WO2020052575A1

WO2020052575A1 - Use of combination of jak kinase inhibitor and egfr inhibitor in preparation of medicament for treating tumor diseases

Info

Publication number: WO2020052575A1
Application number: PCT/CN2019/105250
Authority: WO
Inventors: 唐蜜; 邓智临; 廖成; 杨昌永; 张连山
Original assignee: 江苏恒瑞医药股份有限公司
Priority date: 2018-09-12
Filing date: 2019-09-11
Publication date: 2020-03-19
Also published as: CN112533606B; TWI754170B; CN112533606A; TW202024067A

Abstract

Use of a combination of a JAK kinase inhibitor and a human epidermal growth factor receptor EGFR inhibitor in preparation of a medicament for preventing or treating tumor diseases.

Description

Application of combination of JAK kinase inhibitor and EGFR inhibitor in preparing medicine for treating tumor disease

This application claims priority from Chinese patent application CN201811060976.2 with a filing date of September 12, 2018. This application cites the full text of the aforementioned Chinese patent application.

Technical field

The disclosure belongs to the field of medicine, and relates to the use of a combination of a JAK kinase inhibitor and a human epidermal growth factor receptor inhibitor (EGFRi) in the preparation of a medicament for preventing or treating a tumor disease.

Background technique

Non-small cell lung cancer (NSCLC) accounts for about 85% of all lung cancers, and about 75% of NSCLC patients are in the middle and advanced stages at the time of discovery, and the 5-year survival rate is very low. For patients with advanced or metastatic NSCLC, there is still a great clinical need to choose appropriate systemic treatments. NSCLC can be divided into squamous cell carcinoma and non-squamous cell carcinoma. Non-squamous cell carcinoma includes adenocarcinoma, large cell carcinoma, and other subtypes of cell carcinoma. Non-squamous cell carcinoma patients were further classified according to the presence or absence of a driver mutation gene (EGFR mutation or ALK gene rearrangement).

EGFR (Epidermal Growth Factor Receptor) is a member of the erbB receptor family of transmembrane protein tyrosine kinases. By binding to its ligands, such as epidermal growth factor (EGF), EGFR can form homodimers on the cell membrane or form heterodimers with other receptors in the family (such as erbB2, erbB3, or erbB4). . The formation of these dimers can cause phosphorylation of key tyrosine residues in EGFR cells, thereby activating multiple downstream signaling pathways in the cell. These intracellular signaling pathways play important roles in cell proliferation, survival, and anti-apoptosis. Imbalanced EGFR signaling pathways, including increased expression of ligands and receptors, EGFR gene amplification, and mutations, can promote the transformation of cells to malignancy and play an important role in tumor cell proliferation, invasion, metastasis, and angiogenesis. EGFR overexpression has been reported in many human malignant diseases, including bladder cancer, brain tumor, head and neck cancer, pancreatic cancer, lung cancer, breast cancer, ovarian cancer, colon cancer, prostate cancer, and kidney cancer. In many cases, overexpression of EGFR is associated with poor prognosis in patients.

Janus kinase (JAK) is a type of tyrosine kinase, including four members, JAK1, JAK2, JAK3 and TYK2. JAKs play an important role in the signaling of multiple cytokines. JAK1, JAK2 and TYK2 are widely present in various tissues and cells, while JAK3 is mainly distributed in lymphocytes. JAK3 can specifically and non-covalently bind to the gamma chain (Fcγ) shared by cytokine receptors, while JAK1 binds to the beta chain. The two are IL-2, IL-4, IL-7, IL-9, and IL-9. Activated by IL-15 cytokines. JAK2 plays an important role in the erythropoietin (EPO) signaling pathway, including erythrocyte differentiation and activation of signal transduction and activator of transcription (STAT).

The JAK-STAT signal transduction pathway is a chain in cells that interacts with proteins and is involved in, for example, process immunity, cell division, cell death, and tumor formation. This pathway passes information from extracellular chemical signals to the nucleus, thereby activating genes through a process called transcription. There are three key components of JAK-STAT signaling: Janus kinase (JAK), signal transduction and transcription protein activating factors (STATs), and receptors (binding chemical signals). The disrupted JAK-STAT signaling can cause a variety of diseases, such as skin diseases, cancer, and disorders affecting the immune system (Science.296 (5573): 1653-5). Since JAK-STAT signaling can allow the transcription of genes involved in cell division, one potential effect of excessive JAK-STAT signaling is cancer formation. High levels of STAT activation are associated with cancer. In particular, a large number of STAT3 and STAT5 activations are mainly associated with more dangerous tumors (British Journal of Cancer. 113 (3): 365–371.). Increasing evidence suggests that signaling through the JAK-STAT (Signal Transduction and Transcription Activator) pathway may be a factor in the resistance of EGFR-mutant NSCLC patients to EGFR TKI therapy. Therefore, blocking JAK and EGFR activity may provide improved targeted therapy benefits in some patients.

The prior art discloses the combination of some CDK kinase inhibitors and EGFR kinase inhibitors. Specifically, the document Synergistic anti-tumor effect of combined EGFR and JAK / STAT3 pathways in humans. A JAK2 inhibitor AZD1480 is disclosed in human ovarian cancer The combination of gefitinib showed a synergistic effect on the treatment of ovarian cancer.

