CN101796019A - 燕麦蒽酰胺的结构类似物，它们的组合物在治疗皮肤病中的用途 - Google Patents

燕麦蒽酰胺的结构类似物，它们的组合物在治疗皮肤病中的用途 Download PDF

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CN101796019A
CN101796019A CN200680005534A CN200680005534A CN101796019A CN 101796019 A CN101796019 A CN 101796019A CN 200680005534 A CN200680005534 A CN 200680005534A CN 200680005534 A CN200680005534 A CN 200680005534A CN 101796019 A CN101796019 A CN 101796019A
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卡罗·吉萨伯提
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Relivia SRL
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Abstract

Description

燕麦蒽酰胺的结构类似物，它们的组合物在治疗皮肤病中的用途
技术水平
本发明涉及具有燕麦蒽酰胺结构的物质的生物电子等排体、氮杂和硫代类似物衍生物，它们可用于制备有效治疗免疫过敏、过度增殖和炎性类型的皮肤病的药物组合物。
湿疹和银屑病形式是所有皮肤病问题的大约30-50％的原因且包含多种复合免疫、过度增殖和炎性病因的皮炎。此疾病的特征是其周期发作，表现为多个症状阶段。单个湿疹反应发病的原因是极为不同的，在一些案例中它们的复杂性还难以阐明。因此分类主要基于触发原因的起始、免疫组分的性质和重要性及基本的遗传因素。
最重要的形式有银屑病、接触性湿疹、脂溢性皮炎和(体质上)特应性皮炎。急性期的表现特征是伴有红斑、水肿、泡罩、糜烂和分泌物、随后脱皮和结痂的侵袭性、渗出性炎症。紧随其后的亚急性期仍出现渗出性症状且还有慢性炎症的特有体征例如泡状丘疹。在已知为慢性期的第三期，炎症性过程减少且发生皮肤表面(苔藓化)和角质层(角化过度)的增厚并随后出现皲裂。慢性形式的复发却导致苔藓化和分泌现象的同时发展。一个在所有期中均存在的主观皮肤症状是强烈瘙痒，它是复发期的特征。由于不停的搔抓，由此产生的破损处形成血痂导致进一步瘙痒发作，从而同时提供了利于真菌、病毒或细菌感染产生的介质。
在许多研究中发现具有燕麦蒽酰胺结构的物质可用于治疗红斑的皮肤病。US3490422和JP487359具体要求保护2-{[3-(3，4-二甲氧基苯基)丙烯酰基]氨基}苯甲酸或曲尼司特在特应性皮炎中的抗变应性作用和用途。
曲尼司特具有成为多功能药物的重要临床历史，例如能够在多种治疗背景下执行药学功能。事实上，除了发挥对肥大细胞瘤的稳定和抑制作用外，曲尼司特看起来不仅充当抗炎药而且还是例如血管平滑肌的纤维化和增殖抑制剂，参见Katon N等人(J.Dermatol.(日本)，23，335-9，1996)。京都和信州大学的研究者证实了曲尼司特抑制子宫平滑肌瘤生长且没有细胞毒性效应的剂量依赖性。曲尼司特似乎能够通过诱导p21(waf1)和p53来抑制CDK2活性(Shime H等人，J Clin Endocrinol Metab 2002；87：5610-5617)。
曲尼司特在结构上属于燕麦蒽酰胺家族，燕麦蒽酰胺家族化合物存在于燕麦颖片中，它们是在燕麦的含水酒精提取液组分中被鉴定出来的邻氨基苯甲酰胺和取代的肉桂酸。主要化合物已知为A、B和C燕麦蒽酰胺-分别是5-羟基-2-{[3-(4-羟苯基)丙烯酰基]氨基}苯甲酸、5-羟基-2-{[3-(4-羟苯基-3-甲氧苯基)丙烯酰基]氨基}苯甲酸和5-羟基-2-{[3-(3，4-二羟苯基)丙烯酰基]氨基}苯甲酸-此外还有由Collins W鉴定出来的以较低浓度存在于燕麦中的其它类似物(J.Agric.Food Chem.37，60-66，1989)。
