WO2018233620A1 - Utilisation de serd avec un inhibiteur de cdk4/6 et un inhibiteur de la voie pi3k/mtor - Google Patents

Utilisation de serd avec un inhibiteur de cdk4/6 et un inhibiteur de la voie pi3k/mtor Download PDF

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WO2018233620A1
WO2018233620A1 PCT/CN2018/091930 CN2018091930W WO2018233620A1 WO 2018233620 A1 WO2018233620 A1 WO 2018233620A1 CN 2018091930 W CN2018091930 W CN 2018091930W WO 2018233620 A1 WO2018233620 A1 WO 2018233620A1
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group
alkyl
cycloalkyl
aryl
heteroaryl
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PCT/CN2018/091930
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Chinese (zh)
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黄晓星
曹国庆
杨昌永
张连山
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江苏恒瑞医药股份有限公司
上海恒瑞医药有限公司
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Priority to CN201880004458.0A priority Critical patent/CN109982701B/zh
Publication of WO2018233620A1 publication Critical patent/WO2018233620A1/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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • C07D401/02—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 two hetero rings
    • C07D401/04—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 two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the invention belongs to the field of medicine and relates to the use of a SERD in combination with one or more selected from the group consisting of a CDK4/6 inhibitor and a PI3K/mTOR pathway inhibitor in the preparation of a medicament for treating breast tumors.
  • Breast cancer is a malignant tumor that occurs in the epithelial tissues of the breast gland.
  • the classification of breast cancer is complex. According to pathological classification, it can be divided into non-invasive breast cancer, early invasive breast cancer, invasive special breast cancer, invasive non-specific breast. Cancer, other rare and special types of breast cancer. According to molecular typing, it can be divided into lumen type A (Luminal A), lumen type B (Luminal B), epidermal growth factor receptor 2 (HER2) overexpression, basal cell type, normal breast type. According to epidemiological statistics, Luminal A and Luminal B breast cancer accounted for 71.6% of all breast cancers. Although both Luminal A and Luminal B breast cancers express hormone receptors (HR), both types have larger difference.
  • HR hormone receptors
  • Luminal type A is generally well pathologically differentiated; Luminal type B is generally poorly pathologically differentiated.
  • Endocrine therapy for HR is one of the important methods for the treatment of breast cancer. Open research shows that there is a significant correlation between endocrine therapy and breast cancer prognosis.
  • endocrine therapy for breast cancer is a very effective treatment for the highest proportion of HR-positive breast cancer
  • some patients gradually develop resistance to endocrine therapy during the course of medication, and some metastatic patients will develop into complete Endocrine therapy is resistant, so for these patients, new medical tools must be sought to overcome the resistance of endocrine therapy and improve the effectiveness of its treatment.
  • drugs not only regulate tumor cell proliferation signaling pathways, but also improve the effectiveness of endocrine therapy for HR-positive breast cancer.
  • a large number of studies have found that tumors are associated with abnormal cell cycle. Most tumors have a large number of mitotic signaling proteins/anti-mitotic signaling protein defects, genomic instability (GIN) and genomic instability (CIN).
  • CDK cyclin-dependent kinase
  • Cyclin B/CDK1, Cyclin A/CDK2, Cyclin E/CDK2, Cyclin D/CDK4, Cyclin D/CDK6 and other heterodimers are important regulators of cell cycle progression, Cyclin/ Additional functions of CDK heterodimers also include regulation of transcription, DNA repair, differentiation, and programmed cell death.
  • Cyclin, CDK, and retinoblastoma protein constitute important cellular proliferation regulatory pathways.
  • Pathological studies have shown that the interaction of Cyclin D1-CDK4/6/Rb in breast cancer samples is out of control, often manifested as Cyclin D1. Overexpression or amplification.
  • WO2016124067 discloses the above-mentioned novel isethionates of CDK4/6 inhibitors.
  • PI3K/Akt/mTOR signaling pathway plays an important role in the development of breast cancer. Activation of the PI3K/Akt/mTOR signaling pathway can inhibit a variety of stimulation-induced apoptosis and promote cell cycle progression. Survival and proliferation, while participating in tumor formation, invasion, and metastasis. Activated mTOR is capable of activating many downstream signaling pathways.
  • ribosomal protein S6 kinase and eukaryotic initiation factor 4EBP-1 these proteins play an important role in ribosome synthesis and protein translation, and inhibition of mTOR phosphorylation can block the activation of these proteins, thereby enabling The transcription level of mRNA is decreased, and these mRNAs are usually involved in the editing of tumor growth factors, oncoproteins and Cyclin. Therefore, hyperphosphorylation of mTOR is bound to exacerbate the overactivity of the Cyclin D1-CDK4/6/Rb pathway and induce downstream apoptosis pathways.
  • PI3K/Akt/mTOR pathway inhibitor is everolimus. Sirolimus, temsirolimus, etc.
  • SERM Estrogen receptor
  • SERMs drugs that have been marketed or are under investigation and target Estrogen receptor (ER) are mainly classified into SERM, SERD, and aromatase inhibitors.
  • SERMs currently on the market have serious side effects.
  • Long-term use of tamoxifen and toremifene can cause endometrial hyperplasia, polyps and endometrial cancer, while common side effects of raloxifene include hot flashes. , leg pain, breast tenderness and venous embolism; in addition, with the prolongation of endocrine therapy, many HR-positive patients gradually resist SERM and aromatase inhibitors, and SERD is different from SERM and aromatase inhibitors due to its mechanism of action.
