CN100390163C - 2-(2,6-二氧哌啶-3-基)-异二氢吲哚衍生物、其制法及其作为炎性细胞因子抑制剂的用途 - Google Patents
2-(2,6-二氧哌啶-3-基)-异二氢吲哚衍生物、其制法及其作为炎性细胞因子抑制剂的用途 Download PDFInfo
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Abstract
公开了式(I)的1-氧-2-(2,6-二氧哌啶-3-基)异二氢吲哚和1,3-二氧-2-(2,6-二氧哌啶-3-基)异二氢吲哚类化合物,式中Y是氧或H2,R1和R2中的一个基团为卤素、烷基、烷氧基、烷基氨基、二烷基氨基、氰基或氨基甲酰基;R1和R2中的另一个基团独立地为氢、卤素、烷基、烷氧基、烷基氨基、二烷基氨基、氰基或氨基甲酰基;和R3为氢、烷基或苄基。还公开了通过施用该类衍生物降低哺乳动物中肿瘤坏死因子α和其他炎性细胞因子水平的方法,以及含有该衍生物的药物组合物。
Description
本申请要求享有美国临时申请No.08/078,180(1998年3月16日提交,名称为“1-氧-和1,3-二氧-异二氢吲哚类化合物以及降低炎性细胞因子水平的方法”)的权利。所述的申请No.08/078,180在此引用作为参考。
发明的背景
肿瘤坏死因子α(TNFα)是主要由单核巨噬细胞对各种免疫刺激剂的应答而释放的细胞因子。它是一种炎症级联反应中关键的原炎性细胞因子,导致产生和/或释放其他细胞因子和物质。将其施加于动物和人时,可引起炎症、发热、心血管影响、出血、凝血及类似于急性感染和休克状态所见的急性反应。因此,在很多疾病状态均可伴有TNFα产生过量或失控。这些疾病包括内毒素血症和/或中毒性休克综合征{Tracey等,Nature 330,662-664(1987)和Hinshaw等,Circ.Shock30,279-292(1990)};恶病质{Dezube等,Lancet,335(8690),662(1990)}和成人呼吸窘迫综合征(ARDS),其中从ARDS患者肺部抽吸物中检出TNFα的浓度超出12,000pg/mL{Millar等,Lancet 2(8665),712-714(1989)}。重组TNFα全身输注也导致ARDS中所见的改变{Ferrai-Baliviera等,Arch.Surg.124(12),1400-1405(1989)}。
TNFα似乎涉及骨吸收疾病,包括关节炎。当发作时,白细胞会产生骨吸收,资料提示TNFα与其发作有关{Bertolini等,Nature 319,516-518(1986)和Johnson等,Endocrinology 124(3),1424-1427(1989).}在体内、外试验中还证明,TNFα通过刺激破骨细胞形成和激活,同时抑制成骨细胞的功能,从而刺激骨吸收和抑制骨生成。尽管TNFα可能涉及很多骨吸收性疾病,包括关节炎,但最令人非相信不可的与疾病的联系是肿瘤或宿主组织TNFα的产生与伴有高钙血症的恶性程度之间的关联{Calci.Tissue Int.(US)46(Suppl.),S3-10(1990)}。急性同种异型骨髓移植后,在移植物对宿主反应中,主要并发症伴有血清TNFα水平的提高{Holler等,Blood,75(4),1011-1016(1990)}。
脑疟疾是伴有TNFα高血浓度的致死性超急性神经综合征,是疟疾患者中出现的最严重的并发症。血清TNFα水平与疟疾急性发作患者疾病的严重程度和预后直接相关{Grau等N.Engl.J.Med.320(24),1586-1591(1989)}。
已知巨噬细胞诱导的血管生成由TNFα介导。Leibovich等{Nature,329,630-632(1987)}在大鼠角膜和发育中的小鸡绒毛尿囊膜上证明,很低剂量的TNFα即引起体内毛细血管的形成,提示TNFα在炎症、伤口修复和肿瘤生长上是诱导血管生成的因素。TNFα的产生还与癌性疾病、特别是诱发肿瘤相关联{Ching等,Brit.J.Cancer,(1955)72,339-343和Koch,Progress in Medicinal Chemistry,22,166-242(1985)}。
TNFα还在慢性肺部炎症性疾病方面起作用。硅石颗粒的沉积导致矽肺,一种纤维变性反应引起的进行性呼吸衰竭疾病。抗TNFα抗体完全阻断硅石引起的小鼠肺纤维变性{Pignet等,Nature,344:245-247(1990)}。在硅石和石棉沉着病导致纤维变性的动物模型上证明,血清和分离出的巨噬细胞中有高水平TNFα的产生{Bissonnette等,Inflammation 13(3),329-339(1989)}。还有人发现,从肺类肉瘤病患者取出的肺泡巨噬细胞与从正常供体而来的巨噬细胞相比,该疾病自发性释放大量TNFα{Baughman等,J.Lab.Clin.Med.115(1),36-42(1990)}。
