WO2006077166A1 - Utilisation de complexes de gallium (iii) pour traiter des tumeurs du tractus urothelial - Google Patents

Utilisation de complexes de gallium (iii) pour traiter des tumeurs du tractus urothelial Download PDF

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Publication number
WO2006077166A1
WO2006077166A1 PCT/EP2006/000615 EP2006000615W WO2006077166A1 WO 2006077166 A1 WO2006077166 A1 WO 2006077166A1 EP 2006000615 W EP2006000615 W EP 2006000615W WO 2006077166 A1 WO2006077166 A1 WO 2006077166A1
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compound according
cycloalkyl
alkyl
aryl
heteroaryl
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PCT/EP2006/000615
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German (de)
English (en)
Inventor
Bernhard Keppler
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Faustus Forschung Translational Drug Development Ag
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    • 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
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis

Definitions

  • gallium (III) complexes for the treatment of tumors of the urothelial tract
  • the invention relates to the use of gallium (IH) complexes for the treatment of tumors of the urothelial tract.
  • IH gallium
  • gallium (III) chloride and gallium nitrate for the control of human tumors.
  • Collery US 4,596,710 describes the use of gallium chloride in the treatment of various human tumors.
  • US Pat. No. 4,529,593 describes the use of inter alia gallium nitrate for the treatment of tumor-associated hypercalcemia.
  • the treatment of tumors of the urothelial tract with gallium nitrate has also been described in the literature (Seligman et al, Proc. Annual Meeting Am Soc So Oncol, 1991, 10, A534, Crawford et al., Urology, 1991, 38 355-357, Seidman et Cancer 1991, 68, 2561-2565).
  • gallium maltolate which is currently in clinical trials (Lawrence Bernstein, WO 93/09776). This compound is characterized by a significantly increased bioavailability.
  • Gallium (III) complexes with nitrogen-containing ligands also show a much higher lipophilicity and improved bioavailability upon oral administration and have shown their antitumor activity in experimental animal tumors such as soft tissue sarcoma (Collery et al., WO 93/02087; Thiel et al., Relevance of Tumor Models for Anticancer Drug Development, Contrib. Oncol., Basel, Karger, 54, 439-442, 1999).
  • Oral administration is particularly desirable for gallium compounds in the treatment of tumors, as these compounds should be given continuously over a longer period, as far as possible, due to the mechanism of ribonucleotide reductase inhibition.
  • gallium (III) complexes with nitrogen-containing ligands in combination with other therapeutically effective cytotoxic agents, e.g. various platinum (II) complexes described.
  • gallium (III) complexes of the general formula (I), even without the combination with other cytotoxic compounds, are particularly suitable for use in the treatment of tumors of the urothelial tract.
  • the invention has for its object to treat tumors of the urothelial tract.
  • R 1 Ci - C 6 alkylene, C 3 - C 3 -cycloalkylene, C 3 - C 8 - cycloalkenylene, C 2 - Ce alkenylene, a mono- or polynuclear, optionally aromatic, C 6 - C 4 ring system or a heterocycle, each of which may be substituted or unsubstituted is;
  • R 2 and R 3 is C 1 - Cio alkyl, C 3 - C 8 - cycloalkyl, C 3 - C 8 - cycloalkenyl, C 2 - Cio-alkenyl, a mono- or Distancekemiges optionally aromatic, C 6 - C 14 - Ring system, or a heterocycle, which may each be substituted or unsubstituted, or is hydrogen; and Ri and R 2 , or R 1 and R 3 , or R 2 and R 3 may form a heterocycle which may optionally contain further nitrogen atoms;
  • R 4 has the same meaning as Ri
  • R 5 has the same meaning as R 2
  • R 4 and R 5 together with N may form an optionally aromatic ring system which may contain further nitrogen atoms;
  • i is an integer from 0 to 3 and corresponds to the sum of the N-containing groups of the formulas (III) and / or (VI);
  • Y is a halogen, pseudohalogen, HCO 3 or R 1 COO, wherein R 1 is C 1 -
  • the heterocycle for R 1 is a mononuclear or polynuclear basic heterocycle having one or more nitrogen atoms.
  • Ri is C 1 - C 6 alkylene, C 3 - C 6 -alkylene -Cycloal-, C 3 - C 6 -cycloalkenylene, C 2 - C 6 alkenylene, C 6 - C 14 - arylene or a heterocycle which may each be substituted or unsubstituted, and R 2 and R 3 Ci - C 10 alkyl, C 3 - C 6 cycloalkyl, C 3 - C 6 cycloalkenyl, C 2 - Cio-alkenyl, C6 - Cu aryl, or heterocycle, each substituted or unsubstituted or hydrogen.
  • R 1 is preferred:
  • C 1 -C 5 -alkylene such as n-butylene or n-pentylene, in particular C 1 -C 3 -
  • Alkylene such as methylene, ethylene, n-propylene or i-propylene
