CN109705033A - N-杂芳基磺酰胺类衍生物及制备和应用 - Google Patents
N-杂芳基磺酰胺类衍生物及制备和应用 Download PDFInfo
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- CN109705033A CN109705033A CN201910058859.0A CN201910058859A CN109705033A CN 109705033 A CN109705033 A CN 109705033A CN 201910058859 A CN201910058859 A CN 201910058859A CN 109705033 A CN109705033 A CN 109705033A
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- China
- Prior art keywords
- luorobenzyl
- base
- sulfonamide
- pyridin
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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- 238000002360 preparation method Methods 0.000 title claims abstract description 28
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- 101000994669 Homo sapiens Potassium voltage-gated channel subfamily A member 3 Proteins 0.000 claims abstract description 40
- 102100034355 Potassium voltage-gated channel subfamily A member 3 Human genes 0.000 claims abstract description 39
- 238000000034 method Methods 0.000 claims abstract description 20
- 150000003839 salts Chemical class 0.000 claims abstract description 16
- 208000023275 Autoimmune disease Diseases 0.000 claims abstract description 11
- 239000012453 solvate Substances 0.000 claims abstract description 7
- -1 alkyl amide Chemical class 0.000 claims description 88
- 150000003456 sulfonamides Chemical class 0.000 claims description 81
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 77
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 34
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 34
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 28
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- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 15
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- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 238000001212 derivatisation Methods 0.000 claims description 4
- UBUCGEQKZOBBLK-UHFFFAOYSA-N ethyl formate;piperazine Chemical compound CCOC=O.C1CNCCN1 UBUCGEQKZOBBLK-UHFFFAOYSA-N 0.000 claims description 4
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Abstract
本发明提供一种N‑杂芳基磺酰胺类衍生物及制备和应用,所述衍生物包括其药学上可接受的盐和/或溶剂合物。本发明经实验证实,提供的N‑杂芳基磺酰胺类衍生物能够特异性结合并抑制或降低钾通道Kv1.3的活性,可应用于治疗人或动物由Kv1.3钾通道异常激活引起的自身免疫性疾病。本发明提供的抑制剂还包括该化合物的药物组合物,以及用于制备此类化合物的方法。所述衍生物通式为:
Description
技术领域
本发明属于医药领域,涉及一种作为Kv1.3钾通道抑制剂的N-杂芳基磺酰胺类衍生物,及其制备方法,以及在制备治疗由Kv1.3介导的自身免疫性疾病药物中的应用。
背景技术
1984年DeCoursey和Matteson等人同时发现了一个电压门控钾通道,其在人体T淋巴细胞中表达(DeCoursey et al.Nature 1984,307:465-468;Matteson et al.Nature1984,307:468-471)。该钾通道于1990年被Grissmer等人正式鉴定为Kv1.3,也称KCNA3(Grissmer et al.PANS1990,87:9411-9415)。现已知Kv1.3是电压门控型钾离子通道Kv1家族的一个重要亚型,其广泛分布在机体组织中,包括人类T淋巴细胞中。通过调控钾离子浓度参与细胞的增殖、迁移、凋亡等多种生理病理过程[Toldi G.et al.Immunol Res.,2016,64(2):627-631]。
电压门控通道Kv1.3是由4个α亚基组成的4聚体,即由这些亚基组装成功能性通道,其中传导钾离子的孔穴位于4聚体的中心。每个亚基含有6个跨膜片段(S1-S6)、一个P环及膜内N-和C-末端。细胞膜的去极化由位于S4片段的4个精氨酸感应,然后导致通道被开放且引起构象改变。已知的Kv1.3肽类阻断剂均作用于膜外端的传导孔穴口,从而抑制其钾离子的传导功能[Chandy and Norton,Curr Opin Chen Biol,2017,38:97-107][Zhaoet.al.Toxins(Basel),2015,7:1749-1764]。
Kv1.3主要在T淋巴细胞表达,与钙激活的Kca3.1钾通道一起,防止细胞膜的去极化。当T细胞激活时,这些通道产生钾离子外流,并通过CRAC(Orai/Stim)通道,促进钙离子内流进入细胞质,以平衡抵消阳离子的流出。最终胞浆内钙离子的升高激活钙调磷酸酶(Calcineurin),导致活化T细胞的转录因子(NFAT)去磷酸化后转位到核内,促成RNA转录而产生一系列免疫激活的生物效应。所以,T细胞中的Kv1.3和Kca3.1通道是细胞膜信号复合体的一部分,即将膜外刺激信号偶联到T细胞内的信号联级传导[Chandy and Norton,CurrOpin Chem Biol,2017,38:97-107]。
据文献报道,当处激活状态时,幼稚T细胞和中央记忆T细胞(TCM)上调Kca3.1表达水平而Kv1.3的数量无显著性变化。相反,处激活状态的已终端分化的效应器记忆T细胞(TEM)和表达CD-45RA的效应器记忆T细胞(TEMRA)上调Kv1.3表达水平而不影响Kca3.1的表达量。因此,选择性地阻断Kca3.1能抑制幼稚T细胞和中央记忆T细胞(TCM)的增殖从而抑制相应的细胞因子产生。另一方面,选择性地阻断Kv1.3能抑制效应器记忆T细胞(TEM和TEMRA)的增殖和所对应的细胞因子的产生,也抑制T细胞的体内迁移,但不影响被Kca3.1通道所保护的幼稚T细胞和中央记忆T细胞(TCM)的功能[Cahalan and Chandy,Immunol Rev,2009,231:59-87][Wulff et al.J Clin Invest,2003,111:1703-1713]。
