CN114404415A - 吲唑类化合物用于治疗银屑病的用途 - Google Patents
吲唑类化合物用于治疗银屑病的用途 Download PDFInfo
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Abstract
Description
技术领域
本发明属于医药领域,具体涉及一种吲唑类化合物用于治疗银屑病的用途。
背景技术
银屑病是一种由免疫介导的由环境因素和遗传因素等多因素共同作用的慢性炎症性病。 银屑病的病因复杂,其发生发展可能涉及T细胞分化、炎症细胞浸润、角质形成细胞增殖等。 此外,遗传、感染、代谢障碍、内分泌异常及其他相关因素(吸烟、饮酒、外伤、劳累、精神 因素等)也可诱发甚至加重银屑病。
目前常用的银屑病外用药物有糖皮质激素、维A酸、维生素D衍生物、地蒽酚、焦油制 剂以及钙调磷酸酶抑制剂等。地蒽酚、焦油制剂和糖皮质激素因副作用较大使用受限,而维 A酸、钙调磷酸酶抑制剂和维生素D衍生物的治疗效果不是十分理想。一些生物制剂虽然疗 效快,但是价格昂贵,而中药类制剂由于成分复杂,往往疗效不明确且容易产生副作用。因 此,有必要找到一种疗效好,使用安全的新药用于治疗银屑病。
发明内容
为解决现有技术中存在的问题,本发明提供式(Ⅰ)化合物、其立体异构体、消旋异构体、 互变异构体、同位素标记物、前药或其药学上可接受的盐在制备用于治疗和/或预防银屑病 的药物中的用途,所述式(I)化合物如下:
其中,
环A为含有至少一个含N的5-14元杂芳基或5-12元杂环基;
每个R1、R2、R3各自独立的选自氢、卤素、CN、OH或任选被一个、两个或更多个R取 代的如下基团:(C1-C12)脂肪烃基,任选地包含一个、两个或更多个杂原子(C1-C12)脂肪烃 基,C3-12环烷基、3-12元杂环基、C6-20芳基或5-14元杂芳基、-NRaRb;
W选自O,S,NH,单键;
每个Ra、Rb独立的选自H、(C1-C12)脂肪烃基;
每个R独立的选自卤素、CN、OH、SH、NRaRb或选自任选被一个、两个或更多个R’取 代的如下基团:(C1-C12)脂肪烃基,任选地包含一个、两个或更多个杂原子(C1-C12)脂肪烃 基,C3-12环烷基、3-12元杂环基、C6-20芳基或5-14元杂芳基;
每个R’独立的选自卤素、CN、OH、SH、NRaRb;
n选自1、2、3;m选自1、2、3、4、5、6。根据本发明的实施方案,
所述“任选地包含一个、两个或更多个杂原子的(C1-C12)脂肪烃基”可以选自(C1-C12) 脂肪烃基氧基、(C1-C12)脂肪烃基巯基,(C1-C6)脂肪烃基氧基(C1-C6)脂肪烃基、(C1-C6)脂肪 烃基巯基(C1-C6)脂肪烃基、N-(C1-C3)脂肪烃基胺基(C1-C6)脂肪烃基、N,N-二-(C1-C3)脂肪烃基 胺基(C1-C6)脂肪烃基;
所述“含有至少一个含N的5-14元杂芳基或5-12元杂环基”是指所述杂芳基或杂环基中 至少含有一个氮原子,还可以含有其他选自N、O、或S的一个或多个杂原子,例如选自吡 啶,吡咯,哌啶或四氢吡咯等。
所述(C1-C12)脂肪烃基可以选自(C1-C12)烷基、(C2-C12)烯基、(C2-C12)炔基,优选的,所述(C1-C12)脂肪烃基可以选自(C1-C6)烷基、(C2-C6)烯基、(C2-C6)炔基;
所述“卤素”选自F、Cl、Br、I;
所述“C3-12环烷基”可以选自环丙基、环丁基、环戊基或环己基。