WO2013091539 provides an effective JAK kinase inhibitor, the structure of which is shown in Formula I, and WO2014194741 discloses the bisulfate salt of JAK kinase inhibitor shown in Formula I,

WO2016054987A discloses a 4-substituted-2- (N- (5-allylamido) phenyl) amino) pyrimidine derivative having the structure shown in formula (II). The compound has the ability to inhibit L858R, EGFR mutant, and T790M. The EGFR mutant and exon 19 deletion activate the activity of the mutant and can be used to treat diseases mediated by EGFR mutant activity alone or in part. WO2017161937 discloses a mesylate salt of an EGFR inhibitor represented by formula (II),

The present disclosure provides the use of a new JAK kinase inhibitor combined with an EGFR inhibitor in the manufacture of a medicament for preventing or treating non-small cell lung cancer.

Summary of the Invention

The present disclosure provides a use of a JAK kinase inhibitor and an EGFR inhibitor in the manufacture of a medicament for preventing or treating a tumor disease.

The tumor diseases described in the present disclosure are selected from breast cancer, ovarian cancer, prostate cancer, melanoma, brain tumor, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer, kidney cancer, skin cancer, glioblastoma , Neuroblastoma, sarcoma, liposarcoma, osteochondroma, osteoma, osteosarcoma, seminoma, testicular tumor, uterine cancer, head and neck tumor, multiple myeloma, malignant lymphoma, polycythemia vera, leukemia , Thyroid tumor, ureter tumor, bladder tumor, gallbladder cancer, non-small cell lung cancer, bile duct cancer or chorionic epithelial cancer, preferably non-small cell lung cancer.

Use of the combination of a JAK kinase inhibitor and an EGFR inhibitor in the preparation of a medicament for the prevention or treatment of a tumor disease, which is an EGFR-mutated tumor disease.

The EGFR-mutated tumor disease described in the present disclosure is preferably non-small cell lung cancer, and the preferred EGFR mutant is selected from L858R EGFR mutant and / or T790M EGFR mutant.

In some embodiments, the non-small cell lung cancer described in the present disclosure is selected from squamous cell carcinoma and non-squamous cell carcinoma, preferably non-phosphorous cell carcinoma, wherein the non-phosphorous cell carcinoma may be adenocarcinoma, large cell carcinoma and Other subtypes of cell carcinoma.

In some embodiments, the JAK kinase inhibitor is selected from the group consisting of PF-06826647, tofacitinib, SNA-125, TD-1473, upadacitinib, ilginatinib, maleate, peficitinib, momomelotinib, panobinostat, AZD-4205, itacitinib, baricitinib, ganetespib, filgotinib, BMS-986165, PF-06700841, PF-04965842, ATI-502, ATI-501, pacritinib, ruxolitinib, WP-1066, ASN-002, INCB-054707, cerdulatinib, TG-02, fedratinib, INCB-52793, PF-06651600, ENMD-2076, TD-3504, delgocitinib, vidofludimus, delgocitinib, R-348 or a compound represented by formula (I) or a complex thereof or a pharmaceutically acceptable salt thereof, preferably tofacitinib, itactinib, AZD-4205, peficitinib , Baricitinib, filgotinib, BMS-986165, PF-04965842, ruxolitinib or a compound represented by formula (I) or a complex thereof or a pharmaceutically acceptable salt thereof, and most preferably a compound represented by formula (I) or a complex thereof or a pharmacological agent thereof With salt,

In some embodiments, the EGFR inhibitor is selected from the group consisting of osimertinib, gefitinib, erlotinib, olmutinib, icotinib, pyrotinib, vandetanib, brigatinib, dacomitinib, afatinib, neratinib, lapatinib, ABT-414, varlitinib, HLX-07, tesevatinib, theliatinib, epitinib, succinate, S-222611, poziotinib, AST-2818, GNS-1480, mavelertinib, AP-32788, AZD-3759, nazartinib, Sym-013, tesevatinib, allitinib tosylate, tarloxotinib, bromide, poziotinib, CK-101, QL -1203, JNJ-61186372, SKLB-1028, TAS-121, Hemay-020, Hemay-022, NRC-2694-A, simotinib hydrochloride, vandetanib, SPH-1188-11, GR-1401, SYN-004, ABBV- 221, MP-0274, GC-1118, BPI-15000, DBPR-112, Pirotinib, PB-357, lifirafenib, SCT-200, QLNC-120, agerafenib hydrochloride or a compound of formula (II) or a stereoisomer, complex Or at least one of pharmaceutically acceptable salts thereof, preferably olmutinib, afatinib, osimertinib, CK-101, erlotinib, icotinib, gefitinib, or a compound of formula (II) or a stereoisomer, complex, or At least one pharmaceutically acceptable salt thereof, most preferably of formula (II), or a stereoisomer, or a pharmaceutically acceptable complex salt thereof,

In some embodiments, the dose of the JAK kinase inhibitor is selected from 1-1000 mg, and the EGFR inhibitor is 1-1000 mg.