  • C 2 -C 5 -alkenylene such as butenylene or pentenylene, in particular C 2 -C 3
  • Alkenylene such as ethenylene or propenylene
  • C 3 -C 6 -cycloalkylene such as cyclopentylene or cyclohexylene, in particular C 3 -C 4 -cycloalkylene, such as cyclopropylene or cyclobutylene
  • C 3 -C 4 -cycloalkylene such as cyclopropylene or cyclobutylene
  • C 3 -C 6 -cycloalkylene in particular C 5 -C 6 -cycloalkenylene, such as cyclopentenylene or cyclohexenylene;
  • R 2 and R 3 are preferred:
  • C 1 -C 6 -alkyl such as n-butyl, n-pentyl, or n-hexyl, in particular C 1 -C 3
  • Alkyl such as methyl, ethyl, n-propyl or i-propyl
  • C 2 - Ce alkenyl such as butenyl, pentenyl, in particular C 2 - C 3 alkenyl, such as ethenyl or propenyl;
  • C 3 -C 6 -cycloalkyl such as cyclopentyl or cyclohexyl, in particular C 3 -
  • C 6 cycloalkyl such as cyclopropyl or cyclobutyl
  • C 3 -C 6 -cycloalkenyl in particular C 5 -C 6 -cycloalkenyl, such as cyclopenttenyl or cyclohexenyl; C 6 - C 10 -aryl, in particular benzyl.
  • R 4 and R 5 form an aromatic ring.
  • R 1 , R 2 and / or R 3 are substituted in preferred embodiments by:
  • groups of the general formula (II) are preferably selected from groups of the formulas (VIII) and (IX)
  • R 2 , R 3 as defined above, R 6 is alkyl, cycloalkyl, aryl or heteroaryl, which may each be substituted or unsubstituted, p is 0 to 4, m, m 'is 0 to 2, especially 1.
  • two ortho-substituents R 6 may form an optionally aromatic cycle.
  • R 6 is substituted in preferred embodiments as defined above for Ri, R 2 and / or R 3 .
  • Groups of the general formula (III) are preferably selected from groups of the formulas (X) and (Xl)
  • R 2 , Rs, Re, P, m, m 1 are as defined above.
  • Groups of the general formula (IV) are preferably from groups of the formulas
  • Groups of the general formula (V) are preferably selected from the formulas (XIV) and (XV)
  • R 6 is as above, R 1 is alkyl, cycloalkyl, aryl or heteroaryl, which may each be substituted or unsubstituted,
  • Halogen, sulfonyl, q is 0 to 3
  • r is 0 to 2
  • n is 0 to 2, especially 1,
  • two ortho substituents R 6 may form an optionally aromatic cycle.
  • Groups of the general formula (VI) are preferably selected from the formulas (XVI) and (XVII)
  • Re, R7, q, r, n are as defined above
  • the invention also relates to the use of gallium (III) complexes of the general formula (I) for the preparation of a medicament for the treatment of tumors of the urothelial tract.
  • the tumors of the urothelial tract which are suitable for treatment by a gallium complex of the general formula (I) may be, for example, renal carcinomas, renal bovine carcinomas, carcinomas of the urether, prostate carcinomas, bladder carcinomas and metastases of these tumor entities in other organs.
  • Testicular tumors and tumors of the penis can also be treated by the gallium complex according to the invention.
  • the gallium complex of the formula (I) is more preferably administered orally, but also intravenously, intramuscularly, intraperitoneally or subcutaneously. Also an external application is possible. Preferably, the administration is by peroral application.
  • gallium (III) complexes can be carried out in any suitable formulation, provided that the formation or maintenance of sufficient active ingredient levels is ensured. This can be achieved for example by oral or parenteral administration in appropriate doses.
  • the pharmaceutical preparation of the active ingredient is in unit dose form adapted to the desired administration.
  • a unit dose may be, for example, a tablet Dragee, a capsule, a suppository or a measured volume amount of a powder, a granulate, a solution, an emulsion or a suspension.
  • unit dose is understood to mean a physically determined unit which contains an individual amount of the active ingredient in combination with a pharmaceutical carrier and whose active ingredient content corresponds to a fraction or multiple of a single therapeutic dose.
  • a single dose preferably contains the amount of active ingredient which is administered in one application and which usually corresponds to a whole, a half, a third or a quarter daily dose. If only a fraction, such as one half or one quarter of the unit dose is needed for a single therapeutic administration, the unit dose is advantageously divisible, e.g. in the form of a tablet with a score.
  • gallium (III) complexes in a suitable drug, when carried out in unit doses and used for applications e.g. is determined in humans, with about 0.1 to 3000 mg, preferably 10 to 2000 mg and in particular 30 to 1500 mg of active ingredient.
  • the drug can be administered once, but also continuously over a longer period of time. For oral treatment, similar dosages may be used.
