CN115772154A - 一类含有氘取代的苯并噻吩类衍生物及其制备与用途 - Google Patents
一类含有氘取代的苯并噻吩类衍生物及其制备与用途 Download PDFInfo
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- CN115772154A CN115772154A CN202111050769.0A CN202111050769A CN115772154A CN 115772154 A CN115772154 A CN 115772154A CN 202111050769 A CN202111050769 A CN 202111050769A CN 115772154 A CN115772154 A CN 115772154A
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Abstract
本发明涉及一类含有氘取代的苯并噻吩类衍生物及其制备与用途。具体地,本发明化合物具有式I所示结构,其中各基团和取代基的定义如说明书中所述。所述化合物具有优异的药代动力学性质和STING激动活性。
Description
技术领域
本发明涉及生物医药领域,具体地涉及一类含有氘取代的苯并噻吩类衍生物及其制备与用途。
背景技术
干扰素基因刺激因子(STING,stimulator of interferon genes)是固有免疫cGAS-STING信号通路的重要信号蛋白,当cGAS识别到内源或外源dsDNA催化生成的2’,3’-cGAMP可结合并激活STING,促使STING从内质网向高尔基体转运,从而招募TBK1并使其磷酸化,以激活IRF3或NF-κB,进而诱导I型干扰素及其他炎症因子的分泌,最终产生抑制肿瘤生长的效果。这便意味着,激活STING可作为抗肿瘤免疫疗法的策略之一。
目前,已有多款STING激动剂处于临床试验阶段,但其结构类型多数为内源性配体2’,3’-cGAMP的环二核苷类衍生物,此类化合物存在分子量大、稳定性差、大多只能通多瘤内注射给药等缺点,极大地限制了STING激动剂在临床上的应用与发展。开发具有良好药代动力学性质,并具有良好生物活性的STING激动剂是该领域目前亟需开展的工作之一。
在药物研发过程中,氘原子的引入,通常有助于优化药物分子的药代动力学性质延长药物作用时间,或能起到降低药物分子的毒性、增强药物分子的生物活性、增加分子稳定性等作用。目前多家国内外制药企业(如BMS、Concert、苏州泽璟等)均在开展氘代药物研发,并且已有含氘药物成功上市(如氘代丁苯那嗪、多纳非尼),此外,多款氘代药物处于临床试验阶段(如BMS-986165、VX-984、CTP-656、AVP-786等)。可见,氘代药物具有广泛的研究价值以及广阔的应用前景。
发明内容
本发明的目的在于提供一种式I所示化合物及其制备方法和用途。
本发明的第一方面,提供了一种式I所示化合物、或其异构体、前药、溶剂合物、水合物或其药学上可接受的盐,
其中,
X选自下组:C(O)、CF2;
Y选自下组:ORa、NHRb、N(Rb)2;
R1、R4分别独立地选自下组:氢、卤素;
R2、R3分别独立地为氘取代或未取代的C1-C4烷基;
R5、R6分别独立地选自下组:氢、卤素、C1-C4烷基;
Ra选自下组:氢、取代或未取代的C1-C4烷基、取代或未取代的氨基,所述取代指被选自下组的1-4个取代基取代:氘、C1-C4烷基、C6-C10芳基、C6-C10芳基-(C1-C4亚烷基);
Rb每次出现时均独立地选自下组:氢、取代或未取代的C1-C4烷基、羟基、取代或未取代的C1-C4烷氧基,所述取代指被选自下组的1-4个取代基取代:氢、氘、卤素、C1-C4烷基、C6-C10芳基;
附加条件是R2、R3、Ra、Rb中至少一个含有氘。
在另一优选例中,
X为C(O);
Y选自下组:ORa、NHRb、N(Rb)2;
R1、R4分别独立地选自下组:氢、卤素;
R2、R3分别独立地为氘取代的C1-C4烷基;
R5、R6分别独立地选自下组:氢、卤素、C1-C4烷基;
Ra选自下组:氢、取代或未取代的C1-C4烷基、取代或未取代的氨基,所述取代指被选自下组的1-4个取代基取代:氘、C1-C4烷基、C6-C10芳基、C6-C10芳基-(C1-C4亚烷基);
Rb每次出现时均独立地选自下组:氢、取代或未取代的C1-C4烷基、羟基、取代或未取代的C1-C4烷氧基,所述取代指被选自下组的1-4个取代基取代:氢、氘、卤素、C1-C4烷基、C6-C10芳基。
在另一优选例中,
X为C(O);
Y选自下组:ORa、NHRb、N(Rb)2;
R1、R4分别独立地选自下组:氢、卤素;
R2、R3分别独立地为氘取代的C1-C4烷基;
R5、R6分别独立地选自下组:氢、卤素、C1-C4烷基;
Ra选自下组:氢、取代或未取代的C1-C4烷基、取代或未取代的氨基,所述取代指被选自下组的1-4个取代基取代:C1-C4烷基、C6-C10芳基、C6-C10芳基-(C1-C4亚烷基);
Rb每次出现时均独立地选自下组:氢、取代或未取代的C1-C4烷基、羟基、取代或未取代的C1-C4烷氧基,所述取代指被选自下组的1-4个取代基取代:氢、卤素、C1-C4烷基、C6-C10芳基。
在另一优选例中,
X为CF2;
Y选自下组:ORa、NHRb、N(Rb)2;
R1、R4分别独立地选自下组:氢、卤素;
R2、R3分别独立地为氘取代的C1-C4烷基;
R5、R6分别独立地选自下组:氢、卤素、C1-C4烷基;
