CN103930409A - 芳香性酰胺基噻唑、含有它的化妆或皮肤科制剂以及它们的克服和预防不期望的皮肤色素沉着的用途 - Google Patents
芳香性酰胺基噻唑、含有它的化妆或皮肤科制剂以及它们的克服和预防不期望的皮肤色素沉着的用途 Download PDFInfo
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- CN103930409A CN103930409A CN201280046278.1A CN201280046278A CN103930409A CN 103930409 A CN103930409 A CN 103930409A CN 201280046278 A CN201280046278 A CN 201280046278A CN 103930409 A CN103930409 A CN 103930409A
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- Prior art keywords
- base
- hydroxy
- phenyl
- side chain
- alkyl
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Classifications
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/38—Nitrogen atoms
- C07D277/44—Acylated amino or imino radicals
- C07D277/46—Acylated amino or imino radicals by carboxylic acids, or sulfur or nitrogen analogues thereof
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
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- A—HUMAN NECESSITIES
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- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
- A61K8/4906—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom
- A61K8/4926—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom having six membered rings
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
- A61K8/4973—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
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- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
- A61Q19/02—Preparations for care of the skin for chemically bleaching or whitening the skin
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/38—Nitrogen atoms
- C07D277/44—Acylated amino or imino radicals
- C07D277/48—Acylated amino or imino radicals by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof, e.g. carbonylguanidines
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
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- Public Health (AREA)
- General Health & Medical Sciences (AREA)
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- Birds (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
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- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Dermatology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Cosmetics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Thiazole And Isothizaole Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
