CN101282722A使用青蒿素及其衍生物治疗和预防良性色素痣（痣）---所述制剂对治疗痣细胞痣最适，对黑素细胞痣特别有效，从而也可用于预防皮肤癌｜CN101282722A Artemisinin and its derivatives for treating and preventing benign melanocytic nevi (moles) --- The preparation is most suitable for treating epidermal nevi, particula
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CN101282722A使用青蒿素及其衍生物治疗和预防良性色素痣（痣）---所述制剂对治疗痣细胞痣最适，对黑素细胞痣特别有效，从而也可用于预防皮肤癌
用青蒿素及其衍生物治疗和预防良性色素斑（痣）
皮肤良性色素痣或脚癣或甲真菌病可用局部给药的、特别是式(I)的局部用配方活性成分来治疗，式中X代表CO、CHOZ或CHNRZ，Z选自氢、直链或支链(C1－C6)烷基、直链或支链(C2－C6)烯基、直链或支链(C2－C6)炔基、(C3－C8)环烷基、(C6－C24)芳基、(C7－C24)芳烷基、间－CH2(C6H4)COOM和对－CH2(C6H4)COOM；COR3；CSR3；C(NR6)R3；SOR4；SO2OM；SO2NR7R8；SO2O－蒿素基；SO2NH－蒿素基；POR4R5和PSR4R5；R3代表直链或支链(C1－C6)烷基、直链或支链(C1－C6)烷氧基；直链或支链(C2－C6)烯基；直链或支链(C2－C6)炔基；(C3－C8)环烷基；(C6－C24)芳基；(C6－C10)芳氧基；(C7－C24)芳烷基；－(CH2)n－COOM，其中n代表1和6之间的整数；或者10α－二氢蒿素基；R4和R5单独选自直链或支链(C1－C6)烷基；直链或支链(C2－C6)烯基；直链或支链(C2－C6)炔基；(C3－C8)环烷基；(C6－C24)芳基；(C7－C24)芳烷基；OM；直链或支链(C1－C6)烷氧基；(C6－C10)芳氧基以及NR7R8；R6选自直链或支链(C1－C6)烷基；直链或支链(C2－C6)烯基；直链或支链(C2－C6)炔基；(C3－C8)环烷基；(C6－C24)芳基和(C7－C24)芳烷基；M代表氢或药学可接受的阳离子；而R7和R8各自代表氢或直链或支链(C1－C6)烷基，或者R7和R8共同形成亚烃基桥键(C4－C6)；同时R选自氢和对R6所举的那些基团。所述化合物对预防后天痣细胞痣也有效。
用青蒿素及其衍生物治疗和预防良性色素斑（痣）
本发明涉及局部给药特别是用局部用配方治疗皮肤和黏膜上良性色素斑(痣)；特别是痣细胞色素痣、着色斑病和黏膜色素斑的治疗。此外，本发明还涉及适宜于此种治疗的局部用配方。
术语痣细胞痣指的是各种微观组织上由所谓痣细胞构成的良性皮肤病变，色素痣(胎痣、肝色痣)。痣细胞是正常色素带有缺陷形成的细胞，即黑素细胞。几乎每个人身上都会出现不同数目、不同大小和不同颜色强度的黑素细胞痣。痣的外表现型可以是很不相同的。它可为与皮肤齐平面的或者高于皮肤平面的色素痣(球形、有蒂或者平放在皮肤上的)点状也如大平面的、疣状的、隆起的或者光滑的，而着色则从肤色经褐色至黑色。后天性黑素细胞痣的数目随生命过程而增加。具有奇特结构的痣细胞色素痣，有高恶变的危险，并被称为发育异常的或者非典型的痣细胞色素痣。
由痣细胞色素痣也许会发展成恶性黑素瘤，也即黑皮肤癌。在60％以上的情况下，它由痣细胞色素痣形成。在近几十年中，人们注意到，黑素瘤发病率明显上升。1960年在美国寿命风险约1∶600，而当今人们观察到寿命风险为1∶100。因此，举例来说，根据Prof.Dr.Matthias Volkenandt(Klinikfür Dermatologie und Allergologie der Ludwig-Maximilians-
München，Frauenlobstrasse 9，80337München)所说，黑素瘤在巴伐利亚州地区的发病率为每100000个居民每年约14(也即14个新病例)。这相当于寿命风险约1％(每100个居民在一生中有一个患黑素瘤)。就这个数字来说，黑素瘤并不是人类最频繁发生的肿瘤，不过，按照Volkenandt所述，发病率上升之高，没有别的肿瘤与之相提并论。
按照现今的知识状况，还没有克服痣细胞色素痣变质的预防性诊治和疗法。具有高危险的痣的变质首先要手术切除。早些时候，激光处理在美容方面，发挥作用。所有两种方法都是侵入性的、带有一定风险(瘢痕形成、皮肤变色等)并且与高费用相联系。
后天性痣的出现，总是一种小的、有时候小得用显微镜才能看见的红小点(出血或血管瘤)。从这种痣最初阶段开始，往往发展成较大的红色、有点隆起的斑点。然后，从这些痣最初阶段起始，形成大小、棕褐色度和结构不同的褐色痣细胞色素痣。
青蒿素(也称Qinghaosu)是一种具有过氧化物基团的倍半萜烯内酯，迄今为止它主要作为对全身起作用的抗疟疾剂来研究和使用。青蒿素很难溶于水；但是青蒿素的水溶性衍生物已被研制出来。在EP-A-0 428 773中，记叙了全身性或局部应用青蒿素及其衍生物来治疗牛皮癣、病毒性疾病(疣、触染性软疣和羊痘)、紫外线诱发的疾病(多形的光致皮肤病、“胶原质脉管疾病”、恶化前的角化病(
Keratosen)、癌前期皮炎、恶性小痣、基底细胞癌、颞鳞小房癌和恶性黑素瘤)、起疱性皮肤病和痔。
本发明的目的是提供局部起作用的、但优选局部用药的配方制剂，该制剂对治疗良性色素痣，特别是对黑素细胞痣有效，因而也可用来预防皮肤癌。
按本发明，该发明目的得以实现的方法是，用选自式(I)的一类化合物来制备局部应用的，特别是局部给药的配方制剂来治疗良性色素痣：
在该式(I)中，X为CO、CHOZ或CHNRZ，其中Z选自：
氢；直链或支链(C1-C6)烷基；直链或支链(C2-C6)烯基；直链或支链(C2-C6)炔基；(C3-C8)环烷基；(C6-C24)芳基；(C7-C24)芳烷基；间-CH2(C6H4)COOM和对-CH2(C6H4)COOM；COR3；CSR3；C(NR6)R3；SOR4；SO2OM；SO2NR7R8；SO2O-蒿素基；SO2NH-蒿素基；POR4R5和PSR4R5；
其中R3为直链或支链(C1-C6)烷基；直链或支链(C1-C6)烷氧基；直链或支链(C2-C6)烯基；直链或支链(C2-C6)炔基；(C3-C8)环烷基；(C6-C24)芳基；(C6-C10)芳氧基；(C7-C24)芳烷基；-(CH2)nCOOM，其中n为1至6的整数；或者为10α-二氢蒿素基；
R4和R5各自单独选自直链或支链(C1-C6)烷基；直链或支链(C2-C6)烯基；直链或支链(C2-C6)炔基；(C3-C8)环烷基；(C6-C24)芳基；(C7-C24)芳烷基；OM；直链或支链(C1-C6)烷氧基；(C6-C10)芳氧基和NR7R8；
R6选自直链或支链(C1-C6)烷基；直链或支链(C2-C6)烯基；直链或支链(C2-C6)炔基；(C3-C8)环烷基；(C6-C24)芳基和(C7-C24)芳烷基；
M为氢或药学可接受的阳离子；以及R7和R8各自单独为氢或者直链或支链(C1-C6)烷基，或者R7和R8共同构成一个(C4-C6)亚烷基桥键；以及
R选自氢和对R6所列举的基团。
现已意外发现，用上述生物活性物质，特别是用局部(例如在皮肤上)用药的配制品处理可以很早成功治疗皮肤色素痣，特别是那些起源于黑素细胞的色素痣。也曾发现，经用式(I)化合物治疗痣细胞色素痣，还可能预防皮肤癌(特别是基底细胞瘤或者黑素瘤)。此外，还发现，这种活性物质在局部应用的情况下，在预防良性色素斑方面，特别是预防后天性痣细胞色素痣方面也是有效的。
在本专利申请范围内，“良性色素痣”特别理解成：
-痣，特别是痣细胞色素痣(普通的或者发育异常的；痣细胞色素痣也常被称为黑素细胞痣)；其下按发生位置可分三个小类，即交界痣细胞色素痣(界层表皮/真皮)、混合痣细胞色素痣(真皮结缔组织)以及真皮痣细胞色素痣(真皮深层)，并按发生时机可区别的小类为先天性痣细胞色素痣(＝胎痣)和后天性痣细胞色素痣。后天性痣细胞色素痣的一个小类是复发痣，它是在外科切除一种其他良性母斑后形成的。先天性交界痣细胞色素痣的一个例子是斑痣，后天性交界痣细胞色素痣或者混合痣细胞色素痣的一个实例是乳晕痣(萨顿氏痣)；而后天性黑素细胞交界痣细胞色素痣、混合痣细胞色素痣或者真皮痣细胞色素痣的例子则是Spitz痣和里德氏痣。先天性真皮痣细胞色素痣的一个例子是mongolenfleck(＝Naevus Bleu)，而先天性交界痣细胞色素痣、混合痣细胞色素痣或者真皮的痣细胞色素痣的一个例子则是先天性Riesenpigmentnaevus(Naevus giganteus)；
-着色斑病(例如肝色痣＝Lentigo simplex、Sonnenflecken＝Lentigosolaris、老年斑＝Lentigo senilis、PUVA-Lentigines)；
-黑色素沉着紊乱(例如雀斑＝ephelides)；以及
-黏膜色素痣(例如眼结膜痣、唇痣、口腔黏膜痣及性器官痣)。
式(I)化合物在诊治所有上述良性色素痣方面，特别是后天性或者先天性痣细胞色素痣方面是有效的。上述这些痣中，发育异常的(非典型的)痣细胞色素痣具有变质成皮肤癌的高可能性，因此，为了预防皮肤癌，优选用式(I)化合物来治疗痣。
(C1-C6)烷基优选是甲基、乙基、正丙基、异丙基、正丁基、仲丁基、叔丁基、正戊基、仲戊基、新戊基、正己基、仲己基以及新己基。更为优选的是直链(C1-C3)烷基，而特别优选的是甲基或者乙基。直链或者支链(C2-C6)烯基优选的是(C2-C4)烯基，例如乙烯基、烯丙基、1-甲基乙烯基、2-甲基乙烯基、丁-1-烯-1-基、丁-2-烯-1-基、丁-3-烯-1-基、丁-1-烯-2-基、丁-2-烯-2-基、丁-3-烯-2-基、2，2-二甲基乙烯基和1，2-二甲基乙烯基。直链或支链(C2-C6)炔基优选的是乙炔基、炔丙基、丙-1-炔-1-基、丁-1-炔-1-基、丁-2-炔-1-基、丁-3-炔-1-基、丁-3-炔-2-基、3-甲基丁-1-炔-1-基、3，3-二甲基丁-1-炔-1-基、1，1-二甲基丁-2-炔-1-基和1，1-二甲基丙-2-炔-1-基。(C3-C8)环烷基优选的是环丙基、环丁基、环戊基和环己基。(C6-C24)芳基优选的是(C6-C10)芳基，例如苯基、萘-1-基和萘-2-基。(C7-C24)芳烷基优选的是(C7-C12)芳烷基，例如苯甲基、苯乙基、(萘-1-基)甲基和(萘-2-基)甲基。(C1-C6)烷氧基中的烷基，是上面对(C1-C6)烷基举例说明的同样基团。优选的是(C1-C3)烷氧基、而更为优选的则是甲氧基、乙氧基或者正丙氧基。(C6-C10)芳氧基中的芳基，是上面对(C6-C24)芳基举例说明的同样基团。更为优选的是苯氧基或者α-萘氧基或β-萘氧基。
在本申请范围内，术语“蒿素基”表示一个具有X＝CH-的式(I)所示的基团，该基团可通过碳的自由价连到氧或氮上。在本申请范围内，术语“10-α-二氢蒿素基”意指-O-蒿素基，其中蒿素基的含义同前所述。
式(I)中，Z优选为氢；直链或支链(C1-C6)烷基；间-CH2(C6H4)COOM和对-CH2(C6H4)COOM；COR3；SOR4；SO2OM；SO2NR7R8；SO2NH-蒿素基和POR4R5。
就符合制药学要求的作为M的阳离子而言，可提及的是，示例性的碱金属阳离子如锂、钠或者钾的阳离子，碱土金属阳离子如镁及钙的阳离子，铵以及H+N(RXRYRZ)，其中Rx、Ry、Rz各自可单独为甲基或者乙基。
