CN104812394A - 吩噻嗪衍生物及其治疗肺结核的用途 - Google Patents
吩噻嗪衍生物及其治疗肺结核的用途 Download PDFInfo
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- CN104812394A CN104812394A CN201380061666.1A CN201380061666A CN104812394A CN 104812394 A CN104812394 A CN 104812394A CN 201380061666 A CN201380061666 A CN 201380061666A CN 104812394 A CN104812394 A CN 104812394A
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Abstract
用于抗微生物剂的式(1)的三环衍生物,其中R1可为烷基磺酸酯或磺酰胺基。所述衍生物可选地被取代,其中R2为氢、卤素、取代的烷基、硫醚或乙酰基;Y可为N或C;X可为S、SO、SO2、N、O、CH2、C(O)、CO2、NHCO,并且环B为6元、7元或8元环烷基环。所述三环衍生物,例如噻吩嗪衍生物,可用于治疗肺结核,尤其是药敏型和耐药型肺结核。本发明的衍生物可单独使用,或者与已知的抗结核药物例如乙硫异烟胺和乙胺丁醇联合使用,并且该组合可作为单一剂量给药,或作为两个分别的剂量给药。所述三环衍生物还可用于制造用于治疗肺结核的药物。
Description
技术领域
本发明涉及吩噻嗪、吩噁嗪、吩嗪、吖啶、氧氮杂卓、二氮杂卓、氧杂蒽、噻吨的三环衍生物及其用途。
背景技术
已证实了吩噻嗪抗精神病药和抗组胺药丙氯拉嗪、氯丙嗪和普马嗪与多种抗微生物剂具有协同相互作用。在吩噻嗪的存在下,这些抗生素的最低抑菌浓度往往被浓缩至8,000倍。
还已知吩噻嗪通过抑制II型NADH:甲基萘醌氧化还原酶而增加结核分枝杆菌(Mycobacterium tuberculosis)的NADH/NAD比。由此它们能增加细胞的还原态,并且能够与需要真菌硫醇(mycothiol)来活化的药物(例如异烟肼和乙硫异烟胺)协同作用。这些联合治疗有助于限制产生对抗微生物剂的抗药性。已证明了吩噻嗪(例如甲硫哒嗪)能有效抵抗结核分枝杆菌的多重和极端耐药型。
虽然吩噻嗪主要用作精神安定药物,但已证实了吩噻嗪广泛的生物活性。这些精神安定特性限制了这些药物在诸如肺结核的疾病中的抗菌效用,因为它们在杀分枝杆菌剂量下可引发不良的中枢神经系统(CNS)副作用。
因此,需要改良的吩噻嗪衍生物,该改良的吩噻嗪衍生物不出现或者出现最小的不良CNS副作用。
发明内容
根据本发明,提供了式(1)的三环衍生物,
其中R1为烷基磺酸酯或磺酰胺基;R2为氢、卤素、取代的烷基、硫醚或乙酰基;Y为N或C;X为S、SO、SO2、N、O、CH2、C(O)、CO2、NHCO,并且环B为6元、7元或8元环烷基环。当(1)为吩噻嗪衍生物时,R2不为氢。
在本发明的一个优选实施方式中,R1为(CH2)nSO3M,其中n=1、2、3或4,并且M=Na、K或H,或者R1为SO2Ar,其中Ar可选地被取代;R2为H、Cl、Br、SMe、C(O)CH3或CF3;Y为N或C,并且X为S、SO、SO2、N、O、CH2、C(O)、CO2、NHCO,并且环B为6元、7元或8元环烷基环。当R1为SO2Ar时,Ar上的取代基包括选自NO2、NH2、SO3M、CO2R的邻位和对位取代基,其中M=Na、K或H,并且R=烷基。
