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WO2016150340A1 - 喹唑啉衍生物的盐及其制备方法 - Google Patents

喹唑啉衍生物的盐及其制备方法 Download PDF

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Publication number
WO2016150340A1
WO2016150340A1 PCT/CN2016/076693 CN2016076693W WO2016150340A1 WO 2016150340 A1 WO2016150340 A1 WO 2016150340A1 CN 2016076693 W CN2016076693 W CN 2016076693W WO 2016150340 A1 WO2016150340 A1 WO 2016150340A1
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Prior art keywords
compound
formula
maleate salt
maleic acid
pharmaceutical composition
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PCT/CN2016/076693
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English (en)
French (fr)
Inventor
张喜全
汤松
丰巍伟
田心
陈智林
顾红梅
徐宏江
刘飞
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Centaurus Biopharma Co Ltd
Chia Tai Tianqing Pharmaceutical Group Co Ltd
Lianyungang Runzhong Pharmaceutical Co Ltd
Original Assignee
Centaurus Biopharma Co Ltd
Chia Tai Tianqing Pharmaceutical Group Co Ltd
Lianyungang Runzhong Pharmaceutical Co Ltd
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Application filed by Centaurus Biopharma Co Ltd, Chia Tai Tianqing Pharmaceutical Group Co Ltd, Lianyungang Runzhong Pharmaceutical Co Ltd filed Critical Centaurus Biopharma Co Ltd
Priority to ES16767717T priority Critical patent/ES2775614T3/es
Priority to JP2017567522A priority patent/JP6704422B2/ja
Priority to HK18103795.1A priority patent/HK1244278B/zh
Priority to US15/560,099 priority patent/US10231973B2/en
Priority to RU2017132330A priority patent/RU2720810C2/ru
Priority to EP16767717.8A priority patent/EP3272746B1/en
Priority to CN201680015924.6A priority patent/CN107406430B/zh
Publication of WO2016150340A1 publication Critical patent/WO2016150340A1/zh
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
    • C07C57/13—Dicarboxylic acids
    • C07C57/145—Maleic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members 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
    • C07D211/40—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/94—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the present application belongs to the field of medicinal chemistry, and in particular relates to a salt of a quinazoline derivative, a process for the preparation thereof, and a medical use thereof.
  • Epidermal growth factor receptor is a tyrosine kinase receptor that is widely distributed on the surface of mammalian epithelial cells, fibroblasts, glial cells, keratinocytes and the like.
  • the EGFR signaling pathway plays an important role in physiological processes such as cell growth, proliferation and differentiation. Loss of protein tyrosine kinase function such as EGFR or abnormal activity or cell localization of key factors in related signaling pathways can cause tumor, diabetes, immunodeficiency and cardiovascular disease.
  • the compound of formula I is a selective epidermal growth factor receptor inhibitor that blocks the interaction with ATP, inhibits tyrosine phosphorylation and downstream by competitively binding to the phosphorylation site of the intracellular tyrosine kinase.
  • the series of signaling which in turn inhibits the growth of tumor cells, can be used to treat a variety of malignancies such as non-small cell lung cancer and breast cancer. See Chinese Patent Application No. 201310452885.4, which is incorporated herein in its entirety by reference.
  • the application provides a maleate salt of a compound of formula I,
  • the molar ratio of maleic acid to the compound of formula I depends on the amount of maleic acid used in preparing the salt.
  • the maleate salt may have a molar ratio of the compound of formula I to maleic acid of 1:0.5-4.
  • the present application provides a process for the preparation of a maleate salt of a compound of formula I, comprising: (1) preparing a solution of a compound of formula I; (2) a solution of said compound of formula I obtained from step (1) Contacting with maleic acid; and (3) spray drying the reaction mixture from step (2) to provide the maleate salt of the compound of formula I.
  • the application provides a pharmaceutical composition
  • a pharmaceutical composition comprising the maleate salt of the compound of Formula I and a pharmaceutically acceptable carrier, excipient, diluent, and/or vehicle.
  • the application provides the use of a maleate salt of a compound of formula I or a pharmaceutical composition thereof for the manufacture of a medicament for the treatment of a tumor.
  • the application provides a method for treating a tumor comprising administering to a subject in need thereof a maleate salt of a compound of formula I or a pharmaceutical composition thereof.
  • the application provides a maleate salt of a compound of formula I or a pharmaceutical composition thereof for use in treating a tumor.
  • references to “an embodiment” or “an embodiment” or “in another embodiment” or “in certain embodiments” throughout this specification are meant to be included in the at least one embodiment.
  • the appearances of the phrase “in one embodiment” or “in an embodiment” or “in another embodiment” or “in some embodiments” are not necessarily all referring to the same embodiment.
