WO2014106763A1 - Pyridopyrazines utilisés en tant qu'agents antinéoplasiques - Google Patents

Pyridopyrazines utilisés en tant qu'agents antinéoplasiques Download PDF

Info

Publication number
WO2014106763A1
WO2014106763A1 PCT/HU2014/000003 HU2014000003W WO2014106763A1 WO 2014106763 A1 WO2014106763 A1 WO 2014106763A1 HU 2014000003 W HU2014000003 W HU 2014000003W WO 2014106763 A1 WO2014106763 A1 WO 2014106763A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
pyrido
substituted
pyrazine
heterocyclyl
Prior art date
Application number
PCT/HU2014/000003
Other languages
English (en)
Inventor
László KÉKESI
Anna SIPOS
Gábor NÉMETH
János PATÓ
György Kéri
László ŐRFI
Original Assignee
Vichem Chemie Kutató Kft.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Vichem Chemie Kutató Kft. filed Critical Vichem Chemie Kutató Kft.
Publication of WO2014106763A1 publication Critical patent/WO2014106763A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to pyridopyrazine derivatives of the general formula (I) and solvates, hydrates and pharmaceutically acceptable salts thereof, , the use of them in the prevention and/or the treatment of cancer diseases, as well as pharmaceutical compositions containing at least one of them as pharmaceutically active agent(s) together with pharmaceutically acceptable carrier, excipient and/or diluents, especially for the prevention and/or treatment of cancer diseases.
  • Said pyridopyrazine compounds have been identified as new drug candidates for the prevention and/or treatment of cancer diseases.
  • Cancer is the malignant growth in any kind of tissues in the whole body system. It is characterized by unregulated proliferation of cells, which leads lethal disease. It is getting a major public health problem in the developed countries. Currently, one in four deaths is due to cancer 1 . Estimated worldwide cancer cases are about 12.7 million and cancer deaths 7.6 million cases per year. In most of the countries cancer is second as cause of death 2 . It can appear in any tissue of body. Each cancer is developed from a single cell and form a group of cells display uncontrolled growth through division beyond normal limits, invasion that intrudes upon and destroys adjacent tissues, and sometimes metastasis, in which cancer cells spread to other locations in the body via lymph or blood.
  • Initiation factors causing cancer such as exposure to radiation or certain chemical substances, smoking, dietary habits, infection, have been described in many studies. In the first place environmental and occupational effect must be identified and eliminated as prevention 3 4 .
  • Tumor cells differ from normal cells in their lack of the right function. Other physiological differences of normal and tumor cells that tumor cells have lower pH, different ion composition, higher free radical and methylated nucleotides character, higher microproteins and mucopolysacharides concentration, tumor associated antigens, produce hormone peptides 5 .
  • Treatments of cancer diseases are cancer surgery, radiology, and drug therapy.
  • cancer chemotherapy Three groups of drugs can be separated in the history of cancer therapy: cancer chemotherapy, endocrine manipulation and cancer biotherapeutics.
  • Chemotherapy drugs alkylating agents such as busulfan, chlorambucil, streptozotocin, temozolomide, are reactive alkyl-groups that can bind to cellular nucleophilic sites, such as bases in DNA.
  • Platinum derivatives such as oxaliplatin, satraplatin, induce their cell killing effects through the development of covalent bifunctional DNA adducts with cellular DNA.
  • Antimetabolites inhibit vital pathway in the cell function such as methotrexate is a dihydrofolate reductase inhibitor, pemetrexed is an antifolate analogue, 5-fuorouracil is a thymidylate synthase inhibitor and incorporate in nucleic acids, as well as nucleoside analogues, such as cytarabine 6-thiopurnes, and cladribine is a purine deoxyadenosine analogue.
  • Topoisomerase-interacting agents such as epipodophyllotoxins, anthracenediones, anthracyclines, camptothecins, are modify these enzymes that alter the topology and due to the double-helical structure of DNA.
  • Antimicrotubule agents such as taxanes, vinca alkaloids, estramustine phosphate, epothilones, LY355703, take part in inhibiting function of microtubules that play a critical role in cell division, directional transports, signaling, cell shape, and polarity. Discrimination between cancer cells and normal, rapidly dividing cells can be increased by small-molecule tyrosine kinase inhibitors, such as imatinib, dasatinib, gefitinib, erlotinib, lapatinib, sunitinib, sorafenib, targeting signal pathways.
  • small-molecule tyrosine kinase inhibitors such as imatinib, dasatinib, gefitinib, erlotinib, lapatinib, sunitinib, sorafenib, targeting signal pathways.
