CN102177162B - Nfat信号抑制剂以及育发剂 - Google Patents
Nfat信号抑制剂以及育发剂 Download PDFInfo
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- CN102177162B CN102177162B CN200980140484.7A CN200980140484A CN102177162B CN 102177162 B CN102177162 B CN 102177162B CN 200980140484 A CN200980140484 A CN 200980140484A CN 102177162 B CN102177162 B CN 102177162B
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- acyloxy
- nfat
- agent
- radix angelicae
- angelicae sinensis
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- 239000000341 volatile oil Substances 0.000 description 1
- 235000020234 walnut Nutrition 0.000 description 1
- 229920003169 water-soluble polymer Polymers 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 230000002087 whitening effect Effects 0.000 description 1
- 239000011787 zinc oxide Substances 0.000 description 1
- 229940043810 zinc pyrithione Drugs 0.000 description 1
- PICXIOQBANWBIZ-UHFFFAOYSA-N zinc;1-oxidopyridine-2-thione Chemical compound [Zn+2].[O-]N1C=CC=CC1=S.[O-]N1C=CC=CC1=S PICXIOQBANWBIZ-UHFFFAOYSA-N 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
- A61K8/4973—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom
- A61K8/498—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom having 6-membered rings or their condensed derivatives, e.g. coumarin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/14—Drugs for dermatological disorders for baldness or alopecia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q7/00—Preparations for affecting hair growth
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/04—Ortho-condensed systems
Abstract
本发明提供一种NFAT信号抑制剂等。所述NFAT信号抑制剂将选自以下述通式(Ⅰ)表示的香豆素衍生物及其药理学上可接受的盐中的至少1种化合物作为有效成分,(在式(Ⅰ)中,R1以及R2各自相同或不同,表示氢原子或者以通式(Ⅱ)表示的基团;在式(Ⅱ)中,R3表示碳原子数为1~20的直链或支链的烷基或烯基)。
Description
技术领域
本发明涉及NFAT(活化T细胞核因子,nuclear factor of activated Tcells)信号抑制剂以及育发剂。
背景技术
据报道活化T细胞核因子(以下,简称为“NFAT”)是作为将对T细胞活化重要的白介素-2(Interleukin-2,IL-2)的转录进行活化的因子而被发现的,通过作为免疫抑制剂的环孢霉素A(cyclosporin A)(以下,简称为“CsA”)和他克莫司(tacrolimus)(以下,简称为“FK506”)的靶点的丝氨酸/苏氨酸脱磷酸化酶钙调磷酸酶(calcineurin)来进行其转录活性调节(参照图5)。即,CsA和FK506通过抑制NFAT信号来抑制T细胞活化。CsA和FK506不仅作为移植免疫抑制剂,还作为已知与免疫系统相关的关节风湿病、干癣、特异性皮炎的治疗药而被认可。将由于上述NFAT与NFAT结合序列(在图2中“NFAT位点(NFATsite)”)相结合,而使得该NFAT结合序列下游的基因转录被促进的体系称为“NFAT信号”。
另外,据报道通过抑制NFAT信号可以期待有育发(包含生发)效果(非专利文献1)。此外,还报道了抑制NFAT信号的CsA衍生物能够作为育发剂来使用(专利文献1和2)。
这里,以往作为育发剂,在男性型脱发症、圆形脱发症等脱发症的治疗中,根据经验使用血液循环促进剂、免疫抑制剂、代谢促进剂、维生素剂、抗雄性激素剂等的药剂。然而,在上述药剂中,由于症状和体质而效果不同的情况较多,从而还不能满足其效果。此外,若大量使用,则会给适用部位造成不快的刺激气味的感觉,继续使用会有发生皮肤炎的情况。男性型脱发症、圆形脱发症等的脱发症大多还未明确其发病机理的详细情况,现在还在研究适合的育发剂。