TNFα还与再灌注后的炎症反应(称作再灌注损伤)有关,是缺血流后组织损伤的主要原因{Vedder等,PNAS 87,2643-2646(1990)}。TNFα还能改变内皮细胞的性质,具有各种促凝血活性,如产生组织因子促凝血活性提高和抗凝血蛋白C途径的抑制,以及下调凝血调节蛋白的表达{Sherry等,J.Cell Biol.107,1269-1277(1988)}。TNFα具有促炎症活性,该活性与TNFα的早期产生(在炎症初期)使其更象是几种重要疾病(包括但不限于心肌梗塞、卒中和循环休克)中组织损伤的介质。特别重要的可以是TNFα诱导的粘合分子如细胞间粘合分子(ICAM)或内皮白细胞粘合分子(ELAM)在内皮细胞上的表达{Munro等,Am.J.Path.135(1),121-132(1989)}。
用抗TNFα单克隆抗体封闭TNFα已被证明对类风湿性关节炎有益{Elliot等,Int.J.Pharmac.1995 17(2),141-145}。高水平的TNFα与Crohn′s病相关{vonDullemen等,Gastroenterology,1995 109(1),129-135},而且用TNFα抗体治疗已获得临床效果。
此外,现已知道,TNFα是逆转录病毒复制(包括HIV-1激活)的强力激活剂{Duh等,Proc.Nat.Acad.Sci.86,5974-5978(1989);Poll等,Proc.Nat.Acad.Sci.87,782-785(1990);Monto等,Blood 79,2670(1990);Clouse等,J.Immunol.142,431-438(1989);Poll等,AIDS Res.Hum.Retrovirus,191-197(1992)}。AIDS由人免疫缺陷病毒(HIV)感染T淋巴细胞而引起。至少有三种类型或三株HIV已被鉴定出来,即HIV-1,HIV-2和HIV-3。作为HIV感染的结果,T细胞介导的免疫受损,受感染的个体出现严重的机会感染和/或异常新生物。HIV进入T淋巴细胞需要T淋巴细胞激活。其他病毒(如HIV-1和HIV-2)在T细胞激活后感染T淋巴细胞,这些病毒蛋白的表达和/或复制由这种T细胞激活所介导或维持。一旦被激活的T淋巴细胞感染了HIV,该T淋巴细胞必须继续维持激活状态,以使HIV基因表达和/或HIV复制。细胞因子,特别是TNFα,通过在维持T淋巴细胞活化中起作用而参与活化T细胞介导的HIV蛋白表达和/或病毒复制。因此,在HIV感染的个体上,诸如通过阻止或抑制细胞因子(值得注意的是TNFα)的产生来干扰细胞因子的活性,有助于限制HIV感染引起的淋巴细胞的维持。
单核细胞、巨噬细胞和相关的细胞(如枯否氏细胞和胶质细胞)也参与HIV感染的维持。这些细胞象T细胞一样,是病毒复制的靶细胞,病毒复制的水平依赖于细胞的激活状态,{Rosenberg等,The Immunopathogenesis of HIV Infection,Advances in Immunology,57(1989)}。细胞因子(如TNFα)已被证明在单核细胞和/或巨噬细胞中激活HIV复制{Poli等,Proc.Natl.Acad.Sci.,87,782-784(1990)},因此,阻止或抑制细胞因子的产生或其活性有助于限制HIV侵入T细胞。另外的研究已将TNFα鉴定为体外HIV激活的共同因子,并提供了通过细胞的胞质中已发现的核调节蛋白起作用的明确的作用机制(Osborn等,PNAS 86 2336-2340)。该证据揭示,TNFα合成的减少通过降低转录从而减少病毒产生,可在HIV感染中具有抗病毒效应。
潜伏在T细胞和巨噬细胞株内的HIV的AIDS病毒复制可被TNFα诱导{Folks等,PNAS 86,2365-2368(1989)}。有人提出,该病毒诱导活性的分子机理系通过TNFα激活在细胞胞质中所发现的基因调节蛋白(NFκB)的能力,该基因调节蛋白通过结合于病毒调节基因序列(LTR)而促进HIV的复制{Osborn等,PNAS 86:2336-2340(1989)}。有人提出,伴有恶病质的AIDS中的TNFα系血清TNFα的提高及患者外周血液单核细胞中高水平自发性TNFα产生所致{Wright等,J.Immunol.141(1).99-104(1988)}。如上面提到的类似的理由,TNFα参与其他病毒感染{如细胞肥大包涵体病毒(CMV)、流感病毒、腺病毒和疱疹病毒族)的各种作用。
