WO2018028591A1 - 一种喹啉衍生物及其用途 - Google Patents

一种喹啉衍生物及其用途 Download PDF

Info

Publication number
WO2018028591A1
WO2018028591A1 PCT/CN2017/096569 CN2017096569W WO2018028591A1 WO 2018028591 A1 WO2018028591 A1 WO 2018028591A1 CN 2017096569 W CN2017096569 W CN 2017096569W WO 2018028591 A1 WO2018028591 A1 WO 2018028591A1
Authority
WO
WIPO (PCT)
Prior art keywords
quinoline derivative
hydrate
pharmaceutically acceptable
acceptable salt
metabolism
Prior art date
Application number
PCT/CN2017/096569
Other languages
English (en)
French (fr)
Inventor
殷建明
Original Assignee
殷建明
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 殷建明 filed Critical 殷建明
Publication of WO2018028591A1 publication Critical patent/WO2018028591A1/zh
Priority to US16/266,000 priority Critical patent/US10689361B2/en

Links

Classifications

    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • 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
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C07D215/233—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 4
    • 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
    • C07D215/38—Nitrogen atoms
    • C07D215/42—Nitrogen atoms attached in position 4
    • C07D215/46—Nitrogen atoms attached in position 4 with hydrocarbon radicals, substituted by nitrogen atoms, attached to said nitrogen atoms
    • 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