Ra选自下组:氢、取代或未取代的C1-C4烷基、取代或未取代的氨基,所述取代指被选自下组的1-4个取代基取代:氘、C1-C4烷基、C6-C10芳基、C6-C10芳基-(C1-C4亚烷基);
Rb每次出现时均独立地选自下组:氢、取代或未取代的C1-C4烷基、羟基、取代或未取代的C1-C4烷氧基,所述取代指被选自下组的1-4个取代基取代:氢、氘、卤素、C1-C4烷基、C6-C10芳基。
在另一优选例中,
X为CF2;
Y选自下组:ORa、NHRb、N(Rb)2;
R1、R4分别独立地选自下组:氢、卤素;
R2、R3分别独立地为氘取代的C1-C4烷基;
R5、R6分别独立地选自下组:氢、卤素、C1-C4烷基;
Ra选自下组:氢、取代或未取代的C1-C4烷基、取代或未取代的氨基,所述取代指被选自下组的1-4个取代基取代:C1-C4烷基、C6-C10芳基、C6-C10芳基-(C1-C4亚烷基);
Rb每次出现时均独立地选自下组:氢、取代或未取代的C1-C4烷基、羟基、取代或未取代的C1-C4烷氧基,所述取代指被选自下组的1-4个取代基取代:氢、卤素、C1-C4烷基、C6-C10芳基。
在另一优选例中,R1、R4分别独立地选自下组:氢、卤素。
在另一优选例中,R2、R3分别独立地为一次或多次氘代或全氘代的C1-C4烷基。
在另一优选例中,R2、R3分别独立地为一次或多次氘代或全氘代的选自下组的基团:甲基、乙基、丙基、异丙基、丁基、叔丁基。
在另一优选例中,R2、R3分别独立地选自下组:全氘代甲基、全氘代乙基、全氘代丙基、全氘代异丙基、全氘代丁基、全氘代叔丁基。
在另一优选例中,R2、R3均为全氘代甲基。
在另一优选例中,R5、R6分别独立地选自下组:氢、C1-C4烷基。
在另一优选例中,Ra选自下组:氢、取代或未取代的氨基,所述取代指被选自下组的1-4个取代基取代:氘、C1-C4烷基。
在另一优选例中,Rb每次出现时均独立地选自下组:氢、取代或未取代的C1-C4烷基、羟基、取代或未取代的C1-C4烷氧基,所述取代指被选自下组的1-4个取代基取代:氘、C1-C4烷基、C6-C10芳基。
在另一优选例中,Ra是未氘代的。
在另一优选例中,Rb是未氘代的。
在另一优选例中,所述化合物选自下组:
本发明的第二方面,提供了一种药物组合物,包含:
(i)一种或多种治疗有效量的本发明第一方面所述的化合物、或其异构体、前药、溶剂合物、水合物或其药学上可接受的盐;和
(ii)药学上可接受的载体。
本发明的第三方面,提供了一种本发明第一方面所述的化合物、或其异构体、前药、溶剂合物、水合物或其药学上可接受的盐或本发明第二方面所述的药物组合物的用途,用于制备制剂,所述制剂用于预防和/或治疗与I型干扰素相关的疾病。
在另一优选例中,所述与I型干扰素相关的疾病选自下组:感染性疾病、癌症、自身免疫病。
在另一优选例中,所述癌症选自下组:乳腺癌、卵巢癌、肝癌、黑色素瘤、前列腺癌、结肠癌、胃癌。
应理解,在本发明范围内中,本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合,从而构成新的或优选的技术方案。限于篇幅,在此不再一一累述。
附图说明
图1是实施例3化合物S1对肿瘤的抑制结果。
具体实施方式
本发明人经过长期而深入的研究,意外地制备了一种具有优异药代动力学性质的式I所示化合物。在此基础上,发明人完成了本发明。
术语
在本发明中,除非特别指出,所用术语具有本领域技术人员公知的一般含义。
在本发明中,术语“卤素”指F、Cl、Br或I。
在本发明中,“C1-C6烷基”是指包括1-6个碳原子的直链或支链的烷基,例如甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、新戊基、特戊基、或类似基团。术语“C1-C4烷基”具有类似含义。
在本发明中,术语“C2-C6烯基”是指具有2-6个碳原子的含有一个双键的直链或支链烯基,非限制性地包括乙烯基、丙烯基、丁烯基、异丁烯基、戊烯基和己烯基等。
在本发明中,术语“C2-C6炔基”是指具有2-6个碳原子的含有一个三键的直链或支链炔基,非限制性地包括乙炔基、丙炔基、丁炔基、异丁炔基、戊炔基和己炔基等。
在本发明中,术语“C3-C8环烷基”是指在环上具有3-8个碳原子的环状烷基,非限制性地包括环丙基、环丁基、环戊基、环己基、环庚基、环辛基等。
在本发明中,术语“C1-C6烷氧基”是指具有1-6个碳原子的直链或支链烷氧基,非限制性地包括甲氧基、乙氧基、丙氧基、异丙氧基和丁氧基等。优选为C1-C4烷氧基。
在本发明中,术语“芳环”或“芳基”具有相同的含义,优选为“C6-C10芳基”。术语“C6-C10芳基”是指在环上不含杂原子的具有6-10个碳原子的芳香族环基,如苯基、萘基等。
在本发明中,术语“卤代”是指被卤素取代。
在本发明中,术语“氘代”是指被氘取代。
在本发明中,术语“取代”指特定的基团上的一个或多个氢原子被特定的取代基所取代。特定的取代基为在前文中相应描述的取代基,或各实施例中所出现的取代基。除非特别说明,某个取代的基团可以在该基团的任何可取代的位点上具有一个选自特定组的取代基,所述的取代基在各个位置上可以是相同或不同的。本领域技术人员应理解,本发明所预期的取代基的组合是那些稳定的或化学上可实现的组合。所述取代基例如(但并不限于):卤素、羟基、羧基(-COOH)、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、3-至12元杂环基、芳基、杂芳基、C1-C8醛基、C2-C10酰基、C2-C10酯基、氨基、C1-C6烷氧基、C1-C10磺酰基等。
