WO2022121929A1 - Utilisation d'un composé pyrido[1,2-a]pyrimidinone dans le traitement de tumeurs gynécologiques - Google Patents

Utilisation d'un composé pyrido[1,2-a]pyrimidinone dans le traitement de tumeurs gynécologiques Download PDF

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WO2022121929A1
WO2022121929A1 PCT/CN2021/136363 CN2021136363W WO2022121929A1 WO 2022121929 A1 WO2022121929 A1 WO 2022121929A1 CN 2021136363 W CN2021136363 W CN 2021136363W WO 2022121929 A1 WO2022121929 A1 WO 2022121929A1
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pharmaceutically acceptable
treatment
compound
formula
acceptable salt
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PCT/CN2021/136363
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English (en)
Chinese (zh)
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杨安琪
张喜全
王训强
于鼎
卢光雪
汪荣亮
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正大天晴药业集团股份有限公司
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Priority to CN202180081060.9A priority Critical patent/CN116761608A/zh
Publication of WO2022121929A1 publication Critical patent/WO2022121929A1/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
    • 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 application belongs to the field of medicinal chemistry, and relates to the use of pyrido[1,2-a]pyrimidinone compounds for treating gynecological tumors.
  • the PI3K pathway is the most frequently mutated place in human cancer cells, leading to cell proliferation, activation, and signal amplification.
  • PI3K kinase (phosphatidylinositol-3-kinase, PI3Ks) belongs to the family of lipid kinases, which can phosphorylate the 3'-OH end of the inositol ring of phosphatidylinositol, which is a regulatory subunit of phosphatidylinositol.
  • PIP2 phosphatidylinositol 4,5-bisphosphate
  • PIP3 phosphatidylinositol 3,4,5-triphosphate
  • the tumor suppressor gene PTEN (phosphatase and tension homolog deleted on chromosome ten) dephosphorylates PIP3 to generate PIP2, thereby realizing the negative regulation of PI3K/Akt signaling pathway, inhibiting cell proliferation and promoting cell apoptosis.
  • PTEN phosphatase and tension homolog deleted on chromosome ten
  • WO2015192760 discloses a series of compounds as PI3K inhibitors, and also specifically discloses the compound of formula I with the following structure:
  • the application provides a compound of formula I, or a pharmaceutically acceptable salt thereof, for use in the treatment of gynecological tumors:
  • the present application provides the use of a compound of formula I, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of gynecological tumors.
  • the application provides a method of treating a gynecological tumor, the method comprising administering to a patient a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof.
  • a compound of formula I of the application is used as the single active agent.
  • the compound of formula I, or a pharmaceutically acceptable salt thereof, of the application may be in the form of a pharmaceutical composition comprising the compound of formula I, or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition is a single dose pharmaceutical composition.
  • the present application provides a pharmaceutical composition for treating gynecological tumors, the pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable salt thereof.
  • the application provides a method of treating gynecological tumors, the method comprising administering to a patient a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • the application provides a kit for the treatment of gynecological tumors, the kit comprising the compound of formula I described in the application, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, preferably in a single dose form; and instructions for use.
  • the gynecological tumor is selected from recurrent or metastatic gynecological tumors. In some aspects, the gynecological tumor comprises Stage I, Stage II, Stage III, and/or Stage IV.
  • the gynecological tumor is selected from locally advanced recurrent or metastatic gynecological tumors.
  • the gynecological tumor is selected from gynecological tumors in which the PIK3CA, PIK3R1 or PIK3R2 genes are altered.
  • the PIK3CA, PIK3R1 or PIK3R2 gene is altered to a mutation, deletion, splicing, fusion, insertion, duplication, or amplification of the PIK3CA, PIK3R1 or PIK3R2 gene.
