EP0391898A1 - Fusidinsäure verwendbar zur behandlung von aids - Google Patents

Fusidinsäure verwendbar zur behandlung von aids

Info

Publication number
EP0391898A1
EP0391898A1 EP88905837A EP88905837A EP0391898A1 EP 0391898 A1 EP0391898 A1 EP 0391898A1 EP 88905837 A EP88905837 A EP 88905837A EP 88905837 A EP88905837 A EP 88905837A EP 0391898 A1 EP0391898 A1 EP 0391898A1
Authority
EP
European Patent Office
Prior art keywords
aids
pharmaceutically acceptable
radical
compound
treatment
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Withdrawn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
EP88905837A
Other languages
English (en)
French (fr)
Inventor
Johan Viggo Faber
Wagn Ole Godtfredsen
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.)
FABER, JOHAN VIGGO
Original Assignee
Leo Pharmaceutical Products Ltd AS
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 EP87110621A external-priority patent/EP0300073A1/de
Application filed by Leo Pharmaceutical Products Ltd AS filed Critical Leo Pharmaceutical Products Ltd AS
Publication of EP0391898A1 publication Critical patent/EP0391898A1/de
Withdrawn legal-status Critical Current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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • 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
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV

Definitions

  • the present invention relates to the use of fusidic acid and certain fusidic acid analogues, i.e. those described in US Patent Nos. 4,060,606, 4,100,276, 4,162,259, 4,315,004, 4,119,717 and in W. von Daehne, W.O. Godtfredsen, and P.R. Rasmussen: "Structure-Activity Relationships in Fusidic Acid-Type Antibiotics", Advances in Applied Microbiology, Volume 25, pp.
  • the present invention relates to the use of fusidic acid and its analogues and their pharmaceutically acceptable salts and in vivo hydrolyzable esters for the manufacture of a medicament fo r the prophylactic or therapeutic treatment of ARC and AIDS.
  • the present invention also relates to a pharmaceutical composition for the prophylaxis in HIV antibody positive subjects or treatment of patients suffering from ARC and AIDS, which comprises fusidic acid or one of its analogues, or a pharmaceutically acceptable salt or in vivo hydrolyzable ester thereof, together with pharmaceutically acceptable, non-toxic excipients. Furthermore, the present invention is directed to a method for prophylaxis in HIV-antibody positive persons, or for the treatment of patients suffering from ARC or AIDS, which comprises administering to said subjects fusidic acid or one of its analogues, or a pharmaceutically acceptable salt or in vivo hydrolyzable ester thereof.
  • Fusidic acid is a narrow spectrum antibiotic having the following structure I
  • fusidic acid Since its introduction in 1962, fusidic acid has been used extensively both systemically and topically in the treatment of bacterial infections, in particular, staphylococcal infections. It has only weak activity against gram negative bacilli and fungi. At usual therapeutic doses (up to 3 g/day) it is essentially non-toxic. In order to control the emergence of fusidic acid-resistant mutants and/or to synergistically potentiate its anti-bacterial activity, fusidic acid is often used in combination with penicillins or other antibiotics (see, for instance, L.P. Garrod, H.P. Lambert, F. O'Grady, and P.M. Waterworth, "Antibiotic and Chemotherapy", Fifth Edition, Churchill Livingstone, 1981 pages 220 to 225; and EP-A-217 580).
  • Q 1 and Q 2 stand for the group or oxygen
  • A represents oxygen or sulphur or a sulphinyl radical
  • R 1 stands for a straight or branched alkyl radical having from 1 to 8 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, the known isomers of pentyl, hexyl, heptyl and octyl, such alkyl radicals being optionally substituted with halogen atoms or hydroxy, alkyloxy, aralkyloxy, aryloxy, alkanoyloxy, aralkanoyloxy, aroyloxy, sulfhydryl, alkylthio, aralkylthio, arylthio, alkanoylthio, aroylthio, azido, nitro, cyano, thiocyano, hydroxycarbonyl,
  • 1-methyl-2-imidazolyl triazolyl e.g. 5-methyl-1,2,4- triazol-3-yl, tetrazolyl e.g. 1-methyl-1H-tetrazol-5-yl, thiazolyl, thiadiazolyl e.g. 5-methyl-1,3,4-thiadiazol-2-yl.
  • R' 1 stands for a straight or branched alkyl radical having from 1 to 12 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, the known isomers of pentyl, hexyl, heptyl, octyl, and dodecyl, such alkyl radicals being optionally substituted with halogen atoms or hydroxy, alkyloxy, aralkyloxy, aryloxy, alkanoyloxy, aralkanoyloxy, aroyloxy, sulfhydryl, alkylthio, aralkylthio, arylthio, alkanoylthio, aroylthio, azido, nitro, cyano, thiocyano, hydroxycarbonyl
