WO2013091052A1 - Molecular compound comprising an acridine molecule chemically linked to a carboxylic group, which can be used for the selective destruction of solid tumour cells - Google Patents

Molecular compound comprising an acridine molecule chemically linked to a carboxylic group, which can be used for the selective destruction of solid tumour cells Download PDF

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Publication number
WO2013091052A1
WO2013091052A1 PCT/BR2012/000518 BR2012000518W WO2013091052A1 WO 2013091052 A1 WO2013091052 A1 WO 2013091052A1 BR 2012000518 W BR2012000518 W BR 2012000518W WO 2013091052 A1 WO2013091052 A1 WO 2013091052A1
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molecular compound
acridine
medicament
preparation
solid tumors
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PCT/BR2012/000518
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French (fr)
Portuguese (pt)
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De Castro Carvalho Marcos
Silva Paiva Gerson
Antonia De Souza Ivone
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Centro Brasileiro De Pesquisas Fisicas - Cbpf
Universidade Federal De Pernambuco - Ufpe
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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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
    • 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D219/00—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems
    • C07D219/04—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
    • C07D219/06—Oxygen atoms

Definitions

  • Molecular compound comprising an acridine molecule chemically linked to a carboxylic group useful for the selective destruction of solid tumor cells.
  • the present invention relates to a molecular compound, referred to herein as "oncollosis”, capable of selectively destroying solid tumor cells without affecting healthy rapidly replicating cells.
  • Chemotherapeutic compounds are those commonly used in the treatment of diseases caused by biological agents. When chemotherapy is applied to cancer, it is called antineoplastic chemotherapy or antiblastic chemotherapy.
  • the first antineoplastic chemotherapy was developed from mustard gas, used in both World Wars as a chemical weapon. After exposure of soldiers to this agent, it was observed that they developed spinal and lymphoid hypoplasia, which led to its use in the treatment of malignant lymphomas. From the publication of clinical studies on mustard gas and observations on the effects of folic acid in children with leukemia, there has been a growing advance in antineoplastic chemotherapy. More active and less toxic chemotherapeutic drugs are currently available for use in clinical practice. Advances in the last decades in the area of antineoplastic chemotherapy have considerably facilitated the application of other types of cancer treatment - and allowed a greater number of cures.
  • Chemotherapy works by stopping or slowing the growth of rapidly growing and dividing cancer cells.
  • chemotherapy can also damage rapidly dividing healthy cells, such as those in the lining of the mouth and intestine, those in defense white cells, or those that make hair. grow up. This can often result in kidney and heart complications.
  • Prodrugs are drugs that are activated at the site or within the target cell, or that are detoxified with non-Ivo cells.
  • azoiidines and acridines are effective in combating infectious processes.
  • Acridine di-benzenc [j, e] pyridine or 10-azaanthracene
  • Acridines were commonly used in manufactured and intermediate dyes, some of these dyes being used as antiseptics such as 9-aminoacridine, acriflavine and proflavine.
  • Patent Document FR2716454 August 25, 1995; Patent Application FR941971, February 22, 199
  • 4- (aminomethyl) -3-dimethylaminoacridine derivatives as anticancer agents.
  • Adjei (Investigational New Drugs, 1999, v. 17, p. 43-48) synthesized pyrazoloacridines (PZA) by combining the activity of DNA-interleaving acridines with selective hypoxia conferred by the reduction of the nitro group of the acridin n: i ring. co.
  • PZA may be a double inhibitor of DNA topoisomerases I and II that exert their effects by decreasing DNA topoisomerase adduct formation.
  • the PZA mechanism of action has exhibited antitumor activity in preclinical models in vivo.
  • the compound used by the author was 9-methoxypyrazoloac.ridine.
  • glucose-borne antineoplastic drugs are D-19575, also known as glufosfamide, published in US Patent No. 5,622,936, and glucose-chiorambucil derivatives (Halmos, T., Santarromana, M., Antonakis, K., Sherman , D. European Journal of Pharmacology: 318: 477-484, 1996).
  • glucose-borne antineoplastic drugs are D-19575, also known as glufosfamide, published in US Patent No. 5,622,936, and glucose-chiorambucil derivatives (Halmos, T., Santarromana, M., Antonakis, K., Sherman , D. European Journal of Pharmacology: 318: 477-484, 1996).
  • these medicines end up affecting healthy cells, as they also need glucose to survive.
  • intercalating agents capable of inserting between the base pair layers of nucleic acids, deforming the double helix and preventing replication and transcription.
  • antitumor antibiotics using this mechanism of action include actinomycin-D, adramycin and proflavin (Patrick, G., In the Introduction to Medicinal Chemistry, Oxford University, 1995).
  • solid tumors have a high acidity in their cell tissue, characterized by the presence of hydrogen ions (H + ). It is well known in the art that when solid tumors reach a certain size, oxygen penetration into it becomes limited. Under such conditions, oxidative phosphorylation cannot normally proceed because of oxygen deficiency, resulting in high lactic acid production, which leads to acidification of malignant tumor tissue, even allowing proliferation (Gatenby, R. A. , Gillies, RJ (Rev. Cancer 4: 891-899, 2004; Warburg, O. A Review. Science 123: 309-315, 1956).
  • Anti-cancer therapies called pH therapies, use local injections of salts of very alkaline (basic) elements, such as cesium, potassium and rubidium, in order to reduce tumor acidity, causing cells to die (Masco, HL US Patent No. 3,614,242, 1972). However, the same therapy does not work when the tumor has already spread throughout the body, causing metastasis.
  • basic elements such as cesium, potassium and rubidium
  • the present invention relates to oncology, in particular to a molecular compound, referred to herein as "oncollosis”, capable of selectively destroying solid tumor cells without affecting rapidly replicating healthy cells.
  • the present invention aims to provide a process for producing an anti-tumor drug capable of selectively reach solid tumor cells without promoting any damage to healthy cells using a carboxyl-type carrier that is sensitive to the acidity present in all types of solid malignant tumors.
  • an acridine intercalation process is provided to the tumor cell DNA, leading to apoptosis, also called programmed cell death.
  • a product comprising a molecular compound called ONCOLOOSE which is selectively guided into the tumors.
