CN110225905B - 用于保护皮肤免受重金属和甲醛影响的组合物 - Google Patents
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Abstract
本发明提供一种用于保护皮肤免受重金属和甲醛影响的组合物,所述组合物包含选自由以下组成的组中的至少一种:式(1)的曲恩汀或曲恩汀衍生物、式(2)的轮环藤宁或轮环藤宁衍生物、式(3)的环拉胺或环拉胺衍生物及它们的盐。
Description
技术领域
本发明涉及用于保护皮肤免受外部环境影响的组合物。特别地,本发明涉及用于有效去除附着或吸附在皮肤上的重金属和甲醛的组合物。
背景技术
随着工业发展,空气污染越来越严重。主要的空气污染物是挥发性有机化合物(VOC)如甲醛,有害气体如二氧化硫、氮氧化物、臭氧和一氧化碳,和重金属如Pb、Cd、As、Cr、Cu、Ni。这些污染物通常被吸附或浓缩到细粉尘(PM10)或超细粉尘(PM2.5)中,并且通过呼吸道进入体内,从而引起各种呼吸***疾病,诸如哮喘和肺功能恶化。这些污染物还引起各种皮肤疾病,诸如皮炎、过敏、特应性等。
甲醛是一种代表性的VOC,其被归类为对人类具有致癌性,并且众所周知其是诱导特应性的物质。
虽然细粉尘的组分取决于地区、环境和季节,但是据报道,在细粉尘中以约20重量%的量含有有害重金属,诸如Hg、Pb、Cd、As、Cr、Cu、Ni、Zn、Mn、Co和Sn。
公开了化妆品形式的各种组合物以保护皮肤免受细粉尘和重金属影响。
韩国专利公开号10-2010-0056239公开了一种化妆品组合物,其包含选自由蘑菇多糖、海藻多糖和人参多糖组成的组中的至少一种作为活性成分,以吸附尘暴、废气、外部污染物和细粉尘中的重金属。
韩国专利注册号10-0715241公开了一种化妆品组合物,其包含羧化海藻酸(通过用过氧化氢处理海藻酸来制备)作为活性成分用以清除重金属。
韩国专利公开号10-2016-0000959公开了一种用于去除重金属和细粉尘的化妆品组合物,其包含酒糟(米酒排出后留下的残余物)作为活性成分,其中酒糟是在制酒过程(诸如米酒)中产生的副产物。
乙二胺四乙酸(EDTA)是乙二胺化合物,其利用四个羧基和两个胺基而与金属离子结合,从而形成水溶性螯合化合物。由于EDTA与Pb2+具有强亲和力,因此其在药学上用作用于铅中毒的治疗。就化妆品而言,EDTA主要用作化妆品中含有的Ca2+和Mg2+的螯合剂,以增加化妆品的稳定性,并且还用作用于使皮肤保湿的组分。尽管EDTA是重金属离子的有效螯合剂,但是由于已知它会引起皮肤刺激,所以通常以基于化妆品总重量0.05重量%以下的量使用,并且通常不多于0.10重量%。
发明内容
技术问题
本发明的一个目的是提供一种金属和甲醛去除能力较高的皮肤用组合物,其中与常规材料相比,不具有皮肤刺激性和毒性或者皮肤刺激性和毒性极低。
问题的解决方案
本发明提供一种用于保护皮肤免受重金属和甲醛影响的组合物,所述组合物包含选自由以下组成的组中的至少一种:式(1)的曲恩汀(trientine)或曲恩汀衍生物、式(2)的轮环藤宁(cyclen)或轮环藤宁衍生物、式(3)的环拉胺(cyclam)或环拉胺衍生物、及它们的盐。
其中:R1、R2、R3、R4、R5和R6各自独立地是氢、-R7-COOH;
R7是C1-C5烷基、未取代或取代的芳族烃基、或未取代或取代的芳族杂环基。
在本发明中,用于保护皮肤免受重金属和甲醛影响的有效成分优选选自式(1a)的曲恩汀、式(2a)的轮环藤宁和式(3a)的环拉胺。
曲恩汀衍生物优选选自式(1b)至(1d)的化合物或其盐。
其中:R8、R9各自独立地是氢或C1-C4烷基;
X是氧、硫或氮原子。
轮环藤宁衍生物优选选自式(2b)至(2d)的化合物或其盐。
其中:R8、R9各自独立地是氢或C1-C4烷基;
X是氧、硫或氮原子。
环拉胺衍生物优选选自式(3b)至(3d)的化合物或其盐。
其中:R8、R9各自独立地是氢或C1-C4烷基;
X是氧、硫或氮原子。
发明的有益效果
与常规螯合剂相比,本发明的皮肤用组合物即使少量也具有除去甲醛的效果并且具有强的重金属去除能力。另一方面,本发明的皮肤用组合物没有或几乎没有皮肤刺激性和毒性,并且因此可以有效地用作用于保护皮肤免受外部环境影响的皮肤组合物。
附图简述
图1是示出了根据实施方案1至12的化合物的0.1重量%水溶液的重金属去除能力的图。
图2是示出了根据实施方案1至12的化合物的0.5重量%水溶液的重金属去除能力的图。
图3是示出了根据实施方案1至12的化合物的1.0重量%水溶液的重金属去除能力的图。
图4是示出了根据实施方案13至27的0.5重量%皮肤用化合物的重金属去除能力的图。
实施发明的最佳方式
本发明的发明人已经对重金属螯合剂进行了各种研究,以开发皮肤用组合物,所述组合物能够有效地去除由暴露于外部污染环境引起的附着或吸附在皮肤上的重金属。
下式(1a)的曲恩汀是三亚乙基四胺(TETA)的一般名称。
