CN113784710A - 用于治疗高血压或心力衰竭的化合物及包含该化合物的组合物 - Google Patents
用于治疗高血压或心力衰竭的化合物及包含该化合物的组合物 Download PDFInfo
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Abstract
本发明涉及化合物、包含该化合物的组合物、用于制备所述化合物的方法以及这些化合物在疗法中的用途。具体地,本发明涉及可用于治疗及预防原发性及继发性动脉性高血压、暴病发作、心肌缺血、心及肾功能不全、心肌梗塞、周围血管疾病、糖尿病性蛋白尿、X综合征及青光眼的化合物。
Description
发明领域
本发明涉及化合物、包含该化合物的组合物、用于制备所述化合物的方法以及此化合物在疗法中的用途。具体地,本发明涉及可用于治疗及预防原发性及继发性动脉性高血压、暴病发作、心肌缺血、心及肾功能不全、心肌梗塞、周围血管疾病、糖尿病性蛋白尿、X综合征及青光眼的化合物。
发明背景
原发性高血压(HTN)及心力衰竭(HF)是心血管疾病的主要病理学中的两种。HTN影响全世界约10亿的个体。其是导致冠心病、HF、中风及肾功能不全的主要风险因素。尽管存在有效且安全的药物的利用度,但HTN及其伴随的风险因素在许多患者中仍未得到控制。HF仍为导致西方国家超过65岁的患者住院的主要原因。在工业化国家中,每一千人中就有一至五个人受HF影响,若考虑所有年龄,则每一千人中有三至二十个人患病。尽管有很多药物可供使用,但HF具有不良预后,因为若考虑所有阶段,则一年存活率是约65%。HF仍为引起心血管死亡的主导原因之一,因此,有关开发新颖高效且安全的药物类别的医学需求仍有待满足。
已知全身肾素-血管紧张素系统(renin-angiotensin system,RAS)在血压(BP)调节及钠代谢中起到关键作用。靶向RAS的全身用药物,诸如血管紧张素I转化酶(ACE)抑制剂及血管紧张素-II受体1型(AT1)拮抗剂在临床上有效降低患者的BP并预防患者的心血管及肾脏发病率及死亡率。另外,在HF患者中肾素-血管紧张素醛固酮系统(RAAS)的活性增加,且其不适应机制可能导致不良作用,诸如心脏重塑及交感神经活化。当前的循证指南IA所推荐的用于伴随射血分数减少的HF的药物主要是RAAS作用分子,诸如ACE抑制剂或AT1受体阻断剂及β-肾上腺素受体阻断剂。
脑中还存在控制心血管功能及体液稳态的功能性RAS。若干研究表明,增加脑RAS的活性引起交感神经神经元活性及血管加压素释放增加,且脑RAS的高活性在介导HTN的各种动物模型的高BP以及HF的动物模型的心脏重塑及功能障碍方面起到重要作用(Marc Y,Llorens-Cortes,C Progress in Neurobiology 2011,95,第89-103页;Westcott KV等人,Can.J.Physiol.Pharmacol.2009,87,第979-988页)。由于近期的证据证明血管紧张素III(Ang III)经由其对AT1受体的作用而可用成为脑RAS进行BP中枢控制的真正肽效应物,故脑氨肽酶A(APA),亦即脑中由血管紧张素II(AngII)产生Ang III的酶构成用于治疗HTN及治疗HF的颇具前景的治疗目标。
氨肽酶A(APA,EC 3.4.11.7)是一种膜结合性锌金属蛋白酶,该酶已表征为负责脑中AngII转化成AngIII的酶(Zini S等人,Proc.Natl.Acad.Sci.USA 1996,93,第11968-11973页)。至今已开发出若干APA抑制剂(Chauvel EN等人,J.Med.Chem.1994,37,第1339-1346页;Chauvel EN等人,J.Med.Chem.1994,37,第2950-2957页;David C等人,J.Med.Chem.1999,42,第5197-5211页;Georgiadis D等人,Biochemistry 2000,39,第1152-1155页;Inguimbert N等人,J.Peptide Res.2005,65,第175-188页)。其中,EC33((3S)-3-氨基-4-硫醇-磺酸丁酯)被报导为具特异性及选择性的APA抑制剂。已发现在高血压的若干实验模型中,中枢输注EC33可抑制脑APA活性,阻断对脑室内(icv)输注Ang II的压力反应,并降低BP(Fournié-Zaluski MC等人,Proc.Natl.Acad.Sci.USA 2004,101,第7775-7780页)。
进一步展示,对有意识的DOCA盐型高血压大鼠及SHR大鼠急性经口施用RB150(又称为非瑞司他(firibastat))(15至150mg/kg),亦即EC33的脑穿透性前药,将诱导BP的剂量依赖性降低(Bodineau L等人,Hypertension 2008,51,第1318-1325页;Marc Y等人,Hypertension 2012,60,第411-418页)。有趣的是,已发现RB150先藉由减少血管加压素释放,增加水利尿(aqueous diuresis)及尿钠排泄,由此将血量及BP减小至控制值,且其次藉由减少交感神经紧张,由此减小血管阻力并因此降低BP来降低DOCA盐型大鼠及SHR大鼠的BP。亦报导,长期经口施用RB150及ACE抑制剂依那普利(enalapril)类似地有效抑制在心肌梗塞(MI)后患上HF的大鼠中所观察到的心脏功能障碍(Boitard S等人,Journal ofMolecular and Cellular Cardiology 2019,127,第215-222页)。RB150在经口施用之后能够进入脑中,阻断脑APA活性,使高血压大鼠的BP正常,并预防大鼠在MI之后发生心脏功能障碍,表明脑APA抑制剂代表一类新的用于治疗HTN及HF的中枢作用药剂。
本发明人现已鉴别出新颖化合物,所述化合物在体内充当强效脑APA抑制剂且就这一点而言,其可有效降低动脉性高血压,并且可在治疗动脉性高血压以及由动脉性高血压间接及直接促成的疾病,诸如心力衰竭方面具有效用。所述化合物亦呈现令人满意的生物利用度及药物动力学参数,使其成为经口或胃肠外施用的良好候选物。
发明概述
因此,本发明提供一种化合物,其具有下式(I):
且更具体地,其具有下式(II):
其中:
AH表示-CO2H、-SO3H、-PO3H2;
m是1、2或3;
R1及R2独立地表示H、C1-6烷基、C2-6烯基或C2-6炔基,各烷基、烯基或炔基任选经至少一个选自以下的下述基团取代:芳基、杂环基、环烷基、O-芳基、O-芳基烷基或O-环烷基;所述芳基、杂环基、环烷基、O-芳基、O-芳基烷基、O-环烷基任选经一或多个选自以下的基团取代:卤素原子、烷基、烷氧基、卤烷基、卤烷氧基、酰基、O-环烷基、杂烷基、O-芳基、O-芳基烷基、芳基、杂环基或芳基烷基;
其医药盐类、溶剂合物、两性离子形式或任何前药。
在另一方面中,本发明公开了一种组合物,其包含所述式(I)且更具体地,式(II)的化合物。更具体地,组合物是一种医药组合物。因此,本发明提供一种医药组合物,其包含至少一种本发明化合物,优选地与医药学上可接受的稀释剂或载剂结合。
根据另一方面,本发明涉及一种用于预防或治疗动脉性高血压以及间接及直接相关的疾病的方法,其包含施用治疗有效量的本发明化合物。在另一方面中,本发明提供本发明化合物,其作为活性医药成分用于疗法或药物中,且具体地,用于人类药物中,且更具体地,用于治疗动脉性高血压以及间接及直接相关的疾病或病症。
