CN105121433B - 抗病毒化合物、其药学上可接受的盐或光学异构体、用于制备它们的方法以及包含它们作为有效成分的用于预防或治疗病毒性疾病的药物组合物 - Google Patents
抗病毒化合物、其药学上可接受的盐或光学异构体、用于制备它们的方法以及包含它们作为有效成分的用于预防或治疗病毒性疾病的药物组合物 Download PDFInfo
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- CN105121433B CN105121433B CN201380073105.3A CN201380073105A CN105121433B CN 105121433 B CN105121433 B CN 105121433B CN 201380073105 A CN201380073105 A CN 201380073105A CN 105121433 B CN105121433 B CN 105121433B
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- indenos
- dihydro
- oxos
- benzofuran
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Classifications
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Abstract
本发明涉及一种新型化合物、其药学上可接受的盐或光学异构体,制备它们的方法以及包含它们作为有效成分的预防或治疗病毒性疾病的药物组合物。依据本发明的新型化合物不仅具有低的细胞毒性,而且具有极好的对抗包括柯萨基病毒、肠病毒、艾柯病毒、脊髓灰质炎病毒和鼻病毒的小核糖核酸病毒的抗病毒活性,因此其可用作预防或治疗病毒性疾病的药物组合物,所述病毒性疾病如脊髓灰质炎、急性出血性结膜炎、病毒性脑膜炎、手足口病、水疱病、甲型肝炎、肌炎、心肌炎、胰腺炎、糖尿病、流行性肌痛、脑炎、感冒、疱疹性咽峡炎、口蹄疫疾病、哮喘、慢性阻塞性肺病、肺炎、鼻窦炎或中耳炎。
Description
技术领域
本发明涉及新型化合物、其药学上可接受的盐或光学异构体、用于制备它们的方法以及包含它们作为有效成分的用于预防或治疗病毒性疾病的药物组合物。
背景技术
小核糖核酸病毒是具有长为7.2-8.5Kb的RNA基因组的无包膜的正单链RNA病毒。这些病毒非常小,呈球状,大小约22-30nm,且很久前即被首次确认。属于小核糖核酸病毒科的病毒为肠病毒属,包括鼻病毒、脊髓灰质炎病毒、柯萨基病毒A、柯萨基病毒B、艾柯病毒以及甲肝病毒。
小核糖核酸病毒和RNA病毒引起的疾病有多种,覆盖范围从呼吸道疾病到消化道疾病、循环系统疾病,再到皮肤类疾病,其实例包括脊髓灰质炎、急性出血性结膜炎、病毒性脑膜炎、手足口病、水疱病、甲型肝炎、肌炎、心肌炎、胰腺炎、糖尿病、流行性肌痛、脑炎、流感、疱疹性咽峡炎和口蹄疫疾病。然而,尚没有治疗这些疾病的治疗制剂。处于研发阶段的大部分药物为脱壳抑制剂。属于小核糖核酸病毒科的病毒会引起包括前述的呼吸道疾病在内的多种疾病,其会引发卫生、社会和经济问题。小核糖核酸病毒是水源性疾病的主要病原体。其十分稳定,难以杀灭,不断地引起相关的病毒性疾病。
人鼻病毒(hRV)最近已经与大多数哮喘急性发作有关,并且被认为甚至存在于许多稳定的哮喘病人的支气管组织中。取自哮喘病人和非哮喘病人的各自的支气管粘膜活检标本的对照显示:与非哮喘病人相比较,哮喘病人下呼吸道中更极高频率地检测出人鼻病毒。目前也已经报道,鼻病毒的存在与哮喘的临床严重程度相关。此外,人鼻病毒会引起慢性阻塞性肺病、肺炎、鼻窦炎、中耳炎以及哮喘。
鼻病毒是普通感冒的主要病因,而肠病毒诱导的疾病包括脑膜炎、呼吸道感染等。提供对抗脊髓灰质炎病毒的疫苗付出的广泛努力已经显著降低世界各地脊髓灰质炎的发作,但在尼日尔、尼日利亚、埃及、印度、巴基斯坦和阿富汗仍然有该疾病病例的报道。甲型肝炎现在在一定程度上可以控制,归因于甲型肝炎病毒的疫苗。然而,迄今为止尚未开发出柯萨基病毒、艾柯病毒或鼻病毒的疫苗。
特别地,柯萨基病毒B是引起心肌炎的主要病因,严重情况下其可能会发展成需要心脏移植的特发性扩张性心肌病。
恩韦肟衍生物被认为是最有前景的候选药,其具有广泛的抗肠病毒活性和抗鼻病毒活性。恩韦肟通过结合至病毒复制中用于形成RNA中间体所需的病毒蛋白3A而干扰正链RNA的合成(Heinz B A and Vance L M:J Virol,1995,69(7),4189-97)。然而,在临床研究中观测到该化合物具有很小或几乎没有治疗效果,检测到其药代动力学不充分,并且检测到不想要的副作用(Miller F D等人:Antimicrob Agents Chemother,1985,27(1),102-6)。
已经基于对病毒蛋白酶2C的复杂结构和功能的了解开发了蛋白酶抑制剂AG7088。在纳摩尔级浓度范围内的细胞培养基中,AG7088已经显示出对抗48种鼻病毒类型和柯萨基病毒A21、B3,肠病毒70以及艾柯病毒11(Pattick AK等人:Antimicrobila AgentsChemother,1999,43(10),2444-50)的作用。
由于病毒衣壳分子结构的清晰化,已经得到用于设计衣壳阻断剂为目的的先决条件——“WIN物质”(Diana GD:Curr Med Chem 2003,2,1-12)。它们会抑制鼻病毒和肠病毒的吸附和/或脱壳。一些WIN物质仅对小核糖核酸病毒的个别种类或病毒类型有高的特异性作用。其他衍生物既抑制鼻病毒又抑制肠病毒的复制。如阿立酮、二恶沙利以及吡罗达韦就属于WIN物质。这些化合物在细胞培养基中显示出非常好的抗病毒作用。然而,差的溶解度(阿立酮)、低的生物利用度(阿立酮和二恶沙利)、快的新陈代谢和排泄(二恶沙利和WIN54954)以及副作用,如皮疹(WIN54954)使得无法进行临床应用。
普拉康纳利(Pleconaril),另外一种类型的WIN物质,具有非常好的口服生物利用度,并且其结合至病毒壳体内的疏水性口袋后会抑制鼻、艾柯(echo)和柯萨基病毒(PevearDC等人:Antimicrob Agents Chemother 1999,43(9),2109-15;McKinlay MA等人:AnnuRev Microbiol 1992,46,635-54)的渗透。因此,普拉康纳利对广谱病毒性疾病,从普通感冒到病毒性脑膜炎或心肌炎有潜在的作用。观察到其对鼻病毒、肠病毒71和柯萨基病毒B3有抗性(Ledford RM等人:J Virol 2004,78(7),3663-74;Groarke JM等人:J Infect Dis1999,179(6),1538-41)。然而,所证明的疗效并不足以使普拉康纳利在美国注册(Picovir,Viropharma,USA)为用于治疗鼻病毒感染的制剂。2002年3月,相应的申请被食品药品管理局(FDA)拒绝,这是因为其治疗成功率太低且观测到有副作用。
当评估BTA-798对鼻病毒的体内和体外功效时,发现其比普拉康纳利具有更高的抗病毒活性,并且现在已处于临床研究(Ryan,J.等人,Antiviral Res[18th Intl ConfAntiviral Res(April 11-14,Barcelona)2005]2005,65(3):Abst LB-11)。
然而,已经开发的用于治疗肠病毒或鼻病毒的抗病毒药物尚未获得批准。
因此,本发明的发明人在研究对抗包括柯萨基病毒、肠病毒、艾柯病毒和脊髓灰质炎病毒的小核糖核酸病毒时合成了本说明书的式1所示的新型化合物并证实了所述化合物具有很好的对抗包括柯萨基病毒、肠病毒、艾柯病毒和脊髓灰质炎病毒的小核糖核酸病毒的抗病毒活性,从而完成了本发明。
发明内容
技术目的
本发明的目的在于提供本说明书式1或式2所示的化合物,以及其药学上可接受的盐或光学异构体。
本发明的另一个目的在于提供一种用于制备上述式1或式2所示的化合物的方法。
本发明的又一个目的在于提供一种包含所述化合物、其药学上可接受的盐或光学异构体作为有效成分的用于预防或治疗病毒性疾病的药物组合物。
技术方案
为实现以上目的,本发明提供以下式1或式2所示的化合物、其药学上可接受的盐或光学异构体。
[式1]
[式2]
在以上式1和式2中,
R1、R2、R3、R4a、R4b、R4c和R4d,X、L以及R5分别如本说明书中所定义的,以上式1和式2所示的化合物彼此以平衡状态存在。
此外,如以下反应方程式1所示,本发明提供一种用于制备以上式1或式2所示的化合物的方法,该方法包括如下步骤(步骤1):将式3或式4所示的化合物以及式5所示的化合物置于有反应催化剂的溶剂中,然后搅拌。
[反应方程式1]
在以上反应方程式1中,
Xa为–OH或–NH2,
R1、R2、R3、R4a、R4b、R4c和R4d,R5、X以及L分别如以上式1和式2中所定义的。
另外,本发明提供一种包含以上式1或式2所示的化合物、其药学上可接受的盐或其光学异构体作为有效成分的用于预防或治疗病毒性疾病的药物组合物。
有益效果
根据本发明,彼此以相互平衡状态存在的式1或式2所示的化合物不仅具有低的细胞毒性,而且具有极好的对抗包括柯萨基病毒、肠病毒、艾柯病毒、脊髓灰质炎病毒和鼻病毒的小核糖核酸病毒的抗病毒活性,因此其可用作用于预防或治疗病毒性疾病的药物组合物,所述病毒性疾病包括脊髓灰质炎、急性出血性结膜炎、病毒性脑膜炎、手足口病、水疱病、甲型肝炎、肌炎、心肌炎、胰腺炎、糖尿病、流行性肌痛、脑炎、流感、疱疹性咽峡炎、口蹄疫疾病、哮喘、慢性阻塞性肺病、肺炎、鼻窦炎或中耳炎。
本发明的最佳实施方式
下面对本发明进行详细描述。
本发明提供如下式1或式2所示的化合物、其药学上可接受的盐或其光学异构体。
[式1]
[式2]
在以上式1和式2中,
R1为–H、直链或支链的C1-6烷基或者–NO2;
R2为–H、直链或支链的C1-6烷基或者–NH2;
R3为–H,或者直链或支链的C1-6烷基;
R4a、R4b、R4c和R4d独立地为–H或者直链或支链的C1-6烷基;
X为-O-,-NH-或–NR6-,其中R6为直链或支链的C1-6烷基;
L为单键,
其中R11为=O、=NH或=S,且a、b、c、d、e独立地为0-5的整数;
R5为–CN;直链或支链的C1-10烷基;直链或支链的C1-10卤代烷基;苯基;苯基直链或支链的C1-6烷基;苯基直链或支链的C1-6烯基;5-6原子的杂芳基,包括一个或多个选自N、O和S中的一种或多种杂原子;5-8原子的杂环烷基,包括一个或多个选自N、O和S中的一种或多种杂原子;5-8原子的杂环烯基,包括一个或多个选自N、O和S中的一种或多种杂原子;
其中,在苯基、苯基直链或支链的C1-6烷基和苯基直链或支链的C1-6烯基中,苯基基团可以用一个或多个选自-OH、卤素、直链或支链的C1-6烷基、直链或支链的C1-6烷氧基和-NO2中的一种或多种取代基取代;
其中,杂芳基、杂环烷基和杂环烯基可以被一个或多个选自-OH、卤素以及直链或支链的C1-6烷基中的一种或多种取代基取代,
R7和R8独立地为-H、直链或支链的C1-6烷基、未被取代的苯基、以一个或多个直链或支链的C1-6烷基取代的苯基,
R9、R10和R11独立地为-H或直链或支链的C1-10烷基,
Z为-O-或-S-,
f、g、h和i独立地为0-5的整数;
以上式1所示的化合物和式2所示的化合物彼此以平衡状态存在。
优选地,
R1为-H、直链或支链的C1-3烷基或-NO2;
R2为-H、直链或支链的C1-3烷基或-NH2;
R3为-H或直链或支链的C1-3烷基;
R4a、R4b、R4c和R4d独立地为-H或直链或支链的C1-4烷基;
X为-O-、-NH-或–NR6-,其中R6为直链或支链的C1-3烷基;
L为单键、其中R11为=O、=NH或=S,其中a、b、c、d和e独立地为0-3的整数;
R5为–CN;直链或支链的C1-8烷基;直链或支链的C1-8卤代烷基;苯基;苯基直链或支链的C1-3烷基;苯基直链或支链的C1-3烯基;包括一个或多个选自N、O和S中的一种或多种杂原子的5-6原子的杂芳基;包括一个或多个选自N、O和S中的一种或多种杂原子的5-6原子的杂环烷基;包括一个或多个选自N、O和S中的一种或多种杂原子的5-6原子的杂环烯基;
其中,在苯基、苯基C直链或支链的1-3烷基和苯基直链或支链的C1-3烯基中,苯基可用一个或多个选自-OH、卤素、直链或支链的C1-3烷基、直链或支链的C1-3烷氧基以及-NO2中的一种或多种取代基取代;
其中,杂芳基、杂环烷基和杂环烯基中可以被选自-OH、卤素以及直链或支链的C1-3烷基中的一个或多个取代基取代,
R7和R8独立地为-H、直链或支链的C1-4烷基、未被取代的苯基或被一个或多个直链或支链的C1-3烷基取代的苯基,
R9、R10和R11独立地为-H或直链或支链的C1-6烷基,
Z为-O-或-S-,
f、g、h和i独立地为0-3的整数。
更优选地,
R1为-H或-NO2;
R2为-H或-NH2;
R3为-H或甲基;
R4a、R4b、R4c和R4d独立地为-H、甲基或异丙基;
X为-O-、-NH-或–N(CH3)-;
L为单键,
R5为–CN;直链或支链的C1-6烷基;直链的C1-2卤代烷基;苯基;苯基直链的C1-2烷基;苯基直链的C2烯基;包括一个或多个选自N、O和S中的一种或多种杂原子的5-6原子的杂芳基;包括一个或多个选自N、O和S中的一种或多种杂原子的6原子杂环烷基;包括一个或多个选自N、O和S中的一种或多种杂原子的5原子的杂环烯基;
其中,在苯基、苯基直链的C1-2烷基、苯基直链的C2烯基中,苯基可以用一个或多个选自-OH、甲基、甲氧基和-NO2中的一种或多种取代基取代;
其中,杂环烷基可以被甲基取代,
R7和R8独立地为-H、甲基、乙基、丙基、异丙基、二甲基苯基、
R9、R10和R11独立地为-H、甲基、乙基或叔丁基,
Z为-O-或-S-,
f、g、h和i独立地为0-2的整数。
上式1所示的化合物的实例可包括以下化合物:
1)N-(4b-羟基-7-异丙基-10-氧代-9b,10-二氢-4bH-苯并[d]茚并[1,2-b]呋喃-9b-基)-2-(1H-吲哚-3-基)-2-氧代乙酰胺;
2)N-(4b-羟基-7-异丙基-10-氧代-9b,10-二氢-4bH-茚并[1,2-b]苯并呋喃-9b-基)-2-氧代-2-(噻吩-2-基)乙酰胺;
3)N-(4b-羟基-7-异丙基-10-氧代-9b,10-二氢-4bH-茚并[1,2-b]苯并呋喃-9b-基)-3-(2-硝基苯基)-2-氧代丙酰胺;
4)N-(4b-羟基-7-异丙基-10-氧代-9b,10-二氢-4bH-茚并[1,2-b]苯并呋喃-9b-基)-2-氧代丙酰胺;
5)N-(4b-羟基-7-异丙基-10-氧代-9b,10-二氢-4bH-茚并[1,2-b]苯并呋喃-9b-基)-2-氧代戊酰胺;
6)N-(4b-羟基-7-异丙基-10-氧代-9b,10-二氢-4bH-茚并[1,2-b]苯并呋喃-9b-基)-2-氧代辛酰胺;
7)2-(呋喃-2-基)-6)N-(4b-羟基-7-异丙基-10-氧代-9b,10-二氢-4bh-茚并[1,2-b]苯并呋喃-9b-基)-2-氧代乙酰胺;
8)N-(4b-羟基-7-异丙基-4-硝基-10-氧代-9b,10-二氢-4bH-茚并[1,2-b]苯并呋喃-9b-基)-2-(1H-吲哚-3-基)-2-氧代乙酰胺;
9)N-(4b-羟基-7-异丙基-10-氧代-9b,10-二氢-4bH-茚并[1,2-b]苯并呋喃-9b-基)-3-(4-羟苯基)-2-氧代丙酰胺;
10)N-(1-氨基-4b-羟基-7-异丙基-10-氧代-9b,10-二氢-4bH-茚并[1,2-b]苯并呋喃-9b-基)-2-(1H-吲哚-3-基)-2-氧代乙酰胺;
11)N-(1-氨基-4b-羟基-7-异丙基-10-氧代-9b,10-二氢-4bH-茚并[1,2-b]苯并呋喃-9b-基)-2-氧代-2-苯基乙酰胺;
12)N-(4b-羟基-7,8-二甲基-10-氧代-9b,10-二氢-4bH-茚并[1,2-b]苯并呋喃-9b-基)-2-氧代-2-苯基乙酰胺;
13)N-(4b-羟基-7,8-二甲基-10-氧代-9b,10-二氢-4bH-茚并[1,2-b]苯并呋喃-9b-基)-(1H-吲哚-3-基)-2-氧代乙酰胺;
14)N-(4b-羟基-7,8-二甲基-10-氧代-9b,10-二氢-4bH-茚并[1,2-b]苯并呋喃-9b-基)-2-(1H-吲哚-3-基)-2-氧代丙酰胺;
15)N-(4b-羟基-7-异丙基-10-氧代-9b,10-二氢-4bH-茚并[1,2-b]苯并呋喃-9b-基)-2-氧代-2-苯基乙酰胺;
16)N-(4b-羟基-7-异丙基-4-硝基-10-氧代-9b,10-二氢-4bH-茚并[1,2-b]苯并呋喃-9b-基)-2-氧代-2-苯基乙酰胺;
17)N-(4b-羟基-7-异丙基-10-氧代-9b,10-二氢-4bH-茚并[1,2-b]苯并呋喃-9b-基)-4-(甲硫基)-2-氧代丁酰胺;
18)4b-羟基-7-异丙基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)丙基氨基甲酸酯;
19)N-(4b-羟基-7-异丙基-4-硝基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)-2-氧代丙酰胺;
20)N1-(2,6-二甲基苯基)-N2-(4b-羟基-7-异丙基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)草酰胺;
21)N1-(4b-羟基-7-异丙基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)-N2,N2-二甲基草酰胺;
22)N-(1-氨基-4b-羟基-7-异丙基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)-2-氧代丙酰胺;
23)N-(4b-羟基-7-异丙基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)-2-氧代-2-(3,4,5-三甲氧基苯基)乙酰胺;
24)(E)-4-(3,4-二甲氧基苯基)-N-(4b-羟基-7-异丙基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)-2-氧代-3-丁酰胺;
25)N-(4b-羟基-7-异丙基-4-硝基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)-3-(2-硝基苯基)-2-氧代丙酰胺;
26)N1-(2,6-二甲基苯基)-N2-(4b-羟基-7-异丙基-4-硝基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)草酰胺;
27)N1-(4b-羟基-7-异丙基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)-N2-甲基草酰胺;
28)N-(4b-羟基-7-异丙基-4-硝基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)-3-甲基-2-氧代戊酰胺;
29)N-(4b-羟基-7-异丙基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)-3-甲基-2-氧代戊酰胺;
30)N1-(4b-羟基-7-异丙基-4-硝基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)-N2-N2-二甲基草酰胺;
31)N1-(1-氨基-4b-羟基-7-异丙基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)-N2-N2-二甲基草酰胺;