在本发明中,术语1-6个指1、2、3、4、5或6个。其他类似术语各自独立地具有类似含义。
术语“氨基”为-NH2。
应理解,当某一基团同时存在于化合物的多个不同位置时,其在各位置的定义是相互独立的,可以相同也可以不同。亦即,术语“选自下组:”与术语“各独立地选自下组:”具有相同含义。
化合物
本发明提供了式I所示化合物、或其异构体、前药、溶剂合物、水合物或其药学上可接受的盐,
其中,各基团如上文所定义。
如本文所用,术语“药学上可接受的盐”指本发明化合物与酸或碱所形成的适合用作药物的盐。药学上可接受的盐包括无机盐和有机盐。一类优选的盐是本发明化合物与酸形成的盐。适合形成盐的酸包括但并不限于:盐酸、氢溴酸、氢氟酸、硫酸、硝酸、磷酸等无机酸;甲酸、乙酸、三氟乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、苯甲酸、甲磺酸、乙磺酸、对甲苯磺酸、苯磺酸、萘磺酸等有机酸;以及脯氨酸、苯丙氨酸、天冬氨酸、谷氨酸等氨基酸。
另一类优选的盐是本发明化合物与碱形成的盐,例如碱金属盐(例如钠盐或钾盐)、碱土金属盐(例如镁盐或钙盐)、铵盐(如低级的烷醇铵盐以及其它药学上可接受的胺盐),例如甲胺盐、乙胺盐、丙胺盐、二甲基胺盐、三甲基胺盐、二乙基胺盐、三乙基胺盐、叔丁基胺盐、乙二胺盐、羟乙胺盐、二羟乙胺盐、三羟乙胺盐,以及分别由吗啉、哌嗪、赖氨酸形成的胺盐。
术语“溶剂合物”指本发明化合物与溶剂分子配位形成特定比例的配合物。“水合物”是指本发明化合物与水进行配位形成的配合物。
此外,本发明化合物还包括式I所示化合物的前药。术语“前药”包括其本身可以是具有生物学活性的或非活性的,当用适当的方法服用后,其在人体内进行代谢或化学反应而转变成式I的一类化合物,或式I的一个化合物所组成的盐或溶液。所述的前药包括(但不局限于)所述化合物的羧酸酯、碳酸酯、磷酸酯、硝酸酯、硫酸酯、砜酯、亚砜酯、氨基化合物、氨基甲酸盐、偶氮化合物、磷酰胺、葡萄糖苷、醚、乙缩醛等形式。
药物组合物和施用方法
本发明还提供了一种药物组合物,包含:
(i)一种或多种治疗有效量的所述的化合物、或其异构体、前药、溶剂合物、水合物或其药学上可接受的盐;和
(ii)药学上可接受的载体。
由于本发明化合物具有优异的抗肿瘤活性,因此本发明化合物及其各种晶型,药学上可接受的无机或有机盐,水合物或溶剂合物,以及含有本发明化合物为主要活性成分的药物组合物可用于治疗、预防以及缓解与肿瘤相关的疾病。
本发明的药物组合物包含安全有效量范围内的本发明化合物或其药理上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全有效量”指的是:化合物的量足以明显改善病情,而不至于产生严重的副作用。通常,药物组合物含有1-2000mg本发明化合物/剂,更佳地,含有10-1000mg本发明化合物/剂。较佳地,所述的“一剂”为一个胶囊或药片。
“药学上可以接受的载体”指的是:一种或多种相容性固体或液体填料或凝胶物质,它们适合于人使用,而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的化合物以及它们之间相互掺和,而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如吐温)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
所述的药物组合物为注射剂、囊剂、片剂、丸剂、散剂或颗粒剂。
本发明化合物或药物组合物的施用方式没有特别限制,代表性的施用方式包括(但并不限于):口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)、和局部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中,活性化合物与至少一种常规惰性赋形剂(或载体)混合,如柠檬酸钠或磷酸二钙,或与下述成分混合:(a)填料或增容剂,例如,淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸;(b)粘合剂,例如,羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶;(c)保湿剂,例如,甘油;(d)崩解剂,例如,琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠;(e)缓溶剂,例如石蜡;(f)吸收加速剂,例如,季胺化合物;(g)润湿剂,例如鲸蜡醇和单硬脂酸甘油酯;(h)吸附剂,例如,高岭土;和(i)润滑剂,例如,滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠,或其混合物。胶囊剂、片剂和丸剂中,剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备,如肠衣和其它本领域公知的材料。它们可包含不透明剂,并且,这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时,活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外,液体剂型可包含本领域中常规采用的惰性稀释剂,如水或其它溶剂,增溶剂和乳化剂,例知,乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油,特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外,组合物也可包含助剂,如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外,悬浮液可包含悬浮剂,例如,乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液,和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂,或必要时可能需要的推进剂一起混合。
