CN101242835A - Src激酶抑制剂对溶骨性病变的抑制 - Google Patents
Src激酶抑制剂对溶骨性病变的抑制 Download PDFInfo
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Abstract
本发明总地包括治疗骨再吸收疾病或与病理情况有关的骨再吸收的方法和组合物,其中所述疾病或情况包括但不限于,骨质疏松症、关节炎、类风湿性关节炎、癌向骨的转移、骨癌、高钙血症、具有矫形外科植入物的溶骨性病变、佩吉特病、和与甲状旁腺功能亢进有关的骨丢失。代表性的癌症包括但不限于,乳腺癌、前列腺癌、结肠癌、子宫内膜癌、多发性骨髓瘤、肾细胞癌、头和颈癌及宫颈癌。关节炎性病症包括但不限于,佐剂-、胶原-、细菌-和抗原-诱发的关节炎,特别是类风湿性关节炎。
Description
本申请要求2005年6月17日提交的美国临时专利申请序列号60/691,933的优先权,通过参考将其以整体引入本文。
发明背景
I.发明领域
本发明总地涉及细胞生物学、细胞生理学、医学和肿瘤学领域。更特别地,它涉及在有此需要的患者中调节破骨细胞发生,特别是与癌症诱导的骨组织破坏有关的破骨细胞发生的方法。
II.相关技术的描述
乳腺癌是美国最常见的女性恶性肿瘤,是导致妇女癌症死亡的第二大原因。患乳腺癌的妇女有骨转移的危险。5到10%的乳腺癌患者在初期即存在向骨转移的疾病。患由转移性乳腺癌导致的溶骨性骨病的患者发生病理性骨折、骨痛、脊髓压迫和高钙血症的危险增加。当前治疗骨转移的护理标准是二碳磷酸盐治疗,它延迟了骨骼事件,但不能完全阻止它们。此外,不是所有的患者都会对该治疗有应答。在需要更有效的治疗的同时,也需要对该疾病进行进一步的生物学和分子水平的剖析。NF-κB的受体激活剂(RANK)及NF-κB配体的受体激活剂(RANKL,也称作TRANCE/ODF/OPGL)是破骨细胞发生的重要介质,与多种疾病有关,包括类风湿性关节炎、骨质疏松症、骨巨细胞瘤、佩吉特病、转移性乳腺和前列腺癌、多发性骨髓瘤和家族性膨胀性骨质溶解(familial expansile osteolysis)。护骨蛋白(OPG,也称作OCIF/TR1)是一种可溶的、诱杀型受体,可以抑制RANKL结合到它的细胞表面受体RANK上。
RANKL、RANK和OPG的敲除型小鼠模型表明了这些分子在破骨细胞发生(即,骨再建)中具有重要作用。这些分子的生物学重要性通过靶向破坏OPG诱导严重的骨质疏松症,通过靶向破坏RANKL或OPG的过度表达诱导骨硬化症得以理解。因此,破骨细胞的形成可以归于骨髓微环境中RANKL和OPG的相对比例,该平衡的改变可能是很多代谢性骨疾病中骨丢失的主要原因。与RANKL-/-小鼠类似,RANK的靶向破坏也导致了骨硬化症表型。RANK-/-和RANKL-/-小鼠都显示了缺乏破骨细胞,表明这些分子是破骨细胞发生的必要条件。此外,RANK和RANKL是淋巴结器官发生及早期B和T细胞发育所需要的。此外,缺乏TRAF6、c-Src、c-Fos或NF-κB亚基p50/p52的小鼠也显示了骨硬化症表型;尽管这些突变小鼠具有破骨细胞,但这些细胞显然在骨再吸收中有缺陷。因此,RANKL和RANK以及它们的细胞质信号传递分子是调节正常的骨内稳态的统治性因子。
RANK/RANKL/OPG在骨再建中的重要性和大多数癌诱导的骨组织破坏是由于破骨活性增强之间的关系,提示RANK/RANKL/OPG在骨疾病和癌症中具有重要作用。除了RANK/RANKL/OPG与骨质疏松症有关外,近来的报道提示这些分子在其它疾病包括类风湿性关节炎、骨巨细胞瘤、佩吉特病和家族性膨胀性骨质溶解(由于RANK的外显子1中的突变)中的潜在作用。转移性乳腺和前列腺癌具有作为骨中的转移灶侵入和生长的能力,导致了溶骨性病变。在其中肿瘤导致增加的破骨细胞发生和骨组织破坏的转移性肿瘤小鼠模型中,全身施用OPG减轻了肿瘤介导的骨组织破坏和与骨癌有关的疼痛。因此,靶向于RANK信号转导机制可能可以用作一种治疗策略来抑制不希望的与癌症和代谢性骨疾病有关的骨组织破坏。需要另外的策略来防止与转移性癌症有关的不希望的骨组织破坏或者伴随骨丢失或与骨丢失有关的病症。
发明简述
根据本发明,提供结构式I,II,III,或IV的化合物:
式I
其中n是1-3的整数;X是N,CH,条件是当X是N时,n是2或3;R是1到3个碳原子的烷基;R(1)是2,4-二Cl,5-OMe;2,4-二Cl;3,4,5-三-OMe;2-Cl,5-OMe;2-Me,5-OMe;2,4-二-Me;2,4-二Me-5-OMe,2,4-二Cl,5-OEt;R(2)是1到2个碳原子的烷基,和其药学可接受的盐。
式II
其中n是2或3;R是1到3个碳原子的烷基;R(2)是1到2个碳原子的烷基,和其药学可接受的盐。
式III
其中n是2或3;R(1)是2,4-二Cl,5-OMe;2,4-二Cl;3,4,5-三-OMe;2-Cl,5-OMe;2-Me,5-OMe;2,4-二-Me;2,4-二Me-5-OMe,2,4-二Cl,5-OEt;R(2)是1到2个碳原子的烷基,和其药学可接受的盐。
式IV
其中n是2或3;R是1到3个碳原子的烷基;R(1)是2,4-二Cl,5-OMe;2,4-二Cl;3,4,5-三-OMe;2-Cl,5-OMe;2-Me,5-OMe;2,4-二-Me;2,4-二Me-5-OMe,2,4-二Cl,5-OEt。
本发明的化合物可以用于治疗、预防或抑制骨再吸收、病理性骨再吸收、破骨细胞活性、破骨细胞发生、溶骨性病变或者其他伴随着骨丢失或破坏的病理性情况。在一些方案中,所述化合物作为药物组合物的一部分使用。
本发明的具体化合物包括:化合物1-4-((2,4-二氯-5-甲氧基苯基)氨基)-6-甲氧基-7-(3-(4-甲基-1-哌嗪基)丙氧基)-3-喹啉腈;化合物2-4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-乙基-1-哌嗪基)丙氧基)-6-甲氧基-3-喹啉腈;化合物3-4-[(2,4-二氯-5-甲氧基苯基)氨基]-6-甲氧基-7-[2-(4-甲基-1-哌嗪基)乙氧基]-3-喹啉腈;化合物4-4-[(2,4-二氯-5-甲氧基苯基)氨基]-7-[2-(4-乙基-1-哌嗪基)乙氧基]-6-甲氧基-3-喹啉腈;化合物5-4-[(2,4-二氯-5-甲氧基苯基)氨基]-6-甲氧基-7-[(1-甲基哌啶-4-基)甲氧基]-3-喹啉腈;化合物6-4-[(2,4-二氯-5-甲氧基苯基)氨基]-6-甲氧基-7-[2-(1-甲基哌啶-4-基)乙氧基]-3-喹啉腈;化合物7-4-[(2,4-二氯-5-甲氧基苯基)氨基]-6-甲氧基-7-[3-(1-甲基哌啶-4-基)丙氧基]喹啉-3-腈;化合物8-4-[(2,4-二氯-5-甲氧基苯基)氨基]-7-[(1-乙基哌啶-4-基)甲氧基]-6-甲氧基喹啉-3-腈;化合物9-4-[(2,4-二氯-5-甲氧基苯基)氨基]-6-乙氧基-7-[3-(4-甲基哌嗪-1-基)丙氧基]喹啉-3-腈;化合物10-4-[(2,4-二氯-5-甲氧基苯基)氨基]-6-乙氧基-7-[(1-甲基哌啶-4-基)甲氧基]喹啉-3-腈;化合物11-4-[(2,4-二氯-5-甲氧基苯基)氨基]-6-乙氧基-7-[3-(4-乙基哌嗪-1-基)丙氧基]喹啉-3-腈;化合物12-4-[(2,4-二氯-5-甲氧基苯基)氨基]-6-乙氧基-7-[3-(1-甲基哌啶-4-基)丙氧基]喹啉-3-腈;化合物13-4-[(2,4-二氯-5-甲氧基苯基)氨基]-6