WO2016075224A1 - 6-amino-7-bicyclo-7-deaza-purine derivatives as protein kinase inhibitors - Google Patents
6-amino-7-bicyclo-7-deaza-purine derivatives as protein kinase inhibitors Download PDFInfo
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- 0 *C(*)(CCCC(CCCC*C(O)=O)CCC1)C1c1c(*)[n](*)c2ncnc(N(*)*)c12 Chemical compound *C(*)(CCCC(CCCC*C(O)=O)CCC1)C1c1c(*)[n](*)c2ncnc(N(*)*)c12 0.000 description 10
- FEXUQZHRFVOCCE-UHFFFAOYSA-N CC(C)[n](cc1-c(cc2)cc(CCC3)c2N3C(C)=O)c2c1c(N)ncn2 Chemical compound CC(C)[n](cc1-c(cc2)cc(CCC3)c2N3C(C)=O)c2c1c(N)ncn2 FEXUQZHRFVOCCE-UHFFFAOYSA-N 0.000 description 1
- DBDARSKSBJNUFN-UHFFFAOYSA-N CC(C)[n](cc1-c(cc2)cc3c2NCCC3)c2c1c(N)ncn2 Chemical compound CC(C)[n](cc1-c(cc2)cc3c2NCCC3)c2c1c(N)ncn2 DBDARSKSBJNUFN-UHFFFAOYSA-N 0.000 description 1
- YEMVJOGXNUKRJN-UHFFFAOYSA-N CC(C)[n](cc1-c2cc3cccc(C(NC4CC4)=O)c3cc2)c2c1c(N)ncn2 Chemical compound CC(C)[n](cc1-c2cc3cccc(C(NC4CC4)=O)c3cc2)c2c1c(N)ncn2 YEMVJOGXNUKRJN-UHFFFAOYSA-N 0.000 description 1
- GTKJRPBCSQINJN-UHFFFAOYSA-N CC(C)[n](cc1I)c2c1c(N)ncn2 Chemical compound CC(C)[n](cc1I)c2c1c(N)ncn2 GTKJRPBCSQINJN-UHFFFAOYSA-N 0.000 description 1
- ZLYOMILQMGZWDZ-UHFFFAOYSA-N CC(C)[n]1c2ncnc(N)c2c(-c(cc2)cc3c2c(C(NC2CCCC2)=O)ccc3)c1 Chemical compound CC(C)[n]1c2ncnc(N)c2c(-c(cc2)cc3c2c(C(NC2CCCC2)=O)ccc3)c1 ZLYOMILQMGZWDZ-UHFFFAOYSA-N 0.000 description 1
- AWXIIMWTYLGGOE-UHFFFAOYSA-N CC1(C)OB(c2cc3cccc(C(NC4CC4)=O)c3cc2)OC1(C)C Chemical compound CC1(C)OB(c2cc3cccc(C(NC4CC4)=O)c3cc2)OC1(C)C AWXIIMWTYLGGOE-UHFFFAOYSA-N 0.000 description 1
- QBWXQZHHVDIJSF-UHFFFAOYSA-N COC(c1c(ccc(O)c2)c2ccc1)=O Chemical compound COC(c1c(ccc(O)c2)c2ccc1)=O QBWXQZHHVDIJSF-UHFFFAOYSA-N 0.000 description 1
- FFWRRNMOWZABTO-UHFFFAOYSA-N COC(c1ccc(cc(cc2)OS(C(F)(F)F)(=O)=O)c2c1)=O Chemical compound COC(c1ccc(cc(cc2)OS(C(F)(F)F)(=O)=O)c2c1)=O FFWRRNMOWZABTO-UHFFFAOYSA-N 0.000 description 1
- QAYAYOJVVWYFQF-UHFFFAOYSA-N FC(C[n](cc1I)c2c1c(Cl)ncn2)(F)F Chemical compound FC(C[n](cc1I)c2c1c(Cl)ncn2)(F)F QAYAYOJVVWYFQF-UHFFFAOYSA-N 0.000 description 1
- TUNONTLSIIBCNR-UHFFFAOYSA-N Nc1c(c(I)c[n]2CC(F)(F)F)c2ncn1 Chemical compound Nc1c(c(I)c[n]2CC(F)(F)F)c2ncn1 TUNONTLSIIBCNR-UHFFFAOYSA-N 0.000 description 1
- GWPVFLJYMHUSBD-UHFFFAOYSA-N OB(c1cc2cccc(C(O)=O)c2cc1)O Chemical compound OB(c1cc2cccc(C(O)=O)c2cc1)O GWPVFLJYMHUSBD-UHFFFAOYSA-N 0.000 description 1
- JCJUKCIXTRWAQY-UHFFFAOYSA-N OC(c1c(ccc(O)c2)c2ccc1)=O Chemical compound OC(c1c(ccc(O)c2)c2ccc1)=O JCJUKCIXTRWAQY-UHFFFAOYSA-N 0.000 description 1
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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
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- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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Definitions
- RET is the signaling component of a multiprotein complex: binding of RET to the glial-derived neurotrophic factor (GDNF) family ligands (GDNF, artemin, neurturin and persephin) through ligand-specific GDNF- family receptor alpha co-receptors (GFRoc1-4) induces the formation of active RET dimers and the autophosphorylation of specific tyrosine residues in the cytoplasmic domain.
- GDNF glial-derived neurotrophic factor
- GFRoc1-4 ligand-specific GDNF- family receptor alpha co-receptors
- RET oncogenic role of RET was firstly described in papillary thyroid carcinoma (PTC) (Grieco et al., Cell, 1990, 60, 557-63), which arises from follicular thyroid cells and is the most common thyroid malignancy.
