CN1100540C - 具有选择性抑制her－2自磷酸化性质的蛋白质酪氨酸激酶芳基和杂芳基喹唑啉化合物 - Google Patents

具有选择性抑制her－2自磷酸化性质的蛋白质酪氨酸激酶芳基和杂芳基喹唑啉化合物 Download PDF

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CN1100540C
CN1100540C CN96194512A CN96194512A CN1100540C CN 1100540 C CN1100540 C CN 1100540C CN 96194512 A CN96194512 A CN 96194512A CN 96194512 A CN96194512 A CN 96194512A CN 1100540 C CN1100540 C CN 1100540C
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dimethoxyquinazoline
hydrogen
pharmaceutically acceptable
acceptable salt
alkyl
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CN1187129A (zh
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M·R·米尔斯
A·P·斯帕达
M·P·马古里
P·E·普桑斯
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Aventis Pharmaceuticals Inc
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Abstract

本发明涉及用于选择性治疗以人表皮生长因子受体2型(HER2)的活性为特征的细胞生长和分化的方法。更具体地说，本发明涉及取代的或未取代的单-环或双-环芳基、杂芳基、环烷基或杂环烷基化合物在选择性地调节细胞生长中的用途。本发明也描述了用于选择性治疗细胞生长和分化的药物组合物。

Description

具有选择性抑制HER-2自磷酸化性质的 蛋白质酪氨酸激酶芳基和杂芳基喹唑啉化合物
                        发明背景
本申请是PCT国际申请PCT/US94/14180(其国际申请日为1994年12月8日，指定美国)、美国08/166,199号申请(其申请日是1993年12月10日，它是1992年12月10日提出申请的美国07/988,515号申请的部分继续申请，后者是1991年5月年10日提出申请的美国07/698,420号申请的部分继续申请)以及PCT国际申请PCT/US92/03736(1992年5月6日提出申请，指定美国，已导致获得美国专利5,409,930)的部分继续申请。
                     发明所属技术领域
本发明涉及用于选择性治疗以人表皮生长因子受体2型(HER2)的活性为特征的细胞生长和分化的方法。更具体地说，本发明涉及取代的或未取代的单-环或双-环芳基、杂芳基、环烷基或杂环烷基化合物在选择性地调节细胞生长中的用途。
正常的细胞复制被认为由细胞底物与一种或多种生长因子的接触触发，生长因子的例子是胰岛素、表皮生长因子(EGF)和血小板来源的生长因子(PDGF)。这样的生长因子受体嵌镶于细胞膜中并穿过细胞膜。当生长因子结合到细胞膜外表面的相应受体上时就认为细胞复制开始发生。该生长因子-受体结合改变了受体(存在于细胞内部，作为催化胞内底物或受体自身磷酸化的酶起作用，后者称为自磷酸化)的结合部分的化学特征。这样的磷酸化酶的例子包括酪氨酸激酶，该酪氨酸激酶催化底物蛋白质的酪氨酸残基的磷酸化。
许多疾病状态的特征在于细胞不受控制的复制。这些疾病状态包括各种细胞类型并包括这样一些病症，如白血病、癌、牛皮癣、炎症性疾病、骨疾病、动脉粥样硬化和血管形成术后的再狭窄。酪氨酸激酶的抑制被认为具有控制不受控制的细胞复制(即细胞增殖病症)的效用。
胞内底物宿主(host)的自磷酸化(即生长因子受体自身的磷酸化)和磷酸化的起始是一些生物化学事件，这些事件包括介质释放导致有丝分裂和细胞增殖。胰岛素受体的自磷酸化以及通过其它受体的底物蛋白质的磷酸化是最早可鉴别的生物化学激素反应。
通过细胞遗传物质(负责胰岛素和EGF的产生)的定点诱变除去胰岛素受体和表皮生长因子(EGF)受体的蛋白质酪氨酸激酶(PTK)活性导致受体生物学活性的完全消除。这不是很合乎需要，因为身体还需要胰岛素完成与细胞增殖无关的其它生物学功能。因此，以小于抑制胰岛素受体的PTK部分所需浓度的浓度抑制EGF和/或PDGF受体的PTK部分的化合物可提供用于选择性地治疗细胞增殖病症的有价值的药剂。
                       已报道的进展