32)2-((4b-羟基-7-异丙基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)氨基)-2-氧代乙酸乙酯;
33)2-((4b-羟基-7-异丙基-4-硝基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)氨基)-2-氧代乙酸乙酯;
34)N-(4b-羟基-7-异丙基-4-硝基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)-2-氧代戊酰胺;
35)N-(4b-羟基-7-异丙基-4-硝基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)-2-氧代辛酰胺;
36)2-((1-氨基-4b-羟基-7-异丙基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)氨基)-2-氧代乙酸乙酯;
37)N-(4b-羟基-7-异丙基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)-3,3-二甲基-2-氧代丁酰胺;
38)N-(4b-羟基-7-异丙基-4-硝基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)-4-甲基-2-氧代戊酰胺;
39)N-(4b-羟基-7-异丙基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)-2-氧代-4-苯基丁酰胺;
40)N-(1-氨基-4b-羟基-7-异丙基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)-3-甲基-2-氧代戊酰胺;
41)3-溴代-N-(4b-羟基-7-异丙基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)-2-氧代丙酰胺;
42)N-(4b-羟基-7-异丙基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)-2,4-二氧代-4-(吡啶-4-基)丁酰胺;
43)4-((4b-羟基-7-异丙基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)氨基)-4-氧代丁酸;
44)N1-(4b-羟基-7-异丙基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)-N4,N4-二甲基琥珀酰胺;
45)N1-(4b-羟基-7-异丙基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)-N4-异丙基琥珀酰胺;
46)N-(4b-羟基-7-异丙基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)氨腈;
47)N1-(4-氨基-(4b-羟基-7-异丙基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)-N2-(2,6-二甲基苯基)草酰胺;
48)N-(4b-羟基-7-异丙基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)-2-(4-甲基哌嗪-1-基)-2-氧代乙酰胺;
49)N-(1-氨基-(4b-羟基-7-异丙基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)-4-甲基-2-氧代戊酰胺;
50)N-(1-氨基-4b-羟基-7-异丙基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)-2-氧代己酰胺;
51)N-(4b-羟基-7-异丙基-1-硝基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)-2均三甲苯基-2-氧代乙酰胺;
52)N-(1-氨基-(4b-羟基-7-异丙基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)-2-氧代戊酰胺;
53)N-(4b-羟基-7-异丙基-4-硝基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)-2-氧代-4-苯基丁酰胺;
54)N-(1-氨基-4b-羟基-7-异丙基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)-2-均三甲苯基-2-氧代乙酰胺;
55)N,N’-二叔丁氧代羰基[1]-(4b-羟基-7-异丙基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)胍;
56)(4b-羟基-7-异丙基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)乙烷-1,2-二基二氨基甲酸叔丁酯;
57)4-((4b-羟基-7-异丙基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)氨基)-4-氧代丁酸;
58)N-(4b-羟基-7-异丙基-4-硝基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)2-氧代-2-(3,4,5-三甲氧基苯基)乙酰胺;
59)N-(4b-羟基-7-异丙基-4-硝基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)-2-氧代-4-苯基丁酰胺;
60)N-(4b-羟基-7-异丙基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)乙酰亚胺酰胺(acetimide amide);
61)1-(4b-羟基-7-异丙基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)硫脲;
62)7-异丙基-4b-甲氧基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基乙基氨基甲酸乙酯;
63)(2-((4b-羟基-7-异丙基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)氨基)-2-氧代乙基)氨基甲酸叔丁酯;
64)2-氨基-N(4b-羟基-7-异丙基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)乙酰胺;
65)4b-羟基-7,8-二甲基-9b-(甲基氨基)-4b,9b-二氢-10H-茚并[1,2-b]苯并呋喃-10-酮;
66)N-叔丁氧基羰基[N3-(4b-羟基-7-异丙基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)]胍;
67)N,N’-二叔丁氧基羰基[1-(4b-羟基-7,8-二甲基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)]-1-甲基胍;
68)N-(4b-羟基-7-异丙基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)噻吩-2-磺酰胺;
69)N-(4b-羟基-7-异丙基-4-硝基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)苯磺酰胺;
70)4b-羟基-7,8-二甲基-9b-(吡啶-2-基氨基)-4b,9b)二氢-10H-茚并[1,2b]苯并呋喃-10-酮;
71)N-(4b-羟基-7-异丙基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)丙烷-1-磺酰胺;
72)1-氯-N-(4b-羟基-7-异丙基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)甲基磺酰胺;
73)9b-((4,5-二氢噻唑基-2-基)氨基)-4b-羟基-7-异丙基-4b,9b-二氢-10H-茚并-[1,2-b]苯并呋喃-10-酮;
74)4b-羟基-7-异丙基-9b-(恶唑-2-基氨基)-4b,9b-二氢-10H-茚并-[1,2-b]苯并呋喃-10-酮;以及
75)4b-羟基-7-异丙基-9b-(吡啶-2-基氨基)-4b,9b-二氢-10H-茚并-[1,2-b]苯并呋喃-10-酮;
本发明上式1或式2所示的化合物可以以药学上可接受的盐的形式使用,由药学上可接受的游离酸形成的酸加成盐是有用的。如果由盐在对病人相对无毒和无害的有效浓度下引起的副作用不会降低式1或式2的碱性化合物的有益效果,“药学上可接受的盐”的表述意指式1或式2的碱性化合物的任何有机或无机盐。
对于有机酸盐,有机酸可用作游离酸,所用的无机酸可包括盐酸、溴酸、硝酸、硫酸、高氯酸以及磷酸,所用有机酸可包括柠檬酸、乙酸、乳酸、马来酸、富马酸、葡萄糖酸、甲磺酸、葡萄糖酸、琥珀酸、酒石酸、半乳糖醛酸、扑酸、谷氨酸、天冬氨酸、草酸、(D)或(L)苹果酸、马来酸、甲磺酸、乙磺酸、4-甲苯磺酸、水杨酸、柠檬酸、苯甲酸、或丙二酸。
此外,此种盐包括碱金属盐(钠盐、钾盐等)和碱土金属盐(钙盐、镁盐等)。如酸加成盐可包括乙酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、碳酸氢盐/碳酸盐、硫酸氢盐/硫酸盐、硼酸盐、樟脑磺酸)、柠檬酸盐、乙二磺酸盐、乙磺酸盐、甲酸盐、延胡索酸盐、葡庚糖酸盐、葡糖酸盐、葡萄糖醛酸盐、六氟磷酸盐、海苯酸盐、盐酸盐/氯化物、氢溴酸盐/溴化盐、氢碘酸盐/碘化盐、羟乙基磺酸盐、乳酸盐、苹果酸盐、马来酸盐、丙二酸盐、甲磺酸盐、甲基硫酸盐、萘盐(naphthylate)、2-萘磺酸盐、烟酸盐、硝酸盐、乳清酸盐、草酸盐、棕榈酸盐、双羟萘酸盐、磷酸盐/磷酸氢盐/磷酸二氢盐、糖酸盐、硬脂酸盐、琥珀酸盐、酒石酸盐、甲苯磺酸盐、三氟乙酸盐、铝盐、精氨酸盐、苄星青霉素盐、钙盐、胆碱盐、二乙胺盐、二乙醇胺盐、甘氨酸盐、赖氨酸盐、镁盐、葡甲胺盐、丙氨酸盐、钾盐、钠盐、氨丁三醇盐和锌盐,其中优选盐酸盐和三氟乙酸盐。
根据本发明的酸加成盐可通过典型方法制备。例如,它们可以通过以下来制备:将式1或式2的化合物溶解于诸如甲醇、乙醇、丙酮、二氯甲烷、乙腈等的有机溶剂中,而后过滤并干燥通过添加有机和或无机酸而形成的沉淀物,或者通过在减压下蒸馏溶剂以及过量的酸,而后在有机溶剂中将其干燥或重结晶。
此外,药学上可接受的金属盐可用底物(bases)制备。比如,碱金属盐或碱土金属盐可通过在过量的碱金属氢氧化物或碱土金属氢氧化物溶液中溶解化合物,过滤未溶解的化合物盐而后蒸发并干燥滤液而获得。此时适于药学上制备钠盐、钾盐或钙盐作为金属盐。此外,通过碱金属盐或碱土金属盐与适合的银盐反应可得到相应的银盐(如硝酸银)。
另外,本发明不仅包括式1或式2所示的化合物及其药学上可接受的盐,还包括可由此制得的溶剂化物、水合物、同分异构体等。
此外,本发明提供一种用于制备上述式1或式2所示的化合物的方法,该方法包括以下反应方程式1所示的步骤(步骤1),将式3或式4所示的化合物以及式5所示的化合物置于具有反应催化剂的溶剂中,然后搅拌。
[反应方程式1]
在以上反应方程式1中,
Xa是–OH或–NH2,
R1、R2、R3、R4a、R4b、R4c、R4d、R5、X和L如以上式1和式2中所定义的。
以下详细描述本发明的制备方法。
在根据本发明的制备方法中,二甲基甲酰胺(DMF)、二氯甲烷(MC)、乙醇、水、二异丙醚、二乙醚、二氧六环、四氢呋喃(THF)、二甲基乙酰胺(DMA)、二甲亚砜(DMSO)、氯苯、甲苯、苯等可以被单独或混合使用,并用作溶剂。
在根据本发明的制备方法中,1-乙基-3-(3-二甲基氨基丙基)碳二亚胺(EDCI)、羟苯并三唑(HOBt)、三乙胺(TEA)、0-(7-偶氮苯并三唑-1-基)-N,N,N’,N’-四甲基脲六氟磷酸酯(HATU)、吡啶、POCl3、Fe、HCl等可以被单独或混合使用,并用作反应催化剂。
在根据本发明的制备方法中,步骤1的反应温度优选0-30℃,反应时间优选1小时至2天但不限于该时间。
另外,本发明提供包含上式1或式2所示的化合物、其药学上可接受的盐或其光学异构体作为有效成分的用于预防或治疗病毒性疾病的药物组合物。
此时,病毒性疾病为由包括柯萨基病毒、肠病毒、脊髓灰质炎病毒和鼻病毒的小核糖核酸病毒引起的疾病。此处,病毒性疾病可以包括脊髓灰质炎、急性出血性结膜炎、病毒性脑膜炎、手足口病、水疱病、甲型肝炎、肌炎、心肌炎、胰腺炎、糖尿病、流行性肌痛、脑炎、感冒、疱疹性咽峡炎以及口蹄疫病。
由于根据本发明的彼此以平衡状态存在的式1或式2所示的化合物不仅具有低的细胞毒性,而且具有极好的对抗包括柯萨基病毒、肠病毒、脊髓灰质炎病毒和鼻病毒的小核糖核酸病毒的抗病毒活性,因此其可有效地用作预防或治疗病毒性疾病的药物组合物,所述病毒性疾病包括脊髓灰质炎、急性出血性结膜炎、病毒性脑膜炎、手足口病、水疱病、甲型肝炎、肌炎、心肌炎、胰腺炎、糖尿病、流行性肌痛、脑炎、流感、疱疹性咽峡炎、口蹄疫疾病、哮喘、慢性阻塞性肺病、肺炎、鼻窦炎或中耳炎。
根据本发明的如式1或式2所示的化合物可以以各种制剂形式施用,包括口服和非口服临床施用,所述化合物用典型的稀释剂或赋形剂,诸如填充剂、增稠剂、粘合剂、润湿剂、崩解剂和表面活性剂等制成制剂。
口服施用的固体制剂包括片剂、丸剂、粉剂、颗粒剂、胶囊剂以及锭剂,这些固体制剂通过将至少一种本发明的化合物与至少一种赋形剂,诸如淀粉、碳酸钙、蔗糖、乳糖或明胶相混合来制备。除了使用简单的赋形剂以外,还会用到润滑剂,诸如硬脂酸镁和滑石粉。而口服施用的液体制剂包括混悬剂、内服溶液剂、乳剂和糖浆剂等,除了使用简单常见的稀释剂,诸如水、液体石蜡等以外,还会用到各种赋形剂,比如,润湿剂、甜味剂、芳香剂和防腐剂等。
非口服施用制剂包括无菌水溶液、无水溶液、混悬剂、乳剂、冻干剂以及栓剂等。丙二醇、聚乙二醇、植物油(如橄榄油)以及酯类(如可注射油酸乙酯)可用于无水溶剂和混悬剂可能会用。栓剂基质可能用到witepsol、聚乙二醇、吐温61、可可脂、月桂精油(laurinbutter)、甘油和明胶。
本发明的化合物以治疗有效量施用。本发明化合物的有效剂量取决于各种因素,包括病人的年龄、体重、性别、投药方法和健康状况以及疾病的严重程度。典型地,本发明的化合物可以以0.001至100mg/kg的日剂量施用,优选地,以0.01至35mg/kg的日剂量施用。对于体重为70kg的成年人,本发明化合物的剂量可典型地为0.07至7000mg/天,优选地,为0.7至2500mg/天。所述化合物的制剂可以以每天单次剂量施用或按照规律的时间间隔分为多次剂量施用,按照负责监督或观察药物施用的医师或药剂师来确定。
本发明的具体实施方式
下面基于以下实施例对本发明进行进一步的细节描述。然而,以下实施例仅用于说明本发明,本发明的细节不局限于以下实施例。
<实施例1>N-(4b-羟基-7-异丙基-10-氧代-9b,10-二氢-4bH-苯并[d]茚并[1,2-b]呋喃-9b-基)-2-(1H-吲哚-3-基)-2-氧代乙酰胺的制备
将2-(1H-吲哚-3-基)-2-氧代乙酸(352mg,1.86mmol)、EDCI(1-乙基-3-(3-二甲基氨基丙基)碳化二亚胺)(355mg,1.86mmol)和HOBt(羟基苯并三唑)(251mg,1.86mmol)溶解于二氯甲烷(MC)(10ml)中,而后加入9b-氨基-4b-羟基-7-异丙基-4bH-苯并[d]茚并[1,2-b]呋喃-10(9bH)-酮(500mg,1.69mmol)并在常温下搅拌该混合物一天。用二氯甲烷萃取所述反应混合物以收集有机层,将该有机层在MgSO4下干燥并在减压下浓缩。用硅胶柱色谱(乙酸乙酯:正己烷=1:1)提纯浓缩化合物以得到N-(4b-羟基-7-异丙基-10-氧代-9b,10-二氢-4bH-苯并[d]茚并[1,2-b]呋喃-9b-基)-2-(1H-吲哚-3-基)-2-氧代乙酰胺(199mg,25%)。
1H-NMR(丙酮,300ΜΗz)δ1.18(d,J=6.8Hz,6H,CH3),2.87(sep,J=6.8Hz,1H,CH),6.72(s,1H,ArH),6.93(d,J=7.9Hz,1H,ArH),7.26-7.29(m,2H,ArH),7.44(d,J=7.8Hz,1H,ArH),7.54-7.57(m,1H,ArH),7.66-7.75(m,1H,ArH),7.81-7.94(m,2H,ArH),7.99-8.03(m,1H,ArH),8.32-8.35(m,1H,ArH),8.80(s,1H,ArH),11.30(br,1H,NH);
LCMS 466.93[M+H]+,933.23[2M+H]+。
<实施例2>N-(4b-羟基-7-异丙基-10-氧代-9b,10-二氢-4bH-茚并[1,2-b]苯并呋喃-9b-基)-2-氧代-2-(噻吩-2-基)乙酰胺的制备
将2-氧代-2-(噻吩-2-基)乙酸(107mg,1.07mmol)溶解于DMF(3ml)后,降低温度至0℃,搅拌溶液。10分钟后,加入三乙胺(TEA)(213mg,1.07mmol)和HATU(407mg,1.07mmol),在温度降至0℃前搅拌10分钟,加入9b-氨基-4b-羟基-7-异丙基-4bH-茚并[1,2-b]苯并呋喃-10(9bH)-酮(300mg,1.02mmol)。而后,温度升高至常温,搅拌溶液过夜。经水清洗后,用Na2SO4除去水分。经过滤、浓缩后,用柱色谱(EA:Hex=3:7)提纯以得到目标化合物(52mg,28%)。
1H-NMR(300MHz,DMS0-d6)δ1.12(d,6H,J=6.0Hz),4.13(q,1H,J=6.0Hz),4.72(s,1H),6.88(d,1H,J=6.0Hz),7.32(d,2H,J=6.0Hz),7.63-7.67(m,1H),7.76-7.78(d-1H),7.87-7.98(m,2H),8.10(s,1H),8.19(d,1H,J=6.0Hz),8.56(s,1H),9.56(s,1H);
LCMS 433.75[M+H]+,866.87[2M+H]+。
<实施例3>N-(4b-羟基-7-异丙基-10-氧代-9b,10-二氢-4bH-茚并[1,2-b]苯并呋喃-9b-基)-3-(2-硝基苯基)-2-氧代丙酰胺的制备
将2-硝基苯基丙酮酸(390mg,1.86mmol)置于DMF:DCM(1:2,15ml)中,在0℃下加入EDCI(487mg,2.54mmol)。然后,加入1-羟基苯并三唑(343mg,2.54mmol)后,在室温下搅拌15-30分钟。然后,加入9b-氨基-4b-羟基-7-异丙基-4bH-茚并[1,2-b]苯并呋喃-10 (9bH)-酮(500mg,1.69mmol)后,再加入TEA(0.709ml,5.09mmol)。60℃下搅拌2天后,加入水(100ml)。收集分离后的有机层与乙酸乙酯(70ml x 3),用水(50ml)和盐水(50ml)清洗,用硫酸钠除去水分。浓缩后,用硅胶柱色谱(25%乙酸乙酯:己烷)提纯以得到目标化合物100mg(24%)。
1H-NMR(300MHz,CDC13)δ1.18(dd,J=2.7Hz,J=6.9Hz,6H,CH3),2.84(sept,J=6.9Hz,1H,CH),4.54(dd,J=19Hz,J=42Hz,2H,CH2),6.73(s,1H,ArH),6.86(d,J=7.5Hz,1H,ArH),7.27-7.34(m,2H,ArH),7.46-7.51(m,1H,ArH),7.55-7.62(m,2H,ArH),7.80-7.84(m,3H,ArH),7.51(d,J=7.8Hz,1H,ArH),8.15(d,J=8.1Hz,1H,ArH);
LCMS:486.90(M+H)+.
