CN111433196B - 缓激肽b2受体拮抗剂及其用途 - Google Patents
缓激肽b2受体拮抗剂及其用途 Download PDFInfo
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- CN111433196B CN111433196B CN201880076162.XA CN201880076162A CN111433196B CN 111433196 B CN111433196 B CN 111433196B CN 201880076162 A CN201880076162 A CN 201880076162A CN 111433196 B CN111433196 B CN 111433196B
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- methyl
- fluoro
- chloro
- compound
- phenyl
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Abstract
本发明为关于通式(I)的化合物:
Description
技术领域
本发明涉及通式(I)的化合物,其用作缓激肽(BK)B2受体拮抗剂;含有一或多种本发明化合物的药物组合物;含有至少一种本发明化合物及至少一种其他活性药物成分的组合制剂;及该(多个)化合物的用途,包括作为药剂的用途。
背景技术
BK(bradykinin)是一种肽激素,其通过活化内皮细胞引起血管舒张、增加血管通透性、产生一氧化氮及花生油酸动员来参与发炎过程。BK也刺激感觉神经末梢,导致灼烧感障碍。因此,发炎的典型参数(例如潮红、发热、肿胀及疼痛)皆可源自BK形成。BK是一种激肽释放酶-激肽系统(kallikrein-kinin system)的短期组分。在正常生理条件下,循环BK的浓度维持在低程度,并且在病理情况下,通过称为激肽原的循环醣蛋白前体的酶降解,其浓度可能会迅速增加。两种最强效的激肽原代谢酶是胰蛋白酶样丝胺酸蛋白酶血浆激肽释放酶及组织激肽释放酶。这些酶的前体通常存在于所有组织中,并准备由生理或病理生理过程活化(Sainz,I.M.等人,Thromb.Haemost.2007,98,77-83)。BK B2受体在大多数细胞及组织类型中组成性表现,且当BK在血浆或组织中产生时,其介导BK的大多数已知效应。(Regoli,D.等人,Pharmacol.Rev.1980,32,1-46)。大量体内研究已显示,阻断BK B2受体的药剂在病理病况(如气喘、过敏性鼻炎、胰脏炎、骨关节炎、创伤性脑损伤、阿兹海默氏病(Alzheimer's disease)及血管水肿)下提供治疗益处。
现有技术中已阐述BK B2受体的许多肽及非肽拮抗剂。具有作为BK B2受体拮抗剂活性的喹啉衍生物揭示于例如WO 2014/159637、WO 2010/031589、WO 2008/116620、WO2006/40004、WO 03/103671、WO 03/87090、WO 00/23439、WO 00/50418、WO 99/64039、WO97/41104、WO 97/28153、WO 97/07115、WO 96/13485、EP 0 795 547、EP 0 796 848、EP 0867 432及EP 1 213 289中。然而,如WO 2014/159637中所揭示,这些化合物显示许多缺陷,阻碍其作为药物的效用,包括低低代谢稳定性、低生物利用度、形成麸胱甘肽加合物及生物活化(毒性)。
鉴于现有技术化合物的不足以及与BK的病理生理程度相关的严重病况,无论是急性或慢性,仍皆需要新颖BK B2受体拮抗剂。
发明内容
本发明是鉴于先前技术及上述需要而作出的,因此,本发明之一目的是提供一种通式(I)的新颖BK B2受体拮抗剂,优选具有一或多种改善性质的BK B2受体拮抗剂,例如改善的药物代谢动力学和/或物理化学性质,包括生物利用度、溶解度、代谢稳定性及LADME(释放、吸收、分布、代谢及排泄)性质。本发明的其他目的是提供一种包含至少一种如本文所述的BK B2受体拮抗剂的药物组合物;含有至少一种本发明化合物及至少一种其他活性药物成分的组合制剂;及提供一种本发明化合物的用途,包括作为药剂的用途。
这些目的由所附权利要求的主题来解决,其在参考以下描述及定义后将变得显而易见。
本发明关于:
[1]通式(I)的化合物:
或其盐,其中
A表示基团:
A1为N或CH;
A2为N或C-RA2;
A3为N或C-RA3;
A4为NH、O或S;
A5为N-RA5;
RA1表示氢原子或甲基;
RA2及RA3各自彼此独立地表示氢原子、卤素原子、OH、CN、NH2;(C1-C3)烷基,其可经一或多个相同或不同的选自以下的基团取代:卤素原子、OH、=O及NH2;(C1-C3)烷氧基,其可经一或多个相同或不同的选自以下的基团取代:卤素原子、OH、=O及NH2;(C2-C5)烷氧基烷基,其可经一或多个相同或不同的选自以下的基团取代:卤素原子、OH、=O及NH2;C(O)NRB1RB2;或NRB1RB2;
RB1、RB2及RA5各自彼此独立地表示氢原子或(C1-C3)烷基,其可经一或多个相同或不同的选自以下的基团取代:卤素原子、OH、=O及NH2;
R1表示(C1-C3)烷基或(C2-C5)烷氧基烷基,该烷基或该烷氧基烷基可经一或多个相同或不同的选自以下的基团取代:氘原子、卤素原子、OH、=O及NH2;
R2表示氢原子或氘原子;
R3表示氢原子、(C1-C3)烷基或(C1-C3)卤烷基;
E表示CRE1RE2RE3或Hce;
Hce表示具有3至10个C原子及1至4个杂原子的单环或二环、部分不饱和或芳香族杂环,该(多个)杂原子各自彼此独立地选自N、O或S,该杂环未经取代或可在每种情况下独立地经以下基团单取代、二取代或三取代:卤素原子、OH、G、NRC1RC2和/或=O;
RC1及RC2各自彼此独立地表示氢原子或(C1-C3)烷基;
G表示(C1-C6)烷基,其中1至7个H原子可在每种情况下独立地经以下基团替代:卤素原子、ORG1、CN、NRG2RG3或(C3-C6)环烷基,和/或其中一个CH2基团或两个不相邻CH2基团可经以下基团替代:O、C(O)、OC(O)、C(O)O、C(O)NH、NH、S、SO、SO2和/或CH=CH基团;
RG1、RG2及RG3各自彼此独立地表示氢原子、(C1-C4)烷基、(C1-C4)卤烷基、(C1-C4)羟烷基、(C1-C4)杂烷基或(C3-C6)环烷基;
RE1及RE2各自彼此独立地表示氢原子、卤素原子或G;或RE1及RE2一起形成=O或Cyc;
RE3表示氢原子、卤素原子、G、OG或OH;且
Cyc表示单环或二环、饱和或部分不饱和的3至10元环烷基或4至10元杂环烷基,该4至10元杂环烷基具有1至3个各自彼此独立地选自N、O或S的杂原子,该环烷基或该杂环烷基未经取代或可在每种情况下独立地经以下基团单取代、二取代、三取代或四取代:卤素原子、OH、G、NRC1RC2和/或=O。
本文通常使用标准术语或下文给出的定义来阐述化合物。对于具有不对称中心的化合物,应理解,除非另有说明,否则涵盖所有光学异构体及其混合物。具有两种或更多种不对称元素的化合物也可以非对映异构体的混合物形式存在。此外,除非另有说明,否则具有碳-碳双键的化合物可以Z及E形式存在,且化合物的所有异构形式皆包括在本发明中。当化合物以各种互变异构形式存在时,所列举化合物并不限于任何一种特定的互变异构体,而是意欲涵盖所有互变异构形式。应明了,本发明化合物可以但不一定以水合物、溶剂合物或非共价复合物的形式存在。此外,各种晶型及多晶型物以及本发明化合物的前药皆在本发明的范围内。所列举化合物进一步意欲涵盖其中一或多个原子经同位素替代的化合物,即具有相同原子数但不同质量数的原子。借助一般实例但不限制地,氢的同位素包括氚及氘,且碳的同位素包括11C、13C及14C。
具有一或多个立体中心的本文所提供的通式的化合物具有至少50%的对映异构过量。举例而言,这样的化合物可具有至少60%、70%、80%、85%、90%、95%或98%的对映异构过量。化合物的一些实施例具有至少99%的对映异构过量。应明了,单一对映异构体(光学活性形式)可由不对称合成、由光学纯前体合成或拆分外消旋物获得。外消旋物的拆分可由例如常规方法完成,例如在拆分剂存在下结晶,或使用例如手性HPLC柱进行色谱分析。
本文使用通式阐述本发明化合物,该通式包括多个变量,例如A、A1-A5、E、R1-R3、RA1-RA5、RB1-RB2、RC1-RC2、RE1-RE3及RG1-RG3。除非另有说明,否则此类式中的每个变量皆是独立于任何其他变量定义,且式中出现一次以上的任何变量皆是在每种情况下独立定义的。因此,例如,若显示基团经0-2个R*取代,则该基团可未经取代或经1或2个基团R*取代,其中R*在每种情况下独立地选自R*的相应定义。此外,仅在取代基和/或变量的组合产生稳定化合物(即可分离、表征及测试生物活性的化合物)时,取代基和/或变量的组合才是允许的。
如本文所用,定义长度范围的限值的词语(例如“1至5”)意指1至5的任何整数,即1、2、3、4及5。换言之,由明确提及的两个整数定义的任何范围意欲包含并揭示定义所述限值的任何整数及包含在该范围内的任何整数。举例而言,术语“C1-C3”是指1至3个、即1个、2个或3个碳原子;且术语“C1-C6”是指1至6个、即1个、2个、3个、4个、5个或6个碳原子。此外,如本文所用是前缀“(Cx-y)”意指作为整体的链、环或链及环结构是组合,以前缀是直接关联表示,可由最少x个和最多y个碳原子组成(即x<y),其中x及y表示界定链长度(碳原子数)和/或环大小(碳原子数)的限值的整数。
本文所揭示化合物的“药理学上可接受的盐”为酸盐或碱盐(acid or basesalt),其在业内通常视为适于与人类或动物的组织接触,而没有过度毒性或致癌性,且优选没有刺激、过敏反应或其他问题或并发症。这样的医药盐包括碱性残基(如胺)的矿物及有机酸盐以及酸性残基(如羧酸)的碱或有机盐。
适宜的药物盐包括(但不限于)诸如以下的酸的盐:盐酸、磷酸、氢溴酸、苹果酸、乙醇酸、富马酸、硫酸、胺磺酸(sulfamic)、对胺基苯磺酸(sulfanilic)、甲酸、甲苯磺酸、甲烷磺酸、苯磺酸、乙二磺酸、2-羟乙基磺酸、硝酸、苯甲酸、2-乙酰氧基苯甲酸、柠檬酸、酒石酸、乳酸、硬脂酸、柳酸、麸胺酸、抗坏血酸、巴莫酸、琥珀酸、富马酸、马来酸、丙酸、羟马来酸、氢碘酸、苯乙酸、链烷酸如乙酸、HOOC-(CH2)n-COOH,其中n是0至4的任一整数(即0、1、2、3或4)及诸如此类。类似地,药学上可接受的阳离子包括(但不限于)钠、钾、钙、铝、锂及铵。本领域技术人员将认识到本文所提供化合物的其他药理学上可接受的盐。一般而言,药理学上可接受的酸盐或碱盐可由任一常规化学方法自含有碱性部分或酸性部分的母体化合物合成。简言之,这样的盐可由使这些化合物的游离酸或游离碱形式与化学计量量的适宜的碱或酸于水中或于有机溶剂中或于两者的混合物中反应来制备。通常,优选使用非水性介质,例如醚、乙酸乙酯、乙醇、异丙醇或乙腈。
如本文所用的“取代基”是指共价键结至所关注分子内的原子的分子部分。举例而言,环上的取代基可以是诸如以下的部分:卤素原子、烷基、卤烷基、羟基、氰基或胺基或共价键结至原子,优选为环成员的碳原子或氮原子的本文所述的任何其他取代基。
如本文所用术语“经取代”意指所指定原子或基团(例如烷基、烷氧基、烷氧基烷基、环烷基、杂环烷基、杂芳基)上的任一或多个氢原子经来自所指示基团的选择替代,其条件是不超过用于取代的可能位点的指定原子的正常化合价或基团数,且取代产生稳定的化合物,即可经分离、表征和测试生物活性的化合物。当取代基为氧代(即=O)时,则该原子上的2个氢被替代。氧代是芳香族碳原子的取代基,其使-CH-转化成-C(=O)-且可引起芳香性损失。举例而言,经氧代的吡啶基为吡啶酮。指示单取代、二取代、三取代或四取代表示具有一个(单)、两个(二)、三个(三)或四个取代基的基团,其条件为取代不超过可能的取代位点数且产生稳定化合物。举例而言,单取代的咪唑基可为(咪唑烷-2-酮)基且二取代的异恶唑基可为((3,5-二甲基)异恶唑基)。
如本文所用“包含”、“包括”、“含有”、“特征在于”及其语法等效形式为包括性或开放性术语,其不排除其他未列举的要素或方法步骤。然而,“包含”等也应理解为分别包括更多限制性术语“基本上由……组成”及“由……组成”。
如本文所用“由……组成”不包括权利要求中未指明的任何要素、步骤或成分。
当在本文中使用商标名时,意欲独立地包括商标名产品调配物、仿制药及商标名产品的活性药物成分。
一般而言,除非另外定义,否则本文中使用的技术及科学术语具有与本发明所属领域的普通技术人员通常所理解相同的含义,并且与普通教科书及词典一致。
表述烷基(alkyl)或烷基(alkyl group)表示含有1至20个碳原子、优选1至12个碳原子、更优选1至6个碳原子或前缀中所指示的碳原子数的饱和、直链或分支链烃基。若烷基经取代,则取代可彼此独立地由分子的个别碳原子的单取代、二取代或三取代进行,例如1个、2个、3个、4个、5个、6个或7个氢原子可在每种情况下独立地经来自所指示取代基的选择来替代。前述内容也适用于烷基形成基团(例如卤烷基、羟烷基、烷基胺基、烷氧基或烷氧基烷基)的一部分时。烷基的实例包括甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、正己基、2,2-二甲基丁基或正辛基,且经取代的烷基或烷基形成基团的一部分的基团的实例包括卤烷基,例如三氟甲基或二氟甲基;羟烷基,例如羟甲基或2-羟乙基及甲氧基甲基。术语“(C1-6)烷基”包括例如H3C-、H3C-CH2-、H3C-CH2-CH2-、H3C-CH(CH3)-、H3C-CH2-CH2-CH2-、H3C-CH2-CH(CH3)-、H3C-CH(CH3)-CH2、H3C-C(CH3)2-、H3C-CH2-CH2-CH2-CH2-、H3C-CH2-CH2-CH(CH3)-、H3C-CH2-CH(CH3)-CH2-、H3C-CH(CH3)-CH2-CH2-、H3C-CH2-C(CH3)2-、H3C-C(CH3)2-CH2-、H3C-CH(CH3)-CH(CH3)-、H3C-CH2-CH(CH2CH3)-、-CH2CH2CH2CH2CH2CH3、-CH(CH3)CH2CH2CH2CH3、(H3CH2C)CH(CH2CH2CH3)-、-C(CH3)2(CH2CH2CH3)、-CH(CH3)CH(CH3)CH2CH3、及-CH(CH3)CH2CH(CH3)2。
表述烷氧基(alkoxy)或烷氧基(alkoxy group)是指单键结合于氧的烷基,即-O-烷基。术语“(C1-C6)烷氧基”包括例如甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、异丁氧基、叔丁氧基、正戊氧基、叔戊氧基或正己氧基,且因此(C1-C3)烷氧基包括甲氧基、乙氧基、正丙氧基、或异丙氧基。
表述烷氧基烷基(alkoxyalkyl)或烷氧基烷基(alkoxyalkyl group)是指单键结和至一或多个烷氧基的烷基,例如-烷基-O-烷基或-烷基-O-烷基-O-烷基。术语“(C2-C5)烷氧基烷基”包括例如甲氧基甲基、甲氧基乙氧基甲基及1-乙氧基乙基。
表述卤烷基(haloalkyl)或卤烷基(haloalkyl group)是指一个、两个、三个或更多个氢原子已彼此独立地经卤素原子替代的烷基。术语“(C1-C3)卤烷基”包括例如氟甲基、二氟甲基、三氟甲基、氯甲基、二氯甲基、溴甲基、二溴甲基、碘甲基、(1-或2-)卤乙基(例如(1-或2-)氟乙基或(1-或2-)氯乙基)、(2-或3-)卤丙基(例如(2-或3-)氟丙基或(2-或3-)氯丙基)。
表述羟烷基(hydroxyalkyl)或羟烷基(hydroxyalkyl group)是指一个、两个、三个或更多个氢原子已彼此独立地经羟基(OH)替代的烷基。术语“(C1-C4)羟烷基”包括例如羟甲基、羟乙基、羟丙基及羟丁基。
如本文所用表述杂烷基(heteroalkyl)或杂烷基(heteroalkyl group)是指如上文所定义的烷基、直链或分支链,其中一或多个、优选1个、2个、3个或4个碳原子已各自彼此独立地经氧、氮、硒、硅或硫原子、优选经氧、硫或氮原子、C(O)、OC(O)、C(O)O、C(O)NH、NH、SO、SO2或经CH=CH基团替代,其中该杂烷基可经取代。举例而言,“(C1-C4)杂烷基”含有1至4个、例如1个、2个、3个或4个碳原子及1个、2个、3个或4个、优选1个、2个或3个选自氧、氮及硫(尤其氧及氮)的杂原子。杂烷基的实例包括烷基胺基、二烷基胺基、烷基胺基烷基、二烷基胺基烷基、酰基、酰基烷基、烷氧基羰基、酰氧基、酰氧基烷基、羧基烷基酰胺、烷氧基羰基氧基、烷基胺甲酰基、烷基酰胺基、烷基胺甲酰基烷基、烷基酰胺基烷基、烷基胺甲酰基氧基烷基、烷基脲基烷基、烷氧基、烷氧基烷基或烷基硫基。表述烷基硫基是指一或多个不相邻CH2基团经硫替代的烷基,其中烷基硫基的烷基部分可经取代。杂烷基的具体实例包括酰基、甲氧基、三氟甲氧基、乙氧基、正丙氧基、异丙氧基、叔丁氧基、甲氧基甲基、乙氧基甲基、甲氧基乙基、甲基胺基、乙基胺基、二甲基胺基、二乙基胺基、异丙基乙基胺基、甲基胺基甲基、乙基胺基甲基、二异丙基胺基乙基、二甲基胺基甲基、二甲基胺基乙基、乙酰基、丙酰基、丁酰基氧基、乙酰基氧基、甲氧基羰基、乙氧基羰基、异丁酰基胺基-甲基、N-乙基-N-甲基胺甲酰基、N-甲基胺甲酰基、氰基、腈、异腈、硫氰酸酯、异氰酸酯、异硫氰酸酯及烷基腈。
表述环烷基(cycloalkyl)或环烷基(cycloalkyl group)是指包含一或多个环(优选1个或2个)且含有3至14个环碳原子、优选3至10个(更优选3个、4个、5个、6个或7个)环碳原子的饱和碳基团;环烷基可经取代且可经由环系统的每个适宜位置键合为取代基。环烷基的实例包括单环烃环、二环烃环及螺烃环。在二环环烷基中,两个环连结在一起,以使其具有至少两个共同碳原子。在螺烃环中,2个或3个环由一个共同原子碳原子(螺原子)连接在一起。若环烷基经取代,则取代可彼此独立地由分子的个别环碳原子的单取代或二取代进行,且环烷基作为整体可携载1个、2个、3个或4个来自所指示取代基选择的取代基,即碳环原子的1个、2个、3个或4个氢原子可在每种情况下独立地经选自所指示取代基列表的取代基替代,由此产生单取代、二取代、三取代或四取代的环烷基。环烷基的实例包括环丙基、环丁基、环戊基、环己基、环庚基、二环[2.2.0]己基、二环[3.2.0]庚基、二环[3.2.1]辛基、二环[2.2.2]辛基、二环[4.3.0]壬基(八氢茚基)、二环[4.4.0]癸基(十氢萘基)、二环[2.2.1]庚基(降莰基)、二环[4.1.0]庚基(降莰烷基)、二环[3.1.1]庚基(蒎烷基)、螺[2.5]辛基及螺[3.3]庚基。若环烷基为部分不饱和的,则该基团含有一个、两个或更多个双键,例如环烯基,包括环丙烯基、环丁烯基、环戊烯基、环己烯基、环庚烯基、环丁二烯基、环戊二烯基、环己二烯基、二环[2.2.1]庚二烯基及螺[4,5]癸烯基。
表述杂环烷基(heterocycloalkyl)或杂环烷基(heterocycloalkyl group)是指饱和或部分不饱和的环烷基,如上文所定义,其中一或多个、优选1个、2个或3个环碳原子已各自彼此独立地经氧、氮或硫原子、优选氧或氮、或经NO、SO或SO2替代;杂环烷基可经取代且可经由环系统的每个适宜位置键合为取代基;在两个氧原子之间及两个硫原子之间或氧与硫原子之间必须存在至少一个碳原子;且环作为整体必须具有化学稳定性。杂环烷基优选具有1或2个含有3至10个(更优选3个、4个、5个、6个或7个,且最佳5个、6个或7个)环原子的环。杂环烷基的实例包括氮丙啶基、环氧乙烷基、硫杂丙环基(thiiranyl)、氧吖丙啶基(oxaziridinyl)、二环氧乙烷基(dioxiranyl)、氮杂环丁基、氧杂环丁烷基、硫杂环丁基、二氮杂环丁基、二氧杂环丁烷基、二硫杂环丁基、吡咯烷基、四氢呋喃基、硫杂环戊烷基(thiolanyl)、吖唑基、噻唑基、异噻唑基、咪唑烷基、吡唑烷基、恶唑烷基、异恶唑烷基、噻唑烷基、异噻唑烷基、二氧戊环基、二硫杂环戊烷基、六氢吡嗪基、吗啉基、硫基吗啉基、三恶基(trioxanyl)、氮杂环庚基、氧杂环庚基、硫杂环庚基、高六氢吡嗪基、乌洛托品基(urotropinyl)、恶唑烷酮基、二氢吡唑基、二氢吡咯基、二氢吡嗪基、二氢吡啶基、二氢嘧啶基、二氢呋喃基、二氢哌喃基,且经取代的杂环烷基的实例包括内酰胺、内酯及环状酰亚胺环系统。
表述芳基(aryl)、Ar或芳基(aryl group)是指含有一或多个含6至14个环碳原子(C6-C14)、优选6至10个(C6-C10)、更优选6个环碳原子的芳香族环的芳香族基团;芳基可经取代且可经由环系统的每个适宜位置键合为取代基。芳基的实例包括苯基、萘基、联苯、二氢茚基、茚基、蒽基、菲基、四氢萘基及茀基。
表述杂芳基(heteroaryl)或杂芳基(heteroaryl group)是指含有一或多个含5至14个环原子、优选5至10个(更优选5个或6个)环原子的芳香族环、且含有一或多个(优选1个、2个、3个或4个)氧、氮、磷或硫环原子(优选O、S或N)的芳香族基团;杂芳基可经取代且可经由环系统的每个适宜位置键合为取代基。未经取代的杂芳基的实例包括2-吡啶基、2-咪唑基、3-苯基吡咯基、噻唑基、恶唑基、三唑基、四唑基、异恶唑基、吲唑基、吲哚基、苯并咪唑基、哒嗪基、喹啉基、嘌呤基、咔唑基、吖啶基、嘧啶基、2,3′-二呋喃基、3-吡唑基及异喹啉基。
表述杂环表示环系统,其包括上文所定义的杂环烷基及杂芳基环系统,例如部分不饱和杂环与部分不饱和杂环烷基同义且芳香族杂环与杂芳基同义。杂环可经取代且可经由环系统的每个适宜位置键合为取代基。部分不饱和或芳香族杂环的实例包括氧杂环丁烷基、thietenyl、氮杂环丁基、2,3-二氢呋喃基、2,5-二氢呋喃基、2,5-二氢噻吩基、2,5-二氢-1H-吡咯基、呋喃基、噻吩基、吡咯基、苯并[b]呋喃基、苯并[b]噻吩基、吲哚基、苯并[c]吡咯基、苯并[a]吡咯基、咪唑基、吡唑基、恶唑基、异恶唑基、噻唑基、异噻唑基、1,2,3-三唑基、1,2,4-三唑基、四唑基、二氢吡啶基、恶嗪基、吡啶基、二氢吡喃基、氮杂卓基(azepinyl)、四氢吡喃基、二氢硫基吡喃基、喹啉基、异喹啉基、喹唑啉基、哒嗪基、嘧啶基、吡嗪基、嘌呤基及喋啶基。
除非另外定义,否则如本文所用一般术语环包括上文所定义的环状基团,例如环烷基、杂环烷基、芳基、杂芳基及杂环。
如本文所用表述卤素或卤素原子意指氟、氯、溴或碘。
如本文所用表述杂原子优选表示氧、氮或硫原子,更优选氮或氧原子。
如本文所用术语“8-苄基氧基-喹啉”是指本文所提供通式(I)的化合物及其盐且优选医药上可接受的盐。应了解,这些化合物可如所指示进一步经取代。
本发明优选涉及以下中之一或多者:
[2]上文根据[1]的化合物或盐,其中A表示:
[3]根据[1]或[2]的化合物或盐,其中A表示:
[4]根据[1]至[3]中任一项的化合物或盐,其中A表示:
[5]根据[1]至[4]中任一项的化合物或盐,其中R1表示(C1-C2)烷基或(C2-C4)烷氧基烷基,该烷基或该烷氧基烷基可经一或多个相同或不同的选自以下的基团取代:氘原子、卤素原子及OH;
[6]根据[1]至[5]中任一项的化合物或盐,其中R1表示甲基、乙基、甲氧基甲基、甲氧基乙基、或乙氧基甲基,其可经一或多个相同或不同的选自以下的基团取代:氘原子、卤素原子及OH;
[7]根据[1]至[6]中任一项的化合物或盐,其中R1表示CH3、C2H5、CD3、C2D5、CH2OH、CH2F、CHF2、CF3、CH2CH2OH、CH2CH2F、CH2CF3、CH2OCH3、CH2OCHF2或CH2OCF3;
[8]根据[1]至[7]中任一项的化合物或盐,其中R1表示CH3、C2H5、CD3或CH2OH;
[9]根据[1]至[8]中任一项的化合物或盐,其中R3表示氢原子或甲基;
[10]根据[1]至[9]中任一项的化合物或盐,其中R2表示氢原子;
[11]根据[1]至[9]中任一项的化合物或盐,其中R2表示氘原子;
[12]根据[1]至[11]中任一项的化合物或盐,其中E为CRE1RE2RE3且RE1、RE2及RE3中的每一个如[1]中所定义;
[13]根据[1]至[12]中任一项的化合物或盐,其中RE1表示氢原子、氟原子、甲基或乙基;
[14]根据[1]至[13]中任一项的化合物或盐,其中RE2表示氢原子、氟原子、(C1-C6)烷基、优选(C1-C3)烷基,其中1至4个H原子可在每种情况下独立地由以下基团替代:氟原子、OH、=O或NRC1RC2;(C1-C6)烷氧基、优选(C1-C3)烷氧基,其中1至4个H原子可在每种情况下独立地由以下基团替代:氟原子、OH、=O、NRC1RC2或环丙基;或(C2-C6)烷氧基烷基、优选(C2-C5)或(C2-C4)烷氧基烷基,其中1至5个H原子可在每种情况下独立地由以下基团替代:氟原子、OH、=O、NRC1RC2或环丙基;且RC1及RC2中的每一个如[1]中所定义;
[15]根据[1]至[14]中任一项的化合物或盐,其中RE3表示氢原子、氟原子、OH、(C1-C6)烷基、优选(C1-C3)烷基,其中1至5个H原子可在每种情况下独立地由以下基团替代:氟原子、OH、=O或NRC1RC2;(C1-C6)烷氧基,其中1至5个H原子可在每种情况下独立地由以下基团替代:氟原子、OH、=O、NRC1RC2或环丙基;(C2-C6)烷氧基烷基、优选(C2-C5)或(C2-C4)烷氧基烷基,其中1至5个H原子可在每种情况下独立地由以下基团替代:氟原子、OH、=O、NRC1RC2或环丙基;且RC1及RC2中的每一个如[1]中所定义;
[16]根据[12]的化合物或盐,其中RE1及RE2一起形成=O或Cyc,其中Cyc选自环丙基、环丁基、环戊基、氧杂环丁烷基、四氢呋喃基、四氢-2H-哌喃基、1,3-二氧戊环基、吗啉基、氮杂环丁基吡咯烷基、六氢吡啶基、六氢吡嗪基、(咪唑烷-2-酮)基及(恶唑烷-2-酮)基,且未经取代或可在每种情况下独立地经以下基团单取代、二取代或三取代:卤素原子、OH、G、NRC1RC2和/或=O;
[17]根据[16]的化合物或盐,其中Cyc未经取代或可在每种情况下独立地经以下基团单取代、二取代或三取代:氟原子、OH、(C1-C3)烷基、(C1-C3)烷氧基、NRC1RC2和/或=O;且RC1及RC2中的每一个如[1]中所定义;
[18]根据[16]或[17]的化合物或盐,其中Cyc为氧杂环丁烷基、四氢呋喃基、1,3-二氧戊环基、吗啉基、氮杂环丁基、吡咯烷基、六氢吡啶基、六氢吡嗪基、(咪唑烷-2-酮)基或(恶唑烷-2-酮)基,其未经取代或可在每种情况下独立地经以下基团单取代、二取代或三取代:氟原子、OH、(C1-C3)烷基和/或(C1-C3)烷氧基;
[19]根据[16]至[18]中任一项的化合物或盐,其中RE3表示氢原子、氟原子、OH或(C1-C3)烷基;
[20]根据[1]至[11]中任一项的化合物或盐,其中E表示Hce;
[21]根据[20]的化合物或盐,其中Hce表示具有3至5个C原子及1至3个N原子;3至5个C原子、1-2个N原子及1个O原子;或3至5个C原子、1-2个N原子及1个S原子的单环、部分不饱和或芳香族杂环;该杂环未经取代或可在每种情况下独立地经以下基团单取代、二取代或三取代:卤素原子、OH、(C1-C3)烷基、(C1-C3)卤烷基、(C1-C3)烷氧基、(C1-C3)卤烷氧基和/或=O;
[22]根据[20]或[21]的化合物或盐,其中E选自:
[23]根据[1]至[15]及[20]至[22]中任一项的化合物或盐,其中E表示基团:
[24]根据[1]至[23]中任一项的化合物或盐,其中化合物选自下组群:
包括根据通式(I)的化合物或其盐的优选实施例的适宜组合(即[2]至[23])的化合物是更优选的;例如包括如本文所揭示[1]、[3]、[6]及[9]的组合的化合物或其盐。换言之,本发明特定涵盖如上文所指示[1]至[23]的所有可能组合,其产生稳定化合物。
本文所提供根据[1]至[24]中任一项的8-苄基氧基-喹啉BK B2受体拮抗剂呈现对人类BK B2受体的高活性,例如在下文所提及分析中,1微摩尔(μM)或以下、例如251纳摩尔(nM)至1μM的抑制BK诱导的BK B2受体活性的抑制常数IC50(半最大抑制浓度);优选250nM或以下、例如51nM至250nM的IC50;更优选50nM或以下的IC50;甚至更优选约10nM或以下或1nM或以下的IC50。根据[1]至[24]中任一项的8-苄基氧基-喹啉BK B2受体拮抗剂可呈现对人类BK B2受体、以及对除人类以外的物种(例如大鼠、小鼠、沙鼠、天竺鼠、兔、狗、猫、猪或食蟹猴)的BK B2受体的高活性。
本发明化合物的活性且更具体而言生物活性可使用本领域技术人员已知的适当分析、例如体外或体内分析来评价。例如,本发明化合物对B2受体活性的抑制效应(表示为IC50值)可经由细胞内钙动员分析(mobilization assay)(例如实例12中所提供的分析)来测定,因此,实例12是标准体外B2受体介导的分析的实施例。在标准体外BK B2受体分析(例如实例12中所提供的分析)中,根据[1]至[24]中任一项的优选化合物或盐呈现50nM或以下的IC50。
通式(I)化合物、其药理学上可接受的盐、溶剂合物或水合物及含有其的调配物或药物组合物的治疗用途在本发明的范围内。本发明也涉及通式(I)化合物作为活性成分的用途,其用于制备或制造药剂。
本发明的药物组合物包含至少一种式(I)化合物或其药理学上可接受的盐、优选根据[1]至[24]中任一项的化合物或其盐及可选的至少一种(即一或多种)载剂物质、赋形剂和/或佐剂。特定而言,本发明的药物组合物可包含一或多种本发明化合物(例如根据[1]至[24]中任一项的化合物)及可选的至少一种载剂物质、赋形剂和/或佐剂。药物组合物可另外包含例如以下中之一或多者:水、缓冲液(例如中性缓冲盐水或磷酸盐缓冲盐水)、乙醇、矿物油、植物油、二甲基亚砜、碳水化合物(例如葡萄糖、甘露糖、蔗糖或右旋糖)、甘露醇、蛋白质、佐剂、多肽或胺基酸(例如甘胺酸)、抗氧化剂、螯合剂(例如EDTA或麸胱甘肽)和/或防腐剂。
另外,一或多种其他活性成分可(但无需)包括在本文所提供的药物组合物中。例如,一或多种本发明化合物可有利地包含在含有至少一种其他活性药物成分的组合制剂中。其他或补充性活性剂或活性药物成分优选为用于预防或治疗一或多种响应于BKB2受体调节的病况的活性剂或活性药物成分,该(多种)病况包括选自包含以下疾病的组群的病况:皮肤病;眼病;耳病;口、喉及呼吸疾病;胃肠疾病;肝脏、胆囊及胰脏疾病;尿道及肾病;雄性生殖器及雌性生殖器疾病;激素系统疾病;代谢疾病;心血管疾病;血液疾病;淋巴疾病;中枢神经系统疾病;脑病;肌肉骨骼系统疾病;过敏病症;疼痛;传染病;发炎性病症;损伤;免疫病症;癌症;遗传病;及水肿。例如,至少一种本发明化合物或医药上可接受的盐可有利地包含在包括以下的组合制剂中:抗生素、抗真菌、或抗病毒剂、抗组胺、非类固醇抗发炎药物、疾病改质抗风湿性药物、细胞生长抑制药物、具有平滑肌活性调节活性的药物、抗体或前述作为其他或补充性活性剂或活性药物成分的混合物。
本发明的药物组合物可经调配用于任一适当给药方式,包括例如局部(例如经皮或眼部)、经口、经颊、经鼻、阴道、直肠或非经肠给药。如本文所用术语非经肠包括皮下、皮内、血管内(例如静脉内)、肌内、脊柱、颅内、鞘内、眼内、眼周、眶内、滑膜内及腹膜内注射以及任何类似注射或输注技术。在某些实施例中,优选呈适于经口使用的形式的组合物。这样的形式包括例如锭剂、口含锭、菱形锭剂、水性或油性悬浮液、可分散粉末或颗粒、乳液、硬或软胶囊或糖浆或酏剂。在其他实施例内,本文所提供的组合物可调配为冻干物。用于局部给药的调配物可优选用于某些病况(例如治疗皮肤病况,例如烧伤或癣)。简单汇总,药物组合物可例如调配为气溶胶、乳霜、凝胶、小丸、胶囊、糖浆、溶液、经皮贴片或医药递送装置。
为预防和/或治疗由BK或其类似物介导的疾病,根据本发明生物活性化合物的剂量可在宽限值内变化且可调节至个别要求。根据本发明的活性化合物通常以治疗有效量给药。优选剂量介于约0.1mg至约140mg/公斤体重/天(约0.5mg至约7g/患者/天)范围内。日剂量可以单一剂量或以复数个剂量给药。可与载剂材料组合产生单一剂型的活性成分的量将根据所治疗宿主及具体给药模式来变化。剂量单位形式通常将含有约1mg至约500mg之间的活性成分。
然而,应理解,用于任一具体患者的特定剂量值将根据多个因素而定,包括所用的具体化合物的活性、年龄、体重、一般健康状况、性别、饮食、给药时间、给药途径及排泄速率、药物组合(即用于治疗患者的其他药物)及经历疗法的特定疾病的严重程度。
本文所提供的8-苄基氧基-喹啉也可在多个应用(体外及体内二者)中用作BK B2受体的拮抗剂。本发明的BK B2受体拮抗剂可用于抑制体外或体内BK B2受体配体(例如BK)与BK B2受体的结合。此用途包括例如抑制体外或体内BK与BK B2受体结合的方法,其中该方法包含使BK B2受体与至少一种本发明化合物或盐(例如根据[1]至[39]中任一项的化合物或盐)在足以可检测地抑制BK或任何其他物质与BK B2受体的结合的条件及量下接触。本文所提供的BK B2受体拮抗剂优选经口或局部给药患者(例如人类),且在调节BK B2受体活性的同时存在于患者的至少一种体液或组织内。
本发明根据[1]至[24]中任一项的BK B2受体拮抗剂、药物组合物或组合制剂可用作为药剂。特定而言,本发明的BK B2受体拮抗剂、药物组合物或组合制剂可用于治疗和/或预防和/或防护响应于BK B2受体调节的病况或疾病。响应于BK B2受体调节的病况或疾病可为皮肤病;眼病、耳病;口、喉及呼吸疾病;胃肠疾病;肝脏、胆囊及胰脏疾病;尿道及肾病;雄性生殖器及雌性生殖器疾病;激素系统疾病;代谢疾病;心血管疾病;血液疾病;淋巴疾病;中枢神经系统疾病;脑病;肌肉骨骼系统疾病;过敏病症;疼痛;传染病;发炎性病症;损伤;免疫病症;癌症;遗传病;水肿或毛细血管渗漏症候群。在下文中,进一步说明上文所指示响应于BK B2受体调节的疾病及病况。
[皮肤病]:在本申请中,术语“皮肤病”涵盖(但不限于)诸如以下等病症:皮肤老化、皮肤风化(包括压疮)、褥疮性溃疡、刺激性、敏感性及异常感觉性皮肤、红斑、疹、皮肤水肿、牛皮癣、湿疹、苔癣、细菌、病毒、真菌及寄生虫诱发的皮肤感染(包括疖、脓疡、蜂窝织炎、丹毒、滤泡炎及脓疱症、虱、疥疮及单纯疱疹)、痤疮、皮疹、皮炎包括异位性皮炎、过敏性接触性皮炎(Scholzen,T.E.;Luger,T.A.Exp Dermatol.2004;13Suppl 4:22-6)、神经性皮炎、辐射损伤、晒伤、搔痒症、搔痒、荨麻疹(EP0622361;Frigas,E.;Park,M.Immunol.Allergy Clin.North Am.2006,26,739-51;Luquin,E.;Kaplan,A.P.;Ferrer,M.Clin.Exp.Allergy 2005,35,456-60;Kaplan,A.P.;Greaves,M.W.J.Am.Acad.Dermatol.2005,53,373-88;quiz 389-92)、牛皮癣、真菌病、组织溃疡形成、大疱性表皮松懈、伤口(包括异常伤口愈合、烧伤)(Nwariaku,F.E.;Sikes,P.J.;Lightfoot,E.;Mileski,W.J.;Baxter,C.Burns 1996,22,324-7;Neely,A.N.;Imwalle,A.R.;Holder,I.A.Burns 1996,22,520-3)、冻疮、由毒液、脱发、毛鳞片、谷物、疣及瘭疽引起的皮肤发炎及水肿。
[眼病]:在本申请中,术语“眼病”涵盖(但不限于)发炎性病症(例如巩膜炎、结膜炎、结膜水肿、虹膜炎、虹膜睫状体炎、眼色素层炎、脉络膜视网膜炎)以及诸如以下等病症:视网膜脉络膜循环病症、细菌性眼感染、非特异性结膜炎及眼刺激、早产儿视网膜病、增生性玻璃体视网膜病、黄斑变性(包括年龄相关性黄斑变性,包括湿式和干式二者)、角膜疾病(包括角膜移植排斥、角膜损伤、角膜疤痕、角膜溃疡形成、角膜混浊、圆锥角膜)、青光眼(优选开角青光眼)、近视、高眼压、眼血管损伤、血管生成、眼纤维化(例如前囊下纤维化、后囊下混浊、后囊混浊、雷射手术后角膜混浊、青光眼手术后结膜下疤痕)、增生性玻璃体视网膜病(proliferative vitreoretinopathy;PVR)、细菌眼部感染,包括麦粒肿及睫毛脱落。
[耳病]:在本申请中,术语“耳病”涵盖(但不限于)诸如以下等病症:梅尼埃病(Meniere’s disease)、中耳发炎、外耳道发炎及急性听力损失。
[口、喉及呼吸疾病]:在本申请中,术语“口、喉及呼吸疾病”涵盖(但不限于)诸如以下等病症:口腔黏膜及牙龈发炎,包括无晶状体及口腔炎、牙周炎、会厌炎、咽炎、喉气管炎、扁桃体炎、普通感冒、心绞痛、鼻炎(包括季节性过敏性鼻炎或常年过敏性鼻炎)、鼻疽、任何类型、病因或发病机制的鼻窦炎或为选自由化脓性或非化脓性鼻窦炎、急性及慢性鼻窦炎及筛窦、额窦炎、上颌窦炎或蝶窦炎组成的组群成员的鼻窦炎、咳痰、任何类型或成因的尘肺(包括例如铝中毒、炭疽病、石棉沉滞症、痱子病、铁沉着症、硅肺、烟草病,特别是鼻窦炎、支气管炎、咳嗽、气管炎、充血、肺炎、嗜酸性粒细胞肺浸润、慢性嗜酸性粒细胞肺炎、特发性肺纤维化及其他纤维化肺疾病)、治疗相关的纤维化肺疾病(例如与辐射、胺甲喋呤、化学疗法、胺碘酮或呋喃妥因(nitrofurantoin)相关)、结节病、急性呼吸窘迫症候群(acute respiratory distress syndrome;ARDS)、支气管收缩、任何类型(Akbary,A.M.;Wirth,K.J.;Scholkens,B.A.Immunopharmacology 1996,33,238-42;WO 00/75107A2)、病因学或发病机制的气喘或为选自异位性气喘、非异位性气喘、过敏性及非过敏性气喘、环境因素引起的外源性气喘、病理生理紊乱引起的内源性气喘、支气管气喘、IgE介导的气喘、原发性气喘及不明或不明原因的原发性气喘、真气喘、肺气肿性气喘、运动诱发的气喘、职业性气喘、细菌、真菌、原生动物或病毒感染引起的感染性气喘、初期气喘、喘息婴儿症候群、支气管高反应性、慢性阻塞性肺疾病(chronic obstructive pulmonary disease;COPD)、特征在于不可逆进行性气道阻塞的COPD、急性呼吸窘迫症候群(ARDS)及由于其他药物疗法导致的气道高反应性恶化、呼吸困难、高氧肺泡损伤、肺气肿、胸膜炎、肺结核、暴露于高海拔(即急性高海拔病)及优选高海拔肺水肿(HAPE)、抗咳嗽、支气管低反应性。
[胃肠疾病]:在本申请中,术语“胃肠疾病”涵盖(但不限于)包括以下的病症:食管炎、胃炎、刺激性腹部、胃及十二指肠溃疡、肠梗阻、结肠过敏、发炎性肠病(包括克罗恩病(Crohn’s disease)及溃疡性结肠炎)、肠炎、高血压性胃肠疾病、结肠炎、腹膜炎、阑尾炎、直肠炎、门静脉高压引起的胃肠出血、侧支循环或充血、胃切除术后倾倒症候群、消化不适、腹泻、痔疮、蠕虫病、腹部绞痛及胃肠系统部分绞痛。
[肝脏、胆囊及胰脏疾病(Cugno,M.;Salerno,F.;Nussberger,J.;Bottasso,B.;Lorenzano,E.;Agostoni,A.Clin.Sci.(Lond)2001,101,651-7;WO 01/56995A1;EP0797997B1;Wirth,K.J.;Bickel,M.;Hropot,M.;Gunzler,V.;Heitsch,H.;Ruppert,D.;Scholkens,B.A.Eur.J.Pharmacol.1997,337,45-53)]:在本申请中,术语“肝脏及胆囊疾病”涵盖(但不限于)诸如以下等病症:肝炎、肝硬化、肝纤维化(例如由于病毒(HBV/HCV)感染、毒素(酒精)、脂肪肝、胆汁淤积、缺氧)、门静脉高压症、肝肾症候群、肝源性水肿、胆管炎、胆囊炎、急性及慢性胰脏炎以及胆绞痛。
[尿道及肾病]:在本申请中,术语“尿道及肾病”涵盖(但不限于)尿道感染,例如急性及慢性膀胱炎、间质性膀胱炎(Campbell,D.J.Clin.Exp.Pharmacol.Physiol.2001,28,1060-5;Meini,S.;Patacchini,R.;Giuliani,S.;Lazzeri,M.;Turini,D.;Maggi,C.A.;Lecci,A.Eur.J.Pharmacol.2000,388,177-82;Zuraw,B.L.;Sugimoto,S.;Parsons,C.L.;Hugli,T.;Lotz,M.;Koziol,J.J.Urol.1994,152,874-8;Rosamilia,A.;Clements,J.A.;Dwyer,P.L.;Kende,M.;Campbell,D.J.J.Urol.1999,162,129-34)、刺激性膀胱,过度活动性膀胱(WO 2007003411 A2)、失禁(包括但不限于压力性、冲动性及反射性失禁)、良性前列腺增生(Srinivasan,D.;Kosaka,A.H.;Daniels,D.V.;Ford,A.P.;Bhattacharya,A.Eur JPharmacol.2004,504(3):155-67)、慢性肾病、尿道炎、发炎性肾病(包括肾小球肾炎、肾小球疾病、间质性肾炎、肾盂肾炎、利尿、蛋白尿、钠尿、钙化、水平衡障碍、电解质平衡障碍、酸碱平衡障碍及肾绞痛)、肾纤维化、慢性肾异种移植功能障碍、造影剂诱发的肾病。
[雄性生殖器及雌性生殖器疾病]:在本申请中,术语“雄性生殖器及雌性生殖器疾病”涵盖(但不限于)精子流动性改变、雄性不育、睪丸炎、前列腺炎、前列腺增强、乳腺炎、发炎性骨盆疾病、阴道感染及疼痛、附件炎、阴道炎、软溃疡、梅毒、淋病及卵巢过度刺激症候群(Ujioka,T.;Matsuura,K.;Tanaka,N.;Okamura,H.Hum Reprod.1998Nov;13(11):3009-15。)。
[激素系统疾病]:在本申请中,术语“激素系统疾病”涵盖(但不限于)月经紊乱及疼痛、更年期障碍、呕吐、子宫收缩过早、早产、子宫内膜异位、子宫内膜炎、肌瘤、子痫前期。
[代谢疾病]:在本申请中,术语“代谢疾病”涵盖(但不限于)诸如以下等病症:糖尿病,包括非胰岛素依赖性糖尿病、糖尿病视网膜病变、糖尿病黄斑水肿(Speicher,M.A.;Danis,R.P.;Criswell,M.;Pratt,L.Expert Opin.Emerg.Drugs 2003,8,239-50;Gao,B.B.;Clermont,A.;Rook,S.;Fonda,S.J.;Srinivasan,V.J.;Wojtkowski,M.;Fujimoto,J.G.;Avery,R.L.;Arrigg,P.G.;Bursell,S.E.;Aiello,L.P.;Feener,E.P.Nat.Med.2007,13,181-8;Tranos,P.G.;Wickremasinghe,S.S.;Stangos,N.T.;Topouzis,F.;Tsinopoulos,I.;Pavesio,C.E.Surv.Ophthalmol 2004,49,470-90)、糖尿病肾病及糖尿病神经病变、胰岛素抗性及糖尿病溃疡形成、蛋白质及嘌呤代谢疾病(如痛风及脂肪代谢紊乱)、低血糖。
[心血管疾病]:在本申请中,术语“心血管疾病”涵盖(但不限于)包括以下的病症:血管通透性、血管舒张、外周循环疾病、动脉循环病症(包括主动脉瘤、腹主动脉瘤、脑主动脉瘤、与脓毒症相关的高血压及低血压)、经皮腔内冠状动脉成形术后再狭窄、动脉粥样硬化(包括动脉粥样硬化斑块破裂)(Fernando,A.N.;Fernando,L.P.;Fukuda,Y.;Kaplan,A.P.Am J Physiol Heart Circ Physiol.2005年7月;289(1):H251-7)、血管瘤、血管纤维瘤、静脉病症如血栓形成、静脉曲张、静脉炎、血栓性静脉炎、静脉血栓形成、心脏病、充血性心力衰竭、冠心病、类癌症候群、心绞痛、心律失常、发炎性心脏病(包括心内膜炎、心包炎及缩窄性心包炎)、心肌炎、心肌梗塞、心肌梗塞后症候群、左心室扩张、缺血再灌注后损伤、休克及虚脱(包括脓毒性、过敏性、创伤后剂血液动力学休克)、羊水栓塞(Robillard,J.;Gauvin,F.;Molinaro,G.;Leduc,L.;Adam,A.;Rivard,G.E.Am J ObstetGynecol.2005Oct;193(4):1508-12。)、全身性发炎性反应症候群(SIRS,包括手术期间由心肺旁路引起的SIRS、脓毒血症以及心肺旁路手术期间的内部和外部并发症(包括但不限于鱼精蛋白硫酸酯逆转肝素后的不良血液动力学效应(Pretorius,M.;Scholl,F.G.;McFarlane,J.A.;Murphey,L.J.;Brown,N.J..Clin Pharmacol Ther.2005Nov;78(5):477-85)。
[血液疾病]:在本申请中,术语“血液疾病”涵盖(但不限于)诸如以下等病症:凝血、弥漫性血管内凝血病、出血、出血素质、高胆固醇血症及高脂血症、低血容量性休克、阵发性夜间血红蛋白尿。
[淋巴疾病]:在本申请中,如本文所用术语“淋巴疾病”涵盖(但不限于)脾肿大、淋巴管炎、淋巴结炎及增生性腺样体。
[中枢神经系统病症]:在本申请中,术语“中枢神经系统病症”涵盖(但不限于)诸如以下等病症:中枢神经系统的发炎性疾病,包括脑炎、脑膜炎、脑脊髓炎、脑膜脑炎、脑积水、肌萎缩性侧索硬化、脊髓创伤、脊髓水肿、神经系统脱髓鞘疾病、多发性硬化、急性及慢性神经变性病症(包括老化、阿兹海默氏病及帕金森氏病(Parkinson’s disease))、神经炎及周围神经病、抑郁症、厌食症、焦虑及精神分裂症、睡眠障碍。
[脑病]:在本申请中,术语“脑病”涵盖(但不限于)包括以下的病症:益智或认知增强、脑淀粉样血管病、中风、头部及脑部创伤、创伤性脑损伤(Marmarou,A.;Guy,M.;Murphey,L.;Roy,F.;Layani,L.;Combal,J.P.;Marquer,C.;American Brain InjuryConsortium J Neurotrauma 2005年12月;22(12):1444-55)、脑肿瘤、脑热损伤、脑缺血、脑出血、创伤后及缺血后脑水肿、一般脑水肿、急性高山病及优选高海拔脑水肿(highaltitude cerebral edema;HACE)、细胞毒性脑水肿、血管源性脑水肿、手术后脑水肿、与代谢疾病相关的脑水肿、血脑障壁或血脑肿瘤障壁通透性增加。
[肌肉骨骼系统疾病]:在本申请中,术语“肌肉骨骼系统疾病”涵盖(但不限于)诸如以下等病症:发炎性肌肉骨骼病症、关节病、骨关节病、骨关节炎、关节创伤后软骨疏松症或半月板或髌骨损伤或韧带撕裂后关节相对较长时间的固定、任何类型、病因或发病机制的类风湿性关节炎(包括急性关节炎、急性痛风性关节炎、慢性发炎性关节炎、退行性关节炎、传染性关节炎、莱姆病关节炎(Lyme arthritis)、增生性关节炎、脊椎关节炎、脓毒性关节炎、银屑病关节炎、慢性多发性关节炎)、风湿病、休格伦氏症候群(Sjogren’ssyndrome)、腰痛、脊椎炎、脊椎关节炎、强直性脊椎炎、骨髓炎、扭伤、腱鞘炎、发炎诱发的骨吸收、骨折或诸如此类、骨质疏松症、肌肉骨骼疼痛及硬化、脊椎盘症候群。
[过敏病症]:在本申请中,术语“过敏病症”涵盖(但不限于)诸如以下等病症:一般过敏反应、食物过敏、过敏性休克、过敏性接触超敏症、过敏性皮肤反应、过敏性气喘、春季结膜炎及季节性或常年性过敏性鼻炎(Summers,C.W.;Pumphrey,R.S.;Woods,C.N.;McDowell,G.;Pemberton,P.W.;Arkwright,P.D.J Allergy Clin Immunol.2008,121(3),632-638)。
[疼痛]:在本申请中,术语“疼痛”涵盖(但不限于)中枢及外周介导的疼痛、血管疼痛、内脏疼痛、发炎介导的疼痛、神经性疼痛、牵涉痛、伤害感受性疼痛、反射性疼痛、心身疼痛、急性疼痛(例如由骨骼、肌肉、组织、软组织、器官的急性损伤、创伤或手术引起)、昆虫叮咬后疼痛、中风后疼痛症候群、手术后疼痛、进行性疾病相关疼痛、慢性疼痛(例如由神经性疼痛病况引起)(WO00/75107A2;Yamaguchi-Sase,S.;Hayashi,I.;Okamoto,H.;Nara,Y.;Matsuzaki,S.;Hoka,S.;Majima,M.Inflamm.Res.2003,52,164-9;Petersen,M.;Eckert,A.S.;Segond von Banchet,G.;Heppelmann,B.;Klusch,A.;Kniffki,K.D.Neuroscience1998,83,949-59;Birklein,F.;Schmelz,M.;Schifter,S.;Weber,M.Neurology 2001,57,2179-84;Weber,M.;Birklein,F.;Neundorfer,B.;Schmelz,M.Pain 2001,91,251-7)、灼痛、萎缩症(morbus sudeck)、反射性交感神经营养不良)、糖尿病周围神经病变、带状疱疹后神经痛、三叉神经痛、癌症相关疼痛、与类风湿性关节炎相关的疼痛、骨关节炎(Bond,A.P.;Lemon,M.;Dieppe,P.A.;Bhoola,K.D.Immunopharmacology 1997,36,209-16;Cassim,B.;Naidoo,S.;Ramsaroop,R.;Bhoola,K.D.Immunopharmacology 1997,36,121-5;Calixto,J.B.;Cabrini,D.A.;Ferreira,J.;Campos,M.M.Pain 2000,87,1-5;Kaneyama,K.;Segami,N.;Sato,J.;Fujimura,K.;Nagao,T.;Yoshimura,H.J.Oral.Maxillofac.Surg.2007,65,242-7)、腱鞘炎、痛风、月经及心绞痛、纤维肌痛、眼痛、背痛、头痛、丛集性头痛、偏头痛(Ebersberger,A.;Ringkamp,M.;Reeh,P.W.;Handwerker,H.O.J Neurophysiol.1997年6月;77(6):3122-33。)、可能与急性发炎或慢性发炎相关的发炎性疼痛。发炎性疼痛包括(但不限于)神经性疼痛、缺血性疼痛、由关节炎引起的疼痛、由急性或慢性发炎引起的肌肉疼痛、由急性或慢性发炎引起的神经痛、痛觉过敏。以及化学疗法诱发的周围神经病变、痛觉过敏、类鸦片物质诱发的痛觉过敏及发热。此外,本发明化合物可用作全身麻醉及监测麻醉期间使用的镇痛剂。
[传染病]:在本申请中,术语“传染病”涵盖(但不限于)包括由细菌、病毒、真菌、寄生虫、原生动物、朊蛋白(prions)或分枝杆菌感染介导的疾病的疾病。特别地,本发明可用于治疗由链球菌(Streptococcus)、埃希氏菌(Escherichia)、沙门氏菌(Salmonella)、葡萄球菌(Staphylococcus)、克雷伯氏菌(Klebsiella)、莫拉赛尔菌(Moracella)、嗜血杆菌(Haemophilus)和耶尔森氏菌(Yersinia)引起的细菌感染。意欲在本发明范围内的细菌感染的实例包括(但不限于)诸如以下等疾病:鼠疫、败血症、流行性斑疹伤寒、食物中毒、破伤风、猩红热、百日咳、白喉。意欲在本发明范围内的病毒感染的实例包括(但不限于)诸如以下等疾病:水痘及带状疱疹、AIDS、流感、天花及儿童疾病,如麻疹、风疹、腮腺炎、急性脊髓灰质炎。本发明可用于治疗由曼氏血吸虫(Schistosoma mansoni)、美洲室尘螨(Dermatophagoides farinae)及疟原虫((Plasmodium)包含疟疾)引起的原生动物及寄生虫感染。意欲在本发明范围内的朊蛋白感染的实例包括(但不限于)诸如以下等疾病:牛海绵状脑病(BSE)、库贾氏病(Creutzfeldt Jakob disease)及库鲁病(kuru)、登革热(denguefever)、出血热。
[发炎性病症]:在本申请中,术语“发炎性病症”涵盖(但不限于)诸如以下等病症:急性期反应、局部及全身发炎以及由任何类型、病因或发病机制的其他疾病引起的发炎以及由本申请中指定的那些发炎性疾病引起的发炎。
[损伤]:在本申请中,术语“损伤”涵盖(但不限于)多重创伤、头创伤、肺创伤、外部、内部及手术伤口。
[免疫病症]:在本申请中,术语“免疫病症”涵盖(但不限于)诸如以下等病症:超敏症、自体免疫病症、移植中的移植物排斥、移植毒性、肉芽肿性发炎/组织重塑、重症肌无力、免疫抑制、免疫复合物疾病、抗体产生过多及过少、血管炎、移植物功能延迟、狼疮。
[癌症]:在本申请中,术语“癌症”涵盖(但不限于)诸如以下等病症:实体肿瘤癌症包括乳癌、肺癌(非小细胞肺癌及小细胞肺癌)、前列腺癌、口腔及咽(唇、舌、口、咽)癌、食管癌、胃癌、小肠癌、大肠癌、结肠癌、直肠癌、胆囊和胆管癌、胰脏癌、喉癌、肺癌、骨癌、骨肉瘤、结缔组织癌、皮肤癌包括卡波西氏症候群(Kaposi’s syndrome)、黑素瘤及皮肤转移、表皮样癌、基底细胞癌、子宫颈癌、子宫内膜癌、卵巢癌、睪丸癌、膀胱癌、输尿管和尿道癌、肾癌、眼癌、脑及中枢神经癌、假性脑肿瘤、肉瘤、肉状瘤、甲状腺癌及其他内分泌腺体癌(包括但不限于类癌)、霍奇金氏病、非霍奇金氏淋巴瘤、多发性骨髓瘤、血液恶性肿瘤(包括白血病及淋巴瘤,包括淋巴细胞、粒细胞和单核细胞淋巴瘤)、肿瘤侵袭、转移、腹水、肿瘤生长及血管生成。
[遗传病]:在本申请中,术语“遗传病”涵盖(但不限于)诸如以下等病症:遗传性血管性水肿(Davis,A.E.等人,3rd Transfus.Apher.Sci.2003,29,195-203;Zuraw,B.L.Immunol.Allergy Clin.North Am.2006,26,691-708;Bas,M.等人,Allergy 2006,61,1490-2)及血管神经性水肿、软骨钙化症、亨庭顿氏病(Huntington’s disease)、黏滞症。
[水肿]:在本申请中,术语“水肿”涵盖(但不限于)发炎引起的一般水肿及水肿、因子XII缺乏引起的水肿、其他药物(例如药物)引起的血管水肿(包括但不限于血管紧张素转化酶抑制剂引起的血管水肿)(Mathelier-Fusade,P.Clin.Rev.Allergy Immunol.2006,30,19-23;Finley,C.J.et al.Am.J.Emerg.Med.1992,10,550-2;Bielory,L.等人,AllergyProc.1992,13,85-7)、感染、烧伤、损伤、创伤、冻疮、手术、扭曲、骨折、暴露于高海拔(例如高海拔肺水肿(high altitude pulmonary edema;HAPE)及高海拔脑水肿(HACE)),遗传性、自体免疫及其他疾病及病症,特别是(但不限于)本申请案中指定的那些病症、应激引起的肠道水肿(明显肿胀)。
[毛细血管渗漏症候群]:在本申请中,术语“毛细血管渗漏症候群”涵盖(但不限于)脓毒症中全身毛细血管渗漏症候群(Marx,G.Eur J Anaesthesiol.2003 20(6):429-42;Traber,D.L.Crit Care Med.2000,28(3):882-3)、晒伤(Jonkam,C.C.;Enkhbaatar,P.;Nakano,Y.;Boehm,T.;Wang,J.;Nussberger,J.Esechie,A.;Traber,L.D.;Herndon,D.;Traber,D.L..Shock.2007年12月;28(6):704-9)、过敏、药物/毒素诱发的病况、器官移植及IL-2细胞介素疗法。
本发明的化合物也可用作或用于制造诊断剂。该诊断剂尤其可用于诊断本文所揭示的疾病及病况,出于治疗及或防护目的,这些疾病及病况可由本发明的化合物来解决。本发明的化合物也用于如下文所揭示的特定方法及诊断中。
[方法及诊断]:本发明的化合物可由同位素、荧光或发光标记物、抗体或抗体片段、任何其他亲和标记如纳米抗体、适配体、肽等、酶或酶受质来标记。这些经标记的本发明化合物可用于映射缓激肽受体在体内、离体、体外及原位(例如通过放射自显影术在组织切片中)的位置,并用作正电子发射断层摄影(positron emission tomography;PET)成像、单光子发射计算机化断层摄影(single photon emission computerized tomography;SPECT)及诸如此类放射示踪剂,以表征活体或其他材料中的那些受体。
本发明也涉及在体外及体内改变缓激肽受体信号转导活性的方法。例如,本发明的化合物及其经标记衍生物可用作测定潜在药物结合至BK B2受体的能力的标准品及试剂。
本发明也提供定位或检测组织、优选组织切片中的BK B2受体的方法,该方法涉及在允许化合物与BK B2受体结合的条件下,使含有BK B2受体的组织样品与本发明的可检测标记化合物接触,并检测结合的化合物。这样的方法及其各自条件对本领域技术人员来说是已知的,且包括例如实例12中所揭示的结合分析。
本发明进一步提供治疗患有响应于上述BK B2受体调节的病况或疾病的患者的方法。用于治疗需要该治疗的个体的方法包含给予本发明(例如根据[1]至[24]中的任一项)的化合物、其药学上可接受的盐、如本文所揭示的药物组合物或如本文所揭示的组合制剂。如本文所用,术语“治疗”涵盖疾病改质治疗及症状治疗,两者皆可为防护性的(即,在症状出现之前,以预防、延迟或减轻症状的严重程度)或治疗性的(即,在症状出现之后,以减轻症状的严重程度和/或持续时间)。若BK B2受体活性的调节使得病况或其症状缓解,则病况“响应于BK B2受体调节”。患者可包括(但不限于)灵长类动物(尤其人类)、驯养伴侣动物(如狗、猫、马)及家畜(如牛、猪、绵羊),剂量如本文所述。
与技术现况中已知的BK B2受体拮抗剂相比,根据本发明的通式(I)化合物具有改善的性质,尤其一或多种改善的药代动力学和/或物理化学性质,包括例如生物利用度、代谢稳定性、改善的活性/选择性、低毒性及低药物药物相互作用。因此,本文所揭示的化合物(或其药学上可接受的盐)、药物组合物或组合制剂可用作药剂。例如,本文所揭示的化合物(或其医药上可接受的盐)、药物组合物或组合制剂可用于治疗和/或预防响应于BK B2受体调节的病况,包括例如上文所列示的病况。
现通过以下实例进一步说明本发明,从中可获得本发明的其他特征、实施例及优点。然而,本发明不应解释为限于这些实例,而是涵盖权利要求中所定义的主题。
具体实施方式
实例
用于以下实例中的缩写如下:
ACN为乙腈
BuLi为正丁基锂
conc.为浓缩
DCM为二氯甲烷
DIPEA为乙基-二异丙基-胺
DMF为二甲基甲酰胺
EA为乙酸乙酯
HPLC为高效液相色谱
MeOH为甲醇
NBS为N-溴带琥珀酰亚胺
NMP为N-甲基吡咯烷酮
PyAOP为7-氮杂苯并三唑-1-基氧基)三吡咯烷基鏻六氟磷酸盐
PyBOP为(苯并三唑-1-基氧基)三吡咯烷基鏻六氟磷酸盐
RT为室温
THF为四氢呋喃
TLC为薄层色谱
TFA为三氟乙酸
sat.为饱和
以下实例提供制备式(I)化合物的具体实例。除非另有说明,否则所有起始原料及试剂皆为标准商业级的,且无需进一步纯化即可使用,或可容易地通过常规方法由这样的原料来制备。有机合成领域的技术人员将认识到,起始材料及反应条件可发生变化,包括用于生产本发明所涵盖的化合物的其他步骤。
实例1:化合物编号1的制备
(R)-N-((S)-1-(3-氯-5-氟-2-((4-(4-氟-1H-吡唑-1-基)-2-甲基喹啉-8-基氧基)甲基)苯基)乙基)-2-羟丙酰胺
[步骤A.]3-胺基-5-氟-2-甲基苯甲酸甲酯的合成
将5-氟-2-甲基-3-硝基苯甲酸甲酯[Gillmore,A.T.等人,Org.ProcessRes.Dev.2012,16,1897-1904](4.69g,22mmol)溶解于MeOH(100mL)中且添加活性炭载钯-10% Pd(200mg)。用氮将溶液吹扫且抽真空三次,然后将其用氢吹扫。在1atm氢下剧烈搅拌反应混合物。如通过TLC所指示完成反应后(21h),经由硅胶过滤溶液。用甲醇(5×20mL)洗涤滤饼。在减压下浓缩滤液且通过快速色谱纯化残余物以产生标题化合物。MS(m/z):184.0[M+H+]。
[步骤B.]3-氯-5-氟-2-甲基苯甲酸甲酯的合成
在0℃下将NaNO2(1.68g,24.4mmol)添加至3-胺基-5-氟-2-甲基苯甲酸甲酯(4.00g,18.8mmol)在半浓缩HCl水溶液(400mL)中的溶液。在0℃下搅拌5min后,将CuCl(3.72g,37.5mmol)添加至反应混合物。在0℃下搅拌2h后,用DCM(2×100mL)萃取反应混合物。用浓NaHCO3水溶液(1×)洗涤合并的有机层,经Na2SO4干燥,过滤,并在真空中浓缩。通过硅胶快速色谱(flash chromatography on silica gel)(用DCM/庚烷洗脱)纯化残余物以获得标题化合物。
[步骤C.]2-(溴甲基)-3-氯-5-氟苯甲酸甲酯的合成
将过氧化苯甲酰(26mg,0.11mmol)及N-溴带琥珀酰亚胺(210mg,1.18mmol)添加至3-氯-5-氟-2-甲基苯甲酸甲酯(200mg,0.99mmol)在苯(7.0mL)中的搅拌后的溶液。在回流下搅拌1.5h后,用EA(20mL)稀释反应混合物且用10% Na2S2O3水溶液(1×5mL)洗涤。经Na2SO4干燥有机层,过滤,并在真空中浓缩以获得标题化合物。
[步骤D.]3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯甲酸甲酯的合成
将Cs2CO3(617mg,3.20mmol)添加至2-(溴甲基)-3-氯-5-氟苯甲酸酯(300mg,1.07mmol)及4-甲氧基酚(172mg,1.39mmol)在ACN(7.0mL)中的搅拌后的溶液。在室温下搅拌过夜后,将反应混合物过滤并在真空中浓缩。通过硅胶快速色谱(用EA/庚烷洗脱)纯化残余物以获得标题化合物。MS(m/z):342.1[M+NH4 +]。
[步骤E.]3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯甲酸的合成
在0℃下将LiOH(2.37g,57mmol)在水(50mL)中的溶液添加至3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯甲酸甲酯(9.16g,28mmol)在二恶烷(100mL)中的搅拌后的溶液。在室温下搅拌2h后,在真空中浓缩反应混合物且通过添加浓HCl水溶液将pH值调节至1-2。用DCM(3×100mL))萃取混合物,通过Na2SO4干燥合并的有机层,过滤,并在真空中浓缩以获得标题化合物。
[步骤F.]1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙酮的合成
在0℃下将甲基锂(1.6M,30.2mL)在二乙基醚中的溶液逐滴添加至3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯甲酸(5.00g,16mmol)在无水二乙基醚(110mL)中的溶液。在0℃下搅拌30min后,在0℃下通过添加饱和NH4Cl水溶液(15mL)淬灭反应。用水(15mL)稀释反应混合物,分离有机层并用二乙基醚(3×50mL)萃取水层。通过Na2SO4干燥合并的有机层,过滤,并在真空中浓缩。通过硅胶快速色谱(用EA/庚烷洗脱)纯化残余物以获得标题化合物。
[步骤G.](R)-N-((S)-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙基)-2-甲基丙烷-2-亚磺酰胺()的合成
将乙醇钛(IV)(2.53mL,12.05mmol)在氩气氛下逐滴添加至1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙酮(1.24g,4.02mmol)及(R)-(+)-2-甲基-2-丙烷亚磺酰胺(535.5mg,4.42mmol)在无水THF(10mL)中的溶液。在回流下加热混合物直至完全转化(TLC)。随后,将混合物冷却至0℃并逐滴添加三异丁基硼氢化锂(L-Selectride)(1M溶液,12.05mL,12.05mmol)。在此温度下搅拌混合物直至完全转化(TLC)。随后,添加甲醇(约10mL)直至气体停止逸出。将溶液倾倒至饱和NaCl水溶液(30mL)中。然后,经由硅藻土垫过滤混合物且用DCM小心地冲洗。用饱和NaCl水溶液洗涤滤液。用DCM萃取水层。通过Na2SO4干燥合并的有机层,过滤,且蒸发至干燥。通过硅胶快速色谱(用EA/庚烷洗脱)纯化剩余残余物以获得标题化合物。MS(m/z):458.2[M+HCO2 -]。
[步骤H.](S)-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙胺的合成
在室温下搅拌(R)-N-((S)-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙基)-2-甲基丙烷-2-亚磺酰胺(2.19g,5.29mmol)在3M甲醇HCl(3.53mL,10.6mmol)中的溶液直至完全转化(TLC)。在真空中浓缩溶液。将剩余残余物溶解于DCM(5mL)中且用饱和NaHCO3水溶液(6mL)及水(6mL)洗涤。经Na2SO4干燥有机层,过滤并在真空中浓缩以获得标题化合物。MS(m/z):354.4[M+HCO2 -]。
[步骤I.](S)-2-(1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙基)异吲哚啉-1,3-二酮的合成
将邻苯二甲酸酐(862mg,5.82mmol)添加至(S)-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙胺(1.64g,5.26mmol)在DCM(20mL)中的溶液。将混合物搅拌15min且然后在真空中浓缩。将剩余残余物在约10min内在开放式器皿中加热至175℃。在此温度下保持45min后,将反应混合物冷却至室温且通过硅胶快速色谱(用庚烷/EA洗脱)纯化以获得标题化合物。MS(m/z):484.3[M+HCO2 -]。
[步骤J.](S)-2-(1-(3-氯-5-氟-2-(羟甲基)苯基)乙基)异吲哚啉-1,3-二酮的合成
在0℃下将硝酸铵铈(IV)(3.36g,6.12mmol)在H2O(4mL)中的溶液添加至(S)-2-(1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙基)异吲哚啉-1,3-二酮(1.07g,2.45mmol)在ACN(20mL)中的搅拌后的溶液。在0℃下搅拌5h后,通过添加盐水(20mL)及H2O(5mL)淬灭反应。用EA(3×100mL)萃取混合物,通过Na2SO4干燥合并的有机层,过滤,并在真空中浓缩。通过硅胶快速色谱(用EA/庚烷洗脱)纯化残余物以获得标题化合物。
[步骤K.](S)-2-(1-(3-氯-2-(氯甲基)-5-氟苯基)乙基)异吲哚啉-1,3-二酮的合成
在室温下将SOCl2(288μL,3.96mmol)及水(4μL)添加至(S)-2-(1-(3-氯-5-氟-2-(羟甲基)苯基)乙基)异吲哚啉-1,3-二酮(662mg,1.98mmol)于DCM(10mL)中的搅拌后的溶液。搅拌后的溶液直至完全转化(TLC)。然后,在真空中移除溶剂且通过硅胶快速色谱(用EA/庚烷洗脱)纯化残余物以获得标题化合物。MS(m/z):396.1[M+HCO2 -]。
[步骤L.](S)-2-(1-(3-氯-5-氟-2-((4-(4-氟-1H-吡唑-1-基)-2-甲基喹啉-8-基氧基)甲基)苯基)乙基)异吲哚啉-1,3-二酮的合成
将Cs2CO3(1.94g,5.95mmol)添加至(S)-2-(1-(3-氯-2-(氯甲基)-5-氟苯基)乙基)异吲哚啉-1,3-二酮(698mg,1.98mmol)及4-(4-氟-1H-吡唑-1-基)-2-甲基喹啉-8-醇(482mg,1.98mmol)在ACN(20mL)中的搅拌后的溶液。在室温下搅拌过夜后,将反应混合物过滤并在真空中浓缩。通过硅胶快速色谱(用EA/庚烷洗脱)纯化残余物以获得标题化合物。MS(m/z):559.3[M+H+]。
[步骤M.](S)-1-(3-氯-5-氟-2-((4-(4-氟-1H-吡唑-1-基)-2-甲基喹啉-8-基氧基)甲基)苯基)乙胺的合成
将肼水合物(371μL)添加至(S)-2-(1-(3-氯-5-氟-2-((4-(4-氟-1H-吡唑-1-基)-2-甲基喹啉-8-基氧基)甲基)苯基)乙基)异吲哚啉-1,3-二酮(1.07g,1.91mmol)在EtOH(30mL)中的溶液。在85℃下搅拌2h后,将反应混合物冷却至室温并过滤。在真空中浓缩滤液且通过快速色谱(用DCM/MeOH/浓NH3水洗脱)纯化残余物以产生标题化合物。MS(m/z):429.4[M+H+]。
[步骤N.](R)-N-((S)-1-(3-氯-5-氟-2-((4-(4-氟-1H-吡唑-1-基)-2-甲基喹啉-8-基氧基)甲基)苯基)乙基)-2-羟丙酰胺的合成
随后在0℃下将PyAOP(90.7mg,174μmol)及DIPEA(29.4mg,227μmol)添加至(S)-1-(3-氯-5-氟-2-((4-(4-氟-1H-吡唑-1-基)-2-甲基喹啉-8-基氧基)甲基)苯基)乙胺(55.1mg,137μmol)及(R)-2-羟丙酸(13.9mg,154μmol)在DMF(4.5mL)中的搅拌后的溶液。在室温下搅拌2h后,在真空中浓缩反应混合物。通过反相HPLC纯化剩余残余物,提供标题化合物。MS(m/z):501.2[M+H+]。
[步骤O.]4-(4-氟-1H-吡唑-1-基)-8-甲氧基-2-甲基喹啉的合成
将K2CO3(4.99g,36.1mmol)添加至4-氯-8-甲氧基-2-甲基喹啉(5.00g,24.0mmol)及4-氟-1H-吡唑(3.85g,28.8mmol)在无水NMP(12mL)中的搅拌后的混合物中。在140℃下搅拌48h后,将反应混合物冷却至室温并过滤。用DMF(13mL)冲洗残余物。然后将水(90mL)添加至合并的滤液。过滤掉沉淀物且通过硅胶快速色谱(用DCM/甲醇洗脱)纯化以获得标题化合物。MS(m/z):258.0[M+H+]。
[步骤P.]4-(4-氟-1H-吡唑-1-基)-2-甲基喹啉-8-醇的合成
将4-(4-氟-1H-吡唑-1-基)-8-甲氧基-2-甲基喹啉(5.51g,21.4mmol)在无水甲苯(37.8mL)中的溶液加热至80℃且逐滴添加至AlCl3(8.58g,64.3mmol)在无水甲苯(32.4mL)中的剧烈搅拌后的混合物中。在80℃下搅拌8h后,将反应混合物冷却至0℃且通过添加水(106mL)及浓氨(conc.NH3)水(27mL)淬灭。在室温下搅拌过夜后,将混合物离心。用EA(3×200mL)萃取上清液且经Na2SO4干燥合并的有机层,过滤,并在真空中浓缩。通过硅胶快速色谱(用DCM/甲醇洗脱)纯化残余物以获得标题化合物。
实例2:化合物编号2的制备
(S)-N-((S)-1-(3-氯-5-氟-2-((4-(4-氟-1H-吡唑-1-基)-2-甲基喹啉-8-基氧基)甲基)苯基)乙基)-2-羟基-N-甲基丙酰胺
[步骤A.](2S)-N-((S)-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙基)-2-(四氢-2H-哌喃-2-基氧基)丙酰胺的合成
使(S)-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙胺(100mg,323μmol)与(2S)-2-(四氢-2H-哌喃-2-基氧基)丙酸[Garner P.等人,J.Org.Chem.(2002),67(17),6195-6209](84.3mg,484μmol)根据N-(1-(3-氯-5-氟-2-((4-(4-氟-1H-吡唑-1-基)-2-甲基喹啉-8-基氧基)甲基)苯基)乙基)-3-羟基-2-甲基丙酰胺的合成来反应通过硅胶快速色谱(用EA/庚烷洗脱)纯化粗产物以获得标题化合物。MS(m/z):488.5[M+Na]。
[步骤B.](2S)-N-((S)-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙基)-N-甲基-2-(四氢-2H-哌喃-2-基氧基)丙酰胺的合成
将(2S)-N-((S)-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙基)-2-(四氢-2H-哌喃-2-基氧基)丙酰胺(50mg,107μmol)溶解于无水DMF(约5ml/mmol)中。在氩气氛下,添加氢化钠[60%于石蜡中](4.7mg,118μmol)且将混合物搅拌20min。然后,添加碘甲烷(33.3μl,535μmol)并继续搅拌直至完全转化(TLC)。添加水且用EA萃取几次。经Na2SO4干燥合并的有机层,过滤并在减压下蒸发至干燥。通过硅胶快速色谱(用EA/庚烷洗脱)纯化粗产物以获得标题化合物。MS(m/z):502.3[M+Na]。
[步骤C.](S)-N-((S)-1-(3-氯-5-氟-2-(羟甲基)苯基)乙基)-2-羟基-N-甲基丙酰胺的合成
使(2S)-N-((S)-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙基)-N-甲基-2-(四氢-2H-哌喃-2-基氧基)丙酰胺(41.0mg,85μmol)与硝酸铵铈(IV)(117.1mg,214μmol)根据(S)-2-(1-(3-氯-5-氟-2-(羟甲基)苯基)乙基)异吲哚啉-1,3-二酮的合成来反应。将粗产物溶解于甲醇中,添加3M甲醇HCl溶液且继续在室温下搅拌直至完全反应(TLC)。在减压下蒸发,获得标题化合物。MS(m/z):312.4[M+Na]。
[步骤D.](S)-N-((S)-1-(3-氯-2-(氯甲基)-5-氟苯基)乙基)-2-羟基-N-甲基丙酰胺的合成
使(S)-N-((S)-1-(3-氯-5-氟-2-(羟甲基)苯基)乙基)-2-羟基-N-甲基丙酰胺(13.70mg,47μmol)与SOCl2(6.82μl,11.18mg,156μmol)根据(S)-2-(1-(3-氯-2-(氯甲基)-5-氟苯基)乙基)异吲哚啉-1,3-二酮的合成来反应以获得标题化合物。MS(m/z):330.4[M+Na]。
[步骤E.](S)-N-((S)-1-(3-氯-5-氟-2-((4-(4-氟-1H-吡唑-1-基)-2-甲基喹啉-8-基氧基)甲基)苯基)乙基)-2-羟基-N-甲基丙酰胺的合成
使(S)-N-((S)-1-(3-氯-2-(氯甲基)-5-氟苯基)乙基)-2-羟基-N-甲基丙酰胺(14.6mg,47μmol)与4-(4-氟-1H-吡唑-1-基)-2-甲基喹啉-8-醇(12mg,47μmol)根据(S)-2-(1-(3-氯-5-氟-2-((4-(4-氟-1H-吡唑-1-基)-2-甲基喹啉-8-基氧基)甲基)苯基)乙基)异吲哚啉-1,3-二酮的合成来反应以获得标题化合物。MS(m/z):515.5[M+H+]。
实例3:化合物编号3的制备
(R)-3-胺基-N-((S)-1-(3-氯-5-氟-2-((4-(4-氟-1H-吡唑-1-基)-2-甲基喹啉-8-基氧基)甲基)苯基)乙基)-2-羟丙酰胺
[步骤A.](R)-3-(叔丁氧基羰基胺基)-2-羟丙酸的合成
将K2CO3(107.mg,0.78mmol)及NaHCO3(107mg,1.27mmol)添加至(R)-3-胺基-2-羟丙酸(668mg,6.36mmol)在二恶烷及水(3:1,v/v,10mL)中的混合物中。添加二碳酸二-叔丁基酯(998mg,6.99mmol)并在室温下继续搅拌过夜。然后,使用1M HCl将混合物酸化至pH 2。随后,用EA将混合物萃取几次。用Na2SO4干燥合并的有机层,过滤,并在真空中浓缩以获得标题化合物。MS(m/z):206.2[M+H+]。
[步骤B.](R)-3-((S)-1-(3-氯-5-氟-2-((4-(4-氟-1H-吡唑-1-基)-2-甲基喹啉-8-基氧基)甲基)苯基)乙基胺基)-2-羟基-3-氧代丙基胺基甲酸叔丁基酯的合成
使(S)-1-(3-氯-5-氟-2-((4-(4-氟-1H-吡唑-1-基)-2-甲基喹啉-8-基氧基)甲基)苯基)乙胺(25mg,0.06mmol)与(R)-3-(叔丁氧基羰基胺基)-2-羟丙酸(18.0mg,0.09mmol)根据(R)-N-((S)-1-(3-氯-5-氟-2-((4-(4-氟-1H-吡唑-1-基)-2-甲基喹啉-8-基氧基)甲基)苯基)乙基)-2-羟丙酰胺的合成来反应以获得标题化合物。粗产物未经进一步纯化即使用。
[步骤C.](R)-3-胺基-N-((S)-1-(3-氯-5-氟-2-((4-(4-氟-1H-吡唑-1-基)-2-甲基喹啉-8-基氧基)甲基)苯基)乙基)-2-羟丙酰胺的合成
将粗制的(R)-3-((S)-1-(3-氯-5-氟-2-((4-(4-氟-1H-吡唑-1-基)-2-甲基喹啉-8-基氧基)甲基)苯基)乙基胺基)-2-羟基-3-氧代丙基胺基甲酸叔丁基酯溶解于DCM(1.5mL)中且添加TFA(200μL)。将混合物搅拌1h。然后,用甲苯(1.5mL)稀释混合物并在真空中浓缩。通过反相HPLC纯化残余物提供标题化合物。MS(m/z):516.5[M+H+]。
实例4:化合物编号4的制备
(S)-N-((S)-1-(3-氯-5-氟-2-((4-(4-氟-1H-吡唑-1-基)-2-甲基喹啉-8-基氧基)甲基)苯基)乙基)-2,3-二羟丙酰胺
[步骤A.](S)-N-((S)-1-(3-氯-5-氟-2-((4-(4-氟-1H-吡唑-1-基)-2-甲基喹啉-8-基氧基)甲基)苯基)乙基)-2,2-二甲基-1,3-二氧戊环-4-甲酰胺的合成
使(S)-1-(3-氯-5-氟-2-((4-(4-氟-1H-吡唑-1-基)-2-甲基喹啉-8-基氧基)甲基)苯基)乙胺(25.0mg,0.06mmol)与(S)-2,2-二甲基-1,3-二氧戊环-4-羧酸(12.8mg,0.09mmol)根据(R)-N-((S)-1-(3-氯-5-氟-2-((4-(4-氟-1H-吡唑-1-基)-2-甲基喹啉-8-基氧基)甲基)苯基)乙基)-2-羟丙酰胺的合成来反应以获得粗制的标题化合物。粗产物未经进一步纯化即使用。
[步骤B.](S)-N-((S)-1-(3-氯-5-氟-2-((4-(4-氟-1H-吡唑-1-基)-2-甲基喹啉-8-基氧基)甲基)苯基)乙基)-2,3-二羟丙酰胺的合成
将粗制的(S)-N-((S)-1-(3-氯-5-氟-2-((4-(4-氟-1H-吡唑-1-基)-2-甲基喹啉-8-基氧基)甲基)苯基)乙基)-2,2-二甲基-1,3-二氧戊环-4-甲酰胺溶解于MeOH(1.0mL)中且添加浓HCl(5滴)。将混合物搅拌20h。然后,在真空中浓缩混合物。通过反相HPLC纯化残余物,提供标题化合物。MS(m/z):517.1[M+H+]。
实例5:化合物编号5的制备
(S)-N-((R)-1-(3-氯-5-氟-2-((4-(4-氟-1H-吡唑-1-基)-2-甲基喹啉-8-基氧基)甲基)苯基)-2-羟乙基)-2-羟基-3-甲基丁酰胺
[步骤A.]3-溴-5-氟-2-甲基苯胺的合成
将1-溴-5-氟-2-甲基-3-硝基苯(3.04mL,22.0mmol)溶解于二恶烷及水的4:1混合物(110mL)中。将溶液冷却至0℃且添加Zn粉(14.4g,220mmol)及NH4Cl(11.8g.220mmol)。将反应混合物在室温下搅拌3h。完全转化后,经由硅藻土垫过滤混合物。将其用EA小心地冲洗且用水洗涤滤液。经Na2SO4干燥有机相,过滤并在真空中浓缩以获得标题化合物。
[步骤B.]1-溴-3-氯-5-氟-2-甲基苯的合成
在0℃下将NaNO2(1.93g,28.0mmol)添加至3-溴-5-氟-2-甲基苯胺(4.40g,21.6mmol)在乙酸(100mL)及半浓缩HCl水溶液(400mL)中的溶液。在0℃下搅拌5min后,将CuCl(3.72g,37.5mmol)添加至反应混合物。在0℃下搅拌2h后,将反应混合物加热至室温并再继续搅拌3h。随后,用Et2O萃取混合物。用浓NaHCO3水溶液(1×)洗涤合并的有机层,经Na2SO4干燥,过滤,并在真空中浓缩(浴最高温度30℃,真空>150mbar)以获得标题化合物。
[步骤C.]1-溴-2-(溴甲基)-3-氯-5-氟苯的合成
将NBS(4.61g,25.9mmol)及AIBN(531mg,3.23mmol)添加至1-溴-3-氯-5-氟-2-甲基苯(5.43g,21.6mmol)在ACN(150mL)中的搅拌后的溶液。在回流下搅拌8h后,在真空中浓缩混合物。通过硅胶快速色谱(用庚烷/EA洗脱)纯化残余物以获得标题化合物。
[步骤D.]1-溴-3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯的合成
将Cs2CO3(14.5g,44.5mmol)添加至1-溴-2-(溴甲基)-3-氯-5-氟苯(4.48g,14.8mmol)及4-甲氧基酚(2.39g,19.3mmol)在ACN(250mL)中的搅拌后的溶液。在室温下搅拌过夜后,将反应混合物过滤并在真空中浓缩。将残余物溶解于DCM中且用水(1×)洗涤。经Na2SO4干燥有机相,过滤并在真空中浓缩。通过硅胶快速色谱(用EA/庚烷洗脱)纯化粗产物以获得标题化合物。
[步骤E.](R)-N-((R)-2-(叔丁基二甲基硅基氧基)-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙基)-2-甲基丙烷-2-亚磺酰胺的合成
在-78℃下将AlMe3(2M于甲苯中,741μL,1.48mmol)添加至(R,E)-N-(2-(叔丁基二甲基硅基氧基)亚乙基)-2-甲基丙烷-2-亚磺酰胺(325mg,1.17mmol)在无水甲苯(1mL)中的溶液。然后,在第二瓶中,在-78℃下将BuLi(2.5M于己烷中,544μL,1.36mmol)添加至1-溴-3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯(427mg,1.24mmol)在无水甲苯中的溶液。在此温度下将溶液搅拌15min。在-78℃下将1-溴-3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯-含有溶液缓慢添加至含有(R,E)-N-(2-(叔丁基二甲基硅基氧基)亚乙基)-2-甲基丙烷-2-亚磺酰胺的溶液。将混合物搅拌22h且允许达到室温。完全转化后,用饱和NH4Cl水溶液淬灭反应混合物。用EA萃取混合物且经Na2SO4干燥合并的有机相,过滤并在真空中浓缩。通过硅胶快速色谱(用EA/庚烷洗脱)纯化粗产物以产生标题化合物。MS(m/z):544.6[M+H+]。
[步骤F.](R)-2-胺基-2-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙醇的合成
使(R)-N-((R)-2-(叔丁基二甲基硅基氧基)-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙基)-2-甲基丙烷-2-亚磺酰胺(149mg,0.27mmol)与3M甲醇HCl(274μL,0.82mmol)根据(S)-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙胺的合成来反应以获得标题化合物。MS(m/z):370.3[M+HCO2 -]。
[步骤G.](S)-N-((R)-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)-2-羟乙基)-2-羟基-3-甲基丁酰胺的合成
在0℃下将PyBOP(279mg,0.53mmol)及DIPEA(114μL mg,0.67mmol)随后添加至(R)-2-胺基-2-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙醇(87.0mg,0.27mmol)及(S)-(+)-2-羟基-3-甲基丁酸(47.3mg,0.40mmol)在DMF(1mL)中的搅拌后的溶液。在室温下搅拌16h后,在真空中浓缩反应混合物。将残余物再溶解于饱和甲醇氨溶液中,在室温下搅拌3h并在真空中浓缩。通过硅胶快速色谱(用EA/庚烷洗脱)纯化剩余残余物,提供标题化合物。MS(m/z):426.4[M+H+]。
[步骤H.]苯甲酸(S)-1-((R)-2-(苯甲酰氧基)-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙基胺基)-3-甲基-1-氧代丁-2-基酯的合成
将吡啶(300μL)及苯甲酰氯(89.3μL,0.77mmol)随后添加至(S)-N-((R)-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)-2-羟乙基)-2-羟基-3-甲基丁酰胺(131mg,0.31mmol)于DCM(1mL)中的搅拌后的溶液。在室温下搅拌23h后,在真空中浓缩反应混合物。将剩余残余物再溶解于甲苯(2mL)中并在真空中浓缩。通过硅胶快速色谱(用EA/庚烷洗脱)纯化粗产物以获得标题化合物。MS(m/z):634.3[M+H+]。
[步骤I.]苯甲酸(S)-1-((R)-2-(苯甲酰氧基)-1-(3-氯-5-氟-2-(羟甲基)苯基)乙基胺基)-3-甲基-1-氧代丁-2-基酯的合成
使ACN(2mL)中的苯甲酸(S)-1-((R)-2-(苯甲酰氧基)-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙基胺基)-3-甲基-1-氧代丁-2-基酯(141mg,0.22mmol)与水(400μL)中的硝酸铵铈(IV)(304mg.0.56mmol)根据(S)-2-(1-(3-氯-5-氟-2-(羟甲基)苯基)乙基)异吲哚啉-1,3-二酮的合成来反应。通过硅胶快速色谱(用EA/庚烷洗脱)纯化粗产物以获得标题化合物。MS(m/z):528.5[M+H+]。
[步骤J.]苯甲酸(S)-1-((R)-2-(苯甲酰氧基)-1-(3-氯-2-(氯甲基)-5-氟苯基)乙基胺基)-3-甲基-1-氧代丁-2-基酯的合成
使苯甲酸(S)-1-((R)-2-(苯甲酰氧基)-1-(3-氯-5-氟-2-(羟甲基)苯基)乙基胺基)-3-甲基-1-氧代丁-2-基酯(48.3mg,0.09mmol)与SOCl2(13.3μL,0.18mmol)根据(S)-2-(1-(3-氯-2-(氯甲基)-5-氟苯基)乙基)异吲哚啉-1,3-二酮的合成来反应以获得标题化合物。MS(m/z):546.6[M+H+]。
[步骤K.]苯甲酸(S)-1-((R)-2-(苯甲酰氧基)-1-(3-氯-5-氟-2-((4-(4-氟-1H-吡唑-1-基)-2-甲基喹啉-8-基氧基)甲基)苯基)乙基胺基)-3-甲基-1-氧代丁-2-基酯的合成
将Cs2CO3(89.4mg,0.28mmol)添加至苯甲酸(S)-1-((R)-2-(苯甲酰氧基)-1-(3-氯-2-(氯甲基)-5-氟苯基)乙基胺基)-3-甲基-1-氧代丁-2-基酯(46.8mg,0.09mmol)及4-(4-氟-1H-吡唑-1-基)-2-甲基喹啉-8-醇(24.5mg,0.10mmol)在无水ACN(1mL)中的搅拌后的溶液。搅拌过夜后,添加水(3mL)且用DCM萃取混合物。用盐水洗涤合并的有机层,经Na2SO4干燥,过滤并在真空中浓缩。通过硅胶快速色谱(用EA/庚烷洗脱)纯化残余物以获得标题化合物。MS(m/z):753.4[M+H+]。
[步骤L.](S)-N-((R)-1-(3-氯-5-氟-2-((4-(4-氟-1H-吡唑-1-基)-2-甲基喹啉-8-基氧基)甲基)苯基)-2-羟乙基)-2-羟基-3-甲基丁酰胺的合成
在室温下将苯甲酸(S)-1-((R)-2-(苯甲酰氧基)-1-(3-氯-5-氟-2-((4-(4-氟-1H-吡唑-1-基)-2-甲基喹啉-8-基氧基)甲基)苯基)乙基胺基)-3-甲基-1-氧代丁-2-基酯(46.2mg,0.06mmol)于浓甲醇氨中的溶液搅拌过夜。完全转化后(TLC),在真空中浓缩反应混合物。通过反相HPLC纯化残余物,提供标题化合物。MS(m/z):545.2[M+H+]。
[步骤M.](R,E)-N-(2-(叔丁基二甲基硅基氧基)亚乙基)-2-甲基丙烷-2-亚磺酰胺的合成
在室温下在氮气氛下将乙醇钛(IV)(363μL,1.73mmol)、(R)-(+)-2-甲基-2-丙烷亚磺酰胺(210mg,1.73mmol)及(叔丁基二甲基硅基氧基)乙醛(300μL,1.58mmol)在无水DCM(15mL)中的溶液搅拌22h。完全转化后(TLC),用水(15mL)淬灭反应并经由硅藻土垫过滤。随后,用DCM(2×15mL)小心地冲洗滤液。用DCM(10mL)萃取水相且经Na2SO4干燥合并的有机层,过滤并在真空中浓缩以产生标题化合物。
实例6:化合物编号6的制备
(S)-N-(1-(3-氯-5-氟-2-((2-甲基-4-(1-甲基-1H-1,2,4-三唑-5-基)喹啉-8-基氧基)甲基)苯基)乙基)-2-(二氟甲氧基)乙酰胺
[步骤A.]8-甲氧基-2-甲基-4-(1-甲基-1H-1,2,4-三唑-5-基)喹啉的合成
将4-氯-8-甲氧基-2-甲基喹啉(5.00g,24.15mmol)、1-甲基-1,2,4-三唑(42.74mL,48.30mmol)、K2CO3(6.67g,48.30mmol)、Pd(OAc)2(0.54g,2.41mmol)、三环己基膦四氟硼酸盐(1.87g,5.07mmol)及三甲基乙酸(2.47g,24.15mmol)悬浮于无水二甲苯(20mL)中。将烧瓶抽真空且随后通入氮。将脱气程序重复两次。将混合物加热至140℃并保持18h。完全转化后,将混合物蒸发且通过硅胶快速色谱(用DCM/甲醇洗脱)纯化以获得标题化合物。MS(m/z):255.4[M+H+]。
[步骤B.]2-甲基-4-(1-甲基-1H-1,2,4-三唑-5-基)喹啉-8-醇的合成
将8-甲氧基-2-甲基-4-(1-甲基-1H-1,2,4-三唑-5-基)喹啉(3.14g,12.35mmol)在无水甲苯(25mL)中的溶液加热至80℃且逐滴添加至AlCl3(4.94g,37.06mmol)在无水甲苯(25mL)中的剧烈搅拌后的混合物中。在80℃下搅拌8h后,将反应混合物冷却至0℃且通过添加水(68mL)并随后添加浓NH3水淬灭直至pH 10(约1.7mL)。将混合物离心。用EA萃取上清液且经Na2SO4干燥合并的有机层,过滤,并在真空中浓缩。通过硅胶快速色谱(用DCM/甲醇洗脱)纯化残余物以获得标题化合物。MS(m/z):239.2[M-H+]。
[步骤C.](S)-2-(1-(3-氯-5-氟-2-((2-甲基-4-(1-甲基-1H-1,2,4-三唑-5-基)喹啉-8-基氧基)甲基)苯基)乙基)异吲哚啉-1,3-二酮的合成
使(S)-2-(1-(3-氯-2-(氯甲基)-5-氟苯基)乙基)异吲哚啉-1,3-二酮(34.3mg,97μmol)与2-甲基-4-(1-甲基-1H-1,2,4-三唑-5-基)喹啉-8-醇(23.4mg,97μmol)根据(S)-2-(1-(3-氯-5-氟-2-((4-(4-氟-1H-吡唑-1-基)-2-甲基喹啉-8-基氧基)甲基)苯基)乙基)异吲哚啉-1,3-二酮的合成来反应以获得标题化合物。MS(m/z):556,3[M-H+]。
[步骤D.](S)-1-(3-氯-5-氟-2-((2-甲基-4-(1-甲基-1H-1,2,4-三唑-5-基)喹啉-8-基氧基)甲基)苯基)乙胺的合成
根据(S)-1-(3-氯-5-氟-2-((4-(4-氟-1H-吡唑-1-基)-2-甲基喹啉-8-基氧基)甲基)苯基)乙胺的合成对(S)-2-(1-(3-氯-5-氟-2-((2-甲基-4-(1-甲基-1H-1,2,4-三唑-5-基)喹啉-8-基氧基)甲基)苯基)乙基)异吲哚啉-1,3-二酮(45.5mg,82μmol)去保护以获得标题化合物。MS(m/z):448,3[M+Na+]。
[步骤E.](S)-N-(1-(3-氯-5-氟-2-((2-甲基-4-(1-甲基-1H-1,2,4-三唑-5-基)喹啉-8-基氧基)甲基)苯基)乙基)-2-(二氟甲氧基)乙酰胺的合成
使(S)-1-(3-氯-5-氟-2-((2-甲基-4-(1-甲基-1H-1,2,4-三唑-5-基)喹啉-8-基氧基)甲基)苯基)乙胺(28.9mg,68μmol)及2-(二氟甲氧基)乙酸(11.1mg,88μmol)根据(R)-N-((S)-1-(3-氯-5-氟-2-((4-(4-氟-1H-吡唑-1-基)-2-甲基喹啉-8-基氧基)甲基)苯基)乙基)-2-羟丙酰胺的合成来反应以获得标题化合物。MS(m/z):535.0[M+H+]。
实例7:化合物编号7的制备
(S)-N-(1-(3-氯-5-氟-2-((4-(4-氟-1H-吡唑-1-基)-2-甲基喹啉-8-基氧基)甲基)苯基)乙基)-2-羟基-2-甲基丙酰胺
[步骤A.](3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)甲醇的合成
在室温下在3h的时间段内将LiBH4(200mg,9.3mmol)分若干份添加至3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯甲酸甲酯(347mg,0.81mmol)在THF(8.9mL)及MeOH(2mL)中的搅拌后的溶液。在室温下搅拌1h后,将反应混合物分配于DCM(20mL)与水(10mL)之间。用DCM(2×15mL)萃取水层。经Na2SO4干燥合并的有机层,过滤,并在真空中浓缩。通过硅胶快速色谱(用EA/庚烷洗脱)纯化残余物以获得标题化合物。
[步骤B.]3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯甲醛的合成
将(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)甲醇(1.70g,5.73mmol)溶解于二恶烷及甲苯的1:1混合物(70mL)中且添加氧化锰(IV)(9.96g,114.59mmol)。在室温下搅拌反应混合物直至完全反应(TLC)。经由硅藻土过滤后,在减压下蒸发滤液以获得标题化合物。
[步骤C.](R,E)-N-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)亚苄基)-2-甲基丙烷-2-亚磺酰胺的合成
在氩气氛下,将3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯甲醛(317mg,1.08mmol)及(R)-tBu-亚磺酰胺(143μL,1.18mmol)溶解于无水THF(5mL)中。随后,逐滴添加乙醇钛(IV)(676.5mL,3.23mmol)。将反应混合物在65℃下搅拌过夜。完成反应后,用水淬灭反应混合物。用DCM将水层萃取3×。经Na2SO4干燥合并的有机层,过滤并在减压下蒸发至干燥以获得标题化合物。MS(m/z):420.1[M+Na]。
[步骤D.](R)-N-((R)-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)丙基)-2-甲基丙烷-2-亚磺酰胺及(R)-N-((S)-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)丙基)-2-甲基丙烷-2-亚磺酰胺的合成
将(R,E)-N-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)亚苄基)-2-甲基丙烷-2-亚磺酰胺(352.0mg,884.67μmol)溶解于THF(20mL)中。逐滴添加乙基溴化镁在THF中的1M溶液(2.21mL,2.21mmol)。在室温下将反应混合物搅拌过夜。小心地添加冰,然后用饱和NH4Cl水溶液稀释。用DCM将水相萃取3×。经Na2SO4干燥合并的有机层且在过滤后,在减压下蒸发至干燥。通过硅胶快速色谱(用EA/庚烷洗脱)纯化粗产物以获得标题化合物。R-异构体:MS(m/z):428.3[M+H+]及S-异构体:MS(m/z):428.0[M+H+]。
[步骤E.](S)-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)丙-1-胺的合成
使(R)-N-((S)-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)丙基)-2-甲基丙烷-2-亚磺酰胺(182mg,425μmol)与3M甲醇HCl溶液根据(S)-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙胺的合成来反应以获得标题化合物。MS(m/z):324.1[M+H+]。
[步骤F.](S)-2-(1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)丙基)异吲哚啉-1,3-二酮的合成
使(S)-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)丙-1-胺(95.4mg,295μmol)与邻苯二甲酸酐(48mg,324μmol)根据(S)-2-(1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙基)异吲哚啉-1,3-二酮的合成来反应以获得标题化合物。MS(m/z):454.6[M+H+]。
[步骤G.](S)-2-(1-(3-氯-5-氟-2-(羟甲基)苯基)丙基)异吲哚啉-1,3-二酮的合成
使(S)-2-(1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)丙基)异吲哚啉-1,3-二酮(102mg,225μmol)与硝酸铵铈(IV)(308mg,562μmol)根据(S)-2-(1-(3-氯-5-氟-2-(羟甲基)苯基)乙基)异吲哚啉-1,3-二酮的合成来反应以获得标题化合物。MS(m/z):370.3[M+Na]。
[步骤H.](S)-2-(1-(3-氯-2-(氯甲基)-5-氟苯基)丙基)异吲哚啉-1,3-二酮的合成
使(S)-2-(1-(3-氯-5-氟-2-(羟甲基)苯基)丙基)异吲哚啉-1,3-二酮(52.9mg,152μmol)与SOCl2(22.06μL,304μmol)根据(S)-2-(1-(3-氯-2-(氯甲基)-5-氟苯基)乙基)异吲哚啉-1,3-二酮的合成来反应以获得标题化合物。MS(m/z):388.3[M+Na]。
[步骤I.](S)-2-(1-(3-氯-5-氟-2-((4-(4-氟-1H-吡唑-1-基)-2-甲基喹啉-8-基氧基)甲基)苯基)丙基)异吲哚啉-1,3-二酮的合成
使(S)-2-(1-(3-氯-2-(氯甲基)-5-氟苯基)丙基)异吲哚啉-1,3-二酮(53.3mg,146μmol)与4-(4-氟-1H-吡唑-1-基)-2-甲基喹啉-8-醇(35.4mg,146μmol)根据甲基(S)-2-(1-(3-氯-5-氟-2-((4-(4-氟-1H-吡唑-1-基)-2-甲基喹啉-8-基氧基)甲基)苯基)乙基)异吲哚啉-1,3-二酮的合成来反应以获得标题化合物。MS(m/z):573.4[M+H+]。
[步骤J.](S)-1-(3-氯-5-氟-2-((4-(4-氟-1H-吡唑-1-基)-2-甲基喹啉-8-基氧基)甲基)苯基)丙-1-胺的合成
使(S)-2-(1-(3-氯-5-氟-2-((4-(4-氟-1H-吡唑-1-基)-2-甲基喹啉-8-基氧基)甲基)苯基)丙基)异吲哚啉-1,3-二酮(80.8mg,141μmol)与肼水合物(27.5μL,282μmol)根据(S)-1-(3-氯-5-氟-2-((4-(4-氟-1H-吡唑-1-基)-2-甲基喹啉-8-基氧基)甲基)苯基)乙胺的合成来反应以获得标题化合物。MS(m/z):444.1[M+H+]。
[步骤K.](S)-N-(1-(3-氯-5-氟-2-((4-(4-氟-1H-吡唑-1-基)-2-甲基喹啉-8-基氧基)甲基)苯基)丙基)-2-羟基-2-甲基丙酰胺的合成
使(S)-1-(3-氯-5-氟-2-((4-(4-氟-1H-吡唑-1-基)-2-甲基喹啉-8-基氧基)甲基)苯基)丙-1-胺(18mg,41μmol)与α-羟基异丁酸(4.9mg,47μmol)根据(R)-N-((S)-1-(3-氯-5-氟-2-((4-(4-氟-1H-吡唑-1-基)-2-甲基喹啉-8-基氧基)甲基)苯基)乙基)-2-羟丙酰胺的合成来反应以获得标题化合物。MS(m/z):529.6[M+H+]。
实例8:化合物编号8的制备
(R)-N-((S)-1-(3-氯-5-氟-2-((4-(4-氟-5-甲基-1H-吡唑-1-基)-2-甲基喹啉-8-基氧基)甲基)苯基)乙基)-2-羟丙酰胺
[步骤A.]4-(4-氟-5-甲基-1H-吡唑-1-基)-8-甲氧基-2-甲基喹啉的合成
将4-肼基-8-甲氧基-2-甲基喹啉(100mg,0.493mmol)及3-氟-4,4-二甲氧基丁-2-酮(110mg,0.739mmol)[Funabiki,K.等人,J.Chem.Soc.,Perkin Trans.1 1997,18,2679-2680]在5MHCl水溶液(5.3mL)中的混合物在90℃下搅拌1.5h。在真空中浓缩反应混合物,分配于饱和NaHCO3水溶液(3mL)及DCM(5mL)之间。用DCM(2×5mL)萃取水层,经Na2SO4干燥合并的有机层,过滤并在真空中浓缩。通过硅胶快速色谱(用MeOH/DCM洗脱)纯化残余物以获得标题化合物。MS(m/z):272.0[M+H+]。
[步骤B.]4-(4-氟-5-甲基-1H-吡唑-1-基)-2-甲基喹啉-8-醇的合成
根据4-(4-氟-1H-吡唑-1-基)-2-甲基喹啉-8-醇的合成使4-(4-氟-5-甲基-1H-吡唑-1-基)-8-甲氧基-2-甲基喹啉(118mg,0.436mmol)去甲基化以获得标题化合物。MS(m/z):258.1[M+H+]。
[步骤C.](S)-2-(1-(3-氯-5-氟-2-((4-(4-氟-5-甲基-1H-吡唑-1-基)-2-甲基喹啉-8-基氧基)甲基)苯基)乙基)异吲哚啉-1,3-二酮的合成
使4-(4-氟-5-甲基-1H-吡唑-1-基)-2-甲基喹啉-8-醇(21.0mg,82μmol)与(S)-2-(1-(3-氯-2-(氯甲基)-5-氟苯基)乙基)异吲哚啉-1,3-二酮(28.8mg,82μmol)根据(S)-2-(1-(3-氯-5-氟-2-((4-(4-氟-1H-吡唑-1-基)-2-甲基喹啉-8-基氧基)甲基)苯基)乙基)异吲哚啉-1,3-二酮的合成来反应以获得标题化合物。MS(m/z):573.1[M+H+]。
[步骤D.](S)-1-(3-氯-5-氟-2-((4-(4-氟-5-甲基-1H-吡唑-1-基)-2-甲基喹啉-8-基氧基)甲基)苯基)乙胺的合成
根据(S)-1-(3-氯-5-氟-2-((4-(4-氟-1H-吡唑-1-基)-2-甲基喹啉-8-基氧基)甲基)苯基)乙胺的合成将(S)-2-(1-(3-氯-5-氟-2-((4-(4-氟-5-甲基-1H-吡唑-1-基)-2-甲基喹啉-8-基氧基)甲基)苯基)乙基)异吲哚啉-1,3-二酮(31.1mg,54μmol)去保护以获得标题化合物。MS(m/z):465.4[M+Na+]。
[步骤E.](R)-N-((S)-1-(3-氯-5-氟-2-((4-(4-氟-5-甲基-1H-吡唑-1-基)-2-甲基喹啉-8-基氧基)甲基)苯基)乙基)-2-羟丙酰胺的合成
使(S)-1-(3-氯-5-氟-2-((4-(4-氟-5-甲基-1H-吡唑-1-基)-2-甲基喹啉-8-基氧基)甲基)苯基)乙胺(20.5mg,46μmol)与(R)-2-羟丙酸(4.8mg,53μmol)根据(R)-N-((S)-1-(3-氯-5-氟-2-((4-(4-氟-1H-吡唑-1-基)-2-甲基喹啉-8-基氧基)甲基)苯基)乙基)-2-羟丙酰胺的合成来偶合以获得标题化合物。MS(m/z):515.9[M+H+]。
实例9:化合物编号9及化合物编号10的制备
(S)-N-(1-(3-氯-5-氟-2-((2-甲基-4-(5-甲基-1H-1,2,4-三唑-1-基)喹啉-8-基氧基)甲基)苯基)乙基)-2-(二氟甲氧基)乙酰胺(9)及(S)-N-(1-(3-氯-5-氟-2-((2-甲基-4-(3-甲基-1H-1,2,4-三唑-1-基)喹啉-8-基氧基)甲基)苯基)乙基)-2-(二氟甲氧基)乙酰胺(10)
[步骤A.]8-甲氧基-2-甲基-4-(5-甲基-1H-1,2,4-三唑-1-基)喹啉及8-甲氧基-2-甲基-4-(3-甲基-1H-1,2,4-三唑-1-基)喹啉的合成
使4-氯-8-甲氧基-2-甲基喹啉(100mg,0.481mmol)与3-甲基-1H-1,2,4-三唑(46.0,0.554mmol)根据4-(4-氟-1H-吡唑-1-基)-8-甲氧基-2-甲基喹啉的合成来反应以获得标题化合物的混合物。MS(m/z):255.3[M+H+]。
[步骤B.]2-甲基-4-(3-甲基-1H-1,2,4-三唑-1-基)喹啉-8-醇及2-甲基-4-(5-甲基-1H-1,2,4-三唑-1-基)喹啉-8-醇的合成
根据4-(4-氟-1H-吡唑-1-基)-2-甲基喹啉-8-醇的合成使8-甲氧基-2-甲基-4-(5-甲基-1H-1,2,4-三唑-1-基)喹啉及8-甲氧基-2-甲基-4-(3-甲基-1H-1,2,4-三唑-1-基)喹啉的混合物(153mg,0.602mmol)去甲基化以获得标题化合物的混合物。MS(m/z):241.1[M+H+]。
[步骤C.](S)-2-(1-(3-氯-5-氟-2-((2-甲基-4-(5-甲基-1H-1,2,4-三唑-1-基)喹啉-8-基氧基)甲基)苯基)乙基)异吲哚啉-1,3-二酮及(S)-2-(1-(3-氯-5-氟-2-((2-甲基-4-(3-甲基-1H-1,2,4-三唑-1-基)喹啉-8-基氧基)甲基)苯基)乙基)异吲哚啉-1,3-二酮的合成
使2-甲基-4-(3-甲基-1H-1,2,4-三唑-1-基)喹啉-8-醇及2-甲基-4-(5-甲基-1H-1,2,4-三唑-1-基)喹啉-8-醇的混合物(48.3mg,0.201mmol)与(S)-2-(1-(3-氯-2-(氯甲基)-5-氟苯基)乙基)异吲哚啉-1,3-二酮(70.7mg,0.201mmol)根据(S)-2-(1-(3-氯-5-氟-2-((4-(4-氟-1H-吡唑-1-基)-2-甲基喹啉-8-基氧基)甲基)苯基)乙基)异吲哚啉-1,3-二酮的合成来反应以获得标题化合物的混合物。MS(m/z):556.4[M+H+]。
[步骤D.](S)-1-(3-氯-5-氟-2-((2-甲基-4-(5-甲基-1H-1,2,4-三唑-1-基)喹啉-8-基氧基)甲基)苯基)乙胺及(S)-1-(3-氯-5-氟-2-((2-甲基-4-(3-甲基-1H-1,2,4-三唑-1-基)喹啉-8-基氧基)甲基)苯基)乙胺的合成
根据(S)-1-(3-氯-5-氟-2-((4-(4-氟-1H-吡唑-1-基)-2-甲基喹啉-8-基氧基)甲基)苯基)乙胺的合成对(S)-2-(1-(3-氯-5-氟-2-((2-甲基-4-(5-甲基-1H-1,2,4-三唑-1-基)喹啉-8-基氧基)甲基)苯基)乙基)异吲哚啉-1,3-二酮及(S)-2-(1-(3-氯-5-氟-2-((2-甲基-4-(3-甲基-1H-1,2,4-三唑-1-基)喹啉-8-基氧基)甲基)苯基)乙基)异吲哚啉-1,3-二酮的混合物(111mg,201μmol)去保护以获得标题化合物。MS(m/z):448.3[M+Na+]。
[步骤E.](S)-N-(1-(3-氯-5-氟-2-((2-甲基-4-(5-甲基-1H-1,2,4-三唑-1-基)喹啉-8-基氧基)甲基)苯基)乙基)-2-(二氟甲氧基)乙酰胺及(S)-N-(1-(3-氯-5-氟-2-((2-甲基-4-(3-甲基-1H-1,2,4-三唑-1-基)喹啉-8-基氧基)甲基)苯基)乙基)-2-(二氟甲氧基)乙酰胺的合成
使(S)-1-(3-氯-5-氟-2-((2-甲基-4-(5-甲基-1H-1,2,4-三唑-1-基)喹啉-8-基氧基)甲基)苯基)乙胺与(S)-1-(3-氯-5-氟-2-((2-甲基-4-(3-甲基-1H-1,2,4-三唑-1-基)喹啉-8-基氧基)甲基)苯基)乙胺的混合物(19mg,43μmol)与2-(二氟甲氧基)乙酸(7.2mg,56μmol)根据(R)-N-((S)-1-(3-氯-5-氟-2-((4-(4-氟-1H-吡唑-1-基)-2-甲基喹啉-8-基氧基)甲基)苯基)乙基)-2-羟丙酰胺的合成来反应且通过HPLC纯化以产生(S)-N-(1-(3-氯-5-氟-2-((2-甲基-4-(5-甲基-1H-1,2,4-三唑-1-基)喹啉-8-基氧基)甲基)苯基)乙基)-2-(二氟甲氧基)乙酰胺(MS(m/z):534.2[M+H+])及(S)-N-(1-(3-氯-5-氟-2-((2-甲基-4-(3-甲基-1H-1,2,4-三唑-1-基)喹啉-8-基氧基)甲基)苯基)乙基)-2-(二氟甲氧基)乙酰胺(MS(m/z):534.0[M+H+])
实例10:化合物编号11的制备
(S)-N-(1-氘代-1-(3-氯-5-氟-2-((2-甲基-4-(1-甲基-1H-1,2,4-三唑-5-基)喹啉-8-基氧基)甲基)苯基)乙基)-2-(二氟甲氧基)乙酰胺
[步骤A.](R)-N-((S)-1-氘代-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙基)-2-甲基丙烷-2-亚磺酰胺的合成
制备氘代-L-Selectride溶液:在0℃下在10min内将无水MeOH(0.591mL,14.6mmol)添加至LiAlD4(203mg,4.86mmol)的搅拌后的悬浮液。使反应混合物达到室温且然后添加三-仲丁基硼烷溶液(1M于THF中,3.6mL,3.6mmol)。在室温下搅拌15min后使用氘代-L-selectride溶液。
在氩气氛下将乙醇钛(IV)(1.02mL,4.86mmol)逐滴添加至1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙酮(0.500g,1.62mmol)及(R)-(+)-2-甲基-2-丙烷亚磺酰胺(216mg,1.78mmol)的无水THF(1.7mL)中的溶液。在回流下加热混合物直至完全转化(TLC)。随后,将混合物冷却至0℃且逐滴添加氘代-L-Selectride溶液。在此温度下搅拌混合物直至完全转化(TLC)。随后,添加甲醇(约10mL)直至气体停止逸出。将溶液倾倒至饱和NaCl水溶液(5mL)中。然后,经由硅藻土垫过滤混合物且用DCM小心地冲洗。用饱和NaCl水溶液洗涤滤液。用DCM萃取水层。经Na2SO4干燥合并的有机层,过滤,且蒸发至干燥。通过硅胶快速色谱(用EA/庚烷洗脱)纯化剩余残余物以获得标题化合物。MS(m/z):415.3[M+H+]。
[步骤B.](S)-1-氘代-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙胺的合成
根据(S)-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙胺的合成使(R)-N-((S)-1-氘代-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙基)-2-甲基丙烷-2-亚磺酰胺(323mg,779μmol)水解以获得标题化合物。MS(m/z):311.7[M+H+]。
[步骤C.](S)-N-(1-氘代-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙基)-2-(二氟甲氧基)乙酰胺的合成
根据(R)-N-((S)-1-(3-氯-5-氟-2-((4-(4-氟-1H-吡唑-1-基)-2-甲基喹啉-8-基氧基)甲基)苯基)乙基)-2-羟丙酰胺的合成使(S)-1-氘代-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙胺(50.0mg,161μmol)与2-(二氟甲氧基)乙酸(26.4mg,209μmol)偶合以获得标题化合物。MS(m/z):419.2[M+H+]。
[步骤D.](S)-N-(1-氘代-1-(3-氯-5-氟-2-(羟甲基)苯基)乙基)-2-(二氟甲氧基)乙酰胺的合成
根据(S)-2-(1-(3-氯-5-氟-2-(羟甲基)苯基)乙基)异吲哚啉-1,3-二酮的合成对(S)-N-(1-氘代-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙基)-2-(二氟甲氧基)乙酰胺(38mg,91μmol)去保护以获得标题化合物。MS(m/z):312.7[M+H+]。
[步骤E.](S)-N-(1-氘代-1-(3-氯-2-(氯甲基)-5-氟苯基)乙基)-2-(二氟甲氧基)乙酰胺的合成
根据(S)-2-(1-(3-氯-2-(氯甲基)-5-氟苯基)乙基)异吲哚啉-1,3-二酮的合成氯化(S)-N-(1-氘代-1-(3-氯-5-氟-2-(羟甲基)苯基)乙基)-2-(二氟甲氧基)乙酰胺(19mg,61μmol)以获得标题化合物。MS(m/z):330.7[M+H+]。
[步骤F.](S)-N-(1-氘代-1-(3-氯-5-氟-2-((2-甲基-4-(1-甲基-1H-1,2,4-三唑-5-基)喹啉-8-基氧基)甲基)苯基)乙基)-2-(二氟甲氧基)乙酰胺的合成
使(S)-N-(1-氘代-1-(3-氯-2-(氯甲基)-5-氟苯基)乙基)-2-(二氟甲氧基)乙酰胺(20mg,57μmol)与2-甲基-4-(1-甲基-1H-1,2,4-三唑-5-基)喹啉-8-醇(14mg,57μmol)根据(S)-2-(1-(3-氯-5-氟-2-((4-(4-氟-1H-吡唑-1-基)-2-甲基喹啉-8-基氧基)甲基)苯基)乙基)异吲哚啉-1,3-二酮的合成来反应以获得标题化合物。MS(m/z):535.4[M+H+]。
实例10A:化合物编号11A的制备
N-[(1S)-1-[3-氯-5-氟-2-({[2-甲基-4-(1-甲基-1H-1,2,4-三唑-5-基)喹啉-8-基]氧基}甲基)苯基](1,2,2,2-2H4)乙基]-2-(二氟甲氧基)乙酰胺
[步骤A]:使(S)-N-[(1,2,2,2-2H4)亚乙基]-2-甲基丙烷-2-亚磺酰胺(1,2,2,2-2H4)乙醛(1.00g,15.6mmol)与(S)-2-甲基丙烷-2-亚磺酰胺(2.07g,17.1mmol)根据(R,E)-N-(2-(叔丁基二甲基硅基氧基)亚乙基)-2-甲基丙烷-2-亚磺酰胺的合成来反应以获得标题化合物。
[步骤B]:(S)-N-[(1S)-1-{3-氯-5-氟-2-[(4-甲氧基苯氧基)甲基]苯基}(1,2,2,2-2H4)乙基]-2-甲基丙烷-2-亚磺酰胺的合成
使1-溴-3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯(272.0mg,0.79mmol)与(S)-N-[(1,2,2,2-2H4)亚乙基]-2-甲基丙烷-2-亚磺酰胺(113mg,0.75mmol)根据(R)-N-((R)-2-(叔丁基二甲基硅基氧基)-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙基)-2-甲基丙烷-2-亚磺酰胺的合成来反应以获得标题化合物。MS(m/z):440.5[M+Na+]
[步骤C]:(1S)-1-{3-氯-5-氟-2-[(4-甲氧基苯氧基)甲基]苯基}(2H4)乙-1-胺的合成
使溶解于甲醇(1mL)中的(S)-N-[(1S)-1-{3-氯-5-氟-2-[(4-甲氧基苯氧基)甲基]苯基}(1,2,2,2-2H4)乙基]-2-甲基丙烷-2-亚磺酰胺(86.5mg,0.21mmol)与3M甲醇HCl(207μL,0.62mmol)根据(S)-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙胺的合成来反应以产生标题化合物。MS(m/z):314.9[M+H+]
[步骤D]:N-[(1S)-1-{3-氯-5-氟-2-[(4-甲氧基苯氧基)甲基]苯基}(1,2,2,2-2H4)乙基]-2-(二氟甲氧基)乙酰胺的合成
使(1S)-1-{3-氯-5-氟-2-[(4-甲氧基苯氧基)甲基]苯基}(2H4)乙-1-胺(32mg.0.10mmol)与2-(二氟甲氧基)乙酸(14mg,0.11mmol)、PyAOP(70mg,0.13mmol)及DIPEA(21μL,0.18mmol)根据(R)-N-((S)-1-(3-氯-5-氟-2-((4-(4-氟-1H-吡唑-1-基)-2-甲基喹啉-8-基氧基)甲基)苯基)乙基)-2-羟丙酰胺的合成来反应,产生粗制的标题化合物。通过硅胶快速色谱(用EA/庚烷洗脱)将其纯化以获得标题化合物。MS(m/z):444.4[M+Na+]。
[步骤E]:N-[(1S)-1-[3-氯-5-氟-2-(羟甲基)苯基](1,2,2,2-2H4)乙基]-2-(二氟甲氧基)乙酰胺的合成
使N-[(1S)-1-{3-氯-5-氟-2-[(4-甲氧基苯氧基)甲基]苯基}(1,2,2,2-2H4)乙基]-2-(二氟甲氧基)乙酰胺(29mg,0.070mmol)与硝酸铵铈(IV)(95.7mg,0.175mmol)根据(S)-2-(1-(3-氯-5-氟-2-(羟甲基)苯基)乙基)异吲哚啉-1,3-二酮的合成来反应以获得标题化合物。
[步骤F]:N-[(1S)-1-[3-氯-2-(氯甲基)-5-氟苯基](1,2,2,2-2H4)乙基]-2-(二氟甲氧基)乙酰胺的合成
使N-[(1S)-1-[3-氯-5-氟-2-(羟甲基)苯基](1,2,2,2-2H4)乙基]-2-(二氟甲氧基)乙酰胺(18mg,0.057mmol)与SOCl2(17μL,0.23mmol)根据(S)-2-(1-(3-氯-2-(氯甲基)-5-氟苯基)乙基)异吲哚啉-1,3-二酮的合成来反应以获得标题化合物。
[步骤G]:N-[(1S)-1-[3-氯-5-氟-2-({[2-甲基-4-(1-甲基-1H-1,2,4-三唑-5-基)喹啉-8-基]氧基}甲基)苯基](1,2,2,2-2H4)乙基]-2-(二氟甲氧基)乙酰胺的合成
使N-[(1S)-1-[3-氯-2-(氯甲基)-5-氟苯基](1,2,2,2-2H4)乙基]-2-(二氟甲氧基)乙酰胺(14.3mg,43μmol)与2-甲基-4-(1-甲基-1H-1,2,4-三唑-5-基)喹啉-8-醇(11mg,47μmol)根据(S)-2-(1-(3-氯-5-氟-2-((4-(4-氟-1H-吡唑-1-基)-2-甲基喹啉-8-基氧基)甲基)苯基)乙基)异吲哚啉-1,3-二酮的合成来反应,通过HPLC纯化粗产物以产生标题化合物。MS(m/z):539.2[M+H+]。
实例10B:化合物编号11B的制备
(R)-N-(1-氘代-1-(3-氯-5-氟-2-((2-甲基-4-(1-甲基-1H-1,2,4-三唑-5-基)喹啉-8-基氧基)甲基)苯基)-2-羟乙基)-2-(二氟甲氧基)乙酰胺
[步骤A.]叔丁基二甲基[2-氧代(2-2H)乙氧基]硅烷的合成
在-78℃下将2-(叔丁基二甲基硅基氧基)乙酸甲酯(2.0g,10mmol)于无水Et2O(8.9mL)中的溶液逐滴添加至LiAlD4(0.49g,12mmol)于无水Et2O(35mL)中的搅拌后的悬浮液。在-78℃下搅拌40min后,通过在-78℃下添加水(0.45mL)及15% NaOH水溶液(0.45mL)淬灭反应。然后添加水(1.34mL)且将混合物升温至室温。经由硅藻土垫过滤混合物并在真空中浓缩滤液。通过硅胶快速色谱(用EA/庚烷洗脱)纯化剩余残余物以获得标题化合物。
[步骤B.](R)-N-[(1E)-2-[(叔丁基二甲基硅基)氧基](1-2H)亚乙基]-2-甲基丙烷-2-亚磺酰胺的合成
将乙醇钛(IV)(794μL,3.79mmol)、(R)-(+)-2-甲基-2-丙烷亚磺酰胺(344mg,2.84mmol)及叔丁基二甲基[2-氧代(2-2H)乙氧基]硅烷于无水DCM(10mL)中的溶液在氮气氛下在室温下搅拌16h。完全转化后(TLC),通过在0℃下添加水(20mL)淬灭反应且经由硅藻土垫过滤所得混合物。随后,用DCM(2×20mL)小心地冲洗滤液。用DCM(20mL)萃取水层且经Na2SO4干燥合并的有机层,过滤并在真空中浓缩。通过硅胶快速色谱(用EA/庚烷洗脱)纯化剩余残余物以获得标题化合物。MS(m/z):279.2[M+H+]。
[步骤C.](R)-N-(2-(叔丁基二甲基硅基氧基)-1-氘代-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙基)特戊酰胺的合成
在-78℃下将AlMe3(2M于甲苯中,551μL,1.10mmol)添加至(R)-N-[(1E)-2-[(叔丁基二甲基硅基)氧基](1-2H)亚乙基]-2-甲基丙烷-2-亚磺酰胺(279mg,1.00mmol)在无水甲苯(1.6mL)中的溶液且在-78℃下将所得溶液搅拌30min。然后,在第二烧瓶中,在-78℃下将BuLi(2.5M于己烷中,508μL,1.27mmol)添加至1-溴-3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯(381mg,1.10mmol)在无水甲苯(3.8mL)中的溶液且在-78℃下将所得溶液搅拌15min。然后在-78℃下将含有(R)-N-[(1E)-2-[(叔丁基二甲基硅基)氧基](1-2H)亚乙基]-2-甲基丙烷-2-亚磺酰胺的溶液缓慢添加至含有1-溴-3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯的溶液。使反应混合物在4.5h内达到室温且通过添加饱和NH4Cl水溶液淬灭。用EA萃取混合物且经Na2SO4干燥合并的有机层,过滤并在真空中浓缩。通过硅胶快速色谱(用EA/庚烷洗脱)纯化剩余残余物以产生标题化合物。MS(m/z):567.0[M+Na+]。
[步骤D.](R)-N-(1-氘代-1-(3-氯-5-氟-2-((2-甲基-4-(1-甲基-1H-1,2,4-三唑-5-基)喹啉-8-基氧基)甲基)苯基)-2-羟乙基)-2-(二氟甲氧基)乙酰胺的合成
根据(R)-2-胺基-2-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙醇的合成对(R)-N-(2-(叔丁基二甲基硅基氧基)-1-氘代-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙基)特戊酰胺(388mg,0.714mmol)去保护,然后用2-(二氟甲氧基)乙酸根据(S)-N-((R)-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)-2-羟乙基)-2-羟基-3-甲基丁酰胺的合成来酰胺化,然后根据苯甲酸(S)-1-((R)-2-(苯甲酰氧基)-1-(3-氯-5-氟-2-(羟甲基)苯基)乙基胺基)-3-甲基-1-氧代丁-2-基酯的合成来苯甲酰化、4-甲氧基酚移除及氯化,然后根据(S)-N-((R)-1-(3-氯-5-氟-2-((4-(4-氟-1H-吡唑-1-基)-2-甲基喹啉-8-基氧基)甲基)苯基)-2-羟乙基)-2-羟基-3-甲基丁酰胺的合成与2-甲基-4-(1-甲基-1H-1,2,4-三唑-5-基)喹啉-8-醇进行反应及随后去苯甲酰化以获得标题化合物。MS(m/z):551.3[M+H+]。
实例10C:化合物编号11C的制备
(R)-N-((S)-1-氘代-1-(3-氯-5-氟-2-((2-甲基-4-(5-甲基-1H-1,2,4-三唑-1-基)喹啉-8-基氧基)甲基)苯基)乙基)-2-氟丙酰胺
[步骤A.]8-甲氧基-2-甲基-4-(5-甲基-1H-1,2,4-三唑-1-基)喹啉醇的合成
在室温下将乙酸酐(0.645mL,0.692g,6.78mmol)添加至乙酸甲脒(0.705g,6.78mmol)在无水DMF(23.1mL)中的搅拌后的混合物中。在室温下搅拌5min后,添加Et3N(1.56mL,1.14g,11.3mmol)。在室温下搅拌5min后,将反应混合物加热至80℃并搅拌直至反应混合物变成澄清溶液。然后使反应混合物冷却至室温,随后添加乙酸(3.10mL,3.25g,54.2mmol)及4-肼基-8-甲氧基-2-甲基喹啉[A.A.Avetisyan等人,Russ.J.ofOrg.Chem.2010 46(3),427-431](0.918g,4.52mmol)。在80℃下搅拌17h后,在真空中浓缩反应混合物。通过硅胶快速色谱(用DCM/MeOH洗脱)纯化残余物以获得标题化合物。MS(m/z):255.2[M+H+]。
[步骤B.]2-甲基-4-(5-甲基-1H-1,2,4-三唑-1-基)喹啉-8-醇的合成
根据4-(4-氟-1H-吡唑-1-基)-2-甲基喹啉-8-醇的合成用AlCl3(1.18g,8.85mmol)使2-甲基-4-(5-甲基-1H-1,2,4-三唑-1-基)喹啉-8-醇(0.750g,2.95mmol)去甲基化以获得标题化合物。MS(m/z):240.8[M+H+]。
[步骤C.](S)-N-((S)-1-氘代-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙基)-2-羟丙酰胺的合成
使(S)-1-氘代-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙胺(250mg,0.804mmol)与L-(+)乳酸(76μL,76mg,0.85mmol)根据(R)-N-((S)-1-(3-氯-5-氟-2-((4-(4-氟-1H-吡唑-1-基)-2-甲基喹啉-8-基氧基)甲基)苯基)乙基)-2-羟丙酰胺的合成来反应以获得标题化合物。MS(m/z):383.7[M+H+]。
[步骤D.](R)-N-((S)-1-氘代-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙基)-2-氟丙酰胺的合成
在0℃下将1,8-二氮杂二环[5.4.0]十一-7-烯(170μL,173mg,1.14mmol)及全氟-1-丁烷磺酰氟(200μL,343mg,1.14mmol)随后添加至(S)-N-((S)-1-氘代-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙基)-2-羟丙酰胺(290mg,0.758mmol)在无水甲苯(8mL)中的搅拌后的溶液。在0℃下搅拌30min后,使反应混合物达到室温且在室温下搅拌过夜。然后将反应混合物倾倒至冰/水上且用DCM(3×20mL)萃取。经Na2SO4干燥合并的有机层,过滤,并在真空中浓缩。通过硅胶快速色谱(用EA/庚烷洗脱)纯化剩余残余物以获得标题化合物。MS(m/z):385.9[M+H+]。
[步骤E.](R)-N-((S)-1-氘代-1-(3-氯-5-氟-2-(羟甲基)苯基)乙基)-2-氟丙酰胺的合成
使(R)-N-((S)-1-氘代-1-(3-氯-5-氟-2-((4-甲氧基苯氧基)甲基)苯基)乙基)-2-氟丙酰胺(96mg,0.25mmol)与硝酸铵铈(IV)(342mg,0.624mmol)根据(S)-2-(1-(3-氯-5-氟-2-(羟甲基)苯基)乙基)异吲哚啉-1,3-二酮的合成来反应以获得标题化合物。MS(m/z):276.8[M-H+]。
[步骤F.](R)-N-((S)-1-氘代-1-(3-氯-2-(氯甲基)-5-氟苯基)乙基)-2-氟丙酰胺的合成
使(R)-N-((S)-1-氘代-1-(3-氯-5-氟-2-(羟甲基)苯基)乙基)-2-氟丙酰胺(47mg,0.17mmol)与SOCl2(49μL,0.68mmol)根据(S)-2-(1-(3-氯-2-(氯甲基)-5-氟苯基)乙基)异吲哚啉-1,3-二酮的合成来反应以获得标题化合物。MS(m/z):294.8[M-H+]。
[步骤G.](R)-N-((S)-1-氘代-1-(3-氯-5-氟-2-((2-甲基-4-(5-甲基-1H-1,2,4-三唑-1-基)喹啉-8-基氧基)甲基)苯基)乙基)-2-氟丙酰胺的合成
使(R)-N-((S)-1-氘代-1-(3-氯-2-(氯甲基)-5-氟苯基)乙基)-2-氟丙酰胺(29mg,0.10mmol)与2-甲基-4-(5-甲基-1H-1,2,4-三唑-1-基)喹啉-8-醇(26mg,0.11mmol)根据(S)-2-(1-(3-氯-5-氟-2-((4-(4-氟-1H-吡唑-1-基)-2-甲基喹啉-8-基氧基)甲基)苯基)乙基)异吲哚啉-1,3-二酮的合成来反应以获得标题化合物。MS(m/z):501.8[M+H+]。
实例11:化合物编号12至213
下表1中所示的化合物编号12至213为本发明通式(I)化合物的其他代表性实例。如本领域技术人员所理解,这些化合物已使用上述方法以及在本文引用的参考文献中所揭示或在合成有机化学领域中已知的合成方法及其变化形式来合成。本文引用的与实例1至10C中所述的合成途径相关的参考文献中的每一个的全文皆以引用方式并入本说明书中。在任一情形下,有机合成领域技术人员将认识到起始材料及反应条件,包括产生化合物的变化形式。
表1:12至213号实例化合物
质量数(Mass#):质谱数据(来自液相色谱质谱术光谱)经指示(m/z)且表示质子化的分子离子的值[M+H+]
实例12:测试化合物对人类B2R的拮抗活性
使用以下基于细胞的人类缓激肽B2受体钙动员(hB2R-CaM)分析来测定选自1至168号实例化合物的化合物对人类缓激肽B2受体(hB2R)的拮抗活性。该分析在本文中定义为标准体外B2受体活性分析,其可用于测定本发明化合物、例如实例1-11中所显示的化合物的IC50值。
利用hB2R-CaM分析使用B2缓激肽受体稳定细胞系HTS041C(Eurofins,St.CharlesMO)及FLIPR钙6分析试剂盒(Molecular Devices,Wokingham,UK)根据提供者的说明书来研究本发明化合物的拮抗活性。用Flexstation 3系统(Molecular Devices)实施CaM分析测量,该系统允许将化合物(B2R拮抗剂)及缓激肽(B2R激动剂)精确地添加至细胞并连续记录时间依赖性CaM分析信号。
[细胞培养、平铺(plating)及饥饿(starvation)]:
在细胞培育器中在37℃下在5% CO2气氛下,将HTS041C细胞培养在补充有10%热不活化FBS(PAN Biotech)、10mM HEPES、青霉素/链霉素(200U/mL,200μg/mL)、1×非必需胺基酸(Lonza)及250μg/mL G418(Invivogen)的高葡萄糖DMEM细胞培养基(Lonza)中。在CaM分析实验前一天,将细胞接种于透明底黑色96孔板(ThermoFisher编号165305)上的200μL含有减少的FBS(5%)且不含G418的DMEM细胞培养基中。通过将70.000个细胞/孔培育(37℃,5% CO2)24h至28h来实施细胞饥饿。在钙染料加载之前不久,小心地抽出培养基且用含有Ca2+、Mg2+及20mM HEPES、调节至pH 7.4(HBSS+)的汉克氏平衡盐溶液(HBSS,Gibco)洗涤细胞。
[细胞的钙染料加载]:
对于钙染料加载,将一个FLIPR 6分析等份溶解于20mL HBSS+中。将150μL染料加载溶液添加至细胞板且在37℃及5% CO2下培育120min。染料加载后,立即将细胞板转移至预热(37℃)的Flexstation 3系统上用于CaM分析。
[细胞内钙动员分析(CaM分析)]:
在开始实验前不久,将非结合板(Costar)中的新鲜制备的化合物(B2受体拮抗剂)稀释系列(8pt,n=2)及缓激肽(B2受体激动剂)溶液转移至Flexstation系统(源板)。以在n>3初步实验中使用8pt浓度反应曲线(n=8))测定的EC80浓度添加缓激肽。通过Flexstation 3系统执行CaM分析,自记录钙敏感性染料荧光开始,采用底部读取Flex模式,ex/em=485nm/525nm,截留(em)=515nM。20s后,将50μL的4倍浓缩化合物稀释物添加至细胞,产生细胞板中0.1%的最终DMSO(Sigma)浓度。在添加后持续80s监测CaM信号以检测潜在激动活性。在缓激肽刺激之前,将化合物及媒剂处理的细胞在Flexstation系统内在37℃下培育25min。然后添加50μL的5倍浓缩缓激肽溶液(HBSS+,0,1% DMSO)以触发CaM信号(读出:最大-最小值),其在缓激肽刺激后80s测量。
使用XLFIT(IDBS)软件通过8pt(n=2)化合物浓度反应曲线的4参数逻辑模型曲线拟合来实施IC50测定。
[测量结果]:
实例化合物编号2、6、9、11、11A、11B、11C、12、14、15、16、17、18、19、20、26、27、29、30、56、57、58、59、60、61、63、64、70、71、82、83、84、85、90、91、92、94、95、101、102、104、106、107、110、116、117、118、120、121、122、124、126、127、128、129、130、131、132、133、134、139、140、141、142、143、144、145、147、148、149、150、155、156、157、158、159、160、161、162、163、164、165、166、167、168、169、170、171、172、173、174、175、176、177、178、179、180、181、182、183、184、185、187、188、189、190、191、192、193、194、195、196、197、198、199、200、201、202、203、204、205、206、207、208、209、210、211、212及213显示等于或低于50nM的对人类缓激肽B2受体(hB2R)的IC50值。
实例化合物编号1、8、10、22、23、24、25、28、31、32、33、34、46、48、49、50、51、54、62、66、67、68、69、86、87、88、89、93、96、97、99、103、105、108、109、111、112、113、114、115、119、123、125、135、136、137、138、146、151、152、153及186显示介于51与250nM之间的对人类缓激肽B2受体(hB2R)的IC50值。
实例化合物编号3、13、21、47、52、53、55、65、72、98及100显示介于251nM与1000nM之间的对人类缓激肽B2受体(hB2R)的IC50值。
所测试化合物在基于细胞的测试系统中皆不显示任何毒性效应。
实例13:生物活性、通透性及代谢稳定性的测定
为更详细地评估本发明的实例化合物编号1、6、11及13的治疗潜能,测试其对hB2R的拮抗活性、其通透性及其代谢稳定性。
在上文或别处引用的现有技术专利申请案中尚未揭示结构相似的化合物。先前技术文件WO 2008/116620揭示杂芳基-喹啉-8-基氧基甲基-吡啶化合物,其可在吡啶环处具有相似的取代基。然而,WO 2008/116620对其化合物的药代动力学性质(例如通透性及代谢稳定性)保持沉默。WO 2010/031589揭示基于WO 2008/116620化合物研发出的第二代化合物,这些WO 2008/116620化合物展示低代谢稳定性、低生物利用度、形成麸胱甘肽加合物及生物活化(毒性),如WO 2014/159637中所揭示。
在已知结构相关化合物的存在下以及为证实本发明新颖结构元素的有利效应,以相同方式评估分别含有WO 2008/116620及WO 2010/031589中所表明的元素的实际比较化合物对hB2R的拮抗活性、其通透性及其代谢稳定性。使用下表2中所显示的比较化合物编号169、170、171、172、173及174作为实际比较化合物。比较化合物编号169、170及171为基于WO2008/116620中所表明的结构元素。比较化合物编号172、173及174实际上组合WO 2008/116620中所表明的结构元素与如WO2010/031589及WO 2014/159637中所表明的吡啶环部分的结构修饰(用苯基环替代)。然而就此而言,已注明,WO 2010/031589及WO 2014/159637无法提供苯基环部分中氯原子的m位的所主张取代基的任何教示或暗示。事实上,WO 2010/031589及WO2014/159637对苯基环部分中氯原子的m位的氟取代基完全保持沉默,且进一步表明苯基环中氯原子的第二位间位的完全不同的取代基。
A:制备比较化合物编号169至174
根据上文所述的方法及WO 2010/031589及WO 2008/116620中所揭示具有适当变化的那些制备下表2中所显示的比较实例化合物编号169至174,这些变化如合成有机化学领域技术人员所了解且已知以产生化合物。
B:测试化合物对hB2R的拮抗活性
使用与实例12中相同的hB2R-CaM分析来测定测试化合物的相对IC50值。结果显示于下表2中。
C:测试化合物的通透性
使用Hubatsch I.等人(Nat.Protoc.2007,2(9),2111-2119)的Caco-2细胞通透性分析来测定测试化合物的通透性。
Caco-2细胞系为异质性人类上皮结肠直肠腺癌细胞的连续细胞。当在可渗透载体如细胞培养插入过滤器上作为铺满单层培养时,细胞分化形成极化上皮细胞单层,为离子及小分子的通过提供物理及生物化学障壁。以铺满单层的形式,Caco-2细胞在制药工业中用作人类小肠黏膜的体外模型,以预测经口给药药物的吸收。评价细胞单层上两个方向(顶向基底外侧(A-B)及基底外侧向顶向基底外侧(B-A))的转运,能够确定外排(efflux)率,此提供化合物是否经历主动外排的指标。当化合物具有较高外排率时,表明该化合物更容易发生主动外排。如将了解,主动外排实质上损害口服生物利用度。
所测定外排率的结果显示于下表2中。
D:测试化合物的代谢稳定性
肝清除率是身体中最重要的药物清除机制且许多市售化合物是通过肝细胞色素P450介导的机制来清除的。测试化合物的排泄或消除性质是使用Obach RS(DrugMetab.Dispos.1999,27(11),1350-1359)的代谢稳定性分析来测定的。
在96深孔板中使用自雄性Wistar大鼠(Corning)汇集的肝脏微粒体实施分析。大鼠肝脏微粒体培育是以一式两份实施的且培育混合物是由总体积为0.7ml磷酸钠缓冲液(100mM,pH 7.4)的肝脏微粒体(0.5mg微粒体蛋白/mL)、测试化合物(1μM)、MgCl2(2mM)及NADPH(1mM)组成的。通过添加NADPH开始反应且在配备有加热模块的水平振荡器上在37℃下振荡。在t=0min及以下时间点:10min,30min及60min,自培育移除多个等份(70μL)且添加至140μl终止混合物。终止混合物由补充有地西泮、双氯芬酸及灰黄霉素的乙腈作为分析内标组成。通过混合及离心(2,200×g,5分钟)来处理淬灭样品。用去离子水1+1稀释不含颗粒的上清液且随后使其经受LC-MS用于测试化合物消耗的定量生物分析(泵流速:600μL/min;Kinetex苯基-己基分析柱2.6μm,50×2.1mm(Phenomenex,Germany))。使用含有浓度为1μM的维拉帕米(verapamil)的培育物作为高清除率阳性对照(PC;n=2),且为验证分析培育中测试项的任何表观损失归因于代谢,使用不含NADPH的培育物(70μl磷酸盐缓冲液(补充有2mM MgCl2)替代70μL NADPH溶液)作为阴性对照(NC;n=2)。
在代谢稳定性分析中,在肝脏微粒体中测量测试化合物随时间的消失速率,且将这些数据用于计算体外固有清除率(Clint)。Clint数据允许预测体内肝清除率,或换言之可用作体内化合物半衰期及其口服生物利用度的指标。高清除化合物通常视为不利的,此乃因其在体内快速清除,产生短作用持续时间。所述另一方式,较低的体外固有清除率通常指示体内较长半衰期及较佳的口服生物利用度。
所获得的Clint数据显示于下表2中。
表2:生物活性、通透性及代谢稳定性
*IC50/(化合物编号6的IC50)
**雄性Wistar大鼠肝脏微粒体中的代谢稳定性,根据Obach RS DrugMetab.Dispos.1999,11,1350-1359。
***Caco-2 BA/AB:分化Caco-2细胞单层分析中的Papp B至A/Papp A至AB,根据Hubatsch I.等人,Nat.Protoc.2007,2,2111-2119。
如可自上表2获得,根据本发明通式(I)化合物展示多个未预测到的重要优点。与包含先前技术中所提出的结构元素的化合物相比,本发明化合物展示:
更具体而言,所例示本发明通式(I)化合物、即实例化合物编号1、6及13显示对hB2R的改善的拮抗活性。例如,实例化合物编号13具有7.6的相对IC50值,其与比较化合物编号169及比较化合物编号172的相对IC50值相比分别改善7.5倍及3.8倍,这些比较化合物缺少本发明的结构元素,即氯原子的m位氟原子与苄基立体中心的所定义立体化学构型的组合。
所例示根据本发明通式(I)化合物、即实例化合物编号1、6及13也显示与相应比较化合物相比改善的外排率。事实上,所有实例化合物皆显示小于1.5的极有利外排率,而比较化合物编号169至171显示大于2的不利的高外排率,此指示化合物将经受主动外排。
所例示根据本发明通式(I)化合物、即实例化合物编号1、6及13也显示与相应比较化合物相比的显著改善的代谢稳定性。事实上,所有实例化合物皆显示了实质上较低的固有清除率,对于缺少本发明结构元素的组合的相应比较化合物。例如,实例化合物编号6具有28的Clint,其与比较化合物编号171及比较化合物编号174的Clint相比分别降低17.8倍及4.8倍。
另外,本发明的在苄基立体中心具有立体化学构型的化合物将展示更多可预测药代动力学、安全性毒性及耐受性,因为所有化合物应以相似的方式进行代谢,此与具有不同立体化学的可能以不同方式或不同速率代谢的化合物不同。
总之,结果展示,根据本发明通式(I)化合物的活性及药代动力学性质(例如吸收及清除)优于缺少本发明结构元素组合(例如苯基部分中氯原子的m位氟原子与本发明的基于烷基取代基的苄基立体中心的立体化学构型的组合)的化合物。另外,这些结果显示,根据本发明通式(I)化合物适宜作为口服药物的活性剂。
本说明书和/或权利要求中所揭示的本发明特征可为单独及以其任一组合以多种形式实现本发明的材料。
Claims (15)
1.一种通式(I)的化合物或其药学上可接受的盐,
其中
A表示以下基团:
A1为N、CH或CMe;
A2为N或C-RA2;
A3为N或C-RA3;
A5为N-RA5;
RA1表示氢原子或甲基;
RA2表示氢原子、卤素原子、CN或未经取代的(C1-C3)烷基;
RA3表示氢原子、卤素原子或未经取代的(C1-C3)烷基;
RA5表示氢原子或未经取代的(C1-C3)烷基;
R1表示(C1-C3)烷基,前述烷基能够经一个或多个相同或不同的选自氘原子和OH的基团取代;
R2表示氢原子或氘原子;
R3表示氢原子或(C1-C3)烷基;
E表示CRE1RE2RE3或Hce;
Hce表示单环、部分不饱和或芳香族杂环,其具有3至10个C原子及1至4个各自彼此独立地选自N、O或S的杂原子,前述杂环未经取代或能够在每种情况下独立地经以下基团单取代、二取代或三取代:卤素原子、OH、(C1-C3)烷基、(C1-C3)卤烷基、(C1-C3)烷氧基、(C1-C3)卤烷氧基和/或=O;
G表示(C1-C6)烷基,其中1至7个H原子能够在每种情况下独立地经以下基团替代:卤素原子、ORG1、CN、NRG2RG3或(C3-C6)环烷基,和/或其中一个
CH2基团或两个不相邻CH2基团能够由以下基团替代:O、C(O)、OC(O)、C(O)O或C(O)NH;
RG1、RG2及RG3各自彼此独立地表示氢原子、(C1-C4)烷基、(C1-C4)卤烷基、(C1-C4)羟烷基、(C1-C4)杂烷基或(C3-C6)环烷基;
RE1及RE2各自彼此独立地表示氢原子、卤素原子或G;或RE1及RE2一起形成=O或Cyc;
RE3表示氢原子、卤素原子、G、OG或OH;且
Cyc表示单环、饱和或部分不饱和的3至10元环烷基或4至10元杂环烷基,前述4至10元杂环烷基,具有1至3个各自彼此独立地选自N、O或S的杂原子,前述环烷基或前述杂环烷基未经取代或能够在每种情况下独立地经以下基团单取代、二取代、三取代或四取代:卤素原子、OH、(C1-C3)烷基、(C1-C3)卤烷基、(C1-C3)烷氧基、(C1-C3)卤烷氧基和/或=O。
2.如权利要求1所述的化合物或其药学上可接受的盐,其中R1表示(C1-C2)烷基,前述烷基能够经一个或多个相同或不同的选自氘原子和OH的基团取代。
3.如权利要求2所述的化合物或其药学上可接受的盐,其中R3表示氢原子或甲基。
4.如权利要求1所述的化合物或其药学上可接受的盐,其中E为CRE1RE2RE3;且RE1表示氢原子、氟原子、甲基或乙基。
5.如权利要求4所述的化合物或其药学上可接受的盐,其中RE2表示氢原子、氟原子、(C1-C3)烷基,其中1至4个H原子能够在每种情况下独立地由以下基团替代:氟原子、OH或NRC1RC2;或(C1-C3)烷氧基,其中1至4个H原子能够在每种情况下独立地由以下基团替代:氟原子、OH、或环丙基;且RC1及RC2中的每一个各自彼此独立地表示氢原子或(C1-C3)烷基。
6.如权利要求5所述的化合物或其药学上可接受的盐,其中RE3表示氢原子、氟原子、OH、(C1-C3)烷基,其中1至5个H原子能够在每种情况下独立地由以下基团替代:氟原子、OH、=O或NRC1RC2;或(C1-C6)烷氧基,其中1至5个H原子能够在每种情况下独立地由以下基团替代:氟原子、OH或环丙基。
7.如权利要求1所述的化合物或其药学上可接受的盐,其中E为CRE1RE2RE3;且RE1及RE2一起形成=O或Cyc,其中前述Cyc选自环丙基、环丁基、环戊基、氧杂环丁烷基、四氢呋喃基、四氢-2H-哌喃基、1,3-二氧戊环基、吗啉基、氮杂环丁基、吡咯烷基、六氢吡啶基、六氢吡嗪基、(咪唑烷-2-酮)基及(恶唑烷-2-酮)基,且未经取代或能够在每种情况下独立地经以下基团单取代、二取代或三取代:卤素原子、OH、(C1-C3)烷基、(C1-C3)卤烷基、(C1-C3)烷氧基、(C1-C3)卤烷氧基和/或=O。
8.如权利要求7所述的化合物或其药学上可接受的盐,其中RE3表示氢原子、氟原子、OH或(C1-C3)烷基。
9.如权利要求1所述的化合物或其药学上可接受的盐,其中E为Hce,且Hce表示具有3至5个C原子及1至3个N原子;3至5个C原子、1-2个N原子及1个O原子;或3至5个C原子、1-2个N原子及1个S原子的单环、部分不饱和或芳香族杂环;前述杂环未经取代或能够在每种情况下独立地经以下基团单取代或二取代:卤素原子、OH、(C1-C3)烷基或(C1-C3)卤烷基。
12.一种药物组合物,其包含如权利要求1所述的化合物或其药学上可接受的盐及至少一种载剂物质、赋形剂和/或佐剂。
13.如权利要求12所述的药物组合物,其中前述药物组合物经调配为气溶胶、乳霜、凝胶、小丸、胶囊、糖浆、溶液或经皮贴片。
14.一种组合制剂,其含有至少一种如权利要求1至11中任一项所述的化合物及至少一种其他活性药物成分。
15.一种如权利要求1至11中任一项所述的化合物、如权利要求12所述的药物组合物或如权利要求14所述的组合制剂作为药剂的用途。
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TW200843767A (en) * | 2007-03-23 | 2008-11-16 | Jerini Ag | Small molecule bradykinin B2 receptor modulators |
EP2344477A1 (en) * | 2008-09-22 | 2011-07-20 | Jerini AG | Small molecule bradykinin b2 receptor modulators |
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