CN111433186A - 谷氨酸衍生物及包含其的组合物 - Google Patents
谷氨酸衍生物及包含其的组合物 Download PDFInfo
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- CN111433186A CN111433186A CN201880071298.1A CN201880071298A CN111433186A CN 111433186 A CN111433186 A CN 111433186A CN 201880071298 A CN201880071298 A CN 201880071298A CN 111433186 A CN111433186 A CN 111433186A
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- Prior art keywords
- glutamine
- amino
- group
- compound
- nevus
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Abstract
本发明涉及一种发挥优秀抗氧化效果的新型化合物或包含其的抗氧化组合物,通过使用本发明组合物来提供抗氧化用化妆料组合物、抗氧化用功能性食品组合物、黑色素过度沉着疾病的预防或治疗用药物组合物或皮肤美白用化妆料组合物。
Description
技术领域
本发明涉及一种谷氨酸衍生物及包含其的抗氧化组合物。
背景技术
人体与环境紧密接触,由于暴露在紫外线或环境污染、化学物质、洗涤剂、花粉等而使人体容易敏感。暴露于外部环境的皮肤容易暴露于活性氧中,活性氧会攻击正常的细胞组织或细胞膜,从而最终导致皮肤炎症。炎性组织对皮肤的蛋白质或遗传物质等进行破坏,从而导致皮肤老化(在皮肤中形成皱纹等)。
通常,有几种解释皮肤老化的理论,但是其中最具有合理性的理论是自由基理论,即皮肤因体内各种原因产生的自由基而发生老化。自由基作为化学反应性非常大的化学物质,也在皮肤被紫外线照射或皮肤内细胞呼吸过程中产生。与皮肤老化有关的自由基的大部分是活性氧(Reactive Oxygen Species,ROS),其种类包含超氧自由基(SuperoxideRadical)、过氧化氢(H2O2)、羟基自由基(Hydroxy Radical)、一重态氧(Single Oxygen)等。
这样的活性氧在被紫外线照射或呼吸过程中产生,并且通过多步链式反应来诱导脂质的过氧化,其中脂质是细胞膜的组成部分。脂质的过氧化产生各种活性种,例如,自由基、过氧化物、醛(Aldehyde)、环氧化合物(Epoxide)等,并且对DNA、RNA、蛋白质、细胞膜及细胞结构进行破坏。这些活性氧的毒性被认为是癌症、组织损伤和老化的主要原因(文献[Black HS,Photochem photobiol,46(2),213,1987])。
为了中和这些活性氧,抗氧化剂,例如,生育酚、多酚类、辅酶(Coenzyme)Q10、BHT(丁基化羟基甲苯(Butylated hydroxyl toluene))和BHA(丁基羟基茴香醚(Butylatedhydroxyl anisol))被广泛使用,但是仍需要进一步开发更优秀的抗氧化剂。
整个说明书参照了多数论文和专利文献,并指示了其引用。所引用的论文和专利文献的公开内容作为整体以参照的方式结合到本说明书中,从而更加明确地描述了本发明所属的技术领域的水平和本发明的内容。
发明内容
发明所要解决的问题
本发明人为了挖掘具有抗氧化活性的新型化合物努力进行了研究。其结果,通过阐明规定的谷氨酸衍生物化合物具有优异的抗氧化活性来完成了本发明。
因此,本发明的目的在于,提供一种谷氨酸衍生物化合物或其的药学上可接受的盐。
本发明的其他目的在于,提供一种抗氧化用化妆料组合物。
本发明的另一目的在于,提供一种抗氧化用功能性食品组合物。
本发明的另一目的在于,提供一种黑色素过度沉着疾病的预防或治疗用药物组合物。
本发明的另一目的在于,提供一种皮肤美白用化妆料组合物。
