EP0435926A1 - Bile acids for treatment of viral infections - Google Patents

Bile acids for treatment of viral infections

Info

Publication number
EP0435926A1
EP0435926A1 EP89910885A EP89910885A EP0435926A1 EP 0435926 A1 EP0435926 A1 EP 0435926A1 EP 89910885 A EP89910885 A EP 89910885A EP 89910885 A EP89910885 A EP 89910885A EP 0435926 A1 EP0435926 A1 EP 0435926A1
Authority
EP
European Patent Office
Prior art keywords
compound
formula
represent
treatment
disease
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.)
Pending
Application number
EP89910885A
Other languages
German (de)
English (en)
French (fr)
Inventor
Christopher James Sharpe
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.)
Fisons Ltd
Original Assignee
Fisons 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
Priority claimed from GB888822012A external-priority patent/GB8822012D0/en
Priority claimed from GB888822015A external-priority patent/GB8822015D0/en
Priority claimed from GB888822020A external-priority patent/GB8822020D0/en
Application filed by Fisons Ltd filed Critical Fisons Ltd
Publication of EP0435926A1 publication Critical patent/EP0435926A1/en
Pending 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • 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

Definitions

  • This invention relates to a new use of certain known compounds in the treatment of viral infections caused by enveloped viruses, and to pharmaceutical compositions containing them.
  • bile acids Naturally occuring bile acids are produced by the liver, and certain of these have been used in the treatment of gallstones for a number of years. More recently, European Patent Application 0285285 disclosed the use of bile acids in the treatment of viral infections.
  • R 1 and R 2 both represent (H, ⁇ -OH) or both represent O;
  • R 3 represents (H,H) or 0; and R 4 represents OH or NH(CH 2 ) 2 S0 3 H; and pharmaceutically acceptable salts thereof; provided that , i) when R 1 and R 2 both represent (H, ⁇ -OH) and R 3 represents (H,H) , then R 4 represents NH(CH 2 ) 2 S0 3 H; and ii) when R 1 and R 2 both represent 0 and R 3 represents 0, then R 4 represents NH(CH 2 ) 2 S0 3 H; for use as a pharmaceutical.
  • the compounds which we provide as pharmaceuticals are also known as 3,7-diketocholanic acid [R 1 and R 2 both represent O, R 3 represents (H,H) and R 4 represents OH]; tauro-3,7-diketocholanic acid [R 1 and R 2 both represent O, R 3 represents (H,H) and R 4 represents NH(CH 2 ) 2 S0 3 H] ; taurodehydrocholic acid [R 1 and R 2 both represent 0, R 3 represents 0 and R 4 represents NH(CH 2 ) 2 S0 3 H] ; taurochenodeoxycholic acid [R 1 and R 2 both represent (H, ⁇ -0H), R 3 represents (H,H) and R 4 represents NH(CH 2 ) S0 3 H] ; 3 ⁇ ,7 ⁇ -dihydroxy-12-ketocholanic acid [R 1 and R 2 both represent (H, -0H) , R 3 represents 0 and R 4 represents OH] ; and tauro-3 ⁇ .,7 ⁇ -dihydroxy
  • dehydrocholic acid [R 1 and R 2 both represent O, R 3 represents O and R 4 represents OH] .
  • Tauro derivatives may be obtained from the parent bile acid by a mixed anhydride synthesis, eg using ethyl chloroformate and taurine.
  • bile acids are usually ionised and the terms 'bile acid 1 and "bile salt 1 are used interchangeably.
  • Pharmaceutically acceptable salts of the compounds which may be mentioned include certain alkali metal salts, particularly the sodium salts, and certain alkaline earth metal salts, particularly the calcium salts.
  • enveloped virus we mean a virus having a lipid outer coat. Included in this definition are the human immunodeficiency, influenza, parainfluenza and herpes viruses. Thus, diseases of particular interest are AIDS, influenza, parainfluenza and herpes.
  • the compound of formula I may be administered to a patient by any convenient means which results in their introduction into the systemic circulation.
  • they may be introduced parenterally eg by injection (intravenously, intramuscularly or subcutaneously) , topically, orally, using plasmaphoresis, or by inhalation in the form of a non-pressurised powder or an aerosol formulation.
  • the invention further provides a pharmaceutical composition
  • a pharmaceutical composition comprising as active ingredient at least one compound of formula I as defined above (preferably less than 80%, and more preferably less than 50% by weight) in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • Suitable adjuvants, diluents or carriers are: for tablets, capsules and dragees - microcrystalline cellulose, calcium phosphate, diatomaceous earth, a sugar such as lactose, dextrose or mannitol, talc, stearic acid, starch, sodium bicarbonate and/or gelatin; for suppositories - natural or hardened oils or waxes; and for inhalation compositions - coarse lactose.
