WO2018029117A1 - Nouveaux inhibiteurs d'atr destinés à être utilisés dans le traitement du cancer - Google Patents

Nouveaux inhibiteurs d'atr destinés à être utilisés dans le traitement du cancer Download PDF

Info

Publication number
WO2018029117A1
WO2018029117A1 PCT/EP2017/069871 EP2017069871W WO2018029117A1 WO 2018029117 A1 WO2018029117 A1 WO 2018029117A1 EP 2017069871 W EP2017069871 W EP 2017069871W WO 2018029117 A1 WO2018029117 A1 WO 2018029117A1
Authority
WO
WIPO (PCT)
Prior art keywords
cancer
carcinoma
cell
methyl
sarcoma
Prior art date
Application number
PCT/EP2017/069871
Other languages
English (en)
Inventor
Carsten Bolm
Christine Maria HENDRIKS
Bernhard LÜSCHER
Jörg HARTKAMP
Original Assignee
Rheinisch-Westfälische Technische Hochschule Aachen (RWTH)
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 Rheinisch-Westfälische Technische Hochschule Aachen (RWTH) filed Critical Rheinisch-Westfälische Technische Hochschule Aachen (RWTH)
Publication of WO2018029117A1 publication Critical patent/WO2018029117A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D241/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with nitrogen atoms directly attached to ring carbon atoms
    • C07D241/28—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with nitrogen atoms directly attached to ring carbon atoms in which said hetero-bound carbon atoms have double bonds to oxygen, sulfur or nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—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
    • A61K31/4965—Non-condensed pyrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/243—Platinum; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • This invention relates to compounds for treating cancer. More specifically, this invention relates to treating cancer with pyrazine compounds either alone, or in combination with other anti-cancer drugs. This invention also relates to a
  • DNA lesions can occur in all living organisms due to deleterious attacks from extrinsic agents as well as intrinsic sources.
  • One of the most harmful lesions found in genomic DNA are double-strand breaks, whose massive cytotoxicity is the basis for
  • ATR ATM and Rad3 related
  • ATM and Rad3 related kinase is a protein kinase involved in cellular responses to certain forms of DNA damage (e.g. double strand breaks and replication stress).
  • ATR kinase acts with ATM ("ataxia telangiectasia mutated") kinase and many other proteins to regulate a cell's response to double strand DNA breaks and replication stress, commonly referred to as the DNA Damage Response ("DDR").
  • the DDR stimulates DNA repair, promotes survival and stalls cell cycle progression by activating cell cycle checkpoints, which provide time for repair. Without the DDR, cells are much more sensitive to DNA damage and readily die from DNA lesions induced by endogenous cellular processes such as DNA replication or exogenous DNA damaging agents commonly used in cancer therapy.
  • Healthy cells can rely on a host of different proteins for DNA repair including the DDR kinases ATR and ATM. In some cases these proteins can compensate for one another by activating functionally redundant DNA repair processes. On the contrary, many cancer cells harbor defects in some of their DNA repair processes, such as ATM signaling, and therefore display a greater reliance on their remaining intact DNA repair proteins which include ATR. In addition, many cancer cells express activated oncogenes or lack key tumour suppressors, and this can make these cancer cells prone to dysregulated phases of DNA replication which in turn cause DNA damage. ATR has been implicated as a critical component of the DDR in response to disrupted DNA replication. As a result, these cancer cells are more dependent on ATR activity for survival than healthy cells. Accordingly, ATR inhibitors may be useful for cancer treatment, either used alone or in combination with DNA damaging agents, because they shut down a DNA repair mechanism that is more important for cellular survival in many cancer cells than in healthy normal cells.
  • ATR inhibitors may be effective both as single agents and as potent sensitizers to radiotherapy or genotoxic chemotherapy.
  • hypoxic cancer cells are known to be resistant to treatment, most notably irradiation treatment, and are highly aggressive.
  • components of the DDR can be activated under hypoxic conditions and it has also been shown that hypoxic cells are more reliant on components of the DDR for survival.