  • Signal transduction can also be targeted by monoclonal antibodies, such as cetuximab, panitumumab, trastuzumab, bevacizumab.
  • Inhibiting proteasome (responsibel protein degradation) activity is a method to follow the mechanism of act of natural agents, such as bortezomib.
  • Further chemotherapic drugs are L-asparaginase that depletes circulating pools of L-asparagine, bleomycin that forms oxygen free radicals, causes DNA breaks and procarbazine that is a nonclassis alkylating agent.
  • hormonal agents used such as aromatase inhibitors, antiandrogens, tamoxifen, toremifene, raloxifene, fulvestrant, megestrol.
  • Cancer biotherapeutic agents have biological origin. Interferons affect the immune system and have direct cytostatic and cytotoxic properties. Interleukins promote inflammation and hematopoietic cells enhance tumor reactivity. G3139 is the object of many studies. Anticancer antisense oligonucleotide down-regulate Blc-2 protein - binding sense mRNA - and decrease resistance and apoptosis prevention in cancer cells.
  • Some of these drugs act as angiogenesis inhibitors, such as monoclonal antibody bevacizumab, kinase inhibitor sorafenib via inhibiting signal pathway through vascular endothelial growth factor, and thalidomide immunomodulatory agent.
  • angiogenesis inhibitors such as monoclonal antibody bevacizumab, kinase inhibitor sorafenib via inhibiting signal pathway through vascular endothelial growth factor, and thalidomide immunomodulatory agent.
  • viruses Human papillomavirus 6 .
  • Gefitinib is a small-molecule tyrosine kinase inhibitor, the first selective inhibitor of epidermal growth factor receptor's (EGFR) tyrosine kinase domain 7 .
  • Gefitinib is currently marketed in over 64 countries. In Europe gefitinib is indicated since 2009 in advanced Non-small-cell lung carcinoma (NSCLC) in all lines of treatment for patients harbouring EGFR mutations. This label was granted after gefitinib demonstrated as a first line treatment to significantly improve progression-free survival vs. a platinum doublet regime in patients harbouring such mutations 8 9 . Studies confirmed gefitinib superiority in this patient population 10 . Gefitinib is indicated in all lines of therapy, patients presenting for the first time with advanced NSCLC can now be offered an orally administered drug rather than conventional chemotherapy 11 .
  • NSCLC Non-small-cell lung carcinoma
  • Eriotinib is other EGFR inhibitor that follows gefitinib, which was the first drug of this type. Eriotinib also targets specifically the EGFR tyrosine kinase. It binds in a reversible fashion to the adenosine triphosphate (ATP) binding site of the receptor 12 . Eriotinib has shown a survival benefit in the treatment of lung cancer in phase III trials. Eriotinib was found that added to chemotherapy improved overall survival by 19%, and improved progression-free survival by 29%, when compared to chemotherapy alone 13 14 5 . The U.S. Food and Drug Administration approved eriotinib in combination with gemcitabine for treatment of locally advanced, unresectable, or metastatic pancreatic cancer in 2005 16 .
  • Bl 2536 is also a small-molecule kinase inhibitor.
  • Bl 2536 is a Dihydropteridinone derivative. It is an ATP-competitor that inhibits polo-like kinase 1 (PLK1 ) with in vitro and in vivo potency.
  • IC 50 value the concentration of the compound which reduces the enzyme activity by half - is 0.8 nM. It shows at least 10,000- fold selectivity for PLK1 against a panel of tyrosine- and serine/threonine-kinases.
  • Bl 2536 inhibits the proliferation of a broad range of human cancer cell lines, irrespective of their tissue origin and oncogenome status, with EC 50 values ranging from 2 to 25 nM.
  • EC 50 values ranging from 2 to 25 nM.
  • multiple human carcinoma xenograft models that use immunodeficient mice the intravenous administration of Bl 2536 once or twice weekly at well-tolerated doses has been shown to result in a strong inhibition of tumour growth and/or tumour regression.
  • Bl 2536 is already tested in clinical Phase I dose-escalation trials and has been found to be well tolerated, with a dose dependent and reversible neutropaenia being the main side effect (which is an expected finding for this class of compounds) 17 .
  • Bl 2536 is currently being tested in clinical phase II trials of acute myeloid leukemia, non-small-cell lung carcinoma, pancreatic neoplasms, prostatic neoplasms, breast cancer, endometrial cancer, head and neck cancer, melanom
  • the antimetabolite and antifolate drug methotrexate have hetero-condensed pyrazine structure. It is used neoplastic disorders, such as acute lymphoblastic leukemia 20 21 .
  • 2,3,7-Tri-thiophen-2-yl-pyrido[2,3-b]pyrazine is described as a PKB kinase inhibitor, and shows 0.1 ⁇ in MCF-7 cells expressing myristoylated PKBa cell based assay measured as IC 50 22 .
