CN116803391A - Wez系列化合物在制备预防或/和治疗脱发产品中的用途 - Google Patents
Wez系列化合物在制备预防或/和治疗脱发产品中的用途 Download PDFInfo
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- CN116803391A CN116803391A CN202310688735.7A CN202310688735A CN116803391A CN 116803391 A CN116803391 A CN 116803391A CN 202310688735 A CN202310688735 A CN 202310688735A CN 116803391 A CN116803391 A CN 116803391A
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- wez
- alopecia
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- hair loss
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Classifications
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- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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- C07D—HETEROCYCLIC COMPOUNDS
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D—HETEROCYCLIC COMPOUNDS
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- Health & Medical Sciences (AREA)
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- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Dermatology (AREA)
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- Epidemiology (AREA)
- Pulmonology (AREA)
- Immunology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Physical Education & Sports Medicine (AREA)
- Pain & Pain Management (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Cosmetics (AREA)
Abstract
本发明公开WEZ系列化合物在制备预防或/和治疗脱发产品中的用途,通过建立脱发动物模型,发现了式Ⅳ、Ⅴ、Ⅵ所示化合物在治疗脱发以及其它类似毛发脱落性疾病,包括但不限于雄激素源性秃发(AGA)(又名脂溢性脱发)、斑秃等中的作用。
Description
技术领域
本发明属于药物化学领域,具体涉及一种WEZ系列化合物在制备预防或/和治疗脱发产品中的用途。
背景技术