  • This compound is attracted into the tumors by the characteristic acidity of solid tumors through a carboxylic group that neutralizes their negative electric charge due to this tumor acidity to carry the acridine drug to the tumor cell DNA, preventing their reproduction. and leading the tumor cells to apoptosis or cellular self-destruction.
  • Figure 1 represents the molecular structure of the anti-tumor compound object of the present invention.
  • Figure 2 represents the types of acridine that will be attached to the carboxylic group, the latter, carrier of the drug into the tumors.
  • Figure 3 shows the antitumor action mechanism of 9-acridine carboxylate.
  • Figure 4 shows the drawing of 9-ac.ridine carboxylate interspersed with DNA.
  • Figure 5 shows the procedure for the synthesis of the compound ONCOLOOSE.
  • Figure 6 presents photos of the in vivo assay performed with Sarcoma 180 mice using doses of 10 mg / kg and 20 mg / kg.
  • the present invention relates to oncology, in particular to a molecular compound, referred to herein as "oncollosis”, capable of selectively destroying solid tumor cells without affecting healthy rapidly replicating cells.
  • the present invention aims to provide a process for producing an antitumor drug capable of selectively reaching solid tumor cells without promoting any damage to healthy cells using a carboxyl-type carrier that is sensitive to the acidity present in all types of solid tumors.
  • chemotherapy works by stopping or slowing the growth of cancer cells, which grow and divide rapidly.
  • chemotherapy can also damage healthy rapidly dividing cells, it is necessary to reduce or eliminate side effects in this type of cell.
  • glucose-borne antineoplastic drugs include D-19575 or glufosfamide and glucose-chlorambucil derivatives, but these drugs also affect healthy cells that also require glucose.
  • Solid tumors have a high acidity in their cell tissue, characterized by the presence of hydrogen ions (H + ).
  • H + hydrogen ions
  • solid tumors reach a certain size, oxygen penetration into it becomes limited. Under such conditions oxidative phosphorylation cannot normally proceed because of insufficient oxygen, resulting in high lactic acid production. This reduction of lactic acid leads to the acidification of malignant tumor tissue, allowing its proliferation.
  • This high acidity feature will be used here to guide a drug into malignant tumors selectively without affecting rapidly multiplying healthy cells, as healthy cells do not produce lactic acid.
  • a carboxylic group will be used to react with the acidity of solid malignant tumors and selectively carry the drug only into the tumor cells.
  • an acridine intercalation process is provided to the tumor cell DNA, leading to apoptosis, also called programmed cell death.
  • a product comprising a molecular compound called ONC0LO0SE that is selectively guided into the tumors.
  • This compound is attracted into the tumors by the characteristic acidity of solid tumors through a carboxylic group that neutralizes their negative electric charge due to this tumor acidity (since electrically charged molecules cross the cell membrane in small amounts while that neutral molecules cross it very easily because they are soluble in the lipid membranes of cells) to carry the acridine drug to the DNA of the tumor cells, preventing their reproduction and leading the tumor cells to apoptosis or cellular self-destruction.
  • the ONCOLOOSE compound comprises an acridine molecule ( Figure 1.1) chemically linked to a carboxylic group ( Figure 1.2) which, in neutral medium (blood and healthy tissues) are negatively charged ( Figure 1.3), the latter with strong affinity for hydrogen ions.
  • tumor Figure 1.4
  • such a combination neutralizes the carboxyl charge ( Figure 1.5) and causes the molecule to be absorbed in this form by the tumor.
  • Absorption requires passage through the lipid membrane of cells, which is determined by the presence or absence of electrical charge in the molecule: electrically charged molecules cross the membrane in small quantities while neutral molecules cross it very easily.
  • the tumors have a pH between 6 and 7, ie there are hydrogen ions (H +) and this favors the neutralization of the negative electrical charge of the molecule ( Figure 1.3), causing them to be absorbed by cancer cells in large quantities.
  • Figure 3 shows that glucose is absorbed by tumor cells containing 10 times more insulin receptors in their membrane than a healthy cell.
  • glucose metabolism in tumor cells reaches pyruvic acid (pyruvate), even in the presence of oxygen.
  • Un metabolized pyruvic acid then tends to concentrate in the cell, raising the acidity of its environment.
  • This protonates 9-acridine carboxylate, making it neutral.
  • This neutral charge facilitates its absorption into the tumor cell.
  • 9-acridine carboxylate interleaves with DNA, thus preventing cell replication, leading the cell to activate certain genes, which in turn leads to programmed death (apoptosis).
  • Pfitzinger reaction also known as a Pfitzinger-Borsche reaction
  • isatin or lH-indol-2,3-dione
  • basic medium usually potassium hydroxide
  • Tumors were implanted in mice following the methodology of Stock et al. (1995) and modified by Kom ⁇ yama (1992).
  • mice weighing 30g each, were divided into two groups, a treatment group and a control group.
  • the treated group received one of the possible chemotherapeutic compounds (9-acridine carboxylate) by intraperitoneal injection at doses of 10 and 20 mg / kg, a daily dose over a period of 6 days.
  • the control group received only placebo (2% solution 'saline) by the same period of time.
  • the purpose of the assay was to evaluate antitumor activity in available tumors (sarcoma 180). The result was positive for the tumors, and the tumor inhibition percentages were 48% and 90% respectively at the 10 mg / kg and 20 mg / kg doses for the mice.
  • Figure 4 shows the illustration of DNA-intercalated 9-acridine carboxylate
  • Figure 5 shows the process of compound synthesis
  • Figure 6 shows photos of the in vivo assay using doses of 10 mg / kg and 20 mg / kg.

Abstract

The present invention relates to oncology, in particular to a molecular compound denominated here as "oncoloose", which is capable of selectively destroying solid tumour cells without affecting rapidly replicating healthy cells. The present invention provides a product comprising a molecular compound denominated oncoloose, which is selectively targeted to the interior of tumours by means of a carboxylic group that neutralizes the negative electrical charge thereof, for transporting the acridine drug to the DNA in the tumour cells, preventing the replication thereof and causing apoptosis or cellular self-destruction of the tumour cells.

Description

Composto molecular que compreende uma molécula de acridina ligada quimicamente a um grupamento carboxílico útil para a destruição seletiva de células de tumores sólidos.  Molecular compound comprising an acridine molecule chemically linked to a carboxylic group useful for the selective destruction of solid tumor cells.
