CN113166166A - 用于治疗睡眠呼吸中止的α2-肾上腺素受体亚型C(α-2C)拮抗剂 - Google Patents
用于治疗睡眠呼吸中止的α2-肾上腺素受体亚型C(α-2C)拮抗剂 Download PDFInfo
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- CN113166166A CN113166166A CN201980076254.2A CN201980076254A CN113166166A CN 113166166 A CN113166166 A CN 113166166A CN 201980076254 A CN201980076254 A CN 201980076254A CN 113166166 A CN113166166 A CN 113166166A
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- azetidine
- represents hydrogen
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- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/10—Spiro-condensed systems
- C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
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- A—HUMAN NECESSITIES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
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Abstract
本发明涉及α2‑肾上腺素受体亚型C(α‑2C)拮抗剂,特别是式(I)的取代的哌啶基‑嘧啶基‑四氢喹啉和哌啶基‑吡啶基‑四氢喹啉,其用于治疗和/或预防与睡眠有关的呼吸疾病的方法中,所述呼吸疾病优选阻塞性和中枢性睡眠呼吸中止和打鼾。式(I)中,X为基团(A)或(B)。
Description
技术领域
本发明涉及α2-肾上腺素受体亚型C(α-2C)拮抗剂,特别是式(I)的取代的哌啶基-嘧啶基-四氢喹啉和哌啶基-吡啶基-四氢喹啉,其用于治疗和/或预防与睡眠有关的呼吸疾病的方法中,所述呼吸疾病优选阻塞性和中枢性睡眠呼吸中止和打鼾。
背景技术
阻塞性睡眠呼吸中止(OSA)是一种与睡眠有关的呼吸系统疾病,其特征是上呼吸道阻塞反复发作。在吸气时,两个相反的力之间的相互作用确保了上呼吸道的通畅。上呼吸道肌肉的扩张作用抵消了管腔内负压,而使管腔收缩。隔膜和其他辅助呼吸肌的主动收缩在呼吸道中产生负压,从而构成呼吸的驱动力。上呼吸道的稳定性实质上取决于上呼吸道扩张肌的协调和收缩特性。
由于一些上呼吸道扩张肌的活动度降低,因此认为OSA的上呼吸道萎陷是在睡眠开始时发生的,其结果是无法保持生理结构上薄弱的(vulnerable)气道开放。但是,某些上呼吸道扩张肌,包括颏舌肌(它是上呼吸道扩张肌中最重要的并且是由舌下神经来支配的),可以对呼吸刺激作出应答而增强在睡眠期间的活动度,从而潜在地抵消一些在睡眠开始时的这些变化。已观察到,OSA患者具有无呼吸中止的间隔期,在此期间的颏舌肌的活动度较具有频繁阻塞呼吸中止的睡眠阶段相比,提高了仅仅25-40%(Jordan AS,White DP,Lo YL等,Airway dilator muscle activity and lung volume during stablebreathing in obstructive sleep apnea.Sleep 2009,32(3):361-8)。去甲肾上腺素是舌下运动神经元活动的最有效力的神经调节剂之一(Horner R.L.Neuromodulation ofhypoglossal motoneurons during sleep.Respir Physiol Neurobiol 2008,164(1-2):179-196)。据认为,降低的去甲肾上腺素能驱动会导致舌下运动神经元兴奋性睡眠依赖性地下降,从而导致上呼吸道扩张肌活动度降低,尤其是舌肌肌肉的活动度降低。
α2C肾上腺素受体调节了由中枢去甲肾上腺素能神经元释放的去甲肾上腺素,它们是参与去甲肾上腺素的突触前反馈抑制作用中的自受体(Hein L等,Two functionallydistinct alpha2-adrenergic receptors regulate sympathetic neurotransmissionNature 1999,402(6758):181-184)。通过α2c肾上腺素受体拮抗作用而增加的舌下神经的运动神经元的活动度,可以稳定上呼吸道并保护它们免于萎陷和阻塞。此外,还可以通过稳定上呼吸道的机制来抑制打鼾。
对于仅是单纯的打鼾,上呼吸道不会阻塞。由于上呼吸道变窄,吸入和呼出的空气的流速增加。这与松弛的肌肉一起导致口腔和喉咙的软组织在气流中颤动。这种轻微的振动会产生典型的鼾声。
阻塞性打鼾(上呼吸道阻力综合症、重度打鼾、呼吸不足综合症)是由睡眠期间的上呼吸道的反复局部阻塞引起的。这导致了气道阻力增加,从而导致在胸廓内压力明显波动时呼吸功的增加。吸气期间胸腔内负压的发展可以达到由于OSA中完全的气道阻塞而导致的值。对心脏、血液循环和睡眠质量的病理生理影响与阻塞性睡眠呼吸中止的相同。其发病机制也可能与OSA相同。阻塞性打鼾通常是OSA的先兆(Hollandt J.H.等,Upper airwayresistance syndrome(UARS)-obstructive snoring.HNO 2000,48(8):628-634)。
中枢性睡眠呼吸中止(CSA)是由于脑功能紊乱或呼吸调节功能受损而导致的。CSA的特征在于睡眠期间缺乏呼吸的驱动力,而导致出现不充分的或缺乏性通气以及气体交换不良的反复时段。CSA有几种表现形式。这些包括高海拔诱导的周期性呼吸、特发性CSA(ICSA)、麻醉药引起的中枢性呼吸中止、肥胖-通气不足综合症(OHS)和Cheyne-Stokes呼吸(CSB)。尽管各种类型的CSA中所涉及的精确的沉淀机制可能会有很大的不同,但是睡眠期间不稳定的通气驱动是主要的潜在特征(Eckert D.J.等,Central sleep apnea:Pathophysiology and treatment.Chest 2007,131(2):595-607)。
