CN115667190B - 双环类化合物及其应用 - Google Patents
双环类化合物及其应用 Download PDFInfo
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- CN115667190B CN115667190B CN202180037613.0A CN202180037613A CN115667190B CN 115667190 B CN115667190 B CN 115667190B CN 202180037613 A CN202180037613 A CN 202180037613A CN 115667190 B CN115667190 B CN 115667190B
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- Prior art keywords
- dihydro
- tetrafluoro
- difluoromethyl
- oxy
- diol
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- -1 hydroxy, amino Chemical group 0.000 claims description 118
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- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
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- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 230000034512 ubiquitination Effects 0.000 description 1
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- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
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- 230000009385 viral infection Effects 0.000 description 1
- 239000011701 zinc Chemical class 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
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Abstract
提供一种如式(I)所示的化合物,包含这类化合物的组合物和制剂,及使用和制备这样的化合物的方法。
Description
技术领域
本发明涉及一种双环类化合物,包含这样的化合物的组合物和制剂,及使用和制备这样的化合物的方法。
背景技术
HIFs(Hypoxia inducible factors)属于转录因子家族成员,是机体感受氧气变化的一个通路,又称缺氧诱导因子,通过控制下游40多个缺氧适应基因而介导细胞缺氧反应。它主要由HIFα(HIF-1α,HIF-2α,HIF-3α)与HIF-1β两部分组成,其中HIF-1β始终在细胞核内,而HIFα位于细胞质。HIFα在氧气充足的条件下,会经过PHD脯氨酰羟化酶羟基化、VHL(Von Hippel—Lindau Syndrome)泛素酶泛素化标记等途径,最后被蛋白酶体降解。但当缺氧或代谢途径异常时,HIFα无法被降解,因而蓄积入核,与HIF-1β结合形成异二聚体,激活下游基因启动子中缺氧反应元件(Hypoxia response element,HRE),进而调控相关基因转录,让细胞在缺氧条件仍然可以存活。这些基因涉及肿瘤血管生成,细胞增殖、生存、代谢、侵袭转移,耐药、炎症和免疫等。其中HIF-2α介导的是慢性缺氧,在生理缺氧条件下即可持续激活,对肿瘤的发生发展具有更关键作用。
目前的研究表明HIF-2α介导肿瘤发生发展的机制主要包括:1、在缺氧或VHL突变等条件下,HIF-2α代谢途径受阻,蓄积进入细胞核,与HIF-1β形成异二聚体,进而激活缺氧反应原件(HRE),调控下游VEGFA、CXCR4、Cyclin D1等癌症相关基因上调,促进肿瘤血管生成;2、HIF-2α还通过上调CD73表达参与免疫抑制性信号的传导,因此靶向HIF-2α可恢复或增强成熟DC细胞、活化B细胞及NK细胞的抗肿瘤免疫功能。
HIF-2α通路的激活与肾细胞癌、胶质瘤、神经母细胞瘤与嗜铬细胞瘤等发生发展有密切关系。VHL蛋白是E3泛素连接酶的重要组成部分,介导蛋白酶体对蛋白质的降解。VHL基因在肾癌细胞(renal cell carcinoma;RCC)中有57%的高突变率或98%的杂合性缺失,导致假性缺氧并诱导HIF-2α活化入核。其中,透明细胞肾细胞癌(Clear cell renal cellcarcinoma;ccRCC)占原发性肾细胞恶性肿瘤的70%-75%,而超过90%的ccRCC患者存在VHL蛋白缺陷。胶质瘤在不血管化的情况下,血液供应不稳定导致低氧微环境,从而诱导HIF-2α局部高表达,促进肿瘤生长。在嗜铬细胞瘤及副神经节瘤中,HIF-2α的529-532位AA突变率高达81%,直接影响HIF-2α的羟基化降解,使HIF-2α持续激活。
HIF-2α活化与HIF-1β形成异二聚体是导致下游激活的关键因素,而二者的PAS结合域是其形成异二聚体的结合位点,Peloton公司的研发团队基于此开发了HIF-2α小分子抑制剂PT2977,通过抑制HIF-2α与HIF-1β结合,从而发挥抗肿瘤效果。
基于HIF-2α通路与肿瘤发生和迁移有非常重要的密切关系,开发更多的高效新分子实体是非常必要。
发明内容
本发明首先提供了式(I)所示的化合物或其立体异构体、互变异构体、药学上可接受的盐、前药、螯合物、非共价复合物或溶剂合物,
R1和R2可以分别独立地选自氢、氘、卤素、C1-C3烷基、C3-C5环烷基,或,
R1和R2与其相连接的C原子共同形成取代或未被取代的C3环烷基或C3杂环基;
R3选自氢、卤素、羟基、氰基、C1-C5烷基、C1-C5烷氧基、C1-C5卤代烷基、C1-C5卤代烷氧基、C3-C5环烷基;
R4选自C1-C10烷基、C1-C10烷氧基、C1-C10卤代烷基、C1-C10卤代烷氧基、C6-C10芳基、C5-C18杂芳基、C3-C10环烷基、C3-C10杂环基;其中,所述C5-C18杂芳基和C3-C10杂环基任意地含有1、2或3个分别独立地选自N、O和S的杂原子;所述R4任选地被一个或多个独立地选自Rj的基团所取代;
Rj选自H、卤素、羟基、氨基、氰基、C1-C5烷基、C1-C5烷氧基、C2-C5烯基、C2-C5炔基、C1-C5卤代烷基、C1-C5卤代烷氧基、C3-C5环烷基、C3-C5杂环基;
R5和R6分别独立地选自H、氘、C1-C8烷基、-C1-8烷基-O-C1-3烷基、C1-3烷基酰基、C3-C8硅烷基,或,
R5和R6与其相连接的O原子共同形成取代或未被取代的C5-C8杂环基;所述C5-C8杂环基可以任选地被一个或多个H或烷基所取代。
一些实施方式中,所述R1和/或R2为卤素。
一些实施方式中,所述R1和/或R2为F。
一些实施方式中,所述R1和R2与其相连接的C原子共同形成取代或未被取代的C3环烷基或C3杂环基。
一些实施方式中,所述R3选自卤素、氰基或C1-C5卤代烷基。
一些实施方式中,所述所述R3选自C1-C5烷基或C3-C5环烷基。
一些实施方式中,所述R4选自C6-C8芳基、C5-C8杂芳基、C3-C5环烷基、C3-C5杂环基;其中,所述C5-C8杂芳基和C3-C8杂环基任意地含有1、2或3个分别独立地选自N、O和S的杂原子;所述R4任选地被一个或多个独立地选自Rj的基团所取代。
