CN105596344A - 一种组合物及其在预防或治疗胰腺纤维化药物中的应用 - Google Patents
一种组合物及其在预防或治疗胰腺纤维化药物中的应用 Download PDFInfo
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4866—Organic macromolecular compounds
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
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- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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Abstract
本发明涉及有机合成和药物化学领域,具体涉及组合物、制备方法及其在制备预防或治疗胰腺纤维化药物上的用途。本发明公开了一种组合物及其制备方法。药理学实验表明,本发明的组合物具有预防或治疗胰腺纤维化的作用,具有开发预防或治疗胰腺纤维化药物的价值。
Description
技术领域
本发明涉及有机合成和药物化学领域,具体涉及组合物、制备方法及其用途。
背景技术
胰腺纤维化是各种原因所致慢性胰腺炎的共同特征,同时也是与其伴随的组织病理学特点,表现为大量成纤维细胞增生和富含连接组织的细胞外基质。是多种原因导致胰腺损伤修复的结果,近期发现胰腺星状细胞和多种细胞因子与胰腺纤维化有关,胰腺纤维化目前发病率愈来愈高,急需研发高效低毒的抗胰腺纤维化药物。
胰腺纤维化的治疗目前已有的药物存在毒性大、安全性低的问题,从天然产物中寻找化合物或先导化合物并进行结构修饰获得其衍生物,从而得到高效低毒的潜在药物最有重要价值。
本发明涉及的化合物I是一个2011年发表(Fan-YuMengetal.,2011.SchiglautoneA,aNewTricyclicTriterpenoidwithaUnique6/7/9-FusedSkeletonfromtheStemsofSchisandraglaucescens.OrganicLetters13(2011)1502–1505)的化合物,我们对化合物I进行了结构修饰,获得了两个新的衍生物即化合物III和化合物IV,并用化合物III和化合物IV制备了组合物并对该组合物抗胰腺纤维化活性进行了评价,其具有抗胰腺纤维化活性。
发明内容
本发明公开了一个新的组合物,该组合物由化合物III和化合物IV组成,该组合物中化合物III和化合物IV的质量百分数分别为65%和35%。
本发明公开的组合物可以制成药学上可接受的盐或药学上可接受的载体。
药效学实验表明,本发明的组合物具有较好的抗胰腺纤维化作用。本发明的药学上可接受的盐具有同样的药效。
以下通过实施例对本发明作进一步详细的说明,但本发明的保护范围不受具体实施例的任何限制,而是由权利要求加以限定。
具体实施方式
实施例1化合物SchiglautoneA的制备
化合物SchiglautoneA(I)的制备方法参照Fan-YuMeng等人发表的文献(Fan-YuMengetal.,2011.SchiglautoneA,aNewTricyclicTriterpenoidwithaUnique6/7/9-FusedSkeletonfromtheStemsofSchisandraglaucescens.OrganicLetters13(2011)1502–1505)的方法。
实施例2SchiglautoneA的O-溴乙基衍生物(II)的合成
将化合物I(502mg,1.00mmol)溶于15mL苯,向溶液中加入四丁基溴化铵(TBAB)(0.08g),1,2-二溴乙烷(7.520g,40.00mmol)和6mL的50%氢氧化钠溶液。混合物在35摄氏度搅拌8h。8h之后将反应液倒入冰水中,立即用二氯甲烷萃取两次,合并有机相溶液。然后对有机相溶液依次用水和饱和食盐水洗涤3次,再用无水硫酸钠干燥,最后减压浓缩去除溶剂得到产物粗品。产物粗品用硅胶柱层析纯化(流动相为:石油醚/丙酮=100:1.0,v/v),收集棕色集中洗脱带并挥去溶剂即得到化合物II的棕色粉末(508mg,71%)。
1HNMR(500MHz,DMSO-d6)δ13.40(s,1H),6.10(s,1H),5.63(s,1H),5.53(s,1H),3.85(d,J=11.2Hz,4H),3.52(d,J=10.8Hz,4H),2.96(s,1H),2.20(s,1H),2.16(s,2H),2.00(s,1H),1.84(d,J=13.9Hz,4H),1.69(s,1H),1.58(dd,J=22.2,8.5Hz,4H),1.51(s,1H),1.47(s,1H),1.26(dd,J=9.1,4.4Hz,4H),1.21(s,1H),1.08–0.98(m,4H),0.96-0.94(m,9H),0.94-0.85(m,6H).