  • the PIK3CA gene alteration occurs in any exon of the gene. In some aspects of the application, the PIK3CA gene alteration comprises an alteration that occurs in exons 1, 2, 5, 7, 9 or 20. In some aspects of the application, the PIK3CA gene alteration comprises one or more of the following site mutations: Q60K, R88Q, E110K, K111N, R263Q, R277W, R278W, K331E, K333N, N345K, G353D, S405F, E418K, E453K , P539R, E542K/Q/V/G, Q546E/H/K/L/P/R, E545A/D/G/K/Q/V, F909L, Y1021C/H/H, T1025A/S, M1043I/V including one or more of the following sites or fragments; Deletion of: W11_P18, G106_N107,
  • the PIK3R1 gene alteration comprises one or more of the following site mutations: A10T/V, S102L, E109K, A201V, I220F, Q221E, G376R/E, K379N/E, S429Y, D440G, I442S , Y452C/N, Q457P, D464N, R465T, R503Q, R514C, R557P, E558Q, I559T/V, D560H/G/Y, N564D/K, S565N/R, K567E, P568T, D569G, L570P, L573P, R574I/T /S, R577K, Y580D/C/N, L584F, W624C, E635K, F646S, R649W, N711S, or V718A; including one or more of the following site or fragment insertion
  • the PIK3R2 gene alteration comprises one or more of the following site mutations: F15V, G28S, G103V, L127I, A298V, Y331C, D334Tfs*7, G373R, K376E, I378S, G385W, S390P, R406H , K435N, M476I, E499D, C501F, R531P, R539H, D557Y/N/H, N561D, K564E, P565S, R571H, R647C, or G722Afs*152; includes splice at any of the following: X431_splice, X473_splice, or X603_splice ; includes fusions of the form: PIK3R2-EEF1A2.
  • the gynecological tumor is selected from recurrent or metastatic gynecological tumors in which the PIK3CA, PIK3R1 or PIK3R2 genes are altered. In some aspects of the application, the gynecologic tumor is selected from locally advanced recurrent or metastatic gynecologic tumors in which the PIK3CA, PIK3R1, or PIK3R2 genes are altered.
  • the gynecological tumor patients are selected from patients with disease progression, recurrence or metastasis after previous treatment with platinum-containing regimens.
  • the gynecological tumor patients are selected from patients with disease progression, locally advanced recurrence or metastasis after previous treatment with platinum-containing regimens.
  • the gynecological tumor patient is selected from patients with PIK3CA, PIK3R1 or PIK3R2 gene alterations, and patients with disease progression, locally advanced recurrence or metastasis after previous platinum-containing regimen treatment.
  • the gynecological tumor may comprise platinum-sensitive or platinum-resistant.
  • the gynecological tumor is selected from endometrial cancer, cervical cancer, or ovarian cancer.
  • the endometrial cancer is selected from endometrioid adenocarcinoma, serous adenocarcinoma, clear cell carcinoma, undifferentiated carcinoma, or carcinosarcoma.
  • the cervical cancer is selected from squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma.
  • the ovarian cancer is selected from epithelial ovarian cancer, fallopian tube cancer, primary peritoneal cancer, high-grade serous ovarian cancer, or endometrioid ovarian cancer >grade II (high-grade serous Type ovarian cancer or endometrioid ovarian cancer grade ⁇ II must have an endometrioid component >50%).
  • the gynecological tumor is selected from the group consisting of endometrioid adenocarcinoma, serous adenocarcinoma, clear cell carcinoma, undifferentiated carcinoma, carcinosarcoma, cervical squamous cell carcinoma, cervical adenocarcinoma, cervical adenosquamous carcinoma, epithelial ovarian cancer, fallopian tube cancer, primary peritoneal cancer, high-grade serous ovarian cancer, or grade ⁇ II endometrioid ovarian cancer (high-grade serous ovarian cancer or grade ⁇ II endometrioid ovarian cancer Endometrioid component must be >50%).
  • the ovarian cancer is selected from platinum-sensitive or platinum-resistant advanced or metastatic ovarian cancer.
  • the platinum-resistant form is a refractory form.
  • the gynecological tumor patient is selected from unresectable, locally advanced recurrent and/or metastatic gynecological tumor patients.
  • the gynecological tumor patient is selected from patients with recurrent or metastatic gynecological tumor who have a PIK3CA, PIK3R1 or PIK3R2 gene alteration, and who have previously received first-, second-, or third-line or above treatment with disease progression.
  • the gynecological tumor patient is selected from locally advanced recurrent or metastatic gynecological tumors with PIK3CA, PIK3R1 or PIK3R2 gene alterations and disease progression after previous first-line, second-line or third-line treatment or more patient.
