EP0403535A1 - Coumarines permettant d'inhiber la transcriptase inverse chez les etres humains - Google Patents

Coumarines permettant d'inhiber la transcriptase inverse chez les etres humains

Info

Publication number
EP0403535A1
EP0403535A1 EP89903438A EP89903438A EP0403535A1 EP 0403535 A1 EP0403535 A1 EP 0403535A1 EP 89903438 A EP89903438 A EP 89903438A EP 89903438 A EP89903438 A EP 89903438A EP 0403535 A1 EP0403535 A1 EP 0403535A1
Authority
EP
European Patent Office
Prior art keywords
coumarin
compound
bromo
carbamoyl
hydroxy
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Withdrawn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
EP89903438A
Other languages
German (de)
English (en)
Inventor
Fritz Reusser
William G. Tarpley
Lester Dolak
Irene W. Althaus
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.)
Pharmacia and Upjohn Co
Original Assignee
Upjohn Co
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 Upjohn Co filed Critical Upjohn Co
Publication of EP0403535A1 publication Critical patent/EP0403535A1/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Withdrawn legal-status Critical Current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
    • A61K31/335—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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • 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

Definitions

  • This invention is a novel treatment of patients infected with a human immunodeficiency virus.
  • AZT zidovudine
  • This invention is a method for treating a human infected with one or more than one strain of a human immunodeficiency virus which comprises administering an effective amount of a compound selected from the group consisting of 6-bromo-3-[(m-chlorophenyl)carbamoyl]-coumarin, 6-bromo-3-[( ⁇ , ⁇ , ⁇ -trifluoro-m-toluyl)carbamoyl]-coumarin, 6-bromo-3-[(2,5-dichlorophenyl)carbamoyl]-coumarin, [[bis(4-hydroxy-2-oxo-2H-1-benzopyran-3-yl)-methyl]cyclopentadienyl]cyclopentadienyliron, 3-cinnamoyl-4-hydroxy-coumarin, hexachlorocoumarin, 7-acetoxy coumarin or [1-(2-oxo-2H-1-benzopyran-3-yl)ethylidene]-hydr
  • human immunodeficiency virus means human immunodeficiency virus type I, human immunodeficiency virus type II, or strains, apparent to one skilled in the art, which belong to the same viral family and which create similar physiological effects in humans as human immunodeficiency virus types I or II.
  • the structural formulas, if known, of each of the compounds used to practice the method claimed in this invention are given in the structure charts.
  • the compound, [[bis- (4-hydroxy-2-oxo-2H-1-benzopyran-3-yl)-methyl]cyclopentadienyl]cyclopentadienyl-iron is prepared by condensing 2.0 equivalents of commercially available 4-hydroxycoumarin with 1.5 equivalents of commercially available ferrocenecarboxaldehyde in ethanol following the general procedures described by Sullivan, et al., JACS, Vol. 65, July-December, pages 2288-2291 (1943) "Studies on 4-Hydroxycoumarins. II. The Condensation of Aldehydes with Hydroxycoumarins".
  • the compound, [1-(2-oxo-2H-1-benzopyran-3-yl)ethylidene]-hydrazinecarboxylic acid phenylmethyl ester is prepared by condensing commercially available 3-acetylcoumarin with commercially available benzyl carbazate in the presence of glacial acetic acid in absolute methanol. The reagents are refluxed, diluted with water, cooled and filtered to provide the crystalline compound.
  • compositions or pharmaceutically acceptable salts thereof can be used and administered in practicing the method claimed in this invention.
  • Pharmaceutically acceptable salts refers to those salts of the compounds claimed in this invention which would be readily apparent to a manufacturing pharmaceutical chemist to be equivalent to the parent compound in properties such as formulation, stability, patient acceptance and bioavailability.
  • dosage forms include oral formulations, such as tablets or capsules, or parenteral formulations, such as sterile solutions.
  • an effective amount is from about 1 to 100 mg per kg per day.
  • a typical unit dose for a 70 kg human would be from about 200 mg to 1000 mg taken one to four times per day.
