CN114716365A - 一类n-取代苯基-2-吡啶酮化合物或其可药用盐在治疗肺纤维化中的应用 - Google Patents
一类n-取代苯基-2-吡啶酮化合物或其可药用盐在治疗肺纤维化中的应用 Download PDFInfo
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- CN114716365A CN114716365A CN202210374113.2A CN202210374113A CN114716365A CN 114716365 A CN114716365 A CN 114716365A CN 202210374113 A CN202210374113 A CN 202210374113A CN 114716365 A CN114716365 A CN 114716365A
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
一类N‑取代苯基‑2‑吡啶酮化合物或其可药用盐在治疗肺纤维化中的应用,属于医药技术领域。本发明提供了该类化合物在治疗肺纤维化中的应用,延缓肺纤维化进展,具有较好的防治肺纤维化的作用,同时具有较好的安全性。相比于临床一线抗肺纤维化药物吡非尼酮,本发明涉及的药物具有更好的抗肺纤维化疗效,有望开发成为治疗肺纤维化的高效药物,为肺纤维化的防治提供更好的药物选择。
Description
技术领域
本发明属于医药技术领域,涉及一类N-取代苯基-2-吡啶酮化合物或其可药用盐在治疗肺纤维化中的应用。
背景技术
肺纤维化特征是纤维细胞增殖和细胞外基质大量聚集,也被看做是正常的肺泡组织被损坏后经过异常修复导致结构异常形成疤痕。绝大部分肺纤维化的病因不明,这样的疾病也被称为特发性间质炎,其中特发性肺纤维化为最常见的肺纤维化病变。特发性肺纤维化是一种能导致肺功能进行性丧失的较为严重的间质性肺疾病。肺纤维化严重影响人的呼吸功能,特发性肺纤维化发病率和死亡率逐渐增加,死亡率远高于许多癌症。目前认为肺纤维化的发病机制主要包括成纤维细胞或肌成纤维细胞的聚集和细胞外基质过量沉积等。
治疗特发性肺纤维化尚无特效药。已经获批的有效治疗特发性纤维化的药物仅有吡非尼酮和尼达尼布。其中吡非尼酮(pirfenidone,PFD)是一种有效的细胞因子抑制剂,能够抑制转化生长因子TGF-β,纤维细胞生长因子bFGF等,进而抑制成纤维细胞的活性,减少细胞增殖和基质胶原的合成。自上市以来,吡非尼酮可延缓肺功能衰竭,减轻病情恶化,但是依旧无法逆转肺纤维化病程。开发更为高效的治疗肺纤维化的药物迫在眉睫。
发明内容
在上述背景下,本发明所要解决的问题是提供高效的治疗肺纤维化的药物,提供一类N-取代苯基-2-吡啶酮化合物或其可药用盐在治疗肺纤维化中的应用。
本发明研究了N-苯基-2-吡啶酮化合物在苯环上取代不同基团的活性,旨在提高抗肺纤维化效果和药代动力学性质。本发明涉及的药物能够高效的降低肺纤维化的严重程度,在治疗肺纤维化中具有重要的临床应用价值。相比于临床一线抗肺纤维化药物吡非尼酮,本发明涉及药物抗肺纤维化效果更为显著,而且安全性较好。
一类N-取代苯基-2-吡啶酮化合物,所述化合物选自如下结构:
一类N-取代苯基-2-吡啶酮化合物或其可药用盐在治疗肺纤维化中的应用,所述化合物的结构式如下:
其中,R1、R2、R3、R4、R5各自独立的为氢原子、氘代甲基、卤素、羟基、氰基、硝基、三氟甲基、羧基、碳原子数为1-6的酰胺基、碳原子数为1-6的烷基、碳原子数为1-6的烷氧基、碳原子数为1-6的硫醚基等。
优选地,所述化合物选自如下结构:
所述的治疗肺纤维化药物剂型为片剂、胶囊剂、颗粒剂、散剂、口服制剂、注射剂、微囊制剂、栓剂。
所述的治疗肺纤维化药物的给药方式可以采用口服给药或者静脉注射。
所述化合物或其可药用盐用于制备治疗由博来霉素或其他因素诱导的肺纤维化的药物。
本发明研究了苯环上不同取代基的N-取代苯基-2-吡啶酮化合物对肺纤维化的治疗作用,文献中已经报道本发明化合物的合成方法,但是从未在之前的报道中涉及防治肺纤维化中的任何药理活性,本发明首次发现,苯环上进行取代基修饰的吡啶酮化合物具有明显优于吡非尼酮的治疗效果,而且具有较好的安全性。
本发明明显的有益效果是:提供一类N-取代苯基-2-吡啶酮化合物或其可药用盐在治疗肺纤维化中的应用。肺组织的HE染色、Masson染色、免疫荧光染色以及小鼠血清中羟脯氨酸含量测定结果表明:该化合物或其可药用盐呈现出色的抗纤维化效果,相比于上市药物吡非尼酮,抗纤维化效果显著提高。此外,安全性评估中证明开发的药物也具有较好的安全性,发挥疗效的同时对其他器官没有明显的伤害。
本发明内容涉及一类N-取代苯基-2-吡啶酮化合物或其可药用盐在治疗肺纤维化中的应用,包括一类N-取代苯基-2-吡啶酮化合物以及其医学上可接收的盐,也可加入制剂领域常规辅料制成片剂、胶囊剂、颗粒剂、散剂、口服液、注射剂等常规剂型。还可包括药学上可接受的的辅料、辅助性成分或其他载体如溶剂、稀释剂、粘合剂、崩解剂、润滑剂、助流剂、矫味剂、包衣剂、明胶胶囊壳、潜溶剂、抛射剂、表面活性剂、防腐剂、冻干保护剂等。
本发明涉及的药物能显著改善小鼠肺纤维化程度,从而保护肺部,相比于上市药物吡非尼酮,疗效有显著的提高。本发明涉及药物有望成为治疗肺纤维化的有效药物。
附图说明
图1小鼠血清中羟基脯氨酸含量测定结果图。
图2是小鼠肺组织切片HE染色结果图。
图3是小鼠肺组织切片MASSON染色结果图。
图4是小鼠肺组织切片免疫荧光染色结果图。
图5是小鼠血清中的AST含量图。
图6是小鼠血清中的ALT含量图。
图7是小鼠血清中的AKP含量图。
图8是小鼠血清中的BUN含量图。
图9是小鼠血清中的SCR含量图。
图10是小鼠心脏组织切片HE染色结果图。
图11是小鼠肝脏组织切片HE染色结果图。
图12是小鼠脾脏组织切片HE染色结果图。
图13是小鼠肾组织切片HE染色结果图。
图14是小鼠肺系数(肺重/体重)测定结果图。
图15是小鼠体重变化曲线图。
具体实施方式
本发明用以下实施例加以说明但不局限于此。
实施例1
化合物P的合成方法采用现有技术,合成通式及过程如下:
将化合物1(20g)、碘苯衍生物2(1.5equiv.)、碳酸钾(1.1equiv.)、氯化亚铜(10mol%)和DMF(300mL)置于500mL反应瓶中,氩气保护下,150℃回流反应10小时。反应结束后冷却至室温,抽滤,滤饼用DMF洗涤三遍,合并滤液,加入活性炭脱色。脱色后的溶液减压蒸干,加入10%乙酸100mL,70℃下搅拌30分钟。静置分层后取上层水相,下层油状物用10%乙酸萃取两遍,合并水相。水相加入氢氧化钠溶液调至pH 13,置于冰箱中过夜析晶。向减压干燥得到的粗品中加入乙酸乙酯100mL,加热回流,趁热抽滤,滤液冷却析晶。抽滤,滤饼减压干燥得到纯品P。
化合物P1合成方法如下:
将化合物1(20g)、4-甲基碘苯2a(68.8g,1.5equiv.)、碳酸钾(32.0g,1.1equiv.)、氯化亚铜(4g,10mol%)和DMF(300mL)置于500mL反应瓶中,氩气保护下,150℃回流反应10小时。反应结束后冷却至室温,抽滤,滤饼用DMF洗涤三遍,合并滤液,加入活性炭脱色。脱色后的溶液减压蒸干,加入10%乙酸100mL,70℃下搅拌30分钟。静置分层后取上层水相,下层油状物用10%乙酸萃取两遍,合并水相。水相加入氢氧化钠溶液调至pH 13,置于冰箱中过夜析晶。向减压干燥得到的粗品中加入乙酸乙酯100mL,加热回流,趁热抽滤,滤液冷却析晶。抽滤,滤饼减压干燥得到纯品P1,产物结构经质谱鉴定。