斑秃(alopecia areata,AA)是一种非瘢痕性脱发,局部皮肤大体正常。通常情况下为突发的脱发斑,严重时可累及整个头皮,此时称为全秃(alopecia totalis,AT),当累及包括腋毛、阴毛在内的全身所有毛发时,称为普秃(alopecia universalis,AU),容易给患者的容貌和心理带来严重的影响。目前病因尚未完全明了,自身免疫功能异常或不稳定、神经精神因素被认为是重要相关因素。斑秃的治愈机率较高,但不同病因引起的斑秃,治愈概率有很大区别。部分斑秃患者可以自然痊愈,还有部分斑秃患者可持续数年。米诺地尔是一种治疗斑秃常见的外用药物,可促进皮肤血管扩张、改善局部血液循环、促进毛发生长。严重斑秃常用的糖皮质激素,主要包括泼尼松龙、复方倍他米松等等,可以口服、外用或皮内注射。对于不适用糖皮质激素类药物的患者,可采用免疫抑制剂治疗,常见的药物有环孢素、甲氨蝶呤、糖皮质激素和免疫抑制剂,这些药物副作用较多。
雄激素源性秃发(AGA)又名脂溢性脱发,是一种雄激素依赖性的遗传性毛发脱落,是常见病、多发病。多为20~30岁左右的男性发病。脱发主要在头顶部,多先从前额两侧发际开始,也有自顶部开始者。脱发区逐渐向上扩延,头发也渐变得稀少纤细,终而头顶部头发大部或全部脱落,但枕后及双侧颞上方头发依存,呈马蹄形外观,此带形区内头发保持正常。脱发处皮肤光亮,毛孔缩小或残留少许细软毳毛。脱发的速度、范围和严重程度,受遗传和个体影响。一般30岁左右发展最快,严重全秃者少见。女性多为发生于头顶的弥漫性脱发,头顶头发变稀疏。我国流行病学调查显示男性雄激素性脱发患病率为21.3%,女性为6.0%。雄激素性脱发的病因及发病机制尚不明确,一般认为雄激素及其受体在本病的发生中起关键作用,Ⅱ型5a-还原酶是其发病的重要因素。正常生理状态下,雄激素在体内对毛发的生长发育起一定的刺激促进作用,但在某些特定部位能诱导毛发脱失;睾酮是体内主要的雄激素,它经5a-还原酶转化为二氢睾酮,后者可引起终毛向毳毛转变,最终导致脱发。目前尚无理想治疗方法,是脱发性疾病难治的类型。米诺地尔是一种非特异性治疗脱发的药物,是FDA批准用于治疗脱发的一线外用药物,但使用过程中可能引起面部和四肢多毛症,停用后治疗效果逐渐消失。由于雄激素在发病中起很大作用,因而近年来的新治疗方法企图通过抗雄激素的效应来终止毛囊的变小。非那雄胺是一种Ⅱ型5a-还原酶选择性抑制剂,近年发现非那雄胺治疗AGA有效,可持续改善头发的生长情况。但非那雄胺存在引起性功能异常,精子一过性减少和男性乳房发育异常等不良反应,在动物实验中发现有致畸作用,故不宜用于小儿和育龄妇女。西咪替丁需连服5个月或更久,副作用为男性乳房发育、阳痿、性欲降低等。口服避孕药:主要有的索高诺酮、左炔诺孕酮(左旋甲基炔诺孕酮)、炔诺孕酮、炔诺酮、诺孕酯(肟炔诺酯)、双酯炔诺醇和醋炔诺酮等。常用来治疗女性AGA,治疗6~12个月后头发会有所改善。
对于上述疾病,目前的治疗方法远不能满足临床需求,需要寻找更多疗效好、副作用少、价格便宜的新药来控制疾病进展,减少复发和并发症的发生。
发明内容
本发明的目的在于提供WEZ系列化合物或其药学上可接受的盐在制备预防或/和治疗脱发产品中的用途。
本发明所述的WEZ系列化合物为具有式I或Ⅱ或Ⅲ结构的化合物:
其中:R1、R2、R3独立地选自氢、卤素、羟基、氨基、甲氧基、氨甲基;
R4独立地选自氢、甲基、乙基、羧基、羟基;R5为 ;其中R6和R8各自独立地选自H、卤素或(C1-C4)烷基,条件是R6和R8不同时为卤素。
在一些具体的实例中,本发明所述的WEZ系列化合物为式Ⅳ或式Ⅴ或式Ⅵ结构的化合物:
。
本发明一方面提供了WEZ系列化合物或其药学上可接受的盐在制备预防或/和治疗毛发脱落有关的产品中的应用。
在一些实施例中,本发明所述毛发脱落为脱发,包括生理性脱发和病理性脱发。所述的生理性脱发为本领域公知的如自然脱发、老年性脱发、产后脱发等。病理性脱发是指头发异常或过度脱落,例如因感染、内分泌疾病、免疫系统疾病和营养缺乏等导致的脱发,例如雄激素源性秃发(AGA)(又名脂溢性脱发)、斑秃等。
