CN1450997A - 含铜的胺氧化酶的抑制剂 - Google Patents
含铜的胺氧化酶的抑制剂 Download PDFInfo
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- CN1450997A CN1450997A CN01815101A CN01815101A CN1450997A CN 1450997 A CN1450997 A CN 1450997A CN 01815101 A CN01815101 A CN 01815101A CN 01815101 A CN01815101 A CN 01815101A CN 1450997 A CN1450997 A CN 1450997A
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- Prior art keywords
- alkyl
- substituted
- aryl
- radical
- heterocyclic ring
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Abstract
本发明涉及作为含铜的胺氧化酶的抑制剂的1,3,4-噁二嗪化合物,含铜的胺氧化酶通常称为对氨基脲敏感的胺氧化酶(SSAO),包括称作血管粘附蛋白-1(VAP-1)的人SSAO。这些SSAO抑制剂具有作为治疗各种症状和疾病,包括但不限于各种炎性症状和疾病(具体有慢性炎症,例如慢性关节炎、肠炎和慢性皮肤病)、与碳水合物代谢有关的疾病和与脂肪细胞分化或功能和平滑肌细胞功能畸变有关的疾病以及血管疾病的药物的医疗用途。所述化合物、其互变异构体、异构体、肼基醇降解产物,药学上可接受的溶剂合物、水合物或盐具有通式(I)的结构,其中R1、R2、R3、R4、R5、R6、R7和R8在本文中作了定义。
Description
发明领域
本发明属于药物化学领域,涉及1,3,4-噁二嗪化合物及其作为含铜的胺氧化酶(E.C.1.4.3.6)及与之明显等同的酶的抑制剂的用途。本发明化合物具有作为治疗各种疾病,包括但不限于各种炎性症状和疾病(尤其是慢性炎性症状或疾病,例如慢性关节炎、肠炎和慢性皮肤病),以及与碳水合物代谢有关的疾病和与脂肪细胞分化或功能和平滑肌细胞功能畸变有关的疾病的药物的医疗用途。
发明背景
VAP-1是人内皮细胞粘附分子,具有多种与其它与炎症相关的粘附分子不同的独特的性能,这些性能将在以下进行描述。VAP-1具有特殊而受限的表达模式,并介导淋巴细胞与血管内皮的结合(Salmi,M.和Jalkanen,S.,Science 257:1407-1409(1992))。炎症引起VAP-1上调至血管内皮细胞的表面,导致白细胞进入皮肤、肠和发炎的滑膜中(Salmi,M.和Jalkanen,S.,Science 257:1407-1409(1992);Salmi,M.等,J.Exp.Med 178:2255-2260(1993);Arvillomi,A.等,Eur.J.Immunol.26:825-833(1996);Salmi,M.等,J.Clin.Invest.99:2165-2172(1997)。VAP-1的快速转移到发炎的部位血管内皮上。(Salmi,M.和Jalkanen,S.,J.Exp.Med.183:569-579(1996);d.Exp.Med.186:589-600(1997))。最后,VAP-1具有催化细胞外的含单胺氧化酶活性的区域(Smith,D.J.等,J.Exp.Med.188:17-27(1998))。
人VAP-1cDNA的克隆和排序表明它对与一类称作含铜的胺氧化酶(E.C.1.4.3.6)的酶同源的跨膜蛋白质进行编码。酶测试表明VAP-1具有单胺氧化酶(MAO)活性,该活性存在于所述蛋白质的细胞外结构域中(Smith,D.J.等,J.Exp.Med.188:17-27(1998))。因此,VAP-1是一种外酶。对VAP-1MAO活性的分析表明VAP-1属于膜结合的MAO的称为对氨基脲敏感的胺氧化酶(SSAO)类。它们在氨基酸序列、辅因子、底物特异性和对某些抑制剂的敏感性方面,与广泛分布的线粒体MAO-A和B黄素蛋白不同。然而,某些底物和抑制剂对SSAO和MAO的活性相同。哺乳类SSAO可代谢各种内源产生的单胺或从食物或异生物质中吸收的单胺。它们主要作用于脂族或芳族一级单胺,例如甲基胺或苄基胺(Lyles,G.A.,Int.J.Biochem.Cell Biol.28:259-274(1996))。所以,位于血管内皮细胞表面中的VAP-1可按以下反应途径对一级单胺的循环发生作用。
在人临床组织样本中,在发炎部位诱导VAP-1的表达。VAP-1水平的提高导致H2O2(由VAP-1SSAO细胞外结构域对存在于血液中的单胺的作用产生)生成量的提高。在内皮细胞的局部环境中生成的H2O2会诱发其它细胞活动。H2O2是已知的信号分子,它可正调节其它粘附分子,而且所增加的粘附分子的表达可使白细胞传入VAP-1表达区域得到增强。使用体外模型得到了支持这种理论的初始数据,在这种体外模型中,在往细胞培养基中加入经纯化的VAP-1SSAO蛋白和苯甲胺(一种SSAO的底物)后,可观察到E-选择蛋白、VCAM-1和ICAM-1在培养的人脐静脉内皮细胞(HUVEC)上的表达的增强。当加入的是突变(酶促失活)的VAP-1SSAO蛋白,而非天然蛋白质时,这种在粘附分子中的表达的增强较不显著。
文献中有许多关于1,3,4-噁二嗪的描述。(参见如SchmiTZ,e.等人,Liebigs Ann.Chem.(6):1043-1046(1983);Samitov,Y.Y.等人,Zh.Org.Khim.22(11):2271-2277(1986);Potekhin,A.A.等人,Khim.Geterotsikl.Soedin.(11):1461-1468(1973);Potekhin,A.A.和Zaitsev,B.D.,Khim.Geterosikl.Soedin.7(3):301-308(1971);Ioffe,B.V.和Potekhin,A.A.,Tetrahedron Lett.(36):3505-3508(1967);和Kaneko,日本专利申请号63256951(1988))。但是,并没有关于明确将这些化合物用作特定的SSAO抑制剂的报导。
在水溶液中,1,3,4-噁二嗪可以以互变异构的腙形式存在。参见例如Potekhin,A.A.和Zaitsev,B.D.,Khim.Geterotsikl.Soedin.7(3):301-308(1971)以及Ioffe,B.V.和Potekhin,AA.,Ttrahedron Lett(36):3505-3508(1967)。
Takahashi,H.等在Yakugaku Zasshi 101(12):1154-1156(1981)中报道了大量关于N-烷基氨基麻黄碱,包括N-(异亚丙基氨基)-麻黄碱(或R,S-(+)-(2-羟基-1-甲基-2-苯基乙基)甲基腙-2-普鲁本辛)的合成:合成这些腙化合物以评价其对支气管肌肉系统的作用,结果发现未表现出任何明显的活性。该参考文献没有提及相应于所报导的腙的1,3,4-噁二嗪。
Grifantini,M.等在Farmaco,Ed,Sci.23(3):197-203(1968)中报道了具有抗抑郁和单胺氧化酶抑制性质的N-氨基-1-麻黄碱和N-氨基-d假麻黄碱的几种烷基和酰基衍生物的合成。在所公开的化合物中有腙赤-(β-羟基-α-甲基苯乙基)甲基腙环己酮,其结构如下:
对调节VAP-1活性的特定VAP-1SSAO抑制剂的研究对治疗慢性炎性症状或疾病,例如慢性关节炎、肠炎和慢性皮肤病,及与碳水合物代谢有关的疾病(包括糖尿病和糖尿病引起的并发症),与脂肪细胞分化或功能和平滑肌细胞功能畸变(尤其是动脉粥样硬化)的疾病,和各种血管病是有益的。
发明概述
本发明主要涉及用作一类称作对氨基脲敏感的胺氧化酶(SSAO)的含铜的胺氧化酶,包括称作血管粘附蛋白-1(VAP-1)的人SSAO的抑制剂的式I的1,3,4-噁二嗪化合物。作为VAP-1SSAO抑制剂,本发明的化合物可起阻止经SSAO活性介导的白细胞粘附的作用。因此本发明的化合物可用于治疗大量结缔组织、皮肤、胃肠道、中枢神经系统和肺系统的炎性症状和疾病,包括慢性关节炎、肠炎和慢性皮肤病。所述化合物也可用于治疗与碳水合物代谢有关的疾病(如糖尿病)、与脂肪细胞分化或功能或平滑肌细胞功能畸变有关的疾病(例如动脉粥样硬化和肥胖症)及各种血管病(例如粉瘤的和非粉瘤性动脉粥样硬化、局部缺血性心脏病和末梢aterial闭塞)。
本发明的另一方面是要提供用于治疗响应于SSAO活性下降的疾病的药用组合物,所述组合物包括有效量的式I的化合物与一种或多种药学上可接受的载体或稀释剂的混合物。
本发明所用的许多化合物迄今未被报导。因此,本发明还涉及式I的新1,3,4-噁二嗪。
本发明的另一个实施方案涉及制备式I的化合物的方法。
本发明的详细描述
本发明一方面使用一组特定的具有如下定义通式I的1,3,4-噁二嗪化合物制备用于抑制含铜的胺氧化酶的药用制剂。
本发明另一方面使用一组特定的具有如下定义通式I的1,3,4-噁二嗪化合物制备用于治疗炎性疾病或病症、与碳水合物代谢相关的疾病、与脂肪细胞分化或功能或平滑肌细胞功能畸变相关的疾病、或血管病的药用制剂。
本发明又一方面涉及抑制含铜的胺氧化酶的方法,所述方法包括使所述胺氧化酶与抑制有效量的式I的1,3,4-噁二嗪化合物或其互变异构体、异构体、肼基醇降解产物,或其药学上可接受的溶剂合物、水合物或盐接触,其中:
R1为氢或C1-C4烷基;
R2为氢、C1-C4烷基、C2-C4链烯基、芳烷基、C2-C6烷酰基、C3-C6链烯酰基(alkenoyl)、任选取代的C7-C11芳酰基;
R3、R4、R5和R6可相同或不同,为氢、C1-C4烷基或任选取代的芳基;
或所述取代基R3、R4、R5和R6中的任两个可与它们连接的碳原子一起形成任选取代的碳环或杂环;
或R2和R3与它们连接的原子一起形成任选取代的杂环;和
R7为氢、C1-C4烷基、芳基、取代芳基、杂芳基或芳烷基;
