CN112138003A - 3-正丁基-异吲哚啉-1-酮在镇静、抗惊厥和抗癫痫的药物中的应用 - Google Patents
3-正丁基-异吲哚啉-1-酮在镇静、抗惊厥和抗癫痫的药物中的应用 Download PDFInfo
- Publication number
- CN112138003A CN112138003A CN201910580960.2A CN201910580960A CN112138003A CN 112138003 A CN112138003 A CN 112138003A CN 201910580960 A CN201910580960 A CN 201910580960A CN 112138003 A CN112138003 A CN 112138003A
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- Prior art keywords
- butyl
- isoindoline
- ketone
- isoindolin
- anticonvulsant
- 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.)
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Abstract
本发明涉及了如通式I所示的化合物3‑正丁基‑异吲哚啉‑1‑酮在镇静、抗惊厥和抗癫痫的药物中的应用。通过药效学研究事实也表明，3‑正丁基‑异吲哚啉‑1‑酮能明显减少自主活动，能明显延长小鼠强直性警觉发作的潜伏期，强直性惊厥发生率降低，惊厥小鼠的病死时间显著延长，病死率降低，镇静、抗癫痫效果均优于丁苯酞。由于3‑正丁基‑异吲哚啉‑1‑酮是白色粉末状固体，适合于制剂的需求，相比于其类似药物3‑丁基‑1‑异苯并呋喃酮的油状液体形态，在制剂方面有更大自由性，为临床用药提供了更多选择，降低了用药成本。
Description
技术领域：
本发明属于化合物医药领域，具体涉及3-正丁基-异吲哚啉-1-酮和含有3-正丁基-异吲哚啉-1-酮的药用组合物在镇静、抗惊厥和抗癫痫的药物中的应用。
背景技术：
脑梗塞(cerebral infarction，CI)，又称为缺血性脑卒中，(cerebral ischemicstroke，CIS)，是危害人类生命健康的三大杀手之一，紧随心脏病和癌症之后。脑梗死后不少患者可继发出现癫痫，称之为“卒中后癫痫”，而癫痫反复发作又会进一步加重脑损伤，严重影响脑梗死患者的预后。但是癫痫治疗复杂且疗程长，目前临床上常用的一线抗癫痫药可使70％-80％各类癫痫患者发作得以控制，余下的难治性癫痫行外科手术治疗，但受到适应症的限制，这不得不开发新的药物同时发现新的适应症
本发明发现了3-正丁基-异吲哚啉-1-酮具有很好的镇静、抗惊厥、抗癫痫的作用。在研究3-正丁基-异吲哚啉-1-酮治疗局部脑缺血引起的脑梗死时，意外发现3-正丁基-异吲哚啉-1-酮具有镇静作用，所以推断3-正丁基-异吲哚啉-1-酮具有镇静、抗惊厥、抗癫痫的作用，而通过药效学研究事实也表明，3-正丁基-异吲哚啉-1-酮能明显减少自主活动，能明显延长小鼠强直性警觉发作的潜伏期，强直性惊厥发生率降低，惊厥小鼠的病死时间显著延长，病死率降低，镇静、抗癫痫效果均优于3-丁基-1-异苯并呋喃酮。由于3-正丁基-异吲哚啉-1-酮是白色粉末状固体，适合于制剂的需求，很可能对于“卒中后癫痫”以及难治性癫痫有一定的治疗效果。
发明内容：
针对通式I所示化合物3-正丁基-异吲哚啉-1-酮具有抗脑卒中作用的研究不足，本发明发现3-正丁基-异吲哚啉-1-酮同时具有镇静、抗惊厥、抗癫痫的作用，并通过药效学实验证明其镇静、抗癫痫作用明显优于3-丁基-1-异苯并呋喃酮，很可能用于“卒中后癫痫”以及难治性癫痫的治疗。
