CN110563709B - 一类嘧啶类化合物及其作为trpv2抑制剂的用途 - Google Patents
一类嘧啶类化合物及其作为trpv2抑制剂的用途 Download PDFInfo
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- CN110563709B CN110563709B CN201810587269.2A CN201810587269A CN110563709B CN 110563709 B CN110563709 B CN 110563709B CN 201810587269 A CN201810587269 A CN 201810587269A CN 110563709 B CN110563709 B CN 110563709B
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Abstract
本发明公开了一类嘧啶类化合物及其作为TRPV2抑制剂的用途,该类化合物的结构如通式I所示。本发明的嘧啶类化合物,具有较佳的TRPV2抑制作用,能够用作TRPV2抑制剂,预防和/或治疗心肌病、前列腺癌或糖尿病。
Description
技术领域
本发明属于医药技术领域,涉及一类嘧啶类化合物及其作为TRPV2抑制剂的用途。
背景技术
心血管病是全球范围内致残、致死率最高的疾病之一。其中,心肌病是引发心衰死亡的重要原因。由于心肌病往往病因不明,故缺乏特殊治疗方法。早期以减少心脏负荷、减轻症状的保守治疗为主。晚期出现心力衰竭症状,则采取一般心衰的治疗方式。常用药物包括强心类药物洋地黄制剂和β-受体阻滞剂等。如果病人经历严重心衰,则必须进行心脏移植。心肌病亟需有针对性的药物与治疗手段。
TRPV2(Transient Receptor Potential Vanilloid 2)通道是一种非选择性阳离子通道。近年来研究发现,TRPV2通道参与心肌细胞机械拉伸的响应过程,协助维持心脏的结构与功能。在杜氏肌营养不良症相关病理过程中,细胞膜发生机械拉伸刺激TRPV2通道开放,导致钙离子流入心肌细胞,引发扩张性心肌病。通过使用抑制剂阻塞TRPV2通道,能够显著抑制扩张性心肌病的发展。因此,TRPV2通道是治疗心肌病的重要药物靶标。靶向TRPV2通道的小分子抑制剂可被用于心肌病等心血管疾病的预防与治疗。
前列腺癌是近年来常见的男性恶性肿瘤之一,病因尚不十分清楚,可能与环境因素、生活方式、遗传因素相关,目前研究表明,雄激素在其发生和发展中起着重要作用。抗雄激素治疗等去势疗法对于雄激素受体阳性前列腺癌具有较好的治疗效果,然而随着长期治疗后,大多数前列腺癌会发展成去势抵抗性前列腺癌。由于现在尚无有效的治疗方法,一旦转成去势抵抗前性列腺癌则患者的存活期通常仅为1-2年。近几年来,针对去势抵抗性前列腺癌的治疗药物层出不穷,其中部分药物获得了较好的治疗效果,尽管如此,目前的药物仍只能以月为单位短期延缓疾病的进程,无法做到长期有效的防治前列腺癌。多西紫杉醇是治疗去势抵抗前列腺癌的一线化疗药物,但是大多数患者最终都会对其产生耐药性。新型的内分泌药物恩杂鲁胺用于治疗多西紫杉醇化疗失败后的去势抵抗前列腺癌的患者,但后者同样存在耐药性。因此,研究新型抗前列腺癌药显得尤为重要,而新型药物靶点的选择是抗前列腺癌药物研究的关键。
研究表明,TRPV2通道在前列腺癌细胞中也具有高表达。TRPV2开放导致的钙离子释放能够刺激前列腺癌细胞的扩增与转移。使用siRNA静息TRPV2通道,能够减少癌细胞增长,降低前列腺肿瘤细胞的侵袭能力。因此,TRPV2通道也是新型抗前列腺癌的靶点。靶向TRPV2通道的抑制剂可用于研发有效的抗前列腺癌药物。
糖尿病是现代社会最常见的严重疾病之一,分为两种,一种产生是由于胰腺无法分泌足够的胰岛素导致体内血糖含量过高的1型糖尿病,一种是体内胰岛素无法发挥降糖效果的2型糖尿病。研究表明,TRPV2通道在胰腺细胞中表达,参与胰岛素的分泌。使用多种抑制剂和基因敲除的手段,Kojima研究小组发现TRPV2通道参与胰岛素分泌的正反馈过程。TRPV2通道的开放能够刺激胰岛素分泌,促进细胞成长;另一方面,胰岛素信号的释放又能够引发TRPV2在细胞中的迁移。因此,TRPV2通道也是治疗糖尿病的潜在药物靶标。靶向TRPV2通道的抑制剂可被用于提高机体内的胰岛素水平,发挥治疗糖尿病的效果。
鉴于TRPV2通道能够作为治疗心肌病、前列腺癌和糖尿病的药物靶标,尚需对其抑制剂进行深入研发,以满足临床需求。
发明内容
本发明的目的在于提供一种具有较好的TRPV2的抑制活性的嘧啶衍生物。
本发明的第一方面,提供通式I化合物,其药学上可接受的盐、前体药物、溶剂化物、氘代物或其立体异构体,
其中,
X选自:-O-、-S-、-NR4-,其中R4选自:氢、C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基、C1-C6卤代烷氧基、卤素、氨基、羟基;
Y选自:-CO-NH-,-NH-CO-,-NR5-,–COO-,-OOC-,其中R5选自:氢、C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基、C1-C6卤代烷氧基、卤素、氨基、羟基;
m选自:0、1、2、3、4、5或6;
n选自:0、1、2、3、4、5或6;
R1、R2独立选自氢、C1-C6烷基、C1-C6卤代烷基、羧基、羟基、被1-4个Q1取代或未取代的C6-C10芳香环、被1-4个Q1取代或未取代的4-10元杂环和-NR′R″,
其中各Q1独立选自:C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基、C1-C6卤代烷氧基、卤素、氨基、羟基;
R′和R″独立地为-(CH2)q-R3,q选自0,1,2,3或4,R3选自H、被1-4个Q2取代或未取代的6-10元芳香环、和被1-3个Q2取代或未取代的4-10元杂环,
其中各Q2独立选自:C1-C6的直链或支链的烷基、C1-C6的直链或支链的烷氧基、C1-C6卤代烷基、C1-C6卤代烷氧基、卤素、氨基、羟基。
在另一优选例中,X为-S-。
在另一优选例中,Y为-CO-NH-或-NH-CO-;
在另一优选例中,R1为被1-3个Q1取代或未取代的4-10元杂环、被1-4个Q1取代或未取代的C6-C10芳香环、-NR′R″或氢,其中,
各Q1独立选自:C1-C6烷基、C1-C6烷氧基、卤素、氨基、羟基;
R′和R″独立地为-(CH2)q-R3,q选自0,1,2,3或4,R3选自H、被1-4个Q2取代或未取代的6-10元芳香环,
其中各Q2独立选自:C1-C6的直链或支链的烷基、C1-C6的直链或支链的烷氧基、卤素、氨基、羟基。
在另一优选例中,R1选自下组:
在另一优选例中,R2为未取代的4-6元芳香杂环、羟基或羧基。
在另一优选例中,所述化合物选自下组:
本发明的第二方面,提供第一方面所述的化合物的制备方法,所述制备方法包括以下步骤:
(i)式I-1化合物与HX-(CH2)n-Ya反应得到式I-2化合物;
式中,Ya为-COOH、-NH2、-NHR3、-SH或-OH,其中R3′选自下组:C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基、C1-C6卤代烷氧基、卤素、氨基、羟基;
(ii)式I-2化合物与Yb-(CH2)m-R2反应得到式I化合物
式中,Yb为-NH2、-COOH、-NHR4、-SH或-OH其中R4′选自下组:C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基、C1-C6卤代烷氧基、卤素、氨基、羟基;
各式中,R1、R2、X、Y、m和n的定义如第一方面所述。
在另一优选例中,所述制备方法包括以下步骤:
2,4-二氯-6-三氟甲基嘧啶(1eq)用无水二氯甲烷溶解放入冰水浴中,R1卤代物(1.1eq)和三乙胺(3eq)加入无水二氯甲烷用恒压漏斗滴加入反应液中,冰浴反应5小时,反应完后将反应液用二氯甲烷和饱和NaCl萃取3次,合并有机相,减压真空旋转蒸干溶剂,粗品经过柱层析得到产物式I-1化合物;或者:2,4-二氯-6-三氟甲基嘧啶(1eq)用溶剂(如1,4-二氧六环)溶解放入茄型瓶中,加入R1硼酸化合物(1eq)和饱和碳酸钠水溶液5ml,加入1,1-双三苯基磷二氯化钯(0.1eq),油浴升温到75℃反应5小时,反应完全后将反应液用二氯甲烷和饱和NaCl萃取3次,合并有机相,减压真空旋转蒸干溶剂,粗品经过柱层析得到产物式I-1化合物;