  • This invention relates to compounds for treating cancer. More specifically, the present invention relates to pyrazine compounds useful as inhibitors of ATR protein kinase. The invention also relates to pharmaceutically acceptable compositions comprising the compounds of this invention, processes of preparing the compounds of this invention.
  • ring Z being a 5 membered heteroaryl ring selected from:
  • R 2 is O or a non-binding electron pair substituting the double bond
  • R 3 is CH 3 ;
  • R 4 is NH, N-CN or N-CH 3 ;
  • R 5 is H, an acetyl group, (1 ,4-diazepan-1-yl) methanone, propane-1 ,3, diamine, (3- amino-1-piperidyl) methanone, pyrrolidin-2-yl, 3-aminoazetidin-1 -yl, pyrazin-3-amine, 5-(mehylaminomethyl)-2-thienyl, 3-nitrilo-2-thienyl, 1 ,2,3,4-tetrahydroisoqunolin-6-yl, 5- (pyrrolidin-2-yl)-2-thienyl, 5-(aminomethyl)-2-thienyl, acetamide, 1 -aminoethyl, 4- (methylaminomethyl)-2-thienyl, 1 ,2,3,6-tetrahydropyridin-4-yl, (2,2- difluroethylamino)
  • R 6 is H, a fluoride, a methyl group or a hydroxyl group
  • R 7 is H, [(methylamino)ethoxy]ethanol, (methylamino)methyl, chloride, (1 R)- 1 aminoethyl, (1 S)-1 -aminoethyl, 1-(tert. butylcarbamoyl)ethyl, a nitrile group, a hydroxyl group, or dimethylaminomethyl, 1-aminoethyl;
  • R 8 is H, [(methylamino)ethoxy] ethanol, methylamine, (propylamino)methyl,
  • R 9 is H, or pyrrolidin-2-yl.
  • the phenyl ring carrying the substituents R 6 -Rg is monosubstituted with one of substituents R 6 -Rg is not H but selected from the further groups as listed above.
  • the phenyl ring carrying the substituents R 6 -Rg is disubstituted with two of the substituents R 6 -Rg being not H but selected from the further groups as listed above.
  • Preferred is a phenyl ring with R 6 being a methyl or methoxy group and R 8 being (methylamino)methyl.
  • ATR Rad3-related protein
  • ATR inhibitors show pro-apoptotic efficacy on its own in a lymphoma cell line which argue for the possibility to use them in a monotherapy for cancer treatment.
  • a pharmaceutically acceptable salt of the compound is provided.
  • the pharmaceutically acceptable salt is preferably selected from the group consisting of sodium, potassium, ammonium, lithium calcium, magnesium, zinc, iron, monoethanolamine, diethanolamine, triethanolamine, lysine, arginine, and tromethamine.
  • said salt is a physiologically acceptable salt of the compound of the invention of the earth or earth alkaline type, most preferably is a lithium, sodium, magnesium or calcium, and specifically the sodium salt of said compound.
  • the compound of the invention has one of the formulas A to D:
  • the compound according formula A, B, C or D is provided in the form of its pharmaceutically acceptable salt.
  • the invention provides also the enantiomers of the chiral compounds according formula I or formulas A to D. These compounds all possess a sulfur atom with three or four different substituents and thus all exhibit a chiral S-atom.
  • the enantiomers of the compounds of formulas A-D are given as follows:
  • the invention provides a pharmaceutically acceptable composition
  • a pharmaceutically acceptable composition comprising a compound of the invention and at least one pharmaceutically acceptable carrier.
  • the pharmaceutically acceptable carrier includes any and all solvents, diluents, or other liquid vehicles, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
  • materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as
  • phosphates glycine, sorbic acid, or potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols; such
  • isotonic saline Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.
  • the present invention provides compounds that are inhibitors of ATR kinase, and thus are useful for treating or lessening the severity of a disease, condition or disorder where ATR is implicated in the disease, condition or disorder.
  • Such diseases include a proliferative or hyperproliferative disease.
  • proliferative and hyperproliferative diseases include, without limitation, various cancer types.
  • the invention relates to a compound of the invention or a
  • composition comprising said compound for use in the treatment of cancer in a patient.
  • the pharmaceutical composition according to the invention can be used to treat malignant as well as benign tumours.