  • the particular elements, structures, or characteristics may be combined in any suitable manner in one or more embodiments.
  • the application provides a maleate salt of a compound of formula I,
  • the molar ratio of maleic acid to the compound of formula I depends on the amount of maleic acid used in preparing the salt.
  • the molar ratio of the compound of formula I to maleic acid in the maleate salt can be from 1:0.5-4.
  • the molar ratio of the compound of formula I to maleic acid in the maleate salt is 1:1. In other embodiments of the present application, the molar ratio of the compound of formula I to maleic acid in the maleate salt is 1:2.
  • the present application provides a process for the preparation of a maleate salt of a compound of formula I, comprising: (1) preparing a solution of a compound of formula I; (2) a solution of said compound of formula I obtained from step (1) Mixing with maleic acid; and (3) spray drying the reaction mixture from step (2) to provide the maleate salt of the compound of formula I.
  • the molar ratio of the compound of formula I to maleic acid in the preparation process is from 1:1 to 20, preferably from 1:1 to 15, most preferably from 1:1 to 10.
  • the compound of the formula I can be dissolved in an organic solvent to prepare a solution of the compound of the formula I.
  • the organic solvent includes all organic solvents capable of dissolving the compound of formula I, such as DMF.
  • the solution of the compound of the formula I obtained in the step (1) may be mixed with a solution of maleic acid or maleic acid, and if necessary, the reaction mixture may be heated to a suitable temperature.
  • a suitable temperature For example, 60-100 ° C, preferably 80 ° C.
  • the maleic acid solution is an organic solution of maleic acid obtained by mixing maleic acid with an organic solvent.
  • the organic solvent is, for example, DMF.
  • a solvent that is miscible with the organic solvent in steps (1) and/or (2), such as water, may be added prior to spray drying.
  • the application provides a pharmaceutical composition
  • a pharmaceutical composition comprising a maleate salt of a compound of formula I and a pharmaceutically acceptable carrier, excipient, diluent, and/or vehicle.
  • pharmaceutical composition refers to a compound, excipient, diluent, and/or medium that is generally accepted in the pharmaceutical arts for delivery of a biologically active compound to an organism (eg, a human). Preparation.
  • the purpose of the pharmaceutical composition is to facilitate administration of the compounds of the present application to an organism.
  • pharmaceutically acceptable carrier refers to those carriers and diluents which do not significantly irritate the organism and which do not impair the biological activity and properties of the active compound.
  • “Pharmaceutically acceptable excipient and/or vehicle” refers to an inert substance that is administered with the active ingredient and which facilitates delivery of the active ingredient to the organism.
  • “Pharmaceutically acceptable carrier, excipient, diluent, and/or vehicle” includes, but is not limited to, any carrier, excipient, vehicle, glidant, sweetener, diluent, which can be used in human or livestock animals, Preservatives, dyes/colorants, flavoring agents, surfactants, wetting agents, dispersing agents, disintegrating agents, suspending agents, stabilizers, isotonic agents, solvents or emulsifiers, and the like.
  • Non-limiting examples of such excipients include calcium carbonate, calcium phosphate, various sugars and various types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols, and the like.
  • the maleate salt of the compound of formula I of the present application can be administered in pure form or in the form of a suitable pharmaceutical composition.
  • the pharmaceutical compositions of the present application can be prepared by combining the maleate salt of the compound of Formula I of the present application with a suitable pharmaceutically acceptable carrier, diluent or excipient, and can be formulated into a solid, semi-solid, Liquid or gaseous preparations such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, solutions, suppositories, injections, inhalants, gels, microspheres and aerosols, and the like.
  • Typical routes of administration of the maleate salt of the compound of Formula I of the present application or a pharmaceutical composition thereof include, but are not limited to, oral, rectal, transmucosal, enteral administration, or topical, transdermal, inhalation, parenteral, sublingual , intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous.
  • a preferred route of administration is oral administration.
  • the pharmaceutical composition of the present application can be prepared by a method known to those skilled in the art, such as a conventional mixing method, a dissolution method, a granulation method, a sugar coating pellet method, a grinding method, an emulsification method, a freeze drying method, and the like.
  • the pharmaceutical compositions of the present application are in a form suitable for oral administration.
  • the pharmaceutical compositions may be formulated by admixing the active compound withpharmaceutically acceptable carriers, excipients, diluents, and/or vehicles which are well known in the art. These carriers, excipients, diluents and/or vehicles enable the pharmaceutical compositions of the present application to be formulated into tablets, pills, troches, dragees, capsules, liquids, gels, slurries, suspensions, and the like.
  • Solid oral compositions can be prepared by conventional methods of mixing, filling or tabletting.
  • the dosage of the maleate salt of the compound of formula I administered per day is preferably from 0.01 to 200 mg/kg body weight.
