CN1842521B - 含异噁唑啉环的胱天蛋白酶抑制物 - Google Patents
含异噁唑啉环的胱天蛋白酶抑制物 Download PDFInfo
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- CN1842521B CN1842521B CN2004800247028A CN200480024702A CN1842521B CN 1842521 B CN1842521 B CN 1842521B CN 2004800247028 A CN2004800247028 A CN 2004800247028A CN 200480024702 A CN200480024702 A CN 200480024702A CN 1842521 B CN1842521 B CN 1842521B
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Abstract
本发明涉及作为针对多种胱天蛋白酶的抑制物的异噁唑啉衍生物、制备它的方法、以及包含它且用于预防炎症和凋亡的治疗性组合物。
Description
技术领域
本发明涉及作为针对多种胱天蛋白酶的抑制物的异噁唑啉衍生物、制备它的方法、以及包含它且用于预防炎症和凋亡的治疗性组合物,其中所述胱天蛋白酶包括胱天蛋白酶-1[白介素-1β转化酶,ICE]和胱天蛋白酶-3[凋亡酶/CPP-32]。
背景技术
胱天蛋白酶是最近十年间发现的α2β2形式的一类新型半胱氨酸蛋白酶。至尽已经发现了大约14类胱天蛋白酶。其中之一,胱天蛋白酶-1(ICE)是一类细胞因子,参与将无活性的白介素原-1β转变成有活性的白介素-1β。白介素-1由白介素-1α和白介素-1β组成,二者都是在单核细胞中以31kDa的前体的形式合成的。只有白介素原-1β被ICE激活。被胱天蛋白酶-1水解的位置是Asp27-Gly28和Asp116-Ala117。后一个位置的水解产生白介素-1β。已有报道,白介素-1β在引起发炎中担当重要介体(1,3)。胱天蛋白酶-1在1989年首次发现,而且是由两个独立的研究小组发现的,已经通过X射线晶体学方法测定了它的三维结构。
胱天蛋白酶-3(CPP-32)的作用或作用机制得到广泛研究,而且在1996年已经测定了它的三维结构(2)。由胱天蛋白酶原-3激活得到的胱天蛋白酶-3(凋亡酶)水解(P4)Asp-X-X-Asp(P1)基序,已知的底物包括多(ADP-核糖)聚合酶、U1 70,000Mr小核内核糖核蛋白、460,000Mr DNA依赖性蛋白激酶的催化亚基等。已有报道,胱天蛋白酶-7的X射线结构与胱天蛋白酶-3非常相似(4)。
胱天蛋白酶-8和9存在于胱天蛋白酶-3、6、7的上游,而且已知这些胱天蛋白酶参与凋亡级联反应。已经在1999年测定了胱天蛋白酶-8的X射线结构(5),特别是,它的抑制物可有利地用于治疗凋亡相关疾病。
胱天蛋白酶抑制物指抑制胱天蛋白酶活性从而控制由胱天蛋白酶活性引起的诸如炎症、凋亡等症状的那些化合物。可以通过施用抑制物来治疗或削弱的疾病或症状包括:类风湿性关节炎、炎性肠病、移植物抗宿主疾病、败血症、骨关节炎、骨质疏松、急性和慢性髓细胞性白血病、脑膜炎、输卵管炎、感染性休克、胆管炎、结肠炎、脑炎、心内膜炎、肾小球肾炎、肝炎、心肌炎、胰腺炎、I型糖尿病、多发性硬化症、阿尔茨海默病、帕金森病、肝硬化(6)。
在至今已知的胱天蛋白酶抑制物中,最著名的不可逆抑制物是:
上面两种抑制物通过相同的机制来展示它们的活性,即它们不可逆的灭活酶从而抑制细胞凋亡(不可逆的广谱抑制物)。已有报道,在比较不可逆与可逆抑制物时,不可逆抑制物具有有效得多的抑制活性(7)。据报道,IDUN公司的IDN-1965和Maxim公司的MX-1013在肝损伤的细胞凋亡模型中都显示活性(8,9)。这些化合物目前处于临床前测试阶段。其结构最近被报道的不可逆抑制物IDN-6556作为肝损伤的治疗剂目前处于II期临床测试阶段(10,11)。
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发明公开
本发明人最近设计并合成了一些化合物,它们可用作胱天蛋白酶的有效抑制剂且具有独特的结构和针对类似酶的高度选择性,并测定了它们对胱天蛋白酶的结合能力和抑制活性。结果是,发明人发现符合如下通式(1)的化合物确实达到了这些要求,并且完成了本发明。
其中
A、B、R、R1、R2、和X的定义与下文所述相同。
因此,本发明提供了具有针对胱天蛋白酶的有效抑制活性的符合通式(1)的新型异噁唑啉衍生物、其盐或立体异构体。
本发明的另一个目的是提供制备符合通式(1)的化合物、其盐或立体异构体的方法。
本发明的还有一个目的是提供用于抑制胱天蛋白酶的组合物、用途、或方法,具体而言就是包含符合通式(1)的化合物、其盐或立体异构体作为活性成分以及制药学可接受载体且用于预防炎症和凋亡的治疗性组合物、用途、或方法。
附图简述
图1显示了化合物(Iii)对由胆汁停滞引起的肝纤维化的抑制活性:图1中的“a)”描绘了假手术的情况,“b)”描绘了结扎胆管后只施用载体的BDL手术的情况,“c)”描绘了结扎胆管1周后每天两次以3mg/kg的剂量口服施用化合物(Iii)达1周的情况,而“d)”描绘了结扎胆管1周后每天两次以10mg/kg的剂量口服施用化合物(Iii)达1周的情况。
图2显示了化合物(Iii)对由胆汁停滞引起的肝细胞凋亡的抑制活性:图2中的“a)”描绘了假手术的情况,“b)”描绘了结扎胆管后只施用载体的BDL手术的情况,“c)”描绘了结扎胆管1周后每天两次以3mg/kg的剂量口服施用化合物(Iii)达1周的情况,“d)”描绘了结扎胆管1周后每天两次以10mg/kg的剂量口服施用化合物(Iii)达1周的情况,而图“e)”显示了每个处理组中进行凋亡的肝细胞数目。
实施本发明的最佳方式
在详细阐述本发明之前,先定义下列重要术语:
a)简单烷基链(下文缩写为SAC)指线性或支化异构体形式的具有1-8个碳原子的烃。
b)简单环烷基链(下文缩写为SCAC)指具有3-10个碳原子的环状基团。
c)芳基(下文缩写为Ar)包括芳香基和杂环芳香基二者。芳香基指5至15元单个或稠的不饱和环。一个或多个氢可以用选自下列的基团取代:酰基、氨基、烷氧羰基、羧基、羧基氨基、氰基、卤素、羟基、硝基、巯基、烷基、环烷基、烷氧基、芳氧基、亚硫酰基(sulfoxy)、和胍基。杂环芳香基指含有1-5个选自下组的杂原子的芳香基:氧、硫、和氮。同样的,一个或多个氢可以用选自下列的基团取代:酰基、氨基、烷氧羰基、羧基、羧基氨基、氰基、卤素、羟基、硝基、巯基、烷基、环烷基、烷氧基、芳基、芳氧基、亚硫酰基(sulfoxy)、和胍基。或者,例如,在吡啶基的情况中,可以向氮原子添加烷基而将吡啶基转变成在氮原子处具有(+)电荷的吡啶鎓基团。
芳基包括苯基、联苯基、1-萘基、2-萘基、吡啶基、N-烷基-吡啶鎓、嘧啶基、喹啉基、苯并噻吩基、吲哚基、吡嗪基、异吲哚基、异喹啉基、喹唑啉基(qunazolinyl)、喹喔啉基、酞嗪基、咪唑啉基、异噁唑基、吡唑基、噁唑基、噻唑基、中氮茚基、吲唑基、苯并噻唑基、苯并咪唑基、苯并呋喃基、噻吩基、吡咯基、噁二唑基、噻二唑基、三唑基、四唑基、噁唑并吡啶基(oxazolopyridinyl)、咪唑并吡啶基、异噻唑基、肉啉基、咔唑基、异苯并二氢吡喃基、苯并二氢吡喃基、四氢异喹啉基、异吲哚啉基、异苯并四氢呋喃基、异苯并四氢噻吩基、异苯并噻吩基、苯并噁唑基、吡啶并吡啶基、苯并四氢呋喃基、苯并四氢噻吩基、嘌呤基、苯并间二氧杂环戊烯基(benzodioxolyl)、三嗪基、吩噁嗪基、吩噻嗪基、蝶啶基、苯并噻唑基、咪唑并吡啶基、咪唑并噻唑基、二氢苯并异噁嗪基、苯并异噁嗪基、苯并噁嗪基、二氢苯并异噻喃基、苯并吡喃基、苯并噻喃基、香豆素基、异香豆素基、色酮基、苯并二氢吡喃-4-酮基、吡啶基-N-氧化物、四氢喹啉基-N-氧化物、二氢喹啉基、二氢喹啉酮基(dihydroquinolinonyl)、二氢异喹啉酮基(dihydroisoquinolinonyl)、二氢香豆素基、二氢异香豆素基、异吲哚满酮基、苯并二噁烷基、苯并噁唑啉酮基(benzoxazolinonyl)、N-烷基-吡啶鎓、吡咯基-N-氧化物、嘧啶基-N-氧化物、吡嗪基-N-氧化物、喹啉基-N-氧化物、吲哚基-N-氧化物、吲哚啉基-N-氧化物、异喹啉基-N-氧化物、喹唑啉基-N-氧化物、喹喔啉基-N-氧化物、酞嗪基-N-氧化物、咪唑啉基-N-氧化物、异噁唑基-N-氧化物、噁唑基-N-氧化物、噻唑基-N-氧化物、中氮茚基-N-氧化物、吲唑基-N-氧化物、苯并噻唑基-N-氧化物、苯并咪唑基-N-氧化物、吡咯基-N-氧化物、噁二唑基-N-氧化物、噻二唑基-N-氧化物、三唑基-N-氧化物、四唑基-N-氧化物等。
d)用芳基取代的简单烷基链(下文缩写为SAC-Ar)指具有1-8个碳原子且用上文所述芳基取代的直链或支化的烷基。
e)天然氨基酸包括:甘氨酸、丙氨酸、缬氨酸、亮氨酸、异亮氨酸、丝氨酸、苏氨酸、半胱氨酸、甲硫氨酸、脯氨酸、天冬氨酸、天冬酰胺、谷氨酸、谷氨酰胺、赖氨酸、精氨酸、组氨酸、苯丙氨酸、酪氨酸、和色氨酸。
f)简单酯的保护基团指线性或支化异构体形式的具有1-8个碳原子的烃。
另外,本说明书还包括下列缩写:
N-氯琥珀酰亚胺:NCS
N-甲基吗啉:NMM
O-(7-氮杂苯并三唑-1-基)-N,N,N′,N′-四甲基脲鎓(tetramethyluronium)六氟磷酸盐:HATU
N,N-二甲基甲酰胺:DMF
1-(3-二甲基氨基丙基)-3-乙基碳二亚胺:EDC
1-羟基苯并三唑水合物:HOBt
三氟乙酸:TFA
叔丁氧基羰基:Boc
苄氧基羰基:Cbz
甲基:Me
乙基:Et
当量:Eq
上文通式(1)中所包含的取代基明确定义如下:
I)R代表H、简单烷基链(-SAC)、简单环烷基链(-SCAC)、芳基(-Ar)、或用芳基取代的简单烷基链(-SAC-Ar),
II)R1代表-SAC、-SCAC、-Ar、-SAC-Ar、或所有天然氨基酸的侧链残基;且当R1所附着的碳由于R1基团而变成立构中心时,符合通式(1)的化合物可以以特定非对映形或其混合物存在;或者,当R1是含羧基部分的氨基酸的侧链残基时,符合通式(1)的化合物可以具有酯形式(-CO2R3,其中R3是-SAC)或磺酰胺形式(-CONHSO2R4,其中R4是-SAC)的保护基团,或可以以制药学可接受盐的形式存在;或者,当R1是含碱部分的氨基酸的侧链残基时,符合通式(1)的化合物也可以以制药学可接受盐的形式存在,
III)R2代表-SAC、-SCAC、-Ar、-SAC-Ar、或天然氨基酸的侧链残基;且当R2所附着的碳由于R2基团而变成立构中心时,符合通式(1)的化合物可以以特定非对映形或其混合物存在;当R2是含羧基部分的氨基酸的侧链残基时,符合通式(1)的化合物可以具有酯形式(-CO2R5,其中R5是-SAC)或磺酰胺形式(-CONHSO2R6,其中R6是-SAC)的保护基团,或可以以制药学可接受盐的形式存在;或者,当R2是含碱部分的氨基酸的侧链残基时,符合通式(1)的化合物也可以以制药学可接受盐的形式存在,或者R2进一步代表H;-(CH2)nOR7,其中R7是-SAC、-SCAC、-Ar、或-SAC-Ar,且n=1或2;或-(CH2)nOC(=O)R8,其中R8是-SAC、-SCAC、-Ar 、或-SAC-Ar,且n=1或2,