Vollhardt和共同研究者再次证明了燕麦蒽酰胺的镇痛和抗氧化作用，提出将它们作为化妆品用途的成分(Proceedings 21st IFSCC Internet Congress，395；Berlin，2000)。
DE 10254872(WO 2004/047833)涉及燕麦蒽酰胺抑制组胺释放的性质，证实了它们作为抗炎药和/或镇痛局部用制剂成分的可能性。
发明概述
本发明涉及用于预防和治疗免疫过敏、过度增殖和炎性成分的皮肤病的具有燕麦蒽酰胺结构的物质的生物电子等排体。本发明的活性成分是式(I)化合物：
Figure G06805534720070823D000021
其中：
X、X’、X”和Y各自独立代表N、N→O或C-R5；
或X’＝X”基团代表硫原子S或氧原子O，X如前定义；
R4代表-OH、O-苄基、O-苯基、-CH2-CH(NHR6)-COOR8
或-CO-R4基团代表-COOH基团的生物电子等排体；
R1、R2、R3和R5各自独立代表-H、OH、CO-R4、-NH2、-NH-CO-R4、-O-COR7、-卤素、-OR7、-R7；
R6代表H或-COR7；
R7和R8各自独立代表直链或支链饱和或不饱和C1-20烷基基团，可被任意取代：优选C1-3烷基、更优选甲基基团；
如果X、X’、X”和Y中至少一个不同于C-R5或如果X、X’、X”和Y全等于C-R5，则R1、R2和R5中至少一个不同于-H、-OH和-OR7；
或它们的盐、溶剂化物或前体药物。
还描述了式(I)化合物通过式(a)和(b)化合物缩合的合成过程。
Figure G06805534720070823D000031
其中R1、R2、X、X’、X”、Y、R3、R4具有前面表明的含义。
本发明还包括：含有式(I)化合物的药物组合物及其治疗前述皮肤病的用途；含有式(I)化合物的化妆品用组合物及将它们用于化妆品治疗皮肤的用途。
发明详述
术语“-COOH基团的生物电子等排体”定义为羧基基团的生物学等价物，例如由Greenwood J R等人在Internet Journal of Chemistry 1，38(1998)中描述的“Heterocycles asbioisosteres for the ω-carboxylate moiety of glutamate in AMPA receptor agonists：Areviewand theoretical study”(杂环作为AMPA受体激动剂中的谷氨酸ω-羧化物部分的生物电子等排体：综述和理论研究)。
式(I)物质的-COOH基团的生物电子等排体的说明性实例是：
-选自以下基团的杂五元环：
Figure G06805534720070823D000032
其中Z和Z’代表N或C-r’；r’代表H或C1-2烷基，优选H或甲基；
-包括在以下基团中含有杂原子和具有吸引电子性质的双键的基团：
Figure G06805534720070823D000041
其中r’代表H或C1-3烷基，优选H或甲基。
术语“可能取代的”指的是用一价或二价基团取代氢。适合的取代基包括例如羟基、硝基、氨基、亚氨基、氰基、卤素、硫、硫代氨基、脒基、氧代、草酰脒基、甲氧脒基(methoxamidino)、二甲酰亚氨基(imidino)、胍基、亚磺酰氨基、羧基、甲酰基、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6烷氧基烷基、烷羰基、芳羰基、芳烷羰基、杂芳羰基、杂芳烷羰基、烷硫基、氨基烷基、氰烷基等等。取代基本身能被取代。取代基中的取代基团可以是例如羧基、卤素、硝基、氨基、氰基、羟基、C1-6烷基、C1-6烷氧基、氨基-CO-、-SR、硫代氨基、-SO2R或环烷基，其中R通常是氢、羟基或C1-6烷基。当所述的二级取代基包含直链基团时，该取代既能够发生在链中(例如2-羟丙基、2-氨基丁基等等)，也能够发生在链末端(例如2-羟乙基、3-氰基丙基等等)。所述二级取代基可以具有直链、支链或环碳原子或杂原子链结构。
