CN102149380B - 包含苄脒衍生物或其盐和阿仑膦酸或其盐、用于预防或治疗骨质疏松症的药物组合物 - Google Patents
包含苄脒衍生物或其盐和阿仑膦酸或其盐、用于预防或治疗骨质疏松症的药物组合物 Download PDFInfo
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- CN102149380B CN102149380B CN2009801335635A CN200980133563A CN102149380B CN 102149380 B CN102149380 B CN 102149380B CN 2009801335635 A CN2009801335635 A CN 2009801335635A CN 200980133563 A CN200980133563 A CN 200980133563A CN 102149380 B CN102149380 B CN 102149380B
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- benzamidine
- isopropyl
- amoxy
- thiazole
- salt
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Abstract
本发明涉及用于预防和治疗骨质疏松症的药物组合物,其包含N-羟基-4-{5-[4-(5-异丙基-2-甲基-1,3-噻唑-4-基)苯氧基]戊氧基}苄脒、4-{5-[4-(5-异丙基-2-甲基-1,3-噻唑-4-基)苯氧基]戊氧基}苄脒或其盐和阿仑膦酸或其盐。作为预防或治疗骨质疏松症的组合物,N-羟基-4-{5-[4-(5-异丙基-2-甲基-1,3-噻唑-4-基)苯氧基]戊氧基}苄脒、4-{5-[4-(5-异丙基-2-甲基-1,3-噻唑-4-基)苯氧基]戊氧基}-苄脒或其盐与阿仑膦酸或其盐的联合治疗与各单独治疗相比,呈现良好的对破骨细胞分化的抑制效应,从而可用于骨质疏松症的预防或治疗。
Description
[技术领域]
本发明涉及用于预防或治疗骨质疏松症的药物组合物,其包含N-羟基-4-{5-[4-(5-异丙基-2-甲基-1,3-噻唑-4-基)苯氧基]戊氧基}苄脒、4-{5-[4-(5-异丙基-2-甲基-1,3-噻唑-4-基)苯氧基]戊氧基}苄脒或其盐和阿仑膦酸或其盐。
[背景技术]
骨是身体骨架的支撑物,并用于保存必要的骨量和结构。骨也起钙(Ca2+)或类似物的贮器作用,并在维持血液钙水平中起重要作用。骨处于动态稳定状态,是通过连续进行骨吸收和骨形成维持精细平衡的“骨再塑”。骨再塑是包括由成骨细胞引起的骨形成以及由破骨细胞引起的骨吸收和降解的复杂过程,并且维持生理和代谢平衡。但是,骨吸收和骨形成之间的平衡被多种因素和疾病破坏,导致骨质疏松症。
骨质疏松症是骨疾病,其由骨吸收和骨形成之间平衡的扰动造成,由具有相对于骨形成较高程度的骨吸收引起。该疾病频繁发生于中年或老年女性。骨质疏松症降低骨组织的钙化,并降低骨中紧密物质的水平,其拓宽了骨髓腔,并引起骨密度或骨量减少,造成骨强度降低。因此,随骨质疏松症进展,骨变脆,并且骨折可甚至在轻微的碰撞下容易发生。
骨折与患有骨质疏松症患者的升高的死亡率相关,而且也引起严重的问题,如对患者生活质量的负面影响。因此,已建立多种策略以制备能提高骨密度和降低骨折风险的药物。