IV)A代表-(CH2)n-(n=0-4)、-O-(CH2)n-(n=0-4)、或-NR9-(CH2)n-(n=0-4),其中R9是-SAC、-SCAC、-Ar、或-SAC-Ar,
V)B代表H、-SAC、-SCAC、-Ar、或-SAC-Ar,或者
VI)R和R1可以与它们所附着的碳原子一起形成环,其中-R-R1-是-(CH2)n-、-(CH2)n-O-(CH2)m-、或-(CH2)n-NR10-(CH2)m-,其中n+m<9且R10是-SAC、-SCAC、-Ar、-SAC-Ar、-C(=O)-SAC、-C(=O)-SCAC、-C(=O)-Ar、或-C(=O)-SAC-Ar,
VII)X代表-C(=O)CH2OR11,其中R11是-SAC、-SCAC、-Ar、或-SAC-Ar;-C(=O)CH2OC(=O)R12,其中R12是-SAC、-SCAC、-Ar、或-SAC-Ar;-CH=CH-CO2R13,其中R13是-SAC、-SCAC、-Ar、或-SAC-Ar;-CH=CH-SO2R14,其中R14是-SAC、-SCAC、-Ar、或-SAC-Ar;-C(=O)CH-CH2;或-COCH2-W,其中W是-N2、-F、-Cl、-Br、-I、-NR15R16(R15和R16各自是-SAC、-SCAC、-Ar、或-SAC-Ar,或者可以一起形成3至6元饱和或不饱和环状基团)、-SR17(R17是-SAC、-SCAC、-Ar、或-SAC-Ar),或是下列通式:
其中
Y是H、-OH、-OR18(R18=-SAC或-SCAC)、-C(=O)R19(R19=-H、-SAC、或-SCAC)、-F、-Cl、-Br、-I、-CN、-NC、-N3、-CO2H、-CF3、-CO2R20(R20=-SAC或-SCAC)、-C(=O)NHR21(R21=-SAC或-SCAC)、或-C(=O)NR22R23(R22和R23各自是-SAC、-SCAC、-Ar、或-SAC-Ar),
R24是H、-SAC、-SAC-Ar、或-Ar。
在上文符合通式(1)的化合物的优选化合物中:
R代表H;
R1代表-CH2COOH、-CH2COOR3(R3=SAC)、或-CH2CONHSO2R4(R4=SAC);
R2代表H、-SAC、-Ar、或-(CH2)nOR7(R7=-SAC、-SCAC、-Ar、或-SAC-Ar,且n=1或2);或者
X代表-C(=O)CH2OAr、-C(=O)CH2OC(=O)Ar、或-COCH2-W,其中W是-N2、-F、-Cl、-Br、-I、-NR15R16(R15和R16各自是-SAC、-SCAC、-Ar、或-SAC-Ar,或者可以一起形成3至6元饱和或不饱和环状基团)、或-SR17(R17是-SAC、-SCAC、-Ar、或-SAC-Ar)。
在上文符合通式(1)的化合物的更加优选的化合物中:
I)R代表H,
II)R1代表-CH2COOH、-CH2COOR3(R3=SAC)、或-CH2CONHSO2R4(R4=SAC),
III)R2代表H、-SAC、-Ar、或-(CH2)nOR7(R7=-SAC、-SCAC、-Ar、或-SAC-Ar,且n=1或2),
IV)A代表-(CH2)n-(n=0-4)或-O-(CH2)n-(n=0-4),
V)B代表H、-SAC、-SCAC、-Ar、或-SAC-Ar,
VI)X代表-COCH2N2、-COCH2F、-COCH2Cl、-COCH2Br、-COCH2I、-COCH2OAr、-COCH2OCOAr、或-COCH2SR17(R17是-SAC、-SCAC、-Ar、或-SAC-Ar)。
特别优选的化合物选自下组:
(1)(3S)-5-[(2,6-二氯苯甲酰)氧基]-3-({[5-甲基-3-苯基-4,5-二氢-5-异噁唑基]羰基}氨基)-4-氧戊酸(Iaa);
(2)(3S)-3-({[5-甲基-3-苯基-4,5-二氢-5-异噁唑基]羰基}氨基)-4-氧-5-苯氧基戊酸(Ibb);
(3)(3S)-3-({[5-乙基-3-苯基-4,5-二氢-5-异噁唑基]羰基}氨基)-4-氧-5-(2,3,5,6-四氟苯氧基)戊酸(Icc);
(4)(3S)-3-({[5-乙基-3-(1-萘基)-4,5-二氢-5-异噁唑基]羰基}氨基)-4-氧-5-(2,3,5,6-四氟苯氧基)戊酸(Idd);
(5)(3S)-3-({[5-乙基-3-(2-萘基)-4,5-二氢-5-异噁唑基]羰基}氨基)-4-氧-5-(2,3,5,6-四氟苯氧基)戊酸(Iee);
(6)(3S)-3-({[5-乙基-3-(1-异喹啉基)-4,5-二氢-5-异噁唑基]羰基}氨基)-4-氧-5-(2,3,5,6-四氟苯氧基)戊酸(Iff);
(7)3-({[5-乙基-3-(1-异喹啉基)-4,5-二氢-5-异噁唑基]羰基}氨基)-5-氟-4-氧戊酸(Igg);
(8)3-({[5-乙基-3-(1-异喹啉基)-4,5-二氢-5-异噁唑基]羰基}氨基)-5-氟-4-氧戊酸乙酯(Ihh);
(9)5-氟-3-({[(5R)-5-异丙基-3-(1-异喹啉基)-4,5-二氢-5-异噁唑基]羰基}氨基)-4-氧戊酸(Iii);
(10)3-({[5-乙基-3-(4-喹啉基)-4,5-二氢-5-异噁唑基]羰基}氨基)-5-氟-4-氧戊酸(Ijj);
(11)3-({[3-(苯并噻吩-2-基)-5-乙基-4,5-二氢-5-异噁唑基]羰基}氨基)-5-氟-4-氧戊酸(Ikk);
(12)(3S)-3-({[3-(1,3-二甲基-1H-吲哚-2-基)-5-乙基-4,5-二氢-5-异噁唑基]羰基}氨基)-4-氧-5-(2,3,5,6-四氟苯氧基)戊酸(Ill);
(13)3-({[3-(1,3-二甲基-1H-吲哚-2-基)-5-乙基-4,5-二氢-5-异噁唑基]羰基}氨基)-5-氟-4-氧戊酸(Imm);
(14)(3S)-3-({[5-乙基-3-(1-萘基甲基)-4,5-二氢-5-异噁唑基]羰基}氨基)-4-氧-5-(2,3,5,6-四氟苯氧基)戊酸(Inn);
(15)(3S)-5-[(2,6-二氯苯甲酰)氧基]-3-[({5-乙基-3-[2-(1-萘基)乙基]-4,5-二氢-5-异噁唑基}羰基)氨基]-4-氧戊酸(Ioo);
(16)(3S)-3-[({5-乙基-3-[(1-萘氧基)甲基]-4,5-二氢-5-异噁唑基}羰基)氨基]-4-氧-5-(2,3,5,6-四氟苯氧基)戊酸(Ipp);
(17)(3S)-3-{[(3-{[(4-氯-1-萘基)氧基]甲基}-5-乙基-4,5-二氢-5-异噁唑基)羰基]氨基}-4-氧-5-(2,3,5,6-四氟苯氧基)戊酸(Iqq);
(18)(3S,4E)-6-乙氧基-3-({[(5R)-5-异丙基-3-(1-异喹啉基)-4,5-二氢-5-异噁唑基]羰基)氨基)-6-氧-4-己烯酸(Irr);
(19)(3S,4E)-3-({[(5R)-5-异丙基-3-(1-异喹啉基)-4,5-二氢-5-异噁唑基]羰基}氨基)-5-(甲磺酰基)-4-戊烯酸(Iss);
(20)5-氟-3-({[(5S)-3-(1-异喹啉基)-5-丙基-4,5-二氢-5-异噁唑基]羰基}氨基)-4-氧戊酸(Itt);
(21)3-({[(5S)-5-乙基-3-(1-萘基)-4,5-二氢-5-异噁唑基]羰基}氨基)-5-氟-4-氧戊酸(Iuu);
(22)3-({[(5S)-5-乙基-3-(2-喹啉基)-4,5-二氢-5-异噁唑基]羰基}氨基)-5-氟-4-氧戊酸(Ivv);
(23)3-({[(5R)-5-乙基-3-(3-异喹啉基)-4,5-二氢-5-异噁唑基]羰基}氨基)-5-氟-4-氧戊酸(Iww);
(24)3-({[5-乙基-3-(8-喹啉基)-4,5-二氢-5-异噁唑基]羰基}氨基)-5-氟-4-氧戊酸(Ixx);
(25)3-({[5-乙基-3-(3-喹啉基)-4,5-二氢-5-异噁唑基]羰基}氨基)-5-氟-4-氧戊酸(Iyy);
(26)5-氟-3-({[(5R)-5-异丙基-3-(2-喹啉基)-4,5-二氢-5-异噁唑基]羰基}氨基)-4-氧戊酸(Izz);
(27)3-({[5-乙基-3-(2-异丙基苯基)-4,5-二氢-5-异噁唑基]羰基}氨基)-5-氟-4-氧戊酸(Iaa1);
(28)3-[({3-[3-(叔丁基)苯基]-5-乙基-4,5-二氢-5-异噁唑基}羰基)氨基]-5-氟-4-氧戊酸(Iaa2);
(29)3-[({3-[4-(叔丁基)苯基]-5-乙基-4,5-二氢-5-异噁唑基}羰基)氨基]-5-氟-4-氧戊酸(Iaa3);
(30)5-氟-3-({[(5R)-5-异丙基-3-(2-异丙基苯基)-4,5-二氢-5-异噁唑基]羰基}氨基)-4-氧戊酸(Iaa4);
(31)3-[({(5R)-3-[3-(叔丁基)苯基]-5-异丙基-4,5-二氢-5-异噁唑基}羰基)氨基]-5-氟-4-氧戊酸(Iaa5);
(32)3-{[(3-[1,1′-联苯]-3-基-5-异丙基-4,5-二氢-5-异噁唑基)羰基]氨基}-5-氟-4-氧戊酸(Iaa6);
(33)3-({[5-乙基-3-(2-吡啶基)-4,5-二氢-5-异噁唑基]羰基}氨基)-5-氟-4-氧戊酸(Iaa7);
(34)3-[({3-[4-(叔丁基)-2-吡啶基]-5-乙基-4,5-二氢-5-异噁唑基}羰基)氨基]-5-氟-4-氧戊酸(Iaa8);
(35)3-[({(5R)-3-[4-(叔丁基)-2-吡啶基]-5-异丙基-4,5-二氢-5-异噁唑基}羰基)氨基]-5-氟-4-氧戊酸(Iaa9);
(36)3-({[5-乙基-3-(4-异丁基-2-吡啶基)-4,5-二氢-5-异噁唑基]羰基}氨基)-5-氟-4-氧戊酸(Iaa10);
(37)3-({[3-(4-乙酰基-2-吡啶基)-5-乙基-4,5-二氢-5-异噁唑基]羰基}氨基)-5-氟-4-氧戊酸(Iaa11);
(38)3-({[3-(4-环丙基-2-吡啶基)-5-乙基-4,5-二氢-5-异噁唑基]羰基}氨基)-5-氟-4-氧戊酸(Iaa12);
(39)3-({[3-(4-环戊基-2-吡啶基)-5-乙基-4,5-二氢-5-异噁唑基]羰基}氨基)-5-氟-4-氧戊酸(Iaa13);
(40)3-({[(5R)-3-(4-环戊基-2-吡啶基)-5-异丙基-4,5-二氢-5-异噁唑基]羰基}氨基)-5-氟-4-氧戊酸(Iaa14);
(41)3-({[3-(4-环己基-2-吡啶基)-5-乙基-4,5-二氢-5-异噁唑基]羰基}氨基)-5-氟-4-氧戊酸(Iaa15);
(42)3-({[5-乙基-3-(5,6,7,8-四氢-1-异喹啉基)-4,5-二氢-5-异噁唑基]羰基}氨基)-5-氟-4-氧戊酸(Iaa16);
(43)5-氟-3-({[5-异丙基-3-(4-苯基-2-吡啶基)-4,5-二氢-5-异噁唑基]羰基}氨基)-4-氧戊酸(Iaa17);