在一些具体的实施例中,本发明所述的毛发脱落为病理性脱发,在一些更具体的实例中,为雄激素源性秃发(AGA)(又名脂溢性脱发)或斑秃。
本发明另一方面还提供了WEZ系列化合物或其药学上可接受的盐在制备促进毛发生长有关的产品中的应用。
本发明所述的产品,包括但不限于药品、洗护用品或保健品。
本发明所述的WEZ系列化合物或其药学上可接受的盐可制备为药学上允许的任何剂型,例如为适于口服、肠胃外、腹膜内、静脉内、动脉内、透皮、舌下、肌内、直肠、透颊、鼻内、吸入、阴道、眼内、局部、皮肤、皮下、脂肪内、关节内、腹膜内或鞘内任意给药方式的制剂。
例如在一种优选的实施方式中,本发明所述的剂型为霜剂、膏剂、片剂、冲剂、口服液剂、胶囊剂、滴丸剂、灌肠剂、膜剂或注射剂。
本发明所述的WEZ系列化合物或其药学上可接受的盐也可制备为洗护用品,例如洗发水、护发素等。
本发明所述的WEZ系列化合物或其药学上可接受的盐还可制备为用于防脱或生发的保健用品。
本发明通过建立脱发动物模型,发现了式Ⅳ、Ⅴ、Ⅵ所示化合物在治疗脱发以及其它类似毛发脱落性疾病,包括但不限于雄激素源性秃发(AGA)(又名脂溢性脱发)、斑秃等中的作用。
附图说明
图1 WEZ化合物能够明显促进脱发模型小鼠的毛发生长。
具体实施方式
下面结合实施例对本发明做进一步说明,应当理解,此处所描述的具体实施例仅用以解释本发明,并不用于限定本发明,凡在本发明的构思前提下对本发明制备方法的简单改进都属于本发明的保护范围之内。下面实施例未注明具体条件的实验方法,通常按照本领域的公知手段。下述实施例中所用的试验材料,如无特殊说明,均为自常规生化试剂商店购买得到的。
若无特别说明,以下实施例中所述的化合物WEZ-4结构如式Ⅳ所示,化合物WEZ-5结构如式Ⅴ所示,化合物WEZ-6结构如式Ⅵ所示:
。
实施例1化合物WEZ系列对大鼠脱发模型的影响
1.实验方法
1.1材料
(1)化合物WEZ-4、WEZ-5、WEZ-6酊制备方法:75%乙醇分别与适量以上化合物混匀配制成不同浓度的酊剂。
(2)阳性治疗药:5%米诺地尔酊(商品名:蔓迪,浙江万马药业有限公司)
(3)实验动物:SPF级Wistar大鼠,雄性,来源于上海斯莱克实验动物有限责任公司。
1.2动物分组与造模
Wistar大鼠按照体重随机分为阴性对照组(外用75%乙醇)、模型组(外用75%乙醇)、阳性对照组(外用5%米诺地尔酊)、WEZ-4外用治疗组(外用5% WEZ-4酊)、WEZ-5外用治疗组(外用5% WEZ-5酊)、WEZ-6外用治疗组(外用5% WEZ-6酊),WEZ-4静脉注射组(2mg/kg.d)、WEZ-5静脉注射组(2mg/kg.d)、WEZ-6静脉注射组(2mg/kg.d),每组各10只。实验前每只大鼠选取背部4cmx5cm面积的区域将毛脱去作为观察区。除阴性对照组外,大鼠颈后皮下注射丙酸睾酮注射液[5ml/(kg·d)],每天1次,连续60d,建立雄激素源性秃发(AGA),又名脂溢性脱发(SA)模型。连续皮下注射丙酸睾丸酮4周后大鼠逐渐出现毛发脱落.残存毛发变得纤细、质脆,证明脱发模型成功建立。同时皮肤涂抹给药,均按2 mL/(只·次)分别涂抹对应药物组大鼠背部观察区,每日2次,给药间隔8h。静脉给药每日一次。阴性对照组和模型对照组涂抹75%乙醇溶液,2 mL/(只·次),每日2次,连续60d。
1.3 观察指标及测试方法
给药每15天于每只大鼠背部观察区拔取10根毛发,用游标卡尺测量毛发长度。给药60d后,取实验观察区皮肤,进行常规组织脱水、石蜡包埋、HE染色,光镜镜检,观察大鼠皮肤毛囊和皮脂腺组织病理学改变。对各组病变进行半定量分析。分级标准如下:皮肤真皮组织细胞和皮下毛囊、皮脂腺结构正常记为“一”:皮肤真皮未见有增生,毛囊、皮脂腺病变局限,皮下未见有炎症记为“±”:皮肤真皮组织未见有明显增生,毛囊明显囊性变.皮脂腺未见有明显增生,皮下未见有炎症记为“+”:皮肤真皮组织有节段性增生,不明显,少部分毛囊有囊性变,皮脂腺有轻度增生肥大.皮下未见有明显炎症记为“++”:皮肤真皮组织细胞有不同程度节段性增生,部分毛囊囊性变,表现毛囊大小不均匀,周边部无细胞。皮脂腺有增生,增生腺体内细胞核较少,个别大鼠皮下有轻度炎性增生记为“+++”。
