CN104470906B - 作为抵抗紫外线辐射的保护剂的亚氨基化合物 - Google Patents
作为抵抗紫外线辐射的保护剂的亚氨基化合物 Download PDFInfo
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- CN104470906B CN104470906B CN201380029426.3A CN201380029426A CN104470906B CN 104470906 B CN104470906 B CN 104470906B CN 201380029426 A CN201380029426 A CN 201380029426A CN 104470906 B CN104470906 B CN 104470906B
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- dimethyl
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Abstract
本发明涉及具有式I的化合物:所述化合物吸收UV辐射并且保护生物材料和非生物材料使其免于有害地暴露于UV辐射。本发明还涉及包含此类化合物以用于吸收UV辐射并且保护生物材料和非生物材料使其抵抗UV辐射的制剂和组合物。
Description
相关申请的交叉引用
本申请要求2012年6月4日提交的美国临时专利申请号61/655,115的权益和优先权,所述临时专利申请的内容以引用的方式整体并入本文。
I.相关技术领域
本发明涉及吸收紫外线辐射并且保护生物材料和非生物材料使其免于有害地暴露于紫外线辐射的化合物。本发明还涉及包含此类化合物以用于吸收紫外线辐射并且保护生物材料和非生物材料使其抵抗紫外线辐射的制剂和组合物。本发明还涉及用于保护生物材料和非生物材料使其免于有害地暴露于紫外线辐射的方法。
II.背景
商业可用的紫外线阻断剂通常包括诸如对-氨基苯甲酸衍生物、苯并三唑、二苯甲酮、甲氧基肉桂酸酯以及水杨酸酯的化合物。霉孢菌素样氨基酸(MAA)也被认定为紫外线吸收剂。MAA为通过生活在具有大量阳光的环境(通常为海洋环境)中的有机体产生的约400Da小分子1。已分辨超过30种MAA的结构并且它们包含中心环己烯酮或环己亚胺环以及各种各样的取代基。认为所述环结构吸收紫外光并且调节自由基2。MAA吸收通常为310nm与360nm之间的紫外光。这种光吸收特性允许MAA保护细胞使其免于有害的紫外线辐射。特定MAA的生物合成途径取决于特定的MAA和产生它的有机体。这些生物合成路径通常与其它主要生物合成路径分享共同的酶和中间体。
有用的紫外线吸收剂如以上提及的那些吸收剂必须符合多种标准,包括稳定性、可接受的持久性、效力、与它们所混合或合并的介质的相容性、无毒性以及对于它们所应用的表面的无害性。这些标准限制用于不同应用的有用紫外线保护剂的选择。因此,在本领域中仍需要符合这些标准的另外的试剂,所述另外的试剂吸收紫外线辐射并且保护生物和非生物材料使其抵抗由紫外线辐射所引起的有害损害并且易于制备。
III.概述
根据一个方面,本发明涉及一种具有式I的化合物:
或其可接受的盐;其中R1为未取代或取代的烷基;未取代或取代的烯烃;未取代或取代的炔烃;未取代或取代的芳基;未取代或取代的杂环;未取代或取代的环烷基;未取代和取代的烷氧基;烷酰基;芳基烷基;羧基;杂芳基;杂芳基烷基;苯基;苄基;羟基;羧酸;酯;亚磺酰基;巯基;硫化物;磺酰基;亚磺基;膦基;膦酰基;磷酸酯;胺;卤代;或甲酰胺;R2为氢、卤代、未取代或取代的烷基;未取代或取代的烯烃;未取代或取代的炔烃;未取代或取代的芳基;未取代或取代的杂环;未取代或取代的环烷基;未取代和取代的烷氧基;烷酰基;羟基;卤代;苯基;苄基;羧酸或酯基;R6并且R7各自独立地为氢;未取代或取代的烷基;未取代或取代的烯烃;未取代或取代的炔烃;未取代或取代的芳基;未取代或取代的杂环;未取代或取代的环烷基;未取代和取代的烷氧基;烷酰基;炔基;羟基;磺酸基;卤代基;膦酰基;酯基;羧酸基;苯基;烷基脂肪酸链或聚醚;X为碳;卤代;氮;氧;硫;-CH2;苯基;环烷基;氨基或螺环烷烃;并且n为整数,其中所述整数为1、2、3或4。
根据另一个方面,本发明涉及一种包含以下的UV-吸收的组合物:如本文所定义的化合物;一种或多种UV-阻断剂;以及一种或多种适合的添加剂。
根据另一个方面,本发明涉及如本文所定义的化合物在制备用于保护生物材料使其抵抗UV辐射的组合物和/或制备用于保护非生物材料使其抵抗UV辐射的组合物中的用途。
根据另一个方面,本发明涉及一种用于保护生物材料和/或非生物材料的表面使其抵抗UV辐射的方法,所述方法包括向所述表面应用如本文所定义的组合物。
根据另一个方面,本发明涉及一种具有以下式的化合物:
以用于保护纺织品使其抵抗UV辐射。
根据另一个方面,本发明涉及一种具有以下式的化合物:
以用于制备用于针对UV辐射进行保护的组合物。
IV.附图简述
图1为霉孢菌素分子的一般结构的示意图。
图2为示出化合物IF1在指定波长下的UV-透光率的表格。
图3为示出化合物IA1在指定波长下的UV-透光率的表格。
图4为示出化合物IA2在指定波长下的UV-透光率的表格。
图5为示出化合物IE4在指定波长下的UV-透光率的表格。
图6为示出化合物IE1在指定波长下的UV-透光率的表格。
图7为示出化合物IF1、IA1、IA2、IE4以及IE1在指定波长下的吸光度的图表。
V.描述
A)定义
除另外指示之外,如本文所用的术语“包含”和“包括”以其开放的非限制性含义使用。
如本文所用的术语“化合物”和“本发明的一种或多种化合物”可互换使用,以指示本文特别地或一般地公开的任何化合物,包括其可接受的盐、水合物或溶剂合物。在一个实施方案中,本发明的化合物为式I化合物或式I的变体以及其药学上可接受的盐、水合物或溶剂合物。
除另外指示之外,如本文所用的表达“生物材料”意图包括人、动物和植物,并且包括例如:细胞、毛发、皮肤以及其它人和动物组织。除另外指示之外,如本文所用的表达“非生物材料”意图包括不属于“生物材料”定义中的所有事物。
除另外指示之外,如本文所用的表达“太阳辐射”意图包括由太阳所发出的电磁辐射的总频率谱,包括无线电波、x-射线、红外线、可见光线以及紫外线(“UV”)。
除另外指示之外,如本文所用的“紫外线”和“UV”意图意指紫外线或紫外光。UV为波长短于可见光的波长但是长于X射线的波长的电磁辐射,波长范围为约10nm至约400nm,并且能量为约3eV至约124eV(缩写“eV”在本文中是指电子伏特)。紫外线A(UVA)是指320nm至400nm之间的光谱中的UV辐射,它也被称为“较长”射线。UVA波段进一步被分为UVA I(340-400nm)和UVA II(320-340nm)。UVA为由于阳光而导致长期皮肤损害的主要原因并且还可导致晒伤。紫外线B(UVB)是指290nm至320nm光谱的辐射,它也被称为“较短”射线。UVB射线为由于阳光暴露而导致的晒伤的主要原因。
除另外指示之外,如本文所用的术语“亚胺”或“亚氨基”包括含有碳-氮双键的官能团或化学化合物。除另外指示之外,如本文所用的表达“亚氨基化合物”是指包含如本文所定义的“亚胺”或“亚氨基”的化合物。
除另外指示之外,如本文所用的术语“羟基”包括-OH。
除另外指示之外,如本文所用的术语“卤代”和“卤代”包括氯、氯代、Cl;氟、氟代、F;溴、溴代、Br;或碘、碘代、I。
除另外指示之外,如本文所用的术语“芳基”包括碳环形芳族基。芳基的实例包括但不限于苯基、苄基、萘基和蒽基。
除另外指示之外,如本文所用的术语“胺”和“氨基”包括含有具有孤对电子的氮原子的官能团,并且其中一个或多个氢原子被一个取代基置换,所述取代基例如但不限于烷基或芳基。
除另外指示之外,如本文所用的术语“烷基”包括具有直链或支链部分的饱和一价烃基,例如但不限于甲基、乙基、丙基、丁基、戊基、己基、辛基等。代表性直链低级烷基包括但不限于,-甲基、-乙基、-正-丙基、-正-丁基、-正-戊基、-正-己基、-正-庚基以及-正-辛基;而支链低级烷基包括但不限于,-异丙基、-仲-丁基、-异丁基、-叔-丁基、-异戊基、2-甲基丁基、2-甲基戊基、3-甲基戊基、2,2-二甲基丁基、2,3-二甲基丁基、2,2-二甲基戊基、2,3-二甲基戊基、3,3-二甲基戊基、2,3,4-三甲基戊基、3-甲基己基、2,2-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、3,5-二甲基己基、2,4-二甲基戊基、2-甲基庚基、3-甲基庚基,不饱和C1-C8烷基包括但不限于,-乙烯基、-烯丙基、-1-丁烯基、-2-丁烯基、-异丁烯基、-1-戊烯基、-2-戊烯基、-3-甲基-1-丁烯基、-2-甲基-2-丁烯基、-2,3-二甲基-2-丁烯基、1-己基、2-己基、3-己基、-乙炔基、-丙炔基、-1-丁炔基、-2-丁炔基、-1-戊炔基、-2-戊炔基、-3-甲基-1丁炔基。
除另外指示之外,如本文所用的术语“羧基”包括由碳原子与氧原子的双键和碳原子与羟基的单键组成的官能团(-COOH)。
除另外指示之外,如本文所用的术语“烯基”包括具有至少一个碳碳双键的烷基部分,其中烷基为如以上所定义的并且包括所述烯基部分的E和Z同分异构体。
除另外指示之外,如本文所用的术语“炔基”包括具有至少一个碳碳三键的烷基部分,其中烷基为如以上所定义的。
除另外指示之外,如本文所用的术语“酰基”包括源于脂肪族羧酸的通过去除羟基(-OH)而得到的官能团。
除另外指示之外,如本文所用的术语“烷氧基”包括O-烷基,其中烷基为如以上所定义的并且O代表氧。代表性烷氧基包括但不限于,-O-甲基、-O-乙基、-O-正-丙基、-O-正-丁基、-O-正-戊基、-O-正-己基、-O-正-庚基、-O-正-辛基、-O-异丙基、-O-仲-丁基、-O-异丁基、-O-叔-丁基、-O-异戊基、-O-2-甲基丁基、-O-2-甲基戊基、-O-3-甲基戊基、-O-2,2-二甲基丁基、-O-2,3-二甲基丁基、-O-2,2-二甲基戊基、-O-2,3-二甲基戊基、-O-3,3-二甲基戊基、-O-2,3,4-三甲基戊基、-O-3-甲基己基、-O-2,2-二甲基己基、-O-2,4-二甲基己基、-O-2,5-二甲基己基、-O-3,5-二甲基己基、-O-2,4-二甲基戊基、-O-2-甲基庚基、-O-3-甲基庚基、-O-乙烯基、-O-烯丙基、-O-1-丁烯基、-O-2-丁烯基、-O-异丁烯基、-O-1-戊烯基、-O-2-戊烯基、-O-3-甲基-1-丁烯基、-O-2-甲基-2-丁烯基、-O-2,3-二甲基-2-丁烯基、-O-1-己基、-O-2-己基、-O-3-己基、-O-乙炔基、-O-丙炔基、-O-1-丁炔基、-O-2-丁炔基、-O-1-戊炔基、-O-2-戊炔基和-O-3-甲基-1-丁炔基、-O-环丙基、-O-环丁基、-O-环戊基、-O-环己基、-O-环庚基、-O-环辛基、-O-环壬基和-O-环癸基、-O-CH2-环丙基、-O-CH2-环丁基、-O-CH2-环戊基、-O-CH2-环己基、-O-CH2-环庚基、-O-CH2-环辛基、-O-CH2-环壬基、-O-CH2-环癸基、-O-(CH2)2-环丙基、-O-(CH2)2-环丁基、-O-(CH2)2-环戊基、-O-(CH2)2-环己基、-O-(CH2)2-环庚基、-O-(CH2)2-环辛基、-O-(CH2)2-环壬基以及-O-(CH2)2-环癸基。
除另外指示之外,如本文所用的术语“环烷基”包括非芳香族的、饱和或部分饱和的、单环或稠合的、螺合或未稠合的双环或三环烃,在本文中指示含有总计3至10个碳原子、优选3至8个环碳原子。环烷基的实例包括但不限于,C3-C8环烷基包括但不限于,-环丙基、-环丁基、-环戊基、-环戊二烯基、-环己基、-环己烯基、-1,3-环己二烯基、-1,4-环己二烯基、-环庚基、-1,3-环庚二烯基、-1,3,5-环庚三烯基、-环辛基以及-环辛二烯基。
术语“环烷基”还包括-低级烷基-环烷基,其中低级烷基和环烷基为如本文所定义的。-低级烷基-环烷基的实例包括但不限于,-CH2-环丙基、-CH2-环丁基、-CH2-环戊基、-CH2-环戊二烯基、-CH2-环己基、-CH2-环庚基以及-CH2-环辛基。
除另外指示之外,如本文所用的术语“杂环”包括其中环碳原子中的一个至四个独立地被选自由O、S和N组成的组的杂原子置换的芳香族或非芳香族环烷基。杂环的代表性实例包括但不限于,苯并呋喃基、苯并噻吩基、吲哚基、苯并吡唑基、香豆素基、异喹啉基、吡咯基、吡咯烷基、噻吩基、呋喃基、噻唑基、咪唑基、吡唑基、三唑基、喹啉基、嘧啶基、吡啶基、吡啶酮基、吡嗪基、哒嗪基、异噻唑基、异噁唑基、(1,4)-二噁烷、(1,3)-二氧戊环、4,5-二氢-1H-咪唑基以及四唑基。杂环可为取代的或未取代的。杂环可键合在任何环原子处(即,在杂环的任何碳原子或杂原子处)。
除另外指示之外,如本文所用的术语“氰基”包括-CN基。
除另外指示之外,如本文所用的术语“醇”包括其中羟基官能团(-OH)键合碳原子的化合物。具体地说,此碳中心应为饱和的,具有与三个另外的原子的单键。
术语“溶剂合物”意图意指特定化合物的溶剂合物形式,其保留此类化合物的有效性。溶剂合物的实例包括本发明的化合物与例如以下各项的组合:水、异丙醇、乙醇、甲醇、二甲亚砜(DMSO)、乙酸乙酯、乙酸或乙醇胺。
如本文所用的术语“mmol”意图意指毫摩尔。如本文所用的术语“equiv”意图意指当量。如本文所用的术语“mL”意图意指毫升。如本文所用的术语“g”意图意指克。如本文所用的术语“kg”意图意指千克。如本文所用的术语“μg”意图意指微克。如本文所用的术语“h”意图意指小时。如本文所用的术语“min”意图意指分钟。如本文所用的术语“M”意图意指摩尔。如本文所用的术语“μL”意图意指微升。如本文所用的术语“μM”意图意指微摩尔。如本文所用的术语“nM”意图意指毫微摩尔。如本文所用的术语“N”意图意指标准的。如本文所用的术语“amu”意图意指原子质量单位。如本文所用的术语“℃”意图意指摄氏度。如本文所用的术语“wt/wt”意图意指重量/重量。如本文所用的术语“v/v”意图意指体积/体积。如本文所用的术语“MS”意图意指质谱。如本文所用的术语“HPLC”意图意指高效液相色谱。如本文所用的术语“RT”意图意指室温。如本文所用的术语“e.g.”意图意指例如。如本文所用的术语“N/A”意图意指未测试到。