本发明化合物可以单独给药,或者与其他药学上可接受的其他化合物(如抗肿瘤药物)联合给药。
本发明治疗方法可以单独施用,或者与其它治疗手段或者治疗药物联用。
使用药物组合物时,是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人),其中施用时剂量为药学上认为的有效给药剂量,对于60kg体重的人而言,日给药剂量通常为1~2000mg,优选50~1000mg。当然,具体剂量还应考虑给药途径、病人健康状况等因素,这些都是熟练医师技能范围之内的。
与现有技术相比,本发明具有以下主要优点:
(1)所述化合物具有优异的药代动力学性质;
(2)所述化合物具有优异的STING激活能力。
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法,通常按照常规条件如Sambrook等人,分子克隆:实验室手册(New York:Cold Spring Harbor LaboratoryPress,1989)中所述的条件,或按照制造厂商所建议的条件。除非另外说明,否则百分比和份数按重量计算。
除非另行定义,文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外,任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。
制备实施例
1.化合物S1的合成
步骤1:将化合物1a(1eq)溶于N,N-二甲基甲酰胺中,加入氢氧化钾(2eq)和氘代碘甲烷(2.5eq),于室温下反应约3小时。待反应完全后,将反应液倾入水中,用乙酸乙酯萃取,收集有机相过柱纯化,得化合物1b。
步骤2:将丁二酸酐(1.5eq)悬浮于1,2-二氯乙烷中,0℃下加入氯化铝(2eq),而后逐滴加入化合物1b(1eq)的1,2-二氯乙烷溶液,约15分钟加毕后,将反应升温至45℃反应约8小时。待反应完全后,将反应液缓慢倾入水中,而后用3倍当量于氯化铝的4N盐酸水溶液中和反应液,充分搅拌约30分钟后过滤,所得滤饼用乙醇打浆,过滤后滤饼烘干得化合物S1。1H NMR(400MHz,DMSO)δ12.18(s,1H),8.20(s,1H),7.59(s,1H),7.47(s,1H),3.26(t,J=6.4Hz,2H),2.60(t,J=6.3Hz,2H).
2.化合物S2的合成
步骤1:将化合物2a(1eq)悬浮于二氯甲烷中,缓慢加入氯化铝(5eq),升温至45℃反应约1.5小时。待反应完全后,将反应液缓慢倾入水中,用3倍当量于氯化铝的4N盐酸水溶液中和反应液,充分搅拌至溶液澄清,用二氯甲烷萃取,收集有机相过柱纯化,得化合物2b和2c。
步骤2:将化合物2b(1eq)溶于N,N-二甲基甲酰胺中,加入氢氧化钾(1.5eq)和氘代碘甲烷(1.5eq),于室温下反应约3小时。待反应完全后,将反应液倾入水中,用乙酸乙酯萃取,收集有机相过柱纯化,得化合物2d。
步骤3:将化合物2d(1eq)悬浮于四氢呋喃中,加入一水合氢氧化锂(3eq)的水溶液,于室温下反应约2小时。待反应完全后,旋去多数有机溶剂,而后向剩余溶液中缓慢滴加1N盐酸水溶液,调节pH至5~6,待固体充分析出后过滤,所得滤饼用乙醇打浆,过滤后滤饼烘干得化合物S2。1H NMR(400MHz,DMSO)δ12.19(s,1H),8.20(s,1H),7.59(s,1H),7.48(s,1H),3.86(s,3H),3.26(t,J=6.4Hz,2H),2.60(t,J=6.4Hz,2H).
3.化合物S3的合成
合成步骤参考化合物S2:用化合物2c替换化合物2b,其他步骤相同,得化合物S3。1H NMR(400MHz,DMSO)δ12.19(s,1H),8.20(s,1H),7.59(s,1H),7.48(s,1H),3.83(s,3H),3.26(t,J=6.4Hz,2H),2.60(t,J=6.4Hz,2H).
4.化合物S4的合成
步骤1:将化合物S1(1eq)悬浮于甲醇中,冰浴下逐滴加入二氯亚砜(10eq),室温下反应约8小时。待反应完全后,将反应液旋干,固体用乙酸乙酯溶解并用饱和碳酸氢钠溶液调节pH至碱性,用乙酸乙酯萃取,收集有机相过柱纯化,得化合物4a。
步骤2:将化合物4a(1eq)溶于二氯甲烷中,随后加入1-氟-2,6-二氯吡啶四氟硼酸盐(3eq),升温至回流反应约2小时。待反应完全后,将反应液旋干,过柱纯化得化合物4b。
步骤3:将化合物4b(1eq)悬浮于四氢呋喃中,加入一水合氢氧化锂(3eq)的水溶液,于室温下反应约2小时。待反应完全后,旋去多数有机溶剂,而后向剩余溶液中缓慢滴加1N盐酸水溶液,调节pH至5~6,待固体充分析出后过滤,所得滤饼用乙醇打浆,过滤后滤饼烘干得化合物S4。1H NMR(400MHz,DMSO)δ12.18(s,1H),8.20(s,1H),7.59(s,1H),7.47(s,1H),3.26(t,J=6.4Hz,2H),2.60(t,J=6.3Hz,2H).