  • the cancer or malignant tumour, either primary or secondary, that can be prevented by the pharmaceutical compositions of the present invention include, but are not limited to, leukaemia, breast cancer, skin cancer, bone cancer, prostate cancer, liver cancer, lung cancer, brain cancer, cancer of the larynx, gallbladder, pancreas, rectum, parathyroid, thyroid, adrenal, neural tissue, head and neck, colon, stomach, bronchi, kidneys, basal cell carcinoma, squamous cell carcinoma of both ulcerating and papillary type, metastatic skin carcinoma, osteo sarcoma, Ewing's sarcoma, veticulum cell sarcoma, myeloma, giant cell tumour, small- cell lung tumour, gallstones, islet cell tumour, primary brain tumour, acute and chronic lymphocytic and granulocytic tumours, hairy-cell tumour, adenoma, hyperplasia, medullary carcinoma, pheochromocytoma, mucosal neuromas, intestinal
  • ganglioneuromas hyperplastic corneal nerve tumour, marfanoid habitus tumour,
  • a benign tumour is usually localized and nonmetastatic.
  • Specific types of benign tumours that can be prevented by the pharmaceutical composition of the present invention include hemangiomas, hepatocellular adenoma, cavernous haemangioma, focal nodular hyperplasia, acoustic neuromas, neurofibroma, bile duct adenoma, bile duct cystanoma, fibroma, lipomas, leiomyomas, mesotheliomas, teratomas, myxomas, nodular regenerative hyperplasia, trachomas and pyogenic granulomas.
  • malignant tumours In the case of malignant tumours, cells become undifferentiated, do not respond to the body's growth control signals, and multiply in an uncontrolled manner.
  • Malignant tumours are invasive and capable of spreading to distant sites (metastasizing). Malignant tumours are generally divided into two categories: primary and secondary. Primary tumours arise directly from the tissue in which they are found. Secondary tumours, or metastases, are tumours that originated elsewhere in the body but have now spread to distant organs. Common routes for metastasis are direct growth into adjacent structures, spread through the vascular or lymphatic systems, and tracking along tissue planes and body spaces (peritoneal fluid, cerebrospinal fluid, etc.).
  • cancer includes, but is not limited to the following cancers.
  • sarcoma angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma
  • myxoma rhabdomyoma
  • fibroma lipoma and teratoma
  • Lung bronchogenic carcinoma
  • liver hepatoma
  • hepatoma hepatoma
  • nephroblastoma nephroblastoma
  • lymphoma leukemia
  • bladder and urethra squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma
  • prostate adenocarcinoma, sarcoma
  • testis seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumours, lipoma
  • Liver hepatoma
  • Bone osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumour chordoma, osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumours; Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningiom
  • Gynecological uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumour cervical dysplasia), ovaries (ovarian carcinoma [serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma], granulosa-thecal cell tumours, Sertoli-Leydig cell tumours, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tubes (carcinoma), breast; Hematologic: blood (myeloid leukemia [acute and chronic]), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple
  • said cancer is lung cancer, head and neck cancer, pancreatic cancer, gastric cancer or brain cancer.
  • said cancer is breast cancer, small cell lung cancer or multiple myeloma.
  • the compound of the invention or a pharmaceutical composition comprising said compound is used on a cancer cell having defects in the ATM signaling cascade.
  • said defect is altered expression or activity of one or more of the following: ATM, p53, CHK2, MREI 1 , RAD50, NBSI, 53BP1 , MDCI or H2AX.
  • the cell is a cancer cell expressing DNA damaging oncogenes.
  • said cancer cell has altered expression or activity of one or more of the following: K-Ras, N-Ras, H-Ras, Raf, Myc, Mos, E2F, Cdc25A, CDC4, CDK2, Cyclin E, Cyclin A and Rb.
  • the compound of the invention or a pharmaceutical composition comprising said compound is used for inhibiting the ataxia telangiectasia and Rad3-related protein (ATR) in a patient.
  • ATR is one of the central kinases involved in the DNA-damage response (DDR).
  • DDR DNA-damage response
  • ATR is activated by single stranded DNA structures, which may for example arise at resected DNA DSBs or stalled replication forks. Once activated, ATR acts via its downstream targets to promote DNA repair, stabilisation and restart of stalled replication forks and transient cell cycle arrest (Weber & Ryan, 2014).
