CN112870195A - 骨质疏松症治疗剂 - Google Patents
骨质疏松症治疗剂 Download PDFInfo
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Abstract
Description
(本申请是2014年9月29日递交的发明名称为“骨质疏松治疗剂”的申请201480049594.3的分案申请)
技术领域
本发明涉及一种将酰基硫脲化合物或其盐作为有效成分的骨质疏松症的治疗剂、及医药组合物。
背景技术
关于骨质疏松症,在2000年的美国国立卫生研究所(NIH)的共识会议中,提出将骨质疏松症定义为“以骨强度的降低为特征且骨折的风险变得容易增大的骨胳疾病:Askeletal disorder characterized by compromised bone strength predisposing toan increased risk of fracture”,实际上,为因骨密度的降低和骨质的劣化而导致骨强度降低的疾病(非专利文献1)。骨质疏松症被分类为伴随年龄增加、闭经或妊娠而使骨密度降低的原发性骨质疏松症和以某些疾病为背景因素的继发性骨质疏松症。
骨密度的降低是由于骨吸收的亢进超过骨形成而产生,但也涉及成骨细胞功能及与其相伴的骨形成的降低(非专利文献2)。即,由于骨吸收与骨形成所引起的骨重塑的平衡失衡、骨吸收占优势的情况较深地干预病情。
目前,将腰椎与大腿骨颈部的骨质疏松症的患者合起来计算,推测在日本有1280万人(2005年),大腿骨颈部骨折产生数量以每年14万8100人急速增加,正在开发各种治疗方法或预防剂。
目前的骨质疏松症治疗剂主要使用有钙吸收促进药、骨形成促进药、骨吸收抑制药。然而,这些治疗剂一方面显示有效性,另一方面也报告有严重的副作用。例如钙制剂中频度最高的副作用为胃肠障碍,且在并用活性型维生素D3制剂的情况下,由于有产生高钙血症的可能性,因此必须定期进行血液检查(非专利文献3)。
作为双膦酸盐制剂的主要的副作用,报告有胃肠障碍、颚骨坏死、大腿骨的非典型骨折、低钙血症、肾损伤、及流行性感冒样症状等(非专利文献4)。另外,其半衰期较长,有在治疗中止后数年间仍残存于骨骼中的可能性。持续长期地过度抑制骨重塑有引起因骨的钙化度上升而导致的脆弱化或微小损伤的增加等不良作用的可能性。
另外,针对闭经后的骨量减少,使用有雌激素制剂、或相较于雌激素制剂对骨的雌激素受体选择性地作用的选择性雌激素调节剂(Selective estrogen receptormodulators;SERM)。然而,对于雌激素制剂而言,除子宫内膜出血、白带的增加、乳房痛等对女性激素特有的副作用以外,报告有深部静脉血栓栓塞症、乳癌及子宫内膜癌的发病风险的增加(非专利文献5),另外,SERM虽可以抑制对乳房、子宫的副作用,但仍然报告有深部静脉血栓栓塞症、热潮红、下肢痉挛(非专利文献6)。
因此,近年来一直进行以Cathepsin K抑制剂、Src激酶抑制剂、抗硬化素抗体(Anti-Sclerostin antibody)等为新目标的骨质疏松症治疗剂的临床开发(非专利文献7、8、9),但现状是作为骨质疏松症治疗药并不存在兼具优异的有效性与安全性的药剂。
另一方面,已知如4-[2-氟-4-[[[(2-苯基乙酰基)氨基]硫代甲基]氨基]-苯氧基]-7-甲氧基-N-甲基-6-喹啉甲酰胺这样在喹啉环的6位具有氨基羰基且在7位具有烷氧基的酰基硫脲化合物为显示出减轻了副作用的强力的c-Met抑制效果及VEGF受体抑制的抗肿瘤剂(专利文献1),另外,与其它抗肿瘤剂并用时显示出优异的增强抗肿瘤效果的作用(专利文献2)。
然而,全然不知该化合物对骨质疏松症有效。
现有技术文献
专利文献
专利文献1:国际公开第2009/125597号
专利文献2:国际公开第2013/100014号
非专利文献
非专利文献1:Osteoporosis prevention,diagnosis,and therapy.JAMA:thejournal of the American Medical Association.2001;285:785-95.