如下通式的芳香性酰胺基噻唑,其中R1=-C3-C24-芳基(必要时用-OH、-F、-Cl、-Br、-I、-OMe、-NH2、-CN、乙酰基单取代或多取代,多羟基取代,其中这些羟基官能团可以以缩醛的形式结合)、-C3-C24-杂芳基(必要时用-OH、-F、-Cl、-Br、-I、-OMe、-NH2、-CN、乙酰基单取代或多取代,多羟基取代,其中这些羟基官能团可以以缩醛的形式结合)、-C3-C24-芳基-C1-C24-烷基(直链和支链的)、-C3-C24-杂芳基-C1-C24-烷基(直链和支链的)、-C3-C24-芳基-C1-C24-烷基-羟基(直链和支链的)、-C3-C24-杂芳基-C1-C24-烷基-羟基(直链和支链的)、-2-羟基苯基、-3-羟基苯基、-4-羟基苯基、-吡啶-2-基、-吡啶-3-基、-吡啶-4-基、吡啶-1(2H)-基、-嘧啶-2-基、-吡嗪-2-基、-嘧啶-4-基、-哒嗪-3-基、-哒嗪-4-基、-嘧啶-2-基、-嘧啶-5-基、-1,2,4-三嗪-3-基、1,3,5-三嗪-2-基、-1,2,3-三嗪-4-基、-1,2,3-三嗪-5-基、-1,2,3,4-四嗪-5-基、-1,2,3,5-四嗪-4-基、-1,2,4,5-四嗪-3-基、-五嗪-6-基、-噻唑、-咪唑、-恶唑、-异恶唑、-NH-芳基(必要时用-OH、-F、-Cl、-Br、-I、-OMe、-NH2、-CN、乙酰基单取代或多取代,多羟基取代,其中这些羟基官能团可以以缩醛的形式结合)、-NH-杂芳基(必要时用-OH、-F、-Cl、-Br、-I、-OMe、-NH2、-CN、乙酰基单取代或多取代,多羟基取代,其中这些羟基官能团可以以缩醛的形式结合)、单(羟基烷基)-苯基-、低聚(羟基烷基)-苯基,以及具有有效含量的一种或多种芳香性酰胺基噻唑的化妆或皮肤科制剂及其用于化妆或皮肤科处理和/或预防不期望的皮肤色素沉着的用途。
Description
技术领域
本发明涉及新颖的芳香性酰胺基噻唑或者说芳酰胺基噻唑,具有一定含量的一种或多种这样的芳香性酰胺基噻唑或者说芳酰胺基噻唑的化妆或皮肤科制剂,以及这样的芳香性酰胺基噻唑或包含这样的芳香性酰胺基噻唑的制剂的用于克服和预防不期望的皮肤色素沉着的用途。
背景技术
黑色素细胞对皮肤色素沉着负责,这些黑色素细胞在表皮最下层(基底层)中,在基底细胞旁作为视皮肤类型而定孤立地或者以或多或少的频率出现的、形成色素的细胞而存在。
黑色素细胞含有作为特征细胞器的黑素体,在该黑素体中形成黑色素。此外在通过紫外线辐射刺激的情况下,黑色素剧烈形成。黑色素通过表皮的活性层(角化细胞)最终转移至角质层(角质细胞),并且或多或少地导致明显的褐色至褐黑色的皮肤颜色。
黑色素作为氧化过程的终产物形成,在该氧化过程中,酪氨酸在酪氨酸酶的协助下通过多个中间体转化为褐色至褐黑色的真黑色素(DHICA(二羟基吲哚羧酸)和DHI-黑色素(二羟基吲哚))或在含硫化合物的参与下转化为发红的褐黑色素。DHICA-黑色素和DHI-黑色素通过共同的中间体多巴醌和多巴色素产生。多巴色素部分地在其他酶的参与下转化为吲哚-5,6-醌-羧酸或吲哚-5,6-醌,由此,产生所述两种真黑色素。
另外,黑色素的产生通过中间产物多巴醌和半胱氨酰多巴来进行。黑色素合成酶的表达通过特异性转录因子(小眼畸形相关转录因子,MITF)来控制。除了所描述的黑色素合成的酶促过程之外,黑色素体中其他蛋白质对于色素生成也是重要的。在此,所谓的P-蛋白质似乎具有重要作用,但其中,确切功能尚不明确。
除了上文描述的黑色素细胞中黑色素合成的过程之外,皮肤色素沉着时黑色素体的转移、其在表皮中的残留及其分解还有黑色素的分解都具有重要意义。可以证实的是,PAR-2-受体对于黑色素体从黑色素细胞转移至角化细胞来说是重要的(M.Seiberg等人,2000,J.Cell.Sci.,113:3093-101)。
此外,黑色素体的尺寸和形状影响其光散射性质并因此影响皮肤的颜色外观。因此,对于非洲黑人的情况,发现极大的独立存在的球状黑色素体,而对于白种人的情况,发现的是较小的以群组出现的黑色素体。
皮肤色素过度沉着的问题具有多种原因,而且是许多生物学过程的伴发症状,例如紫外线辐射(例如晒斑、雀斑)、遗传倾向、皮肤在伤口治愈或愈合(炎症后色素过度沉着)时的或皮肤老化(例如老年斑)时的异常色素沉着。
炎症反应之后,皮肤的色素系统发生反应,并伴随有部分相反的反应。这既可导致炎症后色素过度沉着,也可导致色素沉着不足。炎症后白化症经常伴随特异反应、红斑狼疮和牛皮癣出现。人类皮肤的色素系统在炎症现象之后的不同反应形式仍未被完全了解。
炎症后色素过度沉着的问题经常出现于更深色的皮肤类型。特别的,对于男性有色人种来说须部假性毛囊炎的问题是公知的,该问题伴随或招致化妆方面不期望的异常色素沉着。黄褐斑的形式(特别在亚洲女性脸部和胸颈部产生)以及皮肤不规则色素沉着的各种形式也属于炎症后色素过度沉着。此外,黑眼圈也被视为一种形式的炎症后色素过度沉着,其中,潜在的炎症通常以亚临床方式发生。
在许多情况下,这种炎症后异常色素沉着通过太阳光(紫外线)的作用而得到强化,但不会导致紫外线引发的炎症(晒伤)。
抵抗皮肤色素沉着的有效成分和制剂是公知的。实际应用中基本是基于对苯二酚的配剂,该配剂一方面在数周应用之后才显示出其效果,另一方面,该配剂过长时间的应用出于毒性原因而令人担心。AlbertKligman等人研发了所谓的“Triformula(三合一处方)”,其表现为0.1%维甲酸、5.0%对苯二酚、0.1%地塞米松的组合(A.Kligman,1975,Arch.Dermatol.,111:40-48)。然而,所述配方由于可能导致皮肤色素系统中不可逆的变化而极具争议。
此外,使用脱皮法(化学的和力学的“去皮/去死皮(Peeling)”),然而脱皮法通常伴随有炎症反应,并且由于随后出现的炎症后色素过度沉着甚至可导致更严重的色素沉着(而非减少的色素沉着)。所有这些常见的方法(其也用于处理炎症后色素过度沉着)的特征在于严重的副作用。
此外公知了各种其他的,以皮肤增白效果加以描述的物质。在此特别要列出的是,十六碳烯-1,16-二羧酸、曲酸及其衍生物、熊果苷、抗坏血酸及其衍生物、黄酮类、鞣花酸及其衍生物、凝血酸及不同的间苯二酚衍生物,例如4-正丁基间苯二酚、4-正己基间苯二酚和4-(1-苯乙基)苯-1,3-二醇。
J.M.Ready在公开文献(Bioorganic&Medicinal Chemistry Letter17(2007)6871-6875)中描述了特别是经取代的噻唑衍生物对于蘑菇酪氨酸酶的抑制作用。
在Shiseido公司的专利申请(WO2009/099195)中描述了用于皮肤增白的经取代的噻唑胺或氢化噻唑胺。
以上所列出的现有技术中描述的物质显示了中等的效果和/或差的盖仑氏稳定性。
黑眼圈同样可能作为色素沉着紊乱的结果而产生,其中,黑眼圈还相应于一般性的压力,例如不足的睡眠或单纯地通过眼睛疲劳而显现。在较年轻的人的情况下,经过充足的夜间睡眠后症状再次消失,但是较长的一段时间后状况可转为慢性的并且对于涉及的人变为非常困扰的。针对这种皮肤表现还缺乏足够有前途的有效物质和处理可能性。
发明内容
如下发明的目的是为有缺陷的现有技术提供补救。
本发明所基于的所述目的的解决方案在于如下通式的芳香性酰胺基噻唑:
其中
R1、R2、X和Y可以不同、部分相同或完全相同,并且可以彼此独立地代表着:
