WO2022199547A1 - Dérivé de 7,9-dihydropurine et son usage pharmaceutique - Google Patents

Dérivé de 7,9-dihydropurine et son usage pharmaceutique Download PDF

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Publication number
WO2022199547A1
WO2022199547A1 PCT/CN2022/082092 CN2022082092W WO2022199547A1 WO 2022199547 A1 WO2022199547 A1 WO 2022199547A1 CN 2022082092 W CN2022082092 W CN 2022082092W WO 2022199547 A1 WO2022199547 A1 WO 2022199547A1
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unsubstituted
alkyl
substituted
cancer
halogenated
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PCT/CN2022/082092
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English (en)
Chinese (zh)
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陈俐娟
杨壮
叶昊宇
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成都赜灵生物医药科技有限公司
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Priority to CN202280015449.8A priority Critical patent/CN116917288A/zh
Publication of WO2022199547A1 publication Critical patent/WO2022199547A1/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
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • 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
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/32—Nitrogen atom

Definitions

  • the invention belongs to the field of chemical medicine, and particularly relates to a 7,9-dihydropurine derivative and its pharmaceutical use.
  • Cancer is the most deadly disease affecting human health and life expectancy. Research on how to effectively fight cancer is the goal of scientists' continuous efforts. At present, there are many methods and drugs for the treatment of cancer, and the more effective methods include surgery, radiotherapy, and drug therapy.
  • the methods of treating cancer include directly killing cancer cells, regulating body immunity, etc.
  • the specific mechanism of directly killing cancer cells includes directly damaging DNA, inhibiting DNA synthesis, inhibiting protein synthesis, and the like. Radiation therapy and a lot of anticancer drugs all achieve the purpose of treating cancer by directly damaging DNA, and DNA damage will trigger the body to repair damaged DNA, and repairing damaged DNA will in turn improve the survival of cancer cells, making cancer cells more viable. cells resist. Therefore, if the repair of DNA damage can be inhibited, the sensitivity of cancer cells can be improved.
  • DNA double strand break In DNA damage, DNA double strand break (DSB) is the most serious, one of the main causes of gene mutation and chromosomal break, and has an important impact on the occurrence and development of tumors.
  • the repair of DSB is mainly carried out by DNA non-homologous end joining (NHEJ) dominated by DNA-dependent protein kinase (DNA-PK). Therefore, inhibiting the function and activity of DNA-PK is an effective way to inhibit the repair of DSB and improve the sensitivity of tumor cells to radiation and anti-tumor drugs.
  • NHEJ DNA non-homologous end joining
  • DNA-PK DNA-dependent protein kinase
  • DNA-PK is a complex composed of catalytic subunit DNA-PKcs and Ku70/80 heterodimer, Ku70 and Ku80 (also known as Ku86) are encoded by the XRCC6 and XRCC5 genes in humans, respectively, and have With strong affinity, this heterodimer can recognize DSBs and recruit the kinase subunit DNA-PKcs.
  • DNA-PK inhibitors have important clinical value as radiosensitizers and antitumor drug sensitizers to improve the effect of tumor therapy.
  • DNA-PK inhibitors can directly inhibit the proliferation of tumor cells, and they also have anti-tumor effects when used alone. Studies have shown that inhibiting the expression of Ku70 or DNA-PKcs can retard the growth of cervical cancer cells.
  • DNA-PK inhibitors include AZD-7648, KU-57788, NU-7441, NU-7026 and the like.
  • AZD-7648 (CAS: 2230820-11-6) is a potent and highly selective DNA-PK inhibitor developed by AstraZeneca.
  • Studies have shown that AZD-7648 can enhance the DNA damage induced by radiotherapy and chemotherapy with the drug doxorubicin.
  • the team demonstrated that combining AZD-7648 with the PARP inhibitor olaparib increases genomic instability in ATM-deficient cells, thereby inhibiting cell growth and promoting apoptosis.
  • AZD-7648 also enhanced the efficacy of olaparib in a xenograft PDX tumor model with sustained tumor growth inhibition.
