CN112745251B - 一种治疗祛痰化合物及其制备方法和用途 - Google Patents
一种治疗祛痰化合物及其制备方法和用途 Download PDFInfo
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- C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
- C07C323/30—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a ring other than a six-membered aromatic ring of the carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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Abstract
本发明公开了一种治疗祛痰化合物,具体公开了式I和式II所示化合物、其药学上可接受的盐或其互变异构体。
Description
技术领域
本发明涉及一种祛痰药物及其制备方法即式I和II的化合物或其药学上可接受的盐和药物组合物在祛痰中的应用。
背景技术
咳痰为呼吸系统疾病的常见症状,痰液的增可刺激呼吸道黏膜引起咳嗽。当阻塞细支气管时。小仅可引起气喘,还能引起继发感染,进一步损伤呼吸道,加重咳嗽、咳痰和气喘。严重者可抑制呼吸或窒息致死。黏液的过度分泌会引起黏液纤毛清除功能障碍和局部防御功能损害,导致感染难以控制和气道阻塞加重,直接影响病情进展和患者主观感受。故使用祛痰药物促进气道内分泌物的尽快外排是治疗气道炎症的重要辅助措施。
祛痰药是一类能使痰液变稀、黏稠度降低而易于咳出,或者能加速呼吸道黏膜纤毛运动、改善痰液转运功能的药物。祛痰药促进呼吸道管腔内积痰的排出,减少对呼吸道黏膜的刺激,间接起到镇咳和平喘的作用,也有利于控制继发感染。祛痰药物从下述诸方面发挥促痰外排作用:(1)改善痰液理化特性,降低黏滞度。(2)恢复气道上皮黏液层正常结构及纤毛清除功能。(3)抑制黏蛋白产生及分泌,减少高黏度黏液的生成。(4)促使脓痰中的DNA解聚。(5)抗炎症,减少DNA的产生。根据药物的主要作用使祛痰药物分为黏液分泌促进药(恶心性祛痰药和刺激性祛痰药)、黏液溶解药。目前临床代表性的化学祛痰药物有氯化铵、乙酰半胱氨酸、氨溴索、厄多司坦等。但以上常用药都存在一定的不良反应,因此开发一种全新的安全有效的祛痰药很有必要。
发明内容
本发明涉及由结构式Ⅰ和II所示的化合物及其非毒性药学上可接受的盐,以及含有这些化合物作为活性成分的药物组合物,以及所述化合物及药物组合物在祛痰药中的用途。本发明的化合物通过将乙酰胱氨酸中的巯基基团,引入到氨溴索类似结构中,结果本发明人惊奇的发现其治疗祛痰效果明显优于现有祛痰药物,本发明的化合物安全性更高,效果更好。
因此本发明的第一个方面提供了式Ⅰ和II所代表的化合物及其可药用盐:
,/>
其中,式Ⅰ所示化合物中:
R1代表H、F、Cl、Br或NH2 ;R2代表H、F、Cl或Br;R3代表H、F、Cl、Br或NH2;R4代表H、F、Cl或Br;R5代表H、F、Cl或Br;R6代表H或CH3;R7代表、/>或/>。
其中,式II所示化合物中:
X代表、/>及其碱金属盐、氨基酸(如L-丙氨酸、L-缬氨酸等)。
优选地,本发明提供式Ⅰ和II所代表的化合物或其可药用盐选自如下结构式所代表的化合物:
I1:反式-4-[(2-氨基-3,5-二溴苄基)氨]-环己硫醇
I2:反式-3-(2-氨基-3,5-二溴-苄氨基)-环己硫醇
I3:顺式-3-(2-氨基-3,5-二溴-苄氨基)-环己硫醇
I4:反式-4-[(2-氨基-3,5-二溴苄基)-甲基-氨基]-环己硫醇
I5:反式-4-[(2-氨基-3,5-二溴苄基)-甲基-氨基]-环己硫醇
I6:顺式-3-[(2-氨基-3,5-二溴苄基)-甲基-氨基]-环己硫醇
I7:反式-2-[(2-氨基-3,5-二溴苄基)-甲基-氨基]-环己硫醇
I8:顺式4-[(2-氨基-3,5-二溴苄基)-甲基氨基]-环己硫醇
I9:顺式-3-(4-氨基-2-氯-苄氨基)-环己硫醇
I10:顺式-3-(2-氨基-5-溴-苄氨基)-环己硫醇
I11:顺式-3-(2-氨基-4-氯-苄氨基)-环己硫醇
I12:反式-4-[(2-氨基-6-氯苄基)-甲基氨基]-环己硫醇
I13:反式3-[4-(2-氨基-3,5-二溴苄基氨基)-环己基硫烷基]-丙烷-1-醇