  • Either solid or fluid dosage forms can be prepared for oral administration.
  • Solid compositions are prepared by mixing the compounds used to practice the method claimed in this invention with conventional ingredients such as talc, magnesium stearate, dicalcium phosphate, magnesium aluminum silicate, calcium sulfate, starch, lactose, acacia, methyl cellulose, or functionally similar pharmaceutical diluents and carriers.
  • Capsules are prepared by mixing the compounds used to practice the method claimed in this invention with an inert pharmaceutical diluent and placing the mixture into an appropriately sized hard gelatin capsule.
  • Soft gelatin capsules are prepared by machine encapsulation of a slurry of the compounds used to practice the method claimed in this invention with an acceptable inert oil such as vegetable oil or light liquid petrolatum.
  • Syrups are prepared by dissolving the compounds used to practice the method claimed in this invention in an aqueous vehicle and adding sugar, aromatic flavoring agents and preservatives .
  • Elixirs are prepared using a hydroalcoholic vehicle such as ethanol, suitable sweeteners such as sugar or saccharin and an aromatic flavoring agent.
  • Suspensions are prepared with an aqueous vehicle and a suspending agent such as acacia, tragacanth, or methyl cellulose.
  • parenteral solutions are prepared by dissolving the compounds used to practice the method claimed in this invention in water and filter sterilizing the solution before placing in a suitable sealable vial or ampule.
  • Parenteral suspensions are prepared in substantially the same way except a sterile suspension vehicle is used and the compounds used to practice the method claimed in this invention are sterilized with ethylene oxide or suitable gas before it is suspended in the vehicle.
  • Patients to be treated would be those individuals: 1) infected with one or more than one strain of a human immunodeficiency virus as determined by the presence of either measurable viral antibody or antigen in the serum and 2) having either a symptomatic AIDS defining infection such as i) disseminated histoplasmosis, ii) isoporiasis, iii) bronchial and pulmonary candidiasis including pneumocystis pneumonia iv) non-Hodgkin's lymphoma or v) Kaposi's sarcoma and being less than sixty years old; or having an absolute CD4 lymphocyte count of less than 200/mm 3 in the peripheral blood. Treatment would consist of maintaining an inhibitory level of the compounds disclosed herein in the patient at all times and would continue until the occurrence of a second symptomatic AIDS defining infection indicates alternate therapy is needed.
  • a symptomatic AIDS defining infection such as i) disseminated histoplasmosis, ii) is
  • One thousand two-piece hard gelatin capsules for oral use, each capsule containing 50 mg of hexachlorocoumarin, are prepared from the following:
  • Example 2 Tablets One thousand tablets, each containing 50 mg of hexachlorocoumarin, are prepared from the following:
  • the hexachlorocoumarin is added to the other ingredients, mixed and slugged.
  • the slugs are broken down by forcing through a number sixteen screen.
  • the resulting granules are then compressed into tablets.
  • a sterile aqueous solution for parenteral intravenous injection containing 150 mg of hexachlorocoumarin in one liter of solution is prepared from the following: Hexachlorocoumarin 150 mg
  • the hexachlorocoumarin is sterilized, added to the sterile water, filled into sterile containers and sealed.
  • Extracts prepared according to the procedure of Kleid, D. G., et al., Science, Vol. 214, No. 4525, pages 1125-1129 (1981) "Cloned Virla Protein Vaccine for Footand-Mouth Disease: Responses in Cattle and Swine" are incubated in a mixture of inhibitor, 20 mM dithiothreitol, 60 mM sodium chloride, 0.05% NP-40, 10 mM magnesium chloride, 50 mM Tris pH 8.3, 10 ⁇ M [ 35 S]-labeled deoxynuleoside-5'-triphosphate, 10 /ig/ml RNA template (poly rC or poly rA) and 5 ⁇ g/ml DNA primer (oligo dG or oligo dT) for 30 minutes at 37oC.
  • Priority Country US ment, The Upjohn Company, Kalamazoo, MI 49 (US).

