CN114181087A - 2,6-二羟基苯甲酸右崁醇酯类化合物及其药物用途 - Google Patents
2,6-二羟基苯甲酸右崁醇酯类化合物及其药物用途 Download PDFInfo
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- CN114181087A CN114181087A CN202111331218.1A CN202111331218A CN114181087A CN 114181087 A CN114181087 A CN 114181087A CN 202111331218 A CN202111331218 A CN 202111331218A CN 114181087 A CN114181087 A CN 114181087A
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- C07C69/84—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of monocyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of a six-membered aromatic ring
- C07C69/88—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of monocyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of a six-membered aromatic ring with esterified carboxyl groups
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Abstract
2,6‑二羟基苯甲酸右崁醇酯类化合物，结构符合通式(I)
其中：R＝‑H，‑OH，‑NR1R2，
或‑CONR3R4。R1，R2＝‑H，1‑6个碳原子的烷基，
或‑COR5；R3，R4，R5＝‑H，1‑3个碳原子的烷基。该类药物具有良好的减少卒中损伤、镇痛的作用，可用于制备治疗脑卒中损伤、神经病理性疼痛的药物。
Description
技术领域
本发明属于制药领域，提供一类2,6-二羟基苯甲酸右崁醇酯类化合物及其药学上可接受的盐及其药物用途。
背景技术
脑卒中严重危害人类健康。(+)-2-莰醇(Borneol)具有明确的抗脑缺血作用(Journal of Biomedical Research,2017,31:306-314)。(+)2-崁醇选择性的激动α2GABAA受体，和非选择性GABAA受体相比，发生嗜睡副作用的可能性较小，具有良好的安全性。但是，(+)2-崁醇口服生物利用度低，难溶于水中，当制成注射液时，需要加入大量有机溶剂，给药物制剂增加了难度，给临床用药增加了风险。因此，临床需要水溶性较好的α2GABAA受体激动剂。
神经病理性疼痛(neuropathic pain，NP)是由躯体感觉***损害或疾病导致的疼痛。临床表现为触诱发疼痛、痛觉过敏和自发性疼痛。NP是临床最常见的慢性疼痛之一，多数神经病理性疼痛患者疼痛可持续数月甚至数年，并常伴有焦虑与抑郁等负面情绪，严重影响患者的生活质量。普瑞巴林(pregabalin)是临床常见的神经病理性疼痛治疗药物，但是长期用药会导致镇痛耐受。(+)2-崁醇具有良好的镇痛作用，神经病理性疼痛需要长期给药，以口服途径更合理，但是(+)2-崁醇口服生物利用度低，限制了其临床应用。因此，临床需要口服有效的α2 GABAA受体激动剂。
因此，获得具有较好水溶解性或者口服有效的α2 GABAA受体激动剂，具有良好的临床应用价值。
文献Theranostics，2021，11(12):5970-5985报导了ZL006-05及其类似物ZL006-05B，具有选择性激动α2 GABAA受体的作用，但是，ZL006-05及其类似物ZL006-05B的水溶性均较差，口服生物利用度低。
中国发明2021103905049公布了一类氨基水杨酸(+)-2-莰醇酯的药物用途，结构符合以下通式：
该类药物水溶性仍然较差，口服生物利用度20％左右。
中国发明2021103911232公布了一类α2 GABAA受体激动剂，结构符合以下通式：
该类药物水溶性较好，口服生物利用度20％左右。
发明内容
解决的技术问题：提供一类2,6-二羟基苯甲酸右崁醇酯类化合物及其药学上可接受的盐及其药物用途。该类药物对体外培养的原代皮层神经元损伤具有良好的保护作用，具有良好的减少卒中损伤、镇痛的作用。可用于制备治疗脑卒中损伤、神经病理性疼痛的药物。
技术方案：一类2,6-二羟基苯甲酸右崁醇酯类化合物，结构符合通式(I)：
优选结构如下1-24任一结构所示：