称取底物式I-1化合物(1eq),用溶剂(如1,4-二氧六环)溶解,加入HX-(CH2)n-Ya(3eq,X、Ya为相应反应基团如巯基、羧基等),DBU(3eq)碱,加热到95℃,反应10小时,在反应后的溶液中加入二氯甲烷进行稀释,然后加入水,利用二氯甲烷进行萃取。萃取后的二氯甲烷层,用盐水进行洗涤,接着用无水硫酸钠干燥,最后通过蒸发除掉溶剂,粗品经过柱层析得到产物式I-2化合物;
称取底物式I-1化合物(1eq),用溶剂(如无水二氯甲烷)溶解,加入Yb-(CH2)m-R2(2eq,Yb为相应反应基团如氨基等),EDCI(2eq),HOBt(2eq),三乙胺(3eq)反应10小时,反应完全后,加入二氯甲烷和水进行萃取3次。萃取后的二氯甲烷层,用盐水进行洗涤,接着用无水硫酸钠干燥,最后通过蒸发除掉溶剂,粗品经过柱层析得到产物式I化合物。
本发明的第三方面,提供一种药物组合物,包含:
第一方面所述的化合物,其药学上可接受的盐、前体药物、溶剂化物、氘代物或其立体异构体;和
药学上可接受的载体。
本发明的第四方面,提供第一方面所述的化合物的用途,用于制备TRPV2抑制剂。
本发明还提供一种抑制TRPV2的方法,包括向由此需要的患者施用第一方面所述的化合物。在另一优选例中,所述患者为人类。
本发明的第五方面,提供第一方面所述的化合物的用途,用于制备预防和/或治疗心肌病、前列腺癌或糖尿病的药物。
本发明还提供一种预防和/或治疗心肌病、前列腺癌或糖尿病的方法,包括向由此需要的患者施用第一方面所述的化合物。在另一优选例中,所述患者为人类。
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。说明书中所揭示的各个特征,可以被任何提供相同、均等或相似目的的替代性特征取代。限于篇幅,在此不再一一赘述。
附图说明
图1为1μM本发明化合物1、化合物4、化合物5、化合物7和化合物9对TRPV2的抑制率结果图。Icontrol为不加化合物记录的细胞电流,I添加1μM化合物后记录的细胞电流。
图2为不同浓度的本发明化合物1对TRPV2的抑制效果图。Icontrol为不加化合物记录的细胞电流,I为添加1μM化合物后记录的细胞电流。
图3为不同浓度的本发明化合物1对细胞的影响结果图,其中,a.不同浓度化合物1对PC-3M细胞迁移影响。b.不同浓度化合物1影响下,PC-3M细胞的迁移率。c.化合物1对PC-3M细胞生存率的影响。**表示P值小于0.05。
具体实施方式
本申请的发明人经过广泛而深入地研究,研发出具有通式I所示结构的化合物,具有较好的TRPV2的抑制活性,能够用于预防和/或治疗心肌病、前列腺癌和糖尿病。在此基础上,完成了本发明。
术语
本发明所述“C1-C6烷基”表示直链或支链的含有1-6个(1、2、3、4、5、6个)碳原子的烷基,如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、2-甲基丁基、新戊基、1-乙基丙基、正己基、异己基、3-甲基戊基、2-甲基戊基、1-甲基戊基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、1,2-二甲基丁基、1,3-二甲基丁基、2,3-二甲基丁基、2-乙基丁基、1,2-二甲基丙基等。优选C1-C4烷基。本发明所述“C1-C4烷基”指含有1-4个碳原子上述实例。
本发明所述“C1-C6烷氧基”指“C1-C6烷基”通过氧原子与其他结构相连接的基团,如甲氧基、乙氧基、丙氧基、1-甲基乙氧基、丁氧基、1-甲基丙氧基、2-甲基丙氧基、1,1-二甲基乙氧基、戊氧基、1-甲基丁氧基、2-甲基丁氧基、3-甲基丁氧基、1,1-二甲基丙氧基、1,2-二甲基丙氧基、2,2-二甲基丙氧基、1-乙基丙氧基、己氧基、1-甲基戊氧基、2-甲基戊氧基、3-甲基戊氧基、4-甲基戊氧基、1,1-二甲基丁氧基、1,2-二甲基丁氧基、1,3-二甲基丁氧基、2,2-二甲基丁氧基、2,3-二甲基丁氧基、3,3-二甲基丁氧基、1-乙基丁氧基、2-乙基丁氧基、1,1,2-三甲基丙氧基、1,2,2-三甲基丙氧基、1-乙基-1-甲基丙氧基和1-乙基-2-甲基丙氧基。术语“C1-C4烷氧基”指上述实例中的含有1-4个碳原子的具体实例。
本发明所述“卤素”是指氟原子、氯原子、溴原子、碘原子等。优选氟原子和氯原子。
本发明所述“卤代”是指所述基团中任意一个或多个能被取代的原子被卤素所取代,可全卤代,即卤素原子取代基团中所有能被取代的位置。
术语“C1-C6卤代烷基”指被相同或不同的1-6个上述卤原子取代的上述C1-C6烷基,例如三氟甲基、五氟乙基、或类似基团。类似地,术语“C1-C6卤代烷氧基”指被相同或不同的1-6个上述卤原子取代的上述C1-C6烷氧基。
术语“芳基”或芳香环“”指单环至三环的芳族烃基,例如苯基、萘基、或类似基团。
术语“杂芳环”、“芳香杂环”或“杂芳基”指含有至少一个杂原子(N、O或S)的芳族烃基,包括但不限于呋喃基、噻吩基、吡啶基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、咪唑基、四唑基等。
术语“杂环”是指含有至少一个杂原子的饱和或不饱和的环状基团或包含至少一个杂原子的杂芳基,包含单环杂环基和多环杂环基,多环杂环基包括螺环、稠环和桥环杂环基。“4-10元杂环”指包含4至10个环原子的杂环基,“3-10元杂环基”指包含3至10个环原子的环基。杂环或杂环基的例子包括但不仅限于包括,但不限于,例如下列基团:氮杂环丁二烯、1,2-二氮杂环丁烯、吡咯、N-烷基吡咯基、4,5-二氢吡咯、2,5-二氢吡咯、咪唑、4,5-二氢咪唑、吡唑、4,5-二氢吡唑、1,2,3-三唑、1,2,4-三唑、吡啶、2-吡啶酮、4-吡啶酮、哒嗪、嘧啶、吡嗪、1,2,3-三嗪、1,2,4-三嗪、氮杂环庚三烯、1,2-二氮杂环庚三烯、1,3-二氮杂环庚三烯、1,4-二氮杂环庚三烯、1,4-二氢-1,4-二氮杂环辛三烯,1,2-二硫杂环丁烯、呋喃、4,5-二氢呋喃、2,5-二氢呋喃、噻吩、2,5-二氢噻吩、4,5-二氢噻吩、1,2-二硫杂环戊烯、1,3-二硫杂环戊烯、2H-吡喃、2H-吡喃-2-酮、3,4-二氢-2H-吡喃、4H-吡喃、4H-吡喃-4-酮、1,4-二氧杂环己二烯、1,4-二硫杂环己二烯、1,4-氧硫杂环己二烯、氧杂环庚三烯、硫杂环庚三烯、噁唑、4,5-二氢噁唑、2,3-二氢噁唑、异噁唑、4,5-二氢异噁唑、2,3-二氢异噁唑、1,2,3-噁二唑、1,2,5-噁二唑、噻唑、4,5-二氢噻唑、2,3-二氢噻唑、异噻唑、1,2,3-噻二唑、2H-1,2-噁嗪、4H-1,2-噁嗪、6H-1,2-噁嗪、2H-1,3-噁嗪、4H-1,3-噁嗪、5,6-二氢-4H-1,3-噁嗪、6H-1,3-噁嗪、2H-1,4-噁嗪、4H-1,4-噁嗪、2H-1,3-噻嗪、4H-1,3-噻嗪、5,6-二氢-4H-1,3-噻嗪、6H-1,3-噻嗪、2H-1,4-噻嗪、4H-1,4-噻嗪基团等。4-10元饱和单杂环基,是指全部为饱和键的含有杂原子的环状基团,优选5-7元饱和单杂环基,具体实例包括但不仅限于:氮杂环丙烷、氮杂环丁烷、1,2-二氮杂环丁烷、吡咯烷、咪唑烷、吡唑烷、氢化吡啶酮、哌啶、哌嗪、环氧乙烷、硫杂环丙烷、氧杂环丁烷、1,2-二氧杂环丁烷、硫杂环丁烷、四氢呋喃、四氢噻吩、1,3-二氧杂环戊烷、1,3-二硫杂环戊烷、四氢吡喃、1,4-二氧杂环己烷、1,3-二氧杂环己烷、1,3-氧硫杂环己烷、噁唑烷、吗啉基团等。单杂环与芳基、杂芳基或环烷基环稠合连接在一起的环也为杂环基,包括但不限于:
本发明所述的“6元环烷基”是指6个碳原子的烷烃部分去除一个氢原子衍生的单环烷基。
术语“含一个至两个氧或者氮的芳香杂环”指呋喃环、吡啶环、嘧啶环、吡咯环、吡嗪环、哒嗪环、三嗪环、或类似的基团。
本发明中,术语“含有”表示各种成分可一起应用于本发明的混合物或组合物中。因此,术语“主要由...组成”和“由...组成”包含在术语“含有”中。
