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WO1992015579A1 - Composes polyaromatiques et multicycliques a base d'amines tertiaires, ayant une fonction inhibitrice de la squalenesynthetase - Google Patents

Composes polyaromatiques et multicycliques a base d'amines tertiaires, ayant une fonction inhibitrice de la squalenesynthetase Download PDF

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Publication number
WO1992015579A1
WO1992015579A1 PCT/US1992/001773 US9201773W WO9215579A1 WO 1992015579 A1 WO1992015579 A1 WO 1992015579A1 US 9201773 W US9201773 W US 9201773W WO 9215579 A1 WO9215579 A1 WO 9215579A1
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WIPO (PCT)
Prior art keywords
compound according
phenyl
hydrogen
hydroxy
alkyl
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PCT/US1992/001773
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English (en)
Inventor
Kent Neuenschwander
Dilip Amin
Anthony C. Scotese
Robert L. Morris
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Rhone-Poulenc Rorer International (Holdings) Inc.
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Application filed by Rhone-Poulenc Rorer International (Holdings) Inc. filed Critical Rhone-Poulenc Rorer International (Holdings) Inc.
Priority to JP4509423A priority Critical patent/JPH06506467A/ja
Publication of WO1992015579A1 publication Critical patent/WO1992015579A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a class of novel compounds useful in the treatment of diseases associated with undesirable cholesterol levels in the body, and particularly of diseases of the cardiovascular system, such as artherosclerosis.
  • LDL binds to specific receptors found on the surfaces of the cells and is internalized by receptor-mediated endocytosis. Inside the cell, the cholesterol ester component is hydrolyzed by lysosomal enzymes to liberate free cholesterol.
  • the free cholesterol has the following four important regulatory actions on the cell's cholesterol metabolism: (1 ) Suppression of cholesterol biosynthesis by down-regulation of the rate limiting enzyme, HMG-CoA reductase;
  • the first three regulatory actions are taken to prevent an overaccumulation of free cholesterol in the cell. Suppression of squalene synthetase activity by free cholesterol, the fourth response above, occurs only after the HMG-CoA reductase enzyme has been supressed by more than 90%, which, accordingly, reduces the synthesis of mevalonic acid and all of its metabolites.
  • Farnesyl pyrophosphate (FPP) is an important mevalonate metabolite, located at the branch point of the mevalonate pathway. It is the immediate precursor of squalene, whose sole fate is cholesterol synthesis, as well as of some vital nonsterol products (e.g. dolichol, ubiquinone, and the farnesylated proteins), which are essential for cell growth.
  • Cholesterol is required in much larger amounts than the nonsterol products and in the absence of LDL supplied cholesterol, the vast bulk of farnesyl pyrophosphate is used to produce cholesterol by way of squalene.
  • squalene synthetase is also supressed in order to divert farnesyl pyrophosphate from the sterol pathway, into the crucial nonsterol pathways.
  • the enzyme is still present in large excess in the cell.
  • suppression of squalene synthetase does not influence the rate of cholesterol biosynthesis. Rather its purpose is to support the synthesis of the nonsterol products by maintaining adequate concentrations of farnesyl pyrophosphate. This is important at a time when the synthesis of farnesyl pyrophosphate has . been greatly reduced.
  • HMG-CoA reductase inhibitor blocks the production of mevalonic acid and thus inhibits the biosynthesis of cholesterol. But unlike the normal physiological regulation of the mevalonate pathway, there is no concurrent suppression of the squalene synthetase enzyme. The small amounts of farnesyl pyrophosphate still being produced still follow the sterol pathway. The intracellular concentration of farnesyl pyrophosphate drops to levels so low that the farnesylated proteins prepared therefrom can no longer be synthesized.
  • farnesylated proteins are involved in feedback supression regulation of HMG CoA reductase, and, accordingly, the loss of this feedback regulation results in a 5- to 10-fold increase in the amount of the HMG-CoA reductase enzyme present in the cell.
  • the increased amount of enzyme can also be inhibited by the HMG CoA reductase inhibitor, but at a higher dose than would have been necessary had the amount of the HMG-CoA reductase enzyme remained the same.
  • HMG CoA reductase is a rate-limiting enzyme in cholesterol biosynthesis
  • inhibitors of HMG CoA reductase are potent hypocholesterolemic agents in humans. Although these inhibitors are relatively safe, side effects like hepatotoxicity and myopathy have been observed. Inhibition of squalene synthetase will not result in reduction of vital mevalonate metabolites and thus a squalene synthetase inhibitor may offer the advantage of fewer side effects compared to that observed with inhibitors of HMG CoA reductase. It may also result in feed-back inhibition of HMG CoA and thus become a more useful hypocholesterolemic agent.
  • the present invention is directed to a class of novel tertiary amino polycyclic compounds which exhibit squalene synthetase inhibition properties.
  • This invention comprises polycyclic compounds containing two mono- and/or bicyclic rings and a basic tertiary amino group.
  • Preferred polycyclic compounds contain a tertiary amino group capable of forming an ammonium ion at biological pH.
  • the compounds of this invention possess properties which reduce levels of serum cholesterol in the body without significantly reducing mevalonic metabolite synthesis and thus provide a therapeutic agent having fewer side effects than agents which act by inhibiting the HMG-CoA reductase enzyme.
  • This invention relates also to pharmacological compositions and method of treatment for lowering serum cholesterol levels using the compounds of this invention.
  • Figure 1 is a schematic diagram of the biosynthetic pathway of cholesterol.
  • the compounds of the present invention comprise polycyclic ring compounds containing two mono- and/or bicyclic aryl and/or carbocyclic and/or heterocyclic rings and a tertiary cyclic amino group.
  • Ar I and Ar II are independently a substituted or unsubstituted mono-, bi- or tricyclic ring;
  • A is referabl selected from the group consisting of
  • Y is NR', O, or S
  • Z is NR', O, S or a bond and m is 1 -2;
  • R'C CR' or C ⁇ C
  • Ri, R 2 , R3, R4, R5, R6. R7 and Rs are independently hydrogen or (CH2 ) ⁇ — X where x is 0-5 and X is hydrogen, alkyl, alkenyl, aralkyl, hydroxy, alkoxy, aryloxy, aralkoxy, acyloxy, aryl, halo, amino, mono-and di-alkylamino or acylamino;
  • Ri and R 3 together and/or R5 and R7 together may be ( CH2 ) ⁇ where n is 1-4: geminal R- * and R2, R3 and R4, R5 and RQ or R7 and Rs groups may be ( CH2 ) p where p is 2-5;
  • R' is hydrogen, alkyl or aralkyl
  • R is hydrogen, alkyl, aralkyl, hydroxy, alkoxy, aralkoxy, acyloxy, halo, haloalkyl, amino, mono- and di-alkylamino or acylamino; and a, b, d and e are 0-4; or a pharmaceutically acceptable salt thereof.