The dosage of the JAK kinase inhibitor described in the present disclosure is selected from the present disclosure

1mg, 2mg, 3mg, 4mg, 5mg, 6mg, 7mg, 8mg, 9mg, 10mg, 11mg, 12mg, 13mg, 14mg, 15mg, 16mg, 17mg, 18mg, 19mg, 20mg, 21mg, 22mg, 23mg, 24mg, 25mg, 26mg, 27mg, 28mg, 29mg, 30mg, 31mg, 32mg, 33mg, 34mg, 35mg, 36mg, 37mg, 38mg, 39mg, 40mg, 41mg, 42mg, 43mg, 44mg, 45mg, 46mg, 47mg, 48mg, 49mg, 50mg, 51mg, 52mg, 53mg, 54mg, 55mg, 56mg, 57mg, 58mg, 59mg, 60mg, 61mg, 62mg, 63mg, 64mg, 65mg, 66mg, 67mg, 68mg, 69mg, 70mg, 71mg, 72mg, 73mg, 74mg, 75mg, 76mg, 77mg, 78mg, 79mg, 80mg, 81mg, 82mg, 83mg, 84mg, 85mg, 86mg, 87mg, 88mg, 89mg, 90mg, 91mg, 92mg, 93mg, 94mg, 95mg, 96mg, 97mg, 98mg, 99mg, 100mg, 101mg, 102mg, 103mg, 104mg, 105mg, 106mg, 107mg, 108mg, 109mg, 110mg, 111mg, 112mg, 113mg, 114mg, 115mg, 116mg, 117mg, 118mg, 119mg, 120mg, 121mg, 122mg, 123mg, 124mg, 125mg, 126mg, 127mg, 128mg, 129mg, 130mg, 131mg, 132mg, 133mg, 134mg, 135mg, 136mg, 137mg, 138mg, 139 mg, 140mg, 141mg, 142mg, 143mg, 144mg, 145mg, 146mg, 147mg, 148mg, 149mg, 150mg, 151mg, 152mg, 153mg, 154mg, 155mg, 156mg, 157mg, 158mg, 159mg, 160mg, 161mg, 162mg, 163mg, 163mg, 164mg, 165mg, 166mg, 167mg, 168mg, 169mg, 170mg, 171mg, 172mg, 173mg, 174mg, 175mg, 176mg, 177mg, 178mg, 179mg, 180mg, 181mg, 182mg, 183mg, 184mg, 185mg, 186mg, 187mg, 188mg, 188mg, 189mg, 190mg, 191mg, 192mg, 193mg, 194mg, 195mg, 196mg, 197mg, 198mg, 199mg, 200mg.

The dosage of the EGFR inhibitor described in the present disclosure is selected from 1 mg, 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, 20 mg, 22.5 mg, 25 mg, 27.5 mg, 30 mg, 32.5 mg, 35 mg, 37.5 mg, 40mg, 42.5mg, 45mg, 47.5mg, 50mg, 52.5mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 105mg, 110mg, 120mg, 130mg, 140mg, 150mg, 160mg , 170mg, 180mg, 190mg, 200mg, 210mg, 220mg, 230mg, 240mg, 250mg, 260mg, 270mg, 280mg, 290mg, 300mg, 350mg, 400mg, 450mg, 500mg, 550mg, 600mg, 650mg, 700mg, 750mg, 800mg, 850mg , 900mg, 950mg, 1000mg.

In some embodiments, the dose of the JAK kinase inhibitor is selected from 1-1000 mg, the frequency of administration may be once a day, twice a day, or three times a day, and the dose of the EGFR inhibitor is selected from 1-1000 mg The frequency of administration can be once a day, twice a day, or three times a day.

In some embodiments, the dose of the JAK kinase inhibitor is selected from 1 to 600 mg, the frequency of administration may be once a day or twice a day, and the dose of the EGFR inhibitor is selected from 1 to 500 mg, the frequency of administration It is once a day.

In some embodiments, the dose of the JAK kinase inhibitor is selected from 1-200 mg, the frequency of administration may be once a day or twice a day, and the dose of the EGFR inhibitor is selected from 1-500 mg, the frequency of administration It is once a day.

In some embodiments, the dose of the JAK kinase inhibitor is selected from 1-100 mg, the frequency of administration may be once a day or twice a day, the dose of the EGFR inhibitor is selected from 1-500 mg, and the frequency of administration It is once a day.

In some embodiments, the dose of the JAK kinase inhibitor is selected from 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18mg, 19mg, 20mg, 21mg, 22mg, 23mg, 24mg, 25mg, 26mg, 27mg, 28mg, 29mg, 30mg, 31mg, 32mg, 33mg, 34mg, 35mg, 36mg, 37mg, 38mg, 39mg, 40mg, 41mg, 42mg, 43mg, 44mg, 45mg, 46mg, 47mg, 48mg, 49mg, 50mg, the frequency of administration is once a day or twice a day, the dose of the EGFR inhibitor is selected from 55mg, 110mg, 220mg, 260mg, the frequency of administration is Once a day.

In some embodiments, the dose of the JAK kinase inhibitor is selected from 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18mg, 19mg, 20mg, the frequency of administration is once a day or twice a day, the dose of the EGFR inhibitor is selected from 55mg, 110mg, 220mg, 260mg, and the frequency of administration is once a day.