迄今为止,二膦酸盐(bisphosphonate)(阿仑膦酸盐(alendronate)、1-羟基-亚乙基-1,1-二膦酸盐(依替膦酸盐,etidronate))、激素(雷洛昔芬(raloxifen))、维生素D、降钙素、钙制剂或类似物已被用作抗骨质疏松剂,以及ForteoTM——引起骨形成的甲状旁腺激素的一种形式,目前被用于治疗晚期骨质疏松症。但是,已知这些物质具有副作用。特别是,必须贯穿患者整个生命给予激素制剂,在长期给药的情况下,可引起副作用,如乳腺癌、子宫癌、胆结石和血栓症。维生素D制剂价格昂贵,并且显示极低的效力,降钙素制剂也非常昂贵,并且难以给予。钙制剂具有极小的副作用,但其效果被限于骨质疏松症的预防,而非其治疗本身。ForteoTM——商用的甲状旁腺激素,具有其刺激骨形成的优势,但已知的药物被限于骨吸收的预防。然而,ForteoTM应当长时期以每日注射给予,并且可能增加骨肉瘤的风险。其应用也由于高昂的成本而受限。
下式表示的二膦酸盐药物、阿仑膦酸盐已广泛用于骨质疏松症的治疗,并显示出作为骨吸收的抑制剂,增加骨密度和预防骨折。由于口服给药和低成本的优势,其已被广泛用于钙代谢疾病——包括骨质疏松症——的临床领域。
但是,二膦酸盐药剂表现低吸收性,并可引起食管炎,从而应当在饭前随足够量水进服。此外,患者应当在摄取其他饮品或食品前等待至少30分钟,并且避免在给药后平躺一定的时间。其也被报道为增加低血钙症的风险。近期的研究已提出问题,如由于骨吸收的过度抑制、骨形成的抑制、胃肠疾病和颌骨坏死引起的骨转换率降低。此外,最近报道其长期给予增加骨折的风险(Andrew S Neviaser等,Journal ofOthopaedic Trauma,2008,22(5),346~350)。
如上所述,当前的骨质疏松症治疗剂不是对骨吸收和骨形成均起作用的治疗剂。因此,为了治疗骨质疏松症,需要开发这样的药物和治疗:造成骨量均衡地增加和骨质量提高,从而降低骨折的风险。
为了克服上述缺陷和提高临床效力,已做出大量研究,近期的研究提出骨吸收抑制剂和促进骨形成的商用甲状旁腺激素的联合治疗。其详细描述如下。
通过阿仑膦酸盐和雌激素(文献-Lindsay等,J.Clin.Endocrinol.Metab.84,3073-3081(1999))、阿仑膦酸盐和雷洛昔芬(文献-Johnell等,J.Clin.Endocrinol.Metab.87,985-992(2002))、阿仑膦酸盐和HRT(激素取代疗法)(文献-Greenspan等,dAMA,289,2525-2533(2003))以及阿仑膦酸盐和钙三醇(WO 01/28564)示例了阿仑膦酸盐和其他骨吸收抑制剂的联合治疗。这些研究证明联合治疗相对其单独的给予显示出骨密度的增加,但没有降低骨折的风险。此外,即使其机制之间有所不同,包括由于对骨吸收的抑制效应和骨形成的抑制引起的骨转换率降低的问题仍然存在。因此,需要有关治疗的考虑和进一步研究。
在这方面,有与骨形成刺激剂联合治疗的试验,该联合治疗意图降低对骨形成的抑制效应和阿仑膦酸盐的副作用。通过两篇文献示例阿仑膦酸盐与甲状旁腺激素的联合治疗:甲状旁腺激素和阿仑膦酸盐在绝经后骨质疏松症中的联合效果(文献-Black等,N.Eng.J.Med.349,1207-1215,(2003))和在男性老年人骨质疏松症中的联合效果(文献-Finkelstein等,N.Eng.J.Med.349,1216-1226,(2003))。但是,这些文献没有证明相比起其单独给予的骨密度的增加。在这方面,一些研究者提出这样的可能性:强骨吸收抑制剂——阿仑膦酸盐抵消了甲状旁腺激素的刺激效应。随后,试验了两种药物的相继给予,但仍需要进一步的研究,以得到有意义的临床结果。
另一方面,本发明人已确定苄脒衍生物——N-羟基-4-{5-[4-(5-异丙基-2-甲基-1,3-噻唑-4-基)苯氧基]戊氧基}苄脒和4-{5-[4-(5-异丙基-2-甲基-1,3-噻唑-4-基)苯氧基]戊氧基}苄脒或其盐作为预防和治疗骨质疏松症的药剂非常有用,这被公开于韩国专利号454767中。
[式1]
[式2]
