CN115124541B - 一类ido1抑制剂的制备和用途 - Google Patents
一类ido1抑制剂的制备和用途 Download PDFInfo
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- CN115124541B CN115124541B CN202110313379.1A CN202110313379A CN115124541B CN 115124541 B CN115124541 B CN 115124541B CN 202110313379 A CN202110313379 A CN 202110313379A CN 115124541 B CN115124541 B CN 115124541B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/10—Spiro-condensed 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
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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)
- Hematology (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明属于医药技术领域,公开了一类IDO1抑制剂的制备和用途。具体包括具有通式Ⅰ所示的化合物或其药学上可接受的盐,这类化合物的制备方法。本发明还涉及含有通式Ⅰ的化合物的药物组合物及其制备方法,这类化合物和药物组合物在抗肿瘤方面的应用。
Description
技术领域
本发明属于医药技术领域,涉及一类IDO1抑制剂exiguamine A的结构类似物或其药学上可以接受的盐,以及含有上述化合物或其药学上可接受盐的抗肿瘤制剂。
背景技术
在中国,每天约1万人被确诊为癌症,平均每分钟就有7.5人,癌症仍然是中国居民死亡的主要原因。目前,癌症的治疗方法主要是手术治疗、放射治疗和化学疗法。手术治疗是早、中期癌症病人最主要的治疗手段,但无法根除肿瘤细胞,并且肿瘤易转移、复发;放射治疗是指通过内照射或者外照射破坏细胞的遗传物质,可阻止细胞生长或分裂,进而控制癌细胞的生长。化学疗法指通过使用化学治疗药物(如紫杉醇)杀灭癌细胞达到治疗目的。近年来在化学疗法中出现一种新的方法——免疫疗法,引起广泛关注。免疫治疗可以通过恢复甚至激活癌症患者天然的免疫系统来识别和消除肿瘤细胞,减少免疫功能损伤,安全无毒副作用。
色氨酸是蛋白质合成所必须的氨基酸,对维持细胞的功能至关重要。体内超过95%的色氨酸沿犬尿氨酸途径分解代谢为犬尿氨酸、犬尿酸、喹啉酸和辅酶NAD+等,该途径的第一步和限速步骤由吲哚胺2,3-双加氧酶1(IDO1)催化。色氨酸的耗竭和犬尿氨酸等代谢物的产生导致肿瘤微环境产生免疫抑制作用,促进癌细胞的免疫逃逸。研究表明IDO1在多种癌症细胞如乳腺癌、宫颈癌、脑癌等上调表达,与肿瘤的侵袭性和患者的不良预后相关,其抑制剂已成为癌症免疫治疗的新策略。
天然产物exiguamine A是从海洋海绵Neopetrosia exigua中提取出来的外消旋体,具有复杂的六环生物碱骨架,其结构特点是含有吲哚醌、N,N-二甲基二氢吲哚鎓、乙内酰脲环和吡喃环组成的螺二环系统。作为IDO1抑制剂,其Ki值是41.2nM,是天然产物中IDO1抑制活性最强的化合物,具有良好的开发前景,因此对该类化合物的合成,开发与改造成为免疫治疗领域的研究热点。
目前,有关天然产物exiguamine A的改造方法的文献如下所示:G.Carr,et al.,J.Med.Chem.2008,51,2634-2637报道了一系列exiguamine A简化物的研究,论证了醌结构是保持活性必不可少的部分。M.Volgraf,et al.,Nature Chemical Biology,2008,4,535-537报道了exiguamine A的全合成,发现了带正电的季胺离子和封闭的吡喃环并不是保持活性所必须的部分。
发明内容
本发明的要解决的技术问题是提供一类具有通式I的exiguamine A结构类似物或其药学上可接受的盐;
本发明的要解决的另一个技术问题是提供含有通式I的化合物或其药学上可接受的盐的药物组合物;
本发明的要解决的再一个技术问题是提供通式I的化合物或其药学上可接受的盐在抗IDO1酶以及抗肿瘤中的应用。
本发明的具有通式Ⅰ的化合物及其药学上可接受的盐,结构特点是:碳骨架C环16位由天然产物exiguamine A的O原子换成电子等排体-CH2-;去掉了天然产物exiguamine A中带正电的二氢吲哚鎓小环;若24位连接酰基,则为芳酰基类、杂芳酰基类、肉桂酸甲酰基、烷酰基;若24位连接烷基,则为芳烷基类、杂芳烷基类、烷基类。
本发明所涉及的具有通式Ⅰ的化合物分子中17位的手性中心和天然产物exiguamine A分子的一致,是外消旋体。
R1、R6、R7独立的选自:H、C1-C8的直链或带支链的烷基、C2-C8的烯基、C2-C4的炔基、C1-C8的烷基酰基、C1-C8的磺酰基、C1-C8的烷氧酰基;
R2、R3、R4、R5独立的选自:H、卤素、OH、SH、NH2、COOH、CF3、醛基、氨基甲酰基、NO2、CN、C1-C6的直链或支链的烷基、C2-C6直链或支链的的烯基、C2-C4的炔基、C1-C6直链或支链的的烷氧基;
R8、R9独立的选自:C6-C10的芳酰基,C4-C10的杂芳酰基,C6-C10芳基取代的C1-C4烷酰基、C4-C10杂芳基取代的C1-C4烷酰基、C6-C10芳基取代的C0-C4肉桂酸甲酰基、C1-C10的直链或带支链的烷酰基,C5-C6环烷基并苯酰基、C6-C10的芳烷基,C4-C10的杂芳烷基,C6-C10芳基取代的C1-C4直链或支链烷基、C4-C10杂芳基取代的C1-C4直链或支链烷基、C1-C10的直链或支链烷基;这些芳基、杂芳基、C5-C6环烷基并苯基上又可以具有一个或多个取代基,取代基选自H、OH、SH、NH2、COOH、CF3、醛基、氨基甲酰基、卤素、NO2、CN、C1-C8直链或支链的烷基、C1-C8直链或支链烷氧基、C1-C8直链或支链烷基胺基、C2-C8直链或支链烯基、C2-C4炔基、C6-C8的芳基、C4-C8的杂环芳基;
R8、R9可分别取自下列基团:
1、苯甲酰基-:苯环上的取代基可以是一个或多个;例如苯环可以是单取代,也可以是二取代和三取代;单取代苯环上的取代位置为2-,3-或4-位;二取代苯环上取代基的位置为2,4-、3,4-、2,3-或3,4-;三取代苯环的取代位置为2,3,4-或3,4,5-位;这些取代基分别独立,可选自下列取代基:
H、OH、SH、NH2、COOH、CF3、醛基、氨基甲酰基、F、Cl、Br、I、NO2、CN、C1-C4直链或支链的烷基、C1-C4直链或支链烷氧基、C1-C4直链或支链烷基氨基、C2-C4直链或支链烯基、C2-C3炔基;当苯环上为双取代时,相邻的两个取代基可以相互连接成C5-C6环烷基并苯基,取代基选自-CH2CH2-、-CH2-。如:四氢萘基。
2、吡啶甲酰基-:2-吡啶环上的取代基可以是一个或多个;例如吡啶环上可以是单取代也可以是二取代;单取代吡啶环上取代基的位置为4-和6-位;二取代吡啶环上取代基的位置为3,5-、3,4-、3,6-位,这些取代基分别独立,选自下列取代基:
H、OH、SH、NH2、COOH、CF3、醛基、氨基甲酰基、F、Cl、Br、I、NO2、CN、C1-C4直链或支链的烷基、C1-C4直链或支链烷氧基、C1-C4直链或支链烷基氨基、C2-C4直链或支链烯基、C2-C3炔基;
3、异烟酸甲酰基-:4-吡啶环上的取代基可以是一个或多个;例如吡啶环上可以是单取代也可以是二取代;单取代吡啶环上取代基的位置为2-和3-位;二取代吡啶环上取代基的位置为2,3-、3,5-、2,6-位,这些取代基分别独立,选自下列取代基:
H、OH、SH、NH2、COOH、CF3、醛基、氨基甲酰基、F、Cl、Br、I、NO2、CN、C1-C4直链或支链的烷基、C1-C4直链或支链烷氧基、C1-C4直链或支链烷基氨基、C2-C4直链或支链烯基、C2-C3炔基;
4、烟酰基-:3-吡啶环上的取代基可以是一个或多个;例如吡啶环上可以是单取代也可以是二取代;单取代吡啶环上取代基的位2-、4-、5-和6-位;二取代吡啶环上取代基的位置为4,6-、5,6-位,这些取代基分别独立,选自下列取代基:
H、OH、SH、NH2、COOH、CF3、醛基、氨基甲酰基、F、Cl、Br、I、NO2、CN、C1-C4直链或支链的烷基、C1-C4直链或支链烷氧基、C1-C4直链或支链烷基氨基、C2-C4直链或支链烯基、C2-C3炔基;
5、α-萘基甲酰基-:α-萘基环上的取代基可以是一个或多个;例如单取代基在萘环上4-、5-、或8-位上;二取代基为萘环上的4,5-、4,8-或5,8-位,这些取代基分别独立,选自下列取代基:
H、OH、SH、NH2、COOH、CF3、醛基、氨基甲酰基、F、Cl、Br、I、NO2、CN、C1-C4直链或支链的烷基、C1-C4直链或支链烷氧基、C1-C4直链或支链烷基氨基、C2-C4直链或支链烯基、C2-C3炔基;
6、β-萘基甲酰基-:β-萘基环上的取代基可以是一个或多个;例如单取代基在萘环上1-、4-、5-、或8-位上;二取代基为萘环上的1,4-、4,5-、4,8-或5,8-位,这些取代基分别独立,选自下列取代基:
H、OH、SH、NH2、COOH、CF3、醛基、氨基甲酰基、F、Cl、Br、I、NO2、CN、C1-C4直链或支链的烷基、C1-C4直链或支链烷氧基、C1-C4直链或支链烷基氨基、C2-C4直链或支链烯基、C2-C3炔基;
7、喹啉-4-甲酰基-:4-喹啉环上的取代基可以是一个或多个;例如单取代基在喹啉环上2-、5-、6-、7-或8-位上;二取代基为喹啉环上的5,6-、5,7-、5,8-或6,7-位,这些取代基分别独立,选自下列取代基:
H、OH、SH、NH2、COOH、CF3、醛基、氨基甲酰基、F、Cl、Br、I、NO2、CN、C1-C4直链或支链的烷基、C1-C4直链或支链烷氧基、C1-C4直链或支链烷基氨基、C2-C4直链或支链烯基、C2-C3炔基;
8、喹啉-3-甲酰基-:3-喹啉环上的取代基可以是一个或多个;例如单取代基在喹啉环2-、4-、5-、6-、7-或8-位上;二取代基为喹啉环上的5,6-、5,7-、5,8-或6,7-位,这些取代基分别独立,选自下列取代基:
H、OH、SH、NH2、COOH、CF3、醛基、氨基甲酰基、F、Cl、Br、I、NO2、CN、C1-C4直链或支链的烷基、C1-C4直链或支链烷氧基、C1-C4直链或支链烷基氨基、C2-C4直链或支链烯基、C2-C3炔基;
9、喹啉-2-甲酰基-:2-喹啉环上的取代基可以是一个或多个;例如单取代基在喹啉环3-、4-、5-、6-、7-或8-位上;二取代基为喹啉环上的5,6-、5,7-、5,8-或6,7-位,这些取代基分别独立,选自下列取代基:
H、OH、SH、NH2、COOH、CF3、醛基、氨基甲酰基、F、Cl、Br、I、NO2、CN、C1-C4直链或支链的烷基、C1-C4直链或支链烷氧基、C1-C4直链或支链烷基氨基、C2-C4直链或支链烯基、C2-C3炔基;
10、吲哚-3-甲酰基-:3-吲哚环上的取代基可以是一个或多个;例如单取代基在吲哚环2-、4-、5-、6-或7-位上;二取代基为吲哚环上的4,5-、5,6-、5,7-、4,6-、4,7-或6,7-位,这些取代基分别独立,选自下列取代基:
H、OH、SH、NH2、COOH、CF3、醛基、氨基甲酰基、F、Cl、Br、I、NO2、CN、C1-C4直链或支链的烷基、C1-C4直链或支链烷氧基、C1-C4直链或支链烷基氨基、C2-C4直链或支链烯基、C2-C3炔基;R’为H、C1-C4直链或支链的烷基。
11、吲哚-2-甲酰基-:2-吲哚环上的取代基可以是一个或多个;例如单取代基在吲哚环3-、4-、5-、6-或7-位上;二取代基为吲哚环上的4,5-、5,6-、5,7-、4,6-、4,7-或6,7-位,这些取代基分别独立,选自下列取代基:
H、OH、SH、NH2、COOH、CF3、醛基、氨基甲酰基、F、Cl、Br、I、NO2、CN、C1-C4直链或支链的烷基、C1-C4直链或支链烷氧基、C1-C4直链或支链烷基氨基、C2-C4直链或支链烯基、C2-C3炔基;R”为H、C1-C4直链或支链的烷基。
12、苯并呋喃-2-甲酰基-:2-苯并呋喃环上的取代基可以是一个或多个;例如单取代基在苯并呋喃环3-、4-、5-、6-或7-位上;二取代基为苯并呋喃环上的4,5-、5,6-、5,7-、4,6-、4,7-或6,7-位,这些取代基分别独立,选自下列取代基:
H、OH、SH、NH2、COOH、CF3、醛基、氨基甲酰基、F、Cl、Br、I、NO2、CN、C1-C4直链或支链的烷基、C1-C4直链或支链烷氧基、C1-C4直链或支链烷基氨基、C2-C4直链或支链烯基、C2-C3炔基;
13、苯并呋喃-3-甲酰基-:3-苯并呋喃环上的取代基可以是一个或多个;例如单取代基在苯并呋喃环2-、4-、5-、6-或7-位上;二取代基为苯并呋喃环上的4,5-、5,6-、5,7-、4,6-、4,7-或6,7-位,这些取代基分别独立,选自下列取代基:
H、OH、SH、NH2、COOH、CF3、醛基、氨基甲酰基、F、Cl、Br、I、NO2、CN、C1-C4直链或支链的烷基、C1-C4直链或支链烷氧基、C1-C4直链或支链烷基氨基、C2-C4直链或支链烯基、C2-C3炔基;
14、苯并噻吩-2-甲酰基-:2-苯并噻吩环上的取代基可以是一个或多个;例如单取代基在苯并噻吩环3-、4-、5-、6-或7-位上;二取代基为苯并噻吩环上的4,5-、5,6-、5,7-、4,6-、4,7-或6,7-位,这些取代基分别独立,选自下列取代基:
H、OH、SH、NH2、COOH、CF3、醛基、氨基甲酰基、F、Cl、Br、I、NO2、CN、C1-C4直链或支链的烷基、C1-C4直链或支链烷氧基、C1-C4直链或支链烷基氨基、C2-C4直链或支链烯基、C2-C3炔基;
15、苯并噻吩-3-甲酰基-:3-苯并噻吩环上的取代基可以是一个或多个;例如单取代基在苯并噻吩环2-、4-、5-、6-或7-位上;二取代基为苯并噻吩环上的4,5-、5,6-、5,7-、4,6-、4,7-或6,7-位,这些取代基分别独立,选自下列取代基:
H、OH、SH、NH2、COOH、CF3、醛基、氨基甲酰基、F、Cl、Br、I、NO2、CN、C1-C4直链或支链的烷基、C1-C4直链或支链烷氧基、C1-C4直链或支链烷基氨基、C2-C4直链或支链烯基、C2-C3炔基;
16、呋喃-2-甲酰基-:2-呋喃环上的取代基可以是一个或多个;例如单取代基在呋喃环3-、4-或5-位上;二取代基为呋喃环上的3,4-、3,5-或4,5-位,这些取代基分别独立,选自下列取代基:H、OH、SH、NH2、COOH、CF3、醛基、氨基甲酰基、F、Cl、Br、I、NO2、CN、C1-C4直链或支链的烷基、C1-C4直链或支链烷氧基、C1-C4直链或支链烷基氨基、C2-C4直链或支链烯基、C2-C3炔基;
17、呋喃-3-甲酰基-:3-呋喃环上的取代基可以是一个或多个;例如单取代基在呋喃环2-、4-或5-位上;二取代基为呋喃环上的2,4-、2,5-或4,5-位,这些取代基分别独立,选自下列取代基:H、OH、SH、NH2、COOH、CF3、醛基、氨基甲酰基、F、Cl、Br、I、NO2、CN、C1-C4直链或支链的烷基、C1-C4直链或支链烷氧基、C1-C4直链或支链烷基氨基、C2-C4直链或支链烯基、C2-C3炔基;
18、噻吩-2-甲酰基-:2-噻吩环上的取代基可以是一个或多个;例如单取代基在噻吩环3-、4-或5-位上;二取代基为噻吩环上的3,4-、3,5-或4,5-位,这些取代基分别独立,选自下列取代基:H、OH、SH、NH2、COOH、CF3、醛基、氨基甲酰基、F、Cl、Br、I、NO2、CN、C1-C4直链或支链的烷基、C1-C4直链或支链烷氧基、C1-C4直链或支链烷基氨基、C2-C4直链或支链烯基、C2-C3炔基;
19、噻吩-3-甲酰基-:3-噻吩环上的取代基可以是一个或多个;例如单取代基在噻吩环2-、4-或5-位上;二取代基为噻吩环上的2,4-、2,5-或4,5-位,这些取代基分别独立,选自下列取代基:
H、OH、SH、NH2、COOH、CF3、醛基、氨基甲酰基、F、Cl、Br、I、NO2、CN、C1-C4直链或支链的烷基、C1-C4直链或支链烷氧基、C1-C4直链或支链烷基氨基、C2-C4直链或支链烯基、C2-C3炔基;
20、肉桂酸甲酰基-:烯烃碳碳双键可以为Z-构型或E-构型;苯环上的取代基可以是一个或多个;例如苯环可以是单取代,也可以是二取代和三取代;单取代苯环上的取代位置为2-,3-或4-位;二取代苯环上取代基的位置为2,4-、3,4-、2,3-或3,4-;三取代苯环的取代位置为2,3,4-或3,4,5-位;这些取代基分别独立,可选自下列取代基:
H、OH、SH、NH2、COOH、CF3、醛基、氨基甲酰基、F、Cl、Br、I、NO2、CN、C1-C4直链或支链的烷基、C1-C4直链或支链烷氧基、C1-C4直链或支链烷基氨基、C2-C4直链或支链烯基、C2-C3炔基;当二取代苯环上的取代基位置为2,3-或3,4-时,相邻的两个取代基可以相互连接成五元或六元环,取代基选自-CH2CH2-、-CH2-。
21、烷酰基-:C1-C4的直链或带支链的烷基;例如,甲基、乙基、异丙基、叔丁基等。
22、苯甲基-:苯环上的取代基可以是一个或多个;例如苯环可以是单取代,也可以是二取代和三取代;单取代苯环上的取代位置为2-,3-或4-位;二取代苯环上取代基的位置为2,4-、3,4-、2,3-或3,4-;三取代苯环的取代位置为2,3,4-或3,4,5-位;这些取代基分别独立,可选自下列取代基:
H、OH、SH、NH2、COOH、CF3、醛基、氨基甲酰基、F、Cl、Br、I、NO2、CN、C1-C4直链或支链的烷基、C1-C4直链或支链烷氧基、C1-C4直链或支链烷基氨基、C2-C4直链或支链烯基、C2-C3炔基;当苯环上为双取代时,相邻的两个取代基可以相互连接成C5-C6环烷基并苯基,取代基选自-CH2CH2-、-CH2-。如:四氢萘基。
23、α-萘甲基-:α-萘基环上的取代基可以是一个或多个;例如单取代基在萘环上4-、5-、或8-位上;二取代基为萘环上的4,5-、4,8-或5,8-位,这些取代基分别独立,选自下列取代基:
H、OH、SH、NH2、COOH、CF3、醛基、氨基甲酰基、F、Cl、Br、I、NO2、CN、C1-C4直链或支链的烷基、C1-C4直链或支链烷氧基、C1-C4直链或支链烷基氨基、C2-C4直链或支链烯基、C2-C3炔基;
24、β-萘甲基-:β-萘基环上的取代基可以是一个或多个;例如单取代基在萘环上1-、4-、5-、或8-位上;二取代基为萘环上的1,4-、4,5-、4,8-或5,8-位,这些取代基分别独立,选自下列取代基:
H、OH、SH、NH2、COOH、CF3、醛基、氨基甲酰基、F、Cl、Br、I、NO2、CN、C1-C4直链或支链的烷基、C1-C4直链或支链烷氧基、C1-C4直链或支链烷基氨基、C2-C4直链或支链烯基、C2-C3炔基;
25、苯并噻吩-2-甲基-:2-苯并噻吩环上的取代基可以是一个或多个;例如单取代基在苯并噻吩环3-、4-、5-、6-或7-位上;二取代基为苯并噻吩环上的4,5-、5,6-、5,7-、4,6-、4,7-或6,7-位,这些取代基分别独立,选自下列取代基:
H、OH、SH、NH2、COOH、CF3、醛基、氨基甲酰基、F、Cl、Br、I、NO2、CN、C1-C4直链或支链的烷基、C1-C4直链或支链烷氧基、C1-C4直链或支链烷基氨基、C2-C4直链或支链烯基、C2-C3炔基;
26、苯并噻吩-3-甲基-:3-苯并噻吩环上的取代基可以是一个或多个;例如单取代基在苯并噻吩环2-、4-、5-、6-或7-位上;二取代基为苯并噻吩环上的4,5-、5,6-、5,7-、4,6-、4,7-或6,7-位,这些取代基分别独立,选自下列取代基:
H、OH、SH、NH2、COOH、CF3、醛基、氨基甲酰基、F、Cl、Br、I、NO2、CN、C1-C4直链或支链的烷基、C1-C4直链或支链烷氧基、C1-C4直链或支链烷基氨基、C2-C4直链或支链烯基、C2-C3炔基;
27、噻吩-2-甲基-:2-噻吩环上的取代基可以是一个或多个;例如单取代基在噻吩环3-、4-或5-位上;二取代基为噻吩环上的3,4-、3,5-或4,5-位,这些取代基分别独立,选自下列取代基:H、OH、SH、NH2、COOH、CF3、醛基、氨基甲酰基、F、Cl、Br、I、NO2、CN、C1-C4直链或支链的烷基、C1-C4直链或支链烷氧基、C1-C4直链或支链烷基氨基、C2-C4直链或支链烯基、C2-C3炔基;
28、噻吩-3-甲基-:3-噻吩环上的取代基可以是一个或多个;例如单取代基在噻吩环2-、4-或5-位上;二取代基为噻吩环上的2,4-、2,5-或4,5-位,这些取代基分别独立,选自下列取代基:H、OH、SH、NH2、COOH、CF3、醛基、氨基甲酰基、F、Cl、Br、I、NO2、CN、C1-C4直链或支链的烷基、C1-C4直链或支链烷氧基、C1-C4直链或支链烷基氨基、C2-C4直链或支链烯基、C2-C3炔基;
29、苯乙基-:苯环上的取代基可以是一个或多个;例如苯环可以是单取代,也可以是二取代和三取代;单取代苯环上的取代位置为2-,3-或4-位;二取代苯环上取代基的位置为2,4-、3,4-、2,3-或3,4-;三取代苯环的取代位置为2,3,4-或3,4,5-位;这些取代基分别独立,可选自下列取代基:
H、OH、SH、NH2、COOH、CF3、醛基、氨基甲酰基、F、Cl、Br、I、NO2、CN、C1-C4直链或支链的烷基、C1-C4直链或支链烷氧基、C1-C4直链或支链烷基氨基、C2-C4直链或支链烯基、C2-C3炔基;当苯环上为双取代时,,相邻的两个取代基可以相互连接成C5-C6环烷基并苯基,取代基选自-CH2CH2-、-CH2-。如:四氢萘基。
30、[1,1'-联苯]-4-甲基-:联苯环上的取代基可以是一个或多个;例如单取代基在联苯环上2-、3-、4-、5-、6-或2’-、3’-、4’-、5’-、6’-位上;二取代基为联苯环上的3’,5’-、2’,4’-位,这些取代基分别独立,选自下列取代基:
H、OH、SH、NH2、COOH、CF3、醛基、氨基甲酰基、F、Cl、Br、I、NO2、CN、C1-C4直链或支链的烷基、C1-C4直链或支链烷氧基、C1-C4直链或支链烷基氨基、C2-C4直链或支链烯基、C2-C3炔基;
31、烷基:C1-C4的直链或带支链的烷基;例如,甲基、乙基、异丙基、叔丁基等。
最优选的式I所示的化合物包括但不限定于I C所示的化合物
所述的选自苯基、吡啶基、呋喃基、噻吩基、萘基、喹啉基、异喹啉基、吲哚基、苯并呋喃基、苯并噻吩基、苯乙烯基,吡嗪基、苯甲酰氨甲基、C1-C6的直链或支链烷基;
R1、R6、R7独立的选自:H,-CH3、-COCH3、-COOC(CH3)3;
R2、R3、R4、R5独立的选自:H、卤素、OH、SH、NH2、COOH、醛基、氨基甲酰基、NO2、CN、-CH3、-C2H5、-OCH3、-OC2H5;
R8独立的选自:H、C1-C4直链或支链的烷基、-COCH3、-COOC(CH3)3;R12表示一个或多个取代基、这些取代基可以和在任意适宜的位置相连接,这些取代基独立的选自H、OH、SH、NH2、COOH、醛基、氨基甲酰基、卤素、NO2、CN、C1-C4直链或支链的烷基、C1-C4直链或支链的烷氧基、C1-C4直链或支链的烷基氨基、C2-C4直链或支链的烯基、C2-C3炔基。
最优选的式I C所示的化合物包括但不限定于I C1所示的化合物
R1、R6、R7独立的选自:H,-CH3、-COCH3、-COOC(CH3)3;
R2、R3、R4、R5独立的选自:H、卤素、OH、SH、NH2、COOH、醛基、氨基甲酰基、NO2、CN、-CH3、-C2H5、-OCH3、-OC2H5;
R8独立的选自:H、C1-C4直链或支链的烷基、-COCH3、-COOC(CH3)3;R121选自H、OH、SH、NH2、COOH、CF3、醛基、氨基甲酰基、F、Cl、Br、I、NO2、CN、C1-C4直链或支链的烷基、C1-C4直链或支链的烷氧基、C1-C4直链或支链的烷基氨基、C2-C4直链或支链的烯基、C2-C3炔基;当苯环上为双取代时,相邻的两个取代基可以相互连接成C5-C6环烷基并苯基,取代基选自-CH2CH2-、-CH2-。如:四氢萘基。
最优选的式I C所示的化合物包括但不限定于I C2所示的化合物
R1、R6、R7独立的选自:H,-CH3、-COCH3、-COOC(CH3)3;
R2、R3、R4、R5独立的选自:H、卤素、OH、SH、NH2、COOH、醛基、氨基甲酰基、NO2、CN、-CH3、-C2H5、-OCH3、-OC2H5;
R8独立的选自:H、C1-C4直链或支链的烷基、-COCH3、-COOC(CH3)3;
R122选自H、OH、SH、NH2、COOH、CF3、醛基、氨基甲酰基、F、Cl、Br、I、NO2、CN、C1-C4直链或支链的烷基、C1-C4直链或支链的烷氧基、C1-C4直链或支链的烷基氨基、C2-C4直链或支链的烯基、C2-C3炔基。
最优选的式I C所示的化合物包括但不限定于I C3所示的化合物
R1、R6、R7独立的选自:H,-CH3、-COCH3、-COOC(CH3)3;
R2、R3、R4、R5独立的选自:H、卤素、OH、SH、NH2、COOH、醛基、氨基甲酰基、NO2、CN、-CH3、-C2H5、-OCH3、-OC2H5;
R8独立的选自:H、C1-C4直链或支链的烷基、-COCH3、-COOC(CH3)3;R123选自H、OH、SH、NH2、COOH、CF3、醛基、氨基甲酰基、F、Cl、Br、I、NO2、CN、C1-C4直链或支链的烷基、C1-C4直链或支链的烷氧基、C1-C4直链或支链的烷基氨基、C2-C4直链或支链的烯基、C2-C3炔基。
最优选的式I C所示的化合物包括但不限定于I C4所示的化合物
R1、R6、R7独立的选自:H,-CH3、-COCH3、-COOC(CH3)3;
R2、R3、R4、R5独立的选自:H、卤素、OH、SH、NH2、COOH、醛基、氨基甲酰基、NO2、CN、-CH3、-C2H5、-OCH3、-OC2H5;
R8独立的选自:H、C1-C4直链或支链的烷基、-COCH3、-COOC(CH3)3;R124选自H、OH、SH、NH2、COOH、CF3、醛基、氨基甲酰基、F、Cl、Br、I、NO2、CN、C1-C4直链或支链的烷基、C1-C4直链或支链的烷氧基、C1-C4直链或支链的烷基氨基、C2-C4直链或支链的烯基、C2-C3炔基。
最优选的式I C所示的化合物包括但不限定于I C5所示的化合物
R1、R6、R7独立的选自:H,-CH3、-COCH3、-COOC(CH3)3;
R2、R3、R4、R5独立的选自:H、卤素、OH、SH、NH2、COOH、醛基、氨基甲酰基、NO2、CN、-CH3、-C2H5、-OCH3、-OC2H5;
R8独立的选自:H、C1-C4直链或支链的烷基、-COCH3、-COOC(CH3)3;
R125选自H、OH、SH、NH2、COOH、CF3、醛基、氨基甲酰基、F、Cl、Br、I、NO2、CN、C1-C4直链或支链的烷基、C1-C4直链或支链烷氧基、C1-C4直链或支链烷基胺基、C2-C4直链或支链烯基、C2-C3炔基。
最优选的式I C所示的化合物包括但不限定于I C6所示的化合物
R1、R6、R7独立的选自:H,-CH3、-COCH3、-COOC(CH3)3;
R2、R3、R4、R5独立的选自:H、卤素、OH、SH、NH2、COOH、醛基、氨基甲酰基、NO2、CN、-CH3、-C2H5、-OCH3、-OC2H5;
R8独立的选自:H、C1-C4直链或支链的烷基、-COCH3、-COOC(CH3)3;R126选自H、OH、SH、NH2、COOH、CF3、醛基、氨基甲酰基、F、Cl、Br、I、NO2、CN、C1-C4直链或支链的烷基、C1-C4直链或支链烷氧基、C1-C4直链或支链烷基胺基、C2-C4直链或支链烯基、C2-C3炔基。
最优选的式I C所示的化合物包括但不限定于I C7所示的化合物
R1、R6、R7独立的选自:H,-CH3、-COCH3、-COOC(CH3)3;
R2、R3、R4、R5独立的选自:H、卤素、OH、SH、NH2、COOH、醛基、氨基甲酰基、NO2、CN、-CH3、-C2H5、-OCH3、-OC2H5;
R8独立的选自:H、C1-C4直链或支链的烷基、-COCH3、-COOC(CH3)3;
R127选自H、OH、SH、NH2、COOH、CF3、醛基、氨基甲酰基、F、Cl、Br、I、NO2、CN、C1-C4直链或支链的烷基、C1-C4直链或支链烷氧基、C1-C4直链或支链烷基胺基、C2-C4直链或支链烯基、C2-C3炔基;
R”为H、C1-C4直链或支链的烷基。
最优选的式I C所示的化合物包括但不限定于I C8所示的化合物