In some embodiments, the dose of the JAK kinase inhibitor is selected from 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, and the frequency of administration is once a day or twice a day. The dose of the EGFR inhibitor is selected from 55 mg, 110 mg, 220 mg, and 260 mg, and the frequency of administration is once a day.

In some embodiments, the dose of the JAK kinase inhibitor is selected from 1 mg, 2 mg, 4 mg, 6 mg, and 8 mg, the frequency of administration is once a day or twice a day, and the dose of the EGFR inhibitor is selected from 55 mg, 110mg, 220mg, 260mg, the frequency of administration is once a day.

In an alternative embodiment, the JAK kinase inhibitor is a compound represented by formula (I) or a stereoisomer, complex, or a pharmaceutically acceptable salt thereof.

In an alternative embodiment, the JAK kinase inhibitor is a compound represented by formula (I) or a stereoisomer, complex or pharmaceutically acceptable salt thereof, wherein the compound represented by formula (I) or a stereoisomer thereof The dose of the EGFR, complex or pharmaceutically acceptable salt thereof is selected from 1-1000 mg, and the frequency of administration may be once a day, twice a day, or three times a day. The dose of the EGFR inhibitor is selected from 1-1000 mg. The frequency of the drug can be once a day, twice a day, or three times a day.

In an alternative embodiment, the JAK kinase inhibitor is a compound represented by formula (I) or a stereoisomer, complex or pharmaceutically acceptable salt thereof, wherein the compound represented by formula (I) or a stereoisomer thereof The dose of the EGFR, complex or pharmaceutically acceptable salt thereof is selected from 1 to 200 mg, and the frequency of administration may be once a day or twice a day. The dose of the EGFR inhibitor is selected from 1 to 500 mg, and the frequency of administration is one day. once.

In an alternative embodiment, the JAK kinase inhibitor is a compound represented by formula (I) or a stereoisomer, complex or pharmaceutically acceptable salt thereof, wherein the compound represented by formula (I) or a stereoisomer thereof The dose of the body, complex or pharmaceutically acceptable salt thereof is selected from 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19mg, 20mg, 21mg, 22mg, 23mg, 24mg, 25mg, 26mg, 27mg, 28mg, 29mg, 30mg, 31mg, 32mg, 33mg, 34mg, 35mg, 36mg, 37mg, 38mg, 39mg, 40mg, 41mg, 42mg, 43mg, 44mg, 45mg, 46mg, 47mg, 48mg, 49mg, 50mg, the frequency of administration can be once a day or twice a day, the EGFR inhibitor dose is selected from 55mg, 110mg, 220mg, 260mg, the frequency of administration is one day once.

In an alternative embodiment, the JAK kinase inhibitor is a compound represented by formula (I) or a stereoisomer, complex or pharmaceutically acceptable salt thereof, wherein the compound represented by formula (I) or a stereoisomer thereof The dose of the body, complex or pharmaceutically acceptable salt thereof is selected from 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19mg, 20mg, the frequency of administration can be once a day or twice a day, the dose of the EGFR inhibitor is selected from 55mg, 110mg, 220mg, 260mg, and the frequency of administration is once a day.

In an alternative embodiment, the JAK kinase inhibitor is a compound represented by formula (I) or a stereoisomer, complex or pharmaceutically acceptable salt thereof, wherein the compound represented by formula (I) or a stereoisomer thereof The dosage of the body, complex or pharmaceutically acceptable salt thereof is selected from 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, and the frequency of administration may be once a day or twice a day. The EGFR inhibitor dose is selected from 55 mg, 110 mg, 220 mg, and 260 mg, and the frequency of administration is once a day.

In an alternative embodiment, the JAK kinase inhibitor is a compound represented by formula (I) or a stereoisomer, complex or pharmaceutically acceptable salt thereof, wherein the compound represented by formula (I) or a stereoisomer thereof The dose of the EGFR, complex or pharmaceutically acceptable salt thereof is selected from 1 mg, 2 mg, 4 mg, 6 mg, and 8 mg, and the frequency of administration may be once a day or twice a day. The dose of the EGFR inhibitor is selected from 55 mg, 110 mg, 220mg, 260mg, dosing frequency is once a day.

In an alternative embodiment, the EGFR inhibitor is a compound of formula (II) or a stereoisomer, complex or pharmaceutically acceptable salt thereof.

In an alternative embodiment, the dose of the JAK kinase inhibitor is selected from 1-1000 mg, the frequency of administration may be once a day, twice a day, or three times a day, and the EGFR inhibitor is a compound of formula (II) Or a stereoisomer, complex or pharmaceutically acceptable salt thereof, wherein the dose of the compound of formula (II) or a stereoisomer, complex or pharmaceutically acceptable salt thereof is selected from 1 to 1000 mg, and the frequency of administration may be Once a day, twice a day, or three times a day.

In an alternative embodiment, the dose of the JAK kinase inhibitor is selected from 1-200 mg, the frequency of administration may be once a day or twice a day, and the EGFR inhibitor is a compound of formula (II) or a steric Structure, complex or pharmaceutically acceptable salt thereof, wherein the dose of the compound of formula (II) or its stereoisomer, complex or pharmaceutically acceptable salt is selected from 1-500 mg, and the frequency of administration may be once a day or Twice a day.

