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WO2012003562A1 - Compositions pharmaceutiques antinéoplasiques contenant des nitroimidazols substitués - Google Patents

Compositions pharmaceutiques antinéoplasiques contenant des nitroimidazols substitués Download PDF

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Publication number
WO2012003562A1
WO2012003562A1 PCT/BR2011/000220 BR2011000220W WO2012003562A1 WO 2012003562 A1 WO2012003562 A1 WO 2012003562A1 BR 2011000220 W BR2011000220 W BR 2011000220W WO 2012003562 A1 WO2012003562 A1 WO 2012003562A1
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WO
WIPO (PCT)
Prior art keywords
mti
antineoplastic pharmaceutical
pharmaceutical composition
opo
oso
Prior art date
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Ceased
Application number
PCT/BR2011/000220
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English (en)
Portuguese (pt)
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WO2012003562A8 (fr
WO2012003562A4 (fr
Inventor
Renata Barbosa De Oliveira
Ricardo José Alves
Maria Betânia FREITAS MARQUES
Mônica CRISTINA DE OLIVEIRA
Cristina Duarte Vianna Soares
Lucas REIS FELÍCIO
Elaine Amaral Leite
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.)
SILVIA LOPES MARCELA
Universidade Federal de Minas Gerais
Original Assignee
SILVIA LOPES MARCELA
Universidade Federal de Minas Gerais
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.)
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Publication date
Application filed by SILVIA LOPES MARCELA, Universidade Federal de Minas Gerais filed Critical SILVIA LOPES MARCELA
Publication of WO2012003562A1 publication Critical patent/WO2012003562A1/fr
Publication of WO2012003562A4 publication Critical patent/WO2012003562A4/fr
Anticipated expiration legal-status Critical
Publication of WO2012003562A8 publication Critical patent/WO2012003562A8/fr
Ceased 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
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/40—Cyclodextrins; 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery

Definitions

  • the present invention describes antineoplastic pharmaceutical compositions containing substituted nitroimidazole compounds.
  • the compositions may be used in the treatment of early stage neoplasms or in combination with drugs with antitumor activity already established in more advanced stages of the disease.
  • Solid tumors such as lung, colon and breast carcinomas
  • hypoxic cells present in solid tumors may limit the effectiveness of radiotherapy.
  • These same cells may also be resistant to many of the commercially available chemotherapeutic agents.
  • this apparent obstacle can be explored for the design of agents with selective cytotoxicity for hypoxic cells (Cerecetto, H., Gonzalez, M., Lavaggi, ML Development of Hypoxia Selective Cytotoxins for Cancer Treatment: An Update. Med. Chem. 2, 315, 2006. Papadopoulou, MV, Bloomer, WD Exploiting hypoxia in solid tumors with DNA-targeted bioreductive drugs Drugs Fut 29, 807, 2004.
  • Wouters BG, Weppler, S.A, Koritzinsky, M., Landuyt, W., Nuyts, S., Theys, J., Chiu, RK, Lambin, P. Hypoxia as a target for combined modality treatments (Eur. J. Cancer. 38, 240, 2002).
  • hypoxic cell regions could have a greater reduction capacity than well-oxygenated cell regions.
  • hypoxic cells in solid tumors could exist in a microenvironment that would allow reductive processes to occur. Therefore, it was concluded that these characteristics of hypoxia cells could be explored in the development of chemotherapeutic agents, which would only become cytotoxic after metabolic activation. Thereafter, the concept of bioreductive activation of substances in hypoxia cells has been extensively studied (Dai, J., Liu, Y., Zhou, Y., Nagle, DG Hypoxia-selective antitumor agents: norsesterterpene peroxides from the marine sponge.
  • Diacarnus / ev / 7 preferentially suppresses the growth of tumor cells under hypoxic conditions. J. Nat. Prod. 70, 130, 2007. Lalani, AS, Alters, SE, Wong, A., Albertella, MR, Cleland, J. L, Henner, WD Selective tumor targeting by the hypoxia-activated prodrug AQ4N blocks preclinical tumor growth and metastasis models of pancreatic cancer. Clin. Cancer Res. 13, 2216, 2007.
  • nitroaromatics to act as bioreducible agents
  • these compounds can be used as hypoxia cell selectivity prodrugs (Abreu, F. C; Ferraz, PA L; Goulart, MOFJ Braz. Chem Soc. V. 13, pp. 19-35,
  • radiosensitizers for hypoxia cells. Such compounds would have the ability to mimic the harmful effects of oxygen. Successful treatment of solid tumors using metronidazole confirmed this hypothesis. These compounds were developed as radiosensitizers, but it has subsequently been shown that prolonged exposure of hypoxia cells to nitroaromatics results in selective cell death even in the absence of radiation.
  • nitroimidazoles such as metroimidazole and misonidazole have selectivity for hypoxic cells, they have low potency, and consequently high doses are required to exert a cytotoxic action.
  • nitroimidazoles such as metroimidazole and misonidazole have selectivity for hypoxic cells, they have low potency, and consequently high doses are required to exert a cytotoxic action.
  • Kajfez et al described the synthesis of 2-methyl-4 (5) nitroimidazole derivatives, including 1- (2-iodoethyl) -2-methyl-5-nitroimidazole with antitricomone activity (Kajfez, F .; Sunjic, V. ; Kolbah, D.; Fajdiga, T.; Oklobdzija, M. 1- Substitution in 2-methyl-4 (5) -nitroimidazole I. Synthesis of compounds with potential antitrichomonal activity J. Med. 167).
  • Busatti et al reported the effects of metronidazole analogs such as 1- (2-iodoethyl-2-methyl-5-nitroimidazole (MTI) on Giardia lambia cultures (HG Busatti, Vieira, JC Viana, HE Silva, EM). Souza-Fagundes, OA Martins-Filho, RJ (Alves and MA Gomes, Parasitol Res. 2007, 102, 145).
  • EP 866709 discloses a parenteral pharmaceutical composition containing tirapazamine for treating cancer, especially solid tumors, used alone or in combination with radiotherapy or other chemotherapeutic agents.
  • WO2008118150 discloses a method for treating, preventing or ameliorating hyperproliferative disorders by determining the level of nitric oxide synthase in body fluids and subsequent administration of bioreductible substances, including banoxantrone.
  • hypoxic cell-selective bioreducible substances Although the treatment of cancer patients using hypoxic cell-selective bioreducible substances is under investigation, these substances are not yet commercially available. New options for substances with selectivity for hypoxia and high potency tumor cells are important in an attempt to overcome the disadvantages of currently investigated options such as normal cell toxicity, inadequate physicochemical properties, and the need for association with classic antitumor drugs.
  • Figure 1 Structural formula of substituted nitroimidazole compounds
  • the present invention describes antineoplastic pharmaceutical compositions containing substituted nitroimidazole compounds having the structural formula of Figure 1.
  • the substituent "X" of Figure 1 being selected from the group comprising I, H, F, Cl, Br, OH, N 3 , OPO 3 H, OPO (OR) 2 , NHR, NR 2 , NR 3 X, OSO 2 R , OSO 2 Ar, OAr, OCOR, OCON, OCONHR, SH, SR, SAr; where R may be H, (C-2 to C-30 alkyl, with or without branching); aryl (aromatic or heteroaromatic); alkyl aryl (C-2 to C-30, with or without branching, aromatic or heteroaromatic).
  • compositions of the present invention are characterized by the use of substituted nitroimidazole compounds combined with pharmaceutically acceptable excipients.
  • Standard compositions may be liquid, solid or semi-solid.
  • the liquid preparations may be in solution, suspension, emulsion, parenteral or oral form.
  • excipients include methylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, carboxymethylcellulose, polymers derived from acrylic and methacrylic acid, polyethylene glycols, solid vaseline, solid paraffin, lanolin, vegetable oils, mineral oil, cetyl alcohol, sterile alcohol, cetostearyl alcohol, glyceryl monostearate, wax of cetyl esters, nonionic and anionic self-emulsifying wax and sodium lauryl sulfate, for semi-solid dosage forms.
  • Binders disintegrants, diluents, lubricants, surfactants such as cellulose, lactose, starch, mannitol, magnesium stearate, talc, colloidal silicon dioxide, magnesium oxide and kaolin for solid preparations.
  • solubilizers and surfactants such as glycerine, propylene glycol, sucrose, sodium lauryl sulfate and polysorbate may be used.
  • water for injections may be used.
  • Excipients may also contain minor amounts of additives such as isotonicity and chemical stability enhancing substances such as preservatives, chelators and stabilizers, examples of such substances include phosphate buffer, bicarbonate buffer and Tris buffer, thimerosal, m- or o-cresol, formalin, alcohol benzyl, parabens, EDTA, BHA, BHT; in addition to sweeteners, colorings and flavorings.
  • compositions may be administered intramuscularly, intravenously, topically, orally, by inhalation or as devices that may be implanted or injected. They can be used in the treatment of early stage neoplasms or in combination with drugs with antitumor activity already established in more advanced stages of the disease.
  • Example 1 Preparation and characterization of MTI inclusion complexes: ⁇ -CD
  • the MTI: ⁇ -CD inclusion complex was prepared by mixing ⁇ -CD and MTI ( Figure 2) in water and acetone at a 1: 1 molar ratio. The mixture was stirred for 48 hours at room temperature. Subsequently, the acetone was evaporated and the resulting mixture was lyophilized. The lyophilized powder was kept in a desiccator under vacuum.
  • the 1: 1 ⁇ -CD-MTI inclusion complex, physical mixtures and pure MTI were characterized by differential exploratory calorimetry (DSC).
  • DSC differential exploratory calorimetry
  • Figure 3 an endothermic event was observed at 101, 20 ° C corresponding to the MTI fusion.
  • Figure 4 the DSC curve of the complex
  • Figure 5 the DSC curve of the complex
  • Figure 5 shows an endothermic event at 103.16 ° C corresponding to fusion of the MTI not found in the ⁇ -CD cavity.
  • the wide peaks below 100 ° C that appear in the DSC curves of the complex ( Figure 4), physical mixture ( Figure 6) and free ⁇ -CD ( Figure 6) correspond to the elimination of water molecules present within the ⁇ -CD cavity. .
  • the concentration of soluble MTI at different concentrations of ⁇ -CD is shown in Table 1.
  • Table 1 Concentration of soluble MTI at different concentrations of ⁇ -CD.
  • T x (L) 2/2 Tumor volumes (mm 3 ) were calculated from measurements of their size (T) and width (L). The tumor volume was then determined using the formula T x (L) 2/2 (Viale, M. Vannozzi, MO, Merlo, F., Cafaggi, S., Parodi, B. Esposito, M. Cisplatin Combined with the New Cisplatin-Procaine Complex DPR: In Vitro and In Vitro Studies (Eur. J. Cancer 1996, 32A, 2327). The animals had free access to water and feed and were kept in an environment with light cycle control.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nanotechnology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Biophysics (AREA)
  • Biotechnology (AREA)
  • General Engineering & Computer Science (AREA)
  • Medical Informatics (AREA)
  • Molecular Biology (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Inorganic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne des compositions pharmaceutiques antinéoplasiques contenant un nitroimidazol substitué. Ces compositions peuvent être utilisées dans le traitement de néoplasies au stade initial ou en combinaison avec des médicaments à activité antitumorale déjà établie à des stades plus avancés de la maladie.
PCT/BR2011/000220 2010-07-07 2011-07-07 Compositions pharmaceutiques antinéoplasiques contenant des nitroimidazols substitués Ceased WO2012003562A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
BRPI1003297-5 2010-07-07
BRPI1003297-5A BRPI1003297A2 (pt) 2010-07-07 2010-07-07 composições farmacêuticas antineoplásicas contendo compostos nitroimidazóis substituìdos

