CN107445919A - Pde10抑制剂以及相关组合物和方法 - Google Patents
Pde10抑制剂以及相关组合物和方法 Download PDFInfo
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- CN107445919A CN107445919A CN201710695057.1A CN201710695057A CN107445919A CN 107445919 A CN107445919 A CN 107445919A CN 201710695057 A CN201710695057 A CN 201710695057A CN 107445919 A CN107445919 A CN 107445919A
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- bases
- phenyl
- dimethoxyphenyls
- bromo
- etoac
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- WEMQMWWWCBYPOV-UHFFFAOYSA-N s-indacene Chemical compound C=1C2=CC=CC2=CC2=CC=CC2=1 WEMQMWWWCBYPOV-UHFFFAOYSA-N 0.000 description 1
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- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
- NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 1
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- LEIMLDGFXIOXMT-UHFFFAOYSA-N trimethylsilyl cyanide Chemical compound C[Si](C)(C)C#N LEIMLDGFXIOXMT-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
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Abstract
公开了抑制PDE10的化合物,其有治疗多种疾病状态的作用,所述疾病状态包括(但不限于)诸如帕金森氏病、亨廷顿氏病、阿尔茨海默氏病、脑炎、恐惧症、癫痫、失语症、贝尔氏麻痹、脑瘫、睡眠障碍、疼痛、妥瑞氏综合症、精神分裂症、妄想症、药源性精神病以及恐慌症和强迫症的精神病、焦虑症、运动障碍和/或神经障碍。还提供了所述化合物的药物可接受的盐、立体异构体、溶剂化物和前药。还公开了包含结合药物可接受的载体的化合物的组合物以及与其用于抑制需要所述组合物的恒温动物中的PDE10的相关方法。
Description
相关申请的引用
本申请依据35U.S.C.§119(e)要求2010年3月12日提交的第61/313,544号美国临时专利申请和2011年1月7日提交的第61/430,841号美国临时专利申请的权益,所述申请以其整体通过引用并入本文。
背景
技术领域
本发明一般地涉及具有作为PDE10抑制剂的活性的化合物和包含所述化合物的组合物以及通过向有需要的恒温动物给予这类化合物治疗各种病症的方法。
相关技术描述
环核苷酸磷酸二酯酶(PDE)由大型超族的酶代表。已知PDE具有模块化结构,具有邻近羧基端的保守催化结构域和常接近氨基端的调节结构域或基序。目前,PDE超族包括归类到11个PDE族的超过20种的不同基因(Lugnier,C.,“Cyclic nucleotidephosphodiesterase(PDE)superfamily:a new target for the development ofspecific therapeutic agents(环核苷酸磷酸二酯酶(PDE)超族:用于开发特异性治疗剂的新靶标)”,Pharmacol Ther.2006年3月;109(3):366-98)。
三个独立的组同时报道了最近描述的PDE、PDE10(Fujishige等人,“Cloning andcharacterization of a novel human phosphodiesterase that hydrolyzes both cAMPand cGMP(PDE10A)(水解cAMP和cGMP二者的新型人磷酸二酯酶(PDE10A)的克隆和表征)”,JBiol Chem 1999,274:18438-18445;Loughney等人,“Isolation and characterizationof PDE10A,a novel human 3’,5’-cyclic nucleotide phosphodiesterase(PDE10A,新型人3’,5’-环核苷酸磷酸二酯酶的分离和表征)”Gene 1999,234:109-117;Soderling等人,“Isolation and characterization of a dual-substrate phosphodiesterase genefamily:PDE10A(双基质磷酸二酯酶基因族:PDE10A的分离和表征)”,Proc Natl Acad SciUSA 1999,96:7071-7076)。PDE10具有水解cAMP和cGMP二者的能力;然而,cAMP的Km为约0.05μM,而cGMP的KM为3μM。此外,cAMP水解的Vmax比cGMP低五倍。由于这些动力学,通过PDE10水解cGMP在体外被cAMP的有效抑制,这表明PDE10可在体内充当cAMP-抑制的cGMP磷酸二酯酶。与PDE8或PDE9不同,PDE10受IBMX抑制,其IC50(50%抑制浓度)为2.6μM。(参见Soderling和Beavo,“Regulation of cAMP and cGMP signaling:newphosphodiesterases and new functions(cAMP和cGMP信号的调节:新型磷酸二酯酶和新功能)”,Current Opinion in Cell Biology,2000,12:174-179)。
PDE10包含两个与PDE2、PDE5和PDE6的cGMP结合结构域相似的氨基端结构域,其为在多种蛋白质之间保守的结构域。由于该结构域的广泛保守,目前将其称为GAF结构域(对于GAF蛋白质:cGMP结合磷酸二酯酶;氰基细菌鱼腥藻腺苷环化酶(cynobacterialAnabaena adenylyl cyclase);和大肠杆菌(Escherichia coli)转录调节因子fhlA)。尽管在PDE2、PDE5和PDE6中,GAF结构域结合cGMP,但这可能不是该结构域在所有情况下的主要功能(例如,不认为大肠杆菌(E.coli)合成cGMP)。有趣地,PDE10的体外结合研究表明cGMP结合的解离常数(Kd)远大于9μM。由于不认为cGMP的体内浓度在大多数细胞中达到如此高的水平,因此看起来可能是PDE10对cGMP的亲合力通过调节而增加,或者PDE10中GAF结构域的主要功能可能用于其它事物而非cGMP结合。
已经广泛寻找酶的PDE族抑制剂的治疗用途的显著指示。报道的PDE抑制剂的治疗用途包括过敏症、强迫性肺病、高血压、肾癌、心绞痛、充血性心力衰竭、抑郁症和勃起功能障碍(WO 01/41807A2)。已经公开用于治疗缺血性心脏病的其它PDE抑制剂(第5,693,652号美国专利)。更具体地,已经公开用于治疗某些神经病和精神病的PDE10抑制剂,包括帕金森氏病、亨廷顿氏病、精神分裂症、妄想症、药源性精神病以及恐慌症和强迫症(第2003/0032579号美国专利申请)。已经证明PDE10在与许多神经病和精神病紧密相关的大脑区域中的神经细胞中以高水平存在。通过抑制PDE10活性,cAMP和cGMP水平在神经细胞内增加,由此适当改善这些神经细胞活动的能力。因此,认为PDE10的抑制用于治疗多种疾病状态或病症,其受益于增加神经细胞内的cAMP和cGMP水平,包括上述那些神经病、精神病、焦虑症和/或运动障碍。
尽管已经取得关于PDE10抑制的进步,但本领域仍亟需PDE10抑制剂以及治疗受益于所述PDE10抑制剂的各种疾病状态和/或病症。
概述
简言之,本发明一般地涉及具有作为PDE10抑制剂的活性的化合物以及其制备方法和用途,并且涉及包含所述化合物的药物组合物。
在一个实施方案中,所述化合物具有下列一般结构(I):
包括其药物可接受的盐、立体异构体、溶剂化物和前药,其中A、R1、R2和R3如下述定义。
本发明的化合物有用于各种治疗的应用,并可用于治疗多种受益于增加cAMP和cGMP水平的疾病状态或病症,特别是在神经细胞内,所述疾病状态或病症包括(但不限于)诸如精神病、焦虑症的神经障碍,诸如帕金森氏病、亨廷顿氏病、阿尔茨海默氏病、脑炎、恐惧症、癫痫、失语症、贝尔氏麻痹、脑瘫、睡眠障碍、疼痛、妥瑞氏综合症、精神分裂症、妄想症、躁郁症、创伤后应激障碍、药源性精神病、恐慌症、强迫症、注意力缺陷障碍、破坏性行为障碍、孤独症、抑郁症、痴呆症、认知障碍、癫痫、失眠症和多发性硬化症的运动障碍和/或神经障碍。
本发明的方法包括向有需要的包括人的哺乳动物给予有效量的前述结构的化合物,通常为药物组合物形式的化合物。因此,在其它实施方案中,公开了包含一种或多种前述结构的化合物结合药物可接受的载体或稀释剂的药物组合物。
通过参考下列详细描述,本发明的这些和其它方面将明显。为了该目的,本文列举了许多参考文献,其更详细地描述某些背景信息、步骤、化合物和/或组合物,并且各自以其整体通过引用并入本文。
附图简述
图1例示了与赋形剂对照相比,通过腹腔注射给予本发明的化合物1-1(实施例1)显著减少精神兴奋剂(PCP)诱导的精神病模型中小鼠的过度活跃(hyperactivity)。
图2例示了与赋形剂对照相比,通过口服灌胃给予本发明的化合物1-1(实施例1)显著减少精神兴奋剂(PCP)诱导的精神病模型中小鼠的过度活跃。
图3例示了与赋形剂对照相比,通过腹腔注射给予本发明的化合物2-1(实施例2)显著减少精神兴奋剂(PCP)诱导的精神病模型中小鼠的过度活跃。
图4例示了与赋形剂对照相比,通过口服灌胃给予本发明的化合物2-1(实施例2)显著减少精神兴奋剂(PCP)诱导的精神病模型中小鼠的过度活跃。
图5例示了与赋形剂对照相比,本发明的化合物2-1(实施例2)显著减少在CAR精神病模型中训练过的小鼠的条件性回避反应(CAR)。
图6例示了与赋形剂对照相比,通过腹腔注射给予本发明的化合物11-1(实施例11)显著减少精神兴奋剂(PCP)诱导的精神病模型中小鼠的过度活跃。
图7例示了与赋形剂对照相比,本发明的化合物34-1(实施例34)显著减少在CAR精神病模型中训练过的小鼠的条件性回避反应(CAR)。
图8例示了与赋形剂对照相比,本发明的化合物36-1(实施例36)显著减少在CAR精神病模型中训练过的小鼠的条件性回避反应(CAR)。
图9例示了与赋形剂对照相比,本发明的化合物47-1(实施例47)显著减少在CAR精神病模型中训练过的小鼠的条件性回避反应(CAR)。
图10例示了与赋形剂对照相比,本发明的化合物61-1(实施例61)显著减少在CAR精神病模型中训练过的小鼠的条件性回避反应(CAR)。
图11例示了与赋形剂对照相比,本发明的化合物63-1(实施例63)显著减少在CAR精神病模型中训练过的小鼠的条件性回避反应(CAR)。
图12例示了与赋形剂对照相比,本发明的化合物49-1(实施例49)显著减少在CAR精神病模型中训练过的小鼠的条件性回避反应(CAR)。
图13例示了与赋形剂对照相比,本发明的化合物65-10(实施例65,表1)显著减少在CAR精神病模型中训练过的小鼠的条件性回避反应(CAR)。
详细描述
如上所述,本发明一般地涉及用作PDE10抑制剂的化合物以及其制备方法和用途,并且涉及包含所述化合物的药物组合物。
在一个实施方案中,所述PDE10抑制剂具有下列结构(I):
或其药物可接受的盐、立体异构体、溶剂化物或前药,
其中:
A为
R1为C1-6烃基、C1-6卤代烃基、C1-6芳烃基、芳基、-(CH2)nO(CH2)mCH3或-(CH2)nN(CH3)2;
R2为(i)取代的或未取代的芳基或(ii)取代的或未取代的杂环基;
R3为取代的或未取代的芳基;
R4为氢、C1-6烃基或C1-6卤代烃基;
n为1、2、3、4、5或6;且
m为0、1、2、3、4、5或6。
如本文使用的,上述术语具有下列含义:
“氨基”是指-NH2基团。
“氰基”是指-CN基团。
“羟基(hydroxy)”或“羟基(hydroxyl)”是指-OH基团。
“亚氨基”是指=NH取代基。
“硝基”是指-NO2基团。
“氧基”是指=O取代基。
“硫基”是指=S取代基。
“C1-6烃基”是指包含1至6个碳原子的直链或支链、非环状或环状、不饱和或饱和的脂肪族烃基团。代表性的饱和直链烃基包括甲基、乙基、正丙基、正丁基、正戊基、正己基等;而饱和支链烃基包括异丙基、仲丁基、异丁基、叔丁基、异戊基等。代表性饱和环烃基包括环丙基、环丁基、环戊基、环己基等;而不饱和环烃基包括环戊烯基和环己烯基等。不饱和烃基在相邻碳原子之间包含至少一个双键或三键(分别称为“烯基”或“炔基”)。代表性直链和支链烯基包括乙烯基、丙烯基、1-丁烯基、2-丁烯基、异丁烯基、1-戊烯基、2-戊烯基、3-甲基-1-丁烯基、2-甲基-2-丁烯基、2,3-二甲基-2-丁烯基等;而代表性直链和支链炔基包括乙炔基、丙炔基、1-丁炔基、2-丁炔基、1-戊炔基、2-戊炔基、3-甲基-1-丁炔基等。
“C1-6亚烃基”或“C1-6亚烃基链”是指连接分子的剩余部分与自由基基团的直链或支链二价烃链,其仅由碳和氢组成,其为饱和的或不饱和的(即,包含一个或多个双键和/或三键)并具有一至六个碳原子,例如,亚甲基、亚乙基、亚丙基、正亚丁基、亚乙烯基、亚丙烯基、正亚丁烯基、亚丙炔基、正亚丁炔基等。亚烃基链通过单键或双键与分子的剩余部分连接并通过单键或双键与自由基基团连接。亚烃基链与分子的剩余部分或与自由基基团的连接点能通过链内的一个碳或任意两个碳。
“C1-6烃氧基”是指通式-ORa的基团,其中Ra为上述定义的烃基,例如,甲氧基、乙氧基等。
“芳基”是指包含氢、6至18个碳原子和至少一个芳香族环的烃环体系。芳基基团可为单环、双环、三环或四环体系,其可包括稠环或桥环体系。芳基包括但不限于衍生自醋蒽烯、苊烯、醋菲烯、蒽、薁、苯、荧蒽、芴、不对称引达省、对称引达省、茚满、茚、萘、萉(phenalene)、菲、七曜烯、芘和苯并菲的芳基。
“C1-6芳烃基”是指通式-Rb-Rc的基团,其中Rb为上述定义的亚烃基链且Rc为一个或多个上述定义的芳基,例如,苄基、二苯基甲基等。
“环烃基”或“碳环”是指仅由碳和氢原子组成的稳定的非芳香族单环或多环烃基团,其可包含稠环或桥环体系,具有三至十五个碳原子,优选具有三至十个碳原子,并且其为饱和的或不饱和的并通过单键与分子的剩余部分连接。单环基团包括例如,环丙基、环丁基、环戊基、环己基、环庚基和环辛基。多环基团包括例如,金刚烷基、降冰片基、十氢萘基、7,7-二甲基-二环[2.2.1]庚烷基等。
“卤代”或“卤素”是指溴、氯、氟或碘。
“C1-6卤代烃基”是指被一个或多个上述定义的卤素基团取代的上述定义的C1-6烃基,例如,三氟甲基、二氟甲基、三氯甲基、2,2,2-三氟乙基、1,2-二氟乙基、3-溴-2-氟丙基、1,2-二溴乙基等。
“杂环”或“杂环基”是指4-至7-元单环或7-至10-元双环、杂环,其为饱和的、不饱和的或芳香族的,并且其包含1至4个独立地选自氮、氧和硫的杂原子,且其中氮和硫杂原子可任选被氧化,并且氮杂原子可任选被季铵化,包括其中任何上述杂环与苯环稠合的双环。杂环可通过任何杂原子或碳原子连接。本文将芳香族杂环称为“杂芳基”,并且包括(但不限于)呋喃基、苯并呋喃基、噻吩基、苯并噻吩基、吡咯基、吲哚基、异吲哚基、氮杂吲哚基、吡啶基、喹啉基、异喹啉基、噁唑基、异噁唑基、苯并噁唑基、吡唑基、咪唑基、苯并咪唑基、噻唑基、苯并噻唑基、异噻唑基、哒嗪基、嘧啶基、吡嗪基、三嗪基、噌啉基、酞嗪基、噁二唑基、噻二唑基、苯并异噁唑基、三唑基、四唑基、吲唑基和喹唑啉基。除了上述列举的杂芳基之外,杂环还包括吗啉基、吡咯烷酮基(pyrrolidinonyl)、吡咯烷基、哌啶基、哌嗪基等。此外,杂环还包括苯并噻吩-2-基、2,3-二氢苯并-1,4-二氧杂环己烯-6-基、苯并-1,3-二氧杂环戊烯-5-基等。
本文使用的术语“取代的”(例如,在取代的杂环基或取代的芳基的上下文中)是指至少一个氢原子被取代基取代。本发明上下文中的“取代基”包括卤素、羟基、氧基、氰基、硝基、亚氨基、硫基、氨基、烃基氨基、二烃基氨基、烃基、烃氧基、烷硫基、卤代烃基、芳基、芳烃基、杂芳基、杂芳基烃基、杂环基和杂环烃基以及-NRaRb、-NRaC(=O)Rb、-NRaC(=O)NRaNRb、-NRaC(=O)ORb、-NRaSO2Rb、-C(=O)Ra、-C(=O)ORa、-C(=O)NRaRb、-OC(=O)NRaRb、-ORa、-SRa、-SORa、-S(=O)2Ra、-OS(=O)2Ra、-S(=O)2ORa、=NSO2Ra和-SO2NRaRb。在前述中,该上下文中的Ra和Rb可相同或不同并可独立地为氢、烃基、卤代烃基、环烃基、芳基、芳烃基、杂环基。此外,前述取代基可被一个或多个上述取代基进一步取代。
在结构(I)的其它实施方案中,所述化合物具有下列结构(I-A):
在结构(I)的其它实施方案中,所述化合物具有下列结构(I-B):
在结构(I)的其它实施方案中,所述化合物具有下列结构(I-C):
在结构(I)的其它实施方案中,所述化合物具有下列结构(I-D):
在结构(I)的其它实施方案中,所述化合物具有下列结构(I-E):
在结构(I)的其它实施方案中,所述化合物具有下列结构(I-F):
在结构(I)的其它实施方案中,所述化合物具有下列结构(I-G):
