WO2023109741A1 - Composition pharmaceutique pour le traitement du cancer - Google Patents

Composition pharmaceutique pour le traitement du cancer Download PDF

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Publication number
WO2023109741A1
WO2023109741A1 PCT/CN2022/138337 CN2022138337W WO2023109741A1 WO 2023109741 A1 WO2023109741 A1 WO 2023109741A1 CN 2022138337 W CN2022138337 W CN 2022138337W WO 2023109741 A1 WO2023109741 A1 WO 2023109741A1
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Prior art keywords
cancer
pharmaceutically acceptable
acceptable salt
compound
formula
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PCT/CN2022/138337
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English (en)
Chinese (zh)
Inventor
李嘉逵
史澂空
徐艳君
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轩竹生物科技股份有限公司
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Publication of WO2023109741A1 publication Critical patent/WO2023109741A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Definitions

  • the present invention belongs to the technical field of medicine, and specifically relates to a pharmaceutical composition for preventing and/or treating cancer, especially containing a compound of formula (I) or a pharmaceutically acceptable salt thereof and a second therapeutic agent or a pharmaceutically acceptable salt thereof A pharmaceutical composition of fixed ratio or fixed dose combination of salts, and use of said pharmaceutical composition for treating cancer.
  • Breast cancer is the most common malignant tumor in women, and there are about 2 million new breast cancer patients worldwide every year. Breast cancer is a class of highly heterogeneous tumors at the molecular level, and there are great differences in histomorphology, immunophenotype, biological behavior and treatment response. Breast cancers are classified into three subtypes based on the expression of three receptors: estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (Her2). Estrogen receptor positive (ER+) breast cancer is the most common molecular subtype of breast cancer, with an incidence rate of about 65%-70% in the population. The prognosis is the best in breast cancer, and there are more patients in the early stage.
  • ER estrogen receptor
  • PR progesterone receptor
  • Her2 human epidermal growth factor receptor-2
  • ER+ breast cancer Compared with other molecular subtypes of breast cancer, ER+ breast cancer has a better prognosis, but there is still a 5-year recurrence and metastasis rate of about 15-30%.
  • the human epidermal growth factor receptor-2 (HER2) molecule is an independent factor for the poor prognosis of breast cancer. About 20%-30% of Chinese breast cancer patients have HER2 gene amplification/overexpression. HER2 overexpression is typically associated with aggressive, metastatic forms of breast cancer that have high recurrence rates and/or are associated with poor patient prognosis.
  • Endocrine (anti-estrogen) drugs are usually used initially and maintained until resistance develops. Their use avoids chemotherapy-based toxicity, but the toxicity and drug resistance of the drug itself still need to be well resolved.
  • Aromatase (aromatase, AR) (also known as estrogen synthase) is a complex enzyme of microsomal cytochrome P450, which is widely present in ovary, liver, muscle, fat and breast cancer cells, and is a catalyst that catalyzes androgen in vivo. Key and rate-limiting enzyme for the conversion of hormones to estrogens and aromatizes androgens to estrone and estradiol.
  • Aromatase inhibitor (aromatase inhibitor, AI) can specifically lead to the inactivation of aromatase, block the aromatization reaction, inhibit the production of estrogen, and reduce the level of estrogen in the blood so as to achieve the purpose of treating breast cancer. It is mostly used for anti-estrogen Postmenopausal women with advanced breast cancer who have failed hormone (tamoxifen) therapy.
  • Anastrozole belongs to the third-generation aromatase inhibitor, which is a potent and selective non-steroidal aromatase inhibitor, which can inhibit the conversion of estrenedione to estrone in postmenopausal patients, thereby significantly Reduce the level of estrogen in the body and inhibit the growth of breast tumors.
  • Anastrozole is suitable for advanced breast cancer in postmenopausal women who cannot be controlled by tamoxifen and other anti-estrogen therapy.
  • Letrozole is also a third-generation aromatase inhibitor, and its in vivo activity is 150-250 times stronger than that of the first-generation aromatase inhibitor aminoglutethimide. Because of its high selectivity, it does not affect the function of glucocorticoids, mineralocorticoids and thyroid gland, and large doses have no inhibitory effect on the secretion of adrenal corticosteroids, so it has a high therapeutic index. It is suitable for postmenopausal advanced breast cancer, and is mostly used for second-line treatment after failure of anti-estrogen therapy.
  • Exemestane is also a third-generation aromatase inhibitor, which can irreversibly bind to aromatase to inactivate it. Once exemestane binds to aromatase, the enzyme can never produce estrogen again. Thereby preventing the biosynthesis of estrogen. Exemestane is indicated for the adjuvant treatment of early invasive breast cancer in postmenopausal women with estrogen receptor positive after 2-3 years of adjuvant tamoxifen therapy until completion of a total of 5 years of adjuvant endocrine therapy and for advanced breast cancer in postmenopausal women whose disease has progressed despite tamoxifen therapy.
  • CDKs cyclin-dependent kinases
  • CDK4/6 plays an irreplaceable role. CDK4/6-specific activation is closely related to the proliferation of some tumors, and about 80% of human tumors have abnormalities in the cyclin D-CDK4/6-INK4-Rb pathway.
