CN116655540A - 一种Cat K抑制剂与制备方法及其应用 - Google Patents
一种Cat K抑制剂与制备方法及其应用 Download PDFInfo
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- CN116655540A CN116655540A CN202210156862.8A CN202210156862A CN116655540A CN 116655540 A CN116655540 A CN 116655540A CN 202210156862 A CN202210156862 A CN 202210156862A CN 116655540 A CN116655540 A CN 116655540A
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- amino
- phenyl
- methyl
- pyrimidine
- carbonitrile
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- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
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Abstract
本发明提供一种氰基取代嘧啶类化合物,结构如式Ⅰ所示,可作为Cat K抑制剂。本发明还提供了其制备方法和应用。本发明提供的Cat K抑制剂具有较高的抑制作用和选择性,有望制备用于包括肿瘤、甲状腺疾病、心血管疾病、骨疾病和牙龈病在内的疾病治疗。
Description
技术领域
本发明涉及医药化学领域,具体涉及具有Cat K抑制活性的一种氰基取代嘧啶类化合物及制备方法以及制备用于与Cat K活性相关或以Cat K活性为特征的疾病中的用途,如骨质疏松。
背景技术
骨质疏松症简称骨质疏松,是一种全身骨量减少、骨密度降低,进而导致患者骨折风险增加的代谢障碍性疾病。随着人口老龄化的加剧,该疾病涉及的健康问题日益严重,骨质疏松患者的骨折几率大大增加,为社会和家庭带来了沉重的负担,严重影响了人们的生活。骨质疏松的发病机制是破骨细胞介导的骨吸收和成骨细胞介导的骨形成失衡所导致,目前市场上常用的骨质疏松治疗药物有骨吸收抑制剂如双磷酸盐,和骨形成促进剂,但这两种药都存在一定的缺陷。长期使用骨吸收抑制剂会使骨细胞的分化增殖受到影响,进一步导致“低骨转换状态”的发生;骨形成促进剂则会增加患者患骨肉瘤的概率。由于目前市场上存在的药物均存在一定缺陷,因此研究能够在发挥骨质疏松治疗作用的同时,不会影响成骨细胞和破骨细胞的增殖、分化,避免低骨转换状态的发生的新型骨质疏松治疗药物,是目前的研究方向。
Cat K(Cathepsin K,组织蛋白酶K)属于木瓜蛋白酶家族的半胱氨酸蛋白酶,在破骨细胞中大量存在,目前成为骨质疏松治疗的新靶点。人体的骨基质由25%的水、25%的有机基质和50%的矿物基质组成,其中有机质的90%组成成分是Ⅰ型胶原蛋白,Ⅰ型胶原蛋白的降解是破骨细胞介导的骨吸收的关键过程,而Cat K对Ⅰ型胶原蛋白的降解起主导作用,Cat K抑制剂通过阻断基质胶原蛋白的降解来抑制成熟破骨细胞的再吸收,与此同时,CatK抑制剂可维持破骨细胞的存活数量,这使得破骨细胞和成骨细胞的耦合信号保持完整,从而避免了“低骨转换状态”的发生。此外,研究发现由先天性Cat K基因缺陷造成的致密性成骨不全症或通过敲除Cat K基因得到的动物模型均表现出骨密度升高等骨吸收抑制现象,证明Cat K的活性与骨吸收作用密切相关,因而Cat K抑制剂用于治疗或预防骨相关疾病具有良好的治疗作用,包括骨质疏松、骨关节炎和骨转移瘤等。另外Cat K在甲状腺疾病、心血管疾病和牙龈病的致病过程中起重要作用。Cat K异常表达或活化为特征的疾病,包括甲状腺疾病、心血管疾病、骨疾病和牙龈病,具体为甲状腺功能亢进、动脉粥样硬化、心肌肥厚、心力衰竭、骨质疏松症、骨关节炎、类风湿性关节炎、牙龈炎和牙周炎。近年关于Cat K的研究越来越多,冠状动脉粥样硬化等病理状态下可引起内皮细胞分泌Cat K增加。Cat K与心肌肥厚、心力衰竭的发生发展有着非常紧密的联系。Garg等(Garg G,Pradeep AR,ThoratMK,et al.Effect ofnonsurgical periodontal therapy on crevicular fluid levelsof Cathepsin K inperiodontitis.Arch Oral Biol,54:1046-1051)通过牙周炎患者基础治疗前后龈沟液中Cat K的变化,证明基础治疗后,随着牙周炎患者临床牙龈指数,牙周探诊深度及附着丧失减少,Cat K的水平也随之降低,Cat K作为牙周炎骨吸收的标记物,在牙周炎治疗中应得到进一步的关注和研究。
目前Cat K抑制剂以及临床研究阶段报道的各类抑制剂的活性均已经得到了很大的提高。但是,仍旧没有针对于该靶点的上市药物,其主要原因是化合物的选择性较差,对其他亚型如B型和S型具有较高的抑制活性,导致药物副作用的产生。因此以减少副作用为目标,开发研究高效、选择性新型Cat K抑制剂,是目前的主要研究方向。
