WO1998002412A1 - Derives de propionanilide ou sels de ceux-ci - Google Patents

Derives de propionanilide ou sels de ceux-ci Download PDF

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Publication number
WO1998002412A1
WO1998002412A1 PCT/JP1997/002385 JP9702385W WO9802412A1 WO 1998002412 A1 WO1998002412 A1 WO 1998002412A1 JP 9702385 W JP9702385 W JP 9702385W WO 9802412 A1 WO9802412 A1 WO 9802412A1
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Prior art keywords
group
propionamide
amino
substituted
pharmaceutically acceptable
Prior art date
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PCT/JP1997/002385
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English (en)
Japanese (ja)
Inventor
Akira Suga
Koyo Matsuda
Hiromi Miyauchi
Osamu Inagaki
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Yamanouchi Pharmaceutical Co., Ltd.
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Priority to AU34586/97A priority Critical patent/AU3458697A/en
Publication of WO1998002412A1 publication Critical patent/WO1998002412A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/63—Esters of sulfonic acids
    • C07C309/72—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C309/73—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton to carbon atoms of non-condensed six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
    • C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C311/03—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atoms of the sulfonamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C311/06—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atoms of the sulfonamide groups bound to hydrogen atoms or to acyclic carbon atoms to acyclic carbon atoms of hydrocarbon radicals substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
    • C07C311/12—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing rings
    • C07C311/13—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing rings the carbon skeleton containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
    • C07C311/19—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/22—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms
    • C07C311/29—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/45—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups at least one of the singly-bound nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfonamides
    • C07C311/46—Y being a hydrogen or a carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/58—Radicals substituted by nitrogen atoms

Definitions

  • the present invention relates to a pharmaceutical, in particular, an ACAT (acyl CoA cholesterol acyltransferase) inhibitory action, in particular, an action of inhibiting macrophage ACAT, an action of suppressing foaming in macrophage, and an action of lowering blood cholesterol.
  • ACAT acyl CoA cholesterol acyltransferase
  • a pharmaceutical composition comprising the propionanilide derivative or a salt thereof and a pharmaceutically acceptable carrier, particularly an ACAT inhibitor, a macrophage ACAT inhibitor, a macrophage foaming inhibitor, a blood cholesterol inhibitor,
  • the present invention relates to a pharmaceutical composition useful as a drug for reducing or reducing cholesterol, an activator of the reverse cholesterol transfer system, a drug for preventing or treating arteriosclerosis, or a drug for preventing or treating various diseases caused by arteriosclerosis.
  • Atherosclerosis is the basis of this problem and is closely related to the pharmacokinetics of cholesterol.
  • Cholesterol ingested from food is absorbed from the small intestine or is biosynthesized in the liver. These cholesterol circulates in the blood, is taken up by peripheral cells and is used as energy, and excess cholesterol is accumulated in the cells and causes arteriosclerosis.
  • ACAT Ancinole CoA cholesterol acyltransferase
  • ACAT is mainly present in organs such as the small intestine and liver, and macrophages, and is known to catalyze the esterification of cholesterol to cholesterol esters (J. Lipid Res. 26, 647). -670 (1985)).
  • ACAT in macrophages is thought to be involved in the reverse cholesterol transfer system.
  • the reverse cholesterol transfer system is a mechanism in which excess cholesterol in peripheral cells is extracted by HDL, transferred to the liver, and excreted as bile acids.
  • the thioacetamide derivative is described in WO92 / 09572 (hereinafter abbreviated as Document 2), the alkylperrea compound is a cyclopentyl compound in JP-A-5-208948, and the substituted pyridine derivative is described in JP-A-5-320143.
  • Azaindole compounds are disclosed in Kaihei 6-1788, and pyrimidine and pyridine derivatives are disclosed in JP-A-7-101940.
  • Japanese Patent Application Laid-Open No. 6-48942 discloses a benzimidazole derivative as a compound that suppresses macrophage foaming.
  • JP-A-3-220164 discloses a lower alkanoanilide derivative substituted with a disubstituted carbamoyl group as a compound having an ACAT inhibitory action and suppressing intestinal absorption and reabsorption of cholesterol. It has been disclosed. However, these compounds have not been reported to inhibit macrophage ACAT. Nor to suppress the foaming of macula phage. Disclosure of the invention
  • the present inventors have conducted intensive studies on a compound having a macrophage ACAT inhibitory action, which suppresses foaming of macrophages, and as a result, a novel disubstituted compound not described in any of the above prior art documents was found. It has been found that propionanilide derivatives substituted with an amino group are compounds having excellent macrophage ACAT inhibitory activity, macrophage foaming inhibitory activity and blood cholesterol lowering activity, and are highly useful as pharmaceuticals. The present invention has been completed based on these findings.
