WO2021104341A1 - 一种取代丁烯酰胺的应用 - Google Patents

一种取代丁烯酰胺的应用 Download PDF

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WO2021104341A1
WO2021104341A1 PCT/CN2020/131638 CN2020131638W WO2021104341A1 WO 2021104341 A1 WO2021104341 A1 WO 2021104341A1 CN 2020131638 W CN2020131638 W CN 2020131638W WO 2021104341 A1 WO2021104341 A1 WO 2021104341A1
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egfr
pharmaceutically acceptable
cancer
acid
rare
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PCT/CN2020/131638
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English (en)
French (fr)
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唐海涛
葛海涛
易年红
张玉强
曹苏闽
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江苏苏中药业集团股份有限公司
江苏苏中药业研究院有限公司
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Priority to JP2022531527A priority Critical patent/JP7430890B2/ja
Priority to US17/780,516 priority patent/US20230000854A1/en
Priority to EP20894208.6A priority patent/EP4066833A4/en
Publication of WO2021104341A1 publication Critical patent/WO2021104341A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • A61K31/4706—4-Aminoquinolines; 8-Aminoquinolines, e.g. chloroquine, primaquine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3

Definitions

  • This application relates to the field of medical technology, in particular to an application of substituted butenamide.
  • Non-small cell lung cancer is a malignant tumor that seriously threatens human health. Despite the continuous improvement of surgery and chemotherapy techniques, the prognosis of patients is still poor, with a 5-year survival rate of less than 20%. At present, molecular targeted therapy targeting human epithelium growth factor receptor (EGFR) has become the most important way to treat NSCLC.
  • EGFR epithelium growth factor receptor
  • EGFR is the expression product of the proto-oncogene C-erbB-1, which is located on chromosome 7 and belongs to the transmembrane receptor tyrosine kinase. After EGFR binds to its ligand, it can activate downstream signaling pathways, regulate tumor cell proliferation, differentiation, angiogenesis, and inhibition of apoptosis, thereby regulating a series of tumor biological behaviors.
  • EGFR-TKI EGFR tyrosine kinase inhibitors
  • EGFR mutations can occur anywhere in the EGFR sequence.
  • EGFR mutant strains are derived from mutations in the kinase domain (ie, exons 18-24 in the EGFR sequence) or the extracellular domain (ie, exons 2-16 in the EGFR sequence).
  • One or more point mutations in exon 18 include L688P, V689M, P694L/S, N700D, L703V, E709K/Q/A/G/V, I715S, L718P, G719C/A/S/R or S720P/F .
  • Deletions in exon 19 include delG719, delE746_E749, delE746_A750, delE746_A750insRP, delE746_A750insQP, delE746_T751, delE746_T751insA/I/V, delE746_T751insVA, delE746_S752, delE746_EinsVA, delE746_S752, delE746_S752insA/L/L747_Eins750, delL747_E747T747, delL747_AinsRP, delE746_A750insRP, delE746_T751 Q, delL747_T751insPI, delL747_S752, delL747_S752insQ, delL747_P753, delL747_P753insS/Q,
  • Replication in exon 19 includes K739_I44dupKIPVAI.
  • Point mutations in exon 19 include L730F, W731Stop, P733L, G735S, V742A, E746V/K, A750P, T751I, S752Y, P753S, A754P, or D761Y.
  • In-frame inserts in exon 20 include D761_E762insEAFQ, A767_S768insTLA, V769_D770insY, V769_D770insCV, V769_D770insASV, D770_N771insD/G, D770_N771insNPG, D770_N771insSVQ, P772_H773_insN/CinsH773_VinsH773_Vins, P772_H773_N771insSVQ, P772_H773_N771insSVQ, P772_H773_N771insSVQ, P772_H773_VinsN/Vins.
  • Deletions in exon 20 include delM766_A767, delM766_A767insAI, delA767_V769, delD770, or dellP772_H773insNP.
  • Replication in exon 20 includes S768_D770dupSVD, A767_V769dupASV, or H773dupH.
  • Point mutations in exon 20 include D761N, A763V, V765A/M, S768I, V769L/M, S768I, P772R, N771T, H773R/Y/L, V774M, R776G/H/C, G779S/F, T783A, T784F , L792P, L798H/F, T790M, R803W, K806E or L814P).
  • Point mutations in exon 21 include G810S, N826S, L833V, H835L, L838V, A839T, K846R, T847I, H850N, V851I/A, I853T, L858M/R, A859T, L861Q/R, G863D, A864T, E866K, or G873E .
  • EGFR-TKI efficacy of EGFR-TKI is closely related to the mutation status of EGFR gene.
  • EGFR gene mutations are mainly concentrated in exons 18-21, including sensitive mutations and drug-resistant mutations.
  • the mutation rate of EGFR accounts for 30-50%.
  • the mutation rate of exon 19 and 21 (L858R, L861I) accounts for about 90% of the total mutation rate
  • the mutation rate of exon 18 accounts for 5 of the total mutation rate.
  • the T790M mutation in exon 20 accounts for about 5% of the mutation rate.
  • the deletion of exon 19 and the L858R mutation are called rare mutations, such as L861Q, G719X, S768I and so on.
  • CN102625797A discloses (E)-N-(3-cyano-7-ethoxy-4-(3-ethynylphenylamino)quinolin-6-yl)-4-(dimethylamino)butyl-
  • 2-enamide on common EGFR mutants such as EGFR mutant L858R/T790M and EGFR mutant E746-A750, but the effect on rare mutations such as L861Q, G719X, S768I, etc. is not recorded.
  • the purpose of the present invention is to provide an application of substituted butenamide, specifically to provide compound (E)-N-(3-cyano-7-ethoxy-4-(3-ethynylphenylamino)quinoline- New applications of 6-yl)-4-(dimethylamino)but-2-enamide and its pharmaceutically acceptable salts and solvent compounds.
