CN101528728B - 6-1h-咪唑并-喹唑啉和喹啉衍生物,镇痛剂和抗炎剂 - Google Patents
6-1h-咪唑并-喹唑啉和喹啉衍生物,镇痛剂和抗炎剂 Download PDFInfo
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- CN101528728B CN101528728B CN200680055991.7A CN200680055991A CN101528728B CN 101528728 B CN101528728 B CN 101528728B CN 200680055991 A CN200680055991 A CN 200680055991A CN 101528728 B CN101528728 B CN 101528728B
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Abstract
本发明涉及式I的新颖6-1H-咪唑并-2-芳基和2-杂芳基喹唑啉和喹啉、其相应盐和溶剂化物,涉及它们的制备方法,和涉及该化合物和相应的药物组合物用于治疗疼痛和炎性相关疾病的用途。除了惊人的抗炎性能之外,已经证实本发明化合物在炎性和神经性疼痛的药理学治疗中非常高效。它们的有效性涉及COX-2和炎性细胞因子表达和形成,除了数种炎性疾病,对于癌症的治疗,同样突显了它们是有利的化合物。式I:
Description
本发明涉及新颖的6-1H-咪唑并-2-芳基和2-杂芳基喹唑啉和喹啉,涉及它们的制备方法,涉及它们的药物组合物和所述化合物和它们的药物组合物用于治疗疼痛和炎性相关疾病的用途。
背景技术
花生四烯酸向前列腺素和其它类花生酸的转化受两种熟知的环氧合酶(COX)同工型COX-1和COX-2的控制。COX-2是可以在多种病理状况中被上调的可诱导同工酶,所述病理状况包括炎症和癌症。用非甾族抗炎剂(NSAIDs)阻断COX活性是广泛选定用于治疗炎性相关疾病和疼痛的临床策略。与常规NSAIDs的长期使用相关的主要副作用是胃肠道的严重副作用和肾毒性。选择性的COX-2抑制剂,虽然其缺少经典NSAIDs的大部分一般胃肠道毒性,但是最近明确发现其具有危急生命的不希望的心血管副作用。NSAIDs的一种替代是使用皮质类固醇激素,然而,在这种情形中,长期使用可以导致严重的副作用。
由于靶向基因转录的方法可以补充酶抑制作用或者甚至是比酶抑制作用更为成功,明确阻断COX基因表达的策略探索是最近十年来卓越科研努力的目标(R.G.Ramsay,Int.J.Immunopathol.Pharmacol.,2003,16(2S),59-67)。最近,已经报道一些NSAIDs(包括西利考昔)直接对COX-2转录调整发挥其部分作用,提出了为什么这种试剂对这种同工型显示出比酶抑制作用数据更大的影响的解释(K.S.Chun,Biochem.Pharmacol.2004,68,1089)。COX-2的上调由多种刺激介导,包括细胞因子、肿瘤启动子、致癌基因和生长因子。可以诱发和调节COX-2表达的胞内信号途径是复杂的,并且因为对细胞系统依赖仍然理解不充分。然而,增加的证据表明IL-1β和COX-2在炎性疾病和肿瘤生长的发病机理中起着至关重要的角色。在大多数组织中,IL-1β诱发的COX-2过表达由蛋白激酶C(PKC)或者增强促分裂原活化蛋白激酶(MAPK)活性并随后激活COX-2以及其它细胞因子的转录的Ras信号转导系统的刺激所介导。最近已经表明,在数种组织中,三种MAP激酶(p38、JNK和ERK 1/2)都在控制COX-2表达和转译中被涉及。例如,对于用 IL-1β刺激的人类软骨细胞(N.Nieminen Mediators of inflammation,2005,5,249-255),或者在用IL-1β刺激的人类结肠直肠癌细胞中(W.Liu,Cancer Research,2003,63,3632;Cellular Signalling,2006,18,1262)和在肾系膜细胞中(J.Biol.Chem.1998,273,28670),已经报道了上述事实。
风湿性关节炎(RA)是特征在于导致软骨退化和骨骼冲蚀的关节滑膜炎的系统炎性疾病。风湿性的滑膜表现出了COX-2的过表达,这随后导致响应血管舒张、流体外渗和疼痛的PGE2大量形成。在影响COX-2表达的多种介质中,IL-1β似乎是主要的引发剂(Arthritis Research,2005,57)。
骨关节炎(OA)是最普通的关节炎形式,并且被基本上认定是老年人严重丧失能力的常见原因。特征在于单核细胞渗透、新血管增殖、前炎性细胞因子形成和关节损伤的其它介质的滑液炎症在患有早期和晚期OA的患者滑液组织中已经被突显(Ann Rheum.Dis.,2005,64,1263-67),和滑膜炎在OA病理生理学中的重要性被越来越认可(Haywood,Arthritis Rheum.,2003,48,2173;Shibakawa,OsteoarthritisCartilage,2003,11,133)。细胞因子、COX-2、粘着分子和血管生成因子的升高的表达是慢性滑膜炎的特征。现在已经表明,由COX-2形成的PGE2在人类骨关节炎外植体中调节软骨蛋白多糖降解,由此突显该炎症介质不仅在炎症过程的蔓延中起作用,而且直接涉及在组织变性中(Arthritis Rheum.,2002,46,1789)。现在还已经表明,在OA滑膜细胞中,COX-2表达的IL-1β诱导机制遵循与以上对于软骨细胞所讨论相同的信号途径(Arthritis & Rheum.,2004,50,2829)。
在受炎症性肠病(IBD)、Crohn’s疾病和溃疡性结肠炎影响的患者中,升高的COX-2表达水平已经与IL-1β的高水平一起被检测到,其中炎性/自身免疫反应由对内脏细菌形成的抗原的升高响应引发。
在人类结肠直肠腺癌和其它肿瘤中,包括乳腺癌、子宫颈癌、前列腺癌和肺癌,已经报道COX-2的表达被升高。已经证实,COX-2和/或它的表达的遗传脱模或者药理学抑制作用预防试验-诱发的致癌作用。据此,通过阻断酶和/或它的表达,使得COX-2的异常或者不适当的升高水平被抑制,还提供了一种最有效和有前景的癌症化学预防策略。