<实施例4>N-(4b-羟基-7-异丙基-10-氧代-9b,10-二氢-4bH-茚并[1,2-b]苯并呋喃-9b-基)-2-氧代丙酰胺的制备
将9b-氨基-4b-羟基-7-异丙基-4bH-茚并[1,2-b]苯并呋喃-10(9bH)-酮(500mg,1.69mmol)加入无水的DCM(15ml)中并降低温度至0℃后,加入吡啶(0.276ml,3.39mmol)。而后在0℃下依次加入丙酮酸(0.13ml,1,86mmol)和POCl3(0.175ml,1.86mmol)。室温下搅拌后,收集用水(100ml)和DCM(100ml x 2)分离的有机层并依次用稀HCl(1N,50ml),水(50ml)和盐水(50ml)清洗。用无水硫酸钠除去水分后,浓缩并快速硅胶柱色谱(己烷中25%的乙酸乙酯)提纯以得到白色目标化合物130mg(21%)。
1H-NMR(300MHz,CDC13)δ1.18(dd,J=3.9Hz,J=6.9Hz,6H,CH3),2.42(s,3H,CH3),2.83(sept,J=6.9Hz,1H,CH),4.93(br,1H,OH),6.73(s,1H,ArH),6.85(d,J=7.5Hz,1H,ArH),7.29(d,J=7.5Hz,1H,ArH),7.56-7.61(m,1H,ArH),7.80-7.84(m,2H,ArH),7.89(br,1H,NH),7.99(d,J=8.4Hz,1H,ArH);
LCMS:365.92(M+H)+。
<实施例5>N-(4b-羟基-7-异丙基-10-氧代-9b,10-二氢-4bH-茚并[1,2-b]苯并呋喃-9b-基)-2-氧代戊酰胺的制备
在无水DCM(15ml)中加入9b-氨基-4b-羟基-7-异丙基-4bH-茚并[1,2-b]苯并呋喃-10(9bH)-酮(500mg,1.69mmol)并降低温度至0℃后,加入吡啶(0.276ml,3.39mmol)。而后在0℃下依次加入2-氧杂戊酸(207mg,1.78mmol)和POCl3(0.175ml,1.86mmol)。在室温下搅拌15小时,收集用水(100ml)和DCM(100ml x 2)分离的有机层并依次用稀HCl(1N,50ml),水(50ml)和盐水(50ml)清洗。用无水硫酸钠除去水分后进行浓缩,并用快速硅胶柱色谱(己烷中25%的乙酸乙酯)提纯以得到白色目标化合物240mg(37%)。
1H-NMR(300MHz,CDCI3)δ0.93(t,J=7.5Hz,3H,CH3),1.18(dd,J=2.7Hz,J=6.9Hz,6H,CH3),1.59-1.69(m,2H,CH2),2.75-2.88(m,3H,CH2+CH),4.88(br,1H,OH),6.73(s,1H,ArH),6.85(d,J=7.8Hz,1H,ArH),7.28(d,J=7.8Hz,1H,ArH),7.56-7.61(m,1H,ArH),7.81-7.85(m,2H,ArH),7.93(br,1H,NH),8.00(d,J=8.1Hz,1H,ArH);
LCMS:393.97(M+H)+。
<实施例6>N-(4b-羟基-7-异丙基-10-氧代-9b,10-二氢-4bH-茚并[1,2-b]苯并呋喃-9b-基)-2-氧代辛酰胺的制备
在无水DCM(15ml)中加入9b-氨基-4b-羟基-7-异丙基-4bH-茚并[1,2-b]苯并呋喃-10(9bH)-酮(500mg,1.69mmol)后,降低温度至0℃。加入吡啶(0.296ml,3.39mmol)后,在0℃下依次加入2-氧杂辛酸(281mg,1.78mmol)和POCl3(0.175ml,1.86mmol)。在室温下搅拌15小时,收集用水(100ml)和DCM(100ml x 2)分离的有机层并依次用稀HCl(1N,50ml),水(50ml)和盐水(50ml)清洗。用无水硫酸钠除去水分后进行浓缩,并用快速硅胶柱色谱(己烷中15%的乙酸乙酯)提纯以得到白色目标化合物140mg(20%)。
1H-NMR(300MHz,CDC13)δ0.86(t,J=7.2Hz,3H,CH3),1.18(dd,J=3.0Hz,J=6.9Hz,6H,CH3),1.26-1.31(m,6H,CH2),1.53-1.60(m,2H,CH2),2.77-2.88(m,3H,CH2+CH),4.90(br,1H,OH),6.73(s,1H,ArH),6.85(d,J=7.8Hz,1H,ArH),7.28(d,J=7.8Hz,1H,ArH),7.56—7.61(m,1H,ArH),7.80-7.85(m,2H,ArH),7.98(br,1H,NH),8.00(d,J=8.4Hz,1H,ArH);
LCMS:435.97(M+H)+。
<实施例7>2-(呋喃-2-基)-N-(4b-羟基-7-异丙基-10-氧代-9b,10-二氢-4bH-茚并[1,2-b]苯并呋喃-9b-基)-2-氧代乙酰胺的制备
将2-氧杂-2-呋喃乙酸(237mg,1.69mmol)加入DMF:DCM(1:2,15ml)中后,在0℃下加入EDCI(487mg,2.54mmol)。加入1-羟基苯并三唑(343mg,2.54mmol),在室温下搅拌15-30分钟。加入9b-氨基-4b-羟基-7-异丙基-4bH-茚并[1,2-b]苯并呋喃-10(9bH)-酮(500mg,1.69mmol)后,室温下搅拌2天。收集用水(100ml)和乙酸乙酯(70ml x 3)分离的有机层并依次用水(50ml)和盐水(50ml)清洗。用无水硫酸钠除去水分后进行浓缩,并用快速硅胶柱色谱(25%乙酸乙酯:己烷)提纯以得到白色目标化合物40mg(6%)。
1H-NMR(300MHz,CDCI3)δ1.18(d,J=6.9Hz,6H,CH3),2.84(sept,J=6.9Hz,1H,CH),4.91(br,1H,OH),6.57-6.59(m,1H,ArH),6.75(s,1H,ArH),6.86(d,J=7.8Hz,1H,ArH),7.33(d,J=7.8Hz,1H,ArH),7.57-7.62(m,1H,ArH),7.76(m,1H,ArH),7.81-7.87(m,2H,ArH),8.00-8.06(m,2H,ArH),8,23(br,1H,NH);
LCMS:417.90(M+H)+。
<实施例8>N-(4b-羟基-7-异丙基-4-硝基-10-氧代-9b,10-二氢-4bH-茚并[1,2-b]苯并呋喃-9b-基)-2-(1H-吲哚-3-基)-2-氧代乙酰胺的制备
将3-吲哚乙醛酸(195mg,1.03mmol)置于DMF:DCM(1:2,10ml)中,在0℃下加入EDCI(296mg,1.54mmol)。加入1-羟基苯并三唑(205mg,1.54mmol)后,在室温下搅拌15-30分钟。加入9b-氨基-4b-羟基-7-异丙基-4bH-茚并[1,2-b]苯并呋喃-10(9bH)-酮(300mg,1.03mmol)后,在室温下搅拌过夜。收集用水(100ml)和乙酸乙酯(70ml x 3)分离的有机层并依次用水(50ml)和盐水(50ml)清洗。用无水硫酸钠除去水分后进行浓缩,并用快速硅胶柱色谱(25%乙酸乙酯:己烷)提纯以得到白色目标化合物(100mg,20%)。
1H-NMR(300MHz,CDC13)δ1.19(dd,J=4.5Hz,J=6.9Hz,6H),2.86(sept,J=6.9Hz,1H),6.71(s,1H),6.94(d,J=8.1Hz,1H,ArH),7.26—7.49(m,5H),8.00-8.17(m,4H,ArH),8.68(s,1H),9.16(s,1H);
LCMS:511.86(M+H)+。
<实施例9>N-(4b-羟基-7-异丙基-10-氧代-9b,10-二氢-4bH-茚并[1,2-b]苯并呋喃-9b-基)-3-(4-羟基苯基)-2-氧代丙酰胺的制备
将3-(4-羟基苯基)-2-氧代丙酸(97mg,0.54mmol)溶解于DMF(3ml)后,降低温度至0℃并进行搅拌。10分钟后,加入三乙胺(TEA)(78mg,0.77mmol)和HATU(205mg,0.54mmol)。搅拌10分钟后,降低温度至0℃,加入9b-氨基-4b-羟基-7-异丙基-4bH-茚并[1,2-b]苯并呋喃-10(9bH)-酮(150mg,0.51mmol)。升高温度至常温,搅拌过夜。用水清洗后,用Na2SO4除去水分,过滤,浓缩,并用柱色谱(EA:Hex=3:7)纯化以得到目标化合物(14mg,6%)。
1H-NMR(300MHz,CDCls)δ1.17(d,6H,J=6.0Hz),2.73-2.90(m,1H),3.98-4.07(m,2H),6.68-6.86(m,5H),7.04(d,2H,J=6.0Hz)7.52-7.59(m,2H),7.80-7.86(m,2H),7.97-8.00(d,1H,J=9.0Hz);
LCMS:457.83[M+H]+,915.14[2M+H]+。
<实施例10>N-(1-氨基-4b-羟基-7-异丙基-10-氧代-9b,10-二氢-4bH-茚并[1,2-b]苯并呋喃-9b-基)-2-(1H-吲哚-3-基)-2-氧代乙酰胺的制备
将b-羟基-7-异丙基-4-硝基-10-氧代-7b,10-二氢-4bH-茚并[1,2-b]苯并呋喃-9b-基)-2-(1H-吲哚-3-基)-2-氧代乙酰胺(70mg,0.14mmol)置于乙醇:水(10:1,10ml:1ml)中,加热该混合物至60℃。加入铁(23mg,0.41mmol)和两滴浓HCl后,加热并回流3小时。得到的化合物在高温下在celite床中滤过后,用乙酸乙酯(15ml x 2)清洗该液体,而后在加入乙酸乙酯(100ml)前进行浓缩。
依次用饱和NaHCO3(20ml)、水(20ml)和盐水(20ml)清洗后,用无水硫酸钠除去水分。浓缩干燥后,加入少量DCM,而后使用超声波处理。过滤此时形成的固体化合物以得到黄色目标化合物(50mg,75%)。
1H-NMR(300MHz,CD30D)δ1.19(d,J=6.9Hz,6H,CH3),2.85(sept,J=6.9Hz,1H,CH),6.67-6.73(m,2H,ArH),6.90(m,1H,ArH),7.03(m,1H,ArH),7:25(m,2H,ArH),7.45(m,3H,ArH),8.29(m,1H,ArH),8.64(m,1H,ArH);
LCMS:481.90(M+H)+。
<实施例11>N-(1-氨基-4b-羟基-7-异丙基-10-氧代-9b,10-二氢-4bH-茚并[1,2-b]苯并呋喃-9b-基)-2-氧代-2-苯基乙酰胺的制备
将N-(4b-羟基-7-异丙基-4-硝基-10-氧代-9b,10-二氢-4bH-茚并[1,2-b]苯并呋喃-9b-基)-2-氧代-2-苯基乙酰胺(100mg,0.21mmol)加入乙醇:水(10:1,10ml:1ml)中,加热该混合物至60℃。加入铁(36mg,0.64mmol)和两滴浓HCl后,通过加热进行回流2小时。得到的化合物在高温下在celite床上过滤后,用乙酸乙酯(15ml x 2)清洗该液体,而后在加入乙酸乙酯(100ml)前进行浓缩。依次用饱和NaHCO3(20ml)、水(20ml)和盐水(20ml)清洗后,用无水硫酸钠除去水分。浓缩干燥后,加入少量DCM,而后使用超声波处理。过滤此时形成的固体化合物以得到黄色目标化合物(90mg,90%)。
1H-NMR(300MHz,CD3OD)δ1.17(d,J-6.9Hz,6H,CH3),2.83(sept,J=6.9Hz,1H,CH),6.67-6.71(m,2H,ArH),6.87(d,J=7.5Hz,1H,ArH),7.03(d,J=7.5Hz,1H,ArH),7.31-7.55(m,4H,ArH),7.64-7.69(m,1H,ArH),8.08-8.16(m,2H,ArH);
LCMS:442.92(M+H)+。
<实施例12>N-(4b-羟基-7,8-二甲基-10-氧代-9b,10-二氢-4bH-茚并[1,2-b]苯并呋喃-9b-基)-2-氧代-2-苯基乙酰胺的制备
将2-氧代-2-苯基乙酸酯(281mg,1.0mmol)溶解于DCM(10.0ml)后,降低温度至0℃。将EDCI(230mg,1.2mmol)在0℃下放置并搅拌10分钟。0℃下加入HOBt(162mg,1.2mmol),而后搅拌10分钟。0℃下加入9b-氨基-4b-羟基-7,8-二甲基-4bH-茚并[1,2-b]苯并呋喃-10(9bH)-酮(281mg,1.0mmol),而后在室温下搅拌12小时。用水清洗后,用Na2SO4除去水分,减压下浓缩,并在色谱柱中提纯,得到目标化合物(219mg,53%)。
1H-NMR(300MHz,CDC13)δ2.17(s,3H),2.19(s,3H),4.87(s,1H),6.68(s,1H),7.18(s,1H),7.42-7.47(m,2H),7.55-7.64(m,2H),7.80-7.85(m,2H),8.01(d,J=7.56Hz,1H),8.11(s,1H)8.26(s,1H),8.29(s,1H);
LCMS:413.86[M+H]+,826.98[2M+H]+。
<实施例13>N-(4b-羟基-7,8-二甲基-10-氧代-9b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)-(1H-吲哚-3-基)-2-氧代乙酰胺的制备
将2-(1H-吲哚-3-基)-2-氧代乙酸(209mg,1.1mmol)溶解于DCM(10.0ml)后,降低温度至0℃。将EDCI(230mg,1.2mmol)放置在0℃下,搅拌10分钟。0℃下加入HOBt(162mg,1.2mmol),而后搅拌10分钟。0℃下加入9b-氨基-4b-羟基-7,8-二甲基-4bH-茚并[1,2-b]苯并呋喃-10(9bH)-酮(281mg,1.0mmol),而后在室温下搅拌12小时。用水清洗后,用Na2SO4除去水分,减压下浓缩,并在色谱柱中提纯,得到目标化合物(194mg,43%)。
1H-NMR(300MHz,CDC13)δ2.14(s,3H),2.17(s,3H),5.23(br s,1H),6.69(s,1H),7.17(s,1H),7.33(s,1H),7.42(s,1H),7.52-7.94(m,4H),8.40(s,1H),8.53(s,1H),8.87(s,2H);
LCMS:452.83[M+H]+,904.95[2M+H]+。
<实施例14>N-(4b-羟基-7,8-二甲基-10-氧代-9b,10-二氢-4bH-茚并[1,2-b]苯并呋喃-9b-基)-2-氧代丙酰胺的制备
将9b-氨基-4b-羟基-7,8-二甲基-4bH-茚并[1,2-b]苯并呋喃-10(9bH)-酮(300mg,1.07mmol)加入DCM(20ml)后,降低温度至0℃。加入吡啶(168mg,2.13mmol)后搅拌10分钟,并加入2-氧代丙酸(94mg,1.07mmol)。在搅拌状态下加入POCl3(0.1ml,1.07mmol)后,在室温下搅拌15小时。用DCM(100ml)和H2O(100ml)分离有机层后,依次用1N HCl和NaCl清洗,用Na2SO4除去水分并进行浓缩。而后在色谱柱中进行提纯以得到目标化合物(56mg,15%)。
1H-NMR(300MHz-CDC13)δ2.16(s,3H),2.18(s,3H),2.44(s,3H),4.86(br s,1H),6.66(s,1H),7.12(s,1H),7.57(t,J=7.2Hz,1H),7.79-7.82(m,2H),7.92-8.00(m,2H);
LCMS:351.83[M+H]+,702.84[2M+H]+。
<实施例15>N-(4b-羟基-7-异丙基-10-氧代-9b,10-二氢-4bH-茚并[1,2-b]苯并呋喃-9b-基)-2-氧代-2-苯基乙酰胺的制备
将苯基乙醛酸(0.30g,2.03mmol)溶解于无水二氯甲烷(10ml)、EDCI(0.38g,2.03mmol)和HOBt(0.27g,2.03mmol)中后,加入3-(2-氨基乙基)-9b-氨基-4b-羟基-7-异丙基-4bH-茚并[1,2-b]苯并呋喃-10(9bH)-酮(0.50g,1.69mmol)和三乙胺(0.25g,2.53mmol),并在室温下搅拌24小时。用二氯甲烷稀释,用水清洗若干次后,干燥有机层并过滤。用柱色谱(乙酸乙酯:己烷=1:2)进行提纯得到目标化合物(0.20g,27%)。
1H-NMR(300MHz,CDCl3)δ1.16-1.19(dd,J=6.9,3.0Hz,2H,CH2)2.77-2.89(m,1H,CH)4.93(s,1H,OH)6.75(s,1H,NH)6.87(d,J=7.8Hz,1H,ArH)7.44(t,J=8.1Hz,2H,ArH)7.57-7.64(m,3H,ArH)7.85(m,1H,ArH)8.02(d,J=7.5Hz,1H,ArH)8.09(s,1H,ArH).8.26(d,J=7.2Hz,2H,ArH);
LCMS:MS(EI)m/e(相对强度)428(M+H)+,855(2M+H)+。
<实施例16>N-(4b-羟基-7-异丙基-4-硝基-10-氧代-9b,10-二氢-4bH-茚并[1,2-b]苯并呋喃-9b-基)-2-氧代-2-苯基乙酰胺的制备
将苯基乙醛酸(155mg,1.03mmol)加入DMF:DCM(1:2,10ml)中,在0℃下加入EDCI(296mg,1.54mmol)。加入1-羟基苯并三唑(205mg,1.54mmol)后,在室温下搅拌15-30分钟。加入9b-氨基-4b-羟基-7-异丙基-4-硝基-4bH-茚并[1,2-b]苯并呋喃-10(9bH)-酮(300mg,1.03mmol)后,室温下搅拌过夜。收集用水(100ml)和乙酸乙酯(70ml x 3)分离的有机层并依次用水(50ml)和盐水(50ml)清洗。用无水硫酸钠除去水分后,浓缩,并用快速硅胶柱色谱(25%乙酸乙酯己烷)提纯以得到目标化合物(125mg,30%)。
1H-NMR(300MHz,CDCI3)δ1.19(dd,J=3.3Hz,J=6.9Hz,6H,CH3),2.86(sept,J=6.9Hz,1H,CH),6.50(s,1H,OH),6.73(s,1H,ArH),6.94(d,J=7.8Hz,1H,ArH),7.41-7.49(m,3H,ArH),7.58-7.63(m,2H,ArH+NH),7.77-7.82(m,1H,ArH),8.26-8.29(m,3H,ArH),8.50(dd,J=8.1Hz,J=1Hz,1H,ArH);
LCMS:472.80(M+H)+。
<实施例17>N-(4b-羟基-7-异丙基-10-氧代-9b,10-二氢-4bH-茚并[1,2-b]苯并呋喃-9b-基)-4-(甲硫基)-2-氧代丁酰胺的制备
将9b-氨基-4b-羟基-7-异丙基-4bH-茚并[1,2-b]苯并呋喃-10(9bH)-酮(500mg,1.7mmol)和吡啶(269mg,3.4mmol)溶解于DCM中。加入POCl3(286mg,1.87mmol)后,然后加入4-(甲硫基)-2-氧代丁酸钠盐(318mg,1.87mmol),常温下搅拌过夜。用水清洗后,用Na2SO4除去水分,过滤,浓缩,用柱色谱(EA:Hex=3:7)提纯以得到目标化合物(50mg。7%)。
1H-NMR(300MHz,DMS0—d6)δ1.12(d,6H,J=6.0Hz),2.53(s,3H),2.78-2.85(m,2H),3.00-3.15(m,3H),6.70(s,1H),6.87(d,1H,J=6.0Hz),7.28(d,1H,J=9.0Hz),7.61-7.65(m,1H),7.73(d,1H,J=6.0Hz),7.87-7.91(m,2H).
