CN115043828B - 一种用于治疗鼻窦炎的药物及其制备方法 - Google Patents
一种用于治疗鼻窦炎的药物及其制备方法 Download PDFInfo
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- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- A—HUMAN NECESSITIES
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- A61P11/00—Drugs for disorders of the respiratory system
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- A—HUMAN NECESSITIES
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Abstract
本发明提供了一种用于治疗鼻窦炎的药物及其制备方法。所述药物为式I所示化合物。所述化合物能够改善鼻窦炎大鼠的流鼻涕、鼻塞现象,降低鼻腔分泌物的pH,降低白细胞计数和中性粒细胞百分比,提高表皮生长因子(EGF)和表皮生长因子受体(EGFR)的表达。因此,本发明化合物具有治疗鼻窦炎的效果,具有良好应用前景。
Description
技术领域
本发明涉及医药领域,具体来说,本发明涉及一种用于治疗鼻窦炎的药物及其制备方法。
背景技术
鼻窦炎是指鼻窦黏膜的炎症,临床上以上颌窦炎最为多见。鼻窦炎的症状有鼻塞、流脓涕、暂时性嗅觉障碍、畏寒、发热、痰多、异物感或咽喉疼痛、食欲不振、便秘、周身不适等。鼻窦炎分急性鼻窦炎和慢性鼻窦炎两种,其病因包括:细菌和真菌的感染、超抗原作用、变态反应、纤毛功能障碍、细菌生物膜作用等。
鼻窦炎的治疗方法主要包括针灸与理疗、中药治疗、西药治疗等,其中西药治疗药物主要有:糖皮质激素,其具有抗感染、免疫抑制和抗水肿作用,是目前治疗鼻窦炎的重要药物;抗生素,包括大环内酯类药物、β-内酰胺类药物、喹诺酮类药物、糖肽类药物、白三烯受体拮抗剂等,主要用于治疗鼻窦炎的急性发作,预防术后感染;抗过敏药物,主要针对伴有过敏性鼻炎和支气管哮喘等的患者;黏液溶解促排剂,可以稀化鼻腔、鼻窦分泌物,促进黏液排出,改善纤毛功能。
但是,仍然需要寻找更多能够有效治疗鼻窦炎的药物。
发明内容
本发明的目的在于提供一种能够治疗鼻窦炎的药物。
因此,本发明提供了一种式I化合物或其立体异构体、互变异构体、前药以及药学上可接受的盐:
其中,R1-R3分别独立地选自氢、氘、卤素、低级烷基、低级烷氧基、卤代低级烷基、氰基、硝基、氨基;
R4选自氢、氘、低级烷基、卤代低级烷基、取代或未取代的芳基、取代或未取代的芳基-亚烷基;
R5、R6分别独立地选自氢、氘、低级烷基、卤代低级烷基、取代或未取代的芳基、取代或未取代的芳基-亚烷基;
R7选自低级烷基、卤代低级烷基、环烷基、取代或未取代的芳基-亚烷基;
m选自1、2、3或4;
n选自1、2、3或4。
在一些实施方案中,R1-R3分别独立地选自氢、卤素、C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷基。
优选的,R1-R3分别独立地选自氢、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、三氟甲基。
在一些实施方案中,R4选自氢、氘、C1-C6烷基、卤代C1-C6烷基、取代或未取代的C6-C10芳基、取代或未取代的C6-C10芳基-C1-C2亚烷基。