  • the inhibitory activity of AZD-7648 on DNA-PK still has room for further improvement, and it also has obvious inhibitory activity on PI3K family isoforms.
  • the oral exposure of AZD-7648 is relatively low in its PK properties, and the half-life and clearance rate also need to be further improvement. Therefore, the development of compounds with more excellent inhibitory activity on DNA-PK and more balanced in vivo and in vitro properties has important clinical application value and social benefits.
  • the purpose of the present invention is to provide a 7,9-dihydropurine derivative and its use in preparing a DNA-PK inhibitor.
  • the present invention provides a compound shown in formula I, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof:
  • R 1 is LR 5 , L is C 1-4 alkylene, NH or none, R 5 is selected from substituted or unsubstituted 3-6 membered saturated heterocyclic group, substituted or unsubstituted 3-6 membered saturated heterocyclic group Cycloalkyl, substituted or unsubstituted bridged cycloalkyl, substituted or unsubstituted C 1-6 alkyl, the substituents are selected from C 1-6 alkyl, SO 2 R 6 , COR 6 , halogen, hydroxyl ; R 6 is selected from halogenated or unsubstituted C 1-6 alkyl, halogenated or unsubstituted 3-6 membered saturated cycloalkyl;
  • R 2 is selected from C 1-6 alkyl, 3-6 membered saturated heterocyclic group, 3-6 membered saturated cycloalkyl;
  • X is NH or none
  • a ring is
  • M 1 , M 2 , M 3 , M 4 , M 5 are each independently selected from CH or N;
  • R 3 is each independently selected from substituted or unsubstituted C 1-5 alkyl, substituted or unsubstituted 5- to 6-membered heteroaryl, substituted or unsubstituted 5- to 6-membered aryl
  • the substituents are each independently selected from halogenated or unsubstituted C 1-5 alkyl, C 1-5 alkoxy, 3-6 membered saturated cycloalkyl, 3-6 membered saturated heterocyclic group, SO 2 R 7 , COR 7 , or two substituents are connected to form a ring;
  • R 7 is selected from hydrogen or C 1-5 alkyl;
  • n is an integer from 1 to 4.
  • R 4 is each independently selected from hydrogen, halogenated or unsubstituted C 1-6 alkyl, halogenated or unsubstituted C 1-6 alkoxy, cyano, nitro, halogen, COOR 8 , COR 8 , SO 2 R 8 , substituted or unsubstituted 5- to 6-membered heteroaryl, substituted or unsubstituted 5- to 6-membered aryl; the substituents are each independently selected from halogenated or unsubstituted C 1-5 alkanes base, R 8 is C 1-6 alkyl;
  • Y is selected from N or CH
  • R 1 is LR 5 , L is C 1-4 alkylene, NH or none, R 5 is selected from substituted or unsubstituted 3-6 membered saturated heterocyclic group, substituted or unsubstituted 3-6 membered saturated cycloalkane R 6 is selected from halogenated or unsubstituted C 1-6 alkyl , Halogenated or unsubstituted 3-6 membered saturated cycloalkyl;
  • R 2 is selected from C 1-6 alkyl
  • X is NH or none
  • a ring is
  • M 1 , M 2 , M 3 , M 4 , M 5 are each independently selected from CH or N;
  • R 3 is each independently selected from substituted or unsubstituted C 1-5 alkyl, substituted or unsubstituted 5- to 6-membered heteroaryl, substituted or unsubstituted 5- to 6-membered aryl
  • the substituents are each independently selected from halogenated or unsubstituted C 1-5 alkyl, C 1-5 alkoxy, 3-6 membered saturated cycloalkyl, 3-6 membered saturated heterocyclic group, SO 2 R 7 , aldehyde group, or two substituents are connected to form a ring;
  • R 7 is selected from C 1-5 alkyl;
  • n is an integer from 1 to 4.
  • R 4 is each independently selected from hydrogen, halogenated or unsubstituted C 1-6 alkyl, halogenated or unsubstituted C 1-6 alkoxy, cyano, nitro, halogen, COOR 8 , COR 8 , SO 2 R 8 , a substituted or unsubstituted 5- to 6-membered heteroaryl group, the substituents are each independently selected from C 1-5 alkyl groups, and R 8 is C 1-6 alkyl groups.