  • CDK4/6 inhibitors currently on the market include PD0332991 (Palbociclib, Ibrance) developed by Pfizer, LY2835219 (Abemaciclib, Verzenio) from Eli Lilly and LEE011 (Ribociclib, Kisqali) from Novartis.
  • the invention provides a high-efficiency and low-toxicity tumor treatment composition, which mainly relates to the combined use of CDK4/6 inhibitors and aromatase inhibitors for treating cancer.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one second therapeutic agent or a pharmaceutically acceptable salt thereof,
  • the second therapeutic agent is selected from aromatase inhibitors, wherein the active ingredient weight ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the second therapeutic agent or a pharmaceutically acceptable salt thereof is 1 :1-1000:1.
  • the weight ratio of active ingredients of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the second therapeutic agent or a pharmaceutically acceptable salt thereof is 1:1-900:1.
  • the weight ratio of active ingredients of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the second therapeutic agent or a pharmaceutically acceptable salt thereof is 1:1-800:1.
  • the weight ratio of active ingredients of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the second therapeutic agent or a pharmaceutically acceptable salt thereof is 1:1-720:1.
  • the active ingredient weight ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the second therapeutic agent or a pharmaceutically acceptable salt thereof is 28.8:1-720:1.
  • the weight ratio of active ingredients of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the second therapeutic agent or a pharmaceutically acceptable salt thereof is 160:1-720:1.
  • the weight ratio of active ingredients of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the second therapeutic agent or a pharmaceutically acceptable salt thereof is 288:1-720:1.
  • the weight ratio of active ingredients of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the second therapeutic agent or a pharmaceutically acceptable salt thereof is 1:1-700:1.
  • the weight ratio of active ingredients of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the second therapeutic agent or a pharmaceutically acceptable salt thereof is 1:1-600:1.
  • the weight ratio of active ingredients of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the second therapeutic agent or a pharmaceutically acceptable salt thereof is 1:1-500:1.
  • the weight ratio of active ingredients of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the second therapeutic agent or a pharmaceutically acceptable salt thereof is 1:1-400:1.
  • the second therapeutic agent is selected from letrozole, anastrozole, or exemestane.
  • the second therapeutic agent is letrozole
  • the active ingredient weight ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof to letrozole or a pharmaceutically acceptable salt thereof is 5:1-400:1.
  • the second therapeutic agent is letrozole
  • the active ingredient weight ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof to letrozole or a pharmaceutically acceptable salt thereof is 10:1-400:1.
  • the second therapeutic agent is letrozole
  • the active ingredient weight ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof to letrozole or a pharmaceutically acceptable salt thereof is 12.5:1-384:1.
  • the second therapeutic agent is letrozole
  • the active ingredient weight ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof to letrozole or a pharmaceutically acceptable salt thereof is 12.5:1-336:1.
  • the second therapeutic agent is letrozole
  • the active ingredient weight ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof to letrozole or a pharmaceutically acceptable salt thereof is 12.5:1-300:1.
  • the second therapeutic agent is letrozole
  • the active ingredient weight ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof to letrozole or a pharmaceutically acceptable salt thereof is 12.5:1-288:1.
  • the second therapeutic agent is letrozole
  • the active ingredient weight ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof to letrozole or a pharmaceutically acceptable salt thereof is 25:1-288:1.
  • the second therapeutic agent is letrozole
  • the active ingredient weight ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof to letrozole or a pharmaceutically acceptable salt thereof is 80:1-400:1.
  • the second therapeutic agent is letrozole
  • the active ingredient weight ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof to letrozole or a pharmaceutically acceptable salt thereof is 160:1-400:1.
  • the second therapeutic agent is letrozole
  • the active ingredient weight ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof to letrozole or a pharmaceutically acceptable salt thereof is 168:1-384:1.
  • the second therapeutic agent is letrozole
  • the active ingredient weight ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof to letrozole or a pharmaceutically acceptable salt thereof is 400:1, 390:1, 385:1, 384:1, 383:1, 380:1, 370:1, 360:1, 352:1, 350:1, 344:1, 340:1, 337: 1, 336:1, 335:1, 330:1, 328:1, 320:1, 312:1, 304:1, 300:1, 296:1, 290:1, 289:1, 288:1, 287:1, 285:1, 280:1, 272:1, 270:1, 264:1, 260:1, 256:1, 250:1, 248:1, 241:1, 240:1, 239: 1, 232:1, 230:1, 220:1, 225:1, 224:1, 223:1, 220:1, 216:1, 210:1, 208:1, 200:1, 193:1, 192:1, 191:1, 190
  • the second therapeutic agent is anastrozole
  • the active ingredient weight ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof to anastrozole or a pharmaceutically acceptable salt thereof is It is 400:1-1000:1, preferably 540:1-960:1, preferably 600:1-960:1, preferably 720:1.
