EP0543855A1 - Utilisation de composes d'aryle hydroxyuree pour le traitement de l'atherosclerose - Google Patents

Utilisation de composes d'aryle hydroxyuree pour le traitement de l'atherosclerose

Info

Publication number
EP0543855A1
EP0543855A1 EP91914214A EP91914214A EP0543855A1 EP 0543855 A1 EP0543855 A1 EP 0543855A1 EP 91914214 A EP91914214 A EP 91914214A EP 91914214 A EP91914214 A EP 91914214A EP 0543855 A1 EP0543855 A1 EP 0543855A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
formula
treatment
prophylaxis
compound
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Withdrawn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
EP91914214A
Other languages
German (de)
English (en)
Inventor
Lawrence George Garland
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.)
Wellcome Foundation Ltd
Original Assignee
Wellcome Foundation 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 Wellcome Foundation Ltd filed Critical Wellcome Foundation Ltd
Publication of EP0543855A1 publication Critical patent/EP0543855A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • 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

Definitions

  • the present invention is concerned with the use of certain aryl hydroxyurea compounds in the manufacture of medicaments for the prophylaxis and treatment of clinical conditions for which inhibition of the oxidative modification of lipids is indicated, for example, atherosclerosis, with the medicaments obtained thereby and with their preparation and use in the prophylaxis and treatment of such conditions.
  • European Patent Specification 0279263 describes a novel class of compounds having 5- and/or 12-lipoxygenase inhibiting properties which have potential utility in the treatment of asthma, allergy, arthritis, psoriasis and inflammation.
  • EPS 0279263 also have the ability to scavenge the peroxyl radicals implicated in the oxidation of low density lipoprotein (LDL) . It follows that these compounds may be suitable for use in the treatment of conditions for which inhibition of the oxidative modification of lipids is indicated, for example, atherosclerosis.
  • LDL low density lipoprotein
  • Y is C. 1f . alkylene or C complaint ⁇ n alkenylene
  • R is hydrogen, C- , alkyl, amino, C. , alkylamino, di-C- , alkylamino, C,. -. cycloalkylamino, C,. ⁇ cycloalkyl C- , alkyl)- amino, anilino, N-C. , alkylanilino, or a group as defined for Ar above;
  • Preferred compounds for use in the manufacture of the medicaments of the invention include those wherein r is benzofur-2-yl or benzothien-2-yl;
  • Y is -CH 2 - or -CH(Me)-;
  • R is hydrogen and R is C. , alkyl, amino, C- , alkylamino, or di-C. , alkylamino;
  • a particularly preferred compound for use in the manufacture of a medicament according to the invention is N-hydroxy-N-(l-benzo[b]thien- 2-ylethyl)urea or a physiologically acceptable base salt or physiologically functional derivative thereof.
  • Physiologically acceptable salts for use in the manufacture of the medicaments of the present invention include ammonium salts, alkali metal salts, such as those of sodium and potassium, alkaline earth salts, such as those of calcium and magnesium, salts with organic bases, such as those of dicyclohexylamine and N-methyl-D-glucamine, and salts with amino acids, such as those of arginine and lysine.
  • medicaments comprising a compound of formula (I) , at least one pharmaceutically acceptable carrier and, optionally, one or more other therapeutiously active compounds, for use in the prophylaxis and treatment of a condition for which inhibition of the oxidative modification of lipids is indicated, for example, atherosclerosis, and
  • a suitable dose for a mammal suffering from, or likely to suffer from, any of the clinical conditions described hereinbefore is in the range O.l ⁇ g to 500mg of compound kg bodyweight.
  • the dose is typically in the range 0.5 to 500mg of compound/kg bodyweight, the most preferred dosage being 0.5 to 50mg kg bodyweight, for example, 5 to 25mg kg, administered two or three times daily.
  • a medicament according to the invention comprises a compound of formula (I) in association with at least one pharmaceutically acceptable carrier and, optionally, one or more other therapeutically active compounds.
  • the carrier must, of course, be compatible with the other ingredients in the medicament and must not be detrimental to the recipient.
  • the compound of formula (I) may comprise from 0.1% to 99.9% by weight of the medicament.