-乙氧基-7-[2-(4-甲基-1-哌嗪基)乙氧基]喹啉-3-腈;化合物14-4-[(2,4-二氯-5-甲氧基苯基)氨基]-6-乙氧基-7-[2-(1-甲基哌啶-4-基)乙氧基]喹啉-3-腈;化合物15-4-[(2,4-二氯-5-甲氧基苯基)氨基]-6-甲氧基-7-[3-(4-丙基-1-哌嗪基)丙氧基]-3-喹啉腈;化合物16-4-[(2,4-二氯苯基)氨基]-6-甲氧基-7-[(1-甲基哌啶-4-基)甲氧基]-3-喹啉腈;化合物17-6-甲氧基-7-[(1-甲基哌啶-4-基)甲氧基]-4-[(3,4,5-三甲氧基苯基)氨基]喹啉-3-腈;化合物18-4-[(2-氯-5-甲氧基苯基)氨基]-6-甲氧基-7-[(1-甲基哌啶-4-基)甲氧基]喹啉-3-腈;化合物19-6-甲氧基-4-[(5-甲氧基-2-甲基苯基)氨基]-7-[(1-甲基哌啶-4-基)甲氧基]喹啉-3-腈;化合物20-4-[(2,4-二甲基苯基)氨基]-6-甲氧基-7-[(1-甲基哌啶-4-基)甲氧基]喹啉-3-腈;化合物21-6-甲氧基-4-[(5-甲氧基-2,4-二甲基苯基)氨基]-7-[(1-甲基哌啶-4-基)甲氧基]喹啉-3-腈;化合物22-4-[(2,4-二氯-5-乙氧基苯基)氨基]-6-甲氧基-7-[(1-甲基哌啶-4-基)甲氧基]喹啉-3-腈;和其药学可接受的盐。在一些实施方案中,一种优选的化合物是化合物1-4-((2,4-二氯-5-甲氧基苯基)氨基)-6-甲氧基-7-(3-(4-甲基-1-哌嗪基)丙氧基)-3-喹啉腈。
考虑到,本文所述的任何方法或组合物可以相对于本文所述的任何其他方法或组合物使用。
当在权利要求和/或说明书中与术语“包含”一起使用时,词语“一”可以意指“一”,但它也具有“一种或多种”,“至少一种”和“一种或一种以上”的含义。
除非另有明确说明是指仅有的供选方案或供选方案是互相排斥的,在权利要求中使用术语“或”是指“和/或”,尽管本公开内容支持意指仅有的供选方案和“和/或”的定义。
根据下文的详细描述,本发明的其他目的、特征和优点将变得显而易见。但是,应当理解的是,详细的描述和具体的实施例尽管指出了本发明具体的实施方案,但它们都是以解释说明的方式给出的,因为根据该详细描述,在本发明的精神和范围内的各种改变和变化对于本领域技术人员将变得显而易见。
附图简述
下面的附图形成了本说明书的一部分,将其包括在内以进一步地说明本发明的一些方面。通过参考这些附图中的一或多幅并结合下文具体实施方案的详细描述,可以更好地理解本发明。
附图1A-1C.SKI606是破骨细胞发生的有效抑制剂。(附图1A)4-苯基氨基-3-喹啉腈SKI606的结构。(附图1B)将BMM细胞接种入48孔板中(2×104个细胞/孔),并用M-CSF(10ng/ml)或M-CSF和RANKL(100ng/ml)刺激,一式四份使用所示浓度的SKI606。在第3天补充M-CSF。在第5天固定细胞并用来自Sigma-Aldrich(St.Louis,MO)的TRAP染色试剂盒进行TRAP染色。(附图1C)显示的是三个试验的代表性数据。显示的是用10x物镜来自不同处理的代表性视野的照片。
附图2A-2B.BMM细胞以时间依赖性的方式应答SKI606。(附图2A)将BMM细胞接种入48孔板中(2×104个细胞/孔),并用M-CSF(10ng/ml)或M-CSF和RANKL(300ng/ml)一式四份预处理指定时间,然后用300nM SKI606处理。在第3天补充M-CSF。在第5天固定细胞并用来自Sigma-Aldrich(St.Louis,MO)的TRAP染色试剂盒进行TRAP染色。(附图2B)显示的是三个试验的代表性数据。照片是用10x物镜来自不同处理的代表性视野。
附图3A-3B.MDA-MB-435细胞在RAW264.7细胞中刺激破骨细胞发生。(附图3A)。将RAW264.7细胞(500细胞/孔;每种处理8个孔)接种入含指定密度MDA-MD-435细胞的96孔板中,并培养5天。(附图3B)如上所述制备条件培养基。RAW264.7细胞(750个细胞/孔;每种处理8个孔)与指定浓度的来自MDA-MB-435的条件培养基培养5天。在第5天固定培养物并用来自Sigma-Aldrich(St.Louis,MO)的TRAP染色试剂盒进行TRAP染色。显示的是五个试验的代表性数据。照片是用10x物镜来自不同处理的代表性视野。
附图4A-4B.SKI606抑制RAW264.7中MDA-MB-435刺激的破骨细胞发生。(附图4A)将RAW264.7细胞(500细胞/孔;每种处理8个孔)接种入含指定密度MDA-MD-435(800细胞/孔)细胞的96孔板中,并在增加剂量的SKI606存在下培养5天。(附图4B)将RAW264.7细胞(750细胞/孔;每种处理8个孔)接种入96孔板中10%来自MDA-MB-435的条件培养基中5天。在第5天固定培养物并用来自Sigma-Aldrich(St.Louis,MO)的TRAP染色试剂盒进行TRAP染色。显示的是五个试验的代表性数据。
附图5A-5C.SKI606显著地减轻了肿瘤生长和溶骨性病变。将小鼠分成3个治疗组。在胫骨注射5×105MDA-MB-435细胞后3天开始每周5天口饲载体(在PBS中的0.5%Methocel/0.4%吐温)、在载体中的150mg/kg SKI606,或S.C.注射在0.1ml PBS中的10mg/kgZomeda(zolendronic acid)治疗,共9周。(附图5A)如下确定肿瘤的重量:注射腿的重量-相同动物未注射后腿的重量。(附图5B)由数字X-射线图像估计溶骨面积;将NIH Scion程序用于测量胫骨的面积和溶骨面积,以计算溶骨区中的像素/胫骨面积中的像素的比例(附图5C)。固定注射了肿瘤的胫骨,并在EDTA中脱钙,用来自Sigma-Aldrich(St.Louis,MO)的TRAP染色试剂盒将切片染色观察多核破骨细胞(>3个核)的存在。
附图6A-6C.SKI606显著地减轻了肿瘤生长和溶骨性病变。在注射后35天摄取X-射线图像,并以14天的间隔摄像。在9周后,对用口饲载体(在PBS中的0.5%Methocel/0.4%吐温)治疗的对照组(附图6A)、用150mg/kg(附图6B)或Zomeda(附图6C)治疗的小鼠摄取最终X-射线图像。
说明性实施方案的描述
活的骨组织通过钙矿物质的再吸收和沉积过程连续地获得补充。该过程称作吸收-再吸收循环,通过两种细胞类型-成骨细胞和破骨细胞来促进。破骨细胞是一种多核细胞,并且是体内已知具有降解(或再吸收)骨的能力的唯一一种细胞。在某些病理情况中,吸收-再吸收循环是有缺陷的,导致骨降解。骨的降解典型地导致病理性骨折、骨痛、脊髓压迫和高钙血症的危险增加。