  • Fig.5. 2,3, 7-Tri-thiophen-2-yl-pyrido[2,3-b]pyrazine Cancer is a leading cause of human death and suffering, often due to the limited efficacy of existing treatment methods.
  • cancers only a subset of malignant cells has the potential to proliferate indefinitely and induce macroscopic metastases or to cause tumor recurrence after treatment.
  • This subset of cells often called cancer stem cells (CSC), that needs to be targeted and eliminated in order to achieve cures, since the remaining cancer cells (called non-tumorigenic cells) are finally stop dividing or die.
  • CSC cancer stem cells
  • the cancer stem cell theory has changed views of tumor initiation, cancer progression, and therapeutic resistance, with a view to develop novel CSC-directed therapeutics that might synergize with currently available treatments targeted to cancer bulk populations, and that might serve to improve clinical cancer therapy. This hypothesis suggests that agents targeting these cells should ultimately lead to improved outcomes for cancer patients.
  • CSC acute myelogenous leukemia
  • AML acute myelogenous leukemia
  • CSC-enriched populations were isolated from many other human malignancies (brain, prostate, colon, head and neck, pancreas, and liver).
  • cancers may also be maintained by stem cells: I.) according to an observation tumor cells are heterogeneous in their capacity to give rise to tumors upon transplantation or to form colonies in culture assays. For in vivo tumor transplantation, this is reflected in the large numbers of tumor cells that must usually be transplanted to form a tumor. II.) tumors often recapitulate the histologic and molecular heterogeneity of the normal tissue from which they are derived. Cancers form morphologically and phenotypically heterogeneous cell populations. Cancer cells may also exhibit functional heterogeneity, as it comes from divergent in vitro clonogenic and proliferative capacities and varying in vivo tumorigenic potentials. CSCs have an exclusive capacity to initiate tumors and drive neoplastic proliferation; have the potential to create endless copies of themselves, and have the ability to give rise to more non-stem cancer cell through a process termed differentiation.
  • CSC-associated resistance mechanisms have been established in solid tumors and in hematological malignancies. Rapidly dividing cells have been known to be more sensitive to cytotoxic therapies than non-dividing cells. Drug- resistant phenotype of physiological stem cells suggest the hypothesis that CSC might also represent a subpopulation within cancers.
  • CSCs can be characterized by increased resistance to chemo- and radiotherapy. Hindered CSC resistance mechanisms may result higher cure rates in cytotoxic therapies. Signals that regulate CSC resistance to chemo- or radiotherapy can be the target of CSC- directed therapeutic strategies.
  • CSC-targeting therapies might not necessarily reduce tumor in the short term. Cancer treatments that target CSC through specific markers or signaling pathways critically involved in CSC function could potentially increase the efficacy of current forms of therapy, by reducing the risk of relapse and dissemination. Combination therapies that involve both CSC-directed and tumor bulk- targeted agents would be expected to be more effective in clinical treatment responses and patient outcomes 23 24
  • Recurrence after gefitinib and/or erlotinib treatment is a published problem 25 .
  • a tiny portion of tumour cells always survive the treatment and therefore can cause resistant recurrence and/or metastasis. The rate of this tiny portion depends on different intrinsic and extrinsic factors 26 .
  • This portion of tumour cells express more survival factors and be more protected than the therapy-sensitive tumour cells, and this is a problem of further therapy for complete healing. Due to their complex survival factors, they can adapt and survive even after radiation therapy and/or chemotherapy, causing recurrence under favorable conditions.
  • the cancer cell population have defined mutations and/or amplifications, the bulk of first generation of the tumour can be eliminated by inhibitor drugs of the target that responsible for the strongest driving force mutation. After a while, a second generation can grow up driven by the signals that did't inhibited. We have to block these signals together at the same time to eliminate the first-treatment resistant cells. Since healthy cells are not dependent on these signals they can survive the treatment 27 .
  • the present invention relates to compounds of the general formula (I) and their solvates, hydrates and pharmaceutically acceptable salts:
  • R-i is substituted or unsubstituted heterocyclyl, with the exception of S-containing heterocyclyl groups;
  • R 2 is hydrogen, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl;