  • a ring group A nitrogen atom, oxygen atom or sulfur atom which may be condensed with cyclopentane, dioxol or dioxane and which may be substituted or aryl group, or which may be substituted 5- or 6-membered heterocyclic group having 1 to 3 heteroatoms selected from
  • R 1 and R 2 are the same or different and are lower alkyl groups
  • R ° hydrogen atom or lower alkyl group
  • n 0, 1 or 2
  • R 4 Condensed with an alkyl group, an aralkyl group, a carboxyl group, a lower alkoxycarbonyl group, a cycloalkyl group, an optionally substituted pyridyl group, cyclopentane, thiadiazole, dioxol or dioxane.
  • R u hydrogen atom or aryl group which may be substituted
  • R 6 imidazolyl group which may be condensed with benzene ⁇ and may be substituted
  • R 7 and R 8 are the same or different and are a hydrogen atom, a lower alkyl group, an optionally substituted aryl group, an aralkyl group, or
  • a 5- or 6-membered nitrogen-containing saturated or unsaturated heterocyclic group which may contain one heteroatom selected from nitrogen, oxygen or sulfur as another heteroatom
  • the nitrogen-containing saturated or unsaturated heterocyclic group may be substituted and is substituted with a substituted or unsubstituted benzene ring. May be combined.
  • the compound (I) of the present invention always has the formula at position 3 of the propionanilide skeleton.
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the propionanilide derivative or a salt thereof and a pharmaceutically acceptable carrier.
  • ACAT inhibitor, macrophage ACAT inhibitor, macrophage foaming inhibitor, cholesterol lowering agent in blood, activator of cholesterol reverse transfer system, prophylactic or therapeutic agent for arteriosclerosis, or caused by arteriosclerosis The present invention relates to a pharmaceutical composition useful as an agent for preventing or treating various diseases.
  • the ring A may have 1 to 3 substituents, and preferred substituents are a lower alkyl group, a lower alkoxy group, a halogen atom, a phenyl group, a lower alkylene group, and a lower alkylene dioxy group. Examples include a quin group, a nitro group, an amino group, and a mono- or di-lower alkylamino group.
  • the aryl group of R 4 , R 5 , R 7 and R ° may have 1 to 3 substituents, and preferred substituents are lower alkyl, lower alkenyl, lower alkoxy, lower alkoxy and lower alkoxy.
  • the heterocyclic group in which R 7 and R 8 are in the form may have 1 to 3 substituents.
  • Preferred substituents are a lower alkyl group, a lower alkoxycarbonyl group and a carboxyl group.
  • lower means a straight or branched carbon chain having 1 to 6 carbon atoms.
  • the “lower alkyl group” is preferably a straight-chain or branched lower alkyl group having 1 to 6 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl and the like.
  • alkyl group is preferably a straight-chain or branched one having 1 to 20 carbon atoms. Specifically, in addition to the specific examples of the above “lower alkyl group”, heptyl, octyl, nonyl Decyl, pendecyl, dodecyl, dodecyl, tridecyl, tetradecyl, pencil decyl, hexadecyl, hepcil decyl, octadecyl, nonadecyl, aicosyl and the like.
  • the “lower alkenyl group” is preferably a straight-chain or branched lower alkenyl group having 2 to 6 carbon atoms, for example, vinyl, aryl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3 —Butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, methallyl, 1,1-dimethylaryl And a lower alkenyl group having 2 to 4 carbon atoms is particularly preferable.
  • an alkylene group having 1 to 6 carbon atoms is preferable, and specific examples include methylene, ethylene, methylmethylene, trimethylene, propylene, tetramethylene, pentamethylene, and hexamethylene. No. Preferably, it is an alkylene group having 1 to 3 carbon atoms, and preferably cow, methylene and ethylene.
  • the “lower alkenylene group” is preferably a straight-chain or branched lower alkenylene group having 2 to 6 carbon atoms, for example, vinylene, 1-propenylene, 2-propenylene, 1-butenylene, 2-butenylene, 3 —Butenylene, and 111-methylpropenylene.
  • the "lower alkynylene group” is preferably a straight-chain or branched lower alkynylene group having 2 to 6 carbon atoms, such as ethynylene, 1-propynylene, and petinylene, and more preferably 2 to 4 carbon atoms. Is a lower alkynylene group.
  • a hydrogen atom at any position is an aryl group, a lower alkyl group, a lower alkoxy group, a hydroxyl group, a halogen atom (each of which is preferable). Specific examples thereof include those described above and below.) And the like.
  • the lower alkyl group of the “lower alkoxy group” is preferably the above lower alkyl group having 1 to 6 carbon atoms.
  • Examples of the lower alkoxy group include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and tert-butyl. Examples thereof include butoxy, pentyloxy, and hexyloxy, and a lower alkoxy group having 1 to 3 carbon atoms is particularly preferable.
  • the lower alkyl group of the “lower alkoxycarbonyl group” is preferably a lower alkyl group having 1 to 6 carbon atoms.
  • Examples of the lower alkoxycarbonyl group include methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, etc., and more preferably a lower alkyloxy group having 1 to 3 carbon atoms.