如本文所用的表达“药学上可接受的盐”是指本发明化合物的药学上可接受的有机盐或无机盐。优选的盐包括但不限于,硫酸盐、柠檬酸盐、乙酸盐、草酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、硝酸盐、硫酸氢盐、磷酸盐、酸式磷酸盐、异烟碱酸盐、乳酸盐、水杨酸盐、酸式柠檬酸盐、酒石酸盐、油酸盐、丹宁酸盐、泛酸盐、酒石酸氢盐、抗坏血酸盐、琥珀酸盐、马来酸盐、龙胆酸盐(gentisinate)、延胡索酸盐、葡糖酸盐、葡糖醛酸盐、蔗糖酸盐、甲酸盐、苯甲酸盐、谷氨酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、对-甲苯磺酸盐、以及双羟萘酸盐(即1,1'-亚甲基-双-(2-羟基-3-萘甲酸盐))。药学上可接受的盐可涉及包含另一种分子,如乙酸盐离子、琥珀酸盐离子或其它抗衡离子。抗衡离子可为使母体化合物上的电荷稳定的任何有机或无机部分。此外,药学上可接受的盐在其结构中可具有多于一个带电原子。其中多个带电原子为药学上可接受的盐的一部分的情况可具有多个抗衡离子。因此,药学上可接受的盐可具有一个或多个带电原子和/或一个或多个抗衡离子。如本文所用的表达“药学上可接受的溶剂合物”是指一个或多个溶剂分子与本发明的化合物的关联。形成药学上可接受的溶剂合物的溶剂的实例包括但不限于,水、异丙醇、乙醇、甲醇、DMSO、乙酸乙酯、乙酸以及乙醇胺。如本文所用的表达“药学上可接受的水合物”是指还包含通过非共价分子间作用力结合的化学计量或非化学计量的量的水的本发明的化合物或其盐。
如本文所用的术语“霉孢菌素”为展示图1所示的一般结构的化合物的通用术语。霉孢菌素具有中心环结构,其中各个氨基改变此环结构(包括例如中心环己烯酮或环己亚胺环以及各种各样的取代基)。霉孢菌素样氨基酸(“MAA”)代表相对广泛的一类水溶性的取代的环己烯,它们连接至氨基酸和亚氨基醇并且在约310nm与约360nm3-6之间具有吸收最大值。在一些海洋有机体中,MAA用作光保护性UV滤光剂和/或用作抗氧化剂。体外研究表明提高的MAA耐光性以及热量在介质中的释放为光刺激分子的松弛路径(relaxation pathway)的结果。这些研究的结果也提供MAA在体外还用作UV滤光剂和/或抗氧化剂的强有力证据7。在本申请中术语霉孢菌素包括单一种的霉孢菌素化合物和若干种霉孢菌素的混合物。通常被称为霉孢菌素的所有化合物均包括在本发明的范围内。典型的MAA包括但不限于:霉孢菌素-甘氨酸、霉孢菌素-牛磺酸、帕里盯(palythine)、海燕(asterina)-330、palythinol、palythene、紫菜(porphyra)-334、霉孢菌素-甘氨酸:缬氨酸、shinorine以及MAA 357。
B)本发明的化合物
来自海洋有机体的MAA为霉孢菌素的亚胺衍生物,其包含连接至氨基酸、氨基醇或氨基的氨基-环己亚氨基8。我们已提出,MAA的化学和结构衍生化合物的某些基团可容易合成制备的并且可表明太阳辐射-吸收特征、UV-保护性质以及抗氧化剂性质。例如对于MAA,这些化合物可能共享吸收光的作用机制,具体地为吸收UV辐射的作用机制;更具体地为吸收UVA和/或UVB辐射的作用机制。而且,例如一些MAA,这些化合物可能共享抗氧化性质。已获得包含至少一个亚氨基的化合物。这些化合物能够进行电子离域和UV辐射吸收。具体地说,已获得具有UV-吸收(如UVA-吸收和/或UVB-吸收性质)和/或抗氧化性质的化合物。
因此,在一个实施方案中,本发明涉及式I的化合物:
具有式I的化合物可通过其环结构吸收UV辐射。因此,它应为允许本文所定义的化合物防止UV辐射的UV吸收性质。在此实施方案的一些实施方式中,式I化合物可通过其环结构调节自由基(例如,电子离域容量)。在一些其它的实施方式中,式I化合物可防止氧化损害。
在此实施方案的一些实施方式中,式I化合物可包含多于一个亚氨基。
因此,本发明的化合物可能适用于吸收UV辐射并且阻断UV辐射穿透生物材料和非生物材料的表面。这些化合物还可能适用于抑制或减小UV在生物材料和非生物材料中的作用。可适用于抑制或减少的一些UV辐射作用为UV辐射的有害作用。在生物材料如人和动物上,一些UV辐射的有害作用包括但不限于:晒伤、皮肤病、皮肤病的恶化、对眼睛的损害、间接DNA损害、黑素瘤以及癌症。在非生物材料上,如在制造物品上,一些UV辐射的有害作用包括但不限于:聚合物的降解、色素的降解、颜色的降解、色牢度、染料的降解、结构的弱化、干燥等等。
在此实施方案的另一种实施方式中,提供式I的化合物:
或其可接受的或适合的盐或溶剂合物;其中
R1为未取代或取代的烷基;未取代或取代的烯烃;未取代或取代的炔烃;未取代或取代的芳基;未取代或取代的杂环;未取代或取代的环烷基;未取代和取代的烷氧基;烷酰基;芳基烷基;羧基;杂芳基;杂芳基烷基;苯基;苄基;羟基;羧酸;酯;亚磺酰基;巯基;硫化物;磺酰基;亚磺基;膦基;膦酰基;磷酸盐;胺;卤代;或甲酰胺。在一些实施方式中,R1可与化合物的其它元素和/或化合物的其它环元素形成杂环。在这些实施方式中的一些中,R1可例如与R7形成杂环。所得的杂环可为未取代的或者可包含一个或多个取代基。由于此杂环化作用,R7被如下所定义的Y置换。
R6和R7各自独立地为氢;未取代或取代的烷基;未取代或取代的烯烃;未取代或取代的炔烃;未取代或取代的芳基;未取代或取代的杂环;未取代或取代的环烷基;未取代和取代的烷氧基;烷酰基;炔基;羟基;磺基;卤代基;膦酰基;酯基;羧酸基;苯基;烷基脂肪酸链或聚醚。
R2为氢;卤代;未取代或取代的烷基;未取代或取代的烯烃;未取代或取代的炔烃;未取代或取代的芳基;未取代或取代的杂环;未取代或取代的环烷基;未取代和取代的烷氧基;烷酰基;羟基;卤代;苯基;苄基;羧酸或酯基。在一些实施方式中,如式I所描绘的芳族环的双键可被在此处以下式I的变体中示出的两个R2基团置换:
X为碳;卤代;氮;氧;硫;-CH2;苯基;环烷基;氨基或螺环烷烃。在一些实施方式中,X可具有一个或多个取代基。
n为整数,其中所述整数为1、2、3或4。
本领域技术人员将了解到,式I的若干结构变型可被认为未背离本发明。
在本实施方案的一些实施方式中,具有式I的化合物的实例包括但不限于,具有如以下所讨论的子式IA、IB、IC、ID、IE或IF的化合物。
式IA化合物的一般子结构为如以下所描绘的:
其中:
R3和R4各自独立地为氢;未取代或取代的烷基;未取代或取代的烯烃;未取代或取代的炔烃;未取代或取代的芳基;未取代或取代的杂环;未取代或取代的环烷基;未取代和取代的烷氧基;烷酰基;磺基;羟基;膦酰基;酯基;羧酸基;或苯基。
R5为未取代或取代的烷基;未取代或取代的烯烃;未取代或取代的炔烃;未取代或取代的芳基;未取代或取代的杂环;未取代或取代的环烷基;未取代和取代的烷氧基;烷酰基;磺基;羟基;膦酰基;酯基;羧酸基;或苯基。
R6为氢;未取代或取代的烷基;未取代或取代的烯烃;未取代或取代的炔烃;未取代或取代的芳基;未取代或取代的杂环;未取代或取代的环烷基;未取代和取代的烷氧基;烷酰基;羟基;磺基;卤代基;膦酰基;酯基;羧酸基;苯基;烷基脂肪酸链或聚醚。
Y为碳;氧;硫;-CH2;苯基;氨基;或螺环烷烃。
n为整数,其中所述整数为1、2、3或4。
本领域技术人员将了解到,式IA的若干结构变型可被认为未背离本发明。在此实施方案的一些实施方式中,具有子式IA的化合物包括但不限于:
式IA1:(R,E)-8-(4-甲氧基苯基亚氨基)-6,6-二甲基-3,4,5,6,7,8-六氢-2H-苯并[b][1,4]噻嗪-3-羧酸
式IA2:(R,E)-8-(2-羧基-4-甲氧基苯基亚氨基)-6,6-二甲基-3,4,5,6,7,8-六氢-2H-苯并[b][1,4]噻嗪-3-羧酸
式IA3:(R,E)-8-(4-甲氧基苯基亚氨基)-6,6-二甲基-3,4,5,6,7,8-六氢-2H-苯并[b][1,4]噁嗪-3-羧酸
式IA4:(E)-5-(4-甲氧基苯基亚氨基)-7,7-二甲基-1,2,3,4,5,6,7,8-八氢喹喔啉-2-羧酸
式IA5:(S,E)-8-((4-甲氧基苯基)亚氨基)-3,4,5,6,7,8-六氢-2H-苯并[b][1,4]噁嗪-3-羧酸乙酯
式IA6:(R,E)-8-((4-甲氧基苯基)亚氨基)-3,4,5,6,7,8-六氢-2H-苯并[b][1,4]噻嗪-3-羧酸乙酯
式IA7:(S,E)-5-((4-甲氧基苯基)亚氨基)-1,2,3,4,5,6,7,8-八氢喹喔啉-2-羧酸乙酯
式IA8:(R,E)-8-(4-(2-乙基己氧基)-2-羟基苯基亚氨基)-6,6-二甲基-3,4,5,6,7,8-六氢-2H-苯并[b][1,4]噻嗪-3-羧酸
式IB化合物的一般子结构为如以下所描绘的:
其中:
R5为未取代或取代的烷基;未取代或取代的烯烃;未取代或取代的炔烃;未取代或取代的芳基;未取代或取代的杂环;未取代或取代的环烷基;未取代和取代的烷氧基;烷酰基;磺基;膦酰基;酯基;羧酸基;羟基;或苯基。
R6为氢;未取代或取代的烷基;未取代或取代的烯烃;未取代或取代的炔烃;未取代或取代的芳基;未取代或取代的杂环;未取代或取代的环烷基;未取代和取代的烷氧基;烷酰基;炔基;羟基;磺基;卤代基;膦酰基;酯基;羧酸基;苯基;烷基脂肪酸链或聚醚。
Y为碳;氧;硫;-CH2;苯基;氨基;或螺环烷烃。
X为氧;硫;芳基;苯基;螺环烷烃;或氨基。
n为整数,其中所述整数为1、2、3或4。
本领域技术人员将了解到,式IB的若干结构变型可被认为未背离本发明。具有子式IB的化合物的实例包括但不限于:
式IB1:(S,E)-8-((4-甲氧基苯基)亚氨基)-3,4,5,6,7,8-六氢-2H-吡啶并[4,3-b][1,4]噁嗪-3-羧酸乙酯
式IB2:(R,E)-8-((4-甲氧基苯基)亚氨基)-3,4,5,6,7,8-六氢-2H-吡啶并[4,3-b][1,4]噻嗪-3-羧酸乙酯
式IB3:(S,E)-8-((4-甲氧基苯基)亚氨基)-1,2,3,4,5,6,7,8-八氢吡啶并[3,4-b]吡嗪-3-羧酸乙酯
式IB4:(S,E)-8-((4-甲氧基苯基)亚氨基)-2,3,4,5,7,8-六氢吡喃并[4,3-b][1,4]噁嗪-3-羧酸乙酯
式IB5:(R)-8-((4-甲氧基苯基)亚氨基)-2,3,4,5,7,8-六氢吡喃并[4,3-b][1,4]噻嗪-3-羧酸乙酯
式IB6:(Z)-8-((4-甲氧基苯基)亚氨基)-2,3,4,5,7,8-六氢-1H-吡喃并[3,4-b]吡嗪-3-羧酸
式IC化合物的一般子结构为如以下所描绘的:
其中:
R6和R7为氢;未取代或取代的烷基;未取代或取代的烯烃;未取代或取代的炔烃;未取代或取代的芳基;未取代或取代的杂环;未取代或取代的环烷基;未取代和取代的烷氧基;烷酰基;炔基;羟基;磺基;卤代基;膦酰基;酯基;羧酸基;苯基;羟基;烷基脂肪酸链或聚醚。
X为氧;硫;芳基;苯基;螺环烷烃;或氨基。
n为整数,其中所述整数选自1、2、3或4。
本领域技术人员将了解到,式IC的若干结构变型可被认为未背离本发明。具有子式IC的化合物的实例包括但不限于:
式IC1:(Z)-2-((5-((4-甲氧基苯基)亚氨基)-1,2,5,6-四氢吡啶-3-基)氨基)乙酸
式IC2:(E)-2-((4-甲氧基-5-((4-甲氧基苯基)亚氨基)-1,2,5,6-四氢吡啶-3-基)氨基)乙酸
式IC3:(Z)-2-((5-((4-甲氧基苯基)亚氨基)-5,6-二氢-2H-吡喃-3-基)氨基)乙酸
式IC4:(E)-2-((4-甲氧基-5-((4-甲氧基苯基)亚氨基)-5,6-二氢-2H-吡喃-3-基)氨基)乙酸
式ID化合物的一般子结构为如以下所描绘的:
其中:
R3和R4各自独立地为氢;未取代或取代的烷基;未取代或取代的烯烃;未取代或取代的炔烃;未取代或取代的芳基;未取代或取代的杂环;未取代或取代的环烷基;未取代和取代的烷氧基;烷酰基;磺基;膦酰基;酯基;羟基;羧酸基;或苯基。
R6和R7为氢;未取代或取代的烷基;未取代或取代的烯烃;未取代或取代的炔烃;未取代或取代的芳基;未取代或取代的杂环;未取代或取代的环烷基;未取代和取代的烷氧基;烷酰基;炔基;羟基;磺基;卤代基;膦酰基;酯基;羧酸基;苯基;烷基脂肪酸链或聚醚。
n为整数,其中所述整数为1、2、3或4。
本领域技术人员将了解到,式ID的若干结构变型可被认为未背离本发明。具有式ID的化合物的实例包括:
式ID1:(E)-2-(2-甲氧基-3-(4-甲氧基苯基亚氨基)-5,5-二甲基环己-1-烯基氨基)乙酸
式ID2:(E)-2-(3-(4-甲氧基苯基亚氨基)-5,5-二甲基环己-1-烯基氨基)乙酸
式ID3:(E)-2-(3-(4-甲氧基苯基亚氨基)环己-1-烯基氨基)乙酸
式ID4:(E)-2-(2-甲氧基-3-(4-甲氧基苯基亚氨基)环己-1-烯基氨基)乙酸
式IE化合物的一般子结构为如以下所描绘的:
其中:
R3和R4各自独立地为氢;未取代或取代的烷基;未取代或取代的烯烃;未取代或取代的炔烃;未取代或取代的芳基;未取代或取代的杂环;未取代或取代的环烷基;未取代和取代的烷氧基;烷酰基;磺基;膦酰基;羟基;酯基;羧酸基;或苯基。
R5为未取代或取代的烷基;未取代或取代的烯烃;未取代或取代的炔烃;未取代或取代的芳基;未取代或取代的杂环;未取代或取代的环烷基;未取代和取代的烷氧基;烷酰基;磺基;膦酰基;羟基;酯基;羧酸基;或苯基。
R6为氢;未取代或取代的烷基;未取代或取代的烯烃;未取代或取代的炔烃;未取代或取代的芳基;未取代或取代的杂环;未取代或取代的环烷基;未取代和取代的烷氧基;烷酰基;炔基;羟基;磺基;羟基;卤代基;膦酰基;酯基;羧酸基;苯基;烷基脂肪酸链或聚醚。
