CN102482269B - 脯氨酸衍生物 - Google Patents
脯氨酸衍生物 Download PDFInfo
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- CN102482269B CN102482269B CN201080002506.6A CN201080002506A CN102482269B CN 102482269 B CN102482269 B CN 102482269B CN 201080002506 A CN201080002506 A CN 201080002506A CN 102482269 B CN102482269 B CN 102482269B
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- pyrrolizidine
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- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
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- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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Abstract
本发明揭露一种本说明书所示的式(I)化合物:
Description
技术领域
本发明是关于一种脯氨酸衍生物。
本案主张于2009年12月4日申请的第61/266,584号美国临时申请案的优先权,其中全部内容合并于此以供参酌。
背景技术
目前估计全世界有1亿7千万人感染C型肝炎病毒(HCV),此疾病主要通过经污染的血液品传染,虽然其传播速度因许多国家血液筛检改善而已经缓慢下来,但仍旧是世界上因肝病致死的首要因素,单以美国举例而言,其每年大约可以造成1万的死亡人数。不过在缺乏有效治疗方法下,预估20年后死亡率会上翻三倍。
现阶段使用干扰素-α的治疗,尤其对于流行于美国、日本及欧洲等地区的基因型-1感染的治疗成功率低,而且其价格昂贵,病人的接受度差。因此,需要发展更好的治疗剂来治疗HCV感染。
发明内容
本发明出乎意料发现某种多环化合物,可以有效治疗C型肝炎病毒感染。
于某一态样,本发明关于一种式(I)化合物。
于式(I)中,A为B为C及D各自为亚芳基或亚杂芳基;R1、R2、R3、R4、R5与R6各自为烷基、烯基、炔基、芳基、杂芳基、环烷基、环烯基、杂环烷基、卤素、杂环烯基、氰基或硝基;R7及R8各自为H、烷基、烯基、炔基、芳基、杂芳基、环烷基、环烯基、杂环烷基或杂环烯基;R9及R10各自为H或烷基;R11及R12各自为H、烷基、烯基、炔基、芳基、杂芳基、环烷基、环烯基、杂环烷基或杂环烯基;X1及X2各自为C(O)或C(S);Y1及Y2不存在或各自为SO、SO2、C(O)、C(O)O、C(O)NRa、C(S)NRa或SO2NRa,其中Ra为H、烷基、环烷基、杂环烷基、芳基或杂芳基;m及n各自为0、1、2、3或4;p及q各自为0或1;r及t各自为1、2或3;以及u及v各自为0、1、2、3、4、5、6、7或8。
举例而言,本发明的化合物为式(II):
式(II)。
具体而言,这些化合物为式(III):
式(III)。
上述化合物可包括一个以上的以下特征。
A及B各为C及D各为亚苯基;X1及X2各为C(O);Y1及Y2各自为SO2、C(O)或C(O)O;R7及R8各为苯基;R11及R12各自为C1-5烷基或C3-5环烷基;t及r各为2;A及B为不同;p、m、n、q、u及v各为0;p、m、n与q各为0,u与v各为1且R5与R6各为F。
「烷基」一词是指直链或支链的单价碳氢基团,其包含1-20个碳原子(例如C1-C10),烷基举例包括但不限于:甲基、乙基、正丙基、异丙基、正丁基、异丁基及叔丁基。「烯基」一词是指直链或支链的单价碳氢基团,其包含2-20个碳原子(例如C2-C10)与一个以上的双键,烯基举例包括但不限于:乙烯基、丙烯基(propenyl)及烯丙基(allyl)。「炔基」一词是指直链或支链的单价碳氢基团,其包含2-20个碳原子(例如C2-C10)与一个以上的三键,炔基举例包括但不限于:乙烯基、1-丙炔基、1-及2-丁炔基与1-甲基-2-丁炔基。
「环烷基」一词是指单价饱和的碳氢环结构,其具有3至30个碳原子(例如C3-C12),环烷基举例包括但不限于:环丙基、环丁基、环戊基、环己基、环庚基及环辛基。「环烯基」一词是指单价非芳香性碳氢环结构,其具有3至30个碳原子(例如C3-C12)及一个以上的双键,环烷基举例包括:环戊烯基、环己烯基及环庚烯基。
「杂环烷基」一词是指单价非芳香性5-8元单环结构、8-12元双环结构或11-14元三环结构,其具有一个以上的杂原子(例如O、N、S或Se),杂环烷基举例包括但不限于:哌嗪基(piperazinyl)、吡咯烷基(pyrrolidinyl)、二恶烷基(dioxanyl)、吗啉基(morpholinyl)及四氢呋喃基(tetrahydrofuranyl)。「杂环烯基」一词是指单价非芳香性5-8元单环结构、8-12元双环结构或11-14元三环结构,其具有一个以上的杂原子(例如O、N、S或Se)及一个以上的双键。
「芳基」一词是指单价C6单环状、C10双环状或C14三环状芳香环系统,芳基举例包括但不限于:苯基、萘基及蒽基。「亚芳基」一词是指双价C6单环状(例如亚苯基)、C10双环状(例如亚萘基)或C14三环状芳香环系统。「杂芳基」一词是指单价芳香性5-8元单环、8-12元双环或11-14元三环结构,其具有一个以上的杂原子(例如O、N、S或Se),杂芳基举例包括:吡啶基(pyridyl)、呋喃基(furyl)、咪唑基(imidazolyl)、苯并咪唑基(benzimidazolyl)、嘧啶基(pyrimidinyl)、噻吩基(thienyl)、喹啉基(quinolinyl)、吲哚基(indolyl)及噻唑基(thiazolyl)。「亚杂芳基」一词是指双价芳香性5-8元单环、8-12元双环或11-14元三环结构,其具有一个以上的杂原子(例如O、N、S或Se)。
本文所述的烷基、烯基、炔基、环烷基、杂环烷基、环烯基、杂环烯基、芳基、亚芳基、杂芳基及亚杂芳基,包括经取代及未经取代的两种基团。在环烷基、杂环烷基、环烯基、杂环烯基、芳基及杂芳基上可能的取代基包括但不限于:C1-C10烷基(例如三氟甲基)、C2-C10烯基、C2-C16炔基(例如芳基炔基)、C3-C20环烷基、C3-C20环烯基、C1-C20杂环烷基、C1-C20杂环烯基、C1-C10烷氧基、芳基(例如卤芳基或以卤素取代的芳基)、芳氧基、杂芳基、杂芳氧基、胺基、C1-C10烷胺基、芳胺基、羟基、卤素、氧代基(O=)、硫代基(S=)、硫醇基、硅烷基、C1-C10烷硫醇基、芳硫醇基、C1-C10烷磺酰基(C1-C10alkylsulfonyl)、芳磺酰基、酰基胺基(acylamino)、胺基酰基(aminoacyl)、胺硫醇酰基(aminothioacyl)、甲脒基(amidino)、巯基(mercapto)、酰胺基(amido)、硫脲基(thioureido)、硫氰酸基(thiocyanato)、磺酰胺基(sulfonamido)、胍基(guanidine)、脲基(ureido)、氰基、硝基、酰基(acyl)、硫酰基(thioacyl)、酰氧基(acyloxy)、脲基(carbamido)、胺甲酰基(carbamyl)、羧酸基(carboxyl)以及碳酸酯基(carboxylic ester)。另一方面,于烷基、酰基或炔基上的可能取代基,包括上述所有取代基,但除了C1-C10烷基以外。环烷基、环烯基、杂环烷基、杂环烯基、芳基与杂芳基也可互相稠合。
上述多环化合物包括化合物本身、以及其可实施的盐类、溶剂化物与前驱药。举例而言,盐类可由多环化合物上带有正电基团(例如铵基)与阴离子所形成,而适合的阴离子包含氯离子、溴离子、碘离子、硫酸根、硫酸氢根、磺胺酸根、硝酸根、磷酸根、柠檬酸根、甲磺酸根、三氟乙酸根、谷胺酸根、醛糖酸根、戊二酸根、苹果酸根、马来酸根、琥珀酸根、延胡索酸根、酒石酸根、甲苯磺酸根、水杨酸根、乳酸根、萘磺酸根及乙酸根。
同样,盐类也可由多环化合物上带有负电的基团(例如羧酸根)与阳离子所形成,而适合的阳离子包含钠离子、钾离子、镁离子、钙离子及铵离子(如四甲基铵离子)。多环化合物亦包括含四级氮原子的这些盐类,而前驱药形式举例包含:酯类及其它医药上可接受的衍生物,根据给主体的投药方式,其能够提供具活性的多环化合物。
于另一态样,本发明关于一种HCV感染的治疗方法,其是通过将一种以上前述具有效剂量的多环化合物投药给一感染HCV的主体。
此外,一种含上述多环化合物且用于治疗HCV感染的医药组合物、以及此治疗用途与使用这些化合物制造HCV感染治疗药剂的用途,同样在本发明的范畴中。
本发明将于后文提出一个以上实施例的详细内容,由此描述及申请专利范围将更为了解本发明的其它特征、目的、以及优点。
具体实施方式
以下表1所示为本发明示例性化合物。
表1
以下亦显示一些额外举例的化合物:
本发明的化合物可使用已知化学转变方法(包括保护基方法论)进行制备,例如R.Larock,Comprehensive Organic Transformations,VCH Publishers(1989);T.W.Greene及P.G.M.Wuts,Protective Groups in Organic Synthesis,3rdEd.,John Wiley and Sons(1999);L.Fieser and M.Fieser,Fieser and Fieser’sReagents for Organic Synthesis,John Wiley and Sons(1994);以及L.Paquette,ed.,Encyclopedia of Reagents for Organic Synthesis,John Wiley and Sons(1995)及其后续版本中所述。以下流程1至13表示合成本发明化合物的转变过程。