R8为C1-C4烷基、芳基、取代芳基、杂芳基或芳烷基;或R7和R8与它们连接的碳原子一起形成任选取代5-12元碳环或杂环。
在一个实施方案中,所述接触在体外发生。在另一个实施方案中,所述接触在体内发生。
R1为氢或C1-C4烷基;
R2为氢、C1-C4烷基、C2-C4链烯基、芳烷基、C2-C6烷酰基、C3-C6链烯酰基、任选取代的C7-C11芳酰基;
R3、R4、R5和R6可相同或不同,为氢、C1-C4烷基或任选取代的芳基;
或所述取代基R3、R4、R5和R6中的任两个可与它们连接的碳原子一起形成任选取代的碳环或杂环;
或R2和R3与它们连接的原子一起形成任选取代的杂环;和
R7为氢、C1-C4烷基、芳基、取代芳基、杂芳基或芳烷基;
R8为C1-C4烷基、芳基、取代芳基、杂芳基或芳烷基;
或R7和R8与它们连接的碳原子一起形成任选取代5-12元碳环或杂环。
在一个实施方案中,所述式I的1,3,4-噁二嗪化合物用于治疗或预防结缔组织的炎性症状和疾病。具体说来,所述化合物可用于治疗诸如类风湿性关节炎、强直性脊椎炎、银屑病关节炎和骨关节炎这类症状或疾病。
在另一个实施方案中,所述式I的1,3,4-噁二嗪化合物用于治疗或预防胃肠道炎性症状和疾病,尤其是例如Crohn氏病、溃疡性结肠炎和肠易激惹综合征。
在又一个实施方案中,所述式I的1,3,4-噁二嗪化合物用于治疗中枢神经系统炎性症状和疾病,包括多发性硬化病、早老性痴呆症和与缺血休克有关的缺血-再灌注损伤。
在另一个实施方案中,所述式I的1,3,4-噁二嗪化合物用于治疗或预防肺炎或肺病。具体说来,所述化合物可用于治疗或预防诸如哮喘和成人呼吸窘迫综合征这类症状或疾病。
在另一个实施方案中,所述式I的1,3,4-噁二嗪化合物用于治疗或预防慢性皮炎,特别如银屑病、变应性损伤、扁平苔癣和玫瑰糠疹的皮炎。
在又一个实施方案中,所述式I的1,3,4-噁二嗪化合物用于治疗或预防与碳水合物代谢有关的病症及其并发症,例如糖尿病和糖尿病引起的并发症、微脉管和大脉管病例如动脉粥样硬化、血管视网膜病、肾病和神经病例如多发性神经病、单神经病和植物神经病。
在又一个实施方案中,所述式I的1,3,4-噁二嗪化合物用于治疗或预防与脂肪细胞分化或功能畸变有关或由其引起的疾病,例如动脉粥样硬化或肥胖症。
在另一个实施方案中,所述式I的1,3,4-噁二嗪化合物用于治疗或预防与平滑肌细胞功能畸变有关或由其引起的疾病,例如动脉粥样硬化。
在另一个实施方案中,所述式I的1,3,4-噁二嗪化合物用于治疗或预防血管疾病,例如粉瘤和非粉瘤性动脉硬化、缺血性心脏病和Raynaud氏病和症状。
本发明的另一方面涉及上述的式I的新化合物,及其互变异构体、或药学上可接受的溶剂合物、水合物或盐;
条件是当R7和/或R8为C1-C4烷基或任选取代的苯基,或当R7和R8与它们连接的碳原子一起形成非取代的C5-C7环烷基时,R3和R4不为氢或C1-C4烷基。
本发明还涉及这些式I的新化合物的药用组合物,以及制备这些新化合物的方法。
优选的化合物是式I中R1和R2为以下基团的那些化合物,其中R1为氢或C1-C4烷基,优选为氢;并且R2为氢,C1-C4烷基、C2-C4链烯基、C6-C10芳基(C1-C4)烷基、C2-C6烷酰基、C2-C6链烯酰基或苯甲酰基,其中任一种基团可任选被取代,优选R2为C1-C4烷基或任选取代的苄基。R2的苄基的优选取代基为低级烷基(特别是甲基)、硝基、甲氧基和卤素(特别是氯)。特别优选的取代苄基的实例有对甲苯基、对硝基苄基、对甲氧基苄基和对氯苄基。R1的适用基团有氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基和叔丁基。R2的适用基团包括氢、甲基、乙基、丙基、异丙基、苄基、乙酰基、苯甲酰基、对甲苯基、对硝基苄基、对甲氧基苄基和对氯代苄基。
优选的式I化合物也包括那些其中R3、R4、R5和R6(可相同或不相同)为氢、任选取代的C1-C4烷基或任选取代的苯基的化合物。R3、R4、R5和R6的优选取代基为氢和任选取代的苯基。优选的取代的苯基是那些被低级烷基(特别是甲基)或卤素(例如氯或氟)所取代的苯基。特别优选的取代苯基包括邻甲苯基、间甲苯基、对甲苯基、对氟代苯基和对氯代苯基。
式I的另一组优选的化合物为那些其中所述取代基R3、R4、R5和R6中的两个一起形成任选取代的5-12元碳环或杂环的化合物。
由所述取代基R3、R4、R5和R6中的两个与它们连接的碳原子形成的环优选为5-7元单环或与其它环稠合而成的环(即环系统)。所述5-7元环可与所述噁二嗪环按顺式或反式稠合,也可以螺环或稠合环形式缩合。所述环可为杂环或碳环,并且该环可为饱和环或可为包括双键的环。该环或环系统可为非取代环或取代环,其中所述取代基可为烷基,优选甲基。优选所述环为饱和碳环。适合的环包括环戊烷、环己烷、4-甲基-环己烷、环庚烷或包括在金刚烷环系统中的环。
当所述取代基R3、R4、R5和R6中的两个形成环时,则优选剩余两个取代基为氢。
另一组优选的化合物为那些式I中R2和R3一起形成任选取代的杂环的那些化合物。
优选由所述取代基R2和R3形成的杂环为5-6元含氮饱和环。所述环可为非取代或取代环。根据一个优选的实施方案,所述取代基为烷基。根据另一个实施方案,该5-6元含氮环可与另一个环缩合形成1,2,3,4-四氢喹啉、1,2,3,4-四氢异喹啉或2,3-二氢吲哚结构。可提及的特别优选的实施方案为哌啶、1,2,3,4-四氢异喹啉和6,7-二甲氧基-1,2,3,4-四氢-异喹啉。
当R2和R3一起形成杂环时,则R4优选为氢。
优选的化合物还包括式I中R7和R8(可相同或不同)为C1-C4烷基,或C6-C10芳基(C1-C4)烷基的那些化合物。R7和R8优选为C1-C4烷基,特别是甲基和乙基。
在式I的另一组优选的化合物中,R7和R8与它们连接的碳原子一起形成任选取代的5-12元碳环或杂环。所述5-12元环可为饱和或不饱和的碳环或杂环,并且所述环可为非取代或取代的环。所述取代基可为烷基、芳烷基或取代的芳烷基。特别优选的取代基为苄基。优选为饱和环。特别优选的螺缩合环为N-苄基哌啶。
一种优选的化合物的亚属,或其互变异构体、异构体、或其药学上可接受的溶剂合物、水合物或盐具有式Ia的结构:其中:
R12为氢、C1-C4烷基或苯基(C1-C3)烷基;
R13为氢、C1-C4烷基或苯基;或
R15为氢或C1-C4烷基;
R13和R15与它们相连的碳原子一起形成5-7元环烷基;
R14和R16独立为氢或C1-C4烷基;和
R17为C1-C4烷基,并且R18为C1-C4烷基,或R17和R18与它们相连的碳原子一起形成5或6元饱和环,其任选包括一个环上的氮(NR19),其中R19为氢、C1-C4烷基或苯基(C1-C3)烷基。
R22为氢、C1-C4烷基或苄基,优选为甲基或苄基;
R23为氢或C1-C4烷基,优选为氢或甲基;
R24为氢或C1-C4烷基;
R25为氢、C1-C4烷基或苯基,优选为氢或苯基;
R26为氢或C1-C4烷基;
R27为C1-C4烷基;
R28为C1-C4烷基;和
X为共价键、-CH2-或-NR19-,其中R19为氢、C1-C4烷基或苄基。
用于本发明的化合物的实例包括:
9-苄基-2-甲基-5-氧杂-1,2,9-三氮杂螺[5.5]十一烷;
9-苄基-2-甲基-4-苯基-5-氧杂-1,2,9-三氮杂螺[5.5]十一烷;
(3S,4R)-9-苄基-2,3-二甲基-4-苯基-5-氧杂-1,2,9-三氮杂螺[5.5]十一烷;
(3R,4S)-2,3-二甲基-4-苯基-5-氧杂-1,2-二氮杂螺[5.5]十一烷;
(4aR*,8aS*)-4-甲基-2,2-五亚甲基-3,4,4a,5,6,7,8,8a-八氢-2H-1,3,4-苯并噁二嗪;
(4aR*,8aR*)-2,2,4-三甲基-3,4,4a,5,6,7,8,8a-八氢-2H-1,3,4-苯并噁二嗪;
(4aR*,8aR*)-4-苄基-2-乙基-2-甲基-3,4,4a,5,6,7,8,8a-八氢-2H-1,3,4-苯并噁二嗪;和
2,2-二甲基-1,2,4a,5-四氢-4H,10H-1,3,4-噁二嗪并[4,5-b]异喹啉;及其药学上可接受的盐,例如包括盐酸盐或二盐酸盐。
此处所用术语“烷基”本身或作为另一种基团的一部分是指最多含有12个碳原子的直链和支链基团,如甲基、乙基、丙基、异丙基、丁基、叔丁基、仲丁基、戊基、己基、异己基、庚基、4,4-二甲基戊基、辛基、2,2,4-三甲基戊基、壬基、癸基、十一烷基、十二烷基。例如,C1-C4烷基为直链烷基或支链烷基,因此可包括甲基、乙基、正丙基、异丙基、正丁基、仲丁基、叔丁基和异丁基。
用于本文的术语“链烯基”是指含有2-20个碳原子(链长有限定的除外)的直链或支链基团,包括(但不限于)乙烯基、1-丙烯基、2-丙烯基、2-甲基-1-丙烯基、1-丁烯基、2-丁烯基等。优选所述链烯基链长为2-10个碳原子、更优选为2-8个碳原子、最优选为2-4个碳原子。
用于本文的术语“芳基”本身或作为另一种基团的一部分是指在环部位含有6-12个碳原子、优选6-10个碳原子的单环或双环芳基,如苯基、萘基或四氢萘基。
用于本文的术语“芳烷基”应解释为与烷基相连的任何芳基,该烷基为1-6个碳原子链且既可为直链也可支链基团。所述链优选含1-3个碳原子。优选的芳基为取代或非取代的苯基。优选的取代基为低级烷基(即C1-C4烷基,特别是甲基),或卤素。可提及的特别优选的实施方案有苄基、对甲基苄基、对氯代苄基、2-苯基乙基和3-苯基丙基。
用于本文的术语“烷酰基”是指与上述任何烷基连接的羰基部分。例如术语“C2-C6烷酰基”包括但不限于乙酰基、丙酰基、丁酰基、2-甲基丙酰基、戊酰基、己酰基。
用于本文的术语“链烯酰基”是指与上述任何链烯基连接的羰基部分。例如术语“C2-C6链烯酰基”包括但不限于乙烯酰基、1-丙烯酰基、2-丙烯酰基、2-甲基-1-丙烯酰基、1-丁烯酰基、2-丁烯酰基等。优选所述链烯基链长为2-10个碳原子、更优选为2-6个碳原子。
用于本文的术语“碳环”本身或作为另一种基团的一部分是指如上述的在环部位含有6-12个碳原子的单环或双环芳基或环系统,或指任何3-至9-元单碳环系统或7-至10-元双碳环系统,这些环中任一种可为饱和或不饱和的。典型的例子包括苯基、萘基和环己基。