当R3是直链或支链(C1-C6)烷基、直链或支链(C1-C6)烷氧基、-(CH2)n-COOM或者蒿素基时，Z优选为COR3。此时特别是，M优选为氢、钠、钾或铵。
当M是碱金属、碱土金属或铵时，Z优选为SO2OM。
当R4和R5选自OM和直链或支链(C1-C6)烷氧基时，Z优选为POR4R5。更为优选的是，R4和R5中之一为OM，其中M特别是钠、钾或铵，以及是其他的直链或支链(C1-C6)烷氧基或者OH。
式(I)所示的化合物已为人所知，或者可制成类似于式(I)所示的已知化合物。在此情况下，X＝CO的这个化合物是青蒿素，而X＝CHOH的化合物是二氢青蒿素。X＝CHOZ且Z不同于氢的化合物，或者X＝CHNRZ的化合物，以下称之为“二氢青蒿素的衍生物”。
式(I)所示的化合物可以如下方法制得：
-青蒿素(X＝CO)可如已知的那样，从植物黄花蒿(ArtemisiaAnnua)植物中分离出来。
-二氢青蒿素(X＝CHOH)是已知的，并可例如在约0℃下，使青蒿素在甲醇中用硼氢化钠还原来制备。
-X＝CHOZ的二氢青蒿素的衍生物，其中Z为直链或支链(C1-C6)烷基、直链或支链(C2-C6)烯基、直链或支链(C2-C6)炔基、(C3-C8)环烷基、(C6-C24)芳基或者(C7-C24)芳烷基，可用二氢青蒿素通过以下方法来制备：首先使二氢青蒿素用氯化三甲硅转化成二氢青蒿素的三甲基甲硅烷基醚，使三甲基甲硅烷氧基同溴化三甲硅交换溴(按照US-A-2005/0119232的实施例1)，然后在碱存在下，使溴原子再按所要求使用过量HOZ进行取代，其中Z的含义已予说明。在这些衍生物之中，蒿甲醚(Z＝Me)和蒿乙醚(Z＝Et)是已知的化合物。
-X＝CHNRZ的二氢青蒿素的衍生物，其中R的含义在式(I)中已予说明，Z＝氢、直链或支链(C1-C6)烷基、直链或支链(C2-C6)烯基、直链或支链(C2-C6)炔基、(C3-C8)环烷基、(C6-C24)芳基或者(C7-C24)芳烷基者，可用二氢青蒿素通过以下方法来制备：首先使二氢青蒿素用氯化三甲硅转化成二氢青蒿素的三甲基甲硅烷基醚，使三甲基甲硅烷氧基同溴化三甲硅交换溴(按照US-A-2005/0119232的实施例1)，然后在碱存在下，使溴原子再按所要求使用过量的胺HNRZ进行取代，其中R和Z的含义已予说明。
-X＝CHOZ或CHNRZ的二氢青蒿素的衍生物，其中R的含义在式(I)中已予说明，而Z＝间-CH2(C6H4)COOM或者对-CH2(C6H4)COOM(M的定义正如在式(I)中所指出)，可由二氢青蒿素或X＝CHNRH的二氢青蒿素衍生物作原料来制取，其方法是，在碱存在下，用间-溴代甲基苯甲酸甲酯或者对-溴代甲基苯甲酸甲酯使所述原料烷基化、继而使甲基酯水解，并当M不应为氢时形成相宜的盐。在这些衍生物之中，X＝CHOZ和Z＝对-CH2(C6H4)COOH的衍生物已知为“蒿酸”
-X＝CHOZ或CHNRZ的二氢青蒿素衍生物，其中R的含义在式(I)中已予说明，Z＝COR3或CSR3以及R3为直链或支链(C1-C6)烷氧基或者(C6-C10)芳氧基，可以通过二氢青蒿素或X＝CHNRH的二氢青蒿素衍生物与适宜的氯代羧酸(C1-C6)烷基酯或者氯代羧酸(C6-C10)芳基酯或者氯硫代羧酸(C1-C6)烷基酯或氯硫代羧酸(C6-C10)芳基酯和一种碱来制备。
-X＝CHOZ或CHNRZ的二氢青蒿素衍生物，其中R的含义在式(I)中已予说明，Z＝COR3以及R3为直链或支链(C1-C6)烷基、直链或支链(C2-C6)烯基、直链或支链(C2-C6)炔基；(C3-C8)环烷基、(C6-C24)芳基或者(C7-C24)芳烷基；可以通过二氢青蒿素或X＝CHNRH的二氢青蒿素衍生物与酰基氯和碱的反应来制备，其中酰基氯与适宜的R3进行取代。
-X＝CHOZ或CHNRZ的二氢青蒿素衍生物，其中R的含义在式(I)中已予说明，Z＝CSR3以及R3为直链或支链(C1-C6)烷基、直链或支链(C2-C6)烯基、直链或支链(C2-C6)炔基；(C3-C8)环烷基、(C6-C24)芳基或者(C7-C24)芳烷基；可以通过Z＝COR3的上述相应衍生物与Lawesson′s试剂发生反应来制取。
-X＝CHOZ或CHNRZ的二氢青蒿素衍生物，其中R的含义在式(I)中已予说明，Z＝COR3和R3-(CH2)n-COOM(其中M的含义已在式(I)中作了说明)，可以通过二氢青蒿素或X＝CHNRH的二氢青蒿素衍生物与环状酸酐反应(当n＝2或者3时)或者与MeOOC(CH2)n-COOMe反应来制取。在后一种情况下，X＝CHOZ时，也可一起加入碱性催化剂如NEt3，而且酯交换反应时释出的甲醇可例如通过减压蒸浓从平衡状态中抽出。当M不是氢时，可以形成相应的盐，其方法是：使残留的甲酯基裂解，例如用M氰化物。在这些衍生物之中，X＝CHOZ、n＝2和M＝氢的已知为“青蒿酯”。
-X＝CHOZ或CHNRZ的二氢青蒿素的衍生物，其中R的含义在式(I)中已予说明、Z＝CSR3和R3-(CH2)n-COOM(其中M的含义在式(I)中已予说明)是可制得的，其方法是：用Lawesson′s试剂使MeOOC(CH2)n-COOMe中的一个或两个羰基氧被硫替代，并使所得半硫代二酯与二氢青蒿素或X＝CHNRH的二氢青蒿素衍生物进行反应，继而使其仍为游离的COOMe基团水解成COOH，并当M不是氢时形成相应的盐。
-可以制得X＝CHOZ或CHNRZ的二氢青蒿素的衍生物，其中R的含义在式(I)中已予说明、Z＝C(NR6)R3(其中R6的含义在式(I)中已予说明)以及R3为直链或支链(C1-C6)烷氧基或者(C6-C10)芳氧基，其方法是：使R6含义已如上说明的异氰酸酯R6-NCO与相应(C1-C6)醇或者(C6-C10)芳醇进行反应，并使这样得到的氨基甲酸乙酯与POCl3反应，然后在碱存在下与二氢青蒿素或X＝CHNRH的二氢青蒿素衍生物进行反应。
-可以制得X＝CHOZ或CHNRZ的二氢青蒿素的衍生物，其中R的含义在式(I)中已予说明、Z＝C(NR6)R3(其中R6的含义在式(I)中已予说明)以及R3为直链或支链(C1-C6)烷基、直链或支链(C2-C6)烯基、直链或支链(C2-C6)炔基；(C3-C8)环烷基、(C6-C24)芳基或者(C7-C24)芳烷基，其方法是：使R6含义已如上说明的异氰酸酯R6-NCO与相应格氏试剂R3MgBr进行反应，其中R3的含义已予说明，并使这样得到的酰胺与POCl3进行反应，然后在碱存在下，与二氢青蒿素或X＝CHNRH的二氢青蒿素衍生物进行反应。
-X＝CHOZ或CHNRZ的二氢青蒿素的衍生物，其中R的含义在式(I)中已予说明、Z＝C(NR6)R3和R3-(CH2)n-COOM(其中M和R6的含义在式(I)中已予说明)可用这样的方法来制取：使n和R6的含义已如上说明的化合物MeOOC-(CH2)n-CONHR6与POCl3进行反应，然后与二氢青蒿素或X＝CHNRH的二氢青蒿素衍生物在碱存在下进行反应，并使甲基酯进行水解，并且如果M不是氢，则形成相宜的盐。
-具有Z＝SOR4和R4＝OMe的X＝CHOZ或CHNRZ的二氢青蒿素衍生物(其中R的含义在式(I)中已予说明)可有选择地在碱性催化剂存在下，通过二氢青蒿素与过量亚硫酸二甲酯(DRP 487253)的反应，馏除释出的甲醇，并接着减压馏除过剩的亚硫酸二甲酯来制取。
-X＝CHOZ或CHNRZ的二氢青蒿素的衍生物，其中R的含义在式(I)已予说明，且Z＝SOR4(其中R4为直链或支链(C1-C6)烷氧基或者(C6-C10)芳氧基)，可以通过X＝CHOH或者CHNRH的相应衍生物与过量亚硫酰(二)氯和适宜的碱如吡啶进行反应，除掉过量亚硫酰(二)氯，并接着使得到的亚硫酸衍生物与相应直链或者支链(C1-C6)醇或者(C6-C10)芳醇在适宜的碱如吡啶存在下进行反应而制得。-X＝CHOZ或CHNRZ的二氢青蒿素的衍生物，其中R的含义在式(I)已予说明，且Z＝SOR4(其中R4为(C1-C6)烷基、直链或支链(C2-C6)烯基、直链或支链(C2-C6)炔基、(C3-C8)环烷基、(C6-C24)芳基或者(C7-C24)芳烷基)，可以通过格氏试剂R4MgBr(其中R4的含义已予说明)与过量亚硫酰(二)氯反应，除掉过量亚硫酰(二)氯，并接着使得到的R4-SOCl与X＝CHOH或者CHNRH的相应二氢青蒿素衍生物在适宜的碱如吡啶存在下进行反应而制得。
-X＝CHOZ或CHNRZ的二氢青蒿素衍生物，其中R的含义在式(I)已予说明，且Z＝SOR4(其中R4为NR7R8、R7和R8的含义在式(I)中已予说明)，可以通过胺HNR7R8与过量亚硫酰(二)氯进行反应，除掉过量亚硫酰(二)氯，并接着使所得的RR7R8NSOCl与X＝CHOH或者CHNRH的相应二氢青蒿素衍生物在适宜的碱如吡啶存在下进行反应而制得。
-X＝CHOZ或CHNRZ的二氢青蒿素的衍生物，其中Z＝SO2OM(M的含义在式(I)中已予说明)，可以通过X＝CHOH或CHNRH的相应衍生物与吡啶-三氧化硫-络合物进行反应，并将所得磺酸盐的吡啶鎓抗衡离子交换成M而制得。
-X＝CHOZ或CNHRZ的二氢青蒿素的衍生物，其中Z＝SO2NR7R8，而且R、R7和R8的含义在式(I)中已予说明，可以通过X＝CHOH或CHNRH的二氢青蒿素衍生物与与1eq.硫酰氯在碱如吡啶存在下进行反应，并接着在碱如吡啶存在下与1eq.胺HNR7R8(其中R7和R8的含义已予说明)进行反应而制得。
-X＝CHOZ且Z＝SO2O-蒿素基的二氢青蒿素衍生物，可通过2eq.二氢青蒿素与1eq.硫酰氯在碱如吡啶存在下进行反应而制得。
-X＝CHOZ且Z＝SO2NH-蒿素基的二氢青蒿素衍生物，可在碱如吡啶存在下，通过二氢青蒿素与1eq.硫酰氯进行反应，并接着在碱如吡啶存在下，与1eq X＝CHNH2的青蒿素衍生物进行反应而制得。这样得到的衍生物与X＝CHNHZ且Z＝SO2O-蒿素基的衍生物是同一种衍生物。而后，由如此所得的衍生物可以通过对磺氨基氮上进行脱质子化，并用烷基溴RBr(其中R的含义已予说明)进行烷基化，来制备X＝CHNRZ、其中R的含义在式(I)已予说明(但除氢以外)的二氢青蒿素衍生物。
-X＝CHNHZ且Z＝SO2NH-蒿素基的二氢青蒿素的衍生物，可以按照US-A-2005/0119232中的实施例2来制备。由该衍生物又可通过脱除两个磺氨基氮中一个上的质子，并用烷基溴RBr(其中R的含义已予说明)进行烷基化，来制备X＝CHNRZ、其中R的含义在式(I)已予说明(但除氢以外)的二氢青蒿素衍生物。
-可以制得X＝CHOZ或CNHRZ、其中Z＝POR4R5或者PSR4R5(R、R4和R5的含义在式(I)中已予说明)的二氢青蒿素衍生物，其方法是：首先使二氢青蒿素或者X＝CHNRH的二氢青蒿素衍生物与与过量POCl3(或PSCl3)进行反应，并馏除过量POCl3(或PSCl3)。向所得X＝CHOPOCl2(或CHOPSCl2)或者CHNRPOCl2(或CHNRPSCl2)的粗产物中，视待引入基团R4和R5的种类而定，作为格氏试剂R4MgBr/R5MgBr(当R4及/或者R5应当为(C1-C6)烷基、直链或支链(C2-C6)烯基、直链或支链(C2-C6)炔基、(C3-C8)环烷基、(C6-C24)芳基或者(C7-C24)芳烷基时)的形式、以醇化物R4O-/R5O-的形式(当R4及/或R5应该为直链或支链(C2-C6)烷氧基或者(C6-C10)芳氧基时)、或者以胺HNR7R8的形式或者以水或氢氧化物的形式引入基团R4和R5；条件是这些试剂优选按亲核性增加的顺序添加，而且在至少是R4及/或R5OM中之一时、将对此必需的MOH是作为最后试剂添加。.
