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WO1992003408A1 - Derives de benzanilide - Google Patents

Derives de benzanilide Download PDF

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Publication number
WO1992003408A1
WO1992003408A1 PCT/GB1991/001376 GB9101376W WO9203408A1 WO 1992003408 A1 WO1992003408 A1 WO 1992003408A1 GB 9101376 W GB9101376 W GB 9101376W WO 9203408 A1 WO9203408 A1 WO 9203408A1
Authority
WO
WIPO (PCT)
Prior art keywords
decyloxybenzamido
group containing
carbon atoms
benzoate
compound
Prior art date
Application number
PCT/GB1991/001376
Other languages
English (en)
Inventor
Andrew William Bridge
David John Lythgoe
Original Assignee
Rhone-Poulenc Rorer Limited
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 Rhone-Poulenc Rorer Limited filed Critical Rhone-Poulenc Rorer Limited
Publication of WO1992003408A1 publication Critical patent/WO1992003408A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/56—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
    • 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
    • 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
    • C07C323/62—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 atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
    • C07C323/63—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 atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups

Definitions

  • This invention relates to new, therapeutically useful benzanilide derivatives, to a process for their production and to pharmaceutical compositions
  • the new benzanilide derivatives of the present invention are the compounds of formula I, hereinafter depicted, wherein R 1 represents a straight- or
  • branched-chain alkyl group containing from about 4 to about 20 carbon atoms, optionally interrupted by one or more hetero atoms, e.g. oxygen, sulphur or nitrogen atoms, preferably an alkyl, alkoxyalkyl, alkylaminoalkyl or dialkylaminalkyl group containing from about 4 to about 20 carbon atoms
  • X 1 represents an oxygen or sulphur atom or a group -NR 5 - wherein R 5 represents a hydrogen atom or a straight- or branched-chain alkyl or alkanoyl group containing up to about 5 carbon atoms, optionally substituted by one or more halogen, e.g.
  • R 2 represents a hydrogen atom or a straight- or branched-chain alkyl group containing from 1 to about 4 carbon atoms
  • R 3 represents a straight- or branched-chain alkyl, alkoxy or alkylthio group
  • R 4 represents a straight- or branched-chain alkyl group containing up to about 10 carbon atoms, optionally containing one or more carbon-carbon double or triple bonds, and
  • hetero atoms e.g. oxygen, sulphur or nitrogen atoms, preferably an alkyl, alkoxyalkyl, alkylaminoalkyl or dialkylaminoalkyl group containing up to about 10 carbon atoms.
  • Especially important compounds of the present invention include those wherein at least one of the symbols has a value selected from the following:-
  • R 1 represents an alkyl group containing from 8 to 12, e.g. 10, carbon atoms
  • X 1 represents an oxygen atom
  • R 2 represents a hydrogen atom
  • (lv) R 3 represents an alkoxy or alkylthio
  • R 4 represents a straight- or branched- chain alkyl group containing up to 5 carbon atoms, optionally containing a carbon-carbon double bond or interrupted by an oxygen atom;
  • Important compounds according to the invention include:- A methyl 3-(4-decyloxybenzamido)-4-methoxybenzoate;
  • the compounds according to the invention are inhibitors of acyl coenzyme-A:cholesterol-O-acyl transferase (ACAT;EC 2.3.1.26). They are therefore of value as anti-atherosclerotic agents and have utility in the treatment of atherosclerosis, hyperlipidaemia, cholesterol ester storage disease and atheroma in vein grafts.
  • ACAT acyl coenzyme-A:cholesterol-O-acyl transferase
  • R 2 , R 3 and R 4 are as hereinbefore defined, with a compound of general formula III, hereinafter depicted, wherein R 1 and X 1 are as hereinbefore defined and Z 1 represents a
  • halogen e.g. chlorine, atom.
  • the reaction may be performed in the presence of a suitable base, such as a tertiary amine, and may be carried put in a suitable solvent, e.g. dichloromethane, optionally with heating.
  • a suitable base such as a tertiary amine
  • a suitable solvent e.g. dichloromethane
  • compounds of formula I are prepared by reacting a compound of general formula:
  • R 4 is as hereinbefore defined, with a compound of formula V, hereinafter depicted, wherein R 1 , R 2 ,
  • R 3 and X 1 are as hereinbefore defined and Z 2 represents a halogen, e.g. chlorine, atom or a hydroxy group.
  • Z 2 represents a halogen atom the reaction may be performed in the presence of a suitable base, such as a tertiary amine.
  • reaction is preferably performed in the presence of a condensing agent, such as dicyclohexylcarbodiimide, or a catalytic quantity of an inorganic acid, e.g. hydrochloric acid, optionally prepared in situ.
  • a condensing agent such as dicyclohexylcarbodiimide
  • a catalytic quantity of an inorganic acid e.g. hydrochloric acid
  • reaction may be carried out in a suitable solvent, e.g. dichloromethane, optionally with heating.
  • a suitable solvent e.g. dichloromethane
  • compounds of general formula I are prepared by the interconversion of other compounds of formula I.
  • compounds wherein R 2 represents a straight- or branched-chain alkyl group containing from 1 to 4 carbon atoms may be prepared from compounds of formula I wherein R 2 represents a hydrogen atom by alkylation by the application or adaptation of known methods.
  • (i) acid halides of formula V wherein Z 2 represents a halogen atom may be prepared from the corresponding carboxylic acids of formula V wherein Z 2 represents a hydroxy group by known methods, e.g., when Z 2 represents a chlorine atom, by reaction with thionyl chloride;
  • the corresponding carboxylic acids of formula V wherein Z 2 represents a hydroxy group may be prepared from compounds of formula I by hydrolysis of the ester grouping -COOR 4 by known methods, for example by reaction with alkali, e.g. aqueous sodium hydroxide solution, followed by neutralisation by treatment with mineral acid, e.g. dilute hydrochloric acid.
  • alkali e.g. aqueous sodium hydroxide solution
  • mineral acid e.g. dilute hydrochloric acid.
  • 3-Methylbut-3-en-1-ol (2.0ml) was treated with a solution of 3-(4-decyloxybenzamido)-4-(methylthio)- benzoyl chloride (2.31g) in toluene (20ml) [prepared from 3-(4-decyloxybenzamido)-4-(methylthio) benzoic acid and thionyl chloride in toluene], and the mixture was stirred vigorously. It was then treated with
  • the present invention also includes within its scope pharmaceutical formulations which comprise at least one of the compounds of formula I in association with a pharmaceutically acceptable carrier or coating.
  • pharmaceutical formulations which comprise at least one of the compounds of formula I in association with a pharmaceutically acceptable carrier or coating.
  • the compounds of the present invention may be administered parenterally, rectally or orally.
  • Solid compositions for oral administration include compressed tablets, pills, powders and
  • one or more of the active compounds is, or are, admixed with at least one inert diluent such as starch, sucrose or lactose.
  • the compositions may also comprise, as is normal practice, additional substances other than inert diluents, e.g. lubricating agents, such as magnesium stearate.
  • Liquid compositions for oral administration include pharmaceutically acceptable emulsions,
  • compositions according to the invention for oral administration also include capsules of absorbable material such as
  • gelatin containing one or more of the active
  • Preparations according to the invention for parenteral administration include sterile aqueous, aqueous-organic, and organic solutions, suspensions and emulsions.
  • organic solvents or suspending media are propylene glycol, polyethylene glycol, vegetable oils such as olive oil and injectable organic esters such as ethyl oleate.
  • the compositions may also contain adjuvants such as stabilising, preserving, wetting, emulsifying and dispersing agents. They may be sterilised, for example, by filtration through a bacteria-retaining filter, by incorporation in the compositions of sterilising agents, by irradiation or by heating. They may also be manufactured in the form of sterile solid compositions, which can be dissolved in sterile water or some other sterile injectable medium immediately before use.
  • Solid compositions for rectal administration include suppositories formulated in accordance with known methods and containing at least one compound of formula I.
  • compositions of the invention may be varied, it being necessary that it should constitute a proportion such that a suitable dosage shall be obtained. Obviously, several unit dosage forms may be administered at about the same time. The dose employed will be determined by the physician, and depends upon the desired
  • the doses are generally from about 0.5 to about 70, preferably about 1 to about 10, mg/kg body weight per day by oral administration.
  • the following Example illustrates pharmaceutical compositions according to the present invention.
  • No. 2 size gelatin capsules each containing:- 3-methylbut-2-enyl 3-(4-decyloxybenzamido)- 4-(methylthio)benzoate 20 mg lactose 100 mg starch 60 mg dextrin 40 mg magnesium stearate 1 mg were prepared in accordance with the usual procedure.

