CN106946873B - 一种面神经损伤的治疗药物及其制备方法 - Google Patents
一种面神经损伤的治疗药物及其制备方法 Download PDFInfo
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- CN106946873B CN106946873B CN201710208375.0A CN201710208375A CN106946873B CN 106946873 B CN106946873 B CN 106946873B CN 201710208375 A CN201710208375 A CN 201710208375A CN 106946873 B CN106946873 B CN 106946873B
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- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明提供了一种具有式(I)结构的苯并噻唑类化合物：
Description
技术领域
本发明属于医药技术领域，具体涉及一种用于治疗神经损伤的药物，所述药物可治疗与神经损伤有关的神经疾病，例如面神经损伤。
背景技术
面神经损伤是神经疾病的一种，按病因可分为创伤性面神经损伤(如交通事故、坠落伤、枪伤、刺伤、电灼损伤等物理性损伤)和医源性创伤。其中外力作用方式又可分为暴露、牵拉、挤压、压榨、锐器切割伤及钝器摩擦伤等类型。神经疾病与神经元细胞的死亡或损伤有关。对神经疾病的典型治疗涉及能够抑制神经元细胞死亡的药物。最近的方法涉及通过促进神经元生长来促使神经再生。
神经生长因子(NGF)是具有神经元营养和促突起生长双重生物学功能的一种神经细胞生长调节因子，它对中枢及周围神经元的发育、分化、生长、再生和功能特性的表达均具有重要的调控作用。例如，胶质细胞系衍生的神经营养因子(GDNF)在体外和体内都表现出神经营养活性，并且正在评价其对于帕金森病治疗的作用。然而，对于神经疾病的治疗，使用神经生长因子会带来几个缺点。它们不能迅速越过血脑屏障，并且在血浆中不稳定，此外，它们具有较差的药物递送性质。
此外，有研究证明某些小分子能够在体内刺激轴突生长，其保护了神经元不发生进一步的变性，并促进了神经细胞的再生。例如，已表明雌激素能够促进轴索和树突生长(C.Dominique Toran-Allerand等人，J.Steroid Biochem.Mol.Biol.，1996，56，pp.169-78；和B.S.McEwen等人，Brain Res.Dev.Brain.Res.，1995，87，pp.91-95)。已有报道，对于抑制亲免素类蛋白的旋转酶活性的FKBP12有亲和力的化合物具有神经生长刺激活性(Lyons等人，Proc.Natl.Acad.Sci.USA，1994，91，pp.3191-3195)。WO 96/41609中描述了哌啶衍生物能刺激神经细胞中的神经轴索。
虽然现有技术中已经描述了很多种用于治疗或预防神经变性疾病的化合物，但是真正进入临床试验的很少，被批准上市的药物更少。因此，仍然需要发现和设计能够预防和治疗与神经疾病有关的损伤如例面神经损伤的新化合物和组合物。
发明内容
本发明的目的在于提供一种能够具有神经损伤治疗活性的药物。
本发明提供了式(I)化合物或其药学上可接受的盐：
[化学式1]
式(I)中，R1选自：氢原子、卤素、氰基、硝基、氨基、羧基、C1-C4烷基、C1-C4卤代烷基、C1-C4烷氧基、C1-C4烷硫基、C1-C4烷基氨基、二(C1-C4烷基)氨基、C1-C4烷氧羰基、C1-C4烷基磺酰基、苯基、苄基、5元或6元杂环烷基以及5元或6元杂芳基；
R2、R3可以相同或不同，各自独立地选自：氢原子、卤素、氰基、硝基、氨基、羧基、C1-C4烷基、C1-C4卤代烷基、C1-C4烷氧基、C1-C4烷硫基、C1-C4烷基氨基、二(C1-C4烷基)氨基、C1-C4烷氧羰基、C1-C4烷基磺酰基、苯基、苄基、5元或6元杂环烷基以及5元或6元杂芳基；或者R2、R3可以与其所连接的碳原子一起形成苯环、或者5元或6元杂芳环；