本文所用的术语“杂环”表示稳定的5-7元单或双环或稳定的7-12元双环杂环系统,这些环中的任一环可为饱和或不饱和,且它由碳原子和1-3个选自N、O和S的杂原子组成,其中的氮和硫杂原子可任选被氧化,所述氮杂原子可任选被季铵化,并包括其中任何上述杂环稠合成一个苯环的任何双环基团。特别有用的是含1个氧或硫、1-3个氮原子,或与1或2个氮原子相连的1个氧或硫的环。所述杂环可在任何使结构稳定的杂原子或碳原子上成键。这类杂环基的实例包括哌啶基、哌嗪基、N-苄基哌啶基、2-氧代哌嗪基、2-氧代哌啶基、2-氧代吡咯烷基(2-oxopyrrolodinyl)、2-氧代氮杂䓬基、氮杂䓬基、吡咯基、4-哌啶酮基、吡咯烷基、吡唑基、吡唑烷基、咪唑基、咪唑啉基、咪唑烷基、吡啶基、吡嗪基、嘧啶基、哒嗪基、噁唑基、噁唑烷基、异噁唑基、异噁唑烷基、吗啉基、噻唑基、噻唑烷基、异噻唑基、奎宁环基、异噻唑烷基、吲哚基、喹啉基、异喹啉基、苯并二氢吡喃基、苯并咪唑基、噻二唑基、苯并吡喃基、苯并噻唑基、苯并[b]噻吩基、苯并[2,3-c]1,2,5-噁二唑基、苯并噁唑基、呋喃基、四氢呋喃基、四氢吡喃基、噻吩基、苯并噻吩基、硫代吗啉基、硫代吗啉基亚砜、硫代吗啉基砜和噁二唑基。这里吗啉代与吗啉基相同。
用于本文的术语“杂芳基”指含有5-14个环原子的基团;6、10或14B电子分布在环上;并含碳原子和1、2或3个氧、氮或硫杂原子(杂芳基实例有:噻吩基、苯并[b]噻吩基、萘并[2,3-b]噻吩基、噻蒽基、呋喃基、吡喃基、异苯并呋喃基、苯并噁唑基、苯并吡喃基、呫吨基、氧硫杂蒽基(phenoxathiinyl)、2H-吡咯基、吡咯基、咪唑基、吡唑基、吡啶基、吡嗪基、嘧啶基、哒嗪基、中氮茚基、异吲哚基、3H-吲哚基、吲哚基、吲唑基、嘌呤基、4H-喹嗪基、异喹啉基、喹啉基、2,3-二氮杂萘基、1,5-二氮杂萘基、喹唑啉基、噌啉基、蝶啶基、4αH-咔唑基、咔唑基、β-咔啉基、菲啶基、吖啶基、啶基、菲咯啉基、吩嗪基、异噻唑基、吩噻嗪基、异噁唑基、呋咱基和吩噁嗪基)。
用于本文的术语“卤素”或“卤代基”本身或作为另一基团的一部分指氯、溴、氟或碘,优选氯。
除非本文中另有说明,否则术语“取代基”指一个或多个独立地选自卤代基、卤代(C1-C6)烷基、芳(C1-6)烷基、芳基、硝基、C1-6烷氧基和C1-6烷基的基团,条件是所生成的化合物稳定。优选的任选取代基包括:卤代基、芳(C1-6)烷基、芳基和C1-6烷基。
用于本文的术语“环烷基”本身或作为其它基团的一部分指含3-9个碳原子的环烷基。典型实例有环丙基、环丁基、环戊基、环己基、环庚基、环辛基和环壬基。
用于本文的术语“羟基烷基”是指被一个或多个羟基取代的上述任何一种烷基。
用于本文的术语“羧基烷基”是指被一个或多个羧酸部分取代的上述任何一种烷基。
用于本文的术语“卤代烷基”指被一或多个氯、溴、氟或碘,优选氟和氯所取代的任何上述烷基,例如氯甲基、碘甲基、三氟甲基、2,2,2-三氟乙基和2-氯乙基。
用于本文的术语“卤代烷氧基”是指与氧原子键合的上述任何一种卤代烷基,如三氟甲氧基、三氯甲氧基等。
用于本文的术语“烷氧基”是指与氧原子键合的含有1-20个碳原子(链长有限定的除外)的直链或支链基团,包括但不限于甲氧基、乙氧基、正丙氧基、异丙氧基等。优选所述烷氧基链的长度为1-10个碳原子、更优选1-8个碳原子。
本发明的各种化合物通常以它们各自的互变异构体形式的平衡状态存在。例如,式I的化合物可以以环(Id)和链(Ie)互变异构体的混合物的溶液存在:其中R1-R8如上定义。应理解式I化合物的所有互变异构体形式及其所有可能的混合物均包括在本发明的范围内。
有证据表明与VAP-1结合并抑制其SSAO活性的是所公开化合物的肼基醇形式。因此,还应理解:当将所公开的化合物的这种肼基醇降解产物用于抑制VAP-1SSAO活性并用于治疗此处描述的由各种VAP-1介导的疾病和症状时,所述降解产物包括在式I化合物的范围内。
本文所公开的部分化合物可含一或多个不对称中心,并因此产生对映异构体、非对映异构体和其它立体异构形式。本发明还包括外消旋混合物、其拆分形式及其混合物,以及可根据本领域技术人员所熟知的方法分离出的单一的对映体。除非另有说明,否则当本文所述化合物含烯属双键或其它几何不对称中心时,将包括E和Z几何异构体。
用于本文的术语“立体异构体”是对仅在其原子的空间取向上有所区别的单个分子的所有异构体的总称。立体异构体包括对映异构体和具有多于一个彼此间不互为镜象的手性中心的化合物的异构体(非对映异构体)。
术语“不对称中心”或“手性中心”指连接有四个不同基团的碳原子。
术语“对映异构体”或“对映异构的”指镜象不能重叠的分子,并因而有光学活性的分子,其中该对映体以一个方向旋转偏振光面,而它的镜象以相反方向旋转偏振光面。
术语“外消旋的”指等量对映异构体的混合物,因此不具光学活性。
术语“拆分”指对一种分子的两种对映异构体形式中的一种的分离、浓缩或消耗。短语“对映体过量”指其中存在的一种对映体的浓度远大于其镜象分子的浓度的混合物。
当任何组成或式I发生不止一次的任意变化时,对每种情况的定义与每次其它情况的定义彼此独立。另外只要取代基的组合和/或变化产生稳定的化合物,则是允许的。
本发明的另一方面涉及制备式I化合物的方法。可通过下列路线中的一种制备本发明的化合物。
以肼基醇II为原料,使用酮IV或酮的等价物,如缩醛V(优选R9为甲基或乙基)作为缩合试剂合成式I的化合物。
在20-120℃,采用或不用酸性或碱性催化剂,或水吸附剂下实施缩合反应。“酸性催化剂”的示例性例子有氢氯酸、对甲苯磺酸、乙酸、酒石酸和草酸。“酸性催化剂”还可包括任何适合于非水催化剂的强酸性树脂离子交换树脂,如Amberlist®15。“碱性催化剂”的示例性例子有三乙胺。术语“水吸附剂”包括无水硫酸镁、硅胶和分子筛4Å。
合成化合物I的另一方法使用氨基醇III和氧杂吖丙啶VI(Schmitz,E.,等,Liebigs Ann.Chem.:1043-1046(1983))。
肼基醇II是文献中已知的,或可根据以下文献提供的方法,以氨基醇前体III为原料制备(Taguchi,T.等人,J.Org.Chem.29:1097-1103(1964);Takahashi,H.等人,Chem.Pharm.Bull.39:836-842(1991);Shen,J.K.等人,J.Chem.Soc.,PerkinTrans.1:2087-2097(1993);Rosling,A.等人,Heterocycles 45:95-106(1997);Rosling,A.等人,J.Chem.Res.(s):492(1998);J.Chem.Res.(M):2237-2250(1998))。在R3≠R4和R5≠R6时,肼基醇II以单一的非对映异构体使用。化合物I的对映异构体的合成以对映异构体纯的肼基醇II为原料,该化合物II为文献中已知的化合物,或可根据以下文献提供的方法制备(Trepanier,D.L.等人,J.Org.Chem.29:668-672(1964))。在没有发生外消旋的情况下进行缩合反应。对映异构体纯的产物I也可以通过标准的对映异构体分离技术,由I的外消旋体制备。
对于其中R7≠R8和R3≠R4或R5≠R6的化合物I,可能存在几何异构现象。如需要,可通过标准有机分离方法分离缩合中形成的非对映异构体。
本发明化合物以酸式加成盐的形式使用。“药学上可接受的酸加成盐”是指式I的碱性化合物的任何无毒的有机和无机酸式加成盐。形成适用盐的示例性无机酸包括氢氯酸、氢溴酸、硫酸和磷酸。形成适用盐的示例性有机酸包括乙酸、乳酸、丙二酸、琥珀酸、戊二酸、富马酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、马来酸、苯甲酸、苯乙酸、肉桂酸和水杨酸。
化合物I在溶液中以环(Id)和链(Ie)互变异构体的混合物形式存在。该平衡强烈依赖于取代基和所用的溶剂(Dorman,L.C.,J.Org.Chem.29:255-260(1967);Potekhin,A.A.和Zaitsev,B.D.,Chem.Heterocyclic Compounds 7:277-301(1971);Potekhin,A.A.和Bogankova,E.A.,Chem.Heterocyclic Compounds9:1321-1461(1973);Valters R.E.等人,Adv.Hetercyclic Chem.66:1-71(1996))。另一方面,I的盐酸盐晶体以环形式独立存在,这由固态NMR图谱证明。
本发明提供一种通过选择性抑制VAP-1SSAO活性来治疗VAP-1介导的疾病的方法,所述方法包括向有需要的动物给服治疗有效量的选自式I所表示的类别的化合物,其中将式I的一种或多种化合物与一种或多种无毒的药学上可接受的载体和/或稀释剂和/或辅剂及其它活性成分(如需要)一起给药。
本发明的化合物可用于治疗炎性症状和疾病,其包括但不限于结缔组织的炎性症状和疾病,例如关节强硬性脊椎炎、Reiter氏综合征、银屑病关节炎、骨关节炎或变性关节病、类风湿性关节炎、Sjögren氏综合征、BehCet氏综合征、复发性多软骨炎、系统性红斑狼疮、盘状红斑狼疮、系统性硬化病、嗜酸性细胞增多性肌膜炎、多发性肌炎和皮肌炎、风湿性多肌痛、脉管炎、颞动脉炎、结节性多动脉炎、Wegener氏肉芽肿病、混合性结缔组织病和幼年型类风湿关节炎;胃肠道炎性症状和疾病,例如Crohn氏病、溃疡性结肠炎、肠易激惹综合征(痉挛性结肠)、肝纤维变性症、口腔粘膜炎(口炎)和复发性阿弗他口腔炎;中枢神经系统炎性症状和疾病,例如多发性硬化、早老性痴呆和与缺血休克有关的缺血-再灌注损伤;肺炎症状和疾病,例如哮喘、慢性阻塞性肺疾病和成人呼吸窘迫综合征;和皮肤炎性症状和疾病,例如接触性皮炎、特应性皮炎、银屑病、玫瑰糠疹、扁平苔癣和毛发红糠疹。
另外,本发明化合物可用来治疗与碳水合物代谢有关的疾病及其并发症,例如糖尿病和糖尿病并发症,包括但不限于微脉管症和大脉管症,例如动脉粥样硬化、血管视网膜病、视网膜病、肾病和肾病综合征;神经病,例如多发性神经病、单神经病、植物神经病,足溃疡、关节病和高风险感染;与脂肪细胞分化或功能的畸变相关或由其引起的疾病,例如动脉粥样硬化和肥胖症;以及血管病,例如粉瘤和非粉瘤性动脉硬化,局部缺血心脏病,包括心肌梗死、末梢aterial阻塞、闭塞性血栓性血管炎(Buerger病)及Raynaud氏病和症状。