在结构(I)的其它实施方案中,所述化合物具有下列结构(I-H):
在结构(I)的其它实施方案中,所述化合物具有下列结构(I-I):
在结构(I)的其它实施方案中,特别地,结构(I-B)和(I-C),R4为氢或R4为C1-6烃基(诸如,例如,甲基)。
在结构(I)的其它实施方案中,R1为C1-6烃基(诸如,例如,R1为甲基或乙基)。
在结构(I)的其它实施方案中,R3为取代的或未取代的苯基(诸如,例如,4-溴-3,5-二甲氧基苯基、4-氯-3,5-二甲氧基苯基或3,4,5-三甲氧基苯基)。
在结构(I)的其它实施方案中,R2为取代的或未取代的芳基,例如取代的或未取代的苯基。在更具体的实施方案中,其中R2为取代的苯基,R2为由C1-6烃氧基取代的苯基或R2为由取代的或未取代的杂环基所取代的苯基(诸如,例如,4-(5-甲基-1,3,4-噁二唑-2-基)苯基、4-(5-甲基-1,3,4-噻二唑-2-基)苯基或4-吗啉基苯基)。
在结构(I)的其它实施方案中,R2为取代的或未取代的杂环基。
通常,可以游离酸或游离碱的形式使用本发明的化合物。或者,可以酸加成盐或碱加成盐的形式使用本发明的化合物。可通过本领域熟知的方法制备本发明的游离氨基化合物的酸加成盐,并可由有机酸和无机酸形成。合适的有机酸包括马来酸、富马酸、苯甲酸、抗坏血酸、琥珀酸、甲磺酸、乙酸、三氟乙酸、草酸、丙酸、酒石酸、水杨酸、柠檬酸、葡萄糖酸、乳酸、扁桃酸、肉桂酸、天冬氨酸、硬脂酸、棕榈酸、乙醇酸、谷氨酸和苯磺酸。合适的无机酸包括盐酸、氢溴酸、硫酸、磷酸和硝酸。碱加成盐包括由羧酸盐阴离子形成的那些盐并包括由有机阳离子和无机阳离子形成的盐,例如选自碱金属和碱土金属(例如,锂、钠、钾、镁、钡和钙)的那些,以及铵离子及其取代的衍生物(例如,二苄基铵、苄基铵、2-羟基乙基铵等)。因此,术语结构(I)的“药物可接受的盐”意图包括任意和所有可接受的盐形式。
此外,前药也包括在本发明的上下文范围内。前药为当给予患者时在体内释放结构(I)的化合物的任何共价结合的载体。通常,通过以能够通过常规处理或断裂修饰的方式修饰官能团来制备前药,从而在体内产生母体化合物。前药包括例如,本发明的化合物,其中将羟基、胺基或巯基与当给予患者时断裂以形成羟基、胺基或巯基的任何基团连接。因此,前药的代表性实例包括(但不限于)结构(I)化合物的醇和胺官能团的乙酸盐、甲酸盐和苯甲酸盐衍生物。此外,在羧酸(-COOH)的情况下,可使用诸如甲酯、乙酯等的酯。
本文公开的本发明还意图包括所有结构(I)的药物可接受的化合物,通过由具有不同原子量或质量数的原子取代一个或多个原子而将其同位素标记。能与公开的化合物结合的同位素的实例包括氢、碳、氮、氧、磷、氟、氯和碘的同位素,例如分别为2H、3H、11C、13C、14C、13N、15N、15O、17O、18O、31P、32P、35S、18F、36Cl、123I和125I。通过表征例如,作用位点或模式或与药理学重要的作用位点的结合亲合力,这些放射性同位素标记的化合物能用于帮助确定或检测化合物的效力。某些结构(I)的同位素标记的化合物,例如包含放射性同位素的那些,能够用于药物和/或基体组织分布研究。放射性同位素氚即3H和碳-14即14C,由于其容易结合和现成的检测方法而特别有用于该目的。使用诸如氘即2H的较重同位素取代,由于较高的代谢稳定性而提供某些治疗优点,例如,提高的体内半衰期或减少的剂量需求,因此在某些情况下可为优选的。使用诸如11C、18F、15O和13N的正离子发射同位素取代能用于检验基质受体占用的正离子断层扫描(PET)研究。通常,能使用合适的同位素标记的试剂代替前面使用的非标记的试剂并通过本领域技术人员已知的常规技术或通过与下文阐述的实施例中的描述相似的方法制备结构(I)同位素标记的化合物。
关于立体异构体,结构(I)的化合物可具有手性中心并可以外消旋体、外消旋混合物和单独的对映异构体或非对映异构体形式存在。所有这种同分异构体形式包括其混合物均包括在本发明范围内。此外,一些结构(I)化合物的晶体形式可以多晶型形式存在,其包括在本发明范围内。此外,一些结构(I)的化合物还可与水或其它有机溶剂形成溶剂化物。这种溶剂化物同样包括在本发明范围内。
在本发明的另一实施方案中,公开了包含一种或多种结构(I)化合物的药物组合物。为了给药目的,可将本发明的化合物配制为药物组合物。本发明的药物组合物包含一种或多种本发明的化合物以及药物可接受的载体和/或稀释剂。PDE10抑制剂在组合物中以对治疗特殊病症有效的量而存在,即,足以实现期望的PDE10抑制的量,且优选对恒温动物具有可接受毒性的量而存在。通常,根据给药途径,本发明的药物组合物可以0.1mg至250mg每剂量的量包含PDE10抑制剂,且更通常1mg至60mg。本领域技术人员能容易地确定合适的浓度和剂量。
一般而言,例如,是否通过一次或多次单独给药,根据疾病的类型和严重程度,典型的每日剂量可为约1μg/kg至100mg/kg,优选为0.01mg/kg-100mg/kg,更优选为0.1mg/kg-70mg/kg。对于几天或更长时间的重复给药,根据疾病状态,持续治疗直至出现疾病症状的期望的抑制。然而,其它给药方案可能有用。能通过标准技术和检验监测该治疗进展。本发明剂量单位形式的规格通过并直接取决于活性化合物的独特特点和待实现的特殊治疗效果以及本领域中为治疗个体而混合这类活性化合物的固有局限性。
药物可接受的载体和/或稀释剂是本领域技术人员熟悉的。对于配制为液体溶液的组合物,可接受的载体和/或稀释剂包括盐水和无菌水,并可任选包括抗氧化剂、缓冲剂、抑菌剂和其它常见添加剂。还能将组合物配制为丸剂、胶囊剂、颗粒剂或片剂,除了PDE10抑制剂之外,其包含稀释剂、分散剂和表面活性剂、粘结剂和以及润滑剂。本领域技术人员还可以合适的方式并根据诸如Remington's Pharmaceutical Sciences(雷明顿药物科学),Gennaro编辑,Mack Publishing Co.,Easton,PA 1990中描述的那些公知手段配制PDE10抑制剂。
在另一实施方案中,本发明提供了用于治疗疾病的方法,所述疾病例如(但不限于)诸如上述帕金森氏病、亨廷顿氏病、阿尔茨海默氏病、脑炎、恐惧症、癫痫、失语症、贝尔氏麻痹、脑瘫、睡眠障碍、疼痛、妥瑞氏综合症、精神分裂症、妄想症、躁郁症、创伤后应激障碍、药源性精神病、恐慌症、强迫症、注意力缺陷障碍、破坏性行为障碍、孤独症、抑郁症、痴呆症、认知障碍、癫痫、失眠症和多发性硬化症的精神病、焦虑症、运动障碍和/或神经障碍。这种方法包括以足以治疗所述疾病状态的量向恒温动物给予本发明的化合物。在该上下文中,“治疗”包括预防性给药。这种方法包括本发明的PDE10抑制剂的全身给药,优选以上述药物组合物的形式。如本文使用的,全身给药包括口服和肠胃外给药方法,包括皮下给药、肌肉给药、颅内给药、眼框内给药、眼内给药、心室内给药、囊内给药、关节内给药、脊柱内给药、脑池内给药、腹膜内给药、鼻内给药、喷雾给药、静脉内给药、皮肤内给药、吸入给药、透皮给药、跨粘膜给药和直肠给药。
对于口服给药,PDE10抑制剂的合适药物组合物包括粉末剂、颗粒剂、丸剂、片剂和胶囊剂以及液体剂、糖浆剂、悬浮剂和乳剂。这些组合物还可包括调味剂、防腐剂、悬浮剂、增稠剂和乳化剂以及其它药物可接受的添加剂和赋形剂。对于肠胃外给药,能以水性注射溶液的形式制备本发明的化合物,除了PDE10抑制剂之外,所述水性注射溶液可包含缓冲剂、抗氧化剂、抑菌剂和这类溶液中通常使用的其它添加剂和赋形剂。可在递送体系中传递本发明的组合物以提供治疗化合物的缓释或增强吸收或活性,例如注射用脂质体或水凝胶体系,口服或肠胃外递送用的微粒、纳米粒或胶束体系,或者口服用的分级胶囊体系。
在本发明的其它优点中,期望结构(I)的化合物避免或减少与常规抗精神病药有关的代谢副作用,特别是治疗诱导的肥胖症的发生率。例如,奥氮平即治疗精神分裂症最常用的药物以及相关的非典型抗精神病药的长期使用与包括肥胖症和诸如糖尿病的相关疾病状态的严重代谢副作用有关。
在动物中,使用奥氮平的亚慢性治疗刺激食物摄取并增加体重,与人类状况一致。此外,奥氮平强烈降低血液瘦素水平。瘦素是由脂肪组织产生的饱腹感荷尔蒙,并且瘦素水平的降低刺激食欲。据推论,奥氮平能至少部分通过降低瘦素水平刺激食物摄取。在葡萄糖耐量试验中,奥氮平的急性给药还改变动物对葡萄糖和胰岛素水平的反应,其也可能与奥氮平对食物摄取和体重增加的影响直接相关。与奥氮平相比,本发明的PDE10抑制剂对代谢急性影响的检验,例如标准动物模型中代谢挑战过程中的瘦素、胰岛素和葡萄糖变化以及本发明的PDE10抑制剂对食物摄取、体重和能量体内平衡的慢性影响的检验,应提供PDE10抑制剂由于较少的副作用影响而作为抗精神病药的药物优点的证明。
可以组合形式或通过同时或相继给药而结合一种或多种附加治疗剂给予本发明的组合物。合适的附加试剂(即,佐剂)可包括诸如氟哌啶醇、氟非那嗪、氯丙嗪的阻滞多巴胺-D2受体和血清素5HT2受体的典型抗精神病药和诸如氯氮平、奥氮平、利培酮、喹硫平、齐拉西酮的非典型抗精神病药。
可通过改变Thompson和Appleman(Biochemistry 10;311-316;1971)的两步骤方法检验本发明的化合物以确定其IC50值。简言之,使用(3H)cAMP掺入cAMP并使用PDE10和各个浓度的结构(I)化合物培养。在合适的培养时间之后,通过加热终止反应。然后,使混合物进行使用蛇毒磷酸酶的处理。磷酸酶使混合物中的任何AMP水解,但使未反应的cAMP完整无损。因此,通过从混合物中分离cAMP并确定其浓度(通过射线照相术),能确定抑制百分比。通过在几种浓度下进行实验而使用标准图形方法能计算IC50值。用于IC50检验的实际技术的详细描述在下列实施例中进行阐述。为了该目的,本发明的PDE10抑制剂具有100μM或更少,通常小于10μM,且通常小于1μM的IC50。
可通过已知的有机合成技术,包括下列实施例中更详细描述的方法制备本发明的化合物。提供下列实施例是为了说明的目的而非限制。
实施例
实施例1
1-(4-(4-溴-3,5-二甲氧基苯基)噻唑-2-基)-2-甲氧基-2-(4-吗啉基苯基)乙酮
将烘干的烧瓶填充4-(4-吗啉基)苯甲醛(10.1g,53mmol)、无水甲醇(60mL)和无水二氧六环(60mL),然后安装加料漏斗。将加料漏斗填充KOH(14.8g,264mmol)的无水甲醇(60mL)溶液并将等分部分(约2mL)加入至反应混合物。将三溴甲烷(5.8mL,67.1mmol)加入至反应混合物,然后在10分钟内滴加剩余的KOH/MeOH溶液。在搅拌18h后,通过硅藻土过滤混合物并用甲醇冲洗。收集滤液并真空浓缩。然后,使用饱和NH4Cl水溶液稀释残留物并用EtOAc萃取。然后,另外的EtOAc用于萃取水相,同时使用浓HCl将pH从约8缓慢调整至约2。总共约1.5L的EtOAc用于萃取过程。在Na2SO4上干燥合并的EtOAc萃取物并过滤。真空浓缩滤液产生黄褐色固体形式的2-甲氧基-2-(4-吗啉基苯基)乙酸(7.25g,58%)。
在氩气下,在烘干的烧瓶中向2-甲氧基-2-(4-吗啉基苯基)乙酸(2.97g,11.8mmol)的无水CH2Cl2(66mL)悬浮液加入N-甲基吗啉(3mL,27.3mmol)并用冰冷却产生的溶液。滴加氯甲酸异丁酯(1.8mL,13.76mmol)。在搅拌50分钟后,加入N,O-二甲基羟胺盐酸盐(1.5g,15.3mmol)并使混合物缓慢升温至室温。在搅拌16小时后,加入饱和NaHCO3水溶液并将混合物搅拌大于15分钟。使用CH2Cl2稀释混合物并使层分离出来。使用盐水洗涤有机物、在MgSO4/Na2SO4上干燥并浓缩。通过层析纯化(60%-85%的EtOAc-己烷)产生淡白色固体形式的N,2-二甲氧基-N-甲基-2-(4-吗啉基苯基)乙酰胺(3.15g,90%的产率)。
在氩气下,将烘干的烧瓶填充4-溴-3,5-二甲氧基苯甲醛(10.08g,41.1mmol)和无水THF(70mL)。在-78℃浴中冷却混合物,然后从加料漏斗中滴加MeMgBr(3.0M的乙醚,17.8mL,53.4mmol)溶液,时间为45分钟。在搅拌20分钟后,使混合物升温至室温并搅拌19小时。在使用NH4Cl水溶液冷却后,用H2O和EtOAc将其稀释,然后在冰浴中冷却。在将混合物冷却后,将层分离。用H2O和盐水洗涤有机物,然后在Na2SO4上干燥并真空浓缩。将残留物溶于二氯甲烷并再次真空浓缩以产生白色固体形式的1-(4-溴-3,5-二甲氧基苯基)乙醇(10.8g,定量的产率)。使用所述产物而不需进一步纯化。
向1-(4-溴-3,5-二甲氧基苯基)乙醇(10.8g,41.1mmol)的无水CH2Cl2(150mL)溶液加入MnO2(48g,552mmol)。在干燥管下放置混合物并在室温下搅拌22小时后,通过硅藻土和硅胶的垫将其过滤并用EtOAc冲洗。真空浓缩滤液产生白色固体形式的1-(4-溴-3,5-二甲氧基苯基)乙酮(10.3g,97%的产率)。使用所述产物而不需进一步纯化。
在干燥管下,向1-(4-溴-3,5-二甲氧基苯基)乙酮(0.895g,3.45mmol)的无水CH2Cl2(5mL)溶液滴加新鲜制备的Br2的CH2Cl2(1.95M,1.9mL,3.7mmol)溶液。将反应在室温下搅拌30分钟,然后用饱和NaHCO3水溶液中和。用CH2Cl2稀释混合物并将层分离。用饱和NaHCO3水溶液和盐水洗涤有机物,然后在MgSO4/Na2SO4上干燥并真空浓缩。以CH2Cl2溶液形式将粗产物吸附在硅胶(2.9g)上。通过层析(0%-20%的EtOAc-己烷)纯化产生白色固体形式的2-溴-1-(4-溴-3,5-二甲氧基苯基)乙酮(0.737g,63%的产率)。进行2-溴-1-(4-溴-3,5-二甲氧基苯基)乙酮的大规模合成而不需层析纯化溴化物。
在氩气下,将烘干的烧瓶填充P2S5(0.53g,1.2mmol)、无水二氧六环(5mL)和甲酰胺(0.53mL,13.3mmol)。将反应烧瓶安装回流冷凝器和干燥管并回流2.25小时。在氩气下,将单独的烘干的烧瓶填充2-溴-1-(4-溴-3,5-二甲氧基苯基)乙酮(0.313g,0.93mmol)和无水二氧六环(6mL)。将硫代甲酰胺混合物(上述)倾入反应烧瓶并使固体留下。将反应烧瓶安装回流冷凝器,放置在干燥管下并回流3小时,然后冷却至室温。在搅拌过夜后,通过添加2M的Na2CO3水溶液使混合物变为碱性,用H2O稀释,然后用EtOAc萃取三次。用盐水洗涤合并的有机物,在Na2SO4上干燥并浓缩。将粗固体溶于CH2Cl2并吸附在硅胶上。通过层析(0%-35%的EtOAc-己烷)纯化产生白色固体形式的4-(4-溴-3,5-二甲氧基苯基)噻唑(0.20g,73%的产率)。
在氩气下,向-78℃的4-(4-溴-3,5-二甲氧基苯基)噻唑(0.096g,0.32mmol)的无水THF(2mL)溶液滴加LiHMDS(1.0M的THF,0.35mmol)溶液。在搅拌30分钟后,滴加N,2-二甲氧基-N-甲基-2-(4-吗啉基苯基)乙酰胺(0.121g,0.41mmol)的无水THF(1.5mL,1.0mL)溶液。在搅拌35分钟后,移去冷却浴并使反应升温至室温。用盐水冷却混合物并用EtOAc稀释。将层分离并用盐水洗涤有机层,在Na2SO4上干燥并浓缩。通过层析(25%-45%的EtOAc-己烷)纯化产生黄色固体形式的1-(4-(4-溴-3,5-二甲氧基苯基)噻唑-2-基)-2-甲氧基-2-(4-吗啉基苯基)乙酮(0.050g,29%的产率)。MS:m/z 533.1[M+H]+。
实施例2
1-(4-(4-溴-3,5-二甲氧基苯基)噁唑-2-基)-2-甲氧基-2-(4-吗啉基苯基)-乙酮
在氩气下,在烘干的烧瓶中将2-溴-1-(4-溴-3,5-二甲氧基苯基)乙酮(0.8g,0.96mmol)的甲酰胺(7mL)溶液在100℃下加热10小时,然后在110℃下加热5小时。在冷却至室温后,小心加入EtOAc和饱和NaHCO3水溶液并将混合物搅拌15分钟。然后,用EtOAc萃取两次并用H2O和盐水洗涤合并的有机物,在Na2SO4上干燥并浓缩。通过层析(20%-40%的EtOAc-己烷)纯化提供黄色固体形式的4-(4-溴-3,5-二甲氧基苯基)噁唑(0.387g,58%的产率)。
在氩气下,在烘干的烧瓶中向-20℃的4-(4-溴-3,5-二甲氧基苯基)噁唑(0.158g,0.56mmol)的无水THF(2mL)溶液滴加LDA(2.0M的THF/庚烷/乙基苯;0.37mL,0.74mmol)溶液。将混合物在-20℃至-10℃下搅拌50分钟,然后冷却至-20℃。加入N,2-二甲氧基-N-甲基-2-(4-吗啉基苯基)乙酰胺(0.245g,0.83mmol)的无水THF(3mL)溶液,然后使混合物缓慢升温至室温并搅拌总共21小时。用H2O冷却反应混合物并用EtOAc萃取。用盐水洗涤合并的有机物,在Na2SO4上干燥并浓缩。通过层析(50%-60%的EtOAc-己烷)纯化提供黄色固体形式的1-(4-(4-溴-3,5-二甲氧基苯基)噁唑-2-基)-2-甲氧基-2-(4-吗啉基苯基)-乙酮(0.097g,34%的产率)。MS:m/z 517.1[M+H]+。
实施例3
2-(4-(1H-吡唑-1-基)苯基)-1-(4-(4-溴-3,5-二甲氧基苯基)噻唑-2-基)-2-甲氧基乙酮
向搅拌的4-(1H-吡唑-1-基)苯甲醛(1.3g,7.55mmol)和三溴甲烷(0.85mL,9.75mmol)的MeOH(10mL)和二氧六环(10mL)溶液滴加氢氧化钾(2.2g,39mmol)的MeOH(10mL)溶液,时间为15分钟。然后继续搅拌23小时。通过硅藻土过滤混合物,使用EtOAc彻底冲洗并减压下浓缩以产生淡黄色固体形式的2-(4-(1H-吡唑-1-基)苯基)-2-甲氧基乙酸钾(3.2g),使用所述产物而不需进一步纯化。参见第7,129,238号美国专利。
在氩气下,向搅拌的2-(4-(1H-吡唑-1-基)苯基)-2-甲氧基乙酸钾(约7.55mmol)的干燥MeOH溶液滴加硫酸(2.0mL)。将混合物在80℃下加热17小时。在冷却至室温后,加入水,然后通过添加饱和NaHCO3水溶液使混合物变为碱性。用EtOAc萃取水相并用水和盐水洗涤合并的有机物,然后在Na2SO4上干燥并真空浓缩。通过层析(20%-35%的EtOAc-己烷)纯化提供无色油状物形式的2-(4-(1H-吡唑-1-基)苯基)-2-甲氧基乙酸甲酯(0.88g,两步47%的产率)。
