CN1133636C - 二芳基1,3,4-噁二唑酮的氨基甲酸酯衍生物 - Google Patents
二芳基1,3,4-噁二唑酮的氨基甲酸酯衍生物 Download PDFInfo
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- CN1133636C CN1133636C CNB008026815A CN00802681A CN1133636C CN 1133636 C CN1133636 C CN 1133636C CN B008026815 A CNB008026815 A CN B008026815A CN 00802681 A CN00802681 A CN 00802681A CN 1133636 C CN1133636 C CN 1133636C
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- phenyl
- compound
- methyl
- oxadiazole
- trifluoromethyl
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Abstract
本发明提供具有通式(I)的新氨基甲酸酯衍生物,其中R1和R2如本发明中定义,或其无毒性的药用盐或溶剂化物,该衍生物对治疗响应大传导率钙激活钾离子通道开启的疾病是有效的。
Description
发明领域
本发明涉及1,3,4-噁二唑-2(3H)-酮化合物的新氨基甲酸酯衍生物,其中所说的化合物是大传导率钙-激活钾离子(BK)通道的调制剂,因而可用于保护神经细胞和因细胞膜极化和传导机能障碍引起的疾病。本发明还提供用新的取代噁二唑酮衍生物的治疗方法以及其药用组合物。
发明背景
中风目前被认为是造成美国和欧洲成人劳动能力丧失和死亡的第三个主要原因。过去十年间,为最大程度地降低中风-有关的脑损害,人们从事了很多治疗研究,包括AMPA/红藻氨酸酯,N-甲基-D-天冬氨酸酯(NMDA)的抑制剂和腺苷重摄取抑制剂。本发明的目的是提供新的化合物,其能够调制钾离子通道,具体说调制大-传导率的钙激活钾离子(BK)通道,可有效减少中风事件中局部缺血发病期间神经细胞的损害。
钾离子通道在调控细胞膜电势和调制细胞应激性中起关键作用。钾离子通道本身由电压、细胞代谢、钙离子和受体介导过程来调控[Cook,N.S.,药理学走向
9,pp.21-28(1988);和Quast,U.和Cook,N.S.,
药理学 走向10,,pp.431-435(1989)]。钙-激活钾离子(KCa)通道是离子通道的异族,其分享了细胞内钙离子对活性的依赖性。KCa通道活性受细胞内[Ca2+]、膜电势和磷酸化作用的调控。以它们在对称K+溶液中的单-通道传导为基础,将KCa通道分成三小类:大传导率(BK)>150pS;中传导率50-150pS;小传导率<50pS(″pS″表示皮西门子,一种电导率单位)。大-传导率的钙-激活钾离子(BK)通道存在于很多应激性细胞中,包括神经细胞、心脏细胞和各种类型的平滑肌细胞[Singer,J.J.和Walsh,J.V.,Pflügers Archiv.,408,pp.98-111(1987);Baró,I.,和Escande,D.,Pflügers Archiv.,414(Suppl.1),pp.S168-S170(1989);以及Ahmed,F.等,英国药理学杂志(Br.J.Pharmacol.),83,pp.227-233(1984)]。
钾离子在控制大部分应激性细胞中静息膜电势和在使K+平衡电势(Ek)附近的跨膜电压维持在约-90mV中起支配作用。据显示,钾离子通道的开启使细胞膜电势向平衡钾离子膜电势(Ek)移动,造成细胞的超极化性[Cook,N.S.,
药理学走向
9,,pp.21-28(1988]。超极化性的细胞对可能的损害性去极化刺激物显出低响应性。受电压和细胞内Ca2+控制的BK通道起限制去极化和钙进入的作用并且对阻断损害性刺激物特别有效。因此,通过BK通道开启使细胞超极化可以保护处于局部缺血状况下的神经细胞。
钾离子通道在人泌尿膀胱平滑肌运转中的作用在S.Trivedi,等的《生物化学和生物物理研究通讯》(1995),213,No.2,pp.404-409中有所讨论。
据报道,有很多合成和天然存在的具有BK开启活性的化合物。使用脂质双层技术从普通
燕麦中提取的
燕麦吡喃酮据识别是BK通道开启子[WO93/08800,1993.5.13公开]。通过使用外部-外用补片发现黄烷类、根皮素可影响
有爪蟾蜍有髓鞘神经纤维中的Ca2+-激活钾离子通道的开启[Koh,D-S.,等,神经科学通信,165,pp.167-170(1994)]。
US 3,971,803(S.Rosenberger和K.Schwarzenbach,1976.7.27)涉及了下式(i)的化合物:其中R1是烷基,环烷基或芳烷基;R2是氢或R1;R3是氢或C1-4烷基;Y和Z各自是O或S;R4要么是(1),如果m=1,则是C1-8亚烷基,-CxH2x-Q-CyH2y-(Q是O或S,x和y是总和为2-4的整数),亚苯基、二亚苯基或萘,或者基团;要么是(2),如果m=2,则是亚烷基,亚烷基醚,亚烷基硫醚,二亚苯基或萘。该化合物是有机聚合物的抗氧化剂。
