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.

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• 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)

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• 1989
  • 1989-09-14 EP EP89309374A patent/EP0365139A3/de not_active Withdrawn
  • 1989-09-14 EP EP89910885A patent/EP0435926A1/de active Pending
  • 1989-09-14 JP JP1509999A patent/JPH04500670A/ja active Pending
  • 1989-09-14 AU AU43281/89A patent/AU4328189A/en not_active Abandoned
  • 1989-09-14 KR KR1019900701043A patent/KR900701278A/ko not_active Application Discontinuation
  • 1989-09-14 WO PCT/GB1989/001080 patent/WO1990003172A2/en not_active Application Discontinuation
  • 1989-09-19 PT PT91745A patent/PT91745B/pt not_active IP Right Cessation

Non-Patent Citations (1)

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