(44)(3S)-5-[(二苯基磷酰基)氧基]-3-({[(5R)-5-异丙基-3-(1-异喹啉基)-4,5-二氢-5-异噁唑基]羰基}氨基)-4-氧戊酸(Iaa18);
(45)(3S)-3-({[(5R)-5-异丙基-3-(1-异喹啉基)-4,5-二氢-5-异噁唑基]羰基}氨基)-4-氧-5-{[1-苯基-3-(三氟甲基)-1H-吡唑-5-基]氧基}戊酸(Iaa19);
(46)(3S)-5-[(4-苄基-5-氧-2,5-二氢-3-呋喃基)氧基-3-({[(5R)-5-异丙基-3-(1-异喹啉基)-4,5-二氢-5-异噁唑基]羰基}氨基)-4-氧戊酸(Iaa20);
(47)(3S)-5-(异丁酰氧基)-3-({[(5R)-5-异丙基-3-(1-异喹啉基)-4,5-二氢-5-异噁唑基]羰基}氨基)-4-氧戊酸(Iaa21);
(48)(3S)-3-({[(5R)-5-异丙基-3-(1-异喹啉基)-4,5-二氢-5-异噁唑基]羰基}氨基)-4-氧-5-己烯酸(Iaa22);
(49)(3S)-3-({[(5R)-5-异丙基-3-(1-异喹啉基)-4,5-二氢-5-异噁唑基]羰基}氨基)-4-氧-5-(2-吡啶氧基)戊酸(Iaa23);
(50)(3S)-3-({[5-乙基-3-(2-异丙基苯基)-4,5-二氢-5-异噁唑基]羰基}氨基)-4-氧-5-(2-吡啶氧基)戊酸(Iaa24);
(51)2-{[(3S)-4-羧基-3-({[(5R)-5-异丙基-3-(1-异喹啉基)-4,5-二氢-5-异噁唑基]羰基}氨基)-2-氧代丁基]氧基}-1-甲基吡啶鎓三氟甲磺酸盐(Iaa25);
(52)2-{[(3S)-4-羧基-3-({[5-乙基-3-(2-异丙基苯基)-4,5-二氢-5-异噁唑基]羰基}氨基)-2-氧代丁基]氧基}-1-甲基吡啶鎓三氟甲磺酸盐(Iaa26);
(53)3-({[3-(5-氯-1-甲基-1H-吲哚-2-基)-5-异丙基-4,5-二氢-5-异噁唑基]羰基}氨基)-5-氟-4-氧戊酸(Iaa27);
(54)3-({[3-(1,5-二甲基-1H-吲哚-2-基)-5-异丙基-4,5-二氢-5-异噁唑基]羰基}氨基)-5-氟-4-氧戊酸(Iaa28);和
(55)(3S)-5-氟-3-({[(5R)-5-异丙基-3-(1-异喹啉基)-4,5-二氢-5-异噁唑基]羰基}氨基)-4-氧戊酸(Iii-1)。
依照本发明的符合通式(1)的化合物具有两个(2)不对称碳原子,因而可以以其立体异构体的形式存在,包括非对映异构体。立体异构体中特别优选的化合物具有如下通式(1a):
因此本发明的另一个目的是提供立体异构体形式的符合通式(1a)的化合物。
在符合通式(1a)的化合物中,例如,化合物(3S)-5-氟-3-({[(5R)-5-异丙基-3-(1-异喹啉基)-4,5-二氢-5-异噁唑基]羰基}氨基)-4-氧戊酸(Iii-1)可以通过包括下列步骤的过程来获得:将(3S)和(3R)混合物溶于甲基叔丁基醚,添加少量结晶的(3S)-5-氟-3-({[(5R)-5-异丙基-3-(1-异喹啉基)-4,5-二氢-5-异噁唑基]羰基}氨基)-4-氧戊酸作为晶种材料以生成晶体,并将该晶体在乙酸乙酯/正己烷溶剂系统中再结晶。
在符合通式(1)和(1a)的化合物中,最优选的化合物是5-氟-3-({[(5R)-5-异丙基-3-(1-异喹啉基)-4,5-二氢-5-异噁唑基]羰基}氨基)-4-氧戊酸(Iii);和(3S)-5-氟-3-({[(5R)-5-异丙基-3-(1-异喹啉基)-4,5-二氢-5-异噁唑基]羰基}氨基)-4-氧戊酸(Iii-1)。
下文反应方案1-5描述了制备显示针对胱天蛋白酶的抑制活性且符合通式(1)的新型异噁唑啉衍生物的方法。然而,下文反应方案所例示的只代表本发明中所使用的典型方法。可以不受限制地改变操作顺序,因而所述方法不限于下文所解释的。
反应方案1
其中
A、B、和R2的定义与上文所述相同,且
P1代表简单烷基链。
在上文反应方案1中,将醛衍生物(II)与羟胺-氢氯化物和碳酸钠在醇-水溶剂混合物中反应以生成肟衍生物(III)(顺式和反式肟的混合物)。在二甲基甲酰胺溶液中用NCS(N-氯琥珀酰亚胺)处理得到的肟衍生物(III)以生成氢草氨酰氯(hydroxamoyl chloride)衍生物(IV)。将由此得到的氢草氨酰氯衍生物(IV)与丙烯酸酯衍生物(V)反应以生成异噁唑啉衍生物(VI),然后根据需要将其水解以生成去保护的异噁唑啉衍生物(VII)。如果合适,可以将肟衍生物(III)、丙烯酸酯衍生物(V)、和NaOCl在反应容器中(原位)一起反应以直接生成异噁唑啉衍生物(VI)(见制剂16和17)。
反应方案2
I(X=COCH2Z(Z=OR11,OC(=O)R12, or W)
其中A、B、R、R1、R2、R11、R12、和W的定义与上文所述相同。
在上文反应方案2中,将羧酸衍生物(VII)偶联天冬氨酸衍生物(VIII)(见下文反应方案3)以生成化合物(IX),然后将其进行Dess-Martin过碘烷(periodinane)氧化反应和根据需要的去保护反应以生成符合通式(I)的期望化合物。
反应方案2的化合物(I)中的官能团Z可以如下文制剂5和7中所述通过几个步骤在左侧羧酸化合物(VII)与天冬氨酸(β-t-Bu)甲酯联合后形成。否则,如下文反应方案3中所述,首先合成已具有期望的Z的化合物(VIII),然后与化合物(VII)偶联(Ref.:WO 00/23421)。另外,当W是F时,可以依照Tetrahedron Letters,1994,35(52),9693-9696中知道的方法制备外消旋化合物。
反应方案3
其中Z的定义与上文所述相同。
可以通过两种(2)途径制备上文反应方案1中用作反应物的丙烯酸酯衍生物(V)。即,可以如下文反应方案4中所述容易地由已知化合物(XIV)制备化合物(XV)(Synthesis,1982,第924页),或者可以由(二乙基)丙二酸二甲酯制备化合物(V),(乙基)2-异丙基丙烯酸甲酯(J.Chemical Society Perkin Trans.1 1997,1559-1570)。
反应方案4
其中P1和R2的定义与上文所述相同。
下文反应方案5显示了制备其中将α,β-不饱和酯或α,β-不饱和砜(sulfon)导入P1位点的化合物的合成方法。据此,将反应方案1中制备的羧酸衍生物(VII)与氨基醇衍生物(XVII)反应以生成化合物(XVI),然后将其进行Dess-Martin氧化和Wittig反应以生成化合物(I)。
反应方案5
3)如果需要,去保护
其中
R、A、B、R1、和R2的定义与上文所述相同,且
Q代表-CO2R13或SO2R14,其中R13和R14的定义与上文所述相同。
根据下文实验结果的证明,依照本发明的符合通式(1)的化合物具有针对胱天蛋白酶的广谱抑制活性,因而具有预防炎症和凋亡的效果。因此,本发明提供了用于抑制胱天蛋白酶的组合物,具体而言就是包含符合通式(1)的化合物作为活性成分以及制药学可接受载体且用于预防炎症和凋亡的治疗性组合物。具体而言,本发明的组合物对痴呆、脑中风、由AIDS引起的脑损伤、糖尿病、胃溃疡、由肝炎引起的脑损伤、由肝炎诱导的肝病、急性肝炎、暴发性肝功能衰竭、肝硬化、败血症、器官移植排斥、风湿性关节炎、或由缺血性心脏病引起的心脏细胞凋亡具有治疗效果,特别是急性肝炎、肝硬化、或风湿性关节炎。
可以根据施用目的将胱天蛋白酶抑制物特别是符合通式(1)的化合物配制成多种药剂形式。为了制备依照本发明的药物组合物,有效量的胱天蛋白酶抑制物特别是符合通式(1)的化合物或其盐与制药学可接受载体混合,所述载体可以根据待制备的配剂而采取多种形式。
胱天蛋白酶抑制物化合物可以根据其用途而配制成肠胃外注射剂,或是经皮或口服的制剂。尤其有利的是将组合物配制成单位剂量形式,以便于施用和统一剂量。
对于口服制剂,可以使用任何常用制药学载体。例如,可以将水、二元醇、油、醇等等用于诸如悬浮液、糖浆、酏剂和溶液的口服液体制剂;或者,可以将淀粉、糖、高岭土、润滑剂、粘合剂、崩解剂等等用于诸如粉剂、丸剂、胶囊和片剂的固体制剂。由于它们易于施用,片剂和胶囊是最有利的剂量单位形式。还希望将片剂和丸剂配制成肠溶衣制剂。
对于肠胃外制剂,常常使用无菌水作为载体,尽管也可以使用其它成分诸如溶解助剂。可以依照已知流程使用合适的分散剂、润湿剂、或悬浮剂制备注射剂,例如无菌的水性或油性注射用悬浮液。可用于制备注射剂的溶剂包括水、林格氏溶液和等渗NaCl溶液,还可以将无菌的固定油(fixing oil)方便地用作溶剂或悬浮介质。任何非刺激性固定油包括单-、二-甘油酯都可用于此目的。脂肪酸诸如油酸也可用于注射剂。
对于经皮施用,载体可以包括渗透增强剂和/或合适的润湿剂,任选联合没有显著皮肤刺激的合适添加剂。所述添加剂可能促进经由皮肤的施用和/或可能有助于制备期望的组合物。这些经皮的制剂可以通过多种方式施用,例如作为经皮贴剂、spot-on、或软膏剂。
在将胱天蛋白酶抑制物特别是符合通式(1)的化合物用于临床用途时,对受试患者施用的量的范围优选是0.1-100mg/kg体重/日。可以一次性或分几次施用全部日剂量。然而,个体患者的具体施用剂量可能随具体的所用化合物、受试患者的体重、性别、卫生状况、或饮食、施用的时间或方法、排泄速率、试剂的混合比例、待治疗疾病的严重程度等而变化。
下文的实施例将更加具体地解释本发明。然而,应当理解,这些实施例意欲例示本发明,绝非限制本发明的范围。
制剂1:苯甲醛肟
将苯甲醛(5.31g,50.0mmol)溶于乙醇(60ml)-水(30ml),并于0℃向其中添加羟胺氢氯化物(5.21g,1.5Eq)和无水碳酸钠(Na2CO3,3.97g,0.75Eq)。在大约一分钟后形成大量固体时,添加水-乙醇(1∶1,60ml),并将混合液搅动一小时。添加饱和氯化钠水溶液(100ml),并将混合液用乙酸乙酯(300ml)萃取两次。将萃取液用1.0N碳酸氢钠水溶液(NaHCO3,100ml×2)清洗,干燥(无水Na2SO4),并在减压下浓缩以生成白色粉状的标题化合物(6.06g,收率99%),是顺式和反式的混合物。
1H-NMR(500MHz,CDCl3)δ8.9(br,1H),8.1(s,1H),7.5(m,2H),7.3(m,3H)
制剂2:苯甲醛氢草氨酰氯
将在制剂1中制备的肟(3.00g,24.8mmol)溶于二甲基甲酰胺(100ml),并添加N-氯琥珀酰亚胺(3.47g,1.05Eq)。将得到的溶液在大约40℃水浴中搅动一小时,并在减压下通过蒸馏除去挥发性溶剂。将残余物溶于乙酸乙酯-己烷(1∶1,150ml),用水(100ml×3)清洗,干燥(无水Na2SO4),并在减压下浓缩以生成标题化合物(3.86g,收率99%)。将此化合物用于下一步反应,无需任何进一步的纯化。
制剂3:5-甲基-3-苯基-4,5-二氢-5-异噁唑羧酸甲酯(VIa)