非专利文献2:Rachner TD,Khosla S,Hofbauer LC.Osteoporosis:now and thefuture.Lancet.2011;377:1276-87.
非专利文献3:Shiraki M,Orimo H,Ito H,Akiguchi I,Nakao J,Takahashi R,etal.Long-term treatment of postmenopausal osteoporosis with active vitamin D3,1-alpha-hydroxycholecalciferol(1alpha-OHD3)and 1,24Dihydroxycholecalciferol(1,24(OH)2D3).Endocrinol Jpn.1985;32:305-15.
非专利文献4:Rizzoli R,Reginster JY,Boonen S,Breart G,Diez-Perez A,Felsenberg D,et al.Adverse reactions and drug-drug interactions in themanagement of women with postmenopausal osteoporosis.Calcif Tissue Int.2011;89:91-104.
非专利文献5:Rossouw JE,Anderson GL,Prentice RL,LaCroix AZ,KooperbergC,Stefanick ML,et al.Risks and benefits of estrogen plus progestin in healthypostmenopausal women:principal results From the Women's Health Initiativerandomized controlled trial.JAMA:the journal of the American MedicalAssociation.2002;288:321-33.
非专利文献6:Bolognese MA.SERMs and SERMs with estrogen forpostmenopausal osteoporosis.Rev Endocr Metab Disord.2010;11:253-9.
非专利文献7:Lim V,Clarke BL.New therapeutic targets for osteoporosis:beyond denosumab.Maturitas.2012;73:269-72.
非专利文献8:Das S,Crockett JC.Osteoporosis-a current view ofpharmacological prevention and treatment.Drug Des Devel Ther.2013;7:435-48.
非专利文献9:Canalis E.New treatment modalities in osteoporosis.EndocrPract.2010;16:855-63.
发明内容
发明所要解决的课题
本发明的目的在于提供一种对骨质疏松症发挥优异的预防或治疗效果的骨质疏松症治疗剂及医药组合物。
用于解决课题的方法
本发明的发明人为了解决上述问题,进行了深入研究,结果发现,下述式(I)所示的酰基硫脲化合物或其盐通过对破骨细胞抑制其分化形成而阻碍骨吸收,并且对成骨细胞具有异形骨形成抑制作用,进而在骨质疏松模型小鼠中显示骨量恢复效果,由此,对骨质疏松症的预防或治疗有用。