5.化合物S5的合成
步骤1:在氮气氛围下,将化合物5a(1eq)溶于二氯甲烷中,-78℃下逐滴加入三溴化硼(1.0M的二氯甲烷溶液,6eq),搅拌1小时后升至室温继续反应约3小时。待反应完全后,缓慢加入冰水淬灭,用二氯甲烷萃取,收集有机相过柱纯化,得化合物5b。
步骤2:将化合物5b(1eq)溶于N,N-二甲基甲酰胺中,加入氢氧化钾(2eq)和氘代碘甲烷(2.5eq),于室温下反应约3小时。待反应完全后,将反应液倾入水中,用乙酸乙酯萃取,收集有机相过柱纯化,得化合物5c。
步骤3:将化合物5c(1eq)溶于乙腈中,加入1-氯甲基-4-氟-1,4-二氮杂双环[2.2.2]辛烷二(四氟硼酸)盐(1.1eq),升温至45℃反应过夜。待反应完全后,加入饱和碳酸氢钠溶液,用乙酸乙酯萃取,收集有机相过柱纯化,得化合物5d。
步骤4:将化合物5d(1eq)悬浮于四氢呋喃中,加入一水合氢氧化锂(3eq)的水溶液,于室温下反应约3小时。待反应完全后,旋去多数有机溶剂,而后向剩余溶液中缓慢滴加1N盐酸水溶液,调节pH至5~6,待固体充分析出后过滤,所得滤饼用乙醇打浆,过滤后滤饼烘干得化合物5e。
步骤5:将化合物5e(1eq)溶于N-甲基吡咯烷酮中,加入碳酸银(1.2eq),升温至170℃反应约1小时。待反应完全后,冷却反应液并过滤,将滤液倾入水中,用乙酸乙酯萃取,收集有机相过柱纯化,得化合物5f。
步骤6:将(S)-3-甲基丁二酸酐(1.5eq)悬浮于1,2-二氯乙烷中,0℃下加入氯化铝(2eq),而后逐滴加入化合物5f(1eq)的1,2-二氯乙烷溶液,约15分钟加毕后,将反应升温至45℃反应约6小时。待反应完全后,将反应液缓慢倾入水中,而后用3倍当量于氯化铝的4N盐酸水溶液中和反应液,充分搅拌约30分钟后用乙酸乙酯萃取,收集有机相过柱纯化,得化合物S5。1H NMR(400MHz,CDCl3)δ7.96(s,1H),7.07(s,1H),3.48(dd,J=17.2,7.7Hz,1H),3.23–3.12(m,1H),3.07(dd,J=17.2,5.7Hz,1H),1.34(d,J=7.2Hz,3H).
6.化合物S6的合成
合成步骤参考化合物S5的步骤6:用化合物1b替换化合物5f,其他操作相同,得化合物S6。1H NMR(400MHz,CDCl3)δ7.82(s,1H),7.25(s,1H),7.24(s,1H),3.96(d,J=10.7Hz,6H),2.62(s,3H).
7.化合物S7的合成
步骤1:将化合物S1(1eq)溶于N,N-二甲基甲酰胺中,加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(2eq),N,N-二异丙基乙胺(3eq)和甲氧基胺盐酸盐(1.5eq),于室温下反应约3小时。待反应完全后,将反应液倾入水中,用乙酸乙酯萃取,收集有机相过柱纯化,得化合物S7。1H NMR(400MHz,DMSO)δ11.07(s,1H),8.20(s,1H),7.59(s,1H),7.47(s,1H),3.57(s,3H),3.27(t,J=6.7Hz,2H),2.35(t,J=6.6Hz,2H).
8.化合物S8的合成
步骤1:在惰性气体氛围下,将化合物8a(1eq)溶于N,N-二甲基甲酰胺中,在冰浴下分批加入氢化钠(60%,1.5eq),于0℃反应约半小时后,在该温度下逐滴加入氘代碘甲烷(1.5eq),随后升温至70℃反应约3小时。待反应完全后,将反应液倾入水中,用乙酸乙酯萃取并用饱和碳酸氢钠溶液洗涤,收集有机相过柱纯化,得化合物8b。
步骤2:将化合物8b溶于冰醋酸/浓盐酸(体积比为2:1)中,升温至回流反应约3小时。待反应完全后,将反应液旋干,得化合物8c的粗品,不作纯化直接用于下一步。
步骤3:将化合物8d(1eq)溶于N,N-二甲基甲酰胺中,加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(2eq),N,N-二异丙基乙胺(3eq)和化合物8c的粗品(1.5eq),于室温下反应约3小时。待反应完全后,将反应液倾入水中,用乙酸乙酯萃取,收集有机相过柱纯化,得化合物S8。1H NMR(400MHz,CD3OD)δ8.09(s,1H),7.44(s,2H),3.93(s,3H),3.91(s,3H),3.38(t,J=6.7Hz,2H),2.49(t,J=6.7Hz,2H).
9.化合物S9的合成
合成步骤参考化合物S8的步骤3:用化合物S1替换化合物8d,其他操作相同,得化合物S9。1H NMR(400MHz,CD3OD)δ8.09(s,1H),7.44(s,2H),3.39(d,J=6.7Hz,2H),2.49(t,J=6.7Hz,2H).