- PTC papillary thyroid carcinoma
- the fusion transcripts are highly expressed and all the resulting chimeric proteins contain the N-terminal portion of the coiled-coil region of KIF5B, which mediates homodimerization, and the entire RET kinase domain. None of RET positive patients harbor other known oncogenic alterations (such as EGFR or K-Ras mutation, ALK translocation), supporting the possibility that KIF5B-RET fusion could be a driver mutation of lung adenocarcinoma.
- KIF5B-RET The oncogenic potential of KIF5B-RET has been confirmed by transfecting the fusion gene into cultured cell lines: similarly to what observed with RET-PTC fusion proteins, KIF5B-RET is constitutively phosphorylated and induces NIH-3T3 transformation and IL-3 independent growth of BA-F3 cells.
- RET fusion proteins have been identified in lung adenocarcinoma patients, such as the CCDC6-RET protein, which has been found to play a key role in the proliferation of the human lung adenocarcinoma cell line LC-2/ad (Journal of Thoracic Oncology, 2012, 7(12):1872-1876).
- MEN2 subtypes MEN2A, MEN2B and Familial MTC/FMTC
- RET gene mutations have a strong phenotype-genotype correlation defining different MTC aggressiveness and clinical manifestations of the disease.
- MEN2A syndrome mutations involve one of the six cysteine residues (mainly C634) located in the cysteine-rich extracellular region, leading to ligand-independent homodimerization and constitutive RET activation.
- Patients develop MTC at a young age (onset at 5-25 years) and may also develop pheochromocytoma (50%) and hyperparathyroidism.
- MEN2B is mainly caused by M918T mutation, which is located in the kinase domain.
- MEN2B syndrome is characterized by an early onset ( ⁇ 1 year) and very aggressive form of MTC, pheochromocytoma (50% of patients) and ganglioneuromas. In FMTC the only disease manifestation is MTC, usually occurring at an adult age. Many different mutations have been detected, spanning the entire RET gene. The remaining 75% of MTC cases are sporadic and about 50% of them harbor RET somatic mutations: the most frequent mutation is M918T that, as in MEN2B, is associated with the most aggressive phenotype.
- Somatic point mutations of RET have also been described in other tumors such as colorectal cancer (Wood et al., Science, 2007, 318, 1108-13) and small cell lung carcinoma (Jpn. J. Cancer Res., 1995, 86, 1127-30).
- RET signaling components have been found to be expressed in primary breast tumors and to functionally interact with estrogen receptor-cc pathway in breast tumor cell lines (Boulay et al., Cancer Res. 2008, 68, 3743-51 ; Plaza- Menacho et al., Oncogene, 2010, 29, 4648-57), while RET expression and activation by GDNF family ligands could play an important role in perineural invasion by different types of cancer cells (Ito et al., Surgery, 2005, 138, 788-94; Gil et al., J Natl Cancer Inst., 2010, 102, 107-18; Iwahashi et al., Cancer, 2002, 94, 167-74).
- RET tyrosine kinase inhibitors could be of high therapeutic value.
- Novel 7-substituted-7-deazaadenosines, useful in the treatment of cancer, have been disclosed in WO2010/121576 in the name of Institute of Organic Chemistry and Biochemistry ASCR, V.V.I.
- Pyrrolo[2,3-d]pyrimidine derivatives as CGRP receptor antagonists have been disclosed in WO2009/080682 in the name of Glaxo Group Limited.
- Indoline derivatives have been disclosed as inhibitors of PERK in WO2011/119663 in the name of Glaxo Smithkline, LLC.
- 4-Aminopyrrolopyrimidines have been disclosed ad kinase inhibitors in the name of Basf Aktiengesellschaft (WO00/17202).
- Pyrrolopyrimidine derivative have been disclosed in WO2004/056830 in the name of Pfizer Products Inc., useful for the treatment of hyperproliferative diseases such as cancer.
- EGFR kinase inhibitors in combination with agents that sentisize tumor cells to the effects of an EGFR kinase inhibitors have been disclosed in US8586546 in the name of OSI Pharmaceuticals, LLC.
- a first object of the present invention is to provide a substituted 6-amino-7-bicyclo-7-deaza-purine compound represented by formula (I)
- R1 and R2 are independently hydrogen or an optionally substituted group selected from straight or branched (d-Ce) alkyl, (C3-C6) cycloalkyl and COR', wherein R' is an optionally substituted group selected from straight or branched (Ci-C 6 ) alkyl and (C 3 -C 6 ) cycloalkyl;
- R3 is hydrogen or an optionally substituted group selected from straight or branched (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C6) cycloalkyl, aryl, heteroaryl and a 3- to 7-membered heterocyclyl ring;
- R4 is hydrogen or an optionally substituted group selected from straight or branched (C1-C6) alkyl, (C2-C6) alkenyl, aryl, heteroaryl or heterocyclyl;
- A is a 5- or 6-membered heteroaryl ring or a phenyl ring
- B is a 5- or 6-membered ring selected from heteroaryl, (C5-C6) cycloalkyl and heterocyclyl ring or a phenyl ring; wherein ring A and ring B are fused together to form a bicyclic system comprising a 6-membered aromatic or 5- to 6-membered heteroaromatic ring fused with a 6-membered aromatic or 5- to 6-membered heteroaromatic, (C5-C6) cycloalkyl or heterocyclyl ring;
- Y is carbon or nitrogen
- X is hydrogen, halogen, hydroxyl, cyano or an optionally substituted group selected from straight or branched ( ⁇ -0 ⁇ ) alkyl and (C1-C6) alkoxyl;
- R5 and R6 are independently hydrogen or an optionally substituted group selected from straight or branched (C1-C6) alkyl, (C3-C6) cycloalkyl, heterocyclyl, aryl and heteroaryl;
- the present invention also provides methods of preparing the substituted 6-amino-7-bicyclo-7-deaza-purine compounds, represented by formula (I), prepared through a process consisting of standard synthetic transformations.