本发明中,“药学上可接受的”成分是适用于人和/或动物而无过度不良副反应(如毒性、刺激和变态反应)即有合理的效益/风险比的物质。
本发明中,“药学上可接受的载体”是用于将本发明的活性物质或其生理上可接受的盐传送给动物或人的药学上可接受的溶剂、悬浮剂或赋形剂。载体可以是液体或固体。
在本发明中,所述的药物组合物含有安全有效量(如0.001-99.9重量份,更佳地,0.01-99重量份,更优选0.1-90重量份)的式(I)所示的化合物或其药学上可接受的盐;以及药学上可接受的载体或赋形剂,其中组合物的总重量为100重量份。
或者,本发明所述的药物组合物含有0.001-99.9wt%,更佳地,0.01-99重量%,更优选占总重量0.1-90重量%的式(I)所示的化合物或其药学上可接受的盐;以及药学上可接受的载体或赋形剂,其中组合物的总重量为100重量%。
在另一优选例中,式(I)化合物与药学上可接受的载体、赋形剂或缓释剂的优选比例是,式(I)作为活性成分占总重量比65%以上,其余部分占总重量比0.5-40%,或更好为1-20%,或最好为1-10%。
本发明药物组合物的各种制剂形式,其单位剂量每剂包含0.05mg-500mg,优选0.5mg-200mg,更优选0.1mg-100mg所述的式(I)化合物、对映异构体、外消旋体、药学上可接受的盐或它们的混合物。
当所述的药物组合物中含有额外的治疗或预防心肌病、前列腺癌和糖尿病等疾病的药物活性成分时,该活性成分的用量通常可以是现有技术中的常规用量或更低。
本发明的药物组合物可以是多种形式,如片剂、胶囊、粉末、糖浆、溶液状、悬浮液和气雾剂等,其中式(I)化合物可以存在于适宜的固体或液体载体或稀释液中。本发明的药物组合物也可以储存在适宜的注射或滴注的消毒器具中。该药物组合物中还可包含气味剂、香味剂等。
所述化合物或其药学上可接受的盐及其组合物可通过口服以及静脉内、肌内或皮下等途径给药。从易于制备和给药的立场看,优选的药物组合物是固态组合物,尤其是片剂和固体填充或液体填充的胶囊。药物组合物的口服给药是优选的。
固态载体包括:淀粉、乳糖、磷酸二钙、微晶纤维素、蔗糖和白陶土,而液态载体包括:无菌水、聚乙二醇、非离子型表面活性剂和食用油(如玉米油、花生油和芝麻油),只要适合活性成分的特性和所需的特定给药方式。在制备药物组合物中通常使用的佐剂也可有利地被包括,例如调味剂、色素、防腐剂和抗氧化剂如维生素E、维生素C、BHT和BHA。
所述活性化合物或其药学上可接受的盐及其组合物也可肠胃外或腹腔内给药。也可在适当混合有表面活性剂(如羟丙基纤维素)的水中制备这些活性化合物(作为游离碱或药学上可接受的盐)的溶液或悬浮液。还可在甘油、液体、聚乙二醇及其在油中的混合物中制备分散液。在常规储存和使用条件下,这些制剂中含有防腐剂以防止微生物的生长。
适应于注射的药物形式包括:无菌水溶液或分散液和无菌粉(用于临时制备无菌注射溶液或分散液)。在所有情况中,这些形式必须是无菌的且必须是流体以易于注射器排出流体。在制造和储存条件下必须是稳定的,且必须能防止微生物(如细菌和真菌)的污染影响。载体可以是溶剂或分散介质,其中含有如水、醇(如甘油、丙二醇和液态聚乙二醇)、它们的适当混合物和植物油。
式(I)所示的化合物或其药学上可接受的盐及其组合物还可与其它治疗或预防心肌病、前列腺癌和糖尿病等疾病的活性成分或药物联合给药。当两种或两种以上的药物联合给药时,一般具有优于两种药物分别单独给药的效果。
本发明上述任一化合物药学上可接受的盐是指由药学上可接受的盐,所述的盐为包括(但不限于):(1)与如下无机酸形成的盐:如盐酸、硫酸、硝酸、磷酸;(2)与如下有机酸形成的盐,如乙酸、草酸、丁二酸、酒石酸、甲磺酸、马来酸、或精氨酸。其它的盐包括与碱金属或碱土金属(如钠、钾、钙或镁)形成的盐,以酯、氨基甲酸酯,或其它常规的“前体药物”的形式。
可将游离形式的本发明化合物转化成盐形式的相应化合物,反之亦然。可将游离形式或盐形式和/或溶剂化物形式的本发明化合物转化成非溶剂化物形式的游离形式或盐形式的相应化合物;反之亦然。
所述的“溶剂化物”在本文中用以描述包含本发明的化合物和化学计量(stoichiometric amount)的一种或多种可药用溶剂分子的分子配合物,所述溶剂有,例如乙醇。当所述溶剂为水时,使用术语“水合物”。
本发明涉及式(I)化合物的“立体异构体”,本发明化合物含有一个或多个不对称中心,因而可作为外消旋体和外消旋混合物、单一对映异构体、非对映异构体混合物和单一非对映异构体。本发明化合物有不对称中心,这类不对称中心各自会独立的产生两个光学异构体,本发明的范围包括所有可能的光学异构体和非对映异构体混合物和纯的或部分纯的化合物。本发明包括这些化合物的所有立体异构形式。本发明式(I)化合物或其药学上可接受的盐由于存在不对称碳原子,可以以一种旋光异构体形式存在,因此,本发明还包括这些旋光异构体及其混合物。本文描述的结构也拟包括所述结构的所有异构(例如对映异构、非对映异构和几何异构(或构象异构))形式;例如,关于每一不对称中心的R和S构型、Z和E双键异构体以及Z和E构象异构体。因此,本发明化合物的单一立体化学异构体以及对映异构体、非对映异构体和几何异构体(或构象异构体)的混合物都在本发明的范围内。除非另作规定,否则本发明化合物的所有互变异构形式都在本发明的范围内。
本发明涉及式(I)化合物的“氘代物”,本发明化合物的结构也包括不同之处仅在于存在一个或一个以上同位素富集的原子的化合物。举例来说,具有本发明的结构但包括氢经氘或氚置换或碳经富集或的碳置换的化合物在本发明的范围内。此类化合物可用作例如分析工具、生物分析中的探针或本发明的治疗剂。在一些实施例中,式(I)中的包含一个或一个以上氘原子。
本发明的化合物有1个或者更多的手性中心。合成得到的是消旋体,所需要的对映体纯的化合物可以通过手性拆分的方法得到:可以通过具有手性固定相的色谱法(像高压制备液相、超临界流体色谱)。手性填料包括但不限于:Chiralcel OJ-H,Chiralpak AD-H,Chiralpak IA,Chiralpak AS-H。
本发明所述的化合物、其药学上可接受的盐、其前体药物、其溶剂化物、氘代物或其立体异构体用于通过TRPV2作用的哺乳动物心肌病、前列腺癌和糖尿病等疾病的感染性疾病药物的应用。
通式I化合物
本发明的化合物,结构如通式I所示,
各取代基的定义如前所述。
在另一优选例中,R1选自氢、C1-C6的直链或支链的烃基、C1-C6卤代烷基、被1-3个Q1取代或不取代的芳香环、苯并二氧杂环、被1-3个Q1取代或不取代的C4-C7元杂环和-NR′R″,其中所述的取代基Q1选自C1-C6的直链或支链的烃基、C1-C6的直链或支链的烷氧基、C1-C6卤代烷基、C1-C6卤代烷氧基、卤素、氨基、羟基;其中所述的取代基R′和R″独立地选自:C1-C6的直链或支链的烃基和-(CH2)q-R3,q选自0,1,2,3或4,
其中所述的取代基R3选自被1-3个Q2取代或不取代的芳香环和被1-3个Q2取代或不取代的C4-C7元杂环,其中所述的取代基Q2选自C1-C6的直链或支链的烃基、C1-C6的直链或支链的烷氧基、C1-C6卤代烷基、C1-C6卤代烷氧基、卤素、氨基、羟基;
R2选自羧基和4-10元芳香杂环;
X选自-O-,-S-,-NH-,-NR4-,其中所述的取代基R4选自C1-C6的直链或支链的烃基、C1-C6的直链或支链的烷氧基、C1-C6卤代烷基、C1-C6卤代烷氧基、卤素、氨基、羟基;
Y选自-CO-NH-,-NH-CO-,-NH-,-NR5-,–COO-,-OOC-,其中所述的取代基R5选自C1-C6的直链或支链的烃基、C1-C6的直链或支链的烷氧基、C1-C6卤代烷基、C1-C6卤代烷氧基、卤素、氨基、羟基;
m选自0,1,2,3,4,5或6;n选自0,1,2,3,4,5或6。
在另一优选例中,化合物具有以下结构:
其中,
R1选自氢、C1-C6的直链或支链的烃基、C1-C6卤代烷基、被1-3个Q1取代或未取代的芳香环、被1-3个Q1取代或未取代的C4-C7元杂环和-NR′R″,其中所述的取代基Q1选自C1-C6的直链或支链的烃基、C1-C6的直链或支链的烷氧基、C1-C6卤代烷基、C1-C6卤代烷氧基、卤素、氨基、羟基;其中所述的取代基R′和R″独立地选自:C1-C6的直链或支链的烃基和-(CH2)q-R3,q选自0,1,2,3或4,
