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
  • 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
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • 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
  • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
  • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
  • C07D257/04—Five-membered rings

Definitions

• the subject of the present invention is new derivatives of ⁇ -phenyl acetanilides, their preparation and their application in human therapy.
• ACAT inhibitor compounds have been previously identified by the Applicant (Patent WO97 / 19918). They have hypocholesterolemic and antioxidant properties allowing them to act on both the quantity and the quality of lipids, thus reducing their atherogenic potential and their long-term deleterious effects on the vascular wall. These compounds however have a low bioavailability and a sensitivity to oxidation limiting the use of formulating agents capable of improving their bioavailability.
• the object of the present invention is to obtain new derivatives having an activity profile comparable to those described by the applicant (WO97 / 19918) with increased bioavailability and chemical and metabolic stability.
• - R represents hydrogen or a fluorine atom - A represents a group
• - n represents an integer from 5 to 11 inclusive terminals
• R, R 5 identical or different, independently represent either hydrogen or a fluorine atom
• the compounds of general formula I having one or more asymmetric centers, the present invention covers the various stereoisomers or enantiomers and their mixtures. These can be obtained by conventional methods such as, for example, chormatographic separation on a chiral column.
• the compounds of general formula I can be used for the preparation of pharmaceutical compositions or of medicaments intended for the treatment of diseases such as hypercholesterolemia and atherosclerosis.
• the compounds of the present invention unexpectedly exhibit cholesterol-lowering activity in vivo superior to the compounds described above.
• the compounds of general formula I can be obtained by treatment of an aniline IN, optionally hydrochloride, with the derivative N, the groups R 1s R, R 3 and A having the same meaning as above, in the presence of an activator such as dicyclohexylcarbodiimide or iodide of 2-chloro-1-methyl pyridinium and triethylamine.
• an activator such as dicyclohexylcarbodiimide or iodide of 2-chloro-1-methyl pyridinium and triethylamine.
• IV aromatic amines are commercial or can be obtained by synthetic methods known to those skilled in the art.
• Nile compounds for which R 4 and R 5 represent a fluorine atom can be prepared by DAST fluorination of bromoaldehyde NUI then reaction of the derivative obtained on the thiomandelic ester IX.
• Example 1 The invention may be illustrated with the aid of the nonlimiting examples which follow and which constitute advantageous embodiments of the compounds of the invention.
• Example 1 The invention may be illustrated with the aid of the nonlimiting examples which follow and which constitute advantageous embodiments of the compounds of the invention.
• the aldehyde (8.74 g; 0.033 mole) is taken up in methylene chloride (170 ml) and added dropwise to diethyl aminosulfide trifluoride (DAST) (5.3 ml; 0.04 mole) in chloride of methylene (120 ml).
• DAST diethyl aminosulfide trifluoride
• This compound is prepared according to the method described in Example 2c using the compound 3c obtained above in place of the compound 2b.
• This compound is prepared according to the method described in Example 2c using the compound 4c obtained above in place of the compound 2b.
• This compound is prepared according to the process described in Example 4b, replacing the dodecyl bromide by the 1-bromo-12,12-difluorododecane obtained as described in Example 2a.
• This compound is obtained according to the process described in Example 2c by replacing 2,3,5-trimethylaminophenol by 2,3,5,6-tetramethyl phenylene diamine and ⁇ - (12,12- difluorododecylthio) phenylacetic acid. with ⁇ - (2-hexyl-2H-5-tetrazolyl) phenyl acetic acid.
• compound 12 After sahfication with hydrochloric acid in isopropanol, compound 12 is obtained by precipitation with ethyl ether.
• Rf 0.48 (CH 2 C1 2 - AcOEt 80-20)
• the compounds of the invention have been subjected to pharmacological tests which have shown their potential interest in the treatment of hypercholesterolemia and in the treatment of atheromatous disease.
• ACAT acyl COA enzyme: cholesterol O acyl transferase
• Male rats (160-180 g) are subjected for 4 days to an altromin C 1061 hypercholesterolemic diet and treated in parallel by oral route with the compounds in suspension in a solution of Tween 80 at 2% in distilled water.
• the effective dose 50 corresponds to the dose which halves the plasma cholesterol concentration compared to the control animals.
• the compounds of the invention are powerful cholesterol-lowering agents, ACAT inhibitors which can be used in the treatment of diseases such as hypercholesterolemia and atherosclerosis.
• compositions can be presented in the form suitable for oral, parenteral or local administration, for example in the form of capsules, tablets, granules, capsules, liquid solutions, syrups, oral suspensions and contain the appropriate excipients.
• the daily dosage can range from 5 to 1000 mg.

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• Organic Chemistry (AREA)
• Chemical & Material Sciences (AREA)
• Health & Medical Sciences (AREA)
• Diabetes (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• General Health & Medical Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Pharmacology & Pharmacy (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Obesity (AREA)
• Hematology (AREA)
• Heart & Thoracic Surgery (AREA)
• Cardiology (AREA)
• Vascular Medicine (AREA)
• Urology & Nephrology (AREA)
• Emergency Medicine (AREA)
• Endocrinology (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Steroid Compounds (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Applications Claiming Priority (3)

Publications (1)

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• 2002
  • 2002-10-16 FR FR0212855A patent/FR2845991B1/fr not_active Expired - Fee Related
• 2003
  • 2003-10-15 US US10/531,234 patent/US20060135785A1/en not_active Abandoned
  • 2003-10-15 JP JP2004544391A patent/JP2006512302A/ja active Pending
  • 2003-10-15 EP EP03780228A patent/EP1558590A1/fr not_active Withdrawn
  • 2003-10-15 WO PCT/FR2003/003038 patent/WO2004035552A1/fr not_active Application Discontinuation
  • 2003-10-15 BR BR0315347-9A patent/BR0315347A/pt not_active Application Discontinuation
  • 2003-10-15 AU AU2003288327A patent/AU2003288327A1/en not_active Abandoned
  • 2003-10-15 CN CNA2003801016613A patent/CN1705648A/zh active Pending
  • 2003-10-15 CA CA002502505A patent/CA2502505A1/fr not_active Abandoned
  • 2003-10-15 MX MXPA05004064A patent/MXPA05004064A/es unknown
• 2005
  • 2005-04-04 ZA ZA200502694A patent/ZA200502694B/en unknown

Non-Patent Citations (1)

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