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WO2013079754A1 - Indolénines fluorées utilisées pour le traitement du cancer - Google Patents

Indolénines fluorées utilisées pour le traitement du cancer Download PDF

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Publication number
WO2013079754A1
WO2013079754A1 PCT/ES2012/070830 ES2012070830W WO2013079754A1 WO 2013079754 A1 WO2013079754 A1 WO 2013079754A1 ES 2012070830 W ES2012070830 W ES 2012070830W WO 2013079754 A1 WO2013079754 A1 WO 2013079754A1
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Prior art keywords
compound
formula
alkyl
compounds
mmol
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English (en)
Spanish (es)
Inventor
Sara Preciado Gallego
Alba PÉREZ PERARNAU
Joan Gil Santano
Fernando Albericio Palomera
Rodolfo LAVILLA GRÍFOLS
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Universitat de Barcelona UB
Fundacio Privada Institut dInvestigacio Biomedica de Bellvitge IDIBELL
Fundacio Privada Institut de Recerca Biomedica IRB
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Universitat de Barcelona UB
Fundacio Privada Institut dInvestigacio Biomedica de Bellvitge IDIBELL
Fundacio Privada Institut de Recerca Biomedica IRB
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Publication of WO2013079754A1 publication Critical patent/WO2013079754A1/fr
Anticipated expiration legal-status Critical
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Classifications