鉴于Cat B与Cat K同属于半胱氨酸蛋白酶,而Cat L为嗜酸性蛋白水解酶,且CatL来源困难,故本发明设计并合成的一种氰基取代嘧啶类化合物针对K、B和S测定了活性,发现具有良好的选择性,以期用于治疗与Cat K活性相关或以Cat K活性为特征的疾病。
发明内容
本发明提供了一种作用于Cat K的新型氰基化合物及其药学上可接受的盐,与其制备方法及其应用。
本发明的目的是提供一种腈类化合物,其结构通式如下所示:
其中:
X为C或N;
R1选自H、取代或未取代的C1-10烷基、取代或未取代的C3-C10环烷基;其中,所述的取代基选自卤素、氨基、氰基、羟基、醛基、羧基、砜基;
Y为环基,位于所连接芳香环的任意位置,任选为C3-10环烷基、C6-12芳香环、C5-12杂环;
其中,所述的C6-12芳香环包含C6-12芳环和C6-12杂芳环;其中所述C6-12杂芳环含有至少一个杂原子;其中所述C5-12杂环为饱和杂环或不饱和杂环,杂环含有1-3个杂原子;其中所述杂原子任选O、N或S;
R5选自H、卤素、氨基、氰基、C1-10烷基、C1-10烷氧基、C3-10环烷基、-S(O)2R2、-C(O)R2、-NR3R4、-SR6、-OR6;其中,所述R2选自H、氨基、卤素、C1-6烷基、C1-6烷氧基、C3-8环烷基;其中,所述R3、R4与它们相连的N共同形成至少含有一个N的4-8元环;其中所述R6选自C1-6烷基;
其中,所述卤素为单取代或者多取代,选自F、Cl、Br、I。
进一步的,X为C或N;
R1选自H、取代或未取代的C1-10烷基、取代或未取代的C3-C10环烷基;其中,所述的取代基选自卤素、氨基、氰基、羟基;
Y为环基,位于芳香环的对位,任选为C3-10环烷基、C6-12芳香环、C5-12杂环;
其中,所述的C6-12芳香环包含C6-12芳环和C6-12杂芳环;其中所述C6-12杂芳环含有至少一个杂原子;其中所述C5-12杂环为饱和杂环或不饱和杂环,杂环含有1-3个杂原子;其中所述杂原子任选O、N或S;
R5选自H、卤素、氨基、氰基、C1-10烷基、C1-10烷氧基、C3-10环烷基、-S(O)2R2、-C(O)R2、-NR3R4、-SR6、-OR6;其中,所述R2选自H、氨基、卤素、C1-6烷基、C1-6烷氧基、C3-8环烷基;其中,所述R3、R4与它们相连的N共同形成至少含有一个N的4-8元环;其中所述R6选自C1-6烷基;
其中,所述卤素为单取代或者多取代,选自F、Cl、Br、I。
进一步的,X为C;
R1选自C1-6烷基、C4-C8环烷基;
Y为环基,位于芳香环的对位,任选为C4-8环烷基、C6-10芳香环、C5-10杂环;
其中,所述的C6-10芳香环包含C6-10芳环和C6-10杂芳环;其中所述C6-10杂芳环含有至少一个杂原子;其中所述C5-10杂环为饱和杂环或不饱和杂环,杂环含有1-3个杂原子;其中所述杂原子任选O、N或S;
R5选自H、卤素、氨基、氰基、C1-6烷基、C1-6烷氧基、C3-8环烷基、-S(O)2R2、-C(O)R2、-NR3R4、-SR6、-OR6;其中,所述R2选自H、氨基、卤素、C1-6烷基、C1-6烷氧基、C3-8环烷基;其中,所述R3、R4与它们相连的N共同形成至少含有一个N的5-8元环;其中所述R6选自C1-6烷基。
其中,所述卤素为单取代或者多取代,选自F、Cl、Br。
进一步的,X为C;
R1选自C1-6烷基、C5-C8环烷基;
Y为环基,位于芳香环的对位,任选为C5-8环烷基、C6-8芳香环、C5-8杂环;
其中,所述C6-8芳香环包含C6-8芳环和C6-8杂芳环;其中所述C6-8杂芳环含有至少一个杂原子;其中所述C5-8杂环为饱和杂环或不饱和杂环,杂环含有1-3个杂原子;其中所述杂原子任选O、N或S;
R5选自H、卤素、氨基、氰基、C1-3烷基、C1-3烷氧基、-S(O)2R2、-C(O)R2、-NR3R4、-SR6、-OR6;其中,所述R2选自氨基、卤素、C1-3烷基;其中,所述R3、R4与它们相连的N共同形成至少含有一个N的5-8元环;其中所述R6选自C1-3烷基。
其中,所述卤素为单取代或者多取代,选自F、Cl、Br。
在一些实施例中,R1选自新戊基、环己基。
在一些实施例中,Y选自以下基团:苯基、吡啶基、噻吩基、噻唑基。
在一些优选实施例中,Y选自苯基、噻唑基。
在一些实施例中,R5选自H、F、Cl、氰基、甲基、甲硫基、甲氧基、甲砜基、甲羰基、甲基哌嗪基。
在一些优选实施例中,R5选自甲基、甲基哌嗪基。
本发明的另一目的是提供上述化合物的制备方法,包含以下步骤:
其中R1、R5、X、Y如上述所定义;
其中L为卤素,卤素选自F、Cl、Br;
步骤1):中间体3与化合物4生成化合物5;
反应条件:在碱性溶剂中进行;
其中所述碱为无机碱,选自碳酸铯、碳酸钠、碳酸钾、碳酸氢钠、碳酸氢钾、氨水、氢化钠、氢氧化钠、氢氧化钾、氢氧化钙中至少一种;
所述溶剂选自水、甲醇、乙醇、甘油、丙二醇、甲酰胺、乙腈、正丁醇、二氧六环、二氯甲烷、氯仿、丙酮、二甲基亚砜、二甲基甲酰胺、醋酸乙酯或四氢呋喃中至少一种;
步骤2):化合物5与化合物6反应生成式Ⅰ化合物;