流程1显示对称二噻唑基联苯类似物7a-c的制备。2-胺基-1-(4-溴苯基)乙酮盐酸盐与N-Boc-L-脯氨酸(N-Boc-L-proline)耦合后产出1,4-二羰基化合物1a-c,而后以劳森试剂(Lawesson’s reagent)处理1,4-二羰基中间物1a-c产出芳基溴化物2a-c。为了建构对称的联苯基骨架,芳基溴化物2a-c与双戊酰二硼(bis(pinacolato)diboron)反应生成对应的芳基硼酸酯3a-c,其于铃木-宫浦耦合条件(Suzuki-Miyaura coupling conditions)下与另一个等价的芳基噻唑溴化物2a-c耦合后可得对称的二噻唑基联苯基(化合物4a-c)。于酸中去除化合物4a-c的N-保护基,可得到衍生物5a-c,其与N-保护的苯基甘胺酸耦合后获得N-保护的对称联苯基肽6a-c,以酸处理6a-c去除Boc-保护基,粗产物接着与不同的烷基或芳基乙酰氯反应,便可获得最终酰化产物7a-c。
流程1
另一个合成途径如以下流程2所示,其可用于获得对称的二噻唑基联苯类似物7a-c。于此合成途径中,必须中间物4,4′-双(2-((S)-吡咯啶-2-基)噻唑-5-基)联苯(4,4′-bis(2-((S)-pyrrolidin-2-yl)thiazol-5-yl)biphenyls,化合物5a-c)可用流程1所示的类似方法制备,接着耦合5a-c与化合物8可获得类似物7a-c。
流程2
将流程1与2所示的合成路径修改后,可以制备出本发明某些化合物。举例而言,本发明化合物的各种多杂芳基团可由杂芳基溴化物(例如以下流程3-6所示的12a~c、16a~c、或21a~c)与芳基硼酸酯衍生物(例如亦于以下流程3-6所示的13a~c、20a~c、或22a~c)耦合而合成。
如以下流程3所示,可利用简单方法,使用碳酸铵直接将市面上可获得的N-Boc-L-脯氨酸9a~c转换成良好产率的初级酰胺10a~c。在温度提高下以劳森试剂处理(S)-N-Boc脯氨酸酰胺10a~c,可得(S)-N-Boc硫代胺甲酰基吡咯啶((S)-N-Boc carbamothioylpyrrolidine)11a~c,将11a~c与4-溴苯甲酰基溴甲烷(4-bromophenacyl bromide)于室温下缩合反应形成高产率的1,3-噻唑12a~c。使用双戊酰二硼做为基质,经由宫浦硼酸化反应(Miyauraboration),制备噻唑芳基硼酸酯衍生物13a~c,其中使用PdCl2(dppf)与醋酸钾做为催化剂。
流程3
如下流程4所示,可在碱性基质中回流反应4-溴苯甲腈(4-bromobenzonitrile)14与羟胺盐酸盐(hydroxylamine hydrochloride)而制备酰胺肟(amidoximes)15(包括协同及/或拮抗异构物),无需进一步纯化,使用酰胺肟15制备溴苯基1,2,4-恶二唑衍生物16a~c。更具体而言,4-溴苄胺肟(4-bromobenzamidoxime)15与市面上可得N-保护的L-脯氨酸9a~c于碱性环境下进行缩合反应,可得产率良好的化合物16a~c。
流程4
如以下流程5所示,胺芳基乙酮盐17与N-Boc-L-脯氨酸9a~c耦合,可获得化合物18a~c,其可用于制备苯基咪唑(如流程5所示)与苯基噻唑(如流程6所示)两者。于具有醋酸铵的加热条件下,化合物18a~c然后可进行环化反应,以形成苯基咪唑溴化物衍生物19a~c,其经过宫浦硼酸化反应可转化成咪唑基芳基硼酸酯衍生物20a~c。
流程5
如以下流程6所示,可使用劳森试剂回流化合物18a~c,于短时间内产生苯基噻唑溴化物21a~c。芳基硼酸酯衍生物22a~c可由苯基噻唑溴化物21a~c经过宫浦硼酸化反应而制备。
流程6
也可如以下流程7所示,由联苯化合物合成本发明的多环化合物。
流程7
以下流程8说明另一种经修改的方法,用以制备本发明多环化合物。于此合成途径中,必须中间物4,4′-双(2-((S)-吡咯啶-2-基)噻唑-5-基)联苯(流程1中的化合物5a),可耦合化合物93或94,以获得类似物95a-105a以及106a-114a。
流程8
以下流程9显示二噻唑基联苯119a的合成方法,其是二噻唑基联苯5a的立体异构物。
流程9
以下所示的流程10说明通过肽耦合条件(例如HOBt·H2O与EDC),由化合物5a与119a合成二噻唑基联苯肽6a、120a、121a与122a,去除该些二噻唑基联苯肽的保护基后,接着再与不同的烷基或芳基醋酸氯反应,产出所需的化合物7a与123a-127a。
流程10
以下流程11至13显示本发明多环化合物的典型合成途径。将芳基溴化物(例如上述12a~c、16a~c、或21a~c)与芳基硼酸酯(例如上述13a~c、20a~c、或22a~c)于铃木-宫浦耦合条件下进行反应,建构出N-保护不对称联苯化合物23a~c(如流程7至9所示)。于室温下,在三氟醋酸中对吡咯啶基团进行去N-保护基,产出N-保护基经去除的衍生物24a~c,然后与N-Boc-D-苯基甘胺酸耦合,获得不对称联苯化合物25a~c。在一步骤的方式中,25a~c可使用三氟醋酸处理而后与不同的烷基或芳基醋酸氯反应,便可提供最终的酰化产物26a~c。同样,可制备出其它经取代的化合物(例如以下流程11至13所示的30a~c、34a~c、38a~c、42a~c与46a~c)。
流程11
流程12
流程13
也可使用流程1至13所述的类似方法,并经过本领域通常知识者认为需要的改良来合成本发明的化合物。
如此所合成的化合物,更可经过快速管柱层析、高效能液相层析、结晶或任何其它适合方法来纯化。
于此所述的化合物,可包括数个非对称中心,因此其能以外消旋物(racemates)及消旋混合物(racemic mixtures)、单一镜像异构物、各自非镜像异构物、非镜像混合物、以及顺式或反式异构物的形式存在,所以所有这类的异构物皆考虑在内。
同样都落于本发明的范畴中者为(1)含一有效剂量的任何本发明化合物及一医药可接受载体的医药组合物、以及(2)将有效剂量的此种化合物投药给治疗所需主体的HCV感染治疗方法。
于此所使用的「治疗」一词,是指将一种化合物投予患有HCV感染、或具有其症状、或倾向这类疾病发展的主体,以期达到治疗、治愈、减轻、减缓、改变、医治、改善、改进、或影响上述病症、其症状、或朝其发展的倾向。「有效剂量」一词是指能够对于受治疗主体产生预期疗效所需的活性药剂量,对于有效剂量,本领域具有通常知识者可了解到其会根据投药路径、使用赋形剂、以及与其它药剂共同使用的可能性而改变。
为实行本发明所述的方法,上述医药组合物可经由口服、非口服、喷雾吸入、局部、经直肠、经鼻、舌下、阴道、或经由植入型药盒(implanted reservoir)等方式投药。于此使用的「非口服」(“parenteral”)是指皮下注射、皮内注射、静脉内注射、肌肉内注射、关节腔内注射、动脉内注射、关节液内注射、胸腔内注射、脊髓内注射、疾病部位内注射、及颅内注射或注入技术。
无菌可注射的组合物,例如无菌可注射水性或油性悬浮液,可根据本领域已知技术,使用适合的分散剂或湿润剂(如Tween 80)及悬浮剂来配制。无菌可注射的配制液可为无菌可注射的溶液、或是悬浮于无毒且非口服可接受的稀释液或溶剂中,例如1,3-丁二醇的溶液。可使用的可接受载体及溶剂为甘露醇(mannitol)、水、林格氏溶液(Ringer’s solution)及等渗透的氯化钠溶液。除此之外,无菌非挥发油是习用的溶剂或是悬浮介质(例如:合成单甘油酯或双甘油酯)。脂肪酸如油酸(oleic acid)与其甘油酯衍生物,亦可用于制备注射剂,天然医药可接受的用油,例如橄榄油或蓖麻油,特别是其多氧乙基化的型态,同样可用于制备。这些油酯溶液或悬浮液,可包含长链醇类稀释液或分散剂、羧甲基纤维素、或类似的分散剂。其它常用的表面活性剂,如Tween或Spans、或其它相似乳化剂、或一般医药制造业所使用于医药可接受的固态、液态或其它可用于剂型开发目的的剂量型式的生物可利用增强剂。
用于口服投药的组合物可为任何一种口服可接受的剂型,包括、但不限于:胶囊、锭片、乳化液与水悬浮液、分散液与溶液。以口服使用的锭片为例,一般所使用的载体为乳糖或是玉米淀粉,润滑剂(如硬脂酸镁)亦常被添入其中。以口服胶囊投药型式而言,可用的稀释剂包括乳糖与干燥玉米淀粉。当以水悬浮液或乳化液经口投药时,活性成分可悬浮或是溶解于混有乳化剂或悬浮剂的油状界面中。如果需要的话,可添加适度的甜味剂、风味剂或是色素。鼻用气化喷雾剂或吸入剂组合物,可根据医药剂型的领域中已知技术进行制备。含化合物的组合物,亦可以栓剂方式进行直肠投药。
医药组合物的载体必须为「可接受性」,即其必须与配方中的活性成份兼容(较佳是能稳定活性成份),并且不能对被治疗的试体造成伤害。举例而言,一种以上能与化合物形成溶解性更佳的复合物的溶解剂,可用为传递活性化合物的医药载体。其它载体举例包括胶质氧化硅、硬脂酸镁、月桂硫酸钠与D&C黄色10号。
本发明上述化合物可先以体外分析对其治疗上述疾病的效果进行筛选,然后再以动物实验及临床试验确认。对于其它方法,本领域通常知识者亦相当知晓。
上述已经足以实施本发明,而无需更多的阐述,因此下列特定具体实施例仅解释为说明性,无论以任何方式皆不限制本发明其余揭示范围。将本文所引述的所有发表文献及专利申请案全部并入本文以供参考。
实施例1:(S)-叔丁基2-(2-(4-溴苯基)-2-氧代乙基胺甲酰基)吡咯啶-1-羧酸酯((S)-tert-butyl 2-(2-(4-bromophenyl)- 2-oxoethylcarbamoyl)pyrrolidine-1-carboxylate(1a))的合成
N-Boc-L-脯氨酸(5.16g,24.0mmol)与HOBt·H2O(3.67g,24.0mmol)的溶液,于室温下搅拌10分钟,然后以N-乙基-N’-(3-二甲基胺基丙基)碳二酰亚胺盐酸盐(N-ethyl-N’-(3-dimethylaminopropyl)carbodiimide hydrochloride,EDC·HCl,4.60g,24.0mmol)处理。所得的混合液在室温下搅拌30分钟,然后以黄色溶液处理,其中该黄色溶液是于室温下经由搅拌2-胺基-4’-溴苯乙酮盐酸盐(2-amino-4’-bromoacetophenone hydrochloride,5.0g,20.0mmol)与N,N-二异丙基乙胺(N,N-diisopropylethylamine,DIPEA,2.58g,20mmol)持续10分钟所形成。所得的混合液在室温下搅拌过夜,然后以硅藻土过滤移除沉淀,滤液以二氯甲烷与水萃取后,有机层以卤水清洗、硫酸镁干燥、过滤并浓缩。残余物以管柱层析(醋酸乙酯∶正己烷=2∶5)纯化,可产出黄色胶体的纯产物1a(7.39g,90%)。