  • R 3 is hydrogen, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl; wherein the heterocyclyl is selected from the group of ring systems containing 4 to 9 carbon atoms and 1 to 4 hetero atom(s) which are selected from the group of N, O and S;
  • aryl selected from the group of aromatic monocyclic or multicyclic ring systems comprising 6 to about 14 carbon atoms.
  • N is nitrogen
  • O oxygen
  • S sulfur atom
  • the heterocyclyl group can be saturated, partially unsaturated or aromatic
  • heterocyclyl is selected from the group of indolyl, indazolyl, 1 ,3-benzodioxolyl, 1 ,4-benzodioxinyl, dihydro-1 ,4-benzodioxinyl, quinolinyl, isoquinolinyl, benzodioxolyl, pyridinyl, dihydropyridinyl, tetrahydropyridinyl, and thienyl.
  • the 1 ,3-benzodioxolyl is preferred.
  • the heterocyclyl is selected from the group of indolyl, indazolyl, 1 ,3-benzodioxolyl, 1 ,4-benzodioxinyl, dihydro-1 ,4-benzodioxinyl, quinolinyl, isoquinolinyl, benzodioxolyl, pyridinyl dihydropyridinyl, tetrahydropyridinyl.
  • thienyl and furanyl is a specific example, preferably thienyl. 3.
  • the substituent is halogen (e.g. fluoro), C -3 alkyl, e.g. methyl, or the alkyl is optionally substituted with carboxylate, e.g. ethyl-propanoate or a saturated ring system containing 4 to 6 carbon atoms and 1 to 3 nitrogen atom(s) (e.g. piperazinyl).
  • saturated heterocyclyl selected from the group of ring systems containing 4 to 9 carbon atoms and 1 to 4 hetero atom(s) which are selected from the group of N, O or S. 6.
  • saturated heterocyclyl is selected from the group of ring systems containing 4 to 6 carbon atoms and 1 to 2 hetero atom(s) selected from the group of N, O and S, especially N and O, e.g. piperidinyl or morpholino.
  • alkylcarbonyl e.g. methylcarbonyl
  • alkoxycarbony! e.g. terc-butylcarbonyl
  • heterocyclyl selected from the group of ring systems containing 4 to 9 carbon atoms and 1 to 4 hetero atom(s) which are selected from the group of N, O or S, which is optionally substituted with alkyl, oxo, alkoxy, halogen, hydroxyl, especially with alkyl.
  • saturated heterocyclyl is selected from the group of ring systems containing 4 to 6 carbon atoms and 1 to 2 hetero atom(s) which are selected from the group of N, O and S, especially N and O, e.g. piperidinyl, piperazinyl, pyrrolidinyl and morpholino, which groups can be optionally substituted with alkyl, e.g. methyl or oxo.
  • Another subject of the invention is providing pharmaceutical composition containing as active ingredient one or more compound(s) of general formula (I) together with one or more usual pharmaceutical auxiliary material(s).
  • auxiliary material is those which are generally applied in the preparation of pharmaceutical compositions, e.g. carriers, diluents, vehicles, coloring agents, flavoring agents, stabilizers, surfactants, carriers for the preparation of sustained release compositions etc. Further details can be found in the following book: Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990, Volume 5., Chapter 25.2).
  • a method for preventing and/or treating cancerous disease comprises administering to the mammal an amount of at least one compound of the present invention, effective to prevent and/or treat said cancerous disease (discussed in details above).
  • cancer embraces adenocarcinomas (breast, colon, colorectal and colorectal adenocarcinoma, epidermoid, lung bronchioalveolar and lung adenocarcinoma), the cancerous disease of the genital system (including uterine cervix, uterine corpus, ovary, vulva, vagina and other genital female, prostate, testis, penis and other genital male), digestive system (including esophagus, stomach, small intestine, colon, rectum, anus anal canal and anorectum, liver and intrahepatic bile duct, gallbladder and other biliary, pancreas, other digestive organs), respiratory system (including larynx, lung and bronchus, other respiratory organs), breast, urinary system (including urinary bladder, kidney and renal pelvis, ureter and other urinary organs), skin (excluding basal and squamous
  • heterocyclyl alone or in combination, means a group derived from a saturated, partially unsaturated or aromatic ring system with 4 to 9 carbon atoms and 1 to 4 or 1 to 3 or 1 or 2 heteroatom(s) selected from the group of N, O and S [i.e.
  • N nitrogen
  • O oxygen
  • S sulfur
  • indolyl 2-oxo-1 ,3-dihydroindolyl
  • indazolyl 1 ,3- benzodioxolyl, dihydro-1 ,4-benzodioxinyl, furanyl, pyrrolyl, pyridinyl, dihydropyridinyl, tetrahydropyridinyl, quinolinyl, isoquinolinyl, pyranyl, oxazinyl, imidazolyl, benzoimidazolyl, pyrazolyl, purinyl, thienyl where indolyl, 2-oxo-1 ,3-dihydroindolyl, indazolyl, 1 ,3-benzodioxolyl, pyridinyl, dihydropyridinyl, tetrahydropyridin
  • R-i saturated, partially unsaturated or aromatic ring system with 4 to 9 carbon atoms and 1 to 3 or 1 or 2 or 1 heteroatom(s) selected from the group of N and O