<实施例18>4b-羟基-7-异丙基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基丙基氨基甲酸酯的制备
将9b-羟基-7-异丙基-4b-甲氧基-4b,9b-二氢-10H-茚并[1,2-b]苯并呋喃-10-酮(300mg,1.0mmol)溶解于DCM(20ml)中,在0℃下进行搅拌。将三光气(碳酰氯)(300mg,1.00mmol)溶解于TEA(0.14mL,1.10mmol)中并在0℃下加入。溶解后,反应10分钟,并在减压下浓缩,除去任何残余的碳酰氯。用TLC验证起始物料已消失后,向DCM(20ml)中加入正丙胺(0.05ml,2eq.)和TEA(2eq.)并在添加前溶解。常温下反应12小时,在反应结束时将反应物浓缩,而后用硅胶柱色谱(己烷中20%EA)提纯以得到目标化合物(106mg,83%)。
1H-NMR(300MHz,CDC13)δ0.71(t,J=7.5Hz,3H),1.18(dd,J=6.9Hz,J=3.0Hz,6H),1.38-1.54(m,2H),2.85(septet J=6.9Hz,1H),3.32-3.37(m,2H),3.89(s,1H),4.47(s,1H),6.73(s,1H),6.87(d,J=7.8Hz,1H),7.47-7.66(m,4H),7.79(d,J=7.8Hz,1H);
LCMS:382.29[M+H]+,763.96[2M+H]+。
<实施例19>N-(4b-羟基-7-异丙基-4-硝基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)-2-氧代丙酰胺的制备
将9b-氨基-4b-羟基-7-异丙基-4-硝基-4b,9b-二氢-10H-茚并[1,2-b]苯并呋喃-10-酮(464mg,1.136mmol)溶解于无水THF(50ml,0.02M)中,缓慢搅拌并加入TEA(0.396ml,2.839mmol)。而后10℃下加入丙酮酸(100mg,1.136mmol)。逐滴缓慢加入三氯氧磷(106mL,1,136)。常温下反应5小时后,在反应结束时用乙酸乙酯(EA)萃取(提取),用水清洗并用Na2SO4除去水分,浓缩反应物。而后用硅胶柱色谱(己烷中15%EA)提纯以得到目标化合物(70mg,15%)并回收100mg起始物料。
1H-NMR(300MHz,CDC13)δ1.18(dd,J=6.9Hz,J=3.0Hz 6H),2.43(s,3H),2.85(sept,J=6.9Hz,1H),6.46(s,1H),6.71(s,1H),6.93(d,J=7.8Hz,1H),7.43(d,J=7.8Ηz,1Η),7.76-7.81(m,1H),8.24(d,J=7.2Hz,1H),8.50(d,J=7.8Hz,1H);
LCMS:410.82[M+H]+,820.82[2M+H]+。
<实施例20>N1-(2,6-二甲基苯基)-N2-(4b-羟基-7-异丙基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)草酰胺的制备
将2-((2,6-二甲基苯基)氨基)-2-氧代乙酸(240mg,1.24mmol)溶解于DCM(20ml)中,边搅拌边在0℃下加入EDCI(357mg,1.86mmol),再加入1-羟基苯并三唑(252mg,1.86mmol)。边搅拌边加入9b-氨基-4b-羟基-7-异丙基-4b,9b-二氢-10H-茚并[1,2-b]苯并呋喃-10-酮(404mg,1.37mmol),而后通过逐滴加入TEA(0.258ml,1.86mmol),常温下反应24小时。反应结束时,用水(100ml)和乙酸乙酯(70ml x 2)萃取,而后用盐水(50ml)再清洗一次。用Na2SO4除去水分后,用硅胶柱色谱(Hex中15-20%EA)提纯经压力浓缩得到的混合物,以得到目标化合物(360mg,62%)。
1H-NMR(300MHz,CD30D)δ1.16(d,J=6.9Hz,6H),2.19(s,6H),2.83(sept,J=6.9Hz,1H),6.68(s,1H),6.90(d,J=7.2Hz,1H),7.09(br,3H),7.42(d,J=7.2Hz,1H),7.65-7.90(br,4H);
LCMS:471.29[M+H]+。
<实施例21>N1-(4b-羟基-7-异丙基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)-N2,N2-二甲基草酰胺的制备
将2-(二甲基氨基)-2-氧代乙酸(200mg,1.71mmol)溶解于DCM(20ml),在搅拌的同时在0℃下加入EDCI(654mg,3.41mmol),并加入1-羟基苯并三唑(346mg,2.56mmol)。搅拌同时加入9b-氨基-4b-羟基-7-异丙基-4b,9b-二氢-10H-茚并[1,2-b]苯并呋喃-10-酮(605mg,2.05mmol),而后通过逐滴加入TEA(0.357ml,2.56mmol),在常温下反应48小时。反应结束时,用水(100ml)和乙酸乙酯(70ml x 2)萃取,而后用盐水(50ml)再清洗一次。用Na2SO4除去水分后,用硅胶柱色谱(己烷中50%EA)提纯经压力浓缩得到的混合物,以得到目标化合物(450mg,67%)。
1H-NMR(300MHz,CD30D)δ1.16(d,J=6.9Hz,6H),2.82(sept,J=6.9Hz,1H),2.95(s,3H),3.16(s,3H),6.67(s,1H),6.87(d,J=7.8Hz,1H),7.37(d,J=7.8Hz,1H),7.62-7.90(br,4H);
LCMS:394.98[M+H]+,789.09[2M+H]+。
<实施例22>N-(1-氨基-4b-羟基-7-异丙基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)-2-氧代丙酰胺的制备
将N-(4b-羟基-7-异丙基-4-硝基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)-2-氧代丙酰胺(200mg,0.49mmol)溶解于乙醇:水(10:1,10ml)中后,加入铁(82mg,1.46mmol)。加入浓盐酸(2滴),在90℃下反应2小时后,在反应结束时的高温下用赛力特硅藻土(celite)进行过滤,而后用乙酸乙酯清洗。用DCM萃取,并用水清洗后,再用盐水(50ml)再清洗一次。用Na2SO4除去水分并浓缩反应物,而后用硅胶柱色谱(己烷中33%EA)纯化,以得到目标化合物(70mg,38%)。
1H-NMR(300MHz,CD30D)δ1.18(d,J=6.9Hz,6H),2.34(s,3H),2.83(sept,J=6.9Hz,1H),6.66-6.70(m,2H),6.87(d,J=8.4Hz,1H),6.98(d,J=8.4Hz,1H),7.34-7.45(m,2H);
LCMS:380.96[M+H]+。
<实施例23>N-(4b-羟基-7-异丙基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)-2-氧代-2-(3,4,5-三甲氧基苯基)乙酰胺的制备
将2-氧代-2-(3,4,5-三甲氧基苯基)乙酸(25mg,0.10mmol)溶解于DCM(1ml)后,在0℃下搅拌并依次加入HATU(59.4mg,0.16mmol)和DIPEA(0.028ml,0.16mmol)。大约5分钟后,加入9b-氨基-4b-羟基-7-异丙基-4b,9b-二氢-10H-茚并[1,2-b]苯并呋喃-10-酮(34mg,0.11mmol),反应12小时。反应结束时,用DCM(50ml x 2)和水萃取并用盐水清洗。用Na2SO4除去水分后,减压下浓缩,用硅胶柱色谱(己烷中40%EA)提纯以得到目标化合物(50mg,93%)。
1H-NMR(300MHz,CD30D)δ1.15(dd,J=6.9Hz,J=1.8Hz,6H),2.81(sept,J=6.9Hz,1H),3.85(s,3H),3.91(s,6H),6.68(s,1H),6.87(d,J=7.8Hz,1H),7.40(d,J=7.8Hz,1H),7.50(s,2H),7.57-7.62(m,1H),7.79-7.90(m,3H),7.99(d,J=7.8Hz,1H);
LCMS:517.85[M+H]+。
<实施例24>(E)-4-(3,4-二甲氧基苯基)-N-(4b-羟基-7-异丙基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)-2-氧代-3-丁酰胺的制备
将(E)-4-(3,4-二甲氧代苯基)-2-氧代-3-丁烯酸(25mg,0.11mmol)溶解于DCM(1ml)中,0℃下搅拌同时依次加入HATU(61mg,0.16mmol)和DIPEA(0.028ml,0.16mmol)。
大约5分钟后,加入9b-氨基-4b-羟基-7-异丙基-4b,9b-二氢-10H-茚并[1,2-b]苯并呋喃-10-酮(35mg,0.12mmol),反应12小时。反应结束时,用DCM(50ml x 2)和水萃取并用盐水清洗。用Na2SO4除去水分,减压下浓缩,用硅胶柱色谱(己烷中40%EA)提纯以得到目标化合物(40mg,74%)。
1H-NMR(300MHz,CD30D)δ1.16(d,J=6.9Hz,6H),2.83(sept,J=6.9Hz,1H),3.84(s,3H),3.86(s,3H),6.68(s,1H),6.90(d,J=7.8Hz,1H),6.98(d,J=7.8Hz,1H),7.25(br,3H)7.31(s,1H),7.41(d,J=7.8Hz,1H),7.59-7.64(m,1H),7.79-7.98(m,4H);
LCMS:513.87[M+H]+。
<实施例25>N-(4b-羟基-7-异丙基-4-硝基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)-3-(2-硝基苯基)-2-氧代丙酰胺的制备
将3-(2-硝基苯基)-2-氧代丙酸(185mg,0.88mmol)溶解于DCM(20ml,0.044M)。0℃下搅拌10分钟后,加入HATU(502.8mg,1.32mmol)和DIPEA(171mg,1.32mmol)。0℃下搅拌10分钟后,加入9b-氨基-4b-羟基-7-异丙基-4-硝基-4b,9b-二氢-10H-茚并[1,2-b]苯并呋喃-10-酮(300mg,0.88mmol),而后常温下搅拌18小时。用乙酸乙酯(EA)萃取用水清洗后,浓缩反应物,用硅胶色谱柱(己烷中50%EA)提纯以得到目标化合物(250mg,53%)。
1H-NMR(300MHz,CDC13):δ1.16-1.19(m,6H),2.80-2.89(m,1H),4.48-4.70(m,2H),6.49(s,1H),6.72(s,1H),6.93(d,J=9.0Hz,1H),7.30(d,J=9.0Hz,1H),7.39-7.53(m,3H),7.62(t,J=9.0Hz,1H),7.80(t,J=9.0Hz,1H),8.18(d,]=9.0Hz,1H),8.27(d,J=9.0Hz,1H),8.52(d,J=9.0Hz,1H);
LCMS:531.88[M+H]+。
<实施例26>N1-(2,6-二甲基苯基)-N2-(4b-羟基-7-异丙基-4-硝基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)草酰胺的制备
将2-((2,6-二甲基苯基)氨基)-2-氧代乙酸(170mg,0.88mmol)溶解于DCM(20ml,0.044M)中。0℃下搅拌10分钟后,加入EDCI(253.5mg,1.32mmol)和Hobt(133.8mg,1.32mmol)。0℃下搅拌10分钟后,加入TEA(178.6mg,1.32mmol)和9b-氨基-4b-羟基-7-异丙基-4-硝基-4b,9b-二氢-10H-茚并[1,2-b]苯并呋喃-10-酮(300mg,0.88mmol),而后常温下搅拌18小时。用乙酸乙酯(EA)萃取用水清洗后,浓缩反应物,用硅胶色谱柱提纯以得到目标化合物(90mg,20%)。
1H-NMR(300MHz,CDC13):δ1.17-1.20(m,6H),2.23(s,6H)2.82-2.91(m,1H),6.49(s,1H),6.73(S,1H),6.93-6.95(m,1H),7.08-7.14(m,3H),7.48-7.50(d,J=6.0Hz,1H),7.81(t,J=9.0Hz 1H),7.95(s,1H),8.27-8.29(d,J=6.0Hz,1H),8.51-8.53(m,2H);
LCMS:515.97[M+H]+。
<实施例27>N1-(4b-羟基-7-异丙基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)-N2-甲基草酰胺的制备
将单-(N-甲基)-酰胺草酸酯(Mono-(N-methyl)-amide oxalate)(104.7mg,1.02mmol)溶解于DCM(6ml,0.1M)中。0℃下搅拌10分钟后,加入HATU(386.2mg,1.02mmol)和DIPEA(131mg,1.02mmol)。0℃下搅拌10分钟后,加入9b-氨基-4b-羟基-7-异丙基-4b,9b-二氢-10H-茚并[1,2-b]苯并呋喃-10-酮(200mg,0.68mmol),而后常温下搅拌18小时。50℃下再搅拌3小时后,加入DMF(6ml),再搅拌1小时。用乙酸乙酯(EA)萃取用水清洗后,浓缩反应物,用硅胶色谱柱(己烷中50%EA)提纯以得到目标化合物(37mg,24%)。
1H-NMR(500MHz,DMSO-d6):δ1.13(d,J=7Hz,6H),2.66(d,J=500Hz,3H),2.79-2.84(m,1H),6.70(s,1H),6.88(d,J=8Hz,1H),7.27-7.34(m,1H),7.56-7.98(m,4H),8.20-8.30(m,1H),8.46-8.54(m,1H),8.66-8.67(m,1H);
LCMS:380.82[M+H]+。
<实施例28>N-(4b-羟基-7-异丙基-4-硝基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)-3-甲基-2-氧代戊酰胺的制备
添加并将3-甲基-2-氧代戊酸钠盐溶解于1N HCl后,搅拌5分钟,用乙酸乙酯萃取,减压下浓缩,得到溶解于THF(0.1M,14ml)的3-甲基-2-氧代戊酸(180mg,1.38mmol)。而后,加入9b-氨基-4b-羟基-7-异丙基-1-硝基-4b,9b-二氢-10H-茚并[1,2-b]苯并呋喃-10-酮(517mg,1.52mmol),-10℃下搅拌15分钟后用注射泵缓慢加入POCl3(14.0ml,(THF中0.2M),2.76mmol)15分钟,搅拌。加入POCl3后,常温下反应2小时,反应结束时,减压下浓缩。用EA和水萃取,用水和盐水清洗有机层,而后用Na2SO4除去水分,减压下浓缩。最后,用填充有硅胶的色谱柱提纯,得到目标化合物(90mg,15%)。
1H-NMR(300MHz,CDC 13):δ0.84-0.94(m,3H),1.07-1.13(m,3H),1.17-1.21(m,6H),1.30-1.46(m,1H),1.65-1.79(m,1H),2.81-2.90(m,1H),3.31-3.41(m,1H),6.71(s,1H),6.93(d,J=7.9Hz,1H),7.43(t,J=7.9Hz,J=10.2Hz,2H),7.75-7.81(m,1H),8.25(d,J=7.7Hz,1H),8.49(d,J=8.0Hz,1H);
LCMS:453.46[M+H]+。
<实施例29>N-(4b-羟基-7-异丙基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)-3-甲基-2-氧代戊酰胺的制备
添加并将3-甲基-2-氧代戊酸钠盐溶解于1N HCl后,搅拌5分钟,用乙酸乙酯萃取,减压下浓缩,得到溶解于THF(0.1M,14ml)的3-甲基-2-氧代戊酸(180mg,1.38mmol)。而后,加入9b-氨基-4b-羟基-7-异丙基-4b,9b-二氢-10H-茚并[1,2-b]苯并呋喃-10-酮(450mg,1.52mmol),-10℃下搅拌15分钟后用注射泵缓慢加入POCl3(14.0ml,(0.2M in THF),2.76mmol)15分钟,搅拌。加入POCl3后,常温下反应2小时,反应结束,减压下浓缩。用EA和水萃取,用水和盐水清洗有机层,而后用Na2SO4除去水分,减压下浓缩。最后,用填充有硅胶的色谱柱提纯,得到目标化合物(190mg,30%)。
1H-NMR(300MHz,CDC13):δ0.82-0.92(m,3H),1.04-1.11(m3H),1.16-1.25(m,6H),1.31-1.42(m,1H),1.63-1.77(m,1H),2.79-2.88(m,1H),3.33-3.39(m,1H),6.84-6.87(m,1H),7.28-7.31(m,1H),7.56-7.61(m,1H),7.80-7.85(m,2H),7.90-7.93(m,1H),8.00(d,J=7.8Hz,1H);
LCMS:407.97[M+H]+。
<实施例30>N1-(4b-羟基-7-异丙基-4-硝基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)-N2-N2-二甲基草酰胺的制备
0℃下向DCM(0.1M,15.0ml)中加入2-(二甲基氨基)-2-氧代乙酸(180mg,1.54mmol),搅拌,搅拌前,加入HATU(878mg,2.31mmol)和DIPEA(0.4ml,2.31mmol)。最后,加入9b-氨基-4b-羟基-7-异丙基-1-硝基-4b,9b-二氢-10H-茚并[1,2-b]苯并呋喃-10-酮(500mg,1.69mmol),然后常温下搅拌12小时。反应结束,用水和DCM萃取,用水再次清洗,用Na2SO4除去水分,然后减压下浓缩。最后,用填充有硅胶的色谱柱提纯,得到目标化合物(550mg,81%)。
1H-NMR(300MHz,CDC13):δ1.17-1.19(m,6H),1.30-1.46(m,1H),2.81-2.87(m,1H),3.02(s,3H),3.34(s,3H),6.70(s,1H),6.91(d,J=7.7Hz,1H),7.43(d,J=7.9Hz,1H),7.75-7.81(m,1H),8.24(d,J=8.0Hz,1H),8.49(d,J=8.0Hz,1H);
LCMS:439.88[M+H]+。
<实施例31>N1-(1-氨基-4b-羟基-7-异丙基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)-N2-N2-二甲基草酰胺的制备
将N1-(4b-羟基-7-异丙基-4-硝基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)-N2-N2-二甲基草酰胺(200mg,0.46mmol)溶解于乙醇:水(10:1)(0.02M,23.0ml)中,而后加入铁粉(77mg,1.38mmol)。搅拌时,缓慢加入浓盐酸(3滴),允许反应在120℃下进行1.5小时。反应结束后,冷却至常温,减压下浓缩,用水和乙酸乙酯萃取,用水再次清洗,用Na2SO4除去水分,然后减压下浓缩。最后,用填充有硅胶的色谱柱提纯,得到目标化合物(75mg,40%)。
1H-NMR(300MHz,CD30D):δ1.17(d,J=6.3Hz,6H),2.78-2.87(m,1H),2.94.(s,3H),3.16(s,3H),6.65-6.72(m,2H),6.83-6.86(m,1H),6.98-7.00(m,1H),7.35-7.37(m,1H),7.42-7.47(m,1H);
LCMS:409.94[M+H]+。
<实施例32>2-((4b-羟基-7-异丙基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)氨基)-2-氧代乙酸乙酯的制备
将9b-氨基-4b-羟基-7-异丙基-4b,9b-二氢-10H-茚并[1,2-b]苯并呋喃-10-酮(0.5g,1.69mmol)溶解于THF(17ml,0.10mmol)中,-10℃下缓慢加入TEA(0.36ml,2.54mmol)和2-氯-2-氧代乙酸乙酯(0.17ml,1.52mmol)。搅拌12小时后,浓缩THF。加入DCM后,用水和盐水清洗。加入Na2SO4后,过滤,浓缩。用填充有硅胶的色谱柱提纯,得到目标化合物(400mg,60%)。