反应条件:在碱性溶剂中加热反应;
其中所述碱和溶剂如步骤1)中所定义;
其中所述加热温度为40-100℃。
另一方面,本发明还提供一种药物组合物,其中含有治疗有效量的一种或多种所述的化合物或其药学上可接受的盐。
本发明的第三个方面,所述的化合物或药物组合物作为Cat K抑制剂,在制备用于预防和/或治疗与Cat K相关疾病的药物中的应用。
进一步的,所述Cat K相关疾病包括甲状腺疾病、心血管疾病、骨疾病、牙龈病和肿瘤。
进一步的,所述甲状腺疾病包括甲状腺功能亢进。
进一步的,所述心血管疾病包括动脉粥样硬化、心肌肥厚、心力衰竭。
进一步的,所述骨疾病包括骨质疏松症、骨关节炎、类风湿性关节炎、骨转移瘤。
进一步的,所述甲牙龈病包括牙龈炎和牙周炎。
进一步的,所述的肿瘤包括肿瘤侵袭和肿瘤转移。
进一步的,所述与Cat K相关疾病为骨质疏松症。
本发明的优点和技术效果在于:
本发明化合物对Cat K酶的抑制率高,IC50数值低,部分化合物在1μM和10μM水平对Cat K酶的抑制率能达到90%以上,部分化合物IC50值小于10nM,对Cat K酶有很好的抑制活性。
本发明化合物具有良好的成药性。
本发明化合物选择性好:在1μM和10μM水平,对Cat B酶、Cat S酶的抑制率均<40%,表明本发明化合物对Cat K酶具有很好的选择性。
该Cat K抑制剂可用于制备治疗以Cat K异常表达或活化为特征的疾病,包括甲状腺疾病、心血管疾病、骨疾病和口腔疾病,具体为甲状腺功能亢进、动脉粥样硬化、心肌肥厚、心力衰竭、骨质疏松症、骨关节炎、类风湿性关节炎、牙龈炎和牙周炎。
本发明的中术语:
除非另有定义,本文所有科技术语具有的涵义与权利要求主题所属领域技术人员通常理解的涵义相同。
应理解,上述简述和下文的详述为示例性且仅用于理解,而不对本发明主题作任何限制。此外,所用术语“包括”以及其他形式,例如“包含”、“含”和“含有”并非限制性。
本文所用的章节标题仅用于组织文章的目的,而不应被理解为对所述主题的限制。本申请中引用的所有文献或文献部分包括但不限于专利、专利申请、文章、书籍、操作手册和论文,均通过引用方式整体并入本文。
在本申请中,作为基团或是其它基团的一部分,术语“烷基”表示具有指定数目的碳原子的直链或支链全饱和脂族烃基。例如,“C1-10烷基”是指含1-10个碳原子的通过除去母体烷的单个碳原子上的一个氢原子衍生的直链或支链烃基,例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、新戊基、正己基等。
术语“C1-10烷氧基”包括-O-C1-10烷基,指C1-10烷基与氧原子相连。
术语“C3-10环烷基”指仅由碳原子和氢原子组成的稳定的非芳香族单环或多环烃基,其可包括稠合环体系、桥环体系或螺环体系,具有3至10个碳原子,且其为饱和或不饱和并可经由任何适宜的碳原子通过单键与分子的其余部分连接。除非本说明书中另外特别指明,环烷基中的碳原子可以任选地被氧化。环烷基的实例包括但不限于环丙基、环丁基、环戊基、环己基、环庚基、环辛基等。
术语“C6-12元芳香环”表示具有共轭的平面环体系,原子间成键并不是不连续的单双键交替,而是被离域π电子云覆盖,具有6-12个原子,可以为碳原子、氮原子、硫原子、氧原子。除非本说明书中另外特别指明,否则芳香环可为单环、双环、三环或更多环的环体系。
术语“C6-12杂芳环”为含有6-12环原子的单环或双环芳环,其中1、2、3或4个环原子选自氮、硫或氧,其中环中的氮或硫可以被氧化。就本发明的目的而言,杂芳环基优选为包含1至3个选自氮、氧和硫的杂原子的稳定的5元至10元芳香性基团,更优选为包含1至2个选自氮、氧和硫的杂原子的稳定的5元至8元芳香性基团。杂芳基的实例包括但不限于噻吩基、咪唑基、吡唑基、噻唑基、噁唑基、噁二唑基、异噁唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基。
术语“C5-12杂环”是含有5-12个环原子的饱和的、不饱和的或部分饱和的单环或双环,其中1、2或3个环原子选自氮、硫或氧,所述环可以由碳或氮连接,其中环中的-CH2-基团任选被-C(O)基团取代;其中环中的氮或硫原子可以任选被氧化形成N-氧化物或S-氧化物;其中环中的-NH-任选被乙酰基、甲酰基、甲基或甲磺酰基取代。
本发明所述的药物组合物包括:本发明第一方面所述的式I化合物,或其光学异构体,药学上可接受的盐,前药。
在本申请中,除非特别说明,术语“药学上可接受的盐”指适合于对象的组织接触,而不会产生不适度的副作用的盐,本申请中的盐主要为药学上可接受的酸加成盐和药学上可接受的碱加成盐。
“药学上可接受的酸加成盐”是指能够保留游离碱的生物有效性而无其它副作用的,与无机酸或有机酸所形成的盐。无机酸盐包括盐酸盐、氢溴酸盐、硫酸盐、硝酸盐、磷酸盐等;有机酸盐包括甲酸盐、乙酸盐、2,2-二氯乙酸盐、三氟乙酸盐、丙酸盐、己酸盐、辛酸盐、癸酸盐、十一碳烯酸盐、乙醇酸盐、葡糖酸盐、乳酸盐、癸二酸盐、己二酸盐、戊二酸盐、丙二酸盐、草酸盐、马来酸盐、琥珀酸盐、富马酸盐、洒石酸盐、柠檬酸盐、棕榈酸盐、硬脂酸盐、油酸盐、肉桂酸盐、月桂酸盐、苹果酸盐、谷氨酸盐、焦谷氨酸盐、天冬氨酸盐、苯甲酸盐、甲磺酸盐、苯磺酸盐、对甲苯磺酸盐、海藻酸盐、抗坏血酸盐、水杨酸盐、4-氨基水杨酸盐、萘二磺酸盐等。这些盐可通过本专业已知的方法制备。