  • SERD is based on the endocrine treatment dilemma of SERM resistance.
  • the only SERD drug currently on the market is fulvestrant (Astrazeneca, AstraZeneca), but there are still some adverse reactions such as fatigue, hot flashes, joint pain, rash and loss of appetite.
  • the researched SERD has AZD-9496 ( Astrazeneca, AstraZeneca, RAD1901 (Eisai, Eisai), ZB-716 (Louisiana University, University of Louisiana).
  • the present invention provides a novel SERD which exhibits good activity in inhibiting binding of E to ER, ER degradation and proliferation of MCF7 cells, in particular, in terms of Emax value of ER degradation, compared with AZD-9496 compound.
  • it has a more prominent advantage, and its structure is as follows:
  • the patent application WO2014183520, US2016090377A, US2016367526A, US2016184311A, WO2014203129, US2016175289A disclose CDK4/6 inhibitors in combination with SERD, PI3K/mTOR pathway inhibitors for the treatment of breast cancer
  • patent application WO2016176666, WO2016146591, WO2015149045, WO2015135061 disclose CDK4/6 inhibition
  • the present invention provides the use of a novel structure of SERD in combination with a CDK4/6 inhibitor, a PI3K/mTOR pathway inhibitor, for the preparation of a medicament for the treatment of breast tumors, And showed a good anti-tumor effect.
  • the technical problem to be solved by the present invention is to provide a use of a SERD in combination with one or more selected from the group consisting of a CDK4/6 inhibitor and a PI3K/mTOR pathway inhibitor in the preparation of a medicament for treating breast tumors.
  • the SERD is a compound of the formula (I), or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or A pharmaceutically acceptable salt wherein the compound of the formula (I) has the following structure:
  • Ring A is selected from the group consisting of a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;
  • Ring B is an aryl or heteroaryl group
  • R 1 is each the same or different and is each independently selected from the group consisting of a hydrogen atom, an alkyl group, a halogenated alkyl group, a hydroxyalkyl group, an alkoxy group, an amino group, a cycloalkyl group, a halogen, a cyano group, a carboxyl group, an aldehyde group, a hydroxyl group, and a nitro group.
  • alkyl group, cycloalkyl group, aryl group and heteroaryl group are optionally selected from the group consisting of alkyl, halogen, amino, nitro, cyano, hydroxy, hydroxyalkyl, alkane Substituted by one or more substituents of an oxy group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;
  • R 2 is each the same or different and is each independently selected from the group consisting of a hydrogen atom, an alkyl group, a halogenated alkyl group, a hydroxyalkyl group, an alkoxy group, an amino group, a cycloalkyl group, a halogen group, a cyano group, a carboxyl group, an aldehyde group, a hydroxyl group, and a nitro group.
  • alkyl group, cycloalkyl group, aryl group and heteroaryl group are optionally selected from the group consisting of alkyl, halogen, amino, nitro, cyano, hydroxy, hydroxyalkyl, alkane Substituted by one or more substituents of an oxy group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;
  • R 3 is each the same or different and is each independently selected from a hydrogen atom, an alkyl group, a halogenated alkyl group, a hydroxyalkyl group, an alkoxy group, an amino group, a cycloalkyl group, a halogen group, a cyano group, a carboxyl group, an aldehyde group, a hydroxyl group, a nitro group.
  • alkyl group, cycloalkyl group, aryl group and heteroaryl group are optionally selected from the group consisting of alkyl, halogen, amino, nitro, cyano, hydroxy, hydroxyalkyl, alkane Substituted by one or more substituents of an oxy group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;
  • R 4 each being the same or different and each independently selected from a hydrogen atom, an alkyl group, a halogenated alkyl group, a halogenated alkyl group, a hydroxyalkyl group, an alkoxy group, an amino group, a cycloalkyl group, a halogen, a cyano group, a carboxyl group, or an aldehyde group.
  • alkyl group, cycloalkyl group, aryl group and heteroaryl group are optionally selected from the group consisting of alkyl, halogen, amino, nitro, cyano, hydroxy, Substituted by one or more substituents of a hydroxyalkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;
  • R 5 is selected from the group consisting of a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group, and heteroaryl group are optionally selected. Substituted from one or more substituents of alkyl, halo, hydroxy, amino, nitro, cyano, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • R 6 is selected from the group consisting of a hydrogen atom, an alkyl group, a hydroxyl group, a halogen, a cyano group, an amino group, a nitro group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group, wherein the alkyl group, the alkoxy group
  • the group, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally selected from the group consisting of alkyl, halogen, hydroxy, amino, nitro, cyano, alkoxy, hydroxyalkyl, cycloalkyl, heterocycle Substituted by one or more substituents in the aryl, aryl and heteroaryl;
  • n 0, 1, 2 or 3;
  • n 0, 1, 2, 3 or 4;
  • x 0, 1, 2 or 3;
  • y is 0, 1, 2, 3, 4 or 5.
  • the SERD is a compound represented by the formula (I-A):
  • Ring B, R 1 to R 6 , m, n and y are as defined in the general formula (I).
  • the SERD is a compound represented by the formula (I-B):
  • R 1 to R 6 , m, n and y are as defined in the formula (I).
  • the SERD is a compound represented by the formula (I-C):
  • R 1 to R 6 , m, n and y are as defined in the formula (I).
  • the SERD is selected from the group consisting of the following compounds or pharmaceutically acceptable salts thereof:
  • the pharmaceutically acceptable salt of the SERD is selected from the group consisting of a lysine salt, a 2-aminoethanol salt, a diethanolamine salt, a sodium salt, a hydrochloride salt or a N-methyl-D-glucosamine salt, preferably Alkaloids.
