CN113166180A - 新的氨基次膦衍生物作为氨肽酶a抑制剂 - Google Patents
新的氨基次膦衍生物作为氨肽酶a抑制剂 Download PDFInfo
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- CN113166180A CN113166180A CN201980070606.3A CN201980070606A CN113166180A CN 113166180 A CN113166180 A CN 113166180A CN 201980070606 A CN201980070606 A CN 201980070606A CN 113166180 A CN113166180 A CN 113166180A
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- phosphoryl
- hydroxy
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- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
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Abstract
本发明涉及一种新的化合物,涉及包含该化合物的组合物,涉及用于制备该化合物的方法,以及该化合物在疗法中的用途。具体而言,本发明涉及可用于治疗和预防原发性和继发性动脉高血压、猝发、心肌缺血、心脏和肾功能不全、心肌梗死、周围血管疾病、糖尿病性蛋白尿、X综合征和青光眼的化合物。
Description
发明领域
本发明涉及一种新的化合物,涉及包含该化合物的组合物,涉及用于制备该化合物的方法,以及这些化合物在疗法中的用途。具体而言,本发明涉及可用于治疗和预防原发性和继发性动脉高血压、猝发、心肌缺血、心脏和肾功能不全、心肌梗死、周围血管疾病、糖尿病性蛋白尿、X综合征和青光眼的化合物。
发明背景
原发性高血压(Essential Hypertension,HTN)和心力衰竭(HF)是心血管疾病的两种主要病理。HTN影响全球约10亿个人。它是冠心病,HF,中风和肾功能不全的主要危险因素。尽管可获得有效和安全的药物,但在许多患者中仍无法控制HTN及其伴随的危险因素。在西方国家,HF仍然是65岁以上患者住院的主要原因。在工业化国家中,HF影响千分之一至五人,考虑所有年龄,患病率为千分之三至二十。在美国,HF医疗保健费用在2012年占210亿美元,大部分费用与住院有关。尽管可获得大量药物,但HF的预后很差,因为考虑所有阶段的一年生存率约为65%。HF仍然是导致心血管死亡的首要原因之一,因此,仍存在未满足的开发新的有效和安全类别药物的医疗需求。
已知系统性肾素-血管紧张素系统(RAS)在血压(BP)调节和钠代谢中起着核心作用。靶向RAS的系统性药物,如血管紧张素I转换酶(ACE)抑制剂和血管紧张素II受体1型(AT1)拮抗剂,在降低BP和预防患者的心血管和肾发病率及死亡率方面是临床有效的。此外,患有HF的患者中肾素-血管紧张素醛固酮系统(RAAS)的活性增加,并且其适应不良性(maladaptive)机制可能导致不良反应,如心脏重塑和交感神经激活。目前基于证据的指南IA推荐的用于射血分数降低的HF的药物主要是作用于RAAS的分子,如ACE抑制剂或AT1受体阻断剂和beta-肾上腺素能受体阻断剂。
控制心血管功能和体液稳态的功能性RAS也存在于脑中。数项研究表明,脑RAS活性的增加导致交感神经元活性和升压素释放的增加,并且脑RAS的过度活性在介导HTN的各种动物模型中的高BP以及HF的动物模型中心脏重塑和功能障碍中起着重要的作用(MarcY,Llorens-Cortes,C Progress in Neurobiology 2011,95,pp 89-103;Westcott KV etal,Can.J.Physiol.Pharmacol.2009,87,pp 979-988)。由于最近的证据支持血管紧张素III(Ang III)通过其对AT1受体的作用可能是脑RAS中心控制BP的真正RAS肽效应物,因此脑中的脑氨肽酶A(APA)(从血管紧张素II(Ang II)产生Ang III的酶)构成了治疗HTN和治疗HF的有希望的治疗靶标。
氨肽酶A(APA,EC 3.4.11.7)是膜结合的锌金属蛋白酶,已被表征为负责在脑中将AngII转化为AngIII的酶(Zini S et al,Proc.Natl.Acad.Sci.USA 1996,93,pp 11968-11973)。迄今为止已经开发了几种APA抑制剂(Chauvel EN et al,J.Med.Chem.1994,37,pp1339-1346;Chauvel EN et al,J.Med.Chem.1994,37,pp 2950-2957;David C et al,J.Med.Chem.1999,42,pp 5197-5211;Georgiadis D et al,Biochemistry 2000,39,pp1152-1155;Inguimbert N et al,J.Peptide Res.2005,65,pp 175–188)。其中,据报道EC33((3S)-3-氨基-4-硫醇-丁基磺酸盐)是一种特异性和选择性的APA抑制剂。在若干高血压实验模型中,发现EC33的中枢输注抑制脑APA活性,阻断对Ang II的脑室内(icv)输注的升压反应并降低BP(Fournié-Zaluski MC et al Proc.Natl.Acad.Sci.USA 2004,101,pp7775-7780)。
还进一步证明,在有意识的高血压DOCA盐大鼠和SHR大鼠中急性口服施用RB150(也称为Firibastat)(15至150mg/kg)(EC33的脑穿透性前药)引起BP剂量依赖性的降低(Bodineau L et al,Hypertension 2008,51,pp1318-1325;Marc Y et al,Hypertension2012,60,pp 411-418)。有趣的是,发现RB150如下降低DOCA-盐大鼠和SHR中的BP:首先通过降低升压素释放,增加水利尿(aqueous diuresis)和尿钠增多,从而将血容量和BP降至控制值,其次通过降低交感紧张,从而减少血管阻力并因此降低BP。也有报道称,慢性中枢输注RB150和AT1R阻断剂氯沙坦(losartan)在抑制患有MI后HF的大鼠中观察到的交感神经亢进(sympathetic hyperactivity)和心功能障碍方面是类似有效的(Huang BS et al,Cardiovascular Res.2013,97,pp 424–431)。因此,RB150构成首个能够进入脑,阻断脑APA活性并使高血压大鼠中BP正常的口服APA抑制剂,因此,脑APA抑制剂代表了用于治疗HTN和HF的新类别的中枢作用剂。
本发明人现已鉴定出新的化合物,其充当有力的APA抑制剂,并且在这方面可以有效降低动脉高血压,并且可以用于治疗动脉高血压及其间接和直接导致的疾病,如心力衰竭。所述化合物还表现出令人满意的生物利用度和药代动力学参数,这使其成为口服或肠胃外施用的良好候选者。
发明概述
因此,本发明提供了化合物,其具有下式(I):
且更具体地具有下式(II):
其中:
AH表示-CO2H,-SO3H,-PO3H2;
l是2或3;
m是0、1、2或3;
R1表示卤素原子,烷基基团,卤代烷基基团,烷氧基基团,卤代烷氧基基团,O-环烷基基团,O-芳基基团,O-芳基烷基基团,杂烷基基团,氨基基团,所述氨基基团任选地被烷基基团,卤代烷基基团,环烷基基团,酰基基团,芳基基团或芳基烷基基团单取代或二取代;
R2和R3独立地表示氢原子,卤素原子,烷基基团,卤代烷基基团或者可以与图(I)或(II)上描绘的相邻碳原子一起形成环烷基基团;
其药用盐,溶剂化物,两性离子形式或前药。
在另一方面,本发明公开了组合物,其包含所述式(I)的化合物,且更具体地式(II)的化合物。该组合物更具体地是药物组合物。因此,本发明提供了药物组合物,其包含至少一种本发明的化合物,优选地与药学上可接受的稀释剂或载体结合。
根据另一方面,本发明涉及用于预防或治疗动脉高血压以及间接和直接相关疾病的方法,其包括施用治疗有效量的本发明的化合物。另一方面,本发明提供了本发明的化合物,其用于疗法或医疗,且更具体地,用于人类医疗中,且更具体地,用于治疗动脉高血压或间接和直接相关的疾病或病症。
在另一方面,本发明提供了本发明的化合物用于制备用于治疗动脉高血压或间接和直接相关疾病或病症的药物中的用途。
在另一方面,本发明提供了治疗患有动脉高血压或间接和直接相关疾病的患者的方法,其包括向有此需要的患者施用治疗有效量的本发明的化合物。
发明详述
因此,本发明涉及化合物,其具有下式(I):
且更具体地具有下式(II):
其中:
AH表示-CO2H,-SO3H,-PO3H2;
l是2或3;
m是0、1、2或3;
R1表示卤素原子,烷基基团,卤代烷基基团,烷氧基基团,卤代烷氧基基团,O-环烷基基团,O-芳基基团,O-芳基烷基基团,杂烷基基团,氨基基团,所述氨基基团任选地被烷基基团,卤代烷基基团,环烷基基团,酰基基团,芳基基团或芳基烷基基团单取代或二取代;
R2和R3独立地表示氢原子,卤素原子,烷基基团,卤代烷基基团或者可以与式(I)或(II)上所绘的相邻碳原子一起形成环烷基基团。
本发明提供预防或治疗动脉高血压以及动脉高血压直接或间接导致的疾病的方法。此类疾病包括心脏,外周和脑血管系统,脑,眼和肾的疾病。具体而言,疾病包括原发性和继发性动脉高血压、猝发(ictus)、心肌缺血、心脏和肾功能不全、心肌梗死、周围血管疾病、糖尿病性蛋白尿(diabetic proteinuria)、X综合征和青光眼。
如本文所用,“本发明的化合物”意指上述化合物或其前药或其药学上可接受的盐、溶剂化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”意指单价或二价的直链或支链的饱和烃链,其具有1至8个碳原子(也称为(C1-C8)烷基),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、正己基、正庚基或正辛基基团。
术语“酰基”意指–C(O)R基团,其中R为如先前定义的烷基基团或苯基基团。酰基基团包括例如乙酰基,乙基羰基或苯甲酰基基团。
术语“烷氧基(alkoxy)”或“烷基氧基(alkyloxy)”意指-OAlk基团,其中Alk是如先前定义的烷基基团。烷氧基基团包括例如甲氧基、乙氧基、正丙氧基或叔丁氧基。
术语“芳基”意指具有4至10个碳原子的芳族单环或双环系统(也称为(C4-C10)芳基),应理解在双环系统的情况下,一个环是芳族的,而另一个环是芳族或不饱和的。芳基基团包括例如苯基、萘基、茚基或苯并环丁烯基基团。
术语“芳基烷基”意指-Alk-Ar基团(即,通过烷基基团与分子的其余部分连接的芳基基团),其中Alk表示如上文所定义的烷基基团,并且Ar表示如上文所定义的芳基基团。
术语“杂烷基”意指直链或支链的饱和烃链,其具有1至5个碳原子和至少1或2个杂原子,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“环烷基”意指饱和的单环或多环系统,如稠合或桥接的双环系统,其具有3至12个碳原子(也称为(C3-C12)环烷基),如环丙基、环丁基、环戊基、环己基、环庚基、环辛基、金刚烷基、十氢化萘基或降冰片基(norbornyl)基团。
术语“O-环烷基”意指通过氧原子与分子的其余部分连接的如先前所定义的环烷基基团。O-环烷基包括例如O-环戊基或O-环己基基团。
术语“O-芳基”意指通过氧原子与分子的其余部分连接的如先前所定义的芳基基团。O-芳基包含例如O-苯基基团。
术语“O-芳基烷基”意指通过氧原子与分子的其余部分连接的如先前所定义的芳基烷基基团。O-芳基烷基包括例如O-苄基基团。
“酯”意指–C(O)OR基团,其中R表示如先前所定义的烷基、芳基或芳基烷基基团。
术语“卤代烷基”意指直链或支链的饱和烃链,其具有1至6个碳原子并被一个或多个,尤其是1-6个卤素原子取代,如三氟甲基或2,2,2-三氟乙基基团。
术语“卤代烷氧基”意指直链或支链的饱和烃链,其具有1至6个碳原子并被一个或多个,尤其是1-6个卤素原子取代,所述链通过氧原子与化合物连接,如三氟甲氧基或2,2,2-三氟乙氧基基团。
术语“氨基基团”意指-NH2基团,其任选地被如上所定义的烷基单或二取代。
术语“保护性基团”或“保护基团”意指选择性地封闭多官能化合物中的反应位点,从而可以在另一个非保护的反应位点上选择性地进行化学反应的基团,其含义通常在合成化学中与后者相关。
在本发明中,术语“药学上可接受的”是指其可以用于制备通常在生物学或其他方面是安全,无毒且不是不期望的药物组合物,并且其通常普遍接受用于兽医或人药物用途。
本发明的化合物的术语“药学上可接受的盐”包括由药学上可接受的无机或有机酸或碱形成的常规盐以及季铵盐。合适的酸盐的更具体的实例包括盐酸、氢溴酸、硫酸、磷酸、硝酸、高氯酸、富马酸、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、富马酸、甲苯磺酸、甲磺酸、萘-2-磺酸、苯磺酸羟基萘、氢碘酸、苹果酸、硬脂酸(steroic)、单宁酸等。合适的碱性盐的更具体的实例包括钠、锂、钾、镁、铝、钙、锌、N,N'-二苄基乙二胺、氯普鲁卡因、胆碱、二乙醇胺、乙二胺、N-甲基葡糖胺和普鲁卡因盐。
例如,优选的盐形式包括氯水合物(chlorhydrate)。
术语“前药”意指化合物的化学衍生物(本发明的目的),其通过与生理介质的自发化学反应,尤其是通过酶促反应、光解和/或代谢反应,在体内产生所述化合物。在当前情况下,本发明的化合物的前药在体内产生鉴定为氨肽酶A的抑制剂的化合物。
可以通过将具有特定不稳定部分的官能团衍生化来获得前药。具有酸官能(如次膦酸、羧酸、磺酸或膦酸)的前药尤其包含酯,具有胺官能的前药尤其包含经由氨基甲酸酯基团的[(2-甲基丙酰基)氧基]乙氧基羰基或包含经由酰胺基基团的2-氧-[1,3-噻唑烷-4-基]甲酰胺。
其他实例描述于T.Higuchi和V.Stella,“Pro-drugs as Novel Deliverysystem”,Vol.14,A.C.S Symposium Series,American Chemical Society(1975)和“Bioreversible Carriers in Grug Design:Theroy and Application”,E.B.Roche编,Pergamon Press:New York,14-21(1987)中。
术语“异构体”是指具有与本文所鉴定的分子式相同但性质,或者其原子的结合顺序或其原子空间布局不同的化合物。其原子在空间上的布局不同的异构体称为“立体异构体”。彼此不是镜像的立体异构体被称为“非对映异构体”,彼此是不可叠加的镜像的立体异构体被称为“对映异构体”或“旋光异构体”。“立体异构体”是指外消旋体、对映异构体和非对映异构体。
本领域技术人员将认识到,本发明的化合物中存在立体中心。本发明的化合物的任何手性中心可以是(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和几何异构体,并且不仅包括外消旋化合物,而且还包括光学活性异构体。根据一个优选的实施方案,本发明的化合物具有式(II)。当期望式(I)的化合物作为单一对映异构体时,它可以通过拆分终产物或通过异构纯的起始材料或任何合适的中间体的立体专一合成而获得。终产物、中间体或起始材料的拆分可以通过本领域已知的任何合适的方法来实现。参见,例如,E.L.Eliel的Stereochemistry of Carbon Compounds(Mcgraw Hill,1962)和S.H.Wilen的拆分剂表。
本领域技术人员将认识到,本发明的化合物可以含有至少一个正电荷和一个负电荷,使得本发明的化合物包括其两性离子形式。在化学中,两性离子(也称为内盐)是具有两个或多个官能团的分子,其中至少一个具有正电荷,一个具有负电荷,并且不同官能团上的电荷彼此平衡,且整个分子是电中性的。发生这种情况的pH称为等电点。因此,本发明的化合物的任何两性离子形式,包括其前药,都在本发明的范围内。
有机化学领域的专家将认识到,许多有机化合物可以与在其中发生反应或从中沉淀或结晶的溶剂形成复合物。这些复合物称为“溶剂化物”。例如,与水的复合物称为“水合物”。式(I)或(II)的化合物的溶剂化物在本发明的范围内。
有机化学专家还将认识到,许多有机化合物可以以超过一种的结晶形式存在。例如,结晶形式可以在溶剂化物之间变化。因此,本发明的化合物或其药学上可接受的溶剂化物的所有晶体形式均在本发明的范围内。
本文中提及的根据本发明的化合物包括式(I)或(II)的化合物及其药学上可接受的盐、溶剂化物或前药。
根据优选的实施方案,本发明的化合物对应于通式(I),且更具体地式(II),其中:
-m是0或1;和/或
-AH是CO2H或SO3H或PO3H2;和/或
-R1表示卤素原子,烷基基团,卤代烷基基团,烷氧基基团,卤代烷氧基基团,O-环烷基基团,O-芳基基团,O-芳基烷基基团,杂烷基基团,卤代烷基基团,环烷基基团,酰基基团,芳基基团或芳基烷基基团。
本文中提及的根据本发明的化合物包括式(I)或(II)的化合物及其药学上可接受的盐、溶剂化物、两性离子形式或前药。
根据具体的实施方案,根据本发明的化合物的前药可以是具有下式(III)的产品:
且更具体地,下式(IV):
其中:
1,m,R1,R2,R3如上所定义;
A表示-SO3Z-CO2Z或–P(O)(OZ)2,Z选自下组:氢原子,烷基和芳基烷基基团;
X表示氢原子,-(CO)-烷基,-(CO)-烷氧基,-(CO)-苄基氧基,
R表示烷基基团,且R’和R”独立地表示氢原子或烷基基团;
Y表示氢原子,烷基,芳基,芳基烷基或
R,R’和R”如上所定义,
其中Z,X和Y中的至少一个不同于氢原子。
根据具体的实施方案,本发明的化合物选自下组:
4-氨基-4-[羟基(3-甲基丁基)磷酰基]丁酸,
4-氨基-4-[羟基(4-甲基戊基)磷酰基]丁酸,
4-氨基-4-[(2-环己基乙基)(羟基)磷酰基]丁酸,
4-氨基-4-[羟基(戊基)磷酰基]丁酸,
4-氨基-4-[己基(羟基)磷酰基]丁酸,
4-氨基-4-[(环丁基甲基)(羟基)磷酰基]丁酸,
4-氨基-4-[(环戊基甲基)(羟基)磷酰基]丁酸,
4-氨基-4-[羟基(5-甲基己基)磷酰基]丁酸,
4-氨基-4-[羟基(4,4,4-三氟丁基)磷酰基]丁酸,
4-氨基-4-[(环己基甲基)(羟基)磷酰基]丁酸,和
4-氨基-4-[羟基({[(丙-2-基)氨基]甲基})磷酰基]丁酸。
本发明的化合物方便地以药物组合物的形式施用。此类组合物可以方便地呈现以常规方式与一种或多种生理上可接受的载体或赋形剂混合使用。在与配制剂的其他成分相容并且对接受它们的受试者无害的意义上,载体必须是“可接受的”。
尽管可以将本发明的化合物作为原料药进行治疗性施用是可行的,但是也可以将活性成分呈现为药物配制剂。
因此,本发明进一步提供了一种药物组合物,其包含与一种或多种药学上可接受的载体以及任选的其他活性成分结合的本发明的化合物。
药物组合物包括适用于口服、肠胃外(包括皮下,例如通过注射或通过贮库片剂,皮内、鞘内、眼内、肌内,例如通过贮库和静脉内)、直肠和局部(包括皮肤(即在皮肤上)的那些,或以适合于通过吸入或吹入施用的形式,尽管最合适的途径可能取决于例如接受者的状况和病症。组合物可以方便地以单位剂型呈现,并且可以通过药学领域公知的任何方法制备。所有方法都包括将本发明的化合物,任选地与至少一种其他活性成分,与构成一种或多种辅助成分的载体相结合的步骤。通常,通过将活性成分与液体载体或细分的固体载体或两者均匀和紧密地结合,且如果需要,将产品成型为所期望的配制剂来制备配制剂。
适用于口服施用的药物组合物可以以离散单位呈现,如胶囊,扁囊剂或片剂(例如特别用于儿科施用的可咀嚼片剂),其各自含有预定量的活性成分;作为粉末或颗粒;作为在水性液体或非水性液体中的溶液或悬浮液;或作为水包油型液体乳剂或油包水型液体乳剂。活性成分也可以作为大丸剂、药糖剂或糊剂呈现。
片剂可以通过压制或模制制成,任选地与一种或多种辅助成分一起制成。可以通过在合适的机器中压制自由流动形式的活性成分(如粉末或颗粒),并任选与其他常规赋形剂如结合剂(例如糖浆,阿拉伯胶,明胶,山梨糖醇,黄芪胶,淀粉的粘液,聚乙烯吡咯烷酮或羟甲基纤维素),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,滑石粉,聚乙二醇或二氧化硅),崩解剂(例如马铃薯淀粉或淀粉羟乙酸钠)或润湿剂如月桂基硫酸钠。模制片剂可以通过在合适的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。片剂可以任选地被包衣或刻痕,并且可以配制以提供其中的活性成分的缓慢或受控释放。可以根据本领域公知的方法将片剂包衣。
或者,可以将本发明的化合物掺入口服液体制剂,如水性或油性悬浮液、溶液、乳剂和例如诸如糖浆或酏剂中。此外,含有这些化合物的药物组合物(或配制剂)可以呈现为干燥产品,以在使用前用水或其他合适的媒介物构成。此类液体制剂可以含有常规的添加剂,如悬浮剂,如山梨糖醇糖浆、甲基纤维素、葡萄糖/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食用脂肪;乳化剂,如卵磷脂、脱水山梨糖醇单油酸酯或阿拉伯胶;非水性媒介物(其可能包括食用油),如杏仁油、分馏椰子油、油性酯、丙二醇或乙醇;和防腐剂,如对羟基苯甲酸甲酯或对羟基苯甲酸丙酯或山梨酸。这些制剂也可以配制成栓剂,例如其含有常规栓剂赋形剂,如可可脂或其他甘油酯。
用于肠胃外施用的配制剂包括水性和非水性无菌注射溶液,其可以含有抗氧化剂、缓冲剂、抑菌剂和溶质,这些使配制剂与预期接受者的血液等渗;以及水性和非水性无菌悬浮液,其可以包括悬浮剂和增稠剂。配制剂可以呈现于单位剂量或多剂量容器中,例如密封的安瓿瓶和小瓶中,并且可以在冷冻干燥(冻干)条件下储存,其仅需要在即将使用前添加无菌液体载体,例如注射用水。临时注射溶液和悬浮液可以由前述种类的无菌粉末、颗粒和片剂制备。
用于直肠施用的组合物可以与常规载体如可可脂、硬脂或聚乙二醇一起呈现为栓剂。
用于在口中例如颊或舌下局部施用的配制剂包括在调味赋形剂如蔗糖和阿拉伯胶或黄芪胶中包含活性成分的锭剂,以及在赋形剂如明胶和甘油或蔗糖和阿拉伯胶中包含活性成分的糖锭。对于在皮肤上的局部施用,可以将化合物配制成乳膏、凝胶、软膏或洗剂或者作为经皮贴剂。对于眼施用,组合物可以是液体溶液(如滴眼液)、凝胶、乳膏或任何类型的眼科组合物。
化合物也可以配制成贮库制剂。这些长效配制剂可以通过植入(例如皮下或肌内)或者通过肌内注射来施用。因此,例如,化合物可以与合适的聚合或疏水材料(例如,作为在可接受的油中的乳剂)或离子交换树脂一起配制,或配制为微溶的衍生物,例如,配制为微溶的盐。
对于鼻内施用,本发明的化合物可以例如以液体喷雾剂、粉末或滴剂形式使用。
为了通过吸入施用,使用合适的推进剂,例如1,1,1,2-三氟乙烷(HFA134A)和1,1,1,2,3,3,3,-七氟丙烷(HFA 227)、二氧化碳或其他合适的气体,本发明的化合物可以方便地以气雾剂喷雾呈现形式从加压容器或喷雾器中递送。在加压气雾剂的情况下,可以通过提供适于递送计量的量的阀来确定确切剂量。可以配制用于吸入器或吹入器中的例如明胶的胶囊和药筒,使其含有本发明的化合物和合适的粉末赋形剂如乳糖或淀粉的粉末混合物。
除了上述特别提及的成分之外,配制剂还可以包括本领域中考虑到所讨论配制剂的类型的其他常规试剂,例如适合于口服施用的配制剂可以包括调味剂。
本领域技术人员将理解的是,本文中提及的治疗扩展至防治以及治疗已确定的疾病或症状。此外,应当理解的是,用于治疗所需的本发明的化合物的量将随所治疗病况的性质以及患者的年龄和状况而变化,并且最终将由主治医师或兽医决定。然而,一般而言,用于成人治疗的剂量通常将在每天0.02-5000mg,优选每天1-1500mg的范围内。期望的剂量可以方便地以单剂量或以适当的间隔施用的分剂量呈现,所述适当的间隔例如每天两个、三个、四个或更多个亚剂量。根据本发明的配制剂可以含有0.1-99%的活性成分,对于片剂和胶囊剂,便利地为30-95%,且对于液体制剂为3-50%。
用于本发明的本发明的化合物可以与一种或多种其他治疗活性剂联合使用,所述治疗活性剂例如,beta-肾上腺素能受体拮抗剂、钙通道阻断剂、噻嗪类利尿剂、血管紧张素受体拮抗剂和血管紧张素转化酶抑制剂。因此,本发明在另一方面提供了包含本发明的化合物与另一治疗剂的组合在治疗动脉高血压中的用途。
当本发明的化合物与其他治疗剂联合使用时,化合物可以通过任何合适的途径顺序或同时施用。
以上提及的联合可以适当地呈现以药物配制剂的形式使用,因此,包含最佳与药学上可接受的载体或赋形剂一起的如上定义的联合的药物配制剂是本发明的另一方面。可以以分开的或组合的药物配制剂顺序或同时施用此类联合的各个组分。
当在同一配制剂中组合时,将理解的是,两种化合物必须是稳定的并且彼此以及与配制剂的其他组分相容,并且可以配制用于施用。当分开配制时,它们可以以任何合适的配制剂形式提供,适当地以本领域中此类化合物已知的方式提供。
当本发明的化合物与对相同疾病具有活性的第二治疗剂联合使用时,每种化合物的剂量可能与单独使用该化合物时施用的剂量不同。合适的剂量将由本领域技术人员容易地确定。
在另一方面,本发明的主题是用于预防或治疗动脉高血压以及直接和间接相关疾病的方法,其包括施用治疗有效量的本发明的化合物。
在另一方面,本发明提供了本发明的化合物,其用于治疗剂,且具体地用于兽医或人药物。
本发明还涉及式(I)或(II)的化合物作为关于氨肽酶A的选择性抑制剂的用途。
在另一方面,本发明提供了本发明的化合物用于生产用于治疗动脉高血压以及直接和间接相关疾病的药用产品中的用途。
在另一方面,本发明提供了治疗患有动脉高血压以及直接和间接相关疾病的患者的方法,其包括施用治疗有效量的本发明的化合物。
本发明提供了用于预防或治疗动脉高血压以及动脉高血压直接或间接导致的疾病的方法。这些疾病包括心脏病,心力衰竭,中风,外周和/或脑血管系统疾病以及脑、眼和肾疾病。具体而言,疾病包括原发性和继发性动脉高血压、猝发、心肌缺血、心脏功能不全和肾功能不全、心肌梗死、周围血管疾病、糖尿病性蛋白尿、X综合征、青光眼、神经变性性疾病和记忆障碍。
式(I)或优选(II)的化合物可以通过几种方法制备。起始产品是商业产品或根据已知合成由商业化合物制备的产品或本领域技术人员已知的产品。更具体地,用于制备本发明的化合物的方法包括以下连续步骤:
式(I)的化合物(本发明的目的)可以通过使用具有下式(V)、(VI)和(VII)的前体,根据以下所述的合成路径来制备,
H2N-X
(VII)
其中l,m,R1,R2,R3,A和X如上所定义。
根据该合成途径,多组分反应例如在乙酸和乙酰氯的存在下,在有机溶剂如甲苯中,在化合物(V)、(VI)和(VII)之间进行,以得到式(VIII)的化合物:
接下来,可以通过氢解作用同时发生官能团A的保护基团和氨基官能团的保护基团X的脱保护,从而导致形成式(I)的本发明的化合物。
在一些情况下,式(VIII)的化合物的基团A被例如氢氧化锂(lithine)选择性地脱保护,以提供式(IX)的中间体化合物,
接下来,将式(IX)的化合物在加热下在有机溶剂如苯甲醚中进行氢解或使其经受酸性条件如三氟乙酸,以提供式(I)的本发明的化合物。
式(I)的化合物(本发明的目的)也可以通过使用具有下式(Vbis)和(X)的前体,根据以下所述的合成路径来制备,
其中l,m,Y,R1,R2,R3和A如上所定义。
根据该合成路径,反应在例如碳酸铯的存在下,在有机溶剂如二氯甲烷中,通过文献中的公知方法获得,在化合物(Vbis)和磺基亚胺(X)之间进行,以得到式(XI)的化合物:
其中l,m,Y,R1,R2,R3和A如上所定义。
值得注意的是,可以通过文献中众所周知的方法以手性形式合成磺基亚胺中间体(X)。当手性电感器保护基团由磺基亚胺(X)支撑时,该合成子可以提供不对称合成式(II)的化合物的前体的途径。
以外消旋形式或手性形式应用于中间体(XI)的适当的脱保护步骤分别提供了获得式(I)或(II)的本发明的化合物的途径。
式(V)的前体可以从下式(XII)的化合物获得,
通过使相应的格氏试剂与氯亚磷酸二乙酯在有机溶剂(如乙醚或四氢呋喃)中在冷却条件下(如0-10℃)反应。
以下实施例举例说明本发明,但不以任何方式限制本发明。
实施例
所用的起始产品是商业产品或根据已知合成由商业化合物制备的产品或本领域技术人员已知的产品。不同的通用规程A,B,C导致可用于制备本发明的化合物的合成中间体。规程D和E导致合成本发明的最终化合物。
根据常规的分光光度法技术(核磁共振(NMR),质谱法,包括电喷雾电离(ESI)…)测定实施例中描述的化合物的结构,并且通过高效液相色谱(HPLC)测定纯度。
根据IUPAC(国际纯化学和应用化学联合会)命名法命名合成中间体和本发明的化合物,并以其中性形式对其进行描述。
使用了以下缩写:
AIBN:偶氮二异丁腈
(Boc)2O:二碳酸二叔丁酯
(n-Bu)4NBr:四正丁基溴化铵
(n-Bu)4NI:四正丁基碘化铵
AcCl:乙酰氯
AcOH:乙酸
BTSP:双(三甲基甲硅烷基)膦酸酯
Cbz:羧苄基
CH2Cl2或DCM:二氯甲烷
CHCl3:氯仿
cHex:环己烷
CuSO4:硫酸铜
DCC:N,N'-二环己基碳二亚胺
DTAD:偶氮二羧酸二叔丁酯
EDCI:1-乙基-3-(3-二甲基氨基丙基)乙基碳二亚胺
Et2O:乙醚
EtOAc:乙酸乙酯
HBF4.Et2O:四氟硼酸二乙醚复合物
HCl:盐酸
HMDS:1,1,1,3,3,3-六甲基二硅氮烷
I2:碘
i-PrOH:异丙醇
K2CO3:碳酸钾
KOtBu:叔丁醇钾
LiAlH4:氢化铝锂
LiHMDS:双(三甲基甲硅烷基)氨基锂(lithium bis(trimethylsilyl)amide)
LiOH.H2O:一水氢氧化锂(lithine)
MeOH:甲醇
Mg:镁
Na2S2O3:硫代硫酸钠
Na2SO4:硫酸钠
NaBH4:硼氢化钠
NaHCO3:碳酸氢钠
NEt3:三乙胺
NH2Cbz:氨基甲酸苄酯
NH4Cl:氯化铵
Pd(PPh3)4:四(三苯基膦)钯(0)
TFA:三氟乙酸
Eq.:当量
ESI:电喷雾电离
HPLC:高效液相色谱
NMR:核磁共振
PTFE过滤器:聚四氟乙烯过滤器
用于制备中间体(V)的通用规程(规程A)
在氩气气氛下将转化为相应的格氏溶液(Grignard solution)(无水THF或Et2O中0.5至1.0M,1.05eq.)的中间体(XII)滴加至无水Et2O中冷却(5℃)的氯亚磷酸二乙酯溶液(1.3mL/mmol的氯亚磷酸二乙酯),在添加期间将内部温度保持在0-10℃之间。在室温下搅拌16小时后,将混合物通过硅藻土(celite)过滤。将滤液在减压下浓缩。将残余物溶解在水中,并用浓HCl水溶液(pH=1)处理。将所得的混合物在室温下搅拌直至获得无色透明溶液(15分钟)。该溶液用EtOAc萃取(三次),且合并的有机层用卤水洗涤,经Na2SO4干燥,过滤并真空浓缩。将澄清的液体用NaOH 2M水溶液稀释,并将所得的溶液搅拌1小时。将水层用Et2O洗涤,然后用浓HCl酸化(直至pH=1)。将所得的酸性水层用DCM萃取(三次)。合并的有机层经Na2SO4干燥,过滤,并在真空下浓缩,以提供所期望的中间体(V)。
用于多组分反应的通用规程(规程B)
向中间体(V)(1.0eq.)和氨基甲酸苄酯(VII)(H2N-X,X=CBz)(1.1eq.)在约6:1的AcOH(0.9-1.8mL/mmol的中间体(V)和AcCl(0.09-0.52mL/mmol的中间体(V))的混合物中的溶液滴加中间体(VI)(1.2eq.)。在室温下搅拌18小时后,将反应混合物与甲苯共蒸发(三次)。将残余物吸收在DCM中,然后添加水以淬灭剩余的AcCl,然后用DCM萃取水层(三次)。合并的有机层经Na2SO4干燥,过滤并真空浓缩。将粗物质在Et2O中研磨,过滤,并将获得的固体干燥以提供所期望的中间体(VIII)。
用于选择性脱保护的通用规程(规程C)
向THF/水(4:1)的混合物中的中间体(VIII)(1.0eq.)在一份中添加LiOH.H2O(3.0eq.)。混合物立即变成橙色,并在室温下搅拌直至反应完成。浓缩混合物以蒸发THF,然后用EtOAc萃取水层(三次)。然后用HCl水溶液将水层酸化至pH 1,期间出现沉淀。大多数时候,用DCM萃取水层(五次),合并的有机层经Na2SO4干燥,过滤并真空浓缩以提供相应的选择性脱保护的中间体(IX)。在一些情况下,将酸处理后获得的沉淀物直接过滤并干燥以提供预期的中间体。
用于在酸性条件下进行最终脱保护的通用规程(规程D)
向根据规程C选择性脱保护的中间体(IX)添加TFA/苯甲醚。将所得的溶液在TFA/苯甲醚条件下于75℃搅拌2至6小时,然后如果需要的话在室温下搅拌。浓缩并与甲苯共蒸发(三次)后,或在出现沉淀的情况下直接过滤后,将粗产物通过研磨,制备型LCMS或反相柱纯化以提供所期望的式(I)的本发明的化合物。
用于氢解的通用规程(规程E)
将中间体(VIII)(1.0eq.)溶解于EtOH/AcOH或MeOH/AcOH的混合物中(总体积:17-34mL/mmol的受保护的化合物,取决于其溶解度)。对粉末进行超声处理以提高溶解度,然后将澄清的溶液送至H-Cube(催化剂=10%Pd/C,T=40℃,流速=0.6-0.8mL/分钟,全H2模式或10bar)。浓缩后,通过研磨或通过反相柱纯化粗产物以提供所期望的式(I)的本发明的化合物。
4-氧代丁酸苄酯的制备
步骤1:4-羟基丁酸苄酯的合成
将gamma-丁内酯(20mL,255mmol,1.0eq.)和NaOH(10.2g,255mmol,1.0eq.)溶于水(170mL)中,并将温度升至70℃。12小时后,将水蒸发,并包括白色糊状物,蒸发甲苯(三次)。将白色固体置于真空下并加热至70℃达2小时。将固体再次用甲苯吸收以除去任何痕量的水。将获得的白色固体悬浮在丙酮(280mL)中。将四丁基碘化铵(4.72g,12.8mmol,0.05eq.)和苄基氯(29.4mL,255mmol,1.0eq.)添加到该悬浮液中。将溶液回流6小时,然后回到室温下过夜。然后将反应混合物在6小时期间再次回流。在室温下,将混合物过滤并蒸发滤液以得到粗产物,将其通过硅胶上的色谱纯化。合并含有预期产物的级分并真空浓缩以提供标题产物(36.5g,74%)。
1H NMR(CDCl3,500MHz)δ(ppm):7.39-7.31(m,5H);5.13(s,2H);3.69(t,2H,J=6.0Hz);2.50(t,2H,J=7.0Hz);1.93-1.88(m,2H)
步骤2:4-氧代丁酸苄酯的合成
将4-羟基丁酸苄酯(10g,51.49mmol,1.0eq.)溶解在二氯甲烷(1.7L)中,并冷却至0℃。添加Dess-Martin高碘烷(33g,77.23mmol,1.5eq.),并将混合物在室温搅拌2h30。将混合物浓缩并将粗产物通过硅胶上的快速色谱纯化。合并含有预期产物的级分并真空浓缩以提供标题化合物(8.0g,81%)为浅黄色油状物。
1H NMR(CDCl3,500MHz)δ(ppm):9.82(s,1H);7.39-7.31(m,5H);5.14(s,2H);2.82(t,2H,J=7.0Hz);2.71-2.67(m,2H)
实施例1:4-氨基-4-[羟基(3-甲基丁基)磷酰基]丁酸
步骤1:(3-甲基丁基)次膦酸
根据规程A从无水Et2O(6mL)中的氯亚磷酸二乙酯(1.90mL,17.4mmol,1.0eq.),随后添加从无水Et2O(9mL)中的1-溴-3-甲基丁烷(2.76g,18.3mmol,1.05eq.)新鲜制备的格氏试剂来制备标题化合物(1.40g,59%)。
MS(ESI+):[M+H]+=137.2;[(Mx2)+H]+=273.2
1H NMR(MeOD,500MHz)δ(ppm):7.02(dt,J=536.2,2.0Hz,1H);1.85-1.71(m,2H);1.71-1.59(m,1H);1.55-1.42(m,2H);0.96(d,J=6.7Hz,6H)
31P NMR(CD3OD,202MHz)δ(ppm):36.32
步骤2:[4-(苄基氧基)-1-{[(苄基氧基)羰基]氨基}-4-氧丁基](3-甲基丁基)次膦酸
根据多组分反应的规程B从AcOH(10mL)和AcCl(1.2mL)中的先前产物(800mg,5.88mmol,1.0eq.)和NH2Cbz(977mg,6.46mmol,1.1eq.),随后添加4-氧代丁酸苄酯(1.36g,7.05mmol,1.2eq.)来制备标题化合物(1.75g,65%),其获得为白色固体。
MS(ESI+):[M+H]+=462.2;[(Mx2)+H]+=923.6
1H NMR(CD3OD,500MHz)δ(ppm):7.54-7.22(m,10H);5.23-5.02(m,4H);4.05-3.89(m,1H);2.54-2.43(m,1H);2.31-2.17(m,1H);1.95-1.79(m,1H);1.78-1.59(m,2H);1.59-1.40(m,3H);1.40-1.24(m,1H);1.06-0.80(m,6H)
31P NMR(CD3OD,202MHz)δ(ppm):51.31
步骤3:4-氨基-4-[羟基(3-甲基丁基)磷酰基]丁酸
根据氢解的规程E从混合物EtOH/AcOH(1:1,18mL)中的先前产物(500mg,1.08mmol,1.0eq.)来制备标题化合物(164mg,76%),其获得为白色粉末。
预期纯度:>95%(基于LCMS和NMR)
MS(ESI+):[(M-H2O)+H]+=220.2;[M+H]+=238.2;[(Mx2)+H]+=475.2;[(Mx3)+H]+=712.4
1H NMR(CD3OD,500MHz)δ(ppm):3.17-3.04(m,1H);2.62(t,J=7.5Hz,2H);2.30-2.13(m,1H);2.05-1.83(m,1H);1.74-1.39(m,5H);0.96(d,J=6.6Hz,6H)
31P NMR(CD3OD,202MHz)δ(ppm):33.08
实施例2:4-氨基-4-[羟基(4-甲基戊基)磷酰基]丁酸
步骤1:(4-甲基戊基)次膦酸
根据规程A从无水Et2O(6mL)中的氯亚磷酸二乙酯(1.26mL,11.5mmol,1.0eq.),随后添加从无水Et2O(6mL)中的1-溴-4-甲基戊烷(2.0g,12.1mmol,1.05eq.)新鲜制备的格氏试剂来制备标题化合物(740mg,43%)。
MS(ESI+):[M+H]+=151.2;[(Mx2)+H]+=301.2
1H NMR(500MHz,MeOD)δ(ppm):7.01(dt,J=536.1,2Hz,1H);1.78-1.67(m,2H);1.67-1.53(m,3H);1.35-1.27(m,2H);0.91(d,J=6.6Hz,6H)
31P NMR(CD3OD,202MHz)δ(ppm):35.69
步骤2:[4-(苄基氧基)-1-{[(苄基氧基)羰基]氨基}-4-氧丁基](4-甲基戊基)次膦酸
根据多组分反应的规程B从AcOH(5mL)和AcCl(428μL)中的先前产物(300mg,2.0mmol,1.0eq.)和NH2Cbz(362mg,2.4mmol,1.2eq.),随后添加4-氧代丁酸苄酯(460.8mg,2.4mmol,1.2eq.)的AcOH(5mL)溶液来制备标题化合物(416mg,44%),其获得为白色固体。
MS(ESI-):[M-H]-=474.2
1H NMR(500MHz,MeOD)δ(ppm):7.39-7.23(m,10H);5.20-5.00(m,4H);3.96(m,1H);2.57-2.43(m,2H);2.27-2.13(m,1H);1.85(m,1H);1.71-1.45(m,5H);1.21(m,2H);0.88(d,J=6.7Hz,6H)
31P NMR(CD3OD,202MHz)δ(ppm):50.75
步骤3:4-氨基-4-[羟基(4-甲基戊基)磷酰基]丁酸
根据氢解的规程E从混合物EtOH/AcOH(1:1,7mL)中的先前产物(200mg,420μmmol,1.0eq.)来制备标题化合物(45mg,42%),其获得为米色粉末。
预期纯度:95%(基于LCMS和NMR)
MS(ESI-):[M-H]-=250.2;[(Mx2)-H]-=501.3;[(Mx3)-H]-=752.5
MS(ESI+):[(M-H2O)+H]+=234.2;[M+H]+=252.2;[(Mx2)+H]+=503.3;[(Mx3)+H]+=754.6
1H NMR(500MHz,MeOD)δ(ppm):3.13-3.05(m,1H);2.64-2.56(m,2H);2.27-2.13(m,1H);2.01-1.87(m,1H);1.67-1.51(m,5H);1.29(q,J=6.9Hz,2H);0.91(d,J=6.6Hz,6H)
31P NMR(CD3OD,202MHz)δ(ppm):32.67
实施例3:4-氨基-4-[羟基(5-甲基己基)磷酰基]丁酸
步骤1:(5-甲基己基)次膦酸
根据规程A从无水Et2O(6mL)中的氯亚磷酸二乙酯(1.15mL,10.54mmol,1.0eq.),随后添加从无水Et2O(5mL)中的1-溴-5-甲基己烷(2.0g,11.17mmol,1.05eq.)新鲜制备的格氏试剂来制备标题化合物(797mg,46%)。
MS(ESI+):[M+H]+=165.2;[(Mx2)+H]+=329.2
1H NMR(500MHz,MeOD)δ(ppm):7.00(dt,J=533.5,1.99Hz,1H);1.73(s,2H);1.62-1.51(m,3H);1.43(dd,J=8.6,7.5Hz,2H);1.23(dd,J=8.6,7.0Hz,2H);0.90(d,J=6.6Hz,6H)
31P NMR(CD3OD,202MHz)δ(ppm):35.5
步骤2:[4-(苄基氧基)-1-{[(苄基氧基)羰基]氨基}-4-氧丁基](5-甲基己基)次膦酸
根据多组分反应的规程B从AcOH(4mL)和AcCl(391μL)中的先前产物(300mg,1.83mmol,1.0eq.)和NH2Cbz(331mg,2.19mmol,1.2eq.),随后添加4-氧代丁酸苄酯(421mg,2.19mmol,1.2eq.)的AcOH(3mL)溶液来制备标题化合物(521mg,58%),其获得为白色固体。
MS(ESI+):[M+H]+=490.2;[(Mx2)+H]+=979.7
1H NMR(500MHz,MeOD)δ(ppm):7.32(dt,J=20.9,6.2Hz,10H);5.23-4.90(m,4H);4.08-3.84(m,1H);2.72-2.34(m,2H);2.21(d,J=13.5Hz,1H);1.86(tt,J=14.0,7.2Hz,1H);1.72-1.38(m,5H);1.37-1.07(m,4H);0.88(d,J=6.8Hz,6H)
31P NMR(CD3OD,202MHz)δ(ppm):50.6
步骤3:4-氨基-4-[羟基(5-甲基己基)磷酰基]丁酸
根据氢解的规程E从混合物EtOH/AcOH(1:1,9mL)中的先前产物(250mg,510μmmol,1.0eq.)来制备标题化合物(32mg,23%),其获得为米色粉末。
预期纯度:95%(基于LCMS和NMR)
MS(ESI-):[M-H]-=264.2;[(Mx2)-H]-=529.3;[(Mx3)-H]-=794.6
MS(ESI+):[(M-H2O)+H]+=248.2;[M+H]+=266.3;[(Mx2)+H]+=531.3;[(Mx3)+H]+=796.6
1H NMR(500MHz,MeOD)δ(ppm):3.13-3.04(m,1H);2.64-2.57(m,2H);2.26-2.14(m,1H);2.00-1.87(m,1H);1.66-1.54(m,5H);1.47-1.36(m,2H);1.27-1.18(m,2H);0.89(d,J=6.6Hz,6H)
31P NMR(CD3OD,202MHz)δ(ppm):32.7
实施例4:4-氨基-4-[羟基(戊基)磷酰基]丁酸
步骤1:戊基次膦酸
根据规程A从无水Et2O(5mL)中的氯亚磷酸二乙酯(1.05mL,9.58mmol,1.0eq.),随后添加戊基溴化镁(Et2O中2.0M溶液,5.03mL,1.05eq.)来制备标题化合物(715mg,55%)。
MS(ESI-):[M-H]-=135.0
MS(ESI+):[M+H]+=137.1;[(Mx2)+H]+=273.1
1H NMR(500MHz,MeOD)δ(ppm):7.01(dt,J=535.4,2.0Hz,1H);1.80-1.67(m,2H),1.66-1.53(m,2H),1.49-1.30(m,4H),0.93(t,J=7.1Hz,3H)
31P NMR(CD3OD,202MHz)δ(ppm):35.8
步骤2:[4-(苄基氧基)-1-{[(苄基氧基)羰基]氨基}-4-氧丁基](戊基)次膦酸
根据多组分反应的规程B从AcOH(9mL)和AcCl(472μL)中的先前产物(300mg,2.2mmol,1.0eq.)和NH2Cbz(400mg,2.64mmol,1.2eq.),随后添加4-氧代丁酸苄酯(508mg,2.64mmol,1.2eq.)的AcOH(5mL)溶液来制备标题化合物(560mg,55%),其获得为白色固体。
MS(ESI-):[M-H]-=460.1;[(Mx2)-H]-=921.5
MS(ESI+):[M+H]+=462.1;[(Mx2)+H]+=923.5
1H NMR(CD3OD,500MHz)δ(ppm):7.40-7.22(m,10H);5.16-5.02(m,4H);3.96(m,1H);2.57-2.42(m,2H);2.22(m,1H);1.85(m,1H);1.73-1.47(m,4H);1.30(m,4H);0.90(t,J=5.2,3.8Hz,3H)
31P NMR(CD3OD,202MHz)δ(ppm):50.8
步骤3:4-氨基-4-[羟基(戊基)磷酰基]丁酸
根据氢解的规程E从混合物EtOH/AcOH(1:1,9mL)中的先前产物(250mg,540μmol,1.0eq.)来制备标题化合物(65mg,50%),其获得为米色粉末。
预期纯度:95%(基于LCMS)和92%(基于NMR)
MS(ESI-):[M-H]-=236.2;[(Mx2)-H]-=473.3;[(Mx3)-H]-=710.5
MS(ESI+):[(M-H2O)+H]+=220.2;[M+H]+=238.2;[(Mx2)+H]+=475.3;[(Mx3)+H]+=712.5
1H NMR(500MHz,MeOD)δ(ppm):3.12-3.07(m,1H),2.63-2.56(m,2H),2.28-2.14(m,1H),2.00-1.87(m,1H),1.68-1.52(m,4H),1.46-1.31(m,4H),0.99-0.85(m,3H)
31P NMR(CD3OD,202MHz)δ(ppm):32.7
实施例5:4-氨基-4-[己基(羟基)磷酰基]丁酸
步骤1:己基次膦酸
根据规程A从无水Et2O(7mL)中的氯亚磷酸二乙酯(1.40mL,12.78mmol,1.0eq.),随后添加己基溴化镁(Et2O中2.0M溶液,6.71mL,1.05eq.)来制备标题化合物(1.21g,63%)。
MS(ESI-):[M-H]-=149.1
MS(ESI+):[M+H]+=151.2;[(Mx2)+H]+=301.2
1H NMR(500MHz,MeOD)δ(ppm):7.01(dt,J=535.4,2.0Hz,1H);1.79-1.67(m,2H),1.65-1.52(m,2H);1.50-1.40(m,2H);1.40-1.27(m,4H);0.96-0.87(m,3H)
31P NMR(CD3OD,202MHz)δ(ppm):35.8
步骤2:[4-(苄基氧基)-1-{[(苄基氧基)羰基]氨基}-4-氧丁基](己基)次膦酸
根据多组分反应的规程B从AcOH(9mL)和AcCl(428μL)中的先前产物(300mg,2.0mmol,1.0eq.)和NH2Cbz(362mg,2.4mmol,1.2eq.),随后添加4-氧代丁酸苄酯(460mg,2.4mmol,1.2eq.)的AcOH(5mL)溶液来制备标题化合物(572mg,60%),其获得为白色固体。
1H NMR(500MHz,MeOD)δ(ppm):7.41-7.21(m,10H);5.17-5.02(m,4H);4.01-3.91(m,1H);2.57-2.40(m,2H);2.28-2.15(m,1H);1.85(m,1H);1.74-1.46(m,4H);1.38-1.21(m,6H);0.90(t,J=7.0Hz,3H)
31P NMR(CD3OD,202MHz)δ(ppm):50.7
步骤3:4-氨基-4-[己基(羟基)磷酰基]丁酸
根据氢解的规程E从混合物EtOH/AcOH(1:1,9mL)中的先前产物(250mg,0.520mmol,1.0eq.)来制备标题化合物(54mg,41%),其获得为米色固体。
预期纯度:97%(基于LCMS)和95%(基于NMR)
MS(ESI-):[M-H]-=250.2;[(Mx2)-H]-=501.3;[(Mx3)-H]-=752.6
MS(ESI+):[(M-H2O)+H]+=234.2;[M+H]+=252.2;[(Mx2)+H]+=503.3;[(Mx3)+H]+=754.6
1H NMR(500MHz,MeOD)δ(ppm):3.13-3.04(m,1H);2.64-2.56(m,2H);2.27-2.14(m,1H);2.00-1.86(m,1H);1.69-1.52(m,4H);1.47-1.27(m,6H);0.97-0.86(m,3H)
31P NMR(CD3OD,202MHz)δ(ppm):30.7
实施例6:4-氨基-4-[羟基(4,4,4-三氟丁基)磷酰基]丁酸
步骤1:(4,4,4-三氟丁基)次膦酸
根据规程A从无水Et2O(6mL)中的氯亚磷酸二乙酯(1.12mL,10.2mmol,1.0eq.),随后添加从无水Et2O(5mL)中的4-溴-1,1,1-三氟丁烷(2.0g,10.0mmol,1.05eq.)新鲜制备的格氏试剂来制备标题化合物(1g,56%)。
MS(ESI-):[M-H]-=175.1
MS(ESI+):[M+H]+=177.1;[(Mx2)+H]+=353.0
1H NMR(500MHz,MeOD)δ(ppm):7.05(dt,J=537.3,1.8Hz,1H);2.38-2.24(m,2H),1.90-1.77(m,4H)
31P NMR(CD3OD,202MHz)δ(ppm):33.5
步骤2:[4-(苄基氧基)-1-{[(苄基氧基)羰基]氨基}-4-氧丁基](4,4,4-三氟丁基)次膦酸
根据多组分反应的规程B从AcOH(9mL)和AcCl(425μL)中的先前产物(350mg,1.99mmol,1.0eq.)和NH2Cbz(360mg,2.39mmol,1.2eq.),随后添加4-氧代丁酸苄酯(458mg,2.38mmol,1.2eq.)的AcOH(5mL)溶液来制备标题化合物(595mg,60%),其获得为白色固体。
MS(ESI+):[M+H]+=502.1
1H NMR(500MHz,MeOD)δ(ppm):7.43-7.20(m,10H);5.18-5.00(m,4H);4.02-3.91(m,1H);2.60-2.42(m,2H);2.30-2.08(m,3H);1.96-1.64(m,5H)
31P NMR(CD3OD,202MHz)δ(ppm):49.1
步骤3:4-氨基-4-[羟基(4,4,4-三氟丁基)磷酰基]丁酸
根据氢解的规程E从混合物EtOH/AcOH(1:1,9mL)中的先前产物(250mg,0.498mmol,1.0eq.)来制备标题化合物(29mg,21%),其获得为米色固体。
预期纯度:95%(基于LCMS和NMR)
MS(ESI-):[M-H]-=276.2;[(Mx2)-H]-=553.2;[(Mx3)-H]-=830.4
MS(ESI+):[(M-H2O)+H]+=260.1;[M+H]+=278.2;[(Mx2)+H]+=555.2;[(Mx3)+H]+=832.4
1H NMR(500MHz,MeOD)δ(ppm):3.15-3.06(m,1H);2.61(t,J=7.3Hz,2H);2.36-2.14(m,3H);2.01-1.80(m,3H);1.72-1.58(m,2H)
31P NMR(CD3OD,202MHz)δ(ppm):30.9
实施例7:4-氨基-4-[(2-环己基乙基)(羟基)磷酰基]丁酸
步骤1:(2-环己基乙基)次膦酸
根据规程A从无水Et2O(6mL)中的氯亚磷酸二乙酯(1.29mL,11.8mmol,1.0eq.),随后添加从无水Et2O(6mL)中的(2-溴乙基)环己烷(2.4g,12.6mmol,1.05eq.)新鲜制备的格氏试剂来制备标题化合物(1.2g,58%)。
MS(ESI+):[M+H]+=177.2;[(Mx2)+H]+=353.2
1H NMR(500MHz,MeOD)δ(ppm):7.01(dt,J=535.8,1.9Hz,1H);1.82-1.63(m,7H);1.52-1.40(m,2H);1.39-1.13(m,4H);1.02-0.86(m,2H)
31P NMR(CD3OD,202MHz)δ(ppm):36.5
步骤2:[4-(苄基氧基)-1-{[(苄基氧基)羰基]氨基}-4-氧丁基](2-环己基乙基)次膦酸
根据多组分反应的规程B从AcOH(9mL)和AcCl(425μL)中的先前产物(350mg,1.99mmol,1.0eq.)和NH2Cbz(360mg,2.39mmol,1.2eq.),随后添加4-氧代丁酸苄酯(458mg,2.38mmol,1.2eq.)的AcOH(5mL)溶液来制备标题化合物(654mg,66%),其获得为白色固体。
MS(ESI-):[M-H]-=474.2
MS(ESI+):[M+H]+=476.2
1H NMR(500MHz,MeOD)δ(ppm):7.41-7.21(m,10H);5.23-4.97(m,4H);3.96(m,1H);2.60-2.42(m,2H);2.32-2.14(m,1H);1.86(m,1H);1.73-1.60(m,7H);1.44(m,2H);1.28-1.10(m,4H);0.85(p,J=11.6Hz,2H)
31P NMR(CD3OD,202MHz)δ(ppm):51.4
步骤3:4-氨基-4-[(2-环己基乙基)(羟基)磷酰基]丁酸
根据氢解的规程E从混合物EtOH/AcOH(1:1,9mL)中的先前产物(250mg,0.498mmol,1.0eq.)来制备标题化合物(63mg,46%),其获得为米色固体。
预期纯度:95%(基于LCMS和NMR)
MS(ESI-):[M-H]-=276.2;[(Mx2)-H]-=553.3;[(Mx3)-H]-=830.6
MS(ESI+):[(M-H2O)+H]+=260.2;[M+H]+=278.2;[(Mx2)+H]+=555.3;[(Mx3)+H]+=832.7
1H NMR(500MHz,MeOD)δ(ppm):3.14-3.04(m,1H);2.64-2.57(m,2H);2.27-2.14(m,1H);2.00-1.86(m,1H);1.82-1.45(m,9H);1.33-1.13(m,4H);1.01-0.86(m,2H)
31P NMR(CD3OD,202MHz)δ(ppm):33.1
实施例8:4-氨基-4-[(环丁基甲基)(羟基)磷酰基]丁酸
步骤1:(环丁基甲基)次膦酸
根据规程A从无水Et2O(6mL)中的氯亚磷酸二乙酯(1.26mL,11.5mmol,1.0eq.),随后添加从无水Et2O(6mL)中的(溴甲基)环丁烷(1.4g,9.4mmol,1.05eq.)新鲜制备的格氏试剂来制备标题化合物(290mg,24%)。
MS(ESI+):[M+H]+=177
1H NMR(500MHz,MeOD)δ(ppm):6.97(dt,J=533.5,2.1Hz,1H),2.76-2.58(m,1H);2.25-2.13(m,2H),1.99-1.76(m,6H)
31P NMR(CD3OD,202MHz)δ(ppm):33.1
步骤2:[4-(苄基氧基)-1-{[(苄基氧基)羰基]氨基}-4-氧丁基](2-环丁基甲基)次膦酸
根据多组分反应的规程B从AcOH(5mL)和AcCl(463μL)中的先前产物(290mg,2.16mmol,1.0eq.)和NH2Cbz(392mg,2.59mmol,1.2eq.),随后添加4-氧代丁酸苄酯(498mg,2.59mmol,1.2eq.)的AcOH(4mL)溶液来制备标题化合物(707mg,71%),其获得为白色固体。
MS(ESI+):[M+H]+=458
1H NMR(500MHz,MeOD)δ(ppm):7.39-7.21(m,10H);5.17-5.01(m,4H);3.89(s,1H);2.64(m,1H);2.48(m,2H);2.26-1.96(m,3H);1.95-1.60(m,7H)
31P NMR(CD3OD,202MHz)δ(ppm):49.4
步骤3:4-氨基-4-[(环丁基甲基)(羟基)磷酰基]丁酸
根据氢解的规程E从混合物EtOH/AcOH(1:1,9mL)中的先前产物(250mg,0.544mmol,1.0eq.)来制备标题化合物(45mg,35%),其获得为米色固体。
预期纯度:97%(基于LCMS)和95%(基于NMR)
MS(ESI-):[M-H]-=234.1;[(Mx2)-H]-=469.2;[(Mx3)-H]-=704.5
MS(ESI+):[(M-H2O)+H]+=218.2;[M+H]+=236.2;[(Mx2)+H]+=471.2;[(Mx3)+H]+=706.4
1H NMR(500MHz,MeOD)δ(ppm):3.02-2.96(m,1H);2.75-2.65(m,1H);2.62-2.56(m,2H);2.22-2.14(m,3H);1.97-1.85(m,2H);1.85-1.77(m,3H);1.74(dd,J=12.9,7.4Hz,2H)
31P NMR(CD3OD,202MHz)δ(ppm):31.1
实施例9:4-氨基-4-[(环戊基甲基)(羟基)磷酰基]丁酸
步骤1:(环戊基甲基)次膦酸
根据规程A从无水Et2O(6mL)中的氯亚磷酸二乙酯(1.26mL,11.5mmol,1.0eq.),随后添加从无水Et2O(6mL)中的(溴甲基)环戊烷(2.0g,12.3mmol,1.05eq.)新鲜制备的格氏试剂来制备标题化合物(607mg,36%)。
1H NMR(500MHz,MeOD)δ(ppm):7.06(dt,J=534.5,2.1Hz,1H);2.20-2.08(m,1H),1.98-1.89(m,2H),1.82(mm,2H),1.73-1.65(m,2H),1.63-1.54(m,2H),1.33-1.21(m,2H)
31P NMR(CD3OD,202MHz)δ(ppm):34.4
步骤2:[4-(苄基氧基)-1-{[(苄基氧基)羰基]氨基}-4-氧丁基](环戊基甲基)次膦酸
根据多组分反应的规程B从AcOH(5mL)和AcCl(433μL)中的先前产物(300mg,2.03mmol,1.0eq.)和NH2Cbz(367mg,2.43mmol,1.2eq.),随后添加4-氧代丁酸苄酯(467mg,2.43mmol,1.2eq.)的AcOH(4mL)溶液来制备标题化合物(541mg,56%),其获得为白色固体。
MS(ESI-):[M-H]-=472.2
MS(ESI+):[M+H]+=274.1
1H NMR(500MHz,MeOD)δ(ppm):7.44-7.18(m,10H);5.21-4.97(m,4H);3.93(m,1H);2.57-2.42(m,2H);2.28-2.17(m,1H);2.12(m,1H);1.84(m,3H);1.79-1.69(m,2H);1.67-1.57(m,2H);1.53(m,2H);1.17(m,2H)
31P NMR(CD3OD,202MHz)δ(ppm):49.8
步骤3:4-氨基-4-[(环戊基甲基)(羟基)磷酰基]丁酸
根据氢解的规程E从混合物EtOH/AcOH(1:1,9mL)中的先前产物(250mg,0.528mmol,1.0eq.)来制备标题化合物(62mg,47%),其获得为米色固体。
预期纯度:95%(基于LCMS)和93%(基于NMR)
MS(ESI-):[M-H]-=248.2;[(Mx2)-H]-=497.2;[(Mx3)-H]-=746.5
MS(ESI+):[(M-H2O)+H]+=232.2;[M+H]+=250.2;[(Mx2)+H]+=499.3;[(Mx3)+H]+=748.5
1H NMR(500MHz,MeOD)δ(ppm):3.10-3.01(m,1H);2.64-2.55(m,2H);2.27-2.12(m,2H);2.02-1.87(m,3H);1.72-1.61(m,4H);1.61-1.51(m,2H);1.31-1.19(m,2H)
31P NMR(CD3OD,202MHz)δ(ppm):31.6
实施例10:4-氨基-4-[(环己基甲基)(羟基)磷酰基]丁酸
步骤1:(环己基甲基)次膦酸
根据规程A从无水Et2O(6mL)中的氯亚磷酸二乙酯(1.15mL,10.5mmol,1.0eq.),随后添加从无水Et2O(5mL)中的(溴甲基)环己烷(2.0g,11.0mmol,1.05eq.)新鲜制备的格氏试剂来制备标题化合物(475mg,28%)。
MS(ESI+):[M+H]+=163.2;[(Mx2)+H]+=325.2
1H NMR(500MHz,MeOD)δ(ppm):7.01(dt,J=533.6,2.2Hz,1H);1.90-1.82(m,2H);1.75-1.62(m,6H);1.34-1.27(m,2H);1.24-1.17(m,1H);1.15-1.04(m,2H)
31P NMR(CD3OD,202MHz)δ(ppm):33.7
步骤2:[4-(苄基氧基)-1-{[(苄基氧基)羰基]氨基}-4-氧丁基](环己基甲基)次膦酸
根据多组分反应的规程B从AcOH(4mL)和AcCl(396μL)中的先前产物(300mg,1.85mmol,1.0eq.)和NH2Cbz(335mg,2.22mmol,1.2eq.),随后添加4-氧代丁酸苄酯(426mg,2.22mmol,1.2eq.)的AcOH(3mL)溶液来制备标题化合物(501mg,55%),其获得为白色固体。
MS(ESI+):[M+H]+=488.2;[(Mx2)+H]+=975.6
1H NMR(500MHz,MeOD)δ(ppm):7.40-7.23(m,10H);5.17-5.01(m,4H);3.90(t,J=9.4Hz,1H);2.56-2.41(m,2H);1.96-1.45(m,10H);1.35-1.20(m,3H);1.06-0.93(m,2H)
步骤3:4-{[(苄基氧基)羰基]氨基}-4-[(环己基甲基)(羟基)磷酰基]丁酸
根据规程C在存在LiOH.H2O(43mg,1.03mmol,2.0eq.)的情况下从THF/水(2/1,5mL)混合物中的先前产物(250mg,0.513mmol,1.0eq.)来制备标题化合物(205mg,100%),其获得为白色固体。
MS(ESI-):[M-H]-=396.2;[(Mx2)-H]-=793.4
MS(ESI+):[M+H]+=398.2;[(Mx2)+H]+=795.4
1H NMR(500MHz,MeOD)δ(ppm):7.42-7.22(m,5H);5.22-5.03(m,2H);3.97-3.86(m,1H);2.51-2.33(m,2H);2.26-2.13(m,1H);1.92-1.53(m,9H);1.35-1.11(m,3H);1.07-0.93(m,2H)
31P NMR(CD3OD,202MHz)δ(ppm):33.1
步骤4:4-氨基-4-[(环己基甲基)(羟基)磷酰基]丁酸
根据规程D从TFA/苯甲醚(1.5mL/355μL)中的先前产物(205mg,510μmol,1.0eq.)来制备标题化合物(27mg,20%),其获得为米色固体。
估计纯度:90%(基于NMR)
MS(ESI-):[M-H]-=262.2;[(Mx2)-H]-=525.3;[(Mx3)-H]-=788.6
MS(ESI+):[(M-H2O)+H]+=246.2;[M+H]+=264.2
1H NMR(400MHz,MeOD)δ(ppm):3.07-2.97(m,1H),2.59(t,J=7.6Hz,2H);2.28-2.12(m,1H);1.99-1.60(m,7H);1.55-1.46(m,2H);1.40-1.26(m,2H);1.26-1.14(m,1H);1.12-0.99(m,2H)
31P NMR(CD3OD,202MHz)δ(ppm):31.8
实施例11:体外APA活性的测量
体外APA活性的测量基于已根据微孔板(Pro BindTM 3915)的测定规模进行了调整的Goldbarg的方案(Chauvel et al.,1994)。在体外,在存在钙离子的情况下,APA将合成的底物α-L-谷氨酰基-β-萘酰胺(GluβNa)水解为谷氨酸盐和β-萘胺(βNa)。在酸性介质中进行重氮化(diazotation)反应使得可以通过形成紫色复合物来揭示β-萘胺:然后通过分光光度法测量,可以了解所形成的复合物的量,并且通过参考随着浓度增加的β-萘胺产生的标准曲线来推断样品的酶促活性。
试剂
将Glu-βNa底物(Bachem)和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的浓度保存。重氮化反应在存在亚硝酸钠(87mM)、氨基磺酸铵(130mM)和N-(1-萘基)-乙二胺二盐酸盐(95%乙醇中23mM)的情况下进行。
酶促反应
反应在存在钙(4mM CaCl2)的情况下,在pH 7.4的50mM tris-HCl缓冲液中进行;重组小鼠APA在存在底物(200μM Glu-βNa)的情况下,在存在或不存在各种浓度的待测试的抑制剂的情况下于37℃温育,最终体积为100μL。通过添加10μL的3N HCl终止反应。通过在0.1N HCl中重氮化增加浓度(高达0.2mM)的2-萘胺,平行制备β-萘胺的标准曲线。
成型产品的揭示
向每个孔中添加以下物质:25μL的亚硝酸钠(NaNO2)(混合,在室温下等待5分钟),50μL的氨基磺酸铵(混合,在室温下等待5分钟),然后添加25μL的N-(1-萘基)乙二胺二盐酸盐(混合,等待紫色稳定,在37℃下约30分钟)。
然后在540nm处测量吸光度。
申请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中报告的结果表明,最佳化合物(a类)显示出最高的APA抑制活性,比参考化合物大至少20倍。
表1.示例性抑制剂对氨肽酶A的体外抑制
Claims (9)
2.根据权利要求1的化合物,其中所述化合物对应于通式(I),且更具体地式(II),其中:
-m是0或1;和/或
-AH是CO2H或SO3H或PO3H2;和/或
-R1表示卤素原子,烷基基团,卤代烷基基团,烷氧基基团,卤代烷氧基基团,O-环烷基基团,O-芳基基团,O-芳基烷基基团,杂烷基基团,卤代烷基基团,环烷基基团,酰基基团,芳基基团或芳基烷基基团。
4.根据权利要求1或2的化合物,其选自下组:
4-氨基-4-[羟基(3-甲基丁基)磷酰基]丁酸,
4-氨基-4-[羟基(4-甲基戊基)磷酰基]丁酸,
4-氨基-4-[(2-环己基乙基)(羟基)磷酰基]丁酸,
4-氨基-4-[羟基(戊基)磷酰基]丁酸,
4-氨基-4-[己基(羟基)磷酰基]丁酸,
4-氨基-4-[(环丁基甲基)(羟基)磷酰基]丁酸,
4-氨基-4-[(环戊基甲基)(羟基)磷酰基]丁酸,
4-氨基-4-[羟基(5-甲基己基)磷酰基]丁酸,
4-氨基-4-[羟基(4,4,4-三氟丁基)磷酰基]丁酸,
4-氨基-4-[(环己基甲基)(羟基)磷酰基]丁酸,和
4-氨基-4-[羟基({[(丙-2-基)氨基]甲基})磷酰基]丁酸。
5.根据前述权利要求中任一项的化合物,其用作药物。
6.药物组合物,其包含至少一种如权利要求1-4中任一项所定义的化合物,优选与药学上可接受的稀释剂或载体结合。
7.根据权利要求1-4中任一项的化合物或根据权利要求6的药物,其用于治疗动脉高血压和直接或间接相关的疾病。
8.根据权利要求7使用的化合物或组合物,其用于治疗与动脉高血压直接或间接相关的病症,所述病症在下组中选择:心脏病,心力衰竭,中风,外周和/或脑血管系统疾病,脑、眼和/或肾疾病。
9.根据权利要求7使用的化合物或组合物,其用于治疗在下组中选择的病症:原发性和/或继发性动脉高血压、猝发、心肌缺血、心脏功能不全、肾功能不全、心肌梗死、周围血管疾病、糖尿病性蛋白尿、X综合征、青光眼、神经变性疾病和记忆障碍。
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EP18306398.1 | 2018-10-26 | ||
EP18306398 | 2018-10-26 | ||
PCT/EP2019/079288 WO2020084147A1 (en) | 2018-10-26 | 2019-10-25 | Novel aminophosphinic derivatives as aminopeptidase a inhibitors |
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EP (1) | EP3870590A1 (zh) |
JP (1) | JP7137010B2 (zh) |
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CN (1) | CN113166180A (zh) |
AR (1) | AR116854A1 (zh) |
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CA (1) | CA3113391A1 (zh) |
EA (1) | EA202191151A1 (zh) |
IL (1) | IL282484B (zh) |
MX (1) | MX2021004728A (zh) |
TW (1) | TW202029965A (zh) |
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TW202207917A (zh) * | 2020-05-06 | 2022-03-01 | 法商量子基因科技有限公司 | 包含腦胺肽酶抑制劑、利尿劑及全身性腎素-血管收縮素系統阻斷劑之醫藥組合物 |
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FR2773712B1 (fr) | 1998-01-16 | 2000-06-02 | Inst Nat Sante Rech Med | Composition pharmaceutique comprenant au moins un inhibiteur de l'aminopeptidase a |
TW202029962A (zh) * | 2018-10-26 | 2020-08-16 | 法商量子基因科技有限公司 | 胺肽酶a抑制劑及包含其的醫藥組合物 |
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US20140271926A1 (en) * | 2013-03-12 | 2014-09-18 | California Institute Of Technology | Methods of use of glutamine synthetase inhibitors |
Non-Patent Citations (2)
Title |
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DIEL, PETER J. ET AL.: "Organic phosphorus compounds. 79. Preparation and properties of α-amino-ω-carboxyalkylphosphonic and -phosphinic acids", PHOSPHORUS AND SULFUR AND THE RELATED ELEMENTS * |
LEJCZAK, BARBARA ET AL.: "Inhibition of aminopeptidases by phosphonic acid and phosphinic acid analogs of aspartic and glutamic acids", JOURNAL OF ENZYME INHIBITION * |
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US20210309677A1 (en) | 2021-10-07 |
WO2020084147A1 (en) | 2020-04-30 |
IL282484B (en) | 2022-03-01 |
IL282484A (en) | 2021-06-30 |
KR20210090636A (ko) | 2021-07-20 |
AR116854A1 (es) | 2021-06-23 |
JP2021535188A (ja) | 2021-12-16 |
AU2019364708B2 (en) | 2021-07-29 |
CA3113391A1 (en) | 2020-04-30 |
BR112021007041A2 (pt) | 2021-07-20 |
JP7137010B2 (ja) | 2022-09-13 |
KR102380036B1 (ko) | 2022-03-28 |
MX2021004728A (es) | 2021-10-13 |
EP3870590A1 (en) | 2021-09-01 |
TW202029965A (zh) | 2020-08-16 |
ZA202103581B (en) | 2022-08-31 |
EA202191151A1 (ru) | 2021-07-15 |
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