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    • 专利摘要:
    New cb2 cannabinoid receptor modulating cromenoquinones with antitumor activity. The present invention provides novel cannabinoids derived from chromenopyrazole-ortho-quinone represented by the formula (I), pharmaceutical compositions containing these compounds and their use as modulators of the cb2 cannabinoid receptor, whereby they are especially useful for the treatment of cancer and cancer. The malignant tumors. (Machine-translation by Google Translate, not legally binding)
    公开号:ES2548789A1
    申请号:ES201430372
    申请日:2014-03-18
    公开日:2015-10-20
    发明作者:Nadine Jagerovic；Paula MORALES LAZARO；María Del Pilar GOYA LAZA；Sandra BLASCO BENITO；María Cristina SÁNCHEZ GARCÍA；María GÓMEZ CAÑAS；José Javier FERNÁNDEZ RUÍZ
    申请人:Consejo Superior de Investigaciones Cientificas CSIC；Universidad Complutense de Madrid；
    IPC主号:
    专利说明:

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    C1-C18 alkyl, C2-C18 alkenyl, C3-C7 cycloalkyl, halogen, hydroxyl, -O-C1-C5 alkyl, -CO C1-C5 alkyl, -CN, -COOH, -COO-C1-C5 alkyl, -CONH- C1-C5 alkyl or -SO2-C1-C5 alkyl. Substituted aryl radicals are, for example, but not limited to 2,4-dichlorophenyl, 1,3-dichlorophenyl, 3,5-difluorophenyl, 3-methoxyphenyl.
    The term "C5-C18 heteroaryl" refers to a stable 5 to 18 membered ring radical consisting of carbon atoms and one to five heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, preferably a 5 or 5 ring 6 members with one or more heteroatoms. The heteroaryl, according to this invention, may be a monocyclic or bicyclic ring system that may include condensed ring systems and the nitrogen atom may be optionally quaternized. Examples of heteroaryl radicals include but are not limited to, imidazole, pyrrole, pyridine, pyridazine, piperidine, pyrazine, quinoline, indole, thiophene, furan, oxazo and pyrazole.
    The term "halogen" refers, in the present invention, to bromine, chlorine, iodine or fluorine. Preferably chlorine.
    It should be understood that the present invention encompasses all isomers of the compounds of formula (I), that is, all geometric, tautomeric and optical forms, and mixtures thereof (eg, racemic mixtures). When there are more chiral centers in the compounds of formula (I), the present invention includes within its scope all possible diastereomers, including mixtures thereof. The different isomeric forms can be separated or resolved from one another by conventional methods, or any given isomer can be obtained by conventional synthetic methods or by stereospecific, stereoselective or asymmetric synthesis. The present invention also includes isotope-labeled compounds, which are identical to those cited in formulas (I), (II), (III) and (IV) except that one or more atoms have been replaced by an atom that has a Atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, iodine and chlorine, such as 3H, 11C, 14C, 18F, 123I and
    125I.
    Within the scope of the present invention are compounds of the present invention and pharmaceutically acceptable salts of said compounds containing the aforementioned isotopes and / or other isotopes of other atoms. The isotope-labeled compounds of the present invention, for example those in which radioactive isotopes such as 3H or 14C are incorporated, are useful in drug and / or tissue distribution assays. Particularly preferred are tritium isotopes, i.e. 3H, and carbon-14, i.e. 14C, for their ease of preparation and detectability. Isotopes 11C and 18F are particularly useful in PET (positron emission tomography), and isotopes 125I are particularly useful in SPECT (single photon emission computed tomography), all useful in brain imaging. In addition, replacement with heavier isotopes such as deuterium, i.e., 2H, may provide some therapeutic advantages that result from increased metabolic stability, for example, longer half-life in vivo or lower dosage requirements, and therefore in some Cases may be preferred. The isotopically labeled compounds of formula (I) can generally be prepared by performing the procedures described in the examples below, substituting an isotopically unlabeled reagent for an easily available isotopically labeled reagent.
    The term "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. For example, protonic tautomers (also known as
    7
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    where,
    - R1 is selected from hydrogen, C1-C18 alkyl, C3-C7 cycloalkyl and C2-C18 alkenyl, optionally substituted;
    - R2 is selected from hydrogen, C1-C18 alkyl, C3-C7 cycloalkyl, C2-C18 alkenyl and C5-C18 aryl, optionally substituted;
    - R3 is selected from hydrogen, C1-C5 alkyl, C3-C7 cycloalkyl and C2-C5 alkenyl, optionally substituted;
    or a pharmaceutically acceptable tautomer, prodrug, salt or solvate thereof.
