyl or 3-butenyl) , hexenyl or the like, in which preferable one is butenyl.
  • Suitable "cyclo(lower)alkenyl” may be cyclopropenyl, cyclobutenyl, cyclopentenyl or cyclohexenyl.
  • Suitable "higher alkyl” may be a straight or branched one such as heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, methylheptyl, methyloctyl, ethylnonyl, methyldecyl, ethylheptyl, ethyloctyl, ethylnonyl, ethyldecyl or the like, in which preferable one is one having 7 to 10 carbon atoms and the most preferable one is heptyl or nonyl.
  • Suitable "eyelo(higher)alkyl” may be cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclotridecyl, cyclotetradecyl, cyclopentadecyl, cyclohexadecyl, cycloheptadecyl, cyclooctadecyl, cyclononadecyl, cycloeicosyl, in which preferable one is one having 7 to 10 carbon atoms and the most preferable one is cycloheptyl.
  • Suitable "lower alkoxy” and lower alkoxy moiety in the term “ar(lower)alkoxy” may be a straight or branched one such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy or the like, in which preferable one is methoxy.
  • Suitable "halogen” may be fluorine, chlorine, bromine and iodine, in which preferable one is fluorine, chlorine or bromine.
  • Suitable "lower alkylthio” may be a straight or branched one such as methylthio, ethylthio, propylthio, isopropylthio, pentylthio or the like, in which preferable one is methylthio.
  • Preferable one in lower alkyl substituted with halogen for R 2 is lower alkyl substituted with fluorine, in which more preferable one is heptafluorobutyl.
  • Preferable one in lower alkyl substituted with lower alkoxy for R 2 is lower alkyl substituted with methoxy, in which more preferable one is methoxyethyl.
  • Preferable one in lower alkyl substituted with lower alkylthio for R 2 is lower alkyl substituted with methylthio, in which more preferable one is methylthioethy1.
  • N-Protective group may be common N-protective group such as acyl, for example, substituted or unsubstituted lower alkanoyl [e.g. formyl, acetyl, propionyl, trifluoroacetyl, etc.], phthaloyl, lower alkoxycarbon l [e.g.
  • aralkyloxycarbonyl e.g. benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, etc.
  • substituted or unsubstituted arenesulfonyl e.g. benzenesulfon
  • Suitable "esterified carboxy” may be substituted or unsubstituted lower alkoxycarbonyl [e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, hexyloxycarbonyl, 2-iodoethoxycarbonyl, 2,2,2- trichloroethoxycarbonyl, etc.], substituted or unsubstituted aryloxycarbonyl [e.g. phenoxycarbonyl, 4- nitrophenoxycarbonyl, 2-naphthyloxycarbonyl, etc. ], substituted or unsustituted ar(lower)alkoxycarbonyl [e.g. benzyloxycarbonyl, phenethyloxycarbonyl, benzhydryloxycarbonyl, 4-nitrobenzyloxycarbonyl, etc.] and the like, in which preferable one is lower alkoxycarbonyl.
  • lower alkoxycarbonyl e.g. me
  • Suitable "aryl” and ar moiety in the term “ar(lower)alkoxy” may be phenyl, naphthyl, phenyl substituted with lower alkyl (e.g. tolyl, xylyl, mesityl, cumenyl, diisopropylphenyl, etc.) and the like, in which preferable one is phenyl or phenyl substituted with lower alkyl.
  • Suitable “lower alkylamino” may be mono or di(lower alkyl)amino such as methylamino, ethylamino, dimethylamino, diethylamino or the like, in which preferable one is dimethylamino.
  • Suitable "ar(lower)alkyl” may be phenyl(lower)alkyl (e.g. benzyl, phenethyl, phenylpropyl, etc. ) , benzhydryl, trityl, tolylmethyl, xylylmethyl, mesitylmethyl. cumenylmethyl, and the like, in which preferable one is phenyl(lower)alkyl and the most preferable one is benzyl.
  • phenyl(lower)alkyl e.g. benzyl, phenethyl, phenylpropyl, etc.
  • benzhydryl e.g. benzhydryl, trityl, tolylmethyl, xylylmethyl, mesitylmethyl. cumenylmethyl, and the like, in which preferable one is phenyl(lower)alkyl and the most preferable one is benzyl.
  • Suitable "lower alkylene” may be a straight or branched one such as methylene, ethylene, trimethylene, propylene, tetramethylene, penta ethylene, hexa ethylene, ethylethylene, or the like.
  • the aryl groups for R ⁇ and R 4 may be substituted with 1 to 5 substituent(s) as mentioned above, wherein the preferable number of the substituent(s) is 1, 2 or 3.
  • the aryl group as substituent of lower alkyl for R 2 may be substituted with 1 to 5 substituent(s) as stated above, wherein the preferable number of the substituent(s) is 1 ' , 2 or 3.
  • aryl substituted with halogen is chlorophenyl, dichlorophenyl, difluorophenyl, trichlorophenyl or trifluorophenyl.
  • Suitable "heterocyclic group” may include saturated or unsaturated, monocyclic or polycyclic one containing at least one .hetero atom such as nitrogen atom, oxygen atom or sulfur .atom. r
  • heterocyclic group may be unsaturated, 3 to 8-membered, more preferably 5 or 6-membered heteromonocyclic group containing 1 to 4-nitrogen atom(s), for example, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridyl N-oxide, dihydropyridyl, tetrahydropyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl, triazolyl, tetrazinyl, tetrazolyl, etc.
  • one in a heterocyclic group for R is pyridyl or quinolyl.
