WO2022184119A1 - 酪氨酸激酶抑制剂及其药物应用 - Google Patents
酪氨酸激酶抑制剂及其药物应用 Download PDFInfo
- Publication number
- WO2022184119A1 WO2022184119A1 PCT/CN2022/078934 CN2022078934W WO2022184119A1 WO 2022184119 A1 WO2022184119 A1 WO 2022184119A1 CN 2022078934 W CN2022078934 W CN 2022078934W WO 2022184119 A1 WO2022184119 A1 WO 2022184119A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- tyrosine kinase
- fluoro
- kinase inhibitor
- chlorophenylamino
- nitroquinazoline
- Prior art date
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- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 230000006965 reversible inhibition Effects 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- NESLWCLHZZISNB-UHFFFAOYSA-M sodium phenolate Chemical compound [Na+].[O-]C1=CC=CC=C1 NESLWCLHZZISNB-UHFFFAOYSA-M 0.000 description 1
- SUBJHSREKVAVAR-UHFFFAOYSA-N sodium;methanol;methanolate Chemical compound [Na+].OC.[O-]C SUBJHSREKVAVAR-UHFFFAOYSA-N 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000012192 staining solution Substances 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 238000005556 structure-activity relationship Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 229940113082 thymine Drugs 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(C)C)[C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C1=CC=C(O)C=C1 VBEQCZHXXJYVRD-GACYYNSASA-N 0.000 description 1
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- 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
- C07D239/93—Sulfur atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- 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
-
- 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
- C07D239/88—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
Definitions
- the present invention relates to a tyrosine kinase inhibitor and its application in a therapeutic drug for inhibiting and treating diseases caused by overexpression of tyrosine kinase.
- Tyrosine kinases play a key role in signaling, and human epidermal growth factor (EGF) and epidermal growth factor receptor (EGFR) binding can activate the activity of tyrosine kinases, resulting in epidermal growth factor in a variety of human solid tumors Overexpression causes uncontrollable cell division.
- Tyrosine Kinase Inhibitors can prevent and control the activity of tyrosine kinases and control cell proliferation. Its mechanism of action is to compete with adenosine triphosphate (ATP) for the ATP binding site of kinases.
- CML chronic myeloid leukemia
- GIST stromal tumor
- NSCLC non-small cell lung cancer
- HCC hepatocellular carcinoma
- RRC renal cancer
- EGFR tyrosine kinase inhibitors have been developed as anti-tumor drugs.
- the first representative tyrosine kinase inhibitors, gefitinib and erlotinib, have good curative effect on recurrent and advanced non-small cell lung cancer . They belong to aniline quinazoline compounds, which mainly act on EGFR.
- the structure is generally modified in the following form: adding a lipophilic substituent to the 3-position substituent of aniline, such as introducing an acetylene group, or replacing the H on the aniline It is F, Cl, Br or I atom; the electron group is connected to the 6 and 7 positions of the quinazoline ring; the N or O atom is introduced into the 7-position substitution position of the quinazoline ring.
- aniline such as introducing an acetylene group, or replacing the H on the aniline It is F, Cl, Br or I atom
- the electron group is connected to the 6 and 7 positions of the quinazoline ring
- the N or O atom is introduced into the 7-position substitution position of the quinazoline ring.
- EGFR mutations mostly occur in gene exons 18, 19, 20, and 21, among which point mutations in exons 18 and 21 and deletion mutations in exon 19 are mainly related to EGFR-TKI sensitivity. Clinical studies have shown that exon 19 and 21 mutations account for about 90% of the mutations in the tyrosine kinase region; gefitinib has a good effect on patients with these mutations.
- T790M is due to the conversion of cytosine (C) at position 2369 of EGFR exon 20 to thymine (T), resulting in the replacement of the encoded product at position 790 by threonine to methionine. resistance to tinib or erlotinib.
