WO2019134082A1 - Nouveaux dérivés de pyrimidine utilisés en tant qu'inhibiteurs de mth1 - Google Patents

Nouveaux dérivés de pyrimidine utilisés en tant qu'inhibiteurs de mth1 Download PDF

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WO2019134082A1
WO2019134082A1 PCT/CN2018/071282 CN2018071282W WO2019134082A1 WO 2019134082 A1 WO2019134082 A1 WO 2019134082A1 CN 2018071282 W CN2018071282 W CN 2018071282W WO 2019134082 A1 WO2019134082 A1 WO 2019134082A1
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cancer
amino
phenyl
methylpyrimidin
diamine
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PCT/CN2018/071282
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English (en)
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Zhihua Zou
Jianzhong TAN
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Wuxi Advant Biotechnology Co., Ltd.
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Priority to CN201880031003.8A priority Critical patent/CN111065635B/zh
Priority to PCT/CN2018/071282 priority patent/WO2019134082A1/fr
Publication of WO2019134082A1 publication Critical patent/WO2019134082A1/fr

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    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • This invention relates to compounds and pharmaceutical compositions comprising these compounds, as well as methods of synthesizing thereof and using such compounds and compositions.
  • the preferred compounds are MTH1 inhibitors and thus are useful in the treatment of diseases, such as cancer, where inhibition of MTH1 activity exerts a therapeutic effect.
  • the current mainstream anticancer therapies such as chemotherapy and radiotherapy, target cancer and normal cells indiscriminately and are often ineffective in the treatment of relapsed and recurrent malignant tumors.
  • More recent treatment strategies such as targeting specific genetic alterations or signaling pathways, are limited by the diversity of cancer genotypes and intratumor heterogeneity, as well as rapid development of drug resistance. Therefore, there is an ongoing need for novel therapeutic agents that can more broadly and effectively kill diverse types of cancer cell, while leaving normal cells unaffected.
  • ROS reactive oxygen species
  • NTPs and dNTPs free nucleotides
  • ROS-oxidized deoxynucleotides can be incorporated into DNA, which may result in accumulation of repair-associated DNA breaks and subsequent induction of programmed cell death (Nakabeppu et al., Mutat Res, 2010, 703: 51–58) ; moreover, elevated ROS-related oxidative pressure in cancer cells also makes them vulnerable to further oxidative insult (Rai et al., PNAS, 2009, 106: 169–174) .
  • MTH1 (MutT homologue 1, also known as NUDT1) is the major nucleotide pool sanitizing enzyme which degrades the most abundant oxidatively modified deoxynucleotides 8-oxodGTP (8-oxo-7, 8-dihydro-deoxyguanosine triphosphate) and 2-OH-dATP (2-hydroxy-deoxyadenosine triphosphate) (Nakabeppu, Int J Mol Sci, 2014, 15: 12543-12557) . By removing 8-oxodGTP and 2-OH-dATP, MTH1 minimizes DNA damage-related cell death and allows ROS-loaded cancer cells to survive.
  • 8-oxodGTP 8-oxo-7, 8-dihydro-deoxyguanosine triphosphate
  • 2-OH-dATP 2-hydroxy-deoxyadenosine triphosphate
  • MTH 1 The expression of MTH 1 was found to be upregulated in various types of cancer, and MTH 1 overexpression was shown to help cells overcome oxidative stress-and oncogenic Ras-induced cellular senescence and programmed cell death (Yoshimura et al., J Biol Chem, 2003, 278: 37965–37973; Rai et al., Oncogene, 2011, 30: 1489–1496) .
  • MTH1 is not essential in normal cells (Tsuzuki et al., Mutat Res, 2001, 477: 71–78) .
  • inhibition of MTH 1 activity will reduce the capacity to eliminate oxidized dNTPs and suppress the survival of cancer cells, and hence is a promising novel strategy to fight most types of cancer, either as monotherapy or in combination with other anticancer agents.
