CN103687846A - 作为血浆激肽释放酶抑制剂的苄胺衍生物 - Google Patents
作为血浆激肽释放酶抑制剂的苄胺衍生物 Download PDFInfo
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- CN103687846A CN103687846A CN201280033711.8A CN201280033711A CN103687846A CN 103687846 A CN103687846 A CN 103687846A CN 201280033711 A CN201280033711 A CN 201280033711A CN 103687846 A CN103687846 A CN 103687846A
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- Prior art keywords
- phenyl
- formyl
- ethyl
- oxyethyl group
- amino methyl
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Abstract
本发明提供下式(I)的化合物;包含这样的化合物的组合物;这样的化合物在治疗(例如在治疗或预防其中涉及血浆激肽释放酶活性的疾病或病症)中的用途;以及用这样的化合物治疗患者的方法;其中R1至R9如本文所定义。
Description
本发明涉及苄胺衍生物并且涉及含有这样的衍生物的药物组合物和这样的衍生物的用途。
发明背景
本发明的苄胺衍生物是血浆激肽释放酶的抑制剂并且具有大量治疗应用,尤其是治疗与糖尿病视网膜病和糖尿病黄斑水肿相关的视网膜血管通透性。
血浆激肽释放酶一种可以从激肽原释放激肽的胰蛋白酶样丝氨酸蛋白酶(参见K.D.Bhoola等,"Kallikrein-Kinin Cascade(激肽释放酶-激肽级联)",Encyclopedia of Respiratory Medicine(呼吸医学百科全书),p483-493;J.W.Bryant等,"Human plasma kallikrein-kinin system:physiological andbiochemical parameters(人血浆激肽释放酶-激肽系统:生理生化参数)"Cardiovascular and haematological agents in medicinal chemistry(药物化学中的心血管和血液病药剂),7,p234-250,2009;K.D.Bhoola等,Pharmacological Rev.,1992,44,1;和D.J.Campbell,"Towardsunderstanding the kallikrein-kinin system:insights from the measurement ofkinin peptides(对激肽释放酶-激肽系统的理解:来自激肽肽类测量的观察结果)",Brazilian Journal of Medical and Biological Research2000,33,665-677)。虽然血浆激肽释放酶在内在凝血级联中的作用不涉及缓激肽的释放或酶裂解,但是它是该级联的必需成员。血浆前激肽释放酶由单一基因编码并在肝脏中合成。其作为无活性的血浆前激肽释放酶由肝细胞分泌,该血浆前激肽释放酶作为与高分子量激肽原结合的异二聚体复合物在血浆中循环,其被活化而产生具有活性的血浆激肽释放酶。激肽是通过G-蛋白偶联受体起作用的炎症的有效介体,并且激肽的拮抗剂(如缓激肽拮抗剂)之前已经研究作为用于治疗多种病症的潜在治疗剂(F.Marceau和D.Regoli,Nature Rev.,Drug Discovery(药物发现),2004,3,845-852)。
血浆激肽释放酶被认为在多种炎性病症中起作用。血浆激肽释放酶的主要抑制剂为丝氨酸蛋白酶抑制蛋白C1酯酶抑制剂(serpin C1esteraseinhibitor)。存在C1酯酶抑制剂遗传缺陷的患者发生遗传性血管性水肿(HAE),其导致脸、手、咽喉、胃肠道和生殖器的间歇性肿胀。急性发病期间所形成的水泡含有高水平的血浆激肽释放酶,其裂解高分子量激肽原释放缓激肽,导致血管通透性增加。利用大蛋白血浆激肽释放酶抑制剂的治疗已显示通过阻止引起血管通透性增加的缓激肽的释放而有效治疗HAE(A.Lehmann"Ecallantide(DX-88),a plasma kallikrein inhibitor for thetreatment of hereditary angioedema and the prevention of blood loss inon-pump cardiothoracic surgery(用于治疗遗传性血管水肿和防止泵上胸心外科手术中失血的血浆激肽释放酶抑制剂)"Expert Opin.Biol.Ther.8,p1187-99)。
血浆激肽释放酶-激肽系统在患有晚期糖尿病性黄斑水肿的患者中异常地丰富。最近已公开,血浆激肽释放酶有助于糖尿病大鼠的视网膜血管功能障碍(A.Clermont等"Plasma kallikrein mediates retinal vasculardysfunction and induces retinal thickening in diabetic rats(血浆激肽释放酶介导视网膜血管功能障碍并减少糖尿病大鼠的视网膜增厚)"Diabetes(糖尿病),2011,60,p1590-98)。此外,施用血浆激肽释放酶抑制剂ASP-440减轻糖尿病大鼠的视网膜血管通透性和视网膜血液流动异常。因此,血浆激肽释放酶抑制剂应该具有作为减轻与糖尿病视网膜病和糖尿病黄斑水肿相关的视网膜血管通透性的治疗剂的效用。
合成的和小分子血浆激肽释放酶抑制剂之前已被描述,例如由以下描述:Garrett等("Peptide aldehyde…."J.Peptide Res.52,p62-71(1998)),T.Griesbacher等("Involvement of tissue kallikrein but not plasma kallikrein inthe development of symptoms mediated by endogenous kinins in acutepancreatitus in rats(由大鼠急性胰腺炎中的内源性激肽介导的症状的发展中涉及组织激肽释放酶而不是血浆激肽释放酶)"British Journal ofPharmacology137,p692-700(2002)),Evans("Selective dipeptide inhibitorsof kallikrein(激肽释放酶的选择性二肽抑制剂)"WO03/076458),Szelke等("Kininogenase inhibitors(激肽原酶抑制剂)"WO92/04371),D.M.Evans等(Immunolpharmacology,32,p115-116(1996)),Szelke等("Kininogeninhibitors(激肽原抑制剂)"WO95/07921),Antonsson等("New peptidesderivatives(新型肽衍生物)"WO94/29335),J.Stürzbecher等(Brazilian J.Med.Biol.Res27,p1929-34(1994)),Kettner等(US5,187,157),N.Teno等(Chem.Pharm.Bull.41,p1079-1090(1993)),W.B.Young等("Smallmolecule inhibitors of plasma kallikrein(血浆激肽释放酶的小分子抑制剂)"Bioorg.Med.Chem.Letts.16,p2034-2036(2006)),Okada等("Developmentof potent and selective plasmin and plasma kallikrein inhibitors and studies onthe structure-activity relationship(有效且选择性的纤溶酶和血浆激肽释放酶抑制剂的开发以及构效关系的研究)"Chem.Pharm.Bull.48,p1964-72(2000)),Steinmetzer等("Trypsin-like serine protease inhibitors and theirpreparation and use(胰蛋白酶样丝氨酸蛋白酶抑制剂及其制备和用途)"WO08/049595),Zhang等("Discovery of highly potent small moleculekallikrein inhibitors(高度有效的小分子激肽释放酶抑制剂的发现)"Medicinal Chemistry2,p545-553(2006)),Sinha等("Inhibitors of plasmakallikrein(血浆激肽释放酶抑制剂)"WO08/016883),和Brandl等(“N-((6-amino-pyridin-3-yl)methyl)-heteroaryl-carboxamides as inhibitors ofplasma kallikrein(作为血浆激肽释放酶的抑制剂的N-((6-氨基-吡啶-3-基)甲基)-杂芳基-甲酰胺”WO2012/017020)。而且,Steinmetzer等(“Serineprotease inhibitors(丝氨酸蛋白酶抑制剂)”WO2012/004678)描述了作为人类纤溶酶和血浆激肽释放酶的抑制剂的环状肽类似物。
至今,没有小分子的合成血浆激肽释放酶抑制剂已被批准用于医学用途。已知技术中描述的分子具有限制,如在相关酶如KLK1、凝血酶和其他丝氨酸蛋白酶方面的较差选择性,以及较差的口服利用性。大蛋白血浆激肽释放酶抑制剂存在过敏性反应的风险,如对艾卡仑肽(Ecallantide)所报道的。因此,对于选择性抑制血浆激肽释放酶、不诱发过敏反应以及口服可利用的化合物仍存在需求。此外,已知技术中的分子具有高度极性和可离子化胍或脒官能度的特征。众所周知,这样的官能度可能局限于肠通透性,且因此局限于口服可利用性。
糖尿病的其他并发症如脑出血、肾病(nepropathy)、心肌病和神经病,所有这些与血浆激肽释放酶相关,也可被视为血浆激肽释放酶抑制剂的靶标。
发明概述
本发明涉及一系列作为血浆激肽释放酶的抑制剂的苄胺化合物。这些化合物显示对于血浆激肽释放酶的良好选择性并且潜在地可用于治疗受损视敏度,糖尿病视网膜病,黄斑水肿,遗传性血管性水肿,糖尿病,胰腺炎(pancreatitus),脑出血,肾病(nepropathy),心肌病,神经病,炎性肠病(inflammaotory bowel disease),关节炎,炎症,感染性休克,低血压,癌症,成人呼吸窘迫综合征,弥散性血管内凝血,心肺旁路手术和外科手术后出血。本发明还涉及所述抑制剂的药物组合物、所述组合物作为治疗剂的用途、以及使用这些组合物的治疗方法。
在一方面,本发明提供式I的化合物
其中:
R1选自H,烷基,-CO烷基,-CO芳基,-CO杂芳基,-CO2烷基,-(CH2)aOH,-(CH2)bCOOR10,-(CH2)cCONH2,-SO2烷基,-SO2芳基,-SO2(CH2)hR13,-CO(CH2)iR14,-CO环烷基,-COCH=CHR15,-CO(CH2)jNHCO(CH2)kR16和-CONR17R18;
R2选自H和烷基;
R3选自H,烷基,-(CH2)d芳基,-(CH2)e杂芳基,-(CH2)f环烷基,-(CH2)g杂环烷基,-CH(环烷基)2,-CH(杂环烷基)2和-(CH2)l芳基-O-(CH2)m-芳基;
R4和R6独立地选自H和烷基;
R5选自H,烷基,烷氧基和OH;
或R4和R5,连同它们连接的原子一起可以连接形成5或6元氮杂环烷基结构;
R7和R8独立地选自H,烷基,烷氧基,CN,卤素和CF3;
R9是芳基或杂芳基;
R10是H或烷基;
a,b,c,d,e,f,g,h,i,j,l和m独立地是1,2或3;
k是0,1,2或3;
*1和*2表示手性中心;
烷基是具有至多可达10个碳原子(C1-C10)的直链饱和烃或具有3至10个碳原子(C3-C10)的支链饱和烃;烷基可以任选地被1或2个独立地选自(C3-C10)环烷基,(C1-C6)烷氧基,OH,CN,CF3,COOR11,氟和NR11R12的取代基取代;
环烷基为3至10个碳原子的单环或双环饱和烃;环烷基可以任选地与芳基稠合;或环烷基是金刚烷基;
杂环烷基是C-连接或N-连接的3至10元饱和的单环或双环,其中所述杂环烷基的环在可能的情况下含有1、2或3个独立地选自N、NR11和O的杂原子;
烷氧基是1至6个碳原子(C1-C6)的直链O-连接烃或3至6个碳原子(C3-C6)的支链O-连接烃;烷氧基可以任选地被1或2个独立地选自(C3-C10)环烷基、OH、CN、CF3、COOR11、氟和NR11R12的取代基取代;
芳基是苯基、联苯基或萘基;芳基可以任选地被至多可达5个独立地选自烷基、烷氧基、OH、卤素、CN、COOR11、CF3和NR11R12的取代基取代;
杂芳基是5、6、9或10元单环或双环芳族环,其在可能的情况下含有1、2或3个独立地选自N、NR11、S和O的环成员;杂芳基可以任选地被1、2或3个独立地选自烷基、烷氧基、OH、卤素、CN、COOR11、CF3、NR11R12和NHR19的取代基取代;
R11和R12独立地选自H和烷基;
R13是芳基或杂芳基;
R14是芳基,杂芳基,环烷基或杂环烷基;
R15是H,烷基,芳基,杂芳基,环烷基或杂环烷基;
R16是H,芳基或杂芳基;
R17是H,烷基,芳基,杂芳基或杂环烷基;
R18是-(CH2)mR21,其中m是0,1,2或3并且R21是H,芳基或杂芳基;
R19-CO烷基,-CO芳基或-CO杂芳基;
及其互变异构体、异构体、立体异构体(包括对映异构体、非对映异构体及其外消旋及非外消旋(scalemic)混合物)、药用盐和溶剂化物。
在另一方面,本发明提供如本文所定义的式(I)化合物的前药,或其药用盐。
在另一方面,本发明提供如本文所定义的式(I)化合物的N-氧化物,或其前药或药用盐。
应理解,本发明的某些化合物可以以溶剂化例如水化形式以及非溶剂化形式存在。应理解,本发明涵盖所有这样的溶剂化形式。
在一方面,本发明包含所述式(I)化合物的子集,其中:
R1选自H,烷基,-CO烷基,-CO芳基,-CO杂芳基,-CO2烷基,-(CH2)aOH,-(CH2)bCOOR10,-(CH2)cCONH2,-SO2烷基和-SO2芳基;
R2选自H和烷基;
R3选自H,烷基,-(CH2)d芳基,-(CH2)e杂芳基,-(CH2)f环烷基,-(CH2)g杂环烷基,-CH(环烷基)2和-CH(杂环烷基)2;
R4和R6独立地选自H和烷基;
R5选自H,烷基,烷氧基和OH;
或R4和R5,连同它们连接的原子一起可以连接形成5或6元氮杂环烷基结构;
R7和R8独立地选自H,烷基,烷氧基,CN和卤素;
R9是芳基或杂芳基;
R10是H或烷基;
a,b,c,d,e,f和g独立地是1,2或3;
*1和*2表示手性中心;
烷基是具有至多可达10个碳原子(C1-C10)的直链饱和烃或具有3至10个碳原子(C3-C10)的支链饱和烃;烷基可以任选地被1或2个独立地选自(C3-C10)环烷基,(C1-C6)烷氧基,OH,CN,CF3,COOR11,氟和NR11R12的取代基取代;
环烷基为3至10个碳原子的单环或双环饱和烃;环烷基可以任选地与芳基稠合;
杂环烷基是C-连接或N-连接的3至10元饱和的单环或双环,其中所述杂环烷基的环在可能的情况下含有1、2或3个独立地选自N、NR11和O的杂原子;
烷氧基是1至6个碳原子(C1-C6)的直链O-连接烃或3至6个碳原子(C3-C6)的支链O-连接烃;烷氧基可以任选地被1或2个独立地选自(C3-C10)环烷基、OH、CN、CF3、COOR11、氟和NR11R12的取代基取代;
芳基是苯基、联苯基或萘基;芳基可以任选地被至多可达5个独立地选自烷基、烷氧基、OH、卤素、CN、COOR11、CF3和NR11R12的取代基取代;
杂芳基是5、6、9或10元单环或双环芳族环,其在可能的情况下含有1、2或3个独立地选自N、NR11、S和O的环成员;杂芳基可以任选地被1、2或3个独立地选自烷基、烷氧基、OH、卤素、CN、COOR11、CF3和NR11R12的取代基取代;
R11和R12独立地选自H和烷基;
及其互变异构体、异构体、立体异构体(包括对映异构体、非对映异构体及其外消旋及非外消旋混合物)、药用盐和溶剂化物。
在另一方面,本发明包含所述式(I)化合物的子集,其中:
R1选自H,烷基,-CO烷基,-CO芳基,-CO2烷基,-CH2CH2OH,-CH2COOR10,-CH2CONH2,-SO2烷基和-SO2芳基;
R2选自H和烷基;
R3选自烷基,-CH2芳基,-CH2环烷基和-CH(环烷基)2;
R4和R6独立地选自H和烷基;
R5选自H,烷基,和OH;
或R4和R5,连同它们连接的原子一起可以连接形成5或6元氮杂环烷基结构;
R7和R8独立地选自H,F,和Cl;
R9是芳基;
R10是H或烷基;
*1和*2表示手性中心;
烷基是具有至多可达6个碳原子(C1-C6)的直链饱和烃或具有3至6个碳原子(C3-C6)的支链饱和烃;烷基可以任选地被1或2个独立地选自(C3-C10)环烷基,(C1-C6)烷氧基,OH,CN,CF3,COOR11,氟和NR11R12的取代基取代;
环烷基为3至10个碳原子的单环或双环饱和烃;
烷氧基是1至6个碳原子(C1-C6)的直链O-连接烃或3至6个碳原子(C3-C6)的支链O-连接烃;烷氧基可以任选地被1或2个独立地选自(C3-C10)环烷基、OH、CN、CF3、COOR11、氟和NR11R12的取代基取代;
芳基是苯基、联苯基或萘基;芳基可以任选地被至多可达5个独立地选自烷基、烷氧基、OH、卤素、CN、COOR11、CF3和NR11R12的取代基取代;
R11和R12独立地选自H和烷基;
及其互变异构体、异构体、立体异构体(包括对映异构体、非对映异构体及其外消旋及非外消旋混合物)、药用盐和溶剂化物。
本发明还包含以下方面及其组合:
在本发明的一方面,R1选自H,烷基,-CO烷基,-CO芳基,-(CH2)aOH,-(CH2)bCOOR10,-(CH2)cCONH2,-SO2烷基和-SO2芳基。
在本发明的一方面,R1选自H,烷基,-CO烷基,-CO芳基,-(CH2)aOH,-CH2COOR10,-CH2CONH2,-SO2烷基和-SO2芳基;其中a是1或2。
在本发明的一方面,R1选自H,-CO芳基,-CO烷基,-CH2COOH,-SO2Ph和-SO2CH3。
在本发明的一方面,R1选自H,-CO乙基,甲基,甲基磺酰基,-CO苯基,苯基砜,-CH2COOH,-CO-i丙基,丙基,-CH2COOCH3,-CH2CONH2,-CH2CH2OH和–CO萘基。
在本发明的一方面,R1选自-CO烷基和–CO苯基。
在本发明的一方面,R1选自H,-CO芳基,CO杂芳基,-CO烷基,-CH2COOH,-SO2Ph和-SO2CH3。
在本发明的一方面,R1选自-CO烷基,CO杂芳基和–CO芳基。
在本发明的一方面,R2选自H和甲基。
在本发明的一方面,R2是H。
在本发明的一方面,R3选自烷基,-(CH2)d芳基,-(CH2)f环烷基,和-CH(环烷基)2;其中d和f独立地是1或2。
在本发明的一方面,R3选自烷基,-CH2芳基,-CH2环烷基,和-CH(环烷基)2。
在本发明的一方面,R3选自-CH2芳基,-CH2环烷基,和-CH(环烷基)2。
在本发明的一方面,R3选自:
在本发明的一方面,R4选自H和甲基。
在本发明的一方面,R4是H。
在本发明的一方面,R5选自H,烷基和OH。
在本发明的一方面,R5选自H和OH。
在本发明的一方面,R5是H。
在本发明的一方面,R4和R5连同它们连接的原子一起结合形成吡咯烷部分。
在本发明的一方面,R4和R5连同它们连接的原子一起结合形成哌啶部分。
在本发明的一方面,R6选自H和甲基。
在本发明的一方面,R6是H。
在本发明的一方面,R7选自H,甲基和卤素。
在本发明的一方面,R7选自H,F和Cl。
在本发明的一方面,R7是H。
在本发明的一方面,R8选自H,甲基和卤素。
在本发明的一方面,R8选自H,F和Cl。
在本发明的一方面,R8选自H和F。
在本发明的一方面,R8是H。
在本发明的一方面,R9是芳基。
在本发明的一方面,R9选自苯基和萘基,其中苯基可以任选地被至多可达3个独立地选自烷基,烷氧基,OH,卤素,CN,COOR11,CF3和NR11R12的取代基取代。
在本发明的一方面,R9是苯基,其中苯基可以任选地被至多可达2个独立地选自烷基,卤素和CF3的取代基取代。
在本发明的一方面,R9选自苯基,1-萘,2,4-二氯苯基,3,4-二氯苯基,3,4-二氟苯基,4-氯苯基,4-三氟甲基苯基和4-乙氧基苯基。
在本发明的一方面,R9选自苯基,杂芳基和萘基,其中苯基可以任选地被至多可达3个独立地选自烷基,烷氧基,OH,卤素,CN,COOR11,CF3和NR11R12的取代基取代。
在本发明的一方面,R9选自苯基,1-萘,3,4-二氯苯基,3,4-二氟苯基,4-氯苯基,4-氟苯基,3-氟苯基,4-三氟甲基苯基,吡啶-3-基(pyrid-3-yl),吡啶-2-基,吡啶-4-基,苯并噻吩-3-基,噻吩-2-基,噻吩-3-基,吲哚-3-基,和噻唑-4基。
在本发明的一方面,R10是H或甲基。
在本发明的一方面,手性中心*1周围的立体化学构型为R。
在本发明的一方面,手性中心*2周围的立体化学构型为S。
在本发明的一方面,a是2并且b,c,d,e,f和g是1。
在本发明的一方面,a是2并且b,c,d,e,f,g,h,j,l和m是1。
在本发明的一方面,k是0或1。
在一方面,本发明包括选自以下的化合物:
(S)-N-(4-氨基甲基-苄基)-2-[(R)-3-(4-乙氧基-苯基)-2-丙酰氨基-丙酰氨基]-3-苯基-丙酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-苯甲酰胺;
{(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-环己基-乙基氨基}-乙酸;
(S)-N-(4-氨基甲基-3-氟-苄基)-2-[(R)-3-(4-乙氧基-苯基)-2-丙酰氨基-丙酰氨基]-3-苯基-丙酰胺;
(S)-N-(4-氨基甲基-2-氯-苄基)-2-[(R)-3-(4-乙氧基-苯基)-2-丙酰氨基-丙酰氨基]-3-苯基-丙酰胺;
(S)-N-(4-氨基甲基-苄基)-3-(3,4-二氯-苯基)-2-[(R)-3-(4-乙氧基-苯基)-2-丙酰氨基-丙酰氨基]-丙酰胺;
(S)-N-(4-氨基甲基-3-氯-苄基)-2-[(R)-3-(4-乙氧基-苯基)-2-丙酰氨基-丙酰氨基]-3-苯基-丙酰胺;
(S)-N-(4-氨基甲基-苄基)-2-{[(R)-3-(4-乙氧基-苯基)-2-丙酰氨基-丙酰]-甲基-氨基}-3-苯基-丙酰胺;
({(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-环己基-乙基}-甲基-氨基)-乙酸;
(S)-N-(4-氨基甲基-3-氟-苄基)-2-{[(R)-3-(4-乙氧基-苯基)-2-丙酰氨基-丙酰]-甲基-氨基}-3-苯基-丙酰胺;
N-[(R)-1-{[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基]-甲基-氨基甲酰}-2-(4-乙氧基-苯基)-乙基]-苯甲酰胺;
N-[(R)-1-{[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基]-甲基-氨基甲酰}-2-(4-乙氧基-苯基)-乙基]-异丁酰胺;
萘-1-甲酸[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-4-氯-苯甲酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-2,4-二氯-苯甲酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-3,4-二氟-苯甲酰胺;