“药学上可接受的碱加成盐”是指能够保持游离酸的生物有效性而无其它副作用的与无机碱或有机碱所形成的盐。衍生自无机碱的盐包括但不限于钠盐、钾盐、锂盐、铵盐、钙盐、镁盐、铁盐、锌盐、铜盐、锰盐、铝盐等。优选的无机盐为铵盐、钠盐、钾盐、钙盐及镁盐。衍生自有机碱的盐包括但不限于以下的盐:伯胺类、仲胺类及叔胺类,被取代的胺类,包括天然的被取代胺类、环状胺类及碱性离子交换树脂,例如氨、异丙胺、三甲胺、二乙胺、三乙胺、三丙胺、乙醇胺、二乙醇胺、三乙醇胺、二甲基乙醇胺、2-二甲氨基乙醇、2-二乙氨基乙醇、二环己胺、赖氨酸、精氨酸、组氨酸、咖啡因、普鲁卡因、胆碱、甜菜碱、乙二胺、葡萄糖胺甲基葡萄糖胺、可可碱、嘌呤、哌嗪、哌啶、N-乙基哌啶、聚胺树脂等。优选的有机碱包括异丙胺、二乙胺、乙醇胺、三甲胺、二环己基胺、胆碱及咖啡因。这些盐可通过本专业已知的方法制备。
本发明还包括上述化合物的前药,在本申请中,术语“前药”表示可在生理学条件下或通过溶剂分解而被转化成本发明的生物活性化合物的化合物。因此,术语“前药”是指本发明的化合物的药学上可接受的代谢前体。当被给予有需要的个体时,前药可以不具有活性,但在体内被转化成本发明的活性化合物。前药通常在体内迅速转化,而产生本发明的母体化合物,例如通过在血液中水解来实现。前药化合物通常在哺乳动物生物体内提供溶解度、组织相容性或缓释的优点。具体的前药制备方法可参照Saulnier,M.G.,et al.,Bioorg.Med.Chem.Lett.1994,4,1985-1990;Greenwald,R.B.,et al.,J.Med.Chem.2000,43,475。
本文所用术语“药学上可接受的”是指不影响本发明化合物的生物活性或性质的物质(如载体或稀释剂),并目相对无毒,即该物质可施用于个体而不造成不良的生物反应或以不良方式与组合物中包含的任意组分相互作用。
本文所用的术语“治疗”和其它类似的同义词包括以下含义:
(i)预防疾病或病症在哺乳动物中出现,特别是当这类哺乳动物易患有该疾病或病症,但尚未被诊断为已患有该疾病或病症时;
(ii)抑制疾病或病症,即遏制其发展;
(iii)缓解疾病或病症,即,使该疾病或病症的状态消退;
(iv)减轻该疾病或病症所造成的症状。
具体实施方式
实施例1:2-[(2,2-二甲基丙基){[4-(4-甲基哌嗪-1-基)苯基]甲基}氨基]嘧啶-4-甲腈(K1)
将化合物M1(500mg,2.47mmol)溶于8mL无水四氢呋喃中,降温至0℃,搅拌下分批加入NaH(178mg,7.41mmol),移至室温下反应2h,搅拌下加入化合物M2(732mg,2.72mmol),室温下反应2h。反应完毕后,加入10mL水淬灭反应,减压蒸除四氢呋喃,用水萃取两次,有机相合并,无水硫酸钠干燥。柱层析纯化(石油醚:乙酸乙酯=20:1)后得到白色固体即为K1化合物,收率60.3%,1H NMR(400MHz,DMSO-d6)δ8.60(d,J=4.7Hz,1H),7.12(d,J=4.7Hz,1H),7.01(d,J=8.1Hz,2H),6.84(d,J=8.3Hz,2H),4.80(s,2H),3.47(s,2H),3.07(t,J=5.0Hz,4H),2.41(t,J=4.9Hz,4H),2.20(s,3H),0.94(s,9H);ESI-MS m/z:379.5[M+H]+。
实施例2:2-[(2,2-二甲基丙基)[(4-苯基苯基)甲基]氨基]嘧啶-4-甲腈(K2)
参照实施例1的合成方法,制备中间体M4。
将中间体M4(291mg,0.81mmol)溶于1mL水和9mL DMF的混合溶液中,搅拌下依次加入苯基硼二醇(108mg,0.89mmol),碳酸钾(223mg,1.616mmol),抽真空,在氩气保护下升温至80℃下反应4h。反应完毕后,恢复至室温,向反应液中加入20mL水稀释,用乙酸乙酯萃取两次,有机相合并,用饱和食盐水洗两次,无水硫酸钠干燥。柱层析(石油醚:乙酸乙酯=12:1)后得白色固体即为K2化合物,,收率54.7%,1HNMR(400MHz,DMSO-d6)δ8.65(s,1H),7.69–7.56(m,4H),7.45(q,J=7.2Hz,2H),7.36(t,J=6.7Hz,1H),7.30–7.15(m,3H),4.96(s,2H),3.58(s,2H),0.99(d,J=13.6Hz,9H);ESI-MS m/z:357.4[M+H]+。
实施例3:2-[(2,2-二甲基丙基)({4-[4-(甲基硫基)苯基]苯基}甲基)氨基]嘧啶-4-甲腈(K3)
参照实施例2的合成方法,其中的原料苯基硼二醇替换为4-甲硫基苯基硼二醇,得到白色固体即为K3化合物,收率48.6%,1HNMR(400MHz,DMSO-d6)δ8.63(s,1H),7.63–7.55(m,4H),7.35–7.30(m,2H),7.23(d,J=7.9Hz,2H),7.17(d,J=4.7Hz,1H),4.95(s,2H),3.58(s,2H),2.51(d,J=1.9Hz,3H),0.97(s,9H);ESI-MS m/z:403.4[M+H]+。
