CN111170895B - 一种2-羟基胍类化合物及其制备方法 - Google Patents
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Abstract
本发明公开了一种2‑羟基胍类化合物，该2‑羟基胍类化合物具有如通式(Ⅰ)所示结构的化合物及其可药用盐，其中，R1和R2表示苯环上邻、间、对位上单取代或多取代的硝基/烷基、取代或未取代的巯基、取代或未取代的氨基、取代或未取代的羟基、卤素中的一种或几种。本发明还公开该化合物的制备方法和该2‑羟基胍类化合物在制备NMDAR表达异常的诊断试剂和NMDAR表达异常所致疾病的治疗药物中的应用。本发明提供的2‑羟基胍类化合物具有良好的NMDAR结合活性，可应用于制备NMDAR表达异常的诊断试剂和NMDAR表达异常所致疾病的治疗药物。
Description
技术领域
本发明涉及药物合成领域，尤其涉及一种2-羟基胍类化合物及其制备方法。
背景技术
多种神经及精神类疾病被认为与NMDAR功能障碍相关，目前研究主要着眼于缺血性脑卒中、癫痫、神经病理性疼痛、阿尔茨海默症(AD)、帕金森病(PD)、药物成瘾、注意缺陷多动障碍及精神分裂症(SZ)等，NMDAR成为一个潜在的药物干预靶点，如NMDAR的部分拮抗剂美金刚被批准用于AD的治疗。
NMDAR表达异常显像在AD、SZ等领域有很重要的应用价值。该靶点显像剂文献报道的比较多，主要是用“18F”“11C”或“123I”标记不同类型的NMDAR拮抗剂如PCP、氯胺酮和MK-801等衍生物、类衍生物等来研制分子探针，除GluN2B或甘氨酸结合位点外，多以结合位点PCP为显像靶点。其中研究较多的此类探针有[11C]MK-801，[18F]MEM，[123I]CNS-1261，[11C]CNS-5161，[11C]GMOM，[18F]GE-179以及[18F]PK-209等。上述标记物中MK-801脂溶性高，体外结合实验结果也并不理想，PCP及噻吩-环苯己哌啶(thienyl-phencyclidine,TCP)类探针除存在脂溶性高的缺陷外，被证实NMDAR表达丰富的脑区(海马、纹状体、皮质)与小脑的摄取比值较低，非特异性结合较高；苯喹嗪类探针由于不能穿过血脑屏障、在脑内并未有特异性结合而被否决。GE-179是目前NMDAR体外和体内水平显像效果最好的药物，但最近的文献对该药物是否对NMDAR结合的特异性指数表示怀疑(Colm J.McGinnity et al.ACSChemical Neuroscience,2018)，在体内水平不能很好对NMDAR进行特异性的表征，所以开发与NMDAR结合活性更好的化合物具有重要的意义。
更为有意义的是，AD和SZ都没有好的诊断药物和治疗药物，尤其是AD，近17年没有新的治疗药物上市，使得该疾病已经成为严重的社会负担和家庭负担。因此，研发具有我国自主知识产权的靶向NMDAR的神经退行性疾病的显像和治疗药物，对减轻我国老年疾病患者的经济负担，提高老年神经退行性疾病的治疗效果，具有重要的意义。
发明内容
本发明为解决现有技术中的上述问题提出的一种2-羟基胍类化合物及其制备方法。
为实现上述目的，本发明采用以下技术方案：
本发明的第一个方面是提供一种2-羟基胍类化合物，该2-羟基胍类化合物具有如通式(Ⅰ)所示结构的化合物及其可药用盐：
其中：
R1表示苯环上邻、间、对位上单取代或多取代的硝基/烷基、取代或未取代的巯基、取代或未取代的氨基、取代或未取代的羟基、卤素中的一种或几种；
R2表示苯环上邻、间、对位上单取代或多取代的硝基/烷基、取代或未取代的巯基、取代或未取代的氨基、取代或未取代的羟基、卤素中的一种或几种。
进一步地，卤素包括氯、溴、碘。
进一步地，该2-羟基胍类化合物选自以下结构所示的化合物及其可药用盐：
本发明的第二方面是提供该2-羟基胍类化合物的制备方法，包括如下步骤：
步骤一，在氩气保护下，将式(1)所示的化合物溶解于DCM，加入式(2)所示的化合物，升温并搅拌；反应完全后，冷却至室温，浓缩除掉溶剂，并使用硅胶柱纯化得到式(3)所示的中间体；