即,本发明提供一种骨质疏松症治疗剂,其含有下述式(I)所示的酰基硫脲化合物或其盐作为有效成分。
另外,本发明提供一种用于治疗骨质疏松症的医药组合物,含有下述式(I)所示的酰基硫脲化合物或其盐、及药学上能够接受的载体。
另外,本发明提供一种骨质疏松症的治疗方法,其特征在于,对患者投予含有下述式(I)所示的酰基硫脲化合物或其盐及药学上能够接受的载体的医药组合物。
式(I):
(式中,R1表示可以具有取代基的C1-6烷基,作为该取代基,表示羟基、C3-10环烷基、可以具有取代基的C1-6烷氧基、可以具有取代基的C1-6烷基氨基、C1-6烷酰基氨基、C1-6烷基磺酰基、可以具有取代基的C6-14芳香族烃基、可以具有取代基的饱和或不饱和杂环基、可以具有取代基的C1-6烷基氨基羰基、可以具有取代基的饱和或不饱和杂环羰基中的任一个,R2表示氟原子或氯原子,R3表示氢原子、氟原子或氯原子。)
发明的效果
本发明化合物主要发挥起因于抑制破骨细胞的分化形成的骨吸收抑制效果,并且发挥成骨细胞的异形骨形成抑制效果,显示骨量恢复效果,由此,对骨质疏松症发挥优异的效果。因此,根据本发明,能够有效地治疗骨质疏松症。
附图说明
图1是人类前列腺癌株PC-3的小鼠胫骨移植部位的μCT图像。
图2是人类肺癌株A549-luc-BM1的小鼠胫骨移植部位的μCT图像。
图3是摘除卵巢的小鼠(OVX小鼠)的大腿骨的骨量变化。
图4是摘除卵巢的小鼠(OVX小鼠)大腿骨部位的μCT图像。
图5是摘除卵巢的小鼠(OVX小鼠)的体重变化。
具体实施方式
关于本发明的通式(I)所示的酰基硫脲化合物(称为“本发明化合物”),在记为“可以具有取代基”的情况下,是指有在该结构上的化学上可能的位置上具有1个或2个以上的“取代基”的情形。
该结构上所存在的取代基的种类、取代基的个数、取代位置并无特别限定,在存在2个以上的取代基的情况下,这些可以相同,也可以不同。作为“取代基”,可以例示卤素原子、羟基、氰基、硝基、C1-6烷酰基、C1-6烷基、C3-10环烷基、C2-6烯基、C1-6烷氧基、氨基、C1-6烷基氨基、C1-6烷酰基氨基、C1-6烷基氨基羰基、C1-6烷基磺酰基、C6-14芳香族烃基、饱和或不饱和杂环基、饱和或不饱和杂环羰基、桥氧基等,在存在上述取代基的情况下,其个数典型而言为1~3个。
式(I)中,R1所示的“可以具有取代基的C1-6烷基”的“C1-6烷基”表示碳原子数为1~6的直链状或支链状烷基,可以例示甲基、乙基、正丙基、异丙基、正丁基、仲丁基、叔丁基、正戊基、异戊基、正己基、异己基,更优选为C1-4烷基,特别优选为甲基、乙基、正丙基、异丙基、正丁基、仲丁基。
式(I)中,作为R1的“可以具有取代基的C1-6烷基”的取代基所示的“C3-10环烷基”表示碳原子数为3~10的环烷基,可以例示环丙基、环丁基、环戊基、环己基,更优选为环己基。
式(I)中,作为R1的“可以具有取代基的C1-6烷基”的取代基所示的“可以具有取代基的C1-6烷氧基”的“C1-6烷氧基”表示碳原子数为1~6的直链状或支链状烷氧基,可以例示甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、正戊氧基、正己氧基,特别优选为甲氧基、乙氧基、异丙氧基。
式(I)中,作为R1的“可以具有取代基的C1-6烷基”的取代基所示的“可以具有取代基的C1-6烷氧基”的“取代基”优选为羟基。