  • the application provides the use of a maleate salt of a compound of formula I or a pharmaceutical composition thereof for the manufacture of a medicament for the treatment of a tumor.
  • the application provides a method for treating a tumor comprising administering to a subject in need thereof a maleate salt of a compound of formula I or a pharmaceutical composition thereof.
  • the application provides a maleate salt of a compound of formula I or a pharmaceutical composition thereof for use in treating a tumor.
  • the tumor includes, but is not limited to, non-small cell lung cancer and breast cancer.
  • Step 3 N-(3-Chloro-4-fluorophenyl)-N-(3,4-dimethoxybenzyl)-7-fluoro-6-nitroquinazolin-4-amine
  • Step 4 N-(3-Chloro-4-fluorophenyl)-N-(3,4-dimethoxybenzyl)-7-methoxy-6-nitroquinazolin-4-amine
  • Step 5 N 4 -(3-chloro-4-fluorophenyl)-N 4 -(3,4-dimethoxybenzyl)-7-methoxyquinazoline-4,6-diamine
  • Step 6 4- ⁇ 4-[(3-Chloro-4-fluorophenyl)(3,4-dimethoxybenzyl)amino]-7-methoxyquinazolin-6-yl ⁇ amino ⁇ piperidine-1-carboxylic acid tert-butyl ester
  • Step 7 N 6 -(piperidin-4-yl)-N 4 -(3-chloro-4-fluorophenyl)-7-methoxyquinazoline-4,6-diamine
  • Step 8 N 6 -(1-acryloylpiperidin-4-yl)-N 4 -(3-chloro-4-fluorophenyl)-7-methoxyquinazoline-4,6-diamine
  • N 6 -(piperidin-4-yl)-N 4 -(3-chloro-4-fluorophenyl)-7-methoxyquinazoline-4,6-diamine monotrifluoroacetate A solution of 258 mg, 0.5 mmol) and triethylamine (202 mg, 2.0 mmol) in tetrahydrofuran (10 mL) was stirred at room temperature for 30 min. After cooling to 0 ° C, a solution of acryloyl chloride (54 mg, 0.6 mmol) in tetrahydrofuran (2 mL) was added dropwise, and the reaction was continued for 30 minutes. After completion of the reaction, the reaction was quenched by slowly adding a 5% NaHCO 3 solution and extracted with ethyl acetate. The obtained organic layer was washed with EtOAc EtOAc m.
  • Citric acid, oxalate and acetate of the compound of formula I can be prepared separately in the same manner as in Example 2.
  • Mass spectrometry conditions ion source: ESI ionization source, SIM mode scanning, curved solvent removal device (CDL) temperature 250 ° C, heating block temperature 200 ° C; CDL voltage 25 V; detection voltage + 1.60 kV; atomization gas flow rate 1.5 L/min; drying gas flow rate 2.0 L/min.
  • ion source ESI ionization source, SIM mode scanning, curved solvent removal device (CDL) temperature 250 ° C, heating block temperature 200 ° C; CDL voltage 25 V; detection voltage + 1.60 kV; atomization gas flow rate 1.5 L/min; drying gas flow rate 2.0 L/min.
  • CDL solvent removal device
  • EGFR EGFR
  • T790M EGFR
  • L858R HER2 kinase
  • the ELISA, EGFR (T790M, L858R) and HER2 kinase activity detection platforms were established by Cisbio's homogeneous time-resolved fluorescence (HTRF) method for the determination of compound activity.
  • the compounds were diluted 3-fold with 100% DMSO starting from 100 nM (EGFR and HER2), 1 ⁇ M (EGFR-T790M/L858R), and 4 ⁇ L of each concentration was added to 96 ⁇ L of reaction buffer (50 mM 4-hydroxyl).
  • Piperazine ethanesulfonic acid (pH 7.0), 0.02% NaN 3 , 0.01% bovine serum albumin (BSA), 0.1 mM sodium orthovanadate (Sodium Orthovanadate), 5 mM MgCl 2 , 50 nM SEB (Cisbio, Item No.: 61SEBALB), 1 mM DTT), 2.5 ⁇ L was added to a 384-well plate (OptiPlate-384, PerkinElmer), then 2.5 ⁇ L of kinase was added, mixed by centrifugation, and 5 ⁇ L of ATP and TK substrate biotin (Substrate- Biotin) initiates the reaction.
  • HEPES Piperazine ethanesulfonic acid
  • Anchorage-independent cell proliferation assay anchor-independent cell proliferation assay
  • Human non-small cell lung cancer cells NCI-H1975, human breast cancer cell line BT474 were cultured in a cell culture incubator (37 ° C, 5% CO 2 ) with RPIM-1640 or DMEM medium plus 10% fetal bovine serum (FBS).