人们普遍接受这样一种观点，即与生长因子受体有关的蛋白质酪氨酸激酶(PTK)活性对配体诱导的生物学反应(如细胞生长和分化)是必需的。J.M.Bishop(1985)细胞，42：23-38和T.Hunter(1987)细胞50：823-829报道了通过酪氨酸磷酸化的异常细胞生长和形态转变的证据，生长因子受体代表了bonafide致癌基因族。这些致癌基因产物中是人表皮生长因子受体2型(HER2；c-erbB-2)。Carpenter等(1987)生物化学年评，56：881-和Gill等(1987)Mol.Cell.Endocrinol.，51：169-报道了c-erbB-1基因编码170kDa的跨膜糖蛋白。HER2基因是大鼠原癌基因neu的人同系物，这由C.I.Bargmann，M.C.Hung和R.A.Weinberg(1986)自然，319：226-229报导，其产物是185-kDa跨膜细胞表面糖蛋白，称为p185HER2，这由Coussens等(1985)科学230：1132-1139和Yamamoto等(1986)自然319：230-234报导。该受体具有内在的酪氨酸-特异性激酶活性(通过把其同源配体结合在受体胞外结构域上，它能够催化自磷酸化反应并介导内源底物磷酸化)。
发现了未改变的HER2基因在各种人肿瘤上扩增。此外，在患几种癌症类型的患者中建立了高水平P185HER2表达和不良预后或短暂存活时间之间的相关性。因为使用抗p185HER2产生的抗体(它封闭受体功能)导致肿瘤细胞系的生长停止和小鼠中抗肿瘤作用，化学-设计的试剂选择性地抑制p185HER2-有关的PTK的策略在癌症治疗中有价值。现在大量文献显示已系统地评价了许多天然产生的和合成的PTK抑制剂的潜在抗肿瘤功效，如由C.Workman，V.G.Brunton和D.J.Robins(1992)在“癌症生物学研论会”，3：369-381以及C.Wasylyk，A.Gutman，R.Nicholson和B.Wasylyk(1991)EMBO杂志，10：1127-1134中报道的。
在本文中申请人描述了一系列喹唑啉衍生物(它们是p185HER2选择性的酪氨酸激酶抑制剂)的鉴别和定性方法。尤其是，申请人证明了保持由p185HER2超量表达诱导的转化的细胞表型，需要与HER2基因产物有关的酪氨酸激酶活性。
                         发明概述
本发明提供了用于选择性治疗以人表皮生长因子受体2型(HER2)的活性为特征的细胞生长和分化的方法，该方法包括对需要这样治疗的患者施用HER2受体抑制有效量的、在本发明中所描述的喹唑啉化合物。
本发明的另一个方面涉及用于选择性地治疗以人表皮生长因子受体2型(HER2)的活性为特征的细胞生长和分化的药物组合物，该药物组合物包含与药学上可接受的载体混合的、治疗有效量的前述类型的化合物。
本发明的另一个方面还包括用于实施本发明的方法的新化合物。
就本发明的各方面而言，由以下式I描述的化合物或其药学上可接受的盐组成了一类前述的、用于实施本发明的喹唑啉化合物：其中
A是大约5至12个原子的取代的或未取代的单-环或双-环芳基、杂芳基、环烷基或杂环烷基环状系统，其中的取代基可位于环状系统的任何适当的位置，并由R代表；
X是化学键、O、S、SO、SO2、OCH2、CR4＝CR4、C≡C、NR4或NR4CH2；
R独立地包括氢、烷基、苯基、卤苯基、芳烷基、羟基、烷氧基、芳氧基、酰氧基、卤素、卤代烷基、氨基、一-和二-烷基氨基、酰基氨基、羧基、酰氨基、一-和二-烷基酰氨基、烷硫基、烷亚硫酰基以及烷磺酰基。
R4是氢、烷基或芳烷基；
R5，R6，R7和R8独立地是氢、烷氧基或芳烷氧基。
                 详述描述及优选的实施方案
除非特别指出，上面与本说明书全文使用的下列术语应理解为具有下列含义：
“单环芳基”或“单环杂芳基”指碳环或杂环芳环。优选的环包括苯基、吡咯基、噻吩基、呋喃基、噻唑基、咪唑基、吡唑基、吡啶基、吡嗪基、嘧啶基、哒嗪基、异噻唑基、异噁唑基和噁唑基。
“双环芳基”或“双环杂芳基”指由两个稠和的环(其中至少之一是碳环或杂环芳环)组成的双环环状系统。优选的环包括取代的和未取代的萘基、1，2，3，4-四氢萘基、1，2，3，4-四氢喹啉基、苯并呋喃基、苯并噻吩基、吲哚基、二氢吲哚基、1，3-苯并间二氧杂环戊烯基、苯并二噁烷基、喹啉基、四氢喹啉基、异喹啉基、喹唑啉基和喹喔啉基。
“单环环烷基”指包含大约四至七个碳原子的脂族环，如取代的和未取代的环戊基、环己基和环庚基。
“双环环烷基”指包含大约8至12个碳原子的、由包含两个稠和的脂族环组成的饱和双环环状系统，如取代的和未取代的十氢萘基。
“单环杂环烷基”指包含大约四至七个原子的饱和环状的脂族环，它包含选自N、O和S的1-2个杂原子(假如所说的杂原子不在氧和/或硫附近)，如取代和未取代的哌啶基、哌嗪基和吗啉基。
“双环杂环烷基”指包含大约8至12个原子的两个稠和的脂族环的饱和双环环状系统，它包含选自N、O和S的1-3个杂原子(假如所说的杂原子不在氧和/或硫附近)，如取代和未取代的十氢喹啉基。
“烷基”指饱和的支链或直链脂族烃。优选的烷基是具有大约1至6个碳原子的“低级烷基”。烷基的例子包括甲基、乙基、正丙基、异丙基、丁基、仲丁基、叔丁基、戊基和己基。
“烷氧基”指烷基-O-基团。优选的烷氧基包括甲氧基、乙氧基、丙氧基和丁氧基。
“芳氧基”指芳基-O-基团。优选的芳氧基是苯氧基。
“芳烷基”指由芳基取代的烷基基团。优选的芳烷基是苯基或苯乙基。
优选的芳烷氧基基团是苄氧基和苯乙氧基。
优选的酰氧基基团是乙酰氧基和苄氧基；
“卤素”指卤素。优选的卤素包括氯、溴和氟。
优选的卤代烷基基团是单-、二-和三氟甲基。
更具体地说，优选的A单环芳基或杂芳基环包括取代的或未取代的苯基、吡咯基、噻吩基、呋喃基、噻唑基、咪唑基、吡唑基、吡啶基、吡嗪基、嘧啶基、哒嗪基、异噻唑基、异噁唑基和噁唑基。