步骤二，将步骤一得到的式(3)所示的中间体溶解于THF中，加入CH3I，密闭搅拌；待反应完全后，冷却至室温，减压浓缩蒸除剩余的CH3I和THF，得到式(4)所示的中间体；
步骤三，将步骤二得到的式(4)所示的中间体加入Et3N和EA，减压蒸干，并使用油泵拉干，用乙醇转移剩余物至封管，加入NH2OH/HCl后，对封管加热并搅拌，生成所述2-羟基胍类化合物。
进一步地，R1表示苯环上邻、间、对位上单取代或多取代的硝基/烷基、取代或未取代的巯基、取代或未取代的氨基、取代或未取代的羟基、卤素中的一种或几种；
R2表示苯环上邻、间、对位上单取代或多取代的硝基/烷基、取代或未取代的巯基、取代或未取代的氨基、取代或未取代的羟基、卤素中的一种或几种。
进一步地，卤素包括氯、溴、碘。
进一步地，步骤一中硅胶柱的洗脱剂PE：EA的体积为20:1～10:1。
进一步地，步骤二中在60-70℃条件下，搅拌3-5h。
进一步地，步骤三中在80-100℃条件下，搅拌16-22h。
进一步地，步骤三之后，需要蒸干溶剂，加入饱和碳酸氢钠和二氯甲烷萃取，无水硫酸钠干燥，然后用硅胶柱纯化。
本发明的第三方面是提供该2-羟基胍类化合物在制备NMDAR表达异常的诊断试剂和NMDAR表达异常所致疾病的治疗药物中的应用。
本发明采用上述技术方案，与现有技术相比，具有如下技术效果：
本发明提供的2-羟基胍类化合物具有良好的NMDAR结合活性，可应用于制备NMDAR表达异常的诊断试剂和NMDAR表达异常所致疾病的治疗药物，上述疾病包括但不限于缺血性脑卒中、癫痫、神经病理性疼痛、阿尔茨海默症(AD)、帕金森病(PD)、药物成瘾、注意缺陷多动障碍及精神分裂症(SZ)等。
具体实施方式
本发明提供了一种2-羟基胍类化合物，该2-羟基胍类化合物具有如通式(Ⅰ)所示结构的化合物及其可药用盐：
其中：
R1表示苯环上邻、间、对位上单取代或多取代的硝基/烷基、取代或未取代的巯基、取代或未取代的氨基、取代或未取代的羟基、卤素(氯、溴、碘)中的一种或几种；
R2表示苯环上邻、间、对位上单取代或多取代的硝基/烷基、取代或未取代的巯基、取代或未取代的氨基、取代或未取代的羟基、卤素(氯、溴、碘)中的一种或几种。
该2-羟基胍类化合物优选以下结构所示的化合物及其可药用盐：
本发明的通式(I)系列化合物的制备过程如下：
下面通过具体实施例对本发明进行详细和具体的介绍，以使更好的理解本发明，但是下述实施例并不限制本发明范围。
实施例1
本实施例提供如式(Ⅱ)所示结构的化合物：(E)-1-(2-氯-5-((2-氟乙基)巯基)苯基)-3-(3-(甲硫基)苯基)-2-羟基胍的制备方法，包括如下步骤：
步骤一，1-(2-氯-5-((2-氟乙基)巯基)苯基)-3-(3-(甲硫基)苯基)硫脲的合成
(2-氯-5-((2-氟乙基)巯基)苯胺(500mg,2.43mmo1)溶解于10mL二氯甲烷，氩气保护，注射器加入3-甲硫代-异硫氰酸苯酯(440mg,2.43mmo1，商购于百灵威)，升温至回流搅拌24小时。TLC检测反应完全(PE:EA＝6:1),反应液冷却至室温，浓缩除掉溶剂，并使用硅胶柱纯化(PE:EA＝20:1～10:1洗脱)，得白色固体810mg，收率86％。
1H NMR(400MHz,Chloroform-d)δ9.72(s,1H),9.28(s,1H),7.88(d,J＝1.5Hz,1H),7.73(t,J＝1.5Hz,1H),7.40–7.34(m,2H),7.33(t,J＝7.4Hz,1H),7.16(dt,J＝7.1,1.6Hz,1H),7.11(dd,J＝7.5,1.6Hz,1H),4.66(t,J＝7.0Hz,1H),4.56(t,J＝7.1Hz,1H),3.15(t,J＝7.1Hz,1H),3.10(t,J＝7.1Hz,1H),2.51(s,2H).HPLC-MS(ESI+):[M+H]+:387.1.8,388.1.