  • R' 1 can further be an alkenyl or alkynyl radical having from 3 to 6 carbon atoms, such as allyl, crotyl or propargyl, a cycloalkyl radical having from 3 to 7 carbon atoms in the alicyclic ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or the mono- or dihalo, lower alkyl, lower alkoxy or hydroxy substituted analogues, an aralkyl or aryl radical, such as benzyl, phenylethyl, phenyl, furfuryl or naphthyl, optionally substituted with halogen, lower alkyl, hydroxy or alkoxy radicals; R' 1 can also be a heterocyclic radical having 5 or
  • 1-methyl-2-imidazolyl triazolyl e.g. 5-methyl-1,2,4-triazol-3-yl, tetrazolyl e.g. 1-methyl-1H-tetrazol-5-yl, thiazolyl, thiadiazolyl e.g. 5-methyl-1,3,4-thiadiazol-2-yl.
  • Q' 1 represents oxygen or one of the groupings Z being a hydroxy group, a halogen atom, an alkylsulfonyloxy or arylsulfonyloxy group, such as methanesulfonyloxy or p-toluenesulfonyloxy, an azido or a nitro group
  • Q 2 is oxygen or the grouping and R 1 stands for a straight or branched alkyl radical having from 1 to 6 carbon atoms, such as methyl, ethyl, propyl, iso- propyl, butyl, isobutyl, tert-butyl or the known isomers of pentyl and hexyl, a phenyl or a heterocyclyl radical having 5 or 6 ring atoms and containing nitrogen, oxygen and/or sulfur atoms, these radicals being optionally substituted with halogen, nitro, lower alkyl or lower alkoxy radicals.
  • the alkyl groups preferably contain 1 to 4 carbon atoms
  • the alkanoyl groups preferably contain 1 (or 2) to 7 carbon atoms and preferred, aryl radicals are phenyl and naphthyl.
  • the preferred aralkyl, alkoxy, aralkyloxy, aryloxy, alkanoyloxy, aralkanoyloxy, aroyloxy, alkylthio, aralkylthio, arylthio, alkanoylthio, aroylthio, alkoxycarbonyl, aryloxycarbonyl, alkylamino, dialkylamino, arylamino, alkanoylamino, aroylamino radicals etc. are derived from the above preferred alkyl, aryl and alkanoyl groups. All of these groups may be straight- chain or branched radicals.
  • fusidic acid and a few related compounds have been shown to have some in vitro activity against certain viruses such as Coxsackie virus A21, and rhinovirus (see, for example, Br. J. Pharm. Chemother., 1967, 31, pageg 210 to
  • fusidic acid and the fusidic acid analogues described above as well as the pharmaceutically acceptable salts and in vivo hydrolyzable esters thereof have a clinical effect against ARC and AIDS caused by the retrovirus HIV (human immunodeficiency virus).
  • fusidic acid sodium salt was administered to AIDS patients with
  • T-4 helper/inducer cells which are phenotypically defined by the presence of CD4 molecules along their surfaces.
  • the CD4 molecule which is used by cells to recognise antigenes in association with the class I major histocompatibility complex is also the receptor for the virus.
  • the T-4 cell has the major responsibility for orchestrating virtually all immune functions in humans and, therefore, HIV can do maximal damage to the immune system by eliminating this particular cell.
  • Plasma concentrations of the active ingredients of the present invention exceeding 100 ⁇ g/ml can easily be attained by, for example, oral or intravenous administration of doses which are essentially non-toxic. Since it is known that fusidic acid concentrations in leucocytes and lymphocytes are 7 to 10 times higher than in the surrounding medium, it should thus be possible to inhibit HIV replication in humans with non-toxic doses (cf. A. Forsgren and A. Belahsene: "Antibiotic Accumulation in Human Polymorphonuclear Leucocytes and Lymphocytes" in Scand. J. Infect. Dis. 1985, Supp. 44, pp. 16-23).
  • the invention is directed to the use of fusidic acid and its analogues, and their pharmaceutically acceptable salts and in vivo hydrolyzable esters, in the manufacture of a medicament for the prophylaxis in HIV antibody positive subjects or treatment of patients suffering from ARC or AIDS. Furthermore, the invention relates to a method for the prophylactic or therapeutic treatment of ARC and AIDS, which comprises administering an effective amount of fusidic acid or one of its analogues or a pharmaceutically acceptable salt or in vivo hydrolyzable ester thereof to a person in need of such treatment.
  • the invention relates to a pharmaceutical composition for the prophylaxis in HIV antibody positive subjects or treatment of patients. suffering from ARC and AIDS, which comprises fusidic acid or one of its analogues, or a pharmaceutically acceptable salts or in vivo hydrolyzable ester thereof, together with pharmaceutically acceptable, non-toxic excipients.