式(I)中,作为R1的“可以具有取代基的C1-6烷基”的取代基所示的“可以具有取代基的C1-6烷基氨基”的“C1-6烷基氨基”表示以上述C1-6烷基单取代或二取代的氨基,可以例示甲基氨基、乙基氨基、二甲基氨基、甲基乙基氨基、正丙基氨基、异丙基氨基、正丁基氨基、仲丁基氨基、叔丁基氨基、正戊基氨基、正己基氨基,更优选为二乙基氨基。
式(I)中,作为R1的“可以具有取代基的C1-6烷基”的取代基所示的“C1-6烷酰基氨基”,可以列举甲酰氨基、乙酰氨基、丙酰氨基、丁酰氨基等,更优选为乙酰氨基。
式(I)中,作为R1的“可以具有取代基的C1-6烷基”的取代基所示的“C1-6烷基磺酰基”表示以上述C1-6烷基取代的磺酰基,更优选为甲磺酰基。
式(I)中,作为R1的“可以具有取代基的C1-6烷基”的取代基所示的“可以具有取代基的C6-14芳香族烃基”的“C6-14芳香族烃基”表示碳原子数为6~14的芳香族烃基,可以例示苯基、萘基等,更优选为苯基。
式(I)中,作为R1的“可以具有取代基的C1-6烷基”的取代基所示的“可以具有取代基的饱和或不饱和杂环基”的“饱和或不饱和杂环基”表示具有1个或2个氧原子、氮原子、硫原子中的任一原子的单环性或二环性的饱和或不饱和杂环基,例如,可以列举吡咯烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌啶基、四氢噻吩基、咪唑基、噻吩基、呋喃基、吡咯基、噁唑基、异噁唑基、噻唑基、异噻唑基、吡唑啉基、三唑基、四唑基、吡啶基、吡嗪基、嘧啶基、哒嗪基、吲哚基、异吲哚基、吲唑基、亚甲基二氧基苯基、亚乙基二氧基苯基、苯并呋喃基、二氢苯并呋喃基、苯并咪唑基、苯并噁唑基、苯并噻唑基、嘌呤基、喹啉基、异喹啉基、喹唑啉基、喹喔啉基等。更优选为含有1~4个氮原子和/或氧原子的5~7元的杂环基,特别优选为吡咯烷基、吗啉基、二氧杂环戊烷、四氢吡喃基、吡啶基、四唑基。该饱和或不饱和杂环基也可以进一步具有取代基,作为取代基,优选为C1-6烷基(尤其是甲基)、桥氧基。
式(I)中,作为R1的“可以具有取代基的C1-6烷基”的取代基所示的“可以具有取代基的C1-6烷基氨基羰基”的“C1-6烷基氨基羰基”表示具有上述C1-6烷基氨基的羰基,更优选为乙基氨基羰基、二甲基氨基、甲基丁基氨基。该C1-6烷基氨基羰基也可以进一步具有取代基,作为取代基,优选为羟基、C1-6烷氧基(尤其是甲氧基)。
式(I)中,作为R1的“可以具有取代基的C1-6烷基”的取代基所示的“可以具有取代基的饱和或不饱和杂环基羰基”的“饱和或不饱和杂环基羰基”表示具有上述饱和或不饱和杂环基的羰基,更优选为具有1~2个氮原子和/或氧原子的5~7元的饱和杂环羰基,特别优选为吡咯烷基羰基、吗啉代羰基。该饱和或不饱和杂环羰基也可以进一步具有取代基,作为取代基,优选为卤素原子(尤其是氟原子)、可以具有羟基的C1-6烷基(尤其是甲基)。
作为R1所示的可以具有取代基的C1-6烷基的C1-6烷基,优选为甲基、乙基、正丙基、异丙基、正丁基或仲丁基,作为该烷基上的取代基,优选为羟基、环己基、甲氧基、乙氧基、异丙氧基、二乙基氨基、乙酰氨基、甲磺酰基、苯基、吡咯烷基、吗啉基、二氧杂环戊烷基、四氢吡喃基、吡啶基、三唑基、乙基氨基羰基、二甲基氨基羰基、甲基丁基氨基羰基、吡咯烷基羰基或吗啉代羰基,该烷氧基也可以进一步具有羟基作为取代基,该杂环基也可以进一步具有甲基或桥氧基作为取代基,该烷基氨基羰基也可以进一步具有羟基或甲氧基作为取代基,该杂环羰基也可以进一步具有氟原子、可以具有羟基的甲基作为取代基。