其中所述的取代基R3选自1-3个被Q2取代或未取代的芳香环和1-3个被Q2取代或未取代的C4-C7元杂环,其中所述的取代基Q2选自C1-C6的直链或支链的烃基、C1-C6的直链或支链的烷氧基、C1-C6卤代烷基、C1-C6卤代烷氧基、卤素、氨基、羟基;
R2选自羧基和芳香杂环;
X选自-O-,-S-,-NH-,-NR4-,其中所述的取代基R4选自C1-C6的直链或支链的烃基、C1-C6的直链或支链的烷氧基、C1-C6卤代烷基、C1-C6卤代烷氧基、卤素、氨基、羟基;
Y选自-CO-NH-,-NH-CO-,-NH-,-NR5-,–COO-,-OOC-,其中所述的取代基R5选自C1-C6的直链或支链的烃基、C1-C6的直链或支链的烷氧基、C1-C6卤代烷基、C1-C6卤代烷氧基、卤素、氨基、羟基;
m选自0,1,2,3,4,5或6;
n选自0,1,2,3,4,5或6。
在另一优选例中,式V中,R1选自氢、被1-3个Q1取代或未取代的芳香环、被1-3个Q1取代或未取代的6元杂环和-NR′R″,其中所述的取代基Q1选自C1-C6的直链或支链的烃基和C1-C6的直链或支链的烷氧基,其中所述的取代基R′和R″独立地选自:C1-C6的直链或支链的烃基和-(CH2)q-R3,q选自0,1,2,3或4,
其中所述的取代基R3选自被1-3个Q2取代或未取代的芳香环,其中所述的取代基Q2选自C1-C6的直链或支链的烃基、C1-C6的直链或支链的烷氧基,
R2选自羧基和4-10元杂芳环;
m选自0,1,2,3,4,5或6;
n选自0,1,2,3,4,5或6。
在另一优选例中,式V中,R1选自氢、哌嗪、吗啉、3,4,5-三甲氧基苯和-NCH3R′,其中所述的取代基R′选自丙基、苄基和3,4-二甲氧基苯乙基;
R2选自羧基和呋喃基团;
m选自0,1,2,3,4,5或6;
n选自0,1,2,3,4,5或6。
在另一优选例中,化合物具有以下结构:
R1选自如下基团:
R2选自如下基团:
本发明化合物与最接近的现有技术相比,具有以下优点:
(1)本发明嘧啶类化合物具有较好的TRPV2的抑制活性;
(2)本发明化合物具有抑制癌细胞迁移的功能;
(3)本发明化合物毒性和副作用较低,安全窗口大;
(4)本发明化合物制备工艺简单,理化性质好,质量稳定,易于进行大规模工业生产。
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,否则百分比和份数是重量百分比和重量份数。
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。
实施例1
N-(呋喃-2-基甲基)-3-((4-(甲基(丙基)氨基)-6-(三氟甲基)嘧啶-2-
基)硫基)丙酰胺(化合物1)的制备
步骤A:2-氯-4-(N-甲基,N-丙基)氨基-6-三氟甲基嘧啶(1a)
2,4-二氯-6-三氟甲基嘧啶(1g,1eq)用无水二氯甲烷10ml溶解放入冰水浴中,氮甲基正丙胺(370mg,1.1eq)和三乙胺(1.4g,3eq)加入1ml无水二氯甲烷用恒压漏斗滴加入反应液中,冰浴反应5小时,反应完后将反应液用二氯甲烷和饱和NaCl萃取3次,合并有机相,减压真空旋转蒸干溶剂,得到油状混合物1.8g,将油状混合物用石油醚和乙酸乙酯过柱得到白色粉末固体(1.1g,87%)。
步骤B:4-(氮甲基,氮丙基)氨基)-2-(硫代)丙酸基-6-(三氟甲基)嘧啶(1b)
称取底物2-氯-4-(N-甲基,N-丙基)氨基-6-三氟甲基嘧啶(1g,1eq),用1,4-二氧六环溶解,加入3-巯基丙酸(1.26g,3eq),DBU(1.8g,3eq)碱,加热到95℃,反应10小时,在反应后的溶液中加入二氯甲烷(50ml)进行稀释,然后加入水,利用二氯甲烷进行萃取。萃取后的二氯甲烷层,用盐水进行洗涤,接着用无水硫酸钠干燥,最后通过蒸发除掉溶剂,得到固体直接进行下一步反应。
步骤C:N-(呋喃-2-基甲基)-3-((4-(甲基(丙基)氨基)-6-(三氟甲基)嘧啶-2-基)硫基)丙酰胺
称取底物1b(500mg,1eq),用5ml无水二氯甲烷溶解,加入2-呋喃甲胺(300mg,2eq),EDCI(609mg,2eq),HOBt(418mg,2eq),三乙胺(469mg,3eq)反应10小时,反应完全后,旋掉二氯甲烷反应溶液,加入二氯甲烷(20ml)进行稀释,然后加入水,利用二氯甲烷进行萃取3次。萃取后的二氯甲烷层,用盐水进行洗涤,接着用无水硫酸钠干燥,最后通过蒸发除掉溶剂,使用石油醚/乙酸乙酯(3:1梯度洗脱)溶剂在硅胶层析柱上进行分离,得到产物N-(呋喃-2-基甲基)-3-((4-(甲基(丙基)氨基)-6-(三氟甲基)嘧啶-2-基)硫基)丙酰胺(497mg,80%)。
1H NMR(400MHz,Chloroform-d)δ7.35(m,1H),6.41(s,1H),6.32(m,1H),6.24(d,J=3.2Hz,1H),6.03(s,1H),4.46(d,J=6.8Hz,2H),3.65(m,1H),3.39(t,J=7.2Hz,2H),3.33(m,1H),3.18-3.06(m,3H),2.69(t,J=7.2Hz,2H),1.64(m,2H),0.95(m,3H)
13C NMR(101MHz,Chloroform-d)δ171.2,161.5,151.1,142.2,122.3,120.5,110.4,107.4,94.7,51.5,36.8,36.5,35.9,26.6,20.4,11.4.
MS(ESI+)m/z 403.1(M+H)+.
实施例2
3-((4-((3,4-二甲氧基苯乙基)(甲基)氨基)-6-(三氟甲基)嘧啶-2-基)
硫基)-N-(呋喃-2-基甲基)丙酰胺(化合物2)的制备
将实施例1中的对氮甲基正丙胺替换成N-甲基-2-(3,4-二甲氧基苯基)乙胺,其余所需原料,试剂及制备方法及步骤同实施例1,得到化合物2。
1H NMR(400MHz,Chloroform-d)δ7.34(d,J=1.8Hz,1H),6.89–6.74(m,3H),6.63(s,1H),6.32(t,J=2.5Hz,1H),6.21(d,J=3.3Hz,1H),5.90(d,J=35.2Hz,1H),4.44(s,2H),3.88-3.8(m,2H)3.83(s,6H),,3.47(t,J=6.9Hz,2H),3.14(s,3H),2.86(dd,J=8.4,6.5Hz,2H)tr,2.63(s,2H).
13C NMR(101MHz,CDCl3)δ171.1,170.3,160.7,154.3(d,JF=144Hz),150.9,148.9,147.5,142.2,131.8,120.8,120.7(d,JF=1096Hz)112.2,110.5,110.4 107.6,102.3,55.9,55.8,51.6,36.5,36.1,35.6,33.1,24.7.
MS(ESI+)m/z 525.1(M+H)+.
实施例3
3-((4-(苄基(甲基)氨基)-6-(三氟甲基)嘧啶-2-基)硫基)-N-(呋喃-2-
基甲基)丙酰胺(化合物3)的制备
将实施例1中的氮甲基正丙胺替换成N-甲基苄胺,其余所需原料,试剂及制备方法及步骤同实施例1,得到化合物3。
1H NMR(400MHz,Chloroform-d)δ7.40–7.29(m,4H),7.19(d,J=1.7Hz,1H),7.17(s,1H),6.50(s,1H),6.33(dd,J=3.2,1.9Hz,1H),6.21(d,J=3.2Hz,1H),5.66(d,J=33.9Hz,1H),4.96(s,2H),4.38(s,2H),3.35(s,3H),3.07(s,2H),2.56(s,2H),1.64(s,3H).
13C NMR(101MHz,CDCl3)δ171.9,170.8,162.1,151.2,142.1,128.9,127.7,120.8(d,JF=144Hz),110.4,107.4,100.0,52.3,36.4,35.6,26.8.
MS(ESI+)m/z 451.1(M+H)+.