将在制剂2中制备的氢草氨酰氯(3.86g,24.8mmol)和甲基丙烯酸甲酯(4.0ml,37.2mmol,1.5Eq)在氮气气氛下溶于无水乙醚(120ml),将混合液置于-78℃,并添加三乙胺(6.9ml,2.0Eq)。将混合液搅动过夜,同时让它缓慢升温至室温。添加水(100ml),然后将混合液用乙酸乙酯(100ml×2)萃取,用水(100ml)清洗,干燥(无水Na2SO4),并在减压下浓缩。通过柱层析(15%乙酸乙酯-己烷)纯化残余物以生成标题化合物(5.34g,收率98%),后来通过1H-NMR鉴定是非对映异构体的1∶1混合物。
1H-NMR(400MHz,CDCl3)δ6.7(m,2H,),6.5(m,3H),3.0(d,J=16.7Hz,1H),2.9(s,3H),2.3(d,J=16.7Hz,1H),0.8(s,3H)
制剂4:5-甲基-3-苯基-4,5-二氢-5-异噁唑羧酸(VIIa)
将在制剂3中制备的化合物(VIa,5.34g)溶于蒸馏的四氢呋喃(120ml),并添加1N氢氧化钠水溶液(36.5ml,1.5Eq)。大约四小时后,用1N盐酸水溶液中和混合液,并在减压下蒸馏以除去大部分四氢呋喃。将残余物溶于过量的乙酸乙酯(>700ml),用水清洗,干燥(无水Na2SO4),并在减压下浓缩以生成白色粉状的标题化合物(4.77g,收率95%)。将此化合物用于下一步反应,无需任何进一步的纯化。
制剂5:(3S)-3-{[(苄氧基)羰基]氨基}-5-(叔丁氧基)-2-羟基-5-氧代戊基2,6-二氯苯甲酸酯(XIIa)
在氮气气氛下向N-苄氧基羰基-β-叔丁基天冬氨酸(5.03g,15.6mmol)和NMM(1.90ml,17.1mmol)中添加无水四氢呋喃(60ml),将混合液置于-15℃,并向其中添加氯甲酸异丁酯(2.12ml,16.3mmol)。将混合液搅动大约20分钟。向置于0℃的反应混合液中添加重氮甲烷-醚溶液(由2.0Eq 1-甲基-3-硝基-1-亚硝基-胍合成,60ml)以制备重氮酮衍生物(约30分钟)。于0℃向其中添加30%HBr/AcOH(6.42ml,2.0Eq)。搅动得到的混合液(30-60分钟),用乙酸乙酯萃取,用饱和碳酸氢钠水溶液清洗两次,用氯化钠水溶液清洗一次,干燥(无水Na2SO4),并在减压下浓缩以生成溴甲基酮衍生物(X,6.4g)。
将由此得到的溴甲基酮衍生物(X,4.36g)和2,6-二氯苯甲酸(2.28g,1.1Eq)溶于二甲基甲酰胺(18ml),添加KF(1.58g,2.5Eq),并将混合液搅动两小时以生成2,6-二氯苯甲酰氧基甲基酮衍生物(XIa)。将此化合物溶于甲醇(20ml),并添加NaBH4(412mg)-甲醇溶液(40ml)进行反应(-10℃~室温,两小时)。添加乙酸终止反应,并将反应溶液在减压下蒸馏以除去甲醇。将残余物用乙酸乙酯(50ml×2)萃取,用水和氯化钠水溶液清洗,干燥(无水Na2SO4),在减压下浓缩,并通过柱层析(乙酸乙酯-己烷,1∶5)分离-纯化以生成非对映形的标题化合物(4.80g,收率86%)。
1H-NMR(400MHz,CDCl3)δ7.3-7.2(m,8H),5.9(m,1H),5.2(m,4H),4.7(m,1H),2.9(m,1H),2.7(m,1H),1.4(s,9H)
制剂6:(3S)-3-氨基-5-(叔丁氧基)-2-羟基-5-氧代戊基2,6-二氯苯甲酸酯(VIIIa)
在氢气环境下(Pd/C)将在制剂5中制备的化合物的苄氧基羰基基团去除40分钟以生成标题化合物(收率100%)。
1H-NMR(400MHz,DMSO-d6)δ8.2(br,2H),7.6-7.5(m,3H),6.1(m,1H),4.4-3.9(m,3H),3.0-2.6(m,2H),1.4(s,9H)
实施例1:(3S)-5-(叔丁氧基)-3-{[(5-甲基-3-苯基-4,5-二氢-5-异噁唑基)羰基]氨基}-2,5-二氧代戊基2,6-二氯苯甲酸酯(Ia)
将在制剂4中制备的羧酸衍生物(VIIa,300mg,1.46mmol)、在制剂6中制备的氨基醇衍生物(VIIIa,667mg,1.1Eq)、和HATU(722mg,1.3Eq)的混合物冷却至0℃,在溶剂DMF(5ml)中添加三乙胺(0.82ml,4.0Eq),并将得到的混合液反应5小时。在减压下蒸馏除去溶剂,并将残余物用乙酸乙酯(200ml×2)萃取,用水、碳酸氢钠水溶液、和氯化钠水溶液清洗,干燥(无水Na2SO4),在减压下浓缩,并通过柱层析纯化以生成化合物(IXa)(810mg,收率98%)。向此化合物和Dess-Martin试剂(1.70g,3.0Eq)中添加无水二氯甲烷(25ml),并将混合液于室温搅动一小时。添加异丙醇(3ml)终止反应。在减压下用Celite(硅藻土)过滤除去固体,并将滤出液用乙酸乙酯(20ml×2)萃取,用水、饱和碳酸氢钠水溶液、和氯化钠水溶液清洗,干燥(无水Na2SO4),在减压下浓缩,并通过柱层析(36%乙酸乙酯-己烷)初步纯化以生成非对映的标题化合物(780mg)。
1H-NMR(400MHz,CDCl3)δ7.8(m,NH,1H),7.6(m,2H),7.3(m,3H),7.2(m,3H),5.1-5.0(m,2H),4.8(m,1H),3.8(m,1H),3.2(m,1H),2.9-2.8(m,2H),1.7(s,3H),1.4(s,9H)
实施例2:(3S)-5-[(2,6-二氯苯甲酰)氧基]-3-{[(5-甲基-3-苯基-4,5-二氢-5-异噁唑基)羰基]氨基}-4-氧戊酸(Iaa)
将实施例1中制备的化合物(44mg)溶于二氯甲烷(2ml),并于0℃添加三氟乙酸(1ml)。将混合液搅动两小时,同时将它缓慢升温至室温,然后在减压下浓缩以生成化学计量数量的标题化合物(Iaa)。
1H-NMR(500MHz,CDCl3)δ8.1(m,1H),7.5((m,2H),7.3(m,3H),7.2(m,3H),5.1-4.9(m,2H),4.9-4.8(m,1H),3.8(m,1H),3.2(m,1H),1.7(m,3H)
制剂7:(3S)-3-氨基-4-羟基-5-苯氧基戊酸叔丁酯(VIIIb)
在氮气气氛下向N-苄氧基羰基-β-叔丁基-天冬氨酸(10.0g,31.0mmol)和NMM(3.75ml,1.1Eq)中添加无水四氢呋喃(120ml),并将混合液置于-15℃。向其中添加氯甲酸异丁酯(4.22ml,1.05Eq),并将混合液搅动大约20分钟。将反应物置于0℃,然后与重氮甲烷-醚溶液(由2.0Eq 1-甲基-3-硝基-1-亚硝基胍合成,60ml)混合以制备重氮酮衍生物(约30分钟)。向其中添加30%HBr/AcOH(12.83ml,2.0Eq)以制备溴甲基酮衍生物(30-60分钟)。将产物用乙酸乙酯萃取,用饱和碳酸氢钠水溶液和氯化钠水溶液清洗两次,干燥(无水Na2SO4),并在减压下浓缩以生成化学计量数量的溴甲基酮衍生物(12.9g)。将由此得到的溴甲基酮衍生物(X,12.9g,31.0mmol)和苯酚(3.23g,1.2Eq)溶于二甲基甲酰胺(30ml),添加KF(4.53g,2.5Eq),并将混合液搅动两小时以生成苯氧基甲基酮衍生物(XIb)。将此化合物溶于甲醇(40ml)-THF(100ml),并添加NaBH4(2.35g)-甲醇溶液(40ml)进行反应(-10℃~室温,两小时)。添加乙酸终止反应,并将反应混合液在减压下蒸馏以除去甲醇。将残余物用乙酸乙酯(50ml×2)萃取,用水和氯化钠水溶液清洗,干燥(无水Na2SO4),在减压下浓缩,并通过柱层析(乙酸乙酯-己烷,1∶7)分离-纯化以生成非对映形的化合物(XIIb,6.50g,收率50%),其氨基基团受到苄氧基羰基的保护。
1H-NMR(400MHz,CDCl3)δ7.3-7.2(m,8H),5.9(m,1H),5.2(m,4H),4.7(m,1H),2.9(m,1H),2.7(m,1H),1.4(s,9H)
在氢气环境下(Pd/C)将上文得到的化合物的苄氧基羰基基团去除以生成标题化合物(4.16g,收率95%)。
1H-NMR(400MHz,DMSO-d6)δ8.1(br,2H),7.3(m,5H),5.6(m,1H),4.1-4.0(m,3H),2.6(m,2H),1.4(s,9H)
实施例3:(3S)-3-{[(5-甲基-3-苯基-4,5-二氢-5-异噁唑基)羰基]氨基}-4-氧-5-苯氧基戊酸叔丁酯(Ib)
将在制剂4中制备的羧酸衍生物(VIIa,273mg,1.33mmol)、在制剂7中制备的氨基醇衍生物(VIIIb,412mg,1.1Eq)、和HATU(657mg,1.3Eq)的混合物冷却至0℃,在溶剂DMF(5ml)中添加三乙胺(0.74ml,4.0Eq),并将得到的混合液反应5小时。在减压下蒸馏除去溶剂,并将残余物用乙酸乙酯(200ml×2)萃取,用水、碳酸氢钠水溶液、和氯化钠水溶液清洗,干燥(无水Na2SO4),在减压下浓缩,并通过柱层析(30-40%EA/Hex)纯化以生成化合物(IXb)(545mg,收率88%)。向此化合物和Dess-Martin试剂(1.43g,3.0Eq)中添加无水二氯甲烷(25ml),并将混合液于室温搅动一小时。添加异丙醇(2ml)终止反应。在减压下用Celite(硅藻土)过滤除去固体,并将滤出液用乙酸乙酯(20ml×2)萃取,用水、饱和碳酸氢钠水溶液、和氯化钠水溶液清洗,干燥(无水Na2SO4),在减压下浓缩,并通过柱层析(洗脱液:25%乙酸乙酯-己烷)初步纯化以生成非对映的标题化合物(540mg,收率99%)。
1H-NMR(400MHz,CDCl3)δ7.8(NH,1H),7.5(m,2H),7.3(m,3H),7.3(m,1H),7.1(m,1H),6.8(m,2H),6.7(m,1H),4.9(s,1H),4.7-4.6(m,2H),3.7(d,J =17Hz,1H),3.2(d,J=17Hz,1H),2.9(m,1H),2.8(m,1H),1.7(s,3H),1.4(s,9H)
实施例4:(3S)-3-{[(5-甲基-3-苯基-4,5-二氢-5-异噁唑基)羰基]氨基}-4-氧-5-苯氧基戊酸(Ibb)
将实施例3中制备的化合物(530mg,1.136mmol)溶于二氯甲烷(6ml),并于0℃添加三氟乙酸(3ml)。将混合液搅动两小时,同时将它缓慢升温至室温,并在减压下浓缩以生成化学计量收率的标题化合物(Ibb)(465mg)。
1H-NMR(400MHz,CDCl3)δ7.5(m,2H),7.3(m,3H),7.1(NH,1H),6.7(m,5H),5.0-4.6(m,2H),4.2(m,1H),3.8(m,1H),3.2(m,1H),3.0-2.7(m,2H),1.6(s,3H)
制剂8:2-乙基丙烯酸乙酯(XVb)