13CNMR(125MHz,DMSO-d6)δ211.46(s),209.14(s),170.06(s),161.12(s),143.51(s),132.01(s),127.77(s),85.96(s),82.40(s),70.19(s),69.10(s),57.14(s),52.73(s),51.90(s),45.77(s),40.67(s),38.57(s),38.32(s),35.04(s),33.55(s),33.27(s),29.85(s),28.98(s),26.71(s),25.50(s),24.05(s),22.31(s),21.06(s),20.56(s),20.00(s),18.69(s),18.11(s),15.07(s).
HRMS(ESI)m/z[M-H]-calcdforC34H51Br2O6:715.2032;found715.2027.
实施例3SchiglautoneA的O-(吗啉基)乙基衍生物(III)的合成
将化合物II(358mg,0.5mmol)溶于20mL乙腈当中,向其中加入无水碳酸钾(345mg,2.5mmol),碘化钾(168mg,1.0mmol)和吗啉(3484mg,40mmol),混合物加热回流4h。反应结束后将反应液倒入20mL冰水中,用等量二氯甲烷萃取2次,合并有机相。依次用水和饱和食盐水洗涤合并之后的有机相,再用无水硫酸钠干燥,减压浓缩去除溶剂得到产物粗品。产物粗品用硅胶柱层析纯化(流动相为:石油醚/丙酮=100:0.5,v/v),收集黄色集中洗脱带并挥去溶剂即得到化合物III的棕色粉末(247.5mg,68%)。
1HNMR(500MHz,DMSO-d6)δ15.28(s,1H),6.10(s,1H),5.55(s,1H),5.30(s,1H),3.53(s,8H),3.46(d,J=4.5Hz,4H),2.98(s,1H),2.52(d,J=1.8Hz,4H),2.45(s,8H),2.28(s,2H),2.16(s,1H),1.87–1.77(m,5H),1.78(s,1H),1.67(s,1H),1.59(s,1H),1.57–1.50(m,3H),1.46(s,1H),1.31(s,1H),1.26(dd,J=19.5,10.5Hz,4H),1.04–0.92(m,10H),0.89(s,3H),0.87(d,J=20.0Hz,3H),0.82(s,3H).
13CNMR(125MHz,DMSO-d6)δ211.29(s),208.87(s),169.90(s),160.93(s),143.32(s),131.85(s),127.58(s),85.77(s),82.24(s),66.79(s),66.55(s),65.94(s),56.97(s),54.25(s),52.72(s),52.54(s),51.71(s),45.61(s),40.48(s),38.38(s),38.16(s),34.85(s),33.36(s),29.67(s),28.80(s),26.53(s),25.32(s),23.87(s),22.13(s),20.88(s),20.38(s),19.82(s),18.51(s),17.93(s),14.89(s).
HRMS(ESI):m/z[M+H]+calcdforC42H69N2O8:729.5054;found:729.5051。
实施例4SchiglautoneA的O-(二羟乙胺基)乙基衍生物的合成
将化合物II(358mg,0.5mmol)溶于15mL乙腈,加入无水碳酸钾(0.345g,2.5mmol),碘化钾(0.084g,0.5mmol)和二乙醇胺(1.0514g,10mmol),混合物加热回流9h。反应结束后将反应液倒入冷水中,用二氯甲烷萃取三次,合并有机相,依次用水和饱和食盐水洗涤,无水硫酸钠干燥,减压浓缩去除溶剂。产物用硅胶柱层析纯化(石油醚/丙酮100:1,v/v),得到SchiglautoneA的O-(二羟乙胺基)乙基衍生物的淡黄色固体(0.199g,52%)。
1HNMR(500MHz,DMSO-d6)δ17.77(s,1H),6.00(s,1H),5.40(s,1H),5.20(s,1H),3.37(d,J=17.8Hz,4H),3.28(s,8H),2.87(s,1H),2.51(d,J=6.5Hz,4H),2.43(s,8H),2.24(s,2H),2.06(d,J=12.7Hz,2H),1.76–1.68(m,5H),1.57(s,1H),1.53–1.39(m,8H),1.36(s,1H),1.24(s,1H),1.20–1.14(m,3H),1.11(s,1H),0.94–0.82(m,10H),0.80(s,3H),0.76(s,3H),0.72(d,J=20.0Hz,3H).