  • Ar I and Ar II are independently a substituted or unsubstituted mono-, bi- or tricyclic system of about 5 to about 14 atoms which may be partially or completely unsaturated carbocyclic or heterocyclic and where each ring of said system contains 0 to about 2 hetero atoms selected from N, O and S provided said hetero atoms are not vicinal oxygen and/or sulfur atoms and where the substituents may be located at any appropriate position of the ring system and are described by the R definition above.
  • Preferred monocyclic rings include aryl and unsaturated carbocyclic and heterocyclic rings.
  • Exemplary rings are substituted or unsubstituted pyrrole, thiophene, furan, cyclopentadiene, imidazole, pyrazole, 1,2,4-triazole, pyridine, pyrazine, pyrimidine, pyridazine, thiazole, isothiazole, isoxazole, s-triazine and benzene.
  • Preferred bicyclic ring systems include bicyclic aryl and bicyclic unsaturated carbocyclic and heterocyclic rings.
  • Exemplary bicyclic rings include substituted and unsubstituted indene, isoindene, benzofuran, dihydrobenzofuran, benzothiophene, indole, 1H-indazole, indoline, imadazoie, azulene, tetrahydroazulene, benzopyrazole, benzoimadazole, benzoxazole, benzothiazole, 1 ,3-benzodioxole, 1 ,4-benzodioxan, purine, naphthalene, tetralin, coumarin, chromone, chromene, 1 ,2-dihydrobenzothiopyran, tetrahydrobenzothiopyran, quinoline, isoquinoline, quinazoline, pyrido[3,4-b]
  • Preferred tricyclic ring systems include tricyclic aryl and tricyclic unsaturated carbocyclic and heterocyclic rings.
  • Exemplary tricyclic rings include substituted and unsubstituted phenanthrene, anthracene, acenaphthylene, perimidine, phenothiazine and phenoxazine.
  • the tertiary amino groups described by A are preferably the following:
  • Bio pH refers to that pH of blood, plasma or serum in the body between about 7.2 and about 7.5 and which does not interfere with normal degradation of materials present therein.
  • the normal pH of blood, plasma or serum values is about 7.35-7.45 and is preferably about pH 7.39-7.41.
  • “Monocyclic aryl” means a carbocyclic and/or heterocyclic aromatic ring. Preferred groups include phenyl, thienyl, pyridinyl, furyl and pyrimidinyl.
  • Bicyclic aryl means a bicyclic ring system composed of two fused carbocyclic and/or heterocyclic aromatic rings. Preferred groups include naphthyl, indolyl, benzothienyl, benzofuranyl, quinolinyl, chromonyl and purinyl.
  • Tricyclic aryl means a tricyclic ring system composed of three fused carbocyclic and/or heterocyclic aromatic rings. Preferred groups include acenaphthylene, phenanthrene, phenothiazine and phenoxazine.
  • Aryl means a carbocyclic or heterocyclic aromatic ring.
  • Alkyl either alone or with various substituents defined herein, means a saturated aliphatic hydrocarbon, either branched- or straight-chained.
  • Preferred alkyl is "Loweralkyl” having about 1 to about 6 carbon atoms. Examples of alkyl include methyl, ethyl, n-propyl, isopropyl, butyl, sec-butyl, t- butyl, amyl and hexyl.
  • Alkoxy refers to an alkyl-O-group.
  • alkenyl refers to a hydrocarbon having at least one point of unsaturation and may be branched- or straight-chained. Preferred alkenyl groups have 2 to about 6 carbon atoms. Exemplary alkenyl groups include vinyl, allyl, ethynyl and isopropenyl.
  • the preferred aryloxy group is phenoxy.
  • Alkyl means an alkyl group substituted by an aryl radical.
  • the preferred aralkyl groups are benzyl or phenethyl.
  • the preferred aryloxy group is phenoxy.
  • the preferred aralkoxy groups are benzyloxy and phenethoxy.
  • the preferred acyloxy group is acetoxy.
  • Halo means a halogen. Preferred halogens include chloride, bromide and fluoride. The preferred haloalkyl group is trifluoromethyl.
  • the more preferred compounds of this invention include those compounds of Formula I where:
  • Ar I is phenyl or naphthyl
  • Ar II is phenyl, naphthyl, benzothiazolyl, benzofuryl, benzoxazolyl benzothienyl, benzodioxanyl, benzodihydrofuranyl, benzofuranyl, benzodioxolyl, quinolinyl, indolyl, acenaphthyl or dihydroacenaphthyl;
  • B is CR'R. O. S or NR';
  • R ⁇ . R 7 and Re are independently hydrogen or (CH2) ⁇ — X where x is 0-5 and X is hydrogen, alkyl, hydroxy, alkoxy, aryloxy, aralkoxy, or aryl;
  • Ri and R3 together and/or R5 and R7 together may be (CH 2 )n where n is 1-4:
  • R3 and R 4 , R5 and Re or R7 and Re groups may be (CH2) P where p is 2-5-,
  • R' is hydrogen, alkyl or aralkyl
  • R is hydrogen, alkyl, hydroxy, alkoxy, halo or haloalkyl
  • a, b, d and e are 0-4.
  • the tertiary amino A group is most preferably one of the following:
  • Ar I is phenyl or naphthyl
  • Ar II is phenyl, naphthyl, benzothiazolyl, benzofuryl, benzoxazolyl, benzothienyl, benzodioxanyl, benzodihydrofuranyl, benzofuranyl, benzodioxolyl, quinolinyl, indolyl, acenaphthyl or dihydroacenaphthyl;
  • B is CR'R or O
  • R3. R4. R5, Re. 7 and Rs are independently hydrogen or (CH2) ⁇ — X where x is 0-3 and X is hydrogen, alkyl, hydroxy or phenyl; -
  • R' is hydrogen or loweralkyi
  • R is hydrogen, loweralkyi, hydroxy, loweralkoxy, halo or trifluoromethyl
  • a, b, d and e are 0-4.
  • B is CR'R' or O
  • R is hydrogen, loweralkyi, hydroxy, loweralkoxy, halo or trifluoromethyl
  • a, b, d and e are 0-4.
  • the compounds of this invention may be prepared by employing procedures known in the literature starting from known compounds or readily preparable intermediates Exemplary general procedures follow.
  • L is a leaving group, preferably halo, tosylate or mesylate.
  • the cyclic amine is protected with the usual protecting groups such as hydroborane complex which is removed at the appropriate time with dilute acid such as HCI.