优选的A双环芳基或杂芳基环包括取代的或未取代的萘基、1，2，3，4-四氢萘基、1，2，3，4-四氢喹啉基、苯并呋喃基、苯并噻吩基、吲哚基、二氢吲哚基、1，3-苯并间二氧杂环戊烯基、苯并二噁烷基、喹啉基、四氢喹啉基、异喹啉基、喹唑啉基和喹喔啉基。
优选的A单环环烷基或杂环烷基环包括取代的或未取代的环戊基、环己基、环庚基、十氢萘基、哌啶基、哌嗪基、吗啉基或十氢喹啉基。
优选的A双环环烷基或杂环烷基环包括取代的或未取代的十氢萘基或十氢喹啉基。
更优选的化合物如下：
A是取代和未取代的苯基、吡啶基、噻吩基、呋喃基、吡唑基、萘基、1，2，3，4-四氢萘基，1，2，3，4-四氢喹啉基、吲哚基、二氢吲哚基、喹啉基、四氢喹啉基、环己基、哌啶基或哌嗪基；
X是化学键、O、S或NR4；
R是氢、烷基、烷氧基、卤素、卤代烷基、烷硫基、烷亚硫酰基、烷磺酰基、苯基和芳烷基；
R4是氢、烷基或芳烷基；
R5，R6，R7和R8独立地是氢或烷氧基。
最优选的化合物如下：
A是取代的和未取代的苯基、萘基或吲哚基；
X是化学键；
R是氢、甲氧基、乙氧基、氯、三氟甲基、甲磺酰基、苯基和苄基；
R4是氢、甲基或苄基；
R5，R6，R7和R8独立地是氢或甲氧基。
在本发明范围之内的化合物是人表皮生长因子受体2型(HER2)的选择性酪氨酸激酶抑制剂。治疗有用的PTK抑制化合物被认为对能够催化自身磷酸化的酪氨酸激酶活性特异。此外，这些化合物应抑制生长因子诱导的细胞增殖。达到此标准的化合物具有重要的价值，在实施本发明时尤其有用。本文描述了表现出对上述受体有选择性的化合物。
本发明的化合物可以以游离碱的形式、盐的形式和以水合物的形式使用。所有形式都在本发明的范围之内。可以形成酸加成盐，这是简单的、更方便的使用形式；在实施中，盐形式的使用本质上相当于碱形式的使用。可以用于制备酸加成盐的酸优选地包括这样的酸，该酸在与游离碱结合时产生药学上可接受的盐(即其阴离子在该盐的药剂量下对动物有机体无毒的盐)以使在游离碱中本质上有益性质不受阴离子的副作用的损害。尽管所说的碱性化合物的药学上可接受的盐是优选的，但所有的酸加成盐可用作游离碱形式的来源(既使上述特定的盐仅需要作为中间产物，例如，在当仅为了纯化和鉴别目的形成盐时，或当通过离子交换方法制备药学上可接受的盐中其作为中间产物时)。
在本发明的范围之内的药学上可接受的盐包括来源于下列酸的盐：无机酸如盐酸、硫酸、磷酸的和氨磺酸；有机酸如乙酸、柠檬酸、乳酸、酒石酸、丙二酸、甲磺酸、乙磺酸、苯磺酸、对甲苯磺酸、环己基氨基磺酸、奎宁酸等。
相应的酸加成盐分别包括下列盐：盐酸盐、硫酸盐、磷酸盐、氨基磺酸盐、醋酸盐、柠檬酸盐、乳酸盐、酒石酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、对甲苯磺酸盐、环己基氨基磺酸盐和奎宁酸盐。
可以通过把游离碱溶解在包含适当酸的水或水-醇溶液中或其它适合溶剂中并通过蒸发溶液分离所述盐，或者通过游离碱与酸在有机溶剂中反应(在这种情况下，直接分离所述盐或通过溶液浓缩获得)制备本发明化合物的酸加成盐。
可以通过使用文献中已知的方法从已知化合物或易于制备的中间产物开始制备本发明的化合物。一般型方法举例说明如下。
一般可以通过钯催化的芳基或杂芳基锡烷与芳基或杂芳基卤化物或三氟甲磺酸酯的偶联反应制备用于选择性治疗以人表皮生长因子受体2型的活性为特征的细胞生长和分化方法的化合物。
式中Y是卤素或三氟甲磺酸酯，Z是三烷基锡烷，R如前所述。
以经典方法制备4-卤喹唑啉起始物质：使用邻氨基苯甲酸衍生物和甲酰胺回流产生中间产物喹唑啉。随后在大约110℃下用POCl3处理大约两小时产生了氯喹唑啉。通过与适当的苯胺衍生物在极性溶剂(如乙醇中)缩合制备最终产物。在苯氧基或噻吩氧基衍生物的情况下，制备金属盐(优选的是钠盐)并与适当的卤喹唑啉在溶剂(如THF)中回流几个小时。
Figure C9619451200131
可以通过与叔丁基锂在低温下(优选的是大约-78℃)反应相应的卤化物(优选的是溴化物或碘化物)转变成烷基锂，随后通过与卤代三烷基锡烷反应制备芳基或杂芳基锡烷。
Figure C9619451200132
当然，这些产物也可以以相反的方式利用芳基或杂芳基卤化物和相应的锡烷制备。
喹唑啉锡烷中间产物可以如在Chem Pharm RUll 1982，30，1731-1737中描述的通过三甲基锡钠作用于芳基卤化物制备。
在本发明中有用的化合物的制备在申请人的共同未决申请PCT/US94/14180(其国际申请日为1994年12月8日，指定美国作为合同国)、美国08/166,199(在1993年12月10日提出申请)和美国08/229,886(在1994年4月19日提出申请)中描述，本申请对所有这些要求优先权。本文引入PCT/US94/14180、U.S.08/166,199和U.S.08/229,886作为参考。
此外，下列实施例是用于合成本发明的化合物的方法的代表。
可按照下列实施例和PCT/US94/14180和U.S.08/166,199中描述的实施例制备任一本发明所需的化合物。可以制备的化合物的代表性例子显示如下。
                           实施例14-(3-氯苯氧基)-6，7-二甲氧喹唑啉
在室温下把THF(5ml)和NaH(在油中的60％分散体，大约28mg)添加到惰性气体下保持的干燥烧瓶中。加入3-氯苯酚(0.09g)的THF(1ml)溶液。持续搅拌直到溶液变得澄清。一次添加所有4-氯-6，7-二甲氧基喹唑啉(固体)，在RT下持续搅拌过夜。使溶液在CH2Cl2和5％NaOH之间分配。以盐水洗涤有机层，干燥(Na2SO4)并浓缩。快速柱层析(40％EtOAc/Hex)给出纯化合物。通过重结晶从EtOAc/Hex获得分析样品，得4-(3-氯苯氧基)-6，7-二甲氧基喹唑啉(0.05g)，白色针状，熔点152-153℃。