R1、R2、R3中的苯基、苄基、5元或6元杂环烷基以及5元或6元杂芳基可以任选地被1-3个选自以下的取代基所取代：卤素、羟基、硝基、氰基、氨甲酰基、C1-C4烷基、C1-C4卤代烷基、C1-C4烷氧基、氨基、C1-C4烷基氨基、二(C1-C4烷基)氨基；
R4、R5可以相同或不同，各自独立地选自：氢原子、卤素、氰基、硝基、氨基、C1-C4烷基、C1-C4卤代烷基、C1-C4烷氧基、C1-C4烷基氨基、二(C1-C4烷基)氨基、C1-C4烷氧羰基、C1-C4烷基磺酰基。
在另一个实施方案中，本发明提供了包含式(I)化合物或其药学上可接受的盐的药物组合物。所述药物组合物可用于在患者中或者在体外神经细胞中促进神经修复或防止神经损伤的方法中。
在另一个实施方案中，本发明提供了式(I)化合物或其药学上可接受的盐在制备治疗疾病的药物中的应用，所述疾病包括与神经损伤有关的疾病。这样的疾病的实例包括面神经损伤、由于身体损伤或疾病例如糖尿病引起的周围神经破坏、由于神经变性所致的神经失调例如帕金森病、阿尔茨海默氏病和肌萎缩性侧索硬化等。
下文将详细的描述本发明。
除非另外定义，本申请使用的所有技术和科学术语具有与本发明所属领域技术人员通常所理解相同的含义。将本申请提及的所有专利和出版物通过引用的方式并入本文。
术语“C1-C4烷基”旨在表示支链或直链且可以包含1-4个、诸如1-3个碳原子、诸如1-2个碳原子、诸如2-3个碳原子的饱和烃基，诸如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基和叔丁基。
术语“卤素”旨在表示氟、氯、溴和碘。
术语“5元或6元杂环烷基”旨在表示包含1-4个选自氧、硫和氮的杂原子的5元或6元单环饱和环基，诸如吡咯烷基、哌啶基、咪唑烷基、吡唑烷基、哌嗪基、高哌嗪基、四氢呋喃基、噁唑烷基、吗啉基、硫代吗啉基等。
术语“5元或6元杂芳基”旨在表示包含1-4个选自氧、硫和氮的杂原子的5元或6元单环芳香族基团，诸如呋喃基、噻吩基、吡咯基、咪唑基、吡唑基、噁唑基、异噁唑基、噁二唑基、噻唑基、异噻唑基、噻二唑基、三唑基、四唑基、吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基等。
在本发明化合物的一些实施方案中，其中R1、R2、R3表示氢。
在本发明化合物的一些实施方案中，其中R3表示5元或6元杂环烷基，优选吡咯烷基。
在本发明化合物的一些实施方案中，其中R4、R5表示C1-C4烷基或C1-C4烷氧基，优选甲基或甲氧基。
在本发明化合物的一些实施方案中，其中R2、R3与其所连接的碳原子一起形成苯环。
在本发明化合物的一些实施方案中，所述化合物选自由以下组成的组：
本发明所述式(I)化合物还包括其可药用衍生物，例如本发明化合物的任何药学上可接受的盐、前药或前药的盐，或对患者给药后能提供本发明化合物的任何其它化合物。
本发明所述式(I)化合物的药学上可接受的盐，是指衍生自无机或有机酸和碱的盐。这样的酸加成盐包括下列盐：乙酸盐、己二酸盐、藻酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、硫酸氢盐、丁酸盐、柠檬酸盐、樟脑酸盐、环戊烷丙酸盐、十二烷基硫酸盐、乙磺酸盐、富马酸盐、葡庚糖酸盐、半硫酸盐、己酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、乳酸盐、马来酸盐、甲磺酸盐、烟酸盐、草酸盐、过硫酸盐、苦味酸盐、新戊酸盐、丙酸盐、琥珀酸盐、酒石酸盐、甲苯磺酸盐和十一烷酸盐。碱加成盐包括铵盐，碱金属盐例如钠盐和钾盐，碱土金属盐例如钙盐和镁盐，与有机碱例如二环己基胺盐形成的盐，和与氨基酸例如精氨酸、赖氨酸等形成的盐。
本发明所述式(I)化合物还可以通过加上合适的官能团来进行修饰，以提高选择性生物特征。这样的修饰是本领域已知的，并包括用于提高进入给定的生物系统(例如血液、淋巴系统、中枢神经系统)的生物穿透力，提高口服利用度，提高溶解度以容许注射给药，改变代谢和改变排泄速度的修饰。
在一个实施方案中，本发明提供了包含式(I)化合物或其药学上可接受的盐和药学上可接受的载体的药物组合物。