  • gallium (III) complexes in a pharmaceutical composition according to the invention may take place 1 to 4 times a day at fixed or varying times, eg before meals and / or in the evening. However, it may be necessary to deviate from the stated dosages, depending on the type, body weight and age of the individuals to be treated, the nature and severity of the disease, the method of preparation and the application of the drugs, and the period or interval within which the Administration takes place. Thus, in some cases it may be sufficient to make do with less than the above-mentioned amount of active ingredient, while in other cases, the above-mentioned amount of active ingredient must be exceeded. It may also be useful to administer the drugs only once or at intervals of several days.
  • gallium (III) complexes may be in the form of drugs which typically comprise the gallium (III) complex and non-toxic pharmaceutically acceptable excipients which may be used as admixture or diluent, for example in solid, semisolid or liquid form or as a wrapping agent, for example in the form of a capsule, a tablet coating, a pouch or other container for the therapeutically active ingredient.
  • a carrier can e.g. serve as a mediator for the ingestion of drug by the body, as a formulation aid, as a sweetener, as a flavoring, as a dye or as a preservative.
  • Tablets dragees e.g. Tablets dragees, hard and soft capsules, e.g. from gelatin, dispersible powders, granules, aqueous and oily suspensions, emulsions, solutions or syrups.
  • Tablets may contain inert diluents, eg calcium carbonate, calcium phosphate, sodium phosphate or lactose; Granulating and distributing agents, for example maize starch, polyvinylpyrrolidone or alginates; Binders, eg starch, gelatin or acacia gum; and lubricants, for example, aluminum or magnesium stearate, talc or silicone oil. She may additionally be provided with a coating which may also be such as to cause a delayed dissolution and absorption of the drug preparation in the gastrointestinal tract, so that, for example, better tolerability, protease or retardation is achieved.
  • Gelatin capsules may contain the drug mixed with a solid, eg calcium carbonate or kaolin, or an oily, eg olive, peanut, or paraffin oil, diluent.
  • Aqueous suspensions may contain suspending agents, e.g. Sodium carboxymethylcellulose, methylcellulose, hydroxypropylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum or acacia gum; Dispersing and wetting agents, e.g. Polyoxyethylene stearate, heptadecaethylene oxycatanol, polyoxyethylene sorbitol monooleate or lecithin; Preservatives, e.g. Methyl or propyl hydroxybenzoates; Flavoring agents; Sweeteners, e.g. Sucrose, lactose, sodium cyclamate, dextrose, invert sugar syrup.
  • suspending agents e.g. Sodium carboxymethylcellulose, methylcellulose, hydroxypropylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum or acacia gum
  • Dispersing and wetting agents e.g. Polyoxyethylene stearate
  • Oily suspensions may e.g. Peanut, olive, sesame, coconut or paraffin oil and thickening agents, e.g. Beeswax, hard paraffin or cetyl alcohol; furthermore sweeteners, flavorings and antioxidants.
  • Peanut olive, sesame, coconut or paraffin oil and thickening agents, e.g. Beeswax, hard paraffin or cetyl alcohol; furthermore sweeteners, flavorings and antioxidants.
  • Water-dispersible powders and granules may be used in the inventive use of gallium (III) complexes in admixture with dispersing, wetting and suspending agents, e.g. the above, as well as sweeteners, flavorings and colorants.
  • gallium (III) complexes in admixture with dispersing, wetting and suspending agents, e.g. the above, as well as sweeteners, flavorings and colorants.
  • Emulsions may contain, for example, olive, peanut, or paraffin oil in addition to emulsifying agents such as acacia, tragacanth, phosphatides, sorbitan monooleate, polyoxyethylene sorbitan monooleate, and sweetening and flavoring agents.
  • Aqueous solutions may contain preservatives, for example methyl or propyl hydroxybenzoates; Thickener; Flavoring agents;
  • Sweeteners e.g. Sucrose, lactose, sodium cyclamate, dextrose, invert sugar syrup, as well as flavorings and colorants.
  • sterile injectable aqueous solutions for parenteral administration of the drugs are sterile injectable aqueous solutions, isotonic saline or other solutions.
  • gallium (III) complexes for the treatment of tumors of the urothelial tract was investigated in a Phase I clinical study.
  • Tris-hydroxyquinolinolato gallium (III) was found to be well tolerated in this study.
  • the activity of the gallium compound in the indication renal tumor was observed in three patients with documented progression on entry into the study in the form of a stabilization in two cases or a partial response in one case.
  • One patient was stable over a period of 36 weeks (patient 1).