  • ATR is a member of the phosphatidylinositol 3-kinase-related kinase (PIKK) family of serine/threonine protein kinases, which also comprises DNA-dependent protein kinase catalytic subunit (DNA-PKcs/PRKDC), mammalian target of rapamycin (MTOR/FRAP) and suppressor of morphogenesis in genitalia (SMG1 ).
  • PIKK phosphatidylinositol 3-kinase-related kinase
  • DDR DNA damage response
  • DDR DNA damage response
  • ATR As a member of the PIKK kinase family, ATR shows considerable similarities with the other members in its domain architecture and extensive sequence homology, particularly in its C-terminal kinase domain and the flanking FAT (FRAP-ATM-TRRAP) and FATC (FAT C-terminal) domains. Even though the functions of the FAT and FATC domains are not yet fully understood, both domains have been implicated in the regulation of kinase activity. The N-terminal region is poorly conserved between PIKK family members and is believed to be important for the interaction with various substrates and adapter proteins.
  • the N-terminus also contains the binding site for ATRIP (ATR-interacting protein), which regulates the localisation of ATR to sites of replication stress and DNA damage and is essential for ATR signalling.
  • ATRIP ATR-interacting protein
  • ATR is one of the central kinases involved in the DDR.
  • ATR is activated by single stranded DNA structures, which may for example arise at resected DNA DSBs or stalled replication forks.
  • ssDNA single stranded DNA
  • RPA replication protein A
  • RPA-ssDNA complexes stimulate the binding of the RAD17/RFC2-5 clamp loader complex to the damage sites.
  • the presence of a dsDNA-ssDNA junction activates this complex to load the RAD9-HUS1-RAD1 (9-1-1 ) heterotrimer onto the DNA ends.
  • the 9-1-1 complex in turn recruits TopBPI which activates ATR.
  • ATR acts via its downstream targets to promote DNA repair, stabilisation and restart of stalled replication forks and transient cell cycle arrest. Many of these functions are mediated through the ATR downstream target CHK1 .
  • ATR plays an important role in the enforcement of the Intra-S-phase cell cycle checkpoint during normal S-phase progression and in response to DNA damage. It inhibits the firing of replication origins via mediating the degradation of Cdc25A through CHK1 , which in turn slows the progression of DNA replication and provides time for resolution of the stress source.
  • ATR is also a principal mediator of the G2/M cell cycle checkpoint to prevent the premature entry of cells into mitosis, before DNA replication is completed or in the presence of DNA damage.
  • This ATR dependent G2/M cell cycle arrest is primarily mediated through two mechanisms: (i) the degradation of Cdc25A and (ii) the phosphorylation of the Cdc25C phosphatase on serine 216 by CHK1 , which creates a binding site for 14-3-3 proteins.
  • the binding of Cdc25C to 14-3-3 proteins facilitates its export from the nucleus and cytoplasmic sequestration, thereby inhibiting its ability to dephosphorylate and activate nuclear Cdc2, which in turn prevents entry into mitosis.
  • an additional therapeutic agent being preferably an anti- cancer agent.
  • said additional therapeutic agent is selected from a DNA- damaging agent; wherein said additional therapeutic agent is appropriate for the disease being treated; and said additional therapeutic agent is administered together with said compound as a single dosage form or separately from said compound as part of a multiple dosage form.
  • said DNA-damaging agent is selected from chemotherapy, ionizing radiation, radiomimetic neocarzinostatin, a platinating agent, a Topo I inhibitor, a Topo II inhibitor, an antimetabolite, an alkylating agent, an alkyl sulphonate, an antimetabolite, or an antibiotic.
  • DNA-damaging agents examples include, but are not limited to Cisplatin, Oxaliplatin, Carboplatin, Nedaplatin, Satraplatin, Lobaplatin, Triplatin, ProLindac, Aroplatin, Tetranitrate, Picoplatin, Camptothecin, Topotecan, lrinotecan/SN38, Rubitecan, Belotecan,
  • Trofosfamide Chlorambucil, Melphalan, Prednimustine, Bendamustine, Uramustine, Estramustine, Carmustine, Lomustine, Semustine, Fotemustine, Nimustine,
  • said DNA-damaging agent is hydroxyurea.
  • Another embodiment provides a method of sensitizing cells to DNA damaging agents comprising administering to a patient a compound described herein, or a composition comprising said compound.