三亚乙基四胺二盐酸盐已显示出在小鼠实验中参与铜的代谢(F.W.Sunderman等人,Toxicol.Appl.Pharmacol.38,177(1976))。三亚乙基四胺二盐酸盐是药理学上众所周知的铜的螯合剂,因而众所周知的是其用作威尔逊病(Wilson’s disease)的治疗(JMWalshe,Prog.Clin.Biol.Res.34,271(1979);RH Haslam等人,Dev.Pharmacol Ther.1,318(1980))。
下式(2a)的轮环藤宁是1,4,7,10-四氮杂环十二烷的一般名称。它通过与钆(Gd)的配位键形成螯合物,并且用于核医学造影剂。
下式(3a)的环拉胺是1,4,8,11-四氮杂环十四烷的一般名称。它还通过与钆(Gd)的配位键形成螯合物,并且用于核医学造影剂。
螯合剂诸如曲恩汀、轮环藤宁和环拉胺因其通过口服或血管施用方法在体内释放铜的能力或其作为造影剂的用途而在药学上众所周知。然而,尚未报道用于保护皮肤的用途(诸如去除皮肤上的重金属)。
本发明公开了曲恩汀、轮环藤宁、环拉胺及其衍生物在从皮肤去除重金属以及皮肤刺激性和毒性方面非常有用。过去已知曲恩汀、轮环藤宁和环拉胺对皮肤有害。作为本发明实验的结果,已发现使用有效量用以去除皮肤上的重金属不会引起皮肤刺激性和毒性,因此它作为用于保护皮肤的成分是可以接受的。
另一方面,本发明公开了曲恩汀、轮环藤宁、环拉胺及其衍生物对于去除作为主要致癌物的甲醛是非常有效的。
本发明提供一种用于保护皮肤免受重金属和甲醛影响的组合物,所述组合物包含选自由以下组成的组中的至少一种:式(1)的曲恩汀或曲恩汀衍生物、式(2)的轮环藤宁或轮环藤宁衍生物、式(3)的环拉胺或环拉胺衍生物及它们的盐。
其中:R1、R2、R3、R4、R5和R6各自独立地是氢、-R7-COOH;
R7是C1-C5烷基、未取代或取代的芳族烃基、或未取代或取代的芳族杂环基。
本发明的皮肤用组合物的特征在于其包含曲恩汀、曲恩汀衍生物、轮环藤宁、轮环藤宁衍生物、环拉胺、环拉胺衍生物或其盐作为用于去除皮肤上的重金属和甲醛的有效成分。
另一方面,在本发明中,证实了在曲恩汀、轮环藤宁和环拉胺的胺位置引入羧基改善了重金属的配位度,同时在胺位置引入了芳族或杂环基团显著减少皮肤刺激性。
根据本发明的曲恩汀衍生物、轮环藤宁衍生物和环拉胺衍生物优选选自下式(1b)至(3d)的化合物。
其中:R8、R9各自独立地是氢或C1-C4烷基;
X是氧、硫或氮原子。
基于组合物的总重量,本发明的曲恩汀或曲恩汀衍生物、轮环藤宁或轮环藤宁衍生物、环拉胺或环拉胺衍生物不限于0.01至5.0重量%,优选0.05至2.0重量%,更优选0.1至1.0重量%。
本发明的曲恩汀或曲恩汀衍生物、轮环藤宁或轮环藤宁衍生物、环拉胺或环拉胺衍生物可以以水溶性盐的形式使用。本发明的所述化合物可以以盐酸盐、钠盐和钾盐的形式使用。本发明的所述盐可以通过已知的制备盐的方法获得。本发明的盐优选二盐酸盐或四盐酸盐,更优选二盐酸盐。
本发明的组合物可以用于去除附着、吸附在皮肤上的重金属离子,诸如Hg、Pb、Cd、As、Cr、Cu、Ni、Zn、Mn、Co和Sn。
根据本发明的皮肤用组合物可以配制成水包油(O/W)乳液或油包水(W/O)乳液或无油乳液。根据本发明的皮肤用组合物可以用于化妆品,诸如基础化妆品、化妆用化妆品、清洁化妆品、洗发剂、肥皂等。本发明的组合物的制剂可以是软肤化妆水、营养化妆水、营养精华、营养油、保湿油、营养霜、保湿霜、粉、面膜、粉底、化妆底霜、棒、清洁剂、洗发剂、凝胶、化妆水和软膏。根据本发明的皮肤用组合物可以以各种形式(诸如液体、乳膏、糊剂和固体)使用,并且可以使用常规化妆品制备方法配制。
本发明的皮肤用组合物还可以包含上述制剂所必需的已知化妆品成分,例如防腐剂、抗菌剂、抗氧化剂、植物提取物、pH调节剂、醇、色素、香料、血液循环促进剂、冷却剂、纯净水和离子水。
另一方面,本发明的皮肤用组合物可以通过有效去除皮肤上的重金属而用作用于脱发治疗或皮肤相关治疗的药物辅助成分。
在下文中,将参考以下实施例详细描述根据本发明的具有重金属和甲醛去除能力的皮肤用组合物。然而,以下实施例仅用于说明本发明,并且不应解释为限制本发明的范围。
发明模式
曲恩汀衍生物的合成
实施方案1
3,6,9,12-四(羧甲基)-3,6,9,12-四氮杂十四烷二酸(式(1e))的制备
将三亚乙基四胺(10.0g)溶解在乙腈(ACN)(400ml)中。加入K2CO3(66.1g)和溴乙酸乙酯(78.8g),并且将反应混合物在搅拌和回流下加热约48小时。反应完成后,将反应混合物冷却至室温,然后过滤。弃去反应混合物的固相,并且将滤液在真空下浓缩。将二氯甲烷(MC)(200ml)和纯净水(300ml)加入到浓缩物中并且搅拌30分钟,然后分离有机层。将有机层用MgSO4处理,在真空下浓缩,然后使用MC-甲醇进行柱纯化。得到29.6g的3,6,9,12-四(2-乙氧基-2-氧代乙基)-3,6,9,12-四氮杂十四烷二酸二乙酯(收率:64.8%)。