  • the compound of the present invention (E)-N-(3-cyano-7-ethoxy-4-(3-ethynylphenylamino)quinolin-6-yl)-4-(dimethylamino) But-2-enamide and its pharmaceutically acceptable salts and solvent compounds have good inhibitory activity against cancers mediated by rare EGFR mutations such as L861Q, G719X, and S768I.
  • the compound of the present invention (E)-N-(3-cyano-7-ethoxy-4-(3-ethynylphenylamino)quinolin-6-yl)-4-(dimethylamino) But-2-enamide and its pharmaceutically acceptable salts and solvent compounds can inhibit the proliferation of cells expressing EGFR mutant strains.
  • the present invention provides (E)-N-(3-cyano-7-ethoxy-4-(3-ethynylphenylamino)quinolin-6-yl)-4-(dimethylamino ) Application of but-2-enamide and its pharmaceutically acceptable salts and solvent compounds in the preparation of drugs for the treatment of rare EGFR mutation-mediated cancers.
  • Another aspect of the present invention is to provide a method for administering a therapeutically effective amount of (E)-N-(3-cyano-7-ethoxy-4-(3-acetylene) to a subject in need Phenylamino)quinolin-6-yl)-4-(dimethylamino)but-2-enamide and its pharmaceutically acceptable salts and solvent compounds to treat or alleviate rare EGFR mutations in subjects To guide the symptoms of cancer.
  • the rare EGFR mutations of the present invention are mutations other than EGFR19 exon deletion and L858R mutation, including any one or a combination of EGFR mutants L861Q, G719X, and S768I, which can be sensitive mutations (non-drug resistant) Mutation) or resistance mutation.
  • EGFR mutation-mediated cancer in the present invention refers to a tumor characterized by EGFR gene mutations (including the specific mutations mentioned herein) that alter the biological activity of EGFR nucleic acid molecules or polypeptides.
  • Tumors mediated by EGFR mutations can appear in any tissue, including brain, blood, connective tissue, liver, mouth, muscle, spleen, stomach, testes and trachea.
  • Cancers mediated by EGFR mutations include non-small cell lung cancer (NSCLS), including one or more squamous cell carcinoma, adenocarcinoma, adenocarcinoma, bronchioloalveolar carcinoma (BAC), focally invasive BAC, and glands with BAC characteristics Cancer, and large cell carcinoma; nerve tumors, such as glioblastoma; pancreatic cancer; head and neck cancer (e.g., squamous cell carcinoma); breast cancer; colorectal cancer; epithelial cancer, including squamous cell carcinoma; ovarian cancer; Prostate cancer; adenocarcinoma; and including EGFR-mediated cancers.
  • NSCS non-small cell lung cancer
  • BAC bronchioloalveolar carcinoma
  • BAC bronchioloalveolar carcinoma
  • BAC focally invasive BAC
  • glands with BAC characteristics Cancer and large cell carcinoma
  • nerve tumors such as glioblastoma
  • pancreatic cancer pancreatic cancer
  • the EGFR mutation-mediated cancer of the present invention is further non-small cell lung cancer.
  • inhibiting the proliferation of cells expressing EGFR mutant strains refers to moderately slowing, stopping or reversing the growth rate of cells expressing EGFR in vitro or in vivo.
  • the growth rate is slowed by at least 10%, 20%, 30%, 50%, or even 70% .
  • the EGFR mutant strain can be any of the EGFR mutant strains described herein.
  • the pharmaceutically acceptable salts of the present invention include salts that are commonly used to form alkali metal salts and form addition salts of free acids or free bases approved by regulatory agencies. Salts are formed through ionic association, charge-charge interaction, covalent bonding, complexation, coordination, etc. As long as the salt is pharmaceutically acceptable, its nature is not critical.
  • the types of the pharmaceutically acceptable salts include, but are not limited to, acid addition salts formed by reacting the free base form of the compound with the following pharmaceutically acceptable acids: inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid Etc.; or organic acids, such as acetic acid, propionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, methanesulfonic acid, benzenesulfonic acid , Toluenesulfonic acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, etc.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid Etc.
  • organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid
  • the phosphoric acid of the compound of the present invention is prepared by mixing the free base of the desired compound in the desired solvent or combination of solvents with the desired stoichiometric amount of phosphoric acid at a desired temperature, usually under heating (depending on the boiling point of the solvent) salt.
  • the salt precipitates and crystallizes (ie if it has crystalline properties) after cooling (slowly or rapidly).
  • this document also includes half-salt, mono-salt, di-salt, tri-salt, and multiple-salt forms of the compounds of the present invention.
  • this document also includes the compound, its salt or hemihydrate, monohydrate, dihydrate, trihydrate, and polyhydrate forms.
  • the compound is hydrochloride, hydrobromide, sulfate, phosphate or metaphosphate, acetate, propionate, caproate, cyclopentane propionate, glycolic acid Salt, pyruvate, lactate, malonate, succinate, malate, maleate, fumarate, trifluoroacetate, tartrate, citrate, benzoate , 3-(4-Hydroxybenzoyl)benzoate, cinnamate, mandelate, methanesulfonate, ethanesulfonate, 1,2-ethanedisulfonate, 2-hydroxyethanesulfonic acid Salt, benzenesulfonate, toluenesulfonate, 2-naphthalenesulfonate, 4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylate, glucoheptonate, 4 '4-Methylene bis-(3-hydroxy-2-ene
  • the compound of the present invention (E)-N-(3-cyano-7-ethoxy-4-(3-ethynylphenylamino)quinolin-6-yl)-4-(dimethylamino) )
  • the but-2-enamide and its pharmaceutically acceptable salts and solvent compounds When the but-2-enamide and its pharmaceutically acceptable salts and solvent compounds are administered to a patient, they form a pharmaceutical composition with pharmaceutically acceptable excipients, and are formulated into a suitable pharmaceutical preparation form for administration.