Definitions

  • the present invention relates to a quinoline derivative and its use in the manufacture of a medicament for preventing and/or treating an indication associated with angiogenesis.
  • Angiogenesis is the growth of new capillary blood vessels in the venules of existing capillaries and capillaries. It is a complex process involving multiple molecules of various cells.
  • VEGF Vascular endothelial growth factor
  • VEGFR vascular endothelial growth factor receptor
  • Angiogenesis plays an important role in the development and metastasis of tumors. Inhibition of this process can significantly prevent the development and spread of tumor tissue. Inhibition of VEGFR can treat tumor growth, as well as other angiogenic metastatic growth diseases such as psoriasis, Kaposi's sarcoma, restenosis such as stent-induced restenosis, endometriosis, Crohn's disease, Hodgkin's disease Disease, leukemia; arthritis, hemangioma, angiofibroma, eye diseases such as diabetic retinopathy and neovascular glaucoma, nephropathy such as glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy syndrome, transplant rejection and Glomerulopathy, fibrotic diseases such as cirrhosis, mesangial cell proliferative diseases, arteriosclerosis, nerve tissue damage and senile keratosis.
  • the technical problem to be solved by the present invention is to provide a novel quinoline derivative which is a pharmaceutically acceptable salt, hydrate, or metabolite formed by metabolism in any form, which is an ideal VEGFR inhibitor.
  • the invention also provides the use of a quinoline derivative, a pharmaceutically acceptable salt, hydrate thereof, or a metabolite formed by metabolism in any form, for the manufacture of a medicament for the prevention and/or treatment of an indication associated with angiogenic function.
  • the present invention adopts the following technical solutions:
  • R 1 is selected from R 5 or NHR 5 , wherein R 5 is cycloalkyl, heterocyclic or substituted heterocyclic;
  • R 2 is selected from the group consisting of hydrogen, halogen, hydroxy, alkoxy or cyano;
  • R 3 and R 4 are independently selected from OR 6 , C(O)NH 2 , C(O)NHR 6 , wherein R 6 is C 1 -C 6 alkyl or haloalkyl;
  • X is selected from NH or O
  • R 2 is preferably Cl or F.
  • R 5 is preferably a cycloalkyl or halocycloalkyl group; a heterocyclic ring containing N or O which is unsubstituted or substituted with one or more substituents of a halogen or a C 1 -C 6 alkyl group Wherein the cycloalkyl carbon number is preferably from 3 to 6.
  • R 5 is a cycloalkyl group having a carbon number of 3; an unsaturated five- or six-membered heterocyclic ring containing 1 or 2 or 3 N, which is unsubstituted or one or two selected from a methyl group, Ethyl substitution.
  • R 5 is a cycloalkyl group having a carbon number of 3; an unsaturated five-membered heterocyclic ring containing 2 N which is unsubstituted or substituted with one methyl group.
  • R 5 is
  • R 6 is preferably a methyl group or an ethyl group.
  • the representative compound of the quinoline derivative is one of the compounds represented by the following structural formula:
  • the compound of the quinoline derivative includes not only a single compound form but also a mixture of a plurality of structures satisfying the requirements of the general formula (I), and different isomers of the same compound. Forms such as racemates, enantiomers, diastereomers and the like.
  • the pharmaceutically acceptable salts include, but are not limited to, hydrochloride, phosphate, sulfate, acetate, maleate, methanesulfonate, besylate, benzoate, toluenesulfonate , succinate, fumarate, fumarate, tartrate, gallate, citrate, and the like.
  • Prodrug of a compound of the formula (I) means a substance which, upon administration by a suitable method, can be converted into a compound of the formula (I) by metabolic or chemical reaction in a subject. Or its salt.
  • the preparation of the quinoline derivatives of the present invention can be carried out by synthetic routes to those analogous methods well known in the chemical arts, particularly in accordance with the description contained herein.
  • the reagents are generally obtained from commercial sources or are readily prepared using methods well known to those skilled in the art.
  • Another technical solution of the present invention is a quinoline derivative intermediate, wherein the intermediate is one of the compounds represented by the following structural formula:
  • Another technical solution adopted by the present invention is that the above quinoline derivative, a pharmaceutically acceptable salt thereof, a hydrate or a metabolite formed by metabolism in any form, is used in the preparation of a medicament for preventing and/or treating an indication related to angiogenesis. use.
  • the indications associated with angiogenesis include malignant tumor diseases.
  • the malignant tumor diseases include lung cancer, mesothelioma, gastrointestinal cancer, breast cancer, pancreatic cancer, bladder cancer, ovarian cancer, esophageal cancer, head and neck cancer, colon cancer, skin cancer, prostate cancer, cervical cancer, lymphoma, A variety of malignant tumor diseases such as leukemia, melanoma, glioma and nasopharyngeal cancer.
  • the indications associated with angiogenesis also include other metastatic disease associated with angiogenesis, such as psoriasis, Kaposi's sarcoma, restenosis such as stent-induced restenosis, endometriosis, Crohn's disease, Hodgkin's disease, leukemia, arthritis, hemangioma, angiofibroma, eye diseases such as diabetic retinopathy and neovascular glaucoma, nephropathy such as glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy syndrome, Transplant rejection and glomerular disease, fibrotic diseases such as cirrhosis, mesangial cell proliferative diseases, arteriosclerosis, nerve tissue damage and senile keratosis.
  • other metastatic disease associated with angiogenesis such as psoriasis, Kaposi's sarcoma, restenosis such as stent-induced reste
  • Another technical solution adopted by the present invention is a medicament for preventing and/or treating an indication related to angiogenesis, comprising the above-mentioned quinoline derivative of the formula (I), a pharmaceutically acceptable salt thereof, a hydrate thereof, Or metabolize the formed metabolites in any form.
  • the present invention has the following advantages compared with the prior art:
  • the compound provided by the present invention is a novel quinoline derivative which is an ideal and highly effective VEGFR inhibitor, which inhibits angiogenesis by acting on VEGFR and has a certain therapeutic effect on angiogenesis-related diseases. Therefore, the compound of the present invention can be used for the preparation of a medicament for treating or preventing various indications related to angiogenesis, and the antitumor effect of other drugs can also be enhanced by inhibition of angiogenesis.
  • the preparation method of the compound of the formula Ia specifically comprises the following steps:
  • the preparation method of the compound of the formula Ib specifically comprises the following steps:
  • the preparation method of the compound of the formula Ic specifically comprises the following steps:
  • the obtained target product of the formula Ic was subjected to hydrogen nuclear magnetic resonance 1 H-NMR (400 MHz, d-DMSO) and mass spectrometry, and the results were as follows:
  • This example provides a test for the enzyme activity test of a compound.
  • the half-inhibitory concentration IC 50 of the compound (the concentration of the compound required to inhibit the enzymatic activity to 50%) is determined by mixing a specific substrate with a fixed enzyme and different concentrations of the test compound.
  • the assay used was Caliper Mobility Shift Assay, and the kinases tested were VEGFR1, VEGFR2, VEGFR3, FLT3, PDGFR, PDGFR, FGFR1, RET, EGFR and IGF1R.
  • the standard reference compound used was star-shaped. Staurosporine.
  • Table 1 summarizes the results of inhibition experiments of the target compounds (Ia, Ib and Ic) against VEGFR1, VEGFR2, VEGFR3, FLT3, PDGFR, PDGFR, FGFR1, RET, EGFR and IGF1R enzyme activities, and the results show that the target compound has strong inhibition of VEGFR2. It has good selective inhibitory activity against other related kinases, especially EGFR and IGF1R. This inhibition of VEGFR2 selectivity is an indication of angiogenesis-related indications including malignant neoplastic disease and other angiogenesis-related metastatic disease Has important therapeutic implications. Table 1 also summarizes the data on the currently available VEGFR2 inhibitor, regorafenib, which has been marketed.
  • This example provides a pharmacokinetic property evaluation test.
  • mice CD-1 mice, males and females; body weight: 20-25 g;
  • the target compound was formulated into 0.2 mg/mL, and was used. Route of administration: intravenous injection. Dosing capacity and frequency: 2 mL/kg, single administration. Dosage: 3 mg/kg.
  • Sample collection Blood was collected at the following time points, and blood was taken at 5 min, 15 min, 30 min, 1 hr, 2 hr, 4 hr, 8 hr, and 24 hr after administration.
  • Sample analysis The collected samples were tested using the LC-MS/MS method.
  • the instrument model is API4000.
  • the compounds of the present invention are ideal highly potent and selective VEGFR2 kinase inhibitors, and are expected to be useful for the treatment or prevention of angiogenesis-related indications including malignant tumor diseases and other angiogenesis-related metastatic growth diseases. Very good results, it can also be combined with different types of medicinal salts to make oral preparations (tablets or capsules, etc.). A tablet or capsule made with a compound of the invention can be taken one or more times a day. The compound of the present invention can also be combined with other drugs to prepare a compound preparation or a topical preparation.