本发明上述目的通过以下技术方案予以实现：
本发明具体涉及了含有3-正丁基-异吲哚啉-1-酮的用于治疗“卒中后癫痫”以及难治性癫痫的的药物或药用组合物的用途。
本发明研究发现，3-正丁基-异吲哚啉-1-酮镇静、抗癫痫作用优于正丁基苯酞本发明通过观察3-正丁基-异吲哚啉-1-酮对小鼠自主活动的影响发现其具有很好的镇静活性。分别为：(1)第一组为阴性对照组(PEG400)；(2)3-正丁基-异吲哚啉-1-酮低剂量组(L-NBI，200mg/kg)；(3)3-正丁基-异吲哚啉-1-酮中剂量组(M-NBI，400mg/kg)；(4)3-正丁基-异吲哚啉-1-酮高剂量组(H-NBI，800mg/kg)；(5)3-丁基-1-异苯并呋喃酮组(NBP，400mg/kg)；(6)***组(DG，1500mg/kg)。各组小鼠均按0.2ml/kg腹腔注射给药。各组小鼠于给药前分别放入GJ-1型光电计数仪的活动箱内适应30min后给药，分别于20min、40min后记录小鼠5min自主活动次数，所得数据用spss.13软件进行统计分析，并比较组间的显著差异。发现L-NBI(P＝0.048)、M-NBI(P＝0.024)、H-NBI(P＝0.009)与对照组相比具有显著性差异。而且3-正丁基-异吲哚啉-1-酮组中、高剂量组的效果均优于3-丁基-1-异苯并呋喃酮组。
本发明结果不仅证实3-正丁基-异吲哚啉-1-酮具有很好的镇静、抗惊厥、抗癫痫作用，而且，由于该化合物是白色粉末状固体，较之于丁基苯酞的油状液体结构，在制剂领域有很大的选择余地，对改变给药方式提供新的可能，有利于降低制药成本，提高用药效率，因此，3-正丁基-异吲哚啉-1-酮具有广阔的应用前景。
本发明涉及含有作为活性成分的本发明化合物和药学可接受的赋形剂或辅料的药用组合物。通常本发明药用组合物含有0.1-95％重量的本发明化合物。
本发明的化合物的药用组合物可根据本领域公知的方法制备。用于此目的时，如果需要，可将本发明化合物和一种或多种固体或液体药物赋形剂和/或辅料结合，制成可作为人药或兽药使用的适当的施用形式或剂量形式。
本发明的化合物由于是晶体形态，在制剂方面，可以将该化合物或含该化合物的药用组合物制成液体剂型、气体剂型、半固体剂型和固体剂型。如液体剂型可以是真溶液类、乳剂剂型、混悬剂型、微粒剂型、胶体剂型等；气体制剂可以是气雾剂、喷雾剂、粉雾剂；半固体制剂可以是服膏滋、外用膏剂、糊剂等；固体剂型可以为片剂、胶囊剂、滴丸、丸剂、粉剂、栓剂、颗粒剂、冻干粉针剂等。
本发明化合物或含该化合物的药用组合物可以单位剂量形式给药，给药途径可以是肠道或非肠道，如口服、肌肉、皮下、鼻腔、口腔黏膜、皮肤、腹膜、直肠等。
本发明化合物或含该化合物的药用组合物的给药途径可以是注射给药，包括静脉注射、肌肉注射、皮下注射、皮内注射及穴位注射等。
本发明化合物或含该化合物的药用组合物既可以制成普通制剂，也可以制成缓控释与靶向制剂及各种微粒给药***。
为了将单位给药剂型制成片剂，可以广泛使用本领域公知的各种载体。关于载体的例子是，例如稀释剂与吸收剂，如淀粉、糊精、硫酸钙、乳糖、甘露醇、蔗糖、氯化钠、葡萄糖、尿素、碳酸钙、白陶土、微晶纤维素、硅酸铝等；湿润剂与粘合剂，如水、甘油、聚乙二醇、乙醇、丙醇、淀粉浆、糊精、糖浆、蜂蜜、葡萄糖溶液、***胶浆、明胶浆、羧甲基纤维素钠、紫胶、甲基纤维素、磷酸钾、聚乙烯吡咯烷酮等；崩解剂，例如干燥淀粉、海藻酸盐、琼脂粉、褐藻淀粉、碳酸氢钠与枸橼酸、碳酸钙、聚氧乙烯山梨糖醇脂肪酸酯、十二烷基磺酸钠、甲基纤维素、乙基纤维素等；崩解抑制剂，例如蔗糖、三硬脂酸甘油酯、可可脂、氢化油等；吸收促进剂，例如季铵盐、十二烷基硫酸钠等；润滑剂，例如滑石粉、二氧化硅、玉米淀粉、硬脂酸盐、硼酸、液体石蜡、聚乙二醇等。还可以将片剂进一步制成包衣片，例如糖包衣片、薄膜包衣片、肠溶包衣片，或双层片和多层片。