A.E.Wilder Smith在Arzneim.Forsch.(1967)67,No.17,pp.768-772中公开了下式(iii)化合物的制备和研究:其中X是H或Cl并且n是1或2。该化合物具有结核菌抑制性能。该式(iii)的化合物不包括羟基的对位取代。
J.L.Romine,等在WO 98/04135(1998.2.5公开)中描述了下式(iv)的一系列二苯基杂环:其中Het是杂环部分,特别选自噁二唑酮。该化合物是大传导率的钙-激活钾离子通道的有效调制剂,并且描述了制备本发明化合物的起始原料,其中Het是1,3,4-噁二唑-2(3H)-酮,m=1且n=0,Rc是氯,Rd是三氟甲基并且Ra=Rb=Re是氢。
这些文献中没有一篇教导或者提出过本发明的新化合物。
发明概述
本发明提供1,3,4-噁二唑酮的新氨基甲酸酯衍生物,该衍生物具有以下通式I:其中R1和R2如下定义,或其无毒性的药用盐或溶剂化物。本发明还提供含有所说衍生物的药用组合物,以及对钾离子通道开启活性敏感的疾病的治疗方法,如局部缺血,中风,惊厥,癫痫,气喘,应激性肠综合症,偏头痛,创伤性脑伤,脊髓损伤,性功能障碍和小便失禁。发明详述
本发明提供3-[(5-氯-2-羟基苯基)甲基]-5-[4-(三氟甲基)苯基]-1,3,4-噁二唑-2(3H)-酮的新氨基甲酸酯衍生物,其是大传导率钙-激活K+-通道(BK通道)的有效开启子,并且该新的衍生物具有以下通式I:其中R1是氢,C1-4烷基,-CR3R4CO2H,-(CH2)2-NR5R6;R2是氢,C1-4烷基;或者R1和R2与和它们相连的氮原子一起形成选自哌嗪,N-甲基哌嗪,哌啶,硫代吗啉和吗啉的杂环;R3是氢或甲基;R4是氢;或者取代或未取代的C1-4烷基,其中取代基选自羟基,氨基,硫甲基,羧基,甲酰胺,胍基,苯基和羟基苯基;并且R5和R6各自独立地是氢,C1-4烷基;或者R5和R6与和它们相连的氮原子一起形成选自哌嗪,N-甲基哌嗪,哌啶,硫代吗啉和吗啉的杂环;或者其无毒性的药用盐或溶剂化物。
本发明还提供治疗或防护哺乳动物中因大传导率钙-激活K+通道(BK通道)开启而引起的疾病的方法,该方法包括给所说的哺乳动物施用疗效量的式I化合物或其无毒性的药用盐。优选,式I的化合物可有效治疗局部缺血,中风,癫痫,惊厥,气喘,应激性肠综合症,偏头痛,创伤性脑伤,脊髓损伤,性功能障碍和小便失禁以及其它对BK通道启动活性敏感的疾病。
这里和权利要求书中所说的术语″C1-4烷基″(除非上下文另有所指)指诸如甲基,乙基,丙基,异丙基,丁基的直链或支链烷基。
这里和权利要求书中所说的术语″无毒性的药用盐″包括无毒性的酸性和碱性盐以及两性离子型的盐。碱性盐包括无机金属盐,如钠,钾,钙和镁盐;铵盐和含有无毒性胺的盐,如三烷基胺,吡啶,甲基吡啶,二苄胺,乙醇胺,N-甲基吗啉和其它用于形成羧酸盐的胺类。适宜的酸性盐包括无机酸盐,如盐酸盐,氢溴酸盐,氢碘酸盐,硫酸盐,磷酸盐等等;以及有机酸盐,如用于形成碱性胺盐的甲酸盐,乙酸盐,马来酸盐,柠檬酸盐,琥珀酸盐,抗坏血酸盐,乳酸盐,富马酸盐和酒石酸盐。
除非另有说明,这里所说的术语″氨基酸″衍生物指天然存在的氨基酸。适宜的氨基酸是这里描述的氨基酸和其它已知的氨基酸,如丙氨酸,甘氨酸,精氨酸,半胱氨酸,异亮氨酸,亮氨酸,赖氨酸,缬氨酸,蛋氨酸,苯丙氨酸,苏氨酸等等。本领域技术人员应当理解,其中R1是-CR3R4CO2H的式I化合物表示天然存在的氨基酸的残基,并且作为前体药物在
体内是活性的,即可以通过主体中的肽酶水解氨基酸残基,产生更活性形式的所需1,3,4-噁二唑啉。而且,本领域技术人员应当理解,非天然氨基酸,诸如D-构型的氨基酸,可以取代L-构型形式的天然存在的氨基酸。
通常来说,本发明的药用盐是其中的抗衡阴离子不明显给盐带来毒性或药理学活性的盐。在某些情况中,它们具有使它们更合意于药用制剂的物理性质,例如溶解性,缺乏吸湿性,可压缩成片剂并且与可以用于药用目的的物质中的其它配料相容。药用盐可以通过将式I化合物与所选择的酸掺混来常规制造,优选通过在溶液中接触,使用过量的常用惰性溶剂,如水、乙醚、二噁烷、二氯甲烷、异丙醇、甲醇、乙醇、乙酸乙酯和乙腈。它们也可以通过置换或者用离子交换树脂处理来制造,处理的条件是其中式I物质的盐的适当离子在允许所需种类分离的条件下被另一个离子替换,例如通过从溶液中沉淀或用溶剂提取,或者由离子交换树脂洗脱或截留在离子交换树脂上。
本发明的某些化合物(包括其药用盐)可以作为溶剂化物的形式存在,包括水合物的形式,如一水合物,二水合物,半水合物,三水合物,四水合物等等。产品可以是纯粹的溶剂化物,而在其它情况中,产品可以只保留偶生的溶剂或者可以是溶剂化物加上一些偶生溶剂的混合物。本领域技术人员应当理解,溶剂化的形式等价于非溶剂化的形式,并且属于本发明的范围。
本发明的方法中,术语″疗效量″指组合物各活性组分足够显出益于患者效果的总量,即治愈以大传导率钙-激活K+通道开启为特征的急性病症患者或增加这种病症的治愈率。当应用于单独施用的单个活性成分时,该术语仅针对单个成分而言。当应用于组合物时,该术语指产生治疗效果的活性成分的结合量,无论这些成分是联合、连续或同时给药。这里和权利要求书中所说的术语″治疗,治疗性,治疗作用″指预防或改善疾病、组织损害和/或与细胞膜极化和传导机能障碍有关的症状。
