CN1993330A - 作为神经激肽受体拮抗剂的喹啉衍生物 - Google Patents
作为神经激肽受体拮抗剂的喹啉衍生物 Download PDFInfo
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- CN1993330A CN1993330A CNA2005800264225A CN200580026422A CN1993330A CN 1993330 A CN1993330 A CN 1993330A CN A2005800264225 A CNA2005800264225 A CN A2005800264225A CN 200580026422 A CN200580026422 A CN 200580026422A CN 1993330 A CN1993330 A CN 1993330A
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- compound
- amino
- phenylquinoline
- carbonyl
- methyl ester
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- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D215/50—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 4
- C07D215/52—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 4 with aryl radicals attached in position 2
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Abstract
本发明涉及式(I)的化合物和它们药学可接受的盐,包含它们的药物组合物以及它们在治疗神经激肽-2和/或神经激肽-3(NK-3)受体所介导的疾病例如精神分裂症中的用途。
Description
本申请涉及在本文定义的取代喹啉-4-羧酸肼类,包含它们的药物组合物,以及它们在治疗由神经激肽-2和/或神经激肽-3(NK-3)受体所介导的疾病方面的用途。因此这些化合物可以在治疗方法中使用以抑制和治疗这些疾病。
在文献综述中可以发现关于NK-3受体拮抗剂的背景信息,例如Giardina和Raveglia,Exp.Opin.Ther.Patents(1997)
7(4):307-323以及Giardina等人,Exp.Opin.Ther.Patents(2000)
10(6):939-960。这些参考文献还包括关于可以使用NK-3拮抗剂治疗的疗法的临床前验证的相关信息。
在本领域作为NK-3拮抗剂制备的化合物的代表性实例记载在WO-A-9719926(SmithKline Beecham S.p.a.)和US-A-5741910(Sanofi)中。作为与NK-3和/或NK-2受体拮抗剂结构相关的化合物已经公开在公开的国际专利申请WO2004/050626和WO2004/050627(均属于SmithKline Beecham公司)和国际专利申请PCT/GB2004/000415中(Merck Sharp&Dohme)。
因此本发明提供一种式(I)的化合物:
或其药学可接受的盐。
优选地,该苯环的2位(所述苯环被连接至喹啉基部分的2位)是未取代的。更优选地,所述苯环是未取代的,或者当所述苯环被取代,在该苯环的3-或4-位为氟原子。
式(I)化合物所包括的化合物为:
2-({3-氨基-2-苯基喹啉-4-基}羰基)-1-苯基肼羧酸甲酯,
2-({3-氨基-2-[2-氟]苯基喹啉-4-基}羰基)-1-苯基肼羧酸甲酯,
2-({3-氨基-2-[3-氟]苯基喹啉-4-基}羰基)-1-苯基肼羧酸甲酯,
2-({3-氨基-2-[4-氟]苯基喹啉-4-基}羰基)-1-苯基肼羧酸甲酯,
2-({3-氨基-2-[2,3-二氟]苯基喹啉-4-基}羰基)-1-苯基肼羧酸甲酯,
2-({3-氨基-2-[2,4-二氟]苯基喹啉-4-基}羰基)-1-苯基肼羧酸甲酯,
2-({3-氨基-2-[2,5-二氟]苯基喹啉-4-基}羰基)-1-苯基肼羧酸甲酯,
2-({3-氨基-2-[2,6-二氟]苯基喹啉-4-基}羰基)-1-苯基肼羧酸甲酯,
2-({3-氨基-2-[3,4-二氟]苯基喹啉-4-基}羰基)-1-苯基肼羧酸甲酯,
2-({3-氨基-2-[3,5-二氟]苯基喹啉-4-基}羰基)-1-苯基肼羧酸甲酯,
和它们药学可接受的盐。
可在治疗中使用这些化合物和由先前的定义所定义的那些化合物,尤其可用作NK-2和/或NK-3拮抗剂,特别是可用作NK-3拮抗剂。