从国际专利文献例如US 6,727,273和说明性实例中能够很容易理解这些和其它术语。
溶剂化物是水合、溶剂化和水脂络合的形式，例如脂质体、纳米球、微乳等等，和例如嵌入环糊精和其它交联聚合物例如PVP XL、葡聚糖、富勒烯中产生的包合物。
式(I)物质的盐是与生理学上可接受的酸或碱抗衡离子形成的。无机碱盐包括钠、钾、锂、铵、钙、镁、锌等等。有机碱盐包括胺、例如异丙胺、二乙醇胺、三乙醇胺、三丙胺、乙醇胺、2-二甲基氨基乙醇、氨基丁三醇、二环己胺、赖氨酸、精氨酸、组氨酸、咖啡因、普鲁卡因、海巴、胆碱、甜菜碱、乙二胺、葡萄糖胺、甲基葡萄糖胺、可可碱、哌嗪、哌啶等等。
酸加成盐是与无机酸例如氢卤酸、硫酸、硝酸、磷酸等等或与有机酸例如乙酸、乙醇酸、丙酮酸、草酸、苹果酸、丙二酸、丁二酸、马来酸、富马酸、酒石酸、柠檬酸、苯甲酸、肉桂酸、扁桃酸、甲磺酸或对甲苯磺酸、水杨酸、壬二酸、十一碳烯酸等等形成的。
能插入到可存在于式(I)物质的结构中的其它功能基团中的前体药物是可在体内释放的基团，例如如Sloan在“Prodrugs：Topical and ocular drug delivery”NY Marcel Dekker；Larsen & Ostergaard在“Textbook of drug design and discovery”，Chapter 14，London-NY，Tailor & Francis中所说明的那样。
式(I)化合物的优选亚类是Y选自N和N→O的那种。
优选的二级亚类是X、X’、X”中至少一个选自N和N→O的那种。优选的三级亚类是X’＝X”基团代表S或O的那种。
为了本发明的目的，结构(II)-(XVI)的物质是优选的：
Figure G06805534720070823D000051
Figure G06805534720070823D000061
Figure G06805534720070823D000071
式(I)物质的合成策略优选包含式(a)的(氮杂)肉桂酸-类型化合物与式(b)的(氮杂)苯胺(anilinic)-类型化合物的缩合反应：
Figure G06805534720070823D000072
其中R1、R2、X、X’、X”、Y、R3、R4具有前面表明的含义。
缩合步骤可以通过任选受保护的化合物(b)与任选受保护的化合物(a)的酰基卤(acidhalid)或酐的反应来进行，后者预先通过将羧基与无机酸性卤化物例如SOCl2、PCl3、PBr3或PCl5，或者可替代的与草酰氯通常在胺作为吸酸剂例如三乙胺、二异丙基乙胺、N-甲基吗啉等等的存在下接触来制备。
或者，化合物(a)和(b)可通过使用任何常规偶联试剂包括碳二亚胺例如二环己基碳二亚胺、N，N’-碳二咪唑、N-羟基琥珀酰亚胺、1-羟基苯并三唑等等来帮助羧基部分与胺基的偶联来缩合。
任选存在于化合物(a)和/或(b)中的功能基团例如氨基、羟基或羧基在任何反应开始前需要保护，其中保护基团的除去可以是一个特殊反应的最后步骤。这些功能基团的适合保护基团对本领域技术人员来说是显而易见的。详细细节参见“Protective Groups inOrganic Synthesis”，Wiley Interscience，TW Green，PGM Wuts。
因此，含有-OH、-NH2或-COOH基团的化合物(a)和(b)将在缩合前被保护，例如O-保护为O-Ac、COO-保护为甲酯、N-或O-用叔丁氧羰基、叔戊氧羰基或苄氧羰基保护等等。
不必总是分离和纯化这些受保护的衍生物。例如，O-保护的中间体(a)可与氯甲酸酯或SOCl2反应而生成的混有酐或酰基氯(acid chloride)的烷基碳酸酯可以不经分离和纯化用于缩合步骤。
反之，如果发现游离-OH、-NH2或-COOH比它们受保护的形式更有生物活性则脱保护反应是必须的。
本发明化合物具有显著抗增殖、免疫抑制和抗炎活性：由于这些性质，已证实它们对治疗和/或预防皮肤病特别是那些有免疫过敏、过度增殖和炎性成分的皮肤病有效。这些病的实例是湿疹(例如接触性湿疹、皮脂溢性湿疹)、银屑病、皮炎(例如特应性；由于药物、接触刺激物、接触变应原；皮脂溢性；由于尿布；小儿丘疹性肢端皮炎)、红斑特征的皮肤病、纤维化、扁平红色苔藓、玫瑰糠疹、自身免疫性大疱病、荨麻疹和血管性水肿。