    When R2 is a hydrogen, the compounds of general formula (I) can be found as tautomers. That is, they are in equilibrium between the structures of formula (II) and formula (III).
    In a preferred example, the compound of formula (I) is a compound wherein R3 is selected from hydrogen and optionally substituted C1-C18 alkyl.
    In a preferred example, the compound of formula (I) is a compound where R3 is hydrogen.
    In another preferred example, the compound of formula (I) is a compound wherein R1 is an optionally substituted C1-C18 alkyl group.
    In another more preferred example, the compound of formula (I) is a compound wherein R 1 is selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl and 1,1-dimethylheptyl.
    In another even more preferred example, the compound of formula (I) is a compound where R 1 is 1,1-dimethylheptyl.
    In another preferred example, the compound of formula (I) is a compound where R2 is a group selected from hydrogen and optionally substituted C1-C18 alkyl.
    In another preferred example, the compound of formula (I) is a compound where R2 is a group selected from hydrogen, methyl, ethyl, propyl and 2-hydroxyethyl.
    In another even more preferred example, the compound of formula (I) is a compound where R3 is a hydrogen and R1 is 1,1-dimethylheptyl.
    According to a preferred embodiment, 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) -1,4-dihydro-4,4-dimethylchromen [4,3-c] pyrazol-8,9-dione; b) 7- (1 ’, 1’-dimethylheptyl) -2,4-dihydro-2,4,4-trimethylchromen [4,3-c] pyrazol-8,9-dione; c) 7- (1 ’, 1’-dimethylheptyl) -1-ethyl-1,4-dihydro-4,4-dimethylchromen [4,3-c] pyrazol-8,9-dione;
    or a pharmaceutically acceptable tautomer, prodrug, salt or solvate thereof. The compound defined in section a) above, consists of a compound of general formula
    (I)  where R1 is 1,1-dimethylheptyl, R2 is hydrogen and R3 is hydrogen.
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    (tablets, pills, capsules, granules, etc.) or liquid (solutions, suspensions or emulsions) for oral, topical or parenteral administration.
    A third aspect of the invention relates to the use of a compound of formula (I) or of a pharmaceutical composition, which contains at least one compound of formula (I) or one of its pharmaceutically acceptable tautomers, prodrugs, salts or solvates thereof. in a therapeutically effective amount for the manufacture of a medicine.
    A fourth aspect of the invention relates to the use of a compound of formula (I) or of a pharmaceutical composition containing at least one compound of formula (I) as described above or a pharmaceutically acceptable tautomer, prodrug, salt or solvate. thereof, for the manufacture of a medicament for the treatment of a cancer or a malignant tumor. Examples of cancer or malignant tumor types are: carcinoma, sarcoma, lymphoma, leukemia, myeloma and melanoma.
    In an even more preferred embodiment, the present invention relates to the use of a compound of formula (I) or of a pharmaceutical composition containing at least one compound of formula (I) as described above or a tautomer, prodrug, salt or pharmaceutically acceptable solvate thereof, for the manufacture of a medicament for the treatment of a carcinoma.
    In the present invention, carcinoma is understood as a form of cancer originating in epithelial or glandular type cells, malignant type. Common places of carcinoma occurrence are: the skin, mouth, lung, breast, digestive tract and uterus.
    In an even more preferred embodiment, the present invention relates to the use of a compound of formula (I) or of a pharmaceutical composition containing at least one compound of formula (I) as described above or a tautomer, prodrug, salt or pharmaceutically acceptable solvate thereof, for the manufacture of a medicament for the treatment of breast cancer.
    In the present invention, breast cancer is understood as the following groups of cancers: hormone-sensitive breast cancers (ER + / PR +), Her2 positive breast cancers and triple negative breast cancers. In an even more preferred embodiment, breast cancer corresponds to triple negative breast cancer.
    In the present invention it is understood as triple negative breast cancer a very heterogeneous group of breast cancers characterized in that it does not express the genes of estrogen receptors (ER), progesterone receptors (PR) and receptors with tyrosine kinase activity Her2 ( HER2 / neu).