优选的,R4选自甲基、乙基、正丙基、异丙基、三氟甲基、苯基、苄基。
在一些实施方案中,R5、R6分别独立地选自氢、卤素、C1-C6烷基、卤代C1-C6烷基。
优选的,R5、R6分别独立地选自氢、甲基、乙基、正丙基、异丙基、三氟甲基。
在一些实施方案中,R7选自C1-C6烷基、卤代C1-C6烷基、C3-C7环烷基、取代或未取代的C6-C10芳基-C1-C2亚烷基。
优选的,R7选自甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基、环丙基、环丁基、环戊基、环己基、苄基、2-苯基乙基。
在一些实施方案中,m选自1或2,n选自1或2。
优选的,m选自1,n选自1。
本发明中,所述“取代或未取代”是指未被取代或者被选自以下的基团取代:氘、卤素、氰基、硝基、C1-C4烷基、C1-C4烷氧基。
优选的,所述“取代或未取代”是指未被取代或者被选自以下的基团取代:氘、氟、氯、溴、碘、氰基、硝基、甲基、乙基、甲氧基、乙氧基。
在一些实施方案中,所述式I化合物选自:
本发明中,术语“卤素”是指氟、氯、溴和碘。术语“卤代”是指被氟、氯、溴或碘取代。
本发明中,术语“低级烷基”包括C1-6烷基,优选C1-4烷基,例如为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基。
本发明中,术语“低级烷氧基”包括C1-6烷氧基,优选C1-4烷氧基,例如为甲氧基、乙氧基。
本发明中,术语“芳基”表示碳环芳基或联芳基。碳环芳基是含有6-18个碳原子优选6-10个碳原子的芳香族环烃。它可以是单环、二环或三环的,例如苯基或萘基等。
本发明中,术语“药学上可接受的盐”,是指游离化合物与常规酸形成的酸加成盐,所述酸包括例如:无机酸,例如:盐酸、氢溴酸、硫酸、硝酸、磷酸;有机酸,例如:甲酸、乙酸、己酸、辛酸、癸酸、酒石酸、乳酸、琥珀酸、顺丁烯二酸、反丁烯二酸、硬脂酸、苯磺酸、对甲苯磺酸、萘-2-磺酸、苯甲酸、乙烷磺酸、4-乙酰氨基苯甲酸、肉桂酸、氨基酸、褐藻酸、抗坏血酸、柠檬酸、半乳糖二酸、龙胆酸、乙醇酸、乳糖酸、萘-1,5-二磺酸、烟酸、油酸、草酸、癸二酸、棕榈酸、双羟萘酸、水杨酸等,但不限于此。
本发明中,术语“立体异构体”,是指其具有相同化学构造,但原子或基团在空间上排列方式不同的化合物。立体异构体包括对映异构体、非对映异构体、几何异构体(顺/反)异构体,等等。
本发明中,术语“互变异构体”是指经由低能垒互相转化的不同能量的结构异构体。本发明化合物可以以不同的互变异构体形式存在,所有这些形式均包括在本发明的范围内。
本发明中,术语“前药”是本发明化合物的衍生物,其是指它们自身可能具有较弱的活性甚至没有活性,但是在给药后,在生理条件下(例如通过代谢、溶剂分解或另外的方式——被转化成相应的生物活性形式。
本发明还提供一种药物组合物,所述药物组合物包括如上文所定义的式I化合物或其立体异构体、互变异构体、前药以及药学上可接受的盐。
在一些实施方案中,所述药物组合物包括药学上可接受的稀释剂或载体。
本文所用的术语“药学上可接受的”指不消除本文所述的化合物的生物学活性或性质的物质,如载体或稀释剂。这类物质被施用于个体不导致不希望的生物学作用或者不以有害方式与包含它的组合物中的任何组分相互作用。
如本文所用的术语“药学上可接受的的稀释剂或载体”包括任何和所有的溶剂、分散介质、包衣材料、表面活性剂、抗氧化剂、防腐剂(例如抗菌剂、抗真菌剂)、等渗剂、吸收延迟剂、盐、防腐剂、药物稳定剂、粘合剂、赋形剂、崩解剂、润滑剂、染料等和其组合,这是本领域技术人员所熟知的(例如参见Remington’s Pharmaceutical Sciences,18th Ed.MackPrinting Company,1990,pp.1289-1329)。除了与活性成分不相容的载体外,在治疗或药物组合物中考虑使用任何常规载体。