R8为氢;未取代或取代的烷基;未取代或取代的烯烃;未取代或取代的炔烃;未取代或取代的芳基;未取代或取代的杂环;未取代或取代的环烷基;未取代和取代的烷氧基;烷酰基;炔基;羟基;磺基;卤代基;膦酰基;酯基;羧酸基;苯基;氨基;烷基脂肪酸链或聚醚。
Y为碳;氧;硫;-CH2;苯基;氨基;或螺环烷烃。
n为整数,其中所述整数为1、2、3或4。
本领域技术人员将了解到,式IE的若干结构变型可被认为未背离本发明。在此实施方案的一些实施方式中,具有子式IE的化合物的实例包括但不限于:
式IE1:(R,E)-8-(4-(叔-丁基氨基甲酰基)苯基亚氨基)-6,6-二甲基-3,4,5,6,7,8-六氢-2H-苯并[b][1,4]噻嗪-3-羧酸
式IE2:(R,E)-8-(苯基亚氨基)-6,6-二甲基-3,4,5,6,7,8-六氢-2H-苯并[b][1,4]噻嗪-3-羧酸
式IE3:(R,E)-8-(4-(二乙基氨基)-2-羟基苯基亚氨基)-6,6-二甲基-3,4,5,6,7,8-六氢-2H-苯并[b][1,4]噻嗪-3-羧酸
式IE4:(R,E)-8-(4-氟苯基亚氨基)-6,6-二甲基-3,4,5,6,7,8-六氢-2H-苯并[b][1,4]噻嗪-3-羧酸
式IF化合物的一般子结构为如以下所描绘的:
其中:
R3和R4各自独立地为氢;未取代或取代的烷基;未取代或取代的烯烃;未取代或取代的炔烃;未取代或取代的芳基;未取代或取代的杂环;未取代或取代的环烷基;未取代和取代的烷氧基;烷酰基;磺基;膦酰基;羟基;酯基;羧酸基;或苯基。
R5为未取代或取代的烷基;未取代或取代的烯烃;未取代或取代的炔烃;未取代或取代的芳基;未取代或取代的杂环;未取代或取代的环烷基;未取代和取代的烷氧基;烷酰基;羟基;磺基;膦酰基;酯基;羧酸基;或苯基。
R6为氢;未取代或取代的烷基;未取代或取代的烯烃;未取代或取代的炔烃;未取代或取代的芳基;未取代或取代的杂环;未取代或取代的环烷基;未取代和取代的烷氧基;烷酰基;炔基;羟基;磺基;羟基;卤代基;膦酰基;酯基;羧酸基;苯基;烷基脂肪酸链或聚醚。
Y为碳;氧;硫;-CH2;苯基;氨基;或螺环烷烃。
n为整数,其中所述整数为1、2、3或4。
本领域技术人员将了解到,式IF的若干结构变型可被认为未背离本发明。
在此实施方案的一些实施方式中,具有子式IF的化合物的实例包括但不限于:
式IF1:(R,E)-8-(3,4-二甲氧基苯基亚氨基)-6,6-二甲基-3,4,5,6,7,8-六氢-2H-苯并[b][1,4]噻嗪-3-羧酸
当本文所述的基团被称为“未取代或取代的”时,在取代时,它们可被任选需要的取代基或不会不利地影响所需化合物活性的取代基取代。优选的取代基的实例为本文所公开的示例性化合物和实施方案中所找到的那些,以及卤素;烷基;烯基;炔基;羟基;烷氧基;氨基;硝基;硫醇;硫醚;亚胺;氰基;酰氨基;膦酸基;磷;羧基;硫代羰基;磺酰基;磺胺;酮;醛;酯;乙酰基;乙酰氧基;氨基甲酰基;氧(=O);卤代烷基(例如,三氟甲基);取代的氨酰基和氨基烷基;碳环环烷基,它可为单环或者稠合或非稠合多环(例如,环丙基、环丁基、环戊基或环己基),或杂环烷基,其可为单环或者稠合或非稠合多环(例如,吡咯烷基、哌啶基、哌嗪基、吗啉基或噻嗪基);碳环或杂环、单环或者稠合或非稠合多环芳基(例如苯基、萘基、吡咯基、吲哚基、呋喃基、噻吩基、咪唑基、噁唑基、异噁唑基、噻唑基、三唑基、四唑基、吡唑基、吡啶基、喹啉基、异喹啉基、吖啶基、吡嗪基、哒嗪基、嘧啶基、苯并咪唑基、苯并噻吩基或苯并呋喃基);氨基(伯、仲或叔);o-低级烷基;o-芳基、芳基;芳基-低级烷基;-CO2CH3;-CONH2;-OCH2CONH2;-NH2;-SO2NH2;-OCHF2;-CF3;-OCF3;并且这些部分也可任选地被稠环结构或桥取代,例如-OCH2O-或-O-低级烷基-O-。这些取代基可任选地进一步被选自此类基团的取代基取代。在一个实施方案中,当取代低级烷基(例如,亚甲基)时,它被天然发生的氨基酸的侧链取代。
其它式I的化合物包括但不限于,具有以下结构的化合物:
(R,E)-8-((4-氟苯基)亚氨基)-6,6-二甲基-3,4,5,6,7,8-六氢-2H-苯并[b][1,4]噻嗪-3-羧酸
(R,E)-8-((3,4-二甲氧基苯基)亚氨基)-6,6-二甲基-3,4,5,6,7,8-六氢-2H-苯并[b][1,4]噻嗪-3-羧酸
(R,E)-6,6-二甲基-8-(苯基亚氨基)-3,4,5,6,7,8-六氢-2H-苯并[b][1,4]噻嗪-3-羧酸
(E)-4-甲氧基-N-(3-((4-甲氧基苯基)氨基)-5,5-二甲基环亚己-2-烯-1-基)苯胺
(E)-2-((3-((4-甲氧基苯基)亚氨基)-5,5-二甲基环己-1-烯-1-基)氨基)乙酸甲酯
在本发明的另一个实施方案中,提供用于制备本文所定义的化合物的方法和工艺。本发明的化合物可使用常规有机合成来制成。本领域技术人员将了解,用于制备本文所定义的化合物的方法和工艺的若干种变型可被认为未背离本发明。
在此实施方案的一个实施方式中,式I的化合物通常可通过二酮,更确切地说通过环形二酮,甚至更确切地说通过卤化环形二酮来获得。例如,子式I的化合物通常可通过环形二酮来获得,所述环形二酮例如但不限于,环己二酮(例如,5,5-二甲基-环己-1,3-二酮;1,3-环己二酮;5-苯基-1,3-环己二酮)、环庚二酮(例如,1,3-环庚二酮)、环戊二酮(例如,1,3-环戊二酮)或茚满二酮(indadione)(例如,1,3-茚二酮)。
例如,式IA1化合物可由5,5-二甲基-环己-1,3-二酮制备。由5,5-二甲基-环己-1,3-二酮制备式IA1化合物可通过在适合溶剂存在下卤化5,5-二甲基-环己-1,3-二酮以产生卤化的5,5-二甲基-环己-1,3-二酮来进行。然后,卤化的5,5-二甲基-环己-1,3-二酮可与乙酯反应,以产生苯并噻嗪中间体化合物。苯并噻嗪中间体化合物然后可与甲氧基苯胺化合物反应,以产生式IA1化合物。
根据此实施方案的另一个实施方式,由5,5-二甲基-环己-1,3-二酮制备式IA1化合物可如以下合成方案中所列出地进行,其中5,5-二甲基-环己-1,3-二酮(1)在二氯甲烷(DCM)存在下溴化,以产生2-溴-5,5-二甲基-环己-1,3-二酮(2)。然后将2-溴-5,5-二甲基-环己-1,3-二酮(2)与L-半胱氨酸乙酯HCl和吡啶反应,以产生(R)-乙基6,6-二甲基-8-氧代-3,4,5,6,7,8-六氢-2H-苯并[b][1,4]噻嗪-3-羧酸酯(3),然后在DCM和二甲基甲酰胺(DMF)存在下将所述羧酸酯与丙二酰氯反应,以产生中间体化合物,然后所述中间体化合物与对-苯胺反应,以产生式IA1化合物(4)。
一旦合成,本发明的化合物就可使用标准纯化技术例如像色谱法(例如,快速柱色谱和HPLC)、不对称的合成方法、重结晶以及差异溶解度来与化学前体或其它化合物中分离。如本文在化合物如本发明的化合物的背景下使用的术语“分离的”是指基本上不含化学前体、在化学合成时的其它化学物或其它异构体的化合物。在一个特定实施方案中,化合物为60%、65%、70%、75%、80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%的不含其它不同化合物(例如,其它异构体)。优选地,本发明的化合物为分离的。
本发明的不同化合物包含一个或多个手性中心,并且可作为对映体的外消旋混合物、非对映体的混合物或者对映体地或光学地纯化合物存在。例如,包含等量或不等量的本发明的特定化合物的对映体的混合物可用于本发明的方法和组合物中。应注意,本发明的化合物包括E和Z异构体或其混合物以及其顺式和反式异构体或混合物。在某些实施方案中,本发明的化合物被分离为E或Z异构体。在其它实施方案中,本发明的化合物为E和Z异构体的混合物。
如本文所用的并且除另外指示之外,术语“立体异构纯的”意指包含化合物的一种立体异构体并且基本上不含该化合物的其它立体异构体的组合物或者基本上不含其它几何异构体的一种几何异构体(例如,约一个双键)。例如,具有一个手性中心的本发明的立体异构纯的化合物或其组合物将基本上不含所述化合物的相反对映体。具有两个手性中心的本发明的立体异构纯的化合物或其组合物将基本上不含所述化合物的其它非对映体。具有能够E/Z异构化的双键的本发明的立体异构纯的化合物或其组合物将基本上不含E/Z异构体之一。典型的立体异构纯的化合物包含按重量计大于约80%的所述化合物的一种立体异构体或E/Z立构体和按重量计小于约20%的所述化合物的其它立体异构体或E/Z异构体,更优选地为按重量计大于约90%的所述化合物的一种立体异构体或E/Z立构体和按重量计小于约10%的所述化合物的其它立体异构体或E/Z异构体,甚至更优选地为按重量计大于约95%的所述化合物的一种立体异构体或E/Z立构体和按重量计小于约5%的所述化合物的其它立体异构体或E/Z异构体,以及最优选地为按重量计大于约97%的所述化合物的一种立体异构体或E/Z立构体和按重量计小于约3%的所述化合物的其它立体异构体或E/Z异构体。如本文所用的并且除另外指示之外,术语“立体异构富集的”意指本发明的化合物或者包含按重量计大于约60%的本发明的化合物的一种立体异构体或E/Z异构体,优选按重量计大于约70%,更优选地按重量计大于约80%的本发明的化合物的一种立体异构体或E/Z异构体的组合物。如本文所用的并且除另外指示之外,术语“对映体纯的”意指具有一个手性中心的本发明的立体异构纯的化合物或其组合物。类似地,术语“立体异构富集的”意指具有一个手性中心的本发明的立体异构富集的化合物或其组合物。
应注意,结构的立体化学或结构的一部分没有用例如粗线或虚线指示,所述结构或所述结构的一部分被理解为涵盖它的所有立体异构体。
在其它实施方案中,本发明提供用于确定如本文所定义的化合物的UV-吸收能力的方法和技术。本文所定义的化合物的UV-吸收性质可根据本领域已熟知的技术和方法通过分光光度计进行确定。例如,可使用紫外-可见光谱学或紫外-可见光分光光度法(UV-Vis或UV/Vis)计算所述化合物的最大吸光度的波长(λmax)。
本领域技术人员将了解,本发明的化合物的光谱特征包括其消光系数(ε)的值和其λmax的值,所述光谱特征通过化合物的结构元素,例如通过存在于化合物上的官能团/取代基的性质进行影响。本发明的化合物中的电子离域越有效率,其消光系数应越高。
本文所定义的化合物的光敏性可指示化合物吸收UV辐射的效力。化合物的光敏性可使用SPF分析器(例如但不限于,Optometrix,SPF 290)测定。在数学上,所述SPF由测量的数据计算为:
在E(λ)为日辐照度光谱,A(λ)为红斑作用光谱并且MPF(λ)为单色光防护因子,它们均为波长的函数。所述MPF大约为给定波长下的透光率的倒数。为了计算本发明的化合物的SPF值,可以适当浓度(例如像约1.10-5至约5.10-5M之间)将所述化合物溶解于适合溶剂(例如像,甲醇或乙醇)中,将其置于石英池中,并且使用金属卤化物灯(IUVB=0.4至8.0mW/cm)照射。对于转换为太阳光谱(CIE D65标准日光,标准化为IUVB=0.127mW/cm2),计算波长分辨的灯强度和化合物在290nm与400nm之间的相应吸光度值的乘积的积分并且将其除以D65光强度与化合物在290nm与400nm之间的范围内的相应吸光度值的乘积的积分。该因子乘以在用金属卤化物灯照射下降解的半衰期值,以便获得在太阳照射下的相应半衰期值。在灯照射下的光降解的半衰期值通过UV光谱学测量在最大吸光度波长下的消光以及随后的指数拟合来确定。使用此方法获得D65光中的光降解的半衰期值。
本文所定义的化合物的其它物理性质的测定或测量可用于评定化合物吸收UV辐射的效力,例如但不限于,熔点测定、旋光性、IR光谱学、MS光谱学、NMR光谱学以及耐水性测量。这些和其它技术以及执行它们的方式为本领域已熟知的。
C)制剂和组合物
本发明的化合物可用于吸收UV辐射。本发明的化合物还可提供对生物材料和非生物材料的保护以使其抵抗UV辐射的损害作用,具体地为抵抗UVA或UVB或两种辐射的损害作用。这些制剂和组合物包含如本文所定义的式I的化合物。
本发明的化合物可与其它化合物组合来配制,以便获得具有所需特征的制剂和/或组合物。此类其它化合物可包括本身不是UV吸收剂/滤光剂/阻断剂,但是有助于控制组合物自身的特征(如膜厚度、不透明度、耐摩性、防水性以及均匀性)的各种各样的成分和化合物。或者,此类其它化合物也可包括用作UV吸收剂/滤光剂/阻断剂的各种各样的成分,如为UVA吸收剂/滤光剂/阻断剂的化合物和为UVB吸收剂/滤光剂/阻断剂的化合物。
根据一个实施方案,本发明的化合物可以制剂和/或组合物的重量的约1%至约99%的量并入到制剂和/或组合物中。其它化合物可以制剂和/或组合物的重量的约99%至约1%的量并入到制剂和/或组合物中。在一个优选的实施方式中,本发明的化合物以制剂和/或组合物重量的约0.2%与约30%之间变化的量并入所述制剂和/或组合物中。本文所定义的化合物的适合质量和浓度以及并入制剂和/或组合物中的其它组分的质量和浓度取决于制剂和/或组合物的性质并且取决于它们所意图用于的生物材料和/或非生物材料。本领域技术人员将使用本领域已知的技术了解此类要素。
本文所定义的化合物的一种可能有用的应用为其并入组合物和/或制剂中,以保护生物材料使其免于UV辐射。此类组合物和/或制剂可为防嗮组合物并且可根据本领域已熟知的技术,具体地为用于制备水包油或油包水乳液的技术来配制。此外,本发明的化合物可被配制到载体中,如水、基于水的液体、洗液、分散体、油、基于油的溶液、粉剂、凝胶、乳液、分散体或其混合物。适合量的载体可容易通过本领域技术人员根据例如实现的防晒系数(SPF)来确定。获得所需防晒系数(SPF)所需要的本文所定义的化合物的特定量可通过本领域已熟知的技术来确定。防晒剂应提供针对UVA和/或UVB射线的最小保护。增加的防晒系数(即,主要为UVB防护)也应包括UVA防护的增加。在一些实施方式中,应涉及针对UVA和UVB辐射的保护。