  • any base normally employed to deprotonate an alcohol or thiol may be used, such as sodium hydride, sodium hydroxide, triethyl amine, sodium bicarbonate or diisopropylethylamine.
  • Reaction temperatures are in the range of -78°C to reflux depending on the reactants involved. (Preferably 0°C to room temperature). Reaction times vary from about 2 to about 96 hours.
  • the reaction is usually carried out in a solvent that will dissolve both reactants and is inert to both as well. Solvents include, but are not limited to, diethyl ether, tetrahydrofuran, N,N-dimethyl formamide, dimethyl sulfoxide, dioxane and the like.
  • B or D is SO or SO2
  • treatment of the thio compound with m-chlorobenzoic acid or sodium periodate results in the sulfinyl compound.
  • Preparation of the sulfonyl compound may be accomplished by known procedures such as dissolving the sulfinyl compound in acetic acid and treating hydrogen peroxide, preferably about 30% aqueous H2O2.
  • metal salt may be used. Any appropriate metal salt such as Li, K, Na, Mg, Br or the like may be used.
  • the substituted metal salt compound such as the lithium, sodium potassium or Grignard compound
  • Wittig reagent is prepared by known art recognized procedures such as reaction of triphenylphosphine or diethylphosphone, with a substituted alkyl bromide followed by treatment with a strong organometallic or alkoxide base, such as n-BuLi or NaOH, results in the desired ylide.
  • a strong organometallic or alkoxide base such as n-BuLi or NaOH
  • a compound having three such centers gives rise to a maximum of eight stereoisomers, while one having four produces sixteen, etc.
  • the product may be synthesized as a mixture of the isomers and then the desired isomer separated by conventional techniques such as chromatography or fractional crystallization from which each diastereomer may be resolved.
  • synthesis may be carried out by known stereospecific processes using the desired form of the intermediate which would result in obtaining the desired stereospecificity.
  • the resolution of the compounds of this invention and their starting materials may be carried out by known procedures. Incorporation by reference is hereby made to the four volume compendium Optical Resolution Procedures for Chemical Compounds: Optical Resolution Information Center, Manhattan College, Riverdale, New York. Such procedures are useful in the practice of this invention. A further useful reference is Enantiomers. Racemates and Resolutions: Jean Jacques, Andre Collet and Samuel H. Wilen; John Wiley & Sons, Inc., New York, 1981. Basically, the resolution of the compounds is based on the differences in the physical properties of diastereomers. Conversion of the racemates into a mixture of diastereomers by attachment of an enantiomerically pure moiety results in forms that are separable by fractional crystallization, distillation or chromatography.
  • the present compounds form salts with acids when a basic amino function is present and salts with bases when an acid function, i.e., carboxyl, is present. All such salts are useful in the isolation and/or purification of the new products.
  • Suitable acids include, for example, hydrochloric, sulfuric, nitric, benzenesulfonic, toluenesulfonic, acetic, maleic, tartaric and the like which are pharmaceutically acceptable.
  • Basic salts for pharmaceutical use are the Na, K, Ca and Mg salts.
  • substituents on the present new compounds can be present in the starting compounds, added to any one of the intermediates or added after formation of the final products by known methods of substitution or conversion reactions. If the substituents themselves are reactive, then the substituents can themselves be protected according to the techniques known in the art. A variety of protecting groups known in the art, may be employed. Examples of many of these possible groups may be found in "Protective Groups in Organic Synthesis" by T.W. Green, John Wiley and Sons, 1981. For example, nitro groups can be added by nitration and the nitro group converted to other groups, such as amino by reduction, and halo by diazotization of the amino group and replacement of the diazo group. Acyl groups can be added by Friedel-Crafts acylation.
  • the acyl groups can then be transformed to the corresponding alkyl groups by various methods, including the Wolff-Kishner reduction and Clemmenson reduction.
  • Amino groups can be alkylated to form mono- and di-alkylamino groups; and mercapto and hydroxy groups can be alkylated to form corresponding ethers.
  • Primary alcohols can be oxidized by oxidizing agents known in the art to form carboxylic acids or aldehydes, and secondary alcohols can be oxidized to form ketones. Thus, substitution or alteration reactions can be employed to provide a variety of substituents throughout the molecule of the starting material, intermediates, or the final product.
  • the compounds of the present invention may be prepared by the following representative examples.
  • the mixture is poured into 50 ml of water and extracted with 100 ml of ether.
  • the ether is washed with water and dried over magnesium sulfate and then filtered.
  • the filtrate is evaporated and the residue purified by flash chromatography using 7:3 hexane:ethyl acetate on silica gel.
  • the product residue is dissolved in 10 ml of acetone and 6 ml of 3N HCI is added.
  • the mixture is then stirred at room temperature for 45 minutes and concentrated in a rotary evaporator.
  • the residue is basified with sodium carbonate and partitioned between 15 ml of brine and 75 ml of chloroform.
  • the mixture is poured into 70 ml of water and extracted with 100 ml of ether.
  • the ether is washed with water and dried over magnesium sulfate and filtered.
  • the filtrate is evaporated and the residue redissolved in 15 ml of acetone and 7 ml of 3N HCI added.
  • the mixture is stirred at room temperature for 24 hours.
  • the mixture is concentrated in vacuo and basified with sodium carbonate.
  • the mixture is partitioned between 15 ml of brine and 70 ml of chloroform.
  • the chloroform is evaporated and the residue dissolved in ethanolic HCI and diluted with petroleum ether.
  • the mixture is stirred for 4 hours warming to room temperature and poured into 100 ml of water.
  • the mixture is extracted with 100 ml of ether and washed with water and dried over magnesium sulfate.
  • the evaporated ether residue is purified by flash chromatography on silica gel using 7:3 hexane:ethyl acetate as the eluent.
  • the product residue is dissolved in 10 ml of acetone and 6 ml of 3N HCI is added.
  • the mixture is stirred at room temperature for 45 minutes and is basified and extracted into chloroform.
  • the evaporated chloroform layer is dissolved in ethanolic HCI and the solution is diluted with petroleum ether.
  • Step B methvl 4-oxocvclohexane-1 -carboxvlate
  • Step C methyl 1.4-dioxaspirof4.51decane-8-carboxylate
  • Step D 1.4-dioxaspiro[4.5]decane-8-carboxamide
  • Step E 8-aminomethyl-1.4-dioxaspirof4.51decane
  • Step F 1-azatricvclof3.3.1.l3J.]decane-4-one
  • Step H 1-azatricvclof3.3.1.ia * Z
  • Step I anti and svn isomer of 4-[4-(2-(E.-phenylethenyl.phenyl- methoxy]-1-azatricvclo[3.3.1.l2_Zldecane. borane complex
  • Step J 4-anti-[4-(2-(E.-phenylethenyl.phenylmethoxy]-1-azatricvclo-
  • Step K 4-svn-f4-(2-.E.-phenylethenyl.phenylmethoxy1-1-azatricvclo-
  • the cooling bath is removed and the mixture is stirred for 1 hour and is poured into 70 ml of water.