    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring

Definitions

  • the present invention is related to new compounds of
  • indolenin indolenin, pharmaceutical compositions containing them and their use for the treatment of cancer.
  • Cancer is a heterogeneous disease characterized by the accumulation of tumor cells, which can cause death in both animals and humans.
  • Conventional methods for cancer treatment include surgical treatments, agent administration
  • chemotherapeutic agents and more recently immune response based treatments, which involve the administration of an antibody or an antibody fragment that can be conjugated to a unit
  • Chemotherapy despite all its limitations, is still today one of the most widespread methods for the treatment of different types of cancer. Therefore, the development of new antitumor therapies of general applicability is one of the main objectives of medical chemistry.
  • the inventors have found a new family of compounds with the indolenin nucleus substituted by fluorine atoms that present
  • antitumor properties apoptotic properties
  • these compounds are useful for the treatment and / or prevention of cancer.
  • the inventors have found that the compounds of the present invention promote apoptosis in several tumor cell lines independently of the p53 protein.
  • the p53 protein prevents the cell from replicating by stopping the cell cycle in the G1 phase, or inferred, allowing DNA repair.
  • it induces apoptosis if cell damage is very extensive and repair attempts fail. Any interruption in the regulation of the p53 pathway, in its functioning or in the target genes increases the possibility of tumor formation.
  • one aspect of the present invention is related to providing compounds of general formula (I), or their pharmaceutically salts.
  • R 6 is selected from the group consisting of H and (Ci-C 4 ) alkyl
  • pharmaceutically acceptable salts used herein comprises any salt formed from non-toxic acids or bases.
  • any compound referred to herein may represent any form of a racemic, one or more enantiomeric forms, one or more forms
  • the compounds of formula (I) are those in which Ri, R 4 and R 5 are H.
  • the compounds of formula (I) are those in which R 6 is H.
  • the compounds of formula (I) are those in which R 2 and R 7 are independently selected from H and Cl.
  • the compounds of formula (I) are those in which R 3 is independently selected from the group consisting of H, Cl, and alkoxycarbonyl (Ci-C 4 ).
  • R 3 is independently selected from the group consisting of H, Cl, and alkoxycarbonyl (Ci-C 4 ).
  • alkoxycarbonyl (Ci-C 4 ) is ethoxycarbonyl.
  • the compounds of the formula (I) according to the above definition are those in which R 8 is H or methyl.
  • the compound of formula (I) is that wherein R1-R2, R4 -Rs is H and R 3 is ethoxycarbonyl. In another particular preferred embodiment, the compound of formula (I) is that wherein R1-R2, R4 -R6, and Rs are HR 3 and R 7 are chloro.
  • the compounds of the present invention can be prepared simply and flexibly from commercial reagents by a variety of procedures For example, they can be prepared by the procedure illustrated in Scheme I.
  • R 6 -R8 have the same meaning as mentioned above for the compound of formula (I).
  • R 9 is a radical selected from the group consisting of: phenyl, phenyl substituted with at least one radical selected from the group consisting of Cl, (Ci-C 4 ) -alkoxy, (Ci-C 4 ) -alkyl , (Ci-C 4 ) alkoxycarbonyl, 4-pyrrolidin-1-carbonyl, and 4-morphol-1-carbonyl.
  • R 9 is selected from the group consisting of phenyl, 4-chlorophenyl, 4-methoxyphenyl, 4-ethoxycarbonylphenyl, 4-ethylphenyl, 3-chlorophenyl, 3,4-dimethoxyphenyl, 4-phenyl-1-pyrrolidine carbonyl, 4 morpholin-1-carbonylphenyl.
  • 3,3-difluoro-3 / - / - indole of formula (I) can be obtained by the oxidative coupling of Suzuki of a compound of formula (III) with a boronic acid of formula R 9 -B (OH) 2 using a palladium catalyst such as Pd (OAc) 2 , an oxidizing agent such as TEMPO, a base such as KF and an appropriate solvent such as propionic acid. Generally, the rection is carried out at room temperature (20-25 ° C).
  • the compounds of formula (I) where R 8 is Br can be prepared by a process comprising direct arylation followed by a fluorination reaction.
  • a palladium (II) catalyst such as palladium acetate
  • a base such as cesium acetate
  • an appropriate solvent such as N, N-dimethylacetamide (DMA).
  • the reaction can be carried out at a temperature between 0 and 130 January 10 C.
  • the subsequent fluorination of the compound indolenine of formula (II) can be carried out as mentioned above.
  • the preparation procedures described above can be modified to obtain enantiopide compounds as well as mixtures of stereoisomers. It is possible to prepare specific stereoisomers or specific mixtures by various procedures, including the use of stereospecific reagents or by introducing chiral centers in the compounds during their preparation process. Furthermore, it is possible to separate the stereoisomers once the compound has been prepared by standard resolution techniques well known to the person skilled in the art.
  • Compounds of formula (I) can be carried out by methods known in the state of the art. For example, they can be prepared from the primary compounds which contain a basic or acid reactive center, by conventional chemical methods. Generally, said salts are prepared, for example, by reacting the free acid or base forms of those compounds with the stoichiometric amount of a pharmaceutically acceptable base or acid in water or in an organic solvent or in a mixture thereof.
  • the compounds of the present invention may be in crystalline form, both as solvent-free compounds or as solvates (for example, hydrates) and it is understood that both forms are within the scope of protection of the present invention. Solvation methods are generally known within the art.
  • An important feature of the compounds of the present invention is their ability to inhibit cell growth in tested tumor lines, and in particular their ability to induce cytotoxicity by promoting apoptosis. As shown in the Examples, the compounds of the present invention have antitumor properties on two cancer cell lines. Thus, another aspect of the present invention is related to the
