WO2014013117A1 - Cromèno-pyrazoldiones utilisées comme dérivés cannabinoïdes de quinones à activité antitumorale - Google Patents

Cromèno-pyrazoldiones utilisées comme dérivés cannabinoïdes de quinones à activité antitumorale Download PDF

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Publication number
WO2014013117A1
WO2014013117A1 PCT/ES2013/070499 ES2013070499W WO2014013117A1 WO 2014013117 A1 WO2014013117 A1 WO 2014013117A1 ES 2013070499 W ES2013070499 W ES 2013070499W WO 2014013117 A1 WO2014013117 A1 WO 2014013117A1
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compound
cancer
formula
hydrogen
malignant tumor
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PCT/ES2013/070499
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English (en)
Spanish (es)
Inventor
Nadine Jagerovic
Paula MORALES LÁZARO
María del Pilar GOYA LAZA
Inés DÍAZ LAVIADA MARTURET
Diana VARA CIRUELOS
Javier FERNÁNDEZ RUIZ
María GÓMEZ RUIZ
María GÓMEZ CAÑAS
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Consejo Superior De Investigaciones Científicas (Csic)
Universidad de Alcalá de Henares
Universidad Complutense De Madrid
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Publication of WO2014013117A1 publication Critical patent/WO2014013117A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered

Definitions

  • the present invention is encompassed in the field of pharmacology. Specifically, the present invention relates to chromene-derived compounds [4,3-c] pyrazol-6,9-diones, their use for the manufacture of a medicament, and the use of this medicament for an antitumor treatment.
  • Quinones are compounds of natural or synthetic origin. Several of them have some physiological functions such as the vitamin K necessary for blood clotting. However, many of them are cytotoxic, which makes them candidates for antitumor drugs. The antineoplastic effects of quinones have been widely described in the literature (C. Asche, Min ⁇ -Rev. Med. Chem. 2005, 5, 449-467). For example, anthracyclines that are antibiotics from bacteria of the genus Streptomyces, are used in the treatment of many types of cancers.
  • Cannabinoids act on the receptors of the endocannabinoid system and can provide therapeutic benefits in various pathologies and in particular they are useful in the treatment of cancer. On the one hand, they have palliative effects: antiemetics and analgesics (RG Pertwee, Br. J. Pharmacol. 2009, 156 (3), 397- 411), and on the other hand, show antitumor properties by themselves (M. Guzman, Nat. Rev. Cancer 2003, 3, 745-765; S. Sarfaraz et al, Cancer Res. 2008, 68, 330-342). Cannabinoids have been shown to inhibit the growth of various tumor cells in laboratory animals, for example glioma (I.
  • Chromenopyrazole structures such as cannabinoids developed by the research group of the authors of the present invention have been the subject of a patent application (WO2010109050), of which their activity as analgesics has been disclosed, without having been attributed antitumor properties .
  • the present invention faces the problem of providing new compounds useful for the treatment of cancer. Due to the potential of quinones as anticancer and cannabinoids as anticancer, antiemetic and analgesic, it is of great interest to have molecules that can combine the characteristics of a quinone and a cannabinoid in the same structure. Preferably, said compounds should preserve and even improve the cytotoxic activity of known compounds while avoiding part of the associated adverse side effects.
  • the authors of the present invention have found that the compounds of formula (I) act as antitumor agents.
  • the compounds of formula (I) claimed in the present invention consist of a series of chromenopyrazoldiones that, in addition to having quinone structures, have in their structure a pyrazole ring that proved necessary to maintain a certain affinity for cannabinoid receptors , and that differentiates them from other quinone structures known in the state of the art, such as those previously described by Mechoulam et al. ⁇ Tetrahedron 1968, 24, 5615-5624; W02005 / O 67917; WO2008 / 107878).
  • the present invention relates to a compound of general formula (I),
  • - R 1 is independently selected from hydrogen or alkyl
  • R 2 is independently selected from hydrogen, alkyl ⁇ -
  • - R 3 is independently selected from hydrogen or alkyl
  • alkyl refers, in the present invention, to aliphatic, linear or branched, saturated or unsaturated chains, having 1 to 18 carbon atoms, preferably 1 to 9 carbon atoms.