R1、R6、R7独立的选自:H,-CH3、-COCH3、-COOC(CH3)3;
R2、R3、R4、R5独立的选自:H、卤素、OH、SH、NH2、COOH、醛基、氨基甲酰基、NO2、CN、-CH3、-C2H5、-OCH3、-OC2H5;
R8独立的选自:H、C1-C4直链或支链的烷基、-COCH3、-COOC(CH3)3;
R128选自H、OH、SH、NH2、COOH、CF3、醛基、氨基甲酰基、F、Cl、Br、I、NO2、CN、C1-C4直链或支链的烷基、C1-C4直链或支链烷氧基、C1-C4直链或支链烷基胺基、C2-C4直链或支链烯基、C2-C3炔基。
最优选的式I C所示的化合物包括但不限定于I C9所示的化合物
R1、R6、R7独立的选自:H,-CH3、-COCH3、-COOC(CH3)3;
R2、R3、R4、R5独立的选自:H、卤素、OH、SH、NH2、COOH、醛基、氨基甲酰基、NO2、CN、-CH3、-C2H5、-OCH3、-OC2H5;
R8独立的选自:H、C1-C4直链或支链的烷基、-COCH3、-COOC(CH3)3;R129选自H、OH、SH、NH2、COOH、CF3、醛基、氨基甲酰基、F、Cl、Br、I、NO2、CN、C1-C4直链或支链的烷基、C1-C4直链或支链烷氧基、C1-C4直链或支链烷基胺基、C2-C4直链或支链烯基、C2-C3炔基。
最优选的式I C所示的化合物包括但不限定于I C10所示的化合物
R1、R6、R7独立的选自:H,-CH3、-COCH3、-COOC(CH3)3;
R2、R3、R4、R5独立的选自:H、卤素、OH、SH、NH2、COOH、醛基、氨基甲酰基、NO2、CN、-CH3、-C2H5、-OCH3、-OC2H5;
R8独立的选自:H、C1-C4直链或支链的烷基、-COCH3、-COOC(CH3)3;
R1210选自H、OH、SH、NH2、COOH、CF3、醛基、氨基甲酰基、F、Cl、Br、I、NO2、CN、C1-C4直链或支链的烷基、C1-C4直链或支链烷氧基、C1-C4直链或支链烷基胺基、C2-C4直链或支链烯基、C2-C3炔基。
最优选的式I C所示的化合物包括但不限定于I C11所示的化合物
R1、R6、R7独立的选自:H,-CH3、-COCH3、-COOC(CH3)3;
R2、R3、R4、R5独立的选自:H、卤素、OH、SH、NH2、COOH、醛基、氨基甲酰基、NO2、CN、-CH3、-C2H5、-OCH3、-OC2H5;
R8独立的选自:H、C1-C4直链或支链的烷基、-COCH3、-COOC(CH3)3;
R1211选自H、OH、SH、NH2、COOH、CF3、醛基、氨基甲酰基、F、Cl、Br、I、NO2、CN、C1-C4直链或支链的烷基、C1-C4直链或支链烷氧基、C1-C4直链或支链烷基胺基、C2-C4直链或支链烯基、C2-C3炔基。
最优选的式I C所示的化合物包括但不限定于I C12所示的化合物
R1、R6、R7独立的选自:H,-CH3、-COCH3、-COOC(CH3)3;
R2、R3、R4、R5独立的选自:H、卤素、OH、SH、NH2、COOH、醛基、氨基甲酰基、NO2、CN、-CH3、-C2H5、-OCH3、-OC2H5;
R8独立的选自:H、C1-C4直链或支链的烷基、-COCH3、-COOC(CH3)3;R1212选自C1-C6的直链或支链的烷基。
所述的选自苯基、吡啶基、呋喃基、噻吩基、萘基、喹啉基、异喹啉基、吲哚基、苯并呋喃基、苯并噻吩基、苯乙烯基,吡嗪基、苯甲酰氨甲基、C1-C6的直链或支链烷基;
R1、R6、R7独立的选自:H,-CH3、-COCH3、-COOC(CH3)3;
R2、R3、R4、R5独立的选自:H、卤素、OH、SH、NH2、COOH、醛基、氨基甲酰基、NO2、CN、-CH3、-C2H5、-OCH3、-OC2H5;
R8独立的选自:H、C1-C4直链或支链的烷基、-COCH3、-COOC(CH3)3;
R13表示一个或多个取代基、这些取代基可以和在任意适宜的位置相连接,这些取代基独立的选自H、OH、SH、NH2、COOH、醛基、氨基甲酰基、卤素、NO2、CN、C1-C4直链或支链的烷基、C1-C4直链或支链的烷氧基、C1-C4直链或支链的烷基氨基、C2-C4直链或支链的烯基、C2-C3炔基。
最优选的式I D所示的化合物包括但不限定于I D1所示的化合物
R1、R6、R7独立的选自:H,-CH3、-COCH3、-COOC(CH3)3;
R2、R3、R4、R5独立的选自:H、卤素、OH、SH、NH2、COOH、醛基、氨基甲酰基、NO2、CN、-CH3、-C2H5、-OCH3、-OC2H5;
R8独立的选自:H、C1-C4直链或支链的烷基、-COCH3、-COOC(CH3)3;
R131选自H、OH、SH、NH2、COOH、CF3、醛基、氨基甲酰基、F、Cl、Br、I、NO2、CN、C1-C4直链或支链的烷基、C1-C4直链或支链烷氧基、C1-C4直链或支链烷基胺基、C2-C4直链或支链烯基、C2-C3炔基;当苯环上为双取代时,相邻的两个取代基可以相互连接成C5-C6环烷基并苯基
最优选的式I D所示的化合物包括但不限定于I D2所示的化合物
R1、R6、R7独立的选自:H,-CH3、-COCH3、-COOC(CH3)3;
R2、R3、R4、R5独立的选自:H、卤素、OH、SH、NH2、COOH、醛基、氨基甲酰基、NO2、CN、-CH3、-C2H5、-OCH3、-OC2H5;
R8独立的选自:H、C1-C4直链或支链的烷基、-COCH3、-COOC(CH3)3;
R132选自H、OH、SH、NH2、COOH、CF3、醛基、氨基甲酰基、F、Cl、Br、I、NO2、CN、C1-C4直链或支链的烷基、C1-C4直链或支链烷氧基、C1-C4直链或支链烷基胺基、C2-C4直链或支链烯基、C2-C3炔基。
最优选的式I D所示的化合物包括但不限定于I D3所示的化合物
R1、R6、R7独立的选自:H,-CH3、-COCH3、-COOC(CH3)3;
R2、R3、R4、R5独立的选自:H、卤素、OH、SH、NH2、COOH、醛基、氨基甲酰基、NO2、CN、-CH3、-C2H5、-OCH3、-OC2H5;
R8独立的选自:H、C1-C4直链或支链的烷基、-COCH3、-COOC(CH3)3;
R133选自H、OH、SH、NH2、COOH、CF3、醛基、氨基甲酰基、F、Cl、Br、I、NO2、CN、C1-C4直链或支链的烷基、C1-C4直链或支链烷氧基、C1-C4直链或支链烷基胺基、C2-C4直链或支链烯基、C2-C3炔基。
最优选的式I D所示的化合物包括但不限定于I D4所示的化合物
R1、R6、R7独立的选自:H,-CH3、-COCH3、-COOC(CH3)3;
R2、R3、R4、R5独立的选自:H、卤素、OH、SH、NH2、COOH、醛基、氨基甲酰基、NO2、CN、-CH3、-C2H5、-OCH3、-OC2H5;
R8独立的选自:H、C1-C4直链或支链的烷基、-COCH3、-COOC(CH3)3;
R134选自H、OH、SH、NH2、COOH、CF3、醛基、氨基甲酰基、F、Cl、Br、I、NO2、CN、C1-C4直链或支链的烷基、C1-C4直链或支链烷氧基、C1-C4直链或支链烷基胺基、C2-C4直链或支链烯基、C2-C3炔基。
最优选的式I D所示的化合物包括但不限定于I D5所示的化合物
R1、R6、R7独立的选自:H,-CH3、-COCH3、-COOC(CH3)3;
R2、R3、R4、R5独立的选自:H、卤素、OH、SH、NH2、COOH、醛基、氨基甲酰基、NO2、CN、-CH3、-C2H5、-OCH3、-OC2H5;
R8独立的选自:H、C1-C4直链或支链的烷基、-COCH3、-COOC(CH3)3;
R135选自H、OH、SH、NH2、COOH、CF3、醛基、氨基甲酰基、F、Cl、Br、I、NO2、CN、C1-C4直链或支链的烷基、C1-C4直链或支链烷氧基、C1-C4直链或支链烷基胺基、C2-C4直链或支链烯基、C2-C3炔基。
最优选的式I D所示的化合物包括但不限定于I D6所示的化合物
R1、R6、R7独立的选自:H,-CH3、-COCH3、-COOC(CH3)3;
R2、R3、R4、R5独立的选自:H、卤素、OH、SH、NH2、COOH、醛基、氨基甲酰基、NO2、CN、-CH3、-C2H5、-OCH3、-OC2H5;
R8独立的选自:H、C1-C4直链或支链的烷基、-COCH3、-COOC(CH3)3;
R136选自H、OH、SH、NH2、COOH、CF3、醛基、氨基甲酰基、F、Cl、Br、I、NO2、CN、C1-C4直链或支链的烷基、C1-C4直链或支链烷氧基、C1-C4直链或支链烷基胺基、C2-C4直链或支链烯基、C2-C3炔基。
最优选的式I D所示的化合物包括但不限定于I D7所示的化合物
R1、R6、R7独立的选自:H,-CH3、-COCH3、-COOC(CH3)3;
R2、R3、R4、R5独立的选自:H、卤素、OH、SH、NH2、COOH、醛基、氨基甲酰基、NO2、CN、-CH3、-C2H5、-OCH3、-OC2H5;
R8独立的选自:H、C1-C4直链或支链的烷基、-COCH3、-COOC(CH3)3;
R137选自:C1-C6的直链或支链的烷基。
最优选的式I D所示的化合物包括但不限定于I D8所示的化合物
R1、R6、R7独立的选自:H,-CH3、-COCH3、-COOC(CH3)3;
R2、R3、R4、R5独立的选自:H、卤素、OH、SH、NH2、COOH、醛基、氨基甲酰基、NO2、CN、-CH3、-C2H5、-OCH3、-OC2H5;R138选自:H、C1-C6的直链或支链的烷基。本发明的C1-C6直链或支链烷基中优选的是C1-C5直链或支链烷基。本发明的C1-C5直链或支链烷基中优选的是C1-C4直链或支链烷基。本发明的C1-C4直链或支链烷基中优选的是甲基或乙基。
本发明的C2-C6烯基中优选的是C2-C5烯基。本发明的C2-C5烯基中优选的是C2-C4烯基。本发明的C2-C4烯基中优选的是乙烯基。
本发明的C2-C6炔基中优选的是C2-C4炔基。本发明的C2-C4炔基中优选的是C2-C3炔基。本发明的C2-C3炔基中优选的是乙炔基。
优选的C1-C6直链或支链烷基选自甲基、乙基、丙基、异丙基、正丁基、叔丁基、戊基、异戊基。
优选的是C1-C4直链或支链烷基选自甲基、乙基、丙基、异丙基、正丁基、叔丁基。
优选的芳基选自苯基、萘基。
优选的杂芳基选自吡啶基、呋喃基、吡嗪基,噻吩基、喹啉基、异喹啉基、吲哚基、苯并噻吩基、苯并呋喃基。
所述的卤素选自、F、Cl、Br、I。
以上优选化合物与酸形成的药学上可接受的盐也构成本发明的一部分,本发明中的化合物分子中的碱性氮原子可以与酸形成盐,只要是与碱能够成盐,且是药学上可以接受的酸都可以,对此没有特别限制。可列举盐酸、氢溴酸、硫酸、磷酸、硝酸等无机酸,草酸、富马酸、马来酸、琥珀酸、柠檬酸、酒石酸、甲磺酸和对甲苯磺酸等有机酸。
本发明中任一项的化合物或其药学上可接受的盐,其特征在于,所述的化合物选自:
本发明中的具有通式(Ⅰ)exiguamine A类似物或其药学上可接受的盐的某些步骤的合成方法在下列有关文献中已有所涉及,可参考文献:M.Volgraf,et al.,NatureChemical Biology,2008,4,535-537。
具体的制备路线如下:
R1、R6、R7独立的选自:H,C1-C8的直链或支链的烷基、C2-C8的直链或支链烯基、C2-C4的炔基、C1-C8的直链或支链烷基酰基、C1-C8的直链或支链磺酰基、C1-C8的直链或支链烷氧酰基;
R2、R3、R4、R5独立的选自:H、卤素、OH、SH、NH2、COOH、CF3、醛基、氨基甲酰基、NO2、CN、C1-C8的直链或支链的烷基、C2-C8的直链或支链烯基、C2-C4的炔基、C1-C8的直链或支链烷氧基;
R8独立的选自:H、C1-C4直链或支链的烷基、C1-C8的直链或支链烷基酰基;
R9选自C6-C10的芳基,C4-C10的杂芳基,C6-C10芳基取代的C1-C4直链或支链烷基、C4-C10杂芳基取代的C1-C4直链或支链烷基、C6-C10芳基取代的C0-C4直链或支链烷基乙烯基、C1-C10的直链或支链烷基,C5-C6环烷基并苯基;这些芳基、杂芳基、C5-C6环烷基并苯基又可以具有一个或多个取代基,取代基选自H、OH、SH、NH2、COOH、CF3、醛基、氨基甲酰基、卤素、NO2、CN、C1-C8直链或支链的烷基、C1-C8直链或支链烷氧基、C1-C8直链或支链烷基胺基、C2-C8直链或支链烯基、C2-C4直链或支链炔基、C6-C8的芳基、C4-C8的杂环芳基;
步骤一:采用原料4-甲氧基-2-硝基苯酚,溶于醋酸,在液溴与KBr作用下生成中间体A’-1;
步骤二:采用中间体A’-1,在碳酸钾和硫酸二甲酯作用下,对羟基进行甲基化,生成中间体A’-2;
步骤三:采用中间体A’-2,与乙烯基溴化镁作用下,生成中间体A’-3;
步骤四:采用中间体A’-3,通过Vilsmeier-Haack反应得到中间体A’-4;
步骤五:采用中间体A’-4,通过Henry反应得到中间体A’-5;
步骤六:采用中间体A’-5,在BH3-THF溶液作用下还原成中间体A’-6;
步骤七:采用中间体A’-6,加入三乙胺和(Boc)2O,得到中间体A’-7;反应可选择的溶剂包括二氯甲烷、二甲基甲酰胺、二甲基亚砜、丙酮;
步骤八:采用中间体A’-7,在Pd(PPh3)4、Xphos、三乙胺和HBPin的作用下,生成硼酸酯中间体A’;
步骤九:采用原料邻溴苯甲醛和咪唑啉-2,4-二酮,在碱性条件下,通过缩合反应得到中间体B’;
步骤十:采用硼酸酯中间体A’和溴中间体B’,通过Suzuki偶联反应,得到中间体1’;
步骤十一:采用中间体1’,在钯/碳催化下,通入氢气,常压常温下还原双键,得到中间体2’;
步骤十二:采用中间体2’,加入三乙胺、DMAP和(Boc)2O,得到中间体3’;反应可选择的溶剂包括二氯甲烷、二甲基甲酰胺、二甲基亚砜、丙酮;
步骤十三:采用中间体3’,在硝酸铈铵的对用下,氧化生成醌类中间体4’;
步骤十四:采用中间体4’,在三氟乙酸的作用下,脱掉吲哚氮原子上的叔丁氧羰基保护基团,得到中间体5’;
步骤十五:采用中间体5’,在碱性条件下发生分子内Michael加成反应,得到中间体6’,适宜的碱性条件包括:正丁基锂、双(三甲基硅基)胺基锂、叔丁醇、二异丙基氨基锂、氢氧化钠水溶液;
步骤十六:采用中间体6’,在盐酸水溶液的作用下,脱掉氮原子上的叔丁氧羰基保护基团,得到中间体C’;