- Threonine as a "gatekeeper group", is located outside the core of the tyrosine kinase contact reaction, and forms a high-affinity hydrogen bond with the aniline group of gefitinib, thus ensuring that the drug binds tightly to the tyrosine kinase without Plays anti-tumor effect; once mutated, threonine is replaced by methionine, which introduces a larger amino acid side chain to form a steric hindrance, thereby affecting the interaction between tyrosine kinase and gefitinib The formation of inter-hydrogen bonds eventually led to the inability of gefitinib to bind to it.
- the first-generation tyrosine kinase inhibitors all work in a way of reversible inhibition (hydrogen bond formation), so generally speaking, the selectivity is not good enough, the efficacy is not strong and durable enough, and it is easy to cause drug resistance.
- Second-generation (such as afatinib) and third-generation (such as osimertinib) tyrosine kinase inhibitors are irreversible TKIs, which usually maintain the basic structural backbone of reversible TKIs and attach an electrophile to an appropriate position.
- this electrophilic functional group can interact with the thiol group on cysteine (electron-rich nucleophilic structure) near the ATP binding domain
- the electrical reaction forms a covalent bond.
- irreversible TKIs have many unique advantages.
- the technical problem to be solved by the present invention is to provide a tyrosine kinase inhibitor, which can irreversibly inhibit the activity of tyrosine kinase, and inhibit and treat diseases caused by overexpression of tyrosine kinase.
- the technical scheme for realizing the first object of the present invention is a tyrosine kinase inhibitor, which is a quinazoline derivative with the following structural formula:
- R1 is selected from alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl containing one to six carbons,
- Phenyl mono- and poly-substituted phenyl, trifluoromethyl, 2,2,2-trifluoroethyl, CH3O(CH2)n-, wherein R is methyl, ethyl, isopropyl, trifluoromethyl, 2,2,2-trifluoroethyl, cyclopropyl, acetyl, acryloyl.
- R2 and R3 are selected from halogen, hydrogen, amino, substituted amino, cyano, hydroxyl, sulfonic acid, sulfonamido, trifluoromethyl, 2,2,2-trifluoroethyl, methyl, methoxy, Ethynyl; the positions of R2 and R3 can be ortho, para or meta.
- Y is NH, O, S, Z-N, wherein Z is selected from methyl, ethyl, isopropyl, trifluoromethyl, 2,2,2-trifluoroethyl, cyclopropyl.
- X is selected from Cl, Br, F.
- n an integer from 0-6.
- R1 is methyl
- R2 is F
- R3 is Cl
- Y is NH
- X is Br
- n 0
- the tyrosine kinase inhibitor is 4-(4-fluoro-3-chlorophenylamino) )-7-methoxy-6-(N-bromoacetyl)aminoquinazoline.
- the technical solution to achieve the second object of the present invention is the application of the above tyrosine kinase inhibitor in the preparation of a therapeutic drug for inhibiting and treating diseases caused by overexpression of tyrosine kinase.
- X is a halogen atom, and n represents an integer of 0-6)
- the nucleophilic reaction binds to the cysteine sulfhydryl group to form a covalent bond, thereby irreversibly inhibiting tyrosine kinase activity.
- Figure 1 is the nuclear magnetic resonance H spectrum of the compound prepared in Example 1.
- Figure 2 is a statistical chart of the proliferation of mesothelioma 40L cells after pretreatment by plate cloning experiments.
- the basic reaction process prepared by the quinazoline derivative of the present invention is as follows:
- 3.13 is the peak of MeOH
- 2.60 is the peak of DMSO.
- 4-(4-Fluoro-3-chlorophenylamino)-7-methoxy-6-aminoquinazoline 160 mg and p-dimethylaminopyridine 60 mg were dissolved in 10 ml of N,N-dimethylformamide, Add 125 mg of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, 70 mg of 3-chloropropionic acid and 129 mg of N,N-diisopropylethylamine, stir After 15 hours, 20 ml of water was added, extracted with 100 ml of ethyl acetate, the ethyl acetate was separated and dried over magnesium sulfate.
