EP0590094A1 - 4-aryl-3-(heteroarylureido)quinoline derivatives - Google Patents

4-aryl-3-(heteroarylureido)quinoline derivatives

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Publication number
EP0590094A1
EP0590094A1 EP92923349A EP92923349A EP0590094A1 EP 0590094 A1 EP0590094 A1 EP 0590094A1 EP 92923349 A EP92923349 A EP 92923349A EP 92923349 A EP92923349 A EP 92923349A EP 0590094 A1 EP0590094 A1 EP 0590094A1
Authority
EP
European Patent Office
Prior art keywords
ureido
chlorophenyl
bis
quinoline
methylthio
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP92923349A
Other languages
German (de)
English (en)
French (fr)
Inventor
Ernest S. Hamanaka
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pfizer Corp Belgium
Pfizer Corp SRL
Pfizer Inc
Original Assignee
Pfizer Corp Belgium
Pfizer Corp SRL
Pfizer Inc
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.)
Filing date
Publication date
Application filed by Pfizer Corp Belgium, Pfizer Corp SRL, Pfizer Inc filed Critical Pfizer Corp Belgium
Publication of EP0590094A1 publication Critical patent/EP0590094A1/en
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • 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
    • 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
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/36—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to new 4-aryl-3- (heteroarylureido)guinoline derivatives, pharmaceutical compositions comprising such compounds, novel 3- nitroguinoline intermediates used in the synthesis of such compounds and the use of such compounds to inhibit intestinal absorption of cholesterol, lower serum cholesterol and reverse the development of atherosclerosis.
  • the compounds are inhibitors of acyl coenzyme A: cholesterol acyltransferase (ACAT).
  • Cholesterol that is consumed in the diet (dietary cholesterol) is absorbed as free cholesterol by the mucosal cells of the small intestine. It is then esterified by the enzyme ACAT, packaged into particles known as chylomicrons, and released into the bloodstream. Chylomicrons are particles into which dietary cholesterol is packaged and transported in the bloodstream.
  • ACAT enzyme-activated Cholesterol that is consumed in the diet
  • Chylomicrons are particles into which dietary cholesterol is packaged and transported in the bloodstream.
  • the compounds of the present invention By inhibiting the action of ACAT, the compounds of the present invention also enable cholesterol to be removed from the walls of blood vessels. This activity renders such compounds useful in slowing or reversing the development of atherosclerosis as well as in preventing heart attacks and strokes.
  • Certain ureas and thioureas as antiatherosclerosis agents are referred to in United States Patent 4,623,662 and in the European Patent Applications having publication numbers 0 335 374, 0 386 487, 0 370 740, 0 405 233 and 0 421 456.
  • the present invention relates to compounds of the formula
  • each m is independently selected from 0 to 4.
  • R 1 is selected from hydrogen, (C 1 -C 6 ) alkyl, (C 6 -C 12 ) aralkyl wherein the aryl moiety is selected from phenyl, thienyl, furyl, and pyridinyl;
  • R 2 is selected from hydrogen, (C 1 -C 6 ) alkyl and (C 1 -C 6 ) alkoxy;
  • Each R 3 and R 4 is independently selected from hydrogen, halogen, (C 1 -C 6 ) alkyl optionally substituted with one or more halogen atoms, (C 1 -C 6 ) alkoxy optionally substituted with one or more halogen atoms, (C 1 -C 6 ) alkylthio optionally substituted with one or more halogen atoms, nitro, carboxyl optionally esterified with a (C 1 -C 6 ) alkyl group, hydroxyl,
  • (C 1 -C 6 ) acyloxy and NR 12 R 13 wherein R 12 and R 13 are the same or different and are selected from the group consisting of hydrogen, (C 1 -C 6 ) alkyl, optionally halogenated (C 1 -C 6 )acyl, optionally halogenated (C 1 -C 6 ) alkylsulfonyl, (C 1 -C 6 ) alkylaminocarbonyl and (C 1 -C 6 )alkoxycarbonyl, or R 12 and R 13 , together with the nitrogen to which they are attached, form a piperidine, pyrrolidine or morpholine ring;
  • X is sulfur or oxygen; and Q is a group of the formula
  • n 0 or 1.