因此,本发明人已研究了:联合常规的骨吸收抑药剂——如二膦酸盐(阿仑膦酸盐)、激素(雷洛昔芬)、维生素D、降钙素和钙剂——以及骨形成刺激剂给予可用于预防和治疗骨质疏松症的式1和2成分,并已建立了新型的治疗以提供其益处,而没有其潜在的缺陷。
由此,本发明人已确定:将能用作单一制剂的N-羟基-4-{5-[4-(5-异丙基-2-甲基-1,3-噻唑-4-基)苯氧基]戊氧基}苄脒、4-{5-[4-(5-异丙基-2-甲基-1,3-噻唑-4-基)苯氧基]戊氧基}苄脒或其盐和阿仑膦酸或其盐联合给予,以提供良好的用于预防或治疗骨质疏松症的药物组合物,从而完成本发明。
[发明内容]
[技术问题]
本发明的目标是提供用于预防或治疗骨质疏松症的药物组合物,其包含N-羟基-4-{5-[4-(5-异丙基-2-甲基-1,3-噻唑-4-基)苯氧基]戊氧基}苄脒、4-{5-[4-(5-异丙基-2-甲基-1,3-噻唑-4-基)苯氧基]戊氧基}苄脒或其盐和阿仑膦酸或其盐,和应用该组合物预防或治疗骨质疏松症的方法。
[问题的解决方案]
根据一方面,本发明涉及预防或治疗骨质疏松症的组合物,其包含以同时、分开或相继用作活性成分为目标的以下化合物(a)和(b)。
(a)选自下列的化合物:由下式1表示的N-羟基-4-{5-[4-(5-异丙基-2-甲基-1,3-噻唑-4-基)苯氧基]戊氧基}苄脒、由下式2表示的4-{5-[4-(5-异丙基-2-甲基-1,3-噻唑-4-基)苯氧基]戊氧基}苄脒、及其盐;和
(b)由下式3表示的阿仑膦酸或其盐,
[式1]
[式2]
[式3]
本文所用的术语“骨质疏松症”意为这样的症状:即使残余骨的结构中没有任何缺陷,形成骨的矿物质和基质异常地大量减少,从而在骨中生成大量孔,使其像海绵,并且更有可能骨折。其可被称为“骨量减少”。
可根据已知的方法(Lee,Sung-Eun,Synthesis and Biological Activityof Natural Products and Designed New Hybrid Compounds for theTreatment of LTB4 Related Disease,Busan National University,a thesis fora Ph.D degree,1999.8)制备本发明中所用的N-羟基-4-{5-[4-(5-异丙基-2-甲基-1,3-噻唑-4-基)苯氧基]戊氧基}苄脒或4-{5-[4-(5-异丙基-2-甲基-1,3-噻唑-4-基)苯氧基]戊氧基}苄脒,但并不限于此。
另一方面,可以无限制地以本领域已知的药学可接受的盐的形式应用N-羟基-4-{5-[4-(5-异丙基-2-甲基-1,3-噻唑-4-基)苯氧基]戊氧基}苄脒或4-{5-[4-(5-异丙基-2-甲基-1,3-噻唑-4-基)苯氧基]戊氧基}苄脒,优选由本领域熟知的方法制备的酸加成盐。作为药学可接受的盐,可应用无机酸或有机酸。无机酸的实例可包括:盐酸、溴酸、硫酸和磷酸,有机酸的实例可包括柠檬酸、醋酸、乳酸、酒石酸、富马酸、蚁酸、丙酸、草酸、三氟乙酸、甲磺酸、马来酸、苯甲酸、葡糖酸、乙醇酸、琥珀酸、4-甲苯磺酸、半乳糖醛酸、扑酸、谷氨酸和天冬氨酸。优选地,可将盐酸用作无机酸,甲磺酸用作有机酸。
N-羟基-4-{5-[4-(5-异丙基-2-甲基-1,3-噻唑-4-基)苯氧基]戊氧基}苄脒、4-{5-[4-(5-异丙基-2-甲基-1,3-噻唑-4-基)苯氧基]戊氧基}苄脒或其盐的剂量是预防或治疗骨质疏松症的有效量,取决于患者的年龄和体重、联合治疗的类型、治疗频率、所需效力的类型或给予方法而确定。在用作治疗或预防剂的情况下,可以通过多种途径以治疗骨质疏松症的有效量给予化合物,并且本领域技术人员考虑给药的目的、途径和对象的健康状况和体重可容易地确定其制剂、剂量或类似物。具体地,可以以约1至500mg的量,优选5至200mg的量给予N-羟基-4-{5-[4-(5-异丙基-2-甲基-1,3-噻唑-4-基)苯氧基]戊氧基}苄脒、4-{5-[4-(5-异丙基-2-甲基-1,3-噻唑-4-基)苯氧基]戊氧基}苄脒或其盐。