因此本发明的一方面是一个或多个前述式(I)化合物用于制备对治疗和/或预防所述皮肤病有效的药物的用途。
本发明的另一方面是包含一个或多个治疗有效量的式(I)化合物和皮肤病学/生理学上可接受的辅料和成分的药物组合物。
皮肤病学/生理学上可接受的辅料和成分还可包括用作组合物中目的物质的稀释剂、分散剂或载体的生理学上可接受的媒介物。除水外的媒介物可包括液体或固体润滑剂、硅酮和溶剂。油和类脂可通过乳化剂和表面活性剂与水组合；此外还可包括防腐剂、色素、遮光剂、香料和其它INCI列表中的化妆品用成分。
在一个优选实施方案中，本发明的组合物与其它抗氧化物质例如那些化妆品领域中可用于此目的的物质组合使用。
这些物质非限制性地包括：类视黄醇(例如视黄酸、视黄醇)、类胡萝卜素(例如α-和β-胡萝卜素)、叶黄素(例如黄体素、玉米黄质)、维生素E(例如α-和γ-维生素E)和衍生物、水杨酸类、维生素C、果酸(例如甘醇酸、乳酸、柠檬酸、它们的盐和酯)、植物黄酮类和多酚类(芸香苷、橙皮苷、槲皮苷、儿茶素、没食子酸和没食子酸盐、OPC、鞣酸)、褪黑激素、黑色素、肌肽和尿刊酸、巯基氨基酸(半胱氨酸、胱氨酸、蛋氨酸、它们的酰胺和盐)、硫辛酸等等。
此外，在保护皮肤的应用中，本发明的物质能与其它镇痛性质的物质例如α-红没药醇、甘菊环烃、愈创蓝油烃、18-β甘草次酸组合使用。
式(I)物质还适合与其它活性成分组合。
说明性实例是具有创伤愈合和镇痛和/或血管生成作用的包含高分子量(MW)透明质酸(HA)和低分子量(MW)透明质酸(OHA)的多糖；硫酸化氨基葡聚糖例如肝素、乙酰肝素、软骨素和硫酸角质素；多聚半乳甘露聚糖例如瓜尔胶、多聚琼脂糖和多聚琼脂胶例如琼脂；多聚糖醛酸例如藻胶和藻酸盐；单独和与阿拉伯糖和半乳糖例如果胶和果胶酸盐组合的聚半乳糖醛酸盐；混合多糖例如阿拉伯胶(阿拉伯)、刺梧桐树胶、黄芪胶(黄蓍胶糖)、κ-角叉菜胶和λ-角叉菜胶；聚甘露-葡萄糖-葡糖醛酸例如黄原胶、乙酰化聚甘露糖(芦荟胶)、甲壳质和壳聚糖；聚糖酐；等等。
本发明尤其优选D-葡糖醛酸和N-乙酰葡糖胺的多糖(GlcA/GlcNAc)，已知为透明质酸，具有创伤愈合活性的高分子量(HA)或具有血管生成作用的低分子量低聚糖(OHA)均对修复皮肤或粘膜上的血管系统的可能缺失有效。其它具有创伤愈合和镇痛作用的优选多糖是芦荟的乙酰化聚甘露糖(醋孟南)和藻酸盐。
其它说明性实例是多聚不饱和脂肪酸包括具有ω-3和-6系的至少两个双键的C16-C24不饱和脂肪酸例如γ-亚油酸、α-亚油酸、亚麻酸、同型-γ-亚麻酸、哥伦比亚酸、二十-(n-6，9，13)-三烯酸、二十碳五烯酸、花生四烯酸、二十二碳五烯酸、二十碳六烯酸等等。
为了本发明的目的，所述的多聚不饱和脂肪酸可以游离形式或作为甘油三酯或其它酯存在。使用的具有高多聚不饱和含量的最常见于植物油，例如琉璃苣油、亚麻籽油、豆油、除臭鱼油、海藻油(选择高DHA含量的种类)、鳄梨油、核桃油、大麻油、玫瑰油、杏仁油、玉米油、葡萄籽油、红花油、芝麻油、葵花油、小麦胚芽油、荷荷芭油、橄榄油等等。
更多实例是甾体(cortisonic)和非甾体抗炎药。后者包括以下几类物质：
1)苯并噻唑类，例如吡罗昔康、伊索昔康、替诺昔康和舒多昔康；
2)水杨酸类，例如阿司匹林、双水杨酯、贝诺酯、briflunisal、safaprin、solprin和二氟苯水杨酸；
3)乙酸衍生物例如双氯芬酸、吲哚美辛、舒林酸、托美汀、芬替酸；
4)芬那酸类，例如甲灭酸、氟灭酸、尼氟灭酸和托灭酸；
5)丙酸衍生物，例如布洛芬、甲氧萘丙酸、苯噁洛芬、氟比洛芬、酮洛芬、非诺洛芬、苯噁丙酸、舒洛芬、阿明洛芬和噻洛芬酸；
6)吡唑类，例如苯保泰松、羟基保泰松、非普拉酮、阿扎丙宗和三甲保泰松。
其它实例有：局部抗真菌药(例如咪唑和三唑衍生物例如咪康唑、益康唑)；润滑剂和防护油脂(如ZnO糊剂)；结瘢剂(例如乙酰半胱氨酸、蛋白水解酶)；局部抗生素(例如夫西地酸、庆大霉素、莫匹罗星)；局部化学疗法(例如磺胺类药物、磺胺嘧啶银)；抗病毒药(例如阿昔洛韦)；防腐剂和消毒剂(例如双胍类和脒类例如氯己定+溴化十六烷基三甲铵、硼酸盐、聚维酮碘、碘、季铵类化合物例如苯扎氯铵、汞制剂例如汞溴红、银、H2O2、NaOCl)；抗痤疮药物(例如视黄酸、甲氯环素)。