US 2018/0235934 A1记载了将用于促进舌下运动神经元兴奋性的试剂应用在治疗例如阻塞性睡眠呼吸中止的疾病的方法。作为促进舌下运动神经元兴奋性的试剂,记载了中枢肾上腺神经元的去抑制剂和/或兴奋剂。在一些实施方案中,中枢去甲肾上腺素能神经元的去抑制剂是α2-肾上腺素受体拮抗剂,例如育亨宾(yohimbine)或α2-肾上腺素受体亚型A(α-2A)拮抗剂或α2-肾上腺素受体亚型C(α-2C)拮抗剂。α2-肾上腺素受体拮抗剂选自阿替帕唑(Atipamezole)、MK-912、RS-79948、RX 821002、[3H]2-甲氧基-咪唑克生(idazoxan)和JP-1302。
α2C肾上腺素受体属于G蛋白偶联受体家族。除了存在不同的α1-肾上腺素受体以外,还存在三种不同的α2-肾上腺素受体亚型(α2A、α2B和α2C)。它们在受到内源性儿茶酚胺(肾上腺素,去甲肾上腺素)的刺激时,参与到不同组织中的几种不同的生理作用的介导中,所述内源性儿茶酚胺来源于突触或经由血液得到。α2肾上腺素受体起着重要的生理作用,主要在心血管系统和中枢神经系统中。α2A和α2C肾上腺素受体是参与中枢神经系统中去甲肾上腺素的突触前反馈抑制的主要自受体。去甲肾上腺素在α2C-肾上腺素受体上的效力和亲和力比在α2A-肾上腺素受体上的更高。α2C-肾上腺素受体在去甲肾上腺素的低内源性浓度下抑制去甲肾上腺素的释放,而α2A-肾上腺素受体在去甲肾上腺素的高内源性浓度下抑制去甲肾上腺素的释放(Uys M.M.等.Therapeutic Potential of SelectivelyTargeting the α2C-Adrenoceptor in Cognition,Depression,and Schizophrenia-NewDevelopments and Future Perspective.Frontiers in Psychiatry 2017,Aug 14;8:144.doi:10.3389/fpsyt.2017.00144.eCollection 2017)。
作为α2-肾上腺素受体亚型C(α2C)拮抗剂的取代的哌啶基-嘧啶基-四氢喹啉和哌啶基-吡啶基-四氢喹啉及其制备方法和其作为药物的用途由WO 2015/091414 A1和WO2015/091417 A1获知,其中公开了该化合物可用于治疗和/或预防原发性和继发性糖尿病微血管病变病、糖尿病创面愈合、糖尿病性四肢溃疡,特别是用于促进糖尿病性足溃疡的创面愈合、糖尿病性视网膜病、糖尿病性肾病、糖尿病性勃起功能障碍(diabetic erectiledysfunction)、糖尿病性心力衰竭、糖尿病性冠状动脉微血管性心脏病、外周和心脏血管疾病、血栓栓塞性疾病和局部缺血、外周循环障碍、雷诺(Raynaud′s)现象、CREST综合征、微循环障碍、间歇性跛行、以及外周和自主神经病变。其中没有公开,这些化合物在治疗与睡眠有关的呼吸疾病,优选阻塞性和中枢性睡眠呼吸中止以及打鼾的用途。
目前OSA患者的黄金标准治疗是持续气道正压治疗(CPAP)。通过气流涡轮泵夹板产生的气流正压力打开了上呼吸道,逆转了所有可能导致咽喉萎陷的原因,从而防止呼吸不足、呼吸中止和睡眠不足。不幸地,所有OSA患者中有多达50%的患者不能长期耐受CPAP(M.Kohler,D.Smith,V.Tippett等,Thorax 2010 65(9):829-32:Predictors of long-term compliance with continuous positive airway pressure)。因此,仍然需要寻找有效的治疗剂以治疗和/或预防与睡眠有关的呼吸疾病,例如阻塞性睡眠呼吸中止。因此,本发明的目的是提供一种有效的治疗剂以治疗和/或预防与睡眠有关的呼吸疾病,例如阻塞性睡眠呼吸中止、中枢性睡眠呼吸中止以及打鼾。
令人惊讶地,现已发现,本发明的式(I)的取代的哌啶基-嘧啶基-四氢喹啉和哌啶基-吡啶基-四氢喹啉可抑制上呼吸道萎陷,因此适用于制备用来治疗和/或预防与睡眠有关的呼吸疾病,优选阻塞性和中枢性睡眠呼吸中止以及打鼾的药物。
本发明涉及式(I)的化合物及其盐、其溶剂合物、和其盐的溶剂合物:
X为基团
R1代表C1-C6-烷基或C3-C5-环烷基,
其中烷基被1至2个彼此独立地选自羟基、C1-C4-烷氧基和卤代烷氧基的取代基取代,
且
R2代表氢或C1-C4-烷基,
或者
R1与R2和它们连接的氮原子一起形成4至7元N-杂环,
其中N-杂环可被1至3个彼此独立地选自以下的取代基取代:氧代、羟基、一氟甲基、二氟甲基、三氟甲基、羟基羰基、叔丁氧基羰基、氨基羰基、C1-C4烷基、C1-C4-烷氧基、C1-C4-烷氧基-C1-C4-烷基、卤素和羟基烷基,
或者
其中N-杂环可以具有两个取代基,这两个取代基和与它们共同连接的N-杂环的碳原子一起形成4至6元杂环,
其中该杂环本身可以被1至3个彼此独立地选自氧代、甲基和乙基的取代基取代,
R3代表氢、氟、甲氧基或乙氧基,
且
R4代表氢、氟、甲氧基或乙氧基,
其用于治疗和/或预防与睡眠有关的呼吸疾病的方法中,所述呼吸疾病优选阻塞性和中枢性睡眠呼吸中止以及打鼾。
在本发明的上下文中,除非另有说明,否则取代基的定义如下:
烷基本身,以及烷氧基、烷氧基烷基、烷基氨基和烷氧基羰基中的“烷基”(“Alk”和 “Alkyl”)代表具有1-6个碳原子、优选1-4个碳原子的直链或支链烷基,例如优选甲基、乙基、正丙基、异丙基、正丁基、仲丁基、叔丁基、正戊基和正己基。
烷氧基,例如且优选地,代表甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基和叔丁氧基。
烷氧基烷基,例如且优选地,代表甲氧基甲基、乙氧基甲基、正丙氧基甲基、异丙氧基甲基、正丁氧基甲基、叔丁氧基甲基、甲氧基乙基、乙氧基乙基、正丙氧基乙基、异丙氧基乙基、正丁氧基乙基和叔丁氧基乙基。