  • the “lower alminylamino group” is preferably a lower alminolylamino group having 1 to 6 carbon atoms, specifically, formylamino, acetamino, propioamino, ptyrylamino, Valeryl amino, bivaloylamino, and the like, and more preferably a lower alkyl group having 1 to 4 carbon atoms. It is an amino group.
  • “Mono or di-lower alkylamino group” means a group in which one or two hydrogen atoms of an amino group are substituted by the above-mentioned “lower alkyl group”.
  • examples of the “mono-lower alkylamino group” include methylamino, ethylamino, n-propylamino, n-butylamino, tert-butylamino, and n-pentylamino. , N-hexylamino and the like.
  • di-lower alkylamino group examples include dimethylamino, getylamino, methylethylamino, di- (n-propyl) amino, di- (n-butyl) amino and the like.
  • a mono- or di-lower alkylamino group substituted with a lower alkyl group having 1 to 3 carbon atoms is preferred.
  • cycloalkyl group is preferably a 3- to 7-membered alicyclic hydrocarbon group having 3 to 10 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl. , Norbornyl, adamantyl and the like, and a cycloalkyl group having 5 to 7 carbon atoms is preferable.
  • the “aryl group” is preferably an aromatic hydrocarbon group having 6 to 12 carbon atoms, for example, phenyl, mono-naphthyl, ⁇ -naphthyl, biphenyl and the like. Further, those having 6 to 10 carbon atoms are preferable, and phenyl and naphthyl are particularly preferable.
  • the “ring group” indicates an “aryl group condensed with cyclopentane, dioxol or dioxane”
  • R 4 indicates “an aryl group condensed with cyclopentene, thiadiazole, dioxol or dioxane.
  • the “aryl group” constituting each group of the “condensed aryl group” is also preferably the above, and a preferred specific example of the “condensed aryl group” is indanyl 2,3—dihydro-1H—cyclopentanaphthyl, benzo-1,3—dioxolyl, naphthol 1,3—dioxolyl, 2,3—dihydrobenzo-1,4 Mono-dioxinyl group, 2,3-dihydronapto 1,4, -dioxinyl group, 2,1,3-benzothiadiazole group C
  • the “aralkyl group” is preferably an aromatic-substituted lower alkyl group having 7 to 12 carbon atoms, such as benzyl, 1-phenylethyl, 2-phenylethyl, phenylpropyl, and naphthylmethyl. Benzyl is particularly preferable.
  • aralkyl group in the “aralkyl group” the above carbon number?
  • the aryl group of the "aralkenyl group” is preferably the above aryl group having 6 to 10 carbon atoms, and the alkenyl group is preferably the lower alkenyl group having 2 to 6 carbon atoms.
  • the alkenyl group is preferably the lower alkenyl group having 2 to 6 carbon atoms.
  • phenyletenyl, phenylpropenyl, naphthylethenyl, naphthylpropenyl and the like are preferable, and an aralkenyl group having 8 to 10 carbon atoms is particularly preferable.
  • the aryl group of the “aralkynyl group” is preferably the above-mentioned aryl group having 6 to 10 carbon atoms, and the alkynyl group is preferably an alkynyl group having 2 to 6 carbon atoms. Examples thereof include phenylethynyl, phenylprovinyl, Naphthylethynyl, naphthylpropynyl and the like.
  • the “aroyl group” specifically includes benzoyl, naphthoyl and the like, and is preferably benzoyl.
  • the arylsulfonyl group of the "arylsulfonyloxy group” is preferably an arylsulfonyl group having 6 to 10 carbon atoms, for example, phenylsulfonyloxy, naphthylsulfonyloxy and the like.
  • aryl group of the "arylcarbamoyl group” the above aryl group having 6 to 10 carbon atoms is preferable, and as the arylcarbamoyl group, phenylcarbamoyl, naphthylcarbamoyl and the like can be mentioned.
  • “Lower alkylenedioxy group” refers to an alkylene chain having 1 to 3 carbon atoms. Oxygen atoms are bonded on both sides, and include methylenedioxy, ethylenedioxy, propylenedioxy and the like, preferably methylenedioxy and ethylenedioxy.
  • halogen atom examples include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
  • Cyclic imid which may be condensed with a benzene ring specifically includes succinimide, glutalimide, phthalimid and the like, with phthalimido being preferred.
  • the "5- or 6-membered heterocyclic group having 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom or a sulfur atom” is a nitrogen atom.
  • rings such as pyridine, pyrimidine, and isoxazole are preferred, and particularly preferred is pyridine.
  • a 5- or 6-membered nitrogen-containing saturated or unsaturated heterocyclic group which may contain one nitrogen atom, oxygen atom or sulfur atom as another hetero atom is a bond of 'and 1 ⁇ 8 Means a 5- or 6-membered saturated or unsaturated heterocyclic group which may contain one heteroatom consisting of a nitrogen atom, an oxygen atom or a sulfur atom as a heteroatom other than the nitrogen atom .
  • the saturated heterocyclic group include pyrrolidinyl, piperidino, piperazinyl, morpholino, and the like, and preferably piperidino, piperazinyl, and morpholino.