Abstract

提供一种新型的喹啉衍生物、其可药用盐、水合物或以任何形式代谢形成的代谢产物，及在制备预防和/或治疗与血管生成有关的适应证的药物中的用途；所述的喹啉衍生物是理想的高效VEGFR抑制剂，可用于治疗或预防肿瘤生长，以及其他与血管生成相关的转移生长疾病。

Description

一种喹啉衍生物及其用途 技术领域
本发明涉及一种喹啉衍生物及其在制备预防和/或治疗与血管生成有关的适应症的药物中的用途。
背景技术
血管生成是在已有毛细血管及毛细血管后微静脉的新的毛细血管性血管生长，是一个涉及多种细胞的多种分子的复杂过程。
血管内皮生长因子(vascular endothelial growth factor，VEGF)是血管内皮细胞特异性的肝素结合生长因子，可在体内诱导血管新生。VEGF的表达与组织中微血管的密度及新生血管的数量密切相关。VEGF受体(VEGFR)家族包括VEGFR-1，VEGFR-2和VEGFR3。
血管生成在肿瘤的发展转移过程中起到重要作用，抑制这一过程能明显阻止肿瘤组织的发展和扩散转移。抑制VEGFR能够治疗肿瘤生长，以及其他与血管生成相关的转移生长疾病，如银屑病、卡波西肉瘤、再狭窄如支架诱导的再狭窄、子宫内膜异位症、克隆病、霍奇金病、白血病；关节炎、血管瘤、血管纤维瘤、眼病如糖尿病性视网膜病变和新生血管性青光眼、肾病如肾小球肾炎、糖尿病肾病、恶性肾硬化、血栓性微血管病综合征、移植排斥和肾小球病，纤维化病如肝硬化、肾小球膜细胞增生性疾病、动脉硬化、神经组织损伤和老年性角化症等。
发明内容
本发明所要解决的技术问题是提供一种新型的喹啉衍生物，其可药用盐、水合物，或以任何形式代谢形成的代谢产物，其是理想的VEGFR抑制剂。
本发明同时还提供喹啉衍生物，其可药用盐、水合物，或以任何形式代谢形成的代谢产物在制备预防和/或治疗与血管生成功能有关的适应症的药物中的用途。
为解决以上技术问题，本发明采取如下技术方案：
具有通式(I)所示结构的喹啉衍生物，其可药用盐、水合物，或以任何形式 代谢形成的代谢产物，
Figure PCTCN2017096569-appb-000001
其中：
R1选自R5或NHR5，其中R5为环烷基、杂环或取代杂环；
R2选自氢、卤素、羟基、烷氧基或氰基；
R3和R4独立地选自OR6、C(O)NH2、C(O)NHR6，其中R6为C1-C6烷基或卤代烷基；
X选自NH或O；
所述具有通式(I)所示结构的喹啉衍生物，其可药用盐、水合物或以任何形式代谢形成的代谢产物中，非交换性的氢未被取代，或部分或全部被氘取代。
本发明中，R2优选为Cl或F。
本发明中，R5优选为环烷基或卤代环烷基；含N或O的杂环，其未被取代或为卤素、C1-C6烷基中的一个或多个取代基取代，其中所述环烷基碳数优选为3～6个。
更优选地，R5为碳数为3的环烷基；含1或2或3个N的不饱和五元或六元杂环，其未被取代或被一个或二个选自甲基、乙基取代。
进一步更优选地，R5为碳数为3的环烷基；含2个N的不饱和五元杂环，其未被取代或被一个甲基取代。
根据本发明的一些优选实施方式，R5为
Figure PCTCN2017096569-appb-000002
本发明中，R6优选为甲基或乙基。
本发明中，所述的喹啉衍生物的代表性化合物为如下结构式表示的化合物中的一种：
Figure PCTCN2017096569-appb-000003
Figure PCTCN2017096569-appb-000004
根据本发明，所述的喹啉衍生物的化合物，其不仅包括单一的某种化合物形式，还包括多种结构满足通式(Ⅰ)要求的化合物的混合物形式，以及同一化合物的不同异构体形式例如外消旋体、对映异构体、非对映异构体等。所述的可药用盐包括但不限于盐酸盐、磷酸盐、硫酸盐、醋酸盐、马来酸盐、甲磺酸盐、苯磺酸盐、苯酸盐、甲基苯磺酸盐、琥珀酸盐、延胡索酸盐、富马酸盐、酒石酸盐、没食子酸盐、柠檬酸盐等。“具有通式(Ⅰ)的化合物的前药”指一种物质，当采用适当的方法施用后，可在受试者体内进行代谢或化学反应而转变成通式(Ⅰ)的至少一种化合物或其盐。
本发明喹啉衍生物的制备可以通过化学领域众所周知的那些类似的方法的合成途径，特别是根据本文包含的描述合成本发明的化合物。试剂一般从商业来源获得或易于使用本领域技术人员众所周知的方法制备。
本发明的又一技术方案：一种喹啉衍生物中间体，所述中间体为如下结构式表示的化合物中的一种：
Figure PCTCN2017096569-appb-000005
本发明采用的另一技术方案：上述喹啉衍生物，其可药用盐、水合物或以任何形式代谢形成的代谢产物在制备预防和/或治疗与血管生成有关的适应症的药物中的用途。
所述与血管生成有关的适应症包括恶性肿瘤疾病。
所述恶性肿瘤疾病包括肺癌、间皮瘤、胃肠癌、乳腺癌、胰腺癌、膀胱癌、卵巢癌、食管癌、头颈癌、结肠癌、皮肤癌、前列腺癌、子宫颈癌、淋巴瘤、白血病、黑素瘤、神经胶质瘤和鼻咽癌等多种恶性肿瘤疾病。
所述与血管生成有关的适应症还包括其他与血管生成相关的转移生长疾病，如银屑病，卡波西肉瘤，再狭窄如支架诱导的再狭窄，子宫内膜异位症，克隆病，霍奇金病，白血病，关节炎，血管瘤，血管纤维瘤，眼病如糖尿病性视网膜病变和新生血管性青光眼，肾病如肾小球肾炎、糖尿病肾病、恶性肾硬化、血栓性微血管病综合征、移植排斥和肾小球病，纤维化病如肝硬化、肾小球膜细胞增生性疾病、动脉硬化、神经组织损伤和老年性角化症等。
本发明采用的又一技术方案：一种预防和/或治疗与血管生成有关的适应症的药物，含有上述的具有通式(I)的喹啉衍生物，其可药用盐、水合物，或以任何形式代谢形成的代谢产物。
由于以上技术方案的实施，本发明与现有技术相比具有如下优点：