在另一方面中,本发明提供本发明化合物用于制造用于治疗动脉性高血压以及间接及直接相关的疾病或病症的药物的用途。
在另一方面中,本发明提供一种治疗罹患动脉性高血压以及间接及直接相关的疾病的患者的方法,其包含施用治疗有效量的本发明化合物。
附图简述
图1.描述在静脉内(i.v.)施用实施例1(50mg/kg)之后小鼠脑APA离体活性的抑制。
图2.描述在口服(p.o.)施用实施例2(8mg/kg)之后高血压大鼠脑APA离体活性的抑制。
图3a.及3b.展示p.o.施用实施例2(8mg/kg)对高血压大鼠的血压及心率的影响。
图4.显示长期经口施用非瑞司他(firibastat)、雷米普利(ramipril)或实施例2对MI后4周的小鼠的左心室射血分数(LVEF)的影响。值以自n=9至n=15的平均值±SEM表示。
发明详述
因此,本发明涉及一种化合物,其具有下式(I):
且更具体地,其具有下式(II):
其中:
AH表示-CO2H、-SO3H、-PO3H2;
m是1、2或3;
R1及R2独立地表示H、C1-6烷基、C2-6烯基或C2-6炔基,各烷基、烯基或炔基任选经至少一个选自以下的下述基团取代:芳基、杂环基、环烷基、O-芳基、O-芳基烷基或O-环烷基;该芳基、杂环基、环烷基、O-芳基、O-芳基烷基、O-环烷基任选经一或多个选自以下之基团取代:卤素原子、烷基、烷氧基、卤烷基、卤烷氧基、酰基、O-环烷基、杂烷基、O-芳基、O-芳基烷基、芳基、杂环基或芳基烷基。
本发明提供根据本发明的化合物,其用于预防或治疗动脉性高血压及动脉性高血压直接地或间接地促成的疾病的方法中。此类疾病包括心脏、周围及脑血管系统、脑、眼及肾脏的疾病。具体地,疾病包括原发性及继发性动脉性高血压、暴病发作(ictus)、心肌缺血、心或肾功能不全、心肌梗塞、周围血管疾病、糖尿病性蛋白尿、X综合征及青光眼。
如本文所使用,“本发明化合物”意指以上描述的化合物、或其前药、或其医药学上可接受的盐、溶剂合物或任何两性离子形式。
在本发明的上下文中:
术语“烷基”或“Alk”意指包含1-6个碳原子的单价或二价、直链或分支链饱和烃链,诸如甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、叔丁基-甲基、正戊基或正己基。在一个优选实施方案中,“烷基”是甲基、乙基、丙基、异丙基或叔丁基,更优选地为甲基或乙基。
术语“烯基”是指包含至少一个碳-碳双键的不饱和直链或分支链脂肪族基团。更具体地,术语“(C2-C6)烯基”包含乙烯基、丙烯基、异丙烯基、丁烯基、异丁烯基、戊烯基或己烯基。
术语“炔基”是指包含至少一个碳-碳三键的不饱和直链或分支链脂肪族基团。更具体地,术语“(C2-C6)炔基”包含乙炔基、丙炔基、丁炔基、戊炔基、异戊炔基或己炔基。
术语“酰基”意指-C(O)R基团,其中R是如前文所定义的烷基、或苯基。酰基包括例如乙酰基、乙基羰基或苯甲酰基。
术语“烷氧基”或“烷基氧基”意指-OAlk基团,其中Alk是如上文所定义的烷基。烷氧基包括例如甲氧基、乙氧基、正丙氧基或叔丁氧基。
术语“芳基”或“Ar”意指包含4-10个碳原子的芳族单环或双环系统,应理解,在双环系统的情况下,环之一是芳族环且另一个环是芳族或不饱和环。芳基包括例如苯基、萘基、茚基或苯并环丁烯基,优选地为苯基。
术语“芳基烷基”意指-Alk-Ar基团,其中Alk表示如前文所定义的烷基,且Ar表示如前文所定义的芳基。
术语“环烷基”意指包含3-12个碳原子的饱和单环或多环系统,诸如稠合或桥连双环系统,诸如环丙基、环丁基、环戊基、环己基、环庚基、环辛基、金刚烷基、十氢萘基(decalinyl)或降冰片烷基(norbornyl)。
术语“O-环烷基”意指经由氧原子连接至分子的其余部分的如前文所定义的环烷基。O-环烷基包括例如O-环戊基或O-环己基。
术语“O-芳基”意指经由氧原子连接至分子的其余部分的如前文所定义的芳基。O-芳基包括例如O-苯基。
术语“O-芳基烷基”意指经由氧原子连接至分子的其余部分的如前文所定义的芳基烷基。O-芳基烷基包括例如O-苯甲基。
术语“卤烷基”意指包含1-6个碳原子且经一或多个且尤其是经1-6个卤素原子取代的直链或分支链饱和烃链,诸如三氟甲基或2,2,2-三氟乙基。
术语“卤烷氧基”意指包含1-6个碳原子且经一或多个且尤其是经1-6个卤素原子取代的直链或分支链饱和烃链,所述链经由氧原子连接至化合物,诸如三氟甲氧基或2,2,2-三氟乙氧基。
术语“杂环基”意指具有3-12个成员且所述成员包含1-4个选自氧、硫及氮的相同或不同杂原子且可能含有1或2个氧基(=O)或硫酮基(thioxo)(=S)的饱和、不饱和或芳族、稠合、螺稠合或桥连单环或双环系统,应理解,在双环系统的情况下,环之一可为芳族环且另一个环是芳族、饱和或不饱和的。杂环包括例如哌啶基、哌嗪基、呋喃基、噻吩基、吡咯基、吡唑基、咪唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、苯并呋喃基、苯并噻吩基、吲哚基、喹啉基、异喹啉基、苯并间二氧杂环戊烯基、苯并间二氧杂环己烯基、苯并[1,2,5]噻二唑基、苯并[1,2,5]恶二唑基、[1,2,3]三唑基或[1,2,4]三唑基。
术语“杂烷基”意指包含1至5个碳原子及至少1或2个杂原子的直链或分支链饱和烃链,该至少1或2个杂原子诸如硫、氮或氧原子。杂烷基例如包括-O(CH2)2OCH3或-(CH2)2OCH3基团。
术语“卤素原子”意指氟、溴、氯或碘原子。
术语“保护基(protective group)”或“保护基(protection group)”意指选择性阻断多官能化合物中的反应位点以使得化学反应可选择性地在另一个未保护的反应位点处进行的基团,且具有在合成化学中通常与后者相关联的含义。
在本发明中,术语“医药学上可接受”是指可用于制备医药组合物,在生物上或在其他方面大体上安全、无毒且并非不合需要的,且通常可接受用于兽医学或人类医药用途。
术语本发明化合物的“医药学上可接受的盐”包括由医药学上可接受的无机酸或有机酸或碱形成的常规盐,以及季铵盐。适合酸盐的更具体实例包括盐酸、氢溴酸、硫酸、磷酸、硝酸、高氯酸、延胡索酸、乙酸、丙酸、琥珀酸、乙醇酸、甲酸、乳酸、马来酸、酒石酸、柠檬酸、棕榈酸、丙二酸、羟基马来酸、苯乙酸、谷氨酸、苯甲酸、水杨酸、延胡索酸、甲苯磺酸、甲磺酸、萘-2-磺酸、苯磺酸、羟基萘甲酸、氢碘酸、苹果酸、硬脂酸、鞣酸等。适合碱性盐的更具体实例包括钠、锂、钾、镁、铝、钙、锌、N,N'-二苯甲基乙二胺、氯普鲁卡因(chloroprocaine)、胆碱、二乙醇胺、乙二胺、N-甲基葡糖胺及普鲁卡因盐。
举例而言,优选的盐形式包括盐酸盐。
术语“前药”意指作为本发明目标的化合物的化学衍生物,其在体内藉由与生理介质的一或多个自发化学反应,尤其是藉由酶反应、光解和/或代谢反应产生所述化合物。在本发明的情况下,本发明化合物的前药在体内产生被鉴别为氨肽酶A抑制剂的化合物。
前药可藉由用特定不稳定部分使官能基衍生化来获得。具有酸官能基(诸如次磷酸、羧酸、磺酸或膦酸)的前药尤其包含酯,具有胺官能基的前药尤其包含[(2-甲基丙酰基)氧基]乙氧基羰基。
