CN100345852C - 喹啉基－吡咯并吡唑化合物 - Google Patents
喹啉基－吡咯并吡唑化合物 Download PDFInfo
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- CN100345852C CN100345852C CNB2003801038400A CN200380103840A CN100345852C CN 100345852 C CN100345852 C CN 100345852C CN B2003801038400 A CNB2003801038400 A CN B2003801038400A CN 200380103840 A CN200380103840 A CN 200380103840A CN 100345852 C CN100345852 C CN 100345852C
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Abstract
根据式II的化合物及其可药用盐和通过向有需要的患者施用所述化合物治疗癌症的方法。
Description
本发明涉及新的喹啉基-吡唑化合物及其作为药物的用途，尤其是其作为TGF-β信号转导抑制剂的用途。
发明背景
转化生长因子β(TGF-beta)(″TGF-β″)多肽可影响多种细胞类型的生长、分化和基因表达。该家族中被定性的第一个多肽是TGF-β1，它具有两个共价连接的相同的112个氨基酸的亚基。TGF-β1是高度保守蛋白，人与小鼠的TGF-β1只有一个氨基酸之差。哺乳动物表达的TGF-β基因家族还有其他两个成员。TGF-β2与TGF-β1有71％的同源性(de Martin等，(1987)EMBO J.6：3673-3677)，而TGF-β3与TGF-β1具有80％的同源性(Derynck等(1988)EMBO J7：3737-3743)。核磁共振测定的TGF-β1结构特征(Archer等(1993)Biochemistry 32：1164-1171)与TGF-β2的晶体结构相符(Daopin等，(1992)Science 257：369-374；Schlunegger和Grutter(1992)Nature 358：430-434)。
至少存在三种不同的胞外TGF-β受体，即与TGF-β1、-β2和-β3的生物功能相关的I、II和III型受体(综述参见Derynck(1994)TIBS 19：548-553和Massague(1990)Ann.Rev.Cell Biol.6：597-641)。I型和II型受体是跨膜丝氨酸/苏氨酸激酶，它们在TGF-β存在下形成异侧信号转导复合体(Wrana等(1992)Cell 71：1003-1014)。
异侧信号传导复合体在细胞表面的激活机理已经阐明(Wrana等(1994)Nature 370：341-347)。TGF-β首先与II型受体结合，II型受体是组成活化的跨膜丝氨酸/苏氨酸激酶。随后I型受体加入复合物中，在GS结构域磷酸化并被激活，从而使下游信号转导组分(例如Smad蛋白)磷酸化以启动细胞内信号转导级联反应。已证实组成活化的I型受体(T204D突变型)可有效转导TGF-β应答，从而绕过对TGF-β和II型受体的需要(Wieser等(1995)EMBO J14：2199-2208)。虽然未发现III型受体的信号转导功能，但它的确可增加TGF-β2对II型受体的亲和力，使其基本上与TGF-β1和TGF-β3等效(Lopez-Casillas等(1993)Cell 73：1435-1444)。