  • the second therapeutic agent is anastrozole
  • the active ingredient weight ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof to anastrozole or a pharmaceutically acceptable salt thereof is 400:1, 420:1, 440:1, 460:1, 480:1, 500:1, 520:1, 540:1, 560:1, 580:1, 600:1, 620:1, 640 :1, 660:1, 680:1, 700:1, 720:1, 740:1, 760:1, 780:1, 800:1, 820:1, 840:1, 860:1, 880:1 , 900:1, 960:1.
  • the second therapeutic agent is exemestane.
  • the second therapeutic agent is exemestane, and the compound of formula (I) or a pharmaceutically acceptable salt thereof and the active ingredient of exemestane or a pharmaceutically acceptable salt thereof
  • the weight ratio is 10:1-100:1, preferably 10:1-50:1, preferably 15:1-40:1.
  • the second therapeutic agent is exemestane
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof and the active ingredient of exemestane or a pharmaceutically acceptable salt thereof Weight ratios are 16.8:1, 19.2:1, 21.6:1, 22.4:1, 23.2:1, 24:1, 24.8:1, 25.6:1, 26.4:1, 27.2:1, 28:1, 28.8:1 , 29.6:1, 30.4:1, 31.2:1, 32:1, 32.8:1, 33.6:1, 34.4:1, 35.2:1, 36:1, 38.4:1.
  • the second therapeutic agent is exemestane, and the compound of formula (I) or a pharmaceutically acceptable salt thereof and the active ingredient of exemestane or a pharmaceutically acceptable salt thereof
  • the weight ratio is 28.8:1.
  • the second therapeutic agent is selected from letrozole or anastrozole, wherein, the compound of formula (I) or its pharmaceutically acceptable salt and letrozole or its pharmaceutically acceptable
  • the active ingredient weight ratio of the salt is 5:1-400:1, preferably 10:1-400:1, preferably 12.5:1-384:1, preferably 12.5:1-336:1, preferably 12.5:1-300:1 , preferably 12.5:1-288:1;
  • the active ingredient weight ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof to Anastrozole or a pharmaceutically acceptable salt thereof is 400:1-1000:1, preferably 540:1-960:1, preferably 600:1-960:1, preferably 720:1.
  • the second therapeutic agent is selected from letrozole or anastrozole, wherein, the compound of formula (I) or its pharmaceutically acceptable salt and letrozole or its pharmaceutically acceptable
  • the active ingredient weight ratio of salt is 400:1, 390:1, 385:1, 384:1, 383:1, 380:1, 370:1, 360:1, 352:1, 350:1, 344:1 , 340:1, 337:1, 336:1, 335:1, 330:1, 328:1, 320:1, 312:1, 304:1, 300:1, 296:1, 290:1, 289 :1, 288:1, 287:1, 285:1, 280:1, 272:1, 270:1, 264:1, 260:1, 256:1, 250:1, 248:1, 241:1 , 240:1, 239:1, 232:1, 230:1, 220:1, 225:1, 224:1, 223:1, 220:1, 216:1, 210:1, 208:1, 200 :1, 193:
  • the second therapeutic agent is selected from letrozole or anastrozole, wherein, the compound of formula (I) or its pharmaceutically acceptable salt and letrozole or its pharmaceutically acceptable
  • the active ingredient weight ratio of the salt is 288:1; the active ingredient weight ratio of the compound of formula (I) or its pharmaceutically acceptable salt to anastrozole or its pharmaceutically acceptable salt is 720:1.
  • the second therapeutic agent is selected from letrozole or exemestane, wherein, the compound of formula (I) or its pharmaceutically acceptable salt and letrozole or its pharmaceutically acceptable
  • the active ingredient weight ratio of the salt is 5:1-400:1, preferably 10:1-400:1, preferably 12.5:1-384:1, preferably 12.5:1-336:1, preferably 12.5:1-300: 1, preferably 12.5:1-288:1; the active ingredient weight ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof to exemestane or a pharmaceutically acceptable salt thereof is 10:1-100:1 , preferably 10:1-50:1, preferably 15:1-40:1.
  • the second therapeutic agent is selected from letrozole or exemestane, wherein, the compound of formula (I) or its pharmaceutically acceptable salt and letrozole or its pharmaceutically acceptable
  • the active ingredient weight ratio of the salt is 400:1, 390:1, 385:1, 384:1, 383:1, 380:1, 370:1, 360:1, 352:1, 350:1, 344: 1, 340:1, 337:1, 336:1, 335:1, 330:1, 328:1, 320:1, 312:1, 304:1, 300:1, 296:1, 290:1, 289:1, 288:1, 287:1, 285:1, 280:1, 272:1, 270:1, 264:1, 260:1, 256:1, 250:1, 248:1, 241: 1, 240:1, 239:1, 232:1, 230:1, 220:1, 225:1, 224:1, 223:1, 220:1, 216:1, 210:1, 208:1, 200:1, 193:1, 192:
  • the second therapeutic agent is selected from letrozole or exemestane, wherein, the compound of formula (I) or its pharmaceutically acceptable salt and letrozole or its pharmaceutically acceptable
  • the active ingredient weight ratio of the salt of the compound is 288:1; the active ingredient weight ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof to exemestane or a pharmaceutically acceptable salt thereof is 28.8:1.