  • the pharmaceutically acceptable excipients include carriers, excipients, binders, fillers, suspending agents, fragrances, sweeteners, disintegrants, dispersants, and surface agents. Active agents, lubricants, colorants, diluents, solubilizers, wetting agents, plasticizers, stabilizers, penetration enhancers, wetting agents, defoamers, antioxidants, preservatives, or one or more of them combination.
  • the pharmaceutical composition facilitates the administration of the compound to the organism.
  • a therapeutically effective amount of the compound described herein is administered in the form of a pharmaceutical composition to a mammal suffering from the disease, disorder, or condition to be treated.
  • the mammal is a human.
  • the therapeutically effective amount can vary widely depending on the severity of the disease, the age and relative health of the individual, the potency of the compound used, and other factors.
  • the compounds can be used alone or as a component of a mixture in combination with one or more therapeutic agents.
  • the pharmaceutical preparations of the present invention include, but are not limited to, aqueous liquid dispersions, self-emulsifying dispersions, solid solutions, liposome dispersions, aerosols, solid dosage forms, powders, immediate release formulations, controlled release formulations, disintegration ( fastmelt) formulations, tablets, capsules, pills, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed rapid release and controlled release formulations.
  • the amount of the compound administered by the patient and the dosage regimen for treating cancer with the compound and/or composition of the present invention depends on a variety of factors, including the age, weight, sex and medical condition of the individual, the type of disease, the severity of the disease, and the administration.
  • the pathway and frequency and the specific compound used. Therefore, the dosage regimen can vary widely, but can be determined routinely using standard methods.
  • a daily dose of about 0.01-500 mg/kg body weight advantageously a daily dose of about 0.01-50 mg/kg body weight, more advantageously a daily dose of about 0.01 to about 30 mg/kg body weight, more advantageously about 0.1
  • a daily dose of -10 mg/kg body weight and even more advantageously a daily dose of about 0.5-3 mg/kg body weight is appropriate and should be available for all methods of use disclosed herein.
  • the daily dose can be administered in 1 to 4 doses per day.
  • the effective therapeutic dose administered to the patient is 50-250 mg, preferably 100 mg once a day for 28 consecutive days.
  • Suitable routes for patient administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ocular, pulmonary, transmucosal, transdermal, vaginal, aural, nasal and topical administration.
  • parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injections.
  • the compound of the present invention (E)-N-(3-cyano-7-ethoxy-4-(3-ethynylphenylamino)quinolin-6-yl)-4-(dimethylamino) )
  • But-2-enamide and its pharmaceutically acceptable salts and solvent compounds have outstanding therapeutic effects on rare EGFR mutation-mediated cancers. Compared with general compounds, they are inferior to unusual EGFR mutation-mediated cancers. Cancers mediated by EGFR mutations are different, and the compounds of the present invention have better therapeutic effects than non-rare EGRR mutations such as T790M or L858R/T790M mutations.
  • the compound tested in this example is (E)-N-(3-cyano-7-ethoxy-4-(3-ethynylphenylamino)quinolin-6-yl)-4-(dimethyl Amino)but-2-enamide.
  • the IC50 of the test compound against protein kinase is set at 10 semi-logarithmic concentrations (1 ⁇ 10 -06 M to 3 ⁇ 10 -11 M), and the IC50 is determined in a single well.
  • test substance is two tubes of solid, and ProQinase is transferred to -20°C for subsequent use.
  • a storage solution of 1 ⁇ 10 -03 M test substance was prepared with 100% DMSO and further diluted to 1 ⁇ 10 -04 M/100% DMSO.
  • test substance was diluted semi-logarithmically into a 96-well plate with 100% DMSO and prepared from 1 ⁇ 10 -04 M to 3 ⁇ 10 -09 M. Before use, the test substance is diluted 1:10 with water to obtain 1 ⁇ 10 -05 M to 3 ⁇ 10 -10 M test substance samples containing 10% DMSO.
  • Protein Kinase Test by Radiometry Determine the activity of 8 protein kinases. All experiments were performed in a 96-well plate of Perkin Elmer (Boston, MA, USA) with a reaction volume of 50 ⁇ l. Reagents and samples are added in 4 steps:
  • test substance containing 10% DMSO
  • the substrate is Poly(Glu, Tyr) 4:1, code name SIG_20K5903.
  • All experiments include 70mM HEPES-NaOH pH7.5 , 3mM MgCl 2 , 3mM MnC, 3 ⁇ M sodium orthovanadate, 1.2mM DTT, ATP (undefined, related to the apparent ATP-Km of each enzyme, see Table 1), [ ⁇ -33P]-ATP (approximately 8 ⁇ 1005 cpm per well), protein kinase (indefinite, see Table 1), and substrate (indefinite, see Table 1).
  • the blank control set up 3 reaction wells without adding enzyme, and take the median of the cpm value of the 3 reaction wells. This value reflects the non-specific binding of radioactivity in the absence of protein kinase or substrate.
  • set 3 reaction wells without adding test substance and take the median of the cpm value of 3 reaction wells as a negative control, that is, the enzyme activity without any inhibitor.
  • the difference between the negative control and the blank is the 100% activity of each enzyme.
  • residual enzyme activity (%) 100 ⁇ [(test substance cpm value-blank control)/(negative control-blank control)].
  • test substance is set to 10 concentrations to act on each enzyme, so the data analysis is based on these 10 residual enzyme activity values.
  • Use Prism5.04 (Graphpad, San Diego, California, USA www.graphpad.com), fix the maximum value of 100%, the minimum value of 0%, and perform S-curve fitting to calculate IC50.
  • Table 2 lists the IC50 values of the tested compounds acting on 8 kinases.
  • Example 2 An exploratory clinical research trial for the treatment of locally advanced or metastatic non-small cell lung cancer
  • the patient's EGFR has one or more of L861Q, G719X, and S768I mutations, and does not have T790M mutation, exon 19 deletion mutation, exon 20 insertion mutation, or L858R mutation.