(R)-2-氨基-N-[(1S,2S)-1-(4-氨基甲基-苄基氨基甲酰)-2-羟基-2-苯基-乙基]-3-(4-乙氧基-苯基)-丙酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-烟酰胺;
(2S,3S)-N-(4-氨基甲基-苄基)-2-[(R)-3-(4-乙氧基-苯基)-2-丙酰氨基-丙酰氨基]-3-羟基-3-苯基-丙酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-异烟酰胺;
噻吩-3-甲酸-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-酰胺;
噻吩-2-甲酸[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-酰胺;
环己烷甲酸[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-酰胺;
吡啶-2-甲酸[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-酰胺;
苯并[b]噻吩-2-甲酸[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-酰胺;
(R)-N-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基]-2-(4-氯-苯磺酰氨基)-3-(4-乙氧基-苯基)-丙酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-3-氯-苯甲酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-2-氯-苯甲酰胺
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-3-三氟甲基-苯甲酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-4-甲基-苯甲酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-3,4-二氯-苯甲酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-4-甲氧基-苯甲酰胺;
(S)-N-(4-氨基甲基-苄基)-2-[(R)-3-(4-乙氧基-苯基)-2-(2-苯基乙酰氨基-乙酰氨基)-丙酰氨基]-3-苯基-丙酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-4-氟-苯甲酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-6-甲基-烟酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-2-甲基-烟酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-2,6-二氯-烟酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-5,6-二氯-烟酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-2,3,6-三氟-异烟酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-3,3,3-三氟-丙酰胺;
2,4-二甲基-噻唑-5-甲酸[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-酰胺;
2-甲基-噻唑-5-甲酸[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-酰胺;
3-氯-噻吩-2-甲酸[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-酰胺;
4-甲基-噻唑-5-甲酸[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-酰胺;
呋喃-2-甲酸[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-酰胺;
3-甲基-噻吩-2-甲酸[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-2-甲氧基-异烟酰胺;
3-甲基-1H-吡咯-2-甲酸[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-酰胺;
3-氨基-噻吩-2-甲酸[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-丙氧基-苯基)-乙基]-苯甲酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-吡啶-2-基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-苯甲酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-(3,4-二氯-苯基)-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-苯甲酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-(4-氯-苯基)-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-苯甲酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-(4-氟-苯基)-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-苯甲酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-吡啶-3-基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-苯甲酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-(4-甲氧基-苯基)-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-苯甲酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-吡啶-4-基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-苯甲酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-(3-氟-苯基)-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-苯甲酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-噻吩-2-基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-苯甲酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-噻吩-3-基-乙基氨基甲酰-2-(4-乙氧基-苯基)-乙基]-苯甲酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-噻唑-4-基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-苯甲酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯并[b]噻吩-3-基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-苯甲酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-3-氟-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-苯甲酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-3-氯-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-苯甲酰胺;
吡啶-2-甲酸[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-噻吩-2-基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-吡啶-2-基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-4-甲氧基-苯甲酰胺;
吡啶-2-甲酸[(R)-1-[(S)-1-(4-氨基甲基-3-氯-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-吡啶-3-基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-4-甲氧基-苯甲酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-(3,4-二氟-苯基)-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-异烟酰胺;
噻吩-2-甲酸[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-吡啶-3-基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-吡啶-2-基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-4-氯-苯甲酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-吡啶-2-基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-4-甲基-苯甲酰胺;
吡啶-2-甲酸[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-(3,4-二氯-苯基)-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-酰胺;
(R)-N-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-吡啶-2-基-乙基]-3-(4-乙氧基-苯基)-2-丙酰氨基-丙酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-3-氟-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-异烟酰胺;
吡啶-2-甲酸[(R)-1-[(S)-1-(4-氨基甲基-3-氟-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-酰胺;
噻吩-2-甲酸[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-(3,4-二氯-苯基)-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-酰胺;
(R)-N-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-吡啶-3-基-乙基]-3-(4-乙氧基-苯基)-2-丙酰氨基-丙酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-(3,4-二氯-苯基)-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-异烟酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-(3,4-二氯-苯基)-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-3,3,3-三氟-丙酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-吡啶-3-基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-4-氯-苯甲酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-吡啶-3-基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-4-甲基-苯甲酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-(3,4-二氟-苯基)-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-苯甲酰胺;
3-氯-噻吩-2-甲酸[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-吡啶-3-基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-(1H-吲哚-3-基)-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-苯甲酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯并[b]噻吩-3-基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-异烟酰胺;
3-乙酰氨基-噻吩-2-甲酸-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-(2-氟-苯基)-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-苯甲酰胺;
3-甲基-噻吩-2-甲酸[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-吡啶-3-基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-3-甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-苯甲酰胺;
3-氨基-噻吩-2-甲酸[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-噻唑-4-基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-酰胺;
3-氯-噻吩-2-甲酸[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-噻唑-4-基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-噻唑-4-基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-4-甲基-苯甲酰胺;
3-甲基-1H-吡咯-2-甲酸[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯并[b]噻吩-3-基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-酰胺;
3-氨基-噻吩-2-甲酸[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-噻唑-4-基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-酰胺;
3-乙酰氨基-噻吩-2-甲酸[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯并[b]噻吩-3-基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-吡啶-3-基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-3-甲基-苯甲酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-吡啶-3-基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-2-甲基-苯甲酰胺;
3,5-二甲基-1H-吡咯-2-甲酸[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-3-甲基-苄基氨基甲酰)-2-吡啶-3-基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-苯甲酰胺;
3-乙酰氨基-噻吩-2-甲酸[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-噻吩-3-基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-酰胺;
3-氨基-噻吩-2-甲酸[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯并[b]噻吩-3-基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-酰胺;
3-乙酰氨基-噻吩-2-甲酸[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯并[b]噻吩-3-基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-酰胺;
3-氯-噻吩-2-甲酸[(R)-1-{[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基]-甲基-氨基甲酰}-2-(4-乙氧基-苯基)-乙基]-酰胺;
N-[(R)-1-[(1S,2R)-1-(4-氨基甲基-苄基氨基甲酰)-2-羟基-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-苯甲酰胺;
3-氯-噻吩-2-甲酸[(R)-1-[(1S,2R)-1-(4-氨基甲基-苄基氨基甲酰)-2-羟基-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-酰胺;
N-{(R,S)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-[4-(2,2,2-三氟-乙氧基)-苯基]-乙基}-苯甲酰胺;
及其药用盐和溶剂化物。
在一方面,本发明包括选自以下的化合物:
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-苯甲酰胺;
萘-1-甲酸[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-4-氯-苯甲酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-2,4-二氯-苯甲酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-3,4-二氟-苯甲酰胺;
及其药用盐和溶剂化物。
在一方面,本发明包括选自以下的化合物:
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-苯甲酰胺;
萘-1-甲酸[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-4-氯-苯甲酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-2,4-二氯-苯甲酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-烟酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-3,4-二氟-苯甲酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-异烟酰胺;
噻吩-3-甲酸-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-酰胺;
噻吩-2-甲酸[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-酰胺;
环己烷甲酸[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-酰胺;
吡啶-2-甲酸[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-酰胺;
(R)-N-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基]-2-(4-氯-苯磺酰氨基)-3-(4-乙氧基-苯基)-丙酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-4-甲基-苯甲酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-3,4-二氯-苯甲酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-3-氯-苯甲酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-4-甲氧基-苯甲酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-4-氟-苯甲酰胺;
3-甲基-噻吩-2-甲酸[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-酰胺;
3-甲基-1H-吡咯-2-甲酸[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-酰胺;