在氩气下,向搅拌的2-(4-(1H-吡唑-1-基)苯基)-2-甲氧基乙酸甲酯(0.204g,0.83mmol)的干燥MeOH(5mL)溶液加入KOH的MeOH(1.6mL的0.5M溶液,8.3mmol)溶液并将反应加热至回流5小时。将反应混合物冷却至室温并减压下去除挥发物。用饱和NH4Cl水溶液稀释残留物并用EtOAc萃取。然后,使用另外的EtOAc萃取水相,同时使用浓HCl将pH从约8调整至约2。在Na2SO4上干燥合并的有机物,过滤并减压下去除溶剂以产生2-(4-(1H-吡唑-1-基)苯基)-2-甲氧基乙酸(0.18g,95%),使用其而不需进一步纯化。
在氩气下,向2-(4-(1H-吡唑-1-基)苯基)-2-甲氧基乙酸甲酯(0.18g,0.77mmol)的干燥二氯甲烷(5mL)溶液加入N-甲基吗啉(0.18mL,1.7mmol)。将反应混合物冷却至0℃,加入氯甲酸异丁酯(0.11mL,0.85mmol)并将混合物搅拌40分钟。然后,一次加入N,O-二甲基羟胺盐酸盐(0.098g,1mmol)并缓慢升温至室温,并搅拌18小时。用饱和NaHCO3水溶液稀释混合物并用EtOAc萃取。用盐水洗涤合并的有机物,在Na2SO4上干燥并真空浓缩。通过层析(0%-80%的EtOAc-己烷)纯化提供2-(4-(1H-吡唑-1-基)苯基)-N,2-二甲氧基-N-甲基乙酰胺(0.16g,76%的产率)。
在氩气下,向-20℃的4-(4-溴-3,5-二甲氧基苯基)噻唑(0.092g,0.305mmol)的无水THF(2mL)溶液滴加LDA(0.18mL的2.0M的THF/庚烷/乙基苯溶液,0.37mmol)溶液。在搅拌30分钟后,将反应冷却至-78℃并滴加2-(4-(1H-吡唑-1-基)苯基)-N,2-二甲氧基-N-甲基乙酰胺(0.15g,0.55mmol)的无水THF(1.5mL,1.0mL)溶液。在搅拌90分钟后,用盐水冷却混合物并用EtOAc稀释。将层分离并用盐水洗涤有机层,在Na2SO4上干燥并浓缩。通过层析(0%-35%的EtOAc-己烷)纯化产生黄色固体形式的2-(4-(1H-吡唑-1-基)苯基)-1-(4-(4-溴-3,5-二甲氧基苯基)噻唑-2-基)-2-甲氧基乙酮(0.030g,20%的产率)。MS:m/z 514.0[M+H]+。
实施例4
1-(4-(4-溴-3,5-二甲氧基苯基)-1-甲基-1H-咪唑-2-基)-2-甲氧基-2-(4-吗啉基苯基)乙酮
在氩气下,向烘干的烧瓶加入4-溴-3,5-二甲氧基苯甲醛(1.0g,4.08mmol)、无水EtOH(34mL)、对甲苯磺酰基甲基异腈(0.78g,4.0mmol)和KCN(0.035g,0.54mmol)。将混合物在室温下搅拌19小时并真空浓缩以产生5-(4-溴-3,5-二甲氧基苯基)-4-甲苯磺酰基-4,5-二氢噁唑,将其用于下一合成步骤而不需纯化。
向烘干的压力管加入5-(4-溴-3,5-二甲氧基苯基)-4-甲苯磺酰基-4,5-二氢噁唑(0.4g,0.91mmol)、甲胺-THF溶液(1.8mL的2.0M溶液,3.6mmol)和二甲苯(5mL)。在氩气下将管密封,然后在135℃下加热15小时。在冷却至室温后,将反应混合物转移并真空浓缩,然后在EtOAc和H2O之间分层。将层分离并用EtOAc萃取水层。用盐水将合并的有机物洗涤两次,在Na2SO4上干燥并浓缩。通过层析(50%-100%的EtOAc-己烷,然后2%-5%的MeOH-EtOAc)纯化提供淡黄色固体形式的4-(4-溴-3,5-二甲氧基苯基)-1-甲基-1H-咪唑(0.056g,21%的产率)。
使用修改的用于实施例3的最后的偶联步骤的方法。使反应升温至室温过夜。通过层析(40%-55%的EtOAc-己烷)纯化提供1-(4-(4-溴-3,5-二甲氧基苯基)-1-甲基-1H-咪唑-2-基)-2-甲氧基-2-(4-吗啉基苯基)乙酮(0.0039g,4%的产率)。MS:m/z 530.1[M+H]+。
实施例5
2-(4-(1H-吡唑-1-基)苯基)-1-(4-(4-溴-3,5-二甲氧基苯基)噁唑-2-基)-2-甲氧基乙酮
除了在-50℃下将酰胺加入至反应混合物之外,通过与用于实施例2的相似方法由2-(4-(1H-吡唑-1-基)苯基)-N,2-二甲氧基-N-甲基乙酰胺和4-(4-溴-3,5-二甲氧基苯基)噁唑合成2-(4-(1H-吡唑-1-基)苯基)-1-(4-(4-溴-3,5-二甲氧基苯基)噁唑-2-基)-2-甲氧基乙酮。MS:m/z498.1[M+H]+。
实施例6
1-(4-(4-溴-3,5-二甲氧基苯基)噁唑-2-基)-2-甲氧基-2-(4-(哌啶-1-基)苯基)乙酮
遵循实施例1的方法,以两步法由4-(哌啶-1-基)苯甲醛合成N,2-二甲氧基-N-甲基-2-(4-(哌啶-1-基)苯基)乙酰胺。遵循实施例5的方法,由N,2-二甲氧基-N-甲基-2-(4-(哌啶-1-基)苯基)乙酰胺和4-(4-溴-3,5-二甲氧基苯基)噁唑合成1-(4-(4-溴-3,5-二甲氧基苯基)噁唑-2-基)-2-甲氧基-2-(4-(哌啶-1-基)苯基)乙酮。MS:m/z 515.1[M+H]+。
实施例7
1-(4-(4-溴-3,5-二甲氧基苯基)噁唑-2-基)-2-甲氧基-2-(4-(吡咯烷-1-基)苯基)乙酮
遵循实施例1的合成的方法,由4-(吡咯烷-1-基)苯甲醛合成N,2-二甲氧基-N-甲基-2-(4-(吡咯烷-1-基)苯基)乙酰胺。除了在-45℃下将酰胺加入至反应混合物之外,遵循实施例2的方法,由N,2-二甲氧基-N-甲基-2-(4-(吡咯烷-1-基)苯基)乙酰胺和4-(4-溴-3,5-二甲氧基苯基)噁唑合成1-(4-(4-溴-3,5-二甲氧基苯基)噁唑-2-基)-2-甲氧基-2-(4-(吡咯烷-1-基)苯基)乙酮。MS:m/z 501.1[M+H]+。
实施例8
1-(4-(4-溴-3,5-二甲氧基苯基)噁唑-2-基)-2-(4-异丙氧基苯基)-2-甲氧基乙酮
将烘干的烧瓶填充4-异丙氧基苯甲醛(4.9g,29.9mmol)、无水甲醇(30mL)和无水二氧六环(30mL),然后安装加料漏斗。将加料漏斗填充KOH(8.4g,149.5mmol)的无水甲醇(30mL)溶液并将等分部分(约2mL)加入至反应混合物。将三溴甲烷(3.4mL,38.8mmol)加入至反应混合物,然后在10分钟内滴加剩余的KOH/MeOH溶液。在搅拌18小时后,真空浓缩混合物。用水稀释残留物并使用浓HCl将pH调整至约2,然后用EtOAc萃取。在Na2SO4上干燥合并的有机物并过滤。真空浓缩滤液产生淡黄色固体形式的2-(4-异丙氧基苯基)-2-甲氧基乙酸(6.8g),使用其而不需进一步纯化。
遵循实施例1的合成方法,由2-(4-异丙氧基苯基)-2-甲氧基乙酸合成2-(4-异丙氧基苯基)-N,2-二甲氧基-N-甲基乙酰胺。遵循实施例7的合成方法,由2-(4-异丙氧基苯基)-N,2-二甲氧基-N-甲基乙酰胺和4-(4-溴-3,5-二甲氧基苯基)噁唑合成1-(4-(4-溴-3,5-二甲氧基苯基)噁唑-2-基)-2-(4-异丙氧基苯基)-2-甲氧基乙酮。MS:m/z 490.1[M+H]+。
实施例9
1-(4-(4-溴-3,5-二甲氧基苯基)噁唑-2-基)-2-甲氧基-2-(喹啉-5-基)乙酮
遵循实施例1的合成方法,以两步法由喹啉-5-甲醛合成N,2-二甲氧基-N-甲基-2-(喹啉-5-基)乙酰胺。遵循实施例2的方法,由N,2-二甲氧基-N-甲基-2-(喹啉-5-基)乙酰胺和4-(4-溴-3,5-二甲氧基苯基)噁唑合成1-(4-(4-溴-3,5-二甲氧基苯基)噁唑-2-基)-2-甲氧基-2-(喹啉-5-基)乙酮。MS:m/z 483.0[M+H]+。
实施例10
1-(4-(4-溴-3,5-二甲氧基苯基)噁唑-2-基)-2-甲氧基-2-(喹啉-3-基)乙酮
遵循实施例1的合成方法,以两步法由喹啉-3-甲醛合成N,2-二甲氧基-N-甲基-2-(喹啉-3-基)乙酰胺。遵循实施例2的方法,由N,2-二甲氧基-N-甲基-2-(喹啉-3-基)乙酰胺和4-(4-溴-3,5-二甲氧基苯基)噁唑合成1-(4-(4-溴-3,5-二甲氧基苯基)噁唑-2-基)-2-甲氧基-2-(喹啉-3-基)乙酮。MS:m/z 483.1[M+H]+。
实施例11
1-(4-(4-溴-3,5-二甲氧基苯基)噁唑-2-基)-2-甲氧基-2-(4-(5-甲基-1,3,4-噁二唑-2-基)苯基)乙酮
遵循实施例1的合成方法,以两步法由4-(5-甲基-1,3,4-噁二唑-2-基)苯甲醛合成N,2-二甲氧基-N-甲基-2-(4-(5-甲基-1,3,4-噁二唑-2-基)苯基)乙酰胺。除了在-30℃下将酰胺加入至反应混合物之外,遵循实施例2的方法,由N,2-二甲氧基-N-甲基-2-(4-(5-甲基-1,3,4-噁二唑-2-基)苯基)乙酰胺和4-(4-溴-3,5-二甲氧基苯基)噁唑合成1-(4-(4-溴-3,5-二甲氧基苯基)噁唑-2-基)-2-甲氧基-2-(4-(5-甲基-1,3,4-噁二唑-2-基)苯基)乙酮。MS:m/z 514.0[M+H]+。
实施例12
1-(5-(4-溴-3,5-二甲氧基苯基)呋喃-2-基)-2-甲氧基-2-(4-吗啉基苯基)乙酮
向包含4-溴-3,5-二甲氧基苯胺(1.99g,8.56mmol;根据US2006/128695合成)的H2O(60mL)悬浮液的烧瓶缓慢加入浓H2SO4(10mL)。通过用冰冷却控制放热,然后将反应冷却至-10℃至-8℃(浴温度)。在6分钟时间内滴加NaNO2(0.70g,10mmol)的H2O(3.5mL)溶液后,将混合物搅拌70分钟。滴加KI(2.8g,16.9mmol)的H2O(3.5mL)溶液并在-10℃至-5℃下将混合物搅拌30分钟。在移去冷却浴后,将混合物搅拌80分钟,然后加入EtOAc并将混合物搅拌另外40分钟。将层分离并用EtOAc将水层萃取几次。用1M的NaOH将合并的有机物洗涤两次,再用10%的Na2S2O3洗涤两次并用盐水洗涤,然后在Na2SO4上干燥。通过层析(0%-20%的EtOAc-己烷)纯化提供2-溴-5-碘-1,3-二甲氧基苯(1.86g,63%的产率)。
根据WO 2008/040669中报道的步骤按如下合成2-(4-溴-3,5-二甲氧基苯基)呋喃。向包含3,5-二甲氧基-4-溴-碘苯(7.9g,85%纯度,19.6mmol)、2-呋喃硼酸(3.4g,30.4mmol)、三苯基膦(0.358g,1.37mmol)、四丁基溴化铵(7.94g,14.6mmol)和Na2CO3(4.9g,46.2mmol)的圆底烧瓶加入THF(87mL)和H2O(87mL)。通过交替放置在室内真空和氩气中三次每次几分钟将混合物脱气。加入10%的Pd/C(1.36g)并在氩气下将混合物在60℃下加热17小时。在冷却至室温后,通过硅藻土过滤混合物并用THF和EtOAc冲洗。将滤液层分离并用盐水洗涤有机层,在Na2SO4上干燥并浓缩。通过柱层析(0%-25%的Et2O-己烷)纯化产生白色固体形式的2-(4-溴-3,5-二甲氧基苯基)呋喃(5.06g,91%的产率)。产物TLC Rf 0.35(15%的EtOAc-己烷TLC洗脱液)。
在氩气下,在烘干的烧瓶中,向冷却至-78℃的2-(4-溴-3,5-二甲氧基苯基)呋喃(0.203g,0.72mmol)的无水THF(2mL)溶液滴加二异丙基氨基锂(2.0M的THF/庚烷/乙基苯;0.4mL,0.8mmol)溶液。在-78℃下搅拌35分钟后,滴加N,2-二甲氧基-N-甲基-2-(4-吗啉基苯基)乙酰胺(0.315g,1.1mmol)的THF(2mL)溶液。在搅拌25分钟后,使混合物升温至室温同时搅拌2小时。通过添加饱和NH4Cl水溶液然后添加盐水冷却反应并加入EtOAc。将层分离并用盐水洗涤有机层,在Na2SO4上干燥并真空浓缩。通过柱层析(35%-65%的EtOAc-己烷)纯化提供油状物,伴随超声处理用MeOH-Et2O(1:1)研磨。在布氏漏斗上收集固体,用MeOH-Et2O(1:1)冲洗并真空干燥以产生黄色固体形式的1-(5-(4-溴-3,5-二甲氧基苯基)呋喃-2-基)-2-甲氧基-2-(4-吗啉基苯基)乙酮。从MeOH-Et2O中收集第二批(约10%)以产生另外的产物(总共0.220g,59%的产率)。MS:m/z 516.1[M+H]+。
实施例13
1-(5-(4-溴-3,5-二甲氧基苯基)呋喃-2-基)-2-甲氧基-2-(4-(5-甲基-1,3,4-噁二唑-2-基)苯基)乙酮
在-15℃至-10℃(浴温度)下,向4-(5-甲基-1,3,4-噁二唑-2-基)苯甲醛(5.12g,27.2mmol)的无水MeOH(27mL)和无水二氧六环(27mL)溶液加入几滴KOH(7.6g,135.4mmol)的MeOH(27mL)溶液。加入三溴甲烷(3mL,34.4mmol),然后在20分钟时间内加入剩余的KOH/MeOH溶液。将混合物搅拌1小时并移去冷却浴。在搅拌30分钟后,将反应置入冰浴中进行并使其缓慢升温至室温过夜,然后浓缩至干燥。在溶于最少量的H2O后,使用6M的HCl将残留物酸化至pH 1。用EtOAc将水性混合物萃取几次,同时在萃取过程中向水层添加盐水。用盐水洗涤合并的有机物,在Na2SO4上干燥并真空浓缩以产生半固体形式的2-甲氧基-2-(4-(5-甲基-1,3,4-噁二唑-2-基)苯基)乙酸(6.8g,定量的产率)。使用所述产物而不需进一步纯化。
在氩气下,向冰冷的2-甲氧基-2-(4-(5-甲基-1,3,4-噁二唑-2-基)苯基)乙酸(6.8g,27.4mmol)的无水CH2Cl2(270mL)和二异丙基乙胺(17mL,97mmol)溶液滴加双(2-甲氧基乙基)氨基三氟化硫(5.6mL,30.3mmol)。在冰浴中搅拌45分钟后,在15分钟时间内以三等分部分加入N,O-二甲基羟胺盐酸盐(3.40g,34.8mmol)。将混合物搅拌15分钟,然后去除冰浴。在3小时后,加入饱和NaHCO3水溶液并搅拌30分钟。将层分离并用CH2Cl2萃取水层。使用饱和NaHCO3水溶液、H2O和盐水洗涤合并的有机物,在MgSO4上干燥,通过硅藻土过滤并真空浓缩。通过层析(75%-100%的EtOAc-己烷然后0%-5%的EtOH-EtOAc)纯化产生经静止凝固的油状物形式的N,2-二甲氧基-N-甲基-2-(4-(5-甲基-1,3,4-噁二唑-2-基)苯基)乙酰胺(2.06g,26%的产率)。
根据用于实施例12的合成方法,将2-(4-溴-3,5-二甲氧基苯基)呋喃与N,2-二甲氧基-N-甲基-2-(4-(5-甲基-1,3,4-噁二唑-2-基)苯基)乙酰胺偶联。通过层析(50%-80%的EtOAc-己烷)纯化提供黄色泡沫形式的1-(5-(4-溴-3,5-二甲氧基苯基)呋喃-2-基)-2-甲氧基-2-(4-(5-甲基-1,3,4-噁二唑-2-基)苯基)乙酮(0.356g,40%的产率)。MS:m/z513.2[M+H]+。
实施例14
2-(4-(1H-吡唑-1-基)苯基)-1-(5-(4-溴-3,5-二甲氧基苯基)呋喃-2-基)-2-甲氧基乙酮
使用用于实施例12的最终偶联步骤的方法。通过层析(20%-55%的EtOAc-己烷)纯化提供淡黄色固体形式的2-(4-(1H-吡唑-1-基)苯基)-1-(5-(4-溴-3,5-二甲氧基苯基)呋喃-2-基)-2-甲氧基乙酮(0.0625g,37%的产率)。MS:m/z 497.2[M+H]+。
实施例15
2-(4-(1H-吡唑-4-基)苯基)-1-(5-(4-溴-3,5-二甲氧基苯基)呋喃-2-基)-2-甲氧基乙酮
在氩气下,向4-溴吡唑(1.5g,10.2mmol)和4,4’,4”-三甲氧基三苯甲基氯(4.5g,12.2mmol)的无水DMF(20mL)悬浮液加入三乙胺(3mL,21.5mmol)并在冰浴中冷却混合物。在搅拌10分钟后,去除冰浴并将反应搅拌2.5小时。用H2O稀释混合物并用EtOAc萃取。用H2O将合并的有机物洗涤三次,然后用饱和NaHCO3水溶液和盐水洗涤。在Na2SO4上干燥溶液并真空浓缩。从异丙醇中将粗油状物重结晶以产生淡白色晶体形式的4-溴-1-(三(4-甲氧基苯基)甲基)-1H-吡唑(两批次;2.55g,52%的产率)。
通过交替放置在室内真空和氩气下三次每次几分钟将4-溴-1-(三(4-甲氧基苯基)甲基)-1H-吡唑(1.47g,3.1mmol)、(4-甲酰基苯基)硼酸(0.94g,6.3mmol)和K2CO3(0.65g,4.7mmol)的DME-H2O(25mL,4:1)混合物脱气。加入四(三苯基膦)钯(0.35g,0.3mmol),然后将混合物再次脱气。在80℃下加热16.5小时并冷却至室温后,加入H2O。用EtOAc萃取混合物并用H2O、饱和NaHCO3水溶液和盐水洗涤合并的有机物,然后在Na2SO4上干燥并真空浓缩。通过层析(20%-30%的EtOAc-己烷;含1%Et3N的EtOAc)纯化产生4-(1-(三(4-甲氧基苯基)甲基)-1H-吡唑-4-基)苯甲醛(1.31g合并来自两个反应的,33%)。
除了分离钾盐之外,使用用于实施例1的合成方法。在室温下反应后,加入EtOAc并通过硅藻土过滤混合物并真空浓缩。将残留物溶于EtOAc,通过硅藻土过滤并真空浓缩。将产物溶于EtOAc-甲苯并浓缩以产生2-甲氧基-2-(4-(1-(三(4-甲氧基苯基)甲基)-1H-吡唑-4-基)苯基)乙酸钾(1.75g,定量的产率),使用其而不需进一步纯化。