一些实施方式中,所述R4选自苯环,吡啶环和嘧啶环。
一些实施放手中,所述R4选自苯环或吡啶环。
一些实施方式中,所述R5和/或R6为H。
一些实施方式中,所述R5和R6分别独立地选自甲基、乙基、乙酰基、三甲基硅烷基,或R5和R6与其相连接的O原子共同形成
一些实施方式中,所述化合物如式(II)所示,
一些实施方式中,所述R4选自C6-C8芳基、C5-C8杂芳基;其中,所述C5-C8杂芳基任意地含有1、2或3个分别独立地选自N、O和S的杂原子;所述R4任选地被一个或多个独立地选自Rj的基团所取代。
一些实施方式中,所述R4选自苯基、吡啶基和嘧啶基。
一些实施方式中,所述R4选自苯基或吡啶基。
一些实施方式中,所述R4为苯基。
一些实施方式中,所述Rj选自H、卤素、氰基、C1-C5烷基、C1-C5卤代烷基、C3-C5环烷基或C3-C5杂环基。
一些实施方式中,所述Rj选自H、卤素、氰基或C1-C5卤代烷基。
一些实施方式中,所述R2为卤素。
一些实施方式中,所述R3为卤素或氰基、二氟甲基或三氟甲基。
一些实施方式中,所述R3为二氟甲基。
一些实施方式中,所述Rj选自H、卤素、氰基、甲基、乙基、环丙基、二氟甲基或三氟甲基。
一些实施方式中,R4选自
本发明进一步提供了一种化合物或其药学上可接受的盐,所述化合物是指:7-(二氟甲基)-6-(3,5-二氟苯氧基)-2,2,3-三氟-2,3-二氢-1H-茚-1,1-二醇;
7-(二氟甲基)-2,2,3,3-四氟-6-(嘧啶-5-氧基)-2,3-二氢-1H-茚-1,1-二醇;
6-(3-溴-5-氟苯氧基)-7-(二氟甲基)-2,2,3,3-四氟-2,3-二氢-1H-茚-1,1-二醇;3-氟-5-((1,2,2,4-四氟-3,3-二羟基-2,3-二氢-1H-茚-5-基)氧基)苯甲腈;
3-((4-(二氟甲基)-1,1,2,2-四氟-3,3-二羟基-2,3-二氢-1H-茚-5-基)氧基)-5-氟苯甲腈;
3-((4-(二氟甲基)-1,1,2,2-四氟-3-羟基-3-甲氧基-2,3-二氢-1H-茚-5-基)氧基)-5-氟苯甲腈;
3-((4-(二氟甲基)-1,1,2,2-四氟-3,3-二羟基-2,3-二氢-1H-茚基-5-基)氧基)-5-氟苯甲腈;
7-(二氟甲基)-2,2,3,3-四氟-6-(3-氟苯氧基)-2,3-二氢-1H-茚基-1,1-二醇;
7-(二氟甲基)-6-(3,5-二氟苯氧基)-2,2,3,3-四氟-2,3-二氢-1H-茚基-1,1-二醇;3-((4-(二氟甲基)-1,1,2,2-四氟-3,3-二甲氧基-2,3-二氢-1H-茚-5-基)氧基)-5-氟苄腈;
6-((5-溴吡啶-3-基)氧基)-7-(二氟甲基)-2,2,3,3-四氟-2,3-二氢-1H-茚基-1,1-二醇;6-((5-溴吡啶-3-基)氧基)-7-(二氟甲基)-2,2,3,3-四氟-2,3-二氢-1H-茚基-1,1-二醇;3-(((7-(二氟甲基)-2,2,3,3-四氟-2,3-二氢螺并[茚-1,2'-[1,3]二氧戊环]-6-基)氧基)-5-氟苄腈;
7-(二氟甲基)-2,2,3,3-四氟-6-((5-氟吡啶-3-基)氧基)-2,3-二氢-1H-茚基-1,1-二醇;6-(3-氯苯氧基)-7-(二氟甲基)-2,2,3,3-四氟-2,3-二氢-1H-茚基-1,1-二醇;
6-(3-氰基-5-氟苯氧基)-7-(二氟甲基)-2,2,3,3-四氟-2,3-二氢-1H-茚-1,1-二乙酸二酯;
3-((7-(二氟甲基)-2,2,3,3-四氟-5',5'-二甲基-2,3-二氢螺[茚-1,2'-[1,3]二恶烷]-6-基)氧基)-5-氟苄腈;
7-(二氟甲基)-2,2,3,3-四氟-6-((5-甲基吡啶-3-基)氧基)-2,3-二氢-1H-茚基-1,1-二醇;
7-(二氟甲基)-2,2,3,3-四氟-6-苯氧基-2,3-二氢-1H-茚基-1,1-二醇;
3-((4-(二氟甲基)-1,1,2,2-四氟-3,3-双((三甲基硅烷基)氧基)-2,3-二氢-1H-茚-5-基)氧基)-5-氟苄腈;
7-(二氟甲基)-2,2,3,3-四氟-6-(吡啶-3-基氧基)-2,3-二氢-1H-茚基-1,1-二醇;7-(二氟甲基)-2,2,3,3-四氟-6-((3-氟吡啶-4-基)氧基)-2,3-二氢-1H-茚基-1,1-二醇;5-(3-氰基-5-氟苯氧基)-1,1,2,2-四氟-3,3-二羟基-2,3-二氢-1H-茚-4-腈;
7-(二氟甲基)-2,2,3,3-四氟-6-(吡啶-4-基氧基)-2,3-二氢-1H-茚基-1,1-二醇;7-(二氟甲基)-2,2,3,3-四氟-6-((2-氟吡啶-4-基)氧基)-2,3-二氢-1H-茚基-1,1-二醇;3-溴-5-((4-(二氟甲基)-1,1,2,2-四氟-3,3-二羟基-2,3-二氢-1H-茚基-5-基)氧基)苯甲腈;
3-((4-环丙基-1,1,2,2-四氟-3,3-二羟基-2,3-二氢-1H-茚-5-基)氧基)-5-氟苄腈;3-氟-5-(((1,1,2,2-四氟-3,3-二羟基-4-(三氟甲基)-2,3-二氢-1H-茚-5-基)氧基)苄腈;
7-(二氟甲基)-2,2,3,3-四氟-6-((5-甲氧基吡啶-3-基)氧基)-2,3-二氢-1H-茚基-1,1-二醇;
6-((5-氯吡啶-3-基)氧基)-7-(二氟甲基)-2,2,3,3-四氟-2,3-二氢-1H-茚基-1,1-二醇;7-(二氟甲基)-2,2,3,3-四氟-6-((2-甲基吡啶-4-基)氧基)-2,3-二氢-1H-茚基-1,1-二醇;
7-(二氟甲基)-2,2,3,3-四氟-6-((2-甲氧基吡啶-4-基)氧基)-2,3-二氢-1H-茚基-1,1-二醇;
3-((4-氯-1,1,2,2-四氟-3,3-二羟基-2,3-二氢-1H-茚-5-基)氧基)-5-氟苄腈;
7-(二氟甲基)-2,2,3,3-四氟-6-((4-甲基吡啶-2-基)氧基)-2,3-二氢-1H-茚基-1,1-二醇;
7-(二氟甲基)-2,2,3,3-四氟-6-(吡啶-3-基氧基)-2,3-二氢-1H-茚基-1,1-二醇;3-氟-5-(((1,1,2,2-四氟-3,3-二羟基-4-甲基-2,3-二氢-1H-茚-5-基)氧基)苄腈;7-(二氟甲基)-2,2,3,3-四氟-6-((2-羟基吡啶-4-基)氧基)-2,3-二氢-1H-茚基-1,1-二醇;
5-(3-氰基-5-甲基苯氧基)-1,1,2,2-四氟-3,3-二羟基-2,3-二氢-1H-茚-4-腈;
5-(3-氰基苯氧基)-1,1,2,2-四氟-3,3-二羟基-2,3-二氢-1H-茚基-4-甲腈;
5-(3-氯-5-氰基苯氧基)-1,1,2,2-四氟-3,3-二羟基-2,3-二氢-1H-茚-4-腈;
6-((4-(二氟甲基)-1,1,2,2-四氟-3,3-二羟基-2,3-二氢-1H-茚基-5-基)氧基)吡啶甲腈;
5-((4-氰基-1,1,2,2-四氟-3,3-二羟基-2,3-二氢-1H-茚-5-基)氧基)烟腈;
6-((2-溴吡啶-4-基)氧基)-7-(二氟甲基)-2,2,3,3-四氟-2,3-二氢-1H-茚基-1,1-二醇;1,1,2,2-四氟-5-((5-氟吡啶-3-基)氧基)-3,3-二羟基-2,3-二氢-1H-茚-4-腈;
7-(二氟甲基)-2,2,3,3-四氟-6-((5-(三氟甲基)吡啶-3-基)氧基)-2,3-二氢-1H-茚基-1,1-二醇;
5-((4-(二氟甲基)-1,1,2,2-四氟-3,3-二羟基-2,3-二氢-1H-茚基-5-基)氧基)吡啶甲腈;
5-(3,5-二氟苯氧基)-1,1,2,2-四氟-3,3-二羟基-2,3-二氢-1H-茚-4-腈;
7-(二氟甲基)-2,2,3,3-四氟-6-((6-羟基吡啶-3-基)氧基)-2,3-二氢-1H-茚基-1,1-二醇;
4'-(二氟甲基)-5'-(3,5-二氟苯氧基)-2',2'-二氟螺[环丙烷-1,1'-茚]-3',3'(2'H)-二醇;
4-((4-(二氟甲基)-1,1,2,2-四氟-3,3-二羟基-2,3-二氢-1H-茚基-5-基)氧基)吡啶甲腈;