上述一类2,6-二羟基苯甲酸右崁醇酯类化合物或其药学上可接受的盐在制备治疗脑卒中损伤或神经病理性疼痛药物中的应用。
有益效果：本发明化合物对体外培养的原代皮层神经元损伤具有良好的保护作用，具有减少卒中损伤、镇痛的作用。可用于制备治疗脑卒中损伤、神经病理性疼痛的药物。同时需要指出的是：本发明所述的化合物，在体外细胞模型中，对体外培养的原代皮层神经元损伤的保护作用强度显著优于中国发明2021103905049实施例化合物(对照化合物1)、中国发明2021103911232所公开的化合物(对照化合物2)或具有2，4-二羟基结构的类似物(对照化合物3)。该实验结果(表1)提示：2，6-二羟基结构对于提高其细胞保护作用具有重要作用。在动物模型中，本发明化合物的抗脑卒中损伤、神经病理性疼痛的药效也显著优于中国发明2021103905049实施例化合物(对照化合物1)、中国发明2021103911232所公开的化合物(对照化合物2)或具有2，4-二羟基结构的类似物(对照化合物3)，提示：2，6-二羟基结构对于提高其药效具有重要作用。说明该类化合物中，2,6-二羟基取代对于获得更好的药效具有结构特异性。
附图说明
图1为目标化合物1、对照化合物3、依达拉奉右崁醇对神经缺陷症状的影响；
图2为目标化合物1、对照化合物3、依达拉奉右崁醇对脑梗死面积(％)的影响；
图3目标化合物2、目标化合物13、目标化合物14、目标化合物16对神经缺陷症状的影响。
图4目标化合物2、目标化合物13、目标化合物14、目标化合物16脑梗死面积(％)的影响。
图5为口服目标化合物13(10mg/kg,i.g.)、目标化合物16(10mg/kg,i.g.)、对照化合物3(10mg/kg,i.g.)对大鼠神经痛的镇痛作用。
具体实施方式
下面的实施例可使本专业技术人员可全面的理解本发明，但不以任何方式限制本发明。
实施例1目标化合物的合成
1.1目标化合物1、2的合成
1)2，6-二羟基苯甲酸右莰醇酯(目标化合物1)的合成
合成路线：
将2，6-二羟基苯甲酸7.8g(5mmol)和右莰醇(4mmol)溶于10mL二氯甲烷中，加入DCC(7.5mmol)，DMAP(1mmol)，55℃反应6h。反应完成后，抽滤取滤液，旋干后加乙酸乙酯(EA)溶解，用饱和食盐水100mL洗涤三次，收集有机层干燥，制沙，石油醚(PE，60-90℃,)：乙酸乙酯(EA)＝30:1的条件过柱，产物旋干后打浆，得白色粉末。1H NMR(400MHz,DMSO-d6)(ppm):δ7.03(t,1H),6.28(d,2H),5.01-4.07(m,1H),2.34-2.26(m,1H),2.04-1.98(m,1H),1.71-1.63(m,2H),1.22–1.13(m,2H),1.06-1.04(m,1H),0.88(s,3H),0.82(s,6H).
2)2，4，6-三羟基苯甲酸右莰醇酯(目标化合物2)的合成
参考目标化合物1同样方法，以2,4,6-三羟基苯甲酸和右莰醇为原料合成，白色粉末。1HNMR(400MHz,DMSO-d6)δ(ppm):5.78(s,2H),4.94(d,1H),2.34-2.28(m,1H),2.09(s,1H),1.68-1.63(m,2H),1.27(d,2H),1.16(t,1H),0.85(s,3H),0.82(s,3H),0.80(s,3H).
1.2目标化合物3的合成
合成路线：
2，6-二羟基-3-硝基苯甲酸右莰醇酯(3-1)的合成
于干燥的茄形瓶中加入乙酸酐10mL，2，6-二羟基苯甲酸右莰醇酯(目标化合物1)2.90g(10.0mmol)，于0-4℃滴加乙酸酐5mL和发烟硝酸0.63g的混合溶液，加毕继续反应1小时，倒入50mL水和50g碎冰的混合物中，搅拌1小时，过滤，得黄色固体(2，6-二羟基-3-硝基苯甲酸右莰醇酯)2.5g。1H NMR(400MHz,DMSO-d6)δ(ppm):8.00(d,1H),6.54(d,1H),5.04(d,1H),2.33-2.29(m,1H),1.86-1.82(m,1H),1.71–1.60(m,2H),1.25-1.13(m,2H),1.07-1.03(m,1H),0.88(s,3H),0.83(s,6H).
2，6-二羟基-3-氨基苯甲酸右莰醇酯(3)的合成
于干燥的茄形瓶中加入1.68g 2，6-二羟基-3-硝基苯甲酸右莰醇酯(5.0mmol)，加50mL甲醇溶解，加入0.7g10％钯碳，加氢还原，于室温下过夜反应。薄层板监测反应完全后，布氏漏斗滤去钯碳，滤液浓缩至10mL，缓慢滴加去离子水，直至有白色固体析出，抽滤得到1.2g白色固体，为2，6-二羟基-3-氨基苯甲酸右莰醇酯。1H NMR(400MHz,DMSO-d6)δ(ppm):6.66(d,1H),6.17(d,1H),5.02(d,1H),2.37-2.29(m,1H),2.07-2.01(m,1H),1.74–1.60(m,2H),1.31-1.02(m,3H),0.88(s,3H),0.83(s,6H).