  • Unsaturated heterocyclic groups include, for example, pivalyl, imidazolyl, thiazolyl, pyrazolyl, isothiazolyl, isoxazolyl, pyridyl, pyrimidyl, pyridazinyl, virazyl, pyridin-13-ene, and pyridin-12. —They are preferred u
  • 5- or 6-membered heteroaryl group having 1 or 2 nitrogen atoms means a 5- or 6-membered heteroaryl group having 1 or 2 nitrogen atoms.
  • Imidazolyl, pyridyl, pyrimidyl and the like are preferred, and pyridyl and pyrimidyl are preferred.
  • preferred compounds are an aryl group or a pyridyl group in which the ring A may be substituted, and B is a lower alkylene group or a group represented by the formula —S (0) n—.
  • R 4 is an alkyl group, an aryl group which may be substituted and may be condensed with dioxotool, or a group represented by the formula:
  • the compound (I) of the present invention has geometric isomers based on amide bonds. Further, depending on the type of substituent, it may have one or more asymmetric carbon atoms, and based on this, optical isomers such as (R) -form and (S) -form, racemic forms, diastereomers, etc. Exists. In addition, some types of substituents have a double bond, and there are geometrical isomers such as (Z) -form and (E) -form. The present invention includes all separated or mixtures of these isomers.
  • the compound (I) of the present invention may form a salt with an acid.
  • Such salts include mineral acids with hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, etc., formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid Acid addition with organic acids such as acid, maleic acid, lactic acid, lingic acid, quinic acid, tartaric acid, carbonic acid, picric acid, methanesulfonic acid, ethanesulfonic acid, and glumic acid Salts may be mentioned.
  • compound (I) may be obtained as a hydrate, a solvate such as ethanol, or various substances forming a polymorph depending on the physicochemical properties or production conditions.
  • the present invention includes all of these hydrates, solvates with ethanol, and the like, and substances in various crystal forms.
  • the compounds of the present invention and salts thereof can be produced by applying various synthetic methods, utilizing characteristics based on the basic skeleton or types of substituents. Hereinafter, a typical production method will be described.
  • the compound (I) of the present invention can be produced by a condensation reaction of the amide represented by ( ⁇ ) and the carboxylic acid represented by ( ⁇ ).
  • This reaction is carried out by using the commonly used condensation reagents (dicyclohexylcarbodiimide, diphenylphosphoryl azide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, 1, ⁇ -carbonyldiimidazo ), A mixed acid anhydride method using ethyl ethyl chloroformate or isobutyl chloroformate, or (1) using a halogenating reagent such as thionyl chloride, oxalyl chloride, or phosphorus chloride.
  • (IV) (V) (la) In the formula, represents a halogen atom or an organic sulfonic acid residue.)
  • (Ia) represents an amide represented by (IV) and a halide or sulfonate represented by (V).
  • the halogen atom include an iodine atom, a bromine atom and a chlorine atom.
  • Organic sulfonic acid residues include alkanesulfonic acid residues such as methanesulfonic acid residues and ethanesulfonic acid residues, toluene sulfonic acid residues (for example, p-toluenesulfonyloxy group), and benzenesulfonic acid residues.
  • An aromatic sulfonic acid residue such as a group is used.
  • the reaction is carried out in an organic solvent that does not normally participate in the reaction, for example, compounds (IV) and (V) in an organic solvent such as tetrahydrofuran, dimethylformamide, and hexamethylphosphoric triamide.
  • (Ia) can also be produced by reductive condensation in which an amide compound represented by (IV) and an aldehyde compound represented by (VI) are reacted in the presence of a reducing agent.
  • the reaction is usually an organic solvent that is inert to the reaction.
  • Compounds (IV) and (VI) in an organic solvent such as tetrahydrofuran, acetate nitrile, dichloromethane, methanol, ethanol, etc. in the presence of a reducing agent.
  • the reaction is carried out under cooling or at room temperature using an excess amount of one or more moles or at room temperature, or using (IV) and (VI) in a solvent-free state or in benzene, toluene, etc., azeotropically or in the presence of a drying agent.
  • a drying agent After synthesizing a Schiff base by condensing while removing, it may be reduced in methanol, ethanol or the like.
  • the reducing agent hydrides such as sodium triacetoxyborohydride, sodium borohydride, and sodium cyanoborohydride are used.
  • an acid catalyst such as acetic acid may be used. If there are other groups that are susceptible to reduction, the desired product can be selectively obtained by selecting the reaction conditions.
  • ⁇ is the same as above, and ⁇ 2 is a halogen atom.
  • (lb) can be produced by reacting the amide compound represented by (IV) with the halide represented by ( ⁇ ).
  • the reaction is usually carried out in an organic solvent which is inert to the reaction, such as dichloromethane, benzene, ether, chloroform, carbon tetrachloride, acetonitrile, etc., with equimolar amounts of (IV) and (W). It is advantageous to use either of them in an excessive amount and to carry out the reaction under cooling (preferably 0) or at room temperature.
  • This reaction is advantageously carried out in the presence of a base.