本发明的实施方案包括治疗溶骨性病变、骨再吸收疾病或与病理情况有关的骨再吸收的方法和组合物,一般包括但不限于,骨质疏松症、关节炎、类风湿性关节炎、癌向骨的转移、骨癌、高钙血症、具有矫形外科植入物的溶骨性病变、佩吉特病、和与甲状旁腺功能亢进有关的骨丢失。代表性的癌症包括但不限于,乳腺癌、前列腺癌、结肠癌、子宫内膜癌、多发性骨髓瘤、肾细胞癌、头和颈癌及宫颈癌。关节炎性病症包括但不限于,佐剂-、胶原-、细菌-和抗原-诱发的关节炎,特别是类风湿性关节炎。溶骨性病变包括但不限于釉质细胞瘤、动脉瘤性骨囊肿(损伤)、血管肉瘤-高分级、血管肉瘤-低分级、高歇病的骨损伤、甲状旁腺功能亢进的棕色瘤、成软骨细胞瘤、软骨粘液样纤维瘤、软骨肉瘤、脊索瘤、透明细胞软骨肉瘤、常规的髓内骨肉瘤、退行性关节病、成纤维细胞性纤维瘤、具有恶性纤维组织细胞瘤的骨干骨髓狭窄、内生软骨瘤、嗜酸细胞肉芽肿、上皮样血管内皮瘤、骨的尤因肉瘤、骨外骨肉瘤、纤维肉瘤、纤维性结构不良、红色反应性骨膜炎、巨细胞瘤、血管球瘤、骨中的绿色肉瘤、hardcastle′s综合征、血管瘤、血管外皮细胞瘤、高分级表面骨肉瘤、骨的霍杰金淋巴瘤、皮质内骨肉瘤、骨内分化良好的骨肉瘤、近皮质软骨瘤、白血病、恶性纤维性组织细胞瘤、肢骨纹状肥大、转移性乳腺癌、转移性肾癌、转移性肺癌、转移性前列腺癌、多病灶性骨肉瘤、多发性骨髓瘤、骨化性肌炎、骨的神经纤维瘤、非霍杰金淋巴瘤、非骨化性纤维瘤(纤维性骨皮质缺损)、nora’s损害、成骨细胞瘤、骨软骨瘤、骨软骨瘤病(hmoce)、骨纤维结构不良、骨样骨瘤、骨瘤、骨髓炎、条纹状骨病、全身脆弱性骨硬化、骨肉瘤、佩吉特病、骨膜外骨肉瘤、骨膜软骨瘤、骨膜骨肉瘤、色素绒毛结节性滑膜炎、佩吉特病后肉瘤(post-paget’ssarcoma)、骨的神经鞘瘤、小细胞骨肉瘤、单一性骨囊肿、单生性纤维瘤、孤立性骨髓瘤(浆细胞瘤)、软骨下囊肿、滑膜性软骨瘤病、毛细血管扩张性骨肉瘤、“Tug”损害-骨干骺端纤维缺损,或单房性骨囊肿。
I.SRC-相关的激酶抑制剂
根据本发明,提供结构式I的化合物:
其中n是1-3的整数;X是N、CH,条件是当X是N时,n是2或3;R是1到3个碳原子的烷基;R(1)是2,4-二Cl,5-OMe;2,4-二Cl;3,4,5-三-OMe;2-Cl,5-OMe;2-Me,5-OMe;2,4-二-Me;2,4-二Me-5-OMe,2,4-二Cl,5-OEt;R(2)是1到2个碳原子的烷基,和/或其药学可接受的盐。
本发明的具体化合物包括:化合物1-4-((2,4-二氯-5-甲氧基苯基)氨基)-6-甲氧基-7-(3-(4-甲基-1-哌嗪基)丙氧基)-3-喹啉腈;化合物2-4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-乙基-1-哌嗪基)丙氧基)-6-甲氧基-3-喹啉腈;化合物3-4-[(2,4-二氯-5-甲氧基苯基)氨基]-6-甲氧基-7-[2-(4-甲基-1-哌嗪基)乙氧基]-3-喹啉腈;化合物4-4-[(2,4-二氯-5-甲氧基苯基)氨基]-7-[2-(4-乙基-1-哌嗪基)乙氧基]-6-甲氧基-3-喹啉腈;化合物5-4-[(2,4-二氯-5-甲氧基苯基)氨基]-6-甲氧基-7-[(1-甲基哌啶-4-基)甲氧基]-3-喹啉腈;化合物6-4-[(2,4-二氯-5-甲氧基苯基)氨基]-6-甲氧基-7-[2-(1-甲基哌啶-4-基)乙氧基]-3-喹啉腈;化合物7-4-[(2,4-二氯-5-甲氧基苯基)氨基]-6-甲氧基-7-[3-(1-甲基哌啶-4-基)丙氧基]喹啉-3-腈;化合物8-4-[(2,4-二氯-5-甲氧基苯基)氨基]-7-[(1-乙基哌啶-4-基)甲氧基]-6-甲氧基喹啉-3-腈;化合物9-4-[(2,4-二氯-5-甲氧基苯基)氨基]-6-乙氧基-7-[3-(4-甲基哌嗪-1-基)丙氧基]喹啉-3-腈;化合物10-4-[(2,4-二氯-5-甲氧基苯基)氨基]-6-乙氧基-7-[(1-甲基哌啶-4-基)甲氧基]喹啉-3-腈;化合物11-4-[(2,4-二氯-5-甲氧基苯基)氨基]-6-乙氧基-7-[3-(4-乙基哌嗪-1-基)丙氧基]喹啉-3-腈;化合物12-4-[(2,4-二氯-5-甲氧基苯基)氨基]-6-乙氧基-7-[3-(1-甲基哌啶-4-基)丙氧基]喹啉-3-腈;化合物13-4-[(2,4-二氯-5-甲氧基苯基)氨基]-6-乙氧基-7-[2-(4-甲基-1-哌嗪基)乙氧基]喹啉-3-腈;化合物14-4-[(2,4-二氯-5-甲氧基苯基)氨基]-6-乙氧基-7-[2-(1-甲基哌啶-4-基)乙氧基]喹啉-3-腈;化合物15-4-[(2,4-二氯-5-甲氧基苯基)氨基]-6-甲氧基-7-[3-(4-丙基-1-哌嗪基)丙氧基]-3-喹啉腈;化合物16-4-[(2,4-二氯苯基)氨基]-6-甲氧基-7-[(1-甲基哌啶-4-基)甲氧基]-3-喹啉腈;化合物17-6-甲氧基-7-[(1-甲基哌啶-4-基)甲氧基]-4-[(3,4,5-三甲氧基苯基)氨基]喹啉-3-腈;化合物18-4-[(2-氯-5-甲氧基苯基)氨基]-6-甲氧基-7-[(1-甲基哌啶-4-基)甲氧基]喹啉-3-腈;化合物19-6-甲氧基-4-[(5-甲氧基-2-甲基苯基)氨基]-7-[(1-甲基哌啶-4-基)甲氧基]喹啉-3-腈;化合物20-4-[(2,4-二甲基苯基)氨基]-6-甲氧基-7-[(1-甲基哌啶-4-基)甲氧基]喹啉-3-腈;化合物21-6-甲氧基-4-[(5-甲氧基-2,4-二甲基苯基)氨基]-7-[(1-甲基哌啶-4-基)甲氧基]喹啉-3-腈;化合物22-4-[(2,4-二氯-5-乙氧基苯基)氨基]-6-甲氧基-7-[(1-甲基哌啶-4-基)甲氧基]喹啉-3-腈;和其药学可接受的盐。
本发明的化合物可以用于治疗、缓解、预防或抑制破骨细胞发生或骨丢失。在一个优选的实施方案中,所述化合物用作药物组合物的一部分。在一个优选的实施方案中,化合物1-4-((2,4-二氯-5-甲氧基苯基)氨基)-6-甲氧基-7-(3-(4-甲基-1-哌嗪基)丙氧基)-3-喹啉腈用于抑制破骨细胞发生或骨丢失。
药学可接受的盐是由有机和无机酸例如醋酸、乳酸、羧酸、柠檬酸、肉桂酸、酒石酸、琥珀酸、延胡索酸、马来酸、丙二酸、扁桃酸、苹果酸、草酸、丙酸、盐酸、氢溴酸、磷酸、硝酸、硫酸、羟乙酸、丙酮酸、甲磺酸、乙磺酸、甲苯磺酸、水杨酸、苯甲酸和类似已知的可接受的酸产生的那些盐。
术语“烷基”是指饱和脂族基团,包括直链烷基、支链烷基、环烷基(脂环族)、烷基取代的环烷基和环烷基取代的烷基。在一个优选的实施方案中,直链或支链烷基在它的主链中具有3个或更少个碳原子。
所述化合物可以通过口服;病损内;腹膜内;肌内或静脉内注射;输注;脂质体介导的递送;局部;鼻;肛门;阴道;舌下;尿道;经皮;鞘内;眼部或耳部递送来提供。为了得到提供本发明的化合物的一致性,优选本发明的化合物是单位剂量的形式。适当的单位剂型包括片剂、胶囊和在囊或小瓶中的粉末。这样的单位剂型可以包含0.1,0.5,1,10,100,200到300ng或mg的本发明的化合物,包括其间的所有值和范围,在某些方面是2到100ng或mg。在另一个实施方案中,单位剂型包含50到150mg的本发明的化合物。本发明的化合物可以口服或以其他公知的施用途径施用。该化合物可以每日施用1,2,3,4,5到6次,更通常是每天、周或月1,2,3到4次,持续数周、月或年。有效量是本领域技术人员可确定的;它也取决于该化合物的形式。本领域技术人员可以常规地进行经验性的活性试验,以确定该化合物在生物测定中的生物活性,由此确定需要施用多大剂量,以及外推和分析临床试验数据。
本发明的化合物可以与常规的赋形剂一起配制,其中赋形剂是例如填充剂、崩解剂、粘合剂、润滑剂、调味剂、色素添加剂或载体。载体可以是例如稀释剂、气雾剂、局部用载体、水性溶液、非水性溶液或固体载体。载体可以是聚合物。本发明的载体包括任何标准的药学可接受的载体,例如磷酸盐缓冲盐溶液、醋酸盐缓冲盐溶液、水、乳剂例如油/水乳剂或甘油三酯乳剂、各种类型的润湿剂、片剂、包衣片和/或胶囊。
当口服或局部提供时,这些化合物可以通过在不同载体中递送来提供给患者。典型地,这些载体包含赋形剂例如淀粉、乳、糖、某些类型的粘土、明胶、硬脂酸、滑石、植物脂肪或油、树胶或二醇。具体的载体需要根据所需的递送方法来选择,例如磷酸盐缓冲盐水(PBS)可以用于静脉内或全身递送,植物脂肪、乳膏、药膏、软膏或凝胶可以用于局部递送。
