CN104703964B - 取代氨基茚满‑和氨基萘满甲酸及其用途 - Google Patents
取代氨基茚满‑和氨基萘满甲酸及其用途 Download PDFInfo
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Abstract
本发明涉及新型的取代氨基茚满‑和氨基萘满甲酸、其制备方法、其用于治疗和/或预防疾病的用途以及其用于制备治疗和/或预防疾病,尤其是治疗和/或预防心血管和心肺疾病的药剂的用途。
Description
本发明涉及新型的取代氨基茚满-和氨基萘满甲酸、其制备方法、其用于治疗和/或预防疾病的用途以及其用于制备治疗和/或预防疾病,尤其是治疗和/或预防心血管和心肺疾病的药剂的用途。
在哺乳动物细胞中一种最重要的细胞传输***是环磷酸鸟苷(cGMP)。连同一氧化氮(NO)(其由内皮释放并且传输激素和机械信号)一起,它形成NO/cGMP体系。鸟苷酸环化酶催化来自鸟苷三磷酸(GTP)的cGMP的生物合成。迄今已知的此族的代表可以通过结构特征或通过配体类型分成两组:可以被利钠肽激发的颗粒状的鸟苷酸环化酶,和可以被NO激发的可溶性鸟苷酸环化酶。可溶解的鸟苷酸环化酶由两个亚单位组成并且很有可能每个杂二聚物包含一个血红素,其是调节中心的一部分。这对于激活机制是具有中心重要性的。NO能够与血红素的铁原子结合并且因此显著地增加该酶的活性。相反,不含血红素的制剂不能通过NO刺激。一氧化碳(CO)还能附着于血红素的中心铁原子,但是通过CO的刺激明显少于通过NO的刺激。
通过形成cGMP,和由于所产生的磷酸二酯酶、离子通道和蛋白激酶的调节,鸟苷酸环化酶在各种生理学过程中,特别是在平滑肌细胞松弛和增生中,在血小板凝聚和血小板粘附中和在神经元信号传递中,以及在基于上述过程断裂的疾病中起关键性的作用。在病理生理条件下,NO/cGMP体系可以被抑制,这可能导致例如高血压、血小板活化、增加细胞的增殖、内皮功能障碍、动脉粥样硬化、心绞痛、心力衰竭、血栓形成、中风和心肌梗死。
由于所期望的高效性和低的副作用水平,所以目的在于影响组织中cGMP信号途径的用于该类病症的可能的不依赖NO治疗是有希望的途径。
迄今为止,对于可溶性鸟苷酸环化酶的治疗刺激,唯一利用的化合物如其作用基于NO的有机硝酸酯。后者通过生物转化形成并且通过附着于血红素的中心铁原子活化可溶性鸟苷酸环化酶。除了所述副作用之外,耐受性的发展也是此治疗模式的重要缺点之一[O.V. Evgenov等,Nature Rev. Drug Disc. 5 (2006), 755]。
近年来已经鉴别出直接刺激可溶性鸟苷酸环化酶,即没有预先释放NO的物质。吲唑衍生物YC-1是第一个描述的非NO-依赖性的但是血红素-依赖性的sGC刺激剂[Evgenov等,同上]。基于YC-1,发现了另外的比YC-1更有效并显示无相关的磷酸二酯酶(PDE)的抑制的物质。这导致吡唑并嘧啶衍生物BAY 41-2272、BAY 41-8543和BAY 63-2521的识别。连同最近公开的结构上不同的物质CMF-1571和A-350619一起,这些化合物形成一类新的sGC刺激剂[Evgenov等,同上]。该类物质的共同的特征是非NO-依赖性的并且选择性活化包含血红素的sGC。另外,与NO结合的sGC刺激剂对于基于亚硝酰-血红素配合物的稳定的sGC活化具有协同效应。sGC刺激剂在sGC的精确结合部位仍然是有争议的。如果由可溶性鸟苷酸环化酶除去血红素基团,酶仍然具有可检测出的催化基本活性,即,始终形成cGMP。不含血红素的酶的剩余的催化基本活性不能通过任何一种以上提到的刺激剂激活[Evgenov等,同上]。
另外,非NO-依赖性的且非血红素依赖性的sGC活化剂,与作为这类原型的BAY 58-2667一起,已被鉴别。这些物质的共同的特征是与NO结合它们仅仅对于酶活化具有累加效应,和氧化的或不含血红素的酶的活化显著地强于包含血红素的酶的活化[Evgenov等,同上;J.P. Stasch等,Br. J. Pharmacol. 136 (2002), 773; J.P. Stasch等, J. Clin. Invest. 116 (2006), 2552]。由光谱研究明显可见BAY 58-2667排斥氧化的血红素基团,由于减弱的铁-组氨酸键,其仅仅微弱地连接到sGC上。还显示特征性的sGC血红素结合主体Tyr-x-Ser-x-Arg对于血红素基团的带负电荷的丙酸的相互作用和对于BAY 58-2667的作用是必需的。在这个背景下,假定BAY 58-2667对sGC的结合部位与血红素基团的结合部位是相同的[J.P. Stasch等,J. Clin. Invest. 116 (2006), 2552]。
在本发明中描述的化合物同样能够活化不含血红素形式的可溶性鸟苷酸环化酶。这也通过如下事实得以确认:首先这些新型的激活剂对含血红素的酶没有显示出与NO的协同作用,另外它们的作用不能被可溶性鸟苷酸环化酶的血红素依赖性抑制剂,1H-1,2,4-噁二唑并[4,3-a]喹噁啉-1-酮(ODQ)所阻断, 而是甚至被此抑制剂赋予能量[参见O.V.Evgenov等,Nature Rev. Drug Disc. 5 (2006), 755;J.P. Stasch等,J. Clin. Invest. 116 (2006), 2552]。
因此,本发明的目的是提供新的化合物,其以上面描述的方式作为可溶性鸟苷酸环化酶的活化剂起作用并且可以因此特别用于治疗和预防心血管和心肺病症。
用于治疗心血管病症的各种氨基二羧酸衍生物由专利申请WO 01/19780-A2、WO02/070459-A1、WO 02/070460-A1、WO 02/070461-A1、WO 02/070462-A1和WO 02/070510-A2已知。WO 95/ 18617-A1和WO 00/35882-A1描述了1-氨基茚满-和1-氨基萘满衍生物用于治疗神经障碍。WO 2006/104826-A2公开了N-酰化的1-氨基茚满-5-甲酰胺和1-氨基萘满-6-甲酰胺作为用于治疗糖尿病的高血糖素受体拮抗剂。
本发明提供了通式(I)的化合物和它们的盐、溶剂化物和所述盐的溶剂化物,
其中
n 代表数字1或2,
和
A 代表下式的基团
其中
*表示与分子剩余部分连接的各点,
L1代表直链(C1-C5)-烷二基,
x代表数字1、2或3,其中这些CH2基团之一可以被-O-代替,
R1A和R1B彼此独立地代表氢或甲基,
L2代表键或直链(C1-C5)-烷二基,
Ar代表苯基或具有最多3个选自系列N、O和/或S的杂原子的5-或6-元杂芳基,
R2代表选自下面系列的取代基:氟、氯、溴、氰基、(C1-C4)-烷基、三氟甲基、(C1-C4)-烷氧基和三氟甲氧基,
p 代表数字0、1或2,
其中在取代基R2出现两次的情况下,它们各自的含义可以相同或不同,
L3代表键、-O-、-CH2-、-CH2-CH2-或-CH=CH-,
和
R3和R4彼此独立地代表氢或选自下面系列的取代基:氟、氯、溴、氰基、(C1-C4)-烷基、三氟甲基、(C1-C4)-烷氧基和三氟甲氧基。
根据本发明的化合物是式(I)化合物和它们的盐,溶剂化物和盐的溶剂化物,在下文中提到的式的式(I)包括的化合物和它们的盐,溶剂化物和盐的溶剂化物,和式(I)包括的和在下文中作为具体实施例提到的化合物和它们的盐,溶剂化物和所述盐的溶剂化物,只要式(I)包括的和在下文中提到的化合物还不是盐,溶剂化物和盐的溶剂化物。
在本发明的上下文中优选的盐是根据本发明的化合物的生理可接受的盐。也包括本身不适合药用但是可以例如用于分离、纯化或储存根据本发明的化合物的盐。
本发明的化合物的生理可接受的盐包括常规无机酸、羧酸和磺酸的酸加成盐,例如盐酸、氢溴酸、硫酸、磷酸、甲烷磺酸、乙烷磺酸、苯磺酸、甲苯磺酸、萘二磺酸、乙酸、三氟乙酸、丙酸、乳酸、酒石酸、苹果酸、柠檬酸、富马酸、马来酸和苯甲酸的盐。
本发明的化合物的生理可接受的盐的也包括常规的碱的盐,例如和优选,碱金属盐(例如钠和钾盐),碱土金属盐(例如钙和镁盐)和衍生自氨或具有1-16个碳原子的有机胺,例如和优选乙胺、二乙胺、三乙胺、N,N-二异丙基乙胺、一乙醇胺、二乙醇胺、三乙醇胺、二甲氨基乙醇、二乙氨基乙醇、普鲁卡因、二环己胺、二苄胺、N-甲基哌啶、N-甲基吗啉、精氨酸、赖氨酸和1,2-乙二胺的铵盐。
在本发明的上下文中溶剂化物被描述为通过与溶剂分子配位形成配合物并呈固态或液态的根据本发明的化合物的那些形式。水合物是溶剂化物的特定形式,其中与水配位。在本发明中优选的溶剂化物是水合物。
根据本发明的化合物取决于它们的结构可以以不同的立体异构的形式,即以构型异构体的形式,或任选地作为构象异构体(对映异构体和/或非对映异构体,包括在阻转同分异构体情况下的那些非对映异构体)存在。本发明因此包括对映异构体和非对映异构体和它们各自的混合物。立体异构一致的组分可以由这种对映异构体和/或非对映异构体的混合物以已知的方式分离;对于这优选使用层析法,特别是在非手性或手性相上的HPLC层析。
如果根据本发明的化合物可以以互变异构形式存在,本发明包括所有的互变异构形式。
本发明还包括根据本发明的化合物所有适合的同位素变体。根据本发明的化合物的同位素变体在此应当理解为是指其中在根据本发明的化合物中至少一个原子与具有相同原子序数,但是具有与天然通常或主要存在的原子质量不同的原子质量的另一原子交换的化合物。可以引入根据本发明的化合物中的同位素的实例是如下的那些:氢、碳、氮、氧、磷、硫、氟、氯、溴和碘,如2H (氘)、3H (氚)、13C、14C、15N、17O、18O、32P、33P、33S、34S、35S、36S、18F、36Cl、82Br、123I、124I、129I和131I。根据本发明的化合物的特定同位素变体,尤其是其中引入了一种或多种放射性同位素的那些,可以例如有利地用于检查作用机理或体内活性化合物的分布;由于比较容易的可制备性和可检测性,所以用3H或14C同位素标记的化合物尤其适合于此目的。另外,同位素的引入,例如氘的引入,由于化合物更大的代谢稳定性,所以可产生特定的治疗益处例如在体内的半衰期延长或需要的活性剂量减小;根据本发明的化合物的如此改性因此在某些情况下也可以构成本发明优选的实施方案。根据本发明的化合物的同位素变体可以通过本领域技术人员已知的通常使用的方法制备,例如通过下面描述的方法和具体实施例中报告的方法,通过在其中使用各种试剂和/或起始化合物的相应的同位素改性。