使用本发明的式(I)物质治疗还可与使用以下药物的全身抗生素疗法组合：四环素类(例如多西环素)、氨苯吡啶酮类(例如氯霉素)；β-内酰胺类(广谱青霉素；耐受内酰胺酶的青霉素；单菌霉素例如阿苏胺；碳青霉烯类例如美罗培南、亚胺培南-西司他丁)；硫酰胺(例如磺胺嘧啶、磺胺甲基异噁唑-甲氧苄啶)；大环内酯类等等例如(红霉素、clarithroymycin、阿奇霉素、林可酰胺类、克林霉素、链阳性菌素类)；氨基糖苷类(例如链霉素、庆大霉素、阿米卡星、奈替米星)；喹诺酮类(例如环丙沙星、诺氟沙星、洛美沙星、左氧氟沙星、莫西沙星)；糖肽类(例如万古霉素、替考拉宁、多粘菌素、多粘菌素E)；咪唑类(例如甲硝唑)；呋喃类(例如呋喃妥因)；和其它抗菌药物(例如利奈唑胺)。
所述物质可通过多种途径给药：口服、静脉内、腹膜内、胃内输注、灌肠、门静脉输注、吸入等等。
本发明组合物含有占组合物重量的0.01-80％间，优选重量的1-20％间的式(I)化合物。化合物(I)的剂量通常在0.01-2000mg/天之间。
该组合物可制成亲脂碱(或者如果需要在水介质中)作为局部应用的皮肤病制剂。局部使用的一般组合物的每克组合物含有在大约1μg-50mg间的活性成分。本发明组合物还可制成洗剂、流体乳膏剂、乳膏剂或凝胶剂形式。该组合物可根据粘性和应用包装在适合的容器中。例如，洗剂或液体乳膏剂可装在瓶子或滚涂的容器中，而稠乳膏剂可装在小管、罐或瓶中。
本发明组合物可通过静脉内注射、皮下注射等等含有式(I)物质的使用已知技术预先灭菌的溶液、混悬液或乳状液来全身给药。
含有式(I)物质的组合物还可通过口服、舌下、经直肠、肺吸入、为避免胃肝路开发的释放药物的技术和/或注射方法给药。
用于变性病理学所得到的明确结果要求提供足量的活性成分以产生所需作用。明确了本发明的治疗疗法可与其它治疗和当前用于前述病症所规定的局部或全身药物同时或交替地组合使用。
式(I)化合物还提供镇痛、抗氧化和皮肤保护活性：除了药学领域，这些性质还使其在单独化妆品应用上有用。因此本发明延伸至化妆品治疗皮肤的方法，该方法以一个或多个式(I)化合物的化妆品用有效量与化妆品用途的辅料组合的局部应用为特征。本发明还包含相关化妆品组合物，其特征在于包括一个或多个式(I)化合物与化妆品用途的辅料组合。以下实施例用来进一步说明本发明并不以任何方式限制本发明。
实施例
合成方法
(a)和(b)的缩合
在氮气环境下，将PCl3(1.6g，2.3eq)滴加到式(a)化合物(1eq)例如3，4-二甲氧基-(氮杂)肉桂酸和式(b)化合物(1.3eq)例如(氮杂)甲基邻氨基苯甲酸酯的无水THF溶液(30ml)中。然后加热回流溶液5小时。反应结束后(TLC)蒸发溶剂。粗产品用硅胶快速色谱法纯化(例如己烷-乙酸乙酯体积比9∶1)。得到式(I)物质。
-OH酯化为-O-Ac
根据常规方法在室温下用吡啶中的乙酸酐通过乙酸基团实现对羟基尤其是酚羟基的保护。
O-Ac基团水解为-OH
将MeOH/H2O/25％NH4OH 50∶35∶15(10ml)中含有酚基(phenolic)或羟烷基的乙酸酯的式(I)物质(0.26mmoles)的溶液加热至50℃，1小时。减压除去溶剂，且用快速色谱法(洗脱液己烷/乙酸乙酯1∶1)纯化粗产品，获得相应水解产物。
-COOH基团酯化为-CO-OMe
在氮气环境下，将浓H2SO4(4.3ml)缓慢滴加至含有-COOH基团的式(a)或(b)中间体(13.7mmoles)的无水MeOH(17.1)溶液中。反应搅拌回流4小时然后倒入H2O(10ml)并添加NaHCO3碱化至pH9。通过布氏漏斗过滤沉淀并用MeOH冲洗。得到相应的酯化产物。
-CO-OMe基团的水解
将0.25M NaOH的MeOH(13ml)中含有甲酯形式的羧基的式(I)物质(0.17mmoles)的溶液加热回流14小时随后减压除去溶剂。残渣再溶解在H2O(5ml)中并用浓HCl酸化至pH4。通过布氏漏斗过滤沉淀且用H2O冲洗，获得相应水解产物。