ANTECEDENTES DA INVENÇÃO BACKGROUND OF THE INVENTION
Campo da Invenção Field of the Invention
A presente invenção refere-se a um composto molecular, denominado aqui de "oncoloose", capaz de destruir seletivamente células de tumores sólidos sem afetar células saudáveis de replicação rápida.  The present invention relates to a molecular compound, referred to herein as "oncollosis", capable of selectively destroying solid tumor cells without affecting healthy rapidly replicating cells.
Antecedentes da Invenção Background of the Invention
Os compostos quimioterápicos são aqueles comumente utilizados no tratamento de doenças causadas por agentes biológicos. Quando a quimioterapia é aplicada ao câncer, é chamada de quimioterapia antineoplásica ou quimioterapia antiblástica .  Chemotherapeutic compounds are those commonly used in the treatment of diseases caused by biological agents. When chemotherapy is applied to cancer, it is called antineoplastic chemotherapy or antiblastic chemotherapy.
O primeiro quimioterápico antineoplásico foi desenvolvido a partir do gás mostarda, usado nas duas Guerras Mundiais como arma química. Após a exposição de soldados a este agente, observou-se que eles desenvolveram hipoplasia medular e linfóide, o que levou ao seu uso no tratamento dos linfomas malignos. A partir da publicação de estudos clínicos feitos com o gás mostarda e das observações sobre os efeitos do ácido fólico em crianças com leucemias, verificou-se avanço crescente da quimioterapia antineoplásica. Atualmente, quimioterápicos mais ativos e menos tóxicos encontram-se disponíveis para uso na prática clínica. Os avanços verificados nas últimas décadas, na área da quimioterapia antineoplásica, têm facilitado consideravelmente a aplicação de outros tipos de tratamento de câncer- e permitido maior número de curas.  The first antineoplastic chemotherapy was developed from mustard gas, used in both World Wars as a chemical weapon. After exposure of soldiers to this agent, it was observed that they developed spinal and lymphoid hypoplasia, which led to its use in the treatment of malignant lymphomas. From the publication of clinical studies on mustard gas and observations on the effects of folic acid in children with leukemia, there has been a growing advance in antineoplastic chemotherapy. More active and less toxic chemotherapeutic drugs are currently available for use in clinical practice. Advances in the last decades in the area of antineoplastic chemotherapy have considerably facilitated the application of other types of cancer treatment - and allowed a greater number of cures.
A quimioterapia funciona ao interromper ou retardar o crescimento de células de câncer, as quais crescem e se dividem rapidamente. Entretanto, a quimioterapia também pode danificar células saudáveis que se dividem rapidamente, como aquelas no revestimento da boca e intestino, as dos glóbulos brancos , responsáveis pela defesa, ou as que fazem o cabelo crescer. Isso pode resultar muitas vezes em complicações renais e cardíacas. Chemotherapy works by stopping or slowing the growth of rapidly growing and dividing cancer cells. However, chemotherapy can also damage rapidly dividing healthy cells, such as those in the lining of the mouth and intestine, those in defense white cells, or those that make hair. grow up. This can often result in kidney and heart complications.
.0 principal objetivo no desenvolvimento de agentes quimioterápicos antineoplásicos é a melhoria da seletividade e a consequente redução dos efeitos colaterais indese áveis. Uma das possibilidades que surgiu no estado da arte para resolver esse problema, mencionada na Patente US 5.622.936, foi o uso de pró-drogas. Pró-drogas são drogas que são ativadas no sítio ou dentro da célula alvo, ou que são detoxicadas com células não-a Ivo. . The main objective in the development of antineoplastic chemotherapeutic agents is the improvement of selectivity and the consequent reduction of undesirable side effects. One of the possibilities that arose in the state of the art to solve this problem, mentioned in US Patent 5,622,936, was the use of prodrugs. Prodrugs are drugs that are activated at the site or within the target cell, or that are detoxified with non-Ivo cells.
Algumas moléculas com atividade antitumoral foram citadas em documentos de patentes, inclusive documentos brasileiros, mas nenhuma delas atingia somente as células tumorais. O pedido de patente brasileiro BR0601827 (Pitta, I.R. et al.) , depositado em 24 de março de 2006, refere-se a compostos derivados acriclino-tiazolidínicos denominados tiazacridinas e imida zacr idinas , que tiveram ação antitumoral, e os respectivos processos de síntese química, bem como seu uso terapêutico como fármaco capaz de produzir . efeitos antitumorais . Some molecules with antitumor activity were cited in patent documents, including Brazilian documents, but none of them affected only tumor cells. Brazilian patent application BR0601827 (Pitta, IR et al.), Filed on March 24, 2006, refers to thiazacridines and imida zacridines, which have had antitumor action, and their synthesis processes. as well as its therapeutic use as a drug capable of producing . antitumor effects.
É conhecido no estado da técnica que azoiidinas e acridinas são eficazes no combate de processos infecciosos. A acridina (di-benzenc [j ,e] piridina ou 10-azaantraceno) foi isolada por Graebe em 1871; isolada a partir de óleos de alto ponto de ebulição em 1926, por Wirth (Patentes DE 440771 e GB 214756) ; preparada a partir do ácido N-fenilantraní lico por Perkin, em 1923 (Patente GB 214756) ; a partir de Ca- antranilato por Koller, em 1928 {Monatsh. 50,51); passando o vapor de benzilanilina por um fio de platina quente por Myer, em 1916 (Monatsh., 37,698) e por Ullmann, em 1907 (Ser.40, 2521) . As acridinas eram comumente utilizadas em corantes manufaturados e intermediários, sendo alguns destes corantes utilizados como antisépticos , como, por exemplo, 9- aminoacridina , acriflavina e proflavina.  It is known in the art that azoiidines and acridines are effective in combating infectious processes. Acridine (di-benzenc [j, e] pyridine or 10-azaanthracene) was isolated by Graebe in 1871; isolated from high boiling oils in 1926 by Wirth (DE 440771 and GB 214756); prepared from N-phenylanthanilic acid by Perkin in 1923 (GB Patent 214756); from Cantranilate by Koller in 1928 {Monatsh. 50.51); passing benzylaniline vapor through a hot platinum wire by Myer in 1916 (Monatsh., 37,698) and by Ullmann in 1907 (Ser.40, 2521). Acridines were commonly used in manufactured and intermediate dyes, some of these dyes being used as antiseptics such as 9-aminoacridine, acriflavine and proflavine.