13CNMR(125MHz,DMSO-d6)δ211.39(s),208.98(s),169.80(s),160.73(s),143.02(s),131.42(s),127.05(s),85.91(s),82.25(s),66.70(s),65.63(s),58.62(s),56.55(s),56.61(s),53.30(s),52.45(s),51.52(s),45.29(s),40.06(s),38.52(s),38.17(s),34.73(s),33.17(s),29.35(s),28.38(s),26.34(s),25.00(s),23.45(s),22.05(s),20.67(s),20.07(s),19.31(s),18.41(s),17.73(s),14.59(s).
HRMS(ESI):m/z[M+H]+calcdforC42H73N2O10:765.5265;found:765.5261。
SchiglautoneA的O-(二羟乙胺基)乙基衍生物
实施例5SchiglautoneA的O-(二氯乙胺基)乙基衍生物(IV)的合成
将实施例4所获得的SchiglautoneA的O-(二羟乙胺基)乙基衍生物(382mg,0.5mmol)溶于8mL氯仿,逐滴加入氯化亚砜(0.238g,2mmol),反应物加热回流2h。将反应物冷却至室温,滴加甲醇分解过量的氯化亚砜,减压浓缩除去溶剂。产物经硅胶柱层析纯化(石油醚/丙酮100:1,v/v),得到化合物IV的淡黄色胶状固体(0.297g,71%)。
1HNMR(500MHz,DMSO-d6)δ13.87(s,1H),6.01(s,1H),5.50(d,J=8.4Hz,2H),3.61(s,4H),3.55(s,4H),3.45(s,2H),3.40(s,2H),2.98(s,1H),2.73(d,J=17.4Hz,4H),2.67–2.57(m,6H),2.54(s,2H),2.40(s,1H),2.10(s,1H),1.99(s,2H),1.78(s,1H),1.73(d,J=16.9Hz,4H),1.58(d,J=3.0Hz,2H),1.46(d,J=3.0Hz,2H),1.43(s,1H),1.37(s,1H),1.22(s,1H),1.17(dd,J=18.9,11.1Hz,4H),0.95–0.83(m,10H),0.80(d,J=20.0Hz,3H),0.78(d,J=20.0Hz,3H),0.73(d,J=20.0Hz,3H).
13CNMR(125MHz,DMSO-d6)δ211.19(s),208.87(s),169.79(s),160.85(s),143.24(s),131.74(s),127.50(s),85.69(s),82.13(s),66.71(s),65.84(s),56.87(s),55.80(s),53.19(s),52.44(s),51.64(s),45.51(s),40.38(s),39.22(s),38.30(s),38.05(s),34.77(s),33.28(s),29.56(s),28.72(s),26.45(s),25.21(s),23.79(s),22.05(s),20.77(s),20.30(s),19.76(s),18.41(s),17.85(s),14.81(s).