本发明的化合物可以与适当的稀释剂、防腐剂、增溶剂、乳化剂、辅剂和/或载体一起递送,用于治疗或预防溶骨性病变和/或骨丢失。这些组合物是液体或冻干或其它干燥制剂,包括各种缓冲内容物(例如,Tris-HCl、醋酸盐、磷酸盐)、pH和离子强度的稀释剂、防止表面吸收的添加剂例如白蛋白或明胶、洗涤剂(例如,吐温20、吐温80、PLURONIC F68、胆汁酸盐)、增溶剂(例如,甘油、聚乙二醇)、抗氧化剂(例如,抗坏血酸、偏亚硫酸氢钠)、防腐剂(例如,硫柳汞、苯甲醇、尼泊金类)、填充物质或张力调节剂(例如,乳糖、甘露醇)、聚合物例如聚乙二醇的共价结合、与金属离子的络合,或者将该化合物掺入到水凝胶或脂质体的颗粒制剂、微乳、胶束、单层或多层囊泡、血影或球芽中或上。这些组成将影响该化合物或组合物的物理状态、溶解性、稳定性、体内释放速率和体内清除率。组成的选择取决于能治疗、缓解或预防特定病症或疾病状态的化合物的物理和化学性质。
本发明的化合物可以通过胶囊局部递送,该胶囊允许在一段时间内持续释放该化合物。控制或持续释放组合物包括在亲脂贮库(例如,脂肪酸、蜡、油)中的制剂。
本发明进一步提供本发明的化合物作为活性治疗物质用于治疗、调节、缓解、预防或抑制破骨细胞发生或骨丢失。
本发明进一步提供治疗人骨丢失的方法,包括给诊断出溶骨性病变或处于发生溶骨性病变的危险的个体施用有效量的本发明的化合物或药物组合物。提供给患者的剂量将是不同的,取决于施用的是什么,施用的目的,施用的方式等等。“治疗有效量”是足以治愈、减轻或缓解骨丢失的症状的量。
本发明的化合物可以单独递送或者与用于治疗任何相关的疾病状态或病理情况的其他化合物组合递送。
可以由下列物质制备本发明的化合物:(a)商业可购的原料(b)可以如文献所述制备的已知原料或(c)本文参考的方案和试验方法中描述的新中间体。本发明包括的化合物可以根据在U.S.专利6,002,008和6,780,996;和U.S.专利申请20050101780A1中公开的合成途径来制备,将每篇都以整体通过参考引入本文。
在适合所使用的试剂和物质和适合所要完成的反应的溶剂中进行反应。有机合成领域的技术人员应当理解,在分子上存在的各种官能团必须与所计划的化学转化相符。当没有指定时,合成步骤的顺序、保护基的选择和脱保护的条件对于本领域技术人员是显而易见的。此外,在一些情况中,原料上的取代基可能与某些反应条件是不相容的。与给定取代基有关的限制是本领域技术人员显而易见的。适当时在惰性气氛中进行反应。
在文献(Boschelli等人,2001a;Boschelli等人,2001b;Boschelli等人,2003;Boschelli等人,2004和Ye等人,2001,将每一篇都通过参考引入本文)中已经报道了式I化合物的制备。
II.骨吸收-再吸收循环
活的骨组织通过钙矿物质的再吸收和沉积过程连续地获得补充。该过程称作吸收-再吸收循环,通过两种细胞类型-成骨细胞和破骨细胞来促进。破骨细胞是一种多核细胞,并且是体内已知具有降解(或再吸收)骨的能力的唯一一种细胞。该再吸收活性是通过骨组织中的破骨细胞形成凹(再吸收腔隙)完成的。事实上,细胞培养物中的破骨细胞活性是通过它们在矿化组织例如骨或抹香鲸牙质的切片上形成这些凹的能力来测量的。破骨细胞来源于与血液的有形成分共有的造血前体(Takahashi等人,1987)。破骨细胞的前体是单核的细胞(具有单个核的细胞),其见于骨髓中,在通过细胞融合方式经历复制和分化后形成成熟和独特的多核破骨细胞。成熟的破骨细胞与其他多核细胞的区别在于酶-耐酒石酸酸性磷酸酶(TRAP)的存在,该酶通常用作破骨细胞的细胞标志物。
在与异常的破骨细胞发育或功能有关的病理情况中有这样的情况,其中骨再吸收增加导致发生骨结构脆弱和/或易碎,例如骨质疏松症,或骨吸收增加导致发生骨量过量,例如骨硬化症。据信,破骨细胞或成骨细胞群体过量或不足的发生是由于特定细胞因子相应缺少或过量所致。
很多已知的细胞因子刺激或抑制血细胞:数种生长调节细胞因子例如M-CSF,转化生长因子α(TGF-α),白细胞介素-1(IL-1)和肿瘤坏死因子(TNF)显示出可以刺激骨髓单核细胞的增殖。尽管细胞因子例如白细胞介素-1、肿瘤坏死因子和白细胞介素-6(IL-6)可影响破骨细胞生成和分化(Mundy,1990),这些因子不是特异性的破骨细胞生长调节因子。
RANKL、RANK和护骨蛋白诱杀型受体(OPG)的敲除型小鼠模型表明了这些分子在破骨细胞发生(即,骨再建)中具有重要作用。这些分子的生物学重要性通过靶向破坏OPG诱导严重的骨质疏松症,通过靶向破坏RANKL或OPG的过度表达诱导骨硬化症得以理解(Bucay等人,1998;Kong等人,1999;Mizuno等人,1998)。因此,破骨细胞的形成可归于骨髓微环境中RANKL和OPG的相对比例,该平衡的改变可能是很多代谢性骨疾病中骨丢失的主要原因。与RANKL-/-小鼠类似,RANK的靶向破坏也导致了骨硬化症表型(Dougall等人,1999;Li等人,2000)。RANK-/-和RANKL-/-小鼠都显示出缺乏破骨细胞,表明这些分子是破骨细胞发生的必要条件。此外,RANK和RANKL是淋巴结器官发生及早期B和T细胞发育所需要的(Dougall等人,1999;Kong等人,1999)。此外,缺乏TRAF6(Lomaga等人,1999)、c-Src(Soriano等人,1991)、c-Fos(Johnson等人,1992)或NF-κB亚基p50/p52(Franzoso等人,1997;Iotsova等人,1997)的小鼠也显示出骨硬化症表型;尽管这些突变小鼠具有破骨细胞,但这些细胞显然在骨再吸收中有缺陷。
维持骨完整性需要骨形成和骨再吸收之间保持动态平衡。通过破骨细胞前体的分化和融合的净效应和通过活性破骨细胞凋亡的活性和速率可以确定活性破骨细胞的净库大小。尽管成骨细胞系细胞表达的各种细胞因子(TNF、IL-1、IL-6、IL-11、TGF)和分子(11α,25-二羟基维生素D3和糖皮质激素)已经在破骨细胞分化中显示出具有一定的作用,但似乎重要的因子是RANKL(由成骨细胞产生)和RANK(在破骨细胞和破骨细胞祖细胞上表达),以及所产生的细胞内信号转导机制和途径。也需要M-CSF,但它的功能仍然难以确定,但是可能仅仅是早期破骨细胞祖细胞分化起始和存活所需要。
人的骨骼是不断重塑的,通常约2年周转一次,允许在钙平衡中使用骨矿物质。骨骼的强度和形状通过节段置换得以维持:由单核细胞-巨噬细胞前体形成的破骨细胞降解一个骨部分(Scheven等人,1986;和Fujikawa等人,1996),而同时,来源于间质细胞的成骨细胞合成新骨(Rickard,等人,1996)。这些不相关的细胞以成对的方式分化,在几周时间里产生新的骨部分。
破骨细胞是多核巨细胞,来源于造血干细胞,是负责生理性和病理性骨再吸收的主要细胞。破骨细胞专门用于除去骨的无机和有机相(Blair等人,1986)。骨微环境中细胞因子和生长因子的水平的改变导致破骨细胞的异常骨再吸收(其综述参见Mundy等人,1997)。因此,在小鼠中IL-4(Lewis,等人,1993)和G-CSF(Takahashi,等人,1996)的强制表达诱发了骨量减少,而过度表达可溶性TNF-α受体(Ammann,等人,1997)或排除IL-6基因(Poli,等人,1994)的小鼠则免于雌激素缺乏而导致的骨丢失。
羟磷灰石矿物相的溶出依赖于通过碳酸酐酶II和质子泵的作用破骨细胞下再吸收腔隙的酸化(Vaes,1968;Baron等人,1985;Blair等人,1992)。