实施例4:2-[(2,2-二甲基丙基){[4-(4-氟苯基)苯基]甲基}氨基]嘧啶-4-甲腈(K4)
参照实施例2的合成方法,其中的原料苯基硼二醇替换为4-氟苯基硼二醇得到白色固体即为K4化合物,收率47.1%,1H NMR(400MHz,DMSO-d6)δ8.63(s,1H),7.62(d,J=20.0Hz,4H),7.49(s,2H),7.24(s,2H),7.17(s,1H),4.95(s,2H),3.58(s,2H),0.97(s,9H);ESI-MS m/z:375.4[M+H]+。
实施例5:2-[(2,2-二甲基丙基){[4-(4-甲氧基苯基)苯基]甲基}氨基]嘧啶-4-甲腈(K5)
参照实施例2的合成方法,其中的原料苯基硼二醇替换为4-甲氧基苯基硼二醇得到白色固体即为K5化合物,收率44.6%,1H NMR(400MHz,DMSO-d6)δ8.63(s,1H),7.55(t,J=8.7Hz,4H),7.20(d,J=7.8Hz,2H),7.16(d,J=4.7Hz,1H),7.00(d,J=8.3Hz,2H),4.93(s,2H),3.78(s,3H),3.56(s,2H),0.97(s,9H);ESI-MS m/z:387.4[M+H]+。
实施例6:2-[(2,2-二甲基丙基)({4-[4-(甲基磺酰基)苯基]苯基}甲基)氨基]嘧啶-4-甲腈(K6)
参照实施例2的合成方法,其中的原料苯基硼二醇替换为4-甲磺酰基苯基硼二醇得到白色固体即为K6化合物,收率53.7%,1H NMR(400MHz,DMSO-d6)δ8.62(s,1H),7.98(d,J=8.5Hz,2H),7.90(d,J=8.2Hz,2H),7.69(d,J=7.9Hz,2H),7.29(d,J=7.8Hz,2H),7.17(d,J=4.7Hz,1H),4.97(s,2H),3.59(s,2H),3.24(s,3H),0.97(s,9H);ESI-MS m/z:435.4[M+H]+。
实施例7:2-({[4-(5-氰基噻吩-2-基)苯基]甲基}(2,2-二甲基丙基)氨基)嘧啶-4-甲腈(K7)
参照实施例2的合成方法,其中的原料苯基硼二醇替换为5-(二羟基硼基)噻吩-2-甲腈,得白色固体即为K7化合物,收率31.7%,1H NMR(400MHz,DMSO-d6)δ8.62(s,1H),7.97(d,J=4.0Hz,1H),7.69(d,J=7.9Hz,2H),7.64(d,J=4.0Hz,1H),7.25(d,J=7.9Hz,2H),7.17(d,J=4.7Hz,1H),4.93(s,2H),3.58(s,2H),0.96(s,9H);ESI-MS m/z:388.4[M+H]+。
实施例8:2-({[4-(6-氯吡啶-3-基)苯基]甲基}(2,2-二甲基丙基)氨基)嘧啶-4-甲腈(K8)
参照实施例2的合成方法,其中的原料苯基硼二醇替换为(2-氯吡啶-5-基)硼二醇,得白色固体即为K8化合物,收率34.5%,1H NMR(400MHz,DMSO-d6)δ8.71(s,1H),8.63(s,1H),8.13(d,J=8.8Hz,1H),7.68(d,J=7.9Hz,2H),7.59(d,J=8.4Hz,1H),7.28(d,J=7.8Hz,2H),7.18(d,J=4.7Hz,1H),4.96(s,2H),3.59(s,2H),0.97(s,9H);ESI-MS m/z:392.4[M+H]+。
实施例9:2-({[4-(3,4-二氯苯基)苯基]甲基}(2,2-二甲基丙基)氨基)嘧啶-4-甲腈(K9)
参照实施例2的合成方法,其中的原料苯基硼二醇替换为(1,2-二氯苯-4-基)硼二醇,得白色固体即为K9化合物,收率52.9%,1HNMR(400MHz,DMSO-d6)δ8.62(s,1H),7.89(d,J=2.1Hz,1H),7.67(s,1H),7.65–7.61(m,3H),7.24(d,J=8.0Hz,2H),7.16(d,J=4.7Hz,1H),4.94(s,2H),3.58(s,2H),0.96(s,9H);ESI-MS m/z:425.4[M+H]+。
实施例10:2-[(2,2-二甲基丙基){[4-(5-甲基噻吩-2-基)苯基]甲基}氨基]嘧啶-4-甲腈(K10)
参照实施例2的合成方法,其中的原料苯基硼二醇替换为(5-甲基噻吩-2-基)硼二醇,得白色固体即为K10化合物,收率34.8%,1H NMR(400MHz,DMSO-d6)δ8.62(s,1H),7.49(d,J=8.0Hz,2H),7.23(d,J=3.6Hz,1H),7.19–7.12(m,3H),6.79(dd,J=3.6,1.2Hz,1H),4.89(s,2H),3.56(s,2H),2.44(d,J=1.1Hz,3H),0.95(s,9H);ESI-MS m/z:377.4[M+H]+。
实施例11:4-(4-{[(4-氰基嘧啶-2-基)(2,2-二甲基丙基)氨基]甲基}苯基)苯甲酸甲酯(K11)
