CN118119610A - A pharmaceutical composition for treating cancer - Google Patents
A pharmaceutical composition for treating cancer Download PDFInfo
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- CN118119610A CN118119610A CN202280068953.4A CN202280068953A CN118119610A CN 118119610 A CN118119610 A CN 118119610A CN 202280068953 A CN202280068953 A CN 202280068953A CN 118119610 A CN118119610 A CN 118119610A
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Classifications
-
- 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
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
A pharmaceutical composition for the prophylaxis and/or treatment of cancer comprising a combination of a CDK4/6 inhibitor compound of formula (I) or a pharmaceutically acceptable salt thereof, and a second therapeutic agent or a pharmaceutically acceptable salt thereof in a fixed ratio or fixed dose, the use of such a pharmaceutical composition in the manufacture of a medicament for the prophylaxis and/or treatment of cancer and a kit comprising such a pharmaceutical composition.
Description
The invention belongs to the technical field of medicines, and particularly relates to a pharmaceutical composition for preventing and/or treating cancers, in particular to a pharmaceutical composition containing a fixed proportion or fixed dose combination of a compound shown as a formula (I) or pharmaceutically acceptable salt thereof and a second therapeutic agent or pharmaceutically acceptable salt thereof, and application of the pharmaceutical composition in treating cancers.
Breast cancer is the most common malignancy in women, with about 200 tens of thousands of new breast cancer patients worldwide each year. Breast cancer is a class of tumors that are highly heterogeneous at the molecular level, with tremendous differences in tissue morphology, immunophenotype, biological behavior, and therapeutic response. Based on three receptors: expression of Estrogen Receptor (ER), progesterone Receptor (PR) and human epidermal growth factor receptor-2 (Her 2) divides breast cancer into three subtypes. Estrogen receptor positive (er+) breast cancer is the most common molecular subtype of breast cancer, with a prevalence of about 65% -70% of the population. The prognosis is best in breast cancer, and more patients are in early stage. Er+ breast cancer is better prognosis compared to other molecular subtypes, but still has a 5-year recurrent metastasis rate of about 15-30%. Human epidermal growth factor receptor-2 (HER 2) molecules are independent factors with poor prognosis of breast cancer, and amplification/overexpression of HER2 gene is present in about 20% -30% of chinese breast cancer patients. HER2 overexpression is typically associated with invasive, metastatic forms of breast cancer that have high recurrence rates and/or are associated with poor prognosis for patients.
A general therapeutic goal of all ER/PR positive metastatic breast cancer patients is to extend survival and improve quality of life. This can be achieved by surgical intervention and, if possible, drug treatment. Endocrine (antiestrogenic) drugs are typically used initially and remain until resistance develops. Their use avoids toxicity based on chemotherapy regimens, but their drug itself toxicity and resistance still need to be well addressed.
Aromatase (AR), also known as estrogen synthase, is a complex enzyme of microsomal cytochrome P450, widely found in ovarian, liver, muscle, fat and breast cancer cells, a key enzyme and rate-limiting enzyme that catalyzes the conversion of androgens to estrogens in organisms, and aromatically converts androgens to estrone and estradiol. The aromatase inhibitor (aromataseinhibitor, AI) can specifically lead to the inactivation of aromatase, block the aromatization reaction, inhibit the generation of estrogen, and reduce the estrogen level in blood so as to achieve the purpose of treating breast cancer, and is widely used for post-menopausal advanced breast cancer patients with failed antiestrogen (tamoxifen) treatment.
Anastrozole belongs to a third-generation aromatase inhibitor, is a powerful and selective nonsteroidal aromatase inhibitor, and can inhibit the conversion of estradione into estrone in a patient after menopause, thereby obviously reducing the in-vivo estrogen level and inhibiting the growth of breast tumors. Anastrozole is useful in the advanced breast cancer in postmenopausal women that have been refractory to tamoxifen and other antiestrogenic therapies.
Letrozole is also a third generation aromatase inhibitor with 150-250 times stronger in vivo activity than the first generation aromatase inhibitor aminoglutethimide. Because the selectivity is higher, the glucocorticoid, mineralocorticoid and thyroid functions are not affected, and the large-dose use has no inhibition effect on the secretion of adrenocortical steroid substances, so the pharmaceutical composition has higher therapeutic index. Is suitable for post-menopausal breast cancer, and is mainly used for two-line treatment after the failure of antiestrogen treatment.
Exemestane is also a third generation aromatase inhibitor which irreversibly binds to and inactivates an aromatase, once exemestane binds to the aromatase, the enzyme can never be used to reproduce estrogen, thus preventing estrogen biosynthesis. Exemestane indication is an adjuvant therapy for early invasive breast cancer in postmenopausal estrogen receptor positive women after 2-3 years of adjuvant therapy with tamoxifen until a total of 5 years of adjuvant endocrine therapy is completed; and advanced breast cancer for natural or artificial postmenopausal women whose condition has progressed following treatment with tamoxifen.
Almost all functional effects of oncogenes, tumor suppressor genes, eventually converge on the cell cycle, regulating or blocking the cell cycle is one of the approaches to treat tumors. Currently, many molecules have been found that are involved in cell cycle regulation, with Cyclin-Dependent kinases (CDKs) being the core molecules of the cell cycle regulating network. CDK4/6 plays an irreplaceable role in CDK subtypes involved in the cell cycle. CDK 4/6-specific activation is closely related to proliferation of some tumors, with abnormalities in the cyclin D-CDK4/6-INK4-Rb pathway in approximately 80% of human tumors. Among the CDK4/6 inhibitors currently marketed are PD0332991 (Palbociclib, ibrance) developed by the company Condui, LY2835219 (Abemaciclib, verzenio) by the company Gift, and LEE011 (Ribociclib, kisqali) by the company North.