  • the compound of formula I is preferably in a form having a mass median diameter of from 0.01 to 10 microns.
  • the compositions may also contain suitable preserving, stabilising and wetting agents, solubilisers, sweetening and colouring agents and flavourings.
  • the compositions may, if desired, be formulated in sustained release form.
  • the dosage administered will vary with the compound employed, the mode of administration and the disease indicated. However, in general, satisfactory results are obtained when the compounds are administered at a dosage which produces a concentration in the blood stream of from l-100 ⁇ g/ml, preferably 5-100 ⁇ g/ml.
  • unit dosage forms suitable for administration comprise from lmg to 2500mg, and preferably 2mg to 2000mg of the compound preferably admixed with a solid or liquid pharmaceutically acceptable diluent, carrier or adjuvant.
  • a method of treatment or prophylaxis of a disease caused by an enveloped virus which comprises administration of a therapeutically effective amount of a compound of formula I as defined above to a patient suffering from or at risk of contracting such a disease.
  • the compounds of formula I have the advantage that they are less toxic, more efficacious, are longer acting, have a broader range of activity, are more potent, produce fewer side effects, are more easily absorbed or have other useful pharmacological properties, than compounds previously used against the diseases mentioned above.
  • Test A The antiviral activity of the compounds of formula I which may be used in the present invention were tested in the procedures set out in Tests A and B below. Test A
  • Mammalian lymphocyte (H9IIIB) cells which were chronically infected with HIV were diluted to a concentration of 2xl0 5 ml "1 in a culture medium (RPMI 1640 - which is a mixture of amino acids, salts, glucose and vitamins available from Gibco) .
  • a culture medium RPMI 1640 - which is a mixture of amino acids, salts, glucose and vitamins available from Gibco.
  • 0.5ml aliguots of this solution were placed in the wells of a tissue culture plate together with 0.5ml aliguots of an aqueous solution of "the compound under test.
  • a range of initial concentrations of test compound solution were used (0.4, 4, 40 and 400mgml _1 ) , thus giving final test compound concentrations of 0.1, 1, 10 and lOOmgml -1 in the wells.
  • Uninfected human lymphocyte (8166) cells (1ml of a lxl0 6 ml _1 solution in
  • the infected cell/test compound mixtures were then incubated at 37 ⁇ C. On following days, for example day 1 and day 4, 200 ⁇ l samples of the supernatant liquor from each well were removed and tested for antigen P24, which is produced by the human immunodeficiency virus using the standard Coulter Antigen (P24) ELISA test. The presence of antigen P24 thus indicates the presence of HIV.
  • Test B The test described above gives an indication both of the test compound's inhibitory effect on virus release, and of the test compound's inhibitory effect on virus attachment and penetration.
  • H9IIIB Mammalian lymphocyte (H9IIIB) cells which were chronically infected with HIV were diluted to a concentration of 2xl0 5 ml ⁇ 1 in a culture medium (RPMI).
  • test compound concentrations 0.1, 1, 10 and lOOmgml "1 in the wells.
  • the infected cell/test compound mixtures were then incubated at 37 ⁇ C. On following days, for example day 1 and day 4, 200 ⁇ l samples of the supernatant liquor from each well were removed and tested for antigen P24, which is produced by the human immunodeficiency virus. The presence of antigen P24 thus indicates the presence of HIV.
  • the test described above gives an indication of the test compound's inhibitory effect on virus release.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Virology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Steroid Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
EP89910885A 1988-09-20 1989-09-14 Bile acids for treatment of viral infections Pending EP0435926A1 (en)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
GB888822012A GB8822012D0 (en) 1988-09-20 1988-09-20 Method of treatment
GB8822015 1988-09-20
GB8822020 1988-09-20
GB8822012 1988-09-20
GB888822015A GB8822015D0 (en) 1988-09-20 1988-09-20 Method of treatment
GB888822020A GB8822020D0 (en) 1988-09-20 1988-09-20 Method of treatment