1H NMR(CDCl3):4.16(q,8H),4.14(q,4H),3.57(s,8H),3.44(s,4H),2.85(t,4H),2.78(t,4H),2.74(s,4H),1.27(t,12H),1.26(t,6H)
加入3,6,9,12-四(2-乙氧基-2-氧代乙基)-3,6,9,12-四氮杂十四烷二酸二乙酯(29.6g)、NaOH(12.33g)、甲醇(180ml)和纯净水(120ml),并且将反应混合物加热至55-60℃,搅拌12小时。反应完成后,将反应混合物冷却至约40℃并且在真空下浓缩。除去溶剂。将反应混合物用10%HCl水溶液调节至pH 5-6,搅拌30分钟,并且用MC(400ml)萃取。用MgSO4处理萃取的有机层。得到15.9g标题化合物(产率:72.3%)。
1H NMR(DMSO):4.57(s,8H),4.55(s,4H),4.22(s,12H)
实施方案2
4,4’,4”,4”’-(((乙烷-1,2-二基双((4-羧苯基)氮烷二基))双(乙烷-2,1-二基))双(氮烷三基))四苯甲酸(式(1f))的制备
加入三亚乙基四胺(10.0g)、4-溴苯甲酸乙酯(108.1g)、t-BuONa(46.0g)和甲苯(600ml),搅拌,然后加热至35℃。加入50%(t-Bu)3P甲苯溶液(2.8g),搅拌约30分钟,然后加热至50℃。加入Pd(dba)2(双(二亚苄基丙酮)钯)(2.0g),在回流下加热。反应完成后,将反应混合物冷却至室温。加入纯净水(1000ml),搅拌30分钟,然后分离有机层。弃去反应混合物的水层。将有机层用MgSO4处理,在真空下浓缩,然后使用MC-甲醇进行柱纯化。得到22.9g的4,4’,4”,4”’-(((乙烷-1,2-二基双((4-(乙氧基羰基)苯基)氮烷二基))双(乙烷-2,1-二基))双(氮烷三基))四苯甲酸四乙酯(收率:32.4%)
1H NMR(CDCl3):7.82(m,4H),7.71(m,8H),7.25(m,8H),6.95(m,4H),4.15(q,8H),4.11(q,4H),3.45~3.18(m,12H),1.27(t,12H),1.26(t,6H)
加入4,4’,4”,4”’-(((乙烷-1,2-二基双((4-(乙氧基羰基)苯基)氮烷二基))双(乙烷-2,1-二基))双(氮烷三基))四苯甲酸四乙酯(22.9g)、NaOH(6.1g)、甲醇(180ml)和纯净水(140ml),并且将反应混合物加热至55-60℃,搅拌12小时。反应完成后,将反应混合物冷却至约40℃并且在真空下浓缩。除去溶剂。将反应混合物用10%HCl水溶液调节至pH 5-6,搅拌30分钟,并且用MC(200ml)萃取。用MgSO4处理萃取的有机层。得到17.0g标题化合物(产率:89.0%)。
1H NMR(DMSO):7.80(m,4H),7.68(m,8H),7.15(m,8H),6.94(m,4H),3.41~3.28(m,12H)
实施方案3
5,5’-((2-((5-羧基吡啶-3-基)(2-((5-羧基吡啶-3-基)(2-((5-羧基吡啶-3-基)(2-羧基吡啶-4-基)氨基)乙基)氨基)乙基)氨基)乙基)氮烷二基)二烟酸(式(1g))的制备
加入三亚乙基四胺(10.0g)、5-溴烟酸乙酯(108.5g)、t-BuONa(46.0g)和二甲苯(600ml),搅拌,然后加热至35℃。加入50%(t-Bu)3P甲苯溶液(2.8g),搅拌约30分钟,然后加热至50℃。加入Pd(dba)2(2.0g),在回流下加热。反应完成后,将反应混合物冷却至室温。加入纯净水(1000ml),搅拌30分钟,然后分离有机层。弃去反应混合物的水层。将有机层用MgSO4处理,浓缩,得到5,5’-((2-((5-(乙氧基羰基)吡啶-3-基)(2-((5-(乙氧基羰基)吡啶-3-基)(2-((5-(乙氧基羰基)吡啶-3-基)(2-(乙氧基羰基)吡啶-4-基)氨基)乙基)氨基)乙基)氨基)乙基)氮烷二基)二烟酸二乙酯(收率:27.8%)。
1H NMR(CDCl3):8.92(d,4H),8.85(d,2H),8.45(d,4H),8.43(d,2H),7.89(d,4H),7.76(d,2H),4.23(q,8H),4.15(q,4H),3.42~3.11(m,12H),1.27(t,12H),1.26(t,6H)
加入5,5’-((2-((5-(乙氧基羰基)吡啶-3-基)(2-((5-(乙氧基羰基)吡啶3-基)(2-((5-(乙氧基羰基)吡啶-3-基)(2-(乙氧基羰基)吡啶-4-基)氨基)乙基)氨基)乙基)氨基)乙基)氮烷二基)二烟酸二乙酯(19.8g)、NaOH(5.3g)、甲醇(160ml)和纯净水(120ml),并且将反应混合物加热至55-60℃,搅拌12小时。反应完成后,将反应混合物冷却至约40℃并且在真空下浓缩。除去溶剂。将反应混合物用10%HCl水溶液调节至pH 5-6,搅拌30分钟,并且用MC(160ml)萃取。用MgSO4处理萃取的有机层。得到13.0g标题化合物(产率:78.4%)。