另一方面,本发明提供3-[(5-氯-2-羟基苯基)甲基]-5-[4-(三氟甲基)苯基]-1,3,4-噁二唑-2(3H)-酮的水溶性前体药物,所说的3-[(5-氯-2-羟基苯基)甲基]-5-[4-(三氟甲基)苯基]-1,3,4-噁二唑-2(3H)-酮描述于WO98/04135。这里所说的术语″前体药物″指活性药物的衍生物,其在施用之后转回成活性药物。更具体说,本发明提供1,3,4-噁二唑-2(3H)-酮化合物的氨基甲酸酯衍生物,其可以是活性药物和/或能够经历酯水解或酯裂解以便释放活性自由药物。其可生理性水解类可以充当通过在体内被水解自身产生母体药物的前体药物,因此,为施用母体药物,本发明优选水溶性前体药物。
另一方面,本发明提供一种治疗或防护哺乳动物中因大传导率钙-激活K+通道(BK通道)开启引起的疾病的方法,该方法包括给所说的哺乳动物施用疗效量的式I化合物或其无毒性的药用盐,溶剂化物或水合物。优选,式I的化合物可有效治疗局部缺血,中风,惊厥,癫痫,气喘,应激性肠综合症,偏头痛,创伤性脑伤,脊髓损伤,小便失禁以及男性性功能障碍(勃起功能障碍,例如,由于糖尿病,脊髓损伤,前列腺切除,精神性病因或其它原因)和女性性功能障碍,通过改良血流动到生殖器,特别是海绵体中,并且可有效治疗其它对BK通道启动活性敏感的疾病。首选,式I的化合物可有效治疗脑部局部缺血/中风。
再一方面,本发明提供含有至少一种式I化合物与药用辅剂,载体或稀释剂相结合的药用组合物。
式I的化合物可以通过各种工艺来制备,如本发明实施例、反应路径中举例说明的工艺,以及对本领域技术人员来说是显而易见的变化方案。由式II的活性药物物质制备式I的各种前体药物化合物是有利的,而所说的式II的活性药物本身通过WO 98/04135和实施例1描述的通用工艺来制备,并且在反应路径1和2所举例的方法中用作起始原料。反应路径1
反应路径1举例说明了制备式Ia的氨基酸氨基甲酸酯衍生物。用芳基氯甲酸酯如对硝基苯基氯甲酸酯在诸如二氯甲烷、氯仿或四氢呋喃等的无水有机溶剂中于诸如吡啶和三乙胺等的碱的存在下处理式II的化合物,得到式III的碳酸酯,然后用所需的氨基酸叔丁酯在诸如三乙胺等的碱的存在下处理,得到式IV的氨基甲酸酯中间体。
当期望制备式Ib的氨基甲酸酯衍生物时,如反应路径2中所述,用所需的胺处理式III的碳酸酯中间体是有利的。将式NR1R2的所需无环或杂环胺添加到含式III碳酸酯化合物的二氯甲烷溶液中,并且添加诸如三乙胺等的碱,得到式Ib的氨基甲酸酯衍生物。有利地,通过用无水HCl醚性溶液处理,分离呈盐酸盐形式的式Ib的产品。
在本发明优选的实施方案中,式I的化合物具有下式Ia:其中R3是氢或甲基,R4是氢;或取代或未取代的C1-4烷基,其中取代基选自羟基,氨基,硫甲基,羧基,甲酰胺,胍基,苯基和羟基苯基;或其无毒性的药用盐或溶剂化物。优选,R3是氢且R4是C1-4烷基,选择性地取代有羟基,氨基,羧基和甲酰胺或其无毒性的药用盐或溶剂化物。
在本发明的另一个优选实施方案中,式I的化合物具有下式Ib其中R1是-(CH2)2-NR5R6;R2是氢,R5和R6各自独立地是氢,C1-4烷基;或R5和R6与和它们相连的氮原子一起形成选自哌嗪,N-甲基哌嗪,哌啶,硫代吗啉和吗啉的杂环;或其无毒性的药用盐或溶剂化物。优选,R1是-(CH2)2-NR5R6且R5和R6各自独立地是氢或C1-4烷基;或其无毒性的药用盐或溶剂化物。
在另一个实施方案中,本发明包括含有至少一种式I化合物与药用辅剂,载体或稀释剂相结合的药用组合物。
在再一个实施方案中,本发明涉及一种治疗或防护哺乳动物中因钾离子通道开启引起的疾病的方法,该方法包括给所说的哺乳动物施用疗效量的式I化合物或其无毒性的药用盐,溶剂化物或水合物。
在又一个实施方案,本发明涉及治疗哺乳动物中局部缺血,惊厥,癫痫,气喘,应激性肠综合症,偏头痛,创伤性脑伤,脊髓损伤,雄性和雌性性功能障碍,小便失禁特别是中风的方法,该方法包括给所说的哺乳动物施用疗效量的式I化合物或其无毒性的药用盐,溶剂化物或水合物。生物学活性
钾离子(K+)通道是K+-选择通道蛋白质中结构和功能各异的族系,K+-选择通道蛋白质在细胞中到处存在,它们的中心重要之处是调控很多关键细胞的功能[Rudy,B.,
神经科学,25,pp.729-749(1988)]。尽管作为一类广泛分布,K+通道作为这类的单个成员或作为族系是以不同方式分布的[Gehlert,D.R.,等,
神经科学,52,pp.191-205(1993)]。总体来说,细胞中特别是在应激性细胞如神经细胞和肌细胞中,K+通道的激活可导致细胞膜的超极化,或者在去极化的细胞中,导致再极化。除起内生膜电压钳的作用外,K+通道可以响应重要的细胞事件,如细胞内ATP浓度的变化或者细胞内钙(Ca2+)浓度的变化。K+通道的中心作用是调控很多细胞功能,这使得它们在治疗学开发中是特别的重点目标[Cook,N.S.,钾离子通道:结构,分类,功能和治疗潜在性,Ellis Horwood,Chinchester(1990)]。一类K+通道,大传导率Ca2+-激活K+通道(BK或BK通道),通过跨膜电压、细胞内Ca2+和各种其它诸如通道蛋白质的磷酸化状态等因素来调控[Latorre,R.,等
Ann.