  • the gynecological tumor patient is selected from recurrent or metastatic endometrial cancer with a PIK3CA, PIK3R1 or PIK3R2 gene alteration and disease progression after previous first-line, second-line or third-line therapy or more patient.
  • the gynecological tumor patient is selected from locally advanced recurrent or metastatic intrauterine disease with PIK3CA, PIK3R1 or PIK3R2 gene alterations and disease progression after previous first-line, second-line or third-line treatment or more Membrane cancer patients.
  • the gynecological tumor patient is selected from patients with recurrent or metastatic cervical cancer who have a PIK3CA, PIK3R1 or PIK3R2 gene alteration and have previously received first-line, second-line or third-line or above treatment with disease progression.
  • the gynecological tumor patient is selected from locally advanced recurrent or metastatic cervical cancer with PIK3CA, PIK3R1 or PIK3R2 gene alteration and disease progression after previous first-line, second-line or third-line treatment and above patient.
  • the gynecological tumor patient is selected from patients with recurrent or metastatic ovarian cancer who have PIK3CA, PIK3R1 or PIK3R2 gene alterations and whose disease has progressed after receiving second-line or third-line or above treatment in the past.
  • the gynecological tumor patient is selected from locally advanced recurrent or metastatic ovarian cancer patients with PIK3CA, PIK3R1 or PIK3R2 gene alterations and disease progression after receiving second-line or third-line or above treatment in the past.
  • the gynecological tumor patient is selected from patients with recurrent or metastatic endometrial cancer who have PIK3CA, PIK3R1 or PIK3R2 gene alterations and whose disease has progressed after receiving second-line or more prior therapy.
  • the gynecological tumor patient is selected from locally advanced recurrent or metastatic endometrial cancer patients with PIK3CA, PIK3R1 or PIK3R2 gene alterations and disease progression after receiving second-line or more prior therapy.
  • the gynecological tumor patient is selected from patients with recurrent or metastatic cervical cancer who have PIK3CA, PIK3R1 or PIK3R2 gene alterations and whose disease has progressed after receiving second-line or more prior therapy.
  • the gynecological tumor patient is selected from locally advanced recurrent or metastatic cervical cancer patients with PIK3CA, PIK3R1 or PIK3R2 gene alterations and disease progression after receiving second-line or above treatment in the past.
  • the gynecological tumor patient is selected from patients with recurrent or metastatic ovarian cancer who have PIK3CA, PIK3R1 or PIK3R2 gene alterations and whose disease has progressed after receiving third-line or more prior therapy.
  • the gynecological tumor patient is selected from locally advanced recurrent or metastatic ovarian cancer patients with PIK3CA, PIK3R1 or PIK3R2 gene alterations and disease progression after receiving third-line or more prior therapy.
  • At least one of the first-line, second-line, or third-line therapy the patient has previously received is selected from platinum-based regimen therapy.
  • the first-line therapy is selected from platinum-based regimen therapy.
  • the gynecological tumor patients are selected from patients who have received standard treatment in the past but have failed treatment or have no existing effective treatment plan for advanced stage.
  • the standard of care treatment is a platinum-based regimen treatment.
  • the treatment failure refers to disease progression, recurrence, or metastasis.
  • the patients with gynecological tumors are selected from patients who have been previously treated with one or more prior treatment regimens. In some aspects of the present application, the patient with a gynecological tumor is selected from patients who have been previously treated with one, two, three, four, or five prior treatment regimens.
  • the prior treatment regimen includes surgery, radiation therapy, or drug therapy.
  • the drug therapy includes chemotherapy, targeted drug therapy, immunotherapy, or endocrine therapy.
  • the prior treatment regimen includes at least one platinum-based regimen treatment.
  • the prior treatment regimen includes at least one treatment with a platinum-based regimen and does not include treatment with a PI3K, AKT, or mTOR inhibitor.
  • the patients with gynecological tumors are selected from patients who have received one or more prior treatment regimens, and the prior treatment regimens include at least one platinum-based regimen treatment .
  • the drug used in the platinum-containing regimen treatment comprises cisplatin, carboplatin, nedaplatin, oxaliplatin, bicycloplatin, picoplatin, meplatin, or lobaplatin.
  • the drug used in the platinum-based regimen treatment includes cisplatin, carboplatin, nedaplatin, or oxaliplatin.