In an alternative embodiment, the dose of the JAK kinase inhibitor is selected from 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg , 18mg, 19mg, 20mg, 21mg, 22mg, 23mg, 24mg, 25mg, 26mg, 27mg, 28mg, 29mg, 30mg, 31mg, 32mg, 33mg, 34mg, 35mg, 36mg, 37mg, 38mg, 39mg, 40mg, 41mg, 42mg , 43mg, 44mg, 45mg, 46mg, 47mg, 48mg, 49mg, 50mg, the frequency of administration may be once a day or twice a day, the EGFR inhibitor is a compound of formula (II) or a stereoisomer, a compound thereof Or a pharmaceutically acceptable salt thereof, wherein the dose of the compound of formula (II) or a stereoisomer, complex or pharmaceutically acceptable salt thereof is selected from 55 mg, 110 mg, 220 mg, and 260 mg, and the frequency of administration is once a day.

In an alternative embodiment, the dose of the JAK kinase inhibitor is selected from 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg , 18mg, 19mg, 20mg, the frequency of administration may be once a day or twice a day, the EGFR inhibitor is a compound of formula (II) or a stereoisomer, a complex or a pharmaceutically acceptable salt thereof, wherein (II) The dose of the compound or its stereoisomer, complex or pharmaceutically acceptable salt is selected from 55 mg, 110 mg, 220 mg, and 260 mg, and the frequency of administration is once a day.

In an alternative embodiment, the dose of the JAK kinase inhibitor is selected from 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, and 10 mg, and the frequency of administration may be once a day or twice a day. The EGFR inhibitor is a compound of formula (II) or a stereoisomer, complex or pharmaceutically acceptable salt thereof, wherein the compound of formula (II) or a stereoisomer, complex or pharmaceutically acceptable salt thereof is The dose is selected from 55mg, 110mg, 220mg, 260mg, and the frequency of administration is once a day.

In an alternative embodiment, the dose of the JAK kinase inhibitor is selected from 1 mg, 2 mg, 4 mg, 6 mg, and 8 mg, and the frequency of administration may be once a day or twice a day. The EGFR inhibitor is of formula (II ) Compound or stereoisomer, complex or pharmaceutically acceptable salt thereof, wherein the dose of the compound of formula (II) or stereoisomer, complex or pharmaceutically acceptable salt thereof is selected from 55 mg, 110 mg, 220 mg, 260 mg The dosing frequency is once a day.

In an alternative embodiment, the JAK kinase inhibitor is a compound represented by formula (I) or a stereoisomer, a complex or a pharmaceutically acceptable salt thereof, and the EGFR inhibitor is a compound of formula (II) or a Stereoisomers, complexes or pharmaceutically acceptable salts thereof.

In an alternative embodiment, the JAK kinase inhibitor is a compound represented by formula (I) or a stereoisomer, a complex or a pharmaceutically acceptable salt thereof, and the EGFR inhibitor is a compound of formula (II) or a Stereoisomers, complexes or pharmaceutically acceptable salts thereof, wherein the dose of the compound represented by formula (I) or a stereoisomers, complexes or pharmaceutically acceptable salts thereof is selected from 1-1000 mg, and the frequency of administration may be one The dose of the compound of formula (II) or its stereoisomers, complexes or pharmaceutically acceptable salts is selected from 1-1000 mg once a day, twice a day, or three times a day. Two times or three times a day.

In an alternative embodiment, the JAK kinase inhibitor is a compound represented by formula (I) or a stereoisomer, a complex or a pharmaceutically acceptable salt thereof, and the EGFR inhibitor is a compound of formula (II) or a Stereoisomers, complexes or pharmaceutically acceptable salts thereof, wherein the dose of the compound represented by formula (I) or a stereoisomers, complexes or pharmaceutically acceptable salts thereof is selected from 1 to 200 mg, and the frequency of administration may be one The dose of the compound of formula (II) or a stereoisomer, complex or pharmaceutically acceptable salt thereof is selected from 1 to 500 mg once a day or twice a day.

In an alternative embodiment, the JAK kinase inhibitor is a compound represented by formula (I) or a stereoisomer, a complex or a pharmaceutically acceptable salt thereof, and the EGFR inhibitor is a compound of formula (II) or a Stereoisomers, complexes or pharmaceutically acceptable salts thereof, wherein the dose of the compound represented by formula (I) or a stereoisomers, complexes or pharmaceutically acceptable salts thereof is selected from 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6mg, 7mg, 8mg, 9mg, 10mg, 11mg, 12mg, 13mg, 14mg, 15mg, 16mg, 17mg, 18mg, 19mg, 20mg, 21mg, 22mg, 23mg, 24mg, 25mg, 26mg, 27mg, 28mg, 29mg, 30mg, 31mg, 32mg, 33mg, 34mg, 35mg, 36mg, 37mg, 38mg, 39mg, 40mg, 41mg, 42mg, 43mg, 44mg, 45mg, 46mg, 47mg, 48mg, 49mg, 50mg, the frequency of administration can be once a day or once Twice a day, the dose of the compound of formula (II) or a stereoisomer, complex or pharmaceutically acceptable salt thereof is selected from 55 mg, 110 mg, 220 mg, and 260 mg, and the frequency of administration is once a day.