Lhome et ai. (Pedido de Patente PCT W09425439, de 14 de novembro de 1994 ; FR935283, de 04 de maio de 1993) prepararam substâncias derivadas de acridina com propriedades antineoplásicas , como o ( 3, 6-bis-dimetilamino-acridin-4-il) - metanol. Compostos conjugados por condensação do ácido porfirínico com derivados de 9-aminoacridinas foram preparados por Karagianis & James, Aust. J. Chem . 1995, 48(10) , p. 1693- 1705. Os compostos conjugados foram isolados por cromatografia de exclusão de tamanho em rendimentos de mais de 35% e purificados por HPLC semi -preparado para pureza de 98%. Duflos et ai. (Documento de Patente FR2716454, de 25 de agosto de 1995; Pedido de Patente FR941971, de 22 de fevereiro de 199 ) sintetizaram derivados de 4- (aminometil) -3- dimetilaminoacridina como agentes anticancerigenos . Novamente, nenhum dos documentos citados apresentou compostos com alta seletividade . Lhome et al. (PCT Patent Application WO9425439 of November 14, 1994; FR935283 of May 4, 1993) prepared acridine-derived substances with antineoplastic properties such as (3,6-bis-dimethylamino-acridin-4-yl) - methanol. Porphyrinic acid condensation conjugated compounds with 9-aminoacridine derivatives were prepared by Karagianis & James, Aust. J. Chem. 1995, 48 (10), p. 1693-1705. Conjugated compounds were isolated by size exclusion chromatography in yields of over 35% and purified by semi-prepared HPLC to 98% purity. Duflos et al. (Patent Document FR2716454, August 25, 1995; Patent Application FR941971, February 22, 199) synthesized 4- (aminomethyl) -3-dimethylaminoacridine derivatives as anticancer agents. Again, none of the documents cited presented compounds with high selectivity.
Ferlin et al. {Eur . J. Med. Chem. 35:827-837, 2000) prepararam derivados substituídos de 9-acridina e azacridina (análogos de m-AMSA) com atividade ant.vtumoral contendo efeito inibitório sobre a DNA-topoisomerase II. Apesar de apresentar atividade seletiva para a DNA-topoisomerase, é conhecido por apresentar uma pequena taxa de toxicidade.  Ferlin et al. {Eur. J. Med. Chem. 35: 827-837, 2000) prepared substituted 9-acridine and azacridine derivatives (m-AMSA analogs) with antitumor activity containing inhibitory effect on DNA topoisomerase II. Although it has selective activity for DNA topoisomerase, it is known to have a small toxicity rate.
Adjei ( Investigational New Drugs, 1999, v. 17, p. 43-48) sintetizou pirazoloacridinas (PZA) combinando a atividade das acridinas de intercalarem o DNA com a hipoxia seletiva conferida pela redução do grupo nitro do anel acridí n:i. co . Estudos recentes sugerem que a PZA pode ser um duplo inibidor das DNA- topoisomerases I e II que exercem seus efeitos pela diminuição da formação de adutores da DNA-topoisomerase. De acordo com o autor, o mecanismo de açâo da PZA tem exibido atividade antitumoral em modelos pré-clínicos in vivo. O composto utilizado pelo autor foi a 9-metoxipirazoloac.ridina .  Adjei (Investigational New Drugs, 1999, v. 17, p. 43-48) synthesized pyrazoloacridines (PZA) by combining the activity of DNA-interleaving acridines with selective hypoxia conferred by the reduction of the nitro group of the acridin n: i ring. co. Recent studies suggest that PZA may be a double inhibitor of DNA topoisomerases I and II that exert their effects by decreasing DNA topoisomerase adduct formation. According to the author, the PZA mechanism of action has exhibited antitumor activity in preclinical models in vivo. The compound used by the author was 9-methoxypyrazoloac.ridine.
Para reduzir seus efeitos colaterais devido a não seletividade desses medicamentos antineoplásicos, estes são unidos quimicamente a moléculas de açúcares, visto que os tumores malignos necessitam de cerca de dez vezes mais glicose que as células saudáveis. Exemplo de fármacos antineoplásicos carreados por glicose são D-19575, também conhecido como glufosfamida , publicado na Patente US n° 5.622.936, e derivados de glicose-ciorambucila (Halmos, T., Santarromana , M., Antonakis, K., Sherman, D. European Journal of Pharmacology: 318: 477-484, 1996) . Contudo, estes medicamentos acabam afetando as células saudáveis, já que estas também necessitam de glicose para sobreviverem. To reduce their side effects due to the non-selectivity of these antineoplastic drugs, they are chemically linked to sugar molecules, as malignant tumors require about ten times more glucose than healthy cells. Examples of glucose-borne antineoplastic drugs are D-19575, also known as glufosfamide, published in US Patent No. 5,622,936, and glucose-chiorambucil derivatives (Halmos, T., Santarromana, M., Antonakis, K., Sherman , D. European Journal of Pharmacology: 318: 477-484, 1996). However, these medicines They end up affecting healthy cells, as they also need glucose to survive.
Uma alternativa utilizada no estado da arte é o uso de agentes intercalantes , com capacidade de se inserir entre as camadas de pares de bases dos ácidos nucléicos, deformando a dupla hélice e impedindo a replicação e a transcrição. Exemplos de antibióticos antitumorais que utilizam esse mecanismo de ação compreendem a actinomicina-D, a adramicina e a proflavina (Patrick, G., Na Introduction to Medicinal Chemistry, Oxford University, 1995) .  An alternative used in the state of the art is the use of intercalating agents, capable of inserting between the base pair layers of nucleic acids, deforming the double helix and preventing replication and transcription. Examples of antitumor antibiotics using this mechanism of action include actinomycin-D, adramycin and proflavin (Patrick, G., In the Introduction to Medicinal Chemistry, Oxford University, 1995).
