WO2017129094A1 - Utilisation d'un inhibiteur des récepteurs à activité tyrosine kinase egfr/her2 dans la préparation de médicaments pour le traitement de cancers induits par une mutation de her2 - Google Patents

Utilisation d'un inhibiteur des récepteurs à activité tyrosine kinase egfr/her2 dans la préparation de médicaments pour le traitement de cancers induits par une mutation de her2 Download PDF

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WO2017129094A1
WO2017129094A1 PCT/CN2017/072212 CN2017072212W WO2017129094A1 WO 2017129094 A1 WO2017129094 A1 WO 2017129094A1 CN 2017072212 W CN2017072212 W CN 2017072212W WO 2017129094 A1 WO2017129094 A1 WO 2017129094A1
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use according
compound
cancer
her2
pharmaceutically acceptable
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PCT/CN2017/072212
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Chinese (zh)
Inventor
邹建军
周彩纯
黄亚玲
任胜祥
张革
曾晓玲
杨昌永
曹国庆
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江苏恒瑞医药股份有限公司
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Priority to CN201780000888.0A priority Critical patent/CN107708698A/zh
Publication of WO2017129094A1 publication Critical patent/WO2017129094A1/fr
Priority to HK18102974.6A priority patent/HK1243352A1/zh

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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
    • A61K31/4709—Non-condensed quinolines and 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
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Definitions

