CN117285485A - 一种双磺酰胺类衍生物及其制备方法和应用 - Google Patents
一种双磺酰胺类衍生物及其制备方法和应用 Download PDFInfo
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Classifications
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- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
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- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
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- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
- C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
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- C07D295/145—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/15—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
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- C—CHEMISTRY; METALLURGY
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- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
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Abstract
本发明提供一种双磺酰胺类化合物及其制备方法,以及作为RORγt激动剂的用途,这类化合物具有RORγt激动活性,有望用于制备预防或治疗与RORγt和/或Th17细胞分化相关的疾病(包括肿瘤或癌症、病毒感染和免疫缺陷障碍等)的药物。
Description
技术领域
本发明属于药物化学领域,具体涉及一种双磺酰胺类化合物及其制备方法,以及作为RORγt激动剂的用途,这类化合物具有RORγt激动活性,有望用于制备预防或治疗与RORγt和/或Th17细胞分化相关的疾病的药物。
背景技术
视黄酸受体相关孤儿受体(retinoic acid receptor-related orphanreceptor,ROR)是配体依赖的转录因子核受体(nuclear receptor,NR)超家族的一员。ROR家族主要包括三种类型:RORα(NR1F1)、RORβ(NR1F2)和RORγ(NR1F3)。三种不同的ROR表达和分布于不同组织中,并调节不同的生理过程。RORα广泛分布于脂肪组织、肝脏、皮肤、肾脏、骨骼肌、肺、胸腺和脑中;RORβ分布范围小,主要在中枢神经系统中表达;RORγ具有两种亚型:RORγ1和RORγ2(也称为RORγt),其中RORγ1分布于骨骼肌、胸腺、睾丸、胰腺、前列腺、心脏和肝脏等处,而RORγt仅表达于某些免疫细胞中。
RORγt是辅助T细胞17(T helper 17cells,简称Th17)分化并产生白细胞介素17(interleukin-17,简称IL-17)的关键调节因子。Th17细胞和其分泌的IL-17在自身免疫病和炎症的发生和发展过程中发挥重要的作用。RORγt抑制剂或反向激动剂可用于治疗自身免疫性疾病(包括类风湿性关节炎、多发性硬化、银屑病和炎症性肠病等)、炎症和某些 RORγt高表达的癌症等。
肿瘤免疫治疗近年来备受关注,是肿瘤治疗领域的焦点。肿瘤免疫疗法通过调动机体的免疫系统,增强肿瘤微环境抗肿瘤免疫力,从而控制和杀伤肿瘤细胞,它的靶标是人体的免疫系统而不是直接针对肿瘤。目前,肿瘤免疫治疗已在一些肿瘤类型如黑色素瘤、非小细胞肺癌等的治疗中展示出了强大的抗肿瘤活性,并已有肿瘤免疫治疗单抗药物获得美国 FDA批准上市。
目前已有研究发现,Th17在肿瘤组织中广泛存在。2009年,董晨教授在《Immunity》上发表了一篇文章,主要解析Th17细胞可促进细胞毒性T细胞(cytotoxic T cell,Tc)激活,发挥肿瘤免疫功能。研究发现,IL-17A缺陷的小鼠更易发生肺黑色素瘤 (一种癌症)。如果对小鼠采取T细胞疗法,用分泌IL-17A的T细胞治疗可有效阻止肿瘤的发生。更重要的是,在IL-17A的辅助下,Th17细胞表现出比Th1细胞更强的治疗效果。更让人意外的是,使用Th17细胞治疗还可有效激活肿瘤特异性的CD8+T细胞,其中,CD8+T细胞是抗肿瘤的必需细胞。研究显示,Th17细胞能召集树突细胞进入肿瘤组织,并且能使CD8α+树突细胞聚集到肿瘤组织中。此外,Th17细胞激活肿瘤组织的趋化因子 CCL20。总的来说,Th17细胞可有效促进肿瘤特异性的CD8+T细胞的活性。这些发现为肿瘤免疫治疗拓宽了视野。
Th17细胞特异性表达RORγt,激活RORγt可促进Th17细胞分化,并产生促炎性细胞因子IL-17。因此,理论上可以通过激活RORγt增加Th17细胞分化,从而促进肿瘤特异性的CD8+T细胞的活性,发挥肿瘤免疫功能。2015年2月,Lycera公司宣布其口服RORγt 激动剂能够改善T细胞的功效,可增加IL-17的产生,促进Tc细胞表达,从而刺激对肿瘤细胞的免疫反应,带来持久的杀死肿瘤细胞效果。2015年6月9日,美国Celgene公司以 8250万美元前期款加上2250万美元近期付款与Lycera就其T细胞抗癌药物达成协议。2016 年12月,药物cintirorgon(LYC-55716)正式进入临床I/II期试验。2018年8月,其与PD- 1单抗pembrolizumab联合治疗转移性非小细胞肺癌的I期临床试验启动。这充分证明了 RORγt激动剂用于肿瘤免疫疗法的巨大潜力。
因此,RORγt可作为潜在的肿瘤免疫疗法的靶点。RORγt激动剂可有效激活RORγt 受体,刺激Th17细胞的分化,增加IL-17的产生,可作为免疫激活剂用于RORγt和/或Th17细胞分化相关疾病(包括肿瘤或癌症、病毒感染和免疫缺陷障碍等)的药物治疗。
发明内容
发明要解决的问题:
本发明的目的在于提供一种双磺酰胺类衍生物作为新颖的RORγt激动剂,具有RORγt激动活性,可用于制备预防或治疗与RORγt和/或Th17细胞分化相关的疾病(包括肿瘤或癌症、病毒感染和免疫缺陷障碍等)的药物。
解决问题的手段:
为了解决上述技术问题,第一个方面,本发明提供如下式化学结构通式I的双磺酰胺类衍生物或其药学上可接受的盐或溶剂化物:
其中,
基团A、B独立地选自取代或未取代的芳基、杂芳基、C3-C8环烷基、C3-C8杂环烷基或C3-C8氧代杂环烷基,所述取代基选自C1-C4烷基、C1-C4烷氧基、C1-C4卤代烷基、C1- C4卤代烷氧基、氰基或卤素;
R1、R2、R3独立地选自氢、C1-C4烷基、C1-C4卤代烷基或卤素;
R4、R5、R6独立地选自氢或C1-C4烷基;
R7选自取代或未取代的C1-C8烷基、C3-C8环烷基、C3-C8杂环烷基、C3-C8氧代杂环烷基、芳基、杂芳基、氰基或羧基,所述取代基选自C1-C4烷基、C1-C4烷氧基、C1-C4卤代烷基、C1-C4卤代烷氧基、氰基或卤素;
Q选自羰基、亚烷基、或者一个共价键。
优选地,所述基团A、B独立地选自取代或未取代的苯基、2-吡啶基、3-吡啶基或4-吡啶基,所述取代基选自C1-C4烷基、C1-C4烷氧基、C1-C4卤代烷基、C1-C4卤代烷氧基、氰基或卤素,更优选地,所述取代基为甲基、三氟甲基或卤素。
优选地,R1和R4连接成亚烷基,并与它们所连接的碳原子一起形成五元至七元脂环;或者,R2和R4连接成亚烷基,并与它们所连接的碳原子一起形成五元至七元脂环;或者R5和R6连接成亚烷基,并和邻近的氮原子一起桥接成五元至七元含氮杂环。
优选地,R1和R4连接成亚烷基,并与它们所连接的碳原子一起形成茚的结构,即或者,R2和R4连接成亚烷基,并与它们所连接的碳原子一起形成茚的结构,即或者,R5和R6连接成亚烷基,并和邻近的氮原子一起形成桥环结构3,8-二氮杂双环[3,2,1]辛烷,即/>
优选地,R7选自取代或未取代的甲基、异丙基、环戊基、环己基、苯基、4-甲磺酰基苯基、吡啶基、吡咯基、呋喃基、噻吩基、吡咯烷基、四氢呋喃基、四氢吡喃基、二氧代四氢噻喃基或羧基,所述取代基选自C1-C4烷基、C1-C4烷氧基、C1-C4卤代烷基、C1-C4卤代烷氧基、氰基或卤素,更优选地,所述取代基为甲基、三氟甲基或卤素。
优选地,所述化合物选自下述化合物:
第二个方面,本发明提供一种如上所述的双磺酰胺类衍生物或其药学上可接受的盐或溶剂化物的制备方法,包括两种合成方案:
第一种合成方案:
反应条件:(a)NaBH(OAc)3,AcOH,DCM,室温,过夜;(b)盐酸/二氧六环, DCM,室温,2h;(c)酰氯(R7-COCl,产物中Q=羰基),DIEA,DCM,0℃至室温,2 h;(d)羧酸(R7-COOH,产物中Q=羰基),HATU或T3P,DIEA或TEA,DCM,室温,过夜;(e)卤代烷(R7-亚烷基氯,产物中Q=亚烷基),DIEA,EtOH,回流,6h;(f)醛 (R7CHO,产物中Q=亚烷基),NaBH(OAc)3,AcOH,DCM,室温,过夜;(g)Zn,HCOONH4,MeOH/H2O,回流,3h;(h)吡啶,THF,室温,6h;(i)TEA,DCM,室温,过夜;
反应过程:以3-硝基苯甲醛或酮为原料,在醋酸和三乙酰氧基硼氢化钠的作用下与 Boc-哌嗪进行还原胺化反应,并用盐酸/二氧六环溶液脱Boc得到苄基哌嗪中间体,然后与不同的酰氯或羧酸进行酰胺缩合,或者与不同的卤代烷进行亲核取代,又或者与不同的醛进行还原胺化反应得到中间体(A),中间体(A)经锌粉和甲酸铵还原得到关键苯胺中间体(B);然后在磺酰氯作用下,经两步磺酰化或一步双磺酰化反应制得所述的目标化合物(I);
第二种合成方案:
反应条件:(a)NaBH(OAc)3,AcOH,DCM,室温,过夜;(b)Zn,HCOONH4, MeOH/H2O,回流,3h;(c)吡啶,THF,室温,6h;(d)TEA,DCM,室温,过夜;(e)盐酸/二氧六环,DCM,室温,2h;(f)酰氯(R7-COCl,产物中Q=羰基),DIEA,DCM, 0℃至室温,2h;(g)羧酸(R7-COOH,产物中Q=羰基),HATU或T3P,DIEA或TEA, DCM,室温,过夜;(h)卤代烷(R7-亚烷基氯,产物中Q=亚烷基),DIEA,EtOH,回流, 6h;(i)醛(R7CHO,产物中Q=亚烷基),NaBH(OAc)3,AcOH,DCM,室温,过夜;
反应过程:以3-硝基苯甲醛或酮为原料,在醋酸和三乙酰氧基硼氢化钠的作用下与Boc-哌嗪进行还原胺化反应,再经锌粉和甲酸铵还原得到苯胺中间体,然后在磺酰氯作用下经两步磺酰化反应,并用盐酸/二氧六环溶液脱Boc得到关键双磺酰胺中间体(C),关键中间体(C)与不同的酰氯或羧酸进行酰胺缩合,或者与不同的卤代烷进行亲核取代,又或者与不同的醛进行还原胺化反应制得所述的目标化合物(I)。
第三个方面,本发明提供一种药物组合物,包括如上所述的双磺酰胺类衍生物或其药学上可接受的盐或溶剂化物,以及药物上可接受的载体。
第四个方面,本发明提供一种如上所述的双磺酰胺类衍生物或其药学上可接受的盐或溶剂化物在制备用于预防或治疗与RORγt和/或Th17细胞分化相关的疾病的药物中的应用,所述疾病包括肿瘤或癌症、病毒感染和免疫缺陷障碍。
第五个方面,本发明提供一种RORγt激动剂,包括如上所述的双磺酰胺类衍生物或其药学上可接受的盐或溶剂化物。
具体实施方式
以下结合实施方式进一步说明本发明,应理解,下述实施方式仅用于说明本发明,而非限制本发明。
本发明提供一种新颖的RORγt激动剂,其如下式化学结构通式I的双磺酰胺类衍生物或其药学上可接受的盐或溶剂化物:
其中,
基团A、B独立地选自取代或未取代的芳基、杂芳基、C3-C8环烷基、C3-C8杂环烷基或C3-C8氧代杂环烷基,所述取代基选自C1-C4烷基、C1-C4烷氧基、C1-C4卤代烷基、C1- C4卤代烷氧基、氰基或卤素;
R1、R2、R3独立地选自氢、C1-C4烷基、C1-C4卤代烷基或卤素;
R4、R5、R6独立地选自氢或C1-C4烷基;
R7选自取代或未取代的C1-C8烷基、C3-C8环烷基、C3-C8杂环烷基、C3-C8氧代杂环烷基、芳基、杂芳基、氰基或羧基,所述取代基选自C1-C4烷基、C1-C4烷氧基、C1-C4卤代烷基、C1-C4卤代烷氧基、氰基或卤素;
Q选自羰基、亚烷基、或者一个共价键。
在本发明的一个优选实施方式中,所述基团A、B独立地选自取代或未取代的苯基、2-吡啶基、3-吡啶基或4-吡啶基,所述取代基选自C1-C4烷基、C1-C4烷氧基、C1-C4卤代烷基、C1-C4卤代烷氧基、氰基或卤素,更优选地,所述取代基为甲基、三氟甲基或卤素。
在本发明的一个优选实施方式中,R1和R4连接成亚烷基,并与它们所连接的碳原子一起形成五元至七元脂环;或者,R2和R4连接成亚烷基,并与它们所连接的碳原子一起形成五元至七元脂环;或者R5和R6连接成亚烷基,并和邻近的氮原子一起桥接成五元至七元含氮杂环。