可用于这些药物组合物中的药学上可接受的载体包括但不限于离子交换剂、矾土、硬脂酸铝、卵磷脂、血清蛋白例如人血清白蛋白，缓冲物质例如磷酸盐，甘氨酸、山梨酸、山梨酸钾、饱和植物脂肪酸的部分甘油酯混合物、水、盐或电解质例如鱼精蛋白硫酸盐、磷酸氢二钠、磷酸氢钾、氯化钠、锌盐，胶态二氧化硅、三硅酸镁、聚乙烯吡咯烷酮、基于纤维素的物质、聚乙二醇、羧甲基纤维素钠、聚丙烯酸酯、蜡、聚乙烯-聚氧丙烯-嵌段聚合物、聚乙二醇和羊毛脂。
所述药物组合物可口服给药、非胃肠道给药、通过吸入喷雾给药、局部给药、直肠给药、经鼻给药、颊给药或经由植入的贮药库给药。本文所用术语“非胃肠道给药”包括皮下、静脉内、肌内、关节内、滑液内、胸骨内、鞘内、肝内、损伤内和颅内注射或输注技术。优选地，组合物可口服、腹膜内或静脉内给药。
可与药学上可接受的载体合并以制成单一剂型的所述化合物的量将取决于所治疗的患者以及特定的给药方式。优选地，组合物应当这样配制，使得可施用剂量为0.01-100mg/kg体重/天的所述化合物。
制备方法
本发明化合物可用已知的合成方法容易地制得。
例如，式(I)化合物可由包含以下步骤的方法制备：
步骤一：
式(II)化合物与式(III)化合物反应以制备式(IV)化合物；
所述反应在钯催化剂和碱的存在下进行，所述钯催化剂包括双(三苯基膦基)二氯化钯、醋酸钯，优选双(三苯基膦基)二氯化钯，所述碱包括醋酸钾、醋酸钠；
步骤二：
式(IV)化合物与羟胺反应以制备式(V)化合物；
所述反应在缩合剂和碱的存在下进行，所述缩合剂包括HBTU，TBTU、HATU或HCTU；所述碱包括三乙胺、吡啶或哌啶；
步骤三：
式(V)化合物与式(VI)化合物反应以制备式(I)化合物；
所述反应在碱的存在下进行，所述碱包括醇钾例如叔丁醇钾，醇钠例如乙醇钠，氢化钠；
其中，R1-R5如权利要求1中所定义，R表示C1-C4烷基，X1、X2各自独立地表示卤素原子，例如氯、溴或碘。
有益效果
本发明化合物对CoCl2引起的神经细胞损伤具有十分优异的保护活性，因此可用于治疗与神经损伤有关的疾病，例如面神经损伤、由于身体损伤或疾病例如糖尿病引起的周围神经破坏、由于神经变性所致的神经失调例如帕金森病、阿尔茨海默氏病和肌萎缩性侧索硬化等。
具体实施方式
本发明实用的且目前优选的实施方式如以下方实施例说明。
所属领域的技术人员将认识到：本发明所描述的化学反应可以用来合适地制备许多本发明的其他化合物，且用于制备本发明的化合物的其它方法都被认为是在本发明的范围之内。例如，根据本发明那些非例证的化合物的合成可以成功地被所属领域的技术人员通过修饰方法完成，如适当的保护干扰基团，通过利用其他已知的试剂除了本发明所描述的，或将反应条件做一些常规的修改。另外，本发明所公开的反应或已知的反应条件也公认地适用于本发明其他化合物的制备。
实施例1：(E)-3-(6-(3,4-二甲基-1H-吡唑-5-基氧基)苯并[d]噻唑-2-基)-N-羟基丙烯酰胺(化合物1)
步骤一：在氩气保护下将2-溴苯并[d]噻唑-2-醇(4.56g)、丙烯酸甲酯1ml、醋酸钾3.9g、双(三苯基膦基)二氯化钯0.1g溶解于DMF100ml，回流下反应6h，TLC检测反应完全。加水200ml搅拌10min，DCM萃取，饱和食盐水洗涤三次，无水硫酸钠干燥，减压蒸干溶剂得到白色固体(E)-3-(6-羟基苯并[d]噻唑-2-基)乙酸甲酯3.83g，产率81.2％。
步骤二：在氩气保护下将步骤一得到的(E)-3-(6-羟基苯并[d]噻唑-2-基)乙酸甲酯2.35g、HATU3.8g和盐酸羟胺0.69g加入DCM500ml中，将反应混合物在20℃下搅拌5h。将混合物倾入水中，用DCM稀释，用水洗涤三次，无水硫酸钠干燥，减压蒸干溶剂得到白色固体(E)-N-羟基-3-(6-羟基苯并[d]噻唑-2-基)乙酰胺1.78g，产率75.4％。
步骤三：在氩气保护下将叔丁醇钾1.12g加入到200ml DMF中，然后在在低于40℃的温度下缓慢滴加步骤二得到的(E)-N-羟基-3-(6-羟基苯并[d]噻唑-2-基)乙酰胺1.18g溶解于DMF 30ml中的溶液，1h左右滴完，继续搅拌30min，加入5-碘-3,4-二甲基-1H-吡唑1.2g，然后缓慢升温至40℃，保温搅拌反应2h。冷却，过滤，滤液减压浓缩，向残余物中加入1000ml水，然后过滤得到粗品。粗品用乙酸乙酯-乙醇(1:1)混合溶液重结晶，得到白色针状固体的标题化合物1.31g，产率79.5％。