  • the second component is selected from the group consisting of a CDK4/6 inhibitor selected from the group consisting of a compound represented by the formula (II), or a tautomer thereof, a mesogen, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof:
  • a 1 or A 2 are each independently selected from -CR' or N;
  • R' is selected from a hydrogen atom, a halogen, a cyano group, a nitro group, an alkyl group, a halogenated alkyl group, a hydroxyalkyl group or an alkoxy group;
  • Y is selected from S or O;
  • R 1 is selected from a hydrogen atom, a halogen, an alkyl group, a halogenated alkyl group, a hydroxyalkyl group or a cycloalkyl group;
  • R 2 is selected from the group consisting of hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -OR 7 , -C(O)R 7 , —C(O)OR 7 , or —OC(O)R 7 , wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl are each independently Optionally further one or more selected from the group consisting of halogen, cyano, nitro, amino, hydroxy, oxo, alkyl, haloalkyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl Substituted by a substituent of a heteroaryl group, a carboxyl group or a carboxylate group;
  • R 3 is selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group or a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocycloalkyl group, aryl group or heteroaryl group are each independently Optionally further selected from one or more selected from the group consisting of halogen, cyano, nitro, amino, hydroxy, oxo, alkyl, haloalkyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocycloalkyl, Substituted with a substituent of an aryl, heteroaryl, carboxy or carboxylate group;
  • R 4 is selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, -OR 7 , -C(O)R 7 or -C(O)OR.
  • alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl are each independently optionally further selected from one or more selected from the group consisting of halogen, cyano and nitro Substituted by a substituent of an amino group, a hydroxyl group, an oxo group, an alkyl group, a halogenated alkyl group, a hydroxyalkyl group, an alkoxy group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, a carboxyl group or a carboxylate group ;
  • R 5 or R 6 are each independently selected from the group consisting of a hydrogen atom, a halogen, a cyano group, a nitro group, an oxo group, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, -OR 7 , -C(O)R 7 , -C(O)OR 7 or -OC(O)R 7 , wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl,
  • the aryl or heteroaryl are each independently optionally further selected from one or more selected from the group consisting of halogen, cyano, nitro, amino, hydroxy, oxo, alkyl, haloalkyl, hydroxyalkyl, alkoxy, cyclo Substituted by a substituent of an al
  • R 7 is selected from a hydrogen atom, an alkyl group, a hydroxyl group, a halogen, an alkoxy group, a cycloalkyl group, a heterocycloalkyl group, an aryl group or a heteroaryl group, wherein the alkyl group, the alkoxy group, the cycloalkyl group, the hetero group
  • the cycloalkyl, aryl or heteroaryl are each independently optionally further selected from one or more selected from the group consisting of halogen, cyano, nitro, amino, hydroxy, oxo, alkyl, haloalkyl, hydroxyalkyl, alkane. Substituents of an oxy group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, a carboxyl group or a carboxylate group are substituted.
  • the CDK4/6 inhibitor or a pharmaceutically acceptable salt thereof is selected from the group consisting of:
  • the pharmaceutically acceptable salt of the CDK4/6 inhibitor is selected from the group consisting of isethionates.
  • a method of treating a breast tumor comprising administering to a patient a combination of the above SERD and one or more selected from the group consisting of a CDK4/6 inhibitor, a PI3K/mTOR pathway inhibitor.
  • the CDK4/6 inhibitor is selected from the group consisting of abemaciclib, ribociclib, palbociclib, alvocidib, trilaciclib, voruciclib, AT-7519, G1T-38, FLX-925, INOC-005, G1T28-1 , BPI-1178, gossypin, G1T30-1, GZ-38-1, P-276-00, staurosporine, R-547, PAN-1215, PD-0183812, AG-024322, NSC-625987, CGP-82996, PD -171851, preferably abemaciclib, ribociclib, palbociclib, alvocidib.
  • the combination comprises a third component selected from the group consisting of PI3K/mTOR pathway inhibitors, wherein the PI3K/mTOR pathway inhibitor is selected from the group consisting of everolimus, sirolimus, and Sirolimus, zotarolimus, Ridaforolimus, neratinib, idlelisib, dactolisib, alpelisib, taselisib, buparlisib, sonolisib, gedatolisib, ipatasertib, apitolisib, pictilisib, INK128, INK1117, OSI-027, CC-223, AZD8055 , SAR245408, SAR245409, PF04691502.PQR-6XX, PQR-530, PQR-514, ME-344, SRX-2523, CC-115, LY-3023414, IM-156, BN-107, I
  • the PI3K/mTOR pathway inhibitor is selected from the group consisting of everolimus, sirolimus, temsirolimus, and Ridaforolimus.
  • the combination is selected from the group consisting of a combination of a SERD and a CDK4/6 inhibitor and a PI3K/mTOR pathway inhibitor, preferably a combination of compound 14 and compound 59 with everolimus.
  • the combination is selected from the group consisting of a combination of SERD and a CDK4/6 inhibitor, preferably a combination of compound 14 and compound 59.
  • the SERD and the CDK4/6 inhibitor have synergistic effects with the PI3K/mTOR pathway inhibitor; more preferably, the compound of the formula 14 or a pharmaceutically acceptable salt thereof and the compound of the formula 59 or
  • the pharmaceutically acceptable salt thereof has a synergistic effect, and the compound of the formula 14 or a pharmaceutically acceptable salt thereof and the compound of the formula 59 or a pharmaceutically acceptable salt thereof have synergistic effect with everolimus .