                           实施例24-(1-甲磺酰吲哚-3-基)-6，7-二甲氧基喹唑啉
步骤A   N-甲磺酰基-3-三甲基甲锡烷基吲哚
以氮充分冲洗5g(15.57mmol)六甲基二锡、5.1g(15.57mmol)N-甲磺酰基-3-碘吲哚和0.89g(0.78mmol)Pd(PPh3)4在75ml干燥甲苯中的溶液，加热至90℃并保持4小时。然后使混合物蒸发并在硅胶上层析(先用己烷，然后用10％乙酸乙酯/己烷洗脱)产生在下一步直接使用的N-甲磺酰基-3-三甲基甲锡烷基吲哚。
步骤B  4-(1-甲磺酰吲哚-3-基)-6，7-二甲氧基喹唑啉
以氮充分冲洗1.33g(4.01mmol)的N-甲磺酰基-3-三甲基甲锡烷基吲哚、750mg(3.34mmol)的4-氯-6，7-二甲氧基喹唑啉和0.19g(5mol％0.16mmol)的Pd(PPh3)4在10ml干燥的N，N-二甲基甲酰胺中的溶液，加热至90℃并保持12小时。以二氯甲烷稀释反应混合物，并用10％氢氧化铵洗涤，剧烈搅拌，然后用水洗涤，用盐水洗涤合并的有机相(75ml)，干燥(MgSO4)并蒸发至干。从乙酸乙酯中重结晶产生4-(1-甲磺酰吲哚-3-基)-6，7-二甲氧基喹唑啉(熔点＞220℃)。
可以按照上述实施例制备任何本发明所需的化合物。可以制备的化合物的代表性例子列于以下。
6，7-二甲氧基-4-萘-2-基乙炔基喹唑啉，熔点158-161℃
4-(4-羟苯基)-6，7-二甲氧基喹唑啉盐酸盐，熔点＞270℃(分解)
4-(萘-1-基)-6，7-二甲氧基喹唑啉，熔点144-147℃
4-(萘-2-基)-6，7-二甲氧基喹唑啉，熔点115-118℃
4-苯乙炔基-6，7-二甲氧基喹唑啉，熔点146-148℃
4-(3-氟-4-甲氧基苯基)-6，7-二甲氧基喹唑啉，熔点207-210℃
4-(3-苯基苯基)-6，7-二甲氧基喹唑啉，熔点160-163℃
4-(2-苯乙烯基)-6，7-二甲氧基喹唑啉，熔点168-169℃
4-(2-甲氧基吡啶-5-基)-6，7-二甲氧基喹唑啉，熔点175-176℃
4-(1-苄基吲哚-3-基)-6，7-二甲氧基喹唑啉，熔点148-150℃
4-(吲哚-3-基)-6，7-二甲氧基喹唑啉，熔点＞240℃(分解)
4-(1-甲基吲哚-3-基)-6，7-二甲氧基喹唑啉盐酸盐，熔点＞230℃(分解)
4-(1-甲磺酰基吲哚-3-基)-6，7-二甲氧喹唑啉，熔点＞220℃(分解)
4-(4-苯基哌啶-1-基)-6，7-二甲氧基喹唑啉，熔点150-151℃
4-[4-(3-氯苯基)哌嗪-l-基]-6，7-二甲氧基喹唑啉，熔点155-156℃
4-(N-甲基-3，4，5-三甲氧基苯胺基)-6，7-二甲氧基喹唑啉，熔点149-151℃
(+-)-4-(2-甲基-1，2，3，4-四氢喹啉-1-基)-6，7-二甲氧基喹唑啉盐酸盐，熔点198-201℃(分解)
4-(1，2，3，4-四氢喹啉-1-基)-6，7-二甲氧基喹唑啉盐酸盐，熔点195-197℃(分解)
4-(5，6，7，8-四氢化萘-1-基)氨基-6，7-二甲氧基喹唑啉盐酸盐，熔点219-222℃
4-(3，6-二噁烷苯胺基)-6，7-二甲氧基喹唑啉，熔点267-269℃(分解)
4-苯乙炔基-6，7-二甲氧基喹唑啉，熔点146-148℃
4-(吲哚-1-基)-6，7-二甲氧基喹唑啉，熔点166-167℃
4-(N-甲基-4-甲氧基苯胺基)-6，7-二甲氧基喹唑啉盐酸盐，熔点202-205℃
4-(N-甲基-4-氯苯胺基)-6，7-二甲氧基喹唑啉盐酸盐，熔点220-222℃
4-(2，3-二氢吲哚-1-基)-6，7-二甲氧基喹唑啉盐酸盐，熔点226-229℃(分解)
N-(6，7-二甲氧基喹唑啉-4-基)-N-甲基-N-(3-三氟甲基苯基)胺盐酸盐，熔点240-243℃
N-(3-氯苯基)-N-(6，7-二甲氧基喹唑啉-4-基)-N-甲基胺盐酸盐，熔点235-237℃
N-(3-氯苯基)-N-(喹唑啉-4-基)-N-甲基-胺盐酸盐，熔点233-235℃
6，7-二甲氧基-4-萘-1-基-乙炔基喹唑啉，熔点175-177℃
4-(噻吩-3-基)-6，7-二甲氧基喹唑啉，熔点148.5-151.5℃
4-苄基-6，7-二甲氧基喹唑啉，熔点122.5-125℃
(6，7-二甲氧基喹唑啉-4-基)-5-吲唑基胺盐酸盐，熔点261-263℃(分解)
N-(6，7-二甲氧基喹唑啉-4-基)-N-苯基-N-乙基胺盐酸盐，熔点227-230℃(分解)
N-苄基-N-(6，7-二甲氧基喹唑啉-4-基)-N-苯基胺盐酸盐，熔点269-271℃
N-(6-氯喹唑啉-4-基)-N-甲基-N-苯基胺，熔点106-108℃
N-(3-氯-苯基)-N-(6，7-二甲氧基喹唑啉-4-基)-N-乙基胺盐酸盐，熔点261-263℃
N-(6，7-二甲氧基喹唑啉-4-基)-N-甲基-N-对甲苯基胺盐酸盐，熔点230-234℃(分解)
N-苄基-N-(6，7-二甲氧基喹唑啉-4-基)胺，熔点220-225℃
N-(4-甲氧苄基)-N-(6，7-二甲氧基喹唑啉-4-基)胺，熔点194-198℃
N-(3，5-二甲氧苄基)-N-(6，7-二甲氧基喹唑啉-4-基)胺盐酸盐，熔点265-269℃