3-氨基-噻吩-2-甲酸[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-丙氧基-苯基)-乙基]-苯甲酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-吡啶-2-基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-苯甲酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-(3,4-二氯-苯基)-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-苯甲酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-(4-氟-苯基)-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-苯甲酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-吡啶-3-基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-苯甲酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-噻吩-2-基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-苯甲酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-噻吩-3-基-乙基氨基甲酰-2-(4-乙氧基-苯基)-乙基]-苯甲酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯并[b]噻吩-3-基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-苯甲酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-3-氟-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-苯甲酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-3-氯-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-苯甲酰胺;
吡啶-2-甲酸[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-噻吩-2-基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-吡啶-2-基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-4-甲氧基-苯甲酰胺;
吡啶-2-甲酸[(R)-1-[(S)-1-(4-氨基甲基-3-氯-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-吡啶-3-基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-4-甲氧基-苯甲酰胺;
噻吩-2-甲酸[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-吡啶-3-基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-吡啶-3-基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-4-甲基-苯甲酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-(3,4-二氟-苯基)-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-苯甲酰胺;
3-氯-噻吩-2-甲酸[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-酰胺;
3-氯-噻吩-2-甲酸[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-吡啶-3-基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-(1H-吲哚-3-基)-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-苯甲酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯并[b]噻吩-3-基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-异烟酰胺;
3-乙酰氨基-噻吩-2-甲酸-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-酰胺;
3-甲基-噻吩-2-甲酸[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-吡啶-3-基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-酰胺;
及其药用盐和溶剂化物。
治疗应用
如之前提及的,本发明的化合物是有效的和选择性的血浆激肽释放酶抑制剂。因此它们可用于治疗血浆激肽释放酶的过度活性是诱发因素的疾病病症。
因此,本发明提供式(I)的化合物,其用于药物。
本发明还提供式(I)的化合物在制备药物中的用途,所述药物用于治疗或预防其中涉及血浆激肽释放酶活性的疾病或病症。
本发明还提供式(I)的化合物,其用于治疗或预防其中涉及血浆激肽释放酶活性的疾病或病症。
本发明还提供一种治疗其中涉及血浆激肽释放酶活性的疾病或病症的方法,所述方法包括向需要其的受试者施用治疗有效量的式(I)的化合物。
在一个方面,所述其中涉及血浆激肽释放酶活性的疾病或病症选自这样的其中涉及血浆激肽释放酶活性的疾病或病症,包括受损视敏度,糖尿病视网膜病,糖尿病黄斑水肿,遗传性血管性水肿,糖尿病,胰腺炎,脑出血,肾病,心肌病,神经病,炎性肠病,关节炎,炎症,感染性休克,低血压,癌症,成人呼吸窘迫综合征,弥散性血管内凝血,心肺旁路手术和外科手术后出血。
在另一方面,所述其中涉及血浆激肽释放酶活性的疾病或病症是与糖尿病视网膜病和糖尿病黄斑水肿相关的视网膜血管通透性。
组合疗法
本发明的化合物可以联合其他治疗剂施用。合适的组合疗法包括式(I)化合物联合一种或多种药剂,所述药剂选自:抑制血小板衍生生长因子(PDGF)的试剂,内皮生长因子(VEGF),整联蛋白α5β,类固醇,抑制血浆激肽释放酶的其他试剂以及其他的炎症抑制剂。可与本发明化合物联合的治疗剂的具体实例包括在EP2281885A中和由S.Patel在Retina,2009Jun;29(6Suppl):S45-8中公开的那些。
当采用组合疗法时,本发明化合物和所述组合药剂可以存在于相同或不同的药物组合物中,并且可以单独地、顺序地或同时地施用。
定义
术语"烷基"包括饱和烃基,其包括:
-至多可达10个碳原子(C1-C10),或至多可达6个碳原子(C1-C6),或至多可达4个碳原子(C1-C4)的直链基团。这样的烷基的实例包括但不限于C1-甲基、C2-乙基、C3-丙基和C4-正丁基。
-3至10个碳原子(C3-C10),或至多可达7个碳原子(C3-C7),或至多可达4个碳原子(C3-C4)的支链基团。这样的烷基的实例包括但不限于C3-异丙基、C4-仲丁基、C4-异丁基、C4-叔丁基和C5-新戊基。
各自任选地如上所述被取代。
术语"烷氧基"包括O-连接的烃基,其包括:
-1至6个碳原子(C1-C6),或1至4个碳原子(C1-C4)的直链基团。这样的烷氧基的实例包括但不限于C1-甲氧基、C2-乙氧基、C3-正丙氧基和C4-正丁氧基。
-3至6个碳原子(C3-C6),或3至4个碳原子(C3-C4)的支链基团。这样的烷氧基的实例包括但不限于C3-异丙氧基及C4-仲丁氧基和叔丁氧基。
各自任选地如上所述被取代。
除非另有说明,卤素选自Cl,F,Br和I。
环烷基如上所定义。环烷基可以含有3至10个碳原子,或4至10个碳原子,或5至10个碳原子,或4至6个碳原子。合适的单环环烷基的实例包括环丙基、环丁基、环戊基、环己基和环庚基。合适的双环环烷基的实例包括十氢萘和八氢-1H-茚。当与芳基融合时,合适的环烷基的实例包括二氢茚基及1,2,3,4-四氢萘基。
杂环烷基如上所定义。合适的杂环烷基的实例包括环氧乙基(oxiranyl)、吖啶丙基(aziridinyl)、氮杂环丁烷基(azetidinyl)、四氢呋喃基、吡咯烷基、四氢吡喃基、哌啶基、N-甲基哌啶基、吗啉基、N-甲基吗啉基、哌嗪基、N-甲基哌嗪基、氮杂环庚烷基(azepanyl)、氧氮杂环庚烷基(oxazepanyl)和二氮杂环庚烷基(diazepanyl)。
芳基如上所定义。典型地,芳基将任选地被1、2或3个取代基取代。任选的取代基选自上述的那些。合适的芳基的实例包括苯基和萘基(各自任选地如上所述被取代)。
杂芳基如上所定义。合适的杂芳基的实例包括噻吩基,呋喃基,吡咯基,吡唑基,咪唑基,唑基,异唑基,噻唑基,异噻唑基,三唑基,二唑基,噻二唑基,四唑基,吡啶基,哒嗪基,嘧啶基,吡嗪基,吲哚基,苯并咪唑基,苯并三唑基,喹啉基和异喹啉基(任选地如上所述被取代)。
术语"C-连接的",如在"C-连接的杂环烷基"中,是指所述杂环烷基经由环碳原子连接至该分子的剩余部分。
术语"N-连接的",如在"N-连接的杂环烷基"中,是指所述杂环烷基经由环氮原子连接至该分子的剩余部分。
术语"O-连接的",如在"O-连接的烃基"中,是指所述烃基经由氧原子连接至该分子的剩余部分。
在基团如-CO烷基和-(CH2)bCOOR10中,"-"表示该取代基与分子的剩余部分的连接点。
"药用盐"是指生理学或毒理学上可耐受的盐,并且在合适时包括药用碱加成盐和药用酸加成盐。例如(i)在本发明化合物含有一个或多个酸性基团(例如,羧基)的情况下,可形成的药用碱加成盐包括钠盐、钾盐、钙盐、镁盐和铵盐或与有机胺(如二乙胺、N-甲基-葡糖胺、二乙醇胺或氨基酸(例如,赖氨酸))的盐等;(ii)在本发明化合物含有碱性基团(如,氨基)的情况下,可形成的药用酸加成盐包括氢氯酸盐、氢溴酸盐、硫酸盐、磷酸盐、乙酸盐、柠檬酸盐、乳酸盐、酒石酸盐、甲磺酸盐、琥珀酸盐、草酸盐、磷酸盐、乙磺酸盐(esylate)、甲苯磺酸盐、苯磺酸盐、萘二磺酸盐、马来酸盐、己二酸盐、延胡索酸盐、马尿酸盐(hippurate)、樟脑酸盐(camphorate)、1-羟基-2-萘甲酸盐(xinafoate)、对乙酰氨基苯甲酸盐(p-acetamidobenzoate)、二羟基苯甲酸盐、羟基萘甲酸盐、琥珀酸盐、抗坏血酸盐、油酸盐、硫酸氢盐等。
也可以形成酸和碱的半盐,例如半硫酸盐和半钙盐。
对于合适盐的综述,参见Stahl和Wermuth的"Handbook ofPharmaceutical Salts:Properties,Selection and Use(药用盐手册:性质、选择和使用)"(Wiley-VCH,Weinheim,德国,2002)。
“前药”是指在体内通过代谢方式(例如,通过水解、还原或氧化)而可转化成本发明化合物的化合物。用于形成前药的合适基团描述于‘ThePractice of Medicinal Chemistry(医药化学实践),2nd Ed.pp561-585(2003)和F.J.Leinweber,Drug Metab.Res.,1987,18,379。
本发明的化合物可以非溶剂化和溶剂化的形式存在。术语'溶剂化物'在本文中用来描述包含本发明化合物和化学计量的一种或多种药用溶剂分子(例如,乙醇)的分子复合物。当溶剂为水时,采用术语'水合物'。
在本发明化合物以一种或多种几何、光学、对映体、非对映异构体和互变异构形式存在的情况下,其包括但不限于顺式和反式形式、E-和Z-形式、R-,S-及内消旋(meso)形式、酮-及烯醇-形式。除非另有说明,提及的特定化合物包括所有这样的异构形式,包括其外消旋及其他混合物。在适合的情况下,这样的异构体通过应用或改编已知的方法(例如,色谱技术和重结晶技术)而从它们的混合物中分离出来。在合适情况下,这样的异构体可应用或改编已知的方法(例如不对称合成)而制得。
在本发明的上下文中,本文中提及的"治疗"包括对治愈性、减轻(palliative)和预防性治疗的提及。
通用方法
式(I)的化合物应对其生物医药特性加以评估,如溶解度及溶液稳定性(横跨pH)、渗透性等,以便选择用于治疗所提议适应证的最适剂型和施用途径。这些化合物可单独施用,或与一种或多种本发明的其他化合组合施用,或与一种或多种其他药物组合(或作为它们的任意组合)施用。通常,这些化合物作为与一或多种药用赋形剂联合的制剂施用。术语‘赋形剂’在本文中用来描述不同于本发明的化合物的任何成分,其可以对所述制剂赋予功能性(即,药物释放速率控制)和/或非功能性(即,加工助剂或稀释剂)。赋形剂的选择很大程度上取决于诸如具体给药方式、赋形剂对溶解度和稳定性的影响、以及剂型的性质等因素。
意图用于药物用途的本发明的化合物可以作为固体或液体,如片剂、胶囊或溶液施用。适用于递送本发明的化合物的药物组合物和用于制备其的方法对于本领域技术人员是明显的。这样的组合物和用于制备其的方法可以例如在雷明顿药物科学(Remington’s Pharmaceutical Sciences)第19版(Mack Publishing Company,1995)中找到。
因此,本发明提供一种药物组合物,所述药物组合物包含式(I)的化合物和药用载体、稀释剂或赋形剂。
对于病症如与糖尿病视网膜病和糖尿病黄斑水肿相关的视网膜血管通透性的治疗,本发明的化合物可以以适于注射到患者眼部区域内的形式,尤其是,以适于玻璃体内注射的形式施用。设想了适于这样的用途的制剂将采用本发明的化合物在合适含水媒介物中的无菌溶液的形式。所述组合物可以在主治医师监督下施用至患者。
本发明的化合物也可以直接施用到血流中、皮下组织中、肌肉中或内部器官中。用于肠胃外施用的合适方式包括静脉内、动脉内、腹膜内、鞘内、心室内、尿道内、胸骨内、颅内、肌肉内、滑膜内及皮下。用于肠胃外施用的合适装置包括针头(包括微针)注射器、无针头注射器和输注技术。
肠胃外制剂典型地为水性溶液或油性溶液。在溶液为水性的情况下,赋形剂如糖(包括但不限于葡萄糖、甘露糖醇、山梨糖醇等)、盐、碳水化合物和缓冲剂(优选为3至9的pH),但对于一些某些应用,其可能更合适配制为无菌非水溶液或作为干燥形式配制以联合合适媒介物如无菌的无热原水使用。
肠胃外制剂可以包括衍生自可降解聚合物的植入物,如聚酯(即,聚乳酸、聚丙交酯、聚丙交酯-共-乙交酯、聚己内酯、聚羟基丁酸酯)、聚原酸酯和聚酸酐。这些制剂可以经由手术切口施用到皮下组织、肌肉组织内或直接施用到特定器官内。
利用对本领域技术人员熟知的标准制药技术可以容易地完成在无菌条件下肠胃外制剂的制备,例如,通过冷冻干燥。
用于制备肠胃外溶液中的式(I)化合物的溶解度可以通过使用合适配制技术而增加,如掺入共溶剂和/或溶解度增强剂如表面活性剂、胶束结构和环糊精。
在一个实施方案中,本发明的化合物可以经口施用。经口施用可以涉及吞咽,以使所述化合物进入肠胃道,和/或通过含服、经舌或舌下施用,通过这样化合物直接从口腔进入血流。
适于经口施用的制剂包括固体栓剂、固体微粒、半固体和液体(包括多相或分散系统)如片剂;容纳多个或纳米颗粒、液体、乳液或粉末的软或硬胶囊;锭剂(包括液体填充的);咀嚼片;凝胶;快速分散剂型;膜剂(film);胚珠剂(ovules);喷雾剂;和颊贴片/粘膜粘附贴片。
适于经口施用的制剂也可以设计为以立即释放方式或以速率保持方式递送本发明化合物,其中释放曲线可以延迟、脉冲、受控、持续,或以优化所述化合物的疗效的方式延迟和持续或更改。以速率保持方式递送化合物的方式在本领域是已知的并且包括可以与所述化合物一起配制以控制其释放的缓释聚合物。
速率保持聚合物的实例包括可降解和非可降解聚合物,该聚合物可以通过扩散或扩散和聚合物磨蚀的组合来释放所述化合物。速率保持聚合物的实例包括羟丙甲基纤维素、羟丙基纤维素、甲基纤维素、乙基纤维素、羧甲基纤维素钠、聚乙烯醇、聚乙烯吡咯烷酮、黄原胶、聚甲基丙烯酸酯、聚环氧乙烷和聚乙二醇。
液体(包括多相及分散系统)制剂包括乳剂、溶液剂、糖浆和酏剂。这样的制剂可以呈现为软或硬胶囊(例如,由明胶或羟丙甲基纤维素制成)中的填料,并且典型地包括载体,例如,水、乙醇、聚乙二醇、丙二醇、甲基纤维素或适当的油,以及一种或多种乳化剂和/或悬浮剂。液体制剂也可以通过例如从药囊中的固体进行重建而制备。
本发明的化合物也可以以快速溶解、快速崩解剂型施用,如在Liang和Chen,Expert Opinion in Therapeutic Patents(治疗专利中的专家意见),2001,11(6),981-986中描述的那些。
片剂的配制在Pharmaceutical Dosage Forms:Tablets(药物剂型:片剂),Vol.1,H.Lieberman和L.Lachman(Marcel Dekker,New York,1980)中讨论。
对于人类患者的施用,本发明化合物的总日剂量典型地在0.01mg至1000mg范围,或0.1mg至250mg,或1mg至50mg,这当然取决于给药方式。例如,如果通过玻璃体内注射施用,则设想了本发明化合物将偶尔给药,例如每月一次。在这种情况下,设想了剂量为0.5mg至20mg,如1mg至10mg。若更频繁给药,例如每日一次,设想了0.005mg至0.02mg的显著更低的剂量。
总剂量可以以单个或分开的剂量施用,并且在医师指示下可以落在本文所给的典型范围之外。这些剂量基于体重约60kg至70kg的平均水平的人类受试者。医师将能够容易地确定体重不在此范围内的受试者,如婴儿和老人的剂量。
合成方法
本发明化合物可以使用适当的材料根据以下方案和实施例的程序制备,并进一步以下文所提供的具体实施例加以举例说明。此外,通过利用本文所述的步骤,本领域普通技术人员可以容易地制备属于本文所要求的本发明范围内的其他化合物。然而,实施例中所举例说明的化合物不被解释为形成被认为是所述发明的仅有物质。实施例进一步举例说明制备本发明化合物的细节。本领域技术人员将容易地理解,以下制备程序的条件和过程的已知改变可以用来制备这些化合物。
本发明化合物可以其药用盐的形式分离,如上文之前描述的那些。
可能有必要保护在制备本发明化合物中使用的中间体中的反应性官能团(例如,羟基,氨基,硫羟基或羧基)以避免它们在导致所述化合物形成的反应中不希望的参与。可以使用常规保护基,例如,由T.W.Greene和P.G.M.Wuts在“Protective groups in organic chemistry”John Wiley和Sons,第4th版,2006中描述的那些。例如,适于本文使用的常用氨基保护基是叔丁氧基羰基(Boc),其通过在有机溶剂如二氯甲烷中的酸如三氟乙酸或盐酸处理而容易除去。备选地,氨基保护基可以是可通过在氢气氛下用钯催化剂氢化除去的苄氧基羰基(Z),或可以通过仲有机胺如二乙胺或哌啶在有机溶剂中的溶液除去的9-芴基甲基氧基羰基(Fmoc)。羧基典型地作为酯如如甲基,乙基,苄基或叔丁基保护,其可以通过在碱如氢氧化锂或氢氧化钠存在下水解而除去。苄基保护基也可以通过在氢气氛下用钯催化剂氢化除去,而叔丁基也可以通过三氟乙酸除去。备选地,三氯乙基酯保护基用在乙酸中的锌除去。适于本文使用的常用羟基保护基是甲基醚,去保护条件包括在48%含水HBr中回流1-24小时,或通过用在二氯甲烷中的三溴化硼烷搅拌1-24小时。备选地,在羟基作为苄基醚保护的情况下,去保护条件包括在氢气氛下用钯催化剂氢化。
根据通式I的化合物可以利用常规合成方法制备,例如但不限于在方案1中概述的路线。在典型的第一步中,胺(2)使用标准肽偶联条件偶联至活化的α氨基酸(1),该α氨基酸用标准保护基如叔丁基氧基羰基(Boc),苄基氧基羰基(Z)或9-芴基甲基氧基羰基(Fmoc)适当地进行氨基保护。活化基团(X)可以是N-羟基琥珀酰亚胺。使用这样的基团在本领域是熟知的。在R5或R9(在方案1中显示为‘芳基’)具有反应性官能团如胺或羧酸的情况下,这种基团也可以被保护。其他标准肽偶联方法包括酸与胺反应,其在羟基苯并三唑和碳二亚胺如水溶性碳二亚胺,或2-(1H-苯并三唑-1-基)-1,1,3,3-四甲基铵六氟磷酸盐或苯并三唑-1-基-氧基-三-吡咯烷基-六氟磷酸鏻或溴-三吡咯烷基-六氟磷酸鏻,在有机碱如三乙胺、二异丙基乙胺或N-甲基吗啉存在下进行。在典型的第二步中,保护基使用如之前描述的标准方法除去。
然后方案1中例举的路线在第三步中经由进一步的标准肽偶联以及在第四步中经由使用如之前描述的标准条件除去Boc保护基进行。在7中揭示的胺在第五步中然后可以典型地用基团R1烷基化或酰化。酰化可以通过用酰化基如酰氯例如乙酰氯或苯甲酰氯,在碱典型地叔胺如三乙胺或二异丙基乙胺存在下处理而进行。烷基化典型地可以通过用烷基卤处理或通过还原性烷基化进行。典型地,在还原性烷基化程序中,使胺与醛或酮在合适还原剂如氰基硼氢化钠或乙酰氧基硼氢化钠存在下在合适溶剂如甲醇中在室温下反应。所得腈化合物8然后可以通过氢化还原。从8至10的转化可以在单一步骤中实现,通过在合适溶剂如甲醇中在合适催化剂如碳负载钯存在下在酸如盐酸存在下进行氢化对腈直接还原,或在合适过渡金属如氯化钴或氯化镍存在下在合适溶剂如甲醇中在室温用合适硼氢化物进行还原。备选地,叔丁氧基羰基(Boc)保护的胺9可以被分离(使用例如在S.Caddick等,Tetrahedron Lett.,2000,41,3513中描述的方法),然后通过之前描述的标准手段去保护而得到胺10。
方案1
附图简述
图1显示实施例3和CH-3457(阳性对照;血浆激肽释放酶抑制剂)对Sprague Dawley大鼠中的CA-I刺激的RVP的抑制作用。
图2显示在IVT施用4.2μg/mL(210ng/眼)后实施例3的眼组织浓度。
实施例
本发明通过以下非限制性实施例进行说明,其中使用以下缩写和定义:
除非另有规定,所有反应在氮气氛下进行。
1H NMR谱在Brucker Avance III(400MHz)光谱仪上记录(关于氘溶剂和在室温下)。
使用LCMS获得分子离子,该LCMS使用Chromolith Speedrod RP-18e柱,50x4.6mm,利用线性梯度10%至90%0.1%HCO2H/MeCN在0.1%HCO2H/H2O中,在11min内,流速1.5mL/min进行。使用利用电喷雾电离的Thermofinnigan Surveyor MSQ质谱仪联合Thermofinnigan SurveyorLC系统收集数据。
利用来自MDL Information Systems的作为ISIS绘图包的一部分提供的Autonom软件生成化学名称。
在产物通过快速色谱法纯化的情况下,‘二氧化硅(silica)’是指用于色谱法的硅胶,0.035至0.070mm(220至440目)(例如Merck硅胶60),并且施加的氮气压力直至10p.s.i加速柱洗脱。反相制备型HPLC纯化使用Waters2525二元梯度泵送洗脱以典型地20mL/min流速,利用Waters2996光电二极管阵列检测器进行。
所有溶剂和商购试剂以原样使用。
实施例1
(S)-N-(4-氨基甲基-苄基)-2-[(R)-3-(4-乙氧基-苯基)-2-丙酰氨基-丙酰氨
基]-3-苯基-丙酰胺
A.(S)-2-[(R)-2-叔丁氧基羰基氨基-3-(4-乙氧基-苯基)-丙酰氨基]-3-苯基-丙酸甲酯
将H-Phe-OMe.HCl(2.3g,10.7mmol)溶解在CH2Cl2(100mL)和DMF(10mL)中。将此溶液冷却至0℃。加入(R)-2-丁氧基氧基羰基氨基-3-(4-乙氧基-苯基)-丙酸(3.0g,9.7mmol),接着加入HOBt(1.57g,11.6mmol)和三乙胺(2.9g,29.0mmol)。然后加入水溶性碳二亚胺(2.04g,10.6mmol)。在18小时后在0℃至室温,反应混合物用氯仿(100mL)稀释并用NaHCO3(1x30mL),水(1x30mL),盐水(1x30mL)洗涤,干燥(Na2SO4)并在真空下蒸发,得到黄色油状物。残留物通过快速色谱法(二氧化硅)纯化,洗脱剂20%石油醚(60-80℃),80%EtOAc,合并级分并在真空下蒸发,得到无色油状物,其被确定为(S)-2-[(R)-2-叔丁氧基羰基氨基-3-(4-乙氧基-苯基)-丙酰氨基]-3-苯基-丙酸甲酯(4.25g,9.03mmol,93%)。
[M+H]+=471.27。
B.(S)-2-[(R)-2-叔丁氧基羰基氨基-3-(4-乙氧基-苯基)-丙酰氨基]-3-苯基-丙酸
将(S)-2-[(R)-2-叔丁氧基羰基氨基-3-(4-乙氧基-苯基)-丙酰氨基]-3-苯基-丙酸甲酯(2.5g,5.3mmol)溶解在THF(100mL)中。加入在水(10mL)中的氢氧化锂一水合物(668mg,15.9mmol)。反应混合物在室温搅拌18小时,之后将反应混合物用EtOAc(150mL)稀释。该溶液用0.3M KHSO4(1x50mL),水(1x30mL),盐水(1x30mL)洗涤,干燥(Na2SO4)并在真空下蒸发,得到白色固体,其被确定为(S)-2-[(R)-2-叔丁氧基羰基氨基-3-(4-乙氧基-苯基)-丙酰氨基]-3-苯基-丙酸(2.095g,4.58mmol,86%)。