所述药物组合物的给药剂型可以是液体剂型、固体剂型或半固体剂型。液体剂型可以是溶液剂,例如真溶液和胶体溶液;乳剂,例如o/w型、w/o型和复乳;混悬剂;注射剂,例如水针剂、粉针剂和输液;滴眼剂;滴鼻剂;洗剂和搽剂等。固体剂型可以是片剂,例如普通片、肠溶片、含片、分散片、咀嚼片、泡腾片、口腔崩解片;胶囊剂,例如硬胶囊、软胶囊、肠溶胶囊;颗粒剂;散剂;微丸;滴丸;栓剂;膜剂;贴片;气雾剂;喷雾剂等。半固体剂型可以是软膏剂、凝胶剂、糊剂等。
本发明中,所述药物组合物中化合物的有效剂量可以根据年龄、体重、性别、给药方法、健康状况和病症严重程度来确定。例如,一个体重70kg的成年人的剂量为0.1-1,000mg/天,优选1-500mg/天。这样的给药可以一天一次至多次,根据医生或者药剂师的决定执行。
本发明还提供了一种药物组合,其是一种药物产品,包括如上文所定义的式I化合物或其立体异构体、互变异构体、前药以及药学上可接受的盐以及可用于治疗鼻窦炎的其他药剂。在一些实施方案中,所述其他药剂可选自:糖皮质激素;抗生素,包括大环内酯类药物、β-内酰胺类药物、喹诺酮类药物、糖肽类药物、白三烯受体拮抗剂等;抗过敏药物;黏液溶解促排剂等。
本发明还提供了如上文所定义的式I化合物或其立体异构体、互变异构体、前药以及药学上可接受的盐,以及本发明药物组合物、药物组合在制备药物中的用途。在一些实施方案中,所述药物用于治疗鼻窦炎。
优选的,所述鼻窦炎由细菌或真菌感染引起。
本发明还提供了如上文所定义的式I化合物的制备方法,其包括以下步骤:
步骤1:
化合物a与化合物b在碱的存在下反应生成中间体c;
步骤2:
中间体c与化合物d在乙酸中、硼氢化钠存在下反应生成中间体e;
步骤3:
中间体e在TEMPO、碱的存在下环合生成中间体f;
步骤4:
中间体f与化合物g在碱的存在下反应生成式I化合物;
其中,R1-R7、m、n的定义如本发明中所述;Xa、Xb分别独立地选自氯、溴或碘。
在一些实施方案中,步骤1和4中的碱分别独立地选自碳酸钠、碳酸钾、碳酸铯、氢氧化钠、氢氢化钾中的至少一种。
在一些实施方案中,步骤2中的碱选自氢化钠、甲醇钠、乙醇钠、叔丁醇钾中的至少一种。
在一些实施方案中,Xa选自溴;Xb选自碘。
有益效果
本发明提供了一种用于治疗鼻窦炎的药物及其制备方法。本发明化合物能够改善鼻窦炎大鼠的流鼻涕、鼻塞现象,降低鼻腔分泌物的pH,降低白细胞计数和中性粒细胞百分比,提高表皮生长因子(EGF)和表皮生长因子受体(EGFR)的表达。因此,本发明化合物具有治疗鼻窦炎的药效,具有良好应用前景。
具体实施方式
在下文中更详细地描述了本发明以有助于对本发明的理解。
所属领域的技术人员将认识到:本发明所描述的化学反应可以用来合适地制备许多本发明的其他化合物,且用于制备本发明的化合物的其它方法都被认为是在本发明的范围之内。例如,根据本发明那些非例证的化合物的合成可以成功地被所属领域的技术人员通过修饰方法完成,如适当的保护干扰基团,通过利用其他已知的试剂除了本发明所描述的,或将反应条件做一些常规的修改。另外,本发明所公开的反应或已知的反应条件也公认地适用于本发明其他化合物的制备。
下面实施例中的实验方法,如无特殊说明,均为常规方法。实施例中未注明具体技术或条件者,按照本领域内的文献所描述的技术或条件,或者按照产品说明书进行。
实施例1:化合物1的制备
步骤1:
将化合物a-1(6.04g,40mmol)溶解于100ml的DMF中,然后加入碳酸铯(26g,80mmol),随后加入化合物b-1(10.05g,50mmol),然后将混合物在70℃剧烈搅拌18小时;反应结束后冷却至室温,向混合物加入500ml的乙酸乙酯和500ml的水,混匀后分层,有机层依次用3%氯化锂水溶液、饱和氯化钠水溶液、水洗涤,无水硫酸钠干燥并真空脱溶。残余物通过乙醇重结晶,得到中间体c-1(7.70g,71%);HR-ESI-MS m/z 272.1269[M+H]+(理论值272.1287)。
步骤2:
将中间体c-1(5.43g,20mmol)溶于50ml乙酸中,向其中加入化合物d-1(2.71g,24mmol),将混合物在室温下搅拌1h。冰浴冷却的同时,分批加入硼氢化钠(1.43g,40mmol),然后自然升至室温并继续搅拌1h。反应结束后,真空脱溶,残余物悬浮在150ml的二氯甲烷中,然后加入饱和碳酸氢钠水溶液洗涤,分离有机层,无水硫酸钠干燥,真空脱溶并通过硅胶柱色谱(流动相为石油醚:乙酸乙酯=8:2)纯化残余物,得到中间体e-1(5.74g,78%);HR-ESI-MS m/z 369.1284[M+H]+(理论值369.1273)。
步骤3:
将中间体e-1(3.68g,10mmol)溶于60ml DMSO中,搅拌下向其中加入四甲基哌啶氧化物TEMPO(3.12g,20mmol)、KOt-Bu(3.36g,30mmol),升温至80℃搅拌5h。反应结束后自然冷却至室温,向混合物中加入120ml饱和氯化铵溶液并用乙酸乙酯(150ml×3)萃取。合并有机层,依次用饱和氯化钠水溶液、水洗涤,无水硫酸钠干燥,真空脱溶后残余物用石油醚和乙醇(1:3)重结晶,得到中间体f-1(3.06g,84%);HR-ESI-MS m/z 365.0948[M+H]+(理论值365.0960)。
步骤4:
将中间体f-1(1.82g,5mmol)溶于40ml DMF中,加入碳酸铯(3.25g,10mmol),然后冷却至0-5℃,搅拌下逐滴加入化合物g-1(0.85g,6mmol),室温搅拌反应15h;反应完毕,将反应混合液倒入150ml水中,乙酸乙酯萃取(150ml×3),合并有机相,依次用饱和氯化钠水溶液、水洗涤,真空脱溶后用甲醇-丙酮(1:1)重结晶,得化合物1(1.74g,92%)。
HR-ESI-MS m/z 379.1103[M+H]+(理论值379.1116)。
元素分析:C21H18N2O3S理论值C,66.65;H,4.79;N,7.40;O,12.68;S,8.47;实测值:C,66.57;H,4.74;N,7.42;O,12.63;S,8.40。
1H NMR(400MHz,DMSO-d6)δ8.07(d,J=8.1Hz,1H),7.91(d,J=4.7Hz,1H),7.59(d,J=4.8Hz,1H),7.35-7.26(m,5H),7.04-7.06(m,2H),6.59(s,1H),5.03(s,2H),4.59(s,2H),3.66(s,3H)。
实施例2:化合物2的制备
与实施例1的方法相同,区别在于:
步骤2:
将中间体c-1(5.43g,20mmol)溶于50ml乙酸中,向其中加入化合物d-2(3.39g,24mmol),将混合物在室温下搅拌1h。冰浴冷却的同时,分批加入硼氢化钠(1.43g,40mmol),然后自然升至室温并继续搅拌1h。反应结束后,真空脱溶,残余物悬浮在150ml的二氯甲烷中,然后加入饱和碳酸氢钠水溶液洗涤,分离有机层,无水硫酸钠干燥,真空脱溶并通过硅胶柱色谱(流动相为石油醚:乙酸乙酯=8:2)纯化残余物,得到中间体e-2(5.79g,73%);HR-ESI-MS m/z 397.1575[M+H]+(理论值397.1586)。