参照实施例2的合成方法,其中的原料苯基硼二醇替换为4-(二羟基硼基)苯甲酸甲酯,得到白色固体即为K11化合物,收率44.7%,1H NMR(400MHz,DMSO-d6)δ8.63(s,1H),8.01(d,J=8.4Hz,2H),7.79(d,J=8.4Hz,2H),7.68(d,J=7.9Hz,2H),7.27(d,J=7.9Hz,2H),7.17(d,J=4.7Hz,1H),4.96(s,2H),3.87(s,3H),3.59(s,2H),0.97(s,9H);ESI-MS m/z:415.4[M+H]+。
实施例12:2-({[4-(4-氯-3-氟苯基)苯基]甲基}(2,2-二甲基丙基)氨基)嘧啶-4-甲腈(K12)
参照实施例2的合成方法,其中的原料苯基硼二醇替换为(1-氯-2-氟苯-4-基)硼二醇,得白色固体即为K12化合物,收率51.8%,1H NMR(400MHz,DMSO-d6)δ8.62(s,1H),7.71(dd,J=11.0,2.1Hz,1H),7.64(t,J=8.2Hz,3H),7.52(dd,J=8.4,2.1Hz,1H),7.25(d,J=7.9Hz,2H),7.16(d,J=4.7Hz,1H),4.95(s,2H),3.58(s,2H),0.96(s,9H);ESI-MS m/z:409.4[M+H]+。
实施例13:2-[(2,2-二甲基丙基)({4-[4-(4-甲基哌嗪-1-基)苯基]苯基}甲基)氨基]嘧啶-4-甲腈(K13)
参照实施例2的合成方法,其中的原料苯基硼二醇替换为4-(4-甲基-1-哌嗪基)苯基硼二醇,得白色固体即为K13化合物,收率68.7%,1H NMR(400MHz,CDCl3)δ8.42(d,J=4.7Hz,1H),7.47(d,J=8.1Hz,4H),7.17(s,2H),6.98(d,J=8.8Hz,2H),6.74(d,J=4.7Hz,1H),4.99(s,2H),3.58(s,2H),3.29–3.23(m,4H),2.59(t,J=5.0Hz,4H),2.36(s,3H),1.01(s,9H);ESI-MS m/z:455.6[M+H]+。
实施例14:2-[(环己基甲基)[(4-苯基苯基)甲基]氨基]嘧啶-4-甲腈(K14)
参照实施例2的合成方法,得到白色固体即为K14化合物,收率53.1%,1H NMR(400MHz,DMSO-d6)δ8.65(s,1H),7.61(m,4H),7.44(m,2H),7.32(m,3H),7.15(m,1H),4.88(s,2H),3.46(m,2H),1.81(s,1H),1.62(m,5H),1.14(m,3H),0.97(m,2H);ESI-MS m/z:383.5[M+H]+。
实施例15:2-[(环己基甲基)({4-[4-(4-甲基哌嗪-1-基)苯基]苯基}甲基)氨基]嘧啶-4-甲腈(K15)
参照实施例2的合成方法,得到白色固体即为K15化合物,收率60.7%,1H NMR(400MHz,DMSO-d6)δ8.63(s,1H),7.51(dd,J=15.1,8.1Hz,4H),7.23(d,J=7.7Hz,2H),7.14(d,J=4.7Hz,1H),6.99(d,J=8.4Hz,2H),4.85(s,2H),3.16(s,4H),2.45(s,4H),2.22(s,3H),1.81(s,1H),1.62(d,J=16.2Hz,5H),1.15(s,3H),0.97(d,J=11.8Hz,2H);ESI-MSm/z:481.7[M+H]+。
实施例16:2-[(环己基甲基)({4-[4-(甲基磺酰基)苯基]苯基}甲基)氨基]嘧啶-4-甲腈(K16)
参照实施例2的合成方法,得到白色固体即为K16化合物,收率49.3%,1H NMR(400MHz,DMSO-d6)δ8.64(s,1H),7.98(d,J=8.5Hz,2H),7.91(d,J=8.3Hz,2H),7.70(d,J=7.8Hz,2H),7.35(d,J=7.9Hz,2H),7.15(d,J=4.7Hz,1H),4.90(s,2H),3.48(d,J=7.4Hz,2H),3.24(s,3H),1.86–1.76(m,1H),1.62(d,J=15.1Hz,5H),1.14(d,J=8.0Hz,3H),0.98(d,J=11.8Hz,2H);ESI-MS m/z:461.6[M+H]+。
实施例17:2-(新戊基(4-(噻唑-4-基)苄基)氨基)嘧啶-4-甲腈(K17)
参照实施例2的合成方法,得到白色固体即为K17化合物,收率32.9%,1H NMR(400MHz,DMSO-d6)δ9.17(s,1H),8.62(s,1H),8.09(s,1H),7.91(s,2H),7.22(s,3H),4.93(s,2H),3.57(s,2H),0.96(s,9H);ESI-MS m/z:364.3[M+H]+。
实施例18:2-((4-(2-(4-甲基哌嗪-1-基)噻唑-4-基)苄基)(新戊基)氨基)嘧啶-4-甲腈(K18)
参照实施例2的合成方法,得到白色固体K18化合物,收率48.1%,1H NMR(400MHz,DMSO-d6)δ8.61(s,1H),7.75(t,J=8.6Hz,2H),7.26–7.07(m,4H),4.91(d,J=8.2Hz,2H),3.56(s,2H),3.43(s,4H),2.42(s,4H),2.22(s,3H),0.95(s,9H);ESI-MS m/z:462.6[M+H]+。