实施例2:(S)-叔丁基2-(5-(4-溴苯基)噻唑-2-基)吡咯啶-1-羧酸酯((S)-tert-butyl2-(5-(4-bromophenyl)thiazol-2-yl)pyrrolidine-1-carboxylate(2a))的合成
酮酰胺基质1a(25.26g,61.42mmol)的四氢呋喃溶液(THF,300ml)中加入劳森试剂(37.21g,92.11mmol),所得的混合液回流6小时后冷却至室温并减压浓缩。残余物以硅土管柱层析(醋酸乙酯∶正己烷=1∶2)纯化,可产出黄色固体的产物2a(19.6g,78%)。
实施例3:(S)-叔丁基2-(5-(4-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)苯基)噻唑-2-基)吡咯啶-1-羧酸酯((S)-tert-butyl 2-(5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)thiazol-2-yl)pyrrolid-ine-1-carboxylate(3a))的合成
填装有Pd(PPh3)4(0.49g,0.43mmol)、醋酸钾(2.09g,21.37mmol)与双戊酰二硼(5.16g,17.1mmol)、化合物2a(3.50g,8.55mmol)与1,4-二恶烷(100mL)的反应瓶中,注满氮气,然后反应混合液于80℃搅拌6小时,待冷却至室温后,过滤所得的混合液,滤液以减压浓缩,残余物以快速层析(醋酸乙酯∶正己烷=1∶2)纯化,可产出黄色胶体的产物3a(3.88g,99%)。
实施例4:(2S,2′S)-二叔丁基2,2′-(5,5′-(联苯-4,4′-二基)双(噻唑-5,2-二基))二吡咯啶-1-羧酸酯((2S,2′S)-di-tert-butyl 2,2′-(5,5′-(biphenyl-4,4′-diyl)bis(thiazole-5,2-diyl))dipyrrolidine-1-carboxyl-ate(4a))的合成
填装有PdCl2(dppf)(0.48g,0.59mmol)、碳酸钾(5.87g,42.5mmol)、2a(3.75g,9.16mmol)、3a(3.88g,8.5mmol)与1,2-二甲氧基乙烷(100mL)的反应瓶中,注满氮气,然后反应混合液于80℃搅拌18小时,待冷却至室温后,过滤所得的混合液,滤液以减压浓缩,残余物以管柱层析(醋酸乙酯∶正己烷=1∶2)纯化,可产出黄色胶体的产物4a(2.66g,47%)。
实施例5:4,4′-双(2-((S)-吡咯啶-2-基)噻唑-5-基)联苯(4,4′-bis(2-((S)-pyrrolidin-2-yl)thiazol-5-yl)biphenyl(5a))的合成
于室温下,化合物4a(2.66g,4.04mmol)的二氯甲烷溶液中加入三氟醋酸,所得的混合液搅拌2小时后减压浓缩可得粘性液体,此液体中加入蒸馏水及二氯甲烷,所得混合液冰浴冷却,加入饱和碳酸氢钠直至pH=8。混合液以二氯甲烷萃取(40mLx8),结合有机层,以硫酸镁干燥,过滤后浓缩。残余物以快速管柱层析(100%醋酸乙酯,然后甲醇∶二氯甲烷=1∶20)纯化,可产出纯产物5a(1.83g,99%)。
实施例6:(1R,1′R)-2,2′-((2S,2′S)-2,2′-(5,5′-(联苯-4,4′-二基)双(噻唑-5,2-二基))双(吡咯啶-2,1-二基))双(2-氧代-1-苯基乙烷-2,1-二基)二胺甲酸酯((1R,1′R)-2,2′-((2S,2′S)-2,2′-(5,5′-(biphenyl-4,4′-diyl)bis(thiazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(2-oxo-1-phenylethane-2,1-diyl)dicarbamate(6a))的合成
于室温下,N-Boc-D-苯基甘胺酸(2.21g,8.8mmol)的二甲基甲酰胺(30ml)溶液中加入全部的HOBt·H2O(1.35g,8.8mmol),该混合液于室温下搅拌10分钟后,加入EDC(1.68g,8.8mmol),所得的混合液搅拌30分钟,加入化合物5a(1.83g,4.0mmol)的二甲基甲酰胺(20ml)溶液。所得的混合液在室温下搅拌过夜,然后以醋酸乙酯及水萃取(去除HOBt盐类),有机层以硫酸镁干燥,过滤后浓缩。残余物以硅胶管柱层析(甲醇∶二氯甲烷=1∶20)纯化,可产出白色固体的纯产物6a(2.77g,75%)。
实施例7:N,N′-(1R,1′R)-2,2′-((2S,2′S)-2,2′-(5,5′-(联苯-4,4′-二基)双(噻唑-5,2-二基))双(吡咯啶-2,1-二基))双(2-氧代-1-苯基乙烷-2,1-二基)二环丙烷甲酰胺(N,N′-(1R,1′R)-2,2′-((2S,2′S)-2,2′-(5,5′-(biphenyl-4,4′-diyl)bis(thiazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(2-oxo-1-phenylethane-2,1-diyl)dicyclopropanecarboxamide(7a-A))的合成
于室温下,化合物6a(2.21g,8.8mmol)的二甲基甲酰胺(25mL)溶液中加入三氟醋酸(5mL),所得的混合液搅拌2小时,待减压浓缩后,冰浴冷却,加入饱和碳酸氢钠直至pH=7~8。所得混合液以二氯甲烷萃取(20mLx8),有机层以硫酸镁干燥,过滤后浓缩。使用粗产物做为起始物进行后续步骤而无须进一步纯化,将粗产物的THF(20mL)溶液冰浴冷却,加入环丙基甲酰氯(cyclopropanecarbonyl chloride,208mg,1.99mmol)与三乙胺(126mg,1.24mmol),移除冰浴且将所得的混合液于室温下搅拌10分钟后减压浓缩。残余物以醋酸乙酯(10mLx4)萃取,收集有机层以卤水清洗,硫酸镁干燥,过滤后浓缩。残余物以管柱层析(甲醇∶二氯甲烷=1∶99)纯化,可产出最终产物7a-A(390mg,54%)。
LC/MS(ESI):[M+2]+/2:431,[M+1]+:861,[M+23]+:883。
实施例8:(S)-叔丁基2-胺甲酰基吡咯啶-1-羧酸酯((S)-tert-butyl2-carbamoylpyrrolidine-1-carboxylate(10a))的合成
N-Boc-L-脯氨酸(5.0g,23.2mmol)于室温下溶解在1,4-二恶烷(110ml),将吡啶(1.1mL,13.9mmol)、二碳酸二叔丁酯(di-tert-butyl dicarbonate,6.6g,30.2mmol)及碳酸铵(2.9g,30.2mmol)加入脯氨酸溶液,然后反应混合液于室温下搅拌19小时,所得的混合液减压蒸发移除挥发成分,残余物中加入醋酸乙酯(50ml)、20%柠檬酸水溶液及卤水(50ml),混合液于室温下搅拌5分钟,水层使用醋酸乙酯萃取后收集有机层,以硫酸镁干燥、过滤,浓缩滤液可得粗产物,然后粗产物以管柱层析(二氯甲烷∶甲醇=9∶1)纯化,可产出10a(4.5g)。
实施例9:(S)-叔丁基2-硫代胺甲酰基吡咯啶-1-羧酸酯((S)-tert-butyl2-carbamothioylpyrrolidine-1-carboxylate(11a))的制备
填装有(S)-叔丁基2-胺甲酰基吡咯啶-1-羧酸酯(化合物10a,3.0g,14.0mmol)及劳森试剂(6.8g,16.8mmol)的圆底瓶中,注满氮气,加入无水THF(40ml)做为溶剂,反应混合液于70℃氮气环境下搅拌8小时,待冷却至室温后,减压浓缩所得的混合液并以管柱层析(醋酸乙酯∶正己烷=1∶2)纯化,可产出纯产物11a(2.7g)。
实施例10:(S)-叔丁基2-(4-(4-溴苯基)噻唑-2-基)吡咯啶-1-羧酸酯((S)-tert-butyl2-(4-(4-bromophenyl)thiazol-2-yl)pyrrolidine-1-carboxylate(12a))的制备
(S)-叔丁基2-硫代胺甲酰基吡咯啶-1-羧酸酯(化合物11a,2.2g,9.6mmol)与4-溴苯甲酰基甲基溴(4-bromophenacyl bromide,2.9g,10.5mmol)的乙醇(50ml)溶液,于室温下搅拌3小时,所得的混合液以醋酸乙酯萃取,有机层使用硫酸镁干燥、过滤,浓缩滤液可得粗产物,粗产物以管柱层析(醋酸乙酯∶正己烷=1∶3)纯化,可产出纯产物12a(3.3g)。
实施例11:(S)-叔丁基2-(4-(4-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)苯基)噻唑-2-基)吡咯啶-1-羧酸酯((S)-tert-butyl 2-(4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)thiazol-2-yl)pyrrolidine-1-carboxylate(13a))的制备
填装有双戊酰二硼(1.1g,4.4mmol)、Pd(PPh3)4(0.13g,0.11mmol)与K2CO3(1.5g,11.0mmol)的圆底瓶中,室温下注满氮气,然后加入(S)-叔丁基2-(4-(4-溴苯基)噻唑-2-基)吡咯啶-1-羧酸酯(化合物12a,1.5g,3.7mmol)的DMSO(20mL)溶液,于80℃下反应搅拌过夜,待冷却至室温后,所得的混合液以醋酸乙酯/H2O萃取,以硫酸镁干燥、过滤并浓缩可得黄色液体,粗产物以管柱层析(醋酸乙酯∶正己烷=1∶5)纯化,可产出白色固体的产物13a(1.1g)。
实施例12:4-溴-N′-羟基苯甲脒(4-bromo-N′-hydroxy-benzimidamide(15))的制备
4-溴苯甲腈(4-bromobenzonitrile,5.0g,27.5mmol)的乙醇(42ml)溶液中,于室温下加入羟胺盐酸盐(hydroxylamine hydrochloride,1.91g,27.5mmol)与DIPEA(4.8ml,27.5mmol),反应混合液于90℃下搅拌5小时,待冷却至室温后,浓缩所得的混合液可得无色液体,液体使用醋酸乙酯萃取,有机层经硫酸镁干燥、过滤而后浓缩可得粗产物,其以正己烷清洗可产出白色固体的产物15(5.0g)。