阻断炎性疾病中的细胞因子,已经导致近年来的药品得到了最显著 的发展。肿瘤坏死因子(TNF)、白细胞间介素-1(IL-1)和白细胞间介素-6(IL-6)是被统称为前炎性细胞因子的重要生物学实体,它们在数种疾病中起作用,例如,比如中毒性休克综合症、RA、OA、糖尿病和IBD。在这些疾病中,炎症的慢性发展加重或者引起了多种可观察到的病理生理学。前炎性细胞因子在炎性产生和破坏性软骨变性以及关节炎中的骨骼冲蚀中起着决定性的作用(B.Moller,Springer Semin.Immunopathol.,2006,391)。由于最终的结构破坏,骨骼冲蚀是关节炎患者残废的主要原因。关节炎中骨骼冲蚀是滑液破骨细胞形成的结果(BF.Boyce,Curr.Opinion Rheumatol,2006,18,427)。在发炎滑膜中形成的炎性细胞因子导致骨髓中破骨细胞前体的释放,其达到发炎的关节和响应细胞因子刺激异化成骨骼-消溶破骨细胞。由此,关节炎中的前炎性细胞因子是导致关节以及骨骼损伤中炎性状态发展和扩散的原因。已经表明,IL-1β拮抗剂降低多种关节炎试验模型中软骨基质组分的降解。白细胞间介素-6(IL-6)是一种主要在活化的单核细胞和巨噬细胞中表达的前炎性细胞因子,其在多种慢性炎性疾病中起着基本性的作用,特别是被暗示在急性期反应中和决定性地涉及在疾病状态的保持中(J.Scheller,Scand.J.Immunol.,2006,63,321)。IL-6的过表达已经被牵涉在IBD、关节炎(RA和OA)、哮喘、结肠癌、多发性骨髓瘤、绝经后骨质疏松症的病理学中。
多种抗细胞因子治疗剂当前都在进行临床试验,和数种对抗TNF的单克隆抗体和重组的可溶性TNF受体(依那西普,Enbrel)以及重组的可溶性IL-1受体(Anakinra,Kineret)已经进入了市场,在治疗比如RA、IBD和Crohn’s疾病的疾病中表明了显著的活性。然而,基于拮抗循环细胞因子的这些生物学高分子量产品是昂贵的,限于胃肠外给药路线和可以产生免疫原性副作用,这可能是由于它们的生物学本性。
目标在于用小分子阻断细胞因子形成的策略仍然具有显著的治疗学吸引力,因为这在阻断细胞因子流通中可以更有效、不具有生物制品的免疫原性副作用、价格更低廉和给药途径更简单。此外,同时阻断COX-2形成和前炎性细胞因子形成应当中断自动传输环线,已经发现自动传输环线与炎性疾病病理学的引发和保持有关。
如上所述,炎症引起COX-2的诱导,导致前列腺素类的释放,敏化末梢损伤感受器末端和形成定位的疼痛超敏性,然而末梢炎症还通过 COX-2表达在脊髓和CNS神经元中的直接广泛诱导而产生中枢敏化,导致增强的神经元兴奋性和疼痛超敏性(J.Neurochem.,2003,86,318)。
虽然关节炎(OA和RA)被定义为关节炎症,诊所中患有该疾病的患者的初始特征为慢性疼痛;即使关节炎并不是唯一可以产生慢性疼痛的病理学,但是它相当普遍和是非常有代表性的这类疼痛。慢性疼痛可以分为炎性疼痛,一种与末梢组织损伤/炎症更相关的疼痛,和神经性疼痛。神经性疼痛在临床上是指一组慢性疼痛综合症。这些综合症的共有特征是它们由初始的神经损伤引起,随后导致在中枢和末梢神经系统中产生异常的感突。神经性疼痛状况是多种疾病的结果,例如糖尿病、癌症、截肢、多发性脑硬化。
末梢致敏和中枢致敏是导致疼痛产生的两种主要机制。当组织损伤存在时,在神经机制和免疫系统机制中都引发致敏剂的释放,比如前炎性前列腺素(PGE2)、5-HT、血管舒缓激肽、组胺、ATP、炎性细胞的细胞因子和神经末端。这些介质通过激发末梢感受神经元引起具体离子通道的活化,涉及胞内激酶的活化和导致末梢致敏。末梢损伤感受器的活化还反映在CNS中从属神经元的可塑性中。这种可塑性通过增强和延长对随后的末梢刺激的反应改变感受途径的性能。脊髓以及脑中的这些改变被称为中枢致敏。中枢致敏在保持升高的疼痛敏感性中起着主要作用,和它是损伤之后由通常良性的低阈向心输入的产生疼痛的原因。如此复杂的疼痛诱导和控制机制可以解释为什么疼痛状况的治疗仍然没有发现令人满意的药理学溶液。
为了鉴定用于疼痛临床管理的有效试剂,在最近十年中已经进行了数种备用的药理学研究,例如COX-2抑制剂在炎性疼痛的处理中显示了良好的效力,但是在神经性疼痛的处理中无效,此外,上述提及的COX-2抑制剂的不希望的危及生命的副作用建议不能将这些药物用于慢性疼痛的临床管理中。可获得的用于处理神经性疼痛的镇痛药,例如一些三环抗抑郁剂(例如:阿米替林)和几种抗癫痫药物(例如卡巴番定、拉莫三嗪和卡马西平)在一些患者中是有效的,然而,仍然强烈需要用于神经性疼痛处理的有效药物。
活性在于控制细胞因子和PGE2表达的药理学试剂可以消除上述的末梢和中枢致敏机制,由此可以作为有效和潜在的镇痛药(M.Schafer,Immune Mechanisms of Pain and Analgesia,pg.41-50 Plenum Publishers, 2003)。
发明描述
本发明包括一类新化合物,式(I)的2-芳基和杂芳基喹唑啉和喹啉的6-1H-咪唑衍生物,可用于炎性疾病(比如关节炎,一般为风湿性关节炎和骨关节炎)、哮喘和呼吸道炎性疾病、慢性阻塞性肺病(COPD)、系统性红斑狼疮、皮肤病(比如湿疹、牛皮癣和皮炎)、胃肠道严重炎性状况(比如炎症性肠病(IBD))、溃疡性结肠炎、Crohn’s疾病(CD)、外科手术后炎性并发症和癌症的药理学处理中,所述癌症包括但不限于:结肠癌、多发性骨髓瘤、乳腺癌、子宫颈瘤、前列腺癌和肺癌。此外,本发明化合物可以用作有效的镇痛药,不论疼痛是炎性疼痛还是神经性疼痛。据此,本发明化合物可以用于处理急性和慢性疼痛,包括但不限于:手术后疼痛、肌肉疼痛、源于多种形式创伤的疼痛以及慢性疼痛、神经性疼痛、癌症疼痛、由关节炎引起的疼痛和内脏疼痛。
式(I)化合物:
其中:
-X独立地选自碳或者氮原子;
-W独立地选自芳基或者式II的杂芳基基团:
式II基团:
-当W为芳基时,意指未被取代或者被一个或多个取代基取代的苯基,所述取代基独立地选自卤素(-F,-Cl,-Br)、三氟甲基(-CF3)、烷基(-R2)、羟基(-OH)、烷氧基(-OR3)、三氟甲氧基(-OCF3)、氰基(-CN)、氨甲酰基(-CONHR3或者-NHCOR3或者-CONR2R3或者 -NHCOR3)、羰基(-CO-R3)、烷硫基(-SR3)、亚硫酰基(-SOR3)和磺酰基(-SO2R3);
-当W为式II的杂芳基时,它是苯并稠合的-5或者-6元杂环,其中:
-Z和Y独立地选自:氧原子(-O-)、硫原子(-S-)或者基团:-SO2-、-CHR3-、-CR3=、-NH-、-N=;
-Q独立地选自:-CHR3-、-CH=、-CR3=、-CHR3-CH2-;
条件是Y、Z、Q基团的结合形成:1,3-苯并二氧杂环戊烯、1,3-苯并二硫基化合物(dithiol)、苯并呋喃、2,3-二氢苯并呋喃、苯并噻吩、2,3-二氢苯并噻吩、2,3-二氢苯并噻吩S,S-二氧化物、吲哚、2,3-二氢吲哚、苯并咪唑、苯并噁唑、苯并噻唑、2H-3,4-二氢苯并吡喃、2H-3,4-二氢苯并噻喃、2H-3,4-二氢苯并噻喃S,S-二氧化物、[1,4]-苯并二噁英、2,3-二氢-[1,4]-苯并二噁英(1,4-苯并二噁烷)、1,4-苯并噻嗪、2,3-二氢-[1,4]-苯并噻嗪、2,3-二氢-[1,4]-苯并噻嗪S,S-二氧化物、[1,4]-苯并噁嗪、2,3-二氢-[1,4]-苯并噁嗪;
-R1独立地选自氢(-H)或者C1-C4烷基或者羟甲基(-CH2OH)、氨甲基(-CH2NH2)、二甲基氨基甲基(-CH2NMe2)、三氟甲基(-CF3);C1-C4烷基为直链或者支链烃链;条件是在式I化合物中,至多两个R1基团同时为C1-C4烷基或者三氟甲基(-CF3)和仅仅一个R1基团为羟甲基(-CH2OH)、氨甲基(-CH2NH2)或者二甲基氨基甲基(-CH2NMe2);