实施例4
N-(呋喃-2-基甲基)-3-(4-吗啉代-6-(三氟甲基)嘧啶-2-基)硫基)丙酰
胺(化合物4)的制备
将实施例1中的对氮甲基正丙胺替换成吗啉,其余所需原料,试剂及制备方法及步骤同实施例1,得到化合物4。
1H NMR(400MHz,Chloroform-d)δ7.36(dd,J=1.9,0.8Hz,1H),6.51(s,1H),6.33(dd,J=3.2,1.9Hz,1H),6.24(dd,J=3.2,0.9Hz,1H),5.98(s,1H),4.46(d,J=5.5Hz,2H),3.80(m,4H),3.70(s,4H),3.39(t,J=7.3Hz,2H),2.67(t,J=7.3Hz,2H).
13C NMR(101MHz,CDCl3)δ172.1,170.8,161.6,154.7(d,JF=144Hz),151.1,142.2,120.7(d,JF=1092Hz),110.4,107.4,94.8,94.7,66.3,66.3,44.3,36.6,36.6,26.7.
MS(ESI+)m/z 417.1(M+H)+.
实施例5
N-(呋喃-2-基甲基)-3-((4-(4-甲基哌嗪-1-基)-6-(三氟甲基)嘧啶-2-
基)硫基)丙酰胺(化合物5)的制备
将实施例1中的氮甲基正丙胺替换成N-甲基哌嗪,其余所需原料,试剂及制备方法及步骤同实施例1,得到化合物5。
1H NMR(400MHz,Chloroform-d)δ7.36(dd,J=1.9,0.8Hz,1H),6.52(s,1H),6.33(dd,J=3.2,1.9Hz,1H),6.24(dd,J=3.3,0.8Hz,1H),6.01(s,1H),4.46(d,J=5.6Hz,2H),3.74(s,4H),3.39(t,J=7.3Hz,2H),2.68(t,J=7.2Hz,2H),2.50(t,J=5.2Hz,4H),2.36(s,3H).
13C NMR(101MHz,CDCl3)δ172.0,170.9,161.3,154.6(d,JF=144Hz),151.1,142.1,120.8(d,JF=1096Hz),110.4,107.4,94.9,54.4,54.4,45.9,43.9,36.7,36.5,29.6,26.8.
MS(ESI+)m/z 430.1(M+H)+.
实施例6
N-(呋喃-2-基甲基)-3-((4-(三氟甲基)嘧啶-2-基)硫基)丙酰胺(化合
物6)的制备
步骤D:3-((4-(甲氧基苯基)嘧啶-2-基)硫代)丙酸(6a)
称取2-氯-4-三氟甲基嘧啶(1g,1eq)用10ml 1,4-二氧六环溶解,加入3-巯基丙酸(1.76g,3eq),DBU碱(2.53g,3eq),加热到95℃,反应10小时,在反应后的溶液中加入二氯甲烷(50ml)进行稀释,然后加入水,利用二氯甲烷进行萃取。萃取后的二氯甲烷层,用盐水进行洗涤,接着用无水硫酸钠干燥,最后通过蒸发除掉溶剂,得到固体直接进行下一步反应。
步骤E:N-(呋喃-2-基甲基)-3-((4-(甲氧基苯基)嘧啶-2-基)硫基)丙酰胺
称取底物6a(500mg,1eq)用5ml无水二氯甲烷溶解,加入2-呋喃甲胺(384mg,2eq),EDCI(781mg,2eq),HOBt(535mg,2eq),三乙胺(601mg,3eq),室温反应10小时,反应完全后,旋掉二氯甲烷反应溶液,加入二氯甲烷(20ml)进行稀释,然后加入水,利用二氯甲烷,饱和NaCl进行萃取3次。萃取后的二氯甲烷层,用盐水进行洗涤,接着用无水硫酸钠干燥,最后通过蒸发除掉溶剂,使用石油醚/乙酸乙酯(3:1梯度洗脱)溶剂在硅胶层析柱上进行分离,得到化合物6(525mg,85%)。
1H NMR(400MHz,Chloroform-d)δ8.76(d,J=4.9Hz,1H),7.36(dd,J=1.9,0.8Hz,1H),7.30(d,J=5.0Hz,1H),6.34(dd,J=3.2,1.9Hz,1H),6.28–6.14(m,1H),5.92(s,1H),4.48(d,J=5.5Hz,2H),3.49(t,J=7.1Hz,2H),2.71(t,J=7.1Hz,2H).
13C NMR(101MHz,CDCl3)δ173.8,170.4,159.5,155.8(d,JF=144Hz),151.0,142.3,120.2(d,JF=1096Hz),111.9,110.5,107.7,36.6,35.9,26.9.
MS(ESI+)m/z 332.1(M+H)+.
实施例7
N-(呋喃-2-基甲基)-3-((4-(三氟甲基)-6-(3,4,5-三甲氧基苯基)嘧
啶-2-基)硫基)丙酰胺(化合物7)的制备
步骤F:2-氯-4-(三氟甲基苯基)-6-(3,4,5-三甲氧基苯基)嘧啶(7a)
2,4-二氯-6-三氟甲基嘧啶(1g,1eq)用1,4-二氧六环10ml溶解放入茄型瓶中,加入对3,4,5-三甲氧基苯硼酸(1074mg,1.1eq)和饱和碳酸钠水溶液5ml,加入1,1双三苯基磷二氯化钯(342mg,0.1eq),油浴升温到75℃反应5小时,反应完全后将反应液用二氯甲烷和饱和NaCl萃取3次,合并有机相,减压真空旋转蒸干溶剂,得到油状混合物1.62g,将油状混合物用石油醚和乙酸乙酯过柱得到白色粉末固体(1.54g.,产率91%)。
步骤G:3-((4-(三氟甲基)-6-(3,4,5-三甲氧基苯基)嘧啶-2-基)硫代)丙酸(7b)
称取底物7a(1g,1eq)用10ml 1,4-二氧六环溶解,加入3-巯基丙酸(913mg,3eq),DBU碱(1.318g,3eq),加热到95℃,反应10小时,在反应后的溶液中加入二氯甲烷(50ml)进行稀释,然后加入水,利用二氯甲烷进行萃取。萃取后的二氯甲烷层,用盐水进行洗涤,接着用无水硫酸钠干燥,最后通过蒸发除掉溶剂,得到固体直接进行下一步反应。
步骤H:N-(呋喃-2-基甲基)-3-((4-(三氟甲基)-6-(3,4,5-三甲氧基苯基)嘧啶-2-基)硫基)丙酰胺
称取底物7b(500mg,1eq)用5ml无水二氯甲烷溶解,加入2-呋喃甲胺(232mg,2eq),EDCI(471mg,2eq),HOBt(322mg,2eq),三乙胺(498mg,3eq),室温反应10小时,反应完全后,旋掉二氯甲烷反应溶液,加入二氯甲烷(20ml)进行稀释,然后加入水,利用二氯甲烷,饱和NaCl进行萃取3次。萃取后的二氯甲烷层,用盐水进行洗涤,接着用无水硫酸钠干燥,最后通过蒸发除掉溶剂,使用石油醚/乙酸乙酯(3:1梯度洗脱)溶剂在硅胶层析柱上进行分离,得到产物化合物7(475mg,80%)。
1H NMR(400MHz,Chloroform-d)δ7.59(s,1H),7.37(s,2H),7.35(dd,J=1.9,0.8Hz,1H),6.33(dd,J=3.2,1.9Hz,1H),6.26–6.22(m,1H),5.89(s,1H),4.47(d,J=5.5Hz,2H),3.99(s,6H),3.96(s,3H),3.55(t,J=7.2Hz,2H),2.76(t,J=7.2Hz,2H).
13C NMR(101MHz,CDCl3)δ173.6,170.5,166.6,165.4,164.1,156.5(q,JF=140Hz),151.0,142.2,131.3,129.7,129.7,120.4(d,JF=1084Hz),116.5,116.3,110.4,107.5,36.6,36.0,26.9.
MS(ESI+)m/z 498.1(M+H)+.