R1=-C3-C24-芳基(必要时以-OH、-F、-Cl、-Br、-I、-OMe、-NH2、-CN、乙酰基单取代或多取代,多羟基取代,其中这些羟基官能团可以以缩醛(Acetal)的形式结合)、-C3-C24-杂芳基(必要时用-OH、-F、-Cl、-Br、-I、-OMe、-NH2、-CN、乙酰基单取代或多取代,多羟基取代,其中这些羟基官能团可以以缩醛的形式结合)、-C3-C24-芳基-C1-C24-烷基(直链和支链的)、-C3-C24-杂芳基-C1-C24-烷基(直链和支链的)、-C3-C24-芳基-C1-C24-烷基-羟基(直链和支链的)、-C3-C24-杂芳基-C1-C24-烷基-羟基(直链和支链的)、-2-羟基苯基、-3-羟基苯基、-4-羟基苯基、-吡啶-2-基、-吡啶-3-基、-吡啶-4-基、吡啶-1(2H)-基、-嘧啶-2-基、-吡嗪-2-基、-嘧啶-4-基、-哒嗪-3-基、-哒嗪-4-基、-嘧啶-2-基、-嘧啶-5-基、-1,2,4-三嗪-3-基、-1,3,5-三嗪-2-基、-1,2,3-三嗪-4-基、-1,2,3-三嗪-5-基、-1,2,3,4-四嗪-5-基、-1,2,3,5-四嗪-4-基、-1,2,4,5-四嗪-3-基、-五嗪-6-基、-噻唑、-咪唑、-恶唑、-异恶唑、-NH-芳基(必要时以-OH、-F、-Cl、-Br、-I、-OMe、-NH2、-CN、乙酰基单取代或多取代,多羟基取代,其中这些羟基官能团可以以缩醛的形式结合)、-NH-杂芳基(必要时用-OH、-F、-Cl、-Br、-I、-OMe、-NH2、-CN、乙酰基单取代或多取代,多羟基取代,其中这些羟基官能团可以以缩醛的形式结合)、单(羟基烷基)-苯基-、低聚(羟基烷基)-苯基,
R2=H、-C1-C24-烷基(直链和支链的)、-C1-C24-烯基(直链和支链的)、-C1-C8-环烷基、-C1-C24-羟基烷基(直链和支链的)、-C1-C24-烷基芳基(直链和支链的)、-C1-C24-烷基杂芳基(直链和支链的),
X=-H、-C1-C24-烷基(直链和支链的)、-C1-C24-烯基(直链和支链的)、-C1-C8-环烷基、-C1-C24-芳基(必要时用-OH、-F、-Cl、-Br、-I、-OMe、-NH2、-CN单取代或多取代)、-C1-C24-杂芳基(必要时用-OH、-F、-Cl、-Br、-I、-OMe、-NH2、-CN单取代或多取代)、-C1-C24-烷基芳基(直链和支链的)、-C1-C24-烷基杂芳基(直链和支链的)、-芳基(必要时用-OH、-F、-Cl、-Br、-I、-OMe、-NH2、-CN单取代或多取代)、-苯基、-2,4-二羟基苯基、-2,3-二羟基苯基、-2,4-二甲氧基苯基、-2,3-二甲氧基苯基,
Y=H、-C1-C24-烷基(直链和支链的)、-C1-C24-烯基(直链和支链的)、-C1-C8-环烷基、-C1-C24-芳基、-C1-C24-杂芳基、-C1-C24-烷基芳基(直链和支链的)、-C1-C24-烷基杂芳基(直链和支链的)、-芳基、-苯基、-2,4-二羟基苯基、-2,3-二羟基苯基、-2,4-二甲氧基苯基、-2,3-二甲氧基苯基、-COO-烷基、-COO-烯基、-COO-环烷基、-COO-芳基、-COO-杂芳基,
并且X、Y必要时地还可以=稠环芳香部分(Aromat),
其中X和Y可以彼此形成具有直至n个成环原子的芳香或脂族同素环或杂环的环体系,并且其中n的数值可以设为5到8,并且各个环体系又可以用直至n-1个烷基、羟基、羧基、氨基、腈官能团、含硫取代基、酯基和/或醚基取代。
所列出的噻唑可以以游离碱的形式以及以盐的形式存在:例如作为氟化物、氯化物、溴化物、碘化物、硫酸盐、碳酸盐、抗坏血酸盐、乙酸盐或磷酸盐存在。特别作为卤素盐例如氯化物和溴化物存在。
本发明的有利的实现方式还在于具有一定有效含量的一种或多种上述芳香性酰胺基噻唑的化妆或皮肤科制剂。
进而,根据本发明,以上列出的芳香性酰胺基噻唑的用途是用于处理和/或预防不期望的皮肤色素沉着。
此外,可以在化妆学和制药学的范畴中实现处理和/或预防不期望的皮肤色素沉着。
此外,在病理性皮肤状况中主要理解为药学(或皮肤科)处理,相反,在化妆学上处理和/或预防不期望的皮肤色素沉着主要涉及健康的皮肤。
有利地,X选自经取代的苯基基团,其中,取代基(Z)可以选自-H、-OH、-F、-Cl、-Br、-I、-OMe、-NH2、-CN、乙酰基基团并且可以是相同或不同的
特别有利地,X选自以一个或多个羟基取代的苯基基团,其中取代基(Z)可以选自-H、-OH、-F、-Cl、-Br、-I、-OMe、-NH2、-CN、乙酰基并且优选如下通用结构,其中,Y、R1和R2可以具有上文限定的特征。
特别地,这些化合物是有利的,在这些化合物中:
Y=H
R1=-C3-C24-芳基(必要时用-OH、-F、-Cl、-Br、-I、-OMe、-NH2、-CN、乙酰基单取代或多取代,多羟基取代,其中这些羟基官能团可以以缩醛的形式结合)、-C3-C24-杂芳基(必要时用-OH、-F、-Cl、-Br、-I、-OMe、-NH2、-CN、乙酰基单取代或多取代,多羟基取代,其中这些羟基官能团可以以缩醛的形式结合)、-C3-C24-芳基-C1-C24-烷基(直链和支链的)、-C3-C24-杂芳基-C1-C24-烷基(直链和支链的)、-C3-C24-芳基-C1-C24-烷基-羟基(直链和支链的)、-C3-C24-杂芳基-C1-C24-烷基-羟基(直链和支链的)、-2-羟基苯基、-3-羟基苯基、-4-羟基苯基、-吡啶-2-基、-吡啶-3-基、-吡啶-4-基、吡啶-1(2H)-基、-嘧啶-2-基、-吡嗪-2-基、-嘧啶-4-基、-哒嗪-3-基、-哒嗪-4-基、-嘧啶-2-基、-嘧啶-5-基、-1,2,4-三嗪-3-基、-1,3,5-三嗪-2-基、-1,2,3-三嗪-4-基、-1,2,3-三嗪-5-基、-1,2,3,4-四嗪-5-基、-1,2,3,5-四嗪-4-基、-1,2,4,5-四嗪-3-基、-五嗪-6-基、-噻唑、-咪唑、-恶唑、-异恶唑、-NH-芳基(必要时用-OH、-F、-Cl、-Br、-I、-OMe、-NH2、-CN、乙酰基单取代或多取代,多羟基取代,其中这些羟基官能团可以以缩醛的形式结合)、-NH-杂芳基(必要时用-OH、-F、-Cl、-Br、-I、-OMe、-NH2、-CN、乙酰基单取代或多取代,多羟基取代,其中这些羟基官能团可以以缩醛的形式结合)、单(羟基烷基)-苯基-、低聚(羟基烷基)-苯基,
R2=H、-C1-C24-烷基(直链和支链的),