本发明的其他目的及优点通过以下发明的详细描述、权利要求及附图会更加明确。
用于解决问题的方案
根据本发明的一方面,本发明提供一种由如下式1来表示的化合物或其的药学上可接受的盐。
上述式1中,
R1为羟基或苄氧基;
R2为氢或苄氧羰基;
R3为被选自由羟基、C1至C4烷基、卤素、氰基及甲磺酰基组成的组的1个至3个取代基来取代的苯基。
根据本发明的另一方面,提供一种包含上述化合物或其药学上可接受的盐作为有效成分的抗氧化用化妆料组合物。
根据本发明的另一方面,提供一种包含上述化合物或其药学上可接受的盐作为有效成分的抗氧化用功能性食品组合物。
根据本发明的另一方面,提供一种包含上述化合物或其药学上可接受的盐作为有效成分的黑色素过度沉着疾病的预防或治疗用药物组合物。
根据本发明的一方面,提供一种包含上述化合物或其药学上可接受的盐作为有效成分的皮肤美白用化妆料组合物。
发明效果
本发明提供一种发挥优秀抗氧化效果的新型化合物,并且利用其来提供抗氧化用化妆料组合物、抗氧化用功能性食品组合物、黑色素过度沉着疾病的预防或治疗用药物组合物或皮肤美白用化妆料组合物。
附图说明
图1是示出试验例2的细胞毒性试验结果的图表。
图2是示出试验例3的NO分析结果的图表。
图3a及图3b是分别示出试验例5的体内抗炎活性试验结果的图及图表。
具体实施方式
以下,对本发明进行详细地描述。
根据本发明的一方面,本发明提供一种由式1来表示的化合物或其药学上可接受的盐。
【式1】
上述式1中,
R1为羟基或苄氧基;
R2为氢或苄氧羰基;
R3为被选自由羟基、C1至C4烷基、卤素、氰基及甲磺酰基组成的组的1个至3个取代基来取代的苯基。
本发明人为了挖掘具有抗氧化活性的新型化合物而努力进行了研究。其结果,阐明了规定的谷氨酸衍生物化合物具有优异的抗氧化活性。
本发明的术语“药学上可接受的盐”是指如本文中所定义的药学上可接受且保留了某化合物的所期望药物活性的盐。
本发明的术语“羟基”是指-OH取代基。
本发明的术语“C1至C4烷基”表示为包含1个至4个碳原子的直链或支链(straightor branched chain)烷基。例如包含,甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基等,但不限于此。
本发明的术语“卤素”表示为卤素取代基,并且表示为-F,-Cl,-Br或-I取代基。
本发明的术语“氰基”是指-CN取代基。
本发明的术语“苄基”是指-Bn取代基。
根据本发明的一实现例,C1至C4烷基可以是甲基、乙基或异丙基。
根据本发明的一实现例,R3取代基中的卤素可以是氟。
根据本发明的一实现例,R3可以被选自由4-氰基苯基、3-氰基苯基、2,3-二甲基苯基、2,5-二甲基苯基、2,4-二羟基苯基、3,5-二羟基苯基、2-氟-4-(甲磺酰基)苯基、4-异丙基苯基、2-乙基苯基、邻甲苯基、间甲苯基、对甲苯基和3-氟苯基组成的组中的任意一个。
根据本发明的一实现例,当R1为羟基时,R2可以是氢;当R1为苄氧基时,R2可以是苄氧羰基。
根据本发明的一实现例,上述由式1来表示的化合物可以选自由下列化合物组成的组:
(1)N5-((4-氰基苯基)氨基)-L-谷氨酰胺;
(2)N5-(对甲苯氨基)-L-谷氨酰胺;
(3)N5-((2,4-二羟基苯基)氨基)-L-谷氨酰胺;
(4)N5-((3,5-二羟基苯基)氨基)-L-谷氨酰胺;
(5)N5-((2-氟-4-(甲磺酰基)苯基)氨基)-L-谷氨酰胺;
(6)N2-((苄氧基)羰基)-N5-((4-氰基苯基)氨基)-D-谷氨酰胺苄酯(Benzyl N2-((benzyloxy)carbonyl)-N5-((4-cyanophenyl)amino)-D-glutaminate);
(7)N5-((4-氰基苯基)氨基)-D-谷氨酰胺;
(8)N5-((3-氰基苯基)氨基)-L-谷氨酰胺;
(9)N5-((3-氰基苯基)氨基)-D-谷氨酰胺;
(10)N5-((2,4-二羟基苯基)氨基)-D-谷氨酰胺;
(11)N5-((3,5-二羟基苯基)氨基)-D-谷氨酰胺;