In an alternative embodiment, the JAK kinase inhibitor is a compound represented by formula (I) or a stereoisomer, a complex or a pharmaceutically acceptable salt thereof, and the EGFR inhibitor is a compound of formula (II) or a Stereoisomers, complexes or pharmaceutically acceptable salts thereof, wherein the dose of the compound represented by formula (I) or a stereoisomers, complexes or pharmaceutically acceptable salts thereof is selected from 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6mg, 7mg, 8mg, 9mg, 10mg, 11mg, 12mg, 13mg, 14mg, 15mg, 16mg, 17mg, 18mg, 19mg, 20mg, the frequency of administration can be once a day or twice a day, the compound of formula (II) or The dosage of the stereoisomer, complex or pharmaceutically acceptable salt thereof is selected from 55mg, 110mg, 220mg, 260mg, and the frequency of administration is once a day.

In an alternative embodiment, the JAK kinase inhibitor is a compound represented by formula (I) or a stereoisomer, a complex or a pharmaceutically acceptable salt thereof, and the EGFR inhibitor is a compound of formula (II) or a Stereoisomers, complexes or pharmaceutically acceptable salts thereof, wherein the dose of the compound represented by formula (I) or a stereoisomers, complexes or pharmaceutically acceptable salts thereof is selected from 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6mg, 7mg, 8mg, 9mg, 10mg, the frequency of administration can be once a day or twice a day, the dose of the compound of formula (II) or its stereoisomers, complexes or pharmaceutically acceptable salts is selected from 55mg, 110mg, 220mg, 260mg, the frequency of administration is once a day.

In an alternative embodiment, the JAK kinase inhibitor is a compound represented by formula (I) or a stereoisomer, a complex or a pharmaceutically acceptable salt thereof, and the EGFR inhibitor is a compound of formula (II) or a Stereoisomers, complexes or pharmaceutically acceptable salts thereof, wherein the dose of the compound represented by formula (I) or a stereoisomers, complexes or pharmaceutically acceptable salts thereof is selected from 1 mg, 2 mg, 4 mg, 6 mg, 8 mg, The frequency of administration may be once a day or twice a day. The dose of the compound of formula (II) or its stereoisomers, complexes or pharmaceutically acceptable salts is selected from 55 mg, 110 mg, 220 mg, and 260 mg. Once a day.

The pharmaceutically acceptable salts of the drugs described in this disclosure may be hydrochloride, phosphate, hydrogen phosphate, sulfate, hydrogen sulfate, sulfite, acetate, oxalate, malonate, valerate , Glutamate, oleate, palmitate, stearate, laurate, borate, p-toluenesulfonate, mesylate, isethionate, maleate, Malate, tartrate, benzoate, paraben, salicylate, vanillate, mandelate, succinate, gluconate, lactobionate or laurylsulfonate.

In some embodiments, the pharmaceutically acceptable salt of the compound represented by formula (I) is a hydrogen sulfate salt.

In some embodiments, the pharmaceutically acceptable salt of the compound represented by formula (II) is a mesylate salt.

The combined administration of the present disclosure includes oral administration, parenteral administration, and transdermal administration. The parenteral administration includes, but is not limited to, intravenous injection, subcutaneous injection, intramuscular injection, and preferably oral administration. .

The present disclosure also provides a pharmaceutical composition of the aforementioned JAK kinase inhibitor and EGFR inhibitor, and one or more pharmaceutically acceptable carriers, excipients, and diluents. The pharmaceutical composition can be made into any pharmaceutically acceptable dosage form. For example, they can be formulated as tablets, capsules, pills, granules, solutions, suspensions, syrups, injections (including injections, sterile powders for injections and concentrated solutions for injections), suppositories, inhalants or sprays Agent.

The present disclosure also provides a method for treating a tumor disease, comprising administering to a patient an effective amount of the aforementioned JAK kinase inhibitor and an effective amount of the aforementioned EGFR inhibitor.

The present disclosure also provides a pharmaceutical kit for use in a medicament for treating a tumor disease, in which a pharmaceutical composition of the JAK kinase inhibitor and the EGFR inhibitor described in the present disclosure is packaged.

The present disclosure combines the administration of a JAK kinase inhibitor and an EGFR inhibitor, thereby enhancing the effect in a medicine for treating a tumor disease.

The "combination" described in the present disclosure is a mode of administration, which means that at least one dose of a JAK kinase inhibitor and at least one dose of an EGFR inhibitor are administered within a certain period of time, both of which show pharmacology学 Role. The time period may be within one administration cycle, preferably within 4 weeks, within 3 weeks, within 2 weeks, within 1 week, or within 24 hours, more preferably within 12 hours. The JAK kinase inhibitor and the EGFR inhibitor may be administered simultaneously or sequentially. This term includes treatments in which JAK kinase inhibitors and EGFR inhibitors are administered by the same route or different routes of administration.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1. The efficacy of the compound methanesulfonate of formula (II) and the compound bisulfate of formula (I) alone or in combination on subcutaneous xenografts of human lung cancer H1975 nude mice;

Figure 2. The effect of the mesylate salt of the compound represented by formula (II) and the bisulfate salt of the compound represented by formula (I) on the body weight of tumor-bearing nude mice.

detailed description

Hereinafter, the present disclosure will be explained in more detail with reference to the embodiments. The embodiments of the present disclosure are only used to explain the technical solutions of the present disclosure, and do not limit the essence and scope of the present disclosure.

