CN111825644B - 2,3-二氢萘并[2,3-b]呋喃-4,9-二酮类化合物及其制备方法和用途 - Google Patents
2,3-二氢萘并[2,3-b]呋喃-4,9-二酮类化合物及其制备方法和用途 Download PDFInfo
- Publication number
- CN111825644B CN111825644B CN201910311646.4A CN201910311646A CN111825644B CN 111825644 B CN111825644 B CN 111825644B CN 201910311646 A CN201910311646 A CN 201910311646A CN 111825644 B CN111825644 B CN 111825644B
- Authority
- CN
- China
- Prior art keywords
- compound
- furan
- dihydronaphtho
- cancer
- nmr
- Prior art date
- Legal status (The legal status 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 status listed.)
- Active
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
-
- 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
- A61P37/00—Drugs for immunological or allergic disorders
-
- 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
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/92—Naphthofurans; Hydrogenated naphthofurans
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/78—Ring systems having three or more relevant rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/94—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems condensed with rings other than six-membered or with ring systems containing such rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明提供了2,3‑二氢萘并[2,3‑b]呋喃‑4,9‑二酮类化合物及其制备方法和用途,属于医药技术领域。具体提供了如通式I‑A和I‑B所示的2,3‑二氢萘并[2,3‑b]呋喃‑4,9‑二酮类化合物,含有这类化合物的药物组合物,这类化合物的制备方法。本发明化合物具有STAT3抑制活性,能用于制备治疗和/或预防与STAT3活性相关的疾病药物,所述的疾病包括多种癌症,例如乳腺癌、肺癌、口腔癌、肾癌、食道癌、肝癌、胃癌、肠癌、宫颈癌以及卵巢癌等。
Description
技术领域
本发明涉及2,3-二氢萘并[2,3-b]呋喃-4,9-二酮类化合物、组合物或药学上可接受的盐、其制备方法及其药物用途。具体涉及新化合物、新的药物作用及其在制备预防、缓解和/或治疗与STAT3(Signal transducer and activator of transcription 3)活性相关的疾病(例如多种癌症,包括乳腺癌、肺癌、口腔癌、肾癌、食道癌、肝癌、胃癌、肠癌、宫颈癌以及卵巢癌等)药物中的应用,属于医药技术领域。
背景技术
众所周知,癌症是威胁人类健康的头号杀手。近些年来,随着老龄化日益加重、饮食结构变化、环境污染以及生活节奏加快导致作息不良等因素,我国癌症发生率和死亡率开始出现逐渐上升的趋势。
信号转导和转录激活因子(Signal transducer and activator oftranscription,STATs)是一类存在于人类细胞质中的胞浆蛋白家族,可被不同的细胞因子激活,并将细胞外的信号传导至细胞核内引发相应的靶基因的转录和表达。STAT蛋白家族主要包括7个主要蛋白,其中STAT3是STATs家族中的重要成员,可与众多的肿瘤细胞的形成息息相关。
应用STAT3抑制剂,对多种癌症(例如乳腺癌、肺癌、口腔癌、肾癌、食道癌、肝癌、胃癌、肠癌、宫颈癌以及卵巢癌等)及其并发症的治疗具有重要意义,对于目前严重危害人类健康的癌症及其并发症的预防和治疗产生积极的作用。
本发明的2,3-二氢萘并[2,3-b]呋喃-4,9-二酮类化合物为新化合物,没有在预防和治疗癌症及其并发症的应用相关报道。
发明内容
本发明要解决的技术问题是提供具有STAT3抑制活性并具有优良抗肿瘤活性的2,3-二氢萘并[2,3-b]呋喃-4,9-二酮类新化合物,其可药用盐,其前药,其多晶或共晶。
本发明要解决的另一技术问题是提供这类化合物的制备方法。
本发明要解决的又一技术问题是提供含有这类化合物的药物组合物。
本发明要解决的再一技术问题是提供这类化合物在制备抗/预防肿瘤中的应用。
为解决本发明的技术问题,本发明提供如下技术方案:
本发明技术方案的第一方面是提供了如通式I-A所示的化合物、异构体及其药学上可接受的盐:
其中:
R1独立的选自氢,C1-10烷基,C3-10环烷基,C0-8链烯基,非取代或取代的苯基,非取代或取代的五元杂芳基,非取代或取代的六元杂芳基,非取代或取代的五元杂环基,非取代或取代的六元杂环基,所述五元杂芳基、六元杂芳基、五元杂环基、六元杂环基,含有2-5个碳原子和1-3个选自氮、氧、硫杂原子,上述非取代或取代中取代基选自C1-6烷基,C1-6烷氧基,卤素,硝基,氰基,甲磺酰基,羟基,氨基,羧基,XmC1-6烷基,其中m选自1、2或3,X选自氟,氯,溴或碘;
R2独立的选自氢,C1-6烷基,-C0-6亚烷基COOH,-C0-6亚烷基COOC1-6烷基;
R3独立选自氢,卤素,C1-6烷基,C1-6烷氧基,XmC1-6烷基,其中m选自1、2或3,X选自氟,氯,溴或碘;
但不包括下列化合物:
如通式I-A所示的化合物、异构体及其药学上可接受的盐,其特征在于:
优选的R1独立的选自氢,C1-8烷基,C3-8环烷基,C0-6链烯基,非取代或取代的苯基,非取代或取代的五元杂芳基,非取代或取代的六元杂芳基,非取代或取代的五元杂环基,非取代或取代的六元杂环基,所述五元杂芳基、六元杂芳基、五元杂环基、六元杂环基,含有2-5个碳原子和1-3个选自氮、氧、硫杂原子,上述非取代或取代中取代基选自C1-4烷基,C1-4烷氧基,卤素,硝基,氰基,甲磺酰基,羟基,氨基,羧基,XmC1-4烷基,其中m选自1、2或3,X选自氟,氯,溴或碘;
优选的R2独立的选自氢,C1-4烷基,-C0-4亚烷基COOH,-C0-4亚烷基COOC1-4
烷基R3独立选自氢,卤素,C1-4烷基,C1-4烷氧基,XmC1-4烷基,其中m选自1、
2或3,X选自氟,氯,溴或碘;
但不包括下列化合物:
如通式I-A所示的化合物、异构体及其药学上可接受的盐,其特征在于:
更优选的R1独立的选自氢,甲基,乙基,丙基,异丙基,正丁基,仲丁基,异丁基,叔丁基,异戊基,环丙基,环丁基,环戊基,环己基,环庚基,甲氧基,乙氧基,丙氧基,乙烯基,丙烯基,1-丁烯基,2-丁烯基,非取代或取代的苯基,非取代或取代的噻唑,非取代或取代的非取代或取代的噻吩,非取代或取代的恶唑,非取代或取代的咪唑,非取代或取代的吡唑,非取代或取代的呋喃,非取代或取代的哒嗪,非取代或取代的吗啉,非取代或取代的哌嗪,非取代或取代的哌啶,上述非取代或取代中的取代基选自甲基,乙基,丙基,异丙基,正丁基,仲丁基,异丁基,叔丁基,甲氧基,乙氧基,丙氧基,氟,氯,溴,碘,硝基,氰基,甲磺酰基,羟基,氨基,羧基,三氟甲基,三氟乙基;
更优的R2独立的选自氢,甲基,乙基,丙基,异丙基,正丁基,-COOH,-CH2COOH,-CH2CH2COOH,-CH2CH2CH2COOH,-COOCH3,-COOCH2CH3,-COOCH2CH2CH3,-CH2COOCH3,-CH2CH2COOCH3,-CH2CH2CH2COOCH3,-CH2COOCH2CH3,-CH2CH2COOCH2CH3,-CH2CH2CH2COOCH2CH3;
更优的R3独立选自氢,氟,氯,溴,碘,甲基,乙基,丙基,异丙基,正丁基,仲丁基,异丁基,叔丁基,甲氧基,乙氧基,丙氧基,三氟甲基,三氟乙基;
但不包括下列化合物:
本发明技术方案的还提供了如通式I-B所示的化合物、异构体及其药学上可接受的盐:
其中:
R5氢,卤素,三氟甲基,硝基,氰基,甲磺酰基,羟基,氨基,羧基,甲氧基,C1-6烷基;
A环表示环戊烯基、环己烯基、环庚烯基、环辛烯基;所述环戊烯基、环己烯基、环庚烯基、环辛烯基可被以下基团取代:氟,氯,溴,碘,三氟甲基,硝基,氰基,甲磺酰基,羟基,氨基,羧基,甲氧基,甲基,乙基,丙基,异丙基,正丁基,仲丁基,异丁基,叔丁基;
n=0、1、2;
但不包括下列化合物:
如通式I-B所示的化合物、异构体及其药学上可接受的盐,其特征在于,
优选的R5、R6、R7、R8、R9、R10、R11、R12任选自氢,氟,氯,溴,碘,三氟甲基,硝基,氰基,甲磺酰基,羟基,氨基,羧基,甲氧基,甲基,乙基,丙基,异丙基,正丁基,仲丁基,异丁基,叔丁基中的1、2、3或4个,且可以同时为不同基团;
但不包括下列化合物:
本发明最优选的化合物及其药学上可接受的盐,其特征在于,所述化合物选自如下群组:
化合物1.(R)-4,4,8-三甲基-1,2,3,4,8,9-六氢菲并[3,2-b]呋喃-7,11-二酮
化合物2.4,4-二甲基-3,4,9,10-四氢-1H-萘并[2,1-g]色烯-7,12(2H,8H)-二酮
化合物3.2,3,8,9-四氢茚并[5,4-g]色烯-6,11(1H,7H)-二酮
化合物4.2,3,7,8-四氢-1H-环戊二烯并[7,8]萘并[2,3-b]呋喃-6,10-二酮
化合物5.3,4,9,10-四氢-1H-萘并[2,1-g]色烯-7,12(2H,8H)-二酮
化合物6.2-(2-甲氧苯基)-2,3-二氢萘并[2,3-b]呋喃-4,9-二酮
化合物7.2-(邻苯甲基)-2,3-二氢萘并[2,3-b]呋喃-4,9-二酮
化合物8.2-(4-(三氟甲基)苯基)-2,3-二氢萘并[2,3-b]呋喃-4,9-二酮
化合物9.2-(2-噻唑基)-2,3-二氢萘并[2,3-b]呋喃-4,9-二酮
化合物10.2-(2-噻吩基)-2,3-二氢萘并[2,3-b]呋喃-4,9-二酮
化合物11.2-(4,9-二羰基-2-苯基-2,3,4,9-四氢萘并[2,3-b]呋喃-3-基)乙酸甲酯
化合物12.4,9-二羰基-2-苯基-2,3,4,9-四氢萘并[2,3-b]呋喃-3-羧酸异丙酯
化合物13.4,9-二羰基-2-(2-噻吩基)-2,3,4,9-四氢萘并[2,3-b]呋喃-3-羧酸甲酯
化合物14.2-环戊基-2,3-二氢萘并[2,3-b]呋喃-4,9-二酮
化合物15.6-(三氟甲基)-2,3-二氢萘并[2,3-b]呋喃-4,9-二酮
化合物16.2-甲基-6-(三氟甲基)-2,3-二氢萘并[2,3-b]呋喃-4,9-二酮
化合物17.2-异丁基-6-(三氟甲基)-2,3-二氢萘并[2,3-b]呋喃-4,9-二酮
化合物18.2-异丙基-6-(三氟甲基)-2,3-二氢萘并[2,3-b]呋喃-4,9-二酮
化合物19.2,6-二甲基-2,3-二氢萘并[2,3-b]呋喃-4,9-二酮
化合物20.2-乙基-6-甲基-2,3-二氢萘并[2,3-b]呋喃-4,9-二酮
化合物21.2-异丙基-6-甲基-2,3-二氢萘并[2,3-b]呋喃-4,9-二酮
化合物22.2-异丁基-6-甲基-2,3-二氢萘并[2,3-b]呋喃-4,9-二酮
化合物23.2-环戊基-6-甲基-2,3-二氢萘并[2,3-b]呋喃-4,9-二酮
化合物24.2-环己基-6-甲基-2,3-二氢萘并[2,3-b]呋喃-4,9-二酮
根据本发明,式I-A和I-B化合物可以异构体的形式存在,式I-A和I-B化合物连接R1,R2,R4基团的碳的构型可为R或S构型。
本发明包括所有可能的立体异构体以及两种或多种异构体的混合物。
如果存在顺/反异构体,本发明涉及顺式形式和反式形式以及这些形式的混合物,如果需要单一异物体可根据常规方法分离或通过立体选择合成制备。
本发明第二方面提供了制备本发明化合物的方法,包括如下路线:
方法一:
通式I-A的制备方法:化合物Ia与硫酸二甲酯反应得到化合物IIa,化合物IIa与多聚甲醛反应得到化合物IIIa,化合物IIIa经NBS氧化得到化合物IVa,化合物IVa脱保护得到化合物Va,化合物Va与化合物Via经CAN介导的环加成反应得到式(I-A);
(a)烷基化反应;(b)羟基邻位甲酰化;(c)氧化反应;(d)脱保护;(e)CAN介导的环加成反应;其中所述R1为非取代或取代的苯基,非取代或取代的五元杂芳基,非取代或取代的六元杂芳基,非取代或取代的五元杂环基,非取代或取代的六元杂环基,所述五元杂芳基、六元杂芳基、五元杂环基、六元杂环基,含有2-5个碳原子和1-3个选自氮、氧、硫杂原子,上述非取代或取代中取代基选自C1-6烷基,C1-6烷氧基,卤素,硝基,氰基,甲磺酰基,羟基,氨基,羧基,R2、R3的定义分别同权利要求1-3任一项的定义,
方法二:
通式I-A的制备方法:化合物Ib与盐酸羟胺经肟化脱水反应得到化合物IIb,化合物IIb与三氟甲磺酸酐反应得到化合物IIIb,化合物IIIb经sonogashira偶联得到化合物IVb,化合物IVb经戴斯马汀氧化剂氧化得到化合物Vb,化合物Vb与格式试剂VIIIb反应得到化合物VIb,化合物VIb在甲醇钠条件下反应得到化合物VIIb,化合物VIIb经Fremy’s盐氧化得到式(I-A);
(a)肟化脱水;(b)酯化反应;(c)sonogashira偶联;(d)氧化反应;(e)格式反应;(f)环合反应;(g)氧化反应,其中所述R1为氢原子,C1-8烷基,C3-8环烷基或C0-6链烯基;R2、R3的定义同权利要求1-3任一项的定义;
方法三:
通式I-B的制备方法:化合物Ic与多聚甲醛反应得到化合物IIc,化合物IIc与盐酸羟胺经肟化脱水反应得到化合物IIIc,化合物IIIc与三氟甲磺酸酐反应得到化合物IVc,化合物IVc与化合物VIIc经sonogashira偶联得到化合物Vc,化合物Vc在甲醇钠作用下发生环合反应得到化合物VIc,化合物VIc经Fremy’s盐氧化得到式(I-B);
(a)羟基邻位甲酰化;(b)肟化脱水;(c)酯化反应;(d)sonogashira偶联;(e)环合反应;(f)氧化反应,在结构式VIIc及结构式Vc中,R4为-(CH2)n+2中取代基,其中n,R4和环A的定义同权利要求4-5任一项的定义。
当R4位于氧的β位时,
(a)羟基邻位甲酰化;(b)肟化脱水;(c)酯化反应;(d)sonogashira偶联;(e)环合反应;(f)氧化反应,其中n,R4和环A的定义同权利要求4-5任一项的定义。
本发明技术方案的第三方面是提供了一种药物组合物,其含有预防和/或治疗有效量的上述的2,3-二氢萘并[2,3-b]呋喃-4,9-二酮类化合物,以及任选的药学可接受的载体和/或辅料。
在本发明中,根据施用途径,所述2,3-二氢萘并[2,3-b]呋喃-4,9-二酮类化合物的药物组合物可呈选自如下剂型:溶液、悬液、乳剂、丸剂、胶囊、粉末、控制释放或持续释放制剂。