  • a base an organic base such as triethylamine, pyridine, dimethylaminopyridine and the like is preferable.
  • R 7, R u represents the aforementioned groups Y. halogen atom or a sulfo down acid residue, m:.. L ⁇ 5 an integer of similar or less
  • (Ic) can be produced by reacting a halide or sulfonate represented by ( ⁇ ) with an amide derivative represented by (DO.
  • the reaction is usually carried out in an organic solvent not involved in the reaction.
  • organic solvent for example, in methanol, ethanol, tetrahydrofuran, acetonitril, dimethylformamide, hexamethylphosphoric triamide, etc., (VB) and (K) are almost Usually, it is advantageous to carry out the reaction in an equimolar amount or one of them in a slightly excessive molar amount while heating, and in some cases, it is advantageous to carry out the reaction in the presence of a base. Bases such as sodium hydride and sodium hydroxide are preferred.
  • R 9 , R 1 () or R 11 are the same or different and represent a hydrogen atom, a lower alkyl group, or an optionally substituted aryl group.
  • (Id) represents a halide or sulfo represented by (Cor).
  • the compound can be produced by reacting the Nate with an imidazole derivative represented by (X).
  • the reaction is usually carried out in an organic solvent that does not participate in the reaction, for example, ethanol, tetrahydrofuran, acetonitril, dimethylformamide, etc., in which (Cor) and (X) are almost equimolar. It is advantageous to carry out the reaction, usually with heating, in a slightly molar amount, or one of them. In some cases, it is advantageous to carry out the reaction in the presence of a base.
  • a base such as potassium carbonate, sodium hydroxide or sodium hydroxide is preferred.
  • R 5 represents the aforementioned group.
  • (Ie) can be produced by reacting with a halide or a sulfonate represented by (Week) or an alcohol derivative or a phenol derivative represented by (XI).
  • the reaction is usually carried out by equimolarly adding (VDI) and () in an organic solvent that does not participate in the reaction, for example, tetrahydrofuran, acetonitrile, dimethylformamide, etc.
  • VDI equimolarly adding
  • an organic solvent that does not participate in the reaction
  • Examples of such a base include potassium carbonate, cesium carbonate, and sodium hydride. Bases such as lime and sodium hydroxide are preferred.
  • R 6 represents the aforementioned group.
  • (If) can be produced by reacting a halide or a sulfonate represented by () with a thiol form represented by (M).
  • the reaction is almost the same as (VI) and () in organic solvents that are not normally involved in the reaction, such as methanol, ethanol, acetonitril, tetrahydrocran, dimethylformamide, and the like. It is usually advantageous to carry out the reaction in a molar amount, or one of them in a slightly excessive molar amount, usually under heating. In some cases, it is advantageous to carry out the reaction in the presence of a base group. As such a base, a base such as sodium carbonate, sodium hydride or sodium hydroxide is preferred. Ninth manufacturing method
  • (xm) (XIV) (I g) in the compound of the present invention, (I g) can be produced by a Mitsunobu reaction in which an alcohol compound represented by (xm) is reacted with a sulfonamide derivative represented by (XIV).
  • the reaction is usually carried out in an organic solvent inert to the reaction, for example, tetrahydrofuran, dichloromethane, benzene, etc., in the presence of a trisubstituted phosphine compound and an azodicarboxylic acid derivative, with the compound (xm) and the compound (X).
  • reaction is carried out at room temperature or under heating using an equimolar amount of (IV) or an excess amount of (XIV) and an equimolar or excess amount of the trisubstituted phosphine compound and the azodicarboxylic acid derivative.
  • trisubstituted phosphine compound triphenylphosphine, tributylphosphine or the like is used.
  • azodicarboxylic acid derivative acetyl azodicarboxylate, diisopropyl azodicarboxylate or the like is preferably used.
  • a compound having an amino group on an aromatic ring as a substituent can be produced by reducing the corresponding nitrogen compound.
  • catalytic reduction using palladium carbon or the like as a catalyst is also possible, but chemical reduction using a metal such as zinc or iron and an acid such as hydrochloric acid is advantageously used.
  • a compound having a hydroxyl group on an aromatic ring as a substituent can be produced by treating the compound having a corresponding benzyloxy group as a raw material with an acid.
  • trifluoroacetic acid is preferably used as the acid, and the reaction may be accelerated in the presence of thioazole or pentamethylbenzene.
  • it can be produced by catalytic reduction using palladium carbon as a usual method for deprotection of the benzyl group.
  • a compound having an alkoxy group on an aromatic ring as a substituent can be produced by alkylating the compound having a corresponding hydroxyl group as a raw material.
  • cesium carbonate, potassium carbonate, or sodium hydroxide is used in a mixed solvent of aceton and dimethylformamide or dimethylformamide, using the corresponding alkyl halide as a reaction reagent. It is preferable to carry out the reaction usually under heating using a base such as
  • a compound having a carboxyl group in its structure can be produced by hydrolyzing the corresponding alkyl ester as a raw material.
  • a conventional method of ester hydrolysis is used, and sodium hydroxide or the like is used as a base.