本发明提供的化合物是新型的喹啉衍生物，其是理想的高效理想的VEGFR抑制剂，通过作用于VEGFR，可以抑制血管生成，在血管生成有关的疾病方面具有一定的药物治疗作用。因此本发明化合物可用于制备治疗或预防各种与血管生成有关的适应症的药物，而且通过对血管生成的抑制也能够增强其他药物的抗肿瘤作用。
具体实施方式
下面结合具体实施例对本发明做进一步详细的说明，但本发明并不限于以下实施例。
实施例1
本实施例提供式Ia化合物，其化学结构如下：
Figure PCTCN2017096569-appb-000006
式Ia化合物可通过如下合成路线获得：
Figure PCTCN2017096569-appb-000007
式Ia化合物的制备方法具体包括如下步骤：
(1)、制备中间体2：在50mL反应瓶中，依次加入化合物1(500mg，2mmol)、NMP(20mL)、化合物1a(471mg，3mmol)和DIPEA(774mg，6mmol)。将混合物加热到160℃搅拌反应2小时。冷却后浓缩，硅胶柱层析分离得到中间体2(0.4g,1.08mmol,收率56％)，为灰色固体。
(2)、制备中间体3：在250mL反应瓶中，依次加入中间体2(400mg，1.08mmol)、MeOH(80mL)和钯碳(5％，100mg)。反应液在氢气中常温搅拌3小时。过滤反应液，滤液浓缩后得到中间体3(0.3g，0.88mmol，收率80％)，为白色固体。LCMS显示分子离子峰m/z[MH]+：342.2。
(3)、制备式Ia化合物：在50mL三口瓶中依次加入中间体3(0.3g，0.88mmol)和干燥THF(20mL)。在氮气保护下将反应液冷却到0℃，缓慢滴加DIPEA(0.227g，1.76mmol)。反应液0℃搅拌反应1小时。向反应液中加入三光气(90mg，0.3mmol)。反应液0℃搅拌反应3小时。然后向反应液中快速加入化合物3a(94mg，0.97mmol)。反应液在室温搅拌过夜，浓缩，HPLC分离得到式Ia化合物(0.12g，0.26mmol，收率29％)，为白色固体。
对得到的目标产品式Ia化合物进行了氢核磁共振1H-NMR(400MHz，d-DMSO)和质谱测试，结果如下：
1H-NMR谱图中吸收峰：δ＝8.99(s,1H,ArH),8.65(d,J＝5.2Hz,1H,ArH),8.59(s, 1H,ArH),8.51(s,1H,ArH),8.37-8.36(m,1H,CONHCH3),7.74-7.71(m,2H,一个CONH，一个ArH),7.50(s,1H,ArH),7.39-7.34(m,2H,一个CONH，一个ArH),7.23(d,J＝8.8Hz,1H,ArH),6.48(d,J＝4.8Hz,1H,ArH),4.00(s,3H,NCH3),3.77(s,3H,OCH3)，2.82(d,J＝4.8Hz,3H,CONHCH3)。
m/z[MH]+：465.2。计算得出产品具有分子式C23H21FN6O4，精确分子质量(exact mass)为464.16。
实施例2
本实施例提供式Ib化合物，其化学结构如下：
Figure PCTCN2017096569-appb-000008
式Ib化合物可通过如下合成路线获得：
Figure PCTCN2017096569-appb-000009
式Ib化合物的制备方法具体包括如下步骤：
(1)、制备中间体5：在150mL三口瓶中依次加入化合物4(1.8g，7.63mmol)、NMP(40mL)、化合物1a(1.797g，11.45mmol)和DIPEA(5.9g，45.78mmol)。将混合物加热到160℃反应2小时。冷却到室温后，将反应液加入到水中，析出固体。过滤混合物，滤饼用水洗涤，干燥得到中间体5(2.2g，收率80％)，为灰色固体。LCMS显示分子离子峰m/z[MH]+：358.1。
(2)、制备中间体6：在500mL三口瓶中依次加入中间体5(700mg，1.96mmol)、MeOH(200mL)和雷尼镍(700mg)。反应液在氢气中常温搅拌反应3小时。过滤反应液，滤液浓缩干燥后得到中间体6(620mg，收率96.7％)，为浅棕色固体。LCMS显示分子离子峰m/z[MH]+：328.1。
(3)、制备式Ib化合物：在10mL三口瓶中依次加入中间体6(163mg，0.5mmol)、三光气(49mg，0.165mmol)和干燥THF(5mL)。在氮气保护下将反应液冷却到0℃，缓慢滴加DIPEA(194mg，1.5mmol)。反应液搅拌反应10分钟。然后向反应液中快速加入化合物3a(62mg，0.5mmol)。反应液在室温搅拌过夜，浓缩，用反相柱层析和HPLC纯化得到式Ib化合物(38mg，收率16.9％)，为白色固体。
对得到的目标产品式Ib化合物进行了氢核磁共振1H-NMR(400MHz，d-DMSO)和质谱测试，结果如下：
1H-NMR谱图中吸收峰：δ＝9.16(s,1H,ArH),8.85(d,J＝6Hz,1H,ArH),8.72(s,1H,ArH),8.67(s,1H,ArH),7.95(b,1H,CONH2),7.86(b,1H,CONH2),7.80(dd,1H,J1＝2.4Hz,J2＝13.2Hz,ArH),7.76(s,1H,ArH),7.59(s,1H,CONH),7.45(t,J＝8.8Hz,1H,ArH),7.40(s,1H,CONH),7.30-7.28(m,1H,ArH),6.76(d,J＝6Hz,1H,ArH),4.07(s,3H,NCH3),3.79(s,3H,OCH3)。