本发明的化合物显示了有益的特性。
特别地,它们与现有技术的化合物相比具有一种或多种下述特性:
(i)在适当剂量后它们提供的药理学活性化合物的体内脑浓度较高;
(ii)在适当剂量后它们提供的药理学活性化合物体内脑:血浓度比较高;
(iii)以给定剂量它们所达到的NK-3受体占有水平较高;这意味着与较低受体占有水平的化合物相比其有效治疗例如CNS疾病所需剂量较低;
(iv)以给定剂量它们导致较低水平的不利的外周效应;
(v)它们改善了对NK-3受体的选择性;
(vi)它们具有更强的有效逆转体内由NK-3激动剂所驱动的行为效应的能力;
(vii)它们在适当模型中具有优良的预示CNS疾病或CNS-介导疾病治疗效力的特性;
(viii)它们改善了作用的持续时间;
(ix)它们还具有使它们开发成为药剂的优异候选的其他性质,包括有助于其配制的物理特性。
应该理解术语化合物“的施用”和或“施用一种”化合物指给需要治疗的个体提供本发明的化合物。
在本文使用的术语“受试者”(可选地在本文称为“患者”)指的是动物,优选哺乳动物,最优选人,其为治疗、观察或实验的对象。
本发明的化合物可以以药学可接受盐的形式施用。术语“药学可接受的盐”意欲包括所有可接受的盐,例如醋酸盐、乳糖醛酸盐、苯磺酸盐、月桂酸盐、苯甲酸盐、苹果酸盐、碳酸氢盐、马来酸盐、酸式硫酸盐、扁桃酸盐、酒石酸氢盐、甲磺酸盐、硼酸盐、甲基溴化物、溴化物、甲硝酸盐、依地酸钙、甲基硫酸盐、樟脑磺酸盐、粘酸盐、碳酸盐、萘磺酸盐、氯化物、硝酸盐、克拉维酸盐、N-甲基葡萄糖胺、柠檬酸盐、铵盐、二盐酸化物(dihydrochloride)、油酸盐、依地酸盐、草酸盐、乙二磺酸盐、palmoate(双羟萘酸盐)、丙酸酯月桂硫酸盐(estolate)、棕榈酸盐、乙磺酸盐、泛酸盐、延胡索酸盐、磷酸盐/二磷酸盐、葡庚糖酸盐(gluceptate)、聚半乳糖醛酸盐、葡糖酸盐、水杨酸盐、谷氨酸盐、硬脂酸盐、乙醇酰对氨基苯基砷酸盐(glycollylarsanilate)、硫酸盐、己基间苯二酚盐(hexylresorcinate)、碱式醋酸盐、哈胺、琥珀酸盐、氢溴化物、鞣酸盐、盐酸化物、酒石酸盐、羟萘酸盐、8-氯茶碱盐、碘化物、甲苯磺酸盐、异硫代硫酸盐、三乙基碘、乳酸盐、扑酸盐(panoate)、戊酸盐等,其可用作剂型以改变溶解性或水解特性或者用于持续释放或前药制剂。根据本发明化合物的具体功能性,本发明化合物的药学可接受的盐包括由阳离子例如钠、钾、铝、钙、锂、镁、锌,和由碱例如氨、乙二胺、N-甲基-谷氨酰胺、赖氨酸、精氨酸、鸟氨酸、胆碱、N,N’-二苄乙二胺、氯普鲁卡因、二乙醇胺、普鲁卡因、N-苄基苯乙基-胺、二乙胺、哌嗪、三(羟甲基)氨基甲烷和氢氧化四甲铵形成的那些。这些盐类可以通过标准常规程序方法来制备,例如通过游离酸与适合的有机碱或无机碱反应来制备。当存在碱基团,例如氨基时,可以将酸式盐,即盐酸盐、氢溴酸盐、醋酸盐、扑酸盐等等用作剂型。
本发明的化合物可以通过口服、肠胃外(例如肌内、腹膜内、静脉、ICV、脑池内注射或输注、皮下注射或植入),通过喷雾吸入、鼻、阴道的、直肠、舌下的或局部途径施用,并且可以单独或一起配制成含有适合各途径施用的常规无毒性药物可接受的载体、辅剂和赋形物的适宜的剂量单元制剂。除治疗温血动物例如小鼠、大鼠、马、牛、羊、狗、猫、猴子等之外,本发明的化合物用于人也是有效的。
用于本发明化合物施用的药物组合物可以适宜地以剂量单元的形式存在,并且可以通过药学领域已知的任何方法来制备。所有方法包括将活性成分结合组成一种或多种配合剂的载体的步骤。通常,药物组合物通过将活性成分均匀且密切结合液体载体或细分散的固体载体或结合两者来制备,然后如果需要,使产物形成所需要的制剂。在药物组合物中所包括的活性目标化合物的量足以对疾病的过程或状况产生需要的效应。当在本文使用时,术语“组合物”意欲包括含有特定量的特定组分的产品,以及任何由特定量的特定组分直接或间接组合获得的产品。
含有活性成分的药物组合物可以是适合口服使用的形式,例如,片剂、糖锭含片(troches)、菱形锭剂(lozenges)、水性或油性混悬液、可分散的粉末剂或颗粒剂、乳剂、硬或软胶囊,或糖浆剂或酏剂。用于口服使用的组合物可以按照本领域任何已知的制造药物组合物的方法来制备,并且该组合物可以包含一种或多种选自甜味剂、矫味剂、着色剂和防腐剂的试剂从而提供药学上美观和可口的制剂。片剂含有与适合制备片剂的无毒药学可接受的赋形剂混合的活性成分。这些赋形剂可以是例如,惰性稀释剂,例如碳酸钙、碳酸钠、乳糖、磷酸钙或磷酸钠;造粒剂和崩解剂,例如,玉米淀粉或藻酸;粘合剂,例如淀粉、明胶或阿拉伯胶,和润滑剂,例如,硬脂酸镁、硬脂酸或滑石粉。片剂可以未包衣,或者它们可以通过已知技术将其包衣以延迟在胃肠道内的崩解和吸收,并由此获得更长时间的持续作用。例如,可以采用延时材料例如单硬脂酸甘油酯或二硬脂酸甘油酯。它们还可以通过美国专利4,256,108、4,166,452和4,265,874所述的技术进行包衣以形成控释的渗透性治疗片剂。