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

Abstract

L'invention concerne l'utilisation de complexes de gallium (lll) pour traiter des tumeurs du tractus urothélial, telles que des cancers rénaux, des cancers du bassinet du rein, des cancers de la prostate, des cancers de la vessie et des tumeurs de l'urètre.
PCT/EP2006/000615 2005-01-24 2006-01-24 Utilisation de complexes de gallium (iii) pour traiter des tumeurs du tractus urothelial WO2006077166A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ATA99/2005 2005-01-24
AT0009905A AT501262B8 (de) 2005-01-24 2005-01-24 Verwendung von gallium(iii)-komplexen zur behandlung von tumoren des urothelialtraktes

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WO2006077166A1 true WO2006077166A1 (fr) 2006-07-27

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002074304A2 (fr) * 2001-03-19 2002-09-26 Faustus Forschungs Cie. Translational Cancer Research Gmbh Commposition, renfermant un complexe de gallium (iii) et un cytostatique a effet therapeutique
US6558650B1 (en) * 1998-04-08 2003-05-06 Oregon Health And Science University Enhancement of cellular gallium uptake

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE69225484T2 (de) * 1991-07-25 1998-12-10 Philippe Reims Collery Gallium iii komplexe, verfahren zu ihrer herstellung und pharmazeutische zusammensetzungen, die sie enthalten

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6558650B1 (en) * 1998-04-08 2003-05-06 Oregon Health And Science University Enhancement of cellular gallium uptake
WO2002074304A2 (fr) * 2001-03-19 2002-09-26 Faustus Forschungs Cie. Translational Cancer Research Gmbh Commposition, renfermant un complexe de gallium (iii) et un cytostatique a effet therapeutique

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
COLLERY P ET AL: "Preclinical toxicology and tissue gallium distribution of a new antitumor gallium compound: Tris (8-chinolinolato) gallium (III)", ANTICANCER RESEARCH, vol. 15, no. 5A, 1995, & FIFTH INTERNATIONAL CONFERENCE OF ANTICANCER RESEARCH; CORFU, GREECE; OCTOBER 17-22, 1995, pages 1758, XP009066232, ISSN: 0250-7005 *
COLLERY PHILIPPE ET AL: "Gallium in cancer treatment", CRITICAL REVIEWS IN ONCOLOGY-HEMATOLOGY, vol. 42, no. 3, June 2002 (2002-06-01), pages 283 - 296, XP002380058, ISSN: 1040-8428 *
EINHORN L: "GALLIUM NITRATE IN THE TREATMENT OF BLADDER CANCER", SEMINARS IN ONCOLOGY, W.B. SAUNDERS,, US, vol. 30, no. 2, SUPPL 5, April 2003 (2003-04-01), pages 34 - 41, XP008051480, ISSN: 0093-7754 *
HOFHEINZ R D ET AL: "Early results from a phase I study on orally administered tris(8-quinolinolato)gallium(III) (FFC11, KP46) in patients with solid tumors--a CESAR study (Central European Society for Anticancer Drug Research--EWIV).", INTERNATIONAL JOURNAL OF CLINICAL PHARMACOLOGY AND THERAPEUTICS. DEC 2005, vol. 43, no. 12, December 2005 (2005-12-01), pages 590 - 591, XP009066236, ISSN: 0946-1965 *
JAKUPEC MICHAEL A ET AL: "Gallium and other main group metal compounds as antitumor agents.", METAL IONS IN BIOLOGICAL SYSTEMS. 2004, vol. 42, 2004, pages 425 - 462, XP009066248, ISSN: 0161-5149 *
THIEL M ET AL: "Tris(8-quinolinolato)gallium(III), a novel orally applied antitumor gallium compound", CONTRIBUTIONS TO ONCOLOGY; RELEVANCE OF TUMOR MODELS FOR ANTICANCER DRUG DEVELOPMENT S. KARGER GMBH {A}, POSTFACH, D-79095, FREIBURG, GERMANY SERIES : CONTRIBUTIONS TO ONCOLOGY (ISSN 0250-3220), 1999, pages 439 - 443, XP001246657, ISSN: 3-8055-6786-3 *

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AT501262B8 (de) 2007-02-15
AT501262A4 (de) 2006-08-15
AT501262B1 (de) 2006-08-15

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