m/z[MH]+：451.2。计算得出产品具有分子式C22H19FN6O4，精确分子质量(exact mass)为450.15。
实施例3
本实施例提供式Ic化合物，其化学结构如下：
Figure PCTCN2017096569-appb-000010
式Ic化合物可通过如下合成路线获得：
Figure PCTCN2017096569-appb-000011
式Ic化合物的制备方法具体包括如下步骤：
(1)、制备中间体8：在500mL三口瓶中依次加入化合物7(11.3g，100mmol)、DMAP(2.44g，20mmol)和DCM(140mL)。将(Boc)2O(26g，120mmol)溶解在DCM(40mL)中，缓慢加入到三口瓶中。反应液在室温搅拌反应1小时。反应液用0.5N HCl(150mL)洗涤两次，饱和食盐水洗涤，Na2SO4干燥浓缩后得到中间体8(20g，收率93.8％)，为白色固体。
(2)、制备中间体9：在250mL三口瓶中依次加入中间体8(10g，46.9mmol)、MeOH(200mL)、EtOH(100mL)和10％Pd/C(2g)。反应液在氢气中室温搅拌反应14小时。反应液过滤浓缩，滤饼干燥后得到中间体9(8.0g，收率93.2％)，为浅紫色固体。
(3)、制备式Ic化合物：在10mL三口瓶中依次加入中间体6(220mg，0.67mmol)、三光气(66mg，0.22mmol)和干燥THF(5mL)。在氮气保护下将反应液冷却到0℃，缓慢滴加DIPEA(173mg，1.34mmol)。反应液搅拌反应10分钟。 然后向反应液中快速加入中间体9(240mg，1.34mmol)。反应液在室温搅拌过夜，浓缩，反相柱层析分离得到中间体10(95mg，收率32.4％)，为白色固体。因为在溶液中有TFA，冻干的过程中中间体10转变为式Ic化合物。
对得到的目标产品式Ic化合物进行了氢核磁共振1H-NMR(400MHz，d-DMSO)和质谱测试，结果如下：
1H-NMR谱图中吸收峰：δ＝9.17-9.14(m,1H,ArH),8.90-8.89(m,1H,ArH),8.73(s,1H,ArH),8.65-8.62(m,1H,ArH),7.97(b,1H,CONH2),7.88(b,1H,CONH2),7.82(dd,1H,J1＝2.0Hz,J2＝13.6Hz,ArH),7.63(s,2H,NHCONH),7.59(m,1H,ArH),7.46(t,J＝8.8Hz,1H,ArH),7.32-7.29(m,1H,ArH),6.83-6.82(m,1H,ArH),4.07(s,3H,OCH3)。
m/z[MH]+：437.2。计算得出产品具有分子式C21H17FN6O4，精确分子质量(exact mass)为436.13。
实施例4
本实施例提供化合物酶活性测试试验。
1、试验方法
化合物的半抑制浓度IC50(把酶活性抑制至50％时所需的化合物的浓度)是以固定的酶混合特定底物及不同浓度的待测化合物来测定的。所用的测定方法是卡尺迁移变动分析(Caliper Mobility Shift Assay)，所测定的激酶为VEGFR1、VEGFR2、VEGFR3、FLT3、PDGFR、PDGFR、FGFR1、RET、EGFR和IGF1R，所应用的标准参照化合物为星形孢菌素(staurosporine)。
2、试验结果
表1总结了目标化合物(Ia、Ib和Ic)对VEGFR1、VEGFR2、VEGFR3、FLT3、PDGFR、PDGFR、FGFR1、RET、EGFR和IGF1R酶活性抑制实验结果，结果显示目标化合物对VEGFR2具有很强的抑制活性，对其他相关激酶，特别是EGFR和IGF1R具有很好的选择性抑制活性。这一对VEGFR2选择性的抑制作用对血管生成有关的适应症包括恶性肿瘤疾病及其他与血管生成相关的转移生长疾病的治疗 具有重要的治疗意义。表1也总结了目前已经上市疗效较好的VEGFR2抑制剂瑞戈非尼的相关数据。
表1化合物酶活性抑制实验结果
Figure PCTCN2017096569-appb-000012
实施例5
本实施例提供药物动力学属性评估试验。
1、实验方法
实验动物：CD-1小鼠、雄性和雌性；体重：20-25g；
供试品配制：将目标化合物配制成0.2mg/mL，待用。给药途径：静脉注射。给药容量及频率：2mL/kg，单次给药。剂量：3mg/kg。
样品采集：按照下列时间点采集血液，给药后5min、15min、30min、1hr、2hr、4hr、8hr和24hr取血。
2、样品分析及结果
样品分析：使用LC-MS/MS方法对采集样品进行检测。使用仪器型号为API4000。
药物动力学数据分析：使用WinNolin按照非房室模型法对所得血药浓度数据进行拟合和计算，部分结果总结在表2中。
表2按照非房室模型法计算出的目标化合物药物动力学参数
Figure PCTCN2017096569-appb-000013
试验结果表明本发明化合物具有与治疗途径相当的药物动力学特征。
以上实施例仅是代表性的。通过上述实施例可见，本发明的化合物是理想的高效选择性VEGFR2激酶抑制剂，可期望用于治疗或预防血管生成有关的适应症包括恶性肿瘤疾病及其他与血管生成相关的转移生长疾病并取得非常好的效果，其还可以和不同类型的药用盐相结合制成口服制剂(片剂或胶囊等)。用本发明化合物制成的片剂或胶囊可被服用每日一次或多次。本发明化合物还可和其他它药物结合制成复方制剂或局部用药制剂。
上述实施例只为说明本发明的技术构思及特点，其目的在于让熟悉此项技术的人士能够了解本发明的内容并据以实施，并不能以此限制本发明的保护范围。凡根据本发明精神实质所作的等效变化或修饰，都应涵盖在本发明的保护范围之内。

