WO2012003563A1

WO2012003563A1 - Antineoplastic pharmaceutical compositions containing substituted nitroaromatic compounds

Info

Publication number: WO2012003563A1
Application number: PCT/BR2011/000221
Authority: WO
Inventors: 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
Original assignee: Universidade Federal De Minas Gerais - Ufmg
Priority date: 2010-07-07
Filing date: 2011-07-07
Publication date: 2012-01-12
Also published as: WO2012003563A4

Abstract

The present invention describes antineoplastic pharmaceutical compositions comprising substituted nitroaromatic compounds. The compositions can be used for treating early-stage neoplasias or in combination with other antitumour drugs for more advanced stages of the disease.

Description

"ANTINEOPLASTIC PHARMACEUTICAL COMPOSITIONS CONTAINING SUBSTITUTED NITROAROMATIC COMPOUNDS"

FIELD OF INVENTION

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.

TECHNICAL STATE

Solid tumors, such as lung, colon and breast carcinomas, are the main types of cancer in men. There is considerable evidence that the presence of 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. However, 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).

In 1972, Lin and colleagues hypothesized that hypoxic cell regions could have a greater reduction capacity than well-oxygenated cell regions. By analogy, 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. From there, the concept of Biorreductive activation of substances in hypoxic 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 // ^' preferentially Suppress 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 tumor growth and metastasis in preclinical models of pancreatic cancer Cancer Clin Res.13, 2216, 2007. Yamazakil, Y., Kunimoto, S., Ikeda, D. Rakicidin A: A Hypoxia Selective Cytotoxin Biol Pharm Bull 30, 261, 2007. Anderson, RF, Shinde, SS, Hay, MP, Gamage, SA, Denny, WA Radical properties governing the hypoxy-selective cytotoxicity of 3-amino-1 antitumor 2,4-benzotriazine 1,4-dioxides Org. Biomol. Chem. 3, 2167, 2005).

The ability of nitroaromatics to act as bioreducible agents is already well established and, therefore, 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 concept of bioreductive activation of substances in hypoxic cells has been extensively studied (Dai, J. et al. J. Nat. Prod. V. 70, p. 130-133, 2007; Lalani, AS et al. Clin. Cancer Res. V. 13, pp. 2216-2225, 2007; Yamazaki, Y. et al., Hypoxia-Selective Cytotoxin., Biol. Pharm. Buli. V.30, pp. 261-265, 2007. H. Gonzalez, M. Lavaggi, ML Med. Chem. V. 2, pp. 315-327, 2006) and it is noteworthy that currently two substances, tirapazamine and banoxantrone (AQ4N) are in the final stages. Clinical Screening Studies (Novacea. About AQ4N. Available at: http://www.redorbit.com/news/health/1255929/novaceas_proofofprinciple_study _of_aq4n_in_solid_tumors_published_in / index.html Accessed March 28, 2009, Marcu, L; Olver, I. Curr, Clin Pharmacol, v. 1, pp. 71-79, 2006). Antitumor activity for hypoxic cells of nitrogen mustards derived from 2,5-dinitrobenzamide is also under investigation, with promising results (Atwell, GJ et al. J. Med. Chem. v.50, p. 1 197-1212, 2007).

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.

Sun et al reported solid phase synthesis of 3,4-hydro-2 (1 H) -quinazolinones and 3,4-dihydro-1 H-quinazoline-2-thione from Rink resin, 4-bromomethyl acid acylation -3-nitrobenzoic acid and amination with primary amines, tin chloride reduction and cyclization (Sun, Q .; Zhou, X .; Kyle, DJ. Solid-phase synthesis of 3,4-dihydro-2 (1 H) -quinazolinones and 3,4-dihydro-1H-quinazolin-2-thiones (Tetrahedron Lett. (2001), 42 (25), 4119-4121).

Additionally, 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).

Currently we find some patents available for the invention:

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.

BRIEF DESCRIPTION OF THE FIGURES

Figure 1: Structural formula of substituted nitroaromatic compounds

Figure 2: Structure of 4-Bromomethyl-3-nitrobenzoic acid (ANB)

Figure 3: DSC (Differential Exploratory Calorimetry) Curve of Pure ANB Figure 4: DSC (Differential Exploratory Calorimetry) Curve of the ANB: β-CD Complex.

