WO2024061346A1 - 乏氧激活的化合物在制备治疗癌症患者的药物中的用途 - Google Patents

乏氧激活的化合物在制备治疗癌症患者的药物中的用途 Download PDF

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WO2024061346A1
WO2024061346A1 PCT/CN2023/120712 CN2023120712W WO2024061346A1 WO 2024061346 A1 WO2024061346 A1 WO 2024061346A1 CN 2023120712 W CN2023120712 W CN 2023120712W WO 2024061346 A1 WO2024061346 A1 WO 2024061346A1
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cancer
drug
hypoxia
group
tumor
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PCT/CN2023/120712
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French (fr)
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齐天阳
孟繁英
段建新
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深圳艾欣达伟医药科技有限公司
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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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • A61K31/06—Phenols the aromatic ring being substituted by nitro groups
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/664—Amides of phosphorus acids
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to the use of hypoxia-activated compounds alone or in combination with PARP inhibitors (PARPi) in the treatment of diseases caused by homologous recombination pathogenic gene mutations, especially in the use of RAD51 pathogenic mutations, and provides corresponding
  • PARPi PARP inhibitors
  • DNA damage can be roughly divided into base damage, DNA cross-linking, single-strand breaks (SSBs), and double-strand breaks (DSBs). Among them, DNA double-strand breaks are the most fatal DNA damage. If not repaired in time and correctly, it can cause chromosome deletion, fusion and translocation, eventually leading to cell death and even the occurrence and development of tumors. Homologous recombination (HR) is the most important mechanism for DNA double-strand repair.
  • DNA damage repair is a tightly controlled complex signaling network that ultimately completes the entire process by monitoring damage, transient cycle regulation, and DNA repair.
  • PARP PARP
  • ATR ATM
  • Wee1 DNA-PK
  • BRCA RAD51
  • PRMT5 PRMT5
  • the RAD51 gene encodes a polypeptide of 339 amino acids and a relative molecular mass of 4.3 ⁇ 10 4. It has five homologs: XRCC2, process.
  • PARP inhibitors can inhibit the DNA single-strand damage repair function of PARP, resulting in a large number of single-stranded DNA damage in cells that cannot be repaired in time. Unrepaired single-stranded DNA damage can trigger replication fork collapse and result in double-stranded DNA damage. Double-stranded DNA damage with strong cytotoxicity can be mediated simultaneously in normal cells by proteins such as BRCA and RAD51. source recombination (HR) repair pathway.
  • HR source recombination
  • niraparib and rucaparib Two PARPi have been approved in ovarian cancer: niraparib and rucaparib: FDA and EMA approved niraparib as a maintenance regimen regardless of BRCA1/2 status; rucaparib It has also been registered by the FDA and EMA as an optional treatment option for patients with BRCA1/2 mutation-related ovarian cancer who have previously received two lines of chemotherapy.
  • Talazoparib has also been approved by the FDA for the treatment of BRCA-mutated/HER-2-negative metastatic breast cancer (Mateo, J., Lord, CJ, Serra, V., Tutt, A., J., Castroviejo-Bermejo, M., Cruz, C., Oaknin, A., Kaye, SB, & de Bono, JS (2019).
  • Annals of oncology official journal of the European Society for Medical Oncology, 30(9),1437-1447. https://doi.org/10.1093/annonc/mdz192).
  • oHSVs osporal glycolytic herpesviruses
  • PARPi-ionizing radiation combination PARPi-immunotherapy combination
  • PARPi-HSP90 inhibitor combination PARPi-WEE1/ATR inhibition agent combination
  • PARPi-DNMTi inhibitor combination PARPi-CDK inhibitor combination
  • TH-302 (Evofosfamide, CAS No. 918633-87-1) and its analogs is a 2-nitroimidazole-induced hypoxia-activated prodrug (HAP) brominated isophosphamide, produced by Threshold in the United States. Company development. Under hypoxic conditions, the inactive TH-302 prodrug can release highly toxic Br-IPM. TH-302 has a broad spectrum of biological activities in vivo and in vitro, as well as specific hypoxia selective activation activity and induces ⁇ H2AX phosphorylation and DNA cross-linking, leading to cell cycle arrest and death. Therefore, this compound is used by many pharmaceutical companies and scientific research institutes. Carry out the development of anti-cancer drugs.
  • HAP hypoxia-activated prodrug
  • TH-302 has broad-spectrum activity against various tumors and has excellent hypoxia-selective activity enhancement effect.
  • the use of human cells overexpressing one-electron reductase (POR) confirmed the principle of single-electron reductase-dependent activity enhancement of TH-302 under hypoxic conditions, as shown in the following reaction equation 1:
  • Cytochrome P450 oxidoreductase reduces the prodrug TH-302 to obtain an intermediate free radical anion, which is then unstable and decomposed into the cytotoxic cytotoxin Br-IPM.
  • the key step in this process is the single-electron reduction process. Studies have shown that the presence of oxygen will reverse the single-electron reduction process, that is, the presence of oxygen will hinder the single-electron reduction process, so only in an oxygen-deficient/hypoxic environment can TH-302 be reduced to produce a more cytotoxic substance.
  • the applicant modified TH-302 modified the amino phosphate part into an aziridine structure, and modified the nitroimidazole part into a fused ring structure containing a nitrobenzene ring (patent application PCT/CN2020/114519, publication number WO2021120717A1 ), also obtained a broad-spectrum anticancer prodrug with hypoxic activity.
  • hypoxia-activated TH-302 and its structurally modified aziridine structural analogs are effective in treating the presence of RAD51D pathogenic gene mutations.
  • Single drug administration in patients has a good tumor suppressive effect, and even if the patient is resistant to PARP inhibitors (PARPi), it still has a good tumor suppressive effect.
  • PARP inhibitors PARPi
  • Further research found that the above-mentioned hypoxia-activated TH-302 and its structurally modified aziridine structural analogues were combined with PARPi, which had a certain synergistic effect compared with the efficacy of a single drug.
  • the present application provides the following methods for treating cancer, pharmaceutical uses, drug combinations and related pharmaceutical preparations.
  • the DNA repair enzyme is impaired by one or more gene defects selected from the following: BRCA1, BRCA2, FANCA, FANCD1, FANCD2, ATM, ATR, CHEK1, CHEK2, CTP, BARD1, BRIP1, PALB2, RAD51, RAD52 , RAD54, RAD55, RAD57, FAM175, NBN, Rad50, MRE11, p53, NBS1, XRS2, XRCC4/XPF, ERCC1, ERCC2/XPD, ERCC3/XPB, ERCC4/XPF, XRCC1, Ku80, MHS6, MGMT, PARP, ERCC5/XPG, CCNH, CDK7, CETN2, DDB1, DDB2, ERCC5/XPG, ERCC6/CSB, ERCC8/CSA, LIG1/DNA Ligase I, MMS19, MNAT1, RAD23A, RAD23B, RPA1, RPA2, TFIIH, XAB2, XPA, LIG
  • the DNA repair enzyme is impaired and is selected from:
  • Homologous recombination DNA repair enzyme (homologous recombination repair) is damaged
  • Nucleotide excision repair enzyme (nucleotide excision repair) is damaged
  • Nonhomologous end joining enzyme is damaged
  • Fanconi s anemia involves damage to one or more of the pathway repair enzymes.
  • any one or more of homologous recombination DNA repair enzymes, nucleotide excision repair enzymes, and base excision repair enzymes are damaged, and further preferably, a single homologous recombination DNA repair enzyme is damaged. Either the homologous recombination DNA repair enzyme is damaged or the nucleotide excision repair enzyme is damaged at the same time.
  • the other drugs mentioned above include PARP inhibitors selected from the group consisting of Olaparib, Rucaparib, Niraparib, Talazoparib, Fluzoparib, Pamiparib.
  • the above-mentioned cancer is selected from ovarian cancer, breast cancer, pancreatic cancer, fallopian tube cancer, primary peritoneal cancer, gastric cancer, prostate cancer, liver cancer, colon cancer, rectal cancer, lung cancer, and bladder cancer.
  • the lung cancer is preferably non-small cell carcinoma. Cell lung cancer, small cell lung cancer.
  • patients are resistant or insensitive to the above-mentioned PARP inhibitors.
  • Susceptibility and resistance are qualitative judgments that evaluate whether a patient is resistant to a drug. They are commonly used in drug susceptibility testing of microbial pathogens and antibacterial (bacteria and fungi) drugs.
  • Sensitivity and resistance are two different results shown in clinical drug susceptibility testing.
  • the so-called sensitivity means that during the drug sensitivity test, it is found that the pathogen is very sensitive to this drug, that is, this drug can kill all pathogens; and drug resistance means that during the experiment, it is found that this drug cannot kill the pathogen, that is, This drug is ineffective. If clinical data on drug resistance are obtained, the treatment of the disease will be very meaningful. Based on this, more sensitive drugs can be selected to kill the pathogen.
  • there is also intermediate sensitivity which means moderately sensitive. It is easy to develop resistance but may be useful, but the efficacy will not be very good and not as effective as sensitive treatments.
  • chemotherapy compared to surgery and radiotherapy, chemotherapy here is broad and refers to the use of drugs to treat cancer
  • a series of chemotherapy drugs are usually used sequentially: when the first drug is administered for a period of After a period of time, when there is no therapeutic effect on the patient or the therapeutic effect is very weak, it is considered that the patient with the cancer has developed resistance, resistance or insensitivity to the drug.
  • other drugs second-line drugs
  • Drug resistance, resistance or insensitivity may also occur after a period of administration, at which time third-line drugs are required. Sensitivity and resistance are diagnosed and judged by medical professionals or clinicians.
  • cancer and tumor patients are sensitive to PARP inhibitors is that they will have an effect after taking a PARP inhibitor or judge that the PARP inhibitor will have an effect after a doctor's diagnosis and treatment.
  • the treatment method uses a hypoxia-activated compound or its salt, ester, solvate, isotopic variant, or isomer as a single agent to treat cancer or tumor patients caused by RAD51D gene defects, wherein, the The cancer is selected from ovarian cancer, breast cancer, pancreatic cancer, fallopian tube cancer, primary peritoneal cancer, gastric cancer, prostate cancer, liver cancer, colon cancer, rectal cancer, lung cancer, and bladder cancer.
  • the treatment method uses a hypoxia-activated compound or its salt, ester, solvate, isotopic variant, isomer combined with a PARP inhibitor to treat cancer or tumor patients caused by RAD51D gene defects, wherein , the cancer is selected from ovarian cancer, breast cancer, pancreatic cancer, fallopian tube cancer, primary peritoneal cancer, gastric cancer, prostate cancer, liver cancer, colon cancer, rectal cancer, lung cancer, and bladder cancer; the PARP inhibitor is selected from Austrian cancer. Olaparib, Rucaparib, Niraparib, Talazoparib, Fluzoparib, Pamiparib.
  • patients are resistant or insensitive to said PARP inhibitors.
  • the medicines described herein refer to medicines or preparations, and the medicines prepared contain hypoxia-activated compounds or salts or solvates thereof of active ingredients in a specific dosage range, and/or the medicines prepared are in a specific dosage form, for a specific administration.
  • Medicinal administration refer to medicines or preparations, and the medicines prepared contain hypoxia-activated compounds or salts or solvates thereof of active ingredients in a specific dosage range, and/or the medicines prepared are in a specific dosage form, for a specific administration.
  • the prepared medicines, medicines and preparations may also contain pharmaceutically acceptable auxiliary materials or excipients.
  • the drug can be in any dosage form for clinical use, such as tablets, suppositories, dispersible tablets, enteric-coated tablets, chewable tablets, orally disintegrating tablets, capsules, sugar-coated agents, granules, dry powders, oral solutions, and small injection needles. , freeze-dried powder for injection or large infusion.
  • pharmaceutically acceptable excipients or excipients in the drug may include one or more of the following: diluents, solubilizers, disintegrants, suspending agents, lubricants, viscosifiers, Mixtures, fillers, flavoring agents, sweeteners, antioxidants, surfactants, preservatives, coating agents, and pigments, etc.
  • hypoxia activated compound is selected from the compounds of the following formula I or II:
  • R is each independently selected from H, -CH 3 , -CH 2 CH 3
  • X is each independently selected from leaving functional groups such as Cl, Br, MsO, TsO;
  • R 1 , R 2 , R 3 and Cx are as recorded in the claims in patent application PCT/CN2020/114519 and publication number WO2021120717A1, the full text of which is incorporated into this application.
  • the modified TH-302 structure of the compound of formula II still has the hypoxia activation mechanism: it has stronger cytotoxicity to cancer cells under hypoxia than under normoxic conditions.
  • the compound of formula II is not a P-gp substrate, can effectively enter the central nervous system such as the brain, can accumulate sufficient concentration to exert its pharmacological effect on the central nervous system, and is expected to become a drug for the treatment of primary brain cancer, tumors, or metastatic cancers and tumors that have metastasized to the brain, or for the treatment of primary brain cancer, tumors, or metastatic cancers and tumors that have metastasized to the brain.
  • the compound of formula II is relatively stable in human plasma and liver microsomes and has the potential to be developed as a drug.
  • the compound of formula II has a higher MTD, that is, the new structure compound is equivalent to the compound disclosed in the previous literature with higher safety and clinical treatment dose, and the therapeutic effect on cancer or tumors may be better; in contrast, its effect of inhibiting tumor growth has obvious advantages over the classic chemotherapy drug ifosfamide (also a drug with a DNA alkylating agent mechanism).