例如为了将给药单元制成丸剂，可以广泛使用本领域公知的各种载体。关于载体的例子是，例如稀释剂与吸收剂，如葡萄糖、乳糖、淀粉、可可脂、氢化植物油、聚乙烯吡咯烷酮、高岭土、滑石粉等；粘合剂，如***胶、黄蓍胶、明胶、乙醇、蜂蜜、液糖、米糊或面糊等；崩解剂，如琼脂粉、干燥淀粉、海藻酸盐、十二烷基磺酸钠、甲基纤维素、乙基纤维素等。
例如为了将给药单元制成胶囊，将有效成分本发明化合物与上述的各种载体混合，并将由此得到的混合物置于硬的明胶胶囊或软胶囊中。也可将有效成分本发明化合物制成微囊剂，混悬于水性介质中形成混悬剂，亦可装入硬胶囊中或制成注射剂应用。
例如，将本发明化合物制成注射用制剂，如溶液剂、混悬剂溶液剂、乳剂、冻干粉针剂，这种制剂可以是含水或非水的，可含一种和/或多种药效学上可接受的载体、稀释剂、粘合剂、润滑剂、防腐剂、表面活性剂或分散剂。如稀释剂可选自水、乙醇、聚乙二醇、1，3-丙二醇、乙氧基化的异硬脂醇、多氧化的异硬脂醇、聚氧乙烯山梨醇脂肪酸酯等。另外，为了制备等渗注射液，可以向注射用制剂中添加适量的氯化钠、葡萄糖或甘油，此外，还可以添加常规的助溶剂、缓冲剂、pH调节剂等。这些辅料是本领域常用的。
此外，如需要，也可以向药物制剂中添加着色剂、防腐剂、香料、矫味剂、甜味剂或其它材料。
为达到用药目的，增强治疗效果，本发明的药物或药物组合物可用任何公知的给药方法给药。
本发明化合物药物组合物的给药剂量取决于许多因素，例如所要预防或治疗疾病的性质和严重程度，患者或动物的性别、年龄、体重、性格及个体反应，给药途径、给药次数、治疗目的，因此本发明的治疗剂量可以有大范围的变化。一般来讲，本发明中药学成分的使用剂量是本领域技术人员公知的。可以根据本发明化合物组合物中最后的制剂中所含有的实际药物数量，加以适当的调整，以达到其治疗有效量的要求，完成本发明的预防或治疗目的。
每一种治疗所需总剂量可分成多次或按一次剂量给药。本发明的化合物或组合物可单独服用，或与其他治疗药物或对症药物合并使用并调整剂量。
以下结合实例对本发明作详述，但不作为对本发明的限定。
具体实施方式
实施例1 3-正丁基-异吲哚啉-1-酮片剂的制备
【处方】
按处方量准确称取恒重的3-正丁基-异吲哚啉-1-酮，研成粉末后过100目筛，备用。准确称取恒重的淀粉，过100目筛。将过筛后的3-正丁基-异吲哚啉-1-酮、淀粉混合均匀，加入适量50％乙醇，制软材，通过18目尼龙筛制粒，60-70℃干燥，用18目筛整粒，然后加入羧甲基淀粉钠、硬脂酸镁，混匀。Φ8mm冲模压片即得。
实施例2 3-正丁基-异吲哚啉-1-酮硬胶囊的制备
【处方】
湿法制粒方法同实施例1。按处方量准确称取恒重的3-正丁基-异吲哚啉-1-酮，研成粉末后过100目筛，备用。准确称取恒重的淀粉，过100目筛。将过筛后的3-正丁基-异吲哚啉-1-酮、淀粉混合均匀，加入适量50％乙醇，制软材，通过18目尼龙筛制粒，60-70℃干燥，用18目筛整粒，检测含量，合格后装入1号胶囊即得。
实施例3 3-正丁基-异吲哚啉-1-酮软胶囊的制备
取制备的3-正丁基-异吲哚啉-1-酮1g，植物油10g，聚甘油酸酯1g，混合后，置球磨机中混匀，制得软胶囊内容物。以明胶∶甘油∶水∶遮光剂＝1∶0.4∶0.8∶0.01为囊材，采用模压法制备软胶囊，软胶囊经冷风固化、干燥，用适当的溶剂洗、终干，制得软胶囊100粒。
实施例4 3-正丁基-异吲哚啉-1-酮冻干粉的制备
取制备的3-正丁基-异吲哚啉-1-酮1g，加入800ml注射用水，溶解后加入甘露醇6g，充分溶解后，补加注射用水至1000ml，活性炭脱碳后过微孔滤膜，分装于7ml西林瓶中，每瓶4ml，加塞，冻干，压盖，即得。规格4mg/瓶。
实施例5 3-正丁基-异吲哚啉-1-酮注射剂的制备