在氩气下,向冰冷的2-甲氧基-2-(4-(1-(三(4-甲氧基苯基)甲基)-1H-吡唑-4-基)苯基)乙酸钾(1.25g,2.1mmol)的无水DMF(10mL)溶液滴加二异丙基乙胺(0.54mL,3.1mmol)和双(2-甲氧基乙基)氨基三氟化硫(0.46mL,2.5mmol)。将反应搅拌30分钟,然后加入N,O-二甲基羟胺盐酸盐(0.303g,3.1mmol)。在冰浴中搅拌另外15分钟后,使混合物升温至室温并搅拌3.5小时。加入H2O并用EtOAc萃取混合物。用H2O、饱和NH4Cl水溶液、饱和NaHCO3水溶液和盐水洗涤合并的有机物,然后在Na2SO4上干燥并真空浓缩。通过层析(45%-90%的EtOAc-己烷;含1%Et3N的EtOAc)纯化以产生N,2-二甲氧基-N-甲基-2-(4-(1-(三(4-甲氧基苯基)甲基)-1H-吡唑-4-基)苯基)乙酰胺(0.478g来自两个反应,32%的总产率)。
除了在室温下反应70分钟的较短反应时间之外,使用用于实施例12的最终偶联步骤的方法。通过层析(35%-90%的EtOAc-己烷;含1%的Et3N的EtOAc)纯化提供固体形式的1-(5-(4-溴-3,5-二甲氧基苯基)呋喃-2-基)-2-甲氧基-2-(4-(1-(三(4-甲氧基苯基)甲基)-1H-吡唑-4-基)苯基)乙酮(0.10g,18%的产率)。
向1-(5-(4-溴-3,5-二甲氧基苯基)呋喃-2-基)-2-甲氧基-2-(4-(1-(三(4-甲氧基苯基)甲基)-1H-吡唑-4-基)苯基)乙酮(0.10g,0.12mmol)的MeOH-H2O(22mL,10:1)悬浮液加入吡啶鎓对甲苯磺酸盐(0.046g,0.16mmol)。在室温下搅拌18小时后,加入饱和NaHCO3水溶液并真空去除挥发物。用少量的H2O稀释残留物,然后用EtOAc萃取。用H2O和盐水洗涤合并的有机物,在Na2SO4上干燥并真空浓缩。通过层析(50%-100%的EtOAc-己烷)纯化提供黄色泡沫形式的2-(4-(1H-吡唑-4-基)苯基)-1-(5-(4-溴-3,5-二甲氧基苯基)呋喃-2-基)-2-甲氧基乙酮(0.010g,17%的产率)。MS:m/z 497.0[M+H]+。
实施例16
1-(5-(4-溴-3,5-二甲氧基苯基)呋喃-2-基)-2-甲氧基-2-(4-(5-甲基呋喃-2-基)苯基)乙酮
使用实施例1描述的方法,由4-(5-甲基呋喃-2-基)苯甲醛合成2-甲氧基-2-(4-(5-甲基呋喃-2-基)苯基)乙酸(3.3g,定量的产率)。使用所述产物而不需进一步纯化。
遵循实施例13的方法,由2-甲氧基-2-(4-(5-甲基呋喃-2-基)苯基)乙酸合成N,2-二甲氧基-N-甲基-2-(4-(5-甲基呋喃-2-基)苯基)乙酰胺。分离橙色油状物形式的产物(0.693g,18%的产率)。
遵循实施例12的最终偶联步骤的方法,将2-(4-溴-3,5-二甲氧基苯基)呋喃与N,2-二甲氧基-N-甲基-2-(4-(5-甲基呋喃-2-基)苯基)乙酰胺偶联。通过层析(30%-60%的EtOAc-己烷)纯化提供淡橙色固体形式的1-(5-(4-溴-3,5-二甲氧基苯基)呋喃-2-基)-2-甲氧基-2-(4-(5-甲基呋喃-2-基)苯基)乙酮(0.172g,47%的产率)。MS:m/z 511.0[M+H]+。
实施例17
2,3-二甲氧基-5-(5-(2-甲氧基-2-(4-(5-甲基-1,3,4-噁二唑-2-基)苯基)乙酰基)呋喃-2-基)苯甲腈
向5-溴-2,3-二甲氧基苯甲腈(0.958g,4.0mmol)、2-呋喃硼酸(0.53g,4.7mmol)、二氧六环(24mL)、H2O(8mL)和Na2CO3(1.1g,10.4mmol)的混合物加入四(三苯基膦)钯(0.23g,0.2mmol)。通过交替放置在室内真空和氩气中三次每次几分钟将混合物脱气,然后在氩气下在85℃下加热16.5小时。在冷却至室温后,用H2O稀释混合物并用EtOAc萃取。用H2O和盐水洗涤合并的有机物,在Na2SO4上干燥并真空浓缩。通过层析(0%-20%的EtOAc-己烷)纯化提供白色固体形式的5-(呋喃-2-基)-2,3-二甲氧基苯甲腈(0.85g,94%的产率)。
除了在-40℃至-25℃下进行反应然后升温至室温之外,将用于实施例12的最终偶联步骤的方法用于5-(呋喃-2-基)-2,3-二甲氧基苯甲腈和N,2-二甲氧基-N-甲基-2-(4-(5-甲基-1,3,4-噁二唑-2-基)苯基)乙酰胺的反应。通过层析(20%-100%的EtOAc-己烷)纯化提供2,3-二甲氧基-5-(5-(2-甲氧基-2-(4-(5-甲基-1,3,4-噁二唑-2-基)苯基)乙酰基)呋喃-2-基)苯甲腈(0.040g,13%的产率)。MS:m/z 460.2[M+H]+。
实施例18
1-(5-(4-溴-3,5-二甲氧基苯基)呋喃-2-基)-2-(4-(5-乙基-1,3,4-噁二唑-2-基)苯基)-2-甲氧基乙酮
向4-(((叔丁基二甲基甲硅烃基)氧基)甲基)苯甲酰肼(6.0g,21.4mmol;Tanaka,A.等人,J.Med.Chem.1998,41,2390中报道的)和丙亚氨酸乙酯盐酸盐(3.5g,25.7mmol;WO2007/73299A1中报道的制备)的EtOH(120mL)溶液加入Et3N(2.59g,25.7mmol)。在室温下将混合物搅拌1小时,然后真空浓缩。在EtOAc和H2O中将残留物分层并用H2O和盐水洗涤有机物,在Na2SO4上干燥并真空浓缩。通过层析(EtOAc-己烷)纯化产生褐色油状物形式的2-(4-(((叔丁基二甲基甲硅烃基)氧基)甲基)苯基)-5-乙基-1,3,4-噁二唑(3.0g,44%的产率)。
向冰冷的2-(4-(((叔丁基二甲基甲硅烃基)氧基)甲基)苯基)-5-乙基-1,3,4-噁二唑(3.0g,9.4mmol)的MeOH(30mL)溶液滴加1M的HCl(20mL,20mmol)。将反应用冰搅拌1小时,然后浓缩。用饱和NaHCO3水溶液冷却残留物并用EtOAc萃取。在Na2SO4上干燥合并的有机物并真空浓缩以产生淡白色固体形式的(4-(5-乙基-1,3,4-噁二唑-2-基)苯基)甲醇(1.92g,93%的产率)。
向(4-(5-乙基-1,3,4-噁二唑-2-基)苯基)甲醇(1.8g,8.8mmol)的CH2Cl2(50mL)溶液加入分子筛并将混合物冷却至0℃。向反应混合物分批加入氯铬酸吡啶鎓(2.27g,10.5mmol),然后将其升温至室温。在搅拌2小时后,通过硅藻土过滤混合物并用另外的CH2Cl2冲洗。真空浓缩滤液。通过层析(EtOAc-己烷)纯化提供淡白色固体形式的4-(5-乙基-1,3,4-噁二唑-2-基)苯甲醛(1.3g,70%)。
向4-(5-乙基-1,3,4-噁二唑-2-基)苯甲醛(1.6g,7.9mmol)的无水DMF(7mL)溶液加入CHCl3(2.13g,17.8mmol)。在冷却至-10℃后,在20分钟内滴加KOH(0.31g,5.5mmol)的无水MeOH(1.5mL)溶液。在-10℃下搅拌1小时后,用1M的HCl冷却反应混合物。在布氏漏斗上收集形成的固体,用H2O洗涤并在真空下干燥以产生白色固体形式的2,2,2-三氯-1-(4-(5-乙基-1,3,4-噁二唑-2-基)苯基)乙醇(2.0g,80%的产率)。
向2,2,2-三氯-1-(4-(5-乙基-1,3,4-噁二唑-2-基)苯基)乙醇(2.0g,6.25mmol)的无水1,4-二氧六环(12.5mL)和无水MeOH(15mL)溶液加入NaOH(1.25g,31.3mmol)的无水MeOH(15mL)溶液。在55℃下搅拌4小时后,将混合物冷却至室温并真空浓缩。使用饱和NH4Cl水溶液将残留物中和,用1M的HCl小心酸化并用EtOAc萃取。在Na2SO4上干燥合并的有机物并真空浓缩。用Et2O研磨残留物以产生淡白色固体形式的2-(4-(5-乙基-1,3,4-噁二唑-2-基)苯基)-2-甲氧基乙酸(1.2g,73%的产率)。
遵循实施例1的合成方法用于由2-(4-(5-乙基-1,3,4-噁二唑-2-基)苯基)-2-甲氧基乙酸合成2-(4-(5-乙基-1,3,4-噁二唑-2-基)苯基)-N,2-二甲氧基-N-甲基乙酰胺。通过层析(20%的EtOAc-己烷)纯化产生非结晶固体形式的2-(4-(5-乙基-1,3,4-噁二唑-2-基)苯基)-N,2-二甲氧基-N-甲基乙酰胺(0.55g,40%的产率)。
用于2-(4-溴-3,5-二甲氧基苯基)呋喃与2-(4-(5-乙基-1,3,4-噁二唑-2-基)苯基)-N,2-二甲氧基-N-甲基乙酰胺的反应遵循实施例12的最终偶联步骤的方法。通过层析(20%-100%的EtOAc-己烷)纯化产生黄色泡沫形式的1-(5-(4-溴-3,5-二甲氧基苯基)呋喃-2-基)-2-(4-(5-乙基-1,3,4-噁二唑-2-基)苯基)-2-甲氧基乙酮(0.037g,12%的产率)。MS:m/z 527.1[M+H]+。
实施例19
1-(5-(4-溴-3,5-二甲氧基苯基)呋喃-2-基)-2-(4-(1,1-二氧代异噻唑啉-2-基)苯基)-2-甲氧基乙酮
遵循实施例1的合成方法,由4-硝基苯甲醛合成2-甲氧基-2-(4-硝基苯基)乙酸。使用水萃取后分离的酸而不需进一步纯化(5.3g,76%的产率)。
根据用于实施例3合成的步骤将2-甲氧基-2-(4-硝基苯基)乙酸酯化。通过层析(15%-22%的EtOAc-己烷)纯化产生黄色油状物形式的2-甲氧基-2-(4-硝基苯基)乙酸甲酯(2.15g,38%的产率)。
通过交替放置在室内真空和氩气下三次每次几分钟将2-甲氧基-2-(4-硝基苯基)乙酸甲酯(0.42g,1.87mmol)的无水EtOH(15mL)溶液脱气,然后加入10%的Pd/C(0.19g)。在H2(1atm.)下将混合物搅拌3小时,然后用EtOAc稀释并通过硅藻土和硅胶的垫过滤。真空浓缩滤液。通过层析(25%-40%的EtOAc-己烷)纯化提供含杂质的黄色油状物形式的2-(4-氨基苯基)-2-甲氧基乙酸甲酯(0.6g来自两批次,77%的产率)。使用所述化合物而不需进一步纯化。
在氩气下,向2-(4-氨基苯基)-2-甲氧基乙酸甲酯(0.6g,3.07mmol)的无水吡啶(6mL)溶液滴加3-氯丙烷-1-磺酰氯(0.5mL,4.11mmol)。在冷的H2O浴中短暂冷却放热反应。在搅拌1小时后,用H2O、1M的HCl和盐水稀释反应并用EtOAc萃取。用1M的HCl、H2O和盐水洗涤合并的有机物,然后在Na2SO4上干燥并真空浓缩以产生橙色油状物形式的2-(4-(3-氯丙基磺酰胺基)苯基)-2-甲氧基乙酸甲酯(1.03g,定量的产率)。使用所述产物而不需进一步纯化。
向2-(4-(3-氯丙基磺酰胺基)苯基)-2-甲氧基乙酸甲酯(1.03g,3.07mmol)的无水DMF(10mL)溶液加入N,N-二异丙基乙胺(2.0mL,11.5mmol)。在氩气下,将混合物在50℃下加热17小时。在冷却至室温后,用H2O、1M的HCl和盐水稀释反应,然后用EtOAc萃取。用1M的HCl、H2O和盐水洗涤合并的有机物,在Na2SO4上干燥并真空浓缩。用Et2O-EtOAc研磨残留物。在放置过夜后,从固体中倾倒出溶液,然后真空浓缩。通过层析(50%-70%的EtOAc-己烷)纯化提供不纯油状物形式的2-(4-(1,1-二氧代异噻唑啉-2-基)苯基)-2-甲氧基乙酸甲酯(0.69g,75%的产率)。将所述产物用于下一合成步骤而不需进一步纯化。
向2-(4-(1,1-二氧代异噻唑啉-2-基)苯基)-2-甲氧基乙酸甲酯(0.48g,1.6mmol)的MeOH(21mL)溶液缓慢加入1M的NaOH(7mL,7mmol)。在室温下搅拌23小时后,真空去除挥发物并将残留物溶于H2O。将EtOAc加入至水溶液以及饱和NH4Cl水溶液并缓慢加入1M的HCl直至pH为约3。用EtOAc萃取混合物,然后将水层酸化至pH 1并用EtOAc再次萃取。用H2O和盐水洗涤合并的有机物,在Na2SO4上干燥并真空浓缩以产生黄色泡沫形式的2-(4-(1,1-二氧代异噻唑啉-2-基)苯基)-2-甲氧基乙酸(0.378g,82%的产率)。将所述产物用于下一合成步骤而不需进一步纯化。
按照实施例13的合成步骤,由2-(4-(1,1-二氧代异噻唑啉-2-基)苯基)-2-甲氧基乙酸合成2-(4-(1,1-二氧代异噻唑啉-2-基)苯基)-N,2-二甲氧基-N-甲基乙酰胺。通过层析(0%-4%EtOH-EtOAc)纯化产生油状物,用Et2O将其研磨。在真空下干燥固体以产生纯净的淡黄色粉末形式的2-(4-(1,1-二氧代异噻唑啉-2-基)苯基)-N,2-二甲氧基-N-甲基乙酰胺(0.182g,64%的产率)。
遵循实施例12的合成步骤,由2-(4-(1,1-二氧代异噻唑啉-2-基)苯基)-N,2-二甲氧基-N-甲基乙酰胺和2-(4-溴-3,5-二甲氧基苯基)呋喃合成1-(5-(4-溴-3,5-二甲氧基苯基)呋喃-2-基)-2-(4-(1,1-二氧代异噻唑啉-2-基)苯基)-2-甲氧基乙酮。通过层析(EtOAc-己烷)纯化提供黄色固体形式的实施例19(0.111g,37%的产率)。MS:m/z 550.1[M+H]+。
实施例20
1-(5-(4-溴-3,5-二甲氧基苯基)呋喃-2-基)-2-甲氧基-2-(喹啉-5-基)乙酮
向冰冷的喹啉-5-甲醛(3.5g,22.3mmol)的无水MeOH(30mL)和无水二氧六环(30mL)溶液加入几滴KOH(6.2g,113.4mmol)的MeOH(30mL)溶液。加入三溴甲烷(2.5mL,30mmol),然后在10分钟时间内加入剩余的KOH/MeOH溶液。在搅拌30分钟后,使反应混合物缓慢升温至室温过夜,然后浓缩至干燥。在溶于最少量的H2O后,用浓HCl将残留物酸化至pH1。用EtOAc将水性混合物萃取几次,同时在萃取过程中向水层加入盐水。用盐水洗涤合并的有机物,在Na2SO4上干燥并真空浓缩以产生半固体形式的2-甲氧基-2-(喹啉-5-基)乙酸(2.8g,58%的产率)。使用所述产物而不需进一步纯化。
在氩气下,向冰冷的2-甲氧基-2-(喹啉-5-基)乙酸(2.8g,12.9mmol)的无水CH2Cl2(50mL)和NMM(3.1mL,29mmol)溶液滴加氯甲酸异丁酯(1.9mL,14mmol)。在冰浴中搅拌40分钟后,在15分钟时间内以三等分部分加入N,O-二甲基羟胺盐酸盐(1.63g,16.8mmol)。将混合物搅拌15分钟,然后去除冰浴。在24小时后,加入饱和NaHCO3水溶液并搅拌30分钟。将层分离并用CH2Cl2萃取水层。用饱和NaHCO3水溶液、H2O和盐水洗涤合并的有机物,在Na2SO4上干燥并真空浓缩。通过层析(0%-100%的EtOAc-己烷)纯化产生油状物形式的N,2-二甲氧基-N-甲基-2-(喹啉-5-基)乙酰胺,其经静止变成晶体(1.8g,60%的产率)。
遵循实施例12的合成步骤,由N,2-二甲氧基-N-甲基-2-(喹啉-5-基)乙酰胺和2-(4-溴-3,5-二甲氧基苯基)呋喃合成1-(5-(4-溴-3,5-二甲氧基苯基)呋喃-2-基)-2-甲氧基-2-(喹啉-5-基)乙酮。通过层析(EtOAc-己烷)纯化提供淡黄色泡沫形式的1-(5-(4-溴-3,5-二甲氧基苯基)呋喃-2-基)-2-甲氧基-2-(喹啉-5-基)乙酮(0.102g,46%的产率)。MS:m/z 482.1[M+H]+。
实施例21
1-(5-(3,5-二甲氧基-4-甲基苯基)呋喃-2-基)-2-甲氧基-2-(4-(5-甲基-1,3,4-噁二唑-2-基)苯基)乙酮
向3,5-二甲氧基-4-甲基苯甲醛(3.0g,16.8mmol)的CH2Cl2(35mL)溶液加入间氯过氧苯甲酸(77%纯度;5.8g,25.9mmol)。在室温下搅拌19小时后,加入另外的间氯过氧苯甲酸(77%纯度;3.5g,15.6mmol)。在40℃下加热4小时并冷却至室温后,加入10%的Na2S2O5水溶液并将混合物搅拌30分钟。用CH2Cl2稀释混合物并将层分离。用10%的Na2S2O5水溶液,约5%的NaHCO3水溶液和盐水洗涤有机物并在MgSO4上干燥并浓缩以产生黄色固体形式的3,5-二甲氧基-4-甲基苯基甲酸酯(2.9g,88%的产率)。
向3,5-二甲氧基-4-甲基苯基甲酸酯(2.9g,14.8mmol)的湿MeOH(81mL)溶液加入K2CO3(8.1g,58.6mmol)。在室温下将混合物搅拌2小时,然后加入H2O(2mL-3mL)。在搅拌21小时后,用H2O稀释混合物,用6M的HCl酸化至pH 3-4,用EtOAc萃取。用盐水洗涤合并的有机物,在Na2SO4上干燥并真空浓缩。通过层析(0%-35%的EtOAc-己烷)纯化产生不纯黄色粉末形式的3,5-二甲氧基-4-甲基苯酚(0.71g,29%的产率)。
在氩气下,向3,5-二甲氧基-4-甲基苯酚的无水CH2Cl2(10mL)悬浮液加入干燥的吡啶(0.4mL,4.9mmol),然后在冰浴中冷却混合物。滴加三氟甲烷磺酸酐(0.52g,3.1mmol)并将反应搅拌1小时。加入饱和NaHCO3水溶液并搅拌,然后将其升温至室温。用CH2Cl2稀释混合物并将层分离。用H2O和饱和NaHCO3水溶液洗涤有机物,然后在MgSO4上干燥并真空浓缩以产生黄色油状物形式的3,5-二甲氧基-4-甲基苯基三氟甲烷磺酸酯(0.508g,60%的产率)。使用所述产物而不需进一步纯化。
向3,5-二甲氧基-4-甲基苯基三氟甲烷磺酸酯(0.50g,1.67mmol)的DME(15mL)溶液加入2-呋喃硼酸(0.245g,2.2mmol)、LiCl(0.149g,3.5mmol)、2M的Na2CO3(1.8mL,3.6mmol)水溶液和四(三苯基膦)钯(0.098g,0.085mmol)并按照前面的描述将混合物脱气。在氩气下,将反应在80℃下加热22小时。在冷却至室温后,用H2O稀释反应并用EtOAc萃取。用H2O、饱和NH4Cl水溶液、H2O和盐水洗涤合并的有机物,在Na2SO4上干燥并真空浓缩。通过层析(0%-25%的Et2O-己烷)纯化产生白色固体形式的2-(3,5-二甲氧基-4-甲基苯基)呋喃(0.28g,77%的产率)。
遵循实施例12合成的步骤,使N,2-二甲氧基-N-甲基-2-(4-(5-甲基-1,3,4-噁二唑-2-基)苯基)乙酰胺与2-(3,5-二甲氧基-4-甲基苯基)呋喃反应。通过层析(EtOAc-己烷)纯化产生黄色泡沫形式的1-(5-(3,5-二甲氧基-4-甲基苯基)呋喃-2-基)-2-甲氧基-2-(4-(5-甲基-1,3,4-噁二唑-2-基)苯基)乙酮(0.148g,29%的产率)。MS:m/z 449.2[M+H]+。