核因子κB(NFκB)是多效转录激活剂(Lenardo等,Cell 1989,58,227-29)。NFκB作为转录激活剂参与各种疾病和炎症状态,被认为能调节细胞因子(包括但不限于TNFα)的水平,并且也是HIV转录的激活剂{Dbaibo等,J.Biol.Chem.1993,17762-66;Duh等,Proc,.Natl.Acad.Sci.1989,86,5974-78;Bachelerie等,Nature1991,350,709-12;Boswas等,J.Acquired Immune Deficiency Syndrome 1993,6,778-786;Suzuki等,Biochem.And Biophys.Res.Comm.1993.193.277-83;SuZuki等,Biochem.And Biophys.Res Comm.1992.189,1709-15;Suzuki等,Biochem.Mol.Bio.Int.1993,31(4),693-700;Shakhov等,Proc.Natl.Acad.Sci.USA 1990,171,35-47;和Staal等,Proc.Natl.Acad.Sci.USA 1990,87,9943-47)。因此,抑制NFκB结合可调节细胞因子基因的转录,通过这一调节和其他机制,用于抑制众多疾病。本说明书中描述的化合物可抑制核内NFκB的作用,从而用于治疗各种疾病,包括但不限于类风湿性关节炎、类风湿性脊椎炎、骨关节炎、其他关节炎、脓毒性休克、脓毒症、内毒素性体克、移植物抗宿主疾病、消耗性疾病、克罗恩氏病、炎性肠疾病、溃疡性结肠炎、多发性硬化、全身性红斑狼疮、麻风中的ENL、HIV、AIDS及AIDS中的机会感染。TNFα和NTκB水平受相互反馈环的影响。如上所述,本发明的化合物对TNFα和NFκB的水平均有影响。
很多细胞功能由3′,5′-环-磷酸腺苷(cAMP)水平介导。这些细胞功能可造成炎性状态和包括哮喘、炎症和其他病状的疾病{Lowe和Cheng,Drugs of the Future,17(9),799-807,1992)。现已证明,炎性白细胞中cAMP的升高抑制这些细胞的活性和炎性介质(包括TNFα和NFκB)的随后释放。cAMP水平的升高还导致呼吸道平滑肌的松驰。磷酸二酯酶通过水解反应控制cAMP的水平,而且已表明,磷酸二酯酶的抑制剂可提高cAMP的水平。
因此,降低TNFα水平和/或提高cAMP水平构成治疗很多炎性、感染性、免疫学或恶性疾病的有价值的治疗战略。这些疾病包括但不限于脓毒性休克、脓毒症、内毒素性休克、血液动力学休克和脓毒综合征、梗塞后再灌注损伤、疟疾、分支杆菌感染、脑脊膜炎、牛皮癣、充血性心力衰竭、纤维化疾病、恶病质、移植物排斥、癌症、自身免疫性疾病、AIDS的机会性感染、类风湿性关节炎、类风湿性脊椎炎、骨关节炎、其他关节炎病症、克罗恩氏病、溃疡性结肠炎、多发性硬化、全身红斑狼疮、麻风中的ENL、放射损伤和高氧性肺泡损伤。关于抑制TNFα效应的以往的努力涉及从利用地塞米松和强的松龙之类甾体药物到使用多克隆和单克隆抗体{Beutler等,Science 234,470-474(1985);WO 92/11383}。
详细描述
本发明基于这样的发现,即本说明书更详细描述的某些种类的非多肽类化合物可降低TNFα的水平,提高cAMP的水平,并抑制炎性细胞因子。因此,本发明涉及在二氢异吲哚环的4位被取代并且还可任选地在2,6-二氧哌啶环的3位取代的1-氧-和1,3-二氧-2-(2,6-二氧哌啶-3-基)-异二氢吲哚,通过服用这类衍生物来降低哺乳动物体内肿瘤坏死因子α和其他炎性细胞因子水平的方法,以及含所述衍生物的药物组合物。
具体地,本发明涉及
(a)以下通式I所示的2-(2,6-二氧哌啶-3-基)-异二氢吲哚
式中,
Y是氧或H2,以及
R1和R2中的第一个基团为卤素、烷基、烷氧基、烷基氨基、二烷基氨基、氰基或氨基甲酰基,
R1和R2中的第二个基团可与第一个基团独立地为氢、卤素、烷基、烷氧基、烷基氨基、二烷基氨基、氰基或氨基甲酰基,和
R3为氢、烷基或苄基,和
(b)含有可被质子化的氮原子的,所述2-(2,6-二氧哌啶-3-基)-异二氢吲哚的酸加成盐。