  • the ECOG physical strength score is 0, 1, or 2.
  • Total bilirubin ⁇ 1.5 ⁇ upper limit of normal (ULN), alanine aminotransferase (ALT) ⁇ 2.5 ⁇ ULN, aspartate aminotransferase (AST) ⁇ 2.5 ⁇ ULN (total bilirubin in patients with liver metastasis ⁇ 3.0 ⁇ ULN , ALT ⁇ 5.0 ⁇ ULN, AST ⁇ 5.0 ⁇ ULN);
  • Eligible patients male and female with fertility must agree to use reliable contraceptive methods (hormonal or barrier method or abstinence) during the trial period and at least 90 days after the last medication; female patients of childbearing age within 7 days before enrollment
  • the blood human chorionic gonadotropin (HCG) pregnancy test must be negative; male patients cannot do sperm donation within 90 days after the first dose to the last dose.
  • EGFR-TKI epidermal growth factor receptor tyrosine kinase inhibitor
  • CCAE chronic chronic gastrointestinal dysfunction
  • malabsorption syndrome or any other conditions that affect the absorption of the gastrointestinal tract (for example: peptic ulcer, intestinal tract) Obstruction, irritable bowel syndrome, Crohn’s disease, gastroesophageal reflux disease, etc.).
  • HIV human immunodeficiency virus
  • CT/MRI computed tomography/magnetic resonance imaging
  • a history of severe cardiovascular disease [New York College of Cardiology (NYHA) Heart Function Grade III or IV], including but not limited to ventricular arrhythmia requiring clinical intervention; within 6 months before enrollment Acute coronary syndrome, congestive heart failure, stroke, or other cardiovascular events of grade III and above; at the time of screening, NYHA cardiac function grade ⁇ grade II or left ventricular ejection fraction (LVEF) ⁇ 50%.
  • NYHA New York College of Cardiology
  • Table 3 The sum of the longest diameters of the target lesions at the end of the treatment cycle
  • Table 4 The sum of the shortest diameters of the target lesions in the treatment cycle

Abstract

一种取代丁烯酰胺的应用，具体为(E)-N-(3-氰基-7-乙氧基-4-(3-乙炔基苯基氨基)喹啉-6-基)-4-(二甲基氨基)丁-2-烯酰胺及其药学上可接受的盐、溶剂化合物在制备治疗罕见EGFR突变介导的癌症药物中的应用。

Description

一种取代丁烯酰胺的应用 技术领域
本申请涉及医药技术领域，具体涉及一种取代丁烯酰胺的应用。
背景技术
非小细胞肺癌(non-smallcelllungcancer，NSCLC)是一种严重威胁人类健康的恶性肿瘤，尽管手术和化疗技术不断提高，但患者的预后仍较差，5年存活率小于20％。目前，以人表皮生长因子受体(epitheliumgrowthfactorrecptor，EGFR)为靶点的分子靶向治疗已成为治疗NSCLC最重要的方式。
EGFR是原癌基因C-erbB-1的表达产物，基因定位于第7号染色体上，属于跨膜受体酪氨酸激酶。EGFR与其配体结合后，能激活下游信号通路，调节肿瘤细胞的增殖、分化、血管生成及凋亡抑制，从而调控一系列肿瘤生物学行为。
目前临床上使用的针对EGFR的靶向药物是EGFR酪氨酸激酶抑制剂(EGFR-TKI)，EGFR-TKI通过抑制EGFR自身磷酸化而阻断EGFR信号传导通路，从而抑制肿瘤细胞增殖分化，实现靶向治疗。