1.3目标化合物4-10的合成
1)2，6-二羟基-3-甲氨基苯甲酸右莰醇酯(目标化合物4)
合成路线：
于干燥的茄形瓶中加入1g 4-氨基水杨酸冰片酯(3.46mmol)，0.62g多聚甲醛(6.92mmol)，加入10mL甲醇完全溶解，加入0.19g钯碳(0.346mmol)，加氢还原，于25℃反应12小时。薄层板反应完全后，布氏漏斗滤去钯碳，旋干滤液，制砂柱层析，分离得到0.81g白色固体，为对甲氨基水杨酸冰片酯(目标化合物6)。1H NMR(400MHz,DMSO-d6)δ(ppm):6.64(d,1H),6.08(d,1H),5.03(d,1H),2.85(s,3H),2.36-2.28(m,1H),2.06-2.00(m,1H),1.73–1.60(m,2H),1.30-1.01(m,3H),0.89(s,3H),0.83(s,6H).
2)2，6-二羟基-3-二甲氨基苯甲酸右莰醇酯(目标化合物5)
参考目标化合物4的合成方法，加氢还原反应温度改为60℃。1H NMR(400MHz,DMSO-d6)δ(ppm):6.69(d,1H),6.18(d,1H),5.02(d,1H),3.01(s,6H),2.36-2.29(m,1H),2.08-2.01(m,1H),1.75–1.60(m,2H),1.31-1.01(m,3H),0.89(s,3H),0.83(s,6H).
3)2，6-二羟基-3-乙氨基苯甲酸右莰醇酯(目标化合物6)
参考目标化合物4的合成方法，以4-氨基水杨酸冰片酯和乙醛为原料合成。1H NMR(400MHz,DMSO-d6)δ(ppm):6.70(d,1H),6.19(d,1H),5.03(d,1H),3.50-3.42(m,2H),2.36-2.29(m,1H),2.08-2.01(m,1H),1.75–1.60(m,2H),1.31-1.01(m,6H),0.89(s,3H),0.83(s,6H).
4)2，6-二羟基-3-异丙氨基苯甲酸右莰醇酯(目标化合物7)
参考目标化合物4的合成方法，以4-氨基水杨酸冰片酯和丙酮为原料合成。1H NMR(400MHz,DMSO-d6)δ(ppm):6.68(d,1H),6.17(d,1H),5.02(d,1H),3.99-3.92(m,1H),2.36-2.28(m,1H),2.08-2.00(m,1H),1.75–1.60(m,2H),1.31-1.01(m,9H),0.89(m,3H),0.83(m,6H).
5)2，6-二羟基-3-异丁氨基苯甲酸右莰醇酯(目标化合物8)
参考目标化合物4的合成方法，以4-氨基水杨酸冰片酯和丁酮为原料合成。1H NMR(400MHz,DMSO-d6)δ(ppm):6.69(d,1H),6.18(d,1H),5.03(d,1H),2.82-2.77(m,1H),2.37-2.29(m,1H),2.08-2.01(m,1H),1.75–1.55(m,4H),1.31-1.01(m,6H),0.91-0.89(m,6H),0.83(s,6H).
6)2，6-二羟基-3-环戊氨基苯甲酸右莰醇酯(目标化合物9)
参考目标化合物4的合成方法，以4-氨基水杨酸冰片酯和环戊酮为原料合成。1HNMR(400MHz,DMSO-d6)δ(ppm):6.68(d,1H),6.17(d,1H),5.02(d,1H),2.65-2.61(m,1H),2.36-2.29(m,1H),2.08-2.01(m,1H),1.87–1.53(m,8H),1.49-1.41(m,2H),1.31-1.01(m,3H),0.89(s,3H),0.83(s,6H).
7)2，6-二羟基-3-环己氨基苯甲酸右莰醇酯(目标化合物10)
参考目标化合物4的合成方法，以4-氨基水杨酸冰片酯和环己酮为原料合成。1HNMR(400MHz,DMSO-d6)δ(ppm):6.69(d,1H),6.18(d,1H),5.02(d,1H),2.59-2.56(m,1H),2.36-2.29(m,1H),2.08-2.01(m,1H),1.75–1.60(m,4H),1.51–1.45(m,4H),1.31-1.01(m,7H),0.89(s,3H),0.83(s,6H).