The present invention provides a highly effective and less toxic tumor treatment composition, mainly relating to the combination of CDK4/6 inhibitor and aromatase inhibitor for treating cancer.
Disclosure of Invention
In one aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, below, and at least one second therapeutic agent or a pharmaceutically acceptable salt thereof,
The second therapeutic agent is selected from an aromatase inhibitor, wherein the weight ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the active ingredient of the second therapeutic agent or a pharmaceutically acceptable salt thereof is 1:1-1000:1.
In certain embodiments, the weight ratio of the active ingredient of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the active ingredient of the second therapeutic agent or a pharmaceutically acceptable salt thereof is from 1:1 to 900:1.
In certain embodiments, the weight ratio of the active ingredient of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the active ingredient of the second therapeutic agent or a pharmaceutically acceptable salt thereof is from 1:1 to 800:1.
In certain embodiments, the weight ratio of the active ingredient of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the active ingredient of the second therapeutic agent or a pharmaceutically acceptable salt thereof is from 1:1 to 720:1.
In certain embodiments, the weight ratio of the active ingredient of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the second therapeutic agent or a pharmaceutically acceptable salt thereof is from 28.8:1 to 720:1.
In certain embodiments, the weight ratio of the active ingredient of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the active ingredient of the second therapeutic agent or a pharmaceutically acceptable salt thereof is 160:1-720:1.
In certain embodiments, the weight ratio of the active ingredient of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the active ingredient of the second therapeutic agent or a pharmaceutically acceptable salt thereof is 288:1-720:1.
In certain embodiments, the weight ratio of the active ingredient of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the active ingredient of the second therapeutic agent or a pharmaceutically acceptable salt thereof is from 1:1 to 700:1.
In certain embodiments, the weight ratio of the active ingredient of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the active ingredient of the second therapeutic agent or a pharmaceutically acceptable salt thereof is from 1:1 to 600:1.
In certain embodiments, the weight ratio of the active ingredient of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the active ingredient of the second therapeutic agent or a pharmaceutically acceptable salt thereof is from 1:1 to 500:1.
In certain embodiments, the weight ratio of the active ingredient of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the active ingredient of the second therapeutic agent or a pharmaceutically acceptable salt thereof is from 1:1 to 400:1.
In certain embodiments, the second therapeutic agent is selected from letrozole, anastrozole, or exemestane.
In certain embodiments, the second therapeutic agent is letrozole, and the weight ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the active ingredient of letrozole or a pharmaceutically acceptable salt thereof is from 5:1 to 400:1.
In certain embodiments, the second therapeutic agent is letrozole, and the weight ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the active ingredient of letrozole or a pharmaceutically acceptable salt thereof is from 10:1 to 400:1.
In certain embodiments, the second therapeutic agent is letrozole, and the weight ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the active ingredient of letrozole or a pharmaceutically acceptable salt thereof is from 12.5:1 to 384:1.
In certain embodiments, the second therapeutic agent is letrozole, and the weight ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the active ingredient of letrozole or a pharmaceutically acceptable salt thereof is from 12.5:1 to 336:1.
In certain embodiments, the second therapeutic agent is letrozole, and the weight ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the active ingredient of letrozole or a pharmaceutically acceptable salt thereof is from 12.5:1 to 300:1.
In certain embodiments, the second therapeutic agent is letrozole, and the weight ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the active ingredient of letrozole or a pharmaceutically acceptable salt thereof is from 12.5:1 to 288:1.
In certain embodiments, the second therapeutic agent is letrozole, and the weight ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the active ingredient of letrozole or a pharmaceutically acceptable salt thereof is from 25:1 to 288:1.
In certain embodiments, the second therapeutic agent is letrozole, and the weight ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the active ingredient of letrozole or a pharmaceutically acceptable salt thereof is from 80:1 to 400:1.
In certain embodiments, the second therapeutic agent is letrozole, and the weight ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the active ingredient of letrozole or a pharmaceutically acceptable salt thereof is 160:1 to 400:1.
In certain embodiments, the second therapeutic agent is letrozole, and the weight ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the active ingredient of letrozole or a pharmaceutically acceptable salt thereof is from 168:1 to 384:1.
In certain embodiments, the second therapeutic agent is letrozole, and the weight ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the active ingredient of 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、190:1、184:1、180:1、176:1、170:1、169:1、168:1、167:1、160:1、150:1、140:1、130:1、120:1、110:1、100:1、90:1、80:1、70:1、60:1、50:1、40:1、35:1、30:1、25:1、20:1、15:1、12.5:1、10:1、5:1.
In certain embodiments, the second therapeutic agent is anastrozole, and the weight ratio of the active ingredient of the compound of formula (I) or a pharmaceutically acceptable salt thereof to anastrozole or a pharmaceutically acceptable salt thereof is 400:1 to 1000:1, preferably 540:1 to 960:1, preferably 600:1 to 960:1, preferably 720:1.
In certain embodiments, the second therapeutic agent is anastrozole, and the weight ratio of the active ingredient of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the active ingredient of 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.
In certain embodiments, the second therapeutic agent is exemestane.
In certain embodiments, the second therapeutic agent is exemestane and the weight ratio of the active ingredient of the compound of formula (I) or a pharmaceutically acceptable salt thereof to exemestane or a pharmaceutically acceptable salt thereof is from 10:1 to 100:1, preferably from 10:1 to 50:1, preferably from 15:1 to 40:1.
In certain embodiments, the second therapeutic agent is exemestane and the weight ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the active ingredient of exemestane or a pharmaceutically acceptable salt thereof is 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.
In certain embodiments, the second therapeutic agent is exemestane and the weight ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the active ingredient of exemestane or a pharmaceutically acceptable salt thereof is 28.8:1.