[M+H]+=457.25。
C.[(R)-1-[(S)-1-(4-氰基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-氨基甲酸叔丁酯
将4-(氨基甲基)苄腈盐酸盐(303mg,1.80mmol)溶解在CH2Cl2(50mL)和DMF(5mL)中。将此溶液冷却至0℃。加入(S)-2-[(R)-2-叔丁氧基羰基氨基-3-(4-乙氧基-苯基)-丙酰氨基]-3-苯基-丙酸(745mg,1.63mmol),接着加入HOBt(265mg,1.96mmol)和三乙胺(495mg,4.9mmol)。然后加入水溶性碳二亚胺(344mg,1.8mmol)。在18小时后在0℃至室温,反应混合物用氯仿(100mL)稀释并用NaHCO3(1x30mL),水(1x30mL),盐水(1x30mL)洗涤,干燥(Na2SO4)并在真空下蒸发,得到黄色油状物。残留物通过快速色谱法(二氧化硅)纯化,洗脱剂20%石油醚(60-80℃),80%EtOAc,合并级分并在真空下蒸发,得到无色油状物,其被确定为[(R)-1-[(S)-1-(4-氰基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-氨基甲酸叔丁酯(493mg,0.86mmol,53%)。
[M+H]+=571.29
D.(R)-2-氨基-N-[(S)-1-(4-氰基-苄基氨基甲酰)-2-苯基-乙基]-3-(4-乙氧基-苯基)-丙酰胺盐酸盐
[(R)-1-[(S)-1-(4-氰基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-氨基甲酸叔丁酯(225mg,0.39mmol)用4M HCl/二烷(50mL)处理。在室温在一小时后,除去溶剂,获得白色固体,其被确定为(R)-2-氨基-N-[(S)-1-(4-氰基-苄基氨基甲酰)-2-苯基-乙基]-3-(4-乙氧基-苯基)-丙酰胺盐酸盐(200mg,0.39mmol,100%)。
[M+H]+=471.26
E.(S)-N-(4-氰基-苄基)-2-[(R)-3-(4-乙氧基-苯基)-2-丙酰氨基-丙酰氨基]-3-苯基-丙酰胺
(R)-2-氨基-N-[(S)-1-(4-氰基-苄基氨基甲酰)-2-苯基-乙基]-3-(4-乙氧基-苯基)-丙酰胺盐酸盐(200mg,0.37mol)溶解在二氯甲烷(50mL)中,将此溶液冷却至0℃。加入三乙胺(111mg,1.1mmol)接着加入丙酰氯(39mg,0.40mmol)。在18小时后在0℃至室温,反应混合物用CHCl3(50mL)稀释,此溶液用饱和NaHCO3(1x20mL),水(1x20mL),盐水(1x20mL)洗涤,干燥(Na2SO4)并在真空下蒸发。残留物通过快速色谱法(二氧化硅)纯化,洗脱剂2%MeOH,98%CHCl3,合并级分并在真空下蒸发,得到无色油状物,其被确定为(S)-N-(4-氰基-苄基)-2-[(R)-3-(4-乙氧基-苯基)-2-丙酰氨基-丙酰氨基]-3-苯基-丙酰胺(189mg,0.36mmol,98%)。
[M+H]+=527.27
F.[4-({(S)-2-[(R)-3-(4-乙氧基-苯基)-2-丙酰氨基-丙酰氨基]-3-苯基-丙酰氨基}-甲基)-苄基]-氨基甲酸叔丁酯
(S)-N-(4-氰基-苄基)-2-[(R)-3-(4-乙氧基-苯基)-2-丙酰氨基-丙酰氨基]-3-苯基-丙酰胺(100mg,0.19mmol)溶解在甲醇(50mL)中。将此溶液冷却至0℃。加入氯化镍(II)六水合物(4.5mg,0.0192mmol)和二碳酸二叔丁酯(83mg,0.38mmol)接着分部分地加入硼氢化钠(50mg,1.33mmol)。反应混合物在0℃至室温搅拌18hrs。通过蒸发除去甲醇。残留物溶解在CHCl3(70mL)中,用饱和NaHCO3(1x30mL),水(1x30mL),盐水(1x30mL)洗涤,干燥(Na2SO4)并在真空下蒸发,得到黄色油状物。通过快速色谱法纯化,洗脱剂1%MeOH,99%CHCl3,得到无色油状物,其被确定为[4-({(S)-2-[(R)-3-(4-乙氧基-苯基)-2-丙酰氨基-丙酰氨基]-3-苯基-丙酰氨基}-甲基)-苄基]-氨基甲酸叔丁酯(89mg,0.14mmol,74%)。
[M+H]+=631.39
G.(S)-N-(4-氨基甲基-苄基)-2-[(R)-3-(4-乙氧基-苯基)-2-丙酰氨基-丙酰氨基]-3-苯基-丙酰胺三氟乙酸盐
[4-({(S)-2-[(R)-3-(4-乙氧基-苯基)-2-丙酰氨基-丙酰氨基]-3-苯基-丙酰氨基}-甲基)-苄基]-氨基甲酸叔丁酯(89mg,0.13mmol)溶解在三氟乙酸(20mL)中。此溶液在室温搅拌一小时,之后在真空下除去溶剂,得到黄色油状物。残留物通过制备HPLC(Sunfire制备型C18OBD柱。19x250mm,10μ)纯化。10至90%0.1%TFA/MeCN到0.1%TFA/H2O,在35min内,以20mL/min。合并级分并冷冻干燥,得到白色固体,其被确定为(S)-N-(4-氨基甲基-苄基)-2-[(R)-3-(4-乙氧基-苯基)-2-丙酰氨基-丙酰氨基]-3-苯基-丙酰胺三氟乙酸盐(38mg,0.056mmol,42%)
[M+H]+=531.31
1H NMR:(CD3OD)1.02(3H,t,J=7.7Hz),1.42(3H,t,J=7.0Hz),2.13-2.21(2H,m),2.71-2.77(1H,m),2.81-2.92(2H,m),3.12-3.16(1H,m),4.05(2H,q,J=6.9Hz),4.13(2H,s),4.37-4.50(3H,m),4.57-4.69(1H,m),6.82(2H,d,J=8.6Hz),7.05(2H,d,J=8.6Hz),7.17-7.19(2H,m),7.24-7.31(5H,m),7.41(2H,d,J=8.1Hz)。
实施例2
(R)-N-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基]-3-(4-乙氧基-苯
基)-2-甲磺酰氨基-丙酰胺
A.(R)-N-[(S)-1-(4-氰基-苄基氨基甲酰)-2-苯基-乙基]-3-(4-乙氧基-苯基)-2-甲磺酰氨基-丙酰胺
(R)-2-氨基-N-[(S)-1-(4-氰基-苄基氨基甲酰)-2-苯基-乙基]-3-(4-乙氧基-苯基)-丙酰胺盐酸盐(150mg,0.30mmol)溶解在CH2Cl2(20mL)中。将此溶液冷却至0℃。加入甲磺酰氯(37mg,0.33mmol)然后加入三乙胺(90mg,0.89mmol)。在18小时后在0℃至室温,反应混合物用氯仿(50mL)稀释并用NaHCO3(1x20mL),水(1x20mL),盐水(1x20mL)洗涤,干燥(Na2SO4)并在真空下蒸发,得到黄色油状物。残留物通过快速色谱法(二氧化硅)纯化,洗脱剂2%MeOH,98%CHCl3,合并级分并在真空下蒸发,得到白色固体,其被确定为(R)-N-[(S)-1-(4-氰基-苄基氨基甲酰)-2-苯基-乙基]-3-(4-乙氧基-苯基)-2-甲磺酰氨基-丙酰胺(110mg,0.20mmol,68%)。
[M+H]+=549.11
B.[4-({(S)-2-[(R)-3-(4-乙氧基-苯基)-2-甲磺酰氨基-丙酰氨基]-3-苯基-丙酰氨基}-甲基)-苄基]-氨基甲酸叔丁酯
(R)-N-[(S)-1-(4-氰基-苄基氨基甲酰)-2-苯基-乙基]-3-(4-乙氧基-苯基)-2-甲磺酰氨基-丙酰胺(110mg,0.20mmol)溶解在甲醇(50mL)中。将此溶液冷却至0℃。氯化镍(II)六水合物(4.8mg,0.02mmol)和二碳酸二叔丁酯(88mg,0.4mmol)接着分部分地加入硼氢化钠(53mg,1.4mmol)。反应混合物在0℃至室温搅拌18hrs。通过蒸发除去MeOH。残留物溶解在CHCl3(70mL)中,用饱和NaHCO3(1x30mL),水(1x30mL),盐水(1x30mL)洗涤,干燥(Na2SO4)并在真空下蒸发,得到黄色油状物。通过快速色谱法纯化,洗脱剂2%MeOH,98%CHCl3,得到白色固体,其被确定为[4-({(S)-2-[(R)-3-(4-乙氧基-苯基)-2-甲磺酰氨基-丙酰氨基]-3-苯基-丙酰氨基}-甲基)-苄基]-氨基甲酸叔丁酯(86mg,0.13mmol,66%)。
[M+H]+=653.23,675.19(M+Na)。
C.(R)-N-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基]-3-(4-乙氧基-苯基)-2-甲磺酰氨基-丙酰胺三氟乙酸盐
[4-({(S)-2-[(R)-3-(4-乙氧基-苯基)-2-甲磺酰氨基-丙酰氨基]-3-苯基-丙酰氨基}-甲基)-苄基]-氨基甲酸叔丁酯(86mg,0.13mmol)用三氟乙酸(20mL)处理。在一小时后在室温,在真空下蒸发溶剂。残留物通过制备HPLC(Sunfire制备型C18OBD柱。19x250mm,10μ)纯化。10至90%0.1%TFA/MeCN到0.1%TFA/H2O,在35min内,在20mL/min。合并级分并冷冻干燥,得到白色固体,其被确定为(R)-N-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基]-3-(4-乙氧基-苯基)-2-甲磺酰氨基-丙酰胺三氟乙酸盐(28mg,0.042mmol,32%)
[M+H]+=553.08
1H NMR:(CD3OD)1.41(3H,t,J=7.0Hz),2.60(3H,s),2.69-2.75(1H,m),2.81-2.91(2H,m),3.09(1H,dd,J=13.7,6.5Hz),4.04(2H,q,J=7.0Hz),4.13(3H,m),4.39(2H,s),4.62(1H,dd,J=8.1,6.6Hz),6.87(2H,d,J=8.6Hz),7.13(2H,d,J=8.6Hz),7.23(2H,t,J=6.6Hz),7.25-7.32(5H,m),7.41(2H,d,J=8.1Hz)。
实施例3
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲
酰]-2-(4-乙氧基-苯基)-乙基]-苯甲酰胺
A.{(S)-1-[4-(叔丁氧基羰基氨基-甲基)-苄基氨基甲酰]-2-苯基-乙基}-氨基甲酸苄基酯
(S)-2-苄氧基羰基氨基-3-苯基-丙酸2,5-二氧代-吡咯烷-1-基酯(4.25g,10.72mmol)溶解在CH2Cl2(100mL)中。将此溶液冷却至0℃。加入1-(N-Boc-氨基甲基)-4-(氨基甲基)苯(2.79g,11.79mmol)接着加入三乙胺(3.25g,32.16mmol)。在18小时后在0℃至室温,反应混合物用氯仿(100mL)稀释并用NaHCO3(1x30mL),水(1x30mL),盐水(1x30mL)洗涤,干燥(Na2SO4),在真空下蒸发,得到黄色油状物。残留物用石油醚(60-80℃)和EtOAc研磨,得到白色固体,其被确定为{(S)-1-[4-(叔丁氧基羰基氨基-甲基)-苄基氨基甲酰]-2-苯基-乙基}-氨基甲酸苄基酯(3.88g,7.49mmol,70%)。
[M+H]+=518.28,540.32(M+Na)。
B.{4-[((S)-2-氨基-3-苯基-丙酰氨基)-甲基]-苄基}-氨基甲酸叔丁酯
{(S)-1-[4-(叔丁氧基羰基氨基-甲基)-苄基氨基甲酰]-2-苯基-乙基}-氨基甲酸苄基酯(3.66g,7.08mmol)溶解在甲醇(200mL)中。此溶液在大气压和室温下在10%Pd/C(500mg)上氢化一小时,之后通过硅藻土滤去催化剂并且残留物用甲醇(30mL)洗涤,合并的滤液在真空下蒸发,得到白色固体,其被确定为{4-[((S)-2-氨基-3-苯基-丙酰氨基)-甲基]-苄基}-氨基甲酸叔丁酯(2.627g,6.85mmol,97%)。
[M+H]+=384.37
C.(R)-2-氨基-3-(4-乙氧基-苯基)-丙酸
(R)-2-丁氧基羰基氨基-3-(4-乙氧基-苯基)-丙酸(4.0g,12.93mmol)溶解在在二烷(150mL)中的4M HCl。在一小时后在室温,真空下除去溶剂,得到白色固体,其被确定为(R)-2-氨基-3-(4-乙氧基-苯基)-丙酸盐酸盐(3.18g,12.9mmol,100%)。
[M+H]+=210.18
D.(R)-2-苄氧基羰基氨基-3-(4-乙氧基-苯基)-丙酸
(R)-2-氨基-3-(4-乙氧基-苯基)-丙酸盐酸盐(3.17g,12.9mmol)溶解在在水(100mL)中的氢氧化钠(1.14g,28.38mmol)溶液中。加入在二烷(100mL)中的氯甲酸苄酯(2.64g,15.48mmol)。反应混合物在室温搅拌18小时,之后在真空下除去二烷。含水残留物用二乙醚(1x100mL)洗涤,用1M HCl酸化至pH2并用氯仿(2x200mL)萃取。合并的萃取物用水(1x50mL),盐水(1x50mL)洗涤,干燥(Na2SO4)并在真空下蒸发,得到白色固体,其被确定为(R)-2-苄氧基羰基氨基-3-(4-乙氧基-苯基)-丙酸(4.0g,11.65mmol,90%)。
[M+H]+=344.20。
E.[(R)-1-{(S)-1-[4-(叔丁氧基羰基氨基-甲基)-苄基氨基甲酰]-2-苯基-乙基氨基甲酰}-2-(4-乙氧基-苯基)-乙基]-氨基甲酸苄基酯
{4-[((S)-2-氨基-3-苯基-丙酰氨基)-甲基]-苄基}-氨基甲酸叔丁酯(2.63g,6.86mmol)溶解在CH2Cl2(100mL)和DMF(5mL)中。将此溶液冷却至0℃.(R)-2-苄氧基羰基氨基-3-(4-乙氧基-苯基)-丙酸(2.59g,7.54mmol)接着加入HOBt(1.11g,8.23mmol)和三乙胺(2.08g,20.57mmol)。然后加入水溶性碳二亚胺(1.45g,7.54mmol)。在18小时后在0℃至室温,反应混合物用氯仿(200mL)稀释并用NaHCO3(1x50mL),水(1x50mL),盐水(1x50mL)洗涤,干燥(Na2SO4)并在真空下蒸发,得到黄色油状物。残留物用乙酸乙酯和石油醚(60-80℃)研磨,得到白色固体,其被确定为[(R)-1-{(S)-1-[4-(叔丁氧基羰基氨基-甲基)-苄基氨基甲酰]-2-苯基-乙基氨基甲酰}-2-(4-乙氧基-苯基)-乙基]-甲酸苄基酯(3.55g,5.01mmol,73%)。
[M+H]+=709.34。
F.[4-({(S)-2-[(R)-2-氨基-3-(4-乙氧基-苯基)-丙酰氨基]-3-苯基-丙酰氨基}-甲基)-苄基]-氨基甲酸叔丁酯
[(R)-1-{(S)-1-[4-(叔丁氧基羰基氨基-甲基)-苄基氨基甲酰]-2-苯基-乙基氨基甲酰}-2-(4-乙氧基-苯基)-乙基]-氨基甲酸苄基酯(3.55g,5.00mmol)溶解在甲醇(200mL)中。此溶液在大气压和室温下在10%Pd/C(500mg)上氢化一小时,之后通过硅藻土滤掉催化剂并且残留物用甲醇(30mL)洗涤,合并的滤液在真空下蒸发,得到白色固体,其被确定为[4-({(S)-2-[(R)-2-氨基-3-(4-乙氧基-苯基)-丙酰氨基]-3-苯基-丙酰氨基}-甲基)-苄基]-氨基甲酸叔丁酯(2.8g,4.87mmol,97%)。
[M+H]+=575.37。
G.[4-({(S)-2-[(R)-2-苯甲酰氨基-3-(4-乙氧基-苯基)-丙酰氨基]-3-苯基-丙酰氨基}-甲基)-苄基]-氨基甲酸叔丁酯
[4-({(S)-2-[(R)-2-氨基-3-(4-乙氧基-苯基)-丙酰氨基]-3-苯基-丙酰氨基}-甲基)-苄基]-氨基甲酸叔丁酯(3.45g,5.99mmol)溶解在二氯甲烷(150mL)中。加入苯甲酰氯(1.01g,7.19mmol)接着加入三乙胺(1.82g,17.98mmol)。反应混合物在室温搅拌5小时并用CHCl3(150mL)稀释,此溶液用0.3M KHSO4(1x50mL),饱和NaHCO3(1x50mL),水(1x50mL),盐水(1x50mL)洗涤,干燥(Na2SO4)并在真空下蒸发。残留物用石油醚(60-80℃)和EtOAc研磨,得到白色固体,其被确定为[4-({(S)-2-[(R)-2-苯甲酰氨基-3-(4-乙氧基-苯基)-丙酰氨基]-3-苯基-丙酰氨基}-甲基)-苄基]-氨基甲酸叔丁酯(3.06g,4.51mmol,75%)。
[M+H]+=679.34。
H.N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-苯甲酰胺盐酸盐
[4-({(S)-2-[(R)-2-苯甲酰氨基-3-(4-乙氧基-苯基)-丙酰氨基]-3-苯基-丙酰氨基}-甲基)-苄基]-氨基甲酸叔丁酯(2.86g,4.21mmol)溶解在在二烷(150mL)中的4M HCl中。在一小时后在室温,在真空下除去溶剂。将残留物从乙醇沉淀,得到白色固体,其被确定为N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-苯甲酰胺盐酸盐(2.1g,3.41mmol,81%)。
[M+H]+=579.34
1H NMR:(CD3OD),1.40(3H,t,J=6.9Hz),2.91-2.99(3H,m),3.14-3.19(1H,m),4.02(2H,q,J=6.9Hz),4.08(2H,s),4.41(1H,d,J=15.5Hz),4.51(1H,d,J=15.5Hz),4.66-4.69(2H,m),6.82(2H,d,J=8.4Hz),7.10(2H,d,J=8.2Hz),7.18-7.20(2H,m),7.25-7.38(7H,m),7.44-7.59(3H,m),7.72(2H,d,J=7.8Hz)。
实施例3b
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲
酰]-2-(4-乙氧基-苯基)-乙基]-苯甲酰胺盐酸盐
[4-({(S)-2-[(R)-2-苯甲酰氨基-3-(4-乙氧基-苯基)-丙酰氨基]-3-苯基-丙酰氨基}-甲基)-苄基]-氨基甲酸叔丁酯(10.0g,14.7mmol)在氯化氢/乙酸乙酯(3.7M,250mL)中在室温搅拌。在两小时后,过滤混合物,用乙酸乙酯(2x50mL)洗涤并干燥,获得固体(7.9g)。将该固体的一部分(0.106g)混悬在乙腈(2.1mL)和水(0.32mL)的混合物中,搅拌,并加热至77℃。另外的水等分试样(0.05mL)连续加入到混合物中直至观察到溶解。然后将搅拌的混合物冷却至室温过夜。所得固体通过过滤分离并在真空在40℃干燥,获得N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-苯甲酰胺盐酸盐(0.067g,3.41mmol,81%)。1H NMR(CD3OD)与实施例3,步骤H的相同。
实施例4
{(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-环
己基-乙基氨基}-乙酸
A.[(S)-1-(4-氰基-苄基氨基甲酰)-2-苯基-乙基]-氨基甲酸叔丁酯
4-氨基甲基苄腈盐酸盐(1.53g,9.1mmol)溶解在CH2Cl2(100mL)中。将此溶液冷却至0℃。加入(S)-2-叔丁氧基羰基氨基-3-苯基丙酸2,5-二氧代-吡咯烷-1-基酯(3.00g,8.3mmol)接着加入三乙胺(2.51g,25mmol)。在18小时后在0℃至室温,反应混合物用氯仿(100mL)稀释并用NaHCO3(1x30mL),水(1x30mL),盐水(1x30mL)洗涤,干燥(Na2SO4)并在真空下蒸发,得到黄色油状物。残留物从EtOAc/石油醚(60-80℃)结晶,得到白色固体,其被确定为[(S)-1-(4-氰基-苄基氨基甲酰)-2-苯基-乙基]-氨基甲酸叔丁酯(2.71g,7.1mmol,86%)。
[M+H]+=380.13
B.(S)-2-氨基-N-(4-氰基-苄基)-3-苯基-丙酰胺盐酸盐
[(S)-1-(4-氰基-苄基氨基甲酰)-2-苯基-乙基]-氨基甲酸叔丁酯(2.71g,7.1mmol)用4M HCl/二烷(150mL)处理。在一小时后在室温,除去溶剂,获得白色固体,其被确定为(S)-2-氨基-N-(4-氰基-苄基)-3-苯基-丙酰胺盐酸盐(2.24g,7.1mmol,99%)。
[M+H]+=280.14
C.{(R)-1-[(S)-1-(4-氰基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-环己基-乙基}-氨基甲酸叔丁酯
(S)-2-氨基-N-(4-氰基-苄基)-3-苯基-丙酰胺盐酸盐(500mg,1.58mmol)溶解在CH2Cl2(30mL)和DMF(3mL)中。将此溶液冷却至0℃。加入Boc-DCha-OH(473mg,1.74mmol)接着加入HOBt(257mg,1.74mmol)和三乙胺(481mg,4.75mmol)。然后加入水溶性碳二亚胺(339mg,1.74mmol)。在18小时后在0℃至室温,反应混合物用氯仿(100mL)稀释并用NaHCO3(1x30mL),水(1x30mL),盐水(1x30mL)洗涤,干燥(Na2SO4)并在真空下蒸发,得到黄色油状物。残留物通过快速色谱法(二氧化硅)纯化,洗脱剂60%环己烷,40%EtOAc,合并级分并在真空下蒸发,得到泡沫状白色固体,其被确定为{(R)-1-[(S)-1-(4-氰基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-环己基-乙基}-氨基甲酸叔丁酯(799mg,1.50mmol,95%)。
[M+H]+=533.18
D.(R)-2-氨基-N-[(S)-1-(4-氰基-苄基氨基甲酰)-2-苯基-乙基]-3-环己基-丙酰胺盐酸盐
{(R)-1-[(S)-1-(4-氰基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-环己基-乙基}-氨基甲酸叔丁酯(799mg,1.5mmol)用4M HCl/二烷(50mL)处理。在一小时后在室温,除去溶剂,获得白色固体,其被确定为(R)-2-氨基-N-[(S)-1-(4-氰基-苄基氨基甲酰)-2-苯基-乙基]-3-环己基-丙酰胺盐酸盐(703mg,1.5mmol,100%)。
[M+H]+=433.06
E.{(R)-1-[(S)-1-(4-氰基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-环己基-乙基氨基}-乙酸叔丁酯
(R)-2-氨基-N-[(S)-1-(4-氰基-苄基氨基甲酰)-2-苯基-乙基]-3-环己基-丙酰胺盐酸盐(290mg,0.62mmol)溶解在乙腈(10mL)中。加入溴乙酸叔丁酯(144mg,0.74mmol)接着加入二异丙基乙胺(160mg,1.24mmol)。反应混合物在60℃搅拌2天,之后将其用氯仿(100mL)稀释,用水(1x30mL),盐水(1x30mL)洗涤,干燥(Na2SO4)并在真空下蒸发,得到黄色油状物。残留物通过快速色谱法(二氧化硅)纯化,洗脱剂25%石油醚(60-80℃),75%EtOAc,合并级分并在真空下蒸发,得到无色油状物,其被确定为{(R)-1-[(S)-1-(4-氰基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-环己基-乙基氨基}-乙酸叔丁酯(240mg,0.44mmol,71%)。
[M+H]+=547.30。
F.((R)-1-{(S)-1-[4-(叔丁氧基羰基氨基-甲基)-苄基氨基甲酰]-2-苯基-乙基氨基甲酰}-2-环己基-乙基氨基)-乙酸叔丁酯