EGFR突变可以发生在EGFR序列的任何部位。通常，EGFR突变株源自激酶结构域(即EGFR序列中的外显子18-24)或胞外结构域(即EGFR序列中的外显子2-16)的突变。外显子18中的一个或多个点突变包括L688P、V689M、P694L/S、N700D、L703V、E709K/Q/A/G/V、I715S、L718P、G719C/A/S/R或S720P/F。外显子19中的缺失包括delG719、delE746_E749、delE746_A750、delE746_A750insRP、delE746_A750insQP、delE746_T751、delE746_T751insA/I/V、delE746_T751insVA、delE746_S752、delE746_S752insA/V/D、delE746_P53insLS、delL747_E749、delL747_A750、delL747_A750insP、delL747_T751、delL747_T751insP/S/Q、delL747_T751insPI、delL747_S752、delL747_S752insQ、delL747_P753、delL747_P753insS/Q、delL747_L754insSR、delE749_A750、delE749_A750insRP、delE749_T751、delT751_I759、delT751_I759insS/N或delS752_I759。外显子19中的复制包括K739_I44dupKIPVAI。外显子19中的点突变包括L730F、W731Stop、P733L、G735S、V742A、E746V/K、A750P、T751I、S752Y、P753S、A754P或D761Y。外显子20中的框内插入包括D761_E762insEAFQ、A767_S768insTLA、V769_D770insY、V769_D770insCV、V769_D770insASV、D770_N771insD/G、D770_N771insNPG、D770_N771insSVQ、P772_H773insN/V、P772_H773insYNP或V774_C775insHV。外显子20中的缺失包括 delM766_A767、delM766_A767insAI、delA767_V769、delD770或dellP772_H773insNP。外显子20中的复制包括S768_D770dupSVD、A767_V769dupASV或H773dupH。外显子20中的点突变包括D761N、A763V、V765A/M、S768I、V769L/M、S768I、P772R、N771T、H773R/Y/L、V774M、R776G/H/C、G779S/F、T783A、T784F、L792P、L798H/F、T790M、R803W、K806E或L814P)。外显子21中的点突变包括G810S、N826S、L833V、H835L、L838V、A839T、K846R、T847I、H850N、V851I/A、I853T、L858M/R、A859T、L861Q/R、G863D、A864T、E866K或G873E。
EGFR-TKI的疗效与EGFR基因突变状况密切相关，EGFR基因突变主要集中在外显子18～21上，包括敏感突变和耐药突变。
在中国肺癌患者中，EGFR突变率占30-50％，其中19和21号(L858R,L861I)外显子突变率占总突变率的90％左右，18号外显子突变占总突变率的5％左右，20号外显子上T790M突变占突变率的5％左右。其中，19号外显子缺失和L858R突变之外的称之为罕见突变，如L861Q，G719X，S768I等。
CN102625797A公开了(E)-N-(3-氰基-7-乙氧基-4-(3-乙炔基苯基氨基)喹啉-6-基)-4-(二甲基氨基)丁-2-烯酰胺对EGFR常见突变体如EGFR突变体L858R/T790M、EGFR突变体E746-A750的作用，但是未记载对罕见突变如L861Q，G719X，S768I等的作用。
明确需要抑制具有罕见EGFR突变(如L861Q、G719X、S768I)的细胞的新方法，治疗与这种突变相关癌症的新疗法将具有深远的利益。
发明内容
本发明的目的是提供一种取代丁烯酰胺的应用，具体提供化合物(E)-N-(3-氰基-7-乙氧基-4-(3-乙炔基苯基氨基)喹啉-6-基)-4-(二甲基氨基)丁-2-烯酰胺及其药学上可接受的盐、溶剂化合物的新的应用。
本发明所述化合物(E)-N-(3-氰基-7-乙氧基-4-(3-乙炔基苯基氨基)喹啉-6-基)-4-(二甲基氨基)丁-2-烯酰胺及其药学上可接受的盐、溶剂化合物具有良好的对罕见EGFR突变如L861Q、G719X、S768I介导的癌症的抑制活性。
所述化合物(E)-N-(3-氰基-7-乙氧基-4-(3-乙炔基苯基氨基)喹啉-6-基)-4-(二甲基氨基)丁-2-烯酰胺结构式如下式所示：
Figure PCTCN2020131638-appb-000001
本发明所述化合物(E)-N-(3-氰基-7-乙氧基-4-(3-乙炔基苯基氨基)喹啉-6-基)-4-(二甲基氨基)丁-2-烯酰胺及其药学上可接受的盐、溶剂化合物可以抑制表达EGFR突变株的细胞增殖。
进一步的，本发明提供(E)-N-(3-氰基-7-乙氧基-4-(3-乙炔基苯基氨基)喹啉-6-基)-4-(二甲基氨基)丁-2-烯酰胺及其药学上可接受的盐、溶剂化合物在制备治疗罕见EGFR突变介导的癌症药物中的应用。
本发明的另一方面是提供一种用于通过向有需要的受试者投予治疗有效量的(E)-N-(3-氰基-7-乙氧基-4-(3-乙炔基苯基氨基)喹啉-6-基)-4-(二甲基氨基)丁-2-烯酰胺及其药学上可接受的盐、溶剂化合物来治疗或缓解受试者的罕见EGFR突变介导的癌症的症状的方法。