- Example 1 The compound prepared in Example 1 and gefitinib were compared and detected, and the results were as follows:
Abstract
本发明公开了一种酪氨酸激酶抑制剂及其药物应用,本发明的酪氨酸激酶抑制剂是喹唑啉衍生物,结构式如下:本发明在喹唑啉结构的基础上引入含有XCH2(CH2)nC=O的官能团,容易通过亲核反应与半胱氨酸巯基结合,形成共价键,从而不可逆地抑制酪氨酸激酶活性。
Description
本发明涉及一种酪氨酸激酶抑制剂,及其在抑制和治疗由于酪氨酸激酶过度表达引起的疾病的治疗药物中的应用。
细胞内有许多信号通路***,它们相互作用来控制细胞的增殖、生长、转移和凋亡。酪氨酸激酶在信号传导中起关键作用,人类表皮生长因子(EGF)和表皮生长因子受体(EGFR)结合,可以激活酪氨酸激酶的活性,导致表皮生长因子在人类多种实体肿瘤中过度表达,引起不可控制的细胞***,酪氨酸激酶抑制剂(Tyrosine Kinase Inhibitors,TKI)可以阻止和控制酪氨酸激酶的活性,控制细胞的增殖。它的作用机制是与三磷酸腺苷(ATP)竞争激酶的ATP结合位点,相对于传统的细胞毒抗癌药物具有高选择性和不良反应少的特点,在慢性粒细胞白血病(CML)、胃肠间质瘤(GIST)、非小细胞肺癌(NSCLC)、肝细胞癌(HCC)和肾癌(RCC)等疾病的治疗中都表现出优越性。
目前已开发出多种EGFR酪氨酸激酶抑制剂作为抗肿瘤的药物,第一代表酪氨酸激酶抑制剂,吉非替尼和厄洛替尼对于复发和进展期非小细胞肺癌具有良好疗效。它们属于苯胺喹唑啉类化合物,主要作用于EGFR,为了提高活性一般采用以下形式对结构进行改造:在苯胺3位取代基添加亲脂性取代基,如引入乙炔基,或将苯胺上的H替换为F、Cl、Br或I原子;在喹唑啉环的6、7位连接上电子基团;在喹唑啉环的7位取代位置引入N或O原子。目前上市的各种含喹唑啉基团的酪氨酸激酶抑制剂的结构均符合以上构效关系。
我国患者EGFR突变比例较高,对EGFR-TKI治疗敏感。但是耐药性的存在是临床上面临的巨大挑战,几乎所有治疗有效的患者在经过一段时间的缓解期后又出现疾病进展。
EGFR突变多发生于基因外显子18、19、20、21,其中与EGFR-TKI敏感性相关的主要是位于外显子18、21的点突变和外显子19的缺失突变。临床研究显示外显子19、21突变约占酪氨酸激酶区域突变的90%;对含有这些突变的患者,吉非替尼有很好的疗效。
T790M是由于EGFR外显子20的第2369位的胞嘧啶(C)转化为胸腺嘧啶(T),从而导致第790位的编码产物由苏氨酸替换为甲硫氨酸,这个替代与吉非替尼或者厄 洛替尼的耐药性有关。苏氨酸作为“看门人基团”位于酪氨酸激酶接触反应核心之外,与吉非替尼的苯胺基团形成具有高度亲和力的氢键,从而保证了药物与酪氨酸激酶紧密结合而发挥抗肿瘤作用;一旦发生突变,苏氨酸被甲硫氨酸取代,使得该位点上引入了一条更大的氨基酸侧链构成空间位阻,从而影响酪氨酸激酶与吉非替尼之间氢键的形成,最终导致吉非替尼无法与其相结合。
