CN101939317A - 取代的芳基*唑和它们的应用 - Google Patents
取代的芳基*唑和它们的应用 Download PDFInfo
- Publication number
- CN101939317A CN101939317A CN2008801002064A CN200880100206A CN101939317A CN 101939317 A CN101939317 A CN 101939317A CN 2008801002064 A CN2008801002064 A CN 2008801002064A CN 200880100206 A CN200880100206 A CN 200880100206A CN 101939317 A CN101939317 A CN 101939317A
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- CN
- China
- Prior art keywords
- compound
- phenyl
- methyl
- group
- represent hydrogen
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
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Abstract
本申请涉及新的取代的芳基噁唑衍生物,它们的制备方法,它们对于治疗和/或预防疾病的应用和它们对于制备用于治疗和/或预防疾病,优选对于治疗和/或预防心血管病和代谢疾病的药物的应用。
Description
本申请涉及新的取代的芳基噁唑衍生物,它们的制备方法,它们对于治疗和/或预防疾病的应用和它们对于制备用于治疗和/或预防疾病,优选对于治疗和/或预防心血管病和代谢疾病的药物的应用。
腺苷,一种嘌呤核苷,存在于所有的细胞中和通过大量生理学和病理生理学刺激释放。腺苷作为在腺苷5′-单磷酸酯(AMP)和S-腺苷高半胱氨酸降解期间的中间体胞内形成,但是它可以由细胞释放,无论在哪种情况下它通过与特定的受体结合作为象荷尔蒙的物质或者神经递质起作用。
在含氧量正常的条件下,在细胞间隙中游离的腺苷的浓度是非常低的。然而,在局部缺血或者含氧量低的条件下,在受影响的脏器中腺苷的细胞外的浓度显著增加。因此,已知,例如,腺苷抑制血小板凝聚并且增加对冠状动脉的供血。此外,它对血压,对心率,对神经递质的释放和对淋巴细胞分化起作用。在脂肪细胞中,腺苷能抑制脂解,因此降低血中游离脂肪酸和甘油三酯的浓度。
腺苷的这些作用的目的是增加受影响脏器的供氧和/或减少这些脏器的代谢作用以便调整在局部缺血或者含氧量低的条件下脏器的代谢到脏器的供血。
腺苷的作用通过特定的受体调节。迄今为止,亚型A1,A2a,A2b和A3是已知的。根据本发明,“腺苷-受体-选择性的配体”是选择性地与一种或者多种腺苷受体的亚型结合的物质,因此或者模仿腺苷的作用(腺苷激动剂)或者阻遏它的作用(腺苷拮抗剂)。
这些腺苷受体的作用通过信使cAMP胞内调节。在腺苷与A2a或者A2b受体结合的情况下,胞内cAMP通过与结合膜的腺苷酸环化酶的激活增加,而通过抑制腺苷酸环化酶腺苷与A1或者A3受体的结合导致胞内cAMP浓度的减少。
在心血管系统中,腺苷受体的激活的主要的结果是:心动过缓,通过A1受体的心抗缺血的减弱收缩和保护(“预适应”),通过A2a和A2b受体的血管的扩张和通过A2b受体成纤维细胞和平滑肌细胞增殖的抑制。
在A1激动剂(优选通过Gi蛋白偶联)情况下,观察到胞内cAMP浓度的减少(优选通过毛喉素腺苷酸环化酶的直接预刺激后)。相应地,A2a和A2b激动剂(优选通过Gs蛋白偶联)导致细胞中cAMP浓度的增加和A2a和A2b拮抗剂导致细胞中cAMP浓度的减少。在A2受体情况下,通过毛喉素腺苷酸环化酶直接预刺激无益。
在人类中,通过特定的A1激动剂A1受体的激活导致依赖速率的心率的降低,对血压没有任何影响。因此,选择性的A1激动剂可尤其对于治疗心绞痛和心房纤维性颤动适合。
通过腺苷或者特定的A2b激动剂A2b受体的激活,通过血管的扩张,导致血压的降低。血压的降低伴随有反射性的心率增加。增加的心率可以通过使用特定的A1激动剂激活A1受体降低。
选择性的A1/A2b激动剂对血管系统和心率的联合作用因此导致全身血压降低,没有相关的心率增加。例如对于治疗人类中的高血压可以使用具有这种药理学性质的双重A1/A2b激动剂。
在脂肪细胞中,A1和A2b受体的激活导致脂解的抑制。因此,A1和A1/A2b激动剂对脂类代谢的选择性或者联合作用导致游离脂肪酸和甘油三酯的降低。这样,在遭受新陈代谢的病人中和在糖尿病患者中,降低的脂质导致较低的胰岛素抵抗力和改善的症状。
上面提到的受体选择性可以通过该物质对细胞系的作用测定,该细胞系,用相应cDNA稳定转染后,表达所讨论的受体亚型[参见出版物M.E.Olah,H.Ren,J.Ostrowski,K.A.Jacobson,G.L.Stiles,“Cloning,expression,and characterization of the unique bovine A1adenosine receptor.Studies on the ligand binding site by site-directedmutagenesis”,J.Biol.Chem.267(1992),10764-10770页,其公开在此全部插入作为参考]。
该物质对这种细胞系的作用可以通过生化测定胞内信使cAMP监控[看到出版物K.N.Klotz,J.Hessling,J.Hegler,C.Owman,B.Kull,B.B.Fredholm,M.J.Lohse,“Comparative pharmacology of humanadenosine receptor subtypes-characterization of stably transfected receptorsin CHO cells“,Naunyn Schmiedebergs Arch.Pharmacol.357(1998),1-9页,其公开在此全部插入作为参考]。
由现有技术已知的“腺苷-受体-特定的”配体主要是基于天然的腺苷的衍生物[S.-A.Poulsen和R.J.Quinn,“Adenosine receptors:Newopportunities for future drugs”,Bioorganic and Medicinal Chemistry 6(1998),619-641页]。然而,具有这类结构的腺苷配体中的大多数具有它们的作用不是真正地受体-特定的,它们的活性小于天然的腺苷的活性或者它们口服后仅仅具有非常弱的活性的缺点。因此,它们主要仅仅用于实验目的。
WO 01/25210,WO 02/070484和WO 02/070485公开了作为腺苷受体配体用于治疗病症的取代的2-硫代-或者2-氧基-3,5-二氰基-4-苯基-6-氨基吡啶。WO 03/053441具体描述了作为腺苷A1受体的选择性配体的特别取代的2-硫代-3,5-二氰基-4-苯基-6-氨基吡啶,和WO 2006/027142要求保护作为双重腺苷A1/A2b激动剂用于治疗高血压和其它的心血管病症的取代的苯基氨基噻唑衍生物。然而,人们发现这些化合物的一些具有缺点,这些缺点相对它们的物理化学性质,例如它们的溶解性和/或成配方能力,或者相对它们的体内性质,例如它们的药效动力学性状,它们的剂量-活性关系和/或它们的代谢途径。
此外,WO 01/62233公开了多种吡啶和嘧啶衍生物和它们作为腺苷受体调质的应用。在EP 1 302 463-A1中要求保护作为依赖钙的钾通道开启工具用于治疗泌尿疾病的取代的3,5-二氰基吡啶。WO 2004/054505要求保护作为MK 2抑制剂用于治疗TNFa-调节的病症的氨基氰基吡啶衍生物的应用。在US 2005/0182105中描述了作为雄激素受体调质的4-芳基-或者4-杂芳基-取代的氨基氰基吡啶的应用。
本发明的目的是提供新的化合物,其作为腺苷A1受体的选择性的激动剂或者作为腺苷A1和A2b受体的选择性的双重激动剂并且其本身适于治疗和/或预防特别是心血管疾病,例如高血压,心绞痛,心肌梗死,心力衰竭和心房纤维性颤动,新陈代谢的综合征,糖尿病和异常脂肪血症和适于在移植和外科手术期间保护脏器,和其另外与由现有技术已知的化合物相比具有改进的治疗性质。
本发明提供了具有下式(I)的化合物
其中
A代表O或者S,
R1代表氢或者(C1-C4)-烷基,
R2代表氢或者可以被羟基,(C1-C4)-烷氧基或者最高被氟三次取代的(C1-C4)-烷基
或者
R1和R2彼此连接和连同它们连接的碳原子形成环丙烷或者环丁烷环,
R3代表氢,卤素或者(C1-C4)-烷基,
R4和R5是相同的或者不同的并且彼此独立地代表氢或者可以被相同的或者不同的选自以下的取代基一-或者二取代的(C1-C6)-烷基:羟基,(C1-C4)-烷氧基,氨基,一-(C1-C4)-烷基氨基,二-(C1-C4)-烷基氨基,羧基,(C1-C4)-烷氧基羰基和4-~7-元杂环,
其中提到的杂环包含一个或者两个选自N,O和S的环杂原子并且对它说来可以被相同的或者不同的选自以下的取代基一-或者二取代:(C1-C4)-烷基,羟基,氧代和(C1-C4)-烷氧基,
或者
R4和R5连同它们连接的氮原子形成4-~7-元杂环,其包含进一步的选自N,O和S的环杂原子并且其可以被相同的或者不同的选自以下的取代基一-或者二取代:(C1-C4)-烷基,羟基,氧代和(C1-C4)-烷氧基,
和(i)
R6代表(C6-C10)-芳基或者具有最高三个选自N,O和S的环杂原子的5-~10-元杂芳基,该基团可以在每一种情况下被相同的或者不同的选自以下的取代基一--三取代:卤素,硝基,氰基,(C1-C4)-烷基,三氟甲基,羟基,(C1-C4)-烷氧基,二氟甲氧基,三氟甲氧基,一-(C1-C4)-烷基氨基羰基,(C1-C4)-烷氧基羰基和羧基,
和
R7代表氢,氟,氯,(C1-C4)-烷基,三氟甲基,(C1-C4)-烷氧基羰基,羧基或者苯基,其中
(C1-C4)-烷基可以被羟基或者(C1-C4)-烷氧基取代
和
苯基可以被卤素,氰基,(C1-C4)-烷基或者三氟甲基取代,
或者(ii)
R6代表氢或者(C1-C4)-烷基
和
R7代表苯基或者具有最高两个选自N,O和S的环杂原子的5-或者6-元杂芳基,该基团可以在每一种情况下被相同的或者不同的选自以下的取代基一-或者二取代:卤素,氰基,(C1-C4)-烷基和三氟甲基,
或者它们的盐,溶剂化物和盐的溶剂化物。
根据本发明的化合物是具有式(I)的化合物,和它们的盐,溶剂化物和盐的溶剂化物,被式(I)包括并且在下式中提到的化合物和它们的盐,溶剂化物和盐的溶剂化物,和被式(I)包括并且作为实施例实施方案提到的化合物,和它们的盐,溶剂化物和盐的溶剂化物,只要被式(I)包括并且以下提到的化合物还不是盐,溶剂化物和盐的溶剂化物。
取决于它们的结构,根据本发明的化合物可以以立体异构的形式(对映异构体,非对应异构体)存在。因此,本发明包括对映异构体或者非对应异构体和它们各自的混合物。可以由这种对映异构体和/或非对应异构体的混合物以已知的方式分离立体异构纯的组分。
如果根据本发明的化合物可以以互变异构形式存在,则本发明包括所有的互变异构形式。
为了本发明的目的优选的盐是根据本发明的化合物的生理可接受的盐。还包括本身不适于药用,但是其可以例如用于分离或者提纯根据本发明的化合物的盐。
根据本发明的化合物的生理可接受的盐包括无机酸,羧酸和磺酸的酸加成盐,例如盐酸,氢溴酸,硫酸,磷酸,甲烷磺酸,乙烷磺酸,甲苯磺酸,苯磺酸,萘二磺酸,乙酸,三氟乙酸,丙酸,乳酸,酒石酸,苹果酸,柠檬酸,富马酸,马来酸和苯甲酸的盐。
根据本发明的化合物的生理可接受的盐还包括常规碱的盐,例如和优选,碱金属盐(例如钠盐和钾盐),碱土金属盐(例如钙盐和镁盐)和铵盐,该铵盐衍生自氨或者具有1到16个碳原子的有机胺,例如和优选,乙胺,二乙胺,三乙胺,乙基二异丙胺,单乙醇胺,二乙醇胺,三乙醇胺,二环己胺,二甲氨基乙醇,普鲁卡因,二苄胺,N-甲基吗啉,精氨酸,赖氨酸,乙二胺和N-甲基哌啶。
为了本发明的目的溶剂化物指根据本发明的化合物的那些形式,其通过与溶剂分子配位形成以固态或者液态的形式的配合物。水合物是其中其中配位与水发生的溶剂化物的特殊形式。为了本发明的目的,优选的溶剂化物是水合物。
此外,本发明还包括根据本发明的化合物的药物前体。术语“药物前体”包括本身可能是生物学活性的或者非活动性的但是它们在身体内停留时间期间转化(例如代谢或者水解)成根据本发明的化合物的化合物。
为了本发明的目的,取代基具有以下意思,除非另外说明:
为了本发明的目的,(C 1 -C 6 )-烷基和(C 1 -C 4 )-烷基是分别具有1-6和1-4个碳原子的直链或者支链烷基基团。优选具有1-4歌碳原子的直链或者支链烷基基团。例如和优选地可以提到以下基团:甲基,乙基,正-丙基,异丙基,正-丁基,异丁基,仲-丁基,叔-丁基,1-乙基丙基,正-戊基和正-己基。
为了本发明的目的,(C 1 -C 4 )-烷氧基代表具有1-4个碳原子的直链或者支链烷氧基基团。例如和优选地可以提到以下基团:甲氧基,乙氧基,正-丙氧基,异丙氧基,正-丁氧基和叔-丁氧基。
为了本发明的目的,(C 1 -C 4 )-烷氧基羰基代表具有1-4碳原子的直链或者支链烷氧基基团,其通过羰基连接。例如和优选地可以提到以下基团:甲氧基羰基,乙氧基羰基,正-丙氧基羰基,异丙氧基羰基和叔丁氧基羰基。
为了本发明的目的,一-(C 1 -C 4 )-烷基氨基代表具有直链或者支链烷基取代基的氨基,该取代基具有1-4个碳原子。例如和优选地可以提到以下基团:甲基氨基,乙基氨基,正-丙基氨基,异丙基氨基,正-丁基氨基和叔-丁基氨基。
为了本发明的目的,一-(C 1 -C 4 )-烷基氨基羰基代表通过羰基基团连接并且具有直链或者支链烷基取代基的氨基,该取代基具有1-4个碳原子。例如和优选地可以提到以下基团:甲基氨基羰基,乙基氨基羰基,正-丙基氨基羰基,异丙基氨基羰基,正-丁基氨基羰基和叔-丁基氨基羰基。
为了本发明的目的,二-(C 1 -C 4 )-烷基氨基代表具有两个相同的或者不同的直链或者支链烷基取代基的氨基,该取代基在每一种情况下具有1-4个碳原子。例如和优选地可以提到以下基团:N,N-二甲基氨基,N,N-二乙基氨基,N-乙基-N-甲基氨基,N-甲基-N-正-丙基氨基,N-异丙基-N-正-丙基氨基,N,N-二异丙基氨基,N-正-丁基-N-甲基氨基和N-叔-丁基-N-甲基氨基。
为了本发明的目的,(C 6 -C 10 )-芳基代表具有6或者10个环碳原子的芳族碳环。优选的芳基是苯基和萘基。
为了本发明的目的,4-~7-元杂环代表具有总共4-7个环原子的饱和杂环,其包含一个或者两个选自N,O和S的环杂原子并且其通过环碳原子或者任选地通过环氮原子连接。优选具有一个或者两个来自N和O的环杂原子的4-~6-元杂环。例如可以提到以下基团:氮杂环丁烷基,氧杂环丁烷基,吡咯烷基,吡唑烷基,四氢呋喃基,哌啶基,哌嗪基,四氢吡喃基,吗啉基,硫代吗啉基,六氢氮杂基和六氢化1,4-二氮杂基。优选氮杂环丁烷基,吡咯烷基,四氢呋喃基,哌啶基,哌嗪基,六氢吡喃基和吗啉基。
为了本发明的目的,氮杂环丁烷子基(azetidino),吡咯烷子基(pyrrolidino),哌啶子基(piperidino)或者吗啉代基团分别是氮杂环丁烷环,吡咯烷环,哌啶环和吗啉环,其通过各自环氮原子连接。
为了本发明的目的,5-~10-元杂芳基代表具有总共5-10个环原子的一-或者任选地二环的芳族杂环(杂芳基),其包含最高达三个相同的或者不同的来自N,O和S的环杂原子并且其通过环碳原子或者任选地通过环氮原子连接。例如可以提到以下基团:呋喃基,吡咯基,噻吩基,吡唑基,咪唑基,噻唑基,噁唑基,异噁唑基,异噻唑基,三唑基,噁二唑基,噻二唑基,吡啶基,嘧啶基,哒嗪基,吡嗪基,三嗪基,苯并呋喃基,苯并噻吩基,苯并咪唑基,苯并噁唑基,苯并噻唑基,苯并三唑基,吲哚基,吲唑基,喹啉基,异喹啉基,萘啶基(Naphthyridinyl),喹唑啉基,喹喔啉基,酞嗪基,吡唑并[3,4-b]吡啶基。优选具有最高达两个来自N,O和S的环杂原子的单环5-或者6- 元杂芳基基团,例如呋喃基,噻吩基,噻唑基,噁唑基,异噻唑基,异噁唑基,吡唑基,咪唑基,吡啶基,嘧啶基,哒嗪基,吡嗪基。
为了本发明的目的,卤素包括氟,氯,溴和碘。优选氯或者氟。
当在根据本发明的化合物中的基团被取代时,基团可以是一或者多取代的,除非另外说明。为了本发明的目的,不止一次出现的所有基团的意思彼此独立。优选被一个,两个或者三个相同的或者不同的取代基取代。非常特别优选被一个或者两个相同的或者不同的取代基取代。
为了本发明的目的,优选具有下式(I)的化合物,其中
A代表O或者S,
R1代表氢或者甲基,
R2代表氢,甲基,羟基甲基,甲氧基甲基或者三氟甲基,
R3代表氢,氟或者甲基,
R4代表氢或者可以被相同的或者不同的选自羟基,(C1-C4)-烷氧基,氨基,一-(C1-C4)-烷基氨基,二-(C1-C4)-烷基氨基,羧基和4-~6-元杂环的取代基一-或者二取代的(C1-C4)-烷基,
其中提到的杂环包含一个或者两个选自N和O的环杂原子并且对它说来可以被相同的或者不同的选自甲基,羟基和甲氧基的取代基一-或者二取代,
R5代表氢或者甲基,
或者
R4和R5连同它们连接的氮原子形成4-~6-元杂环,其可以包含进一步的选自N和O的环杂原子并且其可以被相同的或者不同的选自以下的取代基一-或者二取代:甲基,羟基和甲氧基,
和(i)
R6代表苯基,吡啶基或者噻吩基,其可以在每一种情况下被相同的或者不同的选自以下的取代基一--三取代:氟,氯,氰基,(C1-C4)-烷基,三氟甲基,(C1-C4)-烷氧基,三氟甲氧基,一-(C1-C4)-烷基氨基羰基,(C1-C4)-烷氧基羰基和羧基,
和
R7代表氢,(C1-C4)-烷基,三氟甲基,(C1-C4)-烷氧基羰基,羧基或者可以被氟或者氯取代的苯基,
或者(ii)
R6代表氢,
和
R7代表可以被相同的或者不同的选自以下的取代基一-或者二取代的苯基:氟,氯,氰基,甲基和三氟甲基,
和它们的盐,溶剂化物和盐的溶剂化物。
在本发明的上下文中,特别优选具有式(I)的化合物,其中
A代表O或者S,
R1代表氢或者甲基,
R2代表氢,甲基,羟基甲基或者三氟甲基,
R3代表氢或者氟,
R4代表氢或者可以被相同的或者不同的选自羟基,氨基,甲基氨基,乙基氨基,二甲基氨基和二乙基氨基的取代基一-或者二取代的(C1-C4)-烷基,
R5代表氢或者甲基,
或者
R4和R5连同它们连接的氮原子形成氮杂环丁烷子基,吡咯烷子基或者哌啶子基环,其中每个可以被羟基取代,或者形成吗啉代环,
R6代表苯基或者噻吩基,其在每一种情况下可以被相同的或者不同的选自以下的取代基一-或者二取代:氟,氯,甲基,三氟甲基,甲氧基和羧基,
和
R7代表氢,甲基,三氟甲基,甲氧基羰基或者羧基,
和它们的盐,溶剂化物和盐的溶剂化物。
在各个基团组合或者优选的基团组合中给出的具体的基团定义,不依赖于各个给出的基团的组合,还任意地被其他组合的基团定义替换。
特别优选以上提到的两个或多个优选的范围的组合。
在本发明的上下文中,以下提到的化合物是特别优选的
2-氨基-6-({[2-(3-氯-4-氟苯基)-1,3-噁唑-4-基]甲基}硫烷基)-4-[4-(2-羟基乙氧基)苯基]吡啶-3,5-二腈;
2-氨基-6-({[2-(3,4-二氟苯基)-1,3-噁唑-4-基]甲基}硫烷基)-4-[4-(2-羟基乙氧基)苯基]吡啶-3,5-二腈;
2-氨基-6-({[2-(4-氟-3-甲基苯基)-1,3-噁唑-4-基]甲基}硫烷基)-4-[4-(2-羟基乙氧基)苯基]吡啶-3,5-二腈;
2-氨基-6-({[2-(4-氯苯基)-1,3-噁唑-4-基]甲基}硫烷基)-4-(4-{[(2S)-2,3-二羟基丙基]氧基}苯基)吡啶-3,5-二腈;
2-氨基-6-({[2-(4-氯苯基)-1,3-噁唑-4-基]甲基}硫烷基)-4-(4-{[(2R)-2,3-二羟基丙基]氧基}苯基)吡啶-3,5-二腈;
2-氨基-4-(4-{[(2S)-2,3-二羟基丙基]氧基}苯基)-6-({[2-(4-氟苯基)-5-甲基-1,3-噁唑-4-基]甲基}硫烷基)吡啶-3,5-二腈;
2-氨基-6-({[2-(4-氯苯基)-5-甲基-1,3-噁唑-4-基]甲基}硫烷基)-4-(4-{[(2S)-2,3-二羟基丙基]氧基}苯基)吡啶-3,5-二腈;
2-氨基-4-(4-{[(2S)-2,3-二羟基丙基]氧基}苯基)-6-({[2-(2-氟苯基)-5-甲基-1,3-噁唑-4-基]甲基}硫烷基)吡啶-3,5-二腈;
2-氨基-4-(4-{[(2R)-2,3-二羟基丙基]氧基}苯基)-6-({[2-(4-甲氧基苯基)-5-甲基-1,3-噁唑-4-基]甲基}硫烷基)吡啶-3,5-二腈;
2-氨基-6-({[2-(4-氯-3-甲基苯基)-1,3-噁唑-4-基]甲基}硫烷基)-4-(4-{[(2R)-2,3-二羟基丙基]氧基}苯基)吡啶-3,5-二腈;
4-{4-[({6-氨基-3,5-二氰基-4-[4-(2-羟基-2-甲基丙氧基)苯基]吡啶-2-基}硫代)甲基]-5-甲基-1,3-噁唑-2-基}苯甲酸;
2-氨基-4-(4-{[(2R)-2,3-二羟基丙基]氧基}苯基)-6-({[2-(4-氟苯基)-1,3-噁唑-4-基]甲基}硫烷基)吡啶-3,5-二腈;
2-氨基-6-{[2-(4-氯苯基)-1,3-噁唑-4-基]甲氧基}-4-[4-(2-羟基乙氧基)苯基]吡啶-3,5-二腈;
2-氨基-6-{[2-(3,4-二氟苯基)-1,3-噁唑-4-基]甲氧基}-4-[4-(2-羟基乙氧基)苯基]吡啶-3,5-二腈;
2-({[2-(4-氯苯基)-1,3-噁唑-4-基]甲基}硫烷基)-4-[4-(2-羟基乙氧基)苯基]-6-(吡咯烷-1-基)吡啶-3,5-二腈;
2-({[2-(4-氯苯基)-1,3-噁唑-4-基]甲基}硫烷基)-4-[4-(2-羟基乙氧基)苯基]-6-[(2-羟基乙基)氨基]吡啶-3,5-二腈;
2-({[2-(4-氯苯基)-1,3-噁唑-4-基]甲基}硫烷基)-6-{[(2R)-2,3-二羟基丙基]氨基}-4-[4-(2-羟基乙氧基)苯基]吡啶-3,5-二腈;
2-({[2-(4-氯苯基)-1,3-噁唑-4-基]甲基}硫烷基)-4-[4-(2-羟基乙氧基)苯基]-6-[(3R)-3-羟基吡咯烷-1-基]吡啶-3,5-二腈;
2-{[2-(4-氯苯基)-1,3-噁唑-4-基]甲氧基}-4-[4-(2-羟基乙氧基)苯基]-6-[(2-羟基乙基)氨基]吡啶-3,5-二腈
和
2-{[2-(4-氯苯基)-1,3-噁唑-4-基]甲氧基}-6-(3-羟基氮杂环丁烷-1-基)-4-[4-(2-羟基乙基)苯基]吡啶-3,5-二腈
和它们的盐,溶剂化物和盐的溶剂化物。
在本发明的上下文中,非常特别优选以下提到的化合物
2-氨基-6-({[2-(3,4-二氟苯基)-1,3-噁唑-4-基]甲基}硫烷基)-4-[4-(2-羟基乙氧基)苯基]吡啶-3,5-二腈;
2-氨基-6-({[2-(4-氯苯基)-1,3-噁唑-4-基]甲基}硫烷基)-4-(4-{[(2S)-2,3-二羟基丙基]氧基}苯基)吡啶-3,5-二腈;
2-氨基-6-({[2-(4-氯苯基)-1,3-噁唑-4-基]甲基}硫烷基)-4-(4-{[(2R)-2,3-二羟基丙基]氧基}苯基)吡啶-3,5-二腈;
2-氨基-6-({[2-(4-氯苯基)-5-甲基-1,3-噁唑-4-基]甲基}硫烷基)-4-(4-{[(2S)-2,3-二羟基丙基]氧基}苯基)吡啶-3,5-二腈;
2-氨基-6-{[2-(4-氯苯基)-1,3-噁唑-4-基]甲氧基}-4-[4-(2-羟基乙氧基)苯基]吡啶-3,5-二腈;
2-({[2-(4-氯苯基)-1,3-噁唑-4-基]甲基}硫烷基)-4-[4-(2-羟基乙氧基)苯基]-6-[(2-羟基乙基)氨基]吡啶-3,5-二腈;
2-({[2-(4-氯苯基)-1,3-噁唑-4-基]甲基}硫烷基)-4-[4-(2-羟基乙氧基)苯基]-6-[(3R)-3-羟基吡咯烷-1-基]吡啶-3,5-二腈
和
2-{[2-(4-氯苯基)-1,3-噁唑-4-基]甲氧基}-6-(3-羟基氮杂环丁烷-1-基)-4-[4-(2-羟基乙基)苯基]吡啶-3,5-二腈
和它们的盐,溶剂化物和盐的溶剂化物。
本发明此外提供了制备具有根据本发明的式(I)的化合物的方法,特征在于具有下式(II)的化合物
其中A,R1,R2,R3,R4和R5每一个具有以上给出的意思,
和
R8代表氢或者临时的羟基保护基
在惰性溶剂中在碱存在的情况下与具有下式(III)的化合物反应
其中R6和R7具有以上给出的意思和
Q代表合适的离去基团,优选卤素,特别是氯,溴或者碘,或者代表甲磺酸根(Mesylat),甲苯磺酸根(Tosylat)或者三氟甲磺酸根(Triflat),
或者,如果A代表O,具有下式(IV)的化合物
其中R1,R2,R3,R4,R5和R8每一个具有以上给出的意思
在惰性溶剂中在碱存在的情况下与具有下式(V)的化合物反应
其中R6和R7具有以上给出的意思,
然后除去任选存在的保护基并且产生的具有式(I)的化合物任选地用适当的(i)溶剂和/或(ii)碱或者酸转化成它们的溶剂化物,盐和/或盐的溶剂化物。
在该方法中,如果有利或者需要,任何在具有式(II)和(IV)的化合物中或者在基团R2,R4和/或R5中任选存在的官能团-例如,特别是氨基,羟基和羧基-还可以以临时保护的形式存在。这里,这种保护基的引入和除去通过所属领域技术人员所知的常见方法进行[参见,例如T.W.Greene和P.G.M.Wuts,Protective Groups in Organic Synthesis,Wiley,纽约,1999;M.Bodanszky和A.Bodanszky,The Practice ofPeptide Synthesis,Springer-Verlag,柏林,1984]。如果存在多个保护基,如合适,除去可以同时在一锅反应(Eintopf-Reaktion)中,或者在单独的反应步骤中进行。
优选的氨基保护基是叔-丁氧基羰基(Boc)或者苄氧基羰基(Z)。对保护的羧基基团适合的特别是相应的甲基,乙基或者叔-丁基酯。对于羟基官能团,使用的保护基优选是苄基或者甲硅烷基基团,例如三甲基甲硅烷基,叔-丁基二甲基甲硅烷基或者二甲基苯基甲硅烷基。如果存在1,2-或者1,3-二醇基团,优选使用衍生自对称酮例如丙酮或者环己酮的缩酮(1,3-二氧戊环或者1,3-二噁烷)作为共同的保护基。
以作例证的方式,以上描述的方法可以通过以下反应方案1和2说明:
方案1
方案2
对于该反应(II)+(III)合适的溶剂是在反应条件下是惰性的所有有机溶剂。这些包括酮,例如丙酮和甲基乙基酮,无环醚和环醚,例如乙醚,甲基叔丁基醚,1,2-二甲氧基乙烷,四氢呋喃和二噁烷,酯,例如乙酸乙酯或者乙酸丁酯,碳氢化合物,例如苯,甲苯,二甲苯,己烷和环己烷,氯代烃,例如二氯甲烷,三氯甲烷和氯苯,或者其它的溶剂,例如二甲基甲酰胺(DMF),二甲基亚砜(DMSO),N-甲基吡咯烷酮(NMP),乙腈或者吡啶。还可以使用以上提到的溶剂的混合物。优选使用二甲基甲酰胺。
对于该反应合适的碱是常见的无机或者有机碱。这些优选包括碱金属氢氧化物,例如氢氧化锂,氢氧化钠或者氢氧化钾,碱金属碳酸盐,例如碳酸锂,碳酸钠,碳酸钾或者碳酸铯,碱金属碳酸氢盐,例如碳酸氢钠或者碳酸氢钾,碱金属醇盐,例如甲醇钠或者甲醇钾,乙醇钠或者乙醇钾或者叔丁醇钾,氨化物,例如氨基钠,双(三甲基甲硅烷基)氨基锂,双(三甲基甲硅烷基)氨基钠或者双(三甲基甲硅烷基)氨基钾或者二异丙基氨基锂,有机金属化合物,例如丁基锂或者苯基锂,或者有机胺,例如三乙胺,二异丙基乙胺,吡啶,1,8-二氮杂双环[5.4.0]十一碳-7-烯(DBU)或者1,5-二氮杂双环[4.3.0]壬-5-烯(DBN)。优选碱金属碳酸盐和碱金属碳酸氢盐,例如碳酸钾和碳酸氢钠。
这里,碱可以以每摩尔具有式(II)的化合物1-10mol,优选1-5mol,特别地1-3mol的量使用。
该反应(II)+(III)通常在-78℃-+140℃温度范围,优选在-20℃-+100℃,特别地在0℃-+60℃(对于A=S)或者+20℃-+100℃(对于A=O)范围进行。反应可以在常压,升压或者降压(例如在0.5-5bar)范围进行。通常,反应在常压下进行。
对于该反应(IV)+(V)合适的惰性的溶剂是无环醚和环醚,例如乙醚,甲基叔丁基醚,1,2-二甲氧基乙烷,四氢呋喃和二噁烷,碳氢化合物,例如苯,甲苯,二甲苯,己烷和环己烷,或者偶极溶剂,例如二甲基甲酰胺(DMF),二甲基亚砜(DMSO),N-甲基吡咯烷酮(NMP)和吡啶。还可以使用这些溶剂的混合物。优选使用1,2-二甲氧基乙烷。
对于该反应合适的碱是特别地碱金属醇盐,例如甲醇钠或者甲醇钾,乙醇钠或者乙醇钾,或者叔丁醇钠或者叔丁醇钾,氨化物,例如氨基钠,双(三甲基甲硅烷基)氨基锂,双(三甲基甲硅烷基)氨基钠或者双(三甲基甲硅烷基)氨基钾或者二异丙基氨基锂,或者有机金属化合物,例如丁基锂或者苯基锂。优选使用叔丁醇钾。
这里,碱通常以每摩尔具有式(V)的化合物1-1.25mol,优选以等摩尔的量使用。
反应(IV)+(V)通常在-20℃-+120℃,优选在+20℃-+100℃温度范围进行。反应可以在常压,升压或者降压(例如在0.5-5bar范围)下进行。通常,反应在常压下进行。
类似于由文献已知的方法,可以例如通过具有下式(VI)的醛
其中R1,R2,R3和R8每一个具有以上给出的意思
在碱存在的情况下与二当量的氰基硫代乙酰胺反应制备具有式(II)的化合物,其中A表示S和R4和R5代表氢[参见方案3;参见例如Dyachenko等,Russ.J.Chem.33(7),1014-1017(1997),34(4),557-563(1998)Dyachenko等,Chemistry of Heterocyclic Compounds 34(2),188-194(1998);Qintela等,Eur.J.Med.Chem.33,887-897(1998);Kandeel等,Z.Naturforsch.42b,107-111(1987);Reddy等,J.Med.Chem.49,607-615(2006);Evdokimov等,Org.Lett.8,899-902(2006)]。
方案3
具有式(II)的化合物,其中A代表S,还可以由具有式(IV)的化合物通过与碱金属硫化物的反应制备:该制备方法通过以下式的方案说明:
方案4
使用的碱金属硫化物优选是硫化钠,以每摩尔具有式(IV)的化合物1-10mol,优选1-8mol,特别地1-5mol的量。
对于该方法步骤合适的溶剂是在反应条件下是惰性的所有有机溶剂。这些包括醇,例如甲醇,乙醇,正-丙醇,异丙醇,正-丁醇和叔-丁醇,酮,例如丙酮和甲基乙基酮,无环醚和环醚,例如乙醚,1,2-二甲氧基乙烷,四氢呋喃和二噁烷,酯,例如乙酸乙酯或者乙酸丁酯,碳氢化合物,例如苯,甲苯,二甲苯,己烷和环己烷,氯代烃,例如二氯甲烷,1,2-二氯乙烷和氯苯,或者偶极溶剂,例如乙腈,吡啶,二甲基甲酰胺,二甲基亚砜,N-甲基吡咯烷酮。同样水用作溶剂是合适的。还可以使用以上提到的溶剂的混合物。优选的溶剂是二甲基甲酰胺。
反应通常在0℃-+180℃温度范围,优选在+20℃-+120℃范围,特别地在+40℃-+100℃下进行。反应可以在常压,升压或者降压(例如在0.5-5bar范围)下进行。通常,反应在常压下进行。
具有式(IV)的化合物,其中两个基团R4和R5中的至少一个不代表氢,可以通过具有式(IVa)的化合物
其中R1,R2,R3和R8每一个具有以上给出的意思
最初用氯化铜(II)和亚硝酸异戊酯在合适的溶剂中转化成为具有下式(VII)的化合物
其中R1,R2,R3和R8每一个具有以上给出的意思
接着与具有下式(VIII)的化合物反应
其中
R4A具有以上R4给出的意思,
R5A具有以上R5给出的意思,
但是两个基团中的至少一个不代表氢,
以产生具有下式(IVb)的化合物
其中R1,R2,R3,R4A,R5A和R8每一个具有以上给出的意思;
任选地,这些之后可以借助于以上描述的碱金属硫化物转化成相应的具有式(II)的化合物,其中A代表S和两个基团R4和R5中的至少一个不代表氢。该方法可以通过以下反应方案说明:
方案5
[Ph=苯基]。
方法步骤(IVa)→(VII)通常使用每摩尔具有式(IVa)的化合物2-12mol氯化铜(II)和2-12mol亚硝酸异戊酯的摩尔比进行。
对于该方法步骤是合适的溶剂在反应条件下是惰性的所有有机溶剂。这些包括无环醚和环醚,例如乙醚和四氢呋喃,酯,例如乙酸乙酯和乙酸丁酯,碳氢化合物,例如苯,甲苯,二甲苯,己烷和环己烷,氯代烃,例如二氯甲烷,1,2-二氯乙烷和氯苯,或者其它的溶剂,例如二甲基甲酰胺,乙腈或者吡啶。还可以使用这些溶剂的混合物。优选的溶剂是乙腈和二甲基甲酰胺。
反应通常在-78℃-+180℃温度范围,优选在+20℃-+100℃范围,特别地在+20℃-+60℃下进行。反应可以在常压,升压或者降压(例如在0.5-5bar范围)下进行。通常,反应在常压下进行。
方法步骤(VII)+(VIII)→(IVb)通常使用每摩尔具有式(VII)的化合物1-8mol具有式(VIII)的化合物的摩尔比进行。
对于该方法步骤合适的溶剂是在反应条件下是惰性的所有有机溶剂。这些包括醇,例如甲醇,乙醇,正-丙醇,异丙醇,正-丁醇和叔-丁醇,酮,例如丙酮和甲基乙基酮,无环醚和环醚,例如乙醚,1,2-二甲氧基乙烷,四氢呋喃和二噁烷,酯,例如乙酸乙酯或者乙酸丁酯,碳氢化合物,例如苯,甲苯,二甲苯,己烷和环己烷,氯代烃,例如二氯甲烷,1,2-二氯乙烷和氯苯,或者其它的溶剂,例如二甲基甲酰胺,乙腈,吡啶或者二甲基亚砜。水用作溶剂同样是合适的。还可以使用这些溶剂的混合物。优选的溶剂是二甲基甲酰胺。
反应通常在0℃-+180℃温度范围,优选在+20℃-+120℃范围,特别地在+20℃-+100℃下进行。反应可以在常压,升压或者降压(例如在0.5-5bar范围)下进行。通常,反应在常压下进行。
具有式(IVa)的化合物可以由具有式(VI)的化合物以类似于在文献中描述的方法制备[参见,例如Kambe等,Synthesis,531-533(1981);Elnagdi等,Z.Naturforsch.47b,572-578(1991);Reddy等,J.Med.Chem.49,607-615(2006);Evdokimov等,Org.Lett.8,899-902(2006)]。
具有式(VIII)的化合物可商购,或者为所属领域技术人员所知或者可通过常见方法制备。
任选地,还可以类似于反应顺序(IVa)→(VII)→(IVb)转化具有式(I)的化合物,其中R4和R5均代表氢,成为相应化合物,其中两个基团R4和R5中的至少一个不代表氢,其中,任选地,其它的官能团的临时保护是有利的。这方法的变换方式在以下反应方案中说明:
方案6
对于该方法路线,以上对于顺序(IVa)→(VII)→(IVb)描述的反应参数,例如溶剂,反应温度和摩尔比以类似的方式使用。
具有式(II)的化合物,其中A代表O,还可以由具有式(IV)的化合物通过与碱金属氢氧化物加热获得。该制备方法通过以下反应方案说明:
方案7
使用的碱金属氢氧化物优选是过量氢氧化钠或者氢氧化钾。合适的溶剂是特别地醇,例如甲醇,乙醇,正-丙醇,异丙醇,正-丁醇和叔-丁醇,和它们与水的混合物。反应通常在+20℃-+120℃温度范围,优选在+50℃-+100℃下进行。
具有式(III)的化合物可商购,由文献已知或者可通过由文献已知的方法制备。例如通过酰胺与1,3-二卤丙酮反应,可以获得2-取代的噁唑衍生物(参见方案8):
方案8
根据式(III)2,5-二取代的噁唑衍生物可以以类似于由文献已知的方法制备,例如如以作例证的方式在以下反应方案9中描述:
方案9
[参见,例如Y.Goto等,Chem.Pharm.Bull.1971,19,2050-2057]。
根据式(III)在5-位置取代的噁唑衍生物可以例如通过相应噁唑-4-羧酸酯的还原和随后的卤化获得,噁唑-4-羧酸酯本身可通过α-异氰酸基乙酸酯的酰化达到(参见方案10):
方案10
[参见,例如M.Suzuki等,J.Org.Chem.1973,38,3571-3575]。
根据式(III)2-芳基噁唑衍生物还可以如同在方案11中以作例证的方式所示通过钯催化的芳基硼酸与2-碘噁唑-4-羧酸酯的偶联获得:
方案11
[参见,例如E.A.Krasnokutskaya等,Synthesis 2007,1,81-84;J.Hassan等,Chem.Rev.2002,102,1359-1469]。
具有式(VI)的化合物最后由文献已知或者可以通过常见的方法由相应4-羟基苯甲醛制备(参见方案12):
方案12
令人惊讶地,根据本发明的化合物具有不可预见的有用的药理学活性谱和因此特别适合于预防和/或治疗疾病,特别是心血管疾病。
与由现有技术已知的物质相比,根据本发明的化合物具有改进的性质概况,例如在与制剂相关的水/有机溶剂体系中增加的溶解性,口服后比较久的药效动力学半衰期和/或增加的新陈代谢的稳定性。
根据本发明的化合物的药理学活性可以通过它们作为对腺苷A1和/或A2b受体有效的、选择性的配体的作用解释。这里,它们作为选择性的A1激动剂或者作为选择性的双重A1/A2b激动剂。
在本发明的上下文中,“对腺苷A1和/或A2b受体的选择性的配体”是腺苷受体配体,其中可以观察到首先对A1和/或A2b腺苷受体亚型显著的活性和其次对A2a和A3腺苷受体亚型没有或者有相当弱的活性(以10分之一或更多),其中相对于对于活性/选择性的试验方法,涉及在段B-1中描述的试验。
取决于它们的各自的结构,根据本发明的化合物作为完全或者作为部分腺苷受体激动剂。这里,部分腺苷受体激动剂定义为对少于通过完全激动剂引起的腺苷受体引起功能反应的受体配体(例如腺苷本身)。因此,部分激动剂相对于受体激活比完全激动剂具有较低的活性。
具有下(I)的化合物,单独或者与一种或者多种其它的活性化合物结合,适于预防和/或治疗多种疾病,例如特别是高血压和其它的心血管系统的疾病(心血管病),适于心损伤后的保护心脏和适于代谢失调。
在本发明的上下文中,心血管系统疾病或者心血管疾病被理解为包括,除高血压外,还有例如以下疾病:外周和心血管疾病,冠心病,冠状动脉再狭窄,例如外周血管气囊扩张后的再狭窄,心肌梗死,急性冠状动脉综合征,伴随ST升高的急性冠状动脉综合征,没有ST升高的急性冠状动脉综合征,稳定型和不稳定型心绞痛,心肌机能不全,普林兹梅塔尔心绞痛,持续性缺血功能障碍(“冬眠心肌”),短暂性缺血后功能障碍(“顿抑心肌”),心力衰竭,心动过速,房性心动过速,心律不齐,心房和心室纤颤,持续性心房纤颤,永久心房纤颤,伴随正常左心室功能的心房纤颤,伴随左心室功能损害的心房纤颤,沃-帕-杯综合征,外周循环减低,纤维蛋白原和具有低密度的LDL的水平上升和血纤蛋白溶酶原激活物抑制剂1(PAI-1)浓度上升,特别是高血压,冠心病,急性冠状动脉综合征,心绞痛,心力衰竭,心肌梗死和心房纤颤。
在本发明的上下文中,术语心力衰竭包括心力衰竭的急性和慢性表现,和该疾病的特定的或者相关的形式,例如急性失代偿性的心力衰竭,右侧心力衰竭,左侧心力衰竭,完全性衰竭,缺血性心肌病,膨胀性心肌病,先天心脏缺陷,心脏瓣膜缺陷,作为心脏瓣膜的缺陷结果的心力衰竭,二尖瓣狭窄,二尖瓣关闭不全,主动脉瓣狭窄,主动脉瓣闭锁不全,三尖瓣狭窄,三尖瓣关闭不全,肺动脉狭窄,肺动脉瓣闭锁不全,合并性心脏瓣膜缺陷,心肌炎,慢性心肌炎,急性心肌炎,病毒性心肌炎,糖尿病性心力衰竭,醇中毒性心肌病,心贮疾病和心脏舒张和心脏收缩心力衰竭。
根据本发明的化合物此外还特别适合于降低受梗塞影响的心肌部位,和适于预防续发性梗塞。
此外,根据本发明的化合物特别适合于预防和/或治疗血栓栓塞病,缺血后的再灌注损伤,微和大血管损伤(脉管炎),动脉和静脉血栓形成,水肿,缺血,例如心肌梗死,中风和暂时性缺血发作,适合于在冠状动脉旁路移植术(CABG)期间的保护心脏,原发性经皮-腔内冠状动脉成形术(PTCAs),血栓溶解后的PTCAs,救护-PTCA,心脏移植术和直视心外科手术,和适于在移植术期间的器官保护,捷径术,导管检查和其它的外科手术。
根据本发明的化合物可以使用的进一步的适应症是,例如预防和/或治疗泌尿生殖系统疾病,例如在刺激性膀胱,勃起功能障碍和雌性性功能障碍中,但是另外还预防和/或治疗炎性疾病,例如哮喘和炎性皮肤病,预防和/或治疗中枢神经系统的疾病和神经变性疾病(中风,阿尔茨海默氏病,帕金森氏病,痴呆,癫痫症,抑郁症,多发性硬化),预防和/或治疗疼痛,和预防和/或治疗肿瘤疾病和与癌症治疗有关的恶心和呕吐。
进一步的适应症是,例如预防和/或治疗呼吸道疾病,例如哮喘,慢性-阻塞性肺病(COPD,慢性支气管炎),肺气肿,支气管扩张,囊性纤维化(囊肿性纤维化)和肺动脉高压,特别是肺动脉高压。
最后,根据本发明的化合物还适合于预防和/或治疗代谢失调,例如糖尿病,特别是糖尿病(diabetes mellitis)的病,妊娠糖尿病,胰岛素依赖型糖尿病和非-依赖胰岛素的糖尿病,糖尿病后遗症,例如视网膜病,肾病和神经病,代谢失调,例如新陈代谢综合征,高血糖,高胰岛素血,胰岛素抗性,葡萄糖不耐受和肥胖(肥胖症),和动脉硬化和异常脂肪血症(高胆固醇血症,高甘油三酯血症,饭后血浆甘油三酯浓度升高,低α-脂蛋白血症,合并性高脂血症,特别是糖尿病,新陈代谢综合征和异常脂肪血症。
本发明此外提供了根据本发明的化合物对于治疗和/或预防疾病,特别是以上提到的疾病的应用。
本发明还提供了根据本发明的化合物对于制备用于治疗和/或预防疾病,特别是以上提到的疾病的药物的应用。
本发明还提供了使用有效量的根据至少一种根据本发明的化合物治疗和/或预防疾病,特别是以上提到的疾病的方法。
根据本发明的化合物可以单独或者,如果需要,与其它的活性化合物结合使用。本发明此外提供了包含至少一种根据本发明的化合物和一种或者多种进一步的活性化合物,特别是用于治疗和/或预防以上提到的疾病的药物。
用于结合的合适的活性化合物是,例如和优选:调整脂类代谢的活性化合物,抗糖尿病药,降血压剂,提高灌注和/或抗血栓的药剂,抗氧化剂,趋化因子受体拮抗剂,p38-激酶抑制剂,NPY激动剂,食欲激动剂,减食欲剂,PAF-AH抑制剂,消炎剂(COX抑制剂,LTB4-受体拮抗剂)和镇痛药,例如阿斯匹林。
本发明特别地提供了包含至少一种根据本发明的化合物和至少一种调节脂类代谢的活性化合物,抗糖尿病药,降血压活性化合物和/或抗血栓剂的结合。
优选地,根据本发明的化合物可以与一种或者多种以下物质结合
●调节脂类代谢的活性化合物,例如和优选HMG-CoA-还原酶抑制剂,HMG-CoA-还原酶表达抑制剂,角鲨烯合成抑制剂,ACAT抑制剂,LDL受体诱导剂,胆固醇吸收抑制剂,聚胆汁酸吸附剂,胆汁酸再吸收抑制剂,MTP抑制剂,脂酶抑制剂,LpL活化剂,贝特类,烟酸,CETP抑制剂,PPAR-α,PPAR-γ和/或PPAR-δ激动剂,RXR调质,FXR调质,LXR调质,甲状腺激素类和/或甲状腺粉模拟物,ATP柠檬酸裂解酶抑制剂,Lp(a)拮抗剂,大麻素受体1拮抗剂,莱普亭受体激动剂,铃蟾素受体激动剂,组胺受体激动剂和抗氧化剂/自由基清除分子;
●在Rote Liste 2004/II,第12章中提到抗糖尿病药,例如和优选来自以下的那些:磺酰尿,双胍,美格列奈衍生物,葡糖苷酶抑制剂,二肽基-肽酶IV的抑制剂(DDP-IV抑制剂),噁二唑烷酮,噻唑烷二酮,GLP1受体激动剂,胰高血糖素拮抗剂,胰岛素敏化剂,CCK1受体激动剂,莱普亭受体激动剂,涉及糖质新生和/或糖原分解的刺激的肝酶抑制剂,葡萄糖吸收的调质和钾通道开启工具,例如在WO 97/26265和WO 99/03861中公开的那些;
●降压活性化合物,例如和优选钙拮抗剂,血管紧张素AII拮抗剂,ACE抑制剂,血管紧张肽原酶抑制剂,β-受体阻滞剂,α-受体阻滞剂,利尿剂,醛甾酮拮抗剂,盐皮质素类受体拮抗剂,ECE抑制剂和血管肽酶抑制剂;
●抗血栓剂,例如和优选血小板聚集抑制剂或者抗凝血剂;
●血管升压素受体拮抗剂;
●有机硝酸盐和NO供体;
●增强收缩力活性的物质;
●抑制环鸟苷酸(cGMP)和/或环腺苷酸(cAMP)降解的化合物,例如磷酸二酯酶(PDE)1,2,3,4和/或5的抑制剂,特别是PDE 5抑制剂,例如西地那非,伐地那非和他达拉非,和PDE 3抑制剂,例如米力农;
●钠尿肽,例如“心钠素”(ANP,阿那立肽),“B型钠尿肽”或者“脑钠尿肽”(BNP,奈西立肽),“C型钠尿肽”(CNP)和尿舒张肽;
●前列环素受体激动剂(IP受体),例如伊洛前列素,贝前列素和西卡前列素;
●钙敏化剂,例如和优选左西孟旦;
●钾添加物;
●不依赖NO和血红素的鸟苷酸环化酶活化剂,例如,特别是在WO 01/19355,WO 01/19776,WO 01/19778,WO 01/19780,WO02/070462和WO 02/070510中描述的化合物;
●不依赖NO,但是依赖血红素的鸟苷酸环化酶激活剂,例如,特别是在WO 00/06568,WO 00/06569,WO 02/42301和WO 03/095451中描述的化合物;
●人嗜中性弹性酶(HNE)的抑制剂,例如西维来司他和DX-890(Reltran);
●抑制信号转导串联得化合物,例如酪氨酸激酶抑制剂,特别是索拉非尼,伊马替尼,吉非替尼和厄洛替尼;和/或
●缓和心的能量代谢的化合物,例如乙莫克舍,二氯乙酸盐,雷诺嗪和三甲氧苄嗪。
改进脂类代谢的活性化合物被理解为意思是,优选地,来自以下的化合物:HMG-CoA-还原酶抑制剂,角鲨烯合成抑制剂,ACAT抑制剂,胆固醇吸收抑制剂,MTP抑制剂,脂酶抑制剂,甲状腺激素类和/或甲状腺粉模拟物,烟酸受体激动剂,CETP抑制剂,PPAR-α激动剂,PPAR-γ激动剂,PPAR-δ激动剂,聚胆汁酸吸附剂,胆汁酸再吸收抑制剂,抗氧化剂/自由基清除分子和大麻素受体1拮抗剂。
在本发明的优选的实施方案中,根据本发明的化合物与来自抑制素一类的HMG-CoA-还原酶抑制剂,例如和优选洛弗斯特丁,斯伐他汀,普伐他汀,氟伐他汀,阿托伐他汀,罗苏伐他汀,西立伐他汀或者匹伐他汀结合服用。
在本发明的优选的实施方案中,根据本发明的化合物与角鲨烯合成抑制剂,例如和优选BMS-188494或者TAK-475结合服用。
在本发明的优选的实施方案中,根据本发明的化合物与ACAT抑制剂,例如和优选阿伐麦布,亚油甲苄胺,帕替麦布,伊鲁麦布或者SMP-79结合服用。
在本发明的优选的实施方案中,根据本发明的化合物与胆固醇吸收抑制剂,例如和优选依泽麦布,替奎安或者帕马奎苷结合服用。
在本发明的优选的实施方案中,根据本发明的化合物与MTP抑制剂,例如和优选英普他派,BMS-201038,R-103757或者JTT-130结合服用。
在本发明的优选的实施方案中,根据本发明的化合物与脂酶抑制剂,例如和优选奥利司他结合服用。
在本发明的优选的实施方案中,根据本发明的化合物与甲状腺激素类和/或甲状腺粉模拟物,例如和优选D-甲状腺素或者3,5,3′-三碘甲腺原氨酸(T3)结合服用。
在本发明的优选的实施方案中,根据本发明的化合物与烟酸受体的激动剂,例如和优选烟酸,阿西莫司,阿昔呋喃或者酒石酸烟醇(radecol)结合服用。
在本发明的优选的实施方案中,根据本发明的化合物与CETP抑制剂,例如和优选托塞匹布,JTT-705,BAY 60-5521,BAY 78-7499或者CETP疫苗(Avant)结合服用。
在本发明的优选的实施方案中,根据本发明的化合物与PPAR-γ激动剂,例如和优选吡格列酮或者罗格列酮结合服用。
在本发明的优选的实施方案中,根据本发明的化合物与PPAR-δ激动剂,例如和优选GW-501516或者BAY 68-5042结合服用。
在本发明的优选的实施方案中,根据本发明的化合物与聚胆汁酸吸附剂,例如和优选消胆胺,考来替泊,colesolvam,考来胶或者colestimide结合服用。
在本发明的优选的实施方案中,根据本发明的化合物与胆汁酸再吸收抑制剂,例如和优选ASBT(=IBAT)抑制剂,例如AZD-7806,S-8921,AK-105,BARI-1741,SC-435或者SC-635结合服用。
在本发明的优选的实施方案中,根据本发明的化合物与抗氧化剂/自由基清除分子,例如和优选普罗布考,AGI-1067,BO-653或者AEOL-10150结合服用。
在本发明的优选的实施方案中,根据本发明的化合物与大麻素受体1拮抗剂,例如和优选利莫纳班或者SR-147778结合服用。
抗糖尿病药被理解优选地为意思是胰岛素和胰岛素衍生物,和口服有效的低血糖的活性化合物。这里,胰岛素和胰岛素衍生物包括动物,人或者生物工艺学起源的胰岛素和它们的混合物。口服有效的血糖过低的活性化合物优选包括磺酰尿,双胍,美格列奈衍生物,葡糖苷酶抑制剂,DDP-IV抑制剂和PPAR-γ激动剂。
在本发明的优选的实施方案中,根据本发明的化合物与胰岛素结合服用。
在本发明的优选的实施方案中,根据本发明的化合物与磺酰尿,例如和优选甲苯磺丁脲,格列本脲,格列美脲,格列甲嗪或者格列齐特结合服用。
在本发明的优选的实施方案中,根据本发明的化合物与双胍,例如和优选二甲双胍结合服用。
在本发明的优选的实施方案中,根据本发明的化合物与美格列奈衍生物,例如和优选瑞格列奈或者内他列奈结合服用。
在本发明的优选的实施方案中,根据本发明的化合物与葡糖苷酶抑制剂,例如和优选米格列醇或者阿卡波糖结合服用。
在本发明的优选的实施方案中,根据本发明的化合物与DPP-IV抑制剂,例如和优选西格列汀或者维格列汀结合服用。
在本发明的优选的实施方案中,根据本发明的化合物与例如来自噻唑烷二酮一类的PPAR-g激动剂,例如和优选吡格列酮或者罗格列酮结合服用。
降血压剂优选被理解为意思是来自以下的化合物:钙拮抗剂,血管紧张素AII拮抗剂,ACE抑制剂,血管紧张肽原酶抑制剂,β-肾腺素受体阻滞剂,α-受体阻滞剂和利尿剂。
在本发明的优选的实施方案中,根据本发明的化合物与血管紧张素AII拮抗剂,例如和优选氯沙坦,缬沙坦,坎地沙坦,恩布沙坦,奥美沙坦(almesartan)或者替米沙坦结合服用。
在本发明的优选的实施方案中,根据本发明的化合物与ACE抑制剂,例如和优选依那普利,卡托普利,赖诺普利,雷米普利,地拉普利,福辛普利,quinopril,培哚普利或者群多普利结合服用。
在本发明的优选的实施方案中,根据本发明的化合物与血管紧张肽原酶抑制剂,例如和优选阿利吉仑,SPP-600或者SPP-800结合服用。
在本发明的优选的实施方案中,根据本发明的化合物与β-肾腺素受体阻滞剂,例如和优选普萘洛尔,阿替洛尔,噻吗洛尔,吲哚洛尔,阿普洛尔,氧烯洛尔,喷布洛尔,布拉洛尔,美替洛尔,纳多洛尔,甲吲洛尔,卡拉洛尔,索他洛尔,美托洛尔,倍他索洛尔,塞利洛尔,比索洛尔,卡替洛尔,艾司洛尔,拉贝洛尔,卡维地洛,阿达洛尔,兰地洛尔,奈必洛尔,依泮洛尔或者布新洛尔结合服用。
在本发明的优选的实施方案中,根据本发明的化合物与α-受体阻滞剂,例如和优选哌唑嗪结合服用。
在本发明的优选的实施方案中,根据本发明的化合物与利尿药,例如和优选呋喃苯胺酸,丁尿胺,托塞米,苄氟噻嗪,氯噻嗪,双氢氯噻嗪,双氢氟噻嗪,甲氯噻嗪,多噻嗪,三氯噻嗪,氯噻酮(chlorothalidone),吲哒帕胺(indapamide),美托拉宗,喹乙宗(quinethazone),乙酸唑胺,二氯苯磺胺,甲醋唑胺,甘油,异山梨糖醇,甘露糖醇,氨氯吡脒或者三氨蝶呤结合服用。
在本发明的优选的实施方案中,根据本发明的化合物与醛甾酮或者盐皮质激素受体拮抗剂,例如和优选螺旋内酯或者依普利酮结合服用。
在本发明的优选的实施方案中,根据本发明的化合物与血管升压素受体拮抗剂,例如和优选conivaptan,托伐普坦(tolvaptan),lixivaptan或者SR-121463结合服用。
在本发明的优选的实施方案中,根据本发明的化合物与有机硝酸盐或者NO供体,例如和优选硝普酸钠,硝酸甘油酯,单硝酸异山梨醇,二硝酸异山梨醇酯,吗斯酮胺或者SIN-1结合,或者与吸入性NO结合服用。
在本发明的优选的实施方案中,根据本发明的化合物与增强收缩力活性的活性化合物,例如和优选强心苷(异羟洋地黄毒甙),β-肾上腺素能药和多巴胺能药激动剂,例如异丙肾上腺素,肾上腺素,去甲基肾上腺素,多巴胺或者多巴酚丁胺结合服用。
在本发明的优选的实施方案中,根据本发明的化合物与抗交感神经药(antisympathotonic),例如利血平,氯压定或者α-甲基多巴结合,或者与钾通道激动剂,例如米诺地尔,二氮嗪,双肼酞嗪或者肼苯哒嗪结合服用。
抗血栓药被理解为意思是,优选地,来自血小板聚集抑制剂或者抗凝血剂的化合物。
在本发明的优选的实施方案中,根据本发明的化合物与血小板聚集抑制剂,例如和优选阿斯匹林,氯吡格列,噻氯匹定或者双嘧达莫结合服用。
在本发明的优选的实施方案中,根据本发明的化合物与凝血抑制因子,例如和优选希美加群,美拉加群,比伐卢定或者克赛结合服用。
在本发明的优选的实施方案中,根据本发明的化合物与GPIIb/IIIa拮抗剂,例如和优选替罗非班或者阿昔单抗结合服用。
在本发明的优选的实施方案中,根据本发明的化合物与因子Xa抑制剂,例如和优选rivaroxaban(BAY 59-7939),DU-176b,apixaban,otamixaban,非德沙班(fidexaban),razaxaban,磺达肝素,idraparinux,PMD-3112,YM-150,KFA-1982,EMD-503982,MCM-17,MLN-1021,DX 9065a,DPC 906,JTV 803,SSR-126512或者SSR-128428结合服用。
在本发明的优选的实施方案中,根据本发明的化合物与肝素或者低分子量(LMW)肝素衍生物结合服用。
在本发明的优选的实施方案中,根据本发明的化合物与维生素K拮抗剂,例如和优选香豆素结合服用。
为了本发明的目的,特别优选包含至少一种根据本发明的化合物和一种或者多种进一步的选自以下的活性化合物的组合:HMG-CoA-还原酶抑制剂(抑制素),利尿剂,β受体阻滞剂,有机硝酸盐和NO供体,ACE抑制剂,血管紧张素AII拮抗剂,醛甾酮和盐皮质激素受体拮抗剂,血管升压素受体拮抗剂,血小板聚集抑制剂和抗凝血剂,和特别优选它们对于治疗和/或预防以上提到的疾病的应用。
本发明此外提供了包含至少一种根据本发明的化合物,通常连同一种或者多种惰性的、无毒的、药理学合适的助剂的药物,和它们对于以上提到的目的的应用。
根据本发明的化合物可以全身和/或局部起作用。为此目的,它们可以以合适的方式,例如通过口,肠外,肺,鼻,舌下,舌,颊,直肠,真皮,经皮,结膜,耳或者作为植入物或者支架服用。
为了这些给药途径,根据本发明的化合物可以以合适的服用形式服用。
适合于口服的是根据现有技术起作用并且迅速地和/或以改进的方式释放根据本发明的化合物和包含以结晶的和/或无定形的和/或溶解的形式的根据本发明的化合物的服用形式,例如片剂(无涂层的或者糖衣片剂,例如具有以延迟方式溶解的或者不能溶解的和控制释放根据本发明的化合物释放的肠溶衣或者涂层),在口中迅速地溶解的膜/薄膜或者片剂,膜/冻干物,胶囊(例如硬的或者软的明胶胶囊),糖衣片,颗粒,丸,粉末,乳剂,悬浮液,烟雾剂或者溶液。
肠胃外投药可以通过避免生物吸收步骤(例如静脉内,动脉内,心内,脊柱内或者腰内),或者伴随生物吸收吸收(例如肌内注射,皮下,皮内,经皮或者腹内)进行。适合于肠胃外投药的服用形式尤其是用于注射的制剂或者以溶液形式的浸剂,悬浮液,乳剂,冻干物或者无菌粉末。
适合于其它的给药途径的是,例如适合于吸入(尤其是粉末吸入器,喷雾器)的药物,滴鼻剂,溶液或者喷雾剂;舌,舌下或者颊服用的片剂,膜/薄膜或者胶囊,栓剂,耳或者眼服用的制剂,阴道胶囊,水悬浮液(洗液,摇动混合物),亲油性的悬浮液,软膏,乳膏,经皮吸收剂型(例如膏药),乳剂,糊剂,泡沫,用于倾倒的粉末,植入物或者支架。
优选口或者肠胃外服用,特别是口和静脉内服用。
根据本发明的化合物可以转变为提到的服用形式。这可以以本身已知的方式通过与惰性的、无毒的、药学合适的助剂混合进行。这些助剂尤其包括载体(例如微晶纤维素,乳糖,甘露糖醇),溶剂(例如液体聚乙二醇),乳化剂和分散剂或者润湿剂(例如十二烷基硫酸钠,聚氧失水山梨糖醇油酸酯),粘合剂(例如聚乙烯吡咯烷酮),合成和天然聚合物(例如白蛋白),稳定剂(例如抗氧化剂,例如抗坏血酸),着色剂(例如无机颜料,例如铁氧化物)和香味和/或气味矫正药。
通常,已经发现在肠胃外投药量的情况下大约0.001-1mg/kg,优选大约0.01-05mg/kg体重的服用量是有利的以获得有效的结果。在口服情况下,剂量是从大约0.01-100mg/kg,优选从大约0.01-20mg/kg,和非常特别优选从0.1-10mg/kg体重。
尽管这样,偏离提到的量可能是必要的,即取决于体重,给药途径,个体对于活性化合物的反应,制剂的种类和服用发生的时间或者间隔。因此,有时服用小于以上提到的最低量可能是足够的,而在其它情况下必须超过提到的上限。在大量服用情况下,一天过程中将这些划分成许多独立的剂量服用可能是有利的。
以下示范性的实施例解释本发明。本发明不局限于该实施例。
除非另外指明,在以下试验和实施例中百分比是重量百分比;份是重量份。液体/液体溶液的溶剂比,稀释比和浓度在每一种情况下基于体积。
A.实施例
使用的缩写:
Ex. 实施例
DBU 1,8-二氮杂双环[5.4.0]十一碳-7-烯
TLC 薄层色谱
DCI 直接化学电离(在MS中)
DME 1,2-二甲氧基乙烷
DMF N,N-二甲基甲酰胺
DMSO 二甲基亚砜
EA 乙酸乙酯
EI 电子碰撞电离(在MS中)
ESI 电喷射离子化作用(在MS中)
Et 乙基
EtOH 乙醇
m.p. 熔点
sat. 饱和的
h 小时
HOAc 乙酸
HPLC 高压-,高效液相色谱
conc. 浓的
KOtBu 叔丁醇钾
LC-MS 液相色谱-质谱联用
LDA 二异丙基氨基锂
lit. 文献(参考)
sol. 溶液
min 分钟
MS 质谱
NMM N-甲基吗啉
NMR 核磁共振波谱法
PBS 磷酸缓冲盐水
PEG 聚乙二醇
Ph 苯基
RP-HPLC 反相HPLC
RT 室温
Rt 驻留时间(在HPLC中)
THF 四氢呋喃
dil. 稀的
aq. 含水的
HPLC和LC-MS方法:
方法1(HPLC):
仪器:Hewlett Packard Series 1050;柱:Symmetry TM C18 3.9x150mm;流速:1.5ml/min;流动相A:水,流动相B:乙腈;梯度:→0.6min 10%B→3.8min 100%B→5.0min 100%B→5.5min 10%B;停止时间:6.0min;注射体积:10μl;二极管阵列检测器信号:214和254nm。
方法2(LC-MS):
MS仪器类型:Micromass ZQ;HPLC仪器类型:Waters Alliance2795;柱:Merck Chromolith SpeedROD RP-18e 100mm x 4.6mm;流动相A:水+500μl 50%浓度甲酸/l,流动相B:乙腈+500μl 50%浓度甲酸/l;梯度:0.0min 10%B→7.0min 95%B→9.0min 95%B;烘箱(Ofen):35℃;流速:0.0min 1.0ml/min→7.0min 2.0ml/min→9.0min2.0ml/min;UV检测:210nm。
方法3(LC-MS):
MS仪器类型:Micromass ZQ;HPLC仪器类型:HP 1100 Series;UV DAD;柱:Phenomenex Gemini 3μ 30mm x 3.00mm;流动相A:1l水+0.5ml 50%浓度甲酸,流动相B:1l乙腈+0.5ml 50%浓度甲酸;梯度:0.0min 90%A→2.5min 30%A→3.0min 5%A→4.5min 5%A;流速:0.0min 1ml/min→2.5min/3.0min/4.5min 2ml/min;烘箱:50℃;UV检测:210nm。
方法4(LC-MS):
仪器:具有HPLC Agilent Serie 1100的Micromass Quattro LCZ;柱:Phenomenex Onyx Monolithic C18,100mm x 3mm;流动相A:1l水+0.5ml 50%浓度甲酸,流动相B:1l乙腈+0.5ml 50%浓度甲酸;梯度:0.0min 90%A→2min 65%A→4.5min 5%A→6min 5%A;流速:2ml/min;烘箱:40℃;UV检测:208-400nm。
方法5(LC-MS):
MS仪器类型:Waters ZQ;HPLC仪器类型:Waters Alliance2795;柱:Merck Chromolith RP-18e,100mm x 3mm;流动相A:1l水+0.5ml 50%浓度甲酸,流动相B:1l乙腈+0.5ml 50%浓度甲酸;梯度:0.0min 90%A→2min 65%A→4.5min 5%A→6min 5%A;流速:2ml/min;烘箱:40℃;UV检测:210nm。
方法6(LC-MS):
仪器:具有HPLC Agilent Serie 1100的Micromass Quattro LCZ;柱:Phenomenex Synergi 2.5μMAX-RP 100A Mercury 20mm x 4mm;流动相A:1l水+0.5ml 50%浓度甲酸,流动相B:1l乙腈+0.5ml 50%浓度甲酸;梯度:0.0min 90%A→0.1min 90%A→3.0min 5%A→4.0min5%A→4.1min 90%A;流速:2ml/min;烘箱:50℃;UV检测:208-400nm。
方法7(LC-MS):
MS仪器类型:Micromass ZQ;HPLC仪器类型:Waters Alliance2795;柱:Phenomenex Synergi 2.5μMAX-RP 100A Mercury 20mm x4mm;流动相A:1l水+0.5ml 50%浓度甲酸,流动相B:1l乙腈+0.5ml50%浓度甲酸;梯度:0.0min 90%A→0.1min 90%A→3.0min5%A→4.0min 5%A→4.01min 90%A;流速:2ml/min;烘箱:50℃;UV检测:210nm。
方法8(LC-MS):
仪器:具有HPLC Agilent Serie 1100的Micromass Platform LCZ;柱:Thermo Hypersil GOLD 3μ 20mm x 4mm;流动相A:1l水+0.5ml50%浓度甲酸,流动相B:1l乙腈+0.5ml 50%浓度甲酸;梯度:0.0min100%A→0.2min 100%A→2.9min 30%A→3.1min 10%A→5.5min 10%A;流速:0.8ml/min;烘箱:50℃;UV检测:210nm。
方法9(LC-MS):
仪器:具有HPLC Agilent Serie 1100的Micromass Quattro LCZ;柱:Phenomenex Synergi 2μ Hydro-RP Mercury 20mm x 4mm;流动相A:1l水+0.5ml 50%浓度甲酸,流动相B:1l乙腈+0.5ml 50%浓度甲酸;梯度:0.0min 90%A→2.5min 30%A→3.0min 5%A→4.5min 5%A;流速:0.0min 1ml/min→2.5min/3.0min/4.5min 2ml/min;烘箱:50℃;UV检测:208-400nm。
方法10(LC-MS):
MS仪器类型:Micromass ZQ;HPLC仪器类型:HP 1100Series;UV DAD;柱:Phenomenex Synergi 2μ Hydro-RP Mercury 20mm x4mm;流动相A:1l水+0.5ml 50%浓度甲酸,流动相B:1l乙腈+0.5ml50%浓度甲酸;梯度:0.0min 90%A→2.5min 30%A→3.0min5%A→4.5min 5%A;流速:0.0min 1ml/min→2.5min/3.0min/4.5min2ml/min;烘箱:50℃;UV检测:210nm。
方法11(LC-MS):
MS仪器类型:Micromass ZQ;HPLC仪器类型:HP 1100 Series;UV DAD;柱:Phenomenex Synergi 2.5μ MAX-RP 100A Mercury20mm x 4mm;流动相A:1l水+0.5ml 50%浓度甲酸,流动相B:1l乙腈+0.5ml 50%浓度甲酸;梯度:0.0min 90%A→0.1min 90%A→3.0min5%A→4.0min 5%A→4.1min 90%A;流速:2ml/min;烘箱:50℃;UV检测:210nm。
方法12(LC-MS):
MS仪器类型:Micromass ZQ;HPLC仪器类型:Waters Alliance2795;柱:Merck Chromolith SpeedROD RP-18e 100mm x 4.6mm;流动相A:水+500μl 50%浓度甲酸/l;流动相B:乙腈+500μl 50%浓度甲酸/l;梯度:0.0min 10%B→7.0min 95%B→9.0min 95%B;流速:0.0min 1.0ml/min→7.0min 2.0ml/min→9.0min 2.0ml/min;烘箱:35℃;UV检测:210nm。
方法13(LC-MS):
MS仪器类型:M-40DCI(NH3);HPLC仪器类型:具有DAD检测的HP 1100;柱:Kromasil 100RP-18,60mm x 2.1mm,3.5μm;流动相A:5ml HClO4(70%浓度)/升水,流动相B:乙腈;梯度:0min2%B→0.5min 2%B→4.5min 90%B→6.5min 90%B→6.7min 2%B→7.5min2%B;流速:0.75ml/min;柱温:30℃;UV检测:210nm。
方法14(LC-MS):
仪器:具有Waters UPLC Acquity的Micromass QuattroPremier;柱:Thermo Hypersil GOLD 1.9μ 50mm x 1mm;流动相A:1l水+0.5ml 50%浓度甲酸,流动相B:1l乙腈+0.5ml 50%浓度甲酸;梯度:0.0min 90%A→0.1min 90%A→1.5min 10%A→2.2min 10%A;流速:0.33ml/min;烘箱:50℃;UV检测:210nm。
方法15(LC-MS):
仪器:具有HPLC Agilent Serie 1100的Micromass Quattro MicroMS;柱:Thermo Hypersil GOLD 3μ 20mm x 4mm;流动相A:1l水+0.5ml 50%浓度甲酸,流动相B:1l乙腈+0.5ml 50%浓度甲酸;梯度:0.0min 100%A→3.0min 10%A→4.0min 10%A→4.01min 100%A(流速2.5ml/min)→5.00min 100%A;烘箱:50℃;流速:2ml/min;UV检测:210nm。
方法16(制备HPLC):
HPLC仪器类型:Abimed/Gilson Pump 305/306;ManometricModule 806;UV Knauer Variable Wavelength Monitor;柱:GromsilC18,10nm,250mm x 30mm;流动相A:1l水+0.5ml 99%浓度三氟醋酸,流动相B:1l乙腈;梯度:0.0min 2%B→10min 2%B→50min90%B;流速:20ml/min;体积:628ml A和372ml B。
方法17(HPLC):
HPLC仪器类型:具有DAD检测的Agilent 1100;柱:MerckChromolith SpeedROD RP-18e,50mm x 4.6mm;流动相A:0.05%浓度H3PO4,流动相B:乙腈;梯度:0min 5%B→2.5min 95%B→3.0min95%B;流速:5ml/min;柱温:40℃;UV检测:210nm。
起始化合物和中间体:
实施例1A
2-氨基-4-[4-(2-羟基乙氧基)苯基]-6-巯基吡啶-3,5-二腈
开始向280ml乙醇中加入14.90g(89.66mmol)4-(2-羟基乙氧基)苯甲醛和17.96g(179.33mmol)氰基硫代乙酰胺。然后添加18.14g(179.33mmol)4-甲基吗啉。反应混合物在回流下加热4h和然后在RT下再搅拌20h。伴随抽吸滤掉产生的沉淀,再用大约20ml乙醇洗涤并干燥。
产率:9.90g(理论的35%)
LC-MS(方法10):Rt=1.63min;MS(ESIpos):m/z=313[M+H]+.
实施例2A
4-(2-羟基-2-甲基丙氧基)苯甲醛
开始向50ml干燥的DMF中加入5.00g(40.94mmol)4-羟基苯甲醛,4.44g(40.94mmol)1-氯-2-甲基-2-丙醇和6.08g(57.32mmol)碳酸钠并且在回流下搅拌24h。冷却到RT后,添加20ml乙酸乙酯和20ml饱和碳酸氢钠水溶液。相分离,并且有机相通过硫酸镁干燥。除去溶剂后,残余物通过在硅胶60上柱层析提纯(流动相梯度:环己烷/乙酸乙酯5∶1→1∶1)。这产生微红的固体,其没有进一步提纯地用于随后的步骤。
产率:4.40g(理论的50%,纯度90%)
LC-MS(方法2):Rt=1.37min;MS(ESIpos):m/z=195[M+H]+.
实施例3A
2-氨基-4-[4-(2-羟基-2-甲基丙氧基)苯基]-6-巯基吡啶-3,5-二腈
开始向50ml乙醇中加入3.38g(15.49mmol)来自实施例2A的化合物和3.26g(32.52mmol)氰基硫代乙酰胺。然后添加3.13g(30.98mmol)4-甲基吗啉。伴随搅拌,混合物在回流下加热6h。冷却到RT后,混合物在该温度下搅拌20h。然后添加50ml饱和碳酸氢钠水溶液,并且混合物在每一种情况下用50ml乙酸乙酯提取四次。合并的有机相通过硫酸镁干燥。除去溶剂后,残余物通过在硅胶60上柱层析提纯(流动相梯度:环己烷/乙酸乙酯2∶1→1∶4)。获得的产物没有进一步提纯地用于随后的步骤。
产率:0.92g(理论的16%,纯度90%)
1H-NMR(400MHz,DMSO-d6):δ=13.00-12.91(br.s,1H),8.09-7.78(br.s,2H),7.46(d,2H),7.09(d,2H),4.68(s,1H),3.79(s,2H),1.22(s,6H).
LC-MS(方法2):Rt=1.46min;MS(ESIpos):m/z=341[M+H]+.
实施例4A
(2S)-1-氯丙-2-醇
开始向100ml THF中加入32.50g(766.66mmol)氯化锂。然后缓慢添加18.75ml(92.97mmol)4.96M盐酸。混合物冷却到-30℃,并且滴加5.40g(92.97mmol)S-(-)-环氧丙烷在10ml THF中的溶液。添加结束后,混合物暖到RT并且再搅拌20h。伴随抽吸滤掉形成的沉淀,并且滤液经过分馏(61mbar,30-40℃塔头温度)。用这样的方式获得的产物混合物没有进一步提纯地用于随后的步骤。
产率:4.50g(理论的16%,纯度32%)
1H-NMR(400MHz,DMSO-d6):δ=5.01(d,1H),3.85-3.74(m,1H),3.49(d,2H),1.12(d,3H).
产物包含大约10%区域异构体(2S)-2-氯丙-1-醇:
1H-NMR(400MHz,DMSO-d6):δ=5.18-5.12(m,1H),4.11-4.03(m,1H),3.49(d,2H),1.41(d,3H).
实施例5A
4-{[(2S)-2-羟基丙基]氧基}苯甲醛
6.30g(51.62mmol)4-羟基苯甲醛和来自实施例4A的4.88g(51.62mmol)产物溶于100ml干燥的DMF。向该溶液中加入16.41g(154.85mmol)碳酸钠,并且混合物在130℃下搅拌20h。冷却到RT后,向混合物中加入100ml乙酸乙酯和50ml饱和碳酸氢钠水溶液。混合物在每一种情况下用50ml乙酸乙酯提取三次。合并的有机相通过硫酸镁干燥。除去溶剂后,残余物通过在硅胶60上柱层析提纯(流动相梯度:环己烷/乙酸乙酯5∶1→2∶1)。
产率:2.40g(理论的26%)
1H-NMR(400MHz,DMSO-d6):δ=7.86(d,2H),7.13(d,2H),4.95(d,1H),4.02-3.92(m,1H),3.91(d,2H),1.16(d,3H).
LC-MS(方法2):Rt=1.19min;MS(ESIpos):m/z=181[M+H]+.
产物包含大约10%区域异构体4-[(1S)-2-羟基-1-甲基乙氧基]苯甲醛。
实施例6A
4-{[(2S)-2-{[叔-丁基(二甲基)甲硅烷基]氧基}丙基]氧基}苯甲醛
开始向60ml干燥的DMF中加入2.40g(13.32mmol)来自实施例5A的化合物,并且添加2.81g(18.65mmol)叔-丁基二甲基甲硅烷基氯和1.72g(25.30mmol)咪唑。反应混合物在RT下搅拌20h。然后向混合物中加入大约30ml乙醚和30ml饱和碳酸氢钠水溶液。相分离并且含水相在每一种情况下用30ml乙醚提取两次。合并的有机相通过硫酸镁干燥并且溶剂在旋转蒸发器上除去。残余物通过在硅胶60上柱层析提纯(流动相梯度:环己烷/乙酸乙酯50∶1→10∶1)。
产率:1.95g(理论的50%)
1H-NMR(400MHz,DMSO-d6):δ=7.82(d,2H),7.07(d,2H),4.18-4.11(m,1H),3.98(dd,1H),3.87(dd,1H),1.13(d,3H),0.81(s,9H),0.3(s,3H),0.1(s,3H).
LC-MS(方法9):Rt=3.30min;MS(ESIpos):m/z=295[M+H]+.
产物包含大约10%区域异构体4-[(1S)-2-{[叔-丁基(二甲基)甲硅烷基]氧基}-1-甲基}乙氧基]苯甲醛。
实施例7A
2-氨基-4-(4-{[(2S)-2-{[叔-丁基(二甲基)甲硅烷基]氧基}丙基]氧基}苯基)-6-巯基吡啶-3,5-二腈
开始向27ml乙醇中加入1.95g(6.62mmol)来自实施例6A的化合物和1.39g(13.91mmol)氰基硫代乙酰胺,并且添加1.34g(13.24mmol)4-甲基吗啉。混合物在回流下加热6h(油浴温度100℃)。混合物然后在RT下再搅拌20h。在旋转蒸发器上除去溶剂后,残余物直接通过在硅胶60上柱层析提纯(流动相梯度:二氯甲烷/乙醇50∶1→5∶1)。
产率:1.30g(理论的29%,纯度65%)
1H-NMR(400MHz,DMSO-d6):δ=7.68-7.48(br.s,2H),7.42(d,2H),7.06(d,2H),4.23-4.15(m,1H),3.96(dd,1H),3.88(dd,1H),1.20(d,3H),0.89(s,9H),0.09(s,3H),0.07(s,3H).
LC-MS(方法2):Rt=2.79min;MS(ESIpos):m/z=441[M+H]+.
产物包含大约10%区域异构体2-氨基-4-{4-[(1S)-2-{[叔-丁基(二甲基)甲硅烷基]氧基}-1-甲基乙氧基]苯基}-6-巯基吡啶-3,5-二腈。
实施例8A
4-{[(4R)-2,2-二甲基-1,3-二氧戊环-4-基]甲氧基}苯甲醛
开始向400ml干燥的DMF中加入31.2g(255.4mmol)4-羟基苯甲醛,并且在RT下添加105.7g(766.1mmol)碳酸钾和50.0g(332.0mmol)(S)-(-)-3-氯-1,2-丙二醇丙酮化物。混合物在160℃下搅拌16h。然后添加4000ml水,并且混合物在每一种情况下用500ml乙酸乙酯提取三次。合并的有机相在每一种情况下用500ml水和500ml饱和氯化钠水溶液洗涤一次。通过硫酸镁干燥后,溶剂在旋转蒸发器上除去并且残余物通过在硅胶60上柱层析提纯(流动相梯度:乙酸乙酯/石油醚1∶9→2∶8)
产率:40.4g(理论的63%)
1H-NMR(400MHz,DMSO-d6):δ=9.90(s,1H),7.85(d,2H),7.03(d,2H),4.50(q,1H),4.22-4.09(m,2H),4.04(dd,1H),3.92(dd,1H),1.48(s,3H),1.41(s,3H).
LC-MS(方法13):Rt=3.97min;MS(ESIpos):m/z=254[M+NH4]+.
实施例9A
4-{[(4S)-2,2-二甲基-1,3-二氧戊环-4-基]甲氧基}苯甲醛
标题化合物类似于实施例8A由适当的起始化合物制备。
产率:理论的79%
1H-NMR(400MHz,DMSO-d6):δ=9.89(s,1H),7.85(d,2H),7.03(d,2H),4.50(q,1H),4.22-4.09(m,2H),4.04(dd,1H),3.92(dd,1H),1.48(s,3H),1.41(s,3H).
LC-MS(方法13):Rt=4.02min;MS(ESIpos):m/z=254[M+NH4]+.
实施例10A
2-氨基-4-(4-{[(4R)-2,2-二甲基-1,3-二氧戊环-4-基]甲氧基}苯基)-6-巯基吡啶-3,5-二腈
开始向700ml乙醇中加入40.4g(171.0mmol)来自实施例8A的化合物和34.2g(342.0mmol)氰基硫代乙酰胺。反应混合物中添加34.5g(342.0mmol)4-甲基吗啉,并且伴随搅拌反应混合物在回流下加热3h。冷却到RT后,混合物在该温度下再搅拌16h。产生的沉淀伴随抽吸滤掉,用大约100ml乙醇洗涤并在干燥箱中干燥。产物没有进一步提纯地用于随后的反应。
产率:19.5g(理论的29%)
1H-NMR(400MHz,DMSO-d6):δ=7.63-7.31(br.s,2H),7.41(d,2H),7.09(d,2H),4.49-4.38(m,1H),4.15-3.99(m,2H),3.78(dd,1H),3.66(dd,1H),2.77-2.68(br.s,1H),1.37(s,3H),1.32(s,3H).
LC-MS(方法9):Rt=1.95min;MS(ESIpos):m/z=424[M+H+CH3CN]+.
实施例11
2-氨基-4-(4-{[(4S)-2,2-二甲基-1,3-二氧戊环-4-基]甲氧基}苯基)-6-巯基吡啶-3,5-二腈
标题化合物类似于实施例10A由来自实施例9A的化合物制备。
产率:理论的32%
1H-NMR(400MHz,DMSO-d6):δ=7.69-7.37(br.s,2H),7.42(d,2H),7.10(d,2H),4.48-4.39(m,1H),4.15-4.02(m,2H),3.78(dd,1H),3.66(dd,1H),2.77-2.68(br.s,1H),1.37(s,3H),1.31(s,3H).
LC-MS(方法2):Rt=1.75min;MS(ESIpos):m/z=383[M+H]+.
实施例12A
3-氟-4-(2-羟基乙氧基)苯甲醛
5.00g(35.69mmol)3-氟-4-羟基苯甲醛溶于50ml干燥的DMF。添加5.35g(42.82mmol)2-溴乙醇和19.73g(142.74mmol)碳酸钾。反应混合物在150℃下搅拌10h。然后过滤混合物,并且滤液在旋转蒸发器上除去溶剂。残余物在30ml乙酸乙酯中吸收,并且添加20ml饱和碳酸氢钠水溶液。相分离并且有机相通过硫酸镁干燥。在旋转蒸发器上除去溶剂。获得的产物没有进一步提纯地用于随后的反应。
产率:4.45g(理论的67%)
LC-MS(方法3):Rt=1.39min;MS(ESIpos):m/z=185[M+H]+.
实施例13A
2-氨基-4-[3-氟-4-(2-羟基乙氧基)苯基]-6-硫烷基吡啶-3,5-二腈
开始向54ml乙醇中加入4.45g(24.16mmol)来自实施例12A的粗产物和4.84g(48.33mmol)氰基硫代乙酰胺并且添加4.89g(48.33mmol)4-甲基-吗啉。反应混合物在+80℃下搅拌4h。混合物然后在RT下搅拌8h。在旋转蒸发器上除去溶剂,并且残余物直接通过在硅胶60上柱层析提纯(流动相梯度:二氯甲烷/乙醇15∶1→5∶1)。获得的产物没有进一步提纯地用于随后的反应。
产率:2.65g(理论的28%,纯度大约90%)
LC-MS(方法3):Rt=1.62min;MS(ESIpos):m/z=331[M+H]+.
实施例14A
4-(3,3,3-三氟-2-羟基丙氧基)苯甲醛
标题化合物类似于实施例12A由4-羟基苯甲醛和3-溴-1,1,1-三氟丙-2-醇制备。
产率:理论的84%
LC-MS(方法6):Rt=1.58min;MS(ESIpos):m/z=235[M+H]+.
实施例15A
2-氨基-6-硫烷基-4-[4-(3,3,3-三氟-2-羟基丙氧基)苯基]吡啶-3,5-二腈
标题化合物类似于实施例10A由来自实施例14A的化合物制备。获得的产物没有进一步提纯地用于随后的反应。
产率:理论的26%(纯度56%)
LC-MS(方法3):Rt=1.98mm;MS(ESIpos):m/z=381[M+H]+.
实施例16A
4-(氯甲基)-2-(4-氟-3-甲基苯基)-1,3-噁唑
2.00g(12.80mmol)4-氟-3-甲基苯甲酰胺和1.79g(14.08mmol)1,3-二氯丙酮在130℃下搅拌2天。形成熔体。混合物然后冷却到RT,小心地在该温度下添加3.0ml浓硫酸并且混合物搅拌15min。产生的悬浮液倒入到20ml冰-水中并且在RT下搅拌过夜。滤掉形成的沉淀并且在40℃下在真空干燥箱中干燥过夜。
产率:2.05g(理论的64%,纯度90%)
LC-MS(方法7):Rt=2.05min;MS(ESIpos):m/z=226[M+H]+.
在表1中列出的化合物类似于实施例16A由适当的起始材料制备:
表1
实施例23A
[2-苯基-5-(三氟甲基)-1,3-噁唑-4-基]甲醇
500mg(1.94mmol)2-苯基-5-(三氟甲基)-1,3-噁唑-4-羧酸溶于40ml干燥的THF并且冷却到-10℃。添加197mg(1.94mmol)4-甲基吗啉和211mg(1.94mmol)氯甲酸乙酯。反应溶液在-10℃下搅拌1h。然后缓慢地滴加3.9ml(3.89mmol)氢化铝锂在THF中的1M溶液。反应混合物搅拌过夜并且缓慢地使得暖到RT。混合物然后再次冷却到0℃,并且小心地添加0.6ml水和1.2ml 1N氢氧化钠水溶液。混合物然后在RT下搅拌过夜。过滤后,在旋转蒸发器上除去溶剂。残余物没有进一步提纯地用于随后的反应。
产率:359mg(理论的58%,纯度76%)
LC-MS(方法8):Rt=3.34min;MS(ESIpos):m/z=244[M+H]+.
实施例24A
4-(氯苯基)-2-苯基-5-(三氟甲基)-1,3-噁唑
开始在0.63ml(8.64mmol)亚硫酰氯中加入359mg(1.137mmol,纯度76%)来自实施例23A的化合物。反应混合物在RT下搅拌48h。在旋转蒸发器上浓缩后,残余物在10ml乙酸乙酯中吸收并用5ml饱和碳酸氢钠水溶液洗涤一次。有机相通过硫酸镁干燥。过滤后,溶剂在旋转蒸发器上除去。残余物通过在硅胶60上柱层析提纯(流动相梯度:环己烷/乙酸乙酯400∶1→60∶1)。这产生淡褐色的固体。
产率:148mg(理论的50%)
LC-MS(方法7):Rt=2.34min;MS(ESIpos):m/z=262[M+H]+.
实施例25A
2-碘-1,3-噁唑-4-羧酸乙基酯
向8.00g(38.43mmol)对-甲苯磺酸二水合物在48ml乙腈中的溶液中添加2.00g(12.81mmol)2-氨基-1,3-噁唑4-羧酸乙基酯。悬浮液冷却到0℃,并且之后添加1.77g(25.62mmol)亚硝酸钠和5.32g(32.02mmol)碘化钾在7.2ml水中的溶液。混合物在0℃下搅拌10min并且,暖到RT后,进一步过夜。混合物之后用200ml水稀释。通过添加1M碳酸氢钠水溶液,pH调整到9。之后添加24ml 2M硫代硫酸钠溶液。含水相在每一种情况下用30ml乙酸乙酯提取三次。合并的有机相通过硫酸镁干燥。过滤后,溶剂在旋转蒸发器上除去。残余物通过在硅胶60上柱层析提纯(流动相梯度:环己烷/乙酸乙酯300∶1→2∶1)。
产率:0.97g(理论的28%)
LC-MS(方法6):Rt=1.41min;MS(ESIpos):m/z=268[M+H]+.
实施例26A
2-(4-氯-3-甲基苯基)-1,3-噁唑-4-羧酸乙基酯
开始在12.7ml干燥的N-甲基-2-吡咯烷酮中加入385mg(1.44mmol)来自实施例25A的化合物和319mg(1.87mmol)4-氯-3-甲基苯基硼酸。之后添加105mg(0.14mmol)双(二苯基膦基)二茂铁氯化钯(II),0.33ml水和940mg(2.88mmol)碳酸铯。反应混合物在50℃下搅拌4h。混合物之后冷却到RT,并且添加20ml乙酸乙酯和10ml水。含水相在每一种情况下用20ml乙酸乙酯提取两次。合并的有机相用10ml饱和氯化钠水溶液洗涤一次并通过硫酸镁干燥。过滤后,溶剂在旋转蒸发器上除去。残余物用制备HPLC提纯(柱:YMC GEL ODS-AQ S-5/15μm;流动相梯度:乙腈/水10∶90→95∶5)。
产率:162mg(理论的42%)
LC-MS(方法7):Rt=2.19min;MS(ESIpos):m/z=266[M+H]+.
实施例27A
[2-(4-氯-3-甲基苯基)-1,3-噁唑-4-基]甲醇
开始在8.0ml THF中加入46mg(1.22mmol)氢化铝锂并冷却到0℃。之后滴加161mg(0.61mmol)来自实施例26A的化合物在2.5ml THF中的溶液。混合物在RT下搅拌2h。反应溶液之后再次冷却到0℃,并且添加0.2ml水和0.4ml 1N氢氧化钠水溶液。混合物在RT下搅拌过夜。滤掉形成的沉淀,并且滤液使用旋转蒸发器除去溶剂。残余物没有进一步提纯地用于随后的反应。
产率:137mg(理论的70%,纯度70%)
LC-MS(方法3):Rt=2.14min;MS(ESIpos):m/z=224[M+H]+.
实施例28A
4-(氯甲基)-2-(4-氯-3-甲基苯基)-1,3-噁唑
136mg(0.61mmol)来自实施例27A的化合物悬浮在2ml二氯甲烷中。悬浮液冷却到0℃,并且缓慢添加49μl(0.67mmol)亚硫酰氯。反应溶液在RT下搅拌过夜。然后在旋转蒸发器上除去溶剂。残余物没有进一步提纯地用于随后的反应。
产率:178mg(理论的42%,纯度35%)
LC-MS(方法7):Rt=2.56min;MS(ESIpos):m/z=242[M+H]+.
实施例29A
2-(4-氯苯基)-5-乙基-4-甲基-1,3-噁唑3-氧化物
开始向2ml(34.94mmol)冰醋酸中加入1.00g(8.69mmol)2,3-戊二酮2-肟和1.34g(9.55mmol)4-氯苯甲醛。伴随反应混合物的冰-冷却,然后加入氯化氢气体30min。然后向反应混合物中加入10ml乙醚。形成沉淀,其伴随抽吸滤掉并且在每一种情况下用2ml乙醚洗涤两次。该沉淀再悬浮在大约5ml水中,并且使用氨使悬浮液呈碱性。然后悬浮液在每一种情况下用10ml二氯甲烷提取四次。合并的有机相通过硫酸镁干燥并且在旋转蒸发器上除去溶剂。残余物没有进一步提纯地用于随后的反应。
产率:1.6g(理论的76%)
1H-NMR(400MHz,DMSO-d6):δ=8.42(d,2H),7.63(d,2H),2.76(q,2H),2.10(s,3H),1.24(t,3H).
LC-MS(方法6):Rt=1.67min;MS(ESIpos):m/z=238[M+H]+.
实施例30A
4-(氯甲基)-2-(4-氯苯基)-5-乙基-1,3-噁唑
1.00g(4.21mmol)来自实施例29A的化合物溶于15ml氯仿,并且小心地添加1.4ml(15.15mmol)磷酰氯。混合物加热至回流并且在该温度下搅拌30min。混合物然后冷却到0℃并且使用氨使稍微呈碱性。反应混合物在每一种情况下用20ml乙酸乙酯提取三次。合并的有机相用10ml水洗涤一次并随后用硫酸镁干燥。在旋转蒸发器上除去溶剂并且残余物在真空干燥箱中干燥。产物没有进一步提纯地用于随后的反应。
产率:1.2g(理论的84%,纯度74%)
1H-NMR(400MHz,DMSO-d6):δ=7.96(d,2H),7.60(d,2H),4.77(s,2H),2.85(q,2H),1.23(t,3H).
LC-MS(方法6):Rt=2.56min;MS(ESIpos):m/z=256[M+H]+.
实施例31A
2-(4-氯苯基)-4,5-二甲基-1,3-噁唑3-氧化物
开始向2ml(34.94mmol)冰醋酸中加入1.00g(9.89mmol)双乙酰一肟和1.53g(10.88mmol)4-氯苯甲醛。伴随反应混合物的冰-冷却,然后加入氯化氢气体30min。然后向反应混合物中加入10ml乙醚。形成沉淀,其伴随抽吸滤掉并且在每一种情况下用2ml乙醚洗涤两次。该沉淀再悬浮在大约5ml水中,并且使用氨使悬浮液呈碱性。然后悬浮液在每一种情况下用10ml二氯甲烷提取四次。合并的有机相通过硫酸镁干燥并且在旋转蒸发器上除去溶剂。残余物没有进一步提纯地用于随后的反应。
产率:1.85g(理论的84%)
LC-MS(方法5):Rt=2.29min;MS(ESIpos):m/z=224[M+H]+.
在表2中列出的化合物类似于实施例31A由适当的起始材料制备:
表2
实施例34A
4-(氯甲基)-2-(4-氯苯基)-5-甲基-1,3-噁唑
开始向15ml氯仿中加入1.00g(4.47mmol)来自实施例31A的化合物,并且小心地添加1.5ml(16.10mmol)磷酰氯。伴随搅拌,反应混合物在回流下加热30min。混合物然后冷却到0℃并且通过添加氨使呈弱碱性。混合物在每一种情况下用20ml乙酸乙酯提取三次。合并的有机相在每一种情况下用5ml水洗涤两次和然后通过硫酸镁干燥。在旋转蒸发器上除去溶剂。残余物没有进一步提纯地用于随后的步骤。
产率:1.33g(理论的96%,纯度78%)
1H-NMR(400MHz,DMSO-d6):δ=7.95(d,2H),7.60(d,2H),4.77(s,2H),2.44(s,3H).
LC-MS(方法3):Rt=2.80min;MS(ESIpos):m/z=242[M+H]+.
在表3中列出的实施例类似于实施例34A由适当的起始化合物制备:
表3
实施例37A
5-(4-氯苯基)-1,3-噁唑-4-羧酸甲基酯
1.40g(8.00mmol)4-氯苯甲酰氯,1.00g(10.09mmol)异氰酸根合乙酸甲基酯和5.9ml(42.39mmol)三乙胺溶于15ml干燥的THF并且在RT下搅拌48h。然后在旋转蒸发器上除去溶剂。残余物在20ml乙酸乙酯中吸收并且用5ml水洗涤一次。有机相通过硫酸镁干燥并且在旋转蒸发器上除去溶剂。残余物悬浮在10ml环己烷中并滤掉。然后由大约10ml甲醇再结晶。这产生针状的晶体,其在干燥箱中在50℃下干燥。重结晶后通过再沉淀再获得产物部分。
产率:0.85g(理论的45%)
1H-NMR(400MHz,DMSO-d6):δ=8.61(s,1H),8.02(d,2H),7.62(d,2H),3.82(s,3H).
LC-MS(方法14):Rt=1.09min;MS(ESIpos):m/z=238[M+H]+.
实施例38A
[5-(4-氯苯基)-1,3-噁唑-4-基]甲醇
开始向10ml干燥的THF中加入166mg(4.38mmol)氢化铝锂并冷却到0℃。滴加260mg(1.09mmol)来自实施例37A的化合物在10ml干燥的THF中的溶液。添加已经结束后,反应溶液缓慢地暖到RT并且在该温度下搅拌1h。伴随搅拌,混合物然后在回流下加热2h。混合物然后再次冷却到0℃,小心地添加0.4ml水和0.8ml 1N氢氧化钠水溶液并且混合物在RT下搅拌3h。滤掉形成的沉淀,并且滤液在旋转蒸发器上除去溶剂。残余物没有进一步提纯地用于随后的反应。
产率:219mg(理论的82%,纯度86%)
LC-MS(方法15):Rt=1.74min;MS(ESIpos):m/z=210[M+H]+.
实施例39A
4-(氯甲基)-5-(4-氯苯基)-5-甲基-1,3-噁唑
开始向0.43ml(5.85mmol)亚硫酰氯中加入269mg(0.77mmol)来自实施例38A的化合物。反应混合物在RT下搅拌12h,然后在减压下除去过量亚硫酰氯。残余物在5ml乙酸乙酯中吸收并且用2ml饱和碳酸氢钠水溶液洗涤一次。有机相通过硫酸镁干燥并且在旋转蒸发器上除去溶剂。获得的产物没有进一步提纯地用于随后的反应。
产率:145mg(理论的62%,纯度76%)
LC-MS(方法14):Rt=1.21min;MS(ESIpos):m/z=228[M+H]+.
实施例40A
2-(4-氯苯基)-4-[(甲氧基甲氧基)甲基]-1,3-噁唑
开始向18.5ml干燥的THF中加入1.32g(7.54mmol)[2-(4-氯苯基)-1,3-噁唑-4-基]甲醇(实施例100A)并冷却到0℃,并且添加0.33g(8.29mmol)氢化钠(在矿物油中浓度60%)。混合物在0℃下搅拌10min和然后在RT下1h。反应混合物再次冷却到0℃,并且滴加0.69ml(9.04mmol)氯二甲醚。混合物在0℃下搅拌10min和然后在RT下搅拌2h。然后添加5ml水,并且反应混合物在每一种情况下用25ml乙酸乙酯提取三次。合并的有机相通过硫酸镁干燥并在旋转蒸发器上除去溶剂。获得的产物没有进一步提纯地用于随后的反应。
产率:1.70g(理论的87%,纯度85%)
LC-MS(方法7):Rt=1.58min;MS(ESIpos):m/z=220[M+H]+.
实施例41A
2-(4-氯苯基)-4-[(甲氧基甲氧基)甲基]-1,3-噁唑-5-甲醛
开始向3.5ml干燥的乙醚中加入200mg(0.91mmol)来自实施例40A的粗产物并且冷却到-78℃。缓慢地滴加0.63ml(1.00mmol)正-丁基锂在己烷中的1.6M溶液。反应混合物在-78℃下搅拌1h。然后缓慢地滴加0.21ml(2.74mmol)N,N-二甲基甲酰胺。使混合物暖到RT并且在RT下再搅拌1h。然后混合物倒入大约3ml水中。混合物在每一种情况下用10ml乙醚提取三次。合并的有机相通过硫酸镁干燥并且在旋转蒸发器上除去溶剂。残余物通过在硅胶60上柱层析提纯(流动相梯度:环己烷/乙酸乙酯20∶1→2∶1)。
产率:161mg(理论的56%,纯度79%)
LC-MS(方法6):Rt=1.74min;MS(ESIpos):m/z=248[M+H]+.
实施例42A
2-(4-氯苯基)-4-[(甲氧基甲氧基)甲基]-1,3-噁唑-5-羧酸
向802mg(4.72mmol)硝酸银(I)在2ml水中的悬浮液中加入556mg(2.25mmol)来自实施例41A的化合物和14.7ml二噁烷。然后缓慢地添加193mg(4.84mmol)氢氧化钠在7.8ml水中的溶液。混合物在RT下搅拌3h。混合物然后通过Celite过滤,其再用温水洗涤。获得的滤液通过添加1N盐酸酸化并且在每一种情况下用20ml乙醚提取三次。合并的有机相通过硫酸镁干燥并且在旋转蒸发器上除去溶剂。残余物通过制备HPLC提纯(柱:YMC GEL ODS-AQ S-5/15μm;流动相梯度:乙腈/水10∶90→95∶5)。
产率:138mg(理论的21%,纯度92%)
LC-MS(方法3):Rt=1.93min;MS(ESIpos):m/z=286[M+Na]+.
实施例43A
2-(4-氯苯基)-4-[(甲氧基甲氧基)甲基]-1,3-噁唑-5-羧酸甲基酯
138mg(0.52mmol)来自实施例42A的化合物溶于3ml甲苯和2.5ml甲醇。然后滴加0.4ml(0.79mmol)三甲基甲硅烷基重氮甲烷在己烷中的2M溶液。混合物在RT下搅拌10min和然后在旋转蒸发器上除去溶剂。残余物没有进一步提纯地用于随后的反应。
产率:144mg(理论的90%,纯度91%)
LC-MS(方法15):Rt=1.98min;MS(ESIpos):m/z=300[M+Na]+.
实施例44A
2-(4-氯苯基)-4-(羟甲基)-1,3-噁唑-5-羧酸甲基酯
开始向0.5ml甲醇中加入144mg(0.52mmol)来自实施例43A的化合物,并且添加0.13ml 4N盐酸。然后添加3滴浓盐酸。反应混合物在RT下搅拌8h。混合物然后用大约5ml水稀释并在每一种情况下用10ml乙醚提取三次。合并的有机相通过硫酸镁干燥并且在旋转蒸发器上除去溶剂。获得的产物没有进一步提纯地用于随后的反应。
产率:100mg(理论的81%,纯度84%)
LC-MS(方法7):Rt=1.29min;MS(ESIpos):m/z=234[M+H]+.
实施例45A
2-(氯甲基)-2-(4-氯苯基)-1,3-噁唑-5-羧酸甲基酯
100mg(0.43mmol)来自实施例44A的化合物,连同0.24ml(3.24mmol)亚硫酰氯,在RT下搅拌8h。在减压下除去过量亚硫酰氯并且残余物在大约5ml乙酸乙酯中吸收。混合物用2ml饱和碳酸氢钠水溶液洗涤一次。有机相通过硫酸镁干燥并且在旋转蒸发器上除去溶剂。获得的产物没有进一步提纯地用于随后的反应。
产率:99mg(理论的92%,纯度98%)
LC-MS(方法7):Rt=1.96min;MS(ESIpos):m/z=252[M+H]+.
实施例46A
2-氨基-6-({[2-(4-氯苯基)-1,3-噁唑-4-基]甲基}硫烷基)-4-(4-{[(4R)-2,2-二甲基-1,3-二氧戊环-4-基]甲氧基}苯基)吡啶-3,5-二腈
70mg(0.18mmol)来自实施例10A的化合物和46mg(0.20mmol)来自实施例17A的化合物,连同46mg(0.55mmol)碳酸氢钠,悬浮在1.9ml干燥的DMF中。反应混合物在RT下搅拌20h。在旋转蒸发器上,混合物除去溶剂,并且残余物通过制备HPLC提纯(柱:YMC GELODS-AQ S-5/15μm;流动相梯度:乙腈/水10∶90→95∶5)。
产率:79mg(理论的75%)
1H-NMR(400MHz,DMSO-d6):δ=8.37(s,1H),8.30-8.01(br.s,2H),7.97(d,2H),7.60(d,2H),7.48(d,2H),7.12(d,2H),4.48-4.40(m,1H),4.42(s,2H),4.16-4.03(m,3H),3.78(dd,1H),1.37(s,3H),1.31(s,3H).
LC-MS(方法3):Rt=2.99min;MS(ESIpos):m/z=574[M+H]+.
实施例47A
2-氨基-6-({[2-(4-氯苯基)-1,3-噁唑-4-基]甲基}硫烷基)-4-(4-{[(4S)-2,2-二甲基-1,3-二氧戊环-4-基]甲氧基}苯基)吡啶-3,5-二腈
150mg(0.39mmol)来自实施例11A的化合物和98mg(0.43mmol)来自实施例17A的化合物,连同99mg(1.18mmol)碳酸氢钠,悬浮在2ml干燥的DMF中。反应混合物在RT下搅拌20h。混合物然后直接通过制备HPLC提纯(柱:YMC GEL ODS-AQ S-5/15μm;流动相梯度:乙腈/水10∶90→95∶5)。
产率:147mg(理论的65%)
1H-NMR(400MHz,DMSO-d6):δ=8.37(s,1H),8.29-7.91(br.s,2H),7.97(d,2H),7.61(d,2H),7.47(d,2H),7.12(d,2H),4.48-4.39(m,1H),4.42(s,2H),4.16-4.03(m,3H),3.77(dd,1H),1.37(s,3H),1.31(s,3H).
LC-MS(方法4):Rt=4.23min;MS(ESIpos):m/z=574[M+H]+.
在表4中列出的实施例类似于实施例46A和47A由适当的起始化合物制备:
表4
实施例95A
2-氨基-4-(4-{[(2S)-2-{[叔-丁基(二甲基)甲硅烷基]氧基}丙基]氧基}苯基)-6-({[2-(4-氟苯基)-5-甲基-1,3-噁唑-4-基]甲基}硫代)吡啶-3,5-二腈
在2ml干燥的DMF中的100mg(0.18mmol)来自实施例7A的化合物,45mg(0.20mmol)4-(氯甲基)-2-(4-氟苯基)-5-甲基-1,3-噁唑和46mg(0.55mmol)碳酸氢钠在RT下搅拌20h。混合物直接通过制备HPLC提纯(柱:YMC GEL ODS-AQ S-5/15μm;流动相梯度:乙腈/水10∶90→95∶5)。在旋转蒸发器上除去溶剂产生作为白色固体的产物。
产率:65mg(理论的57%)
LC-MS(方法3):Rt=3.53min;MS(ESIpos):m/z=630[M+H]+.
在表5中列出的实施例类似于实施例95A由适当的起始化合物制备:
表5
实施例98A
2-氨基-4-(4-{[(4S)-2,2-二甲基-1,3-二氧戊环-4-基]甲氧基}苯基)-6-(苯基硫代)吡啶-3,5-二腈
开始向25ml无水乙醇中加入1.63g(6.90mmol)来自实施例9A的化合物,并顺次添加957mg(14.49mmol)丙二腈,798mg(7.24mmol)苯硫酚和21mg(0.21mmol)三乙胺。反应混合物在回流下加热2h。冷却到RT后,在旋转蒸发器上除去溶剂并且残余物直接通过在硅胶60上柱层析提纯(流动相:二氯甲烷/甲醇60∶1)。通过制备HPLC进行进一步提纯(柱:YMC GEL ODS-AQ S-5/15μm;流动相梯度:乙腈/水10∶90→95∶5)。
产率:850mg(理论的27%)
LC-MS(方法3):Rt=2.63min;MS(ESIpos):m/z=459[M+H]+.
实施例99A
2-氨基-4-[4-(2-羟基乙氧基)苯基]-6-(苯基硫烷基)吡啶-3,5-二腈
标题化合物类似于实施例98A由4-(2-羟基乙氧基)-苯甲醛制备。
产率:理论的21%
1H-NMR(400MHz,DMSO-d6):δ=7.83-7.19(br.s,2H),7.64-7.58(m,2H),7.53-7.48(m,5H),7.12(d,2H),5.10-4.75(br.s,1H),4.10(t,2H),3.75(t,2H).
LC-MS(方法7):Rt=1.76min;MS(ESIpos):m/z=389[M+H]+.
实施例100A
[2-(4-氯苯基)-1,3-噁唑-4-基]甲醇
2.00g(8.77mmol)来自实施例17A的化合物悬浮在175ml(17.54mmol)0.1N氢氧化钠水溶液中。反应混合物在回流下搅拌2h。使用冰,混合物然后冷却到0℃,并且缓慢地形成沉淀。向混合物中加入大约100ml二氯甲烷和5ml乙醇。相分离。含水相调整到pH 7并且在每一种情况下用50ml二氯甲烷(在每一种情况下用3ml乙醇)提取两次。合并的有机相通过硫酸镁干燥。在旋转蒸发器上除去溶剂后。残余物在减压下干燥。
产率:1.20g(理论的65%)
LC-MS(方法8):Rt=3.05min;MS(ESIpos):m/z=210[M+H]+.
实施例101A
2-氨基-6-{[2-(4-氯苯基)-1,3-噁唑-4-基]甲氧基}-4-(4-{[(4S)-2,2-二甲基-1,3-二氧戊环-4-基]甲氧基}苯基)吡啶-3,5-二腈
122mg(1.09mmol)叔-丁醇钾悬浮在2ml干燥的1,2-二甲氧基乙烷中。然后先后添加229mg(1.09mmol)来自实施例100A的化合物和100mg(0.22mmol)来自实施例98A的化合物。反应混合物在60℃下搅拌2h和,冷却后,进一步在RT下搅拌10h。然后向混合物中加入5ml水。伴随抽吸滤掉形成的沉淀并大约2ml冷水洗涤一次。这继之以通过制备HPLC提纯(柱:YMC GEL ODS-AQ S-5/15μm;流动相梯度:乙腈/水10∶90→95∶5)。
产率:70mg(理论的58%)
1H-NMR(400MHz,DMSO-d6):δ=8.47(s,1H),8.18-7.89(br.s,2H),8.01(d,2H),7.62(d,2H),7.48(d,2H),7.12(d,2H),5.41(s,2H),4.48-4.41(m,1H),4.15-4.04(m,3H),3.79(dd,1H),1.37(s,3H),1.31(s,3H).
LC-MS(方法3):Rt=2.82min;MS(ESIpos):m/z=558[M+H]+.
实施例102A
6-氨基-4-[4-(2-羟基乙氧基)苯基]-2-氧代-1,2-二氢吡啶-3,5-二腈
开始向6.4ml乙醇中加入500mg(1.29mmol)来自实施例99A的化合物。添加2.57g(28.96mmol)氢氧化钠后,混合物在80℃下搅拌30min,并形成透明溶液。冷却到RT后,在旋转蒸发器上除去溶剂。残余物在3ml水中吸收并用1N盐酸酸化直到形成淡黄色的沉淀。悬浮液在RT下搅拌3h。滤掉该沉淀,用大约5ml水和少许乙醇洗涤和然后由大约10ml乙醇重结晶。用这样的方式获得的产物没有进一步提纯地用于随后的反应。
产率:153mg(理论的36%,纯度89%)
1H-NMR(400MHz,DMSO-d6):δ=11.85-11.72(br.s,1H),7.87-7.60(br.s,2H),7.43(d,2H),7.10(d,2H),5.08-4.52(br.s,1H),4.08(t,2H),3.74(t,2H).
LC-MS(方法3):Rt=1.29min;MS(ESIpos):m/z=297[M+H]+.
实施例103A
2-氯-6-({[2-(4-氯苯基)-1,3-噁唑-4-基]甲基}硫代)-4-(4-{[(2S)-2,3-二羟基丙基]氧基}苯基)吡啶-3,5-二腈
开始向20ml干燥的乙腈中加入569mg(4.86mmol)亚硝酸异戊酯和653mg(4.86mmol)氯化铜(II),并添加465mg(0.81mmol)来自实施例58A的化合物。反应混合物在60℃下搅拌3h。冷却到RT后,向混合物中加入20ml 1N盐酸。含水相在每一种情况下用30ml乙酸乙酯提取两次。合并的有机相在每一种情况下用10ml饱和碳酸氢钠水溶液和10ml饱和氯化钠水溶液洗涤一次。通过硫酸镁干燥后,在旋转蒸发器上除去溶剂。残余物通过制备HPLC提纯(柱:YMC GEL ODS-AQS-5/15μm;流动相梯度:乙腈/水10∶90→95∶5)。在旋转蒸发器上除去溶剂产生产物,其没有进一步提纯地用于随后的反应。
产率:108mg(理论的18%,纯度73%)
LC-MS(方法5):Rt=3.85min;MS(ESIpos):m/z=553[M+H]+.
在表6中列出的实施例类似于实施例46A由适当的起始化合物制备:
表6
在表7中列出的化合物可以类似于实施例16A和34A的步骤由适当的起始材料制备:
表7
实施例123A
2-氯-6-({[2-(4-氯苯基)-1,3-噁唑-4-基]甲基}硫烷基)-4-[4-(2-羟基乙氧基)苯基]吡啶-3,5-二腈
开始向17ml干燥的乙腈中加入156mg(1.33mmol)亚硝酸异戊酯和179mg(1.33mmol)氯化铜(II),并添加336mg(0.67mmol)来自实施例15的化合物。反应混合物在60℃下搅拌3h。然后添加17ml 1N盐酸,并且混合物在每一种情况下用30ml乙酸乙酯提取两次。合并的有机相通过硫酸镁干燥。除去溶剂后,粗产物没有进一步提纯地用于随后的反应。
产率:410mg(理论的78%,纯度67%)。
85mg部分粗产物通过制备HPLC提纯(柱:YMC GEL ODS-AQS-5/15μm;流动相梯度:乙腈/水10∶90→95∶5)。这产生14mg纯的目标化合物。
1H-NMR(400MHz,DMSO-d6):δ=8.18(s,1H),7.98(d,2H),7.62(dd,4H),7.19(d,2H),4.98-4.88(br.s,1H),4.58(s,2H),4.11(t,2H),3.79-3.71(br.s,2H).
LC-MS(方法14):Rt=1.46min;MS(ESIpos):m/z=523[M+H]+.
实施例124A
2-氯-6-{[2-(4-氯苯基)-1,3-噁唑-4-基]甲氧基}-4-[4-(2-羟基乙氧基)苯基]吡啶-3,5-二腈
标题化合物类似于实施例123A的方式从实施例110开始制备。
LC-MS(方法3):Rt=2.76min;MS(ESIpos):m/z=507[M+H]+.
实施例125A
2-氯-6-({[2-(4-氯苯基)-1,3-噁唑-4-基]甲基}硫烷基)-4-[3-氟-4-(2-羟基乙基)苯基]吡啶-3,5-二腈
开始向20ml乙腈中加入150mg(0.287mmol)2-氨基-6-({[2-(4-氯苯基)-1,3-噁唑-4-基]甲基}硫烷基)-4-[3-氟-4-(2-羟基乙氧基)苯基]吡啶-3,5-二腈(实施例20),添加258μl(1.724mmol)亚硝酸异戊酯和232mg(1.724mmol)氯化铜(II)并且混合物在室温下搅拌过夜。然后向饱和氯化铵溶液中加入反应混合物并用乙酸乙酯提取。用饱和氯化钠溶液洗涤有机相,通过硫酸钠干燥并浓缩。残余物通过制备HPLC提纯(流动相梯度:乙腈/水10∶90→95∶5)。这产生25mg(理论的16%)目标化合物。
LC-MS(方法7):Rt=2.43min;MS(ESIpos):m/z=541[M+H]+.
操作实施例:
实施例1
2-氨基-6-({[2-(4-氯-3-甲基苯基)-1,3-噁唑-4-基]甲基}硫代)-4-[4-(2-羟基乙基)苯基]吡啶-3,5-二腈
52mg(0.17mmol)来自实施例1A的化合物和89mg(0.18mmol)来自实施例28A的化合物,连同42mg(0.50mmol)碳酸氢钠,悬浮在1.8ml干燥的DMF中。反应混合物在RT下搅拌12h。混合物然后过滤并且滤液直接通过制备HPLC提纯(柱:YMC GEL ODS-AQ S-5/15μm;流动相梯度:乙腈/水10∶90(95∶5)。在旋转蒸发器上除去溶剂后,获得作为白色固体的产物。
产率:16mg(理论的38%)
1H-NMR(400MHz,DMSO-d6):δ=8.36(s,1H),8.30-7.90(br.s,2H),7.96(s,1H),7.79(d,1H),7.58(d,1H),7.47(d,2H),7.10(d,2H),4.91(t,1H),4.41(s,2H),4.12-4.05(m,2H),3.73(dt,2H),2.41(s,3H).
LC-MS(方法6):Rt=2.36min;MS(ESIpos):m/z=518[M+H]+.
在表8中列出的实施例类似于实施例1由适当的起始化合物制备:
表8
实施例44
(+)-2-氨基-6-({[2-(4-氯苯基)-1,3-噁唑-4-基]甲基}硫烷基)-4-[4-(3,3,3-三氟-2-羟基丙氧基)苯基]吡啶-3,5-二腈
来自实施例33的外消旋化合物(67mg)通过在手性相上HPLC色谱分离成两种对映异构体(也参见实施例45)[柱:Daicel ChiralpakAD-H,5μm,250mm x 20mm;流动相:乙醇;流速:10ml/min;温度:35℃;检测:220nm]。
(+)-对映异构体
产率:33mg
Rt=6.86min[柱:Daicel Chiralpak AD-H,5μm,250mm x4.6mm;流动相:乙醇;流速:1ml/min;温度:40℃]
比旋光度:+1.2°(c=0.43g/100ml,甲醇,n=589nm,T=20.4℃)
1H-NMR(400MHz,DMSO-d6):δ=8.37(s,1H),8.28-7.91(br.s,2H),7.98(d,2H),7.61(d,2H),7.49(d,2H),7.15(d,2H),6.70(d,1H),4.49-4.39(m,1H),4.43(s,2H),4.28(dd,1H),4.16(dd,1H).
LC-MS(方法7):Rt=2.34min;MS(ESIpos):m/z=572[M+H]+.
实施例45
(-)-2-氨基-6-({[2-(4-氯苯基)-1,3-噁唑-4-基]甲基}硫烷基)-4-[4-(3,3,3-三氟-2-羟基丙氧基)苯基]吡啶-3,5-二腈
来自实施例33的外消旋化合物(67mg)通过在手性相上HPLC色谱分离成两种对映异构体(也参见实施例44)[柱:Daicel ChiralpakAD-H,5μm,250mm x 20mm;流动相:乙醇;流速:10ml/min;温度:35℃;检测:220nm]。
(-)-对映异构体
产率:33mg
Rt=8.73min[柱:Daicel Chiralpak AD-H,5μm,250mm x4.6mm;流动相:乙醇;流速:1ml/min;温度:40℃]
1H-NMR(400MHz,DMSO-d6):δ=8.37(s,1H),8.29-7.90(br.s,2H),7.98(d,2H),7.61(d,2H),7.49(d,2H),7.16(d,2H),6.70(d,1H),4.49-4.39(m,1H),4.43(s,2H),4.28(dd,1H),4.16(dd,1H).
LC-MS(方法7):Rt=2.35min;MS(ESIpos):m/z=572[M+H]+.
实施例46
(+)-2-氨基-6-({[2-(4-氯苯基)-5-甲基-1,3-噁唑-4-基]甲基}硫烷基)-4-[4-(3,3,3-三氟-2-羟基丙氧基)苯基]吡啶-3,5-二腈
来自实施例34的外消旋化合物(87mg)通过在手性相上HPLC色谱分离成两种对映异构体(也参见实施例47)[柱:Daicel ChiralpakAD-H,5μm,250mm x 20mm;流动相:异己烷/异丙醇1∶1(v/v);流速:15ml/min;温度:40℃;检测:220nm]。
(+)-对映异构体:
产率:30mg
Rt=4.58min[柱:Daicel Chiralpak AD-H,5μm,250mm x4.6mm;流动相:异己烷/异丙醇1∶1(v/v);流速:1ml/min;温度:40℃]
比旋光度:+11.1°(c=0.435g/100ml,DMF,n=589nm,T=19.6℃)
1H-NMR(400MHz,DMSO-d6):δ=8.20-7.88(br.s,2H),7.92(d,2H),7.58(d,2H),7.49(d,2H),7.15(d,2H),6.70(d,1H),4.52(s,2H),4.48-4.37(m,1H),4.28(dd,1H),4.17(dd,1H),2.48(s,3H).
LC-MS(方法7):Rt=2.43min;MS(ESIpos):m/z=586[M+H]+.
实施例47
(-)-2-氨基-6-({[2-(4-氯苯基)-5-甲基-1,3-噁唑-4-基]甲基}硫烷基)-4-[4-(3,3,3-三氟-2-羟基丙氧基)苯基]吡啶-3,5-二腈
来自实施例34的外消旋化合物(87mg)通过在手性相上HPLC色谱分离成两种对映异构体(参见实施例46)[柱:Daicel ChiralpakAD-H,5μm,250mm x 20mm;流动相:异己烷/异丙醇1∶1(v/v);流速:15ml/min;温度:40℃;检测:220nm]。
(-)-对映异构体:
产率:31mg
Rt=5.56min[柱:Daicel Chiralpak AD-H,5μm,250mm x4.6mm;流动相:异己烷/异丙醇1∶1(v/v);流速:1ml/min;温度:40℃]
1H-NMR(400MHz,DMSO-d6):δ=8.21-7.89(br.s,2H),7.92(d,2H),7.58(d,2H),7.50(d,2H),7.16(d,2H),6.70(d,1H),4.52(s,2H),4.48-4.39(m,1H),4.29(dd,1H),4.17(dd,1H),2.48(s,3H).
LC-MS(方法7):Rt=2.43min;MS(ESIpos):m/z=586[M+H]+.
实施例48
2-氨基-6-({[2-(4-氯苯基)-1,3-噁唑-4-基]甲基}硫烷基)-4-(4-{[(2S)-2,3-二羟基丙基]氧基}苯基)吡啶-3,5-二腈
开始在17ml乙酸中加入400mg(0.70mmol)来自实施例46A的化合物,并之后小心地添加8.6ml水。混合物在RT下搅拌12h。反应混合物在旋转蒸发器上浓缩后,残余物直接通过制备HPLC提纯(柱:YMCGEL ODS-AQ S-5/15μm;流动相梯度:乙腈/水10∶90→95∶5)。在旋转蒸发器上除去溶剂后,获得作为白色固体的产物。
产率:340mg(理论的91%)
1H-NMR(400MHz,DMSO-d6):δ=8.37(s,1H),8.27-7.91(br.s,2H),7.98(d,2H),7.60(d,2H),7.47(d,2H),7.10(d,2H),5.00(d,1H),4.70(t,1H),4.42(s,2H),4.09(dd,1H),3.96(dd,1H),3.70(q,1H),3.46(t,2H).
LC-MS(方法3):Rt=2.48min;MS(ESIpos):m/z=534[M+H]+.
实施例49
2-氨基-6-({[2-(4-氯苯基)-1,3-噁唑-4-基]甲基}硫烷基)-4-(4-{[(2R)-2,3-二羟基丙基]氧基}苯基)吡啶-3,5-二腈
开始在23.5ml乙酸中加入403mg(80%纯,0.56mmol)来自实施例47A的化合物,并之后小心地添加23.5ml水。反应混合物在RT下搅拌过夜和之后在旋转蒸发器上浓缩。残余物在少许DMF中吸收并用制备HPLC提纯(柱:YMC GEL ODS-AQ S-5/15μm;流动相梯度:乙腈/水10∶90→95∶5)。在旋转蒸发器上除去溶剂后,获得作为白色固体的产物。
产率:259mg(理论的86%)
1H-NMR(400MHz,DMSO-d6):δ=8.37(s,1H),8.30-7.89(br.s,2H),7.98(d,2H),7.61(d,2H),7.48(d,2H),7.10(d,2H),5.00(d,1H),4.70(t,1H),4.42(s,2H),4.09(dd,1H),3.98-3.92(m,1H),3.81(q,1H),3.50-3.43(m,2H).
LC-MS(方法3):Rt=2.51min;MS(ESIpos):m/z=534[M+H]+.
在表9中列出的实施例类似于实施例48和49由合适的起始化合物制备:
表9
实施例95
4-{4-[({6-氨基-3,5-二氰基-4-[4-(2-羟基-2-甲基丙氧基)苯基]吡啶-2-基}硫代)甲基]-5-甲基-1,3-噁唑-2-基}苯甲酸
40mg(0.07mmol)来自实施例17的化合物和11mg(0.28mmol)氢氧化钠溶于12.8ml1,2-二甲氧基乙烷,0.7ml甲醇和2.8ml水。反应溶液在RT下搅拌3h。混合物之后在旋转蒸发器上浓缩。向残余物中添加5ml水。通过添加1N盐酸,pH调整到4。滤掉产生的沉淀并用制备HPLC提纯(柱:YMC GEL ODS-AQ S-5/15μm;流动相梯度:乙腈/水10∶90→95∶5)。在旋转蒸发器上除去溶剂后,获得作为白色固体的产物。
产率:19mg(理论的47%)
1H-NMR(400MHz,DMSO-d6):δ=13.19(s,1H),8.23-7.96(br.s,2H),8.09-8.02(m,4H),7.48(d,2H),7.10(d,2H),4.69(s,1H),4.53(s,2H),3.80(s,2H),2.50(s,3H),1.21(s,6H).
LC-MS(方法3):Rt=2.41min;MS(ESIpos):m/z=556[M+H]+.
在表10中列出的实施例类似于实施例95由合适的起始化合物制备:
表10
实施例98
4-[4-({[6-氨基-3,5-二氰基-4-(4-{[(2S)-2,3-二羟基丙基]氧基}苯基)吡啶-2-基]硫代}甲基)-5-甲基-1,3-噁唑-2-基]苯甲酸
63mg(0.11mmol)来自实施例57的化合物溶于3ml THF,并添加220μl(0.22mmol)1M氢氧化锂水溶液。在微波中,反应混合物加热到140℃,并且混合物在该温度下搅拌15min。之后在旋转蒸发器上除去溶剂。残余物在3ml水中吸收并使用大约0.5ml 1N盐酸调整到pH4。形成沉淀,其滤掉并用制备HPLC提纯(柱:YMC GEL ODS-AQS-5/15μm;流动相梯度:乙腈/水10∶90→95∶5)。在旋转蒸发器上除去溶剂后,获得作为白色固体的产物。
产率:3mg(理论的5%)
1H-NMR(400MHz,DMSO-d6):δ=13.19(br.s,1H),8.19-7.91(m,6H),7.49(d,2H),7.11(d,2H),5.00(d,1H),4.70(t,1H),4.53(s,2H),4.09(dd,1H),3.95(dd,1H),3.82(q,1H),3.46(t,2H),2.50(s,3H).
LC-MS(方法11):Rt=1.56min;MS(ESIpos):m/z=558[M+H]+.
实施例99
2-氨基-4-(4-{[(2S)-2,3-二羟基丙基]氧基}苯基)-6-({[2-(3-氟苯基)-1,3-噁唑-4-基]甲基}硫代)吡啶-3,5-二腈
75mg(0.17mmol)来自实施例10A的化合物和38mg(0.18mmol)来自实施例21A的化合物溶于2ml干燥的DMF,添加50mg(0.36mmol)碳酸钾并且混合物在RT下搅拌8h。之后滴加0.82ml(1.65mmol)2N盐酸,并且混合物在RT下再搅拌1h。过滤后,在旋转蒸发器上除去溶剂。残余物用制备HPLC提纯(柱:YMC GEL ODS-AQ S-5/15μm;流动相梯度:乙腈/水10∶90→95∶5)。在旋转蒸发器上除去溶剂后,获得作为白色固体的产物。
产率:17mg(理论的20%)
1H-NMR(400MHz,DMSO-d6):δ=8.39(s,1H),8.27-7.89(br.s,2H),7.81(d,1H),7.70(d,1H),7.59(q,1H),7.46(d,2H),7.39(dt,1H),7.09(d,2H),5.00(d,1H),4.69(t,1H),4.42(s,2H),4.09(dd,1H),3.94(dd,1H),3.81(q,1H),3.47(t,2H).
LC-MS(方法2):Rt=2.06min;MS(ESIpos):m/z=518[M+H]+.
在表11中列出的实施例类似于实施例99由合适的起始化合物制备:
表11
实施例104
2-氨基-6-({[2-(4-氟苯基)-5-甲基-1,3-噁唑-4-基]甲基}硫代)-4-(4-{[(2S)-2-羟基丙基]氧基}苯基)吡啶-3,5-二腈
65mg(0.10mmol)来自实施例95A的化合物溶于4ml甲醇,并且添加1.5ml 1N盐酸。混合物在RT下搅拌12h。然后在旋转蒸发器上除去溶剂,并且残余物通过制备HPLC提纯(柱:YMC GEL ODS-AQS-5/15μm;流动相梯度:乙腈/水10∶90→95∶5)。在旋转蒸发器上除去溶剂后,获得作为白色固体的产物。
产率:48mg(理论的91%)
1H-NMR(400MHz,DMSO-d6):δ=8.20-7.91(br.s,2H),7.49(d,2H),7.35(pseudo-t,2H),7.09(d,2H),4.91(d,1H),4.50(s,2H),4.02-3.94(m,1H),3.92-3.86(m,2H),2.48(s,3H),1.18(s,3H).
LC-MS(方法3):Rt=2.67min;MS(ESIpos):m/z=516[M+H]+.
在表12中列出的实施例类似于实施例104由适当的起始化合物制备:
表12
实施例107
4-({[6-氨基-3,5-二氰基-4-(4-{[(2R)-2,3-二羟基丙基]氧基}苯基)吡啶-2-基]硫烷基}甲基)-2-苯基-1,3-噁唑-5-羧酸
30mg(0.05mmol)来自实施例103的化合物和0.22ml(0.22mmol)1N氢氧化钠水溶液溶于2ml1,2-二甲氧基乙烷,2ml水和0.5ml甲醇并且在RT下搅拌3h。然后在旋转蒸发器上除去溶剂并且残余物在2ml水中吸收。通过添加1N盐酸pH调整到4。形成白色沉淀,其伴随抽吸滤掉并且在减压下干燥。
产率:8mg(理论的26%)
1H-NMR(400MHz,DMSO-d6):δ=14.15-13.93(br.s,1H),8.08-7.92(br.s,2H),8.04(d,2H),7.67-7.57(m,3H),7.50(d,2H),7.11(d,2H),5.05-4.97(br.s,1H),4.71(s,2H),4.74-4.66(br.s,1H),4.09(dd,1H),3.99-3.89(m,1H),3.87-3.79(br.s,1H),3.51-3.43(m,2H).
LC-MS(方法3):Rt=2.19min;MS(ESIpos):m/z=544[M+H]+.
实施例108
N-[6-({[2-(4-氯苯基)-1,3-噁唑-4-基]甲基}硫代)-3,5-二氰基-4-(4-{[(2S)-2,3-二羟基丙基]氧基}苯基)吡啶-2-基]-N-甲基甘氨酸甲基酯
108mg(0.20mmol)来自实施例103A的化合物溶于3ml干燥的DMF,并添加54mg(0.39mmol)N-甲基甘氨酸甲基酯盐酸盐和59mg(0.59mmol)三乙胺。反应混合物在RT下搅拌8h。然后在旋转蒸发器上除去溶剂并且残余物直接通过制备HPLC提纯(柱:YMC GELODS-AQ S-5/15μm;流动相梯度:乙腈/水10∶90→95∶5)。在旋转蒸发器上除去溶剂后,获得作为白色固体的产物。
产率:13mg(理论的11%)
1H-NMR(400MHz,DMSO-d6):δ=8.19(s,1H),7.98(d,2H),7.62(d,2H),7.55(d,2H),7.11(d,2H),5.01(d,1H),4.71(t,1H),4.61(s,2H),4.41(s,2H),4.09(dd,1H),3.97(dd,1H),3.87-3.78(m,1H),3.65(s,3H),3.51-3.43(m,5H).
LC-MS(方法5):Rt=3.65min;MS(ESIpos):m/z=620[M+H]+.
实施例109
2-氨基-6-{[2-(4-氯苯基)-1,3-噁唑-4-基]甲氧基}-4-(4-{[(2R)-2,3-二羟基丙基]氧基}苯基)吡啶-3,5-二腈
65mg(0.12mmol)来自实施例101A的化合物溶于6ml乙酸,并添加3ml水。混合物在RT下搅拌30min。混合物然后加热到70℃并在该温度下再搅拌30min。形成透明溶液。混合物之后在旋转蒸发器上除去溶剂并且残余物通过制备HPLC提纯(柱:YMC GEL ODS-AQ S-5/15μm;流动相梯度:乙腈/水10∶90→95∶5)。在旋转蒸发器上除去溶剂后,获得作为白色固体的产物。
产率:60mg(理论的100%)
1H-NMR(400MHz,DMSO-d6):δ=8.48(s,1H),8.25-7.80(br.s,2H),8.01(d,2H),7.61(d,2H),7.47(d,2H),7.10(d,2H),5.42(s,2H),5.01(d,1H),4.70(t,1H),4.09(dd,1H),3.95(dd,1H),3.87-3.77(m,1H),3.48(t,2H).
LC-MS(方法3):Rt=2.30min;MS(ESIpos):m/z=518[M+H]+.
实施例110
2-氨基-6-{[2-(4-氯苯基)-1,3-噁唑-4-基]甲氧基}-4-[4-(2-羟基乙氧基)苯基]吡啶-3,5-二腈
72mg(0.64mmol)叔-丁醇钾悬浮在1ml干燥的1,2-二甲氧基乙烷中。然后顺次地添加270mg(1.29mmol)来自实施例100A的化合物和50mg(0.13mmol)来自实施例99A的化合物。反应混合物在60℃下搅拌2h和然后冷却到RT并且在该温度下再搅拌8h。然后向混合物中加入5ml水和1ml 2N乙酸。形成沉淀,其伴随抽吸滤掉并且通过制备HPLC提纯(柱:YMC GEL ODS-AQ S-5/15μm;流动相梯度:乙腈/水10∶90→95∶5)。在旋转蒸发器上除去溶剂产生作为黄色固体的产物。
产率:44mg(理论的70%)
1H-NMR(400MHz,DMSO-d6):δ=8.48(s,1H),8.18-7.85(br.s,2H),8.00(d,2H),7.62(d,2H),7.48(d,2H),7.11(d,2H),5.41(s,2H),4.91(t,1H),4.08(t,2H),3.73(q,2H).
LC-MS(方法14):Rt=1.22min;MS(ESIpos):m/z=488[M+H]+.
在表13中列出的实施例类似于实施例110由适当的起始化合物制备:
表13
实施例113
2-氨基-6-{[2-(4-氟苯基)-5-甲基-1,3-噁唑-4-基]甲氧基}-4-[4-(2-羟基乙氧基)苯基]吡啶-3,5-二腈
开始向8.6ml干燥的DMF中加入250mg(0.81mmol)来自实施例102A的化合物,228mg(1.013mmol)4-(氯甲基)-2-(4-氟苯基)-5-甲基-1,3-噁唑和224mg(1.62mmol)碳酸钾并在70℃下搅拌2h。然后在旋转蒸发器上除去溶剂并且残余物通过制备HPLC提纯(柱:YMC GELODS-AQ S-5/15μm;流动相梯度:乙腈/水10∶90→95∶5)。产物然后再次通过HPLC提纯(柱:Waters Sunfire C18 5μm,250mm x 20mm;流动相梯度:水/乙醇55∶45→5∶95;流速:25ml/min;温度:30℃;检测:210nm)。
产率:56mg(理论的14%)
1H-NMR(400MHz,DMSO-d6):δ=8.07-7.87(br.s,2H),8.03-7.98(m,2H),7.48(d,2H),7.37(t,2H),7.10(d,2H),5.40(s,2H),4.91(t,1H),4.08(t,2H),3.74(q,2H),2.49(s,3H).
LC-MS(方法14):Rt=1.18min;MS(ESIpos):m/z=486[M+H]+.
在表14中列出的实施例类似于实施例113由适当的起始化合物制备:
表14
实施例116
2-({[2-(4-氯苯基)-1,3-噁唑-4-基]甲基}硫烷基)-4-[4-(2-羟基乙氧基)苯基]-6-(吡咯烷-1-基)吡啶-3,5-二腈
开始向2ml干燥的THF中加入80mg(0.15mmol)来自实施例123A的化合物,并添加22mg(0.31mmol)吡咯烷。反应混合物在RT下搅拌10h。然后添加大约2ml水,并且混合物直接通过制备HPLC提纯(柱:YMC GEL 0DS-AQ S-5/15μm;流动相梯度:乙腈/水10∶90→95∶5)。在旋转蒸发器上除去溶剂后,获得作为白色固体的产物。
产率:26mg(理论的30%)
1H-NMR(400MHz,DMSO-d6):δ=8.20(s,1H),7.97(d,2H),7.61(d,2H),7.49(d,2H),7.11(d,2H),4.91(t,1H),4.51(s,2H),4.09(t,2H),3.91-3.81(br.s,4H),3.74(q,2H),2.02-1.91(br.s,4H).
LC-MS(方法3):Rt=3.02mm;MS(ESIpos):m/z=558[M+H]+.
在表15中列出的实施例类似于实施例116由适当的起始化合物制备:
表15
在表16中列出的实施例类似于实施例48由适当的起始化合物制备:
表16
实施例122
2-({[2-(4-氯苯基)-1,3-噁唑-4-基]甲基}硫烷基)-4-[3-氟-4-(2-羟基乙氧基)苯基]-6-[(2-羟基乙基)氨基]吡啶-3,5-二腈
开始向1ml THF中加入25mg(0.046mmol)2-氯-6-({[2-(4-氯苯基)-1,3-噁唑-4-基]甲基}硫烷基)-4-[3-氟-4-(2-羟基乙氧基)苯基]吡啶-3,5-二腈(实施例125A),添加6μl 2-氨基乙醇并且混合物在室温下搅拌30分钟。反应混合物然后直接通过制备HPLC提纯(流动相梯度:乙腈/水10∶90→95∶5)。这产生24mg(理论的94%)目标化合物。
1H-NMR(400MHz,DMSO-d6):δ=8.20(s,1H),8.08(t,1H),7.98(d,2H),7.61(d,2H),7.51(dd,1H),7.39-7.31(m,2H),4.51(s,2H),4.16(t,2H),3.76(t,2H),3.67-3.62(m,2H),3.58-3.55(m,2H).
LC-MS(方法3):Rt=2.52min;MS(ESIpos):m/z=566[M+H]+.
实施例123
4-[({6-氨基-3,5-二氰基-4-[4-(2-羟基乙氧基)苯基]吡啶-2-基}硫烷基)甲基]-2-苯基-1,3-噁唑-5-羧酸
开始向6ml THF中加入100mg(0.190mmol)4-[({6-氨基-3,5-二氰基-4-[4-(2-羟基乙氧基)苯基]吡啶-2-基}硫烷基)甲基]-2-苯基-1,3-噁唑-5-羧酸甲基酯(实施例36),添加379μl(0.379mmol)1N氢氧化锂水溶液并且混合物在室温下搅拌30分钟。反应混合物然后浓缩,向残余物中加入水并且混合物用1N盐酸酸化。滤掉沉淀固体并且通过制备HPLC提纯(流动相梯度:乙腈/水10∶90→95∶5)。这产生23mg(理论的23%)目标化合物。
1H-NMR(400MHz,DMSO-d6):δ=8.03(dd,2H),7.98-7.95(m,2H),7.63-7.56(m,3H),7.50(d,2H),7.11(d,2H),4.80(s,2H),4.08(t,2H),3.74(t,2H).
LC-MS(方法3):Rt=2.38min;MS(ESIpos):m/z=514[M+H]+.
在表17中列出的实施例类似于实施例116由适当的起始化合物制备:
表17
*反应在作为溶剂的DMF(代替THF)中进行
B.评价药理学和生理活性
根据本发明的化合物的药理学和生理活性可以在以下试验中显示:
B-1.通过基因表达腺苷激动的间接测定
CHO(中国仓鼠卵巢)细胞永久细胞系细胞系用cDNA稳定地转染用于腺苷受体亚型A1,A2a和A2b。腺苷A1受体通过Gi蛋白偶联到腺苷酸环化酶上,而腺苷A2a和A2b受体通过Gs蛋白偶联。与这一致,分别抑制或者刺激细胞中的cAMP的形成。然后,荧光素酶的表达通过依赖于cAMP的促进剂调节。为了高灵敏度和可再现性,低差异和在自动控制系统上实施的优良适合性,通过改变几个试验参数,例如细胞密度,生长期的持续时间和试验培养,毛喉素浓度和培养基组成优化荧光素酶试验。以下试验规程用于药理学特征细胞和用于机器人帮助的物质筛选:
储用培养物在37℃下和在5%CO2下,在包含10%FCS(胎儿小牛血清)的DMEM/F12培养基中生长并且每一种情况下2-3天后1∶10分离。该试验培养物在384-孔板中用每孔2000个细胞接种并且在37℃下生长大约48小时。培养基然后用生理氯化钠溶液(130mM氯化钠,5mM氯化钾,2mM氯化钙,20mM HEPES,1mM氯化镁六水合物,5mM碳酸氢钠,pH 7.4)替换。要试验的物质,其溶于DMSO,以从5×10-11M到3×10-6M(最后浓度)的稀释系列移液到试验培养物(在试验混合物中DMSO的最大最后浓度:0.5%)中。10分钟过后,向A1细胞中加入毛喉素并且所有的培养物随后在37℃下培养四小时。然后,向试验培养物中加入35μl由50%溶胞试剂(30mM磷酸氢二钠,10%甘油,3%TritonX100,25mM TrisHCl,2mM二硫苏糖醇(DTT),pH 7.8)和50%荧光素酶底物溶液(2.5mM ATP,0.5mM莹光素,0.1mM辅酶A,10mM曲辛,1.35mM硫酸镁,15mM DTT,pH 7.8)组成的溶液,其振荡大约1分钟并且使用照相机系统测定荧光素酶活性。测定EC50值,即,在A1细胞情况下50%荧光素酶响应被抑制的浓度,并且,分别在A2b和A2a细胞情况下获得用相应物质最大刺激的50%。腺苷-类似的化合物NECA(5-N-乙基甲酰胺腺苷),其与所有的具有高亲合力的腺苷受体亚型结合并且具有对抗作用,作为参考化合物用于这些实验[Klotz,K.N.,Hessling,J.,Hegler,J.,Owman,C.,Kull,B.,Fredholm,B.B.,Lohse,M.J.,“Comparative pharmacology ofhuman adenosine receptor subtypes characterization of stably transfectedreceptors in CHO cells”,Naunyn Schmiedebergs Arch.Pharmacol.,357(1998),1-9)。
以下表18列出了用于对腺苷A1,A2a和A2b受体亚型的受体刺激的代表性操作实施例的EC50值:
表18
实施例号 | EC50A1[nM](1μM毛喉素) | EC50A2a[nM] | EC50A2b[nM] |
10 | 0.5 | 1130 | 922 |
11 | 0.3 | 703 | 845 |
31 | 0.9 | 467 | 315 |
48 | 0.3 | 138 | 4.4 |
49 | 0.4 | 300 | 100 |
50 | 0.4 | 3000 | 118 |
57 | 0.2 | 525 | 44 |
60 | 0.3 | 3000 | 236 |
61 | 0.7 | 439 | 221 |
66 | 0.9 | 575 | 370 |
80 | 0.8 | 461 | 89 |
81 | 0.3 | 64 | 20 |
93 | 8.9 | 522 | 336 |
95 | 0.5 | 3000 | 3000 |
101 | 0.4 | 72 | 226 |
106 | 0.3 | 318 | 48 |
110 | 0.3 | 497 | 95 |
114 | 0.2 | 1970 | 969 |
116 | 0.4 | 3000 | 698 |
117 | 0.2 | 1440 | 1090 |
119 | 0.3 | 1950 | 3000 |
122 | 4.1 | 3000 | 2250 |
实施例号 | EC50A1[nM](1μM毛喉素) | EC50A2a[nM] | EC50A2b[nM] |
126 | 0.5 | 684 | 78 |
127 | 0.4 | 984 | 283 |
128 | 0.1 | 1050 | 237 |
129 | 0.4 | 3000 | 3000 |
130 | 0.6 | 3000 | 245 |
B-2.对离体血管的研究
切除麻醉大鼠的尾动脉并且装在常规仪器上用于测定离体血管。在热浴中灌注血管并且使用去氧肾上腺素收缩。使用收缩仪测定收缩的程度。向预收缩的血管中加入试验物质,并且测定血管收缩的减少。收缩的减少相当于血管的扩张。血管收缩减少50%时的浓度作为试验物质相对于其松驰性质的EC50值给出。
B-3.对醒觉大鼠血压和心率的测定
口服各种剂量的试验物质以唤醒携带能够永久测定血压和心率的内部发射器的SHR大鼠(自发高血压大鼠)(遥测监控血液动力学参数)。然后在24小时期间内记录血压,心率和它们的变化。
B-4.对醒觉绒猴血压和心率的测定
口服各种浓度的试验物质以唤醒携带能够测定血压和心率的内部发射器的绒猴(遥测监控血液动力学参数)。然后在6-24小时期间内记录血压,心率和它们的变化。
B-5.静脉内服用和口服后药效动力学参数的测定
作为给动物(例如小鼠,大鼠,狗)的溶液静脉内服用要试验的物质,并且口服作为溶液或者悬浮液通过填喂法进行。服用该物质后,在固定时间由动物身上采血并且肝素化,然后从此通过离心作用获得血浆。该物质通过LC/MS-MS在血浆中量化分析。通过确认的药效动力学计算机程序以这种方法发现的血浆浓度/时间过程用于计算药效动力学参数,例如AUC(在量时曲线下的面积),Cmax(最大血浆浓度),T1/2(半衰期)和CL(廓清(clearance))。
B-6.溶解性的测定
需要的试剂:
●PBS缓冲液pH 6.5:90.00g NaCl p.a.(例如来自Merck,物品编号1.06404.1000),13.61g KH2PO4 p.a.(例如来自Merck,物品编号1.04873.1000)和83.35g 1N氢氧化钠水溶液(例如来自Bernd Kraft有限公司,物品编号01030.4000)称重加入到1升容量瓶中,该容量瓶用蒸馏水加满到1升并且混合物搅拌1小时。之后使用1N盐酸(例如来自Merck,物品编号1.09057.1000)将pH调整到6.5。
●PEG/水溶液(70∶30v/v):在100ml容量瓶中均化70ml聚乙二醇400(例如来自Merck,物品编号8.17003.1000)和30ml蒸馏水。
●PEG/PBS缓冲液pH 6.5(20∶80v/v):在100ml容量瓶中均化20ml聚乙二醇400(例如来自Merck,物品编号8.17003.1000)和80mlPBS缓冲液pH 6.5。
●二甲基亚砜(例如来自Baker,物品编号7157.2500)
●蒸馏水
起始溶液(原始溶液)的制备:
精确称量至少4mg试验物质到具有装配螺帽和隔膜的广颈10mm螺旋V管瓶(来自Glastechnik有限公司,物品编号8004-WM-H/V15μ)中,在自动移液装置中DMSO添加到50mg/ml浓度并且混合物振荡10分钟。
校准溶液的制备:
用于校准溶液的起始溶液(储备溶液)的制备:借助于自动移液装置,10μl原始溶液转移到微量滴定板中并且用DMSO配制到600μg/ml浓度。振荡样品直到所有东西已经溶解。
校准溶液1(20μg/ml):向34.4μl储备溶液中添加1000μlDMSO,并且均化混合物。
校准溶液2(2.5μg/ml):向100μl校准溶液1中添加700μlDMSO,并且均化混合物。
样品溶液的制备:
在PBS缓冲液pH 6.5中最多5g/升溶解度的样品溶液:10μl原始溶液转移到微量滴定板中,并且添加1000μl PBS缓冲液pH 6.5。
在PEG/水(70∶30)中最多5g/升溶解度的样品溶液:10μl原始溶液转移到微量滴定板中,并且添加1000μl PEG/水(70∶30)。
在PBS/PBS缓冲液pH 6.5(20∶80)中最多5g/升溶解度的样品溶液:10μl原始溶液转移到微量滴定板中,并且添加1000μl PEG/PBS(20∶80)缓冲液pH 6.5。
实践:
在20℃下用这样的方式制备的样品溶液在温度可调的振动器(例如具有可互换的部件物品编号5362.000.019的Eppendorf Thermomixercomfort物品编号5355000.011)中在1400rmp下振荡24小时。在每一种情况下由这些溶液取180μl并且转移到Beckman PolyallomerCentrifuge Tubes(物品编号343621)中。这些溶液在大约223000xg下离心一个小时(例如在42000rmp下具有Type 42.2 Ti Rotor的Beckman Optima L-90K Ultracentrifuge)。由样品溶液中的每一个,除去100μl上清液并且用DMSO 1∶5和1∶100稀释。由每个稀释液,样品转移到容器中用于HPLC分析。
分析:
通过RP-HPLC分析样品。在DMSO中使用试验化合物的两点校准曲线进行量化。溶解度用mg/升表示。分析顺序:1)校准溶液2.5mg/ml;2)校准溶液20μg/ml;3)样品溶液1∶5;4)样品溶液1∶100。
用于酸的HPLC方法:
具有DAD(G1315A)的Agilent 1100,定量泵(G1311A),自动取样器CTC HTS PAL,脱气装置(G1322A)和柱恒温箱(G1316A);柱:Phenomenex Gemini C18,50mm x 2mm,5μ;温度:40℃;流动相A:水/磷酸pH 2;流动相B:乙腈;流速:0.7ml/min;梯度:0-0.5min 85%A,15%B;坡度(ramp):0.5-3min 10%A,90%B;3-3.5min 10%A,90%B;坡度:3.5-4min 85%A,15%B;4-5min85%A,15%B。
用于碱的HPLC方法:
具有DAD(G1315A)的Agilent 1100,定量泵(G1311A),自动取样器CTC HTS PAL,脱气装置(G1322A)和柱恒温箱(G1316A);柱:VDSoptilab Kromasil 100 C18,60mm x 2.1mm,3.5μ;温度:30℃;流动相A:水+5ml高氯酸/升;流动相B:乙腈;流速:0.75ml/min;梯度:0-0.5min 98%A,2%B;坡度:0.5-4.5min 10%A,90%B;4.5-6min 10%A,90%B;坡度:6.5-6.7min 98%A,2%B;6.7-7.5min 98%A,2%B。
B-7.新陈代谢稳定性的测定
为了测定试验化合物的新陈代谢稳定性,该化合物用肝微体或者优选用多种动物种类(例如来自大鼠和狗)和人起源的初级新生肝细胞离体培养以获得和以比较尽可能完全的肝相I和相II代谢作用的代谢物概貌。
试验化合物在10-20μM浓度下培养。为此,制备在乙腈中1-2mM浓度的该物质的储备溶液和之后在1∶100的稀释度下移液到培养混合物中。肝微体在37℃下在50mM磷酸钾缓冲液(pH 7.4)中有和没有由1mM NADP+,10mM葡糖-6-磷酸盐和1单位葡糖-6-磷酸脱氢酶组成的NADPH-生成系统地培养。初级肝细胞同样在37℃下在悬浮液中在Williams E培养基中培养。0-4小时培养时间后,培养混合物用乙腈(最后浓度大约30%)停止并且在大约15000xg下离心掉蛋白质。用这样的方式抑制的样品直接分析或者在-20℃下存储直到分析。
分析使用具有紫外线和质谱检测的高效液相色谱(HPLC-UV-MS/MS)进行。为此,培养样品的上清液使用合适的C18反相柱和乙腈和10mM甲酸铵水溶液的可变流动相混合物层析。UV色谱与质谱测定的MS/MS数据结合用来识别代谢物和以解释它们的结构。
C.药物组合物的操作实施例
本发明的化合物可以以以下方法转变成药物制剂:
片剂:
组合物:
100mg本发明的化合物,50mg乳糖(一水化物),50mg玉米淀粉(国产),10mg聚乙烯吡咯烷酮(PVP 25)(来自BASF,Ludwigshafen,德国)和2mg硬脂酸镁。
片剂重量212mg,直径8mm,曲率半径12mm。
生产:
本发明的化合物,乳糖和淀粉的混合物用水中PVP的5%浓度溶液(m/m)制粒。干燥颗粒并且与硬脂酸镁混合5分钟。该混合物在常规压片机中压缩(对于片剂的形式参见上面)。对于压缩指导压力是15kN。
可以口服的悬浮液:
组合物:
10ml口服悬浮液相当于具有100mg本发明的化合物的单剂量。
生产:
Rhodigel悬浮在乙醇中,并且向悬浮液中加入本发明的化合物。添加水同时搅拌。混合物搅拌大约6h直到Rhodigel的溶胀结束。
可以口服的溶液:
组合物:
500mg本发明的化合物,2.5g聚山梨酸酯和97g聚乙二醇400。20g口服溶液相当于具有100mg本发明的化合物的单剂量。
生产:
伴随搅拌,本发明的化合物悬浮在聚乙二醇和聚山梨酸酯的混合物中。继续搅拌过程直到本发明的化合物已经完全溶解。
体内溶液:
本发明的化合物以低于在生理耐受的溶剂(例如等渗盐水,5%葡萄糖溶液和/或30%PEG 400溶液)中的饱和溶解度的浓度溶解。溶液通过过滤杀菌并且用于灌装无菌的和无热原的注射容器。
Claims (13)
1.具有下式(I)的化合物
其中
A代表O或者S,
R1代表氢或者(C1-C4)-烷基,
R2代表氢或者可以被羟基,(C1-C4)-烷氧基或者最高被氟三次取代的(C1-C4)-烷基
或者
R1和R2彼此连接和连同它们连接的碳原子形成环丙烷或者环丁烷环,
R3代表氢,卤素或者(C1-C4)-烷基,
R4和R5是相同的或者不同的并且彼此独立地代表氢或者可以被相同的或者不同的选自以下的取代基一-或者二取代的(C1-C6)-烷基:羟基,(C1-C4)-烷氧基,氨基,一-(C1-C4)-烷基氨基,二-(C1-C4)-烷基氨基,羧基,(C1-C4)-烷氧基羰基和4-~7-元杂环,
其中提到的杂环包含一个或者两个选自N,O和S的环杂原子并且对它说来可以被相同的或者不同的选自以下的取代基一-或者二取代:(C1-C4)-烷基,羟基,氧代和(C1-C4)-烷氧基,
或者
R4和R5连同它们连接的氮原子形成4-~7-元杂环,其包含进一步的选自N,O和S的环杂原子并且其可以被相同的或者不同的选自以下的取代基一-或者二取代:(C1-C4)-烷基,羟基,氧代和(C1-C4)-烷氧基,
和(i)
R6代表(C6-C10)-芳基或者具有最高三个选自N,O和S的环杂原子的5-~10-元杂芳基,该基团可以在每一种情况下被相同的或者不同的选自以下的取代基一--三取代:卤素,硝基,氰基,(C1-C4)-烷基,三氟甲基,羟基,(C1-C4)-烷氧基,二氟甲氧基,三氟甲氧基,一-(C1-C4)-烷基氨基羰基,(C1-C4)-烷氧基羰基和羧基,
和
R7代表氢,氟,氯,(C1-C4)-烷基,三氟甲基,(C1-C4)-烷氧基羰基,羧基或者苯基,其中
(C1-C4)-烷基可以被羟基或者(C1-C4)-烷氧基取代
和
苯基可以被卤素,氰基,(C1-C4)-烷基或者三氟甲基取代,或者(ii)
R6代表氢或者(C1-C4)-烷基
和
R7代表苯基或者具有最高两个选自N,O和S的环杂原子的5-或者6-元杂芳基,该基团可以在每一种情况下被相同的或者不同的选自以下的取代基一-或者二取代:卤素,氰基,(C1-C4)-烷基和三氟甲基,
或者它们的盐,溶剂化物和盐的溶剂化物。
2.权利要求1的具有式(I)的化合物,其中
A代表O或者S,
R1代表氢或者甲基,
R2代表氢,甲基,羟基甲基,甲氧基甲基或者三氟甲基,
R3代表氢,氟或者甲基,
R4代表氢或者可以被相同的或者不同的选自羟基,(C1-C4)-烷氧基,氨基,一-(C1-C4)-烷基氨基,二-(C1-C4)-烷基氨基,羧基和4-~6-元杂环的取代基一-或者二取代的(C1-C4)-烷基,
其中提到的杂环包含一个或者两个选自N和O的环杂原子并且对它说来可以被相同的或者不同的选自甲基,羟基和甲氧基的取代基一-或者二取代,
R5代表氢或者甲基,
或者
R4和R5连同它们连接的氮原子形成4-~6-元杂环,其可以包含进一步的选自N和O的环杂原子并且其可以被相同的或者不同的选自以下的取代基一-或者二取代:甲基,羟基和甲氧基,
和(i)
R6代表苯基,吡啶基或者噻吩基,其可以在每一种情况下被相同的或者不同的选自以下的取代基一--三取代:氟,氯,氰基,(C1-C4)-烷基,三氟甲基,(C1-C4)-烷氧基,三氟甲氧基,一-(C1-C4)-烷基氨基羰基,(C1-C4)-烷氧基羰基和羧基,
和
R7代表氢,(C1-C4)-烷基,三氟甲基,(C1-C4)-烷氧基羰基,羧基或者可以被氟或者氯取代的苯基,
或者(ii)
R6代表氢,
和
R7代表可以被相同的或者不同的选自以下的取代基一-或者二取代的苯基:氟,氯,氰基,甲基和三氟甲基,
和它们的盐,溶剂化物和盐的溶剂化物。
3.权利要求1或者2的具有式(I)的化合物,其中
A代表O或者S,
R1代表氢或者甲基,
R2代表氢,甲基,羟基甲基或者三氟甲基,
R3代表氢或者氟,
R4代表氢或者可以被相同的或者不同的选自羟基,氨基,甲基氨基,乙基氨基,二甲基氨基和二乙基氨基的取代基一-或者二取代的(C1-C4)-烷基,
R5代表氢或者甲基,
或者
R4和R5连同它们连接的氮原子形成氮杂环丁烷子基,吡咯烷子基或者哌啶子基环,其中每个可以被羟基取代,或者形成吗啉代环,
R6代表苯基或者噻吩基,其在每一种情况下可以被相同的或者不同的选自以下的取代基一-或者二取代:氟,氯,甲基,三氟甲基,甲氧基和羧基,
和
R7代表氢,甲基,三氟甲基,甲氧基羰基或者羧基,
和它们的盐,溶剂化物和盐的溶剂化物。
4.制备在权利要求1-3任何一项中定义的具有下式(I)的化合物的方法,其特征在于具有下式(II)的化合物
其中A,R1,R2,R3,R4和R5每一个具有权利要求1-3给出的意思,
和
R8代表氢或者临时的羟基保护基
在惰性溶剂中在碱存在的情况下与具有下式(III)的化合物反应
其中R6和R7具有权利要求1-3给出的意思和
Q代表合适的离去基团,优选卤素,特别是氯,溴或者碘,或者代表甲磺酸根,甲苯磺酸根或者三氟甲磺酸根,
或者,如果A代表O,具有下式(IV)的化合物
其中R1,R2,R3,R4,R5和R8每一个具有以上给出的意思
在惰性溶剂中在碱存在的情况下与具有下式(V)的化合物反应
其中R6和R7具有在权利要求1-3中给出的意思,
然后除去任选存在的保护基并且产生的具有式(I)的化合物任选地用适当的(i)溶剂和/或(ii)碱或者酸转化成它们的溶剂化物,盐和/或盐的溶剂化物。
5.在权利要求1-3任何一项中定义的化合物,用于治疗和/或预防疾病。
6.在权利要求1-3任何一项中定义的化合物对于制备用于治疗和/或预防高血压,冠心病,急性冠状动脉综合征,心绞痛,心力衰竭,心肌梗死和心房纤颤的药物的应用。
7.在权利要求1-3任何一项中定义的化合物对于制备用于治疗和/或预防糖尿病,新陈代谢综合征和异常脂肪血症的药物的应用。
8.包含与一种或者多种惰性的、无毒的、药学合适的助剂结合的在权利要求1-3任何一项中定义的化合物的药物。
9.包含在权利要求1-3任何一项中定义的化合物的药物,该化合物与一种或者多种选自以下的进一步的活性化合物结合:改进脂类代谢的活性化合物,抗糖尿病药,抗高血压药和抗血栓药。
10.权利要求8或者9的药物,用于治疗和/或预防高血压,冠心病,急性冠状动脉综合征,心绞痛,心力衰竭,心肌梗死和心房纤颤。
11.权利要求8或者9的药物,用于治疗和/或预防糖尿病,新陈代谢综合征和异常脂肪血症。
12.使用有效量的至少一种在权利要求1-3任何一项中定义的化合物或者在权利要求8-10任何一项中定义的药物治疗和/或预防在人和动物中的高血压,冠心病,急性冠状动脉综合征,心绞痛,心力衰竭,心肌梗死和心房纤颤的方法。
13.使用有效量的至少一种在权利要求1-3任何一项中定义的化合物或者在权利要求8,9和11任何一项中定义的药物治疗和/或预防在人和动物中的糖尿病,新陈代谢综合征和异常脂肪血症的方法。
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DE102007035367A DE102007035367A1 (de) | 2007-07-27 | 2007-07-27 | Substituierte Aryloxazole und ihre Verwendung |
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EP (1) | EP2185550B1 (zh) |
JP (1) | JP5307136B2 (zh) |
KR (1) | KR20100039358A (zh) |
CN (1) | CN101939317A (zh) |
AR (1) | AR067646A1 (zh) |
AT (1) | ATE531712T1 (zh) |
CA (1) | CA2694270A1 (zh) |
CL (1) | CL2008002076A1 (zh) |
DE (1) | DE102007035367A1 (zh) |
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2007
- 2007-07-27 DE DE102007035367A patent/DE102007035367A1/de not_active Withdrawn
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- 2008-07-15 CL CL2008002076A patent/CL2008002076A1/es unknown
- 2008-07-16 PE PE2008001198A patent/PE20090904A1/es not_active Application Discontinuation
- 2008-07-16 UY UY31228A patent/UY31228A1/es not_active Application Discontinuation
- 2008-07-17 ES ES08774012T patent/ES2375506T3/es active Active
- 2008-07-17 JP JP2010518527A patent/JP5307136B2/ja not_active Expired - Fee Related
- 2008-07-17 WO PCT/EP2008/005833 patent/WO2009015776A1/de active Application Filing
- 2008-07-17 CA CA2694270A patent/CA2694270A1/en not_active Abandoned
- 2008-07-17 KR KR1020107001748A patent/KR20100039358A/ko not_active Application Discontinuation
- 2008-07-17 EP EP08774012A patent/EP2185550B1/de not_active Not-in-force
- 2008-07-17 CN CN2008801002064A patent/CN101939317A/zh active Pending
- 2008-07-17 AT AT08774012T patent/ATE531712T1/de active
- 2008-07-17 US US12/671,019 patent/US8440700B2/en not_active Expired - Fee Related
- 2008-07-22 AR ARP080103173A patent/AR067646A1/es unknown
- 2008-07-25 TW TW097128216A patent/TW200922575A/zh unknown
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---|---|---|---|---|
CN103570705A (zh) * | 2012-07-18 | 2014-02-12 | 中国医学科学院医药生物技术研究所 | 取代的n-((1',3'-杂唑-4'-基)-甲基)-4-苯甲酰基六氢吡啶类化合物及其用途 |
CN103570705B (zh) * | 2012-07-18 | 2017-01-25 | 中国医学科学院医药生物技术研究所 | 取代的n‑((1',3'‑杂唑‑4'‑基)‑甲基)‑4‑苯甲酰基六氢吡啶类化合物及其用途 |
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WO2009015776A1 (de) | 2009-02-05 |
CL2008002076A1 (es) | 2009-01-30 |
ES2375506T3 (es) | 2012-03-01 |
TW200922575A (en) | 2009-06-01 |
US9095582B2 (en) | 2015-08-04 |
ATE531712T1 (de) | 2011-11-15 |
AR067646A1 (es) | 2009-10-21 |
US20140162981A1 (en) | 2014-06-12 |
JP2010534693A (ja) | 2010-11-11 |
CA2694270A1 (en) | 2009-02-05 |
PE20090904A1 (es) | 2009-08-08 |
UY31228A1 (es) | 2009-03-02 |
EP2185550B1 (de) | 2011-11-02 |
US8440700B2 (en) | 2013-05-14 |
JP5307136B2 (ja) | 2013-10-02 |
US20110130377A1 (en) | 2011-06-02 |
KR20100039358A (ko) | 2010-04-15 |
EP2185550A1 (de) | 2010-05-19 |
DE102007035367A1 (de) | 2009-01-29 |
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