此外,可根据已知的方法制备本发明所用的阿仑膦酸,并且可无限制地应用其盐或药学可接受的盐,优选其钠盐。阿仑膦酸或其盐的剂量是预防或治疗骨质疏松症的有效量,并且取决于患者的年龄和体重、联合治疗的类型、治疗频率、所需效力的类型或给予方法而确定。在用作治疗或预防制剂的情况下,可以以一般的剂量给予化合物。具体地,可以以5至40mg的每日剂量给予阿仑膦酸或其盐。
在本发明中,可以以其任意组合应用N-羟基-4-{5-[4-(5-异丙基-2-甲基-1,3-噻唑-4-基)苯氧基]戊氧基}苄脒、4-{5-[4-(5-异丙基-2-甲基-1,3-噻唑-4-基)苯氧基]戊氧基}苄脒或其盐和阿仑膦酸或其盐。
在本发明中,可通过混合在一起同时给予N-羟基-4-{5-[4-(5-异丙基-2-甲基-1,3-噻唑-4-基)苯氧基]戊氧基}苄脒、4-{5-[4-(5-异丙基-2-甲基-1,3-噻唑-4-基)苯氧基]戊氧基}苄脒或其盐和阿仑膦酸或其盐,或者可同时或相继分开给予其中每一个,或者可在不同的时间分开给予其中每一个。在分开给予的情况下,可交替给予两种活性成分,或者一种活性成分可在其他活性成分的给予完成后给予。
在本发明中,只要药物包含N-羟基-4-{5-[4-(5-异丙基-2-甲基-1,3-噻唑-4-基)苯氧基]戊氧基}苄脒、4-{5-[4-(5-异丙基-2-甲基-1,3-噻唑-4-基)苯氧基]戊氧基}苄脒或其盐和阿仑膦酸或其盐作为活性成分,其可被制成任何药学剂量形式,例如,包含两种活性成分的联合制剂或各个单一制剂。如本文所用,联合制剂意为两种或多种活性成分被混合在一个制剂中,单一制剂意为一种活性成分被包含在一个制剂中。在这方面,可根据其药理和药代动力学性质将各活性成分制成不同的制剂(例如,速释或缓释形式),然后可彼此组合。此外,可将联合制剂制成多层片剂或包衣片剂,这里各个不同的活性成分被包含在各个层或包衣和核中。在本发明中,如果将两种活性成分制成单一制剂,本发明所述的治疗和预防剂指以其组合应用单一制剂的药物或方法。因此,可将含有活性成分的各个药物制成各个不同的制剂。如果将两种活性成分制成单一制剂,可在一个试剂盒提供两种制剂。
可每日或间歇地给予,和一天1次或2~3次地给予本发明所述的预防或治疗骨质疏松症的药剂。如果各活性成分是单一制剂,则其给药频率可彼此相同或不同。
可通过已知的方法单独制备或连同药学上可接受的载体或赋形剂制备本发明所述的N-羟基-4-{5-[4-(5-异丙基-2-甲基-1,3-噻唑-4-基)苯氧基]戊氧基}苄脒或其盐和阿仑膦酸或其盐。制剂的具体实例包括口服剂型——如软胶囊、硬胶囊、片剂和糖浆,以及可注射和局部的剂型。
药学可接受的载体包括用于已知制剂的制备的任何标准药物载体,已知制剂如无菌液体、片剂、包衣片剂和胶囊。一般,这样的载体包括赋形剂如聚乙烯吡咯烷酮、糊精、淀粉、乳液、糖、某些类型的粘土、明胶、硬脂酸、滑石、植物油(例如,食用油、棉花籽油、椰子油、杏仁油、花生油)、液体酯类——如甘油三酯、矿物油、vassline、动物油、纤维素衍生物(例如,晶状纤维素、羟丙基纤维素、羟丙基甲基纤维素、甲基纤维素)和其他已知赋形剂。这样的载体也可包括抗氧化剂、润湿剂、粘度稳定剂、调味剂、着色添加剂和其他添加剂。可通过已知的方法制备含有这些载体的组合物。
本发明所述的预防和治疗骨质疏松症的药剂意为彼此具有不同机制、包含N-羟基-4-{5-[4-(5-异丙基-2-甲基-1,3-噻唑-4-基)苯氧基]戊氧基}-苄脒、4-{5-[4-(5-异丙基-2-甲基-1,3-噻唑-4-基)苯氧基]戊氧基}-苄脒或其盐和阿仑膦酸或其盐的两种类型活性成分被联合应用,并相对于其他单一药物提供良好的提高骨密度和强度的效果。