1H NMR(DMSO):8.95(d,4H),8.87(d,2H),8.46(d,4H),8.44(d,2H),7.89(d,4H),7.75(d,2H),3.41~3.11(m,12H)
实施方案4
5,5’,5”,5”’-(((乙烷-1,2-二基双((5-羧基呋喃-2-基)氮烷二基))双(乙烷-2,1-二基))双(氮烷三基))四(呋喃-2-甲酸)(式(1h))的制备
加入三亚乙基四胺(10.0g)、5-溴呋喃-2-甲酸乙酯(103.3g)、t-BuONa(46.0g)和甲苯(600ml),搅拌,然后加热至35℃。加入50%(t-Bu)3P甲苯溶液(2.8g),搅拌约30分钟,然后加热至50℃。加入Pd(dba)2(2.0g),在回流下加热。反应完成后,将反应混合物冷却至室温。加入纯净水(1000ml),搅拌30分钟,然后分离有机层。弃去反应混合物的水层。将有机层用MgSO4处理,在真空下浓缩,然后使用MC-甲醇进行柱纯化。得到25.3g的5,5’,5”,5”’-(((乙烷-1,2-二基双((5-(乙氧基羰基)呋喃-2-基)氮烷二基))双(乙烷-2,1-二基))双(氮烷三基))四(呋喃-2-甲酸)四乙酯(收率:37.9%)。
1H NMR(CDCl3):7.42(m,12H),4.31(q,8H),4.28(q,4H),3.65~3.15(m,12H),1.27(t,12H),1.25(t,6H)
加入5,5’,5”,5”’-(((乙烷-1,2-二基双((5-(乙氧基羰基)呋喃-2-基)氮烷二基))双(乙烷-2,1-二基))双(氮烷三基))四(呋喃-2-甲酸)四乙酯(25.3g)、NaOH(7.2g)、甲醇(200ml)和纯净水(150ml),并且将反应混合物加热至55-60℃,搅拌12小时。反应完成后,将反应混合物冷却至约40℃并且在真空下浓缩。除去溶剂。将反应混合物用10%HCl水溶液调节至pH 5-6,搅拌30分钟,并且用MC(200ml)萃取。用MgSO4处理萃取的有机层。得到15.0g标题化合物(产率:71.8%)。
1H NMR(DMSO):7.41(m,12H),3.67~3.15(m,12H)
轮环藤宁衍生物的合成
实施方案5
2,2’,2”,2”’-(1,4,7,10-四氮杂环十二烷-1,4,7,10-四基)四乙酸(式(2e))的制备
将轮环藤宁(10.0g)溶解在乙腈(400ml)中。加入K2CO3(40.1g)和溴乙酸乙酯(42.7g),并且将反应混合物在搅拌和回流下加热约40小时。反应完成后,将反应混合物冷却至室温,然后过滤。弃去反应混合物的固相,并且将滤液在真空下浓缩。将MC(200ml)和纯净水(300ml)加入到浓缩物中并且搅拌30分钟,然后分离有机层。将有机层用MgSO4处理,在真空下浓缩,然后使用MC-甲醇进行柱纯化。得到15.7g的2,2’,2”,2”’-(1,4,7,10-四氮杂环十二烷-1,4,7,10-四基)四乙酸四乙酯(收率:52.3%)。
1H NMR(CDCl3):4.19(q,8H),3.19(s,8H),2.48(s,16H),1.27(t,12H)
加入2,2’,2”,2”’-(1,4,7,10-四氮杂环十二烷-1,4,7,10-四基)四乙酸四乙酯(15.7g)、NaOH(5.6g)、甲醇(95ml)和纯净水(60ml),并且将反应混合物加热至55-60℃,搅拌12小时。反应完成后,将反应混合物冷却至约40℃并且在真空下浓缩。除去溶剂。将反应混合物用10%HCl水溶液调节至pH 5-6,搅拌30分钟,并且用MC(200ml)萃取。用MgSO4处理萃取的有机层。得到9.9g标题化合物(产率:80.5%)。
1H NMR(DMSO):3.88(s,8H),3.23(s,16H)
实施方案6
4,4’,4”,4”’-(1,4,7,10-四氮杂环十二烷-1,4,7,10-四基)四苯甲酸(式(2f))的制备
加入轮环藤宁(10.0g)、4-溴苯甲酸乙酯(58.5g)、t-BuONa(27.9g)和甲苯(400ml),搅拌,然后加热至35℃。加入50%(t-Bu)3P甲苯溶液(2.4g),搅拌约30分钟,然后加热至50℃。加入Pd(dba)2(1.7g),在回流下加热。反应完成后,将反应混合物冷却至室温。加入纯净水(1000ml),搅拌30分钟,然后分离有机层。弃去反应混合物的水层。将有机层用MgSO4处理,在真空下浓缩,然后使用MC-甲醇进行柱纯化。得到15.8g的4,4’,4”,4”’-(1,4,7,10-四氮杂环十二烷-1,4,7,10-四基)四苯甲酸四乙酯(收率:35.6%)
1H NMR(CDCl3):7.81(d,8H),6.98(d,8H),4,15(q,8H),3.48(s,16H),1,25(t,12H)
