CN107903245A - 一种化合物及其在制备治疗类风湿性关节炎药物中的应用 - Google Patents
一种化合物及其在制备治疗类风湿性关节炎药物中的应用 Download PDFInfo
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- CN107903245A CN107903245A CN201810033310.1A CN201810033310A CN107903245A CN 107903245 A CN107903245 A CN 107903245A CN 201810033310 A CN201810033310 A CN 201810033310A CN 107903245 A CN107903245 A CN 107903245A
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
Abstract
本发明公开了一种化合物式（Ⅰ），其中R选自或
Description
技术领域
本发明属于医药领域，涉及一种化合物及其在制备治疗类风湿性关节炎药物中的应用。
背景技术
类风湿性关节炎是以关节滑膜慢性炎症为主的自身免疫性疾病，可引起关节肿痛，继而导致软骨破坏，引起关节畸形，最终出现不同程度的残疾。如不给予适当治疗，通常会导致关节破坏和畸形，并且影响到患者的生活质量。
IL-12是近年发现的一种细胞炎症因子，主要由T、B淋巴细胞和单核-巨噬细胞产生，具有多种炎症作用，促进T淋巴细胞IFN-γ的产生，抑制IL-10、IL-11等的合成，并且对TH前体细胞的TH 1分化必不可少，IL-12还可直接促进B淋巴细胞增生、分化，分泌自身抗体，诱导自身免疫性疾病发生。IL-12是由p35和p40两个亚基组成的p70异二聚体。有研究表明：老年RA患者PBMC细胞上清液 IL-12水平高于正常对照组，活动期又明显高于静止期，这提示IL-12参与类风湿性关节炎的发病过程，并且与RA活动度存在着一定关系，进一步说明RA中PBMC存在异常活化，处于激活状态，合成IL-12增高。从活动期RA IL-12水平高于静止期IL-12水平更充分说明与PBMC本身异常有关。
发明内容
本发明的目的之一在于提供一种化合物，其结构如式（Ⅰ）所示，
，
其中R选自、或。
*表示成键位置。
本发明的另一目的在于提供一种化合物式（Ⅰ）的合成路线：
。
本发明的另一目的在于提供一种化合物式（Ⅰ）的合成路线的合成步骤如下：
1）在低温下向氢化钠的溶液中逐滴加入环己醇，搅拌30min后，再通过注射器滴加2,4,6-三氯-3-甲基吡啶的THF溶液，升至室温搅拌2-5小时，再冷却至0℃，加饱和氯化铵水溶液以终止反应。经升温、稀释、洗涤之后，分离、萃取，干燥，过滤、浓缩之后再经硅胶柱色谱的纯化，得到产品；
2）在三颈烧瓶中装入乙醇、水和4-丙基哌啶，冷却至约0℃，滴加2,4-二氯-6-（环己基氧基）-3-甲基吡啶，保持温度低于10℃。反应结束后，加冰水并搅拌，沉淀完全后滤出白色固体，经过洗涤、真空干燥，得4-氯-6-（环己基氧基）-3-甲基-2-（4-丙基哌嗪-1-基）吡啶；
3）在氮气吹扫下，将4-氯-6-（环己基氧基）-3-甲基-2-（4-丙基哌嗪-1-基）吡啶和一水合肼在二恶烷中的搅拌悬浮液煮沸，回流，经过后续处理得到6-（环己基氧基）-4-肼基-3-甲基-2-（4-丙基哌嗪-1-基）吡啶；
4）将6-（环己基氧基）-4-肼基-3-甲基-2-（4-丙基哌嗪-1-基）吡啶、相应的和催化量的乙酸在无水乙醇-乙酸乙酯混合物加热直至形成澄清溶液，反应完成后冷却至30℃并过滤。经过后续处理得到粗产品，后将其在无水乙醇溶液中继续加热回流冷却析晶得到纯度大于99.5%的最终产品。
进一步地，所述步骤1）中的低温是指0-10℃，优选0℃，反应时间为2-5小时，优选3小时。
进一步地，所述步骤1）中洗涤液用饱和碳酸氢钠水溶液和饱和硫代硫酸钠水溶液，还可以用水或者无水乙醇进行洗涤，优选饱和碳酸氢钠水溶液和饱和硫代硫酸钠水溶液。
进一步地，所述步骤3）中回流时间为4-8小时，优选回流5个小时。
本发明的另一目的在于提供一种化合物式（Ⅰ）在制备降低IL-12药物中的应用。
本发明的另一目的在于提供一种化合物式（Ⅰ）在制备预防和/或治疗类风湿性关节炎药物中的应用。