在X＝CHOZ或CHNRZ的化合物的情况下，碳原子(也即倍半萜烯构架上C10-原子)的构型可以是(R)或者(S)。式(I)所示的化合物也可以C10-差向异构体混合物的形式来使用，其中两种差向异构体的比例可以通过青蒿素的在前还原及/或通过C10-羟基对其他源自水的羟基或者对合成时所用亲核体进行置换来加以改变。
优选的是上述式(I)所示的那些活性物质，它们选自青蒿素、二氢青蒿素、含羧基的衍生物(特别是青蒿酯)、蒿甲醚(Artemeter)、蒿乙醚、二氢青蒿素的碳酸丙酯和蒿酸
特别优选的是青蒿素、二氢青蒿素和青蒿酯。
式(I)所示的化合物可以单独使用，或者以两种或多种这些化合物的组合形式来使用。
式(I)的化合物，特别是青蒿酯，对预防后天性痣细胞色素痣也有效。为预防痣细胞色素痣起见，将式(I)的化合物，特别是青蒿酯，大面积涂到整个皮肤上，涂到具有形成痣的高可能性的皮肤痛觉过敏带上，或者涂到已看得见的早期痣上。具有形成痣的高可能性的皮肤痛觉过敏带，一方面是频繁暴露于紫外线照射的皮肤局部。另一方面，这种皮肤痛觉过敏带，常存在于已形成痣细胞色素痣的周围(例如典型地以多达5cm的半径围绕已存在的痣)。此外，式(I)所示的化合物，特别是青蒿酯，还具有其他有利的特性，即它们显然已存在早期痣，但还如此微小使得凭裸眼几乎辨别不出。在式(I)所示化合物的作用下，这种仍辨认不清的早期痣首先形成小红点，数日之后变成深色至黑色，而且部分像深色、具有位于微孔中的结晶体。在一些有利的情况下，顶射显微镜检查法预先检查成问题的皮肤部位就成为不必要。
为应用起见，可将式(I)的活性物质配制成适于局部使用，特别是适于局部表面(皮肤)应用的配方制剂。所制配方制剂(配制品)中的活性物质浓度并不特别关键。以配方制剂的总重量计可以制备浓度约0.1％(重量)至约40％(重量)的配方制剂。为了治疗痣细胞色素痣(先天性＝胎痣，或者后天性)，以配方制剂的总重量计，配方制剂优选含有约5％(重量)至约20％(重量)的活性物质，特别优选含有约10％(重量)。为预防后天性痣细胞色素痣起见，以配方制剂的总重量计配方制剂优选含有至多约5％(重量)的式(I)所示化合物；更确切地说，优选含有约1％(重量)至约5％(重量)。生物活性物质的确切治疗所需量，取决于有效物质本身、所用的基料(Grundlage)、所制盖伦剂型(例如软膏、悬浮液、药膏、硬膏、乳膏剂、凝胶、溶液)以及所用的添加剂，而且可以由技术人员通过简单的效果试验来确定。
存在的痣细胞色素痣(先天性＝胎痣，或者后天性)的治疗时间取决于痣的种类、大小、结构、色素沉着以及年代。优选以高浓度的式(I)所示化合物进行周期性的治疗。第一疗程(Behandlungstagen)后，第一反应通常是明显的。直到明显好转或者变化，即表现出痣细胞色素痣逐渐退色或者消失，可以持续二至数月。就陈旧性患者而言，此时间段会更长一些，因为表皮更新随陈旧性增加而持续得更长一些。
就预防后天性痣细胞色素痣而言，应用2～3次即足矣。较大的早期痣最好治疗更长一些时间，直到早期痣逐渐退色或消失为止。
式(I)所示的活性物质应该视治疗措施(Therapieansatz)而定，不同程度地深深侵入皮肤：
-就治疗痣细胞色素痣(先天性＝胎痣，或者后天性)而言，应视痣的类型及陈旧程度而定，活性物质优选进入上真皮。
-就预防后天性痣细胞色素痣而言，活性物质最好通过真皮直抵表皮及真皮间边界的交界区域。
对惰性的通常用于局部配方制剂的底料来说，作为式(I)活性物质的配方制剂底料适于所有这些活性物质。特别是用于局部配方制剂的这种底料：凡士林、脂肪、蜡、脂肪酸酯、石蜡、油、硅酮及其聚合物。优选是将活性物质和约60％(重量)至约99.9％(重量)，更优选与约％(重量)80至约95％(重量)以制成的配方制剂计的配方制剂底料一起进行配制。如果使用亲水/含水局部配方制剂底料如水凝胶、乳膏剂，则活性物质可借助纳米胶囊封装，包封在脂质体内(Einschluss in Liposomen)或者例如与环糊精形成络合物，来防止其分解。关于青蒿素及其衍生物与环糊精的络合，举例来说，请参见US-A-2005/187189。
按照德国药典，具有非水单相底料如无水纯脂肪相的局部配方制剂被称作软膏。其中使用了本发明式(I)活性物质的软膏，由这样一种软膏底料组成，该软膏底料可含有一种或多种细微分散的活性物质，以在皮肤上应用。
当该局部配方制剂应为软膏时，该配方制剂底料可优选由室温下具有正辛醇/水的分配系数约1至约105，更优选约10至约105，特别优选约50至约104的亲油组分组成。在此场合下，该配方制剂底料的例子是凡士林、脂肪、蜡、脂肪酸酯、石蜡、油、硅酮及其聚合物(例如聚二烷基硅氧烷、硅酮弹性体、硅酮-蜡、硅酮乳化剂)。
涂敷软膏时，式(I)活性物质从包围它的局部制剂底料中出来，并进入皮肤中。该亲脂性底料与皮肤粘附得非常牢固，并向外形成拒水层。此层同样还阻止了水分从皮肤向外逸出(阻碍作用)。由于这种作用，皮肤被保持湿润，并变得暖和，因为可以蒸发的水不多。由于湿度提高，皮肤也更具弹性，这促进了活性物质的吸收。
跟软膏相反，二相体系(水相和脂肪相)被命名为乳膏。式(I)所示的化合物也可配制成乳膏。就脂肪相而言，可以采用诸如上面对软膏底料举例说明的同一类物质。水相中除水之外也可有选择地含有各种能使皮肤耐受的水相pH的缓冲剂物质，或者也可含有已知的成凝胶聚合物如羟基丙基甲基纤维素、羧甲基纤维素、含有交联剂(例如硼砂或者诸如Mg2+或者Ca2+的多价金属阳离子)的聚乙烯醇以及以及类似物质。为了进行乳化，可以使用常用的皮肤耐受性表面活性物质，例如脂肪酸一甘油酯和脂肪酸二甘油酯、聚氧乙烯(40)氢化的蓖麻油(Cremophor
)或者卵磷脂。
作为局部配方制剂的辅料，可以是常用的渗透促进剂(诸如二甲基乙酰胺、二甲基甲酰胺、丙二醇、脂肪醇、三乙醇胺、二甲亚砜、氮酮以及其他)、改进效果的角质层分离药(例如水杨酸、尿素、类维生素A)和防腐剂。添加剂一般用于改进盖伦剂型的效果、稳定性、持久性和坚度。
优选将式(I)所示的化合物配制成基本上不含增强渗透的材料的局部配方制剂。还优选配制式(I)所示的化合物，使之基本上不含(C5-C19)一元羧酸、其酯及其酰胺。在本专利申请范围内，“基本上不含”应理解为，局部配方制剂以配方制剂的总量计含有小于1％(重量)，优选小于0.1％(重量)的增渗材料。
用于糊剂、软膏、乳膏剂、溶液、凝胶、喷雾剂或者悬浮液的式(I)化合物，优选是所有含有一个羧基的衍生物，特别是青蒿酯。在此情况下，羧基可以有选择地以碱金属盐、碱土金属盐或铵盐的形式存在。
为在皮肤上应用或者应用到皮肤中，将式(I)活性物质以局部配方制剂形式、特别是以糊剂、软膏、悬浮液、溶液、凝胶、喷雾剂或者乳膏的形式、特别优选以软膏的形式、涂到硬膏(Pflaster)上。硬膏可以有选择地是一种吸收或吸入局部配方制剂的材料。活性物质当然也可直接悬浮于或者溶于硬膏的惰性粘合剂中；在类似于先前已知的硬膏中，例如用于东莨菪碱(例如“Scopoderm TTS”)或者用于雌二醇(例如“Estraderm TTS”)中的硬膏。以此方式，活性物质可直接并且在长时间内与待处理部位接触。另外还产生闭塞作用，该作用改进了活性物质的渗透。
式(I)活性物质的其他给药方式是糊剂、溶液、悬浮液、凝胶与乳膏剂以及喷雾剂。所列举活性物质的半固态或者液态配方，也可以栓(Stift)的形式(例如类似毡棒那样
以精确剂量)或者以卷(Roller)(在相宜的底料(Grundlage)、溶液、悬浮液、软膏、乳膏剂中含有活性物质)的形式存在。
其他局部的、可按本发明使用式(I)化合物的用药形式实例是涂药器，该涂药器借助超声波、借助电场或者借助微型针来促进式(I)化合物渗入皮肤或黏膜。使用超声波并按本发明可使用的先前已知的涂药器，例如在US-B6,908,448中已予公开，特此一并资作参考。使用电场投药活性物质(因此，其采用离子电渗疗法原理)的涂药器，久已为人所知。按本发明，它们适用于那些属盐类的式(I)活性物质，即如式中X为CHOZ或者CHNRZ，其中Z选自间-CH2(C6H4)COOM和对-CH2(C6H4)COOM、SO2OM和POR4R5，式中R4和R5中之一为OM，并为其他直链或支链的(C1-C6)烷氧基或OH，而M则为药学上可接受的阳离子。就用于将本发明活性物质局部投药到皮肤上的、带微型针的先前已知涂药器而言，请参阅US-A-2005/065463，该文件同样特此一并资作参考。
按本发明可以使用的局部投药方式的另一个实例是一项技术，其中借助吸盘将待处理部位的皮肤吸起，并在皮肤的提高部位上，将真皮的部分层厚用机械方式切除，例如用刀刃。部分切除真皮的皮肤部位，对式(I)所示化合物来说是渗透性的，并允许在这些部位上，进行深入真皮下层的局部治疗。为此必需的器械已描述于作为参考而包括在本申请内的WO-A-95/15783中。
用蒿素及其衍生物(二氢青蒿素，蒿乙醚，蒿甲醚，青蒿酯及其半合成衍生物和合成的类似化合物)进行一种少风险、非侵入的预防性或治疗性处理后天性痣细胞色素痣或者后天性或先天性痣细胞色素痣(＝胎痣)，是处理痣细胞色素痣中的一个巨大进步，并能有力减少皮癌危险。因此，本发明不仅在医学上而且在社会经济学上都具有巨大意义。在所记载的、用式(I)所示化合物，特别是青蒿酯进行的局部治疗中，未观察到该化合物对皮肤的变应性反应。值得注意的还有，健康组织不受损害，而且治疗是无痛、简易的。
鉴于迄今为止获得结果，可看出：用青蒿素及其衍生物进行的局部治疗(lokale Therapie)，特别是局部定位治疗(topische Therapie)非常有效，而且作为痣的预防和治疗，在更长时间内可注意到，比传统的介入性医治方法费用不大，而且风险更小。
现在以下面各实施例来进一步阐明本发明。
实施例1：局部配方制剂
将3g青蒿酯同27g Excipial
油脂的软膏均匀拌和。
油脂的软膏均匀拌和。
实施例2a～8h：局部配方制剂
将不同量青蒿酯(见表1)加到不同底料中。有的也向配方制剂添加表面活性材料。
表1：
| 实施例编号 | 青蒿酯(g) | 添加剂 | 底料足量，加至100g |
| 2a～2h | 2a：0.12b：0.52c：1.02d：5.02e：10.02f：15.02g：302h：40 | - | 白凡士林 |
| 3a～3h | 3a：0.13b：0.53c：1.03d：5.03e：10.03f：15.03g：303h：40 | 聚山梨醇酯0.5g；聚乙二醇(2000)硬脂酸酯0.5g聚氧乙烯(40)失水山梨醇醚油酸酯0.5g | 白凡士林 |
| 4a～4h | 4a：0.14b：0.54c：1.04d：5.04e：10.04f：15.0 | 蜂蜡 |
| 4g：304h：40 | |||
| 5a～5h | 5a：0.15b：0.55c：1.05d：5.05e：10.05f：15.05g：305h：40 | 大豆卵磷脂2g | 石蜡 |
| 6a～6h | 6a：0.16b：0.56c：1.06d：5.06e：10.06f：15.06g：306h：40 | 聚乙二醇(2000)硬脂酸酯2g | 菜籽油 |
| 7a～7h | 7a：0.17b：0.57c：1.07d：5.07e：10.07f：15.0 | 肉豆蔻酸异丙酯1g | 十甲基环戊硅氧烷(19g)硅酮高弹体凝胶(加至100g) |
| 8a～8h | 8a：0.18b：0.58c：1.08d：5.08e：10.08f：15.0 | 十甲基环戊硅氧烷25g矿物油加至100g |
实施例9a～9i：治疗或预防色素痣中的局部(皮肤)应用
a)一名13岁男孩，有深褐色隆起胎痣(发育异常的胸痣细胞痣)，结构不平整，直径约1.2厘米，用实施例2a的10％青蒿酯凡士林软膏每周治疗2～3次。2周后，胎痣为淡褐色，带有一对深色、小点状部位，看起来像“结晶出来的”染料。所述胎痣是干燥的并有鳞屑，看起来象从“内部”开始萎缩。
b)一名妇女，在皮肤表面有3个黑色隆起的胎痣(躯干交界痣)，直径为0.5至1.0cm，应用实施例2a的10％青蒿酯凡士林软膏，在闭塞的条件下(以硬膏形式)，每周3次过夜。一周后，在每一胎痣上，可辨认出深色部位。3周后，皮肤连同深色晶体样形成物一起脱落。留下三处浅色母斑，带有无色素部位，该部位不再突起于皮肤平面。继续治疗导致所处理部位皮肤上的母斑逐渐退色并成鳞片状脱落。
c)治疗2颗早期痣细胞痣，也即称为皮下淤血，皮肤部位隆起直径0.3～0.4cm：三次应用实施例2a的含10％青蒿酯软膏的硬膏过夜，两周后颜色发生变化，浅红色形成物带有深色小点。可将隆起的有变化皮肤部位揭下。留下两个小伤口，由于提前揭下，伤口痊愈了。
d)一名女受检者，有一颗痣直径约3～4cm(基底细胞癌)，用实施例1的10％青蒿酯软膏超过3月(周期性的，晚上，每隔2周)。该痣表示初期的(类似炎症过程的)发红。3个月后，可以看得出来萎缩(关于颜色和结构)约90％。约5个月后，该痣不再可见。
e)一名女性受检者，臂上有一颗痣(交界痣)，同样用实施例1的10％青蒿酯软膏。因为该女性受检者未注意观察，故而不能在此精确说明给药频繁程度；但给软膏持续数周以上。而今该痣勉强还能看得出来。
f)一名13岁男性受检者，在鼻根-眼区有一颗先天性痣，在闭塞(硬膏)的条件下，两个月内每周用实施例1的10％青蒿酯软膏2至3次。该痣有初期的许多深色小点。它反应得很慢。然而，最初的成功已经呈现。它总起来变浅许多，而且具有多个肤色的区域。
g)一名13岁女患者，有一颗真皮痣，3日内用实施例1的10％青蒿酯软膏。发生立即集中在痣中形成的3个深色部位，而且剩余范围几乎无色。
h)一名女性受检者，在已有大量痣细胞色素痣(交界痣)的腹部，大面积使用实施例1的10％青蒿酯软膏两次(每隔2天1次)。早在第2个治疗日，除了已经存在的痣之外，红色的、初期所述种类的部分早期痣，以细微小点形式可见，它们不均匀地分布在整个已处理的表面上。该早期痣本身是已有，但仅仅由于用软膏治疗而首次可见。2～3日后它们变为深色至黑色。在有些部分上，它们看来象深色、位于微孔中的晶体。在2～3周内，当用指甲在其上稍稍搔刮时，它们随同表皮角质层脱落或剥离。