  • R 1 is LR 5 , L is C 1-3 alkylene, NH or none, and R 5 is selected from substituted or unsubstituted 3- to 6-membered saturated heterocyclic groups, substituted or unsubstituted 3- to 6-membered saturated heterocyclic groups Cycloalkyl, substituted or unsubstituted bridged cycloalkyl, the substituent is selected from C 1-5 alkyl, SO 2 R 6 , COR 6 ; R 6 is selected from halogenated or unsubstituted C 1-5 alkane group, halogenated or unsubstituted 3- to 6-membered saturated cycloalkyl;
  • R 2 is selected from C 1-3 alkyl
  • M 1 , M 2 , M 3 , M 4 , M 5 are each independently selected from CH or N;
  • R 3 is a C 1-3 alkyl group, and the other R 3 is selected from substituted or unsubstituted 5- to 6-membered heteroaryl, substituted or unsubstituted 5- to 6-membered aryl;
  • Each group is independently selected from halogenated or unsubstituted C 1-5 alkyl, C 1-5 alkoxy, 3-6 membered saturated cycloalkyl, 3-6 membered saturated heterocyclic group, SO 2 R 7 , Aldehyde group, or two substituent groups are connected to form a ring;
  • R 7 is selected from C 1-5 alkyl groups.
  • R 1 is selected from the following groups substituted or unsubstituted: wherein L is methylene, NH or none; the substituent is selected from C 1-3 alkyl, SO 2 R 6 , COR 6 ; R 6 is selected from halogenated or unsubstituted C 1-3 alkyl, halogen substituted or unsubstituted cyclopropyl;
  • R a1 , R b1 , R b2 , R c1 , R c2 , R d1 , R e1 , R e2 , R f1 are each independently selected from substituted or unsubstituted following groups:
  • the substituents are each independently selected from halogenated or unsubstituted C 1-3 alkyl, C 1-3 alkoxy, 3-6 membered saturated cycloalkyl, 3-6 membered saturated heterocyclic group, SO 2 R 7 , an aldehyde group, or two substituents are connected to form a ring;
  • R 7 is selected from C 1-3 alkyl groups.
  • R 1 is LR 5 , L is C 1-3 alkylene, NH or none, and R 5 is selected from substituted or unsubstituted 3- to 6-membered saturated heterocyclic groups, substituted or unsubstituted 3- to 6-membered saturated heterocyclic groups Cycloalkyl, substituted or unsubstituted bridged cycloalkyl, the substituent is selected from C 1-5 alkyl, SO 2 R 6 , COR 6 ; R 6 is selected from halogenated or unsubstituted C 1-5 alkane group, halogenated or unsubstituted 3- to 6-membered saturated cycloalkyl;
  • R 2 is selected from C 1-3 alkyl
  • n is an integer from 1 to 4.
  • R 4 is each independently selected from hydrogen, halogenated or unsubstituted C 1-5 alkyl, halogenated or unsubstituted C 1-5 alkoxy, cyano, nitro, halogen, COOR 8 , COR 8 , SO 2 R 8 , a substituted or unsubstituted 5- to 6-membered heteroaryl group, the substituents are each independently selected from C 1-5 alkyl groups, and R 8 is C 1-5 alkyl groups.
  • n is an integer from 1 to 2;
  • R 4 is each independently selected from hydrogen, halogenated or unsubstituted C 1-3 alkyl, halogenated or unsubstituted C 1-3 alkoxy, cyano, nitro, halogen, COOR 8 , COR 8 , SO 2 R 8 , substituted or unsubstituted
  • the substituents are each independently selected from C 1-3 alkyl groups, and R 8 is C 1-3 alkyl groups.
  • the compound is one of the following compounds:
  • the compound is one of the following compounds:
  • the present invention also provides the use of the above-mentioned compound, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof in the preparation of a DNA-PK inhibitor.