  • the breast tumor is selected from the group consisting of an estrogen receptor-positive breast tumor
  • the estrogen receptor-positive breast tumor is selected from the group consisting of a papillary tumor, a male breast tumor, a breast malignant lymphoma, and a fibroepithelial tumor.
  • epithelial-muscle epithelial tumor intraductal carcinoma, lobular carcinoma in situ, papillary eczema-like breast cancer, early invasive ductal carcinoma, early invasive lobular carcinoma, papillary carcinoma, medullary carcinoma, tubular carcinoma, adenoid cystic Cancer, mucinous adenocarcinoma, apocrine adenoid carcinoma, squamous cell carcinoma, invasive lobular carcinoma, invasive ductal carcinoma, hard cancer.
  • the breast tumor is selected from the group consisting of a tube type A breast cancer and a lumen type B breast cancer.
  • the estrogen receptor-positive breast tumor is a postmenopausal estrogen receptor-positive breast tumor.
  • the estrogen receptor-positive breast tumor is resistant to endocrine therapy, and the endocrine therapy is selected from the group consisting of a selective estrogen receptor modulator (SERM), an aromatase inhibitor, Fulvestrant.
  • SERM selective estrogen receptor modulator
  • Fulvestrant an aromatase inhibitor
  • the SERM is selected from the group consisting of tamoxifen, raloxifene, lasofoxifene, toremifene, apeledoxifene, droloxifene, dextrozine, and ipoxifen.
  • the aromatase inhibitor is selected from the group consisting of aminoglutethimide, roastamide, lantalol, letrozole, liazodazole, and fluconazole ,Frhizozole, anastrozole, fenoxazole, exemestane, atamestane, minnamer, osilodrostat, pentrozole, BGS-649, TMD-322, SEF-19, NKS-01
  • the weight ratio of the SERD to the CDK4/6 inhibitor is selected from the group consisting of 0.1-150, preferably 1:0.1, 1:0.125, 1:0.14, 1:0.15, 1:0.175, 1:0.1875 , 1:0.2, 1:0.25, 1:0.28, 1:0.3, 1:0.35, 1:0.4, 1:0.5, 1:0.7, 1:0.75, 1:1, 1:1.25, 1:1.75, 1 : 2, 1:2.5, 1:3.5, 1:4, 1:5, 1:8, 1:10, 1:15, 2:15, 1:20, 1:25, 3:1, 3:2 , 6:1, 6:5, 6:7, 8:5, 8:7, 12:1, 15:7, 16:3, 16:5, 16:7, 16:15, 16:25, 16 : 35, 24:5, 24:7, 60:7, more preferably 1:4, 1:5, 1:8, 1:10, 1:15, 2:15, 1:20, 1:25, 16 :25, 16:35; the weight ratio of the SERD to the group consisting of 0.1
  • the SERD dosage range is selected from the group consisting of 1-1000 mg, preferably from 5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70mg, 75mg, 80mg, 90mg, 100mg, 125mg, 150mg, 175mg, 200mg, 225mg, 250mg, 275mg, 300mg, 325mg, 350mg, 375mg, 400mg, 425mg, 450mg, 475mg, 500mg, 600mg, 700mg, 750mg, 800mg, 900mg, 1000mg.
  • the SERD is selected from the compound of the formula 14 or a pharmaceutically acceptable salt thereof, and the dosage range is selected from the group consisting of 20-600 mg, preferably from 20 mg, 25 mg, 40 mg, 50 mg, 60 mg, 70, 75, 80, 90, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 600 mg.
  • the dose of the CDK4/6 inhibitor is selected from the group consisting of 1-1000 mg, preferably from 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 600 mg, 700 mg, 750 mg, 800 mg, 900 mg, 1000 mg.
  • the CDK4/6 inhibitor is selected from the compound of the formula 59 or a pharmaceutically acceptable salt thereof, and the dosage range is selected from the group consisting of 20-600 mg, preferably from 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 250 mg, 300 mg, 400 mg, 500 mg, 600 mg.
  • the PI3K/mTOR pathway inhibitor dose range is selected from the group consisting of 1-500 mg, preferably from 0.5 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5mg, 6mg, 7mg, 7.5mg, 8mg, 9mg, 10mg, 12mg, 12.5mg, 14mg, 15mg, 16mg, 17.5mg, 18mg, 20mg, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, 75mg, 100mg, 125mg 150mg, 160mg, 175mg, 180mg, 200mg, 250mg, 500mg.
  • the PI3K/mTOR pathway inhibitor is selected from the group consisting of everolimus, sirolimus, temsirolimus, Ridaforolimus, and the dose range is selected from 1-100 mg, preferably from 0.5mg, 1mg, 1.5mg, 2mg, 2.5mg, 3mg, 3.5mg, 4mg, 4.5mg, 5mg, 6mg, 7mg, 7.5mg, 8mg, 9mg, 10mg, 12mg, 12.5mg, 14mg, 15mg, 16mg, 17.5 Mg, 18 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 75 mg, 100 mg.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the above-mentioned SERD and one or more selected from the group consisting of a CDK4/6 inhibitor, a PI3K/mTOR pathway inhibitor, and one or more pharmaceutically acceptable excipients, diluted Agent or carrier.
  • the present invention provides a combination of the above-described SERD and one or more selected from the group consisting of a CDK4/6 inhibitor and a PI3K/mTOR pathway inhibitor as a medicament for treating a breast tumor.