{(R)-1-[(S)-1-(4-氰基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-环己基-乙基氨基}-乙酸叔丁酯(240mg,0.44mmol)溶解在甲醇(25mL)中。将此溶液冷却至0℃。加入氯化镍(II)六水合物(10.4mg,0.44mmol)和二碳酸二叔丁酯(192mg,0.88mmol)接着分部分地加入硼氢化钠(116mg,3.1mmol)。反应混合物在0℃至室温搅拌3天。通过蒸发除去MeOH。残留物溶解在CHCl3(70mL)中,用饱和NaHCO3(1x30mL),水(1x30mL),盐水(1x30mL)洗涤,干燥(Na2SO4)并在真空下蒸发,得到黄色油状物。通过快速色谱法纯化,洗脱剂40%石油醚(60-80℃),60%EtOAc,得到白色固体,其被确定为((R)-1-{(S)-1-[4-(叔丁氧基羰基氨基-甲基)-苄基氨基甲酰]-2-苯基-乙基氨基甲酰}-2-环己基-乙基氨基)-乙酸叔丁酯(65mg,0.10mmol,23%)。
[M+H]+=651.44。
G.{(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-环己基-乙基氨基}-乙酸二三氟乙酸盐
((R)-1-{(S)-1-[4-(叔丁氧基羰基氨基-甲基)-苄基氨基甲酰]-2-苯基-乙基氨基甲酰}-2-环己基-乙基氨基)-乙酸叔丁酯(65mg,0.1mmol)用三氟乙酸(4mL)和CH2Cl2(2mL)处理。在一小时后在室温,在真空下蒸发溶剂。残留物通过制备HPLC(Sunfire制备型C18OBD柱。19x250mm,10μ)纯化。10至90%0.1%TFA/MeCN到0.1%TFA/H2O,在35min内以20mL/min。合并级分并冷冻干燥,得到白色固体,其被确定为{(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-环己基-乙基氨基}-乙酸二三氟乙酸盐(46mg,0.064mmol,64%)。
[M+H]+=495.28
1H NMR:(CD3OD)0.78-0.98(2H,m),1.10-1.25(4H,m),1.53-1.70(7H,m),2.97(1H,dd,J=14.0,10.5Hz),3.25(1H,dd,J=14.1,5.2Hz),3.74(2H,s),4.01(1H,dd,J=8.1,6.1Hz),4.15(2H,s),4.47(2H,s),4.76(1H,dd,J=10.5,5.2Hz),7.28-7.38(7H,m),7.45(2H,d,J=8.2Hz),8.83(1H,t,J=5.9Hz)。
表1至5中的化合物如关于实施例1至4(上文)和199至201(下文)所述进行合成。
表1
表2
表3
表4
表5
表6
表7
实施例的NMR数据
实施例199
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-吡啶-3-基-乙基氨基甲
酰]-2-(4-乙氧基-苯基)-乙基]-4-甲基-苯甲酰胺
A.[4-(叔丁氧基羰基氨基-甲基)-苄基]-氨基甲酸苄基酯
4-(氨基甲基)苄基氨基甲酸叔丁酯(7.5g,31.74mmol)溶解在二氯甲烷(250mL)中。将此溶液冷却至0℃并加入三乙胺(9.63g,93.2mmol)接着加入碳酸苄基酯2,5-二氧代-吡咯烷-1-基酯(9.5g,38.09mmol)。反应混合物在0℃至室温搅拌18小时并用CHCl3(200mL)稀释,滤液用0.3M KHSO4(1x50mL),饱和NaHCO3(1x50mL),水(1x50mL),盐水(1x50mL)洗涤,干燥(Na2SO4)并在真空下蒸发,得到白色固体。该固体用EtOAc/石油醚60-80℃研磨,得到白色固体,其被确定为[4-(叔丁氧基羰基氨基-甲基)-苄基]-氨基甲酸苄基酯(11.3g,30.5mmol,96%)。
[M+H]+=392.98(M+Na)
B.(4-氨基甲基-苄基)-氨基甲酸苄基酯盐酸盐
[4-(叔丁氧基羰基氨基-甲基)-苄基]-氨基甲酸苄基酯(10.8g,29.15mmol)溶解在在二烷(400mL)中的4M HCl中。在一小时后在室温,在真空下除去溶剂。残留物用丙酮调浆并滤掉固体,得到白色固体,其被确定为(4-氨基甲基-苄基)-氨基甲酸苄基酯盐酸盐(11.9g,30.135mmol,99%)。
[M+H]+=359.15
C.{(S)-1-[4-(苄氧基羰基氨基-甲基)-苄基氨基甲酰]-2-吡啶-3-基-乙基}-氨基甲酸叔丁酯
(S)-2-叔丁氧基羰基氨基-3-吡啶-3-基-丙酸(2.12g,7.96mmol)溶解在CH2Cl2(100mL)中,并加入HBTU(3.29g,8.68mmol)和三乙胺(2.20g,21.71mmol)。在20min后在室温,反应混合物冷却至0℃并加入(4-氨基甲基-苄基)-氨基甲酸苄基酯盐酸盐(1.96g,7.24mmol)。在2小时后在0℃,反应混合物用CHCl3(200mL)稀释,此溶液用0.3M KHSO4(1x50mL),饱和NaHCO3(1x50mL),水(1x50mL),盐水(1x50mL)洗涤,干燥(Na2SO4)并在真空下蒸发,得到白色固体。该固体用EtOAc/石油醚60-80℃研磨,得到白色固体,其被确定为{(S)-1-[4-(苄氧基羰基氨基-甲基)-苄基氨基甲酰]-2-吡啶-3-基-乙基}-氨基甲酸叔丁酯(2.53g,4.88mmol,67%)。
[M+H]+=519.16
D.{4-[((S)-2-氨基-3-吡啶-3-基-丙酰氨基)-甲基]-苄基}-氨基甲酸苄基酯二盐酸盐
{(S)-1-[4-(苄氧基羰基氨基-甲基)-苄基氨基甲酰]-2-吡啶-3-基-乙基}-氨基甲酸叔丁酯(2.52g,4.89mmol)用4M HCl/二烷(50mL)处理。在一小时后在室温,除去溶剂,获得白色固体,其被确定为{4-[((S)-2-氨基-3-吡啶-3-基-丙酰氨基)-甲基]-苄基}-氨基甲酸苄基酯二盐酸盐(2.31g,4.71mmol,97%)。
[M+H]+=419.18
1H NMR:(d6-DMSO)δ:9.38(1H,t,J=5.7Hz),8.87(1H,s),8.81(1H,d,J=5.4Hz),8.42-8.49(2H,br s),8.41(1H,d,J=8.0Hz),7.93(1H,dd,J=7.9,5.8Hz),7.87(1H,t,J=6.2Hz),7.28-7.38(4H,m),7.16-7.25(4H,m),5.03(2H,s),4.22-4.43(4H,m),4.18(2H,d,J=6.1Hz),3.39(1H,dd,J=14,5.6Hz),3.26(1H,dd,J=14.0,8.2Hz)。
E.[(R)-1-{(S)-1-[4-(苄氧基羰基氨基-甲基)-苄基氨基甲酰]-2-吡啶-3-基-乙基氨基甲酰}-2-(4-乙氧基-苯基)-乙基]-氨基甲酸叔丁酯
(R)-2-苄氧基羰基氨基-3-(4-乙氧基-苯基)-丙酸(870mg,2.80mmol)溶解在CH2Cl2(100mL)中,并加入HBTU(1.21g,3.20mmol)和三乙胺(1.35g,13.33mmol)。在20min中在室温,反应混合物冷却至0℃并加入{4-[((S)-2-氨基-3-吡啶-3-基-丙酰氨基)-甲基]-苄基}-氨基甲酸苄基酯二盐酸盐(1.31g,2.67mmol)。在2小时后在0℃,反应混合物用CHCl3(200mL)稀释,此溶液用0.3M KHSO4(1x50mL),饱和NaHCO3(1x50mL),水(1x50mL),盐水(1x50mL)洗涤,干燥(Na2SO4)并在真空下蒸发,得到白色固体。该固体用EtOAc/石油醚60-80℃研磨,得到白色固体,其被确定为[(R)-1-{(S)-1-[4-(苄氧基羰基氨基-甲基)-苄基氨基甲酰]-2-吡啶-3-基-乙基氨基甲酰}-2-(4-乙氧基-苯基)-乙基]-氨基甲酸叔丁酯(2.40g,1.70mmol,90%)。
[M+H]+=710.18
F.[4-({(S)-2-[(R)-2-氨基-3-(4-乙氧基-苯基)-丙酰氨基]-3-吡啶-3-基-丙酰氨基}-甲基)-苄基]-氨基甲酸苄基酯二盐酸盐
[(R)-1-{(S)-1-[4-(苄氧基羰基氨基-甲基)-苄基氨基甲酰]-2-吡啶-3-基-乙基氨基甲酰}-2-(4-乙氧基-苯基)-乙基]-氨基甲酸叔丁酯(1.70,2.42mmol)用4M HCl/二烷(100mL)处理。在一小时后在室温,除去溶剂,获得白色固体,其被确定为[4-({(S)-2-[(R)-2-氨基-3-(4-乙氧基-苯基)-丙酰氨基]-3-吡啶-3-基-丙酰氨基}-甲基)-苄基]-氨基甲酸苄基酯二盐酸盐(1.50g,2.32mmol,97%)。
[M+H]+=609.99
1H NMR:(d6-DMSO)δ:9.29(1H,d,J=8.4Hz),8.96(1H,t,J=5.8Hz),8.83(1H,s),8.77(1H,d,J=5.4Hz),8.39(1H,d,J=8.2Hz),8.28-7.98(2H,brs),7.92(1H,dd,J=8.0,5.7Hz),7.86(1H,t,J=6.2Hz),7.28-7.38(4H,m),7.11-7.20(4H,m),6.95(2H,d,J=8.6Hz),6.79(2H,d,J=8.6Hz),5.02(2H,s),4.68-4.75(1H,m),4.23-4.25(2H,m),4.16(2H,d,J=6.1Hz),3.83-4.13(4H,m),3.22(1H,dd,J=14.0,4.4Hz),3.03(1H,dd,J=13.7,9.7Hz),2.84(1H,dd,J=14.0,5.9Hz),2.63(1H,dd,J=13.8,6.1Hz),1.29(3H,t,J=7.0Hz)。
G.[4-({(S)-2-[(R)-3-(4-乙氧基-苯基)-2-(4-甲基-苯甲酰氨基)-丙酰氨基]-3-吡啶-3-基-丙酰氨基}-甲基)-苄基]-氨基甲酸苄基酯
[4-({(S)-2-[(R)-2-氨基-3-(4-乙氧基-苯基)-丙酰氨基]-3-吡啶-3-基-丙酰氨基}-甲基)-苄基]-氨基甲酸苄基酯二盐酸盐(150mg,0.23mol)溶解在二氯甲烷(50mL)中,将此溶液冷却至0℃。加入三乙胺(70mg,0.70mmol)接着加入对甲苯酰氯(39mg,0.26mmol)。在18小时后在0℃至室温,反应混合物用CHCl3(50mL)稀释,此溶液用饱和NaHCO3(1x20mL),水(1x20mL),盐水(1x20mL)洗涤,干燥(Na2SO4)并在真空下蒸发。残留物通过快速色谱法(二氧化硅)纯化,洗脱剂2%MeOH,98%CHCl3,合并级分并在真空下蒸发,得到无色油状物,其被确定为[4-({(S)-2-[(R)-3-(4-乙氧基-苯基)-2-(4-甲基-苯甲酰氨基)-丙酰氨基]-3-吡啶-3-基-丙酰氨基}-甲基)-苄基]-氨基甲酸苄基酯(130mg,0.18mmol,77%)。
[M+H]+=728.14
H.N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-吡啶-3-基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-4-甲基-苯甲酰胺二盐酸盐
[4-({(S)-2-[(R)-3-(4-乙氧基-苯基)-2-(4-甲基-苯甲酰氨基)-丙酰氨基]-3-吡啶-3-基-丙酰氨基}-甲基)-苄基]-氨基甲酸苄基酯(98mg,0.13mmol)溶解在甲醇(100mL)中,加入1M盐酸(0.263mL,0.263mmol)并将反应混合物在10%Pd/C(50mg)上是大气压下氢化2小时,之后滤掉催化剂并用甲醇(100mL)洗涤,合并的滤液在真空下蒸发,得到白色固体,将其从乙醇重结晶,得到白色固体,其被确定为N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-吡啶-3-基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-4-甲基-苯甲酰胺二盐酸盐。
收率=340mg,0.498mmol,57%
[M+H]+=593.99
1H NMR:(d6-DMSO)δ:1.28(3H,t,J=7.05Hz),2.34(3H,s),2.72(2H,d,J=8.16Hz),3.01-3.06(1H,m),3.25-3.28(1H,m),3.91-3.98(4H,m),4.32-4.38(2H,m),4.54-4.57(1H,m),4.70-4.73(1H,m),6.75(2H,d,J=6.83Hz),7.18(2H,d,J=8.56Hz),7.24(2H,d,J=7.56Hz),7.25-7.27(1H,m),7.28(2H,d,J=6.78Hz),7.39(2H,d,J=7.51Hz),7.67(1H,d,J=7.51Hz),7.76(1H,s,br),8.22(1H,d,J=7.56Hz),8.33(3H,s,br),8.71-8.77(4H,m)。
实施例200
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-(3,4-二氟-苯基)-乙基氨
基甲酰]-2-(4-乙氧基-苯基)-乙基]-苯甲酰胺
A.[4-(叔丁氧基羰基氨基-甲基)-苄基]-氨基甲酸9H-芴-9-基甲酯
4-(氨基甲基)苄基氨基甲酸叔丁酯(7.5g,31.74mmol)溶解在二氯甲烷(250mL)中。将此溶液冷却至0℃并加入三乙胺(9.63g,93.2mmol)接着加入碳酸2,5-二氧代-吡咯烷-1-基酯9H-芴-9-基甲基酯(12.85g,38.09mmol)。反应混合物在0℃至室温搅拌3小时并用CHCl3(200mL)稀释,滤液用0.3MKHSO4(1x50mL),饱和NaHCO3(1x50mL),水(1x50mL),盐水(1x50mL)洗涤,干燥(Na2SO4)并在真空下蒸发,得到白色固体。该固体用EtOAc/石油醚60-80℃研磨,得到白色固体,其被确定为[4-(叔丁氧基羰基氨基-甲基)-苄基]-氨基甲酸9H-芴-9-基甲基酯(13.96g,30.44mmol,96%)。
[M+H]+=359.14(M-Boc)
B.(4-氨基甲基-苄基)-氨基甲酸9H-芴-9-基甲基酯盐酸盐
[4-(叔丁氧基羰基氨基-甲基)-苄基]-氨基甲酸9H-芴-9-基甲基酯(13.9g,31.41mmol)溶解在在二烷(400mL)中的4M HCl中。在一小时后在室温,在真空下除去溶剂。残留物用丙酮研磨,滤掉固体,得到白色固体,其被确定为(4-氨基甲基-苄基)-氨基甲酸9H-芴-9-基甲基酯盐酸盐(11.9g,30.135mmol,99%)
[M+H]+=359.15
C.((S)-2-(3,4-二氟-苯基)-1-{4-[(9H-芴-9-基甲氧基羰基氨基)-甲基]-苄基氨基甲酰}-乙基)-氨基甲酸叔丁酯
(S)-2-叔丁氧基羰基氨基-3-(3,4-二氟-苯基)-丙酸(2.1g,6.96mmol)溶解在CH2Cl2(250mL)和DMF(25mL)中。将此溶液冷却至0℃。加入(4-氨基甲基-苄基)-氨基甲酸9H-芴-9-基甲基酯盐酸盐(2.5g,6.33mmol)接着加入HOBt(940mg,6.96mmol)和三乙胺(1.92g,18.99mmol)。然后加入水溶性碳二亚胺(1.45g,7.6mmol)。在18小时后在0℃至室温,反应混合物用氯仿(400mL)稀释,用0.3MKHSO4(1x30mL),NaHCO3(1x30mL),水(1x30mL),盐水(1x30mL)洗涤并在真空下蒸发,得到白色固体。残留物用乙酸乙酯/石油醚60-80℃研磨,得到白色固体,其被确定为((S)-2-(3,4-二氟-苯基)-1-{4-[(9H-芴-9-基甲氧基羰基氨基)-甲基]-苄基氨基甲酰}-乙基)-氨基甲酸叔丁酯(2.60g,4.05mmol,64%)。
[M+H]+=641.9,664.07(M+Na)
D.(4-{[(S)-2-氨基-3-(3,4-二氟-苯基)-丙酰氨基]-甲基}-苄基)-氨基甲酸9H-芴-9-基甲酯盐酸盐
((S)-2-(3,4-二氟-苯基)-1-{4-[(9H-芴-9-基甲氧基羰基氨基)-甲基]-苄基氨基甲酰}-乙基)-氨基甲酸叔丁酯(2.5g,3.90mmol)溶解在在二烷(150mL)中的4M HCl中。在一小时后在室温,真空下除去溶剂,得到白色固体,其被确定为(4-{[(S)-2-氨基-3-(3,4-二氟-苯基)-丙酰氨基]-甲基}-苄基)-氨基甲酸9H-芴-9-基甲酯盐酸盐(2.25g,3.89mmol,100%)。
[M+H]+=542.12
E.[(R)-1-((S)-2-(3,4-二氟-苯基)-1-{4-[(9H-芴-9-基甲氧基羰基氨基)-甲基]-苄基氨基甲酰}-乙基氨基甲酰)-2-(4-乙氧基-苯基)-乙基]-氨基甲酸叔丁酯
(R)-2-叔丁氧基羰基氨基-3-(4-乙氧基-苯基)-丙酸(895mg,2.90mmol)溶解在CH2Cl2(250mL)和DMF(25mL)中。将此溶液冷却至0℃。加入(4-{[(S)-2-氨基-3-(3,4-二氟-苯基)-丙酰氨基]-甲基}-苄基)-氨基甲酸9H-芴-9-基甲酯盐酸盐(1.5g,2.63mmol)接着加入HOBt(391mg,2.90mmol)和三乙胺(800mg,7.89mmol)。然后加入水溶性碳二亚胺(605mg,3.16mmol)。在18小时后在0℃至室温,反应混合物用氯仿(200mL)洗涤,用0.3MKHSO4(1x30mL),NaHCO3(1x30mL),水(1x30mL),盐水(1x30mL)洗涤并在真空下蒸发,得到白色固体。残留物用乙酸乙酯/石油醚60-80℃研磨,得到白色固体,其被确定为[(R)-1-((S)-2-(3,4-二氟-苯基)-1-{4-[(9H-芴-9-基甲氧基羰基氨基)-甲基]-苄基氨基甲酰}-乙基氨基甲酰)-2-(4-乙氧基-苯基)-乙基]-氨基甲酸叔丁酯(2.1g,2.52mmol,96%)。
[M+H]+=733.15(M-Boc)
F.(4-{[(S)-2-[(R)-2-氨基-3-(4-乙氧基-苯基)-丙酰氨基]-3-(3,4-二氟-苯基)-丙酰氨基]-甲基}-苄基)-氨基甲酸9H-芴-9-基甲酯盐酸盐
[(R)-1-((S)-2-(3,4-二氟-苯基)-1-{4-[(9H-芴-9-基甲氧基羰基氨基)-甲基]-苄基氨基甲酰}-乙基氨基甲酰)-2-(4-乙氧基-苯基)-乙基]-氨基甲酸叔丁酯(2.1g,2.52mmol)溶解在在二烷(150mL)中的4M HCl中。在一小时后在室温,在真空下除去溶剂并且残留物用丙酮研磨,得到白色固体,其被确定为(4-{[(S)-2-[(R)-2-氨基-3-(4-乙氧基-苯基)-丙酰氨基]-3-(3,4-二氟-苯基)-丙酰氨基]-甲基}-苄基)-氨基甲酸9H-芴-9-基甲酯盐酸盐(1.9g,2.47mmol,98%)。
[M+H]+=73.12
G.(4-{[(S)-2-[(R)-2-苯甲酰氨基-3-(4-乙氧基-苯基)-丙酰氨基]-3-(3,4-二氟-苯基)-丙酰氨基]-甲基}-苄基)-氨基甲酸9H-芴-9-基甲酯
(4-{[(S)-2-[(R)-2-氨基-3-(4-乙氧基-苯基)-丙酰氨基]-3-(3,4-二氟-苯基)-丙酰氨基]-甲基}-苄基)-氨基甲酸9H-芴-9-基甲酯盐酸盐(410mg,0.53mmol)溶解在二氯甲烷(50mL)中。将此溶液冷却至0℃并加入三乙胺(162mg,1.60mmol)接着加入苯甲酰氯(82mg,0.59mmol)。反应混合物在0℃至室温搅拌3小时并用CHCl3(100mL)稀释。滤液用0.3M KHSO4(1x30mL),饱和NaHCO3(1x30mL),水(1x30mL),盐水(1x30mL)洗涤,干燥(Na2SO4)并在真空下蒸发,得到白色固体。该固体用热乙醇研磨,并过滤冷却的混悬液,得到白色固体,其被确定为(4-{[(S)-2-[(R)-2-苯甲酰氨基-3-(4-乙氧基-苯基)-丙酰氨基]-3-(3,4-二氟-苯基)-丙酰氨基]-甲基}-苄基)-氨基甲酸9H-芴-9-基甲基酯(240mg,0.34mmol,99%)。
[M+H]+=697.18
H.N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-(3,4-二氟-苯基)-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-苯甲酰胺盐酸盐
(4-{[(S)-2-[(R)-2-苯甲酰氨基-3-(4-乙氧基-苯基)-丙酰氨基]-3-(3,4-二氟-苯基)-丙酰氨基]-甲基}-苄基)-氨基甲酸9H-芴-9-基甲基酯(180mg,0.215mmol)溶解在二乙胺/THF(1:1,100mL)中,反应混合物在室温搅拌3小时,之后在真空下除去溶剂并且残留物用乙酸乙酯/石油醚60-80℃研磨,得到白色固体,确定,将其用在二烷(20mL)中的4M HCl处理,在真空下除去溶剂并且残留物从EtOH重结晶,得到白色固体,其被确定为N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-(3,4-二氟-苯基)-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-苯甲酰胺盐酸盐(62mg,0.095mmol,44%)。
[M+H]+=614.68
1H NMR:(d6-DMSO)δ:1.26(3H,t,J=6.79Hz),2.65-2.84(3H,m),3.03-3.08(1H,m),3.92(2H,q,J=6.11Hz),3.96(2H,s),4.27-4.35(2H,m),4.57-4.63(2H,m),6.75(2H,d,J=8.03Hz),7.16(2H,d,J=8.76Hz),7.23-7.25(1H,m),7.26-7.27(2H,m),7.37-7.51(6H,m),7.43(1H,d,J=7.3Hz),7.73-7.75(2H,m),8.24(2H,s),8.50(1H,d,J=7.40Hz),8.67-8.71(2H,m).
实施例201
N-{(R,S)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲
酰]-2-[4-(2,2,2-三氟-乙氧基)-苯基]-乙基}-苯甲酰胺
A.(R,S)-2-苄氧基羰基氨基-3-[4-(2,2,2-三氟-乙氧基)-苯基]-丙酸
(R)-2-苄氧基羰基氨基-3-(4-羟基-苯基)-丙酸(1.0g,3.17mmol)溶解在THF(70mL)中,加入三氟甲磺酸2,22-三氟乙酯(883mg,3.81mmol)和碳酸铈(3.1g,9.51mmol)。反应混合物在65℃搅拌18小时,之后在真空下除去溶剂并且残留物放入EtOAc(100ml)中,此溶液用1M HCl(1x30mL),水(1x30mL),盐水(1x30mL)洗涤,干燥(Na2SO4)并在真空下蒸发。残留物通过快速色谱法(二氧化硅)纯化,洗脱剂1%AcOH,5%MeOH,94%CHCl3,合并级分并在真空下蒸发,得到无色油状物,其被确定为(R,S)-2-苄氧基羰基氨基-3-[4-(2,2,2-三氟-乙氧基)-苯基]-丙酸(380mg,0.96mmol,30%)。
[M+H]+=395.11
B.{(R,S)-1-{(S)-1-[4-(叔丁氧基羰基氨基-甲基)-苄基氨基甲酰]-2-苯基-乙基氨基甲酰}-2-[4-(2,2,2-三氟-乙氧基)-苯基]-乙基}-氨基甲酸苄基酯
(R,S)-2-苄氧基羰基氨基-3-[4-(2,2,2-三氟-乙氧基)-苯基]-丙酸(200mg,0.50mmol)溶解在CH2Cl2(50mL)和DMF(2.5mL)中。将此溶液冷却至0℃。加入{4-[((S)-2-氨基-3-苯基-丙酰氨基)-甲基]-苄基}-氨基甲酸叔丁酯(231mg,0.60mmol)接着加入HOBt(75mg,0.55mmol)和三乙胺(153mg,1.51mmol)。然后加入水溶性碳二亚胺(116mg,0.60mmol)。在18小时后在0℃至室温,反应混合物用氯仿(400mL)稀释,用0.3M KHSO4(1x30mL),NaHCO3(1x30mL),水(1x30mL),盐水(1x30mL)洗涤,干燥(Na2SO4)并在真空下蒸发,得到黄色油状物。残留物通过快速色谱法(二氧化硅)纯化,洗脱剂3%MeOH,97%CHCl3,合并级分并在真空下蒸发,得到白色固体,其被确定为{(R,S)-1-{(S)-1-[4-(叔丁氧基羰基氨基-甲基)-苄基氨基甲酰]-2-苯基-乙基氨基甲酰}-2-[4-(2,2,2-三氟-乙氧基)-苯基]-乙基}-氨基甲酸苄基酯(350mg,0.46mmol,92%)。