  • Typical unit doses of a medicament according to the invention contain from O.lmg to lg of the active ingredient.
  • Medicaments according to the invention include those in a form suitable for oral, pulmonary, rectal, or parenteral (including subcutaneous, intramuscular and intravenous) administration.
  • Medicaments according to the invention may conveniently be presented in unit dosage form and may be prepared l - any method known in the art of pharmacy. All such methods include the step of bringing the compound of formula (I) into association with a carrier which may contain one or more accessory ingredients.
  • the medicaments of the invention are prepared by uniformly and intimately bringing the compound of formula (I) into association with a liquid carrier or a finely divided solid carrier, or both, and then, if desired, shaping the product into the required form, for example, by compression or moulding.
  • Medicaments according to the invention which are suitable for oral administration may be in the form of discrete units, such as capsules, cachets, tablets, or lozenges, each containing a predetermined amount of the compound of formula (I); in the form of a powder or granules; in the form of a solution or a suspension in an aqueous or non-aqueous liquid; or in the form of an oil-in-water or water-in-oil emulsion.
  • the medicament may also be in the form of a bolus, electuary, or paste.
  • Medicaments suitable for parenteral administration typically comprise a sterile aqueous preparation of the compound of formula (I) which is preferably isotonic with the blood of the intended recipient.
  • medicaments according to the invention may include one or more additional ingredients selected from diluents, buffers, flavouring agents, binders, surface- active agents, thickeners, lubricants, preservatives, anti-oxidants and emulsifying agents.
  • the compounds of formula (I) may also be advantageously employed in combination with one or more other therapeutically active compounds selected, for example, from an antibiotic (for example, an anti-bacterial) , anti-fungal, or anti-viral agent, an anti- .stamine (particularly a peripherally-acting anti-histamine) , or a non-steroidal anti-inflamma ⁇ tory drug (NSAID) .
  • antibiotic for example, an anti-bacterial
  • anti-fungal anti-fungal
  • anti-viral agent an anti- .stamine (particularly a peripherally-acting anti-histamine)
  • NSAID non-steroidal anti-inflamma ⁇ tory drug
  • the “active ingredient” in the following formulations may be any compound of formula (I) as hereinbefore defined.
  • the active ingredient is dissolved in half of the Water for Injections and then made up to volume and sterilised by filtration. The resulting solution is distributed into ampoules under aseptic conditions.
  • LDL low density lipoprotein
  • Addition of copper to human low density lipoprotein (LDL) results in the initiation of a peroxidative reaction. This results in the formation of conjugated dienes in the lipid phase and a consequent increase in UV-absorbance at 234nm.
  • Chain-breaking peroxyl radical scavengers inhibit this increase in absorbance at 234nm and this is used as the basis for an assay to estimate the ability of a compound to inhibit the peroxidation of LDL.
  • the reaction was initiated by the addition of 10 ⁇ M CuSO ⁇ to a solution of LDL (125 g/ml) in phosphate-buffered saline.
  • the test compounds were added as ethanolic solutions while ensuring the ethanol content of the resulting solution did not exceed 1% v/v.
  • Cultured endothelial cells can modify low density lipoprotein (LDL) so that It is rapidly taken up by the macrophage scavenger receptor.
  • LDL low density lipoprotein
  • the modification involves peroxidation of LDL and brings about changes in the physiocochemical properties of LDL including an increase in electrophoretic mobility.
  • Peroxyl radical scavengers have been shown to inhibit the endothelial cell modification of LDL as determined by a decrease in the electrophoretic mobility of the sample.
  • Porcine aortic endothelial cells at confluence were incubated for 24 hours at 37 C in Hams F10 medium containing 0.2mg/ml of LDL and a range of concentrations of the test compound in ethanolic solution. The ethanol concentration was always 0.5% w/v. At the end of the incubation, the samples were concentrated and changes in the electrophoretic mobility relative to native LDL measured.