用t-BOC保护-OH或-NH2基团
在氮气环境下，无水Et3N(425μl，3mmoles)和BOC2O(1g，4.6mmoles)加入至式(b)物质(3mmoles)的无水CH2Cl2(30ml)溶液中。搅拌反应12小时，减压除去溶剂。
前述方法也可按下列方式改变：在CH2Cl2(1ml)中的式(b)物质0.61mmoles和在CH2Cl2(1ml)中的BOC2O(440.4mg，2.02mmoles)在0℃下加入至NaOH(67.2mg，1.68mmoles)和Bu4NHSO4(5mg，0.012mmoles)的CH2Cl2(1ml)混悬液中。反应混合物室温下保持搅拌12小时然后加入H2O(10ml)并用CH2Cl2萃取。Na2SO4干燥有机相，过滤，并减压除去溶剂。
得到的粗产品用硅胶快速色谱法纯化，例如己烷/乙酸乙酯75∶25作为洗脱液。
-O-Ac、-CO-OMe和-O-tBOC基团的同时水解
甲酯也可用含有0.25M NaOH的MeOH回流14小时直接水解，同时除去所有保护基团。在经典条件下进行随后的工作来获得式(I)物质。
式(X)物质的合成
获得式(X)物质的经典方法是转化N-(3’，4’-二甲氧基肉桂酰基)邻氨基苯甲酸或相应腈，通常用叠氮酸源(例如叠氮化钠和氯化铵)与受体例如腈基在惰性溶剂中高温下反应。
作为另一种选择，应用Wittenberger和Donner合成法使用腈和三甲基甲硅烷基叠氮(TMS-N3)与在甲苯中的二烷基锡氧化物回流催化。
式(XI)物质的合成
式(XI)物质可从N-(3’，4’-二甲氧基肉桂酰基)邻氨基苯甲酸中获得，如Weinstock等人在J.Org.Chem.，1967，32，2823中的描述。
生物学实施例
T细胞抑制活性
鼠胸腺细胞和Th1细胞上的选择性细胞凋亡活性可根据Puccetti P等人Cell DeathDifferent.(2002)9：1069-1077用体外方法来评价。
来自4±6周大的DBA/2小鼠(Charles River，Calco，Italy)的胸腺细胞通过尼龙羊毛柱富集。C57BL/6-lpr/lpr小鼠(Jackson Laboratory，Bar Harbor，ME，USA)也如此使用。细胞生存力(＞95％)和它们如巨噬细胞的总体(＞99％)的特征用显微镜分析和非特异性酯酶染色证实。
材料和方法
细胞在含有10％FCS的RPMI培养基中用10mM式(I)化合物培养24小时。然后用流式血细胞术根据Puccetti P等人(1997)J.Immunol.158：3593-3602所描述的方法检测细胞凋亡。简言之，培养后离心细胞，颗粒轻轻重悬于0.3ml低渗碘化丙啶(PI)溶液中(PI，在0.1％柠檬酸钠中和0.1％Triton X-100中含有50mg/ml PI；Sigma Chemical Co.)。黑暗中保存小管于48℃1小时。用流式血细胞术在标准FACScan设备(Becton Dickinson，Mountain View，CA，USA)下用488-nm氩激光器和560-nm dichroid镜(DM 570)和600nm带通滤波器(带宽35nm)的入射光束检测单个细胞核的PI荧光，用PI DNA染色收集红色荧光。用Hewlett Packard(HP 9000，model 310；Palo Alto，CA，USA)计算机对数标度记录数据，其中细胞凋亡的细胞核(DNA荧光直方图中的亚二倍体DNA峰)的％用FACScan研究软件(Lysis II)来计算。
结果
在式(I)物质大约10mM浓度下观察到的T细胞凋亡范围是20％-75％。这些数据说明T淋巴细胞的缺失可能显示了式(I)物质对改善免疫、过敏、过度增殖和炎性局部反应持续的皮肤病的主要贡献。
Figure G06805534720070823D000131
实施例1-乳膏剂
100g乳剂中含有：
                                                                    