  • FBS fetal bovine serum
  • concentration of the underlying substrate was 0.6%, and after the cells were reselected with 0.3% of low melting point agar, 10,000 cells per well (100 ⁇ L) were plated in 96-well plates.
  • the compound was subjected to 3-fold serial dilution from 10 mM, and 2 ⁇ L of each concentration was added to 98 ⁇ L of the medium, and then 5.3 ⁇ L was added to the cell culture medium (final concentration of DMSO 0.1%, v/v) for one week (7 days). ), add 20 ⁇ L of CellTiter- (Promega) reagent, incubated for 4 hours at 37 ° C, read the fluorescence signal on Envison (Perkin Elmer), and calculate the IC 50 value of the compound for cell proliferation inhibition using GraphPad Prism 5.0.

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Abstract

本申请涉及式I化合物的马来酸盐、其制备方法、其药物组合物及其在治疗肿瘤如非小细胞肺癌、乳腺癌等多种恶性肿瘤中的用途。

Description

喹唑啉衍生物的盐及其制备方法
相关申请的引用
本申请要求于2015年03月20日向中华人民共和国国家知识产权局提交的第201510125962.4号中国发明专利申请的权益，在此将其全部内容以援引的方式整体并入本文中。
技术领域
本申请属于药物化学领域，具体而言涉及喹唑啉衍生物的盐、其制备方法及其医药用途。
背景技术
表皮生长因子受体(EGFR)是一种酪氨酸激酶受体，其广泛分布于哺乳动物上皮细胞、成纤维细胞、胶质细胞、角质细胞等细胞表面。EGFR信号通路对细胞的生长、增殖和分化等生理过程发挥重要的作用。EGFR等蛋白酪氨酸激酶功能缺失或其相关信号通路中关键因子的活性或细胞定位异常，均会引起肿瘤、糖尿病、免疫缺陷及心血管疾病的发生。
N6-(1-丙烯酰基氮杂环己烷-4-基)-N4-(3-氯-4-氟苯基)-7-甲氧基喹唑啉-4，6-二胺具有如式I所示的结构。
Figure PCTCN2016076693-appb-000001
式I化合物是选择性表皮生长因子受体抑制剂，可通过竞争性结合胞内段酪氨酸激酶的磷酸化位点，阻断其与ATP的相互作用，抑制酪氨酸磷酸化及下游一系列的信号传导，继而抑制肿瘤细胞的生长，可用于治疗非小细胞肺癌和乳腺癌等多种恶性肿瘤。参见中国专利申请第201310452885.4号，在此通过引用方式将其全文并入本文中。
发明概述
一方面，本申请提供了式I化合物的马来酸盐，
Figure PCTCN2016076693-appb-000002
其中马来酸与式I化合物的摩尔比取决于制备所述盐时马来酸的用量。例如，所述的马来酸盐中式I化合物与马来酸的摩尔比可为1∶0.5-4。
另一方面，本申请提供了式I化合物的马来酸盐的制备方法，包括：(1)制备式I化合物的溶液；(2)将得自步骤(1)的所述式I化合物的溶液与马来酸接触；以及(3)将得自步骤(2)的反应混合物喷雾干燥，得到所述式I化合物的马来酸盐。
另一方面，本申请提供了药物组合物，其包含所述式I化合物的马来酸盐和药学上可接受的载体、赋形剂、稀释剂和/或介质。
再一方面，本申请提供了式I化合物的马来酸盐或其药物组合物在制备用于治疗肿瘤的药物中的用途。
再一方面，本申请提供了用于治疗肿瘤的方法，其包括向有需要的个体给予式I化合物的马来酸盐或其药物组合物。
再一方面，本申请提供了用于治疗肿瘤的式I化合物的马来酸盐或其药物组合物。
发明详述
在以下的说明中，包括某些具体的细节以对各个公开的实施方案提供全面的理解。然而，相关领域的技术人员会认识到，不采用一个或多个这些具体的细节，而采用其它方法、部件、材料等的情况下可实现实施方案。