  • the second therapeutic agent is selected from exemestane or anastrozole, wherein, the compound of formula (I) or a pharmaceutically acceptable salt thereof and exemestane or a pharmaceutically acceptable salt thereof
  • the active ingredient weight ratio of the accepted salt is 10:1-100:1, preferably 10:1-50:1, preferably 15:1-40:1; formula (I) compound or its pharmaceutically acceptable salt and A
  • the weight ratio of active ingredients of nastrozole or a pharmaceutically acceptable salt thereof is 400:1-1000:1, preferably 540:1-960:1, preferably 600:1-960:1, preferably 720:1.
  • the second therapeutic agent is selected from exemestane or anastrozole, wherein, the compound of formula (I) or a pharmaceutically acceptable salt thereof and exemestane or a pharmaceutically acceptable salt thereof Accepted salts are active ingredient weight ratios of 16.8:1, 19.2:1, 21.6:1, 22.4:1, 23.2:1, 24:1, 24.8:1, 25.6:1, 26.4:1, 27.2:1, 28 :1, 28.8:1, 29.6:1, 30.4:1, 31.2:1, 32:1, 32.8:1, 33.6:1, 34.4:1, 35.2:1, 36:1, 38.4:1; formula (I ) compound or its pharmaceutically acceptable salt and the active ingredient weight ratio of anastrozole or its pharmaceutically acceptable salt is 400:1, 420:1, 440:1, 460:1, 480:1, 500: 1, 520:1, 540:1, 560:1, 580:1, 600:1, 620:1, 640:1, 660:1, 680:1, 700:1, 720:1, 740:1,
  • the second therapeutic agent is selected from exemestane or anastrozole, wherein, the compound of formula (I) or a pharmaceutically acceptable salt thereof and exemestane or a pharmaceutically acceptable salt thereof
  • the weight ratio of the active ingredients of the accepted salt is 28.8:1; the weight ratio of the active ingredients of the compound of formula (I) or its pharmaceutically acceptable salt to anastrozole or its pharmaceutically acceptable salt is 720:1.
  • the second therapeutic agent is selected from letrozole or anastrozole or exemestane, wherein, the compound of formula (I) or a pharmaceutically acceptable salt thereof and letrozole or its
  • the active ingredient weight ratio of the pharmaceutically acceptable salt is 5:1-400:1, preferably 10:1-400:1, preferably 12.5:1-384:1, preferably 12.5:1-336:1, preferably 12.5:1 1-300:1, preferably 12.5:1-288:1;
  • the active ingredient weight ratio of formula (I) compound or its pharmaceutically acceptable salt and Anastrozole or its pharmaceutically acceptable salt is 400:1- 1000:1, preferably 540:1-960:1, preferably 600:1-960:1, preferably 720:1;
  • the accepted salts have a weight ratio of active ingredients of 10:1-100:1, preferably 10:1-50:1, preferably 15:1-40:1.
  • the second therapeutic agent is selected from letrozole or anastrozole or exemestane, wherein, the compound of formula (I) or a pharmaceutically acceptable salt thereof and letrozole or its
  • the active ingredient weight ratio of the pharmaceutically acceptable salt is 400:1, 390:1, 385:1, 384:1, 383:1, 380:1, 370:1, 360:1, 352:1, 350: 1, 344:1, 340:1, 337:1, 336:1, 335:1, 330:1, 328:1, 320:1, 312:1, 304:1, 300:1, 296:1, 290:1, 289:1, 288:1, 287:1, 285:1, 280:1, 272:1, 270:1, 264:1, 260:1, 256:1, 250:1, 248: 1, 241:1, 240:1, 239:1, 232:1, 230:1, 220:1, 225:1, 224:1, 223:1, 220:1, 216:1, 210:1, 208:1, 200:1,
  • the second therapeutic agent is selected from letrozole or anastrozole or exemestane, wherein, the compound of formula (I) or a pharmaceutically acceptable salt thereof and letrozole or its
  • the active ingredient weight ratio of the pharmaceutically acceptable salt is 288:1; the active ingredient weight ratio of the compound of formula (I) or its pharmaceutically acceptable salt to Anastrozole or its pharmaceutically acceptable salt is 720:1 ;
  • the active ingredient weight ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof to exemestane or a pharmaceutically acceptable salt thereof is 28.8:1.
  • the daily dosage of the active ingredient of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 200-2000 mg.
  • the daily dosage of the active ingredient of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 200-1000 mg.
  • the daily dosage of the active ingredient of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 400-1000 mg.
  • the daily dosage of the active ingredient of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 960 mg, 840 mg, 720 mg, 600 mg, 560 mg, 480 mg or 420 mg.
  • the daily dosage of the active ingredient of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 900mg, 880mg, 860mg, 820mg, 800mg, 780mg, 760mg, 740mg, 700mg, 680mg, 660mg, 640mg , 620mg, 580mg or 540mg.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once a day, twice a day, or three times a day.
  • the second therapeutic agent or a pharmaceutically acceptable salt thereof, is administered once a day, twice a day, or three times a day.