防晒产品的UV吸光度可使用衬底分光光度法对整个UV光谱(290nm-400nm)进行体外测定。例如,将均匀的量和厚度的防晒剂应用于载玻片并且将其暴露于UV光;该UV辐射的吸光度根据本领域已熟知的技术进行测量。所获得的UV吸光度曲线证明穿过UV光谱所提供(从290nm至400nm)的保护的幅度和宽度。吸光度曲线的“幅度”反映保护的程度。曲线幅度越高,吸光度越长并且在该波长下提高的保护越大。在光谱(290nm-320nm)的UVB部分,此幅度与SPF相关联。曲线的“宽度”越大,针对较长波长的UV辐射提供的保护越大。换言之,曲线的“宽度”越大,所提供的防晒光谱越宽。对290nm至400nm测量的光谱吸光度求数学积分以计算曲线下面积。“临界波长”(λc)为其下方存在90%的吸光度曲线下面积的波长。SPF值2通常吸收50%UVB,SPF值15通常吸收93.3%UVB,SPF 30吸收96.7%UVB并且SPF 50吸收98%UVB。
在防晒组合物的制备中,本文所定义的化合物可与本领域已知的其它UV-吸收剂组合使用,所述其它UV-吸收剂例如但不限于,UV-阻断剂、亲水性或亲脂性有机UV-A和/或UV-B防晒剂。可在本发明的制剂和/或组合物中包含的其它UV-吸收剂的实例包括但不限于:氨基苯甲酸;帕地马酯O;苯基苯并咪唑磺酸;西诺沙酯、双羟苯宗;氧苯酮;胡莫柳酯;邻氨基苯甲酸薄荷酯、氰双苯丙烯酸辛酯;甲氧基肉桂酸辛酯;水杨酸辛酯;磺异苯酮;水杨酸三乙醇胺;阿伏苯宗;依莰舒(ecamsule);二氧化钛;4-甲基苯亚甲基樟脑;天来施(tinosorb)M;天来施S;neo heliopan AP;麦素宁(mexoryl)XL;二苯甲酮-9;uvinul T150;uvinul A Plus;uasorb HEB;parsol SLX和异戊烯基-4-甲氧基肉桂酸酯;4-二甲基氨基苯甲酸2-乙基己酯;水杨酸衍生物,例如水杨酸2-乙基己基酯;二苯甲酮衍生物,例如2-羟基-4-甲氧基二苯甲酮及其5-磺酸衍生物;二苯甲酰甲烷衍生物,例如1-(4-叔丁基苯基)-3-(4-甲氧基苯基)-丙烷-1,3-二酮;二苯基丙烯酸酯,例如2-乙基己基-2-氰基-3,3-二苯基丙烯酸酯和3-(苯并呋喃基)-2-氰基丙烯酸;3-咪唑-4-基丙烯酸和酯;苯并呋喃衍生物,例如2-(对-氨基苯基)苯并呋喃衍生物;聚合物UV吸收剂,例如丙二酸苯二甲基酯衍生物;肉桂酸衍生物,例如4-甲氧基肉桂酸2-乙基己基酯和异戊酯或肉桂酸衍生物;樟脑衍生物,例如3-(4'-甲基)亚苄基-樟脑-2-酮、3-亚苄基-樟脑-2-酮、N-[2(和4)-2-氧代亚龙脑-3-基-甲基)-苄基]]丙烯酰胺聚合物、3-(4'-三甲基铵)-亚苄基-樟脑-2-酮硫酸甲酯、3,3'-(1,4-亚苯基二次甲基)-双(7,7-二甲基-2-氧代-二环[2,2,1]庚烷-1-甲磺酸)和盐、3-(4'-磺基)亚苄基-樟脑-2-酮和盐;樟脑苯甲烃铵甲硫酸酯;羟基苯基三嗪化合物,例如2-(4'-甲氧基苯基)-4,6-双(2'-羟基-4'-正-辛氧基苯基)-1,3,5-三嗪;2,4-双{[4-(3-(2-丙氧基)-2-羟基-丙氧基)-2-羟基]-苯基}-6-(4-甲氧基苯基)-1,3,5-三嗪;2,4-双{[4-(2-乙基-己氧基)-2-羟基]-苯基}-6-[4-(2-甲氧基乙基-羧基)-苯基氨基]-1,3,5-三嗪;2,4-双{[4-(三(三甲基甲硅烷氧基-甲硅烷基丙氧基)-2-羟基]-苯基}-6-(4-甲氧基苯基)-1,3,5-三嗪;2,4-双{[4-(2"-甲基丙烯氧基)-2-羟基]-苯基}-6-[(4-甲氧基苯基)-1,3,5-三嗪;2,4-双{[4-(1',1',1',3',5',5',5'-七甲基三甲硅烷基-2"-甲基-丙氧基)-2-羟基]-苯基}-6-(4-甲氧基苯基)-1,3,5-三嗪;2,4-双{[4-(3-(2-丙氧基)-2-羟基-丙氧基)-2-羟基]-苯基}-6-[4-乙基羧基)-苯氨基]]-1,3,5-三嗪;苯并三唑化合物,例如2,2'-亚甲基-双(6-(2H-苯并三唑-2-基)-4-(1,1,3,3--四甲基丁基)-苯酚;三苯胺基-s-三嗪衍生物,例如2,4,6-三苯胺-(对-羰-2'-乙基-1'-氧基)-1,3,5-三嗪;2-苯基苯并咪唑-5-磺酸及其盐;薄荷基-o-氨基苯甲酸酯;物理防晒剂涂覆或未涂覆的,例如二氧化钛、氧化锌、氧化铁、云母、MnO、Fe2O3、Ce2O3、Al2O3、ZrO2(表面涂层:聚甲基丙烯酸甲酯、聚甲基硅氧烷(甲基氢聚硅氧烷)、聚二甲基硅氧烷、三异硬脂酸钛异丙酯、金属皂例(如硬脂酸镁)、全氟醇磷酸酯(如C9-15氟代醇磷酸酯))。
UVA吸收剂的实例包括但不限于,阿伏苯宗(Parsol 1789)、bisdisulizoledisodium(Neo Heliopan AP)、二乙氨基-羟基-苯甲酰基-苯甲酸己酯(Uvinul A Plus)、依莰舒(Mexoryl SX)以及邻氨基苯甲酸甲酯。
UVB阻断剂的实例包括但不限于,4-氨基苯甲酸(PABA)、西诺沙酯、乙基己基三嗪酮(Uvinul T 150)、胡莫柳酯、4-甲基亚苄基樟脑(Parsol 5000)、甲氧基肉桂酸辛酯(奥西诺酯)、水杨酸辛酯(奥替柳酯)、帕地马酯O(Escalol 507)、苯基苯并咪唑磺酸(恩索利唑)、聚硅酮-15(Parsol SLX)以及水杨酸三乙醇胺。
阻断UVA和UVB二者的试剂的实例包括但不限于,双-乙基己氧苯酚甲氧苯基三嗪(bemotrizinol)(Tinosorb S)、二苯甲酮1-12、氧苯酮(ioxybenzone)、苯并三唑基甲基苯酚三硅氧烷(Mexoryl XL)、二乙基己基丁酰胺基三嗪酮(iscotrizinol)(Uvasorb HEB)、氰双苯丙烯酸辛酯、氧苯酮(oxybenzone)(Eusolex 4360)、磺异苯酮、混合物(化学/物理):比索曲唑(bisoctrizole)(Tinosorb M)、二氧化钛以及氧化锌。
此外,防晒组合物还可包括佐剂和添加剂,如防腐剂、有机溶剂、褐变剂、抗氧化剂、稳定剂、润肤剂、硅酮、α-羟基酸、缓和剂、消泡剂、润湿剂、维生素、芳香剂、离子或非离子型增稠剂、表面活性剂、填充剂、增稠剂、螯合剂、聚合物、推进剂、碱化剂或酸化剂、遮光剂、脂肪化合物(例如,油、蜡、醇、酯、脂肪酸)、着色剂或其混合物或者可用于生产防晒组合物的任何其它成分。
本发明的防晒组合物可为水溶液、乳液(水包油或油包水)、水醇媒剂、膏棒、软膏、凝胶、气溶胶(泡沫、喷雾推进泵等)的形式。
在本发明的另一个实施方案中,本文所定义化合物可配制在化妆品和/或个人护理产品中。所述化合物可以制剂或组合物重量的约0.2%至约30%,更优选地为制剂或组合物重量的约1%至约15%的量并入到化妆品和/或个人护理产品制剂或组合物中。
本发明的化合物可被包括在用于制备化妆产品的制品中,所述化妆产品如彩妆,例如隔离霜、眼部护理制品、眼影制剂、睫毛膏、眼线膏、眼霜或定眼霜;唇部护理制品,例如唇膏、润唇膏、唇线笔;指甲护理制品,如指甲油、指甲油清洗剂、指甲硬化剂或角质层去除剂。这些产品根据本领域的已知方法配制。
本发明的化合物还可配制到个人护理产品中,如片形或液体皂形式的皮肤清洗和清洁制品、清洁剂或洗涤膏、浴用制品,例如液体(泡沫浴、牛奶、淋浴制品)或固体沐浴制品,例如洗浴香精块和浴用盐;皮肤护理制品,例如皮肤乳液、多元乳液或皮肤油脂;化妆品个人护理制品,例如日霜或粉霜形式的面部化妆品、搽脸粉(松装或压装);足部护理制品,例如足浴、足粉、护脚膏或香脚液、特殊除臭剂和止汗药或去斑制品(callus-removingpreparation);防晒制品,如防晒乳、洗液、乳膏或油、晒前制品或晒后制品;皮肤晒黑制品,例如自晒面霜;脱色制品,例如用于漂白皮肤的制品或皮肤增白制品;驱虫剂,例如驱虫油、洗液、喷雾剂或棒剂;除臭剂,例如除臭喷雾剂、泵作用喷雾剂、除臭凝胶、棒或滚球;止汗剂,例如止汗棒剂、霜或滚球;用于清洁和护理有瑕疵皮肤的制品,例如合成洗涤剂(固体或液体)、去皮或擦洗制品或剥离面膜;化学形式的脱发制品(脱毛),例如脱毛粉、液体脱毛制品、膏状或糊状脱毛制品、凝胶或气溶胶泡沫形式的脱毛制品;剃须制品,例如,剃须皂、泡沫剃须膏、非泡沫剃须膏、泡沫和凝胶、用于干式剃须的剃须前制品、须后水或须后洗液;香料制品,例如香料、芳香油或香料乳膏;化妆品毛发处理制品,例如洗发剂和调理剂形式的洗发制品、护发制品(例如预处理制品、生发油、定型膏、定型凝胶、润发油、头发漂洗剂、疗发包、强力毛发处理剂)、头发结构化制品(例如,用于长效波浪(热波浪、温和波浪、冷波浪)的卷发制品)、直发制品、头发定型液体制品、头发泡沫、头发定型剂、漂白制品(例如,过氧化氢溶液、增亮洗发剂、漂白乳膏、漂白粉、漂白糊或油)、临时、半永久或永久染发剂、含有自氧化染料的制品或天然染发剂(例如,指甲花染料或甘菊)。这些产品根据本领域的已知方法配制。
如本文所定义的化合物还可并入到用于保护毛发(人或动物的毛发)抵抗光化学损害的制剂中,以便防止彩色色调改变、褪色或机械性质的损害。
除本文所定义的化合物之外,化妆品制剂可包含在这种类型的组合物中使用的各种佐剂,例如表面活性剂、增稠剂、聚合物、软化剂、防腐剂、泡沫稳定剂、电解质、有机溶剂、硅酮衍生物、抗油剂、给组合物或毛发本身染色的染料和/或颜料、或通常用于头发护理的其它成分。
本发明的化合物也可包括在药物制剂和/或组合物中。这些制剂和/或组合物根据本领域的已知方法制备。
包含本发明的化合物的软膏、糊剂、霜剂以及凝胶剂可包括一种或多种载体,例如但不限于,动物和植物油脂、蜡、石蜡、淀粉、黄蓍胶、纤维素衍生物、聚乙二醇、硅酮、膨润土、二氧化硅、滑石和氧化锌或者这些物质的混合物。粉剂和喷雾剂可包含载体,例如但不限于,乳糖、滑石、二氧化硅、氢氧化铝、硅酸钙和聚酰胺粉末或这些物质的混合物;推进剂,例如但不限于氯氟烃、丙烷/丁烷或二甲醚。溶液和乳液可包含载体,例如但不限于,溶剂、溶解度促进剂和乳化剂,例如水、乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苄醇、苯甲酸苄酯、丙二醇、1,3-丁基二醇、油(具体地为棉籽油、花生油、小麦胚芽油、橄榄油、蓖麻油以及芝麻油)、甘油脂肪酸酯、聚乙二醇和山梨聚糖的脂肪酸酯或这些物质的混合物。肥皂可包含载体,例如但不限于,脂肪酸的碱金属盐、脂肪酸单酯的盐、脂肪酸蛋白质水解液、羟乙基磺酸盐、羊毛脂、脂肪醇、植物油、植物提取物、甘油、糖或这些物质的混合物。护肤油和护体油可包含载体物质,例如但不限于,合成油,如脂肪酸酯、脂肪醇、硅油、天然油(如植物油和含油植物提取物)、石蜡油、羊毛脂油或这些物质的混合物。
本发明的化合物也可配制用于局部施用。如本文所用的术语“局部”包括使化合物能够布置于皮肤或黏膜组织的任何施用路径。
本发明的制剂和组合物还提供针对皮肤老化过程以及针对氧化应激、针对由自由基(例如,如通过太阳照射、热量或其它影响因素产生的)引起的损害的保护。
本发明的化合物以及本发明的制剂和组合物可用于制备和制造用于防止对皮肤的损害的药物,所述损害例如但不限于,晒伤和太阳引起的红斑。
根据本发明的化妆品或药物制剂和/或组合物也可包含一种或多种另外的化合物,例如但不限于:醇、多醇、脂肪醇、脂肪酸酯、天然或合成的甘油三酸酯(包括甘油酯和衍生物)、珠光蜡、烃油、硅酮或硅氧烷、氟化或全氟化油、乳化剂、表面活性剂、聚合物、脱臭活性成分、抗氧化剂、水溶助长剂、防腐剂和细菌抑制剂、香料、着色剂、防腐剂、杀菌剂和抑菌剂、香料、染料、颜料、增稠剂、增湿剂、湿润剂、脂肪、油、蜡、聚合物、电解质、有机溶剂、硅衍生物、润肤剂、乳化剂或乳化表面活性剂、表面活性剂、分散剂、抗氧化剂、抗刺激剂以及抗炎剂。
在本发明的制剂和/或组合物中可包含的乳化剂的实例包括但不限于,椰油酰葡糖苷、椰油酰葡糖苷/鲸蜡硬脂醇、椰油酰基乙基葡糖苷、椰油基-葡糖苷柠檬酸二钠、月桂基葡糖苷、椰油基葡糖苷基磺基琥珀酸二钠、月桂酰基乙基葡糖苷、豆蔻酰基乙基葡糖苷、辛基二甲基硅氧烷乙氧基葡萄糖苷、油酰基乙基葡糖苷、椰油基-葡糖苷酒石酸钠、丁基化PVP、鲸蜡醇、丙烯酸钠/丙烯酰二甲基牛磺酸钠共聚物、萘二甲酸二乙基己酯、脱水山梨糖醇油酸酯、脱水山梨糖醇倍半油酸酯、脱水山梨糖醇异硬脂酸酯、失水山梨糖醇三油酸酯、聚甘油基-3-二异硬脂酸酯、油酸/异硬脂酸的聚甘油酯、聚甘油基-6六蓖麻醇酸酯、聚甘油基-4-油酸酯、聚甘油基-4-油酸酯/PEG-8丙二醇椰油酸酯、油酰胺DEA、油酸甘油酯磷酸钠、氢化植物甘油磷酸酯、丁基化PVP、鲸蜡醇、丙烯酸钠/丙烯酰二甲基牛磺酸钠共聚物、萘二甲酸二乙基己酯、硬脂酰谷氨酸钠(如SG、N-硬脂酰L-谷氨酸钠、二辛基十二烷硬脂酰谷氨酸盐、TEA椰油酰基谷氨酸盐、TEA-月桂酰谷氨酸盐、TEA-硬脂酰谷氨酸、硬脂酰谷氨酸铝、谷氨酸一钠、谷氨酸二钠)以及其任何混合物。
在其它实施方案中,本发明提供预防和/或处理生物材料使其免于有害日光作用的方法。具体地说,本发明提供一种用于防止对受试者如人的有害日光作用的方法。有害日光作用的实例包括但不限于,晒伤、炎症、黑素瘤、恶性黑素瘤、DNA损害、眼损害、红斑以及局部或系统免疫抑制。
在此实施方案的一个实施方式中,所述方法用于预防UV辐射对于受试者如人的有害作用;包括将含有本发明的化合物中的一种或多种的制剂和/或组合物应用于人受试者皮肤上的步骤。所述方法还可用于保护动物受试者的皮肤。
除另外指定之外,如本文所用的术语受试者的“治疗”是指治疗性治疗以及预防性和防御性措施。需要治疗的那些受试者包括已患有疾病或病症或病状的那些受试者以及其中预防疾病、病症或病状的那些受试者。需要治疗的受试者也为其中已发生所述病症、疾病或病状并且留下副作用或疤痕的那些受试者。治疗也是指施用有效于提高或减轻与疾病、病症或病状有关的症状的治疗性物质,以减小疾病、病症或病状的严重性或治愈疾病、病症或病状,或者防止疾病、病症或病状发生。
在本发明的另一个实施方案中,非生物材料(例如但不限于,制造的物品)可用包含本文所定义的化合物的制剂和/或组合物浸渍或者可用所述制剂和/或组合物覆盖。此类非生物材料的实例包括但不限于,窗和其它玻璃、有机玻璃、透明聚合物、塑料或类似产品、车挡风玻璃、太阳能面板、眼镜、体育用品、纺织品以及织物。用于在制造的物品上浸渍和/或涂覆本发明的制剂/或组合物的技术和方法为本领域已知的。