加入4,4’,4”,4”’-(1,4,7,10-四氮杂环十二烷-1,4,7,10-四基)四苯甲酸四乙酯(15.8g)、NaOH(3.8g)、甲醇(130ml)和纯净水(100ml),并且将反应混合物加热至55-60℃,搅拌12小时。反应完成后,将反应混合物冷却至约40℃并且在真空下浓缩。除去溶剂。将反应混合物用10%HCl水溶液调节至pH 5-6,搅拌30分钟,并且用MC(130ml)萃取。用MgSO4处理萃取的有机层。得到11.5g标题化合物(产率:85.2%)。
1H NMR(DMSO):7.82(d,8H),6.97(d,8H),3.45(s,16H)
实施方案7
5,5’,5”,5”’-(1,4,7,10-四氮杂环十二烷-1,4,7,10-四基)四烟酸(式(2g))的制备
加入轮环藤宁(10.0g)、5-溴烟酸酯(58.7g)、t-BuONa(27.9g)和二甲苯(400ml),搅拌,然后加热至35℃。加入50%(t-Bu)3P甲苯溶液(2.4g),搅拌约30分钟,然后加热至50℃。加入Pd(dba)2(1.7g),在回流下加热。反应完成后,将反应混合物冷却至室温。加入纯净水(1000ml),搅拌30分钟,然后分离有机层。弃去反应混合物的水层。将有机层用MgSO4处理,在真空下浓缩,然后使用MC-甲醇进行柱纯化。得到17.9g的5,5’,5”,5”’-(1,4,7,10-四氮杂环十二烷-1,4,7,10-四基)四烟酸四乙酯(收率:40.1%)
1H NMR(CDCl3):8.95(d,4H),8.46(d,4H),7.83(d,4H),4,21(q,8H),3.38(s,16H),1,24(t,12H)
加入5,5’,5”,5”’-(1,4,7,10-四氮杂环十二烷-1,4,7,10-四基)四烟酸四乙酯(17.9g)、NaOH(4.3g)、甲醇(150ml)和纯净水(110ml),并且将反应混合物加热至55-60℃,搅拌12小时。反应完成后,将反应混合物冷却至约40℃并且在真空下浓缩。除去溶剂。将反应混合物用10%HCl水溶液调节至pH 5-6,搅拌30分钟,并且用MC(160ml)萃取。用MgSO4处理萃取的有机层。得到11.6g标题化合物(产率:75.6%)。
1H NMR(DMSO):8.96(d,4H),8.44(d,4H),7.84(d,4H),3.36(s,16H)
实施方案8
5,5’,5”,5”’-(1,4,7,10-四氮杂环十二烷-1,4,7,10-四基)四(呋喃-2-甲酸)(式(2h))的制备
加入轮环藤宁(10.0g)、5-溴呋喃-2-甲酸乙酯(56.0g)、t-BuONa(27.9g)和甲苯(400ml),搅拌,然后加热至35℃。加入50%(t-Bu)3P甲苯溶液(2.4g),搅拌约30分钟,然后加热至50℃。加入Pd(dba)2(1.7g),在回流下加热。反应完成后,将反应混合物冷却至室温。加入纯净水(1000ml),搅拌30分钟,然后分离有机层。弃去反应混合物的水层。将有机层用MgSO4处理,在真空下浓缩,然后使用MC-甲醇进行柱纯化。得到12.6g的5,5’,5”,5”’-(1,4,7,10-四氮杂环十二烷-1,4,7,10-四基)四(呋喃-2-甲酸)四乙酯(收率:30.0%)
1H NMR(CDCl3):7.39(d,8H),4.35(q,8H),3.28(s,16H),1,35(t,12H)
加入5,5’,5”,5”’-(1,4,7,10-四氮杂环十二烷-1,4,7,10-四基)四(呋喃-2-甲酸)四乙酯(12.6g)、NaOH(3.2g)、甲醇(100ml)和纯净水(75ml),并且将反应混合物加热至55-60℃,搅拌12小时。反应完成后,将反应混合物冷却至约40℃并且在真空下浓缩。除去溶剂。将反应混合物用10%HCl水溶液调节至pH 5-6,搅拌30分钟,并且用MC(100ml)萃取。用MgSO4处理萃取的有机层。得到7.9g标题化合物(产率:73.9%)。
1H NMR(DMSO):7.40(d,8H),3.29(s,16H)
环拉胺衍生物的合成
实施方案9
2,2’,2”,2”’-(1,4,8,11-四氮杂环十四烷-1,4,8,11-四基)四乙酸(式(3e))的制备
将环拉胺(10.0g)溶解在乙腈(400ml)中。加入K2CO3(34.5g)和溴乙酸乙酯(36.7g),并且将反应混合物在搅拌和回流下加热约40小时。反应完成后,将反应混合物冷却至室温,然后过滤。弃去反应混合物的固相,并且将滤液在真空下浓缩。将MC(200ml)和纯净水(300ml)加入到浓缩物中并且搅拌30分钟,然后分离有机层。将有机层用MgSO4处理,在真空下浓缩,然后使用MC-甲醇进行柱纯化。得到15.4g的2,2’,2”,2”’-(1,4,8,11-四氮杂环十四烷-1,4,8,11-四基)四乙酸四乙酯(收率:56.8%)。