[M+H]+=663.43(M-Boc),785.44(M+Na)
C.{4-[((S)-2-{(R,S)-2-氨基-3-[4-(2,2,2-三氟-乙氧基)-苯基]-丙酰氨基}-3-苯基-丙酰氨基)-甲基]-苄基}-氨基甲酸叔丁酯
{(R,S)-1-{(S)-1-[4-(叔丁氧基羰基氨基-甲基)-苄基氨基甲酰]-2-苯基-乙基氨基甲酰}-2-[4-(2,2,2-三氟-乙氧基)-苯基]-乙基}-氨基甲酸苄基酯(350mg,0.46mmol)溶解在甲醇(100mL)中。此溶液在10%Pd/C(50mg)上在大气下氢化2小时,之后滤掉催化剂并用甲醇(100ml)洗涤,合并的滤液在真空下蒸发,得到白色固体,其被确定为{4-[((S)-2-{(R,S)-2-氨基-3-[4-(2,2,2-三氟-乙氧基)-苯基]-丙酰氨基}-3-苯基-丙酰氨基)-甲基]-苄基}-氨基甲酸叔丁酯(270mg,0.43mmol,94%)。
[M+H]+=629.40
D.{4-[((S)-2-{(R,S)-2-苯甲酰氨基-3-[4-(2,2,2-三氟-乙氧基)-苯基]-丙酰氨基}-3-苯基-丙酰氨基)-甲基]-苄基}-氨基甲酸叔丁酯
{4-[((S)-2-{(R,S)-2-氨基-3-[4-(2,2,2-三氟-乙氧基)-苯基]-丙酰氨基}-3-苯基-丙酰氨基)-甲基]-苄基}-氨基甲酸叔丁酯(250mg,0.40mmol)溶解在二氯甲烷(50mL)中。将此溶液冷却至0℃并加入三乙胺(121mg,1.19mmol)接着加入苯甲酰氯(61mg,0.44mmol)。反应混合物在0℃至室温搅拌18小时并用CHCl3(100ml)稀释,滤液用0.3M KHSO4(1x30mL),饱和NaHCO3(1x30mL),水(1x30mL),盐水(1x30mL)洗涤,干燥(Na2SO4)并在真空下蒸发,得到白色固体。该固体用乙酸乙酯/石油醚60-80℃研磨,得到白色固体,其被确定为{4-[((S)-2-{(R,S)-2-苯甲酰氨基-3-[4-(2,2,2-三氟-乙氧基)-苯基]-丙酰氨基}-3-苯基-丙酰氨基)-甲基]-苄基}-氨基甲酸叔丁酯(190mg,0.26mmol,65%)。
[M+H]+=733.357,755.49(M+Na)
E.N-{(R,S)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-[4-(2,2,2-三氟-乙氧基)-苯基]-乙基}-苯甲酰胺二三氟乙酸盐
{4-[((S)-2-{(R,S)-2-苯甲酰氨基-3-[4-(2,2,2-三氟-乙氧基)-苯基]-丙酰氨基}-3-苯基-丙酰氨基)-甲基]-苄基}-氨基甲酸叔丁酯(190mg,0.26mmol)用4M HCl/二烷(50mL)处理。在一小时后在室温,除去溶剂。残留物通过制备HPLC(Sunfire制备型C18OBD柱。19x250mm,10μ)纯化。10至90%0.1%TFA/MeCN到0.1%TFA/H2O,在35min内,以20ml/min。合并级分并冷冻干燥,得到白色固体,其被确定为N-{(R,S)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-[4-(2,2,2-三氟-乙氧基)-苯基]-乙基}-苯甲酰胺二三氟乙酸盐(56mg,0.075mmol,29%)。
[M+H]+=632.51
1H NMR(d6-DMSO)δ:2.68(1H,d,J=7.44Hz),2.82-3.08(5H,m),3.98(2H,d,J=5.92Hz),4.31-4.34(2H,m),4.60-4.70(4H,m),6.90-6.94(2H,m),7.16-7.28(6H,m),7.34-7.37(2H,m),7.43-7.52(3H,m),7.74-7.79(2H,m),8.09(3H,s,br),8.47(1H,d,J=8.45Hz),8.58-8.62(2H,m)。
在磷酸盐缓冲液中的动力学溶解度的确定
使用标准公开的方法通过比浊法测定溶解度(Lipinski等.AdvancedDrug Delivery Reviews23(1997)3-25)。在DMSO中制备10mM化合物储液,将其加入到25mM pH7.0磷酸钠缓冲液中以制备范围为12至235μM的浓度。在振荡大约30秒后,测量这些样品在650nm的光透射减少(Molecular Devices Spectromax UV/可见光分光光度计)。在大约30秒后进行第二次测量。采用大于0.005的吸光度来指示化合物发生的一些沉淀,并因此该化合物在该浓度下是不溶的。
从这些测定中获得的数据显示在下表8中:
表8
在磷酸盐缓冲液中的热力学溶解度的确定
化合物的热力学溶解度在磷酸铝缓冲液(pH7.4,290mOsm)中测定。以1mg/mL的标称浓度制备化合物,涡旋然后在振荡器上放置1h,37℃,大约950rpm。在温育后,将样品转移到eppendorf管并在37℃以15,000g(r.c.f.)离心10分钟。上清中的化合物的浓度使用制备自DMSO储液的校准线通过LC-MS/MS分析测定。
从这些测定中获得的数据显示在下表9中:
表9
生物学方法
式(I)化合物抑制血浆激肽释放酶的能力可以使用以下生物学测定确定:
血浆激肽释放酶的IC
50
的确定
血浆激肽释放酶体外抑制活性使用标准公开的方法确定(参见例如Johansen等,Int.J.Tiss.Reac.1986,8,185;Shori等,Biochem.Pharmacol.,1992,43,1209;Stürzebecher等,Biol.Chem.Hoppe-Seyler,1992,373,1025)。人血浆激肽释放酶(Protogen)在37℃与荧光底物H-DPro-Phe-Arg-AFC和各种浓度的试验化合物温育。残留的酶活性(初始反应速率)通过测量在410nm的光学吸光度的变化确定并且确定试验化合物的IC50值。
从此测定获得的数据显示在下表10和11中:
表10
表11
实施例编号 | IC50(人PKal)(μM) |
68 | 0.861 |
69 | 0.621 |
70 | 0.126 |
71 | 0.077 |
72 | 0.046 |
73 | 0.025 |
74 | 0.545 |
75 | 0.270 |
76 | 0.452 |
77 | 1.959 |
78 | 10.000 |
79 | 0.038 |
80 | 0.398 |
81 | 0.040 |
82 | 0.539 |
83 | 0.254 |
84 | 0.219 |
85 | 0.485 |
86 | 0.423 |
87 | 0.755 |
88 | 0.090 |
89 | 0.099 |
90 | 0.276 |
91 | 2.083 |
92 | 0.032 |
93 | 0.175 |
94 | 1.080 |
95 | 0.046 |
96 | 0.764 |
97 | 0.241 |
98 | 0.576 |
99 | 0.095 |
100 | 0.474 |
101 | 1.113 |
102 | 10.000 |
103 | 10.000 |
104 | 0.159 |
105 | 0.185 |
106 | 0.256 |
107 | 0.133 |
108 | 0.232 |
109 | 0.155 |
110 | 0.598 |
111 | 0.058 |
112 | 0.298 |
113 | 0.455 |
114 | 0.427 |
115 | 0.417 |
116 | 0.018 |
117 | 0.048 |
118 | 0.061 |
119 | 0.015 |
120 | 0.540 |
121 | 0.310 |
122 | 0.519 |
123 | 0.214 |
124 | 0.020 |
125 | 0.010 |
126 | 4.013 |
127 | 0.521 |
128 | 2.009 |
129 | 10.000 |
130 | 2.491 |
131 | 0.040 |
132 | 1.209 |
133 | 10.000 |
134 | 10.000 |
135 | 0.424 |
136 | 1.017 |
137 | 7.540 |
138 | 0.310 |
139 | 1.141 |
140 | 0.045 |
141 | 0.055 |
142 | 0.096 |
143 | 0.083 |
144 | 0.340 |
145 | 0.025 |
146 | 0.232 |
147 | 0.284 |
148 | 0.934 |
149 | 0.091 |
150 | 0.051 |
151 | 0.009 |
152 | 0.023 |
153 | 0.010 |
154 | 0.021 |
155 | 0.022 |
156 | 1.083 |
157 | 0.036 |
158 | 0.047 |
159 | 0.015 |
160 | 0.010 |
161 | 0.049 |
162 | 0.010 |
163 | 0.064 |
164 | 0.050 |
165 | 0.070 |
166 | 0.262 |
167 | 0.080 |
168 | 0.076 |
169 | 0.044 |
170 | 0.051 |
171 | 0.123 |
172 | 0.881 |
173 | 0.213 |
174 | 0.045 |
175 | 0.003 |
176 | 0.028 |
177 | 0.457 |
178 | 0.042 |
179 | 0.022 |
180 | 0.073 |
181 | 0.010 |
182 | 0.015 |
183 | 0.016 |
184 | 0.010 |
185 | 0.049 |
186 | 0.014 |
187 | 0.007 |
188 | 0.036 |
189 | 0.023 |
190 | 0.028 |
191 | 0.020 |
192 | 0.012 |
193 | 0.025 |
194 | 0.013 |
195 | 0.014 |
196 | 0.032 |
197 | 0.012 |
198 | 0.007 |
199 | 0.010 |
200 | 0.045 |
201 | 0.012 |
对于针对相关酶KLK1的抑制活性进一步筛选所选的化合物。式(I)化合物抑制KLK1的能力可以使用以下生物学测定确定:
对于KLK1的IC50的确定
体外KLK1抑制活性使用标准公开的方法确定(参见例如Johansen等,Int.J.Tiss.Reac.1986,8,185;Shori等,Biochem.Pharmacol.,1992,43,1209;Stürzebecher等,Biol.Chem.Hoppe-Seyler,1992,373,1025)。人KLK1(Callbiochem)在37℃与荧光底物H-DVal-Leu-Arg-AFC和各种浓度的试验化合物温育。残留酶活性(初始反应速率)通过测量在410nm的光学吸光度的变化确定并确定试验化合物的IC50值。
从此测定获得的数据显示在下表12和13中:
表12
表13
实施例编号 | IC50(人KLK1)(μM) |
68 | >10 |
69 | >10 |
70 | 7.5 |
71 | >10 |
72 | 9.1 |
73 | 9.3 |
74 | >10 |
75 | >10 |
76 | 3.6 |
77 | >10 |
78 | >10 |
79 | 8.6 |
80 | >10 |
81 | >10 |
82 | >10 |
83 | >10 |
84 | 1.2 |
85 | 2.9 |
86 | >10 |
87 | 3.4 |
88 | >10 |
89 | 3.7 |
90 | >10 |
91 | >10 |
92 | >10 |
93 | >10 |
94 | >10 |
95 | >10 |
96 | >10 |
97 | 4.7 |
98 | 5.1 |
99 | >10 |
100 | 2.9 |
101 | >10 |
102 | 9.0 |
103 | >10 |
104 | >10 |
105 | >10 |
106 | 8.4 |
107 | 7.5 |
108 | >10 |
109 | >10 |
110 | >10 |
111 | >10 |
112 | >10 |
113 | >10 |
114 | >10 |
115 | 9.0 |
116 | 6.3 |
117 | 6.1 |
118 | >10 |
119 | 6.1 |
120 | >10 |
121 | >10 |
122 | 4.8 |
123 | >10 |
124 | 8.4 |
125 | 7.0 |
126 | >10 |
127 | >10 |
128 | >10 |
129 | >10 |
130 | >10 |
131 | 9.5 |
132 | >10 |
133 | >10 |
134 | >10 |
135 | >10 |
136 | >10 |
137 | >10 |
138 | >10 |
139 | >10 |
140 | >10 |
141 | >10 |
142 | >10 |
143 | >10 |
144 | >10 |
145 | >10 |
146 | >10 |
147 | >10 |
148 | >10 |
149 | >10 |
150 | >10 |
151 | >10 |
152 | >10 |
153 | >10 |
154 | >10 |
155 | >10 |
156 | >10 |
157 | >10 |
158 | >10 |
159 | >10 |
160 | >10 |
161 | 6.9 |
162 | >10 |
163 | >10 |
164 | >10 |
165 | >10 |
166 | >10 |
167 | >10 |
168 | >10 |
169 | 9.9 |
170 | >10 |
171 | 9.4 |
172 | >10 |
173 | >10 |
174 | >10 |
175 | >10 |
176 | >10 |
177 | >10 |
178 | >10 |
179 | 7.2 |
180 | >10 |
181 | >10 |
182 | >10 |
183 | >10 |
184 | >10 |
185 | >10 |
186 | 3.8 |
187 | >10 |
188 | >10 |
189 | >10 |
190 | >10 |
191 | >10 |
192 | >10 |
193 | >10 |
194 | 7.1 |
195 | >10 |
196 | 9.9 |
197 | >10 |
198 | 9.1 |
199 | >10 |
200 | 7.6 |
201 | >10 |
对于针对相关酶纤溶酶、凝血酶、胰蛋白酶、因子Xa和因子XIIa的抑制活性进一步筛选所选的化合物。式(I)化合物对这些酶的能力使用以下生物学测定确定:
酶选择性的确定
使用适当荧光底物测定人丝氨酸蛋白酶纤溶酶、凝血酶、胰蛋白酶、因子Xa和因子XIIa的酶活性。蛋白酶活性通过监测在5分钟内从所述底物释放的荧光的累积进行测量。每分钟荧光增加的线性速率表示为百分比(%)活性。每种底物分解的Km通过Michaelis-Menten方程的标准转换确定。以底物Km浓度进行化合物抑制剂测定并且将活性计算为获得未抑制的酶活性(100%)的50%抑制的抑制剂的浓度(IC50)。
从这些测定获得的数据显示在下表14中:
表14(选择性数据)
表15(选择性数据:因子XIIa)
实施例编号 | IC50(因子XIIa)(μM) |
3 | >10 |
85 | >10 |
91 | >10 |
92 | >10 |
93 | >10 |
94 | >10 |
95 | >10 |
96 | >10 |
157 | >10 |
182 | >10 |
183 | >10 |
184 | >10 |
185 | >10 |
186 | >10 |
187 | >10 |
188 | >10 |
189 | >10 |
190 | >10 |
191 | >10 |
192 | >10 |
193 | >10 |
194 | >10 |
195 | >10 |
196 | >10 |
197 | >10 |
198 | >10 |
199 | >10 |
201 | >10 |
碳酸酐酶I诱导的视网膜血管通透性模型
实施例3的活性已在大鼠中利用此体内模型建立。在时间0,大鼠接受玻璃体内注射(5μL)的磷酸缓冲盐水(PBS),CH-3457(一种血浆激肽释放酶抑制剂阳性对照)(10μM)或实施例3(1μM)。在30min后,给予第二次玻璃体内注射(5μL)的PBS或CA-I(200ng/眼)。在15分钟后,灌注10%荧光素钠并在初始IVT注射后75分钟后通过玻璃体荧光光度测定法测量视网膜血管通透性(RVP)。实施例3的数据呈现在图1中,其中下虚线指示PBS/PBS后的基础RVP并且上虚线指示最大刺激。相比于单独的PBS,单独的玻璃体内注射1μM实施例3对基础RVP没有影响(3.29±0.21vs.3.64±0.48)。玻璃体内注射实施例3降低了53±21%的RVP(通过CA-I注射刺激的)。
药代动力学
进行实施例3的药动学研究以评估在花兔(荷兰黑带兔)中单次IVT剂量后的眼部和系统药动学。对每个剂量水平六只兔给予单次、两侧、IVT注射50μL的4.2μg/mL(210ng/眼)实施例3(配制在磷酸缓冲盐水中)。在每个时间点(在IVT施用后4,8,24,48,96和168小时)使一只兔安乐死并且测量在玻璃体、视网膜/脉络膜和眼房水中的实施例3的眼组织浓度。在存活兔中收集系列血液样品。
眼组织浓度数据呈现在图2中,其中对于每个眼组织浓度的实线是每只兔的左右眼的平均值。实施例3的眼组织浓度的下降在7天内最小。在IVT施用后实施例3的血浆浓度在所有时间点都低于1ng/mL。
Claims (19)
1.一种下式I的化合物,
其中:
R1选自H,烷基,-CO烷基,-CO芳基,-CO杂芳基,-CO2烷基,-(CH2)aOH,-(CH2)bCOOR10,-(CH2)cCONH2,-SO2烷基,-SO2芳基,-SO2(CH2)hR13,-CO(CH2)iR14,-CO环烷基,-COCH=CHR15,-CO(CH2)jNHCO(CH2)kR16和-CONR17R18;
R2选自H和烷基;
R3选自H,烷基,-(CH2)d芳基,-(CH2)e杂芳基,-(CH2)f环烷基,-(CH2)g杂环烷基,-CH(环烷基)2,-CH(杂环烷基)2和-(CH2)l芳基-O-(CH2)m-芳基;
R4和R6独立地选自H和烷基;
R5选自H,烷基,烷氧基和OH;
或R4和R5,连同它们连接的原子一起,可以连接形成5或6元氮杂环烷基结构;
R7和R8独立地选自H,烷基,烷氧基,CN,卤素和CF3;
R9是芳基或杂芳基;
R10是H或烷基;
a,b,c,d,e,f,g,h,i,j,l和m独立地是1,2或3;
k是0,1,2或3;
*1和*2表示手性中心;
烷基是具有至多可达10个碳原子(C1-C10)的直链饱和烃或具有3至10个碳原子(C3-C10)的支链饱和烃;烷基可以任选地被1或2个独立地选自(C3-C10)环烷基、(C1-C6)烷氧基、OH、CN、CF3、COOR11、氟和NR11R12的取代基取代;
环烷基为3至10个碳原子的单环或双环饱和烃;环烷基可以任选地与芳基稠合;或环烷基是金刚烷基;
杂环烷基是C-连接或N-连接的3至10元饱和的单环或双环,其中所述杂环烷基的环在可能的情况下含有1、2或3个独立地选自N、NR11和O的杂原子;
烷氧基是1至6个碳原子(C1-C6)的直链O-连接烃或3至6个碳原子(C3-C6)的支链O-连接烃;烷氧基可以任选地被1或2个独立地选自(C3-C10)环烷基、OH、CN、CF3、COOR11、氟和NR11R12的取代基取代;
芳基是苯基、联苯基或萘基;芳基可以任选地被至多可达5个独立地选自烷基、烷氧基、OH、卤素、CN、COOR11、CF3和NR11R12的取代基取代;
杂芳基是5、6、9或10元单环或双环芳族环,其在可能的情况下含有1、2或3个独立地选自N、NR11、S和O的环成员;杂芳基可以任选地被1、2或3个独立地选自烷基、烷氧基、OH、卤素、CN、COOR11、CF3、NR11R12和NHR19的取代基取代;
R11和R12独立地选自H和烷基;
R13是芳基或杂芳基;
R14是芳基,杂芳基,环烷基或杂环烷基;
R15是H,烷基,芳基,杂芳基,环烷基或杂环烷基;
R16是H,芳基或杂芳基;
R17是H,烷基,芳基,杂芳基或杂环烷基;
R18是-(CH2)mR21,其中m是0,1,2或3并且R21是H,芳基或杂芳基;
R19是-CO烷基,-CO芳基或-CO杂芳基;
及其互变异构体、异构体、立体异构体(包括对映异构体、非对映异构体、及其外消旋及非外消旋混合物)、药用盐和溶剂化物。
2.根据权利要求1的化合物,其中R9选自苯基和萘基,其中苯基可以任选地被至多可达3个独立地选自烷基,烷氧基,OH,卤素,CN,COOR11,CF3和NR11R12的取代基取代。
3.根据权利要求1或权利要求2的化合物,其中R9选自苯基,1-萘,2,4-二氯苯基,3,4-二氯苯基,3,4-二氟苯基,4-氯苯基,4-三氟甲基苯基和4-乙氧基苯基。
4.根据权利要求1至3中任一项的化合物,其中R1选自H,-CO芳基,-CO烷基,-CH2COOH,-SO2Ph和-SO2CH3。
5.根据权利要求1至4中任一项的化合物,其中R1选自-CO烷基和–CO芳基。
7.根据权利要求1至6中任一项的化合物,其中R4和R6选自H和CH3。
8.根据权利要求1至7中任一项的化合物,其中在手性中心*1周围的立体化学构型为R。
9.根据权利要求1至8中任一项的化合物,其中在手性中心*2周围的立体化学构型为S。
10.根据权利要求1至9中任一项的化合物,其中a是2并且b,c,d,e,f,g,h,j,l和m是1。
11.根据权利要求1的化合物,其选自:
(S)-N-(4-氨基甲基-苄基)-2-[(R)-3-(4-乙氧基-苯基)-2-丙酰氨基-丙酰氨基]-3-苯基-丙酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-苯甲酰胺;
{(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-环己基-乙基氨基}-乙酸;
(S)-N-(4-氨基甲基-3-氟-苄基)-2-[(R)-3-(4-乙氧基-苯基)-2-丙酰氨基-丙酰氨基]-3-苯基-丙酰胺;
(S)-N-(4-氨基甲基-2-氯-苄基)-2-[(R)-3-(4-乙氧基-苯基)-2-丙酰氨基-丙酰氨基]-3-苯基-丙酰胺;
(S)-N-(4-氨基甲基-苄基)-3-(3,4-二氯-苯基)-2-[(R)-3-(4-乙氧基-苯基)-2-丙酰氨基-丙酰氨基]-丙酰胺;
(S)-N-(4-氨基甲基-3-氯-苄基)-2-[(R)-3-(4-乙氧基-苯基)-2-丙酰氨基-丙酰氨基]-3-苯基-丙酰胺;
(S)-N-(4-氨基甲基-苄基)-2-{[(R)-3-(4-乙氧基-苯基)-2-丙酰氨基-丙酰]-甲基-氨基}-3-苯基-丙酰胺;
({(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-环己基-乙基}-甲基-氨基)-乙酸;
(S)-N-(4-氨基甲基-3-氟-苄基)-2-{[(R)-3-(4-乙氧基-苯基)-2-丙酰氨基-丙酰]-甲基-氨基}-3-苯基-丙酰胺;
N-[(R)-1-{[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基]-甲基-氨基甲酰}-2-(4-乙氧基-苯基)-乙基]-苯甲酰胺;
N-[(R)-1-{[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基]-甲基-氨基甲酰}-2-(4-乙氧基-苯基)-乙基]-异丁酰胺;
萘-1-甲酸[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-4-氯-苯甲酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-2,4-二氯-苯甲酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-3,4-二氟-苯甲酰胺;
(R)-2-氨基-N-[(1S,2S)-1-(4-氨基甲基-苄基氨基甲酰)-2-羟基-2-苯基-乙基]-3-(4-乙氧基-苯基)-丙酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-烟酰胺;
(2S,3S)-N-(4-氨基甲基-苄基)-2-[(R)-3-(4-乙氧基-苯基)-2-丙酰氨基-丙酰氨基]-3-羟基-3-苯基-丙酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-异烟酰胺;
噻吩-3-甲酸-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-酰胺;
噻吩-2-甲酸[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-酰胺;
环己烷甲酸[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-酰胺;
吡啶-2-甲酸[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-酰胺;
苯并[b]噻吩-2-甲酸[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-酰胺;
(R)-N-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基]-2-(4-氯-苯磺酰氨基)-3-(4-乙氧基-苯基)-丙酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-3-氯-苯甲酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-2-氯-苯甲酰胺
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-3-三氟甲基-苯甲酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-4-甲基-苯甲酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-3,4-二氯-苯甲酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-4-甲氧基-苯甲酰胺;
(S)-N-(4-氨基甲基-苄基)-2-[(R)-3-(4-乙氧基-苯基)-2-(2-苯基乙酰氨基-乙酰氨基)-丙酰氨基]-3-苯基-丙酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-4-氟-苯甲酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-6-甲基-烟酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-2-甲基-烟酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-2,6-二氯-烟酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-5,6-二氯-烟酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-2,3,6-三氟-异烟酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-3,3,3-三氟-丙酰胺;
2,4-二甲基-噻唑-5-甲酸[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-酰胺;
2-甲基-噻唑-5-甲酸[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-酰胺;
3-氯-噻吩-2-甲酸[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-酰胺;
4-甲基-噻唑-5-甲酸[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-酰胺;
呋喃-2-甲酸[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-酰胺;
3-甲基-噻吩-2-甲酸[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-2-甲氧基-异烟酰胺;
3-甲基-1H-吡咯-2-甲酸[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-酰胺;
3-氨基-噻吩-2-甲酸[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-丙氧基-苯基)-乙基]-苯甲酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-吡啶-2-基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-苯甲酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-(3,4-二氯-苯基)-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-苯甲酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-(4-氯-苯基)-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-苯甲酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-(4-氟-苯基)-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-苯甲酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-吡啶-3-基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-苯甲酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-(4-甲氧基-苯基)-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-苯甲酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-吡啶-4-基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-苯甲酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-(3-氟-苯基)-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-苯甲酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-噻吩-2-基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-苯甲酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-噻吩-3-基-乙基氨基甲酰-2-(4-乙氧基-苯基)-乙基]-苯甲酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-噻唑-4-基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-苯甲酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯并[b]噻吩-3-基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-苯甲酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-3-氟-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-苯甲酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-3-氯-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-苯甲酰胺;
吡啶-2-甲酸[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-噻吩-2-基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-吡啶-2-基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-4-甲氧基-苯甲酰胺;
吡啶-2-甲酸[(R)-1-[(S)-1-(4-氨基甲基-3-氯-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-吡啶-3-基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-4-甲氧基-苯甲酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-(3,4-二氟-苯基)-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-异烟酰胺;
噻吩-2-甲酸[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-吡啶-3-基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-吡啶-2-基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-4-氯-苯甲酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-吡啶-2-基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-4-甲基-苯甲酰胺;
吡啶-2-甲酸[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-(3,4-二氯-苯基)-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-酰胺;
(R)-N-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-吡啶-2-基-乙基]-3-(4-乙氧基-苯基)-2-丙酰氨基-丙酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-3-氟-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-异烟酰胺;
吡啶-2-甲酸[(R)-1-[(S)-1-(4-氨基甲基-3-氟-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-酰胺;
噻吩-2-甲酸[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-(3,4-二氯-苯基)-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-酰胺;
(R)-N-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-吡啶-3-基-乙基]-3-(4-乙氧基-苯基)-2-丙酰氨基-丙酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-(3,4-二氯-苯基)-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-异烟酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-(3,4-二氯-苯基)-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-3,3,3-三氟-丙酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-吡啶-3-基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-4-氯-苯甲酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-吡啶-3-基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-4-甲基-苯甲酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-(3,4-二氟-苯基)-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-苯甲酰胺;
3-氯-噻吩-2-甲酸[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-吡啶-3-基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-(1H-吲哚-3-基)-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-苯甲酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯并[b]噻吩-3-基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-异烟酰胺;
3-乙酰氨基-噻吩-2-甲酸-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-(2-氟-苯基)-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-苯甲酰胺;
3-甲基-噻吩-2-甲酸[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-吡啶-3-基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-3-甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-苯甲酰胺;
3-氨基-噻吩-2-甲酸[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-噻唑-4-基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-酰胺;
3-氯-噻吩-2-甲酸[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-噻唑-4-基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-噻唑-4-基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-4-甲基-苯甲酰胺;
3-甲基-1H-吡咯-2-甲酸[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯并[b]噻吩-3-基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-酰胺;
3-氨基-噻吩-2-甲酸[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-噻唑-4-基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-酰胺;
3-乙酰氨基-噻吩-2-甲酸[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯并[b]噻吩-3-基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-吡啶-3-基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-3-甲基-苯甲酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-吡啶-3-基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-2-甲基-苯甲酰胺;
3,5-二甲基-1H-吡咯-2-甲酸[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-3-甲基-苄基氨基甲酰)-2-吡啶-3-基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-苯甲酰胺;
3-乙酰氨基-噻吩-2-甲酸[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-噻吩-3-基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-酰胺;
3-氨基-噻吩-2-甲酸[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯并[b]噻吩-3-基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-酰胺;
3-乙酰氨基-噻吩-2-甲酸[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯并[b]噻吩-3-基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-酰胺;
3-氯-噻吩-2-甲酸[(R)-1-{[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基]-甲基-氨基甲酰}-2-(4-乙氧基-苯基)-乙基]-酰胺;
N-[(R)-1-[(1S,2R)-1-(4-氨基甲基-苄基氨基甲酰)-2-羟基-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-苯甲酰胺;
3-氯-噻吩-2-甲酸[(R)-1-[(1S,2R)-1-(4-氨基甲基-苄基氨基甲酰)-2-羟基-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-酰胺;
N-{(R,S)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-[4-(2,2,2-三氟-乙氧基)-苯基]-乙基}-苯甲酰胺;
及其药用盐和溶剂化物。
12.根据权利要求1的化合物,其选自:
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-苯甲酰胺;
萘-1-甲酸[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-4-氯-苯甲酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-2,4-二氯-苯甲酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-烟酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-3,4-二氟-苯甲酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-异烟酰胺;
噻吩-3-甲酸-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-酰胺;
噻吩-2-甲酸[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-酰胺;
环己烷甲酸[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-酰胺;
吡啶-2-甲酸[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-酰胺;
(R)-N-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基]-2-(4-氯-苯磺酰氨基)-3-(4-乙氧基-苯基)-丙酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-4-甲基-苯甲酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-3,4-二氯-苯甲酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-3-氯-苯甲酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-4-甲氧基-苯甲酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-4-氟-苯甲酰胺;
3-甲基-噻吩-2-甲酸[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-酰胺;
3-甲基-1H-吡咯-2-甲酸[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-酰胺;
3-氨基-噻吩-2-甲酸[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-丙氧基-苯基)-乙基]-苯甲酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-吡啶-2-基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-苯甲酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-(3,4-二氯-苯基)-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-苯甲酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-(4-氟-苯基)-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-苯甲酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-吡啶-3-基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-苯甲酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-噻吩-2-基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-苯甲酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-噻吩-3-基-乙基氨基甲酰-2-(4-乙氧基-苯基)-乙基]-苯甲酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯并[b]噻吩-3-基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-苯甲酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-3-氟-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-苯甲酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-3-氯-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-苯甲酰胺;