1,1,2,2-四氟-5-(3-氟苯氧基)-3,3-二羟基-2,3-二氢-1H-茚基-4-甲腈;
6-((4-氰基-1,1,2,2-四氟-3,3-二羟基-2,3-二氢-1H-茚基-5-基)氧基)吡啶甲腈;7-(二氟甲基)-6-(3,5-二氟苯氧基)-2,2-二氟-3,3-二甲基-2,3-二氢-1H-茚-1,1-二醇;
5-(3-溴-5-氟苯氧基)-1,1,2,2-四氟-3,3-二羟基-2,3-二氢-1H-茚基-4-甲腈;
3-氟-5-(((1,2,2,4-四氟-3,3-二羟基-2,3-二氢-1H-茚-5-基)氧基)苄腈;
5-(3,3-二氟环丁氧基)-1,1,2,2-四氟-3,3-二羟基-2,3-二氢-1H-茚基-4-甲腈;7-(二氟甲基)-2,2,3,3-四氟-6-(哒嗪-3-基氧基)-2,3-二氢-1H-茚基-1,1-二醇;7-(二氟甲基)-2,2,3,3-四氟-6-((6-氟吡啶-2-基)氧基)-2,3-二氢-1H-茚基-1,1-二醇;6-(3-环丙基-5-氟苯氧基)-7-(二氟甲基)-2,2,3,3-四氟-2,3-二氢-1H-茚-1,1-二醇;5-((4-(二氟甲基)-1,1,2,2-四氟-3,3-二羟基-2,3-二氢-1H-茚-5-基)氧基)间苯二甲腈;
3-((4-(二氟甲基)-1,1,2,2-四氟-3,3-二羟基-2,3-二氢-1H-茚-5-基)氧基)苄腈;6-(环己氧基)-7-(二氟甲基)-2,2,3,3-四氟-2,3-二氢-1H-茚-1,1-二醇;
6-((5-氯吡啶-3-基)氧基)-7-(二氟甲基)-2,2,3,3-四氟-2,3-二氢-1H-茚基-1,1-二醇;5-((4-(二氟甲基)-1,1,2,2-四氟-3,3-二羟基-2,3-二氢-1H-茚基-5-基)氧基)烟酸腈;7-(二氟甲基)-2,2,3,3-四氟-6-(3-氟-5-(三氟甲基)苯氧基)-2,3-二氢-1H-茚-1,1-二醇;
6-(3-氯-5-氟苯氧基)-7-(二氟甲基)-2,2,3,3-四氟-2,3-二氢-1H-茚-1,1-二醇;3-氯-5-((4-(二氟甲基)-1,1,2,2-四氟-3,3-二羟基-2,3-二氢-1H-茚-5-基)氧基)苯甲腈;
7-(二氟甲基)-2,2,3,3-四氟-6-((5-氟吡啶-3-基)氧基)-2,3-二氢-1H-茚-1,1-二醇;7-(二氟甲基)-2,2,3,3-四氟-6-(嘧啶-2-氧基)-2,3-二氢-1H-茚-1,1-二醇;
5-(3,3-二氟环丁氧基)-1,1,2,2-四氟-3,3-二羟基-2,3-二氢-1H-茚-4-腈;
3-氯-7-(二氟甲基)-6-(3,5-二氟苯氧基)-2,2-二氟-2,3-二氢-1H-茚-1,1-二醇;或
3-((1-氯-4-(二氟甲基)-2,2-二氟-3,3-二羟基-2,3-二氢-1H-茚-5-基)氧基)-5-氟苄腈。
本发明还提供了化合物的制备方法,本发明式(I)所述的化合物或具体实施例所述的化合物都可使用已知的有机合成技术制备获得。
本发明还提供了一种药物组合物,包含治疗有效量的至少一种上述化合物和药学上可接受的辅料,例如羟丙基甲基纤维素。在一些组合物中,所述化合物与所述辅料的重量比大约为0.001~10。
此外,本发明还提供一种治疗患有对HIF-2α介导疾病或病症的受试者的方法,包括给药治疗有效量的式(I)的化合物或其可药用盐。
在某些方面,疾病或病症选自VHL综合征、自身免疫疾病、炎性疾病、神经变性疾病、心血管障碍、肾病症、病毒感染和肥胖。在某些方面,所述疾病或病症选自类风湿性关节炎、骨关节炎、动脉粥样硬化、银屑病、系统性红斑狼疮、多发性硬化、炎性肠病、哮喘、慢性阻塞性气道病、肺炎、皮炎、脱发、肾炎、血管炎、动脉粥样硬化、阿尔茨海默病、肝炎、原发性胆汁性肝硬变、硬化性胆管炎、糖尿病(包括I型糖尿病)、移植器官的急性排斥反应。在某些方面,所述疾病或病症是癌症,包括血液学癌症、淋巴瘤、多发性骨髓瘤、消化系统肿瘤、生殖系统肿瘤、脑瘤、神经系统肿瘤赘瘤。
在某些方面,所述疾病或病症为透胶质瘤、嗜铬细胞瘤、副神经节瘤、结肠、直肠、前列腺(例如去势抗性(castrate resistant)前列腺癌)、肺癌(例如非小细胞肺癌和/或小细胞肺癌)、胰腺、肝、肾、子宫颈、子宫、胃、卵巢、乳腺(例如基底或基底样乳腺癌和/或三重阴性乳腺癌)、皮肤(例如黑素瘤)、神经系统(包括脑、脑脊膜、和中枢神经系统,包括成神经细胞瘤、成胶质细胞瘤、脑膜瘤和髓母细胞瘤)的瘤或癌症。
在某些方面,所述疾病或病症为VHL综合征。在某些方面,所述疾病或病症为肾癌。在在某些方面,所述受试者是人类。
在某些方面,所述化合物是静脉内、肌内、胃肠外、鼻或口服给药的。在一个方面,所述化合物是口服给药的。
本发明还提供式(I)的化合物或其可药用盐在制备用于治疗由HIF-2α介导的疾病或病症的药物中的用途。
本发明还提供用于治疗的式(I)所示化合物或其可药用盐。进一步提供用于治疗患有由HIF-2α介导的疾病或病症的受试者的式(I)的化合物或其可药用盐。
本发明可以在不脱离其精神或基本属性的情况下以其他特定形式实施。本发明涵盖本文提到的本发明的优选方面的所有组合。应理解,“发明内容”中公开的主题没有穷尽或完整地公开了本发明技术或其任意实施方案的全部范围,可以采用本发明的任何和所有实施方案结合任何其他一个或多个实施方案来描述另外的实施方案。还应理解,实施方案的每个单独要素是其本身的独立实施方案。此外,实施方案的任何要素意在与来自任何实施方案中的任何和所有其他要素组合来描述另外的实施方案。
本发明中,除另有说明,术语“卤素”(halogen)是指氟、氯、溴或碘。优选的卤素基团是指氟、氯和溴。
本发明中,除另有说明,术语“烷基”包括直链、支链或环状的饱和单价烃基。例如,烷基包括甲基、乙基、丙基、异丙基、环丙基、正丁基、异丁基、仲丁基、叔丁基、环丁基、正戊基、3-(2-甲基)丁基、2-戊基、2-甲基丁基、新戊基、环戊基、正己基、2-己基、2-甲基戊基和环己基。类似的,C1-6烷基中的“C1-6”是指含有1、2、3、4、5或6个碳原子以直链或支链形式排列的基团。
术语“烷氧基”是指由上述的直链、支链或环状烷基所形成的氧醚。
术语“亚烷基”是指二价烷基连接基团。亚烷基在形式上是指两个C-H键替换为亚烷基与化合物其余部分的连接点的烷烃。类似的,C1-4亚烷基中的“C1-4”是指含有1、2、3或4个碳原子的亚烷基。
术语“卤代烷基”是指一个或多个H已经被卤素原子置换的烷基。术语“卤代烷氧基”是指-O-卤代烷基的基团。
术语“氧代”或“氧代基”是指呈二甲取代基形式的氧原子,其与C连接时形成羰基,其与杂原子连接时形成亚砜基或砜基或N-氧化物基团。
本发明中,除另有说明,术语“芳香环”、“芳香族环”或“芳香族杂环”即为具有芳香族特征(具有(4n+2)个非定域π电子,其中n为整数)的多不饱和环的碳环或杂环。
术语“芳基”取代或未取代的稳定的6到10个环碳原子的芳香族烃基,其可以包含1个芳香环或多个芳香环(例如稠和双环)。所述的芳香环不含有杂原子。芳基的实施例包括但不限于,苯基、萘基、茚基等。
术语“杂芳基”是指具有至少一个杂原子环成员的单环或多环(例如稠合双环)芳香族杂环,所述杂原子选自N、O和/或S。此类杂芳基的实例包括但不限于,吡啶基、嘧啶基、吡咯基、咪唑基、噻唑基、噻吩基、苯并咪唑、苯并噻吩基、苯并呋喃基等。
术语“环烷基”是指具有至少一个环化烷基的环系统。术语C3-10环烷基中的“C3-10”是指环烷基可以具有3、4、5、6、7、8、9或10个成环原子。环烷基可以包括单环和多环(例如具有2、3或4个稠合环,螺环、并环等)。一些实施例中环烷基包括但不限于环丙基、环丁基、环戊基等;在一些实施例中环烷基还包括具有一个或多个与环化烷基环稠合的芳香族环的部分,例如环己烷的苯并或噻吩基衍生物等。
术语“环烯基”是指具有至少一个环化烯基的环系统,所述环烯基中具有一个或多个碳碳双键。术语C3-10环烯基中的“C3-10”是指环烯基可以具有3、4、5、6、7、8、9或10个成环原子。环烯基可以包括单环和多环(例如具有2、3或4个稠合环,螺环、桥环等)。一些实施例中环烯基包括但不限于环己烯基、环己二烯、环庚三烯基等;在一些实施例中环烯基还包括具有一个或多个与环化烯基环稠合的芳香族环的部分,例如环己烯环的苯并或噻吩基衍生物等。