化合物P2合成方法如下:
将化合物1(20g)、4-刀代甲基碘苯(69.8g,1.5equiv.)、碳酸钾(32.0g,1.1equiv.)、氯化亚铜(4g,10mol%)和DMF(300mL)置于500mL反应瓶中,氩气保护下,150℃回流反应10小时。反应结束后冷却至室温,抽滤,滤饼用DMF洗涤三遍,合并滤液,加入活性炭脱色。脱色后的溶液减压蒸干,加入10%乙酸100mL,70℃下搅拌30分钟。静置分层后取上层水相,下层油状物用10%乙酸萃取两遍,合并水相。水相加入氢氧化钠溶液调至pH 13,置于冰箱中过夜析晶。向减压干燥得到的粗品中加入乙酸乙酯100mL,加热回流,趁热抽滤,滤液冷却析晶。抽滤,滤饼减压干燥得到纯品P2,产物结构经质谱鉴定。
化合物P3合成方法如下:
化合物P3的合成方法参照化合物P1的合成,其中所用碘苯为化合物2b。化合物P3的结构经质谱鉴定。
化合物P5合成方法如下:
化合物P5的合成方法参照化合物P1的合成,其中所用碘苯为化合物2c。化合物P5的结构经质谱鉴定。
化合物P7合成方法如下:
化合物P7的合成方法参照化合物P1的合成,其中所用碘苯为化合物2d。化合物P7的结构经质谱鉴定。
化合物P10合成方法如下:
化合P10的合成方法参照化合物P1的合成,其中所用碘苯为化合物2e。化合P10的结构经质谱鉴定。
化合物P11合成方法如下:
化合P11的合成方法参照化合物P1的合成,其中所用碘苯为化合物2f。得到的中间体P11a在TFA/DCM的处理下得到化合物P11。化合物P11结构经质谱鉴定。
化合物P11合成:
化合P12的合成方法参照化合物P1的合成,其中所用碘苯为化合物2g,K2CO3为2.1当量。化合P12的结构经质谱鉴定。
化合物P14的合成:
化合P14的合成方法参照化合物P1的合成,其中所用碘苯为化合物2h。化合P15的结构经质谱鉴定。
化合物P16-P34的合成:
化合物P16-P34的合成方法参照化合物P1的合成,其中所用碘苯结构分别如下:
化合物P16-P34的结构经质谱鉴定。
实施例2
动物分组、手术造模及给药:小鼠随机分为空白对照组、模型对照组、吡非尼酮治疗组、新药治疗组。小鼠适应3天后(体重约20g),第4天手术造模。方法如下:小鼠称重后,腹腔注射戊巴比妥钠麻醉,将麻醉后小鼠取仰卧位,用鼠板固定小鼠四肢和头部,头高脚低,充分暴露颈部皮肤。小鼠颈前区常规脱毛,消毒,行正中纵向切口,钝性分离肌肉、组织直至暴露气管。用无菌生理盐水配制博来霉素溶液(2mg/ml),注射器经气管软骨环间隙朝向心端刺入气管,回抽见空气且无阻力后,将50uL药液缓慢注入气管,空白对照组注入相同体积生理盐水。注入结束后将鼠板直立并迅速旋转抖动,让药液在小鼠肺内均匀分布,缝合切口,右侧卧静置,待其自然苏醒。造模3天后开始灌胃给药,将药物用5%羧甲基纤维素钠(CMC-Na)配成溶液,每只小鼠按照400mg/KG给药,空白对照组和模型组灌胃相同剂量CMC-Na溶液。灌胃期间检测小鼠体重及存活情况。用药16天后处死小鼠,小鼠摘眼球取血后脱颈处死,收集肺等器官,一部分肺组织及其他组织置于4%中性福尔马林中固定,一部分液氮处理后置于-80℃冰箱,用于组织形态观察和后续相关指标的检测。
化合物P1的小鼠给药结果分析
(1)小鼠血清中羟脯氨酸含量分析
