CN109745323A - 氮哌酮类化合物提高副交感神经活性的用途 - Google Patents
氮哌酮类化合物提高副交感神经活性的用途 Download PDFInfo
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Abstract
氮哌酮类化合物提高副交感神经活性的用途。式I化合物或其药学上可接受的盐在制备治疗副交感神经活性不足综合征的药物中的用途;在副交感神经活性测定中作为阳性对照品的用途;以及在制备治疗由副交感神经活性不足导致的高血压、高血糖、高血脂、糖尿病、神经性食欲不振、痛风、甲状腺功能亢进症、消化性溃疡、肠易激综合征、头痛、癫痫、帕金森病、脑卒中、睡眠障碍、慢性疲劳、肥胖症、体位性低血压、抑郁症、焦虑、注意力低下、哮喘、肌纤维痛、慢性类风湿性关节炎、慢性阻塞性肺疾病、冠心病、心肌梗死、心律失常、粉刺、性功能障碍、干眼、口干或免疫功能紊乱的药物中的用途:在式I中,n为4或5;R为:或
Description
技术领域
本发明涉及氮哌酮类化合物的新用途,特别涉及氮哌酮类化合物提高副交感神经活性的相关用途。
背景技术
副交感神经系统是植物性神经系统的主要部分,它发自中脑、桥脑、延脑及脊髓的骶部。它的节前纤维在副交感神经节中交换神经元,然后由此发出节后纤维,至平滑肌、心肌和腺体。副交感神经节一般位于脏器附近或脏器壁内。
副交感神经系统可保持身体在安静状态下的生理平衡,其作用有三个方面:①增进胃肠的活动、消化腺的分泌、促进大小便的排出、保持身体的能量。②瞳孔缩小以减少刺激,促进肝糖原的生成以储蓄能源。③心跳减慢、血压降低、支气管缩小,以节省不必要的消耗;协助生殖活动,如使生殖血管扩张、性器官分泌液增加。随着现代人们生活节奏的加快,压力的增大,越来越多的人出现副交感神经功能紊乱,造成严重疾病,或者身体其他指标基本正常,但副交感神经功能失调的亚健康问题,副交感神经功能不足引发的各种病症和不适越来越普遍。
副交感神经功能不足还可引起血压升高、身心紧张、唾液和泪液分泌减少、血糖升高等。因此,提高副交感神经活性对治疗高血压、高血糖、高血脂、糖尿病、神经性食欲不振、痛风、甲状腺功能亢进症、消化性溃疡、肠易激综合征、头痛、癫痫、帕金森病、脑卒中、睡眠障碍、慢性疲劳、肥胖症、体位性低血压、抑郁症、焦虑、注意力低下、哮喘、肌纤维痛、慢性类风湿性关节炎、慢性阻塞性肺疾病、冠心病、心肌梗死、心律失常、粉刺、性功能障碍、干眼、口干或免疫功能紊乱等具有非常重要的意义。
已有文献报道了氮哌酮类化合物作为治疗精神病类药物的用途(例如CN1115317)。但目前,尚未有此类化合物用于提高副交感神经功能的相关报道。
发明内容
本发明人研究发现,氮哌酮类化合物具有提高副交感神经功能的活性
鉴于此,本发明提供式I的氮哌酮类化合物的新用途,具体地,是式I化合物或其药学上可接受的盐在制备治疗副交感神经活性不足综合征的药物中的用途;在副交感神经活性测定中作为阳性对照品的用途;以及在制备治疗由副交感神经活性不足导致的高血压、高血糖、高血脂、糖尿病、神经性食欲不振、痛风、甲状腺功能亢进症、消化性溃疡、肠易激综合征、头痛、癫痫、帕金森病、脑卒中、睡眠障碍、慢性疲劳、肥胖症、体位性低血压、抑郁症、焦虑、注意力低下、哮喘、肌纤维痛、慢性类风湿性关节炎、慢性阻塞性肺疾病、冠心病、心肌梗死、心律失常、粉刺、性功能障碍、干眼、口干或免疫功能紊乱的药物中的用途:
在式I中,n为4或5;
R为:
或
优选地,在上述式I中,n为4。
