Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C317/00—Sulfones; Sulfoxides
  • C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/16—Amides, e.g. hydroxamic acids
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
  • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
  • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
  • C07C323/60—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C327/00—Thiocarboxylic acids
  • C07C327/20—Esters of monothiocarboxylic acids
  • C07C327/32—Esters of monothiocarboxylic acids having sulfur atoms of esterified thiocarboxyl groups bound to carbon atoms of hydrocarbon radicals substituted by carboxyl groups

Definitions

• the present invention relates to a compound having an inhibitory action on ACA (acyl-coenzyme-cholesterol acyltransferase).
• ACAT is an enzyme that catalyzes the synthesis of cholesterol ester from fatty acid acyl-enzyme A and cholesterol, and most of the esterification of cholesterol in vivo is achieved by the action of ACAT.
• ACAT inhibitors act on atherosclerotic lesions to suppress the accumulation of cholesterol esters, thereby suppressing the formation and progression of atherosclerosis, and also act on the small intestinal mucosa to suppress cholesterol absorption. Can be considered.
• ACAT inhibitors examples include substituted urea derivatives disclosed in Amerili Patent No. 4.623.662 and Anilil disclosed in JP-A-60-41655 and JP-A-63-253-60. Derivatives, etc., but their effects are not yet sufficient.
• An object of the present invention is to provide a compound having ACA C inhibitory activity having a stronger action.
• X represents an alkyl group having 1 to 4 carbon atoms or an alkoxy group having 1 to 4 carbon atoms
• Y represents a hydrogen atom or an alkoxy group having 1 to 4 carbon atoms
• Z represents 1 to 4 carbon atoms.
• A represents an alkyl group or an alkoxy group having 1 to 4 carbon atoms
• A represents an alkylene group having 1 to 4 carbon atoms
• R represents an alkyl group having 6 to 20 carbon atoms, an alkanol group having 2 to 20 carbon atoms or "It may be substituted by an alkyl group having 1 to 4 carbon atoms.” It represents a benzyl group, and n represents 0, 1 or 2.).
• an alkyl group is a linear or branched alkyl group, for example, an alkyl group represented by X and Z is a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group. , Isobutyl, t-butyl and the like, and the alkyl represented by R includes octyl, decyl, dodecyl, tetradecyl, aminodecyl, eicosanyl and the like.
• the alkyl group represented by X is an isopropyl group
• the alkyl group represented by R is an alkyl group having 8 to 16 carbon atoms.
• the alkoxy group is a linear or branched alkoxy group, for example, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, and a t-butoxy group.
• the alkylene group is a linear or branched alkylene group, such as a methylene group, an ethylene group, a trimethylene group, a dimethylmethylene group, and a tetramethylene group.
• the compound of formula I can be produced, for example, by the following method. That is,
• the compound of formula I wherein n is 1 or 2 can be obtained by oxidizing the compound obtained above in a solvent inert to the reaction.
• the oxidizing agents used here include hydrogen peroxide, m-chloroperbenzoic acid, peracetic acid, and the like.
• the solvents inert to the reaction include water, acetic acid, methanol, ethanol, and isopropyl alcohol. And alcohols such as t-butyl alcohol, ethers such as dioxane and tetrahydrofuran, dimethylformamide, dimethylsulfoxide, methylene chloride, ⁇ form, and acetone.
• the compound of the formula I can also be produced by the following method. That is, the following formula III
• Preferred compounds of the present invention include N- (2,6-diisopropylphenyl) 121- (tetradecylthio) acetamide and N- [2,6-diisopropylphenyl) 1-2- (Acetyl decylthio) asemid, N— (2,6-diisobutylpyruphenyl) -1- (tetradecylthio) butamide, N— (2.6-diisopropylphenyl) 1-3- (Tetradecylthio) propaneamide and N- (2-methyl-6-t-butylphenyl) -12- (tetradecylthio) acetamide.
• the compound of the formula I is administered orally or parenterally in dosage forms such as tablets, pills, capsules, granules and injections.
• dosage forms such as tablets, pills, capsules, granules and injections.
• Each of the above formulations are manufactured according to conventional formulation techniques, and include the usual bulking agents, binders, PH --Additives such as modifiers and solubilizers can be added.
• the dose of the compound of formula I to the treated patient may vary depending on the patient's age, type of disease and condition, etc., but usually 2 to 200 mg per day in 1 to several doses. Can be.
• the compound of the present invention has a significant activity in an ACAT inhibition test using small intestinal microsomes of egrets, and thus is useful as an agent for arteriosclerosis.
• Tablets were produced by a conventional method according to the following formulation.
• Granules were produced according to the following formulation by a conventional method.
• the portion corresponding to the cholesterol age plate was scraped off, and the radioactivity was measured with a liquid scintillation counter, Yuichi (ARCA LSC-300000). Samples to which no test drug was added were processed and measured in the same manner. From these results, the inhibition rate (%) of ACAT activity was determined using the following formula, and the IC 50 value was calculated.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Epidemiology (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Cosmetics (AREA)
• Polysaccharides And Polysaccharide Derivatives (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

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Citations (2)

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• 1991
  • 1991-11-21 US US08/064,073 patent/US5475130A/en not_active Expired - Fee Related
  • 1991-11-21 CA CA002096970A patent/CA2096970C/en not_active Expired - Fee Related
  • 1991-11-21 DE DE69119434T patent/DE69119434T2/de not_active Expired - Fee Related
  • 1991-11-21 WO PCT/JP1991/001602 patent/WO1992009572A1/ja not_active Ceased
  • 1991-11-21 AT AT92902521T patent/ATE137744T1/de not_active IP Right Cessation
  • 1991-11-21 KR KR1019930701531A patent/KR0169501B1/ko not_active Expired - Fee Related
  • 1991-11-21 ES ES92902521T patent/ES2088574T3/es not_active Expired - Lifetime
  • 1991-11-21 DK DK92902521.1T patent/DK0559898T3/da active
  • 1991-11-21 EP EP92902521A patent/EP0559898B1/en not_active Expired - Lifetime
  • 1991-11-21 JP JP4500533A patent/JP2650096B2/ja not_active Expired - Lifetime
• 1996
  • 1996-06-19 GR GR960401636T patent/GR3020257T3/el unknown

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