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WO1992003130A1 - 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 Download PDF

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Publication number
WO1992003130A1
WO1992003130A1 PCT/GB1991/001320 GB9101320W WO9203130A1 WO 1992003130 A1 WO1992003130 A1 WO 1992003130A1 GB 9101320 W GB9101320 W GB 9101320W WO 9203130 A1 WO9203130 A1 WO 9203130A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
formula
treatment
prophylaxis
hydrogen
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.)
Ceased
Application number
PCT/GB1991/001320
Other languages
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 WO1992003130A1 publication Critical patent/WO1992003130A1/fr
Anticipated expiration legal-status Critical
Priority to US08/325,941 priority Critical patent/US5461072A/en
Ceased legal-status Critical Current

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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.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (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 C¿1-10 alkylène ou C¿2-10? alkénylène; Q représente la formule (II), dans laquelle R?1¿ représente hydrogène, C¿1-4? alkyle, un groupe comme défini ci-dessus pour Ar ou un groupe de formule -N(R4)R5 dans lequel R?4¿ représente hydrogène, C¿1-4? alkyle et R?5¿ représente hydrogène, C¿1-4? 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 R?2¿ représente hydrogène, C¿1-4? 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 états ci-dessus mentionnés, font également partie du contexte de l'invention.
PCT/GB1991/001320 1990-08-02 1991-08-02 Utilisation de composes d'aryle hydroxyuree pour le traitement de l'atherosclerose Ceased WO1992003130A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US08/325,941 US5461072A (en) 1990-08-02 1994-10-17 Use of aryl hydroxyurea compounds for the treatment of atherosclerosis

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9017351.9 1990-08-08
GB909017351A GB9017351D0 (en) 1990-08-08 1990-08-08 Medicaments for treatment of atherosclerosis

Publications (1)

Publication Number Publication Date
WO1992003130A1 true WO1992003130A1 (fr) 1992-03-05

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PCT/GB1991/001320 Ceased WO1992003130A1 (fr) 1990-08-02 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)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5260316A (en) * 1991-07-30 1993-11-09 Ciba-Geigy Corporation Isoquinolyl substituted hydroxylamine derivatives
US5334600A (en) * 1991-07-30 1994-08-02 Ciba-Geigy Corporation Isoquinolyl substituted hydroxylamine derivatives
US5350761A (en) * 1991-07-30 1994-09-27 Ciba-Geigy Corporation Indolyl 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
US5428048A (en) * 1993-11-08 1995-06-27 American Home Products Corporation Aryl-N-hydroxyureas as inhibitors of 5-lipoxygenase and anto-arteriosclerotic agents
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
WO1998006400A3 (fr) * 1996-08-09 1998-03-26 Biorex Kutato Fejlesztoe Kft Produits pharmaceutiques preventifs et curatifs de maladies liees a des defaillances de cellules de l'endothelium vasculaire
EP1448794A4 (fr) * 2001-10-24 2005-06-01 Univ California Identification de 5-lipoxydase en tant qu'oligogene favorisant l'atherosclerose
US7361655B2 (en) 2002-01-11 2008-04-22 Cytrx Corporation Pharmaceutically effective compounds

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0128374A2 (fr) * 1983-05-12 1984-12-19 Kyowa Hakko Kogyo Co., Ltd. Composition préventive et curative pour maladies causées par les produits métaboliques de la lipoxigenase
EP0183159A2 (fr) * 1984-11-28 1986-06-04 Bayer Ag 1-Hétéroaryl-4-aryl-pyrazolin-5-ones pour application en tant que médicaments
EP0279263A2 (fr) * 1987-02-10 1988-08-24 Abbott Laboratories Composés inhibant la lipoxygénase, contenant de l'indole, du benzofurane ou du benzothiophène

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0128374A2 (fr) * 1983-05-12 1984-12-19 Kyowa Hakko Kogyo Co., Ltd. Composition préventive et curative pour maladies causées par les produits métaboliques de la lipoxigenase
EP0183159A2 (fr) * 1984-11-28 1986-06-04 Bayer Ag 1-Hétéroaryl-4-aryl-pyrazolin-5-ones pour application en tant que médicaments
EP0279263A2 (fr) * 1987-02-10 1988-08-24 Abbott Laboratories Composés inhibant la lipoxygénase, contenant de l'indole, du benzofurane ou du benzothiophène

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
FEBS Letters, volume 245, no. 1,2, March 1989, Elsevier Science Publishers B.V., M.A. Barradas et al.: "Iron chelators inhibit human platelet aggregation, thromboxane A2 synthesis and lipoxygenase activity", pages 105-109, see page 105, column 1, line 17 - column 2, line 10; abstract; page 108, column 2, line 25 - page 109, column 1, line 4 *
Medicina Clinica, volume 84, no. 3, 26 January 1985, J. Santafé Oroz et al.: "Terapeutica farmacologica de la arteriosclerosis (II). Nuevas orientaciones", pages 115-122, see page 120, line 64 - page 121, line 24 *

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5334600A (en) * 1991-07-30 1994-08-02 Ciba-Geigy Corporation Isoquinolyl substituted hydroxylamine derivatives
US5350761A (en) * 1991-07-30 1994-09-27 Ciba-Geigy Corporation Indolyl substituted hydroxylamine derivatives
US5260316A (en) * 1991-07-30 1993-11-09 Ciba-Geigy Corporation Isoquinolyl substituted hydroxylamine derivatives
US5629337A (en) * 1993-05-10 1997-05-13 Sepracor, Inc. Methods for treating asthma using optically pure (-)-zileuton
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
US5428048A (en) * 1993-11-08 1995-06-27 American Home Products Corporation Aryl-N-hydroxyureas as inhibitors of 5-lipoxygenase and anto-arteriosclerotic agents
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
US5541205A (en) * 1993-11-08 1996-07-30 American Home Products Corporation Aryl-n-hydroxyureas as inhbitors of 5-lipoxygenase and anti-arteriosclerotic agents
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
WO1998006400A3 (fr) * 1996-08-09 1998-03-26 Biorex Kutato Fejlesztoe Kft Produits pharmaceutiques preventifs et curatifs de maladies liees a des defaillances de cellules de l'endothelium vasculaire
US6143741A (en) * 1996-08-09 2000-11-07 BIOREX Kutato es Fejleszo Rt. Pharmaceutical products for curing and preventing illnesses connected with the malfunction of vascular endothelial cells
EP1448794A4 (fr) * 2001-10-24 2005-06-01 Univ California Identification de 5-lipoxydase en tant qu'oligogene favorisant l'atherosclerose
US7241571B2 (en) 2001-10-24 2007-07-10 The Regents Of The University Of California Identification of 5-lipoxygenase as a major gene contributing to atherosclerosis
AU2002336657B2 (en) * 2001-10-24 2008-01-03 The Regents Of The University Of California Identification of 5-lipoxygenase as a major gene contributing to atherosclerosis
US7361655B2 (en) 2002-01-11 2008-04-22 Cytrx Corporation Pharmaceutically effective compounds
US7384936B2 (en) 2002-01-11 2008-06-10 Cytrx Corporation Carboxamidine derivatives and their use in the treatment of vascular diseases
US7550457B2 (en) 2002-01-11 2009-06-23 Cytrx Corporation Pharmaceutically effective compounds
US7691849B2 (en) 2002-01-11 2010-04-06 Cytrx Corporation Carboxamidine derivatives and their use in the treatment of vascular diseases

Also Published As

Publication number Publication date
JPH06500537A (ja) 1994-01-20
GB9017351D0 (en) 1990-09-19
EP0543855A1 (fr) 1993-06-02

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