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WO2008041264A1 - Dérivés d'isoindoloquinoxaline à activité antitumorale, leur procédé de production et leur utilisation - Google Patents

Dérivés d'isoindoloquinoxaline à activité antitumorale, leur procédé de production et leur utilisation Download PDF

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Publication number
WO2008041264A1
WO2008041264A1 PCT/IT2007/000689 IT2007000689W WO2008041264A1 WO 2008041264 A1 WO2008041264 A1 WO 2008041264A1 IT 2007000689 W IT2007000689 W IT 2007000689W WO 2008041264 A1 WO2008041264 A1 WO 2008041264A1
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isoindolo
quinoxaline
formula
general formula
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Girolamo Cirrincione
Patrizia Diana
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Universita degli Studi di Palermo
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Universita degli Studi di Palermo
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention concerns new isoindolo-quinoxaline derivatives with antitumor activity, a procedure for their production and their use in anticancer therapy.
  • the invention corcems the synthesis and the study of isoindolo[2,1-a]quinoxaline derivatives which have shown a potent in vitro antitumor activity and are therefore proposed for the production of drugs to be used for anticancer therapy either alone or in combination with other chemotherapy agents.
  • DNA represents one of the most important targets for several chemotherapeutic drugs.
  • anticancer drugs include as widespread members the alkylating agents, which can non-selectively modify cellular DNA and RNA, and the antimetabolites which, by mimicking the bases of DNA and of other natural molecules, interfere with the synthesis of nucleic acids, proteins and with other vital metabolic processes, acting as antagonists and inhibitors.
  • Polycyclic nitrogen heterocycles with planar structure can be good pharmacophores for some classes of antitumor drugs since they can intercalate between the base pairs of double-stranded DNA.
  • chemotherapeutic agents such as acridines, amsacrines, anthracyclines, characterized by planar polycyclic systems, are able to interfere with DNA- processing enzymes (Topoisomerases I and II) by forming ternary complexes involving the drug, the DNA and the enzyme.
  • Quinoxalines or 1 ,4-benzodiazines, aromatic bicyclic compounds containing two nitrogen atoms, and the structurally related quinoxalinones represent an important class of heterocycles that are found in a variety of biologically and medicinally useful agents and a large number of them, at various experimental levels, showed antineoplastic activity.
  • WO 94/13647 (assignee The Du Pont Merck Pharmaceutical Co.). concerns a class of quinoxalinoxy-phenoxy- propanoic esters that resulted active as antineoplastic agents on the basis of in vivo experiments conducted animal models. Also in the field of aromatic bicyclic structures, Lawrence et al. (Lawrence, D. S.; Copper, J. E.; Smith, CD. Structure-activity studies of substituted quinoxalinones as multiple-drug- resistance antagonists. J. Med.
  • Novel functionalized pyrido[2,3-g]quinoxalinones as antibacterial, antifungal and anticancer agents, // Farmaco 2001 , 56, 933-938).
  • some pyrrolo[1 ,2-a]quinoxaline derivatives showed to posses potent antiproliferative activity on cellular cell lines derived from hematological and solid tumors (Alleca S. et al. Quinoxaline Chemistry. Part 16.
  • Imidazo-quinoxalines were studied by Chen et al., who reported that a class of aniline-imidazo[1 ,5-a]quinoxalines showed an excellent inhibition of the enzyme Lck (IC50 ⁇ 5 nM) and of the proliferation of the T cells, activity useful for the for the treatment of autoimmune and inflammatory diseases mediated by T cells (Chen P. et al. Synthesis and SAR of Novel Imidazoqui- noxaline-Based Lck Inhibitors: Improvements of Cell Potency. Bioorg. Chem. Lett, 2002, 12, 3153-3156).
  • Lck enzyme
  • SAR of Novel Imidazoqui- noxaline-Based Lck Inhibitors Improvements of Cell Potency. Bioorg. Chem. Lett, 2002, 12, 3153-3156.
  • nitrogen tricyclic hetero- cycles proposed for the antiproliferative therapy, the international patent appli- cation publ. No.