-R2独立地选自C1-C6烷基或者芳基;在此,C1-C6烷基意指任选被芳基取代的直链或者支链、饱和或者不饱和的C1-C6烃链,在此芳基如上所定义。
-R3独立地选自氢、C1-C6烷基和芳基。在此,C1-C6烷基意指任选被芳基取代的直链或者支链、饱和或者不饱和的C1-C6烃链,在此芳基如上所定义。
根据本发明,式(I)化合物可以以游离碱或者其药学上可接受的盐、或者所述盐的溶剂化物或者水合形式使用。
式(I)化合物的盐是药学上可接受的无机和有机酸加成盐。无机盐的非限制性代表例为:盐酸盐、氢溴酸盐、硫酸氢盐和硫酸盐。有机盐的非限制性代表例为:马来酸盐、富马酸盐、乙二酸盐、甲磺酸盐、琥珀酸盐、抗坏血酸盐、酒石酸盐。
在另一实施方案中,本发明提供了制备式(I)化合物的方法。
在另一实施方案中,本发明提供了式(I)化合物的药物组合物,可用于如上所述的疼痛和炎性疾病的治疗中。在本发明范围内,术语药物组合物(药物产品)是指任何适于以上病理学治疗的口服、胃肠外或者局部剂型,其含有有效量的至少一种活性药物成分(药物物质),式(I)化合物、它的盐或者其溶剂化物,和以下定义的用于口服、胃肠外或者局部给药的药学上可接受的载体、赋形剂或者稀释剂。
式(I)化合物的非限制性代表例列于表1中。
表1
本发明化合物的制备
式(I)化合物可以通过使式III化合物与式(IV)的咪唑衍生物反应进行制备,如方案1中所示,其中X、W和R1具有如以上对式(I)化合物所述相同的含义,和Hal为卤素原子,比如氟、氯、溴和碘,一般为溴和碘。
方案1:
式III化合物的反应可以使用为游离碱或者它的碱金属盐(钠、锂或者钾盐)的式IV的咪唑衍生物,在适宜的催化剂存在下,在比如二甲基甲酰胺(DMF)、二甲亚砜(DMSO)、乙腈、N-甲基吡咯烷酮(NMP)、乙二醇二甲醚、四氢呋喃(THF)、甲苯或者二甲苯的溶剂中,在50℃~200℃的温度范围内进行。
式IV的咪唑衍生物与式III的芳基卤化物的反应可以,例如在铜催化剂(CuI)存在下,使用碳酸钾或者碳酸铯作为碱,在DMF中在100℃下进行,如对于其它被作用物质所报道(J.Med.Chem.,2002,45,1697-1711)。另外地,可以将Cu/CuO的混合物用作催化剂,在DMSO-甲苯混合物中进行(Chem.Comm.,2004,7,778-779)。其中在2位的R1为烷基的式IV咪唑衍生物与式III的芳基卤化物的反应可以使用三乙基碳酸铵为碱,CuI为催化剂,8-羟基喹啉为配体,在DMF-水的混合物 作为溶剂中进行,如对于其它被作用物质所报道(J.Org.Chem.,2005,70,10135)。其中4位上的R1为烷基或者羟甲基的式I化合物可以通过使5位上的R1为烷基或者羟甲基的式IV化合物与式IV的卤化物反应轻易获得,使用CuI作为催化剂,Cs2CO3作为碱和DMF作为溶剂,如对于其它被作用物质所报道(J.Org.Chem.2004,69,5578;Bioorg.MedChem Lett.,2003,13,3521)。其中4位上的R1为氨甲基或者二甲基氨基甲基的式I化合物可以利用与对其它被作用物质所述相似的方法轻易获得(J.Med.Chem.,1987,12,2163-9;Synthesis,1983,1,47-9)。
式IV的咪唑衍生物与式III的芳基卤化物的反应还可以使用铜催化剂和式IV的衍生物的钠盐进行,与文献类似(Bioorg.Med.Chem.,2004,12,2251)。为钠盐的式IV化合物与芳基卤化物在催化量的CuO存在下,在DMF中,在150℃下反应。另外地,通过用两当量的咪唑(为游离碱),在溴化铜或者碘化铜(10% mol)和碳酸钾存在下,在NMP中,在微波辐射下处理芳基溴化物,可以将其转化为相应的N-咪唑基衍生物(Terahedron Lett.,2003,4217-4218)。Buchwald等人表明,咪唑的N-芳基化可以使用Cu(OTf)2.苯配合物作为铜源和碳酸铯作为碱,在作为添加剂的1,10-菲罗啉和dba(二亚苄基丙酮)存在下,在二甲苯中,在110-125℃下以高产率和避免过于剧烈的条件下实现(Tetrahedron Lett.,1999,40,2657);该方法可以成功用于将式III化合物转化为式I化合物。式IV的咪唑衍生物与式III的芳基卤化物的催化加成还可以利用单独的或者协同铜使用的钯催化剂进行。在作为溶剂的DMF中,利用Binap[2,2’-二(二苯膦基)-1,1’-联萘]或者Dppf[1,3-二(二苯膦基丙烷]钯可溶性催化剂和作为碱的叔丁基钾,在微波加热下将咪唑加成到芳基溴化物的Buchwald-Hartwig方法(Y.Wan,Synthesis 2002,11,1597-1600)可以成功扩展至由式III的卤化物开始制备式I化合物。其中至少一个R1取代基为三氟甲基的式I化合物可以通过类似的方法利用N-芳基化制备(J.Med.Chem.,1989,32,575)。
另外地,式I化合物可以由式V化合物通过在甲醛或者式R1CHO的醛和氯化铵存在下与乙二醛或者式VI的二羰基衍生物反应得到制备,如方案2中所示。
方案2:
其中X、W和R1具有对式(I)化合物所述的相同含义。
该反应通常在甲醇或者乙醇中,在适宜的酸催化剂(比如磷酸)存在下进行。其中所有的R1为氢原子的式I化合物,通过用乙二醛,在甲醇中,一般在室温下处理式V化合物,然后加入NH4Cl和甲醛,和在回流下加热,最后加入磷酸,可以以满意的收率获得。带有取代咪唑的式I化合物可以通过对其它被作用物质所述的相同方法,但是使用式VI的二羰基化合物(其中至少一个R1不是氢)制备(Synthesis,2003,2661-2666)。可以任选使用式R1CHO的醛而不是甲醛。
另外地,2和5位上的R1为氢的式I化合物可以由式V化合物进行制备,通过与硫光气反应,随后与式(VII)的胺加成和环化,然后对所得的咪唑-2-硫酮进行去硫成为相应的式I化合物,如方案3中所概述。
方案3:
其中X、W和R1具有对式(I)化合物所述的相同含义。该反应涉及将硫光气加入到式V化合物的含水盐酸溶液中形成硫氰酸酯。使所得的异硫氰酸酯与氨基乙醛二烷基缩醛(通常二甲基或者二乙基缩醛)在作为溶剂的醇中,在回流温度下和在有机碱存在下反应。所得的喹啉或 者喹唑啉咪唑-2-硫酮衍生物用20%硝酸处理和在大约100℃下加热,从而提供式I化合物。根据Bioorg.& Med.Chem.,2004,13,363-386,涉及在不超过0℃的温度下使用稀硝酸和亚硝酸钠的更温和的方法可以用于敏感的化合物。此外,对酸敏感的2-硫代咪唑基-取代的喹啉或者喹唑啉衍生物可以使用raney镍在醇性溶剂(比如乙醇或者甲醇)中去硫形成式I化合物(Archiv.Der Pharmazie,2002,335,69-76),或者使用H2O2在乙酸中去硫形成式I化合物(J.Het.Chem.,2003,40,229),或者在过渡金属催化剂存在下使用H2O2去硫形成式I化合物(Org.Process Res.& Dev.,2002,674)。在2-硫代咪唑基-取代的喹啉或者喹唑啉衍生物的制备中,一些适用于制备数种式I化合物的变体可以根据用于合成其它被作用物质的文献中报道的方法进行(Synthetic Commun.1997,27,3565;Synthesis,1987,12,1136;Synthesis 1978,10,741)。