口服使用的制剂也可以以硬明胶胶囊的形式存在,其中将活性成分与惰性固体稀释剂,例如碳酸钙、磷酸钙或高岭土混合,或以软明胶胶囊的形式存在,其中将活性成分与水或油性介质例如花生油、液体石蜡或橄榄油混和。
水性混悬液含有与适合制备水性混悬液的赋形剂混合的活性成分。这些赋形剂为助悬剂,例如羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、海藻酸钠、聚乙烯吡咯烷酮、西黄著胶和阿拉伯胶;分散剂或湿润剂可以是天然存在的磷脂,例如卵磷脂,或烯化氧与脂肪酸的缩合产物,例如聚氧乙烯硬脂酸酯,或环氧乙烷和长链脂肪醇例如十七亚乙基氧基鲸蜡醇的缩合产物,或环氧乙烷与衍生自脂肪酸和己糖醇的偏酯的缩合产物,例如聚乙烯去水山梨糖醇单油酸酯。水性混悬液还可以含有一种或多种防腐剂,例如对羟基苯甲酸乙酯或正丙酯,一种或多种着色剂,一种或多种矫味剂,和一种或多种甜味剂,例如蔗糖或糖精。
油性混悬液可以通过将活性成分悬浮在植物油,例如花生油、橄榄油、芝麻油或椰子油,或矿物油例如液体石蜡中来配制。油性混悬液可以含有增稠剂,例如蜂蜡、硬石蜡或鲸蜡醇。甜味剂例如上述那些,并且可以加入矫味剂以提供可口的口服制剂。这些组合物可以通过加入抗氧剂如抗坏血酸来保存。
适合通过加入水制备水性混悬液的可分散粉末和颗粒剂提供了与分散剂或湿润剂、助悬剂和一种或多种防腐剂混合的活性成分。适合的分散剂或湿润剂和助悬剂是例如上文提及的那些。也可以存在其他赋形剂例如甜味剂、矫味剂和着色剂。
本发明的药物组合物还可以是水包油乳液的形式。油相可以是植物油,例如橄榄油或花生油,或矿物油,例如液体石蜡或其混和物。适合的乳化剂可以是天然存在的树胶,例如阿拉伯胶、西黄著胶,天然存在的磷脂,例如大豆卵磷脂,衍生自脂肪酸和己糖醇酐的酯或偏酯,例如去水山梨糖醇单油酸酯,所述偏酯与环氧乙烷的缩合产物,例如聚氧乙烯去水山梨糖醇单油酸酯。乳液还可以含有甜味剂和矫味剂。
糖浆剂和酏剂可以用甜味剂,例如甘油、丙二醇、山梨糖醇或蔗糖来配制。此类制剂还可以含有缓和剂、防腐剂、矫味剂和着色剂。
该药物组合物可以是无菌可注射水性或油状混悬液的形式。该混悬液可以按照本领域已知的方法采用上文提及的适当的分散剂或湿润剂和助悬剂来配制。无菌可注射制剂还可以是无毒肠胃外可接受的稀释剂或溶剂中的无菌可注射溶液或混悬液,例如1,3-丁二醇中的溶液。在可接受载体和溶剂中可以使用的是水、林格氏溶液和等渗氯化钠溶液。此外,无菌的、非挥发性油通常用作溶剂或悬浮介质。出于此目的,可以使用任何刺激性少的非挥发性油,包括合成的甘油单酯-或二酯。此外,脂肪酸例如油酸可以用于注射剂的制备。
本发明的化合物还可以以栓剂的形式用于直肠药物施用。可以通过将药物与适宜的无刺激性赋形剂混合来制备这些组合物,所述无刺激性赋形剂在常温下为固体而在直肠温度下为液体并由此在直肠内融化释放药物。此类材料为可可脂和聚乙二醇。
对于局部使用,可以使用含有本发明化合物的乳膏、软膏、凝胶剂、溶液或混悬液等。(对于该应用而言,局部应用应包括漱口剂和含漱液)。
本发明的药物组合物和方法可以进一步包含在本文提及的其它治疗活性化合物,这些化合物通常用于治疗上文提及的病理状态。
在需要NK-3受体调节的病症的治疗或预防中,适宜的剂量水平通常约为每天每kg患者体重0.01至500mg,可以以单一剂量或多剂量施用。优选地,剂量水平约为每天0.1至约250mg/kg,更优选约每天0.5至约100mg/kg。适合的剂量水平可以约为每天0.01至250mg/kg,约每天0.05至100mg/kg,或约每天0.1至50mg/kg。在该范围内,剂量可以为每天0.05至0.5、0.5至5或5至50mg/kg。对于口服施用,优选地以片剂形式来提供组合物,片剂含有1.0至1000毫克活性成分,特别地根据所治疗患者的症状调节活性成分的剂量为1.0、5.0、10.0、15.0、20.0、25.0、50.0、75.0、100.0、150.0、200.0、250.0、300.0、400.0、500.0、600.0、750.0、800.0、900.0和1000.0毫克。可以每日1至4次的服用方案施用化合物,优选每天一次或两次。
但是可以理解,对于任何特定患者,具体的剂量水平和给药频率可以变化并且取决于多种因素,包括所使用的具体化合物的活性、该化合物的代谢稳定性和作用时间的长短、年龄、体重、一般健康、性别、饮食、施用的方式和时间、排泄速率、药物联合、特定症状的严重程度和主体所进行的治疗。
本发明还提供包含式I的化合物或其药学可接受的盐和药学可接受的赋形剂的药物组合物。
因此,提供用于治疗的式I化合物或其药学可接受的盐。
同样地,提供式I化合物或其药学可接受的盐用于制备治疗神经激肽-2和/或神经激肽-3所介导的疾病的药剂的用途。