Rev.
Physiol.,51,pp.385-399(1989)]。大的单通道-传导率(通常>150pS)和对BK通道之K+的高度特异性说明了少量通道可以深切影响膜的传导率和细胞应激性。此外,开启机率随细胞内Ca2+增加而增加说明BK通道参与了Ca2+-依赖性现象如分泌和肌肉收缩的调制[Asano,M.,等,药理学和实验治疗学杂志(J.Pharmacol.Exp.Ther.),267,pp.1277-1285(1993)]。
BK通道的开启子通过增加这些通道的开启机率来发挥它们的细胞性作用[McKay,M.C.,等,神经生理学杂志,71,pp.1873-1882(1994);和Olesen,S.-P.,Exp.Opin.Invest.Drugs,3,pp.1181-1188(1994)]。这种各个BK通道开启的增加结果导致细胞膜的超极化,特别是去极化细胞,这是由于全-细胞BK-介导的传导率显著增加产生的。
在电压钳条件下,评价实施例1化合物开启BK通道和增加全-细胞向外(K+)BK-介导电流的能力,通过测定它们增加克隆哺乳动物(mSlo或hSlo)BK-介导向外电流的能力,所说的电流异种表达在非洲蟾蜍属卵母细胞中[Butler,A.,等.,科学,261,pp.221-224(1993);和Dworetzky,S.I.,等,Mol.Brain Res.,27,pp.189-193(1994)]。这两种BK构件使用结构几乎相同的同源蛋白,并且据证实与我们的测试在药理学方面是相同的。为从本地(背景,非-BK)电流中分离BK电流,使用超大浓度(50nM)的特异且有效BK通道阻塞毒素iberio毒素(IBTX)[Galvez,A.,等.,生物化学杂志(J.Biol.Chem),265,pp.11083-11090(1990)]。通过从所有其它实验环境条件(对照、药物和冲洗)中获得的电流分布中减去在IBTX(非-BK电流)的存在下剩余的电流,测得BK通道电流对总向外电流的相对供量。经测定,在测试浓度下,分布的化合物不影响卵母细胞中的非-BK本地电流。在至少5个卵母细胞中显示,实施例1的化合物在1μM浓度下使BK电流增加到对照IBTX-敏感电流的126%。使用标准双电极电压钳技术完成记录[Stuhmer,W.,等.,酶学方法,207,pp.319-339(1992)];在从-60mV的持续电势到+140mV的以20mV步骤的去极化期间,电压钳方案由500-750ms组成。实验介质(改良的Barth氏溶液)由(以mM计):NaCl(88),NaHCO3(2.4),KCl(1.0),HEPES(10),MgSO4(0.82),Ca(NO3)2(0.33),CaCl2(0.41)组成;pH7.5。
如下进行快速筛选以测定前体药物水解和释放药物(实施例1的化合物)的能力。在蒸馏水或乙腈或PEG-400中制备前体药物的1mg/mL原液。在此试验中使用从大鼠或人血液中新收集的血浆。向1mL 37℃的血浆中添加10μL前体药物原液并且轻微混合。混合后立即去除100μL血浆并且用300μL乙腈中止反应(零时间样品)。还在30分钟时获得样品并且立即中止反应。将反应中止的样品离心获得澄清上清液用于分析。通过HPLC试验,从前体药物中分离药物,来分析原液,T=0和T=30的样品。根据这些样品中前体药物和药物的相对峰面积,将不同的前体药物按快速、中速和慢速释放剂来表征。例如,按此模式,将实施例2的化合物以1mg/mL的浓度溶解于PEG-400中并且在10μg/mL的37℃新大鼠血浆中保温。分析保温5分钟后的溶液,经显示实施例2的化合物转变成了实施例1的化合物。
为测定本发明化合物减少神经细胞局部缺血所造成细胞损失的能力,这是Wistar大鼠中左中脑动脉(MCA)和普通颈动脉(CCA)持久阻塞诱发的标准病灶脑局部缺血,伴随右CCA一小时阻塞。使用A.Tamura等,J
.Cereb.Blood Flow Metab.1,pp.53-60(1981)及其改良[K.Osborne等J.NeurolNeurosurg.Psychiatry,50,pp.402-410(1987)和S.Menzies,等.,
神 经外科学,31,pp.100-107,(1992)]的颞下方案进行手术。
在病灶中风模型中评价实施例1的化合物,所说的中风模型包括Wistar大鼠中的左MCA(MCAO)和CCA(CCAO)的持久阻塞以及右CCA的暂时阻塞。通过在MCAO 24小时后连续切片中经过脑部排斥活体染料的方式测定,这个过程产生确实大的皮质梗塞容量。在本试验中,阻塞两小时之后,使用静脉注射或腹膜内给药途径施用化合物。例如,在此模型中,当中脑动脉阻塞之后两小时,将实施例1的化合物作为单剂大丸剂静脉内地注射(10μg/kg)时,与赋形剂处理的(水)对照相比,明显减少皮质梗塞容量约18%。
