WO2005011673A1 - Utilisation de composes antitumoraux - Google Patents

Utilisation de composes antitumoraux Download PDF

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Publication number
WO2005011673A1
WO2005011673A1 PCT/GB2004/003177 GB2004003177W WO2005011673A1 WO 2005011673 A1 WO2005011673 A1 WO 2005011673A1 GB 2004003177 W GB2004003177 W GB 2004003177W WO 2005011673 A1 WO2005011673 A1 WO 2005011673A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
formula
cancer
compounds
pharmaceutically acceptable
Prior art date
Application number
PCT/GB2004/003177
Other languages
English (en)
Inventor
Julia Pérez Baz
Fernando DE LA CALLE VERDÚ
Luis Francisco GARCIA FERNÁNDEZ
Original Assignee
Instituto Biomar S.A.
Ruffles, Graham, Keith
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 Instituto Biomar S.A., Ruffles, Graham, Keith filed Critical Instituto Biomar S.A.
Publication of WO2005011673A1 publication Critical patent/WO2005011673A1/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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to the use of antitumoral macrolides for the treatment of cancer, and to pharmaceutical compositions containing them.
  • Hitachimycin has the following structure:
  • Apoptolidin can selectively sensitise cancer cells to apoptosis with considerable potency.
  • the IC50 of this compound was 100 nM and in breast carcinoma cell line MCF-7 the ICso was 90 nM.
  • Apoptolidin has the following structure:
  • compound FD-891 was shown to have in vitro cy to toxic activity against several tumor cell lines.
  • the compound FD-891 has the following structure:
  • Cancer is a leading cause of death in animals and humans. Several efforts have been and are still being undertaken in order to obtain an antitumor agent active and safe to be administered to patients suffering from a cancer.
  • the present invention provides compounds that are useful in the treatment of cancer.
  • Ri is selected from the group consisting of H,
  • Ri has the stereochemical formula: I -O ⁇ ⁇ O OCONH 2 'OH
  • Venturicidin A was originally isolated in 1961 (Rhodes et al. Nature 192, 952-954 (1961)). It is known to have antibiotic and antifungal properties by inhibiting mitochondrial ATP synthesis (Walter et al. J. Biol. Chem., 242, 5014-8 (1967)). No mention is made in the literature about the use of Venturicidin A and related compounds as antitumoral agents.
  • the present invention is also directed to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound as previously defined and a pharmaceutically acceptable carrier, which may take the form of a vehicle or diluent.
  • the present invention further provides a method of treating any mammal, notably a human, affected by cancer which comprises administering to the affected individual a therapeutically effective amount of a compound as defined above.
  • the present invention is directed to the use of a compound as defined above in the manufacture of a medicament for the treatment of cancer.
  • kits comprising separate containers containing a pharmaceutical composition comprising a compound as defined above and a reconstituting agent. Methods of reconstitution are also provided.
  • pharmaceutically acceptable salts, derivatives, prodrugs refers to any pharmaceutically acceptable salt, ester, solvate, hydrate or any other compound which, upon administration to the recipient is capable of providing (directly or indirectly) a compound of the invention or a metabolite or a residue thereof.
  • non-pharmaceutically acceptable salts also fall within the scope of the invention since those may be useful in the preparation of pharmaceutically acceptable salts.
  • the preparation of salts, prodrugs and derivatives can be carried out by methods known in the art.
  • Particularly favourite derivatives and prodrugs are those that increase the bioavailability of the compounds of this invention when such compounds are administered to a patient (e.g., by allowing an orally administered compound to be more readily absorbed into the blood), enhance delivery of the parent compound to a given biological compartment, increase solubility to allow administration by injection, alter metabolism or alter rate of excretion.
  • the compounds of the present invention have asymmetric centers and therefore exist in different enantiomeric and diastereomeric forms.
  • This invention relates to the use of all optical isomers and stereoisomers of the compounds of the present invention, and mixtures thereof, and to all pharmaceutical compositions and methods of treatment that may employ or contain them.
  • the present invention includes the compounds of the present invention, and the pharmaceutically acceptable salts thereof, wherein one or more hydrogen, carbon or other atoms are replaced by isotopes thereof.
  • Such compounds may be useful as research and diagnostic tools in metabolism pharmacokinetic studies and in binding assays.
  • Salts of the compounds of the present invention may comprise acid addition salts derived from a nitrogen in the compound of formula 1 or 2.
  • the therapeutic activity resides in the moiety derived from the compound of the invention as defined herein and the identity of the other component is of less importance although for therapeutic and prophylactic purposes it is, preferably, pharmaceutically acceptable to the patient.
  • Pharmaceutically acceptable salts of compounds provided herein are synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts are, for example, prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent or in a mixture of the two.
  • nonaqueous media like ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred.
  • pharmaceutically acceptable acid addition salts include those derived from mineral acids, such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric and sulphuric acids, and organic acids, such as tartaric, acetic, trifluoroacetic, citric, malic, lactic, fumaric, benzoic, glycolic, gluconic, succinic and methanesulphonic and arylsulphonic, for example p-toluenesulphonic, acids.
  • mineral acids such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric and sulphuric acids
  • organic acids such as tartaric, acetic, trifluoroacetic, citric, malic, lactic, fumaric, benzoic, glycolic, gluconic, succinic and methanesulph