- the present invention also provides a method for treating diseases caused by and/or associated with dysregulated protein kinase activity, particularly RET, RAF family, protein kinase C in different isoforms, Abl, Aurora A, Aurora B,
- RET family kinases which comprises administering to a mammal in need thereof, more particularly a human, an effective amount of a substituted 6-amino-7-bicyclo-7-deaza-purine compound represented by formula
- a preferred method of the present invention is to treat a disease caused by and/or associated with dysregulated protein kinase activity selected from the group consisting of cancer, cell proliferative disorders, viral infections, immune-related disorders and neurodegenerative disorders.
- carcinoma such as bladder, breast, colon, kidney, liver, lung, including small cell lung cancer, esophagus, gallbladder, ovary, pancreas, stomach, cervix, thyroid, prostate and skin, including squamous cell carcinoma
- hematopoietic tumors of lymphoid lineage including leukaemia, acute lymphocitic leukaemia, acute lymphoblastic leukaemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma and Burkett's lymphoma
- hematopoietic tumors of myeloid lineage including acute and chronic myelogenous leukemias, myelodysplasia syndrome and promyelocytic leukaemia
- tumors of mesenchymal origin including fibrosarcoma and r
- Another preferred method of the present invention is to treat specific cellular proliferation disorders such as, for example, benign prostate hyperplasia, familial adenomatosis, polyposis, neurofibromatosis, psoriasis, vascular smooth cell proliferation associated with atherosclerosis, pulmonary fibrosis, arthritis, glomerulonephritis and post- surgical stenosis and restenosis.
- specific cellular proliferation disorders such as, for example, benign prostate hyperplasia, familial adenomatosis, polyposis, neurofibromatosis, psoriasis, vascular smooth cell proliferation associated with atherosclerosis, pulmonary fibrosis, arthritis, glomerulonephritis and post- surgical stenosis and restenosis.
- Another preferred method of the present invention is to treat viral infections, comprising the prevention of AIDS development in HIV-infected individuals.
- Another preferred method of the present invention is to treat immune-related disorders including but not limited to: transplant rejection, skin disorders like psoriasis, allergies, asthma and autoimmune-mediated diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Crohn's disease and amyotrophic lateral sclerosis.
- RA rheumatoid arthritis
- SLE systemic lupus erythematosus
- SLE systemic lupus erythematosus
- amyotrophic lateral sclerosis amyotrophic lateral sclerosis.
- Another preferred method of the present invention is to treat neurodegenerative disorders including but not limited to: Alzheimer's disease, degenerative nerve diseases, encephalitis, Stroke, Parkinson's Disease, Multiple Sclerosis, Amyotrophic Lateral Sclerosis (ALS or Lou Gehrig's Disease), Huntington's Disease and Pick's Disease.
- neurodegenerative disorders including but not limited to: Alzheimer's disease, degenerative nerve diseases, encephalitis, Stroke, Parkinson's Disease, Multiple Sclerosis, Amyotrophic Lateral Sclerosis (ALS or Lou Gehrig's Disease), Huntington's Disease and Pick's Disease.
- the method of the present invention also provides tumor angiogenesis and metastasis inhibition as well as the treatment of organ transplant rejection and host versus graft disease.
- the method of the present invention further comprises subjecting the mammal in need thereof to a radiation therapy or chemotherapy regimen in combination with at least one cytostatic or cytotoxic agent.
- the present invention also provides a pharmaceutical composition
- a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined above, and at least one pharmaceutically acceptable excipient, carrier and/or diluent.
- the present invention further provides a pharmaceutical composition of a compound of the formula (I) further comprising one or more chemotherapeutic - e.g. cytostatic or cytotoxic - agents, antibiotic-type agents, alkylating agents, antimetabolite agents, hormonal agents, immunological agents, interferon-type agents, cyclooxygenase inhibitors (e.g. COX-2 inhibitors), matrixmetalloprotease inhibitors, telomerase inhibitors, tyrosine kinase inhibitors, anti-growth factor receptor agents, anti-HER agents, anti-EGFR agents, anti-angiogenesis agents (e.g.
- chemotherapeutic e.g. cytostatic or cytotoxic - agents, antibiotic-type agents, alkylating agents, antimetabolite agents, hormonal agents, immunological agents, interferon-type agents, cyclooxygenase inhibitors (e.g. COX-2 inhibitors), matrixmetalloprotease inhibitors, telomerase inhibitors, tyrosine
- angiogenesis inhibitors farnesyl transferase inhibitors, ras-raf signal transduction pathway inhibitors, cell cycle inhibitors, other cdks inhibitors, tubulin binding agents, topoisomerase I inhibitors, topoisomerase II inhibitors, and the like.
- the invention provides an in vitro method for inhibiting the RET family protein activity which comprises contacting the said protein with an effective amount of a compound of formula (I) as defined above.
- the invention provides a product comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined above, and one or more chemotherapeutic agents, as a combined preparation for simultaneous, separate or sequential use in anticancer therapy.
- the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined above, for use as a medicament.
- the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined above, for use in a method of treating cancer.
- the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined above, in the manufacture of a medicament with anticancer activity.
- the present invention includes all of the hydrates, solvates, complexes, metabolites, prodrugs, carriers, N-oxides and pharmaceutically acceptable salts of the compounds of this invention.
- a metabolite of a compound of formula (I) is any compound into which this same compound of formula (I) is converted in vivo, for instance upon administration to a mammal in need thereof.
- this same derivative may be converted into a variety of compounds, for instance including more soluble derivatives like hydroxylated derivatives, which are easily excreted.
- any of these hydroxylated derivatives may be regarded as a metabolite of the compounds of formula (I).
- Prodrugs are any covalently bonded compounds, which release in vivo the active parent drug according to formula (I).
- a stereogenic center or another form of an asymmetric center is present in a compound of the present invention, all forms of such isomer or isomers, including enantiomers and diastereomers, are intended to be covered herein.