实施例19:化合物对Cat K酶的抑制效果
试剂信息:Cat K抑制剂筛选试剂盒:批号,6L23K01500;供应商,BiVision。药物制备:化合物用DMSO溶解,配制成10mM储备液。使用时用Buffer配制成所需浓度。
实验方法
1.药物初筛
组织蛋白酶K(CTSK,EC 3.4.22.38)是一种溶酶体半胱氨酸蛋白酶,参与破骨细胞骨重塑和再吸收,还能降解胶原蛋白、明胶和弹性蛋白。Biovision的组织蛋白酶K抑制剂筛选试剂盒利用活性组织蛋白酶K切割合成的基于AFC的肽底物以释放AFC的能力,可使用荧光计或荧光微孔板读取器轻松量化AFC。在存在组织蛋白酶K特异性抑制剂的情况下,该底物的裂解减少/消除,导致AFC荧光减少或完全丧失。这种简单且高通量的适应性分析试剂盒可用于筛选/研究/表征组织蛋白酶K的潜在抑制剂。
在96孔板中分别加入20μL的buffer、Cat K抑制剂、待测化合物(1μM、10μM)分别作为EC孔、IC孔、S孔;所有孔分别加入50μL的Cat K Enzyme Solution,室温孵育10-15min,以建立酶抑制剂复合物;所有孔加入30μL的Cat K Substrate Solution,室温孵育30-60min;反应的最终体积为100μL。在30-60min,选择两个时间点T1、T2检测荧光吸收值(Ex/Em=400/505nm),荧光吸收值记为RFU1、RFU2,并计算待测化合物对Cat K酶的抑制率(%)。
斜率=(RFU2-RFU1)/(T2-T1)
抑制率(%)=(EC斜率–S斜率)/EC斜率×100
2.IC50测定
筛选方法同1.1,待测化合物浓度设置在0.1nM-10μM之间,选择4-5个浓度进行检测,绘制IC50曲线,并计算IC50值,IC50<10uM为有效。
数据处理:所有的数据用Graphpad进行统计学分析。
实验结果
本发明的化合物均有活性,部分化合物的结果见表1。
部分结果见表1。
表1化合物抑制率及IC50(nM)
注:A、B和C代表IC50值的活性范围,其中A:<10nM,B:10-100nM,C:100-500nM。
本发明化合物对Cat K酶的抑制率高,IC50数值低,对Cat K酶有很好的抑制活性。部分化合物在1μM水平10μM水平Cat K酶的抑制率能达到90%以上,在10μM水平对Cat K酶的抑制率能达到99%以上,部分化合物的IC50值小于10nM,因此本发明化合物对Cat K酶具有较好的抑制作用。
实施例20:化合物对Cat B酶、Cat S的抑制效果
组织蛋白酶B筛选
在96孔板中分别加入10μL的buffer、Cat B抑制剂、待测化合物(1μM、10μM)分别作为EC孔、IC孔、S孔;所有孔分别加入50μL的Cat B Enzyme Solution,室温孵育10-15min,以建立酶抑制剂复合物;所有孔加入40μL的Cat B Substrate Solution,室温孵育30-60min;反应的最终体积为100μL。在30-60min,选择两个时间点T1、T2检测荧光吸收值(Ex/Em=400/505nm),荧光吸收值记为RFU1、RFU2,并计算待测化合物对Cat B酶的抑制率(%)。
斜率=(RFU2-RFU1)/(T2-T1)
抑制率(%)=(EC斜率–S斜率)/EC斜率×100
IC50测定
筛选方法同上,待测化合物浓度设置在0.1nM-10μM之间,选择4-5个浓度进行检测,绘制IC50曲线,并计算IC50值。
数据处理:所有的数据用Graphpad进行统计学分析。
组织蛋白酶S筛选
在96孔板中分别加入10μL的buffer、Cat S抑制剂、待测化合物(1μM、10μM)分别作为EC孔、IC孔、S孔;所有孔分别加入50μL的Cat B Enzyme Solution,室温孵育10-15min,以建立酶抑制剂复合物;所有孔加入40μL的Cat S Substrate Solution,室温孵育30-60min;反应的最终体积为100μL。在30-60min,选择两个时间点T1、T2检测荧光吸收值(Ex/Em=400/505nm),荧光吸收值记为RFU1、RFU2,并计算待测化合物对Cat S酶的抑制率(%)。
斜率=(RFU2-RFU1)/(T2-T1)
抑制率(%)=(EC斜率–S斜率)/EC斜率×100
IC50测定
筛选方法同上,待测化合物浓度设置在0.1nM-10μM之间,选择4-5个浓度进行检测,绘制IC50曲线,并计算IC50值。
数据处理:所有的数据用Graphpad进行统计学分析。
结果见表2。
表2化合物抑制率及IC50(μM)
上述化合物对Cat S酶抑制作用的IC50值>10μM,同时对Cat B酶抑制作用的IC50值>10μM,因此本发明化合物对Cat K酶具有良好的选择性。
Claims (10)
1.一种式I化合物或其药学上可接受的盐或光学异构体,其结构如下所示:
其中:
X为C或N;
R1选自H、取代或未取代的C1-10烷基、取代或未取代的C3-C10环烷基;其中,所述的取代基选自卤素、氨基、氰基、羟基、醛基、羧基、砜基;
Y为环基,位于所连接芳香环的任意位置,任选为C3-10环烷基、C6-12芳香环、C5-12杂环;
