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WO1996031206A2 - Flavones et coumarines utilisees en tant qu'agents dans le traitement de l'atherosclerose - Google Patents

Flavones et coumarines utilisees en tant qu'agents dans le traitement de l'atherosclerose Download PDF

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Publication number
WO1996031206A2
WO1996031206A2 PCT/US1996/004028 US9604028W WO9631206A2 WO 1996031206 A2 WO1996031206 A2 WO 1996031206A2 US 9604028 W US9604028 W US 9604028W WO 9631206 A2 WO9631206 A2 WO 9631206A2
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WO
WIPO (PCT)
Prior art keywords
chromen
phenyl
hydroxy
methoxy
methyl
Prior art date
Application number
PCT/US1996/004028
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English (en)
Other versions
WO1996031206A3 (fr
Inventor
Uday Saxena
Bharat Kalidas Trivedi
Original Assignee
Warner-Lambert Company
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 Warner-Lambert Company filed Critical Warner-Lambert Company
Priority to AU52592/96A priority Critical patent/AU5259296A/en
Publication of WO1996031206A2 publication Critical patent/WO1996031206A2/fr
Publication of WO1996031206A3 publication Critical patent/WO1996031206A3/fr

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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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • A61K31/37—Coumarins, e.g. psoralen
    • 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
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 