- Compounds containing a stereogenic center may be used as a racemic mixture, an enantiomerically enriched mixture, or the racemic mixture may be separated using well-known techniques and an individual enantiomer may be used alone. In cases in which compounds have unsaturated carbon-carbon double bonds, both the cis (Z) and trans (E) isomers are within the scope of this invention.
- each tautomeric form is contemplated as being included within this invention whether existing in equilibrium or predominantly in one form.
- Pharmaceutically acceptable salts of the compounds of formula (I) include the salts with inorganic or organic acids, e.g., nitric, hydrochloric, hydrobromic, sulfuric, perchloric, phosphoric, acetic, trifluoroacetic, propionic, glycolic, lactic, oxalic, fumaric, malonic, malic, maleic, tartaric, citric, benzoic, cinnamic, mandelic, methanesulphonic, isethionic and salicylic acid.
- inorganic or organic acids e.g., nitric, hydrochloric, hydrobromic, sulfuric, perchloric, phosphoric, acetic, trifluoroacetic, propionic, glycolic, lactic, oxalic, fumaric, malonic, malic, maleic, tartaric, citric, benzoic
- Pharmaceutically acceptable salts of the compounds of formula (I) also include the salts with inorganic or organic bases, e.g., alkali or alkaline-earth metals, especially sodium, potassium, calcium ammonium or magnesium hydroxides, carbonates or bicarbonates, acyclic or cyclic amines.
- inorganic or organic bases e.g., alkali or alkaline-earth metals, especially sodium, potassium, calcium ammonium or magnesium hydroxides, carbonates or bicarbonates, acyclic or cyclic amines.
- straight or branched ( ⁇ -0 ⁇ ) alkyl we intend any of the groups such as, for instance, methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, n-hexyl, and the like.
- (C3-C6) cycloalkyi we intend, unless otherwise provided, 3- to 6-membered all-carbon monocyclic ring, which may contain one or more double bonds but does not have a completely conjugated ⁇ -electron system.
- Examples of cycloalkyi groups are cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexene and cyclohexadiene.
- the (C3-C6) cycloalkyi ring can be optionally further fused or linked to aromatic and non-aromatic carbocyclic and heterocyclic rings.
- heterocyclyl we intend a 3- to 7-membered, saturated or partially unsaturated carbocyclic ring where one or more carbon atoms are replaced by heteroatoms such as nitrogen, oxygen and sulfur.
- heterocyclyl groups are, for instance, pyrane, tetrahydropyrane, pyrrolidine, pyrroline, imidazoline, imidazolidine, pyrazolidine, pyrazoline, thiazoline, thiazolidine, dihydrofuran, tetrahydrofuran, 1 ,3-dioxolane, piperidine, piperazine, morpholine and the like.
- the heterocyclyl ring can be optionally further fused or linked to aromatic and non-aromatic carbocyclic and heterocyclic rings.
- (C2-C6) alkenyl we intend an aliphatic (C2-C6) hydrocarbon chain containing at least one carbon- carbon double bond and which can be straight or branched. Representative examples include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1- or 2-butenyl, and the like.
- (C2-C6) alkynyl we intend an aliphatic (C2-C6) hydrocarbon chain containing at least one carbon- carbon triple bond and which can be straight or branched. Representative examples include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1- or 2-butynyl, and the like.
- aryl refers to a mono-, bi- or poly-carbocyclic hydrocarbon with from 1 to 4 ring systems, optionally further fused or linked to each other by single bonds, wherein at least one of the carbocyclic rings is "aromatic", wherein the term “aromatic” refers to completely conjugated ⁇ -electron bond system.
- Non limiting examples of such aryl groups are phenyl, a- or ⁇ -naphthyl, a- or ⁇ -tetrahydronaphthalenyl, biphenyl, and indanyl groups.
- the aryl ring can be optionally further fused or linked to aromatic and non-aromatic carbocyclic and heterocyclic rings.
- heteroaryl refers to aromatic heterocyclic rings, typically 5- to 7-membered heterocycles with from 1 to 3 heteroatoms selected among N, 0 or S; the heteroaryl ring can be optionally further fused or linked to aromatic and non-aromatic carbocyclic and heterocyclic rings.
- heteroaryl groups are, for instance, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, imidazolyl, thiazolyl, pyrrolyl, phenyl-pyrrolyl, furyl, phenyl-furyl, oxazolyl, isoxazolyl, pyrazolyl, thienyl, thiadiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, indazolyl, cinnolinyl, benzo[1,3]dioxolyl, benzo[1 ,4]dioxinyl, benzothiazolyl, benzothienyl, isoindolinyl, benzoimidazolyl, quinolinyl, isoquinolinyl, 1 ,2,3-triazolyl, 1 -phenyl-1 ,2,3
- halogen we intend a fluorine, chlorine, bromine or iodine atom.
- polyfluorinated alkyl or “polyfluorinated alkoxy” we intend any of the above straight or branched (Ci- Ce) alkyl or (C1-C6) alkoxy groups which are substituted by more than one fluorine atom such as, for instance, trifluoromethyl, trifluoroethyl, 1 ,1 ,1 ,3,3,3-hexafluoropropyl, trifluoromethoxy and the like.
- hydroxyalkyl we intend any of the above (C1-C6) alkyl, bearing a hydroxyl group such as, for instance, hydroxy methyl, 2-hydroxyethyl, 3-hydroxypropyl and the like. From all of the above, it is clear to the skilled person that any group which name is a composite name such as, for instance, "arylamino" has to be intended as conventionally constructed by the parts from which it derives, e.g. by an amino group which is further substituted by aryl, wherein aryl is as above defined.