Z=-H、-OH、-F、-Cl、-Br、-I、-OMe、-NH2、-CN、乙酰基。
在本发明的意义上优选如下结构的化合物:
其中R3和R4可以彼此独立地表示:
R3=H、-C1-C24-烷基(直链和支链的),
R4=H、-C1-C24-烷基(直链和支链的)。
特别优选的是这样的化合物,其中
Y=H
R1=-C3-C24-芳基(必要时用-OH、-F、-Cl、-Br、-I、-OMe、-NH2、-CN、乙酰基单取代或多取代,多羟基取代,其中这些羟基官能团可以以缩醛的形式结合)、-C3-C24-杂芳基(必要时用-OH、-F、-Cl、-Br、-I、-OMe、-NH2、-CN、乙酰基单取代或多取代,多羟基取代,其中这些羟基官能团可以以缩醛的形式结合)、-C3-C24-芳基-C1-C24-烷基(直链和支链的)、-C3-C24-杂芳基-C1-C24-烷基(直链和支链的)、-C3-C24-芳基-C1-C24-烷基-羟基(直链和支链的)、-C3-C24-杂芳基-C1-C24-烷基-羟基(直链和支链的)、-2-羟基苯基、-3-羟基苯基、-4-羟基苯基、-吡啶-2-基、-吡啶-3-基、-吡啶-4-基、吡啶-1(2H)-基、-嘧啶-2-基、-吡嗪-2-基、-嘧啶-4-基、-哒嗪-3-基、-哒嗪-4-基、-嘧啶-2-基、-嘧啶-5-基、-1,2,4-三嗪-3-基、-1,3,5-三嗪-2-基、-1,2,3-三嗪-4-基、-1,2,3-三嗪-5-基、-1,2,3,4-四嗪-5-基、-1,2,3,5-四嗪-4-基、-1,2,4,5-四嗪-3-基、-五嗪-6-基、-噻唑、-咪唑、-恶唑、-异恶唑、-NH-芳基(必要时用-OH、-F、-Cl、-Br、-I、-OMe、-NH2、-CN、乙酰基单取代或多取代,多羟基取代,其中这些羟基官能团可以以缩醛的形式结合)、-NH-杂芳基(必要时用-OH、-F、-Cl、-Br、-I、-OMe、-NH2、-CN、乙酰基单取代或多取代,多羟基取代,其中这些羟基官能团可以以缩醛的形式结合)、单(羟基烷基)-苯基-、低聚(羟基烷基)-苯基,
R2=H
Z=-H、-OH、-F、-Cl、-Br、-I、-OMe、-NH2、-CN。
根据本发明优选如下化合物:
N-(4-(2,4-二羟基苯基)噻唑-2-基)-4-(羟基甲基)苯甲酰胺
N-(4-(2,4-二羟基苯基)噻唑-2-基)-4-(2-羟基丙烷-2-基)苯甲酰胺
N-(4-(2,4-二羟基苯基)噻唑-2-基)-6-(羟基甲基)烟酰胺
N-(4-(2,4-二羟基苯基)噻唑-2-基)苯甲酰胺
4-氰基-N-(4-(2,4-二羟基苯基)噻唑-2-基)苯甲酰胺
4-乙酰基-N-(4-(2,4-二羟基苯基)噻唑-2-基)苯甲酰胺
N-(4-(2,4-二羟基苯基)噻唑-2-基)苯并[d][1,3]二氧杂环戊烯-5-甲酰胺
N-(4-(2,4-二羟基苯基)噻唑-2-基)吡啶酰胺
4-(叔丁基)-N-(4-(2,4-二羟基苯基)噻唑-2-基)苯甲酰胺
N-(4-(2-氟-4-羟基苯基)噻唑-2-基)苯甲酰胺
出人意料地显示,根据本发明的芳香性酰胺基噻唑相比于相应的芳香性氨基噻唑具有更高的盖仑氏稳定性和/或升高的效果。
具体实施方式
参见表1。
效果测试的方法描述:
噻唑的效果通过酶测定判定,在酶测定中测量通过人酪氨酸酶发生的由左旋多巴(L-DOPA)向左旋多巴醌(L-Dopachinon)的转化。在这种在文献中公知的方法(Winder,A.J.和Harris,H.,New assays forthe tyrosine hydroxylase and dopa oxidase activities of tyrosinase(对酪氨酸酶的酪氨酸羟化酶活性和多巴氧化酶活性的新的分析方法).Eur.J.Biochem.(1991),198,317-26)中,反应产物左旋多巴醌(L-Dopaquinone)与MBTH(3-甲基-2-苯并噻唑啉酮腙)向一种粉色物质转化,该粉色物质的随时间的增加通过在490nm下的吸收度测量。在表中示例性地示出了对于一些所主张的物质的效果数据。由此表明,根据本发明的物质是非常有效的色素沉着抑制物质。
示例性地选择的芳香性酰胺基噻唑的合成规则:
2-溴-2',4'-双-甲氧基羰基氧基-苯乙酮:
其中,quant.=一定量的;THF=四氢呋喃
Mitchell,David;Doecke,Christopher W.;Hay,Lynne A.;Koenig,Thomas M.;Wirth,David D.Tetra hedron Letters,1995
在900ml四氢呋喃中的60g(369mmol)2,4-二羟基苯乙酮和186ml三乙胺的溶液被冷却至0℃,并且缓慢地滴加在400ml四氢呋喃中的93ml氯甲酸甲酯。形成白色沉淀。在室温下搅拌3小时后反应完成(DC(薄层色谱)-作对照)。吸取沉淀并且以充足的四氢呋喃洗涤。滤液进行旋转蒸发从而干燥,置入乙酸乙酯中,用1N HCl和NaCl溶液(饱和的)洗涤并且经由硫酸镁干燥,过滤硫酸镁并且在旋转蒸发仪上浓缩乙酸乙酯。获得105g2,4-双-甲氧基羰基氧基-苯乙酮。1HNMR(DMSO-D6):8.05(d,1H),7.38(d,1H),7.36(s,1H),3.86(d,6H)。产物无需进一步净化地使用。在3h内,向在氯仿(1000ml)中的105g的2,4-双-甲氧基羰基氧基-苯乙酮溶液中滴加在450ml氯仿中的63g(392mmol)溴。之后该反应在室温下再搅拌15分钟,旋转蒸发溶剂。残余物在乙酸乙酯/正己烷中搅拌,吸取所产生的沉淀。由乙酸乙酯/正己烷的重结晶提供了100g的2-溴-2',4'-双-甲氧基羰基氧基-苯乙酮。1H NMR(DMSO-D6):8.11(d,1H),7.42(m,2H),4.87(s,2H),3.87(s,3H),3.85(s,3H)ppm;熔点73-74℃。
N-(4-(2,4-二羟基苯基)噻唑-2-基)-4-(羟基甲基)苯甲酰胺:
其中,Pyridin=吡啶
根据文献进行。产量:88%
BANYU Pharmaceutical Co.,Ltd.,EP2072519A1,2009
其中,Toluol=甲苯
73.06g(380mmol)4-乙酰氧基甲基苯甲酸在350ml亚硫酰氯中在回流下加热2小时。在真空中除去过量的亚硫酰氯之后,将剩余物置入1000ml甲苯并且加入57g(750mmol)硫脲。反应溶液在回流下煮沸3小时,然后在真空中除去溶剂。将固体与500ml甲醇和500ml乙酸乙酯煮沸并且热过滤。产量:55g。1H NMR(DMSO-D6):11.25(bs,1H),9.85(bs,1H),9.56(bs,1H),7.93(d,2H),7.47(d,2H),5.15(s,2H),2.10(s,3H)ppm。