本发明没有对化合物式（Ⅰ）或包含化合物式（Ⅰ）的组合物的施用方式进行特别限制，代表性的施用方式包括（但并不限于）：口服、肠胃外（静脉内、肌肉内或皮下）、和局部给药。用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，化合物式（Ⅰ）与至少一种常规惰性赋形剂（或载体）混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：（a）填料或增容剂，例如淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；（b）粘合剂，例如羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；（c）保湿剂，例如甘油；（d）崩解剂，例如琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、碳酸钠；（e）缓溶剂，例如石蜡；（f）吸收加速剂，例如季胺化合物；（g）润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；（h）吸附剂，例如高岭土；（i）润滑剂，例如滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。
其中，胃肠道给药制剂是目前最为常见的用药形式，且实验操作方便，因此，本发明具体实施方式中采用灌胃给药进行化合物式（Ⅰ）的药效试验，但这并不表示，化合物式（Ⅰ）的用药形式仅限于胃肠道给药，本领域技术人员可以根据化合物式（Ⅰ）的物理化学性质，结合现代制剂技术和病患的实际需要，将其制备成注射剂、头皮吸收制剂、植入制剂等多种制剂，从而扩大其给药途径，并提高药物靶向性或有效避免不必要的毒副作用。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外，悬浮液可包含悬浮剂，例如乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。
本发明化合物可以单独给药，或者与其他药学上可接受的其他药物联合给药。
显然，根据本发明的上述内容，按照本领域的普通技术知识和手段，在不脱离本发明上述基本技术思想前提下，还可以做出其他多种形式的修改、替换或变更。
具体实施方式
实施例1：2,4-二氯-6-（环己基氧基）-3-甲基吡啶的合成
在0℃向氢化钠NaH（4.51g，0.188mmol，60wt％，在矿物油中）的THF（200mL）溶液中逐滴加入环己醇（15.6mL，0.15mol）。在0℃下搅拌30分钟后，通过注射器滴加2,4,6-三氯-3-甲基吡啶（化合物1）（26.52g，0.135mol）的THF（40mL）溶液。将反应混合物加热至室温并搅拌4小时。将反应冷却至0℃，缓慢加入饱和氯化铵水溶液以终止反应。使反应混合物升温至室温，用乙酸乙酯稀释，并用饱和碳酸氢钠水溶液和饱和硫代硫酸钠水溶液洗涤。将有机层分离并将水层用乙酸乙酯萃取两次。将合并的有机层用硫酸钠干燥，过滤并浓缩。通过柱色谱法（乙酸乙酯/己烷梯度）纯化，得到33.37g的2,4-二氯-6-（环己基氧基）-3-甲基吡啶（化合物2），产率为95%。1H-NMR (400 MHz, CDCl3) δ: 1.08-1.29(m, 5H), 1.58-1.71(m, 3H),1.90-1.98(m, 2H), 2.40(s, 3H), 4.19(m, 1H), 7.01(s, 1H). 13C-NMR (125 MHz,CDCl3) δ: 18.26, 24.60, 25.92, 30.44, 76.82, 116.48, 121.22, 146.78, 147.96,160.53.LC-MS(ESI, pos, ion) m/z: 260[M+H]。
实施例2：4-氯-6-（环己基氧基）-3-甲基-2-（4-丙基哌嗪-1-基）吡啶的合成
在配备有机械搅拌器、温度计和滴液漏斗的2L三颈烧瓶中装入乙醇（375mL），水（375mL）和4-丙基哌啶（19.08g，0.15mol），将所得溶液冷却（用冰盐浴）至约0℃，并将2,4-二氯-6-（环己基氧基）-3-甲基吡啶（26.02g，0.10mol）的乙酸乙酯（37.5mL）溶液在约20分钟内滴加，保持温度低于10℃。将滴液漏斗用乙酸乙酯（15mL）冲洗两次，将冲洗液转移到反应混合物中。通过TLC检查反应以确定何时反应完成。反应结束后，加入冰水（375mL），搅拌30分钟，使沉淀完全。滤出白色固体，用水洗涤6次（每次洗涤225mL），并在40-50℃下真空干燥，直到维持恒重的，得到产物4-氯-6-（环己基氧基）-3-甲基-2-（4-丙基哌嗪-1-基）吡啶，34.39g，产率为98％。1H-NMR (400 MHz, CDCl3) δ: 0.89(t, 3H), 1.13-1.42(m, 12H),1.61-1.77(m, 5H), 1.91-1.98(m, 2H), 2.40(s, 3H), 3.20-3.30(m, 2H), 3.37-3.46(m, 2H),4.20(m, 1H), 6.36(s, 1H). 13C-NMR (125 MHz, CDCl3) δ: 12.53, 14.20,20.79, 24.60, 25.92, 30.44, 31.06, 35.70,36.20, 47.28, 76.82, 102.35, 113.49,147.28, 158.64, 165.91.LC-MS(ESI, pos, ion) m/z: 351[M+H]。
