EP0543891A1 - Derives de diphenyluree - Google Patents

Derives de diphenyluree

Info

Publication number
EP0543891A1
EP0543891A1 EP91914898A EP91914898A EP0543891A1 EP 0543891 A1 EP0543891 A1 EP 0543891A1 EP 91914898 A EP91914898 A EP 91914898A EP 91914898 A EP91914898 A EP 91914898A EP 0543891 A1 EP0543891 A1 EP 0543891A1
Authority
EP
European Patent Office
Prior art keywords
urea
carbon atoms
group containing
compound
formula
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Withdrawn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
EP91914898A
Other languages
German (de)
English (en)
Inventor
David John Lythgoe
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.)
Rhone Poulenc Rorer Ltd
Original Assignee
Rhone Poulenc Rorer Ltd
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 Ltd filed Critical Rhone Poulenc Rorer Ltd
Publication of EP0543891A1 publication Critical patent/EP0543891A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C275/42—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by carboxyl groups
    • 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
    • C07C323/23—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 nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C323/39—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 nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton at least one of the nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom
    • C07C323/40—Y being a hydrogen or a carbon atom
    • C07C323/42—Y being a carbon atom of a six-membered aromatic ring
    • 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 diphenylurea derivatives, to a process for their production and to pharmaceutical compositions containing them, and methods for their use.
  • the new diphenylurea derivatives of the present invention are the compounds of formula I, hereinafter depicted, wherein R represents a straight- or branched-chain alkyl group containing from about 4 to about 18 carbon atoms, X represents an oxygen atom, or a group of the formula -OCH-- or -S(O) -, wherein n represents zero, 1 or 2, R 2 and R3 may be the same or different and each represents a hydrogen atom or a
  • R represents a straight- or branched-chain alkyl group containing up to about 6 carbon atoms, a dimethylamino group or a group of the formula -OR or -S(O) R , wherein represents zero, l or 2 and R represents a straight- or branched-chain alkyl group containing up to about 6 carbon atoms, optionally containing one or more carbon-carbon double bonds, and optionally interrupted by one or more hetero atoms, e.g.
  • oxygen, sulphur or nitrogen atoms preferably an alkyl, alkenyl, alkoxyalkyl, a_lkyl1_ oalkyl, a_U ⁇ la ⁇ _ir_oa_l_kyl or dia__-kylaro___noal_yl group containing up to about 6 carbon atoms, and R 5
  • R7 and R8 may be the same or different and each represents a hydrogen atom or a straight- or branched- chain alkyl group containing up to about 6 carbon atoms, optionally containing one or more carbon-carbon double bonds, and optionally interrupted by one or more hetero atoms, e.g. oxygen, sulphur or nitrogen atoms, preferably an alkyl, alkenyl, alkoxyalkyl, a_l_kylthioaIkyl, al_kylami.noa1.Tyl or dia_U ⁇ lam___r_oaIkyl group
  • R represents a straight- or branched-chain alkyl group containing up to about 6 carbon atoms, optionally containing one or more carbon-carbon double bonds, and optionally interrupted by one or more hetero atoms, e.g. oxygen, sulphur or nitrogen atoms, preferably an alkyl, alkenyl, alkoxyalkyl, alkylthioalkyl, alkylaminoalkyl or dialkyla inoalkyl group containing up to about 6 carbon atoms.
  • hetero atoms e.g. oxygen, sulphur or nitrogen atoms
  • R represents an alkyl group containing from 8 to 12, e.g. 9, 10 or 11, carbon atoms
  • R2 and R3 each represents a hydrogen atom;
  • R represents an alkyl, alkoxy or alkylthio group containing 1 or 2, preferably 1, carbon atoms;
  • R represents a hydrogen atom
  • R represents a straight- or branched-chain alkyl group containing up to 5, preferably 3 or 4 carbon atoms, optionally interrupted by an oxygen or sulphur atom, preferably an alkyl, alkoxyalkyl or alkylthioalkyl group containing up to 5, preferably 3 or 4 carbon atoms; and/or (vii) R represents an alkyl group containing up to 3 carbon atoms, e.g. a methyl group; the other symbols being as hereinbefore defined.