  • acylamino may be carboxy; esterified carboxy; carbamoyl optionally substituted with substituent(s) selected from the group consisting of lower alkyl, cyclo(lower)alkyl, aryl and hydroxy; lower alkanoyl; a heterocycliccarbonyl; lower alkylsulfonyl; and the like.
  • the esterified carboxy may be substituted or unsubstituted lower alkoxycarbonyl [e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, hexyloxycarbonyl, 2-iodoethoxycarbonyl, 2,2,2- trichloroethoxycarbonyl, etc.], substituted or unsubstituted aryloxycarbonyl [e.g. phenoxycarbonyl, 4- nitrophenoxycarbonyl, 2-naphthyloxycarbonyl, etc.], substituted or unsubstituted ar(lower)alkoxycarbonyl [e.g. benzyloxycarbonyl, phenethyloxycarbonyl, benzhydryloxycarbonyl, 4-nitrobenzyloxycarbonyl, etc.] and the like.
  • lower alkoxycarbonyl e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbony
  • the lower alkanoyl may be for yl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl and the like, in which preferable one is acetyl.
  • the heterocyclic moiety in the term is for yl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl and the like, in which preferable one is acetyl.
  • heterocycliccarbonyl may be the same as those exemplified for “heterocyclic group”.
  • the lower alkylsulfonyl may be methylsulfonyl, ethylsulfonyl, propylsulf ⁇ nyl and the like, in which the preferable one is methylsulfonyl.
  • acylamino may be lower alkanoylamino and lower alkylsulfonylamino, in which preferable one is acetylamino or methylsulfonylamino.
  • the heterocyclic group for R may be substituted with singular or plural substituent(s) as mentioned above, wherein the preferable number of the substituent(s) is 1 to 3.
  • Preferable compound (I) is one which has a heterocyclic group (more preferably pyridyl or quinolyl) optionally substituted with substituent(s) selected from the group consisting of lower alkyl and lower alkylthio for R 1 , alkyl, cycloalkyl, or lower alkyl substituted with cyclo(lower)alkyl, a heterocyclic group (more preferably furyl or thienyl), aryl (more preferably phenyl or phenyl substituted with lower alkyl) optionally substituted with halogen, hydroxy, lower alkoxy, ar(lower)alkoxy or lower alkylamino for R 2 , aryl except phenyl (more preferably phenyl substituted with lower alkyl) or aryl (more preferably phenyl or phenyl substituted with lower alkyl) substituted with halogen for R 3 , lower alkyl or halogen for R 4 , hydrogen for R ⁇ ,
  • More preferable compound (I) is one which has a heterocyclic group (more preferably pyridyl or quinolyl) optionally substituted with substituent(s) selected from the group consisting of lower alkyl and lower alkylthio for R x , alkyl, or lower alkyl substituted with furyl or aryl (more preferably phenyl or phenyl substituted with lower alkyl) for R 2 , aryl except phenyl (more preferably phenyl substituted with lower alkyl) or aryl (more preferably phenyl or phenyl substituted with lower alkyl) substituted with halogen for R 3 , lower alkyl for R 4 , hydrogen for R ⁇ , a single bond for A, and O for X.
  • substituent(s) selected from the group consisting of lower alkyl and lower alkylthio for R x , alkyl, or lower alkyl substituted with furyl or aryl (more preferably pheny
  • Most preferable compound (I) is one which has pyridyl or quinolyl, each of which is substituted with substituent(s) selected from the group consisting of lower alkyl and lower alkylthio for R x , alkyl having 3 to 7 carbon atoms, or lower alkyl substituted with furyl or phenyl for R 2 , phenyl substituted with lower alkyl or halogen for R 3 , lower alkyl for R 4 , hydrogen for R ⁇ , a single bond for A, and O for X.
  • substituent(s) selected from the group consisting of lower alkyl and lower alkylthio for R x , alkyl having 3 to 7 carbon atoms, or lower alkyl substituted with furyl or phenyl for R 2 , phenyl substituted with lower alkyl or halogen for R 3 , lower alkyl for R 4 , hydrogen for R ⁇ , a single bond for A, and O for X.
  • Suitable pharmaceutically acceptable salts of the object compound (I) are conventional non-toxic salts such as an inorganic acid addition salt [e.g. hydrochloride, hydrobromide, sulfate, phosphate, etc.], an organic acid addition salt [e.g. formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.], an alkali metal salt [e.g. sodium salt, potassium salt, etc.] or the like.
  • an inorganic acid addition salt e.g. hydrochloride, hydrobromide, sulfate, phosphate, etc.
  • an organic acid addition salt e.g. formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.
  • an alkali metal salt
  • the object compound (I) or its salt can be prepared by reacting a compound (II) with a compound (III) or its salt.
  • Suitable salt of the compound (III) may include an acid addition salt such as an inorganic acid addition salt [e.g. hydrochloride, hydrobromide, sulfate, phosphate, etc.], an organic acid addition salt [e.g. formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.], an inorganic base salt [e.g. sodium salt, potassium salt, etc.] or the like.
  • an inorganic acid addition salt e.g. hydrochloride, hydrobromide, sulfate, phosphate, etc.
  • an organic acid addition salt e.g. formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.
  • an inorganic base salt e.g. sodium salt
  • the reaction is usually carried out in a conventional solvent such as dioxane, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, or any other organic solvent which does not adversely influence the reaction.
  • a conventional solvent such as dioxane, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, or any other organic solvent which does not adversely influence the reaction.
  • the reaction may also be carried out in the presence of an inorganic or organic base such as an alkali metal bicarbonate, tri(lower)alkylamine, pyridine, N- (lower)alkylmorphorine, N,N-di(lower)alkylbenzylamine, or the like.