  • ROS ROS-mediated oxidative stress
  • MTH1 inhibitors As such, there exists a significant need for compounds with highly effective and specific MTH 1 inhibitory activity. To date, several classes of chemical compounds have been proposed as MTH1 inhibitors. However, most of them show only weak or no anticancer activity (Kettle et al, J Med Chem, 2016, 59:2346-2361; Petrocchi et al, Bioorg Med Chem Lett, 2016, 26: 1503-1507; Kawamura et al, Sci Rep, 2016, 6: 26521; Ellermann et al, ACS Chem Biol, 2017, 12: 1986-1992) or are disclosed with no biological data (Streib et al, Angew Chem Int Ed Engl, 2014, 53: 305-309; WO 2015/172747; WO 2016/128140 A1; WO 2016/145383 A1; WO 2016/135137; WO 2016/135138; WO 2016/135139; WO 2016/135140) .
  • WO 2014/033136 describes aminoheteroaryl compounds as MTH1 inhibitors with some biological data, wherein the compounds have no structural relationship to the compounds of this invention.
  • Pyrimidine derivatives have been disclosed in WO 2014/084778 and WO 2015/187088 as MTH1 inhibitors with some biological data, wherein all compounds share a 2, 4-diamino-pyrimidine structure and the pyrimidine ring is substituted at position 6 by a (hetero) aryl, ethynyl or nonaromatic ring moiety.
  • the present invention provides new pyrimidine derivatives as novel MTH1 inhibitors, which may advantageously be used for the treatment and prevention of diseases such as cancer.
  • compounds of the present invention not only have advantageous superior MTH 1 inhibitory activity (some IC 50 values are in the low-nanomolar range) , but also demonstrate outstanding cytotoxicity to cancer cells (some IC 50 values are in the sub-micromolar range) .
  • the invention provides a compound of Formula I:
  • R 1 represents alkyl, cycloalkyl or heterocycloalkyl
  • R 2 and R 3 each independently represents H, oxo, alkyl, propanone, aryl, heteronaphthalene optionally substituted by alkoxy and hydroxyl, and pyrimidine optionally substituted by one or more R 4 ;
  • R 4 is chosen from alkyl, halogen and NR 5 R 6 ;
  • R 5 and R 6 are chosen from H, alkoxy, alkylene, trialkylamine, cycloalkyl, aryl optionally substituted by one or more halogen, and alkyl optionally substituted by R 7 , or
  • R 5 and R 6 together with the atoms to which they attach, form a heterocycloalkyl ring optionally substituted by alkyl or -NH 2 ;
  • R 7 represents furan, cycloalkyl, heterocycloalkyl, and aryl optionally substituted by one or more substituents chosen from halogen, methyl halogen, alkyl, alkoxy, -NO 2 and -CN.
  • R 1 is methyl
  • both R 2 and R 3 are H or oxo.
  • R 2 is H and R 3 is alkyl, alkoxy, aryl, or heteronaphthalene substituted by alkoxy and hydroxyl.
  • R 2 is H and R 3 is pyrimidine optionally substituted by one or more R 4 .
  • R 2 is H and R 3 is pyrimidine substituted by two R 4 , wherein one R 4 is H or methyl, and the other R 4 is halogen.
  • R 2 is H and R 3 is pyrimidine substituted by two R 4 , wherein one R 4 is H or methyl, and the other R 4 is NR 5 R 6 .
  • R 5 is H
  • R 6 is H, alkoxy, cycloalkyl, alkylene, trialkylamine, alkyl, or aryl substituted by halogen.
  • R 5 is H
  • R 6 is alkyl substituted by R 7 .
  • R 7 is furan, or aryl substituted by a substituent chosen from halogen, methyl halogen, alkyl, alkoxy, -NO 2 and -CN.
  • R 5 and R 6 together with the atoms to which they attach, form a heterocycloalkyl ring optionally substituted by alkyl or -NH 2 .
  • the compound is chosen from:
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formula I and a pharmaceutically acceptable carrier, adjuvant or vehicle.
  • the invention provides a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, for use in the preparation of a pharmaceutical.
  • the invention provides a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, for use in the preparation of a medicament.
  • the invention provides a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment and prevention of diseases, such as cancer.
  • the invention also provides a method of treating a MTH1-mediated disorder in a subject in need thereof, comprising the step of administering to the subject a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof.
  • the subject is a human.
  • the MTH1-mediated disorder is cancer.