  • the active ingredient of the second therapeutic agent or a pharmaceutically acceptable salt thereof is 0.2-400 mg, such as 0.5-200 mg, such as 0.5-100 mg, such as 0.5-50 mg, such as 1- 25 mg, such as 1-10 mg, such as 1-5 mg, such as 25 mg, such as 2.5 mg, such as 1 mg.
  • the active ingredient of the second therapeutic agent or a pharmaceutically acceptable salt thereof is 100 mg, 75 mg, 50 mg, 25 mg, 10 mg, 7.5 mg, 5 mg, 2.5 mg, 1 mg or 0.5 mg per dosage. .
  • the second therapeutic agent is letrozole
  • the active ingredient of letrozole or a pharmaceutically acceptable salt thereof is 1-5 mg each time, preferably 2.5 mg, and the administration frequency is one day once.
  • the second therapeutic agent is anastrozole
  • the active ingredient of anastrozole or a pharmaceutically acceptable salt thereof is 0.5-2.5 mg each time, preferably 1 mg, and the administration frequency is one day once.
  • the second therapeutic agent is exemestane
  • the active ingredient of exemestane or a pharmaceutically acceptable salt thereof is 12.5-50 mg each time, preferably 25 mg, and the administration frequency is one once a day.
  • the second therapeutic agent is letrozole or anastrozole, wherein the active ingredient of letrozole or a pharmaceutically acceptable salt thereof is 2.5 mg each time, and the dosing frequency is one Once a day; the active ingredient of anastrozole or a pharmaceutically acceptable salt thereof is 1 mg each time, and the administration frequency is once a day.
  • the second therapeutic agent is letrozole or exemestane, wherein the active ingredient of letrozole or a pharmaceutically acceptable salt thereof is 2.5 mg each time, and the administration frequency is Once a day; the active ingredient of exemestane or a pharmaceutically acceptable salt thereof is 25 mg each time, and the administration frequency is once a day.
  • the second therapeutic agent is exemestane or anastrozole, wherein the active ingredient of exemestane or a pharmaceutically acceptable salt thereof is 25 mg each time, and the administration frequency is Once a day; the active ingredient of anastrozole or a pharmaceutically acceptable salt thereof is 1 mg each time, and the administration frequency is once a day.
  • the second therapeutic agent is letrozole or exemestane or anastrozole, wherein the active ingredient of letrozole or a pharmaceutically acceptable salt thereof is 2.5 mg each time, The dosing frequency is once a day; the active ingredient of exemestane or its pharmaceutically acceptable salt is 25 mg each time, and the dosing frequency is once a day; the effective dosage of anastrozole or its pharmaceutically acceptable salt The dosage of each component is 1 mg, and the administration frequency is once a day.
  • the compound of formula (I) and the second therapeutic agent are administered simultaneously or sequentially.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered orally.
  • the second therapeutic agent or a pharmaceutically acceptable salt thereof is administered orally.
  • the present invention also provides a pharmaceutical preparation, comprising the aforementioned pharmaceutical composition, and one or more pharmaceutically acceptable excipients, and the pharmaceutical preparation can be in any pharmaceutically acceptable dosage form.
  • a pharmaceutically acceptable excipient is a substance that is nontoxic, compatible with the active ingredient and otherwise biologically suitable for the organism. The choice of a particular excipient will depend on the mode of administration or the type and state of the disease being used to treat the particular patient.
  • the pharmaceutical formulations described above may be administered orally, parenterally, rectally, or pulmonary to a patient or subject in need of such treatment.
  • the pharmaceutical composition can be made into oral preparations, for example, it can be made into conventional oral solid preparations, such as tablets, capsules, pills, granules, etc.; it can also be made into oral liquid preparations, such as Oral solution, oral suspension, syrup, etc.
  • parenteral administration the above pharmaceutical preparations can also be made into injections, including injections, sterile powders for injections and concentrated solutions for injections.
  • the pharmaceutical composition can be made into suppositories and the like.
  • the pharmaceutical composition can be made into inhalation preparations, aerosols, powder mists or sprays and the like.
  • the present invention also relates to the application of the aforementioned pharmaceutical composition in the preparation of a medicament for the prevention and/or treatment of cancer, the cancer being selected from brain tumor, lung cancer, squamous cell carcinoma, bladder cancer, gastric cancer , ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, head and neck cancer, cervical cancer, endometrial cancer, rectal cancer, liver cancer, kidney cancer, esophageal adenocarcinoma, esophageal squamous cell carcinoma, prostate cancer, female reproductive tract cancer , Lymphoma, Neurofibroma, Thyroid Cancer, Bone Cancer, Skin Cancer, Brain Cancer, Colon Cancer, Testicular Cancer, Gastrointestinal Stromal Tumor, Prostate Tumor, Mast Cell Tumor, Multiple Myeloma, Melanoma, Glial Cancer Tumor or sarcoma, preferably breast cancer.
  • the cancer being selected from brain tumor, lung cancer, squamous cell carcinoma, bladder cancer, gastric cancer
  • the cancer is selected from HR + , HER2- breast cancer.
  • the cancer is selected from postmenopausal HR + , HER2- breast cancer.
  • the cancer is selected from locally advanced or metastatic breast cancer.