    In general, although the activity tests shown in the present invention have been carried out exclusively on a triple-negative breast tumor, there are studies that show that cannabinoids and cannabinoid derivatives that act as cannabinoids can have antitumor effects in various types of cancer. For example, cannabinoid WIN-55,212-3 was shown to be effective in breast cancer cell line (Qamri Z. et al., Cancer Ther. 2009, 8, 3117-3129), prostate cancer (Sarfaraz S. et al, Cancer Res. 2005, 65, 1635-1641) and colon (Sreevalsan S. et al, Mol. Cancer Ther. 2013, 12, 2483-2493). Similarly, cannabinoid delta (9) -tetrahydrocannabinoid has been positively evaluated in several types of cancer. In vitro studies have shown that a cannabinoid can inhibit the proliferation and / or migration of different breast carcinomas (MCF-7, EFM
    12
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    Figure 2. Involvement of cannabinoid receptors in the antiproliferative mechanism of example 3 of the present description. Signaling mechanisms involved in the antiproliferative effect of compound 3. Cells derived from triple negative breast tumor MDA-MB-231 were incubated for 48 hours with different antagonists (from CB1 receptors [SR141716 (SR1)], CB2 [SR144528 (SR2) ], GPR55 [CID16020046 (CDI)] and an antioxidant [αtocopherol (Toc)]) in the absence or presence of compound 3 of the present description at a dose of 6 µM. The cells were pre-treated with the aforementioned inhibitors one hour before adding the compound under study. Cell viability was determined by MTT. Data are averages of three independent experiments performed in triplicate ± D.E. A value of p <0.05 was considered statistically significant. The levels of significance are indicated in the figures: *, p <0.05 and **, p <0.01 vs cells treated in vehicle; #, p <0.05 and #, p <0.01 vs cells treated with example 3. Treatment in the presence of CB1 antagonist, (SR1, 1 µM), CB2 antagonist (SR2, 1 µM) and antioxidant (Toc, 10 µM) . Treatment in the presence of the GPR55 antagonist (CID, 25 µM).
    Figure 3. Cytotoxicity against normal breast cells. Evaluation of the viability of normal human mammary epithelial cells (HMEC) 48 h after being treated with increasing doses (from 0.5-10 µM) of the example compound 3. The data are averages of two independent experiments performed in triplicate ± D.E.
    Figure 4. Analysis of the mechanism of antiproliferative action of example 3 of the present description. The MDA-MB-231 cell line was treated with a 6 µM dose of compound 3 (24h). Subsequently, an apoptosis biomarker was analyzed by Western Blot (panel A). A very significant increase in the levels of active caspase 3 was observed in the cells treated with example 3 of the present patent causes the death of the tumor cells by apoptosis. Panel B shows the quantification of 2 different Western blots.
    The following examples and drawings are provided by way of illustration, and are not intended to be limiting of the present invention. EXAMPLES
    For the synthesis of the compounds of formula (I) of the present invention, 4,4-dimethyl-7- (H or alkyl) dihydrochromen [4,3-c] pyrazol-9- has been used as starting products corresponding oles. The starting 4,4-dimethyl-7- (H or alkyl) -dihydrochromen [4,3-c] pyrazol-9-ols 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. General procedure for the synthesis of ortho-quinones derived from chromene [4,3c] pyrazole.
    The 4,4-dimethyl-dihydrochromen [4,3-c] pyrazol-8,9-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 o-iodoxibenzoic acid (IBX) that allows to obtain the desired ortho-quinone.
    This procedure is summarized in the following scheme (A):
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    权利要求:
    Claims (1)
    [1]
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    同族专利:
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    WO2015140377A1|2015-09-24|
    ES2548789B1|2016-08-08|
    引用文献:
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    US10435412B2|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|IL159892D0|2004-01-15|2004-06-20|Yissum Res Dev Co|Use of quinonoid derivatives of cannabinoids in the treatment of malignancies|
    EP2139847A1|2007-03-05|2010-01-06|Yissum Research Development Company, of The Hebrew University of Jerusalem|Novel quinonoid derivatives of cannabinoids and their use in the treatment of malignancies|
    JP5575324B2|2010-03-26|2014-08-20|ビバセルバイオテクノロジイエスパーニャ、エス．エル|Cannabinoid quinone derivatives|
    WO2014013117A1|2012-07-18|2014-01-23|Consejo Superior De Investigaciones Científicas |Chromenopyrazole diones as cannabinoid quinone derivatives having anti-tumour activity|
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    PCT/ES2015/070184| WO2015140377A1|2014-03-18|2015-03-17|Novel chromene quinones for modulating cannabinoid receptors cb2having antitumor activity|
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