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WO2012003563A1 - Compositions pharmaceutiques antinéoplasiques contenant des composés nitroaromatiques substitués - Google Patents

Compositions pharmaceutiques antinéoplasiques contenant des composés nitroaromatiques substitués Download PDF

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Publication number
WO2012003563A1
WO2012003563A1 PCT/BR2011/000221 BR2011000221W WO2012003563A1 WO 2012003563 A1 WO2012003563 A1 WO 2012003563A1 BR 2011000221 W BR2011000221 W BR 2011000221W WO 2012003563 A1 WO2012003563 A1 WO 2012003563A1
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Prior art keywords
aromatic
heteroaromatic
aryl
alkyl
branching
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PCT/BR2011/000221
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English (en)
Portuguese (pt)
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WO2012003563A4 (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
Marcela Silva Lopes
Elaine De Souza Fagundes
Camila Frizzola De Andrade
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Universidade Federal de Minas Gerais
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Universidade Federal de Minas Gerais
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Priority to PCT/BR2011/000221 priority Critical patent/WO2012003563A1/fr
Publication of WO2012003563A1 publication Critical patent/WO2012003563A1/fr
Publication of WO2012003563A4 publication Critical patent/WO2012003563A4/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C233/77—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups
    • C07C233/78—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
    • C07C205/49—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups
    • C07C205/57—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C07C205/58—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton the carbon skeleton being further substituted by halogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C233/67—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/68—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/69—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom of an acyclic saturated carbon skeleton