在氮气气氛下向CuCN(26.9g,预先在真空下干燥)中添加大约500ml无水四氢呋喃。将混合液置于-78℃,并在机械搅动下向其中缓慢添加100ml甲基镁化溴(3.0M乙醚溶液)。将浓稠的混合液于-78℃搅动大约30分钟。向其中缓慢添加溶于大约30ml无水四氢呋喃的2-溴甲基丙烯酸乙酯(28.9g,150mmol,合成方法:Villieras,J.和Rambaud,M.Synthesis,1982,914)。用两小时将反应混合液的温度缓慢升温至室温。缓慢添加饱和氯化铵溶液(约50ml)完成反应。用Celite(硅藻土)过滤反应混合液以除去沉淀,然后用乙醚清洗。用水和饱和碳酸氢钠溶液(300ml×2)清洗有机层,干燥(无水Na2SO4),并在减压下浓缩以生成26.7g(化学计量收率)透明液体。通过1H-NMR(500MHz,CDCl3)鉴定此液体,并确认是具有大约75%w/w纯度的标题化合物。
1H-NMR(500MHz,CDCl3)δ6.12(1H,s),5.50(1H,s),4.20(2H,q,J=7.3Hz),2.31(2H,qt),1.28(3H,t,J=7.3Hz),1.07(3H,t,J=7.8Hz)
制剂9:5-乙基-3-苯基-4,5-二氢-5-异噁唑羧酸乙酯(VIb)
依照制剂3的相同流程使制剂8的化合物(XVa)进行反应以生成标题化合物。
1H-NMR(400MHz,CDCl3)δ7.6(m,2H),7.4-7.3(m,3H),4.3-4.2(m,2H),4.0(d,J =17.2Hz,1H),3.4(d,J=17.2Hz,1H),2.1-2.0(m,2H),1.3(t,3H),1.0(t,3H)
制剂10:(3S)-3-氨基-4-羟基-5-(2,3,5,6-四氟苯氧基)戊酸叔丁酯(VIIIc)
依照制剂5和6的相同流程使2,3,5,6-四氟苯酚进行反应以生成总收率72%的标题化合物。
1H-NMR(400MHz,DMSO-d6)δ8.2(br,2H),7.6-7.5(m,1H),5.9(m,1H),4.3-4.1(m,3H),3.6(m,1H),2.7(m,1H),1.4(s,9H)
实施例5:(3S)-3-{[(5-乙基-3-苯基-4,5-二氢-5-异噁唑基)羰基]氨基}-4-氧-5-(2,3,5,6-四氟苯氧基)戊酸叔丁酯(Ic)
依照制剂4和实施例1的相同流程使制剂9和10的化合物进行反应以生成标题化合物。
1H-NMR(400MHz,CDCl3)δ7.6(dd,J =3.6,1.6Hz,1H),7.6(m,2H),7.4-7.3(m,3H),6.7(m,1H),5.1-4.9(m,2H),4.9-4.8(m,1H),3.7(dd,J=17.6,17.2Hz,1H),3.3(1H,d,J=17.2Hz),3.0-2.8(m,1H),2.8-2.7(m,1H),2.1(m,1H),1.9(m,1H),1.4-1.3(two s,9H,),1.0(m,3H)
实施例6:(3S)-3-{[(5-乙基-3-苯基-4,5-二氢-5-异噁唑基)羰基]氨基}-4-氧-5-(2,3,5,6-四氟苯氧基)戊酸(Icc)
依照实施例2的相同流程使实施例5的化合物进行反应以生成标题化合物。
1H-NMR(400MHz,DMSO-d6)δ7.6(br,1H),7.6-7.5(m,2H),7.4-7.3(m,3H),6.8-6.7(m,1H),4.9-4.8(m,1H),4.5(br,2H),3.7(d,J=16Hz,1H),3.3(d,J=16Hz,1H),3.3-3.0(m,1H),2.8-2.7(m,1H),2.1(m,1H),2.0-1.9(m,1H),1.0(m,3H)
MS[M+H]+497
制剂11:5-乙基-3-(1-萘基)-4,5-二氢-5-异噁唑羧酸乙酯(VIc)
依照制剂1、2、和3的相同流程使1-萘甲醛和2-乙基丙烯酸乙酯进行反应以生成标题化合物。
1H-NMR(400MHz,CDCl3)δ8.9(d,J=8.8Hz,1H),7.9-7.8(m,2H),7.6-7.4(m,4H),4.3-4.2(m,2H),4.0(d,J=17.2Hz,1H),3.4(d,J=17.2Hz,1H),2.1-2.0(m,2H),1.3(t,3H),1.0(t,3H)
实施例7:(3S)-3-({[5-乙基-3-(1-萘基)-4,5-二氢-5-异噁唑基]羰基}氨基)-4-氧-5-(2,3,5,6-四氟苯氧基)戊酸叔丁酯(Id)
依照制剂4和实施例1的相同流程使制剂11和10的化合物进行反应以生成标题化合物。
1H-NMR(400MHz,CDCl3)δ8.9(m,1H),7.9-7.8(m,3H),7.6-7.4(m,4H),6.5-6.9(m,1H),5.1-4.9(m,2H),4.9(m,1H),3.9(dd,1H),3.5(d,J=17.2Hz,1H),3.0-2.9(m,1H),2.8(m,1H),2.2(m,1H),2.0(m,1H),1.4-1.3(two s,9H),1.1(m,3H)
实施例8:(3S)-3-({[5-乙基-3-(1-萘基)-4,5-二氢-5-异噁唑基]羰基}氨基)-4-氧-5-(2,3,5,6-四氟苯氧基)戊酸(Idd)
依照实施例2的相同流程使实施例7的化合物进行反应以生成标题化合物。
1H-NMR(400MHz,CDCl3)δ8.8(m,1H),7.9-7.7(m,3H),7.6-7.4(m,4H),6.7(m,1H),4.9(m,1H),4.5(br,2H),3.9(d,J=17.2Hz,1H),3.5(d,J=17.2Hz,1H),3.1-2.9(m,1H),2.8-2.7(m,1H),2.2(m,1H),2.0(m,1H),1.0(m,3H)
MS[M+MeOH+Na]+601
制剂12:5-乙基-3-(2-萘基)-4,5-二氢-5-异噁唑羧酸乙酯(VId)
依照制剂1、2、和3的相同流程使2-萘甲醛和2-乙基丙烯酸乙酯进行反应以生成标题化合物。
1H-NMR(500MHz,CDCl3)δ8.7(d,J=8.8Hz,1H),7.8-7.7(m,2H),7.5-7.3(m,4H),4.3-4.2(m,2H),4.0(d,J=17.2Hz,1H),3.4(d,J =17.2Hz,1H),2.1-2.0(m,2H),1.3(t,3H),1.0(t,3H)
实施例9:(3S)-3-({[5-乙基-3-(2-萘基)-4,5-二氢-5-异噁唑基]羰基}氨基)-4-氧-5-(2,3,5,6-四氟苯氧基)戊酸叔丁酯(Ie)
依照制剂4和实施例1的相同流程使制剂12和10的化合物进行反应以生成标题化合物。
1H-NMR(400MHz,CDCl3)δ7.8-7.7(m,6H),7.5(m,2H),6.7&6.5(m,1H),5.1-4.9(m,2H),4.9-4.8(m,2H),3.8(dd,J=16Hz,1H),3.4(d,J=16Hz,1H),3.0(m,1H),2.8(m,1H),2.8-2.7(m,1H),2.2-2.1(m,1H),2.0(m,1H),1.4-1.3(two s,9H),1.1-1.0(m,3H)
实施例10:(3S)-3-({[5-乙基-3-(2-萘基)-4,5-二氢-5-异噁唑基]羰基}氨基)-4-氧-5-(2,3,5,6-四氟苯氧基)戊酸(Iee)
依照实施例2的相同流程使实施例9的化合物去保护,并通过制备性TLC拆分异构体以生成如下两种化合物。
弱极性非对映异构体:
1H-NMR(400MHz,DMSO-d6)δ12.4(br,1H),8.7(br,1H),8.1(s,1H),7.9-8.0(m,3H),7.8-7.9(m,1H),7.5-7.6(m,3H),5.2(br,2H),4.7(br,1H),3.8(d,J=17.2Hz,1H),3.5(d,J =17.6Hz,1H),2.7(m,1H),2.5(m,1H),2.0(m,1H),1.9(m,1H),0.9-0.8(m,3H)
MS[M+H]+547
高极性非对映异构体:
1H-NMR(400MHz,DMSO-d6)δ8.6(br,1H),8.2(s,1H),8.0-7.9(m,3H),7.9(m,1H),7.6(m,2H),7.4(m,1H),5.0(br,2H),4.8(m,1H),3.9(d,J=17.6Hz,1H,),3.6(d,J=17.6Hz,1H,),2.9-2.7(m,2H),2.1-2.0(m,1H),2.0-1.9(m,1H),0.9(m,3H)
制剂13:5-乙基-3-(1-异喹啉基)-4,5-二氢-5-异噁唑羧酸乙酯(VIe)
依照制剂1、2、和3的相同流程使1-异喹啉甲醛和2-乙基丙烯酸乙酯进行反应。通过Chiral OD HPLC(Daicel Chemical Industries,2.00cm×25cm,OD00CJ-1C005,3%i-PrOH溶于己烷,220nm)分离活性手性异构体形式的标题化合物,然后用于下一步反应。
1H-NMR(400MHz,CDCl3)δ9.25(m,1H),8.55(d,1H),7.85(d,1H),7.74-7.65(m,3H),4.29(m,2H),4.13(d,1H),3.71(d,1H),2.11(m,2H),1.33(t,3H),1.06(t,3H)
实施例11:(3S)-3-({[5-乙基-3-(1-异喹啉基)-4,5-二氢-5-异噁唑基]羰基}氨基)-4-氧-5-(2,3,5,6-四氟苯氧基)戊酸叔丁酯(If)
依照制剂4和实施例1的相同流程使制剂13和10的化合物进行反应以生成标题化合物。
1H-NMR(400MHz,CDCl3)δ9.14(m,1H),8.53(m,1H),7.91-7.85(m,2H),7.74-7.64(m,3H),6.73-6.62(m,1H),5.30-4.91(m,3H),4.09(two d,1H),3.72(two d,1H),3.04-2.76(m,2H),2.24(m,1H),2.04(m,1H),1.45&1.35(two s,9H),1.08(twot,3H)
实施例12:(3S)-3-({[5-乙基-3-(1-异喹啉基)-4,5-二氢-5-异噁唑基]羰基}氨基)-4-氧-5-(2,3,5,6-四氟苯氧基)戊酸(Iff)
依照实施例2的相同流程使实施例11的化合物进行反应以生成标题化合物。
1H-NMR(400MHz,DMSO-d6)δ9.02(m,1H),8.76(m,1H),8.59(m,1H),8.08-7.73(m,4H),7.61-7.32(m,1H),5.19-5.10(m,2H),4.93-4.65(m,1H),3.91(two d,1H),3.68(two d,1H),2.91-2.52(m,2H),2.10-1.94(m,2H),0.94(two t,3H)
Ms M+H 548
实施例13:3-({[5-乙基-3-(1-异喹啉基)-4,5-二氢-5-异噁唑基]羰基}氨基)-5-氟-4-氧戊酸叔丁酯(Ig)
依照制剂4和实施例1的相同流程使制剂13的化合物和3-氨基-5-氟-4-羟基戊酸叔丁酯进行反应以生成标题化合物。
1H-NMR(400MHz,CDCl3)δ9.15(m,1H),8.55(d,1H),7.87-7.66(m,5H),5.22-4.89(m,3H),4.12(two d,1H),3.72(twod,1H),3.05-2.75(m,2H),2.22(m,1H),2.04(m,1H),1.45&1.34(two s,9H),1.07(two t,3H)