Publications (1)

Publication Number Publication Date
EP0435926A1 true EP0435926A1 (en) 1991-07-10

Family

ID=27264092

Family Applications (2)

Application Number Title Priority Date Filing Date
EP89910885A Pending EP0435926A1 (en) 1988-09-20 1989-09-14 Bile acids for treatment of viral infections
EP89309374A Withdrawn EP0365139A3 (en) 1988-09-20 1989-09-14 Bile acids for the treatment of viral infections

Family Applications After (1)

Application Number Title Priority Date Filing Date
EP89309374A Withdrawn EP0365139A3 (en) 1988-09-20 1989-09-14 Bile acids for the treatment of viral infections

Country Status (6)

Country Link
EP (2) EP0435926A1 (pt)
JP (1) JPH04500670A (pt)
KR (1) KR900701278A (pt)
AU (1) AU4328189A (pt)
PT (1) PT91745B (pt)
WO (1) WO1990003172A2 (pt)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9136083B2 (en) 2013-03-15 2015-09-15 Regal Beloit America, Inc. Enclosed bus bar fuse holder

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IT1255450B (it) * 1992-06-30 1995-10-31 Montefarmaco Spa Uso di acidi biliari come agenti antivirali
US5639866A (en) * 1993-02-23 1997-06-17 Princeton University Single-step formation of multiple glycosidic linkages
IL108748A0 (en) * 1993-02-23 1994-08-26 Univ Princeton Solution and solid-phase formation of glycosidic linkages
DE4316347C1 (de) * 1993-02-26 1994-08-18 Ina Dr Levi Verfahren zur Herstellung einer pharmazeutischen Zubereitung und Verwendung derselben zur Behandlung bestimmter Erkrankungen
US5846964A (en) * 1993-07-19 1998-12-08 Tokyo Tanabe Company Limited Hepatitis C virus proliferation inhibitor
JP2025014084A (ja) * 2021-12-07 2025-01-29 慶應義塾 ウイルス増殖抑制剤
CN115414370A (zh) * 2022-10-14 2022-12-02 华中农业大学 牛磺胆酸钠在制备治疗或预防流感病毒感染的药物中的应用

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3591687A (en) * 1968-03-13 1971-07-06 George A Bray Bile acids and derivatives thereof as anorectic agents
BE792826A (fr) * 1971-12-16 1973-03-30 Intellectual Property Dev Corp Composition et procede pour abaisser les taux de cholesterol etde lipides chez les mammiferes
IT1101649B (it) * 1978-12-15 1985-10-07 Lehner Ag Composizione farmaceutica ad azione prolungata contenente acidi biliari
AU2272883A (en) * 1982-12-22 1984-06-28 Herpes Pharmaceutical Inc. Pharmaceutical compositions of steriods for treatment of herpes simplex infections
GB8417895D0 (en) * 1984-07-13 1984-08-15 Marples B A Pharmaceutical anti-fungal composition
GB8706313D0 (en) * 1987-03-17 1987-04-23 Health Lab Service Board Treatment & prevention of viral infections
JPH06302932A (ja) * 1993-04-09 1994-10-28 Toyo Electric Mfg Co Ltd プリント配線基板

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9003172A2 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9136083B2 (en) 2013-03-15 2015-09-15 Regal Beloit America, Inc. Enclosed bus bar fuse holder

Also Published As

Publication number Publication date
PT91745B (pt) 1995-05-31
AU4328189A (en) 1990-04-18
JPH04500670A (ja) 1992-02-06
WO1990003172A3 (en) 1990-06-28
PT91745A (pt) 1990-03-30
EP0365139A2 (en) 1990-04-25
WO1990003172A2 (en) 1990-04-05
KR900701278A (ko) 1990-12-01
EP0365139A3 (en) 1990-08-01

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Free format text: VERFAHREN ABGESCHLOSSEN INFOLGE VERBINDUNG MIT 89309374.0/0365139 (EUROPAEISCHE ANMELDENUMMER/VEROEFFENTLICHUNGSNUMMER) VOM 27.11.91.