步骤3:
将中间体e-2(3.96g,10mmol)溶于60ml DMSO中,搅拌下向其中加入四甲基哌啶氧化物TEMPO(3.12g,20mmol)、KOt-Bu(3.36g,30mmol),升温至80℃搅拌5h。反应结束后自然冷却至室温,向混合物中加入120ml饱和氯化铵溶液并用乙酸乙酯(150ml×3)萃取。合并有机层,依次用饱和氯化钠水溶液、水洗涤,无水硫酸钠干燥,真空脱溶后残余物用石油醚和乙醇(1:3)重结晶,得到中间体f-2(3.37g,86%);HR-ESI-MS m/z 393.1263[M+H]+(理论值393.1273)。
步骤4:
将中间体f-2(1.96g,5mmol)溶于40ml DMF中,加入碳酸铯(3.25g,10mmol),然后冷却至0-5℃,搅拌下逐滴加入化合物g-1(0.85g,6mmol),室温搅拌反应15h;反应完毕,将反应混合液倒入150ml水中,乙酸乙酯萃取(150ml×3),合并有机相,依次用饱和氯化钠水溶液、水洗涤,真空脱溶后用甲醇-丙酮(1:1)重结晶,得化合物2(1.83g,90%)。
HR-ESI-MS m/z 407.1445[M+H]+(理论值407.1429)。
元素分析:C23H22N2O3S理论值C,67.96;H,5.46;N,6.89;O,11.81;S,7.89;实测值:C,67.90;H,5.42;N,6.87;O,11.71;S,7.96。
1H NMR(400MHz,DMSO-d6)δ8.07(d,J=8.1Hz,1H),7.35-7.26(m,5H),7.04-7.06(m,2H),6.62(s,1H),5.03(s,2H),4.59(s,2H),3.66(s,3H),2.34(s,3H),2.29(s,3H)。
实施例3:化合物3的制备
与实施例1的方法相同,区别在于:
步骤4:
将中间体f-1(1.82g,5mmol)溶于40ml DMF中,加入碳酸铯(3.25g,10mmol),然后冷却至0-5℃,搅拌下逐滴加入化合物g-3(1.00g,6mmol),室温搅拌反应24h;反应完毕,将反应混合液倒入150ml水中,乙酸乙酯萃取(150ml×3),合并有机相,依次用饱和氯化钠水溶液、水洗涤,真空脱溶后用甲醇-丙酮(1:1)重结晶,得化合物3(1.79g,88%)。
HR-ESI-MS m/z 407.1413[M+H]+(理论值407.1429)。
元素分析:C23H22N2O3S理论值C,67.96;H,5.46;N,6.89;O,11.81;S,7.89;实测值:C,67.92;H,5.43;N,6.94;O,11.77;S,7.85。
1H NMR(400MHz,DMSO-d6)δ8.07(d,J=8.1Hz,1H),7.91(d,J=4.8Hz,1H),7.59(d,J=4.8Hz,1H),7.35-7.26(m,5H),7.04-7.06(m,2H),6.59(s,1H),5.03(s,2H),4.59(s,2H),4.57(m,1H),1.42(d,J=6.7Hz,6H)。
实施例4:药效学试验
3月龄SD大鼠,体重:220±20g,雌雄各半(来源于成都达硕生物科技有限公司),自由喂养7天后,将50只SD大鼠根据体重随机分为5组,即空白组、模型组、给药组(化合物1组-3组),每组10只,其中模型组、给药组大鼠进行造模。
造模时,将金黄色葡萄球菌标准菌株CMCC(B)26003(来源于中国医学细菌保藏管理中心)配制成0.3×109CFU/ml的细菌悬液。模型组、给药组大鼠采用10%水合氯醛(4.5m1/kg)进行腹腔注射以麻醉,在右侧鼻腔用眼科镜置入修剪好的棒状医用海绵(2mm×3mm×20mm),随即滴入0.1ml金黄色葡萄球菌悬液于医用海绵上。