  • the platinum-based regimen treatment includes the following regimens: cisplatin, carboplatin, nedaplatin, oxaliplatin, cisplatin in combination with 5-fluorouracil, cisplatin in combination with paclitaxel, cisplatin in combination with topology Tecan, cisplatin combined with gemcitabine, cisplatin combined with vinorelbine, cisplatin combined with irinotecan, cisplatin combined with ifosfamide, cisplatin combined with etoposide, bleomycin combined with etoposide combined with cisplatin, cisplatin combined with ifosfamide Platinum combined with paclitaxel combined with bevacizumab, cisplatin combined with topotecan combined with bevacizumab, cisplatin combined with vincristine combined with bleomycin, cisplatin combined with bleomycin combined with
  • the drugs used in the chemotherapy include cisplatin, carboplatin, nedaplatin, oxaliplatin, bicycloplatin, picoplatin, meplatin, lobaplatin, doxorubicin, liposome Mycin, paclitaxel, nab-paclitaxel, docetaxel, capecitabine, cyclophosphamide, melphalan, docetaxel, 5-fluorouracil, gemcitabine, ifosfamide, irinotecan, mitomycin , topotecan, pemetrexed, etoposide, bleomycin, leucovorin, vincristine, or vinorelbine.
  • the drugs used in the targeted drug therapy include bevacizumab, cetuximab, nimotuzumab, pazopanib ), rucaparib, veliparib, niraparib, olaparib, gefitinib, erlotinib, entrectinib, Rotinib, or tramitinib.
  • the drug used in the immunotherapy comprises pembrolizumab, ipilimumab, or PD-1 antibody.
  • the drugs used for endocrine therapy include anastrozole, letrozole, exemestane, leuprolide acetate, tamoxifen, megestrol acetate, or fulvestrant group.
  • the drugs used in the drug treatment include cisplatin, carboplatin, nedaplatin, oxaliplatin, bicycloplatin, picoplatin, meplatin, lobaplatin, doxorubicin, liposome Doxorubicin, paclitaxel, nab-paclitaxel, docetaxel, capecitabine, cyclophosphamide, melphalan, docetaxel, 5-fluorouracil, gemcitabine, ifosfamide, irinotecan, mitosis Vincristine, topotecan, pemetrexed, etoposide, bleomycin, leucovorin, vincristine, vinorelbine, bevacizumab, cetuximab, nimotuzumab , pazopanib, lucaparib, veliparib, niraparib, olaparib, gefitini
  • the radiation therapy comprises conventional radiation therapy, radioactive seed inter-tissue brachytherapy, or intraoperative radiation therapy.
  • the patient with endometrial cancer is selected from patients who have failed standard therapy or who have no existing effective treatment options for advanced stage, and the patient with endometrial cancer is selected from patients who have received at least 1 standard therapy , and patients with stage I/II relapsed disease who have received ⁇ 1 line of platinum-containing regimens; or, selected from patients with advanced (III/IV) relapsed disease who have received ⁇ 1 line of platinum-containing regimens in the past or, selected from patients with imaging-proven disease progression or recurrence during or within 6 months of treatment; or, selected from patients who have previously received neoadjuvant or adjuvant platinum-based regimens during or 6 months after treatment Patients with imaging-proven disease progression or relapse within
  • the standard of care treatment is a platinum-based regimen treatment.
  • the patient with cervical cancer is selected from patients who have failed standard treatment or who have no existing effective treatment options for advanced stage, and the patient with cervical cancer is selected from patients who cannot undergo radical surgery, and/or radical surgery Patients with recurrence/metastasis after radiotherapy and who have received ⁇ 1 line of platinum-based chemotherapy after recurrence; or, selected from patients with imaging-confirmed disease progression or recurrence during treatment or within 6 months after treatment; or, selected from Patients with imaging-proven disease progression or relapse during or within 6 months of prior neoadjuvant or adjuvant platinum-containing regimens.
  • the standard of care treatment is a platinum-based regimen treatment.
  • the ovarian cancer patient is selected from patients who have failed standard therapy or who have no existing effective treatment options for advanced stage, and the ovarian cancer patient is selected from platinum-sensitive patients who have received ⁇ 2 lines of therapy in the past type or platinum-resistant advanced or metastatic disease.