N-杂环在基团R1和R2的定义中,代表具有4至7个环原子的饱和及部分不饱和的单环基团,所述环原子包含氮杂原子和最高达3个选自S、O、N、SO和SO2的其他杂原子和/或杂原子基团(hetero group),其中氮原子也可以形成N-氧化物;所述N-杂环例如优选地代表氮杂环丁烷、吡咯烷、哌啶、氮杂环庚烷、哌嗪、吗啉、硫代吗啉、1-氧化硫代吗啉(1-oxidothiomorpholine)和1,1-二氧化硫代吗啉(1,1-dioxidothiomorpholine),特别优选氮杂环丁烷、吡咯烷、吗啉和1,1-二氧化硫代吗啉。
杂环在基团R1和R2的定义中,具有和与其连接的N-杂环中共同的碳原子,该杂环代表具有4至6个环原子和最高达4个选自以下的杂原子和/或杂原子基团的饱和及部分不饱和的单环基团,所述杂原子和/或杂原子基团为S、O、N、SO和SO2,其中氮原子也可以形成N-氧化物;所述N-杂环例如优选地代表氮杂环丁烷、氧杂环丁烷、硫杂环丁烷、吡咯烷、四氢呋喃、哌啶、吗啉、硫代吗啉、哌嗪、四氢吡喃和1,1-二氧化硫代吗啉,特别优选氮杂环丁烷和氧杂环丁烷,甚至更优选氧杂环丁烷。
卤素代表氟、氯、溴和碘,优选氟和氯。
术语“羟基”,如在本文中以其本身或作为另一个基团的一部分使用,是指-OH基团。
如本文使用的表达“本发明的化合物”是指式I的化合物。
在药物领域中,药学上可接受的盐例如包含有机酸和无机酸的酸加成盐是已知的。药学上可接受的酸加成盐的代表性实例包括,但不限于,氯化物、溴化物、硫酸盐、硝酸盐、磷酸盐、磺酸盐、甲磺酸盐、甲酸盐、酒石酸盐、马来酸盐、柠檬酸盐、苯甲酸盐、水杨酸盐、抗坏血酸盐、乙酸盐和草酸盐。
根据本发明,将水合物或溶剂合物指定为式(I)的化合物的那些形式,其中所述式(I)的化合物以固态或液态与水发生水合或与溶剂分子发生配位而形成的分子化合物或络合物。水合物的实例为倍半水合物、一水合物、二水合物或三水合物。同样,本发明的化合物的盐的水合物或溶剂合物也是合适的。
药学上可接受的酯,如果合适,可以通过已知方法,使用在药学领域中常规并且保留其游离形式的药理作用的药学上可接受的酸来制备。这些酯的非限制性实例包括脂族醇的酯或芳族醇的酯。药学上可接受的酯的代表性实例包括,但不限于,甲酯、乙酯、正丙酯、异丙酯、正丁酯、异丁酯、仲丁酯、叔丁酯、和苄酯。
本发明在其范围内包括化合物的所有可能的几何异构体,例如Z和E异构体(顺式和反式异构体),以及化合物的所有可能的旋光异构体,例如非对映异构体和对映异构体。此外,本发明在其范围内既包括单独的异构体也包括其任意混合物,例如外消旋混合物。单独的异构体可以使用具有相应异构体形式的起始材料来获得,或者可以根据常规分离方法,在制备最终化合物之后进行分离得到。为了从其混合物中分离出旋光异构体,例如对映异构体,可以使用常规拆分方法例如分步结晶法。
本发明的一个特别的实施方案涉及以下的式(I)的化合物及其盐、其溶剂合物、和其盐的溶剂合物,其中
R1代表C1-C6-烷基或C3-C5-环烷基,
其中烷基被1至2个彼此独立地选自羟基和C1-C4-烷氧基的取代基取代,
且
R2代表氢或C1-C4-烷基,
或者
R1与R2和它们连接的氮原子一起形成4至7元N-杂环,
其中N-杂环可被1至3个彼此独立地选自以下的取代基取代:氧代、羟基、一氟甲基、二氟甲基、三氟甲基、羟基羰基、叔丁氧基羰基、氨基羰基、C1-C4烷基、C1-C4-烷氧基和卤素,
或者
其中N-杂环可以具有两个取代基,这两个取代基和与它们共同连接的N-杂环的碳原子一起形成4至6元杂环,
其中该杂环本身可以被1至3个彼此独立地选自氧代、甲基和乙基的取代基取代,
R3代表氢、氟、甲氧基或乙氧基,
且
R4代表氢、氟、甲氧基或乙氧基,
其用于治疗和/或预防与睡眠有关的呼吸疾病的方法中。
本发明的另一个具体的实施方案涉及以下的式(I)的化合物及其盐、其溶剂合物、和其盐的溶剂合物,其中
R1代表C2-C6-烷基,
其中烷基被选自羟基、甲氧基和乙氧基的取代基取代,
且
R2代表氢,
或者
R1与R2和它们连接的氮原子一起形成氮杂环丁烷、吡咯烷、哌啶、氮杂环庚烷、哌嗪、吗啉、硫代吗啉、1-氧化硫代吗啉或1,1-二氧化硫代吗啉,
其中氮杂环丁烷、吡咯烷、哌啶、氮杂环庚烷、哌嗪、吗啉、硫代吗啉、1-氧化硫代吗啉或1,1-二氧化硫代吗啉可以被1至2个彼此独立地选自以下的取代基取代:羟基、三氟甲基、羟基羰基、C1-C3-烷基、甲氧基和甲氧基甲基,
或者
其中氮杂环丁烷、吡咯烷、哌啶、氮杂环庚烷、哌嗪、吗啉可以具有两个取代基,这两个取代基和它们共同连接的氮杂环丁烷、吡咯烷、哌啶、氮杂环庚烷、哌嗪或吗啉中的碳原子一起形成氮杂环丁烷、氧杂环丁烷或1,1-二氧化硫杂环丁烷(1,1-dioxidothietane),
其中所述氮杂环丁烷、氧杂环丁烷或1,1-二氧化硫杂环丁烷本身可以被1至2个彼此独立地选自甲基和乙基的取代基取代,
R3代表氢,
且
R4代表氢、氟或甲氧基,
或者
R3代表氢、氟或甲氧基,
且
R4代表氢,
其用于治疗和/或预防与睡眠有关的呼吸疾病的方法中。
本发明的另一个特别的实施方案涉及以下的式(I)的化合物及其盐、其溶剂合物、和其盐的溶剂合物,其中
R1代表C2-C4-烷基,
其中烷基被选自羟基和甲氧基的取代基取代,
且
R2代表氢,
或者
R1与R2和它们连接的氮原子一起形成氮杂环丁烷、吡咯烷、吗啉或1,1-二氧化硫代吗啉,
其中氮杂环丁烷、吡咯烷、吗啉或1,1-二氧化硫代吗啉可以被1至2个彼此独立地选自以下的取代基取代:羟基羰基、甲基、三氟甲基、甲氧基和甲氧基甲基,
或者
R1与R2和它们连接的氮原子一起形成氮杂环丁烷,
其中氮杂环丁烷可以具有两个取代基,这两个取代基和它们共同连接的氮杂环丁烷中的碳原子一起形成氧杂环丁烷或1,1-二氧化硫杂环丁烷,
R3代表氢、氟或甲氧基,
且
R4代表氢,
或者
R3代表氢,
且
R4代表氢、氟或甲氧基,
其用于治疗和/或预防与睡眠有关的呼吸疾病的方法中。
本发明的另一个特别的实施方案涉及以下的式(I)的化合物及其盐、其溶剂合物、和其盐的溶剂合物,其中
R1代表C2-C4-烷基,
其中烷基被选自羟基和甲氧基的取代基取代,
且
R2代表氢,
或者
R1与R2和它们连接的氮原子一起形成氮杂环丁烷、吡咯烷、吗啉或1,1-二氧化硫代吗啉,
其中氮杂环丁烷、吡咯烷、吗啉或1,1-二氧化硫代吗啉可以被1至2个彼此独立地选自以下的取代基取代:羟基羰基和甲基、三氟甲基、甲氧基和甲氧基甲基,