1H-NMR(300MHz,CDC13)δ1.16-1.39(m,9H),2.78-2.87(m,1H),4.31-4.39(m,2H).4.91(br,1H),6.73(s,1H),6.84(d,J=8.1Hz,1H),7.29(d,J=8.1Hz,1H),7.58(t,J=7.5Hz,1H),7.80-7.93(m,2H),7.80(d,J=8.1Hz,1H),8.11(br,1H);
LCMS:396.24[M+H]+。
<实施例33>2-((4b-羟基-7-异丙基-4-硝基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)氨基)-2-氧代乙酸乙酯的制备
将9b-氨基-4b-羟基-7-异丙基-4b,9b-二氢-10H-茚并[1,2-b]苯并呋喃-10-酮(0.5g,1.47mmol)溶解于THF(15ml,0.10mmol)中,-10℃下缓慢加入TEA(0.31ml,2.21mmol)和2-氯-2-氧代乙酸乙酯(0.15 ml,1.32mmol)。搅拌12小时后,浓缩THF。加入DCM后,用水和盐水清洗。加入Na2SO4后,过滤,浓缩。用填充有硅胶的色谱柱提纯,得到目标化合物(240mg,60%)。
1H-NMR(300MHz,CDC13)δ1.17-1.22(m,6H),1.36(t,J=7.2Hz,3H),2.79-2.90(m,1H),4.30-4.37(m,2H),6.44-6.53(m,1H),.71(br,1H),6.93(d,J=7.8Hz,1H),7.46(d,J=7.8Ηz,1Η),7.54(br,1H),7.77(t,J=7.8Hz,1H),8.21(d,J=6.6Hz,1H),8.48(d,J=7.8Hz,1H);
LCMS:441.21[M+H]+。
<实施例34>N-(4b-羟基-7-异丙基-4-硝基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)-2-氧代戊酰胺的制备
将2-氧代戊酸(100mg,0.86mmol)溶解于THF(17ml,0.05M)中。而后加入9b-氨基-4b-羟基-7-异丙基-4b,9b-二氢-10H-茚并[1,2-b]苯并呋喃-10-酮(351.3mg,1.03mmol)和TEA(0.30ml,2.25mmol),降低温度至-10℃后,缓慢逐滴加入POCl3(0.12ml,1.29mmol)。缓慢升温至常温,搅拌4小时并浓缩THF。加入DCM后,用水和盐水清洗。加入Na2SO4后,过滤,浓缩。用填充有硅胶的色谱柱提纯,得到目标化合物(150mg,39%)。
1H-NMR(300MHz,CDC13)δ0.93(t,J=7.2Hz,3H),1.16-1.20(m,6H),1.6(t,J=7.2Hz,3H),1.60-1.67(m,2H),2.81-2.90(m,3H),6.45(br,1H),6.71(br,1H),6.93(d,J=8.1Hz,1H),7.43(d,J=7.8Hz,2H),7.78(t,J=7.8Hz,1H),8.24(d,J=7.8Hz,1H),8.50(d,J=8.1Hz,1H);
LCMS:439.25[M+H]+。
<实施例35>N-(4b-羟基-7-异丙基-4-硝基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)-2-氧代辛酰胺的制备
将2-氧代辛酸(100mg,0.63mmol)溶解于THF(13ml,0.05M)中。而后加入9b-氨基-4b-羟基-7-异丙基-4b,9b-二氢-10H-茚并[1,2-b]苯并呋喃-10-酮(257.3mg,0.76mmol)和TEA(0.22ml,1.58mmol),降低温度至-10℃后,缓慢逐滴加入POCl3(0.09ml,1.26mmol)。缓慢升温至常温,搅拌4小时并浓缩THF。加入DCM后,用水和盐水清洗。加入Na2SO4后,过滤,浓缩。用填充有硅胶的色谱柱提纯,得到目标化合物(70mg,23%)。
1H-NMR(300MHz,CDC13)δ0.82-0.88(m,3H),1.16-1.29(m,12H),1.49-1.62(m,3H),2.81-2.90(m,2H),6.44(br,1H),6.71(br,1H),6.92(d,J=7.5Hz,1H),7.42(d,J=8.1Hz,2H),7.78(t J=8.1Hz,1H),8.24(d,J=7.5Hz,1H),8.49(d,J=8.1Hz,1H);
LCMS:481.20[M+H]+。
<实施例36>2-((1-氨基-4b-羟基-7-异丙基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)氨基)-2-氧代乙酸乙酯的制备
将2-((4b-羟基-7-异丙基-1-硝基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)氨基)-2-氧代乙酸乙酯(100mg,0.23mmol)溶解于乙醇:水=10:1(5ml,0.05M)中。加入Fe(38.5mg,0.69mmol)和1滴HCl(催化剂)。回流2小时。用乙酸乙酯(EA)稀释后用水清洗,萃取EA层。浓缩乙酸乙酯,将反应物溶于DCM。用水和盐水清洗后,加入Na2SO4,过滤,浓缩。用填充有硅胶的色谱柱提纯,得到目标化合物(47mg,50%)。
1H-NMR(300MHz,CD30D)δ1.17(d,J=6.9Hz,6H),1.29-1.35(m,1H),4.27-4.34(m,2H),6.67(s,2H),6.87(d,J=7.8Hz,1H),6.99(d,J=6.9Hz,1H),7.34-7.47(m,2H);
LCMS:410.7[M+H]+。
<实施例37>N-(4b-羟基-7-异丙基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)-3,3-二甲基-2-氧代丁酰胺的制备
将9b-氨基-4b-羟基-7-异丙基-4b,9b-二氢-10H-茚并[1,2-b]苯并呋喃-10-酮(500mg,1.26mmol)加入到THF(25ml,0.05M)中。加入3,3-二甲基-2-氧代丁酸(137mg,1.05mmol)后,然后加入TEA(0.4ml,2.64mmol)后,冷却至-10℃。缓慢加入POCl3(0.149mg,1.56mmol)并维持该温度,搅拌3小时。减压下浓缩,加入过量的乙酸乙酯,用Na2SO4除去水分,减压下浓缩,而后用硅胶柱色谱法分离,以得到目标化合物(247mg,36%)。
1H-NMR(300MHz,CDC13):δ1.15(d,J=6.6Hz,6H),1.24(s 9H), 2.82(m,1H),5.48(s,1H),6.65(s,1H),6.87(d,J=7.2Hz,1H),7.34(d,J=8.4Hz,1H),7.59(m,1H),7.81(m,2H),7.92(s,1H);
LCMS:407.92[M+H]+。
<实施例38>N-(4b-羟基-7-异丙基-4-硝基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)-4-甲基-2-氧代戊酰胺的制备
将9b-氨基-4b-羟基-7-异丙基-1-硝基-4b,9b-二氢-10H-茚并[1,2-b]苯并呋喃-10-酮(300mg,0.88mmol)加入到DCM(6ml,0.15M)中。再加入EDCI(340mg,1.76mmol)和TEA(0.4ml,2.64mmol)。加入HOBT(240mg,1.76mmol)和4-甲基-2-氧代戊酸(120mg,0.88mmol)后,常温下搅拌12小时。进一步加入DCM进行稀释,而后用水清洗。用Na2SO4除去水分,减压下浓缩,而后用硅胶柱色谱法提纯,以得到目标化合物(68mg,16%)。
1H-NMR(300MHz,CDC13):δ0.92(t,J=5.3.Hz,6H),1.17(t,J=3.9Hz,6H),2.16(m,2H),2.70(m,2H),2.74(m,2H),6.70(s,1H),6.92(d,J=7.9Hz,1H),7.43(d,J=7.9Hz,2H),7.77(t,J=7.8Hz,1H),8.23(d,5=7.6Hz,1H),8.48(d,J=7.9Hz,1H);
LCMS:452.90[M+H]+。
<实施例39>N-(4b-羟基-7-异丙基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)-2-氧代-4-苯基丁酰胺的制备
0℃下将2-氧代-4-苯基丁酸(50mg,0.28mmol)加入到DCM(0.1M,3.0ml)中,搅拌,搅拌前先后加入HATU(160mg,0.42mmol)和DIPEA(0.07ml,0.42mmol)。最后,加入9b-氨基-4b-羟基-7-异丙基-4b,9b-二氢-10H-茚并[1,2-b]苯并呋喃-10-酮(83mg,0.28mmol),然后常温下搅拌12小时。反应结束,用水和DCM萃取,用水再次清洗后,用Na2SO4除去水分,然后减压下浓缩。最后,用填充有硅胶的色谱柱提纯,得到目标化合物(35mg,28%)。
1H-NMR(300MHz,CD30D):δ1.15-1.18(m,6H),1.91-.2.15(m,2H),2.72-2.88(m,3Η),3.07-3.11(m,1Η),6.67(s,1H),6.88-6.90(m,1H),7.14-7.22(m,4H),7.34-7.39(m,1H),7.52-8.03(m,5H);
LCMS:456.51[M+H]+。
<实施例40>N-(1-氨基-4b-羟基-7-异丙基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)-3-甲基-2-氧代戊酰胺的制备
将N-(4b-羟基-7-异丙基-4-硝基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)-3-甲基-2-氧代戊酰胺(80mg,0.18mmol)溶解于乙醇:水(10:1)(0.02M,9.0ml)中,加入铁粉(30mg,0.54mmol)并搅拌,最后缓慢加入浓盐酸(2滴),而后在120℃下反应3小时。
反应结束后,冷却至常温,减压下浓缩,用水和乙酸乙酯萃取,再次用水清洗后用Na2SO4除去水分,然后减压下浓缩。最后,用填充有硅胶的色谱柱提纯,得到目标化合物(40mg,53%)。
1H-NMR(300MHz,CD30D):δ0.85-0.94(m,3H),1.04-1.09(m3Η),1.18(d,J=6.7Hz,6H),1.30-1.40(m,2H),2.77-2.89(m,1H)6.65-6.71(m,2H),6.86-6.88(m,1H),6.98-7.01(m,1H),7.32-7.38(m,1H),7.42-7.48(m,1H);
LCMS:422.89[M+H]+。
<实施例41>3-溴-N-(4b-羟基-7-异丙基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)-2-氧代丙酰胺的制备
向THF(10ml,0.1M)中加入9b-氨基-4b-羟基-7-异丙基-4-硝基-4b,9b-二氢-10H-茚并[1,2-b]苯并呋喃-10-酮(425mg,1.44mmol)。缓慢加入TEA(0.417ml,1.29mmol)后,再加入3-溴-2-氧代丙酸(200mg,1.198mmol)。冷却至-10℃后,缓慢加入0.2M的三氯氧磷溶液(12.0ml,2.40mmol),搅拌5-6小时。反应结束后,减压下浓缩以除去THF,并且用水和乙酸乙酯萃取。再次用水清洗后,用Na2SO4除去水分,然后减压下浓缩。最后,用填充有硅胶的色谱柱提纯,得到目标化合物(70mg,13%)。
1H-NMR(300MHz,CDC13)δ1.19(dd,J=6.9Hz,J=2.4Hz,6H),2.87(sept,J=6.9Hz,1H),4.28-4.51(m,2H),6.79(s,1H)6.97(d,J=8.1Hz,1H),7.64-7.71(m,2H),7.88-7.93(m,2H),8.07(d,J=7.8Hz,1H).
<实施例42>N-(4b-羟基-7-异丙基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)-2,4-二氧代-4-(吡啶基-4-基)丁酰胺的制备
将2,4-二氧代-4-(吡啶-4-基)丁酸(25mg,0.13mmol)加入到DCM(1.5ml)中并冷却至0℃。再加入HATU(74mg,0.19mmol)和DIPEA(0.034ml,0.19mmol)。5分钟后,加入9b-氨基-4b-羟基-7-异丙基-4b,9b-二氢-10H-茚并[1,2-b]苯并呋喃-10-酮(42mg,0.14mmol),而后搅拌24小时。用水淬火时,加入DCM(50ml x 2)。用水和乙酸乙酯萃取后,再次用水清洗,用Na2SO4除去水分,然后减压下浓缩。最后,用填充有硅胶的色谱柱提纯,得到目标化合物(45mg,74%)。
1H-NMR(300MHz,CD30D)δ1.19(d,J=6.9Hz,6H),2.83(sept,J=6.9Hz,1H),6.70(s,1H),6.91(s,1H),7.38(s,1H)7.64(s,1H),7.83-7.85(m,4H),7.97(s,1H),8.67-8.76(m,2H);
LCMS:470.77[M+H]+。
<实施例43>4-((4b-羟基-7-异丙基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)氨基)-4-氧代丁酸的制备
向EtOAc(10ml,0.06M)中加入4-((4b-羟基-7-异丙基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)氨基)-4-氧代丁酸三乙胺盐(300mg,0.60mmol)。常温下加入HCl(1N,10ml)后,搅拌5分钟。用水和乙酸乙酯萃取后,再次用水清洗,用Na2SO4除去水分,然后减压下浓缩。最后,用填充有硅胶的色谱柱提纯,得到目标化合物(240mg,计算)。
1H-NMR(300MHz,CD30D)δ1.16(d,J=6.9Hz,6H),2.53-2.60(m,4H),2.83(sept,J=6.9Hz,1H),6.87(d,J=7.8Hz,1H),7.37(d,J=7.8Hz,1H),7.57-7.60(m,1H),7.74-7.83(m,2H),7.90(s,1H);
LCMS:395.92[M+H]+。
<实施例44>N1-(4b-羟基-7-异丙基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)-N4,N4-二甲基琥珀酰胺的制备
向DCM(2.5ml)中加入4-((4b-羟基-7-异丙基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)氨基)-4-氧代丁酸(100mg,0.25mmol)并冷却至0℃。加入HATU(144mg,0.38mmol)和DIPEA(0.110ml,0.63mmol)后,搅拌5分钟。加入氯化二甲基胺(25mg,0.30 mmol)后,搅拌24小时。用水淬火时,加入DCM(50ml x 2)。用水和乙酸乙酯萃取后,再次用水清洗,用Na2SO4除去水分,然后减压下浓缩。最后,用填充有硅胶的色谱柱(2:1=EtOAc:己烷)提纯,得到目标化合物(60mg,56%)。
1H-NMR(300MHz,CD30D)δ1.16(d,J=6.9Hz,6H),2.59(m,4H),2.81(sept,J=6.9Hz,1H),2.90(s,3H),3.01(s,3H),6.86(d,J=7.8Hz,1H),7.36(d,J=7.8Hz,1H),7.56-7.59(m,1H),7.73-7.82(m,2H),7.90-7.92(m,1H);
LCMS:422.96[M+H]+,844.92[2M+H]+。
<实施例45>N1-(4b-羟基-7-异丙基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)-N4-异丙基琥珀酰胺的制备
向DCM(2.5ml)中加入4-((4b-羟基-7-异丙基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)氨基)-4-氧代丁酸(100mg,0.25mmol)并冷却至0℃。加入HATU(144mg,0.38mmol)和DIPEA(0.066ml,0.38mmol)后,搅拌5分钟。加入异丙胺(0.025ml,0.30mmol)后,搅拌24小时。用水淬火时,加入DCM(50ml x 2)。用水和乙酸乙酯萃取后,再次用水清洗,用Na2SO4除去水分,然后减压下浓缩。最后,用填充有硅胶的色谱柱(DCM:EtOAc=1:1)提纯,得到目标化合物(30mg,27%)。
1H-NMR(300MHz,CD30D)δ1.10(d,J=6.6Hz,6H),1.16(d,J=6.9Hz,6H),2.38(t,J=7.8Hz,2H),2.55(t,J=7.8Hz,2H),2.82(sept,J=6.9Hz,1H),3.92(sept,J=6.6Hz,1H)6.64(s,1H),6.86(d,J=7.8Hz,1H),7.35(d,J=7.8Hz,1H),7.53-7.83(m,4H);
LCMS:436.91[M+H]+,873.01[2M+H]+。
<实施例46>N-(4b-羟基-7-异丙基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)氨腈的制备
向THF(5ml,0.1M)中加入9b-氨基-4b-羟基-7-异丙基-4b,9b-二氢-10H-茚并[1,2-b]苯并呋喃-10-酮(295mg,1.0mmol)并冷却至0℃。缓慢加入TEA(0.14ml,1.0mmol)。缓慢加入5ml溴化氰(95.2mg,0.9mmol)溶液15分钟并搅拌。搅拌在0℃下进行3小时。过滤并分离固体并用THF清洗该固体。过滤分离的液体在减压下(DCM/己烷)浓缩并重新结晶以得到目标化合物(150mg,47%)。
1H-NMR(300MHz,CD30D)δ1.14-1.20(s.6H),2.86(sept,J=6.9Hz,1H),6.80(s,1H),6.95(d,J=7.8Hz,1H),7.51(d,J=7.8Hz,1H),7.67-7.72(m,1H),7.84-8.10(m,3H);
LCMS:320.77[M+H]+,640.86[2M+H]+。
<实施例47>N1-(4-氨基-(4b-羟基-7-异丙基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)-N2-(2,6-二甲基苯基)草酰胺的制备
向10ml的10:1的乙醇与水的混合物中加入N1-(2,6-二甲基苯基)-N2-(4b-羟基-7-异丙基-4-硝基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)草酰胺(70mg,0.136mmol)、Fe(23mg,0.407mmol)和HCl(两滴),90℃下搅拌2小时。用赛力特硅藻土(celite)过滤后进行浓缩。用乙酸乙酯(EA)稀释后用水清洗,萃取EA层。浓缩反应物并用硅胶色谱柱(己烷中50%EA)提纯,以得到目标化合物(43mg,65%)。
1H-NMR(500MHz,DMS0-d6):δ1.14(s,6H),2.12(s-6H),2.75-2.91(m,1H),6.66-6.70(m,3H),6.85-6.92(m,2H),7.05-7.10(m,3H),8.09(s,1H),8.39(s,1H),10.12(s,1H);
LCMS:485.74[M+H]+971.09[2M+H]+。
<实施例48>N-(4b-羟基-7-异丙基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)-2-(4-甲基哌嗪-1-基)-2-氧代乙酰胺的制备
0℃下向DCM(0.1M,5.0ml)中加入2-(4-甲基哌嗪-1-基)-2-氧代乙酸(80mg,0.46mmol)并搅拌后,加入HATU(262mg,0.69mmol)和DIPEA(0.12ml,0.69mmol)并搅拌。最后,加入9b-氨基-4b-羟基-7-异丙基-4b,9b-二氢-10H-茚并[1,2-b]苯并呋喃-10-酮(150mg,0.51mmol),然后常温下搅拌12小时。反应结束后,过滤形成的固体并在EA中再次溶解。用水和乙酸乙酯萃取用水清洗后,用Na2SO4除去水分,然后减压下浓缩以得到目标化合物(70mg,33%)。
1H-NMR(300MHz,CD30D):δ1.15(d,J=6.9Hz,6H),2.54(s,3H),2.79-2.81(m,4H),3.70(s,2H),3.82(s,2H),6.66(s,1H),6.87(d,J=7.9Hz,1H),7.36(d,J=7.9Hz,1H),7.71(s,2H),7.84(s,2H):
449.86[M+H]+for LCMS.