Definitions

  • the present invention describes antineoplastic pharmaceutical compositions comprising substituted nitroaromatic compounds.
  • the compositions may be used in the treatment of early stage neoplasms or in combination with other antitumor drugs in later 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.
  • 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, 2002; Hay, MP et al., J. Med. Chem. V. 38, pp. 1928-1941, 1995).
  • the 4-bromomethyl-3-nitrobenzoic acid compound is widely used as a substrate in syntheses.
  • Zhang et al described the use of 4-bromomethyl-3-nitrobenzoic acid as a key precursor of benzodiazepine-2-3-dione through a four step sequence including nucleophilic displacement, acylation, simultaneous cyclization reduction and alkylation (Zhang Jinfang; Lou Boliang; Saneii Hossain Application of polymer-bound 4- (bromomethyl) -3-nitrobenzoic acid for synthesis of trisubstituted 1,4-benzodiazepine-2,3-diones Molecular Diversity (2003), 6, 13-17.
  • Oliveira et al evaluated the activity of aromatic nitrocompounds against Trypanossama cruzi, including the trypanocidal activity of 4-bromomethyl-3-nitrobenzoic acid (RB Oliveira, APF Passos, RO Alves, AJ Romanha, .AF Prado, J. Dias de Souza Filho and RJ Alves, Mem. Inst. Oswaldo Cruz (2003), 98, p. 141).
  • 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.
  • Patent application WO2008118150 discloses a method for treating, preventing or ameliorating hyperprollferative disorders by determining the level of nitric oxide synthase in body fluids and the subsequent administration of bioreducible substances, including banoxantrone.
  • Treatment of cancer patients using hypoxic cell-selective bioreducible substances is under investigation, but these substances are not yet commercially available.
  • New options for substances showing selectivity for hypoxia 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 13 Comparison between tumor weights of Control Group (Group 1), AANC-treated Group (Group 2) and AANC-DHA-treated Group (Group 3).
  • Figure 14 Structural formulas of nitrocomposites used for activity assays against tumor cell lines and PBMC.
  • the present invention describes substituted nitroaromatic containing antineoplastic pharmaceutical compositions having the structural formula of Figure 1.
  • the substituent "X" of Figure 1 being selected from the group comprising COOH, SO 3 H, tetrazoyl, CHO, CH 3, CH 2 OH, CN, COOR, CONHR, SONHR, NHSO 2 R, NHCOOR, 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).
  • substituent "Y" of Figure 1 is selected from the group comprising H, F, Cl, Br, I, OH, N 3 , OPO (OR) 2 , NHR, NR 2 , NR 3 , OSO 2 R, OSO 2 Ar, OAr, OCOR, OCON, SH, SR, SAr; where R may be H, (C-2 to C-30 alkyl, with or without branch); 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 nitroaromatic 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 and sucrose 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.
  • the compositions may be used in the treatment of early-stage neoplasms or in combination with drugs with established antitumor activity at later stages of the disease.
  • Example 1 Preparation and characterization of ANB inclusion complexes: HP- ⁇ -CD
  • HP-CD inclusion complex was prepared by mixing HP- ⁇ -CD and ANB ( Figure 2) in water and acetone at a 1: 1 molar ratio. The mixture was stirred for 2 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 pure ANB DSC curve ( Figure 3) shows an endothermic event at 134.6 ° C corresponding to the ANB fusion peak and the exothermic event at 183.07 ° C corresponding to its degradation product, indicating that The substance is unstable at temperatures above 150 ° C (temperature at which substance begins the degradation process).
  • the DSC curves of the complex ( Figure 4) and the physical mixture ( Figure 5) were very similar.
  • Figure 6 shows the C- ⁇ -CD DSC curve.
  • the endothermic event at ⁇ 42 ° C related to water loss, only exothermic events above 180 ° C are observed, corresponding to the formation of degradation products. The intensity of these peaks is lower in the DSC curve of the complex ( Figure 4), which may indicate greater protection of the substance within the DC cavity.
  • the ANB: HP-p-CD inclusion complex presented a type A solubility diagram, ie when the solubility of the substrate increases with increasing CD concentration ( Figure 7). A linear increase in soluble ANB concentration is observed with the increase in ⁇ - ⁇ -CD concentration. This type of diagram is characteristic of the formation of soluble inclusion complex.
  • Example 2 Evaluation of ANB's in vivo antitumor activity and its inclusion complex
  • ANB was administered in a group of 11 animals at a dose of 50 mg / kg, solubilized in saline containing PEG 400 (polyethylene glycol) (40%), 5 in tumors with volumes of 250 and 6 with volume of 400 mm 3 . The same number of animals was used in the control group.
  • the 50 mg / kg ANB: HP-CD complex was administered to 4 animals and the same number of animals were used as controls.
  • 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 32A, 2327, 1996). The animals had free access to water and feed and were kept in an environment with light cycle control.
  • Example 3 Preparation of inclusion complexes in cyclodextrins and solid lipid nanoparticles containing ANB
  • inclusion complexes in cyclodextrins and solid lipid nanoparticles (NLS) containing ANB were prepared. Because it is a carboxylic acid, ANB ionizes the pH used in the preparation of NLS, which made it difficult to incorporate it into the oil phase of the formulation. To work around this problem, methyl 4-bromomethyl-3-nitrobenzoate (ENB), the methyl ester of ANB ( Figure 12), which is easily incorporated into the oil phase and can be prepared can be prepared. considered as a prodrug, ie will release the ANB after ester hydrolysis in vivo.
  • ENB 4-bromomethyl-3-nitrobenzoate
  • Figure 12 the methyl ester of ANB
  • the NLS will be prepared by the hot homogenization technique.
  • the nitroaromatic to be incorporated (ENB) will be dispersed in the molten oil phase.
  • the oily (FO) and aqueous (FA) phases will be pre-weighed and heated separately to a temperature of 75 ° C.
  • the AF will be slowly poured into the FO using Ultra Turrax T-25 homogenizer (Ika Labortechnik, Germany) while stirring at 11000 rpm for 5 minutes.
  • the NLS will be sonicated at 21% amplitude (Ultra-cell, 750 W; Sonics Materials Inc., USA) for 5 minutes.
  • the pH of the formulation will be adjusted with 0.1 M HCl solution to obtain the final pH between 7-7.5.
  • the NLS will be packed in an amber bottle and kept in the refrigerator.
  • the synthesis of new ANB derivatives was performed. Improved bioavailability of a substance may result in a decrease in the effective dose and, consequently, a decrease in the possible toxic effects.
  • the activity of the new synthesized nitrocompounds was evaluated in vitro using 3 human tumor cell lines: HL60 (leukemia), Jurkat (lymphoma) and MCF-7 (breast tumor). The toxicity of the substances to normal cells was also assessed using peripheral blood mononuclear cells (PBMC).
  • PBMC peripheral blood mononuclear cells
  • PBMC Human peripheral blood mononuclear cells
  • AANC 4- (Chloromethyl) -3-nitro-N- (2-hydroxyethyl) benzamide
  • PBMC normal cells
  • DHA cis-4, 7, 10,13, 16,19-docosahexanoic acid
  • Figure 11 Some natural fatty acids, such as DHA, are eagerly consumed by tumor cells for use as biochemical precursors or energy sources.
  • certain essential fatty acids also exhibit synergism with antitumor drugs.
  • Example 5 Evaluation of antitumor activity of AANC and its DHA conjugate in vivo
  • AANC and its DHA conjugate were evaluated in vivo using Ehrlich solid tumor bearing mice.
  • AANC and AANC-DHA were administered to a group of 5 animals at a dose of 30 mg / kg. Both were solubilized in saline containing 35% PEG 400 and 5% Tween 80. The same number of animals was used in the control group. Doses were administered intratumorally twice a week for 14 days. Forty-eight hours after the end of treatment the animals were euthanized, the tumors were desiccated and weighed.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (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)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne des compositions pharmaceutiques antinéoplasiques comprenant des composés nitroaromatiques substitués. Ces compositions peuvent être utilisées dans le traitement de néoplasies au stade initial ou en combinaison avec d'autres médicaments antitumoraux à des stades plus avancés de la maladie.
PCT/BR2011/000221 2010-07-07 2011-07-07 Compositions pharmaceutiques antinéoplasiques contenant des composés nitroaromatiques substitués Ceased WO2012003563A1 (fr)