  • the mixture is extracted with 100 ml of ether.
  • the ether layer is washed with water and is dried over magnesium sulfate and filtered.
  • the filtrate is diluted to the cloudy point with petroleum ether to give solid melting at 135-8°C. This solid is suspended in 10 ml of acetone and 6 ml of 3N HCI is added.
  • Z is m. p. °C where: Z is m. p. °C
  • Step A 4-methvl-3'.4'-methvlenedioxv-1 .1 -biphenvl
  • Step B 4-bromomethyl-3'.4'-methylenedioxy-1.1 -biphenyl
  • Step C 3-f4-.1.3-benzodioxol-5-yl .
  • the squalene synthetase assay used is a modification of the procedures described by Popjak (1969) and Poulter et al. (1989):
  • Anhydrous MgCl2 (M-8266), ⁇ -NADPH tetrasodium salt, reduced form (N-1630), Bovine serum albumin (A-6003), Cholesterol (C-8503);
  • Bio-Rad protein assay dye concentrate Bio-Rad Laboratories, Richmond, CA
  • Non-radiolabeled FPP is prepared in-house.
  • the solid FPP is aliquoted and stored at -80°C.
  • FPP is dissolved in 70% ethanol/30% 0.25 M NH4HCO3 at the concentration of 10 mM and the solution is aliquoted (200 ⁇ l each) and stored at -80°C.
  • Test solutions are prepared fresh in 100% DMSO or dH2 ⁇ . Subsequent dilutions are made in the same solvent. Compounds are tested initially at 1 or 10 ⁇ M (final concentrations).
  • Potassium Phosphate (50 mM, 8.71 g/l) pH 7.5 stock buffer is prepared and stored at 4°C until use.
  • Anhydrous MgCt ⁇ is added to the phosphate buffer on the day of assay for a final concentration of 10mM (95 mg/100 ml).
  • the buffer is flushed with N2 before use.
  • Non-radiolabeled FPP is diluted to 50 ⁇ M (100 ⁇ l 10 mM cold FPP +19.9 ml phosphate buffer). Then, 14 ⁇ l (20 x 10 6 dpm) of 3 H-FPP (0.5 mCi/ml, .011 mg/ml) is added. 200 ⁇ l of this mixture is added per assay tube for a final reaction concentration of 10 ⁇ M FPP (-200,000 dpm/assay tube).
  • ⁇ -NADPH 37.5 mg of ⁇ -NADPH is added to 9 ml assay buffer for a 5 mM concentration of ⁇ -NADPH. The mixture is vortexed and 100 ⁇ l of this solution is added to each tube for a final assay concentration of 0.5 mM ⁇ -NADPH.
  • livers are removed one at a time from four rats.
  • the livers are combined and weighed in a tared beaker.
  • Assay buffer is added equal to three times the liver weight.
  • the liver is first homogenized with a blender for thirty seconds, and then by a motor driven teflon pestle at a speed of 2.5. During homogenization, the liver is kept on ice.
  • the homogenate is centrifuged at 10,000 g for 30 min at 4°C in 50 ml capacity centrifuge tubes.
  • the mitochondrial pellet is discarded and the supernatant is filtered through a layer of gauze moistened with a little buffer. This supernatant is recentrifuged at 105,000 g for one hour at 0°C in an ultracentrifuge in 25 ml capacity ultracentrifuge tubes.
  • the sediment pellet consists of 2 layers: a transparent inner layer of glycogen, surrounded by an opaque brown layer of microsomes.
  • the brown outer microsomal layer is carefully removed with a spatula and placed in a beaker on ice.
  • Assay buffer is added in an amount equal to one half the original homogenate volume, and this mixture is poured into ultracentrifuge tubes. These tubes are recentrifuged at 105,000 g for 1 hour at 4°C.
  • the assay 20 ⁇ l of the compound of this invention or vehicle solution is added to each 16 x 150 screw-cap culture tube on ice. Then 580 ⁇ l of N 2 flushed assay buffer is pipetted into each tube. 100 ⁇ l of cofactor is next added to each tube, followed by 100 ⁇ l of a dilution of microsomal enzyme (approximately 80 ug protein). The tubes are preincubated for 10 minutes at 37°C, and 200 ⁇ l of the 3 H-FPP (200,000 dpm, 10 ⁇ M final cone.) is added to each tube at two second intervals. The tubes are then incubated for exactly 10 minutes, shaking at 150 oscillations per minute.
  • the reaction is stopped by the addition of 1 ml of 15% KOH in ethanol, and the tubes are incubated for 30 minutes in a 65°C water bath for saponification of lipids and solubilization of proteins.
  • the tubes are cooled on ice for five minutes.
  • the samples are next extracted with 5 ml of petroleum ether by shaking for 10 minutes at low speed on a metabolic shaker.
  • Each lower aqueous layer is frozen in a dry ice/alcohol bath (2-propanol/methanol, 1 :1 ), and each organic layer is poured into another set of 16 x 150 screw-top. culture tubes containing 2 ml of deionized water. Each ether layer is washed by vortexing each tube for 5 seconds.
  • aqueous layers are again frozen in the dry ice/alcohol bath, and the ether is poured into scintillation vials. 10 ml of AquaSol® is next added to each vial, and the vials are counted for 5 minutes in a scintillation counter. Percent inhibitions are calculated from the counts obtained.
  • the samples are counted as dpm using a Beckman Scintillation counter (Model LS-9000). Percent inhibition is calculated using a Lotus 1-2-3 program.
  • the IC50 values are calculated using a linear regression program of Tallarida and Murray (1987). Tallarida, R.J. and Murray, R.B. Manual of pharmacologic calculations with computer programs. Springer-Verlag, 1987.
  • compounds within the scope of Formula I inhibit squalene synthetase enzyme activity and are useful as hypocholesterolemic or hypolipidemic agents by virtue of their ability to inhibit the biosynthesis of cholesterol. Having such ability, the compounds are incorporated into pharmaceutically acceptable carriers and administered to a patient in need of such cholesterol biosynthesis inhibition.
  • These pharmaceutical formulations contain at least one compound according to this invention.