ESI-MS：331.08[M+H]+
元素分析：理论值/实测值，C(54.53/54.59)，H(4.27/4.20)，N(16.96/16.88)，O(14.53/14.58)，S(9.71/9.68)
1H NMR(400MHz,CDCl3)δ13.75(s,1H),8.03(s,1H),7.73(d,1H),7.49(d,1H),7.31(s,1H),6.94(d,1H),6.76(d,1H),2.16(s,1H),2.06(s,3H),1.91(s,3H)。
按照类似的方法，合成以下化合物：
化合物2：(E)-3-(6-(3,4-二甲基-1H-吡唑-5-基氧基)-4-(吡咯烷-1-基)苯并[d]噻唑-2-基)-N-羟基丙烯酰胺(化合物2)
ESI-MS：400.14[M+H]+
元素分析：理论值/实测值，C(57.13/57.19)，H(5.30/5.20)，N(17.53/17.58)，O(12.02/12.08)，S(8.03/7.95)
1H NMR(400MHz,CDCl3)δ13.75(s,1H),8.03(s,1H),7.73(d,1H),6.81(s,1H),6.34(s,1H),6.76(d,1H),3.46(t,4H),2.16(s,1H),2.06(s,3H),1.91(s,3H),1.82(t,4H)。
化合物3：(E)-3-(5-(3,4-二甲氧基-1H-吡唑-5-基氧基)萘并[1,2-d]噻唑-2-基)-N-羟基丙烯酰胺(化合物3)
ESI-MS：413.08[M+H]+
元素分析：理论值/实测值，C(55.33/55.29)，H(3.91/3.80)，N(13.58/13.52)，O(19.40/19.48)，S(7.77/7.91)
1H NMR(400MHz,CDCl3)δ13.45(s,1H),8.03(s,1H),7.99(d,1H),7.84(d,1H),7.51(m,2H),7.36(s,1H),7.76(d,1H),6.72(d,1H),4.06(s,3H),3.91(s,3H),2.16(s,1H)。
接下来，通过实验例具体解释代表性化合物的药理效应。
测试实验例1：目标化合物的神经保护测定
可用本领域已知的几种细胞培养分析法来测定本发明化合物的神经生长刺激活性。本发明使用嗜铬细胞瘤PC12细胞神经突分枝测定以测试本发明化合物的神经保护活性(“Immunosuppressant FK506promotes neurite outgrouwth in cultures of PC12cellsand sensory ganglia”,Lyons W.E.,et al,PNAS,1994,91,pp.3191-3195)具体操作如下：
PC12细胞生长至80-90％汇合进行传代，先将疏松贴壁的细胞用一次性滴管轻轻的吹打下来，收集该培养液于15ml的离心管中，剩余的贴壁细胞用胰蛋白酶消化液消化，消化液为0.05胰酶+0.02％EDTA。倒置显微镜下观察细胞消化状态，待细胞间隙增大，大部分变圆，立即加入2mL完全培养基终止消化后，轻拍培养瓶，使全部细胞脱壁，合并两次含细胞培养液，离心800rpm/min，3min，弃上清，重悬细胞，加入完全培养基，接种在新的培养瓶中，置37℃恒温、、饱和湿度培养箱中继续培养。将PC12细胞正常培养72小时后，倒掉培养基(含5％HS+10％FBS+1％双抗的RPMI1640)，以无血清培养基(RPMI1640)培养12-16小时，备用。
将血清饥饿的PC12细胞制成单细胞混悬液，调细胞密度为7×104个/mL，培养基改为含10％FBS的RPMI1640，种入PLL包被的96孔板，每孔100μL。以终浓度为50ng/mL NGF加到96孔板中，继续培养36h。
待细胞分化后，将细胞分为正常对照组，NGF组，给药组，分别按3.75、7.5、15、30、60nmol/L为终浓度加入96孔板中，每组6个复孔，至培养箱中培养24h后，将终浓度为200μmol/L CoCl2溶液加入到96孔板中，继续培养12h后。每孔分别加入20μL的MTT(5mg/ml)，孵育4h后用酶标仪在490nm处测定OD值。