  • the cancer is chosen from: lung cancer, breast cancer, prostate cancer, ovarian cancer, bladder cancer, colon cancer, rectal cancer, renal cancer, pancreatic cancer, thyroid cancer, endometrial cancer, leukemia, melanoma, brain tumor, cervical cancer, esophageal cancer, Ewing Sarcoma, extracranial germ cell tumor, extrahepatic bile duct cancer, eye cancer, Fallopian tube cancer, gallbladder cancer, gastric cancer, germ cell tumor, head and neck cancer, heart cancer, hepatocellular cancer, liver cancer, lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, islet cell cancer, Kaposi sarcoma, laryngeal cancer, lip and oral cavity cancer, Merkel cell carcinoma, mesothelioma, myeloma, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, parathyroid cancer, pharyngeal cancer, pit
  • Figure 1 shows inhibition of MTH1 activity measured by an in vitro MTH1 enzymatic assay.
  • Data are shown for Examples 38, 41 and 43 of the present invention, together with two positive controls: TH588, a compound from Gad et al., Nature, 2014, 508: 215-221; and (S) -crizotinib, a compound from Huber et al., Nature, 2014, 508: 222-227.
  • the IC 50 for Examples 38, 41, 43, and the two positive controls TH588 and (S) -crizotinib is 4.238 nM, 2.410 nM, 1.952 nM, 33.54 nM and 258.4 nM respectively.
  • Listing of IC 50 for all Examples of this invention is presented in Table 1 of the present invention.
  • Figure 2 shows suppression of cancer cell survival measured by the MTT assay.
  • A Growth suppression of human SW480 colon cancer cells by Examples 17, 28 and 39 of the present invention, and the two positive controls TH588 and (S) -crizotinib.
  • the IC 50 for Examples 17, 28, 39, and the controls TH588 and (S) -crizotinib, is 0.8058 ⁇ M, 2.335 ⁇ M, 2.110 ⁇ M, 8.769 ⁇ M and 5.183 ⁇ M respectively.
  • Listing of IC 50 for all Examples of this invention is presented in Table 1 of the invention.
  • B Growth suppression of various human cancer and normal cell lines by Example 28 of the present invention.
  • Example 28 reduced the survival of human MG63 osteosarcoma, HepG2 hepatocellular carcinoma, SW480 colon cancer, SW116 colon cancer, MCF7 breast cancer, Hela cervical cancer and A549 lung cancer cells, while survival of the normal human skin fibroblast HSF cells is less affected.
  • Figure 3 shows intracellular binding to MTH1 protein measured by the cellular thermal shift assay. Data are shown for Examples 1, 16, 20, 21, 22 and 28 of the present invention. In the control where no MTH1-binding chemical was included, the intensity of the MTH1 protein decreased significantly when the temperature was increased to 57.1°C, and disappeared completely when the temperature was increased to 61.5°C; however, when 10 ⁇ M chemical compound of Example 1, 16, 20, 21, 22 or 28 of the invention was included, the MTH1 protein was still detectable up to 67.7°C.
  • R 1 represents alkyl, cycloalkyl or heterocycloalkyl
  • R 2 and R 3 each independently represents H, oxo, alkyl, propanone, aryl, heteronaphthalene optionally substituted by alkoxy and hydroxyl, and pyrimidine optionally substituted by one or more R 4 ;
  • R 4 is chosen from alkyl, halogen and NR 5 R 6 ;
  • R 5 and R 6 are chosen from H, alkoxy, alkylene, trialkylamine, cycloalkyl, aryl optionally substituted by one or more halogen, and alkyl optionally substituted by R 7 , or
  • R 5 and R 6 together with the atoms to which they attach, form a heterocycloalkyl ring optionally substituted by alkyl or -NH 2 ;
  • R 7 represents furan, cycloalkyl, heterocycloalkyl, and aryl optionally substituted by one or more substituents chosen from halogen, methyl halogen, alkyl, alkoxy, -NO 2 and -CN.
  • R 1 is methyl
  • both R 2 and R 3 are H or oxo.
  • R 2 is H and R 3 is alkyl, alkoxy, aryl, or heteronaphthalene substituted by alkoxy and hydroxyl.
  • R 2 is H and R 3 is pyrimidine optionally substituted by one or more R 4 .
  • R 2 is H and R 3 is pyrimidine substituted by two R 4 , wherein one R 4 is H or methyl, and the other R 4 is halogen.
  • R 2 is H and R 3 is pyrimidine substituted by two R 4 , wherein one R 4 is H or methyl, and the other R 4 is NR 5 R 6 .
  • R 5 is H
  • R 6 is H, alkoxy, cycloalkyl, alkylene, trialkylamine, alkyl, or aryl substituted by halogen.