  • R 1 , R 2 , R 3 and Cx are defined as follows:
  • Cx is a 5-10-membered aromatic ring or aromatic heterocyclic ring, aliphatic heterocyclic ring or cycloalkane, which shares two carbon atoms with the nitrobenzene ring to form a fused ring structure;
  • R 1 is connected to any skeleton atom of the Cx ring, and is selected from hydrogen, halogen atom, cyano or isocyanate, hydroxyl, mercapto, amino, OTs, C 1 -C 6 alkyl or Z substituted alkyl, C 2 -C 6 alkenyl or Z substituted alkenyl, C 2 -C 6 alkynyl or Z substituted alkynyl, C 3 -C 8 cycloalkyl or Z substituted cycloalkyl, C 6 -C 10 aryl or Z substituted aryl base, 4-15 membered heterocycle or Z-substituted heterocycle, 5-15-membered heteroaryl or Z-substituted heteroaryl, 1-6 carbon atoms alkoxy group or Z-substituted 1-6 carbon atoms alkane Oxygen group, -CONR 6 R 7 , -SO 2 NR 6 R 7 , -SO 2 R 6 , -OC
  • R 2 and R 3 are each independently hydrogen, C 1 -C 6 alkyl or Z substituted alkyl, C 2 -C 6 alkenyl or Z substituted alkenyl, C 2 -C 6 alkynyl or Z substituted alkynyl, C 3 -C 8 cycloalkyl or Z substituted cycloalkyl, C 6 -C 10 aryl or Z substituted aryl, 4-15 membered heterocycle or Z substituted heterocycle, 5-15 membered heteroaryl or Z substituted
  • the heteroaryl group or R 2 , R 3 and the benzylic carbon atom to which they are bonded together form a 3-6 membered ring;
  • the group can replace the hydrogen atom at any position on the carbon atom of the fused ring, and the number of substitutions is 1;
  • the Z substituent is a halogen atom, cyano group or isocyanate group, hydroxyl group, mercapto group, amino group, C 1 -C 3 alkyl group or substituted alkyl group, C 1 -C 3 alkoxy group or substituted alkoxy group, C 2 - C 3 alkenyl or substituted alkenyl, C 2 -C 3 alkynyl or substituted alkynyl, C 3 -C 8 cycloalkyl or substituted cycloalkyl;
  • R 6 and R 7 are each independently hydrogen, C 1 -C 6 alkyl or Z-substituted C 1 -C 6 alkyl, C 2 -C 6 alkenyl or Z-substituted C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or Z substituted C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl or Z substituted C 3 -C 8 cycloalkyl, C 6 -C 10 aryl or Z substituted C 6 -C 10 aryl, 4-15 membered heterocyclyl or Z-substituted 4-15-membered heterocyclyl, 5-15-membered heteroaryl or Z-substituted 5-15-membered heteroaryl, or R 6 , R 7 and the atom to which it is bonded together form a 5-7 membered heterocyclyl group or a Z-substituted 5-7 membered heterocyclyl group.
  • the compound of formula I is selected from the group consisting of compounds of the following structure:
  • the compound of formula II is selected from the group consisting of compounds of the following structure:
  • Preparations related to TH-302 or its similar formula I structural compounds include oral preparations, lyophilized preparations and concentrated injections, and the relevant prescriptions, preparation methods, clinical compatibility, and administration methods are covered by Threshold's relevant patents: WO2010048330A1, WO2012142520A2, WO2008083101A1 Described and disclosed in detail, the present invention hereby incorporates the entire text of the above-mentioned application text.
  • TH-302 or its similar compound of formula I is a DNA alkylating agent anti-cancer drug with extensive cancer treatment potential.
  • TH-302-related cancer indication experiments and clinical trials have been disclosed in relevant Threshold companies and other pharmaceutical companies.
  • Cancer refers to leukemias, lymphomas, carcinomas, and other malignancies (including solid tumors) with potentially unrestrained growth that can expand locally by invasion and systemically by metastasis.
  • cancers that can be treated by TH-302 or its similar formula I structural compounds include (but are not limited to) adrenal gland, bone, brain, breast, bronchi, colon and/or rectum, gallbladder, head and neck, kidney, larynx , liver, lung, nervous tissue, pancreas, prostate, parathyroid, skin, stomach and thyroid cancer.
  • cancers include acute and chronic lymphocytic and granulocytic tumors, adenocarcinoma, adenoma, basal cell carcinoma, cervical dysepithelial carcinoma and carcinoma in situ, Ewing's sarcoma, epidermoid carcinoma, giant cell tumor, multiple glioblastoma, pilocytic tumors, intestinal ganglioneuroma, proliferative corneal neurotumor, islet cell carcinoma, Kaposi's sarcoma, leiomyoma, leukemia, lymphoma, malignant carcinoid tumor, malignant melanoma , malignant hypercalcemia, Marfanoid tumor, medullary epithelial carcinoma, metastatic skin cancer, mucosal neuroma, myeloma, mycosis fungoides, neuroblastoma, osteosarcoma, osteogenic and other sarcomas, Ovarian tumors, pheochromocytoma, polycythemia, poly
  • PARP is an enzyme, its full name is poly(ADP-ribose Polymerase, PARP).
  • PARP is a DNA repair enzyme that plays a key role in the DNA repair pathway. PARP is activated when a single strand of DNA is damaged and broken. As a molecular sensor of DNA damage, it has the function of identifying and binding to the location of DNA breaks, thereby activating and catalyzing the polyADP ribosylation of the receptor protein and participating in DNA repair. process.
  • PARP inhibitors By inhibiting the work of PARP enzymes, PARP inhibitors prevent these "repairman" PARP enzymes from working properly. If DNA damage cannot be repaired, cells may die.
  • PARP inhibitors are compounds that inhibit PARP enzyme. That is, any substance that can inhibit the activity of PARP enzyme is a PARP inhibitor.
  • the PARP inhibitor of the present application is selected from the following group: ABT-767, AZD 2461, BGB-290, BGP 15, CEP 8983, CEP 9722, DR2313, E7016, E7449, fluzoparib, IMP 4297, INO1001, JPI 289, JPI 547, monoclonal antibody B3-LysPE40 conjugate, MP 124, niraparib, NU 1025, NU1064, NU 1076, NU1085, olaparib, ONO2231, PD 128763, R 503, R554, Lu Caparib, SBP 101, SC 101914, Simiparib, Pamiparib, Talazoparib, Veliparib, WW 46, 2-(4-(Trifluoromethyl)phenyl)-7 ,8-dihydro-5H-thiofuro[4,3-d]pyrimidin-4-ol and its salts or derivatives.
  • the PARP inhibitor is selected from the five drugs already on the market, namely Olaparib, Rucaparib, Niraparib, Talazoparib, Fluzoparib and those entering clinical trials.
  • Pamiparib is an early-stage drug.
  • the PARP inhibitors here essentially refer to drugs containing the active ingredients of PARP inhibitors.
  • Talazoparib is indicated for the treatment of adults with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) HER2-negative locally advanced or metastatic breast cancer.
  • the commercially available dosage form of talazoparib tosylate capsule is 0.25 mg/1 mg, 1 mg taken orally once a day. In case of adverse reactions, treatment interruption or dose reduction should be considered:
  • the oral dose is reduced to 0.75 mg (three 0.25 mg capsules), once a day;
  • the oral dose is reduced to 0.5 mg (two 0.25 mg capsules), once a day;
  • the oral dose was reduced to 0.25 mg (one 0.25 mg capsule), once a day.
  • Niraparib is indicated for the maintenance treatment of adult patients with platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who have achieved complete or partial response to platinum-containing chemotherapy.
  • the commercially available dosage form of niraparib tosylate capsule is 100 mg. Take 300 mg orally once a day until disease progression or intolerable adverse reactions occur. In the case of adverse reactions, consider treatment interruption or dose reduction:
  • the dosage is first reduced from 3 capsules per day (300mg) to 2 capsules per day (200mg);
  • the dose can be reduced a second time from 2 capsules per day (200mg) to 1 capsule per day (100mg);
  • Rucaparib is for women with advanced ovarian cancer whose tumors carry a specific gene mutation (a harmful BRCA) and have been treated with two or more chemotherapy drugs.
  • the commercially available dosage forms are tablets: 200mg, 250mg and 300mg, in three strengths.
  • the recommended dose is 600 mg taken orally twice daily with or without food. Continue treatment until disease progression or unacceptable toxicity. For adverse reactions, consider interrupting treatment or reducing the dose.
  • Olaparib is used for maintenance treatment of adult patients with advanced epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer who have germline or somatic BRCA mutations (gBRCAm or sBRCAm) after achieving complete remission or partial remission with platinum-containing chemotherapy; maintenance treatment of adult patients with platinum-sensitive recurrent epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer after achieving complete remission or partial remission with platinum-containing chemotherapy.
  • the commercial dosage form is tablets: 150 mg and 100 mg, in two specifications. The recommended dose is 300 mg (2 150 mg tablets), twice a day, equivalent to a total daily dose of 600 mg. The 100 mg tablet is used for dose reduction:
  • treatment interruption or dose reduction may be considered;
  • the recommended dose is reduced to 250 mg (one 150 mg tablet, one 100 mg tablet), taken twice daily (equivalent to a total daily dose of 500 mg);
  • the recommended dose is reduced to 200 mg (two 100 mg tablets) taken twice daily (equivalent to a total daily dose of 400 mg).
  • Fluzoparib is used for the treatment of patients with platinum-sensitive recurrent ovarian cancer, fallopian tube cancer or primary peritoneal cancer with germline BRCA mutations (gBRCAm) who have received second-line or above chemotherapy.
  • Commercially available dosage form capsule 50mg specification.
  • TH-302 or its similar compound of formula I for treating cancer
  • TH-302 (concentrate for administration solution) used in clinical trials is a sterile liquid formulation of TH-302.
  • TH-302 was formulated with 70% absolute ethanol, 25% dimethylacetamide and 5% polysorbate 80. It is supplied by the sponsor in 10 mL glass vials with rubber stoppers and flip-off closures.
  • TH-302 drug product is a clear, colorless to pale yellow solution that contains essentially no visible particles.
  • each single-use vial contains a nominal fill volume of 6.5 mL of TH-302 drug product (equivalent to 100 mg/mL) and is clearly labeled with the The batch number, route of administration, required storage conditions, name of the sponsor and appropriate warning labeling required by applicable regulations are disclosed. It needs to be diluted according to the pharmacy manual before administration.
  • TH-302 Dilute to a total volume of 500 mL (1000 mL for total doses ⁇ 1000 mg) with commercially available 5% aqueous glucose solution prior to administration to obtain the desired final concentration.
  • Each dose of TH-302 is prepared with a 5% aqueous dextrose solution without di(2-ethylhexyl) phthalate (DEHP-free) and administered intravenously using a DEHP-free intravenous infusion administration device.
  • DEHP-free di(2-ethylhexyl) phthalate
  • a solution (20 mL) of TH-302 (100 mg) and sucrose (1 g) was added to a lyophilized vial and lyophilized to produce a lyophilized unit dosage form of TH-302 with a drug loading of less than 5 mg/cm 3 .
  • the follow-up dosing regimen for the Phase I clinical trial of TH-302 in human patients uses a lyophilized preparation.
  • the TH-302 lyophilized preparation for injection is prepared in a 100 mL glass vial with a drug loading of 100 mg/100 ml, and is maintained at a controlled temperature of 2-8°C.
  • Monotherapy refers to the use of only one anticancer drug in a course of treatment.
  • Combination therapy refers to the simultaneous or sequential use of two or more anti-cancer drugs in one course of treatment.
  • combination therapy requires exploring different dosages and administration cycles based on the characteristics of the disease and the types of combined drugs. Only based on the above conditions, the explored combination drug treatment plan can achieve better therapeutic effects than single drug treatment.
  • This application further provides steps for the above treatment method, including:
  • a drug containing a hypoxia-activated compound of the following formula I or II as a single agent or in combination with a PARP inhibitor:
  • R is each independently selected from H, -CH 3 , -CH 2 CH 3
  • X is each independently selected from leaving functional groups such as Cl, Br, MsO, TsO;
  • R 1 , R 2 , R 3 and Cx are as recorded in the claims in patent application PCT/CN2020/114519 and publication number WO2021120717A1, the full text of which is incorporated into this application.
  • R 1 , R 2 , R 3 , and Cx are defined as follows:
  • Cx is a 5-10-membered aromatic ring or aromatic heterocyclic ring, aliphatic heterocyclic ring or cycloalkane, which shares two carbon atoms with the nitrobenzene ring to form a fused ring structure;
  • R1 is connected to any backbone atom of the Cx ring and is selected from hydrogen, a halogen atom, a cyano group or an isocyano group, a hydroxyl group, a thiol group, an amine group, OTs, a C1 - C6 alkyl group or a Z-substituted alkyl group, a C2 - C6 alkenyl group or a Z-substituted alkenyl group, a C2 -C6 alkynyl group or a Z-substituted alkynyl group, a C3 - C8 cycloalkyl group or a Z-substituted cycloalkyl group, a C6- C10 aryl group or a Z-substituted aryl group, a 4-15-membered heterocycle or a Z-substituted heterocycle, a 5-15-membered heteroaryl group or a Z-
  • R 2 and R 3 are each independently hydrogen, C 1 -C 6 alkyl or Z substituted alkyl, C 2 -C 6 alkenyl or Z substituted alkenyl, C 2 -C 6 alkynyl or Z substituted alkynyl, C 3 -C 8 cycloalkyl or Z substituted cycloalkyl, C 6 -C 10 aryl or Z substituted aryl, 4-15 membered heterocycle or Z substituted heterocycle, 5-15 membered heteroaryl or Z substituted
  • the heteroaryl group or R 2 , R 3 and the benzylic carbon atom to which they are bonded together form a 3-6 membered ring;
  • the group can replace the hydrogen atom at any position on the carbon atom of the fused ring, and the number of substitutions is 1;
  • the Z substituent is a halogen atom, cyano group or isocyanate group, hydroxyl group, mercapto group, amino group, C 1 -C 3 alkyl group or substituted alkyl group, C 1 -C 3 alkoxy group or substituted alkoxy group, C 2 - C 3 alkenyl or substituted alkenyl, C 2 -C 3 alkynyl or substituted alkynyl, C 3 -C 8 cycloalkyl or substituted cycloalkyl;
  • R 6 and R 7 are each independently hydrogen, C 1 -C 6 alkyl or Z-substituted C 1 -C 6 alkyl, C 2 -C 6 alkenyl or Z-substituted C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or Z substituted C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl or Z substituted C 3 -C 8 cycloalkyl, C 6 -C 10 aryl or Z substituted C 6 -C 10 aryl, 4-15 membered heterocyclyl or Z-substituted 4-15-membered heterocyclyl, 5-15-membered heteroaryl or Z-substituted 5-15-membered heteroaryl, or R 6 , R 7 and the atom to which it is bonded together form a 5-7 membered heterocyclyl group or a Z-substituted 5-7 membered heterocyclyl group.