本发明的进一步特征提供了选自以下的三环衍生物:
本发明的另外的特征提供了选自以下的三环衍生物:
本发明提供了式(1)的三环衍生物,如以上定义,包括式(1)的吩噻嗪衍生物,其中n=3,并且R2=H,所述三环衍生物用于治疗肺结核,优选地治疗药敏型和耐药型肺结核,对于用于治疗肺结核的衍生物,其中所述衍生物独立地使用或者与已知的抗结核药物联合使用。
本发明还提供了治疗肺结核的方法,其中所述方法包括向有需要的患者给药治疗有效量的式(1)的三环衍生物,所述三环衍生物如以上定义并且包括式(1)的吩噻嗪衍生物,其中n=3,并且R2=H,对于将与第二抗结核药物联合的衍生物的给药,两者可作为单一的剂量给药,或者作为两个分别的剂量给药。
本发明的进一步的特征提供了选自异烟肼、乙硫异烟胺、乙胺丁醇、吡嗪酰胺、利福平、阿米卡星、卡那霉素、卷曲霉素、紫霉素、恩维霉素、环丙沙星、左氧氟沙星、莫西沙星、利福布汀、克拉霉素、利奈唑胺、氨硫脲、丙硫异烟胺的抗结核药物。
本发明进一步提供了式(1)的三环衍生物在制备用于治疗肺结核的药物中的用途,所述三环衍生物如以上定义并且包括式(1)的吩噻嗪衍生物,其中n=3,并且R2=H。
本发明还进一步提供了单位剂型的药物,其特征在于,每个单位剂量包括式(1)的三环衍生物和第二抗结核药物,所述三环衍生物如以上定义并且包括式(1)的吩噻嗪衍生物,其中n=3,并且R2=H。
本发明的进一步的特征提供了选自异烟肼、乙硫异烟胺、乙胺丁醇、吡嗪酰胺、利福平、阿米卡星、卡那霉素、卷曲霉素、紫霉素、恩维霉素、环丙沙星、左氧氟沙星、莫西沙星、利福布汀、克拉霉素、利奈唑胺、氨硫脲、丙硫异烟胺的抗结核药物。
附图说明
现将仅参考附图,通过实施例描述本发明,其中:
图1显示了使用GFAP微孔板测试测定的异烟肼(INH)、甲硫哒嗪(TZ)和合成的吩噻嗪衍生物C3、C4、C31、C32和C33直接抗M.tb H37Rv.gfp的抗微生物活性,以及总结所获得的MIC50值的表;
图2显示了抗细胞内M.tb H37Rv的测试化合物的活性,其中以指定的浓度用INH、TZ和测试化合物分别处理被感染的巨噬细胞五天;
图3a和3b显示了放射性配体结合测定的结果,表明了与多巴胺受体亚型D1、D2、D3以及血清素受体亚型5-HT1A、5-HT2A和5-HT2C的结合没有活性;
图3c是C3(D50031)对多巴胺和血清素抑制剂的抑制百分比的图示;
图3d是C4(D50032)对多巴胺和血清素抑制剂的抑制百分比的图示;
图3e是C31(D50033)对多巴胺和血清素抑制剂的抑制百分比的图示;
图3f是C32(D50034)对多巴胺和血清素抑制剂的抑制百分比的图示;
图3g是C33(D50035)对多巴胺和血清素抑制剂的抑制百分比的图示;
图4是显示接受日剂量为100mg/kg的C3或C4的小鼠和未处理的小鼠在14天期间每天的体重变化的图;
图5是显示受到日剂量为100mg/kg的C3或C4处理的小鼠以及未处理的小鼠在14天实验结束时的小鼠脏器重量的图。
具体实施方式
提供了通式(1)的三环衍生物,如下图所示,
其中R1为烷基磺酸酯或磺酰胺基;R2为氢、卤素、取代的烷基、硫醚或乙酰基;Y为N或C;X为S、SO、SO2、N、O、CH2、C(O)、CO2、NHCO,并且环B为6元、7元或8元环烷基环。当(1)为吩噻嗪衍生物时,R2不为氢。