  • the cancer is selected from HR + , HER2- advanced or metastatic breast cancer.
  • the cancer is selected from HR + , HER2- advanced or metastatic breast cancer that has progressed after endocrine therapy alone.
  • the present invention also relates to the combination of a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof and letrozole or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing and/or treating cancer
  • the cancer is selected from brain tumor, lung cancer, squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, head and neck cancer, cervical cancer, endometrial cancer, Rectal cancer, liver cancer, kidney cancer, esophageal adenocarcinoma, esophageal squamous cell carcinoma, prostate cancer, female reproductive tract cancer, lymphoma, neurofibroma, thyroid cancer, bone cancer, skin cancer, brain cancer, colon cancer, testicular cancer , gastrointestinal stromal tumor, prostate tumor, mast cell tumor, multiple myeloma, melanoma, glioma or sarcoma, preferably breast cancer.
  • the cancer is selected from HR + , HER2- breast cancer.
  • the cancer is selected from postmenopausal HR + , HER2- breast cancer.
  • the cancer is selected from locally advanced or metastatic breast cancer.
  • the cancer is selected from HR + , HER2- advanced or metastatic breast cancer.
  • the cancer is selected from HR + , HER2- advanced or metastatic breast cancer that has progressed after endocrine therapy alone.
  • the present invention also relates to the application of the pharmaceutical preparation containing the aforementioned pharmaceutical composition in the preparation of medicines for preventing and/or treating cancer.
  • the present invention also provides a kit comprising the aforementioned pharmaceutical composition, and instructions for explaining how to administer the pharmaceutical composition or the compound of formula (I) and the second therapeutic agent contained therein.
  • the present invention also provides a method for treating cancer, the method comprising administering an effective amount of the aforementioned pharmaceutical composition and a pharmaceutical preparation containing the pharmaceutical composition to a patient in need; the cancer is as described above .
  • a compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a second therapeutic agent or a pharmaceutically acceptable salt thereof according to a specific dosage regimen.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof is orally administered at a dose of 400-1000 mg of active ingredient per day.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof is orally administered at a dose of 960 mg, 840 mg, 720 mg, 600 mg, 560 mg, 480 mg or 420 mg of the active ingredient per day.
  • the second therapeutic agent is letrozole, administered orally at a dose of 1-5 mg active ingredient per day.
  • the second therapeutic agent is letrozole, administered orally at a dose of 2.5 mg of active ingredient per day.
  • the second therapeutic agent is anastrozole, administered orally at a dose of 0.5-2.5 mg of active ingredient per day.
  • the second therapeutic agent is anastrozole, administered orally at a dose of 1 mg of active ingredient per day.
  • the second therapeutic agent is exemestane, administered orally at a dose of 12.5-50 mg active ingredient per day.
  • the second therapeutic agent is exemestane, administered orally at a dose of 25 mg of the active ingredient per day.
  • the second therapeutic agent is letrozole or anastrozole, wherein letrozole is administered orally at a dose of 1-5 mg active ingredient per day or anastrozole is effective at 0.5-2.5 mg per day The dosage of the ingredients is administered orally.
  • the second therapeutic agent is letrozole or anastrozole, wherein letrozole is administered orally at a dose of 2.5 mg active ingredient per day or anastrozole is orally administered at a dose of 1 mg active ingredient per day medication.
  • the second therapeutic agent is letrozole or exemestane, wherein letrozole is administered orally at a dose of 1-5 mg of the active ingredient per day or exemestane at a dose of 12.5-50 mg per day The dosage of the active ingredient is administered orally.
  • the second therapeutic agent is letrozole or exemestane, wherein letrozole is administered orally at a dose of 2.5 mg active ingredient per day or exemestane is administered at a dose of 25 mg active ingredient per day Dosage is administered orally.
  • the second therapeutic agent is exemestane or anastrozole, wherein exemestane is administered orally at a dose of 12.5-50 mg active ingredient per day or anastrozole at a dose of 0.5-2.5 mg per day The dose of active ingredient in mg is administered orally.
  • the second therapeutic agent is exemestane or anastrozole, wherein exemestane is administered orally at a dose of 25 mg active ingredient per day or anastrozole is administered at a dose of 1 mg active ingredient per day Oral administration.
  • the second therapeutic agent is letrozole or anastrozole or exemestane, wherein letrozole is administered orally at a dose of 1-5 mg of the active ingredient per day or anastrozole is administered at a dose of The active ingredient is administered orally at a dose of 0.5-2.5 mg or exemestane is administered orally at a dose of 12.5-50 mg active ingredient per day.
  • the second therapeutic agent is letrozole or anastrozole or exemestane, wherein letrozole is administered orally at a dose of 2.5 mg of the active ingredient per day or anastrozole is administered at a dose of 1 mg per day Dosage of the active ingredient orally or exemestane at a dose of 25 mg of the active ingredient per day.
  • HR positive (HR + ) in the present invention refers to positive expression of ER (estrogen receptor) and/or positive expression of PR (progesterone receptor), that is, HR + includes ER + , PR + or ER + /PR + .
  • HER2- in the present invention means that the expression of human epidermal growth factor receptor 2 (HER2) is negative.