在自身免疫性疾病中,如多发性硬化症、类风湿性关节炎、I型糖尿病和银屑病等,其自身抗原特异性的幼稚T细胞能逃避免疫调节。通过同源自身抗原的反复刺激,这些细胞最终被分化成TEM和TEMRA细胞。故这些与疾病相关的自身反应性T细胞主要为TEM和TEMR细胞。根据其产生的细胞因子的种类,具体可以分为Th1和/或Th17等细胞[Beeton et al.PNAS2006,103:17414-17418]。在动物模型中,选择性地阻断Kv1.3通道或敲除Kv1.3基因能预防和治疗多种自身免疫性疾病,同时不损害具保护作用的幼稚T细胞和中央记忆T细胞(TCM)的免疫应答功能。实验证明,当Kv1.3完整时,TEM细胞激活后被转化成效应细胞,而缺乏Kv1.3时,这些TEM细胞激活后可转变为起抗原特异性抑制效应的细胞。这种可塑性极大地支持了基于Kv1.3通道的靶向治疗,即抑制有害的自身反应性TEM细胞和TEMRA细胞,同时,通过诱导具有自身抗原特异性抑制效应的细胞的产生,促进长期的免疫耐受性[Chandy andNorton,Curr Opin Chem Biol,2017,38:97-107]。
近些年来,已报道发现了数个Kv1.3的特异性肽类阻断剂(如SHK-186等)或小分子阻断剂(如PAP-1等),并用于治疗TEM细胞介导的自身免疫性疾病的动物模型的研究,如大鼠慢性多发性自身免疫性脑脊髓炎(EAE)、普利司坦诱导的关节炎、自发性自身免疫性糖尿病和肾小球肾炎。结果十分令人鼓舞。例如用SHK-186阻断Kv1.3能抵抗EAE的诱导发生并抑制IFN-γ和IL-17的产生,结果提示阻断Kv1.3可用于治疗多化性硬化症[Gocke et al,JImmunol 2012,188:5877-5886]。同样,在用卵清蛋白诱发的哮喘大鼠模型中,SHK-186能有效抑制Kv1.3高表达的Th2TEM细胞增殖和细胞因子的产生[Valverde et al,J Bone MinerRes 2004,19:155-164]。在自身免疫性肾小球基底膜肾炎的大鼠模型中,给大鼠腹腔内注射一个小分子Kv1.3阻断剂Psora-4,能显著减少蛋白尿和新月体肾小球,提示了Psora-4在治疗快速发展性肾小球肾炎具有重要作用[Hyodo et al,Am J Physial Renal Physiol2010,299:F1258-69]。另一个Kv1.3小分子阻断剂PAP-1应用于大鼠局部皮肤模型时,能有效地抑制过敏性接触性皮炎(ACD)[Azam et al,J Invest Dermatal 2007,127(6):1419-1427]。进一步在SCID小鼠银屑病异种移植模型的实验中,注射或皮肤局部应用PAP-1能够将病变表皮增生的厚度减少约50%,并将所浸润的CD3+淋巴细胞减少了85%,显著性地改善了银屑病症状[Kun clu-Raychaudhuri et al,J Antoimmun 2014,55:63-72]。值得一提的是,据最新报道,Kv1.3肽类阻断剂SHK-186(Dalazatide)和小分子阻断剂PAP-1均已被用于治疗银屑病的I/II期临床试验,证明了其在人体内应用的安全性及有效性,统计学结果显示对银屑病症状的改善率高达90%以上[Tarch et al,PLoS ONE 2017,12(7):1-19][Press Relase by Circassia,13August 2018]。
发明内容
本发明的一个目的是提供一种N-杂芳基磺酰胺类衍生物,具有通式(Ⅰ)或通式(Ⅱ)的化合物或其药学上可接受的盐或溶剂合物,
其中:
环A选自包含1-2个含O、N和S的取代五元或六元芳杂环,优选下列五元或六元芳杂环:
环B选自取代或无取代的包含1-2个选自O、N和S的五元或六元脂杂环基,所述取代的取代基选自Z和R4;其中环B优选下列含氧、氮的五元或六元脂杂环:
R1选自C1-6直链、支链烷基、环状烷基或卤代的C1-6直链、支链烷基,无取代或取代的苯基或包含1-2个氮原子的五元或六元芳杂环,苯环或芳杂环上取代为单取代、双取代或三取代,所述的取代基选自Ra基团;
Ra任选自H、卤素、硝基、氰基、C1-3烷基、C1-3烷氧基、-C-O-C-;
R2选自无取代或取代的苯基、包含1-2个选自O、N和S的五元或六元芳杂环,取代为单取代、双取代或三取代,所述的取代基选自Rb基团;
Rb任选自H、卤素、氰基、C1-3烷基、C1-3烷氧基、-C-O-C-;
R3选自H、氰基、三氟甲基、烷酰胺基;
R4选自H、卤素、=O、OH、NH2、甲酸酯基、氨基甲酸酯基、烷酰基、乙酸酯基、磺酰胺基、吡咯烷酮基、环丙基、氨基甲酰胺基,二甲基氨基乙氧基,烷酰氧基、烷酰胺基;E、W、X、Y、相同或不同,分别独立选自N、O、S或C;
Z选自O、S、NH、C=O或缺失;
除非另有说明,本文所述被任选取代的成分可以在任何化学上可能的位置被取代。
更具体地,本发明通式(I)或通式(II)化合物优选自如下化合物:
N-苄基-N-(6-(哌啶-1-基)吡啶-3-基)丙磺酰胺
N-(4-氟苄基)-N-(6-(哌啶-1-基)吡啶-3-基)丙磺酰胺
N-(6-(4,4-二氟哌啶-1-基)吡啶-3-基)-N-(4-氟苄基)丙磺酰胺
N-(4-氟苄基)-N-(6-吗啉基吡啶-3-基)丙磺酰胺
N-(4-氟苄基)-N-(6-(吡咯烷-1-基)吡啶-3-基)丙磺酰胺
N-(6-(哌啶-1-基)吡啶-3-基)-N-(吡啶-4-基甲基)丙磺酰胺
N-(6-(哌啶-1-基)吡啶-3-基)-N-(嘧啶-4-基甲基)丙磺酰胺
N-(6-(哌啶-1-基)吡啶-3-基)-N-((1-(三氟甲基)-1H-吡唑-3-基)甲基)丙磺酰胺
N-(4-氟苄基)-2-甲基-N-(6-(哌啶-1-基)吡啶-3-基)丙基-1-磺酰胺
3,3,3-三氟甲基-N-(4-氟苄基)-N-(6-(哌啶-1-基)吡啶-3-基)丙基-1-磺酰胺
N-(6-(哌啶-1-基)吡啶-3-基)-N-(吡啶-2-基甲基)苯磺酰胺
4-氟-N-(6-哌啶-1-基)吡啶-3-基-N-(嘧啶-4-基甲基)苯磺酰胺
4-氟-N-(4-氟苄基)-N-(6-吗啉基吡啶-3-基)苯磺酰胺
N-(1-(5-(N-(4-氟苄基)丙磺酰胺基)吡啶-2-基)吡咯烷-3-基)乙酰胺
N-(4-氟苄基)-N-(6-(4-乙酰氧基哌啶-1-基)吡啶-3-基)丙磺酰胺
N-(4-氟苄基)-N-(6-(4-乙酰氨基哌啶-1-基)吡啶-3-基)丙磺酰胺
1-(5-(N-(4-氟苄基)丙磺酰胺基)吡啶-2-基)哌啶-4-基)氨基甲酸乙酯
N-(4-氟苄基)-N-(6-(4-吡咯烷-1-酮)哌啶-1-基)吡啶-3-基)丙磺酰胺
N-(4-氟苄基)-N-(6-(4-(2-氧代吡咯烷-1-基)哌啶-1-基)吡啶-3-基)丙磺酰胺
1-(5-(N-(4-氟苄基)丙磺酰胺基)吡啶-2-基)-N,N-二甲基哌啶-4-磺酰胺
1-(5-(N-3-氟-4-甲氧基芐基)丙磺酰胺基)吡啶-2-基)哌啶-4-甲酸乙酯
N-(4-氟苄基)-N-(6-(4-氧代哌啶-1-基)吡啶-3-基)丙磺酰胺
N-(4-氟苄基)-N-(6-(4-氧代哌啶-1-基)吡啶-3-基)苯磺酰胺
N-(4-氟苄基)-N-(6-(4-氧代哌啶-1-基)吡啶-3-基)2,2-二甲基丙烷-1-磺酰胺
N-(4-氟苄基)-N-(6-(4-羟基哌啶-1-基)吡啶-3-基)丙磺酰胺
N-(4-((1-乙酰基哌啶-4-基)硫)-3-腈基苯基)-N-(4-氟苄基)苯磺酰胺
N-(4-氟苄基)-N-(6-(4-羟基哌啶-1-基)吡啶-3-基)2,2-二甲基丙烷-1-磺酰胺
N-(4-氟苄基)-N-(6-(4-乙酰氧基哌啶-1-基)吡啶-3-基)丙磺酰胺
N-苄基-N-(6-(哌嗪-1-基)吡啶-3-基)丙烷磺酰胺
4-(5-(N-(4-氟苄基)丙磺酰胺基)吡啶-2-基)哌嗪-4-甲酸乙酯
4-(5-(N-(4-氟苄基)丙磺酰胺基)吡啶-2-基)-N,N-二甲基哌嗪-1-甲酰胺
4-(5-(N-(4-氟苄基)丙磺酰胺基)吡啶-2-基)-N,N-二甲基哌嗪磺酰胺
N-(6-(4-乙酰基哌嗪-1-基)吡啶-3-基)-N-(4-氟苄基)丙磺酰胺
N-(4-氟苄基)-N-(6-(4-甲磺酰基)哌嗪-1-基)吡啶-3-基)丙磺酰胺
N-(6-(4-环丙基哌嗪-1-基)吡啶-3-基)-N-(4-氟苄基)丙烷-1-磺酰胺
N-(5-腈基-6-(哌啶-1-基)吡啶-3-基)-N-(4-氟苄基)丙基磺酰胺
N-(5-腈基-6-(哌啶-1-基)吡啶-3-基)-N-(吡啶-2-基甲基)苯磺酰胺
N-(5-腈基-6-(哌啶-1-基)哌啶-3-基)-N-(吡啶-2-基甲基)丙磺酰胺
N-(5-腈基-6-(哌啶-1-基)吡啶-3-基)-N-(4-甲氧基苄基)-4-氟苯磺酰胺
N-(4-氯苄基)-N-(5-腈基-6-吗啉基吡啶-3-基)丙磺酰胺
N-(5-腈基-6-吗啉基吡啶-3-基)-N-(4-氟苄基)-4-氟苯磺酰胺
N-(5-腈基-6-吗啉基吡啶-3-基)-N-(2,4-二氟苄基)-1-环丙基甲磺酰胺
N-(5-腈基-6-吗啉基吡啶-3-基)-N-(2-氟苄基)-2-甲基丙烷-1-磺酰胺
N-(5-腈基-6-吗啉基吡啶-3-基)-N-(4-氟苄基)丙磺酰胺