  • treatment with a combination of an HMG-CoA reductase inhibitor and a squalene synthetase inhibitor could have a synergistic effect on inhibiting cholesterol biosynthesis. Inhibiting the squalene synthetase enzyme and the HMG-CoA reductase enzyme at the same time would most closely resemble the physiological conditions of cholesterol homeostasis.
  • a squalene synthetase inhibitor could keep cellular concentrations of farnesyl pyrophosphate high enough for the synthesis of the small amounts of dolichol, ubiquinone, and the farnesylated proteins required by the cell. This would maintain some feedback regulation of the HMG-CoA reductase enzyme and allow smaller amounts of the HMG-CoA reductase inhibitor to be used.
  • the compounds of the present invention can be administered to a mammalian host in a variety of forms adapted to the chosen route of administration, i.e., orally, or parenterally.
  • Parenteral administration in this respect includes administration by the following routes: intravenous, intramuscular, subcutaneous, intraocular, intrasynovial, transepithelially including transdermal, opthalmic, sublingual and buccal; topically including opthalmic, dermal, ocular, rectal and nasal inhalation via insufflation and aerosol and rectal systemic.
  • the active compound may be orally administered, for example, with an inert diluent or with an assimilable edible carrier, or it may be enclosed in hard or soft shell gelatin capsules, or it may be compressed into tablets, or it may be incorporated directly with the food of the diet.
  • the active compound may be incorporated with excipient and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
  • Such compositions and preparations should contain at least 0.1% of active compound.
  • the percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 2 to about 6% of the weight of the unit.
  • the amount of active compound in such therapeutically useful compositions is such that a suitable dosage will be obtained.
  • Preferred compositions or preparations according to the present invention are prepared so that an oral dosage unit form contains between about 50 and 300 mg of active compound.
  • the tablets, troches, pills, capsules and the like may also contain the following: A binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin may be added or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring.
  • a binder such as gum tragacanth, acacia, corn starch or gelatin
  • excipients such as dicalcium phosphate
  • a disintegrating agent such as corn starch, potato starch, alginic acid and the like
  • a lubricant such as magnesium stearate
  • a sweetening agent such as sucrose, lactose or saccharin may be added or a flavoring agent such as peppermint,
  • tablets, pills, or capsules may be coated with shellac, sugar or both.
  • a syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl and propylparabens a preservatives, a dye and flavoring such as cherry or orange flavor.
  • any material used in preparing any dosage unit form should be pharmaceutically pure and substantially non-toxic in the amounts employed.
  • the active compound may be incorporated into sustained-release preparations and formulations.
  • the active compound may also be administered parenterally or intraperitoneally.
  • Solutions of the active compound as a free base or pharmacologically acceptable salt can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose.
  • Dispersion can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
  • the form must be sterile and must be fluid to the extent that easy syringability exists. It may be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent of dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils.
  • the proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • the prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimersal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of the injectable compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.
  • Sterile injectable solutions are prepared by incorporating the active compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the various sterilized active ingredient into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
  • the preferred methods of preparation are vacuum drying and the freeze drying technique which yield a powder of the active ingredient plus any additional desired ingredient from previously sterile-filtered solution thereof.
  • the therapeutic compounds of this invention may be administered to a mammal alone or in combination with pharmaceutically acceptable carriers, as noted above, the proportion of which is determined by the solubility and chemical nature of the compound, chosen route of administration and standard pharmaceutical practice.
  • the physician will determine the dosage of the present therapeutic agents which will be most suitable for prophylaxis or treatment and it will vary with the form of administration and the particular compound chosen, and also, it will vary with the particular patient under treatment. He will generally wish to initiate treatment with small dosages by small increments until the optimum effect under the circumstances is reached.
  • the therapeutic dosage will generally be from about 0.1 to about 100 mg/kg/dy, and preferably from about 10 mg to about 1000 mg day, or from about 0.1 mg to about 50 mg/kg of body weight per day and preferably from about 0.1 to about 20 mg/kg of body weight per day and may be administered in several different dosage units. Higher dosages on the order of about 2x to about 4x are required for oral administration.

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Abstract

L'invention se rapporte à des composés polycycliques contenant deux chaînes monocycliques et/ou bicycliques et un groupe aminé tertiaire basique qui est capable de former an ion ammonium à un pH biologique et qui réduit les niveaux de cholestérol séral dans l'organisme sans réduire de façon sensible la synthèse des métabolites mévaloniques. L'invention se rapporte également à des compositions pharmacologiques et à des procédés de traitement pour abaisser les niveaux de cholestérol séral au moyen desdits composés.