  • R 5 is H
  • R 6 is alkyl substituted by R 7 .
  • R 5 is H
  • R 6 is alkyl substituted by R 7 , wherein R 7 is furan, or aryl substituted by a substituent chosen from halogen, methyl halogen, alkyl, alkoxy, -NO 2 and -CN.
  • R 5 and R 6 together with the atoms to which they attach, form a heterocycloalkyl ring optionally substituted by alkyl or -NH 2 .
  • the compound according to the invention is selected from the compounds of Examples 1-44 as disclosed herein.
  • a pharmaceutical composition comprising a compound of Formula I and a pharmaceutically acceptable carrier, adjuvant or vehicle.
  • a compound of the invention for use in the treatment and prevention of diseases, more preferably for use in the treatment and prevention of cancer.
  • a compound of Formula I for use in the preparation of a pharmaceutical.
  • a compound of Formula I for use in the preparation of a medicament.
  • “Pharmaceutically acceptable salts” include acid addition salts and base addition salts of the compounds of this invention. Additionally, it is understood that the solvates of the salts are also included within the scope of the invention.
  • Pharmaceutically acceptable salts include those formed with both organic and inorganic acids and bases by procedures known in the art. Salts prepared with inorganic bases include, but are not limited to, aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like.
  • Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, diethylamine, ethanolamine, ethylenediamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydramine, isopropylamine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
  • Suitable acid addition salts include, but are not limited to, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acetate, lactate, salicylate, citrate, tartrate, bitartrate, pantothenate, ascorbate, succinate, maleate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, and glutamate.
  • Certain compounds or pharmaceutical compositions may possess no or minimal pharmacological activity as such, but may be metabolized in the body to form compounds of the invention that possess pharmacological activity. Such compounds or compositions may be described as “prodrugs” of the compounds of the invention. All prodrugs of the compounds of the invention are included within the scope of the invention.
  • Compounds of the invention may exist in the form of distinct stereoisomers, geometric isomers or tautomers. It is understood that all stereoisomers, geometric isomers and tautomers of the compounds of Formula I, as well as mixtures thereof, are encompassed within the compounds of the invention.
  • the compounds of the invention also include those having one or more atoms replaced by an isotope, and thus, isotopically-labeled compounds of the invention are included within the scope of the invention.
  • isotopically-labeled compounds of the invention include deuterated compounds, i.e. in which one or more hydrogen atoms are replaced by the hydrogen isotope deuterium.
  • optionally substituted means that the hydrogen radicals in a given structure may be substituted or unsubstituted with specified substituents. Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group, and the substituents may be either the same or different at each substituted position.
  • alkyl refers to a linear or branched hydrocarbon-based chain containing from 1 to 15 carbon atoms and preferably 1 to 10 carbon atoms.
  • alkylene by itself or as part of another substituent, refers to a divalent radical derived from an alkyl. Unless otherwise specified, the term “alkyl” may include “alkylene” groups.
  • cycloalkyl means mono-or polycyclic saturated carbocyclic rings, preferably a cyclopentyl or cyclohexyl group.
  • heterocycloalkyl refers to a saturated or unsaturated monocyclic or polycyclic heterocyclic group containing at least one heteroatom as a ring member, wherein each heteroatom may be independently selected from O, S and N.
  • alkoxy refers to an alkyl-O-group. Preferred examples of alkoxy groups are methoxy or ethoxy groups.
  • aryl means monocyclic or polycyclic rings containing only carbon atoms wherein at least one ring is aromatic.
  • heteroaryl refers to mono-or polycyclic rings wherein at least one ring is aromatic, and at least one aromatic ring contains at least one heteroatom selected from O, S and N.
  • -CN designates a nitrile group connected via the carbon atom.
  • Halo or halogen refers to fluorine, chlorine, bromine, or iodine.
  • IC 50 means the concentration of inhibitor that reduces the activity of MTH1 to half-maximal level.
  • compounds will exhibit an IC 50 with respect to MTH 1 of no more than 100 n ⁇ ; in further embodiments, compounds will exhibit an IC 50 with respect to MTH 1 of no more than 10 n ⁇ ; in yet further embodiments, compounds will exhibit an IC 50 with respect to MTH1 of not more than 5 n ⁇ , as measured in the MTH 1 enzymatic assay described herein.