本发明的2,3-二氢萘并[2,3-b]呋喃-4,9-二酮类化合物药物组合物可以用已知的方法配制,使用几种途径对受试者施用,包括但不限于肠胃外、经口、局部、皮内、肌肉内、腹膜内、皮下、静脉、鼻内途径。
本发明的2,3-二氢萘并[2,3-b]呋喃-4,9-二酮类化合物药物组合物任选的可以通过任何常规方法用一种或多种药学可接受的载体和/或赋形剂来配制。因此,2,3-二氢萘并[2,3-b]呋喃-4,9-二酮类化合物和它药学可接受的盐可特别配制为例如吸入或吹入(通过口或鼻)或经口、含化、肠胃外或直肠给药。
2,3-二氢萘并[2,3-b]呋喃-4,9-二酮类化合物药物组合物也可以采用溶液、悬液、乳剂、丸剂、胶囊、粉末、控制释放或持续释放制剂。这些制剂将含有治疗有效量的2,3-二氢萘并[2,3-b]呋喃-4,9-二酮类化合物,优选为纯化形式,以及适量的载体,以提供对患者适当给药的形式。
本发明技术方案的第四个方面是提供了本发明第一方面所述化合物或其药学上可接受盐在制备预防、缓解和/或治疗癌症及其并发症的产品中的应用。所述的癌症选自乳腺癌、肺癌、口腔癌、肾癌、食道癌、肝癌、胃癌、肠癌、宫颈癌以及卵巢癌。所述的癌症并发症包括上腔静脉综合症、恶性体腔积液、机体免疫缺陷、粒细胞减少以及屏障防御破坏。只要这些2,3-二氢萘并[2,3-b]呋喃-4,9-二酮类化合物及其盐应用于癌症及其并发症,均属于本发明的化合物保护范围。
在本发明中,所述预防、缓解和/或治疗的癌症及其并发症选自对靶点蛋白STAT3的抑制作用。
本发明是通过如下技术方案来实现:通过人工合成制备获得一系列2,3-二氢萘并[2,3-b]呋喃-4,9-二酮类化合物;利用Invivogen公司稳定表达IL-6受体及可启动子含有STAT3结合区域的分泌胚胎碱性磷酸酶(secreted embryonic alkaline phosphatase,SEAP)报告基因的HEK-Blue IL-6细胞。在IL-6刺激下,细胞质内磷酸化的STAT3形成二聚体转位进入细胞核产生可分泌到细胞外的SEAP。取细胞培养上清中的SEAP与QUANTI-Blue反应,通过655nm处的产物吸收计算SEAP的生成量,以评价化合物对IL-6刺激的STAT3信号通路的抑制作用。
本发明的2,3-二氢萘并[2,3-b]呋喃-4,9-二酮类化合物在制成任何一种剂型时,均具有预防、缓解和/或治疗癌症及其并发症的药物作用。任何药剂,如果其组分中含有2,3-二氢萘并[2,3-b]呋喃-4,9-二酮类化合物通式I-A及I-B或者仅以2,3-二氢萘并[2,3-b]呋喃-4,9-二酮类化合物通式I-A及I-B单独成分制备成药,在其包装或说明书等标识上或者其他任何宣传品上只要注明或提示具有治疗癌症及其并发症的作用,也属于本发明的保护范围之内。
在本发明中,所述纯化形式的2,3-二氢萘并[2,3-b]呋喃-4,9-二酮类化合物是指基本上纯的,尤其是纯度大于80%,优选的大于85%,特别优选的大于90%,甚至更优选的大于95%的结构2,3-二氢萘并[2,3-b]呋喃-4,9-二酮类化合物。所述纯化形式的2,3-二氢萘并[2,3-b]呋喃-4,9-二酮类化合物纯度范围可以是90-96%。
有益技术效果:
2,3-二氢萘并[2,3-b]呋喃-4,9-二酮类化合物通式Ⅰ-A及I-B为单体新化合物,具有毒性较低、制备工艺简单等优点;
具有很好的应用与开发前景,是一种理想的预防和治疗癌症及其并发症的新化合物,可应用于药物的制备。
2,3-二氢萘并[2,3-b]呋喃-4,9-二酮类化合物具有抑制STAT3蛋白活性的作用。是一类防治癌症方面极有药用价值的新化合物,具有很好的应用与开发前景。
具体实施方式
下面结合本发明,进一步说明2,3-二氢萘并[2,3-b]呋喃-4,9-二酮类化合物的制备过程及其抑制STAT3蛋白活性的作用。下述实施例更详细地举例说明本发明,并不是对本发明的任何限制。
实施例
中间体28的制备
步骤A:向1L单口瓶中加入5,5-二甲基四氢萘酚(17.6g,100.2mmol,1.0equiv),无水THF(200mL),无水MgCl2(14.3g,15.4mmol,1.5equiv),Et3N(52.6mL,38.3mmol,3.8equiv),多聚甲醛(20.4g,68.2mmol,6.8equiv),加毕,氩气保护下回流24h,反应毕自然冷却至室温,向反应液中缓慢加入1N HCl(50mL),过滤,收集滤液,将滤液倒入水中(300mL),水相用乙酸乙酯萃取(3×300mL),合并有机相,饱和氯化钠溶液洗涤(300mL),有机相干燥、蒸干、柱层析(PE:EA=1:5),得化合物26为15.6g,收率76.5%
1H NMR(500MHz,CDCl3)δ11.41(s,1H,CHO),9.80(s,1H,OH),7.33(d,J=8.3Hz,1H,Ar-H),7.01(d,J=8.3Hz,1H,Ar-H),2.70(t,J=6.5Hz,2H,CH2 of cyclohexane),1.77-1,84(m,2H,CH2 of cyclohexane),1.70-1.62(m,2H,CH2 of cyclohexane),1.29(s,6H,CH3×2);13C NMR(125MHz,CDCl3)δ196.12,159.80,156.10,130.13,125.38,118.11,117.36,38.46,34.78,31.15,23.09,18.50;HRMS(ESI)m/z Calcd.for C13H17O2[M+H]+205.2649,Found 205.2647.
步骤B:向1L单口瓶中加入化合物26(15.6g,76.4mmol,2.0equiv),无水DMF(200mL),盐酸羟胺(6.4g,91.2mmol,2.4equiv),FeCl3(6.2g,38.6mmol,1.0equiv),加毕Ar保护下升温至150℃反应4h,TLC检测。反应毕,自然冷却至室温,将上述反应液倒入水中(300mL),水相用乙酸乙酯萃取(3×300mL),合并有机相,饱和氯化钠溶液洗涤(300mL),有机相干燥、蒸干、柱层析(PE:EA=1:5),得化合物27为13.3g g,收率86.7%
1H NMR(400MHz,CDCl3)δ7.25(d,J=8.3Hz,1H,Ar-H),6.97(d,J=8.3Hz,1H,Ar-H),2.65(t,J=6.4Hz,2H,CH2 of cyclohexane),1.80-1.83(m,2H,CH2 of cyclohexane),1.62-1.65(m,2H,CH2 of cyclohexane),1.26(s,6H,CH3×2);13C NMR(100MHz,CDCl3)δ156.31,153.69,128.59,124.70,119.28,117.09,95.12,37.95,34.33,31.13,31.12,23.55,18.26;HRMS(ESI)m/z Calcd.for C13H15NO[M+H]+206.2643,Found 206.2650.
步骤C:向1L单口瓶中加入化合物27(13.3g,66.3mmol,1.0equiv),吡啶(10.6mL,132.4mmol,2.0equiv),DMAP(0.7g,6.1mmol,0.1equiv),CH2Cl2(300mL)。加毕,冷却至0℃,向上述反应液中缓慢滴加Tf2O(16.6mL,0.099mol,1.5equiv),滴毕,升至室温继续反应12h。反应毕,将反应液倒入冰水中(300mL),水相用乙酸乙酯萃取(3×300mL),合并有机相,饱和氯化钠溶液洗涤(300mL),有机相干燥、蒸干、柱层析(PE:EA=1:5),得化合物28为20.3g,收率92.4%。
1H NMR(400MHz,CDCl3)δ7.53(d,J=8.2Hz,1H,Ar-H),7.47(d,J=8.2Hz,1H,Ar-H),2.86(t,J=6.3Hz,2H,CH2 of cyclohexane),1.80-1.86(m,2H,CH2 of cyclohexane),1.69-1.71(m,2H,CH2 of cyclohexane),1.32(s,6H,CH3×2);13C NMRδ(100MHz,CDCl3)δ155.45,147.26,132.67,131.15,127.44,120.01,116.82,114.31,104.61,37.67,34.99,31.54,25.33,18.29;HRMS(ESI)m/z Calcd.for C14H15F3NO3S[M+H]+334.0719,Found334.0722.
实施例1、化合物1的制备
步骤A:向1mL单口瓶中加入化合物28(2.0g,6.0mmol,1equiv),无水DMF(20mL),三苯基膦氯化钯(0.1g,0.14mmol,0.2equiv),(R)-2甲基戊炔-1-醇(1.47g,15.0mmol,2.5equiv),Et3N(1mL,7.0mmol,1.2equiv)。加毕,Ar保护下升温至80℃反应3h。TLC检测,反应毕,自然冷却至室温,将上述反应液倒入水中(20mL),水相用乙酸乙酯萃取(3×30mL),合并有机相,饱和氯化钠溶液洗涤(30mL),有机相干燥、蒸干、柱层析(PE:EA=1:3),得化合物29为1.4g,收率85.6%。
[α]D 25.0=-5.6(c 1.07,CHCl3);1H NMR(400MHz,CDCl3)δ7.38(d,J=8.1Hz,1H,Ar-H),7.32(d,J=8.1Hz,1H,Ar-H),3.68-3.71(m,2H,CH2CHCH2OH),2.87(t,J=6.5Hz,2H,CH2of cyclohexane),2.60(d,J=6.1Hz,2H,CH2CHCH2OH),2.01-2.07(m,1H,CH2 CH(CH3)CH2OH),1.81-1.84(m,2H,CH2 of cyclohexane),1.74(bs,1H,OH),1.63-1.66(m,2H,CH2 ofcyclohexane),1.27(s,6H,CH3×2),1.10(d,J=6.8Hz,CH3);13C NMR(100MHz,CDCl3)δ151.44,139.45,129.33,127.48,126.31,118.80,112.58,99.91,77.79(CN),66.73,38.23,35.21,34.58,31.44,29.47,23.52,18.96,16.41;HRMS(ESI)m/z Calcd.for C19H24NO[M+H]+282.1852,Found 282.1850.
步骤B:向100mL单口瓶中加入化合物29(1.4g,4.9mmol,1.0equiv),DMSO(10mL),NaOMe(0.26g,4.9mmol,1.0equiv)。加毕,Ar保护下升温至100℃反应1h。TLC检测,反应毕,自然冷却至室温,将上述反应液倒入水中(20mL),水相用乙酸乙酯萃取(3×30mL),合并有机相,饱和氯化钠溶液洗涤(30mL),有机相干燥、蒸干、柱层析(PE:EA=1:3),得化合物30为1.1g,收率78.8%。
[α]D 23.5=-54.9(c 1.22,CHCl3);1H NMR(400MHz,CDCl3)δ7.53(d,J=8.9Hz,1H,Ar-H),7.28(d,J=8.9Hz,1H,Ar-H),6.80(s,1H,Ar-H),4.64(t,J=8.4Hz,1H,CH ofdihydrofuran),4.22-4.25(m,1H,CH of dihydrofuran),4.10(bs,2H,NH2),3.51-3.56(m,1H,CH of dihydrofuran),2.95(t,J=6.4Hz,2H,CH2 of cyclohexane),1.89-1.95(m,2H,CH2 of cyclohexane),1.68-1.71(m,2H,CH2 of cyclohexane),1.32-1.35(m,9H,CH3×3);13C NMR(100MHz,CDCl3)δ158.68,137.69,135.74,135.08,126.52,123.89,119.97,117.72,109.36,94.46,79.59,34.12,21.82,21.30;HRMS(ESI)m/z Calcd.for C19H24NO[M+H]+282.1852,Found 282.1848.
步骤C:向250mL单口瓶中加入KH2PO4(1.6g,11.4mmol,3.0equiv),H2O(50mL),丙酮(100mL),化合物30(1.1g,3.8mmol,1.0equiv),加毕,室温下剧烈搅拌10min,加入Fremy’s盐(3.0g,11.4mmol,3.0equiv),加毕,Ar保护下室温反应24h。TLC检测,反应毕,将上述反应液倒入水中(100mL),水相用乙酸乙酯萃取(3×40mL),合并有机相,饱和氯化钠溶液洗涤(40mL),有机相干燥、蒸干、柱层析(PE:EA=1:3),得化合物1为0.66g,收率58.7%。
[α]D 22.9=-50.8(c 1.02,CHCl3);1H NMR(400MHz,CDCl3)δ7.95(d,J=8.2Hz,1H,Ar-H),7.70(d,J=8.2Hz,1H,Ar-H),4.81(t,J=9.5Hz,1H,CH of dihydrofuran),4.27-4.31(m,1H,CH of dihydrofuran),3.64-3.67(m,1H,CH of dihydrofuran),3.24(t,J=6.4Hz,2H,CH2 of cyclohexane),1.79-1.82(m,2H,CH2 of cyclohexane),1.64-1.67(m,2H,CH2 of cyclohexane),1.39(d,J=6.9Hz,3H,CH3),1.31(d,J=1.7Hz,6H,CH3×2);13CNMR(100MHz,CDCl3)δ182.26(C=O),180.57(C=O),160.94,153.12,141.02,132.94,132.57,128.82,125.53,124.19,80.25,37.83,35.60,34.92,31.98,31.92,29.96,19.28,18.94;HRMS(ESI)m/z Calcd.for C19H21O3[M+H]+297.1485,Found 297.1479.ee>98.8%,determined by HPLC;
实施例2、化合物2的制备
步骤A:参照化合物29的合成方法,由化合物28(2g,6.0mmol)和己炔-1-醇制备得到化合物31(1.2g,71.1%yield)。
1H NMR(400MHz,CDCl3)δ7.37(d,J=8.4Hz,1H,Ar-H),7.30(d,J=8.4Hz,1H,Ar-H),3.71(t,J=6.4Hz,2H,CH2 of CH2CHCH2 OH),2.85(t,J=6.4Hz,2H,CH2 of CH2CHCH2 OH),2.57(d,J=6.8Hz,2H,CH2 of CH2 CHCH2OH),1.71-1.84(m,7H,CH2×3 of cyclohexane,OH),1.62-1.65(m,2H,CH2 of CH2CHCH2 OH),1.26(s,6H,CH3×2);13C NMR(100MHz,CDCl3)δ151.32,139.31,129.23,127.39,126.14,118.61,112.36,101.44,76.86,62.31,38.12,34.46,31.71,31.33,29.31,24.72,19.48,18.84;HRMS(ESI)m/z Calcd.for C19H24ON[M+H]+282.1852,Found 282.1855.