Definitions

  • the present invention relates to pharmaceutical compositions which include these compounds and a pharmaceutically acceptable carrier for administering an effective amount of the aforementioned compounds in unit dosage form in the treatment methods mentioned above.
  • Atherosclerosis is viewed as a chronic inflammatory disease of the artery involving monocyte accumulation, smooth muscle proliferation, and cholesteryl ester accumulation by both these cell types.
  • Monocyte accumulation in atherosclerosis begins with the adherence of blood-borne monocytes to defined areas of aortic endothelium (Ross R., Nature, 1993;362:801-809) .
  • the attachment of monocytes is mediated by VCAM-1 expression on endothelial cell- surface as suggested by studies in animal models of atherosclerosis (Li H., et al . , Arteriosclerosis Throm.
  • flavones and/or coumarins are inhibitors of VCAM-1 and ICAM-1 and additionally are active in blocking leukocyte adhesion in a rat model and are thus useful as agents for the treatment of atherosclerosis, restenosis, and immune disorders such as arthritis and transplant rejection.
  • a still further embodiment of the present invention is a method of treatment of atherosclerosis in mammals in need thereof comprising administering to such mammal an effective amount of a compound selected from the group consisting of: a flavone and a coumarin in combination with one or more agents selected from the group consisting of: (a) ACAT inhibitor; (b) HMG-CoA reductase inhibitor;
  • cycloalkyl means a saturated hydrocarbon ring which contains from 3 to 12 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, and the like.
  • alkoxy and thioalkoxy are O-alkyl or
  • flavone means 2-phenyl-4H-l-benzopyran- 4-one or a substituted 2-phenyl-4H-l-benzopyran-4-one, i.e. ,
  • R is hydrogen, alkyl, alkoxy, hydroxy, -N-R 10 wherein R 10 and R 11 are each R 11 independently the same or different and each is hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, or
  • R 2 and R 3 may be joined to form a ring selected from the group consisting of: further, R 2 and R 3 or R 7 and R 8 may be joined by a methylenedioxy group; and in a compound of Formula II R is hydrogen, aryl, arylalkyl, -CH 2 -NH-CH 2 -phenyl,
  • R 2 , R 3 , R 4 , and R 5 are each independently the same or different, and each is hydrogen, alkyl, methoxy, halogen, hydroxy,
  • R 3 and R 4 may be joined to form a ring which is
  • Particularly valuable compounds of Formula I and Formula II are selected from the group consisting of:
  • 6-Chloro-2- (5-chloro-2-hydroxy-phenyl) -chromen- 4-one; 2- (2-Amino-phenyl) -chromen-4-one; 6-Bromo-2- (3 -hydroxy-4-methoxy-phenyl ) -chromen- -one ;
  • Preferred compounds used in the second embodiment of the present invention include one or more agents selected from the group consisting of an acyl CoA:cholesterol acyltransferase (ACAT) inhibitor;
  • ACAT acyl CoA:cholesterol acyltransferase
  • HMG-CoA reductase 3-hydroxy-3-methyglutaryl-coenzyme A reductase (HMG-CoA reductase) inhibitor; lipid regulator; and bile acid sequestrant.
  • ACAT inhibitors include DL-melinamide disclosed in British Patent 1,123,004 and Japan. J. Pharmacol. , 1986;42:517-523; 2, 2-dimethyl-N- (2, 4, 6- trimethoxyphenyDdodecanamide disclosed in U.S. Patent 4,716,175; N- [2, 6-bis (1-methylethyl)phenyl] -N' - [ [1- (4-dimethylaminophenyl) cyclopentyl]methyl]urea disclosed in U.S.
  • Patent 5,015,644; 2, 6-bis (1-methyl- ethyl)phenyl[[2,4, 6-tris (1-methylethyl)phenyl]acetyl] - sulfamate disclosed in copending U.S. Patent Application Serial Number 08/233,932 filed April 13, 1994; and the like.
  • U.S. Patents 4,716,175 and 5,015,644 and U.S. Patent Application Serial Number 08/233,932 and British Patent 1,123,004 and Japan. J. Pharmacol.. 1986;42:517-523 are hereby incorporated by reference.
  • HMG-CoA reductase inhibitors include lovastatin disclosed in U.S. Patent 4,231,938; pravastatin disclosed in U.S. Patent 4,346,227; simvastatin disclosed in U.S. Patent 4,444,784; fluvastatin disclosed in U.S. Patent 4,739,073; atorvastatin disclosed in U.S. Patents 4,681,893 and 5,273,995; and the like.