1.4目标化合物11的合成
目标化合物11合成路线：
于干燥的茄形瓶中加入乙酸酐20mL，3,5-二特丁基-2,6-二羟基苯甲酸(11-1,参考化学世界,1987(08):10-12合成)5.32g(20.0mmol)，于0-4℃滴加乙酸酐5mL和发烟硝酸1.26g的混合溶液，加毕继续反应1小时，倒入100mL水和50g碎冰的混合物中，搅拌1小时，过滤，得4-硝基-3,5-二特丁基-2,6-二羟基苯甲酸(11-2)5.50g。
于干燥的茄形瓶中加入4-硝基-3,5-二特丁基-2,6-二羟基苯甲酸(11-2)3.11g，加25mL甲苯，3.25g硝基甲烷，搅拌下于10-20℃分批加入7.5g三氯化铝，加完后于25℃继续搅拌5小时，然后加入100mL水。水相加入30mL浓盐酸，用100mL甲基异丁酮，蒸除溶剂得4-硝基-2,6-二羟基苯甲酸粗品,2.0g。
将4-硝基-2,6-二羟基苯甲酸1.0g(5mmol)和右莰醇(4mmol)溶于10mL二氯甲烷中，加入DCC(7.5mmol)，DMAP(1mmol)，55℃反应6h。反应完成后，抽滤取滤液，旋干后加乙酸乙酯(EA)溶解，用饱和食盐水100mL洗涤三次，收集有机层干燥，制沙，石油醚(PE，60-90℃,)：乙酸乙酯(EA)＝30：1的条件过柱，产物旋干后打浆，得白色粉末。为4-硝基-2,6-二羟基苯甲酸莰醇酯(1.0g,11-4)。
于干燥的茄形瓶中加入0.8g 4-硝基-2,6-二羟基苯甲酸右莰醇酯(11-4)，加50mL甲醇溶解，加入0.2g10％钯碳，加氢还原，于室温下过夜反应。薄层板监测反应完全后，布氏漏斗滤去钯碳，滤液浓缩至10mL，缓慢滴加去离子水，直至有白色固体析出，抽滤得到0.6g白色固体，为4-氨基-2,6-二羟基苯甲酸右莰醇酯(目标化合物11)。1H NMR(400MHz,DMSO-d6)δ(ppm):6.98(t,1H),6.23(d,2H),5.02-4.07(m,1H),2.34-2.25(m,1H),2.04-1.96(m,1H),1.71-1.62(m,2H),1.23–1.13(m,2H),1.07-1.04(m,1H),0.88(s,3H),0.83(s,6H).
1.5目标化合物12-13的合成
1)2，6-二羟基-4-二甲氨基苯甲酸右莰醇酯(目标化合物12)合成：参考目标化合物5的合成方法，以2，6-二羟基-4-氨基苯甲酸右莰醇酯(目标化合物11)和多聚甲醛为原料合成。1H NMR(400MHz,DMSO-d6)δ7.04(ppm):(t,1H),6.28(d,2H),5.00-4.07(m,1H),3.01(s,6H),2.33-2.25(m,1H),2.05-1.96(m,1H),1.70-1.62(m,2H),1.22–1.13(m,2H),1.06-1.04(m,1H),0.88(s,3H),0.83(s,6H).
2)2，6-二羟基-4-(2-羟基-3，5-二氯)苄氨基苯甲酸右莰醇酯(目标化合物13)合成：
合成路线：
将4-氨基-2,6-二羟基苯甲酸右莰醇酯3.0g(10mmol)的10mL乙醇溶液和3,5-二氯水杨醛1.9g(10mmol)的10mL乙醇溶液混合，室温搅拌2小时，过滤得亚胺(13-1).将亚胺混悬于20mL甲醇溶液中，于0-4℃分批加入硼氢化钠，至溶液褪色，加水10mL，用盐酸调至中性，继续加水20mL。过滤，得白色粉末。为2，6-二羟基-4-(2-羟基-3，5-二氯)苄氨基苯甲酸右莰醇酯(目标化合物13)。1H NMR(400MHz,DMSO-d6)7.38(s,1H),7.14(s,1H),5.94(d,1H),5.78(s,2H),4.98(d,1H),4.31(s,2H),0.85-2.05(m,16H)。
1.6目标化合物14的合成:
将16wt.％(质量浓度)的盐酸溶液6.2mL用冰水浴降温到0～5℃，然后保持搅拌向其中加入2，6-二羟基-4-氨基苯甲酸右莰醇酯(目标化合物11)2.9g，加完以后，再向其中滴加由亚硝酸钠0.7g和1.2mL水配成的溶液，保持温度在8～10℃，滴加完毕以后保温搅拌30min，即得到重氮化产物；将重氮化产物滴加到温度为80～85℃的5.0mL 8M亚硫酸氢钠溶液中，滴加完毕后，保温搅拌30min。再向其中滴加30wt.％盐酸25mL溶液，得到中间体14-1盐酸盐；将上述反应液冷却到室温以后，用氨水调节pH到6，然后保持搅拌向其中滴加1.3g乙酰乙酸乙酯，滴加完毕以后，升温至95℃回流搅拌反应3h，停止加热，冷却抽滤，得到目标化合物3。1H NMR(400MHz,Chloroform-d)δ6.93(s,2H),5.92(s,1H),4.80(dt,1H),2.34-30(m,1H),2.28(s,3H),1.86-1.80(m,1H),1.75-1.70(m,1H),1.68-1.66(m,1H),1.32–1.17(m,2H),1.01(dd,1H),0.85(s,3H),0.81(s,6H).