实施例13:(S)-叔丁基2-(3-(4-溴苯基)-1,2,4-恶二唑-5-基)吡咯啶-1-羧酸酯((S)-tert-butyl 2-(3-(4-bromo-phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate(16a))的制备
于N-Boc-L-脯氨酸(2.5g,11.6mmol)的N,N-二甲基甲酰胺(N,N-dimethylformamide,18mL)溶液中,加入O-(苯并三唑-1-基)-N,N,N′,N′-四甲基脲四氟硼酸(O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate,TBTU,3.73g,11.6mmol)、HOBt·H2O(0.36g,2.32mmol)及DIPEA(10.2ml,58.1mmol),待反应混合液于室温下搅拌5分钟,再加入4-溴-N′-羟基苯甲脒15(2.5g,11.6mmol),然后混合液于110℃搅拌2.5小时,待冷却至室温后,所得的反应液以醋酸乙酯萃取后,以硫酸镁干燥、过滤、浓缩后可得黄色液体粗产物,其以硅胶管柱层析(醋酸乙酯∶正己烷=1∶10)纯化,可产出所欲产物16a(2.5g)。
实施例14:(S)-叔丁基2-(2-(4-溴苯基)-2-氧代乙基胺甲基)吡咯啶-1-羧酸酯((S)-tert-butyl 2-(2-(4-bromophenyl)-2- oxoethylcarbamoyl)pyrrolidine-1-carboxylate(18a))的制备
于2-胺基-4’-溴苯乙酮盐酸盐17(2-amino-4’-bromo-acetophenonehydrochloride,5.0g,20.0mmol)的二氯甲烷(150mL)悬浮液中,于室温下加入DIPEA(2.6g,20mmol),待搅拌10分钟后,悬浮液变成黄色溶液。装有N-Boc-L-脯氨酸(5.2g,24.0mmol)的二氯甲烷(100mL)溶液中,于室温下加入HOBt·H2O(3.7g,24.0mmol),脯氨酸混合液中再加入EDC·HCl(4.6g,24.0mmol),此混合液连续在室温下搅拌30分钟,上述黄色溶液加入脯氨酸混合液,并于室温下搅拌过夜。所得混合液以硅藻土过滤移除沉淀,滤液以水及二氯甲烷萃取后,有机层以卤水清洗、硫酸镁干燥、过滤,待减压浓缩后,粗产物以管柱层析(醋酸乙酯∶正己烷=2∶5)纯化,可产出黄色胶体的纯产物18a(7.4g)。
实施例15:(S)-叔丁基2-(5-(4-溴苯基)-1H-咪唑-2-基)吡咯啶-1-羧酸酯((S)-tert-butyl 2-(5-(4-bromophenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(19a))的制备
于(S)-叔丁基2-(2-(4-溴苯基)-2-氧代乙基胺甲基)吡咯啶-1-羧酸酯(化合物18a,5.0g,12.2mmol)的二甲苯(75ml)溶液中,于室温下加入醋酸铵(23.4g,304mmol)与醋酸(5ml),反应混合液置于油浴中并与水(做为共沸物)于迪安-斯塔克装置中加热至160℃,待3小时后,所得的混合物冷却至室温,然后以醋酸乙酯与蒸馏水萃取,有机层以硫酸镁干燥、过滤、减压浓缩后,可得粗产物,其以管柱层析(100%醋酸乙酯)纯化,可产出纯产物19a(4.4g)。
实施例16:(S)-叔丁基2-(5-(4-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)苯基)-1H-咪唑-2-基)吡咯啶-1-羧酸酯((S)-tert-butyl2-(5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(20a))的制备
填装有双戊酰二硼(0.8g,3.2mmol)、Pd(PPh3)4(0.06g,0.05mmol)与醋酸钾(0.37g,3.81mmol)的圆底瓶中,室温下注满氮气,然后加入(S)-叔丁基2-(5-(4-溴苯基)-1H-咪唑-2-基)吡咯啶-1-羧酸酯(化合物19a,0.5g,1.3mmol)的1,4-二恶烷(15mL)溶液,反应混合液于80℃下搅拌过夜然后冷却至室温。所得的混合液以醋酸乙酯与蒸馏水萃取,有机层使用硫酸镁干燥,过滤并减压浓缩后可得黄色液体粗产物,其以管柱层析(醋酸乙酯∶正己烷=2∶1)纯化,可产出白色固体的产物20a(0.53g)。
实施例17:(S)-叔丁基2-(5-(4-溴苯基)噻唑-2-基)吡咯啶-1-羧酸酯((S)-tert-butyl2-(5-(4-bromophenyl)thiazol-2-yl)pyrrolidine-1-carboxylate(21a))的制备
化合物21a的制法类似实施例2所述方法。
实施例18:(S)-叔丁基2-(5-(4-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)苯基)噻唑-2-基)吡咯啶-1-羧酸酯((S)-tert-butyl 2-(5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)thiazol-2-yl)pyrrolidine-1-carboxylate(22a))的制备
以类似实施例3所述方法,由化合物21a制备化合物22a。
实施例19:(S)-叔丁基2-(4-(4′-(5-((S)-1-(叔丁氧羰基)吡咯啶-2-基)-1,2,4-恶二唑-3-基)联苯-4-基-1H-咪唑-2-基)吡咯啶-1-羧酸酯((S)-tert-butyl2-(4-(4′-(5-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1,2,4-oxadiazol-3-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(23a))的制备
填装有PdCl2(dppf)(0.04g,0.051mmol)、碳酸氢钠(0.37g,4.45mmol)与(S)-叔丁基2-(3-(4-溴苯基)-1,2,4-恶二唑-5-基)吡咯啶-1-羧酸酯(化合物16a,0.50g,1.27mmol)的反应瓶中,注满氮气,然后加入(S)-叔丁基2-(5-(4-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)苯基)-1H-咪唑-2-基)吡咯啶-1-羧酸酯(化合物20a,0.67g,1.52mmol)的1,2-二甲氧基乙烷(15ml)溶液,反应混合液于80℃搅拌6小时,待冷却至室温后,所得的混合液使用醋酸乙酯/水萃取,而后用硫酸镁干燥、过滤并浓缩,可得粗产物,其以层析(醋酸乙酯∶正己烷=4∶1)纯化,可产出白色固体的产物23a(0.57g)。
实施例20:5-((S)-吡咯啶-2-基)-3-(4′-(2-((S)-吡咯啶-2-基-1H-咪唑-4-基)联苯-4-基-1,2,4-恶二唑(5-((S)-pyrrolidin-2-yl)-3-(4′-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-4-yl)biphenyl-4-yl)-1,2,4-oxadiazole(24a))的制备
以类似实施例5所述方法,由化合物23a制备化合物24a。
实施例21:化合物25a的制备
于室温下,N-Boc-D-苯基甘胺酸(0.29g,1.15mmol)的二氯甲烷(10mL)溶液中加入全部的HOBt·H2O(0.18g,1.15mmol),该混合液于室温下搅拌10分钟后,加入EDC(0.22g,1.15mmol),待10分钟后,加入全部的5-((S)-吡咯啶-2-基)-3-(4′-(2-((S)-吡咯啶-2-基-1H-咪唑-4-基)联苯-4-基-1,2,4-恶二唑(化合物24a,0.20g,0.48mmol)。混合液在室温下搅拌过夜后,加入10%柠檬酸(水溶液),然后混合液搅拌10分钟,使用饱和碳酸氢钠(水溶液)调整pH值至约为8,所得的反应液以醋酸乙酯萃取,有机层以硫酸镁干燥,过滤后浓缩可得黄色液体粗产物,其以管柱层析(醋酸乙酯∶正己烷=2∶1)纯化,可产出白色固体的产物25a(0.37g)。
实施例22:N-((R)-2-((S)-2-(4-(4′-(5-((S)-1-((R)-2-(环丙烷甲酰胺基)-2-苯基乙酰基)吡咯啶-2-基)-1,2,4-恶二唑-3-基)联苯-4-基)-1H-咪唑-2-基)吡咯啶-1-基)-2-氧代-1-苯基乙基)环丙烷甲酰胺(N-((R)-2-((S)-2-(4-(4′-(5-((S)-1-((R)-2-(cyclopropanecarboxamido)-2-phenylacetyl)pyrrolidin-2-yl)-1,2,4-oxadiazol-3-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-phenylethyl)cyclopropanecarboxamide(26a))的制备
以类似实施例7所述方法,由化合物25a制备化合物26a。
实施例23:(S)-叔丁基2-(4-(4′-(5-((S)-1-(叔丁氧羰基)吡咯啶-2-基)-1,2,4-恶二唑-3-基)联苯-4-基)噻唑-2-基)吡咯啶-1-羧酸酯((S)-tert-butyl2-(4-(4′-(5-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1,2,4-oxadiazol-3-yl)biphenyl-4-yl)thiazol-2-yl)pyrrolidine-1-carboxylate(27a))的制备
化合物27a的制法类似实施例4所述方法,但除了使用化合物13a与16a取代化合物2a与3a之外。
实施例24:5-((S)-吡咯啶-2-基)-3-(4′-(2-((S)-吡咯啶-2-基)噻唑-4-基)联苯-4-基)-1,2,4-恶二唑(5-((S)-pyrrolidin-2-yl)-3-(4′-(2-((S)-pyrrolidin-2-yl)thiazol-4-yl)biphenyl-4-yl)-1,2,4-oxadiazole(28a))的制备