或者
R1与R2和它们连接的氮原子一起形成氮杂环丁烷,
其中氮杂环丁烷可以具有两个取代基,这两个取代基和它们共同连接的氮杂环丁烷中的碳原子一起形成氧杂环丁烷、或1,1-二氧化硫杂环丁烷,
R3代表氢或氟,
且
R4代表氢、氟或甲氧基,
其用于治疗和/或预防与睡眠有关的呼吸疾病的方法中。
本发明的另一个特别的实施方案涉及以下的式(I)的化合物及其盐、其溶剂合物、和其盐的溶剂合物,其中
X为基团
R1代表C2-C4-烷基,
其中烷基被选自羟基和甲氧基的取代基取代,
且
R2代表氢,
或者
R1与R2和它们连接的氮原子一起形成氮杂环丁烷、吡咯烷、吗啉或1,1-二氧化硫代吗啉,
其中氮杂环丁烷、吡咯烷、吗啉或1,1-二氧化硫代吗啉可以被1至2个独立地选自羟基羰基和甲基的取代基取代,
或者
R1与R2和它们连接的氮原子一起形成氮杂环丁烷,
其中氮杂环丁烷可以具有两个取代基,这两个取代基和它们共同连接的氮杂环丁烷中的碳原子一起形成氧杂环丁烷,
R3代表氢、氟或甲氧基,
且
R4代表氢,
或
R3代表氢,
且
R4代表氢、氟或甲氧基,
其用于治疗和/或预防与睡眠有关的呼吸疾病的方法中。
本发明的另一个具体的实施方案涉及以下的式(I)的化合物及其盐、其溶剂合物、和其盐的溶剂合物,其中
X为基团
R1与R2和它们连接的氮原子一起形成氮杂环丁烷,
其中氮杂环丁烷可以具有两个取代基,这两个取代基和它们共同连接的氮杂环丁烷中的碳原子一起形成氧杂环丁烷,
R3代表氢,
且
R4代表氢,
其用于治疗和/或预防与睡眠有关的呼吸疾病的方法中。
还优选式(I)的化合物,其中R2代表氢。
还优选式(I)的化合物,其中R1与R2和它们连接的氮原子一起代表2-氧杂-6-氮杂螺[3.3]庚-6-基。
还优选式(I)的化合物,其中R1与R2和它们连接的氮原子一起代表1,1-二氧化硫代吗啉-4-基。
还优选式(I)的化合物,其中R3代表氢。
还优选式(I)的化合物,其中R4代表氢。
还优选式(I)的化合物,其中R3和R4代表氢。
在优选的实施方案中,本发明涉及选自以下的式(I)的化合物:
[4-(3,4-二氢异喹啉-2(1H)-基)哌啶-1-基]{2-[(2-甲氧基乙基)氨基]嘧啶-5-基}甲酮、[4-(7-氟-3,4-二氢异喹啉-2(1H)-基)哌啶-1-基]{2-[(1-甲氧基丁-2-基)氨基]嘧啶-5-基}甲酮、[4-(6-氟-3,4-二氢异喹啉-2(1H)-基)哌啶-1-基]{2-[(1-甲氧基丁-2-基)氨基]嘧啶-5-基}甲酮、{2-[(1-甲氧基丁-2-基)氨基]嘧啶-5-基}[4-(7-甲氧基-3,4-二氢异喹啉-2(1H)-基)哌啶-1-基)甲酮、{2-[(1-甲氧基丁-2-基)氨基]嘧啶-5-基}[4-(6-甲氧基-3,4-二氢异喹啉-2(1H)-基)哌啶-1-基)甲酮、[4-(3,4-二氢异喹啉-2(1H)-基)哌啶-1-基]{2-[(1-甲氧基丁-2-基)氨基]嘧啶-5-基}甲酮、[4-(3,4-二氢异喹啉-2(1H)-基)哌啶-1-基]{2-[(1-甲氧基丁-2-基)氨基]嘧啶-5-基}甲酮、[4-(3,4-二氢异喹啉-2(1H)-基)哌啶-1-基][2-(2-氧杂-6-氮杂螺[3.3]庚-6-基)嘧啶-5-基)甲酮、[4-(7-氟-3,4-二氢异喹啉-2(1H)-基)哌啶-1-基][2-(2-氧杂-6-氮杂螺[3.3]庚-6-基)嘧啶-5-基)甲酮、[4-(6-甲氧基-3,4-二氢异喹啉-2(1H)-基)哌啶-1-基][2-(2-氧杂-6-氮杂螺[3.3]庚-6-基)嘧啶-5-基)甲酮、1-(5-{[4-(3,4-二氢异喹啉-2(1H)-基)哌啶-1-基]羰基}吡啶-2-基)-D-脯氨酸盐酸盐、[4-(3,4-二氢异喹啉-2(1H)-基)哌啶-1-基][2-(1,1-二氧化硫代吗啉-4-基)嘧啶-5-基)甲酮、[4-(3,4-二氢异喹啉-2(1H)-基)哌啶-1-基][2-(2,6-二甲基吗啉-4-基)嘧啶-5-基)甲酮、[4-(3,4-二氢异喹啉-2(1H)-基)哌啶-1-基][2-(2,6-二甲基吗啉-4-基)嘧啶-5-基)甲酮、[4-(3,4-二氢异喹啉-2(1H)-基)哌啶-1-基][2-(2,2-二甲基吗啉-4-基)嘧啶-5-基)甲酮,
[4-(3,4-二氢异喹啉-2(1H)-基)哌啶-1-基]{6-[(2-甲氧基乙基)氨基]吡啶-3-基}甲酮、[4-(7-氟-3,4-二氢异喹啉-2(1H)-基)哌啶-1-基]{6-[(2-甲氧基乙基)氨基]吡啶-3-基}甲酮、[4-(3,4-二氢异喹啉-2(1H)-基)哌啶-1-基][6-(吗啉-4-基)吡啶-3-基)甲酮、[4-(3,4-二氢异喹啉-2(1H)-基)哌啶-1-基][6-(1,1-二氧化硫代吗啉-4-基)吡啶-3-基)甲酮、[4-(3,4-二氢异喹啉-2(1H)-基)哌啶-1-基]{6-[(2R)-2-甲氧基甲基)吡咯烷-1-基]吡啶-3-基}甲酮、1-(5-{[4-(3,4-二氢异喹啉-2(1H)-基)哌啶-1-基]羰基}吡啶-2-基)-D-脯氨酸,[4-(3,4-二氢异喹啉-2(1H)-基)哌啶-1-基](6-{[(2S)-1-羟基丁-2-基]氨基}吡啶-3-基)甲酮、[4-(6-氟-3,4-二氢异喹啉-2(1H)-基)哌啶-1-基][6-(3-甲氧基吡咯烷-1-基)吡啶-3-基)甲酮、[4-(6-甲氧基-3,4-二氢异喹啉-2(1H)-基)哌啶-1-基][6-(3-甲氧基吡咯烷-1-基)吡啶-3-基)甲酮、[4-(3,4-二氢异喹啉-2(1H)-基)哌啶-1-基][6-(2-氧杂-6-氮杂螺[3.3]庚-6-基)吡啶-3-基)甲酮、[4-(3,4-二氢异喹啉-2(1H)-基)哌啶-1-基][6-(2,6-二甲基吗啉-4-基)吡啶-3-基)甲酮、[4-(3,4-二氢异喹啉-2(1H)-基)哌啶-1-基][6-(2,6-二甲基吗啉-4-基)吡啶-3-基)甲酮、[4-(3,4-二氢异喹啉-2(1H)-基)哌啶-1-基][6-(2,2-二甲基吗啉-4-基)吡啶-3-基)甲酮、[4-(3,4-二氢异喹啉-2(1H)-基)哌啶-1-基]{6-[2-(三氟甲基)吗啉-4-基]吡啶-3-基}甲酮、[4-(3,4-二氢异喹啉-2(1H)-基)哌啶-1-基][6-(2,2-二氧化(dioxido)-2-硫杂-6-氮杂螺[3.3]庚-6-基)吡啶-3-基)甲酮,以及它们的盐、溶剂合物,和所述盐的溶剂合物;其用于治疗和/或预防与睡眠有关的呼吸疾病的方法中,所述呼吸疾病优选阻塞性和中枢性睡眠呼吸中止以及打鼾。