1.7目标化合物15-20的合成
目标化合物15合成路线：
目标化合物16的合成:参考目标化合物15合成方法,以2，6-二羟基-3-氨基苯甲酸右莰醇酯(目标化合物3)和乙酰氯为原料合成.白色固体。1H NMR(400MHz,DMSO-d6)δ(ppm):7.11(d,1H),6.31(d,1H),5.01(d,1H),2.31(ddt,1H),2.01(s,3H),1.99–1.93(m,1H),1.65(q,2H),1.27–1.09(m,2H),1.05(dd,2H),0.88(s,3H),0.83(s,6H).
目标化合物17的合成:参考目标化合物15合成方法,以2，6-二羟基-3-氨基苯甲酸右莰醇酯(目标化合物3)和丙酰氯为原料合成.白色固体。1H NMR(400MHz,DMSO-d6)δ(ppm):7.11(d,1H),6.31(d,1H),5.01(d,1H),2.45-2.42(m,2H),2.33-2.30(m,1H),1.99–1.93(m,1H),1.65(q,2H),1.27–1.09(m,2H),1.05-1.01(m,5H),0.88(s,3H),0.83(s,6H).
目标化合物18的合成:参考目标化合物15合成方法,以2，6-二羟基-3-氨基苯甲酸右莰醇酯(目标化合物3)和丁酰氯为原料合成.白色固体。1H NMR(400MHz,DMSO-d6)δ(ppm):7.10(d,1H),6.31(d,1H),5.00(d,1H),2.41-2.38(m,2H),2.31(ddt,1H),2.01(s,3H),1.99–1.93(m,1H),1.79–1.75(m,1H),1.65(q,2H),1.26–1.09(m,2H),1.05(dd,2H),0.90-0.88(m,6H),0.83(s,6H).
目标化合物19的合成:参考目标化合物15合成方法,以2，6-二羟基-3-甲氨基苯甲酸右莰醇酯(目标化合物4)和乙酰氯为原料合成.白色固体。1H NMR(400MHz,DMSO-d6)δ(ppm):7.11(d,1H),6.31(d,1H),5.01(d,1H),2.31(ddt,1H),2.01(s,3H),1.99–1.93(m,1H),1.65(q,2H),1.27–1.09(m,2H),1.05(dd,2H),0.88(s,3H),0.83(s,6H).
目标化合物20的合成:参考目标化合物15合成方法,以2，6-二羟基-4-氨基苯甲酸右莰醇酯(目标化合物11)和乙酰氯为原料合成.白色固体。1H NMR(400MHz,DMSO-d6)δ(ppm):6.97(t,1H),6.22(d,2H),5.02-4.08(m,1H),2.34-2.24(m,1H),2.04-1.96(m,4H),1.71-1.62(m,2H),1.23–1.13(m,2H),1.07-1.04(m,1H),0.88(s,3H),0.83(s,6H).
1.8目标化合物21-24的合成
目标化合物21的合成:
合成路线：
将2，6-二羟基-4-甲酯基苯甲酸10.6g(50mmol，参考浙江工业大学学报2014:627-631制备)和右莰醇6.6g(40mmol)溶于30mL二氯甲烷中，加入DCC(75mmol)，DMAP(10mmol)，55℃反应6h。反应完成后，抽滤取滤液，旋干后加乙酸乙酯(EA)30mL溶解，用饱和食盐水100mL洗涤三次，有机层和100mL氨水溶液混合，搅拌24小时，30mL二氯甲烷中提取三次，有机层干燥，制沙，石油醚(PE，60-90℃,)：乙酸乙酯(EA)＝30:1的条件过柱，产物旋干后打浆，得白色粉末。为2，6-二羟基-4-甲酰胺基苯甲酸右莰醇酯(目标化合物21)。1H NMR(400MHz,DMSO-d6)δ(ppm):7.15(s,2H),4.95(d,1H),2.36-2.28(m,1H),2.10(s,1H),1.68-1.64(m,2H),1.26(d,2H),1.16(t,1H),0.87(s,3H),0.83(s,6H).
目标化合物22的合成:参考目标化合物21合成方法,以2，6-二羟基-4-甲酯基苯甲酸和二甲胺为原料合成，白色固体。1H NMR(400MHz,DMSO-d6)δ(ppm):7.16(s,2H),4.95(d,1H),2.93(s,6H),2.36-2.28(m,1H),2.11(s,1H),1.68-1.64(m,2H),1.26(d,2H),1.16(t,1H),0.87(s,3H),0.83(s,6H).