在本发明的一个优选实施方式中,R1为(CH2)nSO3M,其中n=1、2、3或4,并且M=Na、K或H,或者R1为SO2Ar,其中Ar可选地被取代;R2为H、Cl、Br、SMe、C(O)CH3或CF3;Y为N或C,并且X为S、SO、SO2、N、O、CH2、C(O)、CO2、NHCO,并且环B为6元、7元或8元环烷基环。
当R1为SO2Ar时,Ar上的取代基包括选自NO2、NH2、SO3M、CO2R的邻位和对位取代基,其中M=Na、K或H,并且R=烷基。
下面的化合物表示通式(1)的三环衍生物的优选实施方式:
在一个更优选的实施方式中,通式(1)的三环衍生物可选自:
制备吩噻嗪的N-烷基磺酸酯的过程包括:
(a)吩噻嗪阴离子的制备,和
(b)所述阴离子与环烷基磺酸酯(例如1,3-丙烷磺酸内酯或1,4-丁烷磺酸内酯)的反应,如在美国专利7,855,287中大致描述的。
在Journal of Physical Chemistry,1986,90,2469-2415中更早公开了一种低效多步合成方法。
本发明的吩噻嗪衍生物已经显示出具有对原代巨噬细胞培养物的有限毒性以及有限的作用于精神的活性。
人们认为吩噻嗪药物的抗精神分裂活性与大脑中突触多巴胺受体的阻塞有关。通过分子空间填充模型已显示,在吩噻嗪的侧链氨基与环A上的2-取代基之间的有利的范德华相互作用可促进模拟多巴胺的构造。因此,偏离该有利方位的改变将减小多巴胺受体结合并且降低CNS作用。
本发明的化合物的标准多巴胺和血清素抑制作用研究已经显示了结合的完全失活,从而表明了CNS活性的完全消除。
本发明的化合物已显示出显著的对病毒性结核分枝杆菌的分枝杆菌抑制作用,显示在直接杀灭测试中最低抑菌浓度为(MIC50)为~6至12μg/ml。
从体外研究中已最终显示,如上所示,当与杆状菌直接接触时,吩噻嗪衍生物的烷基磺酸酯衍生物十分有效地杀灭了病毒性结核分枝杆菌,表明了该化合物绕过了结核分枝杆菌用来诱导耐受的机制,例如外排泵。此外,已证明结核分枝杆菌在巨噬细胞的吞噬体(杆菌的原代宿主细胞)内持续,其中特异性逃避策略允许其防止与溶酶体融合,从而防止被溶酶体酶降解。潜在的新的候选药物的关键挑战之一是横跨这些膜体系中的几个以到达靶生物体并诱导杀灭。获得的数据清楚证实了本发明的这些化合物具有穿过所有膜体系并抑制结核分枝杆菌复制的能力。与精神安定和细胞毒素的甲硫哒嗪相比,这些化合物的细胞毒性更高,并且没有精神安定性能。
已知吩噻嗪能改善体内和体外潜伏性模型中的异烟肼的功效。然而,倾向于其精神病属性的药物动力学和药效学已经排除了其作为体内抗菌药物的效用。
本发明的吩噻嗪衍生物可单独使用,或者与已知的抗结核药物联合使用,例如第一行药物:乙胺丁醇、异烟肼、吡嗪酰胺、利福平;第二行药物:氨基糖苷类(例如阿米卡星、卡那霉素)、多肽(例如,卷曲霉素、紫霉素、恩维霉素);氟喹诺酮类(例如,环丙沙星、左氧氟沙星、莫西沙星)、硫代酰胺类(例如乙硫异烟胺、丙硫异烟胺);第三行:利福布汀、大环内酯类(例如,克拉霉素)、利奈唑胺、氨硫脲、甲硫哒嗪、精氨酸、维生素D和R207910。
据信,该类联合治疗的的潜在协同效应尤其适用于药敏型和耐药型结核分枝杆菌。
本发明提供了治疗肺结核的方法,其中所述方法包括向有需要的患者给药有效量的本发明的三环衍生物。在本发明的一个实施方式中,化合物的给药与第二抗结核药物联合进行。通过给药本发明的三环衍生物和第二抗结核药物两者作为单一药物治疗来进行该联合治疗的实施,或者作为两个连续的分别的剂量来进行给药。