血管内皮细胞不含III型受体而表达一种被称为内皮因子(endoglin)的结构相关蛋白(Cheifetz等(1992)J.Biol.Chem.267：19027-19030)，该蛋白只与TGF-β1和TGF-β3以高亲和力结合。因此，TGF-β的相对效力可反映一个细胞或器官系统所表达的受体类型。除了对多因素信号转导路径中各组分的调控外，TGF-β多肽合成的分布还影响生理功能。TGF-β2和TGF-β3的分布较TGF-β1更为有限(Derynck等(1988)EMBO J7：3737-3743)，例如，TGF-β3限于间质源组织，而TGF-β1在间质源组织和上皮源组织中都存在。
TGF-β1是对组织修复起关键作用的多功能细胞因子。高浓度的TGF-β1由血小板颗粒运送至损伤处(Assoian和Sporn(1986)J.Cell Biol.102：1217-1223)。TGF-β1引发一系列促进愈合的事件，包括细胞如白细胞、单核细胞和成纤维细胞的趋化性，和与血管生成有关的生长因子和细胞因子的调控、与组织修复和炎症反应有关的细胞分裂。TGF-β1还刺激细胞外基质组分的合成(Roberts等(1986)Proc.Natl.Acad.Sci.USA 83：4167-4171；Sporn等(1983)Science 219：1329-1330；Massague(1987)Cell49：437-438)，和自身调节自己的合成，这一点对理解TGF-β1的病理生理最为重要(Kim等(1989)J.Biol.Chem.264：7041-7045)。
这里公开的化合物还可表现其他激酶活性，如p38激酶抑制和/或KDR(VEGFR2)激酶抑制。测定这种激酶活性的方法是本领域熟知的，本领域技术人员能够测定所公开化合物的此种活性。
发明概述
本发明还涉及式II的化合物：
式II
2-(6-甲基-吡啶-2-基)-3-[6-酰氨基-喹啉-4-基]-5，6-二氢-4H-吡咯并[1，2-b]吡唑及其可药用盐。
在2002年5月13日递交的PCT专利申请PCT/US02/11884中以通式的形式公开并要求了上述化合物的权利，该申请要求2001年5月24日递交的美国专利申请U.S.S.N.60/293,464的优先权，在此将其引入作为参考。与上面引用的申请中具体公开的化合物相比，上述化合物具有惊人优异的毒理学特征，其因此而被选中。
发明详述
用于例如″有效量的式I化合物，″中的术语″有效量″指能够抑制TGF-β的本发明化合物的量。
术语μM指微摩尔。
这里使用的一般化学术语具有它们通常的意义。
下列缩略语用于整个合成方案和实施例中：
DMF指二甲基甲酰胺
THF指四氢呋喃
Ms指甲磺酰基，即甲基磺酰基
THP指四氢吡喃
这里公开的化合物可根据下列方案和实施例制备。这些实施例绝不应被理解为以任何方式限制如何制备这些化合物。
以下方案举例说明式I化合物的制备。
方案I
以下方案举例说明式II化合物的制备。
方案II
下列实施例进一步举例说明方案I和方案II图示的本发明化合物的制备。
实施例1
7-(2-吗啉-4-基-乙氧基)-4-(2-吡啶-2-基-5，6-二氢-4H-吡咯并[1，2-b]吡唑-3-基)-喹啉的制备
A.4-(2-吡啶-2-基-5，6-二氢-4H-吡咯并[1，2-b]吡唑-3-基)-7-[2-(四氢吡喃-2-基氧基)乙氧基]喹啉的制备
于120℃加热4-(2-吡啶-2-基-5，6-二氢-4H-吡咯并[1，2-b]吡唑-3-基)-喹啉-7-醇(376mg，1.146mmol)、碳酸铯(826mg，2.54mmol)和2-(2-溴乙氧基)-四氢-2H-吡喃(380μl，2.52mmol)在DMF(5mL)中的溶液4小时。用饱和氯化钠溶液使反应骤停并用氯仿萃取。将有机层用硫酸钠干燥并真空浓缩。用硅胶柱纯化反应混合物，用二氯甲烷至10％甲醇的二氯甲烷溶液洗脱，得到所需的副标题中间产物，为黄色油(424mg，81％)。MS ES+m/e 457.0(M+1)。
B.2-[4-(2-吡啶-2-基-5，6-二氢-4H-吡咯并[1，2-b]吡唑-3-基)-喹啉-7-基氧基]-乙醇的制备