此外,本发明还包括根据本发明的化合物的药物前体。术语“药物前体”这里是指本身可以是生物活性或非活性的,但是当在体内存在时,例如通过代谢或水解途径转化成根据本发明的化合物的化合物。
本发明特别地包含根据本发明的式(I)羧酸的可水解的酯衍生物作为药物前体。这理解为这样的酯,其可以在生理性介质中,在下文描述的生物试验条件下和特别是在体内,通过酶或化学途径,水解成游离的羧酸作为主要生物活性的化合物。(C1-C4)-烷基酯,其中烷基基团可以是直链或支链的,优选作为这样的酯。特别优选甲酯、乙酯或叔丁酯。
在本发明的上下文中,除非另外具体说明,所述取代基如下定义:
在本发明的上下文中(C1-C4)-烷基代表具有1-4个碳原子的直链或支链烷基。优选的实例包括:甲基、乙基、正丙基、异丙基、正-丁基、异丁基、仲-丁基和叔-丁基。
在本发明的上下文中(C 1 -C 5 )-烷二基、(C 1 -C 4 )-烷二基与(C 2 -C 4 )-烷二基代表分别具有1-5、1-4和2-4个碳原子的直链α、ω-二价烷基。优选的实例包括:亚甲基、乙-1,2-二基(1,2-亚乙基)、丙-1,3-二基(1,3-亚丙基)、丁-1,4-二基(1,4-亚丁基)和戊-1,5-二基(1,5-亚戊基)。
在本发明的上下文中(C1-C4)-烷氧基代表具有1-4个碳原子的直链或支链烷氧基。优选的实例包括:甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲-丁氧基和叔-丁氧基。
在本发明的上下文中5-或6-元杂芳基代表具有总计5或6个环原子的芳族杂环(杂芳环),其含有至多3个相同或不同的环杂原子,所述杂原子选自系列N、O和/或S和通过环碳原子或任选地通过环氮原子连接。优选的实例包括:呋喃基、吡咯基、噻吩基、吡唑基、咪唑基、1,2-噁唑基(异噁唑基)、1,3-噁唑基、1,2-噻唑基(异噻唑基)、1,3-噻唑基、1,2,3-***基、1,2,4-***基、1,2,4-噁二唑基、1,3,4-噁二唑基、1,2,4-噻二唑基、1,3,4-噻二唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基、1,2,4-三嗪基和1,3,5-三嗪基。
在本发明的上下文中,对于所有的多次出现的基团,其含义彼此独立。如果在根据本发明的化合物中的基团被取代,则该基团可以是一-或多取代的,除非另外说明。优选被一个或两个相同的或不同的取代基取代。特别优选被一个取代基取代。
本发明一个特别的实施方案包括式(I)化合物和它们的盐、溶剂化物和所述盐的溶剂化物,其中
n 代表数字2,
和
A 具有上面给出的含义。
本发明一个进一步特别的实施方案包括式(I)化合物和它们的盐、溶剂化物和所述盐的溶剂化物,其中
n 代表数字1或2,
和
A 代表下式的基团
,其中
*表示与分子剩余部分连接的点,
L1代表直链(C1-C4)-烷二基,
和
x代表数字1或2,其中这些CH2基团之一可以被-O-代替。
本发明一个进一步特别的实施方案包括式(I)化合物和它们的盐、溶剂化物和所述盐的溶剂化物,其中
n 代表数字1或2,
和
A 代表下式的基团
,其中
*表示与分子剩余部分连接的点,
L2代表键或直链(C1-C4)-烷二基,
Ar代表苯基,
R2代表选自下面系列的取代基:氟、氯、氰基、(C1-C4)-烷基和三氟甲基,
和
p 代表数字0、1或2,
其中在取代基R2出现两次的情况下,它们各自的含义可以相同或不同。
本发明一个进一步特别的实施方案包括式(I)化合物和它们的盐、溶剂化物和所述盐的溶剂化物,其中
n 代表数字1或2,
和
A 代表下式的基团
,其中
*表示与分子剩余部分连接的点,
L3代表键、-CH2-CH2-或-CH=CH-,
和
R3和R4彼此独立地代表氢或选自下面系列的取代基:氟、氯、氰基、(C1-C4)-烷基和三氟甲基。
在本发明的上下文中优选式(I)化合物和它们的盐、溶剂化物和所述盐的溶剂化物,其中
n 代表数字1或2,
和
A 代表下式的基团
其中
*表示与分子剩余部分连接的各点,
L1代表直链(C2-C4)-烷二基,
x代表数字1或2,其中这些CH2基团之一可以被-O-代替,
L2代表键或直链(C1-C4)-烷二基,
Ar代表苯基,
R2代表选自下面系列的取代基:氟、氯、氰基、(C1-C4)-烷基和三氟甲基,
p 代表数字0或1,
L3代表键或-CH2-CH2-,
和
R3和R4彼此独立地代表氢或选自下面系列的取代基:氟、氯、氰基、(C1-C4)-烷基和三氟甲基。
在本发明的上下文中,特别优选式(I)化合物和它们的盐、溶剂化物和所述盐的溶剂化物,其中
n 代表数字1或2,
和
A 代表下式的基团
其中
*表示与分子剩余部分连接的各点
和
R2代表甲基、乙基、异丙基或叔丁基。
在基团的各种组合或优选组合中单独给出的基团定义也可按照需要被其它组合的基团定义代替,这与分别给出的基团组合无关。
非常特别优选上面提及的优选范围中两种或更多种的组合。
本发明还提供了制备根据本发明的式(I)化合物的方法,特征在于式(II)的化合物
其中n具有上面给出的含义,
和
T1和T2相同或不同和代表(C1-C4)-烷基,
在碱存在的条件下与式(III)的化合物反应
其中A具有上面给出的含义,
和
X1代表离去基团,例如氯、溴、碘、甲磺酸根、三氟甲磺酸根或甲苯磺酸根,
以产生式(IV)的化合物
其中n、A、T1和T2各自具有以上提到的含义,
和其接着通过酯基团-C(O)OT1和-C(O)OT2水解转化成式(I)相应的二羧酸,
并将所得式(I)的化合物任选地分离成其对映异构体和/或非对映异构体和/或任选地与合适的(i)溶剂和/或(ii)碱或酸反应得到其溶剂化物、盐和/或所述盐的溶剂化物。
对于方法步骤(II)+(II)→(IV)的合适的惰性溶剂是,例如,醚,例如***、二异丙基醚、甲基叔丁基醚、四氢呋喃、1,4-二氧杂环己烷、1,2-二甲氧基乙烷或双(2-甲氧基乙基)醚,碳氢化合物,如苯、甲苯、二甲苯、戊烷、己烷、庚烷、环己烷或石油级分,或偶极非质子溶剂如丙酮、甲乙酮、乙腈、N,N-二甲基甲酰胺(DMF)、N,N-二甲基乙酰胺(DMA)、二甲基亚砜(DMSO)、N,N'-二甲基丙烯基脲(DMPU)或N-甲基吡咯烷酮(NMP)。也可以使用这些溶剂的混合物。优选使用乙腈或二甲基甲酰胺。
对于方法步骤(II) + (III) → (IV)合适的碱特别是碱金属碳酸盐如碳酸钠、碳酸钾或碳酸铯,碱金属醇盐如甲醇钠或甲醇钾、乙醇钠或乙醇钾或叔丁醇钠或叔丁醇钾,碱金属氢化物如氢化钠或氢化钾,酰胺如氨基钠、双(三甲基甲硅烷基)氨基锂或双(三甲基甲硅烷基)氨基钾或二异丙基氨基锂,或金属有机化合物如正丁基锂或苯基锂。使用的碱优选为碳酸钠、碳酸钾或碳酸铯。如果合适的话,加入烷基化催化剂,例如溴化锂、碘化钠、碘化钾、四正丁基溴化铵或苄基三乙基氯化铵是有利的。
反应(II) + (III) → (IV)通常在从0℃到+150℃,优选从+20℃到+100℃温度范围进行。
在方法步骤(IV) → (I)中酯基团-C(O)OT1和-C(O)OT2的水解使用常规的方法通过在惰性溶剂中用酸或碱处理所述酯进行,其中在后面的变型方案中开始形成的盐通过用酸处理转化成游离的羧酸。在叔丁酯情况下,酯裂解优选使用酸进行。
在不同的基团T1和T2的情况下,水解可以任选地以单釜反应同时进行或在两个单独的反应步骤中进行。
对于该反应合适的惰性溶剂是水或对于酯裂解常见的有机溶剂。这些优选包括醇如甲醇、乙醇、正-丙醇、异丙醇、正-丁醇或叔-丁醇,醚如***、四氢呋喃、1,4-二氧杂环己烷或1,2-二甲氧基乙烷,或其它溶剂如二氯甲烷、丙酮、甲乙酮、N,N-二甲基甲酰胺或二甲基亚砜。同样可以使用这些溶剂的混合物。在碱性酯水解情况下,优选使用水与二氧杂环己烷、四氢呋喃、甲醇、乙醇、二甲基甲酰胺和/或二甲基亚砜的混合物。在用三氟乙酸反应的情况下,优选使用二氯甲烷,和在用氯化氢反应的情况下,优选使用四氢呋喃,***,二氧杂环己烷或水。
合适的碱是通常的无机碱。这些特别地包括碱金属或碱土金属氢氧化物,例如氢氧化锂、氢氧化钠、氢氧化钾或氢氧化钡,或碱金属或碱土金属碳酸盐,如碳酸钠、碳酸钾或碳酸钙。优选氢氧化锂,氢氧化钠或氢氧化钾。
对于酯裂解合适的酸通常是硫酸、氯化氢/盐酸、溴化氢/氢溴酸、磷酸、乙酸、三氟乙酸、甲苯磺酸、甲磺酸或三氟甲磺酸或其混合物,任选地添加水。在叔-丁酯情况下优选氯化氢或三氟乙酸和在甲酯情况下优选盐酸。
酯裂解通常在从-20℃到+120℃,优选在0℃到+80℃的温度范围进行。
上面描述的方法步骤可以在常压下、在升压下或在减压下(例如在从0.5到5巴范围)进行;通常,所述反应各自在常压下进行。
式(II)的化合物本身可以通过使式(V)的酮化合物
其中n和T1具有以上给出的含义,
与2-(2-甲氧基苯基)乙胺(VI)以还原性氨基化反应制备,
以产生式(VII)的仲胺,
其中n和T1具有以上提到的含义,
随后在碱存在的条件下用式(VIII)的5-卤代戊酸酯烷基化
其中T2具有上面给出的含义,
和
X2代表氯、溴或碘,
以产生式(IX)的叔胺,
其中n、T1和T2各自具有以上给出的含义,
和接着通过用三溴化硼或溴化氢处理除去酚甲醚基团。
(V) + (VI) → (VII)的反应在常用于还原性氨基化和在所述反应条件下惰性的溶剂中,任选地在酸和/或脱水剂作为催化剂存在下进行。这些溶剂包括,例如四氢呋喃、甲苯、二氯甲烷、1,2-二氯乙烷、N,N-二甲基甲酰胺和醇如甲醇、乙醇、正丙醇或异丙醇;也可以使用该类溶剂的混合物。优选使用甲醇或乙醇。合适的催化剂是常规的有机酸如乙酸或对-甲苯磺酸。
用于这些氨基化反应的合适的还原剂特别是硼氢化物,例如硼氢化钠、氰基硼氢化钠、三乙酰氧基硼氢化钠或四正丁基硼氢化铵;优选使用硼氢化钠。
反应(V) + (VI) → (VII)通常在从-20℃到+50℃,优选从0℃到+30℃温度范围进行。
方法步骤(VII) + (VIII) → (IX)中的烷基化在溶剂、碱和温度方面在类似的反应条件下进行,如上述对于反应(II) + (III) → (IV)所描述。这里,使用的优选的碱和溶剂分别是碱金属碳酸盐和乙腈。烷基化通常在+50℃至+100℃的温度范围内进行。
在方法步骤(IX) → (II)中酚甲醚基团的裂解通过常规的方法通过用三溴化硼在二氯甲烷中在-20℃至+10℃下处理或通过用溴化氢在冰醋酸或水中的溶液加热至+100℃至+130℃来进行。如果在这些反应条件下,全部或部分的所述酯基团-C(O)OT1和-C(O)OT2也同时裂解得到式(X)的相应的游离羧酸
其中n具有上面给出的含义,