造模后进行自由喂养,7天后造模成功,判定标准为:具有鼻窦炎典型症状,诸如鼻塞以及鼻腔可见黏脓性分泌物;病理切片可见炎症病理改变。从第8天,治疗组大鼠开始灌胃给药,剂量为20mg/kg·d,连续给药7天。空白组和模型组给予等量溶剂。
1、一般观察
造模后大鼠从第2天开始出现打喷嚏、流清涕、频繁搔抓鼻部等症状,并随时间加重,部分大鼠鼻腔可见脓涕,并有鼻腔阻塞、精神差的症状。空白组大鼠未见异常。给予化合物1-3后,大鼠的流鼻涕、鼻塞现象得到明显缓解,精神活跃。模型组大鼠由于未用药,症状持续且有一只大鼠在实验过程中死亡。
2、鼻腔pH值测定
鼻腔分泌物pH值的高低可用于评估鼻腔内环境及鼻粘膜的病理状态。正常鼻分泌物偏酸性,但鼻腔有炎症时,其分泌物偏碱性,鼻粘液的粘稠度在pH值7.5时将发生变化。
用药7天后,测量各组大鼠的鼻腔pH值,将精密试纸剪成约2mm×20mm大小,固定大鼠头部,鼻前庭消毒,用眼科镊将pH试纸送入鼻腔紧贴黏膜,30秒后取出,与标准比色卡对照,读出该侧鼻分泌液pH值。两侧鼻腔pH值取平均值。结果如表1所示:
表1:各组大鼠鼻分泌物pH值
注:与模型组相比,**P<0.01
与空白组相比,模型组大鼠鼻腔分泌物pH值显著升高,而给药组大鼠与模型组相比有不同程度的降低,并且已接近正常范围,说明鼻窦炎得到改善。
3、白细胞(WBC)计数和中性粒细胞百分比(N%)测定
白细胞(WBC)计数与中性粒细胞百分比(N%)是反映急性感染的常规指标之一,急性细菌性感染会导致白细胞百分比升高,且正比于感染程度。
实验过程:各组大鼠股静脉取血,测量白细胞(WBC)计数和中性粒细胞(N)百分比。结果如表2所示:
表2:各组大鼠的白细胞计数和中性粒细胞百分比
组别 | n | 白细胞计数(109/L) | N百分比(%) |
空白组 | 10 | 7.94±0.21** | 35.44±2.59** |
模型组 | 9 | 13.69±0.32 | 47.58±3.67 |
化合物1组 | 10 | 7.85±0.19** | 32.14±2.07** |
化合物2组 | 10 | 8.42±0.20** | 33.19±2.23** |
化合物3组 | 10 | 8.74±0.21** | 36.61±2.77** |
注:与模型组相比,**P<0.01
与空白组相比,模型组大鼠的白细胞计数与中性粒细胞百分比均明显升高,而给药组大鼠与模型组相比下降明显,说明大鼠炎症得到改善。
4、免疫法测定大鼠鼻黏膜组织表皮生长因子(EGF)和表皮生长因子受体(EGFR)表达。
EGF是最早报道的一类多肽生长因子,对多种细胞具有促增殖作用,能加速上皮及黏膜组织的再生和修复。现代研究已表明,EGF能促进皮肤溃疡、角膜损伤、口腔溃疡、外伤性鼓膜穿孔等创面的修复与愈合,并且已有学者的研究表明,EGF在急慢性鼻窦炎鼻窦黏膜修复过程中存在强表达,并且认为EGFR信号通路与慢性鼻窦炎的治疗有一定关系。
实验过程:断头处死大鼠,将上领骨从颅骨中游离出来,沿着鼻中隔剪开鼻腔,暴露鼻中隔及双侧鼻腔,游离鼻中隔,剥离双侧鼻中隔粘膜,4%多聚甲醛固定,常规修剪、石蜡包埋、切片。染色操作:材料:兔抗人EGF多克隆抗体、兔抗人EGFR多克隆抗体:Santa Cruz公司;异硫酸酯荧光素(FITC)标记羊抗兔IgG:美国KPL公司。1)石蜡切片脱蜡至水。(2)3%H2O2室温孵育5~10min,以消除内源性过氧化物酶的活性。(3)蒸馏水冲洗,PBS浸泡5min。(4)5%~10%的正常山羊血清(PBS稀释)封闭,室温孵育10min。