N-(5-腈基-6-(哌嗪-1-基)吡啶-3-基)-N-(4-氟苄基)-4-氟苯磺酰胺
N-(5-腈基-6-(哌嗪-1-基)吡啶-3-基)-N-(4-氟苄基)丙磺酰胺
4-(3-腈基-5-(N-(4-氟苄基)丙磺酰胺基)吡啶-2-基)哌嗪-1-甲酸乙酯
4-(3-腈基-5-(N-(4-氟苄基)丙磺酰胺基)吡啶-2-基)-N,N-二甲基哌嗪-1-甲酰胺
4-(3-腈基-5-(N-(4-氟苄基)丙磺酰胺基)吡啶-2-基)-N,N-二甲基哌嗪-1-磺酰胺
N-(6-(4-乙酰基哌嗪-1-基)-5-腈基吡啶-3-基)-N-(4-氟苄基)丙磺酰胺
N-(5-腈基-6-(4-(甲磺酰基)哌嗪-1-基)吡啶-3-基)-N-(4-氟苄基)丙磺酰胺
N-(4-氟苄基)-N-(2-(哌啶-1-基)嘧啶-5-基)丙磺酰胺
4-氟-N-(4-氟苄基)-N-(2-(哌啶-1-基)嘧啶-5-基)苯磺酰胺
1-环丙基-N-(4-氟苄基)-N-(2-(哌啶-1-基)嘧啶-5-基)甲磺酰胺
4-氟-N-(4-氟苄基)-N-(2-吗啉基嘧啶-5-基)苯磺酰胺
N-(4-氟苄基)-N-(2-吗啉基嘧啶-5-基)丙磺酰胺
N-(4-氟苄基)-N-(2-(哌嗪-1-基)嘧啶-5-基)丙磺酰胺
4-(5-(N-(4-氟苄基)丙磺酰胺基)嘧啶-2-基)哌嗪-1-甲酸乙酯
4-(5-(N-(4-氟苄基)丙磺酰胺基)嘧啶-2-基)-N,N-二甲基哌嗪-1-甲酰胺
4-(5-(N-(4-氟苄基)丙磺酰胺基)嘧啶-2-基)-N,N-二甲基哌嗪-1-磺酰胺
N-(2-(4-乙酰基哌嗪-1-基)嘧啶-5-基)-N-(4-氟苄基)丙磺酰胺
N-(4-氟苄基)-N-(2-(4-甲磺酰基)哌嗪-1-基)嘧啶-5-基)丙磺酰胺
N-(6-((1-乙酰基哌啶-4-基)氧)吡啶-3-基)-N-(4-氟苄基)丙烷磺酰胺
N-(6-((1-乙酰基哌啶-4-基)硫)吡啶-3-基)-N-(4-氟苄基)丙烷磺酰胺
N-(4-氟苄基)-N-(1-(哌啶-4-基)-1-H-吡唑-4-基)丙磺酰胺
N-(1-(1-乙酰哌啶-4-基)-1-H-吡唑-4-基)-N-(4-氟苄基)丙磺酰胺
N-(4-氟苄基)-N-(1-甲基-3-(哌啶-1-基)-1H-吡唑-5-基)丙磺酰胺
N-(4-氟苄基)-N-(1-甲基-2-(哌啶-1-基)-1-H-咪唑-4-基)丙磺酰胺
N-(4-氟苄基)-N-(2-(哌啶-1-基)噻唑-4-基)丙磺酰胺
及其上述化合物的药学上可接受的盐或溶剂合物。
本发明的另一个目的是提供具有通式(I)或通式(II)的化合物的制备方法,可以通过以下步骤实现;
1.具有通式(I)化合物的制备方法:
(1)当通式(I)的化合物中,环A为吡啶环或嘧啶环或R3-吡啶环,同时Z缺失时,其制备方法采用方案一,以环A为吡啶环作为实例说明:
2-卤代-5-硝基吡啶在碱性条件下与含氮五元或六元脂杂环(B环)缩合,将所得缩合物中的硝基在钯碳/和或氯化亚锡存在下还原成氨基;
氨基物进而分别与芳醛(选用取代苯甲醛、吡啶甲醛、嘧啶甲醛或N-三氟甲基吡唑甲醛)经还原胺化制得N-苄基衍生物,再经磺酰胺化制得目标分子;若所得磺酰胺分子B环上存在保护基时,再经脱保护基、末端羟基或胺基衍生化得到目标化合物。
也可以采用2-卤代-5-硝基吡啶先经硝基还原,进而经还原胺化,磺酰胺化,所得中间体再在碱性条件下与含O、N五元或六元脂杂环(B环)缩合制得目标分子;若所得缩合物分子B环上存在保护基时,再经脱保护基、末端羟基或胺基衍生化得到目标化合物。
正如对本领域技术人员而言是熟悉的,当环A为嘧啶环或R3-吡啶环,可采用方案一类似的方法制备通式(I)的化合物,仅是反应条件有所不同,具体参见实施例。
化合物1-62按照下列合成路线制备:
(2)当通式(I)的化合物中,环A为吡啶环,环B为哌啶,Z选自O、S、NH时,其制备方法采用方案二:
2-卤代-5-硝基吡啶在碱性条件下与N-取代4-羟基或4-巯基或4-氨基哌啶反应,再将硝基还原成氨基,进而经还原胺化,磺酰胺化得目标分子。
化合物63,64按照下列合成路线制备:
2.具有通式(II)的化合物的制备方法:
(1)具有通式(II)的化合物环A为吡唑,N-甲基吡唑,噻唑,咪唑时,其制备方法采用方案三:
氨基五元芳杂环衍生物经还原胺化,磺酰胺化制得目标分子;若所得磺酰胺化产物B环上有保护基时,再经脱保护基,进而在环上引入酰基得到目标化合物;
化合物65-69按照下列合成路线制备:
本发明的再一个目的是提供所述N-芳杂基磺酰胺类衍生物在制备治疗由Kv1.3介导的自身免疫性疾病药物中的应用。本发明化合物能够特异性结合并抑制或降低钾通道Kv1.3的活性。所述药物包含至少一种活性组分以及一种或多种药学上可接受的载体或赋形剂,所述的活性组分可以是本发明的N-杂芳基磺酰胺类化合物及其在药学上可接受的盐、溶剂合物中的任意一种或任意多种。
所述载体或赋形剂包括药学领域的常规稀释剂,填充剂,粘合剂,湿润剂,崩解剂,吸收促进剂,表面活性剂,吸附载体,润滑剂等,必要时还可以加入香味剂,甜味剂等。本发明药物可以制成片剂、胶囊、贴剂、乳剂、混悬剂、凝胶剂,粉剂、颗粒剂、口服液及注射剂等多种形式,上述各剂型的药物均可以按照药学领域的常规方法制备。
本发明采用本领域技术人员所熟知的方法可以制备本发明所述的N-杂芳基磺酰胺类化合物的盐。所述的盐可以是无机酸盐、有机酸盐等,所述的无机酸盐包括与氢卤酸(如氢氟酸、氢溴酸、氢碘酸、盐酸),硝酸,碳酸,硫酸,磷酸等形成相应的盐;所述的有机酸盐包括与苹果酸、L-苹果酸、D-苹果酸、枸橼酸、富马酸、草酸、乳酸、樟脑磺酸、L-樟脑磺酸、D-樟脑磺酸、对甲苯磺酸、甲磺酸、苯甲酸等形成相应的盐。
本发明还提供通式(I)和通式(II)所述的化合物、及其药学上可接受的盐或溶剂合物单独和/或与其他药物联合使用在制备Kv1.3抑制剂,特别是在制备治疗相关自身免疫性疾病中的应用。
Kv1.3钾通道已被视为是自身免疫性疾病治疗的重要靶点,因此,选择性Kv1.3钾通道抑制剂可用于治疗自身免疫性疾病。所述的自身免疫性疾病包括银屑病、银屑病性关节炎、变应性以及刺激性接触性皮炎、特应性皮炎、白癜风、类风湿性关节炎、I型糖尿病、多发性硬化、哮喘、肾小球肾炎、牙周疾病、睫状体扁平部炎、移植排斥、神经退行性变、肥胖症、高血压。
本发明通过实验证实,本发明中的大部分化合物可选择性抑制Kv1.3钾通道活性,可应用于治疗人或动物由Kv1.3钾通道异常激活引起的自身免疫性疾病的药物中。本发明提供的抑制剂还包括该化合物的药物组合物。
具体实施方式
本发明结合实施例作进一步的说明,以下实施例仅是说明本发明,而不是以任何方式限制本发明。
制备实施例1.N-苄基-N-(6-(哌啶-1-基)吡啶-3-基)丙磺酰胺(化合物1)的合成
步骤1. 5-硝基-2-(哌啶-1-基)吡啶(中间体1a)的合成
将2-溴-5-硝基吡啶(2.0g,9.8mmol)溶于四氢呋喃30mL中,加入碳酸钾(2.7g,19.7mmol)和哌啶(1.3g,14.8mmol),加热回流4h。反应结束后将反应液过滤,滤液浓缩,残留物用硅胶柱层析分离(PE:EA=4:1,v/v),得类白色固体1a,收率58.3%;ESI-MS:m/z=208[M+1]+。
步骤2. N-苄基-6-(哌啶-1-基)吡啶-3-胺(中间体1c)的合成
将1a(2.0g,9.6mmol)溶于醋酸20mL,加入10%钯碳0.2g,于30℃加氢还原1h。反应结束后,过滤,滤液直接投下步反应。
在滤液中加入苯甲醛(1.02g,9.6mmol),室温搅拌1h,然后降温至10℃左右,加入硼氢化钠(0.55g,14.4mmol),加完后保持此温度反应30min。将反应液倒入水中,碳酸钠溶液碱化,乙酸乙酯萃取,合并有机相,用饱和食盐水洗涤,无水硫酸钠干燥,过滤并减压浓缩,残留物用硅胶柱层析纯化(PE:EA=4:1,v/v),得到固体1c,两步收率68.0%;ESI-MS:m/z=268[M+1]+。
步骤3. N-苄基-N-(6-(哌啶-1-基)吡啶-3-基)丙磺酰胺(化合物1)的合成
将1c(1.74g,6.5mmol),溶于二氯甲烷20mL,再加入吡啶(2.83g,35.8mmol)和丙磺酰氯(0.93g,6.5mmol),室温反应6h。反应结束后将反应液倒入水中,用稀盐酸酸化,二氯甲烷萃取,合并有机相,饱和食盐水洗涤,无水硫酸钠干燥,过滤,减压浓缩,残留物用硅胶柱层析纯化(PE:EA=3:1,v/v),得到白色固体1,收率34.2%。1H NMR(500MHz,DMSO-d6)δ7.94(d,J=2.6Hz,1H),7.44(dd,J=9.1,2.6Hz,1H),7.33-7.20(m,5H),6.71(d,J=9.1Hz,1H),4.79(s,2H),3.47-3.45(m,4H),3.21-3.16(m,2H),1.82-1.73(m,2H),1.60-1.53(m,2H),1.51-1.47(m,4H),1.01(t,J=7.4Hz,3H);ESI-MS:m/z=374[M+1]+。