一种优选的实施方案,所述R1、R2、R3可以各自独立的选自任选被一个、两个或更多个 R取代的如下基团:甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、新戊基、正己基、乙烯基、1-丙烯基、2-丙烯基、1-甲基乙烯基、1-丁烯基、1-乙基乙烯基、1-甲基-2-丙烯基、2-丁烯基、3-丁烯基、2-甲基-1-丙烯基、2-甲基-2-丙烯基、1-戊烯基、 1-己烯基、乙炔基,1-丙炔基、2-丙炔基、1-丁炔基、1-甲基-2-丙炔基、3-丁炔基、1-戊炔基、 1-己炔基、环丙基、环丁基、环戊基、环己基、甲氧基,乙氧基,丙氧基,丁氧基,戊氧基, 甲氧基甲基,乙氧基甲基、丙氧基甲基、甲氧基乙基、乙氧基乙基、丙氧基乙基、甲氧基丙 基、乙氧基丙基、丙氧基丙基、N-甲基胺甲基、N-甲基胺乙基、N-乙基胺乙基、N,N-二甲基胺甲基、N,N-二甲基胺乙基、N,N-二乙基胺乙基、氨基、N,N-二甲基氨基、N,N-二乙基氨基、四氢吡咯基、哌啶基、吡啶基,吡嗪基、吡咯基,咪唑基、吡唑基、恶唑基、异恶唑基、
一种优选的实施方案,所述式I所示的化合物可以选自如下式Ia、式Ib、式Ic、式Id、 式Ie结构:
所述式Ia、式Ib、式Ic、式Id、式Ie中,R1,R2,R3,m,n,W如式I所定义。
一种更优选的实施方案,所述式I所示的化合物可以选自如下结构:
根据本发明的实施方案,所述银屑病包括寻常性银屑病、关节病性银屑病、脓疱型银屑 病、红皮病型银屑病。
根据本发明的实施方案,所述式(Ⅰ)化合物、其立体异构体、消旋异构体、互变异构体、 同位素标记物、前药或其药学上可接受的盐经口服、肠胃外给药或其它给药途径。优选为口 服或肠胃外给药。更优选为口服。
所述肠胃外给药,例如,可以经皮肤局部施用给药;所述其它的给药途径,例如可吸入 药物形式、滴鼻剂、溶液剂或喷雾剂,舌、舌下或颊给药的片剂、软片/扁圆片或胶囊剂,栓 剂、耳用或眼用制剂、阴道胶囊剂、水悬剂、亲脂性悬浮剂、软膏剂、乳膏、经皮治疗系统 (例如贴剂)、乳剂、糊剂、泡沫剂、喷粉剂、植入物或支架。
所述口服给药的剂型为片剂、软片剂、胶囊剂、糖衣片剂、颗粒剂、丸剂、粉末剂、乳剂、悬浮剂或溶液剂。
另一方面,本发明提供一种治疗和/或预防银屑病的方法,给予治疗有效量的所述式(Ⅰ) 化合物、其立体异构体、消旋异构体、互变异构体、同位素标记物、前药或其药学上可接受 的盐。
有益效果
本发明化合物具有良好的治疗以及缓解银屑病的作用,具体的,如本发明实验所验证, 对小鼠的体重下降有一定的改善,并且对小鼠的耳朵厚度增加有显著的抑制作用,对小鼠的 脾脏的增加有明显的抑制剂作用。此外,采用本发明的化合物对小鼠治疗后,小鼠的银屑明 显减少。
附图说明
图1示意小鼠体重数值变化
图2示意小鼠右耳耳厚数值变化
图3示意小鼠背部皮肤评分数值变化
图4示意小鼠脾脏重量数值(mg)
图5示意小鼠皮肤病理评分
具体实施方式
下文将结合具体实施例对本发明的技术方案做更进一步的详细说明。应当理解,下列实 施例仅为示例性地说明和解释本发明,而不应被解释为对本发明保护范围的限制。凡基于本 发明上述内容所实现的技术均涵盖在本发明旨在保护的范围内。
除非另有说明,以下实施例中使用的原料和试剂均为市售商品,或者可以通过已知方法 制备。
化合物制备例1
1.化合物3的合成
15摄氏度下依次向化合物1(50g)的二氯甲烷溶液(500mL)中加入DMAP(42.5g),化合 物2(63.4g),和三乙胺(63.9g),并在25摄氏度下搅拌反应18小时。向反应液中加入二氯甲 烷(200mL)用水洗涤(300mL*2),1M的稀盐酸(300mL*3)洗涤,有机相用无水硫酸钠干燥,过滤,减压浓缩得到化合物3(98g,收率:99%)。