Claims (10)

  1. 具有通式(I)所示结构的喹啉衍生物，其可药用盐、水合物或以任何形式代谢形成的代谢产物，
    Figure PCTCN2017096569-appb-100001
    其中：
    R1选自R5或NHR5，其中R5为环烷基、杂环或取代杂环；
    R2选自氢、卤素、羟基、烷氧基或氰基；
    R3和R4独立地选自OR6、C(O)NH2、C(O)NHR6，其中R6为C1-C6烷基或卤代烷基；
    X选自NH或O；
    所述具有通式(I)所示结构的喹啉衍生物，其可药用盐、水合物或以任何形式代谢形成的代谢产物中，非交换性的氢未被取代，或部分或全部被氘取代。
  2. 根据权利要求1所述的喹啉衍生物，其可药用盐、水合物或以任何形式代谢形成的代谢产物，其特征在于：R2为Cl或F。
  3. 根据权利要求1所述的喹啉衍生物，其可药用盐、水合物或以任何形式代谢形成的代谢产物，其特征在于：R5为环烷基或卤代环烷基；含N或O的杂环，其未被取代或为卤素、C1-C6烷基中的一个或多个取代基取代，其中所述环烷基碳数优选为3～6个。
  4. 根据权利要求3所述的喹啉衍生物，其可药用盐、水合物或以任何形式代谢形成的代谢产物，其特征在于：R5为碳数为3的环烷基；含1或2或3个N的不饱和五元或六元杂环，其未被取代或被一个或二个选自甲基、乙基取代。
  5. 根据权利要求4所述的喹啉衍生物，其可药用盐、水合物或以任何形式代谢形成的代谢产物，其特征在于：R5为碳数为3的环烷基；含2个N的不饱和五元杂环，其未被取代或被一个甲基取代。
  6. 根据权利要求1所述的喹啉衍生物，其可药用盐、水合物或以任何形式代谢形成的代谢产物，其特征在于：R6为甲基或乙基。
  7. 根据权利要求1所述的喹啉衍生物，其可药用盐、水合物或以任何形式代谢形成的代谢产物，其特征在于：所述的喹啉衍生物为如下结构式表示的化合物中的一种：
    Figure PCTCN2017096569-appb-100002
    Figure PCTCN2017096569-appb-100003
  8. 一种制备如权利要求1至7中任一项权利要求所述的喹啉衍生物，其可药用盐、
    水合物的中间体，其特征在于：所述中间体为如下结构式表示的化合物中的一种：
    Figure PCTCN2017096569-appb-100004
  9. 如权利要求1至7中任一项权利要求所述的喹啉衍生物，其可药用盐、水合物，或以任何形式代谢形成的代谢产物在制备预防和/或治疗与血管生成有关的适应症的药物中的用途。
  10. 一种预防和/或治疗与血管生成有关的适应症的药物，其特征在于：含有如权利要求1至7中任一项权利要求所述的喹啉衍生物，其可药用盐、水合物，或以任何形式代谢形成的代谢产物。
PCT/CN2017/096569 2016-08-09 2017-08-09 一种喹啉衍生物及其用途 WO2018028591A1 (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US16/266,000 US10689361B2 (en) 2016-08-09 2019-02-02 Quinoline derivative and use thereof