在更优选的实施方案中,本发明涉及化合物[4-(3,4-二氢异喹啉-2(1H)-基)哌啶-1-基][2-(2-氧杂-6-氮杂螺[3.3]庚-6-基)嘧啶-5-基)甲酮,及其盐、溶剂合物,和所述盐的溶剂合物;其用于治疗和/或预防与睡眠有关的呼吸疾病的方法中,所述呼吸疾病优选阻塞性和中枢性睡眠呼吸中止以及打鼾。
WO 2015/091414和WO 2015/091417宽泛地公开了式(I)的化合物、它们的制备以及它们作为α的化拮抗剂用于治疗和/或预防原发性和继发性糖尿病微血管病变病、糖尿病创面愈合、糖尿病性四肢溃疡的作用,特别是用于促进以下疾病的作用:糖尿病性足溃疡的创面愈合、糖尿病性视网膜病、糖尿病性肾病、糖尿病性勃起功能障碍、糖尿病性心力衰竭、糖尿病性冠状动脉微血管性心脏病、外周和心脏血管疾病、血栓栓塞性疾病和局部缺血、外周循环障碍、雷诺现象、CREST综合征、微循环障碍、间歇性跛行、以及外周和自主神经病变,特别是,这些化合物具体地是本发明说明书中的明确的一部分,因此通过引用的方式纳入本文。
如本文所用的术语“有效量”是指有效地治疗和/或预防与睡眠有关的呼吸疾病,优选阻塞性和中枢性呼吸中止以及打鼾的式(I)化合物的量。
本发明涉及(α-2C)拮抗剂,尤其是式(I)的取代的哌啶基-嘧啶基-四氢喹啉和哌啶基-吡啶基-四氢喹啉,其用于治疗和/或预防与睡眠有关的呼吸疾病的方法中,所述呼吸疾病优选阻塞性和中枢性呼吸中止以及打鼾。
本发明还涉及式(I)的化合物在制备用于治疗和/或预防与睡眠有关的呼吸疾病、优选阻塞性和中枢性呼吸中止以及打鼾的药物中的用途。
本发明的另一个主题是一种或多种式(I)的化合物与一种或多种其他活性化合物的结合物在治疗和/或预防与睡眠有关的呼吸疾病、优选阻塞性和中枢性呼吸中止以及打鼾的方法中的用途。
本发明的另一个主题是包含与一种或多种惰性非毒性的药学上合适的赋形剂结合的至少一种式(I)的化合物的药物组合物,其用于治疗和/或预防与睡眠有关的呼吸疾病、优选阻塞性和中枢性呼吸中止以及打鼾的方法中。
本发明还涉及包含具有与一种或多种惰性非毒的药学上合适的赋形剂结合的一种或多种其他活性化合物的结合物的药物组合物,其用于治疗和/或预防与睡眠有关的呼吸疾病、优选阻塞性和中枢性呼吸中止以及打鼾的方法中。
本发明还涉及用于治疗和/或预防与睡眠有关的呼吸疾病的方法,该方法通过全身性和/或局部性地给予治疗有效量的至少一种式(I)的化合物或包含与惰性非毒的药学上合适的添加剂结合的至少一种式(I)的化合物的药物组合物来进行。
本发明的另一个主题是一种或多种式(I)的化合物与一种或多种其他活性化合物的结合物,其用于治疗和/或预防与睡眠有关的呼吸疾病、优选阻塞性和中枢性呼吸中止以及打鼾的方法中。
根据本发明,式(1)的取代的哌啶基-嘧啶基-四氢喹啉和哌啶基-吡啶基-四氢喹啉可以单独使用或者如果需要也可以与一种或多种其他药学活性物质结合使用,条件是该结合不会导致不希望的和不可接受的副作用。适用于该目的从而治疗与睡眠有关的呼吸系统疾病、优选阻塞性和中枢性睡眠呼吸中止以及打鼾的结合物的优选实例包括:
·呼吸兴奋剂,例如且优选茶碱(theophylline)、多沙普兰(doxapram)、尼克乙酰胺(nikethamide)、或咖啡因(caffeine);
·精神兴奋剂,例如且优选莫达非尼(modafinil)或阿莫非尼(armodafinil);
·苯丙胺和苯丙胺衍生物,例如且优选苯丙胺、甲基苯丙胺(metamphetamine)或哌醋甲酯(methylphenidate);
·血清素再摄取抑制剂,例如且优选氟西汀(fluoxetine)、帕罗西汀(paroxetine)、西酞普兰(citalopram)、依他普仑(escitalopram)、舍曲林(sertraline)、氟伏沙明(fluvoxamine)或曲唑酮(trazodone);
·血清素前体,例如且优选L-色氨酸;
·选择性血清素去甲肾上腺素再摄取抑制剂,例如且优选文拉法辛(venlafaxine)或度洛西汀(duloxetine);
·去甲肾上腺素能及特定的血清素能抗抑郁药,例如且优选米氮平(mirtazapine);
·选择性去甲肾上腺素再摄取抑制剂,例如且优选瑞波西汀(reboxetine)或阿托西汀(atomoxetine);
·三环抗抑郁药,例如且但优选阿米替林(amitriptyline)、普罗替林(protriptyline)、多塞平(doxepine)、曲米帕明(trimipramine)、丙咪噻(imipramine)、氯米帕明(clomipramine)或地昔帕明(desipramine);
·毒蕈碱受体拮抗剂,例如且优选奥昔布宁(oxybutynin);
·GABA激动剂,例如且优选巴氯芬(baclofen);
·糖皮质激素,例如且优选氟替卡松(fluticasone)、布地奈德(budesonide)、倍氯米松(beclometasone)、莫米松(mometasone)、替可的松(tixocortol)或曲安西龙(triamcinolone);
·大麻素受体激动剂;
·碳酸酐酶抑制剂,例如且优选乙酰唑酰胺(acetazolamide)、醋甲唑胺(methazolamide)或双氯非那胺(diclofenamide);
·阿片样物质和苯并二氮杂(benzodiazepine)受体拮抗剂,例如且优选氟马西尼(flumazenil)、纳洛酮(naloxone)或纳曲酮(naltrexone);
·胆碱酯酶抑制剂,例如且优选新斯的明(neostigmine)、吡啶斯的明(pyridostigmine)、毒扁豆碱多奈哌齐(physostigmine donepezil)、加兰他敏(galantamine)或利凡斯的明(rivastigmine);
·食欲抑制剂,例如且优选西布曲明(sibutramin)、托吡酯(opiramate)、芬特明(phentermine)、脂肪酶抑制剂(lipase inhibitors)或大麻素受体拮抗剂;
·盐皮质激素受体拮抗剂。