  • the combined modes of administration of the present invention are selected from the group consisting of simultaneous administration, independent formulation and co-administration or independent formulation and sequential administration.
  • the invention further relates to the use of a SERD in combination with a CDK4/6 inhibitor for the preparation of a medicament for treating breast tumors, wherein the frequency of administration of the SERD is once a day, twice a day, once a week, once every two weeks, three weeks, three weeks Once and once a month, the frequency of administration of CDK4/6 inhibitors was once a day, twice a day.
  • the invention further relates to a use of a SETD and a CDK4/6 inhibitor and a PI3K/mTOR pathway inhibitor for the treatment of a breast tumor drug, wherein the frequency of administration of the SERD inhibitor is once a day, twice a day, once a week, Once every two weeks, once every three weeks, once a month, the frequency of administration of CDK4/6 was once a day, twice a day, and the frequency of administration of PI3K/mTOR pathway inhibitors was once a day, twice a day.
  • the SERD of the present invention has synergistic pharmacological effects in combination with a CDK4/6 inhibitor, and the SERD inhibitor of the present invention has a synergistic effect with a CDK4/6 inhibitor in combination with a PI3K/mTOR pathway inhibitor.
  • the invention also relates to a pharmaceutical composition of a SERD and a CDK4/6 inhibitor, a pharmaceutical composition of a SERD and CDK4/6 inhibitor and a PI3K/mTOR pathway inhibitor, comprising optionally one or more pharmaceuticals Carrier, excipient and/or diluent.
  • the pharmaceutical composition can be formulated into any of the pharmaceutically acceptable dosage forms.
  • a pharmaceutical preparation comprising an active ingredient is a SERD, a CDK4/6 inhibitor
  • a pharmaceutical preparation comprising an active ingredient of a SERD, a CDK4/6 inhibitor, and a PI3K/mTOR pathway inhibitor which can be formulated into tablets, capsules, pills, Granules, solutions, suspensions, syrups, injections (including injections, sterile powder for injection and concentrated solutions for injection), suppositories, inhalants or sprays.
  • the pharmaceutical composition of the present invention can also be administered to a patient or subject in need of such treatment by any suitable mode of administration, such as oral, parenteral, rectal, pulmonary or topical administration.
  • the pharmaceutical composition can be formulated into an oral preparation, such as an oral solid preparation such as a tablet, a capsule, a pill, a granule, or the like; or an oral liquid preparation such as an oral solution or an oral mixture. Suspension, syrup, and the like.
  • the pharmaceutical preparation may further contain a suitable filler, binder, disintegrant, lubricant, and the like.
  • the pharmaceutical composition of the SERD and CDK4/6 inhibitor of the present invention may be administered alone or in combination with one or more therapeutic agents use.
  • the components to be combined can be administered simultaneously or sequentially.
  • the ingredients to be combined may also be administered in combination in the form of the same formulation or in separate separate formulations.
  • the term "combination or combination” is a mode of administration comprising two or more drugs sequentially or simultaneously, and the term “simultaneously” means the same administration.
  • Periodically administering SERD and CDK4/6 inhibitors, or SERD and CDK4/6 inhibitors with PI3K/mTOR pathway inhibitors for example, within 1 day, or within 2 days, or within 3 days, or within 14 days, or within 21 days, or within 28 days Give two or more drugs.
  • the so-called “sequential or sequential" administration includes the administration of SERD and CDK4/6 inhibitors, or SERD and CDK4/6 inhibitors and PI3K/mTOR pathway inhibitors, respectively, in different administration cycles.
  • an "effective amount” as used herein includes an amount sufficient to ameliorate or prevent a symptom or condition of a medical condition.
  • An effective amount also means an amount sufficient to allow or facilitate the diagnosis.
  • An effective amount for a particular patient or veterinary subject can vary depending on factors such as the condition to be treated, the overall health of the patient, the route and dosage of the method of administration, and the severity of the side effects.
  • An effective amount can be the maximum dose or dosing regimen that avoids significant side effects or toxic effects.
  • halogen or halogen atom as used in the present invention means a fluorine atom, a chlorine atom, a bromine atom, an iodine atom or the like.
  • cyano group as used in the present invention means a group such as -CN.
  • the "hydroxy group” in the present invention means a group such as -OH.
  • amino group in the present invention means a group such as -NH.
  • the "carboxy group” in the present invention means a group such as -COOH.
  • carbonyl group as used in the present invention means a group such as -CO-.
  • nitro group as used in the present invention means a group such as -NO 2 .
  • alkyl group in the present invention means a linear or branched alkyl group having 1 to 20 carbon atoms, and includes, for example, "C 1-6 alkyl group", “C 1-4 alkyl group”, etc., specific examples Including but not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, Neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2, 2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2- Ethyl butyl,
  • alkynyl group as used in the present invention means a linear or branched alkynyl group having at least one triple bond and having 2 to 20 carbon atoms, and includes, for example, "C 2-6 alkynyl group, C 2-4 alkynyl group”. Wait. Examples thereof include, but are not limited to, ethynyl, propynyl, 2-butynyl, 2-pentynyl, 3-pentynyl, 4-methyl-2-pentynyl, 2-hexynyl, 3 - hexynyl, 5-methyl-2-hexynyl and the like.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent which includes from 3 to 14 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably cycloalkyl.
  • the ring contains from 3 to 8 carbon atoms, and most preferably the cycloalkyl ring contains from 5 to 6 carbon atoms, most preferably a cyclopropyl group.
  • Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene
  • the alkenyl group, the cyclooctyl group and the like are preferably a cyclopropyl group or a cyclohexenyl group.
  • Polycyclic cycloalkyl groups include spiro, fused, and bridged cycloalkyl groups.
  • the "fused ring group” as used in the present invention refers to a cyclic structure having 4 to 15 carbon atoms formed by two or more ring structures sharing two adjacent atoms with each other, including, for example, "6" a -11 membered fused ring group, a “5-9 membered fused ring group", a “7-10 membered fused ring group”, a “9-10 membered fused ring group”, etc., optionally, a carbon atom in the cyclic structure Can be oxidized. Examples include, but are not limited to: Wait.
  • the "spirocyclic group” as used in the present invention means a cyclic structure having 5 to 15 ring carbon atoms formed by sharing two carbon atoms with each other in two or more cyclic structures.
  • the carbon atoms in the cyclic structure can be oxidized. Examples include “6-11 element spiro group”, “5-10 member spiro group”, “7-8 member spiro group”, “9-10 member spiro group”, and the like. Specific examples include, but are not limited to: Wait.
  • the "bridged ring group” as used in the present invention means a cyclic structure having 5 to 15 ring carbon atoms formed by two or more ring structures sharing two non-adjacent carbon atoms with each other.
  • the carbon atoms in the cyclic structure can be replaced by oxo. Examples include "6-11 yuan bridged ring base”, “7-10 yuan bridged ring base”, “9-10 yuan bridged ring base”, and the like. Specific examples include, but are not limited to: Wait.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent which includes from 3 to 14 ring atoms wherein one or more of the ring atoms are selected from nitrogen, oxygen or S. (O) a hetero atom of m (where m is an integer of 0 to 2), but excluding the ring moiety of -OO-, -OS- or -SS-, the remaining ring atoms being carbon.
  • It preferably comprises from 3 to 12 ring atoms, wherein from 1 to 4 are heteroatoms, more preferably the heterocyclyl ring contains from 3 to 8 ring atoms, more preferably the heterocyclyl ring contains from 5 to 6 ring atoms.
  • monocyclic heterocyclic groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, tetrahydrofuranyl and the like.
  • Polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups.
  • the "fused heterocyclic group” as used in the present invention refers to a group of 4 to 15 ring atoms formed by two or more ring structures sharing two adjacent atoms with each other (at least one of the ring atoms is hetero A cyclic structure of an atom such as a nitrogen atom, an oxygen atom or a sulfur atom.
  • a ring atom eg, a carbon atom, a nitrogen atom, or a sulfur atom
  • a ring atom in the cyclic structure can be oxidized.
  • pyrrolidino-cyclopropyl cyclopentyl-azacyclopropyl
  • pyrrolidinocyclobutyl pyrrolidinopyrrolidinyl
  • pyrrolidinopiperidinyl pyrrole Alkylpiperazinyl
  • pyrrolidinomorpholinyl piperidinylmorpholinyl
  • benzopyrrolidinyl tetrahydroimidazo[4,5-c]pyridyl, 3,4-dihydroquinoline Oxazolinyl, 1,2-dihydroquinoxalinyl, benzo[d][1,3]dioxolyl, 1,3-dihydroisobenzofuranyl, 2H-chromogen Base, 2H-chromogen-2-one, 4H-chromenyl, 4H-chromen-4-one, chromanyl, 4H-1,3-benzoxazinyl, 4,6-
  • the "spiroheterocyclic group" as used in the present invention means a ring atom formed by sharing two ring atoms with two or more ring structures, wherein at least one ring atom is a hetero atom, for example, A cyclic structure of a nitrogen atom, an oxygen atom or a sulfur atom, optionally, a ring atom (for example, a carbon atom, a nitrogen atom or a sulfur atom) in the cyclic structure may be oxidized.
  • Examples include, for example, "5-11 membered spiroheterocyclyl”, “6-11 membered spiroheterocyclyl”, “6-9 membered spiroheterocyclyl”, “9-10 membered spiroheterocyclyl”, and the like. Specific examples include, but are not limited to: Wait.
  • the "bridge heterocyclic group” as used in the present invention refers to a group of 5 to 15 ring atoms (including at least one ring atom) formed by two or more ring structures sharing two non-adjacent ring atoms with each other.
  • a cyclic structure which is a hetero atom such as a nitrogen atom, an oxygen atom or a sulfur atom, optionally, a ring atom (for example, a carbon atom, a nitrogen atom or a sulfur atom) in the cyclic structure may be oxidized.
  • Examples include, for example, “5-10 membered bridged heterocyclic group”, “6-11 membered bridged heterocyclic group”, “6-9 membered bridged heterocyclic group”, “7-9 membered bridged heterocyclic group”, and the like. Specific examples include, but are not limited to: Wait.
  • haloalkyl refers to a group derived by substituting one or more "halogen atoms” for one or more hydrogen atoms on an "alkyl group” as described above. Defined.
  • hydroxyalkyl refers to a radical derived from one or more "hydroxy” groups substituted by one or more hydrogen atoms on an "alkyl group” as defined above.
  • alkoxy group, haloalkoxy group, alkylcarbonyl group, alkoxycarbonyl group, alkylcarbonylamino group, alkylaminocarbonyl group, dialkylaminocarbonyl group, alkylaminocarboxy group, haloalkylcarbonyl group, cycloalkyl group according to the invention.