4-(3，4，5-三甲氧基苯氧基)-6，7-二甲氧基喹唑啉，熔点228-232℃
N-(喹唑啉-4-基)-N-苯基-N-甲基胺盐酸盐，熔点242-246℃(分解)
N-(6，7-二甲氧基喹唑啉-4-基)-N-(4-吗啉-4-基苯基)胺盐酸盐，熔点231-235℃(分解)
4-(3-甲氧基噻吩氧基)-6，7-二甲氧基喹唑啉，熔点139.5-141.5℃
4-[N-(5-二氢茚基)氨基)-6，7-二甲氧基喹唑啉盐酸盐，熔点244-246℃(分解)
4-(3-氯噻吩氧基)-6，7-二甲氧基喹唑啉，熔点152-153.5℃
4-(3-氨基吡唑基)-6，7-二甲氧基喹唑啉盐酸盐，熔点262-264℃(分解)
4-(1，4-苯并二噁烷-6-基氨基)-6，7-二甲氧基喹唑啉盐酸盐，熔点267-269℃(分解)
6，7-二甲氧基-4-(α-萘氨基)喹唑啉盐酸盐，熔点＞250℃
6，7-二甲氧基-4-(β-萘氨基)喹唑啉盐酸盐，熔点＞250℃
4-(环己基苯胺基)-6，7-二甲氧基喹唑啉，熔点239-244℃
4-(3，4，5-三甲氧基苯胺基)-6，7-二甲氧喹唑啉盐酸盐，熔点260-265℃
6，7-二甲氧基-4-(N-甲基苯胺基)喹唑啉盐酸盐，熔点＞230℃
4-(3-氯苯氧基)-6，7-二甲氧基喹唑啉，熔点152-153℃
6，7-二甲氧-4-(1-萘硫基)-喹唑啉，熔点174.5-176.5℃
6，7-二甲氧基-4-(2-萘硫基)-喹唑啉，熔点178-179℃
6，7-二甲氧基-4-(1-萘氧基)-喹唑啉，熔点214-215.5℃
6，7-二甲氧基-4-(2-萘氧基)-喹唑啉，熔点169-170℃
N-(6，7-二甲氧基-喹唑啉-4-基)-N-(萘-2-基)-N-乙基胺盐酸盐，熔点236-239℃(分解)
6，7-二甲氧基-4-(萘-2-亚硫酰基)喹唑啉，熔点182.5-185℃
6，7-二甲氧基-4-(萘-2-磺酰基)喹唑啉
4-(3-氯苯胺基)-6，7-二甲基喹唑啉盐酸盐，熔点271-274℃
4-(3，5-二甲基苯胺基)-6，7-二甲基喹唑啉盐酸盐，熔点＞275℃
4-(N-甲基-4-甲基苯胺基)-6，7-二甲基喹唑啉盐酸盐，熔点235-238℃
6，7-二甲基-4-(1-萘氨基)喹唑啉盐酸盐，熔点244-247℃
6，7-二甲基-4-(7-三氟甲基-3，4-二氢-2H-喹啉-1-基)喹唑啉盐酸盐，熔点240℃
4-(N-甲基-3-甲基苯胺基)-6，7-二甲基喹唑啉盐酸盐，熔点205-207℃
4-(3-氯苯硫基)-6，7-二甲基喹唑啉盐酸盐，熔点197-202℃
4-(1-萘硫基)-6，7-二甲基喹唑啉盐酸盐，熔点204-209℃
4-(3，4-二甲氧基苯硫基)喹唑啉，熔点115-117℃
            药物组合物的制备与药理学试验部分
为了确定本发明的化合物的效能，使用了如下描述的药理学实验，该实验在本领域可以被接受并被认为与在哺乳动物中的药理活性相关。对本发明范围内的化合物进行了各种实验，获得的结果被认为与有用地抑制生长因子-诱导的细胞增殖相关。下面描述的实验可用于测定本发明的化合物的抑制作用。
实验方法
材料：把实验材料在实验即时溶解在DMSO中以制作母液，随后以培养基稀释该母液以达到所需的化合物的浓度(0.1％的载体最终浓度)。所利用的材料如下：Dulbecco’s改进Eagle培养基(DMEM)，RPMI 1640，胎牛血清(FCS)，青霉素-链霉素溶液(10,000IU/ml青霉素和10,000μg/ml链霉素)从GIBCO BPL购得。3-(4，5-二甲基噻唑-2-基)-2，5-二苯基四唑鎓溴化物(MTT)和遗传霉素购自Sigma。放射性标记的[γ-32P]ATP(cat#NEG002H；3,000Ci/mmol)购自NEN。抗-c neu抗体(Ab-5；cat#OP39)来源于Oncogene Science。小鼠单克隆抗磷酸酪氨酸抗体(单克隆IgG2bk)得自UBI，辣根过氧化物酶缀合的兔抗小鼠IgG得自北欧免疫学实验室。按照C.Wasylyk，A.Gutman，R.Nicholson和B.Wasylyk，(1991)EMBO杂志，10：A127-A134的方法，制备溶基质素启动子片段-1100/+8控制的溶基质素-CAT质粒DNA构建体(由氯霉素乙酰转移酶cDNA组成)。所有其它化学药品是可得到的最好质量的药品。
细胞系和细胞培养：小鼠胚胎成纤维细胞(NIH3T3)、人表皮样瘤(A431)癌细胞系以及胸部(SK-BR-3)和卵巢(SK-OV-3)腺癌细胞系、人肺脏(A549)和乳腺(BT474和BT20)癌细胞系从ATCC购得。按照R.M.Hudziak，J.Schlessinger和A.Ulirich(1987)美国科学院学报，84：7159-7163的方法制备用HER2构建体转染的超量表达p185HER2的NIH3T3细胞，NIH/HER2。通过按照I.Barlat，F.Schweighoffer，M.C.Chevalier-Multon，M.Duchesne，I.Faith，D.Landais，M.Jacquet和B.Tocqué(1993)癌基因8：215-218的方法用Val2Ha-ras转化NIH3T3细胞建立NIH/Ha-Ras细胞系。用包含突变Y527F的活化的v-src(NIH/v-Src)转染的NIH3T3细胞得自Dr.B.Wasylyk。HIR3.5(NIH/IR)细胞系代表超量表达人胰岛素受体的NIH3T3细胞，它由Dr.J.Whitaker提供。所有细胞系于37℃下的CO2恒温箱(5％CO2/95％的湿空气)中在补加有10％FCS和1％青霉素链霉素溶液的培养基中培养。除非特别指出，培养基每隔一天换一次。