1H NMR(CDCl3):4.12(q,8H),3.36(s,8H),2,69~2.73(m,16H),1,60(m,4H),1.26(t,12H)
加入2,2’,2”,2”’-(1,4,8,11-四氮杂环十四烷-1,4,8,11-四基)四乙酸四乙酯(15.4g)、NaOH(5.2g)、甲醇(90ml)和纯净水(60ml),并且将反应混合物加热至55-60℃,搅拌12小时。反应完成后,将反应混合物冷却至约40℃并且在真空下浓缩。除去溶剂。将反应混合物用10%HCl水溶液调节至pH 5-6,搅拌30分钟,并且用MC(200ml)萃取。用MgSO4处理萃取的有机层。得到9.3g标题化合物(产率:75.9%)。
1H NMR(D2O):3.51(s,8H),3.14(s,8H),3.07(t,8H),1.85(q,4H)
实施方案10
4,4’,4”,4”’-(1,4,8,11-四氮杂环十四烷-1,4,8,11-四基)四苯甲酸(式(3f))的制备
加入环拉胺(10.0g)、4-溴苯甲酸乙酯(50.3g)、t-BuONa(24.0g)和甲苯(400ml),搅拌,然后加热至35℃。加入50%(t-Bu)3P甲苯溶液(2.0g),搅拌约30分钟,然后加热至50℃。加入Pd(dba)2(1.5g),在回流下加热。反应完成后,将反应混合物冷却至室温。加入纯净水(1000ml),搅拌30分钟,然后分离有机层。弃去反应混合物的水层。将有机层用MgSO4处理,在真空下浓缩,然后使用MC-甲醇进行柱纯化。得到12.3g的4,4’,4”,4”’-(1,4,8,11-四氮杂环十四烷-1,4,8,11-四基)四苯甲酸四乙酯(收率:31.0%)
1H NMR(CDCl3):7.80(d,8H),6.94(d,8H),4.13(q,8H),2,65~2.71(m,16H),1,65(m,4H),1.26(t,12H)
加入4,4’,4”,4”’-(1,4,8,11-四氮杂环十四烷-1,4,8,11-四基)四苯甲酸四乙酯(12.3g)、NaOH(2.6g)、甲醇(70ml)和纯净水(100ml),并且将反应混合物加热至55-60℃,搅拌12小时。反应完成后,将反应混合物冷却至约40℃并且在真空下浓缩。除去溶剂。将反应混合物用10%HCl水溶液调节至pH 5-6,搅拌30分钟,并且用MC(100ml)萃取。用MgSO4处理萃取的有机层。得到8.6g标题化合物(产率:81.2%)。
1H NMR(DMSO):7.83(d,8H),6.95(d,8H),2,63~2.73(m,16H),1,62(m,4H)
实施方案11
5,5’,5”,5”’-(1,4,8,11-四氮杂环十四烷-1,4,8,11-四基)四烟酸(式(3g))的制备
加入环拉胺(10.0g)、5-溴烟酸乙酯(50.3g)、t-BuONa(24.0g)和二甲苯(400ml),搅拌,然后加热至35℃。加入50%(t-Bu)3P甲苯溶液(2.0g),搅拌约30分钟,然后加热至50℃。加入Pd(dba)2(1.5g),在回流下加热。反应完成后,将反应混合物冷却至室温。加入纯净水(1000ml),搅拌30分钟,然后分离有机层。弃去反应混合物的水层。将有机层用MgSO4处理,在真空下浓缩,然后使用MC-甲醇进行柱纯化。得到11.1g的5,5’,5”,5”’-(1,4,8,11-四氮杂环十四烷-1,4,8,11-四基)四烟酸四乙酯(收率:27.8%)
1H NMR(CDCl3):8.91(d,4H),8.37(d,4H),7.85(d,4H),4.15(q,8H),2.67~2.64(m,16H),1,71(m,4H),1.24(t,12H)
加入5,5’,5”,5”’-(1,4,8,11-四氮杂环十四烷-1,4,8,11-四基)四烟酸四乙酯(11.1g)、NaOH(2.6g)、甲醇(90ml)和纯净水(70ml),并且将反应混合物加热至55-60℃,搅拌12小时。反应完成后,将反应混合物冷却至约40℃并且在真空下浓缩。除去溶剂。将反应混合物用10%HCl水溶液调节至pH 5-6,搅拌30分钟,并且用MC(120ml)萃取。用MgSO4处理萃取的有机层。得到7.4g标题化合物(产率:77.6%)。
1H NMR(DMSO):8.93(d,4H),8.38(d,4H),7.85(d,4H),2.67~2.66(m,16H),1,72(m,4H)
实施方案12
5,5’,5”,5”’-(1,4,8,11-四氮杂环十四烷-1,4,8,11-四基)四(呋喃-2-甲酸)(式(3h))的制备
加入环拉胺(10.0g)、5-溴呋喃-2-甲酸乙酯(48.1g)、t-BuONa(24.0g)和甲苯(400ml),搅拌,然后加热至35℃。加入50%(t-Bu)3P甲苯溶液(2.0g),搅拌约30分钟,然后加热至50℃。加入Pd(dba)2(1.5g),在回流下加热。反应完成后,将反应混合物冷却至室温。加入纯净水(1000ml),搅拌30分钟,然后分离有机层。弃去反应混合物的水层。将有机层用MgSO4处理,在真空下浓缩,然后使用MC-甲醇进行柱纯化。得到14.1g的5,5’,5”,5”’-(1,4,8,11-四氮杂环十四烷-1,4,8,11-四基)四(呋喃-2-甲酸)四乙酯(收率:37.5%)