此外,NFAT在生发作用和对免疫系统的作用方面不停止,在心肌·骨骼肌的分化调节导致的肌组织形成、脑中的神经网络的形成、成骨细胞分化调节导致的骨代谢等较多的脏器中表达,作为产生重要作用的“多功能转录因子”被捕捉。
作为NFAT信号在生物体中产生的作用为如上所述,但是据报道通过抑制NFAT信号,可以期待作为免疫抑制作用(非专利文献2)、干癣治疗(非专利文献3)、特异性皮炎治疗(非专利文献4)、(心)肌肥大抑制(非专利文献5)、作为抗风湿药的可能性(非专利文献6)以及破骨细胞分化抑制作用(非专利文献7)等。
此外,如上所述由于NFAT介导产生免疫性细胞因子IL-2的路径,因而NFAT信号抑制剂对包含自身免疫性疾病的被认为是与免疫性细胞因子相关的疾病的治疗或者预防有用的。
作为涉及的疾病对象,例如可以列举出各种癌症、各种白血病、各种肝炎、各种感染、系统性红斑狼疮、炎症性肠病(溃疡性大肠炎、克隆氏病(Crohn′s disease))、多发性硬化、胰岛素依赖性糖尿病、消化性溃疡、败血症休克、结核、不孕症、动脉硬化、白塞氏综合征(Behcet′sSyndrome)、哮喘、肾炎、急性细菌性脑膜炎、急性心肌梗塞、急性胰腺炎、急性病毒性脑炎、成人呼吸窘迫综合征、细菌性肺炎、慢性胰腺炎、周围血管病、败血症、间质性肝病、局限性回肠炎、多发性硬化症等。
因此,如果确定了新型NFAT信号抑制剂,那么可以期待免疫抑制剂、干癣治疗剂、特异性皮炎治疗剂、(心)肌肥大抑制剂、抗风湿药、骨代谢疾病治疗剂以及上述列举的新型医药用途。此外,如果确定了新型NFAT信号抑制剂,那么可以期待作为育发剂、生发促进剂的医药部外品和化妆品的用途。
同时,也报道了对于属于当归属的植物,认可其提取物的育发、生发或者养发效果(专利文献3~6)。具体地,在专利文献3中公开了含有中华当归(Angelica sinensis)提取物的养发·育发剂。在专利文献4中公开了含有灰叶当归(Angelica glauca)的精油的养发剂。在专利文献5中公开了含有白芷(Angelica dahurica Benth.Et Hook.)提取物的生发·育发促进剂。在专利文献6中公开了含有滨海当归(AngelicaKeiskei Koidz)提取物的育发养发等美发剂。
此外,对于当归植物中所含有的成分可以参照非专利文献8、9,表明暗紫茎当归提取物中含有欧前胡素、花椒毒素等的线型呋喃香豆素(furanocoumarin),以及白芷素(angelicin)等的角型呋喃香豆素。此外,尽管在非专利文献10中有关于欧前胡素等的线型呋喃香豆素具有NFAT信号抑制作用的记载,但是关于本发明涉及的角型呋喃香豆素,迄今为止还未知其与NFAT信号的关联以及与育发、生发或者养发效果的关联。
另外,现今作为上述以外的具有NFAT信号抑制活性的化合物,已知有在各种食用植物中所含的芹菜素(非专利文献11)以及迷迭香酸(非专利文献12);此外,作为具有NFAT信号亢进活性的化合物,已知有大豆异黄酮(Genistein)(非专利文献13)。
现有技术文献
专利文献
专利文献1:国际公开第01/035914号小册子(日本特表2003-514000号公报)
专利文献2:国际公开第2004/041221号小册子(日本特表2006-508103号公报)
专利文献3:日本专利3527584号公报
专利文献4:日本特开2005-89392号公报
专利文献5:日本特开平1-38013号公报
专利文献6:日本特开昭63-145216号公报
非专利文献
非专利文献1:Gafter-Gvili A,Sredni B,Gal R,Gafter U,andKalechman Y,Cyclosporin A-induced hair growth in mice is associatedwith inhibition of calcineurin-dependent activation of NFAT in follicularkeratinocytes,Am J Physiol Cell Physiol,284:C1593-C603,2003
非专利文献2:Lee M and Park J,Regulation of NFAT activation:apotential therapeutic target for immunosuppression,Mol Cells,22:1-7,2006
非专利文献:3:Feldman S,Advances in psoriasis treatment,DermatolOnline J,6:4,2000
非专利文献4:Hultsch T,Immunomodulation and safety of topicalcalcineurin inhibitors for the treatment of atopic dermatitis,Dermatology,211:2,2005
非专利文献5:Molkentin JD,Lu JR,Antos CL,Markham B,Richardson J,Robbins J,Grant SR,and Olson EN,A calcineurin-dependenttranscriptional pathway for cardiac hypertrophy,Cell,93:215-228,1998
非专利文献6:Urushibara M,Takayanagi H,Koga T,Kim S,Isobe M,Morishita Y,Nakagawa T,Loeffler M,Kodama T,Kurosawa H,andTaniguchi T,Antirheumatic drug,leflunomide,inhibits osteoclastgenesis byinterfering with RANKL-stimulated induction of NFATc1,Arthritis andRheumatism,50:794-804,2004