74.3g(218mmol)2-溴-2',4'-双-甲氧基羰基氧基-乙酰苯和55g(218mmol)硫脲和28g(327mmol)NaHCO3在1000ml乙醇中在回流下煮沸0.5小时。反应溶液冷却并且与在300ml水中的70g(1.74mol)NaOH混合。在60℃下搅拌2小时之后,将反应溶液置入500ml水并且用2N HCl调节至pH=6。过滤出所产生的沉淀并且从乙醇/水中重结晶。获得46g噻唑。1H NMR(DMSO-D6):12.62(bs,1H),11.08(bs,1H),9.50(bs,1H),8.08(d,2H),7.70(d,1H),7.51(d,2H),7.48(s,1H),6.32(m,2H),5.38(t,1H),4.61(d,2H)ppm.熔点:251-254℃。
N-(4-(2,4-二羟基苯基)噻唑-2-基)-4-(2-羟基丙烷-2-基)苯甲酰胺:
根据文献进行。产量:37%
US-20070032484A1第48页
在室温下搅拌4.9g(12.2mmol)噻唑氢溴酸盐和2.2g(12.2mmol)4-(羟基-1-甲基-乙基)苯甲酸与4.3g(13.4mmol)TBTU以及在50mlDMF中的6.17g(61mmol)三乙胺过夜。在旋转蒸发器上除去二甲基甲酰胺,将反应混合物置入150ml乙醇中,加入在15ml水中的2.5g(61mmol)NaOH并且在室温下搅拌一小时。然后加入30ml水并且用1N HCl调节至pH=5。在真空中除去溶剂并且通过柱色谱在硅胶60上用9/1/0.1的氯仿/甲醇/NH3进行剩余物的净化。产量:1.3g。1H NMR(DMSO-D6):12.59(br,1H),11.06(br,1H),9.49(br,1H),8.05(d,2H),7.70(d,1H),7.65(d,2H),7.48(s,1H),6.30(m,2H),5.20(s,1H),1.46(s,6H)ppm;熔点:152-154℃。
N-(4-(2,4-二羟基苯基)噻唑-2-基)-6-(羟基甲基)烟酰胺:
其中,THF=四氢呋喃
根据文献进行。产量:50%
1.Sirtris Pharmaceuticals Inc.,WO2010/56549A1,2010
2.Pfizer Inc.,US2007/270438A1,2007
其中,Pyridin=吡啶
根据文献进行。
BANYU Pharmaceutical Co.,Ltd.,EP2072519A1,2009
产量:91%,1H NMR(DMSO-D6):13.27(bs,1H),9.03(d,1H),8.29(dd,1H),7.54(d,1H),5.22(s,2H),2.15(s,3H)ppm;
其中,Toluol=甲苯、THF=四氢呋喃
将5.0g(26mmol)6-乙酰氧基甲基烟酸溶解在100ml THF中,加入3.7g(31mmol)乙二酰氯然后在回流下加热15分钟。加入3.9g(51mmol)硫脲然后在回流下加热反应溶液3小时。在真空中除去溶剂并且通过柱色谱在硅胶上用9/1的氯仿/甲醇进行净化。产量:1.2g。1H NMR(DMSO-D6):11.54(s,1H),9.77(bs,1H),9.62(bs,1H),8.98(d,1H),8.28(dd,1H),7.52(d,1H),5.21(s,2H),2.15(s,3H)ppm;
1.6g(4.7mmol)2-溴-2',4'-双-甲氧基羰基氧基-乙酰苯和1.2g(4.7mmol)N-(6-乙酰氧基甲基烟酰基)硫脲和0.6g(7.1mmol)NaHCO3在20ml乙醇中在回流下煮沸0.5小时。反应溶液冷却并且与在10ml水中的2.0g(50mmol)NaOH混合。在60℃下搅拌2小时之后,将反应溶液置入50ml水并且用2N HCl调节至pH=6。反应混合物在真空中浓缩至约20ml并且过滤出所产生的沉淀。通过准备的HPLC(硅胶,RP18,水/乙腈/TFA50/50/0.1)进行净化,然后以盐酸盐的形式沉淀。获得0.3g噻唑。1H NMR(DMSO-D6):13.00(bs,1H),9.22(bs,1H),8.61(d,1H),7.79(d,1H),7.71(d,1H),7.53(s,1H),6.37(d,1H),6.33(dd,2H),5.80(bs,4H),4.79(s,2H)ppm.熔点:>202℃分解。
4-氰基-N-(4-(2,4-二羟基苯基)噻唑-2-基)苯甲酰胺:
其中,Toluol=甲苯
将10.6g(139mmol)硫脲预置在甲苯(100ml)中并且滴加11.5g(69.5mmol)4-氰基苯甲酰氯。反应溶液在回流下煮沸4小时。旋转蒸发出溶剂并且剩余物与乙腈煮沸三次并且热过滤。抽取从冷却溶液中沉淀出的晶体并且干燥。产量:7.7g。1H NMR(DMSO-D6):11.54(bs,1H),9.74(bs,1H),9.64(bs,1H),8.05(d,2H),8.02(d,2H)ppm。
13.02g(37mmol)2-溴-2',4'-双-甲氧基羰基氧基-乙酰苯和7.7g(37mmol)4-氰基苯甲酰基硫脲和4.72g(56mmol)NaHCO3在100ml乙醇中在回流下煮沸40分钟。反应溶液冷却并且与在100ml水中的6.0g(148mmol)NaOH混合。在室温下搅拌30分钟之后,反应溶液与50ml水混合并且以2N HCl调节至pH=4,并且在旋转蒸发器上除去乙醇。过滤出所产生的沉淀并且与乙醇煮沸两次并且热过滤。从冷却溶液中获得6.3g噻唑。1H NMR(DMSO-D6):12.92(bs,1H),10.93(bs,1H),9.52(bs,1H),8.24(d,2H),8.06(d,2H),7.71(d,1H),7.70(s,1H),6.33(m,2H)ppm.熔点:301-303℃。
4-(叔丁基)-N-(4-(2,4-二羟基苯基)噻唑-2-基)苯甲酰胺:
其中,Toluol=甲苯
将7.74g(102mmol)硫脲预置在甲苯(75ml)中并且滴加10g(50.8mmol)对叔丁基-苯甲酰氯。反应溶液在回流下煮沸4小时并且冷却。从乙醇中重结晶所沉淀的浅黄色晶体两次。产量:4.1g。1H NMR(DMSO-D6):11.11(bs,1H),9.88(bs,1H),9.53(bs,1H),7.90(d,2H),7.53(d,2H),1.30(s,9H)ppm.