制备实施例2.化合物2-5的合成
步骤1.中间体2a-5a的合成
在一组平行反应瓶中,分别加入2-氯-5-硝基吡啶(2.5mmol),并均用四氢呋喃20mL溶解,再分别加入碳酸钾1.74g(12.62mmol)和相应的脂环胺(哌啶、4-二氟哌啶,吗啉、四氢吡咯,各9.47mmol),回流反应2h。反应结束后将反应液冷却至室温,减压过滤,滤液减压浓缩,残留物后用乙酸乙酯重结晶,得到固体物2a-5a。
步骤2.中间体2c-5c的合成
合成步骤参考实施案例1步骤2,只是2a-5a和对氟苯甲醛为原料制备化合物2c-5c。
表1.1中间体2a-5a,2c-5c的质谱数据
步骤3.化合物2-5的合成
合成步骤参考实施案例1步骤3,只是用2c-5c和丙磺酰氯为原料制备化合物2-5。
制备实施例3.化合物6-12的合成
步骤1.中间体6c-12c的合成
合成步骤参考实施案例1步骤1.只是2a和相应的芳醛/杂芳醛为原料制备化合物6c-12c
步骤2.化合物6-12的合成
合成步骤参考实施案例1步骤3.只是用6c-12c和相应的磺酰氯为原料制备化合物6-12。
制备实施例4. 4-氟-N-(4-氟苄基)-N-(6-吗啉基吡啶-3-基)苯磺酰胺(化合物13)的合成
合成步骤参考实施案例1步骤3.只是用4c和4-氟苯磺酰氯为原料制备化合物13。
制备实施例5.化合物14-20的合成
步骤1. N-(4-氟苄基)-2-氟-5-氨基吡啶(14a)的合成
将2-氟-5-氨基吡啶(0.09mol)溶于醋酸60mL,向其中加入4-氟苯甲醛(0.1mol),室温搅拌1h,将反应液冷却至10-15℃,加入氰基硼氢化钠(0.2mol),保温搅拌30min,然后用碳酸钠溶液碱化,乙酸乙酯萃取,有机层用无水硫酸钠干燥,过滤并减压浓缩,残留物用乙酸乙酯重结晶得到固体14a,收率75.6%;ESI-MS:m/z=221[M+1]+。
步骤2. N-(4-氟苄基)-N-(6-氟吡啶-3-基)丙磺酰胺(14b)的合成合成步骤参考实施案例1步骤3.只是用14a和丙磺酰氯为原料制备化合物14b,收率73.5%;ESI-MS:m/z=327[M+1]+。
步骤3.化合物14-20的合成通法
将14b(0.5mmol),相应的4-取代哌啶或取代四氢吡咯(0.55mmol),碳酸钾(1.3mmol)加入到DMF4mL中,升温至80℃反应2h,反应完后将反应液冷却至室温,加水稀释,乙酸乙酯萃取,饱和食盐水洗涤,无水硫酸钠干燥,过滤,浓缩,残留物用硅胶柱层析纯化(DCM:MeOH=15-20:1),得到固体物14-20。
表1.2化合物2-20的核磁及质谱数据
制备实施例6. 1-(5-(N-3-氟-4-甲氧基芐基)丙磺酰胺基)吡啶-2-基)哌啶-4-甲酸乙酯(化合物21)的合成
步骤1. N-(3-氟-4-甲氧基苄基)-2-氟-5-氨基吡啶(21a)的合成
合成步骤参考实施案例5.步骤1.只是用2-氟-5-氨基吡啶和3-氟-4-甲氧基苯甲醛为原料制备化合物21a,收率80.0%;ESI-MS:m/z=251[M+1]+。
步骤2. N-(3-氟-4-甲氧基苄基)-N-(6-氟吡啶-3-基)丙磺酰胺(21b)的合成
合成步骤参考实施案例5.步骤2.只是用21a和丙磺酰氯为原料制备化合物21b,收率70.5%;ESI-MS:m/z=357[M+1]+。
步骤3. 1-(5-(N-3-氟-4-甲氧基芐基)丙磺酰胺基)吡啶-2-基)哌啶-4-甲酸乙酯(化合物21)的合成合成步骤参考实施案例5.步骤3.只是用21b和哌啶-4-甲酸乙酯为原料制备化合物21,收率60.8%;1HNMR(500MHz,CDCl3)δ8.02(s,1H),6.97(m,2H),6.89(m,1H),6.80(d,J=7.5Hz,1H),6.69(d,J=7.5Hz,1H),4.73(s,1H),4.16(q,J=7.1Hz,2H),3.83(s,3H),3.14-3.02(m,6H),2.33(m,1H),1.98-1.69(m,6H),1.22(t,J=7.2Hz,3H),0.97(t,J=7.2Hz,3H);ESI-MS:m/z=494[M+1]+。
制备实施例7.化合物22-27的合成
步骤1. 8-(5-硝基吡啶-2-基)-1,4-二氧杂-8-氮杂螺[4.5]癸烷(22a)的合成
将2-氯-5-硝基吡啶(14.0g,88.0mmol)溶于四氢呋喃200mL中,加入碳酸钾(32.4g,234.4mmol)和1,4-二氧杂-8-氮杂螺[4.5]癸烷盐酸盐(150.8g,88.0mmol),回流反应12h。反应结束后将反应液冷却至室温,减压过滤,滤液浓缩,残留物用硅胶柱层析纯化(PE:EA=4:1,v/v),得到固体22a,收率62.1%;ESI-MS:m/z=266[M+1]+。
步骤2. N-(4-氟苄基)-6-(1,4-二氧杂-8-氮杂螺[4.5]癸-8-基)-3-氨基吡啶(22c)的合成
将22a(3.0g 11.3mmol)溶于甲醇100mL,加入10%钯碳0.6g,于30℃加氢还原1h。反应结束后减压过滤,滤液浓缩后直接投下步反应。将上述浓缩物溶于醋酸150mL,再加入对氟苯甲醛(1.8g,14.5mmol)和分子筛1.8g,室温搅拌1h,冷却至10~15℃,加入硼氢化钠(0.47g,12.4mmol),加完后保温反应0.5h,反应毕,将反应液慢慢加入冰的碳酸氢钠溶液中,乙酸乙酯萃取,合并有机相,用饱和食盐水洗涤,无水硫酸钠干燥,过滤并减压浓缩,残留物用硅胶柱层析纯化(PE:EA=4:1,v/v),得到固体物22c,两步收率33.2%;ESI-MS:m/z=344[M+1]+。
步骤3.中间体22d-24d的合成在三个平行反应瓶中,分别加入将22c(0.26g0.76mmol),二氯甲烷15mL,吡啶(0.32g4.14mmol)和相应的磺酰氯(1.12mmol),40℃反应10h。反应结束后将反应液倒入水中,用稀盐酸酸化,乙酸乙酯萃取,合并有机相,用饱和食盐水洗涤,无水硫酸钠干燥,过滤,减压浓缩,残留物用硅胶柱层析纯化(DCM:EA=10:1,v/v),分别得到中间体22d-24d。
步骤4.化合物22-24的合成
将22d-24d(各0.44mmol)分别溶于四氢呋喃6mL中,再分别加入10%稀硫酸6mL,室温反应12h。反应结束后将反应液倒入水中,碳酸钠溶液碱化,乙酸乙酯萃取,合并有机相,用饱和食盐水洗涤,无水硫酸钠干燥,过滤并减压浓缩,残留物用硅胶柱层析纯化(PE:EA=1.0-1.5:1,v/v),得到化合物22-24。
步骤5.化合物25-27的合成
将化合物22-24(各0.25mmol)分别溶于乙醇5mL中,再分别加入硼氢化钠(0.15mmol),室温反应6h。将反应液慢慢加入预先冷却的碳酸氢钠溶液中,乙酸乙酯萃取,合并有机相,先后用水洗,饱和食盐水洗,无水硫酸钠干燥,过滤并减压浓缩,残留物用硅胶柱层析纯化(PE:EA=3:1,v/v),得到化合物25-27。
表1.3化合物22-27的核磁及质谱数据
制备实施例8. N-(4-氟苄基)-N-(6-(4-乙酰氧基哌啶-1-基)吡啶-3-基)丙磺酰胺(化合物28)的合成
合成步骤:将化合物25(0.23g 0.56mmol)溶于二氯甲烷20mL,再加入三乙胺0.084g(0.83mmol)和乙酰氯(0.052g,0.67mmol),室温搅拌1h。反应结束后,有机层用饱和食盐水洗涤,无水硫酸钠干燥,过滤,减压浓缩,残留物用硅胶柱层析纯化(PE:EA=2:1,v/v),得化合物28,收率为61.2%。1HNMR(500MHz,CDCl3):δ8.01(d,J=2.0Hz,1H),7.37(dd,J=7.5,5.0Hz,2H),7.12(m,2H),6.80(d,J=7.5Hz,1H),6.67(d,J=7.5Hz,1H),5.22(m,1H),4.73(s,2H),3.24-3.00(m,6H),2.03(s,1H),1.87-1.62(m,6H),1.01(t,J=7.2Hz,3H);ESI-MS:m/z=450[M+1]+。
制备实施例9.化合物29-34的合成
步骤1. 4-(5-硝基吡啶-2-基)哌嗪-1-甲酸叔丁酯(29a)的合成
将2-溴-5-硝基吡啶(20.0g,98.0mmol)溶于四氢呋喃300mL,加入碳酸钾(27.0g,197.0mmol)和哌嗪-1-甲酸叔丁酯(27.5g,148.0mmol),加热回流4h。反应结束后将反应液过滤,滤液浓缩后用硅胶柱层析提纯(PE:EA=3:1,v/v),得到固体29a,收率60.3%;ESI-MS:m/z=309[M+1]+。
步骤2. 4-(5-((4-氟苄基)氨基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(29c)的合成