  • More specific examples can be selected from the following group: indolyl, indazolyl, 1 ,3-benzodioxolyl, 1 ,4-benzodioxinyl, dihydro-1 ,4-benzodioxinyl, quinolinyl, isoquinolinyl, benzodioxolyl, pyridinyl dihydropyridinyl and tetrahydropyridinyl.
  • R 2 and R 3 aromatic or unsaturated ring system with 4 to 5 carbon atoms and 1 to 3 or 1 or 2 heteroatom(s) selected from the group of N, O and S.
  • the ring system contains 4 to 5 carbon atoms and 1 heteroatom selected from the group of 0 and S, e.g. thienyl, where furanyl is a more specific example, preferably thienyl.
  • substituted heterocyclyl groups are also within the scope which contain one or more substituent(s) usually applied in the organic chemistry for substitution of heterocyclyl groups.
  • the substituted heterocyclyl groups carry one or more, preferably 1 to 4 substituent(s), e.g. 1 to 3 or 1 to 2 substituent(s), independently selected from the group of halogen, alkyl, hydroxy!, hydroxyalkyl, saturated, partially unsaturated or aromatic ring systems containing 4 to 6 carbon atoms and 1 to 3 nitrogen atom(s), e.g.
  • morpholinyl piperidinyl, piperazinyl, methylpiperazinyl [preferably the substituent is halogen, more preferably a saturated ring system containing 4 to 6 carbon atoms and 1 to 3 nitrogen atom(s)], carboxyl, alkoxy, haloalkyl, nitro, sulphate, amino, acylamino, carboxylate (alkoxycarbonyl), alkyl-carboxilate (alkyl optionally substituted with alkoxycarbonyl), optionally substituted amide, monoalkylamino, dialkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl and cyano, where alkyl (more preferably methyl), carboxyl, carboxylate, alkyl-carboxilate (e.g.
  • amide optionally substituted amide, halogen, acetyl, hydroxyalkyl, piperazinyl, methylpiperazinyl are preferred [especially C 1-3 alkyl, e.g. methyl, halogen (e.g. fluoro) or a saturated ring system containing 4 to 6 carbon and 1 to 3 N (e.g. piperazinyl)].
  • halogen e.g. fluoro
  • N e.g. piperazinyl
  • substituted or unsubstituted aryl alone or in combinations means an aromatic monocyclic or multicyclic ring system comprising 6 to 14 carbon atoms, preferably 6 to 10 carbon atoms.
  • suitable aryl groups include phenyl, and naphthyl, where phenyl is a preferred embodiment.
  • substituted aryl groups are also within the scope which contain one or more substituent(s) usually applied in the organic chemistry for substitution of aryl groups. So, the substituted aryl groups carry one or more, preferably 1 to 4, e.g. 1 to 3 or 1 to 2 substituent(s), independently selected from the group of halogen, optionally substituted alkyl, hydroxyl, optionally substituted saturated heterocyclyls, e.g.
  • morpholinyl piperazinyl, piperidinyl, methylpiperazinyl, carboxyl, optionally substituted alkoxycarbonyl, optionally substituted alkoxy, haloalkyi, nitro, sulphate, amino, optionally substituted amide, acylamino, monoalkylamino, dialkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl and cyano.
  • the substituent of the aryl can be optionally substituted alkyl (more preferably methyl and trifluoromethyl), halogen, hydroxyl, morpholinyl, piperidinyl, alkoxy (more preferably methoxy), nitro, carboxyl, alkoxycarbonyl, e.g. metoxycarbonyl or butoxycarbonyl, amino, optionally N-substituted amide.
  • the substituent of the aryl group can be an N-substituted amide group.
  • a preferred substituent of the amide group is an alkyl group, which alkyl can be further substituted with a substituent selected from following group: amino, optionally substituted with 1 or 2 alkyl, alkylcarbonyl or alkoxycarbonyl group(s) [forming e.g. aminoethyl, (dimethylamino)propyl, 2- acetamidoethyl substituent on the amide group]; saturated heterocyclyl selected from the group of ring systems containing 4 to 9 carbon atoms and 1 to 4 hetero atom(s) which are selected from the group of N, O or S.
  • the preferred heterocyclyl ring systems can be e.g. morpholinyl, piperazinyl, piperazinyl, piperidinyl, pyrrolidinyl, which groups optionally may be substituted with alkyl, e.g. with methyl) or 1 to 3 oxo.
  • the aryl group can also be substituted with C -4 alkylenedioxy, e.g. with 1 ,3-benzodioxolyl or dihydro-1 ,4-benzodioxinyl.
  • C 1-4 alkylenedioxy means a -0-(CH 2 ) n -0- group, where n is 1 , 2, 3 or 4.
  • R 2 and R 3 when they are selected from the above possibilities, can be the same or different.
  • halogen means fluorine, chlorine, bromine or iodine.
  • alkyl alone or in combinations means a straight or branched-chain alkyl group containing from 1 to 6, preferably 1 to 5 carbon atom(s) (i.e. "C 1-6 " or “Ci_ 5 " alkyl groups), such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, f-butyl and pentyl.
  • this phrase can relate to alkyl groups containing from 1 to 4, or 1 to 3 or 1 to 2 carbon atom(s) (i.e. "C -4 " or "C1.3” or "C 1-2 " alkyl groups).