10.化合物S10的合成
步骤1:在惰性气体氛围下,将化合物4a(1eq)溶于二氯甲烷中,在冰浴下加入1,3-丙二硫醇(2eq)和三氟化硼乙醚(48%,1eq),于0℃反应约1小时后,升至室温继续反应约4小时。待反应完全后,将反应液倾入饱和碳酸氢钠溶液中,用二氯甲烷萃取,收集有机相过柱纯化,得化合物10a。
步骤2:将化合物10a(1eq)溶于二氯甲烷中,室温下加入二乙胺基三氟化硫(20eq),反应约1小时。待反应完全后,将反应液缓慢倾入饱和氯化铵溶液中,用二氯甲烷萃取,收集有机相过柱纯化,得化合物10b。
步骤3:将化合物10b(1eq)悬浮于四氢呋喃中,加入一水合氢氧化锂(3eq)的水溶液,于室温下反应约3小时。待反应完全后,旋去多数有机溶剂,而后向剩余溶液中缓慢滴加1N盐酸水溶液,调节pH至5~6,用二氯甲烷萃取,收集有机相过柱纯化,得化合物S10。1HNMR(400MHz,CDCl3)δ7.35(s,1H),7.25(s,1H),7.20(s,1H),2.71–2.63(m,4H).
11.化合物S11的合成
合成步骤参考化合物S7:用化合物S2替换化合物S1,其他操作相同,得化合物S11。1HNMR(400MHz,DMSO)δ11.07(s,1H),8.20(s,1H),7.59(s,1H),7.48(s,1H),3.86(s,3H),3.57(s,3H),3.27(t,J=6.7Hz,2H),2.35(t,J=6.5Hz,2H).
12.化合物S12的合成
合成步骤参考化合物S7:用化合物S3替换化合物S1,其他操作相同,得化合物S12。1HNMR(400MHz,DMSO)δ11.07(s,1H),8.20(s,1H),7.59(s,1H),7.48(s,1H),3.83(s,3H),3.57(s,3H),3.27(t,J=6.7Hz,2H),2.35(t,J=6.5Hz,2H).
13.化合物S13的合成
合成步骤参考化合物S7:用O-苯甲基羟胺替换甲氧基胺盐酸盐,其他操作相同,得化合物S13。1H NMR(400MHz,CDCl3)δ8.39(s,1H),7.89(s,1H),7.41–7.36(m,5H),7.25(d,J=1.6Hz,2H),4.91(s,2H),3.37(t,J=6.0Hz,2H),2.50(br,2H).
14.化合物S14的合成
合成步骤参考化合物S7:用甲氧基甲基胺替换甲氧基胺盐酸盐,其他操作相同,得化合物S14。1H NMR(400MHz,DMSO)δ8.20(s,1H),7.59(s,1H),7.47(s,1H),3.68(s,3H),3.26(t,J=6.4Hz,2H),2.65(s,3H),2.60(t,J=6.3Hz,2H).
15.化合物S15的合成
步骤1:合成步骤参考化合物S7:用O-(叔丁基二苯基甲硅烷基)-N-甲基羟胺替换甲氧基胺盐酸盐,其他操作相同,得化合物15a。
步骤2:将化合物15a(1eq)溶于四氢呋喃中,冰浴下加入吡啶氢氟酸盐(3eq),反应约2小时。待反应完全后,用饱和碳酸氢钠溶液淬灭反应液,用乙酸乙酯萃取,收集有机相过柱纯化,得化合物S15。1H NMR(400MHz,DMSO)δ9.89(s,1H),8.19(s,1H),7.59(s,1H),7.48(s,1H),3.22(t,J=6.4Hz,2H),3.08(s,3H),2.77(t,J=6.2Hz,2H).
16.化合物S16的合成
步骤1:在惰性气体氛围下,将氢氧化钾(3eq)溶液甲醇中,加入盐酸羟胺(3eq),反应约30分钟后加入化合物4a(1eq),继续反应约6小时。待反应完全后,直接过柱纯化,得化合物S16。1H NMR(400MHz,DMSO)δ10.45(s,1H),8.69(s,1H),8.21(s,1H),7.59(s,1H),7.47(s,1H),3.26(t,J=6.6Hz,2H),2.33(t,J=6.4Hz,2H).
17.化合物S17的合成
步骤1:合成步骤参考化合物4a:用化合物S5替换化合物S1,其他操作相同,得化合物17a。
步骤2:合成步骤参考化合物S10:用化合物17a替换化合物4a,其他操作相同,得化合物S17。1H NMR(400MHz,CDCl3)δ7.47(s,1H),7.08(s,1H),2.98–2.83(m,2H),2.39–2.26(m,1H),1.34(d,J=6.6Hz,3H).
18.化合物S18的合成
步骤1:将化合物S1(1eq)溶于N,N-二甲基甲酰胺中,加入2-(1H-苯并三偶氮L-1-基)-1,1,3,3-四甲基脲四氟硼酸酯(2eq),N,N-二异丙基乙胺(3eq)和N-异丙基羟胺盐酸盐(1.5eq),于室温下反应约2小时。待反应完全后,将反应液倾入水中,用乙酸乙酯萃取,收集有机相过柱纯化,得化合物S18。1H NMR(400MHz,CDCl3)δ7.89(s,1H),7.35(br,1H),7.25(s,1H),7.25(s,1H),3.37(t,J=6.8Hz,2H),3.29–3.23(m,2H),2.83(t,J=6.8Hz,2H),1.12(d,J=6.3Hz,6H).