  • Important compounds according to the invention include:-
  • the compounds according to the invention are inhibitors of acyl coenzyme-A:cholesterol-0-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-0-acyl transferase
  • the reaction between the compound of formula II and the compound of formula III preferably takes place in a suitable solvent, for example dichloromethane, toluene, or a mixture thereof.
  • a suitable solvent for example dichloromethane, toluene, or a mixture thereof.
  • the reaction preferably takes place at an elevated temperature, for example at or near 100 ⁇ C.
  • Preparation of the intermediate of formula III in situ can be carried out by the reaction of a compound such as bis(trichloromethyl) carbonate with a compound of the general formula IV, hereinafter depicted, wherein Rl and Xl are as hereinbefore defined.
  • the reaction is preferably carried out in a solvent such as toluene, in the presence of a tertiary amine, e.g. triethylamine, preferably at an elevated temperature.
  • compounds of formula I are prepared by reacting a compound of general formula:
  • R , R , R , R and X are as hereinbefore defined and
  • Z represents a halogen, e.g. chlorine, atom, preferably in the presence of a base, such as a tertiary amine and optionally in a solvent, e.g. toluene, optionally with heating.
  • a base such as a tertiary amine
  • a solvent e.g. toluene
  • compounds of formula I wherein at least one of m and n is zero may be converted into a compound of formula
  • n is greater than in the starting material, the other symbols being as hereinbefore defined, by oxidation using a conventional oxidant, such as a percarboxylic acid (e.g. m-chloroperbenzoic acid) , in an inert solvent, such as dichloromethane, at or below room temperature.
  • a conventional oxidant such as a percarboxylic acid (e.g. m-chloroperbenzoic acid)
  • an inert solvent such as dichloromethane
  • compounds of general formula I are prepared by the interconversion of other compounds of formula I.
  • compounds of formula I wherein R 2 and/or R3 are prepared by the interconversion of other compounds of formula I.
  • compounds of formula I wherein R 2 and/or R3 are prepared by the interconversion of other compounds of formula I.
  • R 7 and/or R8 is other than a hydrogen atom
  • R and/or R 3 and/or R7 and/or R8 represents a hydrogen atom by the application or adaptation of known methods of alkylation.
  • Compounds of formulae II, III, IV, V, VI and VII may be prepared by the application or adaptation of known methods.
  • N-(5-N-butylcarbamoyl-2-methoxyphenyl)-N -(4-decyloxy ⁇ phenyl)urea in the form of off-white crystals, m.p. 62-63°C [purification by plc on silica gel, eluting with a mixture of diethyl ether and methanol (19:lv/v)] [Elemental analysis:- C,69.80;H,8.80;N,8.40%; calculated:- C,69.99;H,8.71;N,8.44%] .
  • 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 granules.
  • 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, solutions, suspensions, syrups and elixirs containing inert diluents commonly used in the art such as water and liquid paraffin. Besides inert diluents such compositions may comprise adjuvants, such as wetting and suspending agents, and sweetening, flavouring, perfuming and preserving agents.
  • the compositions according to the invention for oral administration also include capsules of absorbable material such as gelatin, containing one or more of the active substances with or without the addition of diluents or excipients.
  • 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.
  • the percentage of active ingredient in the 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 therapeutic effect, the route of administration and the duration of the treatment, and the condition of the patient. In the adult, 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.
  • COMPOSITION EXAMPLE 1 No. 2 size gelatin capsules each containing:- N-(4-decyloxyphenyl)-N'-[2-methylthio-5-(2- methylthioethylcarbamoy1)phenyl]urea 20 mg lactose 100 mg starch 60 mg dextrin 40 mg magnesium stearate 1 mg were prepared in accordance with the usual procedure.