(12)N2-((苄氧基)羰基)-N5-((4-氰基苯基)氨基)-L-谷氨酰胺苄酯(Benzyl N2-((benzyloxy)carbonyl)-N5-((4-cyanophenyl)amino)-L-glutaminate);
(13)N5-((2-氟-4-(甲磺酰基)苯基)氨基)-D-谷氨酰胺;
(14)N5-((2,3-二甲基苯基)氨基)-L-谷氨酰胺;
(15)N5-((2,3-二甲基苯基)氨基)-D-谷氨酰胺;
(16)N5-((2,5-二甲基苯基)氨基)-L-谷氨酰胺;
(17)N5-((2,5-二甲基苯基)氨基)-D-谷氨酰胺;
(18)N5-((4-异丙基苯基)氨基)-L-谷氨酰胺;
(19)N5-((4-异丙基苯基)氨基)-D-谷氨酰胺;
(20)N5-((2-乙基苯基)氨基)-L-谷氨酰胺;
(21)N5-((2-乙基苯基)氨基)-D-谷氨酰胺;
(22)N5-(邻甲苯基氨基)-L-谷氨酰胺;
(23)N5-(邻甲苯基氨基)-D-谷氨酰胺;
(24)N5-(间甲苯基氨基)-L-谷氨酰胺;
(25)N5-(间甲苯基氨基)-D-谷氨酰胺;
(26)N5-((3-氟苯基)氨基)-L-谷氨酰胺;
(27)N5-((4-(甲磺酰基)苯基)氨基)-L-谷氨酰胺;
(28)N5-((2-氟苯基)氨基)-L-谷氨酰胺;
(29)N5-((3-羟苯基)氨基)-L-谷氨酰胺;
(30)N5-((4-氟苯基)氨基)-L-谷氨酰胺;及
(31)N5-((2,4-二甲基苯基)氨基)-L-谷氨酰胺。
根据本发明的另一方面,本发明提供一种包含上述化合物或其药学上可接受的盐作为有效成分的抗氧化用化妆料组合物。
本发明的化妆料组合物也可以制造成本领域中常规制造的任何剂型。例如,能够以溶剂、混悬液、乳浊液、膏、凝胶、霜、乳液、粉末、肥皂、含表面活性剂的清洁剂、油、粉底、粉底乳、蜡状粉底和喷雾剂等方式剂型化,但是不限于此。更具体地,可以制造成柔润化妆水、营养化妆水、乳液、营养霜、按摩霜、精华液、眼霜、洁面霜、洁面泡沫、洁面水、面膜、喷雾剂或粉末的剂型。
当本发明的剂型为膏、霜、乳液或凝胶时,作为载体成分可以利用动物油、植物油、蜡、石蜡、淀粉、胺黄树胶(traganth)、纤维素衍生物、聚乙二醇、硅、皂土、二氧化硅、滑石、氧化锌等。
当本发明的剂型为粉末或喷雾剂时,作为载体成分可以利用乳糖、滑石、二氧化硅、羟基铝、硅酸钙、聚酰胺粉末,特别是在喷雾剂的情况下,可以进一步包含如氯氟烃、丙烷/丁烷或二甲醚的推进剂。
当本发明的剂型为溶液或乳浊液时,作为载体成分可以利用溶剂、溶解剂或乳化剂。例如,可以利用水、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-丁基乙二醇油、甘油脂肪酯、聚乙二醇、脱水山梨醇的脂肪酸酯。
当本发明的剂型为混悬液时,作为载体成分可以利用如水、乙醇或丙二醇的液相稀释剂;如乙氧基化异硬脂醇、聚氧乙烯山梨醇酯和聚氧乙烯脱水山梨醇酯的混悬剂;微晶纤维素;偏氢氧化铝(Aluminum metahydroxide);皂土;琼脂或胺黄树胶等。
当本发明的剂型为含表面活性剂的清洁剂时,作为载体成分可以利用脂肪醇硫酸盐、脂肪醇醚硫酸盐、磺基琥珀酸单酯、羟乙基磺酸盐、咪唑啉衍生物、甲基牛磺酸盐、肌氨酸盐、脂肪酸酰胺醚硫酸盐、烷基酰胺甜菜碱、脂肪醇、脂肪酸甘油酯、脂肪酸二乙醇酰胺、植物油、羊毛脂衍生物、乙氧基化甘油脂肪酸酯等。
本发明的化妆料组合物中含有的成分除了有效成分和载体成分以外还可以包含常规用于化妆品学组合物中的成分。例如,可以包含如抗氧化剂、稳定剂、溶解剂、维生素、颜料及香料的辅剂。
根据本发明的另一方面,本发明提供一种包含上述化合物作为有效成分的抗氧化用功能性食品组合物。
本发明的功能性食品组合物包含食品制造时常规添加的成分,例如,可以包含蛋白质、碳水化合物、脂肪、营养素及佐料等。例如,在制造为饮料时,除了有效成分以外作为附加成分可以包含香味剂或天然碳水化合物。例如,天然碳水化合物可以包含单糖(例如,葡萄糖、果糖等)、二糖(例如,麦芽糖、蔗糖等)、寡糖、多糖(例如,糊精、环糊精等)、糖醇(例如,木糖醇、山梨糖醇、赤藓醇等)。
另外,作为香味剂可以利用天然香味剂(例如,索马甜、甜菊提取物等)及合成香味剂(例如,糖精、阿斯巴甜等)。