2.化合物4的合成
15摄氏度下向化合物3(50g)的四氢呋喃溶液(300mL)中加入1M稀盐酸(300mL)并在25 摄氏度下搅拌反应20小时。冷却到0摄氏度,用1M的氢氧化钠溶液调到PH=9,用乙酸乙酯(200 mL×3)萃取,萃取液用饱和氯化钠溶液(300mL)洗涤,无水硫酸钠干燥,过滤,减压浓缩, 残留物用石油醚(150mL)打浆得化合物4(39g,收率91%)。
3.化合物5&6的合成
-40摄氏度下向甲基溴化镁(85.8mL)的四氢呋喃溶液(500mL)中滴加化合物4(34.5g)的四氢呋 喃溶液(200mL),并在-40摄氏度下搅拌反应4小时,用饱和氯化铵溶液(100mL)淬灭反应,用 乙酸乙酯(500mL×3)萃取,萃取液用饱和食盐水(300mL)洗涤,无水硫酸钠干燥,过滤,减压 浓缩,残留物用硅胶色谱柱纯化(石油醚:乙酸乙酯=5:1)得化合物5(4.3g,收率10%),化合物6 (7.0g,收率17%)和混合物12g。
化合物5
1H NMR(400MHz,CDCl3):δ7.79(d,J=8.0Hz,2H),7.32(d,J=8.4Hz,2H),4.52-4.41(m,1H), 2.44(s,3H),1.95-1.80(m,2H),1.77-1.61(m,4H),1.46-1.35(m,2H),1.19(s,3H)。
化合物6
1H NMR(400MHz,CDCl3):δ7.79(d,J=8.4Hz,2H),7.33(d,J=8.0Hz,2H),4.74-4.64(m,1H), 2.44(s,3H),1.92-1.79(m,2H),1.77-1.62(m,4H),1.49-1.38(m,2H),1.23(s,3H)。
4.化合物8的合成
零下15摄氏度下向化合物7(2.0g)的浓硫酸(12mL,98%)溶液中滴加硝酸(1.6mL,70%) 的浓硫酸(1.6mL,98%)混合溶液。加完后混合体系零下15摄氏度搅拌2小时,将反应液缓慢 倾倒入冰水中并搅拌5分钟,抽滤,用水洗涤,收集固体减压干燥得到化合物8(2.5g,收率: 97%)。
5.化合物9的合成
室温下向化合物8(2.0g)的DMF(20mL)溶液中加入水合肼(2.4mL,98%),加完后混合 体系加热到120摄氏度搅拌16小时,冷却到室温,混合体系慢慢倒入冰水中并搅拌,抽滤,用 水洗涤固体,收集固体减压浓缩得到化合物9(1.3g,收率:67%)。
6.化合物10的合成
15摄氏度下将化合物9(12.4g)和钯碳(7g,10%)依次加入到400mL乙酸乙酯中。加完后 混合体系在15摄氏度氢气保护下搅拌18小时,将反应液中钯碳滤掉后将滤液浓缩蒸干得到化 合物10(10.4g,收率99%)。
7.化合物12的合成
25摄氏度下将EDCI.HCl(2.6g)加到化合物10(1.5g)和化合物11(1.4g)的Py(15mL)溶液 中,反应液25摄氏度搅拌16小时。反应液浓缩蒸干,残留物通过MeOH/H2O=20mL/20mL打 浆得到化合物12(1.3g,收率48%)。
8.化合物001即2-((2-(反式-4-羟基-顺式-4-甲基环己基)-6-甲氧基-2H-吲唑-5-基)氨甲酰基)-6- 甲基吡啶1-氧化物的合成