除非本申请中另外要求，在整个说明书和其后的权利要求书中，词语“包括(comprise)”及其英文变体例如“包括(comprises)”和“包括(comprising)”应解释为开放式的、含括式的意义，即“包括但不限于”。
在整个本说明书中提到的“一实施方案”或“实施方案”或“在另一实施方案中”或“在某些实施方案中”意指在至少一实施方案中包括与该实施方案所述的相关的具体参考要素、结构或特征。因此，在整个说明书中不同位置出现的短语“在一实施方案中”或“在实施方案中”或“在另一实施方案中”或“在某些实施方案中”不必全部指同一实施方案。此外，具体要素、结构或特征可以任何适当的方式在一个或多个实施方案中结合。
应当理解，在本申请说明书和附加的权利要求书中用到的单数形式的冠词“一”(对应于 英文“a”、“an”和“the”)包括复数的对象，除非文中另外明确地规定。因此，例如提到的包括“催化剂”的反应包括一种催化剂，或两种或多种催化剂。还应当理解，术语“或”通常以其包括“和/或”的含义而使用，除非文中另外明确地规定。
一方面，本申请提供了式I化合物的马来酸盐，
Figure PCTCN2016076693-appb-000003
其中马来酸与式I化合物的摩尔比取决于制备所述盐时马来酸的用量。例如，所述马来酸盐中式I化合物与马来酸的摩尔比可为1∶0.5-4。
在本申请的一些实施方案中，所述马来酸盐中式I化合物与马来酸的摩尔比为1∶1。在本申请的另一些实施方案中，所述马来酸盐中式I化合物与马来酸的摩尔比为1∶2。
另一方面，本申请提供了式I化合物的马来酸盐的制备方法，包括：(1)制备式I化合物的溶液；(2)将得自步骤(1)的所述式I化合物的溶液与马来酸混合；以及(3)将得自步骤(2)的反应混合物喷雾干燥，得到所述式I化合物的马来酸盐。
在一些实施方案中，在所述制备方法中式I化合物与马来酸的用量摩尔比为1∶1-20，优选1∶1-15，最优选1∶1-10。
在所述制备方法的步骤(1)中，可以将式I化合物溶于有机溶剂中以制备式I化合物的溶液。所述有机溶剂包括所有能够溶解式I化合物的有机溶剂，例如DMF。
在所述制备方法的步骤(2)中，可以将得自步骤(1)的式I化合物的溶液与马来酸或马来酸的溶液混合，并且如果需要，可加热反应混合物至合适的温度，例如60-100℃，优选为80℃。在一些实施方案中，马来酸的溶液为将马来酸与有机溶剂混合后得到的马来酸的有机溶液。在本申请的一些实施方案中，所述有机溶剂例如为DMF。
在一些实施方案中，在喷雾干燥前可加入与步骤(1)和/或(2)中的有机溶剂混溶的溶剂，例如水。
再一方面，本申请提供了药物组合物，其包含式I化合物的马来酸盐和药学上可接受的载体、赋形剂、稀释剂和/或介质。
本文所用的术语“药物组合物”是指本申请的化合物与医药领域中通常接受的用于将生物活性化合物递送至有机体(例如人)的载体、赋形剂、稀释剂和/或介质配制成的制剂。药物组合物的目的是有利于向有机体给予本申请的化合物。
本文所用的术语“药学上可接受的载体”是指对有机体无明显刺激作用，而且不会损害活性化合物的生物活性及性能的那些载体和稀释剂。“药学上可接受的赋形剂和/或介质”是指与活性成分一同给药的并有利于向有机体递送活性成分的惰性物质。“药学上可接受的载体、赋形剂、稀释剂和/或介质”包括但不限于可用于人或家畜动物的任何载体、赋形剂、介质、助流剂、增甜剂、稀释剂、防腐剂、染料/着色剂、矫味剂、表面活性剂、润湿剂、分散剂、崩解剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂等等。所述赋形剂的非限制性实例包括碳酸钙、磷酸钙、各种糖和各类淀粉、纤维素衍生物、明胶、植物油和聚乙二醇等等。
本申请的式I化合物的马来酸盐可以纯的形式或以适宜的药物组合物的形式给药。本申请的药物组合物可通过将本申请的式I化合物的马来酸盐与适宜的药学上可接受的载剂、稀释剂或赋形剂组合而制备，且可配制成固态、半固态、液态或气态制剂，如片剂、丸剂、胶囊剂、粉剂、颗粒剂、膏剂、乳剂、悬浮剂、溶液剂、栓剂、注射剂、吸入剂、凝胶剂、微球及气溶胶等等。
本申请的式I化合物的马来酸盐或其药物组合物的典型给药途径包括但不限于口服、直肠、透黏膜、经肠给药，或者局部、经皮、吸入、肠胃外、舌下、阴道内、鼻内、眼内、腹膜内、肌内、皮下、静脉内给药。优选的给药途径是口服给药。