还公开了一种治疗患有神经激肽-2和/或神经激肽-3所介导疾病的受试者的方法,包括给患者施用治疗有效量的式I化合物或其药学可接受的盐。
由神经激肽-2和/或神经激肽-3介导疾病的实例包括CNS疾病,例如抑郁症(该术语包括两极性(狂躁的)抑郁症(包括I型和II型),单相抑郁症,带有或不带有精神病特征、紧张性精神症特征、忧郁症特征、非典型特征(例如嗜睡、暴食/肥胖症、睡眠过度)或产后初发特性的单次或多次严重抑郁发作,季节性情感障碍和胸腺机能障碍,抑郁相关的焦虑,精神病性抑郁症和由通常的医学病症产生的抑郁症,所述医学病症包括但是不限于心肌梗塞,糖尿病,流产或堕胎);焦虑障碍(包括一般焦虑障碍(GAD)、社交焦虑障碍(SAD)、精神激动、紧张、精神病患者的社交或情绪退缩、惊恐性障碍和强制性障碍);恐怖症(包括广场恐怖症和社交恐怖症);精神病和精神障碍(包括精神分裂症、情感分裂性精神障碍、精神分裂症样疾病、急性精神病、酒精性精神病、孤独症、谵妄、躁狂症(包括急性躁狂症)、躁狂抑郁症、幻觉、内因性精神病、器质性心理综合征、偏执和妄想性精神障碍、产褥期精神病和与神经变性疾病有关的精神病例如阿尔茨海默氏病);创伤后精神紧张性精神障碍;注意力缺陷多动障碍(ADHD);认知缺损(例如治疗损失的认知功能包括注意力、定向力、记忆力(记忆障碍、健忘症、遗忘障碍和年龄相关的记忆缺陷)和语言功能,还包括由于中风、阿尔茨海默氏病、艾滋病相关的痴呆或其它痴呆状态的认知缺损,以及其它可能导致认知减退的急性或亚急性病症例如谵妄或抑郁(假性痴呆状态));惊厥性疾患例如癫痫症(其包简单部分发作、复杂部分发作、继发性全身性发作,全身性发作包括癫痫小发作、肌阵挛性癫痫发作、阵挛性发作、强直性癫痫发作、强直阵挛发作和失张力发作);性心理的功能障碍(包括性欲抑制(低性欲)、抑制性唤起或兴奋抑制、性高潮缺乏、女性性高潮抑制和男性性高潮抑制、机能减退的性欲障碍(HSDD)、女性性欲障碍(FSDD)和由使用SSRI-类抗抑郁药治疗诱发的性功能障碍副作用);睡眠障碍(包括昼夜节律紊乱、睡眠障碍、失眠症、睡眠性呼吸暂停和昏睡病);进食行为障碍(包括神经性厌食症和神经性贪食症);神经变性疾病(例如阿尔茨海默氏病、ALS、运动神经元病和其它运动障碍,例如帕金森氏病(包括运动缺陷和/或运动性残疾的缓解,包括有目的的运动的缓慢丧失、震颤、运动过慢、运动过度(中度和严重)、运动不能症、强直、平衡和协调障碍、和姿势障碍),帕金森氏病中的痴呆、亨延顿氏舞蹈病中的痴呆、精神安定剂诱发的帕金森综合征和迟发性运动障碍、中风后的神经变性、心脏停搏、肺旁路、外伤性脑损伤、脊髓损伤等,脱髓鞘性病,例如多发性硬化症和肌萎缩侧索硬化症);药品滥用的戒断症状,包括戒烟或此类活动(例如可卡因、酒精、尼古丁、苯并二氮类、醇类、咖啡因、苯环己哌啶和苯环己哌啶样化合物、阿片制剂例如大麻、海洛因、吗啡、镇静药、安眠药、安非他明或安非他明相关的药物例如右旋安非他明、甲基苯丙胺或其组合的滥用)在水平上或频率上的减少;疼痛(包括神经性疼痛(包括糖尿病性神经病、坐骨神经痛、非特异下腰痛、多发性硬化症疼痛、纤维肌痛或癌症相关的疼痛、AIDS-相关的和HIV-相关的神经病、化疗诱发的神经病;神经痛,例如带状疱疹后神经痛和三叉神经痛、交感神经维持性疼痛和物理创伤引发的疼痛、截肢术、癌症、毒素或慢性炎症性病症例如类风湿性关节炎和骨关节炎;交感反射性营养不良例如肩/手综合征)、急性疼痛(例如肌肉骨骼痛、术后疼痛和手术疼痛)、炎性痛和慢性痛、正常的非疼痛性感觉相关的疼痛例如“发麻”(感觉异常和感觉迟钝)、增加的触觉敏感性(感觉过敏),非伤害性刺激后的疼痛感觉(动态、静态或热的异常性疼痛)、增加的伤害性刺激敏感性(热、冷、机械痛觉增敏)、除去刺激后的持续性痛觉(痛觉过敏)或在选择性感觉传导路的缺失或缺陷(痛觉感退)、偏头痛有关的疼痛和非心脏性胸痛);某些CNS-介导的疾病例如呕吐、过敏性肠综合征、非溃疡性消化不良;COPD、哮喘、咳嗽、胃-食道反射诱发的咳嗽和加重的哮喘;尿失禁;高血压;和血小板过度聚集有关的症状例如组织溃疡、肾病综合征、糖尿病、偏头疼、冠心病、先兆子痫和中风。优选地,本发明的组合物可用于治疗抑郁症;焦虑症;恐怖症;精神病和精神障碍;伤后精神紧张性精神障碍;注意力缺陷多动障碍(ADHD);药品滥用包括戒烟和此类活动在水平上或频率上的减少的戒断症状;和肠易激综合征。更优选,本发明的化合物可用于治疗抑郁症;焦虑症;恐怖症;精神病和精神障碍(尤其是精神分裂症、情感分裂性精神障碍和精神分裂症样疾病)。最优选地,本发明的化合物可用于治疗精神分裂症。
在本发明中使用的化合物在下述实验中通常是有活性的。它们通常具有小于1μM的IC50,优选地小于100nM。