1H NMR(CDCl3):7.40(d,8H),4.23(q,8H),2,65~2.71(m,16H),1,66(m,4H),1.29(t,12H)
加入5,5’,5”,5”’-(1,4,8,11-四氮杂环十四烷-1,4,8,11-四基)四(呋喃-2-甲酸)四乙酯(14.1g)、NaOH(3.5g)、甲醇(110ml)和纯净水(85ml),并且将反应混合物加热至55-60℃,搅拌12小时。反应完成后,将反应混合物冷却至约40℃并且在真空下浓缩。除去溶剂。将反应混合物用10%HCl水溶液调节至pH 5-6,搅拌30分钟,并且用MC(120ml)萃取。用MgSO4处理萃取的有机层。得到9.4g标题化合物(产率:78.1%)。
1H NMR(DMSO):7.41(d,8H),2.69~2.72(m,16H),1.68(m,4H)
实验例1:有效成分的重金属去除测试
(1)重金属污染源和猪皮样品的制备
将162.1mg Pb(NO3)2、211.2mg Cd(NO3)2和292.3mg Zn(NO3)2加入到1L蒸馏水中,以分别制备重金属污染源的100ppm水溶液。
将实施方案1至12所制备的曲恩汀、轮环藤宁、环拉胺及其衍生物和作为比较例1的EDTA加入到100ml蒸馏水中,以分别制备0.1重量%、0.5重量%和1.0重量%的活性成分样品。
将猪宰杀,剥皮,并且剃去鬃毛。切分猪皮以分别制备5*5cm大小的皮肤样品。
(2)测试
将1.0ml重金属污染源分别处理(treated)至猪皮样品,并且将皮肤样品在室温放置10分钟以使重金属附着或吸附在皮肤样品上,然后将所述活性成分样品处理至污染的样品,并且将皮肤样品放置2分钟。将所述皮肤样品用湿纱布擦拭干净,然后加入到50ml甲醇中,并且用超声振荡提取60分钟。进一步加入50ml甲醇并且混合。从提取的溶液中取出猪皮样品以制备测试溶液。
使用电感耦合等离子体质谱仪(ICP-MS,XseriesTM 2,Thermo FisherScientific,UK)分析测试溶液的重金属组分。
在ICP-MS中,铅(Pb)的比质荷比(m/z)为206-208,镉(Cd)的比质荷比(m/z)为114,并且锌(Zn)的比质荷比(m/z)为66-68。根据以下等式1计算重金属去除率,并且测试结果示于表1和图1至图3中。
等式1
表1
如表1和图1至3所示,0.1重量%的根据本发明的重金属螯合化合物具有89.2%的Pb去除率、88.4%的Cd平均去除率、93.7%的Cu去除率。与比较例1的EDTA(Pb 84.3%、Cd82.3%、Cu 86.5%)和不具有螯合剂的对照1(Pb 74.6%、Cd 76.2%、Cu 76.8%)相比,本发明的这些化合物对附着或吸附在皮肤上的重金属具有显著的去除能力。
甚至在0.5重量%和1.0重量%的水溶液中也获得了相同的结果。然而,所述实施例的重金属去除率在0.5重量%和1.0重量%之间的差异不显著。这意味着可以以0.5重量%的水溶液充分去除重金属。
实验例2:有效成分的皮肤刺激性测试
根据CTFA(化妆品、洗漱用品和香水协会(The Cosmetic,Toiletry&FragranceAssociation,Inc.),Washington,DC)的指南,使用贴剂法测试总计20人(20至30岁的10名男性和10名女性)的皮肤刺激性。
将滤纸片放置在8mm直径的10板针室中。然后,将20μl的根据实验例1的每种组合物滴在滤纸片上,自然干燥10分钟,然后用Scanpor胶带将针室附于受试者的背部区域。
24小时后,移除针室,并且目视观察皮肤状况。根据以下等式2计算皮肤刺激性的程度和等级,并且结果示于下表2中。
等式2
[皮肤刺激性标准]
(-):无红斑或特别是无症状;(±):比周围相比略微偏红;(+):比周围相比明显变红;(++):比周围相比更加红肿。
[皮肤刺激性等级]
刺激程度0-0.1:I级(无刺激);
刺激程度0.11-0.3:II级(弱刺激);
刺激程度0.31-0.5:III级(中刺激);
刺激程度0.51或以上:IV级(强刺激)
表2
如表2所示,在人皮肤刺激性测试中,在0.5重量%的浓度范围内,根据本发明的所有化合物具有I级,其为非刺激范围。在1.0重量%的浓度范围内,曲恩汀、轮环藤宁和环拉胺具有II级(轻微刺激范围),而所有这些芳族和杂环衍生物具有I级,表明皮肤刺激性减小得到改善。另一方面,比较例1的EDTA在1.0重量%的浓度下被评价为III级(中等刺激范围),表明皮肤刺激性高于本发明化合物的皮肤刺激性。
实验例3:甲醛去除能力测试