  • Each 1 is independently selected from 0 to 3;
  • Each R 6 and R 7 is independently selected from the group consisting of halogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, optionally halogenated (C 1 -C 6 ) alkoxy, optionally halogenated (C 1 -C 6 ) alkylthio, (C 5 -C 7 ) cycloalkylthio, phenyl (C 1 -C 6 ) alkylthio, substituted phenylthio, heteroarylthio, heteroaryloxy, (C 1 -C 6 ) alkylsulfinyl, (C 1 -C 6 ) alkylsulfonyl, (C 5 -C 7 ) cycloalkylsulfinyl, (C 5 -C 7 ) cycloalkylsulfonyl, phenyl (C 1 -C 6 ) alkylsulfinyl, phenyl
  • B, D, E and G are selected from the group consisting of nitrogen and carbon, with the proviso that one or more of B, D and E is nitrogen, and with the proviso that when G is nitrogen, the group XVI is attached to the nitrogen of formula I at the 4 or 5 position of the pyrimidine ring (designated by a and b) wherein any of said nitrogens may be oxidized;
  • halogen includes fluoro, chloro, bromo and iodo.
  • alkyl may be straight, branched or cyclic, and may include straight and cyclic moieties as well as branched and cyclic moieties.
  • substituents refers to from one to the maximum number of substituents possible based on the number of available bonding sites.
  • the present invention also relates to compounds of the formula
  • Preferred compounds of formula I are those wherein Q is
  • R 1 is hydrogen and R 2 is selected from hydrogen and methoxy and each R 3 and R 4 is selected from (C 1 -C 6 )alkyl, chlorine, fluorine and trifluoromethyl.
  • More preferred compounds of the formula I are those wherein Q is 6-methoxyquinolin-5-yl, 6-methylthioquinolin-5-yl, 6-methoxyisoquinolin-5-yl, 6-methylthioisoquinolin-5-yl, 2-methyl-4,6-bis(methylthio)pyrimidin-5-yl, 6-methyl-2,4-bis(methylthio)pyridin-3-yl, 2,4-bis(ethylthio)pyridin-3-yl, 2,4,6-trimethylpyridin-3-yl, 2,4-dimethoxy-6-methylpyridin-3-yl, 6-(4-methoxyphenylthio)-quinolin-5-yl and 6-pentylthioquinolin-5-yl.
  • the present invention also relates to all radiolabelled forms of the compounds of the formulae I and II, including those comprising tritium and/or carbon-14 ( 14 C).
  • radiolabelled compounds are useful as research and diagnostic tools in metabolism pharmacokinetic studies and in binding assays in both animals and man.
  • the present invention also relates to a pharmaceutical composition for inhibiting ACAT, inhibiting intestinal absorption of cholesterol, reversing or slowing the development of atherosclerosis, or lowering the concentration of serum cholesterol in a mammal, including a human, comprising an amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, effective in inhibiting ACAT, inhibiting intestinal absorption of cholesterol, reversing or slowing the development of atherosclerosis, or lowering the concentration of serum cholesterol, and a pharmaceutically acceptable carrier.
  • the present invention also relates to a method for inhibiting ACAT, inhibiting intestinal absorption of cholesterol, reversing or slowing the development of atherosclerosis, or lowering the concentration of serum cholesterol in a mammal, including a human, comprising administering to a mammal an amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, effective in inhibiting ACAT, inhibiting intestinal absorption of cholesterol, reversing or slowing the development of atherosclerosis, or lowering the concentration of serum cholesterol.
  • Examples of pharmaceutically acceptable acid addition salts of the compounds of formula I are the salts of hydrochloric acid, p-toluenesulfonic acid, fumaric acid, citric acid, succinic acid, salicyclic acid, oxalic acid, hydrobromic acid, phosphoric acid, methanesulfonic acid, tartaric acid, di-p-toluoyl tartaric acid, and mandelic acid.
  • Reaction schemes 1-3 below illustrate the synthesis of the compounds of this invention. Except where otherwise stated, R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 10 , R 11 , R 12 , R 13 , Q, X, B, D, E, G, l, m and n in the reaction schemes and discussion that follows are defined as above.