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

Abstract

Dérivés de benzanilide de la formule (I) où R1 représente alkyle, éventuellement interrompu par un hétéroatome ou plus, X1 représente oxygène, soufre ou -NR?5-, où R5¿ représente hydrogène ou alkyle ou alcanoyle éventuellement substitué par de l'halogène, R2 représente hydrogène ou alkyle, R3 représente alkyle, alcoxy, alkylthio, diméthylamino ou un groupe hétérocyclo contenant au moins un atome d'azote et lié par cet atome d'azote au reste de la molécule, ou un atome d'halogène, et R4 représente un alkyle contenant jusqu'à 10 atomes de carbone, contenant facultativement une ou plusieurs double(s) ou triple(s) liaison(s) carbone-carbone, et facultativement interrompu par un ou plusieurs hétéroatome(s).
PCT/GB1991/001376 1990-08-13 1991-08-13 Derives de benzanilide WO1992003408A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB909017710A GB9017710D0 (en) 1990-08-13 1990-08-13 New compositions of matter
GB9017710.6 1990-08-13

Publications (1)

Publication Number Publication Date
WO1992003408A1 true WO1992003408A1 (fr) 1992-03-05

Family

ID=10680575

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB1991/001376 WO1992003408A1 (fr) 1990-08-13 1991-08-13 Derives de benzanilide

Country Status (10)