术语“杂环基”是指具有至少一个含有杂环子的环化烷基或环化烯基的环系统,所述杂原子选自N、O和/或S。所述杂环基可以包括单环或多环(例如具有2、3或4个稠合环,螺环、桥环等)。杂环基可以经由成环碳原子或成环杂原子与化合物其他部分相连接。所述杂环基的定义中还包括具有一个或多个与环化烷基或环化烯基环稠合的芳香族环的部分,例如哌啶、吗啉等的苯并或噻吩基衍生物。在一些实施方案中,杂环基包括但不限于吡咯烷基、吡咯啉基、四氢噻吩基、四氢呋喃基、哌啶基、吗啉基、氮杂环庚烷、二氢苯并呋喃基等。
本发明中术语“组合物”旨在包括含有特定数量的特定组分的产品,也包括任何由特定数量的特定组分直接或间接得到的产品。因此,包含本发明中的化合物作为活性组分的药物组合物和制备该化合物的方法也是本发明的内容。而且,一些化合物的晶型可以多晶型形式存在,这些也包括在本发明中。此外,一些化合物与水(如水合物)或普通有机溶剂形成溶剂化物,这些溶剂化物也包含在本发明中。
本发明化合物的药物前体(前药)包含在本发明的保护范围内。通常,所述药物前体是指很容易在体内转化成所需要的化合物的功能性衍生物。因此,本发明提供的治疗方法中的术语“给药”包括施用本发明公开的化合物,或虽未明确公开但对受试者给药后能够在体内转化为本发明公开的前药化合物。有关选择和制备合适药物前体衍生物的常规方法,已记载在例如《药物前体设计》(Design of Prodrugs,ed.H.Bundgaard,Elsevier,1985)这类书中。
显然的,一个分子中任何取代基或特定位置的变量的定义是独立于分子中其他位置的。很容易理解,本领域普通技术人员可以通过现有技术手段及本发明中所述的方法,选择本发明中的化合物的取代基或取代形式,以提供化学上稳定且容易合成的化合物。
本发明所述化合物可能含有一个或多个不对称中心,并可能由此产生非对映异构体和光学异构体。本发明包括所有可能的非对映异构体及其外消旋混合物、其基本上纯的拆分对映异构体、所有可能的几何异构体及其药学上可接受的盐。
上述式(I)没有确切定义该化合物某一位置的立体结构。本发明包括式(I)所示化合物的所有立体异构体及其药学上可接受的盐。进一步地,立体异构体的混合物及分离出的特定的立体异构体也包括在本发明中。制备此类化合物的合成过程中,或使用本领域普通技术人员公知的外消旋化或差向异构化方法的过程中,制得的产品可以是立体异构体的混合物。
当式(I)所示化合物存在互变异构体时,除非特别声明,本发明包括任何可能的互变异构体和其药学上可接受的盐,及它们的混合物。
当式(I)所示化合物及其药学上可接受的盐为溶剂化物或多晶型的形式时,本发明包括任何可能的溶剂化物和多晶型。形成溶剂化物的溶剂类型没有特别的限定,只要该溶剂是药理学上可以接受的。例如,水、乙醇、丙醇、丙酮等类似的溶剂都可以采用。
术语“药学上可接受的盐”是指从药学上可接受的无毒的碱或酸制备的盐。当本发明提供的化合物是酸时,可以从药学上可接受的无毒的碱,包括无机碱和有机碱,方便地制得其相应的盐。从无机碱衍生的盐包括铝、铵、钙、铜(高价和低价)、三价铁、亚铁、锂、镁、锰(高价和低价)、钾、钠、锌之类的盐。特别优选铵、钙、镁、钾和钠的盐。能够衍生成药学上可接受的盐的无毒有机碱包括伯胺、仲胺和叔胺,也包括环胺及含有取代基的胺,如天然存在的和合成的含取代基的胺。能够成盐的其他药学上可接受的无毒有机碱,包括离子交换树脂以及精氨酸、甜菜碱、咖啡因、胆碱、N',N'-二苄乙二胺、二乙胺、2-二乙氨基乙醇、2-二甲胺基乙醇、乙醇胺、乙二胺、N-乙基吗啉、N-乙基哌啶、还原葡萄糖胺、氨基葡萄糖、组氨酸、哈胺、异丙胺、赖氨酸,甲基葡萄糖胺、吗啉、哌嗪、哌啶、多胺树脂、普鲁卡因、氯普鲁卡因、嘌呤、可可碱、三乙胺、三甲胺、三丙胺、氨丁三醇等。
当本发明提供的化合物是碱时,可以从药学上可接受的无毒的酸,包括无机酸和有机酸,方便制得其相应的盐。这样的酸包括,如,醋酸、苯磺酸、苯甲酸、樟脑磺酸、柠檬酸、乙磺酸、甲酸、富马酸、葡萄糖酸、谷氨酸、氢溴酸、盐酸、羟乙磺酸、乳酸、马来酸、苹果酸、扁桃酸、甲磺酸、黏酸、硝酸、扑酸、泛酸、磷酸、琥珀酸、硫酸、草酸、丙酸、乙醇酸、氢碘酸、高氯酸、环己氨磺酸、水杨酸、2-萘磺酸、糖精酸、三氟乙酸、酒石酸和对甲苯磺酸等。较优地,柠檬酸、氢溴酸、甲酸、盐酸、马来酸、磷酸、硫酸和酒石酸。更优地,甲酸和盐酸。由于式(I)所示化合物将作为药物应用,所以优选使用基本上纯的形式,例如,至少60%纯度,更适当地至少75%的纯度,特别地至少98%的纯度(%是重量比)。
本发明提供的药物组合物包括作为活性组分的式(I)所示化合物(或其药学上可接受的盐)、一种药学上可接受的赋形剂及其他可选的治疗组分或辅料。尽管任何给定的情况下,最适合的活性组分给药方式取决于接受给药的特定的主体、主体性质和病情严重程度,但是本发明的药物组合物包括适于口腔、直肠、局部和不经肠道(包括皮下给药、肌肉注射、静脉给药)给药的药物组合物。本发明的药物组合物可以方便地以本领域公知的单位剂型存在和药学领域公知的任何制备方法制备。
实际上,根据常规的药物混合技术,本发明式(I)所示化合物,或药物前体,或代谢物,或药学上可接受的盐,可以作为活性组分,与药物载体混合成药物组合物。所述药物载体可以采取各种各样的形式,这取决于期望采用的给药方式,例如,口服或注射(包括静脉注射)。因此,本发明的药物组合物可以采用适于口服给药的独立单位的形式,如包含预定剂量的活性组分的胶囊剂、扁囊剂或片剂。进一步地,本发明的药物组合物可采用粉末、颗粒、溶液、水性悬浮液、非水液体、水包油型乳液,或油包水型乳液形式。另外,除了上述提到的常见的剂型,式(I)所示化合物或其药学上可接受的盐,也可以通过控释的方式和/或输送装置给药。本发明的药物组合物可以采用任何制药学上的方法制备。一般情况下,这种方法包括使活性组分和组成一个或多个必要成分的载体缔合的步骤。一般情况下,所述药物组合物经由活性组分与液体载体或精细分割的固体载体或两者的混合物经过均匀的密切的混合制得。然后,该产品可以方便地制备成所需要的外观。
因此,本发明的药物组合物包括药学上可接受的载体和式(I)所示化合物或其药学上可接受的盐。式(I)所示化合物或其药学上可接受的盐,与其他一种或多种具有治疗活性的化合物也包括在本发明的药物组合物中。
本发明采用的药物载体可以是,例如,固体载体、液体载体或气体载体。固体载体,包括乳糖、石膏粉、蔗糖、滑石粉、明胶、琼脂、果胶、阿拉伯胶、硬脂酸镁、硬脂酸。液体载体,包括糖浆、花生油、橄榄油和水。气体载体,包括二氧化碳和氮气。制备药物口服制剂时,可以使用任何方便的制药学上的介质。例如,水、乙二醇、油类、醇类、增味剂、防腐剂、着色剂等可用于口服的液体制剂如悬浮剂、酏剂和溶液剂;而载体,如淀粉类、糖类、微晶纤维素、稀释剂、造粒剂、润滑剂、粘合剂、崩解剂等可用于口服的固体制剂如散剂、胶囊剂和片剂。考虑到易于施用,口服制剂首选片剂和胶囊,在此应用固体药学载体。可选地,片剂包衣可使用标准的水制剂或非水制剂技术。
含有本发明化合物或药物组合物的片剂可通过,任选一种或多种辅助组分或辅药一起压制或成型制备。活性组分以自由流动的形式如粉末或颗粒,与粘合剂、润滑剂、惰性稀释剂、表面活性剂或分散剂混合,在适当的机器中,通过压制可以制得压制片剂。用一种惰性液体稀释剂浸湿粉末状的化合物或药物组合物,然后在适当的机器中,通过成型可以制得模制片。较优地,每个片剂含有大约0.05mg到5g的活性组分,每个扁囊剂或胶囊剂含有大约0.05mg到5g的活性组分。例如,拟用于人类口服给药的剂型包含约0.5mg到约5g的活性组分,与合适且方便计量的辅助材料复合,该辅助材料约占药物组合物总量的5%至95%。单位剂型一般包含约1mg到约2g的活性组分,典型的是25mg、50mg、100mg、200mg、300mg、400mg、500mg、600mg、800mg或1000mg。