根据另一方面,本发明涉及预防或治疗骨质疏松症的方法,包括给予N-羟基-4-{5-[4-(5-异丙基-2-甲基-1,3-噻唑-4-基)苯氧基]戊氧基}-苄脒、4-{5-[4-(5-异丙基-2-甲基-1,3-噻唑-4-基)苯氧基]戊氧基}-苄脒或其盐和阿仑膦酸或其盐的步骤。
如上所述,化合物的剂量取决于多种因素变化,并且给药途径也取决于多种因素变化,该因素包括患者的年龄、体重、给药周期、疾病严重程度、感觉水平、联合药物的类型。可通过多种途径给予化合物,如口服和肠胃外途径,并且可分别同时或相继或分别在不同的时间给予各化合物。
[附图简述]
图1是显示0.1μM N-羟基-4-{5-[4-(5-异丙基-2-甲基-1,3-噻唑-4-基)苯氧基]戊氧基}苄脒二甲磺酸盐(dimethanesulfonate)和0.2μM阿仑膦酸的单独或联合治疗对破骨细胞分化的效果的图表,其中通过骨髓细胞和成骨细胞的共培养诱导破骨细胞分化,用各个样本物质单独或同时处理细胞,并培养7天,然后进行TRAP染色,以计算具有6个或多个核的成熟破骨细胞,其被表示为相对于对照组的百分数。
图2是显示0.3μM N-羟基-4-{5-[4-(5-异丙基-2-甲基-1,3-噻唑-4-基)苯氧基]戊氧基}苄脒二甲磺酸盐和0.2μM阿仑膦酸的单独或联合治疗对破骨细胞分化的效果的图表,其中通过骨髓细胞和成骨细胞的共培养诱导破骨细胞分化,用各个样本物质单独或同时处理细胞,并培养7天,然后进行TRAP染色,以计算具有6个或多个核的成熟破骨细胞,其被表示为相对于对照组的百分数。
图3是显示0.5μM N-羟基-4-{5-[4-(5-异丙基-2-甲基-1,3-噻唑-4-基)苯氧基]戊氧基}苄脒二甲磺酸盐和0.2μM阿仑膦酸的单独或联合治疗对破骨细胞分化的效果的图表,其中通过骨髓细胞和成骨细胞的共培养诱导破骨细胞分化,用各个样本物质单独或同时处理细胞,并培养7天,然后进行TRAP染色,以计算具有6个或多个核的成熟破骨细胞,其被表示为相对于对照组的百分数。
[本发明的最佳实施方式]
在下文中,将参考实施例更加详细地说明本发明。但是,这些实施例仅以示例为目的,并非意图由这些实施例限制本发明。
为了评价对骨质疏松症的治疗效果,以其组合给予本发明所述的N-羟基-4-{5-[4-(5-异丙基-2-甲基-1,3-噻唑-4-基)苯氧基]戊氧基}苄脒或其盐和阿仑膦酸或其盐,或以单一制剂应用其中每一个。
通过骨髓细胞和carvarial细胞之间的共培养体系诱导破骨细胞分化,并且通过单独或联合制剂的治疗评价药物对破骨细胞分化的抑制效应。
实施例1:骨髓细胞和成骨细胞的制备
从6~8周大的雄性ddY小鼠无菌地切除股骨和胫骨,根据一般的方法利用注射器得到骨髓细胞。将细胞从骨髓细胞去除,然后离心。将骨髓细胞悬浮在用10%FBS补充的α-MEM基质中后,计算所获得的骨髓细胞中真核细胞的数量,然后立即用于共培养体系。
从1~2天大的新生ICR小鼠无菌地分离鼠颅盖,通过0.2%胶原酶的酶溶液的相继处理分离carvarial细胞(颅盖细胞)——初级成骨细胞。将分离的carvarial细胞离心,用含10%FBS的α-MEM再次悬浮,并培养至汇合。然后,将这些细胞稀释至所需的细胞数量,并用于实验。
实施例2:通过共培养体系测定破骨细胞分化
利用补充10%FBS的α-MEM培养基将上述制备的骨髓细胞(1×105个细胞/孔)和成骨细胞(3,000个细胞/孔)接种于96孔板。此时,将分化因子——1α,25-二羟基维生素D3(10-8M,下文中被称为维生素D3)和地塞米松(10-8M)共同加入破骨细胞培养基。每2至3天用含有分化因子的新鲜培养基替换培养基。