Publications (3)

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WO2012003562A1 true WO2012003562A1 (fr) 2012-01-12
WO2012003562A4 WO2012003562A4 (fr) 2012-03-29
WO2012003562A8 WO2012003562A8 (fr) 2013-07-04

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3280139A (en) * 1962-04-06 1966-10-18 Delmar Chem Substituted nitroimidazoles
US5929104A (en) * 1997-04-02 1999-07-27 Pola Chemical Industries, Inc. Method for inducing apoptosis of cancer cell
WO2003066052A1 (fr) * 2002-02-07 2003-08-14 Hypoxi Co., Ltd. Agent anticancereux renfermant du nitro-imidazole et un inhibiteur de la topoisomerase comme ingredients actifs
WO2010047831A1 (fr) * 2008-10-23 2010-04-29 Nycomed Us Inc. Formulations de gel de métronidazole stables

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3280139A (en) * 1962-04-06 1966-10-18 Delmar Chem Substituted nitroimidazoles
US5929104A (en) * 1997-04-02 1999-07-27 Pola Chemical Industries, Inc. Method for inducing apoptosis of cancer cell
WO2003066052A1 (fr) * 2002-02-07 2003-08-14 Hypoxi Co., Ltd. Agent anticancereux renfermant du nitro-imidazole et un inhibiteur de la topoisomerase comme ingredients actifs
WO2010047831A1 (fr) * 2008-10-23 2010-04-29 Nycomed Us Inc. Formulations de gel de métronidazole stables

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
HAY, MP ET AL.: "Selective Antitumor Agents. 10. Bis(nitroimidazoles) and Related Bis(nitroheterocycles): Development of Derivatives with Higher Rates of Metabolic Activation under Hypoxia and Improved ; Aqueous Solubility", J. MED. CHEM., vol. 38, 1995, pages 1928 - 1941, XP002686339, DOI: doi:10.1021/jm00011a013 *
LAHIANI-SKIBA ET AL.: "Optimization of entrapment of metronidazole in amphiphilic beta-cyclodextrin nanospheres", JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS, vol. 41, 2006, pages 1017 - 1021, XP028005379, DOI: doi:10.1016/j.jpba.2006.01.021 *
MARTIN, DB ET AL.: "Betacyclodextrin for improved stability and delivery of anti-infective drugs", INDIAN JOURNAL OF PHARMACEUTICAL SCIENCES, vol. 57, no. 5, 1995, pages 203 - 206 *
SWENSON, DH ET AL.: "Synthesis and Evaluation of a Boronated Nitroimidazole for Boron Neutron Capture Therapy", J. MED. CHEM., vol. 39, 1996, pages 1540 - 1544 *

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WO2012003562A8 (fr) 2013-07-04
BRPI1003297A2 (pt) 2012-04-10
WO2012003562A4 (fr) 2012-03-29

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