步骤十七:采用前体胺C’,在缩合剂EDCI的作用下,和取代基R9为前面通式I所列举情况的羧酸进行脱水缩合;或在氰基硼氢化钠作用下,和取代基R9为前面通式I所列举情况的醛发生还原胺化反应,得到具有通式I的目标产物。R9的定义和前述相同;
本发明再一方面还涉及以本发明化合物作为活性成份的药物组合物。该药物组合物可根据本领域公知的方法制备。可通过将本发明化合物与一种或多种药学上可接受的固体或液体赋形剂和/或辅剂结合,制成适于人或动物使用的任何剂型。本发明化合物在其药物组合物中的含量通常为0.1-95重量%。
本发明化合物或含有它的药物组合物可以单位剂量形式给药,给药途径可为肠道或非肠道,如口服、静脉注射、肌肉注射、皮下注射、鼻腔、口腔粘膜、眼、肺和呼吸道、皮肤、阴道、直肠等。
给药剂型可以是液体剂型、固体剂型或半固体剂型。液体剂型可以是溶液剂(包括真溶液和胶体溶液)、乳剂(包括o/w型、w/o型和复乳)、混悬剂、注射剂(包括水针剂、粉针剂和输液)、滴眼剂、滴鼻剂、洗剂和搽剂等;固体剂型可以是片剂(包括普通片、肠溶片、含片、分散片、咀嚼片、泡腾片、口腔崩解片)、胶囊剂(包括硬胶囊、软胶囊、肠溶胶囊)、颗粒剂、散剂、微丸、滴丸、栓剂、膜剂、贴片、气(粉)雾剂、喷雾剂等;半固体剂型可以是软膏剂、凝胶剂、糊剂等。
本发明化合物可以制成普通制剂、也制成是缓释制剂、控释制剂、靶向制剂及各种微粒给药系统。
为了将本发明化合物制成片剂,可以广泛使用本领域公知的各种赋形剂,包括稀释剂、黏合剂、润湿剂、崩解剂、润滑剂、助流剂。稀释剂可以是淀粉、糊精、蔗糖、葡萄糖、乳糖、甘露醇、山梨醇、木糖醇、微晶纤维素、硫酸钙、磷酸氢钙、碳酸钙等;湿润剂可以是水、乙醇、异丙醇等;粘合剂可以是淀粉浆、糊精、糖浆、蜂蜜、葡萄糖溶液、微晶纤维素、阿拉伯胶浆、明胶浆、羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、乙基纤维素、丙烯酸树脂、卡波姆、聚乙烯吡咯烷酮、聚乙二醇等;崩解剂可以是干淀粉、微晶纤维素、低取代羟丙基纤维素、交联聚乙烯吡咯烷酮、交联羧甲基纤维素钠、羧甲基淀粉钠、碳酸氢钠与枸橼酸、聚氧乙烯山梨糖醇脂肪酸酯、十二烷基磺酸钠等;润滑剂和助流剂可以是滑石粉、二氧化硅、硬脂酸盐、酒石酸、液体石蜡、聚乙二醇等。
还可以将片剂进一步制成包衣片,例如糖包衣片、薄膜包衣片、肠溶包衣片,或双层片和多层片。
为了将给药单元制成胶囊剂,可以将有效成分本发明化合物与稀释剂、助流剂混合,将混合物直接置于硬胶囊或软胶囊中。也可将有效成分本发明化合物先与稀释剂、黏合剂、崩解剂制成颗粒或微丸,再置于硬胶囊或软胶囊中。用于制备本发明化合物片剂的各稀释剂、黏合剂、润湿剂、崩解剂、助流剂品种也可用于制备本发明化合物的胶囊剂。
为将本发明化合物制成注射剂,可以用水、乙醇、异丙醇、丙二醇或它们的混合物作溶剂并加入适量本领域常用的增溶剂、助溶剂、pH调剂剂、渗透压调节剂。增溶剂或助溶剂可以是泊洛沙姆、卵磷脂、羟丙基-β-环糊精等;pH调剂剂可以是磷酸盐、醋酸盐、盐酸、氢氧化钠等;渗透压调节剂可以是氯化钠、甘露醇、葡萄糖、磷酸盐、醋酸盐等。如制备冻干粉针剂,还可加入甘露醇、葡萄糖等作为支撑剂。
此外,如需要,也可以向药物制剂中添加着色剂、防腐剂、香料、矫味剂或其它添加剂。为达到用药目的,增强治疗效果,本发明的药物或药物组合物可用任何公知的给药方法给药。本发明中的化合物可以和其他抗癌药物一起用于治疗肿瘤,这也是本发明的一部分,这些抗癌药物包括:taxol,paclitaxel,taxotere,docetaxel,vincristine,vinblastine,5-fluorouracil,cytarabine,gemcitabine,pentostatin,methotrexane,cyclophosphamide,ifosphamide,adriamycin,doxorubicin,pharmorubicin,epirubicin,etoposide,tamoxifen,flutamide,leuprorelin,goserelin,cyorotrone,octreotide,herceptin,cis-platin,carboplatin,oxaplatin,dexamethasone等。
本发明的化合物还可与属于以下各类抗肿瘤药物中的化合物联合使用,这也是本发明的一部分,这些药物包括:紫杉醇类、鬼臼毒素类、长春碱类、氮芥类、蒽醌类、雌激素类、抗雌激素类、雄激素类、抗雄激素类、抗体衍生物类、铂类、基质蛋白酶抑制剂类等。
本发明的化合物也可以和属于下列各类抗肿瘤药物的化合物联合使用,这也构成本发明的一部分,这些抗肿瘤药物包括:微管蛋白调节剂、抗代谢药物、烷基化药物、以DNA为靶标的抗肿瘤药物、以拓扑异构酶为靶标的药物、激素类和激素激动剂或拮抗剂、以癌细胞内信号传导为靶标的药物、基因治疗或反义治疗药物、抗体治疗药物、海洋来源的活性化合物、激素类似物、抗炎药物或止吐药物。
本发明的化合物单独或作为药用活性成分可用于治疗患有自白血病、黑色素瘤、胃癌、肺癌、乳腺癌、肾癌、肝癌、口腔表皮癌、宫颈癌、卵巢癌、胰腺癌、前列腺癌、结肠癌等病人。本发明化合物药物组合物的给药剂量依照所要预防或治疗疾病的性质和严重程度,患者或动物的个体情况,给药途径和剂型等可以有大范围的变化。一般来讲,本发明化合物的每天的合适剂量范围为0.001-150mg/Kg体重,优选为0.1-100mg/Kg体重,更优选为1-60mg/Kg体重,最优选为2-30mg/Kg体重。上述剂量可以一个剂量单位或分成几个剂量单位给药,这取决于医生的临床经验以及包括运用其它治疗手段的给药方案。
本发明的化合物或组合物可单独服用,或与其他治疗药物或对症药物合并使用。当本发明的化合物与其它治疗药物存在协同作用时,应根据实际情况调整它的剂量有益技术效果:本发明的化合物均为未报道过的化合物,丰富了化合物库,完善了这类天然产物的构效关系,对该类型天然产物的开发提供了有力的数据支持。经过体外IDO1酶学测试发现本发明大部分化合物具有良好的抗IDO1酶学效果,在医药领域有利于IDO1抑制剂新药的开发。
具体实施方式
下面列举实施例对本发明进行更为详细的说明,但本发明并不仅限于这些实施例。
1,中间体A的制备
a:Br2,KBr,CH3COOH/H2O;b:Me2SO4,K3CO3,acetone;c:isopropenyl magnesiumbromide,THF,-60℃;d:POCl3,DMF;e:CH3NO2,CH3COONH4;f:BH3·THF,THF;g:(Boc)2O,Et3N,DCM;h:Pd2(dba)3,HBPin,Et3N,1.4-dioxane.
中间体A-1的制备:将1g 4-甲氧基-2-硝基苯酚溶于15mL CH3COOH中,加入溴化钾0.7g在5mL水中的溶液,然后缓慢滴加0.32mL的溴,滴加完毕,移至70℃下反应16h。用饱和硫代硫酸钠溶液淬灭,乙酸乙酯萃取,合并有机层用用饱和氯化钠洗涤,无水硫酸钠干燥,减压蒸干。硅胶柱层析得橙黄色固体1.3g,收率89.0%;1H NMR(400MHz,Chloroform-d)δ10.79(1H,s),7.50-7.53(2H,m),3.82(3H,s);13C NMR(100MHz,Chloroform-d)δ152.2,147.1,133.6,129.8,113.8,106.3,56.2;
中间体A-2的制备:将0.5g中间体A-1溶于10mL丙酮,加入415mg碳酸钾,缓慢滴加0.3mL硫酸二甲酯,反应混合物回流反应8h。冷却至室温,过滤抽去碳酸钾,滤液蒸除大部分丙酮,随后用乙酸乙酯和水溶解残留物,饱和氯化钠水溶液洗涤,无水硫酸钠干燥,减压蒸干有机相,硅胶柱层析得黄色固体421mg,收率80%。1H NMR(400MHz,Chloroform-d)δ7.35(d,J=3.2Hz,1H),7.28(d,J=3.2Hz,1H),3.96(s,3H),3.83(s,3H).13C NMR(100MHz,CDCl3)δ155.6,145.1,144.6,123.9,120.2,109.3,62.8,56.3.
中间体A-3的制备:将5g中间体A-2溶于无水50mLTHF中,氩气保护,降至-60℃,缓慢滴加乙烯基溴化镁,滴毕,反应1h。滴加饱和氯化铵溶液淬灭反应,乙酸乙酯萃取,合并有机层用用饱和氯化钠洗涤,无水硫酸钠干燥,减压蒸干。硅胶柱层析得黄色固体2.69g,收率55.0%。1H NMR(400MHz,Chloroform-d)δ8.38(s,1H),7.10(d,J=2.4Hz,1H),6.62(d,J=2.4Hz,1H),6.59(s,1H),3.94(s,3H),3.91(s,3H).13C NMR(100MHz,Chloroform-d)δ149.9,137.7,130.7,123.3,119.9,107.7,104.1,101.3,61.2,55.9.
中间体A-4的制备:在0℃下,向5mL DMF中加入新鲜蒸馏的0.27mL POCl3,反应混合物搅拌15分钟,然后在10分钟内逐滴加入1g中间体A-3在5mL DMF中的溶液。将所得的混合物在0℃下搅拌30分钟,移至40℃反应1小时。然后将反应液冷却至0℃,逐滴加入1M的NaOH水溶液调节至碱性。用200mL的水稀释,并用EtOAc萃取。合并有机层,依次用饱和NaCl溶液洗涤、无水硫酸钠干燥,减压蒸干,硅胶柱层析得黄色固体1.02g,收率92.7%。1H NMR(400MHz,Chloroform-d)δ10.43(s,1H),9.20(s,1H),7.90(d,J=2.8Hz,1H),6.78(s,1H),3.96(s,3H),3.96(s,3H).13C NMR(125MHz,Chloroform-d)δ187.9,150.8,137.9,131.2,128.1,120.6,117.1,109.0,106.8,61.5,55.9.
中间体A-5的制备:向0.8g中间体A-4中加入10mL硝基甲烷,再加入261mg醋酸铵,将反应混合物加热至100℃,反应1小时。冷却至室温,用水和二氯甲烷萃取,分离有机层,用饱和食盐水洗涤,无水硫酸钠干燥,减压蒸干。硅胶柱层析得橙黄色固体0.75g,收率81.6%。1H NMR(400MHz,DMSO-d6)δ12.59(s,1H),8.51(d,J=13.2Hz,1H),8.29(s,1H),8.11(d,J=13.2Hz,1H),6.84(s,1H),3.94(s,3H),3.84(s,3H).13C NMR(100MHz,DMSO-d6)δ150.6,138.5,135.0,133.7,132.6,132.3,117.2,109.3,106.6,61.7,56.6.
中间体A-6的制备:将1g中间体A-5溶于无水10mL THF中,0℃下缓慢滴加1M的BH3-THF溶液18.4mL,回流反应48h。将反应液冷却至0℃,缓慢加入冰水和1M的HCl淬灭,然后在60℃下搅拌1小时,冷却至0℃,用2.5M的NaOH溶液调至碱性,乙酸乙酯萃取,合并有机层,依次用饱和NaCl溶液洗涤、无水硫酸钠干燥,减压蒸干,产物不经纯化直接用于下步反应。
中间体A-7的制备:冰浴中将0.9g中间体A-6溶于10mL二氯甲烷,依次加入1.06mL(Boc)2O和0.64mL三乙胺,室温反应1h。用EtOAc稀释反应混合物,饱和NaHCO3溶液和饱和NaCl溶液洗涤、无水硫酸钠干燥,减压蒸干。硅胶柱层析得白色固体0.79g,两步收率64.8%。1H NMR(400MHz,Chloroform-d)δ8.48(s,1H),6.86(s,1H),6.54(s,1H),4.83(s,1H),3.91(s,3H),3.87(s,3H),3.42(d,J=5.6Hz,2H),2.99(t,J=5.6Hz,2H),1.40(s,9H).13C NMR(100MHz,Chloroform-d)δ156.2,151.0,137.6,131.6,121.8,118.5,114.9,107.6,103.6,79.0,61.1,55.7,42.0,28.5(3C),26.8.
中间体A的制备:向50mL干燥的双颈瓶中,加入0.5g中间体A-7、17mg Pd2(dba)3、35mg Xphos,氩气置换3次。加入10mL 1,4-二氧六环,0.52mL三乙胺、0.66mL频哪醇硼烷,反应混合物回流40minor。冷却至室温后,用水淬灭反应并用乙酸乙酯进行萃取。合并有机层,依次用饱和NaCl溶液洗涤、无水硫酸钠干燥,减压蒸干,硅胶柱层析得白色固体400mg,收率71.6%。1H NMR(500MHz,Chloroform-d)δ8.37(s,1H),6.94(s,1H),6.72(s,1H),4.89(s,1H),3.93(s,6H),3.42(s,2H),3.02(t,J=5.5Hz,2H),1.39(s,9H),1.38(s,12H).13C NMR(125MHz,Chloroform-d)δ156.2,150.2,147.2,131.5,122.6,121.7,114.7,104.3,101.5,83.4(2C),78.8,62.9,55.3,42.1,28.4(3C),26.8,24.9(3C),24.6.
2,中间体B的制备
a:LDA,DMF,THF,-78℃;b:CH3ONa,CH3OH;c:CH3(CH2)3NH2,CH3COOH
中间体B-1的制备:将10g原料2-溴-4-氟甲苯溶于100mL无水THF中,冷却至-78℃,缓慢滴加二异丙基氨基锂31.8mL,混合液在-78℃下搅拌2h,然后加入N,N-二甲基甲酰胺4.9mL,继续搅拌1小时。用饱和氯化铵溶液淬灭反应,乙酸乙酯萃取,合并有机层用用饱和氯化钠洗涤,无水硫酸钠干燥,减压蒸干有机相。硅胶柱层析得黄色油状物9.1g,收率79.3%。1H NMR(500MHz,Chloroform-d)10.39(s,1H),7.42(t,J=9Hz,1H),7.05(t,J=9Hz,1H),2.44(s,3H).中间体B-2的合成:向18.4mL的5M甲醇钠溶液中加入中间体B-1 15g,回流反应16h。反应完毕,冰浴下用2N的HCl溶液淬灭,并调Ph值至2,蒸除大部分甲醇,随后用乙酸乙酯和水稀释,饱和氯化钠水溶液洗涤,无水硫酸钠干燥,减压蒸干有机相,硅胶柱层析得黄白色固体3.69g,收率70.0%。1H NMR(400MHz,Chloroform-d)δ10.42(s,1H),7.36(d,J=8.8Hz,1H),6.87(d,J=8.8Hz,1H),3.88(s,3H),3.39(s,3H).13C NMR(100MHz,Chloroform-d)δ191.3159.5 135.3,131.3,126.9,124.1,110.7,56.2,22.4.