本发明所述罕见EGFR突变为EGFR19外显子缺失和L858R突变之外的突变，包括EGFR突变体L861Q、G719X、S768I中的任意一种或几种的组合，可以为敏感突变(非耐药性突变)或耐药突变。
本发明所述“EGFR突变介导的癌症”是指以改变EGFR核酸分子或多肽的生物活性的EGFR基因突变(包括本文提到的具体突变)为特征的肿瘤。EGFR突变介导的肿瘤可出现在任何组织，包括脑、血液、结缔组织、肝、口、肌肉、脾、胃、睾丸和气管。EGFR突变介导的癌症包括非小细胞肺癌(NSCLS)，包括一个或多个鳞状细胞癌、腺癌、腺癌、细支气管肺泡癌(BAC)、局灶侵入性BAC，具有BAC特征的腺癌，以及大细胞癌；神经肿瘤，如胶质母细胞瘤；胰腺癌；头颈癌症(例如，鳞状细胞癌)；乳腺癌；结肠直肠癌；上皮癌，包括鳞状细胞癌；卵巢癌；前列腺癌；腺癌；以及包括EGFR介导的癌症。
本发明所述的EGFR突变介导的癌症进一步的为非小细胞肺癌。
本发明所述“抑制表达EGFR突变株的细胞增殖”是指适度地减缓、停止或逆转表达EGFR的细胞在体外或在体内的生长速率。理想的是，当使用合适的测定细胞生长速率的方法进行测定时(例如，本文所述的细胞生长测定法)，生长速率至少减慢10％、20％、30％、50％或甚至70％。EGFR突变株可以是本文所述的任何EGFR突变株。
本发明所述药学上可接受的盐包括经管理机构批准的常用于形成碱金属盐和形成游离酸或游离碱的加成盐的盐。盐是通过离子缔合、电荷-电荷相互作用、共价键合、络合、配位等作用形成的。只要盐是药学上可接受的，则其性质不是关键性的。
所述药学可接受的盐的类型包括但不限于通过使所述化合物的游离碱形式与以下药学可接受的酸反应形成的酸加成盐：无机酸，例如盐酸、氢溴酸、硫酸、磷酸等；或有机酸，例如乙酸、丙酸、乙醇酸、丙酮酸、乳酸、丙二酸、琥珀酸、苹果酸、马来酸、富马酸、酒石酸、柠檬酸、甲磺酸、苯磺酸、甲苯磺酸、葡糖酸、谷氨酸、羟基萘甲酸、水杨酸等。
这样的盐的其他实例可参见Berge等人，J.Pharm.Sci，66，1(1977)。在一些实施方案中， 使用常规方法形成盐。例如，通过在期望的温度下，通常在加热下(取决于溶剂的沸点)将期望的溶剂或溶剂组合中的期望的化合物游离碱与期望的化学计算量的磷酸混合来制备本发明化合物的磷酸盐。在一实施方案中，在(缓慢或迅速)冷却后所述盐沉淀并结晶(即如果具有结晶性质)。另外，本文还包括本发明化合物的半盐、单盐、二盐、三盐和多盐形式。相似地，本文还包括所述化合物、其盐或半水合物、一水合物、二水合物、三水合物和多水合物形式。
在一些实施方案中，所述化合物是盐酸盐、氢溴酸盐、硫酸盐、磷酸盐或偏磷酸盐、乙酸盐、丙酸盐、己酸盐、环戊烷丙酸盐、乙醇酸盐、丙酮酸盐、乳酸盐、丙二酸盐、琥珀酸盐、苹果酸盐、马来酸盐、富马酸盐、三氟乙酸盐、酒石酸盐、柠檬酸盐、苯甲酸盐、3-(4-羟基苯甲酰基)苯甲酸盐、肉桂酸盐、扁桃酸盐、甲磺酸盐、乙磺酸盐、1，2-乙二磺酸盐、2-羟基乙磺酸盐、苯磺酸盐、甲苯磺酸盐、2-萘磺酸盐、4-甲基二环-[2.2.2]辛-2-烯-1-羧酸盐、葡庚糖酸盐、4′4-亚甲基双-(3-羟基-2-烯-1-羧酸)盐、3-苯基丙酸盐、三甲基乙酸盐、叔丁基乙酸盐、月桂基硫酸盐、葡糖酸盐、谷氨酸盐、羟基萘甲酸盐、水杨酸盐、硬脂酸盐、粘康酸盐、丁酸盐、苯基乙酸盐、苯基丁酸盐、丙戊酸盐等。在优选的实施方案中，化合物是盐酸盐、苯磺酸盐、甲磺酸盐、马来酸盐，或其水合物，例如一水合物。
本发明所述的化合物(E)-N-(3-氰基-7-乙氧基-4-(3-乙炔基苯基氨基)喹啉-6-基)-4-(二甲基氨基)丁-2-烯酰胺及其药学上可接受的盐、溶剂化合物在给予患者时，与药学上可接受的辅料形成药物组合物，并制成合适的药物制剂形式进行给药。
本发明使用的药物组合物中，所述药学上可接受的辅料包括载体、赋形剂、粘合剂、填充剂、助悬剂、芳香剂、甜味剂、崩解剂、分散剂、表面活性剂、润滑剂、着色剂、稀释剂、增溶剂、湿润剂、增塑剂、稳定剂、渗透促进剂、润湿剂、消泡剂、抗氧化剂、防腐剂或者一种或多种它们的组合。所述药物组合物有助于将所述化合物给药至有机体。在实施本文提供的治疗或使用方法时，以药物组合物的形式将治疗有效量的本文所述化合物给药至患有待治疗的疾病、病症或病况的哺乳动物。在一些实施方案中，所述哺乳动物是人。治疗有效量可随疾病的严重性、个体的年龄和相对健康状况、所用化合物的效力和其他因素而大幅变化。所述化合物可单独使用或者作为混合物的组分与一种或多种治疗剂组合使用。
本发明所述药物制剂包括但不限于水性液体分散体、自乳化分散体、固体溶液剂、脂质体分散体、气雾剂、固体剂型、散剂、速释制剂、控释制剂、崩解(fastmelt)制剂、片剂、胶囊剂、丸剂、延迟释放制剂、延长释放制剂、脉冲释放制剂、多颗粒制剂以及混合型速释和控释制剂。
患者给药化合物的量和用本发明的化合物和/或组合物治疗癌症的剂量方案取决于多种因素，包括个体的年龄、体重、性别和医疗状况，疾病类型，疾病的严重性，给药途径和频 率以及所使用的具体化合物。因此，剂量方案可大幅度变化，但是能够使用标准方法常规性地确定。在一些实施方案中，约0.01-500mg/kg体重的日剂量、有利地约0.01-50mg/kg体重的日剂量、更有利地约0.01-约30mg/kg体重的日剂量、更有利地约0.1-10mg/kg体重的日剂量并且甚至更有利地约0.5-3mg/kg体重的日剂量是适当的，并且应对于本文公开的所有使用方法是可用的。该日剂量可以每日1至4次剂量给药。在一些实施方案中，患者给药有效治疗量为50-250mg，优选每日一次100mg，连续给药28天。
患者给药适合的给药途径包括但不限于口服、静脉内、直肠、气雾剂、肠胃外、眼、肺、经粘膜、经皮、阴道、耳、鼻和局部给药。另外，仅举例而言，肠胃外递送包括肌内、皮下、静脉内、髓内注射以及鞘内、直接心室内、腹膜内、淋巴管内和鼻内注射。