PCT/US1992/001773 1991-03-08 1992-03-03 Composes polyaromatiques et multicycliques a base d'amines tertiaires, ayant une fonction inhibitrice de la squalenesynthetase WO1992015579A1 (fr)

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JP4509423A JPH06506467A (ja) 1991-03-08 1992-03-03 多環式三級アミンポリ芳香族スクアレンシンセターゼインヒビター

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CA (1) CA2105655A1 (fr)
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WO1993015073A1 (fr) * 1992-01-28 1993-08-05 Smithkline Beecham Plc Composes azabicycliques servant d'antagonistes des canaux calciques
EP0567026A1 (fr) * 1992-04-20 1993-10-27 Takeda Chemical Industries, Ltd. Dérivés de 4,1-benzoxazepine comme inhibiteurs de la synthétase du squalène et leur application dans le traitement d'hypercholesteremie et comme fongicides
WO1993021183A1 (fr) * 1992-04-10 1993-10-28 Zeneca Limited Derives de quinuclidine utiles comme inhibiteurs de squalene synthase
WO1993021184A1 (fr) * 1992-04-10 1993-10-28 Zeneca Limited Derives de biphenylylquinuclidine utilises comme inhibiteurs de la squalene syntase
WO1994003451A1 (fr) * 1992-08-06 1994-02-17 Zeneca Limited Derives de la quinuclidine utilises comme inhibiteurs de la squalene synthetase
WO1994005660A1 (fr) * 1992-08-28 1994-03-17 Zeneca Limited Derives de la quinuclidine utilises comme inhibiteurs de la squalene synthetase
WO1994014435A1 (fr) * 1992-12-29 1994-07-07 Rhone-Poulenc Rorer Pharmaceuticals Inc. Inhibiteurs de squalene synthase cycloalkylamine bis-aryle
WO1994014803A1 (fr) * 1992-12-21 1994-07-07 Zeneca Limited Derives de quinuclidine comme inhibiteurs de la squalene synthetase
WO1994014804A1 (fr) * 1992-12-21 1994-07-07 Zeneca Limited Derives de la quinuclidine utilises comme inhibiteurs de la squalene synthetase
WO1994014805A1 (fr) * 1992-12-21 1994-07-07 Zeneca Limited Derives de la quinuclidine comme inhibiteurs de la squalene synthetase
EP0611749A1 (fr) * 1993-02-12 1994-08-24 Banyu Pharmaceutical Co., Ltd. Acides amiques substitués utilisables pour le traitement d'artiosclérosis
WO1994025459A1 (fr) * 1993-04-29 1994-11-10 Zeneca Limited Derives heterocycliques
EP0645378A1 (fr) * 1993-09-24 1995-03-29 Takeda Chemical Industries, Ltd. Composés hétérocycliques à sept ou huit chaînons condensés utiles comme inhibiteurs de squalène-synthétase
WO1995035295A1 (fr) * 1994-06-17 1995-12-28 Zeneca Limited Derives de quinuclidine en tant qu'inhibiteurs de squalene synthase
US5554613A (en) * 1992-06-04 1996-09-10 Zeneca Limited Heterocyclic derivatives
US5556990A (en) * 1994-12-16 1996-09-17 Rhone-Poulenc Rorer Pharmaceuticals Inc. Polyarylcarbamoylaza- and -carbamoylalkanedioic acids
US5792777A (en) * 1991-10-30 1998-08-11 Zeneca Limited Biphenyl quinuclidines
US5885979A (en) * 1992-04-02 1999-03-23 Takeda Chemical Industries, Ltd. N-containing condensed heterocyclic compounds, their production, and their uses
US6297198B1 (en) 1996-05-14 2001-10-02 Syngenta Participations Ag Isoxazole derivatives and their use as herbicides
US6479510B2 (en) 2000-08-18 2002-11-12 Pharmacia & Upjohn Company Quinuclidine-substituted aryl compounds for treatment of disease
US6486172B2 (en) 2000-08-18 2002-11-26 Pharmacia & Upjohn Company Quinuclidine-substituted aryl compounds for treatment of disease
US6492385B2 (en) 2000-08-18 2002-12-10 Pharmacia & Upjohn Company Quinuclidine-substituted heteroaryl moieties for treatment of disease
EP1217001A4 (fr) * 1999-09-28 2002-12-18 Eisai Co Ltd Composes de quinuclidine et medicaments contenant ces composes comme principe actif
US6500840B2 (en) 2000-08-21 2002-12-31 Pharmacia & Upjohn Company Quinuclidine-substituted heteroaryl moieties for treatment of disease
US6562816B2 (en) 2001-08-24 2003-05-13 Pharmacia & Upjohn Company Substituted-heteroaryl-7-aza[2.2.1]bicycloheptanes for the treatment of disease
US6599916B2 (en) 2000-08-21 2003-07-29 Pharmacia & Upjohn Company Quinuclidine-substituted heteroaryl moieties for treatment of disease
EP1375496A4 (fr) * 2001-03-27 2004-06-16 Eisai Co Ltd Derive d'amine cyclique a substitution n-aryle et medicament contenant ledit derive en tant que principe actif
US6852716B2 (en) 2002-02-15 2005-02-08 Pfizer Inc Substituted-aryl compounds for treatment of disease
US6869946B2 (en) 2001-04-19 2005-03-22 Pfizer Inc Substituted azabicyclic moieties for the treatment of disease
US6903085B1 (en) 1999-08-24 2005-06-07 Astrazeneca, Ab Substituted piperidine compounds useful as modulators of chemokine receptor activity
US6919359B2 (en) 2001-11-08 2005-07-19 Pfizer Inc Azabicyclic-substituted-heteroaryl compounds for the treatment of disease
US6958350B2 (en) 2001-02-19 2005-10-25 Astrazeneca Ab Chemical compounds
US6960602B2 (en) 2001-03-22 2005-11-01 Astrazeneca Ab Piperidine derivatives as modulators of chemokine receptors
WO2006065233A1 (fr) * 2004-12-10 2006-06-22 Abbott Laboratories Dérivés polycycliques de quinuclidine substitués par un bicyclohétérocycle condensé
US7160876B2 (en) 2003-12-22 2007-01-09 Abbott Laboratories Fused bicycloheterocycle substituted quinuclidine derivatives
US7176198B2 (en) 2002-08-01 2007-02-13 Pfizer Inc. 1H-pyrazole and 1H-pyrrole-azabicyclic compounds for the treatment of disease
US7192973B2 (en) 2001-11-15 2007-03-20 Astrazeneca Ab Piperidine derivatives and their use as modulators of chemokine receptor activity (especially CCR5)
WO2007018738A3 (fr) * 2005-06-15 2007-03-29 Abbott Lab Derives de quinuclidine substitues par un bicycloheterocycle substitues condense
US7294636B2 (en) 2003-05-09 2007-11-13 Astrazeneca Ab Chemical compounds
US7297704B2 (en) 2005-02-17 2007-11-20 Wyeth Cycloalkyfused indole, benzothiophene, benzofuran and idene derivatives
US7579362B2 (en) 2002-09-04 2009-08-25 Novartis Ag Aza-bicycloalkyl ethers and their use as alpha7-nAChR agonists