具体说来,本发明化合物可用于治疗动脉粥样硬化。已知VAP-1在脂肪细胞、平滑肌细胞、内皮细胞中表达,并与炎症相关。动脉粥样硬化斑由蓄积的细胞间和细胞外脂质、平滑肌细胞、结缔组织和葡糖胺聚糖构成。动脉硬化的最早观测到的损害是产生了脂肪条纹(由装脂泡沫细胞构成,它是随单核白细胞的循环而迁移进入内膜的内皮下层的巨噬细胞),它后来参与形成了纤维斑(由结缔组织包围的内膜平滑肌细胞、细胞间和细胞外脂质构成)。
术语“治疗炎症”是指为预防、缓解、控制或治疗炎性症状或疾病,而给有需要的患者服用本发明化合物,这种治疗不必完全缓解炎性症状或疾病。而且,这种治疗可与其它本领域技术人员所知的减轻炎症常规疗法相结合。
可将本发明化合物在约0.1μg/kg-300mg/kg,优选0.1μg/kg-10mg/kg体重的有效范围内进行给药。可将本发明化合物以一次日剂量给药,或将总日剂量以每日两、三或四次的分剂量进行给药。
可将本发明的药用组合物给予可获得本发明化合物的有益效果的任何动物。所述动物主要指人,但本发明并不受其限定。
可将本发明的药用组合物以任何可达到所需目的的方式进行给药。例如,可经胃肠外、皮下、静脉内、肌内、腹膜内或真皮内注射给药,或者经皮、口腔或经眼给药。另外或者可同时,可经口服途径给药。特别优选口服给药。给药量取决于受体的年龄、病况、体重、结合治疗的药物种类(如果有)、治疗次数、所需效果的性质。
除所述药理学活性化合物外,所述化合物的药用制剂可含适用的药学上可接受的载体,这些载体包括促进活性化合物形成可药用的制剂的赋形剂和辅剂。本发明的药用制剂可通过已知的方法,例如通过常规的混合、制粒、制糖锭剂、溶解或冻干方法制备。因此,可通过将所述活性化合物与固体赋形剂相混合,如需要或必要在加入适用辅剂后,任选研磨所生成的混合物并将所述颗粒混合物加工得到片剂或糖锭芯,来制备所述口服药用制剂。
适用的赋形剂具体有填充剂,例如糖类例如乳糖或蔗糖、甘露糖醇或山梨糖醇、纤维素制剂和/或磷酸钙,如磷酸三钙或磷酸氢钙;粘合剂,例如淀粉糊,例如用玉米淀粉、小麦淀粉、大米淀粉、马铃薯淀粉、明胶、西黄蓍胶、甲基纤维素、羟丙基甲基纤维素、羧甲基纤维素钠和/或聚乙烯吡咯烷酮。如需要,可加入崩解剂,例如上述淀粉和羧甲基淀粉、交联聚乙烯吡咯烷酮、琼脂或藻酸或其盐(例如藻酸钠)。辅剂有上述所有试剂、流动调节剂和润滑剂,例如硅胶、滑石、硬脂酸或其盐(例如硬脂酸镁或硬脂酸钙)和/或聚乙二醇。如需要,可将糖锭芯适当包衣以抵抗胃液。为此目的,可采用浓缩糖类溶液,它可任选含有阿拉伯胶、滑石、聚乙烯吡咯烷酮、聚乙二醇和/或二氧化钛、漆液和适用的有机溶剂或溶剂混合物。为制备抵抗胃液的包衣,采用适用的纤维素制剂溶液,例如乙酰纤维素邻苯二甲酸酯或羟丙基甲基纤维素邻苯二甲酸酯。例如,可将染料或颜料加入片剂或糖锭剂包衣中,以区别或以对活性化合物药剂的组合作出鉴别。
其它可用于口服的药用制剂包括由明胶制成的推入配合胶囊,和由明胶和增塑剂例如甘油或山梨糖醇制成的软密封胶囊。所述推入配合胶囊可含颗粒状的活性化合物,该化合物可与填充剂(例如乳糖)、粘合剂(例如淀粉)和/或润滑剂(例如滑石或硬脂酸镁)和任选的稳定剂相混合。在软胶囊中,优选将所述活性化合物溶于或悬浮于适当的液体例如脂肪油或液体石蜡中。另外还可加入稳定剂。
适用于胃肠外给药的制剂包括水溶形式的活性化合物的水溶液,例如水溶性盐和碱性溶液。特别优选的碱性盐为由例如采用Tris、氢氧化胆碱、双-Tris丙烷、N-甲基葡糖胺或精氨酸制备的铵盐。另外,所述活性化合物的悬浮液以适当的油性注射悬浮液形式进行给药。适用的亲油溶剂或溶媒包括脂肪油,例如芝麻油或合成脂肪酸酯,例如油酸乙酯或甘油三酯或聚乙二醇-400(所述化合物可溶于PEG-400)。水性注射混悬液可含有提高所述悬浮液粘度的物质,例如羧甲基纤维素钠、山梨糖醇和/或葡聚糖。所述混悬液也可任选含有稳定剂。
下列实施例是对本发明的方法和组合物的举例说明,但并不对其作出限定。在本发明的精神和范围内,通常可对本发明的各种条件和参数作出适当的变化和调整,这对本领域的技术人员而言将是显而易见的。
实施例19-苄基-2-甲基-5-氧杂-1,2,9-三氮杂螺[5.5]十一烷二盐酸盐
使用以下三种合成方法中的一种合成题述化合物。
方法1a:往2-(N1-甲基肼基)乙醇(0.30g,3.3mmol)的无水甲苯(10ml)溶液中加入1-苄基哌啶-4-酮(0.63g,3.3mmol),将所得的反应混合液在室温下静置24小时。从分离出的水层上倾析出甲苯溶液,并蒸发至干燥。加入无水甲苯(10ml),然后重复蒸发操作。将所得的浅黄色油状物溶解在乙醇(2ml)中,通过使用含22%氯化氢的乙醇(1ml)和乙醚将其转化为结晶的二盐酸盐。过滤出晶体,并从乙醇/乙醚中重结晶。13C-NMR(500MHz,固态):δ26.61(宽峰),33.81,44.1,52.2,57.93,83.44(C-2),128.42,130.0,133.04。
方法1b:往2-(N1-甲基肼基)乙醇(0.30g,3.3mmol)的无水甲苯(10ml)溶液中加入1-苄基哌啶-4-酮(0.63g,3.3mmol)。将所得的反应混合物回流5小时,随后蒸发至干燥。加入无水甲苯(10ml),然后重复蒸发操作。将所得的浅黄色油状物溶解在乙醇(2ml)中,通过使用含22%氯化氢的乙醇(1ml)和乙醚将其转化为结晶的二盐酸盐。过滤出晶体,并从乙醇/乙醚中重结晶。13C-NMR:参见方法1a。
方法1c:往2-(N1-甲基肼基)乙醇(0.30g,3.3mmol)的无水甲苯(10ml)溶液中加入1-苄基哌啶-4-酮(0.63g,3.3mmol)。将所得的反应混合物在Dean-Stark(迪安-斯达克塌)装置中回流5小时,随后蒸发至干燥。将所得的油状残余物溶解在乙醇(2ml)中,通过使用含22%氯化氢的乙醇(1ml)和乙醚将其转化为结晶的二盐酸盐。过滤出晶体,并从乙醇/乙醚中重结晶。13C-NMR:参见方法1a。
实施例29-苄基-2-甲基-4-苯基-5-氧杂-1,2,9-三氮杂螺[5.5]十一烷二盐酸盐
使用以下两种合成方法中的一种合成题述化合物。
方法2a:往2-(N1-甲基肼基)-1-苯基乙醇(0.50g,3mmol)的无水甲苯(25ml)溶液中加入1-苄基哌啶-4-酮(0.57g,3mmol),以及催化量(1滴)的冰醋酸。将所得的反应混合液在室温下静置24小时,随后蒸发至干燥。加入无水甲苯(10ml),然后重复蒸发操作。将所得的浅黄色油状物溶解在乙醇(2ml)中,通过使用含22%氯化氢的乙醇(1ml)和乙醚将其转化为结晶的二盐酸盐。过滤出晶体,并从乙醇/乙醚中重结晶。13C-NMR(500MHz,固态):δ26.61(宽峰),33.81,44.1,52.2,57.93,83.44(C-2),128.42,130.0,133.04。
方法2b:往2-(N1-甲基肼基)-1-苯基乙醇(0.50g,3mmol)的无水甲苯(25ml)溶液中加入1-苄基哌啶-4-酮(0.57g,3mmol),以及催化量(1滴)的三乙胺。将所得的反应混合液在室温下静置24小时,随后蒸发至干燥。加入无水甲苯(10ml),然后重复蒸发操作。将所得的浅黄色油状物溶解在乙醇(2ml)中,通过使用含22%氯化氢的乙醇(1ml)和乙醚将其转化为结晶的二盐酸盐。过滤出晶体,并从乙醇/乙醚中重结晶。13C-NMR:参见方法2a。
实施例3(3S,4R)-9-苄基-2,3-二甲基-4-苯基-5-氧杂-1,2,9-三氮杂螺[5.5]十一烷二盐酸盐
使用以下两种合成方法中的一种合成题述化合物。
方法3a:往(1R,2S)-N-氨基麻黄碱(0.30g,1.7mmol)的无水苯(30ml)溶液中加入1-苄基哌啶-4-酮(0.31g,1.6mmol)。将所得的反应混合液在室温下静置6小时,随后蒸发至干燥。将所得的残余物溶解在5ml含22%氯化氢的乙醇中,几分钟后将所得溶液蒸发至干燥,将残余物从乙醇/乙醚混合物中重结晶。13C-NMR(500MHz,固态):δ4.97,28.42,41.01,46.9,49.5,59.57,71.69,83.87(C-2),129.67。
方法3b:往(1R,2S)-N-氨基麻黄碱(0.30g,1.7mmol)的无水苯(30ml)溶液中加入1-苄基哌啶-4-酮(0.31g,1.6mmol),随后加入几滴含22%氯化氢的乙醇。将所得的反应混合液在室温下静置6小时,随后蒸发至干燥。将所得的残余物溶解在5ml含22%氯化氢的乙醇中,几分钟后将所得溶液蒸发至干燥,将残余物从乙醇/乙醚混合物中重结晶。13C-NMR:参见方法3a。
实施例4(3R,4S)-2,3-二甲基-4-苯基-5-氧杂-1,2-二氮杂螺[5.5]十一烷盐酸盐
使用以下四种合成方法中的一种合成题述化合物。
方法4a:往(1S,2R)-N-氨基麻黄碱(0.30g,1.7mmol)的无水苯(40ml)溶液中加入环己酮(0.83g,8.5mmol)。将所得的反应混合液在室温下静置6小时,随后蒸发至干燥。将所得的残余物溶解在5ml含22%氯化氢的乙醇中,几分钟后将所得溶液蒸发至干燥,将所得半固体残余物从乙醇/乙醚混合物中重结晶。13C-NMR(500MHz,固态):δ4.28,24.0(宽峰),38.25,45.05,58.98,70.53,87.5(C-2),129.67。
方法4b:往(1S,2R)-N-氨基麻黄碱(0.30g,1.7mmol)的无水苯(40ml)溶液中,加入环己酮(0.83g,8.5mmol)和催化量(一些晶体)的对甲苯磺酸。将所得的反应混合液在室温下静置6小时,随后蒸发至干燥。将所得的残余物溶解在5ml含22%氯化氢的乙醇中,几分钟后,将所得溶液蒸发至干燥,将所得半固体残余物从乙醇/乙醚混合物中重结晶。13C-NMR参见方法4a。
方法4c:往(1S,2R)-N-氨基麻黄碱(0.30g,1.7mmol)的无水苯(40ml)溶液中加入环己酮(0.83g,8.5mmol)和Amberlist®15离子交换树脂(0.1g)。将所得的反应混合液在室温下搅拌5小时,过滤出所述离子交换树脂,将滤液蒸发至干燥。将所得的残余物溶解在5ml含22%氯化氢的乙醇中,几分钟后将所得溶液蒸发至干燥,将所得半固体残余物从乙醇/乙醚混合物中重结晶。13C-NMR参见方法4a。