加热4-(2-吡啶-2-基-5，6-二氢-4H-吡咯并[1，2-b]吡唑-3-基)-7-[2-(四氢吡喃-2-基氧基)乙氧基]喹啉(421mg，0.92mmol)于乙酸∶四氢呋喃∶水(4∶2∶1)(20mL)中的溶液。真空除去溶剂，残余物用氯仿∶异丙醇(3∶1)溶解。有机层用饱和碳酸氢钠洗涤并用硫酸钠干燥。真空浓缩。残余物的纯度足够用于方案中的下一步骤(425mg，100％)。MS ES+m/e 373.1(M+1)。
C.甲磺酸2-[4-(2-吡啶-2-基-5，6-二氢-4H-吡咯并[1，2-b]吡唑-3-基)-喹啉-7-基氧基]-乙酯的制备
将2-[4-(2-吡啶-2-基-5，6-二氢-4H-吡咯并[1，2-b]吡唑-3-基)-喹啉-7-基氧基]-乙醇(293mg，0.78mmol)和甲磺酰氯(68μl，0.81mmol)于无水吡啶(5mL)中的溶液搅拌2小时。真空除去吡啶，残余物用氯仿溶解。有机层用饱和碳酸氢钠洗涤并用硫酸钠干燥，得到所需的副标题中间产物，为白色泡沫状物(425mg，100％)。MS ES+m/e 451.1(M+1)。
D.7-(2-吗啉-4-基-乙氧基)-4-(2-吡啶-2-基-5，6-二氢-4H-吡咯并[1，2-b]吡唑-3-基)-喹啉的制备
将甲磺酸2-[4-(2-吡啶-2-基-5，6-二氢-4H-吡咯并[1，2-b]吡唑-3-基)-喹啉-7-基氧基]-乙酯(87mg，0.19mmol)与吗啉(1mL)于50℃加热4小时。真空除去吗啉，用异丙醇∶氯仿(1∶3)萃取产物。有机层用氯化钠洗涤，硫酸钠干燥。真空浓缩得到所需的标题产物，为淡黄色固体(83mg，100％)。MS ES+m/e 442.0(M+1)。
实施例2
2-(6-甲基-吡啶-2-基)-3-[6-酰氨基-喹啉-4-基]-5，6-二氢-4H-吡咯并[1，2-b]吡唑的制备
A.6-溴-4-甲基-喹啉的制备
搅拌4-溴-苯胺(1当量)于1，4-二烷中的溶液并冷却至约12℃。缓慢加入硫酸(2当量)并回流加热。向回流的溶液中滴入甲基乙烯基酮(1.5当量)。加完后加热溶液1小时。将反应溶液蒸发至干并用二氯甲烷溶解。溶液用1M碳酸钠调至pH 8，并用水萃取3次。残余物进行SiO2色谱分离(70/30己烷/乙酸乙酯)得到所需的副标题中间产物。MS ES+m/e＝158.2(M+1)。
B.6-甲基-吡啶-2-甲酸甲酯的制备
将6-甲基-吡啶-2-甲酸(10g，72.9mmol)悬浮于二氯甲烷(200mL)，冷却至0℃。加入甲醇(10mL)、4-二甲基氨基吡啶(11.6g，94.8mmol)和1-(3-二甲基氨基丙基)-3-乙基碳二亚胺盐酸盐(EDC)(18.2g，94.8mmol)。室温下搅拌混合物6小时，用水和盐水洗涤、用硫酸钠干燥。将混合物过滤并真空浓缩。残余物经SiO2色谱分离(50％乙酸乙酯/己烷)得到所需的副标题中间产物9.66g(92％)，为无色液体。1H NMR(CDCl3)δ7.93-7.88(m，1H)，7.75-7.7(m，1H)，7.35-7.3(m，1H)，4.00(s，3H)，2.60(s，3H)。
C.2-(6-溴-喹啉-4-基)-1-(6-甲基-吡啶-2-基)-乙酮的制备
将6-溴-4-甲基-喹啉(38.5g，153mmol)溶于600mL无水THF中。冷却至-70℃并在保持温度低于-65℃的情况下，于2小时内滴入0.5M六甲基二硅胺烷基钾(KN(SiMe3)2(400mL，200mmol)。于-70℃下搅拌所得溶液1小时，15分钟内滴入6-甲基吡啶-2-甲酸甲酯(27.2，180mmol)于100mL无水THF中的溶液。加入过程中，混合物由深红色变为淡绿色并形成沉淀。于-70℃搅拌2小时以上然后升温至室温搅拌5小时。冷却混合物然后用12N HCl调至pH＝1终止反应。用固体碳酸钾使pH升至9。滗留固体将溶液轻轻倒出并用200mL乙酸乙酯萃取两次。合并有机萃取液，用水洗涤、用碳酸钾干燥。将固体在200mL水和200mL乙酸乙酯中搅拌并另加碳酸钾处理。分离有机部分并与前面的乙酸乙酯萃取液一同干燥。真空浓缩溶液得到深色油。将该油通过300mL二氧化硅填料，依次用二氯甲烷和乙酸乙酯洗脱。合并适当的馏分，真空浓缩得到琥珀色油。用二氯甲烷将该油沿烧瓶壁冲入瓶中，然后一边回荡烧瓶一边用己烷稀释，得到38.5g(73.8％)所需的副标题中间产物，为黄色固体。MS ES+＝341(M+1)。