其中,所述的C6-12芳香环包含C6-12芳环和C6-12杂芳环;其中所述C6-12杂芳环含有至少一个杂原子;其中所述C5-12杂环为饱和杂环或不饱和杂环,杂环含有1-3个杂原子;其中所述杂原子任选O、N或S;
R5选自H、卤素、氨基、氰基、C1-10烷基、C1-10烷氧基、C3-10环烷基、-S(O)2R2、-C(O)R2、-NR3R4、-SR6、-OR6;其中,所述R2选自H、氨基、卤素、C1-6烷基、C1-6烷氧基、C3-8环烷基;其中,所述R3、R4与它们相连的N共同形成至少含有一个N的4-8元环;其中所述R6选自C1-6烷基;
其中,所述卤素为单取代或者多取代,选自F、Cl、Br、I。
2.一种如权利要求1所述的化合物或其药学上可接受的盐或光学异构体,其中,
X为C或N;
R1选自C1-10烷基、C3-C10环烷基;
Y为环基,任选为C3-10环烷基、C6-12芳香环、C5-12杂环;
其中,所述的C6-12芳香环包含C6-12芳环和C6-12杂芳环;其中所述C6-12杂芳环含有至少一个杂原子;其中所述C5-12杂环为饱和杂环或不饱和杂环,杂环含有1-3个杂原子;其中所述杂原子任选O、N或S;
R5选自H、卤素、氨基、氰基、C1-10烷基、C1-10烷氧基、C3-10环烷基、-S(O)2R2、-C(O)2R2、-NR3R4、-SR7、-OR7;其中,所述R2选自H、氨基、卤素、C1-6烷基、C1-6烷氧基、C3-8环烷基;其中,所述R3、R4与它们相连的N共同形成至少含有一个N的4-8元环;其中所述R7选自C1-6烷基;
其中,所述卤素为单取代或者多取代,选自F、Cl、Br、I。
3.一种如权利要求1所述的化合物或其药学上可接受的盐或光学异构体,Y选自以下基团:苯基、吡啶基、噻吩基、噻唑基。
4.一种如权利要求1所述的化合物或其药学上可接受的盐或光学异构体,R5选自H、F、Cl、氰基、甲基、甲硫基、甲氧基、甲砜基、甲羰基、甲基哌嗪基。
5.一种式Ⅰ化合物或其药学上可接受的盐或光学异构体,选自:
1)2-[(2,2-二甲基丙基){[4-(4-甲基哌嗪-1-基)苯基]甲基}氨基]嘧啶-4-甲腈
2)2-[(2,2-二甲基丙基)[(4-苯基苯基)甲基]氨基]嘧啶-4-甲腈
3)2-[(2,2-二甲基丙基)({4-[4-(甲基硫基)苯基]苯基}甲基)氨基]嘧啶-4-甲腈
4)2-[(2,2-二甲基丙基){[4-(4-氟苯基)苯基]甲基}氨基]嘧啶-4-甲腈
5)2-[(2,2-二甲基丙基){[4-(4-甲氧基苯基)苯基]甲基}氨基]嘧啶-4-甲腈
6)2-[(2,2-二甲基丙基)({4-[4-(甲基磺酰基)苯基]苯基}甲基)氨基]嘧啶-4-甲腈
7)2-({[4-(5-氰基噻吩-2-基)苯基]甲基}(2,2-二甲基丙基)氨基)嘧啶-4-甲腈
8)2-({[4-(6-氯吡啶-3-基)苯基]甲基}(2,2-二甲基丙基)氨基)嘧啶-4-甲腈
9)2-({[4-(3,4-二氯苯基)苯基]甲基}(2,2-二甲基丙基)氨基)嘧啶-4-甲腈
10)2-[(2,2-二甲基丙基){[4-(5-甲基噻吩-2-基)苯基]甲基}氨基]嘧啶-4-甲腈
11)4-(4-{[(4-氰基嘧啶-2-基)(2,2-二甲基丙基)氨基]甲基}苯基)苯甲酸甲酯
12)2-({[4-(4-氯-3-氟苯基)苯基]甲基}(2,2-二甲基丙基)氨基)嘧啶-4-甲腈
13)2-[(2,2-二甲基丙基)({4-[4-(4-甲基哌嗪-1-基)苯基]苯基}甲基)氨基]嘧啶-4-甲腈
14)2-[(环己基甲基)[(4-苯基苯基)甲基]氨基]嘧啶-4-甲腈
15)2-[(环己基甲基)({4-[4-(4-甲基哌嗪-1-基)苯基]苯基}甲基)氨基]嘧啶-4-甲腈
16)2-[(环己基甲基)({4-[4-(甲基磺酰基)苯基]苯基}甲基)氨基]嘧啶-4-甲腈
17)2-(新戊基(4-(噻唑-4-基)苄基)氨基)嘧啶-4-甲腈
18)2-((4-(2-(4-甲基哌嗪-1-基)噻唑-4-基)苄基)(新戊基)氨基)嘧啶-4-甲腈。
6.一种如权利要求1所述的式II化合物,其制备方法包括步骤:
L为卤素化合物5与化合物6反应生成式Ⅰ化合物;其中R1、R5、X、Y如权利要求1中所定义。
7.一种如权利要求8所述的制备方法,其特征在于,其中化合物5的制备方法如下:
化合物3与化合物4反应生成化合物5。
8.一种药用组合物,包含权利要求1-5任一权利要求所述化合物或其药学上可接受的盐或其光学异构体。
9.一种如权利要求1-5任一权利要求所述化合物或其药学上可接受的盐或其光学异构体,在制备治疗以组织蛋白酶K为靶向的疾病的药物中的应用。
10.一种如权利要求9所述的应用,其特征在于,所述以组织蛋白酶K为靶向的疾病包括肿瘤、甲状腺疾病、心血管疾病、骨疾病和牙龈病;优选的,所述甲状腺疾病包括甲状腺功能亢进;优选的,所述心血管疾病包括动脉粥样硬化、心肌肥厚、心力衰竭;优选的,所述骨疾病包括骨质疏松症、骨关节炎、类风湿性关节炎;优选的,所述甲牙龈病包括牙龈炎和牙周炎;优选的,所述以组织蛋白酶K为靶向的疾病为骨质疏松症。
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