以类似实施例5所述方法,由化合物27a制备化合物28a,使用产物做为后续步骤的起始物而无须进一步纯化。
实施例25:化合物29a的制备
以类似实施例21所述方法,由化合物28a制备化合物29a。
实施例26:N-((R)-2-((S)-2-(4-(4′-(5-((S)-1-((R)-2-(环丙烷甲酰胺基)-2-苯基乙酰基)吡咯啶-2-基)-1,2,4-恶二唑-3-基)联苯-4-基)-噻唑-2-基)吡咯啶-1-基)-2-氧代-1-苯基乙基)环丙烷甲酰胺(N-((R)-2-((S)-2-(4-(4′-(5-((S)-1-((R)-2-(cyclopropanecarboxamido)-2-phenylacetyl)pyrrolidin-2-yl)-1,2,4-oxadiazol-3-yl)biphenyl-4-yl)thiazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-phenylethyl)cyclopropanecarboxamide(30a))的制备
于室温下,化合物29a(0.20g,0.22mmol)的二氯甲烷(10mL)溶液中加入三氟醋酸(5mL),反应混合液搅拌2小时,加入饱和碳酸氢钠调整pH值至约为8。所得混合液以二氯甲烷萃取、以硫酸镁干燥、过滤后浓缩。使用粗产物做为起始物进行后续步骤而无须进一步纯化。
于白色固体的二氯甲烷(5ml)溶液中,在-10℃下加入全部的环丙基甲酰氯(cyclopropanecarbonyl chloride,0.058g,0.55mmol)与三乙胺(0.08ml),反应混合液于-10℃下搅拌15分钟,于室温下加入蒸馏水,而后以二氯甲烷萃取。有机层以硫酸镁干燥,过滤后浓缩,可获得粗产物,其以层析(醋酸乙酯∶正己烷=2∶1)纯化,可产出白色固体的产物30a(0.07g)。
实施例27:(S)-叔丁基2-(5-(4′-(5-((S)-1-(叔丁氧羰基)吡咯啶-2-基)-1,2,4-恶二唑-3-基)联苯-4-基)噻唑-2-基)吡咯啶-1-羧酸酯((S)-tert-butyl2-(5-(4′-(5-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1,2,4-oxadiazol-3-yl)biphenyl-4-yl)thiazol-2-yl)pyrrolidine-1-carboxylate(31a))的制备
化合物31a的制法类似实施例4所述方法,但除了使用化合物16a与22a取代化合物2a与3a之外。
实施例28:5-((S)-吡咯啶-2-基)-3-(4′-(2-((S)-吡咯啶-2-基)噻唑-5-基)联苯-4-基)-1,2,4-恶二唑(5-((S)-pyrrolidin-2-yl)-3-(4′-(2-((S)-pyrrolidin-2-yl)thiazol-5-yl)biphenyl-4-yl)-1,2,4-oxadiazole(32a))的制备
以类似实施例5所述方法,由化合物31a制备化合物32a,使用产物做为后续步骤的起始物而无须进一步纯化。
实施例29:化合物33a的制备
以类似实施例21所述方法,由化合物32a制备化合物33a。
实施例30:n-((R)-2-((S)-2-(5-(4′-(5-((S)-1-((R)-2-(环丙烷甲酰胺基)-2-苯基乙酰基)吡咯啶-2-基)-1,2,4-恶二唑-3-基)联苯-4-基)-噻唑-2-基)吡咯啶-1-基)-2-氧代-1-苯基乙基)环丙烷甲酰胺(N-((R)-2-((S)-2-(5-(4′-(5-((S)-1-((R)-2-(cyclopropanecarboxamido)-2-phenylacetyl)pyrrolidin-2-yl)-1,2,4-oxadiazol-3-yl)biphenyl-4-yl)thiazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-phenylethyl)cyclopropanecarboxamide(34a))的制备
以类似实施例26所述方法,由化合物33a制备化合物34a。
实施例31:(S)-叔丁基2-(4-(4′-(2-((S)-1-(叔丁氧羰基)吡咯啶-2-基)-1H-咪唑-5-基)联苯-4-基)噻唑-2-基)吡咯啶-1-羧酸酯((S)-tert-butyl2-(4-(4′-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)thiazol-2-yl)pyrrolidine-1-carboxylate(35a))的制备
填充有化合物12a(0.46g,1.13mmol)、(S)-叔丁基2-(5-(4-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)苯基)-1H-咪唑-2-基)吡咯啶-1-羧酸酯(化合物20a,0.55g,1.25mmol)、PdCl2(dppf)(0.036g,0.04mmol)与碳酸氢钠(0.33g,3.93mmol)的烧瓶中,注满氮气后,加入1,2-二甲氧基乙烷(6ml)及蒸馏水(2ml)做为溶剂。反应混合液于80℃氮气环境下搅拌5小时,待冷却至室温后,混合液以醋酸乙酯/水萃取、以硫酸镁干燥、过滤并减压浓缩后,可得粗产化合物。粗产化合物以管柱层析(醋酸乙酯∶正己烷=4∶1)纯化,可产出黄色固体(0.47g)。
实施例32:2-((S)-吡咯啶-2-基)-4-(4′-(2-((S)-吡咯啶-2-基)-1H-咪唑-5-基)联苯-4-基)噻唑(2-((S)-pyrrolidin-2-yl)-4-(4′-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)thiazole(36a))的制备
以类似实施例5所述方法,由化合物35a制备化合物36a,使用产物做为后续步骤的起始物而无须进一步纯化。
实施例33:化合物37a的制备
于室温下,N-Boc-D-苯基甘胺酸(0.37g,0.15mmol)的N,N-二甲基甲酰胺(8mL)溶液中加入全部的HOBt·H2O(0.25g,1.63mmol),该混合液搅拌15分钟后,加入全部的EDC(0.31g,1.63mmol)与2-((S)-吡咯啶-2-基)-4-(4′-(2-((S)-吡咯啶-2-基)-1H-咪唑-5-基)联苯-4-基)噻唑(化合物36a,0.30g,0.68mmol)。待搅拌过夜,所得的混合液以醋酸乙酯萃取,再以硫酸镁干燥,过滤后浓缩可得粗产物,粗产物以管柱层析(醋酸乙酯∶正己烷=2∶1)纯化,可产出白色固体的产物37a(0.42g)。
实施例34:n-((R)-2-((S)-2-(4-(4′-(2-((S)-1-((R)-2-(环丙烷甲酰胺基)-2-苯基乙酰基)吡咯啶-2-基)-1H-咪唑-5-基)联苯-4-基)-噻唑-2-基)吡咯啶-1-基)-2-氧代-1-苯基乙基)环丙烷甲酰胺(N-((R)-2-((S)-2-(4-(4′-(2-((S)-1-((R)-2-(cyclopropane-carboxamido)-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)thiazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-phenylethyl)cyclopropanecarboxamide(38a))的制备
以类似实施例26所述方法,由化合物37a制备化合物38a。
实施例35:(S)-叔丁基2-(5-(4′-(2-((S)-1-(叔丁氧羰基)吡咯啶-2-基)-1H-咪唑-4-基)联苯-4-基)噻唑-2-基)吡咯啶-1-羧酸酯((S)-tert-butyl2-(5-(4′-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-imidazol-4-yl)biphenyl-4-yl)thiazol-2-yl)pyrrolidine-1-carboxylate(39a))的制备
化合物39a的制法类似实施例4所述方法,但除了使用化合物20a与21a取代化合物2a与3a之外。
实施例36:2-((S)-吡咯啶-2-基)-5-(4′-(2-((S)-吡咯啶-2-基)-1H-咪唑-4-基)联苯-4-基)噻唑(2-((S)-pyrrolidin-2-yl)-5-(4′-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-4-yl)biphenyl-4-yl)thiazole(40a))的制备
以类似实施例5所述方法,由化合物39a制备化合物40a,使用产物做为后续步骤的起始物而无须进一步纯化。
实施例37:化合物41a的制备
于室温下,N-Boc-D-苯基甘胺酸(0.14g,0.56mmol)的二甲基甲酰胺(5ml)溶液中,加入全部的HOBt·H2O(0.086g,0.56mmol),该混合液搅拌10分钟后,加入EDC(0.11g,0.56mmol),所得混合液持续搅拌30分钟,加入全部的2-((S)-吡咯啶-2-基)-5-(4′-(2-((S)-吡咯啶-2-基)-1H-咪唑-4-基)联苯-4-基)噻唑(化合物40a,0.10g,0.23mmol),反应混合液于室温下搅拌过夜。HOBt先以蒸馏水洗除后,所得的混合液以醋酸乙酯萃取,有机层以硫酸镁干燥,过滤后浓缩可得粗产物,其以管柱层析(醋酸乙酯∶正己烷=1∶1)纯化,可产出白色固体的产物41a(0.072g)。
实施例38:N-((R)-2-((S)-2-(5-(4′-(2-((S)-1-((R)-2-(环丙烷甲酰胺基)-2-苯基乙酰基)吡咯啶-2-基)-1H-咪唑-4-基)联苯-4-基)-噻唑-2-基)吡咯啶-1-基)-2-氧代-1-苯基乙基)环丙烷甲酰胺(N-((R)-2-((S)-2-(5-(4′-(2-((S)-1-((R)-2-(cyclopropane-carboxamido)-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-4-yl)biphenyl-4-yl)thiazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-phenyl-ethyl)cyclopropanecarboxamide(42a))的制备