吡啶-2-甲酸[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-噻吩-2-基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-吡啶-2-基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-4-甲氧基-苯甲酰胺;
吡啶-2-甲酸[(R)-1-[(S)-1-(4-氨基甲基-3-氯-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-吡啶-3-基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-4-甲氧基-苯甲酰胺;
噻吩-2-甲酸[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-吡啶-3-基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-吡啶-3-基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-4-甲基-苯甲酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-(3,4-二氟-苯基)-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-苯甲酰胺;
3-氯-噻吩-2-甲酸[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-酰胺;
3-氯-噻吩-2-甲酸[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-吡啶-3-基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-(1H-吲哚-3-基)-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-苯甲酰胺;
N-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯并[b]噻吩-3-基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-异烟酰胺;
3-乙酰氨基-噻吩-2-甲酸-[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-苯基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-酰胺;
3-甲基-噻吩-2-甲酸[(R)-1-[(S)-1-(4-氨基甲基-苄基氨基甲酰)-2-吡啶-3-基-乙基氨基甲酰]-2-(4-乙氧基-苯基)-乙基]-酰胺;
及其药用盐和溶剂化物。
13.一种药物组合物,所述药物组合物包含:根据权利要求1至12中任一项的化合物;和药用载体、稀释剂或赋形剂。
14.根据权利要求1至12中任一项的化合物,其用在药品中。
15.根据权利要求1至12中任一项的化合物在制备药物中的用途,所述药物用于治疗或预防其中涉及血浆激肽释放酶活性的疾病或病症。
16.一种治疗其中涉及血浆激肽释放酶活性的疾病或病症的方法,所述方法包括向需要其的受试者施用治疗有效量的根据权利要求1至12中任一项的化合物。
17.根据权利要求1至12中任一项的化合物,其用于治疗其中涉及血浆激肽释放酶活性的疾病或病症的方法。
18.根据权利要求15的用途、根据权利要求16的方法或根据权利要求17的化合物,其中涉及血浆激肽释放酶活性的疾病或病症选自:受损视敏度,糖尿病视网膜病,糖尿病黄斑水肿,遗传性血管性水肿,糖尿病,胰腺炎,脑出血,肾病,心肌病,神经病,炎性肠病,关节炎,炎症,感染性休克,低血压,癌症,成人呼吸窘迫综合征,弥散性血管内凝血,心肺旁路手术和外科手术后出血。
19.根据权利要求15的用途、根据权利要求16的方法或根据权利要求17的化合物,其中涉及血浆激肽释放酶活性的疾病或病症是与糖尿病视网膜病和糖尿病黄斑水肿相关的视网膜血管通透性。
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US201161505305P | 2011-07-07 | 2011-07-07 | |
GB1111682.9A GB2494851A (en) | 2011-07-07 | 2011-07-07 | Plasma kallikrein inhibitors |
GB1111682.9 | 2011-07-07 | ||
US61/505,305 | 2011-07-07 | ||
PCT/GB2012/051588 WO2013005045A1 (en) | 2011-07-07 | 2012-07-06 | Benzylamine derivatives as inhibitors of plasma kallikrein |
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN113474318A (zh) * | 2019-04-22 | 2021-10-01 | 南京明德新药研发有限公司 | 用作血浆激肽释放酶抑制剂的双环烷类化合物 |
Families Citing this family (34)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
MY172013A (en) * | 2011-10-26 | 2019-11-12 | Allergan Inc | Amide derivatives of n-urea substituted amino acids as formyl peptide receptor like-1 (fprl-1) receptor modulators |
GB201212081D0 (en) * | 2012-07-06 | 2012-08-22 | Kalvista Pharmaceuticals Ltd | New polymorph |
GB2510407A (en) | 2013-02-04 | 2014-08-06 | Kalvista Pharmaceuticals Ltd | Aqueous suspensions of kallikrein inhibitors for parenteral administration |
TWI636047B (zh) | 2013-08-14 | 2018-09-21 | 英商卡爾維斯塔製藥有限公司 | 雜環衍生物 |
USRE49816E1 (en) | 2014-01-10 | 2024-01-30 | Cornell University | Dipeptides as inhibitors of human immunoproteasomes |
EP3193904A4 (en) | 2014-08-18 | 2018-04-11 | Cornell University | Dipeptidomimetics as inhibitors of human immunoproteasomes |
GB201421085D0 (en) | 2014-11-27 | 2015-01-14 | Kalvista Pharmaceuticals Ltd | New enzyme inhibitors |
GB201421083D0 (en) | 2014-11-27 | 2015-01-14 | Kalvista Pharmaceuticals Ltd | Enzyme inhibitors |
EP3362754B1 (en) | 2015-10-15 | 2021-12-22 | Cornell University | Proteasome inhibitors and uses thereof |
HUE049918T2 (hu) | 2016-05-31 | 2020-11-30 | Kalvista Pharmaceuticals Ltd | Pirazol-származékok mint plazma kallikrein inhibitorok |
GB201609607D0 (en) | 2016-06-01 | 2016-07-13 | Kalvista Pharmaceuticals Ltd | Polymorphs of N-(3-Fluoro-4-methoxypyridin-2-yl)methyl)-3-(methoxymethyl)-1-({4-((2-oxopy ridin-1-yl)methyl)phenyl}methyl)pyrazole-4-carboxamide and salts |
GB201609603D0 (en) | 2016-06-01 | 2016-07-13 | Kalvista Pharmaceuticals Ltd | Polymorphs of N-[(6-cyano-2-fluoro-3-methoxyphenyl)Methyl]-3-(methoxymethyl)-1-({4-[(2-ox opyridin-1-YL)Methyl]phenyl}methyl)pyrazole-4-carboxamide |
GB201713660D0 (en) * | 2017-08-25 | 2017-10-11 | Kalvista Pharmaceuticals Ltd | Pharmaceutical compositions |
EP3694605A4 (en) | 2017-10-11 | 2021-10-27 | Cornell University | PEPTIDOMIMETIC PROTEASOME INHIBITORS |
GB201719881D0 (en) | 2017-11-29 | 2018-01-10 | Kalvista Pharmaceuticals Ltd | Solid forms of plasma kallikrein inhibitor and salts thereof |
LT3716952T (lt) | 2017-11-29 | 2022-04-11 | Kalvista Pharmaceuticals Limited | Vaisto formos, apimančios plazmos kalikreino inhibitorių |
EP3765459A1 (en) | 2018-03-13 | 2021-01-20 | Shire Human Genetic Therapies, Inc. | Substituted imidazopyridines as inhibitors of plasma kallikrein and uses thereof |
CN111217670B (zh) * | 2018-11-25 | 2021-04-09 | 中国科学院大连化学物理研究所 | 一种催化还原化合物中羰基为亚甲基的方法 |
GB201910116D0 (en) | 2019-07-15 | 2019-08-28 | Kalvista Pharmaceuticals Ltd | Treatments of hereditary angioedema |
GB201910125D0 (en) | 2019-07-15 | 2019-08-28 | Kalvista Pharmaceuticals Ltd | Treatments of angioedema |
WO2021028645A1 (en) | 2019-08-09 | 2021-02-18 | Kalvista Pharmaceuticals Limited | Plasma kallikrein inhibitors |
JP2022549601A (ja) | 2019-09-18 | 2022-11-28 | 武田薬品工業株式会社 | ヘテロアリール血漿カリクレインインヒビター |
CN114728962A (zh) | 2019-09-18 | 2022-07-08 | 武田药品工业有限公司 | 血浆激肽释放酶抑制剂及其用途 |
GB2591730A (en) | 2019-12-09 | 2021-08-11 | Kalvista Pharmaceuticals Ltd | New polymorphs |
GB201918994D0 (en) | 2019-12-20 | 2020-02-05 | Kalvista Pharmaceuticals Ltd | Treatments of diabetic macular edema and impaired visual acuity |
EP4116299A4 (en) | 2020-03-04 | 2024-03-27 | Medshine Discovery Inc | HETEROCYCLIC COMPOUND |
WO2021198534A1 (en) | 2020-04-04 | 2021-10-07 | Oxurion NV | Plasma kallikrein inhibitors for use in the treatment of coronaviral disease |
WO2022079446A1 (en) | 2020-10-15 | 2022-04-21 | Kalvista Pharmaceuticals Limited | Treatments of angioedema |
EP4232031A1 (en) | 2020-10-23 | 2023-08-30 | Kalvista Pharmaceuticals Limited | Treatments of angioedema |
EP4291186A1 (en) | 2021-02-09 | 2023-12-20 | Kalvista Pharmaceuticals Limited | Treatments of hereditary angioedema |
WO2023002219A1 (en) | 2021-07-23 | 2023-01-26 | Kalvista Pharmaceuticals Limited | Treatments of hereditary angioedema |
WO2023144030A1 (en) | 2022-01-31 | 2023-08-03 | Oxurion NV | Plasma kallikrein inhibitor therapy for anti-vegf sensitization |
WO2023148016A1 (en) | 2022-02-04 | 2023-08-10 | Oxurion NV | Biomarker for plasma kallikrein inhibitor therapy response |
EP4288036A1 (en) | 2022-04-27 | 2023-12-13 | Kalvista Pharmaceuticals Limited | Formulations of a plasma kallikrein inhibitor |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1364960A1 (en) * | 2001-02-02 | 2003-11-26 | Chugai Seiyaku Kabushiki Kaisha | Peptide derivatives |
CN1274713C (zh) * | 2002-03-08 | 2006-09-13 | 凡林有限公司 | 激肽释放酶抑制剂 |
CN101341129A (zh) * | 2005-12-14 | 2009-01-07 | 布里斯托尔-迈尔斯斯奎布公司 | 作为因子xia抑制剂的芳基丙酰胺,芳基丙烯酰胺,芳基丙炔酰胺,或芳基甲基脲类似物 |
CN101541742A (zh) * | 2006-10-24 | 2009-09-23 | 药物公司(莱比锡)有限公司 | 胰蛋白酶样丝氨酸蛋白酶抑制物、其制备和用途 |
CN101784516A (zh) * | 2007-06-13 | 2010-07-21 | 百时美施贵宝公司 | 作为凝血因子抑制剂的二肽类似物 |
Family Cites Families (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5187157A (en) | 1987-06-05 | 1993-02-16 | Du Pont Merck Pharmaceutical Company | Peptide boronic acid inhibitors of trypsin-like proteases |
GB9019558D0 (en) | 1990-09-07 | 1990-10-24 | Szelke Michael | Enzyme inhibitors |
SE9301911D0 (sv) | 1993-06-03 | 1993-06-03 | Ab Astra | New peptide derivatives |
US5589467A (en) | 1993-09-17 | 1996-12-31 | Novo Nordisk A/S | 2,5',N6-trisubstituted adenosine derivatives |
IL112795A (en) * | 1994-03-04 | 2001-01-28 | Astrazeneca Ab | Derivatives of peptides as antithrombotic drugs, their preparation, and pharmaceutical preparations containing them |
US5914319A (en) * | 1995-02-27 | 1999-06-22 | Eli Lilly And Company | Antithrombotic agents |
EP0820453A4 (en) * | 1995-04-04 | 2001-08-29 | Merck & Co Inc | THROMBIN INHIBITORS |
DE10301300B4 (de) | 2003-01-15 | 2009-07-16 | Curacyte Chemistry Gmbh | Verwendung von acylierten 4-Amidino- und 4-Guanidinobenzylaminen zur Inhibierung von Plasmakallikrein |
NZ592039A (en) | 2003-08-27 | 2013-03-28 | Ophthotech Corp | Combination therapy for the treatment of ocular neovascular disorders |
WO2008016883A2 (en) | 2006-07-31 | 2008-02-07 | Activesite Pharmaceuticals, Inc. | Inhibitors of plasma kallikrein |
JP5537442B2 (ja) | 2008-03-13 | 2014-07-02 | ブリストル−マイヤーズ スクイブ カンパニー | 第xia因子阻害剤としてのピリダジン誘導体 |
SG181811A1 (en) | 2009-12-18 | 2012-07-30 | Activesite Pharmaceuticals Inc | Prodrugs of inhibitors of plasma kallikrein |
ES2569983T3 (es) * | 2010-01-28 | 2016-05-13 | The Medicines Company (Leipzig) Gmbh | Inhibidores de serinproteasa de tipo tripsina y su preparación y uso |
JP2013121919A (ja) | 2010-03-25 | 2013-06-20 | Astellas Pharma Inc | 血漿カリクレイン阻害剤 |
ES2483802T3 (es) | 2010-07-07 | 2014-08-07 | The Medicines Company (Leipzig) Gmbh | Inhibidores de serina proteasa |
US9290485B2 (en) | 2010-08-04 | 2016-03-22 | Novartis Ag | N-((6-amino-pyridin-3-yl)methyl)-heteroaryl-carboxamides |
US8691861B2 (en) | 2011-04-13 | 2014-04-08 | Activesite Pharmaceuticals, Inc. | Prodrugs of inhibitors of plasma kallikrein |
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Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1364960A1 (en) * | 2001-02-02 | 2003-11-26 | Chugai Seiyaku Kabushiki Kaisha | Peptide derivatives |
CN1274713C (zh) * | 2002-03-08 | 2006-09-13 | 凡林有限公司 | 激肽释放酶抑制剂 |
CN101341129A (zh) * | 2005-12-14 | 2009-01-07 | 布里斯托尔-迈尔斯斯奎布公司 | 作为因子xia抑制剂的芳基丙酰胺,芳基丙烯酰胺,芳基丙炔酰胺,或芳基甲基脲类似物 |
CN101541742A (zh) * | 2006-10-24 | 2009-09-23 | 药物公司(莱比锡)有限公司 | 胰蛋白酶样丝氨酸蛋白酶抑制物、其制备和用途 |
CN101784516A (zh) * | 2007-06-13 | 2010-07-21 | 百时美施贵宝公司 | 作为凝血因子抑制剂的二肽类似物 |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN113474318A (zh) * | 2019-04-22 | 2021-10-01 | 南京明德新药研发有限公司 | 用作血浆激肽释放酶抑制剂的双环烷类化合物 |
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