式(II)化合物                                          0.5g
硬脂酸                                                1.75g
单硬脂酸丙二醇酯                                      2.7g
辛酸/癸酸丙二醇的有机皂土胶                           6.0g
棕榈酸异丙酯                                          6.5g
硅氧烷液体345                                         3.0g
脱水山梨糖醇硬脂酸酯                                  1.8g
PEO-脱水山梨糖醇硬脂酸酯                              1.5g
十六醇                                                0.6g
UVA和UVB过滤剂                          2.0g
EDTA钠                                  0.1g
硅酸铝                                  0.8g
羟甲基纤维素                            0.15g
丙二醇                                  4.0g
软化水              补充至              100g
实施例2-高内相W/O乳剂
100g乳剂含有：
                                                     
式(IV)化合物                            0.3g
视黄醇                                  0.5g
氢化椰子油                              5.9g
油烯基-(2)-POE                          5.0g
有机皂土38                              0.5g
MgSO4×7H2O                             0.3g
软化水              补充至              100g
实施例3-抗红斑制剂
100g乳剂含有：
                                                    
式(VIII)化合物                          0.3g
环甲基硅氧烷                            2.0g
脂肪醇+氢化蓖麻油PEG-40+高级醇硫酸钠    4.5g
硬脂酸辛酯                              3.0g
蓖麻油                                  4.0g
甘油                                    3.0g
卡波普                                  0.3g
羟丙基甲基纤维素                        0.3g
甲氧肉桂酸辛酯                          5.0g
丁基-甲氧基-二苯酰基甲烷                0.5g
EDTA钠                                  1.5g
软化水           补充至                 100g
实施例4-抗皮炎乳膏剂
100g乳剂含有：
                                                 
式(XVI)化合物                           0.2g
蜂蜡                                    1.5g
杏仁油                                  13.0g
黄原胶                                  0.5g
超氧化物歧化酶(SOD)                     0.004g
环戊二甲基硅硅氧烷                      5.0g
蔗糖单-和双-棕榈酸盐/-硬脂酸盐          3.0g
甲基葡萄糖倍半硬脂酸酯                  3.0g
硬脂酸                                  1.0g
十六醇                                  3.0g
防腐剂                                  0.3g
软化水             补充至               100g
实施例5-抗湿疹乳膏
100g乳膏含有：
                                                    
式(III)化合物                           0.3g
液体凡士林                              2.0g
十六醇-(10)-POE                         4.0g
脂肪醇                                  4.0g
三乙醇胺                                1.75g
丁-1，3-二醇                            3.0g
黄原胶                                  0.3g
软化水               补充至             100g
实施例6-抗红斑痤疮含水酒精洗剂
100g洗剂含有：
                                            
式(VI)化合物                              1.5g
醋酸维生素E                               0.15g
壬二酸                                    2.0g
95°乙醇                                  20g
软化水                 补充至             100g
实施例7-无水化妆品用制剂
100g无水组合物含有：
                                                       
式(XII)组合物                             0.5g
β-胡萝卜素                               0.15g
硅氧烷SE-30(1)                            10g
硅氧烷液体345(2)                          18g
硅氧烷液体344(3)                          55.79g
琉璃苣油                                  10.0g
胆固醇                                    0.03g
2-羟基-n-辛酸                             0.7g
95°乙醇                                  2.0g
(1)二甲基硅酮聚合物MW 50000D；25℃时粘性10000厘司托克
(2)环二甲基硅氧烷五聚物
(3)二甲基硅氧烷四聚物
实施例8-小儿制剂
100g乳膏剂含有：
                                                     
式(XV)化合物                              0.3g
硬脂醇醚                                  0.1g
脂肪醇                                    0.4g
液体凡士林                                12.5g
蜡状凡士林                                11.0g
鲸蜡6-硬脂醇                              6.0g
超氧化物歧化酶                            0.008g
茶提取物                               2.9g
L-蛋氨酸                               0.7g
软化水              补充至             100g
实施例9-镇痛洗剂
100g洗剂含有：
                                                    
式(X)化合物                            0.1g
95°乙醇                               30g
香料                                   0.3g
软化水              补充至             100g
实施例10-安瓿剂
在60升双蒸水中的1kg式(XI)物质溶液无菌过滤，分装至安瓿中，无菌条件下冻干且无菌密封。每个安瓿含有20mg活性化合物。
实施例11-注射用管形瓶
200g式(XIII)物质和5g pH6.5的磷酸氢二钠缓冲溶液溶解于3升含有少量稀HCl的双蒸水中，然后无菌过滤，分装至注射用管形瓶中，无菌条件下冻干且无菌密封。每个注射用管形瓶含有10mg活性化合物。
实施例12-栓剂
将40g式(XIV)物质和100g大豆卵磷脂和及1400g可可豆脂油的混合物熔化，倒入模具中冷却获得40g活性物质的栓剂。
实施例13-片剂
压制2kg式(V)物质、4kg乳糖、1.2kg马铃薯淀粉、0.2kg滑石粉和0.1kg硬脂酸镁的混合物以获得每片含有20mg活性化合物的片剂。
实施例14-包衣片剂
类似实施例13制备的片剂用蔗糖、马铃薯淀粉、黄芪胶和染料包衣。
实施例15-胶囊剂
4kg重量的式(VII)物质插入硬明胶胶囊，使每个胶囊含有40mg活性化合物。