Landscapes

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

Abstract

Dérivés de diphénylurée correspondant à la formule (I), où R1 représente alkyle, X1 représente oxygène, -OCH2- ou -S(O)n-, où n vaut zéro, 1 ou 2, R2 et R3 représentent chacun hydrogène, méthyle ou éthyle, R4 représente alkyle, diméthylamino, -OR6 ou -S(O)mR6, où m vaut zéro, 1 ou 2 et R6 représente alkyle, contenant éventuellement une ou plusieurs double(s) liaison(s) carbone-carbone, et éventuellement interrompu par un ou plusieurs hétéroatomes, et R5 représente -NR7R8 ou -OR9, où R7 et R8 représentent chacun hydrogène ou alkyle contenant éventuellement une ou plusieurs double(s) liaison(s) carbone-carbone, et éventuellement interrompu par un ou plusieurs hétéroatomes, et R9 représente alkyle, contenant éventuellement une ou plusieurs double(s) liaison(s) carbone-carbone et éventuellement interrompu par un ou plusieurs hétéoatomes. Ces dérivés possèdent des caractéristiques pharmacologiques utiles.
EP91914898A 1990-08-15 1991-08-14 Derives de diphenyluree Withdrawn EP0543891A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB909017892A GB9017892D0 (en) 1990-08-15 1990-08-15 New compositions of matter
GB9017892 1990-08-15

Publications (1)

Publication Number Publication Date
EP0543891A1 true EP0543891A1 (fr) 1993-06-02

Family

ID=10680688

Family Applications (1)

Application Number Title Priority Date Filing Date
EP91914898A Withdrawn EP0543891A1 (fr) 1990-08-15 1991-08-14 Derives de diphenyluree

Country Status (10)

Country Link
EP (1) EP0543891A1 (fr)
JP (1) JPH06500095A (fr)
AU (1) AU8411591A (fr)
CA (1) CA2089165A1 (fr)
GB (1) GB9017892D0 (fr)
IE (1) IE912889A1 (fr)
IL (1) IL99174A0 (fr)
PT (1) PT98684A (fr)
WO (1) WO1992003413A1 (fr)
ZA (1) ZA916412B (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2352273A (en) * 1999-07-16 2001-01-24 Scroll Tech Eccentric back-pressure chamber seals for a scroll compressor

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU672699B2 (en) * 1993-06-30 1996-10-10 Sankyo Company Limited Amide and urea derivatives having anti-hypercholesteremic activity, their preparation and their therapeutic uses
DE19624155A1 (de) * 1996-06-18 1998-01-08 Hoechst Ag Substituierte Benzoesäurederivate, Verfahren zu ihrer Herstellung und die Anwendung der Verbindungen zur Behandlung von Krankheiten
EP1158985B1 (fr) 1999-01-13 2011-12-28 Bayer HealthCare LLC DIPHENYLE UREES A SUBSTITUTION OMEGA-CARBOXY ARYLE EN TANT QU'INHIBITEURS DE LA KINASE p38
US8124630B2 (en) 1999-01-13 2012-02-28 Bayer Healthcare Llc ω-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors
US20030216396A1 (en) 2002-02-11 2003-11-20 Bayer Corporation Pyridine, quinoline, and isoquinoline N-oxides as kinase inhibitors
PT1478358E (pt) 2002-02-11 2013-09-11 Bayer Healthcare Llc Tosilato de sorafenib para o tratamento de doenças caracterizadas por angiogénese anormal
JP2007511203A (ja) 2003-05-20 2007-05-10 バイエル、ファーマシューテイカルズ、コーポレイション キナーゼ阻害活性を有するジアリール尿素
DE602004010407T2 (de) 2003-07-23 2008-10-16 Bayer Pharmaceuticals Corp., West Haven Fluorsubstituierter omega-carboxyaryldiphenylharnstoff zur behandlung und prävention von krankheiten und leiden

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9203413A1 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2352273A (en) * 1999-07-16 2001-01-24 Scroll Tech Eccentric back-pressure chamber seals for a scroll compressor
GB2352273B (en) * 1999-07-16 2004-02-11 Scroll Tech Eccentric back chamber seals for scroll compressor

Also Published As

Publication number Publication date
ZA916412B (en) 1992-04-29
JPH06500095A (ja) 1994-01-06
AU8411591A (en) 1992-03-17
IE912889A1 (en) 1992-02-26
WO1992003413A1 (fr) 1992-03-05
IL99174A0 (en) 1992-07-15
CA2089165A1 (fr) 1992-02-16
PT98684A (pt) 1992-07-31
GB9017892D0 (en) 1990-09-26

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