取制备的3-正丁基-异吲哚啉-1-酮1g以及氯化钠9g，加注射用水约900ml，调节PH至6.5-7.2，加入3g针用碳，搅匀，煮沸15min，溶液趁热用滤纸过滤除碳，然后经0.22μm微孔滤膜精滤。加注射用水至1000ml，检查滤液澄明度，合格后分装于5ml安瓿瓶中，熔封，110℃加压灭菌30min即可。
实施例6 3-正丁基-异吲哚啉-1-酮对小鼠自主活动的影响
(1)动物分组
选取20-22g(雌雄各半)昆明小鼠，实验前将小鼠放入GJ-1型光电计数仪的活动箱内，启动记录仪，记录小鼠在5min的活动次数，选取自主活动数130次左右作为正常小鼠，然后根据自主活动次数分配到各个实验组，实验前各组小鼠的自主活动无明显差异。
实验分组
选取昆明小鼠60只，随机分成6组，每组10只，分别为：(1)第一组为阴性对照组(PEG400)；(2)3-正丁基-异吲哚啉-1-酮低剂量组(L-NBI，200mg/kg)；(3)3-正丁基-异吲哚啉-1-酮中剂量组(M-NBI，400mg/kg)；(4)3-正丁基-异吲哚啉-1-酮高剂量组(H-NBI，800mg/kg)；(5)3-丁基-1-异苯并呋喃酮组(NBP，400mg/kg)；(6)***组(DG，1500mg/kg)。各组小鼠均按0.2ml/kg腹腔注射给药。各组小鼠于给药前分别放入GJ-1型光电计数仪的活动箱内适应30min后给药，分别于20min、40min后记录小鼠5min自主活动次数，所得数据用spss.13软件进行统计分析，并比较组间的显著差异。
实验结果
3-正丁基-异吲哚啉-1-酮对小鼠自主活动的影响(表-1)
实验数据用统计学软件SPSS17.0进行处理，用单因素方差分析法(ANOVA)检验各组间神经行为学的差异，结果表明：3-正丁基-异吲哚啉-1-酮组低、中、高剂量组均能明显抑制小鼠的自发活动次数，L-NBI(P＝0.048)、M-NBI(P＝0.024)、H-NBI(P＝0.009)与对照组相比具有显著性差异。在统计学分析上具有显著的线性正相关，剂量越高，抑制小鼠的自发活动越明显，镇静作用越强。而且3-正丁基-异吲哚啉-1-酮组中、高剂量组的效果均优于3-丁基-1-异苯并呋喃酮组。
实施例7 3-正丁基-异吲哚啉-1-酮对***致小鼠癫痫的影响
(1)实验分组
选取健康昆明小鼠60只，体重20-22g，随机分成6组，每组10只，分别为：(1)第一组为阴性对照组(PEG400)；(2)3-正丁基-异吲哚啉-1-酮低剂量组(L-NBI，200mg/kg)；(3)3-正丁基-异吲哚啉-1-酮中剂量组(M-NBI，400mg/kg)；(4)3-正丁基-异吲哚啉-1-酮高剂量组(H-NBI，800mg/kg)；(5)3-丁基-1-异苯并呋喃酮组(NBP，400mg/kg)；(6)***那(PG，20g/kg)。各组小鼠均按0.2ml/kg腹腔注射给药。将小鼠分组给药40min后，腹腔注射硝酸***2mg/kg致娴，2h内观察并记录强直性惊厥发作潜伏期、病死时间、强直性惊厥发生率及病死率
(2)分级标准
观察各组大鼠癫痫样发作的潜伏期、持续时间、发作形式。潜伏期指腹腔注射硝酸***后至开始有抽搐反应的时间。持续时间指开始有抽搐反应至停止发作的时间。参照RACINE分级标准对痫性发作行为分级。
0级：无反应或抽搐停止；
I级：节律性嘴和面部抽动；
II级：点头或甩尾；
III级：单肢抽动；
IV级：多肢抽动或强直；
V级：全面性强直阵挛发作。
实验结果
3-正丁基-异吲哚啉-1-酮对***致小鼠癫痫的影响(表-2)
实验数据用统计学软件SPSS17.0进线处理，用单因素方差分析法(ANOVA)检验各组间神经行为学的差异，表明与模型组相比，3-正丁基-异吲哚啉-1-酮组低、中、高剂量组均能明显延长小鼠强直性警觉发作的潜伏期，强直性惊厥发生率降低，惊厥小鼠的病死时间显著延长，病死率降低，L-NBI(P＝0.038)、M-NBI(P＝0.007)、H-NBI(P＜0.001)与模型组相比均有明显统计学差异，而且具有剂量正相关性，剂量越高，作用效果越强，同时M-NBI与3-丁基-1-异苯并呋喃酮组效果相当，差异无统计学差异(P＝0.391)。