另一方面,本发明提供上述式Ⅰ、II所示的化合物的制备方法,通过如下步骤制备;
本发明的第二个方面涉及药物组合物,其包括至少一种式Ⅰ和II所代表的化合物或其可药用盐,以及一种或多种药学上可接受的载体或赋形剂。
本发明的第三个方面涉及式Ⅰ和II所示的化合物及其非毒性药学上可接受的盐,以及包含式Ⅰ和II所示的化合物及其非毒性药学上可接受的盐作为活性成分的药物组合物作为祛痰的用途。
式Ⅰ和II所代表的化合物可以与无机酸形成药用盐,如盐酸盐、氢溴酸盐、硫酸盐等。选择和制备适当的盐是本领域技术人员公知技术。
本发明化合物或其可药用盐可以单独或以药物组合物的形式给药。本发明药物组合物可根据给药途径配成各种适宜剂型。使用一种或多种生理学上可接受的载体,包含赋形剂和助剂,它们有利于将活性化合物加工成可以在药学上使用的制剂。适当的制剂形式取决于所选择的给药途径,可以按照本领域熟知的常识进行制备。
给药途径可以是口服、非肠道或局部给药,优选口服、雾化吸入和注射形式给药。可以口服的药物制剂包括口服液、颗粒剂或片剂等。本领域技术人员可以理解,本发明化合物可以采用合适的药物释放系统(DDS)以得到更有利的效果。
具体实施方式
下面的实施例可以使本专业技术人员更全面的理解本发明,但不以任何方式限制本发明。
实施例1:反式-4-氨基环己硫醇盐酸盐的制备
取反式-4-乙酰胺基环己硫醇40g,氢氧化钾40g和水350ml加入500ml反应瓶,置油浴锅,加热回流10小时,反应完成后降至室温,加入二氯甲烷(100ml×3次)萃取,合并有机相,用无水碳酸钠干燥,过滤,滤液通入氯化氢,当没有固体产生后,降温至0℃搅拌析晶10小时,过滤,得反式-4-氨基环己硫醇盐酸盐38g。
实施例2:反式-4-[(2-氨基-3,5-二溴苯亚甲基)氨基]环己硫醇的制备
取反式-4-氨基环己硫醇盐酸盐50g、氢氧化钠13g、碳酸钾18g、乙二醇单甲醚400ml加入1000ml三口瓶中,置油浴锅中,加热至120℃时,分4次加入N-(2-氨基-3,5-二溴苯甲酰)-N,-甲磺酰肼78g,加毕,回流反应2h,降至室温加入水400ml搅拌析晶,过滤,得反式-4-[(2-氨基-3,5-二溴苯亚甲基)氨基]环己硫醇132g。
实施例3 反式-4-[(2-氨基-3,5-二溴苄基)氨]-环己硫醇盐酸盐(I1)的制备
取反式-4-[(2-氨基-3,5-二溴苯亚甲基)氨基]环己硫醇100g,冰醋酸300ml,5%pd/C 1.0g加入氢化反应釜中,于0.2MPa,60℃氢化8h,反应结束后减压蒸干,残余物溶解到400ml丙酮中,滴加盐酸10ml,降温至0℃析晶4h,过滤,干燥,得反式-4-[(2-氨基-3,5-二溴苄基)氨]-环己硫醇盐酸盐(I1)。
实施例4-5
参照实施例1、2、3的操作,区别在于将反式-4-氨基环己硫醇盐酸盐替换成3-氨基环己硫醇盐酸盐进行反应,得到下述式Ⅰ的化合物。
实施例6 反式-4-[(2-氨基-3,5-二溴苄基)-甲基-氨基]-环己硫醇盐酸盐(I4)的制备
参照实施例1、2、3的操作,区别在于将反式-4-氨基环己硫醇盐酸盐替换成4-(甲胺基)环己硫醇盐酸盐进行反应,得化合物I6。
实施例7-10
参照实施例6的操作,区别在于将4-(甲胺基)环己硫醇盐酸盐替换成不同的SH位置及异构的甲基氨基环己硫醇,得到下述式Ⅰ的化合物。
实施例11:顺式-3-(4-氨基-2-氯-苄氨基)-环己硫醇(I9)的制备
取10g顺式-3-(2-氯-4-硝基-苄氨基)-环己硫醇盐酸盐溶于150ml乙醇和20ml水中,将该溶液与0.2g钯炭混合,室温氢化还原该混合物,吸氢完全后,过滤除去钯炭,滤液加入少量乙醚,析出固体,乙醇重结晶,得化合物(I9)。
实施例12:顺式-3-(2-氨基-5-溴-苄氨基)-环己硫醇(I10)的制备
将30g氢化铝锂加入到3L无水四氢呋喃中,并将该混合物在室温下滴加到100g顺式- 2-氨基-4-氯-N-(3-巯基-环己基)-苯甲酰胺和无水四氢呋喃的溶液中,滴毕,搅拌回流24小时。加乙酸乙酯和5N氢氧化钠淬灭未反应的氢化铝锂,过滤,滤液真空浓缩至干,硅胶柱层析纯化,得化合物(I10)。
实施例13-14
参照实施例12的操作,区别在于通过还原不同的苯甲酰胺类化合物,得到下述式Ⅰ的化合物。
实施例15:反式3-[4-(2-氨基-3,5-二溴苄基氨基)-环己基硫烷基]-丙烷-1-醇(I13)的制备