可以在Gerard等人,J.Biol.Chem.,265:20455-20462,1990和Huang等人,Biochem.33:3007-3013,1994中找到NK-2受体和其异源表达(heterologous expression)的详细内容。后者的文章中还包含突变体扫描的详细内容。
可以在Huang等人,BBRC,1992,184:966-972和Sadowski等人,Neuropeptides,1993,24:317-319中找到NK-3受体和其异源表达(heterologous expression)的详细内容。
膜制备按如下制备进行。用稳定表达NK-3受体的CHO细胞接种10层细胞工厂(factory)。该CHO细胞在三部分(triple)的T175烧瓶中在11生长培养基中制备,培养基含有Iscore′s改良的Dulbecco′s介质,其含有10ml/l 200mM L-谷氨酰胺、10ml/l青霉素-链霉素、一管形瓶的次黄嘌呤-脱氧胸腺嘧啶苷500x/l、1mg/ml遗传霉素和10%胎牛血清(灭活)。细胞在保温箱中生长3天。洗掉培养基,细胞工厂用400mlPBS(无钙,镁)冲洗两次。加入400ml无酶分裂溶液(EFDS),细胞工厂在室温下保持10分钟。取出细胞并将混悬液倾倒进500ml离心瓶中。用200ml EFDS重复该过程,收集的混合物总共获得6瓶,将其在离心机中以2200rpm旋转10分钟。
吸取上清液并在-80℃冷冻剩余的细胞粒30分钟以改善细胞胞溶。然后每个细胞工厂在具有抑制剂的40ml Tris中再悬浮。在8冲程(8strokes)的玻璃-特氟纶(glass-teflon)研磨器中设定40将细胞以40ml等分试样匀浆化。该匀浆转移至50ml离心管中,在室温并放置在震荡器上15分钟。将匀浆重新匀浆化,在如上文离心前如果需要则放置在冰上。
将上清液转移至用于SS-34转子的Sorvall管中,并放置在冰上。
使用含有抑制剂的冷却的40ml Tris将其再悬浮,并将如上再次旋转的团粒合并。将上清液再次转移至上述那些Sorvall管中,以18000rpm旋转20分钟。
将上清液丢弃并在由2.50ml 1M Tris pH 7.4,50μl 1000x蛋白酶抑制剂(全部溶解在水中的4mg/ml亮肽酶素(Sigmo),40mg/ml杆菌肽(Sigma)和10mM phosphoranidon(Peninsula)和0.5ml 0.5MMnCl2组成由H2Odd补足至50ml的贮存缓冲液中将该团粒再悬浮。连续使用具有20-、23-和25-规格针头的10ml注射器。
在将500-1000μl等分试样用液氮快速冷冻以在-80℃贮存以前,使用BSA作为标准在2-10μl的等分试样上进行Bradford蛋白分析。
膜结合分析按如下进行。预先测定特异性结合≤10%的125I-神经激肽B所需要的膜的量。然后将冷冻原料稀释,加入50μl。
将测试实验的化合物溶解在DMSO中。对自动化装置(Tecan)编程以加入5μl化合物或DMSO、在20μl缓冲液中的大约100,000cpm的同位素(该缓冲液由以下制备:50μM Tris,pH7.5、150μM NaCl、至0.02%的牛血清白蛋白,和在贮存缓冲液中的蛋白酶抑制剂,制成0.5M储备液原料)以及175μl分析用缓冲液(与贮存缓冲液一样,但是含有5μM MnCl2并且不含有NaCl)到96孔板形式的Marsh boxes深井盒(Marsh Biomedical产品)中。通过如下指明的通过手工加入过量的未标记的竞争肽用于非特异性结合。通过加入50μl细胞膜开始结合反应。试管在室温下用振荡法培养1小时,并在使用Mach III过滤垫的Tomtec 96孔细胞收集器上(Tomtec)或使用Unifilter GF/C(Packard)的Packard 96孔收集器或Tomtec 9600上进行过滤,在0.25%聚乙烯亚胺中预浸渍,并用1X洗涤缓冲液(0.1M.Tris,pH7.4和1M NaCl,1X=100ml的10X储备液/1升冷却蒸馏水)洗涤5次。如果使用Unifilter盘板,将则向每孔中加入60μl Microscint 20(packard),然后在Packard Topcount计数前将该板加热密封。可选择地,将来自filtermat的过滤器放置在75×100mm塑料管中,并用Cobraγ计数器计数。
对于该分析,通常在25,000cpm下使用10μg的膜,其在经0.5%BSA中预浸渍的Unifilter GF/C上过滤。
可以用类似的方法进行神经激肽-2受体的结合分析。
本发明的化合物很容易根据下述的反应方案和实施例或其改进来制备。起始材料可以由本领域已知的或如举例说明的方法来制备。在这些反应中,还可以使用其本身对于本领域普通技术人员是已知的,但是并未进一步详述的变体。此外,制备本发明化合物的其它方法对于本领域普通技术人员来说根据以下的反应方案和实施例是显而易见的。
在本说明书,特别是方案和实施例中使用的缩写包括以下缩写:DMSO=二甲基亚砜;EDAC=1-(3-二甲氨基)丙基-3-乙基碳化二亚胺;Et2O=二乙醚;EtOAc=醋酸乙酯;h=小时;HOBT=1-羟基苯并三唑水合物;sat′d=饱和水溶液;rt=室温;THF=四氢呋喃。
式I的化合物可以通过式II的化合物与氯甲酸甲基酯反应来制备:
反应通常在升高温度下在溶剂例如甲苯中进行。
式II的化合物通常在本领域是已知的或者可以通过本领域已知的方法由已知化合物来制备。例如式II的化合物可以通过式III的化合物与苯肼反应来制备:
该反应通常在碱例如三乙胺和凝缩剂(condensing agent)例如HOBT的存在下与EDAC在溶剂例如THF中进行。
式III的化合物在本领域是已知的或者可以通过本领域已知的方法由已知化合物来制备。
本发明的化合物很容易根据下面的实施例或其改进来制备。起始材料可由本领域已知的或所述的工序制得。在这些反应中,还可以使用其本身对于本领域普通技术人员是已知的,但是并未进一步详述的变体。此外,根据以下实施例制备本发明化合物的其它方法对于本领域普通技术人员来说是显而易见的。除非另外说明,变量如上定义。
下述实施例用于说明本发明:
实施例1:2-({3-氨基-2-苯基喹啉-4-基}羰基)-1-苯肼羧酸甲基酯
步骤1:3-氨基-N’,2-二苯基-4-喹啉碳酰肼
向在THF(100ml)中的3-氨基-2-苯基-喹啉-4-羧酸(根据Giardina等人,Journal of Heterocyclic Chemistry(1997),34(2),557-559的方法制备,0.95g,0.0036mol)、HOBT(0.84g,0.0056mol)和三乙胺(0.78ml,0.0056mol)的混合物中加入EDAC·HCl(1.04g,0.0056mol),接着加入苯肼(0.39ml,0.004mol),反应混合物在室温下搅拌16小时。真空除去所有溶剂,将残留物溶解在CH2Cl2(100ml)中,并用2M柠檬酸水溶液(2×60ml)、饱和NaHCO3溶液(2×60ml)和饱和盐水(1×60ml)洗涤。有机相在无水硫酸钠上干燥、真空过滤并浓缩。残留物用Et2O研制,过滤收集黄色的固体(0.9g)。
1H NMRδ(ppm)(DMSO-d6,500MHz):10.50(1H,d,J 2.8Hz),7.97(1H,d,J 2.8Hz),7.90(1H,d,J 7.7Hz),7.74(3H,t,J 4.2Hz),7.60-7.46(5H,m),7.23(2H,t,J 7.9Hz),6.89(2H,d,J 7.6Hz),6.78(1H,t,J 7.3Hz),5.10(2H,s);MS:m/z显示MH+=355;C22H18N5O理论M=354。
步骤2:2-({3-氨基-2-苯基喹啉-4-基}羰基)-1-苯肼羧酸甲基酯
向在甲苯(100ml)中的3-氨基-N’,2-二苯基-4-喹啉碳酰肼溶液中(由步骤1获得,0.5g,0.00094mol)加入氯甲酸甲基酯(0.11ml,0.00141mol),将反应混合物在60℃加热14小时。加入另一份量的氯甲酸甲基酯(0.45ml),并另外继续加热24小时,此时间后加入另一份量的氯甲酸甲基酯(0.45ml)并继续加热另外6小时。真空除去溶剂,并将残留物溶解在CH2Cl2(100ml)中,用饱和NaHCO3溶液(2×50ml)洗涤、干燥(Na2SO4)、真空过滤并浓缩。残留物通过色谱法在硅胶上使用在异已烷中的0-35%EtOAc作为洗脱液进行纯化,将所得固体由Et2O重结晶,通过过滤收集获得的黄色固体(0.15g)。
1H NMRδ(ppm)(CDCl3,500MHz):8.31(1H,s),8.00(1H,d,J 7.4Hz),7.88(1H,s),7.69(2H,d,J 7.0Hz),7.56-7.42(9H,m),7.34(1H,d,J 7.1Hz),5.17(2H,s),3.87(3H,s);MS:m/z显示MH+=413;C24H20N4O3理论M=412。
实施例2:2-({3-氨基-2-[4-氟]苯基喹啉-4-基}羰基)-1-苯肼羧酸甲基酯
步骤1:3-氨基-N’-苯基-2-[4-氟]苯基-4-喹啉碳酰肼
向在THF(100ml)中的3-氨基-2-(4-氟-苯基-喹啉)-4-羧酸(根据公开的国际专利申请WO2004/050627的方法制备;0.7g,0.0026mol)、HOBT(0.5g,0.0039mol)和三乙胺(0.52ml,0.0039mol)的混合物中加入EDAC·HCl(0.713g,0.0039mol),接着加入苯肼(0.295ml,0.003mol),反应混合物在室温下搅拌16小时。真空除去所有溶剂,并将残留物溶解在CH2Cl2(100ml)中,用2摩尔柠檬酸水溶液(2×60ml)、饱和NaHCO3溶液(2×60ml)和饱和盐水(1×60ml)洗涤。有机相在无水硫酸钠上干燥、真空过滤并浓缩。残留物用Et2O研制,通过过滤收集黄色的固体(0.3g)。