  • Scheme 1 illustrates the preparation of compounds of the formula I wherein R 1 is hydrogen.
  • the starting material of formula III which may be prepared by procedures referred to in Synthesis. 677 (1980)
  • This reaction is generally carried out in an inert solvent such as acetic acid, propionic acid or polyphosphoric acid at a temperature from about 100°C to about 160°C for about 2 to 24 hours. It is preferably carried out in acetic acid at about 120°C for about 16 hours.
  • the compound of formula II formed in the foregoing reaction is then reduced to form the corresponding compound of formula V.
  • the reduction and desulfurization is carried out in one step using an excess of Raney nickel in a suitable inert solvent such as ethanol, methanol, dioxane, acetone, tetrahydrofuran or dimethylformamide, with or without the addition of water.
  • a suitable inert solvent such as ethanol, methanol, dioxane, acetone, tetrahydrofuran or dimethylformamide, with or without the addition of water.
  • This reaction is usually carried out for about 1 to 8 hours.
  • the reaction temperature may range from about 20°C to about 100°C.
  • the compound of formula II is reduced and desulfurized in the presence of excess Raney nickel in ethanol at about 80°C for about 2 to 3 hours.
  • the compound of formula V may be prepared from the corresponding compound of formula II in a two step procedure wherein the compound of formula II is first reduced to the corresponding amino derivative which is then, in the second step, desulfurized to the compound of formula V.
  • Suitable reducing agents for the first step include stannous chloride, titanium (III) chloride, iron or zinc, with or without an acid catalyst (e.g., hydrochloric or acetic acid), or hydrogen gas with an appropriate catalyst, for about 2 to 16 hours at a temperature of about 0°C to about 100°C.
  • the desulfurization is carried out using an excess of Raney nickel as described above.
  • the reductive desulfurization of compounds of the formula II may also be carried out using a copper-aluminum alloy as described in Helv. Chem. Acta. 71, 531 (1988) or using nickel boride as described in J. Chem. Soc. Chem. Commun., 819 (1990) and J. Chem. Soc. (C), 1122 (1968).
  • an appropriate reagent such as phosgene, trichloromethyl chloroformate or bis(trichloromethyl) carbonate.
  • the reaction is generally carried out in an inert ether, aromatic hydrocarbon or chlorinated hydrocarbon solvent such as dioxane, diisopropyl ether, benzene, toluene, dichloromethane or chloroform. It may be conducted in the presence of a base such as a tertiary amine (e.g., pyridine, triethylamine or quinoline).
  • a base such as a tertiary amine (e.g., pyridine, triethylamine or quinoline).
  • Reaction temperatures may range from about 0°C to about 120°C, and are preferably from about 20°C to about 100°C.
  • the heterocyclic amine of formula QNH 2 is reacted with 1 to 2 equivalents of trichloromethyl chloroformate in refluxing dichloromethane for about 18 hours.
  • anhydrous solvent such as chloroform, benzene, dimethylformamide, dioxane or tetrahydrofuran
  • the R 1 substituent is added to the compound of formula VI by reacting it with a compound of the formula R 1 Z wherein Z is a leaving group.
  • Appropriate leaving groups include halogen, (C 1 -C 6 ) alkanesulfonyloxy groups (e.g., methanesulfonyloxy, ethanesulfonyloxy, etc.) and (C 6 -C 10 ) arylsulfonyloxy groups (e.g., benzenesulfonyloxy, ptoluenesulfonyloxy, etc.).
  • Suitable solvents for this reaction include inert solvents such as tetrahydrofuran (THF), dimethoxyethane (DME), and N,N-dimethylformamide.
  • THF tetrahydrofuran
  • DME dimethoxyethane
  • N,N-dimethylformamide N,N-dimethylformamide.
  • the reaction is accelerated in the presence of a base such as sodium hydride, sodium methylate, sodium ethylate, sodium amide or potassium t-butoxide.
  • the reaction is usually carried out at a temperature from about 20°C to about 120°C, and is preferably carried out at a temperature about 0°C to about 100°C.