US7655657B2 (en) 2003-12-22 2010-02-02 Abbott Laboratories Fused bicycloheterocycle substituted quinuclidine derivatives
US7973069B2 (en) 2004-07-14 2011-07-05 Ptc Therapeutics, Inc. Methods for treating hepatitis C
US8012981B2 (en) 2006-06-15 2011-09-06 Glaxo Group Limited Benzylpiperazine derivatives as motilin receptor agonists
US8048885B2 (en) 2005-12-16 2011-11-01 Novartis Ag Organic compounds
US8173667B2 (en) 2005-10-21 2012-05-08 Novartis Ag 1-aza-bicycloalkyl derivatives
US8314119B2 (en) 2006-11-06 2012-11-20 Abbvie Inc. Azaadamantane derivatives and methods of use
US8609662B2 (en) 2004-07-14 2013-12-17 Novartis Ag 3-(heteroaryl-oxy)-2-alkyl-1-aza-bicycloalkyl derivatives as alpha. 7-nachr ligands for the treatment of CNS diseases
US8759346B2 (en) 2005-12-16 2014-06-24 Novartis Ag Organic compounds
US8933090B2 (en) 2004-06-18 2015-01-13 Novartis Ag 1-aza-bicyclo[3.3.1]nonanes
US9464078B2 (en) 2010-09-23 2016-10-11 Abbvie Inc. Monohydrate of azaadamantane derivatives
CN108884079A (zh) * 2016-02-15 2018-11-23 赛诺菲 作为雌激素受体调节剂的6,7-二氢-5h-苯并[7]轮烯衍生物
US11149031B2 (en) 2016-11-17 2021-10-19 Sanofi Substituted N-(3-fluoropropyl)-pyrrolidine compounds, processes for their preparation and therapeutic uses thereof
US11260057B2 (en) 2017-07-24 2022-03-01 Sanofi Combination comprising palbociclib and 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7] annulene-2-carboxylic acid and its use for the treatment of cancer
US11713296B2 (en) 2018-09-07 2023-08-01 Sanofi Salts of methyl 6-(2,4-dichlorophenyl)-5-[4-[(3S)-l-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylate and preparation process thereof
US12427142B2 (en) 2020-02-27 2025-09-30 Sanofi Combination comprising alpelisib and 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl[oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid

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US5792777A (en) * 1991-10-30 1998-08-11 Zeneca Limited Biphenyl quinuclidines
US5770608A (en) * 1991-12-23 1998-06-23 Imperial Chemical Industries Plc Heterocyclic derivatives
WO1993013096A1 (fr) * 1991-12-23 1993-07-08 Imperial Chemical Industries Plc Derives de la quinuclidine utilises comme inhibiteurs de la squalene synthase
US5654315A (en) * 1991-12-23 1997-08-05 Imperial Chemical Industries Plc Quinuclidine compounds useful in treating diseases
WO1993015073A1 (fr) * 1992-01-28 1993-08-05 Smithkline Beecham Plc Composes azabicycliques servant d'antagonistes des canaux calciques
US5885979A (en) * 1992-04-02 1999-03-23 Takeda Chemical Industries, Ltd. N-containing condensed heterocyclic compounds, their production, and their uses
US5612352A (en) * 1992-04-10 1997-03-18 Zeneca Limited Heterocyclic compounds
WO1993021184A1 (fr) * 1992-04-10 1993-10-28 Zeneca Limited Derives de biphenylylquinuclidine utilises comme inhibiteurs de la squalene syntase
WO1993021183A1 (fr) * 1992-04-10 1993-10-28 Zeneca Limited Derives de quinuclidine utiles comme inhibiteurs de squalene synthase
EP0567026A1 (fr) * 1992-04-20 1993-10-27 Takeda Chemical Industries, Ltd. Dérivés de 4,1-benzoxazepine comme inhibiteurs de la synthétase du squalène et leur application dans le traitement d'hypercholesteremie et comme fongicides
US5554613A (en) * 1992-06-04 1996-09-10 Zeneca Limited Heterocyclic derivatives
US5691349A (en) * 1992-08-06 1997-11-25 Zeneca Limited Quinclidine derivatives as squalene synthase inhibitors
WO1994003451A1 (fr) * 1992-08-06 1994-02-17 Zeneca Limited Derives de la quinuclidine utilises comme inhibiteurs de la squalene synthetase
WO1994005660A1 (fr) * 1992-08-28 1994-03-17 Zeneca Limited Derives de la quinuclidine utilises comme inhibiteurs de la squalene synthetase
US5714496A (en) * 1992-08-28 1998-02-03 Zeneca Limited Quinuclidine derivatives as squalene synthase inhibitors
WO1994014805A1 (fr) * 1992-12-21 1994-07-07 Zeneca Limited Derives de la quinuclidine comme inhibiteurs de la squalene synthetase
WO1994014804A1 (fr) * 1992-12-21 1994-07-07 Zeneca Limited Derives de la quinuclidine utilises comme inhibiteurs de la squalene synthetase
WO1994014803A1 (fr) * 1992-12-21 1994-07-07 Zeneca Limited Derives de quinuclidine comme inhibiteurs de la squalene synthetase
US5731323A (en) * 1992-12-21 1998-03-24 Zeneca Limited Quinuclidine derivatives as squalene synthase inhibitors
US5451596A (en) * 1992-12-29 1995-09-19 Rhone Poulenc Rorer Pharmaceuticals Inc. Cycloalkyl amine bis-aryl squalene synthase inhibitors
WO1994014435A1 (fr) * 1992-12-29 1994-07-07 Rhone-Poulenc Rorer Pharmaceuticals Inc. Inhibiteurs de squalene synthase cycloalkylamine bis-aryle
US5488149A (en) * 1993-02-12 1996-01-30 Banyu Pharmaceutical Co., Ltd. Substituted amic acid derivatives
EP0611749A1 (fr) * 1993-02-12 1994-08-24 Banyu Pharmaceutical Co., Ltd. Acides amiques substitués utilisables pour le traitement d'artiosclérosis
US5919793A (en) * 1993-04-29 1999-07-06 Zeneca Limited Heterocyclic derivatives
WO1994025459A1 (fr) * 1993-04-29 1994-11-10 Zeneca Limited Derives heterocycliques
US5677298A (en) * 1993-09-24 1997-10-14 Takeda Chemical Industries Benzoxazepine-2-one compounds and their use
EP0645377A1 (fr) * 1993-09-24 1995-03-29 Takeda Chemical Industries, Ltd. Dérivés de benzoxazépine utiles comme inhibiteurs de squalène-synthétase
EP0645378A1 (fr) * 1993-09-24 1995-03-29 Takeda Chemical Industries, Ltd. Composés hétérocycliques à sept ou huit chaînons condensés utiles comme inhibiteurs de squalène-synthétase
US5698691A (en) * 1993-09-24 1997-12-16 Takeda Chemical Industries, Ltd. Condensed cyclic compounds and their use
WO1995035295A1 (fr) * 1994-06-17 1995-12-28 Zeneca Limited Derives de quinuclidine en tant qu'inhibiteurs de squalene synthase
US5556990A (en) * 1994-12-16 1996-09-17 Rhone-Poulenc Rorer Pharmaceuticals Inc. Polyarylcarbamoylaza- and -carbamoylalkanedioic acids
EP0801644A4 (fr) * 1994-12-16 2001-03-07 Rhone Poulenc Rorer Pharma Acides polyarylcarbamoylazadioques et carbamoylalcanedio ques