根据本发明的另一方面,本发明提供一种包含上述化合物或其药学上可接受的盐作为有效成分的黑色素过度沉着疾病的预防或治疗用药物组合物。
本发明的“黑色素过度沉着疾病”具体地可以例举黄褐斑、雀斑、老人斑(liverspot)、斑点(blemish)、牛奶咖啡斑(Cafe's aulait macules)、贝克痣(Becker's Nevus)、斑痣(Nevus spilus)、蒙古斑(Mongolian spot)、太田痣(Nevus of Ota)、获得性双侧太田痣样斑(Acquired bilateral nevus of Ota-like macules)、伊藤痣(Nevus of Ito)、蓝痣(Blue nevus)、交界痣(Junctional nevus)、混合痣(Compound nevus)、皮内痣(Intradermal nevus)、晕痣(Halo nevus)、先天性黑色素细胞痣(Congenital nevocyticnevus)、斯皮茨痣(Spitz nevus)、发育不良性痣(Dysplastic nevus)、晒斑(solartigines)和手足综合征(Hand-and-Foot syndrome)等,但不限于此。
本发明的药物组合物除了有效成分以外包含药学上可接受的载体。在本发明的药物组合物中含有的药学上可接受的载体通常在制剂时利用,并且包含乳糖、右旋糖、蔗糖、山梨醇、甘露醇、淀粉、阿拉伯胶、磷酸钙、藻酸盐、明胶、硅酸钙、微晶纤维素、聚乙烯吡咯烷酮、纤维素、水、糖浆、甲基纤维素、羟基苯甲酸甲酯、羟苯苯甲酸丙酯、滑石、硬脂酸镁、矿物油等,但不限于此。本发明的药物组合物除了上述成分以外可以进一步包含润滑剂、润湿剂、甜味剂、香味剂、乳化剂、混悬剂、防腐剂等。合适的药学上可接受的载体及制剂详细记载于文献【雷明顿药物科学(Remington's Pharmaceutical Sciences)(1995年第19版)】中。
本发明的药物组合物的合适给药量可以通过制剂化方法、给药方式、患者年龄、体重、性别、病态、食物、给药时间、给药途径、排泄速度及反应敏感性等因素来以各种方式进行确定。另外,本发明的药物组合物的给药量优选每日0.001mg/kg至1000mg/kg(体重)。
本发明的药物组合物可以通过口服或非口服给药,在非口服给药时,可以通过在皮肤局部地进行涂覆、静脉内注射、皮下注射、肌肉注射、腹腔内注射、经皮注射、鼻腔给药等方式进行给药。考虑到将本发明的药物组合物适用于治疗黑色素过度沉着疾病,给药方式优选在皮肤局部地进行涂覆的方式。
根据该发明所属技术领域的技术人员能够容易进行实施的方法,通过利用药学上可接受的载体和/或赋形剂来对本发明的药物组合物进行制剂化,可以制造为单位容量形态或以装入在大容量容器内的方式来进行制造。此时,剂型可以是油;或者水性介质中的溶液、混悬液或乳化液形态;或者提取剂、粉剂、颗粒剂、片剂或胶囊剂的形态,并且可以进一步包含分散剂或稳定剂。
本发明的药物组合物可以制造为皮肤外用剂型形态。本发明并不特别限定上述皮肤外用剂型,但是优选粉末、凝胶、软膏、霜、液体或气雾剂型。
本发明中皮肤外用剂型的凝胶基料可以使用选自卡波普(Carbopol)、卡波姆(Carbomer)、聚乙二醇(Polyethyleneglycol)、聚丙二醇(Polypropylene glycol)、聚丙烯酸(Polyacrylic acid)、羧甲基纤维素(Carboxymethyl cellulose)、羟甲基纤维素(Hydroxymethyl cellulose)、聚乙烯吡咯烷酮(Polyvinylpyrrolidone)、明胶(Gelatine)、海藻酸盐(Alginate Salt)、壳多糖(Chitin)衍生物或壳聚糖(Chitosan)衍生物、透明质酸(Hyaluronic acid)、胶原(collagen)中的一种或两种以上,但不限于此。