7天后,当观察到多核破骨细胞时,从孔去除培养基,然后用含10%福尔马林的PBS固定细胞。通过计算抗酒石酸酸性磷酸酶阳性的多核破骨细胞(在此下文中被称为TRAP(+)MNCs)确定破骨细胞形成的指数。TRAP染色液含有萘酚AS-MX磷酸盐(pH 5.0)作底物、Fast Red紫色LB(Fast Red violet LB)作着色剂以及50mM酒石酸,并于冷藏器中保存直至使用。在显微镜下对含有多于6-7个或更多个核的TRAP(+)MNCs的数量进行计数。
实施例3:测试物对破骨细胞分化的效果
A.样本的制备
可根据已知的方法(Lee,Sung-Eun,Synthesis and BiologicalActivity of Natural Products and Designed New Hybrid Compounds for theTreatment of LTB4Related Disease,Busan National University,a thesisfor a Ph.D degree,1999.8)制备本发明所述的N-羟基-4-{5-[4-(5-异丙基-2-甲基-1,3-噻唑-4-基)苯氧基]戊氧基}-苄脒和4-{5-[4-(5-异丙基-2-甲基-1,3-噻唑-4-基)苯氧基]戊氧基}-苄脒,并且同样可根据已知的方法(美国专利号4,407.761、4,621,077、4,705,651、5,039,819和5,159,108)制备阿仑膦酸钠。
进行N-羟基-4-{5-[4-(5-异丙基-2-甲基-1,3-噻唑-4-基)苯氧基]戊氧基}苄脒二甲磺酸盐或阿仑膦酸钠的单独治疗以及N-羟基-4-{5-[4-(5-异丙基-2-甲基-1,3-噻唑-4-基)苯氧基]戊氧基}苄脒二甲磺酸盐与阿仑膦酸钠的联合治疗,从而通过上述实验评价其对破骨细胞分化的效果。全部实验均利用含有维生素D3和地塞米松的破骨细胞培养基进行。
将N-羟基-4-{5-[4-(5-异丙基-2-甲基-1,3-噻唑-4-基)苯氧基]戊氧基}苄脒二甲磺酸盐以浓度0.1mM、0.3mM和0.5mM溶于DMSO,然后用破骨细胞培养基稀释1,000倍至最终浓度0.1μM、0.3μM和0.5μM。将阿仑膦酸钠水合物以浓度0.2mM溶于纯水,然后用破骨细胞培养基稀释1,000倍至最终浓度0.2μM。在这方面,将对照组保持在0.1%DMSO中。通过单独或联合治疗进行各实验,如下。
实验实施例1:0.1μM N-羟基-4-{5-[4-(5-异丙基-2-甲基-1,3-噻唑
-4-基)苯氧基]戊氧基}苄脒二甲磺酸盐与0.2μM阿仑膦酸钠的单独或
联合治疗对破骨细胞分化的效果
A.对照(0.1%DMSO溶剂)
B.N-羟基-4-{5-[4-(5-异丙基-2-甲基-1,3-噻唑-4-基)苯氧基]戊氧基}苄脒二甲磺酸盐(0.1μM)的单独治疗
C.阿仑膦酸钠(0.2μM)的单独治疗
D.N-羟基-4-{5-[4-(5-异丙基-2-甲基-1,3-噻唑-4-基)苯氧基]戊氧基}苄脒二甲磺酸盐(0.1μM)与阿仑膦酸钠(0.2μM)的联合治疗
将如上述共培养体系制备的细胞接种于各孔,并在样本物质或载体的存在下培养。在培养的第3天和第5天,用含样本物质的新鲜分化培养基替换培养基。在培养的第7天,将细胞固定,并TRAP染色。在显微镜下计数具有6个或更多个核的TRAP(+)MNCs的数量。结果被表示为在各实验组中观察到的成熟破骨细胞的相对数量的百分数,此时对照组(仅溶剂)的成熟破骨细胞的数量被视为100%。以每实验组4个孔(n=4)进行实验,并将结果表示为平均值±标准偏差。此外,重复实验至少两次,并且将Student t测验应用于实验组间的显著差异。结果显示在表1中。