在本发明的一个优选实施方式中,R1和R4连接成亚烷基,并与它们所连接的碳原子一起形成茚的结构,即或者,R2和R4连接成亚烷基,并与它们所连接的碳原子一起形成茚的结构,即/>或者,R5和R6连接成亚烷基,并和邻近的氮原子一起形成桥环结构3,8-二氮杂双环[3,2,1]辛烷,即/>
在本发明的一个优选实施方式中,R7选自取代或未取代的甲基、异丙基、环戊基、环己基、苯基、4-甲磺酰基苯基、吡啶基、吡咯基、呋喃基、噻吩基、吡咯烷基、四氢呋喃基、四氢吡喃基、二氧代四氢噻喃基或羧基,所述取代基选自C1-C4烷基、C1-C4烷氧基、 C1-C4卤代烷基、C1-C4卤代烷氧基、氰基或卤素,更优选地,所述取代基为甲基、三氟甲基或卤素。
在本发明的一个优选实施方式中,所述化合物选自下述化合物:
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本发明提供的化学结构通式I的化合物可以通过下述合成方案合成:
第一种合成方案:
反应条件:(a)NaBH(OAc)3,AcOH,DCM,室温,过夜;(b)盐酸/二氧六环, DCM,室温,2h;(c)酰氯(R7-COCl,产物中Q=羰基),DIEA,DCM,0℃至室温,2 h;(d)羧酸(R7-COOH,产物中Q=羰基),HATU或T3P,DIEA或TEA,DCM,室温,过夜;(e)卤代烷(R7-亚烷基氯,产物中Q=亚烷基),DIEA,EtOH,回流,6h;(f)醛 (R7CHO,产物中Q=亚烷基),NaBH(OAc)3,AcOH,DCM,室温,过夜;(g)Zn, HCOONH4,MeOH/H2O,回流,3h;(h)吡啶,THF,室温,6h;(i)TEA,DCM,室温,过夜;
反应过程:以3-硝基苯甲醛或酮为原料,在醋酸和三乙酰氧基硼氢化钠的作用下与 Boc-哌嗪进行还原胺化反应,并用盐酸/二氧六环溶液脱Boc得到苄基哌嗪中间体,然后与不同的酰氯或羧酸进行酰胺缩合,或者与不同的卤代烷进行亲核取代,又或者与不同的醛进行还原胺化反应得到中间体(A),中间体(A)经锌粉和甲酸铵还原得到关键苯胺中间体(B);然后在磺酰氯作用下,经两步磺酰化或一步双磺酰化反应制得所述的目标化合物(I);
第二种合成方案:
反应条件:(a)NaBH(OAc)3,AcOH,DCM,室温,过夜;(b)Zn,HCOONH4, MeOH/H2O,回流,3h;(c)吡啶,THF,室温,6h;(d)TEA,DCM,室温,过夜;(e)盐酸/二氧六环,DCM,室温,2h;(f)酰氯(R7-COCl,产物中Q=羰基),DIEA,DCM, 0℃至室温,2h;(g)羧酸(R7-COOH,产物中Q=羰基),HATU或T3P,DIEA或TEA, DCM,室温,过夜;(h)卤代烷(R7-亚烷基氯,产物中Q=亚烷基),DIEA,EtOH,回流, 6h;(i)醛(R7CHO,产物中Q=亚烷基),NaBH(OAc)3,AcOH,DCM,室温,过夜;
反应过程:以3-硝基苯甲醛或酮为原料,在醋酸和三乙酰氧基硼氢化钠的作用下与 Boc-哌嗪进行还原胺化反应,再经锌粉和甲酸铵还原得到苯胺中间体,然后在磺酰氯作用下经两步磺酰化反应,并用盐酸/二氧六环溶液脱Boc得到关键双磺酰胺中间体(C),关键中间体(C)与不同的酰氯或羧酸进行酰胺缩合,或者与不同的卤代烷进行亲核取代,又或者与不同的醛进行还原胺化反应制得所述的目标化合物(I)。
除非另有说明,上述合成方案中所述基团、术语的含义与通式I化合物中的含义相同。
上述合成方案只是列举了本发明中部分化合物的制备方法,参考本领域中常用技术手段及现有技术,本领域技术人员在上述合成方案的基础上,可采用类似的方法合成本发明的化合物。
本发明所述的“化合物”,包括所有立体异构体、几何异构体、互变异构体和同位素。
本发明所述的“化合物”,可以是不对称的,例如,具有一个或多个立体异构体。除非另有说明,所有立体异构体都包括,如对映异构体和非对映异构体。本发明中含有不对称碳原子的化合物,可以光学活性纯的形式或外消旋形式被分离出来;光学活性纯的形式可以从外消旋混合物拆分,或通过使用手性原料或手性试剂合成。
本发明所述的“化合物”,还包括互变异构体形式;互变异构体形式来源于一个单键与相邻的双键交换并一起伴随一个质子的迁移。
本发明还包括所有同位素的原子,无论是在中间体或最后的化合物;同位素的原子包括具有相同的原子数、但不同质量数的,例如,氢的同位素包括氘和氚。又,如果需要的话,例如为了特别的治疗或者诊断治疗,本发明的化合物可以引入现有技术已知的同位素或放射性同位素,例如3H、15O、13C或13N同位素。
“药学上可接受的盐”是指药学上可接受的盐,保持其母体化合物的药理活性的同时改善理化性质或者代谢性质等。这类盐包括由药学上可接受的酸或碱(包括有机酸、无机酸、有机碱、无机碱)制备的酸加成盐和碱加成盐,或者两者混合物。在本发明中,合适的无机酸例如盐酸、氢溴酸、硫酸、硝酸、磷酸,或类似的酸;合适的有机酸例如,乙酸、丙酸、己酸、环戊基丙酸、乙醇酸、丙酮酸、乳酸、丙二酸、琥珀酸、苹果酸、马来酸、富马酸、酒石酸、柠檬酸、扁桃酸,甲磺酸,三氟甲磺酸,乙磺酸、1,2-乙二磺酸、2-羟基乙磺酸、苯磺酸、水杨酸、硬脂酸、粘康酸,或其类似物。
根据本发明的化合物还可以以其溶剂化物形式存在。例如水合物(半水合物、一水合物、二水合物、三水合物等)。
本发明中,除特殊说明外,所用的术语具有如下含义。
术语“卤素”是指氟、氯、溴或碘,优选氟或氯。
术语“氧代基”,指=O。
术语“羰基”,指C=O。
术语“羧基”,指-(C=O)OH。
术语“氰基”,指-CN。
术语“磺酰基”,指-S(=O)2(烷基)或-S(=O)2(环烷基),其中烷基、环烷基如上定义。
术语“亚磺酰基”,指-S(=O)(烷基)或-S(=O)(环烷基),其中烷基、环烷基如上定义。
术语“烷基”,指由碳原子和氢原子组成的直链或支链的饱和脂肪族烃基团,为包含 1至20个碳原子的直链或支链烷基(C1-C20烷基),优选为C1-C8烷基,更优选为C1-C6烷基,更加优选为C1-C4卤代烷基,例如,甲基、乙基、丙基(包括正丙基和异丙基)、丁基 (包括正丁基、异丁基、仲丁基或叔丁基)、戊基(包括正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基)、己基(正己基、1-乙基- 2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基)等;所述烷基可以是非取代的、或是被一个或多个取代基所取代,取代基包括但不限于烷基、卤素,例如形成卤代烷基,优选C1-C8卤代烷基,更优选为C1-C6卤代烷基,更加优选为C1-C4卤代烷基。
术语“烷氧基”,指-O-烷基,其中烷基如上所定义。
术语“环烷基”,指饱和或部分不饱和的单环或多环(稠合环、螺环或桥环)的环状烃取代基,环烷基包含3至8个碳原子,优选包含3至6个碳原子。例如,环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、螺[3.4]辛烷基、二环[3.1.1]己烷基等。所述环烷基可以是非取代的、或被一个或多个取代基所取代,取代基包括但不限于烷基、卤素、磺酰基、亚磺酰基,例如形成卤代环烷基,优选C3-C8卤代环烷基,更优选为 C3-C6卤代环烷基。
术语“杂环烷基”,指饱和或部分不饱和的含1个或多个N、O或S的杂原子的单环或多环(稠合环、螺环或桥环)的环状烃取代基,杂环烷基包含3至8个环原子,其中1-3 个是杂原子;优选包含3至6个环原子,其中1-2个是杂原子。典型地为含1个或多个N、 O或S的杂原子的3-6元杂环基,例如,氮杂环丙烷-1-基、氧杂环丁烷-3-基、氮杂环丁烷- 3-基、氮杂环丁烷-1-基、吡咯烷基、四氢呋喃基、哌啶子基、哌嗪子基、四氢吡喃基、四氢噻喃基、二氧代四氢噻喃基、吗啉代基及其衍生物。所述杂环烷基可以是非取代的、或被一个或多个取代基所取代,取代基包括但不限于烷基、卤素、磺酰基、亚磺酰基、氧代基,例如形成卤代杂环烷基,优选含有3-8个环原子的卤代杂环烷基。
术语“亚烷基”,指烷基失去一个氢原子所得到的二价基团,其中烷基如上定义。亚烷基包含1至6个碳原子,优选包含1至4个碳原子。例如,亚甲基、亚乙基、亚丙基、亚丁基等。
术语“芳基”,指具有完全共轭的π电子体系的全碳单环或稠合环,通常具有6-14个碳原子,优选具有6-12个碳原子,最优选具有6个碳原子。芳基可以是非取代的、或被一个或多个取代基所取代,所述的取代基包括但不限于烷基、烷氧基、烷硫基、烷基氨基、卤素、氨基、氰基、硝基、羟基、巯基、芳基、杂芳基、羰基、羧基、羧酸酯基、磺酰基、亚磺酰基、磷酰基。非取代的芳基的实例包括但不限于苯基、萘基和蒽基。
术语“杂芳基”是指包含5-12个环原子的单环或稠合环,其中含有1-4个选自N、 O、S的环原子,其余环原子为C,且具有完全共轭的π-电子体系,包括但不限于吡咯基、呋喃基、噻吩基、咪唑基、吡唑基、噁唑基、异噁唑基、噻唑基、噻二唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、喹啉基、异喹啉基、三唑基、四唑基。杂芳基可以是非取代的或取代的,所述的取代基包括但不限于烷基、烷氧基、烷硫基、烷基氨基、卤素、氨基、氰基、硝基、羟基、巯基、芳基、杂芳基、羰基、羧基、羧酸酯基、磺酰基、亚磺酰基、磷酰基。
给药以及药物组合物
本发明所述的“药物组合物”,指一种或多种本发明的化合物或其盐与在本领域中通常接受的用于将生物活性化合物输送至有机体(例如人)的载体的制剂。药物组合物的目的是有利于对有机体给药输送。
术语“药学上可接受的载体”,指与活性成份共同给药的、且有利于活性成份给药的物质,包括但不限于国家食品药品监督管理局许可的可接受的用于人或动物(例如家畜)的任何助流剂、增甜剂、稀释剂、防腐剂、染料/着色剂、矫味增强剂、表面活性剂、润湿剂、分散剂、崩解剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂。例如包括但不限于碳酸钙、磷酸钙、各种糖和各类淀粉、纤维素衍生物、明胶、植物油和聚乙二醇。
本发明所述的药物组合物,可配制成固态、半固态、液态或气态制剂,如片剂、丸剂、胶囊剂、粉剂、颗粒剂、膏剂、乳剂、悬浮剂、溶液剂、栓剂、注射剂、吸入剂、凝胶剂、微球及气溶胶等等。
本发明所述的药物组合物,可以采用本领域熟知的方法制造,如常规的混合法、溶解法、制粒法、制糖衣药丸法、磨细法、乳化法、冷冻干燥法等。
本发明所述的化合物或其药学上可接受的盐或其药物组合物的给药途径,包括但不限于口服、直肠、透黏膜、经肠给药,或者局部、经皮、吸入、肠胃外、舌下、阴道内、鼻内、眼内、腹膜内、肌内、皮下、静脉内给药。优选的给药途径是口服给药。
对于口服给药,可以通过将活性化合物与本领域熟知的药学上可接受的载体混合,来配制该药物组合物。这些载体能使本发明的化合物被配制成片剂、丸剂、锭剂、糖衣剂、胶囊剂、液体、凝胶剂、浆剂、悬浮剂等,以用于对患者的口服给药。例如,用于口服给药的药物组合物,可采用如下方式获得片剂:将活性成分与一种或多种固体载体合并,如果需要将所得混合物制粒,并且如果需要加入少量的赋形剂加工成混合物或颗粒,以形成片剂或片芯。片芯可与任选适合肠溶的包衣材料结合,加工成更有利于有机体(例如人)吸收的包衣制剂形式。
“治疗”意味着对哺乳动物体内疾病的任何治疗,包括:(1)防止疾病,即造成临床疾病的症状不发展;(2)抑制疾病,即阻止临床症状的发展;(3)减轻疾病,即造成临床症状的消退。
本发明提供了一类具有通式I结构特征的双磺酰胺类衍生物,该类化合物可有效激活RORγt受体,刺激Th17细胞的分化,增加IL-17的产生,可作为免疫激活剂用于RORγt和/或Th17细胞分化相关疾病(包括肿瘤或癌症、病毒感染和免疫缺陷障碍等)的药物治疗。
以下结合具体实施例进一步详细说明本发明。同样应理解,以下实施例只用于对本发明进行进一步说明,不能理解为对本发明保护范围的限制,本领域的技术人员根据本发明的上述内容作出的一些非本质的改进和调整均属于本发明的保护范围。下述示例具体的工艺参数等也仅是合适范围中的一个示例,即本领域技术人员可以通过本文的说明做合适的范围内选择,而并非要限定于下文示例的具体数值。
本发明提供的目标化合物制备方法中,柱层析色谱采用乳山太阳干燥剂有限公司生产的硅胶(200-300目);薄层色谱采用GF254;核磁共振色谱(NMR)使用Varian-400核磁共振仪测定;液质连用(LC/MS)使用Agilent TechnologiESI 6120液质联用仪。
此外,凡涉及易氧化或易水解的原料的所有操作都在氮气保护下进行。除非另有说明,本发明使用的原料都是市售原料,无需进一步纯化可以直接使用。
实施例一:化合物1的制备
3-氯-N-(3-((4-(环己烷羰基)哌嗪-1-基)甲基)苯基)-N-(苯基磺酰基)苯磺酰胺的制备
步骤1:4-(3-硝基苄基)哌嗪-1-羧酸叔丁酯的制备
室温下,于100mL单口瓶中加入间硝基苯甲醛(3.02g,20.0mmol),Boc-哌嗪(4.09g,22.0mmol),乙酸(4.60g,80.0mmol)和二氯甲烷(50mL),混合物在室温下搅拌反应1小时,加入三乙酰氧基硼氢化钠(6.36g,30.0mmol),继续反应过夜,TLC检测原料反应完全后,加入水(50mL)淬灭反应,分液,有机相用去离子水和饱和NaCl溶液洗涤,无水Na2SO4干燥,过滤,滤液减压除去溶剂,剩余混合物经硅胶柱层析纯化得到4- (3-硝基苄基)哌嗪-1-甲酸叔丁酯4.80g,产率74.8%。MS(ESI)m/z:322.3[M+H]+.