  • U.S. Patents 4,231,938, 4,346,227, 4,444,784, 4,681,893, 4,739,073, and 5,273,995 are hereby incorporated by reference.
  • bile acid sequestrants include colestipol disclosed in U.S. Patents 3,692,895 and 3,803,237; cholestyramine disclosed in U.S. Patent 3,383,281 and Casdorph R. in Lipid Pharmacology..
  • U.S. Patents 3,692,895, 3,803,237, and 3,383,281 and R. Casdorph, supra, 1976, are hereby incorporated by reference.
  • Examples of lipid regulators include gemfibrozil described in U.S. Patent 3,674,836; bezafibrate disclosed in U.S. Patent 3,781,328; clofibrate disclosed in U.S. Patent 3,262,850; fenofibrate disclosed in U.S. Patent 4,058,552; niacin disclosed in McElvain, et al . , Or ⁇ . Svn.. 1925;4:49; and the like.
  • the flavones and coumarins of the present invention are prepared by standard procedures known to those skilled in the art. For example, methods of preparing flavones are disclosed in "The Flavonoids" eds . , Harborne J.B. , Marby T.J. , and Marby H. , Chapman and Hall, London 1975:693-707; Banerji A., and Goomer N.C., Synthesis. 1980:874; Allan J. and Robinson R. , J. Chem. Soc . , 1926; 129 :2334;
  • the flavones and coumarins are valuable agents for the treatment of atherosclerosis, restenosis, and immune disorders such as arthritis and transplant rejection.
  • the tests employed indicate that the compounds possess activity against VCAM-1 and ICAM-1.
  • FBS fetal bovine serum
  • TNF recombinant Tumor necrosis factor-alpha (Genzyme!
  • BSA Bovine serum albumin
  • Anti-ICAM-1 antibody R&D System, BBA#3
  • Anti-VCAM-1 antibody (R&D System, BBA#6)
  • HAEC Human aortic endothelial cells
  • the cells were incubated with anti-VCAM-1 monoclonal antibody (1.25 ⁇ g/mL) for 2 hours at 37°C. The unbound antibody was aspirated, cells washed
  • Anti-ICAM-1 monoclonal antibody (0.5 ⁇ g/mL) was added to the cells and incubated for 2 hours at 37°C. The media was aspirated, cells washed 4 times with 2% BSA-DMEM, and second antibody added (sheep anti-mouse IgG, 1:3000 dilution) , and cells incubated for 1 hour at 37°C. After removal of the unbound antibody and 4 washes with DMEM alone, the cells were incubated with the HRP color reagent for 15 minutes at 37°C in the dark. Fifty microliters of the color reagent from each well was transferred to 96 well plates and absorbance read at 414 run on a Titertek ELISA reader. Cell- surface ICAM-1 expression is presented as OD 414 . The data in the table show the VCAM-1 and ICAM-1 activity of representative flavones and coumarins of the present invention.
  • the lungs and hearts are placed in separate tubes containing 3 mL of a solution of normal saline containing 1 mg/mL of aprotinin and phenylmethyl sulfonyl fluoride (PMSF) .
  • the tissue is then homogenized using a polytron on the high setting. All samples are held on ice. The samples are then aliquoted and frozen at 20°C.
  • the myeloperoxidase assay was standardized with the linear portion of the curve identified. Lowry protein assays were performed and the samples were diluted to obtain optical densities in the linear range.
  • Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents .
  • viscous material such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents .
  • solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration.
  • Such liquid forms include solutions, suspensions, and emulsions.
  • These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Les flavones et les coumarines ou leurs sels pharmaceutiquement acceptables sont des inhibiteurs de VCAM-1 et ICAM-1 et sont donc utiles dans le traitement de l'athérosclérose, de la resténose et de troubles immunitaires tels que l'arthrite et le rejet des transplantations.
PCT/US1996/004028 1995-04-07 1996-03-25 Flavones et coumarines utilisees en tant qu'agents dans le traitement de l'atherosclerose WO1996031206A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU52592/96A AU5259296A (en) 1995-04-07 1996-03-25 Flavones and coumarins as agents for the treatment of athero sclerosis