4.71g(13.6mmol)2-溴-2',4'-双-甲氧基羰基氧基-乙酰苯和3.21g(13.6mmol)对叔丁氧基苯甲酰基硫脲和1.72g(20.4mmol)NaHCO3在45ml乙醇中在回流下煮沸0.5小时。冷却反应溶液并且与在15ml水中的2.0g(50mmol)NaOH混合。在室温下搅拌30分钟之后,将反应溶液置入30ml水并且以2N HCl调节至pH=6。过滤出所产生的沉淀并且从乙醇/水中重结晶两次。获得3.2g噻唑。1H NMR(DMSO-D6):12.59(bs,1H),11.06(bs,1H),9.50(bs,1H),8.06(d,2H),7.70(d,1H),7.59(d,2H),7.48(s,1H),6.32(m,2H),1.33(s,9H)ppm.熔点:228-229℃。
具有一定含量的芳香性酰胺基噻唑的化妆或皮肤科制剂或者其用于处理和/或预防不期望的皮肤色素沉着的用途,同样为本发明的有利的具体化。
特别有利的是,这些制剂含有以制剂的总重量计的0.000001至10重量%,特别是0.0001至3重量%,非常特别是0.001至1重量%的一种或多种根据本发明所使用的芳香性酰胺基噻唑。
根据本发明的化妆和皮肤科制剂可以以不同形式存在。因此,其可以是溶液、无水制剂、油包水(W/O)类型的或水包油(O/W)类型的乳剂或微乳剂、例如水包油包水(W/O/W)类型的多重乳剂、凝胶、固体棒、软膏或气溶胶。根据本发明同样有利的是,根据本发明所使用的物质和/或其衍生物例如在胶原基质中或其他常见的胶囊材料中呈现胶囊的形式,例如作为纤维素胶囊被包封在明胶或在脂质体中。
在本发明的意义上同样可行并且有利的是,根据本发明所使用的物质和/或其衍生物被加入到用来清洁皮肤和头发的含水体系或表面活性剂制剂中。
根据本发明的化妆和皮肤科配方可以包含如通常在这些制剂中使用的化妆助剂,例如防腐剂,杀菌剂,香精,防止起泡的物质,具有着色作用的染料、颜料,增稠剂,表面活性物质,乳化剂,增塑、湿润和/或保湿物质,脂肪,油、蜡或化妆或皮肤科制剂的其他常见成分,例如醇,多元醇,聚合物,泡沫稳定剂,电解质,有机溶剂或硅酮衍生物。
脂质相可以有利地选自以下物质的组:
-矿物油、矿物蜡
-油类,如癸酸或辛酸的甘油三酯,此外还有天然油,如蓖麻油;
-脂肪、蜡和其它天然和合成的脂肪体,优选脂肪酸与低碳数的醇的酯类,该醇例如为异丙醇、丙二醇或甘油,或者脂肪醇与低碳数的烷酸或与脂肪酸的酯;
-烷醇苯甲酸酯;
-硅油,如二甲基聚硅氧烷、二乙基聚硅氧烷、二苯基聚硅氧烷及其混合形式。
在本发明的意义上,乳剂、油凝胶或者水分散体或脂分散体的油相优选选自以下组,即,由饱和和/或不饱和、支链和/或非支链、链长为3至30个碳原子的烷烃羧酸,和饱和和/或不饱和、支链和/或非支链、链长为3至30个碳原子的醇所构成的酯;以及选自以下组,即,由芳香性羧酸和饱和和/或不饱和、支链和/或非支链、链长为3至30个碳原子的醇所构成的酯。这些酯油则可以优选选自以下组,即,肉豆蔻酸异丙酯、棕榈酸异丙酯、硬脂酸异丙酯、油酸异丙酯、硬脂酸正丁酯、月桂酸正己酯、油酸正癸酯、硬脂酸异辛酯、硬脂酸异壬酯、异壬酸异壬酯、棕榈酸-2-乙基己酯、月桂酸-2-乙基己酯、硬脂酸2-己基癸酯、棕榈酸2-辛基-十二酯、油醇油酸酯、油醇芥酸酯、瓢儿菜醇油酸酯、瓢儿菜醇芥酸酯以及这些酯的合成的、半合成的和天然的混合物,例如荷荷芭油。
根据本发明的制剂的水相包含必要时有利的保湿剂,例如丙二醇、泛醇或透明质酸,以及特别是一种或多种增稠剂,所述一种或多种增稠剂有利地可以选自以下组,即,二氧化硅、硅酸铝、羟丙基甲基纤维素,特别有利的是聚丙烯酸酯,例如980型卡波姆,上述物质分别单独或组合。
特别使用以上所列出溶剂的混合物。在醇性溶剂的情况下,另一种组分可以是水。
根据本发明的乳剂是有利的并且包含例如所列出脂肪、油、蜡和其他脂肪体,以及水和例如通常针对这种类型的配方所使用的乳化剂。
根据本发明的凝胶通常在增稠剂的存在下包含低碳数醇,例如乙醇、丙二醇,和水或以上所列出的油类,该增稠剂在油-醇凝胶的情况下优选为二氧化硅或硅酸铝,在水-醇或醇凝胶的情况下优选为聚丙烯酸酯。
作为用于根据本发明的,可由气溶胶容器喷射的制剂的推进剂适用的是通常公知的易挥发的液化的推进剂,例如碳氢化合物(丙烷、丁烷、异丁烷),它们可以单独地或者彼此混合地使用。使用压缩空气也是有利的。
有利地,根据本发明的制剂还可以包含吸收UVB范围中的UV-辐射的材料,其中过滤材料的总量为例如以制剂总重量计的0.1重量%至30重量%,优选0.5至10重量%,特别是1.0至6.0重量%,从而提供针对整个紫外辐射范围保护头发或皮肤的化妆制剂。其也可以充当头发或皮肤的防晒剂。
如下实施例用于解释本发明而不限制本发明。所有数量说明、份数和百分比份数,只要没有另加说明,涉及以制剂的重量和总量计或以制剂的总重量计的重量百分比。
配方实施例
O/W–乳液
W/O乳剂
Deo/AT-示例配方
实施例配方
将通过混合各个成分所获得的液相与丙烷-丁烷-混合物(2.7)以39:61的比例装入气溶胶容器。
Claims (12)
1.一种根据以下通式的芳香性酰胺基噻唑:
其中
R1、R2、X和Y能够是不同的、部分相同的或完全相同的,并且能够彼此独立地代表着:
R1=-C3-C24-芳基(必要时用-OH、-F、-Cl、-Br、-I、-OMe、-NH2、-CN、乙酰基单取代或多取代,多羟基取代,其中这些羟基官能团能够以缩醛的形式结合)、-C3-C24-杂芳基(必要时用-OH、-F、-Cl、-Br、-I、-OMe、-NH2、-CN、乙酰基单取代或多取代,多羟基取代,其中这些羟基官能团能够以缩醛的形式结合)、-C3-C24-芳基-C1-C24-烷基(直链和支链的)、-C3-C24-杂芳基-C1-C24-烷基(直链和支链的)、-C3-C24-芳基-C1-C24-烷基-羟基(直链和支链的)、-C3-C24-杂芳基-C1-C24-烷基-羟基(直链和支链的)、-2-羟基苯基、-3-羟基苯基、-4-羟基苯基、-吡啶-2-基、-吡啶-3-基、-吡啶-4-基、吡啶-1(2H)-基、-嘧啶-2-基、-吡嗪-2-基、-嘧啶-4-基、-哒嗪-3-基、-哒嗪-4-基、-嘧啶-2-基、-嘧啶-5-基、-1,2,4-三嗪-3-基、-1,3,5-三嗪-2-基、-1,2,3-三嗪-4-基、-1,2,3-三嗪-5-基、-1,2,3,4-四嗪-5-基、-1,2,3,5-四嗪-4-基、-1,2,4,5-四嗪-3-基、-五嗪-6-基、-噻唑、-咪唑、-恶唑、-异恶唑、-NH-芳基(必要时用-OH、-F、-Cl、-Br、-I、-OMe、-NH2、-CN、乙酰基单取代或多取代,多羟基取代,其中这些羟基官能团能够以缩醛的形式结合)、-NH-杂芳基(必要时用-OH、-F、-Cl、-Br、-I、-OMe、-NH2、-CN、乙酰基单取代或多取代,多羟基取代,其中这些羟基官能团能够以缩醛的形式结合)、单(羟基烷基)-苯基-、低聚(羟基烷基)-苯基,
R2=H、-C1-C24-烷基(直链和支链的)、-C1-C24-烯基(直链和支链的)、-C1-C8-环烷基、-C1-C24-羟基烷基(直链和支链的)、-C1-C24-烷基芳基(直链和支链的)、-C1-C24-烷基杂芳基(直链和支链的),
X=-H、-C1-C24-烷基(直链和支链的)、-C1-C24-烯基(直链和支链的)、-C1-C8-环烷基、-C1-C24-芳基(必要时用-OH、-F、-Cl、-Br、-I、-OMe、-NH2、-CN单取代或多取代)、-C1-C24-杂芳基(必要时用-OH、-F、-Cl、-Br、-I、-OMe、-NH2、-CN单取代或多取代)、-C1-C24-烷基芳基(直链和支链的)、-C1-C24-烷基杂芳基(直链和支链的)、-芳基(必要时用-OH、-F、-Cl、-Br、-I、-OMe、-NH2、-CN单取代或多取代)、-苯基、-2,4-二羟基苯基、-2,3-二羟基苯基、-2,4-二甲氧基苯基、-2,3-二甲氧基苯基,
Y=H、-C1-C24-烷基(直链和支链的)、-C1-C24-烯基(直链和支链的)、-C1-C8-环烷基、-C1-C24-芳基、-C1-C24-杂芳基、-C1-C24-烷基芳基(直链和支链的)、-C1-C24-烷基杂芳基(直链和支链的)、-芳基、-苯基、-2,4-二羟基苯基、-2,3-二羟基苯基、-2,4-二甲氧基苯基、-2,3-二甲氧基苯基、-COO-烷基、-COO-烯基、-COO-环烷基、-COO-芳基、-COO-杂芳基,
并且X、Y必要时还能够=稠环芳香部分,
其中,X和Y彼此能够形成具有直至n个成环原子的芳香或脂族同素环或杂环环体系,并且其中n的数值能够设为5到8,并且各个环体系又能够用直至n-1个烷基、羟基、羧基、氨基、腈官能团、含硫取代基、酯基和/或醚基取代,
其中,所述噻唑既能够作为游离碱存在也能够作为化妆和皮肤科能使用的盐存在。
2.根据权利要求1所述的芳香性酰胺基噻唑,其特征在于,X选自经取代的苯基基团,并且Y、R1和R2具有在权利要求1中所定义的特征。
3.根据权利要求2所述的芳香性酰胺基噻唑,其特征在于,X选自经取代的苯基基团,其中取代基(Z)能够选自-H、-OH、-F、-Cl、-Br、-I、-OMe、-NH2、-CN、乙酰基并且能够是相同的或不同的,并且Y、R1和R2具有在权利要求1中所定义的特征
4.根据权利要求或3所述的芳香性酰胺基噻唑,其特征在于,所述芳香性酰胺基噻唑具有如下结构:
,其中,取代基(Z)能够选自-H、-OH、-F、-Cl、-Br、-I、-OMe、-NH2、-CN、乙酰基,并且Y、R1和R2具有在权利要求1中所定义的特征。
5.根据前述权利要求任一项所述的芳香性酰胺基噻唑,其特征在于,所述芳香性酰胺基噻唑具有如下结构:
Y=H,
R1=-C3-C24-芳基(必要时用-OH、-F、-Cl、-Br、-I、-OMe、-NH2、-CN、乙酰基单取代或多取代,多羟基取代,其中这些羟基官能团能够以缩醛的形式结合)、-C3-C24-杂芳基(必要时用-OH、-F、-Cl、-Br、-I、-OMe、-NH2、-CN、乙酰基单取代或多取代,多羟基取代,其中这些羟基官能团能够以缩醛的形式结合)、-C3-C24-芳基-C1-C24-烷基(直链和支链的)、-C3-C24-杂芳基-C1-C24-烷基(直链和支链的)、-C3-C24-芳基-C1-C24-烷基-羟基(直链和支链的)、-C3-C24-杂芳基-C1-C24-烷基-羟基(直链和支链的)、-2-羟基苯基、-3-羟基苯基、-4-羟基苯基、-吡啶-2-基、-吡啶-3-基、-吡啶-4-基、吡啶-1(2H)-基、-嘧啶-2-基、-吡嗪-2-基、-嘧啶-4-基、-哒嗪-3-基、-哒嗪-4-基、-嘧啶-2-基、-嘧啶-5-基、-1,2,4-三嗪-3-基、-1,3,5-三嗪-2-基、-1,2,3-三嗪-4-基、-1,2,3-三嗪-5-基、-1,2,3,4-四嗪-5-基、-1,2,3,5-四嗪-4-基、-1,2,4,5-四嗪-3-基、-五嗪-6-基、-噻唑、-咪唑、-恶唑、-异恶唑、-NH-芳基(必要时用-OH、-F、-Cl、-Br、-I、-OMe、-NH2、-CN、乙酰基单取代或多取代,多羟基取代,其中这些羟基官能团能够以缩醛的形式结合)、-NH-杂芳基(必要时用-OH、-F、-Cl、-Br、-I、-OMe、-NH2、-CN、乙酰基单取代或多取代,多羟基取代,其中这些羟基官能团能够以缩醛的形式结合)、单(羟基烷基)-苯基-、低聚(羟基烷基)-苯基,
R2=H、-C1-C24-烷基(直链和支链的),
Z=-H、-OH、-F、-Cl、-Br、-I、-OMe、-NH2、-CN。
6.根据前述权利要求任一项所述的芳香性酰胺基噻唑,其特征在于,所述芳香性酰胺基噻唑具有如下结构:
Y=H,