测试实施例
实施例1化合物S7的药代动力学(PK)性质研究
为了显示氘原子取代后的原子效应,本发明将公开专利CN111393404A中不含氘原子取代的化合物ⅠA与本发明中所描述的含氘取代的化合物S7、S8、S9在大鼠体内的药代动力学性质进行了比较。
实验方法:雄性SD大鼠12只,体重223-254g,随机分成4组,每组3只,静脉给予ⅠA/S7/S8/S9,给药剂量为1mg/kg。给药前禁食过夜,给药后4h统一进食,自由饮水。在5min,0.25,0.5,1.0,2.0,4.0,8.0和24h通过颈静脉从大鼠身上采集60μL血液样本到微型K2EDTA管中,8000rpm离心6min,分离血浆,于-20℃冰箱中冷冻。
采用LC-MS/MS法测定大鼠血浆中ⅠA、S7、S8、S9的浓度,采用WinNonlin8.2.0软件(美国Pharsight公司)的非房室模型计算给药后的药代动力学参数。
实验结果:如表1所示。
表1.化合物IA、S7、S8、S9在大鼠中药代动力学性质对比
以上数据显示,相比于专利CN111393404A中的化合物ⅠA,苯环上的两个甲氧基氘代化合物S7静脉给药暴露量(AUClast)及最大血药浓度(Cmax)显著提高,是化合物ⅠA的8倍以上,并且具有显著降低的清除率;末端氮甲氧基氘代物S8及同时对两部分进行氘代的S9药代性质提升不明显。由此可见,化合物氘代的位置对化合物代谢性质改善的程度密切相关,本发明中所描述的苯环上的两个甲氧基氘代能够显著改善药代动力学性质。
此外,按照本实施例相同的方法得到化合物ⅡA和化合物S1的药代性质如表2所示。
表2
以上数据显示,相比于专利WO2018067423中的化合物ⅡA,本发明中所描述的含氘取代的化合物S1的半衰期(t1/2)、稳态分布体积(Vss)、口服生物利用度(F)均得到了明显提升。
实施例2部分化合物对THP-1细胞中IFNb、CXCL10 mRNA表达量的影响
实验方法:THP-1细胞以6*105/mL密度接种于12孔板,12h后加入10μM化合物处理,8h后500g离心5min收集细胞,每份细胞沉淀中加入1mL TRIzol裂解细胞。按照TRIzol操作说明提取mRNA并测定其浓度,根据测定结果取500ng mRNA使用PrimeScriptTMRT MasterMix试剂盒(TAKARA)将其反转录为cDNA,使用qPCR Mix试剂盒(TOYOBO)与480(Roche)对样品中靶基因含量进行测定,采用2^(-ΔΔCt)相对定量法计算目的基因含量。
实验结果:如表3所示。
表3.化合物对THP-1细胞中IFNb、CXCL10 mRNA表达量的影响
以上活性数据说明,本发明中的化合物对STING具有显著的激活活性。
为了验证不同位置氘取代对化合物的活性的影响,我们对比化合物IA、S7、S8和S9对STING的激动活性(表4)。苯环上的两个甲氧基氘代化合物S7活性显著提升,末端氮甲氧基氘代物S8的活性较IA下降近9倍,同时对两部分进行氘代的S9活性较IA仍然显著下降。由此可见,本发明中所描述的苯环上两个甲氧基氘代的化合物不仅能够显著改善化合物的代谢性质,而且能够提升对STING的激动活性。
表4.化合物IA不同位点氘代物对THP-1细胞中IFNb、CXCL10 mRNA表达量的影响
实施例3化合物S1在CT26小鼠结直肠癌模型中的体内药效
实验方法:4-6周龄Balb/C雌性小鼠16只,每只小鼠各注射CT-26细胞(2.5*105),待肿瘤体积长到50-100mm3。将小鼠随机分为2组,每组8只,分别在第1、4、7天经瘤内注射给化合物S1(10mg/kg),共3次。动物随机分组并记录体重,分组后对组内每只小鼠进行标记;每两天测量一次老鼠体重以及肿瘤体积,随时观察老鼠状态并进行记录。
实验结果:如图1所示。
从图1可知,本发明中所描述的化合物S1在CT26小鼠结直肠癌模型中能够有效抑制肿瘤生长,瘤内注射给药10mg/kg,给药3次后,肿瘤生长抑制率达79.74%。
由此可见,本发明所描述的含氘取代后的化合物对STING具有较高的激活能力,在大鼠体内的药代动力学性质得到改善,这使得本发明的化合物进入体内药效学和安全性评价时其药效得以充分暴露,与迄今报道的STING激动剂相比具有显著的优势和进一步研发的潜力。
在本发明提及的所有文献都在本申请中引用作为参考,就如同每一篇文献被单独引用作为参考那样。此外应理解,在阅读了本发明的上述讲授内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。
Claims (10)
1.一种式I所示化合物、或其异构体、前药、溶剂合物、水合物或其药学上可接受的盐,
其中,
X选自下组:C(O)、CF2;
Y选自下组:ORa、NHRb、N(Rb)2;
R1、R4分别独立地选自下组:氢、卤素;