本发明的一个优选主题是,一种或多种式(I)的化合物与一种或多种选自毒蕈碱受体拮抗剂、盐皮质激素受体拮抗剂、利尿剂、皮质类固醇的其他活性化合物的结合物,其用于治疗和/或预防与睡眠有关的呼吸疾病、优选阻塞性和中枢性呼吸中止以及打鼾的方法中。
在本发明的优选实施方案中,本发明的化合物与毒蕈碱受体拮抗剂结合给药,所述毒蕈碱受体拮抗剂例如且优选奥昔布宁。
在本发明的优选实施方案中,本发明的化合物与盐皮质激素受体拮抗剂结合给药,所述盐皮质激素受体拮抗剂例如且优选螺内酯(spironolactone)、依普利酮(eplerenone)或芬尼酮(finerenone)。
在本发明的优选实施方案中,本发明的化合物与利尿剂结合给药,所述利尿剂例如且优选呋塞米(furosemide)、布美他尼(bumetanide)、托拉塞米(torsemide)、苄氟噻嗪(bendroflumethiazide)、氯噻嗪(chlorothiazide)、氢氯噻嗪(hydrochlorothiazide)、氢氟噻嗪(hydroflumethiazide)、甲氯噻嗪(methyclothiazide)、泊利噻嗪(polythiazide)、三氯甲噻嗪(trichlormethiazide)、氯噻酮(chlorthalidone)、吲达帕胺(indapamide)、美托拉宗(metolazone)、喹乙宗(quinethazone)、乙酰唑酮(acetazolamide)、双氯非那胺(dichlorphenamide)、醋甲唑胺(methazolamide)、甘油(glycerol)、异山梨醇(isosorbide)、甘露醇(mannitol)、阿米洛利(amiloride)或氨苯蝶啶(triamterene)。
在本发明的优选实施方案中,本发明的化合物与皮质类固醇结合给药,所述皮质类固醇例如且优选泼尼松(prednisone)、泼尼松龙(prednisolone)、甲泼尼龙(methylprednisolone)、曲安西龙(triamcinolone)、地塞米松(dexamethasone)、倍他米松(betamethasone)、倍氯米松(beclomethasone)、氟尼缩松(flunisolide)、布地奈德(budesonide)或氟替卡松(fluticasone)。
如果需要,本发明的式(I)的芳基哌嗪还可以与一种或多种医疗技术设备或辅助器联合使用,条件是不会导致不想要的和不可接受的副作用。适用于这种组合应用的医疗设备和辅助器为,例如且优选:
·气道正压通气设备,例如且优选CPAP(持续气道正压)设备、BiPAP(双水平气道正压)设备和IPPV(间歇性正压通气)设备;
·神经下垂的神经刺激器;
·口腔用具,例如且优选下颌前伸装置(mandibular advancement devices);
·鼻用一次性瓣膜;
·鼻支架。
本发明的式(I)的取代的哌啶基-嘧啶基-四氢喹啉和哌啶基-吡啶基-四氢喹啉可以全身性和/或局部性作用。为此目的,它们可以以合适的方式给药,例如通过口服、肠胃外、经肺、肺内(吸入性)、经鼻、鼻内、咽部、经舌、舌下、经颊、经直肠、经真皮、经皮、经结膜或经耳道途径,或作为植入物或支架。
本发明的另一个主题是包含式(I)的化合物的药物组合物用于全身性和/或局部性给药,所述给药通过以下途径进行:口服、肠胃外、经肺、肺内(吸入性)、经鼻、鼻内、咽部、经舌、舌下、经颊、经直肠、经真皮、经皮、经结膜或经耳道途径,或作为植入物或支架。优选的给药是口服途径。
对于这些给药途径,本发明的方法可以以合适的给药形式进行给药。
对于口服给药,给药形式是根据现有技术起作用的那些形式,其可以快速和/或以改进的方式释放本发明的化合物,并且其含有结晶和/或无定形和/或溶解形式的本发明的化合物,例如片剂(未包衣或包衣片剂,例如其具有控制本发明化合物释放的抗胃液或延迟溶解或不溶性包衣)、在口腔中快速崩解的片剂或薄膜剂/糯米纸囊剂、薄膜剂/冻干剂或胶囊剂(例如硬或软明胶胶囊剂)、糖锭剂、颗粒剂、丸剂、粉剂、乳剂、混悬剂、气雾剂或溶液剂。
肠胃外给药可省略吸收步骤(例如通过静脉内、动脉内、心脏内、脊柱内或腰内给药)或包括吸收步骤(例如通过肌肉内、皮下、皮内、经皮或腹膜内给药)而进行。适合于肠胃外给药的给药形式包括溶液剂、混悬剂、乳剂、冻干剂或无菌粉末形式的注射制剂和输液制剂。
对于其他给药途径,合适的是例如可吸入药物形式(包括粉末吸入器和喷雾器)、滴鼻剂、溶液剂或喷雾剂、用于舌、舌下或含服给药的片剂、片剂、薄膜剂/糯米纸囊剂或胶囊剂、栓剂、口服制剂或眼制剂、阴道胶囊、水性悬浮液(乳液、摇动混合物)、亲脂性混悬剂、软膏剂、乳膏剂、经皮治疗系统(例如硬膏剂)、乳剂、糊剂、泡沫剂、撒粉剂、植入物或支架。
优选口服或肠胃外给药,尤其是口服和静脉内给药。
本发明的化合物可以转换成所述的给药形式。这可以本身已知的方式,通过与惰性无毒的药学上合适的添加剂混合来进行。这些添加剂包括载体(例如微晶纤维素、乳糖、甘露醇)、溶剂(例如液态聚乙二醇)、乳化剂和分散剂或湿润剂(例如十二烷基硫酸钠、聚氧山梨糖醇酐油酸酯(polyoxysorbitan oleate))、粘合剂(例如聚乙烯吡咯烷酮)、合成和天然聚合物(例如白蛋白)、稳定剂(例如抗氧化剂、例如抗坏血酸)、染料(例如无机颜料、例如氧化铁)和矫味剂和/或气味矫正剂。
一般而言,为达到在肠胃外给药的情况下的有效的结果,已发现有利的是给药量为约0.001至10mg/kg体重,优选约0.01至1mg/kg体重。在口服给药的情况下,剂量为约0.01至100mg/kg体重,优选约0.01至20mg/kg体重,非常特别优选0.1至15mg/kg体重。
然而,有时可能必须偏离所规定的量,即根据体重、给药途径、对活性化合物的个体反应、制剂的性质以及给药的时间或时间间隔而定。因此,在某些情况下,用少于上述最低量处理可能是足够的,而在其他情况下必须超过所规定的上限。在以相对更大的量给药的情况下,建议可以在一天内将其分为数个单独剂量。
以下实施例说明本发明。本发明不限于这些实施例。
实施例
A.实验方法
本发明化合物的有利的药理性质可以通过以下方法确定。
本发明的式(I)化合物对于睡眠呼吸中止的治疗潜力已经在阻塞性睡眠呼吸中止(OSA)的猪的模型中进行了临床前评估。