  • WO 2004/085439 (assignee Pfizer Products Inc.), concerns a class of substituted triazolo-quinoxaline derivatives, in particular 4- amino[1 ,2,4]triazolo[4,3-a]quinoxalines, which showed to be active as inhibi- tors of the glycogen synthase kinase-3 (GSK-3), and therefore potentially useful for the treatment of several pathologies such as tumor pathologies.
  • 5- substituted 2-bromoindolo[3,2-/b]quinoxalines showed a broad spectrum of antitumor activity with GI50, TG50 and LC50 mean values of 14.2, 31.6, and 66.2 ⁇ M respectively.
  • Such compounds also inhibited both cdc2 kinase and cdc25 phosphatase with IC50 of 70 and 25 ⁇ M respectively (Abadi, A.H. 5- Substituted 2-bromoindolo[3,2-jb]quinoxalines. A class of potential antitumor agents with cdc25 phosphatase inhibitory properties. Arch. Pharm. Pharm. Med. Chem., 1998, 331, 352-358).
  • the object of the present invention is, thus, to furnish new antineoplastic agents possessing potent activity on a wide range of human cell lines and whose synthesis is straightforward and at the same time economically advantageous to carry out, related to the necessary starting materials.
  • the present invention specifically provides isoindolo- quinoxaline compounds of the general formula (1):
  • R represents H or OH
  • R 5 represents H or CN
  • Ri, R 2 , R 3 and R 4 are independently chosen from the group consisting of
  • R 3 and R b are independently chosen from the group consisting of H, linear, cyclic or branched alkyl, alkenyl or alkynyl with up to 12 carbon atoms, aryl or heterocyclic groups with up to 12 carbon atoms.
  • Ri, R 2 , R 3 and R 4 can be independently chosen from the group consisting of H, alkyl, alkoxy with up to 6 carbon atoms and halogen.
  • a particularly studied subgroup of compounds according to this preferred embodiment bears Ri representing H or methyl, R 4 representing H, R 2 and R 3 independently chosen from H, methyl, methoxy and chlorine.
  • the said subgroup includes the isoindolo-quinoxaline compound of the formula (2a):
  • a preferred subgroup is constituted by those wherein R 1 , R 2 , R 3 , and R 4 are independently chosen from H, alkyl, alkoxy with up to 6 carbon atoms and halogen. More specifically, a preferred group of compounds (3) is that in which Ri represents H or methyl, R 4 represents H, R 2 and R 3 are independently chosen from H, methyl methoxy and chlorine.
  • the above definition includes, in particular, the isoindolo-quinoxaline derivatives having one of the following structures:
  • Literature reported that only two isoindolo[2,1-a]quinoxaline derivatives were incidentally obtained during attempts to synthesize the benzoimi- dazo[2,1-a]isoquinoline system (Dyker, G.; et al. Oxidative heterocyclization of 2-alkylylbenzaldehydes with 1 ,2-phenylendiamine. Eur. J. Org. Chem., 2000, 1433-1441).
  • the isoindolo-quinoxaline derivatives of formula (2) [i.e. 2' or 2"] can be prepared by reaction of the corresponding isoindole intermediate of formula (4) (2-(2'- aminophenyl)-1-cyanoisoindoles) with acetic acid.
  • refluxing compounds of formula (4) in which R 1 -R 4 represent desired groups in the final compound, in acetic acid brings about the reaction of the amino group with the carbonitrile leading to quinoxaline ring system.
  • isoindolo-quinoxaline derivatives of formula (3) (11-cyano-isoindolo[2,1-a]quinoxalines) can be prepared easily as well and with excellent yields, by heating (for instance under reflux) with formic acid.
  • the present invention further specifically provides a process for the preparation of isoindolo-quinoxaline compounds of formula (1) as above specified, comprising the step of reacting the intermediate of the general formula (4), illustrated above, wherein Ri, R 2 , R 3 , and R 4 have the signifi- cance above stated, with acetic acid or formic acid, under heating conditions.
  • the procedure when the procedure is aimed at producing isoindolo-quinoxaline derivatives of formula (2'), it includes the step of reacting an intermediate of the general formula (4) with refluxing acetic acid.