步骤二，(Z)-N'-(2-氯-5-((2-氟乙基)巯基)苯基)-N-(3-(甲硫基)苯基)甲硫脲的合成
1-(2-氯-5-((2-氟乙基)巯基)苯基)-3-(3-(甲硫基)苯基)硫脲(150mg,0.39mmo1)溶解于10mL四氢呋喃，加入碘甲烷(0.1mL,1.6mmo1)，密闭封管65℃搅拌4小时。TLC检测原料转化完全(PE:EA＝4:1),反应液冷却至室温，减压浓缩蒸除剩余的碘甲烷和四氢呋喃，得到淡黄色油状物170mg，无须纯化直接用于下一步反应。
HPLC-MS(ESI+):[M+H]+:401.1,402.1。
步骤三，(E)-1-(2-氯-5-((2-氟乙基)巯基)苯基)-2-羟基-3-(3-(甲硫基)苯基)胍的合成
步骤二得到的黄色油状物(170mg,0.42mmol)，加入三乙胺(0.1mL,0.72mmol)EA(10mL)，反应液较初始状态稍黄和浑浊。减压蒸干，并使用油泵拉干，用乙醇(10mL)转移剩余物至封管，加入盐酸羟胺(291mg,4.2mmol)，封管加热至90℃搅拌20h，LC-MS检测原料消耗完全，且有产物生成。蒸干溶剂，加入饱和碳酸氢钠50mL之后，用50mL二氯甲烷萃取3次，无水硫酸钠干燥。硅胶柱纯化(DCM:MeOH＝20:1洗脱)，得白色固体80mg，收率49％。
1H NMR(400MHz,Chloroform-d)δ9.64(s,1H),8.20(s,1H),7.93(s,1H),7.89(d,J＝1.5Hz,1H),7.39–7.31(m,3H),7.27(t,J＝7.5Hz,1H),7.11–7.02(m,2H),4.65(t,J＝7.0Hz,1H),4.56(t,J＝7.1Hz,1H),3.15(t,J＝7.1Hz,1H),3.10(t,J＝7.1Hz,1H),2.51(s,2H).HPLC-MS(ESI+):[M+H]+:386.1,387.1.
实施例2
本实施例提供如式(Ⅲ)所示结构的化合物：(E)-1-(2-氯-5-((2-氟乙基)巯基)苯基)-3-(4-(甲硫基)苯基)-2-羟基胍的制备方法，其合成路线如下所示：
同实施例1的过程，以4-甲硫代-异硫氰酸苯酯替代3-甲硫代-异硫氰酸苯酯即可，4-甲硫代-异硫氰酸苯酯是商业可获得的。
1H NMR(400MHz,Chloroform-d)δ9.64(s,1H),8.40(s,1H),8.20(s,1H),7.89(d,J＝1.5Hz,1H),7.78–7.72(m,2H),7.36–7.28(m,3H),7.04(dd,J＝7.5,1.5Hz,1H),4.65(t,J＝7.0Hz,1H),4.56(t,J＝7.1Hz,1H),3.15(t,J＝7.1Hz,1H),3.10(t,J＝7.1Hz,1H),2.47(s,2H).HPLC-MS(ESI+):[M+H]+:386.1,387.1.
实施例3
本实施例提供如式(Ⅳ)所示结构的化合物：(E)-1-(2-氯-4-硝基苯基)-3-(2-氯-5-((2-氟乙基)巯基)苯基)-2-羟基胍的的制备方法，其合成路线如下所示：
同实施例1的过程，以2-氯-4-硝基-异硫氰酸苯酯替代3-甲硫代-异硫氰酸苯酯即可，2-氯-4-硝基-异硫氰酸苯酯是商业可获得的。
1H NMR(500MHz,Chloroform-d)δ9.88(s,3H),8.51(s,3H),8.33(d,J＝1.5Hz,4H),8.11(dd,J＝7.5,1.5Hz,4H),8.03(d,J＝7.5Hz,4H),7.89(d,J＝1.5Hz,4H),7.68(s,3H),7.35(d,J＝7.5Hz,4H),7.04(dd,J＝7.5,1.5Hz,4H),4.65(t,J＝7.1Hz,4H),4.55(t,J＝7.1Hz,4H),3.16(t,J＝7.0Hz,4H),3.11(t,J＝7.1Hz,4H).HPLC-MS(ESI+):[M+H]+:420.1,421.1.
