CN1331683A - 2-苯基苯并咪唑化合物和2-苯基吲哚化合物,它们的制备和用途 - Google Patents
2-苯基苯并咪唑化合物和2-苯基吲哚化合物,它们的制备和用途 Download PDFInfo
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- CN1331683A CN1331683A CN99814810A CN99814810A CN1331683A CN 1331683 A CN1331683 A CN 1331683A CN 99814810 A CN99814810 A CN 99814810A CN 99814810 A CN99814810 A CN 99814810A CN 1331683 A CN1331683 A CN 1331683A
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- KLLLJCACIRKBDT-UHFFFAOYSA-N 2-phenyl-1H-indole Chemical class N1C2=CC=CC=C2C=C1C1=CC=CC=C1 KLLLJCACIRKBDT-UHFFFAOYSA-N 0.000 title abstract 2
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Abstract
本发明涉及具有通式Ⅰ的2-苯基苯并咪唑类和2-苯基吲哚类作为多聚(ADP-核糖)聚合酶抑制剂用于制备药物:其中A为N或CH,R1为氢,支链和直链的C1-C6-烷基,其中烷基基团的一个碳原子可以进一步携带OR11或基团R5,R2为氢,氯,氟,溴,碘,支链和直链的C1-C6-烷基,硝基,CF3,CN,NR21R22,NH-CO-R23,OR21,R3为-(CH2)q-NR31R32,其中q为0,1,2或3,R4为氢,支链和直链的C1-C6-烷基,氯,溴,氟,硝基,氰基,NR41R42,NH-CO-R43,OR41。
Description
本发明涉及新的2-苯基苯并咪唑类和2-苯基吲哚类化合物,它们的制备方法以及它们用于制备作为聚(ADP-核糖)聚合酶或PARP(EC2.4.2.30)抑制剂药物的用途。
聚(ADP-核糖)聚合酶(PARP)或又称为聚(ADP-核糖)合成酶(PARS)是一种在细胞核中发现的调节性酶(K.Ikai等人,J.Histochem.Cytochem.1983,31,1261-1264)。人们假设PARP在DNA桥的修复中起着作用(M.S.Satoh等人,Nature 1992,356,356-358)。DNA链的损伤或断裂活化了酶PARP,后者活化后,可以催化从NAD的ADP-核糖的转化(S.Shaw,Adv.Radiat.Biol.,1984,11,1-69)。在此过程期间,尼古丁酰胺从NAD中释放出来。伴随着其它酶的能量载体ATP的消耗,尼古丁酰胺再次转化为NAD。因此,PARP的过度活化可以导致ATP消耗非生理性的增高,这种现象在极端的情况下将导致细胞损伤和细胞死亡。已知象超氧阴离子、NO和过氧化氢的游离基可以导致细胞内DNA的损伤及随后的PARP活化。在许多病理状况下观察到有大量游离基形成,因此人们由此假设积蓄的游离基可以导致细胞和器官的损伤或对所观察到的细胞和器官的损伤有所贡献。这不仅包括器官的例如在中风、心肌梗塞中所出现的局部缺血(C.Thiemermann等人,Proc.Natl.Acad.Sci.USA,1997,94,679-683)或肾脏的局部缺血,而且还包括再灌注损伤,例如心肌梗塞症状消退后出现的局部缺血(参见上文:C.Thiemermann等人)。因此可以将PARP的抑制作为防止或减轻这类损伤(至少是部分地)的一种方法,PARP抑制剂也成为治疗许多疾病的一种新治疗手段。
PARP酶可以影响DNA的修复并因此可以在肿瘤疾病的治疗过程中起到一定的作用,因为在与抑制细胞生长的其它活性物质联合使用时,观察到更强的抗肿瘤组织活性作用(G.,Chen等人,Cancer Chemo.Pharmacol.1988,22,303)。
非限定性的肿瘤的实例有白血病、成胶质细胞瘤[sic]、淋巴瘤、黑色(素)瘤、乳房瘤和子宫颈瘤。
进一步地,现已发现PARP抑制剂具有免疫抑制作用(D.Weltin等人,Int.J.Immunopharmacol.1995,17,265-271)。
现还发现,PARP涉及一些免疫失调或疾病,在这些免疫失调或疾病中免疫系统起着重要的作用,例如风湿性关节炎和脓毒性休克,PARP抑制剂对控制这些疾病的进程显示出有益的作用(H.Kroger等人,Inflammation1996,20,203-215;W.Ehrlich等人Rheumatol.Int.1995,15,171-172;C.Szabo等人,Proc.Natl.Acad.Sci.USA,1998,95,3867-3872;S.Cuzzocrea等人,Eur.J.Pharmacol.1998,342,67-76)。