  • Another aspect of the present invention is related to the preparation of compounds of formula (I), or their pharmaceutically acceptable salts, or their stereoisomers or mixture of stereoisomers, including the compounds of formula (I) where Ri-R 8 is H and the compound of formula (I) where Ri and R 3 -R 8 are H and R 2 is methoxy, for use in the treatment and / or prevention of cancer, since they are active against all types of cancer that have been tested.
  • compounds of formula (I), or their pharmaceutically acceptable salts, or their stereoisomers or mixture of stereoisomers for use in the treatment and / or prevention of tumors with mutated p53 are provided.
  • the compounds of the present invention are especially active against acute T-cell leukemia and cervical cancer.
  • This aspect of the invention can also be formulated as the use of the compounds of formula (I) as defined above, for the preparation of a medicament for the treatment and / or prevention of cancer in a mammal, including humans. .
  • the invention also relates to a method of treating cancer in a mammal, including the human being, who suffers or is susceptible to cancer, in particular to the aforementioned types of cancer, said method comprising the administration to said patient of an amount
  • the compounds of the present invention can be used in the same manner as other known chemotherapeutic agents. They can be used alone or in combination with other suitable bioactive compounds.
  • Another aspect of the present invention is related to a pharmaceutical composition containing a therapeutically effective amount of the compounds of the present invention, of a compound of formula (I) where Ri-R 8 is H or the compound of formula (I) where Ri and R 3 -R 8 are H and R 2 is methoxy, together with appropriate amounts of pharmaceutically acceptable excipients or carriers.
  • terapéuticaally effective amount refers to the amount of a compound that, when administered, is sufficient to prevent the development of, or relieve to some degree, one or more of the symptoms of the disease a The one that goes.
  • the particular dose of compound administered according to this invention will of course be determined by the particular conditions surrounding the case, including the compound administered, the route of administration, the particular condition being treated, and similar considerations.
  • pharmaceutically acceptable excipients or carriers refers to pharmaceutically acceptable materials, components or vehicles. Each component must be pharmaceutically acceptable in the sense of being compatible with the other ingredients of the pharmaceutical composition.
  • the chemotherapeutic treatment derived from the present invention is a new approach to cancer therapy and has the advantage of being useful for the treatment of various types of cancer.
  • FIG. 1 shows the dose response of compound l c from 2 ⁇ to 40 ⁇ in the Jurkat cell line (T lymphocytes from an acute type T leukemia, with mutated p53) at 24 hours of incubation. Viability was measured by flow cytometry and expressed as the percentage of non-apoptotic cells (annexin V APC negative).
  • FIG. 2 shows the dose-response of compound l c from 5 ⁇ to 40 ⁇ in the HeLa cell line (cervical adenocarcinoma epithelial cell line with p53 inactivated) at 48 hours of incubation. Viability was measured by flow cytometry and expressed as the percentage of non-apoptotic cells (annexin V APC negative).
  • FIG. 3 shows the dose response of compound l d from 2 ⁇ to 40 ⁇ in the Jurkat cell line (T lymphocytes from an acute type T leukemia, with mutated p53) at 24 hours of incubation. Viability was measured by flow cytometry and expressed as the percentage of non-apoptotic cells (annexin V APC negative).
  • FIG. 4 shows the dose response of compound l d from 5 ⁇ to 40 ⁇ in the HeLa cell line (cervical adenocarcinoma epithelial cell line with p53 inactivated) at 48 hours of incubation. Viability was measured by flow cytometry and expressed as the percentage of non-apoptotic cells
  • silica gel column purification silica gel (particle size 35-70 pm) was used. Symmetry C18 reverse phase columns of dimensions 4.6 mm ⁇ 150 mm, 5 pm (column A) of HPLC were used.
  • the HPLC analyzes were performed in an apparatus composed of two solvent supply pumps, an automatic injector and a variable wavelength detector and a system controller (Breeze V3.20).
  • MALDI-TOF analyzes were performed using the ACH matrix. IR spectra were obtained with a Thermo Nicolet Nexus spectrophotometer and absorption bands are indicated in cm "1. Melting points were performed in a Büchi Melting Point B-540.
  • Example 3 Preparation of 2- (4-ethoxycarbonylphenyl) -1 / - / - indole
  • the title compound was prepared analogously to Example 1 from indole (240 mg, 2.00 mmol) and p-ethoxycarbonylphenylboronic acid (388 mg, 2.00 mmol) for 24 h at room temperature.
  • the residue was purified by flash chromatographic column (S02, hexane: AcOEt, 9: 1),
  • Example 4 Preparation of 6-chloro-2- (4-chlorophenyl) -1 / - / - indole
  • the title compound was prepared analogously to Example 1 from 6-chloroindole (310 mg, 2.00 mmol) and p-chlorophenylboronic acid (388 mg, 2.00 mmol) for 24 h at room temperature.
  • the residue was purified by flash chromatographic column (S02, hexane: AcOEt, 9: 1),
  • Example 7 Preparation of 2- (2-chlorophenyl) -1 / - / - indole
  • the title compound was prepared analogously to Example 1 from indole (200 mg, 1.65 mmol) and o-chlorophenylboronic acid (310.8 mg, 2.00 mmol) for 48 h at room temperature.
  • the residue was purified by flash chromatographic column (S02, hexane: AcOEt, 7: 3),
  • the title compound was prepared analogously to Example 1 from 6-chloroindole (200 mg, 1.30 mmol) and p-ethoxycarbonylphenylboronic acid (320 mg, 1.56 mmol) for 24 h at room temperature.
  • the residue was purified by flash chromatographic column (S02, hexane: AcOEt, 9: 1), obtaining 64.5 mg of 6-chloro-2- (4-ethoxycarbonylphenyl) -1 / - / - indole as a white solid (17% yield).
  • Example 12 Preparation of 7-ethyl-2-phenyl-1 H-indole
  • the title compound was prepared analogously to Example 10 from 7-ethylindole (145 g, 1.03 mmol) and iodobenzene (160 ⁇ _, 1. 40 mmol) for 72 h at 125 ° C.
  • the residue was purified by flash chromatographic column (SOO2, hexane: AcOEt, 95: 5), obtaining 82 mg of 7-ethyl-2-phenyl-1 H-indole as a white solid (36% yield) .
  • Example 14 Preparation of 2- (4-pyrrolidine-1-carbonylphenyl) -1 H-indole
  • the title compound was prepared analogously to Example 10 from indole (100 mg, 0.85 mmol) and 4-iodophenyl (pyrrolidin-1-yl) methanone (360 mg, 1.19 mmol) for 48 h at 125 ° C.
