WO1994002153A1 - Utilisation du soufre contenant des phospholipides dans le traitement de la leishmaniose - Google Patents

Utilisation du soufre contenant des phospholipides dans le traitement de la leishmaniose Download PDF

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Publication number
WO1994002153A1
WO1994002153A1 PCT/EP1992/001674 EP9201674W WO9402153A1 WO 1994002153 A1 WO1994002153 A1 WO 1994002153A1 EP 9201674 W EP9201674 W EP 9201674W WO 9402153 A1 WO9402153 A1 WO 9402153A1
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WIPO (PCT)
Prior art keywords
group
carbon atoms
use according
substituted
alkoxy
Prior art date
Application number
PCT/EP1992/001674
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English (en)
Inventor
Simon L. Croft
Dieter Herrmann
Original Assignee
Boehringer Mannheim Gmbh
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 Boehringer Mannheim Gmbh filed Critical Boehringer Mannheim Gmbh
Priority to PCT/EP1992/001674 priority Critical patent/WO1994002153A1/fr
Publication of WO1994002153A1 publication Critical patent/WO1994002153A1/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
    • A61K31/66—Phosphorus compounds
    • A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
    • A61K31/685—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • subjects of the present invention are the use of sulphur containing phospholipids and pharmacological acceptable salts thereof for treating leishmaniasis, especially visceral and cutaneous leishmaniasis, and pharmaceutical compositions containing these substances for the treatment of leishmaniasis .
  • the usual drugs for the clinical treataent of visceral and cutaneous leishmaniasis are the pentavalent antimonial ⁇ sodium stibogluconate ( ' Pentostam' ) and meglu ⁇ tine antinoniate ( 'Glucantime' ) which require the use of high doses, long courses of treatment and parenteral administration (see the WHO Technical Report Series,701. The Lei ⁇ hmaniases 1984).
  • Leishmania major Leishmania mexicana
  • Leishmania panamensis see the article "Anti-leishmanial activity of ether analogues of lysophospholipids" of N.P.Fiavey and B.Z.Ngwenya, Am.J.Trop. Med.Hyg.
  • alkanol phosphoric acid monoammonium alkyl esters which are substituted by an alkylated thio, sulphinyl or sulphonyl group, are especially and surprisingly active against leishmaniasis.
  • Such sulphur containing phospholipids are known for their anti-tumoral properties. They are described in the European Patent No. 0.050.327 and in the EP Application No. 90103661.6-.
  • X signifies a valency bond, oxygen, sulphur, the sulphinyl or sulphonyl group, the -NHCO-, -CONH- or -NHCONH- group, a cycloalkylene with 3 to 8 carbon atoms or phenylene radical, Y oxygen or sulphur, R-.
  • R z a straight-chained or branched, saturated or unsaturated alkylene chain with 1 to 18 carbon atoms, which is possibly substituted one or more times by aryl, halogen, a lower alkoxy, alkylmercapto, alkoxycarbonyl, alkane ⁇ ulphinyl or alkanesulphonyl group
  • R z a straight-chained or branched, saturated or unsaturated alkylene chain with 1 to 18 carbon atoms, which is possibly substituted one or more times by aryl, halogen, a lower alkoxy, alkylmercapto, alkoxycarbonyl, alkanesulphinyl or alkanesulphonyl group
  • R 3 a straight-chained or branched, saturated or unsaturated alkylene chain with 2 to 8 carbon atoms, which can also be part of a cyclopentane, cyclohexane or cycloheptane ring, possibly substituted by
  • the group R_.-R 2 is preferably straight-chained or branched ond optionally substituted and contains up to 20 carbon atoms.
  • the group R 3 consists preferably of a -CH 2 -CH 2 -CH 2 - group the middle carbon atom of which is once or twice substituted by ydroxyl, lower alkyl or an alkoxy group, where both groups can, in turn, be substituted by alkoxy.
  • the group R ⁇ and the group R 5 signify preferably the -CH 2 -CH a - group or methyl respectively.
  • esters are the following esters:
  • Ilmofosine having the formula (3-hexa- decylthio-2-methoxymethylpropyl)-(2-trimethylammonioethyl) phosphate and (3-hexadecanesulphonyl-2-methoxymethylpropyl)- (2-trimethylammonioethyl) phosphate.