非专利文献7:Takayanagi H,Kim S,Koga T,Nishina H,Isshiki M,Yoshida H,Saiura A,Isobe M,Yokochi T,Inoue J,Wagner EF,Mak TW,Kodama T,and Taniguchi T,Induction and activation of the transcriptionfactor NFATc1(NFAT2)integrate RANKL signaling in termialdifferentiation of osteoclasts,Developmental Cell,3:889-901,2002
非专利文献8:S.D.Sarker and L.Nahar,Natural Medicine:TheGenus Angelica,Current Medicinal Chemistry,11,1479-1500,2004
非专利文献9:Berenbaum,M.,Patterns of furanocoumarindistribution and insect herbivory in the Umbelliferaae:plant chemistry andcomunity structure,Ecology,62(5),1254-1266,1981
非专利文献10:Marquez,Nieves et al.,Imperatorin inhibits T-cellproliferation by targeting the transcription factor NFAT,Planta Medica,70(11),1016-1021,2004
非专利文献11:Jin Park et al.,Immunology Letters,103,108-114,2006
非专利文献12:Mi-Ae Kang et al.,Blood,101,3534-3542,2003
非专利文献13:Jin Park et al.,Toxicology and Applied Pharmacology,212,188-199,2006
发明内容
本发明涉及以下1)~9)。
1)一种NFAT信号抑制剂,将选自以下述通式(Ⅰ)表示的香豆素衍生物及其药理学上可接受的盐中的至少1种化合物作为有效成分,
(在上述通式(Ⅰ)中,R1以及R2可以各自相同、也可以各自不同,表示氢原子或者以通式(Ⅱ)表示的基团;
在上述通式(Ⅱ)中,R3表示碳原子数为1~20的直链或支链的烷基或烯基。)
2)如上所述的NFAT信号抑制剂,其中,在上述通式(Ⅰ)中,R1是选自当归酰基(angeloyl)、异戊酰基(isovaleryl)以及异戊烯酰基(senecioyl)中的至少1种官能团,R2是选自当归酰基、异戊酰基、2-甲基丁基以及异戊烯酰基中的至少1种官能团。
3)如上所述的NFAT信号抑制剂,其中,以上述通式(Ⅰ)表示的香豆素衍生物为选自圆白芷素(Archangelicin)、3’-当归酰氧基-4’-异戊酰氧基-2’,3’-二氢山芹醇(3’-angeloyloxy-4’isovaleryloxy-2’,3’-dihydrooroselol)、3’-当归酰氧基-4’-异戊烯酰氧基-2’,3’-二氢山芹醇(3’-angeloyloxy-4’-senecioyloxy-2’,3’-dihydrooroselol)以及3’-羟基-4’-当归酰氧基-2’,3’-二氢山芹醇中的至少1种化合物。
4)一种育发剂,将选自以上述通式(Ⅰ)表示的香豆素衍生物及其药理学上可接受的盐中的至少1种化合物作为有效成分。
5)以下述通式(Ⅲ)表示的化合物。
6)选自以上述通式(Ⅰ)表示的香豆素衍生物及其药理学上可接受的盐中的至少1种化合物在制造NFAT信号抑制剂中的用途。
7)选自以上述通式(Ⅰ)表示的香豆素衍生物及其药理学上可接受的盐中的至少1种化合物在制造育发剂中的用途,
8)一种NFAT信号抑制方法,给予选自以上述通式(Ⅰ)表示的香豆素衍生物及其药理学上可接受的盐中的至少1种化合物。
9)一种育发方法,给予选自以上述通式(Ⅰ)表示的香豆素衍生物及其药理学上可接受的盐中的至少1种化合物。
附图说明
图1是表示从暗紫茎当归中分离活性成分类时的洗脱组分的模式图。
图2是对于暗紫茎当归提取液以及馏分物中Fr.E~Fr.J,进行HPLC分析的结果。
图3是表示对于暗紫茎当归提取液以及馏分物,计算出NFAT信号抑制率的结果的特性图。
图4是表示对于实施例1中得到的成分A、成分B以及成分C,以及实施例3中制备的成分A的脱酰基体,计算出NFAT信号抑制率的结果的特性图。
图5是表示NFAT与NFAT结合部位的结合及其下游基因转录促进的NFAT信号概略构成图。
图6是表示对于实施例1中得到的成分A以及成分B,计算出毛发伸长率的结果的特性图。
具体实施方式
本发明涉及提供具有NFAT信号抑制作用或育发作用的医药品、外用剂、化妆品等。
本申请发明人对于具有NFAT信号抑制作用或育发作用的物质进行了潜心研究,其结果发现:由于以上述通式(Ⅰ)表示的化合物、特别是在暗紫茎当归中所含有的已知化合物以及上述通式(Ⅲ)的新型化合物具有优异的NFAT信号抑制作用以及育发作用,因而以上述通式(Ⅰ)表示的化合物发挥预防、改善或者治疗由于NFAT的转录促进活性的亢进所导致的疾病,或者育发·养发、促进生发等的效果,作为医药品、外用剂、化妆品等是有用的。
根据本发明的NFAT信号抑制剂以及育发剂(以下也称为“NFAT信号抑制剂等”),能够预防、改善或者治疗由NFAT的转录促进活性的亢进所导致的症状和疾病,或者育发·养发。