倾去血清,勿洗,滴加适当比例稀释的一抗工作液,37℃孵育1~2h或4℃过夜;用PBS代替一抗作阴性对照。(5)PBS冲洗,5min×3次。(6)滴加适当比例稀释的生物素标记二抗(1%BSA-PBS稀释),37℃孵育10~30min。(7)PBS冲洗,5min×3次。(8)滴加适当比例稀释的辣根酶标记链霉卵白素(PBST稀释),37℃孵育10~30min。(9)PBS冲洗,5min×3次。(10)显色剂DAB显色。(11)自来水充分冲洗,复染,封片。(12)镜检,测定积分光密度。结果如表3所示:
表3:各组大鼠的EGF和EGFR表达
组别 | n | EGF(MD) | EGFR(MD) |
空白组 | 10 | 0.133±0.029* | 0.117±0.024** |
模型组 | 9 | 0.084±0.009 | 0.034±0.008 |
化合物1组 | 10 | 0.158±0.021* | 0.133±0.015** |
化合物2组 | 10 | 0.145±0.024* | 0.130±0.016** |
化合物3组 | 10 | 0.149±0.019* | 0.123±0.010** |
注:与模型组相比,*P<0.05,**P<0.01
与空白组相比,模型组大鼠的EGF和EGFR表达显著降低,而给药组大鼠与模型组相比有强表达,说明大鼠鼻窦炎导致的损伤正被修复。
上述药理活性测试结果表明,本发明化合物对于鼻窦炎有着优异的治疗效果;而对于金黄色葡萄球菌诱导的鼻窦炎,在无用药干预的情况下,无法自愈。
以上所述仅是本发明的优选实施方式,应当指出,对于本技术领域的普通技术人员,在不脱离本发明方法的前提下,还可以做出若干改进和补充,这些改进和补充也应视为本发明的保护范围。
Claims (8)
1.一种式I化合物或其互变异构体、药学上可接受的盐:
其中,R1-R3分别独立地选自氢、氘;
R4选自氢、氘;
R5、R6分别独立地选自氢、氘、C1-C6烷基;
R7选自C1-C6烷基;
m选自1;
n选自1。
2.根据权利要求1所述的式I化合物或其互变异构体、药学上可接受的盐,其特征在于,R5、R6分别独立地选自氢、甲基、乙基、正丙基、异丙基。
3.根据权利要求1所述的式I化合物或其互变异构体、药学上可接受的盐,其特征在于,R7选自甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基。
4.根据权利要求1所述的式I化合物或其互变异构体、药学上可接受的盐,其特征在于,所述式I化合物选自:
5.一种药物组合物,其包括根据权利要求1-4任一项所述的式I化合物或其互变异构体、药学上可接受的盐。
6.一种药物组合,其包括根据权利要求1-4任一项所述的式I化合物或其互变异构体、药学上可接受的盐以及可用于治疗鼻窦炎的其他药剂。
7.根据权利要求1-4任一项所述的式I化合物或其互变异构体、药学上可接受的盐、根据权利要求5所述的药物组合物或者根据权利要求6所述的药物组合在制备药物中的用途,所述药物用于治疗鼻窦炎。
8.根据权利要求1中所述的式I化合物的制备方法,其包括以下步骤:
步骤1:
化合物a与化合物b在碱的存在下反应生成中间体c;
步骤2:
中间体c与化合物d在乙酸中、硼氢化钠存在下反应生成中间体e;
步骤3:
中间体e在TEMPO、碱的存在下环合生成中间体f;
步骤4:
中间体f与化合物g在碱的存在下反应生成式I化合物;
其中,R1-R7、m、n的定义如权利要求1中所述;Xa、Xb分别独立地选自氯、溴或碘。
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