另外地,其中X为碳原子的式I化合物可以由式VIII化合物,通过与式IX或者IXa的硼酸酯反应得到制备(方案4)。
方案4:
式VIII化合物可以根据方案5,由式VIIIa的喹诺酮(carbostiryl)衍生物制备。式VIIIa的喹诺酮衍生物根据已知的方法由6-溴-喹诺酮制备(Walker等人,US 4792561,Dec.20,1988)。用于将VIIIa转化成VIII的适当反应条件如文献中所述(Biochemistry,2005,44,9637;Bioorg.Med.Chem Lett.,2002,12,1361;Gazzetta Chimica It.,1989, 119,163)。式IX和IXa化合物为市售化合物或者可以由市售化合物根据标准方法制备。
方案5:
其中卤素原子为溴的式III化合物可以由式V化合物,通过在HBr和CuBr存在下根据已知的方法进行重氮化获得(J.of LabelledCompounds,1991,29,415),如方案6中所表明,其中X和W具有以上对式(I)化合物所述的相同含义。芳基碘化物可以通过使式V化合物与NaNO2和HCl在KI存在下反应获得(J.Med.Chem.,2001,15,2391)。芳基氯化物可以通过在CuCl存在下进行重氮化获得(J.Het.Chem.1991,28,1981)。式VIIIa化合物可以利用与方案1所述类似的方法由6-溴喹诺酮获得(J.Med.Chem.,1989,32,1173)。
方案6:
另外地,当在式I化合物中X为氮时,式III化合物可以通过使式X或者Xa的酰氯与式XI的苄胺衍生物反应,随后进行如方案7中所概述的环化和芳香化获得。
方案7:
其中R3、Y、Z和Q具有对式(I)化合物所述的相同含义。式XI化合物根据已知的方法制备。
式(I)化合物制备的非限制性代表例报道如下。
实施例1:[2-苯基-6-(1H-咪唑-1-基)]喹唑啉
在N2下,向咪唑(1.53g,2.24mmol)的DMF(3ml)溶液中分份加入NaH(60%油分散体,0.85g,2.2mmol),在室温下将混合物搅拌10分钟。然后将6-溴-2-苯基-喹唑啉(2.0g,0.7mmol)和CuO(0.19g,0.24mmol)加入其中,在150℃下将混合物加热6小时,冷却和倾倒在水上。将沉淀过滤、用水洗涤和溶于热AcOEt/THF 1/1中。将不溶性物质滤出和对滤液进行浓缩。获得的固体与异丙醚一起进行研磨和在真空中进行干燥(1.08g,产率57%)。C17H12N4;MW:272.31;mp153.8-158.7℃;1H NMR(DMSO-d6)9.72(s,1H),8.39 8.63(m,5H),8.23(d,1H),8.00(s,1H),7.58-7.62(m,3H),7.23(s,1H);IR(KBr)1556,1506,1379;TLC(CHCl3∶MeOH 9∶1)Rf=0.50
6-溴-2-苯基-喹唑啉
在0℃下,向5-溴-2-氨基-苄胺二盐酸化物(38g,0.138mol)的二氯甲烷(DCM)(1升)悬浮液中加入三乙胺(TEA)(67.5ml,0.485mol)和苯甲酰氯(17ml,0.145mol)的DCM(200ml)溶液。在室温下将此混合物搅拌1小时。将水加入其中和将有机相分离、用水洗涤和用Na2SO4进行干燥。在真空中(i.v.)将溶剂除去和将所得残余物悬浮在POCl3(200ml)中。在回流下将混合物加热1小时,然后将溶剂i.v.除去,和将所得残余物分配在AcOEt和0.1N NaOH之间。所得有机相用0.1N NaOH和水洗涤,然后用Na2SO4干燥和真空浓缩,从而提供固体。在回流下将获得的固体和四氯苯醌(35g,0.138mol)的甲苯(600ml)混合物加热4小时。对混合物进行i.v.浓缩和所得残余物用DCM处理。将不溶性物质滤出和用DCM洗涤。合并的滤液用0.1N NaOH洗涤,然后用水洗涤。所得溶液用Na2SO4干燥并且进行i.v.浓缩。获得的固体与甲醇一起研磨和进行i.v.干燥(22g,产率56%)。C14H9BrN2;MW:285.15; 1H NMR(DMSO-d6)9.70(s,1H),8.49 8.56(m,3H),8.17(dd,1H),8.02(d,1H),7.58-7.61(m,3H);TLC(AcOEt∶PE 2∶8)Rf=0.70.
5-溴-2-氨基-苄胺二盐酸化物
在N2下,在0℃下将硼烷的THF溶液(1M,400ml)加入到5-溴-邻氨基苯甲腈(60g,0.304mol,如S.M.Mackenzie等人,J.Chem.Soc.C,1970,17,2298-2308所述制备)的THF(450L)悬浮液中。在室温下将此混合物搅拌72小时。冷却至0℃之后,将绝对EtOH加入其中,然后使HCl鼓泡通过溶液。对混合物进行i.v.压力浓缩和使所得残余物与异丙醚一起研磨。对获得的固体进行i.v.干燥,从而给出标题产品(76.6g,产率91.4%)。C7H9BrN2.2HCl,MW 273.9;1H NMR(DMSO-d6)8.57(s,2H),7.73(s,1H),7.55(dd,1H),7.24(d,1H),5,82(s,4H),4.13 (s,2H);TLC(CHCl3∶MeOH∶H2O∶NH3 85∶25∶2∶1)Rf=0.3.
实施例2:[2-苯基-6-(1H-咪唑-1-基)]喹啉
在室温下,将溶于甲醇(20ml)中的2-苯基-6-氨基-喹啉(1.0g,4.54mmol)(如EP1571142中所述制备)用40% aq乙二醛(0.52ml,4.54mmol)处理20小时。将NH4Cl(486mg,9.08mmol)加入其中,随后将37% aq.甲醛(0.68ml,9.08mmol)加入其中。所得混合物用甲醇(200ml)稀释和回流1小时。在10分钟时间内,将H3PO4(0.64ml,85%)加入其中。然后,在回流下将所得混合物进一步搅拌20小时。除去溶剂之后,将暗色残余物倾倒在冰上和用aq 30% NaOH中和,直至pH 9为止。所得混合物用Et2O进行提取。将有机相合并和用水、盐水洗涤并进行干燥(Na2SO4)。将溶剂除去,和所得残余物与异丙醚一起研磨,从而提供700mg标题产品(产率:57%)。C18H13N3,M.W.271.32.mp:141.7-147.5℃,1H-NMR(d6-DMSO):8.52(d,1H);8.30-7.92(m,6H);7.60-7.25(m,5H);7.20(s,1H).MS:M+272;IR(KBr):3391,3055,1620,1598,1499cm-1.TLC:(9/1氯仿/甲醇)Rf=0.50.