  • the DNA-PK inhibitor is a drug that inhibits the repair of damaged DNA of tumor cells.
  • the DNA-PK inhibitor is an antitumor drug sensitizer, a radiosensitizer, or a drug for treating tumors.
  • the antitumor drug sensitizer is a chemotherapeutic drug sensitizer.
  • the chemotherapeutic drugs include cisplatin, doxorubicin, olaparib, bleomycin, doxorubicin, etoposide, oxaliplatin, carboplatin, valrubicin, idarubicin Star, pirarubicin, irinotecan, topotecan, amrubicin, epirubicin, mitomycin, bendamustine, chlorambucil, cyclophosphamide, ifosfamide , carmustine, melphalan, MEDI4736, AZD1775, AZD6738, AZD1390, or AZD0156.
  • the tumors include hematological malignancies, myelodysplastic syndromes, breast cancer, lung cancer, endometrial cancer, central nervous system tumors, gastric cancer, esophageal cancer, liver cancer, cholangiocarcinoma, colon cancer, and rectal cancer.
  • small bowel cancer pancreatic cancer, melanoma, thyroid cancer, head and neck cancer, salivary gland cancer, prostate cancer, testicular cancer, ovarian cancer, cervical cancer, uterine cancer, vulvar cancer, bladder cancer, kidney cancer, squamous cell cancer, osteosarcoma , chondrosarcoma, leiomyosarcoma, soft tissue sarcoma, Ewing's sarcoma, gastrointestinal stromal tumor, Kaposi's sarcoma, rhabdomyosarcoma, neuroblastoma;
  • the malignant tumor of the blood system is preferably leukemia, multiple myeloma, lymphoma;
  • the lung cancer is preferably non-small cell lung cancer, small cell lung cancer, squamous cell carcinoma;
  • the central nervous system tumor is preferably glioma , dysembryoplastic neuroepithelial tumor, glioblastoma multiforme, mixed glioma, medulloblastoma, retinoblastoma, neuroblastoma, germ cell tumor, teratoma;
  • said Renal cancer is preferably renal cell carcinoma, clear cell, renal oncocytoma.
  • the present invention also provides an anti-tumor combination drug, which contains the above-mentioned compound and anti-tumor drug for simultaneous or separate administration in the same or different specification unit preparations, and a pharmaceutically acceptable carrier.
  • the antitumor drug is a chemotherapeutic drug.
  • chemotherapeutic drugs are cisplatin, doxorubicin, olaparib, bleomycin, doxorubicin, etoposide, oxaliplatin, carboplatin, valrubicin, idarubicin Star, pirarubicin, irinotecan, topotecan, amrubicin, epirubicin, mitomycin, bendamustine, chlorambucil, cyclophosphamide, ifosfamide , carmustine, melphalan, MEDI4736, AZD1775, AZD6738, AZD1390, or AZD0156.
  • the present invention also provides an anti-tumor composition, which is composed of the above-mentioned compound and an anti-tumor drug.
  • the antitumor drug is a chemotherapeutic drug.
  • chemotherapeutic drugs are cisplatin, doxorubicin, olaparib, bleomycin, doxorubicin, etoposide, oxaliplatin, carboplatin, valrubicin, idarubicin Star, pirarubicin, irinotecan, topotecan, amrubicin, epirubicin, mitomycin, bendamustine, chlorambucil, cyclophosphamide, ifosfamide , carmustine, melphalan, MEDI4736, AZD1775, AZD6738, AZD1390, or AZD0156.
  • the present invention also provides an anti-tumor drug, which is characterized in that: it uses the above-mentioned compound, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof as an active ingredient, plus a pharmaceutically acceptable carrier. prepared preparations.
  • the present invention also provides a method for treating tumors, which is to use the above-mentioned compound, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof in combination with an antitumor drug or radiotherapy.
  • the antitumor drug is a chemotherapeutic drug.