除非另外说明,术语“烷基”指含有1-4个碳原子的直链或支链一价饱和烃链。这样的烷基的代表为甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基和叔丁基。“烷氧基”指通过醚氧原子键合到分子其余部分的烷基。这样的烷氧基的代表为甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、仲丁氧基和叔丁氧基。
卤素包括溴、氯、氟和碘。
在有资格的专门医师指导下,式I化合物被用来抑制TNFα和其他炎性细胞因子(包括白细胞介素IL-1、IL-6和IL-12)的不良作用。这些化合物可单独地或与其它治疗剂(包括抗生素、甾类化合物、化疗剂等)合用,给需要治疗的哺乳动物口服给药、直肠给药或胃肠外给药。例如,用于治疗癌症、类风湿性关节炎、炎性肠疾病、肌营养障碍、Crohn氏病等。
本发明的化合物还可局部用于由过量TNFα的产生分别介导或加剧的局部病症的治疗或预防,例如病毒感染(如由疱疹病毒引起的感染)或病毒性结膜炎、牛皮癣、特应性皮炎等。
这些化合物还可用于需要阻止或抑制TNFα产生的人以外的哺乳动物的兽医治疗。在动物上处理(治疗或预防)的TNFα介导的疾病包括上面所述的那些病症,但特别是病毒感染。其例子包括猫免疫缺陷病毒、马感染性贫血病毒、羊关节炎病毒、绵羊脱髓鞘性脑白质炎病毒和梅迪(maedi)病毒,以及其它慢病毒(lentiviruses)。
式I化合物可方便地通过多种途径制备。在第一个实例中,酸酐或内酯与3-氨基-2,6-二氧哌啶反应:
在上述反应中,各R1、R2、R3和Y如上所定义。
从相应的谷氨酸酐通过常规的酰胺化反应,或者从合适的谷氨酰胺衍生物通过环化反应,可获得3-氨基-2,6-二氧哌啶。
或者Y为H2的化合物可根据如下反应,在酸受体如二甲基氨基吡啶或三乙胺存在下,从二取代的苯甲酸酯中间体获得:
其中,R4是CHO或CH2Br。
二取代的苯甲酸酯中间体是已知的,或者可通过常规方法获得。例如,在光的影响下,3,6-二取代邻-甲苯甲酸的低级烷基酯用N-溴代琥珀酰亚胺进行溴化,以形成2-(溴甲基)-3,6-二取代苯甲酸低级烷基酯。
或者,让二醛与氯化2,6-二氧哌啶-3-铵反应,以获得Y为H2的式I化合物:
最后,将二醛与谷氨酰胺反应,形成的2-(1-氧-异二氢吲哚-2-基)谷氨酸再被环化,形成Y为H2的式I的4,7-二取代的1-氧-2-(2,6-二氧哌啶-3-基)-异二氢吲哚:
在式I化合物中,与R3键合的碳原子成为手性中心,从而产生光学异构体:
这些异构体的外消旋体及其各自的异构体,以及非对映异构体(当还具有第2个手性中心时)均在本发明的范围内。外消旋体可直接使用,或可用物理方法,如通过使用手性吸附剂的色谱法将其分离成各个异构体。或者,可以手性形式制备各个异构体,或用化学方法,通过与手性酸或碱成盐(例如,10-樟脑磺酸、樟脑酸、α-溴代樟脑酸、甲氧基乙酸、酒石酸、二乙酰基酒石酸、苹果酸、吡咯烷酮-5-羧酸等的各个对映体),从混合物中分离各个异构体,然后将拆分开的一个碱或两个碱均游离出来,可任意地重复此过程,以获得基本上不含另一个的任何一个或两个各自的异体构,即光学纯度>95%的形式。
本发明还涉及通式I化合物(它含有可质子化的基团如氨基)的生理学上可接受的无毒酸加成盐。这样的盐包括从有机和无机酸生成的盐,例如(但不限于),盐酸、氢溴酸、磷酸、硫酸、甲磺酸、乙酸、酒石酸、乳酸、琥珀酸、柠檬酸、苹果酸、马来酸、山梨酸、阿康酸、水杨酸、苯二甲酸、双羟萘酸、庚酸等。
特别优选的化合物包括:1,3-二氧-2-(2,6-二氧哌啶-3-基)-4-甲基异二氢吲哚、1,3-二氧-2-(2,6-二氧哌啶-3-基)-4-乙基异二氢吲哚、1,3-二氧-2-(2,6-二氧-3-甲基哌啶-3-基)-4-甲基异二氢吲哚、1,3-二氧-2-(2,6-二氧哌啶-3-基)-4,7-二甲基异二氢吲哚、1-氧-2-(2,6-二氧-3-甲基哌啶-3-基)-4-乙基异二氢吲哚、1-氧-2-(2,6-二氧-3-甲基哌啶-3-基)-4-甲基异二氢吲哚、1-氧-2-(2,6-二氧-3-甲基哌啶-3-基)-7-乙基异二氢吲哚、1-氧-2-(2,6-二氧-3-甲基哌啶-3-基)-7-甲基异二氢吲哚、1-氧-2-(2,6-二氧哌啶-3-基)-4-丙基异二氢吲哚、1,3-二氧-2-(2,6-二氧哌啶-3-基)-4-氯异二氢吲哚、1,3-二氧-2-(2,6-二氧哌啶-3-基)-4-氨基甲酰基异二氢吲哚、1,3-二氧-2-(2,6-二氧哌啶-3-基)-4-甲氧基异二氢吲哚、1-氧-2-(2,6-二氧哌啶-3-基)-4,7-二甲基异二氢吲哚、1-氧-2-(2,6-二氧哌啶-3-基)-4-甲基-7-乙基异二氢吲哚、和1-氧-2-(2,6-二氧哌啶-3-基)-4,7-二乙氧基。其中,1,3-二氧-2-(2,6-二氧哌啶-3-基)-4-甲基异二氢吲哚、1,3-二氧-2-(2,6-二氧哌啶-3-基)-4,7-二甲基异二氢吲哚、1-氧-2-(2,6-二氧哌啶-3-基)-4-甲基异二氢吲哚和1-氧-2-(2,6-二氧哌啶-3-基)-4,7-二甲基异二氢吲哚是特别优选的。