在本发明的含义中,PARP还被理解为上述PARP酶的同功酶。
进一步地,PARP抑制剂3-氨基苯甲酰胺在循环休克的模型中显示出保护活性(S.Cuzzocrea等人,Br.J.Parmacol.1997,121,1065-1074)。
还存在同样的实验指征,它们显示PARP酶抑制剂可用作治疗糖尿病的药物(V.Burkart等人,Nature Med.1999,5,314-319)。
2-苯基苯并咪唑类化合物被广泛描述。在DE 38 30 060中描述了作为红细胞聚集抑制剂的烷基化衍生物。在DE 35 22 230中提到作为血小板聚集抑制剂的2-苯基苯并咪唑的酯类衍生物。在WO 98/06703中描述了作为MCP-1拮抗剂的卤素-取代的2-苯基苯并咪唑类,其在苯环上带有取代胺基团。
已知2-苯基苯并咪唑类化合物的苯并咪唑类基团上带有酰胺基基团。在WO94/12461中描述了作为cAMP磷酸二酯酶抑制剂的2-苯基苯并咪唑类化合物的5-酰胺基衍生物(其在苯环上携带烷氧基基团)。对于同类衍生物来说,已发现在DE 35 46 575中(例如实施例15)描述了这些化合物可以具有阳性的影响肌收缩力效应。在WO 97/48697中也描述了作为cAMP磷酸二酯酶抑制剂的4-酰胺基衍生物(其在3-位上携带了一个吡啶基团)。
在J.Chem.Soc.Perkin Trans 1,1979,2303-2307中描述了2-苯基苯并咪唑-4-酰胺的合成。在J.Med.Chem.1990,33,814-819中描述了在酰胺基团上携带进一步的取代烷基链的同类化合物,它们被认为具有细胞毒作用。在WO 97/04771中提到了抑制PARS的苯并咪唑-4-酰胺。特别地,描述了作为活性成分的在2-位上携带苯环的衍生物,还可以用其它简单的取代基来取代苯环,例如硝基、甲氧基和CF3。尽管在某些情况下这些取代基对PARP酶显示出良好的抑制作用,但是所描述的衍生物也有不足之处:在水溶液中它们仅显示出非常小的水溶解度或根本不溶于水,因此无法以水溶液的形式进行给药。
在中风的许多疗法中,活性化合物是以滴注溶液的形式经静脉内给药。为了达到这个目的,必须首先获得在生理pH或大约生理pH(例如pH5-8)条件下具有足够的水中溶解度的物质,从而才能制备滴注溶液。许多描述的PARP抑制剂,尤其是那些具有较好活性的PARP抑制剂具有这点不足,在这种pH条件下它们仅显示出非常低的水溶解度或根本不溶于水,因此不适合用于静脉给药。这种类型的活性化合物仅可与倾向于介导水溶性的辅助剂一起给药(参见WO 97/04771)。这些辅助剂的实例有聚乙二醇和二甲亚砜,它们经常会引起副反应甚至是无法忍受的。迄今为止尚未有关于具有足够水溶解度的高效PARP抑制剂的描述。
现已令人惊奇地发现,在苯环上另外携带胺基团的2-苯基苯并咪唑类化合物是高效的抑制剂,由于引入了脂肪性的胺基团,使之可与酸形成盐类,结果显著地提高了化合物的水溶解度。
在本发明中,描述了具通式I的新2-苯基苯并咪唑类和2-苯基吲哚类化合物,与已描述的化合物相比较,它们显示出一定的优势,是强PARP抑制剂,同时它们也显示出足够的水溶解度,从而使得以滴注溶液的形式进行给药成为可能。
本发明涉及取代的具有通式I的2-苯基苯并咪唑类和2-苯基吲哚类化合物:
其中
A为N或CH,
R1为氢,支链和直链C1-C6-烷基,其中烷基的一个碳原子可以进一步携带OR11或基团R5,其中
R11为氢或C1-C4-烷基,并且R2为氢,氯,氟,溴,碘,支链和直链C1-C6-烷基,硝基,CF3,CN,NR21R22,NH-CO-R23,OR21,其中
R21和R22各自独立,为氢或C1-C4-烷基,并且
R23为氢或C1-C4-烷基或苯基,并且
R3为-(CH2)q-NR31R32,-(CH2)q-NR33R34,其中q为0,1,2或3,
R31为氢或C1-C6-烷基,(CH2)4NR33R34,
R32[sic]为氢或(CH2)rNR33R34,
其中,如果R31和R32各自独立,r为2,3,4,5或6,并且R33和R34各自独立,为氢,C1-C6-烷基,与氮原子一起形成可额外带选自O杂原子的3-8元环,N-C1-C4-烷基,N-C0-C2-苯基或NH,苯基C1-C4-烷基,其中苯环上可被上至3个相同或不同的取代基所取代,所述的取代基选自C1-C6-烷基,卤素,硝基,SO2NR35R36(其中R35,R36各自独立,为氢,C1-C6-烷基,与氮原子一起形成可以携带其它选自O,S,SO2杂原子的3-8元环,N-C1-C4-烷基,N-C0-C2-苯基或NH),C1-C4-烷氧基,S(O)0-2-R37(其中R37为氢,C1-C4-烷基),CF3,(CH2)0-4-COR37,(CH2)0-4NR35R36,(CH2)0-4CONR35R36,(CH2)0-4OR37-CH2COOR37,R4为氢,支链和直链C1-C6-烷基,氯,溴,氟,硝基,氰基,NR41R42,NH-CO-R43,OR41,其中