中间体B的制备:将0.62g 1,3-二甲基咪唑啉-2,4-二酮溶于15mL醋酸,依次加入正丁胺0.95mL、中间体B-2 1g,并且将所得混合物回流反应10h。冰浴下滴加NaHCO3淬灭反应,二氯甲烷萃取,合并有机层,依次用饱和NaCl溶液洗涤、无水硫酸钠干燥,减压蒸干,硅胶柱层析得白色固体1.15g,收率77.7%。1H NMR(400MHz,Chloroform-d)δ7.19~7.16(m,1.55H),6.81~6.78(m,1.55H),6.61(s,1H),5.99(s,0.55H),3.78(s,3H),3.75(s,1.65H),3.27(s,1.65H),3.13(s,3H),3.03(s,1.65H),2.79(s,3H),2.37(s,3H),2.36(s,1.65H).13CNMR(100MHz,Chloroform-d)δ163.4,156.5,156.1,155,131.3,131.2,130.8,130.5,130.4,130.0,128.8,127.5,127.2,123.1,120.0,109.6,109.3,109.0,107.9,56.1,55.8,27.9,26.4,25.0,24.6,22.79,22.78.(Z:E=9:5)
3,前体胺C的制备:
a:Pd(OAc)2,BI-DIME,K3PO4,1.4-dioxane;b:Pd(C),H2,CH3OH;c:(Boc)2O,DMAP,Et3N,DCM;d:CAN,CH3CN/H2O;e:THF,DCM;f:n-BuLi,THF,-78℃;g:HCl,MeOH
中间体1的制备:在100mL单颈瓶中,依次加入中间体B 760mg、磷酸三钾1.43g、醋酸钯10mg、配体BI-DIME 30mg、中间体A1.1g,最后加入20mL1.4-二氧六环。氩气置换10分钟,回流反应24h。冷却至室温,用水和二氯甲烷萃取,分离有机层,饱和食盐水洗涤,无水硫酸钠干燥,减压蒸干。硅胶柱层析得黄色固体1.02g,收率78.4%。1H NMR(400MHz,Chloroform-d)δ8.16(s,0.5H),8.13(s,1H),7.27~7.22(m,1.5H),6.90~6.86(m,3H),6.33(s,1H),6.07(s,0.5H),6.01(s,1H),5.77(s,0.5H),4.87(s,1H),3.80~3.79(m,9H),3.50~3.45(m,6H),3.39(s,1.5H),3.06~2.99(m,7.5H),2.93(s,3H),2.83(s,1.5H),2.12(m,3H),2.11(s,1.5H),1.42(s,9H),1.42(s,9H).13C NMR(100MHz,Chloroform-d)δ163.4,161.3,156.2,155.6,155.6,154.8,154.2,150.5,149.9,140.7,139.7,137.4,131.5,131.4,130.8,130.7,130.4,129.3,128.8,123.8,123.5,122.3,121.8,121.6,118.9,118.3,114.4,114.2,109.9,109.6,109.5,108.5,78.8,60.3,60.3,55.8,55.4,55.4,42.0,41.9,29.7,28.5,27.9,27.0,26.2,24.8,24.4,19.9,19.8.(Z:E=2:1)
中间体2的制备:将1.02g中间体1置于100mL单颈瓶中,加入10mL无水甲醇溶解,向反应体系中加入0.1g钯/碳,通入氢气,反应10个小时。过滤,滤液蒸除大部分甲醇,随后用乙酸乙酯和水溶解残留物,饱和氯化钠水溶液洗涤,无水硫酸钠干燥,减压蒸干有机相,硅胶柱层析得白色固体0.84g,收率82.6%。1H NMR(400MHz,Chloroform-d)δ8.18(s,0.7H),8.17(s,1H),7.19(d,J=8.4Hz,1.7H),6.92(d,J=1.2Hz,1.7H),6.86~6.83(m,1.7H),6.09(s,0.7H),6.03(s,1H),4.87(s,1H),4.27(dd,J=9.6,5.6Hz,1H),4.13(dd,J=8,7.2Hz,0.7H),3.87(s,3H),3.84(s,2.1H),3.84(s,2.1H),3.81(s,3H),3.49~3.45(m,5.5H),3.43(s,3H),3.20(dd,J=13.6,5.6Hz,1H),3.10~3.02(m,4.1H),2.90(s,3H),2.87(s,2.1H),2.82(dd,J=13.6,8Hz,0.7H),2.75(dd,J=13.6,9.6Hz,1H),2.68(s,2.1H),2.46(s,3H),2.07(s,2.1H),2.04(s,3H),1.42(s,15.3H).13C NMR(125MHz,Chloroform-d)δ173.3,172.8,157.3,156.9,156.2,156.0,150.6,150.2,140.5,140.2,137.1,131.5,131.4,129.6,129.3,129.2,123.9,123.7,123.7,123.2,121.6,118.4,114.3,109.5,109.3,102.0,100.9,78.9(2C),60.3,60.2,60.1,59.8,55.5,55.4(2C),55.4,42.0,41.9,30.6,29.7,29.6,29.2,28.5,28.2,27.0,24.8,24.6,20.5,20.4.(立体异构体比例为7:5)
中间体3的制备:将0.8g中间体2溶于10mL二氯甲烷中,加入0.45g(Boc)2O、17mgDMAP和0.29mL三乙胺,室温搅拌1小时。反应液依次用饱和NaHCO3洗涤、饱和NaCl洗涤、无水硫酸钠干燥,减压蒸干有机相,硅胶柱层析得白色固体0.9g,收率95.5%1H NMR(400MHz,Chloroform-d)δ7.22(s,1.5H),7.17(d,J=8.4Hz,1.5H),6.85~6.82(m,1.5H),6.37(s,0.5H),6.27(s,1H),4.77(s,1H),4.27~4.20(m,1.5H),3.86~3.84(m,6H),3.80(s,3H),3.46(dd,J=13.6,6.4Hz,3H),3.35(s,1.5H),3.34(s,3H),3.22~3.13(m,1.5H),3.00(dd,J=13.6,6.4Hz,3H),2.91(s,3H),2.85(s,1.5H),2.77~2.71(m,2.5H),2.66(dd,J=13.6,9.2Hz,0.5H),2.48(s,3H),2.04(s,1.5H),2.03(s,3H),1.60(s,4.5H),1.59(s,9H),1.44(s,13.5H).13C NMR(100MHz,Chloroform-d)δ173.2,172.6,157.4,156.7,156.2,156.1,155.8,150.3,149.8,148.9,140.6,140.3,139.5,129.8,129.6,129.3,129.2,129.0,125.4,123.5,122.9,122.2,122.1,117.7,109.6,109.3,107.1,105.5,83.4,83.3,79.0(2C),60.4,60.1,60.0,59.8,55.7(2C),55.6,55.4,41.0(2C),30.7,29.5,29.3,28.5,28.0,28.0,27.2,24.8,24.5,20.6,20.5.(立体异构体比例为2:1)
中间体4的制备:将0.5g中间体3溶于3.5mL乙腈和1.5mL水的混合液中,0℃缓慢滴加1g硝酸铈铵在2.5mL乙腈和2.5mL水中的混合液,保持温度搅拌1小时。反应完毕,用饱和碳酸氢钠溶液淬灭反应,水和乙酸乙酯萃取,分离有机层,饱和食盐水洗涤,无水硫酸钠干燥,减压蒸干。硅胶柱层析得黄色固体0.23g,收率49.6%。1H NMR(400MHz,Chloroform-d)δ7.34(s,1.7H),7.15(d,J=8.4Hz,1.7H),6.85(d,J=8.4Hz,1.7H),6.46(s,0.7H),6.44(s,1H),4.76(s,1H),4.28(dd,J=7.6,6.8Hz,0.7H),3.99(dd,J=10,4.4Hz,1H),3.86(s,2.1H),3.83(s,3H),3.45~3.41(m,3.4H),3.26(dd,J=14,4.4Hz,1H),3.18(dd,J=14,6.8Hz,0.7H),3.03~2.95(m,6.4H),2.93(s,2.1H),2.88~2.82(m,3.1H),2.64~2.59(m,3.7H),2.10(s,3H),2.09(s,2.1H),1.57(s,6.3H).1.56(s,9H),1.44(s,15.3H).13C NMR(125MHz,Chloroform-d)δ184.2,184.0,175.4,175.0,172.8,172.5,157.2,156.8,156.0,155.9,155.6,148.0,147.9,147.5,135.9,135.5,135.3,135.1,131.2,129.7,129.6,128.5,128.3,128.2,128.0,127.9,123.4,122.8,122.6,122.4,110.8,110.5,86.4,86.3,79.2(2C),61.1,59.9,55.5,55.4,40.0(2C),30.5,30.0,29.3,28.4,28.1,28.0,27.5,26.0,24.9,24.7,20.0,20.0.(立体异构体比例为7:5)
中间体5的制备:将0.5g中间体4溶于无水10mL二氯甲烷中,冰浴条件下缓慢滴加0.6mL三氟乙酸,保持温度搅拌3小时。反应完毕,饱和碳酸氢钠将反应液pH值调至8,二氯甲烷萃取,合并有机层,依次用饱和氯化钠洗涤、无水硫酸钠干燥,减压蒸干,硅胶柱层析得橙黄色固体0.3g,收率69.3%。1H NMR(400MHz,Chloroform-d)δ9.60(s,1.7H),7.16(d,J=8.4Hz,1.7H),6.93(s,1H),6.90(s,0.7H),6.85(d,J=8.4Hz,1.7H),6.42(s,0.7H),6.40(s,1H),4.80(s,1.7H),4.28(t,J=7.2Hz,0.7H),4.05(dd,J=9.2,4.8Hz,1H),3.86(s,2.1H),3.84(s,3H),3.46~3.41(m,3.4H),3.24(dd,J=14.4,4.8Hz,1H),3.09(dd,J=13.6,7.6Hz,0.7H),3.04~2.97(m,8.5H),2.84(dd,J=14.4,9.2Hz,1H),2.76(dd,J=13.6,7.2Hz,0.7H),2.73(s,2.1H),2.59(s,3H),2.09(s,3H),2.09(s,2.1H),1.43(s,15.3H).13C NMR(100MHz,Chloroform-d)δ184.0,183.9,176.4,176.3,173.1,172.8,157.3,157.0,156.3,156.2,155.9,155.7,146.3,146.3,138.2,137.5,135.2,134.8,131.2,131.2,129.8,129.6,128.5,128.4,125.3,125.2,123.8,123.6,123.3,123.2,122.4,110.6,110.4,79.3(2C),60.8,60.0,55.6,55.5,40.7(2C),30.7,30.3,29.8,29.4,28.8,28.5,26.2,25.0,24.9,20.1(2C).(立体异构体比例为7:5)
中间体6(化合物21)的制备:在-78℃下,将1.6M的正丁基锂溶液0.2mL滴加150mg中间体5在5mL无水四氢呋喃中的溶液,所得混合液在-78℃下搅拌12h。反应完毕,用NH4Cl的饱和溶液淬灭反应混合物,并用乙酸乙酯和水稀释,分离出有机层并用饱和食盐水洗涤、无水硫酸钠干燥,减压蒸干有机相。硅胶柱层析得橙黄色固体60mg,收率40.5%。1H NMR(400MHz,Methanol-d4)δ7.22(d,J=8.4Hz,1H),7.06(d,J=8.4Hz,1H),7.01(s,1H),3.86(s,3H),3.39(d,J=16.8Hz,1H),3.29~3.21(m,2H),3.14(s,3H),2.99(d,J=16.8Hz,1H),2.93~2.86(m,1H),2.82(dd,J=13.6,6.8Hz,1H),2.24(s,3H),2.21(s,3H),1.40(s,9H).13C NMR(125MHz,Methanol-d4)δ181.0,176.6,175.2,157.0,155.8,154.2,146.8,137.5,131.4,131.0,129.2,129.0,125.4,123.6,122.1,122.0,112.8,78.5,61.9,55.0,40.1,32.0,27.5(3C),25.8,25.7,24.5,21.9.前体胺C的制备:将0.18mL 6M的HCl水溶液滴加到100mg中间体6在5mL甲醇中的溶液,40℃下反应12小时。反应完毕,用2.5M的NaOH溶液调pH至碱性。并用二氯甲烷和水稀释,分离出有机层并用饱和食盐水洗涤、无水硫酸钠干燥,减压蒸干有机相。产物不经纯化直接用于下步反应。
化合物1的制备:
将10mg胺前体C溶于1.5mL二氯甲烷中,冰浴条件下缓慢加入3.5mg苯甲酸,5.9mgEDCI,8.1mg DMAP,移至室温,氩气保护下反应1小时。饱和碳酸氢钠溶液淬灭,二氯甲烷萃取,合并有机层,饱和氯化钠溶液洗涤,无水硫酸钠干燥。减压蒸去溶剂,残留物经硅胶柱层析分离,得黄色固体6.7mg,收率68.1%。1H NMR(400MHz,Methanol-d4)δ7.75~7.73(m,2H),7.50~7.47(m,1H),7.46~7.41(m,2H),7.21(d,J=8.8Hz,1H),7.07~7.05(m,2H),3.86(s,3H),3.67~3.57(m,2H),3.40(d,J=16.8Hz,1H),3.13(s,3H),3.07~2.98(m,3H),2.21(s,3H),2.20(s,3H);13C NMR(100MHz,Methanol-d4)δ186.5,176.6,168.8,155.8,154.2,146.9,137.4,131.1,130.9,129.0,128.1,126.7,125.5,123.4,122.0,112.7,61.9,54.9,39.9,25.7,24.9,24.3,21.7.
化合物2的制备:
化合物2的制备方法同化合物1,将苯甲酸替换成对甲氧基苯甲酸。1H NMR(400MHz,Methanol-d4)δ7.71(d,J=9.2Hz,2H),7.21(d,J=8.4Hz,1H),7.07~7.05(m,2H),6.96(d,J=9.2Hz,2H),3.86(s,3H),3.83(m,3H),3.64~3.57(m,2H),3.40(d,J=16.4Hz,1H),3.14(s,3H),3.07~2.98(m,3H),2.21(s,3H),2.20(s,3H);13C NMR(100MHz,Methanol-d4)δ181.2,176.6,172.7,168.4,162.4,154.2,131.4,130.9,129.2,129.11,129.05,128.7,128.6,125.5,123.5,122.0,113.3,112.8,61.9,54.9,54.4,40.0,32.0,25.7,24.9,24.3,21.7.
化合物3的制备:
化合物3的制备方法同化合物1,将苯甲酸替换成间三氟甲基苯甲酸。1H NMR(400MHz,Methanol-d4)δ8.09(s,1H),8.00(dd,J=8,0.8Hz,1H),7.81(dd,J=8,0.8Hz,1H),7.66(t,J=8Hz,1H),7.22(d,J=8.8Hz,1H),7.07~7.05(m,2H),3.86(s,3H),3.69~3.59(m,2H),3.40(d,J=16.8Hz,1H),3.13(s,3H),3.07~2.98(m,3H),2.21(s,6H);13C NMR(100MHz,Methanol-d4)δ182.6,178.1,176.7,168.5,157.3,156.9,155.7,148.4,138.9,136.8,133.0,132.4,131.8,130.7,130.61,130.55,129.1,126.9,125.3,124.8,123.5,114.3,63.4,56.4,41.4,33.4,27.1,26.4,25.8,23.2.
化合物4的制备:
化合物4的制备方法同化合物1,将苯甲酸替换成4-氯萘甲酸。1H NMR(400MHz,Methanol-d4)δ7.74~7.71(m,2H),7.46~7.44(m,2H),7.21(d,J=8.8Hz,1H),7.07~7.05(m,2H).3.86(s,3H),3.66~3.57(m,2H),3.40(d,J=16.8Hz,1H),3.05~2.98(m,3H),2.204(s,3H),2.197(s,3H);13CNMR(100MHz,Methanol-d4)δ182.7,178.0,176.7,169.1,157.3,155.7,148.4,138.9,138.7,134.4,133.0,132.4,130.6,130.4,129.9,129.8,127.0,124.9,123.5,114.3,63.44,56.4,41.6,33.4,27.1,26.4,25.8,23.2.
化合物5的制备:
化合物5的制备方法同化合物1,将苯甲酸替换成4-异丙基苯甲酸。1H NMR(400MHz,Methanol-d4)δ7.69~7.65(m,2H),7.31(d,J=8.4Hz,2H),7.21(d,J=8.8Hz,1H),7.07~7.04(m,2H),3.86(s,3H),3.65~3.57(m,2H),3.40(d,J=16.8Hz,1H),3.14(s,3H),3.08~2.90(m,4H),2.21(s,3H),2.20(s,3H),1.25(s,3H),1.24(s,3H);13C NMR(100MHz,Methanol-d4)δ182.7,178.1,176.7,170.3,157.3,155.7,154.1,148.4,138.9,133.2,133.0,132.4,130.62,130.55,128.4,127.7,127.0,125.0,123.5,114.3,63.4,56.4,41.5,35.4,33.5,27.2,26.4,25.8,24.2,23.3.
化合物6的制备:
化合物6的制备方法同化合物1,将苯甲酸替换成邻溴苯甲酸。1H NMR(400MHz,Methanol-d4)7.60~7.58(m,1H),7.40~7.36(m,1H),7.33~7.28(m,2H),7.22(d,J=8.4Hz,1H),7.12(s,2H),7.06(d,J=8.4Hz,1H),3.86(s,3H),3.71~3.64(m,1H),3.61~3.56(m,1H),3.39(d,J=16.8Hz,1H),3.12(s,3H),3.06~2.97(m,3H),2.22(s,3H),2.21(s,3H);13C NMR(125MHz,Methanol-d4)δ181.1,176.7,175.3,169.6,155.8,154.3,146.9,138.6,137.4,132.8,131.6,131.0,130.7,129.2,129.1,128.3,127.2,125.7,123.3,122.1,118.9,112.8,61.9,54.9,39.5,32.0,25.7,24.9,24.4,21.9.
化合物7的制备:
化合物7的制备方法同化合物1,将苯甲酸替换成3,4,5-三甲氧基苯甲酸。1H NMR(400MHz,Methanol-d4)7.22(d,J=8.8Hz,1H),7.11(s,2H),7.06~7.04(m,2H),3.87(s,6H),3.87(s,3H),3.79(s,3H),3.65~3.56(m,2H),3.40(d,J=16.8Hz,1H),3.13(s,3H),3.07~2.97(m,3H),2.21(s,6H);13C NMR(125MHz,Methanol-d4)δ181.0,176.7,175.3,168.2,155.8,154.3,153.0,146.9,140.6,137.4,134.7,131.6,131.0,129.7,129.2,129.1,125.5,125.3,123.4,122.1,122.0,112.8,104.4,61.9,59.7,55.3,55.0,39.7,32.0,25.7,25.1,24.4,21.8.
化合物8的制备:
化合物8的制备方法同化合物1,将苯甲酸替换成吡啶-2-甲酸。1H NMR(400MHz,Methanol-d4)δ8.60~8.58(m,1H),8.04(dt,J=8,0.8Hz,1H),7.92(dt,J=7.6,1.6Hz,1H),7.52~7.49(m,1H),7.21(d,J=8.4Hz,1H),7.07~7.05(m,2H),3.86(s,3H),3.71~3.61(m,2H),3.39(d,J=16.8Hz,1H),3.14(s,3H),3.10~2.97(m,3H),2.21(s,3H),2.20(s,3H);13C NMR(100MHz,Methanol-d4)δ181.0,176.6,175.2,155.8,154.2,148.4,146.8,137.3,130.9,129.1,126.2,125.4,125.2,123.2,122.0,121.5,118.5,115.0,112.7,61.9,54.9,39.3,31.9,25.6,25.0,24.3,21.7.