In certain embodiments, the second therapeutic agent is selected from letrozole or anastrozole, wherein the weight ratio of the active ingredient of the compound of formula (I) or a pharmaceutically acceptable salt thereof to letrozole or a pharmaceutically acceptable salt thereof is from 5:1 to 400:1, preferably from 10:1 to 400:1, preferably from 12.5:1 to 384:1, preferably from 12.5:1 to 336:1, preferably from 12.5:1 to 300:1, preferably from 12.5:1 to 288:1; the weight ratio of the active ingredients of the compound of formula (I) or a pharmaceutically acceptable salt thereof to anastrozole or a pharmaceutically acceptable salt thereof is 400:1 to 1000:1, preferably 540:1 to 960:1, preferably 600:1 to 960:1, preferably 720:1.
In certain embodiments, the second therapeutic agent is selected from the group consisting of letrozole and anastrozole, wherein the weight ratio of the active ingredient of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the active ingredient of 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、190:1、184:1、180:1、176:1、170:1、169:1、168:1、167:1、160:1、150:1、140:1、130:1、120:1、110:1、100:1、90:1、80:1、70:1、60:1、50:1、40:1、35:1、30:1、25:1、20:1、15:1、12.5:1、10:1、5:1; and the weight ratio of the active ingredient of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the active ingredient of 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.
In certain embodiments, the second therapeutic agent is selected from letrozole or anastrozole, wherein the weight ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the active ingredient of letrozole or a pharmaceutically acceptable salt thereof is 288:1; the weight ratio of the compound of the formula (I) or the pharmaceutically acceptable salt thereof to the active ingredient of anastrozole or the pharmaceutically acceptable salt thereof is 720:1.
In certain embodiments, the second therapeutic agent is selected from letrozole or exemestane, wherein the weight ratio of the active ingredient of the compound of formula (I) or a pharmaceutically acceptable salt thereof to letrozole or a pharmaceutically acceptable salt thereof is from 5:1 to 400:1, preferably from 10:1 to 400:1, preferably from 12.5:1 to 384:1, preferably from 12.5:1 to 336:1, preferably from 12.5:1 to 300:1, preferably from 12.5:1 to 288:1; the weight ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the active ingredient of exemestane or a pharmaceutically acceptable salt thereof is from 10:1 to 100:1, preferably from 10:1 to 50:1, preferably from 15:1 to 40:1.
In certain embodiments, the second therapeutic agent is selected from the group consisting of letrozole or exemestane, wherein the weight ratio of the active ingredient of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the active ingredient of 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、190:1、184:1、180:1、176:1、170:1、169:1、168:1、167:1、160:1、150:1、140:1、130:1、120:1、110:1、100:1、90:1、80:1、70:1、60:1、50:1、40:1、35:1、30:1、25:1、20:1、15:1、12.5:1、10:1、5:1; and the weight ratio of the active ingredient of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the active ingredient of exemestane or a pharmaceutically acceptable salt thereof is 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.
In certain embodiments, the second therapeutic agent is selected from letrozole or exemestane, wherein the weight ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the active ingredient of letrozole or a pharmaceutically acceptable salt thereof is 288:1; the weight ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the active ingredient of exemestane or a pharmaceutically acceptable salt thereof is 28.8:1.
In certain embodiments, the second therapeutic agent is selected from exemestane or anastrozole, wherein the weight ratio of the active ingredient of the compound of formula (I) or a pharmaceutically acceptable salt thereof to exemestane or a pharmaceutically acceptable salt thereof is from 10:1 to 100:1, preferably from 10:1 to 50:1, preferably from 15:1 to 40:1; the weight ratio of the active ingredients of the compound of formula (I) or a pharmaceutically acceptable salt thereof to anastrozole or a pharmaceutically acceptable salt thereof is 400:1 to 1000:1, preferably 540:1 to 960:1, preferably 600:1 to 960:1, preferably 720:1.
In certain embodiments, the second therapeutic agent is selected from exemestane or anastrozole, wherein the weight ratio of the active ingredient of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the active ingredient of exemestane or a pharmaceutically acceptable salt thereof is 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; and the weight ratio of the active ingredient of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the active ingredient of 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.
In certain embodiments, the second therapeutic agent is selected from exemestane or anastrozole, wherein the weight ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the active ingredient of exemestane or a pharmaceutically acceptable salt thereof is 28.8:1; the weight ratio of the compound of the formula (I) or the pharmaceutically acceptable salt thereof to the active ingredient of anastrozole or the pharmaceutically acceptable salt thereof is 720:1.
In certain embodiments, the second therapeutic agent is selected from letrozole or anastrozole or exemestane, wherein the weight ratio of the active ingredient of the compound of formula (I) or a pharmaceutically acceptable salt thereof to letrozole or a pharmaceutically acceptable salt thereof is from 5:1 to 400:1, preferably from 10:1 to 400:1, preferably from 12.5:1 to 384:1, preferably from 12.5:1 to 336:1, preferably from 12.5:1 to 300:1, preferably from 12.5:1 to 288:1; the weight ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the active ingredient of anastrozole or a pharmaceutically acceptable salt thereof is 400:1 to 1000:1, preferably 540:1 to 960:1, preferably 600:1 to 960:1, preferably 720:1; the weight ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the active ingredient of exemestane or a pharmaceutically acceptable salt thereof is from 10:1 to 100:1, preferably from 10:1 to 50:1, preferably from 15:1 to 40:1.