使用负压,可能会导致麻醉的、自发呼吸的猪的上呼吸道萎陷并因此阻塞(WirthK.J.等,Sleep 36(5)(2013),第699-708页)。
在该模型中使用德国长白猪(German Landrace pigs)。将猪麻醉并且切开气管。将两个气管插管插入气管中,一个插入气管的头部,另一个插入气管的尾部。使用连接件,将头部套管连接到通至负压设备和末端气管套管的管子。将末端的气管套管经由一个连接件而另外连接到具有通向大气的开放端的管子,所述连接件用于气管的自由呼吸,从而绕过上呼吸道。通过适当地打开和夹紧这些管,呼吸可以从鼻呼吸切换至通过尾部气管套管的呼吸,从而绕过上呼吸道,并且(隔离的)上呼吸道可以连接至负压设备,由此产生吸气方向上的气流。
在某些时间点,通过使猪经由尾部套管进行呼吸,并且对上呼吸道施加-50、-100和-150cm水位差(cm H2O)的负压来测试上呼吸道的萎陷性。这导致上呼吸道萎陷,其表现为气流中断和管路系统中的压降。该测试在给予测试物质之前,以及在给予测试物质之后以某些间隔时段进行。适当有效的测试物质可以防止在吸气阶段的呼吸道萎陷。
在该OSA猪模型中,在-50cm水位差的负压下持续最高达2小时且在-100cm水位差的负压下持续最高达90min的条件下,将式(I)的α2-肾上腺素受体亚型C(α-2C)拮抗剂[4-(3,4-二氢异喹啉-2(1H)-基)哌啶-1-基][2-(2-氧杂-6-氮杂螺[3.3]庚-6-基)嘧啶-5-基]甲酮以静脉推注0.007mg/kg,接着以0.0025mg/kg/h静脉输液4h的方式进行全身性施用,抑制了上呼吸的萎陷。在-150cm水位差的负压下持续最高达2小时且在-50cm和-100cm水位差的负压下持续最高达4小时的条件下,将[4-(3,4-二氢异喹啉-2(1H)-基)哌啶-1-基][2-(2-氧杂-6-氮杂螺[3.3]庚-6-基)嘧啶-5-基]甲酮以静脉推注0.07mg/kg,接着以0.025mg/kg/h静脉输液4h的方式进行全身性施用,抑制了上呼吸的萎陷。
图1:在时间点0min时,以静脉推注0.007mg/kg,接着以0.0025mg/kg/h静脉输液4h的方式,给予[4-(3,4-二氢异喹啉-2(1H)-基)哌啶-1-基][2-(2-氧杂-6-氮杂螺[3.3]庚-6-基)嘧啶-5-基]甲酮,在不同的负压水平下,对于上呼吸道的萎陷性的效果。给出未萎陷的猪的百分比。平均值。
图2:在时间点0min时,以静脉推注0.07mg/kg,接着以0.025mg/kg/h静脉输液4h的方式,给予[4-(3,4-二氢异喹啉-2(1H)-基)哌啶-1-基][2-(2-氧杂-6-氮杂螺[3.3]庚-6-基)嘧啶-5-基]甲酮,在不同的负压水平下,对于上呼吸道的萎陷性的效果。给出未萎陷的猪的百分比。平均值。
由上述数据可以推断,式(I)的α2-肾上腺素能受体C亚型(α-2C)拮抗剂适用于治疗与睡眠有关的呼吸疾病,优选阻塞性和中枢性睡眠呼吸中止以及打鼾。
Claims (14)
1.式(I)的化合物及其盐、其溶剂合物、和其盐的溶剂合物
其中
X为基团
R1代表C1-C6-烷基或C3-C5-环烷基,
其中烷基被1至2个彼此独立地选自羟基、C1-C4-烷氧基和卤代烷氧基的取代基取代,
且
R2代表氢或C1-C4-烷基,
或者
R1与R2和它们连接的氮原子一起形成4至7元N-杂环,
其中N-杂环可被1至3个彼此独立地选自以下的取代基取代:氧代、羟基、一氟甲基、二氟甲基、三氟甲基、羟基羰基、叔丁氧基羰基、氨基羰基、C1-C4烷基、C1-C4-烷氧基、C1-C4-烷氧基-C1-C4-烷基、卤素和羟基烷基,
或者
其中N-杂环可以具有两个取代基,这两个取代基和与它们共同连接的N-杂环的碳原子一起形成4至6元杂环,
其中该杂环本身可以被1至3个彼此独立地选自氧代、甲基和乙基的取代基取代,
R3代表氢、氟、甲氧基或乙氧基,
且
R4代表氢、氟、甲氧基或乙氧基,
其用于治疗和/或预防与睡眠有关的呼吸疾病的方法中。
2.根据权利要求1的化合物及其盐、其溶剂合物、和其盐的溶剂合物,其中
R1代表C1-C6-烷基或C3-C5-环烷基,
其中烷基被1至2个彼此独立地选自羟基和C1-C4-烷氧基的取代基取代,
且
R2代表氢或C1-C4-烷基,
或者
R1与R2和它们连接的氮原子一起形成4至7元N-杂环,
其中N-杂环可被1至3个彼此独立地选自以下的取代基取代:氧代、羟基、一氟甲基、二氟甲基、三氟甲基、羟基羰基、叔丁氧基羰基、氨基羰基、C1-C4烷基、C1-C4-烷氧基和卤素,
或者
其中N-杂环可以具有两个取代基,这两个取代基和与它们共同连接的N-杂环的碳原子一起形成4至6元杂环,
其中该杂环本身可以被1至3个彼此独立地选自氧代、甲基和乙基的取代基取代,
R3代表氢、氟、甲氧基或乙氧基,
且
R4代表氢、氟、甲氧基或乙氧基,
其用于治疗和/或预防与睡眠有关的呼吸疾病的方法中。
3.根据权利要求1的化合物及其盐、其溶剂合物、和其盐的溶剂合物,其中
R1代表C2-C6-烷基,
其中烷基被选自羟基、甲氧基和乙氧基的取代基取代,
且
R2代表氢,
或者
R1与R2和它们连接的氮原子一起形成氮杂环丁烷、吡咯烷、哌啶、氮杂环庚烷、哌嗪、吗啉、硫代吗啉、1-氧化硫代吗啉或1,1-二氧化硫代吗啉,
其中氮杂环丁烷、吡咯烷、哌啶、氮杂环庚烷、哌嗪、吗啉、硫代吗啉、1-氧化硫代吗啉或1,1-二氧化硫代吗啉可以被1至2个彼此独立地选自以下的取代基取代:羟基、三氟甲基、羟基羰基、C1-C3-烷基、甲氧基和甲氧基甲基,
或者
其中氮杂环丁烷、吡咯烷、哌啶、氮杂环庚烷、哌嗪和吗啉可以具有两个取代基,这两个取代基和它们共同连接的氮杂环丁烷、吡咯烷、哌啶、氮杂环庚烷、哌嗪或吗啉中的碳原子一起形成氮杂环丁烷、氧杂环丁烷或1,1-二氧化硫杂环丁烷,
其中所述氮杂环丁烷、氧杂环丁烷或1,1-二氧化硫杂环丁烷本身可以被1至2个彼此独立地选自甲基和乙基的取代基取代,
R3代表氢,
且
R4代表氢、氟或甲氧基,
或者
R3代表氢、氟或甲氧基,
且
R4代表氢,
其用于治疗和/或预防与睡眠有关的呼吸疾病的方法中。
4.根据权利要求1的化合物及其盐、其溶剂合物、和其盐的溶剂合物,其中
R1代表C2-C4-烷基,
其中烷基被选自羟基和甲氧基的取代基取代,
且
R2代表氢,
或者
R1与R2和它们连接的氮原子一起形成氮杂环丁烷、吡咯烷、吗啉或1,1-二氧化硫代吗啉,