i)一名女性受检者，用实施例1的软膏处理了其手背，手背上有一些大小不等的色素痣(肝色痣)。这些已有的痣和早期痣明显退色，并随着处理时间延长(7或者10天)逐渐消失。停止治疗后，色素痣颜色变浅。4周后，它们勉强还可见至不再可见。
实施例10：局部应用于甲真菌感染治疗
甲真菌侵袭中足趾和大足趾：半数大足趾的指甲遭侵害。用常规药物如Lamisil进行治疗，成效甚微。实施例2a的10％青蒿酯凡士林软膏每周用3～4次。该软膏主要应用于甲床和指甲下。2周后，早已可观察到明显好转。4周后，中足趾上的变色完全消失，或者不再变深。坏死的大足趾甲部剥落。其余指甲的治疗，更容易且更有效。活性物质无阻碍地达到健康甲部的交界部位。重新长出来的指甲是正常的，没有浅的色变。在真菌感染时，特别在指甲感染真菌时，可预期，没有必要用抗真菌药进行另外的全身性治疗，从而不仅该费用低，而且抗真菌治疗的副作用危险也低微。
1.式(I)化合物的应用，其用于制备可局部使用的、优选治疗良性色素痣或者治疗脚癣或甲癣的局部配方制剂，
在该式(I)中，X为CO、CHOZ或CHNRZ，其中Z选自：
氢；直链或支链(C1-C6)烷基；直链或支链(C2-C6)烯基；直链或支链(C2-C6)炔基；(C3-C8)环烷基；(C6-C24)芳基；(C7-C24)芳烷基；间-CH2(C6H4)COOM及对-CH2(C6H4)COOM；COR3；CSR3；C(NR6)R3；SOR4；SO2OM；SO2NR7R8；SO2O-蒿素基；SO2NH-蒿素基；POR4R5和PSR4R5；其中
R3为直链或支链(C1-C6)烷基；直链或支链(C1-C6)烷氧基；直链或支链(C2-C6)烯基；直链或支链(C2-C6)炔基；(C3-C8)环烷基；(C6-C24)芳基；(C6-C10)芳氧基；(C7-C24)芳烷基；-(CH2)n-COOM，其中n为1至6的整数；或者为10α-二氢蒿素基；
R4和R5各自单独选自直链或支链(C1-C6)烷基；直链或支链(C2-C6)烯基；直链或支链(C2-C6)炔基；(C3-C8)环烷基；(C6-C24)芳基；(C7-C24)芳烷基；OM；直链或支链(C1-C6)烷氧基；(C6-C10)芳氧基和NR7R8；
R6选自直链或支链(C1-C6)烷基；直链或支链(C2-C6)烯基；直链或支链(C2-C6)炔基；(C3-C8)环烷基；(C6-C24)芳基和(C7-C24)芳烷基；
M为氢或药学可接受的阳离子；以及R7和R8各自单独为氢或直链或支链(C1-C6)烷基，或者R7和R8共同构成(C4-C6)烷基桥键；
而R选自氢和对R6所举的那些基团。
2.权利要求1所述的应用，其特征在于，所述良性色素痣选自后天性痣细胞色素痣；先天性痣细胞色素痣，也即胎痣；着色斑病，特别是肝色痣、日晒斑或老年斑；黑色素沉着紊乱，例如雀斑；以及黏膜色素斑。
3.权利要求2所述的应用，其特征在于，所述色素痣是后天性痣细胞色素痣、先天性痣细胞色素痣(也即胎痣)或者肝色痣。
4.权利要求3所述的应用，其特征在于，所述配方制剂也用于预防皮肤癌。
5.权利要求1中所定义式(I)化合物的应用，其用于制备后天性痣细胞色素痣预防用的局部，特别是局部配方制剂。
6.前列各权利要求中任何一项所述的应用，其特征在于，式(I)化合物选自青蒿素；二氢青蒿素；式(I)所示含羧基的衍生物，特别是青蒿酯；蒿甲醚；蒿乙醚；二氢青蒿素的碳酸丙酯以及蒿酸。
7.权利要求6所述的应用，其特征在于，式(I)化合物是青蒿素、二氢青蒿素或者青蒿酯。
8.包含局部用配方制剂的硬膏，该配方制剂含有式(I)的活性物质：
在该式(I)中，X为CHOZ或者CHNRZ，其中Z选自：
氢；直链或支链(C1-C6)烷基；直链或支链(C2-C6)烯基；直链或支链(C2-C6)炔基；(C3-C8)环烷基；(C6-C24)芳基；(C7-C24)芳烷基；间-CH2(C6H4)COOM和对-CH2(C6H4)COOM；COR3；CSR3；C(NR6)R3；SOR4；SO2OM；SO2NR7R8；SO2O-蒿素基；SO2NH-蒿素基；POR4R5和PSR4R5；其中
R3为直链或支链(C1-C6)烷基；直链或支链(C1-C6)烷氧基；直链或支链(C2-C6)烯基；直链或支链(C2-C6)炔基；(C3-C8)环烷基；(C6-C24)芳基；(C6-C10)芳氧基；(C7-C24)芳烷基；-(CH2)n-COOM，其中n为1至6的整数；或者为10α-二氢蒿素基；
R4和R5各自单独选自直链或支链(C1-C6)烷基；直链或支链(C2-C6)烯基；直链或支链(C2-C6)炔基；(C3-C8)环烷基；(C6-C24)芳基；(C7-C24)芳烷基；OM；直链或支链(C1-C6)烷氧基；(C6-C10)芳氧基和NR7R8；
R6选自直链或支链(C1-C6)烷基；直链或支链(C2-C6)烯基；直链或支链(C2-C6)炔基；(C3-C8)环烷基；(C6-C24)芳基和(C7-C24)芳烷基；
M为氢或药学可接受的阳离子；以及R7和R8各自单独为氢或直链或支链(C1-C6)烷基，或者R7和R8共同构成一个(C4-C6)亚烷基桥键；而R选自氢和对R6所举的基团；
而且该局部用配方制剂基本不含渗透增强物质。
9.权利要求8所述的硬膏，其特征在于，X为CHOZ，Z选自间-CH2(C6H4)COOM与对-CH2(C6H4)COOM以及COR3，其中R3为-(CH2)n-COOM。
10.权利要求9所述的硬膏，其特征在于，式(I)化合物是青蒿酯。
11.权利要求10所述的硬膏，其特征在于，该局部配方制剂为糊剂、软膏、糊剂、悬浮液、溶液、凝胶、喷雾剂或者乳膏剂，特别是软膏。
12.治疗人类患者身上良性色素斑或皮肤霉菌病的方法，其特征在于，将式(I)所示化合物以治疗色素痣或治疗皮肤霉菌病有效的量涂到色素痣或皮肤霉菌病局部部位，特别是局部表面：
在该式(I)中，X为CO、CHOZ或CHNRZ，其中Z选自：
氢；直链或支链(C1-C6)烷基；直链或支链(C2-C6)烯基；直链或支链(C2-C6)炔基；(C3-C8)环烷基；(C6-C24)芳基；(C7-C24)芳烷基；间-CH2(C6H4)COOM及对-CH2(C6H4)COOM；COR3；CSR3；C(NR6)R3；SOR4；SO2OM；SO2NR7R8；
SO2O-蒿素基；SO2NH-蒿素基；POR4R5和PSR4R5；其中
R3为直链或支链(C1-C6)烷基；直链或支链(C1-C6)烷氧基；直链或支链(C2-C6)烯基；直链或支链(C2-C6)炔基；(C3-C8)环烷基；(C6-C24)芳基；(C6-C10)芳氧基；(C7-C24)芳烷基；-(CH2)n-COOM，其中n为1至6的整数；或者为10α-二氢蒿素基；
R4和R5各自单独选自直链或支链(C1-C6)烷基；直链或支链(C2-C6)烯基；直链或支链(C2-C6)炔基；(C3-C8)环烷基；(C6-C24)芳基；(C7-C24)芳烷基；OM；直链或支链(C1-C6)烷氧基；(C6-C10)芳氧基和NR7R8；
R6选自直链或支链(C1-C6)烷基；直链或支链(C2-C6)烯基；直链或支链(C2-C6)炔基；(C3-C8)环烷基；(C6-C24)芳基和(C7-C24)芳烷基；
M为氢或药学可接受的阳离子；以及R7和R8各自单独为氢或者直链或支链(C1-C6)烷基，或者R7和R8共同构成一个(C4-C6)亚烷基桥键；以及R选自氢和对R6所举的基团。
13.权利要求12所述的方法，其特征在于，所述良性色素痣选自后天性痣细胞色素痣；先天性痣细胞色素痣，也即胎痣；着色斑病，特别是肝色痣、日晒斑或老年斑；黑色素沉着紊乱，例如雀斑；以及黏膜色素斑。
14.权利要求13所述的方法，其特征在于，所述色素痣是后天性痣细胞色素痣、先天性痣细胞色素痣(也即胎痣)或者肝色痣。
15.预防后天性痣细胞色素痣的方法，其特征在于，将权利要求1所定义的式(I)化合物以预防后天性痣细胞色素痣有效的量在有痣处，优选在局部给药。
16.权利要求12至15中任何一项所述的方法，其特征在于，将式(I)化合物以一种糊剂、软膏、悬浮液、溶液、凝胶、喷雾剂或者乳膏剂，特别以软膏制剂来施用。
17.权利要求16所述的方法，其特征在于，将式(I)所示的化合物制成软膏，并阻止水份经涂抹软膏而从皮肤中逸出。
18.权利要求12至17中任何一项所述的方法，其特征在于，将该配方制剂和橡皮膏一起敷覆。
19.权利要求12至18中任何一项所述的方法，其特征在于，式(I)所示的化合物选自青蒿素；二氢青蒿素；式(I)所示含羧基的衍生物，特别是青蒿酯；蒿甲醚；蒿乙醚；二氢青蒿素的碳酸丙酯以及蒿酸。
20.权利要求19所述的方法，其特征在于，式(I)所示的化合物是青蒿素、二氢青蒿素或者青蒿酯。
21.权利要求14所述的方法，其特征在于，也用于预防皮肤癌。
Treatment and prevention of benign pigmented moles (naevi) using artemisinine and the derivatives thereof
Benign pigmented moles or athlete's foot or ringworm of the nails can be treated with locally applicable, especially topically formulated active ingredients of formula (I) wherein X represents CO, CHOZ or CHNRZ, Z is selected from hydrogen, linear or branched (C1-C6) alkyl, linear or branched (C2-C6) alkenyl, linear or branched (C2-C6) alkynyl, (C3-C8) cycloalkyl, (C6-C24) aryl, (C7-C24) aralkyl, m- und p- represent CH2(C6H4)COOM; COR<3>; CSR<3>; C (NR<6>) R<3>; SOR<4>; SO2OM; SO2NR<7>R<8>; SO2O- artemisinyl; SO2NH-artemisinyl; POR<4>R<5> and PSR<4>R<5>; R<3> represents a linear or branched (C1-C6) alkyl, a linear or branched (C1-C6) alkoxy; a linear or branched (C2-C6) alkenyl; a linear or branched (C2-C6) alkynyl; (C3-C8) cycloalkyl; (C6-C24) aryl; (C6-C10) aryloxy; (C7-C24) aralkyl; -(CH2)n-COOM, where n represents a whole number between 1 and 6; or 10a-dihydroartemisinyl; R<4> and R<5> are independently selected from linear or branched (C1-C6) alkyl; linear or branched (C2-C6) alkenyl; linear or branched (C2-C6) alkynyl; (C3-C8) cycloalkyl; (C6-C24) aryl; (C7-C24) aralkyl; OM; linear or branched (C1-C6) alkoxy; (C6-C10) aryloxy and NR<7>R<8>; R<6> is selected from linear or branched (C1-C6) alkyl; linear or branched (C2-C6) alkenyl; linear or branched (C2-C6) alkynyl; (C3-C8) cycloalkyl; (C6-C24) aryl and (C7-C24) aralkyl; M represents hydrogen or a pharmaceutically acceptable cation; and R<7> and R<8> independnetly represent hydrogen or a linear or branched (C1-C6) alkyl, or R<7> and R<8> together form am alkylene bridge (C4-C6); and R is selected from hydrogen and the groups cited for R<6>. Said compounds are also effective in the prevention of acquired Naevus cell naevi.
With arteannuin and derivatives for treatment and prevention of benign pigmented moles (nevus)
The present invention relates to topical and particularly treat benign pigmented moles (nevus) on skin and the mucosa with prescription with local; The particularly treatment of nevus cytochrome nevus, lentiginosis and mucosa pigmented spots.In addition, the invention still further relates to the part prescription that is suitable for this kind treatment.