本发明提供的适用于胃肠外给药的药物组合物可将活性组分加入水中制备成水溶液或悬浮液。可以包含适当的表面活性剂如羟丙基纤维素。在甘油、液态聚乙二醇,及其在油中的混合物,也可以制得分散体系。进一步地,防腐剂也可以包含在本发明的药物组合物中用于防止有害的微生物生长。
本发明提供适用于注射的药物组合物,包括无菌水溶液或分散体系。进一步地,上述药物组合物可以制备成可用于即时配制无菌注射液或分散液的无菌粉末的形式。无论如何,最终的注射形式必须是无菌的,且为了易于注射,必须是易于流动的。此外,所述药物组合物在制备和储存过程中必须稳定。因此,优选抗微生物如细菌和真菌污染的保存。载体可以是溶剂或分散介质,例如,水、乙醇、多元醇(如甘油、丙二醇、液态聚乙二醇)、植物油及其适当的混合物。
本发明提供的药物组合物,可以是适于局部用药的形式,例如,气溶胶、乳剂、软膏、洗液、撒粉或其他类似的剂型。进一步地,本发明提供的药物组合物可以采用适于经皮给药装置使用的形式。利用本发明式(I)所示化合物,或其药学上可接受的盐,通过常规的加工方法,可以制备这些制剂。作为一个例子,乳剂或软膏剂的制备是通过在约5wt%到10wt%的上述化合物中加入亲水性材料和水,制得具有预期一致性的乳剂或软膏。
本发明提供的药物组合物,可以制成以固体为载体,适用于直肠给药的形式。优选的剂型为混合物形成单位剂量的栓剂。适当的辅料包括本领域常用的可可脂和其他材料。栓剂可以方便地制备,首先药物组合物与软化或熔化的辅料混合,然后冷却和模具成型而制得。
除了上述提到的载体组分外,上述药学制剂还可以包括,适当的,一种或多种附加的辅料组分,如稀释剂、缓冲剂、调味剂、粘合剂、表面活性剂、增稠剂、润滑剂和防腐剂(包括抗氧化剂)等。此外,其他的辅药还可以包括调节药物与血液等渗压的促渗剂。包含式(I)所示化合物,或其药学上可接受的盐的药物组合物,也可以制备成粉剂或浓缩液的形式。
一般情况下,治疗上述所示的状况或不适,药物的剂量水平约为每天0.01mg/kg体重到150mg/kg体重,或者每个病人每天0.5mg到7g。但是,可以理解,任何特定病人的具体剂量水平将取决于多种因素,包括年龄、体重、综合健康状况、性别、饮食、给药时间、给药途径、排泄率、药物联用的情况和接受治疗的特定疾病的严重程度。
具体实施方式
为使本发明更加容易理解,下面将结合实施例来详细说明本发明,这些实施例仅起说明性作用,并不局限于本发明的应用范围,下列实施例中未提及的具体实验方法,通常按照常规实验方法进行。
除另有说明,所有的部分和百分数均以重量计算,所有的温度均为摄氏度。
实施例中使用了下列缩略语:
DAST:二乙胺基三氟化硫;
Dess-Martin:戴斯-马丁氧化剂;
DMF:N,N-二甲基甲酰胺;
DMSO:二甲基亚砜;
DIBAL-H:二异丁基氢化铝
EA:乙酸乙酯;
ESI-MS:电喷雾电离质谱;
IBX:2-碘酰基苯甲酸;
LDA:二异丙基氨基锂;
Prep-TLC:制备薄层色谱;
THF:四氢呋喃;
1H NMR:核磁共振氢谱;
h:小时;
min:分钟。
实施例1 7-(二氟甲基)-6-(3,5-二氟苯氧基)-2,2,3-三氟-2,3-二氢-1H-茚-1,1-二醇的合成(化合物1)
步骤1:化合物1-1的合成
氮气保护下,反应瓶中依次加入2-溴-4-对氟苯氰(3g)和THF(20mL),冷却至-78℃,加入LDA(7.5mL,2M THF溶液),低温搅拌1小时,然后加入DMF(1.16mL),低温搅拌小时,升温至-15℃搅拌1小时。反应混合液饱和氯化铵水溶液淬灭,EA萃取(50mL*3),合并有机相,食盐水洗,干燥,浓缩,柱层析纯化,得1.5g目标化合物1-1。
步骤2:化合物1-2的合成
氮气保护下,反应瓶中依次加入化合物1-1(2g),二氯甲烷(20mL),冰水浴冷却加入DAST(3.53g),室温搅拌过夜。反应混合液浓缩,二氯甲烷(1000mL)溶解稀释,冰浴下加入饱和碳酸氢钠溶液调至碱性,分离有机相,依次用水和饱和食盐水洗涤,干燥浓缩,柱层析纯化,得2g目标化合物1-2。
步骤3:化合物1-3的合成
氮气保护下,反应瓶中依次加入化合物1-2(0.5g),二氯甲烷(10mL),冰水浴冷却加入DIBAL-H(1.5mL,1.5M甲苯溶液),室温搅拌2小时。反应混合液用1N盐酸淬灭,二氯甲烷萃取,有机相干燥,浓缩,Prep-TLC纯化,得200mg目标化合物1-3。
步骤4:化合物1-4的合成
氮气保护下,反应瓶中依次加入3,5-二氟苯酚(925mg),化合物1-3(1.5g),碳酸铯(3.87g)和DMF(15mL),80℃搅拌3小时。反应混合液冰水浴冷却,加水淬灭,乙酸乙酯稀释,分离有机相,有机相依次用水和饱和食盐水洗涤,干燥,浓缩,柱层析纯化,得1.5g目标化合物1-4。
步骤5:化合物1-5的合成
氮气保护下,反应瓶中依次加入四氢呋喃(10mL),锌粉(270mg),1,2-二溴乙烷(51mg),水浴下滴加2-溴-2,2-二氟乙酸乙酯(838mg),滴加完毕后搅拌20min,滴加化合物1-4(1g)的THF溶液(5mL),升温至50℃反应过夜。反应体系用EA(1000mL)稀释,过滤,滤液浓缩,柱层析纯化,得250mg目标化合物1-5。
步骤6:化合物1-6的合成
氮气保护下,反应瓶中依次加入化合物1-5(250mg),二氯甲烷(5mL),-60℃下滴加DAST(124mg),滴加完毕室温搅拌1小时。反应液浓缩,二氯甲烷(50mL)稀释,分离有机相,有机相分别用饱和碳酸氢钠和饱和食盐水洗涤,干燥,浓缩,柱层析纯化,得200mg目标化合物1-6。
步骤7:化合物1-7的合成
氮气保护下,反应瓶中依次加入化合物1-6(0.24g),THF(5mL),-78℃下加入正丁基锂(0.25mL,2.5M正己烷溶液),室温搅拌1小时。反应混合液中加入饱和氯化铵淬灭,乙酸乙酯萃取,有机相干燥,浓缩,Prep-TLC纯化,得30mg目标化合物1-7。
1H NMR(500MHz,CDCl3)δ7.87-7.82(m,1H),7.67(s,0.23H),7.56(s,0.50H),7.47-7.40(m,1.35H),6.66-6.60(m,1H),6.55-6.50(m,2H),5.83(dd,J=53.7,10.8Hz,1H)。
步骤8:化合物1的合成
反应瓶中依次加入化合物1-7(20mg),氘代DMSO(0.5mL),水(2uL),超声1分钟,即得目标化合物1。
MS[M-H]-:381.10。
实施例2 7-(二氟甲基)-2,2,3,3-四氟-6-(嘧啶-5-氧基)-2,3-二氢-1H-茚-1,1-二醇的合成(化合物2)
步骤1:化合物2-1的合成
氮气保护下,反应瓶中依次加入7-(二氟甲基)-2,2,3,3,6-五氟吲哚-1-酮(80mg),DMF(2mL),5-羟基嘧啶(36mg),碳酸铯(143.68mg),反应混合液升温至50℃反应4小时。EA(50mL)稀释反应体系,混合液水洗3遍,盐水洗一遍,有机相旋干,Prep-TLC纯化,得到75mg目标化合物2-1。
MS[M+H]+:349.03。
1H NMR(500MHz,DMSO)δ9.11(s,1H),8.78(s,2H),8.44(d,J=8.6Hz,1H),7.99(d,J=8.7Hz,1H),7.78(s,0.34H),7.68(s,0.52H),7.57(s,0.34H)。
步骤2:化合物2的合成
反应瓶中依次加入化合物2-1(20mg),氘代DMSO(0.5mL),水(2uL),超声1分钟,即得目标化合物2。
MS[M+H]+:367.12。
1H NMR(500MHz,DMSO)δ9.08(s,1H),8.68(s,2H),8.15(s,2H),8.02(d,J=8.6Hz,1H),7.72(s,0.34H),7.62(s,0.52H),7.51(s,0.32H),7.46(d,J=8.6Hz,1H)。
实施例3 6-(3-溴-5-氟苯氧基)-7-(二氟甲基)-2,2,3,3-四氟-2,3-二氢-1H-茚-1,1-二醇的合成(化合物3)
步骤1:化合物3-1的合成