实施例3：6-（环己基氧基）-4-肼基-3-甲基-2-（4-丙基哌嗪-1-基）吡啶的合成
在氮气吹扫下，将实施例2合成得到的4-氯-6-（环己基氧基）-3-甲基-2-（4-丙基哌嗪-1-基）吡啶（30.00g，0.085mol）和一水合肼（6.00g，0.10mol）在二恶烷（225mL）中的悬浮液煮沸，并回流5个小时。向反应混合物中加入冰水（400mL），并放置过夜。滤出产生的沉淀，用水洗涤3次（每次260mL），并在40-50℃下真空干燥直至恒重，得到6-（环己基氧基）-4-肼基-3-甲基-2-（4-丙基哌嗪-1-基）吡啶，18.26g，产率为62％。1H-NMR (400 MHz, CDCl3) δ:0.89(t, 3H), 1.13-1.41(m, 12H), 1.61-1.76(m, 7H), 1.90-1.98(m, 3H), 2.40(s,3H), 3.20-3.30(m, 2H), 3.37-3.46(m, 2H),4.19(m, 1H), 5.21(s, 1H). 13C-NMR (125MHz, CDCl3) δ: 11.50, 14.20, 20.79, 24.60, 25.92, 30.44, 31.06, 35.70, 36.20,47.28, 76.82, 85.95, 109.94, 147.44, 161.81,164.78.LC-MS(ESI, pos, ion) m/z:347[M+H]。
实施例4：(E)-4-（2-亚丁基肼基）-6-（环己基氧基）-3-甲基-2-（4-丙基哌嗪-1-基）吡啶的合成
.
将实施例3中合成得到的产物6-（环己基氧基）-4-肼基-3-甲基-2-（4-丙基哌嗪-1-基）吡啶（12.13g，0.035mol），丁醛（9.37g，0.13mol）和催化量的乙酸（0.67g，11mmol）在无水乙醇-乙酸乙酯混合物（1:1体积，各162mL）加热直至形成澄清溶液（55-75℃），TLC显示所有起始物质消耗完成（至少30分钟）。将反应混合物冷却至30℃并过滤。用乙醇-乙酸乙酯1:1混合物（各80mL）洗涤反应器和过滤器，将合并的滤液和洗涤液浓缩成具有约三分之一的初始溶剂体积的油状混合物。为了促进沉淀，将油性混合物搅拌至少2小时（或至多12小时）。滤出固体，用无水乙醇（每次115mL）洗涤两次并干燥。获得4-（2-亚丁基肼基）-6-（环己基氧基）-3-甲基-2-（4-丙基哌嗪-1-基）吡啶为纯度大于98％的灰白色或无色固体（13.6g，产率97％）。为了获得更高纯度，将4-（2-亚丁基肼基）-6-（环己基氧基）-3-甲基-2-（4-丙基哌嗪-1-基）吡啶（13.6g，0.034mol）的无水乙醇（400mL）溶液加热至回流并回流直至形成澄清溶液。在减压下从溶液中蒸出约200mL的乙醇，在室温下搅拌至沉淀结束（约3小时）。滤出沉淀物，用乙醇（100mL）洗涤两次，并在40-50℃下真空干燥至恒重，得到4-（2-亚丁基肼基）-6-（环己基氧基）-3-甲基-2-（4-丙基哌嗪-1-基）吡啶，其为纯度大于99.5％的无色固体（13.2g，90％产率）。1H-NMR (400 MHz, CDCl3) δ: 0.89(m, 3H), 0.94(m, 3H), 1.13-1.46(m, 12H), 1.59-1.73(m, 7H), 1.90-1.98(m, 2H), 2.19(q, 2H), 2.40(s, 3H),3.21-3.30(m, 2H), 3.36-3.45(m, 2H),4.19(m, 1H), 5.21(s, 1H),5.92(t, 1H), 7.95(s, 1H). 13C-NMR (125 MHz, CDCl3) δ: 11.50, 12.96, 14.20, 20.76,20.79, 24.60,25.92, 30.44, 31.06, 31.66, 35.70, 36.20, 47.28, 76.82, 92.47, 109.06,140.78, 152.74, 160.35,164.49.LC-MS(ESI, pos, ion) m/z: 401[M+H]。
试验例1：体外抑制IL-12实验
一、THP-1 细胞培养
细胞培养：THP-1是人外周血的单核细胞系，THP-1细胞培养于含有10%FBS+1%P/S的RPMI-1640培养基中，培养环境为37℃，5%CO2。可以每隔3-4天加一些新鲜的培养基，或直接传代。
二、细胞处理
将THP-1细胞加入IFN-γ（100U/mL）预处理22小时，在不同浓度待测化合物存在下加入金黄色葡萄球菌（0.03%，质量分数）进行刺激，18小时后，1000×g 离心20分钟，取上清。
三、IL-12检测
采用人白细胞介素12p70（IL-12）检测试剂盒（上海康朗生物科技有限公司 商品名为Abcam）测定。本试剂盒运用双抗体夹心ELISA法定量测定人血清、血浆、组织匀浆、细胞裂解液、细胞培养上清液和其他生物液体中白细胞介素12p70（IL-12）含量。具体使用和计算方法详见说明书。