本发明进一步提供了本发明的三环衍生物的用途,用来制备用于治疗肺结核的药物。制备该药物作为片剂、丸剂或胶囊的固体口服剂型,或者作为液体口服剂型,或者作为雾化粉末用于肺部传输,该药物包含三环衍生物和第二抗结核药物两者,或者各个活性成分分别连续给药。
具有三环衍生物和第二抗结核药物的活性成分的组合的药物将优选地为单位剂型。即,将优选地以单个片剂、丸剂、胶囊等形式包含两种活性成分。因为以单位剂量的两种活性成分简化了对患者的给药,尤其是当患者需要自行给药药物时。这还导致了改善的患者依从性并减少了由于局部的或不依从性的给药方案导致耐药微生物型发展的可能性。
本发明的化学修饰的吩噻嗪保持了抗菌活性并且对巨噬细胞无毒。本领域技术人员应认识到的是,新的吩噻嗪在穿过血脑屏障时将具有改变的药物动力学和药效学,并因此减轻或消除精神病的影响。应进一步认识到的是,有许多对本领域技术人员显而易见的本发明的实施方式的变形和改变,这被认为是在本发明的范围内,其实质是由以上描述和实施例决定的。
实施例
吩噻嗪衍生物显示对培养物中的结核分枝杆菌的直接抗菌活性
使用GFAP微孔板测定法(GFPMA)评价C3、C4、C31、C32和C33五种化合物(在下面显示)抗结核分枝杆菌,以为了吩噻嗪衍生物的杀菌/抑菌活性进行筛选。
将结果与已知的吩噻嗪衍生物甲硫哒嗪(TZ)和第一行药物异烟肼(INH)对比,其用作抗分枝杆菌功效的阳性对照。获得的结果已显示了,除了C33以外,所有测试化合物显示出对M.tb H37Rv.gfp的生长的剂量依赖性抑制作用,并且总结了获得的MIC50值(图1)。INH和TZ的MIC50值与公布的数据相似。证实了C3和C4的显著的抗结核活性,其具有最低的MIC,C31和C32也如此。
吩噻嗪衍生物对源自培养物中的巨噬细胞的骨髓无毒
检查0.1953至25μg/ml的浓度范围的C3、C4、C31、C32和C33对源自巨噬细胞的骨髓(BMDM)的体外毒性效应。从原态C57Bl/6小鼠的股骨分离骨髓,并且在5%CO2下于37℃培养巨噬细胞直至成熟。数据显示,在5天的培养后,在所有浓度下,化合物对细胞活力根本没有影响(下表1)。相反,TZ是有毒的,并且在3天的培养后诱发了死亡(数据未显示)。在用TZ培养5天后,在25μg/ml至6.25μg/ml的范围的浓度下观察到100%的细胞死亡。在分析中还包括0,00078μg/ml至0.1μg/ml之间的浓度范围的INH,并且没有发现其有毒(数据未显示)。
表1:测试化合物对巨噬细胞的细胞毒性。巨噬细胞被处理5天并且评定细胞活力。
吩噻嗪衍生物对巨噬细胞中的结核分枝杆菌复制的细胞内抑制作用
为了研究本发明的化合物是否能横跨细胞膜体系并且接近细胞内杆菌以抑制复制,用BMDM感染结核分枝杆菌,并且将感染的细胞培养物用吩噻嗪衍生物C3和C4处理5天。计算细胞内细菌生长受C3和C4的抑制作用,并且表示为在未处理的细胞培养物中所得值的百分比。同时,还使用CellTiter-Blue细胞活力测试测定药物对感染的巨噬细胞的毒性。根据感染的细胞(处理过的和未处理的)的值与未感染的细胞的值计算细胞活力的百分比。如图2所示,INH和TZ两者分别在1μg/ml和3μg/ml的浓度下均可抑制大于90%的细胞内结核分枝杆菌生长。有趣的是,但在25μg/ml下测试的C3和C4显示出40%至50%之间显著的抗菌活性,虽然没有INH和TZ有效。值得注意的是,所有感染的巨噬细胞在药物处理后几乎都能存活。此后,溶解巨噬细胞并且平皿培养上清液用于CFU测定。