  • the TMB (tumor gene mutation burden) level of the above-mentioned RAD51D gene mutation is moderate.
  • TMB Tumor mutation load (burden), that is, tumor gene mutation load
  • burden Tumor mutation load
  • TMB Tumor mutation load
  • BMS Bristol-Myers Squibb
  • the effective rates of the three groups are 62%, 20%, and 23% respectively.
  • the effective rate of the people with high TMB is higher 3 times; and the median overall survival of the three groups were: 22.0 months, 3.6 months, 3.4 months - 22.0 months and 3.4 months, a 6-fold difference!
  • the PARP inhibitor is selected from the group consisting of Olaparib, Rucaparib, Niraparib, Talazoparib, Fluzoparib, and Pamiparib.
  • patients are resistant or insensitive to the above-mentioned PARP inhibitors.
  • hypoxia-activated compounds of the following formula I or II or their salts, esters, solvates, isotopic variants, and isomers, which are used to prepare single drugs or in combination with other therapeutic drugs to treat RAD51D.
  • R is independently selected from H, -CH 3 , -CH 2 CH 3 , and X is independently selected from leaving functional groups such as Cl, Br, MsO, and TsO;
  • R 1 , R 2 , R 3 and Cx are as recorded in the claims in patent application PCT/CN2020/114519 and publication number WO2021120717A1, the full text of which is incorporated into this application.
  • the TMB (Tumor Mutation Burden) level of the RAD51D gene mutation is moderate for the above pharmaceutical uses.
  • the other therapeutic drugs include PARP inhibitors selected from the group consisting of Olaparib, Rucaparib, Niraparib, Talazoparib, Fluzoparib, Pamiparib;
  • the cancer is selected from the group consisting of ovarian cancer, breast cancer, pancreatic cancer, fallopian tube cancer, primary peritoneal cancer, gastric cancer, prostate cancer, liver cancer, colon cancer, rectal cancer, lung cancer, and bladder cancer.
  • patients are insensitive or resistant to the above-mentioned PARP inhibitors.
  • This application also provides a drug for treating cancer caused by RAD51D pathogenic gene mutation, which contains a hypoxia-activated compound of the following formula I or II or its salt, ester, solvate, isotope variant, and isomer:
  • R is independently selected from H, -CH 3 , -CH 2 CH 3 , and X is independently selected from leaving functional groups such as Cl, Br, MsO, and TsO;
  • R 1 , R 2 , R 3 and Cx are as recorded in the claims in patent application PCT/CN2020/114519 and publication number WO2021120717A1, the full text of which is incorporated into this application.
  • the PARP inhibitor is selected from the group consisting of Olaparib, Rucaparib, Niraparib, Talazoparib, Fluzoparib, and Pamiparib.
  • the TMB (Tumor Mutation Burden) level of gene mutations is medium.
  • the cancer is selected from the group consisting of ovarian cancer, breast cancer, pancreatic cancer, fallopian tube cancer, primary peritoneal cancer, gastric cancer, prostate cancer, liver cancer, colon cancer, rectal cancer, lung cancer, and bladder cancer.
  • patients are resistant or insensitive to the PARP inhibitors.
  • This application also provides a pharmaceutical combination, which includes the following substances as active ingredients:
  • the active ingredients are formulated together or separately for combined use, simultaneous use or separate use.
  • the active ingredients characterizing the pharmaceutical combinations described herein may be formulated together (single dosage units) or separately (sets).
  • the two active ingredients may generally be administered simultaneously; or, given the nature of their respective formulations, separately with a time interval which is conducive to optimizing the synergistic effects of the two active ingredients.
  • the drug combination may be a compound drug, which is a pharmaceutical composition consisting of one active ingredient being the above-mentioned hypoxia-activated compound or its salt, ester, solvate, isotope variant, isomer and another active ingredient being a PARP inhibitor.
  • the above-mentioned active ingredients are co-formulated and used simultaneously.
  • the drug combination can also be a set similar to Pfizer's COVID-19 drug Paxlovid, which can be sold together or separately.
  • the above active ingredients are prepared separately, but the two or more separately prepared drugs can be administered simultaneously or separately at a certain time interval according to the properties of each preparation.
  • the prepared medicine when separately formulated, contains the above-mentioned hypoxia-activated compound or its salt, ester, solvate, isotopic variant, isomer and pharmaceutically available excipients , another drug containing PARP inhibitors and pharmaceutically available excipients.
  • the drug combination composed of the above two drugs can be administered at the same time, or can be administered separately at a certain time interval according to the properties of the respective preparations.
  • the drug combination provided by this application is used to treat cancer or tumor patients with damaged DNA repair enzymes. That is, the drug combination may have better therapeutic effects on cancer or tumor patients with damaged DNA repair enzymes.
  • the DNA repair enzyme is impaired by one or more gene defects selected from the following: BRCA1, BRCA2, FANCA, FANCD1, FANCD2, ATM, ATR, CHEK1, CHEK2, CTP, BARD1, BRIP1, PALB2, RAD51, RAD52 ,RAD54,RAD55,RAD57,FAM175,NBN,Rad50,MRE11,p53,NBS1,XRS2,XRCC4/XPF,ERCC1,ERCC2/XPD,ERCC3/XPB,ERCC4/XPF,XRCC1,Ku80,MHS6,MGMT,PARP,ERCC5 /XPG, CCNH, CDK7, CETN2, DDB1, DDB2, ERCC5/XPG, ERCC6/CSB, ERCC8/CSA, LIG1/DNA Ligase I, MMS19, MNAT1, RAD23A, RAD23B, RPA1, RPA2, TFIIH, XAB2, XPA, XPC , MBD4,
  • the cancer is selected from the group consisting of ovarian cancer, breast cancer, pancreatic cancer, fallopian tube cancer, primary peritoneal cancer, gastric cancer, prostate cancer, liver cancer, colon cancer, rectal cancer, lung cancer, and bladder cancer, and the lung cancer is preferably non- Small cell lung cancer, small cell lung cancer.
  • the active ingredient PARP inhibitor in the drug combination is selected from the group consisting of Olaparib, Rucaparib, Niraparib, Talazoparib, Fluzoparib Fluzoparib, Pamiparib;
  • the hypoxia-activated compound as the active ingredient in the drug combination is selected from the compounds of the following formula I or II:
  • R is each independently selected from H, -CH3, -CH2CH3, and X is each independently selected from leaving functional groups such as Cl, Br, MsO, TsO;
  • R1, R2, R3, and Cx are as recorded in the claims in patent application PCT/CN2020/114519 and publication number WO2021120717A1.
  • hypoxia-activated compound of formula I is selected from compounds with the following structures:
  • hypoxia-activated compound of formula II is selected from compounds with the following structures:
  • This application also provides a pharmaceutical preparation, which is prepared from the active ingredients of the above-mentioned pharmaceutical combination and pharmaceutically available excipients.
  • the dosage form of the above-mentioned pharmaceutical preparation is selected from granules, tablets, pills, capsules, injections or freeze-dried powder injections.
  • This application also provides the use of the above-mentioned drug combination and/or the above-mentioned pharmaceutical preparation in the preparation of anti-tumor drugs.
  • the tumor is selected from ovarian cancer, breast cancer, pancreatic cancer, fallopian tube cancer, primary peritoneal cancer, gastric cancer, prostate cancer, liver cancer, colon cancer, rectal cancer, lung cancer, bladder cancer, and the lung cancer is preferably non-small cell lung cancer and small cell lung cancer.
  • the above-mentioned drugs should also add pharmaceutically acceptable excipients or pharmaceuticals based on the characteristics of the drugs, drugs, and preparations. excipient.
  • the drug can be in any dosage form for clinical use, such as tablets, suppositories, dispersible tablets, enteric-coated tablets, chewable tablets, orally disintegrating tablets, capsules, sugar-coated agents, granules, dry powders, oral solutions, and small injection needles. , freeze-dried powder for injection or large infusion.
  • pharmaceutically acceptable excipients or excipients in the drug may include one or more of the following: diluents, solubilizers, disintegrants, suspending agents, lubricants, viscosifiers, Mixtures, fillers, flavoring agents, sweeteners, antioxidants, surfactants, preservatives, coating agents, and pigments, etc.
  • Figure 1 shows the growth curve of tumor volume of mice in each treatment group in the LD1-2032-361588 human ovarian cancer in vivo xenograft tumor PDX model
  • Figure 2 is a graph showing the percentage change in body weight of mice in each treatment group over time in the LD1-2032-361588 human ovarian cancer xenograft tumor PDX model.
  • a patient and “individual” are used interchangeably and refer to a mammal in need of cancer treatment. Typically, the patients are humans. Typically, a patient is a human being diagnosed with cancer. In certain embodiments, a "patient” or “individual” may refer to a non-human mammal, such as a non-human primate, dog, cat, rabbit, pig, mouse, used for screening, characterizing, and evaluating drugs and therapies. Or rats.
  • Prodrug refers to a compound that is metabolized or otherwise converted to a compound (or drug) that is biologically active or more active with respect to at least one property after administration or administration.
  • a prodrug is chemically modified relative to the drug in a manner that renders it less or inactive relative to the drug, but the chemical modification is such that the corresponding drug is produced by metabolism or other biological processes upon administration of the prodrug.
  • Prodrugs may have altered metabolic stability or delivery characteristics, fewer side effects or lower toxicity, or improved flavor relative to the active drug. Prodrugs can be synthesized using reactants other than the corresponding drug.
  • Treatment or “treating a patient” refers to administering, using or applying to a patient a therapeutically effective amount of a drug related to the present invention.
  • administer or “administer” a drug to a patient.
  • “Use” means direct administration or administration (which may be administered or administered to the patient by a medical professional or may be self-administered or administered) and/or indirect administration or administration, which may be a prescribed drug. the behavior of. For example, a physician who instructs a patient to self-administer or administer a drug and/or provides a prescription for a drug to the patient is administering or administering the drug to the patient.
  • a "therapeutically effective amount" of a drug is one that, when administered or administered to a patient with cancer, will have the desired therapeutic effect (e.g., alleviation, amelioration, alleviation, or elimination of the clinical manifestations of one or more cancers in the patient) the amount of drug.
  • the therapeutic effect does not necessarily occur by administering or administering one dose, and may occur only after administering or administering a series of doses.
  • a therapeutically effective amount may be administered or administered in one or more times.
  • Treatment of a condition or patient means taking steps to obtain beneficial or desired results (including clinical results).
  • beneficial or desired clinical results include (but are not limited to) alleviation or improvement of one or more cancer symptoms; reduction in disease severity; delay or slowing of disease progression; improvement, remission, or stabilization of disease status; or other beneficial results.
  • treatment of cancer can result in partial response or stabilization of the disease.
  • Tumor cells refers to tumor cells of any appropriate species (eg, mammal, eg, murine, canine, feline, equine, or human).
  • test protocol any modifications, animal welfare and use of animal experiments during the test process disclosed in this invention were reviewed and approved by the IACUC committee of the CRO (Contract Research Organization) where it is located. During the test, animal welfare and experimental operations complied with AAALAC requirements.
  • Compound AST is the S isomer of compound 01 in Table 1 in patent application PCT/CN2020/114519, publication number WO2021120717A1, which is also compound B in patent application PCT/CN2021/101870, publication number WO2022052564A1, and its structural formula is as follows :
  • the model was established on LD1-2032-361588 human ovarian cancer tumor tissue and passed to the FP3+3 generation for use in this drug efficacy experiment.
  • the tumor originated from a 62-year-old female patient with liver metastases from ovarian cancer.
  • the pathological diagnosis was low-to-moderately differentiated adenocarcinoma, and she developed resistance to PARPi during treatment.
  • this model is a PDX model with a RAD51D pathogenic gene mutation, and the mutation site is p.Lys91Ilefs*13.
  • the tumor mass of the LD1-2032-361588 human ovarian cancer transplanted tumor was cut into tumor tissue with a size of approximately 3 mm ⁇ 3 mm ⁇ 3 mm (approximately 45-60 mg), and the tumor tissue was inoculated subcutaneously in NU/NU mice. Observe the mice after vaccination and monitor the growth of the tumors. On the 27th day after vaccination, when the average tumor volume of the tumor-bearing mice is 183.67mm3 , group administration will be carried out. The day of group administration is defined as day 0.
  • the specific administration route, dosage and The program information is as follows in Table 1.
  • Table 1 Administration routes, dosages and regimens Note: N: number of animals; Dosing volume: adjusted according to the weight of tumor-bearing mice (0.2 mL/20 g); po: intragastric administration; iv: tail vein injection; QW: once a week; QD: once a day.
  • the tumor growth of each treatment group and control group was recorded on different days of the test, as shown in Table 2.
  • the corresponding growth curve of tumor volume of mice in each group is shown in Figure 1.