体外p185HER2自磷酸化测定：ER22或A431以及NIH/HER2细胞系用作p185Her2的来源。在4℃下于包含1％Triton X-100和1mM PMSF的HNEG(HNEG：50mM Hepes缓冲液，pH7.5，150mM NaCl，1mMEDTA和10％甘油)缓冲液中裂解半丰细胞单层10分钟。然后用包含0.1％Triton X-100和1％BSA的HNEG缓冲液(裂解缓冲液)稀释细胞裂解物，通过在12,000.g下离心5分钟使细胞提取物澄清。自磷酸化测定如S.M.Smyth，I.Stefanova，F.Hartman，I.D.Horak，N.Osherov，A.Levitzki和T.R.Burke(1993)医学化学杂志36：3010-3014所述进行。简言之，在37℃下用10μg/ml浓度的100μl山羊抗小鼠免疫球蛋白(Biosys)涂覆96孔U形底塑料平板2小时。用包含0.05％Tween的PBS洗涤后，将100μl的抗c-neu抗体在37℃下温育2小时(两种抗体都以1μg/ml使用)。通过在37℃下和在PBS中的2％BSA温育1小时封闭未结合的结合位点。细胞裂解物于4℃下在包被的孔中温育1小时。在用裂解缓冲液洗涤几次后，于室温下在申请人的化合物不存在或存在的情况下，自磷酸化测定直接在孔中在包含2mM MnCl2、0.1％Triton和5μCi[γ-32P]ATP的25mM Hepes缓冲液(pH7.4)中进行20分钟。通过添加按照U.K.Laemmli(1970)(自然，225：680-685)制备的Laemmli’s样品缓冲液终止磷酸化反应，通过SDS-PAGE在4-12％聚丙烯酰胺梯度凝胶上分析[32P]-标记的受体。磷酸化强度通过在Instant Imager(Packard)上扫描干燥的凝胶估计。
完整细胞酪氨酸磷酸化：汇生细胞单层在血清饥饿过夜后用指定的化合物浓度培养2小时。然后抽吸培养基，通过直接把Laemmli’s SDS样品缓冲液添加到细胞单层上灭活细胞。然后在试验包含磷酸酪氨酸的蛋白质前，在100℃下处理样品5分钟。通过SDS-PAGE在4-20％聚丙烯酰胺梯度凝胶上使蛋白质分级分离，其后使蛋白质电泳转移到聚偏二氟乙烯膜(PVDF膜，PolyScreen，NEN)上。利用小鼠单克隆抗磷酸酪氨酸抗体进行包含磷酸酪氨酸的蛋白质的免疫检测。通过增强化学发光法(ECL，NEN)使用辣根过氧化酶缀合的兔抗小鼠IgG显示印迹。
细胞增殖：把细胞以大约20,000细胞/孔接种于24孔细胞培养平板上。使细胞在1ml培养基中对塑料粘附8小时，其后在各种浓度的化合物存在下培养细胞72-96小时。按照表明的培养时间，估计了每孔的细胞数目。作为相对生存的细胞数目的测定，按照M.C.Alley，D.A.Scudiero，A.Monks，M.L.Hursey，M.J.Czerwinski，D.L.Fine，B.J.Abbot，J.G.Mayo，R.H.Shoemaker和M.R.Boyd(1988)癌症研究48：589-601的方法使用了MTT的线粒体还原。简言之，向每个孔添加100μl在磷酸盐缓冲盐水中的MTT的5mg/ml溶液，平板于37℃下在CO2恒温箱中培养4小时。然后，为了溶解在活细胞的线粒体中形成的甲的黑紫色晶体，除去650μl的培养基并以750μl的异丙醇/HCl(1N)溶液(25∶1)代替。随搅拌在室温下培养5-10分钟后，从每个孔中把200μl等分试样转移到96孔细胞培养平板上，由于所获得的蓝色程度与细胞数量直接成比例，就可以在微滴定板自动读数仪上于590nm通过分光光度测定该值。
不依赖贴壁细胞的生长：通过检查悬浮在软琼脂中的所说的细胞的菌落形成能力研究不依赖贴壁细胞的生长。利用50mm直径的细胞培养皿进行实验。4ml无细胞饲养底层由补加有10％FCS和指定浓度的化合物的培养基中的0.5％琼脂组成。4ml上层包含在补加有10％FCS和相应浓度的化合物的培养基内的0.3％琼脂中的大约10,000个细胞。于37℃下培养2周后，测定菌落数目。
细胞转染和CAT测定：使用脂转染胺试剂通过转染把溶基质素-CAT质粒DNA构建体(STRM-CAT)导入细胞。简言之，使细胞的50-70％铺满培养皿(3.5cm)于37℃下接触在1ml无血清的DMEM中的1μg质粒DNA和10μg脂转染胺试剂4小时。然后使细胞在37℃下和补加有0.5％FCS和指定浓度的化合物的DMEM培养36小时。细胞通过与包含3mM EDTA的PBS培养从平板上分离下来，通过在1,500rpm下离心5分钟沉淀。把细胞重新悬浮在0.25M Tris/HCl缓冲液pH 7.8中并进行重复冷冻-解冻循环。把细胞提取物加热到65℃并保持15分钟；冷却后，在14,000rpm下微离心15分钟。按照J.R.Neumann，C.A.Morency和K.O.Russian(1987)生物技术，5：444-447的方法测定上清液中CAT活性。
在本发明范围之内的化合物显示了作为蛋白质酪氨酸激酶抑制剂的明显的特异性活性，并具有抑制生长因子诱导的细胞增殖的治疗价值。本发明的化合物还是人表皮生长因子受体2型的特异性抑制剂，因此可用于治疗细胞生长和分化。
下表显示了本发明的代表性化合物的例子及其通过上述人表皮生长因子受体2型的抑制测定的试验结果。通过上述实验方法获得的结果证明了在本发明范围内的化合物的有用的HER2受体蛋白质酪氨酸激酶抑制性质，并在异常细胞生长的调节中具有治疗价值。