  • the reaction mixture is rapidly cooled and the resulting precipitate, containing the desired compound of formula (2 1 ), is collected by filtration.
  • the procedure when the procedure is aimed at producing isoindolo-quinoxaline derivatives of formula (3), it includes the step of reacting an intermediate of the general formula (4) with refluxing formic acid. Also in this case, preferably, at the end of the reaction with formic acid the reaction mixture is rapidly cooled, and the resulting precipitate, containing the desired compound of formula (3), is collected by filtration.
  • the present invention also concerns the use of one or more isoindolo-quinoxaline derivatives of the general formula (1) as above specified, for the production of a pharmaceutical compo- sition, in particular, a preparation having antitumor activity.
  • the said one or more isoindolo-quinoxaline derivatives utilized are compounds of the general formula (2') or (2"), whilst according to other embodiments of this invention the one or more isoindolo-quinoxaline derivatives utilized are com- pounds of general formula (3).
  • a further aspect of the present invention concerns a pharmaceutical preparation containing as active ingredient at least one of the isoindolo- quinoxaline derivatives of the general formula (1), along with one or more pharmaceutically acceptable adjuvants and/or carriers.
  • the pharmaceutical preparation contains as active ingredient an isoindolo-quinoxaline derivative of the general formula (2 1 ) or (2").
  • one of the compounds of formula (2) according to the present invention showed a value of Gl 5 o (Growth inhibition) at nanomolar level, against 88% of the ca 60 human cell lines belonging to the nine subpanels: leukemia, non-small-cell lung, colon, central nervous system, melanoma, ovarian, renal, prostate and breast tumors cell lines.
  • the pharmaceutical preparations suitable for the therapeutic administration of the isoindolo-quinoxalines can be formulated on the basis of conventional techniques known to those skilled in the art, by using pharmaceutically acceptable excipients and vehicles in order to obtain preparations suitable for parenteral injection (intravenous, intramuscular or subcutaneous injection), for oral administration in solid or liquid form, for transdermal, rectal, intravaginal or local administration, for example, on the mucous membrane of the oronasal tract and the like.
  • the percentage of the active ingredient in the composition and the anticancer treatment method may be varied in order to obtain an optimal dosage.
  • the dose to be administered takes the following factors into account: the administration route, the duration of treatment, the patient's weight and conditions, the effectiveness of the active ingredient and the patient's responsiveness.
  • Figure 1 shows the effect of isoindolo-quinoxaline derivative (2a), according to the present invention, on microtubule assembly: purified tubulin was incubated in the absence or in the presence of the compound at the indicated concentrations; the behavior in time of the fluorescence, due to the incorporation of a fluorescent reporter into microtubules as polymerization occurs, was detected;.
  • Figure 2 shows the effect of increasing concentrations of the isoin- dolo-quinoxaline derivative (2a), according to the present invention, on the relaxation of pBR322 plasmid DNA by human topoisomerase I 1 as detected by electrophoresis on agarose gel without (panel B) or containing ethidium bromide (panel A). (Sc: supercoiled, ReI: relaxed. Nick: nicked).
  • This compound was purified by flash chromatography using dichloro- methane as eluant to give a solid: yield 65%; Mp 150-151 C C;
  • This compound was purified by Sepacore Buchi apparatus using di- chloromethane: cyclohexane (7:3) as eluant: yield 40%; Mp 62-63°C;
  • the isoindolo-quinoxaline derivatives of this invention have been evaluated by the National Cancer Institute (NCI, Bethesda, USA), in the 3-cell line (MCF7-breast, NCI-H460-Non small cell lung, SF-268-CNS), one dose primary anticancer assay. In this test, a compound is considered active when it reduces the growth of any of the cell lines to 32% or less (negative numbers indicate cell kill). The results obtained are shown in Table 1.