HRMS(ESI):m/z[M+H]+calcdforC42H69Cl4N2O6:839.3880;found:839.3881。
实施例6组合物抗胰腺纤维化活性
1材料
1.1动物Wistar大鼠,雄性,体重180-200g。
1.2组合物剂量:0.9mg/kg。
组合物的制备:将研磨之后过200目网的65mg化合物III的粉末和研磨之后过200目网的35mg化合物IV的粉末装入带盖的小管中并用涡轮搅拌仪混合即得到100mg组合物,使用时用水溶解这100mg的组合物即得到组合物的溶液。
2实验方法
2.1造模方法:Wistar大鼠以腹腔注射dl-乙硫氨酸250mg/天,连续2个月,可出现胰脏腺细胞减少,间质内脂肪及结缔组织的增生。
2.2分组及给药方法
模型大鼠随机分为模型组,组合物0.9mg/kg组、化合物III0.9mg/kg组和化合物IV0.9mg/kg组,另设空白对照组。给药组于造模开始后给药,口服连续30天;60天时解剖动物。
2.3检测指标
2.3.1实验结束时取胰脏称重。
2.3.2胰脏羟脯氨酸含量测定取100mg样本在水中匀浆,110℃10NHCl中水解20小时。HCl用氮气挥发,水解产物用双蒸水溶解后过滤。取0.5ml液体与3ml枸橼酸磷酸缓冲液(0.15M枸橼酸加0.6M磷酸氢二钠)和0.5ml溶于9M磷酸的1M过碘酸混合。加1.75ml提取缓冲液(5份甲苯:5份2-甲基-1-丙醇:2份1-丙醇),震荡30min,离心。组织相(0.6ml)与Ehrlich,s试剂混合放置15min。在565nm测定吸收度,用4-羟-1-脯氨酸制作标准曲线计算浓度,含量以ug/g组织表示。
2.3.3组织学检查胰脏组织用10%福尔马林固定,石蜡包埋,染色后镜检。对纤维化情况评分(0-3分)。
3结果
3.1组合物对大鼠胰脏脏器系数的影响
实验结束时,将大鼠处死、解剖,称量体重和胰脏重并计算其与体重的比值(胰脏脏器系数),结果见表1。组合物对胰脏脏器系数的影响,与模型组比较有显著性差异。化合物III和化合物IV对胰脏脏器系数的影响,与模型组比较无显著性差异。
表1
*表示p<0.05,与模型组比较
3.2胰脏羟脯氨酸含量测定
实验结束时,对各组大鼠进行肺部羟脯氨酸含量测定,结果如表2。组合物对羟脯氨酸含量的影响,与模型组比较有显著性差异。化合物III和化合物IV对羟脯氨酸含量的影响,与模型组比较无显著性差异。
表2
*表示p<0.05,与模型组比较
3.3组织学检查
实验结束时,将大鼠处死、解剖;标本常规包埋、固定、HE染色,镜检。
结果:模型组第60天可见胰导管周围严重炎症反应;嗜中粒细胞核淋巴细胞浸润,间质水肿,出血以及偶见胰泡细胞坏死;胰泡细胞消失位置及胰泡间出现纤维化。
组合物可减少炎症反应和纤维化。评分结果见表3。组合物对评分的影响,与模型组比较有显著性差异。
表3
*表示p<0.05,与模型组比较;空白对照组的炎症细胞浸润和纤维化评分都为0.
结论:本发明通过组合物对大鼠胰腺纤维化的影响,证实了组合物具有抗胰腺纤维化的作用。因此,组合物可作为活性成分用于制备抗胰腺纤维化的药物。而化合物III和化合物IV无此活性,不能用于制备抗胰腺纤维化的药物。
实施例7本发明所涉及组合物片剂的制备
取2克组合物,加入制备片剂的常规辅料18克,混匀,常规压片机制成100片。
实施例8本发明所涉及组合物胶囊的制备
取2克组合物,加入制备胶囊剂的常规辅料如淀粉18克,混匀,装胶囊制成100粒。
Claims (6)
1.一种组合物,其特征为该组合物由化合物III和化合物IV组成,该组合物中化合物III和化合物IV的质量百分数分别为65%和35%,
2.如权利要求1所述的组合物的制备方法,其特征为:将化合物III的粉末和化合物IV的粉末按照质量百分数分别为65%和35%充分混合。
3.一种如权利要求1所述的组合物在治疗胰腺纤维化药物中的应用。
4.如权利要求3所述的组合物在治疗胰腺纤维化药物中的应用,其特征为:所述组合物逆转胰腺纤维化所引起的胰脏脏器系数下降。
5.如权利要求3所述的组合物在治疗胰腺纤维化药物中的应用,其特征为:所述组合物逆转胰腺纤维化所引起的羟脯氨酸含量升高。
6.如权利要求3所述的组合物在治疗胰腺纤维化药物中的应用,其特征为:所述组合物逆转胰腺纤维化所引起的炎症细胞浸润升高。
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