根据本发明的另一方面,本发明提供一种包含上述化合物或其药学上可接受的盐作为有效成分的皮肤美白用化妆料组合物。本发明的化妆料组合物的皮肤美白效果是利用了对上述本发明的另一方面的抗氧化化妆料进行描述的本发明的化合物的抗氧化效果,对于化妆料组合物的剂型及根据上述剂型的载体、进一步包含的辅助成分等可以参考对上述化妆料组合物的上述内容,并且对于重复的内容将要省略,以避免本说明书描述的过于复杂。
最佳实施方式
以下,通过实施例,对本发明进行更加详细地说明。这些实施例仅旨在更详细地说明本发明,并且对于本领域技术人员而言,根据本发明主旨,本发明的范围不受这些实施例的限制是显而易见的。
实施例
实施例1:N5-((4-氰基苯基)氨基)-L-谷氨酰胺的制造
将催化量为10mg的10%的Pd/C加入到100mL的甲醇内的N2-((苄氧基)羰基)-N5-((4-氰基苯基)氨基)-L-谷氨酰胺苄酯(100mg,0.206mmol)的混悬液中。从烧瓶上端上的球囊(balloon)将氢气施加到上述混悬液中并搅拌2小时。之后,对混合物进行过滤,并蒸发滤液。利用甲醇对残渣进行研磨(triturated),并对固体进行过滤,从而获得白色固体N5-((4-氰基苯基)氨基)-L-谷氨酰胺(41mg,收率76%)。所获得的化合物的NMR数据为如下:
1H NMR(300MHz,DMSO-d6):δ8.58(s,1H),7.90(bs,2H),7.52(d,J=8.11Hz,2H),6.74(d,J=8.21Hz,2H),3.32-3.14(m,1H),2.44-2.25(m,2H),2.04-1.78(m,2H)。
实施例2:N5-(对甲苯氨基)-L-谷氨酰胺的制造
将催化量为40mg的40%的Pd/C加入到100mL的甲醇内的N2-((苄氧基)羰基)-N5-((4-氰基苯基)氨基)-L-谷氨酰胺苄酯(100mg,0.206mmol)的混悬液中。从烧瓶上端上的球囊将氢气施加到上述混悬液中并搅拌6小时。之后,对混合物进行过滤,并蒸发滤液。利用甲醇对残渣进行研磨,并对固体进行过滤,从而获得白色固体N5-(对甲苯氨基)-L-谷氨酰胺(39mg,收率75%)。所获得的化合物的NMR数据为如下:
1H NMR(300MHz,DMSO-d6):δ9.80(s,1H),7.67(bs,2H),7.48(s,1H),6.93(d,J=8.09Hz,2H),6.60(d,J=8.21Hz,2H),3.19(t,J=6.30Hz,1H),2.32(t,J=6.78Hz,2H),2.16(s,3H),2.01-1.77(m,2H)。LC-MS(m/z):252.1(MH+)。
实施例3:N5-((2,4-二羟基苯基)氨基)-L-谷氨酰胺的制造
将催化量为60mg的20%的Pd/C加入到200mL的甲醇内的N2-((苄氧基)羰基)-N5-((2,4-双(苄氧基)苯基)-L-谷氨酰胺(N2-((benzyloxy)carbonyl)-N5-((2,4-bis(benzyloxy)phenyl)-L-glutaminate)(300mg,0.445mmol)的混悬液中。从烧瓶上端上的球囊将氢气施加到上述混悬液中并搅拌2小时。之后,对混合物进行过滤,并蒸发滤液。利用甲醇对残渣进行研磨,并对固体进行过滤,从而获得深的淡黄色(dark pale yellow)固体N5-((2,4-二羟基苯基)氨基)-L-谷氨酰胺(82mg,收率72%)。所获得的化合物的NMR数据为如下:
1H NMR(300MHz,DMSO-d6):δ9.65-8.85(m,3H),7.26-7.10(m,1H),6.28(s,1H),6.16(d,J=8.43Hz,1H),3.36-3.24(m,1H),2.06-1.80(m,2H),1.32-1.12(m,2H)。
实施例4:N5-((3,5-二羟基苯基)氨基)-L-谷氨酰胺的制造
将催化量为70mg的20%的Pd/C加入到250mL的甲醇内的N2-((苄氧基)羰基)-N5-((3,5-双(苄氧基)苯基)-L-谷氨酰胺苄酯(350mg,0.519mmol)的混悬液中。从烧瓶上端上的球囊将氢气施加到上述混悬液中并搅拌2小时。之后,对混合物进行过滤,并蒸发滤液。利用甲醇对残渣进行研磨,并对固体进行过滤,从而获得淡黄色固体N5-((3,5-二羟基苯基)氨基)-L-谷氨酰胺(86mg,收率61%)。所获得的化合物的NMR数据为如下:
1H NMR(300MHz,DMSO-d6):δ10.08(s,1H),9.213(s,1H),7.74(bs,2H),6.56(s,2H),5.87(s,1H),3.31-3.18(m,1H),2.43(t,J=7.37Hz,2H),2.02-1.82(m,2H)。
实施例5:N5-((2-氟-4-(甲磺酰基)苯基)氨基)-L-谷氨酰胺的制造
将催化量为25.5mg的10%的Pd/C加入到100mL的甲醇内的N2-((苄氧基)羰基)-N5-((2-氟-4-(甲磺酰基)苯基)氨基)-L-谷氨酰胺苄酯(255mg,0.457mmol)的溶液中。通过使用氢气球囊将氢气施加到所获得的混合物中。反应结束后,对催化剂进行过滤,并且用甲醇来进行洗涤。将过滤物进行真空浓缩,并且用甲醇对粗残渣进行研磨。之后,将固体进行过滤,并用甲醇来洗涤,从而获得白色固体N5-((2-氟-4-(甲磺酰基)苯基)氨基)-L-谷氨酰胺(130mg,收率85%)。所获得的化合物的NMR数据为如下:
1H NMR(300MHz,DMSO-d6):δ8.50(s,1H),7.66-7.46(m,2H),7.41-7.28(m,1H),6.98-6.82(m,1H),3.29-3.19(m,1H),3.14(s,3H),2.40(t,J=7.28Hz,2H),2.12-1.74(m,2H)。
将利用上述化合物,及上述步骤来制造的化合物与NMR数据或LC-MS(m/z)数据共同显示在表1中。
【表1】
比较例1:拉马林(Ramalin)的制造
通过利用上述实施例所记载的方法,制造由下述化学结构式来表示的化合物(通用名称为拉马林(Ramalin))。
试验例1:根据DPPH分析的抗氧化效果实验
为了试验上述实施例中所制造的化合物的抗氧化效果,进行了2,2-二苯基三硝基苯肼(DPPH)分析。DPPH分析广泛用于评价由清除自由基而带来的抗氧化活性,并且本文说明书试验例1中根据文献【布兰德-威廉姆斯,库维利尔和伯塞特(1995)】记载的步骤进行了分析。
在DMSO内,以10mg/ml的浓度准备实施例中所制造的化合物中的一部分化合物,在转移到96-孔微孔板之前,以3.1μg/mL、6.3μg/mL、12.5μg/mL、25.0μg/mL、50.0μg/mL、100.0μg/mL的浓度进行稀释,并作为试样溶液。每孔含有100μL的DPPH(0.2mM)的甲醇溶液和100μL的试样溶液。在暗室条件下,在室温中将微孔板放置30分钟,并利用微孔板读取器(佛蒙特州威努斯基市的生物技术仪器)在540nm处测量吸光度。空白组(Blank)为甲醇和DMSO混合物(200μL),并且,抗坏血酸则作为阳性对照组来进行了测定。DPPH自由基清除能力是通过利用如下公式来进行了计算,并且其结果显示在下述表2。
DPPH自由基清除能力(抑制%)={(AB-AS)/AB*100}
(式中,AB为空白组反应的吸光度,AS为谷氨酸衍生物试样及阳性对照组存在下的吸光度。重复测试3次,并记载了其平均结果值。IC50表示为通过试验样品清除50%自由基的水平(level)。)
【表2】
实施例 | IC50(μg/ml) |
实施例1 | 8.21 |
实施例2 | 9.99 |
实施例3 | 28.01 |
实施例4 | 316.86 |
实施例5 | 8.72 |
实施例7 | 6.72 |
实施例8 | 10.82 |
实施例9 | 9.31 |
实施例13 | 8.60 |
实施例14 | 7.88 |
实施例16 | 8.73 |
实施例17 | 8.60 |
实施例18 | 7.88 |
实施例19 | 6.23 |
实施例20 | 17.14 |
实施例22 | 6.24 |
实施例24 | 10.1 |
实施例26 | 11.44 |
实施例27 | 9.57 |
实施例28 | 10.86 |
实施例29 | 10.67 |
实施例30 | 13.77 |
实施例31 | 15.75 |
比较例1 | 8.67 |
试验例2:细胞毒性试验