  • the compounds, which passed the criteria set by the NCI for activity in this assay were scheduled automatically for evaluation against the full panel of tumor cell lines (Monks, A.; et al. Feasibility of a high-flux anticancer drug screen using a diverse panel of cultured human tumor cell lines. J. Natl. Cancer Inst., 1991 , 83, 757-766). All isoindoloquinoxaline derivatives of formula (2) were selected for evaluation against the full NCI panel of approximately 60 human cancer cell lines that have grouped in disease sub-panels including leukemia, non-small-cell lung, colon, central nervous system, melanoma, ovarian, renal, prostate and breast tumors cell lines.
  • b pGI 50 is the -log of the molar concentration that inhibits 50% net cell growth.
  • cpTGI is the -log of the molar concentration giving total growth inhibition.
  • d pLC 50 is the -log of the molar concentration leading to 50% net cell death.
  • Table 3 shows the pGI 50 of compounds of formula (2a-e) against all the cell lines utilized in the tests.
  • the isoindoloquinoxalines showed inhibitory effects in the growth of all cancer cell lines from micromolar to nanomolar concentration.
  • Gl so values at 10 ⁇ 8 M level.
  • the most sensitive cell lines are HL-60(TB) (pGI 5 o 7.94), SR (pGI 50 8.00), and K562 (pGI 50 8.05) belonging to the leukemia sub- panel; MALME-3M (pGI 50 8.00) and M14 (pGI 50 8.00) of the melanoma sub- panel and MDA-MB-435 (pGI 50 8.39) belonging to the breast cancer sub- panel.
  • Compound (2c) bearing a methyl group in position 4, showed selectivity with respect to the leukemia subpanel having pGUo for all the sub- panel cell lines in the range 5.70-5.92. Compound (2c) also showed excellent response in the breast cancer sub-panel.
  • the most sensitive cell lines resulted MCF7 (pGI 50 >8.00), M DA- M B-231 /ATC C (pGI 50 5.62) and MDA-MB-435 (pGI 50 5.50).
  • Derivative (2b) was selectively active with respect to the breast cancer and especially active against HS 578T (pGI 50 6.28) and MDA-MB- 231/ATCC (pGI 5 o 6.02).
  • the dichloro derivative (2e) had a low pGI 50 mean value (4.74) but showed a good selectivity with respect to HCC-2998 cell line (pGI 50 6.09), belonging to the colon cancer sub-panel.
  • bpGI 50 is the -log of the molar concentration causing 50% growth inhibition of tumor cells.
  • the assay utilized a fluorescent compound which binds to tubulin and microtubules. Polymerization was followed by fluorescent enhancement due to incorporation of a fluorescent reporter into microtubules as polymerisation occurred (Bonne, D. et al. 4',6-Diamidino-2-phenylindole, a fluorescent probe for tubulin and microtubule. J. Biol. Chem., 1985, 260, 2819-2825). For the experiment a microtubule polymerization assay kit (Cytoskele- ton USA) was utilized, following the recommended protocol.
  • the assay was carried out in 96-well microtiter plates and the reaction was initiated with the addition of tubulin.
  • the plate was incubated at 37°C in a fluorescence mi- croplate reader (Fluoroskan Ascent FL Labsystems) and the fluorescence measurement ( ⁇ ex 355 nm; ⁇ em 450 nm) was determined every minute for 60 min.
  • fluorescence mi- croplate reader Fluoroskan Ascent FL Labsystems
  • As reference compounds taxol (Cytoskeleton USA) and colchicine (Sigma) were used.
  • Supercoiled pBR322 DNA (Fermentas) was incubated with 5 units of Human Topoisomerase I at 37 0 C for 30 min in relaxation buffer (50 mM Tris- HCL pH 7.8, 50 mM KCI 10 mM MgCI 2 , 1 mM dithiothreitol, 1 mM EDTA) in the presence of varying concentration of the drug (0.5 - 50 ⁇ M). Reactions were terminated by adding SDS to 0.25% and Proteinase K to 250 ⁇ g/ml. DNA samples were then added to loading buffer and electropho- resed in a 1% agarose gel at room temperature overnight at 20 V.