于室温下,化合物41a(0.072g,0.08mmol)的二甲基甲酰胺(2ml)溶液中加入三氟醋酸(1mL),反应混合液搅拌2小时,加入饱和碳酸氢钠调整pH值至约为8。所得混合液以二氯甲烷萃取、再以硫酸镁干燥、过滤后浓缩。使用粗产物做为起始物进行后续步骤而无须进一步纯化。
于前述白色固体的THF(20ml)溶液中,在-40℃下加入全部的环丙基甲酰氯(0.030g,0.2mmol)与三乙胺(0.02ml),反应混合液于-40℃下搅拌2小时。待移除溶剂后,粗产物以管柱层析(甲醇∶醋酸乙酯=1∶40)纯化,可产出白色固体的产物42a(0.033g)。
实施例39:(S)-叔丁基2-(5-(4′-(2-((S)-1-(叔丁氧羰基)吡咯啶-2-基)噻唑-4-基)联苯-4-基)噻唑-2-基)吡咯啶-1-羧酸酯((S)-tert-butyl2-(5-(4′-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)thiazol-4-yl)biphenyl-4-yl)thiazol-2-yl)pyrrolidine-1-carboxylate(43a))的制备
化合物43a的制法类似实施例4所述方法,但除了使用化合物13a与21a取代化合物2a与3a之外。
实施例40:(S)-4,5′-(联苯-4,4′-二基)双(2-((S)-吡咯啶-2-基)噻唑((S)-4,5′-(biphenyl-4,4′-diyl)bis(2-((S)-pyrrolidin-2-yl)thiazole)(44a))的制备
以类似实施例5所述方法,由化合物43a制备化合物44a,使用产物做为后续步骤的起始物而无须进一步纯化。
实施例41:化合物45a的制备
以类似实施例21所述方法,由化合物44a制备化合物45a。
实施例42:N-((R)-2-((S)-2-(5-(4′-(2-((S)-1-((R)-2-(环丙烷甲酰胺基)-2-苯基乙酰基)吡咯啶-2-基)噻唑-4-基)联苯-4-基)-噻唑-2-基)吡咯啶-1-基)-2-氧代-1-苯基乙基)环丙烷甲酰胺(N-((R)-2-((S)-2-(5-(4′-(2-((S)-1-((R)-2-(cyclopropanecarboxamido)-2-phenylacetyl)pyrrolidin-2-yl)thiazol-4-yl)biphenyl-4-yl)thiazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-phenylethyl)cyclopropanecarboxamide(46a))的制备
以类似实施例26所述方法,由化合物45a制备化合物46a。
实施例43:化合物47
溴(1.3mL,25.0mmol)的冰醋酸(15mL)溶液于50℃下滴入4,4’-二乙酰联苯(4,4’-diacetylbiphenyl,3.0g,12.5mmol)的醋酸(40mL)溶液,待添加完后,反应混合液于室温下搅拌过夜。过滤沉淀并以氯仿再结晶,可获得白色固体的1,1’-(联苯-4,4’-二基)双(2-溴乙酮)47(1,1’-(biphenyl-4,4’-diyl)bis(2-bromoethanone),3.84g,77.5%)。
LC/MS(ESI):[M+1]+:397。
实施例44:化合物48
二甲酰胺钠(Sodium diformylamide,3.66g,38.5mmol)加入1,1’-(联苯-4,4’-二基)双(2-溴乙酮)47(6.1g,15.4mmol)的乙腈(85mL)悬浮液中,反应混合液回流4小时,然后减压浓缩,残余物悬着于5%HCl的乙醇(300mL)后在回流4小时。反应混合液冷却至室温并置于冷冻库中1小时后,收集沉淀物,以乙醚清洗(200mLx3),真空干燥后可得1,1’-(联苯-4,4’-二基)双(2-胺基乙酮)二盐酸盐48(1,1’-(biphenyl-4,4’-diyl)bis(2-aminoethanone)dihydrochloride,4.85g,92%),产物无须进一步纯化。
LC/MS(ESI):[M+1]+:269。
实施例45:化合物49a
于1,1’-(联苯-4,4’-二基)双(2-胺基乙酮)二盐酸盐48(0.7g,2.1mmol)、N-Boc-L-脯氨酸(0.9g,4.2mmol)及HATU(1.68g,4.4mmol)的二甲基甲酰胺(15mL)搅拌溶液中,在5分钟期间滴入二异丙基乙基胺(diisopropylethyl amine,1.5mL,8.4mmol),所得混合液于室温下搅拌过夜后减压浓缩。残余物以20%甲醇/氯仿及水萃取,水相再以20%甲醇/氯仿清洗一次后,收集有机层并以卤水清洗,再以硫酸镁干燥、过滤并减压浓缩后,粗产物以硅胶管柱层析法纯化,其中以10-50%醋酸乙酯/二氯甲烷做为梯度流洗液,可得产物49a(0.97g,69%)。
LC/MS(ESI):[M+1]+:663。
实施例46:化合物50a及51a
于室温下,化合物6a(462mg,0.5mmol)的二氯甲烷(5mL)溶液中加入三氟醋酸(1mL),然后反应于室温下搅拌2小时。待反应完成后,冰浴冷却并加入饱和碳酸氢钠直至pH=7~8。所得混合液以二氯甲烷(10mLx8)萃取,有机层以硫酸镁干燥、过滤后浓缩,可得粗产物,其是做为起始物进行后续步骤而无须进一步纯化。冰浴冷却粗产物的THF(5ml)溶液,依序加入乙酰氯(acetylchloride,94mg,1.2mmol)及三乙胺(121mg,1.2mmol),移除冰浴后,反应混合液于室温下搅拌10分钟而后减压浓缩。残余物以醋酸乙酯(10mLx4)萃取,收集有机层并以卤水清洗,再以硫酸镁干燥、过滤并浓缩,残余物以硅胶管柱层析法(二氯甲烷含1%甲醇)纯化,可得最终产物50a(160mg,40%)与51a(50mg,12%)。
LC/MS(ESI):[M+2]+/2:405,[M+1]+:809,[M+23]+:831。
实施例47:化合物52a及53a
化合物52a及53a的制法同于实施例46所述方法,但除了使用丙酰氯(propionyl chloride)取代乙酰氯之外。
LC/MS(ESI):[M+2]+/2:419,[M+1]+:837,[M+23]+:859。
实施例48:化合物54a及55a
化合物54a及55a的制法同于实施例46所述方法,但除了使用丁酰氯(butyryl chloride)取代乙酰氯之外。
LC/MS(ESI):[M+2]+/2:433,[M+1]+:865,[M+23]+:887。
实施例49:化合物56a及57a
化合物56a及57a的制法同于实施例46所述方法,但除了使用戊酰氯(pentanoyl chloride)取代乙酰氯之外。
LC/MS(ESI):[M+2]+/2:447,[M+1]+:893,[M+23]+:915。
实施例50:化合物58a及59a
化合物58a及59a的制法同于实施例46所述方法,但除了使用己酰氯(hexanonyl chloride)取代乙酰氯之外。
LC/MS(ESI):[M+2]+/2:461,[M+1]+:921,[M+23]+:943。
实施例51:化合物60a及61a
化合物60a及61a的制法同于实施例46所述方法,但除了使用异丁酰氯(isobutyryl chloride)取代乙酰氯之外。
LC/MS(ESI):[M+2]+/2:433,[M+1]+:865,[M+23]+:887。
实施例52:化合物62a及63a
化合物62a及63a的制法同于实施例46所述方法,但除了使用2-乙基丁酰氯(2-ethyl-butyryl chloride)取代乙酰氯之外。
LC/MS(ESI):[M+2]+/2:461,[M+1]+:921,[M+23]+:943。
实施例53:化合物64a及65a
化合物64a及65a的制法同于实施例46所述方法,但除了使用2,2-甲基丙酰氯(2,2-dimethyl propionyl chloride)取代乙酰氯之外。
LC/MS(ESI):[M+2]+/2:447,[M+1]+:893,[M+23]+:915。
实施例54:化合物66a及67a
化合物66a及67a的制法同于实施例46所述方法,但除了使用环丁烷甲酰氯(cyclobutane carbonyl chloride)取代乙酰氯之外。
LC/MS(ESI):[M+2]+/2:445,[M+1]+:889,[M+23]+:911。
实施例55:化合物68a及69a
化合物68a及69a的制法同于实施例46所述方法,但除了使用环戊烷甲酰氯(cyclopentane carbonyl chloride)取代乙酰氯之外。
LC/MS(ESI):[M+2]+/2:459,[M+1]+:917,[M+23]+:939。
实施例56:化合物70a及71a
化合物70a及71a的制法同于实施例46所述方法,但除了使用环己烷甲酰氯(cyclohexane carbonyl chloride)取代乙酰氯之外。
LC/MS(ESI):[M+2]+/2:473,[M+1]+:945,[M+23]+:967。
实施例57:化合物72a及73a
化合物72a及73a的制法同于实施例46所述方法,但除了使用苯甲酰氯(benzoyl chloride)取代乙酰氯之外。
LC/MS(ESI):[M+2]+/2:467,[M+1]+:933,[M+23]+:955。
实施例58:化合物74a及75a
化合物74a及75a的制法同于实施例46所述方法,但除了使用苯基乙酰氯(phenylacetyl chloride)取代乙酰氯之外。
LC/MS(ESI):[M+2]+/2:481,[M+1]+:961,[M+23]+:983。
实施例59:化合物76a及77a
化合物76a及77a的制法同于实施例46所述方法,但除了使用呋喃-2-甲酰氯(furan-2-carbonyl chloride)取代乙酰氯之外。
LC/MS(ESI):[M+2]+/2:457,[M+1]+:913,[M+23]+:935。
实施例60:化合物78a及79a