步骤2:1-(3-硝基苄基)哌嗪的制备
向含有4-(3-硝基苄基)哌嗪-1-甲酸叔丁酯(4.80g,14.95mmol)的100mL反应瓶中加入二氯甲烷(20mL),搅拌溶解后,加入盐酸二氧六环溶液(4M,10mL),室温下继续搅拌反应2小时,TLC检测原料反应完全后,停止搅拌,将上清液倒掉,将残余白色固体减压旋干,直接投入到下一步反应。MS(ESI)m/z:222.3[M+H]+.
步骤3:环己基(4-(3-硝基苄基)哌嗪-1-基)甲酮的制备
将上一步反应得到的粗产物1-(3-硝基苄基)哌嗪(3.30g,14.95mmol)溶于二氯甲烷(50mL)和N,N-二异丙基乙胺(5.79g,44.85mmol)中,向反应混合物中缓慢滴加环己基甲酰氯(3.29g,22.43mmol),滴加完毕后继续室温下反应2小时。TLC检测原料反应完全后,加入甲醇(5mL)淬灭反应,将反应混合物减压旋干,残余物经硅胶柱层析纯化得到目标化合物2.10g,产率42.4%。MS(ESI)m/z:332.2[M+H]+.
步骤4:(4-(3-氨基苄基)哌嗪-1-基)(环己基)甲酮的制备
于50mL反应瓶中加入环己基(4-(3-硝基苄基)哌嗪-1-基)甲酮(2.00g,6 mmol),锌粉(1.17g,18mmol)和甲酸铵(1.19g,30mmol),甲醇和水各15mL,油浴加热回流3小时。TLC检测原料反应完全后,过滤,滤液减压旋干。残余物用二氯甲烷(50 mL)溶解,饱和碳酸氢钠溶液洗涤,过滤除去不溶物,分液,有机相用去离子水和饱和 NaCl溶液洗涤,无水Na2SO4干燥,过滤,滤液减压除去溶剂,残余物经硅胶柱层析纯化得到目标化合物(4-(3-氨基苄基)哌嗪-1-基)(环己基)甲酮1.50g,产率82.9%。MS(ESI) m/z:302.2[M+H]+.
步骤5:3-氯-N-(3-((4-(环己烷羰基)哌嗪-1-基)甲基)苯基)苯磺酰胺的制备
室温下,将间氯苯磺酰氯(68mg,0.32mmol)缓慢滴加至含有(4-(3-氨基苄基) 哌嗪-1-基)(环己基)甲酮(81mg,0.27mmol),三乙胺(138μL,1mmol)的二氯甲烷溶液中,在室温下继续反应6小时。TLC检测反应完全后,加入甲醇(1mL)淬灭反应,将反应混合物减压除去溶剂,剩余混合物经硅胶在层析纯化得到目标化合物70mg,产率: 54.5%,白色固体。1HNMR(400MHz,CDCl3)δ7.78-7.77(m,1H),7.69-7.67(m,1H),7.55- 7.51(m,1H),7.42-7.38(m,1H),7.27-7.24(m,1H),7.13-7.09(m,3H),3.65-3.53(m,6H),2.47- 2.39(m,5H),1.83-1.81(m,2H),1.74-1.71(m,3H),1.59-1.50(m,2H),1.30-1.26(m,3H).MS (ESI)m/z:476.2[M+H]+.
步骤6:3-氯-N-(3-((4-(环己烷羰基)哌嗪-1-基)甲基)苯基)-N-(苯基磺酰基)苯磺酰胺的制备
室温下,将苯磺酰氯(74mg,0.42mmol)缓慢滴加到含有3-氯-N-(3-((4-(环己烷羰基)哌嗪-1-基)甲基)苯基)苯磺酰胺(100mg,0.21mmol),三乙胺(139μL,1 mmol)和二氯甲烷(3mL)的混合物中,反应过夜,TLC检测原料反应完全后,加入甲醇(1mL)淬灭反应,将反应混合物减压除去溶剂,剩余混合物经硅胶柱层析和反相中压制备系统纯化得到目标化合物55mg,产率:42.5%。1H NMR(400MHz,CDCl3)δ7.96-7.89(m, 2H),7.90-7.89(m,2H),7.75-7.67(m,2H),7.61-7.52(m,4H),7.42-7.38(m,1H),7.03(m,2H), 3.63-3.56(m,5H),2.48-2.42(m,4H),1.83-1.50(m,10H),1.33-1.28(m,2H).MS(ESI)m/z:616.2 [M+H]+.
实施例二:化合物2的制备
N-(3-((4-(环己烷羰基)哌嗪-1-基)甲基)苯基)-N-(苯基磺酰基)苯磺酰胺的制备
按实施例一的步骤1-4合成中间体(4-(3-氨基苄基)哌嗪-1-基)(环己基)甲酮。按实施例一步骤5,以苯磺酰氯(105mg,0.5mmol),(4-(3-氨基苄基)哌嗪-1-基)(环己基)甲酮(60mg,0.2mmol),三乙胺(138μL,1mmol)为原料得到目标化合物93mg,产率71.5%。1H NMR(400MHz,CDCl3)δ7.93(d,J=8.0Hz,2H),7.69(t,J=8.0Hz,2H),7.55(t, J=8.0Hz,4H),7.43-7.33(m,2H),6.99(s,2H),3.57-3.49(m,5H),2.46-2.32(m,4H),1.80-1.47(m, 9H),1.31-1.25(m,3H).MS(ESI)m/z:581.8[M+H]+.
实施例三:化合物3的制备
3-氯-N-(3-氯苯基)磺酰基)-N-(3-((4-(环己烷羰基)哌嗪-1-基)甲基)苯基)苯磺酰胺的制备
参照实施例一的合成路线。按实施例一步骤6,以间氯苯磺酰氯(87mg,0.42mmol),3-氯-N-(3-((4-(环己烷羰基)哌嗪-1-基)甲基)苯基)苯磺酰胺(100mg,0.21mmol),三乙胺(139μL,1mmol)为原料得到目标化合物65mg,产率:47.5%。1H NMR (400MHz,CDCl3)δ7.87-7.85(m,4H),7.68-7.66(m,2H),7.55-7.51(m,3H),7.41-7.38(m,1H), 7.01-7.00(m,2H),3.60-3.52(m,5H),2.46-2.39(m,4H),1.80-1.46(m,10H),1.31-1.27(m,2H).MS(ESI)m/z:650.1[M+H]+.
实施例四:化合物4的制备
2-氯-N-((3-氯苯基)磺酰基)-N-(3-((4-(环己烷羰基)哌嗪-1-基)甲基)苯基)苯磺酰胺的制备
参照实施例一的合成路线。按实施例一步骤6,以邻氯苯磺酰氯(68mg,0.32mmol),3-氯-N-(3-((4-(环己烷羰基)哌嗪-1-基)甲基)苯基)苯磺酰胺(100mg,0.21mmol),三乙胺(87.6μL,0.63mmol)为原料得到目标化合物45mg,产率:33.0%。1H NMR(400MHz,CDCl3)δ8.34(dd,J=8.0,1.2Hz,1H),7.70-7.57(m,5H),7.53-7.37(m,4H), 7.21(m,2H),7.01-7.00(m,2H),3.52(m,5H),2.46-2.34(m,4H),1.81-1.47(m,10H),1.31-1.28(m,2H).MS(ESI)m/z:650.1[M+H]+.
实施例五:化合物5的制备
2-氯-N-((2-氯苯基)磺酰基)-N-(3-((4-(环己烷羰基)哌嗪-1-基)甲基)苯基)苯磺酰胺的制备
按实施例一的步骤1-4得到中间体(4-(3-氨基苄基)哌嗪-1-基)(环己基)甲酮。接着按实施例一步骤5,以邻氯苯磺酰氯(105.5mg,0.5mmol),(4-(3-氨基苄基)哌嗪-1- 基)(环己基)甲酮(60mg,0.2mmol),三乙胺(138μL,1mmol)为原料得到目标化合物 64mg,产率49.2%。1H NMR(400MHz,CDCl3)δ8.18(dd,J=8.0,1.2Hz,2H),7.71-7.68(m, 2H),7.63-7.56(m,2H),7.52-7.37(m,5H),7.24-7.18(m,3H),3.57(m,5H),2.46-2.40(m,4H), 1.80-1.47(m,10H),1.30-1.25(m,2H).MS(ESI)m/z:649.7[M+H]+.
实施例六:化合物6的制备
2-氯-N-((2-氯苯基)磺酰基)-N-(3-((4-乙酰基哌嗪-1-基)甲基)苯基)苯磺酰胺的制备
步骤1:4-(3-氨基苄基)哌嗪-1-甲酸叔丁酯的制备
于100mL反应瓶中加入4-(3-硝基苄基)哌嗪-1-甲酸叔丁酯(4.63g,14.4 mmol),锌粉(2.80g,43,2mmol)和甲酸铵(4.54g,72mmol),甲醇和水各30mL,油浴加热回流3小时。TLC检测原料反应完全后,过滤,滤液减压旋干。残余物用二氯甲烷(100 mL)溶解,饱和碳酸氢钠溶液洗涤,过滤除去不溶物,分液,有机相用去离子水和饱和 NaCl溶液洗涤,无水Na2SO4干燥,过滤,滤液减压除去溶剂,残余物经硅胶柱层析纯化得到目标化合物4-(3-氨基苄基)哌嗪-1-甲酸叔丁酯3.32g,产率79.2%。MS(ESI)m/z:292.1 [M+H]+.