R2、R3分别独立地为氘取代或未取代的C1-C4烷基;
R5、R6分别独立地选自下组:氢、卤素、C1-C4烷基;
Ra选自下组:氢、取代或未取代的C1-C4烷基、取代或未取代的氨基,所述取代指被选自下组的1-4个取代基取代:氘、C1-C4烷基、C6-C10芳基、C6-C10芳基-(C1-C4亚烷基);
Rb每次出现时均独立地选自下组:氢、取代或未取代的C1-C4烷基、羟基、取代或未取代的C1-C4烷氧基,所述取代指被选自下组的1-4个取代基取代:氢、氘、卤素、C1-C4烷基、C6-C10芳基;
附加条件是R2、R3、Ra、Rb中至少一个含有氘。
2.如权利要求1所述的化合物、或其异构体、前药、溶剂合物、水合物或其药学上可接受的盐,其特征在于,
X为C(O);
Y选自下组:ORa、NHRb、N(Rb)2;
R1、R4分别独立地选自下组:氢、卤素;
R2、R3分别独立地为氘取代的C1-C4烷基;
R5、R6分别独立地选自下组:氢、卤素、C1-C4烷基;
Ra选自下组:氢、取代或未取代的C1-C4烷基、取代或未取代的氨基,所述取代指被选自下组的1-4个取代基取代:氘、C1-C4烷基、C6-C10芳基、C6-C10芳基-(C1-C4亚烷基);
Rb每次出现时均独立地选自下组:氢、取代或未取代的C1-C4烷基、羟基、取代或未取代的C1-C4烷氧基,所述取代指被选自下组的1-4个取代基取代:氢、氘、卤素、C1-C4烷基、C6-C10芳基。
3.如权利要求1所述的化合物、或其异构体、前药、溶剂合物、水合物或其药学上可接受的盐,其特征在于,
X为C(O);
Y选自下组:ORa、NHRb、N(Rb)2;
R1、R4分别独立地选自下组:氢、卤素;
R2、R3分别独立地为氘取代的C1-C4烷基;
R5、R6分别独立地选自下组:氢、卤素、C1-C4烷基;
Ra选自下组:氢、取代或未取代的C1-C4烷基、取代或未取代的氨基,所述取代指被选自下组的1-4个取代基取代:C1-C4烷基、C6-C10芳基、C6-C10芳基-(C1-C4亚烷基);
Rb每次出现时均独立地选自下组:氢、取代或未取代的C1-C4烷基、羟基、取代或未取代的C1-C4烷氧基,所述取代指被选自下组的1-4个取代基取代:氢、卤素、C1-C4烷基、C6-C10芳基。
4.如权利要求1所述的化合物、或其异构体、前药、溶剂合物、水合物或其药学上可接受的盐,其特征在于,
X为CF2;
Y选自下组:ORa、NHRb、N(Rb)2;
R1、R4分别独立地选自下组:氢、卤素;
R2、R3分别独立地为氘取代的C1-C4烷基;
R5、R6分别独立地选自下组:氢、卤素、C1-C4烷基;
Ra选自下组:氢、取代或未取代的C1-C4烷基、取代或未取代的氨基,所述取代指被选自下组的1-4个取代基取代:氘、C1-C4烷基、C6-C10芳基、C6-C10芳基-(C1-C4亚烷基);
Rb每次出现时均独立地选自下组:氢、取代或未取代的C1-C4烷基、羟基、取代或未取代的C1-C4烷氧基,所述取代指被选自下组的1-4个取代基取代:氢、氘、卤素、C1-C4烷基、C6-C10芳基。
5.如权利要求1所述的化合物、或其异构体、前药、溶剂合物、水合物或其药学上可接受的盐,其特征在于,
X为CF2;
Y选自下组:ORa、NHRb、N(Rb)2;
R1、R4分别独立地选自下组:氢、卤素;
R2、R3分别独立地为氘取代的C1-C4烷基;
R5、R6分别独立地选自下组:氢、卤素、C1-C4烷基;
Ra选自下组:氢、取代或未取代的C1-C4烷基、取代或未取代的氨基,所述取代指被选自下组的1-4个取代基取代:C1-C4烷基、C6-C10芳基、C6-C10芳基-(C1-C4亚烷基);
Rb每次出现时均独立地选自下组:氢、取代或未取代的C1-C4烷基、羟基、取代或未取代的C1-C4烷氧基,所述取代指被选自下组的1-4个取代基取代:氢、卤素、C1-C4烷基、C6-C10芳基。
7.一种药物组合物,其特征在于,包含:
(i)一种或多种治疗有效量的权利要求1或6所述的化合物、或其异构体、前药、溶剂合物、水合物或其药学上可接受的盐;和
(ii)药学上可接受的载体。
8.一种权利要求1或6所述的化合物、或其异构体、前药、溶剂合物、水合物或其药学上可接受的盐或权利要求7所述的药物组合物的用途,其特征在于,用于制备制剂,所述制剂用于预防和/或治疗与I型干扰素相关的疾病。
9.如权利要求8所述的用途,其特征在于,所述与I型干扰素相关的疾病选自下组:感染性疾病、癌症、自身免疫病。
10.如权利要求9所述的用途,其特征在于,所述癌症选自下组:乳腺癌、卵巢癌、肝癌、黑色素瘤、前列腺癌、结肠癌、胃癌、胰腺癌、胆管癌、头颈癌、脑胶质瘤、子宫内膜瘤、肺癌。
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