  • the preferred solvent is dimethylformamide and the preferred base is sodium hydride.
  • Hydrolysis of the resulting amide of formula VII yields the corresponding amine of formula VIII.
  • the hydrolysis reaction is usually conducted in a protic solvent such as a lower alcohol (e.g. methanol, ethanol, or propanol) or acetic acid. It is preferably conducted in the presence of a mineral acid (e.g. hydrochloric acid, hydrobromic acid or sulfuric acid) in an amount of about 2 to 20 moles (preferably about 3 to 15 moles) per mole of compound of formula VII.
  • the reaction temperature may range from about 60°C to about 120°C. It is preferably between about 70°C and 100°C.
  • compounds of the formula VIII wherein R 1 is other than hydrogen may be prepared by acylating the corresponding compound of formula V with an appropriate acylating agent such as R 15 COCl or [R 15 CO] 2 O, wherein R 15 is the same as R 1 except that it contains one less methylene group than R 1 , according to the method described in United States Patent No. 3,798,226, and then reducing the resulting amide to the desired compound of formula VIII using an appropriate reducing agent such as lithium aluminum hydride, sodium bis(2-methoxyethoxy) aluminum hydride or diborane.
  • the reduction is generally carried out in an inert solvent such as tetrahydrofuran, dioxane or dimethoxyethane at a temperature from about 25°C to about 110°C.
  • the compound of formula VIII may be converted into the desired corresponding compound of formula I-B by the method described above and illustrated in scheme 1 for preparing compounds of the formula I-A from compounds of the formula
  • aminopyrimidine and aminopyridine intermediates used in the present invention are known in the literature or may be prepared by methods known in the art from various pyrimidine and pyridine intermediates that are known in the literature or commercially available.
  • the pyrimidine and pyridine intermediates that are commercially available include 4,6- dichloro-5-nitropyrimidine, 2,4-dihydroxy-6- methylpyrimidine, 4,6-dihydroxy-2-methylpyrimidine, 5- nitrobarbituric acid, 2-hydroxy-4-methyl-3-nitropyridine and 2,3-dihydroxypyridine.
  • 4,6-Disubstituted-5-aminopyrimidine derivatives may be prepared by reacting the appropriately substituted 4,6-dihydroxypyrimidine with a nitrating agent such as fuming nitric acid in acetic acid at a temperature from about 15°C to about 40°C for a period of about 1 to about 5 hours.
  • a nitrating agent such as fuming nitric acid in acetic acid
  • the resulting 5-nitropyrimidines may be converted to the 4,6-dichloro-5-nitropyrimidine intermediates using a chlorinating agent such as phosphoryl chloride, alone or in the presence of a base, preferably diethylaniline, at a temperature from about 100 to about 115°C for a period of about 0.5 to about 2 hours.
  • 4,6-bis(alkylthio)-5-nitropyrimidine derivatives may be prepared by reacting the appropriate dichloro intermediate with two equivalents of sodium alkylthiolate in a solvent such as dimethylformamide or methanol, preferably methanol, for about 4 to about 16 hours at a temperature from about 0°C to about 30°C, preferably at ambient temperature.
  • a solvent such as dimethylformamide or methanol, preferably methanol
  • Monosubstitution of the 4,6-dichloro-5-nitropyrimidine intermediates is accomplished by reacting them with one equivalent of nucleophile at a reaction temperature from about 0°C to about 100°C (depending on the reactivity of the nucleophile) in an inert solvent such as dimethylformamide or tetrahydrofuran for a period of about 4 to about 16 hours.
  • the resulting monochloro derivative is then reacted with one equivalent of a different nucleophile to yield a disubstituted derivative with different substitutents on the carbon atoms at positions 4 and 6 of the pyrimidine ring.
  • Reduction of the 4,6-disubstituted-5-nitropyrimidines using a reducing agent such as stannous chloride in concentrated hydrochloric acid or hydrogen gas with an appropriate catalyst yields the corresponding 5-aminopyrimidine derivatives.
  • 2,4-Disubstituted-3-aminopyridine derivatives may be prepared by reacting the appropriate 2,4-dihydroxypyridines with a nitrating agent such as concentrated nitric acid at a temperature from about 80°C to about 100°C for about 15 to 60 minutes.