Purpose

Evaluation of the combination of a compound represented by formula (I) with hydrogen sulfate (drug A in the experiment) and a compound represented by formula (II) with mesylate (drug B in the experiment) against human lung cancer H1975 (EGFR ^{L858R / T790M} ). Efficacy of Subcutaneous Xenografts in Mice.

Drug Information

The hydrogen sulfate salt of the compound represented by formula (I) is prepared by the method disclosed in WO2014194741; the mesylate salt of the compound represented by formula (II) is prepared by the method disclosed in WO2017161937. Both were formulated with 0.1% Tween80 and 0.5% CMC and diluted.

cell

Human H1975 lung cancer cells were purchased from the Cell Bank of the Chinese Academy of Sciences. H1975 cells were adhered to a 10-cm petri dish and cultured under the condition that RPMI 1640 medium was supplemented with 10% fetal bovine serum and penicillin and streptomycin, and cultured in an incubator at 37 ° C and 5% CO ₂ air. Passage 2-3 times a week. When the cells are in exponential growth phase, trypsinize, collect cells, count, and inoculate.

Experimental animal

BALB / c nude mice, 6-7 weeks, ♀, purchased from Shanghai Lingchang Biotechnology Co., Ltd. Production license number: SCXK (Shanghai) 2013-0018; animal certificate number 2013001834447. Rearing environment: SPF level.

Experimental steps

Nude mice were subcutaneously inoculated with 5.5 × 10 ⁶ human H1975 lung cancer cells. After the tumor grew to 100-200 mm ³ , the animals were grouped according to tumor volume (D0). Mice were administered orally (ig) once a day (QD) or twice a day (BID); the administration volume was 10 mL / kg; the solvent group was given the same volume of "solvent" (0.1% Tween80 + 0.5% CMC); See Table 1 for specific dosages and schedules. The tumor volume was measured twice a week, the weight of the mice was weighed, and the data was recorded.

The use and benefits of this experimental animal are in accordance with the regulations of the International Laboratory Animal Evaluation and Accreditation Committee (AAALAC). Monitor the animal's health and death every day. Routine inspections include observing the effects of test substances and drugs on the daily behavioral performance of animals, such as behavioral activity, weight changes, appearance and signs.

Experimental index

The experimental index is to examine the effect of the drug on tumor growth, and the specific index is T / C% or tumor inhibition rate TGI (%). The tumor diameter is measured twice a week with a vernier caliper, and the tumor volume (V) calculation formula is:

V = 1/2 × a × b ² where a and b represent length and width, respectively.

T / C (%) = (T-T0) / (C-C0) × 100, where T and C are tumor volumes at the end of the experiment; T0 and C0 are tumor volumes at the beginning of the experiment.

Tumor inhibition rate (TGI) (%) = 100-T / C (%).

When the tumor regressed, the tumor inhibition rate (TGI) (%) = 100- (T-T0) / T0 × 100.

If the tumor is smaller than the initial volume, that is, T <T0 or C <C0, it is defined as tumor partial regression (PR); if the tumor completely disappears, it is defined as tumor complete regression (CR).

After the end of the experiment, tumor tissues were taken at 2 and 8 hours after the last dose, liquid nitrogen was quickly frozen, and stored at -70 ° C for future use.

Statistical analysis

Two-tailed Student's test was used to compare the tumor volume between the two groups, and P <0.05 was defined as a statistically significant difference.

result

Drug B (5mg / kg, ig, QD × 12) inhibited the growth of human lung cancer H1975 (EGFR ^{L858R / T790M} ) subcutaneously transplanted tumors in nude mice with a tumor suppression rate of 47%; drug A (10, 30mg / kg, ig, (BID × 12) The tumor inhibition rates of H1975 subcutaneously transplanted tumors were -24% and 5%, respectively; the combined tumor inhibition rates of the two increased to 70% and 90%, of which drug A 30mg / kg + drug B 5mg / kg combined group The effect was significantly stronger than that of the single drug (P <0.01, compared with the single drug); tumor-bearing mice were well tolerated by the above drugs, and no significant weight loss and other symptoms occurred. The results indicate that the combination of drug A and drug B has a synergistic effect on human lung cancer H1975 subcutaneously transplanted tumors in nude mice.

Table 1. Efficacy of drug A and drug B alone or in combination on subcutaneous xenografts of human lung cancer H1975 nude mice

D0: time of first administration; P value means compared with solvent; * P <0.05, ** P <0.01, compared with drug B 5mg / kg.

in conclusion

Methanesulfonate (5 mg / kg, ig, QD × 12) of the compound represented by formula (II) inhibits the growth of human lung cancer H1975 (EGFR ^{L858R / T790M} ) subcutaneously transplanted tumors in nude mice; hydrogen sulfate of the compound represented by formula (I) Salt (10, 30mg / kg, ig, BID × 12) had no obvious effect on H1975 subcutaneous transplantation tumors; the tumor inhibition rate of the two combined treatments increased significantly (P <0.01). The tumor-bearing mice are well tolerated by the above drugs.