Figure 5: DSC (Differential Exploratory Calorimetry) curve of the physical mixture ANB: ΗΡ-β-CD

Figure 6: DSC (Differential Exploratory Calorimetry) curve of ΗΡ-β-CD

Figure 7: ABN Solubility Diagram: HP-CD

Figure 8: Comparison graph of tumor growth between control group and ANB at a dose of 50 mg / kg (n = 5) and initial tumor volume ~ 250 mm ³ .

Figure 9: Comparison chart of tumor growth between control group and ANB at a dose of 50 mg / kg (n = 6) and initial tumor volume ~ 400 mm ³ .

Figure 10: Comparison graph of tumor growth between control group and ANB complex: ΗΡ-β-CD at a dose of 50 mg / kg (n = 4) and initial tumor volume ~ 400 mm ³ .

Figure 11: AANC-DHA Conjugate

Figure 12: ENB synthesis scheme, ANB prodrug

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.

DETAILED DESCRIPTION OF TECHNOLOGY

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).

And the 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).

The 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. Semisolids in the form of gels, ointments, creams or pastes and solids in the form of capsules, tablets, dragees or lozenges.

Examples of 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.

For liquid dosage forms solubilizers and surfactants such as glycerine, propylene glycol and sucrose may be used. For injections, 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.

Such 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.

The present invention may be better understood by the following non-limiting examples of technology: Example 1: Preparation and characterization of ANB inclusion complexes: HP-β-CD

A) Preparation of inclusion complexes

The ANB: HP-CD inclusion complex was prepared by mixing HP-β-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.

B) Characterization of inclusion complexes by differential exploratory calorimetry (DSC) The inclusion complex ΗΡ-β-Οϋ: ΑΝΒ 1: 1, the physical mixture and the pure substances were characterized by differential exploratory calorimetry (DSC).

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-β-CD DSC curve. In addition to 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.

C) Solubility isotherm measurement

The concentration of soluble ANB at different concentrations of ΗΡ-β-CD is shown in Table 1.

Table 1: Concentration of soluble ANB at different concentrations of ΗΡ-β-CD

[ΗΡ-β-CD] mol / L [ANB] mol / L [ANB] soluble mol / L

0.0 0.02 0.00069

0.004 0.02 0.00096

0.008 0.02 0.00127

0.010 0.02 0.00136

0.015 0.02 0.00171

0.02 0.02 0.00192

0.04 0.02 0.00242

0.06 0.02 0.00250

0.08 0.02 0.00238

0.01 0.02 0.00246 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 ΗΡ-β-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

A) Induction of Ehrlich ascites tumor in mice

For ascites tumor induction, three female Swiss mice weighing between 25 and 30 grams were used for each experiment. Ehrlich cells that were conserved in liquid nitrogen were thawed in a water bath at 37 ° C. They were transferred to a previously cleaned Falcon tube and 0.9% saline was slowly and gradually added thereto until the total cell suspension volume was approximately 20 ml. The suspension was immediately centrifuged for 5 minutes at 5 ° C and 3000 RPM speed. The medium in which the cells were conserved was removed as supernatant. The cells were resuspended with the aid of a Pasteur pipette in about 1.5 ml of 0.9% saline and then the cell concentration in the suspension was determined using the Neubauer chamber. The suspension was properly diluted and 1x10 ⁶ cells were injected intraperitoneally into each mouse in a total volume of 0.5 ml.

B) Ehrlich solid tumor induction in mice

Initially, 2 x 10 ⁶ Ehrlich tumor cells were taken from ascitic tumor mice and implanted in female Swiss mice, weighing 20 to 25 grams subcutaneously, dorsolaterally. After 10 days, the tumors were measured and the samples to be tested were administered intratumorally. C) Evaluation of antitumor activity in mice

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.

Doses were administered intratumorally twice a week for 3 weeks. 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.

Pure ANB demonstrated antitumor activity when compared to the control group, as can be seen in the graphs of figures 8 and 9. The disappearance of solid tumor was also observed in an animal treated with ANB. Animals treated with ANB: HP-CD showed significant reduction in tumor volume (Figure 10).