Sem exceção, os tumores sólidos apresentam uma elevada acidez em seu tecido celular, caracterizada pela presença de ions de hidrogénio (H+) . É bem conhecido no estado da arte que quando tumores sólidos atingem determinado tamanho, a penetração do oxigénio no mesmo torna-se limitada. Sob tais condições, a f os for ilação oxidativa não pode prosseguir normalmente por causa da insuficiência de oxigénio, resultando em elevada produção de ácido láctico, o que leva à acidificação do tecido tumoral maligno, permitindo inclusive a sua proliferação ( Gatenby , R . A . , Gillies, R. J. Na t . Rev . Câncer 4:891-899, 2004; Warburg, O. A Review. Science 123: 309-315, 1956) . Without exception, solid tumors have a high acidity in their cell tissue, characterized by the presence of hydrogen ions (H + ). It is well known in the art that when solid tumors reach a certain size, oxygen penetration into it becomes limited. Under such conditions, oxidative phosphorylation cannot normally proceed because of oxygen deficiency, resulting in high lactic acid production, which leads to acidification of malignant tumor tissue, even allowing proliferation (Gatenby, R. A. , Gillies, RJ (Rev. Cancer 4: 891-899, 2004; Warburg, O. A Review. Science 123: 309-315, 1956).
Terapias anti-câncer, chamadas terapias pH, utilizam injeções locais de sais de elementos muito alcalinos (básicos), como o césio, o potássio e o rubidio, com a finalidade de reduzirem a acidez do tumor, levando as células à morte (Masco, H.L. Patente US n° 3.614.242, 1972) . Entretanto, a mesma terapia não funciona quando o tumor já se espalhou pelo corpo, causando a metástase.  Anti-cancer therapies, called pH therapies, use local injections of salts of very alkaline (basic) elements, such as cesium, potassium and rubidium, in order to reduce tumor acidity, causing cells to die (Masco, HL US Patent No. 3,614,242, 1972). However, the same therapy does not work when the tumor has already spread throughout the body, causing metastasis.
RESUMO DA INVENÇÃO SUMMARY OF THE INVENTION
A presente invenção refere-se à oncologia, em particular a um composto molecular, denominado aqui de "oncoloose", capaz de destruir seletivamente células de tumores sólidos sem afetar células saudáveis de replicação rápida. The present invention relates to oncology, in particular to a molecular compound, referred to herein as "oncollosis", capable of selectively destroying solid tumor cells without affecting rapidly replicating healthy cells.
Adicionalmente, a presente invenção visa proporcionar um processo para produção de um fármaco antitumoral capaz de chegar seletivamente às células de tumores sólidos sem promover quaisquer danos às células saudáveis utilizando um carreador do tipo carboxila que é sensível à acidez presente em todos os tipos de tumores sólidos malignos. Additionally, the present invention aims to provide a process for producing an anti-tumor drug capable of selectively reach solid tumor cells without promoting any damage to healthy cells using a carboxyl-type carrier that is sensitive to the acidity present in all types of solid malignant tumors.
Em um aspecto da invenção, é fornecido um processo de intercalação da acridina ao DNA das células tumorais, levando- as a apoptose, também denominada morte celular programada.  In one aspect of the invention, an acridine intercalation process is provided to the tumor cell DNA, leading to apoptosis, also called programmed cell death.
Dessa forma, na presente invenção, é fornecido um produto que compreende um composto molecular denominado ONCOLOOSE que é guiado de forma seletiva para o interior dos tumores. Este composto é atraído para o interior dos tumores pela acidez característica dos tumores sólidos, através de um grupamento carboxílico que neutraliza a sua carga elétrica negativa, devido a esta acidez tumoral, para carrear o fármaco acridina ao DNA das células tumorais, impedindo a sua reprodução e levando as células tumorais à apoptose ou auto-destruição celular .  Thus, in the present invention, there is provided a product comprising a molecular compound called ONCOLOOSE which is selectively guided into the tumors. This compound is attracted into the tumors by the characteristic acidity of solid tumors through a carboxylic group that neutralizes their negative electric charge due to this tumor acidity to carry the acridine drug to the tumor cell DNA, preventing their reproduction. and leading the tumor cells to apoptosis or cellular self-destruction.
Estes e outros objetos da presente invenção serão melhor compreendidos e valorizados a partir da descrição detalhada da invenção e das reivindicações anexas.  These and other objects of the present invention will be better understood and appreciated from the detailed description of the invention and the appended claims.
BREVE DESCRIÇÃO DAS FIGURAS BRIEF DESCRIPTION OF THE FIGURES
A Figura 1 representa a estrutura molecular do composto anti- tumoral objeto da presente invenção. Figure 1 represents the molecular structure of the anti-tumor compound object of the present invention.
A Figura 2 representa os tipos de acridina que serão ligados ao grupo carboxílico, este último, carreador do fármaco para dentro dos tumores. Figure 2 represents the types of acridine that will be attached to the carboxylic group, the latter, carrier of the drug into the tumors.
A Figura 3 apresenta o mecanismo de açâo antitumoral da 9- acridina-carboxilato. Figure 3 shows the antitumor action mechanism of 9-acridine carboxylate.
A Figura 4 apresenta o desenho da 9-ac.ridina-carboxilato intercalada ao DNA. Figure 4 shows the drawing of 9-ac.ridine carboxylate interspersed with DNA.
A Figura 5 apresenta o procedimento para a síntese do composto ONCOLOOSE A Figura 6 apresenta fotos do ensaio in vivo realizado com camundongos com Sarcoma 180, utilizando doses de 10 mg/Kg e 20 mg/Kg . Figure 5 shows the procedure for the synthesis of the compound ONCOLOOSE. Figure 6 presents photos of the in vivo assay performed with Sarcoma 180 mice using doses of 10 mg / kg and 20 mg / kg.
DESCRIÇÃO DETALHADA DA INVENÇÃO DETAILED DESCRIPTION OF THE INVENTION
A presente invenção refere-se à oncologia, em particular a um composto molecular, denominado aqui de "oncoloose", capaz de destruir selet ivãmente células de tumores sólidos sem afetar células saudáveis de replicação rápida. The present invention relates to oncology, in particular to a molecular compound, referred to herein as "oncollosis", capable of selectively destroying solid tumor cells without affecting healthy rapidly replicating cells.