R41和R42各自独立,为氢或C1-C4-烷基,并且
R43为C1-C4-烷基或苯基。
通式I中基团R2优选的位置是苯并咪唑环的3-位和4-位,对于基团R3来说,位于苯并咪唑环的3-位或4-位上同样是优选的。
A的优选的定义是氮。
R1的优选的定义是氢。
R2的优选的定义是氢,支链和直链C1-C6-烷基,硝基,CN,NH2,O-C1-C4-烷基。R2特别优选的是氢。
R3为(CH2)1-2NR35R36和N(R37)-(CH2)2-3NR35R36,其中R37为氢或C1-C4-烷基,R35和R36各自独立,为氢和C1-C4-烷基,NR35R36还可一起构成环状的脂肪胺,例如,哌啶,吡咯烷,氮杂和哌嗪,其中哌嗪的第二个N原子可以进一步被氢或C1-C4-烷基取代。
R4优选的定义是氢。
上述优选含义各自的结合是特别优选的。
式I化合物可以其外消旋、对映体纯化合物或非对映体形式应用。如果需要对映体纯化合物,可以采用合适的光学活性碱或酸,对式I化合物或其中间体进行经典的拆分来获得。
本发明还涉及式I化合物的内消旋体和互变异构体。
本发明进一步涉及式I化合物生理上可耐受的盐类,它们可以通过使式I化合物与合适的酸或碱反应得到。在Fortschritte derArzneimittelforschung,1966,Birkhauser Verlag,Vol.10,pp.224-285中例举了合适的酸和碱。它们包括,例如,盐酸、柠檬酸、酒石酸、乳酸、磷酸、甲磺酸、乙酸、甲酸、马来酸、富马酸等,以及氢氧化钠、氢氧化锂、氢氧化钾和tris。
前药的含义是它们可在体内代谢为通式I化合物。典型的前药为磷酸盐、氨基酸的氨甲酸盐、酯和其它化合物。
根据本发明,物质I的制备可以采用各种方法,它们与WO 98/06703中所列的用于苯并咪唑和吲哚的方法以及合成路线1-3相类似。合成路线1:
使苯甲醛与亚苯基二胺进行缩合可以得到苯并咪唑VII。该反应优选的是在极性溶剂中进行,例如乙醇或二甲基甲酰胺,并在提高的温度(通常为80-120℃)下加入酸,例如乙酸,加入弱氧化剂(例如铜(II)盐,以水溶液的形式加入)对于反应来说是有利的。合成路线2:
如果亚苯基二胺VII中的R=NH2,则根据本发明可在缩合反应中直接形成式I化合物。另外,如果R=O-烷基,此酯可与氨反应(如果合适可在提高的温度和压力下),得到酰胺I。或者,酯VIII可在提高的温度(优选的是为80-130℃)和压力下,与肼在极性溶剂(例如醇类,如丁醇和乙醇或二甲基甲酰胺)中进行反应,得到酰肼VIII[sic](R=NHNH2),后者可在还原条件下进行还原,例如在回流的醇中使用Raney镍,得到式I酰胺。
就路线I中所示的式VI苯甲醛而言,可用如式XI的苯甲酸(参见路线2)或如式XIV的苯甲腈(参见路线3)来代替它。按照制备取代的式V苯甲醛相类似的方法可以制备这些衍生物。从式XI开始,得到式VII的缩合反应可分两步进行。首先,使式XI苯甲酸与式VI苯胺以肽样的偶联方式进行反应,得到式XII酰胺。此反应采用常规的条件进行,例如其在Houben-Weyl,“有机化合物方法”,第4版,E5,第V章或C.R.Larock,“复杂有机变化”,VCH出版社,1989,pp.972ff中有所描述。然后在提高的温度(例如60-180℃)[sic]下,进行生成苯并咪唑的环合反应,该反应可在有(例如二甲基甲酰胺)或没有溶剂的情况下,通过加入酸(例如乙酸)或直接在乙酸中进行。
式VII亚苯基二胺与式XIV苯甲腈的反应可在常规的条件下进行。在这种情况下,反应可在溶剂中(例如二甲基甲酰胺)并加入酸下进行,或也可在提高的温度下(例如60-200℃)于多膦酸中进行。然而,也可以采用从苯甲腈制备脒类的常规方法,例如在Houben-weyl“有机化合物方法”,E5,p1304f.,J.Amer.Chem.Soc.1957,427和J.Org.Chen.1987,1017中所描述的方法。
本发明中含有的取代的式I2-苯基苯并咪唑和2-苯基吲哚是多聚(ADP-核糖)聚合酶或PARP的抑制剂(EC2.4.2.30)。
可以采用文献中已知的酶测试方法来测定式I2-苯基苯并咪唑和2-苯基吲哚的抑制作用,以测定的K值作为活性标准。用这种方式测定了式I2-苯基苯并咪唑和2-苯基吲哚对多聚(ADP-核糖)聚合酶或PARP的抑制作用(EC2.4.2.30)。
通式I的取代2-苯基苯并咪唑和2-苯基吲哚I是多聚(ADP-核糖)聚合酶(PARP)或也称为多聚(ADP-核糖)合成酶(PARS)的抑制剂,因此其可以用来治疗和预防与这些酶活性增加有关的疾病。
式I化合物可以用来制备治疗局部缺血后损伤的药物,并可用来预防各种器官可预期的局部缺血。