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201610649732.2 2016-08-09
CN201610649732 2016-08-09

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US16/266,000 Continuation-In-Part US10689361B2 (en) 2016-08-09 2019-02-02 Quinoline derivative and use thereof

Publications (1)

Publication Number Publication Date
WO2018028591A1 true WO2018028591A1 (zh) 2018-02-15

Family

ID=61161721

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2017/096569 WO2018028591A1 (zh) 2016-08-09 2017-08-09 一种喹啉衍生物及其用途

Country Status (3)

Country Link
US (1) US10689361B2 (zh)
CN (1) CN107698562A (zh)
WO (1) WO2018028591A1 (zh)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018145621A1 (zh) * 2017-02-07 2018-08-16 恩瑞生物医药科技（上海）有限公司 喹啉类化合物、其制备方法及其医药用途
WO2020214734A1 (en) 2019-04-16 2020-10-22 Vivace Therapeutics, Inc. Bicyclic compounds
US11866431B2 (en) 2018-11-09 2024-01-09 Vivace Therapeutics, Inc. Bicyclic compounds

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113480479B (zh) * 2021-08-12 2022-08-02 上海爱博医药科技有限公司 脲类多靶点酪氨酸激酶抑制剂及其医药应用
CN115215799A (zh) * 2022-08-12 2022-10-21 上海爱博医药科技有限公司 脲类多靶点酪氨酸激酶抑制剂及其多种医药应用

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1478078A (zh) * 2000-10-20 2004-02-25 ������������ʽ���� 含氮芳环衍生物
CN1543459A (zh) * 2001-04-27 2004-11-03 ������������ʽ���� 具有唑基的喹啉衍生物和喹唑啉衍生物
CN101998951A (zh) * 2008-04-10 2011-03-30 大鹏药品工业株式会社 酰基硫脲化合物或其盐及其用途
WO2012008564A1 (ja) * 2010-07-16 2012-01-19 協和発酵キリン株式会社 含窒素芳香族複素環誘導体
CN103003262A (zh) * 2010-07-16 2013-03-27 协和发酵麒麟株式会社 含氮芳香族杂环衍生物
CN103124729A (zh) * 2010-08-28 2013-05-29 利德探索中心有限公司 作为Axl抑制剂的药物活性化合物
CN103405429A (zh) * 2013-08-22 2013-11-27 中国药科大学 一类vegfr-2抑制剂及其用途
WO2013180949A1 (en) * 2012-05-27 2013-12-05 Ning Xi Substituted quinoline compounds and methods of use