Although the specific embodiments of the present invention are described above, those skilled in the art should understand that these are merely examples, and that various changes or modifications may be made to these embodiments without departing from the principle and essence of the present invention. modify. Therefore, the protection scope of the present invention is defined by the appended claims.

Claims

Use of a JAK kinase inhibitor combined with an EGFR inhibitor in the manufacture of a medicament for preventing or treating a tumor disease.
The use according to claim 1, the tumor disease is selected from the group consisting of breast cancer, ovarian cancer, prostate cancer, melanoma, brain tumor, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer, kidney cancer, skin Cancer, glioblastoma, neuroblastoma, sarcoma, liposarcoma, osteochondroma, osteoma, osteosarcoma, seminoma, testicular tumor, uterine cancer, head and neck tumor, multiple myeloma, malignant lymphoma , Polycythemia vera, leukemia, thyroid tumor, ureteral tumor, bladder tumor, gallbladder cancer, non-small cell lung cancer, bile duct cancer or chorionic epithelial cancer, preferably non-small cell lung cancer.
The use according to claim 1, wherein the tumor disease is an EGFR-mutated tumor disease.
The use according to claim 3, wherein the EGFR-mutated tumor disease is non-small cell lung cancer, and the preferred EGFR mutant is selected from the group consisting of L858R EGFR mutant and / or T790M EGFR mutant.
The use according to claim 2, wherein the non-small cell lung cancer is selected from squamous cell carcinoma and non-squamous cell carcinoma, preferably non-phosphorous cell carcinoma.
The use according to any one of claims 1-5, the JAK kinase inhibitor is selected from the group consisting of PF-06826647, tofacitinib, SNA-125, TD-1473, upadacitinib, ilginatinib, maleate, peficitinib, momometinib, panobinostat, AZD- 4205, itacitinib, baricitinib, ganetespib, filgotinib, BMS-986165, PF-06700841, PF-04965842, ATI-502, ATI-501, pacritinib, ruxolitinib, WP-1066, ASN-002, INCB-054707, cerdulatinib, TG- 02, fedratinib, INCB-52793, PF-06651600, ENMD-2076, TD-3504, delgocitinib, vidofludimus, delgocitinib, R-348 or a compound represented by formula (I) or a complex thereof or a pharmaceutically acceptable salt thereof, preferably tofacitinib , Itacitinib, AZD-4205, peficitinib, baricitinib, filgotinib, BMS-986165, PF-04965842, ruxolitinib, or a compound represented by formula (I) or a complex thereof or a pharmaceutically acceptable salt thereof, most preferably a compound represented by formula (I) Or a complex thereof or a pharmaceutically acceptable salt thereof,
The use according to any one of claims 1-5, the EGFR inhibitor is selected from the group consisting of osimertinib, gefitinib, erlotinib, olmutinib, icotinib, pyrrotib, vandetanib, brigatinib, dacomitinib, afatinib, neratinib, lapatinib, ABT-414, varlitinib, HLX-07, tesevatinib, theliatinib, epitinib, succinate, S-222611, poziotinib, AST-2818, GNS-1480, mavelertinib, AP-32788, AZD-3759, nazartinib, Sym-013, tesevatinib, allitinib tosylate, tarloxotinib , Poziotinib, CK-101, QL-1203, JNJ-61186372, SKLB-1028, TAS-121, Hemay-020, Hemay-022, NRC-2694-A, simotinib hydrochloride, vandetanib, SPH-1188-11, GR- 1401, SYN-004, ABBV-221, MP-0274, GC-1118, BPI-15000, DBPR-112, Pirotinib, PB-357, lifirafenib, SCT-200, QLNC-120, agerafenib hydrochloride or compound of formula (II) Or at least one of its stereoisomers, complexes or pharmaceutically acceptable salts thereof, preferably olmutinib, afatinib, osimertinib, CK-101, erlotinib, icotinib, gefitinib or a compound of formula (II) or a stereoisomer thereof At least one of a compound, a complex or a pharmaceutically acceptable salt thereof, most preferably a compound of formula (II) or a stereoisomer, a complex or a pharmaceutically acceptable salt thereof,
The use according to any one of claims 1-7, wherein the dose of the JAK kinase inhibitor is selected from 1-1000 mg, preferably 1-600 mg, and the frequency of administration is once a day, twice a day, or three times a day ; The dosage range of the EGFR inhibitor is selected from 1-1000 mg, preferably 1-500 mg, and the frequency of administration is once a day, twice a day, or three times a day.
The use according to claim 8, wherein the frequency of JAK kinase inhibitor administration is once a day or twice a day, and the dosage is selected from 1 to 600 mg; the frequency of EGFR inhibitor administration is once a day, and The drug dose is selected from 55mg, 110mg, 220mg, 260mg.
The use according to any one of claims 6, 8-9, wherein the pharmaceutically acceptable salt of the compound represented by formula (I) is a hydrogen sulfate.
The use according to any one of claims 7, 8-9, wherein the pharmaceutically acceptable salt of the compound represented by formula (II) is a mesylate salt.
A pharmaceutical composition comprising the JAK kinase inhibitor and the EGFR inhibitor according to any one of claims 1-11, and one or more pharmaceutically acceptable carriers, excipients, and diluents.
A pharmaceutical kit, comprising the pharmaceutical composition according to claim 12.