  • a pharmaceutical composition comprising a compound of the invention, and a pharmaceutically acceptable carrier, adjuvant or vehicle.
  • the carrier (s) must be "acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • compositions suitable for the route of administration chosen will be prepared in convenient unit dosage form, including tablets or capsules for oral administration, suppositories for rectal administration, sterile solutions or suspensions for parenteral or intramuscular administration, and the like.
  • the formulation may also be in the form of creams, gels or foams that can be applied to the skin, or as an inhalant that can be applied nasally.
  • the formulations can be prepared following standard and accepted processes known in the pharmaceutical art.
  • the active-ingredient component can be combined with a nontoxic and pharmaceutically acceptable inert excipient, such as ethanol, glycerol, water and the like.
  • a nontoxic and pharmaceutically acceptable inert excipient such as ethanol, glycerol, water and the like.
  • Powders are prepared by comminuting the compound to a suitable fine size and mixing it with a pharmaceutical excipient, such as an edible carbohydrate comminuted in a similar manner.
  • a flavor, preservative, dispersant and dye may likewise be present.
  • compositions adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions comprising antioxidants, buffers, bacteriostatics and solutes, by means of which the formulation is rendered isotonic with the blood of the recipient.
  • the formulations can be presented in single-dose or multidose containers, for example sealed ampoules and vials, and stored in freeze-dried (lyophilized) state.
  • the invention also provides a method of treating a MTH 1-mediated disorder in a subject in need thereof, comprising the step of administering to the subject a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof.
  • the subject is a human.
  • the MTH1-mediated disorder is cancer.
  • the present invention concerns methods of treating cancer in a patient by administering to the patient a therapeutically effective amount of a compound of the invention.
  • the cancer to be treated includes, but is not limited to, lung cancer, breast cancer, prostate cancer, ovarian cancer, bladder cancer, colon cancer, rectal cancer, renal cancer, pancreatic cancer, thyroid cancer, endometrial cancer, leukemia, melanoma, brain tumor, cervical cancer, esophageal cancer, Ewing Sarcoma, extracranial germ cell tumor, extrahepatic bile duct cancer, eye cancer, Fallopian tube cancer, gallbladder cancer, gastric cancer, germ cell tumor, head and neck cancer, heart cancer, hepatocellular cancer, liver cancer, lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, islet cell cancer, Kaposi sarcoma, laryngeal cancer, lip and oral cavity cancer, Merkel cell carcinoma, mesothelioma, myeloma, nasal cavity and paran
  • the present invention concerns methods of treating cancer in a patient by administering to the patient a combination of compounds comprising one or more compounds of the invention and one or more additional pharmaceutically active compounds.
  • the compound (s) of the present invention and the additional pharmaceutically active compound (s) can be administered simultaneously (either in the same dosage form or in separate dosage forms) or sequentially.
  • the one or more additional pharmaceutically active compounds can be selected from: (1) alkylating agents, including but not limited to cisplatin (PLATIN) , carboplatin (PARAPLATIN) , oxaliplatin (ELOXATIN) , streptozocin (ZANOSAR) , busulfan (MYLERAN) and cyclophosphamide (ENDOXAN) ; (2) anti-metabolites, including but not limited to mercaptopurine (PURINETHOL) , thioguanine, pentostatin (NIPENT) , cytosine arabinoside (ARA-C) , gemcitabine (GEMZAR) , fluorouracil (CARAC) , leucovorin (FUSILEV) and methotrexate (RHEUMATREX) ; (3) plant alkaloids and terpenoids, including but not limited to vincristine (ONCOVIN) , vinblastine and paclitaxel (TAXOL)
  • the compounds of the invention are also expected to be useful as sensitizers for current anticancer therapies including surgery, chemotherapy, radiotherapy, and immunotherapy, wherein immunotherapy includes anticancer treatment using monoclonal antibodies, adoptive cell transfer, cytokines and vaccines.
  • immunotherapy includes anticancer treatment using monoclonal antibodies, adoptive cell transfer, cytokines and vaccines.
  • the present disclosure provides a combination of one or more of the compounds of the invention with another type of anticancer treatment for simultaneous, separate or sequential administration.