Adicionalmente, a presente invenção visa proporcionar um processo para produção de um fármaco antitumoral capaz de chegar seletivamente às células de tumores sólidos sem promover quaisquer danos às células saudáveis utilizando um carreador do tipo carboxila que é sensível à acidez presente em todos os tipos de tumores sólidos malignos.  Additionally, the present invention aims to provide a process for producing an antitumor drug capable of selectively reaching solid tumor cells without promoting any damage to healthy cells using a carboxyl-type carrier that is sensitive to the acidity present in all types of solid tumors. Evil
Conforme já explicitado anteriormente, a quimioterapia funciona interrompendo ou retardando o crescimento de células cancerosas, as quais crescem e se dividem rapidamente. Entretanto, como a quimioterapia também pode danificar células saudáveis de divisão rápida, é necessário reduzir ou eliminar os efeitos colaterais nesse tipo de célula.  As explained earlier, chemotherapy works by stopping or slowing the growth of cancer cells, which grow and divide rapidly. However, because chemotherapy can also damage healthy rapidly dividing cells, it is necessary to reduce or eliminate side effects in this type of cell.
Para reduzir seus efeitos colaterais devido a não seletividade dos medicamentos antineoplásicos , estes são unidos quimicamente a moléculas de açúcares, visto que os tumores malignos necessitam de cerca de dez vezes mais glicose que as células saudáveis. Podem ser citados como exemplos de medicamentos antineoplásicos carreados por glicose o D-19575 ou glufosfamida e derivados de glicose-clorambucila , porém estes medicamentos também afetam células saudáveis que também necessitam de glicose.  To reduce their side effects due to non-selectivity of antineoplastic drugs, they are chemically linked to sugar molecules, as malignant tumors require about ten times more glucose than healthy cells. Examples of glucose-borne antineoplastic drugs include D-19575 or glufosfamide and glucose-chlorambucil derivatives, but these drugs also affect healthy cells that also require glucose.
Tumores sólidos apresentam uma elevada acidez em seu tecido celular, caracterizada pela presença de íons de hidrogénio (H+ ) . Entretanto, quando tumores sólidos atingem determinado tamanho, a penetração do oxigénio no mesmo torna- se limitada. Sob tais condições, a fosforilação oxidativa não pode prosseguir normalmente por causa da insuficiência de oxigénio, resultando em elevada produção de ácido láctico. Essa redução de ácido láctico leva à acidificação do tecido tumoral maligno, permitindo a sua proliferação. Essa característica de elevada acidez será aproveitada aqui para guiar um fármaco para o interior de tumores malignos de forma seletiva sem afetar células saudáveis que se multiplicam rapidamente, visto que as células saudáveis não produzem ácido láctico. Um grupamento carboxílico será usado para reagir com a acidez dos tumores sólidos malignos e carrear o fármaco de forma seletiva apenas para o interior das células tumorais. Solid tumors have a high acidity in their cell tissue, characterized by the presence of hydrogen ions (H + ). However, when solid tumors reach a certain size, oxygen penetration into it becomes limited. Under such conditions oxidative phosphorylation cannot normally proceed because of insufficient oxygen, resulting in high lactic acid production. This reduction of lactic acid leads to the acidification of malignant tumor tissue, allowing its proliferation. This high acidity feature will be used here to guide a drug into malignant tumors selectively without affecting rapidly multiplying healthy cells, as healthy cells do not produce lactic acid. A carboxylic group will be used to react with the acidity of solid malignant tumors and selectively carry the drug only into the tumor cells.
Em um aspecto da invenção, é fornecido um processo de intercalação da acridina ao DNA das células tumorais, levando- as a apoptose, também denominada morte celular programada.  In one aspect of the invention, an acridine intercalation process is provided to the tumor cell DNA, leading to apoptosis, also called programmed cell death.
Em outro aspecto da invenção, é fornecido um produto que compreende um composto molecular denominado ONC0LO0SE que é guiado de forma seletiva para o interior dos tumores. Este composto é atraído para o interior dos tumores pela acidez característica dos tumores sólidos, através de um grupamento carboxílico que neutraliza a sua carga elétrica negativa devido a esta acidez tumoral (visto que moléculas dotadas de carga elétrica atravessam a membrana das células em pequenas quantidades enquanto que moléculas neutras atravessam a mesma com grande facilidade, pois são solúveis nas membranas lipídicas das células) para carrear o fármaco acridina ao DNA das células tumorais, impedindo a sua reprodução e levando as células tumorais à apoptose ou auto-destruição celular.  In another aspect of the invention, there is provided a product comprising a molecular compound called ONC0LO0SE that is selectively guided into the tumors. This compound is attracted into the tumors by the characteristic acidity of solid tumors through a carboxylic group that neutralizes their negative electric charge due to this tumor acidity (since electrically charged molecules cross the cell membrane in small amounts while that neutral molecules cross it very easily because they are soluble in the lipid membranes of cells) to carry the acridine drug to the DNA of the tumor cells, preventing their reproduction and leading the tumor cells to apoptosis or cellular self-destruction.
0 composto ONCOLOOSE compreende uma molécula de acridina (Figura 1.1) ligada quimicamente a um grupamento carboxílico (Figura 1.2) que, em meio neutro (sangue e tecidos saudáveis) têm carga negativa (Figura 1.3) , esta última com forte afinidade a íons de hidrogénio do tumor (Figura 1.4) , sendo que tal combinação neutraliza a carga da carboxila (Figura 1.5) e leva a molécula a ser absorvida nesta forma pelo tumor. A absorção requer a passagem através da membrana lipídica das células, que é determinada pela presença ou não de carga elétrica na molécula: moléculas dotadas de carga elétrica atravessam a membrana em pequenas quantidades enquanto que moléculas neutras atravessam a mesma com grande facilidade. Os tumores têm pH entre 6 e 7, ou seja, há íons de hidrogénio (H+) e isso favorece a neutralização da carga elétrica negativa da molécula (Figura 1.3), fazendo com que sejam absorvidas pelas células cancerosas em grande quantidade. The ONCOLOOSE compound comprises an acridine molecule (Figure 1.1) chemically linked to a carboxylic group (Figure 1.2) which, in neutral medium (blood and healthy tissues) are negatively charged (Figure 1.3), the latter with strong affinity for hydrogen ions. tumor (Figure 1.4), whereby such a combination neutralizes the carboxyl charge (Figure 1.5) and causes the molecule to be absorbed in this form by the tumor. Absorption requires passage through the lipid membrane of cells, which is determined by the presence or absence of electrical charge in the molecule: electrically charged molecules cross the membrane in small quantities while neutral molecules cross it very easily. The tumors have a pH between 6 and 7, ie there are hydrogen ions (H +) and this favors the neutralization of the negative electrical charge of the molecule (Figure 1.3), causing them to be absorbed by cancer cells in large quantities.