In certain embodiments, the second therapeutic agent is selected from the group consisting of letrozole or anastrozole or exemestane, wherein the weight ratio of the active ingredient of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the active ingredient of 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、190:1、184:1、180:1、176:1、170:1、169:1、168:1、167:1、160:1、150:1、140:1、130:1、120:1、110:1、100:1、90:1、80:1、70:1、60:1、50:1、40:1、35:1、30:1、25:1、20:1、15:1、12.5:1、10:1、5:1; and the weight ratio of the active ingredient of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the active ingredient of 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; and the weight ratio of the active ingredient of the compound of formula (I) or a pharmaceutically acceptable salt thereof to exemestane or a pharmaceutically acceptable salt thereof is 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.
In certain embodiments, the second therapeutic agent is selected from letrozole or anastrozole or exemestane, wherein the weight ratio of the active ingredient of the compound of formula (I) or a pharmaceutically acceptable salt thereof to letrozole or a pharmaceutically acceptable salt thereof is 288:1; the weight ratio of the active ingredients of the compound of the formula (I) or the pharmaceutically acceptable salt thereof and anastrozole or the pharmaceutically acceptable salt thereof is 720:1; the weight ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the active ingredient of exemestane or a pharmaceutically acceptable salt thereof is 28.8:1.
In certain embodiments, the active ingredient of the compound of formula (I) or a pharmaceutically acceptable salt thereof is used in an amount of 200-2000mg per day.
In certain embodiments, the active ingredient of the compound of formula (I) or a pharmaceutically acceptable salt thereof is used in an amount of 200-1000mg per day.
In certain embodiments, the active ingredient of the compound of formula (I) or a pharmaceutically acceptable salt thereof is used in an amount of 400-1000mg per day.
In certain embodiments, the active ingredient of the compound of formula (I), or a pharmaceutically acceptable salt thereof, is used in a daily amount of 960mg, 840mg, 720mg, 600mg, 560mg, 480mg, or 420mg.
In certain embodiments, the active ingredient of the compound of formula (I), or a pharmaceutically acceptable salt thereof, is used in an amount of 900mg, 880mg, 860mg, 820mg, 800mg, 780mg, 760mg, 740mg, 700mg, 680mg, 660mg, 640mg, 620mg, 580mg, or 540mg per day.
In certain embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered once a day, twice a day, or three times a day.
In certain embodiments, the second therapeutic agent or pharmaceutically acceptable salt thereof is administered once a day, twice a day, or three times a day.
In certain embodiments, the effective ingredient of the second therapeutic agent or pharmaceutically acceptable salt thereof is used in an amount of 0.2-400mg, such as 0.5-200mg, such as 0.5-100mg, such as 0.5-50mg, such as 1-25mg, such as 1-10mg, such as 1-5mg, such as 25mg, such as 2.5mg, such as 1mg, per time.
In certain embodiments, the effective ingredient of the second therapeutic agent or pharmaceutically acceptable salt thereof is used in an amount of 100mg, 75mg, 50mg, 25mg, 10mg, 7.5mg, 5mg, 2.5mg, 1mg, or 0.5mg per time.
In certain embodiments, the second therapeutic agent is letrozole, letrozole or a pharmaceutically acceptable salt thereof, and the active ingredient is administered at a rate of 1-5mg, preferably 2.5mg, per time and once daily.
In certain embodiments, the second therapeutic agent is anastrozole, the active ingredient of anastrozole or a pharmaceutically acceptable salt thereof is administered in an amount of 0.5 to 2.5mg, preferably 1mg, per time, at a frequency of once daily.
In certain embodiments, the second therapeutic agent is exemestane, exemestane or a pharmaceutically acceptable salt thereof, and the active ingredient is administered in an amount of 12.5-50mg, preferably 25mg, per time, at a frequency of once daily.
In certain embodiments, the second therapeutic agent is letrozole or anastrozole, wherein the amount of the active ingredient of letrozole or a pharmaceutically acceptable salt thereof is 2.5mg per time and the dosing frequency is once a day; the active ingredient of anastrozole or pharmaceutically acceptable salt thereof is used in an amount of 1mg each time, and the administration frequency is once a day.
In certain embodiments, the second therapeutic agent is letrozole or exemestane, wherein the effective ingredient of letrozole or a pharmaceutically acceptable salt thereof is administered at a rate of 2.5mg per time and once a day; the amount of active ingredient of exemestane or its pharmaceutically acceptable salt is 25mg per time, and the administration frequency is once a day.
In certain embodiments, the second therapeutic agent is exemestane or anastrozole, wherein the active ingredient of exemestane or a pharmaceutically acceptable salt thereof is administered at a rate of 25mg per time and once a day; the active ingredient of anastrozole or pharmaceutically acceptable salt thereof is used in an amount of 1mg each time, and the administration frequency is once a day.
In certain embodiments, the second therapeutic agent is letrozole or exemestane or anastrozole, wherein the effective ingredient of letrozole or a pharmaceutically acceptable salt thereof is administered at a dose of 2.5mg each time, at a frequency of once daily; the effective component of exemestane or its pharmaceutically acceptable salt is used in an amount of 25mg per time, and the administration frequency is once a day; the active ingredient of anastrozole or pharmaceutically acceptable salt thereof is used in an amount of 1mg each time, and the administration frequency is once a day.
In certain embodiments, the compound of formula (I) is administered simultaneously or sequentially with the second therapeutic agent.
In certain embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered orally.
In certain embodiments, the second therapeutic agent or pharmaceutically acceptable salt thereof is administered orally.
In another aspect, the invention also provides a pharmaceutical formulation comprising the aforementioned pharmaceutical composition, and one or more pharmaceutically acceptable excipients, which may be in any pharmaceutically acceptable dosage form. Pharmaceutically acceptable excipients are non-toxic, compatible with the active ingredient and otherwise biologically compatible substances for use in the organism. The choice of a particular excipient will depend on the mode of administration or type and state of disease used to treat a particular patient.