优选地,式I化合物或其药学上可接受的盐为坦度螺酮、丁螺环酮、伊沙匹隆、吉哌隆、扎螺酮(WY-47846)或它们药学上可接受的盐。
优选地,在本发明的用途中,如权利要求1-4任一项所述的用途,其中,所述药学上可接受的盐为盐酸盐、硫酸盐、酒石酸盐、草酸盐、马来酸盐、富马酸盐、枸橼酸盐;更优选为盐酸盐或枸橼酸盐。
优选地,在本发明的用途中,所述药物的给药途径包括口服或经肠胃外给药,可选地,所述给药途径为口服、静脉内、经皮下、肌内、透皮或吸入给药。
优选地,在本发明的用途中,所述药物的剂型为:片剂、胶囊剂、颗粒剂、口服液、膜剂、贴剂或注射剂;可选地,所述药物剂型为:缓释片剂、舌下含片、口腔速崩片、分散片、肠溶片、肠溶胶囊、延迟释放片、定时/位释放片、缓释胶囊、控释胶囊、含有微丸或小片的胶囊、含有微丸或小片的pH依赖型胶囊。
优选地,在本发明的用途中,所述药物包括所述式I化合物或其药学上可接受的盐和药用辅料,所述药用辅料包括下述辅料中的一种或多种:
稀释剂,所述稀释剂优选乳糖、糊精、预胶化淀粉、玉米淀粉、微晶纤维素、硫酸钙、磷酸钙、磷酸氢钙、沉降碳酸钙、甘露醇、琼脂粉中的一种或多种;
粘合剂,所述粘合剂优选糖浆、阿拉伯胶、明胶、山梨醇、黄芪胶、淀粉浆、聚维酮、微晶纤维素、羧甲基纤维素钠、乙基纤维素、羟丙甲基纤维素中的一种或多种;
崩解剂,所述崩解剂优选干淀粉、羧甲淀粉钠、低取代羟丙基纤维素、交联聚维酮中的一种或多种;
润滑剂,所述润滑剂优选羧甲基淀粉钠、淀粉乙醇酸钠、预胶化淀粉、改良淀粉、羟丙基淀粉、玉米淀粉、交联聚维酮、微晶纤维素、羧甲基纤维素钠、乙基纤维素、羟丙甲基纤维素中的一种或多种;
助流剂,所述助流剂优选微粉硅胶、硬脂酸镁、滑石粉、氢化植物油、聚乙二醇类中的一种或多种;
矫味剂,所述矫味剂优选蔗糖、甜橘苷、糖精钠、蛋白糖、山梨醇、阿斯巴甜中的一种或多种。
优选地,在本发明所述的用途中,所述药物或药物组合物的给药剂量为每日每公斤体重0.1-2.4mg,优选为每日每公斤体重0.2-1.2mg有效药物。
本发明对所述药物组合物的各种剂型的制备方法并没有特别的限定,均可通过现有报道的常规的制备方法得到。
有益效果:
试验表明,式I的化合物或其药学上可接受的盐具有显著提高副交感神经功能的活性,因而,可以用于治疗副交感神经功能不足综合征。可以对各项体检指标正常但副交感神经功能不足的亚健康患者进行治疗,改善人们的生活质量,以及用于对由副交感神经功能不足导致的各种病症进行针对性的精准治疗。
另外,在药物研发或药效测试中,可将通式I的化合物及其药学上可接受的盐作为阳性对照工具药,用于评价待开发化合物是否具有调节副交感神经功能的活性,为新药的研发提供了药效参照。
具体实施方式
以下对本发明的具体实施方式进行详细说明。应当理解的是,此处所描述的具体实施方式仅用于示例性地对本发明进行说明,并不用于限制本发明。
本发明以下实施例中所用到的原料和辅料药均可在商业上购买获得。
实施例1
药物的制备
坦度螺酮 | 0.007mol(1000粒胶囊或1000片) |
淀粉 | 200g |
微晶纤维素 | 5g |
将坦度螺酮与淀粉通过等量递增法混匀后,再与微晶纤维素混匀,制粒,压片,即得片剂;或装胶囊,即得胶囊剂。
实施例2
药物的制备
盐酸坦度螺酮 | 0.157mol(1000粒丸剂) |
矫味剂 | 1.5g |
蒸馏水 | 500ml |
淀粉 | 80g |
糊精 | 20g |
将盐酸坦度螺酮与淀粉通过等量递增法混匀后,再与糊精、矫味剂混匀,乏丸,干燥即得。