  • the platinum-resistant type is the refractory type, including disease progression or recurrence during the treatment of the previous platinum-containing chemotherapy regimen or within ⁇ 6 months after the end of the platinum-containing treatment.
  • the platinum-sensitive type that is, disease progression or relapse after ⁇ 6 months after the end of the platinum-based chemotherapy regimen, includes ⁇ 2 different platinum-based regimens (including the initial platinum-based chemotherapy regimen) received in the past. disease progression or relapse after treatment.
  • the standard of care treatment is a platinum-based regimen treatment.
  • the dosing cycle for treating a patient's gynecological tumor is 2-6 weeks. In some aspects of the present application, the administration period for treating a patient's gynecological tumor is 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, or a range formed by any of the above values. In some aspects of the application, the dosing cycle for treating a patient's gynecological tumor is 4 weeks.
  • the daily dose for treating a patient's gynecological tumor is selected from 1-100 mg. In some aspects of the application, the daily dose for treating a patient's gynecological tumor is selected from 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg , 16mg, 17mg, 18mg, 19mg, 20mg, 21mg, 22mg, 23mg, 24mg, 25mg, 26mg, 27mg, 28mg, 29mg, 30mg, 31mg, 32mg, 33mg, 34mg, 35mg, 36mg, 37mg, 38mg, 39mg, 40mg , 41mg, 42mg, 43mg, 44mg, 45mg, 46mg, 47mg, 48mg, 49mg, 50mg, 51mg, 52mg,
  • the number of daily administrations for treating a patient's gynecological tumor is 1, 2, or 3 times.
  • the treatment of the patient's gynecological tumor may be administered once a day.
  • the dosing regimen for treating gynecological tumors in the patient includes: the dosing cycle is 2-6 weeks, the daily dose is 1-40 mg, and the daily administration frequency is 1-3 times.
  • the compound of formula I of the present application, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof can be administered by various routes, including but not limited to the following routes: oral, parenteral, intraperitoneal, intravenous , intraarterial, transdermal, sublingual, intramuscular, rectal, buccal, intranasal, inhalation, vaginal, intraocular, topical, subcutaneous, intraadipose, intraarticular or intrathecal. In one specific regimen, it is administered orally.
  • the method of administration can be comprehensively determined according to factors such as drug activity, toxicity, and patient tolerance.
  • a compound of the present application, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is administered in spaced dosing.
  • the pharmaceutical composition of the present application can be prepared by combining the compound of formula I of the present application, or a pharmaceutically acceptable salt thereof, with suitable pharmaceutically acceptable excipients, for example, it can be formulated into a solid, semi-solid, liquid or gaseous preparation , such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols.
  • the pharmaceutical composition of the present application can be manufactured by methods well known in the art, such as conventional mixing method, dissolving method, granulation method, sugar-coated pill method, grinding method, emulsification method, freeze-drying method and the like.
  • Suitable pharmaceutically acceptable adjuvants include, but are not limited to, binders, diluents, wetting agents, disintegrating agents, lubricants, glidants, sweeteners or flavoring agents, and the like.
  • the pharmaceutical composition is a preparation suitable for oral administration, including tablets, capsules, powders, granules, dropping pills, pastes, powders, etc., preferably tablets and capsules.
  • the oral preparations can be prepared by conventional methods using pharmaceutically acceptable excipients/carriers known in the art.
  • Pharmaceutically acceptable carriers include diluents, binders, wetting agents, disintegrating agents, lubricants and the like.
  • Diluents include microcrystalline cellulose, mannitol, lactose, sucrose, starch, pregelatinized starch, dextrin or mixtures thereof, etc.; binders include hypromellose, carboxymethylcellulose, sodium carboxymethylcellulose , ethyl cellulose, methyl cellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, gelatin, polyvinylpyrrolidone, starch, sucrose, glucose, gelatin or mixtures thereof, etc.; wetting agents include stearic acid Magnesium, talc, polyethylene glycol, sodium lauryl sulfate, micronized silica gel, talc or mixtures thereof, etc.; disintegrants include sodium carboxymethyl starch, dry starch, microcrystalline cellulose, hydroxyethyl methyl Cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, low-substituted hydroxypropyl
  • the pharmaceutical composition is a single-dose pharmaceutical composition.