第一代酪氨酸激酶抑制剂都是以可逆性抑制(氢键形成)的方式发挥作用,所以一般来说选择性不够好,药效不够强烈和持久,容易引起耐药性。第二代(如阿法替尼)和第三代(如奥希替尼)酪氨酸激酶抑制剂属于不可逆TKI,通常保持可逆性TKI的基本结构骨架,在合适的位置连接上一个亲电的功能团,如α,β-不饱和醛/酮、丙烯酰胺或炔基,这个亲电的功能团可以与ATP结合域附近的半胱氨酸上巯基(富电子的亲核结构)发生亲电反应形成共价键。与可逆性TKI相比,不可逆性TKI具有诸多独特的优势。
发明内容
本发明所要解决的技术问题是,提供一种酪氨酸激酶抑制剂,能够不可逆地抑制酪氨酸激酶活性,抑制和治疗由于酪氨酸激酶过度表达引起的疾病。
实现本发明第一目的的技术方案是一种酪氨酸激酶抑制剂,是一种喹唑啉衍生物,结构式如下:
其中R1选自含有一个碳至六个碳的烷基,烯基,取代烯基,炔基,取代炔基,
R2、R3选自卤素,氢,氨基,取代氨基,氰基,羟基,磺酸基,磺酰胺基,三氟甲基,2,2,2-三氟乙基,甲基,甲氧基,乙炔基;R2、R3的位置可以是邻位、对位或间位。
Y为NH,O,S,Z-N,其中Z选自甲基,乙基,异丙基,三氟甲基,2,2,2-三氟乙基,环丙基。
X选自Cl,Br,F。
n代表0-6的一个整数。
作为可选的,R1为甲基,R2为F,R3为Cl,Y为NH,X为Br,n=0;该酪氨酸激酶抑制剂为4-(4-氟-3-氯苯氨基)-7-甲氧基-6-(N-溴乙酰基)氨基喹唑啉。
实现本发明第二目的的技术方案是上述酪氨酸激酶抑制剂在制备抑制和治疗因酪氨酸激酶过表达所致疾病的治疗药物中的应用。
本发明的酪氨酸激酶抑制剂活性成分在喹唑啉结构的基础上引入含有XCH2(CH2)nC=O的官能团(X为卤素原子,n代表0-6的一个整数),它很容易通过亲核反应与半胱氨酸巯基结合,形成共价键,从而不可逆地抑制酪氨酸激酶活性。
图1是实施例1制备得到化合物的核磁共振H谱图。
图2是平板克隆实验分析预处理后间皮瘤40L细胞增殖情况的统计图表。
本发明的喹唑啉衍生物制备的基本反应过程如下:
以下面结合具体实施例对本发明作进一步说明:
(实施例1)
制备4-(4-氟-3-氯苯氨基)-7-甲氧基-6-(N-溴乙酰基)氨基喹唑啉,步骤如下:
(1)制备4-氯-7-氟-6硝基喹唑啉。
在250毫升圆底瓶中加入4-羟基-7-氟-6硝基喹唑啉8.5克和三氯氧磷150毫升,混合物在搅拌下加热回流6小时。旋转蒸化去掉过量的三氯氧磷,然后用10:1的石 油醚/乙酸乙酯洗涤,得固体4-氯-7-氟-6硝基喹唑啉8克,MS(m/z):227.78(M+1)
+。
(2)制备4-(4-氟-3-氯苯氨基)-7-氟-6-硝基喹唑啉。
4-氯-7-氟-6硝基喹唑啉2.3克,4-氟-3-氯苯胺1.6克,碳酸钾1.73克加入N,N二甲基甲酰胺30毫升,混合物搅拌加热到50度,10小时后,在减压蒸馏下除去溶剂,加入乙酸乙酯100毫升,用30毫升水洗涤,分离出乙酸乙酯并用硫酸镁干燥。过滤浓缩,残余物用二氯甲烷/甲醇过柱分离,得产物4-(4-氟-3-氯苯氨基)-7-氟-6-硝基喹唑啉3.0克,MS(m/z):336.80(M+1)
+。
(3)制备4-(4-氟-3-氯苯氨基)-7-甲氧基-6-硝基喹唑啉。