本申请的药物组合物可以采用本领域技术人员已知的方法制备，如常规的混合法、溶解法、制粒法、制糖衣药丸法、磨细法、乳化法、冷冻干燥法等。
在优选的实施方案中，本申请的药物组合物是适于口服给药的形式。对于口服给药，可以通过将活性化合物与本领域中熟知的药物可接受的载体、赋形剂、稀释剂和/或介质混合来配制该药物组合物。这些载体、赋形剂、稀释剂和/或介质能使本申请的药物组合物被配制成片剂、丸剂、锭剂、糖衣剂、胶囊剂、液体、凝胶剂、浆剂、悬浮剂等，用于向患者的口服给药。可以通过常规的混合、填充或压片方法来制备固体口服组合物。
在所述给药方法中，每天给予的式I化合物的马来酸盐的剂量优选为0.01-200mg/kg体重。
再一方面，本申请提供了式I化合物的马来酸盐或其药物组合物在制备用于治疗肿瘤的药物中的用途。
再一方面，本申请提供了用于治疗肿瘤的方法，其包括向有需要的个体给予式I化合物的马来酸盐或其药物组合物。
再一方面，本申请提供了用于治疗肿瘤的式I化合物的马来酸盐或其药物组合物。
在一些实施方案中，所述肿瘤包括但不限于非小细胞肺癌和乳腺癌。
实施例
实施例1制备式I化合物
步骤1：4-氯-7-氟-6-硝基喹唑啉
Figure PCTCN2016076693-appb-000004
将7-氟-6-硝基喹唑啉-4(3H)-酮(2.0g，9.6mmol)和一滴N，N-二甲基甲酰胺在二氯亚砜(6mL)中回流过夜，然后真空浓缩反应混合物。向残渣中加入甲苯后再次真空浓缩以去除残余的二氯亚砜，得到标题化合物(2g，92％)。
1H NMR(CDCl3)：δ9.18(1H，s)，9.05(1H，d，J＝7.6Hz)，7.95(1H，d，J＝10.4)。
步骤2：3-氯-N-(3，4-二甲氧基苄基)-4-氟苯胺
Figure PCTCN2016076693-appb-000005
将3-氯-4-氟苯胺(2.9g，20mmol)和3，4-二甲氧基苯甲醛(3.3g，20mmol)加入1，2-二氯乙烷(30mL)中，室温搅拌1小时。然后加入三乙酰基硼氢化钠(10g，50mmol)，将反应混合液在室温下搅拌过夜。将反应混合液倾入100mL水中，用二氯甲烷萃取。分离有机相，饱和食盐水洗涤后，经无水硫酸钠干燥，真空浓缩有机相，得到标题化合物(5.5g，93％)。
1H NMR(CDCl3)：δ6.94-6.82(4H，m)，6.63-6.61(1H，m)，6.45-6.41(1H，m)，4.18(2H，s)，3.98(1H，br)，3.87(3H，s)，3.86(3H，s)。
步骤3：N-(3-氯-4-氟苯基)-N-(3，4-二甲氧基苄基)-7-氟-6-硝基喹唑啉-4-胺
Figure PCTCN2016076693-appb-000006
将4-氯-7-氟-6-硝基喹唑啉(2.1g，9.2mmol)和3-氯-N-(3，4-二甲氧基苄基)-4-氟苯胺(2.7g，9.2mmol)加入乙腈(20mL)中，回流3小时。冷却后，加入碳酸钠溶液中和，乙酸乙酯萃取，分离有机相，饱和食盐水洗涤后，经无水硫酸钠干燥，真空浓缩得到标题化合物(3.6g，80％)。
步骤4：N-(3-氯-4-氟苯基)-N-(3，4-二甲氧基苄基)-7-甲氧基-6-硝基喹唑啉-4-胺
Figure PCTCN2016076693-appb-000007
将金属钠(113mg，5.0mmol)加入无水甲醇(20mL)中，室温搅拌10分钟，然后加入N-(3-氯-4-氟苯基)-N-(3，4-二甲氧基苄基)-7-氟-6-硝基喹唑啉-4-胺(2.4g，5.0mmol)，混合液在40℃下搅拌6小时。冷却后，将混合液倾入100mL水中，乙酸乙酯萃取，有机相用饱和食盐水洗涤后，经无水硫酸钠干燥，真空浓缩得到标题化合物(2.35g，94％)。
1H NMR(CDCl3)：δ8.85(1H，s)，7.57(1H，s)，7.35(1H，s)，7.23-7.19(2H，m)，7.00-6.96(1H，m)，6.84-6.78(2H，m)，5.35(2H，s)，4.05(3H，s)，3.88(3H，s)，3.83(3H，s)。
步骤5：N4-(3-氯-4-氟苯基)-N4-(3，4-二甲氧基苄基)-7-甲氧基喹唑啉-4，6-二胺
Figure PCTCN2016076693-appb-000008
将N-(3-氯-4-氟苯基)-N-(3，4-二甲氧基苄基)-7-甲氧基-6-硝基喹唑啉-4-胺(2.35g，4.7mmol)和雷尼镍(约0.5g)加入四氢呋喃(100mL)中，氢气置换，在氢气氛下(1atm)室温搅拌过夜。过滤，滤液经真空浓缩得到标题化合物(2g，90％)。