  • the pharmaceutical composition contains 1 mg to 50 mg of a compound of formula I of the present application, or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition contains 1 mg, 2 mg, 5 mg, 8 mg, 10 mg, 12 mg, 15 mg, 18 mg, 20 mg, 22 mg, 25 mg, 28 mg, 30 mg, 32 mg, 35 mg, 38 mg, 40 mg, 42 mg, 45 mg, 48 mg or 50 mg, or any of the foregoing values as endpoints constitute a range or any value therein of a compound of the present application, or a pharmaceutically acceptable salt thereof, for example 1 mg to 50 mg, 2 mg to 50 mg, 10 mg to 40 mg, 5 mg to 30 mg, 5mg to 20mg, etc.
  • the compound of formula I of the present application or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof produces a good curative effect in the treatment of gynecological tumors, has a certain objective remission rate, and provides a good disease control rate to the treated patient,
  • the treated patients have a longer survival period and a longer duration of disease remission.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms that are within the scope of sound medical judgment suitable for use in contact with human and animal tissue without excessive of toxicity, irritation, allergic reactions or other problems or complications commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt includes salts of base ions with the free acid or salts of acid ions with the free base.
  • the amount of a compound of formula I or a pharmaceutically acceptable salt thereof eg, the amount administered, dosage, content in a pharmaceutical composition, is calculated as its free base form.
  • compounds in this application can form acid addition salts if they have, for example, at least one basic center.
  • Corresponding acid addition salts with additionally present basic centers can also be formed, if desired.
  • Compounds having at least one acidic group eg COOH
  • Corresponding internal salts can also be formed if the compounds contain, for example, both carboxyl and amino groups.
  • patient is a mammal. In some embodiments, the patient is a human.
  • pharmaceutical composition refers to a mixture of one or more compounds of the present application, or a pharmaceutical combination thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • the purpose of a pharmaceutical composition is to facilitate administration of a compound of the present application or a pharmaceutical combination thereof to a patient.
  • treating generally refers to obtaining a desired pharmacological and/or physiological effect.
  • the effect may be therapeutic in terms of partial or complete stabilization or cure of the disease and/or side effects due to the disease.
  • Treatment encompasses any treatment of a disease in a patient, including: (a) inhibiting the symptoms of the disease, ie, preventing its progression; or (b) alleviating the symptoms of the disease, ie, causing regression of the disease or symptoms.
  • the term "effective amount” means (i) treating a particular disease, condition or disorder, (ii) alleviating, ameliorating or eliminating one or more symptoms of a particular disease, condition or disorder, or (iii) delaying the described herein
  • the amount of a compound of the present application that constitutes a "therapeutically effective amount” will vary depending on the compound or a pharmaceutically acceptable salt thereof, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but may vary, for example. The feasibility is determined by those skilled in the art based on their own knowledge and the present disclosure.
  • single-dose refers to the smallest packaged unit containing a certain amount of medicine, for example, each tablet is a single dose; a box of medicines contains seven capsules, each capsule is a single dose; or each injection bottle is a single dose.
  • carboplatin combined with paclitaxel and bevacizumab refers to the combination of carboplatin, paclitaxel, and bevacizumab.
  • Capecitabine with oxaliplatin with or without bevacizumab refers to the combination of capecitabine, oxaliplatin, and bevacizumab, or capecitabine with oxaliplatin without bevacizumab Monoclonal antibody use.
  • the term "refractory” refers to a particular cancer that is resistant or unresponsive to therapy with a particular therapeutic agent. Cancers that are refractory to therapy with a specific therapeutic agent can begin when treatment with the specific therapeutic agent is initiated (ie, there is no response upon initial exposure to the therapeutic agent); or, when the therapeutic agent is used for the first time The development of resistance to the therapeutic agent results in the course of its treatment or during subsequent treatment with the therapeutic agent.
  • platinum-refractory refers to cancers that do not respond to treatment with anticancer drugs containing metallic platinum, such as cisplatin and carboplatin.
  • recurrence refers to the recurrence of cancer, usually after a period of undetectable cancer. Cancer may return to the same location as the original (primary) tumor, or to another location in the body, also known as a recurrence. In the present invention, recurrence includes local recurrence.
  • the term “locally recurrent” refers to a recurrence in the same or near the same place as the primary tumor, usually after a period of undetectable cancer.