口服剂型包括片剂、胶囊剂、糖锭剂(dragees),及类似形状的压制的药物剂型,每单位剂量包含1-100mg药物。可用含20-100mg/ml的等渗盐水溶液作为非胃肠道给药,包括肌内、鞘内、静脉内和动脉内途径给药。使用从常规载体如可可脂制成的栓剂可进行直肠给药。
药物组合物包括一种或几种式I的化合物,以及至少一种药学上可接受的载体、稀释剂或赋形剂。在制备这些组合物时,通常将活性成分与赋形剂混合,或用赋形剂稀释,或包在可以胶囊或药囊形式存在的载体中。当赋形剂起稀释剂作用时,它可以是固体、半固体或液体材料作为赋形剂、载体或活性成分的介质。因此,组合物可以是片剂、丸剂、粉剂、酏剂、混悬剂、乳剂、溶液剂、糖浆剂、软和硬明胶胶囊、栓剂、灭菌可注射溶液和灭菌包装粉剂。合适的赋形剂的例子包括乳糖、葡萄糖、蔗糖、山梨醇、甘露醇、淀粉、阿拉伯胶、硅酸钙、微晶纤维素、聚乙烯吡咯烷酮、纤维素、水、糖浆和甲基纤维素,制剂还可包括润滑剂(如滑石粉、硬脂酸镁和矿物油),湿润剂,乳化剂和悬浮剂,防腐剂(如羟基苯甲酸甲酯和丙酯),甜味剂或矫味剂。
组合物以制成单位剂量形式为宜,即适合作为单一剂量的物理学上分开的单位,或准备以一次或多次剂量方案对人和其他哺乳动物投药的单一剂量的预定部分,每一单位包含为产生所期望的治疗效应而计算出预定量的活性物质,以及合适的药剂学赋形剂。采用本领域熟知的方法,可将组合物制成给患者投药后能立即、持续或缓慢释放活性成分的制剂。
TNFα的酶联免疫吸附测定按常规方式进行。用Ficoll-Hypaque密度离心法从正常供体中获得PBMC。将细胞在补加10%AB+血清、2mM L-谷氨酰胺、100U/mL青霉素和100mg/mL链霉素的RPMI中培养。将药物溶解在二甲亚砜(SigmaChemical)中,然后用补加型RPMI进行稀释。在PBMC悬液中,在有或没有药物存在时的二甲亚砜最终浓度均为0.25%(重量)。以起始浓度为50mg/mL的半对数稀释液来测定药物。在加入LPS前一小时,将药物加入96孔板的PBMC(106细胞/mL)中。用1mg/mL来自明尼苏达沙门氏菌(Salmonella minnesota)R595(List BiologicalLabs,Campbell,CA)的LPS处理来刺激有或没有药物存在的PBMC(106细胞/mL)。然后将细胞在37℃下培育18-20小时。收获上清液,立即测定TNFα水平或保藏在-70℃(不超过4天)下直至测定。用人TNFα ELISA试剂盒(ENDOGEN,Boston,MA),根据生产商的说明测定上清中的TNFα浓度。
下面的实施例将进一步作为本发明实质的典型,但不应看作对其范围的限制,该范围只能由所附的权利要求来限定。
实施例1
2-(2,6-二氧哌啶-3-基)-4-甲基异二氢吲哚-1,3-二酮
将3-甲基邻苯二甲酸酐(2.96克,18.2毫摩尔)、3-氨基哌啶-2,6-二酮氯化氢(3.00克,18.2毫摩尔)和乙酸钠(1.57克,19.1毫摩尔)在乙酸(30毫升)中的搅拌溶液回流加热23小时。真空去除溶剂,得到一固体。该固体用水(40毫升)一起搅拌1小时,过滤,用水(30毫升)洗涤,然后与脱色炭(1克)在丙酮(2升)中在回流温度下加热30分钟。悬浮液用硅藻土(Celite)垫过滤,得到澄清溶液。滤液的溶剂被真空去除,得到2-(2,6-二氧哌啶-3-基)-4-甲基异二氢吲哚-1,3-二酮,为白色固体(4.08克,82%产率),熔点
290.0-292.0℃;1H NMR(DMSO-d6);δ2.03-2.09(m,1H,CHH),2.50-2.60(m,2H,CH2),2.63(s,3H,CH3),2.83-2.95(m,IH,CHH),5.13(dd,J=5.4,12.3Hz,IH,NCH),7.65-7.79(m,3H,Ar),11.13(br s,IH,NH);13C NMR(DMSO-d6)δ17.04,21.99,30.93,48.76,121.05,127.89,131.63,134.37,136.91,137.61,167.04,167.83,169.87,172.74;分析值C14H12N2O4:C,61.76;H,4.44;N,10.29.测量值:C,61.68;H,4.37;N,10.17.