实施例3:[2-(1,3-苯并二氧杂环戊烯-5-基)-6-(1H-咪唑-1-基)]喹唑啉
在室温下,将6-氨基-2-(1,3-苯并二氧杂环戊烯-5-基)-喹唑啉(2.5g,9.4mmol)和40%含水乙二醛(1.1ml,9.4mmol)的甲醇(20ml)悬 浮液搅拌18小时。将NH4Cl(1.0g,0.019mol)、37%含水甲醛(1.4ml,19mmol)和甲醇(200ml)加入其中并且将混合物回流1小时。将85%H3PO4(1.4ml)加入其中和在回流下将混合物进一步加热4小时。将溶剂除去和将所得残余物倾倒在水上,并且用含水NaOH进行碱化。将沉淀滤出、用水洗涤和溶于DCM中。产品用含水HCl(0.001N)提取三次。收集水层、用Na2CO3进行碱化和用氯仿提取。所得有机层用水洗涤和用Na2SO4干燥。对溶液进行i.v.浓缩,和使所得残余物与异丙醚一起研磨。对固体进行过滤和干燥,从而给出标题产品(2.0g,29%产率)。C18H12N4O2,MW:316.32.mp 217-218℃;1H NMR(DMSO-d6)9.65(s,1H),8.36-8.50(m,3H),8.14-8.22(m,2H),8.00(d,2H),7.21(s,1H),7.12(d,1H),6.16(s,2H);IR(KBr)1504,1446,1251;TLC(CHCl3∶MeOH9∶1)Rf=0.30.
6-氨基-2-(1,3-苯并二氧杂环戊烯-5-基)-喹唑啉
将6-硝基-2-(1,3-苯并二氧杂环戊烯-5-基)-喹唑啉(37g,0.126mol)和SnCl2.2H2O(117.2g,0.504mol)的乙醇(500ml)悬浮液回流加热1小时。冷却至室温之后,将溶剂i.v.除去,将氯仿加入其中和混合物用氨进行碱化。将沉淀滤出和用氯仿洗涤。收集滤液、用水洗涤和用Na2SO4干燥。对溶液进行i.v.浓缩,和使所得残余物与异丙醚/石油醚一起研磨。对固体进行过滤和i.v.干燥,从而给出标题产品(21.2g,产率64%)。C15H11N3O2,MW:265.27.mp 191-192℃;1H NMR(DMSO-d6)9.24(s,1H),8.05(dd,1H),7.91(d,1H),7.73(d,1H),7.39(dd,1H),7.03(d,1H),6.90(d,1H),6.11(s,2H),5.93(s,2H);IR(KBr)3319,3203,1631,1500,1446;TLC(CHCl3/MeOH 9/1)Rf=0.3.
6-硝基-2-(1,3-苯并二氧杂环戊烯-5-基)-喹唑啉
在0℃下,向5-硝基-2-氨基-苄胺盐酸盐(31g,0.152mol)的DCM(450ml)悬浮液中加入TEA(52.6ml,0.38mol)和胡椒基酰氯(27.3g,0.16mol)的DCM(80ml)溶液。在室温下将此混合物搅拌2小时。将溶剂i.v.除去,和使所得残余物与乙醇/水1/9一起研磨,然后与异丙醚一起研磨。对获得的固体进行干燥和将其悬浮在甲苯(900ml)和POCl3(670ml)中。在回流下将混合物加热2小时,然后将溶剂i.v.除去和使所得残余物与水/氨一起研磨、用水洗涤和用P2O5进行干燥。将获得的产品和四氯苯醌(32.7g,0.129mol)的甲苯(500ml)混合物回流加热2小时。对混合物进行i.v.浓缩和使所得残余物与NaOH 1M一起研磨,用水和甲醇洗涤。对获得的固体进行i.v.干燥(37g,产率82.5%)。C15H9N3O4,MW:295.26,mp 220-222℃.
5-硝基-2-氨基-苄胺盐酸盐
在N2下,在0℃下将硼烷的THF(1M,840ml)溶液加入到5-硝基-邻氨基苯甲腈(120g,0.70mol)的THF(1.2L)悬浮液中。在室温下将此混合物搅拌2小时。在0℃下冷却之后,将绝对EtOH(400ml)加入其中,并且使HCl鼓泡通过溶液。在减压下对混合物进行浓缩,和使所得残余物与乙醇一起研磨,然后与异丙醚一起研磨。获得的固体在真空中干燥,从而给出标题产品(140g,产率98.6%)。C7H9N3O2.HCl,MW:203.63.TLC(CHCl3∶MeOH∶H2O∶NH3 85∶25∶2∶1)Rf=0.3.
实施例4:[2-(苯并呋喃-5-基)-6-(1H-咪唑-1-基)]喹唑啉二盐酸化物
该化合物由6-氨基-2-(5-苯并呋喃)-喹唑啉开始,根据实施例3合成[2-(1,3-苯并二氧杂环戊烯-5-基)-6-(1H-咪唑-1-基)]喹唑啉中所述的方法,以20%的产率得到合成。C19H12N4O.2HCl;MW:385.25;mp284.7-285.1℃;1H NMR(DMSO-d6)10.00(s,1H),9.78(s,1H),8.90(s,1H),8.71(d,1H),8.58(d,1H),8.47(m,2H),8.29(d,1H),8.10(d,1H),8.02(s,1H),7.78(d,1H),7.15(s,1H);IR(KBr)3399,3097,1614;TLC(CHCl3∶MeOH 9∶1)Rf=0.38.
6-氨基-2-(5-苯并呋喃)-喹唑啉
该化合物由苯并呋喃-5-羧酸开始,根据实施例3合成6-氨基-2-(1,3-苯并二氧杂环戊烯-5-基)-喹唑啉中所述的方法以59%的产率得到合成。 1H NMR(DMSO-d6)9.31(s,1H),8.77(s,1H),8.48(dd,1H),8.06(d,1H),7.68-7.80(m,2H),7.41(dd,1H),7.10(d,1H),6.93(d,1H);TLC(tol/AcOEt 7/3)Rf=0.35.
6-硝基-2-(5-苯并呋喃)-喹唑啉的合成
该化合物根据实施例2合成6-硝基-2-(1,3-苯并二氧杂环戊烯-5-基)-喹唑啉中所述的方法以76%的产率得到合成。TLC(tol/AcOEt 7/3)Rf=0.80;mp.293-7℃.
实施例5:[2-(2,3-二氢-1,4-苯并二噁英-6-基)-6-(1H-咪唑-1-基)喹唑啉
该化合物根据实施例3合成[2-(1,3-苯并二氧杂环戊烯-5-基)-6-(1H-咪唑-1-基)]喹唑啉中所述的方法,以25%的产率得到合成。C19H14N4O2,MW:330.35;mp 131.5-131.9℃;1H NMR(DMSO-d6)9.64(s,1H),8.49(s,1H),8.32-8.43(m,2H),8.18(s,1H),8.03-8.13(m,2H),7.97(d,1H),7.21(s,1H),7.04(d,1H),4.34(s,4H);IR(KBr)1555,1507,1286;TLC(CHCl3∶MeOH 9∶1)Rf=0.38.
6-氨基-2-(2,3-二氢-1,4-苯并二噁英-6-基)-喹唑啉
该化合物根据实施例3合成6-氨基-2-(3,4-亚甲基二氧基-苯基)-喹唑啉中所述的方法以67%的产率得到合成。C16H13N3O2,MW:279.30.mp179.4-181.6℃;1H NMR(DMSO-d6)9.24(s,1H),7.92-7.98(m,2H),7.72(d,1H),7.38(dd,1H),6.89-6.99(m,2H),5.91(s,2H),4.31(s,4H);IR(KBr)1555,1507,1286;TLC(CHCl3/MeOH 9/1)Rf=0.65.
6-硝基-2-(2,3-二氢-1,4-苯并二噁英-6-基)-喹唑啉
该化合物根据实施例3合成6-硝基-2-(3,4-亚甲基二氧基-苯基)-喹唑啉中所述的方法以70%的产率得到合成。C16H11N3O4,MW:309,28;mp:263-265;TLC(tol/AcOEt 7/3)Rf=0.80.