In certain embodiments, the above pharmaceutical formulations may be administered orally, parenterally, rectally, or pulmonary, etc., to a patient or subject in need of such treatment. For oral administration, the pharmaceutical composition may be formulated into oral preparations, for example, into conventional oral solid preparations such as tablets, capsules, pills, granules, etc.; can also be made into oral liquid preparation such as oral solution, oral suspension, syrup, etc. For parenteral administration, the pharmaceutical preparations may also be formulated as injections, including injectable solutions, injectable sterile powders, and injectable concentrated solutions. For rectal administration, the pharmaceutical composition may be formulated as suppositories and the like. For pulmonary administration, the pharmaceutical composition may be formulated as an inhalation, aerosol, powder spray or spray.
In a further aspect, the invention also relates to the use of the aforementioned pharmaceutical composition for the preparation of a medicament for the prevention and/or treatment of a cancer 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 genital 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.
In certain embodiments, the cancer is selected from HR +、HER2 - breast cancer.
In certain embodiments, the cancer is selected from post-menopausal HR +、HER2 - breast cancer.
In certain embodiments, the cancer is selected from locally advanced or metastatic breast cancer.
In certain embodiments, the cancer is selected from advanced HR +、HER2 - or metastatic breast cancer.
In certain embodiments, the cancer is selected from advanced HR +、HER2 - or metastatic breast cancer that progresses after endocrine treatment alone.
In a further aspect, the invention also relates to the use of a therapeutically effective amount of a combination of a compound of formula (I) or a pharmaceutically acceptable salt thereof and letrozole or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the prevention and/or treatment of a cancer 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, renal cancer, esophageal adenocarcinoma, esophageal squamous cell carcinoma, prostate cancer, female genital tract cancer, lymphoma, neurofibromas, 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.
In certain embodiments, the cancer is selected from HR +、HER2 - breast cancer.
In certain embodiments, the cancer is selected from post-menopausal HR +、HER2 - breast cancer.
In certain embodiments, the cancer is selected from locally advanced or metastatic breast cancer.
In certain embodiments, the cancer is selected from advanced HR +、HER2 - or metastatic breast cancer.
In certain embodiments, the cancer is selected from advanced HR +、HER2 - or metastatic breast cancer that progresses after endocrine treatment alone.
Furthermore, the invention also relates to the application of the pharmaceutical preparation containing the pharmaceutical composition in preparing medicines for preventing and/or treating cancers.
In another aspect, the invention also provides a kit comprising the aforementioned pharmaceutical composition, and instructions for how to administer the pharmaceutical composition or a compound of formula (I) and a second therapeutic agent contained therein.
In another aspect, the present invention also provides a method of treating cancer comprising administering to a patient in need thereof an effective amount of the aforementioned pharmaceutical composition, a pharmaceutical formulation comprising the pharmaceutical composition; the cancer is as described hereinbefore.
In certain embodiments, 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 particular dosage regimen.
In certain embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered orally at a dosage of 400-1000mg of active ingredient per day.
In certain embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered orally at a dose of 960mg, 840mg, 720mg, 600mg, 560mg, 480mg, or 420mg of active ingredient per day.
In certain embodiments, the second therapeutic agent is letrozole, which is administered orally at a dose of 1-5mg of active ingredient per day.
In certain embodiments, the second therapeutic agent is letrozole, which is administered orally at a dose of 2.5mg of active ingredient per day.
In certain embodiments, the second therapeutic agent is anastrozole, administered orally at a dose of 0.5-2.5mg active ingredient per day.
In certain embodiments, the second therapeutic agent is anastrozole, administered orally at a dose of 1mg of active ingredient per day.
In certain embodiments, the second therapeutic agent is exemestane, administered orally at a dose of 12.5-50mg active ingredient per day.
In certain embodiments, the second therapeutic agent is exemestane, administered orally at a dose of 25mg active ingredient per day.
In certain embodiments, the second therapeutic agent is letrozole or anastrozole, wherein letrozole is orally administered at a dose of 1-5mg of the active ingredient per day or anastrozole is orally administered at a dose of 0.5-2.5mg of the active ingredient per day.
In certain embodiments, the second therapeutic agent is letrozole or anastrozole, wherein letrozole is orally administered at a dose of 2.5mg of the active ingredient per day or anastrozole is orally administered at a dose of 1mg of the active ingredient per day.
In certain embodiments, the second therapeutic agent is letrozole or exemestane, wherein letrozole is orally administered at a dose of 1-5mg of active ingredient per day or exemestane is orally administered at a dose of 12.5-50mg of active ingredient per day.
In certain embodiments, the second therapeutic agent is letrozole or exemestane, wherein letrozole is orally administered at a dose of 2.5mg of active ingredient per day or exemestane is orally administered at a dose of 25mg of active ingredient per day.
In certain embodiments, the second therapeutic agent is exemestane or anastrozole, wherein exemestane is administered orally at a dose of 12.5-50mg of active ingredient per day or anastrozole is administered orally at a dose of 0.5-2.5mg of active ingredient per day.
In certain embodiments, the second therapeutic agent is exemestane or anastrozole, wherein exemestane is administered orally at a dose of 25mg of active ingredient per day or anastrozole is administered orally at a dose of 1mg of active ingredient per day.
In certain embodiments, the second therapeutic agent is letrozole or anastrozole or exemestane, wherein letrozole is orally administered at a dose of 1-5mg of active ingredient per day or anastrozole is orally administered at a dose of 0.5-2.5mg of active ingredient per day or exemestane is orally administered at a dose of 12.5-50mg of active ingredient per day.