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BR014110002138 2010-07-07
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9085527B2 (en) 2008-07-08 2015-07-21 Catabasis Pharmaceuticals, Inc. Fatty acid acylated salicylates and their uses
US9139516B2 (en) 2008-07-08 2015-09-22 Catabasis Pharmaceuticals, Inc. Fatty acid acetylated salicylates and their uses

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5464871A (en) * 1993-05-12 1995-11-07 Octamer, Inc. Aromatic nitro and nitroso compounds and their metabolites useful as anti-viral and anti-tumor agents

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5464871A (en) * 1993-05-12 1995-11-07 Octamer, Inc. Aromatic nitro and nitroso compounds and their metabolites useful as anti-viral and anti-tumor agents

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
CHEN, M. ET AL.: "Study of inclusion complex of b- cyclo-dextrin and nitrobenzene.", CHEMOSPHERE, vol. 63, 2006, pages 522 - 529 *
HONE, N.D. ET AL.: "Solid phase synthesis of tetrahy- dro-1,4-benzodiazepin-2-ones.", TETRAHEDRON LETTERS, vol. 44, 2003, pages 8493 - 8495 *
PROSSER, G.A. ET AL.: "Discovery and evaluation of Escherichia coli nitroreductases that activate the anti- cancer prodrug CB1954.", BIOCHEMICAL PHARMACOLOGY, vol. 79, 21 October 2009 (2009-10-21), pages 678 - 687, XP026808701 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9085527B2 (en) 2008-07-08 2015-07-21 Catabasis Pharmaceuticals, Inc. Fatty acid acylated salicylates and their uses
US9139516B2 (en) 2008-07-08 2015-09-22 Catabasis Pharmaceuticals, Inc. Fatty acid acetylated salicylates and their uses
US9272984B2 (en) 2008-07-08 2016-03-01 Catabasis Pharmaceuticals, Inc. Fatty acid acetylated salicylates and their uses
US9458094B2 (en) 2008-07-08 2016-10-04 Catabasis Pharmaceuticals, Inc. Fatty acid acetylated salicylates and their uses
US9708245B2 (en) 2008-07-08 2017-07-18 Catabasis Pharmaceuticals, Inc. Fatty acid acylated salicylates and their uses

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