将29a(15.0g54.0mmol)溶于醋酸150mL,加入10%钯碳1.6g,于30℃加氢还原1h。反应结束后,减压过滤,滤液直接投下步反应,在滤液中加入4-氟苯甲醛(8.9g,72.0mmol),室温搅拌1h,然后降温至10℃左右,加入硼氢化钠(4.13g,108.0mmol),加完后保温反应30min。反应结束后将反应液倒入水中,碳酸钠溶液碱化,乙酸乙酯萃取,合并有机相,用饱和食盐水洗涤,无水硫酸钠干燥,过滤并减压浓缩,残留物用硅胶柱层析纯化(PE:EA=4:1,v/v),得到固体29c,两步收率65.0%;ESI-MS:m/z=387[M+1]+。
步骤3. 4-(5-(N-(4-氟代苄基)丙基磺酰胺基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(29d)的合成
将29c(12.0g,32.5mmol),溶于二氯甲烷100mL,再加入吡啶(14.15g,179.0mmol)和丙磺酰氯(4.65g,32.5mmol),室温反应6h。反应结束后将反应液倒入水中,用稀盐酸酸化,二氯甲烷萃取,合并有机相,饱和食盐水洗涤,无水硫酸钠干燥,过滤,减压浓缩,残留物用硅胶柱层析纯化(PE:EA=3:1,v/v),得29d,收率58.2%;ESI-MS:m/z=493[M+1]+。
步骤4. N-(4-氟苄基)-N-(6-(哌嗪-1-基)吡啶-3-基)丙烷-1-磺酰胺(29)的合成
将化合物29d(4.0g,7.5mmol)溶于DCM120mL中,向其中加入三氟乙酸(25.0g,215.5mmol),室温搅拌1h,用碳酸钠溶液碱化,二氯甲烷萃取,无水硫酸钠干燥,过滤,减压浓缩,残留物用硅胶柱层析纯化(DCM:MeOH=20:1,v/v),得到固体29,收率78.0%。
步骤5.化合物30-34的合成
将29(0.45mmol)溶于DCM5mL中,加入三乙胺(0.49mmol),冰浴冷却下,再加入氯甲酸乙酯(0.67mmol),保持此温度搅拌30分钟,室温搅拌1h,将反应液倒入5%碳酸钠水溶液中,分出有机层,水层用DCM提取,有机液用饱和NaCl溶液洗,无水Na2SO4于燥,减压浓缩,残留物用硅胶柱层析纯化(DCM:EtOH=15:1,v/v),得到化合物30。
化合物31-34按同法制备,只是分别用二甲氨基甲酰氯、二甲氨基磺酰氯、乙酰氯、甲磺酰氯替代氯甲酸乙酯。
制备实施例10.N-(6-(4-环丙基哌嗪-1-基)吡啶-3-基)-N-(4-氟苄基)丙烷-1-磺酰胺(化合物35)的合成
合成步骤参考实施案例9步骤1-3.只是用1-(环丙甲基)哌嗪替代哌嗪-1-甲酸叔丁酯制备化合物35。
表1.4化合物29-35的核磁及质谱数据
制备实施例11.N-(5-腈基-6-(哌啶-1-基)吡啶-3-基)-N-(4-氟苄基)丙基磺酰胺(化合物36)的合成
步骤1. 5-硝基-2-(哌啶-1-基)-3-腈基吡啶(36a)的合成
将2-溴-5-硝基-3-腈基吡啶(2.28g,10.0mmol)溶于四氢呋喃30mL,加入碳酸钾2.76g(20.0mmol)和哌啶1.3g(14.8mmol),加热回流4h。反应结束后将反应液过滤,滤液浓缩后用硅胶柱层析提纯(PE:EA=4:1,v/v),得中间体36a,收率60.3%;ESI-MS:m/z=233[M+1]+。
步骤2. 5-氨基-2-(哌啶-1-基)-3-腈基吡啶(36b)的合成
在反应瓶中加入36a(2.32g,10.0mmol),二水合氯化亚锡11.12g(49.3mmol)和无水乙醇110mL,回流反应1.5h,反应毕,将反应液冷却至室温,加入碳酸钠溶液碱化,抽滤,滤液用乙酸乙酯萃取,有机层用无水硫酸钠干燥,过滤,浓缩,残留物用乙酸乙酯重结晶得固体36b,收率68.3%;ESI-MS:m/z=203[M+1]+。
步骤3. 5-((4-4-氟苄基)氨基)-2-(哌啶-1-基)-3-腈基吡啶(36c)的合成
将36b(2.03g 10.0mmol)溶于醋酸10mL中,加入4-氟苯甲醛(1.6g,13.0mmol),室温搅拌1h,将反应液冷却至10-15℃,向其中加入硼氢化钠(0.4g,11.0mmol),保温反应10min,然后将反应液用碳酸钠溶液碱化,乙酸乙酯萃取,有机层用无水硫酸钠干燥,过滤,浓缩,残留物用乙酸乙酯重结晶,得中间体36c,收率85.0%;ESI-MS:m/z=311[M+1]+。
步骤4. N-(5-腈基-6-(哌啶-1-基)吡啶-3-基)-N-(4-氟苄基)丙基磺酰胺(化合物36)的合成
合成步骤参考实施案例5.步骤2.只是用36c和丙磺酰氯为原料制备化合物36,收率45.5%;1HNMR(500MHz,CDCl3):δ8.05(s,1H),7.67(s,1H),7.40(dd,J=7.5,5.0Hz,2H),7.08(dd,J=8.7,2.5Hz,2H),4.64(s,2H),3.74-3.65(m,4H),3.10(t,J=7.2Hz,2H),1.63-1.55(m,8H),1.00(t,J=7.2Hz,3H);ESI-MS:m/z=417[M+1]+。
制备实施例12.化合物37-39的合成
步骤1.中间体37a-39a的合成
合成步骤参考实施案例11.步骤3.只是用36b和2-吡啶甲醛或4-甲氧基苯甲醛为原料制备化合物37a-39a。
步骤2.化合物37-39的合成
合成步骤参考实施案例5.步骤2.只是用37a-39a分别和相应的磺酰氯反应制备化合物37-39。制备实施例13.化合物40-43的合成
步骤1.中间体40a的合成
合成步骤参考实施案例11.步骤1.只是用2-溴-5-硝基-3-腈基吡啶和吗啉为原料制备化合物40a,收率65.5%;ESI-MS:m/z=235[M+1]+。
步骤2.中间体40b的合成
合成步骤参考实施案例11.步骤2.只是用40a为原料制备化合物40b,收率63.5%;ESI-MS:m/z=204[M+1]+。
步骤3.中间体40c-44c的合成通法
合成步骤参考实施案例11.步骤3.只是用40c-44c和相应的磺酰氯为原料制备化合物40-44。
制备实施例14.化合物45,46的合成
步骤1. 4-(3-腈基.-5-硝基吡啶-2-基)哌嗪-1-甲酸叔丁酯(45a)的合成
合成步骤参考实施案例11.步骤1.只是用2-溴-5-硝基-3-腈基吡啶和哌嗪-1-甲酸叔丁酯为原料制备化合物45a,收率67.8%;ESI-MS:m/z=334[M+1]+。
步骤2. 4-(3-腈基-5-((4-氟苄基)氨基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(45c)的合成
合成步骤参考实施案例9.步骤2.只是用45a和4-氟苯甲醛为原料制备化合物45c,收率62.0%;ESI-MS:m/z=412[M+1]+。
步骤3.中间体45d,46d的合成
合成步骤参考实施案例9.步骤3.只是用45c分别与4-氟苯磺酰氯或丁磺酰氯反应制备化合物45d,46d。
步骤4.化合物45,46的合成
合成步骤参考实施案例9.步骤4.只是用45d,46d为原料分别制备化合物45,46。
制备实施例15.化合物47-51的合成
合成步骤参考实施案例9.步骤5.只是用46为原料分别与氯甲酸乙酯、二甲氨基甲酰氯、二甲氨基磺酰氯、乙酰氯、甲磺酰氯反应制备化合物47-51。
表1.4化合物37-51的核磁及质谱数据
制备实施例16.化合物52-54的合成
步骤1.N-(4-氟苄基)-2-(哌啶-1-基)-5-氨基嘧啶(52a)的合成
合成步骤参考实施案例1.步骤2.只是用5-氨基-2-(哌啶-1-基)嘧啶和4-氟苯甲醛为原料制备化合物52a;ESI-MS:m/z=287[M+1]+。
步骤2.化合物52-54的合成
合成步骤参考实施案例1.步骤3.只是用52a分别与丙磺酰氯、4-氟苯磺酰氯、环丙甲基磺酰氯反应制备化合物52-54。
制备实施例17.化合物55,56的合成
步骤1.N-(4-氟苄基)-2-吗啉基-5-氨基嘧啶(55a)的合成
合成步骤参考实施案例1.步骤2.只是用2-吗啉基-5-氨基嘧啶和4-氟苯甲醛为原料制备化合物55a;ESI-MS:m/z=289[M+1]+。
步骤2.化合物55,56的合成
合成步骤参考实施案例1.步骤3.只是用55a分别与4-氟苯磺酰氯、丙磺酰氯反应制备化合物55,56。
表1.5化合物52-56的核磁及质谱数据
制备实施例18.N-(4-氟苄基)-N-(2-(哌嗪-1-基)嘧啶-5-基)丙磺酰胺(化合物57)的合成
步骤1. 4-(5-硝基嘧啶-2-基)哌嗪-1-甲酸叔丁酯(57a)的合成
将2-氯-5-硝基嘧啶(2.5g,15.7mmol)溶于干燥DMF25mL中,加入哌嗪甲酸-1-叔丁酯(3.2g,17.2mmol),搅拌下再加入三乙胺(6.5mL,46.9mmol),加热到90℃反应10小时,减压蒸除溶剂,残留物加二氯甲烷(50mL)稀释,水洗,有机层用无水Na2SO4干燥,过滤,蒸除溶剂,残留物乙酸乙酯/石油醚重结晶,得57a,收率75.0%;ESI-MS:m/z=310[M+1]+。