方法4d:往(1S,2R)-N-氨基麻黄碱(0.30g,1.7mmol)的无水二氯甲烷(25ml)溶液中加入环己酮(0.83g,8.5mmol)和无水硫酸镁(5g)。将所得的反应混合液在室温下搅拌10小时,过滤出硫酸镁,将滤液蒸发至干燥。将所得的残余物溶解在5ml含22%氯化氢的乙醇中,几分钟后将所得溶液蒸发至干燥,将所得半固体残余物从乙醇/乙醚混合物中重结晶。13C-NMR参见方法4a。
实施例5(4aR*,8aS*)-4-甲基-2,2-五亚甲基-3,4,4a,5,6,7,8,8a-八氢-2H-1,3,4-苯并噁二嗪盐酸盐
使用以下三种合成方法中的一种合成题述化合物。
方法5a:往1-氧杂-2-氮杂螺[2.5]辛烷(0.60g,5.3mmol)的乙醚(20ml)溶液中加入顺-2-(甲氨基)环己醇(0.68g,5.3mmol)的乙醚(5ml)溶液。将所得的反应混合液在室温下搅拌30分钟,随后蒸发至干燥。将所得的残余物溶解在5ml含22%氯化氢的乙醇中,几分钟后将所得溶液蒸发至干燥,将所得半固体残余物从乙醇/乙醚混合物中重结晶。13C-NMR(500MHz,固态):δ24.01(宽峰),42.6,60.1,65.9,86.86(C-2)。
方法5b:往顺-2-(N1-甲基肼基)环己醇(0.43g,3mmol)的无水苯(40ml)溶液中加入环己酮(1.47g,15mmol)和分子筛4Å(8g)。将所得的反应混合液在室温下搅拌10小时,随后过滤出分子筛,将滤液蒸发至干燥。将所得的残余物溶解在5ml含22%氯化氢的乙醇中,几分钟后将所得溶液蒸发至干燥,将所得半固体残余物从乙醇/乙醚混合物中重结晶。13C-NMR参见方法5a。
方法5c:往顺-2-(N1-甲基肼基)环己醇(0.43g,3mmol)的无水甲苯(40ml)溶液中加入环己酮(1.47g,15mmol)和硅胶(0.035-0.07mm,2g)。将所得的反应混合液在室温下搅拌8小时,随后过滤出硅胶,将滤液蒸发至干燥。将所得的残余物溶解在5ml含22%氯化氢的乙醇中,几分钟后将所得溶液蒸发至干燥,将所得半固体残余物从乙醇/乙醚混合物中重结晶。13C-NMR参见方法5a。
实施例6(4aR*,8aR*)-2,2,4-三甲基-3,4,4a,5,6,7,8,8a-八氢-2H-1,3,4-苯并噁二嗪盐酸盐
使用以下两种合成方法中的一种合成题述化合物。
方法6a:使反-2-(N1-甲基肼基)环己醇(0.35g,2.4mmol)的无水丙酮(40ml)溶液在室温下静置6小时。随后将所得溶液蒸发至干燥,加入5ml含22%氯化氢的乙醇。几分钟后将所得溶液蒸发至干燥,将所得残余物从乙醇/乙醚混合物中重结晶。13C-NMR(500MHz,固态):δ21.2,25.2,27.6,31.5,42.3,68.5,74.3,88.46(C-2)。
方法6b:使反-2-(N1-甲基肼基)环己醇(0.35g,2.4mmol)在无水丙酮(40ml)和催化量的含22%氯化氢的乙醇(1滴)的混合物的溶液在室温下静置72小时。随后将所得溶液蒸发至干燥,将所得残余物从甲醇/乙醚混合物中重结晶。13C-NMR:参见方法6a。
实施例7(4aR*,8aR*)-4-苄基-2-乙基-2-甲基-3,4,4a,5,6,7,8,8a-八氢-2H-1,3,4-苯并噁二嗪盐酸盐
方法7a:往反-2-(N1-甲基肼基)环己醇(0.66g,3mmol)的2-丁酮(25ml)溶液中加入催化量的草酸。将所得的反应混合液在室温下静置24小时,随后蒸发至干燥。将浅黄色的油状产物溶解在甲醇(2ml)中,通过使用含22%氯化氢的乙醇(1ml)和乙醚将所述产物转化为结晶的二盐酸盐。过滤出晶体并从甲醇/乙醚中重结晶。13C-NMR(500MHz,固态):δ7.98,16.9,23.4,26.2,30.1,59.9,67.2,90.49(C-2),128.1,139.3。
实施例82,2-二甲基-1,2,4a,5-四氢-4H,10H-1,3,4-噁二嗪并[4,5-b]异喹啉盐酸盐
使用以下三种合成方法中的一种合成题述化合物。
方法8a:往2-氨基-1,2,3,4-四氢异喹啉-3-甲醇(0.53g,3mmol)的2,2-二甲氧基丙烷(25ml)溶液中加入催化量的对甲苯磺酸。将所得的反应混合液在室温下静置24小时,随后蒸发至干燥。将浅黄色的油状产物溶解在甲醇(2ml)中,通过使用含22%氯化氢的乙醇(1ml)和乙醚将所述产物转化为结晶的二盐酸盐。过滤出晶体并从甲醇/乙醚中重结晶。13C-NMR(500MHz,固态):δ15.1,20.7,27.8,56.14,63.0,89.90(C-2),127.4,130.1。
方法8b:往2-氨基-1,2,3,4-四氢异喹啉-3-甲醇(0.53g,3mmol)的无水丙酮(25ml)溶液中加入催化量的L-酒石酸(少量晶体)。将所得的反应混合液在室温下静置24小时,随后蒸发至干燥。将浅黄色的油状产物溶解在甲醇(2ml)中,通过使用含22%氯化氢的乙醇(1ml)和乙醚,将所述产物转化为结晶的二盐酸盐。过滤出晶体,并从甲醇/乙醚中重结晶。13C-NMR:参见方法8a。
方法8c:将2-氨基-1,2,3,4-四氢异喹啉-3-甲醇盐酸盐(0.64g,3mmol)悬浮在无水丙酮(40ml)。将所得的反应混合液在室温下搅拌36小时,随后蒸发至干燥。在采用甲醇/乙醚处理过程中所述半固体残余物发生结晶。过滤出晶体,并从甲醇/乙醚中重结晶。13C-NMR:参见方法8a。
实施例9反2-[1-甲基-2-(4-吡啶基亚甲基)肼基]-1-环己醇
往反2-(1-甲基肼基)-1-环己醇(0.43g,3mmol)的无水甲醇(15ml)溶液中加入4-吡啶甲醛(0.33g,3mmol)。将所得的反应混合液在室温下静置2小时,随后真空蒸发。在用正己烷和乙醚的混合物处理所得的油状残余物时发生结晶。过滤出析出的晶体,并从二异丙醚和乙酸乙酯的混合物中重结晶。物理数据在表3中给出。1H NMR(400MHz,CDCl3)δ1.20-1.45(4H,om,(CH2)4),1.77(2H,m,(CH2)4),1.86(1H,m(CH2)4),2.14(1H,m(CH2)4),2.99(3H,s,NCH3),3.10(2H,m,NCH),3.96(1H,m,OCH),7.06(1H,s,N=CH),7.36(m,2H,C5H4N),8.47(M,2H,C5H4N).13C NMR(100.6MHz,CDCl3)δ24.7,25.4,29.2,33.9,36.8,71.6,73.7,119.9(N=C),127.2,150.2.表1.合成的外消旋化合物的物理参数 表2.合成的对映异构体化合物的物理参数表3
实施例10VAP-1SSAO活性的体外抑制作用
基本如文献所述,用所述配对比色法(coupled colourimetric method)测定VAP-1SSAO对单胺氧化酶和相关酶的活性(Holt,A,等,Anal.BioChem.244:384-392(1997))。将表达于中国仓鼠卵巢(CHO)细胞的重组人体VAP-1SSAO用作活性测定的VAP-1SSAO的来源。天然CHO细胞的SSAO活性很小。这些细胞及其培养现有技术已有描述(Smith,D.J.,等,J.Exp.Med.188:17-27(1998))。通过将约3.6×108个细胞悬浮在25ml溶胞缓冲液(150mM NaCl、10mM Tris-Base pH7.2,1.5mM MgCl2,1%NP40,1%抑肽酶和1mM的PMSF)中,并在旋转台上于4℃下培养过夜,制备细胞裂解液。在4℃下经21200g离心该裂解液30分钟,使其澄清,其上清液直接用于本测试。如下所述,在96孔微量滴定板中进行所述VAP-1SSAO测试。如需要,向每一孔中加入预定量的抑制剂。各测试中抑制剂的量不同,但总的来说,其终浓度在10nM-2.5mM间。对照物不含抑制剂。该抑制剂在水中占总体积的1/20。然后加入下列试剂。为使总反应体积达到200μl而加入的0.2M的磷酸钾缓冲液(pH7.6)、45μl的含1mM 2,4-二氯苯酚的新配制的显色溶液、500μM的4-氨基安替比林和4:g/ml辣根过氧化物酶及一定量的含VAP-1SSAO的CHO细胞裂解液(引起每小时0.6A490的变化)。这都处于所述测试的线性响应区域。在37℃下温育该板30分钟,用Wallac Victor II多标记计数器,在490nm下测定背景吸收。加入20μl10mM的苄基胺(最终浓度=1mM),并于37℃下温育该板1小时以引发所述酶的反应。在490nm处测得吸光度的增加,表明VAP-1SSAO具有活性。经校正背景吸光度后,采用与对照物相比的抑制率来表示抑制作用。
实施例11VAP-1SSAO活性与总的人MAO活性的对比
通过采用手动操作的Ten Broeck匀浆器,按照1∶25(w/v)的比例,将人肝样本在冰冷却的磷酸钾缓冲液(0.2M,pH7.6)中均化,由人肝样本制得人MAO。在4℃及1000g下离心15分钟后,小心取出上清液,用作MAO的来源。除用1mM香草酸代替2,4-二氯苯酚外,用与测定VAP-1SSAO相同的方法测定总MAO活性。如需要,向每一孔中加入预定量的抑制剂。各测试中抑制剂的量不同,但总体上最终浓度在10nM-2.5mM间。对照物不含抑制剂。所述抑制剂在水中占总体积的1/20。然后加入下列试剂。为使总反应体积达到300μl而加入的0.2M的磷酸钾缓冲液(pH7.6)、50μl新配制的显色溶液(同上)和50μlMAO制剂。在37℃下将该板温育30分钟,用Wallac VictorII多标签计数器在490nm下测定背景吸光度。加入20μl5mM的酪胺(最终浓度为0.5mM)并于37℃下培养该板1小时,引发所述酶的反应。在490nm处测得吸光度的增加,表明MAO具有活性。在校正背景吸光度后,采用与对照物相比的抑制率表示抑制作用。加入氯吉兰和帕吉林(各为MAO-A和-B的抑制剂)到一些孔中(使得浓度为0.5μM),作为对MAO抑制作用的阳性对照。