目标化合物22的合成:参考目标化合物21合成方法,以2，6-二羟基-4-甲酯基苯甲酸和二乙胺为原料合成，白色固体。1H NMR(400MHz,DMSO-d6)δ(ppm):7.14(s,2H),4.94(d,1H),3.99(t,4H),2.36-2.28(m,1H),2.10(s,1H),1.68-1.63(m,2H),1.35(q,4H),1.26(d,2H),1.16(t,1H),0.87(s,3H),0.83(s,6H).
目标化合物22的合成:参考目标化合物21合成方法,以2，6-二羟基-4-甲酯基苯甲酸和异丙胺为原料合成，白色固体。1H NMR(400MHz,DMSO-d6)δ(ppm):7.13(s,2H),4.93(d,1H),4.17-4.15(m,1H),2.36-2.28(m,1H),2.10(s,1H),1.68-1.64(m,2H),1.28-1.24(d,8H),1.15(t,1H),0.88(s,3H),0.83(s,6H).
实施例2目标化合物对体外培养的原代皮层神经元损伤的保护作用
2.1原代神经元培养
胎龄16d的孕鼠颈椎脱臼处死，取胎鼠，置于冰盒上，依次用新洁尔灭溶液和75％乙醇溶液进行全身消毒，然后用碘伏对头部皮肤进行消毒。小心取出双侧皮层，置于预冷的D-Hank’s溶液(10mL)中，清洗后剥离脑膜，D-Hank’s溶液清洗两遍，吸干D-Hank’s，剪碎皮层组织，转移至37℃预热的0.125％胰酶消化液(4mL)中，37℃消化8min后取出，加入5mLDMEM/F12+10％FBS终止消化，轻柔吹打分散组织。2500rpm离心3分钟，弃去上清，加入含有2％B27的Neuralbasal培养基，混匀，400目筛网过滤，滤液进行细胞计数后，按1×105个/cm2接种于PORN包被的24孔板中，置37℃，95％空气+5％CO2的混合湿润气体的细胞孵箱中培养。在细胞培养第1、4天半量换液。
2.2谷氨酸造模
在神经元体外培养第8天，进行Glu和Gly造模，测试药物对损伤的保护作用。受试药物设置0.1μmol/L、1μmol/L、10μmol/L三个浓度(DMSO配制成1000×母液，用培养基稀释)，预先孵育30min；正常对照和模型对照加入等浓度的DMSO(0.1％)进行孵育。孵育结束后，模型对照组、受试药物组更换含Glu(终浓度10μmol/L)和Gly(终浓度50μmol/L)的培养基孵育30min，模拟缺血损伤造模；正常对照更换不含Glu和Gly的培养基孵育。造模结束后将24孔板中的培养基弃干净，每孔加300μL新培养基，收集漏出的LDH。6小时后，回收300μL培养基(即细胞外液)，各孔加300μL ddH2O，放入-80℃冰箱，反复冻融3次，回收300μL ddH2O(即细胞內液)。收集的细胞内、外液置-80℃保存，待测。
2.3 LDH测定
冻存细胞内、外液冰上解冻，使用LDH试剂盒(南京建成生物A020-2-2)，按照说明书测定吸光度。细胞内、外液OD值＝测定OD值-对照OD值，LDH漏出率＝细胞外液OD值/(细胞外液OD值+细胞内液OD值)。
细胞保护率＝(模型组LDH漏出率-样品组LDH漏出率)/(模型组LDH漏出率-正常组LDH漏出率)*100％
表1目标化合物对谷氨酸损伤神经元细胞保护率
由表1可见：目标化合物对谷氨酸损伤神经元细胞具有良好的保护作用，具有较好的量效关系，其药效显著优于对照化合物，右崁醇在较低浓度下具有较好的神经保护作用，但是在较高浓度(10-6mol/L、10-5mol/L)下，其神经保护作用减弱。
实施例3目标化合物在大鼠局灶性脑缺血再灌注模型的保护作用
采用大脑中动脉线栓法制备大鼠大脑中动脉阻塞(Middle cerebral arteryocclusion,MCAO)脑缺血再灌注模型。药效学研究：共设5个组，即模型组、依达拉奉组(6.0mg/kg)化合物1组(10mg/kg)、化合物2组(10mg/kg)、化合物3组(10mg/kg)。各组动物于脑缺血再灌注后1小时尾静脉注射给药1次脑缺血再灌注后24小时观察神经缺陷症状，测定脑梗死面积。
3.1脑缺血模型的制备