  • said additional therapeutic agent is selected from radiation therapy, chemotherapy, or other agents typically used in combination with radiation therapy or chemotherapy, such as radiosensitizers and chemosensitizers.
  • Yet another embodiment provides use of a compound described herein as a radio- sensitizer or a chemo-sensitizer.
  • radiosensitizers are agents that can be used in combination with radiation therapy. Radiosensitizers work in various different ways, including, but not limited to, making cancer cells more sensitive to radiation therapy, working in synergy with radiation therapy to provide an improved synergistic effect, acting additively with radiation therapy, or protecting surrounding healthy cells from damage caused by radiation therapy. Likewise chemosensitizers are agents that can be used in combination with chemotherapy. Similarly, chemosensitizers work in various different ways, including, but not limited to, making cancer cells more sensitive to chemotherapy, working in synergy with chemotherapy to provide an improved synergistic effect, acting additively to chemotherapy, or protecting surrounding healthy cells from damage caused by chemotherapy.
  • a compound of formula I as a single agent (monotherapy) for treating cancer.
  • the compounds of formula I are used for treating patients having cancer with a DNA-damage response (DDR) defect.
  • said defect is a mutation or loss of ATM, p53, CHK2, MREI 1 , RAD50, NBSI, 53BP1 , MDCI, or H2AX or any combination thereof.
  • an ex vivo method of inhibiting ATR in a biological sample comprising the step of contacting a compound described herein with said biological sample.
  • said biological sample is a cell.
  • treating refers to any medical measure for preventing, reducing, mitigating or curing physiological disorders within a patient in the need thereof.
  • a “therapeutically effective amount” is defined as the amount of active ingredient that will reduce the symptoms and/or improve the outcome associated with a cancer, such as reduction of tumour size, stop of tumour growth or reduced tumour growth.
  • “Therapeutically effective” also refers to any improvement in disorder severity or the frequency of incidences compared to no treatment.
  • treatment encompasses either curing or healing as well as mitigation, remission or prevention.
  • carrier applied to pharmaceutical compositions of the invention refers to a diluent, excipient, or vehicle with which the therapeutically active compounds of the invention is administered.
  • Such pharmaceutical carriers can be sterile liquids, such as water, saline solutions, aqueous dextrose solutions, aqueous glycerol solutions, and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Suitable pharmaceutical carriers are described in "Remington The Science and Practice of Pharmacy,” 21 th edition (David B. Troy ed., 2006, p. 745-775, p. 802-836 and p. 837 - 849).
  • a "pharmaceutically acceptable excipient” means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes an excipient that is acceptable for veterinary use as well as human
  • a "pharmaceutically acceptable excipient" as used in the present application includes both one and more than one such excipient.
  • the term "pharmaceutical composition” refers to any composition comprising at least one pharmaceutically active ingredient and at least one other ingredient, as well as any product which results, directly or indirectly, from combination, complexation, or aggregation of any two or more of the ingredients, from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the term “pharmaceutical composition” as used herein may encompass, inter alia, any composition made by admixing a
  • pharmaceutically active ingredient and one or more pharmaceutically acceptable carriers.
  • Example I New ATR inhibitors interfere with DNA damaged induced CHK-1 activation in U20S tumour cells
  • All cell lines were cultured at 37°C with 5% C0 2 , using either Dulbecco ' s modified Eagle ' s medium Glutamax I (U20S and HeLa cells) or RPMI 1640 medium (Ramos cells) supplemented with 10% fetal calf serum.
  • Antibodies used in this study are anti-phospho-Chk2 (recognizing phosphorylated Thr68), anti-phospho-Chkl (recognizing phosphorylated Ser345), anti- Chk1 , anti-PARP-1/ARTD-1 (Cell Signaling) and anti-GAPDH (Santa Cruz). Secondary antibodies used were horseradish peroxidase-labeled IgG goat anti-rabbit from Dako.