因此通式I的2-苯基苯并咪唑和2-苯基吲哚I可以用来治疗和预防局部缺血、创伤(颅脑创伤)、大出血、蛛网膜下出血以及中风后的神经变性疾病,还可以治疗和预防其它神经变性疾病,例如多发性梗塞痴呆,Alzheimer’s疾病、Huntington’s疾病,还可以治疗和预防癫痫,特别是一般性癫痫发作(例如癫痫小发作、紧张性阵挛发作)以及部分癫痫发作(例如颞叶和复合部分发作)。进一步地,它们可用来治疗和预防心脏局部缺血后的心脏损伤以及肾脏局部缺血后的肾损伤,例如急性肾功能不全,急性肾衰或在肾移植过程中或之后出现的损伤。式I化合物可进一步用来治疗和预防急性心肌梗塞及出现在药物溶解过程中或之后的损伤(例如TPA、reteplase、链激酶或者因激光或Rotablator导致的机械性损伤),还可用来治疗和预防心脏瓣膜替换、动脉瘤切除及心脏移植过程中或之后出现的微梗塞。本发明式I2-苯基苯并咪唑和2-苯基吲哚I同样可以用来治疗临界压缩的冠状动脉的再血管化(例如在PCTA和心脏分流手术中)、临界压缩的外周动脉的再血管化(例如腿部动脉)。更进一步地,式I2-苯基苯并咪唑和2-苯基吲哚对于肿瘤及其转移的化疗是有益的,另外它们还可以治疗炎症和风湿性失调,例如风湿性关节炎。除了常规的制药辅助剂外,本发明药物制剂含有治疗有效剂量的式I化合物。
对于局部外用而言,在粉末、软膏剂或喷雾剂中可以含有常规浓度的活性化合物。作为常规,活性化合物的含量为0.001-1%(重量比),优选的是0.001-0.1%(重量比)。
在用于内部给药时,以个体剂量给药。个体剂量的给药量为0.1-100mg/Kg体重。根据疾病的性质和严重程度,每日给药一或多次。
根据需要的给药类型,本发明药物制剂中除了活性化合物外还含有常规的载体和稀释剂。对于局部外用而言,可以使用制药用辅助剂,例如乙醇、异丙醇、乙氧化蓖麻油、乙氧化氢化蓖麻油、聚丙烯酸、聚乙二醇、聚乙二醇硬脂酸酯、乙氧化脂肪醇、石蜡油、石油胶和羊毛脂。对于内部给药而言,合适的辅助剂有乳糖、丙二醇、乙醇、淀粉、滑石以及聚乙烯吡咯烷酮。
药物制剂还可以进一步含有抗氧剂,例如维生素E和丁基化羟基茴香醚和丁基化羟基甲苯,芳香增强添加剂,稳定剂,乳化剂和润滑剂。除了活性化合物外,在制剂中含有的物质以及在制备药物制剂过程中所用的物质是毒理学上可接受的,并可以与有关的活性化合物相配伍。药物制剂的制备是以常规的方式进行的,例如将活性化合物与其它载体和稀释剂相混合。
可以各种方式给予药物制剂,例如经口服和非肠道如静脉内滴注、皮下、腹膜内和局部途径。可能的制剂形式有片剂、乳化剂、滴注和注射溶液、膏剂、软膏剂、凝胶、霜剂、洗剂、粉剂和喷雾剂。
实施例12-(4-N,N-2-(N,N-二乙基氨基)乙-1-基甲基氨基)苯基)苯并咪唑-4-甲酰胺a)2-(4-N,N-2-(N,N-二乙基氨基)乙-1-基甲基氨基)苯基)苯并咪唑-4-羧酸乙酯
将2.0g(12mmol)2,3-二氨基苯甲酸乙酯溶于100ml甲醇中,并与1.7ml(27.7mmol)的乙酸进行混合。在30分钟内,将溶于100ml甲醇中的2.4g(10.1mmol)4-(2-(N,N-二乙基氨基)乙-1-基甲基氨基)苯甲醛滴加到其中。再向其中滴加1.7g(8.5mol)的乙酸酮(II)的30ml水溶液,回流加热50分钟。冷却至50℃,小心加入20ml 32%的浓盐酸溶液。再向其中滴加3.9g(16.2mmol)硫化钠水合物的20ml水溶液,搅拌10分钟。抽滤过滤沉淀,加入碳酸氢钠水溶液使溶液碱化。水相用乙酸乙酯提取,分出有机层,干燥,真空浓缩,得到2.6g产物。b)2-(4-N,N-2-(N,N-二乙基氨基)乙-1-基甲基氨基)苯基)苯并咪唑-4-酰肼
将2.6g(6.8g mmol)的中间体1和3.4g(68.3mmol)水合肼一起加到70ml正丁醇中,混合物在120℃下加热12小时。减压蒸除丁醇,得到的残余物在水和乙酸乙酯之间进行分配。分出有机相,干燥,真空浓缩,得到1.1g产物。c)2-(4-N,N-2-(N,N-二乙基氨基)乙-1-基甲基氨基)苯基)苯并咪唑-4-甲酰胺
将1g Raney镍加到1.1g(2.9g mmol)中间体1b的30ml二甲基甲酰胺中,混合物在120℃下加热8小时。过滤混合物,真空浓缩滤液。得到的残余物在水和乙酸乙酯之间进行分配。分出有机相,干燥,真空浓缩,得到0.9g产物。
1H-NMR(D6-DMSO):δ=2.2(6H),2.4(2H),3.0(3H),3.5(2H),
6.8(2H),7.2(1H),7.6-7.8(3H),8.1(2H),9.5(1H)和
13.2(1H)ppm.实施例22-(4-N,N-2-(N,N-二甲基氨基)乙-1-基甲基氨基)苯基)苯并咪唑-4-甲酰胺
按照与实施例1相似的方法进行制备。
1H-NMR(D6-DMSO):δ=2.2(6H),2.55(2H),3.1(2H),7.4(1H),
7.8(2H),7.9(1H),8.1(1H),8.3(1H),8.4(1H),9.2(1H)ppm.