  • the efficacy was evaluated based on the relative tumor proliferation rate and relative tumor inhibition rate.
  • the efficacy analysis of each group is shown in Table 3, and the statistical analysis of significance is shown in Table 4.
  • the results of the weight changes of the mice are shown in Table 5.
  • the percentage of weight change of each treatment group changes with time.
  • Measurement of tumor volume and body weight of tumor-bearing mice Use vernier calipers to measure twice a week.
  • Table 3 Summary of anti-tumor efficacy evaluation of test compounds on the LD1-2032-361588 human ovarian cancer subcutaneous xenograft tumor model
  • the relative tumor volume (RTV) is calculated based on the results of tumor measurement.
  • TGI (%) [1-(T i -T 0 )/(V i -V 0 )] ⁇ 100
  • Ti is the average tumor volume after the start of administration of the compound group
  • T 0 is the compound group
  • V 0 is the average tumor volume at the first administration in the vehicle control group
  • Vi is the average tumor volume after the first administration in the vehicle control group.
  • the average tumor volume of the tumor-bearing mice in the control group was 1709.32 ⁇ 271.80 mm 3
  • the average tumor volumes of the tumor-bearing mice in the test compound Olaparib (50 mg/kg, PO, QD*32 days) monotherapy group, TH-302 (80 mg/kg, IV, QW ⁇ 3) monotherapy group
  • Olaparib combined with TH-302 administration group AST (20 mg/kg, IV, QD ⁇ 5, 2 days off; 2 weeks off; QD ⁇ 5) monotherapy group and Olaparib combined with AST administration group were 1261.91 ⁇ 136.43 mm 3 , 239.28 ⁇ 101.70 mm 3 , 118.07 ⁇ 25.29 mm 3 , 823.26 ⁇ 100.46 mm 3 and 476.89 ⁇ 73.20 mm 3 , respectively.
  • the relative tumor proliferation rates T/C (%) were 73.82%, 14.04%, 6.91%, 42.28% and 27.96% respectively; the tumor volume growth inhibition rates TGI (%) were 29.33%, 96.33%, 104.32%, 58.06% and 80.77% respectively.
  • the experimental results show that in the human ovarian cancer tumor model with RAD51D pathogenic gene mutation, the test compound Olaparib alone has poor tumor inhibitory effect, proving that the tumor model is indeed resistant to Olaparib; the test compound Compared with the control group, the TH-302 single drug group, Olaparib combined with TH-302 administration group, AST single drug group, and Olaparib combined with AST administration group all showed statistically significant inhibitory effects on tumor growth (p ⁇ 0.05 and T/C% ⁇ 40%); there was no statistically significant difference between the Olaparib combined with TH-302 administration group and the TH-302 single drug group, and there was no statistically significant difference between the Olaparib combined with AST administration group and the AST single drug group. There was a statistically significant difference, indicating that the combination of AST and Olaparib can improve its ability to inhibit tumor growth to a certain extent.
  • mice in each administration group showed significant weight loss after administration, indicating that tumor-bearing mice tolerated the treatment of each drug well at the experimental dose.
  • TH-302 and AST are small molecule prodrugs that can be activated under hypoxic/hypoxic conditions and release cytotoxins to specifically kill tumor cells and tumor tissues.
  • TH-302 and AST are hypoxic.
  • Activated DNA alkylating agent is hypoxic.
  • the PARP inhibitor selected in the embodiments of this application is Olaparib, Rucaparib, Niraparib, Talazoparib, Fluzoparib, Pamiparib, etc. It is also a PARP inhibitor, and its mechanism of action is similar to that of Olaparib. They both block the enzymes involved in repairing damaged DNA. Therefore, it can be inferred that Rucaparib, Niraparib, and Talazopar PARPi such as Talazoparib, Fluzoparib, and Pamiparib have similar tumor inhibitory effects to Olaparib in the above experiments.

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Abstract

提供乏氧激活的化合物单药或联用PARP抑制剂在制备治疗癌症患者中的用途，特别地，该患者被检测出具有RAD51D等治病基因突变，同时，提供治疗癌症的方法、药物联用物及药物制剂。该方法、药物联用物及药物制剂对于存在RAD51D等致病基因突变的患者单药给药具有很好的肿瘤抑制效果，并且，即使该患者对PARP抑制剂耐药仍然具有良好的肿瘤抑制效果。该药物与PARP抑制剂联用，相比于单药的药效具有一定的协同效应。

Description

乏氧激活的化合物在制备治疗癌症患者的药物中的用途 技术领域
本发明涉及乏氧激活的化合物单药或联用PARP抑制剂(PARPi)在治疗由于同源重组致病基因突变引起的疾病中的用途，特别是在RAD51致病突变中的用途，并提供相应的治疗方法、药物联用物和药物制剂，属于生物医药领域。
背景技术
细胞代谢产生的活性氧，以及紫外线、遗传毒性化学物质等多种内源性和外源性因素可不断诱发DNA损伤。DNA损伤的类型大致可以分为碱基损伤、DNA交联、单链断裂(single-strand breaks,SSBs)、双链断裂(double-strand breaks,DSBs)。其中DNA双链断裂是最具致命性的DNA损伤，若没有得到及时且正确的修复，可造成染色体的缺失、融合和异位，最终导致细胞死亡甚至肿瘤的发生和发展。而同源重组(homologous recombination，HR)是DNA双链修复最主要的机制。
DNA损伤修复是一个受到严格控制的复杂信号网络，通过监控损伤、短暂的周期调节和DNA修复，最终完成整个过程。其中，PARP、ATR、ATM、Wee1、DNA-PK、BRCA、RAD51、PRMT5等多种蛋白在这一过程中发挥重要的作用。
RAD51基因是编码一条339个氨基酸且相对分子质量为4.3×104的多肽，具有XRCC2、XRCC3、RAD51B(RAD51L1)、RAD51C(RAD51L2)、RAD51D(RAD551L3)5个同系物，它们与RAD51共同参与HR过程。
PARP抑制剂可以抑制PARP的DNA单链损伤修复功能，导致细胞内大量单链DNA损伤不能及时修复。未被修复的单链DNA损伤会引发复制叉崩解并由此产生双链DNA损伤，具有较强细胞毒性的双链DNA损伤在正常细胞内可通过BRCA、RAD51等蛋白共同参与介导的同源重组(HR)修复途径进行修复。
PARPi在卵巢癌中的最初研究入组人群均是既往已接受过铂类化疗，且研究发现铂类敏感与PARPi响应有直接关联(铂类化疗药是DNA损伤剂，会导致DNA交联，部分可由HR通路修复，因此DNA修复缺陷型肿瘤预期会对铂类化疗敏感)。有两个PARPi已在卵巢癌中获批：尼拉帕利Niraparib和芦卡帕利Rucaparib：FDA和EMA批准了尼拉帕利的维持治疗方案(不管BRCA1/2状态如何)；芦卡帕利也被FDA和EMA登记为BRCA1/2突变相关卵巢癌患者，既往接受过两线化疗方案之后的可选治疗方案。而他拉唑帕利现也得到了FDA的获批，用于治疗BRCA突变/HER-2阴性转移性乳腺癌(Mateo,J.,Lord,C.J.,Serra,V.,Tutt,A.,J.,Castroviejo-Bermejo,M.,Cruz,C.,Oaknin,A.,Kaye,S.B.,&de Bono,J.S.(2019).A decade of clinical development of PARP inhibitors in perspective.Annals of oncology:official journal of the European Society for Medical Oncology,30(9),1437-1447.https://doi.org/10.1093/annonc/mdz192)。
现有技术WO2019133697A1(对应中国申请CN111801117A)中，研究人员使用PARP抑制剂尼拉帕利Niraparib可在有同源重组修复(HRR)缺陷(非BRCA1或BRCA2)的患者中获益。随着PARPi在临床的应用，PARPi耐药已成为其在临床应用的不可避免的问题。现有的研究表明同源重组修复(Homologous recombination repair restoration，HRR)、DNA复制叉保护、PARPi药代动力学改变等是导致PARPi耐药的主要原因。为了克服PARPi耐药，增加PARPi药物敏感性，多种的联合治疗手段正在被开发，其中许多联合治疗手段已经进入临床阶段。主要包括：PARPi-DNA烷化剂联合；PARPi-单孢酵解性疱疹病毒(oHSVs)联合；PARPi-离子辐射联合；PARPi-免疫治疗联合；PARPi-HSP90抑制剂联合；PARPi-WEE1/ATR抑制剂联合；PARPi-DNMTi抑制剂联合；PARPi-CDK抑制剂联合等(He Li,Zhao-Yi Liu,Nayiyuan Wu,Yong-Chang Chen,Quan Cheng and Jing Wang.PARP inhibitor resistance:the underlying mechanisms and clinical implications.Mol Cancer,2020 Jun 20；19(1):107.2020.https://doi.org/10.1186/s12943-020-01227-0；Rose,M.,Burgess,J.T.,O'Byrne,K.,Richard,D.J.,&Bolderson,E.(2020).PARP Inhibitors:Clinical Relevance,Mechanisms of Action and Tumor Resistance.Frontiers in cell and developmental biology,8,564601.https://doi.org/10.3389/fcell.2020.564601)。