  • an inorganic or organic base such as an alkali metal bicarbonate, tri(lower)alkylamine, pyridine, N- (lower)alkylmorphorine, N,N-di(lower)alkylbenzylamine, or the like.
  • the reaction temperature is not critical, and the reaction is preferably carried out under cooling or at ambient temperature.
  • the object compound (I) or its salt can be prepared by subjecting a compound (IV) or its salt and a compound (III) or its salt to formation reaction of ureido group.
  • Suitable salts of the compounds (III) and (IV) may be the same as those exemplified for the compound (I) .
  • This reaction is carried out in the presence of reagent which introduces carbonyl group such as phosgene, halofor ate compound [e.g. ethyl chloroformate, trichloro- methyl chloroformate, phenyl chloroformate, etc.], N,N'- carbonyldii idazole, metal carbonyl compounds [e.g. cobalt carbonyl, manganese carbonyl, etc.], a combination of carbon monoxide and catalysts such as palladium chloride, etc., or the like.
  • carbonyl group such as phosgene, halofor ate compound [e.g. ethyl chloroformate, trichloro- methyl chloroformate, phenyl chloroformate, etc.], N,N'- carbonyldii idazole, metal carbonyl compounds [e.g. cobalt carbonyl, manganese carbonyl, etc.], a combination of carbon
  • This reaction is usually carried out in a solvent such as dioxane, tetrahydrofuran, benzene, toluene, chloroform, methylene chloride, N,N-dimethylformamide, ethyl acetate or any other organic solvent which does not adversely influence the reaction.
  • a solvent such as dioxane, tetrahydrofuran, benzene, toluene, chloroform, methylene chloride, N,N-dimethylformamide, ethyl acetate or any other organic solvent which does not adversely influence the reaction.
  • the reaction temperature is not critical and the reaction is usually carried out under cooling to heating.
  • reaction in case that a compound (IV) or its salt is firstly reacted with a reagent introducing carbonyl group and the product obtained thereby is stable, that product may be isolated and then reacted with a compound (III) or its salt to obtain a compound (I) or its salt.
  • a base such as N,N-dimethylaniline, triethylamine or the like.
  • the object compound (lb) or its salt can be prepared by subjecting a compound (la) or its salt to dealkylation reaction.
  • Suitable salts of the compounds (la) and (lb) may be acid addition salts as exemplified for the compound (I) .
  • the reaction is carried out in the presence of an acid including Lewis acid [e.g. hydrochloric acid, 15 -
  • hydrobromic acid hydroiodic acid, boron tribromide, boron trichloride, etc.
  • tri(lower alkyl)silyliodide e.g. trimethylsilyliodide, etc.
  • the reaction is usually carried out in a solvent such as water, acetic acid, methylene chloride, tetrahydrofuran, a mixture thereof or any other solvent which does not adversely influence the reaction.
  • a solvent such as water, acetic acid, methylene chloride, tetrahydrofuran, a mixture thereof or any other solvent which does not adversely influence the reaction.
  • the reaction temperature is not critical and the reaction is usually carried out under cooling to heating.
  • R 2 , R 3 , R 4 , R 5 , A and X are each as defined above, R 6 is carboxy or esterified carboxy, R 7 is hydrogen or N-protective group, and
  • R a is N-protective group.
  • the compound (VII) or its salt can be prepared by reacting a compound (V) or its reactive derivative at the carboxy group or a salt thereof with a compound (VI) or its salt.
  • Suitable salts of the compounds (V), its reactive derivative and the compounds (VI) and (VII) may be the same as those exemplified for the compound (I) .
  • Suitable reactive derivative of the compound (V) may include an acid halide, an acid anhydride, an activated amide, an activated ester, and the like.
  • the suitable example a y be an acid chloride; an acid azide; a mixed acid anhydride with an acid such as substituted phosphoric acid (e.g. dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid, halogenated phosphoric acid etc.), dialkylphosphorous acid, sulfurous acid, thiosulfuric acid, sulfuric acid, sulfonic acid (e.g. methanesulfonic acid, etc.), alkylcarbonic acid, aliphatic carboxylie acid (e.g.
  • pivalic acid pentanoic acid, isopentanoic acid, 2-ethylbutyric acid or trichloroacetic acid, etc.
  • aromatic carboxylic acid e.g. benzoic acid, etc.
  • a symmetrical acid anhydride an activated amide with imidazole, 4-substituted imidazole, dimethylpyrazole, triazole or tetrazole; or an activated ester (e.g.
  • These reactive derivatives can optionally be selected from them according to the kind of the compound (V) to be used.
  • the reaction is usually carried out in a conventional solvent such as water, an alcohol (e.g.
  • the reaction is preferably carried out in the presence of a conventional condensing agent such as N,N'-dicyclohexylcarbodiimide; ' N-cyclohexyl-N'-morpholinoethylcarbodiimide; N-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodii ide; N,N'-diethylcarbodiimide, N,N'-diisopropylcarbodiimide; N-ethyl- '-(3-dimethylaminopropyl)carbodiimide;
  • a conventional condensing agent such as N,N'-dicyclohexylcarbodiimide; ' N-cyclohexyl-N'-morpholinoethylcarbodiimide; N-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodii ide
  • N,N-carbonylbis-(2-methylimidazole) pentamethyleneketene- N-cyclohexylimine; diphenylketene-N-cyclohexylimine; ethoxyacetylene; 1-alkoxy-l-chloroethylene; trialkyl phosphite; ethyl polyphosphate; isopropyl polyphosphate; phosphorus oxychloride (phosphoryl chloride) ; phosphorus trichloride; thionyl chloride; oxalyl chloride; triphenylphosphine; 2-ethyl-7-hydroxybenzisoxazolium salt; 2-ethyl-5-(m-sulfophenyl)isoxazolium hydroxide intra ⁇ molecular salt; l-(p-chlorobenzenesulfonyloxy)-6-chloro- IH-benzotriazole; so-called Vilsmeier reagent prepared by the reaction
  • the reaction may also be carried out in the presence of an inorganic or organic base such as an alkali metal bicarbonate, tri(lower)alkylamine, pyridine, N-(lower)alkylmorpholine, N,N-di(lower)alkylbenzylamine, or the like.