目标化合物在相应浓度下对损伤PC12细胞增殖计算公式为：[OD490(化合物)-OD490(CoCl2)]/[OD490(NGF)-OD490(CoCl2)]×100％；最终EC50的计算公式为：-pEC50＝logCmax-log2×(∑P-0.75+0.25Pmax+0.25Pmin)，其中，Cmax＝最大浓度，∑P＝总增殖率，Pmax＝最大增殖率，Pmin＝最小增殖率。结果示于以下表1中：
表1：目标化合物对损伤神经细胞的保护活性
| 化合物 | EC<sub>50</sub>(nm) |
| 1 | 43.5 |
| 2 | 52.7 |
| 3 | 29.0 |
上述结果表明，本发明化合物对CoCl2引起的神经细胞损伤具有十分优异的保护活性，因此可以用于各种神经损伤疾病，例如面神经损伤的治疗。
以上描述了本发明优选实施方式，然其并非用以限定本发明。本领域技术人员对在此公开的实施方案可进行并不偏离本发明范畴和精神的改进和变化。
Claims (16)
1.一种式(I)化合物或其药学上可接受的盐：
[化学式1]
式(I)中，R1选自：氢原子、卤素、C1-C4烷基以及C1-C4卤代烷基；
R2、R3可以相同或不同，各自独立地选自：氢原子、C1-C4烷基氨基、二(C1-C4烷基)氨基以及5元或6元杂环烷基；或者R2、R3可以与其所连接的碳原子一起形成苯环；
R2、R3中的5元或6元杂环烷基可以任选地被1-3个选自以下的取代基所取代：卤素、羟基、硝基、氰基、C1-C4烷基、C1-C4卤代烷基；
R4、R5可以相同或不同，各自独立地选自：C1-C4烷基、C1-C4卤代烷基、C1-C4烷氧基；
其中，所述5元或6元杂环烷基选自吡咯烷基、哌啶基、咪唑烷基、吡唑烷基、哌嗪基、吗啉基、硫代吗啉基。
2.根据权利要求1所述的化合物，其特征在于，所述R1、R2、R3表示氢。
3.根据权利要求1所述的化合物，其特征在于，所述R3表示吡咯烷基。
4.根据权利要求1所述的化合物，其特征在于，所述R4、R5表示C1-C4烷基或C1-C4烷氧基。
5.根据权利要求4所述的化合物，其特征在于，所述R4、R5表示甲基或甲氧基。
6.根据权利要求1所述的化合物，其特征在于，所述R2、R3与其所连接的碳原子一起形成苯环。
7.根据权利要求1所述的化合物，所述化合物选自由以下组成的组：
8.一种药物组合物，其包含根据权利要求1-7任一项所述的式(I)化合物或其药学上可接受的盐和药学上可接受的载体。
9.根据权利要求1-7任一项所述的式(I)化合物或其药学上可接受的盐或者根据权利要求8所述的药物组合物在制备药物中的应用，所述药物用于治疗与神经损伤有关的疾病。
10.根据权利要求9所述的应用，其特征在于，所述与神经损伤有关的疾病选自面神经损伤、由于身体损伤或疾病引起的周围神经破坏、帕金森病、阿尔茨海默氏病和肌萎缩性侧索硬化。
11.根据权利要求10所述的应用，其特征在于，所述身体损伤或疾病为糖尿病。
12.根据权利要求9所述的应用，其特征在于，所述药物用于治疗面神经损伤。
13.一种制备根据权利要求1所述的式(I)化合物的方法，该制备方法包括以下步骤：
步骤一：
式(II)化合物与式(III)化合物反应以制备式(IV)化合物；
所述反应在钯催化剂和碱的存在下进行，所述钯催化剂选自双(三苯基膦基)二氯化钯、醋酸钯，所述碱选自醋酸钾、醋酸钠；
步骤二：
式(IV)化合物与羟胺反应以制备式(V)化合物；
所述反应在缩合剂和碱的存在下进行，所述缩合剂选自HBTU，TBTU、HATU或HCTU；所述碱选自三乙胺、吡啶或哌啶；
步骤三：
式(V)化合物与式(VI)化合物反应以制备式(I)化合物；
所述反应在碱的存在下进行，所述碱选自醇钾，醇钠，氢化钠；
其中，R1-R5如权利要求1中所定义，R表示C1-C4烷基，X1、X2各自独立地表示卤素原子。
14.根据权利要求13所述的方法，其特征在于，在步骤一中，所述钯催化剂为双(三苯基膦基)二氯化钯。
15.根据权利要求13所述的方法，其特征在于，在步骤三中，所述碱选自叔丁醇钾或乙醇钠。
16.根据权利要求13所述的方法，其特征在于，所述X1、X2各自独立地表示氯、溴或碘。
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