  • the term “locally advanced” refers to the spread of the primary lesion to nearby tissues or lymph nodes.
  • first-line therapy refers to the first treatment for the disease. It is usually part of a set of standard treatments, such as chemotherapy and radiation after surgery. First-line therapy, when used alone, is recognized as the best therapy. If it does not cure the disease or causes serious side effects, other treatments may be added or used.
  • second-line therapy refers to treatment given when the initial treatment (first-line treatment) is ineffective or stops working.
  • third-line treatment or multi-line treatment can be deduced by analogy.
  • metastatic refers to the spread or metastases of cancer from a primary site to other areas of the body, forming cancerous lesions that behave biologically in new locations.
  • standard therapy refers to an approach accepted by medical professionals as an appropriate treatment for a particular type of disease, and is widely used by medical professionals.
  • adjuvant therapy refers to the administration of additional cancer treatment after the first treatment to reduce the risk of cancer recurrence.
  • Adjuvant therapy may include chemotherapy, radiation therapy, hormone therapy, targeted therapy, or biological therapy.
  • neoadjuvant therapy refers to treatment given as a first step before primary treatment (eg, surgery) to shrink a tumor.
  • primary treatment eg, surgery
  • neoadjuvant therapy include chemotherapy, radiation therapy, and hormone therapy. This is an induction therapy.
  • the drugs used in the prior treatment regimen may refer to the following contents, and may also refer to treatment guidelines or textbooks related to medicine and pharmacy:
  • ICON-7&GOG-218 regimen Paclitaxel combined with carboplatin combined with bevacizumab, and then continued with bevacizumab maintenance therapy.
  • the doxorubicin is the same as doxorubicin, and the two can be used interchangeably.
  • the doxorubicin liposome, the liposomal doxorubicin and the liposomal doxorubicin are all the same, and the three can be used interchangeably.
  • step 3 Transfer the premixed material in step 1) to a wet granulation pot and add the binder obtained in step 2) to start granulation.
  • the prepared soft wet wood is granulated, dried, and mixed with magnesium stearate.
  • the resulting tablet is coated.
  • the compound of formula I is prepared according to the method disclosed in WO2015192760.
  • Administration method oral administration once a day on an empty stomach (QD administration, 15 mg or 30 mg dose), continuous administration for 28 days as a treatment cycle.
  • Medication Tablets of the compound of formula I, 5 mg or 20 mg.
  • Endometrial cancer Endometrial cancer confirmed by histopathology, including endometrioid adenocarcinoma, serous adenocarcinoma, clear cell carcinoma, undifferentiated carcinoma, carcinosarcoma;
  • Cervical cancer Histopathologically confirmed cervical cancer, including squamous cell carcinoma, adenocarcinoma and adenosquamous carcinoma;
  • Ovarian cancer Histopathologically confirmed epithelial ovarian cancer, fallopian tube cancer, primary peritoneal cancer, high-grade serous ovarian cancer and endometrioid ovarian cancer grade ⁇ II (high-grade serous ovarian cancer or ⁇ Grade II endometrioid ovarian cancer must have an endometrioid component >50%).
  • Subjects must have a positive sample for PIK3CA, PIK3R1 or PIK3R2 gene alteration (mutation or amplification) to be enrolled: ⁇ 10 freshly cut unstained sections of tumor tissue obtained within 2 years are preferred for genetic testing ; If tumor tissue sections cannot be provided, 10 mL of peripheral blood should be provided for genetic testing.