The term nevus cell nevus refers on the various microstructures the optimum dermatosis by so-called nevus cellularity, nevus cell nevus (birthmark, Hepatic nevus).The nevus cell is that normal pegmentation has the cell that defective forms, i.e. melanocyte.Almost everyone can occur the melanocytic nevus of different numbers, different size and different colours intensity on one's body.The outer Phenotype of nevus can be very inequality.It can be with the nevus cell nevus skin flush or that be higher than skin plane (spherical, the base of a fruit is arranged or lie on the skin) point-like also as planar greatly, verrucose, protuberance or slick, painted then from the colour of skin through brown to black.The number of posteriority melanocytic nevus increases with life process.Nevus cytochrome nevus with fanciful structures, the danger that has height to cancerate, and be called as dysplastic or atypical nevus cytochrome nevus.
Perhaps can develop into malignant melanoma by nevus cytochrome nevus, also be the casting skin cancer.Under the situation more than 60%, it is formed by nevus cytochrome nevus.In nearly decades, it should be noted that the melanoma sickness rate obviously rises.Nineteen sixty is about 1: 600 of U.S.'s life-span risk, and current people to observe the life-span risk be 1: 100.Therefore, for instance, according to Prof.Dr.Matthias Volkenandt (Klinikf ü r Dermatologie und Allergologie der Ludwig-Maximilians-
M ü nchen, Frauenlobstrasse 9,80337M ü nchen) said, melanoma is annual about 14 (they also being 14 new cases) of per 100000 residents at the geographic sickness rate in state, Bavaria.This is equivalent to about 1% (per 100 residents are having a trouble melanoma in life) of life-span risk.With regard to this numeral, melanoma is not the tumor of human the most frequent generation, and but described according to Volkenandt, the height of sickness rate rising does not have other tumor to mention in the same breath with it.
According to knowledge situation now, also do not overcome nevus cytochrome nevus rotten preventative diagnosis and treatment and therapy.The rotten excision of at first wanting with nevus of high-risk.In early time, laser treatment plays a role aspect beauty treatment.All two kinds of methods all be invasive, have certain risk (cicatrization, dyschromasia etc.) and interrelate with high cost.
The appearance of posteriority nevus, always a kind of red point (hemorrhage or hemangioma) little, that sometimes little handy microscope just can be seen.From this nevus initial period, the speckle that often develop into bigger redness, a bit swells.Then, initial from these nevus initial periods, form the brown nevus cytochrome nevus big or small, that brown colourity is different with structure.
Arteannuin (also claiming Qinghaosu) is a kind of Sesquiterpene with peroxide group, and it is studied mainly as the antimalaric that whole body is worked and uses up to now.Arteannuin is difficult to water-soluble; But the soluble derivative of arteannuin is developed out.In EP-A-0 428 773, narrated general or topical application arteannuin and derivant thereof treat the disease that psoriasis, viral disease (wart, molluscum contagiosum and sheep pox), ultraviolet bring out (the photic dermatosis of multiform, " collagen vascular disease ", premalignant keratosis (
Keratosen), precancer dermatitis, malignant lentigo, basal cell carcinoma, temporo squama houselet cancer and malignant melanoma), blister dermatoses and hemorrhoid.
The purpose of this invention is to provide pharmaceutical formulation that work in the part but preferred local application, said preparation is to treating optimum nevus cell nevus, and is particularly effective to melanocytic nevus, thereby also can be used to prevent skin carcinoma.
By the present invention, the method that this goal of the invention is achieved is, prepares topical application with a compounds that is selected from formula (I), and particularly the pharmaceutical formulation of topical is treated optimum nevus cell nevus:
In this formula (I), X is CO, CHOZ or CHNRZ, and wherein Z is selected from:
Hydrogen; Straight or branched (C 1-C 6) alkyl; Straight or branched (C 2-C 6) thiazolinyl; Straight or branched (C 2-C 6) alkynyl; (C 3-C 8) cycloalkyl; (C 6-C 24) aryl; (C 7-C 24) aralkyl; Between-CH 2(C 6H 4) COOM and right-CH 2(C 6H 4) COOM; COR 3CSR 3C (NR 6) R 3SOR 4SO 2OM; SO 2NR 7R 8SO 2O-artemisin base; SO 2NH-artemisin base; POR 4R 5And PSR 4R 5
R wherein 3Be straight or branched (C 1-C 6) alkyl; Straight or branched (C 1-C 6) alkoxyl; Straight or branched (C 2-C 6) thiazolinyl; Straight or branched (C 2-C 6) alkynyl; (C 3-C 8) cycloalkyl; (C 6-C 24) aryl; (C 6-C 10) aryloxy group; (C 7-C 24) aralkyl;-(CH 2) nCOOM, wherein n is 1 to 6 integer; It perhaps is 10 α-dihydro artemisin base;
R 4And R 5Be selected from straight or branched (C separately separately 1-C 6) alkyl; Straight or branched (C 2-C 6) thiazolinyl; Straight or branched (C 2-C 6) alkynyl; (C 3-C 8) cycloalkyl; (C 6-C 24) aryl; (C 7-C 24) aralkyl; OM; Straight or branched (C 1-C 6) alkoxyl; (C 6-C 10) aryloxy group and NR 7R 8
R 6Be selected from straight or branched (C 1-C 6) alkyl; Straight or branched (C 2-C 6) thiazolinyl; Straight or branched (C 2-C 6) alkynyl; (C 3-C 8) cycloalkyl; (C 6-C 24) aryl and (C 7-C 24) aralkyl;
M is hydrogen or the acceptable cation of pharmacy; And R 7And R 8Be separately hydrogen or straight or branched (C separately 1-C 6) alkyl, perhaps R 7And R 8(C of common formation 4-C 6) the alkylidene bridged bond; And
R is selected from hydrogen and to R 6Cited group.
Now unexpected the discovery used above-mentioned bioactive substance, particularly uses the preparation of part (for example on skin) medication to handle and can successfully treat pigmented vevus of skin very early, and particularly those originate from melanocytic nevus cell nevus.Also once found,, also may prevent skin carcinoma (particularly basal cell tumor or melanoma) through with formula (I) compounds for treating nevus cytochrome nevus.In addition, find that also this active substance is under the situation of topical application, aspect prevention of benign pigmented moles, it also is effective particularly preventing posteriority nevus cytochrome nevus aspect.
In the present patent application scope, " optimum nevus cell nevus " is understood as especially:
-nevus, particularly nevus cytochrome nevus are (common or dysplastic; Nevus cytochrome nevus also often is called as melanocytic nevus); It can divide three groups by occurrence positions down, be junctional nevus cytochrome nevus (interlayer epidermis/corium), compound nevus cytochrome nevus (corium connective tissue) and dermal nevus cytochrome nevus (corium deep layer), and be congenital nevus cytochrome nevus (=birthmark) and posteriority nevus cytochrome nevus by the diacritic group of occurrence time.The group of posteriority nevus cytochrome nevus is the recurrence nevus, and it forms behind a kind of other optimum mother's marks of surgical excision.The example of congenital junctional nevus cytochrome nevus is a macle, and the example of posteriority junctional nevus cytochrome nevus or compound nevus cytochrome nevus is halo naevus (a Sa Dun Shi nevus); The example of posteriority melanocyte junctional nevus cytochrome nevus, compound nevus cytochrome nevus or dermal nevus cytochrome nevus then is Spitz nevus and Li Deshi nevus.The example of congenital dermal nevus cytochrome nevus is mongolenfleck (=Naevus Bleu), and the example of the nevus cytochrome nevus of congenital junctional nevus cytochrome nevus, compound nevus cytochrome nevus or corium then is congenital Riesenpigmentnaevus (Naevus giganteus);
-lentiginosis (for example Hepatic nevus=Lentigo simplex, Sonnenflecken=Lentigosolaris, senile plaque=Lentigo senilis, PUVA-Lentigines);
-melanin pigmentation disorder (freckle=ephelides) for example; And
-mucosa nevus cell nevus (for example eye conjunctiva nevus, lip nevus, oral mucosa nevus and sexual organ nevus).
Formula (I) chemical compound is aspect all above-mentioned optimum nevus cell nevuss of diagnosis and treatment, and particularly posteriority or congenital nevus cytochrome nevus aspect are effective.In above-mentioned these nevuss, dysplastic (atypical) nevus cytochrome nevus has the high likelihood that goes bad into skin carcinoma, therefore, in order to prevent skin carcinoma, preferably uses formula (I) compounds for treating nevus.
(C 1-C 6) alkyl preferably methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, sec-butyl, the tert-butyl group, n-pentyl, sec-amyl, neopentyl, n-hexyl, Sec-Hexyl and new hexyl.Straight chain (C more preferably 1-C 3) alkyl, and particularly preferably be methyl or ethyl.Straight chain or side chain (C 2-C 6) thiazolinyl (C preferably 2-C 4) thiazolinyl, for example vinyl, pi-allyl, 1-methyl ethylene, 2-methyl ethylene, but-1-ene-1-base, but-2-ene-1-base, fourth-3-alkene-1-base, but-1-ene-2-base, but-2-ene-2-base, fourth-3-alkene-2-base, 2,2-dimethyl vinyl and 1,2-dimethyl vinyl.Straight or branched (C 2-C 6) alkynyl preferably acetenyl, propargyl, third-1-alkynes-1-base, fourth-1-alkynes-1-base, fourth-2-alkynes-1-base, fourth-3-alkynes-1-base, fourth-3-alkynes-2-base, 3-methyl fourth-1-alkynes-1-base, 3,3-dimethyl butyrate-1-alkynes-1-base, 1,1-dimethyl butyrate-2-alkynes-1-base and 1,1-dimethyl propylene-2-alkynes-1-base.(C 3-C 8) cycloalkyl preferably cyclopropyl, cyclobutyl, cyclopenta and cyclohexyl.(C 6-C 24) aryl (C preferably 6-C 10) aryl, for example phenyl, naphthalene-1-base and naphthalene-2-base.(C 7-C 24) aralkyl (C preferably 7-C 12) aralkyl, for example benzyl, phenethyl, (naphthalene-1-yl) methyl and (naphthalene-2-yl) methyl.(C 1-C 6) alkyl in the alkoxyl, be top to (C 1-C 6) the illustrational same group of alkyl.(C preferably 1-C 3) alkoxyl more preferably then is methoxyl group, ethyoxyl or positive propoxy.(C 6-C 10) aryl in the aryloxy group, be top to (C 6-C 24) the illustrational same group of aryl.More preferably phenoxy group or alpha-naphthoxy base or β-naphthoxy.
In the application's scope, one of term " artemisin base " expression has the group shown in the formula (I) of X=CH-, and this group can be linked on oxygen or the nitrogen by the free valency of carbon.In the application's scope, term " 10-α-dihydro artemisin base " means-O-artemisin base, and wherein the implication of artemisin base is ditto described.
In the formula (I), Z is preferably hydrogen; Straight or branched (C 1-C 6) alkyl; Between-CH 2(C 6H 4) COOM and right-CH 2(C 6H 4) COOM; COR 3SOR 4SO 2OM; SO 2NR 7R 8SO 2NH-artemisin base and POR 4R 5
With regard to meet the pharmacopedics requirement as with regard to the cation of M, that can mention is the cation of exemplary alkali metal cation such as lithium, sodium or potassium, the cation of alkaline earth metal cation such as magnesium and calcium, ammonium and H +N (R XR YR Z), R wherein x, R y, R zCan be separately methyl or ethyl separately.
Work as R 3Be straight or branched (C 1-C 6) alkyl, straight or branched (C 1-C 6) alkoxyl ,-(CH 2) nWhen-COOM or artemisin base, Z is preferably COR 3This moment, particularly M was preferably hydrogen, sodium, potassium or ammonium.
When M was alkali metal, alkaline-earth metal or ammonium, Z was preferably SO 2OM.
Work as R 4And R 5Be selected from OM and straight or branched (C 1-C 6) during alkoxyl, Z is preferably POR 4R 5More preferably, R 4And R 5In one of be OM, particularly sodium, potassium or ammonium of M wherein, and be other straight or branched (C 1-C 6) alkoxyl or OH.
Chemical compound shown in the formula (I) is known, perhaps can be made into the known compound shown in the formula of being similar to (I).In the case, this chemical compound of X=CO is an arteannuin, and the chemical compound of X=CHOH is a dihydroartemisinine.X=CHOZ and Z are different from the chemical compound of hydrogen, and perhaps the chemical compound of X=CHNRZ below is referred to as " derivant of dihydroartemisinine ".
Chemical compound shown in the formula (I) can following method make:
-arteannuin (X=CO) can be separated from plant Artemisia annua (ArtemisiaAnnua) plant as known.
-dihydroartemisinine (X=CHOH) is known, and can for example under about 0 ℃ arteannuin be prepared in methanol with sodium borohydride reduction.
The derivant of the dihydroartemisinine of-X=CHOZ, wherein Z is straight or branched (C 1-C 6) alkyl, straight or branched (C 2-C 6) thiazolinyl, straight or branched (C 2-C 6) alkynyl, (C 3-C 8) cycloalkyl, (C 6-C 24) aryl or (C 7-C 24) aralkyl, available dihydroartemisinine prepares by the following method: at first make dihydroartemisinine change into the trimethyl silyl ether of dihydroartemisinine with chlorination front three silicon, make trimethylsiloxy with bromination front three silicon exchange bromine (according to the embodiment 1 of US-A-2005/0119232), then in the presence of alkali, make bromine atoms use excessive HOZ to replace by institute's requirement again, wherein the implication of Z has been given explanation.Among these derivants, Artemether (Z=Me) and arteether (Z=Et) are compound known.
The derivant of the dihydroartemisinine of-X=CHNRZ, wherein the implication of R has been given explanation in formula (I), Z=hydrogen, straight or branched (C 1-C 6) alkyl, straight or branched (C 2-C 6) thiazolinyl, straight or branched (C 2-C 6) alkynyl, (C 3-C 8) cycloalkyl, (C 6-C 24) aryl or (C 7-C 24) the aralkyl person, available dihydroartemisinine prepares by the following method: at first make dihydroartemisinine change into the trimethyl silyl ether of dihydroartemisinine with chlorination front three silicon, make trimethylsiloxy with bromination front three silicon exchange bromine (according to the embodiment 1 of US-A-2005/0119232), then in the presence of alkali, make bromine atoms again by requirement use excessive amine HNRZ to replace, wherein the implication of R and Z has been given explanation.