本发明所述的化合物(E)-N-(3-氰基-7-乙氧基-4-(3-乙炔基苯基氨基)喹啉-6-基)-4-(二甲基氨基)丁-2-烯酰胺及其药学上可接受的盐、溶剂化合物对罕见EGFR突变介导的癌症具有突出的治疗效果，与一般化合物对罕见EGFR突变介导的癌症劣于非一般的非罕见EGFR突变介导的癌症不同，本发明所述化合物相对于T790M或L858R/T790M突变等非罕见EGRR突变而言，具有更良好的治疗效果。
具体实施方式
以下结合实施例用于进一步描述本发明，但这些实施例并非限制着本发明的范围。
本申请实施例涉及的(E)-N-(3-氰基-7-乙氧基-4-(3-乙炔基苯基氨基)喹啉-6-基)-4-(二甲基氨基)丁-2-烯酰胺按照WO2010151710所述方法制备得到，(E)-N-(3-氰基-7-乙氧基-4-(3-乙炔基苯基氨基)喹啉-6-基)-4-(二甲基氨基)丁-2-烯酰胺马来酸盐一水合物按CN104513200A所述方法制备得到，其亦命名为(E)-N-{4-[(3-乙炔基苯氨基)-3-氰基-7-乙氧基-6-喹啉基]}-4-(二甲基氨基)-2-丁烯酰胺的马来酸盐。
实施例1 蛋白激酶的IC50测定
本实施例测试的化合物为(E)-N-(3-氰基-7-乙氧基-4-(3-乙炔基苯基氨基)喹啉-6-基)-4-(二甲基氨基)丁-2-烯酰胺。
1.实验设计
测试化合物对蛋白激酶的IC50，受试物设10个半对数浓度(1×10 -06M到3×10 -11M)，单孔，测定IC50。
2.受试物
受试物为两管固体，ProQinase转移至-20℃待后续使用。
试验前，用100％DMSO配制成1×10 -03M受试物的储存液并进一步稀释至1×10 -04M/100％DMSO。
用100％DMSO将受试物半对数稀释到96孔板，配制成从1×10 -04M到3×10 -09M。使用前，受试物与水1:10稀释，获得1×10 -05M到3×10 -10M的受试物样品,含10％DMSO。
每个浓度加5μl到试验中(见第3部分蛋白激酶试验)，试验终体积为50μl。受试物以1×10 -06M到3×10 -11M的浓度测定。所有反应孔中的DMSO终浓度都为1％。
3.蛋白激酶试验
用放射测定的蛋白激酶试验(
Figure PCTCN2020131638-appb-000002
活性测定法)测定8种蛋白激酶的活性。所有试验用50μl反应体积，在Perkin Elmer(Boston,MA,USA)的96孔板内完成。试剂、样品等分4步加入：
10μl非放射的ATP水溶液；
25μl缓冲液/[γ -33P]-ATP混合液；
5μl受试物，含10％DMSO；
10μl酶/底物混合物。
底物为Poly(Glu,Tyr)4:1,代号SIG_20K5903。
所有试验包括70mM HEPES-NaOH pH7.5，3mM MgCl 2，3mM MnC，3μM正钒酸钠盐，1.2mM DTT，ATP(不定，与各个酶的表观ATP-Km有关，见表1)，[γ-33P]-ATP(每孔约8×1005cpm)，蛋白激酶(不定，见表1)，和底物(不定，见表1)。
试验中所用酶和底物的浓度见表1：
表1 所用酶和底物的浓度
Figure PCTCN2020131638-appb-000003
反应体系于39℃孵育60分钟。用50μl 2％(v/v)H 3PO 4终止反应，板子用200μl0.9％(w/v)NaCl洗两次。微孔板闪烁计数仪(Microbeta,Wallac)测定 33Pi(以"cpm"计)的酶活依赖性转移。
所有试验都用BeckmanCoulterBiomek 2000/SL机器人完成。
4.数据分析
空白对照设3个反应孔，不加酶，取3个反应孔的cpm值中位数。这个值反映了在没有蛋白激酶、底物时，放射性的非特异性结合。另外，设3个反应孔，不加受试物，取3个反应孔的cpm值中位数，为阴性对照，即没有任何抑制剂下的酶活力。阴性对照与空白差值即为每个酶的100％活力。
与阴性对照扣除空白值一样，对应的10个受试物的值也应减去空白值。每个孔的残留酶活力按下面的公式计算：残留酶活(％)＝100×[(受试物cpm值–空白对照)/(阴性对照–空白对照)]。
每个受试物都设了10个浓度作用于每个酶，因此数据分析基于这10个残留酶活值。用Prism5.04(Graphpad,San Diego,California,USA www.graphpad.com)，固定最大值100％，最小值0％，进行S曲线拟合计算IC50。
5.结果
表2中列出了被测化合物作用于8个激酶的IC50值。
表2 被测化合物作用于8个激酶的IC50值
Figure PCTCN2020131638-appb-000004
以上数据表明，被测试化合物对罕见突变的抑制效果优于一般的非罕见突变抑制效果。
实施例2 治疗局部晚期或转移性非小细胞肺癌的探索性临床研究试验
一、受试者选择标准
1、入选标准：
(1)年龄18～75(含18、75)周岁，性别不限。
(2)经病理组织学和/或细胞学确认的局部晚期或转移性NSCLC患者。
(3)患者的EGFR具有L861Q、G719X、S768I突变中的一种或几种，且不具有T790M突变、19号外显子缺失突变、20号外显子插入突变、L858R突变。
(4)ECOG体力评分为0、1或2分。
(5)预期生存时间>3个月。
(6)根据实体瘤疗效评价标准(RECIST)1.1版，至少有一个可评估的肿瘤病灶。
(7)有足够的血液系统功能、肝功能、肾功能和凝血功能：
中性粒细胞绝对计数≥1.5×109/L，血小板计数≥90×109/L，血红蛋白≥90g/L；
总胆红素≤1.5×正常值上限(ULN)，丙氨酸转氨酶(ALT)≤2.5×ULN，天冬氨酸转氨酶(AST)≤2.5×ULN(肝转移患者总胆红素≤3.0×ULN，ALT≤5.0×ULN，AST≤5.0×ULN)；
肌酐≤1.0×ULN，或者肌酐清除率≥60mL/min(采用Cockcroft-Gault方法)；
国际标准化比值(INR)≤1.5。