羟脯氨酸(HYP)是胶原蛋白特有的非必需氨基酸,是胶原组织的主要成分之一,可用于评估成纤维细胞的活化程度。各组小鼠血清HYP含量检测结果如图1所示。与空白组小鼠血清中HYP含量(206±4ng/ml)相比,模型组小鼠的HYP含量(360±7ng/ml)大幅度提高,纤维化情况较为严重。相比于模型组,吡非尼酮治疗组小鼠的HYP含量(286±4ng/ml)有所下降,呈现出一定的缓解作用。P1治疗组小鼠的HYP含量(210±4ng/ml)相比于吡非尼酮治疗组(286±4ng/ml)更低,接近于空白组(206±4ng/ml),表明P1有着比吡非尼酮更好的抗纤维化疗效,P1用药后羟脯氨酸含量接近于正常值。
(2)肺组织病理变化分析
通过肺组织切片HE染色、MASSON染色以及α-SMA免疫荧光染色对比空白组、模型组、吡非尼酮治疗组和P1治疗组的肺组织病理变化。如图2-4所示,空白组肺组织结构清晰,肺泡间隔未见增厚,无充水水肿,无明显肌成纤维细胞,无炎症及肺纤维化表现,肺泡腔内无明显渗出。模型组肺泡结构破坏严重,萎缩塌陷严重,胶原肺纤维显著增多,出现大量炎症细胞浸润,有大量肌成纤维细胞。吡非尼酮治疗组肺泡结构破坏程度减轻,胶原肺纤维略有减少,成纤维细胞减少,肺纤维化程度得到缓解。P1治疗组肺组织结构更为清晰,胶原肺纤维大幅度减少,成纤维细胞大幅度减少,无限接近空白组。以上数据表明,本发明新药P1的抗肺纤维化效果比上市药物吡非尼酮更为显著,治疗后肺组织的纤维化程度得到了极大程度的缓解。
(3)安全性评估
a.肝、肾功能评价
如图5-9所示,吡非尼酮治疗组和P1治疗组小鼠血浆中的AST、ALT、AKP、BUN以及SCR含量与模型组对比,均有着大幅度的下降,和空白组的数值持平,证明药物P1有着较好的安全性。
b.心脏、肝脏、脾脏及肾组织的HE染色情况
分别对空白组、模型组、吡非尼酮治疗组和P1治疗组小鼠的心脏、肝脏、脾脏及肾组织进行HE染色,评估药物对其他脏器的影响,证明药物安全性。由图10-13可见,相比于空白组,连续使用吡非尼酮和P1均对小鼠其他脏器无明显损伤,再次证明P1有着较好的安全性。
c.肺系数
肺系数(肺重/体重)是一项动物实验的测量指标。如图14所示,模型组的肺系数相比于空白组有一定程度提高。而相比于空白组,吡非尼酮治疗组和P1治疗组均无明显的肺系数变化,进一步表明P1优异的安全性。
(4)小鼠体重
试验中小鼠体重的变化可评估药物使用对小鼠的影响。如图15所示,相比于空白组,吡非尼酮治疗组和P1治疗组均无明显的体重降低,进一步表明新药P1出色的安全性。
实施例3
其他化合物的测试数据以如下表格的形式给出,其中,测试过程及方法参照实施例2。
表1其他化合物的性质数据表
通过表中实验数据可以看出,上述N-取代苯基-2-吡啶酮化合物治疗后肺组织的纤维化程度得到了很大程度的缓解。
Claims (6)
4.根据权利要求1-2任意一项所述的化合物,其特征在于,所述的治疗肺纤维化药物剂型为片剂、胶囊剂、颗粒剂、散剂、口服制剂、注射剂、微囊制剂或者栓剂。
5.根据权利要求1-2任意一项所述的化合物,其特征在于,所述的治疗肺纤维化药物采用口服给药或者静脉注射。
6.根据权利要求1-2任意一项所述的化合物,其特征在于,所述化合物或其可药用盐用于制备治疗由博来霉素或其他因素诱导的肺纤维化的药物。
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CN102099036A (zh) * | 2008-06-03 | 2011-06-15 | 英特芒尼公司 | 用于治疗炎性疾患和纤维化疾患的化合物和方法 |
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