步骤2. 4-(5-氨基嘧啶-2-基)哌嗪-1-甲酸叔丁酯(57c)的合成
将57a(2.1g,6.79mmol)溶于甲醇25mL,加入10%钯碳0.22g,于室温加氢还原3h。反应结束后,过滤,滤液直接投下步反应。在滤液中加入4-氟苯甲醛(0.58g,6.8mmol),室温搅拌1.5h,然后降温至10℃左右,加入硼氢化钠(0.55g,14.4mmol),保持此温度反应30min。将反应液倒入水中,10%碳酸钠溶液碱化,乙酸乙酯萃取,合并有机相,用饱和食盐水洗涤,无水硫酸钠干燥,过滤并减压浓缩,残留物用硅胶柱层析纯化(PE:EA=3:1,v/v),得到固体57c,两步收率63.0%;ESI-MS:m/z=388[M+H]+。
步骤3. 4-(5-(N-(4-氟苄基)丙磺酰胺基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯(57d)的合成
合成步骤参考实施案例1.步骤3.只是用57c和丙磺酰氯为原料制备化合物57d;ESI-MS:m/z=494[M+1]+。
步骤4. N-(4-氟苄基)-N-(2-(哌嗪-1-基)嘧啶-5-基)丙磺酰胺(化合物57)的合成
将57d(2.76g,5.6mmol)加入到二氧六环6mL中,冷至0℃,加入饱和氯化氢二氧六环溶液15mL,室温反应3小时,减压蒸除溶剂,残畄物用5%Na2CO3液调pH到8,二氯甲烷萃取,饱和食盐水洗,过滤,滤液无水Na2SO4干燥,过滤,蒸除溶剂,残留物用硅胶柱层析纯化(PE:EA=2.5:1,v/v),得化合物57,收率82.0%;1HNMR(500MHz,CDCl3):δ9.85(br,1H),8.14(s,2H),7.38(dd,J=7.5,5.0Hz,2H),7.07(m,2H),4.70(s,2H),3.30-3.21(m,4H),3.10(t,J=7.1Hz,2H),2.79-2.67(m,4H),1.68(m,2H),1.01(t,J=7.4Hz,3H);ESI-MS:m/z=394[M+1]+。
制备实施例19.化合物58-62的合成
合成步骤参考实施案例9.步骤5.只是用57为原料分别与氯甲酸乙酯、二甲氨基甲酰氯、二甲氨基磺酰氯、乙酰氯、甲磺酰氯反应制备化合物58-62。
制备实施例20.化合物63,64的合成
步骤1.化合物63a,64a的合成
将N-乙酰基4-羟基哌啶(0.72g,5.0mmol),溶于无水DMF10mL中,降温至0℃,加入60%氢化钠(0.24g,6.0mmol),保温搅拌0.5h,再加入2-溴-5-硝基吡啶(0.97g,4.8mmol),室温反应2h,将反应液倒入水中,乙酸乙酯萃取,饱和食盐水洗涤,无水硫酸钠干燥,过滤,减压浓缩,残留物用硅胶柱层析纯化(PE:EA=1:1,v/v),得到固体63a,收率59.8%;ESI-MS:m/z=266[M+1]+。
中间体64a用同法制备,只是用N-乙酰基4-巯基哌啶为原料,收率67.2;ESI-MS:m/z=282[M+1]+。
步骤2.化合物63a,64a的合成
合成步骤参考制备实施例18.步骤2.只是用63a,64a和4-氟苯甲醛为原料制备63c,64c。
步骤3.化合物63,64的合成
合成步骤参考实施案例1.步骤3.只是用63c,64c和丙磺酰氯为原料制备化合物63,64。
表1.6化合物58-64的核磁及质谱数据
制备实施例21.化合物65,66的合成
步骤1. 4-(4-硝基-1H-吡唑-1-基)哌啶-1-甲酸叔丁酯(65a)的合成
将4-硝基吡唑(0.56g,5.0mmol),4-羟基哌啶-1-甲酸叔丁酯(1.1g,5.5mmol),三苯基膦(1.97g,7.5mmol)溶于无水四氢呋喃20mL中,氮气保护下于0~5℃缓慢滴加DEAD(2.61g,7.5mmol)的THF溶液5mL,加毕,保温反应4h,反应完后加水20mL稀释,乙酸乙酯萃取,饱和食盐水洗涤,有机层用无水硫酸钠干燥,过滤并减压浓缩,残留物用硅胶柱层析纯化(PE:EA=1:1,v/v),得到固体物65a,收率85.0%;ESI-MS:m/z=297[M+H]+。
步骤2. 4-(4-((4-氟苄基)氨基)-1H-吡唑-1-基)哌啶-1-甲酸叔丁酯(65c)的合成
合成步骤参考制备实施例18.步骤2,只是用65a和4-氟苯甲醛为原料制备65c,收率40.9%;ESI-MS:m/z=375[M+1]+。
步骤3. 4-(4-(N-(4-氟苄基)丙磺酰胺基)-1H-吡唑-1-基)哌啶-1-甲酸叔丁酯(65d)的合成
合成步骤参考实施案例1.步骤3.只是用65c和丙磺酰氯为原料制备化合物65d,收率73.3%;ESI-MS:m/z=481[M+1]+。
步骤4. N-(4-氟苄基)-N-(1-(哌啶-4-基)-1H-吡唑-4-基)丙磺酰胺(化合物65)的合成
合成步骤参考实施案例18.步骤4.只是用65d为原料制备化合物65,收率83.2%。
步骤5. N-(1-(1-乙酰哌啶-4-基)-1H-吡唑-4-基)-N-(4-氟苄基)丙磺酰胺(化合物66)的合成合成步骤参考实施案例9.步骤5.只是用65和乙酰氯为原料制备化合物66,收率80.6%。
制备实施例22. N-(4-氟苄基)-N-(1-甲基-3-(哌啶-1-基)-1H-吡唑-5-基)丙磺酰胺(化合物67)的合成
步骤1. N-(4-氟苄基)-1-甲基-3-(哌啶-1-基)-1H-吡唑-5-胺(67a)的合成
将1-甲基-3-(哌啶-1-基)-1H-吡唑-5-胺(1.26g,7.0mmol)溶于甲醇20mL,再加入4-氟苯甲醛(0.58g,6.8mmol),室温搅拌1.5h,然后降温至10℃左右,加入硼氢化钠(0.55g,14.4mmol),保持此温度反应30min。将反应液倒入水中,10%碳酸钠溶液碱化,乙酸乙酯萃取,合并有机相,用饱和食盐水洗涤,无水硫酸钠干燥,过滤并减压浓缩,残留物用硅胶柱层析纯化(PE:EA=2:1,v/v),得到固体67a,收率63.0%;ESI-MS:m/z=289[M+1]+。
步骤2. N-(4-氟苄基)-N-(1-甲基-3-(哌啶-1-基)-1H-吡唑-5-基)丙磺酰胺(化合物67)的合成
合成步骤参考实施案例1.步骤3.只是用67a和丙磺酰氯为原料制备化合物67,收率53.0%
制备实施例23.化合物68,69的合成
步骤1.中间体68a,69a的合成
合成步骤参考实施案例22.步骤1.只是用1-甲基-2-(哌啶-1-基)-1H-咪唑-4-胺或2-(哌啶-1-基)噻唑-4-胺分别与4-氟苯甲醛反应制备68a,69a。
步骤2.化合物68,69的合成
合成步骤参考实施案例1.步骤3.只是用68a,69a分别与丙磺酰氯反应制备化合物68,69。
表1.7化合物65-69的核磁及质谱数据
实施例24生物学评估一、对Kv1.3的抑制活性的IonWorks全自动膜片钳测定
对于Kv1.3IonWorks测定的原理和方法参见施罗德等人的文献报道[Schroederet al.J Biomol Screen 2003,8(1):50-64]
1、细胞培养
化合物对Kv1.3抑制活性的评估使用稳定表达人体Kv1.3的CHO-K1重组细胞株(Charles River,California)。细胞在含有5%小牛血清F-12K培养液(Invitrogen,Carlsbad.CA)在37℃和含6%CO2的空气湿度条件的培养箱中培养。在IonWorks系统中使用之前,用凡尔赛(Versene)在37℃下处理粘附细胞6-7分钟,轻轻敲打培养瓶后,重新将细胞悬浮在PBS磷酸盐缓冲液,然后经50x g离心4分钟。在短暂的研磨后,最终将细胞以大约1x106/ml的密度重新悬浮在外部记录溶液中。
2、化合物测定板的准备
化合物经DMSO溶解后,在母板上制成300x倍的最终测定梯度浓度。最终测定的梯度浓度为0.00384,0.00192,0.096,0.048,0.24,1.2,6和30μM。将所有300x倍浓度的化合物DMSO原液转移到384-孔的化合物测定板,每孔放置2μl。将化合物测定板密封后在-80℃保存至测定当天。
测定当天,将化合物测定板在室温下解冻,经离心后,加入198μl的外部记录溶液(其成分为:130mM Na-Gluconate,20mM NaCl,4mM KCl,1mM MgCl2,1.8mM CaCl2,5mMGlucose和10mM HEPES,pH7.3)并充分混合。这步骤提供了化合物1:100的稀释。在IonWorks中加入细胞后进一步稀释1:3,故总稀释度为1:300。每个测定板上至少保留8个孔用于空白对照,即仅含0.3%DMSO,另外至少保留8个孔用于阳性对照,以检测细胞信号的特异性。用于阳性对照的化合物为氟西汀(Fluoxetine),在其最大阻断浓度(100μM)和次级最大阻断浓度(10μM)下进行测试。另外,在测试用的内部记录溶液(其成分为:100mM K-Gluconate,40mM KCl,1mM MgCl2,1mM EGTA和10mM HEPES,pH7.3)中含有最终浓度为200μg/ml的两性霉素B(Amphotericin B),以获得细胞内的电流通道。溶液的渗透压用蔗糖调节。