R1=-C3-C24-芳基(必要时用-OH、-F、-Cl、-Br、-I、-OMe、-NH2、-CN、乙酰基单取代或多取代,多羟基取代,其中这些羟基官能团能够以缩醛的形式结合)、-C3-C24-杂芳基(必要时用-OH、-F、-Cl、-Br、-I、-OMe、-NH2、-CN、乙酰基单取代或多取代,多羟基取代,其中这些羟基官能团能够以缩醛的形式结合)、-C3-C24-芳基-C1-C24-烷基(直链和支链的)、-C3-C24-杂芳基-C1-C24-烷基(直链和支链的)、-C3-C24-芳基-C1-C24-烷基-羟基(直链和支链的)、-C3-C24-杂芳基-C1-C24-烷基-羟基(直链和支链的)、-2-羟基苯基、-3-羟基苯基、-4-羟基苯基、-吡啶-2-基、-吡啶-3-基、-吡啶-4-基、吡啶-1(2H)-基、-嘧啶-2-基、-吡嗪-2-基、-嘧啶-4-基、-哒嗪-3-基、-哒嗪-4-基、-嘧啶-2-基、-嘧啶-5-基、-1,2,4-三嗪-3-基、-1,3,5-三嗪-2-基、-1,2,3-三嗪-4-基、-1,2,3-三嗪-5-基、-1,2,3,4-四嗪-5-基、-1,2,3,5-四嗪-4-基、-1,2,4,5-四嗪-3-基、-五嗪-6-基、-噻唑、-咪唑、-恶唑、-异恶唑、-NH-芳基(必要时用-OH、-F、-Cl、-Br、-I、-OMe、-NH2、-CN、乙酰基单取代或多取代,多羟基取代,其中这些羟基官能团能够以缩醛的形式结合)、-NH-杂芳基(必要时用-OH、-F、-Cl、-Br、-I、-OMe、-NH2、-CN、乙酰基单取代或多取代,多羟基取代,其中这些羟基官能团能够以缩醛的形式结合)、单(羟基烷基)-苯基-、低聚(羟基烷基)-苯基,
R2=H,
Z=-H、-OH、-F、-Cl、-Br、-I、-OMe、-NH2、-CN。
7.根据前述权利要求任一项所述的芳香性酰胺基噻唑,其特征在于,所述芳香性酰胺基噻唑具有如下结构:
其中,R3和R4能够彼此独立地代表着:
R3=H、-C1-C24-烷基(直链和支链的),
R4=H、-C1-C24-烷基(直链和支链的)。
8.根据前述权利要求任一项所述的芳香性酰胺基噻唑,其特征在于,所述芳香性酰胺基噻唑具有如下结构之一:
N-(4-(2,4-二羟基苯基)噻唑-2-基)-4-(羟基甲基)苯甲酰胺,
N-(4-(2,4-二羟基苯基)噻唑-2-基)-4-(2-羟基丙烷-2-基)苯甲酰胺,
N-(4-(2,4-二羟基苯基)噻唑-2-基)-6-(羟基甲基)烟酰胺,
N-(4-(2,4-二羟基苯基)噻唑-2-基)苯甲酰胺,
4-氰基-N-(4-(2,4-二羟基苯基)噻唑-2-基)苯甲酰胺,
4-乙酰基-N-(4-(2,4-二羟基苯基)噻唑-2-基)苯甲酰胺,
N-(4-(2,4-二羟基苯基)噻唑-2-基)苯并[d][1,3]二氧杂环戊烯-5-甲酰胺,
N-(4-(2,4-二羟基苯基)噻唑-2-基)吡啶酰胺,
4-(叔丁基)-N-(4-(2,4-二羟基苯基)噻唑-2-基)苯甲酰胺,
N-(4-(2-氟-4-羟基苯基)噻唑-2-基)苯甲酰胺。
9.根据前述权利要求任一项所述的制剂,其特征在于,一种或多种所述噻唑作为卤化物、碳酸盐、抗坏血酸盐、硫酸盐、乙酸盐和/或磷酸盐存在。
10.一种具有一定含量的、如所述在前述权利要求中任一所定义的那样的一种或多种芳香性酰胺基噻唑的化妆或皮肤科制剂。
11.根据权利要求8所述的制剂,所述制剂含有相对于制剂的总重量的0.000001至10重量%,特别是0.0001至3重量%,非常特别是0.001至1重量%的一种或多种根据前述权利要求任一项中所定义的芳香性酰胺基噻唑。
12.一种或多种根据前述权利要求任一项所定义的芳香性酰胺基噻唑的、或者含有一种或多种所述芳香性酰胺基噻唑的制剂的、用于化妆或皮肤科处理和/或预防不期望的皮肤色素沉着的用途。
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CN105439978A (zh) * | 2015-12-15 | 2016-03-30 | 山东金城医药化工股份有限公司 | 阿考替胺中间体的制备方法 |
CN105439978B (zh) * | 2015-12-15 | 2018-02-16 | 山东金城医药化工股份有限公司 | 阿考替胺中间体的制备方法 |
CN108929271A (zh) * | 2018-06-29 | 2018-12-04 | 中国药科大学 | 酪氨酸酶抑制剂及其制备方法与用途 |
CN108929271B (zh) * | 2018-06-29 | 2021-08-31 | 中国药科大学 | 酪氨酸酶抑制剂及其制备方法与用途 |
CN116554122A (zh) * | 2023-06-29 | 2023-08-08 | 南京桦冠生物技术有限公司 | α-酮酸酰胺或取代草酸酰胺酯类化合物及其组合物 |
CN116554122B (zh) * | 2023-06-29 | 2023-09-19 | 南京桦冠生物技术有限公司 | α-酮酸酰胺或取代草酸酰胺酯类化合物及其组合物 |
Also Published As
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CN103930409B (zh) | 2016-08-24 |
DE102011083271A1 (de) | 2013-03-28 |
EP2758383B1 (de) | 2016-11-09 |
WO2013041535A1 (de) | 2013-03-28 |
PL2758383T3 (pl) | 2017-07-31 |
MX2014003450A (es) | 2015-06-05 |
ES2609580T3 (es) | 2017-04-21 |
EP2758383A1 (de) | 2014-07-30 |
JP2017141242A (ja) | 2017-08-17 |
JP2014526536A (ja) | 2014-10-06 |
JP6157475B2 (ja) | 2017-07-05 |
JP6584443B2 (ja) | 2019-10-02 |
MX349081B (es) | 2017-07-10 |
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