  • compositions of the present invention are, generally, prepared by bringing the active ingredient (fusidic acid or one of its analogues or a pharmaceutically acceptable salt or in vivo hydrolyzable ester thereof) into association with one or more pharmaceutically acceptable non-toxic excipients.
  • salts of fusidic acid with alkali metals, alkaline earth metals, amines and alkanolamines for instance, the water-soluble sodium, potassium, ammonium, triethylamine, piperidine, morpholine, cyclohexylamine, monoethanolamine and diethanolamine salts and the slightly water-soluble calcium, magnesium, sym-dibenzylethylenediamine, benzyl- ⁇ -phenyl- -ethylamine and procaine salts.
  • Suitable salts are, for instance, those with pyrrolidine, piperazine, guanidine, methylamine, ethylamine, benzylamine or similar unsubstituted or substituted amines, furthermore, quaternary amines such as choline and its derivatives,and salts with basic antibiotics such as aminoglycosides and ansamycines such as rifampicin.
  • in vivo hydrolyzable ester groups are: alkanoyloxymethyl with from 3 to 8 carbon atoms, 1-(alkanoyloxy) ethyl with from 4 to 9 carbon atoms, alkoxycarbonyloxy-methyl with from 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy)-ethyl with from 4 to 7 carbon atoms, and ⁇ -aminoalkanoyloxy-methyl with from 2 to 6 carbon atoms.
  • Other preferred esters are lactonyl esters, e.g. 3-phthalidyl, 4-crotonolactonyl or ⁇ -butyrolacton-4-yl esters.
  • methoxy- methyl, cyanomethyl, or mono- or dialkyl substituted amino- alkyl esters e.g. 3-dimethylaminoethyl, 2-diethylaminoethyl, or 3-dimethylaminopropyl esters.
  • a pharmaceutically acceptable excipient is to be broadly understood to include any carrier, diluent, filler, binder or other substance such as an inert pharmaceutical additive to facilitate formulation that is acceptable for administration to a human patient from a toxicity viewpoint and that will not substantially interfere with the administration of the active compound.
  • the compositions may be in the form of solid, semi-solid or liquid dosage forms such as, for example, tablets, capsules, sterile powders for reconstitution before parenteral administration, suppositories, pills, liquids, suspensions or the like, preferably in unit dosage forms suitable for single administration of precise dosages.
  • unit dosage forms preferably contain the active ingredient in an amount of from 0.025 g to 1 g per dosage unit.
  • conventional non-toxic solid excipients include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate and the like.
  • the active ingredient as defined above may be formulated as suppositories using, for example, polyalkylene glycols, for example, propylene glycol, as the carrier.
  • Liquid pharmaceutically administerable compositions can, for example, be prepared by dissolving, dispersing etc., an active compound as defined above and optional pharmaceutical adjuvants in a carrier such as, for example, water, saline, aqueous dextrose, glycerol, ethanol and the like to thereby form a solution or suspension.
  • the pharmaceutical composition to be administered may also contain minor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like, for example, sodium acetate, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate, etc.
  • auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like, for example, sodium acetate, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate, etc.
  • a particularly preferred formulation of this type is a film-coated tablet which comprises the following components:
  • fillers such as lactose and microcrystalline cellulose
  • binders such as gelatine and polyvinylpyrrolidone
  • glidants such as silica
  • lubricants such as talc and magnesium stearate
  • disintegrants preservatives
  • flavouring agents etc.
  • the film coating for instance, consists of hydroxy- propylmethylcellulose and may contain a colouring agent such as titanium dioxide.
  • the film-coated tablets is fast disintegrating and shows good bioavailability without any local irritation.
  • Administration of the active ingredients according to the present invention and of the pharmaceutical compositions described above can be via any of the accepted modes of administration for antiviral agents. These methods include oral, parenteral, and otherwise systemic administration. Parenteral administration is generally characterized by intravenous injection or infusion.
  • the amount of active ingredient administered will, of course, be dependent on the subject being treated, the severity of the affliction, the manner of administration and the judgement of the prescribing physician.