实施例32-(3-2-(N,N-二甲基氨基)乙-1-基)-4-硝基苯基)苯并咪唑-4-甲酰胺a)3-(E-2-N,N-二甲基氨基乙-1-基)-4-硝基苯甲酸甲酯
将10g(47.8mmol)的3-甲基-4-硝基苯甲酸乙酯和N,N-二甲基甲酰胺二甲缩醛在100ml的二甲基甲酰胺中回流8小时。真空浓缩混合物,将残渣溶于100ml甲苯中,加入石油醚沉淀出产品,,得到7.5g产品。b)3-(2-N,N-二甲基氨基乙-1-基)-4-硝基苄醇
将2.0g(53mmol)硼氢化钠分份加到7g(26.5mmol)中间体3a的70ml乙醇溶液中。回流加热30分钟,真空浓缩。得到的残余物在水和乙酸乙酯之间进行分配。分出有机相,用水和氯化钠水溶液洗涤,干燥,真空浓缩。将得到的油状物溶于乙醇中,用醚性盐酸溶液洗涤。产物以盐酸盐形式结晶,得到2.5g产品。c)3-(2-N,N-二甲基氨基乙-1-基)-4-硝基苯甲醛
将2.35g(9mmol)中间体3b和6.3ml(45mol)三乙胺溶于50ml二甲基亚砜中。向其中分份加入2.9g(18mmol)吡啶-三氧化硫加成物。混合物搅拌60分钟,真空浓缩,得到的残余物在水和乙酸乙酯之间进行分配。分出有机相,进一步用水洗涤两次,干燥,真空浓缩,得到1.8g产品。d)2-(3-2-(N,N-二甲基氨基)乙-1-基)-4-硝基苯基)苯并咪唑-4-甲酰胺
按照与实施例29a、b和c相类似的方法,使中间体51c[sic]进行反应得到产物。
1H-NMR(D6-DMSO):δ=1.25(6H),3.1(3H),3.2(4H),3.9(2H),
7.0(2H),7.2(1H),7.6-7.9(3H),8.1(2H),9.5(1H),
10.9(1H)和13.5(宽峰)ppm.
类似地,按照WO 98/06703中所述的方法或本专利申请中所述的方法可以制备下列化合物:1. 2-(4-(二甲基氨基)甲基)苯基苯并咪唑-4-羧酰胺2. 2-(4-(二甲基氨基)甲基)苯基苯并咪唑-4-羧酰胺3. 2-(4-(吡咯烷-1-基)甲基)苯基苯并咪唑-4-羧酰胺4. 2-(4-(哌啶-1-基)甲基)苯基苯并咪唑-4-羧酰胺5. 2-(4-氨基甲基)苯基苯并咪唑-4-羧酰胺6. 2-(4-(甲基氨基)甲基)苯基苯并咪唑-4-羧酰胺7. 2-(4-(丙基氨基)甲基)苯基苯并咪唑-4-羧酰胺8. 2-(4-(2-(二乙基氨基)乙-1-基)苯基苯并咪唑-4-羧酰胺9. 2-(4-(2-(二甲基氨基)乙-1-基)苯基苯并咪唑-4-羧酰胺10. 2-(4-(2-氨基乙-1-基)苯基)苯并咪唑-4-羧酰胺11. 1-(2-(2-(甲基氨基)乙-1-基)苯基)苯并咪唑-4-羧酰胺12. 2-(4-(2-(乙基氨基)乙-1-基)苯基)苯并咪唑-4-羧酰胺13. 2-(4-(2-(吡咯烷-1-基)乙-1-基)苯基)苯并咪唑-4-羧酰胺14. 2-(4-(2-(哌啶-1-基)乙-1-基)苯基)苯并咪唑-4-羧酰胺15. 2-(3-(二乙基氨基)甲基)苯基苯并咪唑-4-羧酰胺16. 2-(3-(二甲基氨基)甲基)苯基苯并咪唑-4-羧酰胺17. 2-(3-(吡咯烷-1-基)甲基)苯基苯并咪唑-4-羧酰胺18. 2-(3-哌啶-1-基)甲基)苯基苯并咪唑-4-羧酰胺19. 2-(3-氨基甲基)苯基苯并咪唑-4-羧酰胺20. 2-(3-(甲基氨基)甲基)苯基苯并咪唑-4-羧酰胺21. 2-(3-(正丙基氨基)甲基)苯基苯并咪唑-4-羧酰胺22. 2-(3-(2-(二乙基氨基)乙-1-基)苯基苯并咪唑-4-羧酰胺23. 2-(3-(2-(二甲基氨基)乙-1-基)苯基苯并咪唑-4-羧酰胺24. 2-(3-(2-氨基乙-1-基)苯基)苯并咪唑-4-羧酰胺25. 2-(3-(2-(N-甲基氨基)乙-1-基)苯基)苯并咪唑-4-羧酰胺26. 2-(3-(2-N-甲基氨基)乙-1-基)苯基)苯并咪唑-4-羧酰胺27. 2-(3-(2-(吡咯烷-1-基)乙-1-基)苯基)苯并咪唑-4-羧酰胺28. 2-(3-(2-(哌啶-1-基)乙-1-基)苯基)苯并咪唑-4-羧酰胺29. 2-(4-N,N-(2-氨基乙-1-基)甲基氨基)苯基)苯并咪唑-4-羧酰胺30. 2-(4-N-(2-(二乙基氨基)乙-1-基)氨基)苯基)苯并咪唑-4-羧酰胺31. 2-(4-N-(2-(二甲基氨基)乙-1-基)氨基)苯基)苯并咪唑-4-羧酰胺32. 2-(4-N-(2-氨基乙-1-基)氨基)苯基)苯并咪唑-4-羧酰胺33. 2-(3-N,N-(2-(二甲基氨基)乙-1-基)甲基氨基)苯基苯并咪唑-4-羧酰胺34. 2-(3-N,N-(2-氨基乙-1-基)甲基氨基)苯基苯并咪唑-4-羧酰胺35. 2-(3-N-(2-(二乙基氨基)乙-1-基)氨基)苯基)苯并咪唑-4-羧酰胺36. 2-(3-N-(2-(二甲基氨基)乙-1-基)氨基)苯基)苯并咪唑-4-羧酰胺37. 2-(3-N-(2-氨基乙-1-基)氨基)苯基)苯并咪唑-4-羧酰胺38. 2-(3-N,N-(d-(二乙基氨基)丙-1-基)甲基氨基)苯基苯并咪唑-4-羧酰胺39. 