破骨细胞的过度骨再吸收促成了许多人疾病的病理学,这些疾病包括关节炎、骨质疏松症、牙周炎和恶性肿瘤性高钙血症。在再吸收过程中,破骨细胞除去了骨的矿物质和有机成分(Blair等人,1986)。当前公众关注的主要骨疾病是骨质疏松症、恶性肿瘤性高钙血症、由于骨转移而导致的骨量减少、牙周病、甲状旁腺功能亢进、类风湿性关节炎中的关节周围侵蚀、佩吉特病、制动诱发的骨量减少和糖皮质激素治疗。所有这些病症的特征在于由骨再吸收(分解)和骨形成之间失去平衡而导致的骨丢失,其以平均每年约14%的速率持续一生。但是,骨周转的速率在各个部位是不同的,例如在椎骨的骨小梁和颌骨的牙槽骨中就高于长骨的皮质。骨丢失的可能性与周转直接相关,在绝经后立即在椎骨中可总计超过每年5%,这种情况导致骨折的危险增加。周转可以受到成骨细胞活性增强或减弱或破骨细胞活性增强或减弱的影响。用于调节患者破骨细胞和/或成骨细胞的组合物和方法可以用于治疗伴随骨丢失的多种疾病或病症。
上述列出的所有病症都可以从用抑制或调节破骨细胞发生或骨再吸收的试剂进行治疗中受益。抑制骨再吸收的一种机制是抑制破骨细胞前体细胞融合。
III.治疗溶骨性病症的方法
本发明涉及对病理性骨再吸收疾病或病症患者的治疗。术语“治疗益处”是指在他/她的病症的医学治疗方面任何促进或增强患者健康的作用,包括治疗溶骨性病症和/或调节骨再吸收、破骨细胞活性、和/或破骨细胞发生。
A.药物制剂和递送
在本发明的一些实施方案中,关注的是涉及递送本发明的一种或多种化合物的方法。可以用本发明的一种或多种化合物预防、缓解或治疗的疾病和病症的例子包括与癌向骨转移有关的骨丢失,包括但不限于肺、头和颈、乳腺、胰、前列腺、肾、骨、睾丸、宫颈、胃肠、结肠、膀胱和其他癌症转移,以及与溶骨性病变有关或伴随溶骨性病变的其他疾病或病症。
药物组合物的“有效量”一般定义为足以可检测和可重复地达到规定的目标结果的量,例如缓解、减轻、最小化或限制溶骨性疾病或病症的程度或其症状。在一些方面,可以使用更严格的定义,包括预防、消除、根除或治愈疾病。
在一些特定的实施方案中,需要用本发明的方法和组合物抑制破骨细胞发生或以其它方式逆转、阻止或减少骨的再吸收。自然,施用途径将随着损害的位置和性质而不同,可以包括例如,真皮内、皮下、局部、胃肠外、静脉内、肌内、鼻内、全身和经口施用和制剂。
如果适合,可以使用连续施用。考虑经注射器或导管递送。这种连续输注可以在开始治疗后持续一段时间,从约1-2小时,到约2-6小时,到约6-12小时,到约12-24小时,到约1-2天,到约1-2周或更长。一般地,经连续输注的治疗组合物的剂量等于通过单次或多次注射给予的剂量,可以在输注期间调整剂量。
该治疗可以包括多种“单位剂量”。单位剂量定义为包含预定量的治疗组合物。所施用的量和具体途径和制剂在临床领域技术人员的技术范围内。单位剂量无需作为单次注射施用,而是可以包含在设定时间段里连续输注。本发明的单位剂量可以方便地以mg/体积的制剂或治疗组合物的重量(例如,毫克或mg)描述。
在一些实施方案中,递送包括一种或多种本发明组合物的组合物的方法包括经全身施用。但是,可替代地,本文公开的药物组合物可以胃肠外、皮下、气管内、静脉内、皮内、肌内或甚至腹膜内施用。可以通过注射器或用于注射溶液的任何其他方法进行注射。
作为游离碱或药学可接受的盐的活性化合物的溶液可以在水中适当地与表面活性剂例如羟丙基纤维素混合来制备。也可以在甘油、液体聚乙二醇及其混合物中和在油中制备分散体。在贮存和使用的一般条件下,这些制剂包含防腐剂以防止微生物生长。适合注射用途的药剂形式包括无菌水性溶液或分散液和临时制备无菌注射溶液或分散液的无菌粉末(U.S.专利5,466,468,特别地以整体通过参考引入本文)。在所有情况中,该形式必须是无菌的,流动性必须达到易于注射的程度。它在制造和贮存条件下必须是稳定的,且必须防止微生物例如细菌和真菌的污染作用。
载体可以是溶剂或分散介质,包含例如水、乙醇、多元醇(例如,甘油、丙二醇和液体聚乙二醇等等),其适当的混合物和/或植物油。可以通过使用包衣例如卵磷脂,通过维持所需的粒度(在分散体的情况中)和通过使用表面活性剂来维持适当的流动性。可以通过各种抗菌剂和抗真菌剂例如尼泊金类、三氯叔丁醇、酚、山梨酸、硫柳汞等等来防止微生物的作用。在很多情况中,优选包括等渗剂例如糖或氯化钠。可以通过在组合物中使用延迟吸收的试剂例如单硬脂酸铝和明胶来实现可注射组合物的延长吸收。
对于水性溶液的胃肠外施用,例如,如果必要该溶液应当是适当缓冲的,液体稀释剂首先以足够的盐水或葡萄糖来使其等渗。这些特定的水性溶液特别适合静脉内、肌内、皮下、瘤内和腹膜内施用。在该方面,可以使用的无菌水性介质是本领域技术人员根据本文公开内容已知的。例如,1个剂量可以溶解于1ml的等渗NaCl溶液中,并加入到1000ml的皮下输液中,或在计划的输注位点注射(参见例如,″Remington′s Pharmaceutical Sciences″,第15版,第1035-1038和1570-1580页)。根据所治疗的患者的情况必然会对剂量进行一些改变。在任意情况中负责施用的人员将会确定个体患者的适当剂量。此外,对于人的施用,制剂应当满足FDA Office of Biologics标准要求的无菌、致热原性、一般安全性和纯度的标准。
制备无菌注射溶液,包括将需要量的活性化合物掺入到按需具有上述列举的各种其他成分的适当溶剂中,然后过滤灭菌。一般地,制备分散液,包括将各种经灭菌的活性成分掺入到无菌载体中,其中无菌载体包含基础分散介质和上述列举的所需的其他成分。在用于制备无菌注射溶液的无菌粉末的情况中,一些制备方法是真空干燥和冻干技术,这些技术从先前无菌过滤的溶液中生产出活性成分加上任何其他所需成分的粉末。
本文公开的组合物可以配制成中性或盐的形式。药学可接受的盐包括酸加成盐(与蛋白质的游离氨基形成),和与无机酸例如盐酸或磷酸或这些有机酸例如醋酸、草酸、酒石酸、扁桃酸等等形成的盐。与游离羧基形成的盐也可以来自无机碱例如氢氧化钠、钾、铵、钙或铁,和有机碱例如异丙胺、三甲胺、组氨酸、普鲁卡因等等。经配制,溶液可以以与剂量制剂相容的方式和治疗有效量施用。这些制剂可以以多种剂型例如注射溶液、药物释放胶囊等等来容易地施用。
本文使用的“载体”包括任意和所有溶剂、分散介质、媒介、包衣、稀释剂、抗菌剂和抗真菌剂、等渗剂和延迟吸收剂、缓冲剂、载体溶液、混悬液、胶体等等。使用这些用于药物活性物质的介质和试剂是本领域公知的。除了与活性成分不相容的任意常规介质或试剂,关注它在治疗组合物中的应用。补充性活性成分也可以掺入到该组合物中。
短语“药学可接受”是指当施用于人时不会产生过敏性或类似的不良反应的分子实体和组合物。包含蛋白质作为活性成分的水性组合物的制备是本领域公知的。典型地,这些组合物可以制成注射剂,为液体溶液或混悬液;也可以制备适合在注射前溶解或混悬在液体中的固体形式。
B.联合治疗
在一些实施方案中,本发明的组合物和方法涉及抑制或调节骨再吸收、破骨细胞活性和/或破骨细胞发生的化合物,其又可与其他试剂或组合物联合使用以增强其他治疗例如抗肿瘤治疗的效果,以改善治疗患者的生活质量。这些组合物可以以组合量提供,有效地实现所需的效果,例如杀灭癌细胞或抑制癌细胞的生长,和抑制破骨细胞形成、破骨细胞的活性或骨的再吸收。这些过程可涉及将细胞与本发明的组合物和第二治疗剂或多种因子同时接触。这可以通过将细胞与包括两种或多种试剂的单一组合物或药理学制剂接触,或将细胞与两种或多种不同的组合物或制剂接触,其中至少一种组合物包括本发明的组合物,一种或多种其他组合物包括至少第二治疗剂。