为了对细胞存活率进行试验,将得自ATCC(美国模式培养物集存库)的小鼠的单核细胞/巨噬细胞细胞系RAW 264.7在37℃,5%的CO2的条件下,在75cm2的组织培养烧瓶内,通过补充了10%的FBS和1%的抗生素的DMEM来进行培养。将所培养的细胞分别用100μg/mL的由实施例2、实施例5、实施例22和比较例1制备的化合物来处理24小时。之后,基于利用琥珀酸-四唑鎓还原酶(Succinate-tetrazolium reductase)的、四唑鎓盐对于水溶性甲瓒的清除,通过EZ-氧化酶细胞存活率检测试剂盒(EZ-Cytox Cell Viability Assay Kit)(韩国Daeil Lab Service)来确定相对存活率。将10μL的EZ-氧化酶以100μL/孔的最终体积添加到培养基。细胞在37℃下进一步培养1小时,并且通过使用微孔板读取器(佛蒙特州威努斯基市的生物技术仪器)在450nm处测量吸光度。其结果显示在图1。
试验例3:NO(一氧化氮)分析
将亚硝酸根离子积累作为培养基中NO生成的指标来使用,并且用格里斯(Griess)反应来进行测定。通过与上述试验例2相同方法来培养RAW 264.7细胞。为了试验由实施例5制造的化合物的NO生成效果,通过使用新的培养基将细胞接种到96-孔板(5x104细胞/孔)。预培养24小时后,在谷氨酸衍生物的浓缩液(3.1μg/mL、6.3μg/mL、12.5μg/mL、25.0μg/mL、50.0μg/mL、100.0μg/mL)存在或不存在的情况下,用LPS(300ng/mL)对细胞进行了刺激。为了测定在24小时的培养时间里所产生的NO的浓度,在室温下将96孔板的每孔100μL的培养上清液与50μL的格里斯试剂A(2.5%的H3PO4中1%的磺胺(sulfanilamide))和50μL的格里斯试剂B(2.5%的H3PO4中1%的盐酸萘乙二胺(Naphthylethylene diaminedihydrochloride))一同培养15分钟。通过使用微孔板读取器来测定540nm处的吸光度(佛蒙特州威努斯基市生物技术仪器)。通过比较A540标准来计算了硝酸盐(Nitrate)的浓度。数据是由对一个孔进行3次测量的值的平均±标准偏差来表示,并且其结果显示在图2中。
试验例4:体外(in vitro)稳定性试验
将由实施例2、实施例5、实施例22及实施例27制造的化合物和由比较例1制造的化合物分别溶解于去离子水(1mg/mL)中,并在45℃下进行培养,并且在4周时间对化学稳定性进行测定。每周对各试样进行分离,用反相HPLC来进行测定。将10μL的各试样以1mL/分钟的方式在30分钟内注入到梯度HPLC系统中,其中梯度HPLC系统包含0.1%甲酸溶液以95-10%的水的梯度洗脱的4.6×150mm的Eclipse XDB-C18柱(安捷伦)。针对洗脱液,监测UV吸光度(254nm),并且将开始时点的值作为100%来计算相对稳定性。其结果显示在表3。
【表3】
试验例5:体内(in vivo)抗炎活性试验
为了调查通过实施例5制造的化合物在体内的抗炎活性而使用了斑马鱼(zebrafish)模型。Tg(mpx:GFP)斑马鱼系是在嗜中性粒细胞的特异性髓过氧化物酶(myeloperoxidase)启动子的调节下表达HFP的、用于分析炎症反应的体内模型。受精后的第三天,用三卡因(Tricaine)对Tg(mpx:GFP)幼虫进行麻醉,并切断尾鳍。切断尾鳍后,表达GFP的嗜中性粒细胞向伤口部位进行移动。切断4小时后,用实施例5制造的化合物处理6小时含受伤的幼虫的胚胎培养基。实施例5制造的化合物降低了嗜中性粒细胞向受伤的尾鳍的流入。然而,未切断尾鳍的幼虫响应于实施例5中制造的化合物的处理,没有发生嗜中性粒细胞的流入。将地塞米松作为阳性对照组来使用,并且将其结果分别显示在图3a和图3b。从图3a和图3b可以确认,通过实施例5制造的化合物抑制嗜中性粒细胞介导的伤口炎症。
Claims (11)
2.根据权利要求1中所述的化合物或其的药学上可接受的盐,其特征在于,
所述C1至C4烷基是甲基、乙基或异丙基。
3.根据权利要求1中所述的化合物或其的药学上可接受的盐,其特征在于,
所述卤素为氟。