实施例8(3-((4-(4-甲氧基苯基)-6-(三氟甲基)嘧啶-2-基)硫基)丙酰基)甘氨酸
(化合物8)的制备
步骤I:2-氯-4-(甲氧基苯基)-6-(三氟甲基)嘧啶(8a)
2,4-二氯-6-三氟甲基嘧啶(1g,1eq)用1,4-二氧六环10ml溶解放入茄型瓶中,加入对甲氧基苯硼酸(780mg,1.1eq)和饱和碳酸钠水溶液5ml,加入1,1-双三苯基磷二氯化钯(342mg,0.1eq),油浴升温到75℃反应5小时,反应完全后将反应液用二氯甲烷和饱和NaCl萃取3次,合并有机相,减压真空旋转蒸干溶剂,得到油状混合物1.62g,将油状混合物用石油醚和乙酸乙酯过柱得到白色粉末固体(1.2g.,产率91%)。
步骤J:3-((4-(4-甲氧基苯基)-6-(三氟甲基)嘧啶-2-基)硫代)丙酸(8b)
称取底物8a(1g,1eq)用10ml 1,4-二氧六环溶解,加入3-巯基丙酸(1.1g,3eq),DBU碱(1.58g,3eq),加热到95℃,反应10小时,在反应后的溶液中加入二氯甲烷(50ml)进行稀释,然后加入水,利用二氯甲烷进行萃取。萃取后的二氯甲烷层,用盐水进行洗涤,接着用无水硫酸钠干燥,最后通过蒸发除掉溶剂,得到固体直接进行下一步反应。
步骤K:甲基(3-((4-(4-甲氧基苯基)-6-(三氟甲基)嘧啶-2-基)硫基)丙酰基)甘氨酸(8c)
称取底物8b(500mg,1eq)用5ml无水二氯甲烷溶解,加入甘氨酸甲酯盐酸盐(349mg,2eq),EDCI(550mg,2eq),HOBt(377mg,2eq),三乙胺(423mg,3eq),室温反应10小时,反应完全后,旋掉二氯甲烷反应溶液,加入二氯甲烷(20ml)进行稀释,然后加入水,利用二氯甲烷,饱和NaCl进行萃取3次。萃取后的二氯甲烷层,用盐水进行洗涤,接着用无水硫酸钠干燥,最后通过蒸发除掉溶剂,使用石油醚/乙酸乙酯(3:1梯度洗脱)溶剂在硅胶层析柱上进行分离,得到产物甲基(3-((4-(4-甲氧基苯基)-6-(三氟甲基)嘧啶-2-基)硫基)丙酰基)甘氨酸(509mg,85%)。
步骤L:(3-((4-(4-甲氧基苯基)-6-(三氟甲基)嘧啶-2-基)硫基)丙酰基)甘氨酸
称取底物8c(300mg,1eq)加入四氢呋喃、甲醇、水(3:1:1)的混合溶液5ml,加入1mol/L的NaOH溶液,调至pH=12进行水解,反应4小时,反应完全后加入二氯甲烷(10ml)进行稀释,然后加入水。利用二氯甲烷,饱和NaCl进行萃取3次。萃取后的二氯甲烷层,用盐水进行洗涤,接着用无水硫酸钠干燥,最后通过蒸发除掉溶剂,使用石油醚/乙酸乙酯(2:1梯度洗脱)溶剂在硅胶层析柱上进行分离得到化合物8(275mg,95%)。
1H NMR(400MHz,DMSO-d6)δ8.35(s,1H),8.33(d,J=2.1Hz,1H),8.28(t,J=5.8Hz,1H),8.17(s,1H),7.14(d,J=2.0Hz,1H),7.12(d,J=2.1Hz,1H),3.88(s,3H),3.78(d,J=5.8Hz,2H),3.42(t,J=6.9Hz,2H),2.70(t,J=7.0Hz,2H).
13C NMR(101MHz,DMSO)δ172.6,171.7,171.1,166.1,163.3,155.5(d,JF=144Hz),130.2,130.2,127.4,121.0(d,JF=1096Hz),115.1,115.1,107.9,56.0,41.1,34.7,26.8.
MS(ESI+)m/z 416.1(M+H)+.
实施例9
N-(呋喃-2-基甲基)-3-((4-(4-甲氧基苯基)-6-(三氟甲基)嘧啶-2-基)
硫基)丙酰胺(化合物9)的制备
步骤M:2-氯-4-(4-甲氧基苯基)-6-(三氟甲基)嘧啶(9a)
2,4-二氯-6-三氟甲基嘧啶(1g,1eq)用1,4-二氧六环10ml溶解放入茄型瓶中,加入对甲氧基苯硼酸(780mg,1.1eq)和饱和碳酸钠水溶液5ml,加入1,1-双三苯基磷二氯化钯(342mg,0.1eq),油浴升温到75℃反应5小时,反应完全后将反应液用二氯甲烷和饱和NaCl萃取3次,合并有机相,减压真空旋转蒸干溶剂,得到油状混合物1.62g,将油状混合物用石油醚和乙酸乙酯过柱得到白色粉末固体(1.2g.,产率91%)。
步骤N:3-((4-(4-甲氧基苯基)-6-(三氟甲基)嘧啶-2-基)硫代)丙酸(9b)
称取底物9a(1g,1eq)用10ml 1,4-二氧六环溶解,加入3-巯基丙酸(1.1g,3eq),DBU碱(1.58g,3eq),加热到95℃,反应10小时,在反应后的溶液中加入二氯甲烷(50ml)进行稀释,然后加入水,利用二氯甲烷进行萃取。萃取后的二氯甲烷层,用盐水进行洗涤,接着用无水硫酸钠干燥,最后通过蒸发除掉溶剂,得到固体直接进行下一步反应。
步骤O:N-(呋喃-2-基甲基)-3-((4-(4-甲氧基苯基)-6-(三氟甲基)嘧啶-2-基)硫基)丙酰胺
称取底物9b(500mg,1eq)用5ml无水二氯甲烷溶解,加入2-呋喃甲胺(271mg,2eq),EDCI(550mg,2eq),HOBt(377mg,2eq),三乙胺(423mg,3eq),室温反应10小时,反应完全后,旋掉二氯甲烷反应溶液,加入二氯甲烷(20ml)进行稀释,然后加入水,利用二氯甲烷,饱和NaCl进行萃取3次。萃取后的二氯甲烷层,用盐水进行洗涤,接着用无水硫酸钠干燥,最后通过蒸发除掉溶剂,使用石油醚/乙酸乙酯(3:1梯度洗脱)溶剂在硅胶层析柱上进行分离,得到产物N-(呋喃-2-基甲基)-3-((4-(4-甲氧基苯基)-6-(三氟甲基)嘧啶-2-基)硫基)丙酰胺(518mg,85%)。
1H NMR(400MHz,Chloroform-d)δ8.14(d,J=2.2Hz,1H),8.12(s,1H),7.61(s,1H),7.35(dd,J=1.9,0.8Hz,1H),7.05(s,1H),7.03(s,1H),6.33(dd,J=3.2,1.8Hz,1H),6.25(d,J=3.2Hz,1H),5.91(s,1H),4.48(d,J=5.2Hz,2H),3.92(s,3H),3.55(t,J=7.1Hz,2H),2.76(t,J=7.1Hz,2H).
13C NMR(101MHz,CDCl3)δ173.1,170.6,165.9,163.1156.1(d,JF=144Hz),151.1,142.2,129.2,129.23,127.4,120.6(d,JF=1096Hz),114.5,114.5,110.4,107.4,106.6,55.5,36.5,36.1,26.9.
MS(ESI+)m/z 438.1(M+H)+.
实施例10
N-(呋喃-2-基甲基)-3-((4-(3-甲氧基苯基)-6-(三氟甲基)嘧啶-2-
基)硫基)丙酰胺(化合物10)的制备
将实施例9中的对甲氧基苯硼酸替换成3-甲氧基苯硼酸,其余所需原料,试剂及制备方法及步骤同实施例9,得到化合物10。
1H NMR(500MHz,Chloroform-d)δ7.58(t,J=2.1Hz,1H),7.56(m,1H),7.55(s,1H),7.34(t,J=8.0Hz,1H),7.24(d,J=1.8Hz,1H),7.02(m,1H),6.21(dd,J=3.2,1.8Hz,1H),6.13(d,J=3.1Hz,1H),5.96(t,J=5.4Hz,1H),4.36(d,J=5.5Hz,2H),3.81(s,3H),3.44(t,J=7.1Hz,2H),2.65(t,J=7.1Hz,2H).
13C NMR(126MHz,CDCl3)δ173.4,170.6,166.4,160.3,156.4(q,JF=144Hz)151.1,142.2,136.5,130.2,120.4(q,JF=1096Hz)119.8,118.1,112.5,110.4,107.7,107.5,55.5,36.5,36.0,26.9.
MS(ESI+)m/z 438.1(M+H)+.
实施例11
N-(呋喃-2-基甲基)-3-((4-(2-甲氧基苯基)-6-(三氟甲基)嘧啶-2-
基)硫基)丙酰胺(化合物11)的制备
将实施例9中的对甲氧基苯硼酸替换成邻甲氧基苯硼酸,其余所需原料,试剂及制备方法及步骤同实施例9,得到化合物11。
1H NMR(400MHz,Chloroform-d)δ8.09(dd,J=7.8,1.8Hz,1H),8.02(s,1H),7.51(ddd,J=8.3,7.4,1.9Hz,1H),7.34(dd,J=1.9,0.8Hz,1H),7.11(td,J=7.6,1.1Hz,1H),7.05(dd,J=8.4,1.0Hz,1H),6.32(dd,J=3.2,1.9Hz,1H),6.23(dd,J=3.2,0.8Hz,1H),6.00(s,1H),4.46(d,J=5.5Hz,2H),3.95(s,3H),3.52(t,J=7.2Hz,2H),2.74(t,J=7.1Hz,2H).
13C NMR(101MHz,CDCl3)δ172.5,170.6,165.4,158.4,155.2(q,JF=144Hz),151.1,142.18,133.0,131.1,124.4,121.2,120.4(d,JF=1096Hz),112.6,111.6,110.4,107.4,55.6,36.5,36.2,27.0.
MS(ESI+)m/z 438.1(M+H)+.