表3中显示出实施例1-8的化合物特异性对人MAO中VAP-1SSAO的抑制活性的能力。该结果表明本发明的化合物(或其它肼基醇降解产物)是人VAP-1SSAO活性的特定的抑制剂,并且与现有技术已知的VAP-1SSAO抑制剂(如氨基脲)比较,其为更有效的VAP-1SSAO抑制剂。因此希望本发明的化合物在治疗其中人粘附分子VAP-1的SSAO活性起主要作用的疾病和症状方面有治疗用途。表3
现己完全对本发明作出了描述,本领域的普通技术人员应明白,可在各种条件、制剂和其它参数的广泛和等价的范围内实施本发明,而不影响本发明或其任何实施方案的范围。本文所引用的各种专利和出版物全部结合到本文中作为参考。
Claims (55)
R1为氢或C1-C4烷基;
R2为氢、C1-C4烷基、C2-C4链烯基、芳烷基、C2-C6烷酰基、C3-C6链烯酰基、或任选取代的C7-C11芳酰基;
R3、R4、R5和R6可相同或不同,为氢、C1-C4烷基或任选取代的芳基;
或所述取代基R3、R4、R5和R6中的任两个可与它们连接的碳原子一起形成任选取代的碳环或杂环;
或R2和R3可与它们连接的原子一起形成任选取代的碳环或杂环;和
R7为氢、C1-C4烷基、芳基、取代芳基、杂芳基或芳烷基;R8为C1-C4烷基、芳基、取代芳基、杂芳基或芳烷基;
或R7和R8与它们连接的碳原子一起形成任选取代5-12元碳环或杂环。
2.权利要求1的化合物在制备用于治疗炎性疾病或症状、与碳水合物代谢有关的疾病,与脂肪细胞分化或功能或平滑肌细胞功能的畸变有关的疾病,或血管疾病的药用制剂中的用途。
3.权利要求1或2的用途,其中R2为被烷基、硝基、甲氧基或卤素取代的苄基。
4.权利要求3的用途,其中R2为在对位被甲基、硝基、甲氧基或氯取代的苄基。
5.权利要求1或2的用途,其中R3、R4、R5和R6中的两个与它们连接的碳原子一起形成5-7元碳环或杂环。
6.权利要求5的用途,其中R4和R6与它们连接的碳原子一起形成5-7元碳环或杂环,并且R3和R5各自为氢。
7.权利要求6的用途,其中所述5-7元环选自环戊烷、环己烷、4-甲基-环己烷和环庚烷。
8.权利要求1或2的用途,其中R2和R3与它们连接的碳原子一起形成任选取代的杂环。
9.权利要求8的用途,其中所述取代基R2和R3一起形成任选被烷基取代的5-6元饱和的含氮杂环。
10.权利要求8的用途,其中R2和R3一起形成任选取代的杂环,所述杂环选自1,2,3,4-四氢喹啉、1,2,3,4-四氢异喹啉、2,3-二氢吲哚、哌啶和6,7-二甲氧基-1,2,3,4-四氢-异喹啉。
11.权利要求1或2的用途,其中R7和R8一起形成任选取代的碳环或杂环。
12.权利要求11的用途,其中所述碳环或杂环被烷基、芳烷基或取代的芳烷基取代。
13.权利要求12的用途,其中所述碳环或杂环为N-苄基哌啶。
14.权利要求2的用途,其中所述炎性疾病或症状为结缔组织炎性疾病或症状。
15.权利要求14的用途,其中所述结缔组织炎性疾病或症状选自关节强硬性脊椎炎、Reiter氏综合征、银屑病关节炎、骨关节炎或变性关节病、类风湿性关节炎、Sjögren氏综合征、BehCet氏综合征、复发性多软骨炎、系统性红斑狼疮、盘状红斑狼疮、系统性硬化病、嗜酸性细胞增多性肌膜炎、多发性肌炎和皮肌炎、风湿性多肌痛、脉管炎、颞动脉炎、结节性多动脉炎、Wegener氏肉芽肿病、混合结缔组织病和幼年型类风湿关节炎。
16.权利要求2的用途,其中所述炎性疾病或症状为胃肠道炎性疾病或症状。
17.权利要求16的用途,其中所述胃肠道炎性疾病或症状选自Crohn氏病、溃疡性结肠炎、肠易激惹综合征(痉挛性结肠)、肝纤维变性症、口腔粘膜炎(口炎)和复发性阿弗他口腔炎。
18.权利要求2的用途,其中所述炎性疾病或症状为中枢神经系统炎性疾病或症状。
19.权利要求18的用途,其中所述中枢神经系统炎性疾病或症状选自多发性硬化、早老性痴呆和与缺血休克有关的缺血-再灌注损伤。
20.权利要求2的用途,其中所述炎性疾病或症状为肺炎疾病或症状。
21.权利要求20的用途,其中所述肺炎疾病或症状选自哮喘、慢性阻塞性肺疾病和成人呼吸窘迫综合征。
22.权利要求2的用途,其中所述炎性疾病或症状为皮肤炎性疾病或症状。
23.权利要求22的用途,其中所述皮肤炎性疾病或症状选自接触性皮炎、特应性皮炎、银屑病、玫瑰糠疹、扁平苔癣和毛发红糠疹。
24.权利要求2的用途,其中所述与碳水合物代谢有关的疾病选自糖尿病、动脉粥样硬化、血管视网膜病、视网膜病、肾病、肾病综合征、多发性神经病、单神经病、植物神经病,足溃疡、关节病和高风险感染。
25.权利要求2的用途,其中所述与脂肪细胞分化或功能或平滑肌细胞功能畸变有关的疾病选自动脉粥样硬化和肥胖症。
26.权利要求2的用途,其中所述血管疾病选自粉瘤性动脉硬化、非粉瘤性动脉硬化,局部缺血性心脏病、末梢aterial阻塞、闭塞性血栓性血管炎(Buerger氏病)及Raynaud氏病和症状。
27.权利要求1或2的用途,其中所述式I的化合物选自:
9-苄基-2-甲基-5-氧杂-1,2,9-三氮杂螺[5.5]十一烷;
9-苄基-2-甲基-4-苯基-5-氧杂-1,2,9-三氮杂螺[5.5]十一烷;
(3S,4R)-9-苄基-2,3-二甲基-4-苯基-5-氧杂-1,2,9-三氮杂螺[5.5]十一烷;
(3R,4S)-2,3-二甲基-4-苯基-5-氧杂-1,2-二氮杂螺[5.5]十一烷;
(4aR*,8aS*)-4-甲基-2,2-五亚甲基-3,4,4a,5,6,7,8,8a-八氢-2H-1,3,4-苯并噁二嗪;
(4aR*,8aR*)-2,2,4-三甲基-3,4,4a,5,6,7,8,8a-八氢-2H-1,3,4-苯并噁二嗪;
(4aR*,8aR*)-4-苄基-2-乙基-2-甲基-3,4,4a,5,6,7,8,8a-八氢-2H-1,3,4-苯并噁二嗪;
2,2-二甲基-1,2,4a,5-四氢-4H,10H-1,3,4-噁二嗪并[4,5-b]异喹啉;和
2,3-二甲基-4-苯基-5-氧杂-1,2-二氮杂螺[5.5]十一烷;或其药学上可接受的盐。
28.权利要求1或2的用途,其中所述式I的化合物为(3S,4R)-9-苄基-2,3-二甲基-4-苯基-5-氧杂-1,2,9-三氮杂螺[5.5]十一烷或(3R,4S)-2,3-二甲基-4-苯基-5-氧杂-1,2-二氮杂螺[5.5]十一烷,或其药学上可接受的盐。
29.一种抑制含铜的胺氧化酶的方法,所述方法包括使所述胺氧化酶与抑制有效量的权利要求1至28中任一项所定义的式I的1,3,4-噁二嗪化合物接触。
30.权利要求29的方法,其中所述接触在体外发生。
31.权利要求29的方法,其中所述接触在体内发生。
32.一种治疗炎性疾病或症状、与碳水合物代谢有关的疾病,与脂肪细胞分化或功能或平滑肌细胞功能畸变有关的疾病,或血管疾病的方法,该方法包括向需要此种治疗或预防的动物给服有效量的权利要求1至28中任一项所定义的式I的噁二嗪化合物。
R1为氢或C1-C4烷基;
R2为氢,C1-C4烷基、C2-C4链烯基、C6-C10芳基(C1-C4)烷基、C2-C6烷酰基、C2-C6链烯酰基或苯甲酰基,这些基团中任一种任选被C1-C4烷基、硝基、甲氧基或卤素取代;
R3、R4、R5和R6可相同或不同,为氢、C1-C4烷基或C6-C10芳基,这些基团中任一种任选被C1-C4烷基或卤素取代;
或所述取代基R3、R4、R5和R6中的两个与它们连接的碳原子一起形成任选被C1-C4烷基或卤素取代的5-12元碳环或杂环;
或R2和R3与它们连接的原子一起形成任选被C1-C6烷基或卤素取代的5-12元碳环或杂环;和
R7为氢、C1-C4烷基、C6-C10芳基、取代的C6-C10芳基、杂芳基或C6-C10芳基(C1-C4)烷基;
R8为C1-C4烷基、C6-C10芳基、取代的C6-C10芳基、杂芳基或C6-C10芳基(C1-C4)烷基;
或R7和R8与它们连接的碳原子一起形成任选被C1-C6烷基或C6-C10芳基(C1-C4)烷基取代的5-12元碳环或杂环;
条件是当R7和/或R8为C1-C4烷基或任选取代的苯基,或当R7和R8与它们连接的碳原子一起形成非取代的C5-C7环烷基时,R3和R4不为氢或C1-C4烷基。
34.权利要求33的化合物,其中R2为被烷基、硝基、甲氧基或卤素取代的苄基。
35.权利要求34的化合物,其中R2为在对位被甲基、硝基、甲氧基或氯取代的苄基。
36.权利要求33的化合物,其中R3、R4、R5和R6中的两个与它们连接的碳原子一起形成5-7元碳环或杂环。
37.权利要求36的化合物,其中R4和R6与它们连接的碳原子一起形成5-7元碳环或杂环,并且R3和R5各自为氢。
38.权利要求37的化合物,其中所述5-7元环选自环戊烷、环己烷、4-甲基-环己烷和环庚烷。
39.权利要求33的化合物,其中R2和R3与它们连接的碳原子一起形成任选取代的杂环。
40.权利要求39的化合物,其中所述取代基R2和R3一起形成任选被烷基取代的5-6元饱和的含氮杂环。
41.权利要求39的化合物,其中R2和R3一起形成任选取代的杂环,所述杂环选自1,2,3,4-四氢喹啉、1,2,3,4-四氢异喹啉、2,3-二氢吲哚、哌啶和6,7-二甲氧基-1,2,3,4-四氢-异喹啉。
42.权利要求33的化合物,其中R7和R8一起形成任选取代的碳环或杂环。
43.权利要求42的化合物,其中所述碳环或杂环被烷基、芳烷基或取代的芳烷基取代。
44.权利要求43的化合物,其中所述碳环或杂环为N-苄基哌啶。
45.权利要求33的化合物,所述化合物选自:
9-苄基-2-甲基-5-氧杂-1,2,9-三氮杂螺[5.5]十一烷;
9-苄基-2-甲基-4-苯基-5-氧杂-1,2,9-三氮杂螺[5.5]十一烷;
(3S,4R)-9-苄基-2,3-二甲基-4-苯基-5-氧杂-1,2,9-三氮杂螺[5.5]十一烷;
(4R*,8aS*)-4-甲基-2,2-五亚甲基-3,4,4a,5,6,7,8,8a-八氢-2H-1,3,4-苯并噁二嗪;
(4aR*,8aR*)-2,2,4-三甲基-3,4,4a,5,6,7,8,8a-八氢-2H-1,3,4-苯并噁二嗪;
(4aR*,8aR*)-4-苄基-2-乙基-2-甲基-3,4,4a,5,6,7,8,8a-八氢-2H-1,3,4-苯并噁二嗪;和