<实施例49>N-(1-氨基-(4b-羟基-7-异丙基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)-4-甲基-2-氧代戊酰胺的制备
向乙醇:水(10:1,5.5ml,0.02M)中加入N-(4b-羟基-7-异丙基-1-硝基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)-4-甲基-2-氧代戊酰胺(50mg,0.11mmol),在加热并于90℃下搅拌3小时进行前加入铁(19mg,0.33mmol)和乙酸(两滴)。用填充有赛力特硅藻土(celite)的分离管除去铁,而后减压下浓缩。加入过量的乙酸乙酯后,用水清洗,用Na2SO4除去水分,然后减压下浓缩,用硅胶柱色谱法提纯,得到目标化合物(36mg,78%)。
1H-NMR(300MHz,CDC13):δ0.93(d,J=4.5Hz,6H),1.16(d,J=6.8Hz,6H),2.13(m,1H),2.65(d,J=6.7Hz,2H),2.84(t,J=3.5Hz,1H),6.67(d,J=11.0Hz,2H),6.86(d,J=7.5Hz,1H),6.97(d,J=7.5Hz,1H),7.34(d,J=8.0Hz,1H),7.44(t,8.1Hz,1H);
LCMS:423.48[M+H]+。
<实施例50>N-(1-氨基-4b-羟基-7-异丙基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)-2-氧代己酰胺的制备
向乙醇:水(10:1,5.5ml,0.02M)中加入N-(4b-羟基-7-异丙基-1-硝基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)-2-氧代己酰胺(50mg,0.11mmol),在加热并于90℃下搅拌3小时进行前加入铁(19mg,0.33mmol)和乙酸(两滴)。用充满硅藻土的分离管除去铁,而后减压下浓缩。加入过量的乙酸乙酯后,用水清洗,用Na2SO4除去水分,然后减压下浓缩,用硅胶柱色谱提纯,得到目标化合物(21mg,42%)。
1H-NMR(300MHz,CD30D):δ0.89(s,4H),1.16(d,J=6.8Hz6H),1.53(m,2H),2.79(m,3H),2.98(s,1H),3.63(s,1H),6.65(m,2H,6.86(d,J-6.3Hz,1H),6.98(d,J=6.2Hz,1H),7.33(m,1H),7.44(m,1H);
LCMS:450.01[M+H]+。
<实施例51>N-(4b-羟基-7-异丙基-1-硝基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)-2均三甲苯基-2-氧代乙酰胺的制备
将均三甲苯基乙醛酸(100mg,0.52mmol)溶解于DCM(5.2ml,0.1M)中,再加入HATU(296.6mg,0.78mmol)和DIPEA(0.136ml,0.78mmol)。最后,在进行搅拌12小时之前加入胺化合物(193.9mg,0.57mmol)。反应结束后,用二氯甲烷、NaHCO3水溶液和水进行清洗并在减压浓缩前用Na2SO4除去水分。用硅胶柱色谱提纯,得到目标化合物(91mg,34%)。
1H-NMR(300MHz,CD30D)δ1.17(d,J=6.6Hz,6H),2.22(d,J=9.6Hz,9H),6.74(s,1H),6.82(s,1H),6.95(d,J=7.8Hz,2H)7.44(d,J=7.8Hz,1H),7.79(s,1H),8.11(d,J=6.9Hz,1H),8.46(s,1H);
LCMS:515.0[M+H]+。
<实施例52>N-(1-氨基-(4b-羟基-7-异丙基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)-2-氧代戊酰胺的制备
向乙醇:水=10:1(5ml,0.02M)中加入N-(4b-羟基-7-异丙基-1-硝基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)-2-氧代戊酰胺(50mg,0.114mmol),然后加入铁(19.1mg,0.34mmol)和一滴HCl(催化),接着在90℃下搅拌4小时。反应结束后,用二氯甲烷和水清洗,用Na2SO4除去水分,用制备TLC得到目标化合物(21mg,42%)。
1H-NMR(300MHz,CD30D)δ0.93(t,7.5Hz,3H),1.17(d6.6Hz,6H),1.28(br,1H),1.57-1.64(m,2H),2.74-2.85(m,2H),6.66-6.70(m,2H),6.86(d,J=7.5Hz,1H),6.99(d,J=7.5Hz,1H)7.35(d,J=7.5Hz,1H),7.43-4.47(m,1H);
LCMS:409.8[M+H]+。
<实施例53>N-(4b-羟基-7-异丙基-4-硝基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)-2-氧代-4-苯基丁酰胺的制备
将2-氧代-4-苯基丁酸(50mg,0.28mmol)溶解于DCM(2.81ml,0.1M)中,再加入HATU(160mg,0.42mmol)和DIPEA(0.073ml,0.42mmol)和硝基化合物(105.1mg,0.31mmol),而后在室温下搅拌12小时。反应结束后,在用Na2SO4除去水分前,用二氯甲烷、NaHCO3水溶液和水进行清洗。用硅胶柱色谱提纯,得到目标化合物(35mg,25%)。
1H-NMR(300MHz,CD30D)δ1.18(d,J=6.3Hz,6H),2.82-2.93(m,4H),3.10-3.11(m,1H),6.73(s,1H),6.94(d,1=7.2Hz,1H),7.14-7.26(m,5H),7.39(t,7.2Hz,1H),7.86-7.89(m,1H),8.51-8.55(m,1H);
LCMS:501.5 1[M+H]+。
<实施例54>N-(1-氨基-4b-羟基-7-异丙基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)-2均三甲苯基-2-氧代乙酰胺的制备
在加入铁(19.1mg,0.34mmol)和一滴HCl(催化)之前,将N-(4b-羟基-7-异丙基-1-硝基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)-2-氧代戊酰胺(50mg,0.114mmol)溶解于乙醇:水=10:1(5ml,0.02M)中,然后在90℃下搅拌4小时。反应结束后,用二氯甲烷和水清洗,用制备TLC得到目标化合物(19.7mg,42%)。
1H-NMR(300MHz,CD30D)δ1.88(d,J=6.6Hz,6H),2.23(d,J=9.6Hz,9H),2.79-2.86(m,1H),6.65(d,7.5Hz,2H),6.83(s,2H),6.89(d,J=7.5Hz,1H),6.98(d,J=7.5Hz,1H),7.41(t,J=8.1Hz,2H);
LCMS:485.8[M+H]+。
<实施例55>N,N’-二叔丁氧基羰基[1]-(4b-羟基-7-异丙基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)胍的制备
向9b-氨基-4b-羟基-7-异丙基-4b,9b-二氢-10H-茚并[1,2-b]苯并呋喃-10-酮(295mg,1.00mmol)中添加DMF(5ml,0.2M)和1,3-双(叔丁氧基羰基)-2-甲基-2-异硫脲(305mg,1.05mmol)。在0℃下加入HgCl2(298mg,1.10mmol)后,再加入三乙胺(0.31ml,2.20mmol),搅拌90分钟。反应结束后,加入乙酸乙酯(50ml)并在赛力特硅藻土(celite)上过滤。用水和盐水清洗后,用Na2SO4除去水分,用硅胶柱色谱(己烷中10%的乙酸乙酯)提纯,得到目标化合物(21mg,42%)。
1H-NMR(300MHz,CD30D)δ1.18(d,J=6.9Hz,6H),1.20(s,9H),1.51(s,9H),2.82(sept,J=6.9Hz,1H),6.66(s,1H),6.87(br,1H),7.34(br,1H),7.72-7.84(m,4H);
LCMS:537.89[M+H]+。
<实施例56>(4b-羟基-7-异丙基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)乙烷-1,2-二基二氨基甲酸叔丁酯的制备
向7-异丙基-10H-4b,9b-(环氧基甲氧基)茚并[1,2-b]苯并呋喃-10,12-二酮(170mg,0.5mmol)中加入THF:DMF(8:1)和(2-氨基乙基)氨基甲酸叔丁酯(80mg,0.50mmol)。在进行室温下搅拌6小时前,加入DMAP(2–3mg)和TEA(0.14ml,1.11mmol)。反应结束后,减压下浓缩,而后用硅胶柱色谱(己烷中20%的乙酸乙酯)提纯,得到目标化合物(200mg,83%)。
1H-NMR(300MHz,CDC13)δ1.15(dd,J=6.9Hz,J=2.4Hz,6H),1.41(s,9H),2.80(septet,J=6.9Hz,1H),3.12-3.22(m,4H),5.03(s,1H),6.65(s,1H),6.77(d,J=7.8Hz,1H),7.34(d,J=7.8Hz,1H),7.48-7.53(m,1H),7.70-7.79(m,2H),7.87(d,J=7.5Hz,1H);
LCMS:483.23[M+H]+,966.40[2M+H]+。
<实施例57>4-((4b-羟基-7-异丙基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)氨基)-4-氧代丁酸的制备
向9b-氨基-4b-羟基-7-异丙基-4b,9b-二氢-10H-茚并[1,2-b]苯并呋喃-10-酮(295mg,1.00mmol)和无水琥珀酸中加入干燥的THF(10ml,0.1M)和TEA(0.167ml,1.20mmol)。加入DMAP(10mg)后,在回流设备中搅拌8小时。反应结束后,冷却至室温,然后过滤固体。滤液用THF清洗以得到目标化合物(360mg,73%)。
1H-NMR(300MHz,DMS0-d6)δ0.97(t,J=7.2Hz,9H),1.11(d,J=6.9Hz,6H),2.28-2.30(m,2H),2.38-2.40(m,2H),2.51-2.55(m,6H),2.79(sept,J=6.9Hz,1H),6.64(s,1H),6.85(d,J=7.8Hz,1H),7.73-7.77(ra,4H),8.72(br,1H);
LCMS:395.85[M+H]+。
<实施例58>N-(4b-羟基-7-异丙基-4-硝基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)2-氧代-2-(3,4,5-三甲氧基苯基)乙酰胺的制备
将9b-氨基-4b-羟基-7-异丙基-4-硝基-4b,9b-二氢-10H-茚并[1,2-b]苯并呋喃-10-酮(72mg,0.21mmol)加入到DMF(3ml,0.1mmol)后,再加入HATU(118mg,0.31mmol)和DIPEA(0.6ml,0.31mmol)。加入2-氧代-2-(3,4,5-三甲氧基苯基)乙酸(50mg,0.21mg)后,常温下搅拌5小时。加入过量的DCM并用水清洗后,用Na2SO4除去水分,减压下浓缩。用硅胶柱色谱提纯得到目标化合物(55mg,46%)。
1H-NMR(300MHz,CDC13):δ1.19(d,J=10.0Hz,6H),2.16(s,9H),2.84(m,1H),6.49(s,1H),6.72(s,1H),6.94(d,J=7.9Hz,1H),7.46(d,J=7.9Hz,1H),7.60(s,1H),7.65(s,2H),7.79(t,J=7.8Hz,1H),8.27(d,J=7.6Hz,1H),8.49(d,J=8.0Hz,1H);
LCMS:562.79[M+H]+。
<实施例59>N-(4b-羟基-7-异丙基-4-硝基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)-2-氧代-4-苯基丁酰胺的制备
将N-(4b-羟基-7-异丙基-4-硝基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)-2-氧代-4-苯基丁酰胺(50mg,0.10mmol)溶解于乙醇:水10:1(2ml,0.05M)后,搅拌。最后,加入一滴HCl,然后在90℃下搅拌12小时。反应结束后,冷却至常温,减压下浓缩。在用水清洗前,用水和乙酸乙酯萃取,用Na2SO4除去水分,减压下浓缩。最后,用填充有硅胶的色谱柱提纯,得到目标化合物(20mg,43%)。
1H-NMR(300MHz,CD30D)δ1.17(d,J=6.3Hz,6H),2.74-2.97(m,4H),3.06-3.13(m,1H),6.66-6.69(m,2H),6.87(d,J=7.2Hz,1H),6.99(t,J=7.2Hz,1H),7.14-7.23(m,5H),7.35(d,J=7.8Hz,1H),7.44(t,J=7.8Hz,1H);
LCMS:471.9[M+H]+。
<实施例60>N-(4b-羟基-7-异丙基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)乙酰亚胺酰胺(acetimide amide)的制备
将9b-氨基-4b-羟基-7-异丙基-4b,9b-二氢-10H-茚并[1,2-b]苯并呋喃-10-酮(150mg,0.5mmol)溶解于乙腈(ACN)(5ml,0.1M)后,搅拌同时加入乙基乙酰亚胺(189mg,1.5mmol)。
加入DIPEA(0.02ml,1.27mmol)后,回流12小时。反应结束后,冷却至常温,然后减压下浓缩。在用水清洗前,用水和乙酸乙酯萃取,用Na2SO4除去水分,减压下浓缩。最后,向混合物中加入DCM/己烷进行重结晶以得到目标化合物(38mg,23%)。
1H-NMR(300MHz,CD30D)δ1.19(d,J=6.9Hz,6H),1.96(s,3H),2.81(sept,J=6.9Hz,1H),6.60(s,1H),6.79(d,J=8.1Hz,1H),7.30(d,J=8.1Hz,1H),7.52-7.54(m,1H),7.73-7.80(m,3H);
LCMS:336.88[M+H]+。
<实施例61>1-(4b-羟基-7-异丙基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)硫脲的制备
将9b-氨基-4b-羟基-7-异丙基-4b,9b-二氢-10H-茚并[1,2-b]苯并呋喃-10-酮(2.95g,10.0mmol)溶解于丙酮:水(2:1,100ml)后,加入硫氰酸钾(4.86g,49.99mmol)。加入5ml浓盐酸后,常温下搅拌12小时。反应结束后,用水和乙酸乙酯萃取,然后再次用盐水清洗。用Na2SO4除去水分后,减压下浓缩,用硅胶柱色谱(己烷中33%EA)提纯以得到目标化合物(2.64g,75%)。
1H-NMR(300MHz,CD30D)δ1.50-1.22(m,6H),2.83(sept,J=6.9Hz,1H),6.61(s,1H),6.86(d,J=8.1Hz,1H),7.35-7.89(m,5H);
LCMS:354.87[M+H]+,708.97[2M+H]+。
<实施例62>7-异丙基-4b-甲氧基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)氨基甲酸乙酯的制备
0℃下向DCM(12ml)中加入9b-羟基-7-异丙基-4b-甲氧基-4b,9b-二氢-10H-茚并[1,2-b]苯并呋喃-10-酮(950g,3.07mmol),在三光气(909mg,3.07mmol)溶解于TEA(0.43ml,3.07mmol)前进行搅拌,而后缓慢加入。大约10分钟后,减压下浓缩以除去任何过量的光气。而后,在加入由乙胺和甲醇(2.0M)混合制得的溶液(0.77ml,1.53mmol)之前,再次溶解DCM(12ml),而后加入TEA(0.43ml,3.07mmol)。常温下反应2小时后,用水和DCM萃取,并再次用盐水清洗。用Na2SO4除去水分后,减压下浓缩,用硅胶柱色谱(己烷中10%EA)提纯以得到目标化合物(350mg,60%)。
1H-NMR(300MHz,CDC13)δ1.09(t,J=7.2Hz,3H),1.20(dd,J=6.9Hz,J=4.8Hz,6H)2.87(septet,J=6.9Hz,1H),3.44-3.55(m,2H),3.65(s,1H),3.71(s,3H),6.77(s,1H),6.88-6.91(d,J=9Hz,1H),7.46-7.55(m,3H),7.61(d,J=7.8Hz,1H),7.72(d,J=7.2Hz,1H);
LCMS:382.29[M+H]+。
<实施例63>(2-((4b-羟基-7-异丙基-10-氧代-4b,10-二氢-9bH- 茚并[1,2-b]苯并呋喃-9b-基)氨基)-2-氧代乙基)氨基甲酸叔丁酯的制备
0℃下将甘氨酸(650mg,3.72mmol)溶解于DCM(20ml,0.2M),而后搅拌,再加入HATU(1.54g,4.06mmol)和DIPEA(0.734ml,4.06mmol)进行反应。大约5分钟后,加入9b-氨基-4b-羟基-7-异丙基-4b,9b-二氢-10H-茚并[1,2-b]苯并呋喃-10-酮(0.025ml,0.30mmol),反应进行6小时。反应结束后,用水和DCM(50ml X 2)萃取,用盐水再次清洗。用Na2SO4除去水分后,减压下浓缩,用硅胶柱色谱(己烷中10%EA)提纯所得混合物以得到目标化合物(1.30g,85%)。
1H-NMR(300MHz,CD30D)δ1.15(d,J=6.9Hz,6H),1.41(s,9H),2.81(sept,J=6.9Hz,1H),3.82(s,2H),6.65(s,1H),6.86(d,J=7.8Hz,1H),7.34(d,J=7.8Hz,1H),7.57(br,1H)7.77-7.90(br,3H);
LCMS:452.83[M+H]+,904.94[2M+H]+
<实施例64>2-氨基-N(4b-羟基-7-异丙基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)乙酰胺的制备
向DCM(10ml,0.2M)中加入(2-((4b-羟基-7-异丙基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)氨基)-2-氧代乙基)氨基甲酸叔丁酯(900mg,2.00mmol),搅拌,并加入三氟乙酸(1.52ml,20.0mmol)。常温下反应12小时后,在反应结束时,用DCM(150ml)和过饱和的NaHCO3(50ml x 2)萃取,而后再用盐水(50ml)进行清洗。用Na2SO4除去水分后,并在减压下浓缩以得到目标化合物(670mg,96%)。