化合物78a及79a的制法同于实施例46所述方法,但除了使用呋喃-3-甲酰氯(furan-3-carbonyl chloride)取代乙酰氯之外。
LC/MS(ESI):[M+2]+/2:457,[M+1]+:913,[M+23]+:935。
实施例61:化合物80a及81a
化合物80a及81a的制法同于实施例46所述方法,但除了使用噻吩-2-甲酰氯(thiophene-2-carbonyl chloride)取代乙酰氯之外。
LC/MS(ESI):[M+2]+/2:473,[M+1]+:945,[M+23]+:967。
实施例62:化合物82a及83a
化合物82a及83a的制法同于实施例46所述方法,但除了使用噻吩-3-甲酰氯(thiophene-3-carbonyl chloride)取代乙酰氯之外。
LC/MS(ESI):[M+2]+/2:473,[M+1]+:945,[M+23]+:967。
实施例63:化合物84a及85a
化合物84a及85a的制法同于实施例46所述方法,但除了使用异烟碱酰氯(isonicotinoyl chloride)取代乙酰氯之外。
LC/MS(ESI):[M+2]+/2:468,[M+1]+:935,[M+23]+:957。
实施例64:化合物86a及87a
化合物86a及87a的制法同于实施例46所述方法,但除了使用烟碱酰氯(nicotinoyl chloride)取代乙酰氯之外。
LC/MS(ESI):[M+2]+/2:468,[M+1]+:935,[M+23]+:957。
实施例65:化合物88a及89a
化合物88a及89a的制法同于实施例46所述方法,但除了使用吡啶-2-甲酰氯(pyridine-2-carbonyl chloride)取代乙酰氯之外。
LC/MS(ESI):[M+2]+/2:468,[M+1]+:935,[M+23]+:957。
实施例66:化合物90a及91a
化合物90a及91a的制法同于实施例46所述方法,但除了使用吡咯啶-1-甲酰氯(pyrrolidine-1-carbonyl chloride)取代乙酰氯之外。
LC/MS(ESI):[M+2]+/2:460,[M+1]+:919,[M+23]+:941。
实施例67:化合物92a
化合物92a的制法同于实施例46所述方法,但除了使用哌啶-1-甲酰氯(piperidine-1-carbonyl chloride)取代乙酰氯之外。
LC/MS(ESI):[M+2]+/2:474,[M+1]+:947,[M+23]+:969。
实施例68:化合物95a
于N-甲氧基羰基-D-缬胺酸(N-methoxycarbonyl-d-valine,420mg,2.4mmol)的二氯甲烷(10mL)溶液中,加入全部的HOBt·H2O(367mg,2.4mmol)后于室温下搅拌10分钟后,将EDC(460mg,2.4mmol)加入反应混合液,所得混合液持续搅拌30分钟后,加入化合物5a(458mg,1.0mmol)的二氯甲烷(5mL)溶液,然后于室温下搅拌过夜。HOBt先以蒸馏水洗除后,有机层以硫酸镁干燥,过滤后浓缩可得黄色粘液,该液体以硅胶管柱层析(甲醇∶二氯甲烷=1∶20)纯化,可产出白色固体95a(425mg,55%)。
LC/MS(ESI):[M+2]+/2:387,[M+1]+:773,[M+23]+:795。
实施例69:化合物96a
化合物96a的制法同于实施例68所述方法,但除了使用N-乙氧基羰基-D-缬胺酸(N-ethoxycarbonyl-D-valine)取代N-甲氧基羰基-D-缬胺酸之外。
LC/MS(ESI):[M+2]+/2:401,[M+1]+:801,[M+23]+:823。
实施例70:化合物97a
化合物97a的制法同于实施例68所述方法,但除了使用N-苯氧基羰基-D-缬胺酸(N-phenoxycarbonyl-D-valine)取代N-甲氧基羰基-D-缬胺酸之外。
LC/MS(ESI):[M+2]+/2:449,[M+1]+:897,[M+23]+:919。
实施例71:化合物98a
化合物98a的制法同于实施例68所述方法,但除了使用N-环丙烷羰基-D-丙胺酸(N-cyclopropanecarbonyl-D-alanine)取代N-甲氧基羰基-D-缬胺酸之外。
LC/MS(ESI):[M+2]+/2:369,[M+1]+:737,[M+23]+:759。
实施例72:化合物99a
化合物99a的制法同于实施例68所述方法,但除了使用(R)-2-(环丙烷羰基-胺基)-丁酸((R)-2-(cyclopropane-carbonyl-amino)-butyric acid)取代N-甲氧基羰基-D-缬胺酸之外。
LC/MS(ESI):[M+2]+/2:383,[M+1]+:765,[M+23]+:787。
实施例73:化合物100a
化合物100a的制法同于实施例68所述方法,但除了使用(R)-2-(环丙烷羰基-胺基)-戊酸((R)-2-(cyclopropane-carbonyl-amino)-pentanoic acid)取代N-甲氧基羰基-D-缬胺酸之外。
LC/MS(ESI):[M+2]+/2:397,[M+1]+:793,[M+23]+:815。
实施例74:化合物101a
化合物101a的制法同于实施例68所述方法,但除了使用(R)-2-(环丙烷羰基-胺基)-己酸((R)-2-(cyclopropane-carbonyl-amino)-hexanoic acid)取代N-甲氧基羰基-D-缬胺酸之外。
LC/MS(ESI):[M+2]+/2:411,[M+1]+:821,[M+23]+:843。
实施例75:化合物102a
化合物102a的制法同于实施例68所述方法,但除了使用N-环丙烷羰基-D-缬胺酸(N-cyclopropanecarbonyl-D-valine)取代N-甲氧基羰基-D-缬胺酸之外。
LC/MS(ESI):[M+2]+/2:397,[M+1]+:793,[M+23]+:815。
实施例76:化合物103a
化合物103a的制法同于实施例68所述方法,但除了使用N-环丙烷羰基-D-白胺酸(N-cyclopropanecarbonyl-D-leucine)取代N-甲氧基羰基-D-缬胺酸之外。
LC/MS(ESI):[M+2]+/2:411,[M+1]+:821,[M+23]+:843。
实施例77:化合物104a
化合物104a的制法同于实施例68所述方法,但除了使用(R)-2-(环丙烷羰基-胺基)-3,3-二甲基-丁酸((R)-2-(cyclopropanecarbonyl-amino)-3,3-dimethyl-butyric acid)取代N-甲氧基羰基-D-缬胺酸之外。
LC/MS(ESI):[M+2]+/2:411,[M+1]+:821,[M+23]+:843。
实施例78:化合物105a
化合物105a的制法同于实施例68所述方法,但除了使用(R)-环己基-(环丙烷羰基-胺基)-醋酸((R)-cyclohexyl-(cyclopropanecarbonyl-amino)-acetic acid)取代N-甲氧基羰基-D-缬胺酸之外。
LC/MS(ESI):[M+2]+/2:437,[M+1]+:873,[M+23]+:895。
实施例79:化合物106a
化合物106a的制法同于实施例68所述方法,但除了使用N-甲氧基羰基-L-丙胺酸(N-methoxycarbonyl-L-alanine)取代N-甲氧基羰基-D-缬胺酸之外。
LC/MS(ESI):[M+2]+/2:359,[M+1]+:717,[M+23]+:739。
实施例80:化合物107a
化合物107a的制法同于实施例68所述方法,但除了使用(S)-2-甲氧基羰基胺基-丁酸((S)-2-methoxycarbonyl-amino-butyric acid)取代N-甲氧基羰基-D-缬胺酸之外。
LC/MS(ESI):[M+2]+/2:373,[M+1]+:745,[M+23]+:767。
实施例81:化合物108a
化合物108a的制法同于实施例68所述方法,但除了使用(S)-2-甲氧基羰基胺基-戊酸((S)-2-methoxycarbonyl-amino-pentanoic acid)取代N-甲氧基羰基-D-缬胺酸之外。
LC/MS(ESI):[M+2]+/2:387,[M+1]+:773,[M+23]+:795。
实施例82:化合物109a
化合物109a的制法同于实施例68所述方法,但除了使用(S)-2-甲氧基羰基胺基-己酸((S)-2-methoxycarbonyl-amino-hexanoic acid)取代N-甲氧基羰基-D-缬胺酸之外。
LC/MS(ESI):[M+2]+/2:401,[M+1]+:801,[M+23]+:823。
实施例83:化合物110a
化合物110a的制法同于实施例68所述方法,但除了使用N-甲氧基羰基-L-白胺酸(N-methoxycarbonyl-L-leucine)取代N-甲氧基羰基-D-缬胺酸之外。
LC/MS(ESI):[M+2]+/2:401,[M+1]+:801,[M+23]+:823。
实施例84:化合物111a
化合物111a的制法同于实施例68所述方法,但除了使用(S)-2-甲氧基羰基胺基-3,3-二甲基-丁酸((S)-2-methoxycarbonylamino-3,3-dimethyl-butyric acid)取代N-甲氧基羰基-D-缬胺酸之外。
LC/MS(ESI):[M+2]+/2:401,[M+1]+:801,[M+23]+:823。
实施例85:化合物112a
化合物112a的制法同于实施例68所述方法,但除了使用N-甲氧基羰基-L-缬胺酸(N-methoxycarbonyl-L-valine)取代N-甲氧基羰基-D-缬胺酸之外。
LC/MS(ESI):[M+2]+/2:387,[M+1]+:773,[M+23]+:795。
实施例86:化合物113a
化合物113a的制法同于实施例68所述方法,但除了使用N-乙氧基羰基-L-缬胺酸(N-ethoxycarbonyl-L-valine)取代N-甲氧基羰基-D-缬胺酸之外。
LC/MS(ESI):[M+2]+/2:401,[M+1]+:801,[M+23]+:823。
实施例87:化合物114a