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1478078A (zh) * 2000-10-20 2004-02-25 ������������ʽ���� 含氮芳环衍生物
CN1543459A (zh) * 2001-04-27 2004-11-03 ������������ʽ���� 具有唑基的喹啉衍生物和喹唑啉衍生物
CN101998951A (zh) * 2008-04-10 2011-03-30 大鹏药品工业株式会社 酰基硫脲化合物或其盐及其用途
WO2012008564A1 (ja) * 2010-07-16 2012-01-19 協和発酵キリン株式会社 含窒素芳香族複素環誘導体
CN103003262A (zh) * 2010-07-16 2013-03-27 协和发酵麒麟株式会社 含氮芳香族杂环衍生物
CN103124729A (zh) * 2010-08-28 2013-05-29 利德探索中心有限公司 作为Axl抑制剂的药物活性化合物
WO2013180949A1 (en) * 2012-05-27 2013-12-05 Ning Xi Substituted quinoline compounds and methods of use
CN103405429A (zh) * 2013-08-22 2013-11-27 中国药科大学 一类vegfr-2抑制剂及其用途

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018145621A1 (zh) * 2017-02-07 2018-08-16 恩瑞生物医药科技（上海）有限公司 喹啉类化合物、其制备方法及其医药用途
US10800741B2 (en) 2017-02-07 2020-10-13 Ancureall Pharmaceutical (Shanghai) Co., Ltd. Quinoline compound, preparation method and medical use therefor
US11866431B2 (en) 2018-11-09 2024-01-09 Vivace Therapeutics, Inc. Bicyclic compounds
WO2020214734A1 (en) 2019-04-16 2020-10-22 Vivace Therapeutics, Inc. Bicyclic compounds
CN114072207A (zh) * 2019-04-16 2022-02-18 维瓦斯治疗公司 双环化合物
US11420935B2 (en) 2019-04-16 2022-08-23 Vivace Therapeutics, Inc. Bicyclic compounds
EP3956033A4 (en) * 2019-04-16 2023-01-11 Vivace Therapeutics, Inc. BICYCLIC LINKS
CN114072207B (zh) * 2019-04-16 2024-03-29 维瓦斯治疗公司 双环化合物

Also Published As

Publication number Publication date
US10689361B2 (en) 2020-06-23
US20190169163A1 (en) 2019-06-06
CN107698562A (zh) 2018-02-16

Similar Documents

Publication Publication Date Title
WO2018028591A1 (zh) 一种喹啉衍生物及其用途
TWI409066B (zh) 作為血管內皮生長因子（ｖｅｇｆ）受體激酶抑制劑之新穎鄰胺基苯醯胺吡啶脲
AU2017287553B2 (en) Imidazopyrazinamine phenyl derivative and use thereof
CN107151249B (zh) 作为flt3抑制剂的蝶啶酮衍生物及应用
JP2011510058A (ja) Ｃ−ｍｅｔの阻害剤として活性な縮合ピリジン
WO2015058589A1 (zh) 吡啶酮类衍生物、其制备方法及其在医药上的应用
WO2012139499A1 (zh) 一种脲类化合物、其制备方法、其中间体及其应用
CN103354809A (zh) 一种芳基脲类化合物、其中间体及其应用
JP2021523168A (ja) がん幹細胞を標的化するがん治療
JP2022517280A (ja) ブルトン型チロシンキナーゼ阻害剤
CN113454081A (zh) 咪唑并吡啶基化合物及其用于治疗增生性疾病的用途
TW202200575A (zh) 一種免疫抑制劑、其製備方法和應用
CA3173804A1 (en) Fused aza-heterocyclic amide compound and use thereof
JP2018509407A (ja) ＭＥＫキナーゼ阻害剤のｐ−トルエンスルホン酸塩、およびその結晶形およびその製造法
JP2022517723A (ja) Ｃｄｋ阻害剤としての大環状化合物、その製造方法及びその医薬品における応用
WO2021164793A1 (zh) 用作激酶抑制剂的化合物及其应用
CA3069602A1 (en) Formylpyridine derivative having fgfr4 inhibitory activity, preparation method therefor and use thereof
WO2021180238A1 (zh) 一类用作激酶抑制剂的化合物及其应用
CA2937012A1 (en) Fused pyrazole derivative
WO2021249324A1 (zh) 烯基嘧啶类化合物、其制备方法与应用
CN109369676B (zh) 一种双-氟喹诺酮噁二唑脲类n-乙酰诺氟沙星衍生物及其制备方法和应用
JP7110335B2 (ja) プロテインキナーゼ阻害剤として有用なピリドキナゾリン誘導体
Murineddu et al. Novel N-aryl nicotinamide derivatives: Taking stock on 3, 6-diazabicyclo [3.1. 1] heptanes as ligands for neuronal acetylcholine receptors
WO2019149128A1 (zh) 作为抗肿瘤药物的5-氯-2,4-嘧啶衍生物
CN109438482B (zh) 一种含芦氟沙星的双-氟喹诺酮基噁二唑脲类衍生物及其制备方法和应用

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 17838721

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 17838721

Country of ref document: EP

Kind code of ref document: A1