步骤2:4-(3-((2-氯-N-((2-氯苯基)磺酰基)苯基)磺酰胺基)苯基)哌嗪-1-甲酸叔丁酯的制备
室温下,将邻氯苯磺酰氯(3.40g,16.07mmol)缓慢滴加到含有4-(3-氨基苄基) 哌嗪-1-甲酸叔丁酯(1.87g,6.43mmol),三乙胺(4.5mL,32.15mmol)和二氯甲烷(60 mL)的混合物中,反应过夜,TLC检测原料反应完全后,加入甲醇(20mL)淬灭反应,将反应混合物减压除去溶剂,剩余混合物经硅胶柱层析和反相中压制备系统纯化得到目标化合物3.34g,产率81.3%。MS(ESI)m/z:639.7[M+H]+.
步骤3:2-氯-N-((2-氯苯基)磺酰基)苯基)磺酰胺基)-N-(3-(哌嗪-1-亚甲基) 苯基)苯磺酰胺的制备
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向含有4-(3-((2-氯-N-((2-氯苯基)磺酰基)苯基)磺酰胺基)苯基)哌嗪-1-甲酸叔丁酯(3.34g,5.2mmol)的100mL反应瓶中加入二氯甲烷(20mL),搅拌溶解后,加入盐酸二氧六环溶液(4M,10mL),室温下继续搅拌反应2小时,TLC检测原料反应完全后,停止搅拌,将上清液倒掉,将残余白色固体减压旋干,直接投入到下一步反应。MS (ESI)m/z:539.7[M+H]+.
步骤4:2-氯-N-((2-氯苯基)磺酰基)-N-(3-((4-乙酰基哌嗪-1-基)甲基)苯基)苯磺酰胺的制备
将上一步反应得到的粗产物2-氯-N-((2-氯苯基)磺酰基)苯基)磺酰胺基)-N-(3-(哌嗪-1-亚甲基)苯基)苯磺酰胺(108mg,0.2mmol)溶于二氯甲烷(3mL)和N,N- 二异丙基乙胺(100μL,0.6mmol)中,向反应混合物中缓慢滴加乙酰氯(24mg,0.3 mmol),滴加完毕后继续室温下反应2小时。TLC检测原料反应完全后,加入甲醇(0.5 mL)淬灭反应,将反应混合物减压旋干,残余物经硅胶柱层析纯化得到目标化合物。1H NMR(400MHz,DMSO-d6)δ7.97(dd,J=7.6Hz,2H),7.83–7.65(m,4H),7.63-7.48(m,2H), 7.39–7.31(m,2H),7.24–7.06(m,2H),3.35–3.27(m,4H),3.18–3.09(m,2H),2.30–2.07(m, 4H),2.02–1.91(m,3H).MS(ESI)m/z:581.7[M+H]+.
实施例七:化合物7的制备
2-氯-N-((2-氯苯基)磺酰基)-N-(3-((4-异丁酰基哌嗪-1-基)甲基)苯基)苯磺酰胺的制备
参照实施例六的合成路线。按实施例六步骤4,以2-氯-N-((2-氯苯基)磺酰基)苯基)磺酰胺基)-N-(3-(哌嗪-1-亚甲基)苯基)苯磺酰胺(108mg,0.2mmol),N,N-二异丙基乙胺(100μL,0.6mmol),异丁酰氯(32mg,0.3mmol)为原料得到目标化合物64mg,产率52.4%。1H NMR(400MHz,CDCl3)δ8.18(dm,J=8.0Hz,2H),7.59-7.55(m,2H),7.50- 7.41(m,5H),7.34-7.31(m,3H),3.58(m,5H),2.80-2.73(m,1H),2.43-2.32(m,3H),1.34-1.28(m, 2H),1.12(d,J=8.0Hz,6H).MS(ESI)m/z:609.7[M+H]+.
实施例八:化合物8的制备
N-(3-((4-苯甲酰哌嗪-1-基)甲基)苯基)-2-氯-N-((2-氯苯基)磺酰基)苯磺酰胺的制备
参照实施例六的合成路线。按实施例六步骤4,以2-氯-N-((2-氯苯基)磺酰基)苯基)磺酰胺基)-N-(3-(哌嗪-1-亚甲基)苯基)苯磺酰胺(108mg,0.2mmol),N,N-二异丙基乙胺(100μL,0.6mmol),苯甲酰氯(42mg,0.3mmol)为原料得到目标化合物74.7 mg,产率57.9%。1H NMR(400MHz,CDCl3)δ8.18(dd,J=8.0,1.2,2H),7.57-7.54(m,2H), 7.49-7.39(m,10H),7.34-7.30(m,3H),3.77-3.45(m,6H),2.43-2.36(m,4H).MS(ESI)m/z:643.6 [M+H]+.
实施例九:化合物9的制备
2-氯-N-((2-氯苯基)磺酰基)-N-(3-((4-(吡啶-2-甲酰基)哌嗪-1-基)甲基)苯基)苯磺酰胺的制备
按照实施例六的步骤1-3合成中间体2-氯-N-((2-氯苯基)磺酰基)苯基)磺酰胺基)-N-(3-(哌嗪-1-亚甲基)苯基)苯磺酰胺。将中间体2-氯-N-((2-氯苯基)磺酰基)苯基)磺酰胺基)-N-(3-(哌嗪-1-亚甲基)苯基)苯磺酰胺(108mg,0.2mmol)溶于二氯甲烷(2mL)和N,N-二异丙基乙胺(100μL,0.6mmol)中,向反应混合物中加入2-吡啶甲酸(25.9mg,0.21mmol)和HATU(114mg,0.3mmol),室温下反应过夜。TLC检测原料反应完全后,将反应混合物减压旋干,残余物经硅胶柱层析和反相中压制备系统纯化得到目标化合物76.7mg,产率59.4%。1H NMR(400MHz,CDCl3)δ8.59-8.57(dm,J=8.0,1H),8.18(dd, J=8.0,1.6Hz,2H),7.81(td,J=8.0,1.6Hz,1H),7.67-7.65(m,1H),7.59-7.55(m,2H),7.52-7.48 (m,3H),7.45-7.41(m,2H),7.37-7.33(m,4H),3.90-3.66(m,6H),2.60(m,4H).MS(ESI)m/z:644.6[M+H]+.
实施例十:化合物10的制备
2-氯-N-((2-氯苯基)磺酰基)-N-(3-((4-(吡啶-3-甲酰基)哌嗪-1-基)甲基)苯基)苯磺酰胺的制备
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参照实施例九的合成路线。按实施例九,以2-氯-N-((2-氯苯基)磺酰基)苯基) 磺酰胺基)-N-(3-(哌嗪-1-亚甲基)苯基)苯磺酰胺(108mg,0.2mmol),N,N-二异丙基乙胺(100μL,0.6mmol),烟酸(25.9mg,0.21mmol)和HATU(114mg,0.3mmol)为原料得到目标化合物66.1mg,产率51.2%。1H NMR(400MHz,CDCl3)δ8.67-8.66(m,2H),8.18 (dd,J=8.0,1.2Hz,2H),7.76-7.74(m,1H),7.59-7.55(m,2H),7.49-7.42(m,5H),7.38-7.35(m, 4H),3.82-3.59(m,6H),2.49(m,4H).MS(ESI)m/z:644.6[M+H]+.
实施例十一:化合物11的制备
2-氯-N-((2-氯苯基)磺酰基)-N-(3-((4-(吡啶-4-甲酰基)哌嗪-1-基)甲基)苯基)苯磺酰胺的制备
参照实施例九的合成路线。按实施例九,以2-氯-N-((2-氯苯基)磺酰基)苯基) 磺酰胺基)-N-(3-(哌嗪-1-亚甲基)苯基)苯磺酰胺(108mg,0.2mmol),N,N-二异丙基乙胺(100μL,0.6mmol),异烟酸(25.9mg,0.21mmol)和HATU(114mg,0.3mmol)为原料得到目标化合物92.4mg,产率71.6%。1H NMR(400MHz,CDCl3)δ8.70-8.69(dm,J=4.0, 2H),8.18(dd,J=8.0,0.8Hz,2H),7.59-7.55(m,2H),7.49-7.39(m,6H),7.35-7.27(m,4H),3.82- 3.44(m,6H),2.51(m,4H).MS(ESI)m/z:644.6[M+H]+.
实施例十二:化合物12的制备
2-氯-N-((2-氯苯基)磺酰基)-N-(3-((4-(4-(甲磺酰基)苯甲酰基)哌嗪-1- 基)甲基)苯基)苯磺酰胺的制备
参照实施例九的合成路线。按实施例九,以2-氯-N-((2-氯苯基)磺酰基)苯基) 磺酰胺基)-N-(3-(哌嗪-1-亚甲基)苯基)苯磺酰胺(108mg,0.2mmol),N,N-二异丙基乙胺(100μL,0.6mmol),对甲砜基苯甲酸(42mg,0.21mmol)和HATU(114mg,0.3 mmol)为原料得到目标化合物30mg,产率20.8%。1H NMR(400MHz,CDCl3)δ8.18(dd, J=8.0,1.2,2H),8.00(d,J=8.0,2H),7.60-7.55(m,4H),7.49-7.40(m,8H),3.79-3.36(m,5H),3.06 (s,3H),2.48-2.39(m,3H),1.27-1.24(m,2H).MS(ESI)m/z:721.5[M+H]+.
实施例十三:化合物13的制备
2-氯-N-((2-氯苯基)磺酰基)-N-(3-((4-(1,1-二氧化四氢-2H-噻喃-4-羰基)哌嗪 -1-基)甲基)苯基)苯磺酰胺的制备
参照实施例九的合成路线。按实施例九,以2-氯-N-((2-氯苯基)磺酰基)苯基) 磺酰胺基)-N-(3-(哌嗪-1-亚甲基)苯基)苯磺酰胺(108mg,0.2mmol),N,N-二异丙基乙胺(100μL,0.6mmol),四氢-2H-噻喃-4-羧酸-1,1-二氧化物(38mg,0.21mmol)和HATU (114mg,0.3mmol)为原料得到目标化合物99mg,产率70.8%。1H NMR(400MHz, DMSO-d6)δ8.01(dd,J=8.4,1.6Hz,2H),7.81-7.73(m,4H),7.61-7.57(m,2H),7.39-7.38(m,2H), 7.22-7.20(m,1H),7.16(s,1H),3.65-3.58(m,1H),3.47-3.43(m,4H),3.24-3.00(m,6H),2.26-2.18 (m,4H),1.99-1.95(m,4H).MS(ESI)m/z:699.5[M+H]+.
实施例十四:化合物14的制备
2-氯-N-((2-氯苯基)磺酰基)-N-(3-((4-(四氢-2H-吡喃-2-羰基)哌嗪-1-基)甲基)苯基)苯磺酰胺的制备
参照实施例九的合成路线。按实施例九,以2-氯-N-((2-氯苯基)磺酰基)苯基) 磺酰胺基)-N-(3-(哌嗪-1-亚甲基)苯基)苯磺酰胺(108mg,0.2mmol),N,N-二异丙基乙胺(100μL,0.6mmol),四氢吡喃-2-羧酸(27.3mg,0.21mmol)和HATU(114mg,0.3 mmol)为原料得到目标化合物49.3mg,产率37.8%。1H NMR(400MHz,DMSO-d6)δ8.03 (dm,J=8.0Hz,2H),7.83-7.74(m,4H),7.63-7.51(m,5H),7.38-7.36(m,1H),4.42(m,2H),4.17 (m,2H),3.89-3.86(m,1H),3.58-3.52(m,3H),3.32(m,1H),3.19(m,2H),2.95-2.84(m,2H),1.81 (m,1H),1.60-1.50(m,5H).MS(ESI)m/z:651.6[M+H]+.
实施例十五:化合物15的制备
2-氯-N-((2-氯苯基)磺酰基)-N-(3-((4-(四氢-2H-吡喃-3-羰基)哌嗪-1-基)甲基)苯基)苯磺酰胺的制备
参照实施例九的合成路线。按实施例九,以2-氯-N-((2-氯苯基)磺酰基)苯基) 磺酰胺基)-N-(3-(哌嗪-1-亚甲基)苯基)苯磺酰胺(108mg,0.2mmol),N,N-二异丙基乙胺(100μL,0.6mmol),四氢吡喃-3-羧酸(27.3mg,0.21mmol)和HATU(114mg,0.3 mmol)为原料得到目标化合物121mg,产率92.7%。1H NMR(400MHz,CDCl3)δ8.18(dd, J=8.0,1,2Hz,2H),7.59-7.55(m,2H),7.50-7.42(m,5H),7.37-7.29(m,3H),3.94-3.91(m,2H), 3.63-3.50(m,6H),3.44-3.37(m,1H),2.81-2.74(m,1H),2.55-2.44(m,3H),1.89-1.64(m,5H), 1.54-1.43(m,1H).MS(ESI)m/z:651.6[M+H]+.