  • NSCLC non-small cell lung cancer
  • the first line of treatment for metastatic NSCLC depends on the type of pathology and genetic changes.
  • EGFR-TKI is recommended for patients with positive EGFR mutations
  • crizotinib is recommended for ALK-positive patients (Shi Yuankai, Sun Yan. Handbook of Clinical Oncology. Beijing: People's Medical Publishing House, 2015: 315-341).
  • Non-squamous cell carcinoma patients with negative gene expression are recommended to receive pemetrexed or other platinum-containing combination chemotherapy, and combined with endostatin (YH-16) or cetuximab (Cetuximab).
  • endostatin YH-16
  • cetuximab cetuximab
  • maintenance therapy is optional.
  • EGFR-TKI epidermal growth factor receptor tyrosine kinase inhibitor
  • second-line treatment docetaxel, pemetrexed, and EGFR-TKI are available.
  • lung cancer studies have also revealed a number of genetic abnormalities, including amplification of MET and FGFR1, PIK3CA, AKT, KRAS, NRAS, BRAF, MEK1, AKT1, FGFR2, DDR2 and HER2 mutations, And RET and ROS1 rearrangement, etc.
  • amplification of MET and FGFR1, PIK3CA, AKT, KRAS, NRAS, BRAF, MEK1, AKT1, FGFR2, DDR2 and HER2 mutations And RET and ROS1 rearrangement, etc.
  • the human epidermal factor receptor 2 (HER2) gene belongs to the HER tyrosine receptor family, and the HER2 mutation mainly occurs in exon 20, accounting for 2-4% of NSCLC patients (Clin Cancer Res. 2012, 18 : 4910-4918; Cancer Res. 2005, 65: 1642-1646; Lung Cancer. 2011, 74: 139-144.).
  • HER2 mutation rate was 0.9% (J Clin Oncol, 2013, 31 (suppl): abstr 8000).
  • HER2 and / or EGFR targeted drugs may have anti-tumor efficacy in HER2 mutant non-small cell lung cancer patients, while some HER2 and / or EGFR targeted drugs are ineffective, as for a specific Whether HER2 and/or EGFR targeted drugs are effective for HER2-mutated cancers is difficult to predict.
  • CN102471312B discloses a compound represented by the following formula A (chemical name (E)-N-[4-[[3-chloro-4-(2-pyridylmethoxy)phenyl]amino]-3-cyano- 7-Ethoxy-6-quinolinyl]-3-[(2R)-1-methylpyrrolidin-2-yl]prop-2-enamide), and disclosed that it has strong EGFR and HER2 Inhibition and anticipation of its possible use in the treatment of cancers overexpressing EGFR and HER2,
  • CN102933574B discloses a series of pharmaceutically acceptable salts of the compounds of formula A.
  • CN103974949B discloses crystalline forms of dimaleate salts of the compounds of formula A.
  • the cancer is a lung cancer, a breast cancer or a gastrointestinal cancer.
  • the lung cancer is non-small cell lung cancer, and further preferably a HER2 mutant non-small cell lung adenocarcinoma, particularly a late stage non-small cell lung adenocarcinoma patient with a HER2 mutation.
  • the gastrointestinal cancer is gastric cancer.
  • the HER2-mutated cancer refers to a cancer driver mutation in which a HER2 gene can be detected in these cancer patients, and the type of the mutation is mainly a non-frameshift insertion mutation of exon 20, followeded by some missense mutations and small insertion and deletion mutations in the tyrosine kinase domain and other segments, such as 772-775 YVMA duplication (the amino acid at position 772-775 in the original protein is a YVMA, due to the insertion of 12 genes in the gene The base forms another pair of YVMA, causing a repetition of YVMA), G776delinsVC (the amino acid G of 776 becomes V due to the insertion of 3 bases at the corresponding site, and the amino acid C is inserted, which can also be expressed as insG776V C Or G776>VC), P780_Y781insGSP (the insertion of GSP three amino acids between amino acids 780-781 due to the insertion of 9 bases
  • the cancer is a cancer that is negative for EGFR mutation or negative for ALK fusion gene, or both are negative.
  • the cancer is a cancer that progresses after chemotherapy, radiation therapy or targeted therapy. That is, the patient with the cancer is not controlled after chemotherapy, radiotherapy or targeted therapy, and continues to progress.
  • the chemotherapy described therein may be treated with various conventional chemotherapeutic drugs, such as alkylating agents (eg, cyclophosphamide, ifosfamide, melphalan, busulfan, nimestin, ramustine, da Carbazine, temozolomide, nitrogen mustard, dibromomannitol, etc.), platinum complexing agents (eg cisplatin, carboplatin, oxaliplatin, etc.), metabolic antagonists (eg methotrexate, 5-fluorouracil, Fluoride, gemcitabine, capecitabine, fulvestrant, pemetrexed, etc.), plant alkaloids (eg vincristine, vinblastine, vindesine, etoposide, docetaxel, paclitaxel