  • Compounds of the invention can be synthesized by using conventional techniques of synthetic organic chemistry which are within the skill of the art. Such techniques are explained fully in literature. See, for example, Tsunashima K. et al., Tetrahedron Letters, 2001, 42, 3607-3611. Compounds of the invention can also be isolated from natural sources. For example, Venturicidin A can be isolated from Streptomyces griseolus (see, Biochem. Soc. Trans., 1974, 2/2, 202- 205).
  • compositions of the compounds of the invention may be adapted for administration by any appropriate route, for example by the oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) route.
  • Such formulations may be prepared by any method known in the art of pharmacy, for example by bringing into association the active ingredient with the carrier (s) or excipient (s) .
  • compositions of the compounds of the invention include liquid (solutions, s ⁇ spensions or emulsions) with suitable composition for intravenous administration, and they may contain the pure compound or in combination with any carrier or other pharmacologically active compounds.
  • kits comprising a pharmaceutical composition comprising a compound of the invention, or a pharmaceutically aceptable salt, derivative, prodrug or stereoisomer thereof, and a reconstituting agent.
  • the reconstituting agent is intended for addition to the pharmaceutical composition to give a dosage form suited for administration to a patient.
  • Administration of the compounds or compositions of the present invention can be by intravenous infusion. Infusion times of up to 72 hours can be used, more preferably 1 to 24 hours, with either about 1 or about 3 hours most preferred. Short infusion times which allow treatment to be carried out without an overnight stay in hospital are especially desirable. However, infusion may be around 24 hours or even longer if required.
  • the administration is performed in cycles.
  • An intravenous infusion of a compound of the invention is given to the patients the first week of each cycle, the patients are allowed to recover for the remainder of the cycle.
  • the preferred duration of each cycle is of either 1, 3 or 4 weeks; multiple cycles can be given as needed.
  • the compound of the invention is administered for say about 1 hour for 5 consecutive days every 3 weeks.
  • Other protocols can be devised as variations.
  • Dose delays and/ or dose reductions and schedule adjustments are performed as needed depending on individual patient tolerance of treatments.
  • the correct dosage of the compound may change according to the particular formulation, the mode of application, and the particular situs, host and tumour being treated. Other factors like age, body weight, sex, diet, time of administration, rate of excretion, condition of the host, drug combinations, reaction sensitivities and severity of the disease shall be taken into account. Administration can be carried out continuously or periodically within the maximum tolerated dose.
  • the compounds and compositions of this invention may be used with other drugs to provide a combination therapy.
  • the other drugs may form part of the same composition, or be provided as a separate composition for administration at the same time or at different time.
  • Antitumoral activities of these compounds include leukaemias, lung cancer, colon cancer, kidney cancer, prostate cancer, ovarian cancer, breast cancer, pancreas cancer, cervix cancer, sarcomas and melanomas.
  • Venturicidin A was isolated from a Streptomyces olivaceus, isolated from the branchia of the mollusc Venus casina collected at Castropol (Asturias, Spain).
  • the finality of these assays is to interrupt the growth of an "in vitro" tumor cell culture by means a continued exposure of the cells to the sample to be testing.
  • LN-caP CRL-1740 human prostate prostate adenocarcinoma, with androgen receptors
  • IGROV-ET human ovary ovary adenocarcinoma characterized as ET-743 resistant cells
  • HeLa-APL CCL-3 human cervix cervix epitheloid carcinoma characterized as aplidine resistant cells
  • PANC1 CRL-1469 human pancreas pancreatic epitheloid carcinoma INHIBITION OF CELLS GROWTH BY COLORIMETRIC ASSAY.
  • This form of assay employs 96 well cell culture microplates of 9 mm diameter (Faircloth, 1988; Mosmann, 1983). Most of the cell lines are obtained from American Type Culture Collection (ATCC) derived from different human cancer types.
  • ATCC American Type Culture Collection
  • Cells are maintained in RPMI 1640 10% FBS, supplemented with 0.1 g/1 penicillin and 0.1 g/1 streptomycin sulfate and then incubated at 37°C, 5% CO2 and 98% humidity. For the experiments, cells were harvested from subconfluent cultures using trypsin and resuspended in fresh medium before plating.
  • Cells are seeded in 96 well microtiter plates, at 5 x 10 3 cells per well in aliquots of 195 ⁇ l medium, and they are allowed to attach to the plate surface by growing in drug free medium for 18 hours. Afterward, samples are added in aliquots of 5 ⁇ l in a ranging from 10 to 10 ⁇ 8 ⁇ g/ml, dissolved in DMSO/EtOH/PBS (0.5:0.5:99). After 48 hours exposure, the antitumor effect are measured by the SRB methodology: cells are fixed by adding 50 ⁇ l of cold 50% (wt/vol) trichloroacetic acid (TCA) and incubated for 60 minutes at 4°C. Plates are washed with deionised water and dried.
  • TCA trichloroacetic acid
  • SRB solution (0.4% wt/vol in 1% acetic acid) is added to each microtiter well and incubated for 10 minutes at room temperature. Unbound SRB is removed by washing with 1% acetic acid. Plates are air dried and bound stain is solubilized with Tris buffer. Optical densities are read on a automated spectrophotometric plate reader at a single wavelength of 490 nm.
  • GI growth inhibition
  • TGI total growth inhibition (cytostatic effect)
  • LC cell killing (cyto toxic effect).
  • Table 1 illustrates data on the biological activity of the compounds of the present invention.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention se rapporte à des composés représentés par la formule (I), dans laquelle R1 est sélectionné dans le groupe constitué par H, le composé représenté par la formule (II) et le composé représenté par la formule (III) ; l'invention se rapporte également à des sels, dérivés, promédicaments, tautomères et solvates, ou stéréoisomères pharmaceutiquement acceptables de ces composés, qui s'avèrent utiles à la préparation de médicaments pour le traitement du cancer.
PCT/GB2004/003177 2003-07-22 2004-07-21 Utilisation de composes antitumoraux WO2005011673A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB0317128.7A GB0317128D0 (en) 2003-07-22 2003-07-22 Use of antitumoral compounds
GB0317128.7 2003-07-22