采用大脑中动脉线栓法制备大脑中动脉阻塞(Middle cerebral arteryocclusion,MCAO)脑缺血再灌注模型。动物用气体麻醉(异氟烷)，采用进行麻醉，首先将大鼠放入MSS-3小动物麻醉机的诱导盒中麻醉，然后将大鼠仰卧位固定于连接呼吸面罩的鼠板上，消毒皮肤，颈部正中切开，分离右侧颈总动脉、颈外动脉、颈内动脉，轻轻剥离迷走神经，结扎并剪断颈外动脉。夹闭颈总动脉近心端，从颈外动脉的结扎线的远端作一切口，***的2438-A5线栓(顶端为半球形，前端5-6mm包被硅胶)，经过颈总动脉分叉进入颈内动脉，然后徐徐***至有轻微阻力为止(自分叉处约20mm)，阻断大脑中动脉的血供，缝合颈部皮肤，消毒，放回笼中。缺血90min后，再次将大鼠诱导麻醉，固定在鼠板上，剪开颈部皮肤，找到线栓将其轻轻拔出，恢复血供进行再灌注，缝合颈部皮肤，消毒，放回笼中饲养。
3.2神经缺陷症状评价
采用改良Bederson 5分制法进行神经缺陷症状评价。
0：提尾悬空时，动物的两前肢均伸向地板方向，且无其他行为缺陷
1：提尾悬空时，动物的手术对(左)侧前肢表现为腕肘屈曲、肩内旋、肘外展、紧贴胸壁
2：将动物置于光滑平板上，推手术侧肩向对侧移动时阻力降低
3：动物自由行走时，向手术对侧环行或转圈
4：肢体软瘫，肢体无自发活动
3.3脑梗死面积测定
采用文献报道的方法进行。动物用10％的水合氯醛麻醉，断头取脑，去除嗅球、小脑和低位脑干，用生理盐水冲洗大脑表面血迹，吸去表面残留水迹，于-80℃放置7min，取出后立即于视线交叉平面垂直向下作冠状切面，并向后每隔2mm切一片，将脑片置于用生理盐水新鲜配制的TTC(20g/L)染液中于37℃温育90min，正常脑组织染成深红色，缺血脑组织则呈苍白色，用生理盐水冲洗后，迅速将脑片从前向后按顺序排列，吸干表面残留水迹，拍照。用图像分析软件(Image Tool)对照片进行统计，圈定右侧缺血面积(白色区域)和右侧面积，用如下公式计算脑梗死面积的百分比。
3.4统计学分析
定量资料表示为均值±标准误。脑梗死面积、神经缺陷症状评分采用单因素方差分析，Scheffe`s检验测定两组间的差异显著性，死亡率、体重采用ANOVA检验，使用Stata统计软件进行分析，将差异P<0.05定义为差异显著。
3.5受试物对神经缺陷症状的影响
目标化合物1、对照化合物3、依达拉奉右崁醇对神经缺陷症状的影响见图1，依达拉奉右崁醇(6.0mg/kg+1.5mg/kg)、目标化合物1组(10.0mg/kg)、对照化合物3组(10.0mg/kg)与模型组相比，对神经缺陷症状有显著的改善作用。目标化合物1组显著优于对照化合物3组，和依达拉奉右崁醇组相当。
3.6受试物对脑梗死面积(％)的影响
目标化合物1、对照化合物3、依达拉奉右崁醇对脑梗死面积(％)的影响见图2依达拉奉右崁醇(6.0mg/kg+1.5mg/kg)、目标化合物1组(10.0mg/kg)、对照化合物3组(10.0mg/kg)与模型组相比与模型组相比，对脑梗死面积有显著的改善作用。目标化合物1组显著优于对照化合物3组，和依达拉奉右崁醇组相当。
采用MCAO模型，同法测定了目标化合物2(10.0mg/kg)、目标化合物13(10.0mg/kg)、目标化合物14(10.0mg/kg)、目标化合物16(10.0mg/kg)在缺血再灌注2小时的保护作用。对神经缺陷症状的影响见图3，对脑梗死面积(％)的影响见图4。
实施例4目标化合物的口服镇痛作用
4.1神经病理性疼痛模型的制作方法
采用脊神经结扎法(scgmcental spinal nerve ligation，SNL)制备神经病理性疼痛模型。腹腔注射2％水合氯醛(0.2mL/10g)麻醉小鼠，翻正反射消失后，固定小鼠于俯卧位。采用Kim和Chung的方法制作模型：在大鼠背部从L4-S2水平钝性分离长约3-5cm的正中皮肤切口，分离椎骨旁肌肉至第六腰椎突，暴露并切除暴露并切除右侧L5/L6关节突，部分咬开L6横突，从而能够暴露右侧的L4-L6脊神经，轻轻分离出L5神经，并用5-0丝线紧紧结扎L5。然后逐层缝合切口，捵伏消毒皮肤，继续饲养。术后动物出现步态异常，手术侧后肢除了轻度外翻、足趾紧收外，无其它畸形改变。采用类似方法制备大鼠SNL模型。
4.2行为学测定
用von frey纤维丝测定大鼠的机械性缩足反应阈值(paw withdrawalthreshold,PWT)来分别评价小鼠机械痛敏。所有各组小鼠在手术前两天测定基础痛阈。给药组分别在给药前、给药后1、2、4、6、8、10、12、24h分别测定PWT和PWL。采用类似方法测定大鼠基础痛阈。