  • a compound having a substituting rubamoyl group as a substituent when a compound having a corresponding carboxyl group as a raw material is used as a raw material, a compound having a substituting rubamoyl group as a substituent can be produced by condensing the compound with a corresponding amide.
  • the reaction can be carried out by a conventional method using a commonly used condensing reagent such as hexylcarbodiimide.
  • a mixed acid anhydride method using ethyl chloroformate or the like or a method in which a raw carboxylic acid is converted into an acid halide using a halogenating reagent such as thionyl chloride or oxalyl chloride, and then reacted with the amide. It is possible.
  • the compound of the present invention thus produced can be purified as a salt, hydrate, solvate, or polymorphic substance as it is in a free state.
  • the salt of the compound (I) of the present invention can also be produced by subjecting the salt to a conventional salt formation reaction.
  • Simple purification is performed by applying ordinary chemical operations such as extraction, concentration, distillation, crystallization, crystallization, recrystallization, and various types of mouth chromatography.
  • the optical isomer can be obtained by selecting an appropriate raw material or by a method of resolving a racemic compound (for example, a method of optically resolving a diastereomer salt with a general optically active base).
  • a method of resolving a racemic compound for example, a method of optically resolving a diastereomer salt with a general optically active base.
  • Three-dimensional It can lead to chemically pure isomers.
  • the mixture of diastereomers can be separated by a conventional method, for example, fractional crystallization or mouth chromatography.
  • An optically active compound can also be produced by using an appropriate optically active raw material.
  • the compound of the present invention has an ACAT inhibitory action, particularly an excellent macrophage ACAT inhibitory action, and suppresses foaming of vascular macula phages, and is therefore expected to act directly on atherosclerotic lesions It is. Furthermore, it is expected to activate the reverse cholesterol transfer system, making it a useful compound as a preventive and therapeutic agent for arteriosclerosis. It also has an ACAT inhibitory effect that is present in the liver, etc., and shows a blood cholesterol lowering effect in in vivo.
  • the compound of the present invention is based on the above-mentioned actions, and is based on atherosclerosis or various diseases caused by atherosclerosis, that is, ischemic heart disease such as angina or myocardial infarction due to coronary atherosclerosis. Cerebrovascular disorders such as cerebral infarction and cerebral hemorrhage due to sclerosis, optic atrophy and hydrocephalus due to mechanical compression of sclerotic cerebral arteries, sclerosis due to renal arteriosclerosis, arterial obstruction due to stenosis of aorta and peripheral arteries It is a very useful compound for the prevention and treatment of arteriosclerosis, hyperlipidemia, hypercholesterolemia, and xanthomas. experimental method
  • the ACAT inhibitory effect of the compound of the present invention on THP-1 cells, the ACAT inhibitory effect on HepG2 cells, the foaming inhibitory effect on macula phage, and the blood cholesterol lowering effect on normal diet hamsters were confirmed as follows. It is a thing.
  • THP—1 cell human monocyte
  • PMA Phorbol Pour the mixture into RPMI1640 + 10% FBS (Fetal Bovine Serum) medium supplemented with 12-Myristate 13-acetate) in a 12-well plate at 75 x 10 4 cells / well, incubate for 4 days, and differentiate into a Mcguchi phage.
  • the medium was replaced with RPMI1640 + 10% LPDS (Lipoprotein Deficient Serum) containing the same concentration of PMA, and the cells cultured for one day were used for measurement.
  • Comparative Example 1 the compound described in Reference 1 (n-butyl N '-[2- [3- (5-ethyl-4-phenyl-1H) -imidazol-1-yl) propoxy] — 6-Methylphenyl] ⁇ rare) (hereinafter abbreviated as Comparative Example 1) was used.
  • the inhibitory effect of foaming on macrophages was evaluated based on the inhibition rate of the increase of ester cholesterol (CE) in macrophage cells.
  • THP-1 cells were seeded on a 12-well plate (75 ⁇ 10 4 cells / ml / well) in RPMI1640 medium containing 10% FBS and 0.1 / M PMA for 4 days to differentiate into macrophages. Then, the same concentration of PMA, 10 After culturing for 1 day after replacing with a medium containing% LPDS, acetylated LDL (prepared LDL prepared from human plasma by ultracentrifugation using acetic anhydride) 50 g / ml, and 10 _Q M A solution dissolved in DMSO (dimethylsulfoxide) was added to achieve a concentration of, and the cells were further cultured for 24 hours.
  • DMSO dimethylsulfoxide
  • the blood cholesterol lowering rate was calculated from the relative value of total cholesterol in serum between the control group and the test compound administration group.
  • Formulations containing one or more of the compounds of the present invention or salts thereof as an active ingredient are prepared using carriers, excipients, and other additives that are commonly used for formulation.
  • Administration may be oral, such as tablets, pills, capsules, granules, powders, or liquids, or parenteral, such as injections such as intravenous and intramuscular injections, suppositories, and transdermals. Good.