In certain embodiments, the second therapeutic agent is letrozole or anastrozole or exemestane, wherein letrozole is orally administered at a dose of 2.5mg of active ingredient per day or anastrozole is orally administered at a dose of 1mg of active ingredient per day or exemestane is orally administered at a dose of 25mg of active ingredient per day.
In the present invention, unless otherwise indicated, scientific and technical terms used herein have the meanings commonly understood by one of ordinary skill in the art, however, for a better understanding of the present invention, the following definitions of some terms are provided. When the definition and interpretation of terms provided by the present invention are not identical to the meanings commonly understood by those skilled in the art, the definition and interpretation of terms provided by the present invention is in control.
HR positive (HR +) in the context of the present invention means that ER (estrogen receptor) expression is positive and/or PR (progestin receptor) expression is positive, i.e. HR + includes ER +、PR + or ER +/PR +.
The HER2 - disclosed by the invention refers to that the expression of the human epidermal growth factor receptor 2 (HER 2) is negative.
The "second therapeutic agent" as used herein refers to an agent having a prophylactic and/or therapeutic effect on a tumor.
By "effective amount" is meant an amount of a drug that is capable of preventing, alleviating, delaying, inhibiting or curing a condition in a subject. The size of the dose administered is related to the mode of administration of the drug, the pharmacokinetics of the agent, the severity of the disease, the individual sign (sex, weight, height, age) of the subject, etc.
The "active ingredient" in the present invention refers to a part of a drug that exerts a drug effect, and if the compound is a free compound, the active ingredient is the compound; in the case of a salt of a compound, the active ingredient is a free compound thereof (excluding a portion forming a salt therewith).
The invention relates to a pharmaceutical composition, which comprises a composition formed by preparing active ingredients such as a compound of formula (I) and a second therapeutic agent into the same compound preparation, and also comprises a composition formed by preparing the active ingredients such as the compound of formula (I) and the second therapeutic agent into single preparations respectively.
The "simultaneous administration" of the compound of formula (I) and the second therapeutic agent according to the present invention includes administration after the compound of formula (I) and the second therapeutic agent are prepared into the same compound preparation, or administration after the compound of formula (I) and the second therapeutic agent are respectively prepared into the preparations.
The "administration of the compound of formula (I) and the second therapeutic agent" according to the present invention means that the compound of formula (I) and the second therapeutic agent are administered separately in succession according to their respective modes of administration after they are formulated separately.
The term "pharmaceutically acceptable salt" as used herein refers to salts of acidic functional groups (e.g., -COOH, -OH, -SO 3 H, etc.) present in the compound with suitable inorganic or organic cations (bases), including salts with alkali metals or alkaline earth metals, ammonium salts, salts with nitrogen-containing organic bases; and salts of basic functional groups (e.g., -NH2, etc.) present in the compounds with suitable inorganic or organic anions (acids), including salts with inorganic or organic acids (e.g., carboxylic acids, etc.).
Advantageous effects of the invention
1. The pharmaceutical composition provided by the invention has excellent synergistic anti-tumor effect in-vitro cell experiments and in-vivo tumor model experiments, and especially has remarkable curative effect on breast cancer.
2. The pharmaceutical composition has good clinical synergistic anti-tumor effect.
3. The pharmaceutical composition of the invention has low toxicity or no toxicity and less side effect.
4. The pharmaceutical composition of the invention can improve the drug substitution property of single-use drugs and increase the exposure.
Experimental protocol
Exemplary protocols for some of the compounds of the present invention are provided below to demonstrate the advantageous activity and beneficial technical effects of the compounds of the present invention. It should be understood that the following experimental schemes are merely illustrative of the present disclosure and are not intended to limit the scope of the present disclosure.
Experimental example 1 in vivo efficacy evaluation test of the Compound of formula (I) of the invention and letrozole administered alone and in combination on a xenograft model of human breast cancer
Test article: the compounds of formula (I) according to the invention are prepared according to the processes of the prior art.
Abbreviations in the following experiments represent the following meanings:
The experimental method comprises the following steps:
1. tumor inoculation and grouping
Patient-derived tumor tissue was inoculated into immunodeficient animals to establish HBCx-34 human breast cancer (ER +,PR +,HER2 -) xenograft PDX model. After the donor mice tumor grows to a certain volume, the tumor is killed and separated, and the tumor is treated into a small block of 20mm 3 tumor and inoculated to the subcutaneous part of the shoulder blade of the test mice. Tumor-bearing mice were supplemented with β -estradiol (8.5 mg/L) by drinking water from tumor inoculation to the period of the group, and after the group, the supplementation with estradiol was stopped.
Tumors were grouped when they grew to a volume of 171.5-405 mm 3, and were divided into 9 groups: solvent control group, compound of formula (I) alone group (50 mg/kg, 25 mg/kg), letrozole alone group (1.25 mg/kg, 2 mg/kg) and combination group, 8 animals per group. The compound of formula (I) and letrozole are administered once daily by intragastric administration for 42 days.
When the two are combined, the same administration mode is adopted as that of single administration. The compound of formula (I) was formulated to the desired concentration using pH4.0 buffer (formulated from citric acid monohydrate and disodium hydrogen phosphate dodecahydrate) and letrozole was formulated to the desired concentration using 0.9% NaCl solution. The solvent control group was administered the vehicle of the compound of formula (I), the above pH4.0 buffer, once daily by gavage for 42 days.
2. Tumor measurement and experimental index
The tumor volume was measured 2 times per week using a vernier caliper, and the long and short diameters of the tumor were measured, and the volume calculation formula was: volume = 0.5 x long diameter x short diameter 2. Average tumor volume values (T/C) were calculated from the measurements, T being the average tumor volume of the dosing group and C being the average tumor volume of the solvent control group.
3. Statistical analysis
The tumor volumes were statistically analyzed between groups using the Mann-Whitney non-reference test, with p <0.05 considered significant differences.