  • chemotherapeutic drugs are cisplatin, doxorubicin, olaparib, bleomycin, doxorubicin, etoposide, oxaliplatin, carboplatin, valrubicin, idarubicin Star, pirarubicin, irinotecan, topotecan, amrubicin, epirubicin, mitomycin, bendamustine, chlorambucil, cyclophosphamide, ifosfamide , carmustine, melphalan, MEDI4736 (durvalumab), AZD1775, AZD6738, AZD1390, or AZD0156.
  • C a-b alkyl denotes any alkyl group containing "a" to "b” carbon atoms.
  • C 1-6 alkyl refers to a straight or branched chain alkyl group containing 1 to 6 carbon atoms.
  • Halogen is fluorine, chlorine, bromine or iodine.
  • “Pharmaceutically acceptable” means that a carrier, vehicle, diluent, adjuvant, and/or salt formed is generally chemically or physically compatible with the other ingredients that make up a pharmaceutical dosage form and physiologically compatible with receptor compatible.
  • Salt is an acid and/or base salt of a compound or its stereoisomer with inorganic and/or organic acids and/or bases, including zwitterionic salts (inner salts), and quaternary ammonium salts , such as alkylammonium salts. These salts can be obtained directly in the final isolation and purification of the compounds. It can also be obtained by mixing a compound, or a stereoisomer thereof, with a certain amount of acid or base as appropriate (eg, equivalent). These salts may be precipitated in solution and collected by filtration, recovered after evaporation of the solvent, or obtained by lyophilization after reaction in an aqueous medium.
  • the pharmaceutically acceptable salts of the present invention can be hydrochloride, sulfate, citrate, benzenesulfonate, hydrobromide, hydrofluoride, phosphate, acetate, propionate of the compound , succinate, oxalate, malate, succinate, fumarate, maleate, tartrate or trifluoroacetate.
  • Bridged cycloalkyl refers to a polycyclic cycloalkyl in which two rings share two non-adjacent carbon atoms.
  • Heterocyclyl refers to a saturated or unsaturated cyclic hydrocarbon substituent; cyclic hydrocarbons may be monocyclic or polycyclic and carry at least one ring heteroatom (including but not limited to O, S or N).
  • “Saturated heterocyclyl” refers to a saturated heterocyclyl group.
  • a 3- to 6-membered saturated heterocyclic group refers to a saturated heterocyclic group having 3 to 6 ring atoms.
  • Cycloalkyl refers to a saturated or unsaturated cyclic hydrocarbon substituent; the cyclic hydrocarbon may be monocyclic or polycyclic.
  • saturated cycloalkyl refers to a saturated cycloalkyl group.
  • a 3- to 6-membered saturated cycloalkyl group refers to a saturated cycloalkyl group having 3 to 6 ring carbon atoms.
  • Aryl refers to an all-carbon monocyclic or fused polycyclic (ie, rings that share adjacent pairs of carbon atoms) groups having a conjugated pi-electron system, such as phenyl and naphthyl.
  • the aryl ring can be fused to other cyclic groups (including saturated and unsaturated rings), but cannot contain heteroatoms such as nitrogen, oxygen, or sulfur, and the point of attachment to the parent must be in a conjugated pi-electron system on the carbon atom of the ring.
  • Aryl groups can be substituted or unsubstituted.
  • Heteroaryl refers to a heteroaromatic group containing one to more heteroatoms.
  • the heteroatoms referred to herein include oxygen, sulfur and nitrogen.
  • the heteroaryl ring can be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl ring.
  • Heteroaryl groups can be optionally substituted or unsubstituted.
  • DNA-PK inhibitors refer to agents that inhibit DNA-PK-led repair of DNA damage, and agents that inhibit the expression of DNA-PK.
  • Antitumor drugs include chemotherapeutic drugs, molecularly targeted drugs and tumor immune drugs.
  • Chemotherapy refers to a method of using chemically synthesized drugs to treat tumors, and it is one of the main methods of treating tumors at present.
  • Chemotherapeutic drugs refer to drugs administered during chemotherapy.
  • Chemotherapy drugs can act on different links of tumor cell growth and reproduction, inhibiting or killing tumor cells.
  • the compounds provided by the invention have broad application prospects in the preparation of DNA-PK inhibitors.