则这些可以例如通过随后在氯化氢或亚硫酰氯存在下用甲醇或乙醇处理再次酯化。
上面描述的反应可以在常压下,在升压下或在减压下(例如在从0.5到5巴范围)进行;通常,它们分别在常压下进行。
如果合适,也可以甚至在化合物(II)、(IV)、(VII)、(IX)或(X)阶段进行根据本发明的化合物到相应的对映异构体和/或非对映异构体的分离,其然后以分离的形式根据以上描述的方法顺序进一步反应。这种立体异构体的分离可以通过本领域技术人员已知的常规方法进行。优选使用在非手性或手性分离相上的层析法;在羧酸作为中间体或最终产物的情况下,分离还可以使用手性碱通过非对映异构体盐进行。
式(V)的化合物可以使用文献方法得到[参见,例如,对于1-氧代茚满-5-甲酸乙酯(n = 1):R. Takeuchi和H. Yasue, J. Org. Chem. 1993, 58 (20), 5386-5392;对于5-氧代-5,6,7,8-四氢萘-2-甲酸甲酯 (n = 2): U. Gerlach和T. Wollmann, Tetrahedron Lett. 1992, 33 (38), 5499-5502]。
式(III)、(VI)和(VIII)的化合物可商购或本身在文献中描述,或它们可以以对本领域技术人员显而易见的方式类似于文献出版的方法制备。大量详细步骤还可以在关于起始化合物和中间体的制备的章节中在实验部分中找到。
根据本发明的化合物的制备可以例如通过以下反应方案阐明:
方案1
根据本发明的化合物具有有价值的药理学性质并且可以用于预防和治疗人和动物的疾病。
在本发明的上下文中,术语“治疗”或“进行治疗”包括疾病、病痛、病症、损伤或健康问题、该类状态的或发展、过程或进展和/或该类状态的症状的抑制、延迟、维持、减轻、减弱、限制、减少、压制、去除或治愈。术语“治疗”这里应当理解为是与术语“治疗”的同义词。
术语“防止”、“预防”和“阻止”在本发明的上下文中同义使用,其指的是避免或减少感染、经历、遭受或患有疾病、病痛、病症、损伤或健康问题、该类状态的发展或进展和/或该类状态的症状的风险。
疾病、病痛、病症、损伤或健康问题的治疗或预防可以是部分的或完全的。
根据本发明的化合物是有效的可溶性鸟苷酸环化酶的活化剂。它们导致血管舒张、抑制血小板凝聚和降低血压,并且它们也增加冠状动脉血流量和微循环。这些作用通过可溶性鸟苷酸环化酶的直接非血红素依赖性的活化和细胞内cGMP的增加而施加。
根据本发明的化合物特别适于治疗和/或预防心血管、肺、血栓栓塞和纤维化病症。
因此,根据本发明的化合物可以在用于治疗和/或预防如下病症的药剂中使用:心血管病症例如高血压(高血压)、心力衰竭、冠心病、稳定和不稳定型心绞痛、肺动脉高血压(PAH)和其它形式的肺动脉高压(PH)、肾性高血压、外周和心血管病症、心律失常、 房性和室性心律失常和传导紊乱例如I-III度房室性传导阻滞、室上性快速性心律失常、心房颤动、心房扑动、心室颤动、心室扑动、室性快速型心律失常、扭转型室性心动过速、房性和室性期外收缩、AV-接合的期外收缩、病态窦房结综合征、晕厥、AV-结节返回型心动过速(AV-Knoten-Reentry-Tachykardie)、Wolff-Parkinson-White综合征、急性冠状动脉综合征(ACS)、自身免疫性心脏病症(心包炎、心内膜炎、瓣膜炎(Valvolitis)、主动脉炎、心肌症)、拳击者心肌症、动脉瘤、休克如心源性休克、感染性休克和过敏性休克,另外用于治疗和/或预防血栓栓塞病症和缺血如心肌缺血、心肌梗塞、中风、心脏肥大、暂时性和局部缺血性发作、先兆子痫、炎性心血管病症、冠状动脉和外周动脉痉挛、水肿形成例如肺水肿、脑水肿、肾水肿或心脏衰竭引起的水肿,外周循环紊乱、再灌注损伤、动脉和静脉血栓形成、微白蛋白尿、心肌机能不全、内皮机能障碍、微血管和大血管损伤(血管炎),以及用于例如在血栓溶解疗法、经皮腔间血管形成术(PTA)、经皮腔间冠状动脉血管形成术(PTCA)、心脏移植和分流手术之后防止再狭窄。
在本发明的上下文中,术语“心力衰竭”包括心力衰竭的急性和慢性表现形式,和更特定或其相关的疾病类型,例如急性失代偿性心力衰竭、右心衰竭、左心衰竭、整体衰竭、缺血性心肌病、扩张性心肌病、肥厚型心肌病、特发性心肌病、先天性心室缺陷、心脏瓣膜缺陷、与心脏瓣膜缺陷有关的心力衰竭、二尖瓣狭窄、二尖瓣关闭不全、主动脉瓣狭窄、主动脉瓣闭锁不全、三尖瓣狭窄、三尖瓣关闭不全、肺动脉口狭窄、肺动脉瓣不全、混合心脏瓣膜缺陷、心肌炎症(心肌炎)、慢性心肌炎、急性心肌炎、病毒性心肌炎、糖尿病性心力衰竭、酒精性心脏病、心蓄积病以及舒张性和收缩性心力衰竭。
另外,根据本发明的化合物也可以用于治疗和/或预防动脉硬化、脂类代谢紊乱、血脂蛋白过少症、血脂障碍、血甘油三酯过多(Hypertriglyceridaemien)、高脂血症、结合高脂血症、血胆固醇过多、无β脂蛋白血症、谷固醇血症、黄瘤症、丹吉尔病、多脂症、肥胖症和代谢综合征。
根据本发明的化合物另外可以用于治疗和/或预防原发性和继发性雷诺氏现象、微循环损伤、跛行、耳鸣、外周和自发神经病、糖尿病性微血管病、糖尿病性视网膜病、糖尿病性肢端溃疡、风湿症、CREST综合症,狼疮,甲癣和风湿性疾病。
另外,根据本发明的化合物可以用于防止缺血-和/或再灌注-有关的器官或组织损伤和作为人或动物来源的器官、部分器官、组织或部分组织的灌注和保存溶液的添加剂,特别是用于外科手术或在移植医学领域。
此外,根据本发明的化合物适于治疗和/或预防肾疾病,特别是肾机能不全和肾衰竭。在本发明的上下文中,术语肾机能不全和肾衰竭包含其急性和慢性表现形式,和潜在的或相关的肾疾病,例如肾低灌注,透析相关性高血压,梗阻性尿路病,肾小球病,肾小球性肾炎,急性肾小球肾炎,肾小球硬化症,肾小管-间质疾病,肾病,例如原发性和先天性肾病,肾炎,免疫学肾疾病,例如肾移植排斥和免疫复合物-诱导的肾疾病,通过有毒物质诱导的肾病,通过造影剂诱导的肾病,糖尿病性和非-糖尿病性肾病,肾盂肾炎,肾囊肿,肾硬化,高血压性肾硬化和肾病综合征,其可以例如通过异常减少的肌酐和/或水***,异常升高的血液尿素,氮,钾和/或肌酐浓度,肾酶例如谷氨酰合成酶活性的改变,改变的尿渗透性或尿量,增加的微量清蛋白尿,高蛋白尿(Makroalbuminurie),对于肾小球和微动脉的损伤,管扩张,高磷酸盐血症和/或需要透渗析诊断性表征。本发明还包含根据本发明的化合物对于治疗和/或预防肾机能不全后遗症,例如高血压,肺水肿,心力衰竭,***,贫血症,电解质紊乱(例如高钙血症,低钠血症)和在骨质和碳水化合物机理中失调的应用。
另外,根据本发明的化合物适合于治疗和/或预防泌尿生殖***的病症例如良性***综合征(BPS)、良性***超常增生(BPH)、良性***增大(BPE)、膀胱出口阻塞(BOO)、下泌尿道综合征(LUTS)、膀胱神经性活动过度(OAB)、失禁例如混合性尿失禁、冲动性尿失禁、应激性尿失禁或溢流性尿失禁(MUI、UUI、SUI、OUI)、骨盆痛以及***机能障碍和女性性功能障碍。
根据本发明的化合物还适合于治疗和/或预防哮喘病、慢性梗阻性肺部疾病(COPD)、急性呼吸性窘迫综合症(ARDS)和急性肺损伤(ALI)、α-1-抗胰蛋白酶缺乏(AATD)、肺纤维化、肺气肿(例如抽烟引起的肺气肿)和囊性纤维化病(CF),以及肺动脉高血压(PAH)和其它形式的肺动脉高压(PH),包括与左侧-心衰竭、HIV、镰状细胞贫血、血栓栓塞、结节病、COPD或肺纤维化相关的肺动脉高压。
在本发明中描述的化合物还有用于控制中枢神经***疾病的活性化合物,这些疾病的特征在于NO/cGMP体系的失调。这些活性化合物特别适合于改进认知损伤后的知觉,专心,学习或记忆,如特别是在状态/疾病/综合症时出现,例如“温和的认知损伤”,年龄-相关的学习或记忆损伤,年龄-相关的记忆损失,血管痴呆,颅脑外伤,中风,中风后发生的痴呆(“中风后痴呆”),外伤后的颅脑外伤,全身性专心损伤,在患有学习和记忆问题的孩子中的专心损伤,阿尔茨海默病,莱维小体病痴呆,伴有前叶突退化的痴呆包括Pick综合征,帕金森病,渐进性核性麻痹,伴有皮质基底核退化的痴呆,肌萎缩侧索硬化(ALS),亨廷顿病,脱髓鞘作用,多发性脑硬化,丘脑退化,克-雅痴呆,HIV痴呆,伴有痴呆的精神***症或柯萨可夫精神病。它们还适合治疗和/或预防中枢神经***疾病,例如焦虑状态,紧张和抑郁症,中枢神经-相关的性功能障碍和睡眠失调,和用于控制食物,兴奋药和上瘾物质的摄入的病理失调。
根据本发明的化合物此外还适于控制脑血流量和是用于控制偏头痛的有效药剂。它们还适于预防和控制脑梗死(脑卒中)的后遗症,例如中风,大脑缺血和颅脑外伤。根据本发明的化合物同样可以用于控制所述的疼痛状态。
另外,根据本发明的化合物具有抗炎作用和可以因此用作用于治疗和/或预防败血症(SIRS),多器官衰竭(MODS、MOF),炎性肾疾病,慢性肠炎(IBD、克罗恩病、溃疡性结肠炎),胰腺炎,腹膜炎,类风湿性疾病,炎性皮肤病疾病和炎性眼病的消炎药剂。
根据本发明的化合物另外适合于治疗和/或预防内脏器官例如肺、心脏、肾脏、骨髓并特别是肝脏的纤维化病症,以及皮肤纤维化病症和纤维化眼疾。在本发明的上下文中,术语纤维性病症特别包括下面的病症,如:肝纤维化、肝硬化、肺纤维化、心肌心内膜纤维化、肾病、肾小球性肾炎、间质性肾纤维化、糖尿病造成的纤维化损伤、骨髓纤维化和类似的纤维化病症、硬皮病、硬斑病、瘢痕疙瘩、肥厚性瘢痕、痣、糖尿病视网膜病、增殖性玻璃体视网膜病变和***病症(例如结节病)。根据本发明的化合物也可用于促进伤口愈合,用于控制例如青光眼手术造成的术后瘢痕,美容性地用于衰老或角质化的皮肤。
由于它们的特性,根据本发明的化合物特别适于治疗和/或预防心血管疾病,例如心力衰竭,心绞痛,高血压和肺动脉高压,以及血栓栓塞疾病和缺血,血管疾病,微循环的失调,肾功能不足,纤维性病变和动脉硬化。
本发明进一步提供了本发明的化合物对于治疗和/或预防疾病,特别是以上提到的疾病的用途。
本发明进一步提供了根据本发明的化合物对于制备治疗和/或预防疾病,特别是以上提到的疾病的药剂的应用。
本发明进一步提供了包含至少一种根据本发明的化合物的用于治疗和/或预防疾病,特别是以上提到的疾病的药剂。
本发明进一步提供了根据本发明的化合物在用于治疗和/或预防疾病,特别是以上提到的疾病的方法中的用途。
本发明进一步提供了使用有效量的至少一种根据本发明的化合物来治疗和/或预防疾病,特别是以上提到的疾病的方法。
根据本发明的化合物可以单独或,如果需要,与其它的活性化合物结合使用。本发明进一步提供了包含至少一种本发明的化合物和一种或多种另外的活性化合物,特别是用于治疗和/或预防以上提到的疾病的药剂。适合用于组合的活性化合物的优选实例包括:
•有机硝酸酯和NO供体,例如,硝普酸钠,***油,单硝酸异山梨醇酯,二硝酸异山梨醇酯,脉心导敏或SIN-1,和吸入NO;
• 抑制环磷酸鸟苷(cGMP)和/或环磷酸腺苷(cAMP)降解的化合物,例如磷酸二酯酶(PDE) 1, 2, 3, 4和/或5抑制剂,尤其是PDE 4抑制剂如罗氟司特或Revamilast和PDE 5抑制剂如昔多芬、伐地那非、他达拉非、乌地那非、达生他非、阿伐那非、米罗那非或洛地那非;
• 非NO依赖性而是血红素依赖性的鸟苷酸环化酶刺激剂,尤其是如利奥西呱和WO00/06568、WO 00/06569、WO 02/42301、WO 03/095451、WO 2011/147809、WO 2012/004258、WO 2012/028647和WO 2012/059549中描述的化合物;
•前列环素类似物和IP受体激动剂,例如和优选伊洛前列素、贝拉普罗、曲罗尼尔、依前列醇或NS-304;
•内皮缩血管肽受体拮抗剂,例如和优选波生坦、波生坦、安贝生坦或塞塔生坦;
•抑制人类中性白细胞弹性蛋白酶(HNE)的化合物,例如和优选西维来司他或DX-890 (Reltran);
•抑制信号传导级联的化合物,特别是选自酪氨酸激酶抑制剂,例如和优选达沙替尼、尼洛替尼、博舒替尼、瑞格非尼、索拉非尼、舒尼替尼、西地尼布、阿西替尼、替拉替尼、伊马替尼、布立尼布、帕唑帕尼、瓦他拉尼、吉非替尼、厄洛替尼、拉帕替尼、卡拉替尼、来他替尼、贝利替尼、Semaxanib、马赛替尼或坦杜替尼;
• ρ激酶抑制性化合物,例如和优选法舒地尔、Y-27632、 SLx-2119、BF-66851、BF-66852、BF-66853、KI-23095或BA-1049;
• 抗梗阻剂,如例如用于治疗慢性阻塞性肺病(COPD)或支气管哮喘,例如和优选吸入或全身给药的β-受体拟态或吸入给药的抗蕈毒碱能(anti-muscarinerg)物质;
• 抗炎剂和和/或免疫抑制剂,例如用于治疗慢性阻塞性肺病(COPD)或支气管哮喘或肺纤维化,例如和优选全身或吸入给药的皮质激素;
•化疗法,如例如用于治疗肺或其它器官中的新形成(Neoplasien)生物使用的那些。
•用于全身和/或吸入治疗肺病的活性化合物,例如用于囊性纤维化(α-1-抗胰蛋白酶、氨曲南、Ivacaftor、Lumacaftor、Ataluren、阿米卡星、左氧氟沙星)、慢性阻塞性呼吸道病(COPD)(LAS40464、PT003、SUN-101)、急性呼吸道综合征(ARDS)和急性肺损伤(ALI)(干扰素-β-1a、菠萝蛋白酶)、阻塞性睡眠呼吸暂停(VI-0521)、 支气管扩张(甘露醇、环丙沙星)、梗阻性细支气管炎(环孢菌素、氨曲南)和脓毒症(帕吉昔单抗、万汶、ART-123);
•抗血栓剂,例如和优选自血小板聚集抑制剂、抗凝剂或纤维蛋白溶解物质;
•降血压的活性化合物,例如和优选自钙拮抗剂,血管紧张素AII拮抗剂,ACE抑制剂,内皮肽拮抗剂,肾素抑制剂,α-受体阻滞剂,β-受体阻滞剂,盐皮质激素受体拮抗剂,和利尿剂;和/或
•改进脂类代谢的活性化合物,例如和优选自甲状腺受体激动剂,胆固醇合成抑制剂,例如和优选HMG-CoA还原酶抑制剂或角鲨烯合成抑制剂,ACAT抑制剂,CETP抑制剂,MTP抑制剂,PPAR-α,PPAR-γ和/或PPAR-Δ激动剂,胆固醇吸收抑制剂,脂酶抑制剂,聚胆汁酸吸附剂,胆汁酸再吸收抑制剂和脂蛋白(a)拮抗剂。
抗血栓剂优选应当理解为是指血小板聚集抑制剂、抗凝剂或纤维蛋白溶解物质。
在本发明一个优选的实施方案中,根据本发明的化合物与血小板聚集抑制剂,例如和优选,阿斯匹林,氯吡格列,噻氯匹定或双嘧达莫结合服用。
在本发明一个优选的实施方案中,根据本发明的化合物与凝血抑制剂,例如和优选,希美加群、美拉加群、达比加群、比伐卢定或克赛结合服用。
在本发明一个优选的实施方案中,根据本发明的化合物与GPIIb/IIIa拮抗剂,例如和优选,替罗非班或阿昔单抗结合服用。
在本发明一个优选的实施方案中,根据本发明的化合物与因子Xa抑制剂,例如和优选,利伐沙班,阿哌沙班,非德沙班,雷扎沙班,磺达肝素,艾屈肝素,DU-176b,PMD-3112,YM-150,KFA-1982,EMD-503982,MCM-17,MLN-1021,DX 9065a,DPC 906,JTV 803,SSR-126512或SSR-128428结合服用。
在本发明一个优选的实施方案中,根据本发明的化合物与肝素或与低分子量(LMW)肝素衍生物结合服用。
在本发明一个优选的实施方案中,根据本发明的化合物与维生素K拮抗剂,例如和优选,香豆素结合服用。
降血压剂优选应当理解为是选自钙拮抗剂,血管紧张素AII拮抗剂,ACE抑制剂,内皮肽拮抗剂,肾素抑制剂,α-受体阻滞剂,β-受体阻滞剂,盐皮质激素受体拮抗剂,和利尿剂的化合物。
在本发明一个优选的实施方案中,根据本发明的化合物与钙拮抗剂,例如和优选,硝苯地平,氨氯地平,维拉帕米或地尔硫卓结合服用。
在本发明一个优选的实施方案中,根据本发明的化合物与α-1-受体阻断剂,例如和优选,哌唑嗪结合服用。
在本发明一个优选的实施方案中,根据本发明的化合物与β-受体阻滞剂,例如和优选,***、阿替洛尔、噻吗咯尔、吲哚洛尔、阿普洛尔、氧烯洛尔、喷布洛尔、布拉洛尔、三甲苯心安、纳多洛尔、甲吲洛尔、卡拉洛尔、索他洛尔、美托洛尔、倍他索洛尔、塞利洛尔、比索洛尔、卡替洛尔、艾司洛尔、拉贝洛尔、卡维地洛、阿达洛尔、兰地洛尔、奈必洛尔、依泮洛尔或布新洛尔结合服用。
在本发明一个优选的实施方案中,根据本发明的化合物与血管紧张素AII拮抗剂,例如和优选,氯沙坦、坎地沙坦、缬沙坦、替米沙坦或恩布沙坦结合服用。
在本发明一个优选的实施方案中,根据本发明的化合物与ACE抑制剂,例如和优选,依那普利、卡托普利、赖诺普利、雷米普利、地拉普利、福辛普利、奎诺普利、培哚普利或群多普利结合服用。
在本发明一个优选的实施方案中,根据本发明的化合物与内皮肽拮抗剂,例如和优选,波生坦、达卢生坦、安立生坦或司他生坦结合服用。
在本发明一个优选的实施方案中,根据本发明的化合物与肾素抑制剂,例如和优选,阿利吉仑、SPP-600或SPP-800结合服用。
在本发明一个优选的实施方案中,根据本发明的化合物与盐皮质激素受体拮抗剂,例如和优选,螺内酯或依普利酮结合服用。
在本发明一个优选的实施方案中,根据本发明的化合物与利尿剂,例如和优选,呋塞米、布美他尼、托塞米、苄氟噻嗪、***、氢***、氢氟噻嗪、甲***、泊利噻嗪、三***、氯噻酮、吲达帕胺、美托拉宗、喹乙宗、乙酰唑胺、二氯磺胺、醋甲唑胺、甘油、异山梨醇、甘露醇、阿米洛利或氨苯蝶啶结合给药。
脂类代谢改进剂优选应当理解为是指选自CETP抑制剂,甲状腺受体激动剂,胆固醇合成抑制剂,例如HMG-CoA还原酶抑制剂或角鲨烯合成抑制剂,ACAT抑制剂,MTP抑制剂,PPAR-α,PPAR-γ和/或 PPAR-Δ激动剂,胆固醇吸收抑制剂,聚胆汁酸吸附剂,胆汁酸再吸收抑制剂,脂酶抑制剂和脂蛋白(a)拮抗剂的化合物。
在本发明一个优选的实施方案中,根据本发明的化合物与CETP抑制剂,例如和优选,托彻普(CP-529 414)、JJT-705或CETP疫苗(Avant)结合服用。
在本发明一个优选的实施方案中,根据本发明的化合物与甲状腺受体激动剂,例如和优选,D-甲状腺素、3,5,3'-三碘甲腺原氨酸(T3)、CGS 23425或阿昔替罗(CGS 26214)结合服用。
在本发明一个优选的实施方案中,根据本发明的化合物与来自抑制素一类的HMG-CoA还原酶抑制剂,例如和优选,洛弗斯特丁、辛伐他汀、普伐他汀、氟伐他汀、阿托伐他汀、瑞舒伐他汀或匹伐他汀结合服用。
在本发明一个优选的实施方案中,根据本发明的化合物与角鲨烯合成抑制剂,例如和优选,BMS-188494或TAK-475结合服用。
在本发明一个优选的实施方案中,根据本发明的化合物与ACAT抑制剂,例如和优选,阿伐麦布、甲亚油酰胺、帕替麦布、伊鲁麦布或SMP-797结合服用。
在本发明一个优选的实施方案中,根据本发明的化合物与MTP抑制剂,例如和优选,英普他派、BMS-201038、R-103757或JTT-130结合服用。
在本发明一个优选的实施方案中,根据本发明的化合物与PPAR-γ激动剂,例如和优选,匹格列酮或罗格列酮结合服用。
在本发明一个优选的实施方案中,根据本发明的化合物与PPAR-Δ激动剂,例如和优选,GW-501516或BAY 68-5042结合服用。
在本发明一个优选的实施方案中,根据本发明的化合物与胆固醇吸收抑制剂,例如和优选,依泽替米、替奎安或帕马喹结合服用。
在本发明一个优选的实施方案中,根据本发明的化合物与脂肪酶抑制剂,例如和优选,奥利斯特结合服用。
在本发明一个优选的实施方案中,根据本发明的化合物与聚没食子酸吸附剂,例如和优选,消胆胺,考来替泊,Colesolvam,考来胶或考来替兰(Colestimid)结合服用。
在本发明一个优选的实施方案中,根据本发明的化合物与胆汁酸再吸收抑制剂,例如和优选,ASBT(=IBAT)抑制剂,例如AZD-7806、S-8921、AK-105、BARI-1741、SC-435或SC-635结合服用。
在本发明一个优选的实施方案中,根据本发明的化合物与脂蛋白(a)拮抗剂,例如和优选,吉卡宾钙(CI-1027)或烟酸结合服用。
本发明进一步的目的是包含至少一种根据本发明的化合物,通常连同一种或多种惰性的、无毒的、药物合适的赋形剂的药剂,和它们对于上述目的的应用。
根据本发明的化合物可以全身和/或局部起作用。为此目的,它们可以以合适的方式,例如通过口,肠胃外,肺,鼻,舌下,舌,颊,直肠,表皮,经皮,结膜,耳途径或作为植入物或支架服用。
根据本发明的化合物可以以适合于这些给药途径的合适的形式服用。
适合于口服给药的给药形式是根据现有技术作用并且迅速地和/或以改进的方式释放根据本发明的化合物,并且包含以结晶的和/或无定形的和/或溶解的形式的本发明的化合物的那些给药形式,例如片剂(无包衣的或包衣片剂,例如具有耐肠胃液的或延迟溶解或不溶的控制释放本发明的化合物的包衣),在口腔中迅速地分解的片剂或膜/胶囊(Oblate),膜/冻干物,胶囊(例如硬的或软的明胶胶囊),糖衣片,颗粒剂,丸剂,粉末剂,乳剂,悬浮剂,气雾剂或溶液。
肠胃外给药可以避免吸收步骤(例如静脉内,动脉内,心内,脊柱内或腰内)或同时包括吸收(例如肌肉内,皮下,皮内,经皮或腹内途径)地进行。适合于肠胃外给药的给药形式包括溶液、悬浮剂、乳剂、冻干物或无菌的粉末形式的注射剂和浸剂。
适合的另外的给药途径是,例如可吸入药剂(包括粉末吸入剂、雾化剂、计量的气溶胶),滴鼻剂,鼻用溶液或鼻用喷雾剂;用于舌,舌下或颊服用的片剂,膜/胶囊或胶囊,栓剂,用于耳和眼的制剂,***胶囊,水悬浮剂(洗液,振荡混合物),亲油性的悬浮剂,软膏,乳膏,经皮治疗性体系(例如贴剂),乳剂,糊剂,泡沫,扑粉,植入物或支架。
优选口服、肺内(吸入的)和静脉给药。
根据本发明的化合物可以转变为所述的服用形式。这可以以本身已知的方式通过与惰性的、无毒的、药理学合适的赋形剂混合进行。这些赋形剂包括载体(例如微晶纤维素,乳糖,甘露糖醇),溶剂(例如液体聚乙二醇),乳化剂和分散剂或润湿剂(例如十二烷基硫酸钠,聚氧脱水山梨糖醇油酸酯),粘合剂(例如聚乙烯吡咯烷酮),合成的和天然的聚合物(例如白蛋白),稳定剂(例如抗氧化剂,例如抗坏血酸),着色剂(例如无机颜料,例如铁氧化物)和香料和/或矫味剂。
通常,已经发现在肠胃外给药的情况下有利的施药量为0.001-1 mg/kg,优选大约0.01-0.5 mg/kg体重以达到有效的效果。在口服给药的情况下,剂量为大约0.01-100 mg/kg,优选大约0.01-20 mg/kg和最优选0.1-10 mg/kg体重。在肺内给药的情况下,所述量通常为每吸大约0.1-50 mg。
然而任选可能需要偏离所述的量,特别是依据体重,给药途径,对于活性化合物的个体反应,制剂种类和服用发生的时间或间隔。例如,在一些情况下,小于上述最小量也可能是足够的,而在另外的情况下必须超过所提到的上限。在更大量给药的情况下,适当的是在一天内分多次单独给药。
下面的具体实施例用于说明本发明。本发明不局限于这些实施例。
除非另外说明,下面的试验和实施例中的百分比是重量百分比;份是重量份。液体/液体溶液的溶剂比、稀释比和浓度数据分别基于体积。
A. 实施例
缩写和缩略词:
abs. 绝对的
Ac 乙酰基
aq. 含水的,水溶液
ATP 腺苷-5'-三磷酸酯
Brij® 聚乙二醇十二烷基醚
BSA 牛血清白蛋白
Ex. 实施例
c 浓度
cat. 催化的
DMF N,N-二甲基甲酰胺
DMSO 二甲基亚砜
d. Th. 理论值(关于收率)
DTT 二硫苏糖醇
ee 对映异构体过量
ent 对映体纯的,对映异构体
eq. 当量
ESI 电喷雾离子化(在MS中)
Et 乙基
GTP 鸟苷-5'-三磷酸酯
h 小时
Hal 卤素
HOAc 乙酸
HPLC 高压高效液相色谱
LC-MS 液相色谱-质谱联用
Me 甲基
min 分钟
MS 质谱
NMR 核磁共振谱
quant. 定量(关于收率)
rac 消旋的,消旋体
RP 反相(在HPLC中)
RT 室温
Rt 保留时间(在HPLC中)
s.a. 参见上述
TEA 三乙醇胺
TFA 三氟乙酸
THF 四氢呋喃
UV 紫外光谱法
v/v (溶液的)体积与体积比
tog. 一起。
HPLC和LC-MS法:
方法1(制备HPLC):
柱:Grom-Sil C18 10 µm,250 mm x 30 mm;流动相A:水+ 0.1%甲酸,流动相B:乙腈;进程:0-5 min 10% B,5-38 min梯度至95% B;流速:50 ml/min;UV检测:210nm。
方法2(LC-MS):
仪器:Waters Acquity SQD UPLC System;柱:Waters Acquity UPLC HSS T3 1.8μ,50mm × 1mm;流动相A:1 l水+ 0.25 ml 99%浓度甲酸,流动相B:1 l乙腈+0.25 ml 99%浓度甲酸;梯度:0.0 min 90% A → 1.2 min 5% A → 2.0 min 5% A;流速:0.40 ml/min;炉:50℃;UV检测:210-400nm。
方法3(LC-MS):
MS仪器类型:Waters Micromass Quattro Micro;HPLC仪器类型:Agilent 1100Series;柱:Thermo Hypersil GOLD 3 µ 20 mm x 4 mm;流动相A:1 l水+ 0.5ml 50%浓度甲酸,流动相B:1 l乙腈+0.5ml 50%浓度甲酸;梯度:0.0 min 100% A → 3.0 min 10% A→ 4.0 min 10% A → 4.01 min 100% A (流速2.5 ml/min) → 5.00 min 100% A;炉:50℃;流速:2 ml/min;UV检测:210nm。
方法4(LC-MS):
仪器:具有Waters UPLC Acquity的Micromass Quattro Premier;柱:ThermoHypersil GOLD 1.9 µ 50 mm x 1 mm;流动相A:1 l水+ 0.5ml 50%浓度甲酸,流动相B:1 l乙腈+0.5ml 50%浓度甲酸;梯度:0.0 min 90% A → 0.1 min 90% A → 1.5 min 10% A→ 2.2 min 10% A;流速:0.33 ml/min;炉:50℃;UV检测:210nm。
方法5(手性分析HPLC):
固定相:Daicel OD-H;柱:250 mm x 4 mm;UV检测:230 nm;流动相:异丙醇/异己烷30:70 (v/v);流速:1.0 ml/min。
方法6(手性分析HPLC):
固定相:Daicel OJ-H, 5 µm;柱:250 mm x 4 mm;UV检测:230 nm;流动相:异己烷/甲醇/乙醇50:25:25 (v/v/v);流速:1.0 ml/min。
方法7(手性分析HPLC):
固定相:Daicel Chiralpak IA;柱:250 mm x 4 mm;UV检测:230 nm;流动相:乙醇/甲基叔丁基醚75:25 (v/v);流速:1.0 ml/min。
方法8(制备LC-MS):
MS仪器:Waters;HPLC仪器:Waters;柱:Waters X-Bridge C18 5 µm,18 mm x 50mm;流动相A:水 + 0.05%三乙胺,流动相B:乙腈 + 0.05%三乙胺;梯度:0.0 min 95% A →0.15 min 95% A → 8.0 min 5% A → 9.0 min 5% A;流速:40 ml/min;UV检测:DAD,210-400 nm。
方法9(制备LC-MS):
MS仪器:Waters;HPLC仪器:Waters;柱:Phenomenex Luna 5 µ C18(2) 100A,50mm x 21.2 mm;流动相A:水 + 0.05%甲酸,流动相B:乙腈 + 0.05%甲酸;梯度:0.0 min 95%A → 0.15 min 95% A → 8.0 min 5% A → 9.0 min 5% A;流速:40 ml/min;UV检测:DAD, 210-400 nm。
方法10(LC-MS):
MS仪器:Waters SQD;HPLC仪器:Waters UPLC;柱:Zorbax SB-Aq (Agilent),50mm x 2.1 mm,1.8 µm;流动相A:水 + 0.025%甲酸,流动相B:乙腈 + 0.025%甲酸;梯度:0.0min 98% A → 0.9 min 25% A → 1.0 min 5% A → 1.4 min 5% A → 1.41 min 98% A→ 1.5 min 98% A;炉:40℃;流速:0.60 ml/min;UV检测:DAD, 210 nm。
起始化合物和中间体:
实施例1A
外消旋-5-{[2-(2-甲氧基苯基)乙基]氨基}-5,6,7,8-四氢萘-2-甲酸甲酯
15.2 g (74.5 mmol)5-氧代-5,6,7,8-四氢萘-2-甲酸甲酯[U. Gerlach和T.Wollmann, Tetrahedron Lett. 1992, 33 (38), 5499-5502]和11.5 g(74.5 mmol)在50ml乙醇中的2-(2-甲氧基苯基)乙基胺在回流下加热2小时。然后在减压下将所述混合物浓缩至干,将残余物吸收在300 ml甲醇中和在20分钟内在RT下在轻微的外部冷却下向所述悬浮液中分批地加入5.6 g(149 mmol)硼氢化钠。所述棕色溶液在RT下搅拌24h和接着倒入900 ml水中并用乙酸乙酯萃取三次。合并的有机相通过硫酸钠干燥和浓缩。残余物(24.5g)通过在硅胶上快速层析纯化(使用流动相环己烷/乙酸乙酯2:1)。
实施例2A
外消旋-5-{(5-乙氧基-5-氧代戊基)[2-(2-甲氧基苯基)乙基]氨基}-5,6,7,8-四氢萘-2-甲酸甲酯
9.0 g (26.5 mmol)实施例1A的化合物溶解在100 ml乙腈中和加入4.6 ml (6.1g, 29.2 mmol)5-溴代戊酸乙酯和5.65 g (53 mmol)碳酸钠。将混合物在回流下搅拌3天。加入另外的1.3 ml (8.2 mmol)5-溴代戊酸乙酯和1.6 g (15.1 mmol)碳酸钠之后,所述混合物在回流下再搅拌一夜。再次加入相同量的5-溴代戊酸乙酯和碳酸钠并将所述混合物再次在回流下加热过夜,直到通过LC-MS不再可以检测到反应物。然后将所述混合物浓缩,加入水并将所述混合物用乙酸乙酯反复萃取。合并的有机相通过硫酸钠干燥和浓缩。粗产物(14.6 g)通过在硅胶上快速层析纯化(使用流动相环己烷/乙酸乙酯5:1)。
实施例3A
外消旋5-{[2-(2-羟基苯基)乙基](5-甲氧基-5-氧代戊基)氨基}-5,6,7,8-四氢萘-2-甲酸甲酯
在氩气下,将653 mg (1.4 mmol)实施例2A的化合物溶解在12 ml二氯甲烷中和将所述混合物冷却到0℃。缓慢滴加三溴化硼在二氯甲烷中的4.6 ml (4.6 mmol)1 M溶液并将所述混合物在0℃下再搅拌4小时(透明的黄色溶液)。然后加入7 ml绝对甲醇并将所述混合物在回流下加热过夜。然后在减压下将所述混合物浓缩至干并将残余物分配在乙酸乙酯和10%浓度的碳酸钠水溶液之间。水相用乙酸乙酯再萃取,并将合并的有机相用饱和的氯化钠水溶液洗涤和在硫酸钠上干燥。浓缩后,残余物(519 mg棕色油)通过柱层析在硅胶上(流动相:梯度异己烷/4-32%乙酸乙酯)纯化。
实施例4A
外消旋-5-{(5-乙氧基-5-氧代戊基)[2-(2-羟基苯基)乙基]氨基}-5,6,7,8-四氢萘-2-甲酸乙酯
8.7 g(18.6 mmol)实施例2A的化合物在90 ml的溴化氢在冰醋酸中的33%浓度的溶液中在回流下搅拌过夜。加入另外90ml溴化氢溶液之后,将所述混合物在135℃浴温下再搅拌过夜。然后将所述混合物在减压下浓缩,向所述残余物中加入另外40ml的溴化氢在冰醋酸中的溶液并将所述混合物在浴温110℃下再搅拌过夜。然后将所述混合物再次浓缩至干。使所述残余物,其包含77%二羧酸化合物5-{(4-羧丁基)[2-(2-羟苯基)乙基]氨基}-5,6,7,8-四氢萘-2-甲酸[LC-MS (方法2):Rt = 0.64 min;MS (ESIpos): m/z = 412 [M+H]+],在190 ml乙醇中经历初期溶解,并滴加1.65 ml亚硫酰氯。所述混合物在70℃下搅拌过夜和然后在减压下浓缩。将所述残余物(大约13g)吸收在乙酸乙酯中和用稀的碳酸钠水溶液洗涤两次。有机相在硫酸钠上干燥和浓缩。粗产物(8.8 g)通过在硅胶上快速层析纯化(使用流动相环己烷/乙酸乙酯5:1)。
实施例5A
外消旋-5-[(2-{2-[(4-叔丁基苄基)氧基]苯基}乙基)(5-甲氧基-5-氧代戊基)氨基]-5,6,7,8-四氢萘-2-甲酸甲酯-甲酸盐
在氩气下,170 mg (0.387 mmol)实施例3A的化合物、104 mg (0.464 mmol)4-叔丁基苄基溴和403 mg (1.238 mmol)碳酸铯在3 ml DMF中在RT下搅拌2小时。然后加入30ml水,和将所述悬浮液用5 N甲酸酸化至pH 5。混合物用乙酸乙酯反复萃取,并将合并的有机相在硫酸钠上干燥和在减压下浓缩。所述残余物(340 mg黄色油)通过制备HPLC纯化(方法1)。
实施例6A和实施例7A
5-[(2-{2-[(4-叔丁基苄基)氧基]苯基}乙基)(5-甲氧基-5-氧代戊基)氨基]-5,6,7,8-四氢萘-2-甲酸甲酯(对映异构体1和2)
100 mg实施例5A的外消旋5-[(2-{2-[(4-叔丁基苄基)氧基]苯基}乙基)(5-甲氧基-5-氧代戊基)氨基]-5,6,7,8-四氢萘-2-甲酸甲酯通过制备HPLC在手性相上分离成对映异构体[样品制备:将所述物质溶解在3 ml异丙醇和7 ml异己烷中;注射体积:分别为1 ml;柱:Daicel Chiralpak OD-H, 250 mm x 20 mm; 流动相:异己烷/异丙醇 50:50 (v/v);流速:15 ml/min;温度:30℃;UV检测:210nm]:
实施例6A (对映异构体1):
。
实施例7A (对映异构体2):
。
实施例8A
外消旋-5-[(2-{2-[(4-叔丁基苄基)氧基]苯基}乙基)(5-乙氧基-5-氧代戊基)氨基]-5,6,7,8-四氢萘-2-甲酸乙酯
500 mg (1.07 mmol)实施例4A的化合物溶解在20 ml的DMF中,加入245 µl(1.23mmol)的4-叔丁基苄基溴和1.12 g (3.4 mmol)碳酸铯并将所述混合物在RT下搅拌过夜。然后向所述混合物中加入水。加入1.4 ml 5 N甲酸后,将所述混合物用甲苯反复萃取并将合并的有机相在硫酸钠上干燥和浓缩。
实施例9A和实施例10A
5-[(2-{2-[(4-叔丁基苄基)氧基]苯基}乙基)(5-乙氧基-5-氧代戊基)氨基]-5,6,7,8-四氢萘-2-甲酸乙酯(对映异构体1和2)
430 mg实施例8A的外消旋5-[(2-{2-[(4-叔丁基苄基)氧基]苯基}乙基)(5-乙氧基-5-氧代戊基)氨基]-5,6,7,8-四氢萘-2-甲酸乙酯通过制备HPLC在手性相上分离成对映异构体[样品制备:将所述物质溶解在20 ml乙醇和20 ml异己烷中;注射体积:分别为0.5ml;柱:Daicel Chiralpak OJ-H,5 µm, 250 mm x 20 mm;流动相:异己烷/乙醇/甲醇95:2.5:2.5 (v/v/v);流速:20 ml/min;温度:25℃;UV检测:230nm]:
实施例9A (对映异构体1):
。
实施例10A (对映异构体2):
。
实施例11A
外消旋-1-{[2-(2-甲氧基苯基)乙基]氨基}茚满-5-甲酸乙酯
类似于实施例1A的步骤以2.0 g (9.73 mmol)1-氧代茚满-5-甲酸乙酯起始制备标题化合物[R. Takeuchi和H. Yasue, J. Org. Chem. 1993, 58 (20), 5386-5392]。
实施例12A
外消旋-1-{(5-乙氧基-5-氧代戊基)[2-(2-甲氧基苯基)乙基]氨基}茚满-5-甲酸乙酯
类似于实施例2A的步骤以2.2 g (6.48 mmol)实施例11A的化合物起始制备标题化合物。
实施例13A
外消旋-1-{(4-羧丁基)[2-(2-羟苯基)乙基]氨基}茚满-5-甲酸
类似于实施例3A的步骤,1.8 g (3.85 mmol)实施例12A的化合物得到1.65 g粗的酚二酯外消旋-1-{(5-乙氧基-5-氧代戊基)[2-(2-羟苯基)乙基]氨基}茚满-5-甲酸乙酯[含量19%; LC-MS (方法2):Rt = 0.88 min; MS (ESIpos): m/z = 454 [M+H]+]。将此粗产物在10ml THF、15 ml甲醇和0.8 ml 5 N氢氧化钠溶液中在回流下加热2小时。然后将此混合物浓缩至体积大约5 ml并用5N甲酸酸化至pH 5-6。这导致无定形沉淀物沉淀,其通过硅胶层析(流动相二氯甲烷/4-34%甲醇)和随后制备HPLC纯化(方法1)。
实施例14A
外消旋-1-{(5-乙氧基-5-氧代戊基)[2-(2-羟苯基)乙基]氨基}茚满-5-甲酸乙酯-盐酸盐
53 mg (0.133 mmol)实施例13A的化合物溶解在3 ml乙醇中,加入19 µl (0.27mmol)亚硫酰氯并将所述混合物在75℃下搅拌4小时。然后加入另外200 µl亚硫酰氯和将所述混合物在75℃继续搅拌过夜。然后将所述混合物浓缩至干并将所述残余物用乙醇共蒸发两次。
以下化合物类似于实施例5A的步骤制备:
1) 用于分离对映异构体的方法:
样品制备:71 mg外消旋化合物溶解在8 ml异丙醇中并向所述溶液中加入10 ml异己烷;注射体积:分别0.8 ml;柱:Daicel Chiralpak OJ-H,5 µm, 250 mm x 20 mm;流动相:异己烷/乙醇/甲醇50:25:25 (v/v/v);流速:20 ml/min;温度:25℃;UV检测:230nm。
具体实施例
实施例1
外消旋-5-[(2-{2-[(4-叔丁基苄基)氧基]苯基}乙基)(4-羧丁基)氨基]-5,6,7,8-四氢萘-2-甲酸
将200 mg实施例8A的化合物(纯度92%,0.3 mmol)溶解在4 ml THF和2 ml甲醇中,并且在加入345 µl (1.73 mmol)5 N的氢氧化钠溶液之后,在回流下搅拌1.5小时。然后将所述混合物用水稀释并随后在减压下除去溶剂。加入650 µl 5 N的乙酸,将所述混合物稍微冷却和将沉淀的无色固体抽吸滤出并在高真空下干燥过夜。
实施例2
5-[(2-{2-[(4-叔丁基苄基)氧基]苯基}乙基)(4-羧丁基)氨基]-5,6,7,8-四氢萘-2-甲酸(对映异构体1)
23 mg (0.039 mmol)实施例6A的化合物溶解在1 ml THF/水中(5:1)并用0.4 ml1 N氢氧化钠溶液在RT下搅拌过夜。然后加入0.2 ml甲醇并将所述混合物在RT下进一步搅拌2小时。然后加入0.08 ml 5 N甲酸并将所述混合物浓缩至干。残余物通过制备HPLC纯化(方法1)。
实施例3
5-[(2-{2-[(4-叔丁基苄基)氧基]苯基}乙基)(4-羧丁基)氨基]-5,6,7,8-四氢萘-2-甲酸(对映异构体2)
类似于实施例2的步骤由21 mg (0.036 mmol)实施例7A的化合物起始获得标题化合物。
以下化合物类似于实施例1和2的步骤制备:
1) 所述酯水解用5 N在THF/甲醇中的氢氧化钠溶液进行(回流下1小时);
2) 所述酯水解用5 N在THF/甲醇中的氢氧化钠溶液进行(RT下过夜);
3) 所述酯水解用5 N在DMSO中的氢氧化钠溶液进行(RT下过夜);
4) 粗产物的纯化通过制备HPLC进行(方法1)。
通过平行合成制备另外的具体实施例的通用步骤:
分别首先在96孔的深孔微量滴定板的孔中装入1.2当量(0.12 mmol)相关卤代烷烃,并加入47 mg (0.1 mmol)实施例4A的化合物在0.6 ml DMF中的溶液。向此混合物中加入44 mg (0.32 mmol)碳酸钾。盖上所述微量滴定板并在80℃下振动过夜。然后过滤所述混合物,向滤液中加入0.6 ml 4 N氢氧化钠溶液并再次盖上所述混合物和在60℃下振动过夜。然后蒸发溶剂。将所述残余物吸收在0.6 ml DMSO中和通过制备LC-MS 直接纯化(方法8或9)。含产物的级分在减压下用离心干燥机浓缩。将各级分的残余物分别溶解在0.6mlDMSO中并合并。最后在离心干燥机中将溶剂完全蒸发。
下面的化合物根据这样的步骤得到:
B. 药理学功效的评价
本发明的化合物的药理学效果可以在以下试验中显示:
B-1. 对重组的鸟苷酸环化酶报道细胞系的作用
用重组鸟苷酸环化酶报道细胞系测定根据本发明的化合物的细胞活性,如F.Wunder等, Anal. Biochem. 339, 104-112 (2005)。
对于根据本发明化合物的代表性的结果在表1中列出:
表1: 在体外在CHO报道细胞中sGC-活化的活性
实施例号 | MEC [nM] |
1 | 0.3 |
2 | 0.2 |
3 | 0.65 |
4 | 3.0 |
8 | 0.3 |
10 | 1000 |
(MEC =最小的有效浓度)。
B-2. sGC酶活性的刺激
可溶性鸟苷酸环化酶(sGC)在刺激下将GTP转化成cGMP和焦磷酸酯(PPi)。PPi借助于以下描述的试验检测。在该试验中产生的信号随着该反应进行而增加并且作为在给出的刺激下sGC酶活性的量度。
为进行该试验,开始向微量培养板中加入29μl酶溶液[在50mM TEA中的0-10nM可溶性鸟苷酸环化酶(根据Hönicka等,J. Mol. Med. 77,14-23(1999)制备),2mM MgCl2,0.1% BSA(级分V),0.005% Brij®,pH 7.5],并且加入1μl要试验的物质(作为在DMSO中系列稀释的溶液)。混合物在室温下培养10 min。然后加入20μl检测混合物[1.2nM萤火虫荧光素酶(北美萤火虫荧光素酶,Promega公司),29μM脱氢荧光素(根据Bitler & McElroy,Arch. Biochem. Biophys. 72,358(1957)制备),122μM荧光素 (Promega公司),153μM ATP(Sigma)和0.4mMDTT(Sigma)在50mM TEA中,2mM MgCl2,0.1% BSA(级分V),0.005% Brij®,pH 7.5]。酶反应通过加入20μl底物溶液[在50mM TEA中的1.25mM鸟嘌呤核苷-5'-三磷酸酯(Sigma),2 mM MgCl2,0.1% BSA(级分V),0.005% Brij®,pH 7.5]起动并且连续在光度计中测定。由要试验的物质带来的刺激的程度可以相对于未刺激的反应的信号测定。
不含血红素的鸟苷酸环化酶的活化通过向酶溶液中添加25μM 1H-1,2,4-噁二唑并[4,3-a]喹喔啉-1-酮(ODQ)并且随后培养30分钟检测,并且与原始的酶的刺激比较。
对于根据本发明化合物的代表性的结果在表2中列出:
表2: 在体外对sGC酶的活化作用
实施例号 | MEC [nM] | EC50 [nM] |
1 | 0.34 | 3 |
2 | 0.11 | 2.5 |
3 | 5 | 43 |
4 | 0.21 | 4.5 |
8 | 0.32 | 7.2 |
10 | 270 | |
11 | 610 | |
13 | 55 | |
16 | 600 |
(MEC =最小有效浓度;EC50 = 半最大有效浓度)。
B-3. 体外血管舒张作用
通过静脉注射硫喷妥钠将家兔麻醉或杀死(大约50 mg/kg)并放血。除去隐动脉并分成3mm宽的环。将各个环分别单独安装到由0.3 mm粗的特殊电线(Remanium®)制成的一对端部开放的三角钩上。在预应力下,将每个环转移到5 ml器官浴槽中,其装有卡波金充气的温度37℃的具有如下组成的Krebs-Henseleit溶液:NaCl 119 mM; KCl 4.8 mM; CaCl2 x2 H2O 1 mM; MgSO4 x 7 H2O 1.4 mM; KH2PO4 1.2 mM; NaHCO3 25 mM; 葡萄糖10 mM; 牛血清清蛋白0.001%。用Statham UC2细胞检测并放大收缩力,经由A/D转换器 (DAS-1802HC, Keithley Instruments,慕尼黑)数字化并且同时在线性记录器上记录。通过加入苯福林诱导收缩。
几个(通常是4个)对照周期后,在下一次运行中以增加剂量加入待研究的物质,将在测试物质的影响下达到的收缩高度与在前面的最后一次运行中到达的收缩高度相比较。由此计算为了前面对照中达到的收缩降低50%(IC50值)必需的浓度。标准施加体积为5 µl。DMSO在浴溶液中的比例相当于0.1%。
对于根据本发明化合物的代表性的结果在表3中列出:
表3: 体外血管舒张作用
实施例号 | IC50 [nM] |
1 | 6 |
2 | 3.8 |
3 | 58 |
4 | 31 |
B-4. 体外和体内的支气管扩张作用
B-4.1 体外支气管松弛
从大鼠、小鼠或天竺鼠上去除支气管环(2-3段)并分别单独安装到由0.3 mm粗的特殊电线(Remanium®)制成的一对端部开放的三角钩上。在预应力下,将每个环导入到5ml器官浴槽中,其装有卡波金充气的温度37℃的缓冲溶液(例如Krebs-Henseleit溶液)中。所述支气管环用乙酰甲胆碱(1 µM)预收缩,然后通过加入增加浓度(10-9至10-6 M)的各试验物质检查支气管松弛。结果参考通过乙酰甲胆碱的预收缩以松弛百分比进行评价。
B-4.2 检查对哮喘模型中支气管收缩作用的动物试验
在激发试验之前,所有动物(大鼠、小鼠)用胃管或气雾吸入器进行胃内治疗。这里,治疗组的动物接收试验物质,对照动物相应地接收媒介物溶液。等待期之后,将所述动物麻醉和插管。一旦食管导管已经放置和呼吸已经达到稳定状态,在激发之前初步测量肺功能。其中,测量的参数是肺阻力(RL)和动态顺应性(Cdyn)以及潮气量(TV)和呼吸频率(f)。数据储存和统计评价用对于这些肺功能试验特别开发的计算程序(Notocord HEM)进行。
接着规定的试验动物吸入暴露于乙酰甲胆碱(MCh)气雾剂(不确定诱导的哮喘支气管收缩模型)。在暴露过程中和暴露后3分钟继续记录肺功能参数。使用开发的反馈剂量控制***(通过测量气溶胶浓度和分钟容量)控制和监测吸入空气中的MCh浓度和剂量。达到目标剂量时停止所述试验。通过与假治疗(scheinbehandelt)的阳性对照比较抵抗力的增加来测定试验物质的抑制作用。
过敏性哮喘模型的研究:
将除了阴性对照的所有动物用变应原卵清蛋白和辅剂(明矾)全身致敏。但是阴性对照组接收生理盐水(NaCl)。然后所有的组用卵清蛋白刺激。所述研究使用6个治疗组—3个剂量组中每组2种试验物质;另外,还有用***腹腔注射治疗的参考组、假-治疗和-激发的阴性对照组和假-治疗和卵清蛋白-激发的阳性对照组。致敏、治疗和激发实验记录:在第0、14和21天,所有动物用卵清蛋白和辅剂腹腔注射致敏,负性对照用NaCl治疗。在第28和29天,所述动物通过卵清蛋白溶液的气管内给药激发。试验物质在每次气管内变应原激发之前1小时胃内给药或吸入给药。在每次气管内变应原激发之前18小时和1小时,参考组用***腹腔注射治疗。阳性和阴性对照组相应地用媒介物治疗。
气道高反应性和炎症应答:
首先检查动物对不确定刺激的气道高反应性。为此,逐渐增加吸入的乙酰甲胆碱激发形式的高反应性试验在卵清蛋白次级之后大约24小时进行。
将所述动物麻醉和口腔插管,并在激发之前身体体积描述地测量肺功能(包括参数如潮气量、呼吸频率、动态顺应性和肺阻力)。一旦测量结束,对每个动物进行剂量/活性曲线作图和相对阴性对照评价阳性对照的高反应性或其在治疗组中的抑制。
然后将所述动物无痛处死,采集血样和对肺进行灌洗(BAL)。使用洗出液测定总的细胞数和血球分类计数包括BAL中的曙红细胞数。首先冻结剩余量的BAL流体。如果要求的话,这允许在后面的阶段测定额外的参数(例如细胞因子)。储存肺组织用于任选的组织病理学检查。
B-5. 根据Langendorff的分离的灌注心脏
体重200-250 g的雄性Wistar大鼠(菌株HsdCpb:WU)用Narcoren® (100 mg/kg)麻醉。打开胸腔和然后使心脏暴露,切开和通过将插管放入主动脉中与Langendorff装置连接。所述心脏以9 ml/min以恒流用Krebs-Henseleit缓冲液(95% O2和5% CO2充气,pH 7.4,35℃;组成,以mmol/l表示:NaCl 118;KCl 3;NaHCO3 22;KH2PO4 1.2;MgSO4 1.2; CaCl21.8;Glucose 10;丙酮酸钠2)逆行地灌注。为了测量心脏的收缩性,将薄塑料膜制成的与PE管相连和用水填充的气球经由心脏左心耳中的开口引入左心室中。将所述气球与压力接收器相连。将最终舒张压通过气球体积调节至5-10mmHg。借助第二压力接收器检测灌注压。数据经由桥式放大器送到计算机并登记。
在40分钟的平衡时间后,将各个试验物质加入到最终浓度10-7 mol/l的灌注液中20分钟,其作为冠状扩张的征兆,导致灌注压降低。然后将所述心脏在不用试验物质的情况下进一步灌注120分钟(洗出阶段)。为了测定灌注压降低的可逆性(洗出痕线(Wash-outScore)),洗出阶段60分钟后的灌注压的值是基于通过试验物质的灌注压的最大降低和以百分数表示。取以此方式获得的洗出痕线作为试验物质在作用位点的停留时间的量度。
B-6. 麻醉小猪中的血液动力学
使用两种性别的具有2-6kg重量的健康Göttingen Minipigs® Ellegaard(Ellegaard, 丹麦)。所述动物通过肌肉注射给药大约25 mg/kg***和大约10 mg/kg阿扎哌隆进行镇定。麻醉通过静脉注射给药大约2 mg/kg***和大约0.3 mg/kg咪达***进行引发。麻醉维持通过静脉注射给药大约7.5-30 mg/kg/h***和大约1-4 mg/kg/h咪达***(注入速率1-4 ml/kg/h)和大约150 µg/kg/h潘库溴铵(例如巴夫龙-阿特维斯)。插管后,所述动物通过通气机以恒定呼吸量(10-12 ml/kg, 35呼吸/分钟;Avea®, ViasysHealthcare, USA,或Engström Carestation, GE Healthcare, Freiburg,德国)通气使得达到大约5%的呼气末CO2浓度。用富含大约40%氧气(常氧)的室内空气进行通气。为了测量血液动力学参数如肺动脉压(PAP)、血压(BP)和心率(HR),将导管***颈动脉以测量血压,Swan-Ganz® 导管以流动指向的方式经由颈静脉导入肺动脉中。通过压力接收器(Combitransducer, B. Braun, Melsungen,德国)/放大器和Ponemah®作为数据采集软件记录和评价血液动力学信号。
将仪器放入动物中之后,开始连续注入血栓素A2类似物以增加肺动脉压。注入溶解在生理盐水中的大约0.3-0.75 µg/kg/min的9,11-二脱氧-9α,11α-环氧基甲烷***素F2α (U-44069; Sigma, 编号D0400,或Cayman Chemical Company, 编号16440)以实现平均肺动脉压增加至25 mmHg以上的值。注入开始后30分钟,达到平台,并开始实验。
试验物质作为静脉注射液或通过吸入给药。为了制备吸入溶液,采用下面的步骤:对于体重4 kg的动物,为了制备储备溶液(300 µg/kg),称出1.2 mg试验化合物并溶解在总体积3 ml中(1% DMSO, 99% 0.2%浓度的柠檬酸溶液,1 N氢氧化钠溶液以调节pH至8)。然后用已经预先用氢氧化钠溶液调节至pH 8的0.2%浓度的柠檬酸将所述溶液稀释至所使用的浓度。在每个试验中,用Aeroneb® 预喷雾器***在呼吸回路的吸入臂中喷雾3ml试验化合物溶液/4kg动物。平均喷雾时间从喷雾开始为大约7分钟。
B-7. PAH 动物模型中的sGC激活剂的吸入给药
实验在麻醉的Göttingen迷你猪、麻醉的大鼠或有知觉的装有遥感仪器的狗上进行。例如通过注入血栓素A2类似物、通过急性缺氧处理或在数周时间内的缺氧处理和/或通过给药农吉利碱诱发急性肺动脉高压。试验物质用Nebutec®或Aeroneb® 预喷雾器***通过用于实验性气管内给药的粉末/或溶液施加器(Liquid MicroSprayer®,Dry PowderInsufflator™, MicroSprayer®, Penn-Century Inc., Wyndmoor, PA, USA)喷雾或在***通气的吸气臂中的固体喷雾之后喷雾。所述物质取决于分子结构作为固体或溶液使用。通过压力接收器(Combitransducer, B. Braun, Melsungen,德国)/放大器和Ponemah®或CardioMems®作为数据采集软件记录和评价血液动力学信号。在长期实验(例如农吉利碱大鼠)后,也可以进行组织学评价。
B-8. 对于有知觉的大鼠无线电遥测血压和心率
对于以下描述的有知觉的大鼠,来自Data Sciences International DSI,美国的可商购的遥测***用于该测定。该***由3个主要部分组成:(1) 可植入的发射器(Physiotel® 遥测发射器),(2) 接收器(Physiotel® 接收器),它们通过多路调制器(DSIData Exchange Matrix)连接到(3)数据采集计算机上。遥测装置使得可以在有知觉的动物的通常生长环境中连续记录它们的血压、心率和身体运动。
对于具有>200g体重的成年雌性Wistar大鼠进行研究。发射器植入后,实验动物单独地在类型3 Makrolon笼中居住。它们自由获得标准饲料和水。在实验室中的白天/夜晚节奏通过在上午6.00点和在下午7.00点的室内照明改变。
发射器植入:
首次实验应用前至少14天,使用的遥测发射器(TA11 PA- C40,DSI))在无菌条件下通过手术植入实验动物。伤口愈合和植入物安放后以这种方法装有测量仪表的动物可以反复使用。
对于该植入,禁食的动物用戊巴比妥(Nembutal®,Sanofi,50mg/kg i.p)麻醉并对大面积的它们的腹部剃毛和消毒。腹腔已经沿着腹白线打开后,体系的充满液体的测定导管向头部方向在分叉以上被***降主动脉中并用组织粘合剂(VetBonDTM,3M)固定。发射器外壳腹膜内固定到腹壁肌上,并分层闭合伤口。手术操作后,给药用于预防感染的抗生素(Oxytetracyclin® 10%,60 mg/kg s.c.,0.06 ml/100 g体重,Beta-Pharma GmbH,德国)和止痛剂(Rimadyl®, 4 mg/kg s.c.,Pfizer,德国)。
物质和溶液:
除非另外说明,待研究的物质通过强饲法分别对动物组(n=6)口服给药。根据5ml/kg体重的给药体积,将所述测试物质溶解在合适的溶剂混合物中或悬浮在0.5%羟乙基纤维素中。使用溶剂治疗的动物组作对照。
试验程序:
为24个动物装备遥测测量***。每一个实验在一个实验编号下记录。
在该体系中生存的每一个装有测量仪表的大鼠被分配单独的接收天线(1010接收器,DSI)。植入的发射器可以通过安装的磁开关外部活化并在实验过程转到发射。发射的信号可以通过数据采集***(DataquestTM A.R.T. for Windows,DSI)在线检测并且相应地处理。数据在每一种情况下在为此目的建立和具有实验编号的文件夹中存储。
在标准步骤中,每隔10-秒钟时间测量:(1)收缩压(SBP),(2)舒张压(DBP),(3)平均动脉压(MAP),(4)心率(HR)和(5)活性(ACT)。
在计算机控制下以5-分钟间隔重复采集测量值。获得的源数据作为绝对值在具有现时测定的气压(环境压力参考监测器,APR-1)的图表中校正并且作为单独的数据存储。在来自制造公司(DSI)的多方面的文献中给出了进一步的技术细节。
除非另外说明,试验物质在实验当天上午9:00点给药。服用后,经过24小时测定上面描述的参数。
评价:
实验结束后,获得的单独的数据使用分析软件(DataquestTM A.R.T. 4.1Analysis)分类。取物质服用前2小时的时间作为空白值,和因此选用的数据组包括从实验当天上午7:00到第二天上午9:00的时间段。
在可预先设定的时间内通过测定平均值(15-分钟平均值)消除数据波动并作为文本文件转到存储介质。以这种方法预分类和压缩的测定值转移到Excel模板中和制表。对于每天的实验,将获得的数据储存在带有实验编号的专用文件夹中。结果和测试记录储存在通过编号分类纸质形式的文件夹中。
文献:
K. Witte, K. Hu, J. Swiatek, C. Müssig, G. Ertl和B. Lemmer,Experimental heart failure in rats: effects on cardiovascular circadian rhythms and on myocardial β-adrenergic signaling, Cardiovasc. Res. 47 (2):350-358 (2000)。
C. 用于药物组合物的具体实施例
根据本发明的化合物可以转变为如下的药物制剂:
片剂:
组合物:
100mg根据本发明的化合物、50mg乳糖(一水化物)、50mg玉米淀粉(国产)、10mg聚乙烯基吡咯烷酮(PVP 25)(BASF,Ludwigshafen,德国)和2mg硬脂酸镁。
片剂重212 mg。直径8 mm,曲率半径12 mm。
制备:
本发明的化合物、乳糖和淀粉的混合物用PVP在水中的5%溶液(m/m)造粒。颗粒干燥后与硬脂酸镁混合5分钟。混合物用常规压片机压制(对于片剂规格参见上面)。作为用于压制的指导值,使用的压力为15 kN。
可以口服给药的悬浮剂:
组合物:
1000 mg根据本发明的化合物、1000 mg乙醇(96%)、400 mg Rhodigel® (黄原酸胶,来自FMC, Pennsylvania, USA) 和99 g水。
10ml口服悬浮剂对应于100mg根据本发明化合物的单剂量。
制备:
将Rhodigel悬浮在乙醇中;向所述悬浮液中加入本发明的化合物。在搅拌下添加水。混合物搅拌大约6h直到Rhodigel的溶胀完成。
可以口服给药的溶液:
组合物:
500mg根据本发明的化合物、2.5g聚山梨醇酯和97g聚乙二醇400。20g口服溶液对应于100mg根据本发明化合物的单剂量。
制备:
本发明的化合物在搅拌下悬浮在聚乙二醇和聚山梨醇酯的混合物中。继续搅拌操作直到根据本发明的化合物已经完全溶解。
静脉内溶液:
根据本发明的化合物以低于在生理可接受的溶剂(例如等渗压盐溶液、5%葡萄糖溶液和/或30% PEG 400溶液)中的饱和溶解度的浓度溶解。使所述溶液经历无菌过滤和分配到无菌和无热源的注射容器中。
Claims (7)
1.式(I)的化合物和它们的盐,
其中
n代表数字1或2,
和
A代表下式的基团
其中
*表示与分子剩余部分连接的各点,
L1代表直链(C1-C5)-烷二基,
x代表数字1、2或3,其中这些CH2基团之一可以被-O-代替,
R1A和R1B彼此独立地代表氢或甲基,
L2代表键或直链(C1-C5)-烷二基,
Ar代表苯基或具有最多3个选自N、O和/或S的杂原子的5-或6-元杂芳基,
R2代表选自下面系列的取代基:氟、氯、溴、氰基、(C1-C4)-烷基、三氟甲基、(C1-C4)-烷氧基和三氟甲氧基,
p代表数字0、1或2,
其中在取代基R2出现两次的情况下,它们各自的含义可以相同或不同,
L3代表键、-O-、-CH2-、-CH2-CH2-或-CH=CH-,
和
R3和R4彼此独立地代表氢或选自下面系列的取代基:氟、氯、溴、氰基、(C1-C4)-烷基、三氟甲基、(C1-C4)-烷氧基和三氟甲氧基。
2.根据权利要求1的式(I)的化合物和它们的盐,其中
n代表数字1或2,
和
A代表下式的基团
其中
*表示与分子剩余部分连接的各点,
L1代表直链(C2-C4)-烷二基,
x代表数字1或2,其中这些CH2基团之一可以被-O-代替,
L2代表键或直链(C1-C4)-烷二基,
Ar代表苯基,
R2代表选自下面系列的取代基:氟、氯、氰基、(C1-C4)-烷基和三氟甲基,
p代表数字0或1,
L3代表键或-CH2-CH2-,
和
R3和R4彼此独立地代表氢或选自下面系列的取代基:氟、氯、氰基、(C1-C4)-烷基和三氟甲基。
3.根据权利要求1或2的式(I)的化合物和它们的盐,其中
n代表数字1或2,
和
A代表下式的基团
其中
*表示与分子剩余部分连接的各点,
和
R2代表甲基、乙基、异丙基或叔丁基。
4.用于制备权利要求1-3中定义的式(I)的化合物的方法,其特征在于:式(II)的化合物
其中n具有权利要求1-3中给出的含义
和
T1和T2相同或不同和代表(C1-C4)-烷基,
在碱存在的条件下与式(III)的化合物反应
其中A具有权利要求1-3中给出的含义
和
X1代表离去基团,选自氯、溴、碘、甲磺酸根、三氟甲磺酸根或甲苯磺酸根,
以产生式(IV)的化合物
其中n、A、T1和T2各自具有以上提到的含义,
和其接着通过酯基团-C(O)OT1和-C(O)OT2水解转化成式(I)相应的二羧酸,
并将所得式(I)的化合物任选地分离成其对映异构体和/或非对映异构体和/或任选地与合适的碱或酸反应得到其盐。
5.权利要求1-3任一项定义的化合物用于制备治疗和/或预防病症的药剂的用途,所述的病症为:心力衰竭、心绞痛、高血压、肺动脉高压、血栓栓塞病症、缺血、血管病症、微循环损伤、肾机能不全、纤维化病症和动脉硬化。
6.药剂,其包含权利要求1-3任一项定义的化合物,该化合物与一种或多种惰性的、非毒性的、药物上适合的赋形剂结合。
7.药剂,其包含权利要求1-3任一项定义的化合物,该化合物与一种或多种另外的活性化合物结合,所述的另外的活性化合物选自:有机硝酸酯、NO供体、cGMP-PDE抑制剂、鸟苷酸环化酶刺激剂、抗血栓形成剂、降血压剂和脂类代谢调节剂。
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US20150174113A1 (en) | 2015-06-25 |
US9387203B2 (en) | 2016-07-12 |
EP2874993B1 (de) | 2016-08-24 |
JP6324956B2 (ja) | 2018-05-16 |
HK1211282A1 (zh) | 2016-05-20 |
JP2015524401A (ja) | 2015-08-24 |
CA2879456A1 (en) | 2014-01-23 |
CN104703964A (zh) | 2015-06-10 |
WO2014012935A1 (de) | 2014-01-23 |
ES2603262T3 (es) | 2017-02-24 |
EP2874993A1 (de) | 2015-05-27 |
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