  • Alkyl, cycloalkylcarbonyl, heterocyclylcarbonyl, alkylamino, alkylaminoalkyl or dialkylamino means alkyl-O-, haloalkyl-O-, alkyl-C(O) -, alkyl-OC(O)-, alkyl-C(O)-NH-, alkyl-NH-C(O)-, (alkyl) 2 -NH-C(O)-, alkyl- C(O)-O-, haloalkyl-C(O)-, cycloalkyl-alkyl-, cycloalkyl-C(O)-, heterocyclyl-C(O)-, alkyl-NH- An alkyl-NH-alkyl-, (alkyl) 2 -N-linked group wherein "alkyl, haloalkyl, cycloalkyl, heterocyclyl" is as defined above.
  • the "aryl group” as used in the present invention means a 6 to 14 membered all-carbon monocyclic or fused polycyclic ring (that is, a ring sharing a pair of adjacent carbon atoms) having a conjugated ⁇ -electron system, preferably 6 to 8
  • the aryl group is more preferably a phenyl group, a fluorenyl group or a phenanthryl group, and most preferably a phenyl group.
  • the aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring wherein the ring to which the parent structure is attached is an aryl ring, non-limiting examples comprising:
  • heteroaryl refers to a 5- to 15-membered all-carbon monocyclic or fused polycyclic group having a conjugated ⁇ -electron system, further comprising from 1 to 4 heteroatoms, wherein the hetero atom is selected from One or more of oxygen, sulfur or nitrogen.
  • Substituted refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3, hydrogen atoms, independently of each other, substituted by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art will be able to determine (by experiment or theory) substitutions that may or may not be possible without undue effort. For example, an amino group or a hydroxyl group having a free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond.
  • the term "synergistic effect” includes, but is not limited to, additive effects, potentiating effects, potentiating effects, and "synergistic effects" of the present invention include, but are not limited to, reduction of SERD, CDK4/6 inhibition alone. Tolerance in the agent, PI3K/mTOR pathway inhibitor, reduce the dose of SETD, CDK4/6 inhibitor, PI3K/mTOR pathway inhibitor alone, reduce SERD, CDK4/6 inhibitor, PI3K/mTOR pathway inhibitor The adverse effects when used alone, enhance the effect of treating breast tumors compared to the same dose of SERD, CDK4/6 inhibitor, PI3K/mTOR pathway inhibitor alone.
  • breast cancer refers to a breast cancer whose gene type is selected from ER and/or PR (progesterone receptor) positive, HER2 negative, and Ki67 (nuclear proliferation index) is low expression
  • Catheter type B breast cancer Refers to a gene type selected from ER and / or PR positive, HER2 negative, Ki67 high expression of breast cancer or ER and / or PR positive, HER2 overexpression or proliferation, Ki67 any level of breast cancer.
  • the combination of the SERD of the present invention and the CDK4/6 inhibitor has a significant inhibitory effect on the human breast cancer MCF7/TamR1 nude mice expressing the estrogen receptor, and has a synergistic effect; the SERD and the CDK4/6 inhibitor of the present invention
  • the combination of PI3K/mTOR pathway inhibitors has a significant and synergistic effect on the subcutaneous xenograft of human breast cancer MCF7/TamR1 nude mice expressing estrogen receptor.
  • the combination of the SERD and the CDK4/6 inhibitor of the invention has a significant inhibitory effect on the human breast cancer MCF7/TamR1 nude mouse subcutaneous xenografts which are resistant to estrogen receptor and endocrine therapy drugs, and has a synergistic effect; the SERD of the present invention
  • the combination of CDK4/6 inhibitor and PI3K/mTOR pathway inhibitor has a significant and synergistic effect on the expression of estrogen receptor and endocrine therapy drug-resistant human breast cancer MCF7/TamR1 nude mice.
  • Figure 1 is a combination of a SERD (Compound 14) of the present invention in combination with a CDK4/6 inhibitor (Compound 59), and a combination of SERD (Compound 14) and a CDK4/6 inhibitor (Compound 59) with everolimus and each individual component Comparison of the therapeutic effects of (Compound 14, Compound 59, Everolimus) on human estrogen receptor-positive, tamoxifen-resistant human breast cancer MCF-7/TamR1 nude mice subcutaneous xenografts;
  • Figure 2 is a combination of a SERD (compound 14) of the present invention in combination with a CDK4/6 inhibitor (compound 59), and a combination of SERD (compound 14) and a CDK4/6 inhibitor (compound 59) with everolimus and each individual component.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS).
  • NMR shift ( ⁇ ) is given in units of 10-6 (ppm).
  • the NMR was measured by a Bruker AVANCE-400 nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD), and the internal standard was tetramethylsilane ( TMS).
  • DMSO-d6 dimethyl sulfoxide
  • CDCl3 deuterated chloroform
  • CD3OD deuterated methanol
  • TMS tetramethylsilane
  • the measurement of the MS was carried out using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).
  • ESI FINNIGAN LCQAd
  • the known starting materials of the present invention may be synthesized by or according to methods known in the art, or may be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Dari Companies such as chemicals.
  • the reactions can all be carried out under an argon atmosphere or a nitrogen atmosphere.
  • An argon atmosphere or a nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon having a volume of about 1 L.
  • the hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1 L volume.
  • the pressurized hydrogenation reaction was carried out using a Parr Model 3916EKX hydrogenation apparatus and a clear blue QL-500 type hydrogen generator or a HC2-SS type hydrogenation apparatus.
  • the hydrogenation reaction is usually evacuated, charged with hydrogen, and operated three times.
  • the microwave reaction used a CEM Discover-S Model 908860 microwave reactor.