血清素和多巴胺结合研究
放射性配体结合测试的结果表明与多巴胺受体亚型D1、D2、D3以及血清素受体亚型5-HT1A、5-HT2A和5-HT2C的结合没有活性(图3a至3g)。选择基准的未修饰的吩噻嗪、甲硫哒嗪和氯丙嗪作为参照点。对于结构同源体,即,C3、C4、C31、C32和C33(标记为DS0031、DS0032、DS0033、DS0034、DS0035),得到的多巴胺和血清素受体结合的几乎完全消除。
化合物C3和C4在小动物模型(C57Bl/6小鼠)中的潜在毒性
评价吩噻嗪衍生物C3和C4在作为最大的起始剂量的100mg/kg的剂量下的毒性,并且测量对已知的临床上认可的吩噻嗪、甲硫哒嗪(TZ)或者对未处理的结果。
由于报导的公布数据的可变性(在160mg/kg至20mg/kg的范围内),进行初始研究以评价小鼠中TZ的最大耐受剂量。通过口腔管饲法以100mg/kg、40mg/kg、20mg/kg和10mg/kg填喂6至8周的成年雌性C57Bl/6小鼠(n=10/组)以进行研究,并且监控动物存活和测量体重变化。在一个初始的亚急性研究中,在实验开始时以200μl的体积一次性给药TZ,并且监控存活和体重变化。发现40mg/kg和100mg/kg的攻击剂量暂时性有毒,因为动物在6小时内产生麻痹。然而,动物在24至28小时内恢复。动物暂时性体重下降,但是在3至4天后恢复。经过2周的时间,以任何测试剂量的TZ的单一剂量给药都没有诱发死亡。
为了评价C3和C4的单一剂量给药(100mg/kg)的毒性,以200μl的体积通过口腔管饲法给药吩噻嗪衍生物,与未处理的动物相似,经过14天的时间,没有动物显示显著的体重下降。同样地,在20mg/kg的单一剂量的给药下没有发现动物损失。小鼠显示了暂时性嗜睡,但是在24小时内恢复。重复该单一剂量研究得到相似结果。
接着,评价每天接受治疗的动物中的毒性。简言之,每天以200μl水通过口腔管饲法向小鼠(n=10-15/组)给药TZ(10mg/kg或20mg/kg)、C3(100mg/kg)或C4(100mg/kg)。每天测量体重变化并记录(图4)。14天之后当人性化处死所有动物时终止实验,并且将脏器(心脏、肺、脑、肾、肝和脾)取出并称重(图5)。收集血液并且储存血清用于进一步分析。
没有接受任何治疗的动物起初增加体重,之后体重稳定。接受100mg/kg的日剂量的动物在第一周显示出大约10%的体重快速下降,之后,体重可能恢复而趋于稳定,直到2周结束。
与未处理的动物相比,两个治疗组中的C3和C4处理的动物中的脏器测量均显示出脾重量的显著下降。所有其它脏器保持未受影响。
C3和C4的对比毒性谱显著优于临床上许可的噻吩嗪,TZ,即使当后者在比C3或C4低10倍的剂量浓度下测试时。虽然100mg/kg或40mg/kg的TZ的日剂量给药导致48小时内100%的动物死亡率,但是所有动物在100mg/kg的C3或C4的给药下存活。然而,虽然小鼠幸免于感染,但是C3和C4处理的动物体重下降了大约10%。在脏器评定中,脑、肝、肺、肾和心脏显示出正常的体重分布,而脾显著下降。总之,经过14天的时间小鼠没有显示出耐受C3和耐受治疗的反常行为。
应认识到的是,有许多对本领域技术人员显而易见的本发明的实施方式的变形和改变,这被认为是在本发明的范围内,其实质是由以上描述和实施例决定的。
Claims (15)
1.一种式(1)的三环衍生物,