实施例2
通过在实施例1程序中用等量的3-乙基邻苯二甲酸酐、3-氟邻苯二甲酸酐、3-氯邻苯二甲酸酐、3-氨基甲酰基邻苯二甲酸酐和3-甲氧基邻苯二甲酸酐加以替换,分别获得1,3-二氧-2-(2,6-二氧哌啶-3-基)-4-乙基异二氢吲哚、1,3-二氧-2-(2,6-二氧哌啶-3-基)-4-氟异二氢吲哚、1,3-二氧-2-(2,6-二氧哌啶-3-基)-4-氯异二氢吲哚、1,3-二氧-2-(2,6-二氧哌啶-3-基)-4-氨基甲酰基异二氢吲哚、1,3-二氧-2-(2,6-二氧哌啶-3-基)-4-甲氧基异二氢吲哚。
实施例3
通过在实施例1程序中用等量的3-氨基-3-甲基哌啶-2,6-二酮氯化氢替换3-氨基哌啶-2,6-二酮氯化氢,获得1,3-二氧-2-(2,6-二氧-3-甲基哌啶-3-基)-4-甲基异二氢吲哚。
实施例4
1-氧-2-(2,6-二氧哌啶-3-基)-4-甲基异二氢吲哚
在室温下,搅拌16.25克氯化2,6-二氧哌啶-3-铵、30.1克2-溴甲基-3-甲基苯甲酸甲酯和12.5克三乙胺在100毫升二甲基甲酰胺中的混合物1 5小时。然后混合物被真空浓缩,残留物与二氯甲烷和水混合。水层被分离,用二氯甲烷反萃取。合并的二氯甲烷溶液用硫酸镁干燥,并真空浓缩,得到1-氧-2-(2,6-二氧哌啶-3-基)-4-甲基异二氢吲哚。
用类似的方式,通过用等量的2-溴甲基-3,6-二甲基苯甲酸甲酯、2-溴甲基-3-乙基苯甲酸甲酯和2-溴甲基-3-甲氧基苯甲酸甲酯分别替换2-溴甲基-3-甲基苯甲酸甲酯,从而分别获得1-氧-2-(2,6-二氧哌啶-3-基)-4,7-二甲基异二氢吲哚、1-氧-2-(2,6-二氧哌啶-3-基)-4-乙基异二氢吲哚和1-氧-2-(2,6-二氧哌啶-3-基)-4-甲氧基异二氢吲哚。
实施例5
2-(2,6-二氧哌啶-3-基)-4,7-二甲基异二氢吲哚-1,3-二酮
用实施例1的程序,从3,6-二甲基邻苯二甲酸酐(220毫克,1.25毫摩尔)、3-氨基哌啶-2,6-二酮氯化氢(204毫克,1.24毫摩尔)和乙酸钠(110毫克,1.34毫摩尔)的乙酸(10毫升)溶液,制得2-(2,6-二氧哌啶-3-基)-4,7-二甲基异二氢吲哚-1,3-二酮。产物为白色固体(200毫克,56%产率),熔点
263.0-265.0℃;1H NMR(DMSO-d6)δ 2.01-2.07(m,1H,CHH),2.50-2.89(m,9H,CH3,CHH,CH2),5.10(dd,J=5.1,12.4Hz,1H,NCH),7.52(s,2H,Ar),11.12(br s,1H,NH);13C NMR(DMSO-d6)δ16.82,22.02,30.97,48.59,128.01,135.04,136.58,167.68,169.98,172.83.
实施例6
2-(2,6-二氧-3-哌啶基)-4-乙基异二氢吲哚-1,3-二酮
用实施例1的程序,从3-乙基邻苯二甲酸酐(0.860克,4.89毫摩尔)、3-氨基哌啶-2,6-二酮氯化氢(0.803克,4.88毫摩尔)和乙酸钠(0.420克,5.12毫摩尔)的乙酸(10毫升)溶液,制得2-(2,6-二氧-3-哌啶基)-4-乙基异二氢吲哚-1,3-二酮。产物为白色固体(1.06克,76%产率),熔点
235.0-236.5℃;1H NMR(DMSO-d6)δ1.22(t,J=7.4Hz,3H,CH3),2.04-2.10(m,1H,CHH),2.47-2.63(m,2H,CH2),2.83-2.98(m,1H,CHH),3.07(q,J=7.5Hz,2H,CH2),5.13(dd,J=5.4,12.5Hz,1H,NCH),7.70-7.82(m,3H,Ar),11.13(br s,1H,NH);13C NMR(DMSO-d6)δ14.84,21.95,23.69,30.90,48.77,121.09,127.26,131.76,134.63,135.39,143.87,166.99,167.58,169.85,172.72;分析值C15H14N2O4:C,62.93;H,4.93;N,9.79.测量值:C,62.74;H,4.84;N,9.54.