D.1-[2-(6-溴-喹啉-4-基)-1-(6-甲基-吡啶-2-基)-亚乙基氨基]-吡咯烷-2-酮的制备
于室温下搅拌2-(6-溴-喹啉-4-基)-1-(6-甲基-吡啶-2-基)-乙酮(38.5g，113mmol)和1-氨基吡咯烷酮盐酸盐(20g，147mmol)于115mL吡啶中的混合物10小时。加入约50g未活化的4埃分子筛。继续搅拌13小时并加入10-15g二氧化硅，将混合物滤过50g二氧化硅填料，用3L乙酸乙酯洗脱。合并洗脱液，真空浓缩。过滤收集腙沉淀，抽吸干燥，得33.3g(69.7％)所需的副标题中间产物，为灰白色固体。MS ES+＝423(M+1)。
E.6-溴-4-[2-(6-甲基-吡啶-2-基)-5，6-二氢-4H-吡咯并[1，2-b]吡唑-3-基]-喹啉的制备
向碳酸铯(1.2当量)和1-[2-(6-溴-喹啉-4-基)-1-(6-甲基-吡啶-2-基)-亚乙基氨基]-吡咯烷-2-酮(33.3g，78.7mmol)的混合物中加入300mL无水N，N-二甲基甲酰胺。于100℃下搅拌混合物20分钟。反应过程中混合物颜色变深。真空除去N，N-二甲基甲酰胺。将残余物于水和二氯甲烷间分配。另用二氯甲烷萃取水相。将有机溶液滤过300mL二氧化硅填料并用1.5L二氯甲烷、1.5L乙酸乙酯和1.5L丙酮洗脱。合并适当的级分，真空浓缩。过滤收集沉淀物得到22.7g(71.2％)所需的副标题中间产物，为灰白色固体。MS ES+＝405(M+1)。
F.4-[2-(6-甲基-吡啶-2-基)-5，6-二氢-4H-吡咯并[1，2-b]吡唑-3-基]-喹啉-6-甲酸甲酯的制备
将6-溴-4-[2-(6-甲基-吡啶-2-基)-5，6-二氢-4H-吡咯并[1，2-b]吡唑-3-基]-喹啉(22.7g，45mmol)加至乙酸钠(19g，230mmol)和钯催化剂[1，1′-二(联苯基膦基)二茂铁]二氯化钯(II)与二氯甲烷的复合物(1∶1)(850mg，1.04mmol)]于130mL甲醇中的混合物中。将混合物置于50psi一氧化碳气氛中，搅拌并于1小时内升温至90℃，同时持续充入一氧化碳。使混合物在8小时内冷却，再次充入一氧化碳并加热至90℃。压力可升至75PSI。约1小时内，当压力稳定并且薄层色谱(1∶1甲苯/丙酮)显示没有残留溴化物时反应完成。将混合物于二氯甲烷(600mL)和水(1L)间分配。用另外的二氯甲烷(400mL)萃取水相。将有机溶液滤过300mL二氧化硅填料，用500mL二氯甲烷、1200mL乙酸乙酯和1500mL丙酮洗脱。弃掉丙酮部分。合并适当的馏分，浓缩得到18.8g(87.4％)所需的副标题中间产物，为粉色粉末。MS ES+＝385(M+1)。
G.2-(6-甲基-吡啶-2-基)-3-[6-酰氨基-喹啉-4-基]-5，6-二氢-4H-吡咯并[1，2-b]吡唑的制备
于不锈钢高压罐中将4-[2-(6-甲基-吡啶-2-基)-5，6-二氢-4H-吡咯并[1，2-b]吡唑-3-基]-喹啉-6-甲酸甲酯在60mL 7N氨/甲醇溶液中的混合物加热并保持在90℃66小时。压力将升至约80PSI。反应过程中保持该压力。将罐冷却，真空浓缩该棕色混合物。将残余固体通过两个串联的12gRedi-Pak料筒，洗脱剂为丙酮。合并适当的级分，真空浓缩。将所得的近白色固体悬浮于二氯甲烷中，用己烷稀释、过滤。收集灰白色固体得到1.104g(63.8％)所需的标题产物。MS ES+＝370(M+1)。
通过以下试验方案测试本文公开的化合物的TGF β抑制活性，如下面试验方案所述。
I型TGF-β受体的纯化和体外激酶反应