  • the targeted therapy can be treatment with one or more selected from the group consisting of an EGFR inhibitor and a VEGFR inhibitor.
  • EGFR inhibitor may be selected from one or more of gefitinib, erlotinib, ectinib and afatinib
  • VEGFR inhibitor is selected from the group consisting of One or more of nitinib, apatinib, and faritinib.
  • the compound A is preferably in the form of a pharmaceutically acceptable salt thereof, particularly a maleate or a dimaleate, in practical use.
  • the daily dose of Compound A or a pharmaceutically acceptable salt thereof may range from 1 mg/kg to 20 mg/kg, preferably from 2 mg/kg to 10 mg/kg, more preferably from 4 to 8 mg/kg. .
  • it is preferably 100 mg to 1000 mg, preferably 240 to 560 mg, more preferably 320 to 480 mg, based on the compound A.
  • the daily dosage can range from 240 to 400 mg, especially 400 mg.
  • Compound A or a pharmaceutically acceptable salt thereof may also be formulated with a pharmaceutically acceptable carrier in the form of a composition well known in the art, such as tablets, capsules, granules, injections and the like.
  • the invention also relates to the use of a pharmaceutical composition comprising Compound A for a HER2 mutated cancer.
  • Figure 1 shows the inhibition of the proliferation of tumor cells in vitro by Compound A and lapatinib (a dose-response curve).
  • Example 1 Effect of Compound A and Lapatinib on Proliferation of ATCC H1781 Cells Cultured in Vitro.
  • Drug name dimaleate salt of Compound A (batch number S0915100514), lapatinib di-p-toluenesulfonate (batch number 20090105). Preparation method: all were prepared in DMSO.
  • ATCC H1781 cells were obtained from Shanghai Pulmonary Hospital.
  • the cells were HER2 mutation (InsG776V, C).
  • the patient was a 66-year-old woman with gestational lung adenocarcinoma and was cultured in PRIM 1640 medium containing 10% fetal bovine serum (FBS).
  • FBS fetal bovine serum
  • PRIM 1640 was purchased from Gibco BRL; fetal bovine serum was purchased from Gibco; a multi-purpose microplate reader was purchased from BioTek; and Sulforhodamine B (SRB) was purchased from Sigma.
  • the inhibitory effect of drugs on the proliferation and growth of tumor cells was detected by SRB protein staining.
  • the main steps are as follows:
  • the logarithmic growth phase cells were seeded in 96-well culture plates, and the corresponding concentrations of the drugs (1-10000 nM) were added, and the respective wells were set at the same concentration, and the corresponding concentration of the vehicle control was set.
  • Tumor cells were cultured for 72 h at 37 ° C under 5% CO 2 .
  • the cells were stained with SRB at room temperature, finally dissolved in Tris solution, and the OD value was measured at a wavelength of 510 nm by a microplate reader (BioTek), and the cell growth inhibition rate was calculated by the following formula:
  • Inhibition rate (OD value control hole- OD value administration hole ) / OD value control hole ⁇ 100%
  • the half-inhibitory concentration IC 50 was calculated according to the nonlinear regression method according to the respective concentration inhibition rates.
  • R is the correlation coefficient
  • Example 2 Effect of Compound A and Lapatinib on the Activity of HER2 Recombinant Protease in Vitro
  • Compound A (batch number SHR120201-002-06), and lapatinib (batch number SHR115758-010-17) were all supplied by Jiangsu Hengrui Medicine, and staurosporin was purchased from MedChem (Monmouth Junction, NJ) (batch number MC). -2104).
  • Recombinant human protein HER2WT (Lot#W353-1) and 5 HER2 mutant proteins (A775_G776insYVMA:lot#Z1251-6; D769H:lot#K1683-5; D769Y:lot#P1688-9; V777_G778insCG:lot#Z1287-3; V777L:lot#K1850-3) are purchased from SignalChem (Richmond, BC V6V 2J2, CANADA). These recombinant proteins are the amino acid 676 amino acid to the C-terminal 1255 amino acid polypeptide, both from baculovirus in Sf9 insect cells. Expressed in it, and the N-terminus is labeled with GST.
  • the EGFR gene index number is NM_004448.
  • the protein purity of WT HER2 and the four HER2 muteins (A775_G776ins YVMA, D769H, D769Y, V777_G778insCG) was greater than 85%, and the other HER2 mutein V777L was greater than 90% pure.
  • bovine serum albumin (BSA) as a substrate, the reaction system (20 mM Hepes (pH 7.5), 10 mM MgCl2, 1 mM EGTA, 0.02% Brij35, 0.02 mg/ml BSA, 0.1 mM Na3VO4, 2 mM DTT, 1% DMSO) Add 10 ⁇ M-0.5 nM of the test compound (Compound A or the positive control staurosporine), and then add 33P-ATP 0.01 ⁇ Ci/ ⁇ l (Perkin Elmer) to initiate the phosphorylation reaction to determine the enzymatic activity of EGFR. .