1H-NMR(300MHz,CD30D)δ1.16(d,J=6.9Hz,6H),2.82(sept,J=6.9Hz,1H),3.34(s,2H),6.65(s,1H),6.86(d,J=7.8Hz,1H),7.35(d,J=7.8Hz,1H),7.69-7.72(m,2H);
LCMS:352.51[M+H]+,704.85[2M+H]+。
<实施例65>4b-羟基-7,8-二甲基-9b-(甲基氨基)-4b,9b-二氢-10H-茚并[1,2-b]苯并呋喃-10-酮的制备
将9b-氯-4b-羟基-7,8-二甲基-4b,9b-二氢-10H-茚并[1,2-b]苯并呋喃-10-酮(2g,6.65mmol)溶解于THF(66ml,0.1M)后,保持反应温度为-200℃。依次加入甲胺(6.65ml,13.30mmol)后,进行反应5 小时。反应结束后,减压下浓缩THF并将其除去,而后在用盐水再次清洗前,用DCM和水萃取。用Na2SO4除去水分后,用硅胶柱色谱提纯以得到目标化合物(710mg,36%)。
1H-NMR(300MHz,CDC13)δ2.17(s,6H),2.31(s,6H),6.64(s,1H),7.13(s,1H),7.49(t,J=7.5Hz,1H),7.76(t,J=7.5Hz,2H),7.98(d,J=7.5Hz,1H);
LCMS:295.44[M+H]+。
<实施例66>N-叔丁氧基羰基[N3-(4b-羟基-7-异丙基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)]胍的制备
将N’,N’-二叔丁氧羰基[11-(4b-羟基-7-异丙基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)]胍(200mg,0.37mmol)溶解于MeOH(2ml,0.2M)后,加入2N HCl(1.0ml,5eq.approx.),同时搅拌。常温下反应12小时后,在反应结束时减压下浓缩,然后立即用硅胶柱色谱(DCM中3%MeOH)提纯,减压下浓缩并干燥以得到目标化合物(115mg,71%)。
1H-NMR(300MHz,CD30D)δ1.19(d,J=6.9Hz,6H),1.50(s,9H),2.85(sept,J=6.9Hz,1H),6.68(s,1H),6.88(d,J=7.8Hz,1H),7.38(d,J=7.8Hz,1H),7.54-7.62(m,2H),7.73-7.78(m,2H);
LCMS:437.86[M+H]+,875.03[2M+H]+。
<实施例67>N,N’-二叔丁氧基羰基[1-(4b-羟基-7,8-二甲基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)]-1-甲基胍的制备
将4b-羟基-7,8-二甲基-9b-(甲基氨基)-4b,9b-二氢-10H-茚并[1,2-b]苯并呋喃-10-酮(295.3mg,1.0mmol)溶解于DMF(0.2M,5ml)中后,加入1,1,2,3,3-五甲基碘化异硫脲(287.7mg,1.05mmol)。0℃下搅拌并加入TEA和HgCl2(298.7mg,1.1mmol)进行反应2小时。反应结束后,用水和乙酸乙酯萃取并用盐水再次清洗。用Na2SO4除去水分后,用硅胶柱色谱提纯以得到目标化合物(120mg,22%)。
1H-NMR(300MHz,CD30D)δ1.46(s,9H),1.49(s,9H),2.21(s,6H),2.26(s,3H),6.62(s,lH),7.20(s,1H),7.74-7.50(m,2H),7.62(d,J=6.9Hz,1H),7.81(d,J=6.9Hz,1H);
LCMS:538.3[M+H]+。
<实施例68>N-(4b-羟基-7-异丙基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)噻吩-2-磺酰胺的制备
向乙腈(ACN)(17ml,0.1M)中添加并溶解9b-氨基-4b-羟基-7-异丙基-4b,9b-二氢-10H-茚并[1,2-b]苯并呋喃-10-酮(500mg,1.69mmol)后,加入苯磺酰氯(0.24ml,1.86mmol)。加入吡啶(0.27,3.38mmol)后,常温下进行反应12小时。反应结束后,用水和DCM萃取,而后用盐水清洗。用Na2SO4除去水分后,用硅胶柱色谱提纯以得到目标化合物(460mg,62%)。
1H-NMR(300MHz,CDC13)δ1.15(d,J=6.9Hz,6H),2.71-2.80(m,1H),6.00(br,1H),6.09(br,1H),6.30(d,J=7.8Hz,1H),6.52(d,J=7.8Hz,1H),6.70(s,1H),6.77(t,J=4.5Hz,1H),6.93-6.94(m,1H),7.45(d,J=4.5Hz,1H),7.55(t,J=7.8Hz,1H),7.75-7.84(m,2H),8.03(d,J=7.8Hz,1H);
LCMS:440.0[M+H]+。
<实施例69>N-(4b-羟基-7-异丙基-4-硝基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)苯磺酰胺的制备
将9b-氨基-4b-羟基-7-异丙基-4b,9b-二氢-10H-茚并[1,2-b]苯并呋喃-10-酮(500mg,1.7mmol)溶解于DCM(17ml,0.1M)并加入苯磺酰氯(0.24ml,1.86mmol)后,加入K2CO3(467mg,3.38mmol)和18-冠醚-6(89mg,0.34mmol),而后在室温下搅拌12小时。用DCM稀释反应混合物后,用水和盐水清洗,用Na2SO4除去水分后,减压下浓缩。用硅胶柱色谱提纯以得到目标化合物(190mg,26%)。
1H-NMR(300MHz,CDC13)δ1.22(d,J=7.8Hz,6H)2 89-2.93(m,1H),6.81(s,1H),7.05(d,J=8.1Hz 1H),7 49(t,J=7.5Hz,2H),7.59-7.69(m,2H),7.83-7.95(m3H),8 11(d,J=7.8Hz,3H);
LCMS:434.0[M+H]+。
<实施例70>4b-羟基-7,8-二甲基-9b-(吡啶-2-基氨基)-4b,9b)二氢-10H-茚并[1,2b]苯并呋喃-10-酮的制备
将9b-氯-4b-羟基-7,8-二甲基-4b,9b-二氢-10H-茚并[1,2-b]苯并呋喃-10-酮(300mg,1.0mmol)溶解于THF(10ml,0.1M)并冷却至-30℃后,加入2-氨基吡啶(98.5mg,1.05mmol)。相同温度下加入TEA(0.153ml,1.10mmol)后,允许反应物放置2小时直至达到室温。反应结束后,减压下进行浓缩。用乙酸乙酯(100ml)稀释浓缩的反应混合物,而后用水和盐水清洗;用Na2SO4除去水分后,减压下浓缩。用硅胶柱色谱(己烷中20–25%EtAc)提纯以得到目标化合物(150mg,42%)。
1H-NMR(300MHz,CDC13)δ2.07(s,3H),2.11(s,3H),5.50(s,1H),6.57(s,1H),6.64-6.68(m,1H),6.74(d,J=8.4Hz,1H),7.01(s,1H),7.43-7.55(m,2H),7.78-7.84(m,2H),7.92(d,J=4.8Hz,1H),8.06(d,J=7.8Hz,1H),9.06(s,1H);
LCMS:359.1[M+H]+for
<实施例71>N-(4b-羟基-7-异丙基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)丙烷-1-磺酰胺的制备
将9b-氯-4b-羟基-7,8-二甲基-4b,9b-二氢-10H-茚并[1,2-b]苯并呋喃-10-酮(300mg,1.0mmol)溶解于乙腈(ACN)(10ml,0.1M)中,加入1-丙酰氯(0.125ml,1.10mmol)。室温下加入吡啶(0.164ml,2.03mmol)后,搅拌10小时。反应结束后,减压下浓缩。用乙酸乙酯(100ml)稀释浓缩的反应混合物后,用水和盐水清洗。用Na2SO4除去水分后,减压下浓缩。用硅胶柱色谱(己烷中20%EA)提纯以得到目标化合物(195mg,48%黄色固体)。
1H-NMR(300MHz,CDC 13)δ0.96(t,J=7.5Hz,3H),1.18(dd,J=6.9Hz,J=4.2Hz,6H),1.78-1.91(m,2H),2.42-2.52(m,1H),2.63-2.77(m,1H),2.84(sept,J=6.9Hz,1H),5.50(s,1H),6.22(s,1H),6.77(s,1H),6.85(d,J=7.8Hz,1H),7.30(d,J=7.8Hz,1H),7.54-7.61(m,1H),7.77-7.94(m,2H),8.02(d,J=7.8Hz,1H);
LCMS:402.1[M+H]+。
<实施例72>1-氯-N-(4b-羟基-7-异丙基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)甲磺酰胺的制备
室温下将9b-氯-4b-羟基-7,8-二甲基-4b,9b-二氢-10H-茚并[1,2-b]苯并呋喃-10-酮(300mg,1.0mmol)溶解于乙腈(ACN)(10ml,0.1M),而后加入氯代甲烷磺酰氯(0.102ml,1.10mmol),进行搅拌10小时前,加入吡啶(0.164ml,2.03mmol)。反应结束后,减压下浓缩。用乙酸乙酯(100ml)稀释浓缩的反应混合物后,用水和盐水清洗。用Na2SO4除去水分后,减压下浓缩。用硅胶柱色谱(己烷中20%EA)提纯以得到目标化合物(150mg,38%黄色固体)。
1H-NMR(300MHz,CDC13)δ1.18(dd,J=6.9Hz,J=4.2Hz,6H),2.84(sept,J=6.9Hz,1H),3.74(d,J=12.0Hz,1H),4.47(d,J=12.0Hz,1H),6.75(s,1H),6.87(d,J=7.8Hz,1H),7.44(d,J=7.8Hz,1H),7.55-7.60(m,1H),7.76—7.86(m,2H),8.02(d,J=7.8Hz,1H);
LCMS:408.1[M+H]+。
<实施例73>9b-((4,5-二氢噻唑基-2-基)氨基)-4b-羟基-7-异丙基-4b,9b-二氢-10H-茚并-[1,2-b]苯并呋喃-10-酮的制备
将9b-氯-4b-羟基-7,8-二甲基-4b,9b-二氢-10H-茚并[1,2-b]苯并呋喃-10-酮(315mg,1.0mmol)溶解于THF(10ml,0.1M)并冷却至-78℃后,加入2-氨基氯化噻唑(146mg,1.05mmol)。相同温度下加入TEA(0.307ml,2.20mmol)。室温下搅拌3小时。反应结束后,减压下进行浓缩。用乙酸乙酯(100ml)稀释浓缩反应混合物,而后用水和盐水清洗。用Na2SO4除去水分后,减压下浓缩。用硅胶柱色谱(2:1=EA:己烷)提纯以得到目标化合物(210mg,55%)。
1H-NMR(300MHz,CD30D)δ1.20(d,J=6.9Hz,6H),2.83(sept,J=6.9Hz,1H),3.49-3.72(br,4H),6.65(s,1H),6.83(d,J=7.8Hz,1H),7.17(d,J=7.8Hz,1H),7.53-7.80(m,4H);
LCMS:381.1[M+H]+。
<实施例74>4b-羟基-7-异丙基-9b-(恶唑-2-基氨基)-4b,9b-二氢-10H-茚并-[1,2-b]苯并呋喃-10-酮的制备
将9b-氯-4b-羟基-7-异丙基-4b,9b-二氢-10H-茚并[1,2-b]苯并呋喃-10-酮(316mg,1.00mmol)溶解于THF(10ml,0.1M)。-30℃下加入3-氨基异恶唑(89mg,1.05mmol)和TEA(0.15ml,1.1mmol)后,室温下搅拌8小时。浓缩THF并将其溶解于DCM后,用水和盐水清洗。萃取有机层,用Na2SO4除去水分后,减压下浓缩。用硅胶柱色谱提纯以得到目标化合物(50mg,14%)。
1H-NMR(300MHz,CDC13)δ1.13-1.16(m,6H),2.75-2.85(m,1Η),5.37(br,1H),5.92(br,1H),6.10(s,1H),6.71(s,1H),6.77(d,J=7.8 Hz,1H),7.22(d,J=7.8Hz,1H),7.55(t,J=7.2Hz,1H),7.79-7.84(m,2H);7.98(s,1H),8.04(d,J=7.8Hz,1H);
LCMS:363.1[M+H]+。
<实施例75>4b-羟基-7-异丙基-9b-(吡啶-2-基氨基)-4b,9b-二氢-10H-茚并-[1,2-b]苯并呋喃-10-酮的制备
将9b-氯-4b-羟基-7-异丙基-4b,9b-二氢-10H-茚并[1,2-b]苯并呋喃-10-酮(315mg,1.0mmol)溶解于THF(10ml,0.1M)中。-30℃下加入2-氨基吡啶(98.5mg,1.05mmol)后,再加入TEA(0.153ml,1.10mmol)。温度升至常温后进行搅拌4小时。反应物浓缩并用乙酸乙酯(100ml)稀释后,用水(50ml x 2)和盐水(50ml)清洗。萃取有机层,用Na2SO4除去水分后,并在减压下浓缩。用硅胶柱色谱(己烷中20%EA)提纯以得到目标化合物(174mg,47%)。
1H-NMR(300MHz,CDC 13)δ1.12(dd,J=6.9Hz,J=3.0Hz6H),2.76(sept,J=6.9Hz,1H),5.48(s,1H),6.64-6.75(m,4H)7.16(d,J=7.8Hz,1H),7.43-7.57(m,2H),7.79-7.85(m,2H),7.91(d,J=4.5Hz,1H),8.07(d,J=7.8Hz,1H),9.05(s,1H);
LCMS:373.1[M+H]+。
以下表1显示以上实施例1-75制备的化合物的化学结构式
[表1]
<实验例1>用细胞病变效应(CPE)抑制试验确定药物对抗小核糖核酸病毒的功效
在该试验中,利用了HeLa(人宫颈癌细胞),MRC-5(人类胎儿肺成纤维细胞)和RD细胞(来自人类横纹肌肉瘤)。为了对比,使用三唑核苷(Riv)、普拉康纳利(pleco)和BTA-798(BTA)作为对照。试剂以10-40mg/ml的浓度溶解于100%的二甲亚砜(DMSO)中。水溶性试剂溶解于PBS(-)溶液并在-20℃下储藏。实验当天,它们按3-5倍的浓度被使用,此种方式使得二甲亚砜在各孔中的浓度均在0.5%和1%之间。
使用病毒诱导的细胞病变效应抑制试验来确定药学上的功效。就这点而言,适于病毒的细胞在96孔板上生长后,将补充有2%FBS的DME(DME/2%FBS)或补充有2%FBS的MEM(MEM/2%FBS)中的病毒的稀释液以100ul的量、以对应于100CCID50(50%细胞培养感染剂量)的浓度接种于板上的每个孔中,并且在33℃或37℃下培养30分钟-1小时以允许病毒吸附到细胞上。在将等份的不同浓度的药物稀释液以100ul的量向每个孔板加入之前,移除培养基。HRV(人类鼻病毒)在33℃下生长时,其他病毒在37℃下CO2培养器中培养2-3天。或者,细胞添加50ul具有2倍高浓度的每种药物稀释液以及然后添加50ul病毒稀释液之后,在不移除培养基的条件下培养它们2-3天。
每种病毒的测试条件总结于以下表2:
[表2]
对于HeLa细胞,使用MTT测试法测量药物的EC50(50%最大有效浓度),其是诱发基线与最大值之间一半响应时的浓度。关于RD和MRC-5细胞,使用FDA(荧光素二乙酸酯)确定CPE。为了确定药物毒性对功效结果的影响,在以病毒接种的同时,向细胞培养基中添加无病毒培养基,然后将其经过相同的处理作为以病毒接种的模拟感染细胞。即培养1小时后移除培养基,多次向培养基中加入药物的稀释液。培养2-3天后,在显微镜下观察细胞,用MTT试验确定药物的CC50(50%细胞毒性浓度),在该浓度下50%的细胞被杀死,其中将包含药物的模拟受感染的孔中的活细胞数与不含药物的对照孔中的活细胞数进行比较。在FDA水解试验中,移除培养基后,向每个孔中加入FDA,在使用与MTT中相同的方式用分光荧光计测量荧光强度以确定CPE之前,培养20-30分钟。
即用以下数学公式1计算模拟受感染的细胞的细胞毒性测量的存活率(存活百分比)
[数学公式1]
尽管100%的细胞存活率意味着该药物没有细胞毒性,0%的细胞存活率反映了细胞具有最高的毒性。50%的细胞毒性浓度定义为降低50%的细胞数量所需浓度。药物的该浓度表示为CC50。较高的数值意味着较低的细胞浓度。
此外,可用以下数学公式2计算抗病毒效果。
[数学公式2]
如果存活率为100%,则其抗病毒效果为100%,而如果存活率为0,则没有抗病毒效果。感染病毒的孔内的细胞呈现50%的存活率的药物浓度计算为EC50,数值越低,则其抗病毒效果越好。
以下表3列出了显示出对抗一些实施例中的化合物的细胞毒性的LC50浓度以及显示出对抗一些属于小核糖核酸病毒的鼻病毒的活性的EC50浓度。
[表3]
如以上表3所示,依据本发明的大部分新型化合物显示出较高的CC50浓度,并因而发现其具有较低的细胞毒性。此外,发现依据本发明的新型化合物大部分对一些鼻病毒(HRV)具有较高的抗病毒活性。
因此,鉴于依据本发明的实施例中的化合物显示出较低的细胞毒性以及对抗各种鼻病毒的高抗病毒活性,其通常可有效地用作预防或治疗由属于小核糖核酸病毒的病毒所引起的疾病。
<实验例2>用多周期细胞病变效应(CPE)降低试验确定药物抗小核糖核酸病毒的功效
多周期CPE降低试验被用于确定药物抗小核糖核酸病毒的功效。化合物的抗病毒活性首先基于MIS[3-(4,5-二甲基噻唑基-2-基)-5-(3-羧基甲氧基苯基)-2-(4-磺苯基)-2H-四唑通过CPE降低试验确定。
具体而言,将生长以聚集在96孔板的细胞以100病毒的50%细胞培养感染剂量(CCID50)感染。37℃下吸附2小时后,移除病毒并加入化合物的系列稀释液。培养基在37℃下进一步培养3天,直至感染和未处理的病毒对照(VC)中均观察到完整的CPE。移除培养基后,向每个孔中加入90ul培养基和10ul MTS-吩嗪硫酸甲酯(Promega,Leiden,TheNetherlands)。37℃下培养2小时后,在酶标仪上498nm处读取每个孔的光密度。
用以下数学公式3计算用于评估抗病毒活性的%CPE:
[数学公式3]
用以下数学公式4计算用于测量药物细胞毒性的%CPE:
[数学公式4]
在以上数学公式3和4中,
OD(CC)代表既没有被病毒诱导又未经化学处理的背景细胞培养基的OD,
OD(VC)代表被病毒诱导但未经化学处理的对照细胞培养基的OD,
OD(病毒+化合物)代表已经被以一定浓度的化合物处理的病毒感染的细胞培养基的OD,