2-(3-N,N-(D-(二甲基氨基)丙-1-基)甲基氨基)苯基苯并咪唑-4-羧酰胺40. 2-(3-N,N-(3-氨基丙-1-基)甲基氨基)苯基苯并咪唑-4-羧酰胺41. 2-(3-N-(D-(二甲基氨基)丙-1-基)甲基氨基)苯基苯并咪唑-4-羧酰胺42. 2-(3-N-(3-(二甲基氨基)丙-1-基)氨基)苯基苯并咪唑-4-羧酰胺43. 2-(3-N-(3-氨基丙-1-基)氨基)苯基苯并咪唑-4-羧酰胺44. 2-(3-N,N-(2-吡咯烷酮-1-基-乙-1-基)甲基氨基)苯基苯并咪唑-4-羧酰胺45. 2-(3-N-(2-吡咯烷酮-1-基)乙-1-基)氨基)苯基苯并咪唑-4-羧酰胺46. 2-(3-N,N-(3-(吡咯烷-1-基)丙-1-基)甲基氨基)苯基苯并咪唑-4-羧酰胺47. 2-(3-N,N-(3-(哌啶-1-基)丙-1-基)甲基氨基)苯基苯并咪唑-4-羧酰胺48. 2-(3-N,N-(2-(哌啶-1-基)乙-1-基)甲基氨基)苯基苯并咪唑-4-羧酰胺实施例A:聚(ADP-核糖)聚合酶或PARP(EC2.4.2.30)的抑制
用组蛋白(II-AS型;SIGMA H7755)涂布96池微滴平皿(Falcon)。首先将组蛋白溶解于碳酸盐缓冲液(0.05M NaHCO3;pH9.4)中,得到的浓度为50μg/ml,在微滴平皿的每个池中加入100μl此组蛋白溶液,使之培养过夜。移除组蛋白溶液,在每个池中加入200μl 1%浓BSA(牛血清白蛋白)溶液的碳酸缓冲溶液并于室温下培养2小时。用洗涤缓冲液(0.05%吐温10的PBS溶液)洗涤3次,为了使酶反应,使每池中含有50μl酶反应溶液(5μl反应缓冲液(1M tris HCl pH8.0,100mM MgCl2,10mM DTT),0.5μl PARP(c=0.22μg/μl),4μl活化的DNA(SIGMA D-4522,1mg/ml水溶液),40.5μl水),并与10μl抑制剂溶液一起预培养10分钟。加入40μl底物溶液(4μl反应缓冲液(同上),8μl NAD溶液(100μM水溶液),28μl水)开始反应。反应于室温下进行20分钟。用洗涤缓冲液(同上)洗涤3次终止反应。接着与特异的抗聚-ADP-核糖抗体一起在室温培养1小时。所用的抗体为单克隆抗-聚-(ADP-核糖)抗体“10H”(Kawamaitsu H.等人(1984),Monoclonal antibodies to poly(adenosinediphosphatr ribose)recognize different structures,生物化学23,3771-3777),也可以采用多克隆抗体。
采用1∶5,000的抗体稀释液,用抗体缓冲液(1%BSA的PBS溶液;0.05%吐温20)来进行稀释。用缓冲液洗涤3次后,与次级抗体在室温下培养1小时。对于单克隆抗体而言,采用偶联过氧化酶(Boehringer Mannheim)的抗小鼠IgG,对于兔子抗体而言,采用偶联过氧化酶(SIGMA A-6154)的抗兔子IgG,均采用用抗体缓冲液稀释的1∶10,000的稀释液。用缓冲液洗涤3次后,采用100μl/池的着色试剂(SIGMA,TMB已混合的T8540)在室温下进行着色反应约15分钟。加入100μl 2M的硫酸终止着色反应,立即进行测定(450nm对620nm;ELISA平皿-读数仪器“Easy Reader”EAR340AT,SLT Labinstruments,Austria)所要测量的抑制剂的IC50值是使最大色浓度出现一半改变时的抑制剂浓度。Ki值为抑制常数。测定了下列Ki值:实施例1: 16nM实施例2: 10nM实施例3: 4nM实施B:水溶解度的测定
将需要测定的化合物直接溶解在一定体积的水中,用乙酸钠溶液调节生成溶液pH值至5-6,从而获得了待测浓度的活性化合物溶液。如果测定物质不存在水溶性的盐类形式,将其溶解于小量的二甲亚砜中,然后用水稀释(二甲亚砜的终浓度<=1%),同上调节pH值。强PARP抑制剂NU1076(WO 97/04771)显示出的溶解度<0.01%,而本发明实施例化合物的溶解度>0.5%。实施例C:PARP抑制剂的细胞分析实验
为了测试PARP抑制剂的作用,用化学品处理真核细胞,以使细胞系DNA受到损伤,结果存在于细胞中的PARP酶被活化。由于酶的活化,在蛋白质上形成了聚-ADP-核糖(PAR)链。这些链与特异的抗体结合。它们反过来又与带有荧光标记的次级抗体结合。用荧光扫描仪测定荧光强度,其中部分是因PARP酶的活性引起的。通过荧光信号的减弱可以鉴别出PARP抑制剂。为了防止因不同的细胞计数而使结果出现假象,进一步用染料标记细胞DNA,并同依然用荧光扫描仪测定荧光强度。