  • an inorganic or organic base such as an alkali metal bicarbonate, tri(lower)alkylamine, pyridine, N-(lower)alkylmorpholine, N,N-di(lower)alkylbenzylamine, or the like.
  • the reaction temperature is not critical and the reaction can be carried out under cooling to heating.
  • the compound (III) or its salt can be prepared by reacting a compound (VII) or its salt with a reducing agent.
  • Suitable salt of the compound (VII) may be the same as those exemplified for the compound (I).
  • Suitable reducing agent may be diborane, metal hydride [e.g. lithium aluminum hydride, etc.], a combination of metal hydride [e.g. lithium aluminum hydride, etc.] and Lewis acid [e.g. aluminum chloride, etc. ], and the like.
  • metal hydride e.g. lithium aluminum hydride, etc.
  • Lewis acid e.g. aluminum chloride, etc.
  • the reaction is usually carried out in a conventional solvent such as diethyl ether, tetrahydrofuran or any other organic solvent which does not adversely influence the reaction.
  • a conventional solvent such as diethyl ether, tetrahydrofuran or any other organic solvent which does not adversely influence the reaction.
  • the reaction temperature is not critical, and the reaction can be carried out under cooling to heating.
  • the compound (IX) or its salt can be prepared by reacting a compound (VIII) or its salt with a reducing agent.
  • Suitable salts of the compounds (VIII) and (IX) may be the same as those exemplified for the compound (I).
  • Suitable reducing agent may be aluminum hydride compound [e.g. lithium aluminum hydride, lithium tri-t- butoxyaluminum hydride, etc.], borohydride compound [e.g. sodium borohydride, etc.], aluminum alkoxide [e.g. aluminum isopropoxide, etc.] and the like.
  • the reaction is usually carried out in a conventional solvent, such as water, an alcohol [e.g.
  • the reaction temperature is not critical, and the reaction is usually carried out under cooling to heating.
  • the compound (XI) or its salt can be prepared by reacting a compound (X) or its salt with a compound (IX) or its reactive derivative at the hydroxy group or a salt thereof.
  • Suitable salt of the compound (X) may be an acid addition salt as exemplified for the compound (I).
  • Suitable salts of the compound (IX) and its reactive derivative at the hydroxy group may be the same as those exemplified for the compound (I).
  • Suitable reactive derivative at the hydroxy group of the compound (IX) may be one having acid residue such as halogen (e.g. fluoro, chloro, bromo, iodo) , arenesulfonyloxy (e.g. benzenesulfonyloxy, tosyloxy, etc.), alkanesulfonyloxy (e.g. mesyloxy, ethanesulfonyloxy, etc.), and the like, in which preferable derivative is one having halogen.
  • halogen e.g. fluoro, chloro, bromo, iodo
  • arenesulfonyloxy e.g. benzenesulfonyloxy, tosyloxy, etc.
  • alkanesulfonyloxy e.g. mesyloxy, ethanesulfonyloxy, etc.
  • preferable derivative is one having halogen.
  • the reaction is usually carried out in a conventional solvent such as diethyl ether, tetrahydrofuran, dioxane, methylene chloride, N,N-dimethylformamide, l,3-dimethyl-2- imidazolidinone or any other organic solvent which does not adversely influence the reaction.
  • a conventional solvent such as diethyl ether, tetrahydrofuran, dioxane, methylene chloride, N,N-dimethylformamide, l,3-dimethyl-2- imidazolidinone or any other organic solvent which does not adversely influence the reaction.
  • the reaction is preferably carried out in the presence of a base such as alkali metal [e.g. lithium, sodium, potassium, etc.], the hydroxide or carbonate or bicarbonate thereof [e.g. sodium hydroxide, potassium carbonate, potassium bicarbonate, etc.], alkaline earth metal [e.g. calcium, magnesium, etc.], alkali metal hydride [e.g. sodium hydride, etc.], alkaline earth metal hydride [e.g. calcium hydride, etc.], alkali metal alkoxide [e.g. sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc. ],.
  • a base such as alkali metal [e.g. lithium, sodium, potassium, etc.], the hydroxide or carbonate or bicarbonate thereof [e.g. sodium hydroxide, potassium carbonate, potassium bicarbonate, etc.], alkaline earth metal [e.g. calcium, magnesium, etc.], alkali metal hydride [e.g.
  • alkaline earth metal alkoxide e.g. magnesium methoxide, magnesium ethoxide, etc.
  • alkali metal iodide e.g. sodium iodide, potassium iodide, etc.
  • the reaction is preferably carried out in the presence of a conventional condensing agent such as N,N'-dichlorohexylcarbodiind.de; N-cyclohexyl-N'-morpholinoethylcarbodiimide;
  • the reaction temperature is not critical, and the reaction is usually carried out under cooling o heating.
  • the compound (III) or its salt can be prepared by subjecting a compound (XIa] or its salt to elimination reaction of the N-protective group.
  • Suitable salts of the compounds (III) and (XIa) may be the same as those exemplified for the compound (I). This reaction is carried out in accordance with a conventional method such as hydrolysis, reduction or the like.