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Virology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyrane Compounds (AREA)

Abstract

Les composés suivants, à savoir 6-bromo-3-[(m-chlorophényle)carbamoyl]-coumarine, 6-bromo-3-[(alpha,alpha,alpha-trifluoro-m-toluyle)carbamoyle]coumarine, 6-bromo-3-[(2,5-dichlorophényle)carbamoyle]coumarine, [[bis(4-hydroxy-2-oxo-2H-1-benzopyrane-3-yl)-méthyl]cyclopentadiényle]cyclopentadiényle-fer, 3-cinnamoyle-4-hydroxy-coumarine, héxachlorocoumarine, 7-acétoxycoumarine ou phénylméthylester de l'acide [1-(2-oxo-2H-1-benzopyrane-3-yl)éthylidène]-hydrazinecarboxylique ou leurs sels pharmaceutiquement acceptables peuvent être utilisés pour traiter des êtres humains infectés par une ou plusieurs souches d'un virus d'immunodéficience humaine.
EP89903438A 1988-03-01 1989-02-08 Coumarines permettant d'inhiber la transcriptase inverse chez les etres humains Withdrawn EP0403535A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US16255388A 1988-03-01 1988-03-01
US162553 1988-03-01
US19003888A 1988-05-04 1988-05-04
US190038 1988-05-04

Publications (1)

Publication Number Publication Date
EP0403535A1 true EP0403535A1 (fr) 1990-12-27

Family

ID=26858857

Family Applications (1)

Application Number Title Priority Date Filing Date
EP89903438A Withdrawn EP0403535A1 (fr) 1988-03-01 1989-02-08 Coumarines permettant d'inhiber la transcriptase inverse chez les etres humains

Country Status (5)

Country Link
EP (1) EP0403535A1 (fr)
JP (1) JPH03503635A (fr)
AU (1) AU4074789A (fr)
DK (1) DK195690A (fr)
WO (1) WO1989007939A2 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5455110A (en) * 1994-06-29 1995-10-03 Kimberly-Clark Corporation Nonwoven laminated fabrics
US8377960B2 (en) 2007-11-15 2013-02-19 Gilead Sciences, Inc. Inhibitors of human immunodeficiency virus replication