- any of the terms such as, for instance, alkylthio, alkylamino, dialkylamino, alkoxycarbonyl, alkoxycarbonylamino, heterocyclylcarbonyl, heterocyclylcarbonylamino, cycloalkyloxycarbonyl and the like, include groups wherein the alkyl, alkoxy, aryl, (C3-C6) cycloalkyl and heterocyclyl moieties are as above defined.
- a preferred class of compounds of formula (I) are the compounds wherein:
- R1 is hydrogen
- R2 is hydrogen, methyl, cyclopropyl or COR' wherein R' is methyl;
- R3 is hydrogen or an optionally substituted group selected from straight or branched ( ⁇ -0 ⁇ ) alkyl, (C3-C6) cycloalkyl, aryl, heteroaryl and a 3- to 7-membered heterocyclyl ring; and
- R4 is hydrogen or an optionally substituted straight or branched ( ⁇ -0 ⁇ ) alkyl.
- a more preferred class of compounds of formula (I) are the compounds wherein:
- R1 , R2 and R4 are hydrogen
- R3 is hydrogen or an optionally substituted group selected from straight or branched ( ⁇ -0 ⁇ ) alkyl, (C3-C6) cycloalkyl, aryl, heteroaryl and a 3- to 7-membered heterocyclyl ring;
- B is a 5- or 6-membered heteroaryl, heterocyclyl ring or phenyl ring;
- X is hydrogen, halogen, cyano or an optionally substituted straight or branched (C1-C3) alkyl
- R5 is hydrogen
- Preferred specific compounds (cmpd) of formula (I) or a pharmaceutically acceptable salt thereof are the compounds listed below:
- 6-(4-Amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-naphthalene-1-carboxylic acid isopropylamide (cmpd 5), 6-(4-Amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-naphthalene-1-carboxylic acid methylamide (cmpd 6), 6-(4-Amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-naphthalene-1-carboxylic acid (2,2,2-trifluoro-ethyl)-amide (cmpd 7),
- non- exemplified compounds according to the invention may be performed by modifications apparent to those skilled in the art, for instance by appropriately protecting interfering groups, by changing to other suitable reagents known in the art, or by making routine modifications of reaction conditions.
- other reactions referred to herein or known in the art will be recognized as having adaptability for preparing other compounds of the invention.
- the compounds of this invention can be prepared from readily available starting materials using the following general methods and procedures. Unless otherwise indicated, the starting materials are known compounds or may be prepared from known compounds according to well known procedures. It will be appreciated that, where typical or preferred process conditions (i.e. reaction temperatures, times, mole ratios of reactants, solvents, pressures) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures. Additionally, as it will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions.
- process conditions i.e. reaction temperatures, times, mole ratios of reactants, solvents, pressures
- Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures. Additionally, as it will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from
- Suitable protecting groups for various functional groups as well as suitable conditions for protecting and deprotecting particular functional groups are well known in the art. For example, numerous protecting groups are described in T.W.Greene and P.G.M.Wuts, Protecting Groups in Organic Synthesis, Second Edition, Wiley, New York, 1991 , and references cited therein.
- a process of the present invention comprises the following steps:
- Step b' reaction of an intermediate of formula (III), wherein Y is nitrogen, B is a 5- or 6-membered heterocyclyl ring and A, R1 , R2, R3, R4 and X are as defined above, with an intermediate of formula (VII), wherein R6 is as defined above, to obtain a compound of formula (I), wherein Y is nitrogen, B is a 5- or 6-membered heterocyclyl ring, R5 is hydrogen and A, R1 , R2, R3, R4, R6 and X are as defined above;
- a process of the present invention comprises the following steps: Step e): halogenation of an intermediate of formula (IX) wherein R4 is hydrogen, Y is carbon, R10 is straight or branched (C1-C4) alkyl and A, B, R1 , R2, R3 and X are as defined above, i.e. an intermediate of formula (IXa), to obtain an intermediate of formula (X) wherein Hal is iodine or bromine, Y is carbon, R10 is straight or branched (O- C4) alkyl, and A, B, R1 , R2, R3 and X are as defined above;
- halogenation of an intermediate of formula (IXa) can be carried out in the presence of N-iodosuccinimide or N-bromosuccinimide to obtain an intermediate of formula (X), wherein Hal is iodine or bromine, in a suitable solvent such as dichloromethane, ⁇ , ⁇ -dimethylformamide or N,N-dimethylacetamide at room temperature for a time period ranging from 1 hour to 48 hours (ref. Bioorg. Med. Chem. Lett. 2000, 2171- 2174; Chem. Commun. 1997, 695-696).
- a suitable solvent such as dichloromethane, ⁇ , ⁇ -dimethylformamide or N,N-dimethylacetamide
- R1 , R2, R3, R4 and X are as defined above, can be carried out as described in the following Scheme 3.
- step g) of the present invention reduction of an intermediate of general formula (Xllla) to obtain an intermediate of formula (III) can be performed in the presence of a reducing agent such as NaBhU, NBU4BH4, NaCNBhh, EtsSiH, BH3 ⁇ 3, with the addition of an acid like acetic acid or TFA (trifluoroacetic acid), in solvents such as methanol, ethanol, dichloromethane and the like at temperatures ranging from room temperature to reflux, for a time period ranging from 1 hour to 48 hours.
- a reducing agent such as NaBhU, NBU4BH4, NaCNBhh, EtsSiH, BH3 ⁇ 3
- an acid like acetic acid or TFA trifluoroacetic acid
- reaction of an intermediate of formula (XI 11 b) to obtain an intermediate of formula (III) can be performed in the presence of a base such as LiOH, NaOH, KOH or an acid such as HCI, TFA in a suitable solvent such as methanol, ethanol, tetrahydrofuran, dioxane, dichloromethane, water and the like at temperatures ranging from room temperature to reflux, for a time period ranging from 1 hour to 48 hours.