采用与实施例2步骤1相似的制备方法,将5-羟基嘧啶替换为3-溴-5氟苯酚,即得化合物3-1。
步骤2:化合物3的合成
反应瓶中依次加入化合物3-1(20mg),氘代DMSO(0.5mL),水(2uL),超声1分钟,即得目标化合物3。
MS[M-H]-:459.03,461.01。
1H NMR(500MHz,DMSO)δ8.26–8.20(m,1.57H),8.07(d,J=8.6Hz,1H),7.74(s,0.30H),7.64(s,0.50H),7.53(s,0.30H),7.50–7.46(m,2H),7.14(s,1H),7.10(dd,J=9.8,2.0Hz,1H)。
实施例4 3-氟-5-((1,2,2,4-四氟-3,3-二羟基-2,3-二氢-1H-茚-5-基)氧基)苯甲腈的合成(化合物4)
步骤1:化合物4-1的合成
氮气保护下,反应瓶中依次加入2-溴-3,4-二氟苯甲酸(2.8g),THF(5mL),冰水浴降温,加入硼烷-四氢呋喃溶液(2M,50mL),室温反应4小时,反应混合液旋干,二氯甲烷(50mL)稀释,滴加饱和碳酸钠溶液,分离有机相,有机相分别用水、1N盐酸和饱和氯化钠水溶液各洗一遍,干燥浓缩得2g目标化合物4-1。
ESI-MS m/z:440.10[M+H]+。
步骤2:化合物4-2的合成
氮气保护下,反应瓶中依次加入化合物4-1(2g),二氯甲烷(10mL),冰水浴降温加入Dess-Martin(5.71g),室温反应过夜。反应液过滤,滤饼用二氯甲烷淋洗,滤液硫代硫酸钠水溶液洗涤,饱和食盐水洗涤后干燥浓缩,得1.9g目标化合物4-2。
步骤3:化合物4-3的合成
氮气保护下,反应瓶中依次加入3-氟-5-羟基苯腈(1.3g),化合物4-2(1.9g),碳酸铯(2.95g)和DMF(15mL),升温至60℃搅拌1小时。冰水浴降温,加水淬灭反应,乙酸乙酯萃取1次,有机相水洗3次,饱和食盐水洗涤,干燥浓缩,柱层析纯化,得2.0g目标化合物4-3。
步骤4:化合物4-4的合成
氮气保护下,反应瓶中依次加入四氢呋喃(10mL),锌粉(567mg),水浴下滴加2-溴-2,2-二氟乙酸乙酯(1.80g),滴加完毕后搅拌20min,滴加化合物4-3(2g)的THF溶液(5mL),升温至50℃反应过夜。反应体系用EA(50mL)稀释,过滤,滤液旋干,柱层析纯化,得到1g目标化合物4-4。
1H NMR(500MHz,DMSO)δ7.73(d,J=8.1Hz,1H),7.55(s,1H),7.52–7.46(m,2H),7.39–7.35(m,1H),7.02(d,J=6.1Hz,1H),5.55(dt,J=18.7,5.2Hz,1H),4.35(q,J=7.1Hz,2H),1.28(t,J=7.1Hz,3H)。
步骤5:化合物4-5的合成
氮气保护下,反应瓶中依次加入化合物4-4(1g),二氯甲烷(5mL),-40℃下滴加DAST(348mg),滴加完毕室温搅拌1小时。反应液浓缩,二氯甲烷(50mL)稀释,饱和碳酸氢钠洗涤,饱和食盐水洗涤,干燥浓缩,柱层析纯化,得0.9g目标化合物4-5。
1H NMR(500MHz,DMSO)δ7.75(d,J=7.7Hz,1H),7.63(s,1H),7.60–7.55(m,1H),7.46–7.38(m,2H),6.46(ddd,J=41.8,15.4,5.4Hz,1H),4.46–4.34(m,2H),1.33–1.24(m,3H)。
步骤6:化合物4-6的合成
氮气保护下,反应瓶中依次加入化合物4-5(0.9g),THF(2mL),乙醇(2mL)和氢氧化锂(139mg),室温搅拌1小时,用1N盐酸调节pH至5-6,乙酸乙酯萃取3次,合并有机相,干燥,浓缩,得0.8g目标化合物4-6。
1H NMR(500MHz,DMSO)δ7.73(d,J=7.6Hz,1H),7.61(s,1H),7.60 -7.55(m,1H),7.43 -7.38(m,1H),6.36(ddd,J=42.8,16.0,5.3Hz,1H)。
步骤7:化合物4-7的合成
氮气保护下,反应瓶中依次加入化合物4-6(0.24g),THF(2mL),-78℃下加入正丁基锂(0.6mL,2.5M的正己烷溶液),室温搅拌1小时。反应混合液加入饱和氯化铵淬灭,乙酸乙酯萃取,有机相干燥浓缩,Prep-TLC纯化,得50mg目标化合物4-7。
1H NMR(500MHz,DMSO)δ7.96(s,1H),7.84(s,1H),7.75–7.72(m,1H),7.61–7.58(m,2H),6.47(dd,J=52.5,8.3Hz,1H)。
步骤8:化合物4的合成
反应瓶中依次加入化合物2-7(20mg),氘代DMSO(0.5mL),水(2uL),超声1分钟,即得目标化合物4。
采用与实施例1-实施例4基本类似的方法,制备以下表1中的实施例。
表1
化合物5、化合物7、化合物40、化合物59、化合物62的1HNMR数据如下所示:
1H NMR(500MHz,DMSO)δ8.17(m,1.4H),8.02(d,J=8.5Hz,1H),7.75–
7.67(m,1.22H),7.59(s,0.52H),7.48(s,0.27H),7.46–7.37(m,3H)。(化合物5)
1H NMR(500MHz,DMSO)δ8.17(d,J=7.8Hz,1H),8.02(d,J=8.5Hz,1H),7.73–7.68(m,1H),7.59(s,1H),7.50–7.37(m,3H)。(化合物7)
1H NMR(500MHz,DMSO)δ8.18(d,J=7.8Hz,1H),8.08(d,J=8.7Hz,1H),7.86–7.77(m,2H),7.76–7.66(m,2H),7.61(ddd,J=8.3,2.3,1.1Hz,1H),7.26(d,J=8.7Hz,1H)。(化合物40)
1H NMR(500MHz,DMSO)δ8.15–7.96(m,2H),7.71–7.36(m,2H),7.10(d,J=8.0Hz,1H),6.96(dd,J=7.9,2.0Hz,1H)。(化合物59)
1H NMR(500MHz,DMSO)δ7.99(d,J=8.5Hz,1H),7.74–7.56(m,4H),7.40(ddd,J=8.3,2.5,1.0Hz,1H),7.31(d,J=8.6Hz,1H)。(化合物62)
对照例1 3-((4-(二氟甲基)-1,1,2,2-四氟-3-羟基-3-甲基-2,3-二氢-1H-茚-5-基)氧基)-5-氟苄氰的合成
基本按照WO2020081695中实施例2所描述的方法制备对照例1化合物。
对照例2 3-氟-5-((1,2,2,4-四氟-3-羟基-2,3-二氢-1H-茚-5-基)氧基)氰苯的合成
氮气保护下,反应瓶中依次加入化合物2-7(50mg),甲醇(2mL),冰水浴冷却加入硼氢化钠(11mg),室温搅拌1小时,反应液浓缩,水淬灭(5mL)稀释,乙酸乙酯萃取,干燥浓缩,Pre-TLC纯化,得9mg得对照例2化合物。
1H NMR(500MHz,DMSO)δ7.75–7.65(m,1H),7.53(d,J=8.3Hz,1H),7.48–7.40(m,3H),6.71(d,J=8.2Hz,1H),6.13–6.05(m,0.5H),6.00–5.95(m,0.5H),5.28(s,1H)。
对照例3 7-(二氟甲基)-6-(3,5-二氟苯氧基)-2,2,3-三氟-2,3-二氢-1H-茚-1-醇的合成
氮气保护下,反应瓶中依次加入化合物3-7(10mg),甲醇(2mL),冰水浴冷却加入硼氢化钠(2.1mg),冰水浴反应30分钟,加水淬灭(5mL)稀释,乙酸乙酯萃取,干燥浓缩,Pre-TLC纯化,得9.3mg对照例3化合物。
MS[M-H]-:365.14。
药理实验
实验例1本发明化合物VEGFA ELISA的检测(IC50)