O mecanismo de açâo do composto ONCOLOOSE, ilustrado na The mechanism of action of the compound ONCOLOOSE, illustrated in
Figura 3, mostra que a glicose é absorvida pelas células tumorais que contém em sua membrana 10 vezes mais receptores de insulina que uma célula saudável. Assim, o metabolismo da glicose nas células tumorais chega ao ácido pirúvico (piruvato) , mesmo na presença de oxigénio. O ácido pirúvico não metabolizado então tende a se concentrar na célula, elevando a acidez do seu meio. Isso faz com que haja a protonação da 9-acridina-carboxilato , tornando este com carga neutra. Essa carga neutra facilita a sua absorção para dentro da célula tumoral. Dentro do núcleo das células, a 9-acridina- carboxilato se intercala ao DNA, impedindo assim a replicação celular, levando a célula a ativar certos genes, o que por sua vez leva a célula à morte programada (apoptose) . SÍNTESE DO COMPOSTO ONCOLOOSE Figure 3 shows that glucose is absorbed by tumor cells containing 10 times more insulin receptors in their membrane than a healthy cell. Thus, glucose metabolism in tumor cells reaches pyruvic acid (pyruvate), even in the presence of oxygen. Un metabolized pyruvic acid then tends to concentrate in the cell, raising the acidity of its environment. This protonates 9-acridine carboxylate, making it neutral. This neutral charge facilitates its absorption into the tumor cell. Within the nucleus of cells, 9-acridine carboxylate interleaves with DNA, thus preventing cell replication, leading the cell to activate certain genes, which in turn leads to programmed death (apoptosis). SYNTHESIS OF ONCOLOOSE COMPOUND
Procedimento para preparação do composto ONCOLOOSE Procedure for preparing ONCOLOOSE compound
A síntese do presente composto anti-tumoral (e seus derivados) segue uma reação de Pfitzinger (também conhecida como reação de Pfitzinger-Borsche) que consiste em uma reação química entre a isatina (ou lH-indol-2 , 3-diona ) e um composto fenólico em meio básico (geralmente hidróxido de potássio) (Figura 5) . The synthesis of the present anti-tumor compound (and its derivatives) follows a Pfitzinger reaction (also known as a Pfitzinger-Borsche reaction) consisting of a chemical reaction between isatin (or lH-indol-2,3-dione) and a phenolic compound in basic medium (usually potassium hydroxide) (Figure 5).
Em um balão de 500 mL são colocados, um derivado de isatina e um derivado fenólico na proporção (m/m) 1:1 em presença de hidróxido de potássio em diclorometano anidro (51 mL) . A mistura reacional é agitada a uma temperatura de 120oC e sob uma atmosfera inerte de argônio por um período de 4 horas. O derivado acridínico deve ser extraído do meio reacional com éter etílico e evaporado à secura. O mesmo deve ser posteriormente purificado através de cromatografia "flash" em sílica gel 60, utilizando como sistema de eluiçâo n- hexano/AcOEt 7:3. In a 500 ml flask is placed an isatin derivative and a phenolic derivative in the ratio (w / w) 1: 1 in the presence of potassium hydroxide in anhydrous dichloromethane (51 mL). The reaction mixture is stirred at a temperature of 120 ° C and under an inert argon atmosphere for a period of 4 hours. The acridine derivative should be extracted from the reaction medium with ethyl ether and evaporated to dryness. It should be further purified by flash chromatography. on silica gel 60 using 7: 3 n-hexane / AcOEt elution system.
COMPOSTOS SINTETIZADOS EXEMPLARES EXAMPLE SYNTHESIZED COMPOUNDS
Os possíveis compostos de acridina que podem funcionar da mesma forma são os compreendidos no esquema da Figura 2. Possible acridine compounds that may function in the same manner are those comprised in the scheme of Figure 2.
A invenção e suas vantagens aparecerão mais claramente a partir do exemplo que se segue, em conjunto com as figuras acrescentadas, mas sem limitar o seu escopo. The invention and its advantages will appear more clearly from the following example, together with the added figures, but without limiting its scope.
AVALIAÇÃO DA ATIVIDADE ANTITUMORAL Para avaliar a atividade tumoral do composto ONCOLOOSE, foram realizados ensaios in vivo em camundongos albinos swiss no Biotério do Departamento de Antibióticos da Universidade Federal de Pernambuco (UFPE) . EVALUATION OF ANTITUMORAL ACTIVITY In order to evaluate the tumor activity of the compound ONCOLOOSE, in vivo assays were carried out on albino swiss mice in the Biotery of the Department of Antibiotics of the Federal University of Pernambuco (UFPE).
Os tumores foram implantados nos camundongos seguindo a metodologia de Stock et al. (1995) e modificado por Komíyama (1992) .  Tumors were implanted in mice following the methodology of Stock et al. (1995) and modified by Komíyama (1992).
Os camundongos, pesando 30g cada um, foram divididos em dois grupos, um grupo que recebeu o tratamento e um grupo controle. O grupo tratado recebeu um dos possíveis comopostos quimioterápicos ( 9-acridina-carboxilato) por injeção intraperitoneal nas doses de 10 e 20 mg/kg, uma dose po dia durante o período de 6 dias. O grupo controle recebeu apenas placebo (solução' salina a 2%) pelo mesmo período de tempo. The mice, weighing 30g each, were divided into two groups, a treatment group and a control group. The treated group received one of the possible chemotherapeutic compounds (9-acridine carboxylate) by intraperitoneal injection at doses of 10 and 20 mg / kg, a daily dose over a period of 6 days. The control group received only placebo (2% solution 'saline) by the same period of time.
O objetivo do ensaio foi avaliar a atividade antitumoral nos tumores disponíveis (sarcoma 180) . O resultado foi positivo para os tumores, sendo os percentuais de inibição tumoral respectivamente 48% e 90% nas doses de 10 mg/kg e 20mg/kg para os camundongos.  The purpose of the assay was to evaluate antitumor activity in available tumors (sarcoma 180). The result was positive for the tumors, and the tumor inhibition percentages were 48% and 90% respectively at the 10 mg / kg and 20 mg / kg doses for the mice.