作为R1所示的可以具有取代基的C1-6烷基的C1-6烷基,优选为甲基、乙基、正丙基、异丙基、正丁基或仲丁基,作为该烷基上的取代基,优选为羟基、甲氧基或吗啉基。
作为R1,更优选为甲基、甲氧基乙基、吗啉代乙基、吗啉代羰基甲基、2-羟基-正丁基、2-羟基-2-甲基正丙基、1-羟基正丁烷-2-基,在为1-羟基正丁烷-2-基的情况下,优选为S体。
作为R2的取代位置,优选为2位或3位,特别优选为2位。另外,作为R2,优选为氟原子或氯原子,更优选为氟原子。
作为R3的取代位置,优选为2位或4位。另外,作为R3,更优选为氢原子或氟原子。
本发明化合物中优选为:R1为可以具有取代基的甲基、乙基、正丙基、异丙基、正丁基或仲丁基,且该烷基上不存在取代基,或取代基为羟基、甲氧基或吗啉基,R2为氟原子,R3为氢原子或氟原子。
另外,作为本发明化合物的优选具体例,可以列举如下化合物。
(1)4-(2-氟-4-(3-(2-苯基乙酰基)硫脲基)苯氧基)-7-甲氧基-N-甲基喹啉-6-甲酰胺
(2)4-(2-氟-4-(3-(2-苯基乙酰基)硫脲基)苯氧基)-7-甲氧基-N-(2-吗啉代乙基)喹啉-6-甲酰胺
(3)(S)-4-(2-氟-4-(3-(2-(4-氟苯基)乙酰基)硫脲基)苯氧基)-N-(1-羟基丁烷-2-基)-7-甲氧基喹啉-6-甲酰胺
其中,更优选为下述式(IA)所示的4-(2-氟-4-(3-(2-苯基乙酰基)硫脲基)苯氧基)-7-甲氧基-N-甲基喹啉-6-甲酰胺[别名:(4-[2-氟-4-[[[(2-苯基乙酰基)氨基]硫代甲基]氨基]-苯氧基]-7-甲氧基-N-甲基-6-喹啉甲酰胺)]。
作为本发明化合物的盐,只要为药学上能够接受的盐即可,例如,可以列举与盐酸、氢溴酸、氢碘酸、硫酸、硝酸、磷酸等无机酸或甲酸、乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、柠檬酸、酒石酸、碳酸、苦味酸、甲磺酸、对甲苯磺酸、谷氨酸等有机酸的酸加成盐;与钠、钾、镁、钙、铝等无机碱或甲胺、乙胺、葡甲胺、乙醇胺等有机碱或赖氨酸、精氨酸、鸟氨酸等碱性氨基酸的盐或铵盐。
其中优选为与有机酸的盐,更优选为甲磺酸盐,更优选为单甲磺酸盐。
另外,本发明化合物中也包含光学异构体,也包含水合物、各种溶剂合物及多晶型。
本发明化合物也可以为药理学上能够接受的前药的形态。所谓药理学上能够接受的前药,只要为通过在活体内的生理学条件下、例如利用胃酸或酶进行水解、氧化、还原反应而转化为通式(I)即可,可以为任意的,例如,能够例示修饰羧基的甲酯、乙酯、丙酯、苯酯、羧氧基甲酯、乙氧羰酯等酯型化合物。形成这些前药的代表性化合物可以列举如广川书店1990年刊《医药品的开发》第7卷,163页至198页所记载的在生理学条件下转化为化合物(I)的化合物等。
本发明化合物为公知化合物,例如,能够依据国际公开第2009/125597号(上述专利文献1)记载的方法来制造。
如后述实施例所示,本发明化合物在移植有癌细胞株的小鼠胫骨内移植模型中,由于抑制骨破坏亢进与异常的弱骨的形成,而维持骨量正常(试验例1和2)。另外,在作为骨质疏松症的典型性模型所知的卵巢摘除模型动物(OVX小鼠)中,显示显著的骨量恢复效果(试验例3)。
因此,本发明化合物或其盐作为适用于骨质疏松症的患者、对该骨质疏松症发挥优异的预防或治疗效果的医药有用。进而,对类风湿性关节炎、牙周病、骨折等的治疗也有用。
关于本发明的骨质疏松症治疗剂及用于治疗骨质疏松症的医药组合物,所谓“治疗”是指用于预防及治疗疾病、以及减轻症状及防止复发的维持疗法。