步骤B:参照化合物30的合成方法,由化合物31(1.2g,4.3mmol)制备得到化合物32(0.9g,74.3%yield)。
1H NMR(400MHz,CDCl3)δ7.52(d,J=8.8Hz,1H,Ar-H),7.27(d,J=8.8Hz,1H,Ar-H),6.87(s,1H,Ar-H),4.19(dd,J=4.8Hz,6.4Hz,2H,CH2 of dihydropyran),2.95(t,J=6.4Hz,2H,CH2 of dihydropyran),2.68(t,J=6.4Hz,2H,CH2 of dihydropyran),2.10-2.16(m,2H,CH2 of cyclohexane),1.89-1.95(m,2H,CH2 of cyclohexane),1.69-1.72(m,2H,CH2 of cyclohexane),1.33(s,6H,CH3×2);13C NMR(100MHz,CDCl3)δ153.95,142.31,140.43,132.69,129.72,121.48,117.93,116.16,104.61,98.70,65.83,38.81,34.04,31.32,26.96,22.35,20.79,19.49;HRMS(ESI)m/z Calcd.for C19H24ON[M+H]+282.2210,Found 282.2214.
步骤C:参照化合物1的合成方法,由化合物32(0.8g,2.8mmol)制备得到化合物2(0.5g,60.2%yield)。
1H NMR(400MHz,CDCl3)δ7.95(d,J=8.4Hz,1H,Ar-H),7.69(d,J=8.4Hz,1H,Ar-H),4.31(t,J=5.2Hz,2H,CH2 of dihydropyran),3.24(t,J=6.0Hz,2H,CH2 ofdihydropyran),2.56(t,J=6.0Hz,2H,CH2 of dihydropyran),1.98-2.02(m,2H,CH2 ofcyclohexane),1.79-1.82(m,2H,CH2 of cyclohexane),1.65-1.68(m,2H,CH2 ofcyclohexane),1.31(d,J=3.0Hz,6H,CH3×2);13C NMR(100MHz,CDCl3)δ184.62(C=O),181.82(C=O),156.24,153.08,140.53,132.37,131.44,128.46,124.20,119.20,67.82,37.90,34.95,31.93,29.97,20.56,19.35,18.00;HRMS(ESI)m/z Calcd.for C19H21O3[M+H]+297.1503,Found 297.1498.
中间体35的制备
步骤A:参照化合物26的合成方法,由4-茚醇(20.2g,150.5mmol)制备得到化合物33(18.6g,76.2%yied)。
1H NMR(400MHz,CDCl3)δ11.12(s,1H,OH),9.82(s,1H,CHO),7.33(d,J=7.7Hz,1H,Ar-H),6.89(d,J=7.7Hz,1H,Ar-H),2.87-8.95(m,4H,CH2×2 of cyclopentane),2.07-2.15(m,2H,CH2 of cyclopentane);13C NMR(100MHz,CDCl3)δ196.17(C=O),158.08,155.89,132.91,131.68,119.35,116.40,34.06,28.42,24.81;HRMS(ESI)m/z Calcd.forC10H11O2[M+H]+163.1852,Found 163.1847.
步骤B:参照化合物27的合成方法,由化合物33(18.4g,113.4mmol)制备得到化合物34(15.2g,84.2%yield)。
1H NMR(400MHz,CDCl3)δ7.27(d,J=7.8Hz,1H,Ar-H),6.83(d,J=7.8Hz,1H,Ar-H),6.55(bs,1H,OH),2.91(m,4H,CH2×2 of cyclopentane),2.11(m,2H,CH2 ofcyclopentane);13C NMR(100MHz,CDCl3)δ155.11,153.17,131.40,131.05,120.00,117.50,96.60(C of CN),33.97,29.14,24.78;HRMS(ESI)m/z Calcd.for C10H10ON[M+H]+160.0772,Found 160.0770.
步骤C:参照化合物28的合成方法,由化合物34(15g,94.2mmol)制备得到化合物35(25.6g,93.3%yield)。
1H NMR(400MHz,CDCl3)δ7.52(d,J=7.7Hz,1H,Ar-H),7.32(d,J=7.7Hz,1H,Ar-H),3.08(m,4H,CH2×2 of cyclopentane),2.18(m,2H,CH2 of cyclopentane);13C NMR(100MHz,CDCl3)δ154.81,145.66,139.11,133.25,124.92,120.12,114.40,104.78,34.06,30.97,25.23;HRMS(ESI)m/z Calcd.for C11H9F3NO3S[M+H]+292.2522,Found 292.2528.
实施例3、化合物3的制备
步骤A:参照化合物29的合成方法,由化合物35(1.0g,3.4mmol)制备得到化合物36(0.6g,73.7%yield)。
1H NMR(400MHz,CDCl3)δ7.37(d,J=7.8Hz,1H,Ar-H),7.16(d,J=7.8Hz,1H,Ar-H),3.69(dt,J=1.5Hz,J=6.2Hz,2H,CH2 of CH2 CH2 CH2 CH2 OH),2.95(m,4H,CH2×2 ofcyclopentane),2.55(t,J=6.2Hz,2H,CH2 of CH2CH2 CH2CH2OH),2.08(m,2H,CH2 ofcyclopentane),1.75(m,4H,CH2×2 of CH2CH2CH2CH2OH);13C NMR(100MHz,CDCl3)δ149.58,147.69,130.94,123.98,123.85,118.74,112.44,99.74,62.40,33.74,32.77,31.78,24.79,24.45,19.54;HRMS(ESI)m/z calcd.for C16H18ON[M+H]+240.1397,Found 240.1400.
步骤B:参照化合物30的合成方法,由化合物36(0.5g,2.1mmol)制备得到化合物37(0.3g,59.7%yield)。
1H NMR(400MHz,CDCl3)δ7.56(d,J=6.7Hz,1H,Ar-H),7.21(d,J=6.7Hz,1H,Ar-H),4.25(m,2H,CH2 of dihydropyran),3.15(m,2H,CH2 of dihydropyran),3.09(m,2H,CH2of dihydropyran),2.73(m,2H,CH2 of cyclopentane),2.44(m,2H,CH2 ofcyclopentane),2.18(m,2H,CH2 of cyclopentane);13C NMR(100MHz,CDCl3)δ153.97,140.70,140.58,138.62,130.72,119.61,118.74,117.25,104.49,99.14,65.82,33.78,31.37,24.36,22.35,21.00;HRMS(ESI)m/z calcd.for C16H18ON[M+H]+240.1386,Found240.1381.
步骤C:参照化合物1的合成方法,由化合物37(0.2g,0.8mmol)制备得到化合物3(90mg,44.2%yield)。
1H NMR(400MHz,CDCl3)δ7.86(d,J=7.7Hz,1H,Ar-H),7.45(d,J=7.7Hz,1H,Ar-H),4.28(t,J=5.2Hz,2H,CH2 of dihydropyran),3.32(t,J=7.6Hz,2H,CH2ofdihydropyran),2.91(t,J=7.6Hz,2H,CH2 of dihydropyran),2.55(t,J=6.3Hz,2H,CH2of cyclopentane),2.11(m,2H,CH2 of cyclopentane),1.97(m,2H,CH2 ofcyclopentane);13C NMR(100MHz,CDCl3)δ184.61(C=O),181.15(C=O),155.51,152.26,146.76,131.12,129.22,126.71,125.42,120.81,67.66,33.76,32.42,25.05,20.63,18.35;HRMS(ESI):Calcd.for C16H15O3[M+H]+255.1016,found 255.1009.
实施例4、化合物4的制备
步骤A:参照化合物29的合成方法,由化合物35(1.0g,3.4mmol)制备得到化合物38(560mg,78.8%yield)。
1H NMR(400MHz,CDCl3)δ7.35(d,J=7.8,1H,Ar-H),7.14(d,J=7.8Hz,1H,Ar-H),3.83(t,J=6.2Hz,2H,CH2 of CH2CH2 CH2 OH),2.94(m,4H,CH2×2 of CH2CH2 CH2OH),2.61(t,J=6.2Hz,2H,CH2 of cyclopentane),2.07(t,J=6.4,Hz,2H,CH2 of cyclopentane),1.75(t,J=6.4Hz,2H,CH2 of cyclopentane);13C NMR(100MHz,CDCl3)δ149.62,147.71,130.90,123.91,123.85,118.72,112.40,99.31,76.64(C of CN),61.24,33.72,32.76,31.15,24.43,16.25;HRMS(ESI):calcd.for C15H16ON[M+H]+226.1187,found 226.1220.
步骤B:参照化合物30的合成方法,由化合物38(0.5g,2.2mmol)制备得到化合物39(360mg,72.2%yield)。
1H NMR(400MHz,CDCl3)δ7.50(d,J=8.4Hz,1H,Ar-H),7.16(d,J=8.4Hz,1H,Ar-H),6.58(s,2H,NH2),4.66(t,J=8.2Hz,2H,CH2 of dihydrofuran),3.16(m,4H,CH2×2 ofcyclopentane),3.05(t,J=7.5Hz,2H,CH2 of dihydrofuran),2.19(m,2H,CH2 ofcyclopentane);13C NMR(100MHz,CDCl3)δ159.40,140.95,139.18,138.65,132.58,119.29,118.86,118.49,108.94,92.34,71.37,33.87,31.68,27.21,24.48;HRMS(ESI):calcd.forC15H16ON[M+H]+226.2990,found 226.2986.
步骤C:参照化合物的1合成方法,由化合物39(300mg,)制备得到化合物4(139mg,46.3%yield)。
1H NMR(400MHz,CDCl3)δ7.84(d,J=7.6,1H,Ar-H),7.45(d,J=7.6Hz,1H,Ar-H),4.73(t,J=9.8Hz,2H,CH2 of dihydrofuran),3.30(t,J=7.6Hz,2H,CH2ofcyclopentane),3.14(t,J=9.8Hz,2H,CH2 of dihydrofuran),2.90(t,J=7.6Hz,2H,CH2of cyclopentane),2.11(m,2H,CH2 of cyclopentane);13C NMR(100MHz,CDCl3)δ182.43(C=O),179.30(C=O),160.82,152.36,147.14,132.28,129.22,127.25,125.40,123.53,73.24,33.70,32.30,27.39,25.05;HRMS(ESI):calcd.for C15H13O3[M+H]+241.2660,found241.2655
中间体42的制备
步骤A:参照化合物26的合成方法,由四氢萘酚(19.7g,132.9mmol)制备得到化合物40(16.4g,70.1%yied)。
1H NMR(400MHz,CDCl3)δ11.45(s,1H,CHO),9.83(s,1H,OH),7.30(d,J=6.0Hz,1H,Ar-H),6.77(d,J=6.0Hz,1H,Ar-H),2.76(m,4H,CH2×2 of cyclohexane),1.90(m,4H,CH2×2 of cyclohexane);13C NMR(100MHz,CDCl3)δ196.03,160.03,147.74,129.92,125.93,120.72,117.80,30.49,22.37,22.18,22.12;HRMS(ESI):calcd.for C11H13O2[M+H]+177.2231,found 177.2234.
步骤B:参照化合物27的合成方法,由化合物40(16.0g,90.8mmol)制备得到化合物41(12.5g,79.4%yield)。
1H NMR(400MHz,CDCl3)δ7.19(d,J=8.0Hz,1H,Ar-H),6.69(d,J=8.0Hz,1H,Ar-H),6.02(bs,1H,OH),2.75(t,J=6.4Hz,2H,CH2 of cyclohexane),2.63(t,J=6.4Hz,2H,CH2 of cyclohexane),1.77(m,4H,CH2×2 of cyclohexane);13C NMR(100MHz,CDCl3)δ156.59,145.33,128.50,125.29,122.09,117.13,95.63,30.09,22.76,22.23,22.21;HRMS(ESI)m/z Calcd.for C11H12ON[M+H]+174.0907,Found 174.0911.
步骤C:参照化合物28的合成方法,由化合物41(12.0g,69.3mmol)制备得到化合物42(20.0g,94.6%yield)。
1H NMR(400MHz,CDCl3)δ7.45(d,J=8.1Hz,1H,Ar-H),7.20(d,J=8.1Hz,1H,Ar-H),2.85(m,4H,CH2×2 of cyclohexane),1.81(m,4H,CH2×2 of cyclohexane);13C NMR(100MHz,CDCl3)δ147.68,146.99,130.99,129.71,120.11,116.92,114.45,104.80,29.87,24.34,21.71;HRMS(ESI)m/z Calcd.for C12H11O3NS[M+H]+306.2792,Found 306.2795.
实施例5、化合物5的制备
步骤A:参照化合物29的合成方法,由化合物42(2.0g,6.5mmol)制备得到化合物43(1.3g,76.5%yield)。
1H NMR(400MHz,CDCl3)δ7.32(d,J=7.9Hz,1H,Ar-H),7.03(d,J=7.9Hz,1H,Ar-H),3.72(t,J=6.1Hz,2H,CH2 of CH2CH2CH2 CH2 OH),2.84(t,J=6.1Hz,2H,CH2 ofCH2 CH2CH2CH2OH),2.77(t,J=6.4Hz,2H,CH2 of CH2CH2 CH2 CH2OH),2.58(t,J=6.4Hz,2H,CH2of CH 2CH2 CH2CH2OH),1.74-1.85(m,8H,CH2×4 of cyclohexane),1.63(s,1H,OH);13C NMR(100MHz,CDCl3)δ142.76,140.18,128.94,128.52,127.58,118.66,112.52,101.71,76.55(C of CN),62.37,31.72,30.03,28.16,24.72,22.56,22.21,19.51;HRMS(ESI)m/zCalcd.for C17H20ON[M+H]+254.1556,Found 254.1558.
步骤B:参照化合物30的合成方法,由化合物43(1.2g,4.7mmol)制备得到化合物44(0.96g,80.1%yield)。
1H NMR(500MHz,CDCl3)δ7.46(d,J=8.6Hz,1H,Ar-H),6.97(d,J=8.6Hz,1H,Ar-H),6.84(s,1H,Ar-H),4.20(bs,4H,NH2and CH2 of dihydropyran),2.93-2.96(m,2H,CH2of dihydropyran),2.83-2.85(m,2H,CH2 of dihydropyran),2.68-2.71(m,2H,CH2 ofdihydropyran),2.13-2.15(m,2H,CH2 of cyclohexane),1.92-1.93(m,2H,CH2 ofcyclohexane),1.83-1.84(m,2H,CH2 of cyclohexane);13C NMR(125MHz,CDCl3)δ153.88,140.43,134.04,132.94,130.59,124.63,117.58,116.66,104.62,98.25,65.84,30.36,25.93,23.37,22.93,22.35,20.86;HRMS(ESI)m/z Calcd.for C17H20ON[M+H]+254.1554,Found 254.1557.