O mecanismo de ação do composto está ilustrado na Figura 3. A Figura 4 apresenta a ilustração da 9-acridina-carboxilato intercalada ao DNA, a Figura 5 apresenta o processo de síntese do composto e a Figura 6 apresenta fotos do ensaio in vivo, utilizando doses de 10 mg/Kg e 20 mg/Kg.  The mechanism of action of the compound is shown in Figure 3. Figure 4 shows the illustration of DNA-intercalated 9-acridine carboxylate, Figure 5 shows the process of compound synthesis, and Figure 6 shows photos of the in vivo assay using doses of 10 mg / kg and 20 mg / kg.

Claims

REIVINDICAÇÕES
1. Composto molecular denominado Oncoloose, caracterizado por compreender uma molécula de acridina ligada quimicamente a um grupamento carboxilico. Molecular compound called Oncoloose, characterized in that it comprises an acridine molecule chemically linked to a carboxylic group.
2. Composto molecular, de acordo com a reivindicação 1, caracterizado pelo fato que, em meio neutro, possui carga negativa . Molecular compound according to Claim 1, characterized in that it has a negative charge in a neutral medium.
3. Composto molecular, de acordo com as reivindicações 1 eMolecular compound according to claims 1 and
2, caracterizado pelo fato que, em meio neutro sua carga negativa possui forte afinidade a ions de hidrogénio presentes em tumores. 2, characterized by the fact that in neutral environment its negative charge has strong affinity to hydrogen ions present in tumors.
4. Composto molecular, de acordo com as reivindicações 1 aMolecular compound according to claims 1 to 4
3, caracterizado por neutralizar a carga da carboxila e levar a molécula a ser absorvida para o interior do tumor . 3, characterized in that it neutralizes the carboxyl charge and causes the molecule to be absorbed into the tumor.
5. Composto molecular, de acordo com as rei indicações 1 a5. Molecular compound according to indications 1 to 5
4, caracterizado por ser capaz de carrear o fármaco acridina ao DNA das células tumorais. 4, characterized in that it is capable of carrying the acridine drug to the tumor cell DNA.
6. Composto molecular, de acordo com as reivindicações 1 a 5, caracterizado por impedir a reprodução de células tumorais gerando apoptose. Molecular compound according to Claims 1 to 5, characterized in that it prevents the reproduction of tumor cells generating apoptosis.
7. Processo para produção de fármaco antitumoral caracterizado por realizar uma reação de Pfitzinger- Borsche. 7. Process for producing antitumor drug characterized by performing a Pfitzinger-Borsche reaction.
8. Processo de acordo com a reivindicação 7, caracterizado por extrair o derivado acridinico do meio reacional com éter etílico e evaporar à seco. Process according to Claim 7, characterized in that the acridinic derivative is extracted from the reaction medium with ethyl ether and evaporated to dryness.
9. Processo de acordo com as reivindicações 7 e 8, caracterizado por purificar o derivado acridinico através de cromatografia "flash" em sílica gel 60. Process according to Claims 7 and 8, characterized in that the acridinic derivative is purified by flash chromatography on silica gel 60.
10. Processo de acordo com as rei indicações 7 a 9, caracterizado por utilizar um sistema de eluição n- hexano/AcOEt 7:3. A process according to indications 7 to 9, characterized in that a 7: 3 n-hexane / AcOEt elution system is used.
11. Processo, de acordo com as reivindicações 7 a 10, caracterizado por ser para a produção de um fármaco antitumoral . Process according to Claims 7 to 10, characterized in that it is for the production of an antitumor drug.
12. Processo, de acordo com as reivindicações 7 a 11, caracterizado por ser capaz de alcançar células tumorais sem promover danos às células saudáveis. Process according to Claims 7 to 11, characterized in that it is capable of reaching tumor cells without causing damage to healthy cells.
13. Uso do processo de acordo com as reivindicações 7 a 12, na preparação de um medicamento para tratar tumores sólidos . Use of the process according to claims 7 to 12 in the preparation of a medicament for treating solid tumors.
14. Uso da acridina-carboxilato , caracterizado por ser na preparação de um medicamento para tratar tumores sólidos . Use of acridine carboxylate, characterized in that it is in the preparation of a medicament for treating solid tumors.
15. Uso da acridina-carboxilato, caracterizado por ser na preparação de um medicamento para tratar tumores sólidos, tratamento este que consiste em administrar doses de 10mg/Kg a 40 mg/Kg. 15. Use of acridine carboxylate, characterized in that it is in the preparation of a medicament for treating solid tumors, which is to administer doses of 10 mg / kg to 40 mg / kg.
16. Uso da acridina-carboxilato, de acordo com a reivindicação 15, caracterizado por ser na preparação de um medicamento para tratar tumores sólidos, tratamento este que consiste em administrar doses de 10mg/Kg a 40 mg/Kg por injeção intraperitoneal . Use of acridine carboxylate according to Claim 15, characterized in that it is in the preparation of a medicament for treating solid tumors, which treatment is to administer doses of 10 mg / kg to 40 mg / kg by intraperitoneal injection.
17. Uso da acridina-carboxilato, de acordo com as reivindicações 15 e 16, caracterizado por ser na preparação de um medicamento para tratar tumores sólidos, tratamento este que consiste em administrar uma dose por dia de 10mg/Kg a 40 mg/Kg por injeção intraperitoneal . Use of acridine carboxylate according to claims 15 and 16, characterized in that it is in the preparation of a medicament for treating solid tumors, This treatment consists of administering a daily dose of 10 mg / kg to 40 mg / kg by intraperitoneal injection.
18. Uso da acridina-carboxilato , de acordo com as reivindicações 15 a 17, caracterizado por ser na preparação de um medicamento para tratar tumores sólidos, tratamento este que consiste em administrar uma dose por dia de 10mg/Kg a 40 mg/Kg por injeção intraperitoneal , por um período de 6 dias. Use of acridine carboxylate according to any one of claims 15 to 17, characterized in that it is in the preparation of a medicament for treating solid tumors, which treatment consists in administering a daily dose of 10 mg / kg to 40 mg / kg per intraperitoneal injection for a period of 6 days.
PCT/BR2012/000518 2011-12-19 2012-12-19 Molecular compound comprising an acridine molecule chemically linked to a carboxylic group, which can be used for the selective destruction of solid tumour cells WO2013091052A1 (en)

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