上述体外和体内测试证明了本发明的新1,3,4-噁二唑-2(3H)-酮化合物可有效治疗人的因细胞膜极化和传导机能障碍引起的疾病,优选治疗局部缺血,中风,惊厥,癫痫,气喘,应激性肠综合症,偏头痛,创伤性脑伤,脊髓损伤,性功能障碍和小便失禁以及其它对BK通道开启活性敏感的疾病。首选,式I的化合物可有效治疗脑部局部缺血/中风。
式I的化合物或其药用组合物可有效治疗、缓解或消除与BK通道有关的疾病或其它疾病。这些疾病包括局部缺血,中风,惊厥,癫痫,气喘,应激性肠综合症,偏头痛,创伤性脑伤,脊髓损伤,性功能障碍和小便失禁以及其它对钾离子通道开启敏感的疾病。
作为治疗用途,式I的药理学活性化合物可以作为药用组合物来正常施用,药用组合物中含有至少一种这种化合物作为基本活性成分,这些基本活性成分使用标准和常规的技术与固体或液体药用载体相结合,并且选择性地与药用辅剂和赋形剂相结合。
药用组合物包括适合口服、肠胃外(包括皮下、肌内、真皮内和静脉内)、支气管或经鼻给药的剂量形式。因此,如果使用固体载体,则可以将制剂压片;以粉剂或小粒的形式放入硬明胶胶囊中或者以锭剂或糖锭的形式。固体载体可以含有常规的赋形剂,如粘合剂、填充剂、制锭润滑剂、崩解剂、润湿剂等等。如果需要,可以通过常规技术给片剂包膜衣。如果使用液体载体,制剂可以是糖浆、乳液、软明胶胶囊、注射用无菌载体、含水或不含水液体悬浮液的形式,或者可以是用水或其它适宜载体在使用前复水的干产品。液体制剂中可以含有常规的添加剂,如悬浮剂、乳化剂、润湿剂、不含水载体(包括食用油)、防腐剂以及风味剂和/或着色剂。对于肠胃外给药,载体正常情况下含有无菌水,至少大部分含无菌水,也可以使用盐水溶液、葡萄糖溶液等。也可以使用可注射的悬浮液,在该情况中,可以使用常规的悬浮剂。也可以向肠胃外的制剂形式添加常规的防腐剂、缓冲剂等等。以肠胃外制剂的形式直接施用式I化合物是特别有效的。药用组合物通过适合于所需制剂的常规技术来制备,所需的制剂中含有适宜量活性成分,即含有本发明的式I化合物。参见例如,Remington药用科学,Mack Publishing Company,Easton,PA,第17版,1985。
式I化合物达到治疗效果的剂量不仅取决于诸如患者年龄、体重和性别以及给药方式的因素,而且还取决于钾离子通道启动活性的所需程度以及用于所关心疾病之具体病症的所用具体化合物的药效。还包括以单位剂量形式施用的具体化合物的治疗和剂量,并且单位剂量形式可以由本领域技术人员来调整以反映活性的相对级别。所用剂量的确定(以及每天施用的次数)属于医师的处理范围,并且可以通过将剂量运用到本发明的具体环境中来改变,以产生所需的治疗效果。
式I化合物或其药用组合物用于患有或可能患有本发明所述任何病症的哺乳动物(包括人)的适宜剂量为活性成分量约0.1ng/kg-10mg/kg体重。肠胃外给药时,静脉内给药剂量可以是0.1ng/kg-1.0mg/kg体重。优选,活性成分通常来说连续施用或者以等份剂量一天分一至四次施用。然而,经常是施用小剂量,并且逐渐增加剂量直至经测定达到处于治疗主体的最佳剂量。
然而,应当理解实际施用的化合物的量由医师根据相关的环境来确定,包括待治疗的疾病;所用化合物的选择;给药途径的选择;患者的年龄、体重和个体响应以及患者症状的严重程度、
以下实施例是以举例说明的方式给出的,不应当解释为是对本发明的限制,本发明的很多可能的变化方案均在本发明的含义范围内。
具体实施方案描述
以下实施例中,所有的温度均以摄氏度给出,在未校正温度的Gallenkamp毛细管熔点装置上记录熔点。在Bruker AC 300上记录质子核磁共振(1H NMR)。所有光谱在所指出的溶剂中测定,并且化学位移按内标四甲基硅烷(TMS)低场中的δ单位报告并且质子间的偶合常数以赫兹(Hz)表示。裂分图形定义如下:s,单峰;d,二重峰;t,三重峰;q,四重峰;m,多重峰;br,宽峰;dd,双二重峰;bd,宽二重峰;dt,双三重峰;bs,宽单峰;dq,双四重峰。使用溴化钾(KBr)在Perkin Elmer 781光谱仪上测定4000cm-1至400cm-1的红外(IR)光谱,将聚苯乙烯膜吸收度校准至1601cm-1并且按厘米的倒数(cm-1)表示。在Finnigen TSQ 7000上测定低分辨质谱(MS)和表观分子(MH+)或(M-H)-。在Kratos MS50上按FAB方式使用碘化铯/甘油作为内参测定高分辨质谱。元素分析以重量百分比报告。
以下实施例举例说明了起始原料、中间体的制备过程以及本发明产品的生产方法。本发明公开的两种原料和方法的适宜替代品和替代方法能够生产出下述举例说明的实例对本领域技术人员也是显而易见的,并且这些替代品和替代方法属于本发明的范围。
实施例13-[(5-氯-2-羟基苯基)甲基]-5-[4-(三氟甲基)苯基]-1,3,4-噁二唑-2(3H)-酮步骤A.5-[4(三氟甲基)苯基]-1,3,4-噁二唑-2(3H)-酮