Claims (19)

1.式(I)化合物
Figure F06805534720070823C000011
其中：
X、X’、X”和Y各自独立代表N、N→O或C-R5；
或X’＝X”基团代表硫原子S或氧原子O，且X如前定义；
R4代表-OH、O-苄基、O-苯基、-CH2-CH(NHR6)-COOR8或-CO-R4基团代表-COOH基团的生物电子等排体；
R1、R2、R3和R5各自独立代表-H、OH、CO-R4、-NH2、-NH-CO-R4、-O-COR7、-卤素、-OR7、-R7；
R6代表H或-COR7；
R7和R8各自独立代表直链或支链饱和或不饱和C1-20烷基基团，可被选择取代，优选C1-3烷基、更优选甲基基团；
如果X、X’、X”和Y中至少一个不同于C-R5或如果X、X’、X”和Y全等于C-R5，则R1、R2和R5中至少一个不同于-H、-OH和-OR7；
或它们的盐、溶剂化物或前体药物。
2.根据权利要求1所述的化合物，其中Y选自N和N→O。
3.根据权利要求1所述的化合物，其中X、X’、X”中至少一个选自N和N→O。
4.根据权利要求1所述的化合物，其中X’和X”共同代表硫原子S或氧原子O。
5.根据权利要求1-4中任一项所述的化合物，其中CO-R4基团代表选自以下的取代基：
Figure F06805534720070823C000012
Figure F06805534720070823C000021
其中Z和Z’代表N或C-r’；r’代表H或C1-3烷基，优选H或甲基。
6.根据权利要求1所述的化合物，具有以下结构(II)-(XVI)中的一种：
Figure F06805534720070823C000022
Figure F06805534720070823C000041
7.权利要求1所述的式(I)化合物的制备方法，包括式(a)化合物和式(b)化合物的缩合反应：
Figure F06805534720070823C000042
其中R1、R2、X、X’、X”、Y、R3、R4具有权利要求1中表明的含义。
8.根据权利要求7所述的方法，其中所述的缩合反应是在偶联试剂的存在下进行的，所述的偶联试剂能促进羧基部分与胺基基团的偶联。
9.根据权利要求7所述的方法，其中所述的缩合反应是通过化合物(b)与活化形式的化合物(a)的反应进行的。
10.根据权利要求9所述的方法，其中所述的活化形式是化合物(a)的酰基卤或酸酐。
11.权利要求1-6中任一项所述的式(I)化合物在制备用于治疗和/或预防皮肤病的药物中的用途。
12.根据权利要求11所述的用途，其中所述的皮肤病是免疫过敏、过度增殖或炎性类型。
13.根据权利要求12所述的用途，用于治疗和/或预防湿疹、银屑病、皮炎、红斑、纤维化、扁平红色苔藓、玫瑰糠疹、自身免疫性大疱病、荨麻疹和血管性水肿。
14.包含一个或多个权利要求1-6中任一项所述的式(I)化合物的药物组合物，所述的式(I)化合物以治疗有效量与辅料和皮肤病学/生理学上可接受的成分组合使用。
15.根据权利要求14所述的组合物，适合于通过局部、口服、静脉内、腹膜内、胃内输注、灌肠、门静脉输注、吸入、舌下、经直肠、肺吸入等途径给药。
16.根据权利要求14-15中任一项所述的药物组合物，包含式(I)化合物的量占所述组合物重量的0.01-80％，优选重量的1-20％。
17.根据权利要求14-16中任一项所述的药物组合物，以洗剂、液体乳膏剂、或凝胶、溶液、混悬液、乳剂的形式存在。
18.包含一个或多个权利要求1-6中任一项所述的式(I)化合物的化妆品用组合物，所述的式(I)化合物以化妆品用有效量与化妆品使用的辅料和成分组合使用。
19.化妆品治疗皮肤的方法，其特征是，局部施用化妆品用有效量的一个或多个权利要求1-6中任一项所述的式(I)化合物，所述的一个或多个式(I)化合物和化妆品使用的辅料和成分组合使用。
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