25摄氏度下将碳酸铯(985mg)加入到化合物12(300mg)和化合物5(344mg)的5mL的DMF溶液中,反应液90摄氏度搅拌16小时。反应液加到30mL水中,乙酸乙酯萃取(10mL*3),有机相减压浓缩,残余物通过高效液相制备色谱柱(CH3CN:H2O(0.1%NH4HCO3)=15-45%,UV:214nm,流速:15ml/min)纯化得到化合物001(70mg,收率17%)。
1H NMR(400MHz,DMSO-d6):δ14.16(s,1H),8.78(s,1H),8.34(s,1H),8.32-8.30(m,1H),7.77 (d,J=7.6Hz,1H),7.58(t,J=8.0Hz,1H),7.13(s,1H),4.45(s,1H),4.43-4.40(m,1H),3.95(s, 3H),2.53(s,3H),2.09-2.00(m,4H),1.68-1.58(m,4H),1.22(s,3H).LCMS:Rt=3.646min,[M+H]+=411.1.
生物实施例本发明化合物的银屑病治疗效果
1.1试剂
本发明化合物可以参照化合物制备例1、WO2021/057785A1中的方法制备 IMQ(咪喹莫特)乳膏:Aldara
凡士林:Aladdin
10%中性福尔马林固定液:无锡市江原实业技贸公司
伊红:中杉金桥
苏木素:中杉金桥
1.2仪器
千分尺:日本三丰,分辨率0.001mm,公制0-25mm
LEICA石蜡脱水机:徕卡,型号:EG1150C
LEICA石蜡切片机:徕卡,型号:RM2235
LEICA石蜡包埋机:徕卡,型号:EG1150H
正置荧光显微镜:OLYMPUS,型号:DP720
1.3实验动物
BALB/c小鼠,雄性,8周,SPF级,上海灵畅生物科技有限公司
化合物A的结构式为
化合物B为化合物001,其结构式为
图示中
化合物组1Vaseline-Topical Vehicle P.O是指正常对照组(溶媒组)
化合物组2IMQ+Vehicle P.O是指模型对照组(溶媒组)
化合物组3IMQ+Dex-Topical是指阳性对照组(地塞米松)
化合物组4IMQ+A 15mg/Kg P.O是指化合物组(A,15mg/kg,灌胃)
化合物组5IMQ+B 15mg/Kg P.O是指化合物组(B,15mg/kg,灌胃)
1.4银屑病小鼠模型以及给药
先将50只小鼠根据体重随机分为5组,分别为化合物组1-正常对照组(溶媒组)、化合物组 2-模型对照组(溶媒组)、化合物组3-阳性对照组(地塞米松)、化合物组4(化合物A,15mg/kg, 灌胃)、化合物组5(化合物B,15mg/kg,灌胃)。在本实验第0天,各组小鼠均给予背部剃毛处 理,剔除背部约2cm*3cm面积毛发;并于本实验第1天至第7天,除正常对照组外给予每只小 鼠背部涂抹62.5mg 5%IMQ乳膏处理,右耳内外两侧涂抹20.0mg 5%IMQ乳膏处理。正常对照 组涂抹凡士林。于本实验第1天至第8天,在IMQ乳膏刺激诱导前2小时,分别给予上述组进行 相应的药物治疗。于给药前称重、剃毛,记为第0天,在第1天至第8天每天给药,1天2次。
1.5试验结果与评估:
1.5.1体重及其变化率:记录体重,并计算体重变化率,结果如图1所示(以均数±标准误(Mean ±SEM)表示,其中*P<0.05,**P<0.01,***P<0.001,V.S.模型对照组,Two-wayANOVA, Bonferroni posttests test,n=10)。