Country Link
EP (1) EP0543884A1 (fr)
JP (1) JPH06500083A (fr)
AU (1) AU8337891A (fr)
CA (1) CA2089166A1 (fr)
GB (1) GB9017710D0 (fr)
IE (1) IE912849A1 (fr)
IL (1) IL99160A0 (fr)
PT (1) PT98665A (fr)
WO (1) WO1992003408A1 (fr)
ZA (1) ZA916339B (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998035937A1 (fr) * 1997-02-12 1998-08-20 Japan Tobacco Inc. Inhibiteurs de l'activite du cetp
US7276536B2 (en) 2003-03-17 2007-10-02 Japan Tobacco Inc. Method for increasing the bioavailability of the active form of S-[2-([[1-(2-ethylbutyl)cyclohexyl]carbonyl]amino) phenyl] 2-methylpropanethioate

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0003532A1 (fr) * 1978-02-03 1979-08-22 Byk Gulden Lomberg Chemische Fabrik GmbH Acides oméga-(2-(N-alcoyl inférieur-benzamido)-phényl)-alcanecarboxyliques, leur application et leur préparation et médicaments les contenant
WO1986003199A1 (fr) * 1984-11-29 1986-06-05 Italfarmaco S.P.A. Derives de l'acide amino-salicylique et compositions pharmaceutiques
EP0232199A2 (fr) * 1986-01-21 1987-08-12 Centre International De Recherches Dermatologiques Galderma - Cird Galderma Composés benzamido aromatiques, leur procédé de préparation et leur utilisation en médecine humaine ou vétérinaire et en cosmétique
US4882357A (en) * 1988-07-15 1989-11-21 Warner-Lambert Company Novel N-(substituted-phenyl)-5-(substituted-2,5-dimethylphenoxy)-2,2-dimethylpentanamides
EP0424194A2 (fr) * 1989-09-27 1991-04-24 Rhone-Poulenc Sante Derivés de benzanilide et leur utilisation comme agents antiartériosclérotiques

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0003532A1 (fr) * 1978-02-03 1979-08-22 Byk Gulden Lomberg Chemische Fabrik GmbH Acides oméga-(2-(N-alcoyl inférieur-benzamido)-phényl)-alcanecarboxyliques, leur application et leur préparation et médicaments les contenant
WO1986003199A1 (fr) * 1984-11-29 1986-06-05 Italfarmaco S.P.A. Derives de l'acide amino-salicylique et compositions pharmaceutiques
EP0232199A2 (fr) * 1986-01-21 1987-08-12 Centre International De Recherches Dermatologiques Galderma - Cird Galderma Composés benzamido aromatiques, leur procédé de préparation et leur utilisation en médecine humaine ou vétérinaire et en cosmétique
US4882357A (en) * 1988-07-15 1989-11-21 Warner-Lambert Company Novel N-(substituted-phenyl)-5-(substituted-2,5-dimethylphenoxy)-2,2-dimethylpentanamides
EP0424194A2 (fr) * 1989-09-27 1991-04-24 Rhone-Poulenc Sante Derivés de benzanilide et leur utilisation comme agents antiartériosclérotiques

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998035937A1 (fr) * 1997-02-12 1998-08-20 Japan Tobacco Inc. Inhibiteurs de l'activite du cetp
US6426365B1 (en) 1997-02-12 2002-07-30 Japan Tobacco Inc. CETP activity inhibitors
RU2188631C2 (ru) * 1997-02-12 2002-09-10 Джапан Тобакко Инк. Ингибитор активности холестерин этерифицированного транспортного белка, профилактическое или терапевтическое средство, производные бис-(2-амидофенил)дисульфида или амидотиофенола
US6753346B2 (en) 1997-02-12 2004-06-22 Japan Tobacco Inc. CETP activity inhibitor
US7271196B2 (en) 1997-02-12 2007-09-18 Japan Tabacco Inc. CETP activity inhibitors
US7579379B2 (en) 1997-02-12 2009-08-25 Japan Tobacco Inc. CETP activity inhibitors
CZ302069B6 (cs) * 1997-02-12 2010-09-29 Japan Tobacco Inc. Inhibitor aktivity proteinu prenášejícího estery cholesterolu
EP2292596A3 (fr) * 1997-02-12 2011-06-15 Japan Tobacco, Inc. Inhibiteur d'activité CETP
US9000045B2 (en) 1997-02-12 2015-04-07 Japan Tobacco Inc. CETP activity inhibitors
US7276536B2 (en) 2003-03-17 2007-10-02 Japan Tobacco Inc. Method for increasing the bioavailability of the active form of S-[2-([[1-(2-ethylbutyl)cyclohexyl]carbonyl]amino) phenyl] 2-methylpropanethioate

Also Published As

Publication number Publication date
EP0543884A1 (fr) 1993-06-02
GB9017710D0 (en) 1990-09-26
JPH06500083A (ja) 1994-01-06
CA2089166A1 (fr) 1992-02-14
AU8337891A (en) 1992-03-17
IE912849A1 (en) 1992-02-26
PT98665A (pt) 1992-06-30
ZA916339B (en) 1992-05-27
IL99160A0 (en) 1992-07-15

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