CN102574789B - 吡咯烷酮甲酰胺衍生物作为趋化素-r(chemr23)调节剂 - Google Patents
吡咯烷酮甲酰胺衍生物作为趋化素-r(chemr23)调节剂 Download PDFInfo
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/36—Oxygen or sulfur atoms
- C07D207/40—2,5-Pyrrolidine-diones
- C07D207/416—2,5-Pyrrolidine-diones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/273—2-Pyrrolidones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
- C07D207/277—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
- C07D209/46—Iso-indoles; Hydrogenated iso-indoles with an oxygen atom in position 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/04—Ortho-condensed systems
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- Animal Behavior & Ethology (AREA)
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- Chemical Kinetics & Catalysis (AREA)
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Abstract
提供了式(I)的吡咯烷酮甲酰胺化合物,其用于抑制配体与ChemR23受体的结合。
Description
相关申请的交叉引用
本申请要求2009年9月21日提交的序列号为61/244,419和2010年4月28日提交的序列号为61/329,046的美国临时申请的权益,其公开内容通过引用并入本文。
针对在由联邦政府资助的研究开发下所获取之发明的权利声明
不适用
利用光盘提交的“序列表”、表格或计算机程序附件
不适用
背景技术
本发明涉及抑制化学引诱肽(chemoattractant peptide)趋化素(chemerin)与G-蛋白偶联受体(G-protein coupled receptor,GPCR)ChemR23结合的新化合物和药物组合物。这些化合物用于预防炎性疾病,包括但不限于银屑病、皮肌炎、系统性红斑狼疮(systemic lupuserythematosus,SLE)、关节炎、多发性硬化和代谢综合征的病症,包括但不限于肥胖、胰岛素抵抗、心血管疾病以及胆固醇转运和代谢。
浆细胞样树突细胞(Plasmacytoid dendritic cells,pDC)代表循环白细胞的较小的(<0.5%)但却多功能的亚群,其在适应性免疫和先天免疫之间的界面发挥作用。pDC存在于多样的组织部位,通常与全身性炎症以及淋巴细胞侵润相关,并且已在反应性扁桃体、发炎的鼻黏膜、胸腺、皮肤损伤(带状疱疹、皮肤水泡、寻常性银屑病(psoriasis vulgaris)、红斑狼疮、接触性皮炎(而非特应性皮炎)、黑色素瘤)、腹膜灌洗液和卵巢上皮肿瘤中被报道。
ChemR23(也称为CMKLR1、ChemerinR和Dez)是与GPR-1(38%总氨基酸同一性)、C3a受体(38%)、C5a过敏毒素受体(36%)和甲酰基Met-Leu-Phe受体(35%)相关的G蛋白偶联受体。ChemR23与趋化因子受体亚家族较远地相关(Methner A,Hermey G,Schinke B,Hermans-Borgmeyer I.(1997)Biochem Biophys Res Commun 233:336-42;Samson M,Edinger A L,Stordeur P,Rucker J,Verhasselt V,Sharron M,Govaerts C,Mollereau C,Vassart G,Doms R W,Parmentier M.(1998)Eur J.Immunol 28:1689-700)。已发现ChemR23的转录物在单核细胞来源的树突细胞和巨噬细胞、浆细胞样DC(pDC)和自然杀伤(naturalkiller,NK)细胞中是丰富的。还可通过逆转录PCR在CD4+T淋巴细胞中检测到低的表达。编码ChemR23的基因定位于人12号染色体的q21.2~21.3区,在所鉴定的化学引诱物受体(chemoattractant receptor)基因簇之外。它是推定的趋化受体,且它可能在白细胞群的招募和/或运输中发挥至关重要的作用。通过其在未成熟的树突细胞群以及巨噬细胞中的特异性表达,ChemR23是参与免疫应答的起始和早期调节的有吸引力的候选受体。
作为cDNA鉴定了ChemR23的配体趋化素,其通过使用视黄酸受体(retinoic acid receptor,RAR)β/γ选择性的抗银屑病的合成类视黄醇他扎罗汀(tazarotene)[AGN 190168/6-[2-(4,4-二甲基硫代苯并二氢吡喃基-6-基)-乙炔基]烟酸乙酯](Nagpal S,Patel S,Jacobe H,DiSepio D,GhosnC,Malhotra M,Teng M,Duvic M,Chandraratna R A.(1997)J.InvestDermatol 109:91-5)处理皮肤筏培养物(skin raft culture)而被上调。首先作为前趋化素原(preprochemerin)而产生趋化素,所述前趋化素原经过蛋白水解加工而暴露对ChemR23的激动剂特征。前趋化素原的基因位于17p13.3位置。前趋化素原的cDNA为830bp长,并且编码163个氨基酸的推定的蛋白质产物。
发明简述
在一个方面中,本发明提供具有式I的化合物及其立体异构体、旋转异构体和同位素富集的变体(isotopically enriched variant):
其中,取代基R1、R2、R3、R3a、R4、R5、R6和R6a具有下文中所提供的含义。
在相关的一些方面中,本发明提供包含一种或更多种式I化合物(任选地与其他治疗剂混合)的药物组合物,以及用于治疗受ChemR23调节的疾病或病症的方法。
附图简述
图1提供本发明化合物的结构和活性,所述化合物是按照实施例中的描述或根据下文中更一般方案制备的。提供如下活性:IC50≤30nM,+++;30nM<IC50≤300nM,++;以及300nM<IC50≤6000nM,+。
发明详述
I.缩写和定义
除非另有说明,术语“烷基”本身或作为其他取代基的一部分意为具有指定碳原子数目(即,C1-8意为1至8个碳)的直链或支链烃基。烷基的实例包括甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、仲丁基、正戊基、正己基、正庚基、正辛基等。术语“烯基”是指具有一个或更多个双键的不饱和烷基。类似地,术语“炔基”是指具有一个或更多个三键的不饱和烷基。这样的不饱和烷基的实例包括乙烯基、2-丙烯基、巴豆基、2-异戊烯基、2-(丁二烯基)、2,4-戊二烯基、3-(1,4-戊二烯基)、乙炔基、1-和3-丙炔基、3-丁炔基,以及更高级的同系物和异构体。术语“环烷基”是指具有指定数目环原子(例如,C3-6环烷基)并且完全饱和或在环的顶角之间具有不超过一个双键的烃环。“环烷基”还意指双环的和多环的烃环,例如双环[2.2.1]庚烷、双环[2.2.2]辛烷等。术语“杂环烷基”是指含有1至5个选自N、O和S的杂原子的环烷基,其中氮和硫原子任选地被氧化,且氮原子任选地被季铵化。杂环烷基可以是单环的、双环的或多环的环系统。杂环烷基的非限制性的实例包括吡咯烷、咪唑烷、吡唑烷、丁内酰胺、戊内酰胺、咪唑啉酮、乙内酰脲、二氧戊环、邻苯二甲酰亚胺、哌啶、1,4-二氧六环、吗啉、硫代吗啉、硫代吗啉-S-氧化物、硫代吗啉-S,S-氧化物、哌嗪、吡喃、吡啶酮、3-吡咯啉、噻喃、吡喃酮、四氢呋喃、四氢噻吩、奎宁定(quinuclidine)等。杂环烷基可以通过环碳或杂原子连接至分子的其余部分。
术语“亚烷基”本身或作为其他取代基的一部分意为源自烷的二价基团,例如-CH2CH2CH2CH2-。通常情况下,烷基(或亚烷基)会具有1至24个碳原子,本发明中优选具有10个或更少碳原子的那些基团。“低级烷基”或“低级亚烷基”是较短的链烷基或亚烷基,通常具有4个或更少的碳原子。类似地,“亚烯基”和“亚炔基”是指分别具有双键或三键的“亚烷基”的不饱和形式。
本文中使用的在本文中描述的任何化学结构中与单键、双键或三键相交的波浪线表示所述单键、双键或三键连接至分子其余部分的点连接。
以其常规含义使用术语“烷氧基”、“烷基氨基”和“烷基硫基”(或硫代烷氧基),其是指分别通过氧原子、氨基或硫原子连接至分子的其余部分的那些烷基。此外,对于二烷基氨基,烷基部分可以相同或不同,并且还可以与各自所连接的氮原子组合形成3~7元环。因此,表示为二烷基氨基或-NRaRb的基团意在包括哌啶基、吡咯烷基、吗啉基、氮杂环丁烷基等。
术语“二-(C1-4烷基)氨基-C1-4烷基”是指带有两个可以相同或不同的C1-4烷基(例如,甲基、乙基、丙基、异丙基、正丁基、仲丁基、异丁基和叔丁基)的氨基,并且其通过C1-4烷基(1至4个碳的亚烷基连接基团)连接至分子的其余部分。二-(C1-4烷基)氨基-C1-4烷基的实例包括二甲基氨基甲基、2-(乙基(甲基)氨基)乙基、3-(二甲基氨基)丁基等。
除非另有说明,术语“卤”或“卤素”本身或作为其他取代基的一部分意为氟、氯、溴或碘原子。此外,术语例如“卤烷基”意在包括单卤烷基和多卤烷基。例如,术语“C1-4卤烷基”意在包括三氟甲基、2,2,2-三氟乙基、4-氯丁基、3-溴丙基等。
除非另有说明,术语“芳基”意为多不饱和的、通常为芳香族的烃基,其可以是单环或者稠和在一起的或共价连接的多环(多达3个环)。术语“杂芳基”是指含有1至5个选自N、O和S的杂原子的芳基(或环),其中氮和硫原子任选地被氧化,且氮原子任选地被季铵化。杂芳基可以通过杂原子连接至分子的其余部分。芳基的非限制性的实例包括苯基、萘基和联苯基,而杂芳基的非限制性的实例包括吡啶基、哒嗪基、吡嗪基、嘧啶基、三嗪基、喹啉基(quinolinyl)、喹喔啉基(quinoxalinyl)、喹唑啉基、噌啉基(cinnolinyl)、酞嗪基(phthalazinyl)、苯并三嗪基、嘌呤基、苯并咪唑基、苯并吡唑基、苯并三唑基、苯并异唑基、异苯并呋喃基、异吲哚基、吲嗪基(indolizinyl)、苯并三嗪基、噻吩并吡啶基、噻吩并嘧啶基、吡唑并嘧啶基、咪唑并吡啶、苯并噻唑基、苯并呋喃基、苯并噻吩基、吲哚基、喹啉基(quinolyl)、异喹啉基、异噻唑基、吡唑基、吲唑基(indazolyl)、蝶啶基、咪唑基、三唑基、四唑基、唑基、异唑基、噻二唑基、吡咯基、噻唑基、呋喃基、噻吩基等。每种上述芳基和杂芳基环系统的取代基选自下文中描述的可接受之取代基的基团。
术语“芳基烷基”意在包括这样的基团,其中芳基连接至烷基(例如,苄基、苯乙基等)。类似地,术语“杂芳基-烷基”意在包括这样的基团,其中杂芳基连接至烷基(例如,吡啶基甲基、噻唑基乙基等)。
在一些实施方案中,上述术语(例如,“烷基”、“芳基”和“杂芳基”),会包括指定基团的取代和未取代的形式。下文中提供每种类型基团的优选取代基。
烷基的取代基(包括经常被称为亚烷基、亚烯基、亚炔基和环烷基的那些基团)可以是数目为0至(2m’+1)的多种基团,其选自:-卤素、-OR’、-NR’R”、-SR’、-SiR’R”R”’、-OC(O)R’、-C(O)R’、-CO2R’、-CONR’R”、-OC(O)NR’R”、-NR”C(O)R’、-NR’-C(O)NR”R”’、-NR”C(O)2R’、-NH-C(NH2)=NH、-NR’C(NH2)=NH、-NH-C(NH2)=NR’、-S(O)R’、-S(O)2R’、-S(O)2NR’R”、-NR’S(O)2R”、-CN和-NO2,其中m’是所述基团中碳原子的总数。R’、R”和R”’各自独立地指氢、未取代的C1-8烷基、未取代的芳基、以1~3个卤素取代的芳基、未取代的C1-8烷基、C1-8烷氧基或C1-8硫代烷氧基或者未取代的芳基-C1-4烷基。当R’和R”连接至相同的氮原子时,它们可以与氮原子组合形成3、4、5、6或7元环。例如,-NR’R”意在包括1-吡咯烷基和4-吗啉基。
类似地,芳基和杂芳基的取代基是多样的,且通常选自:-卤素、-OR’、-OC(O)R’、-NR’R”、-SR’、-R’、-CN、-NO2、-CO2R’、-CONR’R”、-C(O)R’、-OC(O)NR’R”、-NR”C(O)R’、-NR”C(O)2R’、-NR’-C(O)NR”R”’、-NH-C(NH2)=NH、-NR’C(NH2)=NH、-NH-C(NH2)=NR’、-S(O)R’、-S(O)2R’、-S(O)2NR’R”、-NR’S(O)2R”、-N3、全氟(C1-C4)烷氧基和全氟(C1-C4)烷基,数目为0至芳香环系统上开放化合价(open valence)的总数;且其中R’、R”和R””独立地选自氢、C1-8烷基、C1-8卤烷基、C3-6环烷基、C2-8烯基、C2-8炔基、未取代的芳基和杂芳基、(未取代的芳基)-C1-4烷基和未取代的芳氧基-C1-4烷基。其他合适的取代基包括通过1~4个碳原子的亚烷基系链(tether)连接至环原子的每种上述芳基取代基。
芳基或杂芳基之临近原子上的两个取代基可以任选地被替换为式-T-C(O)-(CH2)q-U-的取代基,其中T和U独立地是-NH-、-O-、-CH2-或单键,且q是0至2的整数。或者,芳基或杂芳基之临近原子上的两个取代基可以任选地被替换为式-A-(CH2)r-B-的取代基,其中A和B独立地是-CH2-、-O-、-NH-、-S-、-S(O)-、-S(O)2-、-S(O)2NR’-或单键,且r是1至3的整数。如此形成的新环的单键之一可以任选地被替换为双键。或者,芳基或杂芳基环之临近原子上的两个取代基可以任选地被替换为式-(CH2)s-X-(CH2)t-的取代基,其中s和t独立地是0至3的整数,且X是-O-、-NR’-、-S-、-S(O)-、-S(O)2-或-S(O)2NR’。-NR’-和-S(O)2NR’-中的取代基R’选自氢或未取代的C1-6烷基。
本文中使用的术语“杂原子”意在包括氧(O)、氮(N)、硫(S)和硅(Si)。
术语“可药用盐”意在包括活性化合物的盐,其是与相对无毒性的酸或碱制备的,取决于本文中所描述的化合物上所发现的具体的取代基。当本发明的化合物含有相对酸性的官能团时,可以通过将所述化合物的中性形式与足量的所需碱(直接地或在合适的惰性溶剂中)相接触而获得碱加成盐。源自可药用无机碱之盐的实例包括铝盐、铵盐、钙盐、铜盐、铁盐、亚铁盐、锂盐、镁盐、锰盐、亚锰盐、钾盐、钠盐、锌盐等。源自可药用有机碱的盐包括伯胺、仲胺和叔胺的盐,所述胺包括经取代的胺、环胺、天然胺等,例如精氨酸、甜菜碱(betaine)、咖啡因、胆碱、N,N’-二苄基乙二胺、二乙胺、2-二乙胺基乙醇、2-二甲基氨基乙醇、乙醇胺、乙二胺、N-乙基吗啉、N-乙基哌啶、葡糖胺(glucamine)、葡糖胺(glucosamine)、组氨酸、海巴明(hydrabamine)、异丙胺、赖氨酸、甲葡糖胺、吗啉、哌嗪、哌啶、多胺树脂、普鲁卡因、嘌呤、可可碱(theobromine)、三乙胺、三甲胺、三丙胺、缓血酸胺(tromethamine)等。当本发明的化合物含有相对碱性的官能团时,可以通过将所述化合物的中性形式与足量的所需酸(直接地或在合适的惰性溶剂中)相接触而获得酸加成盐。可药用的酸加成盐的实例包括源自无机酸(例如,盐酸、氢溴酸、硝酸、碳酸、碳酸氢盐、磷酸、磷酸一氢盐、磷酸二氢盐、硫酸、硫酸氢盐、氢碘酸或亚磷酸等)的盐,以及源自相对无毒性的有机酸(例如,醋酸、丙酸、异丁酸、丙二酸、苯甲酸、琥珀酸、辛二酸、富马酸、扁桃酸、苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸、甲磺酸等)的盐。还包括氨基酸的盐(例如,精氨酸盐等)或有机酸(例如,葡糖醛酸或半乳糖醛酸)的盐(参见例如Berge,S.M.,et al,“Pharmaceutical Salts”,Journal ofPharmaceutical Science,1977,66,1-19)。本发明的某些具体化合物含有碱性和酸性官能团,这允许所述化合物被转化成为碱或酸的加成盐。
可以通过将所述盐与碱或酸接触并以常规方式分离母体化合物来生成化合物的中性形式。化合物的母体形式在某些物理性质(例如,在极性溶剂中的溶解度)上不同于多种盐形式,但除此之外,对于本发明的目的而言,所述盐等同于化合物母体形式。
除了盐形式之外,本发明提供前药形式的化合物。本文中描述的化合物的前药是这样的化合物:其在生理条件下很容易发生化学改变以提供本发明的化合物。此外,可通过化学或生化方法在离体环境中将前药转化成为本发明的化合物。例如,当与合适的酶或化学试剂一起被置于透皮贴剂储层(reservoir)中时,前药可被缓慢地转化成为本发明的化合物。
本发明的某些化合物可以以非溶剂化形式以及溶剂化形式(包括水化形式)存在。一般来说,溶剂化形式等同于非溶剂化形式,并且意在包括在本发明的范围之内。本发明的某些化合物可以以多种结晶或无定型形式存在。一般来说,对于本发明所构想的应用来说,所有物理形式是等同的,并且意在包括在本发明的范围之内。
本发明的某些化合物具有非对称碳原子(手性中心)或双键;外消旋体、非对映体、几何异构体、位置异构体(regioisomer)和单个异构体(例如,分开的对映体)都意在包括在本发明的范围之内。本发明的化合物还可以在组成所述化合物的一个或更多个原子处含有非天然比例的原子同位素。非天然比例的同位素可被定义为从自然中所发现的量至组成所涉原子100%的量。例如,所述化合物可并入放射性同位素,例如氚(3H)、碘-125(125I)或碳-14(14C),或非放射性同位素,例如氘(2H)或碳-13(13C)。这种同位素变体可为本申请别处描述的化合物提供其他功用。例如,本发明化合物的同位素变体可找到其他功用,包括但不限于作为诊断和/或成像试剂(imaging reagent),或者作为细胞毒性/放射毒性的治疗剂。此外,本发明化合物的同位素变体可具有改变的药物代谢动力学和药物效应动力学特征,这可贡献于治疗过程中所提高的安全性、耐受性或有效性。本发明化合物的所有同位素变体(无论是否是放射性的)均意在包括在本发明的范围之内。
“ChemR23”(也称为“ChemerinR”、“CMKLR1”或“DEZ”)是指推测具有7次跨膜结构域的G-蛋白偶联受体(GPCR)。
II.概述
本发明的化合物可抑制配体与ChemR23受体的结合,并且可用于治疗多种疾病,包括银屑病、多发性硬化和代谢综合征。
III.本发明的实施方案
A.化合物
在一个方面中,本发明提供具有式I的化合物:
及其立体异构体、旋转异构体和同位素富集的变体,及其可药用盐,其中
R1是选自以下的成员:氢、羟基、C1-8烷基、C2-8烯基、C1-8烷氧基、C1-8烷氧基-C1-8烷基、C1-8卤烷基、C1-8羟基烷基、C3-8环烷基、C3-8环杂烷基、C3-8环烷基-C1-3烷基、C3-8环杂烷基-C1-3烷基、杂芳基、杂芳基-C1-4烷基、芳氧基C1-4烷基、芳基-C1-2烷氧基-C1-4烷基、-NRaRb和RaRbN-C1-4烷基,其中Ra和Rb各自独立地选自H、C1-8烷基、C3-8环烷基、C1-8卤烷基、C3-8环杂烷基、C1-8烷氧基-C1-8烷基、一-或二-(C1-4烷基)氨基-C1-4烷基和C1-8羟基烷基,或者Ra和Rb与各自所连接的氮组合形成4至7元环,所述环任选地具有附加的O或N作为环成员并且任选地被1至4个选自羟基、卤素、C1-4烷基和C1-4卤烷基的取代基所取代;
R2是选自以下的成员:H、C1-8烷基、C2-8烯基、C1-8烷氧基、C1-8烷氧基-C1-8烷基、C1-8卤烷基、C1-8羟基烷基、一-或二-(C1-4烷基)氨基-C1-4烷基、C3-8环烷基、C3-8环杂烷基、C3-8环烷基-C1-3烷基和C3-8环杂烷基-C1-3烷基;
或者任选地,R1和R2组合形成与吡咯烷酮(pyrrolidinone)环稠合的并且具有至少一个选自O、S和N的环顶角杂原子的4至6元环;或者组合形成与吡咯烷酮环稠合的并且具有0至2个连接环顶角之双键的3至6元碳环;
R3和R3a各自是选自以下成员:H、卤素、C1-4烷基、C2-6烯基、C3-6环烷基、C3-8环杂烷基、C3-8环烷基-C1-3烷基和C3-8环杂烷基-C1-3烷基;
R4是选自以下成员:H、卤素、C1-4烷基、C2-6烯基、C1-4羟基烷基、C1-4烷氧基、C1-4烷氧基-C1-4烷基、C1-6卤烷基和一-或二-(C1-4烷基)氨基;
R5是选自以下成员:CF3、卤素、氰基、C1-4烷基、C2-6烯基、C1-4羟基烷基、C1-5烷氧基、C1-4烷氧基-C1-4烷基、C1-4烷氧基-C1-4烷氧基、C3-8环烷基、C3-8环烷基氧基、C3-8环杂烷基、C3-8环杂烷基-C1-3烷基和一-或二-(C1-4烷基)氨基;
R6和R6a各自是选自以下的成员:氢、卤素、氰基、C1-4烷基、C1-4卤烷基、C2-6烯基、C1-4羟基烷基、C1-5烷氧基、C1-4烷氧基-C1-4烷基、C1-4烷氧基-C1-4烷氧基、C3-8环烷基、C3-8环烷基氧基、C3-8环杂烷基、C3-8环杂烷基-C1-3烷基和一-或二-(C1-4烷基)氨基;
其中R1、R2、R3、R3a、R4、R5、R6和R6a(包括任选的稠合环)的任何环部分任选地被1至3个取代基所取代,所述取代基独立地选自卤素、C1-4烷基、苄基、氧代和C1-6烷氧基羰基,并且任何环烷基和环杂烷基部分任选地具有环顶点之间的双键。
在一组实施方案中,提供了具有式Ia的化合物:
及其立体异构体、旋转异构体和同位素富集的变体,及其可药用盐,其中
R1是选自以下的成员:羟基、C1-8烷基、C2-8烯基、C1-8烷氧基、C1-8烷氧基-C1-8烷基、C1-8卤烷基、C1-8羟基烷基、C3-8环烷基、C3-8环杂烷基、C3-8环烷基-C1-3烷基、C3-8环杂烷基-C1-3烷基、杂芳基、杂芳基-C1-4烷基、芳氧基C1-4烷基、芳基-C1-2烷氧基-C1-4烷基、-NRaRb和RaRbN-C1-4烷基,其中Ra和Rb各自独立地选自H、C1-8烷基、C3-8环烷基、C1-8卤烷基、C3-8环杂烷基、C1-8烷氧基-C1-8烷基、一-或二-(C1-4烷基)氨基-C1-4烷基和C1-8羟基烷基,或者Ra和Rb与各自所连接的氮组合形成4至7元环,所述环任选地具有附加的O或N作为环成员并且任选地被1至4个选自羟基、卤素、C1-4烷基和C1-4卤烷基的取代基所取代;
R2是选自以下的成员:H、C1-8烷基、C2-8烯基、C1-8烷氧基、C1-8烷氧基-C1-8烷基、C1-8卤烷基、C1-8羟基烷基、一-或二-(C1-4烷基)氨基-C1-4烷基、C3-8环烷基、C3-8环杂烷基、C3-8环烷基-C1-3烷基和C3-8环杂烷基-C1-3烷基;
或者任选地,R1和R2组合形成与吡咯烷酮环稠合的并且具有至少一个选自O、S和N的环顶角杂原子的4至6元环;
R3是选自以下成员:H、卤素、C1-4烷基、C2-6烯基、C3-6环烷基、C3-8环杂烷基、C3-8环烷基-C1-3烷基和C3-8环杂烷基-C1-3烷基;
R4是选自以下成员:H、卤素、C1-4烷基、C2-6烯基、C1-4羟基烷基、C1-4烷氧基、C1-4烷氧基-C1-4烷基、C1-6卤烷基和一-或二-(C1-4烷基)氨基;
R5是选自以下成员:CF3、卤素、氰基、C1-4烷基、C2-6烯基、C1-4羟基烷基、C1-5烷氧基、C1-4烷氧基-C1-4烷基、C1-4烷氧基-C1-4烷氧基、C3-8环烷基、C3-8环烷基氧基、C3-8环杂烷基、C3-8环杂烷基-C1-3烷基和一-或二-(C1-4烷基)氨基;