将4-(三氟甲基)苯甲酸酰肼(Maybridge Chemicals出品)(5g,24.5mmol)在N2条件下溶解于THF(250ml)/三乙胺(2.7ml,26mmol)中,并且加入1,1’-羰基二咪唑(4.2g,26mmol)。将溶液在24℃下搅拌18h,浓缩,并且将残余物溶解于乙酸乙酯,用1N HCl溶液、饱和NaHCO3溶液和盐水洗涤,然后干燥(MgSO4)。浓缩得到5g(89%)标题化合物,从中用乙醚/己烷重结晶出样品:mp214-216℃,MS m/z 231(MH+)。IR(KBr)3280,1778,1608,1420,1318,1170,1114cm-1;1H NMR(DMSO-d6)δ7.87(2H,d,J=8.3Hz),7.96(2H,d,J=8.3Hz),12.77(1H,br.s);C9H5F3N2O2·0.64H2O的理论值:C,46.74;H,2.24;N,12.11实测值:C,47.07;H,2.10;N,12.34步骤B.3-[(5-氯-2-甲氧基苯基)甲基]-5-[4-(三氟甲基)-苯基]-1,3,4-噁二唑-2(3H)-酮
将5-[4-(三氟甲基)苯基]-1,3,4-噁二唑-2(H)-酮(11.75g,51mmol)和5-氯-2-甲氧基苄基溴[N.Meanwell,等,“生物有机医学化学通信(Bioora.Med.Chem.Lett.)”6,pp.1641-1646(1996)](12.0g,51mmol)和11.2g(81mmol)碳酸钾在氮气条件下添加到CH3CN(300ml),并且加入碘化钾(0.2g,1.2mmol)。将溶液回流16h,冷却,倾入水中(1500ml)并且剧烈搅拌。过滤沉淀得到固体,用CH3CN重结晶,获得15.2g(78%)标题化合物。mp144-145℃,MS(ESI)m/z:385(MH+)IR(KBr)3440,1782,1492,1324,1248,1168cm-1;1H NMR(300MHz,DMSO)δ3.79(3H,s),4.91(2H,s),7.07(1H,d,J=8.8Hz),7.35-7.38(2H,m),7.88(2H,d,J=8.4Hz),7.96(2H,d,J=8.2Hz);C17H12ClF3N2O3·0.1H2O的理论值:C,52.81;H,3.19;N,7.25。实测值:C,53.03;H,3.20;N,7.31。步骤C.3-[(5-氯-2-羟基苯基)甲基]-5-[4-(三氟甲基)苯基]-1,3,4-噁二唑-2(3H)-酮
将3-[(5-氯-2-甲氧基苯基)甲基]-5-[4-(三氟甲基)-苯基]-1,3,4-噁二唑-2(3H)-酮(15.2g,39.6mmol)与盐酸吡啶(19.7g,0.17mol)混合,并且在225℃下加热2h。
将热的溶液倾入800ml 1N HCl中,并且将混合物搅拌10分钟。收集固体,用1N HCl洗涤并且在80℃下真空干燥,得到13.1g灰白色固体。用乙腈重结晶得到10.8g绒毛针状的标题化合物,mp217-218℃,MS m/z 371(MH+)。IR(KBr)3354,1762,1500,1324,1068cm-1;1H NMR(DMSO-d6)δ4.98(2H,s),6.84(1H,d,J=8.7Hz),7.20(1H,dd,J=8.7Hz,2.6Hz),7.30(1H,d,J=2.5Hz),7.89(2H,d,J=8.6Hz),7.97(1H,d,J=8.6Hz),10.11(1H,br.s);C16H10ClF3N2O3的理论值:C,51.84;H,2.72;N,7.56.实测值:C,51.88;H,2.58;N,7.57.制备实施例2-5之氨基酸氨基甲酸酯(Ia)的通用过程
将3-[(5-氯-2-羟基苯基)甲基]-5-[4-(三氟甲基)苯基]-1,3,4-噁二唑-2(3H)-酮(740mg,2mmol)、对硝基苯基氯甲酸酯(407mg,2.02mmol)和吡啶(330mg,4.17mmol)的无水二氯甲烷(20mL)溶液室温下搅拌3小时。加入相应的氨基酸叔丁酯(2mmol)和无水三乙胺(405mg,4mmol),并且将所得的反应混合物室温下搅拌过夜。经蒸发后,将残余物在乙醚和稀NaOH之间分配。将有机层用水、稀HCl和盐水洗涤,然后经硫酸镁干燥。通过研制或重结晶纯化粗产物。将叔丁酯在二氯甲烷(5mL)中与三氟乙酸(1mL)在室温下搅拌过夜。待蒸发掉CH2Cl2和过量的TFA之后,残余物用苯-丙酮重结晶,获得纯的所需产物。
实施例2N-[[4-氯-2-[[5-[4-(三氟甲基)苯基]-2,3-二氢-2-氧代-1,3,4-噁二唑-3-基]甲基]苯氧基]羰基]天冬氨酸(Ia,R3=H,R4=CH2CO2H)mp185-187℃(分解);MS m/e 530(MH+)1H NMR(DMSO-d6)δδ2.62-2.83(m,2H),4.38(m,1H),4.91(s,2H),7.22(d,J=8.4Hz,1H),7.47(dd,J=8.4,2.7Hz,1H),7.55(d,J=2.7Hz,1H),7.92(d,J=8.7Hz,2H),8.02(d,J=8.4Hz,2H),8.28(d,J=8.4Hz,1H)C21H15ClF3N3O8的理论值:C,47.61;H,2.85;N,7.93实测值:C,47.04;H,2.66;N,7.75