  • DIPEA N N-diisopropylethylamine (Hunigs base)
  • Tetrakis (triphenylphosphine) palladium (0) (2.29 g, 1.98 mmol) , potassium acetate (11.64 g, 118.8 mmol) and 1-bromo-4-nitrobenzene (8 g, 39.6 mmol) were added separately to a mixture of bis (pinacolato) diboron (12.065 g, 47.5 mmol) and 1, 4-dioxane (70 ml) under N 2 .
  • N 1 , N 1 -diethylethane-1, 2-diamine (1.9 g, 14.4 mmol, 1.5 eq) was added to a mixture of Intermediate 4 (3 g, 9.6 mmol, 1.0 eq) and TsOH (2.7 g, 14.4 mmol, 1.5 eq) in dioxane (20 mL) .
  • the reaction mixture was diluted in 10 ml of DCM, sequentially washed in 2 M aq NaOH and brine, and dried by Na 2 SO 4 .
  • the organic layer was concentrated and purified by chromatography to afford the product.
  • MTH1 can hydrolyze deoxyguanosine triphosphate to generate deoxyguanosine monophosphate and pyrophosphate. In the presence of excess inorganic pyrophosphatase, all pyrophosphates are converted into inorganic phosphates, which can be quantified using a malachite green-based absorbance assay, thus allowing for measurement of MTH1 activity.
  • Serial dilutions of compounds to be tested were prepared in an assay buffer consisting of 100 mM Tris-acetate (pH 8.0) , 40 mM sodium chloride, 10 mM magnesium acetate, 0.005%Tween 20, and 1 mM DTT.
  • an assay buffer consisting of 100 mM Tris-acetate (pH 8.0) , 40 mM sodium chloride, 10 mM magnesium acetate, 0.005%Tween 20, and 1 mM DTT.
  • 0.5 nM recombinant human MTH1 (ab99390, Abcam, Cambridge, UK)
  • 100 ⁇ M dGTP R0106, Thermo Fisher Scientific, Waltham, MA, USA
  • 0.2 U/mL inorganic pyrophosphatase EF0221, Thermo Fisher Scientific
  • the final reaction volume was 100 ⁇ L in a 96-well plate. At the end of the reaction, malachite green was added, and the plates were incubated at room temperature for another 15 minutes. Absorbance at 630 nm was measured by a microplate reader. Half maximal inhibitory concentration (IC 50 ) values were determined by nonlinear regression analysis using the GraphPad Prism software.
  • IC 50 values for the Examples of this invention are shown in Figure 1 and Table 1 of this invention.
  • Figure 1 shows data for Examples 38, 41 and 43 of the present invention, together with two positive controls: TH588, a representative compound from Gad et al., Nature, 2014, 508: 215-221; and (S) -crizotinib, a representative compound from Huber et al., Nature, 2014, 508: 222-227. Both TH588 and (S) -crizotinib have been proposed as strong MTH1 inhibitors with significant anticancer activity.
  • the IC 50 for TH588 and (S) -crizotinib is 33.54 nM and 258.4 nM respectively, while many of the compounds of the invention have an IC 50 below 5 nm. Results of this assay show that compounds of the present invention have far more superior MTH1 inhibitory activity.
  • Anticancer activity i.e., cytotoxicity to various types of cancer cell, of the compounds of the present invention was studied and measured by several assays as exemplified by the MTT assay below.
  • the cancer cells to be tested were seeded in 96-well plates at a concentration of 1 ⁇ 10 4 cells per well, followed by treatment with different concentrations of the compounds in question for 24 hours or 48 hours.
  • the medium was removed, and the cells were washed with PBS, and then, 20 ⁇ L of 3- (4, 5-dimethylthiazol-2-yl) -2, 5-diphenyl tetrazolium bromide (MTT) solution (5 mg/mL in PBS, pH 7.2) (M6494, Thermo Fisher Scientific) was added to each well.
  • the plates were incubated at 37 °C for another 4 hours. At the end, the MTT solution was removed and 150 ⁇ L of DMSO was added to each well.
  • the plates were incubated on a plate shaker for 10 minutes, and absorbance at 570 nm was measured by a microplate reader. Each experiment was conducted twice in triplicate. Data were analyzed using the GraphPad Prism software. IC 50 values were determined using nonlinear regression analysis.
  • Figure 2 shows representative results of growth suppression of various cancer cells (MG63 osteosarcoma, HepG2 hepatocellular carcinoma, SW480 colon cancer, SW116 colon cancer, MCF7 breast cancer, Hela cervical cancer, A549 lung cancer cell lines) , following treatment by compounds of this invention and the two positive controls, TH588 and (S) -crizotinib.