在本发明的另一个实施方案中,本文所定义的化合物可并入适合应用于非生物材料如制造的物品的表面上的组合物中。此类组合物包括但不限于:涂料、油漆、密封剂、粘合剂、染料、用于应用到织物上的组合物、用于应用到纺织品或纤维上的组合物、清漆、染色剂、着色组合物、阻燃涂料组合物、粘合剂、漆以及类似涂料。包含本发明的化合物的此类组合物防止对这些制造物品表面的过早光损害和光漂白。本发明的此类组合物可通过将本文所定义的化合物与任何另外的任选组分混合(或机械搅拌)以形成均质混合物来制备。这可通过本领域已知的任何常规混合方法来实现,所述方法的实例为刮刀、机械搅拌器、含有挡板和/或叶片的在线混合系统、动力在线混合器、均化器、转鼓滚筒、三辊磨机、σ形叶片式混合器、发酵面团混合器以及双辊磨机。
在此实施方案的一些实施方式中,本发明的化合物可应用于纺织品或织物上,以便防止这些纺织品或织物暴露于引起纺织品或织物老化和/或其结构和强度弱化的UV辐射。包含本发明的化合物的组合物可应用于纺织品或织物上。可选地或者在补充中,纺织品或织物可部分或全部浸入到包含本发明的化合物以及其它组分(如本文所讨论的)的溶液中。已应用本发明的化合物的纺织品或织物在本文中被称为“处理的纺织品”和“处理的织物”。处理的纺织品或处理的织物对于暴露于UV辐射的抵抗力可通过在UV暴露之后通过带状法测定处理的纺织品和处理的织物的此类性质来评定,所述性质例如但不限于,色牢度和抗断强度。用于测定处理的纺织品或处理的织物的这些性质的技术为本领域已熟知的。
本发明还包括一种减少对UV光敏感的化学物的降解的方法,所述方法包括将本发明的制剂和/或组合物应用于所述化学物。所述化学物为除草剂、杀虫剂、植物生长素、脱落酸、细胞分裂素、类胡萝卜素衍生物、多酚化合物、霉孢菌素氨基酸和或以上任一种的衍生物(混合物或纯制备物)。
在另一个实施方案中,本发明的化合物可并入到构成用于制造非生物材料的基础制剂的底物中。例如,本发明的化合物可并入到构成液体涂料或粉状涂料的基础制剂或者待使用常规塑料复合、模塑或挤压方法制造的物品的基础树脂的底物中。本发明的化合物可并入的底物包括各种各样的树脂和塑料材料,例如,聚烯烃、聚乙烯芳香烃、丙烯酸树脂、聚碳酸酯、聚酯、聚酰胺、聚酰亚胺、聚芳酯、聚砜、聚丁烯、聚丙烯、环氧树脂和聚卤乙烯树脂以及通常已知对暴露于紫外光辐射而引起的降解敏感的任何树脂。自然,必须做出并入此类底物中的本发明的化合物的选择,以使得在用于处理油漆、涂料、抛光剂(finish)或热塑性物品的温度下,本发明的化合物不会经受大量的降解或与制剂的任何其它成分的交叉反应。特定聚合树脂材料的代表性但非限制性的实例包括聚烯烃树脂,如聚乙烯和聚丙烯等;聚乙烯基芳族树脂,如聚苯乙烯及其共聚物和三元共聚物,如聚(苯乙烯-丙烯腈)和聚(苯乙烯-丁二烯-丙烯腈)等;丙烯酸树脂,如聚(丙烯酸)、聚(甲基丙烯酸)、聚(丙烯酸甲酯)、聚(甲基丙烯酸甲酯)等;聚碳酸酯树脂,如通过二羟基脂族和芳族单体如乙二醇、丙二醇、双酚A(即4,4'-异亚丙基二酚)等的光气化作用,或通过双酚A与碳酸二苯酯的碱催化酯交换反应来生产双酚A聚碳酸酯而获得的那些;聚酯树脂,如聚(对苯二甲酸乙烯酯)、聚(对苯二甲酸丁烯酯)等;聚酰胺树脂,如尼龙-6、尼龙-6,6等;环氧树脂,如聚(环氧氯乙醇/双酚A)等及其酯,例如通过聚(环氧氯乙醇/双酚A)与脂肪酸、松香酸、妥尔油酸或其混合物的酯化制备的环氧树脂酯;以及酚醛树脂,例如通过甲醛与苯酚、间苯二酚、甲酚、二甲苯酚、对叔丁基苯酚等的反应制备的那些酚醛树脂。
在其它实施方案中,本发明提供用于测定针对太阳光辐射进行保护的本发明的制剂和/或组合物的方法和技术。此类方法和技术包括但不限于,制剂和/或组合物的λmax的测量、SPF的测量、化合物稳定性的评定、耐水性的测量以及光敏感度的测量。
D)实施例
本发明的实施方案现在通过(但以非限制性方式)以下实施例进行说明。
实施例1
用于制备2-溴-5,5-二甲基-1,3-环己二酮中间体的合成方案:
在250mL圆底烧瓶中,经30min,将溴(28.5g,178.3mmol)在二氯甲烷(DCM)(20mL)中的溶液添加到0℃的双甲酮(25g,178.3mmol)在DCM(200mL)中的悬浮液中。所述悬浮液在5min之后变为溶液并且在10min之后变为悬浮液,然后在RT下将其搅拌18h。然后将悬浮液过滤,用DCM(50mL)和Hex(2x 150mL)洗涤,然后在真空下干燥2h。将固体悬浮于水(500ml)中并且在80℃下加热1小时,冷却至RT下,用水(2x 100mL)洗涤,然后在真空下干燥2h并且在真空炉中在60℃下干燥20h。
实施例2
用于制备(R)-6,6-二甲基-8-氧代-3,4,5,6,7,8-六氢-2H-苯并[b][1,4]噻嗪-3-羧酸中间体的合成方案:
在100mL圆底烧瓶中,将L-半胱氨酸(1.21g,10.04mmol)添加到2-溴-5,5-二甲基-环己-1,3-二酮(2g,9.13mmol)和吡啶(1.47mL,18.25mmol)在MeOH(30mL)中的溶液中。在RT下将悬浮液搅拌18h,然后浓缩。添加MeOH(20mL),以获得浆液,然后过滤并用MeOH(2x 5mL)洗涤。将包含产物的滤液浓缩。将浓缩的滤液与EA(2x 25mL)共沸。添加EA(20mL)并研磨30min,然后过滤,用EA(2x 15mL)洗涤并在真空下干燥1h。
实施例3
用于制备2-溴环己-1,3-二酮中间体的合成方案:
经30min的时段,将溴(34.6g,0.216mol)在DCM(20ml)中的溶液中缓慢添加到在0℃(冰浴)下并且在空气气氛下环己-1,3-二酮(25g,0.216mol)在DCM(70ml)中的悬浮液中。允许所述温度增加至RT并且添加50ml DCM以形成糊状的反应混合物。将所述反应混合物在RT下搅拌4h并且通过过滤收集固体,依次用DCM(50ml)和己烷(3x200ml)冲洗,并且进行风干。将固体悬浮于水(500ml)中并且将悬浮液搅拌并在80℃下加热1h,然后在RT下过夜。通过过滤收集固体,用水(1000ml)冲洗,风干并且在高真空下在55℃下干燥一天,以提供所需化合物(30.53g,0.160mol,74%产率)。表征:1H RMN(400MHz,CDCl3):δ(ppm)=2.62(t,J=6.5Hz,4H),2.62(五重峰,J=6.5Hz,2H)。MS(m/z):190.9-192.9[M+H]+。
实施例4
用于制备2-((3-氧代环己-1-烯-1-基)氨基)乙酸甲酯中间体的合成方案:
在90℃下将在氮气气氛下的环己-1,3-二酮(5g,43.25mmol)和甘氨酸甲酯盐酸盐(7.42g,58.51mmol)在甲苯(100ml)中的搅拌悬浮液加热5h,然后至RT。通过倾析去除液相(通过MS主要为3-甲氧基环己-2-烯酮),将粘性残余物(通过MS主要为2-(3-氧代环己-1-烯基氨基)-乙酸甲酯)溶解于水中,并且通过添加饱和碳酸氢钠水溶液将pH调整至7-8,并且用DCM(x7)提取。用无水硫酸镁干燥合并的有机层(DCM),过滤并且浓缩。通过Biotage(Snap100g柱,用超过30CV的MeOH/DCM:1/99至10/90洗脱,在254nm进行波长收集)纯化粗残余物。将所需的级分合并,浓缩并在高真空下干燥,以提供所需产物。表征:1H RMN(400MHz,DMSO-d6):δ(ppm)=7.36-7.20(m,1H),4.67(s,1H),3.87(d,J=5.9Hz,2H),3.66(s,3H),2.35(t,J=6.2Hz,2H),2.07(t,J=6.5Hz,2H),1.79(五重峰,J=6.2Hz,2H),MS(m/z):183.96[M+H]+。
实施例5
用于制备(R)-8-氧代-3,4,5,6,7,8-六氢-2H-苯并[b][1,4]噻嗪-3-羧酸中间体的合成方案:
在RT下并且在氮气气氛下将吡啶缓慢添加(8471,10.47mmol)到2-溴-环己-1,3-二酮(1g,5.24mmol)和L-半胱氨酸(698mg,5.76mmol)在无水MeOH(20ml)中的搅拌悬浮液中。在60℃下将反应混合物加热1h(通过MS完全转化),然后在RT下搅拌过夜,浓缩,用水稀释,并且振摇并超声一会儿。通过过滤收集固体(A),用水冲洗,风干并且在高真空下干燥。所述固体(A)(177mg)可溶于TFA中。将母液浓缩,并且以少量MeOH研磨并超声。通过过滤收集固体(B),用MeOH冲洗,风干并且在高真空下干燥,以提供作为乳白色固体的所需化合物(580mg,2.71mmol,51%产率)。表征:1H RMN(400MHz,DMSO-d6):(ppm)=13.15-12.80(m,1H),7.57(d,J=4.3Hz,1H),4.38(q,J=4.0Hz,1H),2.99(dd,J=12.9,4.3Hz,1H),2.80(dd,J=12.9,3.3Hz,1H),2.45(t,J=6.2Hz,2H),2.25-2.17(m,2H),1.87-1.76(m,2H)。MS(m/z):213.9[M+H]+。
实施例6
用于制备8-氧代-3,4,5,6,7,8-六氢-2H-苯并[b][1,4]噁嗪-3-羧酸甲酯中间体的合成方案:
在10min内,将丝氨酸甲酯盐酸盐(1.792g,11.52mmol)分批添加到在0℃下并且在氮气气氛下氢化钠(1.466g,36.645mmol,在矿物油中)在无水THF(30ml)中的搅拌悬浮液中。在10min之后,添加2-溴环己-1,3-二酮(2g,10.47mmol)在无水THF(20ml)中的悬浮液中。经3h,允许温度升温至RT,然后在之后2h添加无水DMF(10ml)。在RT下将反应混合物搅拌过夜,通过添加水、1N HCl(pH~1)淬火,并且用AcOEt分配。在分离之后,依次用水(x3)和盐水洗涤有机层,用无水硫酸镁干燥,过滤,并且浓缩,以提供含有矿物油的未反应起始材料。表征:1H RMN(400MHz,DMSO-d6):δ(ppm)=MS(m/z):[M+H]+。
实施例7
用于制备(R)-8-氧代-3,4,5,6,7,8-六氢-2H-苯并[b][1,4]噻嗪-3-羧酸甲酯和(3R)-8-氧代-3,4,5,6,7,8-六氢-2H-苯并[b][1,4]噻嗪-3-羧酸甲酯1-氧化物以及2-溴-3-甲氧基环己-2-烯酮中间体的合成方案:
在RT下将2-溴环己-1,3-二酮(3g,15.71mmol)和L-半胱氨酸(3.07g,17.89mmol)在无水MeOH(50ml)中的溶液搅拌1h(通过MS,完全转化为2-溴-3-甲氧基环己-2-烯酮),然后缓慢添加吡啶(2.54ml,31.41mmol)。在RT下将反应混合物搅拌过夜(通过MS,反应不完全,形成所需MW+氧化)。添加500mg L-半胱氨酸甲酯盐酸盐,并且在RT下将反应混合物搅拌过夜(通过MS,更多氧化)。将反应混合物浓缩,用水稀释,并且振摇并超声一会儿。通过过滤收集固体A,用水冲洗,风干(通过MS,主要为吡啶和2-溴-3-甲氧基环己-2-烯酮)。用饱和碳酸氢钠水溶液碱化母液(pH~9)并且用AcOEt提取。依次用饱和NaHCO3、饱和NH4Cl、水以及盐水洗涤有机层,用无水硫酸镁干燥,过滤并且浓缩。通过Biotage(SiliaFlash 80g柱,用超过30CV的MeOH/DCM:0/100至05/95洗脱)纯化粗残余物。合并所需级分,浓缩,并且在高真空下干燥,以提供2-溴-3-甲氧基环己-2-烯酮(682mg,3.33mmol,21%产率)。表征:1H RMN(400MHz,DMSO-d6):δ(ppm)=3.93(s,3H),2.80(t,J=6.2Hz,2H),2.44-2.37(m,2H),1.96-1.87(m,2H)。MS(m/z):204.8-206.8[M+H]+。
实施例8
用于制备3-((4-甲氧基苯基)氨基)-5,5-二甲基环己-2-烯酮和(E)-4-甲氧基-N-(3-((4-甲氧基苯基)氨基)-5,5-二甲基环己-2-烯-1-亚基)苯胺中间体的合成方案:
将草酰氯(601μl,7.10mmol)和无水DMF(3滴)缓慢添加到在0℃下并且在氮气气氛下3-甲氧基-5,5-二甲基环己-2-烯酮(1g,4.73mmol)在无水DCM(30ml)中的搅拌溶液中。在50min(通过TLC,几乎完全转化),添加更多草酰氯(50μl)。在20min之后,将反应混合物浓缩,溶解于无水DCM(30min)中,冷却至0℃下,并且分别添加4-甲氧基苯胺(612mg,4.97mmol)和三乙胺(1.98ml,14.20mmol)。在RT下将反应混合物搅拌过夜,浓缩,以乙醇(20ml)稀释,并且再次搅拌过夜。通过过滤收集固体,用乙醇冲洗并且风干[通过MS,3-(4-甲氧基苯基氨基)-5,5-二甲基环己-2-烯酮存在于母液中]。通过Biotage(Snap 25g柱,用超过30CV的MeOH/DCM:5/95至20/80洗脱)纯化粗残余物。将所需的级分合并,浓缩,以少量DCM研磨,过滤,用DCM冲洗,风干并且在高真空下干燥,以提供(E)-N,N’-(5,5-二甲基环己-1-烯-1-基-3-亚基)双(4-甲氧基苯胺)(198mg,0.51mmol,7.9%产率,HCl盐)。表征:1H RMN(400MHz,DMSO-d6):δ(ppm)=11.40-10.65(m,2H),AB系统(δA=7.19,δB=7.01,JAB=8.2Hz,8H),5.90-5.44(m,1H),3.76(s,6H),2.60(bs,4H),1.08(bs,6H)。MS(m/z):351.15[M+H]+HPLC:>97%UV:λmax~345nm(MeOH/水)。
实施例9
用于制备2-((3-氧代环己-1-烯-1-基)氨基)乙酸甲酯中间体的合成方案:
将浓硫酸(0.523ml,9.82mmol)添加到在氮气气氛下2-((3-氧代环己-1-烯-1-基)氨基酸)乙酸(1.51g,8.93mmol)在MeOH(30ml)中的搅拌溶液中。反应混合物变为溶液,并且在30min之后,将其在回流下加热4h,然后至RT。将反应混合物浓缩,用饱和碳酸氢钠水溶液中和(pH 8-9)并且用AcOEt分配。在分离之后,依次用饱和NaHCO3(x2)、水和盐水洗涤有机层。用二氯甲烷(6x)提取水层,并且用无水硫酸镁干燥合并的有机层,过滤并浓缩。通过Biotage(Snap 50g柱,用超过15CV的MeOH/DCM:0/100至03/97洗脱、然后用超过20CV的3/97至10/90洗脱)纯化粗残余物。将所需的级分合并,浓缩并在高真空下干燥,以提供所需产物(260mg,0.142mmol)。表征:1H RMN(400MHz,DMSO-d6):δ(ppm)=7.28(bt,J=5.9Hz,1H),4.66(s,1H),3.87(d,J=5.9Hz,2H),3.66(s,3H),2.35(t,J=6.1Hz,2H),2.07(t,J=6.5Hz,2H),1.79(五重峰,J=6.4Hz,2H),MS(m/z):183.9[M+H]+。
实施例10
用于制备2-(苄基(2-氧代丙基)氨基)乙酸乙酯中间体的合成方案:
在500mL圆底烧瓶中,将氯丙酮(12.97mL,163mmol)添加到50℃的N-苄基甘氨酸乙酯(30g,155mmol)和NaHCO3(14.34g,170mmol)在THF(333mL)/水(21mL)中的悬浮液中。在50℃下将所述悬浮液加热4H。添加氯丙酮(0.5eq,0.65ml)和NaHCO3(1.1eq,1.43g)并且在50℃下加热溶液达18h,并且然后浓缩。添加EA(100mL)和水(100mL)并且将层分离。用EA(2x50mL)、水(50mL)、盐水(50mL)进行提取,然后用Na2SO4干燥并且浓缩。1H NMR显示1/1的SM/产物比率。
实施例11
用于制备(E)-2-((3-((4-甲氧基苯基)氨基)环己-1-烯-1-基)氨基)乙酸中间体的合成方案:
将草酰氯(177μl,2.09mmol)和无水DMF(3滴)缓慢添加到在0℃下并且在氮气气氛下2-((3-氧代环己-1-烯-1-基)氨基)乙酸甲酯(255mg,1.39mmol)在无水DCM(20ml)中的搅拌溶液中。在1h之后,将反应混合物浓缩,冷却至0℃,溶解于异丙醇(15ml)中,并且添加4-甲氧基苯胺(171mg,1.39mmol)在异丙醇(5ml)中的溶液。在0℃下将反应混合物搅拌15min,在RT下搅拌3h,浓缩,并且在AcOEt与水+一些饱和NaHCO3之间分配。在分离之后,依次用饱和NaHCO3、水(x2)和盐水洗涤有机层。所需产物保留在水相中。用二氯甲烷(x9)提取水层(pH~9)并且浓缩合并的有机层(仅DCM)。将水层浓缩,悬浮于MeOH中,过滤,与粗残余物(来自DCM)合并,并且浓缩。通过Biotage(反相C18-Snap 30g柱,用超过50CV的MeOH/水:5/95至95/05洗脱,波长收集为254nm)。在纯化期间发生部分甲酯的水解。将所需的级分合并,在40℃下浓缩一半,用1N NaOH(10ml)处理,在40℃下浓缩,将其悬浮于MeOH中,过滤,浓缩,并且通过Biotage(反相C18-Snap 30g柱,用超过50CV的MeOH/水:5/95至95/05洗脱,波长收集为320nm)。将所需的级分合并,浓缩,并且在高真空下干燥,以提供作为浅褐色/浅棕色粉末的所需产物(114mg,0.416mmol,在三个步骤为30%产率)。表征:1H RMN(400MHz,CDCl3):δ(ppm)=互变异构体和/或同分异构体的混合物,一个H丢失,7.14-6.70(m,4H),5.80-5.00(2m,1H),3.86-3.30(m,6H),2.80-2.10(m,4H),1.93-1.54(m,2H)。MS(m/z):275.05[M+H]+HPLC:>98%UV:λmax~318nm(MeOH/水,二者均具有0.1%甲酸);范围为280nm至380nm。
实施例12
用于制备2-((5,5-二甲基-3-氧代环己-1-烯-1-基)氨基)乙酸甲酯和3-甲氧基-5,5-二甲基环己-2-烯酮中间体的合成方案:
在60-65℃下,在氮气气氛下,将双甲酮(5g,35.67mmol)和甘氨酸甲酯盐酸盐(4.926g,39.24mmol)在甲醇(50ml)中的搅拌溶液加热过夜,然后添加更多甘氨酸甲酯盐酸盐(4.926g,39.24mmol)。在70℃下将反应混合物加热几小时,将其浓缩,用水稀释,放置于冷冻器中一个周末,然后至RT,并且用AcOEt稀释。在分离之后,依次用水、饱和碳酸氢钠水溶液和盐水洗涤有机层。用AcOEt提取水层一次,并且之后用水和盐水洗涤。用无水硫酸镁干燥合并的有机层,过滤并浓缩。在下一个步骤中使用粗产物(3-甲氧基-5,5-二甲基环己-2-烯酮,4.581g)而无需任何另外的纯化。表征:1H NMR(400MHz,DMSO-d6):δ(ppm)=5.31(s,1H),3.67(s,3H),2.28(s,2H),2.11(s,2H),0.97(s,6H)。MS(m/z):154.93[M+H]和211.97(痕量)。
实施例13
用于制备(R)6,6-二甲基-8-氧代-3,4,5,6,7,8-六氢-2H-苯并[b][1,4]噻嗪-3-羧酸乙酯中间体的合成方案:
在500mL圆底烧瓶中,将L-半胱氨酸乙酯HCl(10.47g,56.38mmol)添加到2-溴-5,5-二甲基-环己-1,3-二酮(11.23g,11.23mmol)和吡啶(12.43mL,153.7mmol)在MeOH(170mL)中的溶液中。在RT下将溶液搅拌2.5天,并且将其浓缩。添加EA(100mL)、水(100mL)和HCl 1N(75mL)。然后将层分离。用EA(2x 100mL)、盐水(50mL)进行提取,用Na2SO4干燥溶液,并且然后浓缩。
实施例14
用于制备(R)8-氯-6,6-二甲基-3,5,6,7-四氢-2H-苯并[b][1,4]噻嗪-3-羧酸乙酯中间体的合成方案:
在100mL圆底烧瓶中,将(COCl)2(4.11ml,48.59mmol)添加到(R)-6,6-二甲基-8-氧代-3,4,5,6,7,8-六氢-2H-苯并[b][1,4]噻嗪-3-羧酸乙酯(11.9g,44.17mmol)在DCM(100mL)中的溶液中。在冷却至-78℃之后,将DMF(2滴)添加到-78℃的溶液中。在-78℃ 1h之后,经1h将溶液升温至0℃并且在0℃下搅拌2h。添加水(100mL)并且分离各层。用DCM(2x50mL)、NaHCO3(50mL)、盐水(50mL)进行提取,用Na2SO4干燥溶液并且将其浓缩。通过Biotage(超过30CV的Hex中的0至30%EA;100g柱)纯化残余物。
实施例15
用于制备(R)8-((4-甲氧基苯基)氨基)-6,6-二甲基-3,5,6,7-四氢-2H-苯并[b][1,4]噻嗪-3-羧酸乙酯中间体的合成方案:
在250mL圆底烧瓶中,将对-甲氧基苯胺(673mg,5.47mmol)添加到(R)8-氯-6,6-二甲基-3,5,6,7-六氢-2H-苯并[b][1,4]噻嗪-3-羧酸乙酯(1.5g,5.21mmol)在EtOH(50mL)中的溶液中。在RT下将溶液搅拌20h,并且浓缩。添加DCM(100ml)、水(100mL)和NaHCO3(50mL),分离各层。用DCM(2x 100mL)提取,用Na2SO4干燥并且浓缩。通过Biotage(超过20CV的DCM中的0至5%MeOH;100g柱)纯化残余物。
实施例16
用于制备(R)-8-((4-甲氧基苯基)氨基)-6,6-二甲基-3,5,6,7-四氢-2H-苯并[b][1,4]噻嗪-3-羧酸中间体的合成方案:
在250mL圆底烧瓶中,将NaOH 1M(10mL,10mmol)添加到(R,E)-8-((4-甲氧基苯基)亚氨基)-6,6-二甲基-3,4,5,6,7,8-六氢-2H-苯并[b][1,4]噻嗪-3-羧酸乙酯(0.5g,1.73mmol)在MeOH(20mL)/THF(20mL)的混合物中的溶液中。在RT下将溶液搅拌1h,并且浓缩。添加水(40mL)和HCl 1M(~30mL),以便pH 7,将其浓缩。与EtOH(2x 40mL)共沸。以EtOH(30mL)研磨10min,过滤,用EtOH(2x 10mL)洗涤。丢弃白色固体的盐。浓缩滤液。通过Biotage(超过60CV的H2O中的20%至95%MeOH;30g KP-C18-HS柱)纯化残余物。
实施例17
用于制备2-((3-氧代环己-1-烯-1-基)氨基)乙酸中间体的合成方案:
在500ml圆底烧瓶中,将甘氨酸(2.28g,30.41mmol)添加到1,3-环己二酮(3.10g,27.64mmol)在MeOH(200mL)中的悬浮液中。在60℃下将悬浮液加热19h。在冷却至RT之后,将悬浮液浓缩并以MeOH(40mL)研磨1h,过滤,用MeOH(2x 10mL)洗涤并且在真空下干燥4h,以得到可溶于水、不溶于丙酮、MeOH并且稍微溶于DMSO的3.56g淡黄色固体。
实施例18
用于制备3-((4-甲氧基苯基)氨基)环己-2-烯酮中间体的合成方案:
在500mL圆底烧瓶中,将对-甲氧基苯胺(800mg,6.50mmol)添加到2-((3-氧代环己-1-烯-1-基)氨基)乙酸(1.00g,5.91mmol)在甲苯(100mL)中的悬浮液中。在回流下用迪安斯塔克装置(dean stark apparatus)将悬浮液加热19h。在冷却至RT之后,将悬浮液过滤,用甲苯(2x 10mL)洗涤,并且在真空下干燥4h。
实施例19
在500mL圆底烧瓶中,将对-甲氧基苯胺(800mg,6.50mmol)添加到2-((3-氧代环己-1-烯-1-基)氨基)乙酸(1.00g,5.91mmol)在对-TSA.H2O(1.12g,5.91mmol)中的悬浮液中。在回流下将悬浮液加热1h。在冷却至RT之后,添加DCM(50mL)、水(100mL)和NH4C1(25mL)。分离所得的层。用DCM(2x 50mL)进行提取。用Na2SO4干燥提取的部分并进行浓缩。通过Biotage(超过20CV的DCM中的0%至10%MeOH;25g柱)纯化残余物。
实施例20
用于制备(R)6,6-二甲基-8-氧代-3,4,5,6,7,8-六氢-2H-苯并[b][1,4]噻嗪-3-羧酸乙酯的合成方案:
在20℃至40℃下,将溴(31.96g,1.0equiv)逐滴添加到双甲酮(43.82g,1.0当量)在392mL AcOH(14体积)中的混合物中。在溴添加期间固体沉淀。在添加之后,将所得悬浮液在约30℃下保持另外约4小时,直到没有双甲酮留下为止。通过抽吸过滤悬浮液,用140mLMTBE(2×5体积)将滤饼洗涤两次,然后收集滤饼并且在50℃下在真空炉中干燥约8小时,以得到作为白色固体的35.1g 2-溴-5,5-二甲基-环己-1,3-二酮。分离的产率为80.1%,纯度为97.4%。将吡啶(31.64g,2.0当量)一次性地加入到2-溴-5,5-二甲基-环己-1,3-二酮(43.82g,1.0当量)和L-半胱氨酸乙酯(32.83g,1.1当量)在350mLTHF(8体积)中的搅拌溶液中。在添加之后,在N2下将反应混合物回流(65℃~70℃)约4小时。将反应混合物冷却并浓缩至干燥。用甲醇(131mL,3体积)稀释残余物并且将溶液倒入冷水(394mL,9体积)中同时搅拌。将所得悬浮液在20℃~30℃保持另外1小时。通过抽吸过滤悬浮液,收集滤饼并在70℃至80℃下将其重新溶解于53mL EA(53mL)中。将溶液冷却至0℃~10℃并且在此温度下将其保另外1小时。通过抽吸过滤悬浮液,用10mL冷EA(0.2体积)洗涤滤饼。收集滤饼并且在45℃以下在真空炉中将其干燥至少4小时,以得到(R)-6,6-二甲基-8-氧代-3,4,5,6,7,8-六氢-2H-苯并[b][1,4]噻嗪-3-羧酸乙酯。
实施例21
将二氧化铜和N-甲基吡啶(1当量)添加到5-溴-2-硝基苯酚在二乙胺中的溶液中,在110℃下将混合物加热20h;进行处理和柱纯化,得到30%产率的5-(二乙基氨基)-2-硝基苯酚。然后使用乙醇中的Pd/C上的氢进行5-(二乙基氨基)-2-硝基苯酚的还原,以得到定量产率的2-氨基-5-(二乙基氨基)苯酚。
实施例22
用于式IE2化合物的合成方案:
在-10℃~0℃下冷却(R)-6,6-二甲基-8-氧代-3,4,5,6,7,8-六氢-2H-苯并[b][1,4]噻嗪-3-羧酸乙酯和3滴DMF在二氯甲烷(11mL,20体积)中的混合物。将草酰氯(0.51g,2.0当量)逐滴添加到-10℃~0℃的混合物中。在搅拌的情况下,将混合物在-10℃~0℃下保持另外1小时。在减压下浓缩溶液,以得到(R)-8-氯-6,6-二甲基-3,5,6,7-四氢-2H-苯并[b][1,4]噻嗪-3-羧酸乙酯。用乙醇(11mL,20体积)稀释残余物,将苯胺(0.37g,2.0当量)添加到8-氯-6,6-二甲基-3,5,6,7-四氢-2H-苯并[b][1,4]噻嗪-3-羧酸乙酯溶液中。在搅拌的情况下,将所得的混合物在20℃~30℃下保持20小时。在40℃~50℃下在减压下浓缩溶液,通过柱色谱法(流动相:DCM/MeOH=100/1—20/1)纯化残余物,以得到(E)-6,6-二甲基-8-(苯基亚氨基)-3,4,5,6,7,8-六氢-2H-苯并[b][1,4]噻嗪-3-羧酸乙酯。将3.6mL 1NNaOH水溶液添加到所得的化合物(0.4g,1.0当量)在THF(4mL)和乙醇(4mL,3体积)中的混合物中,同时搅拌。将混合物在20℃~30℃下保持1~2小时。用1N HCl水溶液中和混合物以便pH=~7,在减压下浓缩混合物。通过柱色谱法(流动相:DCM/MeOH=50/1-5/1)纯化残余物,以得到(E)-6,6-二甲基-8-(苯基亚氨基)-3,4,5,6,7,8-六氢-2H-苯并[b][1,4]噻嗪-3-羧酸。
实施例23
用于式IF1化合物的合成方案:
在-10℃~0℃下冷却(R)-6,6-二甲基-8-氧代-3,4,5,6,7,8-六氢-2H-苯并[b][1,4]噻嗪-3-羧酸乙酯(1.5g,1.0当量)和3滴DMF在二氯甲烷(15mL,10体积)中的混合物。将草酰氯(1.4g,2.0当量)逐滴添加到-10℃~0℃的混合物中,将所述混合物在-10℃~0℃下保持另外1小时同时搅拌。在减压下在NMT 40℃下浓缩溶液,以得到(R)-8-氯-6,6-二甲基-3,5,6,7-四氢-2H-苯并[b][1,4]噻嗪-3-羧酸乙酯。用乙醇(15mL,10体积)稀释残余物,将EK-B7(1.7g,2.0当量)添加到(R)-8-氯-6,6-二甲基-3,5,6,7-四氢-2H-苯并[b][1,4]噻嗪-3-羧酸乙酯溶液,将所得混合物在20℃~30℃下保持20小时同时搅拌。在40℃~50℃下在减压下浓缩溶液,通过柱色谱法(流动相:DCM/MeOH=100/1-20/1)纯化残余物,以得到(E)-8-((3,4-二甲氧基苯基)亚氨基)-6,6-二甲基-3,4,5,6,7,8-六氢-2H-苯并[b][1,4]噻嗪-3-羧酸乙酯。将1N NaOH水溶液添加到(E)-8-((3,4-二甲氧基苯基)亚氨基)-6,6-二甲基-3,4,5,6,7,8-六氢-2H-苯并[b][1,4]噻嗪-3-羧酸乙酯(1.0g,1.0当量)在THF(5mL)和乙醇(5mL,5体积)中的混合物中,将混合物在20℃~30℃下保持1~2小时。用1N HCl水溶液中和混合物以便pH=~7,并且在减压下浓缩混合物。通过柱色谱法(流动相:DCM/MeOH=50/1-5/1)纯化残余物,以得到化合物IF1。
实施例24
用于式ID2化合物的合成方案:
将TEA(4.0g,2.8当量)添加到双甲酮(2.0g,1.0当量)、甘氨酸乙酯(1.9g,1.3当量)和60mL甲苯(30体积)的混合物中,同时搅拌。将所得混合物回流过夜。将水(20mL)添加到反应混合物中,用乙酸乙酯(30mL*2)提取两次,用盐水(20mL)洗涤合并的有机层,并且然后在减压下浓缩,以得到(R)-6,6-二甲基-8-氧代-3,4,5,6,7,8-六氢-2H-苯并[b][1,4]噻嗪-3-羧酸乙酯。分离的产率为90.6%,纯度为77.8%。在-10℃~0℃下冷却(R)-6,6-二甲基-8-氧代-3,4,5,6,7,8-六氢-2H-苯并[b][1,4]噻嗪-3-羧酸乙酯(2.5g,1.0当量)和3滴DMF在二氯甲烷(50mL,20体积)中的混合物。将草酰氯(2.82g,2.0当量)逐滴添加到-10℃~0℃的混合物中,将所述混合物在-10℃~0℃下保持另外1小时同时搅拌。在减压下浓缩溶液,以得到2-((3-氯-5,5-二甲基环己-1,3-二烯-1-基)氨基)乙酸乙酯。用乙醇(50mL,20体积)稀释残余物,将苯胺(2.73g,2.0当量)添加到2-((3-氯-5,5-二甲基环己-1,3-二烯-1-基)氨基)乙酸乙酯溶液中,将所得溶液在20℃~30℃下保持20小时,同时搅拌。在减压下浓缩溶液。通过柱色谱法(流动相:DCM/MeOH=100/1-20/1)纯化残余物,以得到(E)-2-((3-((4-甲氧基苯基)亚氨基)-5,5-二甲基环己-1-烯-1-基)氨基)乙酸乙酯。将18mL 1N NaOH水溶液添加到(E)-2-((3-((4-甲氧基苯基)亚氨基)-5,5-二甲基环己-1-烯-1-基)氨基)乙酸乙酯(1.2g,1.0当量)在THF(12mL)和乙醇(12mL)中的混合物中,同时搅拌,将混合物在20℃~30℃下保持1~2小时。用1N HCl水溶液中和混合物以便pH=~7,并且在40℃~50℃下在减压下浓缩混合物。通过柱色谱法(流动相:DCM/MeOH=50/1-5/1)纯化残余物,以得到化合物ID2。
实施例25
用于式ID3化合物的合成方案:
将EA(5.0g,2.8当量)添加到1,3-环己二酮(2.0g,1.0当量)、甘氨酸乙酯(2.4g,1.3当量)和60mL甲苯(30体积)的混合物中,同时搅拌,将混合物回流过夜。通过添加水(20mL)淬火反应,并且用乙酸乙酯(30mL*2)提取两次。用盐水(20mL)洗涤合并的有机层并且然后在减压下浓缩,以得到2-((3-氧代环己-1-烯-1-基)氨基)乙酸乙酯。可在下一个步骤中直接使用粗产物。在-10℃~0℃下冷却2-((3-氧代环己-1-烯-1-基)氨基)乙酸乙酯(2.3g,1.0当量)和3滴DMF以及二氯甲烷(46mL,20体积)的混合物。将草酰氯(3.0g,2.0当量)逐滴添加到-10℃~0℃的混合物中,将所述混合物在-10℃~0℃下保持另外1小时同时搅拌。在减压下浓缩溶液,以得到2-((3-氯环己-1,3-二烯-1-基)氨基)乙酸乙酯。用乙醇(46mL,20体积)稀释以上残余物,将4-甲氧基苯胺(2.9g,2.0当量)添加到2-((3-氯环己-1,3-二烯-1-基)氨基)乙酸乙酯溶液中,将所得溶液在20℃~30℃下保持20小时,同时搅拌。在减压下浓缩溶液。通过柱色谱法(流动相:DCM/MeOH=100/1-20/1)纯化残余物,以得到1.7g(E)-2-((3-((4-甲氧基苯基)亚氨基)环己-1-烯-1-基)氨基)乙酸乙酯。将28mL 1NNaOH水溶液添加到(E)-2-((3-((4-甲氧基苯基)亚氨基)环己-1-烯-1-基)氨基)乙酸乙酯(1.7g,1.0当量)在THF(17mL)和乙醇(17mL)中的混合物中,同时搅拌,将混合物在20℃~30℃下保持1~2小时。用1N HCl水溶液中和混合物以便pH=~7,在减压下浓缩混合物。通过柱色谱法(流动相:DCM/MeOH=50/1-5/1)纯化残余物,以得到化合物ID3。
实施例26
用于式IE1化合物的合成方案:
在-10℃~0℃下冷却6,6-二甲基-8-氧代-3,4,5,6,7,8-六氢-2H-苯并[b][1,4]噻嗪-3-羧酸酯(2.0g,1.0当量)、3滴DMF以及二氯甲烷(20mL,10体积)的混合物。将草酰氯(1.9g,2.0当量)逐滴添加到-10℃~0℃的混合物中,将所得的混合物在-10℃~0℃下保持另外1小时,同时搅拌。在减压下浓缩溶液,以得到(R)-8-氯-6,6-二甲基-3,5,6,7-四氢-2H-苯并[b][1,4]噻嗪-3-羧酸乙酯。用乙醇(20mL,10体积)稀释残余物,将4-氨基-N-(叔丁基)苯甲酰胺(2.8g,2.0当量)添加到(R)-8-氯-6,6-二甲基-3,5,6,7-四氢-2H-苯并[b][1,4]噻嗪-3-羧酸乙酯溶液中。将混合物在20℃-30℃下在N2下保持20小时,同时搅拌。在40℃~50℃下在减压下浓缩溶液,通过柱色谱法(流动相:DCM/MeOH=100/1-20/1)纯化残余物,以得到(E)-8-((4-(叔丁基氨基甲酰)苯基)亚氨基)-6,6-二甲基-3,4,5,6,7,8-六氢-2H-苯并[b][1,4]噻嗪-3-羧酸乙酯。在20℃~30℃下,将1N NaOH水溶液添加到(E)-8-((4-(叔丁基氨基甲酰)苯基)亚氨基)-6,6-二甲基-3,4,5,6,7,8-六氢-2H-苯并[b][1,4]噻嗪-3-羧酸乙酯(0.8g,1.0当量)在THF(4mL)和乙醇(4mL,3体积)中的搅拌溶液中,将所得溶液在此温度下保持另外1~2小时。用1N HCl水溶液中和混合物以便pH=~7,在减压下浓缩所得的溶液。通过柱色谱法(流动相:DCM/MeOH=50/1-5/1)纯化残余物,以得到化合物IE1。
实施例27
用于式IA2化合物的合成方案
在-10℃~0℃下冷却6,6-二甲基-8-氧代-3,4,5,6,7,8-六氢-2H-苯并[b][1,4]噻嗪-3-羧酸酯(0.54g,1.0当量)和3滴DMF在二氯甲烷(10mL)中的混合物。将草酰氯(0.51g,2.0当量)逐滴添加到-10℃~0℃的混合物中,将所述混合物在-10℃~0℃下保持另外1小时同时搅拌。在减压下浓缩溶液,以得到作为黄色油的(R)-8-氯-6,6-二甲基-3,5,6,7-四氢-2H-苯并[b][1,4]噻嗪-3-羧酸乙酯。用乙醇(11mL,20体积)稀释残余物,将2-氨基-5-甲氧基苯甲酸甲酯(0.72g,2.0当量)添加到(R)-8-氯-6,6-二甲基-3,5,6,7-四氢-2H-苯并[b][1,4]噻嗪-3-羧酸乙酯溶液中,将所得的混合物在20℃~30℃下保持20小时同时搅拌。在减压下浓缩溶液。通过柱色谱法(流动相:DCM/MeOH=100/1-20/1)纯化残余物,以得到(E)-2-((3-((2-乙氧基-2-氧代乙基)氨基)-5,5-二甲基环己-2-烯-1-亚基)氨基)-5-甲氧基苯甲酸甲酯。将1N NaOH水溶液添加到(E)-2-((3-((2-乙氧基-2-氧代乙基)氨基)-5,5-二甲基环己-2-烯-1-亚基)氨基)-5-甲氧基苯甲酸甲酯(0.45g,1.0当量)在THF(4.5mL)和乙醇(4.5mL)中的混合物中,同时搅拌,将所述混合物在20℃~30℃下保持1-2小时。用1N HCl水溶液中和混合物以便pH=~7,并且在减压下浓缩混合物。通过柱色谱法(流动相:DCM/MeOH=50/1-5/1)纯化残余物,以得到化合物IA2。
实施例28
用于式IE4化合物的合成方案
在-10℃~0℃下冷却6,6-二甲基-8-氧代-3,4,5,6,7,8-六氢-2H-苯并[b][1,4]噻嗪-3-羧酸酯(1.5g,1.0当量)和3滴DMF在二氯甲烷(15mL,10体积)中的混合物。将草酰氯(1.4g,2.0当量)逐滴添加到-10℃~0℃的混合物中,将所述混合物在-10℃~0℃下保持另外1小时同时搅拌。在减压下浓缩溶液,以得到(R)-8-氯-6,6-二甲基-3,5,6,7-四氢-2H-苯并[b][1,4]噻嗪-3-羧酸乙酯。用乙醇(15mL,10体积)稀释以上残余物,将4-氟苯胺(1.2g,2.0当量)添加到(R)-8-氯-6,6-二甲基-3,5,6,7-四氢-2H-苯并[b][1,4]噻嗪-3-羧酸乙酯溶液中,将所得溶液在20℃~30℃下保持20小时同时搅拌。在减压下浓缩溶液。通过柱色谱法(流动相:DCM/MeOH=100/1-20/1)纯化残余物,以得到1.6g(E)-2-((3-((4-氟苯基)亚氨基)环己-1-烯-1-基)氨基)乙酸乙酯。将1N NaOH水溶液添加到(E)-2-((3-((4-甲氧基苯基)亚氨基)环己-1-烯-1-基)氨基)乙酸乙酯(1.6g,1.0当量)在THF(8mL)和乙醇(8mL,5体积)中的混合物中,同时搅拌,将混合物在20℃~30℃下保持1~2小时。用1N HCl水溶液中和混合物以便pH=~7,并且在减压下浓缩混合物。通过柱色谱法(流动相:DCM/MeOH=50/1-5/1)纯化残余物,以得到(E)-2-((3-((4-氟苯基)亚氨基)环己-1-烯-1-基)氨基)乙酸乙酯。通过用5mL MTBE再浆化化合物IE4来进一步处理化合物IE4。
实施例29
用于式IA1化合物的合成方案:
在-10℃~0℃下冷却6,6-二甲基-8-氧代-3,4,5,6,7,8-六氢-2H-苯并[b][1,4]噻嗪-3-羧酸酯(260g,1.0当量)和3滴DMF在二氯甲烷(135mL,10体积)中的混合物。将草酰氯(12.69g,2.0当量)逐滴添加到-10℃~0℃的混合物中,将所述混合物在-10℃~0℃下保持另外1小时同时搅拌。在减压下浓缩溶液,以得到(R)-8-氯-6,6-二甲基-3,5,6,7-四氢-2H-苯并[b][1,4]噻嗪-3-羧酸乙酯。用乙醇(67mL,5体积)稀释以上残余物,将4-甲氧基苯胺(12.31g,2.0当量)添加到(R)-8-氯-6,6-二甲基-3,5,6,7-四氢-2H-苯并[b][1,4]噻嗪-3-羧酸乙酯溶液中,将所得混合物在20℃~30℃下保持20小时同时搅拌。在减压下浓缩,通过柱色谱法(流动相:DCM/MeOH=100/1-20/1)纯化残余物,以得到(E)-2-((3-((4-甲氧基苯基)亚氨基)环己-1-烯-1-基)氨基)乙酸乙酯。将120mL 1N NaOH水溶液添加到(E)-2-((3-((4-甲氧基苯基)亚氨基)环己-1-烯-1-基)氨基)乙酸乙酯(15.0g,1.0当量)在THF(60mL)和乙醇(60mL,3体积)中的混合物中,同时搅拌,将混合物在20℃~30℃下保持1~2小时。用1N HCl水溶液中和混合物以便pH=~7,并且在减压下浓缩混合物。通过柱色谱法(流动相:DCM/MeOH=50/1-5/1)纯化残余物,以得到化合物IA1。将45mL甲醇中的固体和活性炭(0.86g,10wt%)在N2下回流2小时。通过抽吸过滤悬浮液以去除活性炭,将滤液浓缩至干燥。通过用45mL MTBE再浆化约2小时来处理残余物。通过抽吸过滤悬浮液,收集滤饼并且在30℃下在真空下干燥至少4小时,以得到化合物IA1。
实施例30
推荐的用于式IA3化合物的合成方案:
推荐的用于式IA4化合物的合成方案:
实施例31
确定本发明的化合物体外UV防护性能。
通过使用Colipa UVA体外方法对体外防晒系数(SPF)、UVA防护系数(UVAPF)和临界波长值进行体外研究来评价以下化合物。
化合物IE1:(R,E)-8-(4-(叔-丁基氨基甲酰基)苯基亚氨基)-6,6-二甲基-3,4,5,6,7,8-六氢-2H-苯并[b][1,4]噻嗪-3-羧酸
化合物IF1:(R,E)-8-(3,4-二甲氧基苯基亚氨基)-6,6-二甲基-3,4,5,6,7,8-六氢-2H-苯并[b][1,4]噻嗪-3-羧酸
化合物IA2:(R,E)-8-(2-羧基-4-甲氧基苯基亚氨基)-6,6-二甲基-3,4,5,6,7,8-六氢-2H-苯并[b][1,4]噻嗪-3-羧酸
化合物IE4:(R,E)-8-(4-氟苯基亚氨基)-6,6-二甲基-3,4,5,6,7,8-六氢-2H-苯并[b][1,4]噻嗪-3-羧酸
化合物IA1:(R,E)-8-(4-甲氧基苯基亚氨基)-6,6-二甲基-3,4,5,6,7,8-六氢-2H-苯并[b][1,4]噻嗪-3-羧酸