- a base such as LiOH, NaOH, KOH or an acid such as HCI, TFA
- a suitable solvent such as methanol, ethanol, tetrahydrofuran, dioxane, dichloromethane, water and the like at temperatures ranging from room temperature to reflux, for a time period ranging from 1 hour to 48 hours.
- step i) of the present invention the reaction of an intermediate of formula (XVa) or (XVb) with an intermediate of formula (XVI) to obtain an intermediate of formula (Xllla) or (XII lb) can be carried out without solvent or in a solvent such as 1 ,4-dioxane, N,N-dimethylformamide, ⁇ , ⁇ -dimethylacetamide or dimethylsulfoxide at a temperature ranging from 60°C to 150°C for a time ranging from 1 to 24 hours in classical thermal conditions or in a microwave apparatus.
- a solvent such as 1 ,4-dioxane, N,N-dimethylformamide, ⁇ , ⁇ -dimethylacetamide or dimethylsulfoxide
- step i) can be carried out in a suitable solvent such as tetrahydrofuran or 1 ,4-dioxane in the presence of a base such as sodium carbonate (Na2C03), caesium carbonate (CS2CO3), potassium phosphate (K3CO4), with a Pd-based catalyst (Pd(OAc)2, Pd2dba3) and in the presence of a ligand such as Xantphos (4,5- bis(diphenylphosphino)-9,9-dimethylxanthene), BINAP (2,2'-bis(diphenylphosphino)-1 ,1'-binaphthyl), P(o-Tol)3 in classical thermal conditions at reflux or in a microwave apparatus for a time ranging from 1 to 24 hours at a temperature ranging from 50°C to 100°C.
- a base such as sodium carbonate (Na2C03), caesium carbonate (CS2CO3), potassium phosphate
- Step e) halogenation of an intermediate of formula (III) wherein R4 is hydrogen, Y is nitrogen, B is a 5- or 6- membered heterocyclyl ring, A, R1 , R2, R3 and X are as defined above, i.e. an intermediate of formula (Ilia), to obtain an intermediate of formula (XVII), wherein Hal is iodine or bromine, Y is nitrogen, B is a 5- or 6-membered heterocyclyl ring and A, R1 , R2, R3 and X are as defined above;
- step e) of Scheme 3a halogenation of an intermediate of formula (Ilia), wherein R4 is hydrogen, can be carried out as described for step e) of Scheme 2a (ref. Bioorg. Med. Chem. Lett. 2000, 2171-2174; Chem. Commun. 1997, 695-696).
- step f) of Scheme 3a the reaction is carried out as described for step f) of Scheme 2a.
- Step k reaction of intermediates of formula (XVIII), wherein R4 is hydrogen or an optionally substituted straight or branched (d-Ce) alkyl, with intermediates of formula (XX), wherein Z is iodine, bromine, mesylate, tosylate, triflate, hydroxyl, boronic acid or boronic ester and R3 is as defined above, to obtain intermediates of formula (XXI), wherein R4 is hydrogen or an optionally substituted straight or branched ( ⁇ -0 ⁇ ) alkyl and R3 is as defined above;
- reaction can be carried out under Mitsunobu condition when Z is hydroxyl in the presence of diethyl or diisopropyl azodicarboxylate and triphenylphosphine, in a suitable solvent such as tetrahydrofuran or dichloromethane at a temperature ranging from 0°C to 70°C.
- the reaction can be carried out in the presence of copper acetate, 2,2'-bipyridyl and sodium carbonate in ⁇ , ⁇ -dimethylacetamide at a temperature ranging from 70°C to 120°C or with cuprous oxide in methanol at reflux.
- AlkyI iodide, bromide, chloride, mesylate, tosylate, triflate, hydroxyl and aryl, heteroaryl or heterocyclyl boronic derivatives employed as reactants in the above mentioned steps k) and k') are commercially available compounds or can be prepared according to methods described in the literature.
- step i) of Scheme 4a the reaction can be carried out as described for step i) of Scheme 3.
- halogenation can be carried out as described for step e) of Scheme 2a (ref.
- step j) of Scheme 4b halogenation is carried out as described for step j) of Scheme 4a.
- step d) of Scheme 5 the reaction is carried out as described for step d) of Scheme 2.
- the reaction of intermediates of formula (XXXI) to obtain intermediates of formula (V) can be performed using a catalyst such as Pd(0), PdCWppf, PdCI 2 (CH 3 CN) 2 , Pd(OAc) 2 , Pd(dba) 2 with a ligand such as diphenylphosphinoferrocene (dppf), bis(2-di-tert-butyl-phosphinophenyl)ether, tricyclohexylphosphine (PCy3), 2-(biphenyl)di-cyclopentylphosphine (PCy 2 (o-biph), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos), a suitable base such as potassium acetate (AcOK), triethylamine (TEA) and in the presence of bis(pinacolato)diboron (B 2 pin 2 ),
- a catalyst such as P
- the reaction can be also performed using catalyst such as [lr(COD)(OMe) 2 ], [lr(COD)CI 2 ], with a ligand such as 2,2'-bipyridine (bpy), 4,4'-di-tert-butyl-2,2'-bipyridine (dtbpy), in solvent like 1 ,2- dimethoxyethane, tetrahydrofuran, benzene, hexane, octane and the like at temperatures ranging from room temperature to reflux, for a time period ranging from 1 hour to 48 hours (Angew. Chem. Int. Ed. 2002, 41 , 3056-3058; Tetrahedron Lett. 2002, 43, 5649-5651).