The derivant of the dihydroartemisinine of-X=CHOZ or CHNRZ, wherein the implication of R has been given explanation in formula (I), and between Z=-CH 2(C 6H 4) COOM or right-CH 2(C 6H 4) COOM (definition of M is as pointed in formula (I)), can produce as raw material by the dihydroqinghaosu of dihydroartemisinine or X=CHNRH, its method is, in the presence of alkali, with-bromomethyl essence of Niobe or right-bromomethyl essence of Niobe make described raw material alkylation, make the methyl ester hydrolysis then, and form suitable salt when M not should be hydrogen.Among these derivants, X=CHOZ and Z=be right-CH 2(C 6H 4) derivant of COOH is known as " artemisic acid "
The dihydroqinghaosu of-X=CHOZ or CHNRZ, wherein the implication of R has been given explanation, Z=COR in formula (I) 3Or CSR 3And R 3Be straight or branched (C 1-C 6) alkoxyl or (C 6-C 10) aryloxy group, can be by the dihydroqinghaosu and suitable chlorinated carboxylic acid (C of dihydroartemisinine or X=CHNRH 1-C 6) Arrcostab or chlorinated carboxylic acid (C 6-C 10) aryl ester or chlorothio carboxylic acid (C 1-C 6) Arrcostab or chlorothio carboxylic acid (C 6-C 10) aryl ester and a kind of alkali prepares.
The dihydroqinghaosu of-X=CHOZ or CHNRZ, wherein the implication of R has been given explanation, Z=COR in formula (I) 3And R 3Be straight or branched (C 1-C 6) alkyl, straight or branched (C 2-C 6) thiazolinyl, straight or branched (C 2-C 6) alkynyl; (C 3-C 8) cycloalkyl, (C 6-C 24) aryl or (C 7-C 24) aralkyl; Can prepare by the dihydroqinghaosu of dihydroartemisinine or X=CHNRH and the reaction of acid chloride and alkali, wherein acid chloride and suitable R 3Replace.
The dihydroqinghaosu of-X=CHOZ or CHNRZ, wherein the implication of R has been given explanation, Z=CSR in formula (I) 3And R 3Be straight or branched (C 1-C 6) alkyl, straight or branched (C 2-C 6) thiazolinyl, straight or branched (C 2-C 6) alkynyl; (C 3-C 8) cycloalkyl, (C 6-C 24) aryl or (C 7-C 24) aralkyl; Can pass through Z=COR 3Above-mentioned corresponding derivative and Lawesson ' s reagent react and produce.
The dihydroqinghaosu of-X=CHOZ or CHNRZ, wherein the implication of R has been given explanation, Z=COR in formula (I) 3And R 3-(CH 2) n-COOM (wherein the implication of M is described in formula (I)), dihydroqinghaosu that can be by dihydroartemisinine or X=CHNRH and cyclic acid anhydride react (when n=2 or 3) or with MeOOC (CH 2) n-COOMe reacts and produces.Under latter event, during X=CHOZ, also can add base catalyst such as NEt together 3, and the methanol that disengages during ester exchange reaction can for example be extracted out from poised state by decompression inspissation.When M is not hydrogen, can form corresponding salt, its method is: make residual carbomethoxy cracking, for example use the M cyanide.Among these derivants, being known as of X=CHOZ, n=2 and M=hydrogen " artesunate ".
The derivant of the dihydroartemisinine of-X=CHOZ or CHNRZ, wherein the implication of R has been given explanation, Z=CSR in formula (I) 3And R 3-(CH 2) n-COOM (wherein the implication of M has been given explanation in formula (I)) can make, and its method is: make MeOOC (CH with Lawesson ' s reagent 2) nOne or two ketonic oxygen among the-COOMe is substituted by sulfur, and the dihydroqinghaosu of gained half sulfo-diester and dihydroartemisinine or X=CHNRH is reacted, then make it still be hydrolyzed into COOH, and when M is not hydrogen, form corresponding salt for free COOMe group.
-can make the derivant of the dihydroartemisinine of X=CHOZ or CHNRZ, wherein the implication of R has been given explanation, Z=C (NR in formula (I) 6) R 3(R wherein 6Implication in formula (I), given explanation) and R 3Be straight or branched (C 1-C 6) alkoxyl or (C 6-C 10) aryloxy group, its method is: make R 6The isocyanates R that implication as above illustrates 6-NCO and corresponding (C 1-C 6) alcohol or (C 6-C 10) the fragrant and mellow reaction, and make urethanes and the POCl that obtains like this 3Reaction is reacted with the dihydroqinghaosu of dihydroartemisinine or X=CHNRH in the presence of alkali then.
-can make the derivant of the dihydroartemisinine of X=CHOZ or CHNRZ, wherein the implication of R has been given explanation, Z=C (NR in formula (I) 6) R 3(R wherein 6Implication in formula (I), given explanation) and R 3Be straight or branched (C 1-C 6) alkyl, straight or branched (C 2-C 6) thiazolinyl, straight or branched (C 2-C 6) alkynyl; (C 3-C 8) cycloalkyl, (C 6-C 24) aryl or (C 7-C 24) aralkyl, its method is: make R 6The isocyanates R that implication as above illustrates 6-NCO and corresponding Grignard reagent R 3MgBr reacts, wherein R 3Implication given explanation, and make amide and the POCl that obtains like this 3React, then in the presence of alkali, react with the dihydroqinghaosu of dihydroartemisinine or X=CHNRH.
The derivant of the dihydroartemisinine of-X=CHOZ or CHNRZ, wherein the implication of R has been given explanation, Z=C (NR in formula (I) 6) R 3And R 3-(CH 2) n-COOM (wherein M and R 6Implication in formula (I), given explanation) available such method produces: make n and R 6The chemical compound MeOOC-(CH that as above illustrates of implication 2) n-CONHR 6With POCl 3React, the dihydroqinghaosu with dihydroartemisinine or X=CHNRH reacts in the presence of alkali then, and methyl ester is hydrolyzed, and if M be not hydrogen, then form suitable salt.
-have a Z=SOR 4And R 4The X=CHOZ of=OMe or the dihydroqinghaosu of CHNRZ (wherein the implication of R has been given explanation in formula (I)) can be selectively in the presence of base catalysts, reaction by dihydroartemisinine and excessive dimethyl sulfite (DRP 487253), heat up in a steamer and remove the methanol that disengages, and the dimethyl sulfite that heats up in a steamer except that superfluous that then reduces pressure is produced.
The derivant of the dihydroartemisinine of-X=CHOZ or CHNRZ, wherein the implication of R has been given explanation in formula (I), and Z=SOR 4(R wherein 4Be straight or branched (C 1-C 6) alkoxyl or (C 6-C 10) aryloxy group), can react with the alkali such as the pyridine that suit by corresponding derivative and excessive thionyl (two) chlorine of X=CHOH or CHNRH, remove excessive thionyl (two) chlorine, and then make sulfurous acid derivant and corresponding straight chain or the side chain (C that obtains 1-C 6) alcohol or (C 6-C 10) fragrant and mellow in the presence of suitable alkali such as pyridine, the reaction and making.The derivant of the dihydroartemisinine of-X=CHOZ or CHNRZ, wherein the implication of R has been given explanation in formula (I), and Z=SOR 4(R wherein 4Be (C 1-C 6) alkyl, straight or branched (C 2-C 6) thiazolinyl, straight or branched (C 2-C 6) alkynyl, (C 3-C 8) cycloalkyl, (C 6-C 24) aryl or (C 7-C 24) aralkyl), can pass through Grignard reagent R 4MgBr (R wherein 4Implication given explanation) with excessive thionyl (two) chlorine reaction, remove excessive thionyl (two) chlorine, and then make the R that obtains 4The corresponding dihydroqinghaosu of-SOCl and X=CHOH or CHNRH reacts in the presence of suitable alkali such as pyridine and makes.
The dihydroqinghaosu of-X=CHOZ or CHNRZ, wherein the implication of R has been given explanation in formula (I), and Z=SOR 4(R wherein 4Be NR 7R 8, R 7And R 8Implication in formula (I), given explanation), can pass through amine HNR 7R 8React with excessive thionyl (two) chlorine, remove excessive thionyl (two) chlorine, and then make the RR of gained 7R 8The corresponding dihydroqinghaosu of NSOCl and X=CHOH or CHNRH reacts in the presence of suitable alkali such as pyridine and makes.
The derivant of the dihydroartemisinine of-X=CHOZ or CHNRZ, wherein Z=SO 2OM (implication of M has been given explanation in formula (I)) can react by corresponding derivative and the pyridine-sulfur trioxide-complex of X=CHOH or CHNRH, and the pyridine counter ion counterionsl gegenions of gained sulfonate are exchanged into M and make.
The derivant of the dihydroartemisinine of-X=CHOZ or CNHRZ, wherein Z=SO 2NR 7R 8, and R, R 7And R 8Implication in formula (I), given explanation, dihydroqinghaosu that can be by X=CHOH or CHNRH with react in the presence of alkali such as pyridine with the 1eq. chlorosulfuric acid, and follow in the presence of alkali such as pyridine and 1eq. amine HNR 7R 8(R wherein 7And R 8Implication given explanation) react and make.
-X=CHOZ and Z=SO 2The dihydroqinghaosu of O-artemisin base can react in the presence of alkali such as pyridine by 2eq. dihydroartemisinine and 1eq. chlorosulfuric acid and makes.
-X=CHOZ and Z=SO 2The dihydroqinghaosu of NH-artemisin base can react by dihydroartemisinine and 1eq. chlorosulfuric acid in the presence of alkali such as pyridine, and then in the presence of alkali such as pyridine, with 1eq X=CHNH 2Artemisinin derivative react and make.Derivant that obtains like this and X=CHNHZ and Z=SO 2The derivant of O-artemisin base is with a kind of derivant.Then, can be by to carrying out deprotonation on the sulfoamino-group nitrogen by the derivant of gained like this, and carry out alkylation with alkyl bromide RBr (wherein the implication of R has been given explanation), prepare X=CHNRZ, the implication of the R dihydroqinghaosu that given explanation (but beyond dehydrogenation) in formula (I) wherein.
-X=CHNHZ and Z=SO 2The derivant of the dihydroartemisinine of NH-artemisin base can prepare according to the embodiment among the US-A-2005/0119232 2.Again can be by this derivant by removing the proton in two sulfoamino-group nitrogen, and carry out alkylation with alkyl bromide RBr (wherein the implication of R has been given explanation), prepare X=CHNRZ, the implication of the R dihydroqinghaosu that given explanation (but beyond dehydrogenation) in formula (I) wherein.
-can make X=CHOZ or CNHRZ, Z=POR wherein 4R 5Perhaps PSR 4R 5(R, R 4And R 5Implication in formula (I), given explanation) dihydroqinghaosu, its method is: the dihydroqinghaosu that at first makes dihydroartemisinine or X=CHNRH with excessive POCl 3(or PSCl 3) react, and heat up in a steamer and remove excessive POCl 3(or PSCl 3).To gained X=CHOPOCl 2(or CHOPSCl 2) or CHNRPOCl 2(or CHNRPSCl 2) crude product in, look radicals R to be introduced 4And R 5Kind and decide, as Grignard reagent R 4MgBr/R 5MgBr (works as R 4And/or person R 5Should be (C 1-C 6) alkyl, straight or branched (C 2-C 6) thiazolinyl, straight or branched (C 2-C 6) alkynyl, (C 3-C 8) cycloalkyl, (C 6-C 24) aryl or (C 7-C 24) during aralkyl) and form, with alcoholates R 4O-/R 5The form of O-(is worked as R 4And/or R 5Should be straight or branched (C 2-C 6) alkoxyl or (C 6-C 10) during aryloxy group) or with amine HNR 7R 8Form or introduce radicals R with the form of water or hydroxide 4And R 5Condition is that these reagent preferably add by the order that nucleophilicity increases, and is being R at least 4And/or R 5In the time of one of among the OM, will be to add this essential MOH as last reagent..
Under the situation of the chemical compound of X=CHOZ or CHNRZ, carbon atom (also is C on the sesquiterpene framework 10-atom) configuration can be (R) or (S).Chemical compound shown in the formula (I) also can C 10The form of-epimer mixture is used, wherein the ratio of two kinds of epimers can by arteannuin at pre reduction and/or pass through C 10-hydroxyl other are derived from the hydroxyl of water or when synthetic used nucleophile replace change.
Those active substances shown in the preferably above-mentioned formula (I), they are selected from the propyl carbonate and the artemisic acid of arteannuin, dihydroartemisinine, carboxylic derivant (particularly artesunate), Artemether (Artemeter), arteether, dihydroartemisinine
Particularly preferably be arteannuin, dihydroartemisinine and artesunate.
Chemical compound shown in the formula (I) can use separately, perhaps uses with two or more these combination of compounds forms.
The chemical compound, particularly artesunate of formula (I), also effective to prevention posteriority nevus cytochrome nevus.For the purpose of prevention nevus cytochrome nevus, with the chemical compound of formula (I), particularly artesunate, large tracts of land is coated onto on the whole skin, is coated onto on the head zone with the high likelihood that forms nevus, perhaps is coated onto on the observable early stage nevus.Head zone with the high likelihood that forms nevus is the local skin that frequently is exposed to ultraviolet radiation on the one hand.On the other hand, this head zone, often be present in formed nevus cytochrome nevus around (for example typically with the radius of 5cm nearly around already present nevus).In addition, the chemical compound, particularly artesunate shown in the formula (I) also has other favourable characteristics, and promptly obviously there has been early stage nevus in they, but also so small making almost can not distinguished with bore hole.Under the effect of chemical compound shown in the formula (I), thisly recognize that still unclear early stage nevus at first forms small red dot, become after a few days dark to black, and the part picture dark, have a crystalline solid that is arranged in micropore.Under some favourable situations, microscopy is penetrated on the top, and to check that in advance debatable skin part just becomes unnecessary.