步骤C:参照化合物1的合成方法,由化合物44(0.8g,3.1mmol)制备得到化合物5(344mg,40.6%yield)。
1H NMR(CDCl3,500MHz)δ7.89(d,J=7.8Hz,1H,Ar-H),7.37(d,J=7.8Hz,1H,Ar-H),4.31(t,J=4.8Hz,2H,CH2 of dihydropyran),3.25(t,J=5.2.Hz,2H,CH2 ofdihydropyran),2.85(t,J=5.7Hz,2H,CH2 of dihydropyran),2.56(t,J=6.2Hz,2H,CH2of cyclohexane),1.79-1.80(m,4H,CH2×2 of cyclohexane);13C NMR(125MHz,CDCl3)δ184.66(C=O),181.80(C=O),156.02,144.49,141.11,134.55,131.70,128.41,123.91,119.28,67.76,31.08,28.79,23.09,21.88,20.53,18.01;HRMS(ESI)m/z Calcd.forC17H17O3[M+H]+269.1175,Found 269.1172.
中间体48的制备
步骤A:向1L单口瓶中分别加入2-羟基萘(30.1g,208.7mmol,1.0equiv),DMF(500mL),无水碳酸钾(43.1g,311.8mmol,1.5equiv),硫酸二甲酯(31.8g,252.1mmol,1.2equiv)。50℃下反应4h,反应毕,抽滤,乙酸乙酯洗涤滤饼(50mL×2),收集滤液,旋去部分溶剂,将残留液倒入水中,乙酸乙酯提取(3×200mL),合并有机相饱和氯化钠溶液洗涤(300mL×1),有机相干燥,旋干,柱层析(EA:PE=1:5)得化合物45为29.9g,收率90.2%。
1H NMR(400MHz,CDCl3)δ7.76-7.82(m,3H,Ar-H),7.46-7.50(m,1H,Ar-H),7.36-7.40(m,1H,Ar-H),7.17-7.21(m,2H,Ar-H),3.94(s,3H,CH3 of OCH3);13C NMR(100MHz,CDCl3)δ157.74,134.71,129.52,129.10,127.79,126.49,123.72,118.85,105.89,55.39(CH3 of OCH3);HRMS(ESI)m/z Calcd.for C11H11O[M+H]+159.2078,Found 159.2077.
步骤B:向1L单口瓶中加入化合物45(29.8g,188.4mmol,1.0equiv),无水氯化镁(27.1g,284.6mmol,1.5equiv),多聚甲醛(39.9g,439.4mmol,2.5equiv),三乙胺(105.3mL,761.1mmol,4.0equiv),干燥THF(500mL)。氩气保护下回流24h,反应毕,自然冷却至室温,加入1M盐酸(50mL)淬灭,将所得反应液倒入水中,乙酸乙酯萃取(200mL×3),合并有机相,饱和氯化钠溶液洗涤(300mL×1),有机相干燥,蒸干,柱层析(EA:PE=1:3)得化合物46为30.6g,收率86.7%。
1H NMR(400MHz,CDCl3)δ10.81(s,1H,CH=O),9.26(d,J=8.7Hz,1H,Ar-H),8.01(d,J=9.1Hz,1H,Ar-H),7.74(d,J=8.1Hz,1H,Ar-H),7.61(t,J=8.7Hz,1H,Ar-H),7.40(t,J=8.1Hz,1H,Ar-H),7.24(d,J=9.1Hz,1H,Ar-H),4.01(s,3H,CH3 of OCH3);13C NMR(100MHz,CDCl3)δ192.07(C=O of CHO),164.03,137.66,131.63,129.95,128.59,128.33,125.00,124.81,116.67,112.61,56.61(CH3 of OCH3);HRMS(ESI)m/z[M+H]+calcd.forC12H11O2[M+H]+187.2066,found 187.0750.
步骤C:向1L单口瓶中加入化合物46(30.2g,162.2mmol,1.0equiv),DMF-H2O(95:5,500mL),NBS(71.2g,400.0mmol,2.5equiv),加毕,室温下剧烈搅拌15min,而后升至80℃继续反应16h。反应毕,将反应液倒入水中,用乙酸乙酯萃取(200mL×3)。合并有机相,饱和氯化钠溶液洗涤(300mL×1),有机相干燥,减压除去溶剂,所得残留液经柱层析(EA:PE=1:3)得黄色油状物化合物47 22.3g,收率74.2%。
1H NMR(400MHz,CDCl3)δ8.06-8.13(m,2H,Ar-H),7.68-7.76(m,2H,Ar-H),6.16(s,1H,CH of C=CHOCH3),3.90(s,3H,CH3 of OCH3);13C NMR(100MHz,CDCl3)δ184.76(C=O ofquinone),180.04(C=O of quinone),160.40(C of HC=C),134.31,133.31,131.99,131.01,126.65,126.14,109.88(CH of HC=C),56.42(CH3 of OCH3);HRMS(ESI)m/z[M+H]+calcd.for C11H9O3[M+H]+189.1899,found 189.1901.
步骤D:向1L单口瓶中加入化合物47(22.0g,116.9mmol,1.0equiv),干燥二氯甲烷(400mL)。冰盐浴下冷却至-5℃以下,分批加入无水三氯化铝(48.0g,359.9mmol,3.0equiv),加毕,升温至40℃继续反应3h,反应毕,将反应液倒入冰水中,用1M盐酸调pH至1-2,所得水相用乙酸乙酯萃取(200mL×3),合并有机相,饱和氯化钠溶液洗涤(300mL×1),有机相干燥,减压除去溶剂,所得残留液经柱层析(EA:PE=1:1)得化合物48为18.2g,收率87.1%。
1H NMR(400MHz,CDCl3)δ8.12(d,J=8.2Hz,2H,Ar-H),7.77-7.81(m,1H,Ar-H),7.69-7.73(m,1H,Ar-H),7.35(bs,1H,OH),6.37(s,2H,CH of C=CHOH);13C NMR(100MHz,CDCl3)δ184.92(C=O of quinone),181.93(C=O of quinone),156.27(C of HC=C),135.29,133.13,132.92,129.40,126.72,126.50,110.67(CH of HC=C);HRMS(ESI)m/z[M+H]+calcd.for C10H7O3[M+H]+175.1624,found 175.1625.
实施例6、化合物6的制备
向100mL单口瓶中分别加入48(0.5g,2.8mmol,1.0equiv),2-甲氧基苯乙烯(1.9g,14.0mmol,5.0equiv),碳酸氢钠(1.2g,14.0mmol,5.0equiv),乙腈(20mL),冰浴下冷却至0℃,分批加入硝酸铈按(2.7g,6.6mmol,2.4equiv),加毕,冰浴下搅拌1h后,升至室温继续搅拌2h,反应毕,将反应液倒入水中,二氯甲烷萃取(30mL×3),合并有机相,饱和氯化钠溶液洗涤(60mL×1),有机相干燥,旋干,柱层析(PE:EA=5:1),得化合物6为257mg,收率30.2%。
/>
1H NMR(400MHz,CDCl3)δ8.06-8.16(m,2H,Ar-H),7.69-7.72(m,2H,Ar-H),7.25-7.68(m,2H,Ar-H),6.92-6.95(m,2H,Ar-H),6.17-6.21(dd,J=8.4Hz,11.0Hz,1H,Ar-H),3.83(s,3H,CH3 of OCH3),3.65(dd,J=11.0Hz,17.4Hz,1H,CH of dihydrofuran),3.07-3.68(m,2H,CH2 of dihydrofuran);13C NMR(100MHz,CDCl3)δ182.48(C=O),177.95(C=O),160.05,156.26,134.20,133.03,129.77,128.20,126.37,126.28,126.09,124.54,120.70,110.73,83.36,55.52(OCH3),34.90;HRMS(ESI):calcd.for C19H15O4[M+H]+307.0926,found 307.0956.
实施例7、化合物7的制备
参照化合物6的制备方法,由化合物48(0.5g,2.8mmol)和2-甲基苯乙烯(1.6g,14.0mmol)制备得到化合物7(225mg,27.7%yield)。
1H NMR(400MHz,CDCl3)δ7.99-8.04(m,2H,Ar-H),7.61-7.66(m,2H,Ar-H),7.31-7.33(m,1H,Ar-H),7.14-7.20(m,3H,Ar-H),6.10(dd,J=8.8Hz,10.6Hz,1H,CH ofdihydrofuran),3.00-3.65(m,2H,CH2 of dihydrofuran);13C NMR(100MHz,CDCl3)δ182.28(C=O),177.75(C=O),159.99,137.99,134.45,134.28,133.13,133.12,131.68,130.90,128.59,126.57,126.42,126.13,124.97,123.90,84.52,34.86,19.35(C of CH3);HRMS(ESI):calcd.for C19H15O3[M+H]+291.0976,found 291.1007.
实施例8、化合物8的制备
参照化合物6的制备方法,由化合物48(0.5g,2.8mmol)和4-三氟甲基苯乙烯(2.4g,14.0mmol)制备得到化合物8(256mg,26.6%yield)。
1H NMR(400MHz,CDCl3)δ8.09-8.14(m,2H,Ar-H),7.71-7.77(m,2H,Ar-H),7.67(d,J=8.0Hz,2H,Ar-H),7.53(d,J=8.0Hz,2H,Ar-H),6.10(dd,J=8.8Hz,10.8Hz,1H,CH ofdihydrofuran),3.00-3.65(m,2H,CH2 of dihydrofuran);13C NMR(100MHz,CDCl3)δ182.09(C=O),177.56(C=O),159.68,143.56,134.39,133.27,132.99,131.57,126.51,126.23,126.13,126.05,126.01,125.97,125.94,123.68,85.53,35.57,29.73;HRMS(ESI)m/zCalcd.for C19H12O3F3[M+H]+345.0710,Found 345.0712.
实施例9、化合物9的制备
参照化合物6的制备方法,由化合物48(0.5g,2.8mmol)和2-乙烯噻唑(2.4g,14.0mmol)制备得到化合物9(191mg,24.1%yield)。
1H NMR(400MHz,CDCl3)δ8.08(t,J=6.6Hz,2H,Ar-H),7.66-7.75(m,2H,Ar-H),7.30(d,J=5.6Hz,1H,Ar-H),7.12(d,J=0.84Hz,1H,Ar-H),6.98-7.00(m,1H,CH ofdihydrofuran),3.35-3.64(m,2H,CH2 of dihydrofuran);13C NMR(100MHz,CDCl3)δ182.38(C=O),177.92(C=O),158.39,147.36,134.25,133.11,131.71,127.06,126.48,126.14,125.86,124.30,123.24,91.45,42.28;HRMS(ESI):calcd.for C15H10O3NS[M+H]+284.3092,found 284.3019.
实施例10化合物10的制备
参照化合物6的制备方法,由化合物48(0.5g,2.8mmol)和2-乙烯噻吩(1.5g,14.0mmol)制备得到化合物10(263mg,33.3%yield)。
1H NMR(400MHz,CDCl3)δ8.08-8.10(m,2H,Ar-H),7.66-7.75(m,2H,Ar-H),7.36(dd,J=5.2Hz,0.8Hz,1H,Ar-H),7.18(d,J=3.6Hz,1H,Ar-H),7.01(dd,J=5.2Hz,0.8Hz,1H,Ar-H),6.18-6.23(m,1H,CH of dihydrofuran),3.85-3.70(m,2H,CH2 ofdihydrofuran);13C NMR(100MHz,CDCl3)δ182.15(C=O),177.68(C=O),159.14,141.68,134.27,133.14,133.04,131.60,127.15,127.04,126.94,126.46,126.17,123.61,82.49,35.36;HRMS(ESI)m/z calcd.for C16H11O3S[M+H]+283.0444,Found 283.0448.
实施例11、化合物11的制备
向100mL单口瓶中分别加入48(0.5g,2.8mmol,1.0equiv),(E)-4-苯基-3丁烯酸甲酯(2.5g,14.0mmol,5.0equiv),乙腈(20mL),冰浴下冷却至0℃,分批加入硝酸铈按(2.7g,6.6mmol,2.4equiv),加毕,冰浴下搅拌1h后,升至室温继续搅拌2h,反应毕,将反应液倒入水中,二氯甲烷萃取(30mL×3),合并有机相,饱和氯化钠溶液洗涤(60mL×1),有机相干燥,旋干,柱层析(PE:EA=5:1),得化合物11为347mg,收率35.6%。
1H NMR(400MHz,CDCl3)δ8.10(m,2H,Ar-H),7.71(m,2H,Ar-H),7.34(m,5H,Ar-H),5.70(t,J=5.8Hz,1H,CH of dihydrofuran),3.97(m,1H,CH of dihydrofuran),3.12(s,3H,OCH3),2.74-2.79(m,2H,CH2);13C NMR(100MHz,CDCl3)δ182.15(C=O),177.84,171.50,159.75,139.04,134.43,133.25,133.16,131.70,128.99,128.91,126.53,126.22,126.20,125.91,124.64,100.00,91.63,52.04,45.89,36.82.;HRMS(ESI):calcd.for C21H17O5[M+H]+349.1087,found 349.1086.
实施例12、化合物12的制备
参照化合物11的制备方法,由化合物48(0.5g,2.8mmol)和肉桂酸乙酯(2.3g,14.0mmol)制备得到化合物12(218mg,23.3%yield)。
1H NMR(400MHz,CDCl3)δ8.06-8.12(m,2H,Ar-H),7.67-7.75(m,2H,Ar-H),7.37-7.42(m,5H,Ar-H),6.06(d,J=7.4Hz,1H,CH of dihydrofuran),5.11-5.17(m,1H,CH(CH3)2),4.32(d,J=7.4Hz,1H,CH of dihydrofuran),1.30(dd,J=6.3Hz,14.4Hz,6H,CH(CH3)2 );13C NMR(100MHz,CDCl3)δ181.01,177.63,169.86,160.24,138.17,134.44,133.17,132.82,131.47,129.14,128.98,126.45,126.25,125.48,121.89,89.66,70.02,54.62,21.65,21.59;HRMS(ESI):calcd.for C22H19O5[M+H]+363.3887,found 363.3896.
实施例13、化合物13的制备
参照化合物11的制备方法,由化合物48(0.5g,2.8mmol)和3-(2-噻吩基)丙烯酸甲酯(2.4g,14.0mmol)制备得到化合物13(260mg,27.3%yield)。
1H NMR(400MHz,CDCl3)δ8.08-8.12(m,2H,Ar-H),7.68-7.77(m,2H,Ar-H),7.37(dd,J=1.2Hz,J=5.1Hz,1H,Ar-H),7.01-7.04(m,1H,Ar-H),7.01(dd,J=3.6Hz,J=5.1Hz,1H,Ar-H),6.33(d,J=7.1Hz,1H,CH of dihydrofuran),4.54(d,J=7.1Hz,1H,CHof dihydrofuran),3.82(s,3H,CH3);13C NMR(100MHz,CDCl3)δ181.08(C=O),177.54(C=O),170.47(C=O),159.73,139.95,134.61,133.39,132.94,131.62,127.50,127.32,127.23,126.66,126.46,121.56,85.74,54.10,53.38.;HRMS(ESI):calcd.for C18H13O5S[M+H]+341.0499,found 341.0477.