- catalyst such as [lr(COD)(OMe) 2 ], [lr(COD)CI 2 ]
- a ligand such as 2,2'-bipyridine (bpy), 4,4'-di-tert-but
- intermediates of formula (VIII) can be prepared by the following reactions: Step q): reaction of intermediates of formula (XXXII), wherein Y is carbon, R11 is hydrogen, iodine, bromine or chlorine and A, B and X are as defined above, to obtain intermediates of formula (XXXIII), wherein Y is carbon, R11 is hydrogen, iodine, bromine or chlorine, R10 is straight or branched (C1-C4) alkyl, and A, B and X are as defined above;
- intermediates of formula (XXXII) are submitted to esterification in alcohols such as methanol, ethanol, propanol and the like in the presence of an acid catalyst such as p-toluenesulfonic acid, sulforic acid, methansulfonic acid at temperatures ranging from room temperature to reflux, for a time period ranging from 1 hour to 48 hours.
- alcohols such as methanol, ethanol, propanol and the like
- an acid catalyst such as p-toluenesulfonic acid, sulforic acid, methansulfonic acid at temperatures ranging from room temperature to reflux, for a time period ranging from 1 hour to 48 hours.
- intermediates of formula (XXXII) can be converted into the corresponding acyl chloride in the presence of thionylchloride or oxalylchloride, with or without a catalytic amount of dimethylaminopyridine (DMAP), without a solvent or in solvents such as dichloromethane, toluene at temperatures ranging from room temperature to reflux and then treated with alcohols such as methanol, ethanol, propanol and the like.
- DMAP dimethylaminopyridine
- reaction can be performed with coupling reagents such as dicyclohexylcarbodiimide (DCC), in the presenze of a catalytic amount of dimethylaminopyridine (DMAP) in solvents like dichloromethane, dimethylformamide and the like at temperatures ranging from zero to room temperature, for a time period ranging from 1 hour to 48 hours.
- DCC dicyclohexylcarbodiimide
- DMAP dimethylaminopyridine
- the reaction can be performed as described for step p) of Scheme 5.
- the reaction can be performed in the presence of tnfluoromethansulfonic anhydride, N-phenyl-bis(trifluoromethanesulphonimide), using a base such as diisopropylethylamine (DIPEA), triethylamine (TEA), with or without a catalytic amount of dimethylaminopyridine (DMAP) in a solvent like dichloromethane, tetrahydrofuran at temperatures ranging from -78°C to room temperature for a time period ranging from 1 hour to 48 hours.
- DIPEA diisopropylethylamine
- TAA triethylamine
- DMAP dimethylaminopyridine
- step s) of Scheme 7 the protection of intermediates of formula (XXXVIb) to intermediates of formula (XXXVII) can be performed with reagents such as acyl chlorides, acetic anhydride, trifluoroacetic anhydride, di- tertbutylcarbamate or ethylchloroformate in the presence of a base such as triethylamine (TEA), diisoproprylamine
- reagents such as acyl chlorides, acetic anhydride, trifluoroacetic anhydride, di- tertbutylcarbamate or ethylchloroformate
- a base such as triethylamine (TEA), diisoproprylamine
- DIPEA DIPEA
- NaH sodium hydride
- DMAP dimethylaminopyridine
- solvents like dichloromethane, tetrahydrofuran, toluene and the like at temperatures ranging from -78°C to room temperature for a time period ranging from 1 hour to 48 hours.
- Step b' reaction of an intermediate of formula (XXXIXa), wherein Y is nitrogen, B is a 5- or 6-membered heteroaryl ring, R1 1 is hydrogen, iodine, bromine or chlorine and A and X are as defined above, with intermediates of formula (VII), wherein R6 is as defined above, to obtain intermediates of formula (XXXI), wherein Y is nitrogen, B is a 5- or 6- membered heteroaryl ring, R1 1 is hydrogen, iodine, bromine or chlorine, R5 is hydrogen and R6, A and X are as defined above;
- Step b' reaction of an intermediate of formula (XXXIXb), wherein Y is nitrogen, B is a 5- or 6-membered heterocyclyl ring, R1 1 is hydrogen, iodine, bromine or chlorine and A and X are as defined above, with intermediates of formula
- a compound of formula (I) To evaluate the antiproliferative activity of a compound of formula (I) the following human cell lines were used: A2780 ovarian carcinoma; TT medullary thyroid carcinoma, harboring a mutated RET-C634W receptor; LC-2/ad human lung adenocarcinoma, harboring the CCDC6-RET fusion protein. Exponentially growing cells were seeded and incubated at 37°C in a humidified 5% CO2 atmosphere using appropriate medium supplemented with 10% Fetal Bovine Serum.
- scalar doses of the compounds dissolved in 0.1% DMSO were added to the medium and cells were exposed to drugs for either 72 hours (A2780) or 144 hours (TT and LC-2/ad), according to their different proliferation rate.
- cell proliferation was determined by an intracellular ATP monitoring system (CellTiterGlo - Promega), following manufacturer's instructions, and using an Envision instrument (PerkinElmer) as reader. Data obtained from compound versus vehicle treated cells were compared using Assay Explorer (Symyx Technologies Inc) software. IC50 values were calculated using sigmoidal interpolation curve fitting.
- novel compounds of formula (I) of the invention appear to be particularly advantageous in the therapy of diseases caused by dysregulated protein kinase activity such as cancer.
- the compounds of the present invention can be administered either as single agents or, alternatively, in combination with known anticancer treatments such as radiation therapy or chemotherapy regimen in combination with, for example, antihormonal agents such as antiestrogens, antiandrogens and aromatase inhibitors, topoisomerase I inhibitors, topoisomerase II inhibitors, agents that target microtubules, platin-based agents, alkylating agents, DNA damaging or intercalating agents, antineoplastic antimetabolites, other kinase inhibitors, other anti-angiogenic agents, inhibitors of kinesins, therapeutic monoclonal antibodies, inhibitors of mTOR, histone deacetylase inhibitors, farnesyl transferase inhibitors, and inhibitors of hypoxic response.
- antihormonal agents such as antiestrogens, antiandrogens and aromatase inhibitors, topoisomerase I inhibitors, topoisomerase II inhibitors, agents that target microtubules, platin-based agents, alky
- such combination products employ the compounds of this invention within the dosage range described below and the other pharmaceutically active agent within the approved dosage range.