  • BSA bovine serum albumin
  • Example 3 Effect of Compound A and Lapatinib on Proliferation of HER2 Mutant MCF10A Cell Line in Vitro.
  • Drug name Compound A (batch number S0915151219), lapatinib (batch number SHR115758-010-17). Preparation method: all were prepared in DMSO.
  • MCF10A cells were purchased from ATCC, and the cells were used as mother cells, and the expression was slow with the vector GV341.
  • Virus then lentivirus infection to establish 19 mixed clone stable cell lines, including empty vector control (NC), HER2WT, HER2YVMAdup, P780_Y781insGSP, G776>VC, V777L, L755S, D769H, G776R, G776C, L755P, V842I, L866M, R896C, S310F, S310Y, G309A, G309E and D769Y.
  • N empty vector control
  • HER2WT HER2YVMAdup
  • P780_Y781insGSP G776>VC, V777L, L755S, D769H, G776R, G776C, L755P, V842I, L866M, R896C, S310F, S310Y, G309
  • All cell cultures were supplemented with DMEM/F12 medium plus 5% horse serum, 20 ng/ml EGF, 10 ⁇ g/ml insulin, 0.5 ⁇ g/ml hydrocortisone, 1% penicillin/streptomycin (P/S) and 100 ng/ml Cholera Toxin.
  • DMEM/F12 (Gibco, 10-092-CVR), horse serum (source leaf organism, MP20006), insulin (source leaf organism, 11070-73-8), epidermal growth factor (Peprotech, AF-100-15-100) Cholera toxin (sigma, 9012-63-9),
  • Hydrocortisone source leaf organism, 50-23-7
  • trypsin Gibco, 25200-072
  • Puromycin ⁇ , 60210ES25
  • RIPA lysate Dingguo, WB-0071
  • MTT Geneview, JT343
  • the inhibitory effect of drugs on the proliferation and growth of tumor cells was detected by MTT susceptibility test. 10 concentration points for each drug, 1 detection time point, 2 double holes. Inoculate 2000 cells per well in a 96-well culture plate (100 ⁇ l/well of medium), add the appropriate concentration of the drug (0.00128-500 nM for compound A; 0.00128-500 ⁇ M for lapatinib), and set a duplicate hole for each concentration. Set the appropriate concentration of the vehicle control. Tumor cells were cultured for 72 h at 37 ° C under 5% CO 2 . Then use MTT test. The absorbance of each well was measured by an enzyme-linked immunosorbent assay at OD490nm, and the cell growth inhibition rate was calculated by the following formula:
  • Inhibition rate (OD value control hole-OD value administration hole) / OD value control hole ⁇ 100%
  • the half-inhibitory concentration IC50 was calculated according to the nonlinear regression method according to the respective concentration inhibition rates.
  • Example 4 A compound A treatment of advanced non-small cell lung adenocarcinoma with HER2 mutation
  • Test method The enrolled subjects were pathologically diagnosed patients with advanced non-small cell lung adenocarcinoma, and confirmed the presence of HER2 gene mutation (using the human HER2 gene detection kit fluorescence of Xiamen Aide Biomedical Technology Co., Ltd.) The PCR method (1st to 7th, 10th) and the NGS second-generation sequencing method (8th, 9th, and 11th cases) were performed on the tumor pathological section of the patient. Subjects who met the enrollment requirements were given Compound A at 320 mg/d and/or 400 mg/d orally once daily for continuous administration until the patient developed disease progression/intolerance. As of August 2016, 11 patients with advanced non-small cell lung adenocarcinoma with HER2 mutations had been enrolled.
  • the average age of the subjects was 58.4 years. All subjects continued to progress after treatment with different means, such as docetaxel or pemetrexed chemotherapy, or targeted drugs such as gefitinib and afatinib. Adverse events were grade 1 to 2, including 1/2 grade diarrhea (4 cases), grade 2 fatigue (2 cases), grade 1 rash (2 cases) and grade 1 dyspnea (1 case), which were clinically controllable. There were no serious adverse events (SAE) and discontinuation due to adverse events, dose reduction, and early out-of-group. Six patients (54.5%) received PR, 3 patients (27.3%) had stable disease, and 2 patients (18.2%) had PD, ORR was 54.5%, and DCR was 81.8%. The median PFS was 6.2 months (95% CI 1.23-11.57). There are still 5 patients in the group treatment.
  • SAE serious adverse events
  • PD disease progression, increase in diameter and minimum of the target lesion diameter by at least 20% and absolute increase in diameter sum by at least 5 mm (one or more new lesions are also considered disease progression); SD: disease stabilization, target The sum of the maximum diameters of lesions did not reach PR, or increased PD PR: partial remission, and the sum of target lesion diameters was reduced by at least 30% from baseline, at least for 4 weeks. UK: Unknown.