其中R1、R2、R3、R4和R5的任何环部分任选地被1至3个取代基所取代,所述取代基独立地选自卤素、C1-4烷基、苄基、氧代和C1-6烷氧基羰基,并且任何环烷基和环杂烷基部分任选地具有环顶点之间的双键。
在一个实施方案中,式Ia的化合物是这样的化合物,其中R3是甲基。在另一个实施方案中,R3是甲基,并且R4是H或C1-4烷基。在另一个实施方案中,R2是H或C1-8烷基,R3是甲基,并且R4是H或C1-4烷基。在另一个实施方案中,R5是CF3。在一组选定的实施方案中,式Ia的化合物是这样的化合物,其中R3是甲基,且R5是CF3。
在另一组实施方案中,式Ia的化合物是式Ib所示的那些化合物,
其中,R1、R2、R3、R4和R5具有参照式Ia所提供的含义。在式Ib的实施方案中,一组选定的化合物是这样的化合物,其中R1选自-NRaRb和RaRbN-C1-4烷基。在一个所选的实施方案中,R1是-NRaRb。在另一个所选的实施方案中,R1是RaRbN-C1-4烷基。在另一些实施方案中,R3和R4分别是甲基。在另一组选定的化合物中,R5是CF3、CN或环丙基。在式Ib的另一组实施方案中,R1是一-或二-(C1-4烷基)氨基-C1-4烷基,且R3是甲基。特别优选这样的化合物,其中R1是二(C1-4烷基)氨基甲基。在式Ib的另一组实施方案中,R2和R3分别是甲基。
在另一组实施方案中,提供了具有式Ic的化合物:
其中,R1、R2、R3、R4和R5具有参照式Ia所提供的含义。在式Ic的一组选定的实施方案中,R2是H,且R3和R4分别是甲基。在另一个所选组的实施方案中,R5是CF3。
本发明的一些具体的实施方案是选自以下的化合物:
另一些选定的实施方案是图1中所提供的任何化合物。
化合物的制备
可按照下文中所描述的方法制备本发明的某些化合物。还可按照本文件的实施例部分中概述的合成方法来制备化合物。此外,下文中描述了用于制备本发明化合物的某些中间体化合物的合成。
本领域技术人员会认识到,有多种可用的方法来合成权利要求书中所示分子。一般来说,用于合成权利要求书中所示化合物的有用方法由4部分组成,其可以以任何顺序进行:形成吡咯烷酮环,在吡咯烷酮环的C3和C4处安装取代基,形成苯胺酰胺键,以及在多种取代基上安装和/或修饰官能团。
下文中举例说明了用于制备所要求保护的化合物的多种方法(反应式1~7)。
反应式1~2说明形成吡咯烷酮环的一些方法。反应式3~5说明通过用碱处理,随后用合适的亲电子试剂(electrophile)烷化,从而向所述环引入取代基的方法。将酯转化成为相应的苯胺酰胺,随后产生本发明的化合物(反应式6和7)。
上文中描述的多种方法已被用于制备本发明的化合物,实施例中描述了其中一些方法。
B.组合物
除了上文中所提供的化合物,用于在人和动物中调节ChemR23活性的组合物通常会含有药用载体或稀释剂。
本文中使用的术语“组合物”意在包括这样的产品,其包含指定量的指定成分,以及直接或间接来自所述指定量的指定成分之组合的任何产品。“可药用”意为载体、稀释剂或赋形剂必须与配方的其他成分相容,并且对其接受者无害。
用于施用本发明化合物的药物组合物可以方便地以单位剂型存在,并可以通过药学和药物递送领域中公知的方法来制备。所有方法均包括使活性成分与载体相联合(association)的步骤,所述载体由一种或更多种助剂(accessory ingredient)构成。一般来说,通过使活性成分均匀地和紧密地与液体载体或细碎的固体载体(或者二者兼有)相联合而制备药物组合物,并随后(如果必要的话)使产品成型为所需的制剂。在药物组合物中包含足以在疾病的过程或状况中产生所需作用之量的活性目标化合物。
含有活性成分的药物组合物可以是适合经口使用的形式,例如片剂、锭剂(troche)、糖锭剂(lozenge)、水或油混悬剂、可分散的散剂或颗粒剂、美国专利申请2002-0012680中所描述的乳剂和自乳化、硬或软胶囊剂、糖浆剂、酏剂、溶液剂、口腔贴剂、经口凝胶剂(oral gel)、口香糖(chewing gum)、咀嚼片剂(chewable tablet)、泡腾散剂和泡腾片剂。可根据制造药物组合物之领域已知的任何方法制备意在用于经口使用的组合物,并且所述组合物可含有一种或更多种选自以下的试剂:甜味剂、矫味剂、着色剂、抗氧化剂和防腐剂,以提供药学上精致的且可口的制剂。片剂含有与适合制造片剂的无毒性的可药用赋形剂混合的活性成分。这些赋形剂可以是例如:惰性稀释剂,例如纤维素、二氧化硅、氧化铝、碳酸钙、碳酸钠、葡萄糖、甘露醇、山梨糖醇、乳糖、磷酸钙或磷酸钠;造粒剂和崩解剂,例如玉米淀粉或海藻酸;粘合剂,例如PVP、纤维素、PEG、淀粉、明胶或阿拉伯胶;以及润滑剂,例如硬脂酸镁、硬脂酸或滑石粉。所述片剂可以是未包衣的或者其可以是通过已知技术包衣的(肠溶衣或其他),以延缓在胃肠道中的崩解和吸收,并因此提供更长期的持久作用。例如,可以使用时间延缓物质,例如单硬脂酸甘油酯或二硬脂酸甘油酯。还可通过U.S.Pat.No.4,256,108、4,166,452和4,265,874中描述的技术对它们进行包衣,以形成用于控释的渗透治疗片剂。
用于经口使用的制剂还可以表现为硬明胶胶囊,其中将活性成分与惰性固体稀释剂(例如,碳酸钙、磷酸钙或高岭土)混合,或者表现为软明胶胶囊,其中活性成分与水或油介质(例如,花生油、液体石蜡或橄榄油)混合。此外,可以用不与水混溶的成分(例如,油)制备乳剂,并用表面活性剂(例如,甘油一酯、甘油二酯、PEG酯等)对其进行稳定。
水混悬剂含有与适合用于制造水混悬剂的赋形剂混合的活性物质。所述赋形剂是助悬剂,例如羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、海藻酸钠、聚乙烯吡咯烷酮、西黄蓍胶和阿拉伯胶;分散或润湿剂可以是天然磷脂(例如,卵磷脂),或者环氧烷与脂肪酸的缩合产物(例如,聚氧乙烯硬脂酸酯),或者环氧乙烷与长链脂肪族醇的缩合产物(例如,十七亚乙基氧基鲸蜡醇(heptadecaethyleneoxycetanol)),或者环氧乙烷与源自脂肪酸和己糖醇之偏酯(partial ester)的缩合产物(例如,聚氧乙烯山梨糖醇单油酸酯),或者环氧乙烷与源自脂肪酸和己糖醇酸酐之偏酯的缩合产物(例如,聚乙烯山梨聚糖单油酸酯)。水混悬剂还可含有一种或更多种防腐剂(例如,对羟基苯甲酸乙酯或正丙酯),一种或更多种着色剂,一种或更多种矫味剂,以及一种或更多种甜味剂(例如,蔗糖或糖精)。
可以通过将活性成分悬于植物油(例如,花生油、橄榄油、芝麻油或椰子油)或矿物油(例如,液体石蜡)中来配制油混悬剂。油混悬剂可以含有增稠剂,例如蜂蜡、硬石蜡或鲸蜡醇。可以添加甜味剂(例如,上文中所列出的那些)和矫味剂以提供可口的经口制剂。可以通过添加抗氧化剂(例如,抗坏血酸)来保存这些组合物。
适于通过添加水而制备水混悬剂的可分散的散剂和颗粒剂提供与分散或润湿剂、助悬剂以及一种或更多种防腐剂混合的活性成分。合适的分散或润湿剂以及助悬剂的例子在上文中已经提到。还可存在其他赋形剂,例如甜味剂、矫味剂和着色剂。
本发明的药物组合物还可以是水包油乳剂的形式。油相可以是植物油(例如,橄榄油或花生油)或者矿物油(例如,液体石蜡)或者这些的混合物。合适的乳化剂可以是天然树胶(例如,阿拉伯胶或西黄蓍胶),天然磷脂(例如,大豆、卵磷脂),以及源自脂肪酸和己糖醇酸酐的酯或偏酯(例如,山梨聚糖单油酸酯),以及所述偏酯与环氧乙烯的缩合产物(例如,环氧乙烯山梨聚糖单油酸酯)。乳剂还可以含有甜味剂和矫味剂。
可以用甜味剂(例如,甘油、丙二醇、山梨糖醇或蔗糖)配制糖浆剂和酏剂。这样的制剂还可以含有缓和剂(demulcent)、防腐剂以及矫味剂和着色剂。可以与例如环糊精、PEG和表面活性剂联合制备经口溶液剂。
药物组合物可以是无菌可注射的水或含油的混悬剂的形式。可以根据已知的技术使用上文中提到的那些合适的分散或润湿剂以及助悬剂来配制该混悬剂。无菌可注射制剂可以是无毒性的肠胃外可接受的稀释剂或溶剂中的无菌的可注射溶液剂或混悬剂,例如作为1,3-丁二醇中的溶液剂。可以使用的可接受的载剂和溶剂是水、林格液(Ringer′s solution)和等渗的氯化钠溶液。此外,无菌的不挥发性油(fixed oil)常规地用作溶剂或混悬介质。为了该目的,可使用任何温和的不挥发性油,包括合成的甘油一酯或甘油二酯。此外,在注射剂的制备中可使用脂肪酸(例如,油酸)。
还可以以用于直肠施用药物的栓剂形式施用本发明的化合物。可以通过将药物与合适的无刺激性的赋形剂混合来制备这些组合物,所述赋形剂在常温下是固体,但在直肠的温度下是液体,并因此将在直肠中熔化以释放药物。这样的物质包括可可豆油和聚乙二醇。此外,可以以溶液剂或软膏剂通过眼递送来施用所述化合物。此外,可以通过离子电渗贴片剂(iontophoretic patch)等实现目标化合物的经皮递送。对于局部使用,采用含有本发明化合物的乳膏剂、软膏剂、胶冻剂、溶液剂或混悬剂等。本文中使用的局部应用还意在包括使用漱口剂和含漱剂。
本发明的化合物还可以结合载体,其为作为可靶向的药物载体的合适的聚合物。所述聚合物可包括聚乙烯吡咯烷酮、吡喃共聚物、聚羟基-丙基-甲基丙烯酰胺-酚、聚羟基乙基-天冬酰胺-酚或者以棕榈酰基残基取代的聚环氧乙烷-聚赖氨酸。此外,本发明的化合物可以与载体结合,所述载体是一类用于实现药物之控释的生物可降解的聚合物,例如聚乳酸、聚乙醇酸、聚乳酸与聚乙醇酸的共聚物、聚ε己内酯、聚羟基丁酸、聚原酸酯、聚缩醛、聚二氢吡喃、聚氰基丙烯酸酯以及水凝胶的交联的或两亲的嵌段共聚物。可使聚合物和半透性聚合物基质形成成形的物品,例如瓣(valve)、支架(stent)、管状物(tubing)、假体(prosthesis)等。
C.使用方法
虽然不希望受到任何具体理论的限制,考虑本发明的化合物和组合物通过与ChemR23受体结合而提供治疗作用。因此,本发明的化合物和组合物可在哺乳动物中用于治疗或预防疾病或病症,其中抑制天然配体与ChemR23受体的结合可提供治疗作用。
在一个实施方案中,抑制趋化因子配体与ChemR23受体之结合的优选方法包括使一个或更多个前述化合物与表达ChemR23受体的细胞接触一段时间,所述时间足以抑制天然趋化因子配体与ChemR23受体的结合。
在一些实施方案中,向患有炎性皮肤疾病的对象施用本发明的化合物和组合物。在一些情况下,施用ChemR23调节剂以治疗银屑病、系统性红斑狼疮、盘状红斑狼疮、皮肌炎、扁平苔癣、大疱性类天疱疮以及脑和神经元功能不良,例如多发性硬化和脱髓鞘病;类风湿性关节炎;动脉粥样硬化;II型糖尿病、胰岛素抵抗、肥胖、代谢综合征、血脂异常、心血管疾病,以及本文中描述的其他病症和疾病。
在治疗或预防需要趋化因子受体调节的病症中,合适的剂量水平通常会是约0.001至100mg/kg患者体重/天,其可以以单剂量或多剂量施用。优选地,剂量水平会是约0.01至约25mg/kg/天;更优选约0.05至约10mg/kg/天。合适的剂量水平可以是约0.01至25mg/kg/天,约0.05至10mg/kg/天,或约0.1至5mg/kg/天。在该范围内,所述剂量可以是0.005至0.05、0.05至0.5或者0.5至5.0mg/kg/天。对于经口施用,优选以片剂的形式提供所述组合物以对要被治疗的患者进行剂量的症状调节,所述片剂含有1.0至1000毫克的活性成分,尤其是1.0、5.0、10.0、15.0、20.0、25.0、50.0、75.0、100.0、150.0、200.0、250.0、300.0、400.0、500.0、600.0、750.0、800.0、900.0和1000.0毫克的活性成分。可以以每天1至4次(优选每天1次或两次)的方案施用所述化合物。
然而,要理解的是,对于任何具体的患者,剂量的具体剂量水平和频率可以不同,且将取决于多种因素,包括所使用的具体化合物的活性、代谢稳定性和所述化合物之作用的长短、年龄、体重、遗传特征、一般健康状况、性别和对象的饮食,以及施用方式和时间、排泄速率、药物联合以及进行治疗的患者之具体病症的严重程度。
本发明的化合物和组合物可与具有相关效用的其他化合物和组合物联合以预防和治疗癌症以及与ChemR23信号相关的疾病或病症。可以通过为此通常使用的途径和量,与本发明的化合物或组合物同时地或顺序地施用所述其他药物。当与一种或更多种其他药物同时使用本发明的化合物或组合物时,优选含有除了本发明的化合物或组合物之外的所述其他药物的药物组合物。因此,本发明的药物组合物包括除了本发明的化合物或组合物之外还含有一种或更多种其他活性成分或治疗剂的药物组合物。可以与本发明的化合物或组合物联合的分别施用或在同一药物组合物中施用的其他治疗剂的实例包括但不限于:顺铂、紫杉醇、甲氨蝶呤、环磷酰胺、异环磷酰胺、苯丁酸氮芥、卡莫司汀、卡铂、长春新碱、长春碱、塞替派、洛莫司汀、司莫司汀、5-氟尿嘧啶和阿糖胞苷。本发明的化合物与第二活性成分的重量比可以不同,并且将取决于每种成分的有效剂量。一般来说,会使用各自的有效剂量。因此,例如,当本发明的化合物与第二抗癌剂联合时,本发明的化合物与第二药剂的重量比通常会是约1000∶1至约1∶1000,优选约200∶1至约1∶200。本发明的化合物与其他活性成分的联合通常还会在前述范围之内,但在各自的情况下,应当使用每种活性成分的有效剂量。
治疗炎症的方法
此外,本发明的化合物和组合物用于治疗炎症,并可与具有治疗效用的其他化合物和组合物联合,其可要求在用本发明化合物治疗癌症或炎症之前、之后治疗或者与之同时治疗。因此,预防和治疗目的病症和疾病(例如,炎症或自身免疫障碍、病症和疾病,包括银屑病、皮肌炎、炎性肠病、类风湿性关节炎、骨关节炎、银屑病关节炎、多关节性关节炎(polyarticulararthritis)、多发性硬化、变应性疾病、特应性皮炎和哮喘,以及如上文所述的那些病理状况)的联合方法和组合物也是本发明的组成部分。
例如,在炎症或自身免疫或例如与骨质流失相关的关节炎的治疗或预防中,可与抗炎或镇痛剂联合使用本发明的化合物和组合物,所述抗炎或镇痛剂例如阿片激动剂、脂氧合酶抑制剂(例如,5-脂氧合酶抑制剂)、环氧合酶抑制剂(例如,环氧合酶-2抑制剂)、白介素抑制剂(例如,白介素-1抑制剂)、NMDA拮抗剂、一氧化氮抑制剂或一氧化氮合成抑制剂、非甾体抗炎剂或抑制细胞因子的抗炎剂,例如与例如以下化合物联合使用:醋氨酚、阿司匹林、可待因、芬太尼、布洛芬、吲哚美辛、酮咯酸、吗啡、萘普生、非那西汀、吡罗昔康、甾体类镇痛剂、苏芬太尼、舒林酸、替尼达普等。类似地,可与以下化合物一起施用本发明的化合物和组合物:上文中所列出的镇痛剂;增效剂,例如咖啡因、H2拮抗剂(例如,雷尼替丁)、二甲基硅油(simethicone)、氢氧化铝或氢氧化镁;减充血剂,例如去氧肾上腺素、苯丙醇胺、伪麻黄碱、羟甲唑啉、肾上腺素(ephinephrine)、萘唑啉、赛洛唑啉、环己丙甲胺、左旋脱氧麻黄碱;镇咳剂,例如可待因、氢可酮、卡拉米芬、喷托维林(carbetapentane)或右美沙芬;利尿剂;以及镇静或非镇静的抗组胺剂。
如前所述,本发明的化合物和组合物可以与其他药物联合用于治疗、预防、抑制或改善疾病或病症(本发明的化合物或组合物对所述疾病或病症有用)。可通过其通常所使用的途径和量与本发明的化合物或组合物同时地或顺序地施用所述其他药物。当本发明的化合物或组合物与一种或更多种其他药物同时使用时,优选含有除了本发明的化合物或组合物之外的所述其他药物的药物组合物。因此,本发明的药物组合物包括除了本发明的化合物之外还含有一种或更多种其他活性成分或治疗剂的药物组合物。可与本发明的化合物或组合物分别施用或在同一药物组合物中联合施用的其他治疗剂的实例包括但不限于:(a)VLA-4,(b)皮质类固醇,例如倍氯米松、甲泼尼龙、倍他米松、强的松、泼尼松龙、地塞米松、氟替卡松、氢化可的松、布地奈德、曲安西龙、沙美特罗、沙美特罗、沙丁胺醇、福莫特诺(formeterol);(c)免疫抑制剂,例如环胞菌素(环胞菌素A、山地明(Sandimmune)、新山地明(Neoral))、他克莫司(FK-506、普乐可复(Prograf))、雷帕霉素(西罗莫司、雷帕鸣(Rapamune))和其他FK-506型免疫抑制剂,以及麦考酚酯(例如,麦考酚吗乙酯(mycophenolate mofetil)(CellCept));(d)抗组胺剂(H1-组胺拮抗剂),例如溴苯那敏、氯苯那敏、右氯苯那敏、曲普利啶、氯马斯汀、苯海拉明、二苯拉林、曲吡那敏、羟嗪、甲地嗪、异丙嗪、阿利马嗪、阿扎他定、赛庚啶、安他唑啉、非尼拉敏、美吡拉敏、阿司咪唑、特非那定、氯雷他定、西替利嗪、非索非那定、去乙酯基氯雷他定(descarboethoxyloratadine)等;(e)非甾体抗哮喘剂(例如,特布他林、奥西那林、非诺特罗、异他林、沙丁胺醇(albuterol)、比托特罗和吡布特罗)、茶碱、色甘酸钠、阿托品、异丙托溴铵、白三烯拮抗剂(例如,扎鲁司特(zafmlukast)、孟鲁司特、普仑司特、伊拉司特、泊比司特和SKB-106,203)、白三烯生物合成抑制剂(齐留通、BAY-1005);(f)非甾体抗炎剂(NSAID),例如丙酸衍生物(例如,阿明洛芬、苯洛芬、布氯酸、卡洛芬、芬布芬、非诺洛芬、氟洛芬、氟比洛芬、布洛芬、吲哚洛芬、酮洛芬、咪洛芬、萘普生、奥沙普秦、吡洛芬、普拉洛芬、舒洛芬、噻洛芬酸和硫洛芬)、乙酸衍生物(例如,吲哚美辛、阿西美辛、阿氯芬酸、环氯茚酸、双氯芬酸、芬氯酸、芬克洛酸、芬替酸、呋罗芬酸、异丁芬酸、伊索克酸、oxpinac、舒林酸、硫平酸、托美汀、齐多美辛和佐美酸)、芬那酸衍生物(例如,氟芬那酸、甲氯芬那酸、甲芬那酸、尼氟酸和托芬那酸)、联苯基羧酸衍生物(例如,二氟尼柳和氟尼柳)、昔康类(例如,伊索昔康、吡罗昔康、舒多昔康和替诺昔康)、水杨酸类(例如,乙酰水杨酸和柳氮磺吡啶)和吡唑啉酮类(例如,阿扎丙宗、苄哌立隆(bezpiperylon)、非普拉宗、莫非保松、羟布宗和保泰松);(g)环氧合酶-2(COX-2)抑制剂,例如塞来昔布(西乐葆(Celebrex))和罗非昔布(万络(Vioxx));(h)IV型磷酸二酯酶(phosphodiesterase typeIV,PDE IV)抑制剂;(i)金化合物,例如金诺芬和金硫葡糖,(j)依那西普(恩利(Enbrel)),(k)抗体治疗,例如orthoclone(OKT3)、达利珠单抗(daclizumab)(赛尼哌(Zenapax))、巴利昔单抗(舒莱(Simulect))和英利昔单抗(瑞米凯德(Remicade)),(l)趋化因子受体(尤其是CCR5、CXCR2、CXCR3、CCR2、CCR3、CCR4、CCR7、CX3CR1和CXCR6)的其他拮抗剂;(m)润滑剂或软化剂,例如矿脂和羊毛脂,(n)角质溶解剂(例如,他扎罗汀),(o)维生素D3衍生物,例如钙泊三烯或卡泊三醇(达力士(Dovonex)),(p)PUVA,(q)地蒽酚(Drithrocreme),(r)依曲替酯(体吉松(Tegison))和异维甲酸,以及(s)多发性硬化的治疗剂,例如干扰素β-1β(Betaseron),干扰素β-1α(Avonex)、硫唑嘌呤(ImurekImuran)、醋酸格拉默(glatiramer acetate)(Capoxone)、糖皮质激素(例如,泼尼松龙)和环磷酰胺(t)DMARDS,例如甲氨蝶呤(u)其他化合物,例如5-氨基水杨酸及其前药;羟氯喹;D-青霉胺;抗代谢物,例如硫唑嘌呤、6-巯嘌呤和甲氨蝶呤;DNA合成抑制剂(例如,羟基脲)以及微管破坏剂(例如,秋水仙素)。本发明的化合物与第二活性成分的重量比可以不同,且取决于每种成分的有效剂量。一般来说,会使用各自的有效剂量。因此,例如,当本发明的化合物与NSAID联合时,本发明的化合物与NSAID的重量比的范围通常会是约1000∶1至约1∶1000,优选约200∶1至约1∶200。本发明的化合物与其他活性成分的联合通常也会在上述范围之内,但在各自的情况下,应使用每种活性成分的有效剂量。
IV.实施例
提供以下实施例来说明,但其不限制所要求保护的发明。
可从商业来源(例如,Aldrich Chemical Co.(Milwaukee,Wisconsin,USA))获得下文中所使用的试剂和溶剂。使用Varian Mercury 400MHzNMR波谱仪记录1H-NMR谱。相对于TMS提供了显著的峰,并按以下顺序制表:多重性(s,单峰;d,双峰;t,三重峰;q,四重峰;m,多重峰)和质子数。以质/荷比和随后每种离子的相对丰度(在括号中)来报告质谱结果。在实施例中,对于含有最常见的原子同位素的M+H(或表示为M-H)离子,报告单个m/e值。同位素型对应于所有情况中所预期的式。使用HP1100HPLC递送样品,用Hewlett-Packard MSD电喷雾质谱仪进行电喷雾离子化(ESI,electrospray ionization)质谱分析。一般来说,将分析物以0.1mg/mL溶于甲醇中,将1微升与递送溶剂一起注入质谱仪,扫描100至1500道尔顿。使用具有1%甲酸的乙腈/水作为递送溶剂,可在正离子ESI模式中分析全部化合物。使用乙腈/水中的2mM NH4OAc作为递送系统,还可在负离子ESI模式中分析下文中所提供的化合物。
本发明的实施例和整个说明书中使用以下缩写:rt,室温;HPLC,高压液相色谱;TFA,三氟乙酸;LC-MSD,液相色谱/质量选择检测器;LC-MS,液相色谱/质谱仪;Pd2dba3,三(二亚苄基丙酮)二钯;THF,四氢呋喃;DMF,二甲基甲酰胺或N,N-二甲基甲酰胺;DCM,二氯甲烷;DMSO,二甲基亚砜;TLC,薄层色谱;KHMDS,六甲基二硅氮基钾(potassium hexamethyldisilazane);ES,电喷雾;sat.,饱和的。
可按照以下的描述使用技术人员已知的多种反应合成本发明的范围之内的化合物。本领域技术人员还会认识到,可采用替代方法合成本发明的目标化合物,并且本文件中描述的方法不是穷举的,但的确提供了广泛适用的和实用的得到目标化合物的途径。
本专利中要求保护的某些分子可以以不同的对映体和非对映体形式存在,要求保护这些化合物的所有这样的变体。
对用于合成本文中关键化合物之实验方法的详细描述产生通过鉴定它们的物理数据以及通过与它们相关的结构描述所描述的分子。
本领域技术人员还会理解,在有机化学中的标准工作流程的过程中,经常使用酸和碱。在本专利中所描述的实验方法的过程中,如果母体化合物具有必要的内在酸性或碱性,有时产生母体化合物的盐。
实施例1:合成1-(2,6-二甲基苯基)-3-异丙基-5-氧代-吡咯烷-3-羧酸[3,5-双(三氟甲基)苯基]酰胺
a)在通向大气的瓶中,将2,6-二甲基苯胺(121g,1mol)和衣康酸(130g,1mol)的混合物加热至130℃45分钟,使所产生的蒸汽放出。除去加热源,当混合物仍是热的之时(开始时允许一些回流),在剧烈搅拌下添加0.8L乙酸乙酯。随后,使混合物在搅拌下冷却至室温。滤出固体,用0.4L乙酸乙酯洗涤,在空气中干燥以产生164g(70%收率)无色晶体。LC-MS Rt(保留时间):0.54分钟,MS:(ES)m/z 234(M+H+)。
b)向400mL甲醇中逐滴添加乙酰氯(2.40g,30.9mmol)。向溶液中添加1-(2,6-二甲基苯基)-5-氧代-吡咯烷-3-羧酸(144g,618mmol,上述步骤a中制备的),随后添加原甲酸三甲酯(67mL,618mmol)。将混合物加热至64℃1小时,随后在真空中浓缩以产生152g(99%收率)油状纯产物。LC-MS Rt(保留时间):1.49分钟,MS:(ES)m/z 248(M+H+)。
c)在氮气气氛下,向冷却至-50℃的反应瓶中THF(7mL)中的1-(2,6-二甲基苯基)-5-氧代-吡咯烷-3-羧酸甲酯(3.44g,13.9mmol)溶液中添加LHMDS(1.0M于THF中,15.3mL,15.3mmol)。使反应混合物升温至0℃,此时添加2-碘丙烷(2.78mL,27.8mmol)。使反应化合物升温至室温,保持搅拌2小时。添加20mL半饱和的氯化铵水溶液,随后添加100mLCH2Cl2。在真空中用硅胶浓缩有机层,通过快速色谱(SiO2,20-60%EtOAc/己烷)纯化以产生1.65g所需的化合物(41%收率)。LC-MS Rt(保留时间):2.24分钟,MS:(ES)m/z 290(M+H+)。
d)在室温下,向甲醇(1mL)和水(1mL)中的来自步骤c的酯(115mg,0.40mmol)的溶液中添加氢氧化锂(96mg,4.00mmol)。在封闭的小瓶中将混合物加热至80℃1小时,此时结束反应。在真空中除去有机溶剂。向所产生的溶液中添加4.0mL 1M盐酸水溶液,在室温下搅拌混合物15分钟。滤出白色固体,用另外5mL水洗涤,真空干燥以产生93mg产物(85%收率)。LC-MS:Rt(保留时间):1.74分钟,MS:(ES)m/z 276(M+H+)。
e)向乙腈(1mL)中的上述制备的酸(51.0mg,0.185mmol)和三乙胺(6当量)的溶液中添加3,5-双(三氟甲基)苯胺(42.0mg,0.185mmol)。随后添加T3P(50%溶液,235mg,0.370mmol),使溶液在85℃下搅拌16小时。在真空中浓缩反应混合物,重新溶于CH2Cl2中。将溶液在真空中用硅胶浓缩,通过快速色谱(SiO2,20-80%EtOAc/己烷)纯化以产生7.0mg所需化合物(8%收率)的白色固体。1H NMR(400MHz,DMSO-d6δ0.96(d,J=6.8,3H),0.97(d,J=6.8,3H),1.98(s,3H),2.16(s,3H),2.38(qq,J=6.8,6.8,1H),2.69(d,J=17.2,1H),3.05(d,J=17.2,1H),3.67(d,J=10.8,1H),3.98(d,J=10.8,1H),7.03-7.15(m,3H),7.80(s,1H),8.35(s,2H),10.31(s,1H)。LC-MS:Rt(保留时间)=2.94分钟,MS:(ES)m/z 487(M+H+)。
实施例2:合成(3R)-1-(2,6-二甲基苯基)-3-异丙基-5-氧代-吡咯烷-3-羧酸[3,5-双(三氟甲基)苯基]酰胺
a)将IPA(20mL)中的1-(2,6-二甲基苯基)-3-异丙基-5-氧代-吡咯烷-3-羧酸(按照实施例1步骤d制备的,2.47g,8.97mmol)和番木鳖碱(3.98g,10.09mmol)的混合物加热至80℃,直至溶液变得澄清。使溶液冷却至室温,接种非对映体纯的结晶,随后使其在室温下放置6天,随后冷却至0℃,陈化(aging)另外4小时。在0℃下滤出结晶,以冷IPA洗涤进入单独的瓶中,作为未来批次的种子而保存。用40mL 1M盐酸水溶液和40mL二乙醚稀释母液(不含有洗涤液),剧烈搅拌15分钟。随后的相分离产生有机层,用无水硫酸镁干燥有机层,过滤并在真空中浓缩以产生1.20g富对映体的酸(ee=76.2%)。将固体从热的甲苯(25mL)和二氧六环(3mL)的混合物中重结晶以产生0.90g进一步富集的酸(ee=97.3%)。再重复两次重结晶以获得0.75g对映体纯(ee>99.8%)酸(30%收率)的无色结晶。LC-MS Rt(保留时间):1.86分钟,MS:(ES)m/z 276(M+H+)。
b)向THF(4mL)中的对映体纯的(3R)-1-(2,6-二甲基苯基)-3-异丙基-5-氧代-吡咯烷-3-羧酸(182mg,0.661mmol,上述步骤中制备的)、N,N-二异丙基乙胺(374mg,2.90mmol)和3,5-双(三氟甲基)苯胺(331mg,1.45mmol)的溶液中逐滴添加甲磺酰氯(167mg,1.45mmol)。在室温下搅拌1小时以使反应完成,此时添加5mL 0.3M盐酸水溶液和10mL DCM,剧烈搅拌混合物5分钟。将所分离的有机相在真空中用硅胶浓缩,通过快速色谱(SiO2,25-60%EtOAc/己烷)纯化以产生灰白色残余物,将残余物从热的乙酸乙酯(2mL)和己烷(7mL)的混合物中重结晶以产生203mg所需化合物(63%收率)的无色结晶。1H NMR(400MHz,CDCl3)δ1.09(d,J=7.4,3H),1.11(d,J=7.4,3H),2.13(s,3H),2.23(s,3H),2.26(qq,J=7.4,7.4,1H),2.81(d,J=17.2,1H),3.09(d,J=17.2,1H),3.61(d,J=10.4,1H),4.17(d,J=10.4,1H),7.02-7.18(m,3H),7.64(s,1H),7.86(s,1H),8.05(s,2H)。LC-MS:Rt(保留时间)=3.10分钟,MS:(ES)m/z 487(M+H+)。
实施例3:合成1-(2,6-二甲基苯基)-3-甲基-5-氧代-吡咯烷-3-羧酸[3,5-双(三氟甲基)苯基]酰胺
a)在氮气气氛下,向冷却至-50℃的反应瓶中THF(20mL)中的1-(2,6-二甲基苯基)-5-氧代-吡咯烷-3-羧酸甲酯(5.53mg,22.4mmol,实施例1步骤b中制备的)溶液中添加LHMDS(1.0M于THF中,26.9mL,26.9mmol)。使反应化合物升温至0℃,随后冷却至-20℃,此时添加碘甲烷(7.0mL,5当量)。使反应化合物升温至室温,保持搅拌15分钟。添加50mL半饱和的氯化铵水溶液,用两份50mL的CH2Cl2萃取。在真空中用硅胶浓缩合并的有机层,通过快速色谱(SiO2,30-100%EtOAc/己烷)纯化以产生4.00g所需的化合物(68%收率)。LC-MS Rt(保留时间):1.87分钟,MS:(ES)m/z 262(M+H+)。
作为次要产物而分离0.54g非对映异构体的1-(2,6-二甲基苯基)-3,4-二甲基-5-氧代-吡咯烷-3-羧酸甲酯的混合物(8.8%收率)。LC-MS Rt(保留时间):2.10分钟,MS:(ES)m/z 276(M+H+)。
b)在室温下,向甲醇(1mL)和水(1mL)中的来自步骤a的酯(146mg,0.56mmol)的溶液中添加氢氧化锂(81mg,3.38mmol)。在封闭的小瓶中将混合物加热至80℃30分钟,此时结束反应。在真空中除去有机溶剂。向所产生的溶液中添加0.28mL 12M盐酸水溶液,在室温下搅拌混合物15分钟。滤出白色固体,用另外5mL水洗涤并真空干燥以产生120mg产物(87%收率)。LC-MS:Rt(保留时间):0.92分钟,MS:(ES)m/z 248(M+H+)。
c)向CH2Cl2(1mL)中的上述制备的酸(60.0mg,0.243mmol)和三乙胺(6当量)溶液中添加3,5-双(三氟甲基)苯胺(56.0mg,0.243mmol)。随后添加T3P(50%溶液,309mg,0.486mmol),使溶液在40℃下搅拌16小时。将溶液在真空中用硅胶浓缩,通过快速色谱(SiO2,30-100%EtOAc/己烷)纯化以产生灰白色残余物,将残余物从热的乙酸乙酯(2mL)和己烷(2mL)的混合物中重结晶以产生37mg所需化合物(33%收率)的无色结晶。1H NMR(400MHz,DMSO-d6)δ1.63(s,3H),2.04(s,3H),2.18(s,3H),2.49(d,J=16.4,1H),3.12(d,J=16.4,1H),3.48(d,J=10.2,1H),4.02(d,J=10.2,1H),7.05-7.18(m,3H),7.79(s,1H),8.35(s,2H),10.22(s,1H)。LC-MS:Rt(保留时间)=2.78分钟,MS:(ES)m/z 459(M+H+)。
实施例4和5:合成(3S*,4S*)-1-(2,6-二甲基苯基)-4-甲基-5-氧代-吡咯烷-3-羧酸[3,5-双(三氟甲基)苯基]酰胺和(3S*,4R*)-1-(2,6-二甲基苯基)-4-甲基-5-氧代-吡咯烷-3-羧酸[3,5-双(三氟甲基)苯基]酰胺
a)在通向大气的瓶中,将2,6-二甲基苯胺(426mg,3.52mmol)和β-甲基衣康酸(507mg,3.52mmol,根据Leitner et al,J.Am.Chem.Soc.1993,115,152-159所描述的方法制备的)的混合物加热至140℃1小时,使所产生的蒸汽放出。除去加热源,当混合物仍是热的之时(开始时允许一些回流),在剧烈搅拌下添加3mL乙酸乙酯。随后,在搅拌下使混合物冷却至室温。将溶液在真空中用硅胶浓缩,通过快速色谱(SiO2,50-100%EtOAc/己烷)纯化以产生410mg所需化合物(47%收率)的白色固体。LC-MS Rt(保留时间):0.84分钟,MS:(ES)m/z 248(M+H+)。
b)向DCM(1mL)中的上述步骤中制备的酸(71.0mg,0.287mmol)和三乙胺(6当量)的溶液中添加3,5-双(三氟甲基)苯胺(66.0mg,0.287mmol)。随后添加T3P(50%溶液,365mg,0.574mmol),使溶液在40℃下搅拌16小时。将溶液在真空中用硅胶浓缩,通过快速色谱(SiO2,30-100%EtOAc/己烷)纯化以产生40mg第一洗脱异构体(3S*,4S*)(31%收率)的白色固体。1H NMR(400MHz,DMSO-d6)δ1.27(d,J=7.6,3H),2.14(s,3H),2.15(s,3H),2.82-2.91(m,1H),3.14-3.23(m,1H),3.64-3.78(m,2H),7.08-7.19(m,3H),7.79(s,1H),8.29(s,2H),10.83(s,1H)。LC-MS:Rt(保留时间)=2.79分钟,MS:(ES)m/z 459(M+H+)
以15%的收率获得第二洗脱异构体(3S*,4R*)的白色固体(19mg)。1HNMR(400MHz,DMSO-d6)δ1.13(d,J=7.2,3H),2.13(s,3H),2.23(s,3H),3.00-3.09(m,1H),3.57-3.65(m,1H),3.65-3.73(m,1H),3.73-3.79(m,1H),7.07-7.18(m,3H),7.78(s,1H),8.27(s,2H),10.81(s,1H)。LC-MS:Rt(保留时间)=2.80分钟,MS:(ES)m/z 459(M+H+)。
实施例6:合成(3aR*,6aS*)-5-(2,6-二甲基苯基)-6-氧代六氢呋喃并[2,3-c]吡咯-3a-羧酸[3,5-双(三氟甲基)苯基]酰胺
在氮气气氛下,向冷却至-50℃的反应瓶中THF(2mL)中的3-[2-(叔丁基二甲基硅烷基氧基)乙基]-1-(2,6-二甲基苯基)-5-氧代-吡咯烷-3-羧酸叔丁酯(实施例6步骤a中制备的,1.69g,3.78mmol)溶液中添加LHMDS(1.0M于THF中,4.54mL,4.54mmol)。使反应化合物升温至0℃,随后立即冷却至-78℃,此时逐滴添加THF(6mL)中的(±)-(樟脑基磺酰基)-哑嗪(1.27g,5.56mmol)溶液。使反应化合物升温至室温,保持搅拌1小时。添加50mL半饱和的氯化铵水溶液,随后添加100mL己烷。在真空中用硅胶浓缩有机层,通过快速色谱(SiO2,5-50%EtOAc/己烷)纯化以产生1.46g残余物。将固体重新溶解于30mL己烷中。过滤悬浮液,弃去固体。在真空中浓缩滤液以产生1.38g所需的化合物(79%收率,以1H NMR观测到80∶20非对应异构体的混合物)。LC-MS Rt(保留时间):3.23分钟,MS:(ES)m/z 464(M+H+)。
b)向聚丙烯小瓶中CH2Cl2(10mL)中的含有上述步骤a中制备的醇(1.38g,2.98mmol)和吡啶(721μL,8.94mmol)的溶液中逐滴添加乙酰氯(334μL,4.68mmol)。使溶液反应30分钟,此时在室温下添加氟化氢-吡啶的复合物(70wt%HF,300μL,11.9mmol)。将混合物加热至35℃3小时。将溶液在真空中使用硅胶浓缩,通过快速色谱(SiO2,30-80%EtOAc/己烷)纯化以产生909mg所需化合物(78%收率)。LC-MS:Rt(保留时间):2.05,2.21分钟(80∶20非对映异构体的混合物),MS:(ES)m/z 392(M+H+)。
c)向CH2Cl2(4mL)中的上述步骤b中制备的醇(905mg,2.31mmol)和三乙胺(451μL,4.17mmol)的溶液中逐滴添加甲磺酰氯(234μL,3.00mmol)。将溶液在室温中陈化10分钟,在真空中用硅胶浓缩,通过快速色谱(SiO2,30-80%EtOAc/己烷)纯化以产生912mg所需的化合物(84%收率)。LC-MS Rt(保留时间):2.37分钟,MS:(ES)m/z 470(M+H+)。
d)向甲醇(15mL)中的上述步骤c中制备的甲磺酸酯(300mg,0.640mmol)的溶液中添加氢化钠(60%,28mg,0.704mmol)。使反应混合物在室温下陈化2小时,此时添加乙酸(45mg,0.75mmol)。在真空中用硅胶浓缩混合物,通过快速色谱(SiO2,20-80%EtOAc/己烷)纯化以产生142mg所需的化合物(67%收率)。LC-MS Rt(保留时间):2.28分钟,MS:(ES)m/z332(M+H+)。
e)将步骤d中制备的双环化合物(71mg,0.215mmol)溶于二氧六环(2mL)中的4N氯化氢溶液中。在密封的容器中,将所产生的溶液加热至65℃5小时,随后在真空中浓缩以产生59mg羧酸。LC-MS Rt(保留时间):0.58分钟,MS:(ES)m/z 276(M+H+)。
f)向THF(0.5mL)中的上述步骤e中制备的羧酸(59mg,0.215mmol)、N,N-二异丙基乙胺(139mg,1.08mmol)和3,5-双(三氟甲基)苯胺(98mg,0.428mmol)的溶液中逐滴添加甲磺酰氯(49mg,0.428mmol)。在50℃下搅拌1小时以使反应完成。添加4mL水和8mL CH2Cl2,剧烈搅拌混合物5分钟。在真空中用硅胶浓缩所分离的有机相,通过快速色谱(SiO2,20-80%EtOAc/己烷)纯化两次以产生60mg所需化合物(57%收率)的白色固体。1H NMR(400MHz,DMSO-d6)δ2.10(s,3H),2.18(s,3H),2.38-2.48(m,1H),2.57-2.67(m,1H),3.70(d,J=11.0,1H),3.82-3.90(m,1H),4.08(d,J=11.0,1H),4.08-4.16(m,1H),4.98(s,1H),7.08-7.20(m,3H),7.80(s,1H),8.34(s,2H),10.36(s,1H)。LC-MS:Rt(保留时间)=2.66分钟,MS:(ES)m/z 487(M+H+)。
实施例7和8:合成(3S*,4S*)-1-(2,6-二甲基苯基)-3,4-二甲基-5-氧代-吡咯烷-3-羧酸[3,5-双(三氟甲基)苯基]酰胺和(3S*,4R*)-1-(2,6-二甲基苯基)-3,4-二甲基-5-氧代-吡咯烷-3-羧酸[3,5-双(三氟甲基)苯基]酰胺
a)在室温下,向甲醇(5mL)和水(5mL)中的实施例3步骤a中制备的1-(2,6-二甲氧基苯基)-3,4-二甲氧基-5-氧代-吡咯烷-3-羧酸甲酯540mg,1.96mmol)的非对映异构体混合物溶液中添加氢氧化锂(283mg,11.8mmol)。将混合物加热至50℃2小时,此时完成反应。在真空中除去有机溶剂。向所产生的溶液中添加11.8mL 1M盐酸水溶液,在室温下搅拌混合物1小时。滤出白色固体,用另外10mL水洗涤,真空干燥以产生480mg产物(94%收率)。LC-MS:Rt(保留时间):1.32分钟,MS:(ES)m/z262(M+H+)。
b)向THF(1.5mL)中的上述步骤a中制备的羧酸(311mg,1.19mmol)、N,N-二异丙基乙胺(738mg,5.72mmol)和3,5-双(三氟甲基)苯胺(654mg,2.86mmol)的溶液中逐滴添加甲磺酰氯(328mg,2.86mmol)。在75℃下搅拌2小时使反应完成。添加5mL水和10mL CH2Cl2,剧烈搅拌混合物5分钟。在真空中用硅胶浓缩所分离的有机相,通过快速色谱(SiO2,25-80%EtOAc/己烷)纯化以产生第一洗脱异构体。从热的乙酸乙酯(2mL)和己烷(2mL)中重结晶以产生82mg(15%收率)白色固体(3S*,4S*)。1H NMR(400MHz,DMSO-d6)δ1.18(d,J=7.6,3H),1.51(s,3H),2.06(s,3H),2.19(s,3H),3.14(q,J=7.6,1H),3.51(d,J=10.0,1H),3.93(d,J=10.0,1H),7.06-7.18(m,3H),7.78(s,1H),8.36(s,2H),10.06(s,1H)。LC-MS:Rt(保留时间)=2.84分钟,MS:(ES)m/z 473(M+H+)。
随后从热的乙酸乙酯(5mL)中重结晶之后,以31%的收率获得第二洗脱异构体(3S*,4R*)的白色固体(174mg)。1H NMR(400MHz,DMSO-d6)δ1.19(d,J=7.4,3H),1.69(s,3H),2.12(s,3H),2.19(s,3H),2.61(q,J=7.4,1H),3.28(d,J=10.4,1H),4.20(d,J=10.4,1H),7.06-7.18(m,3H),7.79(s,1H),8.36(s,2H),10.15(s,1H)。LC-MS:Rt(保留时间)=2.89分钟,MS:(ES)m/z 473(M+H+)。
实施例9:合成(±)-1-(2,6-二甲氧基苯基)-3-羟基甲基-5-氧代-吡咯烷-3-羧酸[3,5-双(三氟甲基)苯基]酰胺
a)在氮气气氛下,向冷却至-50℃的反应瓶中THF(1mL)中的1-(2,6-二甲基苯基)-5-氧代-吡咯烷-3-羧酸甲酯(实施例1步骤b中制备的,432mg,1.75mmol)溶液中添加LHMDS(1.0M于THF中,2.4mL,2.4mmol)。使反应化合物升温至0℃,随后冷却回到-30℃,此时添加固体多聚甲醛(263mg,8.75mmol)。使反应混合物升温至室温,保持搅拌1小时。添加5mL半饱和的氯化铵水溶液,随后添加10mL CH2Cl2。在真空中用硅胶浓缩有机层,通过快速色谱(SiO2,40-100%EtOAc/己烷)纯化以产生136mg所需的化合物(28%收率)。LC-MS Rt(保留时间):0.81分钟,MS:(ES)m/z278(M+H+)。
b)在室温下,向甲醇(1mL)和水(1mL)中的来自步骤a的酯(136mg,0.49mmol)的溶液中添加氢氧化锂(71mg,2.94mmol)。在封闭的小瓶中将混合物加热至75℃1小时,此时结束反应。向所产生的溶液中添加2.7mL1M盐酸水溶液,在真空中除去溶剂。LC-MS:Rt(保留时间):0.39分钟,MS:(ES)m/z 264(M+H+)。
c)将来自步骤b的干燥残余物溶解/悬浮于吡啶(2mL)中。在45分钟内,分三份添加苯甲酰氯(300μL,2.58mmol)。在真空中除去溶剂,将残余物放入二乙醚(10mL)和水(10mL)中。用1N盐酸水溶液将混合物酸化至pH=4。在真空中除去有机层的溶剂。LC-MS:Rt(保留时间):2.07分钟,MS:(ES)m/z 368(M+H+)。
d)向CH2Cl2(2mL)中的上述制备的苯甲酸酯和三乙胺(1.6mL,11.5mmol)的悬浮液中添加3,5-双(三氟甲基)苯胺(600mg,2.62mmol)。随后添加T3P(50%溶液,2.3mL,3.87mmol),使溶液在室温下搅拌4小时。将溶液在真空中用硅胶浓缩,通过快速色谱(SiO2,20-80%EtOAc/己烷)纯化以产生19mg所需化合物的灰白色固体。LC-MS:Rt(保留时间):3.03分钟,MS:(ES)m/z 579(M+H+)。
e)在室温下,向甲醇(0.2mL)和水(0.2mL)中的来自步骤d的苯甲酸酯(10mg,0.017mmol)的溶液中添加氢氧化锂(2.5mg,0.104mmol)。将混合物在室温下陈化2小时,此时完成反应。向所产生的溶液中添加0.11mL1M盐酸水溶液,在真空中除去溶剂。通过快速色谱(SiO2,30-100%EtOAc/己烷)纯化残余物以产生4mg所需化合物的灰白色固体。1H NMR(400MHz,DMSO-d6)δ2.07(s,3H),2.16(s,3H),2.61(d,J=16.8,1H),3.02(d,J=16.8,1H),3.58(d,J=10.2,1H),3.86(d,J=5.2,2H),3.98(d,J=10.2,1H),5.54(t,J=5.2,1H),7.05-7.18(m,3H),7.78(s,1H),8.36(s,2H),10.17(s,1H)。LC-MS:Rt(保留时间):2.57分钟,MS:(ES)m/z 475(M+H+)。
LC-MS法:Agilent Zorbax SB-C18,2.1×50mm,5μ,35℃,1mL/分钟流速,20%至100%B梯度2.5分钟,以100%B清洗1.0分钟;A=0.1%甲酸/5%乙腈/94.9水,B=0.1%甲酸/5%水/94.9乙腈
实施例10:合成3,4-二甲基-5-氧代-1-临甲苯基-吡咯烷-3-羧酸(3,5-双-三氟甲基-苯基)酰胺
a)向2-甲基苯胺(10g,93mmol)的溶液中添加衣康酸(12.1g,93mmol),在140℃下加热反应物1小时。随后将溶液冷却至65℃,添加EtOAc(100mL)以产生固体。通过过滤收集固体,用己烷冲洗,以55%的收率产生所需的酸(10.7g)。LC-MS Rt(保留时间):0.41分钟,MS:(ES)m/z 220.2(M+H+)。
b)在0℃下,向MeOH(17mL)中的来自步骤a的酸(0.75g,3.4mmol)的溶液中添加TMSCHN2(2.0M于Et2O中,7mL,14mmol)。在室温下搅拌反应物15分钟,用乙酸(~0.5mL)终止。在减压下浓缩溶液。通过快速色谱纯化残余物(SiO2,0-40%己烷/EtOAc),以99%收率产生所需产物(0.79g)。LC-MS Rt(保留时间):0.99分钟,MS:(ES)m/z 234.1(M+H+)。
c)在-50℃下,向反应瓶中THF(36mL)中的来自步骤b的酯(0.79g,3.4mmol)的溶液中添加双(三甲基硅基)氨基锂(1.0M于THF中,5.1mL,5.1mmol),搅拌5分钟。使反应物升温至0℃,随后添加MeI(2.5g,18mmol)。随后,在室温下搅拌反应物2小时。随后用饱和的NH4Cl终止反应。将层分离,用EtOAc(3×)萃取水层。干燥(MgSO4)合并的有机层,在减压下浓缩。通过快速色谱(SiO2,0-50%己烷/EtOAc)纯化残余物以产生所需的化合物(29%收率)(0.27g)。LC-MS Rt(保留时间):2.25分钟,MS:(ES)m/z 262.3(M+H+)。
d)向MeOH(5ml)中的来自步骤c的酯(0.27g,1.03mmol)的溶液中添加氢氧化锂(1.0M于H2O中,10mL,10mmol)。在75℃下加热所产生的溶液18小时。将溶液在减压下浓缩以产生原体积的1/4,逐滴添加6MHCl水溶液(~1mL)以调节pH至约4。随后用EtOAc(3×)萃取水层。干燥(MgSO4)合并的有机层,在减压下浓缩,以产生粗制产物(0.075g,28%)。LC-MS:Rt(保留时间):1.02分钟和1.15分钟(两种非对映体),MS:(ES)m/z 248.2(M+H+)。
e)在室温下,向THF(2.9ml)中的来自步骤d的酸(0.075g,0.29mmol)的溶液中添加甲磺酸(0.04g,0.43mmol,)和iPr2NEt(0.11mL,0.63mmol)。在室温下搅拌所产生的混合物5分钟,随后添加3,5-双(三氟甲基)苯胺(0.066g,0.29mmol)。在75℃下加热反应物直到完成反应(4小时)。在减压下浓缩混合物。通过快速色谱(SiO2,0-75%己烷/EtOAc)纯化,以23%的收率作为2∶1的非对映体混合物而产生所需的产物(0.031g)。1H NMR(400MHz,DMSO-d6):δ10.11(s,0.7H),10.09(s,0.3H),8.36(s,2H),7.79(s,1H),7.26-7.21(m,4H),4.28(d,J=10.0Hz,0.3H),4.13(d,J=10.0Hz,0.7H),3.54(d,J=9.6Hz,0.7H),3.38(d,J=10.4Hz,0.3H),3.14(q,J=7.2Hz,0.7H),2.62(q,J=7.2Hz,0.3H),2.17(s,1H),2.15(s,2H),1.63(s,1H),1.45(s,2H),1.16(d,J=7.2Hz,1H),1.15(d,J=7.2Hz,2H)。LC-MS:Rt(保留时间):2.28分钟,MS:(ES)m/z 459.4(M+H+)。
实施例11:合成1-(2,6-二甲基苯基)-3-甲氧基甲基-5-氧代-吡咯烷-3-羧酸(3,5-双-三氟甲基苯基)酰胺
a)在-50℃下,向反应瓶中THF(16mL)中的1-(2,6-二甲基苯基)-5-氧代-吡咯烷-3-羧酸甲酯(0.4g,1.6mmol)的溶液中添加双(三甲基硅基)氨基锂(1.0M于THF中,1.9mL,1.9mmol),搅拌5分钟。使反应物升温至0℃,随后添加MOMBr(0.29g,4.0mmol)。在室温下搅拌反应物2小时,用饱和NH4Cl终止。将层分离,用EtOAc(3×)萃取水层。干燥(MgSO4)合并的有机层,在减压下浓缩。通过快速色谱(SiO2,0-60%己烷/EtOAc)纯化残余物,以43%的收率产生所需的化合物(0.2g)。LC-MS Rt(保留时间):1.83分钟,MS:(ES)m/z 292.3(M+H+)。
b)向MeOH(3ml)中的来自步骤a的酯(0.2g,0.68mmol)的溶液中添加氢氧化锂(1.0M于H2O中,6.8mL,6.8mmol)。在75℃下加热所产生的溶液2小时。在减压下浓缩溶液以产生原体积的1/4,逐滴添加6M HCl水溶液(~0.5mL)以调节pH至约4。用EtOAc(3×)萃取水层。干燥(MgSO4)合并的有机层,在减压下浓缩以产生粗制产物(0.18g,96%)。LC-MS:Rt(保留时间):1.11,MS:(ES)m/z 278.3(M+H+)。
c)在室温下,向THF(2.7ml)中的来自步骤b的酸(0.075g,0.27mmol)的溶液中添加甲磺酸(0.038g,0.32mmol,)和iPr2NEt(0.1mL,0.59mmol)。在室温下搅拌所产生的混合物5分钟,随后添加3,5-双(三氟甲基)苯胺(0.06g,0.27mmol)。在75℃下加热反应物直到完成反应(3小时)。在减压下浓缩混合物。通过快速色谱(SiO2,0-75%己烷/EtOAc)纯化,以22%的收率产生所需的产物(0.035g)。1H NMR(400MHz,DMSO-d6):δ11.25(s,1H),8.36(s,2H),7.79(s,1H),7.14-7.09(m,3H),4.01(d,J=10.0Hz,1H),3.82(s,2H),3.60(d,J=10.4,1H),3.32(s,3H),3.08(d,J=17.2Hz,1H),2.63(d,J=16.8Hz,1H),2.17(s,3H),2.06(s,3H)。LC-MS:Rt(保留时间):2.34分钟,MS:(ES)m/z 489.4(M+H+)。
实施例12:合成1-(2,6-二甲基苯基)-3-异丁基-5-氧代-吡咯烷-3-羧酸(3,5-双-三氟甲基苯基)酰胺
a)在-50℃下,向反应瓶中THF(16mL)中的1-(2,6-二甲基苯基)-5-氧代-吡咯烷-3-羧酸甲酯(0.4g,1.6mmol)的溶液中添加双(三甲基硅基)氨基锂(1.0M于THF中,1.9mL,1.9mmol),搅拌5分钟。随后使反应物升温至0℃,随后添加1-碘-2-甲基丙烷(0.73g,4.0mmol)。将反应物升温至室温,搅拌1小时。用饱和NH4Cl终止反应。将层分离,用EtOAc(3×)萃取水层。干燥(MgSO4)合并的有机层,在减压下浓缩。通过快速色谱(SiO2,0-70%己烷/EtOAc)纯化以残余物,以43%的收率产生所需的化合物(0.18g)。LC-MS Rt(保留时间):2.56分钟,MS:(ES)m/z 304.4(M+H+)。
b)向MeOH(5ml)中的来自步骤a的酯(0.18g,0.59mmol)的溶液中添加氢氧化锂(1.0M于H2O中,10mL,10mmol)。在75℃下加热所产生的溶液2小时。在减压下浓缩溶液以产生原体积的1/4,逐滴添加6M HCl水溶液(~0.5mL)以调节pH至约4。用EtOAc(3×)萃取水层。干燥(MgSO4)合并的有机层,在减压下浓缩以产生粗制产物(0.13g,83%)。LC-MS:Rt(保留时间):2.00分钟,MS:(ES)m/z 290.3(M+H+)。
c)在室温下,向THF(4.7ml)中的来自步骤b的酸(0.13g,0.47mmol)的溶液中添加甲磺酸(0.065g,0.56mmol,)和iPr2NEt(0.16mL,0.96mmol)。在室温下搅拌所产生的混合物5分钟,随后添加3,5-双(三氟甲基)苯胺(0.06g,0.27mmol)。在75℃下加热反应物直到完成反应(3小时)。在减压下浓缩混合物。通过快速色谱(SiO2,0-75%己烷/EtOAc)纯化,以22%的收率产生所需的产物(0.051g)。1H NMR(400MHz,DMSO-d6):δ10.38(s,1H),8.34(s,2H),7.79(s,1H),7.12-7.05(m,3H),3.99(d,J=10.4Hz,1H),3.61(d,J=10.4,1H),3.13(d,J=16.4Hz,1H),2.60(d,J=16.8Hz,1H),2.15(s,3H),2.05(dd,J=6.0,5.8Hz,1H),1.97(s,3H),1.96(dd,J=6.0,5.8Hz,1H),1.23(p,J=6.5Hz,1H),0.87(d,J=6.4Hz,3H),0.85(d,J=7.2Hz,3H)。LC-MS:Rt(保留时间):3.09分钟,MS:(ES)m/z 501.5(M+H+)。
实施例13:合成3-(3,6-二氢-2H-吡喃-4-基)-1-(2,6-二甲基苯基)-5-氧代-吡咯烷-3-羧酸(3,5-双-三氟甲基苯基)酰胺
a)在-78℃下,向反应瓶中THF(16mL)中的1-(2,6-二甲基苯基)-5-氧代-吡咯烷-3-羧酸甲酯(0.4g,1.6mmol)的溶液中添加双(三甲基硅基)氨基锂(1.0M于THF中,1.9mL,1.9mmol)。在-78℃下搅拌反应物5分钟,随后添加四氢-4H-吡喃-4-酮(0.4g,4.0mmol)。在1小时内使反应物缓慢升温至室温。用乙酸(1mL)终止反应。在减压下浓缩混合物。通过快速色谱(SiO2,0-100%己烷/EtOAc)纯化残余物,以32%的收率产生所需的化合物(0.18g)。LC-MS:Rt(保留时间):1.32分钟,MS:(ES)m/z 348.4(M+H+)。
b)向THF(4ml)中的来自步骤a的酯(0.15g,0.43mmol)的溶液中添加伯吉斯试剂(Burgess reagent)(0.12g,0.2mmol)。在75℃下加热所产生的溶液1小时。在减压下浓缩混合物。通过快速色谱(SiO2,0-100%己烷/EtOAc)纯化残余物,以76%的收率产生所需的化合物(0.05g)。LC-MS:Rt(保留时间):1.86分钟,MS:(ES)m/z 330.3(M+H+)。
c)向MeOH(0.8ml)中的来自步骤b的酯(0.05g,1.5mmol)的溶液中添加氢氧化锂(1.0M于H2O中,1.5mL,1.5mmol)。在75℃下加热所产生的溶液1小时。在减压下浓缩溶液以产生原体积的1/4,逐滴添加6M HCl水溶液(~0.5mL)以调节pH至约4。用EtOAc(3×)萃取水层。干燥(MgSO4)合并的有机层,在减压下浓缩以产生粗制产物(0.041g,87%)。LC-MS:Rt(保留时间):1.15分钟,MS:(ES)m/z 316.3(M+H+)。
d)在室温下,向THF(1.3ml)中的来自步骤c的酸(0.041g,0.13mmol)的溶液中添加甲磺酸(0.018g,0.15mmol,)和iPr2NEt(0.042mL,0.28mmol)。在室温下搅拌所产生的混合物5分钟,随后添加3,5-双(三氟甲基)苯胺(0.029,0.13mmol)。在75℃下加热反应物直到完成反应(18小时)。在减压下浓缩混合物。通过快速色谱(SiO2,0-75%己烷/EtOAc)纯化,以39%的收率产生所需的产物(0.027)。1H NMR(400MHz,DMSO-d6):δ10.17(s,1H),8.36(s,2H),7.80(s,1H),7.14-7.07(m,3H),5.92(s,1H)4.17-4.12(m,3H),3.74-3.71(m,2H),3.64-3.63(m,1H),3.16(d,J=16.4Hz,1H),2.93(d,J=16.4,1H),2.12-2.01(m.2H),2.10(s,3H),2.03(s,3H)。LC-MS:Rt(保留时间):2.77分钟,MS:(ES)m/z 527.5(M+H+)。
实施例14:合成1-(2,6-二甲基苯基)-5-氧代-3-(四氢-吡喃-4-基)-吡咯烷-3-羧酸(3,5-双-三氟甲基苯基)酰胺
a)向反应瓶中MeOH(1.9mL)中的酰胺(0.01g,0.019mmol)溶液中添加10%Pd/C(0.002g),在室温下在H2下搅拌5小时。随后将反应混合物过滤通过硅藻土(Celite),用MeOH洗涤,在减压下浓缩滤液。通过快速色谱(SiO2,0-75%己烷/EtOAc)纯化,以100%的收率产生所需的产物(0.01g)。1H NMR(400MHz,DMSO-d6):δ10.38(s,1H),8.36(s,2H),7.79(s,1H),7.12-7.06(m,3H),4.04(d,J=10.4Hz,1H),3.92-3.88(m,2H),3.75(d,J=10.8,1H),3.28-3.23(m,2H),3.09(d,J=16.8Hz,1H),2.72(d,J=17.6Hz,1H),2.39(bs,1H),2.14(s,3H),1.95(s,3H),1.62-1.51(m,2H),1.39-1.33(m,2H)。LC-MS:Rt(保留时间):2.72分钟,MS:(ES)m/z 529.5(M+H+)。
实施例15:合成2-(2,6-二甲基苯基)-1-氧代-六氢-吡喃并[3,4-c]吡咯-3a-羧酸(3,5-双-三氟甲基苯基)酰胺
a)在-50℃下,向反应瓶中THF(40mL)中的1-(2,6-二甲基苯基)-5-氧代-吡咯烷-3-羧酸甲酯(5g,20.2mmol)的溶液中添加双(三甲基硅基)氨基锂(1.0M于THF中,24mL,24mmol)。在-50℃下搅拌反应物10分钟,随后添加THF(10mL)中的多聚甲醛(6g,200mmol)。随后使反应物升温至室温,搅拌1小时。用饱和NH4Cl终止反应。将层分离,用EtOAc(3×)萃取水层。干燥(MgSO4)合并的有机层,在减压下浓缩。通过快速色谱(SiO2,0-60%己烷/EtOAc)纯化残余物,以47%的收率产生所需的化合物(2.6g)。LC-MS Rt(保留时间):0.81分钟,MS:(ES)m/z 278.0(M+H+)。
b)在0℃下,向反应瓶中THF(72mL)中的来自步骤a的醇(4.0g,14.4mmol)和溴乙酸乙酯(4.8g,29mmol)的溶液中缓慢地添加NaH(60%分散在矿物油中,0.7g,17.3mmol)。在室温下搅拌反应物18小时,用饱和NH4Cl终止。将层分离,用EtOAc(3×)萃取水层。干燥(MgSO4)合并的有机层,在减压下浓缩。通过快速色谱(SiO2,0-45%己烷/EtOAc)纯化残余物,以56%的收率产生所需的化合物(2.9g)。LC-MS:Rt(保留时间):2.05分钟,MS:(ES)m/z 364.4(M+H+)。
c)在-78℃下,向反应瓶中THF(80mL)中的来自步骤b的酯(2.9g,8.1mmol)的溶液中添加双(三甲基硅基)氨基锂(1.0M于THF中,20mL,20mmol)。在-78℃下搅拌反应物1小时,随后用饱和NH4Cl终止。将层分离,用EtOAc(3×)萃取水层。干燥(MgSO4)合并的有机层,在减压下浓缩。通过快速色谱(SiO2,0-60%己烷/EtOAc)纯化残余物,以50%的收率产生所需的化合物(1.3g)。LC-MS:Rt(保留时间):1.74分钟,MS:(ES)m/z318.3(M+H+)。
d)在0℃下,向反应瓶中THF(11mL)中的来自步骤c的酮(0.35g,1.1mmol)的溶液中缓慢地添加硼氢化钠(0.053g,1.43mmol)。在室温下搅拌反应物1小时,用H2O(5mL)终止。将层分离,用EtOAc(3×)萃取水层。干燥(MgSO4)合并的有机层,在减压下浓缩。通过快速色谱(SiO2,0-70%己烷/EtOAc)纯化残余物,以83%的收率产生所需的化合物(0.29g)。LC-MS:Rt(保留时间):1.27分钟,MS:(ES)m/z 320.3(M+H+)。
e)向THF(17ml)中的来自步骤d的醇(0.55g,1.7mmol)的溶液中添加伯吉斯试剂(0.73g,2.6mmol)。在75℃下加热所产生的溶液2小时。在减压下浓缩混合物。通过快速色谱(SiO2,0-100%己烷/EtOAc)纯化残余物,以46%的收率产生所需的化合物(0.25g)。LC-MS:Rt(保留时间):1.54分钟,MS:(ES)m/z 302.3(M+H+)。
f)在-78℃下,向THF(4mL)中的3,5-双(三氟甲基)苯胺(0.56g,2.5mmol)溶液中添加n-BuLi(2.5M于己烷中,0.91mL,2.3mmol)。在-78℃下搅拌反应物30分钟,随后升温至室温。随后添加来自步骤e的酯(0.25g,0.82mmol),在75℃下加热所产生的混合物2小时。在减压下浓缩混合物。通过快速色谱(SiO2,0-75%己烷/EtOAc)纯化,以7%的收率产生所需的产物(0.027g)。LC-MS:Rt(保留时间):2.78分钟,MS:(ES)m/z 499.4(M+H+)。
g)向反应瓶中MeOH(1.2mL)和EtOAc(1.2mL)中的酰胺(0.006g,0.012mmol)溶液中添加10%Pd/C(0.003g),在室温下在H2下搅拌24小时。随后将反应混合物过滤通过硅藻土,用MeOH洗涤,在减压下浓缩滤液。通过快速色谱(SiO2,0-100%己烷/EtOAc)纯化,以83%的收率产生所需的产物(0.005g)。1H NMR(400MHz,DMSO-d6):δ10.21(s,1H),8.33(s,2H),7.79(s,1H),7.16-7.08(m,3H),4.42(d,J=12.4Hz,1H),3.80(d,J=9.2,2H),3.73(d,J=12.4,1H),3.46(d,J=10.4,1H),3.38-3.3(m,4H),2.24(s,3H),2.06(s,3H)。LC-MS:Rt(保留时间):2.79分钟,MS:(ES)m/z 501.4(M+H+)。
实施例16:合成3-((1H-咪唑-2-基)甲基)-N-(3,5-双(三氟甲基)苯基)-1-(2,6-二甲基苯基)-5-氧代吡咯烷-3-甲酰胺
a)在-50℃下,向反应瓶中THF(48mL)中的1-(2,6-二甲基苯基)-5-氧代-吡咯烷-3-羧酸叔丁酯(7g,24.2mmol)的溶液中添加双(三甲基硅基)氨基锂(1.0M于THF中,27mL,27mmol),搅拌5分钟。使反应物升至0℃,添加烯丙基溴(5.8g,48.4mmol)。随后使反应物升温至室温,搅拌2小时,用饱和NH4Cl终止。将层分离,用EtOAc(3×)萃取水层。干燥(MgSO4)合并的有机层,在减压下浓缩。通过快速色谱(SiO2,0-60%己烷/EtOAc)纯化残余物,以62%的收率产生所需的化合物(5.0g)。LC-MS Rt(保留时间):2.68分钟,MS:(ES)m/z 330.4(M+H+)。
向tBuOH(88ml)、THF(22mL)和H2O(11mL)中的来自步骤a的酯(5.02g,15.2mmol)和4-甲基吗啉N-氧化物(2.6g,23mmol)的溶液中添加OsO4(0.08M于t-BuOH中,19mL,1.52mmol)。在室温下搅拌所产生的溶液18小时。用饱和Na2S2O3(40mL)终止反应。将层分离,用EtOAc(3×)萃取水层。干燥(MgSO4)合并的有机层,在减压下浓缩。不经进一步纯化地使用粗品(2.5g,45%)。LC-MS:Rt(保留时间):1.71,MS:(ES)m/z364.4(M+H+)。
c)用NaIO4(1.4g,6.6mmol)和水(2mL)处理溶于THF(8mL)中的3-(2,3-二羟基丙基)-1-(2,6-二甲基苯基)-5-氧代吡咯烷-3-羧酸叔丁酯(1.2g,3.3mmol)溶液。在室温下过夜搅拌之后,添加甲醇(2mL),用乙酸乙酯(15mL)稀释混合物,用水洗涤。用乙酸乙酯洗涤水相,合并有机层,干燥,蒸发溶剂。通过快速色谱(SiO2,10-100%EtOAc/己烷)纯化残余物以获得1-(2,6-二甲基苯基)-5-氧代-3-(2-氧代乙基)吡咯烷-3-羧酸叔丁酯(980mg,88%收率)。LC-MS Rt(保留时间):2.28分钟,MS:(ES)m/z 332(M+H+)。
d)在40℃下过夜搅拌THF-MeOH混合物(1∶1,10mL)中的1-(2,6-二甲基苯基)-5-氧代-3-(2-氧代乙基)吡咯烷-3-羧酸叔丁酯(863mg,2.5mmol)、乙二醛三聚体二水合物(210mg,1.0mmol)、乙酸铵(635mg,8mmol)和乙酸(180mg,3mmol)的混合物。冷却至RT之后,用25mL乙酸乙酯稀释反应混合物,用水(2×15mL)洗涤。用乙酸乙酯(15mL)反萃取水相。干燥合并的有机层,蒸发溶剂。通过快速色谱(SiO2,10-100%EtOAc/己烷)纯化残余物以获得467mg 3-((1H-咪唑-2-基)甲基)-1-(2,6-二甲基苯基)-5-氧代吡咯烷-3-羧酸叔丁酯(52%收率)。LC-MS Rt(保留时间):0.51分钟MS:(ES)m/z 370(M+H+)。
e)将上述步骤b中制备的3-((1H-咪唑-2-基)甲基)-1-(2,6-二甲基苯基)-5-氧代吡咯烷-3-羧酸叔丁酯(460mg,1.2mmol)溶于4mL二氧六环中的4M HCl中,在60℃下加热2小时。蒸发溶剂至干燥,用羰基二咪唑(201mg,1.2mmol)和二异丙基乙胺(626μL,3.6mmol)处理悬于THF(5mL)中的残余物,在40℃下加热1小时。用3,5-双(三氟甲基)苯胺(550mg,2.4mmol)处理温暖的反应混合物,再继续加热2小时。冷却至室温,用25mL乙酸乙酯稀释反应混合物,用水洗涤。干燥有机相,蒸发溶剂,通过快速色谱(SiO2,0-15%MeOH/DCM)纯化残余物以提供260mg 3-((1H-咪唑-2-基)甲基)-N-(3,5-双(三氟甲基)苯基)-1-(2,6-二甲基苯基)-5-氧代吡咯烷-3-甲酰胺(42%收率)。1H NMR(400MHz,CDCl3)δ2.14(s,3H),2.19(s,3H),2.52(d,1H,J=17Hz),3.28(d,1H,J=17Hz),3.38-3.42(m,3H),3.59(d,1H,J=10.6Hz),4.20(d,1H,J=10.6Hz),1.60(bs,2H),7.00-7.20(m,3H),7.57(s,1H),8.18(s,2H)。LC-MS:Rt(保留时间)=2.57分钟,MS:(ES)m/z 525(M+H+)。
实施例17:合成3-苄基氧基甲基-1-(2,6-二甲基苯基)-5-氧代-吡咯烷-3-羧酸(3,5-双-三氟甲基苯基)酰胺
a)向THF(50mL)中的1-(2,6-二甲基苯基)-5-氧代-吡咯烷-3-羧酸甲酯(2g,8.09mmol)的冷却(-50℃)溶液中缓慢地添加LHMDS(THF中的1M溶液,9.72mL,9.72mmol)。在-50℃下搅拌溶液5分钟,随后升温至0℃,再搅拌5分钟。冷却回到-50℃之后,添加BOMCl(~90%纯的,2.46mL,17.8mmol),将所产生的混合物升温至室温,搅拌2小时。添加饱和NH4Cl水溶液(25mL),用EtOAc(3×75mL)萃取水溶液。用水(100mL)、盐水(100mL)洗涤合并的有机层,干燥(Na2SO4),蒸发。通过自动快速色谱(SiO2,10→50%EtOAc/己烷)纯化残余物以产生3-苄基氧基甲基-1-(2,6-二甲基苯基)-5-氧代-吡咯烷-3-羧酸甲酯(653mg,22%收率)。LC-MS:Rt(保留时间):2.72分钟,MS:(ES)m/z 368.1(M+H+)。
b)向THF(3mL)中的3,5-双-三氟甲基苯胺(84.5μL,0.545mmol)的冷却(-50℃)溶液中添加n-BuLi(己烷中的2.8M溶液,183μL,0.513mmol)。将所产生的暗棕色溶液缓慢地升温至室温,搅拌1小时。添加THF(2mL)中的3-苄基氧基甲基-1-(2,6-二甲基苯基)-5-氧代-吡咯烷-3-羧酸甲酯(步骤a制备的,100mg,0.27mmol)溶液,在70℃下搅拌溶液2小时。随后将反应混合物冷却至室温,添加AcOH(100μL),通过自动快速色谱(SiO2,10→50%EtOAc/己烷)纯化溶液,随后用制备型HPLC(15→85%MeCN-H2O梯度,具有0.1%TFA)纯化。将纯的级分冻干以提供3-苄基氧基甲基-1-(2,6-二甲基苯基)-5-氧代-吡咯烷-3-羧酸(3,5-双-三氟甲基苯基)-酰胺(15mg,10%收率)。LC-MS:Rt(保留时间):3.38分钟,MS:(ES)m/z 565.2(M+H+)。1H NMR(400MHz,DMSO-d6)δ10.2(s,1H),8.28(s,2H),7.8(s,1H),7.2-7.28(m,5H),7.05-7.15(m,3H),4.5-4.58(m,2H),4.03(d,1H,J=8Hz),3.86-3.92(m,2H),3.6(d,1H,J=8Hz),3.08(d,1H,J=16Hz),2.64(d,1H,J=16Hz),2.05(s,3H),2.06(s,3H)。
实施例18:合成3-环戊基-1-(2,6-二甲基苯基)-5-氧代-吡咯烷-3-羧酸(3,5-双-三氟甲基苯基)酰胺
a)向THF(5mL)中的1-(2,6-二甲基苯基)-5-氧代-吡咯烷-3-羧酸甲酯(494mg,2mmol)的冷却(-50℃)溶液中缓慢地添加LHMDS(THF中的1M溶液,2.4mL,2.4mmol)。在-50℃下搅拌5分钟,随后升温至0℃,再搅拌5分钟。冷却回到-50℃之后,添加碘环戊烷(462.5μL,4mmol),将所产生的反应混合物升温至室温,搅拌2小时。添加饱和NH4Cl水溶液(10mL),用EtOAc(3×25mL)萃取水溶液。用水(50mL)、盐水(50mL)洗涤合并的有机层,干燥(Na2SO4),蒸发。通过快速色谱(SiO2,20→50%EtOAc/己烷)纯化残余物以产生3-环戊基-1-(2,6-二甲基苯基)-5-氧代-吡咯烷-3-羧酸甲酯(120mg,19%收率)。LC-MS:Rt(保留时间):2.54分钟,MS:(ES)m/z 316.4(M+H+)。
b)在室温下,向THF(3mL)中的3,5-双-三氟甲基苯胺(177μL,0.1.14mmol)溶液中添加n-BuLi(己烷中的2.5M溶液,456μL,1.14mmol)。在室温下搅拌所产生的暗棕色溶液10分钟。添加THF(2mL)中的3-环戊基-1-(2,6-二甲基苯基)-5-氧代-吡咯烷-3-羧酸甲酯(步骤a制备的,120mg,0.38mmol)溶液,在70℃下搅拌2小时。随后通过自动快速色谱纯化反应混合物。合并纯的级分,在减压下浓缩。将物质从MeOH中重结晶以获得所需产物3-环戊基-1-(2,6-二甲基苯基)-5-氧代-吡咯烷-3-羧酸(3,5-双-三氟甲基-苯基)-酰胺(60mg,31%收率)的白色结晶。LC-MS:Rt(保留时间):3.32分钟,MS:(ES)m/z 513.2(M+H+)。1H NMR(400MHz,CDCl3)δ8.4(s,1H),8.05(s,2H),7.6(s,1H),7.08-7.13(m,2H),7.02-7.06(m,2H),4.14(d,1H,J=11.5Hz),3.56(d,1H,J=11.5Hz)3.17(d,1H,J=16.9Hz),2.74(d,1H,J=16.9Hz),2.42-2.52(m,1H),2.2(s,3H),2.14(s,3H),1.75-1.88(m,2H),1.6-1.68(m,4H),1.25-1.48(m,2H)。
实施例19:合成cis-1-(2,6-二甲基苯基)-3-乙基-4-甲氧基-5-氧代-吡咯烷-3-羧酸(3,5-双-三氟甲基苯基)-酰胺
a)向THF(25mL)中的1-(2,6-二甲基苯基)-5-氧代-吡咯烷-3-羧酸甲酯(5g,20.24mmol)的冷却(-50℃)溶液中缓慢地添加LHMDS(THF中的1M溶液,24.3mL,24.3mmol)。在-50℃下搅拌溶液5分钟,随后升温至0℃,进一步搅拌5分钟。冷却回到-50℃之后,添加碘乙烷(3.27mL,40.48mmol),将所产生的反应混合物升温至室温,搅拌2小时。添加饱和NH4Cl水溶液(50mL),用EtOAc(3×100mL)萃取溶液。用水(100mL)、盐水(100mL)洗涤合并的有机层,干燥(Na2SO4),蒸发。通过快速色谱(SiO2,20→50%EtOAc/己烷)纯化残余物以产生1-(2,6-二甲基苯基)-3-乙基-5-氧代-吡咯烷-3-羧酸甲酯(3.3g,59%收率)。LC-MS:Rt(保留时间):2.21分钟,MS:(ES)m/z 276.1(M+H+)。
b)向THF(15mL)中的1-(2,6-二甲基苯基)-3-乙基-5-氧代-吡咯烷-3-羧酸甲酯(步骤1中制备的,1.1g,4mmol)的冷却(-50℃)溶液中缓慢地添加LHMDS(THF中的1M溶液,6mL,6mmol)。在-50℃下搅拌溶液5分钟,随后升温至0℃,再搅拌5分钟。冷却回到-50℃之后,添加(R,S)-樟脑磺哑嗪(1.1g,4.8mmol),将所产生的反应混合物升温至室温,搅拌2小时。添加饱和NH4Cl水溶液(30mL),用EtOAc(3×75mL)萃取溶液。用水(50mL)、盐水(50mL)洗涤合并的有机层,干燥(Na2SO4),在减压下浓缩。通过快速色谱(SiO2,30→70%EtOAc/己烷)纯化残余物以产生1-(2,6-二甲基-苯基)-3-乙基-4-羟基-5-氧代-吡咯烷-3-羧酸甲酯(1.1g,定量的收率)。LC-MS:Rt(保留时间):1.89分钟,MS:(ES)m/z 292.1(M+H+)。
c)向THF(5mL)中的1-(2,6-二甲基苯基)-3-乙基-4-羟基-5-氧代-吡咯烷-3-羧酸甲酯(步骤b中制备的,146mg,0.5mmol)的冷却(0℃)溶液中缓慢地添加NaH(60%分散在矿物油中,50mg,~2.0mmol)。搅拌5分钟之后,添加MeI(62.5μL,1mmol),将所产生的反应混合物缓慢升温至室温,进一步搅拌12小时。添加饱和NH4Cl水溶液(10mL),用EtOAc(3×25mL)萃取溶液。用水(50mL)、盐水(50mL)洗涤合并的有机层,干燥(Na2SO4),蒸发。通过快速色谱(SiO2,10→50%EtOAc/己烷)纯化残余物以产生1-(2,6-二甲基苯基)-3-乙基-4-甲氧基-5-氧代-吡咯烷-3-羧酸甲酯(70mg,46%收率)。LC-MS:Rt(保留时间):2.31,2.44分钟(两种非对映体),MS:(ES)m/z 306.2(M+H+)。
d)在室温下,向THF(3mL)中的3,5-双-三氟甲基苯胺(107μL,0.688mmol)溶液中添加n-BuLi(己烷中的2.5M溶液,300μL,0.688mmol)。在室温下搅拌所产生的暗棕色溶液10分钟。添加THF(2mL)中的1-(2,6-二甲基苯基)-3-乙基-4-甲氧基-5-氧代-吡咯烷-3-羧酸甲酯(步骤c中制备的,70mg,0.229mmol),在70℃下搅拌2小时。添加饱和NH4Cl水溶液(5mL),用EtOAc(3×25mL)萃取溶液。用水(25mL)、盐水(25mL)洗涤合并的有机层,干燥(Na2SO4)、蒸发。随后,通过自动快速色谱(SiO2,10→50%EtOAc/己烷)纯化残余物。合并纯的级分,在减压下浓缩。通过制备型HPLC(30→85%MeCN-H2O梯度,具有0.1%TFA)进一步纯化所获得的产物。将纯的级分冻干以提供cis-1-(2,6-二甲基-苯基)-3-乙基-4-甲氧基-5-氧代-吡咯烷-3-羧酸(3,5-双-三氟甲基-苯基)-酰胺(10mg,9%收率)。LC-MS:Rt(保留时间):3.24分钟,MS:(ES)m/z 503.1(M+H+)。1H NMR(400MHz,CDCl3)δ8.25(s,1H),8.0(s,2H),7.62(s,1H),7.05-7.18(m,3H),4.27(s,1H),3.95-4.02(m,4H),3.45(d,1H,J=11.85Hz),2.26(s,3H),2.18(s,3H),1.92-2.02(m,2H),1.02(t,3H,J=6.5Hz)。
实施例20:合成3-环丁基-1-(2,6-二甲基苯基)-5-氧代-吡咯烷-3-羧酸(3,5-双-三氟甲基苯基)-酰胺
a)向THF(5mL)中的1-(2,6-二甲基苯基)-5-氧代-吡咯烷-3-羧酸甲酯(494mg,2mmol)的冷却(-50℃)溶液中缓慢地添加LHMDS(THF中的1M溶液,2.4mL,2.4mmol)。在-50℃下搅拌5分钟,随后升温至0℃,搅拌5分钟。冷却回到-50℃之后,添加碘环丁烷(736mg,4mmol),将所产生的反应混合物升温至室温,搅拌2小时。添加饱和NH4Cl水溶液(10mL),用EtOAc(3×25mL)萃取。用水(50mL)、盐水(50mL)洗涤合并的有机层,干燥(Na2SO4),蒸发,以产生粗制产物3-环丁基-1-(2,6-二甲基-苯基)-5-氧代-吡咯烷-3-羧酸甲酯,其直接用于下一个步骤。MS:(ES)m/z 302.3(M+H+)。
b)在室温下,向THF(5mL)中的3,5-双-三氟甲基苯胺(437μL,2.82mmol)中添加n-BuLi(己烷中的2.5M溶液,1.13mL,2.82mmol)。在室温下搅拌所产生的暗棕色溶液10分钟。添加THF(3mL)中的3-环丁基-1-(2,6-二甲基苯基)-5-氧代-吡咯烷-3-羧酸甲酯(步骤a中制备的,283mg,0.94mmol)溶液,在密封的小瓶中在100℃下搅拌30分钟。添加饱和NH4Cl水溶液(10mL),用EtOAc(3×25mL)萃取。用水(40mL)、盐水(40mL)洗涤合并的有机层,干燥(Na2SO4),蒸发。随后通过自动快速色谱(SiO2,20→70%EtOAc/己烷)纯化反应混合物。合并所选择的级分,在减压下浓缩。通过制备型HPLC(5→90%MeCN-H2O梯度,具有0.1%TFA)进一步纯化所获得的产物两次,以获得所需的产物3-环丁基-1-(2,6-二甲基苯基)-5-氧代-吡咯烷-3-羧酸(3,5-双-三氟甲基苯基)-酰胺(7mg,1.5%收率)。LC-MS:Rt(保留时间):3.17分钟,MS:(ES)m/z 499.1(M+H+)。1HNMR(400MHz,CDCl3)δ8.08(s,3H),7.63(s,1H),7.12-7.16(m,1H),7.04-7.09(m,2H),4.18(d,1H,J=8.5Hz),3.58(d,1H,J=8.5Hz),3.18(d,1H,J=17Hz),2.8(d,1H,J=17Hz),2.2(s,3H),2.17(s,3H),1.85-2.0(m,2H),0.68-0.8(m,1H),0.5-0.62(m,2H),0.15-0.2(m,2H)。
实施例21:合成cis-1-(2,6-二甲基苯基)-3-异丁基-4-甲基-5-氧代-吡咯烷-3-羧酸(3,5-双-三氟甲基苯基)-酰胺
a)向THF(170mL)中的1-(2,6-二甲基苯基)-5-氧代-吡咯烷-3-羧酸甲酯(17g,68.83mmol)的冷却(-50℃)溶液中添加LHMDS(THF中的1M溶液,83mL,83mmol)。5分钟之后,在-50℃下缓慢地添加3-溴-2-甲基丙烯(13.8mL,136.8mmol),使所产生的反应混合物升温至室温,搅拌2小时。添加饱和NH4Cl水溶液(50mL),用EtOAc(3×100mL)萃取水溶液。用水(100mL)、盐水(100mL)洗涤合并的有机层,干燥(Na2SO4),蒸发。通过自动快速色谱(SiO2,20→60%MTBE/己烷)纯化残余物,以产生1-(2,6-二甲基苯基)-3-(2-甲基烯丙基)-5-氧代-吡咯烷-3-羧酸甲酯(10.9g,53%收率)。LC-MS:Rt(保留时间):2.44分钟,MS:(ES)m/z 302.1(M+H+)。
b)向MeOH(100mL)中的1-(2,6-二甲基苯基)-3-(2-甲基烯丙基)-5-氧代-吡咯烷-3-羧酸甲酯(步骤a中制备的,10.9g,36.21mmol)溶液中添加1M LiOH(100mL,100mmol),使所产生的澄清溶液回流(70℃)1小时。随后,使反应混合物冷却至室温,在减压下除去MeOH,在剧烈搅拌下,将所获得的碱性水溶液添加至冷却的(0℃)2N HCl(200mL)中。过滤所产生的白色固体,用水(3×300mL)、庚烷(200mL)洗涤,在高真空下干燥,以获得1-(2,6-二甲基苯基)-3-(2-甲基烯丙基)-5-氧代-吡咯烷-3-羧酸(10g,定量的收率)。LC-MS:Rt(保留时间):1.98分钟,MS:(ES)m/z 288.1(M+H+)。
c)向1-(2,6-二甲基苯基)-3-(2-甲基烯丙基)-5-氧代-吡咯烷-3-羧酸(步骤b中制备的,9g,31.36mmol)和番木鳖碱(12.37g,31.35mmol)的混合物中添加iPrOH(75mL),在75℃下搅拌加热,直至其变为澄清溶液,随后使其缓慢地冷却至室温。过滤并弃去所产生的白色固体。随后用Et2O(100mL)稀释滤液,用2N HCl(2×100mL)洗涤,干燥(Na2SO4),在减压下浓缩,以获得(S)-1-(2,6-二甲基-苯基)-3-(2-甲基-烯丙基)-5-氧代-吡咯烷-3-羧酸(550mg,对映体比率:9∶1,使用RegisWhelk手性分析柱和己烷中的10%EtOH恒溶剂组成的溶剂系统(流速:1mL/分钟,运行30分钟)测定所述对映体比率)。将上述羧酸衍生物从热的甲苯/二氧六环(9∶1,14mL)中进一步重结晶,浓缩对映体比率至99.2∶0.8,提供430mg(S)-1-(2,6-二甲基苯基)-3-(2-甲基烯丙基)-5-氧代-吡咯烷-3-羧酸。
d)向MeOH(5mL)中的(S)-1-(2,6-二甲基苯基)-3-(2-甲基烯丙基)-5-氧代-吡咯烷-3-羧酸(从c中制备的,430mg,1.49mmol)溶液中逐滴添加TMS-CHN2(2.24mL,4.49mmol,己烷中的2M溶液)。在室温下搅拌黄色澄清溶液10分钟之后,在减压下除去MeOH,用EtOAc(50mL)稀释溶液,用饱和的NaHCO3溶液(25mL)、水(25mL)、盐水(25mL)洗涤,干燥(Na2SO4),蒸发,以获得(S)-1-(2,6-二甲基-苯基)-3-(2-甲基-烯丙基)-5-氧代-吡咯烷-3-羧酸甲酯(474mg),其不经进一步纯化用于下一个步骤。LC-MS:Rt(保留时间):2.14分钟,MS:(ES)m/z 302.3(M+H+)。
e)向MeOH(5mL)中的(S)-1-(2,6-二甲基-苯基)-3-(2-甲基-烯丙基)-5-氧代-吡咯烷-3-羧酸甲酯(步骤d制备的,474mg,1.57mmol)溶液中添加10%Pd/C(120mg),在室温下,在使用气囊(balloon)的H2气下,过夜搅拌所产生的黑色悬浮液。随后用EtOAc(25mL)稀释反应混合物,过滤通过硅藻土,用MeOH(25mL)洗涤,从滤液中蒸发挥发物以获得粗制产物,通过快速色谱(SiO2,20→60%EtOAc/己烷)纯化粗制产物以获得(S)-1-(2,6-二甲基-苯基)-3-异丁基-5-氧代-吡咯烷-3-羧酸甲酯(450mg,94%收率)。LC-MS:Rt(保留时间):2.55分钟,MS:(ES)m/z 304.1(M+H+)。
向THF(10mL)中的(S)-1-(2,6-二甲基苯基)-3-异丁基-5-氧代-吡咯烷-3-羧酸甲酯(步骤e中制备的,450mg,1.48mmol)的冷却(-50℃)溶液中缓慢地添加LHMDS(THF中的1M溶液,1.78mL,1.78mmol)。5分钟之后,在-50℃下添加碘甲烷(185μL,2.97mmol),将所产生的反应混合物立即升温至室温,进一步搅拌2小时。添加饱和的NH4Cl水溶液(25mL),用EtOAc(3×50mL)萃取溶液。用水(50mL)、盐水(50mL)洗涤合并的有机层,干燥(Na2SO4),蒸发。通过快速色谱(SiO2,20→60%MTBE/己烷)纯化残余物以产生(S)-1-(2,6-二甲基苯基)-3-异丁基-4-甲基-5-氧代-吡咯烷-3-羧酸甲酯(130mg,28%收率)。LC-MS:Rt(保留时间):2.68分钟,MS:(ES)m/z 318.2(M+H+)。
g)在室温下,向THF(3mL)中的3,5-双-三氟甲基苯胺(492μL,1.23mmol)溶液中添加n-BuLi(己烷中的2.5M溶液,0.492mL,1.23mmol)。在室温下搅拌所产生的暗棕色溶液10分钟。添加THF(3mL)中的(S)-1-(2,6-二甲基苯基)-3-异丁基-4-甲基-5-氧代-吡咯烷-3-羧酸甲酯(步骤f中制备的,130mg,0.41mmol),在75℃下,在密封的小瓶中过夜搅拌。添加饱和NH4Cl水溶液(10mL),用EtOAc(3×25mL)萃取溶液。用水(30mL)、盐水(30mL)洗涤合并的有机层,干燥(Na2SO4),蒸发。随后通过快速色谱(SiO2,20→70%EtOAc/己烷)纯化反应混合物。合并所选择的级分,在减压下浓缩。通过制备型HPLC(50→90%MeCN-H2O梯度,具有0.1%TFA)进一步纯化所获得的产物,将纯的级分冻干以获得所需的产物cis-1-(2,6-二甲基-苯基)-3-异丁基-4-甲基-5-氧代-吡咯烷-3-羧酸(3,5-双-三氟甲基-苯基)-酰胺(45mg,21%收率)。LC-MS:Rt(保留时间):3.26分钟,MS:(ES)m/z 515.2(M+H+)。1H NMR(400MHz,DMSO-d6)δ10.38(s,1H),8.35(s,2H),7.8(s,1H),7.02-7.14(m,3H),4.04(d,1H,J=9.9Hz),3.68(d,1H,J=9.9Hz),3.05-3.13(m,1H),2.12(s,3H),1.98(s,3H),1.78-1.95(m,2H),1.53-1.65(m,1H),1.3(d,3H,J=7.4Hz),0.82-0.88(m,6H)。
实施例22:合成cis-1-(2,6-二甲基苯基)-3-[(乙基甲基氨基)-乙基]-4-甲基-5-氧代-吡咯烷-3-羧酸(3,5-双-三氟甲基苯基)-酰胺
a)向THF(10mL)中的1-(2,6-二甲基苯基)-3-羟基甲基-5-氧代-吡咯烷-3-羧酸甲酯(上述实施例中制备的,1g,3.61mmol)的冷却(0℃)溶液中缓慢地添加NaH(60%分散在矿物油中,260mg,5.41mmol)。搅拌5分钟之后,添加PMBCl(737μL,5.41mmol),将所产生的反应混合物缓慢升温至室温,进一步搅拌2小时。添加饱和NH4Cl水溶液(10mL),用EtOAc(3×25mL)萃取溶液。用水(30mL)、盐水(30mL)洗涤合并的有机层,干燥(Na2SO4),蒸发。通过快速色谱(SiO2,10→60%EtOAc/己烷)纯化残余物以产生1-(2,6-二甲基-苯基)-3-(4-甲氧基-苄基氧基甲基)-5-氧代-吡咯烷-3-羧酸甲酯(767mg,54%收率)。LC-MS:Rt(保留时间):2.37分钟,MS:(ES)m/z 398.3(M+H+)。
b)向THF(7mL)中的1-(2,6-二甲氧基苯基)-3-(4-甲氧基苄基氧基甲基)-5-氧代-吡咯烷-3-羧酸甲酯(步骤a中制备的,767mg,1.93mmol)的冷却(-50℃)溶液中缓慢地添加LHMDS(THF中的1M溶液,2.32mL,2.32mmol)。5分钟之后,在-50℃下添加碘甲烷(602μL,9.65mmol),将所产生的反应混合物升温至室温,进一步搅拌2小时。添加饱和NH4Cl水溶液(25mL),用EtOAc(3×50mL)萃取溶液。用水(75mL)、盐水(75mL)洗涤合并的有机层,干燥(Na2SO4),蒸发,通过快速色谱纯化残余物(SiO2,20→70%EtOAc/己烷)以产生1-(2,6-二甲基苯基)-3-(4-甲氧基苄基氧基甲基)-4-甲基-5-氧代-吡咯烷-3-羧酸甲酯(736mg,93%收率)。LC-MS:Rt(保留时间):2.39分钟,MS:(ES)m/z 412.4(M+H+)。
c)在室温下,向剧烈搅拌的5∶1CH2Cl2/H2O(12mL)中的1-(2,6-二甲基苯基)-3-(4-甲氧基-苄基氧基甲基)-4-甲基-5-氧代-吡咯烷-3-羧酸甲酯(步骤b中制备的,736mg,1.79mmol)的混合物中添加2,3-氯-5,6-二氰基苯醌(609.5mg,2.68mmol),在相同温度下搅拌2小时。用CH2Cl2(25mL)稀释反应混合物,过滤通过硅藻土,用CH2Cl2(3×25mL)洗涤。随后用饱和NaHCO3溶液(3×30mL)、水(30mL)、盐水(30mL)洗涤滤液,干燥,蒸发。通过快速色谱(SiO2,20→70%EtOAc/己烷)纯化所获得的残余物以产生1-(2,6-二甲基苯基)-3-羟基甲基-4-甲基-5-氧代-吡咯烷-3-羧酸甲酯(373mg,72%收率)。LC-MS:Rt(保留时间):1.2分钟,MS:(ES)m/z 292.2(M+H+)。
d)向甲苯(15mL)中的1-(2,6-二甲基苯基)-3-羟基甲基-4-甲基-5-氧代-吡咯烷-3-羧酸甲酯(步骤c中制备的,373mg,1.28mmol)溶液中依次添加咪唑(261.5mg,3.84mmol)、三苯基膦(670.7mg,2.56mmol)和I2(487.3mg,1.92mmol),在100℃下搅拌加热所产生的反应混合物1小时。随后,将反应混合物冷却至室温,用EtOAc(50mL)稀释,用水(30mL)、饱和NH4Cl(30mL)洗涤,干燥(Na2SO4),蒸发。随后通过快速色谱(SiO2,20→70%EtOAc/己烷)纯化残余物以获得1-(2,6-二甲基苯基)-3-碘甲基-4-甲基-5-氧代-吡咯烷-3-羧酸甲酯(427mg,83%收率)。LC-MS:Rt(保留时间):2.32分钟,MS:(ES)m/z 402.2(M+H+)。
e)向CH3CN(3mL)中的1-(2,6-二甲基苯基)-3-碘甲基-4-甲基-5-氧代-吡咯烷-3-羧酸甲酯(步骤d中制备的,100mg,0.25mmol)溶液中添加N-乙基甲胺(215μL,2.5mmol),在80℃下过夜搅拌。在减压下蒸发挥发物,通过自动快速色谱(SiO2,20→70%EtOAc/己烷)纯化以获得1-(2,6-二甲基-苯基)-3-[(乙基甲基氨基)-甲基]-4-甲基-5-氧代-吡咯烷-3-羧酸甲酯(10mg,12%收率)。LC-MS:Rt(保留时间):0.61分钟,MS:(ES)m/z 333.3(M+H+)。
f)在室温下,向THF(2mL)中的3,5-双-三氟甲基苯胺(20μL,0.09mmol)的溶液中添加n-BuLi(己烷中的2.5M溶液,50μL,0.09mmol)。在室温下搅拌所产生的暗棕色溶液10分钟。添加THF(2mL)中的1-(2,6-二甲基苯基)-3-[(乙基甲基氨基)甲基]-4-甲基-5-氧代-吡咯烷-3-羧酸甲酯(步骤e中制备的,10mg,0.03mmol)溶液,在70℃下,在密封的小瓶中搅拌2小时。添加饱和的NH4Cl水溶液(10mL),用EtOAc(3×25mL)萃取溶液。用水(20mL)、盐水(20mL)洗涤合并的有机层,干燥(Na2SO4),蒸发。通过制备型HPLC(50→90%MeCN-H2O梯度,具有0.1%TFA)纯化残余物,将纯的级分冻干以获得所需的产物cis-1-(2,6-二甲基苯基)-3-[(乙基甲基氨基)甲基]-4-甲基-5-氧代-吡咯烷-3-羧酸(3,5-双-三氟甲基苯基)-酰胺(5mg,25%收率)。LC-MS:Rt(保留时间):2.9分钟,MS:(ES)m/z 530.5(M+H+)。1H NMR(400MHz,CDCl3)δ10.75(s,1H),8.26(s,2H),7.65(s,1H),7.16-7.2(m,1H),7.05-7.1(m,2H),4.26(d,1H,J=10.7Hz),4.0(d,1H,J=10.7Hz),3.55-3.62(m,1H),3.34-3.44(m,2H),3.15-3.28(m,2H),2.85(s,3H),2.24(s,3H),2.13(s,3H),1.54(d,3H,J=7.14Hz),1.39(t,3H,J=6.5Hz)。
实施例23.(3R,4S)-3-((4,4-二氟哌啶-1-基)甲基)-1-(2,6-二甲基苯基)-N-(3-异丙氧基-5-(三氟甲基)苯基)-4-甲基-5-氧代吡咯烷-3-甲酰胺
以与实施例22类似的方式制备(3R,4S)-3-((4,4-二氟哌啶-1-基)甲基)-1-(2,6-二甲基苯基)-N-(3-异丙氧基-5-(三氟甲基)苯基)-4-甲基-5-氧代吡咯烷-3-甲酰胺。1H NMR(400MHZ,DMSO):δ9.93(s,1H),7.55(d,J=11.7Hz,2H),7.07-7.14(m,3H),6.91(s,1H),4.65(七重峰,J=5.9Hz,1H),4.07(d,J=10.3Hz,1H),3.79(d,J=10.3Hz,1H),3.04-3.13(m,2H),2.90(d,J=13.9Hz,1H),2.50-2.59(m,4H),2.17(s,3H),2.06(s,3H),1.74-1.94(m,4H),1.26-1.32(m,9H)。LC-MS Rt(保留时间):2.96分钟;MS:(ES)m/z 583(M+H+)。
实施例24.(3R,4S)-N-(3,5-双(三氟甲基)苯基)-3-((环丁基(甲基)氨基)甲基)-1-(2,6-二甲基苯基)-4-甲基-5-氧代吡咯烷-3-甲酰胺
以与实施例22类似的方式制备(3R,4S)-N-(3,5-双(三氟甲基)苯基)-3-((环丁基(甲基)氨基)甲基)-1-(2,6-二甲基苯基)-4-甲基-5-氧代吡咯烷-3-甲酰胺。1H NMR(400MHZ,DMSO):δ10.6(s,1H),8.30(s,2H),7.81(s,1H),7.05-7.15(m,3H),4.13(d,J=10.3Hz,1H),3.79(d,J=9.9Hz,1H),3.11(q,J=7.3Hz,1H),2.97(d,J=13.6Hz,1H),2.86(p,J=7.7Hz,1H),2.64(d,J=13.6Hz,1H),2.16(s,3H),2.04(s,3H),2.01(s,3H),1.88-1.97(m,2H),1.66(p,J=8.9Hz,2H),1.42-1.52(m,2H),1.32(d,J=7.3Hz,3H)。LC-MS Rt(保留时间):2.33分钟;MS:(ES)m/z556(M+H+)。
实施例25:合成N-(3,5-双(三氟甲基)苯基)-3-(1-羟基乙基)-1-(2,6-二甲基苯基)-5-氧代吡咯烷-3-甲酰胺
将80mL THF中的1-(2,6-二甲基苯基)-5-氧代吡咯烷-3-羧酸甲酯(8.1g,33mmol)溶液冷却至-78℃。添加LHMDS(1.0M于THF中,36mL,36mmol)的溶液,-78℃下维持温度80分钟。随后添加乙醛(5.0mL,89mmol),使反应混合物升温至室温。16小时之后,用饱和氯化铵水溶液终止反应混合物。用乙酸乙酯萃取所产生的水层,干燥(Na2SO4)合并的有机层,过滤,在减压下浓缩。通过快速色谱(SiO2,40-100%EtOAc/己烷)纯化所产生的残余物,以24%的收率获得所需的产物(2.33g)。LC-MS Rt(保留时间):1.27分钟,MS:(ES)m/z 292(M+H+)。
b)向乙醇(25mL)中的来自步骤a的醇(2.0g,6.9mmol)的溶液中添加1M NaOH水溶液。在80℃下搅拌混合物2小时。在真空中除去乙醇,用6M HCl酸化溶液,用EtOAc萃取,用MgSO4干燥,过滤,在减压下浓缩以提供易碎的泡沫(1.46g,76%)。LC-MS Rt(保留时间):0.62分钟,MS:(ES)m/z 278(M+H+)。
c)在0℃下,在吡啶(2mL,25mmol)存在下,向CH2Cl2(20mL)中的来自步骤b的酸(1.41g,5.1mmol)的溶液中添加三氟甲磺酸酐(1.0mL,5.9mmol)。使反应混合物升温至室温,搅拌16小时。用1M NaHSO4水溶液洗涤反应混合物,随后用饱和NaHCO3水溶液洗涤。分离有机层,用无水MgSO4干燥,在减压下浓缩。通过快速色谱(SiO2,60%EtOAc/己烷)纯化,产生600mg(41%收率)产物的白色固体。LC-MS Rt(保留时间):1.71分钟,MS:(ES)m/z 260(M+H+)。
将溶于THF(5mL)中的3,5-双(三氟甲基)苯胺(1.2g,5.3mmol)溶液冷却至-78℃;向其中添加正丁基锂(2.5M于己烷中,2.1mL,5.3mmol)的溶液。5分钟之后,向THF(5mL)中的来自步骤c的内酯的溶液中添加该溶液。使反应混合物升温至室温,搅拌14小时。用饱和NH4Cl水溶液终止反应混合物,添加水。分离有机层,用EtOAc萃取水层。干燥(MgSO4)合并的有机层,在减压下浓缩。通过快速色谱(SiO2,70%EtOAc/己烷)纯化残余物以产生664mg所需化合物(64%收率,非对映异构体的混合物)。1H NMR(400MHz,CD3OD):δ8.26(s,0.7H),8.24(s,1.3H),7.66(s,1H),7.11(m,3H),4.23(m,1H),4.14(d,0.4H,J=11Hz),4.10(d,0.6H,J=11Hz),4.04(d,0.6H,J=11Hz),3.79(d,0.4H,J=11Hz),3.19(d,0.6H,J=18Hz),3.16(d,0.4H,J=18Hz),3.03(d,0.4H,J=18Hz),2.71(d,0.6H,J=18Hz),2.23(s,3H),2.16(s,1.2H),2.11(s,1.8H),1.22(d,3H,J=6Hz)。LC-MS Rt(保留时间):2.68分钟,MS:(ES)m/z 489(M+H+)。
实施例26:合成N-(3-氯-5-(三氟甲基)苯基)-3-乙基-1-(2,6-二甲基苯基)-5-氧代吡咯烷-3-甲酰胺
a)在-78℃,向THF(150mL)中的1-(2,6-二甲基苯基)-5-氧代吡咯烷-3-羧酸甲酯(9.2g,37mmol)溶液中添加LHMDS(1M于THF中,39mL,39mmol)的溶液。在相同的温度下搅拌45分钟之后,一次性添加碘乙烷(200mL,63mmol)。除去冷却浴,使反应混合物升温至室温。4小时之后,用饱和NH4Cl水溶液终止反应混合物。用乙酸乙酯萃取水层,干燥(Na2SO4)合并的有机层,过滤,在减压下浓缩。通过快速色谱(SiO2,30-50%EtOAc/己烷)纯化所产生的残余物,以59%的收率获得所需的产物(5.99g)。LC-MS Rt(保留时间):2.23分钟,MS:(ES)m/z 276(M+H+)。
向溶于THF(1mL)中的3-氯-5-三氟甲基苯胺(94mg,0.48mmol)溶液中添加正丁基锂(2.5M于己烷中,0.20mL,0.50mmol)的溶液。5分钟之后,向THF(1mL)中的步骤a中制备的酯(60mg,0.22mmol)的溶液中添加该溶液。搅拌反应混合物10小时,随后用饱和的NaCl水溶液洗涤,用MgSO4干燥,过滤,在减压下浓缩。通过快速色谱(SiO2,10-80%EtOAc/己烷)纯化所产生的残余物,以59%的收率获得所需的产物(124mg)。1HNMR(400MHz,CD3OD):δ8.01.(s,1H),7.91(s,1H),7.41(s,1H),7.1(m,3H),4.13(d,1H,J=12Hz)3.67(d,1H,J=12Hz)3.25(d,1H,J=18Hz),2.23(s,3H),2.12(s,3H),2.10(m,2H),0.98(t,3H,J=18Hz)。LC-MS Rt(保留时间):3.03分钟,MS:(ES)m/z 439(M+H+)。
实施例27:合成cis-N-(3-氯-5-(三氟甲基)苯基)-3-乙基-4-甲基-1-(2,6-二甲基苯基)-5-氧代吡咯烷-3-甲酰胺
a)在-78℃下,向THF(30mL)中的3-乙基-1-(2,6-二甲基苯基)-5-氧代吡咯烷-3-羧酸甲酯(3.0g,11mmol)溶液中添加LHMDS(1M于THF中,12mL,12mmol)的溶液。在相同的温度下搅拌20分钟之后,添加碘甲烷(2.5mL,40mmol)。除去冷却浴,使反应混合物升温至室温。1小时之后,用饱和NH4Cl水溶液终止反应混合物。用乙酸乙酯萃取水层,干燥(Na2SO4)合并的有机层,过滤,在减压下浓缩。通过快速色谱(SiO2,30%EtOAc/己烷)纯化所产生的残余物,以76%的收率获得所需的产物(2.38g)。LC-MS Rt(保留时间):2.37分钟,MS:(ES)m/z 230(M+H+)。
b)向溶解于THF(1mL)中的3-氯-5-三氟甲基苯胺(94mg,0.48mmol)的溶液中添加正丁基锂(2.5M于己烷中,0.20mL,0.50mmol)的溶液。5分钟之后,向THF(1mL)中的步骤a中制备的酯(64mg,0.22mmol)的溶液中添加该溶液。在60℃下加热反应混合物2小时,随后用饱和NH4Cl水溶液终止反应混合物,用乙酸乙酯稀释,用饱和NaCl水溶液洗涤,用MgSO4干燥,过滤,在减压下浓缩。通过反相制备型HPLC(15-95%CH3CN/H2O梯度,具有0.1%TFA改性剂)纯化残余物,干燥(冻干器),以33%的收率产生主要的非对映异构体(60mg)。1H NMR(400MHz,CD3OD):δ8.01(s,1H),7.91(s,1H),7.41(s,1H),7.1(m,3H),4.13(d,1H,J=11Hz),3.70(d,1H,J=11Hz),3.21(q,J=8Hz),2.20(s,3H),2.11(s,3H),2.05(m,2H),1.49(d,3H,J=8Hz),0.94(t,3H,J=7Hz)。LC-MS Rt(保留时间):3.11分钟,MS:(ES)m/z 453(M+H)+。
实施例28:合成cis-3-乙基-N-(3-(三氟甲基)-5-异丙氧基苯基)-4-甲基-1-(2,6-二甲基苯基)-5-氧代吡咯烷-3-甲酰胺
a)向溶于DMF(3mL)中的3-硝基-5-三氟甲基酚(250mg,1.2mmol)溶液中添加2-碘丙烷(0.50mL,5.0mmol),随后添加K2CO3(640mg,4.6mmol)。搅拌混合物24小时,随后核对TLC,显示原料完全消耗,形成单个新产物。在真空中除去DMF,将反应混合物放入醚中,过滤通过硅藻土,浓缩以获得固体残余物,其不经进一步纯化而用于下一个步骤。TLC Rf(保留因子)=0.67(20%EtOAc/己烷)。
b)向甲醇(100mL)中的3-(2′-丙基氧基)-5-硝基三氟甲苯(0.80g,3.2mmol)的溶液中添加钯碳(palladium on carbon)(10重量%,湿润,Degussa类型E101NE/W,100mg),用氢气囊(1大气压)氢化溶液24小时。将反应混合物过滤通过硅藻土,用甲醇冲洗滤饼。浓缩滤液,通过快速色谱(SiO2,20%EtOAc/己烷)纯化残余物,以88%的收率产生纯的化合物(620mg)。LC-MS Rt(保留时间):2.48分钟;MS:(ES)m/z 220(M+H+)。
c)向溶于THF(1mL)中的3-(2′-丙基氧基)-5-氨基三氟甲苯(105mg,0.48mmol)溶液中添加正丁基锂(2.5M于己烷中,0.20mL,0.50mmol)的溶液。5分钟之后,向THF(1mL)中的3-乙基-4-甲基-1-(2,6-二甲基苯基)-5-氧代吡咯烷-3-羧酸甲酯(之前已描述其制备)(56mg,0.19mmol)溶液中添加该溶液。在60℃下加热反应混合物2小时,随后用饱和NH4Cl水溶液终止,用乙酸乙酯稀释,用饱和的NaCl水溶液洗涤,用MgSO4干燥,过滤,在减压下浓缩。通过快速色谱(SiO2,0-20%EtOAc/己烷)纯化残余物,随后重结晶(EtOAc/甲苯/己烷),以50%的收率获得所需的化合物(45mg)。1H NMR(400MHz,CD3OD):δ7.51(s,1H),7.47(s,1H),7.41(m,3H),6.88(s,1H),4.63(m,1H),4.12(d,1H,J=10Hz),3.71(d,1H,J=10Hz),3.24(m,1H),2.23(s,3H),2.12(s,3H),2.02(m,2H),1.40(d,3H,J=9Hz),1.35(d,6H,J=6Hz),0.95(t,3H,J=8Hz)。LC-MS Rt(保留时间):2.91分钟,MS:(ES)m/z 477(M+H)+。
实施例29:合成cis-3-乙基-N-(3-(三氟甲基)-5-(吡咯烷-1-基)苯基)-4-甲基-1-(2,6-二甲基苯基)-5-氧代吡咯烷-3-甲酰胺
a)将3-氨基-5-溴三氟甲苯(1.0g,4.2mmol)溶于DMSO(2mL)中。在室温下添加吡咯烷(1.0mL,13mmol),随后添加K3PO4(1.9g,8.4mmol)、CuI(80mg,0.42mmol)和脯氨酸(97mg,0.84mmol)。在90℃下搅拌16小时之后,LC-MS和TLC显示反应完成。用EtOAc(50mL)稀释反应混合物,用NH4OH水溶液(30%,60mL)和盐水(20mL)洗涤,在减压下浓缩所获得的溶液。通过快速色谱(SiO2,10-35%EtOAc/己烷)纯化残余物以产生800mg黄褐色粉末(83%收率)。LC-MS Rt(保留时间):2.44分钟,MS:(ES)m/z 231(M+H+)。
b)向溶于THF(1mL)中的3-(吡咯烷-1-基)-5-氨基三氟甲苯(94mg,0.41mmol)溶液中添加正丁基锂(2.5M于己烷中,0.16mL,0.41mmol)的溶液。5分钟之后,向THF(1mL)中的3-乙基-4-甲基-1-(2,6-二甲基苯基)-5-氧代吡咯烷-3-羧酸甲酯(之前已描述其制备)(53mg,0.18mmol)溶液中添加该溶液。在60℃下加热反应混合物2小时,随后用饱和NH4Cl水溶液终止反应混合物,用乙酸乙酯稀释,用饱和NaCl水溶液洗涤,用MgSO4干燥,过滤,在减压下浓缩。通过快速色谱(SiO2,40%EtOAc/己烷)初始纯化残余物,随后通过反相制备型HPLC(15-95%CH3CN/H2O梯度,具有0.1%TFA改性剂)纯化,干燥(冻干器),以50%的收率产生主要的非对映异构体(44mg)。1H NMR(400MHz,CD3OD):δ7.10(m,5H),6.52(s,1H),4.10(d,1H,J=10Hz),3.71(d,1H),J=10Hz),3.25(q,1H,J=8Hz),2.20(s,3H),2.13(s,3H),2.00(m,2H),1.38(d,3H,J=8Hz),0.96(t,3H,J=7Hz)。LC-MS Rt(保留时间):3.19分钟,MS:(ES)m/z 488(M+H+)。
实施例30:合成cis-N-(3-环丙基-5-(三氟甲基)苯基)-3-乙基-4-甲基-1-(2,6-二甲基苯基)-5-氧代吡咯烷-3-甲酰胺
a)将3-氨基-5-溴三氟甲苯(275mg,1.15mmol)、环丙基硼酸(128mg,1.5mmol)、Pd(OAc)2(13mg,0.06mmol)、三环己基膦(38mg,0.13mmol)和K3PO4(488mg,2.3mmol)装入40mL的小瓶中。随后,用隔片衬里的螺帽密封小瓶,用氮气吹扫,随后添加脱气的甲苯(4mL)和脱气的水(1mL)。在100℃下搅拌反应混合物2小时,在乙酸乙酯(50mL)中稀释混合物,用盐水洗涤有机层,干燥(MgSO4),在真空中浓缩。通过快速色谱(SiO2,10-40%EtOAc/己烷)纯化残余物,以55%的收率产生所需的产物(126mg)。LC-MS Rt(保留时间):2.46分钟,MS:(ES)m/z 202(M+H+)。
b)向THF(1mL)中的3-(环丙基)-5-氨基三氟甲苯(126mg,0.626mmol)的溶液中添加正丁基锂(2.5M于己烷中,0.25mL,0.63mmol)的溶液。5分钟之后,向THF(1mL)中的3-乙基-4-甲基-1-(2,6-二甲基苯基)-5-氧代吡咯烷-3-羧酸甲酯(之前已描述其制备)(74mg,0.27mmol)溶液中添加该溶液。在60℃下加热反应混合物1小时,随后用饱和NH4Cl水溶液终止反应混合物,用乙酸乙酯稀释,用饱和NaCl水溶液洗涤,用MgSO4干燥,过滤,在减压下浓缩。通过快速色谱(SiO2,40%EtOAc/己烷)初始纯化残余物,随后以反相制备型HPLC(15-95%CH3CN/H2O梯度,具有0.1%TFA改性剂)纯化,干燥(冻干器),以20%的收率产生主要的非对映异构体(25mg)。1H NMR(400MHz,CD3OD):δ7.74(s,1H),7.51(s.1H),7.10(m,4H),4.10(d,1H,J=10Hz),3.70(d,1H,J=10Hz),3.23(q,1H,J=8Hz),2.20(s,3H),2.11(s,3H),2.03(m,2H),1.39(d,3H,J=8Hz),1.05(m,2H),0.93(t,3H,J=7Hz),0.74(m,2H)。LC-MS Rt(保留时间):3.02分钟,MS:(ES)m/z 459(M+H+)。
实施例31:合成1-(2,6-二甲基苯基)-5-氧代吡咯烷-3-羧酸叔丁酯
a)向2L的三颈瓶中添加1-(2,6-二甲基苯基)-5-氧代吡咯烷-3-羧酸(93g,0.40mol)、无水叔丁醇(60mL,0.63mol)、TEA(110mL,0.79mol)、DMAP(5.0g,41mmol)和CH2Cl2(800mL)。在氮气气氛下,在机械搅拌的冰浴中冷却混合物之后,在15分钟的过程中分份添加2,4,6-三氯苯甲酰氯(108g,0.443mol),以使温度不超过10℃。添加完之后,除去冰浴,使混合物升温至室温,再搅拌14小时。TLC和LCMS显示原料完全消耗,并且形成所需的产物。过滤混合物,用EtOAc(100mL)和醚(150mL)洗涤滤饼。用两份200mL的1M NaHSO4、四份200mL的饱和NaHCO3水溶液和盐水(100mL)洗涤滤液。用MgSO4干燥之后,用24g硅胶处理有机相,过滤。将滤液浓缩至250mL,用己烷稀释。结晶沉淀开始形成,回收第一批66g。回收滤液并重结晶(醚/己烷)以提供第二批(27g);总收率,93g(81%)。LC-MS Rt(保留时间):2.28分钟,MS:(ES)m/z 290(M+H+)。
实施例32:合成(S)-N-(3,5-双(三氟甲基)苯基)-1-(2,6-二甲基苯基)-3-乙基-5-氧代吡咯烷-3-甲酰胺
a)在-50℃下,通过加料漏斗向250mL无水THF中的1-(2,6-二甲基苯基)-5-氧代吡咯烷-3-羧酸甲酯(21.8g,88.2mmol)溶液中逐滴添加LHMDS(91mL,1.0M)。将均匀的溶液搅拌30分钟,随后添加乙基碘(10mL,125mmol)。随后除去冷浴,在环境温度下搅拌反应物2.5小时。用100mL饱和氯化铵终止所产生的溶液,用乙酸乙酯分配,用EtOAc萃取。随后将合并的有机层用饱和NaHSO3洗涤,用盐水洗涤,用硫酸钠干燥。通过硅胶色谱(MTBE/己烷)纯化粗制产物,以60%的收率提供烷基化的产物(14.5g)。LC-MS Rt(保留时间):2.17分钟;MS:(ES)m/z 276(M+H+)。
b)将来自步骤a的酯(1.4g,4.9mmol)、NaOH(40mL,1.0M)和EtOH(20mL)装入500mL的瓶中。将所产生的混合物搅拌105分钟,随后缓慢地添加6M HCl以使所需的酸沉淀。用10%HCl彻底地洗涤沉淀,在减压下干燥,以定量的收率产生所需的酸(1.3g)。LC-MS Rt(保留时间):1.42分钟;MS:(ES)m/z 262(M+H+)。
c)在0℃下,向1-(2,6-二甲基苯基)-3-乙基-5-氧代吡咯烷-3-羧酸(500mg,1.91mmol)、甲磺酰氯(0.233mL,2.86mmol)和THF(4mL)的溶液中添加二异丙基乙胺(1.0mL,5.73mmol)。在0℃下搅拌溶液15分钟,升温至环境温度,随后再搅拌20分钟。随后添加(S)-苯基甘氨醇(523mg,3.82mmol),在55℃下过夜加热溶液。次日,用10%HCl终止反应混合物,用EtOAc萃取水层三次。用碳酸氢钠洗涤合并的有机层,用硫酸钠干燥,在真空中浓缩,通过制备型HPLC纯化以提供两种非对映体的酰胺(较快洗脱的非对映体:128mg,18%收率;较慢洗脱的非对映体:132mg,18%收率),其中前一种是所需的非对映体。第1非对映体:LC-MS Rt(保留时间):1.81分钟;MS:(ES)m/z 381(M+H+)。第2非对映体:LC-MS Rt(保留时间):1.94分钟;MS:(ES)m/z 381(M+H+)。
d)将来自步骤c的酰胺(140mg,0.367mmol)、浓硫酸(1.4mL)和二氧六环(1.4mL)装入25mL的闪烁瓶中。将溶液密封,在110℃下过夜加热。次日,用二乙醚和盐水分配反应物,用二乙醚萃取水层三次,用硫酸钠干燥合并的有机层,以86%的收率提供所需的酸(83mg)。通过手性HPLC(Regis Whelk,88%己烷:12%,具有0.1%AcOH,1mL/分钟流速,Rt(保留时间):19.8分钟)测定对映体纯度为>97%。LC-MS Rt(保留时间):1.39分钟;MS:(ES)m/z 262(M+H+)。
e)在0℃下,向THF(0.38mL)中的来自步骤d的粗制的酸(10mg,0.038mmol)和甲磺酰氯(6μL,0.076mmol)的溶液中添加二异丙基乙胺(0.027mL,0.15mmol)。将溶液在0℃下搅拌15分钟,升温至环境温度,随后添加3,5-双(三氟甲基)苯胺(0.018mL,0.12mmol),在55℃下加热溶液过夜。次日,通过制备型HPLC纯化反应混合物以提供所需酰胺的白色固体。1H NMR(400MHZ,CDCl):δ8.06(s,2H),7.67(s,1H),7.64(s,1H),7.04-7.17(m,3H),4.16(d,J=10.4Hz,1H),3.50(d,J=10.4Hz,1H),3.14(d,J=16.8Hz,1H),2.67(d,J=16.8Hz,1H),2.24(s,3H),2.17(s,3H),1.95-2.14(m,2H),1.06(t,J=7.2Hz,3H)。LC-MS Rt(保留时间):3.00分钟;MS:(ES)m/z 473(M+H+)。
实施例33:合成(3S,4S)-N-(3,5-双(三氟甲基)苯基)-1-(2,6-二甲基苯基)-3-乙基-4-甲基-5-氧代吡咯烷-3-甲酰胺
a)向MeOH(4.0mL)中的(S)-1-(2,6-二甲基苯基)-3-乙基-5-氧代吡咯烷-3-羧酸(79mg,0.30mmol)的溶液中添加三甲基甲硅烷基重氮甲烷(2.0M),直到试剂的黄颜色持续存在。将均匀的溶液再搅拌30分钟,随后添加乙酸以终止过量的试剂。随后用EtOAc/饱和碳酸氢钠分配粗制的混合物,用EtOAc萃取水层两次。用硫酸钠干燥合并的有机层,在真空中浓缩以提供所需的甲酯(82mg,定量的收率),其直接用于下一个步骤。LC-MS Rt(保留时间):2.15分钟;MS:(ES)m/z 276(M+H+)。
b)在-78℃下,向3mL无水THF中的粗制(S)-1-(2,6-二甲基苯基)-3-乙基-5-氧代吡咯烷-3-羧酸甲酯(82mg,0.30mmol)中添加LHMDS(0.31mL,1.0M)。将均匀的溶液搅拌30分钟,随后添加甲基碘(0.037mL,0.59mmol)。使反应物缓慢升温至室温(如丙酮/干冰升温),搅拌过夜。次日,用10%HCl终止溶液,用乙酸乙酯分配,分离有机层。随后将有机层用10%HCl洗涤,用盐水洗涤,用硫酸钠干燥,在真空中浓缩,以产生83mg(定量的收率)甲基化的吡咯烷酮的非对映体混合物,其直接用于下一个步骤。LC-MS Rt(保留时间):2.33分钟;MS:(ES)m/z 290(M+H+)。
c)在0℃下,向THF(3.6mL)中的3,5-双(三氟甲基)苯胺(500mg,2.18mmol)溶液中添加nBuLi(0.83mL,2.5M)。将溶液搅拌20分钟以使阴离子形成。在另外的瓶中,将来自步骤b的粗制的酯(83mg,0.30mmol)溶于THF(0.8mL),将溶液冷却至0℃。随后将3,5-双(三氟甲基)苯胺(1.62mL,0.46M)的锂阴离子添加至粗制的酯中,将瓶升温至环境温度,搅拌过夜。次日,通过制备型HPLC纯化粗制的反应物,其无法提供足够纯的所需产物。随后,通过硅胶色谱(EtOAc/己烷)纯化最纯的级分以提供所需产物的白色固体。1H NMR(400MHZ,CDCl):δ8.04(s,2H),7.64(s,1H),7.56(s,1H),7.04-7.16(m,3H),4.20(d,J=10.3Hz,1H),3.46(d,J=10.3Hz,1H),3.06(q,J=7.0Hz,1H),2.22(s,3H),2.17(s,3H),1.94(q,J=7.2Hz,2H),1.46(d,J=7.2Hz,3H),1.05(t,J=7.2Hz,3H)。LC-MS Rt(保留时间):3.01分钟;MS:(ES)m/z 487(M+H+)。
实施例34:合成(R)-N-(3-环丙基-5-(三氟甲基)苯基)-1-(2,6-二甲基苯基)-3-异丙基-5-氧代吡咯烷-3-甲酰胺
a)将3-氨基-5-溴三氟甲苯(275mg,1.15mmol)、环丙基硼酸(128mg,1.5mmol)、Pd(OAc)2(13mg,0.06mmol)、三环己基膦(38mg,0.13mmol)和K3PO4(488mg,2.3mmol)装入40mL的小瓶中。随后用隔片衬里的螺帽密封小瓶,用氮气吹扫,随后添加脱气的甲苯(4mL)和脱气的水(1mL)。在100℃下搅拌反应混合物2小时,在乙酸乙酯(50mL)中稀释混合物,用盐水洗涤有机层,干燥(MgSO4),在真空中浓缩。通过快速色谱(SiO2,10-40%EtOAc/己烷)纯化残余物,以55%的收率产生所需的产物(126mg)。LC-MS Rt(保留时间):2.46分钟,MS:(ES)m/z 202(M+H+)。
b)在0℃下,向THF(0.6mL)中的(R)-1-(2,6-二甲基苯基)-3-异丙基-5-氧代吡咯烷-3-羧酸(32mg,0.12mmol)和甲磺酰氯(12μL,0.15mmol)的溶液中添加二异丙基乙胺(0.060mL,0.35mmol)。将溶液在0℃下搅拌15分钟,升温至环境温度,随后添加3-环丙基-5-(三氟甲基)苯胺(47mg,0.23mmol),在55℃下过夜加热溶液。次日,通过制备型HPLC纯化反应混合物以提供所需酰胺的白色固体。1H NMR(400MHZ,CDCl):δ9.89(s,1H),7.86(s,1H),7.56(s,1H),7.05-7.17(m,4H),3.97(d,J=10.4Hz,1H),3.67(d,J=10.4Hz,1H),3.04(d,J=17.2Hz,1H),2.65(d,J=17.2Hz,1H),2.36(七重峰,J=6.8Hz,1H),2.16(s,3H),1.99-2.08(m,1H),1.99(s,3H),1.00-1.06(m,2H),0.96(t,J=6.8Hz,6H),0.70-0.75(m,2H)。LC-MS Rt(保留时间):3.02分钟;MS:(ES)m/z 459(M+H+)。
实施例35:合成(R)-N-(3-氰基-5-(三氟甲基)苯基)-1-(2,6-二甲基苯基)-3-异丙基-5-氧代吡咯烷-3-甲酰胺
在0℃下,向THF(0.9mL)中的(R)-1-(2,6-二甲基苯基)-3-异丙基-5-氧代吡咯烷-3-羧酸(25mg,0.091mmol)和甲磺酰氯(9μL,0.12mmol)溶液中添加二异丙基乙胺(0.047mL,0.27mmol)。在0℃下搅拌溶液15分钟,冷却至环境温度,随后添加3-氨基-5-(三氟甲基)苄腈(34mg,0.18mmol),将溶液在55℃下加热过夜。次日,通过制备型HPLC纯化反应混合物,其无法提供足够纯度的所需产物。向2mL THF中的粗制混合物(14mg)的溶液中添加NaOH水溶液(3mL,1.0M),在50℃下过夜搅拌溶液。次日,用10%HCl终止溶液,用乙酸乙酯分配,分离有机层。随后用硫酸钠干燥有机层,在真空中浓缩,通过制备型HPLC纯化以提供所需酰胺的白色固体。1H NMR(400MHZ,CDCl):δ10.28(s,1H),8.39(s,1H),8.30(s,1H),8.05(s,1H),7.04-7.17(m,3H),3.99(d,J=11.2Hz,1H),3.67(d,J=10.8Hz,1H),3.05(d,J=17.2Hz,1H),2.70(d,J=17.2Hz,1H),2.38(七重峰,J=6.8Hz,1H),2.17(s,3H),2.00(s,3H),0.98(t,J=6.8Hz,6H)。LC-MS Rt(保留时间):2.81分钟;MS:(ES)m/z 444(M+H+)。
实施例36:合成(R)-1-(2,6-二甲基苯基)-N-(3-异丙氧基-5-(三氟甲基)苯基)-3-异丙基-5-氧基吡咯烷-3-甲酰胺
a)向丙酮(60mL)中的3-硝基-5-(三氟甲基)酚(6.0g,29.0mmol)溶液中添加碳酸钾(12.0g,87.0mmol)和异丙基碘(4.35mL,43.5mmol)。随后在环境温度下过夜搅拌均匀的混合物。次日,用二乙醚/水分配反应混合物,用二乙醚萃取水层两次。用硫酸钠干燥合并的有机层,在真空中浓缩,通过快速色谱(SiO2,25%EtOAc/己烷)纯化粗制的产物,以提供所需醚的黄色油状物。LC-MS Rt(保留时间):2.98分钟。
b)将来自步骤a的醚(~29.0mmol)、10%Pd/C(1.0g,0.94mmol)和MeOH(50mL)装入Parr摇床瓶中。以40psi(磅/平方英寸)使用Parr摇床过夜氢化均匀的溶液。将反应混合物过夜通过硅藻土,用MeOH清洗滤饼。浓缩滤液,通过快速色谱(SiO2,25%EtOAc/己烷)纯化残余物以提供所需苯胺和部分还原的亚硝基化合物的化合物。向甲醇(15mL)中的亚硝基中间体(~6g)的溶液中添加10%氧化铂(1.0g,0.44mmol),使用Parr摇床以40psi过夜氢化溶液。将反应混合物过滤通过硅藻土,用甲醇冲洗滤饼。浓缩滤液,通过快速色谱(SiO2,25%EtOAc/己烷)纯化残余物以提供所需的苯胺(4.5g,71%两步的收率)。LC-MS Rt(保留时间):2.47分钟;MS:(ES)m/z 220(M+H+)。
c)在0℃下,向THF(0.9mL)中的(R)-1-(2,6-二甲基苯基)-3-异丙基-5-氧代吡咯烷-3-羧酸(25mg,0.091mmol)和甲磺酰氯(9μL,0.12mmol)的溶液中添加二异丙基乙胺(0.047mL,0.27mmol)。在0℃下搅拌溶液15分钟,升温至环境温度,随后添加3-异丙氧基-5-(三氟甲基)苯胺(39mg,0.18mmol),将溶液在55℃下加热过夜。次日,通过制备型HPLC纯化反应混合物以提供所需酰胺的白色固体。1H NMR(400MHZ,CDCl):δ9.91(s,1H),7.59(s,1H),7.56(s,1H),7.04-7.16(m,3H),6.90-6.94(m,1H),4.65(七重峰,J=6.0Hz,1H),3.97(d,J=10.4Hz,1H),3.66(d,J=10.8Hz,1H),3.04(d,J=17.2Hz,1H),2.66(d,J=17.2Hz,1H),2.36(七重峰,J=6.8Hz,1H),2.16(s,3H),2.00(s,3H),1.29(d,J=6.0Hz,6H),0.96(t,J=6.4Hz,6H)。LC-MS Rt(保留时间):3.08分钟;MS:(ES)m/z 477(M+H+)。
实施例37:合成(1S*,5S*)-3-(2,6-二甲基苯基)-4-氧代-3-氮杂双环[3.2.0]庚烷-1-羧酸[3,5-双(三氟甲基)苯基]酰胺
a)在氮气气氛下,向冷却至-50℃的反应瓶中THF(6mL)中的1-(2,6-二甲基苯基)-5-氧代-吡咯烷-3-羧酸叔丁酯(3.53g,12.2mmol)溶液中添加LHMDS(1.0M于THF中,13.4mL,13.4mmol)。使反应混合物升温至0℃(沉淀形成),此时添加叔丁基-(2-碘乙氧基)-二甲基硅烷(3.84g,13.4mmol),彻底振摇混合物。使反应混合物升温至室温,保持搅拌1小时。添加20mL半饱和的氯化铵水溶液,随后添加100mL DCM。在真空中用硅胶浓缩有机层,通过快速色谱(SiO2,5-35%EtOAc/己烷)纯化以产生3.28g所需的化合物(60%收率)。LC-MS Rt(保留时间):3.41分钟,MS:(ES)m/z 448(M+H+)。
b)在室温下,向THF(3mL)中的来自步骤a的甲硅烷基醚(298mg,0.67mmol)的溶液中添加氟化氢-吡啶的复合物(70重量%HF,118μL,4.83mmol)。在聚丙烯小瓶中将混合物加热至50℃1小时。在真空中用硅胶浓缩溶液,通过快速色谱(SiO2,20-100%EtOAc/己烷)纯化以产生200mg所需化合物(90%收率)的白色固体。LC-MS:Rt(保留时间):1.94分钟,MS:(ES)m/z 334(M+H+)。
c)向DCM(1mL)中的咪唑(62mg,0.905mmol)和三苯基膦(237mg,0.905mmol)的溶液中逐份添加碘(230mg,0.905mmol)。碘溶解时,添加醇(步骤b中制备的,200mg,0.601mmol)。使反应混合物在室温下陈化16小时,在真空中使用硅胶浓缩,通过快速色谱(SiO2,0-50%EtOAc/己烷)纯化以产生223mg所需的化合物(84%收率)。LC-MS Rt(保留时间):2.80分钟,MS:(ES)m/z 444(M+H+)。
d)在氮气气氛下,向冷却至-78℃的反应瓶中THF(6mL)中的步骤c中制备的碘化物(223mg,0.50mmol)的溶液中添加LHMDS(1.0M于THF中,0.55mL,0.55mmol)。使反应混合物升温至室温,保持搅拌30分钟。添加20mL半饱和的氯化铵水溶液,随后添加100mLDCM。在真空中用硅胶浓缩有机层,通过快速色谱(SiO2,20-60%EtOAc/己烷)纯化以产生156mg所需的化合物(98%收率)。LC-MS Rt(保留时间):2.48分钟,MS:(ES)m/z 316(M+H+)。
e)将步骤d中制备的双环化合物(156mg,0.49mmol)溶于二氧六环(2mL)中的4N氯化氢溶液中。在密封的容器中,将所产生的溶液加热至60℃1小时,随后在真空中浓缩以产生146mg羧酸。LC-MS Rt(保留时间):0.90分钟,MS:(ES)m/z 260(M+H+)。
f)向THF(0.5mL)中的上述步骤e中制备的羧酸(75mg,0.290mmol)和N,N-二异丙基乙胺(224mg,1.74mmol)的溶液中逐滴添加甲磺酰氯(67mg,0.580mmol)。将溶液在室温下陈化5分钟,此时添加3,5-双(三氟甲基)苯胺(133mg,0.58mmol)。在60℃下搅拌30分钟,随他添加另外33mg甲磺酰氯,使反应完成。添加3mL水和10mL DCM,剧烈搅拌混合物5分钟。在真空中用硅胶浓缩所分离的有机相,通过快速色谱(SiO2,30-80%EtOAc/己烷)纯化以产生灰白色残余物,将其从热的乙酸乙酯和己烷的混合物中重结晶,以产生57mg所需化合物(42%收率)的无色结晶。1H NMR(400MHz,DMSO-d6)δ2.03-2.14(m,1H),2.13(s,3H),2.28(s,3H),2.47-2.59(m,2H),2.75-2.86(m,1H),3.43-3.51(m,1H),3.72(d,J=10.4,1H),3.88(d,J=10.4,1H),7.08-7.19(m,3H),7.79(s,1H),8.36(s,2H),10.33(s,1H)。LC-MS:Rt(保留时间)=2.74分钟,MS:(ES)m/z 471(M+H+)。
实施例38:合成2-(2,6-二甲基-苯基)-1-氧代-八氢-异吲哚-3a-羧酸(3,5-双-三氟甲基-苯基)-酰胺
a)在-50℃下,向反应瓶中THF(16mL)中的1-(2,6-二甲基-苯基)-5-氧代-吡咯烷-3-羧酸甲酯(0.4g,1.6mmol)的溶液中添加双(三甲基硅基)氨基锂(1.0M于THF中,3.8mL,2.4mmol),搅拌5分钟。随后将反应物升温至0℃,随后添加1,4-二碘丁烷(0.79g,2.6mmol)。使反应物升温至室温,搅拌1小时。用饱和NH4Cl终止反应。将层分离,用EtOAc(3×)萃取水层。干燥(MgSO4)合并的有机层,在减压下浓缩。通过快速色谱(SiO2,0-50%己烷/EtOAc)纯化残余物,以63%的收率产生所需的化合物(0.3g)。
b)向MeOH(5ml)中的来自步骤a的酯(0.3g,1.0mmol)的溶液中添加氢氧化锂(1.0M于H2O中,10mL,10mmol)。在75℃下加热所产生的溶液2小时。将溶液在减压下浓缩以产生原体积的1/4,逐滴添加6M HCl水溶液(~0.5mL)以调节pH至约4。用EtOAc(3×)萃取水层。干燥(MgSO4)合并的有机层,在减压下浓缩以产生粗制产物(0.28g,100%)。LC-MS:Rt(保留时间):1.76分钟,MS:(ES)m/z 288.3(M+H+)。
c)在室温下,向THF(4.7ml)中的来自步骤b的酸(0.28g,1.0mmol)的溶液中添加甲磺酸(0.14g,1.2mmol,)和iPr2NEt(0.28mL,2.2mmol)。在室温下搅拌所产生的混合物5分钟,随后添加3,5-双(三氟甲基)苯胺(0.06g,0.27mmol)。在75℃下加热反应物,直到反应完成(18小时)。在减压下浓缩混合物。通过快速色谱(SiO2,0-75%己烷/EtOAc)纯化,以75%的收率产生所需的产物(0.37g)。1H NMR(400MHz,DMSO-d6)):δ10.12(s,1H),8.35(s,2H),7.78(s,1H),7.14-7.07(m,3H),3.74(d,J=9.6Hz,1H),3.55(d,J=9.6,1H),3.09(s,1H),2.32(bd,J=13.6Hz,1H),2.25(s,3H),2.04(s,3H),1.98-1.80(m,3H),1.60-1.5(m,2H),1.26-1.18(m,2H)。LC-MS:Rt(保留时间):2.94分钟,MS:(ES)m/z 499.4(M+H+)。
实施例39:合成3-(2,6-二甲基-苯基)-4-氧代-3-氮杂-双环[3.1.0]己烷-1-羧酸(3,5-双-三氟甲基-苯基)-酰胺
向THF(50mL)中的1-(2,6-二甲基-苯基)-5-氧代-吡咯烷-3-羧酸甲酯(2g,8.1mmol)的冷却(-50℃)溶液中缓慢地添加LHMDS(THF中的1M溶液,9.72mL,9.72mmol)。在-50℃下搅拌5分钟,随后升温至0℃,进一步搅拌5分钟。冷却回到-50℃之后,添加(CH2O)n(1.2g,40.5mmol),使所产生的反应混合物升温至室温,搅拌2小时。添加饱和的NH4Cl水溶液(25mL),用EtOAc(3×75mL)萃取。用水(100mL)、盐水(100mL)洗涤合并的有机层,干燥(Na2SO4),蒸发。通过自动快速色谱(SiO2,20→50%EtOAc/己烷)纯化残余物以产生1-(2,6-二甲基-苯基)-3-羟基甲基-5-氧代-吡咯烷-3-羧酸甲酯(762mg,34%收率)。LC-MS:Rt(保留时间):0.9分钟,MS:(ES)m/z 278.1(M+H+)。
b)向THF(5mL)中的1-(2,6-二甲基-苯基)-3-羟基甲基-5-氧代-吡咯烷-3-羧酸甲酯(步骤a中制备的,250mg,0.9mmol)和Et3N(375μL,2.7mmol)的冷却(0℃)溶液中添加MsCl(105μL,1.35mmol)。在室温下过夜搅拌所产生的反应混合物。添加水(10mL),用EtOAc(3×25mL)萃取。用水(50mL)、盐水(50mL)洗涤合并的有机层,干燥(Na2SO4),蒸发。将所获得的粗制产物1-(2,6-二甲基-苯基)-3-甲磺酰基氧基甲基-5-氧代-吡咯烷-3-羧酸甲酯用于下一个步骤。LC-MS:Rt(保留时间):1.73分钟,MS:(ES)m/z 356.3(M+H+)。
c)在室温下,向THF(3mL)中的3,5-双-三氟甲基苯胺(216.5μL,0.545mmol)溶液中添加n-BuLi(己烷中的2.5M溶液,560μL,1.39mmol)。在室温下搅拌所产生的暗棕色溶液10分钟。添加THF(2mL)中的1-(2,6-二甲基-苯基)-3-甲磺酰基氧基甲基-5-氧代-吡咯烷-3-羧酸甲酯(步骤b中制备的,165mg,0.465mmol)溶液,在75℃下搅拌2小时。随后通过制备型HPLC(15→85%MeCN-H2O梯度,具有0.1%TFA)纯化反应混合物。将纯的级分冻干以提供3-(2,6-二甲基-苯基)-4-氧代-3-氮杂-双环[3.1.0]己烷-1-羧酸(3,5-双-三氟甲基-苯基)-酰胺(22mg,10%收率)。LC-MS:Rt(保留时间):2.98分钟,MS:(ES)m/z 457.2(M+H+)。1H NMR(400MHz,DMSO-d6)δ9.88(s,1H),8.32(s,2H),7.78(s,1H),7.02-7.18(m,3H),4.18(d,1H,J=9.7Hz),3.68(d,1H,J=9.7Hz),2.68-2.75(m,1H),2.18(s,3H),2.08-2.12(m,1H),2.05(s,3H),1.45(t,1H,J=3.9Hz)。
实施例40:合成N-(3,5-双(三氟甲基)苯基)-2-(2,6-二甲基苯基)-1-氧代八氢环戊烷[c]吡咯-3a-甲酰胺
a)用注射器向溶于5mL无水THF中的并且冷却至-40℃的1-(2,6-二甲基苯基)-5-氧代吡咯烷-3-羧酸甲酯(1.5g,6.1mmol)中添加双(三甲基硅基)氨基锂(1.0M于THF中,6.1mL,6.1mmol)。搅拌10分钟之后,用0℃浴器(bath)替换该浴器,继续再搅拌10分钟。随后,将反应化合物冷却至-40℃,添加另外6.1mL双(三甲基硅基)氨基锂溶液(6.1mmol)。在-40℃下搅拌10分钟之后,使反应混合物逐渐升温至室温,用饱和氯化铵溶液(15ml)终止,用醚萃取粗制的产物。用无水Na2SO4干燥合并的有机层,蒸发溶剂,通过快速色谱(SiO2,10-100%EtOAc/己烷)纯化残余物以获得920mg 2-(2,6-二甲基苯基)-1-氧代八氢环戊烷[c]吡咯-3a-羧酸甲酯(32%收率)。LC-MS Rt(保留时间):2.12分钟,MS:(ES)m/z288(M+H+)。
b)在70℃下加热5mL 90%甲醇中的1M LiOH中悬浮的2-(2,6-二甲基苯基)-1-氧代八氢环戊烷[c]吡咯-3a-羧酸甲酯(400mg,1.4mmol)。冷却至室温之后,用水稀释反应混合物,用浓HCl调节pH至~1,用乙酸乙酯(15mL)萃取产物两次。用无水Na2SO4干燥合并的有机层,蒸发溶剂以获得2-(2,6-二甲基苯基)-1-氧代八氢环戊烷[c]吡咯-3a-羧酸(315mg,82%收率)。LC-MS Rt(保留时间):1.44分钟,MS:(ES)m/z 274(M+H+)。
c)向THF中的2-(2,6-二甲基苯基)-1-氧代八氢环戊烷[c]吡咯-3a-羧酸(86mg,0.3mmol)和二异丙基乙胺(104μL,0.6mmol)的溶液中添加甲磺酰氯(32μL,0.4mmol)。用3,5-双(三氟甲基)苯胺(137mg,0.6mmol)处理混合物,在75℃下加热3小时。蒸发溶剂之后,将粗制的产物应用至C18制备型HPLC柱,用乙腈/水溶剂系统(5-80%乙腈梯度,具有0.1%TFA)洗脱。中和以及将含有级分之合并产物的溶剂蒸发之后,获得80mgN-(3,5-双(三氟甲基)苯基)-2-(2,6-二甲基苯基)-1-氧代八氢环戊烷[c]吡咯-3a-甲酰胺(53%收率)。1H NMR(400MHz,CDCl3)δ1.72-1.84(m,1H),1.94-2.04(m,1H),2.09(s,3H),2.18(s,3H),2.24-2.40(m,4H),3.43(d,1H,J=11Hz),3.52-3.58(m,1H,4.06(d,1H,J=11Hz),7.00-7.17(m,3H),7.61(s,1H)8.13(s,2H),8.61(s,1H)。LC-MS:Rt(保留时间)=2.99分钟,MS:(ES)m/z 485(M+H+)。
生物实施例1
为了证明上文中描述的化合物是趋化因子与ChemR23之结合的有用调节剂,体外筛选所述化合物以测定其在多个浓度下从ChemR23受体置换趋化素的能力。在125I标记的趋化素存在下,将所述化合物与表达ChemR23受体(例如,原代人树突细胞或被转染的表达ChemR23的细胞)的细胞组合,详见IC50值的测定,试剂和细胞(见下文)。随后以筛选方法测定所述化合物在多个浓度下从ChemR23受体位点置换标记的趋化素的能力。
被视为有效调节剂的化合物能够以6微摩尔/升(μM)(或更低,但>300nM)的浓度(+)从ChemR23受体上置换至少50%的趋化素;并且更优选>30nM至≤300nM的浓度(++)。目前,尤其优选的化合物可以以30nM或更低的浓度(+++)从ChemR23受体上置换至少50%的趋化素。满足这些标准的示例化合物显示在图1中。按照上文中的实施例中的描述制备所有化合物,或通过替换很容易获得的原料的相关方法而制备。
1.测定IC50值。
试剂和细胞。125I标记的趋化素是从Perkin-Elmer Life Sciences,Inc.(Boston,MA)定制生产的。BaF3(鼠的祖B细胞)细胞系获自美国典型培养物保藏中心(American Type Culture Collection,ATCC,Manassas,VA),在37℃下,在5%CO2/空气混合物的潮湿培养箱中,所述细胞培养于补充了10%胎牛血清(fetal bovine serum,FBS)(HyClone Logan,UT)的DMEM(Mediatech,Herndon,VA)中。按照下文的描述产生转染了ChemR23的BaF3细胞。使用μMACs mRNA分离试剂盒(MiltenyiBiotec,Auburn,CA),从原代巨噬细胞中分离编码ChemR23(a.k.a.CMKLR1,DEZ)之基因的完整编码序列。经过RNeasy柱(Qiagen,Inc.,Valencia,CA),通过DNA酶(DNase)消化而除去DNA污染,使用GeneAmp RNA PCR Core Kit(Applied Biosystems,Foster City,CA)生成cDNA。使用Taq PCR Master Mix kit(Qiagen,Inc.)进行cDNA样品的PCR。使用标准技术(Molecular Cloning:A Laboratory Manual,Sambrook and Maniatis)将开放读码框克隆进入pcDNA3.1(Invitrogen,CA),并转染进入BaF3细胞。以800ug/ml使用G418选择被转染的细胞,通过抗体(R&D Systems)标记细胞的荧光激活分选(fluorescence activatedsorting)分离最佳的克隆。
结合分析。测试目标化合物以测定其与BaF3 ChemR23转染的细胞上的ChemR23位点结合的能力。使用Dairaghi DJ,et al.,HHV8-encodedvMIP-I selectively engages chemokine receptor CCR5.Agonist andantagonist profiles of viral chemokines.,J.Biol.Chem.1999 Jul 30;274(31):21569-74和Gosling J,et al.,Cutting edge:identification of a novelchemokine receptor that binds dendritic cell-and T cell-active chemokinesincluding ELC,SLC,and TECK.,J.Immunol.2000 Mar 15;164(6):2851-6中描述的使用过滤方案的效率最大化的放射性配体结合。
在这些测定中,用目标化合物测试BaF3 ChemR23转染的细胞,使用Dairaghi和Gosling中描述的方案评价这些化合物置换125I放射性标记之趋化素的能力。向板中添加目标化合物至指定的浓度,随后将其与细胞一起孵育,随后在4℃下,在以下结合介质(25mM HEPES,140mM NaCl,1mM CaCl2,5mM MgCl2和0.2%牛血清白蛋白,调节至pH 7.1)中添加放射性标记的配体(125I趋化素)3小时。随后,在4℃下轻微震荡孵育所有的测定3小时。在所有结合测定中的孵育之后,使用细胞收集器(Packard)将反应物吸到经PEI处理的GF/B玻璃滤器(Packard)上,洗涤两次(25mM HEPES,500mM NaCl,1mM CaCl2,5mM MgCl2,调节至pH 7.1)。向孔中添加闪烁剂(MicroScint10,Packard),将所述滤器在Packard Topcount闪烁计数器中计数。使用GraphPad Prism(GraphPad Software)分析数据并作图。
穿越内皮细胞的迁移测定(Transendothelial migration assay)。在穿越内皮细胞的迁移测定中进一步评价本发明化合物抑制细胞迁移的能力。在该测定中,分析细胞朝向趋化因子源迁移通过内皮细胞层的能力。在该测定的一个实例中,将100,000个人脐静脉内皮细胞(HUVEC,可获自Lonza)接种进入具有5uM滤器孔径的transwell培养皿(Corning Costar)的上室。添加培养基,在37℃下,将板置于具有5%CO2的培养箱中过夜。HUVEC过夜黏附至滤器形成单层之后,将含有趋化因子(例如,趋化素,终浓度10nM)的培养基添加至下室。随后,在受试化合物存在或不存在下,将500,000个从全血中所分离的原代人浆细胞样树突细胞(pDC)或由原代单核细胞衍生的树突细胞(从原代人PBMC分化而来)添加至上室,将板放回培养箱中3小时至过夜。向不同的孔中添加多种浓度的化合物以建立剂量响应。在该孵育结束时,除去上室,对下室中的细胞进行定量。通过用荧光染料Cyquant(Invitrogen,CA)标记而对细胞进行定量,在合适的读板器上对荧光进行定量。使用GraphPad Prism(GraphPad Software)分析数据并作图。以化合物抑制这些细胞迁移至下室的能力来测量化合物的效力。
迁移至源自单核细胞的上清液:进一步评价本发明所选择的化合物抑制细胞迁移至含有活性趋化素之上清液的能力,所述活性趋化素源自成熟的人脂肪细胞。在该测定中,在脂肪细胞分化培养基(Zenbio,catalog #DM-2)中培养人前脂肪细胞(Zenbio,NC),在37℃和5%CO2下孵育7天。7天之后,用新鲜的脂肪细胞培养基(Zenbio,产品编号AM-1)替换分化培养基。分化两周之后,用10ng/ml TNFa刺激成熟的脂肪细胞72小时。随后收集上清液,将其添加至96孔迁移板(Neuroprobe,MD)的底室,向上室中添加100,000个BAF3-ChemR23转染子(transfectant)细胞。将板在37℃下孵育2小时。向不同的孔中添加多种浓度的化合物以建立剂量响应。在该孵育结束时,除去上室,并对下室中的细胞进行定量。通过用荧光染料Cyquant(Invitrogen,CA)标记而对细胞进行定量,在合适的读板器上对荧光进行定量。使用GraphPad Prism(GraphPadSoftware)分析数据并作图。以化合物抑制这些细胞迁移至下室的能力来测量化合物的效力。
体内效力
a)实验性自身免疫性脑脊髓炎的啮齿类动物模型
可进行实验性自身免疫性脑脊髓炎(experimental autoimmuneencephalomyelitis,EAE)研究以评价目标化合物对EAE所诱导的麻痹(paralysis)的作用。啮齿类动物EAE是多发性硬化(multiple sclerosis,MS)的实验性模型,其已经广泛地用于临床前测试用于治疗复发性和进行性MS的多种药剂。该模型的标志是可靠的发病、强大的进展、可容易地测量的尾和四肢的麻痹、神经元的炎症、响应于神经抗原的显著脱髓鞘。
在本研究的第0天,用异氟烷麻醉雌性啮齿类动物,在背部的两个位点注射含有1mg/mL神经元抗原(例如,髓鞘碱性蛋白、髓鞘少突胶质细胞糖蛋白、蛋白脂质蛋白)和4mg/mL结核分支杆菌(mycobacteriumtuberculosis)的弗氏不完全佐剂(Freund’s Incomplete Adjuvant)。从第0天直至研究结束,以有效剂量以皮下、腹膜内或经口方式每天给以目标化合物。每天观察麻痹的程度作为效力的度量。
(b)在饮食诱导的肥胖胰岛素抵抗的小鼠模型中评价目标化合物。
在胰岛素抵抗研究中,使用C57Bl/6来源的雄性小鼠(24±2g)。将小鼠置于高脂饮食(60%千卡来自脂肪)或对照饮食(10%千卡来自脂肪)中12~24周时间。12~24周之后,测量空腹血糖水平以确定胰岛素抵抗的程度。随后将动物随机分入治疗组。每天以有效剂量通过皮下、腹膜内或经口途径施用受试化合物或载剂,直到研究结束。所进行的测量包括空腹血糖、空腹胰岛素、游离脂肪酸、总胆固醇、对全身性葡萄糖激发(systemicglucose challenge)的响应、对全身性胰岛素激发(systemic insulinchallenge)的响应。在每个测量时间点,可应用非成对Student t检验以在治疗组和载剂组之间进行比较。P<0.05水平的差异被认为是统计学显著的。
(c)在皮肤炎症的动物模型中评价目标化合物
在皮肤炎症研究中,可使用多个物种,例如但不限于非人灵长类、小鼠、大鼠、兔等。将皮肤刺激物注射进入皮肤或局部应用。测量疹块·红斑反应(Wheal and flare reaction),以及从受影响的区域进行钻取活组织检查(punch biopsy)。使用免疫组织化学和免疫荧光来定义炎症的程度。每天以有效剂量通过皮下、腹膜内或经口途径施用受试化合物或载剂,直到研究结束。在每个测量时间点,可应用非成对Student t检验以在治疗组和载剂组之间进行比较。P<0.05水平的差异被认为是统计学显著的。
(d)动物皮肤炎症评价的结果
在皮肤炎症的鼠咪喹莫特模型中评价本发明的化合物。简单地说,从第0天起,每天用应用至剃毛的背部和耳部的5%咪喹莫特乳膏局部处理8~10周龄的雌性BALB/c小鼠。此外,从第0天开始,每天用3mg/kg化合物或玉米油:Solutol(70∶30)载剂经口治疗。从第3至第10天,使用卡尺测量对皮肤厚度和耳厚度进行评价。与载剂处理的对照相比,以化合物处理的动物具有显著降低的耳肿胀和皮肤厚度,表明化合物介导咪喹莫特所诱导之炎症的降低。
Claims (23)
1.具有下式的化合物:
或其可药用盐及其立体异构体,
其中
R1是选自以下的成员:羟基、C1-8烷基、C2-8烯基、C1-8烷氧基、C1-8烷氧基-C1-8烷基、C1-8卤烷基、C1-8羟基烷基、C3-8环烷基、C3-8环杂烷基、C3-8环烷基-C1-3烷基、C3-8环杂烷基-C1-3烷基、-NRaRb和RaRbN-C1-4烷基;其中Ra和Rb各自独立地选自H、C1-8烷基、C3-8环烷基、C1-8卤烷基、C3-8环杂烷基、C1-8烷氧基-C1-8烷基、一-或二-(C1-4烷基)氨基-C1-4烷基和C1-8羟基烷基,或者Ra和Rb与各自所连接的氮组合形成4至7元环,所述环任选地具有附加的O或N作为环成员并且任选地被1至4个选自羟基、卤素、C1-4烷基和C1-4卤烷基的取代基所取代;
R2是选自以下的成员:H、C1-8烷基、C2-8烯基;
或者任选地,R1和R2组合形成与吡咯烷酮环稠合的并且具有至少一个选自O、S和N的环顶角杂原子的4至6元环;
R3是选自以下成员:H、卤素、C1-4烷基、C2-6烯基、C3-6环烷基、C3-8环杂烷基、C3-8环烷基-C1-3烷基和C3-8环杂烷基-C1-3烷基;
R4是选自以下成员:H、卤素、C1-4烷基、C2-6烯基、C1-4羟基烷基、C1-4烷氧基、C1-4烷氧基-C1-4烷基、C1-6卤烷基和一-或二-(C1-4烷基)氨基;
R5是选自以下成员:CF3、卤素、氰基、C1-4烷基、C2-6烯基、C1-4羟基烷基、C1-5烷氧基、C1-4烷氧基-C1-4烷基、C1-4烷氧基-C1-4烷氧基、C3-8环烷基、C3-8环烷基氧基、C3-8环杂烷基、C3-8环杂烷基-C1-3烷基和一-或二-(C1-4烷基)氨基;
R6是选自以下的成员:氢、卤素、氰基、C1-4烷基、C1-4卤烷基、C2-6烯基、C1-4羟基烷基、C1-5烷氧基、C1-4烷氧基-C1-4烷基、C1-4烷氧基-C1-4烷氧基、C3-8环烷基、C3-8环烷基氧基、C3-8环杂烷基、C3-8环杂烷基-C1-3烷基和一-或二-(C1-4烷基)氨基;
其中烷基、芳基和杂芳基为指定基团的未取代的形式,以下情况除外
其中R1、R2、R3、R4、R5和R6的任何环部分,包括任选的稠合环,任选地被1至3个取代基所取代,所述取代基独立地选自卤素、C1-4烷基、苄基、氧代和C1-6烷氧基羰基,并且任何环烷基和环杂烷基部分任选地具有环顶点之间的双键。
2.权利要求1的化合物,其中R3是甲基。
3.权利要求1的化合物,其中R3是甲基,并且R4是H或C1-4烷基。
4.权利要求1的化合物,其中R2是H或C1-8烷基,R3是甲基,并且R4是H或C1-4烷基。
5.权利要求1的化合物,其中R5是CF3。
6.权利要求1的化合物,其中R3是甲基,并且R5是CF3。
7.权利要求1的化合物,其具有下式:
8.权利要求7的化合物,其中R1选自-NRaRb和RaRbN-C1-4烷基。
9.权利要求8的化合物,其中R1是RaRbN-C1-4烷基。
10.权利要求8的化合物,其中R1是-NRaRb。
11.权利要求7的化合物,其中R3和R4分别是甲基。
12.权利要求11的化合物,其中R5选自CF3、CN和环丙基。
13.权利要求7的化合物,其中R1是一-或二-(C1-4烷基)氨基-C1-4烷基,并且R3是甲基。
14.权利要求13的化合物,其中R1是二(C1-4烷基)氨基甲基。
15.权利要求7的化合物,其中R2和R3分别是甲基。
16.权利要求1的化合物,其具有下式:
17.权利要求16的化合物,其中R2是H,并且R3和R4分别是甲基。
18.权利要求17的化合物,其中R5是CF3。
19.选自以下的化合物:
20.药物组合物,其包含权利要求1的化合物和可药用赋形剂。
21.权利要求20的药物组合物,其中所述化合物是选自以下的化合物:
22.权利要求1的化合物在制备治疗哺乳动物中疾病或病症的药物中的用途,所述疾病或病症选自炎性病症以及神经、皮肤或代谢细胞病症。
23.权利要求22的用途,其中所述化合物是选自以下的化合物:
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Families Citing this family (19)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ES2558629T3 (es) | 2008-12-29 | 2016-02-05 | Trevena, Inc. | Efectores de beta-arrestina y composiciones y métodos de uso de los mismos |
EP3815685A3 (en) * | 2011-10-31 | 2021-10-13 | The Methodist Hospital Research Institute | Compound comprising a mao targeting/seeker moiety for treating human gliomas |
WO2013116312A1 (en) | 2012-01-31 | 2013-08-08 | Trevena, Inc. | ß-ARRESTIN EFFECTORS AND COMPOSITIONS AND METHODS OF USE THEREOF |
DE102012017739A1 (de) * | 2012-09-07 | 2014-03-13 | Clariant International Ltd. | Verfahren zur Herstellung von N-substituierten Pyrrolidoncarbonsäureestern |
TWI507873B (zh) | 2013-07-29 | 2015-11-11 | Hon Hai Prec Ind Co Ltd | 電源適配器及電子裝置 |
US9518086B2 (en) | 2014-02-07 | 2016-12-13 | Trevena, Inc. | Crystalline and amorphous forms of a β-arrestin effector |
WO2015179349A2 (en) | 2014-05-19 | 2015-11-26 | Trevena, Inc. | Synthesis of beta-arrestin effectors |
KR101503647B1 (ko) * | 2014-07-03 | 2015-03-18 | 주식회사 큐리언트 | 염증성 질환 치료용 약학적 조성물 |
ES2820073T3 (es) | 2014-12-22 | 2021-04-19 | Basf Se | Refuerzo de fibra de espumas que contienen agentes expansores |
US20170361545A1 (en) | 2014-12-22 | 2017-12-21 | Basf Se | Fiber-reinforcement of foam materials, consisting of interconnected segments |
CN109196031B (zh) | 2016-05-25 | 2022-01-28 | 巴斯夫欧洲公司 | 通过模塑发泡法制得的纤维增强的反应性泡沫 |
JP7034099B2 (ja) | 2016-05-25 | 2022-03-11 | ビーエーエスエフ ソシエタス・ヨーロピア | ダブルストリップ発泡法またはブロック発泡法により得られる反応性発泡体材料の繊維強化 |
CN106831787B (zh) | 2017-01-20 | 2018-10-23 | 成都倍特药业有限公司 | 用作布鲁顿酪氨酸激酶抑制剂的化合物及其制备方法和应用 |
WO2019119307A1 (zh) * | 2017-12-20 | 2019-06-27 | 深圳先进技术研究院 | 一种cmklr1拮抗多肽及其衍生物与应用 |
JP7396682B2 (ja) | 2018-06-29 | 2023-12-12 | エルゴン ファーマシューティカルズ エルエルシー | イタコン酸誘導体の組成物及び使用方法 |
US11034669B2 (en) | 2018-11-30 | 2021-06-15 | Nuvation Bio Inc. | Pyrrole and pyrazole compounds and methods of use thereof |
US11730705B2 (en) | 2019-05-02 | 2023-08-22 | The Board Of Trustees Of The Leland Stanford Junior University | Small molecule CMKLR1 antagonists in inflammatory disease |
US11872217B2 (en) | 2019-07-10 | 2024-01-16 | Chemocentryx, Inc. | Indanes as PD-L1 inhibitors |
WO2022268520A1 (de) | 2021-06-21 | 2022-12-29 | Bayer Aktiengesellschaft | Verwendung von substituierten pyrrolidinonen oder deren salzen zur steigerung der stresstoleranz in pflanzen. |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1610678A (zh) * | 2001-12-31 | 2005-04-27 | 埃科特莱茵药品预先公司 | 吡咯烷酮羧酰胺 |
Family Cites Families (30)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4166452A (en) | 1976-05-03 | 1979-09-04 | Generales Constantine D J Jr | Apparatus for testing human responses to stimuli |
US4256108A (en) | 1977-04-07 | 1981-03-17 | Alza Corporation | Microporous-semipermeable laminated osmotic system |
US4265874A (en) | 1980-04-25 | 1981-05-05 | Alza Corporation | Method of delivering drug with aid of effervescent activity generated in environment of use |
US6093737A (en) * | 1996-12-30 | 2000-07-25 | Merck & Co., Inc. | Inhibitors of farnesyl-protein transferase |
EP1087937A1 (en) * | 1998-06-17 | 2001-04-04 | Du Pont Pharmaceuticals Company | Cyclic hydroxamic acids as metalloproteinase inhibitors |
US6294192B1 (en) | 1999-02-26 | 2001-09-25 | Lipocine, Inc. | Triglyceride-free compositions and methods for improved delivery of hydrophobic therapeutic agents |
IL158491A0 (en) * | 2001-04-19 | 2004-05-12 | Eisai Co Ltd | 2-iminopyrrolidine derivatives |
US6861529B2 (en) * | 2001-07-06 | 2005-03-01 | Pfizer Inc | Cycloalkypyrrole-3-carboxylic acid derivatives and heterocycloalkylpyrrole-3-carboxylic acid derivatives |
WO2003053941A2 (en) * | 2001-12-20 | 2003-07-03 | Bristol-Myers Squibb Company | Barbituric acid derivatives as inhibitors of tnf-alpha converting enzyme (tace) and/or matrix metalloproteinases |
US7067549B2 (en) | 2001-12-31 | 2006-06-27 | Actelion Pharmaceuticals Ag | Pyrrolidone carboxamides |
GB0203104D0 (en) | 2002-02-11 | 2002-03-27 | Ici Plc | Surfactants and surfactant compositions |
US7087631B2 (en) * | 2002-07-18 | 2006-08-08 | Inotek Pharmaceuticals Corporation | Aryltetrazole compounds, and compositions thereof |
US7078423B2 (en) * | 2002-07-18 | 2006-07-18 | Inotek Pharmaceuticals Corporation | 5-Aryltetrazole compounds, compositions thereof, and uses therefor |
US7205318B2 (en) * | 2003-03-18 | 2007-04-17 | Bristol-Myers Squibb Company | Lactam-containing cyclic diamines and derivatives as a factor Xa inhibitors |
WO2005000793A1 (ja) | 2003-06-26 | 2005-01-06 | Taisho Pharmaceutical Co., Ltd. | 2位置換シクロアルキルカルボン酸誘導体 |
WO2005032490A2 (en) * | 2003-10-08 | 2005-04-14 | Bristol-Myers Squibb Company | Cyclic diamines and derivatives as factor xa inhibitors |
DE10348022A1 (de) * | 2003-10-15 | 2005-05-25 | Imtm Gmbh | Neue Dipeptidylpeptidase IV-Inhibitoren zur funktionellen Beeinflussung unterschiedlicher Zellen und zur Behandlung immunologischer, entzündlicher, neuronaler und anderer Erkrankungen |
DE102004047840A1 (de) * | 2004-09-29 | 2006-03-30 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Neue substituierte Thiophencarbonsäureamide, deren Herstellung und deren Verwendung als Arzneimittel |
EP1824843A2 (en) * | 2004-12-07 | 2007-08-29 | Locus Pharmaceuticals, Inc. | Inhibitors of protein kinases |
JO2787B1 (en) * | 2005-04-27 | 2014-03-15 | امجين إنك, | Alternative amide derivatives and methods of use |
WO2008029152A2 (en) | 2006-09-08 | 2008-03-13 | Summit Corporation Plc | Treatment of duchenne muscular dystrophy |
WO2008124085A2 (en) | 2007-04-03 | 2008-10-16 | Exelixis, Inc. | Methods of using combinations of mek and jak-2 inhibitors |
TW201242961A (en) * | 2007-06-20 | 2012-11-01 | Ironwood Pharmaceuticals Inc | FAAH inhibitors |
US20090053192A1 (en) * | 2007-08-10 | 2009-02-26 | Burnham Institute For Medical Research | Tissue-nonspecific alkaline phosphatase (tnap) activators and uses thereof |
US7994174B2 (en) * | 2007-09-19 | 2011-08-09 | Vertex Pharmaceuticals Incorporated | Pyridyl sulfonamides as modulators of ion channels |
RU2549895C2 (ru) * | 2007-10-05 | 2015-05-10 | Сенхва Байосайенсиз,Инк. | Аналоги хинолона и относящиеся к ним способы |
EP2219646A4 (en) | 2007-12-21 | 2010-12-22 | Univ Rochester | METHOD FOR MODIFYING THE LIFETIME OF EUKARYOTIC ORGANISMS |
CA2723617A1 (en) | 2008-05-14 | 2009-11-19 | Amgen Inc. | Combinations vegf(r) inhibitors and hepatocyte growth factor (c-met) inhibitors for the treatment of cancer |
TW201011009A (en) * | 2008-09-15 | 2010-03-16 | Priaxon Ag | Novel pyrrolidin-2-ones |
CA2735719C (en) | 2008-09-16 | 2017-08-29 | The Lubrizol Corporation | Engine lubricants comprising furan esters |
-
2010
- 2010-09-21 ES ES10757922.9T patent/ES2528948T3/es active Active
- 2010-09-21 CN CN201080047867.2A patent/CN102574789B/zh active Active
- 2010-09-21 WO PCT/US2010/049718 patent/WO2011035332A1/en active Application Filing
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Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1610678A (zh) * | 2001-12-31 | 2005-04-27 | 埃科特莱茵药品预先公司 | 吡咯烷酮羧酰胺 |
Non-Patent Citations (2)
Title |
---|
Pyrrolidine Carboxamides as a Novel Class of Inhibitors of Enoyl Acyl Carrier Protein Reductase from Mycobacterium tuberculosis;Xin He et al.;《Journal of Medicinal Chemistry》;20060927;第49卷(第21期);6308-6323页 * |
Xin He et al..Pyrrolidine Carboxamides as a Novel Class of Inhibitors of Enoyl Acyl Carrier Protein Reductase from Mycobacterium tuberculosis.《Journal of Medicinal Chemistry》.2006,第49卷(第21期),6308-6323页. * |
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CN102574789A (zh) | 2012-07-11 |
US8293925B2 (en) | 2012-10-23 |
US20110082172A1 (en) | 2011-04-07 |
US8716494B2 (en) | 2014-05-06 |
EP2480531A1 (en) | 2012-08-01 |
ES2528948T3 (es) | 2015-02-13 |
WO2011035332A1 (en) | 2011-03-24 |
US20130237514A1 (en) | 2013-09-12 |
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