  • alkyl refers, in the present invention, to aliphatic, linear or branched, saturated or unsaturated chains, having 1 to 18 carbon atoms, preferably 1 to 9 carbon atoms.
  • the alkyl groups may be optionally substituted by one or more substituents such as halogen, hydroxyl or carboxylic acid.
  • Said substituted alkyl groups are for example, but not limited to, 1- (1, 3-dithiolane) hexyl, 1-hydroxyethyl, hydroxymethyl, etc.
  • aryl refers, in the present invention, to single or multiple aromatic rings, having between 5 and 18 links in which a proton has been removed from the ring.
  • the aryl groups are for example, but not limited to, phenyl, naphthyl, diphenyl, indenyl, phenanthryl or anthracil.
  • the aryl group has 5 to 7 carbon atoms and more preferably the aryl group is a phenyl.
  • Aryl radicals may be optionally substituted by one or more substituents such as alkyl (Ci-C 6), halogen, hydroxyl or carboxylic acid.
  • Substituted aryl radicals are, for example, but not limited to 2,4-dichlorophenyl, 1,3-dichlorophenyl, 3,5-difluorophenyl, 3- methoxyphenyl.
  • halogen refers, in the present invention, to bromine, chlorine, iodine or fluorine. Preferably chlorine.
  • the size of the substituents R 1 to R 3 is important for the functionality of the compounds of formula (I), such as when they are intended to modify, among others, their pharmacokinetic, bioavailability, solubility or stability properties.
  • possible carbon chain substitutions in R 3 are those in which said substituent does not exceed 5 carbon atoms, while in the case of the substituents of R 1 and R 2 the number of atoms can be quite greater .
  • the positions defined by the substituents R 1 and R 2 can be functionalized with long carbon chains, such as fatty acids, where the most commonly used include chains of up to 18 carbon atoms.
  • substituents such as 1,1-dimethylheptyl (of 9 carbon atoms) constitute a good example of an intermediate carbon chain between the maximum and minimum values contemplated herein.
  • the compounds of the invention also include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • the compounds having the present structures, except for the replacement of a hydrogen with a deuterium or tritium, or the replacement of a carbon with a carbon enriched in 13 C or 14 C or a nitrogen enriched in 15 N are within the scope of this invention.
  • tautomer or “tautomeric form”, as used in the present invention, refers to structural isomers of different energies that are interconvertible via a low energy barrier.
  • protonic tautomers also known as prototropic tautomers
  • Valencia tautomers include interconversions by reorganization of some bond electrons.
  • pharmaceutically acceptable salts, solvates, prodrugs refers to any pharmaceutically acceptable salt, ester, solvate, or any other compound that, when administered to a receptor, is capable of providing (directly or indirectly) a compound as described in This document.
  • pharmaceutically acceptable salts are also within the scope of the invention since these may be useful in the preparation of pharmaceutically acceptable salts.
  • the preparation of salts, prodrugs and derivatives can be carried out by methods known in the art.
  • salts of compounds provided herein are synthesized by conventional chemical methods from an original compound containing a basic or acidic moiety.
  • such salts are prepared, for example, by reacting the free acid or base forms of the compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent or in a mix of the two.
  • non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred.
  • acid addition salts include mineral acid addition salts such as, for example, hydrochloride, hydrobromide, iodhydrate, sulfate, nitrate, phosphate and organic acid addition salts such as, for example, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate and p-toluenesulfonate.
  • mineral acid addition salts such as, for example, hydrochloride, hydrobromide, iodhydrate, sulfate, nitrate, phosphate
  • organic acid addition salts such as, for example, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate and p-toluenesulfonate.
  • base addition salts include inorganic salts such as, for example, sodium, potassium, calcium, ammonium, magnesium, aluminum and lithium salts, and salts of organic bases such as, for example, ethylenediamine, ethanolamine, N, - dialkylene ethanolamine, triethanolamine, glucamine and basic amino acid salts.
  • Particularly preferred derivatives or prodrugs are those that increase the bioavailability of the compounds of this invention when such compounds are administered to a patient (for example, by making a compound administered orally more easily absorbed by blood), or that enhance the release of the original compound in a biological compartment (for example, the brain or lymphatic system) in relation to the original species.