TH-302(Evofosfamide，埃夫索胺，cas号918633-87-1)及其类似物是一种2-硝基咪唑引发的乏氧激活前药(HAP)溴代异磷酰胺，由美国Threshold公司开发。在乏氧情况下，无活性TH-302前药可释放高毒性的Br-IPM。TH-302具有广谱的体内外生物活性以及特异的乏氧选择性激活活性以及诱导γH2AX磷酸化、DNA交联，从而导致细胞周期停滞和死亡，因而该化合物被多家制药公司以及科研院所进行抗癌药物的开发。
Meng F Y(孟繁英)等人发表的研究文章指出：TH-302对于各种肿瘤具有广谱活性，并且具有优异的缺氧选择性的活性增强效应。研究表明，缺氧条件下32个人癌细胞系中TH-302的体外细胞毒性均明显强于常氧条件下的，显示该化合物对于缺氧环境下的癌细胞具有缺氧选择性的细胞毒性。使用单电子还原酶(POR)过表达的人源细胞证实了TH-302在乏氧条件下单电子还原酶依赖性的活性增强原理，如下反应式1：
细胞色素P450氧化还原酶将TH-302这个前药进行还原，得到中间体自由基负离子，然后自由基负离子不稳定而被分解为具有细胞毒性的细胞毒素Br-IPM发挥作用。该过程的关键步骤是单电子还原过程，研究证实氧气的存在会使得单电子还原过程逆转，也就是说，氧气的存在会阻碍单电子还原过程，所以只有缺氧/乏氧的环境下，TH-302才可还原产生具有更强的细胞毒性。
申请人对TH-302进行改造，将胺基磷酸酯部分修饰为氮丙啶结构，将硝基咪唑部分修饰为含有硝基苯环的稠环结构(专利申请PCT/CN2020/114519，公开号WO2021120717A1)，同样得到了具有乏氧活性的广谱抗癌前药。
发明内容
申请人的研究人员在药效试验中发现乏氧活化的TH-302及其经过结构修饰的氮丙啶结构类似物(专利申请PCT/CN2020/114519，公开号WO2021120717A1)对于存在RAD51D致病基因突变的患者单药给药具有很好的肿瘤抑制效果，并且，即使该患者对PARP抑制剂(PARPi)耐药仍然具有良好的肿瘤抑制效果。进一步研究发现，上述乏氧激活的TH-302及其经过结构修饰的氮丙啶结构类似物分别与PARPi联用，相比于单药的药效具有一定的协同效应。
基于此，本申请提供以下的治疗癌症的方法、制药用途、药物联用物及相关药物制剂。
治疗方法，其使用乏氧激活的化合物或其盐、酯、溶剂合物、同位素变体、异构体单药或联用其他药物治疗DNA修复酶受损的癌症或肿瘤患者。
特别地，所述DNA修复酶受损选自以下的一个或多个基因缺陷：BRCA1、BRCA2、FANCA、FANCD1、FANCD2、ATM、ATR、CHEK1、CHEK2、CTP、BARD1、BRIP1、PALB2、RAD51、RAD52、RAD54、RAD55、RAD57、FAM175、NBN、Rad50、MRE11、p53、NBS1、XRS2、XRCC4/XPF、ERCC1、ERCC2/XPD、ERCC3/XPB、ERCC4/XPF、 XRCC1、Ku80、MHS6、MGMT、PARP、ERCC5/XPG、CCNH、CDK7、CETN2、DDB1、DDB2、ERCC5/XPG、ERCC6/CSB、ERCC8/CSA、LIG1/DNA Ligase I、MMS19、MNAT1、RAD23A、RAD23B、RPA1、RPA2、TFIIH、XAB2、XPA、XPC、MBD4、NEIL1、BAP1、CDK12、EXO1、FAAP20、FAN1、FANCE、FANCM、MDC1、NONO、POLQ、RBBP8、SMC5、USP11、WRN；所述RAD51选自XRCC2、XRCC3、RAD51B、RAD51C、RAD51D，优选为RAD51D。
在一个实施例中，DNA修复酶受损选自：
同源重组DNA修复酶(homologous recombination repair)受损、
核苷酸切除修复酶(nucleotide excision repair)受损、
非同源末端连接酶(nonhomologous end joining)受损、
碱基切除修复酶(base excision repair)受损、
错配修复酶(mismatch repair)受损、
范康尼贫血(Fanconi’s anemia)途径修复酶受损中的一种或更多种。
更优选为同源重组DNA修复酶受损、核苷酸切除修复酶受损、碱基切除修复酶受损中的任意一种或更多种，进一步优选为单独的同源重组DNA修复酶受损或同时具有同源重组DNA修复酶受损与核苷酸切除修复酶受损。
特别地，上述其他药物包括PARP抑制剂，所述PARP抑制剂选自奥拉帕利Olaparib、芦卡帕利Rucaparib、尼拉帕利Niraparib、他拉唑帕利Talazoparib、氟唑帕利Fluzoparib、帕米帕利Pamiparib。
特别地，上述癌症选自卵巢癌、乳腺癌、胰腺癌、输卵管癌、原发性腹膜癌、胃癌、前列腺癌、肝癌、结肠癌、直肠癌、肺癌、膀胱癌，所述肺癌优选为非小细胞肺癌、小细胞肺癌。
特别地，患者对上述PARP抑制剂耐药或不敏感。
敏感和耐药是评价患者对于一种药物是否具有抗性的定性判断，常见于微生物病原体与抗菌(细菌和真菌)药的药敏实验中。
敏感和耐药是临床在进行药敏试验时，表现出来的两种不同的结果。所谓敏感就是在做药敏试验的时候，发现病原体对这种药物很敏感，也就是这种药能全部杀死病原体；而耐药就是在实验的时候发现这种药不能杀死病原体，也就是这种药物是没有效果的。临床如果得到了是否耐药的数据，对疾病的治疗会很有意义，可以据此选择比较敏感的药物来杀死病原体。同时除了敏感和耐药，还有一个是中敏，就是中度敏感的意思，很容易产生耐药但也有可能有用，但疗效不会很好，不如敏感的治疗有效果。
在癌症治疗的化疗(相对于手术和放疗，这里的化疗是广义的，指使用药物治疗癌症)方案中，根据临床治疗指南，通常是次第使用一系列化疗药物：当首次施用的药物在施用一段时间后已经对于患者没有治疗效果或治疗效果很弱时，就认为该癌种患者已经对这种药物产生耐药、抵抗或不敏感，此时需要使用其他药物(二线药物)，对应的可能二线药物也会在施用一段时间后出现耐药、抵抗或不敏感，此时需要使用三线药物。敏感和耐药是由医学专业人员或临床医师进行诊断、判断的。
显然，癌症、肿瘤患者对PARP抑制剂敏感的具体意思是，在施用PARP抑制剂后有效果或通过医生的诊疗后判断PARP抑制剂将有效果。
在一个实施例中的治疗方法，其使用乏氧激活的化合物或其盐、酯、溶剂合物、同位素变体、异构体单药治疗RAD51D基因缺陷引起的癌症或肿瘤患者，其中，所述癌症选自卵巢癌、乳腺癌、胰腺癌、输卵管癌、原发性腹膜癌、胃癌、前列腺癌、肝癌、结肠癌、直肠癌、肺癌、膀胱癌。
在一个实施例中的治疗方法，其使用乏氧激活的化合物或其盐、酯、溶剂合物、同位素变体、异构体联用PARP抑制剂治疗RAD51D基因缺陷引起的癌症或肿瘤患者，其中，所述癌症选自卵巢癌、乳腺癌、胰腺癌、输卵管癌、原发性腹膜癌、胃癌、前列腺癌、肝癌、结肠癌、直肠癌、肺癌、膀胱癌；所述PARP抑制剂选自奥拉帕利Olaparib、芦卡帕利Rucaparib、尼拉帕利Niraparib、他拉唑帕利Talazoparib、氟唑帕利Fluzoparib、帕米帕利Pamiparib。
特别地，患者对所述PARP抑制剂耐药或不敏感。
关于本文所述药物是指药品或制剂，所制得的药品包含特定剂量范围的有效成分的乏氧激活化合物或其盐或溶剂合物，和/或所制得的药物为特定剂型、特定给药方式施用。
所制得的药品、药物、制剂还可包含药学上可接受的辅料或赋形剂。所述药物可以为临床施用的任何剂型，例如片剂、栓剂、分散片、肠溶片、咀嚼片、口崩片、胶囊、糖衣剂、颗粒剂、干粉剂、口服溶液剂、注射用小针、注射用冻干粉针或大输液。根据具体剂型和施用方式，所述药物中的药学上可接受的辅料或赋形剂可以包括下述的一种或多种：稀释剂、增溶剂、崩解剂、悬浮剂、润滑剂、粘合剂、填充剂、矫味剂、甜味剂、抗氧化剂、表面活性剂、防腐剂、包裹剂、和色素等。
特别地，在上述治疗方法中，乏氧激活的化合物选自下式Ⅰ或Ⅱ的化合物：
其中，R各自独立地选自H、-CH3、-CH2CH3，X各自独立地选自Cl、Br、MsO、TsO等离去官能团；
其中，R1、R2、R3、Cx的定义如专利申请PCT/CN2020/114519，公开号WO2021120717A1中的权利要求书所记载，在此将其全文引入本申请之中。
对TH-302结构进行修饰后的式Ⅱ结构化合物，依然是乏氧活化作用机理：在乏氧条件下对癌细胞具有比常氧条件下更强的细胞毒性。式Ⅱ结构化合物不是P-gp底物，能有效的进入脑部等中枢神经系统，能积累足够的浓度而发挥对中枢神经系统的药效，有望成为治疗原发性脑癌、肿瘤或转移至脑的转移性癌症、肿瘤的药物或用于治疗原发性脑癌、肿瘤或转移至脑的转移性癌症、肿瘤。式Ⅱ结构化合物在人的血浆和肝微粒体中比较稳定，具备开发为药物的潜力。研究人员进一步通过体内动物实验证明：式Ⅱ结构化合物具有更高的MTD，即新结构化合物相当于在先文献中公开的化合物具有更高的安全性和临床治疗剂量，对癌症或肿瘤的治疗效果可能会更好；作为对比，其抑制肿瘤生长的效果较经典的化疗药物异环磷酰胺(也是一种DNA烷化剂机理的药物)具有明显优势。
具体的，R1、R2、R3、Cx的定义如下：
Cx为5-10元的芳环或芳杂环、脂杂环或环烷烃，其与硝基苯环共用两个碳原子形成稠环结构；
R1连接在Cx环的任意骨架原子上，选自氢、卤素原子、氰基或异氰基、羟基、巯基、胺基、OTs、C1-C6烷基或Z取代烷基、C2-C6烯基或Z取代烯基、C2-C6炔基或Z取代炔基、C3-C8环烷基或Z取代环烷基、C6-C10芳基或Z取代芳基、4-15元杂环或Z取代杂环、5-15元杂芳基或Z取代杂芳基、1-6个碳原子的烷氧基或Z取代的1-6个碳原子的烷氧基、-CONR6R7、-SO2NR6R7、-SO2R6、-OCOO-R6、-COOR6、-NR6COR7、-OCOR6、-NR6SO2R7、-NR6SO2NR6R7，
R2、R3各自独立地是氢、C1-C6烷基或Z取代烷基、C2-C6烯基或Z取代烯基、C2-C6炔基或Z取代炔基、C3-C8环烷基或Z取代环烷基、C6-C10芳基或Z取代芳基、4-15元杂环或Z取代杂环、5-15元杂芳基或Z取代杂芳基或者R2、R3和与其所键结的苄位碳原子一起形成3-6元环；
基团可取代稠环碳原子上任意位置的氢原子，取代的个数为1；
Z取代基为卤素原子、氰基或异氰基、羟基、巯基、胺基、C1-C3烷基或取代烷基、C1-C3烷氧基或取代烷氧基、C2-C3烯基或取代烯基、C2-C3炔基或取代炔基、C3-C8环烷基或取代环烷基；
R6、R7各自独立地是氢、C1-C6烷基或Z取代的C1-C6烷基、C2-C6烯基或Z取代的C2-C6烯基、C2-C6炔基或Z取代的C2-C6炔基、C3-C8环烷基或Z取代的C3-C8环烷基、C6-C10芳基或Z取代的C6-C10芳基、4-15元杂环基或Z取代的4-15元杂环基、5-15元杂芳基或Z取代的5-15元杂芳基，或者R6、R7和与其所键结的原子一起形成5-7元杂环基或Z取代的5-7元杂环基。
特别地，式Ⅰ的化合物选自以下结构的化合物：
特别地，式Ⅱ的化合物选自以下结构的化合物：

与TH-302或其类似式Ⅰ结构化合物相关的制剂包括口服制剂、冻干制剂和浓缩注射液，并且相关处方、制备方法和临床配伍、施用方法被Threshold公司的相关专利：WO2010048330A1、WO2012142520A2、WO2008083101A1所详细说明并公开，在此本发明将上述申请文本的全文引入。
TH-302或其类似式Ⅰ结构化合物是一个DNA烷化剂类抗癌药，具有广泛的癌症治疗潜力，TH-302相关的癌症适应症实验、临床试验被公开在相关的Threshold公司及其他制药公司的专利申请文本中(比如WO2016011195A2、WO2004087075A1、WO2007002931A1、WO2008151253A2、WO2009018163A1、WO2009033165A2、WO2010048330A2、WO2012142520A1、WO2008083101A2、WO2020007106A1、WO2020118251A1、WO2014169035A1、WO2013116385A1、WO2019173799A2、WO2016081547A1、WO2014062856A1、WO2015069489A1、WO2012006032A2、WO2018026606A2、WO2010048330A2、WO2015171647A1、WO2013096687A1、WO2013126539A2、WO2013096684A2、WO2012009288A2、WO2012145684A2、WO2016014390A2、WO2019055786A2、WO2012135757A2、WO2015013448A2、WO2016011328A2、WO2013177633A2、WO2016011195A2、WO2015051921A2)以及FDA登记的临床试验中(NCT02402062、NCT02020226、NCT02076230、NCT01381822、NCT02093962、NCT01440088、NCT02255110、NCT02342379、NCT01864538、NCT01149915、NCT02433639、NCT00743379、NCT01485042、NCT01721941、NCT02047500、NCT00742963、NCT01497444、NCT00495144、NCT01746979、NCT01144455、NCT01403610、NCT01522872、NCT01833546、NCT02598687、NCT03098160、NCT02496832、NCT02712567)，在此本发明将上述相关申请文本以及临床试验信息全部引入。