  • Suitable base may include an inorganic base and an organic base such as an alkali metal [e.g. sodium, potassium, etc.], an alkaline earth metal [e.g. magnesium, calcium, etc.], the hydroxide or carbonate or bicarbonate thereof, hydrazine, trialkylamine [e.g. trimethylamine, triethylamine, etc.], picoline, l,5-diazabicyclo[4.3.0]- non-5-ene, 1,4-diazabicyclo[2.2.2]octane, l,8-diazabicyclo[5.4.0]undec-7-ene, or the lie.
  • an alkali metal e.g. sodium, potassium, etc.
  • an alkaline earth metal e.g. magnesium, calcium, etc.
  • the hydroxide or carbonate or bicarbonate thereof hydrazine
  • trialkylamine e.g. trimethylamine, triethylamine, etc.
  • picoline l,
  • Suitable acid may include an organic acid [e.g. formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.], an inorganic acid [e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide, hydrogen fluoride, etc.] and an acid addition salt compound [e.g. pyridine hydrochloride, etc. ] .
  • the elimination using trihaloacetic acid e.g. trichloroacetic acid, trifluoroacetic acid, etc.] or the like is preferably carried out in the presence of cation trapping agents [e.g. anisole, phenol, etc.].
  • the reaction is usually carried out in a solvent such as water, an alcohol [e.g. methanol, ethanol, etc.], methylene chloride, chloroform, tetrachloro ethane, tetrahydrofuran, a mixture thereof or any other solvent which does not adversely influence the reaction.
  • a liquid base or acid can be also used as the solvent.
  • the reaction temperature is not critical and the reaction is usually carried out under cooling to heating.
  • the reduction method applicable for the elimination reaction may include chemical reduction and catalytic reduction.
  • Suitable reducing agents to be used in chemical reduction are a combination of metal [e.g. tin, zinc, iron, etc.] or metallic compound [e.g. chromium chloride, chromium acetate, etc.] and an organic or inorganic acid [e.g. formic acid, acetic acid, propionic acid, trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, etc.].
  • metal e.g. tin, zinc, iron, etc.
  • metallic compound e.g. chromium chloride, chromium acetate, etc.
  • organic or inorganic acid e.g. formic acid, acetic acid, propionic acid, trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, etc.
  • Suitable catalysts to be used in catalytic reduction are conventional ones such as platinum catalysts [e.g. platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.], palladium catalysts [e.g. spongy palladium, palladium black, palladium oxide, palladium on carbon, colloidal palladium, palladium on barium sulfate, palladium on barium carbonate, etc.], nickel catalysts [e.g. reduced nickel, nickel oxide, Raney nickel, etc.], cobalt catalysts [e.g. reduced cobalt, Raney cobalt, etc.], iron catalysts [e.g. reduced iron, Raney iron, etc.], copper catalysts [e.g.
  • platinum catalysts e.g. platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.
  • palladium catalysts e.g. spongy palladium, palladium black, palladium oxide, palladium on carbon
  • the reduction is preferably carried out in the presence of a combination of palladium catalysts [e.g. palladium black, palladium on carbon, etc.] and formic acid or its salt [e.g. ammonium formate, etc.].
  • the reduction is usually carried out in a conventional solvent which does not adversely influence the reaction such as water, an alcohol [e.g. methanol, ethanol, propanol, etc.], chlorobenzene, N,N-dimethylformamide, or a mixture thereof.
  • a suitable solvent to be used in catalytic reduction may be the above-mentioned solvent, and other conventional solvent such as diethyl ether, dioxane, tetrahydrofuran, etc. or a mixture thereof.
  • reaction temperature of this reduction is not critical and the reaction is usually carried out under cooling to heating.
  • the compounds obtained by the above processes can be isolated and purified by a conventional method such as pulverization, recrystallization, column chromatography, reprecipitation, or the like.
  • the compound (I) and the other compounds may include one or more stereoisomer(s) such as optical isomer(s) and geometrical isomer(s) due to asymmetric carbon atom(s) and double bond(s), and all of such isomers and mixture thereof are included within the scope of this invention.
  • the object compounds (I) and pharmaceutically acceptable salts thereof possess a strong inhibitory activity against ACAT, and are useful for the prevention and/or treatment of hypercholesterolemia, hyperlipidemia, atherosclerosis or diseases caused thereby.
  • Acyl-CoA cholesterol acyltransferase (ACAT) inhibitory activity
  • ACAT activity was measured by the method of Heider et al. described in Journal of Lipid Research, Vol. 24, page 1127 (1983).
  • the enzyme ACAT was prepared from the mucosal microsome fraction of the small intestine of male, 18-week old Japanese white rabbits which had been fed diet containing 2% cholesterol for 8 weeks.
  • the inhibitory activity of compounds were calculated by measuring the amount of the labeled cholesterol ester produced from [ C]oleoyl-CoA and endogenous cholesterol as follows. [ 1 C]Oleoyl-CoA and microsome were incubated with test compounds at 37°C for 5 minutes. The reaction was stopped by the addition of chloroform-methanol (2:1, V/V) . Cholesterol ester fraction in the chloroform-methanol extracts was isolated by thin-layer chromatography and was counted their label. Result
  • the compound (I) of the present invention can be used in a form of pharmaceutical preparation containing one of said compounds, as an active ingredient, in admixture with a pharmaceutically acceptable carrier such as an organic or inorganic solid or liquid excipient suitable for oral, parenteral or external (topical) administration, wherein more preferable one is oral administration.
  • a pharmaceutically acceptable carrier such as an organic or inorganic solid or liquid excipient suitable for oral, parenteral or external (topical) administration, wherein more preferable one is oral administration.