实施例22
1-(5-(4-溴-3,5-二甲氧基苯基)呋喃-2-基)-2-(4-(5-环丙基-1,3,4-噁二唑-2-基)苯基)-2-甲氧基乙酮
遵循实施例18的合成步骤,使4-(((叔丁基二甲基甲硅烃基)氧基)甲基)苯甲酰肼与乙基环丙烷碳二亚胺盐酸盐反应。通过层析(EtOAc-己烷)纯化产生褐色油状物形式的2-(4-(((叔丁基二甲基甲硅烃基)氧基)甲基)苯基)-5-环丙基-1,3,4-噁二唑(3.7g,40%的产率)。
根据实施例18的步骤,由2-(4-(((叔丁基二甲基甲硅烃基)氧基)甲基)苯基)-5-环丙基-1,3,4-噁二唑合成(4-(5-环丙基-1,3,4-噁二唑-2-基)苯基)甲醇。分离淡白色固体形式的(4-(5-环丙基-1,3,4-噁二唑-2-基)苯基)甲醇并将其用于下一合成步骤而不需进一步纯化(2.2g,84%的产率)。
根据实施例18的步骤,由(4-(5-环丙基-1,3,4-噁二唑-2-基)苯基)甲醇合成4-(5-环丙基-1,3,4-噁二唑-2-基)苯甲醛。通过层析(EtOAc-己烷)纯化产生白色固体形式的4-(5-环丙基-1,3,4-噁二唑-2-基)苯甲醛(1.8g,82%的产率)。
遵循实施例18的合成步骤,由4-(5-环丙基-1,3,4-噁二唑-2-基)苯甲醛合成2,2,2-三氯-1-(4-(5-环丙基-1,3,4-噁二唑-2-基)苯基)乙醇。分离白色固体形式的产物并使用而不需进一步纯化(2.5g,89%的产率)。
遵循实施例18的合成步骤,由2,2,2-三氯-1-(4-(5-环丙基-1,3,4-噁二唑-2-基)苯基)乙醇合成2-(4-(5-环丙基-1,3,4-噁二唑-2-基)苯基)-2-甲氧基乙酸。分离黄色半固体形式的产物并用于下一合成步骤而不需进一步纯化(1.8g,90%的产率)。
遵循实施例18的合成步骤,由2-(4-(5-环丙基-1,3,4-噁二唑-2-基)苯基)-2-甲氧基乙酸合成2-(4-(5-环丙基-1,3,4-噁二唑-2-基)苯基)-N,2-二甲氧基-N-甲基乙酰胺。分离白色半固体形式的产物(0.56g,27%的产率)。
遵循实施例12的合成步骤,使2-(4-(5-环丙基-1,3,4-噁二唑-2-基)苯基)-N,2-二甲氧基-N-甲基乙酰胺与2-(4-溴-3,5-二甲氧基苯基)呋喃反应。通过层析(EtOAc-己烷)纯化产生黄色泡沫形式的1-(5-(4-溴-3,5-二甲氧基苯基)呋喃-2-基)-2-(4-(5-环丙基-1,3,4-噁二唑-2-基)苯基)-2-甲氧基乙酮(0.126g,31%的产率)。MS:m/z 539.2[M+H]+。
实施例23
1-(5-(4-溴-3,5-二甲氧基苯基)呋喃-2-基)-2-甲氧基-2-(6-(哌啶-1-基)吡啶-3-基)乙酮
除了在添加KOH-MeOH溶液之前将反应混合物用冰冷却之外,遵循实施例1的合成步骤由6-(哌啶-1-基)烟碱醛合成2-甲氧基-2-(6-(哌啶-1-基)吡啶-3-基)乙酸。分离淡米黄色泡沫形式的产物并使用而不需进一步纯化(0.569g,52%的产率)。
遵循实施例13的合成步骤,由2-甲氧基-2-(6-(哌啶-1-基)吡啶-3-基)乙酸合成N,2-二甲氧基-N-甲基-2-(6-(哌啶-1-基)吡啶-3-基)乙酰胺。通过层析(50%-100%的EtOAc-己烷)纯化产生橙色油状物形式的产物(0.295g,46%的产率)。
根据实施例12的步骤,使N,2-二甲氧基-N-甲基-2-(6-(哌啶-1-基)吡啶-3-基)乙酰胺与2-(4-溴-3,5-二甲氧基苯基)呋喃反应。通过层析(20%-75%的EtOAc-己烷)纯化产生淡黄色固体形式的1-(5-(4-溴-3,5-二甲氧基苯基)呋喃-2-基)-2-甲氧基-2-(6-(哌啶-1-基)吡啶-3-基)乙酮(0.328g,65%的产率)。MS:m/z 515.4[M+H]+。
实施例24
2,6-二甲氧基-4-(5-(2-甲氧基-2-(4-吗啉基苯基)乙酰基)呋喃-2-基)苯基苯甲酸酯
遵循实施例21的合成步骤,将4-溴-2,6-二甲氧基苯酚(Lee,H.;等人,Tetrahedron Letters,2004,45,1019)与2-呋喃硼酸偶联。通过层析(20%-40%的EtOAc-己烷)纯化产生淡橙色固体形式的4-(呋喃-2-基)-2,6-二甲氧基苯酚(1.95g,79%的产率)。
在氩气下,向4-(呋喃-2-基)-2,6-二甲氧基苯酚(1.3g,5.9mmol)的无水CH2Cl2(20mL)溶液加入Et3N(1.6mL,11.5mmol),然后在冰浴中冷却混合物。滴加苯甲酰氯(0.75mL,6.4mmol)并将反应搅拌3小时。加入10%的NaHCO3水溶液和CH2Cl2,搅拌并将层分离。用H2O和饱和NaHCO3水溶液洗涤有机物,在MgSO4上干燥并真空浓缩。通过层析(0%-25%的EtOAc-己烷)纯化产生淡黄色固体形式的4-(呋喃-2-基)-2,6-二甲氧基苯基苯甲酸酯(0.54g从层析分离约一半的粗产物;57%的产率)。
除了将反应仅升温至0℃之外,根据对实施例12的合成描述的步骤,使4-(呋喃-2-基)-2,6-二甲氧基苯基苯甲酸酯与N,2-二甲氧基-N-甲基-2-(4-吗啉基苯基)乙酰胺反应。通过层析(EtOAc-己烷)纯化提供黄色固体形式的2,6-二甲氧基-4-(5-(2-甲氧基-2-(4-吗啉基苯基)乙酰基)呋喃-2-基)苯基苯甲酸酯(0.257g,50%的产率)。MS:m/z 558.2[M+H]+。
实施例25
1-(5-(4-溴-3,5-二甲氧基苯基)呋喃-2-基)-2-甲氧基-2-(1-甲基-1H-苯并[d][1,2,3]三唑-5-基)乙酮
根据实施例23的合成步骤,由1-甲基-1H-苯并[d][1,2,3]三唑-5-甲醛合成2-甲氧基-2-(1-甲基-1H-苯并[d][1,2,3]三唑-5-基)乙酸。分离黄色固体形式的产物(1.5g,96%的产率)。
遵循实施例13的合成方法,由2-甲氧基-2-(1-甲基-1H-苯并[d][1,2,3]三唑-5-基)乙酸合成N,2-二甲氧基-N-甲基-2-(1-甲基-1H-苯并[d][1,2,3]三唑-5-基)乙酰胺。通过层析(60%-100%的EtOAc-己烷)纯化产生黄色固体形式的N,2-二甲氧基-N-甲基-2-(1-甲基-1H-苯并[d][1,2,3]三唑-5-基)乙酰胺(1.02g,57%的产率)。
根据实施例13的合成步骤,将N,2-二甲氧基-N-甲基-2-(1-甲基-1H-苯并[d][1,2,3]三唑-5-基)乙酰胺与2-(4-溴-3,5-二甲氧基苯基)呋喃偶联。通过层析纯化提供淡黄色泡沫形式的1-(5-(4-溴-3,5-二甲氧基苯基)呋喃-2-基)-2-甲氧基-2-(1-甲基-1H-苯并[d][1,2,3]三唑-5-基)乙酮(0.153g,34%的产率)。MS:m/z 486.1[M+H]+。
实施例26
1-(5-(4-溴-3,5-二甲氧基苯基)呋喃-2-基)-2-甲氧基-2-(4-(吗啉基甲基)苯基)乙酮
按照实施例23的合成步骤,由4-(吗啉基甲基)苯甲醛合成2-甲氧基-2-(4-(吗啉基甲基)苯基)乙酸。在反应后,真空去除挥发物。将残留物再溶于最少量的H2O并用1M的HCl酸化至pH 3。真空浓缩水层并将残留物悬浮在MeOH中并超声处理和缓慢升温。通过硅藻土过滤混合物并真空浓缩以产生白色固体(3g,定量的产率)。将产物进行下一合成步骤而不需纯化。
遵循实施例13的步骤,由2-甲氧基-2-(4-(吗啉基甲基)苯基)乙酸合成N,2-二甲氧基-N-甲基-2-(4-(吗啉基甲基)苯基)乙酰胺。通过层析(0%-7%的NH3-MeOH溶液的CH2Cl2;0.7M的NH3-MeOH)纯化产生橙色油状物形式的N,2-二甲氧基-N-甲基-2-(4-(吗啉基甲基)苯基)乙酰胺(0.743g,41%的产率)。
按照实施例12的步骤,将N,2-二甲氧基-N-甲基-2-(4-(吗啉基甲基)苯基)乙酰胺与2-(4-溴-3,5-二甲氧基苯基)呋喃偶联。通过层析(0%-9%的NH3-MeOH的CH2Cl2;使用0.7M的NH3-MeOH)纯化产生混合物,在30℃-40℃下用EtOAc将其消化(digested)。在冷却至室温后,在布氏漏斗上收集晶体,用EtOAc冲洗并真空干燥以产生白色固体形式的1-(5-(4-溴-3,5-二甲氧基苯基)呋喃-2-基)-2-甲氧基-2-(4-(吗啉基甲基)苯基)乙酮。还将第二批分离(0.125g对于两批次,13%的产率)。MS:m/z 530.1[M+H]+。
实施例27
1-(5-(3,5-二甲氧基苯基)呋喃-2-基)-2-甲氧基-2-(4-吗啉基苯基)乙酮
按照实施例21的步骤,将1-溴-3,5-二甲氧基苯与2-呋喃硼酸偶联。分离无色液体形式的2-(3,5-二甲氧基苯基)呋喃(0.746g,79%的产率)。
参照实施例12的步骤,将N,2-二甲氧基-N-甲基-2-(4-吗啉基苯基)乙酰胺与2-(3,5-二甲氧基苯基)呋喃偶联。分离黄色油性泡沫形式的1-(5-(3,5-二甲氧基苯基)呋喃-2-基)-2-甲氧基-2-(4-吗啉基苯基)乙酮(0.343g,62%的产率)。MS:m/z 438.2[M+H]+。
实施例28
1-(5-(4-(二氟甲氧基)-3,5-二甲氧基苯基)呋喃-2-基)-2-甲氧基-2-(4-吗啉基苯基)乙酮
根据Zafrani,Y.Tetrahedron 2009,65,5278的步骤如下由4-溴-2,6-二甲氧基苯酚合成5-溴-2-(二氟甲氧基)-1,3-二甲氧基苯。向4-溴-2,6-二甲氧基苯酚(1.08g,4.6mmol)的MeCN(27mL)溶液加入KOH(5.0g,89mmol)的H2O(27mL)溶液。将混合物立即在-78℃浴中冷却并加入二乙基(溴二氟甲基)磷酸酯(1.6mL,8.9mmol)。用隔膜将烧瓶密封并移去冷却浴。将混合物搅拌总共3.5小时,在该时间过程中隔膜从烧瓶中喷出。用EtOAc稀释反应并将层分离。用EtOAc萃取水层并用1M的NaOH、H2O和盐水洗涤合并的有机物,然后在Na2SO4上干燥并真空浓缩。通过层析(0%-30%的EtOAc-己烷)纯化提供白色固体形式的5-溴-2-(二氟甲氧基)-1,3-二甲氧基苯(0.808g,62%的产率)。
按照实施例21的合成步骤,将5-溴-2-(二氟甲氧基)-1,3-二甲氧基苯与2-呋喃硼酸偶联。通过层析(0%-30%的EtOAc-己烷)纯化提供白色晶体物质形式的2-(4-(二氟甲氧基)-3,5-二甲氧基苯基)呋喃(0.555g,67%的产率)。
遵循实施例12的合成步骤,将2-(4-(二氟甲氧基)-3,5-二甲氧基苯基)呋喃与N,2-二甲氧基-N-甲基-2-(4-吗啉基苯基)乙酰胺偶联。通过层析(EtOAc-己烷)纯化提供褐色油状物形式的1-(5-(4-(二氟甲氧基)-3,5-二甲氧基苯基)呋喃-2-基)-2-甲氧基-2-(4-吗啉基苯基)-乙酮(0.021g,6%的产率)。MS:m/z 504.2[M+H]+。
实施例29
1-(5-(4-乙氧基-3,5-二甲氧基苯基)呋喃-2-基)-2-甲氧基-2-(4-吗啉基苯基)乙酮
在氩气下,向4-(呋喃-2-基)-2,6-二甲氧基苯酚(0.493g,2.24mmol)的无水DMF(10mL)悬浮液加入Cs2CO3(1.2g,3.7mmol)和碘乙烷(0.22mL,2.7mmol)。将混合物搅拌20分钟,然后在80℃下加热2小时。在冷却至室温后,用H2O和EtOAc稀释反应并通过添加6M的HCl将其酸化。将层分离并用EtOAc萃取水层。用己烷稀释合并的有机物并用H2O和盐水洗涤,在Na2SO4上干燥并通过硅藻土上的硅胶垫过滤。真空浓缩滤液以产生米黄色固体形式的2-(4-乙氧基-3,5-二甲氧基苯基)呋喃(0.513g,92%的产率)。使用所述产物而不需进一步纯化。
根据实施例12的合成步骤,将2-(4-乙氧基-3,5-二甲氧基苯基)呋喃与N,2-二甲氧基-N-甲基-2-(4-吗啉基苯基)乙酰胺偶联。通过层析(EtOAc-己烷)纯化产生黄色泡沫形式的1-(5-(4-乙氧基-3,5-二甲氧基苯基)呋喃-2-基)-2-甲氧基-2-(4-吗啉基苯基)乙酮(0.263g,58%的产率)。MS:m/z 482.2[M+H]+。
实施例30
2-(4-(2H-1,2,3-三唑-2-基)苯基)-1-(5-(4-溴-3,5-二甲氧基苯基)呋喃-2-基)-2-甲氧基乙酮
在0℃(浴温度)下,伴随搅拌向4-(2H-1,2,3-三唑-2-基)苯甲醛(1.0g,5.77mmol)的无水MeOH(15mL)溶液加入三溴甲烷(1.82g,7.21mmol)。在10分钟时间内,以等分部分加入固体KOH(1.62g,28.9mmol)。将混合物搅拌1小时并移去冷却浴。在搅拌30分钟后,使反应缓慢升温至室温过夜,然后浓缩至干燥。在溶于最少量的H2O后,使用6M的HCl将残留物酸化至pH 1。用EtOAc将水性混合物萃取几次,同时在萃取过程中向水层加入盐水。用盐水洗涤合并的有机物,在Na2SO4上干燥并真空浓缩以产生油状物形式的2-(4-(2H-1,2,3-三唑-2-基)苯基)-2-甲氧基乙酸(1.19g,88%的产率)。使用所述产物而不需进一步纯化。
向2-(4-(2H-1,2,3-三唑-2-基)苯基)-2-甲氧基乙酸(1.19g,5.1mmol)的无水CH2Cl2(15ml)溶液加入4-甲基吗啉(1.55g,15.3mmol)并在冰浴中将其冷却。加入氯甲酸异丁酯(0.84g,6.12mmol)并搅拌45分钟。加入N,O-二甲基羟胺HCl(0.746g,7.65mmol)并使混合物搅拌过夜同时升温至室温。加入饱和NaHCO3水溶液(15ml)并搅拌5分钟。在Na2SO4上干燥有机层并蒸发至干燥。通过层析(100%的EtOAc)纯化产生白色固体形式的2-(4-(2H-1,2,3-三唑-2-基)苯基)-N,2-二甲氧基-N-甲基乙酰胺(0.63g,44%的产率)。
在氩气下,在烘干的烧瓶中向冷却至-78℃的2-(4-溴-3,5-二甲氧基苯基)呋喃(0.20g,0.71mmol)的无水THF(10mL)溶液滴加二异丙基氨基锂(2.0M的THF/庚烷/乙基苯;0.43mL,0.85mmol)。在-78℃下搅拌1小时后,滴加2-(4-(2H-1,2,3-三唑-2-基)苯基)-N,2-二甲氧基-N-甲基乙酰胺(0.195g,0.71mmol)的THF(2mL)溶液。在搅拌25分钟后,使混合物升温至室温同时搅拌2小时。通过添加饱和NH4Cl水溶液冷却反应并加入EtOAc。将层分离并用盐水洗涤有机层,在Na2SO4上干燥并真空浓缩。通过层析(30%的EtOAc-己烷)纯化提供黄色固体形式的2-(4-(2H-1,2,3-三唑-2-基)苯基)-1-(5-(4-溴-3,5-二甲氧基苯基)呋喃-2-基)-2-甲氧基乙酮(0.07g,10%的产率)。MS:m/z 497.9[M+H]+。
实施例31
2-(4-(1H-1,2,3-三唑-1-基)苯基)-1-(5-(4-溴-3,5-二甲氧基苯基)呋喃-2-基)-2-甲氧基乙酮
遵循实施例30的步骤,由4-(1H-1,2,3-三唑-1-基)苯甲醛制备2-(4-(1H-1,2,3-三唑-1-基)苯基)-2-甲氧基乙酸。获得油状物形式的产物并使用而不需进一步纯化(1.02g,76%的产率)。
遵循实施例30的步骤,由2-(4-(1H-1,2,3-三唑-1-基)苯基)-2-甲氧基乙酸制备2-(4-(1H-1,2,3-三唑-1-基)苯基)-N,2-二甲氧基-N-甲基乙酰胺。通过层析(60%的EtOAc/己烷)纯化产生油状物形式的产物(0.73g,58%的产率)。
遵循实施例30的步骤,由2-(4-溴-3,5-二甲氧基苯基)呋喃和2-(4-(1H-1,2,3-三唑-1-基)苯基)-N,2-二甲氧基-N-甲基乙酰胺制备2-(4-(1H-1,2,3-三唑-1-基)苯基)-1-(5-(4-溴-3,5-二甲氧基苯基)呋喃-2-基)-2-甲氧基乙酮。通过层析(50%的EtOAc/己烷)纯化产生黄色固体形式的2-(4-(1H-1,2,3-三唑-1-基)苯基)-1-(5-(4-溴-3,5-二甲氧基苯基)呋喃-2-基)-2-甲氧基乙酮(0.025g,7%的产率)。MS:m/z 498.2[M+H]+。
实施例32
2-(4-(1H-1,2,4-三唑-1-基)苯基)-1-(5-(4-溴-3,5-二甲氧基苯基)呋喃-2-基)-2-甲氧基乙酮
遵循实施例30的步骤,由4-(1H-1,2,4-三唑-1-基)苯甲醛制备2-(4-(1H-1,2,4-三唑-1-基)苯基)-2-甲氧基乙酸。获得白色固体形式的粗产物并使用而不需进一步纯化(1.9g,47%的产率)。
遵循实施例30的步骤,由2-(4-(1H-1,2,4-三唑-1-基)苯基)-2-甲氧基乙酸制备2-(4-(1H-1,2,4-三唑-1-基)苯基)-N,2-二甲氧基-N-甲基乙酰胺。通过层析(100%的EtOAc)纯化产生淡白色固体形式的产物(0.30g,26%的产率)。
遵循实施例30的步骤,由2-(4-溴-3,5-二甲氧基苯基)呋喃和2-(4-(1H-1,2,4-三唑-1-基)苯基)-N,2-二甲氧基-N-甲基乙酰胺制备2-(4-(1H-1,2,4-三唑-1-基)苯基)-1-(5-(4-溴-3,5-二甲氧基苯基)呋喃-2-基)-2-甲氧基乙酮。通过层析(60%的EtOAc-己烷)纯化,随后另外纯化(40%的丙酮-己烷)产生淡黄色固体形式的2-(4-(1H-1,2,4-三唑-1-基)苯基)-1-(5-(4-溴-3,5-二甲氧基苯基)呋喃-2-基)-2-甲氧基乙酮(0.078g,11%的产率)。MS:m/z 498.2[M+H]+。
实施例33
1-(5-(4-溴-3,5-二甲氧基苯基)呋喃-2-基)-2-甲氧基-2-(4-(2-甲基-2H-四唑-5-基)苯基)乙酮
遵循实施例30的步骤,由4-(2-甲基-2H-四唑-5-基)苯甲醛制备2-甲氧基-2-(4-(2-甲基-2H-四唑-5-基)苯基)乙酸。获得油状物形式的粗产物并使用而不需进一步纯化(0.88g,86%的产率)。