其中氮杂环丁烷、吡咯烷、吗啉或1,1-二氧化硫代吗啉可以被1至2个彼此独立地选自以下的取代基取代:羟基羰基、甲基、三氟甲基、甲氧基和甲氧基甲基,
或者
R1与R2和它们连接的氮原子一起形成氮杂环丁烷,
其中氮杂环丁烷可以具有两个取代基,这两个取代基和它们共同连接的氮杂环丁烷中的碳原子一起形成氧杂环丁烷或1,1-二氧化硫杂环丁烷,
R3代表氢、氟或甲氧基,
且
R4代表氢,
或者
R3代表氢,
且
R4代表氢、氟或甲氧基,
其用于治疗和/或预防与睡眠有关的呼吸疾病的方法中。
5.权利要求1的化合物及其盐、其溶剂合物、及其盐的溶剂合物,其中
R1代表C2-C4-烷基,
其中烷基被选自羟基和甲氧基的取代基取代,
且
R2代表氢,
或者
R1与R2和它们连接的氮原子一起形成氮杂环丁烷、吡咯烷、吗啉或1,1-二氧化硫代吗啉,
其中氮杂环丁烷、吡咯烷、吗啉或1,1-二氧化硫代吗啉可以被1至2个彼此独立地选自以下的取代基取代:羟基羰基和甲基、三氟甲基、甲氧基和甲氧基甲基,
或者
R1与R2和它们连接的氮原子一起形成氮杂环丁烷,
其中氮杂环丁烷可以具有两个取代基,这两个取代基和它们共同连接的氮杂环丁烷中的碳原子一起形成氧杂环丁烷、或1,1-二氧化硫杂环丁烷,
R3代表氢或氟,
且
R4代表氢、氟或甲氧基,
其用于治疗和/或预防与睡眠有关的呼吸疾病的方法中。
6.根据权利要求1的化合物及其盐、其溶剂合物、和其盐的溶剂合物,其中
X为基团
R1代表C2-C4-烷基,
其中烷基被选自羟基和甲氧基的取代基取代,
且
R2代表氢,
或者
R1与R2和它们连接的氮原子一起形成氮杂环丁烷、吡咯烷、吗啉或1,1-二氧化硫代吗啉,
其中氮杂环丁烷、吡咯烷、吗啉或1,1-二氧化硫代吗啉可以被1至2个独立地选自羟基羰基和甲基的取代基取代,
或者
R1与R2和它们连接的氮原子一起形成氮杂环丁烷,
其中氮杂环丁烷可以具有两个取代基,这两个取代基和它们共同连接的氮杂环丁烷中的碳原子一起形成氧杂环丁
烷,
R3代表氢、氟或甲氧基,
且
R4代表氢,
或
R3代表氢,
且
R4代表氢、氟或甲氧基,
其用于治疗和/或预防与睡眠有关的呼吸疾病的方法中。
7.根据权利要求6的化合物及其盐、其溶剂合物、和其盐的溶剂合物,其中
R1与R2和它们连接的氮原子一起形成氮杂环丁烷,
其中氮杂环丁烷具有两个取代基,这两个取代基和它们共同连接的氮杂环丁烷中的碳原子一起形成氧杂环丁烷,
R3代表氢,
且
R4代表氢,
其用于治疗和/或预防与睡眠有关的呼吸疾病的方法中。
8.权利要求1至7的化合物的用途,其中与睡眠有关的呼吸疾病是阻塞性和中枢性呼吸中止以及打鼾。
9.一种或多种式(I)的化合物与一种或多种其他活性化合物的结合物,其用于根据权利要求1至8中任一项的用途。
10.药物组合物,包含与一种或多种惰性非毒的药学上合适的赋形剂结合的根据权利要求1至7中任一项的至少一种式(I)的化合物,用于根据权利要求1至7中任一项的用途。
11.药物组合物,包含与一种或多种惰性非毒的药学上合适的赋形剂结合的根据权利要求9的结合物,用于根据权利要求1至8中任一项的用途。
12.治疗和/或预防与睡眠有关的呼吸疾病的方法,通过全身性和/或局部性地给予治疗有效量的根据权利要求1至7中任一项的至少一种化合物或包含与惰性非毒的药学上可接受的添加剂结合的权利要求1至7中任一项的至少一种化合物的药物来进行。
13.根据权利要求12的方法,其中药物还包含至少一种选自以下的其他活性化合物:毒蕈碱受体拮抗剂、盐皮质激素受体拮抗剂、利尿剂、皮质类固醇。
14.一种药物,其包含与一种或多种其他活性成分结合的如权利要求1至7中任一项所定义的式(I)的化合物,所述其他活性成分选自毒蕈碱受体拮抗剂、盐皮质激素受体拮抗剂、利尿剂、皮质类固醇。
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PCT/EP2019/081133 WO2020104266A1 (en) | 2018-11-20 | 2019-11-13 | α2-ADRENOCEPTOR SUBTYPE C (ALPHA-2C) ANTAGONISTS FOR THE TREATMENT OF SLEEP APNEA |
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- 2019-11-13 EP EP19805600.4A patent/EP3883933A1/en active Pending
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- 2019-11-13 AU AU2019382737A patent/AU2019382737A1/en active Pending
- 2019-11-13 CN CN201980076254.2A patent/CN113166166A/zh active Pending
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KR20210093949A (ko) | 2021-07-28 |
JP2022507733A (ja) | 2022-01-18 |
EP3883933A1 (en) | 2021-09-29 |
CL2021001315A1 (es) | 2021-10-22 |
JOP20210113A1 (ar) | 2023-01-30 |
UA127906C2 (uk) | 2024-02-07 |
CA3120152A1 (en) | 2020-05-28 |
BR112021007830A2 (pt) | 2021-08-03 |
WO2020104266A1 (en) | 2020-05-28 |
US20220016113A1 (en) | 2022-01-20 |
AU2019382737A1 (en) | 2021-05-20 |
EA202191375A1 (ru) | 2021-09-21 |
IL283183A (en) | 2021-06-30 |
MX2021005842A (es) | 2021-07-15 |
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