实施例3
药物的制备
枸橼酸坦度螺酮 | 0.026mol(1000粒胶囊或1000片) |
淀粉 | 80g |
微晶纤维素 | 20g |
将枸橼酸坦度螺酮与淀粉通过等量递增法混匀后,在与微晶纤维素混匀,制粒,压片,即得片剂;或装胶囊,即得胶囊剂。
实施例4
药物的制备
枸橼酸坦度螺酮 | 0.078mol(1000袋颗粒) |
糖粉 | 400g |
糊精 | 200g |
可溶性淀粉 | 400g |
将枸橼酸坦度螺酮与糊精通过等量递增法混匀,再与其他辅料混匀,制粒即得。
实施例5
药物的制备
马来酸坦度螺酮 | 0.026mol(1000粒胶囊或1000片) |
淀粉 | 200g |
微晶纤维素 | 5g |
将马来酸坦度螺酮与淀粉通过等量递增法混匀后,再与微晶纤维素混匀,制粒,压片,即得片剂;或装胶囊,即得胶囊剂。
实施例6
药物的制备
L-酒石酸坦度螺酮 | 0.026mol(1000粒胶囊或1000片) |
淀粉 | 200g |
微晶纤维素 | 5g |
将马来酸坦度螺酮与淀粉通过等量递增法混匀后,再与微晶纤维素混匀,制粒,压片,即得片剂;或装胶囊,即得胶囊剂。
实施例7
药物的制备
草酸坦度螺酮 | 0.026mol(1000粒胶囊或1000片) |
淀粉 | 200g |
微晶纤维素 | 5g |
将马来酸坦度螺酮与淀粉通过等量递增法混匀后,再与微晶纤维素混匀,制粒,压片,即得片剂;或装胶囊,即得胶囊剂。
实施例8
药物的制备
硫酸坦度螺酮 | 0.026mol(1000粒胶囊或1000片) |
淀粉 | 200g |
微晶纤维素 | 5g |
将马来酸坦度螺酮与淀粉通过等量递增法混匀后,再与微晶纤维素混匀,制粒,压片,即得片剂;或装胶囊,即得胶囊剂。
实施例9
药物的制备
盐酸丁螺环酮 | 0.0237mol(1000粒胶囊或1000片) |
淀粉 | 200g |
微晶纤维素 | 5g |
将盐酸丁螺环酮与淀粉通过等量递增法混匀后,再与微晶纤维素混匀,制粒,压片,即得片剂;或装胶囊,即得胶囊剂。
实施例10
药物的制备
盐酸丁螺环酮 | 0.0237mol(1000袋颗粒) |
糖粉 | 400g |
糊精 | 200g |
可溶性淀粉 | 400g |
阿斯巴甜 | 1g |
将盐酸丁螺环酮与糊精通过等量递增法混匀,再与其他辅料混匀,制粒即得。
试验例1:枸橼酸坦度螺酮对副交感神经功能的活性
1、研究对象:
病例选择:选取副交感神经功能低下患者108例,男女各54例,年龄分布在20-49岁。随机分为9组:枸橼酸坦度螺酮胶囊5mg组,枸橼酸坦度螺酮胶囊10mg组,枸橼酸坦度螺酮胶囊15mg组,枸橼酸坦度螺酮胶囊20mg组,盐酸丁螺环酮片5mg组,盐酸丁螺环酮片10mg组,盐酸丁螺环酮片15mg组,盐酸丁螺环酮片20mg组,安慰剂组,其中每组都是男女各六例,各组之间性别、年龄、职业分布均无明显差异。
1.1入选标准
(1)年龄在20-49岁之间
(2)采用SA-3000P精神分析压力仪测定HF值,HF值较正常人低下的。HF是HRV频域指标中的高频功率,是评估副交感神经活性的指标。HF值增大,副交感神经活性增高。
1.2排除标准
(1)长期大量吸烟酗酒者。
(2)冠心病、瓣膜病等心脏器质性疾病;
(3)心房颤动、室上速等心律失常;
(4)神经系统器质性疾病;
(5)甲状腺功能亢进、甲低等;
(6)合并消化性溃疡、哮喘、慢性阻塞性肺疾病、慢性肾功能不全。
2、研究方法:
所有入选患者停用影响心率及副交感神经的药物五个半衰期以上。
2.1给药方法
治疗组服用:枸橼酸坦度螺酮胶囊5mg、10mg、15mg、20mg(四川科瑞德制药股份有限公司提供);盐酸丁螺环酮片5mg、10mg、15mg、20mg(市售产品)。
对照组服用:安慰剂。
2.2检查方法
2.2.1、所有入选患者服药前采用SA-3000P精神分析压力仪测定HF值,服药后避免剧烈运动及情绪激动,禁用含有咖啡因等影响副交感神经活性的饮料或药物,2小时后再次采用SA-3000P精神分析压力仪测定各组患者的HF值。
2.2.2、所有入选患者服药前测定血压值,服药后避免剧烈运动及情绪激动,禁用含有咖啡因等影响副交感神经活性的饮料或药物,2小时后再次测定血压值。
3、观察指标
本研究所涉及的频域指标是短时程指标(仰卧30min内任选一段平稳的5min时程作为研究指标)。
4、统计学方法
采用SPSS软件进行数据处理,计量资料用均数±标准差表示,采用方差分析及t检验,P值<0.05为有统计学意义。
结果如下表1:
表1
各组治疗前后P<0.05,可知HF值有显著性增加,收缩压有显著性降低;对照组治疗前后P>0.05,没有显著性差异。可见枸橼酸坦度螺酮对于提高副交感神经活性有明显作用,对于收缩压降低也有明显作用。
试验例2:动物实验
无特定病原体(specific pathogen free,SPF)级Wistar雄性大鼠66只,体质量180~220g,分笼饲养,12h/12h昼夜交替,温度控制在23~26℃,相对湿度控制在40%~70%,自由进食、饮水,适应性喂养1周。
将上述66只大鼠随机分成11组,其中10组是实验组,分别给予实施例1-10提供的药品,按照10mg/kg/day的剂量连续给药三天。第11组是空白对照组,不给药。末次给药后24h,用70g/L的水合氯醛按3mL/kg的剂量腹腔注射麻醉大鼠,待大鼠进入昏迷状态后把大鼠置于实验台上连接4个皮下标准肢体导联,待心电波形稳定后通过标准Ⅱ型肢体导联记录大鼠肢体表心电图和心率的变化,将采集数据保存计算机,应用BL-420F生物机能实验系统分析大鼠HRV频域指标中的高频功率(HF),HF反映副交感神经调节功能,HF值增大,副交感神经活性强度升高。同时测定给首次药前、末次给药后各组大鼠的血压值。
采用SPSS软件进行数据处理,计量资料以均数±标准差表示,实验组和空白对照组间比较采用两独立样本t检验,P<0.05为有统计学意义。
结果如下表2:
表2
组别 | 所给药物 | HF(ms2/HZ) | 降压幅度(mmHg) |
空白对照组 | 不给药 | 42.75±7.23 | 1.6±2.4 |
实验组1 | 实施例1药物10mg/kg | 56.80±6.49# | 15.3±2.9* |
实验组2 | 实施例2药物10mg/kg | 55.35±5.88# | 16.4±3.2* |
实验组3 | 实施例3药物10mg/kg | 56.20±7.69# | 14.3±2.3* |
实验组4 | 实施例4药物10mg/kg | 55.29±6.97# | 14.4±3.7* |
实验组5 | 实施例5药物10mg/kg | 57.21±5.76# | 15.2±2.5* |
实验组6 | 实施例6药物10mg/kg | 54.97±6.80# | 15.6±2.8* |
实验组7 | 实施例7药物10mg/kg | 53.65±7.23# | 14.7±3.1* |