  • Ilmofosine is currently in Phase II clinical trials for efficacy against malignant tumours (see the articles "Ilmofosine (BM41.440) a new cytotoxic etherphospholipid" of D.B.J.Herrmann and U.Bicker, Drug ⁇ of the Future,13,543-554 , 1988 and "Short- and long-term tolerability study of the thioether pho ⁇ pholipid derivative Ilmofosine (BM41.440) in cancer patients" of D.B.J.Herrmann et al., in Contributions to Oncology: New Drugs in Oncology, (Eckardt,S. ,Holzner,J.H. and Nagel,G.A. ,Eds) , Karger, Basel., pp.236-247,1989)
  • Leishmania donovani (MHOM/ET/67/L82) was routinely maintained in male golden hamsters (Wright's strain) by passage every 6 to 8 weeks.
  • the antimony-resistant line of Leishmania infantum was developed by V.Waits and W.L.Hanson (University of Georgia) and was maintained in hamsters (see the article "Reversal of drug resistance in Trypanosoma cruzi and Leishmania donovani by verapamil" of R.A.Neal et al., Transactions of the Royal Society of Tropical Medicine and Hygiene,83,197-198,1989) .
  • Ilmofosine molecular weight 525
  • Mou ⁇ - eritoneal acrophages were isolated from outbred CD1 mice (Charles Rivers Ltd.) und cultured in Labtek 8 chamber slides in RPMI 1640 medium with 10% heat inactivated foetal calf serum at 37 ⁇ C in a 5% C0 2 -air mixture. Macrophage ⁇ were infected with amastigotes derived from hamster spleen 24 hours prior to drug treatment following the procedure described in the article "An in vitro system for determining the activity of compounds against the intracellular amastigote form of Leishmania donovani" of R.A.Neal and S.L.Croft, published in J.Anti ic.Chemoth. , 14,463-475,1984.
  • Infected cultures were maintained in medium containing Ilmofosine for 7 days including two changes of fresh medium with drug, in a three-fold dilution series from 30 ⁇ M with quadruplicate cultures at each concentration. After the 7 day exposure the proportion of infected acrophages in Giemsa stained preparations of each culture was determined. ED S o values were calculated by linear regression analysis.
  • Ilmofosine showed high activity against intracellular Leish ⁇ mania donovani amastigotes, clearing 90% of macrophages at 10 -M and having an ED so value of 3.74 - ⁇ -M as shown in table 1.
  • mice Male BALB/c mice (Olac Ltd) were infected with 5 x 10 6 amastigotes by the tail vein and randomly assorted into groups of five. Starting one week after infection mice were dosed with Ilmofosine as formulated in 0.25% cellacol by either the oral or the subcutaneous route once/day for 5 consecutive days and sacrificed 4 days after the completion of the treatment. Drug activity was determined by counting the number of amastigotes/liver cell in smears prepared from weighed livers of treated and untreated mice. ED so values were determined by linear regression analysis.
  • Liver load No. of amastigotes/500 liver cell x liver weight in mg x 10 s , mean of 5 animals/group ⁇ SEM) .
  • ⁇ EDso value
  • * " EDso value
  • the compounds of the general formula I can be administered enterally or parenterally in liquid or solid form.
  • use can be made of all forms of administration, for example, tablets, capsules, dragee ⁇ , syrups, solutions and the like.
  • injection medium it is preferred to use water which contains the additives usual in the case of injection solutions, such as stabilizing agents and/or buffers.
  • Additives of this kind include, for example, tartrate and citrate buffers, ethanol, complex formers (such as ethylene- diamine-tetraacetic acid and the non-toxic salts thereof) and high molecular weight polymers (such as liquid poly-ethylene oxide) for viscosity regulation.
  • Liquid carrier materials for injection solutions must be sterile and are preferably placed into ampoules.
  • Solid carrier materials include, for example, starch, lactose, mannitol, methylcellulose, talc, highly dispersed silicic acids, high molecular weight fatty acids (such as stearic acid), gelatine, agar-agar, calcium phosphate, magnesium stearate, animal and vegetable fats and solid high molecular polymers (such as polyethylene glycols) .
  • Compositions suitable for oral administration can, if desired, contain flavouring and/or sweetening agents.
  • the dosage used depends upon various factors, such as the mode of administration, species, age and/or individual conditions.
  • the dosage to be administered daily is usually from about 0.05 to 100 mg/kg and preferably 1 to 25 mg/kg of body weight, where for long-term applications the preferred maximum tolerated daily oral dose in patients is about 5 mg/kg of body weight.