在本发明的一个实施方案中,关注的是除了促细胞凋亡、抗血管形成、抗癌或细胞周期调节剂外,抗破骨细胞治疗与免疫治疗干预联合使用。可替代地,该治疗可以是在其他试剂治疗前或后,间隔几分钟到几周。在其中分别将一种或多种第二治疗剂和抗破骨细胞治疗应用于细胞、组织、器官或患者的实施方案中,通常确保每次递送的时间之间不经过显著的时间段,以使得第二试剂和本发明的组合物仍然能够对患者发挥有利的联合效果。在这些情况中,关注的是,可以在彼此间隔约12-24小时之内,更优选在彼此间隔约6-12小时之内,使细胞与两种治疗形式接触。但在一些情况中可能需要显著地延长治疗的时间间期,在各次施用之间经过数天(2,3,4,5,6或7)到数周(1,2,3,4,5,6,7或8)。
可以使用各种组合,例如本发明的组合物是“A”和第二疗法例如化学疗法是“B”:
A/B/A B/A/B B/B/A A/A/B A/B/B B/A/A A/B/B/B B/A/B/B
B/B/B/A B/B/A/B A/A/B/B A/B/A/B A/B/B/A B/B/A/A
B/A/B/A B/A/A/B A/A/A/B B/A/A/A A/B/A/A A/A/B/A
遵循施用这些组合物的一般方案将本发明的抗破骨细胞组合物施用于患者,考虑其毒性(如果有的话)。预期如果必要该治疗循环可以重复。同时关注的是,各种标准疗法及外科手术干预可以与所述的疗法联合应用。
在特定的实施方案中,关注的是抗癌疗法例如化学疗法、放射疗法或免疫疗法与本文所述的抗破骨细胞疗法联合使用。
1.化学疗法
癌症疗法也包括各种基于化学和放射治疗的联合疗法。联合化疗包括例如顺铂(CDDP)、卡铂、丙卡巴肼、氮芥、环磷酰胺、喜树碱、异磷酰胺、美法仑、苯丁酸氮芥、白消安、亚硝脲、更生霉素、柔红霉素、多柔比星、博来霉素、plicomycin、丝裂霉素、依托泊苷(VP16)、他莫昔芬、雷洛昔芬、雌激素受体结合剂、紫杉酚、吉西他滨、诺维本、法尼基-蛋白质转移酶抑制剂、反铂、5-氟尿嘧啶、长春新碱、长春碱和甲氨蝶呤,或上述物质任意的类似物或衍生物变体。
2.放射疗法
导致DNA损害并已经被广泛使用的其他因素包括通常所知的γ-射线、X-射线和/或定向递送放射性同位素给肿瘤细胞。DNA损害因子的其他形式也是我们关注的,例如微波、质子束辐射(U.S.专利5,760,395和U.S.专利4,870,287)和UV-辐射。非常可能的是,所有这些因子实现对DNA、对DNA的前体、对DNA的复制和修复、和对染色体的装配和维持的宽范围的损害。X-射线的剂量范围是在较长时间里(3到4周)每日剂量为50到200伦琴,到单剂量为2000到6000伦琴。放射性同位素的剂量范围变化较大,取决于同位素的半衰期、所发出的辐射的强度和类型以及肿瘤细胞的摄取。
当用于细胞时,术语“接触”和“暴露”在本文中是用于描述一个过程,治疗组合物和化学治疗或放射治疗剂通过该过程递送到靶细胞、组织或患者,或置于其邻近。
3.免疫疗法
在癌症治疗中,免疫疗法一般依赖于使用免疫效应细胞和分子(例如,单克隆抗体)来靶向和破坏癌细胞。曲妥单抗(HerceptinTM)就是这样的一个例子。免疫效应物可以是,例如对肿瘤细胞表面上的一些标记物具有特异性的抗体。抗体单独可以用作治疗的效应物,或者它可募集其他细胞来实际上实现细胞杀灭。抗体也可以与药物或毒素(化学治疗剂、放射性核素、蓖麻毒素A链、霍乱毒素、百日咳毒素等等)缀合,仅仅用作靶向剂。可替代地,效应物可以是载有表面分子的淋巴细胞,所述表面分子直接或间接地与肿瘤细胞靶相互作用。各种效应细胞包括细胞毒T细胞和NK细胞。治疗方式的组合,即,直接的细胞毒性和抑制或减少ErbB2将会为治疗ErbB2过度表达的癌症提供治疗益处。
存在多种不同的癌症被动免疫疗法的途径。它们可以大致分为下列种类:只注射抗体;注射与毒素或化学治疗剂偶联的抗体;注射与放射性同位素偶联的抗体;注射抗独特型抗体;及最后,清除骨髓中的肿瘤细胞。
在主动免疫疗法中,施用抗原性肽、多肽或蛋白质,或自体或同种异体肿瘤细胞组合物或“疫苗”,一般连同特殊的细菌佐剂(Ravindranath和Morton,1991;Morton等人,1992;Mitchell等人,1990;Mitchell等人,1993)。在黑素瘤免疫疗法中,引发高IgM应答的那些患者通常比那些未引发IgM抗体或引发低IgM抗体者生存得更好(Morton等人,1992)。IgM抗体通常是过渡抗体,该规则的例外似乎是抗-神经节苷脂或抗碳水化合物抗体。
在过继免疫治疗中,在体外分离患者的循环淋巴细胞或肿瘤浸润的淋巴细胞,通过淋巴因子例如IL-2活化或用肿瘤坏死的基因转导,并重新再施用(Rosenberg等人,1988;1989)。为了完成这一点,可以给动物或人类患者施用免疫有效量的活化淋巴细胞联合本文描述的掺入佐剂的抗原性肽组合物。活化的淋巴细胞最优选是患者自己的细胞,该细胞是早先从血或肿瘤样品中分离并体外活化(或“扩充”)的。该形式的免疫疗法产生了几例黑素瘤和肾癌的消退,但与无应答者相比,应答者的百分比很小。
4.手术
约60%的癌症患者会经历某种类型的手术,包括预防性、诊断性或分期性、治疗性和姑息性手术。治疗性手术包括下列的切除术,其中物理性地除去、切除和/或破坏所有或部分的癌组织。肿瘤切除术是指物理性地除去肿瘤的至少一部分。除了肿瘤切除术,通过手术治疗包括激光手术、冷冻手术、电外科和显微镜控制的手术(Mohs’手术)。进一步关注的是,本发明可以与除去浅表癌、初期癌或附带量的正常组织联合使用。
实施例
包括下列实施例用于展示本发明的优选实施方案。本领域的技术人员应当理解,下列实施例中公开的技术代表本发明人发现在本发明的实施中运行良好的技术,由此可以认为其构成了优选实施方式。但是,根据本公开内容,本领域技术人员应当理解,可以在所公开的具体实施方案中做出很多改变,而仍得到类似或相似的结果,不脱离本发明的精神和范围。
实施例1
方法
动物和细胞系.雄性无胸腺的NCr裸鼠得自Animal ProductionArea of the National Cancer Institute,Frederick CancerResearch Facility(Frederick,MD)。Black 6小鼠(C57BL/6J)得自Charles Rivers(Wilmington,MA)。将小鼠保持在无特异病原体条件下的层流箱中,并在8周大时使用。所有的设备都根据UnitedStates Department of Agriculture,the Department of Health andHuman Services,和NIH的当前规程和标准得到了the AmericanAssociation for Accreditation of Laboratory Animal Care(AAALAC)的认可。用Purina啮鼠动物食物喂食小鼠,随意获取自来水。将乳腺癌细胞系MDA-MB-435细胞保持在补充有10%FBS和1mM丙酮酸钠(Invitrogen,Carlsbad,CA)的D-MEM(Invitrogen,Carlsbad,CA)中。将小鼠巨噬细胞系RAW264.7保持在补充有10%FBS(Invitrogen,Carlsbad,CA)的DMEM/F12(Invitrogen,Carlsbad,CA)中。所有培养基包含1∶100稀释的Fungizone(最终浓度:青霉素G,链霉素100单位/ml和两性霉素B 250ng/ml)。