Example 3: Preparation of inclusion complexes in cyclodextrins and solid lipid nanoparticles containing ANB

In order to increase stability and solubility in water to facilitate in vivo administration and improve bioavailability, 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.

The NLS will be prepared by the hot homogenization technique. In this method, 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. Subsequently, the NLS will be sonicated at 21% amplitude (Ultra-cell, 750 W; Sonics Materials Inc., USA) for 5 minutes. After cooling to room temperature, 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.

Example 4: Synthesis and Characterization of ANB Derivatives

In the search for new bioactive substances, presenting higher potency and better physicochemical properties, 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. Initially, 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).

Human peripheral blood mononuclear cells (PBMC) will be separated according to the method described by Souza-Fagundes and colleagues (Souza-Fagundes et al., Intern. Immunopharmacol. 3, 383-392, 2003). Phenotype analysis of peripheral blood leukocyte populations (T-lymphocytes, B, monocytes and NK-cells, granulocytes), whether or not treated with nitrocompounds, was performed by studying cell surface markers after antibody labeling. phycoerythrin (PE) or fluorescein isothiocyanate (FITC) conjugated monoclonal compounds. Five hundred microlites of peripheral blood was diluted with RPMI and cultured in polypropylene tubes. in the presence or absence of different sample concentrations for 14 hours at 37 ° C in a 5% CO ₂ atmosphere. After incubation, the samples were subjected to the erythrocyte lysis step using 2 ml of Facs Lysing Solution (Becton Dickinson) diluted 10 times in distilled water. After lysis, the samples were centrifuged at 400 g for 10 minutes at 18 ° C. The supernatant was discarded and the cells homogenized in 400 µL of 0.015 M PBS containing 0.01% sodium azide. This suspension was divided into the different tubes containing the diluted antibodies (00μΙ per tube) and incubated at room temperature for 30 minutes. After the incubation period, these cells were washed with 0.015 M PBS containing 0.01% sodium azide, resuspended in 300 μΙ of a solution containing paraformaldehyde, 1%, sodium cacodylate 1% and 0.67% NaCl in PBS, being fixed for at least 30 minutes and kept at 4 ^o C until flow cytometric analysis. Data were acquired using a FACscan flow cytometer (Becton-Dickinson Immunocytometry Systems, San Jose, CA, US) and identification of cell populations of interest as well as determination of the percentage value of cell populations and subpopulations were performed using the Cell Quest program. The results obtained are illustrated in Table 2.

Table 2 - Results of activity assays against tumor cell lines and PBMC using derived compounds (Figure 14)

Compound R1 R2 R3 IC50 (µM)

HL60 Jurkat MCF-7 PBMC

ABB OH H Br 36.30> 100 23.63 88.75

ANB OH N0 ₂ Br 72.71 68.95 44.09> 100

ANBEM OCH3 N0 ₂ Br 90, 13> 80 - 44.06

ANOH OH N0 ₂ OH>100> 100 -> 100

EANB NH (CH ₂ ) ₂ OH N0 ₂ Br 14.92 53.28 30.54 53.87

AANC NH (CH ₂ ) ₂ OH N0 ₂ Cl 9.09 19.36 79.89> 100

AAMs NH (CH ₂ ) ₂ CI N0 ₂ Cl 49.23 85 63> 100

AANEB NH (CH ₂ ) ₂ 0 ₂ C (CH ₂ ) ₂ CH ₃ N0 ₂ Cl 15.96> 100 29.54 -

ASNCI NH (CH ₂ ) ₂ OH H Cl>100>100>100> 100

DIAANC - - - 9.36 30.20 22.92 - etoposide - - - 8.419 2.471>100> 100 To date, 12 substances were synthesized and tested of which 7 showed significant cytotoxic activity, being more active than etoposide (positive control) against the breast tumor cell line (MCF-7). The synthesis of a new series of molecules is underway.