其中R1为烷基磺酸酯或磺酰胺基;R2为氢、卤素、取代的烷基、硫醚或乙酰基;Y为N或C;X为S、SO、SO2、N、O、CH2、C(O)、CO2、NHCO,并且环B为6元、7元或8元环烷基环,并且当(1)为吩噻嗪衍生物时,R2不为氢。
2.如权利要求1所述的三环衍生物,其中R1为(CH2)nSO3M,其中n=1、2、3或4,并且M=Na、K或H,或者R1为SO2Ar,其中Ar可选地为取代的;R2为H、Cl、Br、SMe、C(O)CH3或CF3;Y为N或C,并且X为S、SO、SO2、N、O、CH2、C(O)、CO2、NHCO,并且环B为6元、7元或8元环烷基环。
3.如权利要求2所述的三环衍生物,其中所述SO2Ar的Ar在邻位或对位上可选地被选自NO2、NH2、SO3M、CO2R的取代基所取代,其中M=Na、K或H,并且R=烷基。
4.如前述任一项权利要求所述的三环衍生物,其中所述三环衍生物选自:
5.如前述任一项权利要求所述的三环衍生物,其中所述三环衍生物选自:
6.一种用于治疗抗菌感染的式(1)的三环衍生物,
其中R1为烷基磺酸酯或磺酰胺基;R2为氢、卤素、取代的烷基、硫醚或乙酰基;Y为N或C;X为S、SO、SO2、N、O、CH2、C(O)、CO2、NHCO,并且环B为6元、7元或8元环烷基环。
7.如权利要求6所述的三环衍生物,所述三环衍生物用于治疗肺结核。
8.如权利要求6所述的三环衍生物,其中所述衍生物单独使用,或与第二抗结核药物联合使用。
9.如权利要求8所述的三环衍生物,其中所述第二抗结核药物选自异烟肼、乙硫异烟胺、乙胺丁醇、吡嗪酰胺、利福平、阿米卡星、卡那霉素、卷曲霉素、紫霉素、恩维霉素、环丙沙星、左氧氟沙星、莫西沙星、利福布汀、克拉霉素、利奈唑胺、氨硫脲和丙硫异烟胺。
10.一种治疗肺结核的方法,所述方法包括对有需要的患者给药治疗有效量的式(1)的三环衍生物,
其中R1为烷基磺酸酯或磺酰胺基;R2为氢、卤素、取代的烷基、硫醚或乙酰基;Y为N或C;X为S、SO、SO2、N、O、CH2、C(O)、CO2、NHCO,并且环B为6元、7元或8元环烷基环。
11.如权利要求10所述的治疗肺结核的方法,其中所述三环衍生物与第二抗结核药物联合作为单一单位剂量给药,或者作为分别的剂量给药。
12.如权利要求11所述的治疗肺结核的方法,其中所述第二抗结核药物选自异烟肼、乙硫异烟胺、乙胺丁醇、吡嗪酰胺、利福平、阿米卡星、卡那霉素、卷曲霉素、紫霉素、恩维霉素、环丙沙星、左氧氟沙星、莫西沙星、利福布汀、克拉霉素、利奈唑胺、氨硫脲和丙硫异烟胺。
13.式(1)的三环衍生物在制造用于治疗肺结核的药物中的用途,
其中R1为烷基磺酸酯或磺酰胺基;R2为氢、卤素、取代的烷基、硫醚或乙酰基;Y为N或C;X为S、SO、SO2、N、O、CH2、C(O)、CO2、NHCO,并且环B为6元、7元或8元环烷基环。
14.一种单位剂型的药物,其特征在于各单位剂量包含式(1)的三环衍生物和第二抗结核药物,
其中R1为烷基磺酸酯或磺酰胺基;R2为氢、卤素、取代的烷基、硫醚或乙酰基;Y为N或C;X为S、SO、SO2、N、O、CH2、C(O)、CO2、NHCO,并且环B为6元、7元或8元环烷基环。
15.如权利要求14所述的药物,其中所述第二抗结核药物选自异烟肼、乙硫异烟胺、乙胺丁醇、吡嗪酰胺、利福平、阿米卡星、卡那霉素、卷曲霉素、紫霉素、恩维霉素、环丙沙星、左氧氟沙星、莫西沙星、利福布汀、克拉霉素、利奈唑胺、氨硫脲和丙硫异烟胺。
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