  • a nitrating agent such as concentrated nitric acid
  • the resulting 2,4-dihydroxy-3-nitro-pyridines are sequentially converted to the 2,4-dichloro-3-nitropyridines, 2,4-disubstituted-3-nitro-pyridines and 2,4-disubstituted-3-aminopyridines using reaction conditions similar to those described above for the pyrimidine series.
  • appropriately substituted monohydroxypyrimidines and pyridines may be converted sequentially to nitro monohydroxy derivatives and nitro monochloro derivatives.
  • the nitro monochloro intermediates are then reacted with the appropriate sulfur, oxygen or nitrogen nucleophiles to yield oxygen, sulfur or nitrogen substituted nitro derivatives which may be reduced to the desired aminopyrimidines or pyridines.
  • 5-aminoquinolines and isoquinolines of the formulae XV and XVII may be prepared as follows.
  • a quinoline or isoquinoline of the formula IX is nitrated at the 5 position, respectively, by reacting it with a nitrating agent such as nitric acid or potassium nitrate with or without an acid catalyst such as sulfuric acid, for from about 2 to 16 hours at a temperature from about 0-100°C.
  • the nitro compound of formula X so formed is then reduced using a reducing agent such as stannous chloride, iron, zinc, or hydrogen gas with an appropriate catalyst, with or without an acid catalyst such as hydrochloric acid, for from about 2 to 16 hours at a temperature from about 0-100°C, to yield the corresponding 5-aminoquinoline or 5-aminoisoquinoline of formula XI.
  • a reducing agent such as stannous chloride, iron, zinc, or hydrogen gas
  • an appropriate catalyst with or without an acid catalyst such as hydrochloric acid
  • This reaction yields a compound of the formula XII, which is then converted to the corresponding 5-aminoquinoline or isoquinoline of the formula XIII by the method described above for reduction of compounds of formula X.
  • novel compounds of formula I and the pharmaceutically acceptable salts thereof are useful as inhibitors of acyl coenzyme A: cholesterol acyltransferase (ACAT). As such they inhibit intestinal absorption of cholesterol in mammals and are useful in the treatment of high serum cholesterol in mammals, including humans. As used herein, treatment is meant to include both the prevention and alleviation of high serum cholesterol.
  • the compound may be administered to a subject in need of treatment by a variety of conventional routes of administration, including orally, parenterally and topically. In general, these compounds will be administered orally or parenterally at dosages between about 0.5 and about 30 mg/kg body weight of the subject to be treated per day, preferably from about 0.8 to 5 mg/kg.
  • the usual dosage would, therefore, be about 3.5 to about 2000 mg per day.
  • some variation in dosage will necessarily occur depending on the condition of the subject being treated and the activity of the compound being employed.
  • the person responsible for administration will, in any event, determine the appropriate dose for the individual subject.
  • a compound of formula I or a pharmaceutically acceptable salt thereof may be administered alone or in combination with pharmaceutically acceptable carriers, in either single or multiple doses.
  • suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solution and various organic solvents.
  • the resulting pharmaceutical compositions are then readily administered in a variety of dosage forms such as tablets, powders, lozenges, syrups, injectable solutions and the like.
  • These pharmaceutical compositions can, if desired, contain additional ingredients such as flavorings, binders, excipients and the like.
  • tablets containing various excipients such as sodium citrate, calcium carbonate and calcium phosphate may be employed along with various disintegrants such as starch, alginic acid and certain complex silicates, together with binding agents such as polyvinylpyrrolidone, sucrose, gelatin and acacia.
  • binding agents such as polyvinylpyrrolidone, sucrose, gelatin and acacia.
  • lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tabletting purposes.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard filled gelatin capsules. Preferred materials for this include lactose or milk sugar and high molecular weight polyethylene glycols.
  • the essential active ingredient therein may be combined with various sweetening or flavoring agents, coloring matter or dyes and, if desired, emulsifying or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin and combinations thereof.