  • Colony formation assay 5x10 2 HeLa cells were seeded in 6 cm dishes in duplicates and medium including ATR inhibitors and Cisplatin was changed every three days. On day 12, the cells were washed once in PBS and subsequently stained with 0.2% methylene blue in methanol for 30 minutes. After washing, dishes were dried and pictured for documentation.
  • Example II New ATR inhibitors stimulate apoptosis, measured as PARP1 cleavage in the Burkitt Lymphoma cell line Ramos
  • the cell proliferation assay with HeLa tumour cells showed an enhanced inhibition of cell proliferation when the treatment of the substances A-D was complemented with 10 ⁇ or 30 ⁇ Cisplatin respectively. While a minor reduction of cell proliferation could be shown in the non-inhibitor treated control after addition of Cisplatin, the 30 ⁇ Cisplatin treatment led in all inhibitor treated samples (2 ⁇ inhibitor each) to a complete reduction of cell proliferation. The most effective combination was the treatment with substance C together with Cisplatin, which was still not as effective as the treatment with VE-821 alone.
  • Example IV ATR inhibition through new ATR inhibitors in combination with hydroxyurea leads to a an enhanced ATM activation
  • ADMET absorption, distribution, metabolism, excretion and toxicity
  • QikProp Small-Molecule Drug Discovery Suite 2016-2: QikProp, version 4.8, Schrodinger, LLC, New York, NY, 2016
  • QikProp generates physically relevant descriptors, and uses them to perform ADMET prediction.
  • An overall ADMET- compliance score - drug-likeness parameter was used to assess the pharmacokinetic profiles of the compounds of the invention.
  • the parameters of the analysis presented in Figures 5 and 6 are defined as follows: LogP: Octanol-water partition coefficient. LogP is used in rational drug design as a measure of molecular hydrophobicity.
  • Hydrophobicity of compounds affects drug absorption, bioavailability, hydrophobic drug-receptor interactions, metabolism of molecules, as well as their toxicity. From the magnitude of the logP of a compound, one can infer its ease of transport through the cell membrane. According to Lipinski ' s rule of five, compounds with logP values greater than 5 are more likely to have poor absorption or permeation.
  • PSA Molecular polar surface area is a very useful parameter for prediction of drug transport properties. Polar surface area is defined as a sum of surfaces of polar atoms (usually oxygens, nitrogens and attached hydrogens) in a molecule. This parameter has been shown to correlate very well with the human intestinal absorption, Caco-2 monolayers permeability and blood-brain barrier penetration.
  • MLP Molecular Lipophilicity Potential (hydrophobic encoded by darker colors in the structures shown in Figures 5 and 6, hydrophilic parts shown in lighter colors in Figures 5 and 6). As general rules of good drug-likeness, the following parameter criteria were analyzed:
  • Fig. 1 New ATR inhibitors interfere with DNA damage induced CHK1 activation in U20S tumour cells.
  • U20S tumour cells were cultivated under standard conditions (see M+M). The cells were treated with DMSO (solvent control), VE-
  • Fig. 2 New ATR inhibitors stimulate apoptosis in the Burkitt Lymphoma Ramos cell line.
  • Ramos cells were treated with DMSO (solvent control), VE-832, substances A, B, C, D or left without treatment (control) for 48 hours. The inhibitors were used at 10 ⁇ .
  • Cell lysates of these treatments were analyzed using a PARP1 , CHK2 and GAPDH (loading control) antibodies in a Western Blot analysis.
  • Fig. 3 New ATR inhibitors cooperate with the DNA damaging agent cisplatin and interfere with cell proliferation in HeLa tumour cells.
  • Cell proliferation assay with HeLa tumour cells treated with VE-821 , substances A, B, C or D (2 ⁇ each) were compared with an untreated control. For each condition 3 different settings were tested: addition of 10 ⁇ Cisplatin, addition of 30 ⁇ Cisplatin or no additional treatment.
  • U20S tumour cells were cultivated under standard conditions (see M+M). The cells were treated with
  • DMSO solvent control
  • VE-821 substance A, B, C, D for 1 hour.
  • the inhibitors were used at a concentration of 10 ⁇ .
  • Subsequently all treated samples were incubated with 2.5 mM hydroxyurea for 1 h. Lysates were prepared and the proteins were subsequently analyzed using Western Blotting. Antibodies for the detection of p-CHK-1 and p-CHK2 were used.