实施例12
3-((4-(3,4-二甲氧基苯基)-6-(三氟甲基)嘧啶-2-基)硫基)-N-(呋
喃-2-基甲基)丙酰胺(化合物12)的制备
将实施例9中的对甲氧基苯硼酸替换成3,4-二甲氧基苯硼酸,其余所需原料,试剂及制备方法及步骤同实施例9,得到化合物12。
1H NMR(400MHz,Chloroform-d)δ7.76(d,J=2.1Hz,1H),7.71(dd,J=8.4,2.1Hz,1H),7.61(s,1H),7.35(dd,J=1.8,0.8Hz,1H),6.99(d,J=8.5Hz,1H),6.32(dd,J=3.3,1.9Hz,1H),6.24(dd,J=3.2,0.9Hz,1H),5.90(s,1H),4.47(d,J=5.5Hz,2H),4.02(s,3H),3.99(s,3H),3.55(t,J=7.2Hz,2H),2.76(t,J=7.2Hz,2H).
13C NMR(101MHz,CDCl3)δ173.1,170.6,165.9,156.0(d,JF=144Hz),152.7,151.0,149.6,142.2,127.7,121.1,120.6(d,JF=1096Hz),111.1,110.4,109.8,107.5,106.8,56.1,56.1,36.5,36.1,26.9.
MS(ESI+)m/z 468.1(M+H)+.
实施例13
3-((4-(苯并[d][1,3]二氧杂环戊烯-5-基)-6-(三氟甲基)嘧啶-2-基)
硫基)-N-(呋喃-2-基甲基)丙酰胺(化合物13)的制备
将实施例9中的对甲氧基苯硼酸替换成苯并[d][1,3]间二氧杂环戊烯-5-基硼酸,其余所需原料,试剂及制备方法及步骤同实施例9,得到化合物13。
1H NMR(400MHz,Chloroform-d)δ7.68(dd,J=8.2,1.8Hz,1H),7.64(d,J=1.8Hz,1H),7.54(s,1H),7.33(dd,J=1.9,0.8Hz,1H),6.92(d,J=8.2Hz,1H),6.31(dd,J=3.2,1.9Hz,1H),6.22(dd,J=3.2,0.8Hz,1H),6.08(s,2H),5.90(s,1H),4.46(d,J=5.5Hz,2H),3.52(t,J=7.1Hz,2H),2.73(t,J=7.1Hz,2H).
13C NMR(101MHz,CDCl3)δ173.2,170.6,165.7,156.6(d,JF=144Hz),151.3,151.1,148.8,142.2,129.3,122.8,120.5(d,JF=1094.4Hz),110.4,108.8,107.5,107.3,106.9,102.0,36.6 36.1,27.0.
MS(ESI+)m/z 452.1(M+H)+.
实施例14
N-(呋喃-2-基甲基)-3-((4-(对-甲苯基)-6-(三氟甲基)嘧啶-2-基)硫
基)丙酰胺(化合物14)的制备
将实施例9中的对甲氧基苯硼酸替换成对甲基苯硼酸,其余所需原料,试剂及制备方法及步骤同实施例9,得到化合物14。
1H NMR(400MHz,Chloroform-d)δ8.03(s,1H),8.01(s,1H),7.63(s,1H),7.34(d,J=1.8Hz,2H),7.32(s,1H),6.32(dd,J=3.2,1.9Hz,1H),6.23(d,J=3.2Hz,1H),6.07(t,J=5.6Hz,1H),4.46(d,J=5.5Hz,2H),3.53(t,J=7.1Hz,2H),2.75(t,J=7.1Hz,2H),2.45(s,3H).
13C NMR(101MHz,CDCl3)δ173.3,170.6,166.4,156.23(q,JF=144Hz)151.1,143.0,142.2,132.3,129.9,129.94,127.4,127.4,120.5(d,JF=1096Hz),110.4,107.5,107.21,36.58,36.1,26.9,21.6.
MS(ESI+)m/z 422.1(M+H)+.
实施例15
3-((4-(4-氟苯基)-6-(三氟甲基)嘧啶-2-基)硫基)-N-(呋喃-2-基甲
基)丙酰胺(化合物15)的制备
将实施例9中的对甲氧基苯硼酸替换成4-氟苯硼酸,其余所需原料,试剂及制备方法及步骤同实施例9,得到化合物15。
1H NMR(400MHz,Chloroform-d)δ8.15(m,2H),7.62(s,1H),7.34(dd,J=1.9,0.8Hz,1H),7.22(m,2H),6.32(dd,J=3.2,1.9Hz,1H),6.24(dd,J=3.3,0.8Hz,1H),6.03(t,J=5.7Hz,1H),4.46(d,J=5.5Hz,2H),3.54(t,J=7.1Hz,2H),2.74(t,J=7.1Hz,2H).
13C NMR(101MHz,CDCl3)δ173.6,170.5,166.6,165.4,164.1,156.5(q,JF=140Hz),151.0,142.2,131.3,129.7,129.7,120.4(d,JF=1084Hz),116.5,116.3,110.4,107.5,36.6,36.0,26.9.
MS(ESI+)m/z 426.1(M+H)+.
实施例16
N-(呋喃-2-基甲基)-3-((4-苯基-6-(三氟甲基)嘧啶-2-基)硫基)丙酰
胺(化合物16)的制备
将实施例9中的对甲氧基苯硼酸替换成苯硼酸,其余所需原料,试剂及制备方法及步骤同实施例9,得到化合物16。
1H NMR(400MHz,Chloroform-d)δ8.14(m,2H),7.68(s,1H),7.62–7.57(m,1H),7.57–7.51(m,2H),7.35(dd,J=1.9,0.8Hz,1H),6.33(dd,J=3.3,1.9Hz,1H),6.24(dd,J=3.2,0.9Hz,1H),5.95(s,1H),4.48(d,J=5.5Hz,2H),3.56(t,J=7.1Hz,2H),2.76(t,J=7.1Hz,2H).
13C NMR(101MHz,CDCl3)δ173.5,170.7,166.6,156.4(d,JF=144Hz),151.0,142.2,135.1,132.2,129.2,129.2,127.5,127.5,120.5(d,JF=1096Hz),110.5,107.6,107.5,36.6,36.1 27.0.
MS(ESI+)m/z 408.1(M+H)+.
实施例17
3-((4-(4-甲氧基苯基)-6-(三氟甲基)嘧啶-2-基)硫基)-N-(噻吩-2-
基甲基)丙酰胺(化合物17)的制备
将实施例9中的2-呋喃甲胺替换成2-噻吩甲胺,其余所需原料,试剂及制备方法及步骤同实施例9,得到化合物17。
1H NMR(600MHz,Chloroform-d)δ8.10(d,J=2.1Hz,1H),8.09(d,J=2.1Hz,1H),7.57(s,1H),7.20(dd,J=5.0,1.3Hz,1H),7.01(d,J=2.1Hz,1H),7.00(d,J=2.0Hz,1H),6.97–6.95(m,1H),6.93(dd,J=5.1,3.5Hz,1H),5.95(d,J=5.9Hz,1H),4.63(d,J=5.6Hz,2H),3.89(s,3H),3.53(t,J=7.2Hz,2H),2.73(t,J=7.1Hz,2H).
13C NMR(151MHz,CDCl3)δ173.1,170.5,165.9,163.0,156.0(d,JF=144Hz),140.6,129.2,129.2,127.4,126.8,126.0,125.2,120.5(d,JF=1096Hz),114.5,114.5,106.7,55.5,38.3,36.2,26.9.
MS(ESI+)m/z 454.1(M+H)+.
实施例18
N-(噻吩-2-基甲基)-3-((4-(对-甲苯基)-6-(三氟甲基)嘧啶-2-基)硫
基)丙酰胺(化合物18)的制备
将实施例9中的对甲氧基苯硼酸替换成对甲基苯硼酸,2-呋喃甲胺替换成2-噻吩甲胺,其余所需原料,试剂及制备方法及步骤同实施例9,得到化合物18。
1H NMR(400MHz,Chloroform-d)δ8.05(s,1H),8.03(s,1H),7.65(s,1H),7.34(s,1H),7.32(s,1H),7.24(d,J=1.3Hz,1H),6.97(d,J=4.9Hz,1H),6.96–6.93(m,1H),5.94(s,1H),4.66(d,J=5.0Hz,2H),3.57(t,J=6.9Hz,2H),2.77(t,J=7.0Hz,2H),2.46(s,3H).
13C NMR(101MHz,CDCl3)δ173.3,170.5,166.5,156.3(d,JF=144Hz),143.0,140.7,132.3,129.9,129.9,127.4,127.4,126.8,126.0,125.2,121.0(d,JF=1096Hz),107.2,38.3,36.1,27.0,21.5.
MS(ESI+)m/z 438.1(M+H)+.