3、实验步骤和数据分析
实验步骤按照IonWorks Quattro系统(Molecular Devices,San Jose,CA)设定的程序进行。人体Kv1.3的电流经持续1秒钟的脉冲诱导至0毫伏(mV),共诱导四次。多脉冲之间维持-80毫伏的电位势,持续5秒钟。首先IonWorks Quattro系统起动前期电压施加程序,然后加入化合物并进行600秒钟的孵育。接下来起动后期电压施加程序,直至完成全部测试过程。在化合物加入前后均测量最大外向峰值电流以及测量在第四脉冲升至0毫伏时诱发的平均末端电流。将化合物加入后所测得的电流幅度除以化合物加入前的电流幅度,即可计算化合物对Kv1.3的抑制活性。
所有数据经IonWorks Quattro系统设置的数据过滤程序校正。其过滤标准为:封接质量>30MΩ,封接电阻下降<50%及电流幅度>200pA。
表2.1化合物对Kv1.3的抑制活性(全自动膜片钳法)
二、对Kv1.3的抑制活性的传统膜片钳测定
为了比较不同测定方法对化合物抑制活性的影响,同时采用传统膜片钳法测定了化合物3、4、9、19、33、36、44对于Kv1.3的抑制活性。传统膜片钳测定的原理和方法参见格里斯默尔等人的文献报道[Grissmer et al.Molecular Pharmacology 1994,45:1227-1234]
1、细胞培养
化合物对Kv1.3抑制活性的评估使用稳定表达人体Kv1.3的CHO-K1重组细胞株(Charles River,California)。细胞在含有5%小牛血清F-12K培养液(Invitrogen,Carlsbad.CA)在37℃和含6%CO2的空气湿度条件的培养箱中培养。
实验时,贴壁细胞放置在倒置显微镜下的记录室中。所有实验都在室温下进行。每个细胞都以自身为对照
2、化合物的测试
测试化合物的最终浓度均在当天配制,再溶于细胞外液。细胞外液(mM)为:NaCl,137;KCl,4;CaCl2,1.8;MgCl2,1;HEPES,10;glucose 10;pH 7.4(NaOH滴定)。所有测试化合物和对照化合物溶液均含0.3%DMSO。
化合物均采用利用自身重力的灌流系统进行灌流。化合物每个浓度至少测试两个细胞。在电流稳定后,再比较化合物使用前后的电流大小变化来计算化合物的阻断作用。阳性对照物使用1000μM 4-AP
3、电生理
将细胞转移到灌流槽中,用细胞外液进行灌流。细胞内液(mM)为:K-aspartate,130;MgCl2,5;EGTA 5;HEPES,10;pH 7.2(KOH滴定)。细胞内液分批少量储存于-80度冰箱,实验当天融化。电极用PC-10(Narishige,Japan)拉制。全细胞膜片钳记录,噪音用采样频率的五分之一进行过滤。
4、测试过程和结果分析
将细胞钳制在–80mV,然后用持续2秒方波去极化到0mV,以得到Kv1.3电流。这一程序每20秒重复一次。检测方波引发的最大电流,待其稳定后,灌流测试化合物,当反应稳定后,计算阻断的强度。
资料采集和分析使用pCLAMP 10(Molecular Devices,Union City,CA)。电流稳定指的是电流随时间变化在有限的范围内。电流稳定后的大小说明用来计算化合物在此溶度的作用。
表2.2部分化合物对Kv1.3的抑制活性(传统膜片钳法)
三、对Kv1.5的抑制活性的传统膜片钳测定
对于Kv1.5传统膜片钳测定的原理和方法参见格里斯默尔等人的文献报道[Grissmer et al.Molecular Pharmacology 1994,45:1227-1234]。
1、细胞培养
化合物对Kv1.5抑制活性的评估使用稳定表达人体Kv1.5的CHO-K1重组细胞。株(Charles River,California)。细胞在含有5%小牛血清F-12K培养液(Invitrogen,Carlsbad.CA)在37℃和含6%CO2的空气湿度条件的培养箱中培养。
实验时,贴壁细胞放置在倒置显微镜下的记录室中。所有实验都在室温下进行。每个细胞都以自身为对照
2、化合物的测试
测试化合物的最终浓度均在当天配制,再溶于细胞外液。细胞外液(mM)为:NaCl,137;KCl,4;CaCl2,1.8;MgCl2,1;HEPES,10;glucose 10;pH 7.4(NaOH滴定)。所有测试化合物和对照化合物溶液均含0.3%DMSO。
化合物均采用利用自身重力的灌流系统进行灌流。化合物每个浓度至少测试两个细胞。在电流稳定后,再比较化合物使用前后的电流大小变化来计算化合物的阻断作用。
阳性对照物使用1000μM 4-AP
3、电生理
将细胞转移到灌流槽中,用细胞外液进行灌流。细胞内液(mM)为:K-aspartate,130;MgCl2,5;EGTA 5;HEPES,10;pH 7.2(KOH滴定)。细胞内液分批少量储存于-80度冰箱,实验当天融化。电极用PC-10(Narishige,Japan)拉制。全细胞膜片钳记录,噪音用采样频率的五分之一进行过滤。
4、测试过程和结果分析
将细胞钳制在–80mV,然后用持续2秒方波去极化到20mV,以得到Kv1.5电流。这一程序每20秒重复一次。检测方波引发的最大电流,待其稳定后,灌流测试化合物,当反应稳定后,计算阻断的强度。
资料采集和分析使用pCLAMP 10(Molecular Devices,Union City,CA)。电流稳定指的是电流随时间变化在有限的范围内。电流稳定后的大小说明用来计算化合物在此溶度的作用。
表2.3部分化合物对Kv1.5的抑制活性(传统膜片钳法)
化合物编号 | Kv1.5(IC<sub>50</sub>,μM) | 化合物编号 | Kv1.5(IC<sub>50</sub>,μM) |
3 | 0.205 | 33 | 2.010 |
4 | 0.588 | 36 | 0.088 |
19 | 1.015 | 44 | 0.056 |
Claims (10)
1.一种N-杂芳基磺酰胺类衍生物,其特征在于,具有通式(I)或通式(II)的化合物或其药学上可接受的盐或溶剂合物,
其中:
环A选自包含1-2个含O、N和S的取代五元或六元芳杂环,所述取代的取代基选自和R3基团;
环B选自取代或无取代的包含1-2个选自O、N和S的五元或六元脂杂环基,所述取代的取代基选自Z和R4;
R1选自C1-6直链、支链烷基、环状烷基或卤代的C1-6直链、支链烷基,无取代或取代的苯基或包含1-2个氮原子的五元或六元芳杂环,苯环或芳杂环上取代为单取代、双取代或三取代,所述的取代基选自Ra基团;
Ra任选自H、卤素、硝基、氰基、C1-3烷基、C1-3烷氧基、-C-O-C-;
R2选自无取代或取代的苯基、包含1-2个选自O、N和S的五元或六元芳杂环,取代为单取代、双取代或三取代,所述的取代基选自Rb基团;
Rb任选自H、卤素、氰基、C1-3烷基、C1-3烷氧基、-C-O-C-;
R3选自H、氰基、三氟甲基、烷酰胺基;
R4选自H、卤素、=O、OH、NH2、甲酸酯基、氨基甲酸酯基、烷酰基、乙酸酯基、磺酰胺基、吡咯烷酮基、环丙基、氨基甲酰胺基,二甲基氨基乙氧基,烷酰氧基、烷酰胺基;
E、W、X、Y、相同或不同,分别独立选自N、O、S或C;
Z选自O、S、NH、C=O或缺失。
2.根据权利要求1所述的一种N-杂芳基磺酰胺类衍生物,其特征在于,其中环A选下列五元或六元芳杂环:
3.根据权利要求1所述的一种N-杂芳基磺酰胺类衍生物,其特征在于,其中环B选下列含氧、氮的五元或六元脂杂环:
4.通式(I)或通式(II)选自以下化合物:
N-苄基-N-(6-(哌啶-1-基)吡啶-3-基)丙磺酰胺
N-(4-氟苄基)-N-(6-(哌啶-1-基)吡啶-3-基)丙磺酰胺
N-(6-(4,4-二氟哌啶-1-基)吡啶-3-基)-N-(4-氟苄基)丙磺酰胺
N-(4-氟苄基)-N-(6-吗啉基吡啶-3-基)丙磺酰胺
N-(4-氟苄基)-N-(6-(吡咯烷-1-基)吡啶-3-基)丙磺酰胺
N-(6-(哌啶-1-基)吡啶-3-基)-N-(吡啶-4-基甲基)丙磺酰胺
N-(6-(哌啶-1-基)吡啶-3-基)-N-(嘧啶-4-基甲基)丙磺酰胺
N-(6-(哌啶-1-基)吡啶-3-基)-N-((1-(三氟甲基)-1H-吡唑-3-基)甲基)丙磺酰胺
N-(4-氟苄基)-2-甲基-N-(6-(哌啶-1-基)吡啶-3-基)丙基-1-磺酰胺
3,3,3-三氟甲基-N-(4-氟苄基)-N-(6-(哌啶-1-基)吡啶-3-基)丙基-1-磺酰胺
N-(6-(哌啶-1-基)吡啶-3-基)-N-(吡啶-2-基甲基)苯磺酰胺
4-氟-N-(6-哌啶-1-基)吡啶-3-基-N-(嘧啶-4-基甲基)苯磺酰胺
4-氟-N-(4-氟苄基)-N-(6-吗啉基吡啶-3-基)苯磺酰胺