四、实验结果
本发明化合物的IC50见下表：
| 不同R基团的式（Ⅰ） | IC50（nM） |
| 63 | |
| 72 |
试验例2：体内抗类风湿性关节炎效果
胶原诱导类风湿性关节炎模型(collagen-induced rheumatoid arthritis，CIA)是目前国际上公认的关节炎模型，主要用于研究类风湿性关节炎发病机制和治疗药物筛选的研究。
一、实验分组、模型建立及给药方案
成年雄性180～220g SD大鼠，按体重随机分组，每组8只，自由饮食、进水。组别为空白组、模型组、阳性药组和若干待测药物组，空白组：不予任何处理；模型组：将牛II型胶原蛋白醋酸溶液与等容量的弗氏不完全佐剂混合，充分乳化，第0天，SD大鼠尾根进行皮内注射(1mg/ml)，每只0.1ml；7日后加强免疫，第15日造成RA动物模型；阳性药组：自第16日起，每日1次地塞米松（0.05mg/kg）灌胃给药，连续给药30d；待测药物组：自第16日起，每日1次待测药物（2mg/kg）灌胃给药，连续给药30d。
二、监测事项
1、TNF-α、IL-12水平检测
在末次给药次日，大鼠尾部静脉取血，置冰浴30min后，以2000r/min离心15min，取上清，用ELISA法测定大鼠血清中TNF-α、IL-12水平，大鼠血清TNF-α、IL-12的ELISA试剂盒均购自美国Sigma公司。
2、形态学观测
给药过程中，大鼠关节肿胀程度和足趾肿胀程度。
三、实验结果
采用SPSS14.0对两组数据进行两样本t检验统计学分析，P<0.05时认为差异有统计学意义。
大鼠血清中TNF-α、IL-12水平（mean±SD，n＝8）
| 组别 | TNF-α（pg/mL） | IL-12（pg/mL） |
| 空白组 | 53.5±4.6 | 22.4±0.8 |
| 模型组 | 96.3±6.7 | 43.6±1.3 |
| 阳性药组 | 62.4±5.4* | 29.4±1.2* |
| 待测药物组实施例4 | 76.4±5.7* | 31.7±1.8* |
注：*表示与模型组比较P<0.05。
上表可以看出，阳性药物组和实施例4的待测药物组TNF-α和IL-12的水平较模型组均显著性降低，而且实施例4的待测药物组TNF-α和IL-12的水平高于阳性药物组。形态学观测发现阳性药物组和实施例4的待测药物组对大鼠关节肿胀程度和足趾肿胀程度均有不同程度的降低。
综上所述，本发明化合物式（Ⅰ）能够体外抑制IL-12的产生，并且在SD大鼠胶原诱导类风湿性关节炎模型中表现出了优秀的活性。说明本发明化合物式（Ⅰ）可以作为制备预防/治疗类风湿性关节炎的候选药物进行更加深入的研发。
Claims (4)
1.一种化合物，其结构如式（Ⅰ）所示，
，
其中R选自或。
2.如权利要求1所述的化合物式（Ⅰ）的合成路线为：
。
3.如权利要求1所述的化合物式（Ⅰ）在制备降低IL-12药物中的应用。
4.如权利要求1所述的化合物式（Ⅰ）在制备预防和/或治疗类风湿性关节炎药物中的应用。
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1394201A (zh) * | 2000-01-21 | 2003-01-29 | 格吕伦塔尔有限公司 | 取代的戊二酰亚胺及其作为il－12产生抑制剂的用途 |
| WO2006053109A1 (en) * | 2004-11-10 | 2006-05-18 | Synta Pharmaceuticals Corp. | Heteroaryl compounds |
| WO2007050980A2 (en) * | 2005-10-27 | 2007-05-03 | Synta Pharmaceuticals Corp. | Process for preparing mesylate salts of il-12 inhibitory compounds |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1394201A (zh) * | 2000-01-21 | 2003-01-29 | 格吕伦塔尔有限公司 | 取代的戊二酰亚胺及其作为il－12产生抑制剂的用途 |
| WO2006053109A1 (en) * | 2004-11-10 | 2006-05-18 | Synta Pharmaceuticals Corp. | Heteroaryl compounds |
| WO2007050980A2 (en) * | 2005-10-27 | 2007-05-03 | Synta Pharmaceuticals Corp. | Process for preparing mesylate salts of il-12 inhibitory compounds |
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