步骤6：4-{{4-[(3-氯-4-氟苯基)(3，4-二甲氧基苄基)氨基]-7-甲氧基喹唑啉-6-基}氨基}哌啶-1-甲酸叔丁酯
Figure PCTCN2016076693-appb-000009
将N4-(3-氯-4-氟苯基)-N4-(3，4-二甲氧基苄基)-7-甲氧基喹唑啉-4，6-二胺(469mg，1.0mmol) 和4-氧代哌啶-1-甲酸叔丁酯(239mg，1.2mmol)的醋酸(10mL)溶液在室温下搅拌2小时，然后一次性加入三乙酰氧基硼氢化钠(254mg，1.2mmol)。反应半小时后，慢慢加入水淬灭反应，并用乙酸乙酯萃取。所得有机相依次用水、5％NaHCO3水溶液和饱和食盐水洗，无水硫酸钠干燥并真空浓缩。残余物经硅胶柱色谱分离得到标题化合物(404mg，62％)。
步骤7：N6-(哌啶-4-基)-N4-(3-氯-4-氟苯基)-7-甲氧基喹唑啉-4，6-二胺
Figure PCTCN2016076693-appb-000010
将4-{{4-[(3-氯-4-氟苯基)(3，4-二甲氧基苄基)氨基]-7-甲氧基喹唑啉-6-基}氨基}哌啶-1-甲酸叔丁酯(0.4g，0.61mmol)的三氟醋酸(8mL)溶液在70℃下搅拌6小时。反应完毕，冷却，真空浓缩，残余物用乙酸乙酯制成浆液、过滤得到标题化合物的三氟醋酸盐(0.26g，83％)。
步骤8：N6-(1-丙烯酰基哌啶-4-基)-N4-(3-氯-4-氟苯基)-7-甲氧基喹唑啉-4，6-二胺
Figure PCTCN2016076693-appb-000011
将N6-(哌啶-4-基)-N4-(3-氯-4-氟苯基)-7-甲氧基喹唑啉-4，6-二胺单三氟醋酸盐(258mg，0.5mmol)和三乙胺(202mg，2.0mmol)的四氢呋喃(10mL)溶液于室温下搅拌30分钟。冷却至0℃后，滴加丙烯酰氯(54mg，0.6mmol)的四氢呋喃溶液(2mL)，加完继续反应30分钟。反应完毕，慢慢加入5％NaHCO3溶液淬灭反应，并用乙酸乙酯萃取。所得有机相用饱和食盐水洗，无水硫酸钠干燥并真空浓缩，残余物经硅胶柱色谱分离得到目标产物(150mg，66％)。
1H NMR(DMSO-d6)：δ9.24(1H，s)，8.33(1H，s)，8.09-8.08(1H，m)，7.77-7.74(1H，m)，7.42-7.40(1H，m)，7.23(1H，s)，7.06(1H，s)，6.85-6.81(1H，m)，6.10-6.06(1H，m)，5.66-5.64(1H，m)，5.32-5.29(1H，m)，4.41-4.38(1H，m)，4.09-4.06(1H，m)，3.93(3H，s)，3.79-3.78(1H，m)，3.35-3.34(1H，m)，2.87-2.84(1H，m)，2.03-2.01(2H，m)，1.44-1.41(2H，m)。
实施例2制备式I化合物的马来酸盐
室温下将5g式I化合物溶于100mL的DMF中，不断搅拌均匀，加入6.3g马来酸，然后升温至80℃反应2h，随后在此温度下加入100ml水，直接喷雾干燥，得4.0g黄色固体粉末， XRD图谱显示为无定形的式I化合物的马来酸盐(1∶1)。
实施例3式I化合物的柠檬酸、草酸盐以及乙酸盐的制备
按照与实施例2相同的方法，可分别制备得到式I化合物的柠檬酸、草酸盐以及乙酸盐。
实施例4生物利用度实验
研究方法：体重7.4～9.4kg的15只比格犬随机分为5组，分别口服给予5mg/kg体重的式I化合物及其马来酸盐、柠檬酸盐、草酸盐、乙酸盐(按式I化合物的量计算)的CMC-Na(羧甲基纤维素钠)混悬液，于给药前和给药后(0.25、0.5、1、2、4、6、8、12、24、48h时间点)采血，采用LC-MS法分别测定犬血浆样品中式I化合物的浓度，计算生物利用度。
检测方法：
色谱条件：流动相A为甲醇，流动相B为0.1％(v/v)的甲酸水溶液。采用等度洗脱方式A∶B＝52∶48，流速：0.2mL/min；柱温35℃；色谱柱为SHIMADZU Shim-pack VP-ODS C18(5.0μm，150mm×2.0mm I.D.岛津公司)。
质谱条件：离子源：ESI电离源，SIM方式扫描，曲型脱溶剂装置(CDL)温度250℃，加热块(block)温度200℃；CDL电压25V；检测电压+1.60kV；雾化气流速1.5L/min；干燥气流速2.0L/min。
研究结果：
Figure PCTCN2016076693-appb-000012