“癌症”是指可通过侵袭而局部扩展且通过转移而全身扩展的潜在无限制生长的白血病、淋巴瘤、癌及其他恶性肿瘤(包括实体肿瘤)。
在此列举TH-302或其类似式Ⅰ结构化合物能治疗的癌症的实例包括(但不限于)肾上腺、骨、脑、乳房、支气管、结肠及/或直肠、胆囊、头及颈、肾、喉、肝、肺、神经组织、胰脏、前列腺、副甲状腺、皮肤、胃及甲状腺的癌症。癌症的某些其他实例包括急性及慢性淋巴细胞及粒细胞肿瘤、腺癌、腺瘤、基底细胞癌、子宫颈上皮分化不良及原位癌、尤文氏肉瘤、表皮样癌、巨细胞瘤、多型性神经胶母细胞瘤、毛细胞肿瘤、肠神经节细胞瘤、增生性角膜神经肿瘤、胰岛细胞癌、卡波西肉瘤、平滑肌瘤、白血病、淋巴瘤、恶性类癌瘤、恶性黑色素瘤、恶性高钙血症、马方样体型肿瘤、髓样上皮癌、转移性皮肤癌、黏膜神经瘤、骨髓瘤、蕈状肉芽肿、神经胚细胞瘤、骨肉瘤、骨原性及其他肉瘤、卵巢瘤、嗜铬细胞瘤、真性红血球增多症、原发性脑瘤、小细胞肺癌、溃疡型及乳头型二者的鳞状细胞癌、增生、精原细胞瘤、软组织肉瘤、视网膜母细胞瘤、横纹肌肉瘤、肾细胞肿瘤、局部皮肤病灶、网状细胞肉瘤及威尔姆氏肿瘤。
PARP是一种酶，全称叫聚腺苷酸二磷酸核糖基聚合酶(Poly ADP-ribose Polymerase，PARP)。PARP是一种DNA修复酶，在DNA修复通路中起关键作用。DNA单链损伤断裂时会激活PARP，它作为DNA损伤的一种分子感受器，具有识别、结合到DNA断裂位置的功能，进而激活、催化受体蛋白的聚ADP核糖基化作用，参与DNA的修复过程。
PARP抑制剂通过抑制PARP酶的工作，让这些相当于“修理工”的PARP酶没法正常工作，DNA的损伤得不到修复，细胞就可能会死亡。PARP抑制剂就是对PARP酶有抑制作用的化合物，即凡是能抑制PARP酶活性的物质均是PARP抑制剂。
特别地，本申请的PARP抑制剂选自下组：ABT-767、AZD 2461、BGB-290、BGP 15、CEP 8983、CEP 9722、DR2313、E7016、E7449、氟唑帕利、IMP 4297、INO1001、JPI 289、JPI 547、单克隆抗体B3-LysPE40缀合物、MP 124、尼拉帕利、NU 1025、NU1064、NU 1076、NU1085、奥拉帕利、ONO2231、PD 128763、R 503、R554、芦卡帕利、SBP 101、SC 101914、希明哌瑞、帕米帕利、他拉唑帕利、维利帕尼、WW 46、2-(4-(三氟甲基)苯基)-7,8-二氢-5H-硫代呋喃并[4,3-d]嘧啶-4-醇及其盐或衍生物。
优选地，PARP抑制剂选自已经上市销售的5个药物即奥拉帕利Olaparib、芦卡帕利Rucaparib、尼拉帕利Niraparib、他拉唑帕利Talazoparib、氟唑帕利Fluzoparib以及进入临床三期的药物帕米帕利Pamiparib，显然此处的PARP抑制剂实质是指含有PARP抑制剂活性成分的药物。
他拉唑帕利Talazoparib，适用于有害或疑似有害种系BRCA突变(gBRCAm)HER2阴性局部晚期或转移性乳腺癌的成人。市售剂型为0.25mg/1mg的他拉唑帕利甲苯磺酸盐胶囊，口服一次1毫克，每天1次，在不良反应的情况下考虑治疗中断或剂量减少：
首次出现不良反应，口服剂量减少到0.75mg(三个0.25mg胶囊)，每天1次；
第二次出现不良反应，口服剂量减少到0.5mg(两个0.25mg胶囊)，每天1次；
第三次出现不良反应，口服剂量减少到0.25mg(一个0.25mg胶囊)，每天1次。
尼拉帕利Niraparib，用于铂敏感的复发性上皮性卵巢癌、输卵管癌或原发性腹膜癌成人患者在含铂化疗达到完全缓解或部分缓解后的维持治疗。市售剂型为100mg的尼拉帕利甲苯磺酸盐胶囊，每天一次口服300mg,直至出现疾病进展或不可耐受的不良反应，在不良反应的情况下考虑治疗中断或剂量减少：
剂量下调首先从每天3粒胶囊(300mg)减少至每天2粒胶囊(200mg)；
如果需要进一步下调剂量，可第二次下调剂量，从每天2粒胶囊(200mg)减少至每天1粒胶囊(100mg)；
如果暂停给药和下调剂量无法控制不良反应，建议停药。
芦卡帕利Rucaparib，用于肿瘤携带一种特定基因突变(有害的BRCA)，且已使用两种或多种化疗药物治疗过的晚期卵巢癌女性。市售剂型为片剂：200mg，250mg和300mg，三种规格。推荐剂量为600毫克，每日口服两次，含或不含食物。继续治疗直至疾病进展或不可接受的毒性。对于不良反应，考虑中断治疗或减少剂量。
奥拉帕利Olaparib，用于携带胚系或体细胞BRCA突变的(gBRCAm或sBRCAm)晚期上皮性卵巢癌、输卵管癌或原发性腹膜癌初治成人患者在含铂化疗达到完全缓解或部分缓解后的维持治疗；铂敏感的复发性上皮性卵巢癌、输卵管癌或原发性腹膜癌成人患者在含铂化疗达到完全缓解或部分缓解后的维持治疗。市售剂型为片剂：150mg和100mg，两种规格。推荐剂量为300mg(2片150mg片剂)，每日2次，相当于每日总剂量为600mg。100mg片剂用于剂量减少时使用：
为处理不良事件，比如恶心、呕吐、腹泻、贫血等，可考虑中断治疗或减量；
如果需要减量，推荐剂量减至250mg(1片150mg片剂，1片100mg片剂)，每日服用2次(相当于每日总剂量为500mg)；
如果需要进一步减量，则推荐剂量减至200mg(2片100mg片剂)，每日服用2次(相当于每日总剂量为400mg)。
氟唑帕利Fluzoparib，用于既往经过二线及以上化疗的伴有胚系BRCA突变(gBRCAm)的铂敏感复发性卵巢癌、输卵管癌或原发性腹膜癌患者的治疗。市售剂型胶囊剂：50mg规格。
其他在研的进入临床的PARPi候选药物参见网页链接https://www.selleckchem.com/PARP.html及相关学术综述文献。
TH-302或其类似式Ⅰ结构化合物治疗癌症的推荐剂量可以参考Threshold公司及其他制药公司的专利申请文本(比如WO2016011195A2、WO2004087075A1、WO2007002931A1、WO2008151253A2、WO2009018163A1、WO2009033165A2、WO2010048330A2、WO2012142520A1、WO2008083101A2、WO2020007106A1、WO2020118251A1、WO2014169035A1、WO2013116385A1、WO2019173799A2、WO2016081547A1、WO2014062856A1、WO2015069489A1、WO2012006032A2、WO2018026606A2、WO2010048330A2、WO2015171647A1、WO2013096687A1、WO2013126539A2、WO2013096684A2、WO2012009288A2、WO2012145684A2、WO2016014390A2、WO2019055786A2、WO2012135757A2、WO2015013448A2、WO2016011328A2、WO2013177633A2、WO2016011195A2、WO2015051921A2)以及FDA登记的临床试验中(NCT02402062、NCT02020226、NCT02076230、NCT01381822、NCT02093962、NCT01440088、NCT02255110、NCT02342379、NCT01864538、NCT01149915、NCT02433639、NCT00743379、NCT01485042、NCT01721941、NCT02047500、NCT00742963、NCT01497444、NCT00495144、NCT01746979、NCT01144455、NCT01403610、NCT01522872、NCT01833546、NCT02598687、NCT03098160、NCT02496832、NCT02712567)中的剂量：
120mg/m2至460mg/m2的日剂量来静脉注射给药；
480mg/m2至大约670mg/m2或者例如575mg/m2的周剂量来静脉注射给药。
用于临床试验的TH-302(用于施用溶液的浓缩物)是TH-302的无菌液体制剂。用70％无水乙醇、25％二甲基乙酰胺和5％聚山梨酯80配制TH-302。它由发起人提供，在具有橡胶塞和flip-off封口的10mL玻璃小瓶中。TH-302药物产品是澄清的、无色至淡黄色的溶液，基本上不含可见颗粒。对于标称总量为650mg的TH-302，每个单次使用的小瓶含有标称填充体积为6.5mL的TH-302药物产品(相当于100mg/mL)，并且被清楚地贴上标签，其公开了批号、施用途径、所需的储存条件、发起人的名称和适用的规定所要求的适宜的预警标记。在施用前需要按照药房手册进行稀释。
在施用前用可商购获得的5％葡萄糖水溶液稀释至总体积为500mL(对于≥1000mg的总剂量为1000mL)施用，以获得所需的终浓度。用不含邻苯二甲酸二(2-乙基己基)酯(无DEHP)的5％葡萄糖水溶液制备每剂TH-302，并使用不含DEHP的静脉输液施用装置静脉滴注。
当然也可以使用Threshold公司开发的冻干制剂：
将TH-302(100mg)和蔗糖(1g)的溶液(20mL)加入冻干小瓶中并冻干以产生TH-302的冻干单位剂型，载药量不到5mg/cm3。为了人类施用的目的，将单位剂型溶解在的5％葡萄糖注射液中，并向患者施用适量的该溶液；
后续人类患者TH-302的I期临床试验给药方案使用冻干制剂，在100mL玻璃小瓶中制备注射用TH-302冻干制剂，载药量为100mg/100ml，在2-8℃的受控条件下储存，使用时注射到冻干制剂瓶中250mL的5％葡萄糖注射液，并通过输注泵在30分钟内静脉滴注。
单药，即单药治疗。联用，即联合用药治疗。单药治疗是指在一个疗程中仅使用一种抗癌药物。联合治疗是指在一个疗程中同时或先后使用两种或两种以上的抗癌药物。
一般而言，联合治疗需要根据病情特点、联用药物种类探索不同的给药剂量、给药周期，只有根据上述情况，探索得到的联合用药治疗方案才可能取得较单一用药治疗好的治疗效果。
单药和联用治疗方案的药物给药剂量、给药周期均需要在参考上述TH-302及其类似化合物和PARPi的剂量、给药方案通过临床试验探索得到。
本申请进一步提供上述治疗方法的步骤，包括：
检测癌症或肿瘤患者的RAD51D基因突变情况；
如该患者或患者的肿瘤组织具有RAD51D致病基因突变，则使用含有下式Ⅰ或Ⅱ的乏氧激活化合物的药物单药或联用PARP抑制剂进行治疗：
其中，R各自独立地选自H、-CH3、-CH2CH3，X各自独立地选自Cl、Br、MsO、TsO等离去官能团；
其中，R1、R2、R3、Cx的定义如专利申请PCT/CN2020/114519，公开号WO2021120717A1中的权利要求书所记载，在此将其全文引入本申请之中。
具体的，R1、R2、R3、Cx的定义如下：
Cx为5-10元的芳环或芳杂环、脂杂环或环烷烃，其与硝基苯环共用两个碳原子形成稠环结构；
R1连接在Cx环的任意骨架原子上，选自氢、卤素原子、氰基或异氰基、羟基、巯基、胺基、OTs、C1-C6烷基或Z取代烷基、C2-C6烯基或Z取代烯基、C2-C6炔基或Z取代炔基、C3-C8环烷基或Z取代环烷基、C6-C10芳基或Z取代芳基、4-15元杂环或Z取代杂环、5-15元杂芳基或Z取代杂芳基、1-6个碳原子的烷氧基或Z取代的1-6个碳原子的烷氧基、-CONR6R7、-SO2NR6R7、-SO2R6、-OCOO-R6、-COOR6、-NR6COR7、-OCOR6、-NR6SO2R7、-NR6SO2NR6R7，
R2、R3各自独立地是氢、C1-C6烷基或Z取代烷基、C2-C6烯基或Z取代烯基、C2-C6炔基或Z取代炔基、C3-C8环烷基或Z取代环烷基、C6-C10芳基或Z取代芳基、4-15元杂环或Z取代杂环、5-15元杂芳基或Z取代杂芳基或者R2、R3和与其所键结的苄位碳原子一起形成3-6元环；
基团可取代稠环碳原子上任意位置的氢原子，取代的个数为1；
Z取代基为卤素原子、氰基或异氰基、羟基、巯基、胺基、C1-C3烷基或取代烷基、C1-C3烷氧基或取代烷氧基、C2-C3烯基或取代烯基、C2-C3炔基或取代炔基、C3-C8环烷基或取代环烷基；
R6、R7各自独立地是氢、C1-C6烷基或Z取代的C1-C6烷基、C2-C6烯基或Z取代的C2-C6烯基、C2-C6炔基或Z取代的C2-C6炔基、C3-C8环烷基或Z取代的C3-C8环烷基、C6-C10芳基或Z取代的C6-C10芳基、4-15元杂环基或Z取代的4-15元杂环基、5-15元杂芳基或Z取代的5-15元杂芳基，或者R6、R7和与其所键结的原子一起形成5-7元杂环基或Z取代的5-7元杂环基。
特别地，上述RAD51D基因突变的TMB(肿瘤基因突变负荷)水平为中。
由于不同瘤种之间TMB(Tumor mutation load(burden)即肿瘤基因突变负荷)高低不同：一般认为，TMB超过20个突变/Mb(Mb代表的就是每百万个碱基)，就是高；低于10个突变/Mb，就是低，处于中间的就是中。2017年世界肺癌大会上，施贵宝公司(BMS)公布过一项名为CheckMate-032的临床试验结果。这是一项纳入了401名一线治疗失败的晚期肺癌患者的II期临床试验，接受PD-1抑制剂单独或联合伊匹木治疗。按照TMB高低划分成TMB高、TMB中、TMB低三类病人，那么在接受联合治疗的人群中，三组的有效率分别为62％、20％、23％，TMB高的人群有效率高3倍；而三组的中位总生存期，分别为：22.0个月、3.6个月、3.4个月——22.0个月与3.4个月，相差6倍！该试验证明，对于不同的癌症治疗药物，不同的TMB水平对于药物的疗效有很大的影响。