中间体52的制备
步骤A:参照化合物27的制备方法,由水杨醛(34.8g,285.0mmol)制备得到化合物49(27.2g,70.2%yield)。
1H NMR(400MHz,CDCl3)δ7.44-7.53(m,1H,Ar-H),6.93-7.08(m,1H,Ar-H);13C NMR(100MHz,CDCl3)δ135.08,134.91,133.21,133.01,121.08,120.76,116.73(C of CN);HRMS(ESI):calcd.for C7H6ON[M+H]+120.1313,found 120.1321
步骤B:参照化合物28的制备方法,由化合物49(21.1g,177.1mmol)制备得到化合物50(39.9g,89.7%yield)。
1H NMR(400MHz,CDCl3)δ7.73-7.80(m,1H,Ar-H),7.50-7.56(m,1H,Ar-H);13C NMR(100MHz,CDCl3)δ149.76(C of OTf),134.87,134.51,128.86,122.79,120.29,113.52,107.46(C of CN);HRMS(ESI):calcd.for C8H5F3O5NS[M+H]+252.1872,found 282.1877.
步骤C:参照化合物29的制备方法,由化合物50(20g,79.6mmol)制备得到化合物51(11.9g,81.1%yield)。
1H NMR(400MHz,CDCl3)δ7.56-7.58(m,1H,Ar-H),7.44-7.50(m,2H,Ar-H),7.29-7.34(m,1H,Ar-H),3.83(m,2H,CH2CH2 CH2 OH),2.60(m,2H,CH2 CH2CH2OH),1.87(m,2H,CH2 CH2 CH2OH),1.22(bs,1H,OH);13C NMR(100MHz,CDCl3)δ132.50,132.46,132.23,127.98,127.81,117.97,115.31(C of C≡C),97.17(C of C≡C),77.71(C of CN),61.19,30.97,16.10;HRMS(ESI)m/z[M+H]+calcd.for C12H12ON 186.0908,Found 186.0911.
步骤D:向250mL单口瓶中加入化合物51(7.0g,37.8mmol,1.0equiv),无水二氯甲烷(100mL),加毕,冰浴下冷却至0℃,再向反应液中分批加入Dess-Martin氧化剂(19.2g,45.4mmol,1.2equiv),加毕,0℃下搅拌10min后,升至室温继续反应,TLC监测(PE:EA=5:1),1.5h反应毕,向反应液中加入碳酸氢钠和硫代硫酸钠(NaCO3:Na2S2O3=1:1)混合饱和溶液(50mL),剧烈搅拌10min,将反应液倒入水中,二氯甲烷萃取(100mL×3),合并有机相,饱和氯化钠溶液洗涤(200mL×1),有机相干燥、蒸干、柱层析(PE:EA=5:1),得化合物52为6.1g,收率88.1%。
1H NMR(400MHz,CDCl3)δ9.85(s,1H,CHO),7.60(d,J=7.4Hz,1H,Ar-H),7.46-7.59(m,2H,Ar-H),7.34(dt,J=1.8Hz,7.4Hz,1H,Ar-H),2.78-2.84(m,4H,CH2×2);13C NMR(100MHz,CDCl3)δ199.99(C=O),132.57,132.41,132.28,128.08,128.07,127.45,115.53(C of C≡C),95.34(C of C≡C),78.06(C of CN),42.40,12.82;HRMS(ESI)m/z[M+H]+calcd.for C12H10NO 184.9848,Found 184.9852.
实施例14、化合物14的制备
步骤A:向100mL三口瓶中加入化合物52(1.0g,5.4mmol,1.0equiv),干燥THF(30mL),氩气保护下冰浴冷却至0℃,缓慢滴加环戊基溴化镁溶液(1M in THF,6.5mL,1.2equiv),加毕,0℃下反应,TLC监测(PE:EA=4:1),3.5h反应完全,加入饱和氯化铵溶液(5mL)淬灭,将反应液倒入水中,乙酸乙酯萃取(50mL×3),合并有机相,饱和氯化钠溶液洗涤(50mL×1),有机相干燥、蒸干、柱层析(PE:EA=5:1),得化合物53为680mg,收率49.7%。
1H NMR(400MHz,CDCl3)δ7.58(d,J=7.7Hz,Ar-H),7.44-7.48(m,2H,Ar-H),7.30-7.34(m,1H,Ar-H),3.63-3.68(m,1H,CH of CHCH2CH2),2.62-2.66(m,2H,CH2 of CHCH2 CH2),1.94-1.97(m,1H,CH of cyclopentane),1.81-1.92(m,2H,CH2 of CHCH2 CH2 ),1.21-1.39(m,8H,CH2×4 of cyclopentane);13C NMR(100MHz,CDCl3)δ132.33,132.22,132.06,127.89,127.55,117.81,115.22,97.65,77.40(C of CN),74.34,46.33,34.38,29.02,28.56,25.64,25.48,16.14;HRMS(ESI):calcd.for C17H20NO[M+H]+254.1500,found254.1544.
步骤B:参照化合物30的制备方法,由化合物53(0.6g,2.4mmol)制备得到化合物54(439mg,73.2%yield)。
1H NMR(400MHz,CDCl3)δ7.64(d,J=8.5Hz,2H,Ar-H),7.35(t,J=6.9Hz,2H,Ar-H),7.24(t,J=6.9Hz,2H,Ar-H),6.64(s,1H,Ar-H),4.66-4.72(m,1H,CH ofdihydrofuran),3.96(s,2H,NH2),2.80-3.17(m,2H,CH2 of dihydrofuran),2.21-2.25(m,1H,CH of cyclopentane),1.36-1.71(m,8H,CH2×4 of cyclopentane);13C NMR(100MHz,CDCl3)δ159.24,137.84,135.78,127.59,125.80,121.98,120.32,119.74,110.72,95.12,87.57,45.43,31.88,29.23,28.64,25.81,25.69.HRMS(ESI):calcd.for C17H20ON[M+H]+254.1500,found 254.1539.
步骤C:参照化合物1的制备方法,由化合物54(0.4g,1.6mmol)制备得到化合物14(217mg,51.2%yield)。
1H NMR(400MHz,CDCl3)δ8.04-8.07(m,2H,Ar-H),7.25-7.72(m,2H,Ar-H),4.89-4.96(m,1H,CH of dihydrofuran),2.87-3.28(m,2H,CH2 of dihydrofuran),2.27-2.37(m,1H,CH of cyclopentane),1.27-1.93(m,8H,CH2×4 of cyclopentane);13C NMR(100MHz,CDCl3)δ182.50(C=O),178.10(C=O),160.43,134.16,133.17,132.95,131.68,126.37,126.03,124.17,90.39,44.96,31.62,28.82,28.18,25.66,25.51;HRMS(ESI)m/zCalcd.for C18H19O3[M+H]+283.1348,Found 282.1350.
中间体58的制备
步骤A:参照化合物27的制备方法,由4-三氟甲基水杨醛(10.0g,52.6mmol)制备得到化合物55(7.1g,72.4%yield)。
1H NMR(400MHz,DMSO)δ12.08(s,1H,OH),8.10(s,1H,Ar-H),7.85(d,J=8.8Hz,1H,Ar-H),7.19(d,J=8.8Hz,1H,Ar-H);13C NMR(125MHz,DMSO)δ163.63,132.04,131.46,125.15,122.99-120.20(C of CF3),117.36,116.06,100.02(C of CN);HRMS(ESI):calcd.for C8H5F3ON[M+H]+188.1292,found 188.1286.
步骤B:参照化合物28的制备方法,由化合物55(7.0g,37.4mmol)制备得到化合物56(10.5g,87.7%yield)。
1H NMR(400MHz,CDCl3)δ8.07(d,J=2.2Hz,1H,Ar-H),8.01(dd,J=2.2Hz,8.7Hz,1H,Ar-H),7.68(d,J=8.7Hz,1H,Ar-H);13C NMR(100MHz,CDCl3)δ151.72,131.37-131.89(Cof CF3),123.52,120.77,120.16,116.97,112.14,108.38,99.92(C of CN);HRMS(ESI):calcd.for C9H4F6O3NS[M+H]+320.1854,found 320.1861.
步骤C:参照化合物29的制备方法,由化合物56(10.0g,31.3mmol)制备得到化合物57(6.2g,78.7%yield)。
/>
1H NMR(400MHz,CDCl3)δ7.87(s,1H,Ar-H),7.76(d,J=8.2Hz,1H,Ar-H),7.61(d,J=8.2Hz,1H,Ar-H),3.86(t,J=6.1Hz,2H,CH2 of CH2CH2 CH2 OH),2.67(t,J=6.9Hz,2H,CH2of CH2 CH2CH2OH),1.89-1.95(m,2H,CH2 of CH2 CH2 CH2OH);13C NMR(100MHz,CDCl3)δ132.67,129.01-129.33(C of CF3),128.98,128.94,124.11,121.40,116.51,116.03,100.56,76.80,60.99,30.67,16.08.HRMS(ESI)m/z calcd.for C13H11ONF3[M+H]+254.0776,Found254.0780.
步骤D:参照化合物52的制备方法,由化合物57(5.0g,19.7mmol)制备得到化合物58(4.6g,93.5%yield)。
1H NMR(400MHz,CDCl3)δ9.88(s,1H,CHO),7.88(s,1H,Ar-H),7.76(d,J=8.1Hz,1H,Ar-H),7.62(d,J=8.1Hz,1H,Ar-H),2.82-2.91(m,4H,CH2×2 of CH2CH2);13C NMR(100MHz,CDCl3)δ199.46(C=O),132.84,129.06-129.52(C of CF3),128.09,126.91,124.20,121.49,116.42,116.34,100.00,98.79,42.16,12.83;HRMS(ESI)m/z Calcd.forC13H9ONF3[M+H]+252.0626,Found 252.0631.
实施例15、化合物15的制备
步骤A:参照化合物30的制备方法,由化合物57(1.0g,3.9mmol)制备得到化合物59(666mg,66.6%yield)。
1H NMR(400MHz,CDCl3)δ7.94(s,1H,Ar-H),7.68(d,J=8.6Hz,1H,Ar-H),7.50(d,J=8.6Hz,1H,Ar-H),6.67(s,1H,Ar-H),4.69(t,J=8.2Hz,2H,CH2),4.16(bs,2H,NH2),3.15(t,J=8.2Hz,2H,CH2);13C NMR(100MHz,CDCl3)δ161.04,138.88,137.27,131.00,128.13,123.49,121.44,118.35,118.21,111.24,95.42,71.54,26.89;HRMS(ESI)m/z calcd.forC13H11ONF3[M+H]+254.0766,Found 254.0771.
步骤B:参照化合物1的制备方法,由化合物59(0.6g,2.4mmol)制备得到化合物15(172mg,27.1%yield)。
1H NMR(400MHz,CDCl3)δ8.32(s,1H,Ar-H),8.19(d,J=8.0Hz,1H,Ar-H),7.92(d,J=8.0Hz,1H,Ar-H),4.83(t,J=9.9Hz,2H,CH2 of CH2CH2),3.26(t,J=9.9Hz,2H,CH2 ofCH2CH2);13C NMR(100MHz,CDCl3)δ180.49(C=O),176.54(C=O),160.88,133.64and 133.54(C of CF3),129.58,129.54,126.89,125.25,123.28,123.24,73.60,27.32;HRMS(ESI)m/zCalcd.for C13H8O3F3[M+H]+269.0424,Found 269.0417.
实施例16、化合物16的制备
步骤A:参照化合物53的制备方法,由化合物58(1.0g,4.0mmol)制备得到化合物60(602mg,56.6%yield)。
1H NMR(400MHz,CDCl3)δ7.90(s,1H,Ar-H),7.79(dd,J=1.4Hz,8.3Hz,1H,Ar-H),7.65(d,J=8.3Hz,1H,Ar-H),4.00-4.18(m,1H,CH),2.67-2.73(m,2H,CH2 of CH2 CH2 CHOH),2.21(bs,1H,OH),1.81-1.86(m,2H,CH2 of CH2 CH2CHOH),1.31(d,J=6.3Hz,3H,CH3);13CNMR(100MHz,CDCl3)δ132.79,131.60,131.58,130.22,129.88,129.03-129.46(C of CF3),124.24,121.53,116.61,116.19,100.98,66.68,37.15,23.59,16.31;HRMS(ESI):calcd.for C14H13ONF3[M+H]+268.0905,found 268.0936.
步骤B:参照化合物30的制备方法,由化合物60(0.5g,1.9mmol)制备得到化合物61(289mg,57.9%yield)。
1H NMR(400MHz,CDCl3)δ7.95(s,1H,Ar-H),7.70(d,J=8.5Hz,1H,Ar-H),7.49(d,J=8.5Hz,1H,Ar-H),6.65(s,1H,Ar-H),5.04-5.09(m,1H,CH of dihydrofuran),4.12(bs,2H,NH2),2.74-3.32(m,2H,CH2 of dihydrofuran),1.53(d,J=6.2Hz,CH3);13C NMR(100MHz,CDCl3)δ160.58,138.84,137.33,128.12,121.40,121.37,118.31,118.20,118.16,111.53,95.43,80.22,34.26,22.01;HRMS(ESI)m/z calcd.for C14H13ONF3[M+H]+268.0941,Found 268.0937.
步骤C:参照化合物1的制备方法,由化合物61(0.2g,0.7mmol)制备得到化合物16(73.1mg,34.6%yield)。
1H NMR(400MHz,CDCl3)δ8.33(s,1H,Ar-H),8.20(d,J=8.0Hz,1H,Ar-H),7.92(d,J=8.0Hz,1H,Ar-H),5.20-5.26(m,1H,CH of dihydrofuran),2.81-3.41(m,2H,CH2 ofdihydrofuran),1.57(d,J=6.3Hz,3H,CH3);13C NMR(100MHz,CDCl3)δ180.69(C=O),176.56(C=O),159.98,133.69and 133.57(C of CF3),129.50,129.46,126.89,124.63,123.25,123.22,83.54,34.31,21.88;HRMS(ESI)m/z calcd.for C14H10O3F3[M+H]+283.2262,Found 283.2257.