  • the daily dosage usually varies from 5 to 75 mg/kg body weight, preferably 10 to 50 mg/kg body weight, and may, for instance, be given orally in one or more, preferably one to three doses per day or continuously as infusion.
  • the treatment with the active ingredient of the present invention with other therapy such as antibacterial, antitubercular, antifungal, antiparasitic, antiviral, and/or immunomodulating drugs.
  • the combined treatment can take place by administration of the drugs individually or in fixed combinations.
  • ⁇ -lactam antibiotics such as:
  • penicillins and their prodrugs for example benzylpenicillin, phenoxymethylpenicillin, methicillin, nafcillin, oxacillin, cloxacillin, dicloxacillin, flucloxacillin, ampicillin, epicillin, amoxicillin, hetacillin, pivampicillin, bacampicillin, talampicillin lenampicillin, carbenicillin, carfecillin, carindacillin, ticarcillin, azlocillin, mezlocillin.
  • prodrugs for example benzylpenicillin, phenoxymethylpenicillin, methicillin, nafcillin, oxacillin, cloxacillin, dicloxacillin, flucloxacillin, ampicillin, epicillin, amoxicillin, hetacillin, pivampicillin, bacampicillin, talampicillin lenampicillin, carbenicillin, carfecillin, carindacillin,
  • cephalosporins and their prodrugs for example cephaloglycin, cephalothin, cephaloridine, cefazolin, cefsulodin, cefalexin, cephradine, cefamandole, cefonicid, cefotiam, cefuroxime, cefuroxime axetil, cefotaxime, ceftizoxime, cefodizime, ceftriaxone, cefmenoxime, ceftazidime, cefoperazone, cefpinazole, cefpiramide, cefpirome, cefminox, cefuzonam, cefepime (BMY)
  • tetracycline antibiotics such as tetracycline, chlorotetracycline, oxytetracyline, rolitetracycline, demeclocycline, lymecycline, methacycline, clomocycline, cloxycycline, and minocycline
  • macrolide and lincosamide antibiotics such as erythromycin and its esters, oleandomycin, josamycin, rosaramycin, spiramycin, roxithromycin, lincomycin, and clindamycin
  • ansamvcin antihiotics such as rifamycin, rifampicin, and
  • antifungal drugs to be used in such combined treatment, mention may be made of amphothericin B, nystatin, griseofulvin, flucytosine, miconazole, clotrimazole, econazole, and ketoconazole.
  • antiparasitic drugs examples include metronidazole, tinidazole, chloroquine, levamisole, and pentamidine.
  • antitnhercular drugs to be used in such combined treatment mention may be made of isoniazide, ethambutol, p-aminosalicylic acid, pyrazinamide, and dapsone.
  • antiviral drugs to be used in such combined treatment mentioned may be made of acyclovir, amphotericin B methyl ester, glycyrrhizin, ribavirin, amantidine, foscarnet, ganciclovir, eflornithine, and desciclovir.
  • immunomodulators to be used in such treatment, mention may be made of ⁇ -interferon, ⁇ -interferon, cyclosporin, interleukin 2, isoprinosine, krestin, lentinan, muramyl tripeptide, and penicillamine.
  • hepatitis HBsAG positive
  • seborrhoic dermatitis The patient, a 58 year old male with a past history of hepatitis (HBsAG positive) and recurrent seborrhoic dermatitis, was well until 1984 when he consulted a physician since he was suffering lethargy, fever and weight loss. Upon examination he was found to have generalised lymphadenopathy. He was found to be HIV positive by ELISA and Western blot with a normal T helper lymphocyte count but was allergic to non-specific mitogens. He remained stable with no further deterioration until 1986 when he suffered further weight loss and diarrhoea.
  • Gastro-enterological investigations revealed atrophic gastritis, B12 malabsorption, candidial esophagitis as well as Entamoeba coli, Entamoeba hartmannii, Endolimax nana, Iodamoeba bfltschlii and Ascaris lumbricoides in the stool.
  • Mycobacterium hominis was grown from both the stool and the flood following the detection of acid fast bacilli in a lymph node biopsy. The patient was given isoniazid, ethambutol and rifampicin as well as antiparasitic and local antifungal therapy. After six weeks of treatment there was no improvement with respect to his symptoms and he continued to lose weight (16 kg since admission).
  • fusidic acid sodium salt 500 mg three times a day orally was added to his regimen. Two weeks following commencement he became afebrile, began to put on weight and was able to undergo a transurethral prostectomy, following which he returned to work and has been well since. Two months later he had increased his weight by 10 kg.
  • a solution for intravenous injection is prepared by dissolving the following dry substance in the solvent prior to use :
  • a solution for intravenous injection is prepared by dissolving the following dry substance in the solvent prior to use:

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Virology (AREA)
  • Epidemiology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Molecular Biology (AREA)
  • AIDS & HIV (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
EP88905837A 1987-07-22 1988-07-21 Fusidinsäure verwendbar zur behandlung von aids Withdrawn EP0391898A1 (de)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
EP87110621A EP0300073A1 (de) 1987-07-22 1987-07-22 Verwendung von Fusidinsäure zur Behandlung von dem Aids verwandten Komplexen und Aids im Endstadium
EP87110621 1987-07-22
EP88100128 1988-01-07
EP88100128 1988-01-07

Publications (1)

Publication Number Publication Date
EP0391898A1 true EP0391898A1 (de) 1990-10-17

Family

ID=26108289

Family Applications (1)

Application Number Title Priority Date Filing Date
EP88905837A Withdrawn EP0391898A1 (de) 1987-07-22 1988-07-21 Fusidinsäure verwendbar zur behandlung von aids

Country Status (4)

Country Link
EP (1) EP0391898A1 (de)
JP (1) JPH03501967A (de)
DK (1) DK17590A (de)
WO (1) WO1989000424A1 (de)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5470324A (en) * 1993-07-01 1995-11-28 Baxter International Inc. Non-refluxing suction canister system and components therefor
US5725516A (en) * 1993-07-01 1998-03-10 Allegiance Healthcare Corp. Suction canister system
GB0209265D0 (en) 2002-04-23 2002-06-05 Novartis Ag Organic compounds
EP2382968A1 (de) * 2010-03-26 2011-11-02 Abdi Ibrahim Ilac Sanayi ve Ticaret Anonim Sirketi Partikel Groesse Verteilung von Fusidinsäure

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3650741T2 (de) * 1985-09-17 2000-10-12 The Wellcome Foundation Ltd., Greenford Kombination therapeutische Nukleoside mit weiteren therapeutisch wirksamen Komponenten.

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO8900424A1 *

Also Published As

Publication number Publication date
JPH03501967A (ja) 1991-05-09
DK17590D0 (da) 1990-01-22
WO1989000424A1 (en) 1989-01-26
DK17590A (da) 1990-01-22

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