  • the pharmaceutical preparations may be capsules, tablets, dragees, granules, suppositories, solution, lotion, suspension, emulsion, ointment, gel, or the like. If desired, there may be included in these preparations, auxiliary substances, stabilizing agents, wetting or emulsifying agents, buffers and other commonly used additives.
  • the dosage of the compound (I) will vary depending upon the age and condition of the patient, an average single dose of about 0.1 mg, 1 mg, 10 mg, 50 mg, 100 mg, 250 mg, 500 mg and 1000 mg of the compound (I) may be effective for treating the above-mentioned diseases. In general, amounts between 0.1 mg/body and about 1,000 mg/body may be administered per day.
  • the following Preparations and Examples are given for the purpose of illustrating this invention.
  • N-benzyl-[3-(4-chlorophenyl)-5-methylbenzofuran-2- yl]methylamine in toluene 23 ml
  • 2N hydrochloric acid 23 ml
  • the precipitate was collected to afford N-benzyl-[ (3-(4- chlorophenyl)-5-methylbenzofuran-2-yl] ethylamine hydrochloride (5.64 g) .
  • Example 3 To a stirred solution of N-[2,4-bis(methylthio)-6- methylp ⁇ ridin-3-yl]-N'-[3-(4-chlorophenyl)-5- methylbenzofuran-2-ylmethyl]-N'-(4-methoxybenzyl)urea (0.43 g) in methylene chloride (10 ml) was added dropwise boron tribromide (0.3 ml) at 0°C. The reaction mixture was stirred at ambient temperature for 2 hours. The mixture was poured into water. The organic solution was washed with water and dried. Evaporation of solvent gave a residue which was chromatographed on silica gel.
  • Example 5 To a stirred solution of 3-amino-2,4-bis(methylthio)- 6-methylpyridine (0.1 g) and N,N-dimethylaniline (0.075 g) in methylene chloride (3 ml) was added dropwise phenyl chloroformate (0.08 g) at ambient temperature, and the mixture was stirred at the same temperature for 3 hours. The reaction mixture was washed with 3% aqueous hydrochloric acid (3 ml x 2) and dilute aqueous sodium bicarbonate (3 ml), and dried.
  • Example 5 The following compounds were obtained according to a similar manner to that of Example 5 except that the corresponding benzofuranylmethylamine derivatives were prepared by treating the corresponding hydrochloride thereof with IN aqueous sodium hydroxide.

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Abstract

L'invention se rapporte à de nouveaux dérivés d'urée, qui possèdent un effet inhibiteur contre l'enzyme acyl-CoA:cholestérol acyltransférase et qui sont représentés par la formule générale (I), où R1 représente un groupe hétérocyclique qui peut être substitué par alkyle inférieur, etc., R2 représente alkyle inférieur, etc., R3 représente hydrogène, alkyle inférieur ou aryle qui peuvent être substitués par halogène, etc., R4 représente hydrogène, halogène, alkyle inférieur, alcoxy inférieur ou acyle qui peuvent être substitués par halogène, R5 représente aryle, etc., A représente une liaison simple, etc., et X représente O, etc., à condition qu'au moins l'un des aryles insubstitués ou substitués que représentent R?3, R4 et R5¿ soit un aryle autre que phényle ou aryle substitué, ainsi qu'à des sels pharmaceutiquement acceptables de ces dérivés, à des proécés pour leur préparation et à une composition pharmaceutique qui les contient.
PCT/JP1994/000785 1993-05-19 1994-05-12 Derives d'uree n'-heterocyclyl-n-benzofuranyle et leurs analogues, utilises comme inhibiteurs de l'acat WO1994026738A1 (fr)

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AU66911/94A AU6691194A (en) 1993-05-19 1994-05-12 N'-heterocyclyl-n-benzofuranyl urea derivatives and their analogs as acat inhibitors
JP6525244A JPH08510233A (ja) 1993-05-19 1994-05-12 Ａｃａｔ阻害剤としてのｎ’−複素環−ｎ−ベンゾフラニル尿素誘導体およびそれらの類縁体

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GB939310320A GB9310320D0 (en) 1993-05-19 1993-05-19 New urea derivatives,processes for the preparation thereof and pharmaceutical composition comprising the same
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GB939323890A GB9323890D0 (en) 1993-11-19 1993-11-19 New urea derivatives,processes for the preparation thereof and pharmaceutical composition comprising the same
GB9323890.5 1993-11-19
GB9403187.9 1994-02-18
GB9403187A GB9403187D0 (en) 1994-02-18 1994-02-18 New urea derivatives, processes for the preparation thereof and pharmaceutical compositioncomprising the same

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Publication number Priority date Publication date Assignee Title
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US6800654B2 (en) 2001-06-20 2004-10-05 Wyeth Substituted naphthyl indole derivatives as inhibitors of plasminogen activator inhibitor type-1 (PAI-1)
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US7056906B2 (en) 2001-09-21 2006-06-06 Schering Corporation Combinations of hormone replacement therapy composition(s) and sterol absorption inhibitor(s) and treatments for vascular conditions in post-menopausal women