本说明书中,所谓“骨质疏松症”是指以因骨量的减少与骨质的劣化而导致骨强度恶化,从而骨折的风险容易增加为特征的、包括原发性及继发性的骨疾病。作为能够利用本发明的骨质疏松症治疗剂及用于治疗骨质疏松症的医药组合物来治疗的骨质疏松症,例如,可以列举闭经后骨质疏松症、男性骨质疏松症、突发性骨质疏松症(妊娠后骨质疏松症等)、以及成骨不全症等。
本发明化合物或其盐能够制备成口服或非口服的任一给药形态,能够使用药学上能够接受的载体,通过公知的方法而制造成医药组合物。作为这样的医药组合物的制剂形态没有特别限制,能够例示片剂、包衣片剂、丸剂、散剂、颗粒剂、胶囊剂、液剂、悬浮剂、乳剂等口服剂;注射剂、栓剂等非口服剂等。
在成型为片剂的形态时,作为载体,例如,能够使用乳糖、白糖、氯化钠、葡萄糖、脲、淀粉、碳酸钙、高岭土、结晶纤维素、硅酸等赋形剂;水、乙醇、丙醇、玉米淀粉、单糖浆、葡萄糖液、淀粉液、明胶溶液、羧甲基纤维素、虫胶、甲基纤维素、羟丙基纤维素、羟丙基甲基纤维素、磷酸钾、聚乙烯吡咯烷酮等结合剂;干燥淀粉、海藻酸钠、琼脂末、海带多糖末、碳酸氢钠、碳酸钙、聚氧乙烯山梨醇酐脂肪酸酯类、月桂基硫酸钠、硬脂酸单甘油酯、乳糖等崩解剂;白糖、硬脂酸、可可脂、氢化油等崩解抑制剂;季铵盐、月桂基硫酸钠等吸收促进剂;甘油、淀粉等保湿剂;淀粉、乳糖、高岭土、膨润土、胶体状硅酸等吸附剂;精制滑石、硬脂酸盐、硼酸末、聚乙二醇等润滑剂等。另外,片剂能够根据需要制成施加有通常的包衣的片剂,例如糖衣药丸、明胶包衣锭、肠溶包衣锭、膜衣锭、双层锭、多层锭等。
在成型为丸剂的形态时,作为载体,例如,能够使用葡萄糖、乳糖、淀粉、可可脂、氢化植物油、高岭土、滑石等赋形剂;阿拉伯胶末、黄蓍胶末、明胶、乙醇等结合剂;海带多糖、琼脂等崩解剂等。胶囊剂根据通常方法与上述所例示的各种载体混合并填充至硬质明胶胶囊、软质胶囊等来制备。
在制成口服用液体制剂的情况下,能够使用矫味/矫臭剂、缓冲剂、稳定剂等,根据通常方法来制造内服液剂、糖浆剂、酏剂等。此时,作为矫味/矫臭剂,可以列举白糖、橙皮、柠檬酸、酒石酸等,作为缓冲剂,可以列举柠檬酸钠等,作为稳定剂,可以列举黄蓍胶、阿拉伯胶、明胶等。
在成型为栓剂的形态时,作为载体,例如,能够使用聚乙二醇、可可脂、高级醇、高级醇的酯类、明胶、半合成甘油酯等。
在制成注射剂的情况下,优选为将液剂、乳剂及悬浮剂杀菌,且与血液等渗,在成型为这些形态时,作为稀释剂,例如,能够使用水、乳酸水溶液、乙醇、丙二醇、聚乙二醇、乙氧化异硬脂醇、聚氧乙烯化异硬脂醇、聚氧乙烯山梨醇酐脂肪酸酯类等。
此外,此时,可以使医药制剂中含有对于制备等渗性的溶液而言充分的量的食盐、葡萄糖或甘油,另外,也可以添加通常的溶解助剂、缓冲剂、无痛化剂等。另外,在上述各制剂中,也可以根据需要配合着色剂、保存剂、香料、调味剂、甜味剂等或其它医药品。
本发明的骨质疏松症治疗剂及用于治疗骨质疏松症的医药组合物的给药方法根据各种制剂形态、患者的年龄、性别及其它条件、患者的症状的程度等来适当确定。例如,片剂、丸剂、散剂、颗粒剂、胶囊剂、液剂、悬浮剂及乳剂口服给药。注射剂单独或与葡萄糖、氨基酸等通常的补液混合而被投予至静脉内,另外,根据需要单独地被投予至动脉内、肌内、皮内、皮下或腹腔内。栓剂被投予至直肠内。