  • the invention provides a new choice for antitumor drug sensitizers, radiotherapy sensitizers and drugs for treating tumors, and also provides a new choice for methods of treating tumors.
  • DNA-PK inhibitors are closely related to antitumor drugs cisplatin, doxorubicin, olaparib, bleomycin, doxorubicin, etoposide, oxaliplatin, carboplatin, Valrubicin, idarubicin, pirarubicin, irinotecan, topotecan, amrubicin, epirubicin, mitomycin, bendamustine, chlorambucil,
  • the combined use of cyclophosphamide, ifosfamide, carmustine, melphalan, MEDI4736, AZD1775, AZD6738, AZD1390 or AZD0156 can improve the therapeutic effect of antitumor drugs. Therefore, the compound provided by the present invention is used in combination with the aforementioned anti-tumor drugs, which provides a new choice for the combined anti-tumor drugs.
  • the present specification also relates to the use of such compounds and their salts in the treatment or prevention of DNA-PK-mediated diseases (including cancer). 7648 exhibited better antiproliferative activity.
  • the raw materials and equipment used in the present invention are all known products, obtained by purchasing commercially available products.
  • CLJ2-CLJ 25 The preparation method of CLJ2-CLJ 25 is the same as that in Example 1, except that the -methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxolaborane of M5 is prepared) -2-yl)-1H-pyrazole was replaced by the corresponding boronate ester.
  • the structure and characterization of CLJ2-CLJ 25 are as follows:
  • the preparation method of CLJ33 is the same as that in Example 1, except that the 4-aminotetrahydropyran hydrochloride for preparing M2 is replaced with memantine hydrochloride, and the subsequent intermediates are replaced accordingly.
  • the preparation method of CLJ34 is the same as that in Example 1, except that the 4-aminotetrahydropyran hydrochloride for preparing M2 is replaced by memantine hydrochloride, and the intermediate M6 is replaced by FM2.
  • the preparation method of FM2 is as follows:
  • CLJ35-CLJ45 The preparation method of CLJ35-CLJ45 is the same as that of Example 1, except that the 4-aminotetrahydropyran hydrochloride for preparing M2 is replaced with memantine hydrochloride, and the subsequent intermediates are replaced accordingly.
  • the structure and characterization of CLJ35-CLJ45 are shown below:
  • CLJ46-CLJ54 The preparation method of CLJ46-CLJ54 is the same as that of Example 1, except that M5 is replaced with the corresponding commercially available secondary amine raw material.
  • the structures and characterizations of CLJ46-CLJ54 are as follows:
  • the preparation of CLJ55 is the same as that in Example 1, except that the intermediate SM6 is replaced by GM3.
  • the preparation method of GM3 is as follows:
  • the preparation of CLJ57 is the same as that in Example 1, except that the intermediate SM6 is replaced by HM2.
  • the preparation method of HM2 is as follows:
  • the preparation of CLJ59 is the same as that of Example 1, except that the 4-aminotetrahydropyran hydrochloride of the preparation M2 is replaced with 1-tert-butoxycarbonyl-4-aminopiperidine, and the subsequent intermediates are replaced accordingly.
  • the enzymatic activity data of the compounds prepared in the examples of the present invention on DNA-PK enzymes at different concentrations were measured according to the above method, and the results are shown in Table 1; and the IC 50 values of some compounds for the inhibition of DNA-PK activity were calculated. , and the results are shown in Table 2.
  • Cmpd DNA-PKIC 50 (nM) Cmpd DNA-PKIC 50 (nM) AZD-7648 1 CLJ29 10 CLJ1 0.1 CLJ31 2 CLJ2 8 CLJ33 1 CLJ3 2 CLJ34 3 CLJ4 0.4 CLJ35 twenty four CLJ5 6 CLJ36 35 CLJ8 0.8 CLJ39 17 CLJ13 2 CLJ40 3 CLJ15 0.7 CLJ41 143 CLJ17 6 CLJ44 twenty one CLJ18 4 CLJ46 6 CLJ20 7 CLJ47 13 CLJ22 0.1 CLJ50 3 CLJ23 0.9 CLJ51 1 CLJ24 0.4 CLJ54 4 CLJ25 0.3 CLJ56 0.4 CLJ26 25 CLJ58 1 CLJ27 161 CLJ59 0.9
  • Table 1 and Table 2 show that the compounds provided by the present invention have good inhibitory activity on DNA-PK.