OD(化合物)代表已经仅以一定浓度的化合物处理的细胞培养基的OD,以及
OD(空白)代表仅加入细胞培养基的孔的OD。
有效浓度(EC50)代表通过诱导的病毒的CPE允许50%的细胞存活的药物浓度,细胞毒性浓度(CC50)代表化合物杀死50%的细胞的药物浓度,其通过对数内插法进行计算。
以下表4列出了实施例中一些化合物对抗各种病毒的毒性浓度(CC50)和有效浓度(EC50)。
[表4]
如以上表4所示,依据本发明的新型化合物大多显示出较高的CC50浓度并且发现具有较低的细胞毒性。此外,发现依据本发明的新型化合物大多具有较高的对抗柯萨基病毒B1(CoxB1)、柯萨基病毒B3(CoxB3)和脊髓灰质炎病毒3(PV3)的抗病毒活性。
因此,由于根据本发明的实施例中的化合物具有较低的细胞毒性并显示出较高的对抗柯萨基病毒、脊髓灰质炎病毒和鼻病毒所属的小核糖核酸病毒的抗病毒活性,因此,其可有效用于预防或治疗由以下病毒引起的疾病,诸如呼吸道、心循环和神经系统疾病,包括脊髓灰质炎、急性出血性结膜炎、病毒性脑膜炎、手足口病、水疱病、甲型肝炎、肌炎、心肌炎、胰腺炎、糖尿病、流行性肌痛、脑炎、流感、疱疹性咽峡炎、口蹄疫疾病、哮喘、慢性阻塞性肺病、肺炎、鼻窦炎或中耳炎。
<制剂实例1>药物制剂的制备
<1-1>粉剂的制备
式1或式2所示的化合物 2g
乳糖 1g
混合以上原料并将其填充于密封囊中以制备粉剂。
<1-2>片剂的制备
混合以上原料并根据制备片剂的典型方法制备成片剂。
<1-3>胶囊剂的制备
混合以上原料并根据制备胶囊剂的典型方法将其放入胶囊内。
<1-4>注射剂的制备
式1或式2所示的化合物 10μg/ml
稀盐酸BP 直至pH达到3.5
注射用氯化钠BP 最大1ml
用注射用氯化钠BP溶解合适体积的依据本发明的化合物,用稀盐酸BP调节溶液pH至3.5,充分混合前,注射用氯化钠BP用于控制体积。将该溶液加入到5ml透明玻璃制成的I型安瓿瓶(ampule)中,通过融熔玻璃将空气密封于上格。120℃下进行高压灭菌并消毒至少15分钟以制备注射剂。
[工业应用]
由于根据本发明的如式1或式2所示的彼此以平衡状态存在的化合物不仅具有低的细胞毒性而且具有非常好的对抗包括柯萨基病毒、肠病毒、艾柯病毒、脊髓灰质炎病毒和鼻病毒的小核糖核酸病毒的抗病毒活性,因此其可有效地用作预防或治疗病毒性疾病的药物组合物,所述病毒性疾病如脊髓灰质炎、急性出血性结膜炎、病毒性脑膜炎、手足口病、水疱病、甲型肝炎、肌炎、心肌炎、胰腺炎、糖尿病、流行性肌痛、脑炎、流感、疱疹性咽峡炎、口蹄疫疾病、哮喘、慢性阻塞性肺病、肺炎、鼻窦炎或中耳炎。
Claims (15)
1.一种如下式1或式2所示的化合物或其药学上可接受的盐:
[式1]
[式2]
其中,在以上式1和式2中,
R1为–H、直链或支链的C1-6烷基或者–NO2;
R2为–H、直链或支链的C1-6烷基或者–NH2;
R3为–H;
R4a,R4b,R4c和R4d独立地为–H或者直链或支链的C1-6烷基;
X-L-R5选自:
2.根据权利要求1所述的化合物或其药学上可接受的盐,其中
式1或式2所示的化合物选自以下化合物中的任一个:
N-(4b-羟基-7-异丙基-10-氧代-9b,10-二氢-4bH-苯并[d]茚并[1,2-b]呋喃-9b-基)-2-(1H-吲哚-3-基)-2-氧代乙酰胺;
N-(4b-羟基-7-异丙基-10-氧代-9b,10-二氢-4bH-茚并[1,2-b]苯并呋喃-9b-基)-3-(2-硝基苯基)-2-氧代丙酰胺;
N-(4b-羟基-7-异丙基-10-氧代-9b,10-二氢-4bH-茚并[1,2-b]苯并呋喃-9b-基)-2-氧代丙酰胺;
N-(4b-羟基-7-异丙基-10-氧代-9b,10-二氢-4bH-茚并[1,2-b]苯并呋喃-9b-基)-2-氧代戊酰胺;
N-(4b-羟基-7-异丙基-10-氧代-9b,10-二氢-4bH-茚并[1,2-b]苯并呋喃-9b-基)-2-氧代辛酰胺;
N-(4b-羟基-7-异丙基-4-硝基-10-氧代-9b,10-二氢-4bH-茚并[1,2-b]苯并呋喃-9b-基)-2-(1H-吲哚-3-基)-2-氧代乙酰胺;
N-(4b-羟基-7-异丙基-10-氧代-9b,10-二氢-4bH-茚并[1,2-b]苯并呋喃-9b-基)-3-(4-羟苯基)-2-氧代丙酰胺;
N-(1-氨基-4b-羟基-7-异丙基-10-氧代-9b,10-二氢-4bH-茚并[1,2-b]苯并呋喃-9b-基)-2-(1H-吲哚-3-基)-2-氧代乙酰胺;
N-(1-氨基-4b-羟基-7-异丙基-10-氧代-9b,10-二氢-4bH-茚并[1,2-b]苯并呋喃-9b-基)-2-氧代-2-苯基乙酰胺;
N-(4b-羟基-7,8-二甲基-10-氧代-9b,10-二氢-4bH-茚并[1,2-b]苯并呋喃-9b-基)-2-氧代-2-苯基乙酰胺;
N-(4b-羟基-7,8-二甲基-10-氧代-9b,10-二氢-4bH-茚并[1,2-b]苯并呋喃-9b-基)-2-(1H-吲哚-3-基)-2-氧代乙酰胺;
N-(4b-羟基-7,8-二甲基-10-氧代-9b,10-二氢-4bH-茚并[1,2-b]苯并呋喃-9b-基)-2-氧代丙酰胺;
N-(4b-羟基-7-异丙基-10-氧代-9b,10-二氢-4bH-茚并[1,2-b]苯并呋喃-9b-基)-2-氧代-2-苯基乙酰胺;
N-(4b-羟基-7-异丙基-4-硝基-10-氧代-9b,10-二氢-4bH-茚并[1,2-b]苯并呋喃-9b-基)-2-氧代-2-苯基乙酰胺;
N-(4b-羟基-7-异丙基-10-氧代-9b,10-二氢-4bH-茚并[1,2-b]苯并呋喃-9b-基)-4-(甲硫基)-2-氧代丁酰胺;
N-(1-氨基-4b-羟基-7-异丙基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)-2-氧代丙酰胺;
N-(4b-羟基-7-异丙基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)-2-氧代-2-(3,4,5-三甲氧基苯基)乙酰胺;
(E)-4-(3,4-二甲氧基苯基)-N-(4b-羟基-7-异丙基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)-2-氧代-3-丁酰胺;
N-(4b-羟基-7-异丙基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)-3-甲基-2-氧代戊酰胺;
N-(4b-羟基-7-异丙基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)-3,3-二甲基-2-氧代丁酰胺;
N-(4b-羟基-7-异丙基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)-2-氧代-4-苯基丁酰胺;
N-(1-氨基-4b-羟基-7-异丙基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)-3-甲基-2-氧代戊酰胺;
N-(4b-羟基-7-异丙基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)-2,4-二氧代-4-(吡啶-4-基)丁酰胺;
N-(1-氨基-4b-羟基-7-异丙基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)-2-氧代己酰胺;
N-(1-氨基-(4b-羟基-7-异丙基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)-2-氧代戊酰胺;
N-(1-氨基-4b-羟基-7-异丙基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)-2均三甲苯基-2-氧代乙酰胺;以及
N-(4b-羟基-7-异丙基-4-硝基-10-氧代-4b,10-二氢-9bH-茚并[1,2-b]苯并呋喃-9b-基)-2-氧代-4-苯基丁酰胺。
3.一种用于制备权利要求1的式1或式2所示的化合物的方法,该方法包括反应方程式1所示的步骤(步骤1),将式3或式4所示的化合物以及式5所示的化合物与反应催化剂一起置于溶剂中,然后搅拌
[反应方程式1]
在以上反应方程式1中,
Xa为–OH或–NH2,
R1、R2、R3、R4a、R4b、R4c、R4d、R5、X以及L如以上式1和式2中所定义的。
4.根据权利要求3所述的方法,其中所述溶剂为选自二甲基甲酰胺(DMF)、二氯甲烷(MC)、乙醇、水、二异丙醚、二乙醚、二氧六环、四氢呋喃(THF)、二甲基乙酰胺(DMA)、二甲亚砜(DMSO)、氯苯、甲苯和苯中的至少一种。
5.根据权利要求3所述的方法,其中所述反应催化剂为选自1-乙基-3-(3-二甲基氨基丙基)碳二亚胺(EDCI)、羟苯并三唑(HOBt)、三乙胺(TEA)、0-(7-偶氮苯并三唑-1-基)-N,N,N’,N’-四甲基脲六氟磷酸酯(HATU)、吡啶、POCl3、Fe和HCl中的至少一种。
6.一种用于治疗或预防病毒性疾病的药剂,其包括根据权利要求1所述的式1或式2的的化合物或其药学上可接受的盐作为活性成分。
7.根据权利要求6所述的药剂,其中所述病毒性疾病由柯萨基病毒引起。
8.根据权利要求6所述的药剂,其中所述病毒性疾病由脊髓灰质炎病毒引起。
9.根据权利要求6所述的药剂,其中所述病毒性疾病由艾柯病毒引起。
10.根据权利要求6所述的药剂,其中所述病毒性疾病由肠病毒引起。
11.根据权利要求6所述的药剂,其中所述病毒性疾病由鼻病毒引起。
12.根据权利要求6所述的药剂,其中所述病毒性疾病由小核糖核酸病毒引起。
13.根据权利要求6所述的药剂,其中所述病毒性疾病为脊髓灰质炎、急性出血性结膜炎、病毒性脑膜炎、手足口病、水疱病、甲型肝炎、肌炎、心肌炎、胰腺炎、糖尿病、流行性肌痛、脑炎、流感、疱疹性咽峡炎、口蹄疫疾病、哮喘、慢性阻塞性肺病、肺炎、鼻窦炎或中耳炎。
14.根据权利要求6所述的药剂,其进一步包含稀释剂或赋形剂。
15.一种药物组合物,其包括治疗有效量的权利要求1或2所述的化合物或其药学上可接受的盐以及稀释剂或赋形剂。
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Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1061341A (zh) * | 1990-11-10 | 1992-05-27 | 曼海姆泊灵格股份公司 | 用作抗病毒药物的噻唑并异二氢氮杂茚酮衍生物) |
TW200306817A (en) * | 2002-04-02 | 2003-12-01 | Fujisawa Pharmaceutical Co | Pharmaceutical composition for treating or preventing virus infectious diseases |
WO2012173448A2 (ko) * | 2011-06-16 | 2012-12-20 | 한국화학연구원 | 인다논 유도체, 이의 약학적으로 허용되는 염 또는 이의 광학 이성질체, 이의 제조방법 및 이를 유효성분으로 함유하는 바이러스성 질환의 예방 또는 치료용 약학적 조성물 |
WO2012173447A2 (ko) * | 2011-06-16 | 2012-12-20 | 한국화학연구원 | 1,3-다이옥소인덴 유도체, 이의 약학적으로 허용되는 염 또는 이의 광학 이성질체, 이의 제조방법 및 이를 유효성분으로 함유하는 항바이러스용 약학적 조성물 |
Family Cites Families (18)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CH583723A5 (zh) | 1972-12-18 | 1977-01-14 | Hoechst Ag | |
GB1425295A (en) | 1974-01-23 | 1976-02-18 | Rizh Politekhn I | Alpha-aminoylidenephthalides and processes for their preparation |
FR2392951A2 (fr) | 1975-02-07 | 1978-12-29 | Creat Lab | Nouveaux derives de la ninhydrine, leurs procedes de preparation et medicaments contenant ces derives |
GB1533388A (en) | 1975-02-07 | 1978-11-22 | Creat | Ninhydrin-phenol condensation products their preparation and use as therapeutic agents |
US3984552A (en) | 1975-02-24 | 1976-10-05 | Merck & Co., Inc. | 6-Oxo-7-substituted and 7,7-disubstituted-6H-indeno-[5,4-b]furan (and thiophene) carboxylic acids |
GB8327598D0 (en) | 1983-10-14 | 1983-11-16 | Akzo Nv | Pharmacologically active diarylindane-13-diones |
SE8902274D0 (sv) | 1989-06-22 | 1989-06-22 | Univ Cincinnati | Indenoidole compounds ii |
CN1061962A (zh) | 1990-10-16 | 1992-06-17 | 巴斯大学 | 茚并吲哚化合物 |
CO4950519A1 (es) | 1997-02-13 | 2000-09-01 | Novartis Ag | Ftalazinas, preparaciones farmaceuticas que las comprenden y proceso para su preparacion |
JP2001089455A (ja) | 1999-09-17 | 2001-04-03 | Maruishi Pharmaceutical Co Ltd | 5,10−ジヒドロ−11H−インデノ〔1,2−b〕キノリン−10−オン誘導体 |
ES2228370T3 (es) | 1999-08-30 | 2005-04-16 | Maruishi Pharmaceutical Co., Ltd. | Compuestos de 1,4-dihidro-4-oxoquinolina 1,2-disustituidos. |
US7371168B2 (en) | 2001-10-05 | 2008-05-13 | Igt | Gaming apparatus and method of gaming including interactive gaming symbols for producing different outcomes |
US7265152B2 (en) | 2002-11-01 | 2007-09-04 | Viropharma Incorporated | Benzofuran compounds, compositions and methods for treatment and prophylaxis of hepatitis C viral infections and associated diseases |
AU2003277988A1 (en) | 2002-11-08 | 2004-06-07 | The Government Of The State Of Sarawak, Malaysia | Therapeutic compounds and methods |
EP1608369B1 (en) | 2003-03-28 | 2013-06-26 | Novartis Vaccines and Diagnostics, Inc. | Use of organic compounds for immunopotentiation |
JP2011526925A (ja) | 2008-07-01 | 2011-10-20 | ザカロン ファーマシューティカルズ,インク. | ヘパラン硫酸阻害剤 |
US20100261706A1 (en) | 2008-12-08 | 2010-10-14 | Inotek Pharmaceuticals Corporation | Substituted tetracyclic 1h-indeno [1,2-b]pyridine-2(5h)-one analogs thereof and uses thereof |
EP2324820B1 (en) | 2009-11-04 | 2016-03-02 | Inopharm Limited | Stable fluindione composition comprising one or more antioxidant agents |
-
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Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1061341A (zh) * | 1990-11-10 | 1992-05-27 | 曼海姆泊灵格股份公司 | 用作抗病毒药物的噻唑并异二氢氮杂茚酮衍生物) |
TW200306817A (en) * | 2002-04-02 | 2003-12-01 | Fujisawa Pharmaceutical Co | Pharmaceutical composition for treating or preventing virus infectious diseases |
WO2012173448A2 (ko) * | 2011-06-16 | 2012-12-20 | 한국화학연구원 | 인다논 유도체, 이의 약학적으로 허용되는 염 또는 이의 광학 이성질체, 이의 제조방법 및 이를 유효성분으로 함유하는 바이러스성 질환의 예방 또는 치료용 약학적 조성물 |
WO2012173447A2 (ko) * | 2011-06-16 | 2012-12-20 | 한국화학연구원 | 1,3-다이옥소인덴 유도체, 이의 약학적으로 허용되는 염 또는 이의 광학 이성질체, 이의 제조방법 및 이를 유효성분으로 함유하는 항바이러스용 약학적 조성물 |
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