上述各给药单位形态中所应配合的本发明化合物或其盐的量根据应适用本发明化合物或其盐的患者的症状、或其剂形等而不同,通常期望为在每给药单位形态中,若为口服剂,则设为约0.005~1,000mg,若为注射剂,则设为约0.001~500mg,若为栓剂,则设为约0.01~1,000mg。另外,具有上述给药形态的药剂的每天的给药量根据患者的症状、体重、年龄、性别等而不同,无法一概而论,通常,设为成人每天约0.005~5,000mg、优选为0.01~1,000mg即可,优选为将其每天1次或分为2~4次左右给药。
以下,列举实施例、试验例对本发明进行更详细的说明,但本发明并不限定于这些。
[实施例]
制造例1
4-[2-氟-4-[[[(2-苯基乙酰基)氨基]硫代甲基]氨基]-苯氧基]-7-甲氧基-N-甲基-6-喹啉甲酰胺(化合物IA)的合成
依据国际公开第2009/125597号(上述专利文献1)的实施例6的记载,合成题述化合物IA(本发明化合物)。
试验例1对人类前列腺癌株PC-3的小鼠胫骨内移植模型的异形骨形成及骨吸收的抑制效果
将人类前列腺癌细胞株PC-3以2×106cells/15μL移植至小鼠胫骨内。在移植第二天以使各组中的小鼠的平均体重成为均等的方式进行分组,将化合物IA以200mg/kg/天连续10天进行口服给药。在自移植起第11天进行移植部位的μCT摄影,实施骨病变的评价。
如图1所示,确认在胫骨移植有人类前列腺癌株PC-3的小鼠中,在其移植部位的骨内部形成异形骨。本发明化合物明显地抑制该异形骨形成。
根据以上内容可知,本发明化合物未显示死亡或体重减少,而是通过抑制人类前列腺癌细胞在胫骨移植系统中的代谢性的骨破坏亢进与异常的弱骨的形成,维持骨量正常。
试验例2对人类肺癌株A549-luc-BM1的小鼠胫骨内移植模型的异形骨形成及骨吸收的抑制效果
将导入有萤光素酶基因的人类肺癌细胞株A549移植至裸鼠的左心室,由此建立骨选择性地转移并增生的肺癌细胞株A549-luc-BM1。将该细胞以2×106cells/15μL移植至小鼠胫骨内。在移植后第7天利用活体成像系统(in vivo imaging system)测定移植部位的萤光素酶活性,并以使各组的平均萤光素酶活性成为相等的方式进行分组,将化合物IA以200mg/kg/天连续28天进行口服给药。治疗对照组中使用作为第三代的双膦酸盐制剂的唑来膦酸,以0.2mg/kg/天每周2次进行皮下给药。关于骨病变的评价,在移植后第36天进行移植部位的μCT摄影。
在图2中表示胫骨移植有人类肺癌株A549-luc-BM1的小鼠中对其移植部位的骨病变的评价。在移植后第36天,对照组中,由于异常的骨破坏与异形骨形成,胫骨大幅变形。另一方面,本发明化合物显著地抑制骨破坏与异形骨形成,维持接近于正常骨(normal bone)的形态。另外,关于作为治疗对照药的唑来膦酸,虽抑制骨破坏,但确认有异形骨形成,产生骨的变形。
根据以上内容可知,本发明化合物的骨代谢(骨吸收与骨形成)异常的抑制效果优于唑来膦酸,作为骨质疏松症治疗剂有用。
试验例3对卵巢摘除小鼠(OVX小鼠)的骨质疏松症模型的骨量降低抑制效果
在麻醉下摘除小鼠的卵巢,并在当天以使小鼠的平均体重成为均等的方式进行分组。作为治疗阳性对照组,将雌二醇(E2)以3μg/kg/天连续4周每天给药。另外,将化合物IA以200mg/kg/天连续4周每天进行口服给药。在各药剂给药后摘除小鼠的大腿骨,利用骨密度测定装置(双能X射线吸收测量法,dual-energy X-ray absorptiometry,DEXA法)及μCT测定骨量并进行评价。将大腿骨的骨量(BMD)、大腿骨的μCT图像、及体重变化分别示于图3、4和5。