实施例7
4-甲氧基-2-(2,6-二氧-3-哌啶基)异二氢吲哚-1,3-二酮
用实施例1的程序,从3-甲氧基邻苯二甲酸酐(1.0克,5.6毫摩尔)(Rao.A.V.R.等人,Indian J.Chem.1981,20(B),248)、3-氨基哌啶-2,6-二酮氯化氢(0.92克,5.6毫摩尔)和乙酸钠(0.48克,6.0毫摩尔)的乙酸(20毫升)溶液,制得4-甲氧基-2-(2,6-二氧-3-哌啶基)异二氢吲哚-1,3-二酮。产物为白色固体(0.44克,27%产率),熔点
281.5-282.5℃;1H NMR(DMSO-d6)δ2.00-2.08(m,1H,CHH),2.56-2.62(m,2H,CH2),2.82-2.91(m,1H,CHH),3.97(s,3H,CH3),5.08(dd,J=5.3,12.8Hz,1H,NCH),7.46(d,J=7.2Hz,1H,Ar),7.52(d,J=8.5Hz,1H,Ar),7.84(d,J=7.8Hz,1H,Ar),11.10(brs,1H,NH);13CNMR(DMSO-d6)δ21.97,30.92,48.73,56.33,115.24,116.11,119.01,133.19,137.15,156.49,165.37,166.84,169.94,172.79;分析值C14H12N2O5:C,58.33;H,4.20;N,9.72.测量值:C,58.23;H,3.90;N,9.53.
实施例8
4-二甲基氨基-2-(2,6-二氧-3-哌啶基)异二氢吲哚-1,3-二酮用实施例1的程序,从3-二甲基氨基邻苯二甲酸酐(1.34克,7.0毫摩尔)、3-氨基哌啶-2,6-二酮氯化氢(1.15克,7.0毫摩尔)和乙酸钠(0.60克,7.3毫摩尔)的乙酸(20毫升)溶液,制得4-二甲基氨基-2-(2,6-二氧-3-哌啶基)异二氢吲哚-1,3-二酮。产物为黄色固体(1.59克,75%产率),熔点
214.5-216.5℃;1H NMR(DMSO-d6)δ1.98-2.09(m,1H,CHH),2.49-2.62(m,2H,CH2),2.81-2.95(m,1H,CHH),3.04(s,6H,CH3),5.08(dd,J=5.5,12.7Hz,1H,NCH),7.23(d,J=6.6Hz,1H,Ar),7.26(d,J=8.1Hz,1H,Ar),7.63(dd,J=6.9,8.6Hz,1H,Ar),11.09(br s,1H,NH);13C NMR(DMSO-d6)δ22.10,30.96,42.95,48.77,112.99,113.41,122.59,133.90,135.22,149.88,166.29,167.13,170.06,172.83;.分析值C15H15N3O4:C,59.80;H,5.02;N,13.95.测量值:C,59.60;H,4.94;N,13.80.
实施例9
2-(2,6-二氧-3-哌啶基)-4-氯异二氢吲哚-1,3-二酮
用实施例1的程序,从3-氯邻苯二甲酸酐(0.40克,2.2毫摩尔)、3-氨基哌啶-2,6-二酮氯化氢(0.36克,2.2毫摩尔)和乙酸钠(0.19克,2.4毫摩尔)的乙酸(10毫升)溶液,制得2-(2,6-二氧-3-哌啶基)-4-氯异二氢吲哚-1,3-二酮。产物为白色固体(0.44克,69%产率),熔点
290.0-291.5℃;1H NMR(DMSO-d6)δ2.05-2.11(m,1H,CHH),2.49-2.64(m,2H,CH2),2.64-2.92(m,1H,CHH),5.17(dd,J=5.2,12.7Hz,1H,NCH),7.86-7.94(m,3H,Ar),11.17(br s,1H,NH);13C NMR(DMSO-d6)δ21.83,30.91,49.12,122.41,126.94,129.84,133.52,136.11,136.39,164.77,165.76,169.73,172.77;分析值C13H9N2O4Cl:C,53.35;H,3.10;N,9.57;Cl,12.11.测量值:C,53.37;H,2.94;N,9.30,Cl,11.97.
实施例10
4-甲基-2-(2,6-二氧-3-甲基-3-哌啶基)异二氢吲哚-1,3-二酮
用实施例1的程序,从3-甲基邻苯二甲酸酐(0.27克,1.7毫摩尔)、3-氨基-3-甲基哌啶-2,6-二酮氯化氢(0.30克,1.7毫摩尔)和乙酸钠(0.1 5克,1.8毫摩尔)的乙酸(10毫升)溶液,制得4-甲基-2-(2,6-二氧-3-甲基-3-哌啶基)异二氢吲哚-1,3-二酮。产物为白色固体(0.13克,27%产率),熔点
248.0-250.0℃;1H NMR(DMSO-d6)δ1.89(s,3H,CH3),2.01-2.08(m,1H,CHH),2.49-2.70(m,3H,CHH,CH2),2.55(s,3H,CH3),7.62-7.74(m,3H,Ar),10.99(br s,1H,NH);13C NMR(DMSO-d6)δ17.0,21.0,28.6,29.1,58.6,120.7,127.5,131.5,134.2,136.8,137.2,167.7,168.6,172.1,172.3;分析值C15H14N2O4+0.3 H2O:C,61.77;H,5.05;N,9.60.测量值:C,62.05;H,4.94;N,9.20.
实施例11
按照以下步骤能够获得每片含50mg 1-氧-2-(2,6-二氧哌啶-3-基)-4-甲基异二氢吲哚的片剂。
组成(1000片)
1-氧-2-(2,6-二氧哌啶-3-基)-4-甲基异二氢吲哚 50.0g
乳糖 50.7g
麦淀粉 7.5g
聚乙二醇6000 5.0g
滑石粉 5.0g
硬脂酸镁 1.8g
软化水 q.s.