US6297198B1 (en) 1996-05-14 2001-10-02 Syngenta Participations Ag Isoxazole derivatives and their use as herbicides
US6903085B1 (en) 1999-08-24 2005-06-07 Astrazeneca, Ab Substituted piperidine compounds useful as modulators of chemokine receptor activity
EP1217001A4 (fr) * 1999-09-28 2002-12-18 Eisai Co Ltd Composes de quinuclidine et medicaments contenant ces composes comme principe actif
US6599917B1 (en) 1999-09-28 2003-07-29 Eisai Co., Ltd. Quinuclidine compounds and drugs containing the same as the active ingredient
US6486172B2 (en) 2000-08-18 2002-11-26 Pharmacia & Upjohn Company Quinuclidine-substituted aryl compounds for treatment of disease
US6492385B2 (en) 2000-08-18 2002-12-10 Pharmacia & Upjohn Company Quinuclidine-substituted heteroaryl moieties for treatment of disease
US6479510B2 (en) 2000-08-18 2002-11-12 Pharmacia & Upjohn Company Quinuclidine-substituted aryl compounds for treatment of disease
US6500840B2 (en) 2000-08-21 2002-12-31 Pharmacia & Upjohn Company Quinuclidine-substituted heteroaryl moieties for treatment of disease
US6599916B2 (en) 2000-08-21 2003-07-29 Pharmacia & Upjohn Company Quinuclidine-substituted heteroaryl moieties for treatment of disease
US6958350B2 (en) 2001-02-19 2005-10-25 Astrazeneca Ab Chemical compounds
US6960602B2 (en) 2001-03-22 2005-11-01 Astrazeneca Ab Piperidine derivatives as modulators of chemokine receptors
US7112593B2 (en) 2001-03-27 2006-09-26 Eisai Co., Ltd. N-aryl-substituted cyclic amine derivative and medicine containing the same as active ingredient
EP1375496A4 (fr) * 2001-03-27 2004-06-16 Eisai Co Ltd Derive d'amine cyclique a substitution n-aryle et medicament contenant ledit derive en tant que principe actif
US6869946B2 (en) 2001-04-19 2005-03-22 Pfizer Inc Substituted azabicyclic moieties for the treatment of disease
US6562816B2 (en) 2001-08-24 2003-05-13 Pharmacia & Upjohn Company Substituted-heteroaryl-7-aza[2.2.1]bicycloheptanes for the treatment of disease
US6919359B2 (en) 2001-11-08 2005-07-19 Pfizer Inc Azabicyclic-substituted-heteroaryl compounds for the treatment of disease
US7192973B2 (en) 2001-11-15 2007-03-20 Astrazeneca Ab Piperidine derivatives and their use as modulators of chemokine receptor activity (especially CCR5)
US6852716B2 (en) 2002-02-15 2005-02-08 Pfizer Inc Substituted-aryl compounds for treatment of disease
US7176198B2 (en) 2002-08-01 2007-02-13 Pfizer Inc. 1H-pyrazole and 1H-pyrrole-azabicyclic compounds for the treatment of disease
US9567343B2 (en) 2002-09-04 2017-02-14 Novartis Ag Aza-bicyloalkyl ethers and their use as alpha7-nachr agonists
US8236803B2 (en) 2002-09-04 2012-08-07 Novartis Ag Aza-bicycloalkyl ethers and their use as alpha7-nAChR agonists
US9012451B2 (en) 2002-09-04 2015-04-21 Novartis Ag Aza-bicycloalkyl ethers and their use as ALPHA7-nachr agonists
US7579362B2 (en) 2002-09-04 2009-08-25 Novartis Ag Aza-bicycloalkyl ethers and their use as alpha7-nAChR agonists
US9849117B2 (en) 2002-09-04 2017-12-26 Novartis Ag Aza-bicycloalkyl ethers and their use as alpha7-nachr agonists
US7294636B2 (en) 2003-05-09 2007-11-13 Astrazeneca Ab Chemical compounds
US7655657B2 (en) 2003-12-22 2010-02-02 Abbott Laboratories Fused bicycloheterocycle substituted quinuclidine derivatives
US7674794B2 (en) 2003-12-22 2010-03-09 Abbott Laboratories Fused bicycloheterocycle substituted quinuclidine derivatives
EP2308875A1 (fr) * 2003-12-22 2011-04-13 Abbott Laboratories Dérivés polycycliques de quinuclidine substitués par un bicyclohétérocycle condensé comme modulateurs d'.alpha.7 nAChR
US7160876B2 (en) 2003-12-22 2007-01-09 Abbott Laboratories Fused bicycloheterocycle substituted quinuclidine derivatives
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US9475811B2 (en) 2004-06-18 2016-10-25 Novartis Ag 1-aza-bicyclo[3.3.1]nonanes
US8609662B2 (en) 2004-07-14 2013-12-17 Novartis Ag 3-(heteroaryl-oxy)-2-alkyl-1-aza-bicycloalkyl derivatives as alpha. 7-nachr ligands for the treatment of CNS diseases
US7973069B2 (en) 2004-07-14 2011-07-05 Ptc Therapeutics, Inc. Methods for treating hepatitis C
US9657010B2 (en) 2004-07-14 2017-05-23 Novartis Ag Substituted quinuclidines as alpha 7-nicotinic acetylcholine receptor activity modulators
WO2006065233A1 (fr) * 2004-12-10 2006-06-22 Abbott Laboratories Dérivés polycycliques de quinuclidine substitués par un bicyclohétérocycle condensé
US8236953B2 (en) 2004-12-29 2012-08-07 Glaxo Group Limited Process for preparing piper azine derivatives
US7297704B2 (en) 2005-02-17 2007-11-20 Wyeth Cycloalkyfused indole, benzothiophene, benzofuran and idene derivatives
WO2007018738A3 (fr) * 2005-06-15 2007-03-29 Abbott Lab Derives de quinuclidine substitues par un bicycloheterocycle substitues condense
US8173667B2 (en) 2005-10-21 2012-05-08 Novartis Ag 1-aza-bicycloalkyl derivatives
US8048885B2 (en) 2005-12-16 2011-11-01 Novartis Ag Organic compounds
US8637517B2 (en) 2005-12-16 2014-01-28 Novartis Ag Organic compounds
US8759346B2 (en) 2005-12-16 2014-06-24 Novartis Ag Organic compounds
US9206181B2 (en) 2005-12-16 2015-12-08 Novartis Ag 1-aza-bicyclo[3.3.1] non-4-yl)-[5-(1H-indol-5-yl)-heteroaryl]-amines as cholinergic ligands of the n-AChR for the treatment of psychotic and neurodegenerative disorders
US8012981B2 (en) 2006-06-15 2011-09-06 Glaxo Group Limited Benzylpiperazine derivatives as motilin receptor agonists
US8987453B2 (en) 2006-11-06 2015-03-24 Abbvie Inc. Azaadamantane derivatives and methods of use
US8314119B2 (en) 2006-11-06 2012-11-20 Abbvie Inc. Azaadamantane derivatives and methods of use
US9464078B2 (en) 2010-09-23 2016-10-11 Abbvie Inc. Monohydrate of azaadamantane derivatives
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US12157721B2 (en) 2018-09-07 2024-12-03 Sanofi Process for the preparation of methyl 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylate
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AU1752792A (en) 1992-10-06
JPH06506467A (ja) 1994-07-21
MX9201030A (es) 1992-09-01

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