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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

L'invention concerne l'utilisation du soufre contenant des phospholipides ayant la formule générale (I) dans laquelle X représente -i.a.- une liaison de valence, oxygène, soufre, le groupe sulphinyle ou sulphonyle, un cycloalkylène possédant de 3 à 8 atomes de carbone ou un radical phénylène, Y représente oxygène ou soufre, R1, hydrogène, un radical alkyle saturé ou insaturé possédant de 1 à 18 atomes de carbone, qui est éventuellement substitué, R2 représente une chaîne alkylène saturée ou insaturée possédant de 1 à 18 atomes de carbone, qui est éventuellement substituée, R3 représente une chaîne alkylène saturée ou insaturée possédant de 2 à 8 atomes de carbone, qui est éventuellement substituée, R4 représente une chaîne alkylène possédant de 2 à 4 atomes de carbone, R5 représente hydrogène ou un groupe alkyle inférieur et n vaut 0, 1 ou 2 ainsi que leurs sels pharmaceutiquement acceptables utiles dans le traitement de la leishmaniose, et les compositions pharmaceutiques contenant au moins un de ces composés.
PCT/EP1992/001674 1992-07-22 1992-07-22 Utilisation du soufre contenant des phospholipides dans le traitement de la leishmaniose WO1994002153A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/EP1992/001674 WO1994002153A1 (fr) 1992-07-22 1992-07-22 Utilisation du soufre contenant des phospholipides dans le traitement de la leishmaniose

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/EP1992/001674 WO1994002153A1 (fr) 1992-07-22 1992-07-22 Utilisation du soufre contenant des phospholipides dans le traitement de la leishmaniose

Publications (1)

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WO1994002153A1 true WO1994002153A1 (fr) 1994-02-03

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0050327A1 (fr) * 1980-10-21 1982-04-28 Roche Diagnostics GmbH Phospholipides contenant du soufre, leur procédé de préparation et médicaments contenant ces composés
EP0050460A2 (fr) * 1980-10-22 1982-04-28 Takeda Chemical Industries, Ltd. Dérivés de tridécyloxy-ou tétradécyloxyl-propane et leur utilisation
EP0416401A2 (fr) * 1989-09-02 1991-03-13 Roche Diagnostics GmbH Utilisation de dérivés de phospholipides comme médicaments et phospholipides
EP0507337A2 (fr) * 1991-04-05 1992-10-07 Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V. Nouveaus dérivés dérucyle, brassidyle et nervonyle
EP0395849B1 (fr) * 1989-03-04 1995-04-19 Roche Diagnostics GmbH Phosphates de [3-(C16-C18)alcane sulfinyl- et sulfonyl-2-méthoxyméthyl-propyl]-(2-triméthylammonio-éthyl), leur procédé de préparation et médicaments les contenant

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0050327A1 (fr) * 1980-10-21 1982-04-28 Roche Diagnostics GmbH Phospholipides contenant du soufre, leur procédé de préparation et médicaments contenant ces composés
EP0050460A2 (fr) * 1980-10-22 1982-04-28 Takeda Chemical Industries, Ltd. Dérivés de tridécyloxy-ou tétradécyloxyl-propane et leur utilisation
EP0395849B1 (fr) * 1989-03-04 1995-04-19 Roche Diagnostics GmbH Phosphates de [3-(C16-C18)alcane sulfinyl- et sulfonyl-2-méthoxyméthyl-propyl]-(2-triméthylammonio-éthyl), leur procédé de préparation et médicaments les contenant
EP0416401A2 (fr) * 1989-09-02 1991-03-13 Roche Diagnostics GmbH Utilisation de dérivés de phospholipides comme médicaments et phospholipides
EP0507337A2 (fr) * 1991-04-05 1992-10-07 Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V. Nouveaus dérivés dérucyle, brassidyle et nervonyle

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
BIOCHEMICAL PHARMACOLOGY vol. 36, no. 16, 1987, pages 2633 - 2636 S.L. CROFT ET AL. 'THE ACTIVITY OF ALKYL PHOSPHORYLCHOLINES AND RELATED DERIVATIVES AGAINST LEISHMANIA DONOVANI' cited in the application *
CANCER DETECTION AND PREVENTION vol. 1, 1987, pages 361 - 371 D.B. HERRMANN ET AL. 'BM 41.440: A NEW ANTINEOPLASTIC, ANTIMETASTATIC, AND IMMUNE-STIMULATING DRUG' *
MOLECULAR AND BIOCHEMICAL PARASITOLOGY vol. 23, no. 2, 1987, pages 117 - 122 V. ACHTERBERG ET AL. 'CYTOTOXICITY OF ESTER AND ETHER LYSOPHOSPHOLIPIDS ON LEISHMANIA DONOVANI PROMASTIGOTES' cited in the application *
THE AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE vol. 45, no. 3, 1991, pages 119 - 120 N.P. FIAVEY ET AL. 'ANTI-LEISHMANIAL ACTIVITY OF ETHER ANALOGUES OF LYSOPHOSPHOLIPIDS' cited in the application *

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