4.3机械性缩足反应阈值(paw withdrawal threshold,PWT)的测定方法
用von frey纤维丝推算50％缩足阈值。50％缩足阈值的测定是指多次机械刺激能够引起50％缩足反应的机械力度，本实验使用接触刺激，采取up-and-down的方法测定小鼠后足50％缩足阈值。依次使用0.02，0/04，0.07,0.16,0.4,0.6,1.0,1.4和2.0g的力度，刺激后肢足底中部。将一有机玻璃箱(45cm*5cm*11cm)置于金属筛网上，待小鼠在有机玻璃箱中适应30分钟后，用von frey纤维丝垂直刺激大鼠后肢足底中部，持续时间＜4s，小鼠出现抬足或舔足行为视为阳性反应，反之为阴性反应。开始使用0.4的力度刺激，若没有缩足反应，则选择其上的一个力度0.6刺激后趾；若有缩足反应，则选择其下的一个力度0.16刺激，依次类推，在出现一次与前一次不同的反应(有缩足反应至无缩足反应或无缩足反应至有缩足反应)时，继续依序刺激4次，一共6次，即完成50％缩足阈值的测定。若需要使用的力度超过2.0或低于0.02，该侧阈值则直接记为2.0或0.02，每次刺激间隔30s。
在实验中尽量保持一致的测量手法，如力方向，加力速度和纤维丝弯曲程度，保持力的稳定性，力的撤除速度等。另外，对小鼠的反应判断标准尽量一致。
50％缩足阈值的计算使用公式：50％缩足阈值＝10log(X)+kδ(X为最后刺激使用的力度；k为不同刺激方式的系数，在系数表中查找；δ是指各刺激力度相邻间距的平均数，此处δ＝0.224)
4.4目标化合物对于大鼠神经病理性疼痛的镇痛作用
目标化合物13(10mg/kg,i.g.)、目标化合物16(10mg/kg,i.g.)、对照化合物3(10mg/kg,i.g.)对大鼠神经痛的镇痛作用见图5。本明所述的目标化合物，对神经病理性疼痛具有显著的镇痛作用，其药效显著优于对照化合物3。
Claims (5)
1.2,6-二羟基苯甲酸右崁醇酯类化合物，结构符合通式(I)
其中：R＝-H，-OH，-NR1R2，
或-CONR3R4；R1，R2＝-H或1-6个碳原子的烷基，
或-COR5；R3，R4，R5＝-H或1-3个碳原子的烷基。
2.权利要求1所述2,6-二羟基苯甲酸右崁醇酯类化合物，其特征在于，所述结构为如下任意一种：
3.权利要求1或2所述2,6-二羟基苯甲酸右崁醇酯类化合物的药学上可接受的盐。
4.权利要求1-3任一所述2,6-二羟基苯甲酸右崁醇酯类化合物及其药学上可接受的盐在制备治疗脑卒中损伤或神经病理性疼痛药物中的应用。
5.治疗脑卒中损伤或神经病理性疼痛药物，其特征在于有效成分包括权利要求1-3任一所述化合物及其药学上可接受的盐。
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN116407529A (zh) * | 2023-03-24 | 2023-07-11 | 南京医科大学 | 3-硝基-2,6-二羟基苯甲酸右崁醇或葑醇的酯的药物用途 |
| CN117045773A (zh) * | 2023-09-11 | 2023-11-14 | 江苏毫末医药生物科技有限公司 | 药物组合物在治疗疼痛上的应用 |
| CN116407529B (zh) * | 2023-03-24 | 2024-05-10 | 南京医科大学 | 3-硝基-2,6-二羟基苯甲酸右崁醇或葑醇的酯的药物用途 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN116407529A (zh) * | 2023-03-24 | 2023-07-11 | 南京医科大学 | 3-硝基-2,6-二羟基苯甲酸右崁醇或葑醇的酯的药物用途 |
| CN116407529B (zh) * | 2023-03-24 | 2024-05-10 | 南京医科大学 | 3-硝基-2,6-二羟基苯甲酸右崁醇或葑醇的酯的药物用途 |
| CN117045773A (zh) * | 2023-09-11 | 2023-11-14 | 江苏毫末医药生物科技有限公司 | 药物组合物在治疗疼痛上的应用 |
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