  • substituted alkyl groups are also within the scope which contain one or more substituent(s) usually applied in the organic chemistry for substitution of alkyl groups. So, the substituted alkyl groups carry one or more, preferably one or two substituent(s), independently selected from the group of halogen, aryl, hydroxyl, carboxyl, carboxylate, benzyloxy, alkoxy, nitro, sulphate, amino, acylamino, monoalkylamino, dialkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl and cyano.
  • alkoxy means an alkyl-O- group in which the alkyl group is as previously described.
  • suitable alkoxy groups include methoxy, ethoxy, n- propoxy, isopropoxy and n-butoxy.
  • the bond to the parent moiety is through the ether oxygen. If the alkoxy group is substituted with halogen then it is named as haloalkoxy group.
  • salt means any ionic compound formed between one of the embodiments of the present invention and an acidic or basic molecule that can donate or accept ionic particle to/from its partner.
  • the quaternary amine salts are also inculded.
  • Salts of the compounds of the formula (I) may be formed, for example, by reacting a compound of formula (I) with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.
  • Exemplary acid addition salts include acetates, adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides, hydrobromides, hydroiodides, 2-hydroxyethanesulfonates, lactates, maleates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oxalates, pectinates, persulfates, 3- phenylpropionates, phosphates
  • solvate means a compound formed by the combination of solvent molecules with molecules or ions of the solute (solvation).
  • Solute can be any of the embodiments of the present invention and the solvent can be water (forming hydrates) or any organic solvent.
  • 1 -(5-Bromo-2-fluorophenyl)ethanone was synthesized via the reaction where 1 -(5-bromo-2- fluorophenyl)ethanol was oxygenated with manganese dioxide.
  • the reaction was carried out according to available literature 28 .
  • R' can be e.g. 2-methoxy, 3-chloro, 4-carboxyl, 4-fluoro-, 4-(trifluoromethyl), 4-methoxy, 4- hydroxy, 4-nitro-, 4-morphotin-4-yl, 4-methyl, 4-chloro- and according to General method A2 4-piperidin-
  • the compounds were synthesized via the reaction where a mixture of corresponding substituted or unsubstituted oxalaldehyde (0-10% excess compared to substituted pyridine-2,3-diamine, e.g. 10%), 7-halogen substituted pyridine-2,3-diamine in proper solvent (e.g. C C 4 alcohols, e.g. EtOH (ethanol)) was at appropriate temperature (e.g. 0 to 80 °C) as long as the 7-halogen substituted pyridine-2,3-diamine component disappeared (followed by TLC). The mixture was cooled, filtered and washed three times with solvent. The product was dried in vacuum to afford corresponding substituted 7-bromopyrido[2,3-6]pyrazine. In case of regioisomers occured, they could be separated by chromatography.
  • proper solvent e.g. C C 4 alcohols, e.g. EtOH (ethanol)
  • Z can be halogen e.g. bromo, or in some synthetic methods Ri is heteroaryl as it is given in Table 1 e.g.
  • the corresponding activated carboxylic acid derivative was made from the corresponding carboxylic acid in appropriate anhydrous solvent or mixture of solvents (e.g. anhydrous THF (tetrahydrofuran), dichloromethane, chloroform, dioxane, acetonitrile, DME (1 ,2-dimethoxyethane), DMF (dimethylformamide), dimethyl sulfoxide, 1 ,2-dichloroethane, ethyl acetate).
  • anhydrous solvent or mixture of solvents e.g. anhydrous THF (tetrahydrofuran), dichloromethane, chloroform, dioxane, acetonitrile, DME (1 ,2-dimethoxyethane), DMF (dimethylformamide), dimethyl sulfoxide, 1 ,2-dichloroethane, ethyl acetate.
  • anhydrous solvent or mixture of solvents e.g. anhydrous THF (te
  • carboxylic acids can be converted to acyl chlorides with e.g. thionyl chloride, phosphoryl chloride, oxalyl chloride, preferably activator 1 ,1'-carbonylbis(1 /-/-imidazole).
  • thionyl chloride phosphoryl chloride
  • oxalyl chloride preferably activator 1 ,1'-carbonylbis(1 /-/-imidazole).
  • the solution was stirred at appropriate temperature (e.g. 35 to 90 °C) until corresponding carboxylic acid reagent was disappeared (followed by TLC).
  • activated carboxylic acid derivative e.g.
  • the corresponding activated carboxylic acid derivative was made from the corresponding carboxylic acid in appropriate anhydrous solvent or mixture of solvents (e.g. anhydrous THF, dichloromethane, chloroform, dioxane, acetonitrile, DME, DMF, dimethyl sulfoxide, 1 ,2-dichloroethane, ethyl acetate).
  • anhydrous solvent or mixture of solvents e.g. anhydrous THF, dichloromethane, chloroform, dioxane, acetonitrile, DME, DMF, dimethyl sulfoxide, 1 ,2-dichloroethane, ethyl acetate.
  • the activator can be a carbonyl imidazolide, carbodiimide derivative (e.g.