化合物114a的制法同于实施例68所述方法,但除了使用N-苯氧基羰基-L-缬胺酸(N-phenoxycarbonyl-L-valine)取代N-甲氧基羰基-D-缬胺酸之外。
LC/MS(ESI):[M+2]+/2:449,[M+1]+:897,[M+23]+:919。
实施例88:化合物115a
化合物115a的制法同于实施例1所述方法,但除了使用N-Boc-D-脯氨酸(N-Boc-D-Proline)取代N-Boc-L-脯氨酸之外。
LC/MS(ESI):[M+1]+:411。
实施例89:化合物116a
化合物116a的制法类似实施例2所述方法。
LC/MS(ESI):[M+1]+:409。
实施例90:化合物117a
化合物117a以实施例3所述方法制备,但除了使用化合物116a取代化合物2a之外。
LC/MS(ESI):[M+1]+:456。
实施例91:化合物118a
化合物118a的制法同于实施例4所述方法,但除了使用化合物116a及117a取代化合物2a及3a之外。
LC/MS(ESI),[M+1]+:659。
实施例92:化合物119a
以类似实施例5所述方法,由化合物118a制备化合物119a。
LC/MS(ESI):[M+2]+/2:230,[M+1]+:459,[M+23]+:481。
实施例93:化合物120a
化合物120a的制法同于实施例68所述方法,但除了使用N-Boc-L-苯基甘胺酸(N-Boc-L-phenylglycine)取代N-甲氧基羰基-D-缬胺酸之外。
LC/MS(ESI):[M+2]+/2:463,[M+1]+:925,[M+23]+:947。
实施例94:化合物121a
化合物121a的制法同于实施例68所述方法,但除了使用N-Boc-D-苯基甘胺酸(N-Boc-D-phenylglycine)取代N-甲氧基羰基-D-缬胺酸之外。
LC/MS(ESI):[M+2]+/2:463,[M+1]+:925,[M+23]+:947。
实施例95:化合物122a
化合物122a的制法同于实施例68所述方法,但除了使用N-Boc-L-苯基甘胺酸(N-Boc-L-phenylglycine)取代N-甲氧基羰基-D-缬胺酸且使用119a取代5a之外。
LC/MS(ESI):[M+2]+/2:463,[M+1]+:925,[M+23]+:947。
实施例96:化合物123a及124a
化合物122a及124a的制法同于实施例46所述方法,但除了使用环丙烷甲酰氯(cyclopropanecarbonyl chloride)取代乙酰氯且使用120a取代6a之外。
LC/MS(ESI):[M+2]+/2:431,[M+1]+:861,[M+23]+:883。
实施例97:化合物125a及127a
化合物125a及127a的制法同于实施例46所述方法,但除了使用环丙烷甲酰氯(cyclopropanecarbonyl chloride)取代乙酰氯且使用121a取代6a之外。
LC/MS(ESI):[M+2]+/2:431,[M+1]+:861,[M+23]+:883。
实施例98:化合物126a及127a
化合物126a及127a的制法同于实施例46所述方法,但除了使用环丙烷甲酰氯(cyclopropanecarbonyl chloride)取代乙酰氯且使用122a取代6a之外。
LC/MS(ESI):[M+2]+/2:431,[M+1]+:861,[M+23]+:883。
实施例99:化合物128a
化合物128a的制法同于实施例68所述方法,但除了使用D-缬胺酸(D-valine)取代N-甲氧基羰基-D-缬胺酸之外。
LC/MS(ESI):[M+1]+:657。
实施例100:化合物129a
化合物129a的制法同于实施例68所述方法,但除了使用L-缬胺酸(L-valine)取代N-甲氧基羰基-D-缬胺酸之外。
LC/MS(ESI):[M+1]+:657。
实施例101:抑制HCV复制
本发明化合物对于抗HCV的抑制活性,根据Lee等人所述方法(Lee et al.,Anal.Biochem.,316:162-70(2003)与Lee et al.,J.Virol Methods,116:27-33(2004)),使用报导基因系细胞株(reporter-based cell line)Ava5-EG(Δ4AB)SEAP来评估。简而言之,Ava5-EG(Δ4AB)SEAP细胞培养在含有500μg/mL G418(geneticin)与10μg/mL杀稻瘟菌素(blasticidin)的培养基中,于5%CO2环境的培养箱中培养,其中G418及杀稻瘟菌素购自莱富生命科技股份有限公司(Invitrogen,Carlsbad,CA)。将细胞接种于96孔盘(每孔100μL 5×103个细胞)并于37℃培养24小时,然后以不同浓度的待测化合物DMSO溶液处理细胞,待48小时后,各孔的培养基替换成含相同浓度待测化合物的新鲜培养基,如此得以去除若有任何细胞分泌累积于培养基的碱性磷酸酶(secreted alkalinephosphatase,SEAP),细胞额外再培养24小时,然后收集培养基并使用冷光分析套组(Phospha-Light assay kit,Tropix,Foster,CA,USA)测试其中的SEAP活性。
化合物6a、7a-A、7b-A、7c-A、7a-B、7b-B、7c-B、25a、26a、29a、30a、33a、34a、37a、38a、41a、42a、45a、46a、50a-77a、80a、81a、84a、85a、88a-98a及100a-129a于此分析中进行测试,所有待测化合物均可抑制HCV复制,其中令人意外的是,化合物6a、7a-A、7b-A、7c-A、7a-B、7b-B、7c-B、25a、26a、29a、30a、33a、34a、37a、38a、41a、42a、45a、46a、50a、51a、52a、54a、56a、58a、60a、61a、66a、67a、68a、70a、74a、76a、84a、90a及92a所展现的EC50值(亦即50%HCV复制作用受到待测化合物抑制的浓度)为0.5μM以下,而更令人意外的是,化合物50a、52a、54a、56a、60a、66a、68a、90a及92a展现的EC50值低于0.04μM。
实施例102:细胞毒性分析
处理后细胞的存活率(上述见实施例43),以Cory等人所述(Cory et al.,Cancer Commun.,3:207-12(1991))的MTS分析测定。简而言之,Ava5-EG(Δ4AB)SEAP细胞以前述待测化合物处理,待48小时后,各培养基替换成含相同浓度待测化合物的新鲜培养基,细胞额外再培养24小时后,各孔中再添加100μl溶液,其中该溶液含有DMEM(不含酚红)、[3-(4,5-二甲基噻唑-2-基)-5-(3-羧基甲氧基苯基)-2-(4-磺苯基)-2H-四唑内盐]([3-(4,5-dimethylthiozol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium,inner salt],Promega,Madison,WI)、以及吩嗪硫酸甲酯(phenazine methosulfate,Sigma,St.Louis,MO)且比例为80∶20∶1。而后,细胞于37℃、5%CO2环境的培养箱中培养1-4小时,测量各孔于490nm的吸光值。
化合物6a、7a-A、7b-A、7c-A、7a-B、7b-B、7c-B、25a、26a、29a、30a、33a、34a、37a、38a、41a、42a、45a、46a、50a-77a、80a、81a、84a、85a、88a-98a与100a-129a于此分析中进行测试,其中令人意外的是,所有待测化合物所展现的CC50值(亦即杀死50%细胞的待测化合物浓度)皆高于50μM。
其它实施例
本说明书中所揭示的全部特征可以任何方式组合。本说明书中所揭示的特征可被相同、相当、或类似目的的另一种特征所取代。因此,除非另有指明,否则所揭示的各特征仅为一般性的相当或类似特征的实例。
藉由上述说明,本发明可轻易的由熟习本项技艺者了解本发明必要的特征,且在不悖离本发明的范畴下,能够对本发明有种种改变及修饰,以适用于种种用途与情况,因此其它具体实施例亦在本申请专利范围内。
Claims (4)
1.一种式(IV)化合物:
其中R11和R12各自为C3-C5环烷基。
2.如权利要求1所述的化合物,其中,该化合物为下列化合物之一:
3.一种医药组合物,包括:一权利要求1的化合物与一医药可接受载体。
4.如权利要求3所述的医药组合物,其是用于治疗C型肝炎病毒感染。
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TW201120035A (en) | 2011-06-16 |
KR101768946B1 (ko) | 2017-08-17 |
WO2011068941A3 (en) | 2011-11-17 |
CN102482269A (zh) | 2012-05-30 |
HK1171439A1 (zh) | 2013-03-28 |
CA2781140A1 (en) | 2011-06-09 |
JP5753185B2 (ja) | 2015-07-22 |
WO2011068941A2 (en) | 2011-06-09 |
US8415482B2 (en) | 2013-04-09 |
EP2507232B1 (en) | 2019-03-20 |
MY179840A (en) | 2020-11-18 |
EP2507232A4 (en) | 2013-12-18 |
AU2010325980B2 (en) | 2016-04-07 |
TWI429645B (en) | 2014-03-11 |
AU2010325980A1 (en) | 2012-06-14 |
KR20120102690A (ko) | 2012-09-18 |
JP2013512915A (ja) | 2013-04-18 |
CA2781140C (en) | 2017-10-24 |
US20110136799A1 (en) | 2011-06-09 |
EP2507232A2 (en) | 2012-10-10 |
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