特别地，PARP抑制剂选自奥拉帕利Olaparib、芦卡帕利Rucaparib、尼拉帕利Niraparib、他拉唑帕利Talazoparib、氟唑帕利Fluzoparib、帕米帕利Pamiparib。
特别地，患者对上述PARP抑制剂耐药或不敏感。
本申请还提供下式Ⅰ或Ⅱ的乏氧激活化合物或其盐、酯、溶剂合物、同位素变体、异构体的制药用途，其用于制备单药或联用其他治疗药物治疗RAD51D致病基因突变的癌症、肿瘤患者的药物：
其中，R各自独立地选自H、-CH3、-CH2CH3，X各自独立地选自Cl、Br、MsO、TsO等离去官能团；
其中，R1、R2、R3、Cx的定义如专利申请PCT/CN2020/114519，公开号WO2021120717A1中的权利要求书所记载，在此将其全文引入本申请之中。
特别地，对于上述制药用途，其RAD51D基因突变的TMB(肿瘤基因突变负荷)水平为中。
特别地，对于上述制药用途，所述其他治疗药物包括PARP抑制剂，所述PARP抑制剂选自奥拉帕利Olaparib、芦卡帕利Rucaparib、尼拉帕利Niraparib、他拉唑帕利Talazoparib、氟唑帕利Fluzoparib、帕米帕利Pamiparib；
特别地，对于上述制药用途，所述癌症选自卵巢癌、乳腺癌、胰腺癌、输卵管癌、原发性腹膜癌、胃癌、前列腺癌、肝癌、结肠癌、直肠癌、肺癌、膀胱癌。
特别地，患者对上述PARP抑制剂不敏感或耐药。
本申请还提供一种治疗由RAD51D致病基因突变引起的癌症的药物，该药物含有下式Ⅰ或Ⅱ的乏氧激活化合物或其盐、酯、溶剂合物、同位素变体、异构体：
其中，R各自独立地选自H、-CH3、-CH2CH3，X各自独立地选自Cl、Br、MsO、TsO等离去官能团；
其中，R1、R2、R3、Cx的定义如专利申请PCT/CN2020/114519，公开号WO2021120717A1中的权利要求书所记载，在此将其全文引入本申请之中。
特别地，对于上述药物，在使用时，其可以单用或与PARP抑制剂联用。
优选地，PARP抑制剂选自奥拉帕利Olaparib、芦卡帕利Rucaparib、尼拉帕利Niraparib、他拉唑帕利Talazoparib、氟唑帕利Fluzoparib、帕米帕利Pamiparib。
优选地，基因突变的TMB(肿瘤基因突变负荷)水平为中。
优选地，癌症选自卵巢癌、乳腺癌、胰腺癌、输卵管癌、原发性腹膜癌、胃癌、前列腺癌、肝癌、结肠癌、直肠癌、肺癌、膀胱癌。
特别地，上述药物中，患者对所述PARP抑制剂耐药或不敏感。
本申请还提供一种药物联用物，其包括如下物质作为活性成分：
乏氧激活的化合物或其盐、酯、溶剂合物、同位素变体、异构体，以及
PARP抑制剂；
将所述活性成分共同配制或分开配制，用于配伍使用、同时使用或分开使。
通常，作为本申请所述的药物联用物特征的活性成分可将所述活性成分共同配制(单剂量单位)或分开配制(套装)。
共同配制或分开配制的两种活性成分通常可同时给药；或鉴于它们各自制剂的性质，相隔一定时间间隔分开给药，所述时间间隔有利于所述两种活性成分配伍作用的最佳化。
药物联用物可以是一种复方药物，其为一种活性成分为上述乏氧激活的化合物或其盐、酯、溶剂合物、同位素变体、异构体和另一种活性成分为PARP抑制剂组成的药物组合物。此种情况下，上述活性成分共同配制，同时使用。
药物联用物也可以是一种类似于辉瑞新冠药物Paxlovid的套装，用于同时售卖或分开售卖。此种情况下，上述活性成分分开配制，但分开配制成的两种或两种以上的药物既可同时给药，也可根据各自制剂的性质，相隔一定时间间隔分开给药。
作为本申请的一个具体实施方式，分开配制时，配制成的一种药物为含有上述乏氧激活的化合物或其盐、酯、溶剂合物、同位素变体、异构体以及药学上可用的辅料，另一种药物为含有PARP抑制剂以及药学上可用的辅料。上述两种药物组成的药物联用物，可以同时给药，也可根据各自制剂的性质，相隔一定时间间隔分开给药。
本申请提供的药物联用物，其用于治疗DNA修复酶受损的癌症或肿瘤患者。也即该药物联用物可能会对具有DNA修复酶受损的癌症或肿瘤患者具有更好的治疗效果。
特别地，所述DNA修复酶受损选自以下的一个或多个基因缺陷：BRCA1、BRCA2、FANCA、FANCD1、FANCD2、ATM、ATR、CHEK1、CHEK2、CTP、BARD1、BRIP1、PALB2、RAD51、RAD52、RAD54、RAD55、RAD57、FAM175、NBN、Rad50、MRE11、p53、NBS1、XRS2、XRCC4/XPF、ERCC1、ERCC2/XPD、ERCC3/XPB、ERCC4/XPF、XRCC1、Ku80、MHS6、MGMT、PARP、ERCC5/XPG、CCNH、CDK7、CETN2、DDB1、DDB2、ERCC5/XPG、ERCC6/CSB、ERCC8/CSA、LIG1/DNA Ligase I、MMS19、MNAT1、RAD23A、RAD23B、RPA1、RPA2、TFIIH、XAB2、XPA、XPC、MBD4、NEIL1、BAP1、CDK12、EXO1、FAAP20、FAN1、FANCE、FANCM、MDC1、NONO、POLQ、RBBP8、SMC5、USP11、WRN；所述RAD51选自XRCC2、XRCC3、RAD51B、RAD51C、RAD51D，优选为RAD51D。
特别地，所述癌症选自卵巢癌、乳腺癌、胰腺癌、输卵管癌、原发性腹膜癌、胃癌、前列腺癌、肝癌、结肠癌、直肠癌、肺癌、膀胱癌，所述肺癌优选为非小细胞肺癌、小细胞肺癌。
作为本申请的一个优选实施例，药物联用物中的活性成分PARP抑制剂选自奥拉帕利Olaparib、芦卡帕利Rucaparib、尼拉帕利Niraparib、他拉唑帕利Talazoparib、氟唑帕利Fluzoparib、帕米帕利Pamiparib；药物联用物中的活性成分乏氧激活的化合物选自下式Ⅰ或Ⅱ的化合物：
其中，R各自独立地选自H、-CH3、-CH2CH3，X各自独立地选自Cl、Br、MsO、TsO等离去官能团；
其中，R1、R2、R3、Cx的定义如专利申请PCT/CN2020/114519，公开号WO2021120717A1中的权利要求书所记载。
作为一种优选，式Ⅰ的乏氧激活化合物选自以下结构的化合物：
作为一种优选，式Ⅱ的乏氧激活化合物选自以下结构的化合物：
本申请还提供一种药物制剂，其由上述药物联用物的活性成分与药学上可用的辅料制备而成。
上述药物制剂的剂型选自颗粒剂、片剂、丸剂、胶囊剂、注射剂或冻干粉针。
本申请还提供上述药物联用物和/或上述药物制剂在制备抗肿瘤药物中的用途。
作为上述药物联用物和/或上述药物制剂在制备抗肿瘤药物中用途的一种优选，该肿瘤选自卵巢癌、乳腺癌、胰腺癌、输卵管癌、原发性腹膜癌、胃癌、前列腺癌、肝癌、结肠癌、直肠癌、肺癌、膀胱癌，所述肺癌优选为非小细胞肺癌、小细胞肺癌。
上述药物除含有式Ⅰ或Ⅱ的乏氧激活化合物或其盐、酯、溶剂合物、同位素变体、异构体外，还应根据药品、药物、制剂的特点，添加药学上可接受的辅料或赋形剂。所述药物可以为临床施用的任何剂型，例如片剂、栓剂、分散片、肠溶片、咀嚼片、口崩片、胶囊、糖衣剂、颗粒剂、干粉剂、口服溶液剂、注射用小针、注射用冻干粉针或大输液。根据具体剂型和施用方式，所述药物中的药学上可接受的辅料或赋形剂可以包括下述的一种或多种：稀释剂、增溶剂、崩解剂、悬浮剂、润滑剂、粘合剂、填充剂、矫味剂、甜味剂、抗氧化剂、表面活性剂、防腐剂、包裹剂、和色素等。
附图说明
图1为LD1-2032-361588人源性卵巢癌体内移植瘤PDX模型中各治疗组小鼠肿瘤体积的生长曲线图；
图2为LD1-2032-361588人源性卵巢癌体内移植瘤PDX模型中各治疗组小鼠体重变化百分比随时间变化曲线图。
具体实施方式
以下参照具体的实施例来说明本发明。本领域技术人员能够理解，这些实施例仅用于说明本发明，其不以任何方式限制本发明的范围。
下述实施例中的实验方法，如无特殊说明，均为常规方法。所用的药材原料、试剂材料等，如无特殊说明，均为市售购买产品。
“患者”及“个体”可互换使用，是指需要癌症治疗的哺乳动物。通常，患者是人类。通常，患者是诊断患有癌症的人类。在某些实施例中，“患者”或“个体”可指用于筛选、表征及评估药物及疗法的非人类哺乳动物，例如非人类灵长类动物、狗、猫、兔、猪、小鼠或大鼠。
“前药”是指投与或施用之后经新陈代谢或以其他方式转化为关于至少一种性质的生物学活性或活性更高的化合物(或药物)的化合物。相对于药物，前药以使其相对于药物活性较低或无活性的方式化学修饰，但化学修饰使得在前药投与之后通过代谢或其他生物过程产生相应药物。前药可相对于活性药物具有改变的代谢稳定性或输送特征、较少副作用或较低毒性或经改良的风味。前药可使用除相应药物以外的反应物来合成。
“治疗”或“治疗患者”是指向患者投与、使用或施用本发明相关的治疗有效量的药物。
向患者“投与”或“施用”“使用”药物是指直接投与或施用(其可由医学专业人士向患者投与或施用或者可自投与或施用)及/或间接投与或施用，其可是开处药物的行为。举例而言，指示患者自投与或施用药物及/或将药物的处方提供给患者的医师是向患者投与或施用药物。
药物的“治疗有效量”是指当向患有癌症的患者投与或施用、使用时，将具有预期的治疗效应(例如患者中一或多种癌症的临床表现的缓和、改善、缓解或消除)的药物的量。治疗效应不必通过投与或施用一个剂量而出现，且可仅在投与或施用一系列剂量后出现。因此，治疗有效量可以一或多次来投与或施用。
病况或患者的“治疗”是指采取步骤以获得有益或期望结果(包括临床结果)。出于本发明的目的，有益或期望临床结果包括(但不限于)一或多种癌症症状的缓和或改善；疾病程度的减弱；疾病进展的延迟或减缓；疾病状态的改善、缓解或稳定；或其他有益结果。在一些情形下，癌症的治疗可使得部分反应或稳定疾病。
“肿瘤细胞”是指任何适当物种(例如，哺乳动物，例如鼠类、犬、猫、马或人类)的肿瘤细胞。
以上对本发明具体实施方式的描述并不限制本发明，本领域技术人员可以根据本发明作出各种改变或变形，只要不脱离本发明的精神，均应属于本发明所附权利要求的范围。
以下提供本发明的具体实验。
本发明披露的试验过程中动物实验的试验方案、任何修改、动物福利和使用均通过所在CRO(合同研究组织)IACUC委员会审核并批准通过。试验过程中，动物福利和实验操作均符合AAALAC的要求。
化合物AST即专利申请PCT/CN2020/114519，公开号WO2021120717A1中的表1中化合物01的S异构体，也即专利申请PCT/CN2021/101870，公开号WO2022052564A1中的化合物B，其结构式如下所示：
一、化合物TH-302、AST和Olaparib单药及TH-302、AST和Olaparib联用药对LD1-2032-361588人源性卵巢癌体内移植瘤PDX模型的抗肿瘤作用及安全性评价
该模型建立于LD1-2032-361588人源性卵巢癌肿瘤组织，传至FP3+3代，用于本次药效实验。肿瘤来源于62岁的卵巢癌肝转移女性患者，病理诊断为低中分化腺癌，且在治疗过程中对PARPi产生耐药。通过基因检测，该模型是带有RAD51D致病基因突变的PDX模型，突变位点为p.Lys91Ilefs*13。
将LD1-2032-361588人源性卵巢癌体内移植瘤的瘤块切成大小约为3mm×3mm×3mm(约45～60mg)的肿瘤组织，并将其接种于NU/NU小鼠皮下。观察接种后小鼠并监测肿瘤的生长，在接种第27天荷瘤小鼠平均肿瘤体积为183.67mm3时进行分组给药，分组给药当天定义为第0天，具体给药途径、剂量及方案信息如下表1。
表1：给药途径、剂量及方案

注：N：动物只数；给药体积：根据荷瘤鼠体重调整给药体积(0.2mL/20g)；p.o.：灌胃给药；i.v.：尾
静脉注射；QW：每周给药一次；QD：每天给药一次。
在试验不同天数记录各治疗组和对照组肿瘤生长情况，如表2所示，相应地各组小鼠肿瘤体积的生长曲线如图1所示。根据相对肿瘤增殖率和相对肿瘤抑制率对疗效进行评价，各组药效分析如表3所示，显著性统计分析如表4所示。记录治疗组和对照组给药后体重变化，研究人源性卵巢癌体内移植瘤PDX模型中各组的安全性，小鼠体重变化结果如表5所示，各治疗组体重变化百分比随时间变化曲线图如图2所示(体重变化百分比：RCBW(％)＝(BWi-BW0)/BW0×100，BWi为开始给药后的体重，BW0为首次给药时的体重)。
表2：各组小鼠肿瘤体积随治疗时间的变化(mm3)

肿瘤体积和荷瘤鼠体重测量：使用游标卡尺每周两次测量，肿瘤体积计算公式为V＝0.5a×b2，a，b分别代表肿瘤的长径和宽径。
表3：受试化合物在LD1-2032-361588人源性卵巢癌皮下异种移植瘤模型上的抗肿瘤药效评价总结
相对肿瘤增殖率T/C(％)，计算公式如下：T/C％＝TRTV/CRTV×100％(TRTV：治疗组RTV；CRTV：阴性对照组RTV)。根据肿瘤测量的结果计算出相对肿瘤体积(relative tumor volume，RTV)，计算公式为RTV＝Vt/V0，其中V0是分组给药时(即d0)测量所得平均肿瘤体积，Vt为某一次测量时的平均肿瘤体积，TRTV与CRTV取同一天数据。
肿瘤生长抑制率TGI(％)＝[1-(Ti-T0)/(Vi-V0)]×100，Ti为化合物组开始给药后的平均肿瘤体积，T0为化合物组首次给药时的平均肿瘤体积，V0为溶媒对照组首次给药时的平均肿瘤体积，Vi为溶媒对照组开始给药后的平均肿瘤体积。
表4：统计分析
表5：小鼠体重(g)随治疗时间变化情况