实施例十六:化合物16的制备
2-氯-N-((2-氯苯基)磺酰基)-N-(3-((4-(四氢-2H-吡喃-4-羰基)哌嗪-1-基)甲基)苯基)苯磺酰胺的制备
参照实施例九的合成路线。按实施例九,以2-氯-N-((2-氯苯基)磺酰基)苯基) 磺酰胺基)-N-(3-(哌嗪-1-亚甲基)苯基)苯磺酰胺(108mg,0.2mmol),N,N-二异丙基乙胺(100μL,0.6mmol),四氢吡喃-4-甲酸(27.3mg,0.21mmol)和HATU(114mg,0.3 mmol)为原料得到目标化合物68.2mg,产率52.3%。1H NMR(400MHz,CDCl3)δ8.18(dm, J=8.0Hz,2H),7.59-7.55(m,2H),7.50-7.42(m,5H),7.36-7.28(m,3H),4.02-3.99(m,2H),3.58 (m,4H),3.48-3.40(m,2H),2.74-2.66(m,1H),2.50-2.39(m,3H),1.95-1.85(m,2H),1.66-1.57(m, 5H).MS(ESI)m/z:651.7[M+H]+.
实施例十七:化合物17的制备
2-氯-N-((2-氯苯基)磺酰基)-N-(3-((4-(四氢呋喃-2-羰基)哌嗪-1-基)甲基)苯基)苯磺酰胺的制备
参照实施例九的合成路线。按实施例九,以2-氯-N-((2-氯苯基)磺酰基)苯基) 磺酰胺基)-N-(3-(哌嗪-1-亚甲基)苯基)苯磺酰胺(108mg,0.2mmol),N,N-二异丙基乙胺(100μL,0.6mmol),2-四氢呋喃甲酸(24.4mg,0.21mmol)和HATU(114mg,0.3 mmol)为原料得到目标化合物45.6mg,产率35.7%。1H NMR(400MHz,CDCl3)δ8.18(dd, J=8.0,1.2Hz,2H),7.62-7.58(m,2H),7.52-7.44(m,5H),7.34(m,3H),4.63-4.60(m,1H),3.99- 3.94(m,1H),3.90-3.84(m,1H),3.68-3.55(m,6H),2.44-2.22(m,5H),2.21-1.98(m,2H),1.94- 1.88(m,1H).MS(ESI)m/z:637.6[M+H]+.
实施例十八:化合物18的制备
2-氯-N-((2-氯苯基)磺酰基)-N-(3-((4-(四氢呋喃-3-羰基)哌嗪-1-基)甲基)苯基)苯磺酰胺的制备
参照实施例九的合成路线。按实施例九,以2-氯-N-((2-氯苯基)磺酰基)苯基) 磺酰胺基)-N-(3-(哌嗪-1-亚甲基)苯基)苯磺酰胺(108mg,0.2mmol),N,N-二异丙基乙胺(100μL,0.6mmol),3-四氢呋喃甲酸(24.4mg,0.21mmol)和HATU(114mg,0.3 mmol)为原料得到目标化合物60.8mg,产率47.6%。1H NMR(400MHz,CDCl3)δ8.18(dd, J=8.0,1.2Hz,2H),7.59-7.55(m,2H),7.49-7.42(m,5H),7.36-7.29(m,3H),4.01-3.97(m,1H), 3.91-3.82(m,3H),3.61-3.55(m,6H),3.25-3.17(m,1H),2.44-2.36(m,4H),2.26-2.18(m,1H), 2.11-2.02(m,1H).MS(ESI)m/z:637.6[M+H]+.
实施例十九:化合物19的制备
2-氯-N-((2-氯苯基)磺酰基)-N-(3-((4-(环己烷甲基)哌嗪-1-基)甲基)苯基)苯磺酰胺的制备
按照实施例六的步骤1-3合成中间体2-氯-N-((2-氯苯基)磺酰基)苯基)磺酰胺基)-N-(3-(哌嗪-1-亚甲基)苯基)苯磺酰胺。将中间体2-氯-N-((2-氯苯基)磺酰基)苯基)磺酰胺基)-N-(3-(哌嗪-1-亚甲基)苯基)苯磺酰胺(108mg,0.2mmol)溶于无水乙醇(2mL)和N,N-二异丙基乙胺(100μL,0.6mmol)中,向反应混合物中加入溴甲基环己烷(39mg,0.22mmol),油浴加热至回流,反应过夜。TLC检测原料反应完全后,将反应混合物减压旋干,残余物经硅胶柱层析和反相中压制备系统纯化得到目标化合物79mg,产率 62%。1H NMR(400MHz,CDCl3)δ8.17(dm,J=8.0Hz,2H),7.57-7.53(m,2H),7.49-7.47(m, 2H),7.44-7.36(m,3H),7.29-7.28(m,3H),3.44(s,2H),2.44-2.20(m,9H),1.80-1.65(m,7H), 1.25-1.17(m,3H),0.94-0.85(m,2H).MS(ESI)m/z:636.7[M+H]+.
实施例二十:化合物20的制备
2-氯-N-((2-氯苯基)磺酰基)-N-(3-((4-((四氢-2H-吡喃-2-基)甲基)哌嗪-1-基)甲基)苯基)苯磺酰胺的制备
参照实施例十九的合成路线。按实施例十九,以2-氯-N-((2-氯苯基)磺酰基)苯基)磺酰胺基)-N-(3-(哌嗪-1-亚甲基)苯基)苯磺酰胺(108mg,0.2mmol),N,N-二异丙基乙胺(100μL,0.6mmol),2-溴甲基四氢吡喃(39.4mg,0.22mmol)为原料得到目标化合物43.4mg,产率34.0%。1H NMR(400MHz,CDCl3)δ8.19(dm,J=8.0Hz,2H),7.60-7.56 (m,2H),7.52-7.50(m,2H),7.46-7.39(m,3H),7.30(m,3H),4.02-4.00(m,1H),3.60-3.41(m,4H),2.61-2.48(m,10H),1.87-1.85(m,1H),1.61-1.51(m,4H),1.33-1.30(m,1H).MS(ESI)m/z:637.5 [M+H]+.
实施例二十一:化合物21的制备
2-氯-N-((2-氯苯基)磺酰基)-N-(3-((4-((四氢-2H-吡喃-3-基)甲基)哌嗪-1-基)甲基)苯基)苯磺酰胺的制备
参照实施例十九的合成路线。按实施例十九,以2-氯-N-((2-氯苯基)磺酰基)苯基)磺酰胺基)-N-(3-(哌嗪-1-亚甲基)苯基)苯磺酰胺(108mg,0.2mmol),N,N-二异丙基乙胺(100μL,0.6mmol),3-溴甲基四氢吡喃(39.4mg,0.22mmol)为原料得到目标化合物20.7mg,产率16.2%。1H NMR(400MHz,CDCl3)δ8.18(dd,J=8.0,1.2Hz,2H),7.57- 7.53(m,2H),7.49-7.47(m,2H),7.43-7.37(m,3H),7.32-7.22(m,3H),3.96-3.83(m,2H),3.44-3.36(m,3H),3.15-3.10(m,1H),2.40-2.19(m,10H),1.85-1.83(m,2H),1.61-1.59(m,2H),1.21 (m,1H).MS(ESI)m/z:637.6[M+H]+.
实施例二十二:化合物22的制备
2-氯-N-((2-氯苯基)磺酰基)-N-(3-((4-((四氢-2H-吡喃-4-基)甲基)哌嗪-1-基)甲基)苯基)苯磺酰胺的制备
参照实施例十九的合成路线。按实施例十九,以2-氯-N-((2-氯苯基)磺酰基)苯基)磺酰胺基)-N-(3-(哌嗪-1-亚甲基)苯基)苯磺酰胺(108mg,0.2mmol),N,N-二异丙基乙胺(100μL,0.6mmol),4-溴甲基四氢吡喃(39.4mg,0.22mmol)为原料得到目标化合物50.7mg,产率39.7%。1H NMR(400MHz,CDCl3)δ8.18(dm,J=8.0Hz,2H),7.58-7.53 (m,2H),7.49-7.47(m,2H),7.44-7.37(m,3H),7.32-7.22(m,3H),3.98-3.94(m,2H),3.48-3.47(m,2H),3.41-3.35(m,2H),2.46-2.26(m,8H),1.78-1.67(m,5H),1.34-1.27(m,2H).MS(ESI)m/z: 637.6[M+H]+.
实施例二十三:化合物23的制备
2-氯-N-((2-氯苯基)磺酰基)-N-(3-((4-((四氢呋喃-2-基)甲基)哌嗪-1-基) 甲基)苯基)苯磺酰胺的制备
参照实施例十九的合成路线。按实施例十九,以2-氯-N-((2-氯苯基)磺酰基)苯基)磺酰胺基)-N-(3-(哌嗪-1-亚甲基)苯基)苯磺酰胺(108mg,0.2mmol),N,N-二异丙基乙胺(100μL,0.6mmol),2-(溴甲基)四氢呋喃(36.3mg,0.22mmol)为原料得到目标化合物46.9mg,产率37.5%。1H NMR(400MHz,CDCl3)δ8.17-8.15(dm,J=8.0Hz,2H),7.57- 7.53(m,2H),7.49-7.47(m,2H),7.43-7.36(m,3H),7.28-7.26(m,3H),4.12-4.06(m,1H),3.91-3.85(m,1H),3.78-3.72(m,1H),3.43(s,2H),2.61-2.44(m,8H),2.05-1.97(m,2H),1.90-1.81(m, 3H),1.53-1.43(m,1H).MS(ESI)m/z:623.7[M+H]+.
实施例二十四:化合物24的制备
2-氯-N-((2-氯苯基)磺酰基)-N-(3-((4-((四氢呋喃-3-基)甲基)哌嗪-1-基) 甲基)苯基)苯磺酰胺的制备
参照实施例十九的合成路线。按实施例十九,以2-氯-N-((2-氯苯基)磺酰基)苯基)磺酰胺基)-N-(3-(哌嗪-1-亚甲基)苯基)苯磺酰胺(108mg,0.2mmol),N,N-二异丙基乙胺(100μL,0.6mmol),3-(溴甲基)四氢呋喃(36.3mg,0.22mmol)为原料得到目标化合物93mg,产率74.4%。1H NMR(400MHz,CDCl3)δ8.18(dd,J=8.0,1.2Hz,2H),7.57-7.53 (m,2H),7.49-7.47(m,2H),7.43-7.36(m,3H),7.29-7.23(m,3H),3.89-3.81(m,2H),3.76-3.70(m, 1H),3.51-3.48(m,1H),3.44(s,2H),2.48-2.32(m,10H),2.06-1.98(m,1H),1.65-1.56(m,1H), 1.30(m,1H).MS(ESI)m/z:623.6[M+H]+.
实施例二十五:化合物25的制备
2-氯-N-((2-氯苯基)磺酰基)-N-(3-((4-(吡啶-2-基甲基)哌嗪-1-基)甲基)苯基)苯磺酰胺的制备
按照实施例六的步骤1-3合成中间体2-氯-N-((2-氯苯基)磺酰基)苯基)磺酰胺基)-N-(3-(哌嗪-1-亚甲基)苯基)苯磺酰胺。室温下,于10mL单口瓶中加入中间体2- 氯-N-((2-氯苯基)磺酰基)苯基)磺酰胺基)-N-(3-(哌嗪-1-亚甲基)苯基)苯磺酰胺 (162mg,0.3mmol),2-吡啶甲醛(70mg,0.6mmol),乙酸(72mg,1.2mmol)和二氯甲烷 (5mL),混合物在室温下搅拌反应1小时,加入三乙酰氧基硼氢化钠(96mg,0.45 mmol),继续反应过夜,TLC检测原料反应完全后,加入水(5mL)淬灭反应,分液,有机相用去离子水和饱和NaCl溶液洗涤,无水Na2SO4干燥,过滤,滤液减压除去溶剂,剩余混合物经硅胶柱层析纯化得到目标化合物40mg,产率21.1%。1H NMR(400MHz,CDCl3)δ 8.59-8.58(d,J=4.4Hz,1H),8.16(dd,J=8.0,1.2Hz,2H),7.70-7.66(m,1H),7.56-7.52(m,2H), 7.48-7.39(m,6H),7.29-7.27(m,3H),7.22-7.19(m,1H),3.76(m,2H),2.64-2.50(m,8H).MS (ESI)m/z:630.7[M+H]+.