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US41870995A 1995-04-07 1995-04-07
US08/418,709 1995-04-07

Publications (2)

Publication Number Publication Date
WO1996031206A2 true WO1996031206A2 (fr) 1996-10-10
WO1996031206A3 WO1996031206A3 (fr) 1996-12-12

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AU (1) AU5259296A (fr)
WO (1) WO1996031206A2 (fr)

Cited By (66)

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US5922719A (en) * 1997-08-11 1999-07-13 Warner-Lambert Company Coumarin dopamine D4 receptor antagonists
FR2781153A1 (fr) * 1998-07-15 2000-01-21 Lafon Labor Composition therapeutique a base de flavonoides destinee a etre utilisee dans le traitement des tumeurs par des agents cytotoxiques
US6020347A (en) * 1997-11-18 2000-02-01 Merck & Co., Inc. 4-substituted-4-piperidine carboxamide derivatives
DE19845372A1 (de) * 1998-10-02 2000-04-20 Gruenenthal Gmbh Verwendung von Katecholderivaten als Proteinaseninhibitoren
WO1999054286A3 (fr) * 1998-04-17 2000-05-04 Wayne Hughes Inst Inhibiteurs btk et leurs procedes d'identification et d'utilisation
US6069163A (en) * 1997-10-21 2000-05-30 Merck & Co., Inc. Azapeptide acids as cell adhesion inhibitors
WO2000035435A1 (fr) * 1998-12-15 2000-06-22 Warner-Lambert Company Technique de prevention du rejet de greffe par utilisation d'un inhibiteur du mek
US6090841A (en) * 1997-11-21 2000-07-18 Merck & Co., Inc. Substituted pyrrole derivatives as cell adhesion inhibitors
WO2000050030A1 (fr) * 1999-02-25 2000-08-31 Ted Ebendal Nouvelle utilisation
US6160010A (en) * 1998-08-21 2000-12-12 Parker Hughes Institute BTK inhibitors and methods for their identification and use
US6191171B1 (en) 1997-11-20 2001-02-20 Merck & Co., Inc. Para-aminomethylaryl carboxamide derivatives
US6221888B1 (en) 1997-05-29 2001-04-24 Merck & Co., Inc. Sulfonamides as cell adhesion inhibitors
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US6291511B1 (en) 1997-05-29 2001-09-18 Merck & Co., Inc. Biarylalkanoic acids as cell adhesion inhibitors
US6331562B1 (en) 1998-12-30 2001-12-18 Signal Pharmaceuticals, Inc. Compounds and methods for modulation of estrogen receptors
WO2002102368A1 (fr) * 2001-06-19 2002-12-27 Tg Biotech, Inc. Procede de production cellulaire de masse de chondrocytes a l'aide d'un inhibiteur d'activite erk, et procede de criblage associe
WO2002102367A1 (fr) * 2001-06-19 2002-12-27 Tg Biotech, Inc. Composition pharmaceutique pour la prevention et le traitement de l'arthrite des articulations, et procede de criblage correspondant
US6645939B1 (en) 1997-11-24 2003-11-11 Merck & Co., Inc. Substituted β-alanine derivatives as cell adhesion inhibitors
JP2004509855A (ja) * 2000-07-21 2004-04-02 中外製薬株式会社 ＴＮＦαインヒビターとして有用なクマリン誘導体
JP2004123728A (ja) * 2002-09-09 2004-04-22 New Industry Research Organization 新規フラボノイド化合物及びその利用
WO2004041279A1 (fr) 2002-10-30 2004-05-21 Merck & Co., Inc. Modulateurs gamma-aminoamides de l'activite de recepteur de chimiokine
WO2004105769A1 (fr) * 2003-05-28 2004-12-09 Universite De Liege Composition pharmaceutique destinee au traitement et/ou a la prevention de l'atherosclerose d'origine infectieuse
WO2007010342A1 (fr) * 2005-07-15 2007-01-25 Sahajanand Biotech Private Limited Dispositifs medicaux implantables comprenant un flavonoide ou un derive de celui-ci pour la prevention de la restenose
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WO2012151137A1 (fr) 2011-05-04 2012-11-08 Merck Sharp & Dohme Corp. Inhibiteurs de tyrosine kinase splénique contenant une aminopyridine
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US9271978B2 (en) 2012-12-21 2016-03-01 Zenith Epigenetics Corp. Heterocyclic compounds as bromodomain inhibitors
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US9757368B2 (en) 2009-04-22 2017-09-12 Resverlogix Corp. Anti-inflammatory agents
US9765039B2 (en) 2012-11-21 2017-09-19 Zenith Epigenetics Ltd. Biaryl derivatives as bromodomain inhibitors
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US9963476B2 (en) 2015-02-19 2018-05-08 Council Of Scientific And Industrial Research Antioxidant compound having anti atherosclerotic effect and preparation thereof
WO2018099675A1 (fr) * 2016-11-30 2018-06-07 Beiersdorf Ag Utilisation de 2'-méthoxyflavones dans des préparations cosmétiques ou dermatologiques pour la prophylaxie et le traitement des peaux sensibles
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EP1009404A4 (fr) * 1997-05-13 2009-07-01 Octamer Inc Procede de traitement de l'inflammation ou de maladies inflammatoires a l'aide d'inhibiteurs de poly-adp ribose polymerase
US6221888B1 (en) 1997-05-29 2001-04-24 Merck & Co., Inc. Sulfonamides as cell adhesion inhibitors
US6291511B1 (en) 1997-05-29 2001-09-18 Merck & Co., Inc. Biarylalkanoic acids as cell adhesion inhibitors
US5922719A (en) * 1997-08-11 1999-07-13 Warner-Lambert Company Coumarin dopamine D4 receptor antagonists
US6069163A (en) * 1997-10-21 2000-05-30 Merck & Co., Inc. Azapeptide acids as cell adhesion inhibitors
US6020347A (en) * 1997-11-18 2000-02-01 Merck & Co., Inc. 4-substituted-4-piperidine carboxamide derivatives
US6191171B1 (en) 1997-11-20 2001-02-20 Merck & Co., Inc. Para-aminomethylaryl carboxamide derivatives
US6090841A (en) * 1997-11-21 2000-07-18 Merck & Co., Inc. Substituted pyrrole derivatives as cell adhesion inhibitors
US6645939B1 (en) 1997-11-24 2003-11-11 Merck & Co., Inc. Substituted β-alanine derivatives as cell adhesion inhibitors
WO1999054286A3 (fr) * 1998-04-17 2000-05-04 Wayne Hughes Inst Inhibiteurs btk et leurs procedes d'identification et d'utilisation
FR2781153A1 (fr) * 1998-07-15 2000-01-21 Lafon Labor Composition therapeutique a base de flavonoides destinee a etre utilisee dans le traitement des tumeurs par des agents cytotoxiques
WO2000003706A1 (fr) * 1998-07-15 2000-01-27 Laboratoire L. Lafon Composition therapeutique a base de flavonoïdes destinee a etre utilisee dans le traitement des tumeurs par des agents cytotoxiques
US6221900B1 (en) 1998-08-21 2001-04-24 Hughes Institute BTK inhibitors and methods for their identification and use
US6160010A (en) * 1998-08-21 2000-12-12 Parker Hughes Institute BTK inhibitors and methods for their identification and use
US6294575B1 (en) 1998-08-21 2001-09-25 Parker Hughes Institute BTK inhibitors and methods for their identification and use
US6303652B1 (en) 1998-08-21 2001-10-16 Hughes Institute BTK inhibitors and methods for their identification and use
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