实施例19
3-((4-(4-氟苯基)-6-(三氟甲基)嘧啶-2-基)硫基)-N-(噻吩-2-基甲
基)丙酰胺(化合物19)的制备
将实施例9中的对甲氧基苯硼酸替换成4-氟基苯硼酸,2-呋喃甲胺替换成2-噻吩甲胺,其余所需原料,试剂及制备方法及步骤同实施例9,得到化合物19。
1H NMR(400MHz,Chloroform-d)δ8.19(m,1H),8.16(s,1H),7.63(s,1H),7.24(d,J=1.6Hz,1H),7.22(m,2H),6.98(dd,J=4.9,3.8Hz,1H),6.95(t,J=2.5Hz,1H),5.93(s,1H),4.66(d,J=5.5Hz,2H),3.57(t,J=7.1Hz,2H),2.75(t,J=7.1Hz,2H).
13C NMR(151MHz,CDCl3)δ173.1,170.5,165.9,163.0,156.0(d,JF=144Hz),140.6,129.2,129.2,127.4,126.8,126.0,125.2,120.5(d,JF=1096Hz),114.5,114.5,106.7,55.5,38.3,36.2,26.9.
MS(ESI+)m/z 442.1(M+H)+.
实施例20
3-((4-(呋喃-2-基)-6-(三氟甲基)嘧啶-2-基)硫基)-N-(呋喃-2-基甲
基)丙酰胺(化合物20)的制备
将实施例9中的对甲氧基苯硼酸替换成呋喃-2-硼酸,其余所需原料,试剂及制备方法及步骤同实施例9,得到化合物20。
1H NMR(400MHz,Chloroform-d)δ7.64(dd,J=1.8,0.8Hz,1H),7.55(s,1H),7.40(dd,J=3.5,0.8Hz,1H),7.33(dd,J=1.9,0.8Hz,1H),6.62(dd,J=3.6,1.7Hz,1H),6.31(dd,J=3.3,1.9Hz,1H),6.23(dd,J=3.3,0.8Hz,1H),5.95(s,1H),4.46(d,J=5.5Hz,2H),3.49(t,J=7.2Hz,2H),2.71(t,J=7.2Hz,2H).
13C NMR(101MHz,CDCl3)δ173.2,170.6,157.4,156.2(q,JF=144Hz),151.0,150.6,146.3,142.2,120.3(d,JF=1096Hz),114.8,113.1,110.4,107.5,105.7,36.5,36.1,27.0.
MS(ESI+)m/z 398.1(M+H)+.
实施例21
N-(呋喃-2-基甲基)-3-((4-(噻吩-2-基)-6-(三氟甲基)嘧啶-2-基)硫
基)丙酰胺(化合物21)的制备
将实施例9中的对甲氧基苯硼酸替换成噻吩-2-硼酸,其余所需原料,试剂及制备方法及步骤同实施例9,得到化合物21。
1H NMR(400MHz,Chloroform-d)δ7.86(dd,J=3.8,1.2Hz,1H),7.61(dd,J=5.0,1.1Hz,1H),7.50(s,1H),7.36(dd,J=1.9,0.9Hz,1H),7.21(dd,J=5.0,3.8Hz,1H),6.34(dd,J=3.2,1.9Hz,1H),6.26(d,J=3.2Hz,1H),5.93(s,1H),4.49(d,J=5.5Hz,2H),3.52(t,J=7.2Hz,2H),2.76(t,J=7.2Hz,2H).
13C NMR(101MHz,CDCl3)δ173.4,170.6,161.2,156.1(q,JF=144Hz),151.1,142.2,140.8,132.1,129.3,128.8,120.3(d,JF=1096Hz),110.4,107.5,105.9,36.6,36.1,27.0.
MS(ESI+)m/z 414.1(M+H)+.
实施例22
3-((4-(4-氯苯基)-6-(三氟甲基)嘧啶-2-基)硫基)-N-(呋喃-2-基甲
基)丙酰胺(化合物22)的制备
将实施例9中的对甲氧基苯硼酸替换成4-氯苯硼酸,其余所需原料,试剂及制备方法及步骤同实施例9,得到化合物22。
1H NMR(400MHz,Chloroform-d)δ8.08(m,2H),7.64(s,1H),7.51(m,2H),7.34(dd,J=1.9,0.8Hz,1H),6.32(dd,J=3.2,1.9Hz,1H),6.24(m,1H),6.01(t,J=5.5Hz,1H),4.47(d,J=5.4Hz,2H),3.54(t,J=7.1Hz,2H),2.74(t,J=7.1Hz,2H).
13C NMR(101MHz,CDCl3)δ173.5,170.6,166.3,160.2,156.4(d,JF=144Hz),151.0,142.2,136.5,130.2,119.8,120.5(d,JF=1096Hz),118.1,112.5,110.4,107.9,107.5,36.6,36.1,26.9.
MS(ESI+)m/z 442.1(M+H)+.
体外活性
细胞转染与培养
鼠源(mouse)TRPV2通道的野生型(WT)cDNA分别被亚克隆到pEGFPN1表达载体中。构建好的的质粒被瞬时转染到HEK293T细胞中,视细胞状态而定,6-24小时换液。细胞培养的条件为DMEM高糖细胞培养基,10% FBS,100μg/ml青霉素-链霉素,5% CO2,温度保持在37℃。PC-3M细胞为PC3细胞的癌转变体。PC-3M细胞的培养条件为DMEM高糖细胞培养基,10% FBS,5% CO2,温度保持在37℃。
电生理实验以及数据分析
实验检测的细胞为转染后培养36-96小时的细胞。电生理实验采用全细胞膜片钳模式。实验记录仪器的放大器型号为Axopatch-200B,显微操作系统品牌为奥林巴斯。实验之前用Flaming/Brown type micropipette puller电极拉制仪拉制电极,并将拉制好的电极进行抛光以使进行全细胞实验时得到高阻抗封接。用于全细胞膜片钳记录模式的电极入水电阻为4-7MΩ。细胞内液成分主要包括:140mM KCl,10mM HEPES,并用KOH将pH调至7.3。细胞外液成分主要包括:165mM NaCl,10mM HEPES,并用NaOH将pH调至7.3。实验所采集的电流信号使用频率为1kHz的低频滤波器进行过滤。数据的采样采用DigiData 1440A,采样的频率为10kHz。数据的统计分析与作图采用软件origin 8.0。电压钳制在-60mV,使用快速灌流系统rapid solution change(RSC-2),使用1mM 2-APB(sigma)作为激动剂,是为control,在此基础上加上抑制剂小分子,观察其对2-APB诱导电流的抑制作用。
癌细胞迁移实验与细胞存活实验
准备24孔Transwell小室(孔径8.0μm),用于癌细胞迁移实验。利用无血清的200μlDMEM培养基备置PC-3M细胞(8×104)悬液。加入抑制剂小分子后,PC-3M细胞被接种到上层小室。含有10% FBS的500μl DMEM培养基被加入到下层小室。在37℃5%CO2的条件下培养24小时后,刮下上层表面细胞,用预热过的4%PFA固定侵袭细胞30分钟,然后用0.2%结晶紫给细胞染色20分钟。显微镜(Olympus,DP71,Japan)下观察细胞并摄影,记录视野范围内(160倍放大)的细胞数。
细胞存活实验由SRB实验检测。PC-3M细胞被接种到96孔板中,每孔约8000细胞,过夜培养。然后,用抑制剂小分子孵育48小时。在4℃条件下,用10%三氯乙酸固定细胞1小时,随后水洗晾干。室温下用50μl 0.4%(w/v)SRB染色细胞20分钟,随后用1%醋酸洗脱晾干。最后100μl 10mM Tris被加入到每个孔中,检测515nm波长的吸光度。
实验结果和结论:
电生理实验结果表明,本发明供试化合物对TRPV2都有较好的抑制活性(表1)。即使在1μM低浓度下,化合物1、化合物4、化合物5、化合物7和化合物9依然能够抑制TRPV2(图1)。其中,化合物1对TRPV2通道更具有亚微摩尔级(IC50=0.46±0.01μM)的抑制效果(图2)。
表1.本发明化合物对TRPV2的抑制活性IC50
肿瘤细胞迁移实验表明,本发明供试化合物1能够显著抑制PC-3M细胞的迁移(图3中a-b)。细胞生存实验表面,本发明供试化合物不影响细胞生存,细胞毒性低(图3中c)。这两项测试结果说明本发明化合物在与TRPV2相关的治疗领域,尤其是癌症治疗领域,具有较好的临床应用潜力。
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)
9.一种如权利要求5所述的化合物的制备方法,其特征在于,所述制备方法包括以下步骤:
(i)式I-1化合物与HX-(CH2)n-Ya反应得到式I-2化合物;
(ii)式I-2化合物与Yb-(CH2)m-R2反应得到式I化合物
各式中,R1、R2、X、Y、m和n的定义如权利要求5所述;
Ya为-COOH、-NH2、-NHR3′、-SH或-OH,其中R3′选自下组:C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基、C1-C6卤代烷氧基、卤素、氨基、羟基;
Yb为-NH2、-COOH、-NHR4′、-SH或-OH,其中R4′选自下组:C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基、C1-C6卤代烷氧基、卤素、氨基、羟基。
10.一种药物组合物,其特征在于,包含:
权利要求5-8任一项所述的化合物或其药学上可接受的盐;和
药学上可接受的载体。
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