  • the compounds of the present invention CLJ1, 4, 8, 15, 22-25, 56, 59, have lower IC50 for inhibiting DNA-PK than the known DNA-PK inhibitor AZD-7648.
  • Inoculation of cells Collect Hct116 cells in a culture dish with a centrifuge tube in an ultra-clean bench, centrifuge at 1000 rpm for 3 min, resuspend the cells in DMED complete medium, count the cells, and plate them at a density of 400 cells/well on 24 In the well plate, each well has a volume of 500 ⁇ L.
  • the 24-well plate was placed in a 5% CO2 incubator and incubated at 37°C for three days.
  • Hct116 cells were treated with the compounds to be tested at a preset concentration for 1 h and then irradiated.
  • Crystal violet staining remove the cell supernatant from the 24-well plate, gently wash the cells in the 24-well plate twice with PBS, and slowly add methanol to fix for 20 min at room temperature. The methanol was discarded, and the 24-well plate was placed on the laboratory bench to evaporate the methanol. Crystal violet was added for staining for 20 min, crystal violet was recovered, and the 24-well plate was washed three times with ultrapure water.
  • Taking pictures taking pictures using a chemiluminescence imaging system.
  • the compounds provided by the present invention can effectively inhibit the sensitization of radiation-induced tumor cells;
  • the IC 50 of Sensitivity is lower than that of the known DNA-PK inhibitor AZD-7648.
  • the compounds provided by the present invention can be used to prepare radiosensitizers.
  • Plasma was separated from blood by centrifugation (4000 g, 15 min at 4°C) and stored in a -80°C freezer. Samples were detected by ultra-high-speed liquid chromatography (UFLC) system (SIL-30AC autosampler, LC-30AD chromatograph, CBM-20A communications bus module, CTO-20AC prominence column oven, Shimadzu Corporation, Japan), and analyzed by non-compartmental analysis method Plasma Concentration Data.
  • ULC ultra-high-speed liquid chromatography
  • the present invention provides 7,9-dihydropurine derivatives represented by formula I and pharmaceutical uses thereof.
  • the compounds provided by the present invention have good inhibitory activity on DNA-PK, especially compounds CLJ1, 4, 8, 15, 22-25, 56, 59, and their inhibitory activity is even better than the known DNA-PK inhibitory activity Agent AZD-7648.
  • the compounds provided by the invention have broad application prospects in the preparation of DNA-PK inhibitors.
  • the invention provides a new choice for antitumor drug sensitizers, radiotherapy sensitizers and drugs for treating tumors, and also provides a new choice for methods of treating tumors.

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Abstract

Dérivé de 7,9-dihydropurine et son usage pharmaceutique. L'invention concerne spécifiquement un composé représenté par la formule I, ou un sel pharmaceutiquement acceptable de celui-ci, ou un stéréoisomère de celui-ci. Des expériences montrent que le composé fourni a une bonne activité inhibitrice sur l'ADN-PK, en particulier les composés CLJ1, 4, 8, 15, 22 à 25, 56 et 59 dont l'activité inhibitrice est encore supérieure à un inhibiteur d'ADN-PK connu AZD-7648. Le composé selon l'invention présente de vastes perspectives d'application dans la préparation d'un inhibiteur d'ADN-PK. L'invention concerne un nouveau choix pour des sensibilisateurs de médicament anti-tumoraux, des sensibilisateurs de radiothérapie et des médicaments pour le traitement de tumeurs, et un nouveau choix pour des procédés de traitement de tumeurs.
PCT/CN2022/082092 2021-03-22 2022-03-21 Dérivé de 7,9-dihydropurine et son usage pharmaceutique WO2022199547A1 (fr)

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