实施例二十六:化合物26的制备
2-氯-N-((2-氯苯基)磺酰基)-N-(3-((4-(吡啶-3-基甲基)哌嗪-1-基)甲基)苯基)苯磺酰胺的制备
参照实施例二十五的合成路线。按实施例二十五,以2-氯-N-((2-氯苯基)磺酰基)苯基)磺酰胺基)-N-(3-(哌嗪-1-亚甲基)苯基)苯磺酰胺(162mg,0.3mmol),3-吡啶甲醛(70mg,0.6mmol),乙酸(72mg,1.2mmol),三乙酰氧基硼氢化钠(96mg,0.45 mmol)为原料得到目标化合物52mg,产率27.4%.1H NMR(400MHz,CDCl3)δ8.55-8.53(m, 2H),8.18(dd,J=8.0,1.6Hz,2H),7.74(m,1H),7.56-7.52(m,2H),7.48-7.40(m,5H),7.31-7.26 (m,4H),3.59-3.53(m,4H),2.56-2.51(m,8H).MS(ESI)m/z:630.7[M+H]+.
实施例二十七:化合物27的制备
2-氯-N-((2-氯苯基)磺酰基)-N-(3-((4-(吡啶-4-基甲基)哌嗪-1-基)甲基)苯基)苯磺酰胺的制备
参照实施例二十五的合成路线。按实施例二十五,以2-氯-N-((2-氯苯基)磺酰基)苯基)磺酰胺基)-N-(3-(哌嗪-1-亚甲基)苯基)苯磺酰胺(162mg,0.3mmol),4-吡啶甲醛(70mg,0.6mmol),乙酸(72mg,1.2mmol),三乙酰氧基硼氢化钠(96mg,0.45 mmol)为原料得到目标化合物93mg,产率49.1%.1H NMR(400MHz,CDCl3)δ8.55(d, J=6.0Hz,2H),8.17(dd,J=8.0,1.2Hz,2H),7.56-7.52(m,2H),7.48-7.40(m,5H),7.33-7.28(m, 5H),3.54(s,4H),2.52(m,8H).MS(ESI)m/z:630.7[M+H]+.
实施例二十八:化合物28的制备
参照实施例二十五的合成路线。按实施例二十五,以2-氯-N-((2-氯苯基)磺酰基)苯基)磺酰胺基)-N-(3-(哌嗪-1-亚甲基)苯基)苯磺酰胺(162mg,0.3mmol),3-吡咯甲醛(57mg,0.6mmol),乙酸(72mg,1.2mmol),三乙酰氧基硼氢化钠(96mg,0.45 mmol)为原料得到目标化合物。1H NMR(400MHz,DMSO-d6)δ11.02(brs,1H),7.97(s,2H), 7.77–7.64(m,5H),7.56(m,2H),7.35(s,2H),7.13(m,2H),6.78(s,1H),6.14(s,1H),4.01(s, 2H),3.43(s,2H),2.69-2.30(m,8H).MS(ESI)m/z:618.7[M+H]+.
实施例二十九:化合物29的制备
参照实施例二十五的合成路线。按实施例二十五,以2-氯-N-((2-氯苯基)磺酰基)苯基)磺酰胺基)-N-(3-(哌嗪-1-亚甲基)苯基)苯磺酰胺(162mg,0.3mmol),3-呋喃甲醛(58mg,0.6mmol),乙酸(72mg,1.2mmol),三乙酰氧基硼氢化钠(96mg,0.45 mmol)为原料得到目标化合物。1H NMR(400MHz,DMSO-d6)δ7.99(m,2H),7.83–7.51(m, 8H),7.36(s,2H),7.19-7.14(m,2H),6.47(s,1H),3.34(m,4H),2.26(m,8H).MS(ESI)m/z:619.6 [M+H]+.
实施例三十:化合物30的制备
参照实施例二十五的合成路线。按实施例二十五,以2-氯-N-((2-氯苯基)磺酰基)苯基)磺酰胺基)-N-(3-(哌嗪-1-亚甲基)苯基)苯磺酰胺(162mg,0.3mmol),3-噻吩甲醛(67mg,0.6mmol),乙酸(72mg,1.2mmol),三乙酰氧基硼氢化钠(96mg,0.45 mmol)为原料得到目标化合物。1H NMR(400MHz,DMSO-d6)δ7.99(d,J=8.2Hz,2H), 7.78-7.70(m,5H),7.66–7.51(m,3H),7.37(s,3H),7.19-7.13(m,2H),3.40(m,4H),2.31(m,8H). MS(ESI)m/z:635.6[M+H]+.
实施例三十一:化合物31的制备
2-氯-N-((2-氯苯基)磺酰基)-N-(3-((4-苯基哌嗪-1-基)甲基)苯基)苯磺酰胺的制备
步骤1:1-(3-硝基苄基)-4-苯基哌嗪的制备
按实施例一步骤1,以间硝基苯甲醛(453mg,3.0mmol),N-苯基哌嗪(535mg,3.3mmol),乙酸(720mg,12.0mmol),三乙酰氧基硼氢化钠(954mg,4.5mmol)为原料得到 1-(3-硝基苄基)-4-苯基哌嗪400mg,产率44.9%.MS(ESI)m/z:298.0[M+H]+.
步骤2:1-(3-氨基苄基)-4-苯基哌嗪的制备
按实施例一步骤4,以1-(3-硝基苄基)-4-苯基哌嗪(400mg,1.35mmol),锌粉(263mg,4.4mmol),甲酸铵(425mg,6.75mmol)为原料得到目标化合物1-(3-氨基苄基)-4-苯基哌嗪295.6mg,产率82.0%。MS(ESI)m/z:268.0[M+H]+.
步骤3:2-氯-N-((2-氯苯基)磺酰基)-N-(3-((4-苯基哌嗪-1-基)甲基)苯基) 苯磺酰胺的制备
按实施例一步骤6,以邻氯苯磺酰氯(171.3mg,0.812mmol),1-(3-氨基苄基)-4-苯基哌嗪(86.7mg,0.325mmol),三乙胺(228μL,1.625mmol)为原料得到目标化合物36.4mg,产率18.2%。1H NMR(400MHz,CDCl3)δ8.21(dd,J=8.0,1.2Hz,1H),7.61-7.57(m,2H),7.52-7.44(m,5H),7.39-7.30(m,5H),6.96-6.89(m,3H),3.65-3.27(m,6H),2.65(m,4H). MS(ESI)m/z:615.6[M+H]+.
实施例三十二:化合物32的制备
2-氟-N-(((2-氟苯基)磺酰基)-N-(3-((4-(四氢-2H-吡喃-4-羰基)哌嗪-1-基)甲基)苯基)苯磺酰胺的制备
步骤1:(4-(3-硝基苄基)哌嗪-1-基)(四氢-2H-吡喃-4-基)甲酮的制备
将按照实施例一步骤1至2反应得到的粗产物1-(3-硝基苄基)哌嗪(9.27g,41.9mmol)溶于二氯甲烷中,冰浴下依次加入三乙胺(63.8mL,459mmol),四氢-2H-吡喃-4- 羧酸(8.724g,67.04mmol),T3P(33.7mL,131.33mmol),滴加完毕后室温反应过夜, TLC确认反应完全后以饱和食盐水洗涤三次,有机相减压浓缩,残余物经硅胶柱层析纯化得到化合物(4-(3-硝基苄基)哌嗪-1-基)(四氢-2H-吡喃-4-基)甲酮12.0g,产率86.0%。
步骤2:(4-(3-氨基苄基)哌嗪-1-基)(四氢-2H-吡喃-4-基)甲酮的制备
室温条件下,将(4-(3-硝基苄基)哌嗪-1-基)(四氢-2H-吡喃-4-基)甲酮溶于甲醇,加入二氧化铂在氢气氛下催化反应过夜,柱层析得化合物(4-(3-氨基苄基)哌嗪-1-基)(四氢-2H-吡喃-4-基)甲酮1.61g,产率14.7%。
步骤3:2-氟-N-(((2-氟苯基)磺酰基)-N-(3-((4-(四氢-2H-吡喃-4-羰基)哌嗪-1-基)甲基)苯基)苯磺酰胺的制备
取(4-(3-氨基苄基)哌嗪-1-基)(四氢-2H-吡喃-4-基)甲酮(152.5mg,0.503mmol)溶于二氯甲烷,加入邻氟苯磺酰氯(0.245mL,2.01mmol)后滴加三乙胺(0.35 mL)搅拌,室温反应过夜,TLC检测反应完全后,加入甲醇(1mL)淬灭反应,将反应混合物减压除去溶剂,残余混合物经柱层析(DCM/MeOH=80/1)分离得到白色固体化合物2- 氟-N-(((2-氟苯基)磺酰基)-N-(3-((4-(四氢-2H-吡喃-4-羰基)哌嗪-1-基)甲基)苯基)苯磺酰胺59.6mg,产率:14.53%。1H NMR(400MHz,DMSO-d6)δ9.02(dd,J=4.8,1.4 Hz,2H),8.96(d,J=2.2Hz,2H),8.30(ddd,J=8.2,2.3,1.6Hz,2H),7.80(dd,J=8.1,4.9Hz, 2H),7.54–7.45(m,2H),7.12(dt,J=6.4,2.2Hz,1H),6.99(s,1H),3.84(dd,J=10.2,3.0Hz,2H), 3.48(d,J=20.6Hz,6H),3.38(td,J=11.5,2.3Hz,2H),2.93–2.81(m,1H),2.28(d,J=21.4Hz,4H),1.66–1.46(m,4H).MS(ESI)m/z:620.3[M+H]+.
实施例三十三:化合物33的制备
3-氟-N-(((3-氟苯基)磺酰基)-N-(3-((4-(四氢-2H-吡喃-4-羰基)哌嗪-1-基)甲基)苯基)苯磺酰胺的制备
参照实施例三十二的合成路线。按实施例三十二步骤3,以(4-(3-氨基苄基)哌嗪-1- 基)(四氢-2H-吡喃-4-基)甲酮(200.6mg,0.662mmol),间氟苯磺酰氯(0.180mL,1.32mmol),三乙胺(0.47mL)为原料得到目标化合物353.8mg,产率86.2%。1H NMR(400 MHz,DMSO-d6)δ7.92–7.65(m,6H),7.62(dd,J=8.2,2.1Hz,2H),7.52–7.39(m,2H),7.07 (dt,J=6.6,2.1Hz,1H),6.93(s,1H),3.84(dd,J=10.3,3.0Hz,2H),3.56–3.33(m,8H),2.93–2.79(m,1H),2.26(d,J=24.7Hz,4H),1.69–1.43(m,4H).MS(ESI)m/z:620.3[M+H]+.
实施例三十四:化合物34的制备
4-氟-N-(((4-氟苯基)磺酰基)-N-(3-((4-(四氢-2H-吡喃-4-羰基)哌嗪-1-基)甲基)苯基)苯磺酰胺的制备
参照实施例三十二的合成路线。按实施例三十二步骤3,以(4-(3-氨基苄基)哌嗪-1- 基)(四氢-2H-吡喃-4-基)甲酮(211.9mg,0.699mmol),对氟苯磺酰氯(0.272g,1.40mmol),三乙胺(0.49mL)为原料得到目标化合物275.9mg,产率63.7%。1H NMR(400 MHz,DMSO-d6)δ7.90(ddd,J=8.1,5.0,2.5Hz,4H),7.64–7.34(m,6H),7.13–6.97(m,1H), 6.88(s,1H),3.84(dd,J=10.4,3.1Hz,2H),3.55–3.33(m,8H),2.86(ddd,J=15.0,9.5,3.9Hz,1H),2.24(dd,J=8.2,3.9Hz,4H),1.67–1.42(m,4H),1.28–1.12(m,1H).MS(ESI)m/z:620.4[M+H]+.
实施例三十五:化合物35的制备
3-甲基-N-(3-((4-(四氢-2H-吡喃-4-羰基)哌嗪-1-基)甲基)苯基)-N-(间甲苯磺酰基)苯磺酰胺的制备
参照实施例三十二的合成路线。按实施例三十二步骤3,以(4-(3-氨基苄基)哌嗪-1- 基)(四氢-2H-吡喃-4-基)甲酮(214.2mg,0.707mmol),间甲苯磺酰氯(0.440mL,2.83mmol),三乙胺(0.50mL)为原料得到目标化合物136.8mg,产率31.6%。1H NMR(400MHz,DMSO-d6)δ9.02(dd,J=4.8,1.4Hz,2H),8.96(d,J=2.2Hz,2H),8.30(ddd,J=8.2, 2.3,1.6Hz,2H),7.80(dd,J=8.1,4.9Hz,2H),7.54–7.45(m,2H),7.12(dt,J=6.4,2.2Hz,1H), 6.99(s,1H),3.84(dd,J=10.2,3.0Hz,2H),3.48(d,J=20.6Hz,6H),3.38(td,J=11.5,2.3Hz, 2H),2.93–2.81(m,1H),2.28(d,J=21.4Hz,4H),1.66–1.46(m,4H).MS(ESI)m/z:612.3 [M+H]+.