实施例4
本实施例提供如式(Ⅴ)所示结构的化合物：(E)-1-(2-氯-5-((3-氟丙基)巯基)苯基)-3-(3-(甲硫基)苯基)-2-羟基胍的的制备方法，其合成路线如下所示：
同实施例1的过程，以(2-氯-5-((3-氟丙基)巯基)苯胺替代(2-氯-5-((2-氟乙基)巯基)苯胺，2-氯-4-硝基-异硫氰酸苯酯替代3-甲硫代-异硫氰酸苯酯即可，(2-氯-5-((3-氟丙基)巯基)苯胺和2-氯-4-硝基-异硫氰酸苯酯是商业可获得的。
1H NMR(500MHz,Chloroform-d)δ9.73(s,1H),8.42(s,1H),8.23(d,J＝1.5Hz,1H),8.19(d,J＝8.0Hz,2H),7.96(d,J＝7.4Hz,1H),7.78(d,J＝1.5Hz,1H),7.27(d,J＝7.5Hz,1H),7.01(dd,J＝7.5,1.5Hz,1H),4.44(t,J＝7.1Hz,1H),4.35(t,J＝7.1Hz,1H),2.93(t,J＝7.1Hz,2H),1.85(m,2H).HPLC-MS(ESI+):[M+H]+:434.2,435.2.
实施例5
本实施例提供如式(Ⅵ)所示结构的化合物：(E)-1-(2-氯-4-硝基苯基)-3-(2-氯-5-((3-氟丙基)巯基)苯基)-2-羟基胍的的制备方法，其合成路线如下所示：
同实施例1的过程，以(2-氯-5-((3-氟丙基)巯基)苯胺替代(2-氯-5-((2-氟乙基)巯基)苯胺即可，(2-氯-5-((3-氟丙基)巯基)苯胺是商业可获得的。
1H NMR(500MHz,Chloroform-d)δ9.64(s,1H),8.07(s,1H),8.02(s,1H),7.89(d,J＝1.5Hz,1H),7.38–7.31(m,3H),7.27(t,J＝7.5Hz,1H),7.08(dt,J＝7.5,1.5Hz,1H),7.03(dd,J＝7.5,1.5Hz,1H),4.52(t,J＝7.1Hz,1H),4.43(t,J＝7.1Hz,1H),3.00(t,J＝7.1Hz,2H),2.51(s,2H),1.87(m,2H).HPLC-MS[M+H]+:400.2,400.2.
实施例6
本实施例提供如式(Ⅶ)所示结构的化合物：(E)-1-(2-氯-5-((3-氟丙基)巯基)苯基)-3-(4-(甲硫基)苯基)-2-羟基胍的的制备方法，其合成路线如下所示：
同实施例1的过程，以(2-氯-5-((3-氟丙基)巯基)苯胺替代(2-氯-5-((2-氟乙基)巯基)苯胺，4-甲硫代-异硫氰酸苯酯替代3-甲硫代-异硫氰酸苯酯即可，4-甲硫代-异硫氰酸苯酯和(2-氯-5-((3-氟丙基)巯基)苯胺是商业可获得的。
1H NMR(500MHz,Chloroform-d)δ9.66(s,1H),8.29(s,1H),8.05(s,1H),7.81(d,J＝1.5Hz,1H),7.78–7.72(m,2H),7.35(d,J＝7.5Hz,1H),7.33–7.28(m,2H),7.23(dd,J＝7.5,1.5Hz,1H),4.42(t,J＝7.1Hz,1H),4.33(t,J＝7.1Hz,1H),3.02(t,J＝7.1Hz,2H),2.37(s,2H),1.77(m,2H).HPLC-MS[M+H]+:400.2,400.2.