实施例14:3-({[5-乙基-3-(1-异喹啉基)-4,5-二氢-5-异噁唑基]羰基}氨基)-5-氟-4-氧戊酸(Igg)
依照实施例2的相同流程使实施例13的化合物进行反应以生成标题化合物。
1H-NMR(400MHz,DMSO-d6)δ9.03(m,1H),8.67-8.59(m,2H),8.08(d,1H),7.97-7.78(m,3H),5.26-5.07(m,2H),4.75(m,1H),3.94(two d,1H),3.67(two d,1H),2.88-2.58(m,2H),2.07-1.94(m,2H),0.96(two t,3H)
Ms M+H 402
实施例15:3-({[5-乙基-3-(1-异喹啉基)-4,5-二氢-5-异噁唑基]羰基}氨基)-5-氟-4-氧戊酸乙酯(Ihh)
依照Tetrahedron Letters,1994,35(52),9693-9696中的已知方法使实施例14的化合物进行反应以生成标题化合物。
1H-NMR(400MHz,CDCl3)δ9.15(m,1H),8.55(d,1H),7.89-7.67(m,5H),5.23-4.94(m,3H),4.18(m,2H),4.11(two d,1H),3.72(two d,1H),3.08-2.82(m,2H),2.22(m,1H),2.05(m,1H),1.29-1.04(m,6H)
制剂14:5-异丙基-3-(1-异喹啉基)-4,5-二氢-5-异噁唑羧酸甲酯和拆分(VIf)
依照制剂1、2、和3的相同流程使1-异喹啉甲醛和2-异丙基丙烯酸甲酯进行反应以生成标题化合物。通过制备性HPLC使用手性OD柱(Daicel Chemical Industries,2.00cm×25cm,OD00CJ-1C005,5%i-PrOH溶于己烷,14ml/分钟,220nm)由如此得到的化合物中分离(5R)活性手性异构体(9.7分钟-11.7分钟)(另一(5S)异构体在15.3-20.1分钟的保留时间内洗脱),然后用于下一步反应(水解后的拆分见制剂23)。
1H-NMR(500MHz,CDCl3)δ9.24(m,1H),8.55(d,1H),7.85(d,1H),7.72(t,3H),7.67(m,2H),4.11(d,1H),3.83(s,3H),3.74(d,1H),2.50(septet,1H),1.07(d,3H),1.02(d,3H)
实施例16:5-氟-3-({[(5R)-5-异丙基-3-(1-异喹啉基)-4,5-二氢-5-异噁唑基]羰基}氨基)-4-氧戊酸叔丁酯(Ih)
依照制剂4和实施例1的相同流程使制剂14的化合物和3-氨基-5-氟-4-羟基戊酸叔丁酯进行反应以生成标题化合物。
1H-NMR(500MHz,CDCl3)δ9.14(m,1H),8.55(d,1H),7.87-7.65(m,5H),5.23-4.93(m,2H),4.90(m,1H),4.05-4.00(twod,1H),3.84-3.79(two,1H),3.06-2.74(m,2H),2.40(m,1H),1.45&1.34(two s,9H),1.12-1.07(m,6H)
实施例17:5-氟-3-({[(5R)(-5-异丙基-3-(1-异喹啉基)-4,5-二氢-5-异噁唑基]羰基}氨基)-4-氧戊酸(Iii)
依照实施例2的相同流程使实施例16的化合物进行反应以生成标题化合物(依照相同流程得到(5S)异构体的化合物,Iii-u)。
1H-NMR(400MHz,DMSO-d6)δ9.00(m,1H),8.63-8.48(m,2H),8.08(d,1H),7.97(m,1H)7.87-7.76(m,2H),5.31-4.82(br,2H),4.74(m,1H),3.91(two d,1H),3.73(two d,1H),2.88-2.61(m,2H),2.33(m,1H),0.98(m,6H)
Ms M+H 416
制剂15:5-乙基-3-(4-喹啉基)-4,5-二氢-5-异噁唑羧酸乙酯(VIg)
依照制剂1、2、和3的相同流程使4-喹啉甲醛和2-乙基丙烯酸乙酯进行反应以生成标题化合物。
1H-NMR(400MHz,CDCl3)δ8.95(d,1H),8.89(m,1H),8.11(d,1H),7.83(m,1H),7.71(m,1H),7.65(d,1H),4.27(m,2H),4.01(d,1H),3.67(d,1H),2.10(m,2H),1.31(t,3H),1.02(t,3H)
实施例18:3-({[5-乙基-3-(4-喹啉基)-4,5-二氢-5-异噁唑基]羰基}氨基)-5-氟-4-氧戊酸叔丁酯(Ii)
依照制剂4和实施例1的相同流程使制剂15的化合物和3-氨基-5-氟-4-羟基戊酸叔丁酯进行反应以生成标题化合物。
1H-NMR(400MHz,CDCl3)δ8.97(d,1H),8.89(m,1H),8.17(d,1H),7.87-7.64(m,3H),7.36(d,1H),5.21-4.93(m,3H),3.93(twod,1H),3.48(two d,1H),3.05-2.78(m,2H),2.24(m,1H),2.03(m,1H),1.46&1.33(two s,9H),1.06(two t,3H)
实施例19:3-({[5-乙基-3-(4-喹啉基)-4,5-二氢-5-异噁唑基]羰基}氨基)-5-氟-4-氧戊酸(Ijj)
依照实施例2的相同流程使实施例18的化合物进行反应以生成标题化合物。
1H-NMR(400MHz,DMSO-d6)δ9.16-9.10(m,2H),8.25-7.86(m,5H),5.20(br,2H),4.75(m,1H),4.00-3.89(two d,1H),3.73(twod,1H),2.87-2.71(m,2H),2.26-2.05(m,2H),1.07(two t,3H)
Ms M+H 402
制剂16:3-(苯并噻吩-2-基)-5-乙基-4,5-二氢-5-异噁唑羧酸乙酯(VIh)
将依照制剂1的相同流程制备的苯并噻吩-2-醛肟衍生物(400mg,2.26mmol)溶于THF(25ml),并将混合液置于0℃。将2-乙基丙烯酸乙酯(434mg,1.5Eq)和三乙胺(7滴)溶于THF(5ml),将由此得到的溶液缓慢添加到上面的混合液中,并另外添加次氯酸钠溶液(6.0ml)。将反应溶液升温至室温并搅动4小时。添加水(20ml),并用乙酸乙酯(40ml×2)萃取混合液,用氯化钠水溶液(20ml)清洗,在硫酸镁上干燥,过滤,并在减压下浓缩。通过柱层析(20%乙酸乙酯-己烷)纯化残余物以生成标题化合物(121mg,收率18%)。
1H-NMR(400MHz,CDCl3)δ7.82-7.75(m,2H),7.40-7.32(m,3H),4.28(m,2H),3.90(d,1H),3.31(d,1H),2.07(m,2H),1.33(t,3H),1.01(t,3H)
实施例20:3-({[3-(苯并噻吩-2-基)-5-乙基-4,5-二氢-5-异噁唑基]羰基}氨基)-5-氟-4-氧戊酸叔丁酯(Ij)
依照制剂4和实施例1的相同流程使制剂16的化合物和3-氨基-5-氟-4-羟基戊酸叔丁酯进行反应以生成标题化合物。
1H-NMR(400MHz,CDCl3)δ7.83-7.68(m,3H),7.42-7.35(m,3H),5.21-4.88(m,3H),3.80(two d,1H),3.38(two d,1H),3.03-2.78(m,2H),2.17(m,1H),2.01(m,1H),1.46&1.38(two s,9H),1.03(two t,3H)
实施例21:3-({[3-(苯并噻吩-2-基)-5-乙基-4,5-二氢-5-异噁唑基]羰基}氨基)-5-氟-4-氧戊酸(3-({[3-(苯并噻吩-2-基)-5-乙基-4,5-二氢-5-异噁唑基]羰基}氨基)-5-氟-4-氧戊酸)(Ikk)
依照实施例2的相同流程使实施例20的化合物进行反应以生成标题化合物。
1H-NMR(400MHz,DMSO-d6)δ8.63(m,1H),8.11-7.79(m,3H),7.47-7.36(m,2H),5.24-5.06(m,2H),4.73(m,1H),3.79(two d,1H),3.53(two d,1H),2.83-2.58(m,2H),2.03-1.86(m,2H),0.91(two t,3H)
Ms M+H 407
制剂17:3-(1,3-二甲基-1H-吲哚-2-基)-5-乙基-4,5-二氢-5-异噁唑羧酸乙酯(VIi)
将1,3-二甲基-1H-吲哚-2-醛肟衍生物(356mg,2.07mmol)溶于二氯甲烷(20ml),并将混合液置于0℃。将2-乙基丙烯酸乙酯(345mg,1.3Eq)和三乙胺(6滴)溶于二氯甲烷(5ml),将由此得到的溶液缓慢添加到上面的混合液中,并另外添加次氯酸钠溶液(5.5ml)。将反应溶液升温至室温并搅动4小时。添加水(20ml),并用二氯甲烷(40ml×2)萃取混合液,用氯化钠水溶液(20ml)清洗,在硫酸镁上干燥,过滤,并在减压下浓缩。通过柱层析(15%乙酸乙酯-己烷)纯化残余物以生成标题化合物(230mg,收率35%)。
1H-NMR(400MHz,CDCl3)δ7.60(d,1H),7.31(m,2H),7.12(m,1H),4.29(m,2H),3.98(d,1H),3.94(s,3H),3.40(d,1H),2.47(s,3H),2.08(m,2H),1.34(t,3H),1.04(t,3H)
Ms M+H 315
实施例22:(3S)-3-({[3-(1,3-二甲基-1H-吲哚-2-基)-5-乙基-4,5-二氢-5-异噁唑基]羰基}氨基)-4-氧-5-(2,3,5,6-四氟苯氧基)戊酸叔丁酯(Ik)
依照制剂4和实施例1的相同流程使制剂17和10的化合物进行反应以生成标题化合物。
1H-NMR(400MHz,CDCl3)δ7.85-7.79(m,1H),7.57(m,1H),7.37-7.26(m,2H),7.13(m,1H),6.75-6.49(m,1H),5.12-4.90(m,3H),3.95(two d,1H),3.89(two s,3H),3.45(twod,1H),3.03-2.79(m,2H),2.44(two s,3H),2.22(m,1H),2.01(m,1H),1.58&1.37(two s,9H),1.05(two t,3H)
实施例23:(3S)-3-({[3-(1,3-二甲基-1H-吲哚-2-基)-5-乙基-4,5-二氢-5-异噁唑基]羰基}氨基)-4-氧-5-(2,3,5,6-四氟苯氧基)戊酸(Ill)
依照实施例2的相同流程使实施例22的化合物进行反应以生成标题化合物。
1H-NMR(400MHz,DMSO-d6)δ8.67(br,1H),7.61-7.43(m,3H),7.27(m,1H),7.08(m,1H),5.20(br,2H),4.83(m,1H),3.84(twos,3H),3.76(two d,1H),3.59(two d,1H),2.91-2.60(m,2H),2.50(two s,3H),2.07-1.91(m,2H),0.95(two t,3H)