结果,N-羟基-4-{5-[4-(5-异丙基-2-甲基-1,3-噻唑-4-基)苯氧基]戊氧基}苄脒二甲磺酸盐(0.1μM)的单独治疗呈现TRAP(+)MNCs的相对数量相对于对照组(仅溶剂)显著减少。阿仑膦酸钠(0.2μM)的单独治疗也明显抑制破骨细胞的分化,相对数量80.6%。当以上述浓度同时进行N-羟基-4-{5-[4-(5-异丙基-2-甲基-1,3-噻唑-4-基)苯氧基]戊氧基}苄脒二甲磺酸盐与阿仑膦酸钠的联合治疗时,多核破骨细胞的相对数量显著减少至36.4%,其远低于各单独治疗的总和,显示出对破骨细胞分化的强抑制效应。总之,结果证明N-羟基-4-{5-[4-(5-异丙基-2-甲基-1,3-噻唑-4-基)苯氧基]戊氧基}苄脒二甲磺酸盐与阿仑膦酸钠的联合治疗显示出比由各单独治疗的总和所预期地大大增强的效力。
实验实施例2:0.3μM N-羟基-4-{5-[4-(5-异丙基-2-甲基-1,3-噻唑
-4-基)苯氧基]戊氧基}苄脒二甲磺酸盐与0.2μM阿仑膦酸钠的单独或
联合治疗对破骨细胞分化的效果
A.对照(0.1%DMSO溶剂)
B.N-羟基-4-{5-[4-(5-异丙基-2-甲基-1,3-噻唑-4-基)苯氧基]戊氧基}苄脒二甲磺酸盐(0.3μM)的单独治疗
C.阿仑膦酸钠(0.2μM)的单独治疗
D.N-羟基-4-{5-[4-(5-异丙基-2-甲基-1,3-噻唑-4-基)苯氧基]戊氧基}苄脒二甲磺酸盐(0.3μM)与阿仑膦酸钠(0.2μM)的联合治疗
以与实施例1相同的方式进行实验。
结果,如图2所示,在N-羟基-4-{5-[4-(5-异丙基-2-甲基-1,3-噻唑-4-基)苯氧基]戊氧基}苄脒二甲磺酸盐(0.3μM)的单独治疗中,发现破骨细胞的相对数量(52.4%)低于上述实验组(0.1μM)的破骨细胞的相对数量,表明对破骨细胞分化的抑制效应增强。如实施例1所示,阿仑膦酸钠的单独治疗显著减少破骨细胞的相对数量。当同时进行两种样本物质的联合治疗时,观察到破骨细胞的相对数量低至20.1。这些结果证明两种物质的联合治疗显示出比由各单独治疗的总和所预期地大大增强的效力。
实验实施例3:0.5μM N-羟基-4-{5-[4-(5-异丙基-2-甲基-1,3-噻唑
-4-基)苯氧基]戊氧基}苄脒二甲磺酸盐与0.2μM阿仑膦酸钠的单独或
联合治疗对破骨细胞分化的效果
A.对照(0.1%DMSO溶剂)
B.N-羟基-4-{5-[4-(5-异丙基-2-甲基-1,3-噻唑-4-基)苯氧基]戊氧基}苄脒二甲磺酸盐(0.5μM)的单独治疗
C.阿仑膦酸钠(0.2μM)的单独治疗
D.N-羟基-4-{5-[4-(5-异丙基-2-甲基-1,3-噻唑-4-基)苯氧基]戊氧基}苄脒二甲磺酸盐(0.5μM)与阿仑膦酸钠(0.2μM)的联合治疗
以与实施例1相同的方式进行实验。
如预期地,N-羟基-4-{5-[4-(5-异丙基-2-甲基-1,3-噻唑-4-基)苯氧基]戊氧基}苄脒二甲磺酸盐(0.5μM)的单独治疗呈现对破骨细胞分化的强抑制效应,其中发现破骨细胞的相对数量为34.5%。当进行与0.2μM阿仑膦酸钠的联合治疗时,观察到细胞的相对数量低至9.7%,其远低于对照组的细胞相对数量。这些结果证明N-羟基-4-{5-[4-(5-异丙基-2-甲基-1,3-噻唑-4-基)苯氧基]戊氧基}苄脒二甲磺酸盐与阿仑膦酸钠的联合治疗显示出对破骨细胞分化比由各单独治疗的总和预所期地大大增强的效力。
[工业应用]
当同时进行N-羟基-4-{5-[4-(5-异丙基-2-甲基-1,3-噻唑-4-基)苯氧基]戊氧基}苄脒二甲磺酸盐与阿仑膦酸钠的联合治疗时,观察到比各单独治疗的总效应大大增强的对破骨细胞分化的抑制效应。因此,N-羟基-4-{5-[4-(5-异丙基-2-甲基-1,3-噻唑-4-基)苯氧基]戊氧基}苄脒、4-{5-[4-(5-异丙基-2-甲基-1,3-噻唑-4-基)苯氧基]戊氧基}苄脒或其盐和阿仑膦酸或其盐的联合治疗与各单独治疗相比,显示出对骨吸收的良好的抑制效应,从而提供良好的治疗和预防骨质疏松症的效果。
Claims (6)