US7056943B2 (en) 2002-12-10 2006-06-06 Wyeth Substituted indole oxo-acetyl amino acetic acid derivatives as inhibitors of plasminogen activator inhibitor-1 (PAI-1)
US7071181B2 (en) 2001-01-26 2006-07-04 Schering Corporation Methods and therapeutic combinations for the treatment of diabetes using sterol absorption inhibitors
US7074817B2 (en) 2001-06-20 2006-07-11 Wyeth Substituted indole acid derivatives as inhibitors of plasminogen activator inhibitor-1 (PAI-1)
US7078429B2 (en) 2002-12-10 2006-07-18 Wyeth Substituted 3-carbonyl-1H-indol-1-yl acetic acid derivatives as inhibitors of plasminogen activator inhibitor-1 (PAI-1)
US7101903B2 (en) 2002-12-10 2006-09-05 Wyeth Substituted dihydropyrano indole-3,4-dione derivatives as inhibitiors of plasminogen activator inhibitor-1 (PAI-1)
US7141592B2 (en) 2003-09-25 2006-11-28 Wyeth Substituted oxadiazolidinediones
US7163954B2 (en) 2003-09-25 2007-01-16 Wyeth Substituted naphthyl benzothiophene acids
US7186749B2 (en) 2004-08-23 2007-03-06 Wyeth Pyrrolo-naphthyl acids and methods for using them
US7192944B2 (en) 2003-03-07 2007-03-20 Schering Corp. Substituted azetidinone compounds, processes for preparing the same, formulations and uses thereof
US7208486B2 (en) 2003-03-07 2007-04-24 Schering Corporation Substituted azetidinone compounds, processes for preparing the same, formulations and uses thereof
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US7259182B2 (en) 2002-12-10 2007-08-21 Wyeth Aryl, aryloxy, and aklyloxy substituted 1H-indol-3-yl glyoxylic acid derivatives as inhibitors of plasminogen activator inhibitor-1 (PAI-1)
US7265148B2 (en) 2003-09-25 2007-09-04 Wyeth Substituted pyrrole-indoles
US7268159B2 (en) 2003-09-25 2007-09-11 Wyeth Substituted indoles
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US7323483B2 (en) 2005-01-27 2008-01-29 Wyeth Processes and compounds for the preparation of substituted naphthylindole derivatives
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US7342039B2 (en) 2003-09-25 2008-03-11 Wyeth Substituted indole oximes
US7348351B2 (en) 2002-12-10 2008-03-25 Wyeth Substituted 3-alkyl and 3-arylalkyl 1H-indol-1yl acetic acid derivatives as inhibitors of plasminogen activator inhibitor-1 (PAI-1)
US7351726B2 (en) 2003-09-25 2008-04-01 Wyeth Substituted oxadiazolidinediones
US7411083B2 (en) 2003-09-25 2008-08-12 Wyeth Substituted acetic acid derivatives
US7417039B2 (en) 2001-01-26 2008-08-26 Schering Corporation Use of substituted azetidinone compounds for the treatment of sitosterolemia
US7420083B2 (en) 2003-09-25 2008-09-02 Wyeth Substituted aryloximes
US7435837B2 (en) 2003-10-24 2008-10-14 Wyeth Dihydrobenzofuranyl alkanamine derivatives and methods for using same
US7442805B2 (en) 2003-09-25 2008-10-28 Wyeth Substituted sulfonamide-indoles
US7446201B2 (en) 2003-09-25 2008-11-04 Wyeth Substituted heteroaryl benzofuran acids
US7459442B2 (en) 2003-03-07 2008-12-02 Schering Corporation Substituted azetidinone compounds, processes for preparing the same, formulations and uses thereof
US7534894B2 (en) 2003-09-25 2009-05-19 Wyeth Biphenyloxy-acids
US7560449B2 (en) 2002-11-06 2009-07-14 Schering Corporation Methods and therapeutic combinations for the treatment of demyelination
US7582773B2 (en) 2003-09-25 2009-09-01 Wyeth Substituted phenyl indoles
US7605172B2 (en) 2004-08-23 2009-10-20 Wyeth Thiazolo-naphthyl acids
US7683091B2 (en) 2005-08-17 2010-03-23 Wyeth Substituted indoles and methods of their use
US7754747B2 (en) 2004-08-23 2010-07-13 Wyeth Llc Oxazolo-naphthyl acids

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0506532A1 (fr) * 1991-03-26 1992-09-30 Lipha, Lyonnaise Industrielle Pharmaceutique Nouveaux dérivés de l'indole, procédé de préparation et médicaments les contenant
EP0512570A1 (fr) * 1991-05-10 1992-11-11 Fujisawa Pharmaceutical Co., Ltd. Dérivés de l'urée, procédé pour leur préparation et compositions pharmaceutiques les contenant
EP0527687A2 (fr) * 1991-08-13 1993-02-17 Adir Et Compagnie Nouveaux dérivés d'aryléthylamines, leurs procédés de préparation et les compositions pharmaceutiques qui les contiennent
WO1993024458A1 (fr) * 1992-05-28 1993-12-09 Pfizer Inc. Nouveau derives n-aryle et de n-heteroaryluree en tant qu'inhibiteurs de l'acylcoenzime a: cholesterol acyltransferase (acat)

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0506532A1 (fr) * 1991-03-26 1992-09-30 Lipha, Lyonnaise Industrielle Pharmaceutique Nouveaux dérivés de l'indole, procédé de préparation et médicaments les contenant
EP0512570A1 (fr) * 1991-05-10 1992-11-11 Fujisawa Pharmaceutical Co., Ltd. Dérivés de l'urée, procédé pour leur préparation et compositions pharmaceutiques les contenant
EP0527687A2 (fr) * 1991-08-13 1993-02-17 Adir Et Compagnie Nouveaux dérivés d'aryléthylamines, leurs procédés de préparation et les compositions pharmaceutiques qui les contiennent
WO1993024458A1 (fr) * 1992-05-28 1993-12-09 Pfizer Inc. Nouveau derives n-aryle et de n-heteroaryluree en tant qu'inhibiteurs de l'acylcoenzime a: cholesterol acyltransferase (acat)