For the purpose of using, the active substance of formula (I) can be mixed with and be suitable for local the use, particularly be suitable for the pharmaceutical formulation that local surfaces (skin) is used.Active material concentration in the made pharmaceutical formulation (preparation) is not crucial especially.Gross weight in pharmaceutical formulation can prepare the pharmaceutical formulation of about 0.1% (weight) of concentration to about 40% (weight).In order to treat nevus cytochrome nevus (congenital=birthmark, perhaps posteriority), in the gross weight of pharmaceutical formulation, pharmaceutical formulation preferably contains 5% (weight) of having an appointment to the active substance of about 20% (weight), especially preferably contains 10% (weight) of having an appointment.For the purpose of prevention posteriority nevus cytochrome nevus, preferably contain chemical compound shown in the formula (I) of about at the most 5% (weight) in the gross weight pharmaceutical formulation of pharmaceutical formulation; Or rather, preferably contain 1% (weight) of having an appointment to about 5% (weight).The definite treatment aequum of bioactive substance, depend on active substance itself, used base material (Grundlage), made lid human relations dosage form (for example ointment, suspension, ointment, plaster, ointment, gel, solution) and used additive, and can determine by simple effect test by the technical staff.
The treatment time of the nevus cytochrome nevus that exists (congenital=birthmark, perhaps posteriority) is depended on kind, size, structure, pigmentation and the age of nevus.Preferably periodically treat with chemical compound shown in the formula (I) of high concentration.After first course of treatment (Behandlungstagen), first reaction is normally tangible.Up to being clearly better or changing, promptly show nevus cytochrome nevus and fade gradually or disappear, can continue two to the several months.With regard to the old patient, this time period can be more longer, continues more longerly because epidermal renewal increases with old.
With regard to prevention posteriority nevus cytochrome nevus, promptly it is enough to use 2～3 times.Bigger early stage nevus is preferably treated the more longer time, till early stage nevus is faded gradually or disappears.
Active substance shown in the formula (I) should be decided on treatment measure (Therapieansatz), invades skin to some extent deeply:
-just treating nevus cytochrome nevus (congenital=birthmark, perhaps posteriority), should decide on type and the outmoded degree of nevus, active substance preferably enters corium.
-with regard to prevention posteriority nevus cytochrome nevus, active substance preferably directes reach the juncture area on border between epidermis and corium by corium.
Concerning the inert bed material that is generally used for the local prescription preparation, be suitable for all these active substances as the pharmaceutical formulation bed material of formula (I) active substance.This bed material especially for the local prescription preparation: vaseline, fat, wax, fatty acid ester, paraffin, oil, silicone and polymer thereof.Preferably with active substance and about 60% (weight) to about 99.9% (weight), more preferably prepare in the pharmaceutical formulation bed material of the pharmaceutical formulation made with about % (weight) 80 to about 95% (weight).If use hydrophilic/aqueous topical pharmaceutical formulation bed material such as hydrogel, ointment, then active substance can encapsulate by Nano capsule, be encapsulated in liposome interior (Einschluss in Liposomen) or for example form complex, prevent its decomposition with cyclodextrin.Complexation about arteannuin and derivant and cyclodextrin for instance, sees also US-A-2005/187189.
According to Deutscher Arzneibucs, the local prescription preparation with the single-phase bed material of non-water such as anhydrous pure fat phase is known as ointment.Wherein used the ointment of formula of the present invention (I) active substance, be made up of a kind of like this ointment bed material, this ointment bed material can contain the active substance of one or more fine dispersion, to use on skin.
When this local prescription preparation should be ointment, this pharmaceutical formulation bed material can be preferably by the partition coefficient that has n-octyl alcohol/water under the room temperature about 1 to about 10 5, more preferably from about 10 to about 10 5, preferred especially about 50 to about 10 4Lipophilic ingredient form.Under this occasion, the example of this pharmaceutical formulation bed material is vaseline, fat, wax, fatty acid ester, paraffin, oil, silicone and polymer thereof (for example polydialkysiloxane, silicone elastomer, silicone-wax, silicone emulsifier).
During coating ointment, formula (I) active substance comes out from the topical formulations bed material that surrounds it, and enters in the skin.This lipotropy bed material and skin adherence get very firm, and outwards form water repellent layer.This layer has equally also stoped moisture from skin outwards overflow (inhibition).Because this effect, it is moistening that skin is held, and become warm, because the water that can evaporate is few.Because humidity improves, skin also has more elasticity, and this has promoted absorption of active agents.
Opposite with ointment, two phase systems (water is with mutually fatty) are named as emulsifiable paste.Chemical compound shown in the formula (I) also can be mixed with emulsifiable paste.With regard to the fat phase, can adopt such as top the illustrational same class material of ointment bed material.Also can contain the various buffer material that can make the water pH of skin tolerance outside aqueous phase dewaters selectively, perhaps also can contain known one-tenth gelatin polymer such as HYDROXY PROPYL METHYLCELLULOSE, carboxymethyl cellulose, contain cross-linking agent (Borax or for example such as Mg 2+Perhaps Ca 2+Multivalent metal cation) polyvinyl alcohol and and similar substance.In order to carry out emulsifying, can use skin-tolerant surfactant commonly used, for example fatty acid monoglyceryl ester and fatty acid two glyceride, the hydrogenant Oleum Ricini (Cremophor of polyoxyethylene (40)
) or lecithin.
As the adjuvant of local prescription preparation, can be the keratolytic (for example salicylic acid, carbamide, biostearin) and the antiseptic of the penetration enhancer used always (such as dimethyl acetylamide, dimethyl formamide, propylene glycol, aliphatic alcohol, triethanolamine, dimethyl sulfoxine, azone and other), improvement effect.Additive generally is used to improve effect, stability, persistency and the firmness that covers the human relations dosage form.
Preferably the chemical compound shown in the formula (I) is mixed with the local prescription preparation that is substantially free of the material that strengthens infiltration.Also preferably prepare the chemical compound shown in the formula (I), make it to be substantially free of (C 5-C 19) monocarboxylic acid, its ester and amide thereof.In the present patent application scope, " being substantially free of " is interpreted as, and the local prescription preparation contains less than 1% (weight) in the total amount of pharmaceutical formulation, preferably less than the anatonosis material of 0.1% (weight).
Be used for formula (I) chemical compound of paste, ointment, ointment, solution, gel, spray or suspension, preferably all contain the derivant of a carboxyl, particularly artesunate.In the case, carboxyl can be selectively exists with the form of alkali metal salt, alkali salt or ammonium salt.
For on skin, using or be applied in the skin, with formula (I) active substance with the local prescription dosage form, particularly with the form of paste, ointment, suspension, solution, gel, spray or emulsifiable paste, especially preferably with ointment form, be coated onto on the plaster (Pflaster).Plaster can be a kind of material that absorbs or suck the local prescription preparation selectively.Active substance also can directly be suspended in or be dissolved in the inert binder of plaster certainly; In being similar to the plaster of previously known, for example being used for scopolamine (for example " Scopoderm TTS ") or being used for the plaster of estradiol (for example " Estraderm TTS ").In this way, active substance can directly and in long-time contact with pending position.Also produce blocking action in addition, this effect has improved the infiltration of active substance.
Other administering modes of formula (I) active substance are paste, solution, suspension, gel and ointment and spray.The semisolid of cited active substance or liquid formulation, (for example similar felt rod like that for form that also can bolt (Stift)
With exact dose) or with the volume form existence of (Roller) (in suitable bed material (Grundlage), solution, suspension, ointment, ointment, containing active substance).
Other are partial, can use the administration form example of formula (I) chemical compound by the present invention is applicator, and this applicator is by ultrasound wave, come promotion formula (I) chemical compound to infiltrate skin or mucosa by electric field or by microneedle.Use ultrasound wave and by the applicator of the spendable previously known of the present invention,, given in 908,448 openly, support for referencial use hereby in the lump for example at US-B6.Use the applicator of electric field dispensing active substance (therefore, it adopts the ionotherapy principle), known for a long time.By the present invention, they are applicable to that those belong to formula (I) active substance of salt, are CHOZ or CHNRZ suc as formula middle X promptly, between wherein Z is selected from-and CH 2(C 6H 4) COOM and right-CH 2(C 6H 4) COOM, SO 2OM and POR 4R 5, R in the formula 4And R 5In one of be OM, and be (the C of other straight or brancheds 1-C 6) alkoxyl or OH, M then is pharmaceutically acceptable cation.See also US-A-2005/065463 with regard to being used for with regard to the active substance topical administration of the present invention previously known applicator to the skin, the band microneedle, this document is supported for referencial use equally hereby in the lump.
Another example by the operable topical administration mode of the present invention is a technology, wherein picks up by the skin of sucker with pending position, and on the raising position of skin, and the part bed thickness of corium is excised with mechanical system, for example uses blade.Part is excised the skin part of corium, is infiltrative to chemical compound shown in the formula (I), and allows to go deep into the topical therapeutic of subcutis on these positions.Essential for this reason apparatus has been described among the WO-A-95/15783 that is included in as a reference in the application.
With artemisin and derivant (dihydroartemisinine thereof, arteether, Artemether, artesunate and semi-synthetic derivant thereof and synthetic similar compound) carry out a kind of few risk, non-invasive preventative or therapeutic treatment posteriority nevus cytochrome nevus or posteriority or congenital nevus cytochrome nevus (=birthmark), be a huge advance made of handling in the nevus cytochrome nevus, and can reduce canceroderm danger effectively.Therefore, the present invention not only medically but also on socioeconomic has huge meaning.In the topical therapeutic of being put down in writing, carry out, do not observe the atopic reaction of this chemical compound to skin with chemical compound, particularly artesunate shown in the formula (I).Noticeable also have, and health tissues is without prejudice, and treatment is painless, easy.
In view of obtaining the result up to now, can find out: the topical therapeutic (lokale Therapie) that carries out with arteannuin and derivant thereof, particularly local positioning treatment (topische Therapie) is very effective, and as prevention and the treatment of nevus, in the longer time, can notice, more little than traditional intervention treatment method expense, and risk is littler.
Further illustrate the present invention with following each embodiment now.
Embodiment 1: the local prescription preparation
With the 3g artesunate with 27g Excipial
Greasy ointment evenly mixes and stirs.
Embodiment 2a～8h: local prescription preparation
Not commensurability artesunate (seeing Table 1) is added in the different bed materials.What have also adds surface active material to pharmaceutical formulation.
Table 1:
| The embodiment numbering | Artesunate (g) | Additive | The bed material capacity adds to 100g |
| 2a～2h | 2a：0.1 2b：0.5 2c：1.0 2d：5.0 2e：10.0 2f：15.0 2g：30 2h：40 | - | White vaseline |
| 3a～3h | 3a：0.1 3b：0.5 3c：1.0 3d：5.0 3e：10.0 3f：15.0 3g：30 3h：40 | Polysorbate 0.5g; Polyethylene Glycol (2000) stearate 0.5g polyoxyethylene (40) anhydrous sorbitol oleic acid ester 0.5g | White vaseline |
| 4a～4h | 4a：0.1 4b：0.5 4c：1.0 4d：5.0 4e：10.0 4f：15.0 | Cera Flava |
| 4g：30 4h：40 | |||
| 5a～5h | 5a：0.1 5b：0.5 5c：1.0 5d：5.0 5e：10.0 5f：15.0 5g：30 5h：40 | Soybean lecithin 2g | Paraffin |
| 6a～6h | 6a：0.1 6b：0.5 6c：1.0 6d：5.0 6e：10.0 6f：15.0 6g：30 6h：40 | Polyethylene Glycol (2000) stearate 2g | Oleum Brassicae campestris |
| 7a～7h | 7a：0.1 7b：0.5 7c：1.0 7d：5.0 7e：10.0 7f：15.0 | Isopropyl myristate 1g | Decamethylcyclopentasiloxane (19g) silicone elastomer gel (adding to 100g) |
| 8a～8h | 8a：0.1 8b：0.5 8c：1.0 8d：5.0 8e：10.0 8f：15.0 | Decamethylcyclopentasiloxane 25 g mineral oil add to 100g |
Embodiment 9a～9i: use the part (skin) in treatment or the prevention nevus cell nevus
A) 13 years old boy has dark brown protuberance birthmark (dysplastic breast nevus cell nevus), the structure out-of-flatness, and about 1.2 centimetres of diameter is treated weekly 2～3 times with the 10% artesunate soft petroleum ointment of embodiment 2a.After 2 weeks, birthmark is filbert, has a pair of dark color, point shape position, looks like " crystallizing out " dyestuff.Described birthmark is exsiccant and squama is arranged, and looks like from " inside " beginning atrophy.
B) women, at skin surface the birthmark (trunk junctional nevus) of 3 black protuberance, diameter being arranged is 0.5 to 1.0cm, the 10% artesunate soft petroleum ointment of Application Example 2a under the condition of obturation (with the plaster form), spends the night for 3 times weekly.After one week, on each birthmark, can recognize dark position.After 3 weeks, skin forms thing together with dark crystal sample and comes off.Stay three places light color mother's mark, have the non-pigment position, this position no longer is projected on skin plane.Continuing treatment causes the mother's mark on the skin of position handled to fade gradually and becomes flakey to come off.
C) 2 early stage nevus cell nevuss of treatment also promptly are called subcutaneous extvavasated blood, and skin part protuberance diameter 0.3～0.4cm: the plaster that contains 10% artesunate ointment of three Application Example 2a spends the night, and color changes after two weeks, and light red forms thing and has dark point.The skin part that changes of protuberance can be taken off.Stay two minor cut or wounds, owing to take off in advance, wound healing.