对于I型TGF-β(RIT204D)受体：
用Sf9昆虫细胞表达、并从溶胞产物中纯化出每个受体的6X-HIS标记的胞质激酶结构域，方法简述如下：
感染48-72小时后将细胞团于溶解缓冲液(LB：50mM Tris pH 7.5、150mM NaCl、50mM NaF、新加入20mM β-巯基乙醇的0.5％NP40、10mM咪唑、1mM PMSF、1X不含EDTA的全蛋白酶抑制剂(BoehringerMannheim))中溶解。
将溶胞产物离心使之澄清并进行0.45μM过滤，然后用Ni/NTA亲和色谱(Qiagen)纯化。
色谱方案：
用10CV的LB平衡，上样，用10CV RIPA缓冲液(50mM Tris pH 7.5、150mM NaCl、1％NP40、1mM EDTA、新加入20mM β-巯基乙醇的0.25％去氧胆酸钠、1mM PMSF)冲洗，用10CV LB冲洗，用10CV 1X KB(50mMTris pH 7.5、150mM NaCl、4mM MgCl2、1mM NaF、2mM β-巯基乙醇)冲洗，用含200mM咪唑的1X KB线性梯度洗脱。
两种酶纯度均为约90％并具有自磷酸化活性。
反应：酶的1X KB溶液浓度为170-200nM，化合物用1X KB/16％DMSO系列稀释(终浓度20μM至1nM，含终浓度为4％的DMSO)，加入ATP混合物(4μM ATP/1μCi33P-γ-ATP终浓度)的1X KB溶液使反应开始。
将反应于30℃下保温1小时。停止反应，用标准TCA/BSA在MilliporeFB玻璃纤维滤板上的沉淀作用并通过在MicroBeta JET上进行液体闪烁计数来定量。
本文公开的化合物抑制I型TGF-β(RIT204D)受体激酶结构域，IC50值＜20μM，并且体内毒性比上述PCT专利申请PCT/US02/11884中公开的结构相关化合物低。
“以TGF-β活性增强为特征”的情况包括TGF-β合成受激所致TGF-β存在水平升高的情况，或者TGF-β潜伏蛋白质非正常激活或者转化为活性TGF-β蛋白质的情况，或者TGF-β受体上调的情况，或者TGF-β蛋白质表现对疾病部位细胞或胞外基质结合力增强的情况。因此，任何情况中的“活性增强”指无论任何原因引起的TGF-β生物活性非正常升高。
已经证实了许多疾病与TGF-β1生成过量有关。TGF-β胞内信号转导路径的抑制剂可用于纤维增生性疾病的治疗。具体而言，纤维增生性疾病包括与TGF-β活性失调和过度纤维化有关的肾病，包括肾小球肾炎(GN)如肾小球系膜增生性GN、免疫GN和新月形GN。其他肾脏病症包括糖尿病性肾病变、肾间质性纤维变性、接受环孢菌素的移植患者的肾纤维变性和HIV相关肾病。胶原血管病症包括进行性全身性硬化症、多肌炎、硬皮病、皮肤肌炎、嗜酸细胞性筋膜炎、硬斑病或与雷诺氏综合征发病相关的病症。TGF-β活性过度导致的肺纤维变性包括成人呼吸窘迫综合征、特发性肺纤维变性和常与自身免疫性疾病如系统性红斑狼疮和硬皮病、化学物质接触或过敏有关的间质性肺纤维变性。与纤维增生特征相关的另一种自身免疫性疾病是类风湿性关节炎。
与纤维增生性病症有关的眼部疾病包括视网膜复置手术伴随增殖性玻璃体视网膜病变、白内障摘出术并植入眼内人工晶状体和与TGF-β1过量生成有关的青光眼后引流手术。
与TGF-β1生成过量有关的纤维变性疾病可分为慢性病症如肾部、肺部和肝脏纤维变性和较急性的病症如皮肤瘢痕化和再狭窄(Chamberlain，J.Cardiovascular Drug Reviews，19(4)：329-344)。肿瘤细胞TGF-β1的合成和分泌可导致免疫抑制例如在侵袭性脑瘤或乳腺瘤患者中所观察到的(Arteaga等，(1993)J.Clin.Invest.92：2569-2576)。小鼠的利什曼原虫感染过程可被TGF-β1彻底改变(Barral-Netto，et al.(1992)Science 257：545-547)。TGF-β1使疾病恶化，而TGF-β1抗体在遗传易感鼠内却使病程停止进展。遗传抗感鼠施用TGF-β1后变得对利什曼原虫易感。