在本发明所涉及的NFAT信号抑制剂等中所使用的活性成分可以从暗紫茎当归植物或者该植物的提取物等中得到。这里,所谓暗紫茎当归是学名称为Angelica atropurpurea,并被分类为伞形科的植物。
这里,所谓“活性成分”是以下述通式(Ⅰ)表示的香豆素衍生物或者其药理学上可接受的盐。
如通式(Ⅰ)所示,上述活性成分是在香豆素衍生物中的角型香豆素衍生物。如后述实施例所示,在将暗紫茎当归分馏并分离活性成分的工序中,由于尽管相对于在含有欧前胡素、花椒毒素等的线型呋喃香豆素衍生物的馏分中,NFAT信号抑制活性完全无法得到确认或者基本上无法得到确认,但在含有本发明涉及的角型呋喃香豆素衍生物的馏分中、进而分离了的成分A、成分B以及成分C中,强NFAT信号抑制活性得到确认,因此发现本发明涉及的角型呋喃香豆素衍生物与已知的作为NFAT信号抑制剂的欧前胡素等的线型呋喃香豆素衍生物相比,具有优异的NFAT信号抑制活性作用。
在上述通式(Ⅰ)中,R1以及R2可以各自相同、也可以各自不同,表示氢原子或者以通式(Ⅱ)表示的基团。
在上述通式(Ⅱ)中,R3表示碳原子数为1~20的直链或支链的烷基或烯基。
即,可以作为上述活性成分使用的香豆素衍生物含有如上述规定的R1、R2以及R3范围内的各种化合物。
特别是,作为上述R1,优选为选自当归酰基、异戊酰基以及异戊烯酰基的官能团。此外,R2优选为选自当归酰基、异戊酰基、2-甲基丁基以及异戊烯酰基的官能团。
进而,通过将上述R2为当归酰基、异戊酰基、2-甲基丁基或异戊烯酰基的香豆素衍生物进行脱酰基化,可以将香豆素骨架的3’位变为羟基(相当于上述R2为氢原子的情况)。
其中,作为上述活性成分,优选R1为当归酰基、R2为当归酰基的香豆素衍生物;R1为异戊酰基、R2为当归酰基的香豆素衍生物;以及R1为异戊烯酰基、R2为当归酰基的香豆素衍生物。此外,作为上述活性成分,也优选将上述香豆素衍生物进行脱酰基化所得到的角型呋喃香豆素衍生物。
特别是,R1为当归酰基、R2为当归酰基的香豆素衍生物是作为圆白芷素而已知抗肿瘤、抗炎症作用的化合物;此外,R1为异戊酰基、R2为当归酰基的香豆素衍生物,例如3’-当归酰氧基-4’-异戊酰氧基-2’,3’-二氢山芹醇是公知化合物,但是如后述实施例所示,可以明确其在本发明中具有育发活性以及NFAT信号抑制活性。
另外,R1为异戊烯酰基、R2为当归酰基的香豆素衍生物,例如3’-当归酰氧基-4’-异戊烯酰氧基-2’,3’-二氢山芹醇如后述实施例所示,在本发明中作为具有NFAT信号抑制活性的新型化合物而被发现。
此外,作为以上述化学式(Ⅰ)表示的公知化合物,例如可以列举出阿塔曼苦素(Athamantin)、乙酰异蛇床素B(Cniforin B)、可食当归素Ⅱ(Edulisin Ⅱ)以及可食当归素Ⅴ(Edulisin Ⅴ)等。
另外,作为上述活性成分,也可以使用选自上述公知化合物以及新型化合物的1种或2种以上的物质。
这里,本发明的香豆素衍生物如上所述,也包含通过公知的化学合成法所得到的化合物、或者含有该化合物作为活性主体成分的植物提取物或者其精制物或分离物。
另外,根据需要,也可以将上述植物等提取物进行活性碳处理、液相色谱法、液液分配、凝胶过滤、精密蒸馏等的分离精制技术,从该提取物中除去惰性夹杂物,精制和分离目标化合物。
作为一个例子,关于作为活性成分的香豆素衍生物,特别是上述圆白芷素、3’-当归酰氧基-4’-异戊酰氧基-2’,3’-二氢山芹醇以及3’-当归酰氧基-4’-异戊烯酰氧基-2’,3’-二氢山芹醇,从伞形科植物(优选为暗紫茎当归植物)或其提取物中可以得到含有作为活性的主体成分的上述香豆素衍生物、特别是选自上述化合物的1种或2种以上的物质的馏分(以下,也称为“活性馏分”),或者从其中分离目标化合物。此外,也可以从植物中提取上述物质的中间体,接着通过化学合成得到目标物。
这里,将上述植物的全株、叶、茎、花、果实、种子、根茎或者根等直接破碎、粉碎、榨取使用,或者可以将经上述处理的物质干燥或者粉末化使用。作为所使用的部位,优选使用根。
所谓上述植物的提取物是指,通过将该植物在一定温度(低温、常温或者加热)下进行提取,或者使用索氏提取器等的提取器具进行提取等的提取方法所得到的各种溶剂提取液、其稀释液、其浓缩液或者其粉末。具体地,提取方法可以使用固液提取、液液提取、浸渍、煎出、浸出、回流提取、超声波提取、微波提取、搅拌等的方法。
作为为了得到上述植物提取物所使用的提取溶剂,可以使用极性溶剂或者非极性溶剂中的任意一种。作为提取溶剂,例如可以列举出水、甲醇、乙醇、丙醇、丁醇等的醇类;丙二醇、丁二醇等的多元醇类;丙酮、甲乙酮等的酮类;乙酸甲酯、乙酸乙酯等的酯类;四氢呋喃、乙醚等的链状和环状醚类;聚乙二醇等的聚醚类;角鲨烷、己烷、环己烷、石油醚等的烃类;甲苯等的芳香族烃类;二氯甲烷、氯仿、二氯乙烷等的卤化烃类;以及二氧化碳等。或者,可以将组合2种以上上述溶剂而成的混合物作为提取溶剂来使用。
优选为醇类(优选为碳原子数为1~4的醇类)、醇类·水混合液,此时,醇类的浓度优选为70~100容量%(优选为80~100容量%)。
提取溶剂的使用量相对于1质量份植物(干燥物换算),优选为1~50质量份,更优选为5~40质量份。提取温度优选为0~100℃,更优选为4~80℃,更优选为10~40℃。提取时间优选为1分钟~50天,更优选为1小时~50天,更优选为1~10天。
此外,从上述植物或者其提取物供给至液相色谱或液液分配等的分离技术,可以得到含有作为活性成分的上述圆白芷素、3’-当归酰氧基-4’-异戊酰氧基-2’,3’-二氢山芹醇以及3’-当归酰氧基-4’-异戊烯酰氧基-2’,3’-二氢山芹醇的活性馏分,也可以将其分离。
具体地,将该提取物附在十八烷基化硅胶、辛基化硅胶、三甲基甲硅烷化硅胶等的反相树脂柱层析中,用乙腈-0.05~0.2%TFA类溶剂洗脱,可以得到含有活性成分的活性馏分。