实施例6:[2-(3,4-二氯苯基)-6-(1H-咪唑-1-基)]喹唑啉
该化合物由6-氨基-2-(3,4-二氯-苯基)-喹唑啉(如EP1571142中所述制备)开始,根据实施例3合成[2-(1,3-苯并二氧杂环戊烯-5-基)-6-(1H-咪唑-1-基)]喹唑啉中所述的方法以32%的产率得到合成。C17H10Cl2N4,MW:341.20;mp 131.5-131.9℃;1H NMR(DMSO-d6)9.70(s,1H),8.41-8.66(m,4H),8.22(d,1H),7.98(s,1H),7.82(m,2H),7.21(s,1H);IR(KBr)1578,1548,1500;TLC(CHCl3∶MeOH 9∶1)Rf=0.41.
实施例7:[2-[(4-苄氧基)苯基-6-(1H-咪唑-1-基)]喹唑啉二盐酸化物
该化合物由6-氨基-2-(4-苄氧基-苯基)-喹唑啉开始,根据实施例3合成[2-(1,3-苯并二氧杂环戊烯-5-基)-6-(1H-咪唑-1-基)]喹唑啉中所述的方法以44%的产率得到合成。通过用甲醇/HCl处理它的甲醇悬浮液和进行蒸发,游离碱被转化成盐酸盐。所得固体在MeCN中研磨和进行i.v.干燥,从而给出标题化合物。C24H18N4O.2HCl,MW:451.36;1H NMR(DMSO-d6)9.81(s,1H),8.02-8.96(m,7H),7.21-7.52(m,8H),5.24(s,2H)mp 170℃;IR(KBr)3399,2925,1603,1512,1259;TLC(CHCl3∶MeOH9∶1)Rf=0.30.
本发明化合物的药理学评价
式(I)化合物用于治疗炎性和神经性疼痛以及炎性相关疾病的效力已经利用以下体外测定和体内动物模型得到了确定。
在用于COX-1或者COX-2酶抑制作用的标准体外试验中,本发明化合物并不能有效抑制环氧合酶(COX-1和COX-2),因为它们已经被证实在高达10-5M浓度时并不有效。此外,在用于iNOS和nNOS酶抑制作用的标准体外试验中,本发明化合物并不能有效抑制氧化氮(nitricoxide)合酶,因为它们已经被证实在高达10-5M浓度时并不有效。据此,本发明化合物不能起经典的COX或者iNOS酶抑制剂的作用。
已经发现,本发明化合物在数种细胞系中有效干涉COX-2和细胞因子形成;在IL-1刺激的人类软骨肉瘤细胞系中,对于COX-2和IL-1β和IL-6细胞因子的这些作用的实例报道于表3中。
表3
化合物 | 浓度 (μM) | COX-2生成的 抑制作用(%) | IL-1生成的 抑制作用(%) | IL-6生成的 抑制作用(%) |
实施例1 | 0.3 | 20 | 10 | 35 |
实施例3 | 0.3 1 10 | 35 64 75(1) | 20 15 40 | 20 35 NA |
实施例5 | 0.3 1 10 | 50 60 70 | 20 30 40 | NE NE 35 |
(1)IC50为0.63±0.24μM.
对该细胞因子的调节剂性能可以完全或者部分归因于本发明化合物在炎症和疼痛的体内模型中显示的抗炎和显著的止痛性能。
Zymosan-诱发的机械痛觉过敏的interplantar注射被用作炎性疼痛的模型(Meller,Neuropharmacology,1994,33,1471-1478)。在该模型中,雄性Sprague-Dawley或Wistar大鼠(200-250g)一般在一个后爪中接受3mg/100μl酵母聚糖的interplantar注射。标记的炎症存在于该后爪上。在炎性损伤前30分钟,将药物口服给药以评价其效力。由酵母聚糖给药诱发的痛觉过敏使用Randall-Selitto方法进行评价(Arch.Int.Pharmacodyn.,1957,111,409)。定量止痛作用由止痛计实现,其包括使得炎性的爪重量增加(从130-140g升高至高达500g)。在炎性激发4小时之后确定的基本值(通常230-250g)和用药物处理的动物耐受值之 间的机械痛觉阈差异被定义为机械痛觉过敏。对于本发明化合物,机械痛觉过敏被表达为ED50,其是同对照动物组相比,能够升高痛觉阈50%的给药化合物的剂量。表示能够降低100%痛觉阈的剂量的相应ED100可以适合于存在线性剂量反应关系的那些情形。由本发明化合物发挥的体内抗炎作用可以在如上所述的相同酵母聚糖诱发的炎症测试中,通过测量由炎性试剂诱发的浮肿体积进行评价。浮肿被测定为0-2小时时间内酵母聚糖注射爪的体积增加。爪浮肿体积的变化测量使用hydroplethysmometer记录,其由含有表面活性剂液体的两个塑料小池组成,较大的一个用于浸泡爪,连接在含有能够记录用于测量的体积的少量排出的传感器的较小一个上。将爪浸入小池中至高达胫跗关节处。被排出的液体体积与炎症的程度成比例。本发明化合物在预防浮肿形成中的效力被表示为ED30,在炎性激发两小时之后测量,和同对照动物(用酵母聚糖处理,但是仅仅用蒸馏水处理而不是用测试化合物处理)相比,表示能够降低30%酵母聚糖诱发的爪体积升高的剂量。表示能够降低50%酵母聚糖诱发的爪体积增加的剂量的相应ED50,对于其中存在线性剂量响应关系的情形可以计算出来。在两种试验中,对于每种测试化合物,至少使用三个剂量,每组10只动物。本发明化合物在10、20和40mg/Kg下进行测试。
在如上所述的测试中,代表性的式(I)化合物的性能,止痛作用和抗炎作用都概述于表4中,其中将本发明化合物的活性与熟知标准样品在相同测试中的性能进行比较。在止痛和抗炎作用测试中,代表性的本发明化合物都表现出了优于或者相当于标准样品的效力。此外,同尼美舒利所显示的副作用相比,即使在更高的测试剂量下,本发明化合物也未显示出溃疡性副作用。
表4:
NE:无效;NC:不可计算
式(I)化合物的止痛活性可以进一步在慢性炎性疼痛的动物模型中进行评价。因为在临床上,炎性疼痛通常与比如关节炎和慢性下背疼痛的长期症状有关,其中末梢和中枢神经系统的任何炎症或者胶质神经元变化将长期存在,在其中炎性侵害有诱发中枢介导变化的时间的慢性动物模型中,结果更具有预示性。慢性炎性疼痛的初始模型基于向大鼠的尾根中注射入炎症介质(添加剂)。由于该处理的原因,在注射位置将产生包括深度炎症和痛觉过敏的初始多发性关节炎。然而,由于T细胞介导的痛觉过敏反应,在几星期之后,疾病发展涉及多个关节和随后使得眼睛、耳朵、鼻子和生殖器产生病变。这些全系统影响并没有反映那些在特征在于慢性炎性疼痛的通常病理学中临床观察到的影响。最近,已经表明如何将Complete Freund’s Adjuvant(CFA;结核分枝杆菌)作为引发试剂用于炎性响应同时使用适当的方案可以产生更适宜的模型。CFA-诱发的延长炎症已经在行为疼痛反应的研究中得到了广泛应用(K.Walker,Mol Med Today,1999,5,319-321),因为认为它还适于研究慢性疼痛的神经元可塑性的复杂情况(R.Sharif Naeini,Eur.J.Neuroscience,2005,22,8,2005-2015)。试验如文献所述进行(C.J.Woolf,Br.J.of Pharmacology,1997,121,417-424);各组使用8只大鼠,各个产品测试三个剂量(3,10,30mg/kg),i.p.激发24小时后,将产品i.p.给药,和止痛活性从激发后24小时时开始测量。在表5中,将代表性的式(I)化合物在CFA模型中获得的结果与吡罗昔康(一种认可的标准)进行对比式的列出。止痛作用利用与先前对Randall-Selitto模型所述相同的设备进行评价,将结果记录为表示用药物处理的动物与仅仅 接受载体的对照之间的痛觉阈差异(%)的最大百分比作用(MPE)(同接受CFA处理的对照相比,由于爪负载有升高的重量而产生的痛觉感受作用的降低)。100%保护意味着用化合物和CFA处理的动物可以容忍与没有接受CFA处理的对照动物相同的刺激(重量)。高于100%的MPE意味着用化合物和CFA处理的动物可以容忍比没有接受CFA处理的对照动物更高的刺激(重量)(痛觉减退)。根据0.5小时时的MPE数据,计算了产生50%(ED50)和100%(ED100)保护的剂量。
表5:CFA
NE:无效;NC:不可计算
在该测试中,在10和30mg/Kg的剂量下,这是具有显著的痛觉减退作用特征的最高剂量,本发明化合物还表明了显著和长期的止痛作用。计算的ED50和ED100值低于10mg/kg。在该剂量下,代表性的化合物比参比标准吡罗昔康更为有效得多。