Experimental results:
TABLE 1 anti-tumor effect of the inventive compounds on HBCx-34 human breast cancer (ER+, HER 2-) xenograft models
a. Mean ± standard error; b. Comparison with the control group; c. Comparison to the single group of corresponding concentration doses; ns, no significant difference. Conclusion of experiment:
The combined group of the compound of the formula (I) and the letrozole has obvious inhibition effect on the tumor growth of a HBCx-34 (ER +,PR +,HER2 -) human breast cancer xenograft PDX model, in particular to the combined group of 50mg/kg of the compound of the formula (I) and 2mg/kg of letrozole and the combined group of 50mg/kg of the compound of the formula (I) and 1.25mg/kg of letrozole, and the inhibition effect is obviously better than that of the compound of the formula (I) and the letrozole which are used singly at corresponding concentration doses respectively.
Experimental example 2 clinical trials of the combination of Compound of formula (I) and letrozole/anastrozole of the invention for the treatment of breast cancer patients
Test article:
The compound tablet of the formula (I) is prepared by adding proper auxiliary materials into the compound tablet of the formula (I) to prepare a tablet with certain specification;
letrozole and anastrozole: purchased or prepared according to prior art methods.
Subject entry criteria:
1. age 18-70 years;
2. Laboratory results confirm that hormone receptor positive (hr+), HER2 negative (HER 2-) breast cancer patients have not previously received systemic anti-cancer therapy;
3. ECOG is scored as 0-1;
4. When the kit is put into a group, the organ function of the subject is good, and laboratory examination data of blood routine, liver function and kidney function meet the standard;
5. the life of the expected subjects is more than or equal to 12 weeks according to the judgment of researchers;
6. a fertility male or female subject must agree to use an effective contraceptive method;
7. Prior to the start of the study, subjects must provide written informed consent.
Evaluation criteria for target lesions
Dosing regimen:
screening a suitable subject, and administering to the subject a compound of formula (I) and letrozole/anastrozole. Wherein,
The compounds of formula (I) are administered in the following manner: 360mg, orally taken twice daily. Every 28 days is 1 treatment cycle.
The administration mode of letrozole is as follows: 2.5mg, orally taken once daily. Every 28 days is 1 treatment cycle.
The anastrozole is administered in the following manner: 1mg, orally taken once daily. Every 28 days is 1 treatment cycle.
The 35 subjects in the group were enrolled and the test results were shown in Table 2 by 2021, 11 months.
TABLE 2 tumor inhibiting effect of Compounds of formula (I) and letrozole/anastrozole combinations on a subject
A, unevaluated (NE).
Disease Control Rate (DCR), which refers to the percentage of subjects in CR and PR and SD in the total population of analytical data.
Conclusion of the test:
as can be seen from the data in table 2, the compound of formula (I) combined with letrozole/anastrozole has significant tumor inhibition effect, and the Disease Control Rate (DCR) reaches 91.4%, with significant benefits from combination therapy.
Experimental example 3 clinical test effects of the Compound of formula (I) of the invention and of the combination of letrozole/anastrozole
Test article:
The compound tablet of the formula (I) is prepared by adding proper auxiliary materials into the compound tablet of the formula (I) to prepare a tablet with certain specification;
letrozole and anastrozole: purchased or prepared according to prior art methods.
Subject entry criteria:
1. age 18-70 years;
2. Laboratory results confirm that hormone receptor positive (hr+), HER2 negative (HER 2-) breast cancer patients have not previously received systemic anti-cancer therapy;
3. ECOG is scored as 0-1;
4. When the kit is put into a group, the organ function of the subject is good, and laboratory examination data of blood routine, liver function and kidney function meet the standard;
5. the life of the expected subjects is more than or equal to 12 weeks according to the judgment of researchers;
6. a fertility male or female subject must agree to use an effective contraceptive method;
7. Prior to the start of the study, subjects must provide written informed consent.
Evaluation criteria for target lesions
Dosing regimen:
screening a suitable subject, and administering to the subject a compound of formula (I) and letrozole/anastrozole. Wherein,
The compounds of formula (I) are administered in the following manner: 360mg, orally taken twice daily. Every 28 days is 1 treatment cycle.
The administration mode of letrozole is as follows: 2.5mg, orally taken once daily. Every 28 days is 1 treatment cycle.
The anastrozole is administered in the following manner: 1mg, orally taken once daily. Every 28 days is 1 treatment cycle.
The 35 subjects in the group were enrolled and the test results were shown in Table 3 by 2022, 11 months.
TABLE 3 tumor inhibiting effect of Compounds of formula (I) and letrozole/anastrozole combinations on a subject
A, unevaluated (NE).
Disease Control Rate (DCR), which refers to the percentage of subjects in CR and PR and SD in the total population of analytical data.
C: clinical Benefit Ratio (CBR), which refers to the percentage of subjects with CR, PR and SD.gtoreq.6 months, in the total population of the analytical data.
Conclusion of the test:
As can be seen from the data in table 3, the compound of formula (I) combined with letrozole/anastrozole has significant tumor inhibition, the Disease Control Rate (DCR) reaches 94.3%, the Clinical Benefit Rate (CBR) reaches 77.2%, and the benefit of the combined treatment is significant.
Experimental example 4 clinical test Effect of the Compound of formula (I) of the invention
Test article:
the compound tablet of the formula (I) is prepared by adding proper auxiliary materials into the compound tablet of the formula (I) to prepare a tablet with a certain specification.