Landscapes

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

Abstract

La présente invention concerne des composés de pyrazine ayant des groupes sulfilimine ou sulfoximine et l'utilisation desdits composés pour le traitement du cancer. En outre, l'invention concerne un traitement combiné utilisant lesdits composés. Enfin, la présente invention concerne également une composition pharmaceutiquement acceptable comprenant les composés de cette invention, et des procédés de préparation des composés de cette invention.
PCT/EP2017/069871 2016-08-10 2017-08-04 Nouveaux inhibiteurs d'atr destinés à être utilisés dans le traitement du cancer WO2018029117A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102016214912 2016-08-10
DE102016214912.1 2016-08-10

Publications (1)

Publication Number Publication Date
WO2018029117A1 true WO2018029117A1 (fr) 2018-02-15

Family

ID=59564178

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2017/069871 WO2018029117A1 (fr) 2016-08-10 2017-08-04 Nouveaux inhibiteurs d'atr destinés à être utilisés dans le traitement du cancer

Country Status (1)

Country Link
WO (1) WO2018029117A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023016525A1 (fr) * 2021-08-13 2023-02-16 苏州爱科百发生物医药技术有限公司 Composé en tant qu'inhibiteur de la kinase atr

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003087062A2 (fr) * 2002-04-05 2003-10-23 Cadila Healthcare Limited Composes heterocycliques, procede de preparation de ces composes et compositions pharmaceutiques les contenant, et utilisations en medecine
WO2010071837A1 (fr) 2008-12-19 2010-06-24 Vertex Pharmaceuticals Incorporated Dérivés pyrazines utiles en tant qu'inhibiteurs d'atr kinase
WO2011154737A1 (fr) * 2010-06-11 2011-12-15 Astrazeneca Ab Morpholinopyrimidines et leur utilisation en thérapie
WO2014055756A1 (fr) * 2012-10-04 2014-04-10 Vertex Pharmaceuticals Incorporated Procédé pour la mesure d'augmentations de lésions d'adn à médiation par l'inhibition d'atr

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003087062A2 (fr) * 2002-04-05 2003-10-23 Cadila Healthcare Limited Composes heterocycliques, procede de preparation de ces composes et compositions pharmaceutiques les contenant, et utilisations en medecine
WO2010071837A1 (fr) 2008-12-19 2010-06-24 Vertex Pharmaceuticals Incorporated Dérivés pyrazines utiles en tant qu'inhibiteurs d'atr kinase
WO2011154737A1 (fr) * 2010-06-11 2011-12-15 Astrazeneca Ab Morpholinopyrimidines et leur utilisation en thérapie
WO2014055756A1 (fr) * 2012-10-04 2014-04-10 Vertex Pharmaceuticals Incorporated Procédé pour la mesure d'augmentations de lésions d'adn à médiation par l'inhibition d'atr

Non-Patent Citations (11)

* Cited by examiner, † Cited by third party
Title
"Handbook of Pharmaceutical Salts: Properties, Selection and Use", 2002, WILEY-VCH/VHCA
"Remington The Science and Practice of Pharmacy", 2006, pages: 745 - 775,802-836,837-849
"Small-Molecule Drug Discovery Suite 2016-2: QikProp", 2016, SCHRODINGER, LLC, article "Schrodinger 2011 package"
CHARRIER, J. D.; DURRANT, S.; KAY, D.; KNEGTEL, R.; MACCORMICK, S.; MORTIMORE, M.; O'DONNELL, M.; PINDER, J.; RUTHERFORD, A.; VIRA, VERTEX PHARMACEUTICALS
DANNENBERG, C. A.; BIZET, V.; BOLM, C., SYNTHESIS, vol. 47, 2015, pages 1951
GARCIA MANCHENO, O.; BOLM, C., ORG. LETT., vol. 9, 2007, pages 2951
GARCIA MANCHENO, O.; DALLIMORE, J.; PLANT, A.; BOLM, C., ADV. SYNTH. CATAL., vol. 352, 2010, pages 309
S.J.PARK ET AL.: "N-Cyano sulfoximines: COX inhibition, anticancer activity, cellular toxicity and mutagenicity", CHEMMEDCHEM, vol. 8, 6 December 2012 (2012-12-06), pages 217 - 220, XP002773964 *
STOSS, P.; SATZINGER, G., TETRAHEDRON LETT., vol. 14, 1973, pages 267
VELIC, D.; COUTURIER, A. M.; FERREIRA, M. T.; RODRIGUE, A.; POIRIER, G. G.; FLEURY, F.; MASSON, J.-Y.: "DNA Damage Signalling and Repair Inhibitors: The Long-Sought-After Achilles' Heel of Cancer", BIOMOLECULES, vol. 5, no. 4, 2015, pages 3204 - 3259, XP055397226, DOI: doi:10.3390/biom5043204
WEBER, A. M.; RYAN, A. J.: "ATM and ATR as therapeutic targets in cancer", PHARMACOLOGY & THERAPEUTICS, vol. 149, 2014, pages 124 - 138, XP029150363, DOI: doi:10.1016/j.pharmthera.2014.12.001