疼痛的糖尿病性神经病变是人类胰岛素-依赖糖尿病的最常见并发症;特别是,糖尿病会与通过经典镇痛药不能处理的神经性疼痛相关。链脲佐菌素(STZ)-诱发的大鼠糖尿病已经逐渐被用作评价潜在止痛剂的效力的疼痛的糖尿病性神经病变的模型(C.Courteix,Pain 1993,53,81-8)。根据文献所述的试验模型,测试本发明化合物在降低与STZ-诱发的大鼠糖尿病相关的机械痛觉过敏中的效力。通过注射一个剂量(75mg/Kg,i.p.)的STZ,产生糖尿病。在诱导糖尿病之后的四周内,对动物逐渐发展的临床症状(重量,主体和表皮温度,运动性和高血糖症)进行严格监控。四周之后,在糖尿病性的大鼠中获得的多种痛觉刺激(特 别是机械刺激)得分大于正常大鼠的得分,则表示痛觉过敏。通过糖尿病诱发的痛觉过敏使用如上所述的Randall-Selitto方法进行评估,和使用痛觉测量器进行定量。在这种情况下,同样将基本值(通常230-250g)和用药物处理的动物的容忍值之间的机械痛觉阈差异定义为机械痛觉过敏。本发明化合物在不同的剂量下i.p.给药(溶液,Tween 80,在盐水中10%),和在报道时间测量机械痛觉过敏,作为最大百分比作用(MPE),其表示用药物处理的动物和仅仅接受载体的对照之间的痛痛觉阈差异(%),与 非糖尿病性对照的承载的重量进行比较。100%保护意味着用化合物处理的糖尿病性动物可以容忍与 非糖尿病性的动物相同的刺激(重量)。高于100%的MPE意味着用化合物处理的糖尿病性动物可以容忍比对照非糖尿病性的动物更高的刺激(重量)(痛觉减退)。
在表6中,将代表性的式(I)化合物在上述神经性疼痛模型中的性能与一些用于临床处理该病理学的已知药理学标准数据进行了比较。特别是,根据0.5小时时的MPE数据,已经计算了产生50%(ED50)和100%(ED100)保护的剂量。
表6:神经性疼痛
NE:无效;NC=不可计算;*)外推值
代表性的式1化合物被证实是非常有效的,特别是在30mg/kg(即高于100%保护)的剂量下,ED50和ED100值低于10mg/kg,如酵母聚糖和CFA测试中所表明。与此相反,所有测试标准都在该范例中表现出了即使有也低得多的效力。事实上,对于曲马多,仅仅ED50值是可以计算的(对于该标准,ED100仅仅是由反应曲线外推接近100%保护的剂量)。
药物组合物
式I化合物可以用于制造用于治疗处理疼痛和炎性相关病症的适宜药物。特别是用于处理慢性疼痛病症和免疫-驱动的炎性事件,它们是多种慢性炎性疾病的显著原因,其中长期炎症会导致组织破坏和导致巨大损伤。
据此,式(I)化合物、它们的盐和其溶剂化物的适当药物组合物可 以用于处理急性和慢性疼痛,包括但不限于炎性疼痛和相关的痛觉过敏和异常性疼痛、骨关节炎疼痛、手术后疼痛、内脏疼痛、与癌症相关的疼痛、三叉神经痛、急性疱疹和疱疹后神经痛、神经性疼痛、糖尿病性神经病变。
此外,式(I)化合物、它们的盐和其溶剂化物的适当药物组合物可以用于处理免疫-驱动的炎性事件,包括但不限于关节炎、风湿性关节炎和骨关节炎、胃肠道的炎性病症(比如炎症性肠病(IBD))、溃疡性结肠炎、Crohn’s疾病(CD)、炎性泌尿膀胱病症、呼吸道的炎性病症(慢性阻塞性肺病(COPD)和哮喘)、术后炎性并发症、炎性眼部病症、系统性红斑狼疮、皮肤病(比如湿疹、牛皮癣和皮炎)。
此外,式(I)化合物、它们的盐和其溶剂化物的适当药物组合物可以用于处理癌症,包括但不限于:结肠癌、多发性骨髓瘤、乳腺癌、子宫颈瘤、前列腺癌和肺癌。
本发明化合物可以以药理学有效量口服、胃肠外或者局部给药。在此使用的术语胃肠外包括静脉内、肌内、皮下、皮内和关节内。
对于本文中对式(I)化合物所讨论的所有治疗方法,每日口服剂量制度将优选为约0.1~约20mg/Kg总体重。本领域熟练技术人员还应当认可,式(I)化合物的最佳量和单个剂量的间隔将由进行处理的症状的性质和程度确定。
本发明还涉及适于处理以上疾病的组合物,其含有药学有效量的式(I)化合物、它的盐、溶剂化物和其前药和药学上可接受的载体或者稀释剂。
为了在治疗学中使用式(I)化合物,通常根据药学常规方法和当前准则和相关的良好实验室与制造实践将其配制成剂型。
对于本发明化合物,优选的给药途径是口服。可以将本发明化合物配制成多种口服剂量形式,比如胶囊、片剂、丸剂、粉末和可分散的微粒。适宜的载体可以为一种或者多种可以充当稀释剂、增香剂、增溶剂、润滑剂、助悬剂、结合剂的物质。
适宜的载体包括但不限于碳酸镁、硬脂酸镁、滑石、乳糖、果胶、糊精、淀粉、甲基纤维素、羧甲基纤维素钠盐、可可脂等等。用于制备口服制剂的工艺为通常的混合、粒化和压缩或者胶囊填装。其它适于口服给药的形式包括乳剂、糖浆剂和含水溶液剂。乳剂可以使用例如卵磷 脂、丙二醇或者去水山梨糖醇单油酸酯的乳化剂制备。含水溶液剂可以通过将活性成分溶于水中和加入适宜的颜料、食用香料、稳定剂进行制备。
可以将本发明化合物配制成用于胃肠外给药(例如,通过注射或者连续输注)的具有适宜载体的组合物,所述载体包括含水载体溶液(即:盐水,葡萄糖)或者和/或含油乳剂。所述药物产品可以以单元剂型的形式存在,例如存在于安瓿或者预填装的注射器中。
适于局部给药的制剂包括适于渗透通过皮肤的液体或者半液体制剂(例如:涂沫剂,洗剂,膏剂,乳膏剂和糊剂)和适于给药至眼睛的滴剂。
Claims (14)
2.根据权利要求1的化合物的药学上可接受的盐,其选自盐酸盐、氢溴酸盐、硫酸氢盐和硫酸盐、马来酸盐、富马酸盐、乙二酸盐、甲磺酸盐、琥珀酸盐、抗坏血酸盐、酒石酸盐。
3.根据权利要求1的化合物或权利要求2的盐在制备药物中的用途,该药物用于药理学治疗疼痛和炎性相关病症。
4.根据权利要求1的化合物或权利要求2的盐在制备药物中的用途,该药物用于药理学治疗急性和慢性疼痛。
5.根据权利要求1的化合物或权利要求2的盐在制备药物中的用途,该药物用于药理学治疗炎性疼痛和相关的痛觉过敏和异常性疼痛。
6.根据权利要求1的化合物或权利要求2的盐在制备药物中的用途,该药物用于药理学治疗骨关节炎和风湿性关节炎疼痛。
7.根据权利要求1的化合物或权利要求2的盐在制备药物中的用途,该药物用于药理学治疗关节炎。
8.药物组合物,包括作为活性物质的至少一种根据权利要求1的化合物或权利要求2的盐,和进一步包括选自载体、结合剂、食用香料、甜味剂、崩解剂、防腐剂、湿润剂和其混合物的药学上的惰性成分,或者促进透皮或者透粘膜吸收或者使得活性物质随时间控制释放的成分。
9.药物组合物,包含作为活性物质的至少一种根据权利要求1的化合物或权利要求2的盐,用于胃肠外应用,和进一步包含选自载体的药学上惰性成分,所述载体包括含水载体溶液和/或含油乳状液。
10.根据权利要求8或者权利要求9的药物组合物,用于药理学治疗与急性或者慢性疼痛相关的病理学状况。
11.根据权利要求8或者权利要求9的药物组合物,用于药理学治疗炎性疼痛和相关的痛觉过敏和异常性疼痛。
12.根据权利要求8或者权利要求9的药物组合物,用于药理学治疗骨关节炎和风湿性关节炎疼痛。
13.根据权利要求8或者权利要求9的药物组合物,用于药理学治疗关节炎。
14.根据权利要求8或者权利要求9的药物组合物,用于药理学治疗风湿性关节炎和骨关节炎。
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DE102008022221A1 (de) | 2008-05-06 | 2009-11-12 | Universität des Saarlandes | Inhibitoren der humanen Aldosteronsynthase CYP11B2 |
BRPI0822462A2 (pt) * | 2008-06-20 | 2015-10-13 | Rottapharm Spa | derivados de 6-1h-imidazo-quinazolina e de quinolinas, novos inibidores de mao e ligantes a receptor de imidazolina. |
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CN105078978A (zh) | 2009-08-17 | 2015-11-25 | 因特利凯公司 | 杂环化合物及其用途 |