  • the dosage is determined as appropriate for each individual case, taking into account the symptoms, age of the subject, gender, etc. Usually, about 0.01 to 50 mg per day per adult for oral administration and per adult per day for parenteral administration. The dose is about 0.001 to 5 mg, and should be administered once or in 2 to 4 divided doses.
  • Solid compositions for oral administration according to the present invention include tablets, powders, Granules and the like are used.
  • the one or more active substances may include at least one inert diluent, such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch. , Polyvinylpyrrolidone, metasilicate, and magnesium aluminate.
  • the compositions may contain, in a conventional manner, additives other than inert diluents, such as lubricants such as magnesium stearate, disintegrants such as calcium cellulose glycolate, stabilizers such as lactose, A solubilizing agent such as glutamate or aspartate may be contained.
  • tablets or pills may be coated with a sugar coating such as sucrose, gelatin, hydroxypropylcellulose, hydroxypropylpyrumethylcellulose phthalate, or a film of a gastric or enteric substance.
  • Liquid compositions for oral administration include pharmaceutically acceptable emulsifiers, solutions, suspensions, syrups, elixirs, etc., and include commonly used inert diluents such as purified Contains water and ethanol.
  • the composition may contain, in addition to the inert diluent, adjuvants such as wetting agents and suspending agents, sweetening agents, flavoring agents, flavoring agents and preservatives.
  • Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions.
  • Aqueous solutions and suspensions include, for example, distilled water for injection and physiological saline.
  • non-aqueous solutions and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, and polysorbate 80 (trade name). Etc.
  • Such compositions may also contain adjuvants such as preserving, wetting, emulsifying, dispersing, and stabilizing agents (eg, lactose) and solubilizing agents (eg, glutamate, aspartic acid). May be.
  • N- (2,6-diisopropylpropyl) 13- (N-phenylamino) is eluted with a mixed solvent of ethyl acetate and n-hexane (1: 5 ⁇ 1: 2).
  • Propionamide (11.8 g) was obtained as a white solid.
  • N- ( 340 mg of 2,6-diisopropylpropylphenyl-3- [N-phenyl-N- [2- (4-phenyl-1-piperazinyl) ethyl] amino] propionamide were obtained as white crystals.
  • Raw material N— (2,6-diisopropylpropyl) (Dienyl) — 3— (N-phenylamino) propionamide and 4-ethylfurnil sulfonyl chloride
  • N- (2,6-diisopropylpropyl) -13- (N-phenylamino) propionamide 320 mg and 980 mg of bromomethylcyclohexane were dissolved in 10 ml of hexanemethylphosphoric acid triamide. To this were added 280 mg of carbon dioxide and 300 mg of sodium iodide sequentially, and the mixture was stirred at 120 for 2 hours. After allowing the reaction mixture to cool, 50 ml of ethyl acetate was added, and the mixture was washed successively with a saturated aqueous solution of sodium hydrogen carbonate and water, and the organic layer was dried over anhydrous magnesium sulfate.
  • N— (2,6-diisopropylpropyl) -13- (N-phenylamino) propionamide was dissolved in 15 ml of N, N-dimethylformamide.
  • 430 mg of anhydrous potassium carbonate, 230 mg of sodium iodide and 260 mg of 4-methylbenzyl chloride were sequentially added at room temperature, followed by heating to 80 and stirring at the same temperature for 1 hour.
  • the reaction mixture was added with 50 ml of ethyl acetate, washed with a saturated aqueous sodium hydrogen carbonate solution, and dried over anhydrous magnesium sulfate.
  • the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography.
  • N- (2,6-Diisopropylpyrenyl) 1-3- [N- (3-Hydroxybenzyl) -1-N-phenylamino] Propionamide 540 mg is dissolved in 20 ml of oral form, and triethylamine 160 mg. And benzenesulfonyl chloride (250 mg) were added sequentially, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was washed with water and a saturated aqueous solution of sodium hydrogen carbonate, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure.
  • N- (2,6-diisopropylphenyl) -1-3-phenylamino 500 mg of oral pionamide and 1.27 g of 1- (3-bromopropyl) -4-phenylpiperazine were dissolved in 10 ml of hexanemethylphosphoric acid triamide, and the mixture was stirred at 100 at 6.5 hours. After allowing the reaction solution to cool, 200 ml of ethyl acetate was added, and the mixture was washed successively with an aqueous solution of sodium hydrogencarbonate and brine, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography.
  • a mixed solvent 50: 1 of chloroform and methanol.
  • Example 8 In the same manner as in Example 8, Examples 148 to 159 and 184 to 186 were obtained. In the same manner as in Example 9, Examples 163 and 168 were obtained.
  • Example 67 was obtained in the same manner as Example 26, Example 66 was obtained in the same manner as Example 27, and Examples 118, 119, 124, 142, 143 and 192 were obtained in the same manner as Example 28.
  • Example 89 and 200 were obtained in the same manner as in Example 29, Example 73 was obtained in the same manner as in Example 30, and Example 180 was obtained in the same manner as in Example 31.