向2-甲氧基-2-(4-(2-甲基-2H-四唑-5-基)苯基)乙酸(0.87g,3.5mmol)的无水CH2Cl2(10ml)溶液加入N,N-二异丙基乙胺(1.36g,10.5mmol)同时在冰浴中冷却。加入双(2-甲氧基乙基)氨基三氟化硫(0.93g,4.2mmol)并搅拌15分钟。加入N,O-二甲基羟胺HCl(0.512g,5.25mmol)并使混合物搅拌过夜同时升温至室温。加入饱和NaHCO3水溶液(15ml)并搅拌5分钟。在Na2SO4上干燥有机层并蒸发至干燥。通过层析(60%的EtOAc-己烷)纯化产生透明油状物形式的N,2-二甲氧基-N-甲基-2-(4-(2-甲基-2H-四唑-5-基)苯基)乙酰胺(0.425g,42%的产率)。
遵循实施例30的步骤,由2-(4-溴-3,5-二甲氧基苯基)呋喃和N,2-二甲氧基-N-甲基-2-(4-(2-甲基-2H-四唑-5-基)苯基)乙酰胺制备1-(5-(4-溴-3,5-二甲氧基苯基)呋喃-2-基)-2-甲氧基-2-(4-(2-甲基-2H-四唑-5-基)苯基)乙酮。通过层析(40%的EtOAc/己烷)纯化产生淡黄色固体形式的产物(0.106g,29%的产率)。MS:m/z 513.3[M+H]+。
实施例34
1-(5-(4-溴-3,5-二甲氧基苯基)呋喃-2-基)-2-甲氧基-2-(4-(5-甲基-1,3,4-噻二唑-2-基)苯基)乙酮
向2-溴-5-甲基-1,3,4-噻二唑(2.0g,11.17mmol)的二氧六环(40ml)溶液加入4-甲酰基苯硼酸(3.35g,22.34mmol)和2M的Na2CO3(23ml)。使用氩气流将该混合物脱气2分钟。加入四(三苯基膦)钯(0.636g,0.55mmol)并在氩气下将该混合物在回流下加热过夜。在冷却至室温后,加入H2O(30ml)和EtOAc(50ml)并搅拌5分钟。将有机层分离并用盐水洗涤,在Na2SO4上干燥并真空浓缩。通过层析(10%至20%的EtOAc/己烷)纯化产生淡黄色液体形式的4-(5-甲基-1,3,4-噻二唑-2-基)苯甲醛(1.16g,51%的产率)。
遵循实施例30的步骤,由4-(5-甲基-1,3,4-噻二唑-2-基)苯甲醛制备2-甲氧基-2-(4-(5-甲基-1,3,4-噻二唑-2-基)苯基)乙酸。获得油状物形式的粗产物并使用而不需进一步纯化(1.12g,75%的产率)。
遵循实施例33的步骤,由2-甲氧基-2-(4-(5-甲基-1,3,4-噻二唑-2-基)苯基)乙酸制备N,2-二甲氧基-N-甲基-2-(4-(5-甲基-1,3,4-噻二唑-2-基)苯基)乙酰胺。通过层析(100%的EtOAc)纯化产生淡黄色油状物形式的产物(0.177g,26%的产率)。
遵循实施例30的步骤,由2-(4-溴-3,5-二甲氧基苯基)呋喃和N,2-二甲氧基-N-甲基-2-(4-(5-甲基-1,3,4-噻二唑-2-基)苯基)乙酰胺制备1-(5-(4-溴-3,5-二甲氧基苯基)呋喃-2-基)-2-甲氧基-2-(4-(5-甲基-1,3,4-噻二唑-2-基)苯基)乙酮。通过层析(70%的EtOAc/己烷)纯化产生淡黄色固体形式的产物(0.044g,15%的产率)。MS:m/z 529.3[M+H]+。
实施例35
1-(5-(4-溴-3,5-二甲氧基苯基)呋喃-2-基)-2-甲氧基-2-(4-(2-甲基噻唑-4-基)苯基)乙酮
遵循实施例30的步骤,由4-(2-甲基噻唑-4-基)苯甲醛制备2-甲氧基-2-(4-(2-甲基噻唑-4-基)苯基)乙酸。获得油状物形式的粗产物并使用而不需进一步纯化(0.972g,78%的产率)。
遵循实施例33的步骤,由2-甲氧基-2-(4-(2-甲基噻唑-4-基)苯基)乙酸制备N,2-二甲氧基-N-甲基-2-(4-(2-甲基噻唑-4-基)苯基)乙酰胺。通过层析(70%的EtOAc/己烷)纯化产生油状物形式的产物(0.516g,46%的产率)。
遵循实施例30的步骤,由2-(4-溴-3,5-二甲氧基苯基)呋喃和N,2-二甲氧基-N-甲基-2-(4-(2-甲基噻唑-4-基)苯基)乙酰胺制备1-(5-(4-溴-3,5-二甲氧基苯基)呋喃-2-基)-2-甲氧基-2-(4-(2-甲基噻唑-4-基)苯基)乙酮。通过层析(60%的EtOAc/己烷)纯化产生淡白色固体形式的产物(0.039g,10%的产率)。MS:m/z 528.2[M+H]+。
实施例36
2-甲氧基-2-(4-(5-甲基-1,3,4-噁二唑-2-基)苯基)-1-(5-(3,4,5-三甲氧基苯基)呋喃-2-基)乙酮
遵循实施例12的步骤,由5-碘-1,2,3-三甲氧基苯制备2-(3,4,5-三甲氧基苯基)呋喃。通过层析(10%的EtOAc/己烷)纯化产生淡白色固体形式的产物(1.2g,60%的产率)。
在氩气下,在烘干的烧瓶中,向冷却至-78℃的2-(3,4,5-三甲氧基苯基)呋喃(1.4g,5.98mmol)的无水THF(70mL)溶液滴加正丁基锂(2.5M的己烷;2.63mL,6.28mmol)。在-78℃下搅拌1小时后,滴加N,2-二甲氧基-N-甲基-2-(4-(5-甲基-1,3,4-噁二唑-2-基)苯基)乙酰胺(1.75g,6.0mmol)的THF(5mL)溶液。在搅拌25分钟后,使混合物升温至室温同时搅拌2小时。通过添加饱和NH4Cl水溶液冷却反应,然后加入盐水和EtOAc。将层分离并用盐水洗涤有机层,在Na2SO4上干燥并真空浓缩。通过柱层析(60%的EtOAc-己烷)纯化产生蓬松黄色固体形式的2-甲氧基-2-(4-(5-甲基-1,3,4-噁二唑-2-基)苯基)-1-(5-(3,4,5-三甲氧基苯基)呋喃-2-基)乙酮(0.81g,29%的产率)。MS:m/z 465.3[M+H]+。
实施例37
1-(5-(4-溴-3,5-二甲氧基苯基)呋喃-2-基)-2-甲氧基-2-(4-(吡啶-3-基)苯基)乙酮
除了在萃取处理过程中使用pH 4之外,遵循实施例30的步骤,由4-(吡啶-3-基)苯甲醛制备2-甲氧基-2-(4-(吡啶-3-基)苯基)乙酸。获得油状物形式的粗产物并使用而不需进一步纯化(0.415g,33%的产率)。
遵循实施例33的步骤,由2-甲氧基-2-(4-(吡啶-3-基)苯基)乙酸制备N,2-二甲氧基-N-甲基-2-(4-(吡啶-3-基)苯基)乙酰胺。通过层析(100%的EtOAc)纯化产生油状物形式的产物(0.232g,48%的产率)。
遵循实施例30的步骤,由2-(4-溴-3,5-二甲氧基苯基)呋喃和N,2-二甲氧基-N-甲基-2-(4-(吡啶-3-基)苯基)乙酰胺制备1-(5-(4-溴-3,5-二甲氧基苯基)呋喃-2-基)-2-甲氧基-2-(4-(吡啶-3-基)苯基)乙酮。通过层析(50%的EtOAc/己烷)纯化产生淡白色固体形式的产物(0.126g,35%的产率)。MS:m/z 508.2[M+H]+。
实施例38
1-(5-(4-溴-3,5-二甲氧基苯基)呋喃-2-基)-2-乙氧基-2-(4-吗啉基苯基)乙酮
除了将EtOH用作溶剂之外,遵循实施例1的合成步骤由4-吗啉基苯甲醛合成2-乙氧基-2-(4-吗啉基苯基)乙酸。分离淡红色油状物形式的产物并使用而不需进一步纯化。
遵循实施例13的步骤,由2-乙氧基-2-(4-吗啉基苯基)乙酸合成2-乙氧基-N-甲氧基-N-甲基-2-(4-吗啉基苯基)乙酰胺。通过层析(EtOAc-己烷)纯化提供黄色固体形式的产物(1.0g,两步31%的产率)。
遵循实施例30的步骤,由2-(4-溴-3,5-二甲氧基苯基)呋喃和2-乙氧基-N-甲氧基-N-甲基-2-(4-吗啉基苯基)乙酰胺制备1-(5-(4-溴-3,5-二甲氧基苯基)呋喃-2-基)-2-乙氧基-2-(4-吗啉基苯基)乙酮。通过层析(50%的EtOAc/己烷)纯化产生黄色固体形式的产物(0.129g,34%的产率)。MS:m/z 530.2[M+H]+。
实施例39
1-(5-(3-溴-4,5-二甲氧基苯基)呋喃-2-基)-2-甲氧基-2-(4-(5-甲基-1,3,4-噁二唑-2-基)苯基)乙酮
遵循实施例21的步骤,由3-溴-4,5-二甲氧基苯甲醛制备3-溴-4,5-二甲氧基苯酚。从乙醚/己烷中结晶产生白色固体形式的产物(2.02g,39%的产率)。
遵循实施例21的步骤,由3-溴-4,5-二甲氧基苯酚制备3-溴-4,5-二甲氧基苯基三氟甲烷磺酸酯。蒸发至干燥产生淡黄色油状物形式的产物(3.3g,100%的产率)。
遵循实施例21的步骤,由3-溴-4,5-二甲氧基苯基三氟甲烷磺酸酯制备2-(3-溴-4,5-二甲氧基苯基)呋喃。通过层析(10%的乙醚/己烷)纯化产生淡黄色油状物形式的产物(1.7g,73%的产率)。
遵循实施例30的步骤,由2-(3-溴-4,5-二甲氧基苯基)呋喃和N,2-二甲氧基-N-甲基-2-(4-(5-甲基-1,3,4-噁二唑-2-基)苯基)乙酰胺制备1-(5-(3-溴-4,5-二甲氧基苯基)呋喃-2-基)-2-甲氧基-2-(4-(5-甲基-1,3,4-噁二唑-2-基)苯基)乙酮。通过层析(70%的EtOAc/己烷)纯化产生淡黄色固体形式的产物(0.037g,10%的产率)。MS:m/z 513.1[M+H]+。
实施例40
1-(5-(3-氯-4,5-二甲氧基苯基)呋喃-2-基)-2-甲氧基-2-(4-(5-甲基-1,3,4-噁二唑-2-基)苯基)乙酮
遵循实施例21的合成步骤,由3-氯-4,5-二甲氧基苯甲醛合成3-氯-4,5-二甲氧基苯酚。在40℃下使用约10%的EtOAc-己烷将获得的粗固体消化(digested)1小时。在冷却至室温后,在布氏漏斗上收集固体并真空干燥以产生米黄色固体形式的晶体(1.44g,两步38%的产率)。
根据实施例21的合成步骤,由3-氯-4,5-二甲氧基苯酚合成3-氯-4,5-二甲氧基苯基三氟甲烷磺酸酯。分离淡黄色液体形式的产物并用于下一合成步骤而不需进一步纯化(2.33g,96%的产率)。
遵循实施例21的合成步骤,由3-氯-4,5-二甲氧基苯基三氟甲烷磺酸酯合成2-(3-氯-4,5-二甲氧基苯基)呋喃。通过层析(10%的Et2O-己烷)纯化产生淡黄色油状物形式的产物(1.6g,94%的产率)。
遵循实施例30的步骤,由2-(3-氯-4,5-二甲氧基苯基)呋喃和N,2-二甲氧基-N-甲基-2-(4-(5-甲基-1,3,4-噁二唑-2-基)苯基)乙酰胺制备1-(5-(3-氯-4,5-二甲氧基苯基)呋喃-2-基)-2-甲氧基-2-(4-(5-甲基-1,3,4-噁二唑-2-基)苯基)乙酮。通过层析(70%的EtOAc/己烷)纯化产生淡黄色固体形式的产物(0.051g,12%的产率)。MS:m/z 469.2[M+H]+。
实施例41
1-(5-(4-溴-3,5-二甲氧基苯基)呋喃-2-基)-2-(环丙基甲氧基)-2-(4-吗啉基苯基)乙酮
在0℃(浴温度)下,向4-(5-甲基-1,3,4-噁二唑-2-基)苯甲醛(5.3g,27.7mmol)的环丙基甲醇(25mL)和无水二氧六环(25mL)溶液加入几滴KOH(7.77g,138.5mmol)的环丙基甲醇(35mL)溶液。加入三溴甲烷(3.1mL,35.2mmol),然后在20分钟时间内加入剩余的KOH/环丙基甲醇溶液。在搅拌30分钟后,使反应混合物缓慢升温至室温过夜并浓缩至干燥。在溶于最少量的H2O后,用浓HCl将残留物酸化至pH 1。用EtOAc将水性混合物萃取几次,同时在萃取过程中向水层加入盐水。用盐水洗涤合并的有机物,在Na2SO4上干燥并真空浓缩以产生半固体形式的2-(环丙基甲氧基)-2-(4-(5-甲基-1,3,4-噁二唑-2-基)苯基)乙酸,然后从Et2O中将其重结晶(0.5g,7%的产率)。
遵循实施例13的合成步骤,由2-(环丙基甲氧基)-2-(4-(5-甲基-1,3,4-噁二唑-2-基)苯基)乙酸合成2-(环丙基甲氧基)-N-甲氧基-N-甲基-2-(4-(5-甲基-1,3,4-噁二唑-2-基)苯基)乙酰胺。通过层析(0%-70%的EtOAc-己烷)纯化产生油状物形式的产物(0.48g,77%的产率)。
遵循实施例30的步骤,由2-(4-溴-3,5-二甲氧基苯基)呋喃和2-(环丙基甲氧基)-N-甲氧基-N-甲基-2-(4-吗啉基苯基)乙酰胺制备1-(5-(4-溴-3,5-二甲氧基苯基)呋喃-2-基)-2-(环丙基甲氧基)-2-(4-吗啉基苯基)乙酮。通过层析(40%的EtOAc/己烷)纯化产生淡黄色固体形式的产物(0.092g,23%的产率)。MS:m/z 556.3[M+H]+。
实施例42
1-(5-(4-溴-3,5-二甲氧基苯基)呋喃-2-基)-2-甲氧基-2-(6-甲氧基吡啶-3-基)乙酮
遵循实施例37的步骤,由6-甲氧基烟碱醛制备2-甲氧基-2-(6-甲氧基吡啶-3-基)乙酸。获得油状物形式的粗产物并使用而不需进一步纯化(5.67g,79%的产率)。
遵循实施例33的步骤,由2-甲氧基-2-(6-甲氧基吡啶-3-基)乙酸制备N,2-二甲氧基-2-(6-甲氧基吡啶-3-基)-N-甲基乙酰胺。通过层析(60%的EtOAc/己烷)纯化产生油状物形式的产物(0.97g,40%的产率)。
遵循实施例30的步骤,由2-(4-溴-3,5-二甲氧基苯基)呋喃和N,2-二甲氧基-2-(6-甲氧基吡啶-3-基)-N-甲基乙酰胺制备1-(5-(4-溴-3,5-二甲氧基苯基)呋喃-2-基)-2-甲氧基-2-(6-甲氧基吡啶-3-基)乙酮。通过层析(50%的EtOAc/己烷)纯化产生淡黄色固体形式的产物(0.092g,28%的产率)。MS:m/z 462.2[M+H]+。
实施例43
1-(5-(4-溴-3,5-二甲氧基苯基)呋喃-2-基)-2-(4-((二甲基氨基)甲基)苯基)-2-甲氧基乙酮
遵循实施例37的步骤,由4-((二甲基氨基)甲基)苯甲醛制备2-(4-((二甲基氨基)甲基)苯基)-2-甲氧基乙酸。在将pH调整至4后,将水溶液蒸发至干燥。伴随搅拌加入MeOH(20ml)并将物质过滤。蒸发至干燥产生粗产物,使用所述粗产物而不需进一步纯化(1.3g,95%的产率)。
遵循实施例33的步骤,由2-(4-((二甲基氨基)甲基)苯基)-2-甲氧基乙酸制备2-(4-((二甲基氨基)甲基)苯基)-N,2-二甲氧基-N-甲基乙酰胺。通过层析(100%的EtOAc)纯化产生油状物形式的产物(0.212g,14%的产率)。
遵循实施例30的步骤,由2-(4-溴-3,5-二甲氧基苯基)呋喃和2-(4-((二甲基氨基)甲基)苯基)-N,2-二甲氧基-N-甲基乙酰胺制备1-(5-(4-溴-3,5-二甲氧基苯基)呋喃-2-基)-2-(4-((二甲基氨基)甲基)苯基)-2-甲氧基乙酮。通过层析(4%的MeOH/CH2Cl2)纯化产生淡黄色油状物形式的产物(0.004g,1%的产率)。MS:m/z 488.3[M+H]+。
实施例44
1-(5-(4-溴-3,5-二甲氧基苯基)呋喃-2-基)-2-甲氧基-2-(6-吗啉基吡啶-3-基)乙酮
除了在萃取处理过程中将水性混合物调整至pH 4之外,遵循实施例30的步骤,由6-吗啉基烟碱醛制备2-甲氧基-2-(6-吗啉基吡啶-3-基)乙酸。获得油状物形式的粗产物并使用而不需进一步纯化(1.17g,89%的产率)。
遵循实施例33的步骤,由2-甲氧基-2-(6-吗啉基吡啶-3-基)乙酸制备N,2-二甲氧基-N-甲基-2-(6-吗啉基吡啶-3-基)乙酰胺。通过层析(80%的EtOAc/己烷)纯化产生油状物形式的产物(0.692g,51%的产率)。
遵循实施例30的步骤,由2-(4-溴-3,5-二甲氧基苯基)呋喃和N,2-二甲氧基-N-甲基-2-(6-吗啉基吡啶-3-基)乙酰胺制备1-(5-(4-溴-3,5-二甲氧基苯基)呋喃-2-基)-2-甲氧基-2-(6-吗啉基吡啶-3-基)乙酮。通过层析(60%的EtOAc/己烷)纯化产生淡黄色固体形式的产物(0.04g,11%的产率)。MS:m/z 517.3[M+H]+。
实施例45
1-(5-(4-溴-3,5-二甲氧基苯基)呋喃-2-基)-2-甲氧基-2-(4-(吡嗪-2-基)苯基)乙酮
除了在萃取处理过程中将水性混合物调整至pH 4之外,遵循实施例30的步骤,由4-(吡嗪-2-基)苯甲醛制备2-甲氧基-2-(4-(吡嗪-2-基)苯基)乙酸。获得油状物形式的粗产物并使用而不需进一步纯化(1.21g,91%的产率)。
遵循实施例33的步骤,由2-甲氧基-2-(4-(吡嗪-2-基)苯基)乙酸制备N,2-二甲氧基-N-甲基-2-(4-(吡嗪-2-基)苯基)乙酰胺。通过层析(80%的EtOAc/己烷)纯化产生油状物形式的产物(0.493g,35%的产率)。
遵循实施例30的步骤,由2-(4-溴-3,5-二甲氧基苯基)呋喃和N,2-二甲氧基-N-甲基-2-(4-(吡嗪-2-基)苯基)乙酰胺制备1-(5-(4-溴-3,5-二甲氧基苯基)呋喃-2-基)-2-甲氧基-2-(4-(吡嗪-2-基)苯基)乙酮。通过层析(60%的EtOAc/己烷)纯化产生淡黄色固体形式的产物(0.060g,17%的产率)。MS:m/z 509.3[M+H]+。
实施例46
2-乙氧基-2-(4-(5-甲基-1,3,4-噁二唑-2-基)苯基)-1-(5-(3,4,5-三甲氧基苯基)呋喃-2-基)乙酮
按照实施例47的步骤,由4-(5-甲基-1,3,4-噁二唑-2-基)苯甲醛合成2-乙氧基-2-(4-(5-甲基-1,3,4-噁二唑-2-基)苯基)乙酸。分离半固体形式的产物并使用而不需进一步纯化(2.6g,93%的产率)。
根据实施例41的合成步骤,由2-乙氧基-2-(4-(5-甲基-1,3,4-噁二唑-2-基)苯基)乙酸合成2-乙氧基-N-甲氧基-N-甲基-2-(4-(5-甲基-1,3,4-噁二唑-2-基)苯基)乙酰胺。通过层析(0%-60%的EtOAc-己烷)纯化产生油状物形式的产物(1.0g,30%的产率)。
遵循实施例30的步骤,由2-(3,4,5-三甲氧基苯基)呋喃和2-乙氧基-N-甲氧基-N-甲基-2-(4-(5-甲基-1,3,4-噁二唑-2-基)苯基)乙酰胺制备2-乙氧基-2-(4-(5-甲基-1,3,4-噁二唑-2-基)苯基)-1-(5-(3,4,5-三甲氧基苯基)呋喃-2-基)乙酮。通过层析(60%的EtOAc/己烷)纯化产生淡黄色固体形式产物(0.060g,15%的产率)。MS:m/z 479.4[M+H]+。
实施例47
1-(5-(4-溴-3,5-二甲氧基苯基)呋喃-2-基)-2-乙氧基-2-(4-(5-甲基-1,3,4-噁二唑-2-基)苯基)乙酮