2.根据权利要求1所述的药物组合物,其中所述N-羟基-4-{5-[4-(5-异丙基-2-甲基-1,3-噻唑-4-基)苯氧基]戊氧基}苄脒或4-{5-[4-(5-异丙基-2-甲基-1,3-噻唑-4-基)苯氧基]戊氧基}-苄脒的盐是氢氯化物或甲磺酸盐。
3.根据权利要求1所述的药物组合物,其中所述阿仑膦酸的盐是其钠盐。
4.根据权利要求1所述的药物组合物,其中以包含(a)和(b)的联合制剂的形式制备所述预防或治疗骨质疏松症的组合物。
5.根据权利要求1所述的药物组合物,其中以包含(a)和(b)其中各一种的单一制剂的形式制备所述预防或治疗骨质疏松症的组合物。
6.根据权利要求1所述的药物组合物,其中在一个试剂盒里提供包含(a)和(b)其中各一种的两种单一制剂。
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PCT/KR2009/004277 WO2010013969A2 (en) | 2008-08-01 | 2009-07-31 | A pharmaceutical composition for preventing or treating osteoporosis comprising benzamidine derivatives or their salts, and alendronic acid or its salt |
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CN1144806A (zh) * | 1996-07-25 | 1997-03-12 | 南京药物研究所 | 氨基二膦酸类骨吸收抑制剂及其钠盐的制备方法 |
CN1533275A (zh) * | 2001-07-19 | 2004-09-29 | ����ҩƷ��ҵ��ʽ���� | 4-[(4-噻唑基)苯氧基]烷氧基-苄脒衍生物用于治疗骨质疏松症的应用 |
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US5998390A (en) * | 1998-09-28 | 1999-12-07 | The Research Foundation Of State University Of New York | Combination of bisphosphonate and tetracycline |
KR100317935B1 (ko) * | 1999-10-20 | 2001-12-22 | 유승필 | 대사성 골질환 치료용 약제조성물 및 이의 제조방법 |
JP2003292453A (ja) * | 2002-04-02 | 2003-10-15 | Asahi Kasei Corp | 骨疾患治療用医薬複合剤 |
JPWO2005002590A1 (ja) * | 2003-07-01 | 2006-08-10 | アステラス製薬株式会社 | 骨量増加誘導剤 |
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CA2564564A1 (en) * | 2004-04-28 | 2005-11-10 | Merck & Co., Inc. | Fluorinated 4-azasteroids as androgen receptor modulators |
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CN1533275A (zh) * | 2001-07-19 | 2004-09-29 | ����ҩƷ��ҵ��ʽ���� | 4-[(4-噻唑基)苯氧基]烷氧基-苄脒衍生物用于治疗骨质疏松症的应用 |
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