2.实验结果
2.1 WEZ对大鼠毛发生长的影响
各治疗组大鼠在给药第15、30、45、60天的毛发长度均长于模型对照组,差异均有统计学意义(P<0.01),与阳性治疗组比较,差异均有统计学意义(P<0.05)。见表1
表1各组对大鼠毛发生长长度的影响
*与模型对照组比较差异均有统计学意义(P<0.01)
2.2 WEZ对大鼠观察区皮肤组织真皮浅层毛囊形态的影响
模型组大鼠部分皮肤真皮组织细胞有不同程度节段性增厚,大鼠皮下有轻度淋巴细胞增生;部分大鼠皮下毛囊有明显囊性变,毛囊大小不等,增大毛囊腔内有脱落角化物.周边有轻度纤维化,毛囊周边细胞消失或细胞层次明显减少,腔内似有钙化物染成蓝色,皮脂腺数目增多,部分腺体有肥大,肥大腺体细胞核明显减少,正常毛囊数减少。各治疗组大鼠皮肤真皮组织细胞及皮下毛囊、皮脂腺病变与模型组比较有不同程度减轻。各治疗组大鼠皮肤损伤毛囊数与模型对照组比较均明显减少,差异有统计学意义(P<0.01)。与模型对照组比较,各治疗组大鼠皮肤真皮组织细胞及皮下毛囊、皮脂腺病变明显减轻,差异有统计学意义(P<0.01)。与阳性治疗组比较,差异均有统计学意义(P<0.05)。见表2。
表2各组对大鼠皮肤毛囊和皮脂腺的影响(只)
注:*为与模型对照组比较差异有统计学意义(P<0.01)
3.实验结论
WEZ-4、WEZ-5、WEZ-6无论外用还是系统应用均能明显促进大鼠脱发模型的毛发生长,减轻对皮下毛囊和皮脂腺的损伤,未见明显不良反应。
实施例2化合物WEZ系列对小鼠脱发模型的影响
1.实验方法
1.1材料
(1)化合物WEZ-4、WEZ-5、WEZ-6酊制备方法:60%乙醇分别与以上化合物混匀配制成2%浓度的酊剂。
(2)阳性治疗药:2%米诺地尔酊(中国医学科学院皮肤病研究所生产)
(3)实验动物:SPF级雄性健康C57BL/6小鼠,雌雄各半,6-8周龄,体重20-25g,由成都药康生物科技有限公司提供。
1.2动物分组与造模
动物房12h-12h昼夜交替,保持动物自由饮水、进食,温度23-25℃,实验动物进入动物房适应性饲养一周后进入实验。实验小鼠分为11组,阴性对照组(外用60%乙醇)、模型组(外用60%乙醇)、阳性对照组(外用2%米诺地尔酊)、WEZ-4外用治疗组(外用2% WEZ-4酊)、WEZ-5外用治疗组(外用2% WEZ-5酊)、WEZ-6外用治疗组(外用2% WEZ-6酊),每组6只,雌雄各半。选取实验小鼠背部4 cm×5 cm面积的区域将毛脱去,用3%苦味酸溶液将脱毛区涂成黄色以确定脱毛实验观察区。除阴性对照组外,其他组小鼠颈后皮下注射丙酸睾酮注射液[8ml/(kg·d)],每天1次,连续60d,建立SA模型。造模同时涂抹给药,均按1 ml/(只·次)分别涂抹对应药物组大鼠背部观察区,每日2次,给药间隔2 h。正常对照组和模型对照组涂抹赋型剂(60%乙醇溶液),1 ml/(只·次),每日2次,连续60天。
1.3 观察指标及测试方法
给药每15天于每只小鼠背部观察区拔取10根毛发,用游标卡尺测量毛发长度。给药60d后,取实验观察区皮肤,进行常规组织脱水、石蜡包埋、HE染色,光镜镜检,观察小鼠皮肤毛囊和皮脂腺组织病理学改变。对各组病变进行半定量分析。分级标准如下:皮肤真皮组织细胞和皮下毛囊、皮脂腺结构正常记为“一”:皮肤真皮未见有增生,毛囊、皮脂腺病变局限,皮下未见有炎症记为“±”:皮肤真皮组织未见有明显增生,毛囊明显囊性变.皮脂腺未见有明显增生,皮下未见有炎症记为“+”:皮肤真皮组织有节段性增生,不明显,少部分毛囊有囊性变,皮脂腺有轻度增生肥大.皮下未见有明显炎症记为“++”:皮肤真皮组织细胞有不同程度节段性增生,部分毛囊囊性变,表现毛囊大小不均匀,周边部无细胞。皮脂腺有增生,增生腺体内细胞核较少,个别皮下有轻度炎性增生记为“+++”。