实施例17、化合物17的制备
步骤A:参照化合物53的制备方法,由化合物58(1.0g,4.0mmol)制备得到化合物62(575mg,46.5%yield)。
1H NMR(400MHz,CDCl3)δ7.87(d,J=0.6Hz,1H,Ar-H),7.75(d,J=0.6Hz,8.4Hz,1H,Ar-H),7.61(d,J=8.4Hz,1H,Ar-H),3.91-3.97(m,1H,CH of CH2CH2CHOH),2.66-2.71(m,2H,CH2 of CH2 CH2CHOH),1.81-1.84(m,2H,CH2 of CH2 CH2 CHOH),1.79-1.80(m,1H,CH ofCHCH2(CH3)2),1.26-1.46(m,2H,CH2 of CHCH2(CH3)2),0.94(dd,J=6.6Hz,2.5Hz,6H,CH3×2of CHCH2(CH3)2);13C NMR(100MHz,CDCl3)δ132.77,131.63,131.62,129.42,129.38,129.35,129.10,129.06,124.25,121.54,116.63,116.21,101.15,68.59,46.80,35.98,24.71,23.47,22.13,16.25;HRMS(ESI)m/z calcd.for C17H19ONF3[M+H]+310.1410,Found310.1408.
步骤B:参照化合物30的制备方法,由化合物62(0.5g,1.6mmol)制备得到化合物63(260mg,52.1%yield)。
1H NMR(400MHz,CDCl3)δ7.94(s,1H,Ar-H),7.68(d,J=8.6Hz,1H,Ar-H),7.48(dd,J=8.6Hz,1.1Hz,1H,Ar-H),6.64(s,1H,Ar-H),4.94-5.01(m,1H,CH of dihydrofuran),4.12(bs,2H,NH2),2.74-3.28(m,2H,CH2 of dihydrofuran),1.83-1.93(m,1H,CH of CHCH2(CH3)2),1.53-1.83(m,2H,CH2 of CHCH2(CH3)2),1.01(dd,J=10.7Hz,6.6Hz,CH3×2 ofCHCH2(CH3)2);13C NMR(100MHz,CDCl3)δ160.74,138.91,137.44,131.00,128.92,128.19,121.45,118.38,118.32,118.27,111.62,95.51,82.62,45.57,33.24,25.17,23.14,22.45;HRMS(ESI)m/z calcd.for C17H19ONF3[M+H]+310.1408,Found 310.1413.
步骤C:参照化合物1的制备方法,由化合物63(0.2g,0.6mmol)制备得到化合物17(57.7mg,27.5%yield)。
1H NMR(400MHz,CDCl3)δ8.38(s,1H,Ar-H),8.24(d,J=8.0Hz,1H,Ar-H),7.97(d,J=8.0Hz,1H,Ar-H),5.17-5.21(m,1H,CH of dihydrofuran),2.87-3.42(m,2H,CH2 ofdihydrofuran),1.91-2.01(m,2H,CH2 of CH2 CH(CH3)2),1.58-1.62(m,2H,CH of CH2 CH(CH3)2),1.04(dd,J=6.0Hz,12.0Hz,6H,CH3×2 of CH2CH(CH3)2 );13C NMR(100MHz,CDCl3)δ180.78(C=O),176.87(C=O),160.19,135.83,135.50,133.77,133.62,129.56,129.53,129.49,129.45,126.94,124.77,123.31,85.86,45.20,33.24,24.70,22.88,22.26;HRMS(ESI)m/z calcd.for C17H16O3F3[M+H]+325.3072,Found 325.3077.
实施例18、化合物18的制备
步骤A:参照化合物53的制备方法,由化合物58(1.0g,4.0mmol)制备得到化合物64(654mg,55.4%yield)。
1H NMR(400MHz,CDCl3)δ7.86(s,1H,Ar-H),7.74(d,J=8.4Hz,1H,Ar-H),7.60(d,J=8.3Hz,1H,Ar-H),3.61-3.65(m,1H,CH of CH2CH2CHOH),2.69(t,J=7.6Hz,2H,CH2 ofCH2 CH2CHOH),1.80-1.87(m,1H,CH of CH(CH3)2),1.66-1.74(m,2H,CH2 of CH2 CH2 CHOH),0.95(dd,J=1.6Hz,6.9Hz,6H,CH2×2 of CH(CH3)2),;13C NMR(100MHz,CDCl3)δ132.70,131.57,130.12,129.78,129.34,129.31,128.99,128.95,116.57,116.13,101.15,75.18,33.79,32.30,18.67,17.27,16.55;HRMS(ESI)m/z calcd.for C16H17ONF3[M+H]+296.1258,Found 296.1252.
步骤B:参照化合物30的制备方法,由化合物64(0.6g,2.0mmol)制备得到化合物65(345mg,57.6%yield)。
1H NMR(400MHz,CDCl3)δ7.93(s,1H,Ar-H),7.69(d,J=8.6Hz,1H,Ar-H),7.49(d,J=8.6Hz,1H,Ar-H),6.65(s,1H,Ar-H),4.63-4.69(m,1H,CH of dihydrofuran),4.13(bs,2H,NH2),2.86-3.19(m,2H,CH2 of dihydrofuran),2.00-2.05(m,1H,CH of CH(CH3)),1.00-1.08(m,6H,CH3×2 of CH(CH3));13C NMR(100MHz,CDCl3)δ161.04,138.63,137.35,128.12,121.38,121.34,118.24,118.19,118.15,111.72,95.11,88.92,33.39,30.00,18.05,17.70;HRMS(ESI)m/z calcd.for C16H17ONF3[M+H]+296.1256,Found 296.1251.
步骤C:参照化合物1的制备方法,由化合物65(0.3g,1.0mmol)制备得到化合物18(101mg,32.1%yield)。
1H NMR(400MHz,CDCl3)δ8.33(s,1H,Ar-H),8.20(d,J=8.1Hz,1H,Ar-H),7.92(d,J=8.1Hz,1H,Ar-H),4.82-4.89(m,1H,CH of dihydrofuran),2.93-3.25(m,2H,CH2 ofdihydrofuran),2.04-2.13(m,1H,CH of CH(CH3)2),1.03(dd,J=6.7Hz,20.8Hz,6H,CH3×2of CH(CH3)2);13C NMR(100MHz,CDCl3)δ180.75(C=O),176.78(C=O),160.40,133.83,133.66,129.56,129.49,126.99,125.06,123.32,123.25,91.89,33.04,29.93,17.62,17.24;HRMS(ESI)m/z calcd.for C16H14O3F3[M+H]+311.2802,Found 311.2876.
中间体69的制备
步骤A:参照化合物27的制备方法,由2-羟基-4-甲基苯甲醛(25g,183.7mmol)制备得到化合物66(20.1g,82.2%yield)。
1H NMR(400MHz,CDCl3)δ7.37(dd,J=8.0Hz,2.0Hz,1H,Ar-H),6.76-6.82(m,2H,Ar-H),2.34(s,3H,CH3);13C NMR(100MHz,CDCl3)δ158.69,146.27,132.56,121.96,117.07,96.27(C of CN),21.85(C of CH3);HRMS(ESI)m/z calcd.for C8H8ON[M+H]+134.1575,Found 134.1584.
步骤B:参照化合物28的制备方法,由化合物66(20g,150.2mmol)制备得到化合物67(36.2g,91.0%yield)。
1H NMR(400MHz,CDCl3)δ7.64(d,J=7.9Hz,1H,Ar-H),7.33(d,J=7.9Hz,1H,Ar-H),7.29(s,1H,Ar-H),2.51(s,3H,CH3);13C NMR(100MHz,CDCl3)δ149.47,146.87,133.90,129.54,123.14,120.13,116.94,113.68,104.07,21.90;HRMS(ESI)m/z calcd.forC16H17ONF3[M+H]+296.1258,Found 296.1252.
步骤C:参照化合物30的制备方法,由化合物67(36.0g,135.7mmol)制备得到化合物68(19.8g,73.4%yield)。
1H NMR(400MHz,CDCl3)δ7.45(d,J=8.0Hz,1H,Ar-H),7.26(s,1H,Ar-H),7.12(d,J=8.0Hz,1H,Ar-H),3.83(t,J=6.2Hz,2H,CH2 of CH2CH2 CH2 OH),2.56(t,J=6.2Hz,2H,CH2of CH2 CH2CH2OH),2.34(s,3H,CH3),1.83-1.89(m,2H,CH2 of CH2 CH2 CH2OH);13C NMR(100MHz,CDCl3)δ143.25,132.70,132.21,128.63,127.63,118.10,112.22,96.37,77.68(Cof CN),61.13,30.88,21.51,15.96;HRMS(ESI)m/z calcd.for C13H14ON[M+H]+200.1051,Found 200.1059.
步骤D:参照化合物52的制备方法,由化合物68(18.0g,90.3mmol)制备得到化合物69(17.0g,95.4%yield)。
1H NMR(400MHz,CDCl3)δ9.87(s,1H,CHO),7.49(d,J=8.0Hz,1H Ar-H),7.29(s,1H,Ar-H),7.17(d,J=8.0Hz,1H,Ar-H),2.80-2.85(m,4H,CH2×2),2.37(s,3H,CH3);13CNMR(100MHz,CDCl3)δ199.97(C=O),143.22,132.66,132.16,128.82,126.93,117.79,112.10,94.49,77.87(C of CN),42.16,21.42,12.54;HRMS(ESI)m/z Calcd.for C13H12ON[M+H]+198.1450,Found 198.14557.
实施例19、化合物19的制备
步骤A:参照化合物53的制备方法,由化合物69(1.0g,5.1mmol)制备得到化合物70(655mg,60.6%yield)。
1H NMR(400MHz,CDCl3)δ7.48(d,J=8.0Hz,1H,Ar-H),7.29(s,1H,Ar-H),7.14(d,J=8.0Hz,1H,Ar-H),4.05-4.13(m,1H,CH of CH2CH2 CHOH),2.54-2.67(m,2H,CH2 ofCH2 CH2CH2OH),2.37(s,3H,CH3 of CH3Ar),2.07(s,1H,OH),1.75-1.80(m,2H,CH2 ofCH2 CH2 CH2OH),1.26(d,J=6.1Hz,3H,CH3);13C NMR(100MHz,CDCl3)δ143.22,132.67,132.19,128.59,127.60,118.06,112.18,96.63,77.55(C of CN),66.56,37.22,23.37,21.49,16.05;HRMS(ESI)m/z Calcd.for C14H16ON[M+H]+214.1883,Found 214.1876.
步骤B:参照化合物30的制备方法,由化合物70(0.6g,2.8mmol)制备得到化合物71(434mg,72.3%yield)。
1H NMR(400MHz,CDCl3)δ7.38(d,J=8.5Hz,1H,Ar-H),7.27(s,1H,Ar-H),6.93(d,J=8.5Hz,1H,Ar-H),6.43(s,1H,Ar-H),4.80-4.86(m,1H,CH of dihydrofuran),3.94(bs,2H,NH2),2.948-3.04(m,2H,CH2 of dihydrofuran),2.31(s,3H,CH3 of CH3Ar),1.35(d,J=6.2Hz,3H,CH3 of CH2CH3);13C NMR(100MHz,CDCl3)δ158.68,137.69,135.74,135.08,126.52,123.89,119.97,117.72,109.36,94.46,79.59,34.12,21.82,21.30;HRMS(ESI)m/zCalcd.for C14H16ON[M+H]+214.1881,Found 214.1874.
步骤C:参照化合物1的制备方法,由化合物71(0.4g,1.9mmol)制备得到化合物19(209mg,48.9%yield)。
1H NMR(400MHz,CDCl3)δ7.94(d,J=7.8Hz,1H,Ar-H),7.87(s,1H,Ar-H),7.50(d,J=7.8Hz,1H,Ar-H),5.15-5.21(m,1H,CH of dihydrofuran),2.76-3.36(m,2H,CH2 ofdihydrofuran),2.47(s,3H,CH3),1.55(dd,J=0.88Hz,6.4Hz,3H,CH3);13C NMR(100MHz,CDCl3)δ182.42(C=O),178.36(C=O),159.72,143.88,134.66,131.45,130.79,126.79,126.15,123.77,83.00,34.35,21.90,21.58;HRMS(ESI)m/z Calcd.for C14H13O3[M+H]+229.2532,Found 229.2523.
实施例20、化合物20的制备
步骤A:参照化合物53的制备方法,由化合物69(1.0g,5.1mmol)制备得到化合物72(697mg,60.1%yield)。
1H NMR(400MHz,CDCl3)δ7.49(d,J=7.9Hz,1H,Ar-H),7.30(s,1H,Ar-H),7.14(d,J=7.9Hz,1H,Ar-H),3.78-3.84(m,1H,CH of CH2CH2 CHOH),2.60-2.66(m,2H,CH2 ofCH2 CH2CH2OH),2.37(s,3H,CH3),2.10(s,1H,OH),1.68-1.87(m,2H,CH2 of CH2 CH2 CH2OH),1.47-1.60(m,2H,CH2 of CH2CH3),0.98(t,J=7.4Hz,3H,CH3 of CH2CH3);13C NMR(100MHz,CDCl3)δ143.18,132.64,132.16,128.54,127.60,118.04,112.15,96.79,77.48(C of CN),71.65,35.04,30.10,21.46,15.99,9.79;HRMS(ESI)m/z Calcd.for C15H18ON[M+H]+228.1385,Found 228.1388.
步骤B:参照化合物30的制备方法,由化合物72(0.6,2.6mmol)制备得到化合物73(359mg,59.8%yield)。
1H NMR(400MHz,CDCl3)δ7.55(d,J=8.5Hz,1H,Ar-H),7.45(s,1H,Ar-H),7.11(d,J=8.5Hz,1H,Ar-H),6.61(s,1H,Ar-H),4.77-4.84(m,1H,CH of dihydrofuran),3.96(bs,2H,NH2),2.71-3.17(m,2H,CH2 of dihydrofuran),2.49(s,3H,CH3),1.76-1.93(m,2H,CH2of CH2CH3),1.09(t,J=7.4Hz,3H,CH3 of CH2CH3);13C NMR(100MHz,CDCl3)δ158.91,137.67,135.80,135.10,126.57,123.90,120.00,117.73,109.38,94.39,84.69,32.05,29.03,21.35,9.52;HRMS(ESI)m/z Calcd.for C15H18ON[M+H]+228.1383,Found 228.1380.
步骤C:参照化合物1的制备方法,由化合物87(0.3g,1.3mmo)制备得到化合物20(184mg,57.7%yield)。
1H NMR(400MHz,CDCl3)δ7.83(d,J=7.8Hz,1H,Ar-H),7.75(s,1H,Ar-H),7.41(d,J=7.8Hz,1H,Ar-H),4.90-4.97(m,1H,CH of dihydrofuran),2.75-3.23(m,2H,CH2 ofdihydrofuran),2.40(s,3H,CH3),1.74-1.90(m,2H,CH2 of CH2CH3),1.01(t,J=7.6Hz,3H,CH3 of CH2CH3);13C NMR(100MHz,CDCl3)δ182.14(C=O),178.03(C=O),159.77,143.68,134.44,131.28,130.58,126.55,125.89,123.75,87.63,31.97,28.65,21.43,8.89;HRMS(ESI)m/z Calcd.for C15H15O3[M+H]+243.2819,Found 243.2813.