Figure C9619451200211
Figure C9619451200221
        X        R5  R6   R7     R8    HER-2           化学键    H    OCH3 OCH3   H      20％，5μM            化学键    H    OCH3 OCH3   H      10％，5μM化学键    H    OCH3 OCH3   H      0.5-1μM            化学键    H    OCH3 OCH3   H      10％，5μM
可以以各种适用于所选择的给药途径的方式(即口服或肠胃外)对哺乳动物宿主施用本发明的化合物。在这方面肠胃外施用包括通过下列途径施用：静脉内、肌肉内、皮下、眼内、滑膜内、经上皮(包括经皮、眼、舌下和颊)；局部施用(包括通过吹入剂与气雾剂的经眼、皮、眼内、直肠和鼻吸入)与直肠全身施用。
活性化合物可以，例如，与惰性稀释剂或与可同化的可食载体口服，或者可以把它装入硬或软壳的明胶胶囊中，或者把它压缩成片剂，或者把它直接与饮食掺合施用。对于口服治疗施用，活性化合物可以与赋形剂掺合并以可消化的片剂、口腔片、锭剂、胶囊、酏剂、悬浮液、糖浆剂、糯米纸囊剂等形式使用。这样的组合物和制剂应包含至少0.1％的活性化合物。当然，组合物与制剂的百分比可以不同，可以方便地在单位重量的大约2至大约6％之间。在这样的治疗用的组合物中的活性化合物的量是可以获得适合剂量的量。制备了本发明优选的组合物或制剂以使口服剂量单位形式包含大约1至1000mg之间的活性化合物。
片剂、锭剂、丸剂、胶囊等也可以包含下列物质：粘合剂如黄蓍胶、阿拉伯胶、玉米淀粉或明胶；赋形剂如磷酸二钙；崩解剂如玉米淀粉、马铃薯淀粉、海藻酸等；润滑剂如硬脂酸镁；可以添加增甜剂如蔗糖、乳糖或糖精或增香剂如薄荷、冬青油或樱桃调味料。当剂量单位形式是胶囊时，除了上述类型的物质外它还可以包含液态载体。可以有各种其它物质如包衣剂，或以其它方式修改剂量单位外形的物质。例如，片剂、丸剂或胶囊可以用紫胶片、食糖或两者包衣。糖浆或酏剂可以包含活性化合物、作为增甜剂的蔗糖，作为防腐剂的对羟基苯甲酸甲酯和对羟基苯甲酸丙酯，染料和调味料如樱桃或桔子调味香料。当然，在制备任何剂量单位形式时使用的物质以所使用的量应该是药学纯度的和实质上无毒的。此外，活性化合物可以制成缓释剂和制剂。
也可以肠胃外或腹膜内施用活性化合物。可以在与表面活性剂(如羟丙基纤维素)适当混合的水中制备作为游离碱或药学可接受的盐的活性化合物的溶液。也可以在甘油、液态聚乙二醇及其混合物、油中制备分散体。在保存和使用的普通条件下，这些制剂包含防腐剂以防止微生物的生长。
适合于可注射用途的药剂形式包括无菌水溶液或分散体以及用于临时制备无菌可注射溶液或分散体的无菌粉剂。在所有情况下制剂必须是无菌的，并且必须是达到易于注射的程度的液体。它在制造和存储条件下可以是稳定的，而且必须受到保护以抗有污染作用的微生物(如细菌和真菌)。载体可以是包含，例如，水、乙醇、多元醇(例如，甘油、丙二醇和液态聚乙二醇等)及其适合的混合物以及植物油的溶剂或分散介质。例如，可以通过利用包衣剂(如卵磷脂)、通过分散情况下保持适当的所需的粒子大小、通过利用表面活性剂保持适当的流动性。可以通过各种杀细菌剂和杀真菌剂(例如，羟苯甲酸甲酯、氯丁醇、酚、山梨酸、乙基汞硫代水杨酸钠等)防止微生物作用。在许多情况下，优选地包括等渗剂(例如，糖或氯化钠)。可以通过使用延缓吸收剂(例如，单硬脂酸铝和明胶)延长可注射组合物的吸收。
通过把活性化合物以所需的量掺入具有上述各种其它成分的适当的溶剂中(如果需要，在其后进行过滤灭菌)制备无菌的可注射溶液。通常，通过把各种灭菌的活性组分掺入无菌载体中制备分散体，在该载体中包含基本的分散介质和所需的上述其它成分。在用于制备无菌可注射溶液的无菌粉剂的情况下，优选的制备方法是真空干燥和冷冻干燥技术，该方法产生活性成分加上前述灭菌过滤溶液中所需任何其它成分的粉剂。
本发明的治疗化合物可以单独或与药学上可接受的载体结合对哺乳动物给药，如上所述，其比例决定于化合物的溶解性和化学性质、选择的给药途径和标准的药学实践。
最适合于预防或治疗的本发明的治疗剂的剂量随给药方式、所选择的特定化合物和治疗的病人的特定的生理特征而变化。通常，最初使用小剂量，如果必要，小量增加，直到达到所述状况下的最佳效果。基于大鼠的生理研究，治疗性人剂量通常是每天从大约0.01mg至大约100mg/kg体重，或从大约0.4mg至大约10g或更高(尽管该剂量可以以一天一次到几次的不同剂量单位施用)。口服需要较高的剂量。

Claims (20)

1.下式化合物或其药学上可接受的盐用于制备选择性治疗以人表皮生长因子受体2型(HER2)的活性为特征的细胞生长和分化的药物中的应用：
Figure C9619451200021
其中
A是5至12个原子的取代的或未取代的单-环或双-环芳基、杂芳基、环烷基或杂环烷基环状系统，其中的取代基可位于环状系统的任何适当的位置，并由R表示；
X是化学键、O、S、SO、SO2、OCH2、CR4＝CR4、C≡C、NR4或NR4CH2；
R独立地包括氢、烷基、苯基、卤苯基、芳烷基、羟基、烷氧基、芳氧基、酰氧基、卤素、卤代烷基、氨基、一-和二-烷基氨基、酰基氨基、羧基、酰氨基、一-和二-烷基酰氨基、烷硫基、烷亚硫酰基以及烷磺酰基；