Families Citing this family (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0494231A4 (en) * 1989-09-26 1992-09-16 The Regents Of The University Of California 6-amino-1,2-benzopyrones useful for treatment of viral diseases
IL99731A0 (en) * 1990-10-18 1992-08-18 Merck & Co Inc Hydroxylated pyridine derivatives,their preparation and pharmaceutical compositions containing them
US5484951A (en) * 1990-10-19 1996-01-16 Octamer, Incorporated 5-iodo-6-amino-6-nitroso-1,2-benzopyrones useful as cytostatic and antiviral agents
EP0533902A1 (fr) * 1991-04-10 1993-03-31 Octamer, Inc. Procede d'inhibition de la replication retrovirale
US5482975A (en) * 1991-10-22 1996-01-09 Octamer, Inc. Adenosine diphosphoribose polymerase binding nitroso aromatic compounds useful as retroviral inactivating agents, anti-retroviral agents and anti-tumor agents
US5877185A (en) * 1991-10-22 1999-03-02 Octamer, Inc. Synergistic compositions useful as anti-tumor agents
US5753674A (en) * 1991-10-22 1998-05-19 Octamer, Inc. Adenosine diphosphoribose polymerase binding nitroso aromatic compounds useful as retroviral inactivating agents, anti-retroviral agents, anti-retroviral agents and anti-tumor agents
US5516941A (en) * 1991-10-22 1996-05-14 Octamer, Inc. Specific inactivators of "retroviral" (asymmetric) zinc fingers
DE4136900C1 (fr) * 1991-11-09 1993-07-29 Schaper & Bruemmer Gmbh & Co Kg, 3320 Salzgitter, De
US5262564A (en) * 1992-10-30 1993-11-16 Octamer, Inc. Sulfinic acid adducts of organo nitroso compounds useful as retroviral inactivating agents anti-retroviral agents and anti-tumor agents
ZA938019B (en) * 1992-11-13 1995-04-28 Upjohn Co Pyran-2-ones and 5,6-dihydropyran-2-ones useful for treating HIV and other retroviruses
IL108459A0 (en) * 1993-02-05 1994-04-12 Opjohn Company 4-Hydroxy-benzopyran-2-ones and 4-hydroxy-cycloalkyl [B] pyran-2-ones useful for treating infections due to hiv and other retroviruses
US5783599A (en) * 1993-02-24 1998-07-21 Octamer Inc Methods of treating cancer and viral infections with 5-iodo-6-amino-and 5-iodo-6-nitroso-1 2-benzopyrones
US5637589A (en) * 1993-10-29 1997-06-10 University Of North Carolina At Chapel Hill Suksdorfin, analogs, compositions thereof, and methods for making and using thereof
US5504104A (en) * 1993-11-19 1996-04-02 Warner-Lambert Company Tricyclic pyrone derivatives as protease inhibitors and antiviral agents
US5840751A (en) * 1993-11-19 1998-11-24 Warner-Lambert Company 5,6-dihydropyrone derivatives as protease inhibitors and antiviral agents
US5510375A (en) * 1993-11-19 1996-04-23 Warner-Lambert Company Coumarin derivatives as protease inhibitors and antiviral agents
US6005103A (en) * 1993-11-19 1999-12-21 Warner-Lambert Company Pyrone derivatives as protease inhibitors and antiviral agents
JP3698435B2 (ja) * 1993-11-19 2005-09-21 パーク・デイビス・アンド・カンパニー プロテアーゼ阻害剤および抗ウイルス剤としての５，６−ジヒドロピロン誘導体
US6319929B1 (en) 1994-04-29 2001-11-20 The University Of North Carolina At Chapel Hill Suksdorfin analogs, compositions thereof, and methods for making and using thereof
IL129871A (en) * 1994-05-06 2003-11-23 Pharmacia & Upjohn Inc Process for preparing 4-phenyl-substituted octanoyl-oxazolidin-2-one intermediates that are useful for preparing pyran-2-ones useful for treating retroviral infections
CA2222471A1 (fr) * 1996-03-27 1997-10-02 Toray Industries, Inc. Derives de cetone et utilisation medicale connexe
CN1506359A (zh) * 2002-12-05 2004-06-23 �й�ҽѧ��ѧԺҩ���о��� 新的香豆素酰胺衍生物及其制法和其药物组合物与用途
WO2005028441A1 (fr) * 2003-09-17 2005-03-31 Sumitomo Chemical Company, Limited Derives de cinnamoyle et utilisation de ceux-ci
WO2006037468A1 (fr) * 2004-09-30 2006-04-13 Istituto Di Ricerche Di Biologia Molecolare P Angeletti Spa Inhibiteurs de la transcriptase inverse du vih
WO2007124617A1 (fr) * 2006-04-28 2007-11-08 Institute Of Mataria Medica, Chinese Academy Of Medical Sciences Dérivés de coumarine, leurs procédés de préparation, compositions pharmaceutiques et utilisations
JP5285709B2 (ja) 2007-11-16 2013-09-11 ギリアード サイエンシス インコーポレーテッド ヒト免疫不全ウイルスの複製阻害薬
CN113402491A (zh) * 2021-06-15 2021-09-17 山东大学苏州研究院 一种香豆素酰胺类化合物及其制备方法与应用

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO8907939A2 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5455110A (en) * 1994-06-29 1995-10-03 Kimberly-Clark Corporation Nonwoven laminated fabrics
US8377960B2 (en) 2007-11-15 2013-02-19 Gilead Sciences, Inc. Inhibitors of human immunodeficiency virus replication

Also Published As

Publication number Publication date
DK195690D0 (da) 1990-08-16
DK195690A (da) 1990-08-16
WO1989007939A3 (fr) 1989-10-19
WO1989007939A2 (fr) 1989-09-08
AU4074789A (en) 1989-09-22
JPH03503635A (ja) 1991-08-15

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