实施例3N-[[4-氯-2-[[5-[4-(三氟甲基)苯基]-2,3-二氢-2-氧代-1,3,4-噁二唑-3-基]甲基]苯氧基]羰基]丙氨酸(Ia,R3=H,R4=CH3)mp137-139℃;MS m/e 486(MH+)1H NMR(DMSO-d6)δ1.22(d,J=7.2Hz,3H),4.01(m,1H),4.91(m,2H),7.19(d,J=8.4Hz,1H),7.45(dd,J=8.4,2.7Hz,1H),7.56(d,J=2.7Hz,1H),7.92(d,J=8.7Hz,2H),8.00(d,J=8.4Hz,2H),8.26(d,J=7.5Hz,1H)C20H15ClF3N3O6的理论值:C,49.45;H,3.11;N,8.65实测值:C,49.35;H,3.18;N,8.61
实施例4N-[[4-氯-2-[[5-[4-(三氟甲基)苯基]-2,3-二氢-2-氧代-1,3,4-噁二唑-3-基]甲基]苯氧基]羰基]谷氨酸(Ia,R3=H,R4=(CH2)2CO2H)mp110-112℃(分解);MS m/e 566(M+Na)+ 1H NMR(DMSO-d6)δ1.84-2.04(m,2H),2.38(m,2H),4.02(m,1H),4.92(m,2H),7.20(d,J=8.4Hz,1H),7.45(dd,J=8.4,2.7Hz,1H),7.56(d,J=2.7Hz,1H),7.91(d,J=8.7Hz,2H),8.00(d,J=8.4Hz,2H),8.26(d,J=7.8Hz,1H)C22H17ClF3N3O8的理论值:C,48.59;H,3.15;N,7.73实测值:C,47.78;H,3.23;N,7.60
实施例5N-[[4-氯-2-[[5-[4-(三氟甲基)苯基]-2,3-二氢-2-氧代-1 3,4-噁二唑-3-基]甲基]苯氧基]羰基]亮氨酸(Ia,R3=H,R4=CH2CH(CH3)2)mp102-104℃(分解);MS m/e 528(MH+)1H NMR(CDCl3)δ0.99(m,6H),1.70(m,2H),4.40(m,1H),4.90(m,2H),6.08(m,1H),7.35-7.44(m,3H),7.71(d,J=7.7Hz,2H),7.92(d,J=7.8Hz,2H).制备实施例6-9之氨基甲酸酯衍生物(Ib)的通用过程
将3-[(5-氯-2-羟基苯基)甲基]-5-[4-(三氟甲基)苯基]-1,3,4-噁二唑-2(3H)-酮(371mg,1mmol)、对硝基苯基氯甲酸酯(202mg,1mmol)和吡啶(160mg,2.1mmol)的无水二氯甲烷(10mL)溶液在室温下搅拌3小时。然后加入存在于无水二氯甲烷(3mL)中的相应的胺(1mmol),并且将所得的反应混合物在室温下搅拌1小时,然后加入无水三乙胺(110mg,1.1mmol)。将混合物在室温下搅拌1小时,之后用二氯甲烷稀释,用饱和碳酸氢钠和水洗涤,然后经硫酸镁干燥。经蒸发后,将残余物通过研制或重结晶纯化。将产物再溶解于乙醚/乙酸乙酯中,然后加入存在于乙醚中的无水HCl。过滤收集沉淀的HCl盐。
实施例63-[[5-氯-2-[[[2-(二甲基氨基)乙基氨基]羰基]氧基]苯基]甲基]-5-[4-(三氟甲基)苯基]-1,3,4-噁二唑-2(3H)-酮mp158-159℃;MS m/e 485(M+H+,ESI)1H NMR(DMSO-d6)δ2.80(s,3H),3.17(s,3H),3.39(m,2H),3.60(t,J=6.9Hz,1H),3.90(t,J=6.3Hz,1H),4.92(d,J=15.3Hz,2H),6.86(d,J=8.7Hz,0.5H),7.20(dd,J=8.7,2.7Hz,0.5H),7.26-7.31(m,1H),7.48(dd,J=8.7,2.7Hz,0.5H),7.61(d,J=2.7Hz,0.5H),7.89-8.00(m,4.5H),8.13(m,0.5H)9.93(br,0.5H),10.15(s,0.5H)C21H20ClF3N4O4·HCl的理论值:C,48.38;H,4.06;N,10.75实测值:C,47.31;H,4.05;N,10.55
实施例73-[[5-氯-2-[[[[2-(二甲基氨基)乙基]甲基氨基]羰基]-氧基]苯基]甲基]-5-[4-(三氟甲基)苯基]-1,3,4-噁二唑2(3H)-酮mp127-129℃;MS m/e 499(M+H+,ESI)1H NMR(DMSO-d6)δ2.78-2.83(m,6H),2.89-3.10(2 s,3H),3.27-3.39(m,2H),3.59-3.90(m,2H),4.99(2s,2H),7.31-7.41(m,1H),7.47-7.51(m,1H),7.62(m,1H),7.92(d,J=8.7Hz,2H),7.98(d,J=8.7Hz,2H),10.25(br,1H)C22H22ClF3N4O4·HCl的理论值:C,49.36;H,4.33;N,10.47实测值:C,47.64;H,4.85;N,10.16