如图3、4所示,OVX小鼠与Sham(假处理)组相比,呈现大腿骨的骨量降低,雌二醇给药组相对于OVX小鼠显示出抑制骨量降低。由此可以确认,本模型系统可适当地进行卵巢摘除,建立骨质疏松症模型(CLINICAL CALCIUM,2011,21(2),p.164)。
本发明化合物给药组对OVX小鼠发挥显著的骨量恢复效果(图3、4)。除了总骨量(Total BMD)的恢复效果以外,在骨质疏松症中尤其被要求改善的远端部(Distal BMD),骨量也恢复(图4)。另一方面,未确认对体重的影响(图5)。
根据以上结果可知,本发明化合物作为安全性高的骨质疏松症治疗剂有用。
Claims (5)
3.如权利要求1所述的骨质疏松症治疗剂或如权利要求2所述的医药组合物,其特征在于:
式(I)所示的酰基硫脲化合物或其盐为4-[2-氟-4-[[[(2-苯基乙酰基)氨基]硫代甲基]氨基]-苯氧基]-7-甲氧基-N-甲基-6-喹啉甲酰胺单甲磺酸盐。
5.如权利要求4所述的骨质疏松症的治疗方法,其特征在于:
式(I)所示的酰基硫脲化合物或其盐为4-[2-氟-4-[[[(2-苯基乙酰基)氨基]硫代甲基]氨基]-苯氧基]-7-甲氧基-N-甲基-6-喹啉甲酰胺单甲磺酸盐。
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CN107614489B (zh) * | 2015-04-30 | 2021-05-11 | 大鹏药品工业株式会社 | 酰基硫脲化合物的甲磺酸盐及其晶体、以及它们的制造方法 |
CN112716952A (zh) | 2015-06-25 | 2021-04-30 | 大鹏药品工业株式会社 | 纤维化病治疗剂 |
KR102323255B1 (ko) | 2017-02-15 | 2021-11-08 | 다이호야쿠힌고교 가부시키가이샤 | 의약 조성물 |
EP3854395A4 (en) | 2018-09-18 | 2022-06-15 | Taiho Pharmaceutical Co., Ltd. | COMBINATION THERAPY OF AN ACYLTHIOREA COMPOUND AND ABIRATERON |
TW202140426A (zh) | 2020-02-14 | 2021-11-01 | 日商大鵬藥品工業股份有限公司 | 醯基硫脲化合物的製造方法 |
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EP3053581A4 (en) | 2017-04-12 |
JP6487845B2 (ja) | 2019-03-20 |
EP3053581B1 (en) | 2020-02-12 |
HK1223853A1 (zh) | 2017-08-11 |
EP3053581A1 (en) | 2016-08-10 |
JPWO2015046484A1 (ja) | 2017-03-09 |
US20150164879A1 (en) | 2015-06-18 |
CN105530939A (zh) | 2016-04-27 |
ES2774773T3 (es) | 2020-07-22 |
WO2015046484A1 (ja) | 2015-04-02 |
TW201529070A (zh) | 2015-08-01 |
US9149471B2 (en) | 2015-10-06 |
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