其他实例描述于T.Higuchi及V.Stella,“Pro-drugs as Novel Deliverysystem”,第14卷,A.C.S Symposium Series,American Chemical Society(1975)及“Bioreversible Carriers in Grug Design:Theroy and Application”,E.B.Roche编辑,Pergamon Press:New York,14-21(1987)中。
根据本发明,术语“异构体”是指具有与本文中所标识的相同分子式但在性质上或其原子的结合顺序或其原子在空间中的布置方面不同的本发明化合物。原子在空间中的布置不同的异构体命名为“立体异构体”。不互为镜像的立体异构体称为“非对映异构体”,且互为不可重叠的镜像的立体异构体称为“对映异构体”或“光学异构体”。“立体异构体”是指外消旋体、对映异构体及非对映异构体。
本领域技术人员应认识到,在本发明化合物中存在立体中心。本发明化合物的任何手性中心可为(R)、(S)或外消旋体。因此,本发明包括式(I)化合物的所有可能的立体异构体及几何异构体且不仅包括外消旋化合物,而且亦包括光活性异构体。根据一个优选实施方案,本发明化合物具有式(II)。当希望式(I)化合物是单一对映异构体时,其可藉由解析最终产物或藉由自异构性纯起始物质或任何适合中间物进行立体特异性合成来获得。最终产物、中间物或起始物质的解析可藉由本领域中已知的任何适合方法实现。参见例如E.L.Eliel的Stereochemistry of Carbon Compounds(Mcgraw Hill,1962)及S.H.Wilen的Tables of Resolving Agents。
本领域技术人员应认识到,本发明化合物可含有至少一个正电荷及至少一个负电荷,以使得本发明化合物包括其两性离子形式。在化学中,两性离子(又称为内盐)是具有两个或多于两个官能基的分子,所述官能基中的至少一个具有正电荷且至少一个具有负电荷,且不同官能基上的电荷彼此相抵,且分子整体上呈电中性。使此情形发生的pH值称为等电点。因此,包括前药在内的本发明化合物的任何两性离子形式均在本发明的范围内。
有机化学领域中的专家应了解,许多有机化合物能与溶剂形成复合物,所述有机化合物在溶剂中反应或自溶剂沉淀或结晶。这些复合物称为“溶剂合物”。举例而言,与水的复合物称为“水合物”。式(I)或(II)的化合物的溶剂合物在本发明的范围内。
有机化学专家亦应了解,许多有机化合物可存在超过一种结晶形式。举例而言,结晶形式可随溶剂合物而变化。因此,本发明化合物或其医药学上可接受的溶剂合物的所有结晶形式均在本发明的范围内。
本文中提到的本发明化合物包括式(I)或(II)的化合物两者及其医药学上可接受的盐、溶剂合物、两性离子形式或前药。
根据一个特定实施方案,本发明化合物对应于通式(I)且更具体地,对应于式(II),其中R1及R2独立地表示H或C1-6烷基,各烷基任选经至少一个选自以下的下述基团取代:芳基、杂环基或环烷基;所述芳基、杂环基、环烷基任选经一或多个选自以下的基团取代:卤素原子、烷基、烷氧基、卤烷基、卤烷氧基、酰基、O-环烷基、杂烷基、O-芳基、O-芳基烷基、芳基、杂环基或芳基烷基。
根据另一个特定实施方案,本发明化合物对应于通式(I)且更具体地,对应于式(II),其中R1及R2均为H,或替代地,R1是H且R2是苯甲基(亦即,-CH2-苯基)或苯乙基(亦即,-(CH2)2苯基)。
根据优选实施方案,本发明化合物对应于通式(I)且更具体地,对应于式(II),其中以下特征中的一个、两个、三个或四个得到满足,优选地每个特征均得到满足:
-m是2或3;和/或
-AH是CO2H或SO3H;和/或
-R1是H;和/或
-R2是H或烷基,优选地为经苯基取代的烷基。
根据更优选的实施方案,本发明化合物对应于通式(I)且更具体地,对应于式(II),其中以下特征中的一个、两个或三个得到满足,优选地每个特征均得到满足:
-m是2;和/或
-AH是SO3H;和/或
-R1及R2均为H,或替代地,R1是H且R2是苯乙基(亦即,-(CH2)2苯基)。
根据具体实施方案,本发明化合物是选自由以下组成的组:
(2R)-2-氨基-3-{[(2S)-2-氨基-4-磺基丁基]二硫基}丙酸,
(2R)-2-氨基-3-{[(3S,4S)-4-氨基-1-苯基-6-磺基己-3-基]二硫基}丙酸,及其医药盐类、溶剂合物、两性离子形式或其任何前药。
根据一个具体实施方案,本发明化合物是用作药物。
本发明化合物以医药组合物形式常规施用。此类组合物宜以常规方式与一或多种生理上可接受的载剂或赋形剂混合来提供使用。在与配制剂的其他成分相容且对接受它们的受试者无害的意义上,载剂必须为“可接受的”。
尽管可将本发明化合物作为化学原料治疗性施用,但其亦可提供作为医药配制剂的活性成分。
因此,本发明进一步提供一种医药组合物,其包含本发明化合物与一或多种医药学上可接受的载剂及任选选用的其他活性成分结合。
医药组合物包括适于经口、胃肠外(包括皮下,例如藉由注射或藉由贮存锭(depottablet);皮内;鞘内;眼内;肌肉内,例如藉由药物贮存(depot);及静脉内)、经眼、直肠及局部(包括经皮(亦即,在皮肤上)、经颊及舌下)施用或呈适于藉由吸入或吹入施用的形式的医药组合物,不过,最适合的途径可取决于例如接受者的状况及病症。组合物可以常规呈单位剂型,且可藉由药剂学领域中熟知的任何方法制备。所有方法均包括使本发明化合物,任选与至少一种其他活性成分,及构成一或多种附属成分的载剂结合的步骤。一般而言,配制剂是藉由使活性成分与液体载剂或细粉状固体载剂或两者均匀且紧密地结合,且接着,必要时使产物成形为所希望的配制剂来制备。
适于经口施用的医药组合物可呈离散单元形式,诸如胶囊、扁囊剂或片剂(例如咀嚼片剂,特别是对于儿科施用而言),每个单元含有预定量的活性成分;呈粉末或颗粒形式;呈于水性液体或非水性液体中的溶液或悬浮液形式;或呈水包油液体乳液或油包水液体乳液形式。活性成分亦可呈推注(bolus)、药糖剂(electuary)或糊剂形式。
片剂可藉由任选在一或多种附属成分存在下压缩或模制来制备。压缩片剂可藉由在适合机器中压缩呈诸如粉末或颗粒等自由流动形式的活性成分来制备,该活性成分任选混有其他常规的赋形剂,诸如粘合剂(例如糖浆、阿拉伯胶、明胶、山梨糖醇、黄蓍胶、淀粉胶浆、聚乙烯吡咯啶酮或羟甲基纤维素)、填充剂(例如乳糖、蔗糖、微晶纤维素、玉米淀粉、磷酸钙或山梨糖醇)、润滑剂(例如硬脂酸镁、硬脂酸、滑石、聚乙二醇或二氧化硅)、崩解剂(例如马铃薯淀粉或羟乙酸淀粉钠)或润湿剂,诸如月桂基硫酸钠。模制锭剂可藉由在适合机器中模制用惰性液体稀释剂润湿的粉末状化合物的混合物来制备。片剂可任选包覆包衣或刻痕,且可经配制以便提供其中活性成分的缓慢或控制释放。片剂可藉由本领域公知的方法包覆包衣。
或者,例如,本发明化合物可并入口服液体制剂,诸如水性或油性悬浮液、溶液、乳液及诸如糖浆或酏剂中。另外,含有这些化合物的医药组合物(或配制剂)可呈干燥产物形式以在使用之前用水或其他适合媒剂复原。此类液体制剂可含有常规的添加剂,诸如悬浮剂,诸如山梨糖醇糖浆、甲基纤维素、葡萄糖/糖的糖浆、明胶、羟乙基纤维素、羧甲基纤维素、硬脂酸铝凝胶或氢化可食用脂肪;乳化剂,诸如卵磷脂、脱水山梨糖醇单油酸酯或阿拉伯胶;非水性媒剂(其可包括食用油),诸如杏仁油、分级的椰子油、油性酯、丙二醇或乙醇;以及防腐剂,诸如对羟基苯甲酸甲酯或对羟基苯甲酸丙酯,或山梨酸。这些制剂亦可配制为栓剂形式,例如含有常规的栓剂赋形剂,诸如可可脂或其他甘油酯。
供胃肠外施用的配制剂包括水性及非水性无菌注射溶液,其可含有抗氧化剂、缓冲剂、抑菌剂及使配制剂与预定接受者的血液等张的溶质;以及水性及非水性无菌悬浮液,其可包括悬浮剂及增稠剂。配制剂可提供于单位剂量或多剂量容器,例如密封的安瓿及小瓶中,且可在冷冻干燥(冻干)条件下储存,只需在临用前添加无菌液体载剂,例如注射用水。即用型注射溶液及悬浮液可由前述种类的无菌散剂、颗粒剂及片剂制备。
供直肠施用的组合物可呈具有常见载剂的栓剂形式,所述常见载剂诸如可可脂、硬脂或聚乙二醇。
用于在口中局部施用,例如经颊或舌下施用的配制剂包括在诸如蔗糖及阿拉伯胶或黄蓍胶等调味用赋形剂中包含活性成分的锭剂,以及在诸如明胶及甘油或蔗糖及阿拉伯胶等赋形剂中包含活性成分的软锭剂(pastille)。对于在皮肤上局部施用,化合物可配制为乳膏、凝胶、软膏或洗剂形式,或配制为经皮贴片形式。对于眼部施用,组合物可为液体溶液(诸如滴眼溶液)、凝胶、乳膏或任何类型的眼用组合物。
化合物亦可配制为储存制剂。这些长效配制剂可藉由植入(例如皮下或肌肉内)或藉由肌肉内注射来施用。因此,例如,化合物可用适合聚合材料或疏水性材料配制(例如配制为于可接受的油中的乳液)或用离子交换树脂配制,或配制为微溶衍生物,例如微溶盐。
对于鼻内施用,本发明化合物可例如以液体喷雾形式、以粉末形式或以液滴形式使用。
对于藉由吸入施用,根据本发明的化合物常规呈气雾剂喷雾形式自加压容器或喷雾器递送,其中使用适合推进剂,例如1,1,1,2-三氟乙烷(HFA134A)及1,1,1,2,3,3,3,-七氟丙烷(HFA227)、二氧化碳或其他适合气体。在加压气雾剂的情况下,确切剂量可藉由提供适合于递送计量的量的阀来确定。用于吸入器或吹入器的例如明胶胶囊及药筒可配制成含有本发明化合物与诸如乳糖或淀粉等适合粉末赋形剂的粉末混合物。
除上文特别提及的成分以外,配制剂亦可包括本领域常规的与所讨论的配制剂类型相关的其他试剂,例如适于经口施用的配制剂可包括调味剂。
本领域技术人员应了解,本文中提及的治疗扩展至预防以及治疗确定的疾病或症状。另外,应了解,用于治疗所需的本发明化合物的量将随所治疗的病况的性质以及患者的年龄及状况而变化,且最终将由主治医师或兽医判断。患者可为任何哺乳动物,包括人类或非人类哺乳动物。更具体地,本发明是针对人类哺乳动物,更具体地,针对成人。一般而言,治疗成人所采用的剂量将典型地在每天0.02-5000mg范围内,优选地在每天1-1500mg范围内。所需剂量可以常规以单次剂量或以适当时间间隔施用的分次剂量,例如以每天两次、三次、四次或多次分剂量提供。根据本发明的配制剂对于片剂及胶囊可含有在0.1-99%之间,常规地30-95%的活性成分,且对于液体制剂可含有3-50%的活性成分。
用于本发明的本发明化合物可与一或多种其他治疗活性剂结合使用,该一或多种其他治疗性活性剂例如β-肾上腺素能激受体拮抗剂、钙通道阻断剂、噻嗪利尿剂、血管紧张素受体拮抗剂及血管紧张素转化酶抑制剂。因此,在另一方面中,本发明提供包含本发明化合物与另一治疗剂的组合在治疗动脉性高血压中的用途。
当本发明化合物与其他治疗剂结合使用时,化合物可藉由任何适合途径依序或同时施用。
上文提及的结合可适当地以医药配制剂形式使用且因此,包含如上文所定义的结合,最佳地连同医药学上可接受的载剂或赋形剂的医药配制剂是本发明的另一方面。此类结合的个别组分可以单独或组合的医药配制剂形式依序或同时施用。
当组合于同一种配制剂中时,应了解,两种化合物必须稳定且彼此及与配制剂中的其他组分相容,且可经配制用于施用。当单独配制时,其可提供于任何适合配制剂中,宜以本领域中已知用于此类化合物的方式提供。
当将本发明化合物与针对同种疾病的另一治疗剂结合使用时,各化合物的剂量可不同于单独使用该化合物时施用的剂量。本领域技术人员将容易地确定适合的剂量。
在另一方面中,本发明的主题是一种用于预防或治疗动脉高血压以及直接地及间接地相关的疾病的方法,其包含施用治疗有效量的本发明化合物。
在另一方面中,本发明提供用于治疗剂,且具体地,用于兽医学或人类药物中的本发明化合物。
本发明亦涉及式(I)或(II)的化合物作为氨肽酶A的选择性抑制剂的用途。
在另一方面中,本发明提供本发明化合物用于制造或制备用于治疗动脉性高血压以及直接地及间接地相关的疾病的药品的用途。
在另一方面中,本发明提供一种治疗罹患动脉性高血压以及直接地及间接地相关的疾病的患者的方法,其包含向所述患者施用治疗有效量的本发明化合物。
本发明提供用于预防或治疗动脉性高血压及动脉性高血压直接地或间接地促成的疾病的方法。这些疾病包含心脏病、心力衰竭、中风、周围和/或脑血管系统疾病、脑病、眼病及肾脏疾病。具体地,疾病包含原发性及继发性动脉性高血压、暴病发作、心肌缺血、心功能不全或肾功能不全、心肌梗塞、周围血管疾病、糖尿病性蛋白尿、X综合征、青光眼、神经退化性疾病及记忆障碍。
式(I)或优选地式(II)的化合物可藉由若干方法制备。起始产品是商购产品,或根据已知合成方法自商购化合物制备或本领域技术人员已知的产品。更具体地,用于制备本发明化合物的方法如下所述,且因此包含以下连续步骤。
式(I)化合物可由中间物(V),藉由以下方法制备:
其中:
R1、R2、m及AH如上文所定义,
X、Y及Z是氨基或酸性官能基的保护基,及
A表示-SO3W、-CO2W或-P(O)(OW)2,其中W选自由烷基及芳基烷基组成的组。
根据此合成途径,在碱性条件下,例如在甲醇与水的混合物中,用氢氧化锂试剂(LiOH.H2O)水解中间物(V),得到中间物(IV)。中间物(IV)可与式(VI)的受保护的2-氨基-3-巯基丙酸反应,以提供式(III)的化合物。接着,可藉由在苯甲醚存在下使三氟乙酸回流来使化合物(III)脱保护,由此形成式(I)的本发明化合物。
在R1=R2=H的情况下,式(I)化合物可由中间物(V)获得,该中间物的合成描述于专利WO2012/045849中。
在R1≠R2≠H的情况下,式(I)化合物可由下式(VII)的前体得到中间物(V)来获得:
其中X及A如以上所定义。
前体(VII)的合成亦描述于专利WO2012/045849中。
或者,式(I)化合物可由中间物(VIII),藉由以下方法制备:
根据此替代性合成途径,式(VIII)的同二聚体可与式(VI)的受保护的2-氨基-3-巯基丙酸反应,以提供式(III)的化合物。接着,可藉由在苯甲醚存在下使三氟乙酸回流来使化合物(III)脱保护,由此形成式(I)的本发明化合物。
中间物(VIII)亦描述于专利WO2012/045849中。
以下实施例给出本发明的其他细节,但不应将其解释为构成对本发明的限制。
实施例
所用起始产品是商购产品,或根据已知合成方法自商购化合物制备或本领域技术人员已知的产品。示例的制备方法得到可用于制备本发明化合物的合成中间物。
实施例中所描述的化合物的结构是根据常见分光光度技术(核磁共振(NMR)、质谱法,包括电喷雾电离(ESI)……)测定且纯度是藉由高效液相层析(HPLC)测定。
合成中间物及本发明化合物是根据国际纯粹与应用化学联合会(TheInternational Union of Pure and Applied Chemistry,IUPAC)命名法命名且以其中性形式描述。
使用以下缩写:
(Boc)2O:二碳酸二叔丁酯
AcSK:硫代乙酸钾
AcOH:乙酸
Cbz:羧基苯甲基
CH2Cl2或DCM:二氯甲烷
CHCl3:氯仿
cHex:环己烷
DMF:二甲基甲酰胺
DIPEA:N,N-二异丙基乙胺
Et2O:乙醚
EtOAc:乙酸乙酯
EtOH:乙醇
HCl:盐酸
I2:碘
i-PrOH:异丙醇
K2CO3:碳酸钾
LiAlH(OtBu)3:三叔丁氧基氢化铝锂
LiAlH4:氢化铝锂
LiOH.H2O:单水合氢氧化锂(氢氧化锂)
MeOH:甲醇
MTBE:甲基叔丁基醚
Na2S2O3:硫代硫酸钠
Na2SO4:硫酸钠
NaBH4:硼氢化钠
NaHCO3:碳酸氢钠
NEt3:三乙胺
NH4Cl:氯化铵
TBTU:四氟硼酸2-(1H-苯并三唑-1-基)-1,1,3,3-四甲基铵
TFA:三氟乙酸
THF:四氢呋喃
Eq.:当量
ESI:电喷雾电离
HPLC:高效液相层析
NMR:核磁共振
制备(2R)-2-{[(叔丁氧基)羰基]氨基}-3-硫基丙酸叔丁酯
步骤1:(2R)-2-{[(叔丁氧基)羰基]氨基}-3-{[(2R)-2-{[(叔丁氧基)羰基]氨基}-2-羧基乙基]二硫基}丙酸
将二碳酸二叔丁酯(12.7g,58.2mmol)添加至L-胱胺酸,又称为(2R)-2-氨基-3-{[(2R)-2-氨基-2-羧基乙基]二硫基}丙酸(5.0g,20.8mmol)于碳酸钠水溶液(10%,72mL)及二恶烷(72mL)的混合物中的0℃冷却溶液中。使介质升温至室温。搅拌隔夜后,真空浓缩混合物。使残余物在EtOAc与水之间分配。用2N HCl溶液将在0℃下冷却的混合物小心地酸化至pH 1。萃取(EtOAc)水层,用盐水洗涤合并的有机层,经Na2SO4干燥,过滤并减压浓缩滤液,得到呈白色固体状的标题化合物(10.1g,定量产率)。
MS(ESI-):[M-H]-=439.3
步骤2:(2R)-3-{[(2R)-3-(叔丁氧基)-2-{[(叔丁氧基)羰基]氨基}-3-氧基丙基]二硫基}-2-{[(叔丁氧基)羰基]氨基}丙酸叔丁酯
向前一步骤中获得的化合物(5.0g,11.3mmol)于DCM(150mL)中的悬浮液中逐滴添加三氯乙酰亚胺酯(13.2mL,79.4mmol)。在室温下搅拌混合物2小时,接着真空浓缩。将残余物溶解于DCM(30mL)中,过滤所得悬浮液,并减压浓缩滤液。藉由柱层析法纯化残余物,得到呈白色固体状的标题化合物(5.10g,81%)。
MS(ESI+):[M+H]+=553.5
1H NMR(CDCl3,500MHz)δ(ppm):5.31(bs,2H);4.44(m,2H);3.19(dd,2H,J=13.7及4.5Hz);3.11(dd,2H,J=13.7及5.4Hz);1.47(s,18H);1.44(s,18H)
步骤3:(2R)-2-{[(叔丁氧基)羰基]氨基}-3-硫基丙酸叔丁酯
向前一化合物(5.0g,9.0mmol)于THF(50mL)中的溶液中逐滴添加三丁基膦(3.35mL,13.6mmol),随后添加水(5mL)。在室温下搅拌混合物隔夜,接着减压浓缩。藉由柱层析法纯化残余物,得到呈白色固体状的标题化合物(2.51g,60%)。
MS(ESI+):[M+H]+=278.3
实施例1:(2R)-2-氨基-3-{[(2S)-2-氨基-4-磺基丁基]二硫基}丙酸
步骤1:(2R)-3-{[(2S)-2-{[(苄氧基)羰基]氨基}-4-[(2,2-二甲基丙氧基)磺酰基]丁基]二硫基}-2-{[(叔丁氧基)羰基]氨基}丙酸叔丁酯
向N-[(2S)-1-{[(2S)-2-{[(苄氧基)羰基]氨基}-4-[(2,2-二甲基丙氧基)磺酰基]丁基]二硫基}-4-[(2,2-二甲基丙氧基)磺酰基]丁-2-基]氨基甲酸苄酯(专利WO2012/045849中所描述之中间物E)(2.0g,2.57mmol)于DMF(35mL)中的溶液中逐滴添加(2R)-2-{[(叔丁氧基)羰基]氨基}-3-硫基丙酸叔丁酯(1.43g,5.15mmol)于DMF(15mL)中的溶液。在室温下搅拌隔夜后,将混合物蒸发至干。将残余物溶解于EtOH(15mL)中并逐滴添加碘于EtOH中的溶液(380mg于约4mL中),直至持久呈现深橙色(约2mL)。真空浓缩混合物。藉由两次连续快速层析纯化残余物,得到呈白色固体状的标题化合物(1.20g,35%)。
MS(ESI+):[M+H]+=665.7
1H NMR(CDCl3,500MHz)δ(ppm):7.37-7.30(m,5H);5.30(m,1H);5.18(m,1H);5.11(m,2H);4.46(m,1H);3.99(m,1H);3.85(s,2H);3.21-3.16(m,3H);3.073.04(m,1H);2.93(m,2H);2.26-2.18(m,1H);2.07-2.04(m,1H);1.46(s,9H);1.44(s,9H);0.97(s,9H)
步骤2:(2R)-2-氨基-3-{[(2S)-2-氨基-4-磺基丁基]二硫基}丙酸
向前一化合物(1.1g,1.65mmol)于苯甲醚(400μL)中的溶液中逐滴添加TFA(2mL)。在75℃下加热混合物,直至完全转化(3小时)并真空浓缩。将残余物溶解于水中并用DCM萃取(六次),且减压浓缩水层。使残余物在EtOH/H2O(95/5)中结晶,得到呈白色固体状的标题化合物(302mg,59%)。
估计纯度:95%(基于NMR)
MS(ESI+):[M+H]+=305.2。
1H NMR(D2O,500MHz)δ(ppm):4.14(dd,1H,J=7.5及4.2Hz);3.90(quint,1H,J=6.5Hz);3.40(dd,1H,J=14.9及4.2Hz);3.29-3.22(m,2H);3.15-3.11(m,2H);3.08(dd,1H,J=14.9Hz及7.5Hz);2.35-2.23(m,2H)
实施例2:(2R)-2-氨基-3-{[(3S,4S)-4-氨基-1-苯基-6-磺基己-3-基]二硫基}丙酸步骤1:(2S)-2-{[(苄氧基)羰基]氨基}-4-[(2,2-二甲基丙氧基)磺酰基]丁酸
在室温下,向(2S)-2-{[(苄氧基)羰基]氨基}-4-[(2,2-二甲基丙氧基)磺酰基]丁酸乙酯(专利WO2012/045849中所描述之中间物A)(5.9g,14.2mmol,1.0当量)于THF/水(5/1,60mL)中的溶液中添加LiOH.H2O(425mg,17.8mmol,1.25当量)。在室温下搅拌混合物2小时。反应混合物用EtOAc稀释并用1N HCl溶液酸化,直至pH=1。分离各层并用EtOAc萃取水相(两次)。合并的有机萃取液经Na2SO4干燥,过滤并减压浓缩,得到呈无色油状的标题化合物(5.9g,定量产率)。
MS(ESI-):[M-H]-=386.1;[(Mx2)-H]-=773.3
1H NMR(CDCl3,500MHz)δ(ppm):7.43-7.28(m,5H);5.47(d,J=6.9Hz,1H);5.13(s,2H);4.51(s,1H);3.87(s,2H);3.47-3.05(m,2H);2.51(s,1H);2.27(s,1H);0.98(s,9H)
步骤2:N-[(1S)-3-[(2,2-二甲基丙氧基)磺酰基]-1-[甲氧基(甲基)氨甲酰基]丙基]氨基甲酸苄酯
在0℃下,向前一化合物(5.5g,14.2mmol,1.0当量)于DMF(50mL)中的溶液中依序添加TBTU(5.01g,15.6mmol,1.1当量)及DIPEA(4.95mL,28.4mmol,2.0当量)。在室温下搅拌所得溶液20分钟,且接着添加N,O-二甲基羟胺盐酸盐(1.52g,15.6mmol,1.1当量)。在室温下搅拌混合物16小时。用MTBE稀释混合物且用NH4Cl饱和水溶液洗涤有机溶液。用MTBE萃取水相(3次)并用NaHCO3半饱和水溶液(3次)及盐水洗涤合并的有机萃取液,经Na2SO4干燥,过滤并减压浓缩。残余物藉由柱层析法纯化,得到呈无色油状的标题化合物(5.15g,84%)。
MS(ESI+):[M+H]+=431.1
1H NMR(CDCl3,500MHz)δ(ppm):7.42-7.28(m,5H);5.63(d,J=8.5Hz,1H);5.20-5.01(m,2H);4.92-4.67(m,1H);3.85(s,2H);3.78(s,3H);3.29-3.06(m,5H);2.49-2.24(m,1H);2.16-2.05(m,1H);0.97(s,9H)
步骤3:N-[(3S)-1-[(2,2-二甲基丙氧基)磺酰基]-4-氧基-6-苯基己-3-基]氨基甲酸苄酯
在0℃下,向前一化合物(5.15g,12.0mmol,1.0当量)于THF(60mL)中的溶液中逐滴添加可商购的氯化苯乙基镁溶液(1M的THF溶液,35.9mL,35.9mmol,3.0当量)。将所得混合物搅拌3小时,随后再添加氯化苯乙基镁(8mL,8mmol,0.63当量)。在0℃下再搅拌1小时之后,将反应混合物缓慢倒入NH4Cl饱和水溶液中。添加EtOAc并分离各层。用EtOAc萃取水相(两次)并用盐水洗涤合并的有机萃取液,经Na2SO4干燥,过滤并减压浓缩。残余物藉由柱层析法纯化,得到呈无色油状的标题化合物(4.75g,84%)。
1H NMR(CDCl3,500MHz)δ(ppm):7.43-7.02(m,10H);5.53(d,J=7.5Hz,1H);5.10(s,2H);4.44(s,1H);3.83(s,2H);3.32-2.99(m,1H);2.99-2.67(m,5H);2.43(td,J=10.2,5.4Hz,1H);1.99(m,1H);0.96(s,9H)
步骤4:N-[(3S,4R)-1-[(2,2-二甲基丙氧基)磺酰基]-4-羟基-6-苯基己-3-基]氨基甲酸苄酯
在-78℃下,向绝对EtOH(170mL)中逐份添加LiAlH(Ot-Bu)3(5.08g,20.0mmol,2.0当量),监测内温不会升高超过-50℃(未观察到完全溶解)。在-78℃下搅拌40分钟后,经10分钟逐滴添加前一步骤中获得的化合物(4.75g,10.0mmol,1.0当量)于绝对EtOH(20mL)中的溶液,监测内温不会升高超过-60℃。在-78℃下搅拌所得混合物1.5小时,接着添加1NHCl(25mL)溶液。使所得混合物在EtOAc与水之间分配。分离各层并用EtOAc萃取水相。合并的有机萃取液经Na2SO4干燥,过滤并减压浓缩。残余物藉由柱层析法纯化,得到呈无色油状的标题化合物(4.5 1g,95%)。
MS(ESI+):[M+H]+=478.2
1H NMR(CDCl3,500MHz)δ(ppm):7.53-6.94(m,10H);5.18(d,J=9.0Hz,1H);5.09(s,2H);3.84(s,2H);3.79-3.54(m,2H);3.29-3.00(m,2H);2.91-2.74(m,1H);2.74-2.54(m,1H);2.21-2.09(m,1H);2.02-1.91(m,1H);1.87-1.71(m,2H);0.96(s,9H)
步骤5:N-[(3S,4R)-1-[(2,2-二甲基丙氧基)磺酰基]-4-(甲烷磺酰基氧基)-6-苯基己-3-基]氨基甲酸苄酯
在0℃下,向前一化合物(2.0g,4.19mmol,1.0当量)于DCM(42mL)中的溶液中依序逐滴添加甲烷磺酰氯(389μL,5.02mmol,1.2当量)及DIPEA(1.48mL,8.37mmol,2.0当量)。在室温下搅拌所得溶液2小时。使反应混合物在MTBE与1N HCl溶液之间分配。分离各层并用MTBE萃取水相。依序用1N HCl溶液、盐水洗涤合并的有机萃取液,接着经Na2SO4干燥,过滤并减压浓缩,得到呈白色泡沫状的标题化合物(2.45g,定量产率)。
MS(ESI+):[M+H]+=556.2
1H NMR(CDCl3,500MHz)δ(ppm):7.32-7.20(m,7H);7.18-7.07(m,3H);5.31(d,J=9.7Hz,1H);5.10-4.98(m,2H);4.85-4.76(m,1H);4.04-3.89(m,1H);3.78(s,2H);3.13-2.98(m,2H);2.94(s,3H);2.78-2.58(m,2H);2.17-1.94(m,2H);1.94-1.79(m,2H);0.90(s,9H)
步骤6:N-[(3S,4S)-4-(乙酰基硫基)-1-[(2,2-二甲基丙氧基)磺酰基]-6-苯基己-3-基]氨基甲酸苄酯
在室温下,向前一步骤中获得的粗甲磺酸酯化合物(4.19mmol,1.0当量)于丙酮(21mL)中的溶液中添加AcSK(957mg,8.38mmol,2.0当量)。在50℃下搅拌反应混合物18小时。使反应混合物在MTBE与NaHCO3饱和水溶液之间分配。分离各层并用MTBE萃取水相。依序用NaHCO3饱和水溶液、盐水洗涤合并的有机萃取液,接着经Na2SO4干燥,过滤并减压浓缩。残余物藉由柱纯化,得到呈浅橙色油状的标题化合物(2.02g,经2个步骤90%)。
MS(ESI+):[M+H]+=536.1
1H NMR(CDCl3,500MHz)δ(ppm):7.42-7.29(m,7H);7.25-7.18(m,1H);7.15(d,J=7.4Hz,2H),5.20-5.06(m,2H);4.81(d,J=10.1Hz,1H);4.09(tt,J=9.6,4.2Hz,1H);3.86(s,2H);3.68-3.60(m,1H);3.20(td,J=11.2,10.4,5.5Hz,1H);3.10(ddd,J=14.0,11.2,4.5Hz,1H);2.84-2.65(m,2H);2.38(s,3H);2.17-1.78(m,4H);1.00(s,9H)
步骤7:N-[(3S,4S)-1-[(2,2-二甲基丙氧基)磺酰基]-6-苯基-4-硫基己-3-基]氨基甲酸苄酯
在室温下,向前一步骤中获得的硫代乙酸酯化合物(2.02g,3.77mmol,1.0当量)于脱气的MeOH(15mL,3个循环的真空-氩气吹扫)中的溶液中添加LiOH.H2O(181mg,7.54mmol,2.0当量)于水(1.6mL)中的溶液。在室温下搅拌所得溶液1小时。使反应混合物在MTBE与NH4Cl饱和水溶液之间分配。分离各层并用MTBE萃取水相。用盐水洗涤合并的有机萃取液,经Na2SO4干燥,过滤并减压浓缩。残余物藉由柱层析法纯化,得到呈浅黄色油状的标题化合物(1.72g,92%)。
MS(ESI+):[M+H]+=494.1
1H NMR(CDCl3,500MHz)δ(ppm):7.44-7.29(m,7H);7.26-7.15(m,3H);5.24-5.02(m,3H);4.03(ddt,J=10.4,6.2,3.5Hz,1H);3.88(s,2H);3.29-3.10(m,2H);2.96-2.73(m,3H);2.23-2.08(m,1H);2.03-1.88(m,2H);1.88-1.74(m,1H);1.35-1.24(m,1H):1.00(s,9H)
步骤8:(2R)-3-{[(3S,4S)-4-{[(苄氧基)羰基]氨基}-6-[(2,2-二甲基丙氧基)磺酰基]-1-苯基己-3-基]二硫基}-2-{[(叔丁氧基)羰基]氨基}丙酸叔丁酯
在-78℃下,向N-氯代苯并三唑(774mg,5.04mmol,1.5当量)及苯并三唑(400mg,3.36mmol,1.0当量)于DCM(25mL)中的溶液中逐滴添加前一步骤中获得的硫醇化合物(1.66g,3.36mmol,1.0当量)于DCM(5mL)中的溶液。在-78℃下搅拌混合物2小时。接着,逐滴添加(2R)-2-{[(叔丁氧基)羰基]氨基}-3-硫基丙酸叔丁酯(1.40g,5.04mmol,1.5当量)于DCM(5mL)中的溶液。在-78℃下搅拌反应混合物4小时。依序添加Na2S2O3水溶液(1.2g于20mL水中)及NaHCO3饱和水溶液(30mL)并使混合物升温至室温,并在室温下搅拌10分钟。分离各层并用DCM萃取水相(两次)。合并的有机萃取液经Na2SO4干燥,过滤并减压浓缩,得到橙色油状物。残余物藉由两次柱层析法纯化,得到呈浅黄色泡沫状的标题化合物,以不同纯度的两份级份获得(1.21g,47%产率,纯级份)及(0.91g,35%产率,80%纯的级份)。
MS(ESI+):[M+H]+=769.4
1H NMR(CDCl3,500MHz)δ(ppm):7.51-7.04(m,10H);5.08(s,2H);4.52-4.29(m,1H);4.11(d,J=10.6Hz,1H);3.90(s,2H);3.31-3.12(m,3H);3.05-2.85(m,3H);2.84-2.69(m,1H);2.33-2.22(m,1H);2.12-1.94(m,2H);1.83-1.65(m,1H);1.54-1.43(m,18H);1.00(s,9H)
步骤9:(2R)-2-氨基-3-{[(3S,4S)-4-氨基-1-苯基-6-磺基己-3-基]二硫基}丙酸
在室温下,向前一步骤中获得的二硫化物(1.2g,1.56mmol,1.0当量)于苯甲醚(4.26mL,39.0mmol,25当量)中的溶液中添加三氟乙酸(6.19mL,78mmol,50当量)。在回流下搅拌混合物16小时。在冷却至室温后,减压浓缩反应混合物。将所得固体/糊状物溶解于水(120mL)中并用DCM(4×50mL)洗涤水溶液。将水相冻干。残余物藉由逆相快速层析法纯化且将所关注的级份合并且冻干,得到呈亮白色固体状的标题化合物(500mg,78%),该化合物是非对映异构体(R,S,S)/(R,R,R)的93/7混合物。
估计纯度:>97%(基于LCMS)及95%(基于NMR)
MS(ESI+):[M+H]+=409.0
MS(ESI-):[M-H]-=407.1
1H NMR(D2O,500MHz)δ(ppm):7.40-7.28(m,4H);7.28-7.22(m,1H);4.04(dd,J=8.4,4.0Hz,1H);3.77(dt,J=7.9,5.0Hz,1H);3.34(dd,J=14.8,4.1Hz,1H);3.10(dd,J=14.8,8.4Hz,1H);3.04(ddd,J=10.6,5.0,3.6Hz,1H);3.00-2.88(m,3H);2.82-2.74(m,1H);2.43-2.31(m,1H);2.13-1.98(m,2H);1.94-1.80(m,1H)
实例3:体外APA活性的量测
体外APA活性的量测是基于被调整成在微量滴定板(Pro BindTM 3915)上分析的规模的Goldbarg方案(Chauvel等人,1994)。在体外,在钙离子存在下,APA将合成底物α-L-谷氨酰基-β-萘酰胺(GluβNa)水解成谷氨酸及β-萘胺(βNa)。在酸性介质中进行的重氮化反应使得有可能藉由形成紫色复合物而显出β-萘胺,分光光度法量测则使得有可能知道所形成的复合物的量,且参照在递增浓度的β-萘胺下产生的标准曲线可推断出样品的酶活性。
试剂
将Glu-βNa底物(Bachem)及β-萘胺(Sigma)分别溶解于50%DMSO(二甲亚砜)和0.1N HCl中,并在-20℃下以10-2M浓度保存。重氮化反应是在亚硝酸钠(87mM)、氨基磺酸铵(130mM)及N-(1-萘基)-乙二胺二盐酸盐(23mM于95%乙醇中)存在下进行。
酶反应
反应是在pH 7.4的50mM tris-HCl缓冲液中,在二硫苏糖醇(每当量抑制剂100当量)及钙(4mM CaCl2)存在下进行;重组小鼠APA在37℃下,在底物(200μM Glu-βNa)存在下且在各种浓度的待测试抑制剂存在或不存在下温育,最终体积为100μL。藉由添加10μL的3NHCl停止反应。藉由在0.1N HCl中使递增浓度(最多0.2mM)的2-萘胺重氮化,并行制备β-萘胺的标准曲线。
揭示所形成的产物
将以下各物添加至各孔中:25μL亚硝酸钠(NaNO2)(混合,在室温下等待5分钟)、50μL氨基磺酸铵(混合,在室温下等待5分钟),接着添加25μL N-(1-萘基)-乙二胺二盐酸盐(混合,在37℃下等待约30分钟以使紫色稳定)。
接着,在540nm下量测吸光度。
申请案WO 99/36066中描述的化合物EC33((S)-3氨基-4-巯基-丁基磺酸)用作参考化合物。
表1中报导的结果显示,实施例1及实施例2展现APA抑制活性。
表1.例示性抑制剂的氨肽酶A体外抑制作用
实施例 | 结果(μM) |
1 | 0.81±0.05 |
2 | 0.18±0.02 |
实施例4:脑APA活性的量测(离体实验)
脑APA活性是如上文所描述测定。
在体内,向小鼠(雄性,18-20g Charles River)静脉内施用实施例1(50mg/kg,体积200μL)。
在体内,向DOCA盐型大鼠(雄性,250g Charles River)口服施用实施例2(8mg/kg,体积400μL)。
对于每种条件,使用四至十六只小鼠及五至七只大鼠。在施用后180分钟,处死动物。立即取出脑并藉由在10体积冰冷的50mM Tris-HCl缓冲液(pH 7.4)中超声处理使其均质化。量测脑匀浆中的APA酶活性。为此目的,在37℃下,将组织匀浆的等分试样(16μL)与含200μM的Glu-βNa、4mM CaCl2及1μM贝他定(bestatin)抑制剂且含或不含5μM EC33的总体积100μL的50mM Tris-HCl缓冲液(pH 7.4)一起温育30分钟。接着,如上文所描述进行分析。
图1展示藉由静脉内途径给与的实施例1穿过血脑屏障且进入脑中的能力,这是藉由量测有意识小鼠的脑APA活性的抑制情况测定。在180分钟之后,实施例1(50mg/kg,静脉内,每只小鼠3285nmol)使脑APA活性明显降低45%(39.6±5.2nmol水解的Glu-βNa/毫克蛋白质/小时相对于72.3±3.7,P<0.001,克鲁斯卡尔-沃利斯(Kruskal-Wallis),随后邓恩氏测试(Dunn's test))。
图2展示藉由口服途径给与的实施例2穿过血脑屏障且进入脑中的能力,这是藉由量测有意识DOCA盐型大鼠的脑APA活性的抑制情况测定。在180分钟之后,实施例2(8mg/kg,口服,每只大鼠4895nmol)使脑APA活性明显降低29%(46.1±2.4nmol水解的Glu-βNa/毫克蛋白质/小时相对于65.4±5.1,P<0.01,曼-惠特尼测试(Mann-Whitney test))。