4.根据权利要求1中所述的化合物或其的药学上可接受的盐,其特征在于,
R3被选自由4-氰基苯基、3-氰基苯基、2,3-二甲基苯基、2,5-二甲基苯基,2,4-二羟基苯基、3,5-二羟基苯基,2-氟-4-(甲磺酰基)苯基、4-异丙基苯基、2-乙基苯基、邻甲苯基、间甲苯基、对甲苯基和3-氟苯基组成的组中的任意一个。
5.根据权利要求1所述的化合物或其的药学上可接受的盐,其特征在于,
当R1为羟基时,R2是氢;当R1为苄氧基时,R2是苄氧羰基。
6.根据权利要求1所述的化合物或其的药学上可接受的盐,其特征在于,
由所述式1来表示的化合物选自由下列化合物组成的组:
(1)N5-((4-氰基苯基)氨基)-L-谷氨酰胺;
(2)N5-(对甲苯氨基)-L-谷氨酰胺;
(3)N5-((2,4-二羟基苯基)氨基)-L-谷氨酰胺;
(4)N5-((3,5-二羟基苯基)氨基)-L-谷氨酰胺;
(5)N5-((2-氟-4-(甲磺酰基)苯基)氨基)-L-谷氨酰胺;
(6)N2-((苄氧基)羰基)-N5-((4-氰基苯基)氨基)-D-谷氨酰胺苄酯;
(7)N5-((4-氰基苯基)氨基)-D-谷氨酰胺;
(8)N5-((3-氰基苯基)氨基)-L-谷氨酰胺;
(9)N5-((3-氰基苯基)氨基)-D-谷氨酰胺;
(10)N5-((2,4-二羟基苯基)氨基)-D-谷氨酰胺;
(11)N5-((3,5-二羟基苯基)氨基)-D-谷氨酰胺;
(12)N2-((苄氧基)羰基)-N5-((4-氰基苯基)氨基)-L-谷氨酰胺苄酯;
(13)N5-((2-氟-4-(甲磺酰基)苯基)氨基)-D-谷氨酰胺;
(14)N5-((2,3-二甲基苯基)氨基)-L-谷氨酰胺;
(15)N5-((2,3-二甲基苯基)氨基)-D-谷氨酰胺;
(16)N5-((2,5-二甲基苯基)氨基)-L-谷氨酰胺;
(17)N5-((2,5-二甲基苯基)氨基)-D-谷氨酰胺;
(18)N5-((4-异丙基苯基)氨基)-L-谷氨酰胺;
(19)N5-((4-异丙基苯基)氨基)-D-谷氨酰胺;
(20)N5-((2-乙基苯基)氨基)-L-谷氨酰胺;
(21)N5-((2-乙基苯基)氨基)-D-谷氨酰胺;
(22)N5-(邻甲苯基氨基)-L-谷氨酰胺;
(23)N5-(邻甲苯基氨基)-D-谷氨酰胺;
(24)N5-(间甲苯基氨基)-L-谷氨酰胺;
(25)N5-(间甲苯基氨基)-D-谷氨酰胺;
(26)N5-((3-氟苯基)氨基)-L-谷氨酰胺;
(27)N5-((4-(甲磺酰基)苯基)氨基)-L-谷氨酰胺;
(28)N5-((2-氟苯基)氨基)-L-谷氨酰胺;
(29)N5-((3-羟苯基)氨基)-L-谷氨酰胺;
(30)N5-((4-氟苯基)氨基)-L-谷氨酰胺;及
(31)N5-((2,4-二甲基苯基)氨基)-L-谷氨酰胺。
7.一种包含权利要求1所述的化合物或其药学上可接受的盐作为有效成分的抗氧化用化妆料组合物。
8.一种包含权利要求1所述的化合物或其药学上可接受的盐作为有效成分的抗氧化用功能性食品组合物。
9.一种黑色素过度沉着疾病的预防或治疗用药物组合物,其包含权利要求1所述的化合物或其药学上可接受的盐作为有效成分。
10.根据权利要求9中所述的黑色素过度沉着疾病的预防或治疗用药物组合物,其特征在于,
所述黑色素过度沉着疾病选自由黄褐斑、雀斑、老人斑、斑点、牛奶咖啡斑、贝克痣、斑痣、蒙古斑、太田痣、获得性双侧太田痣样斑、伊藤痣、蓝痣、交界痣、混合痣、皮内痣、晕痣、先天性黑色素细胞痣、斯皮茨痣、发育不良性痣、晒斑和手足综合征组成的组。
11.一种包含权利要求1的化合物或其药学上可接受的盐作为有效成分的皮肤美白用化妆料组合物。
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WO2019088642A1 (ko) | 2019-05-09 |
KR20190048846A (ko) | 2019-05-09 |
KR102393317B1 (ko) | 2022-05-03 |
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