将24.55g(0.057mol)化合物I1投入100ml水中,搅拌使溶解,在搅拌下依次加入12.40g(0.172mol)烯丙醇,1g(0.0037mol)K2S2O8,0.38g(0.0037mol)NaHSO3,加热至50℃,搅拌8小时,反应完成后蒸除水和过量的烯丙醇,加入200ml无水乙醇,搅拌析出固体,纯化,得化合物I13。
实施例16:体内药效学试验-小鼠酚红祛痰试验
本实施例检测了本发明的化合物I1、I4、 I13以及已知化合物的体内药效。
取健康小鼠90只随机分为9组,具体分组情况见表2,阳性对照药用氯化铵和盐酸氨溴索口服溶液,正常对照组给予等量生理盐水,其他各组灌胃给予相应的药物。实验前2天上、下午各灌胃给药1次(氯化铵除外),实验当天上午灌胃给药1小时后,小鼠腹腔注射苯酚红0.5ml/只,0.5小时后处死小鼠,剥离器官周围组织,剪下自甲状软骨下至气管分支处的一段气管放入盛有2ml生理盐水的试管中,振荡30分钟,丢弃气管,每份标本液中加入1mol/L氢氧化钠溶液0.2ml,用紫外-可见分光光度计,波长546nm测OD值,根据酚红标准曲线,将吸光度值换算成酚红含量。
注:与正常组比较△△P<0.01;与氨溴索口服溶液组比较*P<0.05;**P<0.01;与氯化铵组比较※P<0.05 ※※P<0.05。
数据处理采用PEMS医学统计软件进行处理,结果各用药组均有显著的促进小鼠气管段酚红的分泌,以氨溴索组和化合物I1和I13的高剂量作用最好,且化合物I13作用最强,各剂量作用均明显优于氯化铵和氨溴索,其中以化合物I13的祛痰作用最为显著。提示化合物I13的祛痰作用随剂量增加而增强,存在较为明显的量效关系,且化合物I13的作用优于化合物I1。
实施例17:本发明化合物对小鼠静脉给药的急性毒性测试
为测试本发明化合物和对比化合物的急性毒性,进行下述实验。
本发明化合物溶解到水中,对5只ICR小鼠给药(5周大,雄性,体重20克±2克的小鼠)。静脉给药以确定半数致死量(LD50,mg/kg)。使用盐酸氨溴索作为对照。结果见下表所示。
试验结果表明:化合物I1、I4和I13的LD50值远高于盐酸氨溴索,提示本发明的化合物安全性优于盐酸氨溴索。
实施例配方:药物组合物的制备
l、粉剂的制备
实施例3
化合物 2克
乳糖 1克
将上述物料混合,然后将混合物填充到密封包装中,以制备粉剂。
2、片剂的制备
实施例4
化合物 500g
玉米淀粉 100g
乳糖 1 00g
硬脂酸镁 2g
将上述物料混合,然后将混合物用己知方法压片制成片剂。
3、胶囊的制备
实施例11
化合物 500g
玉米淀粉 100g
乳糖 100g
硬脂酸镁 2g
将上述物料混合并通过己知方法将混合物填充到明胶胶囊中制成胶囊。
4、注射剂的制备
实施例13
化合物 20克
pH调节剂 保持pH为4.0-9.0
葡萄糖 赋形剂
水 溶剂
取实施例13化合物、葡糖糖加水溶解,用pH调节剂调节pH至4.0-9.0置冷冻干燥箱冷冻干燥,干燥完加塞,轧盖。
5、吸入剂的制备
实施例13
化合物 15克
pH调节剂 保持pH为4.0-9.0
氯化钠 15g等渗调节剂
水 2000ml
取实施例13化合物、氯化钠加水溶解,用pH调节剂(盐酸或氢氧化钠)调节pH至4.0-9.0,灌装,轧盖,置灭菌柜中121℃灭菌12分钟,即得。
Claims (4)
1.式Ⅰ所示化合物、其药学上可接受的盐,所述式Ⅰ化合物为:I13:反式3-[4-(2-氨基-3,5-二溴苄基氨基)-环己基硫烷基]-丙烷-1-醇。
2.根据权利要求1所述的式Ⅰ所示化合物、其药学上可接受的盐,所述盐为盐酸盐、氢溴酸盐、硫酸盐。
3.一种药物组合物,其特征在于,包括权利要求1或2所述的具有式Ⅰ结构的化合物或其药学上可接受的盐,以及一种或多种药学上可接受的载体或赋形剂。
4.根据权利要求1或2所述的具有式Ⅰ结构的化合物或其药学上可接受的盐在制备祛痰药中的用途。
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US11993561B2 (en) | 2024-05-28 |
WO2021082501A1 (zh) | 2021-05-06 |
US20220388952A1 (en) | 2022-12-08 |
AU2020375675A1 (en) | 2022-05-12 |
EP4053103A1 (en) | 2022-09-07 |
AU2020375675B2 (en) | 2023-11-09 |
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