1H NMRδ(ppm)(CDCl3,500MHz):8.06(1H,dd,J 8.0Hz),7.96(1H,d,J 8.4Hz),7.90(1H,s),7.72(2H,dd,J 5.3,8.6Hz),7.62-7.47(3H,m),7.33-7.29(2H,m),7.22(2H,s),6.99(2H,t,J 8.7Hz),6.49(1H,s),4.91(2H,s);MS:m/z显示MH+=373;C22Hl7FN5O理论M=372。
步骤2:2-({3-氨基-2-[4-氟]苯基喹啉-4-基}羰基)-1-苯肼羧酸甲基酯
向在甲苯(50ml)中的3-氨基-N’-苯基-2-[4-氟]苯基-4-喹啉碳酰肼溶液中(由步骤1获得,0.3g,0.0008mol)加入氯甲酸甲基酯(0.124ml,0.0016mol),将反应混合物在60℃加热14小时。加入另一份量的氯甲酸甲基酯(0.062ml),并另外继续加热24小时,此时间后加入另一份量的氯甲酸甲基酯(0.062ml)并继续加热另外6小时。真空除去溶剂,并将残留物溶解在CH2Cl2(100ml)中,用饱和NaHCO3溶液(2×50ml)洗涤、干燥(Na2SO4)、真空过滤并浓缩。残留物通过色谱法在硅胶上使用在异已烷中的0-35%EtOAc作为洗脱液,然后用在CH2Cl2中的0-15%EtOAc作为洗脱液进行纯化,将所得固体由Et2O重结晶,通过过滤收集获得的黄色固体(0.078g)。
1H NMRδ(ppm)(CDCl3,500MHz):8.26(1H,s),7.99(1H,d,J 9.2Hz),7.86(1H,s),7.71(2H,dd,J 5.4,8.6Hz),7.55(2H,d,J 7.7Hz),7.49-7.43(4H,m),7.34(1H,t,J 7.4Hz),7.22(2H,m),5.12(2H,s),3.87(3H,s);MS:m/z显示MH+=431;C24H19FN4O3理论M=430。
实施例3:2-({3-氨基-2-[3-氟]苯基喹啉-4-基}羰基)-1-苯肼羧酸甲基酯
步骤1:3-氨基-N’-苯基-2-[3-氟]苯基-4-喹啉碳酰肼
向在THF(200ml)中的3-氨基-2-(3-氟-苯基-喹啉)-4-羧酸(根据公开的国际专利申请WO2004/050626的方法制备;1.4g,0.0052mol)、HOBT(1.0g,0.0078mol)和三乙胺(1.04ml,0.0078mol)的混合物中加入EDAC·HCl(1.426g,0.0039mol),接着加入苯肼(0.59ml,0.006mol),反应混合物在室温下搅拌16小时。真空除去所有溶剂,并将残留物溶解在CH2Cl2(200ml)中,用2摩尔柠檬酸水溶液(2×100ml)、饱和NaHCO3溶液(2×100ml)和饱和盐水(1×100ml)洗涤。该有机相在无水硫酸钠上干燥、真空过滤并浓缩。残留物用Et2O研制备,通过过滤收集黄色的固体(0.57g)。
1H NMRδ(ppm)(CDCl3):8.05(1H,d,J 8.0Hz),7.97(1H,d,J 7.7Hz),7.88(1H,s),7.56-7.49(4H,m),7.45(1H,d,J 8.3Hz),7.32(2H,t,J 7.8Hz),7.23-7.19(1H,m),6.99(3H,m),6.49(1H,s),4.94(2H,s);MS:m/z显示MH+=373;C22H17FN5O理论M=372。
步骤2:2-({3-氨基-2-[3-氟]苯基喹啉-4-基}羰基)-1-苯肼羧酸甲基酯
向在甲苯(50ml)中的3-氨基-N’-苯基-2-[3-氟]苯基-4-喹啉碳酰肼溶液中(由步骤1获得,0.55g,0.00147mol)加入氯甲酸甲基酯(0.32ml,0.0041mol),并将反应混合物在60℃加热14小时。加入另一份量的氯甲酸甲基酯(0.2ml),并另外继续加热24小时,此时间后加入另一份量的氯甲酸甲基酯(0.5ml)并继续加热另外6小时。真空除去溶剂,并且将残留物溶解在CH2Cl2(100ml)中,用饱和NaHCO3溶液(2×50ml)洗涤、干燥(Na2SO4)、真空过滤并浓缩。残留物通过色谱法在硅胶上使用在CH2Cl2中的0-15%EtOAc作为洗脱液进行纯化,将所得固体由Et2O重结晶,通过过滤收集获得的黄色固体(0.32g)。
1H NMRδ(ppm)(CDCl3,500MHz):8.25(1H,s),8.00(1H,d,J 9.2Hz),7.88(1H,s),7.56-7.43(9H,m),7.34(1H,t,J 7.4Hz),7.20(1H,m),5.15(2H,s),3.88(3H,s),MS:m/z显示MH+=431;C24H19FN4O3理论M=430。