实验组8 | 实施例8药物10mg/kg | 54.68±6.93# | 15.1±3.6* |
实验组9 | 实施例9药物10mg/kg | 55.32±8.18# | 13.9±3.4* |
实验组10 | 实施例10药物10mg/kg | 56.08±6.49# | 16.0±2.7* |
注:#、*代表与空白对照组比较,P<0.05。
由上述结果可知,各给药组大鼠的HF值相比于空白对照组都有显著性增加,各给药组大鼠的血压值相比于空白对照组也有显著性降低。
Claims (9)
1.式I化合物或其药学上可接受的盐在制备治疗副交感神经活性不足综合征的药物中的用途:
在式I中,n为4或5;
R为:
2.式I化合物或其药学上可接受的盐在副交感神经活性测定中作为阳性对照品的用途:
在式I中,n为4或5;
R为:
3.式I化合物或其药学上可接受的盐在制备治疗由副交感神经活性不足导致的高血压、高血糖、高血脂、糖尿病、神经性食欲不振、痛风、甲状腺功能亢进症、消化性溃疡、肠易激综合征、头痛、癫痫、帕金森病、脑卒中、睡眠障碍、慢性疲劳、肥胖症、体位性低血压、抑郁症、焦虑、注意力低下、哮喘、肌纤维痛、慢性类风湿性关节炎、慢性阻塞性肺疾病、冠心病、心肌梗死、心律失常、粉刺、性功能障碍、干眼、口干或免疫功能紊乱的药物中的用途,
在式I中,n为4或5;
R为:
4.如权利要求1-3任一项所述的用途,其中,n为4。
5.如权利要求1-4任一项所述的用途,其中,式I化合物或其药学上可接受的盐为坦度螺酮、丁螺环酮、伊沙匹隆、吉哌隆、扎螺酮或它们药学上可接受的盐。
6.如权利要求1-5任一项所述的用途,其中,所述药学上可接受的盐为盐酸盐、硫酸盐、酒石酸盐、草酸盐、马来酸盐、富马酸盐、枸橼酸盐;更优选为盐酸盐或枸橼酸盐。
7.如权利要求1-6任一项所述的用途,其中,所述药物的给药途径包括口服或经肠胃外给药,可选地,所述给药途径为口服、静脉内、经皮下、肌内、透皮或吸入给药。
8.如权利要求1-6任一项所述的用途,其中,所述药物的剂型为:片剂、胶囊剂、颗粒剂、口服液、膜剂、贴剂或注射剂;可选地,所述药物剂型为:缓释片剂、舌下含片、口腔速崩片、分散片、肠溶片、肠溶胶囊、延迟释放片、定时/位释放片、缓释胶囊、控释胶囊、含有微丸或小片的胶囊、含有微丸或小片的pH依赖型胶囊。
9.如权利要求1-6任一项所述的用途,其中,所述药物包括所述式I化合物或其药学上可接受的盐和药用辅料,所述药用辅料包括下述辅料中的一种或多种:
稀释剂,所述稀释剂优选乳糖、糊精、预胶化淀粉、玉米淀粉、微晶纤维素、硫酸钙、磷酸钙、磷酸氢钙、沉降碳酸钙、甘露醇、琼脂粉中的一种或多种;
粘合剂,所述粘合剂优选糖浆、阿拉伯胶、明胶、山梨醇、黄芪胶、淀粉浆、聚维酮、微晶纤维素、羧甲基纤维素钠、乙基纤维素、羟丙甲基纤维素中的一种或多种;
崩解剂,所述崩解剂优选干淀粉、羧甲淀粉钠、低取代羟丙基纤维素、交联聚维酮中的一种或多种;
润滑剂,所述润滑剂优选羧甲基淀粉钠、淀粉乙醇酸钠、预胶化淀粉、改良淀粉、羟丙基淀粉、玉米淀粉、交联聚维酮、微晶纤维素、羧甲基纤维素钠、乙基纤维素、羟丙甲基纤维素中的一种或多种;
助流剂,所述助流剂优选微粉硅胶、硬脂酸镁、滑石粉、氢化植物油、聚乙二醇类中的一种或多种;
矫味剂,所述矫味剂优选蔗糖、甜橘苷、糖精钠、蛋白糖、山梨醇、阿斯巴甜中的一种或多种。
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Application publication date: 20190514 |