遵循实施例30的步骤,由2-(4-溴-3,5-二甲氧基苯基)呋喃和2-乙氧基-N-甲氧基-N-甲基-2-(4-(5-甲基-1,3,4-噁二唑-2-基)苯基)乙酰胺制备1-(5-(4-溴-3,5-二甲氧基苯基)呋喃-2-基)-2-乙氧基-2-(4-(5-甲基-1,3,4-噁二唑-2-基)苯基)乙酮。通过层析(60%的EtOAc/己烷)纯化产生淡黄色固体形式的产物(0.070g,19%的产率)。MS:m/z527.3[M+H]+。
实施例48
1-(5-(4-氟-3,5-二甲氧基苯基)呋喃-2-基)-2-甲氧基-2-(4-吗啉基苯基)乙酮
遵循实施例15的步骤,由5-溴-2-氟-1,3-二甲氧基苯(US6177154B1)制备2-(4-氟-3,5-二甲氧基苯基)呋喃。通过层析(10%的EtOAc/己烷)纯化产生白色固体形式的产物(2.1g,58%的产率)。
遵循实施例30的步骤,由2-(4-氟-3,5-二甲氧基苯基)呋喃和N,2-二甲氧基-N-甲基-2-(4-吗啉基苯基)乙酰胺制备1-(5-(4-氟-3,5-二甲氧基苯基)呋喃-2-基)-2-甲氧基-2-(4-吗啉基苯基)乙酮。通过层析(60%的EtOAc/己烷)纯化产生淡黄色固体形式的产物(0.072g,16%的产率)。MS:m/z 456.4[M+H]+。
实施例49
1-(5-(4-氯-3,5-二甲氧基苯基)呋喃-2-基)-2-甲氧基-2-(4-(5-甲基-1,3,4-噻二唑-2-基)苯基)乙酮
遵循实施例30的步骤,由2-(4-氯-3,5-二甲氧基苯基)呋喃和N,2-二甲氧基-N-甲基-2-(4-(5-甲基-1,3,4-噻二唑-2-基)苯基)乙酰胺制备1-(5-(4-氯-3,5-二甲氧基苯基)呋喃-2-基)-2-甲氧基-2-(4-(5-甲基-1,3,4-噻二唑-2-基)苯基)乙酮。通过层析(80%的EtOAc-己烷)纯化产生淡黄色固体形式的产物(0.106g,26%的产率)。MS:m/z 485.4[M+H]+。
实施例50
1-(5-(4-氯-3,5-二甲氧基苯基)呋喃-2-基)-2-甲氧基-2-(4-吗啉基苯基)乙酮
遵循实施例15的步骤,由5-溴-2-氯-1,3-二甲氧基苯(EP1568691A1)制备2-(4-氯-3,5-二甲氧基苯基)呋喃。通过层析(10%的乙醚/己烷)纯化产生白色固体形式的产物(1.24g,75%的产率)。
遵循实施例30的步骤,由2-(4-氯-3,5-二甲氧基苯基)呋喃和N,2-二甲氧基-N-甲基-2-(4-吗啉基苯基)乙酰胺制备1-(5-(4-氯-3,5-二甲氧基苯基)呋喃-2-基)-2-甲氧基-2-(4-吗啉基苯基)乙酮。通过层析(70%的EtOAc/己烷)纯化产生淡黄色固体形式的产物(0.201g,43%的产率)。MS:m/z 472.2[M+H]+。
实施例51
1-(3-(3,4-二甲氧基苯基)-1H-吡唑-1-基)-2-(4-氟苯基)-2-甲氧基乙酮
在室温下,向2-(4-氟苯基)-2-甲氧基乙酸(0.11g,0.61mmol)的无水THF(2mL)溶液一次加入DCC(0.14g,0.67mmol)。在搅拌10分钟后,一次加入3-(3,4-二甲氧基苯基)-1H-吡唑(0.14g,0.67mmol)。在48小时后,用EtOAc稀释反应混合物并通过过滤去除固体。真空浓缩滤液。通过层析(0%-30%的EtOAc-己烷)纯化产生油状物形式的产物(0.12g,46%的产率)。MS:m/z 371.1[M+H]+。
实施例52
1-(3-(4-溴-3,5-二甲氧基苯基)-1H-吡唑-1-基)-2-甲氧基-2-(4-吗啉基苯基)乙酮
使用与实施例51相似的步骤,由3-(4-溴-3,5-二甲氧基苯基)-1H-吡唑(根据Journal of Org.Chem.,2003,68,5381制备的)和2-甲氧基-2-(4-吗啉基苯基)乙酸合成1-(3-(4-溴-3,5-二甲氧基苯基)-1H-吡唑-1-基)-2-甲氧基-2-(4-吗啉基苯基)乙酮以产生固体形式的1-(3-(4-溴-3,5-二甲氧基苯基)-1H-吡唑-1-基)-2-甲氧基-2-(4-吗啉基苯基)乙酮(0.065g,22%的产率)。MS:m/z 516.1[M+H]+。
实施例53
1-(3-(3,4-二甲氧基苯基)-1H-吡唑-1-基)-2-甲氧基-2-(4-吗啉基苯基)乙酮
在室温下,向2-甲氧基-2-(4-吗啉基苯基)乙酸(0.1g,0.42mmol)和3-(3,4-二甲氧基苯基)-1H-吡唑(0.86g,0.42mmol)的无水DMF(4mL)溶液加入二异丙基乙胺(0.22ml,1.26mmol),然后加入三吡咯烷基溴代鏻六氟磷酸盐(0.23g,0.50mmol)。在24小时后,加入饱和NaHCO3水溶液。将层分离并用EtOAc萃取水层。用H2O和盐水洗涤合并的有机物,在Na2SO4上干燥并真空浓缩。通过层析(0%-60%的EtOAc-己烷)纯化产生白色固体形式的1-(3-(3,4-二甲氧基苯基)-1H-吡唑-1-基)-2-甲氧基-2-(4-吗啉基苯基)乙酮(0.90g,50%的产率)。MS:m/z 438.2[M+H]+。
实施例54
1-(5-(4-溴-3,5-二甲氧基苯基)-1,2,4-噁二唑-3-基)-2-甲氧基-2-(4-吗啉基苯基)乙酮
在-78℃下,向N,2-二甲氧基-N-甲基-2-(4-吗啉基苯基)乙酰胺(1.5g,5.1mmol)的无水CH2Cl2(12mL)和无水甲苯(6mL)溶液滴加DIBALH(1M的己烷,7.8mL,7.8mmol)溶液,时间为5分钟。在-78℃下搅拌1小时后,通过滴加EtOAc冷却反应。将混合物搅拌2分钟,然后加入Et2O和饱和NH4Cl水溶液并将混合物升温至室温。在搅拌30分钟后,用EtOAc和H2O稀释混合物并将层分离。将10%的酒石酸钾钠水溶液加入至水层并用EtOAc/Et2O将其萃取。用饱和NH4Cl水溶液洗涤合并的有机物并在Na2SO4上干燥以产生黄色油状物形式的2-甲氧基-2-(4-吗啉基苯基)乙醛(1.27g)。将所述产物用于下一合成步骤而不需进一步纯化。
在干燥管下,向2-甲氧基-2-(4-吗啉基苯基)乙醛(1.27g,约5.1mmol)的Et2O(35mL)溶液加入三甲基氰硅烷(1mL,8mmol)和ZnI2(50mg,0.16mmol)。在室温下搅拌15.5小时后,加入饱和NaHCO3水溶液并将混合物搅拌几小时。用EtOAc和H2O稀释混合物并将层分离。用饱和NaHCO3水溶液洗涤有机层,在Na2SO4上干燥并真空浓缩以产生橙色泡沫形式的2-羟基-3-甲氧基-3-(4-吗啉基苯基)丙腈(1.26g)。使用所述产物而不需进一步纯化。
在氩气下,向2-羟基-3-甲氧基-3-(4-吗啉基苯基)丙腈(约5.1mmol)的无水CH2Cl2(17mL)溶液加入吡啶鎓对甲苯磺酸盐(0.094g,0.37mmol)和乙基乙烯基醚(17mL,178mmol)。将混合物放置在干燥管下并在室温下搅拌16小时。加入另外的乙基乙烯基醚(4mL,42mmol)和吡啶鎓对甲苯磺酸盐(0.11g,0.44mmol)并将混合物搅拌另外24小时。将饱和NaHCO3水溶液加入至混合物,然后用H2O和CH2Cl2将其稀释。将层分离并用CH2Cl2萃取水层。用盐水洗涤合并的有机物,在MgSO4上干燥并真空浓缩。通过层析(20%-35%的含1%的Et3N的EtOAc-己烷)纯化产生2-(1-乙氧基乙氧基)-3-甲氧基-3-(4-吗啉基苯基)丙腈(0.606g,三步35%)。
在氩气下,向2-(1-乙氧基乙氧基)-3-甲氧基-3-(4-吗啉基苯基)丙腈(0.60g,1.8mmol)的无水MeOH(10mL)溶液加入NH2OH·HCl(0.175g,2.5mmol)和NaHCO3(0.234g,2.8mmol)。将反应在75℃下短暂加热然后在60℃下加热16小时。在冷却至室温后,将混合物真空浓缩以产生(Z)-2-(1-乙氧基乙氧基)-N’-羟基-3-甲氧基-3-(4-吗啉基苯基)丙脒,将其用于下一合成步骤而不需进一步纯化(0.777g)。
在氩气下,向冰冷的(Z)-2-(1-乙氧基乙氧基)-N’-羟基-3-甲氧基-3-(4-吗啉基苯基)丙脒(约1.41mmol)的无水CH2Cl2悬浮液加入Et3N(0.8mL,5.7mmol)、4-溴-3,5-二甲氧基苯甲酰氯(0.434g,1.6mmol)和4-二甲基氨基吡啶(0.015g,0.12mmol)。在冰浴中将反应搅拌1小时,然后使其升温至室温。在室温下搅拌3小时后,加入另外的4-溴-3,5-二甲氧基苯甲酰氯(0.047g,0.17mmol)并将混合物搅拌另外的1小时。加入10%的NaHCO3水溶液并搅拌20分钟。将层分离并用H2O、盐水洗涤有机层,在MgSO4上干燥并真空浓缩以产生淡白色泡沫。
在氩气下,将该合成中间体溶于无水DMF(15mL),然后在120℃下加热7小时。在冷却至室温后,用H2O稀释反应并用EtOAc萃取。用H2O和盐水洗涤合并的有机物,在Na2SO4上干燥并真空浓缩。通过层析(25%-35%的含1%的Et3N的EtOAc-己烷)纯化产生淡黄色油状物形式的4-(4-(2-(5-(4-溴-3,5-二甲氧基苯基)-1,2,4-噁二唑-3-基)-2-(1-乙氧基乙氧基)-1-甲氧基乙基)苯基)吗啉(0.335g,40%的产率)。
向4-(4-(2-(5-(4-溴-3,5-二甲氧基苯基)-1,2,4-噁二唑-3-基)-2-(1-乙氧基乙氧基)-1-甲氧基乙基)苯基)吗啉(0.335g,0.57mmol)的MeOH(15mL)溶液加入吡啶鎓对甲苯磺酸盐(0.15g,0.6mmol)并将混合物在室温下搅拌16.5小时。然后在40℃下将反应加热6小时,冷却至室温并真空浓缩。将残留物溶于EtOAc并用H2O、饱和NaHCO3和盐水洗涤,然后在Na2SO4上干燥并真空浓缩。通过层析(50%-60%的EtOAc-己烷)纯化产生无色沉淀物形式的1-(5-(4-溴-3,5-二甲氧基苯基)-1,2,4-噁二唑-3-基)-2-甲氧基-2-(4-吗啉基苯基)乙醇(0.234,79%的产率)。
在氩气下,向1-(5-(4-溴-3,5-二甲氧基苯基)-1,2,4-噁二唑-3-基)-2-甲氧基-2-(4-吗啉基苯基)乙醇(0.18g,0.35mmol)的无水CH2Cl2(4mL)溶液加入1,1,1-三(乙酰基氧基)-1,1-二氢-1,2-苯碘酰-3-(1H)-酮(0.198g,0.47mmol)。在室温下搅拌50分钟后,用Et2O、饱和NaHCO3水溶液和20%的Na2S2O3稀释混合物。将层分离并用饱和NaHCO3洗涤有机层,在Na2SO4上干燥并真空浓缩。通过层析(40%-50%的EtOAc-己烷)纯化产生亮黄色固体形式的产物(0.1249g,70%的产率)。MS:m/z 518.1[M+H]+。
实施例55
1-(4-(4-溴-3,5-二甲氧基苯基)-5-甲基噁唑-2-基)-2-甲氧基-2-(4-吗啉基苯基)乙酮
在氩气下,将烘干的烧瓶填充4-溴-3,5-二甲氧基苯甲醛(5.0g,20.4mmol)和无水THF(30mL)。用冰冷却混合物,然后从加料漏斗中滴加乙基溴化镁(3.0M的乙醚,8.2mL,24.5mmol)溶液,时间为45分钟。在搅拌20分钟后,使混合物升温至室温并拌19小时。在用NH4Cl水溶液冷却后,用H2O和EtOAc将其稀释,然后在冰浴中冷却。在将混合物冷却后,将层分离。用H2O和盐水洗涤有机物,然后在Na2SO4上干燥并真空浓缩。将残留物溶于CH2Cl2并再次真空浓缩以产生透明油状物形式的1-(4-溴-3,5-二甲氧基苯基)丙烷-1-醇(5.43g,97%的产率)。使用所述产物而不需进一步纯化。
向1-(4-溴-3,5-二甲氧基苯基)丙烷-1-醇(5.4g,19.6mmol)的无水CH2Cl2(75mL)溶液加入MnO2(17g,196mmol)。在将混合物放置在干燥管下并在室温下搅拌22小时后,通过硅藻土和硅胶的垫将其过滤并用EtOAc冲洗。真空浓缩滤液产生白色固体形式的1-(4-溴-3,5-二甲氧基苯基)丙烷-1-酮(5.4g,100%的产率)。使用所述产物而不需进一步纯化。
向1-(4-溴-3,5-二甲氧基苯基)丙烷-1-酮(1.50g,5.49mmol)的无水THF(20mL)溶液加入三溴吡啶鎓(1.93g,6.04mmole)。将反应在室温下搅拌2小时,然后用饱和NaHCO3水溶液中和。用EtOAc萃取混合物并用饱和NaHCO3水溶液和盐水洗涤合并的有机物,然后在Na2SO4上干燥并真空浓缩。通过层析(10%-20%的EtOAc-己烷)纯化产生橙色油状物形式的2-溴-1-(4-溴-3,5-二甲氧基苯基)丙烷-1-酮(1.09g,56%的产率)。
在氩气下,在烘干的烧瓶中将2-溴-1-(4-溴-3,5-二甲氧基苯基)丙烷-1-酮(1.07g,3.04mmol)的甲酰胺(10mL)溶液在110℃下加热16小时。在冷却至室温后,小心加入EtOAc和饱和NaHCO3水溶液并将混合物搅拌15分钟。然后用EtOAc将其萃取两次并用H2O和盐水洗涤合并的有机物,在Na2SO4上干燥并浓缩。通过层析(30%的EtOAc-己烷)纯化产生黄色固体形式的4-(4-溴-3,5-二甲氧基苯基)-5-甲基噁唑(0.496g,55%的产率)。
遵循实施例30的步骤,由4-(4-溴-3,5-二甲氧基苯基)-5-甲基噁唑和N,2-二甲氧基-N-甲基-2-(4-吗啉基苯基)乙酰胺制备1-(4-(4-溴-3,5-二甲氧基苯基)-5-甲基噁唑-2-基)-2-甲氧基-2-(4-吗啉基苯基)乙酮。通过层析(40%的EtOAc-己烷)纯化产生黄色固体形式的产物(0.048g,13%的产率)。MS:m/z 531.1[M+H]+。
实施例56
1-(5-(4-溴-3,5-二甲氧基苯基)噁唑-2-基)-2-甲氧基-2-(4-吗啉基苯基)乙酮
将4-溴-3,5-二甲氧基苯甲醛(5.04g,20.57mmole)和甲苯磺酰基甲基异腈(4.22g,21.6mmole)的MeOH(50ml)溶液在回流下加热3小时。在蒸发至接近干燥后,伴随搅拌加入H2O(50ml)和EtOAc(200ml)。将有机层分离并用盐水(50ml)洗涤,在Na2SO4上干燥并真空浓缩。在涡流下加入Et2O(50ml)并通过过滤收集产物,用Et2O(2×25ml)洗涤并干燥产生淡黄色固体形式的5-(4-溴-3,5-二甲氧基苯基)噁唑(2.25g,39%的产率)。
遵循实施例30的步骤,由5-(4-溴-3,5-二甲氧基苯基)噁唑和N,2-二甲氧基-N-甲基-2-(4-吗啉基苯基)乙酰胺制备1-(5-(4-溴-3,5-二甲氧基苯基)噁唑-2-基)-2-甲氧基-2-(4-吗啉基苯基)乙酮。从EtOAc中重结晶产生黄色固体形式的产物(0.308g,56%的产率)。MS:m/z 517.3[M+H]+。
实施例57
1-(5-(4-溴-3,5-二甲氧基苯基)噻吩-2-基)-2-甲氧基-2-(4-(5-甲基-1,3,4-噁二唑-2-基)苯基)乙酮
遵循实施例12的步骤,由2-溴-5-碘-1,3-二甲氧基苯和噻吩-2-基硼酸制备2-(4-溴-3,5-二甲氧基苯基)噻吩。通过层析(0%-10%的EtOAc-己烷)纯化产生黄色固体(0.624g,55%的产率)。
遵循实施例30的步骤,由2-(4-溴-3,5-二甲氧基苯基)噻吩和N,2-二甲氧基-N-甲基-2-(4-(5-甲基-1,3,4-噁二唑-2-基)苯基)乙酰胺制备1-(5-(4-溴-3,5-二甲氧基苯基)噻吩-2-基)-2-甲氧基-2-(4-(5-甲基-1,3,4-噁二唑-2-基)苯基)乙酮。通过层析(70%的EtOAc-己烷)纯化产生黄色泡沫形式的产物(0.031g,11%的产率)。MS:m/z 529.2[M+H]+。
实施例58
1-(4-(4-溴-3,5-二甲氧基苯基)-5-(三氟甲基)噁唑-2-基)-2-甲氧基-2-(4-吗啉基苯基)乙酮
遵循实施例30的步骤,由4-(4-溴-3,5-二甲氧基苯基)-5-(三氟甲基)噁唑(根据Heterocycles,1992,34,1047,由4-溴-3,5-二甲氧基苯甲醛制备)和N,2-二甲氧基-N-甲基-2-(4-吗啉基苯基)乙酰胺制备1-(4-(4-溴-3,5-二甲氧基苯基)-5-(三氟甲基)噁唑-2-基)-2-甲氧基-2-(4-吗啉基苯基)乙酮。通过层析(20%-40%的EtOAc-己烷)纯化产生黄色固体形式的产物(0.032g,14%的产率)。MS:m/z 585.3[M+H]+。
实施例59
1-(5-(4-溴-3,5-二甲氧基苯基)噻吩-2-基)-2-甲氧基-2-(4-吗啉基苯基)乙酮
遵循实施例30的步骤,由2-(4-溴-3,5-二甲氧基苯基)噻吩和N,2-二甲氧基-N-甲基-2-(4-吗啉基苯基)乙酰胺制备1-(5-(4-溴-3,5-二甲氧基苯基)噻吩-2-基)-2-甲氧基-2-(4-吗啉基苯基)乙酮。通过层析(40%的EtOAc-己烷)纯化产生黄色固体形式的产物(0.122g,46%的产率)。MS:m/z 532.4[M+H]+。
实施例60
2-(4-(5-环丙基-1,3,4-噁二唑-2-基)苯基)-2-甲氧基-1-(5-(3,4,5-三甲氧基苯基)呋喃-2-基)乙酮
遵循实施例30的步骤,由2-(3,4,5-三甲氧基苯基)呋喃和2-(4-(5-环丙基-1,3,4-噁二唑-2-基)苯基)-N,2-二甲氧基-N-甲基乙酰胺制备2-(4-(5-环丙基-1,3,4-噁二唑-2-基)苯基)-2-甲氧基-1-(5-(3,4,5-三甲氧基苯基)呋喃-2-基)乙酮。通过层析(60%的EtOAc-己烷)纯化产生淡黄色固体形式的产物(0.129g,42%的产率)。MS:m/z 491.1[M+H]+。
实施例61
1-(5-(4-氯-3,5-二甲氧基苯基)呋喃-2-基)-2-甲氧基-2-(4-(5-甲基-1,3,4-噁二唑-2-基)苯基)乙酮
遵循实施例30的步骤,由2-(4-氯-3,5-二甲氧基苯基)呋喃和N,2-二甲氧基-N-甲基-2-(4-(5-甲基-1,3,4-噁二唑-2-基)苯基)乙酰胺制备1-(5-(4-氯-3,5-二甲氧基苯基)呋喃-2-基)-2-甲氧基-2-(4-(5-甲基-1,3,4-噁二唑-2-基)苯基)乙酮。通过层析(60%的EtOAc-己烷)纯化产生淡黄色固体形式的产物(0.116g,25%的产率)。MS:m/z 469.1[M+H]+。