(8)有生育能力的合格患者(男性和女性)必须同意在试验期间和末次用药后至少90天内使用可靠的避孕方法(激素或屏障法或禁欲)；育龄期的女性患者在入选前7天内的血人绒毛膜促性腺激素(HCG)妊娠检查必须为阴性；男性患者在首次给药至末次给药后90天内不能进行精子捐献。
(9)所有患者必须在开始接受任何本试验规定的检查之前对本研究知情，并自愿签署经伦理委员会批准的书面知情同意书(ICF)。
2、排除标准：
(1)入组前接受过任何表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKI)抗肿瘤治疗。
(2)既往接受过化疗、抗血管生成等系统性抗肿瘤治疗患者，需要4周及以上洗脱期；既往接受过抗PD-1/PD-L1等免疫治疗，未出现过免疫性肺炎的患者，需要4周及以上洗脱期；既往接受过以缓解症状为目的对非靶病灶的放疗、抗肿瘤中成药的患者，需2周及以上洗脱期。
(3)入组前4周内接受过主要脏器外科手术(不包括穿刺活检)或出现过显著外伤。
(4)筛选时，既往任何治疗的不良反应(ADR)尚未恢复到不良事件通用术语标准(CTCAE)5.0等级评价≤1级(脱发除外)。
(5)无法口服药物，有严重(CTCAE 5.0等级评价≥3级)的慢性胃肠功能紊乱，存在吸收障碍综合征或其他任何对胃肠道吸收有影响的状况(例如：消化性溃疡、肠梗阻、肠易激综合征、克罗恩病、胃食管反流病等)。
(6)有免疫缺陷，包括但不限于人类免疫缺陷病毒(HIV)抗体检测(酶联免疫法或Western斑点法)阳性，有活动性风湿免疫性疾病。
(7)存在不稳定的具有临床症状的中枢神经系统转移或脑膜转移，或有其他证据表明患者中枢神经系统转移或脑膜转移灶尚未控制，经研究者判断不适合入组；临床症状怀疑存在脑或者软脑膜病变的患者需计算机断层扫描/核磁共振成像(CT/MRI)检查予以排除。
(8)有严重(CTCAE 5.0等级评价≥3级)的大疱性或剥脱性皮肤病病史。
(9)筛选时，有未控制的活动性感染【如梅毒、HIV、乙型肝炎病毒(HBsAg阳性，HBV-DNA>1000cps/ml且AST/ALT>2.0xULN)或丙型肝炎病毒(HCV)感染】。
(10)有严重【美国纽约心脏病学会(NYHA)心脏功能分级为Ⅲ级或IV级】的心血管疾病史，包括但不限于需要临床干预的室性心律失常；入组前6个月内有急性冠脉综合征、充血性心力衰竭、脑卒中或其他III级及以上心血管事件；筛选时，NYHA心功能分级≥II级或左室射血分数(LVEF)<50％。
(11)有其它严重(CTCAE 5.0等级评价≥3级)的系统性疾病史，经研究者判断不适合参加临床试验。
(12)入组前4周内参与过其它临床试验。
(13)已知有酒精或药物依赖。
(14)精神障碍类疾病患者或研究者认为依从性差者不适合参加研究。
(15)妊娠期或哺乳期女性。
(16)已知对试验药物的活性成分或辅料过敏。
(17)需要长期服用肾上腺类固醇激素治疗(相当于泼尼松龙每日剂量≥20mg，剂量换算表详见附录四)。
(18)既往5年内或同时患有其他恶性肿瘤(已治愈的皮肤基底细胞癌和宫颈原位癌除外；乳腺癌根治术后＞3年无复发者除外)。
二、给药方法与剂量
(E)-N-(3-氰基-7-乙氧基-4-(3-乙炔基苯基氨基)喹啉-6-基)-4-(二甲基氨基)丁-2-烯酰胺马来酸盐一水合物胶囊(参考中国专利申请201911180660.1)，餐前至少1小时或餐后2小时口服；每日一次100mg，疗程为28天。自给药开始每四周为一个周期。
三、治疗效果
表3 治疗周期末靶病灶最长直径之和
Figure PCTCN2020131638-appb-000005
Figure PCTCN2020131638-appb-000006
表4 治疗周期中靶病灶最短直径之和
Figure PCTCN2020131638-appb-000007
PFS：无进展生存期
以上治疗结果表明，具有罕见EGFR突变介导的癌症患者，治疗后均表现出良好的治疗效果。

Claims (10)

  1. (E)-N-(3-氰基-7-乙氧基-4-(3-乙炔基苯基氨基)喹啉-6-基)-4-(二甲基氨基)丁-2-烯酰胺及其药学上可接受的盐、溶剂化合物在制备治疗罕见EGFR突变介导的癌症药物中的应用。
  2. 如权利要求1所述的应用，其特征在于药学上可接受的盐为盐酸盐、苯磺酸盐、甲磺酸盐、马来酸盐。
  3. 如权利要求1所述的应用，其特征在于所述药学上可接受的盐进一步为水合物，优选为半水合物、一水合物。
  4. 如权利要求1所述的应用，其特征在于所述罕见EGFR突变包括但不限于EGFR突变体L861Q、G719X、S768I中的任意一种或几种的组合。
  5. 如权利要求1所述的应用，其特征在于所述癌症为非小细胞肺癌。
  6. 一种罕见EGFR突变介导的癌症的治疗方法，其特征在于通过向有需要的受试者投予治疗有效量的(E)-N-(3-氰基-7-乙氧基-4-(3-乙炔基苯基氨基)喹啉-6-基)-4-(二甲基氨基)丁-2-烯酰胺及其药学上可接受的盐、溶剂化合物。
  7. 如权利要求6所述的治疗方法，其特征在于所述治疗有效量为每日50-250mg，优选每日一次100mg。
  8. 如权利要求6所述的治疗方法，其特征在于所述治疗有效量为0.01-500mg/kg、优选为0.01-50mg/kg、进一步为0.01-30mg/kg、更进一步为0.1-10mg/kg或0.5-3mg/kg体重的日剂量。
  9. 如权利要求6所述的治疗方法，其特征在于所述罕见EGFR突变包括但不限于EGFR突变体L861Q、G719X和/或S768I。
  10. 如权利要求6所述的治疗方法，其特征在于所述药学上可接受的盐为盐酸盐、苯磺酸盐、甲磺酸盐、马来酸盐，进一步优选为该盐的半水合物、一水合物。
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