  • Example 197 was obtained in the same manner as in Example 38.
  • Example 57 was obtained in the same manner as Example 43, Example 132 was obtained in the same manner as Example 44, Example 160 was obtained in the same manner as Example 45, and Examples 161 and 162 were obtained in the same manner as Example 47. Was. In the same manner as in Example 49, Examples 166, 167 and 183 were obtained.
  • Examples 181 and 182 were obtained in the same manner as in Example 51, Example 169 was obtained in the same manner as in Example 52, and Examples 170 to 174 were obtained in the same manner as in Example 53.
  • Example 177 and 178 were obtained in the same manner as in Example 54, and Examples 187 to 189 were obtained in the same manner as in Example 56.
  • Example 193
  • Example 199 Theoretical 64.78 6.56 7.82 5.96 Experimental 64.85 6.46 7.84 5.97 Examples 203, 205, 206, 207, 208, 209, 210 in the same manner as in Example 198. , 212, 213, 214 were obtained.
  • Example 199 Theoretical 64.78 6.56 7.82 5.96 Experimental 64.85 6.46 7.84 5.97 Examples 203, 205, 206, 207, 208, 209, 210 in the same manner as in Example 198. , 212, 213, 214 were obtained. Example 199
  • N- (2,6-diisopropylphenyl) -13- [N- (3,5-xylyl) amino] propionamide 600 mg was dissolved in 20 ml of porcine, and 200 mg of pyridine was added to this solution.
  • (1,3-benzodioxol 5-yl) Sulfonyl chloride 450 mg was sequentially added, and the mixture was stirred at room temperature for 9 hours.
  • the solvent was distilled off under reduced pressure, 50 ml of toluene was added, and the solvent was distilled off again under reduced pressure.
  • the pale-yellow solid obtained by eluting with a black hole form was crystallized from a mixed solvent of acetate and n-hexane (1: 1) to give 3- [N-[(1,3– Benzodoxo-l-5-yl) sulfonyl] -N- (3,5-xylyl) amino] -N- (2,6-diisopropylpropyl) propionamide 480 mg was obtained as white crystals.

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Abstract

L'invention concerne des dérivés de propionanilide de formule générale I ou des sels pharmaceutiquement acceptables de ceux-ci, ainsi que des compositions médicamenteuses utiles en tant qu'inhibiteur D'ACAT ou similaire et comprenant lesdits dérivés ou sels ainsi que des excipients pharmaceutiquement acceptables. Dans ladite formule (I), les symboles ont les significations suivantes: A représente un groupe hétérocyclique à 5 ou 6 éléments ou aryle; R1 et R2 représentent chacun alkyle inférieur; R3 représente hydrogène ou alkyle inférieur; B représente une liaison, alkylène inférieur, alcénylène inférieur, alcynylène inférieur ou -S(O)¿n?-, n valant 0, 1 ou 2; et R?4¿ représente alkyle, aralkyle, carboxyle, alcoxycarbonyle inférieur, cycloalkyle ou aryle tel que pyridyle.
PCT/JP1997/002385 1996-07-12 1997-07-10 Derives de propionanilide ou sels de ceux-ci WO1998002412A1 (fr)

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Application Number Priority Date Filing Date Title
AU34586/97A AU3458697A (en) 1996-07-12 1997-07-10 Propionanilide derivatives or salts thereof

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JP8/183070 1996-07-12

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7429593B2 (en) 2001-09-14 2008-09-30 Shionogi & Co., Ltd. Utilities of amide compounds
WO2017041665A1 (fr) * 2015-09-11 2017-03-16 沈阳药科大学 Dérivé de 3-(groupe amino n,n-disubstitué)-propanamide, procédé de préparation correspondant et utilisation correspondante en médecine

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH03218345A (ja) * 1989-11-06 1991-09-25 Warner Lambert Co Ａｃａｔ阻害剤
JPH04327564A (ja) * 1991-03-08 1992-11-17 Adir 新規アシルアミノフェノール化合物、それらの製造方法およびこれらの化合物を含有する医薬組成物

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH03218345A (ja) * 1989-11-06 1991-09-25 Warner Lambert Co Ａｃａｔ阻害剤
JPH04327564A (ja) * 1991-03-08 1992-11-17 Adir 新規アシルアミノフェノール化合物、それらの製造方法およびこれらの化合物を含有する医薬組成物

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7429593B2 (en) 2001-09-14 2008-09-30 Shionogi & Co., Ltd. Utilities of amide compounds
US8106051B2 (en) 2001-09-14 2012-01-31 Shionogi & Co., Ltd. Utilities of amide compounds
WO2017041665A1 (fr) * 2015-09-11 2017-03-16 沈阳药科大学 Dérivé de 3-(groupe amino n,n-disubstitué)-propanamide, procédé de préparation correspondant et utilisation correspondante en médecine
CN106518808A (zh) * 2015-09-11 2017-03-22 沈阳药科大学 3-(n,n-双取代胺基)丙酰胺类衍生物、其制备方法及其在医药上的应用

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