- the compounds of formula (I) of the present invention suitable for administration to a mammal, e.g. to humans, can be administered by the usual routes and the dosage level depends upon the age, weight, and conditions of the patient and administration route.
- a suitable dosage adopted for oral administration of a compound of formula (I) may range from about 10 mg to about 1g per dose, from 1 to 5 times daily.
- the compounds of the invention can be administered in a variety of dosage forms, e.g. orally, in the form tablets, capsules, sugar or film coated tablets, liquid solutions or suspensions; rectally in the form suppositories; parenterally, e.g. intramuscularly, or through intravenous and/or intrathecal and/or intraspinal injection or infusion.
- the present invention also includes pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable excipient, which may be a carrier or a diluent.
- a pharmaceutically acceptable excipient which may be a carrier or a diluent.
- compositions containing the compounds of the invention are usually prepared following conventional methods and are administered in a suitable pharmaceutical form.
- the solid oral forms may contain, together with the active compound, diluents, e.g. lactose, dextrose saccharose, sucrose, cellulose, corn starch or potato starch; lubricants, e.g. silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols; binding agents, e.g. starches, arabic gum, gelatine methylcellulose, carboxymethylcellulose or polyvinyl pyrrolidone; disintegrating agents, e.g.
- diluents e.g. lactose, dextrose saccharose, sucrose, cellulose, corn starch or potato starch
- lubricants e.g. silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols
- binding agents e.g. starches, arabic gum, gelatine methylcellulose, carboxymethylcellulose or polyvinyl pyr
- starch alginic acid, alginates or sodium starch glycolate
- effervescing mixtures dyestuffs; sweeteners; wetting agents such as lecithin, polysorbates, laurylsulphates; and, in general, non-toxic and pharmacologically inactive substances used in pharmaceutical formulations.
- These pharmaceutical preparations may be manufactured in known manner, for example, by means of mixing, granulating, tabletting, sugar-coating, or film-coating processes.
- liquid dispersions for oral administration may be, e.g. syrups, emulsions and suspensions.
- the syrups may contain, as a carrier, saccharose or saccharose with glycerine and/or mannitol and sorbitol.
- the suspensions and the emulsions may contain, as examples of carriers, natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose or polyvinyl alcohol.
- the suspension or solutions for intramuscular injections may contain, together with the active compound, a pharmaceutically acceptable carrier, e.g. sterile water, olive oil, ethyl oleate, glycols, e.g. propylene glycol and, if desired, a suitable amount of lidocaine hydrochloride.
- a pharmaceutically acceptable carrier e.g. sterile water, olive oil, ethyl oleate, glycols, e.g. propylene glycol and, if desired, a suitable amount of lidocaine hydrochloride.
- the solutions for intravenous injections or infusions may contain, as a carrier, sterile water or preferably they may be in the form of sterile, aqueous, isotonic, saline solutions or they may contain propylene glycol as a carrier.
- the suppositories may contain, together with the active compound, a pharmaceutically acceptable carrier, e.g. cocoa butter, polyethylene glycol, a polyoxyethylene sorbitan fatty acid ester surfactant or lecithin.
- a pharmaceutically acceptable carrier e.g. cocoa butter, polyethylene glycol, a polyoxyethylene sorbitan fatty acid ester surfactant or lecithin.
- Na2C03 sodium carbonate
- K2CO3 potassium carbonate
- DIPEA N,N-diisopropyl-N-ethylamine
- Hex hexane
- NaHC03 sodium bicarbonate
- OTf triflate group
- HPLC was performed on Waters X Terra RP 18 (4,6 x 50 mm, 3.5 ⁇ ) column using a Waters 2790 HPLC system equipped with a 996 Waters PDA detector and Micromass mod. ZQ single quadrupole mass spectrometer, equipped with an electrospray (ESI) ion source.
- Mobile phase A was ammonium acetate 5 mM buffer (pH 5.2 with acetic acid- acetonitrile 95:5), and Mobile phase B was water-acetonitrile (5:95). Gradient from 10 to 90% B in 8 min, hold 90% B 2 min. UV detection at 220 nm and 254 nm. Flow rate 1 mL/min.
- 6-(4-Amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-naphthalene-1-carboxylic acid isopropylamide (cmpd 5)
- 6-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-naphthalene-1-carboxylic acid 100 mg, 0.29 mmol
- DIPEA 0.198 mL, 1.16 mmol
- HBTU HBTU
- isopropylamine 0.05 mL, 0.58 mmol
Abstract
Description
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MX2017006366A MX2017006366A (en) | 2014-11-14 | 2015-11-12 | 6-amino-7-bicyclo-7-deaza-purine derivatives as protein kinase inhibitors. |
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CN107108631A (en) | 2017-08-29 |
CA2967125A1 (en) | 2016-05-19 |
AU2015345054B2 (en) | 2020-03-05 |
MX2017006366A (en) | 2018-02-01 |
CL2017001204A1 (en) | 2017-12-29 |
AU2015345054A1 (en) | 2017-06-29 |
US20170327506A1 (en) | 2017-11-16 |
KR20170082637A (en) | 2017-07-14 |
JP6421241B2 (en) | 2018-11-07 |
ES2792036T3 (en) | 2020-11-06 |
JP2017533932A (en) | 2017-11-16 |
CA2967125C (en) | 2022-10-25 |
EP3218378A1 (en) | 2017-09-20 |
EA201791018A1 (en) | 2018-03-30 |
EA039885B1 (en) | 2022-03-23 |
US10221181B2 (en) | 2019-03-05 |
CN107108631B (en) | 2020-06-16 |
PL3218378T3 (en) | 2020-10-19 |
EP3218378B1 (en) | 2020-01-08 |
KR102562866B1 (en) | 2023-08-04 |
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