将纯净水加入到35.0%甲醛溶液中以制备2.0%甲醛稀溶液。将3摩尔当量的曲恩汀、轮环藤宁、环拉胺和本发明的衍生物化合物加入到稀溶液中,并且在室温进行搅拌的同时通过气相色谱(GC)分析甲醛量的变化。
在初始状态、30分钟后和180分钟后,在以下分析条件下测量甲醛含量,结果示于表3中。
<GC分析条件>
-检测器:火焰离子化检测器
-柱:ZB-1(0.32mm x 30m,3.00m)或类似的柱。
-顶空条件:平衡温度为60℃,平衡时间为10分钟,传输线温度为65℃
-柱温:前5分钟保持在50℃,然后以30℃/分钟升温至200℃,并且在200℃保持10分钟。
-样品入口温度:140℃左右的恒温。
-检测器温度:250℃左右的恒温。
-载气:氮气
-分流比:约1:20
-流速:2.5mL/min
-注射量:用微量注射器将5μL样品溶液注到小瓶中。根据顶空条件将1mL气相注到柱中。
-分析时间:20分钟
表3
如表3所示,GC分析示出了在加入本发明化合物后30分钟内甲醛显著降低约40%至45%,并且在180分钟后完全未检测到甲醛。这意味着本发明的化合物有效地去除甲醛。
实施方案13至27:用于保护皮肤的组合物的制备
将包含5重量%的曲恩汀、轮环藤宁、环拉胺以及实施方案1至12中制备的曲恩汀衍生物、轮环藤宁衍生物和环拉胺衍生物的组合物制备成水包油(O/W)乳液制剂。
组合物的成分示于下表4中。
表4
皮肤用组合物按以下步骤制备。
(1)将活性成分加入到纯净水中,混合以溶解。
(2)将甘油、丁二醇,透明质酸钠和十六十八醇加入到所述纯净水中,并且将混合物加热至70℃并且使之溶解以制备水溶液。
(3)将硬脂酸、PEG-100硬脂酸酯、角鲨烷、聚山梨醇酯60、防腐剂和香料混合并且加热至70℃以制备油性溶液。
(4)将油性溶液逐渐加入到水溶液中,同时搅拌,以制备水包油乳液制剂的皮肤用组合物。
实验例4:皮肤用组合物的重金属去除能力
测试根据实施方案13至27、比较例2和对照2制备的皮肤用组合物的重金属去除能力。
以与实验例1相同的方式进行测试,并且结果示于下表5中。
表5
如表5和图4所示,0.5重量%的根据实施方案13至27的重金属螯合组合物具有91.8%的Pb去除率、91.3%的Cd平均去除率、96.5%的Cu去除率。与比较例2的EDTA(Pb88.6%、Cd 87.5%、Cu 89.1%)和不具有螯合剂的对照2(Pb 76.8%、Cd 77.5%、Cu78.1%)相比,本发明的这些化合物对附着或吸附在皮肤上的重金属具有显著的去除能力。
实验例5:皮肤用组合物的皮肤刺激性测试
测试根据实施方案13至27、比较例2制备的皮肤用组合物的皮肤刺激性。
以与实验例2相同的方式进行测试,并且结果示于下表6中。
表6
如表6所示,0.5重量的所有根据本发明的皮肤用组合物都具有I级,这是非刺激范围,而比较例2的EDTA被评价为II级(弱刺激范围),表明皮肤刺激性高于本发明化合物的皮肤刺激性。
工业适用性
本发明涉及用于保护皮肤免受外部环境影响的皮肤组合物,并且更特别地涉及用于有效去除皮肤中存在的重金属和甲醛的皮肤组合物以及包含其的组合物。
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- 2017-06-02 JP JP2019527797A patent/JP7125145B2/ja active Active
- 2017-06-02 CN CN201780084371.4A patent/CN110225905B/zh active Active
- 2017-06-02 WO PCT/KR2017/005821 patent/WO2018097431A1/en unknown
- 2017-06-02 US US16/464,209 patent/US11090247B2/en active Active
- 2017-06-02 EP EP17874838.0A patent/EP3544953A4/en active Pending
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US20190388323A1 (en) | 2019-12-26 |
EP3544953A4 (en) | 2020-07-08 |
CN110225905A (zh) | 2019-09-10 |
EP3544953A1 (en) | 2019-10-02 |
KR101851981B1 (ko) | 2018-04-25 |
WO2018097431A1 (en) | 2018-05-31 |
JP2020513400A (ja) | 2020-05-14 |
US11090247B2 (en) | 2021-08-17 |
JP7125145B2 (ja) | 2022-08-24 |
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