  • the residue was purified by flash chromatographic column (S02, hexane: AcOEt, 30:70), yielding 75 mg of 2- (4-pyrrolidine-1-carbonylphenyl) -1 / - / - indole as a white solid (30% yield).
  • Example 18 The title compound was prepared analogously to Example 18 from the compound of Example 1 (59 mg, 0.25 mmol) in anhydrous ACN (7 ml_), Na 2 C0 3 (s) (500 mg) and the Selectfluor fluorinating agent ® (227.3 mg, 0.61 mmol). The mixture was stirred at room temperature for 2 h, obtaining 50.8 mg of 2- (4-chlorophenyl) -3,3-difluoro-3 / - / - ndol as an orange solid (77% yield).
  • Example 18 The title compound was prepared analogously to Example 18 from the compound of Example 3 (70 mg, 0.264 mmol) in anhydrous ACN (7 mL), Na 2 C0 3 (s) (600 mg) and the Selectfluor fluorinating agent ® (236.1 mg, 0.63 mmol). The mixture was stirred at room temperature for 3 h, obtaining 58.6 mg of ethyl 4- (3,3-difluoro-3 / - / - indole-2-yl) benzoate as an orange solid (74% yield).
  • Example 21 Preparation of 6-chloro-2- (4-chlorophenyl) -3,3-difluoro-3 / - / - indole (le),
  • the title compound was prepared analogously to Example 18 from the compound of Example 4 (80 mg, 0.34 mmol) in anhydrous ACN (7.5 ml_), Na 2 C0 3 (s) (340 mg) and the Selectfluor fluorinating agent ® (282.5 mg, 0.76 mmol).
  • the mixture was stirred at room temperature for 2 h, obtaining 71 mg of 6-chloro-2- (4-chlorophenyl) -3,3-difluoro-3 / - / - indole as an orange solid (70% yield).
  • Example 18 The title compound was prepared analogously to Example 18 from the compound of Example 6 (10 mg, 0.044 mmol) in anhydrous ACN (1.5 mL), Na 2 C0 3 (s) (100 mg) and the agent Selectfluor® fluorine (34 mg, 0.09 mmol). The mixture was stirred at room temperature for 2 h, obtaining 7.3 mg of 2- (3-chlorophenyl) -3,3-difluoro-3 / - / - indole as an orange solid (63% yield).
  • Example 18 The title compound was prepared analogously to Example 18 from the compound of Example 9 (49 mg, 0.16 mmol) in anhydrous ACN (3.2 mL), Na 2 C0 3 (s) (160 mg) and the Selectfluor fluorinating agent ® (134.1 mg, 0.36 mmol). The mixture was stirred at room temperature for 5 h, obtaining 49 mg of ethyl 4- (6-chloro-3,3-difluoro-3 / - / - indol-2-yl) benzoate as an orange solid (86% of performance).
  • Example 24 Biological assays for the detection of antitumor activity
  • Jurkat human cell lines T lymphocytes from acute T-cell leukemia
  • HeLa epidermaal cell line
  • cervical adenocarcinoma were obtained from the European Cell Culture Collection.
  • the Jurkat cell line grew in RPMI-1640 medium and the HeLa cell line in DMEM. Both culture media were supplemented with 10% inactivated fetal serum (veal), 1% glutamine, and 1% penicillin-streptomycin and were grown at 37 ° C in an atmosphere dampened with 5% carbon dioxide.
  • DMSO dimethyl sulfoxide
  • the propidium iodide (“propidium iodide”, Pl) was obtained from Bender MedSystems (Vienna, Austria). Annexin V-APC was obtained from eBioscience (St Diego, USA). Analysis of apoptosis by flow cytometry
  • Apoptosis or programmed cell death, is a general physiological mechanism for the removal of unwanted cells. It is characterized by chromatin condensation, a reduction in cell volume, and DNA cutting carried out by endonucleases that results in fragments of oligonucleosomal length. Apoptosis is also accompanied by a loss of asymmetry of the phospholipid membrane, resulting in the exposure of phosphatidylserine on the cell surface. The expression of phosphatidylserine on the cell surface plays an important role in the recognition and elimination of apoptotic cells carried out by macrophages. This is one of the earliest events of the apoptotic process.
  • the method for the detection of apoptotic cells by flow cytometry uses the binding of annexin V labeled with a fluorochrome to phosphatidylserine.
  • the plasma membrane is disturbed during late apoptosis but also during necrosis, since it becomes permeable to substances such as Pl.
  • Pl is a fluorescent molecule with a molecular weight of 668.4 Da that is sandwiched between double nucleic acids chain and that can be used to stain the DNA.
  • Pl is excluded by viable cells but can penetrate the cell membranes of dying and dead cells.
  • viable cells are annexin-V and Pl double negative
  • early apoptotics are annexin-V positive and Pl negative
  • late apoptotic cells are annexin V and Pl double positive.
  • a fourth population of positive Pl cells correlates with necrotic cells.
  • Results 1 Exploratory test of cell viability in Jurkat cells An exploration of the effect of some compounds of formula (I) on the Jurkat cell line (T lymphocytes from an acute T-cell leukemia) was performed at a single maximum dose of 40 ⁇ during a 24-hour incubation. The structure of the tested compounds are shown in Table 1. It has been also tested the 5 compound of formula (I) where Ri-R8 are H (compound l 0).
  • Jurkat cells were chosen among other leukemic tumor cell lines because they have the mutated p53 protein. 1 o All the mentioned compounds were dissolved in the minimum amount of DMSO needed to be completely dissolved. Cell viability was measured by flow cytometry. It was verified that DMSO alone did not decrease cell viability. Thus, all the effects observed in cell viability were due to the activity of these compounds.
  • a dose-response analysis of compounds l c and I d was performed on Jurkat cells or cells with mutated p53 and on HeLa cells with inactivated p53.
  • Cell viability was measured by flow cytometry and expressed as a percentage of non-apoptotic cells (annexin V negative) with respect to untreated cells at 24 and 48 hours of incubation. Therefore, values below 5% are indicative of apoptosis or loss of cell viability.
  • Jurkat cells which are T lymphocytes from an acute type T leukemia, with mutated p53
  • a dose range from 2 ⁇ to 40 ⁇ for each compound for 24 and 48 hours. All compounds induced or apoptosis in a dose-dependent manner. The viability was measured by
  • HeLa cells cervical adenocarcinoma epithelial cell line with inactivated p53
  • Apoptosis in a dose-dependent manner was measured by flow cytometry (cf. FIG. 2 and 4).
  • the IC5 0 at 24 hours was calculated for each compound using the values of 0 viability obtained by flow cytometric analysis.
  • Results are expressed in Table 4 as the percentage of non-apoptotic cells (annexin V negative) with respect to untreated cells at 24 and 48 hours. 5 Table 4:

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  • Chemical & Material Sciences (AREA)
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  • Health & Medical Sciences (AREA)
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Abstract

L'invention concerne des composés de formule (I) ou leurs sels pharmaceutiquement acceptables, ou leurs stéréoisomères ou un mélange de stéréoisomères. Dans la formule (I), R1, R2, R4, R5, et R7, sont sélectionnés de manière indépendante dans le groupe constitué de H,Cl,C(=O)O(C1-C4)alkyle, O(C1-C4)alkyle; et (C1-C4)alkyle; R3 est sélectionné dans le groupe constitué de H1, Cl, C(=O)O(C1-C4)alkyle, O(C1-C4)alkyle, (C1-C4)alkyle, pyrrolidinyl-1-carbonyle, et morpholine-1-carbonyle; R6 est sélectionné dans le groupe constitué de H et (C1-C4)alkyle; et R8 est sélectionné dans le groupe constitué de H, F, Br, (C1-C4)alkyle, et phényle. Les composés de l'invention inhibent la prolifération cellulaire de cellules tumorales indépendamment de la protéine p53 et peuvent également induire l'apoptose dans diverses cellules tumorales indépendamment de la protéine p53, c'est pourquoi ils sont utilisés dans le traitement de divers types de cancer.
PCT/ES2012/070830 2011-11-28 2012-11-27 Indolénines fluorées utilisées pour le traitement du cancer Ceased WO2013079754A1 (fr)