以上结果说明，3-正丁基-异吲哚啉-1-酮具有很好的镇静、抗惊厥、抗癫痫的作用。
Claims (7)
1.一种如通式I所示的3-正丁基-异吲哚啉-1-酮在镇静、抗惊厥和抗癫痫的药物中的应用
2.根据权利要求1所述的化合物，其特征是：3-正丁基-异吲哚啉-1-酮为(±)-3-正丁基-异吲哚啉-1-酮、(+)-3-正丁基-异吲哚啉-1-酮或(-)-3-正丁基-异吲哚啉-1-酮。
3.根据权利要求1所述的应用，其特征在于，惊厥与癫痫为临床各种疾病引起，尤其适用于脑梗死后引起的“卒中后癫痫”。
4.根据权利要求1所述的应用，其特征在于，所述化合物的有效治疗剂量为：0.1-200mg/kg/天。
5.一种用于镇静、抗惊厥和抗癫痫的药用组合物，其特征在于，包含有效治疗量的如通式I所示3-正丁基-异吲哚啉-1-酮及药用载体或赋形剂，
6.根据权利要求5所述的药用组合物，其特征在于，所述的药用组合包括片剂、胶囊剂、注射剂、颗粒剂、丸剂、散剂、缓释制剂、控释制剂及各种微粒给药***。
7.根据权利要求5所述的药用组合物，其特征在于，所述的药用组合物用于制备预防或治疗由局部脑缺血导致的脑梗塞的药物中的应用。
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| US4898871A (en) * | 1986-12-02 | 1990-02-06 | Rhone-Poulenc Sante | Pyrrole derivatives and pharmaceutical compositions which contain them as hypnotics and anticonvulsants |
| US4960779A (en) * | 1986-12-02 | 1990-10-02 | Rhone-Poulenc Sante | Pyrrole derivatives, and pharmaceutical compositions which contain them and pharmacological methods of use |
| CN103655555A (zh) * | 2012-09-14 | 2014-03-26 | 中山大学 | 3-n-异吲哚啉-1-酮在制备预防和治疗脑梗塞的药物中的应用 |
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| US4898871A (en) * | 1986-12-02 | 1990-02-06 | Rhone-Poulenc Sante | Pyrrole derivatives and pharmaceutical compositions which contain them as hypnotics and anticonvulsants |
| US4960779A (en) * | 1986-12-02 | 1990-10-02 | Rhone-Poulenc Sante | Pyrrole derivatives, and pharmaceutical compositions which contain them and pharmacological methods of use |
| CN103655555A (zh) * | 2012-09-14 | 2014-03-26 | 中山大学 | 3-n-异吲哚啉-1-酮在制备预防和治疗脑梗塞的药物中的应用 |
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