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US7417039B2 (en) 2001-01-26 2008-08-26 Schering Corporation Use of substituted azetidinone compounds for the treatment of sitosterolemia
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US6969730B2 (en) 2001-03-16 2005-11-29 Abbott Laboratories Amines as histamine-3 receptor ligands and their therapeutic applications
US7538138B2 (en) 2001-03-16 2009-05-26 Abbott Laboratories Amines as histamine-3 receptor ligands and their therapeutic applications
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US7074817B2 (en) 2001-06-20 2006-07-11 Wyeth Substituted indole acid derivatives as inhibitors of plasminogen activator inhibitor-1 (PAI-1)
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US7056906B2 (en) 2001-09-21 2006-06-06 Schering Corporation Combinations of hormone replacement therapy composition(s) and sterol absorption inhibitor(s) and treatments for vascular conditions in post-menopausal women
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US7078429B2 (en) 2002-12-10 2006-07-18 Wyeth Substituted 3-carbonyl-1H-indol-1-yl acetic acid derivatives as inhibitors of plasminogen activator inhibitor-1 (PAI-1)
US7235543B2 (en) 2003-03-07 2007-06-26 Schering Corporation Substituted azetidinone compounds, processes for preparing the same, formulations and uses thereof
US7192944B2 (en) 2003-03-07 2007-03-20 Schering Corp. Substituted azetidinone compounds, processes for preparing the same, formulations and uses thereof
US7378518B2 (en) 2003-03-07 2008-05-27 Schering Corporation Substituted azetidinone compounds, processes for preparing the same, formulations and uses thereof
US7208486B2 (en) 2003-03-07 2007-04-24 Schering Corporation Substituted azetidinone compounds, processes for preparing the same, formulations and uses thereof
US7459442B2 (en) 2003-03-07 2008-12-02 Schering Corporation Substituted azetidinone compounds, processes for preparing the same, formulations and uses thereof
US7368562B2 (en) 2003-03-07 2008-05-06 Schering Corporation Substituted azetidinone compounds, processes for preparing the same, formulations and uses thereof
US7368563B2 (en) 2003-03-07 2008-05-06 Schering Corporation Substituted azetidinone compounds, processes for preparing the same, formulations and uses thereof
US7268159B2 (en) 2003-09-25 2007-09-11 Wyeth Substituted indoles
US7446201B2 (en) 2003-09-25 2008-11-04 Wyeth Substituted heteroaryl benzofuran acids
US7342039B2 (en) 2003-09-25 2008-03-11 Wyeth Substituted indole oximes
US7332521B2 (en) 2003-09-25 2008-02-19 Wyeth Substituted indoles
US7411083B2 (en) 2003-09-25 2008-08-12 Wyeth Substituted acetic acid derivatives
US7803835B2 (en) 2003-09-25 2010-09-28 Wyeth Llc Substituted acetic acid derivatives
US7420083B2 (en) 2003-09-25 2008-09-02 Wyeth Substituted aryloximes
US7582773B2 (en) 2003-09-25 2009-09-01 Wyeth Substituted phenyl indoles
US7442805B2 (en) 2003-09-25 2008-10-28 Wyeth Substituted sulfonamide-indoles
US7351726B2 (en) 2003-09-25 2008-04-01 Wyeth Substituted oxadiazolidinediones
US7265148B2 (en) 2003-09-25 2007-09-04 Wyeth Substituted pyrrole-indoles
US7141592B2 (en) 2003-09-25 2006-11-28 Wyeth Substituted oxadiazolidinediones
US7534894B2 (en) 2003-09-25 2009-05-19 Wyeth Biphenyloxy-acids
US7163954B2 (en) 2003-09-25 2007-01-16 Wyeth Substituted naphthyl benzothiophene acids
US7649005B2 (en) 2003-10-15 2010-01-19 Newron Pharmaceuticals S.P.A. Substituted benzylaminoalkylene heterocycles
AU2004283816B2 (en) * 2003-10-15 2009-07-16 Newron Pharmaceuticals S.P.A. Substituted benzylaminoalkylene heterocycles
EP1524267A1 (fr) * 2003-10-15 2005-04-20 Newron Pharmaceuticals S.p.A. Heterocycles benzyleaminoalkylene substitues
WO2005040138A1 (fr) * 2003-10-15 2005-05-06 Newron Pharmaceuticals S.P.A. Heterocycles de benzylaminoalkylene substitues
US7435837B2 (en) 2003-10-24 2008-10-14 Wyeth Dihydrobenzofuranyl alkanamine derivatives and methods for using same
WO2005112640A2 (fr) * 2004-05-13 2005-12-01 Viropharma Incorporated Composes, compositions et methodes de traitement et de prophylaxie des infections provoquees par le virus de l'hepatite c et des maladies associees
WO2005112640A3 (fr) * 2004-05-13 2007-03-29 Viropharma Inc Composes, compositions et methodes de traitement et de prophylaxie des infections provoquees par le virus de l'hepatite c et des maladies associees
US7605172B2 (en) 2004-08-23 2009-10-20 Wyeth Thiazolo-naphthyl acids
US7186749B2 (en) 2004-08-23 2007-03-06 Wyeth Pyrrolo-naphthyl acids and methods for using them
US7754747B2 (en) 2004-08-23 2010-07-13 Wyeth Llc Oxazolo-naphthyl acids
US7323483B2 (en) 2005-01-27 2008-01-29 Wyeth Processes and compounds for the preparation of substituted naphthylindole derivatives
US7683091B2 (en) 2005-08-17 2010-03-23 Wyeth Substituted indoles and methods of their use

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HUT68843A (en) 1995-08-28
AU6691194A (en) 1994-12-12
TW262466B (fr) 1995-11-11
IL109568A0 (en) 1994-08-26
JPH08510233A (ja) 1996-10-29

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