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ES201131915A ES2410704B1 (es) 2011-11-28 2011-11-28 Indoleninas fluoradas útiles para el tratamiento del cáncer.
ESP201131915 2011-11-28

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105884673A (zh) * 2016-06-03 2016-08-24 温州大学 一种吲哚衍生物的合成方法
CN106083707A (zh) * 2016-06-01 2016-11-09 温州大学 一种非对称杂芳基硫醚的合成方法

Citations (1)

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Publication number Priority date Publication date Assignee Title
WO2009037308A1 (fr) * 2007-09-21 2009-03-26 Janssen Pharmaceutica Nv Inhibiteurs de l'interaction entre mdm2 et p53

Patent Citations (1)

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Publication number Priority date Publication date Assignee Title
WO2009037308A1 (fr) * 2007-09-21 2009-03-26 Janssen Pharmaceutica Nv Inhibiteurs de l'interaction entre mdm2 et p53

Non-Patent Citations (1)

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Title
R LIN ET AL.: "An efficient difluorohydroxylation of indoles using Selectfluor as a fluorinating reagent", ORGANIC LETTERS 2011, vol. 13, no. 17, September 2011 (2011-09-01), pages 4498 - 4501, XP055070873 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106083707A (zh) * 2016-06-01 2016-11-09 温州大学 一种非对称杂芳基硫醚的合成方法
CN105884673A (zh) * 2016-06-03 2016-08-24 温州大学 一种吲哚衍生物的合成方法
CN105884673B (zh) * 2016-06-03 2018-05-11 温州大学 一种吲哚衍生物的合成方法

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