实施例62
1-(5-(4-氟-3,5-二甲氧基苯基)呋喃-2-基)-2-甲氧基-2-(4-(5-甲基-1,3,4-噁二唑-2-基)苯基)乙酮
遵循实施例30的步骤,由2-(4-氟-3,5-二甲氧基苯基)呋喃和N,2-二甲氧基-N-甲基-2-(4-(5-甲基-1,3,4-噁二唑-2-基)苯基)乙酰胺制备1-(5-(4-氟-3,5-二甲氧基苯基)呋喃-2-基)-2-甲氧基-2-(4-(5-甲基-1,3,4-噁二唑-2-基)苯基)乙酮。通过层析(60%的EtOAc-己烷)纯化产生淡黄色固体形式的产物(0.036g,8%的产率)。MS:m/z 453.2[M+H]+。
实施例63
1-(5-(4-氯-3,5-二甲氧基苯基)呋喃-2-基)-2-乙氧基-2-(4-(5-甲基-1,3,4-噁二唑-2-基)苯基)乙酮
遵循实施例30的步骤,由2-(4-氯-3,5-二甲氧基苯基)呋喃和2-乙氧基-N-甲氧基-N-甲基-2-(4-(5-甲基-1,3,4-噁二唑-2-基)苯基)乙酰胺制备1-(5-(4-氯-3,5-二甲氧基苯基)呋喃-2-基)-2-乙氧基-2-(4-(5-甲基-1,3,4-噁二唑-2-基)苯基)乙酮。通过层析(60%的EtOAc-己烷)纯化产生淡黄色固体形式的产物(0.122g,25%的产率)。MS:m/z483.1[M+H]+。
实施例64
1-(5-(4-氯-3,5-二甲氧基苯基)呋喃-2-基)-2-乙氧基-2-(4-吗啉基苯基)乙酮
遵循实施例30的步骤,由2-(4-氯-3,5-二甲氧基苯基)呋喃和2-乙氧基-N-甲氧基-N-甲基-2-(4-吗啉基苯基)乙酰胺制备1-(5-(4-氯-3,5-二甲氧基苯基)呋喃-2-基)-2-乙氧基-2-(4-吗啉基苯基)乙酮。通过层析(60%的EtOAc-己烷)纯化产生淡黄色固体形式的产物(0.127g,26%的产率)。MS:m/z 486.5[M+H]+。
实施例65
其它代表性化合物的合成
根据(i)通过选择合适的起始原料的前述步骤以及(ii)已知的有机合成技术来合成表1中的下列代表性化合物。
表1
根据(i)通过选择合适的起始原料的前述步骤以及(ii)已知的有机合成技术来合成表2中的下列代表性化合物。
表2
实施例66
化合物检验
PDE10生物化学检验
使用在用Sf9细胞的杆状病毒系统中表达的重组人PDE 1A3、2A3、3催化区、4催化区、5催化区、7A、8A、9A2、10A1和11A1酶进行磷酸二酯酶(PDE)检验。使用修改的适于96孔板格式的上述Thompson和Appleman两步骤方法检测PDE活性。通过在测试化合物浓度和低于Km的底物浓度存在下检验定量的酶来测定PDE抑制剂的影响,这样Ki等于IC50。使用检验缓冲液(10mM MgCl2;40mM Tris.HCl;pH 7.4),最终的检验体积为110μl。反应通过酶开始并通过(3H)-底物和物质在30℃下培养20分钟。通过使酶变性(将反应加热至70℃,持续2分钟)终止反应。然后,在添加蛇毒(响尾蛇,0.2mg/ml)之前将反应在4℃下冷却10分钟,在30℃下冷却10分钟,由此允许氚化底物非特异性水解。通过使混合物与活化的Dowex(200μl)阴离子交换树脂分批结合完成剩余未水解的环核苷酸的分离。阴离子交换树脂结合带电的核苷酸,仅留下水解的(3H)底物在溶解部分中。然后,将溶解部分(50μl)加入至microscint-20(200μl)并在顶置计数板读数器(Top Count Plate reader)上计数。针对使用Graph Pad Prism软件获得的抑制剂浓度和IC50值绘制放射性单元。
或者,通过使用[3H]-cGMP作为底物的闪烁亲近检验(SPA)检测磷酸二酯酶活性。将纯的PDE10稀释并储存在25mM的Tris-Cl(pH 8.0)/100mM的NaCl/0.05%的吐温20/50%的丙三醇/3mM的DTT中。在0.1mL的最终体积中检验包含(最终浓度):50mM的Tris-Cl(pH7.5)/8.3mM的MgCl2/1.7mM的EGTA/0.5mg/ml的BSA/5%的DMSO和2ng的PDE10。每个样品在8个浓度下评价抑制两次。通过添加酶开始反应并在20分钟后在30℃下通过添加50μl的含Zn++的SPA珠终止。将混合物震荡,使其静止3小时,并在Wallac板计数器中计数。使用Excel将结果(净cpm)拟合为四参数logistic模型。
此外,除了优化针对各个PDE加入的酶的量之外,在上述用于PDE10的相同条件下评价通过PDE10抑制剂的其它PDE酶的抑制。在四个浓度(0.1μM、1μM、10μM和100μM)下评价分级抑制。在最高浓度下的抑制小于50%的情况下,将logistic模型中的下限值固定为0%活性。
在上述检验中,本发明的化合物为具有100μM或更少,通常小于10μM,且通常小于1μM的IC50的PDE10抑制剂。为了该目的,例如,发现化合物1-1、2-1、3-1、4-1、5-1、6-1、7-1、8-1、9-1、10-1、11-1、12-1、13-1、14-1、15-1、16-1、17-1、18-1、19-1、20-1、21-1、22-1、23-1、25-1、26-1、27-1、28-1、29-1、30-1、31-1、32-1、33-1、34-1、35-1、36-1、37-1、38-1、39-1、40-1、41-1、42-1、43-1、44-1、45-1、46-1、47-1、48-1、49-1、50-1、51-1、52-1、53-1、54-1、55-1、56-1、57-1、58-1、59-1、60-1、61-1、62-1、63-1、64-1、65-1、65-2、65-3、65-4、65-5、65-6、65-7、65-8、65-9、65-10、65-11、65-12、65-13、65-14和65-15具有小于或等于1μM的IC50值。
实施例67-77
行为模型中代表性化合物的评价
精神分裂症与多巴胺能、谷氨酸能和血清素能神经传递的功能紊乱有关。这三类精神兴奋剂药物,多巴胺能激动剂(例如安非他明和阿扑吗啡)、谷氨酸能拮抗剂(例如苯环利定(PCP)和克他命)以及血清素能激动剂(例如LSD和MDMA)均诱导动物的拟精神病状态(例如,过度活跃并干扰预脉冲抑制),其与人的精神分裂症非常类似。已知的抗精神病药物,包括典型抗精神病药(例如,氟哌啶醇)和非典型抗精神病药(例如,奥氮平),完全改变动物的这种拟精神病状态。下述实施例67-77评价动物行为模型中本发明的代表性化合物以将产生的效果与已知的抗精神病药相比较。用于实施例67-77的方法如下。
通过腹腔(i.p.)注射或口服灌胃(p.o.)给予化合物。通过使动物暴露腹部并正好在小鼠右侧上的膝盖上方插入针头完成腹腔注射。通过以将其头向后倾斜并使食管相对直的方式使动物进行口服灌胃。与身体成直线而将灌胃针头(20G×1.5”,Cadence Science)插入口中并沿着食管轻轻推进并插入胃。如果遇到阻力则拔出针头并再插入。
通过使动物注射PCP检测神经刺激剂诱导的过度活跃并监测动物在检测40cm×40cm的VersaMax室(Accuscan Instruments,Columbus,OH)中的活性水平。通过当动物穿过各光束时产生光束中断来检测自主活动。将动物放置在场地的中心20分钟且不加以干扰以检测其在新环境中的自发活动。用于评价自主活动的检测包括:水平活动、运动的总距离、垂直活动(记录事件-动物靠下肢直立)、旋转、刻板行为以及与运动的总距离相比的在中心运动的距离(中心:总距离比例)。NMDA拮抗剂PCP诱导表现为过度活跃的精神病样综合症并增加刻板行为。已知的抗精神病药能够完全改变精神兴奋剂诱导的过度活跃和刻板行为。
条件性回避反应(CAR)是评价测试化合物的抗精神病效果的行为试验。其使用具有通过伸缩门分隔的两个相同室的穿梭箱(Med Associates,St.Albans,VT)。各个室安装有金属格地板,其能够独立地传递电击。将计算机程序用于实施测试模式以及通过红外光束传感器记录动物在两个室之间的运动。测试模式如下。将小鼠放置在一个室中。开启光(条件刺激,CS)。5秒后,进行轻度电击(0.4mA;(非条件刺激,US)传递至其中小鼠所处的室(如通过红外光束检测的)直至小鼠逃脱至邻近的室或直至10秒以后。US和CS常同时结束。在平均15秒的随机试验间隔之间,每天给予各个小鼠30次这种CS-US配对试验。对于各个试验,如果小鼠在被电击后穿过至其它室则记录为逃脱反应(即,在10秒US时间过程中),并且如果仅在第一个5秒CS时间过程中小鼠穿过至其它室则登记为回避反应。将动物在该模式中训练30天-40天,在该过程中回避反应的平均百分比提高至80%-90%。这表明经CS(光)的刺激,动物已经学会通过移动至对面的室避开足底电击的攻击。然后,使用相同的模式将这些训练过的动物用于化合物测试。发现已知的抗精神病药抑制条件性回避反应,并且认为通过新化合物抑制该反应的能力能够预测对人的抗精神病效果。
实施例67
通过化合物1-1减少PCP诱导的过度活跃
如图1和2所示,发现化合物1-1(实施例1)能够减少PCP诱导的过度活跃。通过腹腔注射(图1)或口服灌胃(图2)给予C57BL/6雄性小鼠化合物1-1或赋形剂。20分钟(对于i.p.)或40分钟(对于p.o.)后,将它们注射PCP(5mg/kg,i.p.)。10分钟后,将小鼠放置在活动室中并通过红外光束中断(如所指出的5次连续的4-分钟间隔(INT))来对其水平范围的自主活动进行监测20分钟。图1示出化合物1-1(10mg/kg)显著减少由PCP诱导的过度活跃,如通过与赋形剂+PCP对照(p=0.0088,n=8每组,单独的样品t-试验)比较所示的。图2示出当通过口服灌胃(p=0.0045,n=8每组,单独的样品t-试验)给予时,化合物1-1也有效。
实施例68
通过化合物2-1减少PCP诱导的过度活跃
如图3和4所示,发现化合物2-1(实施例2)能够减少PCP诱导的过度活跃。通过腹腔注射(图3)或口服灌胃(图4)给予C57BL/6雄性小鼠化合物2-1或赋形剂。20分钟(对于i.p.)或40分钟(对于p.o.)后,给它们注射PCP(5mg/kg,i.p.)。10分钟后,将小鼠放置在活动室中并通过红外光束中断(如所指出的5次连续的4-分钟间隔(INT))来对其水平范围的自主活动进行监测20分钟。图3示出化合物2-1(10mg/kg)显著减少由PCP诱导的过度活跃,如通过与赋形剂+PCP对照(p=0.0021,n=8每组,单独的样品t-试验)比较所示的。图4示出当通过口服灌胃(对于10mg/kg剂量p=0.000005,n=8每组,单独的样品t-试验)给予时,化合物2-1也有效。
实施例69
通过化合物2-1减少条件性回避反应
如图5所示,发现化合物2-1(实施例2)能够减少条件性回避反应(CAR)。以CAR模式形式训练C57BL/6雄性小鼠以预测并避免有害刺激(足底电击),达到每天每30次试验约25次回避反应的稳定水平。在以CAR模式形式测试30次试验30分钟之前,通过口服灌胃给予小鼠赋形剂或化合物2-1。隔日将赋形剂治疗和化合物治疗给予相同动物,并通过个体内比较(配对t-试验)分析化合物对减少回避反应的效果。赋形剂暴露不改变这些训练过的动物的回避反应。图5示出化合物2-1(12mg/kg)显著减少回避反应的数量(p=0.0048,n=7每组,配对t-试验)。
实施例70
通过化合物11-1减少PCP诱导的过度活跃
如图6所示,发现化合物11-1(实施例11)减少PCP诱导的过度活跃。通过腹腔注射给予C57BL/6雄性小鼠化合物11-1或赋形剂。5分钟后,给它们注射PCP(5mg/kg,i.p.)。10分钟后,将小鼠放置在活动室中并通过红外光束中断(如所指出的5次连续的4-分钟间隔(INT))对其水平范围的自主活动进行监测20分钟。图6示出化合物11-1(10mg/kg)显著减少由PCP诱导的过度活跃,如通过与赋形剂+PCP对照(p=0.00040,n=8每组,单独的样品t-试验)比较所示的。
实施例71
通过化合物34-1减少条件性回避反应
如图7所示,发现化合物34-1(实施例34)减少条件性回避反应(CAR)。以CAR模式形式训练C57BL/6雄性小鼠以预测并避免有害刺激(足底电击),达到每天每30次试验(“训练稳定水平”)约25-28次回避反应的稳定水平。然后,通过口服灌胃给予小鼠赋形剂或化合物(试验之前25分钟),然后以CAR模式形式测试30次试验。隔日将赋形剂治疗和化合物治疗给予相同动物,并通过个体内比较(配对t-试验)分析化合物对减少回避反应的效果。赋形剂暴露(“赋形剂”)不改变这些训练过的动物的回避反应。图7示出化合物34-1在10mg/kg下显著减少回避反应的数量(p=0.0003,n=7每组)。
实施例72
通过化合物36-1减少条件性回避反应
如图8所示,发现化合物36-1(实施例36)减少条件性回避反应(CAR)。以CAR模式形式训练C57BL/6雄性小鼠以预测并避免有害刺激(足底电击),达到每天每30次试验(“训练稳定水平”)约25-28次回避反应的稳定水平。然后,通过口服灌胃给予小鼠赋形剂或化合物(试验之前25分钟),然后以CAR模式形式测试30次试验。隔日将赋形剂治疗和化合物治疗给予相同动物,并通过个体内比较(配对t-试验)分析化合物对减少回避反应的效果。赋形剂暴露(“赋形剂”)不改变这些训练过的动物的回避反应。图8示出化合物36-1在15mg/kg下显著减少回避反应的数量(p=0.000014,n=5每组)并示出在5mg/kg和10mg/kg下没有达到显著性的趋势。
实施例73
通过化合物47-1减少条件性回避反应
如图9所示,发现化合物47-1(实施例47)减少条件性回避反应(CAR)。以CAR模式形式训练C57BL/6雄性小鼠以预测并避免有害刺激(足底电击),达到每天每30次试验(“训练稳定水平”)约25-28次回避反应的稳定水平。然后,通过口服灌胃给予小鼠赋形剂或化合物(试验之前55分钟),然后以CAR模式形式测试30次试验。隔日将赋形剂治疗和化合物治疗给予相同动物,并通过个体内比较(配对t-试验)分析化合物对减少回避反应的效果。赋形剂暴露(“赋形剂”)不改变这些训练过的动物的回避反应。图9示出化合物47-1在5mg/kg和10mg/kg下显著减少回避反应的数量(分别p=0.0002和p=3.3E-10,n=8每组)并示出在2mg/kg下没有达到显著性的趋势。
实施例74
通过化合物61-1减少条件性回避反应
如图10所示,发现化合物61-1(实施例61)减少条件性回避反应(CAR)。以CAR模式形式训练C57BL/6雄性小鼠以预测并避免有害刺激(足底电击),达到每天每30次试验(“训练稳定水平”)约25-28次回避反应的稳定水平。然后,通过口服灌胃给予小鼠赋形剂或化合物(试验之前55分钟),然后以CAR模式形式测试30次试验。隔日将赋形剂治疗和化合物治疗给予相同动物,并通过个体内比较(配对t-试验)分析化合物对减少回避反应的效果。赋形剂暴露(“赋形剂”)不改变这些训练过的动物的回避反应。图10示出化合物61-1在2mg/kg、5mg/kg和10mg/kg下显著减少回避反应的数量(分别p=0.015,p=0.00008和p=2.1E-7,n=5每组)。
实施例75
通过化合物63-1减少条件性回避反应
如图11所示,发现化合物63-1(实施例63)减少条件性回避反应(CAR)。以CAR模式形式训练C57BL/6雄性小鼠以预测并避免有害刺激(足底电击),达到每天每30次试验(“训练稳定水平”)约25-28次回避反应的稳定水平。然后,通过口服灌胃给予小鼠赋形剂或化合物(试验之前55分钟),然后以CAR模式形式测试30次试验。隔日将赋形剂治疗和化合物治疗给予相同动物,并通过个体内比较(配对t-试验)分析化合物对减少回避反应的效果。赋形剂暴露(“赋形剂”)不改变这些训练过的动物的回避反应。图11示出化合物63-1在2mg/kg、5mg/kg和10mg/kg下显著减少回避反应的数量(分别p=0.0099,p=0.00011和p=6.6E-16,n=6每组)。
实施例76
通过化合物49-1减少条件性回避反应
如图12所示,发现化合物49-1(实施例49)减少条件性回避反应(CAR)。以CAR模式形式训练C57BL/6雄性小鼠以预测并避免有害刺激(足底电击),达到每天每30次试验(“训练稳定水平”)约25-28次回避反应的稳定水平。然后,通过口服灌胃给予小鼠赋形剂或化合物(试验之前55分钟),然后以CAR模式形式测试30次试验。隔日将赋形剂治疗和化合物治疗给予相同动物,并通过个体内比较(配对t-试验)分析化合物对减少回避反应的效果。赋形剂暴露(“赋形剂”)不改变这些训练过的动物的回避反应。图12示出化合物49-1在10mg/kg下显著减少回避反应的数量(p=5.7E-9,n=8每组)。
实施例77
通过化合物65-10减少条件性回避反应
如图13所示,发现化合物65-10(实施例65,表1)减少条件性回避反应(CAR)。以CAR模式形式训练C57BL/6雄性小鼠以预测并避免有害刺激(足底电击),达到每天每30次试验(“训练稳定水平”)约25-28次回避反应的稳定水平。然后,通过口服灌胃给予小鼠赋形剂或化合物(试验之前55分钟),然后以CAR模式形式测试30次试验。隔日将赋形剂治疗和化合物治疗给予相同动物,并通过个体内比较(配对t-试验)分析化合物对减少回避反应的效果。赋形剂暴露(“赋形剂”)不改变这些训练过的动物的回避反应。图13示出化合物65-10在5mg/kg和10mg/kg下显著减少回避反应的数量(p=0.0145和p=0.00011;n=8每组)。
应当理解,尽管为了说明目的而描述本发明的具体实施方案,但在不违背本发明实质和范围下可进行各种修改。因此,除了受附加的权利要求限制之外,本发明不受限制。
Claims (1)
1.具有以下结构的化合物:
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