实施例21、化合物21的制备
步骤A:参照化合物53的制备方法,由化合物69(1.0g,5.1mmol)制备得到化合物74(789mg,64.1%yield)。
1H NMR(400MHz,CDCl3)δ7.45(d,J=7.9Hz,1H,Ar-H),7.26(s,1H,Ar-H),7.11(d,J=7.9Hz,1H,Ar-H),3.59-3.64(m,1H,CH of CH2CH2 CHOH),2.61(t,J=6.6Hz,2H,CH2 ofCH2 CH2CH2OH),2.34(s,3H,CH3),1.77-1.86(m,1H,CH of CH(CH3)2),1.63-1.69(m,2H,CH2of CH2 CH2 CH2OH),0.91-0.93(m,6H,CH3 of CH(CH3)2);13C NMR(100MHz,CDCl3)δ143.22,132.68,132.22,128.60,127.67,118.10,112.27,96.81,77.60(C of CN),68.53,46.63,36.06,24.58,23.38,22.04,21.53,16.02;HRMS(ESI)m/z Calcd.for C16H20ON[M+H]+242.1537,Found 242.1531.
步骤B:参照化合物30的制备方法,由化合物74(0.7g,2.9mmol)制备得到化合物75(491mg,70.2%yield)。
1H NMR(400MHz,CDCl3)δ7.55(d,J=8.5Hz,1H,Ar-H),7.43(s,1H,Ar-H),7.09(d,J=8.5Hz,1H,Ar-H),6.58(s,1H,Ar-H),4.57-4.63(m,1H,CH of dihydrofuran),3.96(bs,2H,NH2),2.81-3.11(m,2H,CH2 of dihydrofuran),2.47(s,3H,CH3),1.96-2.07(m,1H,CH2of CH of CH(CH3)2),1.01-1.10(m,6H,CH3×2 of CH2(CH3)2);13C NMR(100MHz,CDCl3)δ1159.24,137.54,135.85,135.15,126.63,123.93,120.00,117.74,109.65,94.30,88.47,33.33,29.99,21.40,18.15,17.72;HRMS(ESI)m/z Calcd.for C16H20ON[M+H]+242.1539,Found 242.1533.
步骤C:参照化合物1的制备方法,由化合物75(0.4g,1.6mmol)制备得到化合物21(188mg,44.4%yield)。
1H NMR(400MHz,CDCl3)δ7.84(d,J=7.8Hz,1H,Ar-H),7.76(s,1H,Ar-H),7.41(d,J=7.8Hz,1H,Ar-H),4.72-4.78(m,1H,CH of dihydrofuran),2.81-3.13(m,2H,CH2 ofdihydrofuran),2.40(s,3H,CH3),2.00-2.05(m,1H,CH of CH(CH3)2),1.00(m,6H,CH3×2of CH(CH3)2);13C NMR(100MHz,CDCl3)δ182.11(C=O),177.91(C=O),159.97,143.67,134.42,131.30,130.56,126.56,125.88,123.95,91.15,32.78,29.67,21.43,17.48,17.02;HRMS(ESI)m/z Calcd.for C16H17O3[M+H]+257.3077,Found 257.3070.
实施例22、化合物22的制备
步骤A:参照化合物53的制备方法,由化合物69(1.0g,5.1mmol)制备得到化合物76(811mg,62.3%yield)。
1H NMR(400MHz,CDCl3)δ7.48(d,J=8.0Hz,1H,Ar-H),7.29(s,1H,Ar-H),7.14(d,J=8.0Hz,1H,Ar-H),3.92-3.98(m,1H,CH of CH2CH2 CHOH),2.58-2.69(m,2H,CH2 ofCH2 CH2CH2OH),2.37(s,3H,CH3),1.79-1.84(m,2H,CH2 of CH2 CH2 CH2OH),1.68-1.73(m,1H,CHof CH2CH(CH3)2),1.25-1.49(m,2H,CH2 of CH2CH(CH3)2),0.94(d,J=6.5Hz,CH3×2 ofCH2CH(CH3)2);13C NMR(100MHz,CDCl3)δ143.22,132.68,132.22,128.60,127.67,118.10,112.27,96.81,77.60(C of CN),68.53,46.63,36.06,24.58,23.38,22.04,21.53,16.02;HRMS(ESI)m/z Calcd.for C17H22ON[M+H]+256.1698,Found 256.1691.
步骤B:参照化合物30的制备方法,由化合物76(0.8g,3.1mmol)制备得到化合物77(625mg,78.1%yield)。
1H NMR(400MHz,CDCl3)δ7.54(d,J=8.5Hz,1H,Ar-H),7.39(s,1H,Ar-H),7.06(d,J=8.5Hz,1H,Ar-H),6.54(s,1H,Ar-H),4.88-4.95(m,1H,CH of dihydrofuran),4.09(bs,2H,NH2),2.71-3.25(m,2H,CH2 of dihydrofuran),2.43(s,3H,CH3),1.86-1.93(m,1H,CHof CH2CH(CH3)2),1.47-1.84(m,2H,CH2 of CH2CH(CH3)2),0.97-1.02(m,6H,CH3×2 ofCH2CH(CH3)2);13C NMR(100MHz,CDCl3)δ158.84,137.46,135.90,135.25,126.69,124.07,120.03,117.87,109.72,94.87,82.04,45.48,33.25,25.08,23.08,22.40,21.45;HRMS(ESI)m/z Calcd.for C17H22ON[M+H]+256.1696,Found 256.1694.
步骤C:参照化合物1的制备方法,由化合物77(0.6g,2.3mmol)制备得到化合物22(279mg,43.9%yield)。
1H NMR(400MHz,CDCl3)δ7.89(d,J=7.8Hz,1H,Ar-H),7.81(s,1H,Ar-H),7.45(d,J=7.8Hz,1H,Ar-H),5.03-5.11(m,1H,CH of dihydrofuran),2.73-3.29(m,2H,CH2 ofdihydrofuran),2.43(s,3H,CH3),1.84-1.92(m,2H,CH2 of CH2CH(CH3)2),1.48-1.55(m,1H,CH of CH2CH(CH3)2),0.95-0.99(m,6H,CH3×2 of CH2CH(CH3)2);13C NMR(100MHz,CDCl3)δ182.31(C=O),178.18(C=O),159.78,143.75,134.52,131.40,130.69,126.67,126.01,123.79,85.20,45.11,33.13,24.58,22.79,22.20,21.52;HRMS(ESI)m/z Calcd.forC17H19O3[M+H]+271.3351,Found 271.3356.
实施例23、化合物23的制备
步骤A:参照化合物53的制备方法,由化合物69(1.0g,5.1mmol)制备得到化合物78(571mg,41.9%yield)。
1H NMR(400MHz,CDCl3)δ7.46(d,J=7.9Hz,1H,Ar-H),7.28(s,1H,Ar-H),7.13(d,J=7.9Hz,1H,Ar-H),3.63-3.68(m,1H,CH of CH2CH2 CHOH),2.62-2.66(m,2H,CH2 ofCH2 CH2CH2OH),2.36(s,3H,CH3),1.84-1.93(m,2H,CH2 of CH2 CH2 CH2OH),1.22-1.92(m,9H,CHand CH2×4 of cyclopentane);13C NMR(100MHz,CDCl3)δ143.19,132.69,132.22,128.56,127.70,118.12,112.26,97.00,77.54(C of CN),74.43,46.36,34.43,29.04,28.58,25.67,25.52,21.52,16.16;HRMS(ESI)m/z Calcd.for C18H22ON[M+H]+268.1690,Found268.1695.
步骤B:参照化合物30的制备方法,由化合物78(0.5g,1.8mmol)制备得到化合物79(386mg,77.2%yield)。
1H NMR(400MHz,CDCl3)δ7.54(d,J=8.5Hz,1H,Ar-H),7.40(s,1H,Ar-H),7.07(d,J=8.5Hz,1H,Ar-H),6.55(s,1H,Ar-H),4.67-4.73(m,1H,CH of dihydrofuran),4.00(bs,2H,NH2),2.80-3.21(m,2H,CH2 of dihydrofuran),2.44(s,3H,CH3),2.22-2.28(m,1H,CHof cyclopentane),1.27-1.93(m,8H,CH2×4 of cyclopentane);13C NMR(100MHz,CDCl3)δ159.30,137.63,136.01,135.32,126.80,124.11,120.11,117.92,109.86,94.66,87.52,45.42,31.85,29.21,28.62,25.78,25.66,21.55;HRMS(ESI)m/z Calcd.for C18H22ON[M+H]+268.1696,Found 268.1694.
步骤C:参照化合物1的制备方法,由化合物79(0.3g,1.1mmol)制备得到化合物23(159mg,50.1%yield)。
1H NMR(400MHz,CDCl3)δ7.91(d,J=7.9Hz,1H,Ar-H),7.83(s,1H,Ar-H),7.48(d,J=7.8Hz,1H,Ar-H),4.87-4.94(m,1H,CH of dihydrofuran),2.85-3.26(m,2H,CH2 ofdihydrofuran),2.46(s,3H,CH3),2.27-2.33(m,1H,CH of cyclopentane),1.34-1.93(m,8H,CH2×4 of cyclopentane);13C NMR(100MHz,CDCl3)δ182.26(C=O),178.10(C=O),160.05,143.70,134.47,131.38,130.65,126.63,125.94,123.90,90.12,44.78,31.44,28.68,28.00,25.48,25.33,21.48;HRMS(ESI)m/z Calcd.for C18H10O3[M+H]+283.3461,Found 283.3455.
实施例24、化合物24的制备
步骤A:参照化合物53的制备方法,由化合物69(1.0g,5.1mmol)制备得到化合物80(809mg,56.4%yield)。
1H NMR(400MHz,CDCl3)δ7.40(d,J=7.9Hz,1H,Ar-H),7.21(s,1H,Ar-H),7.07(d,J=7.9Hz,1H,Ar-H),3.53-3.58(m,1H,CH of CH2CH2 CHOH),2.56(t,J=7.0Hz,2H,CH2 ofCH2 CH2CH2OH),2.29(s,3H,CH3),1.72-1.78(m,2H,CH2 of CH2 CH2 CH2OH),1.57-1.71(m,5H,CHand CH2×2 of cyclohexane),0.95-1.31(m,6H,CH2×3 of cyclohexane);13C NMR(100MHz,CDCl3)δ143.18,132.68,132.21,128.55,127.70,118.11,112.24,96.99,77.53(Cof CN),74.58,43.71,32.47,29.04,27.81,26.43,26.22,26.09,21.51,16.31;HRMS(ESI)m/z Calcd.for C19H24ON[M+H]+282.1850,Found 282.1854.
步骤B:参照化合物30的制备方法,由化合物80(0.8g,2.8mmol)制备得到化合物81(525mg,65.7%yield)。
1H NMR(400MHz,CDCl3)δ7.52(d,J=8.5Hz,1H,Ar-H),7.39(s,1H,Ar-H),7.05(d,J=8.5Hz,1H,Ar-H),6.54(s,1H,Ar-H),4.54-4.60(m,1H,CH of dihydrofuran),3.98(bs,2H,NH2),2.82-3.11(m,2H,CH2 of dihydrofuran),2.43(s,3H,CH3),1.76-1.79(m,1H,CHof cyclohexane),1.08-1.71(m,10H,CH2×5 of cyclopentane);13C NMR(100MHz,CDCl3)δ159.17,137.50,135.88,135.18,126.68,123.97,120.00,117.77,109.68,94.38,87.73,43.29,30.24,28.64,28.31,26.43,25.91,25.75,21.44;HRMS(ESI)m/z Calcd.forC19H24ON[M+H]+282.1852,Found 282.1851.
步骤C:参照化合物1的制备方法,由化合物81(0.5g,1.8mmol)制备得到化合物24(281mg,53.3%yield)。
1H NMR(400MHz,CDCl3)δ7.91(d,J=7.8Hz,1H,Ar-H),7.84(s,1H,Ar-H),7.47(d,J=7.8Hz,1H,Ar-H),4.75-4.82(m,1H,CH of dihydrofuran),2.91-3.18(m,2H,CH2 ofdihydrofuran),2.46(s,3H,CH3),1.95-1.98(m,1H,CH of cyclohexane),1.07-1.81(m,10H,CH2×5 of cyclohexane);13C NMR(100MHz,CDCl3)δ182.32(C=O),178.17(C=O),160.08,143.78,134.55,131.46,130.75,126.73,126.05,124.03,90.59,42.70,30.00,28.00,27.56,26.19,25.63,25.51,21.55;HRMS(ESI)m/z calcd.for C19H21O3[M+H]+297.3733,Found 297.3737.