实施例83-[[5-氯-2-[[[4-甲基哌嗪-1-基]羰基]氧基]苯基]甲基]-5-[4-(三氟甲基)苯基]-1,3,4-噁二唑-2(3H)-酮mp170-172℃(分解);MS m/e 497(M+H+,ESI)1H NMR(DMSO-d6)δ2.80(s,3H),3.05-3.70(br m,6H),4.06(br,1H),4.33(br,1H),4.98(s,2H),7.26(d,J=8.7Hz,1H),7.50(dd,J=8.7,2.7Hz,1H),7.65(d,J=2.7Hz,1H),7.92(d,J=8.7Hz,2H),7.98(d,J=8.7Hz,2H),10.92(br,1H)C22H20ClF3N4O4·HCl的理论值:C,49.55;H,3.97;N,10.51实测值:C,47.93;H,4.18;N,10.25
实施例93-[[5-氯-2-[[[2-(吗啉代)乙基氨基]羰基]氧基]苯基]甲基]-5-[4-(三氟甲基)苯基]-1,3,4-噁二唑-2(3H)-酮mp143-144℃;MS m/e 527(M+H)+,ESI)1H NMR(CDCl3)δ2.54(br,6H),3.38(br,2H),3.78(br,4H),4.91(s,2H),7.27-7.38(m,2H),7.44(d,J=2.4Hz,1H),7.72(d,J=8.4Hz,2H),7.94(d,J=8.4Hz,2H)C23H22ClF3N4O5的理论值:C,52.43;H,4.21;N,10.63实测值:C,52.16;H,4.25;N,10.55
Claims (6)
2、权利要求1的化合物,其中R1是-CR3R4CO2H,或其无毒性的药用盐或溶剂化物,R3是氢;R4是氢;或者羧基取代或未取代的C1-4烷基。
3、权利要求2的化合物,其中R4是羧基取代或未取代的C1-4烷基,或其无毒性的药用盐或溶剂化物。
4、权利要求1的化合物,其中R1是-(CH2)2NR5R6,或其无毒性的药用盐或溶剂化物,R5和R6各自独立地是氢,C1-4烷基;或者R5和R6与和它们相连的氮原子一起形成吗啉环。
5、权利要求4的化合物,其中R5和R6各自是氢或甲基,或其无毒性的药用盐或溶剂化物。
6、权利要求1的化合物,选自:N-[[4-氯-2-[[5-[4-(三氟甲基)苯基]-2,3-二氢-2-氧代-1,3,4-噁二唑-3-基]甲基]苯氧基]羰基]天冬氨酸;N-[[4-氯-2-[[5-[4-(三氟甲基)苯基]-2,3-二氢-2-氧代-1,3,4-噁二唑-3-基]甲基]苯氧基]羰基]丙氨酸;N-[[4-氯-2-[[5-[4-(三氟甲基)苯基]-2,3-二氢-2-氧代-1,3,4-噁二唑-3-基]甲基]苯氧基]羰基]谷氨酸;N-[[4-氯-2-[[5-[4-(三氟甲基)苯基]-2,3-二氢-2-氧代-1,3,4-噁二唑-3-基]甲基]苯氧基]羰基]亮氨酸;3-[[5-氯-2-[[[2-(二甲基氨基)乙基氨基]羰基]氧基]苯基]甲基]-5-[4-(三氟甲基)苯基]-1,3,4-噁二唑-2(3H)-酮;3-[[5-氯-2-[[[[2-(二甲基氨基)乙基]甲基氨基]羰基]氧基]苯基]甲基]-5-[4-(三氟甲基)苯基]-1,3,4-噁二唑-2(3H)-酮;3-[[5-氯-2-[[[4-甲基哌嗪-1-基]羰基]氧基]苯基]甲基]-5-[4-(三氟甲基)苯基]-1,3,4-噁二唑-2(3H)-酮;和3-[[5-氯-2-[[[2-(吗啉代)乙基氨基]羰基]氧基]苯基]甲基]-5[4-(三氟甲基)苯基]-1,3,4-噁二唑-2(3H)-酮。
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US20020045566A1 (en) * | 2000-10-13 | 2002-04-18 | Gribkoff Valentin K. | Selective maxi-K potassium channel openers functional under conditions of high intracellular calcium concentration, methods and uses thereof |
CA2708281A1 (en) | 2007-12-11 | 2009-08-27 | Viamet Pharmaceuticals, Inc. | Metalloenzyme inhibitors using metal binding moieties in combination with targeting moieties |
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