US8541404B2 (en) | 2009-11-09 | 2013-09-24 | Elexopharm Gmbh | Inhibitors of the human aldosterone synthase CYP11B2 |
WO2011149937A1 (en) * | 2010-05-24 | 2011-12-01 | Intellikine, Inc. | Heterocyclic compounds and uses thereof |
TW201210597A (en) * | 2010-06-09 | 2012-03-16 | Gilead Sciences Inc | Inhibitors of hepatitis C virus |
UA113280C2 (xx) | 2010-11-11 | 2017-01-10 | АМІНОСПИРТЗАМІЩЕНІ ПОХІДНІ 2,3-ДИГІДРОІМІДАЗО$1,2-c]ХІНАЗОЛІНУ, ПРИДАТНІ ДЛЯ ЛІКУВАННЯ ГІПЕРПРОЛІФЕРАТИВНИХ ПОРУШЕНЬ І ЗАХВОРЮВАНЬ, ПОВ'ЯЗАНИХ З АНГІОГЕНЕЗОМ | |
JP5808826B2 (ja) | 2011-02-23 | 2015-11-10 | インテリカイン, エルエルシー | 複素環化合物およびその使用 |
US8725124B2 (en) | 2012-03-05 | 2014-05-13 | Enterproid Hk Ltd | Enhanced deployment of applications |
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BR112019027719A2 (pt) | 2017-06-28 | 2020-07-28 | Ptc Therapeutics, Inc. | métodos para tratar a doença de huntington |
US11382918B2 (en) | 2017-06-28 | 2022-07-12 | Ptc Therapeutics, Inc. | Methods for treating Huntington's Disease |
JP7399870B2 (ja) | 2018-03-27 | 2023-12-18 | ピーティーシー セラピューティクス, インコーポレイテッド | ハンチントン病を処置するための化合物 |
JP7421507B2 (ja) | 2018-06-27 | 2024-01-24 | ピーティーシー セラピューティクス, インコーポレイテッド | ハンチントン病を処置するためのヘテロ環式およびヘテロアリール化合物 |
EP3735974A1 (en) | 2019-05-10 | 2020-11-11 | Rottapharm Biotech S.r.l. | Use of 2-phenyl-6-(1h-imidazol-1-yl)quinazoline for treating neurodegenerative diseases, preferably alzheimer's disease |
CN113874360A (zh) * | 2019-05-10 | 2021-12-31 | 瑟赛治疗公司 | 噻唑啉抗痛觉过敏剂的制造方法和多晶型物 |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005046698A1 (en) * | 2003-11-10 | 2005-05-26 | Synta Pharmaceuticals, Corp. | Fused heterocyclic compounds |
EP1571142A1 (en) * | 2004-03-01 | 2005-09-07 | Rottapharm S.p.A. | Novel anti-inflammatory and analgesic heterocyclic amidines that inhibit nitrogen oxide (NO) production |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4792561A (en) | 1986-05-29 | 1988-12-20 | Syntex (U.S.A.) Inc. | Carbostyril derivatives as combined thromboxane synthetase and cyclic-AMP phosphodiesterase inhibitors |
US5455252A (en) | 1993-03-31 | 1995-10-03 | Syntex (U.S.A.) Inc. | Optionally substituted 6,8-quinolines |
JPH0733743A (ja) * | 1993-07-22 | 1995-02-03 | Kyorin Pharmaceut Co Ltd | 2−アリール−4−キノリノール誘導体 |
US6627647B1 (en) * | 2000-03-23 | 2003-09-30 | Boehringer Ingelheim Pharmaceuticals, Inc. | Substituted 1-(4-aminophenyl)imidazoles and their use as anti-inflammatory agents |
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- 2006-08-03 EP EP06778146A patent/EP2066653B1/en active Active
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005046698A1 (en) * | 2003-11-10 | 2005-05-26 | Synta Pharmaceuticals, Corp. | Fused heterocyclic compounds |
EP1571142A1 (en) * | 2004-03-01 | 2005-09-07 | Rottapharm S.p.A. | Novel anti-inflammatory and analgesic heterocyclic amidines that inhibit nitrogen oxide (NO) production |
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WO2008014822A1 (en) | 2008-02-07 |
CA2659696A1 (en) | 2008-02-07 |
JP5095736B2 (ja) | 2012-12-12 |
US20110257209A1 (en) | 2011-10-20 |
CN101528728A (zh) | 2009-09-09 |
PT2066653E (pt) | 2012-10-22 |
PL2066653T3 (pl) | 2013-02-28 |
ES2394971T3 (es) | 2013-02-07 |
AU2006346931B2 (en) | 2012-07-19 |
CA2659696C (en) | 2014-04-22 |
HK1131987A1 (en) | 2010-02-12 |
EP2066653A1 (en) | 2009-06-10 |
JP2009545540A (ja) | 2009-12-24 |
AU2006346931A1 (en) | 2008-02-07 |
EP2066653B1 (en) | 2012-09-12 |
DK2066653T3 (da) | 2012-12-10 |
US7994181B2 (en) | 2011-08-09 |
US20090264451A1 (en) | 2009-10-22 |
US8193353B2 (en) | 2012-06-05 |
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