验证实施例
本实施例对实施例1-6提供的化合物进行生物活性测试，采用大鼠脑组织匀浆(购自上海诺辰生物技术有限公司)来完成，采用[3H]-MK-801作为放射配体，实验测试在具有放射性同位素使用资质的实验室完成。验证过程如下：
(1)[3H]-MK-801溶解于Tris Buff(5mM,pH7.4)的溶液，待测试样品用乙醇溶解。[3H]-MK-801(放射活度：22.5Ci/mmol；PerkinElmer；100μL)、L-谷氨酸溶液(50μL)和甘氨酸溶液(50μL)加至测试池，三个样品的终浓度为：0.5nM、100μM、30μM。
(2)待测试样品连续用Tris Buff(5mM,pH7.4)稀释，并加至测试池，终浓度分别为：0.001、0.01、0.03、0.1、0.3、1.0、3.0、10、30、100、1000和10000nM。
(3)然后加入脑组织匀浆准备液(700μL；终浓度约150μg/mL组织)，加毕，23℃下孵育2h，通过检测MK-801的存在测试配体的非特异结合(30μM；100μL)，竞争实验重复三次。IC50及Ki通过GraphPad Prism 5软件后处理数据计算得到。
由表1可知，本发明中优选的化合物显示出较好的NMDAR亲和活性，1μmol浓度下对NMDAR的结合活性都超过了90％。因此，本发明的化合物可以进一步研制开发NMDAR表达异常的诊断和治疗药物。
表1：本发明化合物的NMDAR亲和力活性测试结果。
以上对本发明的具体实施例进行了详细描述，但其只是作为范例，本发明并不限制于以上描述的具体实施例。对于本领域技术人员而言，任何对本发明进行的等同修改和替代也都在本发明的范畴之中。因此，在不脱离本发明的精神和范围下所作的均等变换和修改，都应涵盖在本发明的范围内。
Claims (7)
1.一种2-羟基胍类化合物在制备NMDAR表达异常的诊断试剂和NMDAR表达异常所致疾病的治疗药物中的应用，所述疾病为缺血性脑卒中、癫痫、神经病理性疼痛、阿尔茨海默症、帕金森病、药物成瘾、注意缺陷多动障碍及精神分裂症中的一种，其特征在于，所述2-羟基胍类化合物选自以下结构所示的化合物及其可药用盐：
2.根据权利要求1所述的应用，其特征在于，所述2-羟基胍类化合物的制备方法包括如下步骤：
步骤一，在氩气保护下，将式(1)所示的化合物溶解于DCM，加入式(2)所示的化合物，升温并搅拌；反应完全后，冷却至室温，浓缩除掉溶剂，并使用硅胶柱纯化得到式(3)所示的中间体；
步骤二，将步骤一得到的式(3)所示的中间体溶解于THF中，加入CH3I，密闭搅拌；待反应完全后，冷却至室温，减压浓缩蒸除剩余的CH3I和THF，得到式(4)所示的中间体；
步骤三，将步骤二得到的式(4)所示的中间体加入Et3N和EA，减压蒸干，并使用油泵拉干，用乙醇转移剩余物至封管，加入NH2OH/HCl后，对封管加热并搅拌，生成所述2-羟基胍类化合物；
3.根据权利要求2所述的应用，其特征在于，R1表示苯环上邻、间、对位上单取代或多取代的硝基/烷基、取代或未取代的巯基、取代或未取代的氨基、取代或未取代的羟基、卤素中的一种或几种；
R2表示苯环上邻、间、对位上单取代或多取代的硝基/烷基、取代或未取代的巯基、取代或未取代的氨基、取代或未取代的羟基、卤素中的一种或几种。
4.根据权利要求2所述的应用，其特征在于，步骤一中所述硅胶柱的洗脱剂PE：EA的体积为20:1～10:1。
5.根据权利要求2所述的应用，其特征在于，所述步骤二在60-70℃条件下，搅拌3-5h。
6.根据权利要求2所述的应用，其特征在于，步骤三中所述搅拌的条件为：在80-100℃条件下搅拌16-22h。
7.根据权利要求2所述的应用，其特征在于，步骤三之后，需要蒸干溶剂，加入饱和碳酸氢钠和二氯甲烷萃取，无水硫酸钠干燥，然后用硅胶柱纯化。
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