药理实验
实验例1部分化合物对IL6-STAT3信号通路抑制作用评价
本研究利用Invivogen公司稳定表达IL-6受体及可启动子含有STAT3(Signaltransducer and activator of transcription 3)结合区域的分泌胚胎碱性磷酸酶(secreted embryonic alkaline phosphatase,SEAP)报告基因的HEK-Blue IL-6细胞。在IL-6刺激下,细胞质内磷酸化的STAT3形成二聚体转位进入细胞核,结合到SEAP报告基因上启动转录,最终产生可分泌到细胞外的SEAP。细胞培养上清中的SEAP可与QUANTI-Blue反应,通过655nm处的产物吸收即可计算SEAP的生成量,从而反应IL6-STAT3通路的活性。因此,将药物处理细胞后,取上清与QUANTI-Blue反应,在655nm检测SEAP的生成量,可以评价化合物对IL-6刺激的STAT3信号通路的抑制作用。
待细胞密度达到80%时,将贴壁生长的细胞轻轻拍下后,用37℃预热的完全培养基重悬并进行计数。采用无菌96孔细胞培养板,每孔加入含有5×104的细胞悬液160μL,不同浓度化合物20μL,终质量浓度1ng/mL的IL-6细胞因子20μL,共200μL体系。阴性对照组为40μL完全培养基和160μL细胞悬液;阳性对照组为IL-6细胞因子20μL、完全培养基20μL和细胞悬液160μL。37℃细胞培养箱孵育16h后,从96孔板中每孔吸取20μL溶液转移至另一块96孔板中,加入37℃预热的QUANTI-Blue显色液180μL,在37℃孵育1h后,于655nm波长下进行检测。
表1.部分化合物对IL6-STAT3信号通路IC50值
实验例2
本研究使用3-(4,5-二甲基噻唑-2)-2,5-二苯基四氮唑溴盐比色法(MTT法)检测化合物对肿瘤细胞的杀伤和生长抑制作用。其原理为MTT可与活细胞线粒体中的琥珀酸脱氢酶结合成甲瓒结晶,在490nm处有较强的吸收峰。分别将人结直肠癌细胞HCT116、人肝癌细胞HepG2、人乳腺癌细胞MCF-7、人肺癌细胞A549、人胶质瘤细胞U251以1500每孔的密度接种至96孔板中,次日加入终浓度为10μM、5μM、2.5μM、1.25μM、0.625μM、0.3125μM化合物,每个浓度设置三个重复孔。化合物作用72h后,每孔加入终浓度0.5mg/ml的MTT,置于37℃细胞孵箱中继续孵育。4h后弃去上清,每孔加入100μL DMSO溶解甲瓒紫色结晶,酶联免疫检测仪OD490nm处测量各孔吸光值。
表2.部分化合物MTT筛选结果
/>
Claims (10)
1.一种如通式I-A所示的化合物及其药学上可接受的盐:
其中:
R1独立的选自:氢,乙基,丙基,异丙基,仲丁基,异丁基,异戊基,环丙基,环丁基,环戊基,环庚基,甲氧基,乙烯基,1-丁烯基,2-丁烯基,取代的苯基,非取代或取代的噻唑,非取代或取代的非取代或取代的噻吩,上述非取代或取代中的取代基选自乙基,丙基,异丙基,正丁基,仲丁基,异丁基,叔丁基,甲氧基,乙氧基,丙氧基,氟,氯,溴,碘,硝基,氰基,甲磺酰基,羟基,氨基,羧基,三氟甲基,三氟乙基;
R2独立的选自:氢,甲基,乙基,丙基,异丙基,正丁基,-COOH,-CH2COOH,-CH2CH2COOH,-CH2CH2 CH2COOH,-COOCH3,-COOCH2CH3,-COOCH2CH2CH3,-CH2COOCH3,-CH2CH2COOCH3,-CH2CH2CH2COOCH3,-CH2COOCH2CH3,-CH2CH2COOCH2CH3,-CH2CH2CH2COOCH2CH3;
R3独立选自:氢,氟,氯,溴,碘,乙基,丙基,异丙基,正丁基,仲丁基,异丁基,叔丁基,乙氧基,丙氧基,三氟甲基,三氟乙基;
但不包括下列化合物:
2.一种如通式I-B所示的化合物及其药学上可接受的盐:
R4任选自:氢,卤素,三氟甲基,硝基,氰基,甲磺酰基,羟基,氨基,羧基,甲氧基,C1-6烷基中的1、2或3个,且可以同时为不同基团;
A环表示环戊烯基、环己烯基;所述环戊烯基、环己烯基可被以下基团取代:氟,氯,溴,碘,三氟甲基,硝基,氰基,甲磺酰基,羟基,氨基,羧基,甲氧基,甲基,乙基,丙基,异丙基,正丁基,仲丁基,异丁基,叔丁基;
n=0、1;
但不包括下列化合物:
3.根据权利要求2的化合物及其药学上可接受的盐,其特征在于,
R5、R6、R7、R8、R9、R10、R11、R12任选自氢,氟,氯,溴,碘,三氟甲基,硝基,氰基,甲磺酰基,羟基,氨基,羧基,甲氧基,甲基,乙基,丙基,异丙基,正丁基,仲丁基,异丁基,叔丁基中的1、2、3或4个,且可以同时为不同基团;
但不包括下列化合物:
4.根据权利要求1-3任一项的化合物及其药学上可接受的盐,其特征在于,所述化合物选自
化合物1.(R)-4,4,8-三甲基-1,2,3,4,8,9-六氢菲并[3,2-b]呋喃-7,11-二酮
化合物2.4,4-二甲基-3,4,9,10-四氢-1H-萘并[2,1-g]色烯-7,12(2H,8H)-二酮
化合物3.2,3,8,9-四氢茚并[5,4-g]色烯-6,11(1H,7H)-二酮
化合物4.2,3,7,8-四氢-1H-环戊二烯并[7,8]萘并[2,3-b]呋喃-6,10-二酮
化合物5.3,4,9,10-四氢-1H-萘并[2,1-g]色烯-7,12(2H,8H)-二酮
化合物6.2-(2-甲氧苯基)-2,3-二氢萘并[2,3-b]呋喃-4,9-二酮
化合物7.2-(邻苯甲基)-2,3-二氢萘并[2,3-b]呋喃-4,9-二酮
化合物8.2-(4-(三氟甲基)苯基)-2,3-二氢萘并[2,3-b]呋喃-4,9-二酮
化合物9.2-(2-噻唑基)-2,3-二氢萘并[2,3-b]呋喃-4,9-二酮
化合物10.2-(2-噻吩基)-2,3-二氢萘并[2,3-b]呋喃-4,9-二酮
化合物11.2-(4,9-二羰基-2-苯基-2,3,4,9-四氢萘并[2,3-b]呋喃-3-基)乙酸甲酯
化合物12.4,9-二羰基-2-苯基-2,3,4,9-四氢萘并[2,3-b]呋喃-3-羧酸异丙酯
化合物13.4,9-二羰基-2-(2-噻吩基)-2,3,4,9-四氢萘并[2,3-b]呋喃-3-羧酸甲酯
化合物14.2-环戊基-2,3-二氢萘并[2,3-b]呋喃-4,9-二酮
化合物15.6-(三氟甲基)-2,3-二氢萘并[2,3-b]呋喃-4,9-二酮
化合物16.2-甲基-6-(三氟甲基)-2,3-二氢萘并[2,3-b]呋喃-4,9-二酮
化合物17.2-异丁基-6-(三氟甲基)-2,3-二氢萘并[2,3-b]呋喃-4,9-二酮
化合物18.2-异丙基-6-(三氟甲基)-2,3-二氢萘并[2,3-b]呋喃-4,9-二酮
化合物19.2,6-二甲基-2,3-二氢萘并[2,3-b]呋喃-4,9-二酮
化合物20.2-乙基-6-甲基-2,3-二氢萘并[2,3-b]呋喃-4,9-二酮
化合物21.2-异丙基-6-甲基-2,3-二氢萘并[2,3-b]呋喃-4,9-二酮
化合物22.2-异丁基-6-甲基-2,3-二氢萘并[2,3-b]呋喃-4,9-二酮
化合物23.2-环戊基-6-甲基-2,3-二氢萘并[2,3-b]呋喃-4,9-二酮
化合物24.2-环己基-6-甲基-2,3-二氢萘并[2,3-b]呋喃-4,9-二酮
5.权利要求1-4任一项所述化合物的制备方法,其包括以下方法:
方法一:
通式I-A的制备方法:化合物Ia与硫酸二甲酯反应得到化合物IIa,化合物IIa与多聚甲醛反应得到化合物IIIa,化合物IIIa经NBS氧化得到化合物IVa,化合物IVa脱保护得到化合物Va,化合物Va与化合物Via经CAN介导的环加成反应得到式(I-A);
(a)烷基化反应;(b)羟基邻位甲酰化;(c)氧化反应;(d)脱保护;(e)CAN介导的环加成反应;其中所述R1为取代的苯基,非取代或取代的噻唑,非取代或取代的非取代或取代的噻吩,上述非取代或取代中取代基选自乙基,丙基,异丙基,正丁基,仲丁基,异丁基,叔丁基,甲氧基,乙氧基,丙氧基,氟,氯,溴,碘,硝基,氰基,甲磺酰基,羟基,氨基,羧基,三氟甲基,三氟乙基,R2、R3的定义分别同权利要求1-4任一项的定义;
方法二:
通式I-A的制备方法:化合物Ib与盐酸羟胺经肟化脱水反应得到化合物IIb,化合物IIb与三氟甲磺酸酐反应得到化合物IIIb,化合物IIIb经sonogashira偶联得到化合物IVb,化合物IVb经戴斯马汀氧化剂氧化得到化合物Vb,化合物Vb与格式试剂VIIIb反应得到化合物VIb,化合物VIb在甲醇钠条件下反应得到化合物VIIb,化合物VIIb经Fremy’s盐氧化得到式(I-A);
(a)肟化脱水;(b)酯化反应;(c)sonogashira偶联;(d)氧化反应;(e)格式反应;(f)环合反应;(g)氧化反应,其中所述R1为氢原子,乙基,丙基,异丙基,仲丁基,异丁基,异戊基,环丙基,环丁基,环戊基,环庚基或乙烯基,1-丁烯基,2-丁烯基;R2、R3的定义同权利要求1-4任一项的定义;
方法三:
通式I-B的制备方法:化合物Ic与多聚甲醛反应得到化合物IIc,化合物IIc与盐酸羟胺经肟化脱水反应得到化合物IIIc,化合物IIIc与三氟甲磺酸酐反应得到化合物IVc,化合物IVc与化合物VIIc经sonogashira偶联得到化合物Vc,化合物Vc在甲醇钠作用下发生环合反应得到化合物VIc,化合物VIc经Fremy’s盐氧化得到式(I-B);
(a)羟基邻位甲酰化;(b)肟化脱水;(c)酯化反应;(d)sonogashira偶联;(e)环合反应;(f)氧化反应,在结构式VIIc及结构式Vc中,R4为-(CH2)n+2中取代基,其中n,R4和环A的定义同权利要求2-3任一项的定义。
6.一种药物组合物,其特征在于,所述药物组合物含有权利要求1-4任一项的化合物及其药学上可接受的盐以及药学上可接受的载体或赋形剂。
7.根据权利要求6的药物组合物,其特征在于,所述药物组合物包括片剂、胶囊、丸剂、注射剂、溶液、悬液、乳剂、粉末、控释制剂或缓释制剂。
8.权利要求1-4任一项的化合物及其药学上可接受的盐在制备预防、缓解和/或治疗癌症及其并发症的药物中的应用。
9.根据权利要求8的应用,其特征在于,所述的癌症选乳腺癌、肺癌、口腔癌、肾癌、食道癌、肝癌、胃癌、肠癌、宫颈癌以及卵巢癌。
10.根据权利要求8的应用,其特征在于,所述的癌症并发症包括上腔静脉综合症、恶性体腔积液、机体免疫缺陷、粒细胞减少以及屏障防御破坏。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201910311646.4A CN111825644B (zh) | 2019-04-18 | 2019-04-18 | 2,3-二氢萘并[2,3-b]呋喃-4,9-二酮类化合物及其制备方法和用途 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201910311646.4A CN111825644B (zh) | 2019-04-18 | 2019-04-18 | 2,3-二氢萘并[2,3-b]呋喃-4,9-二酮类化合物及其制备方法和用途 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN111825644A CN111825644A (zh) | 2020-10-27 |
CN111825644B true CN111825644B (zh) | 2023-07-28 |
Family
ID=72914419
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201910311646.4A Active CN111825644B (zh) | 2019-04-18 | 2019-04-18 | 2,3-二氢萘并[2,3-b]呋喃-4,9-二酮类化合物及其制备方法和用途 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN111825644B (zh) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN115054608B (zh) * | 2022-06-24 | 2023-11-03 | 澳门大学 | 隐丹参酮类物质及其联用组合物的应用 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101518538A (zh) * | 2009-01-14 | 2009-09-02 | 中国药科大学 | 丹参酮类化合物作为cyp1家族特异性抑制剂的用途 |
CN103025159A (zh) * | 2010-03-19 | 2013-04-03 | 波士顿生物医学公司 | 靶向癌症干细胞的新方法 |
CN106890171A (zh) * | 2017-03-14 | 2017-06-27 | 中国药科大学 | 丹参酮类化合物在制备抗肿瘤药物中的应用 |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20080187608A1 (en) * | 2007-02-05 | 2008-08-07 | Savipu Pharmaceuticals | Enriched fractions from clary sage for the treatment of cancer, cardiovascular and inflammatory diseases |
-
2019
- 2019-04-18 CN CN201910311646.4A patent/CN111825644B/zh active Active
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101518538A (zh) * | 2009-01-14 | 2009-09-02 | 中国药科大学 | 丹参酮类化合物作为cyp1家族特异性抑制剂的用途 |
CN103025159A (zh) * | 2010-03-19 | 2013-04-03 | 波士顿生物医学公司 | 靶向癌症干细胞的新方法 |
CN106890171A (zh) * | 2017-03-14 | 2017-06-27 | 中国药科大学 | 丹参酮类化合物在制备抗肿瘤药物中的应用 |
Non-Patent Citations (4)
Title |
---|
Arylated - and -dihydrofuran naphthoquinones: Electrochemical parameters, evaluation of antitumor activity and their correlation;Fabricia da Rocha Ferreira et al;《Electrochimica Acta》;20131231;第1-7页 * |
Base-Mediated Cyclization Reaction of 2‑(5-Hydroxy-1-pentynyl)benzonitriles to 4‑Amino-2,3-dihydronaphtho[2,3‑b]furanes and Synthesis of Furanonaphthoquinones;Chih-Jyun Tsai et al;《J.Org.Chem.》;20160405;第3882-3889页 * |
STN检索报告;审查员;《STN检索报告》;20160422;第1-5页 * |
Synthesis, Anti-Proliferative Activity Evaluation and 3D-QSAR Study of Naphthoquinone Derivatives as Potential Anti-Colorectal Cancer Agents;Julio Acuna et al;《Molecules》;20180101(第23期);第1-21页 * |
Also Published As
Publication number | Publication date |
---|---|
CN111825644A (zh) | 2020-10-27 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US6861530B2 (en) | Piperidine derivatives | |
RU2125564C1 (ru) | Производные бензофуранилалкан-карбоновой кислоты, или смесь их изомеров, или отдельные изомеры, или их соли | |
KR20210089195A (ko) | 비페닐계 화합물, 이의 중간체, 제조 방법, 약학 조성물 및 용도 | |
KR910002583B1 (ko) | 피페라진 유도체 또는 이의 염, 이의 제조방법 및 활성 성분으로서 이를 함유하는 약제학적 조성물 | |
KR20190026827A (ko) | 방향족 아세틸렌 또는 방향족 에틸렌계 화합물, 그의 중간체, 제조 방법, 약물 조성물 및 용도 | |
AU2008323561A1 (en) | Inhibitors of human immunodeficiency virus replication | |
CA2065644C (en) | Pyrazolopyridine compound and processes for preparation thereof | |
CA3142295A1 (en) | Benzotriazole derivative | |
KR20180108675A (ko) | 브로모도메인 억제제인 카르볼린 유도체 | |
AU2006334856A1 (en) | Novel, acyclic substituted furopyrimidine derivatives and use thereof for treating cardiovascular diseases | |
CN111825644B (zh) | 2,3-二氢萘并[2,3-b]呋喃-4,9-二酮类化合物及其制备方法和用途 | |
CN115403511B (zh) | 荜茇酰胺类似物、药物组合物及其制备方法和应用 | |
CA2690527A1 (en) | Substituted furopyrimidines and use thereof | |
CA2690545A1 (en) | Substituted bicyclic heteroaryl compounds and their use | |
WO2009074020A9 (zh) | α-氨基-N-取代酰胺化合物、包含该化合物的药物组合物及其用途 | |
JP2008539181A (ja) | Ep1受容体アンタゴニストとして有用なフラン化合物 | |
KR20120122705A (ko) | 혈관 신생 억제 및 항산화 효과를 가지는 이미다졸계 알칼로이드 유도체 및 이의 제조방법 | |
US6143780A (en) | N-arylmethylthioanilide compounds useful for the inhibition of the replication of HIV | |
CN113801088B (zh) | 苯并六元环衍生物及其应用 | |
JPH01216961A (ja) | 12−リポキシゲネース阻害剤 | |
CN108976248B (zh) | 一种含杂环的高价碘化合物及其制备方法和应用 | |
CN113683613B (zh) | 一种多环吡啶肟基化合物及其药物组合物和用途 | |
WO2017173960A1 (zh) | 一类抑制丙肝病毒的大环状杂环化合物及其制备和用途 | |
CN112824416A (zh) | 一种脱n-甲基左氧氟沙星的丙烯酮衍生物及其制备方法和应用 | |
CN112824414A (zh) | 一种n-乙酰基氧氟沙星的丙烯酮衍生物及其制备方法和应用 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |