CN101610751A - 脱发症的预防或治疗剂 - Google Patents
脱发症的预防或治疗剂 Download PDFInfo
- Publication number
- CN101610751A CN101610751A CNA2007800465806A CN200780046580A CN101610751A CN 101610751 A CN101610751 A CN 101610751A CN A2007800465806 A CNA2007800465806 A CN A2007800465806A CN 200780046580 A CN200780046580 A CN 200780046580A CN 101610751 A CN101610751 A CN 101610751A
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- China
- Prior art keywords
- baldness
- prevention
- hair
- therapeutic agent
- methyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Abstract
本发明的目的是提供脱发症的预防或治疗中有用的新型的治疗剂。该治疗剂是脱发症的预防或治疗剂,其特征在于,含有1-[2-((2S)-2-{5-[(3,4-二甲氧基苯氧基)甲基]-1,2,4-噁二唑-3-基}吡咯烷-1-基)-1,1-二氟-2-氧代乙基]-3,3,5,5-四甲基环己醇作为有效成分。
Description
技术领域
本发明涉及脱发症(alopecia)的预防或治疗剂,更详细地涉及以特定的芳氧基甲基噁二唑衍生物作为有效成分的脱发症的预防或治疗剂。
背景技术
对于脱发症,包括雄激素性脱发症、老年性脱发症、局限性脱发症、绝经后妇女的脱发症等各种类型。其大多并不危及生命,但由于其外观上的问题因而大多伴随着精神上的痛苦,脱发症的优异的预防或治疗剂受到人们的期待。
毛发经过生长期(anagen)、过渡期(catagen)和终期(telogen)的各阶段来进行更新(毛发周期)。该毛发周期通常1个循环需要2~7年的时间,但如果产生任何异常而使该期间缩短,则毛发没有充分生长就停止生长。其结果为,随着脱发数增加而导致毛发的密度降低、且每根毛发变细。作为破坏该毛发周期的节律的因素,可列举:睾酮和二氢睾酮等雄性激素、放射线、抗癌剂等药物、衰老以及压力等。
以开发出脱发症的治疗药为目的,使用各种化合物进行了研究,例如,报道了在多个动物模型中发现免疫抑制剂FK506(他克罗姆,tacrolimus)具有毛发生长促进效果(参照专利文献1和非专利文献1)。不仅在认为是自身免疫性疾病的局限性脱发症的模型中(参照非专利文献2和3)确认其作用,而且在使用正常小鼠和药物性脱发症模型的毛发生长试验中也确认其作用(参照非专利文献4和5)。但是,FK506由于具有免疫抑制作用因而副作用的危险较高,故作为脱发症的治疗剂,需要不具有免疫抑制作用,更加安全的化合物。
近年来发现,不具有免疫抑制作用的、与抑免蛋白(immunophilin)FKBP12(与FK506结合的分子量为12kDa的蛋白质)结合的化合物,具有与FK506同样的细胞保护作用,并且发现了多种衍生物(参照专利文献2~9)。公开了其中一部分衍生物显示出发毛生长促进作用(参照专利文献10)。但是,没有关于其它衍生物的发毛生长促进作用的报道,对于与抑免蛋白FKBP12的结合活性以及毛发生长促进活性之间的关系,存在较多不明确之处。
作为与FKBP12结合的化合物,公开了芳氧基甲基噁二唑衍生物(参照专利文献11),但并没有关于这些衍生物的发毛生长促进作用的报道。
[专利文献1]日本专利2925285号公报
[专利文献2]WO96/40633国际公开公报
[专利文献3]WO92/19593国际公开公报
[专利文献4]WO00/27811国际公开公报
[专利文献5]WO99/62511国际公开公报
[专利文献6]WO99/45006国际公开公报
[专利文献7]WO00/05231国际公开公报
[专利文献8]WO01/42245国际公开公报
[专利文献9]日本特开2004-123556号公报
[专利文献10]WO98/55090国际公开公报
[专利文献11]日本特开2004-123557号公报
[非专利文献1]Yamamoto等,“J.Invest.Dermatol.”,102,160-164,1994
[非专利文献2]Freyschmidt-Paul等,“Eur.J.Dermatol.”,11,405-409,2001
[非专利文献3]McElwee等,“Br.J.Dermatol.”,137,491-497,1997
[非专利文献4]Jiang等,“J.Invest.Dermatol.”,104,523-525,1995
[非专利文献5]Maurer等,“Am.J.Pathol.”,150,1433-1441,1997
发明内容
本发明的目的是提供对脱发症的预防或治疗有用的新型治疗药。
本发明人等着眼于芳氧基甲基噁二唑衍生物,对于这些化合物研究其药理作用,结果发现其中的特定化合物具有优异的发毛生长促进作用,而且不存在有问题的副作用,从而完成本发明。
即,本发明为以下的内容:
(1)脱发症的预防或治疗剂,其特征在于,含有1-[2-((2S)-2-{5-[(3,4-二甲氧基苯氧基)甲基]-1,2,4-噁二唑-3-基}吡咯烷-1-基)-1,1-二氟-2-氧代乙基]-3,3,5,5-四甲基环己醇作为有效成分;
(2)脱发症的预防或治疗方法,其特征在于,对哺乳动物给予有效量的1-[2-((2S)-2-{5-[(3,4-二甲氧基苯氧基)甲基]-1,2,4-噁二唑-3-基}吡咯烷-1-基)-1,1-二氟-2-氧代乙基]-3,3,5,5-四甲基环己醇;
(3)1-[2-((2S)-2-{5-[(3,4-二甲氧基苯氧基)甲基]-1,2,4-噁二唑-3-基}吡咯烷-1-基)-1,1-二氟-2-氧代乙基]-3,3,5,5-四甲基环己醇在制备脱发症的预防或治疗剂中的应用。
在本发明中发现,在与抑免蛋白FKBP12结合、抑制其旋转异构酶活性的属于芳氧基甲基噁二唑衍生物的化合物中,1-[2-((2S)-2-{5-[(3,4-二甲氧基苯氧基)甲基]-1,2,4-噁二唑-3-基}吡咯烷-1-基)-1,1-二氟-2-氧代乙基]-3,3,5,5-四甲基环己醇显示出优异的发毛生长促进作用。
由于该化合物几乎没有免疫抑制作用等作用,因此含有该化合物的制剂可以有效用作脱发症的预防或治疗剂。
附图说明
图1表示小鼠剃毛模型中本发明化合物和GPI-1511的毛发生长促进效果。
具体实施方式
本说明书中,“脱发症”是指,毛发的一部分或全部脱落、消失的状态,或者变细和变短的状态。对于脱发症,包括但不限于:雄激素性脱发症、脂溢性脱发症、老年性脱发症、局限性脱发症、给予抗癌剂等而导致的药物性脱发症、瘢痕性脱发症、生产后引起的产后脱发症。脱发症大多是由于毛发周期的破坏而引起的,细胞增殖的停止等引起的生长期的期间缩短是其诱因。
而且,“毛发周期”是指毛发的生长循环,其包括三个阶段:(1)生长期(这是毛囊细胞反复分裂,毛发积极生长的期间,对于短发其持续2~6年)、(2)过渡期(这是毛发的生长变弱,毛囊萎缩的期间,对于短发其持续1~2周)、以及(3)终期(这是毛囊完全退缩,休止的期间,对于短发其持续3~4个月)。通常,80%至90%的毛发处于生长期,不足1%的毛发处于过渡期,剩余的处于终期。脱发症中,毛发周期产生异常,特别是雄激素性脱发症中,生长期的期间缩短,在毛发生长成粗硬毛发之前进入过渡期/终期,因而导致终期毛发比例的增加以及使毛发从硬毛发变成细软毛发。
另外,本发明的“脱发症的预防或治疗剂”是指具有以下任一种作用的药物:(1)从终期诱导至生长期(诱导毛发生长)、(2)促进毛发生长、(3)延长生长期、(4)抑制、迟延或减少脱发,期待具有上述中的多种作用的药物。
本发明的脱发症的预防或治疗剂的有效成分,即1-[2-((2S)-2-{5-[(3,4-二甲氧基苯氧基)甲基]-1,2,4-噁二唑-3-基}吡咯烷-1-基)-1,1-二氟-2-氧代乙基]-3,3,5,5-四甲基环己醇(以下称为“本发明化合物”)为下式表示的化合物。
[化1]
该化合物与日本特开2004-123557公报的实施例1中公开的化合物相同,可以通过该公报中记载的方法或者后述实施例中记载的方法制得。另外,该公报中还记载了本发明化合物具有抑制FKBP12的旋转异构酶活性的活性。
本发明化合物还能以各种溶剂合物的形式存在。另外,从适于药物的方面考虑,还优选作为水合物。
本发明中的脱发症的预防或治疗剂可以采用口服给药、非口服给药或者局部给药的任一种给药方式。从能直接向患部给药、易于给药、降低发生全身副作用的可能性等方面考虑,优选的剂型可列举外用剂(external preparation)。另外,由于本发明化合物产生全身副作用的可能性低,故还可用作口服制剂。
本发明的脱发症的预防或治疗剂可以通过适当使用上述的本发明化合物和公知的载体、稀释剂等而制剂形成合适的药物组合形态。具体而言,对于口服制剂,可作为片剂、粉末、散剂、颗粒剂、以及液体制剂、胶囊剂、干糖浆剂(dry syrup)、凝胶剂等使用;对于外用剂,可作为液体制剂、洗剂、软膏、外敷剂(pack)以及霜剂等使用。
本发明的脱发症的预防或治疗剂作为口服制剂的形态时,在不损害发明效果的质量和数量的范围内,根据需要可以混合其它公知的添加剂,例如:维生素、氨基酸、草药、天然物、赋形剂、pH调节剂、清凉剂、悬浮剂、增稠剂、溶解助剂、崩解剂、粘合剂、润滑剂、抗氧化剂、涂布剂、着色剂、矫味剂、表面活性剂、增塑剂、香料等。
另一方面,本发明的脱发症的预防或治疗剂用作外用剂时,在不损害发明效果的质量和数量的范围内,根据需要可以混合其它公知的添加剂,例如:1,3-丁二醇、乙醇、甲醇和纯净水等溶剂;对羟基苯甲酸脂等防腐剂;扁柏酚等杀菌剂;白凡士林、角鲨烷和石蜡等油成分;异辛酸鲸蜡酯、癸酸鲸蜡酯和单油酸甘油酯等酯;有机硅树脂和硅油等有机硅衍生物;聚氧乙烯固化蓖麻籽油等表面活性剂;羧基乙烯基聚合物、聚乙烯醇等凝胶化剂;pH调节剂;抗氧化剂;着色剂等。
如上述那样制得的本发明的脱发症的预防或治疗剂的给药量,可根据患者的体重、年龄、性别等而适当增减。具体而言,作为外用剂使用时,使用以0.0001%~20%的浓度含有本发明化合物的外用剂,可以一天给予1次~数次。这时,对毛发的使用量为0.00001至4mg/cm2左右,优选为0.01至1mg/cm2左右。
另外,作为口服制剂使用时,成人每天给予本发明化合物1~100mg/kg,可以一天给予1次~数次。
进一步,本发明化合物还可以并用其它的脱发症预防剂或治疗剂的有效成分。作为可并用的药物,可列举米诺地尔、非那雄胺,但不限于这些。另外,还可并用其它的毛发促长剂/生发剂、血管扩张剂、抗雄激素剂、环孢霉素衍生物、抗菌剂、抗炎症剂、甲状腺激素衍生物、前列腺素激动剂或拮抗剂、视黄醛衍生物、三萜烯等药物。
[实施例]
以下采用合成例、制剂例、试验例等更详细地说明本发明,但本发明并不受这些例子的任何限定。
合成例
本发明化合物可以根据日本特开2004-123557中公开的制造方法进行制造,通过下述记载的制造方法也可以得到本发明的化合物。
1-[2-((2S)-2-{5-[(3,4-二甲氧基苯氧基)甲基]-1,2,4-噁二唑-3-基}吡咯 烷-1-基)-1,1-二氟-2-氧代乙基]-3,3,5,5-四甲基环己醇的合成:
(1)(2S)-2-[(Z)-氨基(肟基)甲基]吡咯烷-1-羧酸叔丁基酯
向(2S)-2-氰基吡咯烷-1-羧酸叔丁基酯(150g、0.76mol)的水和甲醇(各700ml)的混合溶液中加入盐酸羟胺(106g、1.53mol)和碳酸钠(162g、1.53mol),在100℃下加热搅拌5小时。反应后减压馏去甲醇,加入水(1500ml),滤取析出物,干燥后得到无色结晶(88.4g)。向滤液中加入氯仿,用饱和盐水洗涤。用硫酸镁干燥后,减压下馏去溶剂,得到无色结晶(77.4g)。合计得到166g。
1H-NMR(200MHz,氯仿-D);
δppm 1.46(s,9H),1.75-2.43(m,4H),3.24-3.56(m,2H),4.12-4.72(m,2H),5.30(m,1H)
(2)(3,4-二甲氧基苯氧基)乙酸
向3,4-二甲氧基苯酚(300g、1.95mol)的丙酮(3000mL)溶液中加入碳酸钾(405g、2.93mol)、溴乙酸乙酯(391g、2.34mol),在60℃下搅拌4小时。然后加入溴乙酸乙酯(33.1g、0.198mol),在65℃下搅拌1.5小时。进一步加入溴乙酸乙酯(33.1g、0.198mol),在65℃下搅拌2.5小时。加入溴乙酸乙酯(33.1g、0.198mol),在65℃下搅拌2小时。
将反应液恢复至室温,过滤除去碳酸钾,减压馏去溶剂和过量的溴乙酸乙酯,得到茶色油状物(485g)。向所得的(3,4-二甲氧基苯氧基)乙酸乙酯粗品的乙醇(1100ml)溶液中加入氢氧化钠(195g)的水(550ml)溶液,室温下搅拌1小时。加入浓盐酸(440ml)后,馏去溶剂
滤取析出物,用水洗涤得到淡茶色固体(335g)。向滤液中加入氯仿,用饱和盐水洗涤。用硫酸镁干燥后,减压下馏去溶剂。从乙酸乙酯-己烷中重结晶,得到淡茶色粉末(33.1g)。合计得到368g。
1H-NMR(200MHz,氯仿-D);
δppm 3.84(s,3H),3.86(s,3H),4.64(s,2H),6.37(dd,J=8.57,2.86Hz,1H),6.61(d,J=2.64Hz,1H),6.77(d,J=8.79Hz,1H),10.45(br.s,1H)
(3)(2S)-2-{5-[(3,4-二甲氧基苯氧基)甲基]-1,2,4-噁二唑-3-基}吡咯 烷-1-羧酸叔丁基酯
用1小时向(2S)-2-[(Z)-氨基(肟基)甲基]吡咯烷-1-羧酸叔丁基酯(319g、1.39mol)、(3,4-二甲氧基苯氧基)乙酸(369g、1.74mol)、1-羟基苯并三唑一水合物(245g、1.81mol)以及1-乙基-3-(3-二甲基氨基丙基)碳二亚胺盐酸盐(347g、1.81mol)的氯仿溶液(2000ml)中加入三乙胺(422g、4.17mol),室温下搅拌19小时。馏去溶剂后,加入乙酸乙酯,依次用水、饱和碳酸氢钠水溶液、饱和盐水洗涤。用硫酸镁干燥后,减压下馏去溶剂,得到茶色油状的粗产物(389g)。
将上述粗产物(389g)在二甲苯(1000ml)中加热回流6小时。馏去溶剂后,加入乙酸乙酯,依次用1mol/L盐酸、饱和碳酸氢钠水溶液、饱和盐水洗涤。用硫酸镁干燥后,减压下馏去溶剂,得到茶色油状物(257g)。
1H-NMR(200MHz,氯仿-D);
δppm 1.04-2.43(m,13H),3.34-3.71(m,2H),3.83(s,3H),3.86(s,3H),4.93-5.14(m,1H),5.21(s,2H),6.46(dd,J=8.79,2.64Hz,1H),6.64(d,J=2.64Hz,1H),6.77(d,J=8.79Hz,1H)
(4)5-[(3,4-二甲氧基苯氧基)甲基]-3-[(2S)-吡咯烷-2-基]-1,2,4-噁二 唑
向(2S)-2-{5-[(3,4-二甲氧基苯氧基)甲基]-1,2,4-噁二唑-3-基}吡咯烷-1-羧酸叔丁基酯(311g、0.77mol)的乙酸乙酯(750ml)溶液中加入4mol/L-盐酸/乙酸乙酯(750ml),室温下搅拌4天。加入水,用乙酸乙酯洗涤后,使用20%NaOH水溶液进行中和。加入乙酸乙酯,用水洗涤。用硫酸镁干燥后,减压下馏去溶剂,得到茶色油状物(186g)。
1H-NMR(200MHz,氯仿-D);
δppm 1.79-2.31(m,4H),2.98-3.22(m,2H),3.84(s,3H),3.86(s,3H),4.39-4.46(m,1H),5.22(s,2H),6.47(dd,J=2.64,8.79Hz 1H),6.64(d,J=2.64Hz,1H),6.77(d,J=8.79Hz,1H)
(5)二氟(1-羟基-3,3,5,5-四甲基环己基)乙酸
在氮气流下,向锌粉末(59.5g、0.91mol)的四氢呋喃(500ml)溶液中,加入1,2-二溴乙烷和三甲基氯硅烷(各3ml),使其活性化。然后滴加3,3,5,5-四甲基环己酮(108g、0.70mol)和溴二氟乙酸乙酯(157g、0.77mol)的四氢呋喃(200ml)混合液,加热回流3.5小时。反应后,加入饱和氯化铵水溶液,然后过滤除去未反应的锌粉末。加入乙酸乙烯,用水和饱和盐水洗涤。用硫酸镁干燥后,减压下馏去溶剂,得到二氟(1-羟基-3,3,5,5-四甲基环己基)乙酸乙酯(201g),其为黄色油状物。
向此处得到的化合物(201g)的乙醇(800ml)溶液中加入氢氧化钠(42.0g、1.05mol)的水(300ml)溶液,室温下搅拌3.5小时。馏去溶剂后,加入6mol/L盐酸,进一步加入乙酸乙酯,用饱和盐水洗涤。用硫酸镁干燥后,减压下馏去溶剂,得到无色固体(169g)。
1H-NMR(200MHz,氯仿-D);
δppm 0.97(s,6H),1.10-1.71(m,6H),1.23(s,6H),5.55(br.s,1H)
(6)1-[2-((2S)-2-{5-[(3,4-二甲氧基苯氧基)甲基]-1,2,4-噁二唑-3-基}吡咯烷-1-基)-1,1-二氟-2-氧代乙基]-3,3,5,5-四甲基环己醇
向5-[(3,4-二甲氧基苯氧基)甲基]-3-[(2S)-吡咯烷-2-基]-1,2,4-噁二唑(180g、0.59mol)的氯仿(900ml)溶液中,加入二氟(1-羟基-3,3,5,5-四甲基环己基)乙酸(177g、0.71mol)、1-羟基苯并三唑一水合物(104g、0.77mol)以及1-乙基-3-(3-二甲基氨基丙基)碳二亚胺盐酸盐(148g、0.77mol),室温下搅拌4小时。进一步加入二氟(1-羟基-3,3,5,5-四甲基环己基)乙酸(14.8g、0.06mol),搅拌14小时。反应后,馏去溶剂,加入乙酸乙酯,用水和饱和碳酸氢钠水溶液洗涤,用硫酸镁干燥。将残留物用硅胶色谱法(乙酸乙酯-己烷)精制,得到黄色油状物(156g)。
1H-NMR(200MHz,氯仿-D);
δppm 0.82-1.88(m,6H),0.90,0.94(s,总6H),1.22,1.24(s,总6H),1.91-2.42(m,4H),3.60,3.84(s,总3H),3.61,3.86(s,总3H),3.68-3.96(m,1H),4.05-4.33(m,1H),5.20,5.22(s,总2H),5.39-5.49,5.58-5.69(m,总1H),6.44(dd,J=8.79,3.08Hz,1H),6.62(d,J=2.64Hz,1H),6.78(d,J=8.79Hz,1H)
制剂例1
洗剂A:
(处方)
99.5%乙醇 76.59g
苄醇 0.4g
本发明化合物 1g
聚乙二醇400 16g
丙酮 6g
1-薄荷醇 0.01g
(制造方法)
混合聚乙二醇400、苄醇和丙酮,向其中添加本发明化合物,搅拌使溶解。向其中添加99.5%乙醇和1-薄荷醇,进行搅拌,得到透明的洗液。
制剂例2
洗剂B:
(处方)
99.5%乙醇 70g
本发明化合物 1g
丙二醇 5g
BHT 0.05g
纯净水 23.95g
(制造方法)
将本发明化合物、丙二醇和BHT加入到99.5%乙醇中,搅拌使溶解。将该溶液和纯净水混合,得到透明的洗液。
制剂例3
洗剂C:
(处方)
99.5%乙醇 79g
丙酮 11g
本发明化合物 5g
1,3-丁二醇 5g
(制造方法)
将本发明化合物和1,3-丁二醇加入到99.5%乙醇与丙酮的混合液中,搅拌使溶解,得到透明的洗液。
制剂例4
洗剂D(乳液):
(处方)
<混合液A>
聚山梨醇酯80 1g
山梨醇聚醚-40四油酸酯 1.5g
硬脂酸甘油酯 1g
硬脂酸 0.5g
棕榈酸鲸蜡酯 0.5g
本发明化合物 2g
角鲨烷 5g
对羟基苯甲酸甲基酯 0.1g
对羟基苯甲酸丙基酯 0.02g
<混合液B>
1,3-丁二醇 5g
羧乙烯基聚合物 0.1g
纯净水 83.28g
(制造方法)
将混合液A和混合液B分别加热至80℃。向混合液A中添加混合液B之后,冷却至40℃,得到乳液。
制剂例5
洗发水:
(处方)
<混合液A>
月桂醇硫酸三乙醇胺盐 20g
N-月桂酰基甲基氨基丙酸钠 15g
椰油酰胺丙基二甲氨基乙酸甜菜碱 25g
异硬脂酸异丙基酯 2g
本发明化合物 1g
氨基苯甲酸乙基酯 0.05g
<混合液B>
氢化大豆磷脂 0.2g
1,3-丁二醇 3g
纯净水 33.75g
(制造方法)
将混合液A加热至70℃,并将其添加到加热至70℃的混合液B中。搅拌混合液,冷却至35℃,得到洗发水。
制剂例6
片剂:
(处方)
本发明化合物 2g
乳糖 12g
α微晶纤维素 10.8g
低取代羟丙基纤维素 4g
羟丙基纤维素 1g
硬脂酸镁 0.2g
纯净水 12mg
(制造方法)
将除硬脂酸镁之外的所有成分在乳钵中混合,加入纯净水进行造粒。对所得的颗粒进行干燥,向其中混合硬脂酸镁后压片,得到直径8mm、重量200mg的片剂。
试验例
小鼠剃毛模型中的发毛促进效果测定试验:
方法:
将C57BL小鼠(雌性、约7周龄)的背部体毛剃去,从剃毛3天后开始给药40天,即一天一次在剃毛部上涂布给予溶于99%乙醇中的被检化合物(90mM)200μL。作为评价化合物,使用本发明化合物以及WO98/55090国际公开公报中公开的化合物(GPI-1511)。作为对照,使用涂布有200μL基质的对照组。
对于各组的10~12只动物,从开始给药日起,每两天或三天,采用以下的毛发生长评分基准,对剃毛部的毛发生长状况进行评分。
(毛发生长评分基准)
1=无毛发生长
2=剃毛部中不足30%生长毛发
3=剃毛部的30%以上、不足60%生长毛发
4=剃毛部的60%以上、不足90%生长毛发
5=剃毛部的90%以上生长毛发
结果:
分别给予本发明化合物和GPI-1511各18μmol的给药组,与给予基质的对照组相比,在较早期显示出毛发生长分数的增加(图1)。本发明化合物给药组的毛发生长分数,在整个试验期间,与GPI-1511给药组的毛发生长分数相比,显示出更高值。特别是在给药第19天以后,本发明化合物给药组的毛发生长分数显著增加,表明本化合物显示出优异的毛发生长促进效果。该毛发生长促进效果是通过除化合物的旋转异构酶抑制活性之外的、优异的稳定性、吸收性、组织渗透性(tissuepenetration property)等多种特性的组合而发挥的。
产业上的可利用性
以本发明化合物为有效成分的脱发症的预防或治疗剂,具有优异的毛发修复、生长作用。因此,本发明的化合物可有效用作药品、类似药品(quasi-drug)或者头发化妆品。
Claims (7)
1.脱发症的预防或治疗剂,其特征在于,含有1-[2-((2S)-2-{5-[(3,4-二甲氧基苯氧基)甲基]-1,2,4-噁二唑-3-基}吡咯烷-1-基)-1,1-二氟-2-氧代乙基]-3,3,5,5-四甲基环己醇作为有效成分。
2.权利要求1所述的脱发症的预防或治疗剂,其为外用剂。
3.权利要求1或2所述的脱发症的预防或治疗剂,其中,以0.00001至4mg/cm2对头皮给予1-[2-((2S)-2-{5-[(3,4-二甲氧基苯氧基)甲基]-1,2,4-噁二唑-3-基}吡咯烷-1-基)-1,1-二氟-2-氧代乙基]-3,3,5,5-四甲基环己醇。
4.脱发症的预防或治疗方法,其特征在于,对哺乳动物给予有效量的1-[2-((2S)-2-{5-[(3,4-二甲氧基苯氧基)甲基]-1,2,4-噁二唑-3-基}吡咯烷-1-基)-1,1-二氟-2-氧代乙基]-3,3,5,5-四甲基环己醇。
5.权利要求4所述的脱发症的预防或治疗方法,其中,哺乳动物为人。
6.权利要求4或5所述的脱发症的预防或治疗方法,其中,以外用剂的形式给药。
7.1-[2-((2S)-2-{5-[(3,4-二甲氧基苯氧基)甲基]-1,2,4-噁二唑-3-基}吡咯烷-1-基)-1,1-二氟-2-氧代乙基]-3,3,5,5-四甲基环己醇在制造脱发症的预防或治疗剂中的用途。
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JP4221989B2 (ja) | 2002-09-30 | 2009-02-12 | 大正製薬株式会社 | オキサジアゾール誘導体 |
US20060122173A1 (en) | 2003-06-06 | 2006-06-08 | Jakob Busch-Petersen | Il-8 receptor antagonists |
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- 2007-12-20 WO PCT/JP2007/074496 patent/WO2008075735A1/ja active Application Filing
- 2007-12-20 TW TW096148988A patent/TW200833323A/zh unknown
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2009
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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CN103502240A (zh) * | 2011-03-15 | 2014-01-08 | 大正制药株式会社 | 吡咯衍生物 |
Also Published As
Publication number | Publication date |
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EP2100588A1 (en) | 2009-09-16 |
HK1138204A1 (en) | 2010-08-20 |
TW200833323A (en) | 2008-08-16 |
NO20092695L (no) | 2009-09-15 |
AU2007335379A1 (en) | 2008-06-26 |
WO2008075735A1 (ja) | 2008-06-26 |
CN101610751B (zh) | 2012-03-21 |
CA2673841A1 (en) | 2008-06-26 |
KR20090100416A (ko) | 2009-09-23 |
RU2457826C2 (ru) | 2012-08-10 |
ZA200904328B (en) | 2010-09-29 |
NZ578391A (en) | 2011-02-25 |
AU2007335379B2 (en) | 2012-06-14 |
RU2009127776A (ru) | 2011-01-27 |
BRPI0717919A2 (pt) | 2013-11-05 |
JPWO2008075735A1 (ja) | 2010-04-15 |
US20100022604A1 (en) | 2010-01-28 |
EP2100588A4 (en) | 2011-01-19 |
IL199177A0 (en) | 2010-03-28 |
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