初级骨髓细胞培养.从8-12周大的Black 6小鼠(C57BU6J)中无菌解剖胫骨和股骨的初级骨髓细胞(BMM)。用不完全D-MEM冲洗出骨髓,并以1200rpm离心3分钟,并重悬在5ml不完全D-MEM中。在室温下将BMM细胞在20ml红细胞裂解缓冲液(8.3g/l NH4Cl,1g/l碳酸氢钠,0.4g/l EDTA)中温育1-2分钟。加入补充有10%FBS和100单位/ml青霉素的25ml D-MEM(完全D-MEM),将BMM细胞以1200rpm离心3分钟。然后将BMM细胞以1.5-2×107细胞/10cm皿与10ml的完全D-MEM进行平板接种,并培养24小时。收集非贴壁细胞,以1200rpm离心5分钟,并以2.5×104细胞/孔的浓度接种到96孔皿中用于细胞毒性分析,以2×104细胞/孔的浓度接种到48孔板中或以5×103细胞/孔的浓度接种到96孔板中用于破骨细胞分化分析。在10ng/ml M-CSF存在下将细胞培养3天,然后洗涤并用于进一步的研究。为了分化成破骨细胞,加入30-100ng/ml RANKL。在2天后给培养基补充新鲜M-CSF和RANKL。
细胞毒性分析.在96-孔平底组织培养皿中进行SKI606对BMM细胞的细胞毒性(分析)。接种BMM细胞(2.5×104)并如上所述处理。将SKI606在培养基中稀释,并以2倍系列稀释加入到孔中。将细胞培养72小时,并用结晶紫(0.5%,在20%甲醇中)将剩余的贴壁细胞染色,并用Sorenson’s缓冲液(0.1M柠檬酸钠,pH4.2,在50%乙醇中)溶解。用Bio-Tek Instruments Inc(Winooski,VT)的EL800通用微量板读板器在630nm处测量吸光度。
体外破骨细胞分化.如上所述,将BMM细胞(2×104)在48-孔板中培养,然后用100ng/ml RANKL和10ng/ml M-CSF处理。将细胞培养物在第3天进行培养基更换。在第5天,固定细胞,并通过使用Sigma-Aldrich(St.Louis,MO)的白细胞酸性磷酸酶试剂盒计数处理后96小时每个孔中的TRAP-阳性、多核(>3个核)细胞的总数来评价破骨细胞分化。
骨再吸收分析.如上所述,将BMM细胞(5×103)在96孔板中培养。简言之,将细胞接种到Cambrex(Rockland,ME)的OsteoAssayTM板上,开始时用100ng/ml RANKL和10ng/ml M-CSF(含或不含300nMSKI606)处理。在第3天用新鲜10ng/ml M-CSF补充细胞培养物。在第5天,将20μl等分的上清液用于评价从OsteoAssayTM板的骨再吸收。通过使用Nordic Bioscience Diagnostics(Portsmouth,VA)的CrossLaps for Culture ELISA试剂盒测量从OsteoAssayTM板释放的胶原I来评价骨再吸收。用Bio-Tek Instruments Inc(Winooski,VT)的EL800通用微量板读板器在450nm处测量吸光度,在650nm处的读数作为参考。
时间-依赖性.如上所述将BMM细胞(2×104)在48-孔板中培养,并在没有或存在300nM SKI606下用RANKL(100ng/ml)处理,其中所述SKI606与RANKL刺激一同加入并在处理后96小时进行TRAP染色,或者在RANKL刺激后12,24或48小时加入并在96小时进行TRAP染色。然后如上所述固定细胞,进行TRAP染色,计数每种情况中的破骨细胞数。
RAW 264.7与MDA MB435细胞和条件培养基共培养。为进行共培养分析,将RAW264.7(500细胞/孔)接种在96孔板中,然后使其贴壁12小时。然后将MDA-MB-435以增加密度引入到RAW264.7培养物中,并培养12小时。然后在有或无指定浓度的SKI606的条件下培养共培养物5天。然后如上所述固定细胞,进行TRAP染色,计数每种情况中的破骨细胞数。
对于条件培养基,将MDA-MB-435细胞接种在10cm板(1×106细胞/板)中并培养36小时。然后取出培养基,以2500rpm离心5分钟,分离上清液并放置在4℃下直至使用。将RAW264.7细胞(750细胞/孔)接种在96孔板中,并使其贴壁12小时。加入来自MDA-MB-435细胞的条件培养基,并在有或没有指定浓度的SKI606的条件下培养5天。然后如上所述固定细胞,进行TRAP染色,计数每种情况中的破骨细胞数。
骨内注射和骨组织样品的处理.用0.025%胰蛋白酶-0.01%EDTA溶液收获MDA-MB-435细胞,在PBS中洗涤该细胞,并重悬于PBS中以准备植入小鼠中。肌内注射氯胺酮(100mg/kg)和乙酰丙嗪(2.5mg/kg)麻醉动物。用28-规格的Hamilton针头将在0.01ml PBS中的5×105MDA-MB-435乳腺癌细胞注射到雌性无胸腺NCr裸鼠中,注射到每只小鼠的胫骨近端。注射后3天,将小鼠分为3组,开始治疗:每日口饲载体(0.5%Methocel/0.4%吐温,在PBS中),在载体中的150mg/kgSKI606或S.C.注射在0.1ml PBS中的10g/kg Zomeda(zolendronicacid)。每日给予治疗,每周5天共9周。在注射后35天摄取X-射线图像,并以14天的间隔摄像。在9周后,摄取最后的X-射线图像,由相同动物荷有肿瘤和不荷有肿瘤的腿的重量差异计算肿瘤重量。固定注射肿瘤的胫骨,并在EDTA中脱钙,并用Sigma-Aldrich(St.Louis,MO)的白细胞酸性磷酸酶试剂盒对切片染色以测定多核破骨细胞(>3个核)的存在。通过检查组织学切片确定胫骨中肿瘤的发生率。如下确定肿瘤的重量:注射腿的重量-相同动物的未注射的后腿的重量。由数字X-射线图像估计溶骨面积;将NIH Scion程序用于测量胫骨的面积和溶骨面积,以计算溶骨区中的像素/胫骨面积中的像素的比例。
结果
为了鉴定可能的激酶抑制剂,测试化合物1,2,3,4和5抑制RANKL-诱导的RAW264.7细胞的破骨细胞分化的能力。选择SKI606,因为相关的化合物已经显示是Src和Abl激酶的双重抑制剂(Boschelli等人,2001b)。鉴定并表征SKI606。发现该化合物在酶分析中抑制Src,IC50为1.2nM,并以相当的浓度抑制Src-依赖性蛋白质酪氨酸磷酸化。
该化合物对于BMM细胞没有细胞毒性,600nM SKI606条件下小于10%的细胞死亡,表明对破骨细胞发生的抑制效果不是由于SKI606对前体细胞的细胞毒性。该4-苯基氨基-3-喹啉腈的结构是已知的(附图1A),并以剂量依赖性方式对BMM中RANKL-介导的破骨细胞分化具有抑制效果(附图1B)。如果在破骨细胞发生开始后加入,BMM细胞表现出对于SKI606的敏感性较低(附图2A和2B)。此外,研究SKI606抑制骨再吸收的能力,通过在有或无SKI606情况下在来自Cambrex(Rockland,ME)的OsteoAssayTM板上用RANKL刺激BMM细胞。与M-CSF和RANKL处理相比,在300nM SKI606存在下用M-CSF和RANKL处理的BMM培养物显示出胶原I释放降低了3.7倍,而胶原I释放是骨再吸收的指示。
检查乳腺癌细胞系MDA-MB-435在RAW264.7细胞中诱导破骨细胞发生的能力。发现这是密度依赖性的,800MDA-MB-435细胞/孔是最佳数目(附图3A)。确定RAW264.7细胞的最佳数目,对于该研究是500个细胞/孔用于与MDA-MB-435细胞共培养(数据未显示)。来自MDA-MB-435细胞的条件培养基也能在RAW264.7细胞培养物中支持破骨细胞发生,在DMEM/F12中10%来自MDA-MB-435细胞的条件培养基是最佳混合物(附图3B)。这表明,MDA-MB-435细胞诱导RAW264.7细胞中破骨细胞发生的能力是由于释放的因子而非细胞与细胞的接触。MDA-MB-435也可释放出抑制因子例如OPG,所形成的破骨细胞的数目随着条件培养基的浓度升高而减少。