1.5.2右耳厚度测量:使用千分尺测量记录各组动物的右耳厚度,结果如图2所示(注:以上 数据以均数±标准误(Mean±SEM)表示,其中*P<0.05,**P<0.01,***P<0.001,V.S.模型对照组,Two-way ANOVA,Bonferroni posttests test,n=10;以上数据以均数±标准 误(Mean±SEM)表示,其中#P<0.5,##P<0.01,###P<0.001,V.S.Group 4,Two-wayANOVA,Bonferroni posttests test,n=10)。
1.5.3背部评分:第1,3,5,7天每组拍摄一张代表性照片,然后对其背部皮肤进行临床评分。临 床评分标准为表1,结果如图3所示(以上数据以均数±标准误(Mean±SEM)表示,其中 *P<0.05,**P<0.01,***P<0.001,V.S.模型对照组,Two-way ANOVA,Bonferroniposttests test,n=10,以上数据以均数±标准误(Mean±SEM)表示,其中#P<0.5,##P<0.01, ###P<0.001,V.S.Group 4,Two-way ANOVA,Bonferroni posttests test,n=10)。
表1临床评分系统(红斑,结痂,皮肤厚度)
1.5.4脾脏重量:在第8天,通过CO2吸入方式安乐死各组小鼠,并迅速摘取小鼠脾脏,收集右 耳和背部皮肤。取1/3背部皮肤,脾脏和右耳组织置于10%中性福尔马林固定液进行组织固定, 用于制备石蜡切片及HE染色;取另1/3背部皮肤液氮速冻,用作ELISA检测;取另1/3背部皮肤 液氮速冻,-80℃冰箱留存备用。结果如图4所示(注:以上数据以均数±标准误(Mean± SEM)表示,其中*P<0.05,**P<0.01,***P<0.001,V.S.模型对照组,One-wayANOVA, Bonferroni posttests test,n=10,以上数据以均数±标准误(Mean±SEM)表示,其中#P<0.5, ##P<0.01,###P<0.001,V.S.Group 4,One-way ANOVA,Bonferroniposttests test,n=10)。
1.5.5背部皮肤病理评分:收集小鼠背部皮肤样本,置于10%中性福尔马林固定液进行组织固 定48h,将组织置于75%酒精中脱脂72小时(每天换液),经系列梯度酒精脱水(详见表2), 制备成石蜡样本。用旋转切片机切片,厚度为4μm,在60℃烘箱干燥2小时。并根据表2和表 3进行HE染色和评分。结果如图5所示(注:以上数据以均数±标准误(Mean±SEM)表示, 其中*P<0.05,**P<0.01,***P<0.001,V.S.模型对照组,One-way ANOVA,Bonferroni posttests test,n=10)。
表2皮肤组织脱水步骤
步骤 | 试剂名称 | 时间(小时:分) | 温度 |
1 | 80%酒精 | 00:45 | 常温. |
2 | 95%酒精 | 00:45 | 常温 |
3 | 95%酒精 | 00:45 | 常温 |
4 | 100%酒精 | 00:45 | 常温 |
5 | 100%酒精 | 00:45 | 常温 |
6 | 100%酒精 | 00:45 | 常温 |
7 | 100%酒精 | 00:45 | 常温 |
8 | 100%酒精 | 00:45 | 常温 |
9 | 二甲苯 | 01:00 | 常温 |
10 | 二甲苯 | 01:00 | 常温 |
11 | 石蜡 | 01:00 | 60℃ |
12 | 石蜡 | 01:00 | 60℃ |
13 | 石蜡 | 01:00 | 60℃ |
表3H.E.染色步骤