4- (Chloromethyl) -3-nitro-N- (2-hydroxyethyl) benzamide (AANC) showed significant activity against the 3 tumor cell lines, being more active against the HL60 and Jurkat lines. In addition, AANC presented low toxicity to normal cells (PBMC), which makes it a promising prototype for further in vivo studies. In addition, the presence of the hydroxyl group in AANC favors its conjugation with cis-4, 7, 10,13, 16,19-docosahexanoic acid (DHA) through an esterification reaction (Figure 11). Some natural fatty acids, such as DHA, are eagerly consumed by tumor cells for use as biochemical precursors or energy sources. In addition, certain essential fatty acids also exhibit synergism with antitumor drugs. Therefore, conjugation of antitumor drugs with DHA is a promising strategy that has been studied with encouraging results (Wang et al., Bioorg. Med. Chem. V. 14, p. 7854-7861, 2006; Wang et al., Bioorg, Med. Chem., V. 13, pp. 5592-5599, 2005; Harries et al., Brit. J. Cancer v. 91, pp. 1651-1655, 2004).

Example 5: Evaluation of antitumor activity of AANC and its DHA conjugate in vivo

The antitumor activity of AANC and its DHA conjugate was 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. Percent inhibition of tumor growth was calculated using the formula% inhibition = [(A - B) / A] x 100, where A represents the average tumor weight of the control group and B represents the average tumor weight in the groups treated. Based on this formula, nitrocompound AANC and its DHA conjugate showed significant antitumor activity, with% tumor growth inhibition of 62% and 44%, respectively (Figure 13). These compounds may also be administered using other routes, such as intravenous and non-limiting oral routes.

Claims

1- SUBSTITUTED NITROAROMATICS characterized by having the following structural formula:

a) X 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) alkyl C-30, with or without branching); aryl (aromatic or heteroaromatic); (C-2 to C-30 alkyl aryl, with or without branching, aromatic or heteroaromatic);

b) Y being selected from the group comprising H, F, Cl, Br, 1, OH, N ₃ , OPO (OR) ₂ , NHR, NR ₂ , NR ₃ , OSO ₂ R, OSO ₂ Ar, OAr, OCOR, OCON where R may be H, alkyl (C-2 to C-30, with or without branching); aryl (aromatic or heteroaromatic); alkyl aryl (C-2 to C-30, with or without branching, aromatic or heteroaromatic).

2. ANTINEOPLASTIC PHARMACEUTICAL COMPOSITION, characterized in that it comprises substituted nitroaromatics having the following structural formula:

- X being selected from the group comprising COOH, SO3 H, tetrazolyl, CHO, CH _3, CH ₂ OH, CN, COOR, CONHR, SONHR, NHSO ₂ R, NHCOOR, where R can be H, alkyl (C 2 to C 30, with or without branch); aryl (aromatic or heteroaromatic); (C-2 to C-30 alkyl aryl, with or without branching, aromatic or heteroaromatic); - Y being 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, where R may be H, (C-2 to C-30 alkyl, with or without branch); aryl (aromatic or heteroaromatic); (C-2 to C-30 alkyl aryl, with or without branching, aromatic or heteroaromatic); and

at least one pharmaceutically and physiologically acceptable excipient or adjuvant.

ANTINEOPLASTIC PHARMACEUTICAL COMPOSITION according to claim 2, characterized in that the substituted nitroaromatic compounds are used in their free form, included or associated with cyclodextrins.

ANTINEOPLASTIC PHARMACEUTICAL COMPOSITION according to Claim 3, characterized in that the cyclodextrins are selected from the group comprising a-cyclodextrin, β-cyclodextrin and γ-cyclodextrin and their derivatives.

ANTINEOPLASTIC PHARMACEUTICAL COMPOSITION according to Claim 3, characterized in that the cyclodextrin is preferably hydroxypropyl-β-cyclodextrin.

6. ANTINEOPLASTIC PHARMACEUTICAL COMPOSITION according to Claims 1 to 5, characterized in that the substituted nitroaromatic compounds are used individually or in combination with other antineoplastic agents.

ANTINEOPLASTIC PHARMACEUTICAL COMPOSITION according to any of claims 1 to 6, characterized in that it is administered by oral, subcutaneous, intramuscular, intravenous, intraperitoneal, intratumoral, transdermal routes or as devices which may be implanted or injected.

8- USE OF SUBSTITUTED NITROAROMATIC COMPOUNDS, characterized by being in the preparation of antitumor drugs.