实施例24:3-({[3-(1,3-二甲基-1H-吲哚-2-基)-5-乙基-4,5-二氢-5-异噁唑基]羰基}氨基)-5-氟-4-氧戊酸叔丁酯(I1)
依照制剂4和实施例1的相同流程使制剂17的化合物和3-氨基-5-氟-4-羟基戊酸叔丁酯进行反应以生成标题化合物。
1H-NMR(400MHz,CDCl3)δ7.79(m,1H),7.60(m,1H),7.32(m,2H),7.13(m,1H),5.20-4.90(m,3H),3.97-3.89(m,4H),3.46(twod,1H),3.03-2.77(m,2H),2.21(m,1H),2.01(m,1H),1.46&1.38(two s,9H),1.05(two t,3H)
实施例25:3-({[3-(1,3-二甲基-1H-吲哚-2-基)-5-乙基-4,5-二氢-5-异噁唑基]羰基}氨基)-5-氟-4-氧戊酸(Imm)
依照实施例2的相同流程使实施例24的化合物进行反应以生成标题化合物。
1H-NMR(400MHz,DMSO-d6)δ8.68(br,1H),7.60(m,1H),7.45(m,1H),7.26(m,1H),7.07(m,1H),5.20(br,2H),4.81(m,1H),3.84(two s,3H),3.76(two d,1H),3.59(two d,1H),2.94-2.59(m,2H),2.38(two s,3H),2.07-1.91(m,2H),0.95(twot,3H)
Ms M+H 418
制剂18:5-乙基-3-(1-萘基甲基)-4,5-二氢-5-异噁唑羧酸乙酯(VIj)
依照制剂1、2、和3的相同流程使1-萘基乙醛和2-乙基丙烯酸乙酯进行反应以生成标题化合物。
1H-NMR(500MHz,CDCl3)δ8.1-8.0(d,J=8Hz,1H),7.8(d,J=7.6Hz,1H,),7.8-7.7(d,J=8Hz,1H),7.5-7.4(m,2H),7.4-7.3(m,2H),4.1-4.0(m,4H),3.1(d,J=17.6Hz,1H),2.6(d,J=17.6Hz,1H),1.8-1.7(m,2H),1.2(t,3H),0.7(t,3H)
实施例26:(3S)-3-({[5-乙基-3-(1-萘基甲基)-4,5-二氢-5-异噁唑基]羰基}氨基)-4-氧-5-(2,3,5,6-四氟苯氧基)戊酸叔丁酯(Im)
依照制剂4和实施例1的相同流程使制剂18和10的化合物进行反应以生成标题化合物。
1H-NMR(400MHz,CDCl3)δ8.0(m,1H),7.8(m,1H),7.8(m,1H),7.7(m,1H),7.5(m,2H),7.4-7.3(m,2H),6.7(m,1H),5.0-4.9(m,2H),4.9-4.8(m,1H),4.2-4.0(m,2H),3.1(dd,J=24.8Hz,1H),2.9-2.6(m,3H),1.9(m,1H),1.7(m,1H),1.4(two s,9H),0.8(m,3H)
实施例27:(3S)-3-({[5-乙基-3-(1-萘基甲基)-4,5-二氢-5-异噁唑基]羰基}氨基)-4-氧-5-(2,3,5,6-四氟苯氧基)戊酸(Inn)
依照实施例2的相同流程使实施例26的化合物进行反应以生成标题化合物。
1H-NMR(400MHz,DMSO-d6)δ12.3(br,1H),8.4(br,1H),8.0(m,1H),7.9(m,1H),7.8(m,1H),7.5-7.4(m,5H),5.0(br,2H),4.7(m,1H),4.0(s,2H),3.3(m,1H),3.1(m,1H),2.8(m,2H),2.5(m,1H),1.8(m,1H),1.7(m,1H),0.8(m,3H)
MS[M+H]+561
实施例28:(3S)-5-(叔丁氧基)-3-[({5-乙基-3-[2-(1-萘基)乙基]-4,5-二氢-5-异噁唑基}羰基)氨基]-2,5-二氧代戊基2,6-二氯苯甲酸酯(In)
依照制剂1、2、3、和4及实施例1的相同流程使1-萘丙醛和制剂6的化合物进行反应以生成标题化合物。
1H-NMR(400MHz,CDCl3)δ8.00(d,1H),7.85(m,1H),7.76(m,2H),7.57-7.28(m,7H),7.34-7.27(m,3H),5.20-5.05(m,2H),4.94&4.88(two m,1H),3.39-3.27(m,3H),2.97-2.72(m,5H),2.07(m,1H),1.86(m,1H),1.46&1.45(two s,9H),1.00&0.96(twot,3H)
实施例29:(3S)-5-[(2,6-二氯苯甲酰)氧基]-3-[({5-乙基-3-[2-(1-萘基)乙基]-4,5-二氢-5-异噁唑基}羰基)氨基]-4-氧戊酸(Ioo)
依照实施例2的相同流程使实施例28的化合物进行反应以生成标题化合物。
1H-NMR(400MHz,DMSO-d6)δ8.45(bd,1H),8.06(d,1H),7.90(d,1H),7.77(d,1H),7.60-7.37(m,7H),5.21-5.03(m,2H),4.73(m,1H),3.06(m,2H),2.65(bd,4H),1.91&1.74(two m,2H),0.84(m,3H)
制剂19:5-乙基-3-[(1-萘氧基)甲基]-4,5-二氢-5-异噁唑羧酸乙酯(VI1)
使2-硝基乙醇吡喃基衍生物(见Synthesis,1993,12,1206-1208)和2-乙基丙烯酸乙酯进行反应并使得到的产物去保护以生成5-乙基-(3-羟甲基)-4,5-二氢-5-异噁唑羧酸乙酯(23%)。将此化合物进行溴化(CBr4,PPh3,94%),然后与1-萘酚进行反应(NaH,DMF,82%)以生成标题化合物。
1H-NMR(500MHz,CDCl3)δ8.20(m,1H),7.81(d,1H),7.55-7.42(m,3H),7.36(m,1H),6.88(d,1H),5.01(dd,2H),4.22(m,2H),3.61(d,1H),3.07(d,1H),1.97(m,2H),1.27(t,3H),0.93(t,3H)
实施例30:(3S)-3-[({5-乙基-3-[(1-萘氧基)甲基]-4,5-二氢-5-异噁唑基}羰基)氨基]-4-氧-5-(2,3,5,6-四氟苯氧基)戊酸(Ipp)
依照制剂4及实施例1和2的相同流程使制剂19和10的化合物进行反应以生成标题化合物。
1H-NMR(400MHz,DMSO-d6)δ8.51(br,1H),8.13(m,1H),7.87(m,1H),7.54-7.38(m,5H),7.02(m,1H),5.18-4.97(m,4H),4.71(m,1H),3.58(two d,1H),3.21(two d,1H),2.68(m,2H),1.97(m,1H),1.81(m,1H),0.86(two t,3H)
Ms M+H 577
实施例31:(3S)-3-{[(3-{[(4-氯-1-萘基)氧基]甲基}-5-乙基-4,5-二氢-5-异噁唑基)羰基]氨基}-4-氧-5-(2,3,5,6-四氟苯氧基)戊酸(Iqq)
依照制剂19的相同流程使在制剂19的过程中作为中间体得到的溴衍生物和4-氯-1-萘酚进行反应以生成5-乙基-3-[(4-氯-1-萘氧基)甲基]-4,5-二氢-5-异噁唑羧酸乙酯,然后依照制剂4及实施例1和2的相同流程使之进行反应以生成标题化合物。
1H-NMR(400MHz,DMSO-d6)δ8.65(m,1H),8.24-8.09(m,2H),7.78-7.35(m,4H),7.06(m,1H),5.17-5.07(m,4H),4.82-4.69(m,1H),3.45(two d,1H),3.23(two d,1H),2.83-2.52(m,2H),1.96-1.79(m,2H),0.86(two t,3H)
Ms M+H 611
制剂20:(3S)-3-氨基-4-羟基丁酸叔丁酯
在氮气气氛下向N-苄氧基羰基-β-叔丁基天冬氨酸(3.0g,9.28mmol)和NMM(1.12ml,1.1Eq)中添加无水四氢呋喃(20ml)。将反应溶液置于0℃。添加氯甲酸异丁酯(1.26ml,1.05Eq),并将混合液搅动大约40分钟。在氮气下将由此得到的浆体过滤,并于-78℃将得到的溶液添加到NaBH4(702mg,2.0Eq)溶液[甲醇(10ml)-无水四氢呋喃(20ml)]中。将得到的混合液缓慢升温至室温(两小时)。添加乙酸(2.3ml)终止反应,并在减压下将反应溶液蒸馏以除去甲醇。用乙酸乙酯(50ml×2)萃取残余物,用水和氯化钠水溶液清洗,干燥(无水Na2SO4),在减压下浓缩,并通过柱层析(乙酸乙酯-己烷,1∶5)分离-纯化以生成醇化合物(2.52g,收率88%)。
在氢气环境下(Pd/C)将上面得到的化合物的苄氧基羰基基团去除一小时以生成标题化合物(收率100%)。
1H-NMR(400MHz,DMSO-d6)δ4.60(bs,1H),3.21(m,2H),2.96(m,1H),2.41(dd,1H),2.03(dd,1H),1.40(s,9H)
制剂21:(3S)-4-羟基-3-({[(5R)-5-异丙基-3-(1-异喹啉基)-4,5-二氢-5-异噁唑基]羰基}氨基)丁酸叔丁酯(XVI)
依照制剂4的相同流程使制剂14的化合物进行反应以生成活性羧酸衍生物(VIIf)。将所述活性羧酸衍生物(VIIf,224mg,0.79mmol)、在制剂20中制备的氨基醇衍生物(166mg,1.2Eq)、和HATU(390mg,1.3Eq)的混合物冷却至0℃,在溶剂DMF(5ml)中添加三乙胺(0.33ml,3.0Eq),并将得到的混合液反应两小时。在减压下蒸馏除去溶剂,并用乙酸乙酯(50ml×2)萃取残余物,用水、碳酸氢钠水溶液、和氯化钠水溶液清洗,干燥(无水Na2SO4),在减压下浓缩,并通过柱层析(60-70%EA/Hex)纯化以生成标题化合物(330mg,收率95%)。
1H-NMR(400MHz,CDCl3)δ9.16(d,1H),8.55(d,1H),7.85(d,1H),7.73-7.70(m,3H),7.56(NH,d,1H),4.26(m,1H),4.12(d,1H),4.04(d,1H),3.79(d,1H),3.75(t,2H),2.94(bs,1H),2.57(m,2H),2.41(m,1H),1.10&1.07(two d,6H)
实施例32:6-(叔丁基)1-乙基(2E,4S)-4-({[(5R)-5-异丙基-3-(1-异喹啉基)-4,5-二氢-5-异噁唑基]羰基}氨基)-2-己烯二酸酯(Iq)
向制剂21的化合物(107mg,0.24mmol)和Dess-Martin试剂(153mg,1.5Eq)中添加无水二氯甲烷(4ml),于室温将混合液搅动一小时,并在减压下浓缩。向残余物中添加无水THF(3ml)和(乙氧羰基亚甲基)三苯基正膦((carboethoxymethylene)triphenylphosphorane)(108mg,1.3Eq),并将混合液回流两小时。用乙酸乙酯(20ml×2)萃取反应混合液,用水、饱和碳酸氢钠水溶液、和氯化钠水溶液清洗,干燥(无水Na2SO4),在减压下浓缩,并通过制备性层析(40%乙酸乙酯-己烷)初步纯化以生成非对映异构体比率为3∶1的标题化合物(98mg,80%)。