此外,通过将圆白芷素脱酰基化可以得到3’-羟基-4’-当归酰氧基-2’,3’-二氢山芹醇。
但是,在本发明中,如果是以上述化学式(Ⅰ)表示的化合物,可以将现有公知化合物作为活性成分使用。作为以上述化学式(Ⅰ)表示的化合物,例如可以列举出阿塔曼苦素(Athamantin)、乙酰异蛇床素B(Cniforin B)、可食当归素Ⅱ(Edulisin Ⅱ)以及可食当归素Ⅴ(Edulisin Ⅴ),可以作为活性成分使用。
此外,本发明的香豆素衍生物通过制成盐可以提高水溶性、增大生理学上的有效性。作为上述化合物的盐,可以是药学上可接受的盐。作为这样的盐形成用碱物质,例如可以使用氢氧化锂、氢氧化钠、氢氧化钾等的碱金属氢氧化物;氢氧化镁、氢氧化钙等的碱土类金属氢氧化物;氢氧化铵等的无机碱;精氨酸、赖氨酸、组氨酸、鸟氨酸等的碱性氨基酸;单乙醇胺、二乙醇胺、三乙醇胺等的有机碱,特别优选碱金属或碱土类金属的氢氧化物。在本发明中,可以先制备这些盐,然后添加至由其它成分组成的组合物中,也可以将绿原酸类等和盐形成成分分别添加入该组合物中,在其中形成盐。
本发明的香豆素衍生物或其盐如后述实施例所示,具有NFAT信号抑制作用以及育发作用。
这里,所谓NFAT信号抑制作用是指对NFAT直接或间接作用,从而降低由NFAT产生的转录促进活性。
此外,上述NFAT信号抑制作用(活性)可以将NFAT信号抑制率作为指标来评价。
作为测定该NFAT信号抑制作用(活性)的方法,没有特别限定,例如可以列举出使用宿主的报告基因检测法,其中,该宿主是在公知的NFAT结合序列和该NFAT结合序列的下游处导入了具有报告基因的质粒。
另外,NFAT的活性由于对钙离子的依赖,因此报告基因检测法在使钙离子流入宿主的条件下进行。作为报告基因,没有特别限定,也可以使用现有的在生化实验的领域内使用的任意的报告基因。例如,作为报告基因,可以列举出荧光素酶基因、β葡糖醛酸糖苷酶基因(GUS基因)以及绿色荧光蛋白基因(GFP基因)等。
所谓NFAT结合序列是NFAT结合的序列组成的寡核苷酸,例如可以列举出以序列号1表示的GGAGGAAAAACTGTTTCATACAGAAGGCGT(pNFAT-Luc、Stratagene)等的碱基序列。另外,在上述质粒中,可以将上述NFAT结合序列作为一组并连接多组而进行导入。通过连结多个NFAT结合序列来使用,可以更高灵敏度地测定NFAT的转录促进活性。另外,NFAT信号抑制活性可以作为从上述报告基因检测法算出的NFAT信号抑制率来评价。
此外,所谓育发作用(活性)是指作用于毛囊,通过促进毛发伸长、增大粗细、促进从毛发周期的休止期到成长期的转移、抑制从成长期到衰退期的转移等,从而使毛发的量增加。因此,育发中包含生发、养发以及预防脱发的概念。
育发作用(活性)可以将毛发伸长促进率作为指标来进行评价。这里,总之,所谓毛发伸长促进率是指相对于不使香豆素衍生物发生作用时的毛发伸长率,使香豆素衍生物发生作用时的该毛发伸长率的促进率。
作为测定该育发作用(活性)的方法,没有特别限定,例如可以列举出将分离的毛囊进行器官培养,测定培养期间中毛发伸长率的方法。
由于上述活性成分使NFAT造成的转录促进(被正控制的转录)活性降低,因此可以抑制细胞和组织中的NFAT信号。具体地,通过使本发明的香豆素衍生物或其盐与作为对象的细胞和组织接触,从而可以抑制该细胞和组织中的NFAT信号。由此,在该细胞和组织中,可以在转录水平上抑制由NFAT信号产生的各种基因表达。
此为,上述活性成分促进育发·生发,对各种脱发症有效。
因此,由于本发明的香豆素衍生物或其盐可以降低由NFAT造成的转录促进活性,并且促进育发·生发,因此可以作为NFAT信号抑制剂和育发·生发促进剂等来使用,可以在制造上述制剂中使用。
本发明涉及的NFAT信号抑制剂等可以作为对由NFAT造成的转录促进活性的亢进所导致的症状和疾病的治疗剂、改善剂或者预防剂来使用。
作为由NFAT造成的转录促进活性的亢进所导致的症状和疾病,可以列举出免疫系统疾病、干癣、特异性皮炎、包含心肌的肌肥大症、风湿、骨代谢疾病、各种癌症、各种白血病、各种肝炎、各种感染、系统性红斑狼疮、炎症性肠病(溃疡性大肠炎、克隆氏病)、多发性硬化、胰岛素依赖性糖尿病、消化性溃疡、败血症休克、结核、不孕症、动脉硬化、白塞氏综合征、哮喘、肾炎、急性细菌性脑膜炎、急性心肌梗塞、急性胰腺炎、急性病毒性脑炎、成人呼吸窘迫综合征、细菌性肺炎、慢性胰腺炎、周围血管病、败血症、间质性肝病、局限性回肠炎、多发性硬化症等。因而,本发明涉及的NFAT信号抑制剂等可以作为免疫抑制剂、干癣治疗剂、(心)肌肥大抑制剂、抗风湿药以及骨代谢疾病治疗剂等来使用。
这样,上述活性成分可以作为发挥NFAT信号抑制作用和育发作用等的医药品、外用剂、化妆品、食品、饲料等来使用。
在作为医药品使用的情况下,其剂型没有特别限定,例如可以列举出散剂、颗粒剂、胶囊剂、丸剂、片剂等的固形制剂,水剂、悬浊剂、乳剂等的液剂,软膏剂等。
在作为经口给药的医药品使用的情况下,可以将上述活性成分单独,或者另外根据经口给药剂的形态而添加通常所使用的赋形剂、崩解剂、结合剂、润滑剂、表面活性剂、醇类、水、水溶性高分子、甜味剂、矫味剂、酸味剂等,按照通常方法进行制造。作为经口给药用医药品,可以列举出免疫抑制剂、干癣治疗剂、(心)肌肥大抑制剂以及抗风湿药等。
在作为经皮给药的医药品使用的情况下,将上述活性成分单独,或者另外根据经皮给药剂的形态添加通常所使用的植物油、动物油、合成油、脂肪酸、以及天然、合成的甘油酯等的油性基剂、润滑剂、表面活性剂、醇类、增粘剂等,按照通常方法进行制造。作为经皮给药用医药品,可以列举出免疫抑制剂、干癣治疗剂、特异性皮炎治疗剂、生发促进剂等。
此外,外用剂以及育发剂是作为例如皮肤用的医药部外品而使用的物质,作为适合使用形态的剂型而被提供。作为具体的剂型,没有特别限制,例如可以列举出软膏、水剂、浸膏剂、洗剂、滋补剂、喷雾剂以及乳剂等。
在该医药部外品中,将上述活性成分单独,或者另外任意组合助剂、稳定剂、湿润剂、乳化剂、吸收促进剂以及表面活性剂等的药学上可接受的载体来进行配合。此外,在育发剂中,除了上述有效成分以外,根据需要适当配合通常所用的养发药效剂,例如毛囊赋活剂、血液循环促进剂、抗菌剂、抗炎症剂、保湿剂、抗皮脂溢剂、局部刺激剂、抗雄性激素剂、钾通道开放剂、抗氧化剂等,可以实现育发效果的提高。作为毛囊赋活剂,可以列举出黄烷酮醇(flavanonol)、N-乙酰基-L-蛋氨酸、泛酸及其衍生物、腺苷及其衍生物、天冬氨酸钾、十五烷酸甘油酯、6-苄氨基嘌呤、单硝基愈疮木酚钠等。作为血液循环促进剂,可以列举出二氧化碳、烟酸酰胺、烟酸苄酯、当药提取物、人参提取物、卡普氯铵、维生素E及其衍生物等。作为抗菌剂,可以列举出异丙基甲基苯酚、苯扎氯铵、羟甲辛吡酮(Octopirox)、吡啶硫酮锌、日扁柏素等。作为抗炎症剂,可以列举出甘草提取物、甘草酸及其衍生物、甘草次酸及其衍生物、薁、愈疮木薁、黄芩提取物、甘菊提取物、山白竹提取物、白桦提取物、锦葵提取物、桃叶提取物、欧蓍草提取物。作为保湿剂,可以列举出小连翘提取物、燕麦提取物、甘油、晚香玉多糖、冬虫夏草提取物、冬凌草提取物、大麦提取物、葡萄提取物、丙二醇、桔梗提取物、薏苡仁提取物等。作为抗皮脂溢剂,可以列举出硫磺、卵磷脂、何首乌提取物、噻克索酮等。作为局部刺激剂,可以列举出樟脑、辣椒酊等。作为抗雄性激素剂,可以列举出醋酸环丙氯地孕酮(cyproterone acetate)、11α-羟孕酮、氟他胺(flutamide)、3-脱氧腺苷(deoxyadenosine)、醋酸氯地孕酮、炔雌醇、螺内酯、炔孕酮(ethisterone)、非那雄胺(finasteride)、芦荟、花椒、丁香提取物、收敛性胡桃提取物(cuachalalate extract)、高丽参等。作为钾通道开放剂,可以列举出米诺地尔、色满卡林(cromakalim)、二氮嗪及其衍生物、吡那地尔等。作为抗氧化剂,可以列举出红茶提取物、茶提取物、蔷薇果提取物、黄杞提取物、维生素C及其衍生物、异抗坏血酸、没食子酸丙酯、二丁基羟基甲苯等。
在作为化妆品使用的情况下,作为剂型没有特别限定,例如可以列举出油包水型或水包油型乳化化妆品、霜、化妆水、凝胶、泡沫、精华、粉底、面膜、口红以及香粉等。
在该化妆品中可以单独配合上述活性成分,或者另外任意组合通常作为化妆品成分使用的油分、表面活性剂、紫外线吸收剂、醇类、螯合剂、pH调节剂、防腐剂、增粘剂、色素类、香料以及各种皮肤营养剂等来进行配合。
具体地,可以在皮肤化妆品中配合的药效成分,可以添加例如氧化锌微粒、氧化钛、PARSOL MCX、PARSOL 1789等的紫外线吸收剂;抗坏血酸等的维生素类;透明质酸钠、凡士林、甘油、尿素等的保湿剂;激素剂;以及曲酸、熊果苷、胎盘提取物、雷琐辛(resorcinol)等其它美白成分;类固醇剂、以花生四烯酸代谢物和组胺等为代表的化学传递物质产生·释放抑制剂(吲哚美辛、布洛芬)、受体拮抗剂等的抗炎症剂;抗雄性激素剂、维生素A酸、蜂王浆提取物、峰王浆酸等的皮脂分泌抑制剂;生育酚烟酸酯、前列地尔、盐酸苯氧丙酚胺、盐酸妥拉唑啉等的周围血管扩张剂以及具有周围血管扩张作用的二氧化碳等;米诺地尔、卡普氯铵、辣椒酊、维生素E衍生物、银杏提取物、当药提取物等的血液循环促进剂;十五烷酸甘油酯、烟酸酰胺等的细胞赋活化剂;日扁柏素、L-薄荷脑、异丙基甲基苯酚等的杀菌剂;甘草酸及其衍生物或其盐等的药剂;神经酰胺及神经酰胺类似化合物等来进行配合。
此外,在上述医药品、医药部外品、化妆品中,可以根据需要适当组合使用例如白垩、滑石、漂白土、高岭土、淀粉、树胶、胶体硅聚丙烯酸钠等的粉体;例如矿物油、植物油、硅油等的油或油状物质;例如失水山梨醇三油酸酯、失水山梨醇三硬脂酸酯、单油酸甘油酯、高分子硅酮表面活性剂等的乳化剂;对羟基苯甲酸酯等的防腐剂;丁基羟基甲苯等的防氧化剂;甘油、山梨醇、2-吡咯烷酮-5-羧酸酯、邻苯甲酸二丁酯、明胶、聚乙二醇等的湿润剂;伴随像三乙醇胺或氢氧化钠那样的碱的乳酸等缓冲剂;甘油脂肪酸酯、失水山梨醇脂肪酸酯、蔗糖脂肪酸酯、烷基糖苷等的表面活性剂;蜂蜡、地蜡、石蜡等的蜡类;增粘剂;活性增强剂;着色剂;香料等。
在将上述活性成分用作医药、医药部外品或者化妆品等的情况下,上述活性成分的配合量以香豆素衍生物换算,通常优选为医药、医药部外品或化妆品等全部组成的0.00001~5质量%,特别优选为0.0001~0.1质量%。此外,在将本发明所涉及的NFAT信号抑制剂作为医药使用的情况下,上述活性成分的给药量按通常成人(60kg)优选为0.01mg~1g/1天。
实施例
以下,通过实施例进一步具体地说明本发明。但是,本发明并没有被下述实施例限定其技术范围。
[实施例1]从暗紫茎当归中分离活性成分类
(1)按照如图1所示工序,从暗紫茎当归(Angelica atropurpurea(伞形科))的根茎中分离本发明的化合物“成分A”、“成分B”以及“成分C”。
(2)将暗紫茎当归(Angelica atropurpurea)的根茎(160g)在95w/v%乙醇-水(1.6L)中常温下(10~40℃)浸渍5天进行提取,得到95w/v%乙醇-水提取液。过滤该提取液后,用旋转蒸发器浓缩,得到14.3g固形组分。将1g该浓缩干固物附在中压ODS柱层析(十八烷基硅烷化硅胶:内径2.6×30cm)中,用乙腈-0.1%TFA体系洗脱得到以下馏分(fr.A~K)。
HPLC分析
色谱柱:Inertsil ODS-3(3μm,2.1×150mm)
洗脱溶剂A:0.1%TFA,B:MeCN
0%B→100%B(30min)→100%B(40min)→0%B(40.1min)→0%B(60min)
柱温37℃,测定波长UV254nm,流速0.25mL/min,5μL inj.
另外,将各馏分固形组分溶解于50mL95w/v%乙醇中,分别用ODS-HPLC(内径2.1×150mm,乙腈-0.1%TFA体系洗脱液)进行分析,确认线型呋喃香豆素的花椒毒素在fr.F以及fr.G中存在,欧前胡素在fr.H中存在(图2)。对于各馏分固形组分的50mL95w/v%乙醇溶液,按后述方法研究NFAT信号抑制活性,确认在fr.I中有最强活性,另一方面,由于在含有欧前胡素和花椒毒素的fr.F、fr.G、fr.H中确认完全没有活性或大部分没有活性(图3),从而可知暗紫茎当归的主要的NFAT信号抑制活性成分是欧前胡素和花椒毒素以外的成分,该结果从所述非专利文献10的记载来看是完全出乎意料的。
fr.A:0.23g
fr.B:0.01g
fr.C:0.03g
fr.D:0.07g
fr.E:0.05g
fr.F:0.02g
fr.G:0.02g
fr.H:0.15g
fr.I:0.24g
fr.J:0.10g
fr.K:0.03g
(3)将上述(2)中得到的作为NFAT信号抑制馏分的fr.I(0.24g)附在制备高效液相色谱(十八烷基硅烷化硅胶:内径10×250mm)中,用乙腈-0.1%TFA体系(58%)洗脱,得到以下的馏分(fr.I-1~I-8)。
fr.I-1:46.5mg
fr.I-2:27.6mg
fr.I-3:3.4mg
fr.I-4:6.3mg
fr.I-5:18.8mg
fr.I-6:84.6mg
fr.I-7:5.4mg
fr.I-8:46.9mg
从分析结果可知,本发明的化合物是在fr.I-6(成分A)、fr.I-8(成分B)、fr.I-5(成分C)中作为基本单一化合物而得到的。
[实施例2]成分A、成分B以及成分C的鉴别
(1)对于实施例1中得到的化合物,进行1H NMR解析以及13CNMR解析。
在表1中表示作为1H NMR(500MHz,CDCl3)以及13C NMR(125MHz,CDCl3)解析结果所得到的数据。
表1:
(2)根据表1所示解析结果表明,成分A、成分B以及成分C的化合物是具有下述结构的角型呋喃香豆素衍生物。
即,可以判断成分A、成分B以及成分C分别是圆白芷素、3’-当归酰氧基-4’-异戊酰氧基-2’,3’-二氢山芹醇以及3’-当归酰氧基-4’-异戊烯酰氧基-2’,3’-二氢山芹醇。这里,成分C的3’-当归酰氧基-4’-异戊烯酰氧基-2’,3’-二氢山芹醇在过去没有报告例,是新型化合物。
[实施例3]成分A(圆白芷素)的脱酰基体的制备
在本实施例中,对在实施例1以及2中作为成分A而分离的圆白芷素进行脱酰基化。首先,将成分A(70mg)溶解于7mL丙酮中,添加7mL浓氨水,室温下搅拌一昼夜。将反应液浓缩后(75mg),附在制备高效液相色谱(内径10×250mm)中,用0.1%蚁酸-乙腈体系洗脱,分取主生成物(17mg)。
[实施例4]成分A(圆白芷素)脱酰基体的鉴别
(1)对于实施例3中得到的化合物,进行1H NMR解析以及13CNMR解析。在表2中表示作为1H NMR(500MHz,CDCl3)以及13C NMR(125MHz,CDCl3)解析结果所得到的数据。
表2:
(2)根据表2所示解析分析表明,实施例3中的生成物是圆白芷素的3’位的当归酰基脱离而成的具有下述结构的角型呋喃香豆素衍生物。
[实施例5]NFAT信号抑制效果
在本实施例中,对实施例1中得到的成分A、成分B和成分C,以及实施例3中制备的成分A的脱酰基体,研究其NFAT信号抑制效果。
(1)用于评价体系的材料和方法
细胞培养
在上述评价体系中,从ATCC(American Type Culture Collection)购入人体肾(HEK293)细胞来使用。HEK293细胞在DMEM(高葡萄糖、10%热灭活FBS)中37℃、5%CO2条件下培养。
质粒、转染
将在NFAT结合序列的下游处导入萤火虫荧光素酶而成的质粒pNFAT-Luc(Stratagene Co.生产)转染入HEK293细胞,在上述评价体系中,使用由此形成的物质。具体而言,将在NFAT转录活性评价用的4连的NFAT结合序列的下游处导入萤火虫荧光素酶基因而成的pNFAT-luc(Stratagene Co.生产)转染入HEK293细胞。此外,以避免由转染效率造成的偏差作为目的,为了补正来源于萤火虫荧光素酶的信号,从而同时转染在CMV启动子的下游处导入了海肾荧光素酶(renilla luciferase)而成的pRL-CMV(Promega Co.生产)。
使用LipofectAMINE 2000试剂(Invitrogen Co.制造),按照使用说明书进行转染。转染8小时后,交换培养基,培养一晚。随后,添加实施例1中得到的成分A、成分B和成分C以及实施例3中制备的成分A的脱酰基体,1小时后添加1μM离子霉素(Ionomycin)。8小时后,进行荧光素酶报告基因检测。