将C4I细胞系中的400,000个细胞在37℃、5%CO2的条件下,于24孔的细胞培养皿(其为带有10%胎儿牛血清的RPMI培养基)中进行培养,直至得到一厚层细胞。用DMEM洗涤细胞,将欲测定的PARP抑制剂以各种浓度加到DMEM中。37℃下培养20分钟后,采用过氧化氢使其浓度达到1mM,混合物继续在37℃下培养10分钟。就对照样品而言,一些孔中的细胞不用过氧化氢处理(不发生PARP活化),或不给予抑制剂(最大的PARP的活化)。用PBS洗涤细胞一次,并通过加入甲醇/丙酮(7;3)混合物(其已被预冷却至-20℃)使细胞在-20℃下固定10分钟。干燥细胞,加入PBS室温脱水10分钟。室温下,于PBS中,用0.05%吐温20和5%干牛奶粉阻断非特异结合部位30分钟。加入小鼠抗体-PAR抗体,浓度为20μg/ml带有0.05%吐温20和5%干牛奶粉的PBS溶液。混合物在37℃下培养1小时。通过用PBS洗涤未结合的抗体移除抗体,共5次,每次5分钟。混合物再于37℃下与稀释的山羊抗-小鼠FITC-偶联的次级抗体(1∶50带有0.05%吐温20、5%干牛奶粉和1μg/ml DAPI(4’,6-二脒基-2-苯基吲哚)的PBS稀释液)一起培养30分钟。通过用PBS洗涤未结合的抗体移除抗体,共5次,每次5分钟。借助荧光扫描仪,在一些孔的几个位置上测定FITC和DAPI荧光强度。为了分析方便,将FITC信号标准化至DAPI信号。以各种抑制剂浓度标准化值的半对数进行绘图,可以计算出IC50值。测定了下列IC50值:实施例1: 115nM实施例2: 119nM实施例3: 118nM
Claims (22)
1.式I化合物及其互变异构体、可能的对映体及外消旋体,它们的前药以及可能的生理上可接受的盐类用于制备治疗出现病理性PARP活性增加疾病药物的用途,其中
A为N或CHR1为氢,支链和直链C1-C6-烷基,其中烷基基团的一个碳原子可以进一步携带OR11或基团R5,其中
R11为氢或C1-C4-烷基,并且R2为氢,氯,氟,溴,碘,支链和直链C1-C6-烷基,硝基,CF3,CN,NR21R22,NH-CO-R23,OR21,其中
R21和R22各自独立,为氢或C1-C4-烷基,并且
R23为氢或C1-C4-烷基或苯基,并且
R3为-(CH2)q-NR31R32,-(CH2)q-NR33R34,其中q为0,1,2或3,
R31为氢或C1-C6-烷基,(CH2)rNR33R34,
R32为(CH2)rNR33R34,
其中,如果R31和R32各自独立,r为2,3,4,5或6,并且R33和R34各自独立,为氢,C1-C6-烷基,与氮原子一起形成额外有选自O杂原子的3-8元环,N-C1-C4-烷基,N-C0-C2-苯基或NH,苯基C1-C4-烷基,其中苯环上可被上至3个相同或不同的取代基所取代,所述的取代基选自C1-C6-烷基,卤素,硝基,SO2NR35R36(其中R35,R36各自独立,为氢,C1-C6-烷基,与氮原子一起形成可以携带其它选自O,S,SO2的杂原子的3-8元环,N-C1-C4-烷基,N-C0-C2-苯基或NH),C1-C4-烷氧基,S(O)0-2-R37(其中R37为氢,C1-C4-烷基),CF3,(CH2)0-4-COR37,(CH2)0-4NR35R36,(CH2)0-4CONR35R36,(CH2)0-4OR37-CH2COOR37,
R4为氢,支链和直链C1-C6-烷基,氯,溴,氟,硝基,氰基,NR41R42,NH-CO-R43,OR41,其中
R41和R42各自独立为氢或C1-C4-烷基,并且
R43为C1-C4-烷基或苯基。
2.权利要求1中所述化合物的用途,就苯并咪唑环而言,其中的R2在3-位并且R3在4-位,或R2在4-位并且R3在3-位。
3.权利要求1或2中所述化合物的用途,其中的R1和R4为氢。
4.权利要求1-3任意一个中所述化合物的用途,其中
R2为氢,支链或直链C1-C6-烷基,硝基,CN,NH2,O-C1-C4-烷基。
5.权利要求1-4任意一个中所述化合物的用途,其中
R3为(CH2)1,2NR34R36和N(R37)-(CH2)2-3NR35R3,其中R37为氢或C1-C4-烷基,R35和R36各自独立为氢和C1-C4-烷基,NR35R36还可一起构成环状的脂肪胺,例如,哌啶,吡咯烷,氮杂和哌嗪,其中在哌嗪的第二个N原子上可以任意的被氢或C1-C4-烷基取代。
6.权利要求1-5任意一个中所述化合物的用途,其中R2为氢并且A为氮原子。
7.权利要求1-6任意一个中所述化合物用于制备治疗神经变性疾病和神经损伤的用途。
8.权利要求7中所述化合物用于治疗由于局部缺血、创伤或大出血导致的神经变性疾病和神经损伤的用途。
9.权利要求7中所述化合物用于治疗中风和颅脑创伤的用途。
10.权利要求8中所述化合物用于治疗Alzheimer’s疾病、Huntington’s疾病的用途。
11.权利要求1-6任意一个中所述式I化合物用于制备治疗或预防由于局部缺血所导致损伤的药物的用途。
12.权利要求1-6任意一个中所述式I化合物用于制备治疗癫痫,特别是一般性癫痫发作,(例如癫痫小发作、紧张性阵挛发作)以及部分癫痫发作(例如颞叶和复合部分发作)药物的用途。
13.权利要求1-6任意一个中所述式I化合物用于制备治疗肾脏局部缺血后的肾损伤以及肾移植过程中或之后出现的肾损伤药物的用途。
14.权利要求1-6任意一个中所述式I化合物用于制备治疗心脏局部缺血后的心脏损伤药物的用途。
15.权利要求1-6任意一个中所述式I化合物用于制备治疗心脏瓣膜替换、动脉瘤切除及心脏移植过程中或之后出现的微梗塞药物的用途。