关于TGF-β1对胞外基质沉积复杂影响的综述参见Rocco和Ziyadeh(1991)，当代肾病学问题v.23，激素、自泌物和肾脏，Jay Stein编，ChurchillLivingston，New York pp.391-410；Roberts等(1988)Rec.Prog.HormoneRes.44：157-197，其中还包括对胞外基质组分的合成刺激作用和降解抑制作用。由于肾小球的结构和过滤性质很大程度上决定于肾小球系膜和肾小球膜胞外基质的构成，所以TGF-β1对肾脏的影响复杂也不足为怪。增生性肾小球肾炎(Border等(1990)Kidney Int.37：689-695)和糖尿病性肾病(Mauer等(1984)J.Clin.Invest.74：1143-1155)中肾小球系膜基质的堆积是该种疾病明确而主要的病理特征。人糖尿病性肾小球硬化症中TGF-β1水平有所升高(高级神经病变)(Yamamoto等(1993)Proc.Natl.Acad.Sci.90：1814-1818)。TGF-β1是许多动物模型中产生肾脏纤维变性的重要介质(Phan等(1990)Kidney Int.37：426；Okuda等(1990)J.Clin.Invest.86：453)。TGF-β1抗血清(Border等(1990)Nature 346：371)和一种可结合TGF-β1的胞外基质蛋白，即核心蛋白多糖(Border，et al.(1992)Nature 360：361-363)在大鼠中显示可抑制实验诱导的肾小球肾炎。
过多的TGF-β1可导致皮肤瘢痕组织形成。注入大鼠正在愈合的伤口边缘后，中和TGF-β1的抗体显示抑制瘢痕形成但却不干扰伤口愈合速度或伤口牵引力强度(Shah，et al.(1992)Lancet 339：213-214)。同时，新血管生成减少、伤口内巨噬细胞和单核细胞数量降低，瘢痕组织中裂解的胶原纤维沉积量降低。
TGF-β1可能是气囊血管成形术后动脉中平滑肌细胞增生和胞外基质沉积导致的进行性动脉壁增厚的一个因素。由于增厚，再狭窄的动脉直径可减小90％，而且由于大部分直径减小是由胞外基质而非平滑肌细胞体引起，所以单单减少广泛的胞外基质沉积即可能打开这些血管的50％。用TGF-β1基因体内转染的完整无损的猪动脉中，TGF-β1基因的表达与胞外基质合成和过度增生都有关(Nabel等(1993)Proc.Natl.Acad.Sci.USA 90：10759-10763)。TGF-β1诱导的过度增生不如PDGF-BB诱导的过度增生广泛，但是胞外基质在TGF-β1转染子中更为广泛。在该转基因猪模型中，未发现胞外基质沉积与FGF-1(FGF的一种分泌形式)诱导的过度增生有关(Nabel(1993)Nature 362：844-846)。
肿瘤产生的TGF-β1在几种类型的癌症中可能有害。MATLyLu大鼠前列腺癌细胞(Steiner和Barrack(1992)Mol.Endocrinol 6：15-25)和MCF-7人乳腺癌细胞(Arteaga等(1993)Cell Growth and Differ.4：193-201)在转染表达小鼠TGF-β1的载体后变得更易发生肿瘤和瘤转移。已经将TGF-β1与新血管生成、人前列腺癌和晚期胃癌的转移和预后不良联系在一起(Wikstrom，P.等(1998)Prostate 37：19-29；Saito，H.等(1999)Cancer86：1455-1462)。