Landscapes

  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Obesity (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Hematology (AREA)
  • Diabetes (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention se rapporte à l'utilisation d'un composé de la formule : Ar-Y-Q dans laquelle Ar représente soit (i) furyle, thiényle, dioxyde de thiényle 1, 1, pyrryle, pyridyle, benzofuryle, benzothiényle, dioxyde de benzothiényle 1, 1, indolyle, naphtyle, quinolyle ou tétrahydronaphtyle, chacun d'entre eux étant éventuellement substitué par un ou plusieurs substituants sélectionnés indépendamment à partir de C1-4 alkyle (qui peut lui-même être éventuellement substitué par un ou plusieurs atomes d'halogène), C1-04 alkoxy, halo, nitro, amino, carboxy, C1-4 alkoxycarbonyle et hydroxy, ou (ii) phényle éventuellement substitué par un ou plusieurs substituants sélectionnés indépendamment à partir de phényle (qui est lui-même éventuellement substitué par un ou plusieurs substituants sélectionnés indépendamment à partir des substituants éventuels spécifiés dans (i) ci-dessus); Y représente C1-10 alkylène ou C2-10 alkénylène; Q représente la formule (II), dans laquelle R1 représente hydrogène, C1-4 alkyle, un groupe comme défini ci-dessus pour Ar ou un groupe de formule -N(R4)R5 dans lequel R4 représente hydrogène, C1-4 alkyle et R5 représente hydrogène, C1-4 alkyle ou phényle éventuellement substitué par un ou plusieurs substituants sélectionnés indépendamment à partir de ceux qui sont spécifiés en tant que substituants éventuels à (i) ci-dessus; et R2 représente hydrogène, C1-4 alkyle, amino, C1-4 alkylamino, di-C1-4 alkylamino, C5-7 cycloalkylamino, C5-7 cycloalkyle (C1-4 alkyle)- amino, anilino, N-C1-4 alkylanilino ou un groupe comme défini ci-dessus pour Ar; ou d'un sel de base acceptable sur le plan physiologique ou un de ses dérivés physiologiques fonctionnels; ceux-ci s'utilisent dans la fabrication d'un médicament servant à la prophylaxie et au traitement d'états préconisant l'inhibition de la modification oxydante des lipides, par exemple, l'athérosclérose. Les médicaments obtenus au moyen du composé décrit par l'invention ainsi que leur préparation et leur utilisation dans la prophylaxie et le traitement des
EP91914214A 1990-08-08 1991-08-02 Utilisation de composes d'aryle hydroxyuree pour le traitement de l'atherosclerose Withdrawn EP0543855A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB909017351A GB9017351D0 (en) 1990-08-08 1990-08-08 Medicaments for treatment of atherosclerosis
GB9017351 1990-08-08

Publications (1)

Publication Number Publication Date
EP0543855A1 true EP0543855A1 (fr) 1993-06-02

Family

ID=10680330

Family Applications (1)

Application Number Title Priority Date Filing Date
EP91914214A Withdrawn EP0543855A1 (fr) 1990-08-08 1991-08-02 Utilisation de composes d'aryle hydroxyuree pour le traitement de l'atherosclerose

Country Status (4)

Country Link
EP (1) EP0543855A1 (fr)
JP (1) JPH06500537A (fr)
GB (1) GB9017351D0 (fr)
WO (1) WO1992003130A1 (fr)

Families Citing this family (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5350761A (en) * 1991-07-30 1994-09-27 Ciba-Geigy Corporation Indolyl substituted hydroxylamine derivatives
US5334600A (en) * 1991-07-30 1994-08-02 Ciba-Geigy Corporation Isoquinolyl substituted hydroxylamine derivatives
US5260316A (en) * 1991-07-30 1993-11-09 Ciba-Geigy Corporation Isoquinolyl substituted hydroxylamine derivatives
WO1994026269A1 (fr) * 1993-05-10 1994-11-24 Sepracor, Inc. Procedes et compositions de traitement de l'asthme, de l'atherosclerose et de maladies inflammatoires a l'aide de (-)-zileuton optiquement pur
US5459154A (en) * 1993-11-08 1995-10-17 American Home Products Corporation N-hydroxyureas as 5-lipoxygenase inhibitors and inhibitors of oxidative modification of low density lipoprotein
US5468760A (en) * 1993-11-08 1995-11-21 American Home Products Corporation Aralkyl-N-hydroxyureas as inhibitors of 5-lipoxygenase and oxidation of low density lipoprotein
US5428048A (en) * 1993-11-08 1995-06-27 American Home Products Corporation Aryl-N-hydroxyureas as inhibitors of 5-lipoxygenase and anto-arteriosclerotic agents
UA64716C2 (en) * 1996-08-09 2004-03-15 Pharmaceuticals for therapy or prevention of illnesses connected with dysfunction of vascular endothelial cells
CN100427609C (zh) 2001-10-24 2008-10-22 加利福尼亚大学董事会 鉴定5-脂氧化酶作为引起动脉硬化症的主要基因
PL371251A1 (en) 2002-01-11 2005-06-13 Biorex Kutato Es Fejlesztö Rt. Carboxamidine derivatives and their use in the treatment of vascular diseases

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS59210021A (ja) * 1983-05-12 1984-11-28 Kyowa Hakko Kogyo Co Ltd リポキシゲナ−ゼ代謝産物に起因する疾患の予防治療剤
DE3443308A1 (de) * 1984-11-28 1986-05-28 Bayer Ag, 5090 Leverkusen 1-heteroaryl-4-aryl-pyrazolin-5-one zur verwendung als arzneimittel
DE3882732T2 (de) * 1987-02-10 1993-12-02 Abbott Lab Indol, Benzofuran, Benzothiophen enthaltende, Lipoxygenase hemmende Verbindungen.

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9203130A1 *

Also Published As

Publication number Publication date
JPH06500537A (ja) 1994-01-20
GB9017351D0 (en) 1990-09-19
WO1992003130A1 (fr) 1992-03-05

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