Claims (11)
1.式(I)化合物:
或其药学可接受的盐。
2.如权利要求1的化合物,其中连接至喹啉基部分的2位的苯环的2位是未取代的。
3.如权利要求1或2的化合物,其中连接至喹啉基部分的2位的苯环是未取代的。
4.如权利要求1的化合物,选自:
2-({3-氨基-2-苯基喹啉-4-基}羰基)-1-苯基肼羧酸甲酯,
2-({3-氨基-2-[2-氟]苯基喹啉-4-基}羰基)-1-苯基肼羧酸甲酯,
2-({3-氨基-2-[3-氟]苯基喹啉-4-基}羰基)-1-苯基肼羧酸甲酯,
2-({3-氨基-2-[4-氟]苯基喹啉-4-基}羰基)-1-苯基肼羧酸甲酯,
2-({3-氨基-2-[2,3-二氟]苯基喹啉-4-基}羰基)-1-苯基肼羧酸甲酯,
2-({3-氨基-2-[2,4-二氟]苯基喹啉-4-基}羰基)-1-苯基肼羧酸甲酯,
2-({3-氨基-2-[2,5-二氟]苯基喹啉-4-基}羰基)-1-苯基肼羧酸甲酯,
2-({3-氨基-2-[2,6-二氟]苯基喹啉-4-基}羰基)-1-苯基肼羧酸甲酯,
2-({3-氨基-2-[3,4-二氟]苯基喹啉-4-基}羰基)-1-苯基肼羧酸甲酯,
2-({3-氨基-2-[3,5-二氟]苯基喹啉-4-基}羰基)-1-苯基肼羧酸甲酯,
和它们药学可接受的盐。
5.包含权利要求1至4任一项的化合物或其药学可接受的盐以及药学可接受的赋形剂的药物组合物。
6.如权利要求1至4任一项的化合物,其用于治疗。
7.如权利要求1至4任一项化合物或其药学可接受的盐用于制备治疗神经激肽-2和/或神经激肽-3介导疾病的药物的用途。
8.如权利要求7的用途,其中神经激肽-2和/或神经激肽-3介导的疾病是精神分裂症。
9.治疗患有神经激肽-2和/或神经激肽-3介导疾病的受试者的方法,其包括给该患者施用治疗有效量的权利要求1至4任一项的化合物或其药学可接受盐。
10.权利要求9的方法,其中神经激肽-2和/或神经激肽-3介导的疾病是精神分裂症。
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2005
- 2005-07-28 EP EP05768021A patent/EP1776343B1/en not_active Not-in-force
- 2005-07-28 CN CNA2005800264225A patent/CN1993330A/zh active Pending
- 2005-07-28 AU AU2005268603A patent/AU2005268603A1/en not_active Abandoned
- 2005-07-28 JP JP2007524404A patent/JP2008509122A/ja not_active Withdrawn
- 2005-07-28 US US11/659,401 patent/US20080312274A1/en not_active Abandoned
- 2005-07-28 DE DE602005013094T patent/DE602005013094D1/de not_active Expired - Fee Related
- 2005-07-28 AT AT05768021T patent/ATE424387T1/de not_active IP Right Cessation
- 2005-07-28 CA CA002575697A patent/CA2575697A1/en not_active Abandoned
- 2005-07-28 WO PCT/GB2005/050121 patent/WO2006013394A1/en active Application Filing
Also Published As
Publication number | Publication date |
---|---|
WO2006013394A1 (en) | 2006-02-09 |
AU2005268603A1 (en) | 2006-02-09 |
DE602005013094D1 (de) | 2009-04-16 |
US20080312274A1 (en) | 2008-12-18 |
JP2008509122A (ja) | 2008-03-27 |
ATE424387T1 (de) | 2009-03-15 |
GB0417559D0 (en) | 2004-09-08 |
CA2575697A1 (en) | 2006-02-09 |
EP1776343A1 (en) | 2007-04-25 |
EP1776343B1 (en) | 2009-03-04 |
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