4-(4-氟-3-氯苯氨基)7-氟-6-硝基喹唑啉3.3克溶解于四氢呋喃100毫升,加入25%甲醇钠甲醇溶液5毫升,室温搅拌8小时,加水50毫升,用乙酸乙酯100毫升萃取,分离出乙酸乙酯并用硫酸镁干燥。过滤浓缩,残余物用二氯甲烷/甲醇过柱分离,得产物4-(4-氟-3-氯苯氨基)-7-甲氧基-6-硝基喹唑啉2.5克,MS(m/z):348.72(M+1)
+。
(4)制备4-(4-氟-3-氯苯氨基)-7-甲氧基-6-氨基喹唑啉。
4-(4-氟-3-氯苯氨基)7-甲氧基-6-硝基喹唑啉3.3克溶解于混合溶剂乙醇150毫升和水8毫升,加入氯化铵1.6克和铁粉2.8克,然后在搅拌下加热回流5小时。过滤浓缩滤液,得到的固体用15毫升水洗涤除出氯化铵,过滤干燥得产物2.6克,MS(m/z):318.74(M+1)
+。
(5)制备4-(4-氟-3-氯苯氨基)-7-甲氧基-6-(N-溴乙酰基)氨基喹唑啉。
4-(4-氟-3-氯苯氨基)7-甲氧基-6-氨基喹唑啉160毫克和三乙胺129毫克溶解于二氯甲烷50毫升,然后冷却至0度,慢慢滴加溴乙酰溴120毫克,搅拌3小时,加水10毫升,分离出二氯甲烷并用无水硫酸镁干燥,过滤浓缩得粗产品,进一步过柱纯化得产物170毫克。
所制得化合物的表征如下:MS(m/z):438.80(M+1)
+。
核磁共振氢谱图见图1。
H NMR(CD
3OD/DMSO-D
6):δ=8.92(s,1H),8.55(s,1H),8.12(m,1H),7.79(m,1H),7.38(m,1H),7.30(s,1H),4.28(s,2H),4.06(s,3H)。
另外,图中δ=4.04是H
2O的峰,3.13是MeOH的峰,2.60是DMSO的峰。
(实施例2)
制备4-(4-氟-3-氯苯氨基)-7-甲氧基-6-(N-氯乙酰基)氨基喹唑啉,步骤如下:
4-(4-氟-3-氯苯氨基)-7-甲氧基-6-氨基喹唑啉160毫克和三乙胺129毫克溶解于二 氯甲烷50毫升,然后冷却至0度,慢慢滴加氯乙酰氯68毫克,搅拌5小时,加水10毫升,分离出二氯甲烷并用无水硫酸镁干燥,过滤浓缩得粗产品,进一步过柱纯化得产物120毫克,MS(m/z):394.68(M+1)
+。
(实施例3)
制备4-(4-氟-3-氯苯氨基)-7-甲氧基-6-(N-3‘-氯丙酰基)氨基喹唑啉,步骤如下:
4-(4-氟-3-氯苯氨基)-7-甲氧基-6-氨基喹唑啉160毫克和对二甲氨基吡啶60毫克溶解于N,N-二甲基甲酰胺10毫升,加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐125毫克,3-氯丙酸70毫克和N,N-二异丙基乙基胺129毫克,搅拌15小时,加水20毫升,用乙酸乙酯100毫升萃取,分离出乙酸乙酯并用硫酸镁干燥。过滤浓缩,残余物用二氯甲烷/甲醇过柱分离,得产物4-(4-氟-3-氯苯氨基)-7-甲氧基-6-(N-3‘-氯丙酰基)氨基喹唑啉55毫克,MS(m/z):408.68(M+1)
+。
(实施例4)
制备4-(4-氟-3-氯苯氨基)-7-炔丙基氧基-6-(N-溴乙酰基)氨基喹唑啉,步骤如下:
(1)制备4-(4-氟-3-氯苯氨基)-7-炔丙基氧基-6-硝基喹唑啉。
炔丙醇6.0克溶解于四氢呋喃300毫升,分批慢慢加入氢化钠4.3克,室温搅拌1小时,然后加入4-(4-氟-3-氯苯氨基)-7-氟-6-硝基喹唑啉13克。继续室温搅拌5小时,向反应液加水100毫升,再用乙酸乙酯300毫升萃取,分离出乙酸乙酯并用硫酸镁干燥。过滤浓缩,得产物4-(4-氟-3-氯苯氨基)-7-炔丙基氧基-6-硝基喹唑啉2.5克,MS(m/z):372.75(M+1)
+。
(2)制备4-(4-氟-3-氯苯氨基)-7-炔丙基氧基-6-氨基喹唑啉。
4-(4-氟-3-氯苯氨基)-7-炔丙基氧基-6-硝基喹唑啉10.0克溶解于混合溶剂乙醇250毫升和水18毫升,加入氯化铵4.5克和铁粉7.0克,然后在搅拌下加热回流15小时。过滤浓缩滤液,得到的固体进一步过柱纯化得产物7.6克,MS(m/z):342.76(M+1)
+。
(3)制备4-(4-氟-3-氯苯氨基)-7-炔丙基氧基-6-(N-溴乙酰基)氨基喹唑啉。
4-(4-氟-3-氯苯氨基)-7-炔丙基氧基-6-氨基喹唑啉343毫克和三乙胺258毫克溶解于二氯甲烷100毫升,然后冷却至0度,慢慢滴加溴乙酰溴220毫克,搅拌3小时,加水20毫升,分离出二氯甲烷并用无水硫酸镁干燥,过滤浓缩得粗产品,进一步过柱纯化得产物300毫克,MS(m/z):462.69(M+1)
+。
(实施例5)
制备4-(4-氟-3-氯苯氨基)-7-苯酚基-6-(N-氯乙酰基)氨基喹唑啉,步骤如下:
(1)制备4-(4-氟-3-氯苯氨基)-7-苯酚基-6-硝基喹唑啉。
4-(4-氟-3-氯苯氨基)-7-氟-6-硝基喹唑啉2.0克溶解于四氢呋喃100毫升,加入苯酚钠2.2克,室温搅拌2小时,加水50毫升,用乙酸乙酯100毫升萃取,分离出乙酸乙酯并用硫酸镁干燥。过滤浓缩,残余物用二氯甲烷/甲醇过柱分离,得产物4-(4-氟-3-氯苯氨基)7-苯酚基-6-硝基喹唑啉1.5克,MS(m/z):410.79(M+1)
+。
(2)制备4-(4-氟-3-氯苯氨基)-7-苯酚基-6-氨基喹唑啉。
4-(4-氟-3-氯苯氨基)-7-苯酚基-6-硝基喹唑啉1.5克溶解于混合溶剂乙醇100毫升和水6毫升,加入氯化铵2.0克和铁粉2.8克,然后在搅拌下加热回流5小时。过滤浓缩滤液,得到的固体用15毫升水和20毫升***洗涤,干燥得产物1.0克,MS(m/z):380.81(M+1)
+。
(3)制备4-(4-氟-3-氯苯氨基)-7-苯酚基-6-(N-氯乙酰基)氨基喹唑啉。
4-(4-氟-3-氯苯氨基)-7-苯酚基-6-氨基喹唑啉160毫克和三乙胺129毫克溶解于二氯甲烷50毫升,然后冷却至0度,慢慢滴加溴乙酰溴120毫克,搅拌3小时,加水10毫升,分离出二氯甲烷并用无水硫酸镁干燥,过滤浓缩得粗产品,进一步过柱纯化得产物170毫克,MS(m/z):456.74(M+1)
+。
(实施例6)
制备4-(3-乙炔基苯氨基)-7-甲氧基-6-(N-溴乙酰基)氨基喹唑啉,步骤如下:
(1)制备4-(3-乙炔基苯氨基)-7-氟-6-硝基喹唑啉。