N-(1-(5-(N-(4-氟苄基)丙磺酰胺基)吡啶-2-基)吡咯烷-3-基)乙酰胺
N-(4-氟苄基)-N-(6-(4-乙酰氧基哌啶-1-基)吡啶-3-基)丙磺酰胺
N-(4-氟苄基)-N-(6-(4-乙酰氨基哌啶-1-基)吡啶-3-基)丙磺酰胺
1-(5-(N-(4-氟苄基)丙磺酰胺基)吡啶-2-基)哌啶-4-基)氨基甲酸乙酯
N-(4-氟苄基)-N-(6-(4-吡咯烷-1-酮)哌啶-1-基)吡啶-3-基)丙磺酰胺
N-(4-氟苄基)-N-(6-(4-(2-氧代吡咯烷-1-基)哌啶-1-基)吡啶-3-基)丙磺酰胺
1-(5-(N-(4-氟苄基)丙磺酰胺基)吡啶-2-基)-N,N-二甲基哌啶-4-磺酰胺
1-(5-(N-3-氟-4-甲氧基芐基)丙磺酰胺基)吡啶-2-基)哌啶-4-甲酸乙酯
N-(4-氟苄基)-N-(6-(4-氧代哌啶-1-基)吡啶-3-基)丙磺酰胺
N-(4-氟苄基)-N-(6-(4-氧代哌啶-1-基)吡啶-3-基)苯磺酰胺
N-(4-氟苄基)-N-(6-(4-氧代哌啶-1-基)吡啶-3-基)2,2-二甲基丙烷-1-磺酰胺
N-(4-氟苄基)-N-(6-(4-羟基哌啶-1-基)吡啶-3-基)丙磺酰胺
N-(4-((1-乙酰基哌啶-4-基)硫)-3-腈基苯基)-N-(4-氟苄基)苯磺酰胺
N-(4-氟苄基)-N-(6-(4-羟基哌啶-1-基)吡啶-3-基)2,2-二甲基丙烷-1-磺酰胺
N-(4-氟苄基)-N-(6-(4-乙酰氧基哌啶-1-基)吡啶-3-基)丙磺酰胺
N-苄基-N-(6-(哌嗪-1-基)吡啶-3-基)丙烷磺酰胺
4-(5-(N-(4-氟苄基)丙磺酰胺基)吡啶-2-基)哌嗪-4-甲酸乙酯
4-(5-(N-(4-氟苄基)丙磺酰胺基)吡啶-2-基)-N,N-二甲基哌嗪-1-甲酰胺
4-(5-(N-(4-氟苄基)丙磺酰胺基)吡啶-2-基)-N,N-二甲基哌嗪磺酰胺
N-(6-(4-乙酰基哌嗪-1-基)吡啶-3-基)-N-(4-氟苄基)丙磺酰胺
N-(4-氟苄基)-N-(6-(4-甲磺酰基)哌嗪-1-基)吡啶-3-基)丙磺酰胺
N-(6-(4-环丙基哌嗪-1-基)吡啶-3-基)-N-(4-氟苄基)丙烷-1-磺酰胺
N-(5-腈基-6-(哌啶-1-基)吡啶-3-基)-N-(4-氟苄基)丙基磺酰胺
N-(5-腈基-6-(哌啶-1-基)吡啶-3-基)-N-(吡啶-2-基甲基)苯磺酰胺
N-(5-腈基-6-(哌啶-1-基)哌啶-3-基)-N-(吡啶-2-基甲基)丙磺酰胺
N-(5-腈基-6-(哌啶-1-基)吡啶-3-基)-N-(4-甲氧基苄基)-4-氟苯磺酰胺
N-(4-氯苄基)-N-(5-腈基-6-吗啉基吡啶-3-基)丙磺酰胺
N-(5-腈基-6-吗啉基吡啶-3-基)-N-(4-氟苄基)-4-氟苯磺酰胺
N-(5-腈基-6-吗啉基吡啶-3-基)-N-(2,4-二氟苄基)-1-环丙基甲磺酰胺
N-(5-腈基-6-吗啉基吡啶-3-基)-N-(2-氟苄基)-2-甲基丙烷-1-磺酰胺
N-(5-腈基-6-吗啉基吡啶-3-基)-N-(4-氟苄基)丙磺酰胺
N-(5-腈基-6-(哌嗪-1-基)吡啶-3-基)-N-(4-氟苄基)-4-氟苯磺酰胺
N-(5-腈基-6-(哌嗪-1-基)吡啶-3-基)-N-(4-氟苄基)丙磺酰胺
4-(3-腈基-5-(N-(4-氟苄基)丙磺酰胺基)吡啶-2-基)哌嗪-1-甲酸乙酯
4-(3-腈基-5-(N-(4-氟苄基)丙磺酰胺基)吡啶-2-基)-N,N-二甲基哌嗪-1-甲酰胺
4-(3-腈基-5-(N-(4-氟苄基)丙磺酰胺基)吡啶-2-基)-N,N-二甲基哌嗪-1-磺酰胺
N-(6-(4-乙酰基哌嗪-1-基)-5-腈基吡啶-3-基)-N-(4-氟苄基)丙磺酰胺
N-(5-腈基-6-(4-(甲磺酰基)哌嗪-1-基)吡啶-3-基)-N-(4-氟苄基)丙磺酰胺
N-(4-氟苄基)-N-(2-(哌啶-1-基)嘧啶-5-基)丙磺酰胺
4-氟-N-(4-氟苄基)-N-(2-(哌啶-1-基)嘧啶-5-基)苯磺酰胺
1-环丙基-N-(4-氟苄基)-N-(2-(哌啶-1-基)嘧啶-5-基)甲磺酰胺
4-氟-N-(4-氟苄基)-N-(2-吗啉基嘧啶-5-基)苯磺酰胺
N-(4-氟苄基)-N-(2-吗啉基嘧啶-5-基)丙磺酰胺
N-(4-氟苄基)-N-(2-(哌嗪-1-基)嘧啶-5-基)丙磺酰胺
4-(5-(N-(4-氟苄基)丙磺酰胺基)嘧啶-2-基)哌嗪-1-甲酸乙酯
4-(5-(N-(4-氟苄基)丙磺酰胺基)嘧啶-2-基)-N,N-二甲基哌嗪-1-甲酰胺
4-(5-(N-(4-氟苄基)丙磺酰胺基)嘧啶-2-基)-N,N-二甲基哌嗪-1-磺酰胺
N-(2-(4-乙酰基哌嗪-1-基)嘧啶-5-基)-N-(4-氟苄基)丙磺酰胺
N-(4-氟苄基)-N-(2-(4-甲磺酰基)哌嗪-1-基)嘧啶-5-基)丙磺酰胺
N-(6-((1-乙酰基哌啶-4-基)氧)吡啶-3-基)-N-(4-氟苄基)丙烷磺酰胺
N-(6-((1-乙酰基哌啶-4-基)硫)吡啶-3-基)-N-(4-氟苄基)丙烷磺酰胺
N-(4-氟苄基)-N-(1-(哌啶-4-基)-1-H-吡唑-4-基)丙磺酰胺
N-(1-(1-乙酰哌啶-4-基)-1-H-吡唑-4-基)-N-(4-氟苄基)丙磺酰胺
N-(4-氟苄基)-N-(1-甲基-3-(哌啶-1-基)-1H-吡唑-5-基)丙磺酰胺
N-(4-氟苄基)-N-(1-甲基-2-(哌啶-1-基)-1-H-咪唑-4-基)丙磺酰胺
N-(4-氟苄基)-N-(2-(哌啶-1-基)噻唑-4-基)丙磺酰胺
及其上述化合物的药学上可接受的盐或溶剂合物。
5.权利要求1或4所述通式(I)或通式(II)化合物的制备方法,其特征在于,通过以下步骤实现;
(1)通式(I)的化合物的制备方法:
(a)当通式(I)的化合物中,环A为吡啶环或嘧啶环或R3-吡啶环,同时Z缺失时,其制备方法以环A为吡啶环作为实例说明:
2-卤代-5-硝基吡啶在碱性条件下与含氮五元或六元脂杂环(B环)缩合,将所得缩合物中的硝基在钯碳/和或氯化亚锡存在下还原成氨基;氨基物进而与芳醛经还原胺化制得N-苄基衍生物,再经磺酰胺化制得目标分子;若所得磺酰胺分子B环上存在保护基时,再经脱保护基、末端羟基或胺基衍生化得到目标化合物。
或者采用2-卤代-5-硝基吡啶先经硝基还原,进而经还原胺化,磺酰胺化,所得中间体再在碱性条件下与含O、N五元或六元脂杂环(B环)缩合制得目标分子;若所得缩合物分子B环上存在保护基时,再经脱保护基、末端羟基或胺基衍生化得到目标化合物;
化合物1-62按照下列合成路线制备:
(b)当通式(I)的化合物中,环A为吡啶环,环B为哌啶,Z选自O、S、NH时,其制备方法通过以下步骤实现:
2-卤代-5-硝基吡啶在碱性条件下与N-取代4-羟基或4-巯基或4-氨基哌啶反应,再将硝基还原成氨基,进而经还原胺化,磺酰胺化得目标分子;
化合物63,64按照下列合成路线制备:
(2)通式(II)的化合物的制备方法:
(a)当通式(II)的化合物环A为吡唑,N-甲基吡唑,噻唑,咪唑时,其制备方法通过以下步骤实现:
氨基五元芳杂环衍生物经还原胺化,磺酰胺化制得目标分子;若所得磺酰胺化产物B环上有保护基时,再经脱保护基,进而在环上引入酰基得到目标化合物;
化合物65-69按照下列合成路线制备:
6.根据权利要求5所述的通式(I)或通式(II)化合物的制备方法,其特征在于,步骤(1)的(a)中所述芳醛选用取代苯甲醛、吡啶甲醛、嘧啶甲醛或N-三氟甲基吡唑甲醛。
7.权利要求1或4所述N-芳杂基磺酰胺类衍生物在制备治疗由Kv1.3介导的自身免疫性疾病药物中的应用,其特征在于,所述的自身免疫性疾病包括银屑病、银屑病性关节炎、变应性以及刺激性接触性皮炎、特应性皮炎、白癜风、类风湿性关节炎、I型糖尿病、多发性硬化、哮喘、肾小球肾炎、牙周疾病、睫状体扁平部炎、移植排斥、神经退行性变、肥胖症、高血压。
8.权利要求7所述的应用,其特征在于,所述药物包含至少一种活性组分以及一种或多种药学上可接受的载体或赋形剂,所述的活性组分是N-芳杂基磺酰胺类衍生物及其在药学上可接受的盐、溶剂合物中的任意一种或任意多种。
9.根据权利要求8所述的应用,其特征在于,所述的N-杂芳基磺酰胺类化合物的盐为无机酸盐、有机酸盐,所述的无机酸盐包括与氢卤酸,硝酸,碳酸,硫酸,磷酸形成的盐;所述的有机酸盐包括与苹果酸、L-苹果酸、D-苹果酸、枸橼酸、富马酸、草酸、乳酸、樟脑磺酸、L-樟脑磺酸、D-樟脑磺酸、对甲苯磺酸、甲磺酸、苯甲酸形成的盐;所述氢卤酸选用氢氟酸、氢溴酸、氢碘酸、盐酸。
10.根据权利要求8所述的应用,其特征在于,所述载体或赋形剂包括药学领域的常规稀释剂,填充剂,粘合剂,湿润剂,崩解剂,吸收促进剂,表面活性剂,吸附载体,润滑剂,香味剂,甜味剂,所述药物的剂型为片剂、胶囊、贴剂、乳剂、混悬剂、凝胶剂,粉剂、颗粒剂、口服液及注射剂。
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