  • the solution means an aqueous solution.
  • reaction temperature is room temperature and is 20 ° C to 30 ° C.
  • the progress of the reaction in the examples was monitored by thin layer chromatography (TLC).
  • TLC thin layer chromatography
  • the system used for the reaction was: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: petroleum ether And the ethyl acetate system, D: acetone, the volume ratio of the solvent is adjusted depending on the polarity of the compound.
  • Purification compounds using column chromatography eluent systems and thin layer chromatography developer systems include: A: dichloromethane and methanol systems, B: n-hexane and ethyl acetate systems, C: dichloromethane and acetone
  • A dichloromethane and methanol systems
  • B n-hexane and ethyl acetate systems
  • C dichloromethane and acetone
  • the volume ratio of the solvent is adjusted depending on the polarity of the compound, and a small amount of an alkaline or acidic reagent such as triethylamine or acetic acid may be added for adjustment.
  • Example 2 Combination of SERD of the present invention with a CDK4/6 inhibitor or a combination of a SETD and a CDK4/6 inhibitor with a PI3K/mTOR pathway inhibitor for human breast cancer expressing estrogen receptor-positive, tamoxifen-resistant Therapeutic effect of subcutaneous transplantation of MCF-7/TamR1 nude mice
  • Test product a compound of the formula 14 (using a lysine salt of the compound 14, a compound obtained by the method described in Example 1 to form a salt with lysine), a compound of the formula 59 (using a hydroxyethyl group of the compound 59) Sulfonate, prepared according to the method of patent application WO2016124067), everolimus and tamoxifen (provided by Jiangsu Hengrui Pharmaceutical Co., Ltd.), estrogen sustained release tablets (0.72 mg / tablet, 60 days release) , purchased from Alternative Research of America).
  • Test animals BALB/cA-nude nude mice, 6-7 weeks, female, purchased from Shanghai Slack Laboratory Animals Co., Ltd. Feeding environment: SPF level.
  • MCF7/TamR1 cells were provided by Kunming Institute of Zoology, Chinese Academy of Sciences; MCF7/TamR1 cells were formed by long-term induction of tamoxifen-sensitive MCF7 cells with tamoxifen. It was significantly resistant to tamoxifen in vitro, and the drug resistance multiple was more than 50 times.
  • the cells were cultured in a 10 cm culture dish under the conditions of Dulbecco's Modified Eagle Medium (DMEM) medium plus 10% fetal bovine serum and cyan. Streptomycin, containing 10 ⁇ M tamoxifen, was cultured in an incubator containing 5% CO 2 air at 37 °C. Passage twice a week; when the cells are exponentially growing, trypsinize, collect cells, count, and inoculate.
  • DMEM Dulbecco's Modified Eagle Medium
  • Compound 14 and tamoxifen were formulated with 0.5% CMC-Na solution and diluted to the corresponding concentrations;
  • Compound 59 was prepared with 0.1% Tween-80 distilled water;
  • Everolimus was diluted with anhydrous ethanol to help dissolve the physiological saline to the corresponding concentration.
  • T/C(%) (TT 0 )/(CC 0 ) ⁇ 100
  • D21 inhibition rate (%) [(TT 0 ) - (CC 0 )] / (TT 0 ) ⁇ 100
  • T is the solvent group
  • C is the tumor volume at the end of the treatment group
  • T 0 is the solvent group
  • C 0 is the tumor volume at the beginning of each group of treatment
  • T/C value percent
  • D21 inhibition rate Percentage
  • D0 first administration time; P value means compared with solvent; PO: intragastric administration; QD: once a day; *** P ⁇ 0.001, vs vehicle control; ## P ⁇ 0.01, ### P ⁇ 0.001, vs compound 14 (1 mg/kg); $ P ⁇ 0.05, vs compound 14 (1 mg/kg) + compound 59 (7.5 mg/kg); dose of each compound in the combination group and single-agent dose the same.
  • tamoxifen (30 mg/kg) had no significant inhibitory effect on the growth of subcutaneous xenografts in MCF7/TamR1 nude mice, and the tumor inhibition rate was 19.3%, indicating that the model was tamoxifen.
  • Subcutaneous xenografts had a certain inhibitory effect, and the tumor inhibition rates were 39.4%, 21.7%, and 55.0%, respectively.
  • the growth rate of subcutaneous xenografts was 70.7%, and the curative effect was significantly stronger than that of compound 14 or compound 59 alone (P ⁇ 0.01); compound 14 (1 mg/kg) and compound 59 (7.5 mg/kg) and The combination of everolimus (1.5mg/kg) also significantly inhibited the growth of subcutaneous xenografts in MCF7/TamR1 nude mice.

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Abstract

L'invention concerne une utilisation de SERD avec un inhibiteur de CDK4/6 et un inhibiteur de la voie PI3K/mTOR. En particulier, l'invention concerne une utilisation d'un régulateur à la baisse sélectif du récepteur des œstrogènes (SERD) en combinaison avec un ou plusieurs éléments choisis parmi un inhibiteur de la kinase dépendante de la cycline 4/6 (CDK4/6), un inhibiteur de la voie phosphatidylinositol 3-kinase (PI3K)/cible de la rapamycine chez les mammifères (mTOR) dans la préparation d'un médicament pour le traitement de tumeurs du sein.
PCT/CN2018/091930 2017-06-21 2018-06-20 Utilisation de serd avec un inhibiteur de cdk4/6 et un inhibiteur de la voie pi3k/mtor WO2018233620A1 (fr)

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