2,2-二甲基-1,2,4a,5-四氢-4H,10H-1,3,4-噁二嗪并[4,5-b]异喹啉;或其药学上可接受的盐。
46.一种药用组合物,所述药用组合物包括权利要求33-45中任一项的化合物和药学上可接受的载体或稀释剂。
47.用于治疗用途的权利要求33-45中任一项的化合物。
48.一种制备权利要求33的1,3,4-噁二嗪化合物,或其互变异构体、异构体、溶剂合物、水合物或其药学上可接受的盐的方法,所述方法包括:使式II的肼基醇:与式IV的酮反应:形成式I的1,3,4-噁二嗪化合物:其中:
R1为氢或C1-C4烷基;
R2为氢,C1-C4烷基、C2-C4链烯基、C6-C10芳基(C1-C4)烷基、C2-C6烷酰基、C2-C6链烯酰基或苯甲酰基,这些基团中任一种任选被C1-C4烷基、硝基、甲氧基或卤素取代;
R3、R4、R5和R6可相同或不同,为氢、C1-C4烷基或C6-C10芳基,这些基团中任一种任选被C1-C4烷基或卤素取代;
或所述取代基R3、R4、R5和R6中的两个与它们连接的碳原子一起形成任选被C1-C4烷基或卤素取代的5-12元碳环或杂环;
或R2和R3与它们连接的原子一起形成任选被C1-C6烷基或卤素取代的5-12元碳环或杂环;和
R7为氢、C1-C4烷基、C6-C10芳基、取代的C6-C10芳基、杂芳基或C6-C10芳基(C1-C4)烷基;
R8为C1-C4烷基、C6-C10芳基、取代的C6-C10芳基、杂芳基或C6-C10芳基(C1-C4)烷基;
或R7和R8与它们连接的碳原子一起形成任选被C1-C6烷基或C6-C10芳基(C1-C4)烷基取代的5-12元碳环或杂环。
49.一种制备权利要求33的1,3,4-噁二嗪化合物,或其互变异构体、异构体、溶剂合物、水合物或其药学上可接受的盐的方法,所述方法包括:使式II的肼基醇与式V的缩醛反应:形成式I的1,3,4-噁二嗪化合物:其中:
R1为氢或C1-C4烷基;
R2为氢,C1-C4烷基、C2-C4链烯基、C6-C10芳基(C1-C4)烷基、C2-C6烷酰基、C2-C6链烯酰基或苯甲酰基,这些基团中任一种任选被C1-C4烷基、硝基、甲氧基或卤素取代;
R3、R4、R5和R6可相同或不同,为氢、C1-C4烷基或C6-C10芳基,这些基团中任一种任选被C1-C4烷基或卤素取代;
或所述取代基R3、R4、R5和R6中的两个与它们连接的碳原子一起形成任选被C1-C4烷基或卤素取代的5-12元碳环或杂环;
或R2和R3与它们连接的原子一起形成任选被C1-C6烷基或卤素取代的5-12元碳环或杂环;和
R7为氢、C1-C4烷基、C6-C10芳基、取代的C6-C10芳基、杂芳基或C6-C10芳基(C1-C4)烷基;
R8为C1-C4烷基、C6-C10芳基、取代的C6-C10芳基、杂芳基或C6-C10芳基(C1-C4)烷基;
或R7和R8与它们连接的碳原子一起形成任选被C1-C6烷基或C6-C10芳基(C1-C4)烷基取代的5-12元碳环或杂环。
50.权利要求48或49的方法,其中所述反应在酸或碱催化剂存在下进行。
51.权利要求48或49的方法,其中所述反应在水吸附剂存在下进行。
52.权利要求50的方法,其中所述酸性催化剂为盐酸、对甲苯磺酸、乙酸、酒石酸或草酸。
53.权利要求50的方法,其中所述酸性催化剂为适用于非水催化剂的酸性离子交换树脂。
54.权利要求50的方法,其中所述碱性催化剂为三乙胺。
55.一种制备权利要求33的1,3,4-噁二嗪化合物,或其互变异构体、异构体、溶剂合物、水合物或其药学上可接受的盐的方法,所述方法包括:
R1为氢或C1-C4烷基;
R2为氢,C1-C4烷基、C2-C4链烯基、C6-C10芳基(C1-C4)烷基、C2-C6烷酰基、C2-C6链烯酰基或苯甲酰基,这些基团中任一种任选被C1-C4烷基、硝基、甲氧基或卤素取代;
R3、R4、R5和R6可相同或不同,为氢、C1-C4烷基或C6-C10芳基,这些基团中任一种任选被C1-C4烷基或卤素取代;
或所述取代基R3、R4、R5和R6中的两个与它们连接的碳原子一起形成任选被C1-C4基或卤素取代的5-12元碳环或杂环;
或R2和R3与它们连接的原子一起形成任选被C1-C6烷基或卤素取代的5-12元碳环或杂环;和
R7为氢、C1-C4烷基、C6-C10芳基、取代的C6-C10芳基、杂芳基或C6-C10芳基(C1-C4)烷基;
R8为C1-C4烷基、C6-C10芳基、取代的C6-C10芳基、杂芳基或C6-C10芳基(C1-C4)烷基;
或R7和R8与它们连接的碳原子一起形成任选被C1-C6烷基或C6-C10芳基(C1-C4)烷基取代的5-12元碳环或杂环。
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN109810041A (zh) * | 2017-11-21 | 2019-05-28 | 南京药捷安康生物科技有限公司 | 卤代烯丙基胺类ssao/vap-1抑制剂及其应用 |
Families Citing this family (34)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
NZ523463A (en) | 2000-07-05 | 2004-06-25 | Biotie Therapies Corp | Inhibitors of copper-containing amine oxidases |
US6982286B2 (en) * | 2001-07-12 | 2006-01-03 | Biotie Therapies Corp. | Carbocyclic hydrazino inhibitors of copper-containing amine oxidases |
CA2514573A1 (en) | 2003-01-27 | 2004-08-12 | Astellas Pharma Inc. | Thiazole derivatives and their use as vap-1 inhibitors |
EP1608365B1 (en) * | 2003-03-31 | 2013-10-02 | R-Tech Ueno, Ltd. | Method for treating vascular hyperpermeable disease |
CA2526675A1 (en) * | 2003-05-26 | 2004-12-02 | Biotie Therapies Corporation | Crystalline vap-1 and uses thereof |
FI20031927A0 (fi) * | 2003-12-31 | 2003-12-31 | Faron Pharmaceuticals Oy | Terapeuttisesti vaikuttavia aineita ja niiden käyttö |
US8119651B2 (en) | 2004-01-30 | 2012-02-21 | Biotie Therapies Corp. | Compositions useful especially for treatment or prevention of metabolic syndrome |
FI20040136A0 (fi) * | 2004-01-30 | 2004-01-30 | Faron Pharmaceuticals Oy | Erityisesti diabeetikoille soveltuvia koostumuksia |
PT1708711E (pt) * | 2004-01-30 | 2010-06-01 | Faron Pharmaceuticals Oy | Composições úteis em especial para o tratamento ou a prevenção da síndrome metabólica |
FI20040270A0 (fi) * | 2004-02-20 | 2004-02-20 | Biotie Therapies Oyj | Kuparia sisältävien amiinioksidaasien imhibiittoreina käyttökelpoiset hydratsinoalkoholijohdannaiset |
KR20070050932A (ko) * | 2004-07-27 | 2007-05-16 | 가부시키가이샤 아루떼꾸 우에노 | Vap―1 억제 활성을 가지는 티아졸 유도체 |
US20080015202A1 (en) * | 2004-09-09 | 2008-01-17 | Astellas Pharma Inc. | Thiazole Derivatives Having Vap-1 Inhibitory Activity |
JP4140630B2 (ja) * | 2005-11-10 | 2008-08-27 | Tdk株式会社 | 磁気ヘッドアセンブリ及び磁気ヘッドアセンブリの製造方法 |
US8372399B2 (en) | 2006-08-31 | 2013-02-12 | Cardiac Pacemakers, Inc. | Bispecific antibodies and agents to enhance stem cell homing |
US8636995B2 (en) * | 2006-08-31 | 2014-01-28 | Cardiac Pacemakers, Inc. | Methods and devices to regulate stem cell homing |
US20080058922A1 (en) * | 2006-08-31 | 2008-03-06 | Cardiac Pacemakers, Inc. | Methods and devices employing vap-1 inhibitors |
FI20061156A0 (fi) | 2006-12-27 | 2006-12-27 | Elina Kivi | Uusia peptidejä |