取对数期生长的786-O细胞接种于96孔板中,细胞浓度为每毫升培养液65000个细胞,180ul每孔。稀释化合物至相应浓度,取20ul不同浓度化合物溶液添加到相应细胞孔,使化合物终浓度分别为(nM):1.5、4.6、13.7、41.2、123.5、370.4、1111.1、3333.3、10000。培养24h,取细胞培养上清液,使用ELISA试剂盒(购自abcam)测定VEGFA浓度,最后终止反应,使用酶标仪在450nm波长测量各孔的光吸收值,通过GraphPadPrism计算IC50。同时采用CellTiter-Glo试剂测定细胞活力。
部分实施例的IC50数据提供于表2中,其中,A表示IC50≤10nM;B表示10nM<IC50≤100nM;C表示100nM<IC50≤250nM;D表示250nM<IC50IC50≤500nM;E表示IC50>500nM。
表2
实施例编号 | IC50(nM) | 实施例编号 | IC50(nM) |
1 | B | 40 | A |
2 | C | 42 | A |
3 | A | 52 | A |
4 | C | 53 | A |
5 | 2.8 | 55 | B |
7 | A | 59 | A |
8 | A | 62 | A |
9 | A | 64 | A |
11 | A | 65 | A |
14 | A | 对照例1 | 770* |
19 | A | 对照例2 | >1×104 |
21 | A | 对照例3 | E |
其中,“*”表示该数据来自于WO2020081695。
荧光素酶实验
将荧光素酶LUC基因用Lipofectamine 3000转染试剂(购自Invitrogen)稳定转入786-O细胞(购自ATCC),构建为HIF2α报告基因细胞(786-O-HIF2α-Luc细胞)。在786-O-HIF2α-Luc细胞处于对数生长期时进行试验,弃去培养基(RPMI MEDIUM 1640,购自Invitrogen),PBS润洗三遍;加入胰蛋白酶(TrypLE,购自invitrogen)消化细胞,用培养基、10%胎牛血清、1%青霉素,链霉素清洗细胞终止消化。离心收集细胞,用PBS吹洗两遍,去除培养基中的酚红,重悬细胞至适当的浓度,检测细胞密度和活率,保证细胞活率在90%以上方可用于实验。
用Echo550(非接触式声波移液系统,购自Labcyte)将梯度浓度化合物转移至384孔内,25nl/孔;将细胞种到384孔板中,4500细胞/孔,25μl培养基,使化合物终浓度分别为10000、3333、1111、370、123、41.1、13.7、4.6、1.5、0.5nM。将细胞至于37℃,5% CO2环境中培养18-20h;加入Steady-GloTM荧光素酶测定系统(购自Promega)至384孔板,25μl/孔;用Envision检测发光值。根据每孔的RLU(Record Luminescence)信号值计算抑制率%,然后通过Graphpad 8.0拟合计算相应化合物的IC50。
体内PK
化合物用5%DMSO、5%Solutol和90%NaCl进行配制。动物选用SD大鼠与Balb/c小鼠进行给药,静脉给药剂量为1mg/kg,口服给药剂量为5mg/kg,分别于5min、15min、30min、1h、2h、4h、7h、24h处眼眶取血。采血后4000rpm离心10min,取上清,在30μL上清中加入200μL内标溶液进行沉淀,涡旋振荡后用12000rpm离心10min,取100μL上清溶液与纯净水按1:1比例进行混合进样。通过高效液质联用仪对血浆内化合物浓度进行检测,采用内标定量法对血浆样品内化合物浓度进行定量分析。测得化合物浓度后通过Winnonln软件计算包括Cmax、AUC等相关的药代动力学参数。经实验发现本发明示例性化合物具有较好的体内PK性质。
Claims (11)
1.式(I)所示的化合物,或其立体异构体、或药学上可接受的盐,
其中,
R1和R2分别独立地选自氢或F;
R3选自卤素、氰基、C1-C5烷基或C1-C5卤代烷基;
R4选自C6-C10芳基或C5-C18杂芳基;其中,所述C5-C18杂芳基含有1、2或3个分别独立地选自N、O和S的杂原子;所述R4任选地被一个或多个独立地选自Rj的基团所取代;
Rj选自H、卤素、羟基、氨基、氰基、C1-C5烷基、C1-C5烷氧基、C2-C5烯基、C2-C5炔基、C1-C5卤代烷基、C1-C5卤代烷氧基、C3-C5环烷基、C3-C5杂环基;
R5和R6分别独立地选自H、氘、C1-C8烷基、-C1-8烷基-O-C1-3烷基、C1-3烷基酰基、C3-C8硅烷基,或,
R5和R6与其相连接的O原子共同形成C5-C8杂环基;所述C5-C8杂环基任选地被一个或多个H或C1-6烷基所取代。
2.根据权利要求1所述的化合物,或其立体异构体、或药学上可接受的盐,其特征在于,所述R4选自C6-C8芳基、C5-C8杂芳基;其中,所述C5-C8杂芳基含有1、2或3个分别独立地选自N、O和S的杂原子;所述R4任选地被一个或多个独立地选自Rj的基团所取代。
3.根据权利要求1所述的化合物,或其立体异构体、或药学上可接受的盐,其特征在于,所述R5和/或R6为H。
4.根据权利要求1所述的化合物,或其立体异构体、或药学上可接受的盐,其特征在于,所述R5和R6分别独立地选自甲基、乙基、乙酰基、三甲基硅烷基,或R5和R6与其相连接的O原子共同形成
5.根据权利要求1所述的化合物,或其立体异构体、或药学上可接受的盐,其特征在于,所述化合物如式(II)所示,
6.根据权利要求1或5所述的化合物,或其立体异构体、或药学上可接受的盐,其特征在于,所述R4选自C6-C8芳基、C5-C8杂芳基;其中,所述C5-C8杂芳基任意地含有1、2或3个分别独立地选自N、O和S的杂原子;所述R4任选地被一个或多个独立地选自Rj的基团所取代。
7.根据权利要求1或5所述的化合物,或其立体异构体、或药学上可接受的盐,其特征在于,所述Rj选自H、卤素、氰基、C1-C5烷基、C1-C5卤代烷基、C3-C5环烷基或C3-C5杂环基。
8.根据权利要求1或5所述的化合物,或其立体异构体、或药学上可接受的盐,其特征在于,所述Rj选自H、卤素、氰基、甲基、乙基、环丙基、二氟甲基或三氟甲基。
9.一种化合物,或其立体异构体、或药学上可接受的盐,其特征在于,所述化合物选自:
7-(二氟甲基)-6-(3,5-二氟苯氧基)-2,2,3-三氟-2,3-二氢-1H-茚-1,1-二醇;
7-(二氟甲基)-2,2,3,3-四氟-6-(嘧啶-5-氧基)-2,3-二氢-1H-茚-1,1-二醇;
6-(3-溴-5-氟苯氧基)-7-(二氟甲基)-2,2,3,3-四氟-2,3-二氢-1H-茚-1,1-二醇;
3-氟-5-((1,2,2,4-四氟-3,3-二羟基-2,3-二氢-1H-茚-5-基)氧基)苯甲腈;
3-((4-(二氟甲基)-1,1,2,2-四氟-3,3-二羟基-2,3-二氢-1H-茚-5-基)氧基)-5-氟苯甲腈;
3-((4-(二氟甲基)-1,1,2,2-四氟-3-羟基-3-甲氧基-2,3-二氢-1H-茚-5-基)氧基)-5-氟苯甲腈;
3-((4-(二氟甲基)-1,1,2,2-四氟-3,3-二羟基-2,3-二氢-1H-茚基-5-基)氧基)-5-氟苯甲腈;
7-(二氟甲基)-2,2,3,3-四氟-6-(3-氟苯氧基)-2,3-二氢-1H-茚基-1,1-二醇;
7-(二氟甲基)-6-(3,5-二氟苯氧基)-2,2,3,3-四氟-2,3-二氢-1H-茚基-1,1-二醇;3-((4-(二氟甲基)-1,1,2,2-四氟-3,3-二甲氧基-2,3-二氢-1H-茚-5-基)氧基)-5-氟苄腈;
6-((5-溴吡啶-3-基)氧基)-7-(二氟甲基)-2,2,3,3-四氟-2,3-二氢-1H-茚基-1,1-二醇;6-((5-溴吡啶-3-基)氧基)-7-(二氟甲基)-2,2,3,3-四氟-2,3-二氢-1H-茚基-1,1-二醇;3-(((7-(二氟甲基)-2,2,3,3-四氟-2,3-二氢螺并[茚-1,2'-[1,3]二氧戊环]-6-基)氧基)-5-氟苄腈;
7-(二氟甲基)-2,2,3,3-四氟-6-((5-氟吡啶-3-基)氧基)-2,3-二氢-1H-茚基-1,1-二醇;6-(3-氯苯氧基)-7-(二氟甲基)-2,2,3,3-四氟-2,3-二氢-1H-茚基-1,1-二醇;