  • various cancer cells MG63 osteosarcoma, HepG2 hepatocellular carcinoma, SW480 colon cancer, SW116 colon cancer, MCF7 breast cancer, Hela cervical cancer, A549 lung cancer cell lines
  • Compounds of the present invention reduce survival of human cancer cells, while survival of normal cells, such as HSF human skin fibroblasts, is less affected.
  • the IC 50 for Examples 17, 28, 39, and the two controls TH588 and (S) -crizotinib is 0.8058 ⁇ M, 2.335 ⁇ M, 2.110 ⁇ M, 8.769 ⁇ M and 5.183 ⁇ M respectively.
  • Listing of IC 50 for all Examples of this invention is presented in Table 1 of this invention, some of the IC 50 are in the low-or sub-micromolar range (Examples 17, 20, 22, 24, 25, 28, 30, 31, 32, 33, 34, 35, 36, 37, 38 and 39) . Results of this assay show that compounds of the present invention have outstanding and selective cytotoxicity in human cancer cells.
  • MCF-7 breast cancer cells were seeded into T225 culture flasks. After 24 h, the cells were treated with 1%DMSO in cell media or 10 ⁇ M compounds of the present invention for 3-5 h. Cells were harvested using trypsin, spun down and subsequently re-suspended in TBS. The cell suspension was aliquoted into 12 PCR tubes and heated for 3 min to 42, 44.5, 47.9, 52.1, 57.1, 61.5, 64.8, 67.7 or 69.2 °C. Cells were lysed by three repeated cycles of freeze-thawing, using ethanol on dry ice. The precipitated proteins were separated from the soluble fraction by centrifugation at 17,000g for 20 min.
  • Figure 3 shows representative results of some Examples of the present invention.
  • the intensity of the MTH1 protein decreased significantly when the temperature was increased to 57.1°C, and disappeared completely when the temperature was increased to 61.5°C; when 10 ⁇ M chemical compound of an Example of the invention was included, the MTH1 protein was still detectable up to 67.7°C.
  • the results of this experiment show that compounds of the present invention can increase the cellular thermal stability of MTH1, demonstrating intracellular binding of MTH1 protein by these compounds.
  • compounds according to the present invention can enter cancer cells to bind the cellular MTH1 protein, and inhibit cellular MTH1 enzymatic activity with an IC 50 below 100 nM, or even below 5 nM, and importantly, compounds of the present invention reduce cell survival in various cancer cell lines (Examples 17, 20, 22, 24, 25, 28, 30, 31, 32, 33, 34, 35, 36, 37, 38 and 39 have an IC 50 below 10 ⁇ M) , with less effect on normal cells.
  • compounds of this invention have advantageous superior MTH1 inhibitory activity as well as outstanding selective cytotoxicity to cancer cells.

Abstract

L'invention concerne des composés de formule I, ou des sels pharmaceutiquement acceptables de ceux-ci. Les composés sont destinés à être utilisés en tant qu'inhibiteurs de MTH1. Les composés préférés selon l'invention sont utiles dans le traitement du cancer ou d'autres maladies, l'inhibition de l'activité de MTH1 assurant un effet thérapeutique.
PCT/CN2018/071282 2018-01-04 2018-01-04 Nouveaux dérivés de pyrimidine utilisés en tant qu'inhibiteurs de mth1 WO2019134082A1 (fr)

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Citations (3)

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CN101111250A (zh) * 2005-01-31 2008-01-23 巴斯福股份公司 用于治疗的取代的5-苯基嘧啶i
CN105143206A (zh) * 2012-11-27 2015-12-09 托马斯·黑勒戴药物研究基金会 用于治疗癌症的嘧啶-2,4-二胺衍生物
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CN101111250A (zh) * 2005-01-31 2008-01-23 巴斯福股份公司 用于治疗的取代的5-苯基嘧啶i
CN105143206A (zh) * 2012-11-27 2015-12-09 托马斯·黑勒戴药物研究基金会 用于治疗癌症的嘧啶-2,4-二胺衍生物
WO2015187088A1 (fr) * 2014-06-04 2015-12-10 Thomas Helledays Stiftelse För Medicinsk Forskning Inhibiteurs mth1 pour le traitement du cancer

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