US20090170770A1 (en) * | 2007-11-06 | 2009-07-02 | Ali Hafezi-Moghadam | Methods and compositions for treating conditions associated with angiogenesis using a vascular adhesion protein-1 (vap 1) inhibitor |
WO2009066152A2 (en) | 2007-11-21 | 2009-05-28 | Pharmaxis Ltd. | Haloallylamine inhibitors of ssao/vap-1 and uses therefor |
TWI437986B (zh) | 2008-01-31 | 2014-05-21 | R Tech Ueno Ltd | 噻唑衍生物及使用該衍生物作為vap-1抑制劑之用途 |
TWI490214B (zh) * | 2008-05-30 | 2015-07-01 | 艾德克 上野股份有限公司 | 苯或噻吩衍生物及該等作為vap-1抑制劑之用途 |
US8906642B2 (en) | 2008-09-03 | 2014-12-09 | Universitat Autonoma De Barcelona | Methods and compositions for the treatment and diagnosis of haemorrhagic conversion |
RU2400233C1 (ru) | 2009-07-07 | 2010-09-27 | Общество с ограниченной ответственностью "Вирфарм" | Способ лечения заболеваний печени различного генеза |
UA112154C2 (uk) * | 2009-09-08 | 2016-08-10 | Біоті Терапіс Корп. | Застосування повністю людського анти-vap-1-антитіла для лікування фіброзних станів |
EP2479165B1 (en) | 2009-09-16 | 2017-10-25 | Astellas Pharma Inc. | Glycine compound |
RU2010145439A (ru) * | 2010-11-08 | 2012-05-20 | Виктор Вениаминович Тец (RU) | Средство для лечения поражений печени, вызванных воздействием химических или биологических агентов |
FI20115234A0 (fi) | 2011-03-08 | 2011-03-08 | Biotie Therapies Corp | Uusia pyridatsinoni- ja pyridoniyhdisteitä |
EA025839B1 (ru) * | 2011-03-15 | 2017-02-28 | Астеллас Фарма Инк. | Гуанидиновые соединения, полезные для предотвращения и/или лечения диабетической нефропатии или диабетического отека желтого пятна |
US20160113893A1 (en) | 2013-06-12 | 2016-04-28 | Proximagen Limited | New therapeutic uses of enzyme inhibitors |
ES2714125T3 (es) | 2014-04-15 | 2019-05-27 | Pecsi Tudomanyegyetem | Inhibidores de la amino oxidasa sensible a la semicarbazida para uso como analgésicos en una neuropatía traumática y una inflamación neurogénica |
WO2015189534A1 (en) | 2014-06-12 | 2015-12-17 | Proximagen Limited | Vap-1 inhibitors for treating muscular dystrophy |
RU2595868C1 (ru) | 2015-03-27 | 2016-08-27 | Виктор Вениаминович Тец | Лекарственное средство с гепатопротекторной активностью |
JP2018076236A (ja) | 2015-06-05 | 2018-05-17 | 株式会社アールテック・ウエノ | がんを処置するための医薬組成物 |
EP3777846A1 (en) | 2015-12-07 | 2021-02-17 | BenevolentAI Cambridge Limited | Vap-1 inhibitors for treating pain |
Family Cites Families (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3377345A (en) * | 1966-09-23 | 1968-04-09 | Dow Chemical Co | Substituted 3, 4, 5, 6-tetrahydro-2h-1, 3, 4-oxadiazin-2-one compounds and method ofpreparation thereof |
US3486916A (en) | 1966-12-22 | 1969-12-30 | William A Cordon | Cement mixes and the production of articles therefrom |
SE320311B (zh) | 1968-07-15 | 1970-02-02 | Mo Och Domsjoe Ab | |
EP0639972A1 (en) * | 1992-05-15 | 1995-03-01 | University Of Saskatchewan | Method for preventing endothelium damage in mammals and for alleviating pain associated with gout and arthritis |
US5413634A (en) | 1993-08-06 | 1995-05-09 | Arco Chemical Technology, L.P. | Cement composition |
CA2117585C (en) | 1993-09-14 | 2001-06-05 | Edward T. Shawl | Cement composition |
WO1996006058A1 (en) | 1994-08-25 | 1996-02-29 | W.R. Grace & Co.-Conn. | Shrinkage reduction cement composition |
US5618344A (en) | 1995-03-06 | 1997-04-08 | W. R. Grace & Co.-Conn. | Cement composition |
US5603760A (en) | 1995-09-18 | 1997-02-18 | W. R. Grace & Co.-Conn. | Cement admixture capable of inhibiting drying shrinkage and method of using same |
US5556460A (en) | 1995-09-18 | 1996-09-17 | W.R. Grace & Co.-Conn. | Drying shrinkage cement admixture |
NZ523463A (en) | 2000-07-05 | 2004-06-25 | Biotie Therapies Corp | Inhibitors of copper-containing amine oxidases |
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2001
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- 2001-07-04 CN CN01815102A patent/CN1450998A/zh active Pending
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- 2001-07-05 US US09/898,003 patent/US6624202B2/en not_active Expired - Fee Related
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN109810041A (zh) * | 2017-11-21 | 2019-05-28 | 南京药捷安康生物科技有限公司 | 卤代烯丙基胺类ssao/vap-1抑制剂及其应用 |
CN109810041B (zh) * | 2017-11-21 | 2023-08-15 | 药捷安康(南京)科技股份有限公司 | 卤代烯丙基胺类ssao/vap-1抑制剂及其应用 |
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