16.权利要求1-6任意一个中所述式I化合物用于制备在临界压缩的冠状动脉的再血管化治疗中(例如在PCTA和心脏分流手术中)或在临界压缩的外周动脉的再血管化治疗中特别是腿部动脉)所用药物的用途。
17.权利要求1-6任意一个中所述式I化合物用于制备治疗急性心肌梗塞及出现在药物或机械溶解过程中或之后的损伤药物的用途。
18.权利要求1-6任意一个中所述式I化合物用于制备治疗肿瘤及其转移药物的用途。
19.权利要求6中所述式I化合物用于制备治疗多发性器官衰竭脓毒症(例如脓毒症休克和“急性呼吸distress综合症”过程中出现的)药物的用途。
20.权利要求1-6任意一个中所述式I化合物用于制备治疗免疫性疾病,例如炎症和风湿性失调(如风湿性关节炎)药物的用途。
21.权利要求6中所述式I化合物用于制备治疗糖尿病药物的用途。
22.选自下列的化合物:
2-(4-N,N-2-(N,N-二乙基氨基)乙-1-基甲基氨基)苯基)苯并咪唑-4-甲酰胺,2-(4-N,N-2-(N,N-二甲基氨基)乙-1-基甲基氨基)苯基)苯并咪唑-4-甲酰胺,2-(3-(2-(N,N-二甲基氨基)乙-1-基)-4-硝基苯基)-苯并咪唑-4-甲酰胺以及它们的前药或盐类。
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US (1) | US6509365B1 (zh) |
EP (1) | EP1131301B1 (zh) |
JP (2) | JP2002529537A (zh) |
KR (1) | KR20010080474A (zh) |
CN (1) | CN1331683A (zh) |
AR (1) | AR021297A1 (zh) |
AT (1) | ATE302758T1 (zh) |
AU (1) | AU755694B2 (zh) |
BG (1) | BG105550A (zh) |
BR (1) | BR9915381A (zh) |
CA (1) | CA2350734C (zh) |
CO (1) | CO5140115A1 (zh) |
CZ (1) | CZ20011724A3 (zh) |
DE (1) | DE59912473D1 (zh) |
DK (1) | DK1131301T3 (zh) |
ES (1) | ES2247867T3 (zh) |
HK (1) | HK1041694A1 (zh) |
HR (1) | HRP20010451A2 (zh) |
HU (1) | HUP0104129A3 (zh) |
ID (1) | ID28846A (zh) |
IL (1) | IL143102A0 (zh) |
NO (1) | NO20012419L (zh) |
PL (1) | PL347684A1 (zh) |
RU (1) | RU2001116581A (zh) |
SI (1) | SI1131301T1 (zh) |
SK (1) | SK6742001A3 (zh) |
TR (1) | TR200101400T2 (zh) |
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CN101511821B (zh) * | 2006-05-02 | 2013-07-17 | Abbvie公司 | 取代的1h-苯并咪唑-4-羧酰胺类化合物是有效的parp抑制剂 |
CN104981468A (zh) * | 2013-06-17 | 2015-10-14 | 上海汇伦生命科技有限公司 | 苯并咪唑-2-哌嗪杂环类化合物、其药物组合物及其制备方法和用途 |
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- 1999-11-05 EP EP99972206A patent/EP1131301B1/de not_active Expired - Lifetime
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
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CN100431606C (zh) * | 2004-11-22 | 2008-11-12 | 山东蓝金生物工程有限公司 | 一种抗癌药物组合物 |
CN101511821B (zh) * | 2006-05-02 | 2013-07-17 | Abbvie公司 | 取代的1h-苯并咪唑-4-羧酰胺类化合物是有效的parp抑制剂 |
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CN104981468B (zh) * | 2013-06-17 | 2018-01-05 | 上海汇伦生命科技有限公司 | 苯并咪唑‑2‑哌嗪杂环类化合物、其药物组合物及其制备方法和用途 |
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