2.实验结果
2.1 WEZ系列对小鼠毛发生长的影响
各组小鼠在给药第15、30、45、60天的毛发长度均长于模型对照组,差异均有统计学意义(P<0.01),与阳性治疗组比较,差异均有统计学意义(P<0.05)。见表3。各组小鼠在给药第30天的毛发生长情况见图1。
表3各组对小鼠毛发生长长度的影响
*与模型对照组比较差异均有统计学意义(P<0.01)
2.2 WEZ对小鼠观察区皮肤组织真皮浅层毛囊形态的影响
模型组小鼠部分皮肤真皮组织细胞有不同程度节段性增厚,小鼠皮下有轻度淋巴细胞增生;部分小鼠皮下毛囊有明显囊性变,毛囊大小不等,增大毛囊腔内有脱落角化物.周边有轻度纤维化,毛囊周边细胞消失或细胞层次明显减少,腔内似有钙化物染成蓝色,皮脂腺数目增多,部分腺体有肥大,肥大腺体细胞核明显减少,正常毛囊数减少。各治疗组小鼠皮肤真皮组织细胞及皮下毛囊、皮脂腺病变与模型组比较有不同程度减轻。各治疗组小鼠皮肤损伤毛囊数与模型对照组比较均明显减少,差异有统计学意义(P<0.01)。与模型对照组比较,各治疗组小鼠皮肤真皮组织细胞及皮下毛囊、皮脂腺病变明显减轻,差异有统计学意义(P<0.01)。见表4。
表4 各组对小鼠皮肤毛囊和皮脂腺的影响(只)
注:*为与模型对照组比较差异有统计学意义(P<0.01)
3.实验结论
WEZ-4、WEZ-5、WEZ-6能明显促进小鼠脱发模型的毛发生长,减轻对皮下毛囊和皮脂腺的损伤。
Claims (9)
1.WEZ系列化合物或其药学上可接受的盐在制备预防或/和治疗毛发脱落有关的产品中的应用,所述的WEZ系列化合物为具有式I或Ⅱ或Ⅲ结构的化合物:
其中:R1、R2、R3独立地选自氢、卤素、羟基、氨基、甲氧基、氨甲基;R4独立地选自氢、甲基、乙基、羧基、羟基;R5为;R6和R8各自独立地选自H、卤素或(C1-C4)烷基,且R6和R8不同时为卤素。
2.根据权利要求1所述应用,其特征在于,所述的WEZ系列化合物为式Ⅳ或式Ⅴ或式Ⅵ结构的化合物:
。
3.根据权利要求1所述应用,其特征在于,毛发脱落具体为脱发。
4.根据权利要求3所述应用,其特征在于,所述脱发为生理性脱发或病理性脱发。
5.根据权利要求4所述应用,其特征在于,所述生理性脱发包括自然脱发、老年性脱发或产后脱发;所述病理性脱发包括脂溢性脱发或斑秃。
6.根据权利要求1~5任一项所述的应用,其特征在于,所述产品为药品、洗护用品或保健品。
7.WEZ系列化合物或其药学上可接受的盐在制备促进毛发生长有关的产品中的应用,所述的WEZ系列化合物为具有式I或Ⅱ或Ⅲ结构的化合物:
其中:R1、R2、R3独立地选自氢、卤素、羟基、氨基、甲氧基、氨甲基;
R4独立地选自氢、甲基、乙基、羧基、羟基;R5为;R6和R8各自独立地选自H、卤素或(C1-C4)烷基,且R6和R8不同时为卤素。
8.根据权利要求7所述应用,其特征在于,所述的WEZ系列化合物为式Ⅳ或式Ⅴ或式Ⅵ结构的化合物:
。
9.根据权利要求7或8所述的应用,其特征在于,所述产品为药品、洗护用品或保健品。
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CNPCT/CN2022/099496 | 2022-06-17 | ||
PCT/CN2022/099496 WO2022262854A1 (zh) | 2021-06-17 | 2022-06-17 | Cly系列化合物及其制备方法和制备药物的用途 |
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