其他研究包括研究SKI606抑制乳腺癌-诱导的破骨细胞形成的能力。在400nM SKI606的浓度下,SKI606显著地抑制了RAW264.7细胞中MDA-MB-435-诱导的破骨细胞发生(附图4A)。SKI606还能以剂量依赖性方式抑制来自MDA-MB-435细胞的条件培养基诱导的破骨细胞发生(附图4B)。
在体内模型中评价SKI606,使用雌性无胸腺的NCr裸鼠(8周大),用28-规格的Hamilton针头将在0.01ml PBS中的5×105MDA-MB-435细胞注射到每只小鼠的胫骨近端。将小鼠分成3个治疗组,通过检查组织学切片和肿瘤重量来确定胫骨中肿瘤的发生率。用SKI606或Zomeda治疗的小鼠中胫骨肿瘤的重量显著小于对照组的肿瘤(附图5A和表1)。用SKI606或Zomeda治疗的小鼠中溶骨面积显著较小(附图5B和表1)。此外,在SKI606-治疗的小鼠的肿瘤切片中TRAP-阳性细胞的数目显著较少(附图5C)。数字图像的合成如附图6A-6C所示。
表1.SKI606对于MDA-MB-435骨肿瘤小鼠模型的评价
实验组 | 胫骨中肿瘤的发生率 | 肿瘤的重量 | 溶骨区的估计 |
对照(载体) | 12/12(100%) | 0.242+/-0.07 | 0.294+/-0.06 |
SKI606 | 9/12(75%) | 0.088+/-0.02 | 0.164+/-0.09 |
Zomeda | 11/12(92%) | 0.073+/-0.02 | 0.099+/-0.05 |
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Claims (15)
4.权利要求1的方法,其中R(2)是甲基。
5.权利要求1的方法,其中X是N。
6.权利要求1的方法,其中X是CH。
7.权利要求1的方法,其中该化合物是4-[(2,4-二氯-5-甲氧基苯基)氨基]-6-甲氧基-7-[3-(4-甲基-1-哌嗪基)丙氧基]-3-喹啉腈或其药学可接受的盐。
8.权利要求1的方法,其中该化合物是4-[(2,4-二氯-5-甲氧基苯基)氨基]-7-[3-(4-乙基-1-哌嗪基)丙氧基]-6-甲氧基-3-喹啉腈;4-[(2,4-二氯-5-甲氧基苯基)氨基]-6-甲氧基-7-[2-(4-甲基-1-哌嗪基)乙氧基]-3-喹啉腈;4-[(2,4-二氯-5-甲氧基苯基)氨基]-7-[2-(4-乙基-1-哌嗪基)乙氧基]-6-甲氧基-3-喹啉腈;4-[(2,4-二氯-5-甲氧基苯基)氨基]-6-甲氧基-7-[(1-甲基哌啶-4-基)甲氧基]-3-喹啉腈;4-[(2,4-二氯-5-甲氧基苯基)氨基]-6-甲氧基-7-[2-(1-甲基哌啶-4-基)乙氧基]-3-喹啉腈;4-[(2,4-二氯-5-甲氧基苯基)氨基]-6-甲氧基-7-[3-(1-甲基哌啶-4-基)丙氧基]喹啉-3-腈;4-[(2,4-二氯-5-甲氧基苯基)氨基]-7-[(1-乙基哌啶-4-基)甲氧基]-6-甲氧基喹啉-3-腈;4-[(2,4-二氯-5-甲氧基苯基)氨基]-6-乙氧基-7-[3-(4-甲基哌嗪-1-基)丙氧基]喹啉-3-腈;4-[(2,4-二氯-5-甲氧基苯基)氨基]-6-乙氧基-7-[(1-甲基哌啶-4-基)甲氧基]喹啉-3-腈;4-[(2,4-二氯-5-甲氧基苯基)氨基]-6-乙氧基-7-[3-(4-乙基哌嗪-1-基)丙氧基]喹啉-3-腈;4-[(2,4-二氯-5-甲氧基苯基)氨基]-6-乙氧基-7-[3-(1-甲基哌啶-4-基)丙氧基]喹啉-3-腈;4-[(2,4-二氯-5-甲氧基苯基)氨基]-6-乙氧基-7-[2-(4-甲基-1-哌嗪基)乙氧基]喹啉-3-腈;4-[(2,4-二氯-5-甲氧基苯基)氨基]-6-乙氧基-7-[2-(1-甲基哌啶-4-基)乙氧基]喹啉-3-腈;4-[(2,4-二氯-5-甲氧基苯基)氨基]-6-甲氧基-7-[3-(4-丙基-1-哌嗪基)丙氧基]-3-喹啉腈;4-[(2,4-二氯苯基)氨基]-6-甲氧基-7-[(1-甲基哌啶-4-基)甲氧基]-3-喹啉腈;6-甲氧基-7-[(1-甲基哌啶-4-基)甲氧基]-4-[(3,4,5-三甲氧基苯基)氨基]喹啉-3-腈;4-[(2-氯-5-甲氧基苯基)氨基]-6-甲氧基-7-[(1-甲基哌啶-4-基)甲氧基]喹啉-3-腈;6-甲氧基-4-[(5-甲氧基-2-甲基苯基)氨基]-7-[(1-甲基哌啶-4-基)甲氧基]喹啉-3-腈;4-[(2,4-二甲基苯基)氨基]-6-甲氧基-7-[(1-甲基哌啶-4-基)甲氧基]喹啉-3-腈;6-甲氧基-4-[(5-甲氧基-2,4-二甲基苯基)氨基]-7-[(1-甲基哌啶-4-基)甲氧基]喹啉-3-腈;4-[(2,4-二氯-5-乙氧基苯基)氨基]-6-甲氧基-7-[(1-甲基哌啶-4-基)甲氧基]喹啉-3-腈;或其药学可接受的盐。
9.权利要求1的方法,其中该化合物是Src激酶抑制剂。
10.权利要求1的方法,其中所述骨丢失与骨质疏松症;骨巨细胞瘤;多发性骨髓瘤;家族性膨胀性骨质溶解;骨量减少;牙周病;甲状旁腺功能亢进;类风湿性关节炎中的关节周围侵蚀;佩吉特病;制动诱导的骨量减少;恶性肿瘤性高钙血症;骨转移;釉质细胞瘤;动脉瘤性骨囊肿(损伤);血管肉瘤(高分级);血管肉瘤(低分级);高歇病的骨损伤;甲状旁腺功能亢进的棕色瘤;成软骨细胞瘤;软骨粘液样纤维瘤;软骨肉瘤;脊索瘤;透明细胞软骨肉瘤;常规的髓内骨肉瘤;退行性关节病;成纤维细胞性纤维瘤;具有恶性纤维组织细胞瘤的骨干骨髓狭窄;内生软骨瘤;嗜酸细胞肉芽肿;上皮样血管内皮瘤;骨的尤因肉瘤;骨外骨肉瘤;纤维肉瘤;纤维性结构不良;红色反应性骨膜炎;血管球瘤;骨中的绿色肉瘤;Hardcastle′s综合征;血管瘤;血管外皮细胞瘤;高分级表面骨肉瘤;骨的霍杰金淋巴瘤;皮质内骨肉瘤;骨内分化良好的骨肉瘤;近皮质软骨瘤;白血病;恶性纤维性组织细胞瘤;肢骨纹状肥大;转移性乳腺癌;转移性肾癌;转移性肺癌;转移性前列腺癌;多病灶性骨肉瘤;骨化性肌炎;骨的神经纤维瘤;非霍杰金淋巴瘤;非骨化性纤维瘤(纤维性骨皮质缺损);Nora’s损害;成骨细胞瘤;骨软骨瘤;骨软骨瘤病;骨纤维性结构不良;骨样骨瘤;骨瘤;骨髓炎;条纹状骨病;全身脆弱性骨硬化;骨膜外骨肉瘤;骨膜软骨瘤;骨膜骨肉瘤;色素绒毛结节性滑膜炎;佩吉特病后肉瘤;骨的神经鞘瘤;小细胞骨肉瘤;单一性骨囊肿;单生性纤维瘤;孤立性骨髓瘤(浆细胞瘤);软骨下囊肿;滑膜性软骨瘤病;毛细血管扩张性骨肉瘤;”Tug”损害-骨干骺端纤维缺损;或单房性骨囊肿有关。
11.权利要求10的方法,其中所述骨转移是肺、头和颈、乳腺、胰腺、前列腺、肾、骨、睾丸、宫颈、胃肠、结肠、膀胱癌转移。
12.权利要求11的方法,其中所述骨转移是乳腺或前列腺癌转移。
13.权利要求11的方法,进一步包括提供抗肿瘤治疗。
14.权利要求13的方法,其中所述抗肿瘤治疗是化学疗法、放射疗法、免疫疗法或手术。
15.权利要求1的方法,其中该化合物是口服的。
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CA2612333A1 (en) | 2006-12-28 |
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