R4是氢、烷基或芳烷基；和
R5，R6，R7和R8独立地是氢、烷氧基或芳烷氧基。
2.按照权利要求1的应用，其中：
A是选自苯基、吡咯基、噻吩基、呋喃基、噻唑基、咪唑基、吡唑基、吡啶基、吡嗪基、嘧啶基、哒嗪基、异噻唑基、异噁唑基和噁唑基的取代的或未取代的单环芳基或杂芳基环。
3.按照权利要求1的应用，其中：
A是选自萘基、1，2，3，4-四氢萘基、1，2，3，4-四氢喹啉基、苯并呋喃基、苯并噻吩基、二氢茚基、吲哚基、二氢吲哚基、1，3-苯并间二氧杂环戊烯基、苯并二噁烷基、喹啉基、四氢喹啉基、异喹啉基、喹唑啉基和喹喔啉基的取代的或未取代的双环芳基或杂芳基环。
4.按照权利要求1的应用，其中：
A是选自环戊基、环己基、环庚基、十氢萘基、哌啶基、哌嗪基、吗啉基或十氢喹啉基的取代的或未取代的单环环烷基或杂环烷基环。
5.按照权利要求1的应用，其中：
A是选自十氢萘基或十氢喹啉基的取代的或未取代的双环环烷基或杂环烷基环。
6.按照权利要求1的应用，其中：
A是取代的和未取代的苯基、吡啶基、噻吩基、呋喃基、吡唑基、萘基、1，2，3，4-四氢萘基，1，2，3，4-四氢喹啉基、二氢茚基、吲哚基、二氢吲哚基、喹啉基、四氢喹啉基、环己基、哌啶基或哌嗪基；
X是化学键、O、S或NR4；
R是氢、烷基、烷氧基、卤素、卤代烷基、烷硫基、烷亚硫酰基、烷磺酰基、苯基和芳烷基；
R4是氢、烷基或芳烷基；
R5，R6，R7和R8独立地是氢或烷氧基。
7.按照权利要求6的方法，其中：
A是取代的和未取代的苯基、萘基或吲哚基；
X是化学键；
R是氢、甲氧基、乙氧基、氯、三氟甲基、甲磺酰基、苯基和苄基；
R4是氢、甲基或苄基；
R5，R6，R7和R8独立地是氢或甲氧基。
8.按照权利要求2的应用，其中所施用的化合物是4-(2-苯乙烯基)-6，7-二甲氧基喹唑啉或其药学上可接受的盐。
9.按照权利要求3的应用，其中所施用的化合物是6，7-二甲氧基-4-萘-1-基-乙炔基喹唑啉或其药学上可接受的盐。
10.按照权利要求6的应用，其中所施用的化合物选自：4-(2-甲氧吡啶-5-基)-6，7-二甲氧基喹唑啉，4-(4-苯哌啶-1-基)-6，7-二甲氧基喹唑啉，4-[4-(3-氯苯基)哌嗪-1-基]-6，7-二甲氧基喹唑啉，和4-(1，2，3，4-四氢喹啉-1-基)-6，7-二甲氧基喹唑啉或它们的药学上可接受的盐。
11.按照权利要求6的应用，其中所施用的化合物选自：6，7-二甲氧基-4-(β-萘氨基)喹唑啉，4-[N-(5-二氢茚基)氨基]-6，7-二甲氧基喹唑啉，N-苄基-N-(6，7-二甲氧基喹唑啉-4-基)-N-苯基胺，6，7-二甲氧基-4-(N-甲基苯胺基)喹唑啉，N-(3-氯苯基)-N-(6，7-二甲氧基喹唑啉-4-基)-N-甲基胺，4-(3-氨基吡唑基)-6，7-二甲氧基喹唑啉，和4-(环己基苯胺基)-6，7-二甲氧基喹唑啉，或它们的药学上可接受的盐。
12.按照权利要求6的应用，其中所施用的化合物是6，7-二甲氧基-4-(α-萘氨基)喹唑啉或其药学上可接受的盐。
13.按照权利要求7的应用，其中所施用的化合物选自：4-(萘-1-基)-6，7-二甲氧基喹唑啉，4-(萘-2-基)-6，7-二甲氧基喹唑啉，4-(3-苯基苯基)-6，7-二甲氧基喹唑啉，4-(吲哚-3-基)-6，7-二甲氧基喹唑啉，和4-(1-甲基吲哚-3-基)-6，7-二甲氧基喹唑啉，或它们的药学上可接受的盐。
14.按照权利要求7的应用，其中所施用的化合物是4-(1-苄基吲哚-3-基)-6，7-二甲氧基喹唑啉或其药学上可接受的盐。
15.一种用于选择性治疗以人表皮生长因子受体2型(HER2)的活性为特征的细胞生长和分化的药物组合物，该药物组合物包含与药学上可接受的载体混合的HER2受体抑制有效量的下式的化合物或其药学上可接受的盐：其中
A是大约5至12个原子的取代的或未取代的单-环或双-环芳基、杂芳基、环烷基或杂环烷基环状系统，其中的取代基可位于环状系统的任何适当的位置，并由R代表；
X是化学键、O、S、SO、SO2、OCH2、CR4＝CR4、C≡C、NR4或NR4CH2；
R独立地包括氢、烷基、苯基、卤苯基、芳烷基、羟基、烷氧基、芳氧基、酰氧基、卤素、卤代烷基、氨基、一-和二-烷基氨基、酰基氨基、羧基、酰氨基、一-和二-烷基酰氨基、烷硫基、烷亚硫酰基以及烷磺酰基；
R4是氢、烷基或芳烷基；和
R5，R6，R7和R8独立地是氢、烷氧基或芳烷氧基。
16.按照权利要求15的组合物，其中：
A是取代的和未取代的苯基、吡啶基、噻吩基、呋喃基、吡唑基、萘基、1，2，3，4-四氢萘基，1，2，3，4-四氢喹啉基、二氢茚基、吲哚基、二氢吲哚基、喹啉基、四氢喹啉基、环己基、哌啶基或哌嗪基；
X是化学键、O、S或NR4；
R是氢、烷基、烷氧基、卤素、卤代烷基、烷硫基、烷亚硫酰基、烷磺酰基、苯基和芳烷基；
R4是氢、烷基或芳烷基；和
R5，R6，R7和R8独立地是氢或烷氧基。
17.按照权利要求16的化合物，其中所说的化合物是6，7-二甲氧基-4-(α-萘氨基)喹唑啉或其药学上可接受的盐。
18.按照权利要求16的化合物，其中所说的化合物是4-(1-苄基吲哚-3-基)-6，7-二甲氧基喹唑啉或其药学上可接受的盐。
19. 6，7-二甲氧基-4-(α-萘氨基)喹唑啉或其药学上可接受的盐。
20. 4-(1-苄基吲哚-3-基)-6，7-二甲氧基喹唑啉或其药学上可接受的盐。
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