实施例三十六:化合物36的制备
N-(吡啶-3-基磺酰基)-N-(3-((4-(四氢-2H-吡喃-4-羰基)哌嗪-1-基)甲基)苯基)吡啶-3-磺酰胺的制备
参照实施例三十二的合成路线。按实施例三十二步骤3,以(4-(3-氨基苄基)哌嗪-1- 基)(四氢-2H-吡喃-4-基)甲酮(217.7mg,0.719mmol),吡啶-3-磺酰氯(0.344mL,2.87mmol),三乙胺(0.50mL)为原料得到目标化合物166.2mg,产率39.5%。1H NMR(400 MHz,DMSO-d6)δ9.02(dd,J=4.8,1.4Hz,2H),8.96(d,J=2.2Hz,2H),8.30(ddd,J=8.2,2.3,1.6Hz,2H),7.80(dd,J=8.1,4.9Hz,2H),7.54–7.45(m,2H),7.12(dt,J=6.4,2.2Hz,1H),6.99 (s,1H),3.84(dd,J=10.2,3.0Hz,2H),3.48(d,J=20.6Hz,6H),3.38(td,J=11.5,2.3Hz,2H), 2.93–2.81(m,1H),2.28(d,J=21.4Hz,4H),1.66–1.46(m,4H).MS(ESI)m/z:585.7[M+H]+.
实施例三十七:化合物37的制备
2-氯-N-(5-氯-2-甲基-3-((4-(四氢-2H-吡喃-4-羰基)哌嗪-1-基)甲基)苯)-N-((2-氯苯基)磺酰基)苯磺酰胺的制备
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步骤1:1-(5-氯-2-甲基-3-硝基苄基)哌嗪的制备
按照实施例一的步骤1至2,以5-氯-2-甲基-3-硝基苯甲醛(1eq)和Boc-哌嗪(1.1eq)为起始原料合成中间体1-(5-氯-2-甲基-3-硝基苄基)哌嗪。
步骤2:(4-(3-氨基-5-氯-2-甲基苄基)哌嗪-1-基)(四氢-2H-吡喃-4-基)甲酮的制备
按照实施例三十二的步骤1至2,以1-(5-氯-2-甲基-3-硝基苄基)哌嗪为原料合成中间体(4-(3-氨基-5-氯-2-甲基苄基)哌嗪-1-基)(四氢-2H-吡喃-4-基)甲酮。
步骤3:2-氯-N-(5-氯-2-甲基-3-((4-(四氢-2H-吡喃-4-羰基)哌嗪-1-基)甲基)苯)-N-((2-氯苯基)磺酰基)苯磺酰胺的制备
按照实施例三十二的步骤3,以(4-(3-氨基-5-氯-2-甲基苄基)哌嗪-1-基)(四氢-2H-吡喃-4-基)甲酮(1eq)和邻氯苯磺酰氯(2.5eq)为原料得到目标化合物。1H NMR(400MHz,DMSO-d6)δ8.07(d,J=8.5Hz,2H),7.85–7.59(m,6H),7.47(s,1H),7.16(s,1H),3.80(s,2H),3.31(m,6H),2.83(m,2H),2.27(m,5H),1.98(s,3H),1.58–1.43(m,4H).MS(ESI) m/z:699.5[M+H]+.
实施例三十八:化合物38的制备
(S)-2-氯-N-((2-氯苯基)磺酰基)-N-(3-((3-甲基-4-(四氢-2H-吡喃-4-羰基)哌嗪-1-基)甲基) 苯基)苯磺酰胺的制备
参照实施例三十七的合成路线。以3-硝基苯甲醛(1eq)和(S)-1-N-Boc-2-甲基哌嗪 (1.1eq)为起始原料,经五步反应得到目标化合物。1H NMR(400MHz,DMSO-d6)δ7.98 (m,3H),7.74(m,4H),7.58(m,2H),7.34(m,2H),7.15(m,1H),4.49(s,1H),4.16(s,1H),3.81(m,3H),3.26(m,2H),2.79-2.43(m,5H),1.87(m,2H),1.48(m,3H),1.23-1.09(m,4H).
实施例三十九:化合物39的制备
2-氯-N-((2-氯苯基)磺酰基)-N-(3-((8-(四氢-2H-吡喃-4-羰基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)甲基)苯基)苯磺酰胺的制备
参照实施例三十七的合成路线。以3-硝基苯甲醛(1eq)和3,8-二氮杂双环[3.2.1]辛烷(1.1eq)为起始原料,经五步反应得到目标化合物。1H NMR(400MHz,DMSO-d6)δ 8.01(m,2H),7.78(m,4H),7.61(m,2H),7.36(m,2H),7.20(m,2H),4.37(m,2H),3.84(s,2H), 3.42(m,2H),3.23–3.13(m,1H),2.75(m,1H),2.43(m,3H),2.08-2.01(m,2H),1.81–1.53(m,8H)..MS(ESI)m/z:677.6[M+H]+.
实施例四十:化合物40的制备
2-氯-N-((2-氯苯基)磺酰基)-N-(3-(4-(四氢-2H-吡喃-4-羰基)哌嗪-1-基)-2,3-二氢-1H-茚- 5-基)苯磺酰胺的制备
参照实施例三十七的合成路线。以6-硝基-1-茚酮(1eq)和Boc-哌嗪(1.1eq)为起始原料,经五步反应得到目标化合物。1H NMR(400MHz,DMSO-d6)δ8.11(d,J=7.9Hz, 1H),7.91-7.55(m,7H),7.27(d,J=7.9Hz,1H),7.15-7.07(m,2H),4.31(d,J=8.4Hz,1H),3.94–3.75(m,2H),3.59–3.25(m,8H),2.94–2.70(m,3H),2.24(m,2H),2.03(s,3H),1.55(m,3H).MS(ESI)m/z:677.6[M+H]+.
实施例四十一:化合物41的制备
2-氯-N-((2-氯苯基)磺酰基)-N-(1-(4-(四氢-2H-吡喃-4-羰基)哌嗪-1-基)-2,3-二氢-1H-茚- 4-基)苯磺酰胺的制备
按照实施例三十七的合成路线。以4-硝基-1-茚酮(1eq)和Boc-哌嗪(1.1eq)为起始原料,经五步反应得到目标化合物。1H NMR(400MHz,DMSO-d6)δ8.26–7.99(m,2H), 7.89–7.60(m,6H),7.47–7.19(m,3H),4.35-4.32(m,1H),3.84(m,2H),3.51–3.37(m,8H), 2.88(m,1H),2.30(m,4H),1.82–1.52(m,6H).MS(ESI)m/z:677.6[M+H]+.
实施例四十二:化合物42的制备
2-氯-N-((4-氯苯基)磺酰基)-N-(3-((4-(环己烷羰基)哌嗪-1-基)甲基)苯基)苯磺酰胺的制备
参照实施例一的合成路线。按实施例一步骤5,以邻氯苯磺酰氯(134mg,0.64mmol),(4-(3-氨基苄基)哌嗪-1-基)(环己基)甲酮(162mg,0.54mmol),三乙胺(225 μL,1.6mmol)为原料得到中间体2-氯-N-(3-((4-(环己烷羰基)哌嗪-1-基)甲基)苯基)苯磺酰胺130mg,产率:50.6%,白色固体。MS(ESI)m/z:476.2[M+H]+。接着按实施例一步骤6,以对氯苯磺酰氯(168.8mg,0.8mmol),中间体2-氯-N-(3-((4-(环己烷羰基)哌嗪-1-基)甲基)苯基)苯磺酰胺(197mg,0.4mmol),三乙胺(276μL,2mmol)为原料得到目标化合物130mg,产率50%。1H NMR(400MHz,CDCl3)δ8.18(dd,J=8.0,1.2Hz, 2H),7.59-7.55(m,2H),7.50-7.41(m,5H),7.33-7.30(m,3H),3.55-3.49(m,5H),2.46-2.31(m, 4H),1.80-1.47(m,10H),1.31-1.25(m,2H).MS(ESI)m/z:649.6[M+H]+.
实施例四十三:化合物43的制备
3-(4-(3-((2-氯-N-((2-氯苯基)磺酰基)苯基)磺酰氨基)苄基)哌嗪-1-基)丙酸的制备
步骤1:3-(4-(3-((2-氯-N-((2-氯苯基)磺酰基)苯基)磺酰氨基)苄基)哌嗪-1-基)丙酸乙酯的制备
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参照实施例十九的合成路线。按实施例十九,以2-氯-N-((2-氯苯基)磺酰基)苯基)磺酰胺基)-N-(3-(哌嗪-1-亚甲基)苯基)苯磺酰胺(108mg,0.2mmol),N,N-二异丙基乙胺(100μL,0.6mmol),3-溴丙酸乙酯(40mg,0.22mmol)为原料得到目标化合物3- (4-(3-((2-氯-N-((2-氯苯基)磺酰基)苯基)磺酰氨基)苄基)哌嗪-1-基)丙酸乙酯99.4mg。
步骤2:3-(4-(3-((2-氯-N-((2-氯苯基)磺酰基)苯基)磺酰氨基)苄基)哌嗪-1-基)丙酸的制备
3-(4-(3-((2-氯-N-((2-氯苯基)磺酰基)苯基)磺酰氨基)苄基)哌嗪-1-基)丙酸乙酯99.4mg 溶于二氧六环和水5:1的混合液,加入NaOH(6.8mg,0.17mmol),常温下水解,TLC检测原料反应完全后,减压旋干二氧六环,用稀HCl调节pH,并用反相中压制备系统纯化得到目标化合物25mg,产率20.4%,白色固体。1H NMR(400MHz,DMSO-d6)δ8.00(dm,J=8.0Hz,2H),7.82-7.73(m,4H),7.61-7.58(m,2H),7.47-7.44(m,1H),7.37-7.25(m,3H),3.55(m,8H), 3.07(m,3H),2.82(m,3H).MS(ESI)m/z:611.7[M+H]+.
实施例四十四:化合物44的制备
3-(4-(3-((2-氯-N-((2-氯苯基)磺酰基)苯基)磺酰氨基)苄基)哌嗪-1-基)乙酸的制备
参照实施例四十三的合成路线。以2-氯-N-((2-氯苯基)磺酰基)苯基)磺酰胺基)-N-(3-(哌嗪-1-亚甲基)苯基)苯磺酰胺(108mg,0.2mmol),N,N-二异丙基乙胺 (100μL,0.6mmol),3-溴乙酸乙酯(40mg,0.22mmol)为原料得到目标化合物65mg,产率54.3%。1HNMR(400MHz,DMSO-d6)δ8.02(dm,J=8.0Hz,2H),7.83-7.74(m,4H),7.62- 7.59(m,2H),7.49-7.34(m,4H),3.40(m,8H),2.98(m,2H),2.77(m,2H).MS(ESI)m/z:597.6 [M+H]+.
对比实施例一:化合物45的制备
3-氯-N-(3-((4-(环己烷羰基)哌嗪-1-基)甲基)苯基)苯磺酰胺的制备
按实施例一步骤1-4得到中间体(4-(3-氨基苄基)哌嗪-1-基)(环己基)甲酮。室温下,间氯苯磺酰氯(68mg,0.32mmol)加入至含有中间体(4-(3-氨基苄基)哌嗪-1-基) (环己基)甲酮(81mg,0.27mmol)和吡啶(217μL,2.7mmol)的四氢呋喃溶液中,在室温下继续反应6小时。TLC检测反应完全后,加入水淬灭反应,乙酸乙酯萃取,合并有机相用去离子水和饱和NaCl溶液洗涤,无水Na2SO4干燥,过滤,滤液减压除去溶剂,剩余混合物经硅胶在层析纯化得到目标化合物70mg,产率:54.5%,白色固体。1H NMR(400MHz, CDCl3)δ7.78-7.77(m,1H),7.69-7.67(m,1H),7.55-7.51(m,1H),7.42-7.38(m,1H),7.27-7.24 (m,1H),7.13-7.09(m,3H),3.65-3.53(m,6H),2.47-2.39(m,5H),1.83-1.81(m,2H),1.74-1.71(m, 3H),1.59-1.50(m,2H),1.30-1.26(m,3H).MS(ESI)m/z:476.2[M+H]+.
对比实施例二:化合物46的制备
2-氯-N-(3-((4-(环己烷羰基)哌嗪-1-基)甲基)苯基)苯磺酰胺的制备
按对比实施例一,以邻氯苯磺酰氯(134mg,0.64mmol),(4-(3-氨基苄基)哌嗪 -1-基)(环己基)甲酮(162mg,0.54mmol)和吡啶(434μL,5.4mmol)为原料得到目标化合物130mg,产率:50.6%,白色固体。1H NMR(400MHz,CDCl3)δ7.99(dd,J=8.0,0.8 Hz,1H),7.52-7.44(m,2H),7.34-7.31(m,1H),7.20-7.14(m,2H),7.07-7.05(m,2H),3.60-3.49(m,6H),2.46-2.39(m,2H),2.29(m,2H),1.82-1.68(m,7H),1.56-1.47(m,2H),1.31-1.28(m,2H). MS(ESI)m/z:476.2[M+H]+.