  • the compounds according to the invention were able to inhibit in vitro tubulin polymerization in a concentration-dependent manner, in a similar way to colchicine and vinblastine, indicating that these compounds can be classified as microtubule depolymerising agents. Moreover, the mitotic index deter- minations and the immunofluorescence studies clearly confirm the interaction with tubulin. It is interesting to note, in this connection, that the structure of isoindolo[2,1-a]quinoxaline derivatives does not resemble any of the known antimitotic drugs.

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Abstract

La présente invention concerne de nouveaux dérivés d'isoindolo[2,1-a]quinoxaline de formule générale (1 ), R représentant H ou OH et R5 représentant H ou CN. Préparés à l'aide de procédés simples, au départ d'intermédiaires bien connus, les dérivés présentent une puissante activité antitumorale in vitro contre une série d'environ 60 lignées cellulaires tumorales humaines différentes appartenant à plusieurs types de tumeurs, tant hématologiques que solides. Les préparations selon l'invention, qui contiennent de tels dérivés en tant que principes actifs, peuvent servir de médicaments à des fins thérapeutiques anticancéreuses, tant individuellement que combinées à d'autres substances chimiothérapeutiques.
PCT/IT2007/000689 2006-10-02 2007-10-02 Dérivés d'isoindoloquinoxaline à activité antitumorale, leur procédé de production et leur utilisation Ceased WO2008041264A1 (fr)

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IT000518A ITRM20060518A1 (it) 2006-10-02 2006-10-02 Derivati isoindolo-chinossalinici ad attivita' antitumorale procedimento per la loro produzione e loro uso
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Cited By (6)

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Publication number Priority date Publication date Assignee Title
ITRM20130588A1 (it) * 2013-10-25 2015-04-26 Univ Palermo Derivati di chinossalina, metodi per la loro produzione e loro uso come agenti antitumorali.
KR101747207B1 (ko) * 2013-05-29 2017-06-15 희성소재 (주) 방향족 축합고리 화합물 및 이를 이용한 유기발광소자
CN115010715A (zh) * 2022-06-24 2022-09-06 河南师范大学 3-(吲哚-2-基)琥珀酰亚胺和吲哚并苯并二氮卓类化合物的合成方法及抗癌活性
CN115819424A (zh) * 2022-12-05 2023-03-21 重庆文理学院 吲唑并喹喔啉衍生物及其合成方法和应用
CN117510501A (zh) * 2022-07-27 2024-02-06 中国科学院大连化学物理研究所 手性四氢异吲哚并[2,1-a]喹喔啉化合物的合成方法
US11918662B2 (en) 2020-06-11 2024-03-05 Chdi Foundation, Inc. Heterocyclic compounds and imaging agents for imaging huntingtin protein

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DATABASE CA [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; PLESHAKOV, V. G. ET AL: "Formation of 9-methylisoindolo[1,2-c]quinoxaline in the catalytic dehydrocyclization of 2-(2,4-dimethylphenyl)quinoxaline", XP002471568, retrieved from STN Database accession no. 1983:422421 *
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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101747207B1 (ko) * 2013-05-29 2017-06-15 희성소재 (주) 방향족 축합고리 화합물 및 이를 이용한 유기발광소자
ITRM20130588A1 (it) * 2013-10-25 2015-04-26 Univ Palermo Derivati di chinossalina, metodi per la loro produzione e loro uso come agenti antitumorali.
US11918662B2 (en) 2020-06-11 2024-03-05 Chdi Foundation, Inc. Heterocyclic compounds and imaging agents for imaging huntingtin protein
CN115010715A (zh) * 2022-06-24 2022-09-06 河南师范大学 3-(吲哚-2-基)琥珀酰亚胺和吲哚并苯并二氮卓类化合物的合成方法及抗癌活性
CN117510501A (zh) * 2022-07-27 2024-02-06 中国科学院大连化学物理研究所 手性四氢异吲哚并[2,1-a]喹喔啉化合物的合成方法
CN115819424A (zh) * 2022-12-05 2023-03-21 重庆文理学院 吲唑并喹喔啉衍生物及其合成方法和应用
CN115819424B (zh) * 2022-12-05 2024-06-04 重庆文理学院 吲唑并喹喔啉衍生物及其合成方法和应用

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