实施例5体外活性试验
1.体外酶学检测方法
EGFR，EGFR(T790M，L858R)，HER2激酶由昆虫表达系统表达纯化得到或通过购买市售产品得到。
采取Cisbio公司的均相时间分辨荧光(HTRF)方法建立了EGFR，EGFR(T790M，L858R)，HER2的激酶活性检测平台，进行化合物活性的测定。将化合物分别从100nM(EGFR和HER2)，1μM(EGFR-T790M/L858R)开始用100％DMSO进行3倍的梯度稀释，每个浓度取4μL加入到96μL的反应缓冲液中(50mM 4-羟乙基哌嗪乙磺酸(HEPES)(pH 7.0)，0.02％NaN3，0.01％牛血清白蛋白(BSA)，0.1mM原钒酸钠(Sodium Orthovanadate)，5mM MgCl2，50nM SEB(Cisbio公司，货号：61SEBALB)，1mM DTT)，取2.5μL加入到384孔板(OptiPlate-384，PerkinElmer)，然后加入2.5μL的激酶，离心混匀，再加入5μL的ATP和TK底物生物素(Substrate-biotin)启动反应。将384孔板放于孵育箱中23℃反应一定时间后，加入5μL的Eu3+-Cryptate标记的TK-Antibody，5μL的链霉亲和素(streptavidin)-XL665停止反应。在孵育箱中孵育1小时后，在Envision(PerkinElmer)上读取荧光值。化合物的IC50值使用GraphPad Prism 5.0软件计算得到。
2.Anchorage-independent细胞增殖试验(锚定非依赖性细胞增殖试验)
人非小细胞肺癌细胞NCI-H1975，人乳腺癌细胞系BT474在细胞培养箱(37℃，5％CO2)中用RPIM-1640或者DMEM培养基加10％胎牛血清(FBS)进行培养。在化合物的检测中，底层基质浓度为0.6％，细胞用0.3％的低熔点琼脂重选后，10,000个细胞每孔(100μL)铺于96孔板中。化合物从10mM进行3倍梯度稀释，每个浓度取2μL加入到98μL的培养基中，然后取5.3μL加入到细胞培养液中(DMSO终浓度为0.1％，v/v)，处理一周(7天)后，加入20μL CellTiter-
Figure PCTCN2016076693-appb-000013
(Promega)试剂，37℃孵育4个小时，在Envison(Perkin Elmer)上读取荧光信号，使用GraphPad Prism 5.0计算化合物对细胞增殖抑制的IC50值。
生物活性列表
Figure PCTCN2016076693-appb-000014

Claims (11)

  1. 式I化合物的马来酸盐
    Figure PCTCN2016076693-appb-100001
  2. 权利要求1所述的式I化合物的马来酸盐，其中所述式I化合物与马来酸的摩尔比为1∶0.5-4。
  3. 权利要求2所述的式I化合物的马来酸盐，其中所述式I化合物与马来酸的摩尔比为1∶1或1∶2。
  4. 制备权利要求1-3中任一项权利要求所述的式I化合物的马来酸盐的方法，其包括：(1)制备式I化合物的溶液；(2)将得自步骤(1)的所述式I化合物的溶液与马来酸混合；以及(3)将得自步骤(2)的反应混合物喷雾干燥，得到所述式I化合物的马来酸盐。
  5. 权利要求4所述的制备方法，其中所述式I化合物与马来酸的用量摩尔比为1∶1-20，优选为1∶1-15，更优选为1∶1-10。
  6. 权利要求4或5所述的制备方法，其中在步骤(1)中，将所述式I化合物溶于有机溶剂中以制备所述式I化合物的溶液，所述有机溶剂优选为DMF。
  7. 权利要求6所述的制备方法，其中在喷雾干燥前加入与所述有机溶剂混溶的溶剂，所述混溶的溶剂优选为水。
  8. 药物组合物，包含权利要求1-3中任一项权利要求所述的式I化合物的马来酸盐和药学上可接受的载体、赋形剂、稀释剂和/或介质。
  9. 权利要求1-3中任一项权利要求所述的式I化合物的马来酸盐或权利要求8所述的药物组合物在制备用于治疗肿瘤的药物中的用途。
  10. 用于治疗肿瘤的方法，其包括向有需要的个体给予权利要求1-3中任一项权利要求所述的式I化合物的马来酸盐或权利要求8所述的药物组合物。
  11. 用于治疗肿瘤的权利要求1-3中任一项权利要求所述的式I化合物的马来酸盐或权利要求8所述的药物组合物。
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