综上,根据图1-5,与模型对照组小鼠相比,采用本发明化合物(参见化合物组5)可以对 小鼠的体重下降、右耳厚度增加以及脾脏重量增加有明显抑制作用,使得小鼠银屑明显减少, PASI临床评分明显降低,同时使得小鼠背部皮肤角蛋白、表皮层和真皮层的疾病症状减轻, 病理评分显著下降。
以上是对本发明具体实施例进行了描述。需要理解的是,本发明并不局限于上述实施例 的限制,上述实施例和说明书中描述的只是为了说明本发明的原理。本领域技术人员在不脱 离本发明构思的前提下,本发明还会有各种非实质性的变化和改进,这些都落入本发明要求 保护的范围内。
Claims (8)
1.一种式I化合物、其立体异构体、消旋异构体、互变异构体、同位素标记物、前药或其药学上可接受的盐在制备用于治疗和/或预防银屑病的药物中的用途,所述式(I)化合物如下:
其中,
环A为含有至少一个含N的5-14元杂芳基或5-12元杂环基;
每个R1、R2、R3各自独立的选自氢、卤素、CN、OH或任选被一个、两个或更多个R取代的如下基团:(C1-C12)脂肪烃基,任选地包含一个、两个或更多个杂原子(C1-C12)脂肪烃基,C3-12环烷基、3-12元杂环基、C6-20芳基或5-14元杂芳基、-NRaRb;
W选自O,S,NH,单键;
每个Ra、Rb独立的选自H、(C1-C12)脂肪烃基;
每个R独立的选自卤素、CN、OH、SH、NRaRb或选自任选被一个、两个或更多个R’取代的如下基团:(C1-C12)脂肪烃基,任选地包含一个、两个或更多个杂原子(C1-C12)脂肪烃基,C3-12环烷基、3-12元杂环基、C6-20芳基或5-14元杂芳基;
每个R’独立的选自卤素、CN、OH、SH、NRaRb;
n选自1、2、3;m选自1、2、3、4、5、6。根据本发明的实施方案,
所述“任选地包含一个、两个或更多个杂原子的(C1-C12)脂肪烃基”可以选自(C1-C12)脂肪烃基氧基、(C1-C12)脂肪烃基巯基,(C1-C6)脂肪烃基氧基(C1-C6)脂肪烃基、(C1-C6)脂肪烃基巯基(C1-C6)脂肪烃基、N-(C1-C3)脂肪烃基胺基(C1-C6)脂肪烃基、N,N-二-(C1-C3)脂肪烃基胺基(C1-C6)脂肪烃基;
所述“含有至少一个含N的5-14元杂芳基或5-12元杂环基”是指所述杂芳基或杂环基中至少含有一个氮原子,还可以含有其他选自N、O、或S的一个或多个杂原子,例如选自吡啶,吡咯,哌啶或四氢吡咯等。
所述(C1-C12)脂肪烃基可以选自(C1-C12)烷基、(C2-C12)烯基、(C2-C12)炔基,优选的,所述(C1-C12)脂肪烃基可以选自(C1-C6)烷基、(C2-C6)烯基、(C2-C6)炔基;
所述“卤素”选自F、Cl、Br、I;
所述“C3-12环烷基”可以选自环丙基、环丁基、环戊基或环己基。
5.根据权利要求1所述的用途,其特征在于,所述银屑病包括寻常性银屑病、关节病性银屑病、脓疱型银屑病、红皮病型银屑病。
6.根据权利要求1所述的用途,其特征在于,所述式(Ⅰ)化合物、其立体异构体、消旋异构体、互变异构体、同位素标记物、前药或其药学上可接受的盐经口服、肠胃外给药或其它给药途径。
7.根据权利要求1所述的用途,其特征在于,所述式(Ⅰ)化合物、其立体异构体、消旋异构体、互变异构体、同位素标记物、前药或其药学上可接受的盐优选经口服给药。
8.根据权利要求7所述的用途,其特征在于,所述口服给药的剂型为片剂、软片剂、胶囊剂、糖衣片剂、颗粒剂、丸剂、粉末剂、乳剂、悬浮剂或溶液剂。
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