  • carboxylic acids can be converted to acyl chlorides with e.g. thionyl chloride, phosphoryl chloride, oxalyl chloride, preferably activator 1 ,1 '-carbonylbis(1 /-/-imidazole).
  • thionyl chloride phosphoryl chloride
  • oxalyl chloride preferably activator 1 ,1 '-carbonylbis(1 /-/-imidazole).
  • the solution was stirred at appropriate temperature (e.g. 35 to 90 °C) until corresponding carboxylic acid reagent was disappeared (followed by TLC).
  • activated carboxylic acid derivative e.g.
  • a mixture of the corresponding carboxylic acid (0.80 mmol) and 1 ,1 '- carbonylbis(I H-imidazole) (108 mg, 0.88 mmol) in 40 ml anhydrous dichloromethane and 40 ml anhydrous THF was refluxed and stirred for 7 hours.
  • the corresponding alcohol (0.93 mmol) was added in anhydrous THF.
  • the mixture was stirred and refluxed 24 hours then allowed to flow through a column with basic aluminium oxide.
  • the solvent was removed under reduced pressure, and the residue was purified with column chromatography (gradient eluent was chloroform:methanol 20:1 - 10:1 - 10:1 + 1 % triethylamine). Solids yielded the corresponding ester.
  • R'" can be e.g. hydroxyl or pinacolato ester of boronic acid
  • a mixture of the corresponding substituted 7-halogen substituted-pyrido[2,3-£>]pyrazine and catalyst (10% of the applied pyrido[2,3-£>]pyrazine compound) in appropriate solvent e.g. THF, dioxane, acetonitrile, DME, DMF, ethyl acetate
  • solvent e.g. THF, dioxane, acetonitrile, DME, DMF, ethyl acetate
  • a mixture of the corresponding substituted 7-bromopyrido[2,3- bjpyrazine (1.22 mmol), Pd(PPh 3 ) 4 (80 mg, 0.07 mmol) in DME (20 ml) was stirred for 1 hour in argon atmosphere at ambient temperature.
  • the corresponding boronic acid material (1 .56 mmol) and 0.66 M aqueous Na 2 C0 3 solution (2.20 ml, 3.35 mmol) were added, and it was stirred in argon atmosphere at 78-82 °C till the substituted 7-bromopyrido[2,3-b]pyrazine component disappeared (followed by TLC, in general 2 - 24 hours) .
  • Ethyl 3-(2-thienyl)propanoate was synthesized with thionyl chloride and methanol from 3-(2- thienyl)propanoic acid. The reaction was carried out according to available literature 36, 37, 38 .
  • 3-(2-thienyl)propanoic acid diethyl 3,3'-[(1 ,2-dioxoethane-1 ,2-diyl)dithiene-5,2-diyl]dipropanoate was synthesized via Friedel-Crafts reaction with ethanedioyl dichloride and aluminium chloride from ethyl 3-(2-thienyl)propanoate. The reaction was carried out according to available literature 39 .
  • UV detector Waters 996 DAD
  • Solvent I Water/ 0.1 % HCOOH
  • Source block temperature 110 °C
  • Desolvation temperature 250 °C Desolvation gas: 500 L/h Cone gas: 80 L/h Capillary voltage: 3000 V Cone voltage: 30 V Extractor voltage: 6 V Rf lens voltage: 0.1 V Scan: 80 to 1000 m/z in 1 Inter-scan delay: 0.1 s
  • Human cultured cancer cell lines A549, H358 were obtained from the American Type Culture Collection (ATCC, Rockville, MD, USA). Tumor cells were cultured in their respective culture medium recommended by ATCC, supplemented with 10% heat-inactivated fetal bovine serum (FBS), (Gibco, Invitrogen, Grand Island, NY, USA) and 1 % Antibiotic-Antimycotic Solution (Gibco, Cat. No: 15240062).
  • FBS heat-inactivated fetal bovine serum
  • the human cultured cell line HCC827 was a kind gift from the 1 st Department of Pathology and Experimental Cancer Research.
  • the A549 cell line was maintained in Dulbecco's Modified Eagle Medium (DMEM) (Sigma Aldrich, St.
  • DMEM Dulbecco's Modified Eagle Medium
  • H358 and HCC827 cell lines were cultured in RPMI-1640 medium (Sigma Aldrich, St. Louis, MO, USA). All cell lines were stored in a humidified 37 °C incubator with 5% C0 2 .
  • Cell viability was determined with CellTiter-Glo Luminescent Cell Viability Assay Kit (PROMEGA Lot 305189). In the presence of ATP (from living cells) Mg 2+ and 0 2 the luciferase catalises the mono-oxygenation of luciferin to oxyluciferin. The luminescence signal was detected by Analyst ® GT Multimode Reader.
  • Cionogenic assay is based on colony-forming ability of a single cell and it describes the proliferating potential of the compound treated cells.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des dérivés de pyridopyrazine et des solvates, des hydrates et des sels pharmaceutiquement acceptable de ceux-ci, leur utilisation pour prévenir et/ou traiter des maladies cancéreuses, ainsi que des compositions pharmaceutiques contenant au moins l'un de ces éléments utilisé en tant qu'agent pharmaceutiquement actif conjointement avec des véhicules, des excipients et/ou des diluants pharmaceutiquement acceptables, en particulier pour prévenir et/ou traiter des maladies cancéreuses.˙
PCT/HU2014/000003 2013-01-07 2014-01-07 Pyridopyrazines utilisés en tant qu'agents antinéoplasiques WO2014106763A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
HUP1300006 2013-01-07
HUP1300006 2013-01-07