D) women person under inspection has about a 3～4cm of nevus diameter (basal cell carcinoma), uses the 10% artesunate ointment of embodiment 1 to surpass March (periodic, evening is every 2 weeks).This nevus represents that the initial stage (similar inflammatory process) is rubescent.After 3 months, can see to draw atrophy (about color and structure) about 90%.After about 5 months, this nevus no longer as seen.
E) women person under inspection has a nevus (junctional nevus) on the arm, use the 10% artesunate ointment of embodiment 1 equally.Because this women person under inspection does not note observing, so can not the frequent degree of administration accurately be described at this; But to ointment more than lasting several weeks.Now this nevus can also see reluctantly and draw.
F) 13 years old male person under inspection, there is a congenital nevus in the district at the nasion-eye, under the condition of inaccessible (plaster), uses the 10% artesunate ointment 2 to 3 times of embodiment 1 in two months weekly.This nevus has the many dark point at initial stage.It reacts very slowly.Yet initial success presents.Its stack up shoals many, and has the zone of a plurality of colours of skin.
G) 13 years old women patient has a dermal nevus, uses the 10% artesunate ointment of embodiment 1 in 3 days.Take place to concentrate on 3 dark positions that form in the nevus immediately, and remaining range is almost colourless.
H) women person under inspection, at the abdominal part of existing a large amount of nevus cytochrome nevuss (junctional nevus), large tracts of land is used the 10% artesunate ointment twice (every 2 days 1 time) of embodiment 1.As far back as the 2nd treatment day, except the nevus that has existed, the early stage nevus of part red, described kind of initial stage, with trickle point form as seen, they are distributed on the whole surface of having handled unevenly.This early stage nevus itself is existing, but only owing to use Ointment in Treatment first as seen.They become dark to black after 2～3 days.On some part, they it seems the crystal that resembles dark color, is arranged in micropore.In 2～3 weeks, when scratching slightly thereon with fingernail when scraping, they come off in company with horny layer of epidermis or peel off.
I) a women person under inspection has handled its back of the hand with the ointment of embodiment 1, and some nevus cell nevuss that differ in size (Hepatic nevus) are arranged on the back of the hand.These existing nevuss and early stage nevus are obviously faded, and along with processing time prolongation (7 or 10 days) fades away.After stopping treatment, the nevus cell nevus color shoals.After 4 weeks, they are also shown in reluctantly to no longer as seen.
Embodiment 10: be applied topically to the fungal infection of nail treatment
Toes and big toes in the first fungal attack: the fingernail of the big toes of half is encroached on.Treat with conventional medicine such as Lamisil, effect is very little.The 10% artesunate soft petroleum ointment of embodiment 2a is used weekly 3～4 times.This ointment is mainly used under nail matrix and the fingernail.After 2 weeks, can be observed already and be clearly better.After 4 weeks, the variable color complete obiteration on the middle toes perhaps no longer deepens.Downright bad big toes first portion peels off.The treatment of all the other fingernails is easier and more effective.Active substance unhinderedly reaches the position, boundary of healthy first portion.Again Chang Chulai fingernail is normal, does not have shallow complexion changed.When fungal infection, when the nail infection fungus, can expect especially, there is no need to carry out other systemic treatment, thereby not only this expense is low, and the danger of side effects of antifungal therapy is also humble with antifungal agent.
1. formula (I) application of compound, it is used to prepare the local prescription preparation of can be local that use, the optimum nevus cell nevus of preferred therapeutic or treatment tinea pedis or tinea unguium,
In this formula (I), X is CO, CHOZ or CHNRZ, and wherein Z is selected from:
Hydrogen; Straight or branched (C 1-C 6) alkyl; Straight or branched (C 2-C 6) thiazolinyl; Straight or branched (C 2-C 6) alkynyl; (C 3-C 8) cycloalkyl; (C 6-C 24) aryl; (C 7-C 24) aralkyl; Between-CH 2(C 6H 4) COOM and right-CH 2(C 6H 4) COOM; COR 3CSR 3C (NR 6) R 3SOR 4SO 2OM; SO 2NR 7R 8SO 2O-artemisin base; SO 2NH-artemisin base; POR 4R 5And PSR 4R 5Wherein
R 3Be straight or branched (C 1-C 6) alkyl; Straight or branched (C 1-C 6) alkoxyl; Straight or branched (C 2-C 6) thiazolinyl; Straight or branched (C 2-C 6) alkynyl; (C 3-C 8) cycloalkyl; (C 6-C 24) aryl; (C 6-C 10) aryloxy group; (C 7-C 24) aralkyl;-(CH 2) n-COOM, wherein n is 1 to 6 integer; It perhaps is 10 α-dihydro artemisin base;
R 4And R 5Be selected from straight or branched (C separately separately 1-C 6) alkyl; Straight or branched (C 2-C 6) thiazolinyl; Straight or branched (C 2-C 6) alkynyl; (C 3-C 8) cycloalkyl; (C 6-C 24) aryl; (C 7-C 24) aralkyl; OM; Straight or branched (C 1-C 6) alkoxyl; (C 6-C 10) aryloxy group and NR 7R 8
R 6Be selected from straight or branched (C 1-C 6) alkyl; Straight or branched (C 2-C 6) thiazolinyl; Straight or branched (C 2-C 6) alkynyl; (C 3-C 8) cycloalkyl; (C 6-C 24) aryl and (C 7-C 24) aralkyl;
M is hydrogen or the acceptable cation of pharmacy; And R 7And R 8Be separately hydrogen or straight or branched (C separately 1-C 6) alkyl, perhaps R 7And R 8Common formation (C 4-C 6) the alkyl bridged bond;
And R is selected from hydrogen and to R 6Those groups of being lifted.
2. the described application of claim 1 is characterized in that, described optimum nevus cell nevus is selected from posteriority nevus cytochrome nevus; Congenital nevus cytochrome nevus also is a birthmark; Lentiginosis, particularly Hepatic nevus, day sunburn or senile plaque; Melanin pigmentation disorder, for example passeris montani saturati speckle; And mucosa pigmented spots.
3. the described application of claim 2 is characterized in that, described nevus cell nevus is posteriority nevus cytochrome nevus, congenital nevus cytochrome nevus (also being birthmark) or Hepatic nevus.
4. the described application of claim 3 is characterized in that described pharmaceutical formulation also is used to prevent skin carcinoma.
5. institute's definition (I) application of compound in the claim 1, it is used to prepare the part, particularly local prescription preparation of posteriority nevus cytochrome nevus prevention usefulness.
6. any one described application in each claim of prostatitis is characterized in that, formula (I) chemical compound is selected from arteannuin; Dihydroartemisinine; Carboxylic derivant, particularly artesunate shown in the formula (I); Artemether; Arteether; The propyl carbonate of dihydroartemisinine and artemisic acid.
7. the described application of claim 6 is characterized in that, formula (I) chemical compound is arteannuin, dihydroartemisinine or artesunate.
8. comprise local plaster with pharmaceutical formulation, this pharmaceutical formulation contains the active substance of formula (I):
In this formula (I), X is CHOZ or CHNRZ, and wherein Z is selected from:
Hydrogen; Straight or branched (C 1-C 6) alkyl; Straight or branched (C 2-C 6) thiazolinyl; Straight or branched (C 2-C 6) alkynyl; (C 3-C 8) cycloalkyl; (C 6-C 24) aryl; (C 7-C 24) aralkyl; Between-CH 2(C 6H 4) COOM and right-CH 2(C 6H 4) COOM; COR 3CSR 3C (NR 6) R 3SOR 4SO 2OM; SO 2NR 7R 8SO 2O-artemisin base; SO 2NH-artemisin base; POR 4R 5And PSR 4R 5Wherein
R 3Be straight or branched (C 1-C 6) alkyl; Straight or branched (C 1-C 6) alkoxyl; Straight or branched (C 2-C 6) thiazolinyl; Straight or branched (C 2-C 6) alkynyl; (C 3-C 8) cycloalkyl; (C 6-C 24) aryl; (C 6-C 10) aryloxy group; (C 7-C 24) aralkyl;-(CH 2) n-COOM, wherein n is 1 to 6 integer; It perhaps is 10 α-dihydro artemisin base;
R 4And R 5Be selected from straight or branched (C separately separately 1-C 6) alkyl; Straight or branched (C 2-C 6) thiazolinyl; Straight or branched (C 2-C 6) alkynyl; (C 3-C 8) cycloalkyl; (C 6-C 24) aryl; (C 7-C 24) aralkyl; OM; Straight or branched (C 1-C 6) alkoxyl; (C 6-C 10) aryloxy group and NR 7R 8
R 6Be selected from straight or branched (C 1-C 6) alkyl; Straight or branched (C 2-C 6) thiazolinyl; Straight or branched (C 2-C 6) alkynyl; (C 3-C 8) cycloalkyl; (C 6-C 24) aryl and (C 7-C 24) aralkyl;
M is hydrogen or the acceptable cation of pharmacy; And R 7And R 8Be separately hydrogen or straight or branched (C separately 1-C 6) alkyl, perhaps R 7And R 8(C of common formation 4-C 6) the alkylidene bridged bond; And R is selected from hydrogen and to R 6The group of being lifted;
And should not contain the infiltration enhancing substance substantially with pharmaceutical formulation in the part.
9. the described plaster of claim 8 is characterized in that, X is CHOZ, between Z is selected from-and CH 2(C 6H 4) COOM and right-CH 2(C 6H 4) COOM and COR 3, R wherein 3For-(CH 2) n-COOM.
10. the described plaster of claim 9 is characterized in that, formula (I) chemical compound is an artesunate.
11. the described plaster of claim 10 is characterized in that, this local prescription preparation is paste, ointment, paste, suspension, solution, gel, spray or ointment, particularly ointment.
12. the treatment human patients is the method for benign pigmented moles or skin fungus disease on one's body, it is characterized in that, chemical compound shown in the formula (I) is coated onto nevus cell nevus or skin fungus sick part, particularly local surfaces with treatment nevus cell nevus or the sick effectively amount of treatment skin fungus:
In this formula (I), X is CO, CHOZ or CHNRZ, and wherein Z is selected from:
Hydrogen; Straight or branched (C 1-C 6) alkyl; Straight or branched (C 2-C 6) thiazolinyl; Straight or branched (C 2-C 6) alkynyl; (C 3-C 8) cycloalkyl; (C 6-C 24) aryl; (C 7-C 24) aralkyl; Between-CH 2(C 6H 4) COOM and right-CH 2(C 6H 4) COOM; COR 3CSR 3C (NR 6) R 3SOR 4SO 2OM; SO 2NR 7R 8
SO 2O-artemisin base; SO 2NH-artemisin base; POR 4R 5And PSR 4R 5Wherein
R 3Be straight or branched (C 1-C 6) alkyl; Straight or branched (C 1-C 6) alkoxyl; Straight or branched (C 2-C 6) thiazolinyl; Straight or branched (C 2-C 6) alkynyl; (C 3-C 8) cycloalkyl; (C 6-C 24) aryl; (C 6-C 10) aryloxy group; (C 7-C 24) aralkyl;-(CH 2) n-COOM, wherein n is 1 to 6 integer; It perhaps is 10 α-dihydro artemisin base;
R 4And R 5Be selected from straight or branched (C separately separately 1-C 6) alkyl; Straight or branched (C 2-C 6) thiazolinyl; Straight or branched (C 2-C 6) alkynyl; (C 3-C 8) cycloalkyl; (C 6-C 24) aryl; (C 7-C 24) aralkyl; OM; Straight or branched (C 1-C 6) alkoxyl; (C 6-C 10) aryloxy group and NR 7R 8
R 6Be selected from straight or branched (C 1-C 6) alkyl; Straight or branched (C 2-C 6) thiazolinyl; Straight or branched (C 2-C 6) alkynyl; (C 3-C 8) cycloalkyl; (C 6-C 24) aryl and (C 7-C 24) aralkyl;
M is hydrogen or the acceptable cation of pharmacy; And R 7And R 8Be separately hydrogen or straight or branched (C separately 1-C 6) alkyl, perhaps R 7And R 8(C of common formation 4-C 6) the alkylidene bridged bond; And R is selected from hydrogen and to R 6The group of being lifted.
13. the described method of claim 12 is characterized in that, described optimum nevus cell nevus is selected from posteriority nevus cytochrome nevus; Congenital nevus cytochrome nevus also is a birthmark; Lentiginosis, particularly Hepatic nevus, day sunburn or senile plaque; Melanin pigmentation disorder, for example passeris montani saturati speckle; And mucosa pigmented spots.
14. the described method of claim 13 is characterized in that, described nevus cell nevus is posteriority nevus cytochrome nevus, congenital nevus cytochrome nevus (also being birthmark) or Hepatic nevus.
15. the method for prevention posteriority nevus cytochrome nevus is characterized in that, the defined formula of claim 1 (I) chemical compound is effectively measured in that the nevus place is arranged, preferably at topical with prevention posteriority nevus cytochrome nevus.
16. any one described method is characterized in that in the claim 12 to 15, and formula (I) chemical compound is used with ointment formulation especially with a kind of paste, ointment, suspension, solution, gel, spray or ointment.
17. the described method of claim 16 is characterized in that, the chemical compound shown in the formula (I) is made ointment, and stops moisture content to be overflowed from skin through smearing ointment.
18. any one described method is characterized in that in the claim 12 to 17, this pharmaceutical formulation and rubber plaster is applied together cover.
19. any one described method is characterized in that in the claim 12 to 18, the chemical compound shown in the formula (I) is selected from arteannuin; Dihydroartemisinine; Carboxylic derivant, particularly artesunate shown in the formula (I); Artemether; Arteether; The propyl carbonate of dihydroartemisinine and artemisic acid.
20. the described method of claim 19 is characterized in that, the chemical compound shown in the formula (I) is arteannuin, dihydroartemisinine or artesunate.
21. the described method of claim 14 is characterized in that, also is used to prevent skin carcinoma.
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