实施例5:平均动脉压(MABP)及心率(HR)的量测(体内实验)
用3%异氟烷(Piramal,UK)诱导雄性DOCA盐型大鼠麻醉并用1.5-2%异氟烷维持麻醉。将导管插入右侧股动脉中以监测MABP及HR。导管穿过皮下隧道离开颈部。将动物在动物房中维持2天,频繁进行观察,随后记录下MABP及HR。在口服施用实施例2(8mg/kg,体积400μL)之前至少60分钟,记录下基线MABP及HR。治疗后,连续地记录MABP及HR,持续6小时。
图3a及3b展示藉由记录有意识DOCA盐型大鼠的MABP及HR测定的口服给与的实施例2降低高血压大鼠的血压的能力。
在图3a中,实施例2(8mg/kg,口服,每只大鼠4895nmol)自施用之后3小时起使DOCA盐型高血压大鼠的MABP降低(且MABP降低-27±11mmHg),且持续至治疗后6小时(且MABP降低-44±8mmHg)。
在图3b中,口服施用实施例2(8mg/kg)对DOCA盐型大鼠的HR没有影响,不管在施用与记录之间经过的时间多长(0至6小时)。
实施例6:藉由超声心动图显象量测左心室射血分数(LVEF)来评价心脏功能(体内实验)
实验程序
经由腹膜内注射,用100mg/kg氯胺酮(ketamine)(Imalgène 1000,Merial,Lyon,France)及10mg/kg甲苯噻嗪(xylazine)(Rompun 2%,Bayer Healthcare,Loos,France)的混合物使成年雄性CD1小鼠麻醉,插管并以200次吹气/分钟的速率通气,且平均吹气体积为0.2mL(Bioseb,France)。将皮肤消毒并在第2与第3肋间间隙之间切开,且藉由左侧开胸术暴露出心脏。打开心包并用8/0丝质缝合线(PVDF单丝,8-0,Peters Surgical,Bobigny,France)在肺动脉主干与左心耳之间永久地结扎,引起左前降支(LAD)冠状动脉梗塞。藉由在结扎下可见左心室(LV)变白来证实局部缺血。接着,藉由缝合三个不连续点(PVDF单丝,6/0,Peters Surgical,Bobigny,France)关闭胸部,随后小鼠接受皮下注射的1mg/kg美洛昔康(Meloxicam)(Metacam,Boehringer Ingelheim,Germany)用于长期镇痛。对气胸进行引流。接着,缝合(普理灵线(prolene thread)6-0,Peters Surgical,France)肌肉及皮肤并用37℃的生理食盐水对动物补液。一旦动物能够自主呼吸,就立即拔管。将动物放入笼中并在48小时内进行规律监测。在术后24小时且直至72小时,小鼠接受1mg/kg美洛昔康注射。在假手术小鼠中,在不结扎LAD冠状动脉情况下执行相同手术程序。
MI后小鼠在花生酱媒剂存在下接受长期口服治疗,亦即150mg/kg非瑞司他(用作脑APA抑制剂的参考物的RB150)、1.25mg/kg雷米普利(作为标准治疗的ACE抑制剂)或25mg/kg实施例2。适应期是在治疗开始之前实施,在适应期中,小鼠每天早晨接受一定剂量施加至笼壁上的花生酱,持续一周。治疗在MI之后2天开始,且不同药物是每日一次在早晨施用,保持连续四周。藉由在MI后4周经胸超声心动图定期评价心脏功能来分析不同长期口服治疗对心脏收缩性的影响。
结果
图4显示长期经口施用非瑞司他、雷米普利或实施例2对MI后4周的小鼠的左心室射血分数(LVEF)的影响。值是以自n=9至n=15的平均值±SEM表示。单因素ANOVA之后为邓尼特测试(Dunnett's test)。MI后四周,经媒剂治疗的小鼠的LVEF相较于假手术组明显降低(图4),MI+媒剂小鼠相对于假手术小鼠,自58±1.5%(n=11)减少至44.5±1%(n=12)(p<0.0001)。LVEF的明显降低反映了MI后心脏收缩性的减退。在本研究中包括雷米普利及非瑞司他作为阳性对照。分别长期口服1.25及150mg/kg非瑞司他及雷米普利治疗4周使得MI后小鼠的心脏功能改善且MI+非瑞司他小鼠及MI+雷米普利小鼠的LVEF相较于MI+媒剂小鼠显著增加(MI+非瑞司他中的50.9±1%,n=14(p=0.0002),MI+雷米普利小鼠中的48.4±1.2%,n=9(p=0.0874)相对于MI+媒剂小鼠中的44.5±1%,n=12)。在图4中,长期口服实施例2治疗(25mg/kg,持续4周)使MI后小鼠的LVEF相较于媒剂治疗明显增加,且其功效与非瑞司他相同,50.6±0.9%,n=15(p=0.0007)。
结论
连续4周给与口服剂量比非瑞司他所用剂量低6倍的实施例2展现出与非瑞司他相同的功效,且在改善MI后小鼠的心脏功能方面甚至优于雷米普利参考治疗。
Claims (11)
2.根据权利要求1的化合物,其中R1及R2独立地表示H或C1-6烷基,各烷基任选经至少一个选自以下的下述基团取代:芳基、杂环基或环烷基;所述芳基、杂环基、环烷基任选经一或多个选自以下的基团取代:卤素原子、烷基、烷氧基、卤烷基、卤烷氧基、酰基、O-环烷基、杂烷基、O-芳基、O-芳基烷基、芳基、杂环基或芳基烷基。
3.根据权利要求1的化合物,其中R1及R2均为H,或替代地,R1是H且R2是苯甲基或苯乙基。
4.根据权利要求1至3中任一项的化合物,其中所述化合物对应于通式(I)且更具体地,对应于式(II),其中以下特征中的一个、两个、三个或四个得到满足,优选地每个特征均得到满足:
-m是2或3;和/或
-AH是CO2H或SO3H;和/或
-R1是H;和/或
-R2是H或烷基,优选地为经苯基取代的烷基。
5.根据权利要求1至4中任一项的化合物,其中所述化合物对应于通式(I)且更具体地,对应于式(II),其中以下特征中的一个、两个或三个得到满足,优选地每个特征均得到满足:
-m是2;和/或
-AH是SO3H;和/或
-R1及R2均为H,或替代地,R1是H且R2是苯乙基。
6.根据前述权利要求中任一项的化合物,其选自由以下组成的组:
(2R)-2-氨基-3-{[(2S)-2-氨基-4-磺基丁基]二硫基}丙酸,
(2R)-2-氨基-3-{[(3S,4S)-4-氨基-1-苯基-6-磺基己-3-基]二硫基}丙酸,及其医药盐类、溶剂合物、两性离子形式或任何前药。
7.根据前述权利要求中任一项的化合物,其用作药物。
8.一种医药组合物,其包含至少一种如前述权利要求中任一项中限定的化合物,优选地与医药学上可接受的载剂结合。
9.根据前述权利要求1至6中任一项的化合物或根据权利要求8的医药组合物,其用于治疗动脉性高血压及直接或间接相关的疾病。
10.根据权利要求9的供使用的化合物或组合物,其用于治疗与动脉性高血压直接或间接相关的病症,所述病症在由以下组成的组中选出:心脏病、心力衰竭、中风、周围和/或脑血管系统疾病、脑病、眼病和/或肾脏疾病。
11.根据权利要求9的供使用的化合物或组合物,其用于治疗在由以下组成的组中选出的病症:原发性和/或继发性动脉性高血压、暴病发作、心肌缺血、心功能不全、肾功能不全、心肌梗塞、周围血管疾病、糖尿病性蛋白尿、X综合征、青光眼、神经退化性疾病及记忆障碍。
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IL285593A (en) | 2021-09-30 |
CA3129677A1 (en) | 2020-09-17 |
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