Publications (1)

Publication Number Publication Date
WO2014106763A1 true WO2014106763A1 (fr) 2014-07-10

Family

ID=89666418

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/HU2014/000003 WO2014106763A1 (fr) 2013-01-07 2014-01-07 Pyridopyrazines utilisés en tant qu'agents antinéoplasiques

Country Status (1)

Country Link
WO (1) WO2014106763A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104610229A (zh) * 2015-01-21 2015-05-13 上海皓元生物医药科技有限公司 一种是atp竞争性小分子akt抑制剂a443654的合成方法
CN107501191A (zh) * 2017-08-15 2017-12-22 上海开荣化工科技有限公司 氰霜唑的合成工艺

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005007099A2 (fr) * 2003-07-10 2005-01-27 Imclone Systems Incorporated Inhibiteurs de la pkb utilises comme agents antitumoraux

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005007099A2 (fr) * 2003-07-10 2005-01-27 Imclone Systems Incorporated Inhibiteurs de la pkb utilises comme agents antitumoraux

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
KUMARI SHARDA ET AL: "Cine and normal substitution reactions on substituted 7-bromo-5-azaquinoxalines by secondary amines", INDIAN JOURNAL OF CHEMISTRY B, NATIONAL INSTITUTE OF SCIENCE COMMUNICATION AND INFORMATION RESOURCES, CSIR, NEW DELHI, INDIA, vol. 31B, no. 2, 1 January 1992 (1992-01-01), pages 92 - 97, XP009176698, ISSN: 0376-4699 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104610229A (zh) * 2015-01-21 2015-05-13 上海皓元生物医药科技有限公司 一种是atp竞争性小分子akt抑制剂a443654的合成方法
CN107501191A (zh) * 2017-08-15 2017-12-22 上海开荣化工科技有限公司 氰霜唑的合成工艺

Similar Documents

Publication Publication Date Title
RU2747260C2 (ru) Ингибитор рфрф4, способ его получения и его фармацевтическое применение
US9566277B2 (en) Methods of using phthalazinone ketone derivatives
CN107427521B (zh) 细胞周期蛋白依赖性激酶的抑制剂
DK2947086T3 (en) UNKNOWN CONDENSED PYRIMIDINE COMPOUND OR SALT THEREOF
ES2536313T3 (es) Imidazo[4,5-c]quinolinas como inhibidores de ADN–-PK
ES2558780T3 (es) Imidazopiridazinas como inhibidores de la cinasa Akt
JP7247092B2 (ja) キナーゼ阻害剤としての置換された縮合ヘテロアリール化合物及びその用途
JP2018522866A (ja) ４，６−ピリミジニレン誘導体およびこれらの使用
Hou et al. Design, synthesis and biological evaluation of novel 7-amino-[1, 2, 4] triazolo [4, 3-f] pteridinone, and 7-aminotetrazolo [1, 5-f] pteridinone derivative as potent antitumor agents
CN113454080A (zh) 化合物、药物组合物和制备化合物的方法以及其使用方法
ES2762641T3 (es) Inhibidores de proteína quinasa de 2-aminopiridina sustituida con piridina
JP2018522867A (ja) 縮合二環式ピリミジン誘導体およびこれらの使用
JP2022532342A (ja) 抗がん核内ホルモン受容体標的化化合物
US20170101418A1 (en) Thienopyranones as Kinase and Epigenetic Inhibitors
BR112012033425A2 (pt) pirazoloquinolinas
JP2019038848A (ja) 白血病を予防および治療するためのマレイミド誘導体の使用
CA2922542A1 (fr) Composes arylquinoleine et analogues de ceux-ci et utilisation de ces derniers pour traiter le cancer
JP2022539208A (ja) チロシンキナーゼ非受容体１（ｔｎｋ１）阻害剤およびその使用
WO2014106763A1 (fr) Pyridopyrazines utilisés en tant qu'agents antinéoplasiques
TWI691500B (zh) 作為tyro3、axl和mertk(tam)家族受體酪胺酸激酶抑制劑之雜環化合物
US9399644B2 (en) [1,3] dioxolo [4,5-G] quinoline-6(5H)thione derivatives as inhibitors of the late SV40 factor (LSF) for use in treating cancer
CN110730782B (zh) 光动力治疗化合物和光动力治疗方法
EP3012248B1 (fr) Substance possédant une activité inhibitrice des tyrosine kinases, son procédé de préparation et son utilisation
US9499552B2 (en) Pyrazolo[1,5-A]pyrimidine derivative and use of anti-tumor thereof
US20230279000A1 (en) Pyridopyrimidine derivatives useful in modulation of ahr signalling

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 14703410

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 14703410

Country of ref document: EP

Kind code of ref document: A1