对于确定体外SPF值,由体外测量的透光率计算化合物针对红斑有效UV辐射的防护性能,所述辐射主要限制为UVB(290-320nm)和短波长UVA(320-340)区域。在照射之后,由测量的体外透光率计算体外UVAPF、UVA防护(320-400nm)。临界波长值被定义为其中光谱吸光度曲线的积分达到290nm至400nm UV光谱的积分的90%的波长。已确定此值必须等于或大于370nm,以便将产品分类为广谱的。所述研究包括比较性测定未处理的板与用每种化合物处理的板,并且基于在暴露于来自UV来源的控制剂量的UV辐射之前和之后通过散布在粗糙衬底上的防嗮样品薄膜的UV透光率的评价。使用装备有UV来源、积分球和能够递送290nm与400nm之间的能量流的单色光的Kontron 933分光光度计。以1nm间隔测量透光率值。使用10-4精确实验室天平控制所沉积的产品的重量。通过具有标准滤光片的Sunset Atlas CPS+提供照射。在25℃-35℃下进行装备的温度调节。递送4次预照射剂量200J/m2-eff(800J/m2-eff)。所述衬底为防晒产品所应用的材料。使用聚甲基甲基丙烯酸酯(PMMA)板并且使其在一侧变粗糙为5微米三维表面形貌。称量每种化合物并且以2阶段扩展将其均匀地应用于PMMA板,以实现0.75mg/cm2重量/表面比率。以光扩展移动进行大约30秒扩展,然后以较大压力扩展30秒。留下所得的样品,在黑暗中在室温下平衡15分钟,以确保公式的自动调平。为了抵消光稳定性的缺乏,预照射为必需的。预照射剂量为4次红斑剂量(MED),等于800J/m2-eff。在预照射防晒产品之后,获得对于每个波长通过用防晒产品涂覆的PMMA板的光谱辐照度的五个测量值[Pl()、P2()、P3()、P4()和P5()]。对于每种化合物,由至少三个单独的PMMA板确定平均吸光度。为了证实结果的准确性,具有建立的18-20SPF的对照产品Lot11T0313与所述化合物同时测试。使用以下等式(Colipa 2011)为每个板计算体外SPF:
其中:
E()=红斑作用光谱(CEI-1987)
I()=UV光源的光谱辐照度
A0()=在每个波长下,在UV暴露之前,每个测试化合物层板的平均单色光吸光度测量值
d=波长步进(1nm)
计算在UV照射之后每个板的UVAPF(Colipa 2011)
其中:
P()=PPD作用光谱
I()=UV光源的光谱辐照度
A()=在每个波长下,在UV暴露之后,每个测试化合物层板的平均单色光吸光度测量值
C=调整系数
d=波长步进(1nm)
计算临界波长(FDA 2011)
其中:
A()=在每个波长下,在UV暴露之后,每个测试化合物层板的平均单色光吸光度测量值
d=波长步进(1nm)
使用通过用于体外确定UVA防护的Colipa方法所提供的excel电子表格。此软件提供以下结果:
-进行测量的统计真实性(波长与波长);
-以光密度和透射率表示的叠加测试曲线;
-每个计算表示为至少4个测量值的统计学评价并且提供平均值和分散结果。
在图2-6中提供从此研究中获得的原始数据。图2提供使用化合物IF1获得的数据。图3提供使用化合物IA1获得的数据。图4提供使用化合物IA2获得的数据。图5提供使用化合物IE4获得的数据。图6提供使用化合物IE1获得的数据。每种化合物的结果的总结提供于以下表2中:
表2:测试化合物的体外SPF、UVAPF和临界波长结果的总结
测试化合物 | 体外SPF | UVAPF | 临界波长λc值 |
IF1 | 2.1 | 4.1 | 390 |
IA1 | 2.4 | 8.7 | 390 |
IA2 | 5.1 | 8.1 | 392 |
IE4 | 4.5 | 8.6 | 390 |
IE1 | 3.4 | 13.5 | 391 |
对照PMMA SPF 18-20 | 21.1 | 4.7 | 359 |
体外UVAPF测量值显示化合物IE1、IA2、IE4和IA1对UVA射线的良好防护。每种化合物的临界波长λc值提供对UVA和UVB射线的光谱防护,如FDA所推荐的。图7示出测试化合物在指定波长下的吸光度。
实施例32
确定一些化合物的UV吸收性质
评价化合物IE1、IF1、IA2、IE4、IA1、IE2、ID2以及ID3的UV吸收性质。按以下制备样品:将20mg的每种化合物溶解于1ml甲醇中,以得到20g/L溶液。然后,将所述溶液各自应用于两个载玻片上。对于每种化合物,将所述载玻片之一在UV下老化20小时(Xenon仪器)。然后以透射率T(%)模式使用UVA-UVB分光光度计分析样品并且将其与未老化载玻片进行比较。使用以下式计算吸光度(A)。A样品=(T载玻片-T载玻片+样品)/T载玻片x100
下表3示出从所测试的化合物中得到的UVA和UVB吸收数据
尽管本发明结合其具体的实施方案进行描述,但应当理解可对它进行进一步的修改并且本申请旨在涵盖基本根据本发明的原理而对本发明进行的任何变动、使用或适应性调整,并且包括虽然不属于本公开内容但属于本发明所属领域的已知或习用实施手段的和属于上文所述的实质特征的以及符合所附权利要求书范围之内的变更。
说明书中提及的所有文献均以引用的方式并入本文。
参考文献
1.Cardozo等人2007.Metabolites from algae with economical impact.Comparative Biochemistry and Physiology Part C:Toxicolog y&Pharmacology,第146卷,第1-2期:60-78。
2.Bandaranayake WM.1998.Mycosporines:are they nature’s sunscreens?Natural Product Reports.15(2):159-72。
3.Garcia-Pichel等人,1992.Evidence for an ultraviolet sunscre en roleof the extracellular pigment scytonemin in the terrestrial cya nobacteriumChlorogloeopsis sp.Photochem Photobiol.56(1):17-23。
4.Garcia-Pichel等人,1993.Evidence Regarding the UV Sunscr een Role ofa Mycosporine-Like Compound in the Cyanobacterium Gloeocapsa sp.AppliedEnviron.Microbiol.59(1):170-176。
5.Ehling-Schilz等人,1997.UV-B-induced synthesis of photopr otectivepigments and extracellular polysaccharides in the terrestrial cyanobacteriumNostoc commune.J.Bacteriol.179(6):1940-5。
6.Carreto等人,2011.Review:Mycosporine-Like Amino Acids:RelevantSecondary Metabolites.Chemical and Ecological Aspects.Mar.Drugs.9(3),387-446。
7.Yoshiki等人,2009.Production of new antioxidant compound frommycosporine-like amino acid,porphyra-334by heat treatment.Food Chem.113,1127-1132。
Claims (17)
1.一种具有式IE的化合物:
其中,
R3和R4各自独立地为氢;烷基;烷氧基;或烷酰基;
R5为烷基;烷氧基;烷酰基;羧酸基;或羟基;
R6为氢;烷基;烷氧基;烷酰基;羟基;卤代基;或羧酸基;
R8为氢;烷基;烷氧基;烷酰基;羟基;卤代基;或氨基;以及
Y为CH2;氧;硫;NH2;以及
n为1,
或其药学上可接受的盐。
2.如权利要求1所述的化合物,其中Y为S。
3.如权利要求1或2所述的化合物,其中R3和R4各自为烷基。
4.如权利要求3所述的化合物,其中R3和R4各自为-CH3。
5.如权利要求1、2和4中任一项所述的化合物,其中R5为羧基。
6.如权利要求1、2和4中任一项所述的化合物,其中R6为氢或羟基。
7.如权利要求1、2和4中任一项所述的化合物,其中R8为烷酰基、氢、卤素或氨基。
8.具有下式的化合物:
9.如权利要求1所述的化合物,其具有式IA:
其中n是1。
10.如权利要求9所述的化合物,其中R3是-CH3或氢。
11.如权利要求9或10所述的化合物,其中R4为-CH3或氢。
12.如权利要求9或10所述的化合物,其中R5为-COOH。
13.如权利要求9或10所述的化合物,其中Y选自由O、S和NH组成的组。
14.如权利要求9或10所述的化合物,其中R6为氢或-COOH。
15.如权利要求9所述的化合物,其中式IA化合物选自:
16.一种具有下式的化合物
在用于保护织物使其抵抗UV辐射中的用途。
17.一种具有下式的化合物:
在制备用于针对UV辐射进行保护的组合物中的用途。
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WO2015195546A1 (en) | 2014-06-17 | 2015-12-23 | TopGeniX, Inc. | Topical formulations for uv protection |
CA2983674A1 (en) | 2015-05-07 | 2016-11-10 | Mutabilis | Heterocyclic compounds and their use in preventing or treating bacterial infections |
ES2550374B1 (es) * | 2015-06-30 | 2016-09-08 | Universidad De La Rioja | Compuestos fotoprotectores análogos de MAA, procedimiento de síntesis y composición que comprende los mismos |
EP3511700B1 (en) * | 2016-09-06 | 2023-10-04 | Keio University | Method for measuring a uv or infrared protection effect of an aqueous composition and device for preparing a measurement sample |
EP3300736B1 (en) | 2016-09-30 | 2021-05-05 | Mutabilis | Composition comprising antibiotic compound and an heterocyclic compound and their use in preventing or treating bacterial infections |
EP3301094A1 (en) | 2016-09-30 | 2018-04-04 | Mutabilis | Heterocyclic compounds and their use in preventing or treating bacterial infections |
CN109156449B (zh) * | 2018-09-28 | 2023-07-25 | 生标(上海)医疗器械科技有限公司 | 书画文物保护装置及其保护方法 |
CN115768755A (zh) * | 2020-02-26 | 2023-03-07 | 爱尔克米亚公司 | 用于在流动条件下合成吸收紫外线辐射的化合物的方法及包含该化合物的制剂 |
CN112080248B (zh) * | 2020-09-24 | 2022-05-17 | 中山沃硅化工科技有限公司 | 一种复合阻燃绝缘电子密封胶及其制备方法 |
EP4367094A1 (en) * | 2021-07-07 | 2024-05-15 | Elkimia Inc. | Ultraviolet and visible radiation absorbing compounds |
FR3124945A1 (fr) | 2021-07-08 | 2023-01-13 | Naos Institute Of Life Science | Composition cosmetique solaire contenant des acides amines analogues de la mycosporine |
FR3128881A1 (fr) | 2021-11-09 | 2023-05-12 | Jean-Noël Thorel | Composition solaire comprenant des filtres UV organiques et des copolymères huileux respectueux de l’environnement |
CN116410107A (zh) * | 2021-12-31 | 2023-07-11 | 中国石油天然气股份有限公司 | 一种含有对称结构的环状1,3-二酮二亚胺化合物及其合成方法与应用 |
CN116410108A (zh) * | 2021-12-31 | 2023-07-11 | 中国石油天然气股份有限公司 | 一种环状1,3-二酮二亚胺化合物及其合成方法与应用 |
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EP2855441A1 (en) | 2015-04-08 |
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US9487474B2 (en) | 2016-11-08 |
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