4-氯-7-氟-6硝基喹唑啉2.3克,3-乙炔基苯胺1.3克,碳酸钾1.73克溶于N,N二甲基甲酰胺30毫升,混合物搅拌加热到50度,10小时后,在减压蒸馏下除去溶剂,加入乙酸乙酯100毫升,用30毫升水洗涤,分离出乙酸乙酯并用硫酸镁干燥。过滤浓缩,残余物用二氯甲烷/甲醇过柱分离,得产物4-(3-乙炔基苯氨基7)-氟-6-硝基喹唑啉2.1克,MS(m/z):308.68(M+1)
+。
(2)制备4-(3-乙炔基苯氨基)-7-甲氧基-6-硝基喹唑啉。
4-(3-乙炔基苯氨基)7-氟-6-硝基喹唑啉1.3克溶解于四氢呋喃100毫升,加入25%甲醇钠甲醇溶液5毫升,室温搅拌8小时,加水50毫升,用乙酸乙酯100毫升萃取,分离出乙酸乙酯并用硫酸镁干燥。过滤浓缩,残余物用二氯甲烷/甲醇过柱分离,得产物4-(3-乙炔基苯氨基)7-甲氧基-6-硝基喹唑啉0.8克,MS(m/z):320.70(M+1)
+。
(3)制备4-(3-乙炔基苯氨基)-7-甲氧基-6-氨基喹唑啉。
4-(3-乙炔基苯氨基)-7-甲氧基-6-硝基喹唑啉0.8克溶解于混合溶剂乙醇50毫升和水5毫升,加入氯化铵0.6克和铁粉1.1克,然后在搅拌下加热回流5小时。过滤浓缩滤液,得到的固体用10毫升水洗涤除出氯化铵,过滤干燥得产物0.5克,MS(m/z):290.80(M+1)
+。
(4)制备4-(3-乙炔基苯氨基)-7-甲氧基-6-(N-溴乙酰基)氨基喹唑啉。
4-(3-乙炔基苯氨基)-7-甲氧基-6-氨基喹唑啉145毫克和三乙胺129毫克溶解于二氯甲烷50毫升,然后冷却至0度,慢慢滴加溴乙酰溴120毫克,搅拌3小时,加水10毫升,分离出二氯甲烷并用无水硫酸镁干燥,过滤浓缩得粗产品,进一步过柱纯化得产物105毫克,MS(m/z):410.84(M+1)
+。
(试验例1)
对实施例1制备的化合物与吉非替尼进行对比检测,结果如下:
一、细胞平板克隆实验检测细胞增殖情况
1.实验步骤:
(1)用30μM的吉非替尼和实施例1药物分别预处理间皮瘤细胞系40L,用PBS作为空白对照组;
(2)收集不同处理组后的40L细胞;显微镜下计数,用相应的完全培养基调整细胞数量为200个/孔(2mL)种于六孔板中,在37℃含5%CO
2培养箱内培养;
(3)每隔3天换一次新鲜完全培养基;
(4)约连续培养7-10天,弃去培养液,用1×PBS小心洗涤3遍,每个培养皿中加入1mL 4%多聚甲醛固定细胞30分钟,弃去多聚甲醛,再次用1×PBS洗涤3遍,在室温下用结晶紫染色10分钟,弃去染液,1×PBS洗涤3遍;
(5)用相机拍照并计数统计分析。
2.实验结果
通过平板克隆实验分析不同药物对40L细胞的增殖能力影响,经过10天的实验结果如图2所示,图中**P<0.01,****P<0.0001。显示实施例1药物表现出具有显著优于吉非替尼的抑制肿瘤细胞增殖的能力。
Claims (3)
- 根据权利要求1所述的酪氨酸激酶抑制剂,其特征在于:R1为甲基,R2为F,R3为Cl,Y为NH,X为Br,n=0。
- 权利要求1所述的酪氨酸激酶抑制剂在制备抑制和治疗因酪氨酸激酶过表达所致疾病的治疗药物中的应用。
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