  • solutions of a compound of formula I or a pharmaceutically acceptable salt thereof in sesame or peanut oil, aqueous propylene glycol, or in sterile aqueous solution may be employed.
  • aqueous solutions should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose.
  • Such solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitioneal administration.
  • the sterile aqueous media employed are all readily available by standard techniques known to those skilled in the art.
  • the activity of the compounds of the present invention as ACAT inhibitors may be determined by a number of standard biological or pharmacological tests. For example, the following procedure was used to determine the ACAT inhibiting activity of compounds of formula I. ACAT was assayed in microsomes isolated from chow fed Sprague-Dawley rats according to Bilheimer, J.T., Meth. Enzymol., 111, ps 286-293 (1985), with minor modifications. Microsomes from rat liver were prepared by differential centrifugation and washed with assay buffer prior to use.
  • the assay mixture was incubated for 30 min at 37°C.
  • the reaction was started by the addition of 20 ul of 14°C-Oleoyl-CoA (1000 uM, 2,000 dpm/nmol) and run for 15 min at 37°C.
  • the activity of the compounds of formula I in inhibiting intestinal absorption of cholesterol may be determined by the procedure of Melchoir and Harwell, J. Lipid. Res., 26, 306-315 (1985).
  • 6-methoxyquinoline 13.80 g was nitrated according to the procedure of Campbell, et. al. (J. Am. Chem. Soc, 1946, 68, 1559) to give 5-nitro-6-methoxyquinoline (17.51 g). This crude product was directly reduced according to the procedure of Jacobs, et. al. (J. Am. Chem. Soc, 1920, 42, 2278) to give 5-amino-6-methoxyquinoline (6.25 g). M.p. 152.5-154.5°C.
  • 6-chloroquinoline (33.3 g) was nitrated according to the procedure described in Example 1 to give 5-nitro-6-chloroquinoline (20.36 g).
  • This material (15 g) was allowed to react with sodium methylthiolate according to the procedure of Massie (Iowa State Coll. J. Sci. 1946, 21, 41; CA 41:3044 g) to give 5-nitro-6-methylthioquinoline (13.61 g).
  • This material (3. 0 g) was reduced using iron (5.62 g) and hydrochloric acid (1.5 ml) in 50% aqueous ethanol (50 ml) to give 5-amino-6-methylthioquinoline (3.0 g). M.p. 88.5-90.5°C.
  • 1,4-dioxane and 300 ml methanol was shaken with hydrogen (15 psi) in a Parr hydrogenation apparatus for 3.5 hours.
  • the catalyst was filtered and the filtrate was concentrated to dryness in vacuo.
  • the solid residue was chromatographed on silica gel (650g), eluting with 9:1 hexane/ethyl acetate to yield 14.0g. (85% yield) of the title compound as an off white solid.

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EP92923349A 1991-04-26 1992-03-16 4-aryl-3-(heteroarylureido)quinoline derivatives Withdrawn EP0590094A1 (en)

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US69232391A 1991-04-26 1991-04-26
US692323 1991-04-26
PCT/US1992/001801 WO1992019614A1 (en) 1991-04-26 1992-03-16 4-aryl-3-(heteroarylureido)quinoline derivatives

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TW197436B (OSRAM) 1993-01-01
NZ242493A (en) 1994-08-26
HUT65748A (en) 1994-07-28
MX9201916A (es) 1992-11-01
CA2108014A1 (en) 1992-10-27
NO933837L (no) 1993-10-25
CZ395592A3 (en) 1994-02-16
JPH06501025A (ja) 1994-01-27
BR9205939A (pt) 1994-09-27
IL101627A0 (en) 1992-12-30
YU44592A (sh) 1994-12-28
FI934710L (fi) 1993-10-25
ZA922976B (en) 1993-10-25
AU1879792A (en) 1992-12-21
PT100426A (pt) 1993-08-31
FI934710A0 (fi) 1993-10-25
HU9303025D0 (en) 1994-01-28
WO1992019614A1 (en) 1992-11-12
JPH0776215B2 (ja) 1995-08-16
CN1066068A (zh) 1992-11-11
FI934710A7 (fi) 1993-10-25
IE921330A1 (en) 1992-11-04

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