化合物9的制备:
化合物9的制备方法同化合物1,将苯甲酸替换成呋喃-2-甲酸。1H NMR(400MHz,Methanol-d4)δ7.62(d,J=2Hz,1H),7.21(d,J=8.4Hz,1H),7.07~7.03(m,3H),6.54(dd,J=3.2,2Hz,1H),3.86(s,3H),3.63~3.54(m,2H),3.40(d,J=16.8Hz,1H),3.14(s,3H),3.05~2.94(m,2H),2.22(s,3H),2.21(s,3H);13C NMR(100MHz,Methanol-d4)δ182.7,178.1,176.7,161.0,157.3,155.7,149.1,148.4,146.3,138.9,133.0,132.4,130.61,130.57,126.9,124.8,123.54,123.50,115.1,114.3,112.9,63.4,56.4,40.7,33.4,27.2,26.4,25.8,23.3.
化合物10的制备:
化合物10的制备方法同化合物1,将苯甲酸替换成噻吩-2-甲酸。1H NMR(400MHz,Methanol-d4)δ7.59(dd,J=5.2,1.2Hz,1H),7.56(dd,J=3.6,1.2Hz,1H),7.21(d,J=8.4Hz,2H),7.09(dd,J=5.2,3.6Hz,1H),7.07~7.04(m,2H),3.85(s,3H),3.61~3.55(m,2H),3.40(d,J=16.8Hz,1H),3.07~2.95(m,3H),2.20(s,6H);13C NMR(100MHz,Methanol-d4)δ176.5,175.2,163.0,155.8,155.4,154.2,138.8,137.4,134.9,131.5,130.9,130.0,129.1,128.1,127.6,127.4,125.5,125.3,123.4,122.0,118.7,116.8,115.1,112.8,61.9,54.9,40.1,31.9,25.7,24.9,24.3,21.7.
化合物11的制备:
化合物11的制备方法同化合物1,将苯甲酸替换成2-萘甲酸。1H NMR(400MHz,Methanol-d4)δ8.30(d,J=1.6Hz,1H),7.96~7.89(m,3H),7.81(dd,J=8.8,2Hz,1H),7.57~7.53(m,2H),7.21(d,J=8.4Hz,1H),7.08(s,1H),7.06(d,J=8.4Hz,1H),3.86(s,3H),3.73~3.74(m,2H),3.39(d,J=16.8Hz,1H),3.14(s,3H),3.11~3.04(m,2H),3.00(d,J=16.8Hz,1H),2.21(s,3H),2.17(s,3H);13C NMR(100MHz,Methanol-d4)δ182.6,178.1,176.7,170.3,157.2,155.7,151.3,148.3,138.9,136.2,134.1,133.0,132.4,130.6,130.5,130.0,129.4,128.8,128.7,127.8,126.9,125.3,124.9,124.8,123.52,123.48,114.2,63.4,56.4,41.3,33.4,27.1,26.5,25.8,23.2.
化合物12的制备:
化合物12的制备方法同化合物1,将苯甲酸替换成喹啉-2-甲酸。1H NMR(400MHz,Methanol-d4)δ8.44(d,J=8.4Hz,1H),8.16~8.11(m,2H),7.97(d,J=8.4Hz,1H),7.80(t,J=7.2Hz,1H),7.66(t,J=7.2Hz,1H),7.21(d,J=8.4Hz,1H),7.09(s,1H),7.05(d,J=8.4Hz,1H),3.85(s,3H),3.76(dd,J=13.6,6.8Hz,1H),3.69(dd,J=13.6,6.8Hz,1H),3.38(d,J=16.8Hz,1H),3.16~3.11(m,3H),3.05(dd,J=13.6,6.8Hz,1H),2.99(d,J=16.8Hz,1H),2.21(s,3H),2.13(s,3H);13C NMR(100MHz,Methanol-d4)δ182.5,178.0,176.7,166.9,157.2,155.7,154.2,151.1,148.3,148.0,139.0,138.9,132.4,131.4,130.77,130.79,130.6,130.5,129.3,129.0,126.9,124.7,123.5,119.5,114.2,63.3,56.4,40.7,33.4,27.0,26.6,25.8,23.2.
化合物13的制备:
化合物13的制备方法同化合物1,将苯甲酸替换成吲哚-2-甲酸。1H NMR(400MHz,Methanol-d4)δ7.62(d,J=8Hz,1H),7.41(d,J=8Hz,1H),7.22~7.179(m,2H),7.06~7.00(m,3H),6.96(s,1H),3.869(s,3H),3.64(d,J=7.2Hz,2H),3.40(d,J=16.8Hz,1H),3.15(s,3H),3.10~2.97(m,3H),2.20(s,3H),2.18(s,3H);13C NMR(100MHz,Methanol-d4)δ184.6,176.6,176.1,175.2,162.7,155.8,154.2,146.9,137.4,136.8,130.9,130.7,129.1,129.0,127.6,125.5,123.5,123.4,122.0,121.4,119.6,112.7,111.5,102.7,61.9,54.9,39.6,31.9,25.6,25.0,24.4,21.7.
化合物14的制备:
化合物14的制备方法同化合物1,将苯甲酸替换成苯并呋喃-2-甲酸。1H NMR(400MHz,Methanol-d4)δ7.70(dd,J=8,0.8Hz,1H),7.56(dt,J=8,0.8Hz,1H),7.45~7.41(m,2H),7.31~7.27(m,1H),7.21(d,J=8.4Hz,1H),7.06~7.04(m,2H),3.85(s,3H),3.70~3.61(m,2H),3.39(d,J=16.8Hz,1H),3.14(s,3H),3.10~2.97(m,3H),2.21(s,3H),2.17(s,3H);13C NMR(100MHz,Methanol-d4)δ181.1,176.6,175.2,159.8,155.8,155.0,154.2,148.6,146.8,137.4,131.5,130.9,129.1,129.0,127.4,126.6,125.4,123.4,123.2,122.3,122.0,112.7,111.4,109.6,61.9,54.9,39.2,31.9,25.6,25.0,24.3,21.7.
化合物15的制备:
化合物15的制备方法同化合物1,将苯甲酸替换成苯并噻吩-2-甲酸。1H NMR(400MHz,Methanol-d4)δ7.91~7.88(m,2H),7.84(d,J=0.8Hz,1H),7.42~7.38(m,2H),7.20(d,J=8.4Hz,1H),7.06~7.04(m,2H),3.85(s,3H),3.65~3.61(m,2H),3.39(d,J=16.8Hz,1H),3.14(s,3H),3.10~2.97(m,2H),2.20(s,3H),2.14(s,3H);13C NMR(100MHz,Methanol-d4)δ181.2,176.8,176.6,175.2,163.3,155.8,154.2,146.9,140.9,139.3,138.6,137.4,130.9,129.0,125.9,125.5,124.9,124.8,124.5,123.3,122.2,122.0,112.7,61.9,54.9,40.1,31.9,25.6,24.9,24.3,21.7.
化合物16的制备:
化合物16的制备方法同化合物1,将苯甲酸替换成苯乙烯酸。1H NMR(400MHz,Methanol-d4)δ7.56(dd,J=8,2Hz,2H),7.49(d,J=15.6Hz,1H),7.40~7.34(m,3H),7.21(d,J=8.4Hz,1H),7.07~7.05(m,2H),6.55(d,J=15.6Hz,1H),3.86(s,3H),3.54(t,J=7.2Hz,2H),3.13(s,3H),3.02~2.96(m,3H),2.22(s,3H),2.21(s,3H);13C NMR(100MHz,Methanol-d4)δ182.7,178.1,176.7,168.7,157.3,155.7,148.4,141.8,138.8,136.3,133.0,132.4,130.8,130.6,130.5,130.0,128.9,126.9,124.8,123.6,123.5,121.9,114.3,63.4,56.4,41.1,33.4,27.1,26.5,25.9,23.3.
化合物17的制备:
化合物17的制备方法同化合物1,将苯甲酸替换成3,5-二甲氧基肉桂酸。1H NMR(400MHz,Methanol-d4)δ7.40(d,J=15.6Hz,1H),7.21(d,J=8.4Hz,1H),7.07~7.05(m,2H),6.71(d,J=2.4Hz,2H),6.52(d,J=15.6Hz,1H),6.48(t,J=2.4Hz,1H),3.86(s,3H),3.79(s,6H),3.54(t,J=6.8Hz,2H),3.39(d,J=16.8Hz,1H),3.13(s,3H),3.00~2.95(m,3H),2.22(s,3H),2.21(s,3H).13C NMR(100MHz,Methanol-d4)δ185.4,178.1,168.7,162.7,155.7,146.1,144.5,141.8,138.28,138.26,133.0,132.4,130.6,126.9,124.8,123.6,123.5,122.4,114.3,106.8,103.0,56.4,56.0,55.9,54.9,41.2,33.4,27.1,26.4,25.9,23.3.
化合物18的制备:
化合物18的制备方法同化合物1,将苯甲酸替换成3-(三氟甲基)苯乙烯酸。1H NMR(400MHz,Methanol-d4)δ7.88(d,J=0.8Hz,1H),7.83(dd,J=7.2,0.8Hz,1H),7.65(dd,J=8,0.8Hz,1H),7.59(d,J=8Hz,1H),7.54(d,J=15.6Hz,1H),7.21(d,J=8.4Hz,1H),7.07~7.05(m,2H),6.65(d,J=15.6Hz,1H),3.86(s,3H),3.55(t,J=6.8Hz,1H),3.40(d,J=16.8Hz,1H),3.13(s,3H),3.01~2.97(m,2H),2.22(s,3H),2.21(s,3H);13C NMR(100MHz,Methanol-d4)δ182.8,176.6,175.2,166.6,155.8,154.2,146.9,138.4,137.3,136.0,130.93,130.90,129.4,129.1,129.0,125.59,125.55,125.4,123.9,123.8,123.3,122.6,122.0,112.8,61.9,54.9,39.8,31.9,25.6,24.9,24.3,21.8.
化合物19的制备:
化合物19的制备方法同化合物1,将苯甲酸替换成3-三氟甲基苯乙酸。1H NMR(400MHz,Methanol-d4)δ7.57(s,1H),7.55~7.47(m,3H),7.22(d,J=8.4Hz,1H),7.07(d,J=8.4Hz,1H),6.92(s,1H),3.86(s,3H),3.52(s,2H),3.47(dd,J=13.2,6.4Hz,1H),3.42~3.37(m,2H),3.14(s,3H),3.00(d,J=16.8Hz,1H),2.90(t,J=6.8Hz,2H),2.23(s,3H),2.21(s,3H);13C NMR(100MHz,Methanol-d4)δ182.6,178.0,176.7,173.2,157.3,155.8,148.4,138.8,138.5,133.9,133.0,132.5,130.6,130.5,130.3,126.9,126.8,124.7,124.6,123.54,123.45,114.3,63.4,56.4,43.5,40.9,33.4,27.1,26.4,25.8,23.3.
化合物20的制备:
化合物20的制备方法同化合物1,将苯甲酸替换成4-甲氧基苯乙酸。1H NMR(400MHz,Methanol-d4)δ7.22(d,J=8.4Hz,1H),7.14~7.07(m,2H),7.06(d,J=8.4Hz,1H),6.89(s,1H),6.84~6.81(m,2H),3.86(s,3H),3.74(s,3H),3.48~3.37(m,3H),3.35(s,2H),3.13(s,3H),3.20(d,J=16.8Hz,1H),2.88(t,J=6.8Hz,1H),2.23(s,3H),2.21(s,3H);13C NMR(100MHz,Methanol-d4)δ181.1,176.5,175.2,173.1,158.7,155.8,154.2,146.9,137.3,131.5,130.9,129.6,129.1,129.0,127.5,125.4,123.2,122.04,121.95,113.5,112.8,61.9,54.9,54.2,41.7,39.1,31.9,25.6,24.8,24.3,21.8.
化合物21的制备:
化合物21的制备方法及数据参见中间体6的制备。
化合物22的制备:
将12mg前体胺C溶于1.5mL无水甲醇中,依次加入2.9mg苯甲醛,2.1mg氰基硼氢化钠和0.023mL冰醋酸,室温反应1小时。反应完毕,冰浴下用饱和碳酸钠水溶液淬灭反应,并调pH值至9,随后用乙酸乙酯萃取,饱和氯化钠水溶液洗涤,无水硫酸钠干燥,减压蒸干有机相,硅胶柱层析得黄色固体6.0mg,收率64.4%。1H NMR(400MHz,Methanol-d4)7.45~7.40(m,5H),7.23(d,J=8.8Hz,1H),7.11~7.07(m,2H),4.14(s,2H),3.87(s,3H),3.42(d,J=16.8Hz,1H),3.24~3.18(m,2H),3.10~3.06(m,5H),3.00(d,J=16.8Hz,1H),2.24(s,3H),2.22(s,3H);13CNMR(175MHz,Methanol-d4)δ182.8,178.0,176.8,157.2,155.8,148.6,138.6,133.5,132.5,130.8,130.6,130.5,130.3,127.1,123.6,123.3,114.4,63.3,56.4,52.5,33.4,27.2,25.8,23.9,23.3.
化合物23的制备:
化合物23的制备方法同化合物22,将苯甲醛替换成邻溴苯甲醛。1H NMR(400MHz,Methanol-d4)δ7.54(dd,J=8,0.8Hz,1H),7.39(dd,J=7.6,1.6Hz,1H),7.33(dt,J=7.6,0.8Hz,1H),7.22(d,J=8.8Hz,1H),7.16(dt,J=8,1.6Hz,1H),7.07(d,J=8.8Hz,1H),7.01(s,1H),3.87(s,2H),3.86(s,3H),3.39(d,J=16.8Hz,1H),3.12(s,3H),3.00(d,J=16.8Hz,1H),2.96~2.91(m,2H),2.88~2.84(m,2H),2.23(s,3H),2.22(s,3H);13C NMR(100MHz,Methanol-d4)δ182.4,178.0,176.7,173.9,155.8,148.3,139.2,138.9,134.0,133.1,132.4,132.0,130.6,130.5,130.3,128.9,126.8,125.0,123.5,123.4,114.3,63.4,56.4,53.8,33.4,27.2,26.3,25.9,23.3.
化合物24的制备:
化合物24的制备方法同化合物22,将苯甲醛替换成3,4,5-三甲氧基苯甲醛。1HNMR(400MHz,Methanol-d4)δ7.22(d,J=8.8Hz,1H),7.08~7.06(m,2H),6.71(s,2H),3.98(d,J=2.8Hz,2H),3.86(s,3H),3.84(s,6H),3.74(s,3H),3.41(d,J=16.4Hz,1H),3.10(s,3H),3.08~2.97(m,5H),2.24(s,3H),2.22(s,3H);13C NMR(100MHz,Methanol-d4)δ182.7,179.7,178.0,176.7,157.2,156.4,155.8,154.9,152.90,152.88,148.4,132.49,132.46,130.6,126.9,123.5,123.2,114.4,111.5,107.6,63.4,61.1,56.7(2C),56.4,53.5,33.4,27.2,25.8,25.0,23.3.
化合物25的制备:
化合物25的制备方法同化合物22,将苯甲醛替换成对三氟甲基苯甲醛。1H NMR(400MHz,Methanol-d4)7.69(d,J=8Hz,2H),7.57(d,J=8Hz,2H),7.22(d,J=8.4Hz,1H),7.08~7.06(m,2H),4.04(s,2H),3.86(s,3H),3.41(d,J=16.4Hz,1H),3.11(s,3H),3.02~2.98(m,5H),2.23(s,3H),2.21(s,3H);13C NMR(175MHz,Methanol-d4)δ182.7,178.0,176.7,157.3,155.8,148.5,138.7,133.2,132.5,130.7,130.5,126.9,126.8(2C),124.9,123.6,123.5,123.4,114.3,63.3,56.4,54.9,52.7,33.4,27.1,25.8,25.2,23.2.
化合物26的制备:
化合物26的制备方法同化合物22,将苯甲醛替换成2.4-二氟苯甲醛。1H NMR(400MHz,Methanol-d4)7.44~7.38(m,1H),7.22(d,J=8.4Hz,2H),7.07(d,J=8.4Hz,1H),7.04(s,2H),6.98~6.92(m,2H),3.88(s,2H),3.86(s,3H),3.40(d,J=16.8Hz,1H),3.12(s,3H),3.00(d,J=16.8Hz,1H),2.96~2.87(m,4H),2.23(s,3H),2.21(s,3H);13C NMR(125MHz,Methanol-d4)δ182.5,178.0,176.7,157.3,155.7,148.4,138.8,133.41,133.37,133.3,133.29,133.1,132.5,130.6,130.5,126.8,124.5,123.5,123.3,114.3,112.6,112.4,104.9,104.7,63.3,56.4,46.3,33.4,27.1,25.9,25.8,23.3.