Publications (1)

Publication Number Publication Date
WO2005011673A1 true WO2005011673A1 (fr) 2005-02-10

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB2004/003177 WO2005011673A1 (fr) 2003-07-22 2004-07-21 Utilisation de composes antitumoraux

Country Status (2)

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GB (1) GB0317128D0 (fr)
WO (1) WO2005011673A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008065636A2 (fr) * 2006-12-01 2008-06-05 University College York - National University Of Ireland, Cork Traitement de la maladie
CN111499674A (zh) * 2020-04-07 2020-08-07 中国人民解放军海军军医大学 大环内酯化合物及其制备方法与应用

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1184458B (de) * 1960-09-23 1964-12-31 Glaxo Group Ltd Herstellung eines neuen Antibiotikums
FR7930M (fr) * 1967-06-30 1970-05-19
WO1999007710A1 (fr) * 1997-08-04 1999-02-18 Instituto Biomar S.A. Macrolides possedant une activite anti-tumorale

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1184458B (de) * 1960-09-23 1964-12-31 Glaxo Group Ltd Herstellung eines neuen Antibiotikums
FR7930M (fr) * 1967-06-30 1970-05-19
WO1999007710A1 (fr) * 1997-08-04 1999-02-18 Instituto Biomar S.A. Macrolides possedant une activite anti-tumorale

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
ATTA, H. M. ET AL: "Fermentation, extraction, physicochemical properties and biological activities of the antifungal agent produced by Streptomyces aureofaciens", AFRICAN JOURNAL OF MYCOLOGY AND BIOTECHNOLOGY , 11(2), 51-67 CODEN: AJMBFV; ISSN: 1110-5879, 2003, XP008036600 *
MALET-CASCON L. ET AL: "IB-00208, a new cytotoxic polycyclic xanthone produced by a marine-derived Actinomadura. I. Isolation of the strain, taxonomy and biological activities.", JOURNAL OF ANTIBIOTICS, (1 MAR 2003) 56/3 (219-225). REFS: 22 ISSN: 0021-8820 CODEN: JANTAJ, March 2003 (2003-03-01), XP008036654 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008065636A2 (fr) * 2006-12-01 2008-06-05 University College York - National University Of Ireland, Cork Traitement de la maladie
WO2008065636A3 (fr) * 2006-12-01 2009-09-24 University College York - National University Of Ireland, Cork Traitement de la maladie
CN111499674A (zh) * 2020-04-07 2020-08-07 中国人民解放军海军军医大学 大环内酯化合物及其制备方法与应用
CN111499674B (zh) * 2020-04-07 2021-05-11 中国人民解放军海军军医大学 大环内酯化合物及其制备方法与应用
CN113181204A (zh) * 2020-04-07 2021-07-30 中国人民解放军海军军医大学 大环内酯化合物及其制备方法与应用
CN113181204B (zh) * 2020-04-07 2023-04-18 中国人民解放军海军军医大学 大环内酯化合物及其制备方法与应用

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