乳腺癌中预后不良与TGF-β升高有关(Dickson等(1987)Proc.Natl.Acad.Sci.USA 84：837-841；Kasid等(1987)Cancer Res.47：5733-5738；Daly等(1990)J.Cell Biochem.43：199-211；Barrett-Lee等(1990)Br.J Cancer 61：612-617；King等(1989)J.Steroid Biochem.34：133-138；Welch等(1990)Proc.Natl.Acad.Sci.USA 87：7678-7682；Walker等(1992)Eur.J.Cancer 238：641-644)，而且发现他莫昔芬治疗对TGF-β1的诱导作用(Butta等(1992)Cancer Res.52：4261-4264)与他莫昔芬治疗乳腺癌失败有关(Thompson等(1991)Br.J.Cancer 63：609-614)。抗TGF-β1抗体可抑制裸鼠体内MDA-231人乳腺癌细胞的生长(Arteaga等(1993)J.Clin.Invest.92：2569-2576)，该效果与脾脏自然杀伤细胞活性升高有关。转染了潜伏TGF-β1的CHO细胞也表现出NK活性下降和裸鼠体内肿瘤生长的增加(Wallick等(1990)J.Exp.Med.172：1777-1784)。因此，乳腺肿瘤分泌的TGF-β可能引起内分泌免疫抑制。高TGF-β1血浆浓度已显示为乳腺癌晚期患者预后不良的象征(Anscher等(1993)N.Engl.J.Med.328：1592-1598)。高剂量化疗和自体骨髓移植之前循环TGF-β高的患者得肝脏静脉闭塞性疾病(占全部患者的15-50％，死亡率可达50％)和自发性间质性肺炎(占全部患者的40-60％)的风险高。这些发现意味着1)TGF-β1血浆水平升高可用于鉴别有危险的患者，并且2)降低TGF-β1可降低乳腺癌患者普通治疗的发病率和死亡率。
许多恶性细胞分泌转化生长因子-β(TGF-β)，由于TGF-β是一种强力的免疫抑制剂，这说明TGF-β的生成是肿瘤能逃过宿主的免疫监视的重要机理。用中断的TGF-β信号转导在带瘤宿主中建立白细胞亚群是癌症免疫治疗的潜在方法。T细胞TGF-β信号转导中断的转基因动物模型能够根除通常是致命的过度表达TGF-β的淋巴瘤，即EL4(Gorelik和Flavell，(2001)Nature Medicine 7(10)：1118-1122)。肿瘤细胞中TGF-β分泌下调致使宿主免疫原性恢复，而T细胞对TGF-β不敏感可促进分化和自身免疫，这些元素可能是耐受的宿主中与表达自身抗原的肿瘤斗争所必须的。一个亚群的HIV患者的免疫反应低于根据他们CD4/CD8T细胞计数的预测，这也隐含说明了TGF-β的免疫抑制效果(Garb等J.Immunology(2002)168：2247-2254)。TGF-β中和性抗体能够在培养基中逆转该效应，表明TGF-β信号转导抑制剂可能在逆转该亚群HIV患者的免疫抑制上有效用。
在致癌作用的最早期，TGF-β1可作为强力的肿瘤抑制剂并介导一些化学预防试剂的作用。然而，在恶性肿瘤的发展和增进过程中的某一点，肿瘤细胞似乎可以逃离TGF-β依赖的生长抑制，同时有生物活性的TGF-β出现在微环境中。TGF-β肿瘤抑制/肿瘤促进的双重作用在利用角质化细胞表达TGF-β的转基因系统中阐明得非常清晰。转基因产物对良性皮肤病损的形成较为抵抗，而转基因产物中转移性转变的速度却明显增加(Cui等(1996)Cell 86(4)：531-42)。原发肿瘤中恶性细胞TGF-β1的生成似乎随着进行性肿瘤的阶段增长而增加。对许多主要上皮癌的研究表明，人癌症生成的TGF-β增加在进行性肿瘤中发生的相对较晚。而且，该肿瘤相关TGF-β向肿瘤细胞提供了选择性优势并促进肿瘤进展。TGF-β对细胞/细胞和细胞/间质相互作用的影响导致更大的侵害和转移倾向。肿瘤相关TGF-β可允许肿瘤细胞逃离免疫监视，因为它是活化淋巴细胞克隆扩增的强力抑制剂。TGF-β还表现出抑制血管抑素生成的作用。癌症治疗方式如放射治疗和化学治疗可诱导肿瘤中活化TGF-β的生成，并藉此选择了拮抗TGF-β生长抑制效果的恶性细胞的向外生长。因此，这些抗癌治疗会增加生长力和侵入力增强的肿瘤发生的风险并加速其发展。在这种形势下，靶向TGF-β介导的信号转导的试剂可能是一个非常有效的治疗策略。已证实肿瘤细胞对TGF-β的抗性可抵消大部分放射治疗和化学治疗的细胞毒性，而且基质中TGF-β的治疗依赖性激活甚至可能是有害的，因为这将使微环境更有利于肿瘤进展和导致纤维变性的组织损伤。TGF-β信号转导抑制剂单独或与其他治疗相结合，可能对癌症晚期治疗大有裨益。