荧光酶素报告基因检测
使用Dual-Glo荧光素酶检测系统(Promega Co.制造),按照使用说明书进行荧光素酶报告基因检测。即,除去培养基后,加入用PBS稀释了2倍的Dual-Glo荧光素酶试剂,搅拌后,20分钟后测定萤火虫荧光素酶活性。随后,加入等量的Dual-Glo Stop&Glo试剂,搅拌后测定海肾荧光素酶活性。使用MiniLumat LB 9506(EG&G BERTHOLD Co.制造)来进行荧光素酶活性的测定,定量检测出由荧光素酶造成的发光量。双方共同的荧光素酶活性的测定时间为2秒。
NFAT信号抑制率的计算
全部NFAT转录活性(萤火虫荧光素酶活性)是通过用为了补正转染效率而被导入的海肾荧光素酶活性来除进行补正。随后,用以下式子计算出NFAT信号抑制率。
通过下述计算,可以计算出试验样品如何%抑制由离子霉素刺激造成的NFAT信号的活化。
NFAT信号抑制率(%)=100-(试验样品以及离子霉素添加群-无刺激群)/(只有离子霉素添加群-无刺激群)×100
结果
在图4中表示计算出NFAT信号抑制率的结果。从图4可以判断,实施例1中得到的成分A、成分B和成分C以及实施例3中制备的成分A的脱酰基体都可以抑制NFAT信号。即,成分A、成分B以及成分A的脱酰基体可以抑制由NFAT正控制的转录。因此,成分A、成分B以及成分A的脱酰基体是优异的NFAT抑制剂,并且被鉴定为例如作为免疫抑制剂、干癣治疗剂、特应性皮炎治疗剂、(心)肌肥大抑制剂以及抗风湿药等的候补物质。
[实施例6]育发效果
在本实施例中,使用可以验证对象物质的育发效果的体外实验体系来检验实施例1中得到的成分A以及成分B的育发效果。
通过猪毛囊器官培养的毛发伸长评价
将食肉用猪种的臀部皮肤切成适当大小,除去多余的脂肪组织。通过将猪皮在无菌条件下在洗必泰液(将5%洗必泰液(住友制药)用水稀释5~20倍)中浸泡5分钟~10分钟来进行消毒后,用D-PBS洗净数次。随后,用体视显微镜从洗净的猪皮中分离毛囊,在William′sMedium E培养基(Invitrogen Co.生产)中集中。
将经分离的毛囊放入1个24孔培养板中,该24孔培养板中每1孔中加入了400μl的William′s Medium E培养基(添加1%青霉素-链霉素溶液(Invitrogen Co.生产))。将毛囊在37℃、5%CO2条件下培养8天,其间,每隔1天或2天进行培养基的交换。
在上述培养基中添加实施例1中得到的成分A、成分B,与作为溶剂对照的乙醇添加群一起培养8天。用CCD照相机(pixeramodel.No.PVC 100C)拍摄培养开始日(第0天)以及第8天的体视显微镜图像,从其图像中测定从毛球部基底部到毛干顶端的长度。随后,将溶剂对照群的培养前后的长发伸长量作为100%,计算出实施例1中得到的成分A以及成分B的毛发伸长率。
结果
在图6中表示计算出毛发伸长率的结果。从图6中可以判断,实施例1中得到的成分A以及成分B的添加群与溶剂对照群相比较,确认有明显的毛发伸长。从该结果可知,实施例1中得到的成分A以及成分B具有育发效果。即,实施例1中所得到的成分A以及成分B是表现出育发效果的活性成分,可以作为育发剂或外用剂使用。
Claims (5)
1.选自香豆素衍生物及其药理学上可接受的盐中的至少1种化合物在制造NFAT信号抑制剂中的用途,
其中,所述香豆素衍生物为选自圆白芷素、3’-当归酰氧基-4’-异戊酰氧基-2’,3’-二氢山芹醇、3’-当归酰氧基-4’-异戊烯酰氧基-2’,3’-二氢山芹醇以及3’-羟基-4’-当归酰氧基-2’,3’-二氢山芹醇中的至少1种化合物。
2.选自香豆素衍生物及其药理学上可接受的盐中的至少1种化合物在制造育发剂中的用途,
其中,所述香豆素衍生物为选自圆白芷素、3’-当归酰氧基-4’-异戊酰氧基-2’,3’-二氢山芹醇以及3’-羟基-4’当归酰氧基-2’,3’-二氢山芹醇中的至少1种化合物。
3.一种非治疗目的的NFAT信号抑制方法,给予选自香豆素衍生物及其药理学上可接受的盐中的至少1种化合物,
其中,所述香豆素衍生物为选自圆白芷素、3’-当归酰氧基-4’-异戊酰氧基-2’,3’-二氢山芹醇、3’-当归酰氧基-4’-异戊烯酰氧基-2’,3’-二氢山芹醇以及3’-羟基-4’-当归酰氧基-2’,3’-二氢山芹醇中的至少1种化合物。
4.一种非治疗目的的育发方法,给予选自香豆素衍生物及其药理学上可接受的盐中的至少1种化合物,
其中,所述香豆素衍生物为选自圆白芷素、3’-当归酰氧基-4’-异戊酰氧基-2’,3’-二氢山芹醇以及3’-羟基-4’-当归酰氧基-2’,3’-二氢山芹醇中的至少1种化合物。
5.一种以下述通式(III)表示的化合物,
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