6-(3-氰基-5-氟苯氧基)-7-(二氟甲基)-2,2,3,3-四氟-2,3-二氢-1H-茚-1,1-二乙酸二酯;
3-((7-(二氟甲基)-2,2,3,3-四氟-5',5'-二甲基-2,3-二氢螺[茚-1,2'-[1,3]二恶烷]-6-基)氧基)-5-氟苄腈;
7-(二氟甲基)-2,2,3,3-四氟-6-((5-甲基吡啶-3-基)氧基)-2,3-二氢-1H-茚基-1,1-二醇;
7-(二氟甲基)-2,2,3,3-四氟-6-苯氧基-2,3-二氢-1H-茚基-1,1-二醇;
3-((4-(二氟甲基)-1,1,2,2-四氟-3,3-双((三甲基硅烷基)氧基)-2,3-二氢-1H-茚-5-基)氧基)-5-氟苄腈;
7-(二氟甲基)-2,2,3,3-四氟-6-(吡啶-3-基氧基)-2,3-二氢-1H-茚基-1,1-二醇;
7-(二氟甲基)-2,2,3,3-四氟-6-((3-氟吡啶-4-基)氧基)-2,3-二氢-1H-茚基-1,1-二醇;5-(3-氰基-5-氟苯氧基)-1,1,2,2-四氟-3,3-二羟基-2,3-二氢-1H-茚-4-腈;
7-(二氟甲基)-2,2,3,3-四氟-6-(吡啶-4-基氧基)-2,3-二氢-1H-茚基-1,1-二醇;
7-(二氟甲基)-2,2,3,3-四氟-6-((2-氟吡啶-4-基)氧基)-2,3-二氢-1H-茚基-1,1-二醇;3-溴-5-((4-(二氟甲基)-1,1,2,2-四氟-3,3-二羟基-2,3-二氢-1H-茚基-5-基)氧基)苯甲腈;
3-((4-环丙基-1,1,2,2-四氟-3,3-二羟基-2,3-二氢-1H-茚-5-基)氧基)-5-氟苄腈;
3-氟-5-(((1,1,2,2-四氟-3,3-二羟基-4-(三氟甲基)-2,3-二氢-1H-茚-5-基)氧基)苄腈;
7-(二氟甲基)-2,2,3,3-四氟-6-((5-甲氧基吡啶-3-基)氧基)-2,3-二氢-1H-茚基-1,1-二醇;
6-((5-氯吡啶-3-基)氧基)-7-(二氟甲基)-2,2,3,3-四氟-2,3-二氢-1H-茚基-1,1-二醇;7-(二氟甲基)-2,2,3,3-四氟-6-((2-甲基吡啶-4-基)氧基)-2,3-二氢-1H-茚基-1,1-二醇;
7-(二氟甲基)-2,2,3,3-四氟-6-((2-甲氧基吡啶-4-基)氧基)-2,3-二氢-1H-茚基-1,1-二醇;
3-((4-氯-1,1,2,2-四氟-3,3-二羟基-2,3-二氢-1H-茚-5-基)氧基)-5-氟苄腈;
7-(二氟甲基)-2,2,3,3-四氟-6-((4-甲基吡啶-2-基)氧基)-2,3-二氢-1H-茚基-1,1-二醇;
7-(二氟甲基)-2,2,3,3-四氟-6-(吡啶-3-基氧基)-2,3-二氢-1H-茚基-1,1-二醇;
3-氟-5-(((1,1,2,2-四氟-3,3-二羟基-4-甲基-2,3-二氢-1H-茚-5-基)氧基)苄腈;
7-(二氟甲基)-2,2,3,3-四氟-6-((2-羟基吡啶-4-基)氧基)-2,3-二氢-1H-茚基-1,1-二醇;
5-(3-氰基-5-甲基苯氧基)-1,1,2,2-四氟-3,3-二羟基-2,3-二氢-1H-茚-4-腈;
5-(3-氰基苯氧基)-1,1,2,2-四氟-3,3-二羟基-2,3-二氢-1H-茚基-4-甲腈;
5-(3-氯-5-氰基苯氧基)-1,1,2,2-四氟-3,3-二羟基-2,3-二氢-1H-茚-4-腈;
6-((4-(二氟甲基)-1,1,2,2-四氟-3,3-二羟基-2,3-二氢-1H-茚基-5-基)氧基)吡啶甲腈;
5-((4-氰基-1,1,2,2-四氟-3,3-二羟基-2,3-二氢-1H-茚-5-基)氧基)烟腈;
6-((2-溴吡啶-4-基)氧基)-7-(二氟甲基)-2,2,3,3-四氟-2,3-二氢-1H-茚基-1,1-二醇;1,1,2,2-四氟-5-((5-氟吡啶-3-基)氧基)-3,3-二羟基-2,3-二氢-1H-茚-4-腈;
7-(二氟甲基)-2,2,3,3-四氟-6-((5-(三氟甲基)吡啶-3-基)氧基)-2,3-二氢-1H-茚基-1,1-二醇;
5-((4-(二氟甲基)-1,1,2,2-四氟-3,3-二羟基-2,3-二氢-1H-茚基-5-基)氧基)吡啶甲腈;
5-(3,5-二氟苯氧基)-1,1,2,2-四氟-3,3-二羟基-2,3-二氢-1H-茚-4-腈;
7-(二氟甲基)-2,2,3,3-四氟-6-((6-羟基吡啶-3-基)氧基)-2,3-二氢-1H-茚基-1,1-二醇;
4'-(二氟甲基)-5'-(3,5-二氟苯氧基)-2',2'-二氟螺[环丙烷-1,1'-茚]-3',3'(2'H)-二醇;
4-((4-(二氟甲基)-1,1,2,2-四氟-3,3-二羟基-2,3-二氢-1H-茚基-5-基)氧基)吡啶甲腈;
1,1,2,2-四氟-5-(3-氟苯氧基)-3,3-二羟基-2,3-二氢-1H-茚基-4-甲腈;
6-((4-氰基-1,1,2,2-四氟-3,3-二羟基-2,3-二氢-1H-茚基-5-基)氧基)吡啶甲腈;
7-(二氟甲基)-6-(3,5-二氟苯氧基)-2,2-二氟-3,3-二甲基-2,3-二氢-1H-茚-1,1-二醇;
5-(3-溴-5-氟苯氧基)-1,1,2,2-四氟-3,3-二羟基-2,3-二氢-1H-茚基-4-甲腈;
3-氟-5-(((1,2,2,4-四氟-3,3-二羟基-2,3-二氢-1H-茚-5-基)氧基)苄腈;
5-(3,3-二氟环丁氧基)-1,1,2,2-四氟-3,3-二羟基-2,3-二氢-1H-茚基-4-甲腈;
7-(二氟甲基)-2,2,3,3-四氟-6-(哒嗪-3-基氧基)-2,3-二氢-1H-茚基-1,1-二醇;
7-(二氟甲基)-2,2,3,3-四氟-6-((6-氟吡啶-2-基)氧基)-2,3-二氢-1H-茚基-1,1-二醇;
6-(3-环丙基-5-氟苯氧基)-7-(二氟甲基)-2,2,3,3-四氟-2,3-二氢-1H-茚-1,1-二醇;
5-((4-(二氟甲基)-1,1,2,2-四氟-3,3-二羟基-2,3-二氢-1H-茚-5-基)氧基)间苯二甲腈;
3-((4-(二氟甲基)-1,1,2,2-四氟-3,3-二羟基-2,3-二氢-1H-茚-5-基)氧基)苄腈;
6-(环己氧基)-7-(二氟甲基)-2,2,3,3-四氟-2,3-二氢-1H-茚-1,1-二醇;
6-((5-氯吡啶-3-基)氧基)-7-(二氟甲基)-2,2,3,3-四氟-2,3-二氢-1H-茚基-1,1-二醇;
5-((4-(二氟甲基)-1,1,2,2-四氟-3,3-二羟基-2,3-二氢-1H-茚基-5-基)氧基)烟酸腈;
7-(二氟甲基)-2,2,3,3-四氟-6-(3-氟-5-(三氟甲基)苯氧基)-2,3-二氢-1H-茚-1,1-二醇;
6-(3-氯-5-氟苯氧基)-7-(二氟甲基)-2,2,3,3-四氟-2,3-二氢-1H-茚-1,1-二醇;
3-氯-5-((4-(二氟甲基)-1,1,2,2-四氟-3,3-二羟基-2,3-二氢-1H-茚-5-基)氧基)苯甲腈;
7-(二氟甲基)-2,2,3,3-四氟-6-((5-氟吡啶-3-基)氧基)-2,3-二氢-1H-茚-1,1-二醇;
7-(二氟甲基)-2,2,3,3-四氟-6-(嘧啶-2-氧基)-2,3-二氢-1H-茚-1,1-二醇;
5-(3,3-二氟环丁氧基)-1,1,2,2-四氟-3,3-二羟基-2,3-二氢-1H-茚-4-腈;
3-氯-7-(二氟甲基)-6-(3,5-二氟苯氧基)-2,2-二氟-2,3-二氢-1H-茚-1,1-二醇;或
3-((1-氯-4-(二氟甲基)-2,2-二氟-3,3-二羟基-2,3-二氢-1H-茚-5-基)氧基)-5-氟苄腈。
10.一种药物组合物,其特征在于,包含治疗有效量的至少一种权利要求1-9任一项所述的化合物和至少一种药学上可接受的辅料。
11.权利要求1-9任一项所述的化合物或权利要求10所述的药物组合物在制备用于治疗肾癌的药物中的应用。
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