  • Endometrial cancer at least 1 standard treatment and ⁇ 1 line of platinum-containing regimen for stage I/II recurrent disease, or ⁇ 1 line of platinum-containing regimen for advanced stage system therapy (Stage III/IV) disease; imaging-proven disease progression or recurrence (according to RECIST 1.1 criteria) during or within 6 months of treatment; Imaging-proven disease progression or recurrence within one month is also counted as first-line systemic therapy for advanced or metastatic disease;
  • Cervical cancer recurrent/metastatic disease for which curative surgery and/or curative radiotherapy cannot be performed, and ⁇ 1 line of platinum-based chemotherapy after recurrence; imaging findings during or within 6 months after treatment Confirmed disease progression or recurrence (according to RECIST 1.1 criteria); imaging-confirmed disease progression or recurrence during or within 6 months after neoadjuvant or adjuvant therapy with platinum-based regimens was also counted as first-line therapy Systemic therapy for advanced or metastatic disease;
  • Ovarian cancer platinum-sensitive or platinum-resistant advanced or metastatic disease (at least 4 cycles of treatment, during or 6 months after previous neoadjuvant or adjuvant therapy with platinum-based regimens) who have received ⁇ 2 lines of therapy Imaging-proven disease progression or recurrence [according to RECIST 1.1 criteria], also counted as first-line treatment), and meet any of the following: (1) Platinum-resistant or refractory type, including previous platinum-containing chemotherapy regimens Disease progression or recurrence during or within ⁇ 6 months after the end of platinum-containing chemotherapy; (2) platinum-sensitive type (ie, disease progression or recurrence ⁇ 6 months after the end of platinum-containing chemotherapy regimen), who have received ⁇ 2 different chemotherapy regimens in the past. Disease progression or recurrence after treatment with platinum-based regimens (including those initially containing platinum-based regimens).
  • contraceptive measures such as intrauterine device [IUD], contraceptives or condoms
  • IUD intrauterine device
  • serum or urine pregnancy test negative within 7 days before study enrollment and must be non-lactating subjects.
  • the main efficacy evaluation index objective response rate (ORR), that is, the number of CR+PR cases/total number of cases, including complete remission (CR) and partial remission (PR) cases.
  • ORR objective response rate
  • PFS progression-free survival
  • DCR disease control rate
  • DOR disease response time
  • OS survival time
  • a 60-year-old female patient who underwent radical resection of ovarian cancer (full uterus with double appendages + rolled carpet rectal fossa peritonectomy - omentectomy + pelvic lymph node dissection + para-aortic lymph node dissection + tumor reduction surgery), postoperative pathological classification It is high-grade serous ovarian cancer with necrosis, showing vascular tumor thrombus, involving the serosal membrane of the left uterine wall, (part of the rectum and sigmoid colon) from the adventitia to the mucosal layer, and metastasizes or infiltrates to 23/60 lymph nodes.
  • TC regimen paclitaxel 270 mg, carboplatin 550 mg
  • 1 cycle of TC regimen paclitaxel 100 mg, carboplatin 300 mg
  • TC regimen paclitaxel 100 mg, carboplatin 250 mg
  • One cycle of chemotherapy oral Nirapari Capsule therapy after chemotherapy, targeted therapy with Oral Olapari Tablets after the end of treatment
  • GP regimen 1.2g gemcitabine, 110mg cisplatin
  • chemotherapy for 2 cycles after treatment
  • GP regimen After the end of the GC regimen (docetaxel 120mg, carboplatin 500mg) chemotherapy for one cycle, the disease progressed after self-stop.

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Abstract

La présente invention concerne l'utilisation d'un composé pyrido[1,2-a]pyrimidinone dans le traitement de tumeurs gynécologiques. En particulier, l'invention concerne un composé pyrido[1,2-a]pyrimidinone pour traiter des tumeurs gynécologiques ou des compositions pharmaceutiques de celui-ci, et un procédé ou une utilisation du composé pyrido[1,2-a]pyrimidinone pour le traitement de tumeurs gynécologiques.
PCT/CN2021/136363 2020-12-08 2021-12-08 Utilisation d'un composé pyrido[1,2-a]pyrimidinone dans le traitement de tumeurs gynécologiques WO2022121929A1 (fr)

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CN105461711A (zh) * 2014-06-17 2016-04-06 南京明德新药研发股份有限公司 作为PI3K抑制剂的吡啶并[1,2-a]嘧啶酮类似物
WO2017101847A1 (fr) * 2015-12-16 2017-06-22 正大天晴药业集团股份有限公司 Analogue de pyrido[1,2-a]pyrimidone, sa forme cristalline, son intermédiaire et son procédé de préparation
WO2021180111A1 (fr) * 2020-03-10 2021-09-16 正大天晴药业集团股份有限公司 Combinaison pharmaceutique comprenant un composé pyridino[1,2-a]pyrimidinone

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WO2021180111A1 (fr) * 2020-03-10 2021-09-16 正大天晴药业集团股份有限公司 Combinaison pharmaceutique comprenant un composé pyridino[1,2-a]pyrimidinone

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