这些化合物在有需要的患者中可通过抑制TGF-β来治疗癌症和受TGF-β影响的其它疾病状态，方法为向所述患者施用上述化合物。TGF-β还可用于对抗动脉粥样硬化(T.A.McCaffrey：动脉粥样硬化中的TGF-β和TGF-β受体：细胞因子和生长因子综述2000，11，103-114)和阿尔茨海默病(Masliah，E.；Ho，G.；Wyss-Coray，T.：TGF-β在阿尔茨海默病微血管损伤中的功能作用：得自转基因小鼠的结果：Neurochemistry International2001，39，393-400)。
药物组合物
本发明的组合物是治疗有效量的TGF-β拮抗剂，如上所述。该组合物可与普通赋形剂、稀释剂或载体配方并压制成片剂，或者为方便口服施用或肌内或静脉注射而制备成酏剂或溶液。该化合物也可经皮施用并制备成缓释剂型等。
根据本发明，治疗人类患者的方法包括施用TGF-β拮抗剂。将TGF-β拮抗剂制备成可通过口服和直肠途径、局部、胃肠外途径如通过注射和连续或非连续动脉内输注施用的制剂，其形式可以为，例如片剂、锭剂、舌下片、小药袋、扁囊剂、酏剂、凝胶剂、混悬液、气雾剂、软膏，例如在适合的基质中含有1至10％重量活性化合物的软膏，软和硬明胶胶囊、栓剂、在生理相容性介质中的可注射溶液和混悬液、吸附于支持材料上的用于制备注射溶液的无菌包装粉末。
为此目的，优选将组合物制成剂量单位形式，优选每个剂量单位含化合物约5至约500mg(胃肠外或吸入给药途径约5至50mg，口服或直肠给药途径约25至500mg)。可以施用约0.5至约300mg/kg，优选0.5至20mg/kg活性成分的日剂量，虽然，无庸置疑，实际施用的化合物量应由医生根据各种相关情况，包括治疗的病症、所施用的化合物和给药途径来确定，因此上述优选剂量范围无意以任何方式限制本发明的范围。
用于单独施用TGF-β拮抗剂的制剂通常包含至少一种本文指定的化合物，混合以载体、或用载体稀释、或用胶囊、小药袋、扁囊、纸或其他外壳形式的可吸收载体或一次性容器如安瓿包附或包封。载体或稀释剂可以是固体、半固体或液体材料，其作为活性治疗物质的载体、赋形剂或介质。本发明的药物组合物中可使用的稀释剂或载体的实施例有乳糖、右旋糖、蔗糖、山梨醇、甘露醇、丙二醇、液体石蜡、白软石蜡、高岭土、火成二氧化硅、微晶纤维素、硅酸钙、二氧化硅、聚乙烯吡咯烷酮、鲸蜡/硬脂醇、淀粉、改性淀粉、阿拉伯胶、磷酸钙、可可脂、乙氧基化的酯、可可油、花生油、藻酸盐、黄蓍胶、明胶、糖浆、甲基纤维素、聚氧乙烯脱水山梨醇单月桂酸酯、乳酸乙酯、羟基苯甲酸甲酯和丙酯、失水山梨醇三油酸酯、失水山梨醇倍半油酸酯、油醇和抛射剂如三氯氟甲烷、二氯二氟甲烷和二氯四氟乙烷。片剂中可加入润滑剂以防止各成分粉末在压片机冲头上和冲模内粘结。为此目的，可用例如硬脂酸铝、硬脂酸镁或硬脂酸钙、滑石粉或矿物油。
本发明优选的药物形式为胶囊、片剂、栓剂、可注射溶液、霜剂和软膏剂。特别优选吸入应用的制剂如气雾剂、注射用制剂和口服制剂。
Claims (3)
1.式II化合物2-(6-甲基-吡啶-2-基)-3-[6-酰氨基-喹啉-4-基]-5，6-二氢-4H-吡咯并[1，2-b]吡唑或其可药用盐
2.药物制剂，其含有根据权利要求1的化合物或其可药用盐与可药用稀释剂、赋形剂或载体。
3.权利要求1的化合物或其可药用盐在制备用于治疗癌症的药物中的用途。
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