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Abstract

La présente invention concerne l'utilisation d'un inhibiteur des récepteurs à activité tyrosine kinase EGFR/HER2 dans la préparation de médicaments pour le traitement de cancers induits par une mutation de HER2. En particulier, la présente invention concerne l'utilisation d'un composé de formule A ou d'un sel de qualité pharmaceutique de ce dernier dans la préparation de médicaments pour le traitement de cancers induits par une mutation de HER2.
PCT/CN2017/072212 2016-01-28 2017-01-23 Utilisation d'un inhibiteur des récepteurs à activité tyrosine kinase egfr/her2 dans la préparation de médicaments pour le traitement de cancers induits par une mutation de her2 WO2017129094A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
CN201780000888.0A CN107708698A (zh) 2016-01-28 2017-01-23 一种egfr/her2受体酪氨酸激酶抑制剂在制备治疗her2突变癌症药物中的用途
HK18102974.6A HK1243352A1 (zh) 2016-01-28 2018-03-01 一種egfr/her2受體酪氨酸激酶抑制劑在製備治療her2突變癌症藥物中的用途

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CN201610060520.0 2016-01-28
CN201610060520 2016-01-28
CN201611129915 2016-12-09
CN201611129915.8 2016-12-09

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CN109504769A (zh) * 2017-09-15 2019-03-22 益善生物技术股份有限公司 检测her2基因突变的特异性引物、液相芯片试剂盒和方法
CN110314159A (zh) * 2018-07-05 2019-10-11 江苏恒瑞医药股份有限公司 酪氨酸激酶抑制剂联合治疗肿瘤疾病的用途
CN111110676A (zh) * 2020-03-07 2020-05-08 天津医科大学总医院 阿帕替尼及联合cci-779在制备肺癌药物中的应用
CN113116879A (zh) * 2020-01-15 2021-07-16 江苏恒瑞医药股份有限公司 法米替尼联合紫杉类和铂类药物在制备治疗肿瘤疾病的药物中的用途

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CN114470216A (zh) * 2020-10-23 2022-05-13 和记黄埔医药（上海）有限公司 多受体酪氨酸激酶抑制剂与化疗剂的药物组合及其使用方法
CN112451527B (zh) * 2020-12-02 2022-08-16 北京鞍石生物科技有限责任公司 氨基嘧啶类化合物的用途
CN115779089A (zh) * 2022-11-28 2023-03-14 中国医学科学院肿瘤医院 用于治疗或改善雄性癌症及抑制其细胞系的药物的相关应用

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109504769A (zh) * 2017-09-15 2019-03-22 益善生物技术股份有限公司 检测her2基因突变的特异性引物、液相芯片试剂盒和方法
CN110314159A (zh) * 2018-07-05 2019-10-11 江苏恒瑞医药股份有限公司 酪氨酸激酶抑制剂联合治疗肿瘤疾病的用途
CN113116879A (zh) * 2020-01-15 2021-07-16 江苏恒瑞医药股份有限公司 法米替尼联合紫杉类和铂类药物在制备治疗肿瘤疾病的药物中的用途
CN111110676A (zh) * 2020-03-07 2020-05-08 天津医科大学总医院 阿帕替尼及联合cci-779在制备肺癌药物中的应用

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