首先,使固体组分过孔径为0.6mm的筛子,然后混合活性组分、乳糖、滑石粉、硬脂酸镁和一半量的淀粉,另一半淀粉被悬浮在40mL水中,再将该悬浮液加入100mL沸腾的聚乙二醇水溶液中,接着,将所得的糊状物加入到粉末状物质中,并将混合物制成颗粒状,如有必要,还可添加水。然后在35℃的温度下彻夜干燥颗粒物,再过孔径为1.2mm的筛子整粒,最后压片,获得直径为6mm、且两边内凹的片剂。
实施例12
按照以下步骤能够获得每个胶囊含100mg 1,3-二氧-2-(2,6-二氧哌啶-3-基)-4-甲基异二氢吲哚的明胶干填胶囊剂。
组成(1000粒胶囊)
1,3-二氧-2-(2,6-二氧哌啶-3-基)-4-甲基异二氢吲哚 100.0g
微晶纤维素 30.0g
十二烷基硫酸钠 2.0g
硬脂酸镁 8.0g
首先,使十二烷基硫酸钠通过孔径为0.2mm的筛子而添加入1,3-二氧-2-(2,6-二氧哌啶-3-基)-4-甲基异二氢吲哚中,充分混合10分钟后,再使微晶纤维素通过孔径为0.9mm的筛子而添加入上述混合物中,然后充分混合10分钟。接着,使硬脂酸镁通过孔径为0.8mm的筛子而添加入混合物中,再混合3分钟,最后将上述混合物(每个胶囊装入140mg)装入型号为0(拉长型)的明胶干填胶囊中。
实施例13
按照以下步骤能够获得0.2%注射剂或输液。
1,3-二氧-2-(2,6-二氧哌啶-3-基)-4,7-二甲基异二 5.0g
氢吲哚
氯化钠 22.5g
pH7.4的磷酸缓冲液 300.0g
软化水 加到2500.0mL
首先将1-氧-2-(2,6-二氧哌啶-3-基)-4,7-二甲基异二氢吲哚溶于1000mL水中,用微孔滤膜过滤后,添加缓冲液,然后加水使容量达到2500mL。最后将上述溶液装入玻璃安瓿(每个瓶装入1.0或2.5mL溶液,即分别含2.0或5.0mg酰亚胺)中。
Claims (21)
2.如权利要求1所述的化合物,其特征在于,Y为氧。
3.如权利要求1所述的化合物,其特征在于,Y是H2。
4.如权利要求1所述的化合物,其特征在于,R1和R3为氢。
5.如权利要求4所述的化合物,其特征在于,R2是甲基、乙基、氯或甲氧基。
6.如权利要求1所述的化合物,其特征在于,R2和R3是甲基,而R1为氢。
7.如权利要求1所述的化合物,其特征在于,它是1,3-二氧-2-(2,6-二氧哌啶-3-基)-4-甲基异二氢吲哚。
8.如权利要求1所述的化合物,其特征在于,它是1,3-二氧-2-(2,6-二氧哌啶-3-基)-4-乙基异二氢吲哚。
9.如权利要求1所述的化合物,其特征在于,它是1,3-二氧-2-(2,6-二氧哌啶-3-基)-4,7-二甲基异二氢吲哚。
10.如权利要求1所述的化合物,其特征在于,它是1,3-二氧-2-(2,6-二氧-3-甲基哌啶-3-基)-4-甲基异二氢吲哚。
11.如权利要求1所述的化合物在制备一种降低哺乳动物中不利的炎性细胞因子水平的药物中的应用。
12.一种药物组合物,其特征在于,它包含其量按单次或多次剂量方案给药后足以降低哺乳动物中炎性细胞因子水平的权利要求1所述的化合物,以及载体。
13.如权利要求1所述的化合物在制备一种治疗哺乳动物炎症的药物中的应用。
14.如权利要求1所述的化合物在制备一种治疗哺乳动物自身免疫疾病的药物中的应用。
15.如权利要求1所述的化合物在制备一种治疗哺乳动物的疾病的药物中的应用,该疾病选自下组:关节炎、类风湿性关节炎、炎性肠疾病、Crohn氏病、口疮性溃疡、恶病质、移植物抗宿主疾病、哮喘、成人呼吸窘迫症和获得性免疫缺陷综合症。
16.如权利要求1所述的化合物在制备一种治疗哺乳动物的癌症的药物中的应用。
17.如权利要求1所述的化合物在制备一种治疗哺乳动物中不利的血管形成的药物中的应用。
18.如权利要求1所述的化合物在制备一种降低或抑制哺乳动物中不利的TNFα水平的药物中的应用。
19.如权利要求1所述的化合物在制备一种治疗哺乳动物中炎性疾病的药物中的应用。
20.如权利要求1所述的化合物,其特征在于,它是2-(2,6-二氧哌啶-3-基)-异二氢吲哚。
21.如权利要求1所述的化合物在制备一种降低或抑制哺乳动物中不利的IL-1水平的药物中的应用。
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