化合物27的制备:
化合物27的制备方法同化合物22,将苯甲醛替换成对叔丁基苯甲醛。1H NMR(400MHz,Methanol-d4)7.49(d,J=8Hz,2H),7.37(d,J=8.4Hz,2H),7.23(d,J=8.4Hz,1H),7.11(s,2H),7.08(d,J=8.4Hz,1H),4.12(s,2H),3.87(s,3H),3.43(d,J=16.8Hz,1H),3.23~3.19(m,2H),3.11~3.07(m,5H),3.01(d,J=16.8Hz,1H),2.24(s,3H),2.21(s,3H),1.32(s,9H);13C NMR(125MHz,Methanol-d4)δ182.9,178.0,176.8,157.2,155.8,152.9,148.6,138.6,133.4,132.5,130.5,130.4,127.3,127.1,123.6,123.4,114.5,63.3,56.4,54.9,52.2,35.6,33.4,31.7(3C)27.2,25.9,23.8,23.3.
化合物28的制备:
化合物28的制备方法同化合物22,将苯甲醛替换成3-氯苯甲醛。1H NMR(400MHz,Methanol-d4)7.44(s,1H),7.38~7.31(m,3H),7.20(d,J=8.4Hz,1H),7.07~7.04(m,2H),4.02(s,2H),3.84(s,3H),3.38(d,J=16.8Hz,1H),3.12~3.06(m,5H),3.03~2.95(m,3H),2.21(s,3H),2.19(s,3H);13C NMR(100MHz,Methanol-d4)δ182.7,178.0,176.7,157.2,155.7,148.5,138.7,137.8,135.8,133.3,132.5,131.6,130.54,130.50,129.9,128.9,127.0,123.5,123.3,122.7,114.4,63.3,56.4,52.3,33.4,27.2,25.8,24.6,23.3.
化合物29的制备:
合物29的制备方法同化合物22,将苯甲醛替换成3-甲醛苯甲酸甲酯。1H NMR(400MHz,Methanol-d4)8.11(t,J=1.6Hz,1H),8.04(dt,J=1.2Hz,7.6Hz,1H),7.67(dd,J=1.2Hz,7.6Hz,1H),7.56(t,J=7.6Hz,1H),7.23(d,J=8.4Hz,1H),7.10~7.06(m,2H),4.16(s,2H),3.91(s,3H),3.86(s,3H),3.41(d,J=16.8Hz,1H),3.22~3.13(m,2H),3.12~3.06(m,2H),3.00(d,J=16.8Hz,1H),2.23(s,3H),2.22(s,3H);13C NMR(100MHz,Methanol-d4)δ182.7,178.0,176.7,168.0,157.2,155.7,148.5,138.7,135.7,135.3,133.4,132.5,132.2,131.6,130.9,130.6,130.5,127.0,123.5,123.3,122.5,114.4,63.3,56.4,52.8,52.4,33.4,27.2,25.8,24.5,23.3.
化合物30的制备:
化合物30的制备方法同化合物22,将苯甲醛替换成2,3-二甲氧基苯甲醛。1H NMR(400MHz,Methanol-d4)7.23(d,J=8.4Hz,1H),7.13~7.11(m,3H),7.08(d,J=8.4Hz,1H),6.96(dd,J=3.2,6.4Hz,1H),4.18(s,2H),3.90(s,2H),3.87(s,3H),3.86(s,3H),3.42(d,J=16.8Hz,1H),3.26~3.21(m,2H),3.11~3.07(m,5H),3.00(d,J=16.8Hz,1H),2.23(s,3H),2.22(s,3H);13CNMR(100MHz,Methanol-d4)δ182.8,178.0,176.8,157.2,155.7,154.1,149.1,148.6,138.6,132.5,130.6,130.5,127.2,126.3,125.7,123.5,123.3,121.6,115.6,114.4,63.3,61.4,56.4,47.7,33.4,27.2,25.8,23.6,23.3.
化合物31的制备:
化合物31的制备方法同化合物22,将苯甲醛替换成邻甲基苯甲醛。1H NMR(400MHz,Methanol-d4)7.33~7.30(m,1H),7.23~7.22(m,4H),7.09~7.06(m,2H),4.02(s,2H),3.86(s,2H),3.41(d,J=16.8Hz,1H),3.16~3.11(m,5H),3.08~2.98(m,3H),2.36(s,3H),2.23(s,3H),2.22(s,3H);13C NMR(125MHz,Methanol-d4)δ182.7,178.0,176.8,157.3,155.8,148.5,138.8,138.1,133.3,132.5,131.8,130.9,130.6,130.54,130.48,129.7,127.8,127.6,127.0,123.6,123.4,123.3,114.4,63.4,56.5,50.6,33.4,27.2,25.8,25.0,23.3,19.2.
化合物32的制备:
化合物32的制备方法同化合物22,将苯甲醛替换成3,4-二甲基苯甲醛。1H NMR(400MHz,Methanol-d4)7.24~7.19(m,2H),7.14(dd,J=1.2Hz,7.6Hz,1H),7.10~7.07(m,2H),4.06(s,2H),3.86(s,2H),3.42(d,J=16.8Hz,1H),3.23~3.16(m,2H),3.11~3.07(m,5H),3.00(d,J=16.8Hz,1H),2.29(s,3H),2.27(s,3H),2.23(s,3H),2.21(s,3H);13C NMR(100MHz,Methanol-d4)δ182.7,178.0,176.8,157.2,155.8,148.5,139.0,138.7,133.4,132.5,131.8,131.4,130.54,130.45,128.1,127.0,123.5,123.3,122.0,114.4,63.3,56.4,52.5,33.4,27.2,25.8,24.1,23.3,19.8,19.6.
化合物33的制备:
化合物33的制备方法同化合物22,将苯甲醛替换成2-噻吩甲醛。1H NMR(500MHz,Methanol-d4)7.54(d,J=5Hz,1H),7.26~7.22(m,2H),7.12~7.07(m,3H),4.43(s,2H),3.87(s,3H),3.42(d,J=17Hz,1H),3.25~3.16(m,2H),3.11~3.07(m,5H),3.01(d,J=17Hz,1H),2.24(s,3H),2.22(s,3H);13C NMR(175MHz,Methanol-d4)δ182.8,178.0,176.8,157.2,155.8,148.6,138.6,133.5,132.53,132.46,130.54,130.45,128.7,127.1,123.6,123.3,114.4,63.3,56.4,48.2,46.4,33.4,27.2,25.9,23.9,23.3.
化合物34的制备:
化合物34的制备方法同化合物22,将苯甲醛替换成苯并[b]噻吩-2-甲醛。1H NMR(400MHz,Methanol-d4)7.90~7.88(m,1H),7.85~7.83(m,1H),7.46(s,1H),7.39~7.36(m,2H),7.23(d,J=8.4Hz,1H),7.12(s,1H),7.08(d,J=8.4Hz,1H),4.44(s,2H),3.87(s,3H),3.42(d,J=16.8Hz,1H),3.27~3.23(m,2H),3.10~3.08(m,2H),3.06(s,3H),3.00(d,J=16.8Hz,1H),3.02(s,3H),2.98(s,3H);13C NMR(175MHz,Methanol-d4)δ182.8,178.0,176.7,157.2,155.8,148.6,141.9,140.9,138.7,133.4,132.5,130.54,130.48,127.1,126.3,125.9,125.1,123.6,123.5,123.4,114.4,63.3,56.4,47.6,33.4,30.8,27.2,25.8,23.3.
化合物35的制备:
化合物35的制备方法同化合物22,将苯甲醛替换成1-萘甲醛。1H NMR(400MHz,Methanol-d4)7.89~7.85(m,4H),7.51~7.47(m,3H),7.22(d,J=8.4Hz,1H),7.07~7.05(m,2H),4.12(s,2H),3.86(s,3H),3.40(d,J=16.8Hz,1H),3.09~2.97(m,8H),2.21(s,3H),2.20(s,3H);13C NMR(125MHz,Methanol-d4)δ182.6,178.0,176.7,157.3,155.7,148.4,138.8,134.9,134.6,133.2,130.5,129.7,129.3,129.0,128.8,127.7,127.5,127.4,126.9,123.6,123.5,123.4,114.3,63.4,56.4,53.5,33.4,27.1,25.8,25.2,23.3.
化合物36的制备:
化合物36的制备方法同化合物22,将苯甲醛替换成4-联苯甲醛。1H NMR(400MHz,Methanol-d4)7.72(d,J=8.4Hz,2H),7.65~7.63(m,2H),7.52(d,J=8.4Hz,2H),7.44(t,J=7.2Hz,2H),7.37~7.33(m,1H),7.21(d,J=8.4Hz,1H),7.13(s,1H),7.08(d,J=8.4Hz,1H),4.20(s,2H),3.86(s,3H),3.42(d,J=16.8Hz,1H),3.28~3.22(m,2H),3.13~3.10(m,2H),3.08(s,3H),3.00(d,J=16.8Hz,1H),2.23(s,3H),2.21(s,3H);13C NMR(150MHz,Methanol-d4)δ182.9,178.0,176.8,157.3,155.8,148.6,143.5,141.5,138.7,132.5,131.2,130.6,130.5,130.0,129.9,128.9,128.2,128.1,128.0,127.1,123.6,123.4,114.5,63.4,56.5,52.3,33.4,30.8,27.2,25.8,24.1,23.3.
化合物37的制备:
化合物37的制备方法同化合物22,将苯甲醛替换成苯乙醛。1H NMR(400MHz,Methanol-d4)7.26~7.33(m,2H),7.28(d,J=7.5Hz,1H),7.24(d,J=8.5Hz,1H),7.13(s,1H),7.09(d,J=8.5Hz,1H),3.87(s,3H),3.43(d,J=16.5Hz,1H),3.28~3.25(m,4H),3.12~3.09(m,2H),3.07(s,3H),3.03~2.97(m,4H),2.24(s,3H),2.22(s,3H);13C NMR(175MHz,Methanol-d4)δ182.9,178.0,176.8,157.2,155.8,148.6,137.8,133.5,132.6,130.6,130.4,130.1,129.8,128.4,127.2,123.6,123.3,121.3,114.5,63.3,56.4,49.9,33.4,33.3,27.2,25.8,23.6.
化合物38的制备:
化合物38的制备方法同化合物22,将苯甲醛替换成特戊醛。1H NMR(400MHz,Methanol-d4)7.23(d,J=8.4Hz,1H),7.15(s,1H),7.08(d,J=8.4Hz,1H),3.86(s,3H),3.42(d,J=16.8Hz,1H),3.26~3.20(m,2H),3.15~3.11(m,5H),3.01(d,J=16.8Hz,1H),2.88(s,2H),2.24(s,3H),2.22(s,3H),1.06(s,9H);13C NMR(100MHz,Methanol-d4)δ182.9,178.0,176.7,157.2,155.8,148.7,138.6,132.5,127.1,123.6,123.3,114.5,63.3,60.5,56.4,50.3,33.4,31.6,27.6(3C),27.2,25.8,23.3.
化合物39的制备:
化合物39的制备方法同化合物22,将苯甲醛替换成甲醛水溶液。1H NMR(400MHz,Methanol-d4)7.23(d,J=8.8Hz,1H),7.17(s,1H),7.08(d,J=8.8Hz,1H),3.86(s,3H),3.42(d,J=16.8Hz,1H),3.28~3.21(m,2H),3.12~3.07(m,5H),3.00(d,J=16.8Hz,1H),2.86(s,6H),2.24(s,3H),2.22(s,3H);13C NMR(100MHz,Methanol-d4)δ181.3,176.6,175.2,155.7,154.3,147.0,137.1,131.0,129.1,128.9,125.6,122.0,121.8,119.8,112.9,61.8,57.3,54.9,42.3,31.8,25.7,24.3,21.8,20.9.
药理实验:化合物对IDO1酶抑制活性测定:
实验材料:
IDO1荧光抑制剂筛选试剂盒(384Well Format)
实验方法:
将含有100mM pH 6.5的磷酸钾缓冲液、40mM用NaOH中和的抗坏血酸、200μg/mL过氧化氢酶、20μM亚甲基蓝和0.05μM rhIDO1的100μL标准反应混合物以确定的浓度添加到含有底物L-色氨酸和供试品的溶液中。在37℃下反应45分钟,通过添加20μL 30%(w/v)三氯乙酸停止反应。然后在65℃下加热15分钟,向每个孔中加入100μL2%(w/v)对二甲氨基苯甲醛的乙酸溶液。在490nm处使用SYNERGY-H1微孔板读取器测量源自犬尿氨酸的黄色色素,IC50值用GraphPad Prism 8.0软件分析。
表1.化合物对IDO1酶的体外抑制活性
酶学活性研究结果分析与讨论:
大部分化合物对IDO1酶的抑制活性在10-7~10-8水平。其中,化合物23展示了最强的抑制活性。由以上数据可以看出,将天然产物exiguamine A的C环O原子换成电子等排体-CH2-并去掉了带正电的二氢吲哚鎓小环得到的衍生物,其IDO1抑制活性与天然产物相当。
本发明化合物N-24位取代基的改变对IDO1抑制活性影响明显。烷胺类化合物的活性普遍高于酰胺类。对于酰胺类化合物,苯甲酰基(化合物1)及呋喃-2-甲酰基(化合物9)取代活性最高。苯环上吸电子基和给电子基对活性没有显著性得影响;对于烷胺类化合物,苯环衍生物的活性要高于杂环衍生物、苯并杂环衍生物。对比化合物23,25,27,28,31,苯环上吸电子取代基的活性要高于给电子取代基;对比化合物23,25,28,邻位取代活性要高于间位或对位;对比22,38,39,烷基取代活性更高。
Claims (25)
1.通式I所示的化合物或其药学上可接受的盐:
R1、R6、R7独立的选自:H,C1-C8的直链或支链的烷基、C2-C8的直链或支链烯基、
C2-C4的炔基、C1-C8的直链或支链烷基酰基、C1-C8的直链或支链磺酰基、C1-C8的直链或支链烷氧酰基;
R2、R3、R4、R5独立的选自:H、卤素、OH、SH、NH2、COOH、CF3、醛基、氨基甲酰基、NO2、CN、C1-C8的直链或支链的烷基、C2-C8的直链或支链烯基、C2-C4的炔基、C1-C8的直链或支链烷氧基;
R8、R9独立的选自C6-C10的芳酰基,C4-C10的杂芳酰基,C6-C10芳基取代的C1-C4直链或支链烷酰基、C4-C10杂芳基取代的C1-C4直链或支链烷酰基、C6-C10芳基取代的C0-C4直链或支链肉桂酸甲酰基、C1-C10的直链或支链烷酰基,C5-C6环烷基并苯酰基、C6-C10的芳烷基,C4-C10的杂芳烷基,C6-C10芳基取代的C1-C4直链或支链烷基、C4-C10杂芳基取代的C1-C4直链或支链烷基、C1-C10的直链或支链烷基;这些芳酰基、杂芳酰基、C5-C6环烷基并苯酰基、芳烷基、杂芳烷基上又可以具有一个或多个取代基,取代基选自H、OH、SH、NH2、COOH、CF3、醛基、氨基甲酰基、卤素、NO2、CN、C1-C8直链或支链的烷基、C1-C8直链或支链烷氧基、C1-C8直链或支链烷基胺基、C2-C8直链或支链烯基、C2-C4直链或支链炔基、C6-C8的芳基、C4-C8的杂环芳基。