Subject entry criteria:
1. The age is more than or equal to 18 years old.
2. Locally advanced, recurrent or metastatic breast cancer diagnosed histologically or cytologically, which cannot be subjected to surgery or radical radiotherapy, and meets the following requirements:
1) HR positive, HER2 negative (based on last immunohistochemical outcome);
2) At least 2 chemotherapy regimens have been previously used:
● A recurrent or metastatic stage, receiving 1 to 2 chemotherapy regimen treatments;
● At least 1 of the prior adjuvant or metastatic stages of chemotherapy contain taxanes.
3) Recurrence or metastatic stage endocrine treatment followed by progression;
4) Disease progression occurs during or after the last anti-tumor treatment.
3. ECOG is scored as 0-1;
4. When the kit is put into a group, the organ function of the subject is good, and laboratory examination data of blood routine, liver function and kidney function meet the standard;
5. the life of the expected subjects is more than or equal to 12 weeks according to the judgment of researchers;
6. a fertility male or female subject must agree to use an effective contraceptive method;
7. Prior to the start of the study, subjects must provide written informed consent.
Evaluation criteria for target lesions
Dosing regimen:
Screening a suitable subject and administering to the subject a compound of formula (I). The administration mode is as follows: 480mg, orally taken twice daily. Every 28 days is 1 treatment cycle.
Preliminary results: the 131 subjects in the group were pooled and the Disease Control Rate (DCR) reached 66.4% by 2022, 09 months.
Claims (10)
- A pharmaceutical composition for the prevention and/or treatment of cancer comprising a therapeutically effective amount of 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 an aromatase inhibitor, wherein the weight ratio of the compound of formula (I) or pharmaceutically acceptable salt thereof to the active ingredient of the second therapeutic agent or pharmaceutically acceptable salt thereof is 1:1-1000:1; preferably 1:1 to 900:1, preferably 1:1 to 800:1, preferably 1:1 to 700:1, preferably 1:1 to 600:1, preferably 1:1 to 500:1, preferably 1:1 to 400:1.
- The pharmaceutical composition of claim 1, wherein the second therapeutic agent is selected from letrozole, anastrozole, or exemestane.
- The pharmaceutical composition of claim 1, wherein the second therapeutic agent is letrozole and the weight ratio of the active ingredient of the compound of formula (I) or a pharmaceutically acceptable salt thereof to letrozole or a pharmaceutically acceptable salt thereof is from 5:1 to 400:1, preferably from 10:1 to 400:1, preferably from 12.5:1 to 384:1, preferably from 12.5:1 to 336:1, preferably from 12.5:1 to 300:1, preferably from 12.5:1 to 288:1.
- The pharmaceutical composition of claim 1, wherein the second therapeutic agent is letrozole and the weight ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the active ingredient 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、190:1、184:1、180:1、176:1、170:1、169:1、168:1、167:1、160:1、150:1、140:1、130:1、120:1、110:1、100:1、90:1、80:1、70:1、60:1、50:1、40:1、35:1、30:1、25:1、20:1、15:1、12.5:1、10:1、5:1.
- The pharmaceutical composition of claim 1, wherein the second therapeutic agent is anastrozole and the weight ratio of the active ingredient of the compound of formula (I) or a pharmaceutically acceptable salt thereof to anastrozole or a pharmaceutically acceptable salt thereof is 400:1 to 1000:1, preferably 540:1 to 960:1, preferably 600:1 to 960:1, preferably 720:1.
- The pharmaceutical composition according to claim 1, wherein the second therapeutic agent is exemestane and the weight ratio of the active ingredient of the compound of formula (I) or a pharmaceutically acceptable salt thereof to exemestane or a pharmaceutically acceptable salt thereof is from 10:1 to 100:1, preferably from 10:1 to 50:1, preferably from 15:1 to 40:1.
- The pharmaceutical composition according to any one of claims 1 to 6, wherein the active ingredient of the compound of formula (I) or a pharmaceutically acceptable salt thereof is used in an amount of 200 to 2000mg, preferably 200 to 1000mg, preferably 400 to 1000mg, per day; wherein the active ingredient of the second therapeutic agent or a pharmaceutically acceptable salt thereof is used in an amount of 0.2 to 400mg, preferably 0.5 to 200mg, preferably 0.5 to 100mg, preferably 0.5 to 50mg, preferably 1 to 25mg, per day.
- Use of a pharmaceutical composition according to any one of claims 1-7 for the manufacture of a medicament for the prophylaxis and/or treatment of cancer selected from brain, lung, squamous cell, bladder, gastric, ovarian, peritoneal, pancreatic, breast, head and neck, cervical, endometrial, rectal, liver, renal, oesophageal adenocarcinoma, oesophageal squamous cell carcinoma, prostate, female genital tract, lymphoma, neurofibromatosis, thyroid, bone, skin, brain, colon, testicular, gastrointestinal stromal, prostate, mast cell, multiple myeloma, melanoma, glioma or sarcoma, preferably breast cancer, preferably HR +、HER2 - breast cancer, preferably locally advanced or metastatic breast cancer.
- Use of a therapeutically effective amount of a combination of a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof and letrozole or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the prevention and/or treatment of cancer selected from brain, lung, squamous cell, bladder, stomach, ovary, peritoneal, pancreas, breast, head and neck, cervical, endometrial, rectal, liver, kidney, oesophageal gland, oesophageal squamous cell, prostate, female genital tract, lymphoma, neurofibromatosis, thyroid, bone, skin, brain, colon, testicular, gastrointestinal stromal, prostate, mast cell, multiple myeloma, melanoma, glioma or sarcoma, preferably breast cancer, preferably HR +、HER2 - breast cancer, preferably locally advanced or metastatic breast cancer.
- A kit comprising a pharmaceutical composition according to any one of claims 1 to 7, and instructions for how to administer the pharmaceutical composition, or a compound of formula (I) and a second therapeutic agent comprised thereof.
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