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023016525A1 (fr) * 2021-08-13 2023-02-16 苏州爱科百发生物医药技术有限公司 Composé en tant qu'inhibiteur de la kinase atr

Similar Documents

Publication Publication Date Title
Leanza et al. Direct pharmacological targeting of a mitochondrial ion channel selectively kills tumor cells in vivo
CA2927631C (fr) Co-cristaux de (s)-n-methyl-8-(1-((2'-methyl-[4,5'-bipyrimidin]-6-yl)amino)propan-2-yl)quinoline-4-carboxamide et leurs derives deuteres utilises comme inhibiteurs de proteine kinase dependante de l'adn (dna-pk)
RU2736219C2 (ru) Способ лечения рака с использованием комбинации ингибиторов снк1 и atr
CN104582795B (zh) 可用作atr激酶抑制剂的化合物及其组合疗法
CA2807199C (fr) Modulateurs du recepteur d'aryl d'hydrocarbone derive de flavonoide utiles dans le traitement du cancer
US20190134056A1 (en) K-ras mutations and antagonists
AU2014337154A1 (en) Co-crystals of (s)-N-methyl-8-(1-((2'-methyl-[4,5'-bipyrimidin]-6-yl)amino)propan-2-yl)quinoline-4-carboxamide and deuterated derivatives thereof as DNA-PK inhibitors
EP2776422A1 (fr) Composés utiles en tant qu'inhibiteurs de la kinase atr
BR112020026086A2 (pt) inibidores da proteína tirosina fosfatase e métodos de uso destes
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
TW200403057A (en) Combination therapy for hyperproliferative diseases
Dubey et al. Anticancer activity and autophagy involvement of self-assembled arene–ruthenium metallacycles
US9867807B2 (en) Compositions and methods for drug-sensitization or inhibition of a cancer cell
WO2016210247A1 (fr) Nouvelles méthodes d'utilisation d'un agent anti-diarrhée
CN114174292A (zh) 作为atr激酶抑制剂的取代的2-吗啉代吡啶衍生物
JP2018538292A (ja) 癌療法のためのモノマレイミド官能化白金化合物
CA2944069C (fr) Conjugues ligand du recepteur sigma-2-medicament en tant que composes antitumoraux, procedes de synthese et utilisations de ces composes
WO2018029117A1 (fr) Nouveaux inhibiteurs d'atr destinés à être utilisés dans le traitement du cancer
Yin et al. Novel mitochondria-based targeting restores responsiveness in therapeutically resistant human lung cancer cells
CN101094838A (zh) 微管蛋白结合抗癌药及其前体药物
CN112533581A (zh) Prc1抑制剂及用其进行治疗的方法
WO2021064175A1 (fr) Composés destinés à prévenir la migration de cellules cancéreuses
WO2023049806A1 (fr) Composés et procédés de traitement de cancers qui sont mgmt déficients indépendamment du statut mmr
Maurya et al. Pi3k Inhibitors
WO2015123392A1 (fr) Compositions et procédés d'inhibition de l'angiogenèse et la lymphangiogenèse

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: 17749439

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: 17749439

Country of ref document: EP

Kind code of ref document: A1