性能测试:体外测定化合物的RORγt Dual FRET活性
对本发明的化合物采用双重荧光共振能量转移(Dual FRET)实验来测定化合物对RORγt蛋白受体的激动活性。该激动活性采用半数活化浓度(EC50)和最大激活百分率 (maxact%)来表示。
实验方法:
在384孔板(Greiner 78407)中,每孔加入10μL缓冲液(50mM氟化钠,50mM 3-(N-吗啉代)丙磺酸,pH 7.5,50μM 3-[(3-胆固醇氨丙基)二甲氨基]丙磺酸盐,0.1mg/mL牛血清白蛋白和10mM二硫苏糖醇)。铕标记的类固醇受体共激活因子1(SRC1)溶液是通过在测试缓冲液中加入适量的生物素化SRC和铕标记的链霉亲和素制备而成,最后浓度分别为27和3.3nM。别藻蓝素(APC)标记LBD的溶液是通过在测试缓冲液中加入适量的生物素化RORc-LBD和APC标记的链霉亲和素制备而成,两者最后浓度均为33nM。室温孵育15min之后,加入20倍过量的生物素以阻挡剩余的自由链霉亲和素。将不同浓度的受试化合物溶解在DMSO中,加到384孔板中,每孔0.1μL。然后将等体积的铕标记的SRC和APC标记的RORc-LBD混合,加到384孔板中,每孔10μL。室温孵育1h之后,在 ViewLux上读取数据,计算半数活化浓度EC50和最大激活百分率。
表1示出了本发明的实施例化合物1-44对RORγt的激动活性。
表1.实施例化合物1-44的RORγt Dual FRET活性测试结果
·测试结果为至少两次试验的平均值,LYC55716为阳性对照
表1的测定结果显示,本发明的双磺酰胺类衍生物化合物1-44对RORγt具有较好的激动活性,与现有技术中的药物cintirorgon(LYC-55716)同样对RORγt具有激动活性。
表2示出了作为对比实施例的单磺酰胺类衍生物化合物45-46对RORγt的活性。
表2.对比实施例化合物45-46的RORγt Dual FRET活性测试结果
·测试结果为至少两次试验的平均值,用负值表示最大抑制率
从表2可以看出,作为对比实施例的化合物45-46,对RORγt表现出反向激动(即抑制)活性,不能作为治疗肿瘤或癌症和免疫缺陷障碍等疾病的RORγt调节剂。
从表1和表2可以看出,本发明的双磺酰胺结构使得化合物具有RORγt激动活性,而作为对比例的单磺酰胺类衍生物化合物45和46表现出很强的RORγt抑制(反向激动) 活性,说明双磺酰胺结构是化合物保持RORγt激动活性的关键。
功能测试:测定化合物的RORγt GAL4细胞活性
对本发明的部分化合物采用双荧光素酶报告基因系统来测定化合物在细胞水平对 RORγt的激动活性。该激动活性采用半数活化浓度(EC50)和最大激动响应值(Emax%)这两个指标来表示。
荧光素酶报告基因系统是利用荧光素作为底物去检测荧光素酶活性的一种报告系统。原理是把荧光素报告基因的编码序列和基因表达调控序列融合形成一个嵌合的基因,从而在调控序列的控制下转录表达,然后利用表达的荧光素酶分解底物的状况来标定目的基因的表达状况。
实验方法:
将hRORγt LBD编码序列插入pBIND表达载体(Promega,E1581)中,以表达 ROR-Gal4结合域嵌合受体。将该表达载体和报告载体(携带稳定整合的Gal4启动子驱动的荧光素酶报告基因[luc2P/9XGal4 UAS/Hygro]的pGL4.35)共转染到HEK293T宿主细胞中。激动剂与相应的ROR-Gal4嵌合受体结合后,该嵌合受体与Gal4结合位点结合并刺激报告基因。在目前的反向激动剂中,激动剂将与核受体竞争性结合并激活报告基因的转录。按照 ATCC的建议,将HEK293T细胞在含有5%木炭处理过的FBS的DMEM组成的培养基中,在37℃,5%CO2气氛下进行培养。在测定之前,将细胞用PBS洗涤除去酚红,并将其悬浮在无酚红培养基中(无酚红DMEM含有5%的木炭处理过的FBS和青霉素-链霉素(10000 U/mL),达到适当的浓度)。6×106HEK293T细胞接种到100mm培养皿中,孵育16h,向Trans-IT试剂和Opti-MEM(Invitrogen)的试剂混合物中加入质粒DNA(0.5mg/mL储备液),含5mg RORγ质粒和5μgpGL4.35荧光素酶质粒,将混合物加入100mm培养皿中的细胞中孵育5-6小时,将测试化合物在DMSO中系列稀释至5-6剂量,使用LYC-55716用阳性对照和100%DMSO作为媒介物对照,使用Echo550将化合物(25nL)转移到384孔板中(白色不透明),然后以15,000个细胞/孔的浓度用苯酚将细胞接种到384孔板中含有 5%木炭处理过的FBS和0.25μM熊果酸的无红DMEM,将细胞在37℃,5%CO2下孵育16- 20小时。将25μLSteady-GloTM萤光素酶测定试剂添加到384孔板中。在平板振荡器上摇动平板(避开光线)5分钟。在Envision 2104读板器上记录发光值。EC50值通过剂量反应曲线的非线性回归分析计算。
表3.实施例化合物16和22的RORγt GAL4功能活性测试结果
从表3可以看出,本发明的双磺酰胺类衍生物化合物具有较好的细胞水平的RORγt 激动活性。
以上的具体实施方式对本发明的目的、技术方案和有益效果进行了进一步详细说明,应当理解的是,以上仅为本发明的一种具体实施方式而已,并不限于本发明的保护范围,在不脱离本发明的基本特征的宗旨下,本发明可体现为多种形式,因此本发明中的实施形态是用于说明而非限制,由于本发明的范围由权利要求限定而非由说明书限定,而且落在权利要求界定的范围,或其界定的范围的等价范围内的所有变化都应理解为包括在权利要求书中。凡在本发明的精神和原则之内的,所做出的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (10)
1.如下式化学结构通式I的双磺酰胺类衍生物或其药学上可接受的盐或溶剂化物:
其中,
基团A、B独立地选自取代或未取代的芳基、杂芳基、C3-C8环烷基、C3-C8杂环烷基或C3-C8氧代杂环烷基,所述取代基选自C1-C4烷基、C1-C4烷氧基、C1-C4卤代烷基、C1-C4卤代烷氧基、氰基或卤素;
R1、R2、R3独立地选自氢、C1-C4烷基、C1-C4卤代烷基或卤素;
R4、R5、R6独立地选自氢或C1-C4烷基;
R7选自取代或未取代的C1-C8烷基、C3-C8环烷基、C3-C8杂环烷基、C3-C8氧代杂环烷基、芳基、杂芳基、氰基或羧基,所述取代基选自C1-C4烷基、C1-C4烷氧基、C1-C4卤代烷基、C1-C4卤代烷氧基、氰基或卤素;
Q选自羰基、亚烷基、或者一个共价键。
2.根据权利要求1所述的双磺酰胺类衍生物或其药学上可接受的盐或溶剂化物,其特征在于,所述基团A、B独立地选自取代或未取代的苯基、2-吡啶基、3-吡啶基或4-吡啶基,所述取代基选自C1-C4烷基、C1-C4烷氧基、C1-C4卤代烷基、C1-C4卤代烷氧基、氰基或卤素,更优选地,所述取代基为甲基、三氟甲基或卤素。
3.根据权利要求1所述的双磺酰胺类衍生物或其药学上可接受的盐或溶剂化物,其特征在于,R1和R4连接成亚烷基,并与它们所连接的碳原子一起形成五元至七元脂环;或者,R2和R4连接成亚烷基,并与它们所连接的碳原子一起形成五元至七元脂环;或者,R5和R6连接成亚烷基,并和邻近的氮原子一起桥接成五元至七元含氮杂环。
4.根据权利要求1或3所述的双磺酰胺类衍生物或其药学上可接受的盐或溶剂化物,其特征在于,R1和R4连接成亚烷基,并与它们所连接的碳原子一起形成茚的结构,即或者,R2和R4连接成亚烷基,并与它们所连接的碳原子一起形成茚的结构,即或者,R5和R6连接成亚烷基,并和邻近的氮原子一起形成桥环结构3,8-二氮杂双环[3,2,1]辛烷,即/>
5.根据权利要求1所述的双磺酰胺类衍生物或其药学上可接受的盐或溶剂化物,其特征在于,R7选自取代或未取代的甲基、异丙基、环戊基、环己基、苯基、4-甲磺酰基苯基、吡啶基、吡咯基、呋喃基、噻吩基、吡咯烷基、四氢呋喃基、四氢吡喃基、二氧代四氢噻喃基或羧基,所述取代基选自C1-C4烷基、C1-C4烷氧基、C1-C4卤代烷基、C1-C4卤代烷氧基、氰基或卤素,更优选地,所述取代基为甲基、三氟甲基或卤素。
6.根据权利要求1-5任一项所述的双磺酰胺类衍生物或其药学上可接受的盐或溶剂化物,其特征在于,所述化合物选自如下化合物:
7.一种如权利要求1-6任一项所述的双磺酰胺类衍生物或其药学上可接受的盐或溶剂化物的制备方法,其特征在于,包括两种合成方案:
第一种合成方案:
反应条件:(a)NaBH(OAc)3,AcOH,DCM,室温,过夜;(b)盐酸/二氧六环,DCM,室温,2h;(c)酰氯(R7-COCl,产物中Q=羰基),DIEA,DCM,0℃至室温,2h;(d)羧酸(R7-COOH,产物中Q=羰基),HATU或T3P,DIEA或TEA,DCM,室温,过夜;(e)卤代烷(R7-亚烷基氯,产物中Q=亚烷基),DIEA,EtOH,回流,6h;(f)醛(R7CHO,产物中Q=亚烷基),NaBH(OAc)3,AcOH,DCM,室温,过夜;(g)Zn,HCOONH4,MeOH/H2O,回流,3h;(h)吡啶,THF,室温,6h;(i)TEA,DCM,室温,过夜;
反应过程:以3-硝基苯甲醛或酮为原料,在醋酸和三乙酰氧基硼氢化钠的作用下与Boc-哌嗪进行还原胺化反应,并用盐酸/二氧六环溶液脱Boc得到苄基哌嗪中间体,然后与不同的酰氯或羧酸进行酰胺缩合,或者与不同的卤代烷进行亲核取代,又或者与不同的醛进行还原胺化反应得到中间体(A),中间体(A)经锌粉和甲酸铵还原得到关键苯胺中间体(B);然后在磺酰氯作用下,经两步磺酰化或一步双磺酰化反应制得所述的目标化合物(I);
第二种合成方案:
反应条件:(a)NaBH(OAc)3,AcOH,DCM,室温,过夜;(b)Zn,HCOONH4,MeOH/H2O,回流,3h;(c)吡啶,THF,室温,6h;(d)TEA,DCM,室温,过夜;(e)盐酸/二氧六环,DCM,室温,2h;(f)酰氯(R7-COCl,产物中Q=羰基),DIEA,DCM,0℃至室温,2h;(g)羧酸(R7-COOH,产物中Q=羰基),HATU或T3P,DIEA或TEA,DCM,室温,过夜;(h)卤代烷(R7-亚烷基氯,产物中Q=亚烷基),DIEA,EtOH,回流,6h;(i)醛(R7CHO,产物中Q=亚烷基),NaBH(OAc)3,AcOH,DCM,室温,过夜;
反应过程:以3-硝基苯甲醛或酮为原料,在醋酸和三乙酰氧基硼氢化钠的作用下与Boc-哌嗪进行还原胺化反应,再经锌粉和甲酸铵还原得到苯胺中间体,然后在磺酰氯作用下经两步磺酰化反应,并用盐酸/二氧六环溶液脱Boc得到关键双磺酰胺中间体(C),关键中间体(C)与不同的酰氯或羧酸进行酰胺缩合,或者与不同的卤代烷进行亲核取代,又或者与不同的醛进行还原胺化反应制得所述的目标化合物(I)。
8.一种药物组合物,其特征在于,包括如权利要求1-6任一项所述的双磺酰胺类衍生物或其药学上可接受的盐或溶剂化物,以及药物上可接受的载体。
9.如权利要求1-6任一项所述的双磺酰胺类衍生物或其药学上可接受的盐或溶剂化物在制备用于预防或治疗与RORγt和/或Th17细胞分化相关的疾病的药物中的应用,所述疾病包括肿瘤或癌症、病毒感染和免疫缺陷障碍。
10.一种RORγt激动剂,其特征在于,包括如权利要求1-6任一项所述的双磺酰胺类衍生物或其药学上可接受的盐或溶剂化物。
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