开始给药后第32天，对照组荷瘤鼠平均肿瘤体积为1709.32±271.80mm3，受试化合物Olaparib(50mg/kg,PO,QD*32days)单药组、TH-302(80mg/kg,IV,QW×3)单药组、Olaparib联合TH-302给药组、AST(20mg/kg,IV,QD×5,2days off；2weeks off；QD×5)单药组和Olaparib联合AST给药组荷瘤鼠的平均肿瘤体积分别为：1261.91±136.43mm3、239.28±101.70mm3、118.07±25.29mm3、823.26±100.46mm3和476.89±73.20mm3；相对肿瘤增殖率T/C(％)分别为73.82％、14.04％、6.91％、42.28％和27.96％；肿瘤体积生长抑制率TGI(％)分别为29.33％、96.33％、104.32％、58.06％和80.77％。
实验结果表明，对于带有RAD51D致病基因突变的人源性卵巢癌肿瘤模型中，受试化合物Olaparib单药组对肿瘤抑制效果差，证明该肿瘤模型对Olaparib确实有耐药性；受试化合物TH-302单药组、Olaparib联合TH-302给药组、AST单药组和Olaparib联合AST给药组与对照组相比，均表现出统计学上的显著的抑制肿瘤生长的作用(p<0.05且T/C％<40％)；Olaparib联合TH-302给药组和TH-302单药组相比无统计学上的显著性差异，Olaparib联合AST给药组和AST单药组相比有统计学上的显著性差异，表明AST与Olaparib联用，可以一定程度提高其抑制肿瘤生长的作用。
实验动物的体重作为监测药物毒性的间接指标，各给药组给药后小鼠均未出现体重明显下降的现象，表明荷瘤小鼠对该实验剂量下各药物的治疗耐受良好。
临床研究中，研究人员使用PARP抑制剂对具有同源重组修复缺陷的患者进行治疗。但是随着PARPi在临床的应用，PARPi耐药已成为其在临床应用的不可避免的问题。现有的研究表明同源重组修复、DNA复制叉保护、PARPi药代动力学改变等是导致PARPi耐药的主要原因。TH-302和AST的作用原理与PARPi完全不同，但对同源重组修复缺陷(RAD51D致病基因突变是同源重组修复缺陷突变之一)的患者同样有效。这就为临床上产生PARPi耐药，且具有同源重组修复缺陷突变的患者提供了新的治疗方案。
我们的研究结果也表明，TH-302和AST在Olaparib耐药的小鼠卵巢癌PDX模型中均具有较好的抑瘤能力，并且AST和Olapairib的联用相较AST单药具有显著的协同效应。这就为我们在临床上治疗带有HRR基因致病突变但是PARPi耐药的患者带来了新的希望，并找到了重要的理论及实验依据。
TH-302和AST是一种在缺氧/乏氧条件下能够被激活，并释放出细胞毒素，进而特异性的杀伤肿瘤细胞和肿瘤组织的小分子前药，TH-302和AST为乏氧活化的DNA烷化剂。
下式I的通式化合物：
在相关专利申请中已被证明具有与TH-302类似的机理，因此这类通式化合物具有与TH-302类似的效果是完全可以预测的。
同理，下式II的通式化合物：
在相关专利申请PCT/CN2020/114519(公开号WO2021120717A1)中也已被证明具有与AST类似的机理，因此这类通式化合物具有与AST类似的效果是完全可以预测的。
虽然本申请实施例中选用的PARP抑制剂为奥拉帕利Olaparib，但芦卡帕利Rucaparib、尼拉帕利Niraparib、他拉唑帕利Talazoparib、氟唑帕利Fluzoparib、帕米帕利Pamiparib等同样属于PARP抑制剂，作用机理与奥拉帕利Olaparib类似，均是阻断参与修复受损DNA酶发挥作用，因此，可以推定，芦卡帕利Rucaparib、尼拉帕利Niraparib、他拉唑帕利Talazoparib、氟唑帕利Fluzoparib、帕米帕利Pamiparib等PARPi具有与上述实验中的奥拉帕利Olaparib类似的肿瘤抑制疗效。

Claims (27)

  1. 治疗方法，其使用乏氧激活的化合物或其盐、酯、溶剂合物、同位素变体、异构体单药或联用其他药物治疗DNA修复酶受损的癌症或肿瘤患者。
  2. 根据权利要求1所述的治疗方法，其中，DNA修复酶受损选自以下的一个或多个基因缺陷：BRCA1、BRCA2、FANCA、FANCD1、FANCD2、ATM、ATR、CHEK1、CHEK2、CTP、BARD1、BRIP1、PALB2、RAD51、RAD52、RAD54、RAD55、RAD57、FAM175、NBN、Rad50、MRE11、p53、NBS1、XRS2、XRCC4/XPF、ERCC1、ERCC2/XPD、ERCC3/XPB、ERCC4/XPF、XRCC1、Ku80、MHS6、MGMT、PARP、ERCC5/XPG、CCNH、CDK7、CETN2、DDB1、DDB2、ERCC5/XPG、ERCC6/CSB、ERCC8/CSA、LIG1/DNA Ligase I、MMS19、MNAT1、RAD23A、RAD23B、RPA1、RPA2、TFIIH、XAB2、XPA、XPC、MBD4、NEIL1、BAP1、CDK12、EXO1、FAAP20、FAN1、FANCE、FANCM、MDC1、NONO、POLQ、RBBP8、SMC5、USP11、WRN；所述RAD51选自XRCC2、XRCC3、RAD51B、RAD51C、RAD51D，优选为RAD51D。
  3. 根据权利要求1所述的治疗方法，其中，
    所述其他药物包括PARP抑制剂，所述PARP抑制剂选自奥拉帕利Olaparib、芦卡帕利Rucaparib、尼拉帕利Niraparib、他拉唑帕利Talazoparib、氟唑帕利Fluzoparib、帕米帕利Pamiparib；
    所述癌症选自卵巢癌、乳腺癌、胰腺癌、输卵管癌、原发性腹膜癌、胃癌、前列腺癌、肝癌、结肠癌、直肠癌、肺癌、膀胱癌，所述肺癌优选为非小细胞肺癌、小细胞肺癌。
  4. 根据权利要求3所述的治疗方法，其中，患者对所述PARP抑制剂耐药或不敏感。
  5. 治疗方法，其使用乏氧激活的化合物或其盐、酯、溶剂合物、同位素变体、异构体单药治疗RAD51D基因缺陷引起的癌症或肿瘤患者，其中，
    所述癌症选自卵巢癌、乳腺癌、胰腺癌、输卵管癌、原发性腹膜癌、胃癌、前列腺癌、肝癌、结肠癌、直肠癌、肺癌、膀胱癌。
  6. 治疗方法，其使用乏氧激活的化合物或其盐、酯、溶剂合物、同位素变体、异构体联用PARP抑制剂治疗RAD51D基因缺陷引起的癌症或肿瘤患者，其中，
    所述癌症选自卵巢癌、乳腺癌、胰腺癌、输卵管癌、原发性腹膜癌、胃癌、前列腺癌、肝癌、结肠癌、直肠癌、肺癌、膀胱癌；
    所述PARP抑制剂选自奥拉帕利Olaparib、芦卡帕利Rucaparib、尼拉帕利Niraparib、他拉唑帕利Talazoparib、氟唑帕利Fluzoparib、帕米帕利Pamiparib。
  7. 根据权利要求6所述的治疗方法，其中，患者对所述PARP抑制剂耐药或不敏感。
  8. 根据权利要求1-7任一项所述的治疗方法，所述乏氧激活的化合物选自下式Ⅰ或Ⅱ的化合物：
    其中，R各自独立地选自H、-CH3、-CH2CH3，X各自独立地选自Cl、Br、MsO、TsO等离去官能团；
    其中，R1、R2、R3、Cx的定义如专利申请PCT/CN2020/114519，公开号WO2021120717A1中的权利要求书所记载。
  9. 根据权利要求8所述的治疗方法，其中，
    式Ⅰ的乏氧激活化合物选自以下结构的化合物：
    式Ⅱ的乏氧激活化合物选自以下结构的化合物：

  10. 治疗方法，包括以下步骤：
    检测癌症或肿瘤患者的RAD51D基因突变情况；
    如该患者或患者的肿瘤组织具有RAD51D致病基因突变，则使用含有下式Ⅰ或Ⅱ的乏氧激活化合物的药物单药或联用PARP抑制剂进行治疗：
    其中，R各自独立地选自H、-CH3、-CH2CH3，X各自独立地选自Cl、Br、MsO、TsO等离去官能团；
    其中，R1、R2、R3、Cx的定义如专利申请PCT/CN2020/114519，公开号WO2021120717A1中的权利要求书所记载。
  11. 根据权利要求10所述的治疗方法，其中，
    所述PARP抑制剂选自奥拉帕利Olaparib、芦卡帕利Rucaparib、尼拉帕利Niraparib、他拉唑帕利Talazoparib、氟唑帕利Fluzoparib、帕米帕利Pamiparib。
  12. 根据权利要求10或11所述的治疗方法，其中，患者对所述PARP抑制剂耐药或不敏感。
  13. 下式Ⅰ或Ⅱ的乏氧激活化合物或其盐、酯、溶剂合物、同位素变体、异构体的制药用途，其用于制备单药或联用其他治疗药物治疗RAD51D致病基因突变的癌症、肿瘤患者的药物：
    其中，R各自独立地选自H、-CH3、-CH2CH3，X各自独立地选自Cl、Br、MsO、TsO等离去官能团；
    其中，R1、R2、R3、Cx的定义如专利申请PCT/CN2020/114519，公开号WO2021120717A1中的权利要求书所记载。
  14. 根据权利要求13所述的制药用途，其中，
    所述其他治疗药物包括PARP抑制剂，所述PARP抑制剂选自奥拉帕利Olaparib、芦卡帕利Rucaparib、尼拉帕利Niraparib、他拉唑帕利Talazoparib、氟唑帕利Fluzoparib、帕米帕利Pamiparib；
    所述癌症选自卵巢癌、乳腺癌、胰腺癌、输卵管癌、原发性腹膜癌、胃癌、前列腺癌、肝癌、结肠癌、直肠癌、肺癌、膀胱癌。
  15. 根据权利要求13或14所述的制药用途，其中，患者对所述PARP抑制剂耐药或不敏感。
  16. 治疗由RAD51D致病基因突变引起的癌症的药物，该药物含有下式Ⅰ或Ⅱ的乏氧激活化合物或其盐、酯、溶剂合物、同位素变体、异构体：
    其中，R各自独立地选自H、-CH3、-CH2CH3，X各自独立地选自Cl、Br、MsO、TsO等离去官能团；
    其中，R1、R2、R3、Cx的定义如专利申请PCT/CN2020/114519，公开号WO2021120717A1中的权利要求书所记载。
  17. 根据权利要求16所述的药物，该药物与PARP抑制剂联用，其中，
    PARP抑制剂选自奥拉帕利Olaparib、芦卡帕利Rucaparib、尼拉帕利Niraparib、他拉唑帕利Talazoparib、氟唑帕利Fluzoparib、帕米帕利Pamiparib；
    所述癌症选自卵巢癌、乳腺癌、胰腺癌、输卵管癌、原发性腹膜癌、胃癌、前列腺癌、肝癌、结肠癌、直肠癌、肺癌、膀胱癌。
  18. 根据权利要求17所述的药物，其中，患者对所述PARP抑制剂耐药或不敏感。
  19. 一种药物联用物，其特征在于，包括如下物质作为活性成分：
    乏氧激活的化合物或其盐、酯、溶剂合物、同位素变体、异构体，以及
    PARP抑制剂；
    其中，将所述活性成分共同配制或分开配制，用于配伍使用、同时使用或分开使用。
  20. 根据权利要求19所述的药物联用物，其特征在于，所述药物联用物用于治疗DNA修复酶受损的癌症或肿瘤患者。
  21. 根据权利要求20所述的治疗方法，其中，
    所述DNA修复酶受损选自以下的一个或多个基因缺陷：BRCA1、BRCA2、FANCA、FANCD1、FANCD2、ATM、ATR、CHEK1、CHEK2、CTP、BARD1、BRIP1、PALB2、RAD51、RAD52、RAD54、RAD55、RAD57、FAM175、NBN、Rad50、MRE11、p53、NBS1、XRS2、XRCC4/XPF、ERCC1、ERCC2/XPD、ERCC3/XPB、ERCC4/XPF、XRCC1、Ku80、MHS6、MGMT、PARP、ERCC5/XPG、CCNH、CDK7、CETN2、DDB1、DDB2、ERCC5/XPG、ERCC6/CSB、ERCC8/CSA、LIG1/DNA Ligase I、MMS19、MNAT1、RAD23A、RAD23B、RPA1、RPA2、TFIIH、XAB2、XPA、XPC、MBD4、NEIL1、BAP1、CDK12、EXO1、FAAP20、FAN1、FANCE、FANCM、MDC1、NONO、POLQ、RBBP8、SMC5、USP11、WRN；所述RAD51选自XRCC2、XRCC3、RAD51B、RAD51C、RAD51D，优选为RAD51D；
    所述癌症选自卵巢癌、乳腺癌、胰腺癌、输卵管癌、原发性腹膜癌、胃癌、前列腺癌、肝癌、结肠癌、直肠癌、肺癌、膀胱癌，所述肺癌优选为非小细胞肺癌、小细胞肺癌。
  22. 根据权利要求19所述的药物联用物，其中，
    所述PARP抑制剂选自奥拉帕利Olaparib、芦卡帕利Rucaparib、尼拉帕利Niraparib、他拉唑帕利Talazoparib、氟唑帕利Fluzoparib、帕米帕利Pamiparib；
    所述乏氧激活的化合物选自下式Ⅰ或Ⅱ的化合物：
    其中，R各自独立地选自H、-CH3、-CH2CH3，X各自独立地选自Cl、Br、MsO、TsO等离去官能团；
    其中，R1、R2、R3、Cx的定义如专利申请PCT/CN2020/114519，公开号WO2021120717A1中的权利要求书所记载。
  23. 根据权利要求22所述的药物联用物，其中，
    式Ⅰ的乏氧激活化合物选自以下结构的化合物：
    式Ⅱ的乏氧激活化合物选自以下结构的化合物：
  24. 一种药物制剂，其特征在于，其由权利要求19所述药物联用物的活性成分与药学上可用的辅料制备而成。
  25. 根据权利要求24所述的药物制剂，其特征在于，所述药物制剂的剂型选自颗粒剂、 片剂、丸剂、胶囊剂、注射剂或冻干粉针。
  26. 一种权利要求19所述的药物联用物和/或权利要求24所述的药物制剂在制备抗肿瘤药物中的用途。
  27. 根据权利要求26所述的用途，其中，所述肿瘤选自卵巢癌、乳腺癌、胰腺癌、输卵管癌、原发性腹膜癌、胃癌、前列腺癌、肝癌、结肠癌、直肠癌、肺癌、膀胱癌，所述肺癌优选为非小细胞肺癌、小细胞肺癌。
PCT/CN2023/120712 2022-09-22 2023-09-22 乏氧激活的化合物在制备治疗癌症患者的药物中的用途 WO2024061346A1 (zh)

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