  • the "second therapeutic agent” in the present invention refers to an agent that has a certain preventive and/or therapeutic effect on tumors.
  • the "effective amount” refers to the dose of the drug that can prevent, alleviate, delay, inhibit or cure the subject's symptoms.
  • the dosage is related to the way of drug administration, the pharmacokinetics of the drug, the severity of the disease, and the individual signs (gender, weight, height, age) of the subject.
  • the “active ingredient” in the present invention refers to the part of the drug that exerts its medicinal effect. If the compound is a free compound, the active ingredient is the compound; if it is a salt of the compound, the active ingredient is the free compound (excluding the part that forms a salt with it).
  • the "pharmaceutical composition” in the present invention includes the composition formed by preparing the same compound preparation from the compound of formula (I) and the active ingredients such as the second therapeutic agent, and also includes the active ingredients such as the compound of formula (I) and the second therapeutic agent A composition formed by making a single preparation, respectively.
  • the "simultaneous administration" of the compound of formula (I) and the second therapeutic agent in the present invention includes administration after the compound of formula (I) and the second therapeutic agent are prepared into the same compound preparation, or the compound of formula (I) and the second therapeutic agent
  • the reagents are prepared into formulations and administered simultaneously.
  • the "separate administration" of the compound of formula (I) and the second therapeutic agent in the present invention means that after the compound of formula (I) and the second therapeutic agent are respectively prepared into preparations, they are administered separately according to their respective preparation administration methods .
  • the “pharmaceutically acceptable salt” in the present invention refers to the salt formed by the acidic functional group (such as -COOH, -OH, -SO 3 H, etc.) present in the compound and an appropriate inorganic or organic cation (base), including Salts formed with alkali metals or alkaline earth metals, ammonium salts, salts formed with nitrogen-containing organic bases; and salts formed by basic functional groups (such as -NH2, etc.) present in compounds with suitable inorganic or organic anions (acids), Salts with inorganic acids or organic acids (eg, carboxylic acids, etc.) are included.
  • the acidic functional group such as -COOH, -OH, -SO 3 H, etc.
  • the pharmaceutical composition of the present invention exhibits excellent synergistic anti-tumor effects in both in vitro cell experiments and in vivo tumor model experiments, especially in breast cancer.
  • the pharmaceutical composition of the present invention has a good clinical synergistic anti-tumor effect.
  • the pharmaceutical composition of the present invention has low or no toxicity and less side effects.
  • the pharmaceutical composition of the present invention can improve the pharmacokinetic properties of the single drug and increase the exposure.
  • Test product the compound of formula (I) of the present invention, prepared according to the method of the prior art.
  • Patient-derived tumor tissues were inoculated into immunodeficient animals to establish HBCx-34 human breast cancer (ER + , PR + , HER2 - ) xenograft PDX models. After the tumors of the donor mice grew to a certain volume, they were sacrificed and the tumors were isolated, processed into 20 mm 3 tumor pieces and inoculated subcutaneously in the scapula of the test mice. Tumor-bearing mice were supplemented with ⁇ -estradiol (8.5 mg/L) through drinking water during the period from tumor inoculation to grouping, and stopped supplementing estradiol after grouping.
  • ⁇ -estradiol 8.5 mg/L
  • the tumors grew to a volume of 171.5-405mm and divided into 9 groups: solvent control group, formula (I) compound single use group (50mg/kg, 25mg/kg), letrozole single use group (1.25mg/kg , 2mg/kg) and the combination group, with 8 animals in each group. Both the compound of formula (I) and letrozole were intragastrically administered once a day for 42 days.
  • the compound of formula (I) was prepared with pH 4.0 buffer (prepared from citric acid monohydrate and disodium hydrogen phosphate dodecahydrate) to the desired concentration, and letrozole was prepared with 0.9% NaCl solution to the desired concentration.
  • the solvent control group was given the vehicle of the compound of formula (I), the above-mentioned pH4.0 buffer solution, and the administration method was intragastric administration once a day for 42 days.
  • the tumor volume was measured twice a week with a vernier caliper, and the long and short diameters of the tumor were measured.
  • the Mann-Whitney non-parametric test was used to conduct statistical analysis on the tumor volume between groups, and p ⁇ 0.05 was considered to have a significant difference.
  • the compound of the present invention is to the antitumor effect of HBCx-34 human source breast cancer (ER+, HER2-) xenograft model
  • the combination of the compound of formula (I) and letrozole has a significant inhibitory effect on the tumor growth of HBCx-34 (ER + , PR + , HER2 - ) human breast cancer xenograft PDX model, especially the compound of formula (I) 50mg /kg and letrozole 2mg/kg combination group, and formula (I) compound 50mg/kg and letrozole 1.25mg/kg combination group, its inhibitory effect is significantly better than the formula (I) compound and Letrozole alone group.
  • the tablet of the compound of formula (I) of the present invention is prepared into a tablet of a certain specification by adding suitable auxiliary materials to the compound of formula (I);
  • Letrozole and Anastrozole purchased or prepared according to the methods of the prior art.
  • the ECOG score is 0-1;
  • the subject's organ function is good at the time of enrollment, and the laboratory test data of blood routine, liver function and kidney function meet the standards;
  • the life expectancy of the subject is ⁇ 12 weeks
  • Suitable subjects are screened, and the compound of formula (I) and letrozole/anastrozole are administered to the subjects. in,
  • the administration method of the compound of formula (I) is: 360mg, orally, twice a day. Every 28 days is a treatment cycle.
  • the administration method of letrozole is: 2.5mg, orally, once a day. Every 28 days is a treatment cycle.
  • the administration method of anastrozole is: 1mg, orally, once a day. Every 28 days is a treatment cycle.
  • DCR Disease control rate
  • the tablet of the compound of formula (I) of the present invention is prepared into a tablet of a certain specification by adding suitable auxiliary materials to the compound of formula (I);
  • Letrozole and Anastrozole purchased or prepared according to the methods of the prior art.
  • the ECOG score is 0-1;
  • the subject's organ function is good at the time of enrollment, and the laboratory test data of blood routine, liver function and kidney function meet the standards;
  • the life expectancy of the subject is ⁇ 12 weeks
  • Suitable subjects are screened, and the compound of formula (I) and letrozole/anastrozole are administered to the subjects. in,
  • the administration method of the compound of formula (I) is: 360mg, orally, twice a day. Every 28 days is a treatment cycle.
  • the administration method of letrozole is: 2.5mg, orally, once a day. Every 28 days is a treatment cycle.
  • the administration method of anastrozole is: 1mg, orally, once a day. Every 28 days is a treatment cycle.
  • DCR Disease control rate
  • CBR Clinical benefit rate
  • the tablet of the compound of formula (I) of the present invention is prepared by adding suitable auxiliary materials to the compound of formula (I) to prepare a tablet of a certain specification.
  • the ECOG score is 0-1;
  • the subject's organ function is good at the time of enrollment, and the laboratory test data of blood routine, liver function and kidney function meet the standards;
  • the life expectancy of the subject is ⁇ 12 weeks
  • Suitable subjects are screened, and the compound of formula (I) is administered to the subjects.
  • the administration method is: 480mg, orally, twice a day. Every 28 days is a treatment cycle.

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  • Pharmacology & Pharmacy (AREA)
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Abstract

L'invention concerne une composition pharmaceutique pour prévenir et/ou traiter le cancer, comprenant une combinaison d'un composé inhibiteur de CDK4/6 représenté par la formule (I) ou d'un sel pharmaceutiquement acceptable de celui-ci et d'un second agent thérapeutique ou d'un sel pharmaceutiquement acceptable de celui-ci dans des proportions ou doses fixes, une application de la composition pharmaceutique ci-dessus dans la préparation d'un médicament pour la prévention et/ou le traitement du cancer, et un kit contenant la composition pharmaceutique.
PCT/CN2022/138337 2021-12-13 2022-12-12 Composition pharmaceutique pour le traitement du cancer WO2023109741A1 (fr)

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015101293A1 (fr) * 2013-12-31 2015-07-09 山东轩竹医药科技有限公司 Inhibiteur kinase et son utilisation
CN107137408A (zh) * 2016-03-01 2017-09-08 江苏恒瑞医药股份有限公司 一种cdk4/6抑制剂与芳香化酶抑制剂联合在制备治疗乳腺癌的药物中的用途
WO2019144759A1 (fr) * 2018-01-29 2019-08-01 海南轩竹医药科技有限公司 Forme cristalline ciblant un inhibiteur de kinase cdk4/6
CN110092775A (zh) * 2018-01-29 2019-08-06 海南轩竹医药科技有限公司 靶向cdk4/6激酶抑制剂的晶型
CN112010839A (zh) * 2019-05-31 2020-12-01 轩竹生物科技有限公司 靶向丝/苏氨酸激酶抑制剂的晶型
WO2021214119A1 (fr) * 2020-04-23 2021-10-28 Ifom - Fondazione Istituto Firc Di Oncologia Molecolare Association thérapeutique pour le traitement du cancer du sein

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015101293A1 (fr) * 2013-12-31 2015-07-09 山东轩竹医药科技有限公司 Inhibiteur kinase et son utilisation
CN107137408A (zh) * 2016-03-01 2017-09-08 江苏恒瑞医药股份有限公司 一种cdk4/6抑制剂与芳香化酶抑制剂联合在制备治疗乳腺癌的药物中的用途
WO2019144759A1 (fr) * 2018-01-29 2019-08-01 海南轩竹医药科技有限公司 Forme cristalline ciblant un inhibiteur de kinase cdk4/6
CN110092775A (zh) * 2018-01-29 2019-08-06 海南轩竹医药科技有限公司 靶向cdk4/6激酶抑制剂的晶型
CN112010839A (zh) * 2019-05-31 2020-12-01 轩竹生物科技有限公司 靶向丝/苏氨酸激酶抑制剂的晶型
WO2021214119A1 (fr) * 2020-04-23 2021-10-28 Ifom - Fondazione Istituto Firc Di Oncologia Molecolare Association thérapeutique pour le traitement du cancer du sein

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