2.根据权利要求1中任一项的化合物或其药学上可接受的盐,其特征在于,所述的化合物如式IA所示
所述的选自苯基、吡啶基、呋喃基、噻吩基、萘基、喹啉基、吲哚基、苯并呋喃基、苯并噻吩基、苯乙烯基,C1-C6的直链或支链烷基;
R1、R6、R7独立的选自:H,-CH3、-COCH3、-COOC(CH3)3;
R2、R3、R4、R5独立的选自:H、卤素、OH、SH、NH2、COOH、醛基、氨基甲酰基、NO2、CN、-CH3、-C2H5、-OCH3、-OC2H5;
R8独立的选自:H、C1-C4直链或支链的烷基、-COCH3、-COOC(CH3)3;
R10表示一个或多个取代基、这些取代基可以和环在任意适宜的位置相连接,这些取代基独立的选自H、OH、SH、NH2、CF3、COOH、醛基、氨基甲酰基、卤素、NO2、CN、C1-C4直链或支链的烷基、C1-C4直链或支链烷氧基、C1-C4直链或支链烷基胺基、C2-C4直链或支链烯基、C2-C3炔基。
3.根据权利要求2中的化合物或其药学上可接受的盐,其特征在于,所述的化合物如式IA1所示
R1、R6、R7独立的选自:H,-CH3、-COCH3、-COOC(CH3)3;
R2、R3、R4、R5独立的选自:H、卤素、OH、SH、NH2、COOH、醛基、氨基甲酰基、NO2、CN、-CH3、-C2H5、-OCH3、-OC2H5;
R8独立的选自:H、C1-C4直链或支链的烷基、-COCH3、-COOC(CH3)3;
R101选自H、OH、SH、NH2、COOH、CF3、醛基、氨基甲酰基、F、Cl、Br、I、NO2、CN、C1-C4直链或支链的烷基、C1-C4直链或支链烷氧基、C1-C4直链或支链烷基胺基、C2-C4直链或支链烯基、C2-C3炔基;当苯环上为双取代时,相邻的两个取代基可以相互连接成C5-C6环烷基并苯基。
4.根据权利要求2中的化合物或其药学上可接受的盐,其特征在于,所述的化合物如式IA2所示
R1、R6、R7独立的选自:H,-CH3、-COCH3、-COOC(CH3)3;
R2、R3、R4、R5独立的选自:H、卤素、OH、SH、NH2、COOH、醛基、氨基甲酰基、NO2、CN、-CH3、-C2H5、-OCH3、-OC2H5;
R8独立的选自:H、C1-C4直链或支链的烷基、-COCH3、-COOC(CH3)3;
R102选自H、OH、SH、NH2、COOH、CF3、醛基、氨基甲酰基、F、Cl、Br、I、NO2、CN、C1-C4直链或支链的烷基、C1-C4直链或支链烷氧基、C1-C4直链或支链烷基胺基、C2-C4直链或支链烯基、C2-C3炔基。
5.根据权利要求2中的化合物或其药学上可接受的盐,其特征在于,所述的化合物如式IA3所示
R1、R6、R7独立的选自:H,-CH3、-COCH3、-COOC(CH3)3;
R2、R3、R4、R5独立的选自:H、卤素、OH、SH、NH2、COOH、醛基、氨基甲酰基、NO2、CN、-CH3、-C2H5、-OCH3、-OC2H5;
R8独立的选自:H、C1-C4直链或支链的烷基、-COCH3、-COOC(CH3)3;
R103选自H、OH、SH、NH2、COOH、CF3、醛基、氨基甲酰基、F、Cl、Br、I、NO2、CN、C1-C4直链或支链的烷基、C1-C4直链或支链烷氧基、C1-C4直链或支链烷基胺基、C2-C4直链或支链烯基、C2-C3炔基。
6.根据权利要求2中的化合物或其药学上可接受的盐,其特征在于,所述的化合物如式IA4所示
R1、R6、R7独立的选自:H,-CH3、-COCH3、-COOC(CH3)3;
R2、R3、R4、R5独立的选自:H、卤素、OH、SH、NH2、COOH、醛基、氨基甲酰基、NO2、CN、-CH3、-C2H5、-OCH3、-OC2H5;
R8独立的选自:H、C1-C4直链或支链的烷基、-COCH3、-COOC(CH3)3;
R104选自H、OH、SH、NH2、COOH、CF3、醛基、氨基甲酰基、F、Cl、Br、I、NO2、CN、C1-C4直链或支链的烷基、C1-C4直链或支链烷氧基、C1-C4直链或支链烷基胺基、C2-C4直链或支链烯基、C2-C3炔基。
7.根据权利要求2中的化合物或其药学上可接受的盐,其特征在于,所述的化合物如式IA5所示
R1、R6、R7独立的选自:H,-CH3、-COCH3、-COOC(CH3)3;
R2、R3、R4、R5独立的选自:H、卤素、OH、SH、NH2、COOH、醛基、氨基甲酰基、NO2、CN、-CH3、-C2H5、-OCH3、-OC2H5;
R8独立的选自:H、C1-C4直链或支链的烷基、-COCH3、-COOC(CH3)3;
R105选自H、OH、SH、NH2、COOH、CF3、醛基、氨基甲酰基、F、Cl、Br、I、NO2、CN、C1-C4直链或支链的烷基、C1-C4直链或支链烷氧基、C1-C4直链或支链烷基胺基、C2-C4直链或支链烯基、C2-C3炔基。
8.根据权利要求2中的化合物或其药学上可接受的盐,其特征在于,所述的化合物如式IA6所示
R1、R6、R7独立的选自:H,-CH3、-COCH3、-COOC(CH3)3;
R2、R3、R4、R5独立的选自:H、卤素、OH、SH、NH2、COOH、醛基、氨基甲酰基、NO2、CN、-CH3、-C2H5、-OCH3、-OC2H5;
R8独立的选自:H、C1-C4直链或支链的烷基、-COCH3、-COOC(CH3)3;
R106选自H、OH、SH、NH2、COOH、CF3、醛基、氨基甲酰基、F、Cl、Br、I、NO2、CN、C1-C4直链或支链的烷基、C1-C4直链或支链烷氧基、C1-C4直链或支链烷基胺基、C2-C4直链或支链烯基、C2-C3炔基。
9.根据权利要求2中的化合物或其药学上可接受的盐,其特征在于,所述的化合物如式IA7所示
R1、R6、R7独立的选自:H,-CH3、-COCH3、-COOC(CH3)3;
R2、R3、R4、R5独立的选自:H、卤素、OH、SH、NH2、COOH、醛基、氨基甲酰基、NO2、CN、-CH3、-C2H5、-OCH3、-OC2H5;
R8独立的选自:H、C1-C4直链或支链的烷基、-COCH3、-COOC(CH3)3;
R107选自H、OH、SH、NH2、COOH、CF3、醛基、氨基甲酰基、F、Cl、Br、I、NO2、CN、C1-C4直链或支链的烷基、C1-C4直链或支链烷氧基、C1-C4直链或支链烷基胺基、C2-C4直链或支链烯基、C2-C3炔基;
R’为H、C1-C4直链或支链的烷基。
10.根据权利要求2中的化合物或其药学上可接受的盐,其特征在于,所述的化合物如式IA8所示
R1、R6、R7独立的选自:H,-CH3、-COCH3、-COOC(CH3)3;
R2、R3、R4、R5独立的选自:H、卤素、OH、SH、NH2、COOH、醛基、氨基甲酰基、NO2、CN、-CH3、-C2H5、-OCH3、-OC2H5;
R8独立的选自:H、C1-C4直链或支链的烷基、-COCH3、-COOC(CH3)3;
R108选自H、OH、SH、NH2、COOH、CF3、醛基、氨基甲酰基、F、Cl、Br、I、NO2、CN、C1-C4直链或支链的烷基、C1-C4直链或支链烷氧基、C1-C4直链或支链烷基胺基、C2-C4直链或支链烯基、C2-C3炔基。
11.根据权利要求2中的化合物或其药学上可接受的盐,其特征在于,所述的化合物如式IA9所示
R1、R6、R7独立的选自:H,-CH3、-COCH3、-COOC(CH3)3;
R2、R3、R4、R5独立的选自:H、卤素、OH、SH、NH2、COOH、醛基、氨基甲酰基、NO2、CN、-CH3、-C2H5、-OCH3、-OC2H5;
R8独立的选自:H、C1-C4直链或支链的烷基、-COCH3、-COOC(CH3)3;
R109选自H、OH、SH、NH2、COOH、CF3、醛基、氨基甲酰基、F、Cl、Br、I、NO2、CN、C1-C4直链或支链的烷基、C1-C4直链或支链烷氧基、C1-C4直链或支链烷基胺基、C2-C4直链或支链烯基、C2-C3炔基。
12.根据权利要求2中的化合物或其药学上可接受的盐,其特征在于,所述的化合物如式IA10所示
R1、R6、R7独立的选自:H,-CH3、-COCH3、-COOC(CH3)3;
R2、R3、R4、R5独立的选自:H、卤素、OH、SH、NH2、COOH、醛基、氨基甲酰基、NO2、CN、-CH3、-C2H5、-OCH3、-OC2H5;
R8独立的选自:H、C1-C4直链或支链的烷基、-COCH3、-COOC(CH3)3;
R1010选自H、OH、SH、NH2、COOH、CF3、醛基、氨基甲酰基、F、Cl、Br、I、NO2、CN、C1-C4直链或支链的烷基、C1-C4直链或支链烷氧基、C1-C4直链或支链烷基胺基、C2-C4直链或支链烯基、C2-C3炔基。
13.根据权利要求2中的化合物或其药学上可接受的盐,其特征在于,所述的化合物如式IA11所示
R1、R6、R7独立的选自:H,-CH3、-COCH3、-COOC(CH3)3;
R2、R3、R4、R5独立的选自:H、卤素、OH、SH、NH2、COOH、醛基、氨基甲酰基、NO2、CN、-CH3、-C2H5、-OCH3、-OC2H5;
R8独立的选自:H、C1-C4直链或支链的烷基、-COCH3、-COOC(CH3)3;
R1011选自H、OH、SH、NH2、COOH、CF3、醛基、氨基甲酰基、F、Cl、Br、I、NO2、CN、C1-C4直链或支链的烷基、C1-C4直链或支链烷氧基、C1-C4直链或支链烷基胺基、C2-C4直链或支链烯基、C2-C3炔基。
14.根据权利要求2中的化合物或其药学上可接受的盐,其特征在于,所述的化合物如式IA12所示
R1、R6、R7独立的选自:H,-CH3、-COCH3、-COOC(CH3)3;
R2、R3、R4、R5独立的选自:H、卤素、OH、SH、NH2、COOH、醛基、氨基甲酰基、NO2、CN、-CH3、-C2H5、-OCH3、-OC2H5;
R8独立的选自:H、C1-C4直链或支链的烷基、-COCH3、-COOC(CH3)3;
R1012选自C1-C6的直链或支链的烷基。
15.根据权利要求1中任一项的化合物或其药学上可接受的盐,其特征在于,所述的化合物如式IB所示
所述的选自苯基、吡啶基、呋喃基、噻吩基、萘基、喹啉基、吲哚基、苯并呋喃基、苯并噻吩基、苯乙烯基,C1-C6的直链或支链烷基;
R1、R6、R7独立的选自:H,-CH3、-COCH3、-COOC(CH3)3;
R2、R3、R4、R5独立的选自:H、卤素、OH、SH、NH2、COOH、醛基、氨基甲酰基、NO2、CN、-CH3、-C2H5、-OCH3、-OC2H5;
R8独立的选自:H、C1-C4直链或支链的烷基、-COCH3、-COOC(CH3)3;
R11表示一个或多个取代基、这些取代基可以和环在任意适宜的位置相连接,这些取代基独立的选自H、OH、SH、NH2、CF3、COOH、醛基、氨基甲酰基、卤素、NO2、CN、C1-C4直链或支链的烷基、C1-C4直链或支链烷氧基、C1-C4直链或支链烷基胺基、C2-C4直链或支链烯基、C2-C3炔基。
16.根据权利要求15中的化合物或其药学上可接受的盐,其特征在于,所述的化合物如式IB1所示
R1、R6、R7独立的选自:H,-CH3、-COCH3、-COOC(CH3)3;
R2、R3、R4、R5独立的选自:H、卤素、OH、SH、NH2、COOH、醛基、氨基甲酰基、NO2、CN、-CH3、-C2H5、-OCH3、-OC2H5;
R8独立的选自:H、C1-C4直链或支链的烷基、-COCH3、-COOC(CH3)3;
R111选自H、OH、SH、NH2、COOH、CF3、醛基、氨基甲酰基、F、Cl、Br、I、NO2、CN、C1-C4直链或支链的烷基、C1-C4直链或支链烷氧基、C1-C4直链或支链烷基胺基、C2-C4直链或支链烯基、C2-C3炔基;当苯环上为双取代时,相邻的两个取代基可以相互连接成C5-C6环烷基并苯基。
17.根据权利要求15中的化合物或其药学上可接受的盐,其特征在于,所述的化合物如式IB2所示
R1、R6、R7独立的选自:H,-CH3、-COCH3、-COOC(CH3)3;
R2、R3、R4、R5独立的选自:H、卤素、OH、SH、NH2、COOH、醛基、氨基甲酰基、NO2、CN、-CH3、-C2H5、-OCH3、-OC2H5;
R8独立的选自:H、C1-C4直链或支链的烷基、-COCH3、-COOC(CH3)3;
R112选自H、OH、SH、NH2、COOH、CF3、醛基、氨基甲酰基、F、Cl、Br、I、NO2、CN、C1-C4直链或支链的烷基、C1-C4直链或支链烷氧基、C1-C4直链或支链烷基胺基、C2-C4直链或支链烯基、C2-C3炔基。
18.根据权利要求15中的化合物或其药学上可接受的盐,其特征在于,所述的化合物如式IB3所示
R1、R6、R7独立的选自:H,-CH3、-COCH3、-COOC(CH3)3;
R2、R3、R4、R5独立的选自:H、卤素、OH、SH、NH2、COOH、醛基、氨基甲酰基、NO2、CN、-CH3、-C2H5、-OCH3、-OC2H5;
R8独立的选自:H、C1-C4直链或支链的烷基、-COCH3、-COOC(CH3)3;
R113选自H、OH、SH、NH2、COOH、CF3、醛基、氨基甲酰基、F、Cl、Br、I、NO2、CN、C1-C4直链或支链的烷基、C1-C4直链或支链烷氧基、C1-C4直链或支链烷基胺基、C2-C4直链或支链烯基、C2-C3炔基。
19.根据权利要求15中的化合物或其药学上可接受的盐,其特征在于,所述的化合物如式IB4所示
R1、R6、R7独立的选自:H,-CH3、-COCH3、-COOC(CH3)3;
R2、R3、R4、R5独立的选自:H、卤素、OH、SH、NH2、COOH、醛基、氨基甲酰基、NO2、CN、-CH3、-C2H5、-OCH3、-OC2H5;
R8独立的选自:H、C1-C4直链或支链的烷基、-COCH3、-COOC(CH3)3;
R114选自H、OH、SH、NH2、COOH、CF3、醛基、氨基甲酰基、F、Cl、Br、I、NO2、CN、C1-C4直链或支链的烷基、C1-C4直链或支链烷氧基、C1-C4直链或支链烷基胺基、C2-C4直链或支链烯基、C2-C3炔基。
20.根据权利要求15中的化合物或其药学上可接受的盐,其特征在于,所述的化合物如式I B5所示
R1、R6、R7独立的选自:H,-CH3、-COCH3、-COOC(CH3)3;
R2、R3、R4、R5独立的选自:H、卤素、OH、SH、NH2、COOH、醛基、氨基甲酰基、NO2、CN、-CH3、-C2H5、-OCH3、-OC2H5;
R8独立的选自:H、C1-C4直链或支链的烷基、-COCH3、-COOC(CH3)3;
R115选自H、OH、SH、NH2、COOH、CF3、醛基、氨基甲酰基、F、Cl、Br、I、NO2、CN、C1-C4直链或支链的烷基、C1-C4直链或支链烷氧基、C1-C4直链或支链烷基胺基、C2-C4直链或支链烯基、C2-C3炔基。
21.根据权利要求15中的化合物或其药学上可接受的盐,其特征在于,所述的化合物如式IB6所示
R1、R6、R7独立的选自:H,-CH3、-COCH3、-COOC(CH3)3;
R2、R3、R4、R5独立的选自:H、卤素、OH、SH、NH2、COOH、醛基、氨基甲酰基、NO2、CN、-CH3、-C2H5、-OCH3、-OC2H5;
R8独立的选自:H、C1-C4直链或支链的烷基、-COCH3、-COOC(CH3)3;
R116选自H、OH、SH、NH2、COOH、CF3、醛基、氨基甲酰基、F、Cl、Br、I、NO2、CN、C1-C4直链或支链的烷基、C1-C4直链或支链烷氧基、C1-C4直链或支链烷基胺基、C2-C4直链或支链烯基、C2-C3炔基。
22.根据权利要求15中的化合物或其药学上可接受的盐,其特征在于,所述的化合物如式I B7所示
R1、R6、R7独立的选自:H,-CH3、-COCH3、-COOC(CH3)3;
R2、R3、R4、R5独立的选自:H、卤素、OH、SH、NH2、COOH、醛基、氨基甲酰基、NO2、CN、-CH3、-C2H5、-OCH3、-OC2H5;
R8独立的选自:H、C1-C4直链或支链的烷基、-COCH3、-COOC(CH3)3;
R117选自:H、C1-C6的直链或支链的烷基。
23.根据权利要求1-22中任一项的化合物或其药学上可接受的盐,其特征在于所述的化合物选自:
24.一种药物组合物,其特征在于,含有权利要求1-23中任一项所述的化合物或其药学上可接受的盐,及药学上可接受的载体或联合给药的其它活性成分。
25.权利要求1-23中任一项的化合物或其药学上可接受的盐在制备治疗癌症药物中的应用,其中,所述癌症选自:白血病、黑色素瘤、胃癌、肺癌、乳腺癌、肾癌、肝癌、口腔表皮癌、宫颈癌、卵巢癌、胰腺癌、前列腺癌或结肠癌。
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