  • prodrug is used in its broadest sense and encompasses those derivatives that are converted in vivo into the compounds of the invention. Such derivatives will be apparent to those skilled in the art, and include, depending on the functional groups present in the molecule and without limitation, the following derivatives of the compounds present: esters, amino acid esters, phosphate esters, salts sulfonate esters metallic, carbamates, and amides.
  • the compounds of formula (I) may be in crystalline form as free compounds or as solvates and it is intended that both forms are within the scope of the present invention.
  • the methods of Solvation are generally known within the art. Suitable solvates are pharmaceutically acceptable solvates. In a particular embodiment, the solvate is a hydrate.
  • the compounds of formula (I) or their salts or solvates are preferably in a pharmaceutically acceptable or substantially pure form.
  • Pharmaceutically acceptable means, among others, that they have a pharmaceutically acceptable level of purity excluding normal pharmaceutical additives such as diluents and carriers, and not including material considered toxic at normal dosage levels.
  • the purity levels for the active ingredient are preferably greater than 50%, more preferably, greater than 70%, more preferably, greater than 90%. In a preferred embodiment, they are greater than 95% of the compound of formula (I), or of its salts, solvates or prodrugs.
  • the compounds of general formula (I) can be found as tautomers of formula (II) or formula (III). However, in the examples described herein, where R 3 is hydrogen, they have been obtained as compounds of formula (III) when R 2 is also hydrogen, and as compounds of formula (II) when R 2 is an alkyl group, as they are the methyl or ethyl groups.
  • the present invention relates to a compound of general formula (II),
  • R 1 is independently selected from hydrogen or Ci Ci _ 8;
  • R 2 is independently selected from hydrogen, ⁇ -Cis alkyl or C 5 -Ci 8 aryl;
  • R 3 is independently selected from hydrogen or C1-C5 alkyl.
  • the present invention relates to a compound of general formula (III),
  • the compound of formula (I), as well as any of its tautomeric forms of formula (II) or (III), is a compound where R 3 is a hydrogen.
  • the compound of formula (I), as well as any of its tautomeric forms of formula (II) or (III), is a compound where R 1 is a 1,1-dimethylheptyl group.
  • the compound of formula (I), as well as any of its tautomeric forms of formula (II) or (III), is a compound where R 2 is a group selected from hydrogen, methyl or ethyl.
  • the compound of formula (I), as well as any of its tautomeric forms of formula (II) or (III), is a compound where R 3 is a hydrogen and R 1 is a 1,1-dimethylheptyl group .
  • the compound of formula (I), as well as any of its tautomeric forms of formula (II) or (III), is a compound where R 3 is a hydrogen and R 2 is a group selected from hydrogen, methyl or ethyl. Even more preferred, it is a compound of formula (II) when R 2 is methyl or ethyl.
  • the compound of formula (I), as well as any of its tautomeric forms of formula (II) or (III), is a compound where R 1 is a 1,1-dimethylheptyl group and R 2 is a group selected from hydrogen, methyl or ethyl.
  • the compound of formula (I), as well as any of its tautomeric forms of formula (II) or (III), is a compound where R 3 is a hydrogen, R 1 is a 1,1-dimethylheptyl group and R 2 is a group selected from hydrogen, methyl or ethyl.
  • the compound of formula (I) or any of its previous preferred embodiments and examples is selected from one of the group consisting of: a) 7- (1 ', 1' -dimethylheptyl) - 1, -dihydro-4, -dimethylchromen [4,3- c] pyrazol-6, 9-dione; b) 7- (1 ', 1' -dimethylheptyl) -2, 4-dihydro-2, 4, 4-trimethylchromen [4,3- c] pyrazol-6, 9-dione; c) 7- (1 ', 1' -dimethylheptyl) -2-ethyl-2, 4-dihydro-4, 4-dimethylchromen [4, 3-c] pyrazol-6, 9-dione; or a tautomer, pharmaceutically acceptable salt, prodrug or solvate thereof.
  • Said compound defined in section a) above consists of a compound of general formula (I) that responds to the structure of formula (II) where R 1 is 1,1-dimethylheptyl, R 2 is hydrogen and R 3 is hydrogen.
  • Said compound defined in section b) above consists of a compound of general formula (I) that responds to the structure of formula (III) where R 1 is 1,1-dimethylheptyl, R 2 is methyl and R 3 is hydrogen.
  • Said compound defined in section c) above consists of a compound of general formula (I) that responds to the structure of formula (III) where R 1 is 1,1-dimethylheptyl, R 2 is ethyl and R 3 is hydrogen.
  • any of the compounds defined above ie those compounds that respond to the general formula (I) (including the compounds of general formulas (II) or (III), or any of the preferred embodiments or examples), they may also be referred to herein as "compound or compounds of the invention".
  • the compounds of the invention have antiproliferative activity.
  • the cannabinoid activity of the compounds of formula (I) is described based on in vitro tests of binding to human CB1 or CB2 receptors.
  • the compounds of formula (I) and their pharmaceutically acceptable salts, prodrugs or solvates thereof, can therefore be used in the prevention and / or treatment of a disorder or a proliferative disease.
  • compositions containing a therapeutically effective amount of a compound of formula (I), its pharmaceutically acceptable salts, prodrugs or solvates thereof, together with pharmaceutically acceptable carriers constitute an additional aspect of the present invention That is, a second aspect of the invention relates to a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and a therapeutically effective amount of at least one compound of the invention.
  • said pharmaceutical composition may also be referred to as "pharmaceutical composition of the invention”.
  • vehicle refers to a diluent, adjuvant or excipient with which the active substance is administered.
  • Such pharmaceutical vehicles may be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like.
  • water or aqueous solutions of saline solution and aqueous solutions of dextrose and glycerol are used as vehicles, particularly for injectable solutions.
  • Suitable pharmaceutical vehicles are described in "Remington's Pharmaceutical Sciences” by EW Martin, 1995.
  • the vehicles of the invention are approved by the regulatory agency of a state government or a federal government, or are listed in the United States Pharmacopoeia, in the European Pharmacopoeia or other pharmacopoeia generally recognized for use in animals, and more particularly in humans.
  • the amount of compound of the invention, its pharmaceutically acceptable salts, prodrugs or solvates thereof, therapeutically effective to be administered (also referred to herein as therapeutically effective or effective amount), as well as its dosage to treat a pathological state with said Compounds will depend on numerous factors, including age, patient status, disease severity, route and frequency of administration, modulator compound to be used, etc.
  • the compounds and pharmaceutical compositions of this invention can be used alone or together with other drugs to provide a combination therapy.
  • the other drugs can form part of the same pharmaceutical composition, or be provided as a separate pharmaceutical composition, for administration at the same time or at a different time.
  • Examples of pharmaceutical compositions include any solid composition (tablets, pills, capsules, granules, etc.) or liquid (solutions, suspensions or emulsions) for oral, topical or parenteral administration.
  • a third aspect of the present invention relates to the use of a compound of the invention for the manufacture of a pharmaceutical composition.
  • the compounds of formula (I) have an antiproliferative activity.
  • antiproliferative activity refers to the proliferation of malignant tumors.
  • malignant tumors refer to blastoma, carcinoma, glioma, leukemia, lymphoma, melanoma.
  • a fourth aspect of the invention thus relates to a compound of the invention, or a pharmaceutical composition of the invention, for use in the treatment of a cancer or a malignant tumor, where preferably the cancer or malignant tumor is selected from blastoma. , carcinoma, glioma, leukemia, lymphoma and melanoma.
  • the cancer or malignant tumor is selected from blastoma. , carcinoma, glioma, leukemia, lymphoma and melanoma.
  • their use in the treatment of cancers or malignant tumors may be advantageous because they combine said cancer or tumor treatment with additional effects derived from their cannabinoid activity (e.g. antiemetic and / or analgesic effects), where such additional effects may be beneficial for the patient by reducing side effects of a cancer treatment such as emesis and / or pain.
  • said cancer or malignant tumor is selected from a malignant liver tumor (eg a hepatocarcinoma) or a malignant prostate tumor (eg a prostate cancer).
  • a malignant liver tumor eg a hepatocarcinoma
  • a malignant prostate tumor eg a prostate cancer
  • the compound of the invention, or the pharmaceutical composition of the invention, for use in the treatment of a cancer or a malignant tumor can obviously be understood as a method of treating said cancer or tumor, which comprises administration to a subject of a therapeutically effective amount of said compound or pharmaceutical composition of the invention.
  • the present invention also relates to a method of treating a cancer or a malignant tumor (preferably selected from blastoma, carcinoma, glioma, leukemia, lymphoma and melanoma; and even more preferably, between a hepatocarcinoma or a cancer prostate), which comprises administering to a subject the compound of the invention in a therapeutically effective amount, or a pharmaceutical composition of the invention comprising the compound of the invention in a therapeutically effective amount.
  • a cancer or a malignant tumor preferably selected from blastoma, carcinoma, glioma, leukemia, lymphoma and melanoma; and even more preferably, between a hepatocarcinoma or a cancer prostate
  • this aspect of the present invention also contemplates the use of the compound of the invention, or of the pharmaceutical composition of the invention, for the manufacture of a pharmaceutical composition, for the treatment of said cancers or malignant tumors.
  • a compound of the invention for the manufacture of a pharmaceutical composition for the treatment of a cancer or a malignant tumor where the cancer or malignant tumor is preferably selected from blastoma, carcinoma, is also the object of the invention.
  • glioma, leukemia, lymphoma and melanoma is also the object of the invention.
  • said cancer or tumor is a hepatocarcinoma or a prostate cancer.
  • a fifth aspect of the invention relates to a process for obtaining a compound of general formula (I), which comprises an oxidation with [bis (trifluoroacetoxy) iodine] benzene of a compound of general formula (IV),
  • R 1 is independently selected from hydrogen or Ci Ci _ 8;
  • R 2 is independently selected from hydrogen, ⁇ -Cis alkyl or C 5 -Ci 8 aryl;
  • R is independently selected from hydrogen or C1-C5 alkyl.
  • FIG. 1 Effect of the compounds of examples 1, 2 and 3 of the present description on cell viability.
  • the HepG2 cell lines (derived from hepatocellular carcinoma), LNCaP (derived from androgen dependent prostate cancer) and PC-3 (derived from androgen independent prostate cancer), were treated with increasing doses of the compounds of examples 1, 2 and 3 for 48 hours after which the viability with MT was determined.
  • the data are averages of two experiments performed in triplicate + D.E. (Standard deviation)
  • FIG. 1 Effect of the compound of example 1 of the present description on the cell cycle.
  • the LNCaP and PC-3 cell lines were treated for 24 hours with the doses of the compound of the Example 1 to which a 50% decrease in cell viability was obtained.
  • A After treatment, the cell cycle was analyzed by flow cytometry.
  • B After the treatment, the cells were stained with Annexin V and with propidium iodide, determining the different cell populations by flow cytometry in order to detect the cells in apoptosis. The image is representative of two independent tests performed in duplicate.
  • FIG. 3 In vivo antitumor effect of the compound of example 1 of the present description on prostate cancer lines.
  • Nu / nu atomic mice were injected subcutaneously with LNCaP cells (A) or PC-3 cells (B).
  • A LNCaP cells
  • B PC-3 cells
  • a 15-day treatment with vehicle (Control) or 2 mg / Kg of the example 1 compound administered intraperitoneally was started.
  • the tumor was measured daily.
  • the figure shows the growth curves of the tumors from the beginning of the treatment. The results are expressed as both by one of the initial tumor size and correspond to the mean ⁇ SE (Standard Error) of 6 mice per group.
  • ⁇ SE Standard Error
  • 4,4-dimethyl-7- (H or alkyl) -dihydrochromen [4, 3-c] pyrazol-9- has been used as starting products corresponding oles.
  • the 4,4-dimethyl-7- (H or alkyl) -dihydrochromen [4, 3- c] pyrazole-9-starting olives can be obtained by a combination of synthetic reactions known in the state of the art such as those mentioned in the article by Cumella J. et al. ChemMedChem 2012, 7, 452-463.
  • the 4,4-dimethyl dihydrochromen [4,3-c] pyrazol-6,9-diones of formula (I) of the present invention are obtained by oxidation of the 4,4-dimethyl-7- (H or alkyl) -dihydrochromen [4,3-c] pyrazol-9-oles corresponding. This oxidation occurs regiospecifically due to the use of [bis (trifluoroacetoxy) iodine] benzene (BTIB) which allows to obtain the desired para-quinone.
  • BTIB [bis (trifluoroacetoxy) iodine] benzene
  • Example 1 Preparation and obtaining 7- (1 ', 1' -dimethylheptyl) -1, 4- dihydro-4, 4-dimethylchromen [4, 3-c] pyrazol-6, 9-dione
  • reaction mixture is neutralized with a saturated solution of NaHC0 3 and extracted with diethyl ether.
  • organic phase is washed with water and dried over anhydrous MgSO 4 .
  • the solvent is evaporated in vacuo and the resulting mixture is purified by chromatographic column using as eluent Hex / AcOEt (1: 2). Rto. : 21% Red solid, mp: 85.7 ° C.
  • Example 2. Preparation and obtaining 7- (1 ', 1' -dimethylheptyl) -2, 4- dihydro-2, 4, 4-trimethylchromen [4, 3-c] pyrazol-6, 9-dione
  • the cannabinoid activity of the compounds of formula (I) was assessed by carrying out in vitro tests of displacement of the cannabinoid radioligand [ 3 H] -CP55940 (10 ⁇ ) and [ 3 H] -WIN 55,212-2 (50 ⁇ ) in cells transfected by human CB1 or CB2 receptors.
  • the affinity constants of the compound of example 1 of the present invention are given below by way of illustration: 7- (1 ', 1' -dimethylheptyl) -1, 4-dihydro-4, 4-dimethylchromen [4, 3- c] pyrazol-6, 9-dione (Example 1) 324 nM (CB1), 134 nM (CB2).
  • LNCaP and PC-3 cells were routinely grown in RPMI 1640 medium supplemented with 10% fetal bovine serum (FBS), 100 IU / ml sodium penicillin G, 100 g / ml streptomycin sulfate and 0.25 g / ⁇ amphotericin B (Invitrogen, Paisley, UK). The cells were kept in a humid environment, at 37 ° C and with 5% C0 2 .
  • FBS fetal bovine serum
  • 100 IU / ml sodium penicillin G 100 g / ml streptomycin sulfate
  • 0.25 g / ⁇ amphotericin B Invitrogen, Paisley, UK.
  • Annexin V-FITC apoptosis detection kit (BD, New Jersey) commercial kit was used.
  • the cells were seeded in six-well plates with a density of 5,000 cells / cm 2 . Once the treatments were carried out, the cells were trypsinized and centrifuged at 400 g for 5 minutes. Subsequently, the cells were incubated 15 minutes in the dark with 5 ⁇ of Annexin V, conjugated with fluorescein isothiocyanate (FITC) and 5 ⁇ of propidium iodide dissolved in 100 ⁇ of binding buffer (0.1 M Hepes pH 7.4 , 1.4 M NaCl, 25 mM CaCl 2 ). After the incubation time, 400 ⁇ of binding buffer was added and analyzed with a FACSCalibur cytometer.
  • FITC fluorescein isothiocyanate
  • the Mice were injected subcutaneously in the right flank, with 0.1 ml of PBS buffer with 10 million PC-3 cells or LNCaP.
  • the tumor size (which is calculated with the formula 0.523xW 2 xL; W being the width of the tumor and L the length thereof) was controlled and calculated daily using a calibrator. After fifteen days of treatment the animals were sacrificed and the tumors were removed calculating the weight and size of the tumor at the end of the treatment.
  • the effect of the compounds examples 1, 2 and 3 on cell viability was analyzed using three cell lines derived from human tumors.
  • the HepG2 cell line comes from a differentiated hepatocellular carcinoma
  • the LNCaP cell line comes from an androgen-dependent prostate tumor
  • the PC-3 cell line comes from an androgen-independent and therefore more aggressive prostate cancer.
  • the three compounds were more effective in prostate cell lines than in hepatocellular carcinoma, highlighting the example 1 compound of the present patent as the most potent in all cell lines with an IC50 of 30 ⁇ in HepG2 and 15 ⁇ cells in LNCaP and PC-3 cells.
  • Antitumor activity in vivo Illustratively, the antitumor activity of 7- (1 ', 1' -dimethylheptyl) -1, 4-dihydro-4, 4-dimethylchromen [4, 3-c] pyrazol-6, 9-dione (example 1) is presented ) in vivo. It was analyzed by subcutaneous induction of xenograph tumors in immunocompromised mice administering the example compound of the present patent (2 mg / Kg) dissolved in olive oil, intraperitoneally for 15 days consecutively. Control animals were given the same volume of olive oil

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Abstract

La présente invention concerne un composé de formule générale (I) ou un tautomère, un sel pharmaceutiquement acceptable, un promédicament ou un solvate de celui-ci, avec R1 choisi indépendamment parmi hydrogène ou alkyle C1-C18; R2 choisi indépendamment parmi hydrogène, alkyle C1-C18 ou aryle C5-C18; et R3 choisi indépendamment parmi hydrogène ou alkyle C1-C5. L'invention concerne également l'utilisation dudit composé de formule (I) pour le traitement d'un cancer ou d'une tumeur maligne, comme par exemple un blastome, un carcinome, un gliome, une leucémie, un lymphome et un mélanome, ainsi qu'un procédé permettant le traitement dudit cancer ou de ladite tumeur, lequel procédé consiste à administrer une quantité thérapeutiquement efficace dudit composé de formule (I). D'autres aspects de l'invention concernent, par conséquent, une composition pharmaceutique comprenant une quantité thérapeutiquement efficace d'un composé de formule générale (I) et au moins un excipient pharmaceutiquement acceptable. En outre, la présente invention concerne le procédé permettant d'obtenir ledit composé de formule générale (I) par oxydation avec du [bis(trifluoroacétoxi)iodo]benzène du dérivé phénolique précurseur correspondant.
PCT/ES2013/070499 2012-07-18 2013-07-12 Cromèno-pyrazoldiones utilisées comme dérivés cannabinoïdes de quinones à activité antitumorale WO2014013117A1 (fr)

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Cited By (5)

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CN104926821A (zh) * 2015-07-10 2015-09-23 南京大学 含苯基磺酰基或烷基磺酰基的香豆素并吡唑衍生物制备与在抑制肿瘤中的应用
WO2015140377A1 (fr) * 2014-03-18 2015-09-24 Consejo Superior De Investigaciones Científicas (Csic) Nouvelles croménoquinones modulatrices de récepteurs cannabinoïdes cb2 à activité antitumorale
CN104961743A (zh) * 2015-07-10 2015-10-07 南京大学 含羰基或肟的香豆素并吡唑类化合物及其制备与在抑制肿瘤细胞中的应用
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WO2015140377A1 (fr) * 2014-03-18 2015-09-24 Consejo Superior De Investigaciones Científicas (Csic) Nouvelles croménoquinones modulatrices de récepteurs cannabinoïdes cb2 à activité antitumorale
WO2016177922A1 (fr) * 2015-05-05 2016-11-10 Consejo Superior De Investigaciones Cienificas (Csic) Modulateurs sélectifs de l'activité du récepteur gpr55: dérivés de chrome-opirazol
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US10435412B2 (en) 2015-05-05 2019-10-08 The Governing Council Of The University Of Toronto Selective modulators of the activity of the GPR55 receptor: chromenopyrazole derivatives
CN104926821A (zh) * 2015-07-10 2015-09-23 南京大学 含苯基磺酰基或烷基磺酰基的香豆素并吡唑衍生物制备与在抑制肿瘤中的应用
CN104961743A (zh) * 2015-07-10 2015-10-07 南京大学 含羰基或肟的香豆素并吡唑类化合物及其制备与在抑制肿瘤细胞中的应用
CN105061442A (zh) * 2015-07-10 2015-11-18 南京大学 含磺酰基哌嗪的香豆素并吡唑类化合物及其制备与在抑制肿瘤细胞中的应用

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