主要异构体的1H-NMR(500MHz,CDCl3)δ9.15(d,1H),8.54(d,1H),7.86(d,1H),7.74-7.62(m,4H),6.93(dd,1H),6.00(dd,1H),4.98(m,1H),4.19(qt,2H),4.02(d,1H),3.81(d,1H),2.58(m,2H),2.43(m,1H),1.36(s,9H),1.27(t,3H),1.07&1.06(two d,6H)
实施例33:(3S,4E)-6-乙氧基-3-({[(5R)-5-异丙基-3-(1-异喹啉基)-4,5-二氢-5-异噁唑基]羰基}氨基)-6-氧-4-己烯酸(Irr)
依照实施例2的相同流程使实施例32的化合物进行反应以生成标题化合物。
主要异构体的1H-NMR(500MHz,MeOD-d3)δ9.04(d,1H),8.61(d,1H),8.52(d,1H),7.95(d,1H),7.81-7.68(m,3H),6.94(dd,1H),6.00(dd,1H),5.01(m,1H),4.17(q t,2H),3.90(d,1H),3.82(d,1H),2.71(d,2H),2.39(septet,1H),1.26(t,3H),1.07&1.06(twod,6H)
MS:M+H 454
实施例34:(3S,4E)-3-({[(5R)-5-异丙基-3-(1-异喹啉基)-4,5-二氢-5-异噁唑基]羰基}氨基)-5-(甲磺酰基)-4-戊烯酸叔丁酯(Ir)
将无水二氯甲烷(4ml)添加到实施例21的化合物(109mg,0.25mmol)和Dess-Martin试剂(157mg,1.5Eq)中,于室温将混合液搅动一小时,并在减压下浓缩。添加异丙醇(0.5ml)终止反应。在减压下使用Celite(硅藻土)过滤以除去固体。用乙酸乙酯(20ml×2)萃取滤出液,用水、饱和碳酸氢钠水溶液、和氯化钠水溶液清洗,干燥(无水Na2SO4),并在减压下浓缩以生成醛化合物(540mg,收率99%)。
将甲磺酰甲膦酸二乙酯(113mg,2.0Eq,Synthesis,1969,170)溶于THF(3ml),添加NaH(60%溶于矿物油,20mg,2.0Eq)和上面得到的醛化合物,并将混合液回流两小时。用乙酸乙酯(20ml×2)萃取后,用水、饱和碳酸氢钠水溶液、和氯化钠水溶液清洗萃取液,干燥(无水Na2SO4),在减压下浓缩,并通过制备性层析(60%乙酸乙酯/己烷)纯化以生成非对映异构体比率为4∶1的标题化合物(52mg,41%)。
主要非对映异构体的1H-NMR(500MHz,CDCl3)δ9.14(d,1H),8.55(d,1H),7.86(d,1H),7.76-7.65(m,4H),6.92(dd,1H),6.57(dd,1H),5.03(m,1H),4.02(d,1H),3.81(d,1H),2.94(s,3H),2.61(m,2H),2.41(septet,1H),1.36(s,9H),1.10&1.08(两组d,6H)
实施例35:(3S,4E)-3-({[(5R)-5-异丙基-3-(1-异喹啉基)-4,5-二氢-5-异噁唑基]羰基}氨基)-5-(甲磺酰基)-4-戊烯酸(Iss)
依照实施例2的相同流程使实施例34的化合物进行反应以生成标题化合物。
主要异构体的1H-NMR(500MHz,MeOD-d3)δ9.04(d,1H),8.52(d,1H),7.95(d,1H),7.82-7.69(m,3H),6.90(dd,1H),6.71(dd,1H),5.06(m,1H),3.86(m,2H),2.98(s,3H),2.76(d,2H),2.39(m,1H),1.08&1.06(两组d,6H)
MS:M+H 460
实施例36-42的制备方法
根据需要,通过制备性HPLC使用手性OD柱,将通过依照制剂1、2、和3(或者制剂1和16)的相同流程使(异)喹啉甲醛(或者1-或2-萘甲醛)和2-乙基丙烯酸乙酯(或是2-丙基丙烯酸乙酯)进行反应而得到的化合物纯化以分离活性手性异构体。依照制剂4的相同流程水解分离的活性手性异构体或无活性手性异构体,并依照实施例1和2的相同流程使得到的化合物与3-氨基-5-氟-4-羟基戊酸叔丁酯进行反应以生成下文实施例36-42的标题化合物。
实施例36:5-氟-3-({[(5S)-3-(1-异喹啉基)-5-丙基-4,5-二氢-5-异噁唑基]羰基}氨基)-4-氧戊酸)(Itt)
1H-NMR(500MHz,DMSO-d6)δ9.02(t,1H),8.61(m,2H),8.08(d,1H),7.96(m,1H),7.85(t,1H),7.78(m,1H),5.05(bs,2H),4.73(m,1H),3.97-3.92(dd,1H),3.70-3.65(two d,1H),2.90-2.70(two m,2H),2.03(m,1H),1.91(m,1H),1.48(m,1H),1.32(m,1H),0.93(m,3H)
Ms M+H 416
实施例37:(3-({[(5S)-5-乙基-3-(1-萘基)-4,5-二氢-5-异噁唑基]羰基}氨基)-5-氟-4-氧戊酸)(Iuu)
1H-NMR(500MHz,DMSO-d6)δ8.84(s,1H),8.59(bs,1H),8.02(m,2H),7.75(s,1H),7.60(m,3H),5.01(bs,2H),4.73(m,1H),3.87-3.82(dd,1H),3.70-3.65(two d,1H),2.82-2.73(two m,2H),2.05(m,1H),1.95(m,1H),0.96(m,3H)
Ms M+H 401
实施例38:(3-({[(5S)-5-乙基-3-(2-喹啉基)-4,5-二氢-5-异噁唑基]羰基}氨基)-5-氟-4-氧戊酸)(Ivv)
1H-NMR(500MHz,DMSO-d6)δ8.61(dd,1H),8.41(m,1H),8.02(m,3H),7.79(t,1H),7.65(t,1H),5.22-5.06(m,1H),4.72(m,1H),4.49-4.28(m,1H),3.84(m,1H),3.54(m,1H),2.99-2.54(twom,2H),2.01(m,1H),1.91(m,1H),0.91(m,3H)
Ms M+H 402
实施例39:(3-({[(5R)-5-乙基-3-(3-异喹啉基)-4,5-二氢-5-异噁唑基]羰基}氨基)-5-氟-4-氧戊酸)(Iww)
1H-NMR(400MHz,CDCl3)δ9.25&9.16(two s,1H),8.08-7.64(m,5H),4.90-4.84(m,1H),4.79-4.54(m,2H),4.01-3.93(two d,1H),3.54(d,1H),3.03-2.87(m,2H),2.27-2.19&2.10-2.01(two m,2H),1.10-1.06(m,3H)
Ms M+H 402
实施例40:3-({[5-乙基-3-(8-喹啉基)-4,5-二氢-5-异噁唑基]羰基}氨基)-5-氟-4-氧戊酸)(Ixx)
1H-NMR(500MHz,CDCl3)δ8.98&8.93(two m,1H),8.56-8.21(m,1H),8.03-7.94(m,2H),7.73(bs,1H),7.60(m,1H),7.53-7.48(twom,1H),4.94-4.64(m,3H),4.27-4.22(two d,1H),3.77(d,1H),3.07&2.92(two m,2H),2.31-2.22(m,1H),2.12-2.05(m,1H),1.10(t,3H)
Ms M+H 402
实施例41:3-({[5-乙基-3-(3-喹啉基)-4,5-二氢-5-异噁唑基]羰基}氨基)-5-氟-4-氧戊酸)(Iyy)
1H-NMR(400MHz,CDCl3)δ9.32&9.25(two d,1H),8.16-8.03(m,2H),7.83-7.73(m,3H),7.62-7.55(m,1H),4.95-4.76(m,3H),3.86(two d,1H),3.45-3.39(two d,1H),3.17-3.01(two m,1H),2.90-2.82(m,1H),2.27-2.20(m,1H),2.09-2.00(m,1H),1.10-1.05(m,3H)
Ms M+H 402
实施例42:5-氟-3-({[(5R)-5-异丙基-3-(2-喹啉基)-4,5-二氢-5-异噁唑基]羰基}氨基)-4-氧戊酸)(Izz)
1H-NMR(400MHz,CDCl3)δ8.24(m,1H),8.14(m,1H),8.04(d,1H),7.88(d,1H),7.79(m,1H),7.65(m,1H),7.51(b s,1H),5.13-4.35(m,3H),4.05-4.00(two d,1H),3.73(d,1H),3.05-2.82(m,2H),2.42(m,1H),1.10(m,6H)
Ms M+H 416
实施例43-48的制备方法
根据需要,通过制备性HPLC使用手性OD柱,将通过依照制剂1、2、和3(或者制剂1和16)的相同流程使芳香醛(Bioorg.Med.Chem.Lett.,1996,6,2173页;J.Org.Chem.,1978,43,1372)和2-乙基丙烯酸乙酯(或者2-异丙基丙烯酸乙酯)进行反应而得到的化合物纯化以分离活性手性异构体。依照制剂4的相同流程水解分离的活性手性异构体或无活性手性异构体,并依照实施例1和2的相同流程使得到的化合物与3-氨基-5-氟-4-羟基戊酸叔丁酯进行反应以生成下文实施例43-48的标题化合物。
实施例43:3-({[5-乙基-3-(2-异丙基苯基)-4,5-二氢-5-异噁唑基]羰基}氨基)-5-氟-4-氧戊酸(Iaa1)
1H-NMR(500MHz,DMSO-d6)δ8.53(bs,1H),7.40(m,2H),7.32(m,1H),7.25(m,1H),5.02(bs,2H),4.72(m,1H),3.60-3.54(two d,1H),3.46-3.43(two d,1H),3.40(m,1H),2.78-2.60(two m,2H),1.95(m,1H),1.85(m,1H),1.14(s,6H),0.88(m,3H)
Ms M+H 393
实施例44:3-[({3-[3-(叔丁基)苯基]-5-乙基-4,5-二氢-5-异噁唑基}羰基)氨基]-5-氟-4-氧戊酸(Iaa2)
1H-NMR(400MHz,DMSO-d6)δ8.56(dd,1H),7.67(s,1H),7.48(m,1H),7.38(d,2H),5.24-5.12(q,1H),4.76-4.69(m,1H),4.59-4.26(m,1H),3.68(m,1H),3.49-3.43(two d,1H),2.96-2.56(two m,2H),1.98(m,1H),1.85(m,1H),1.29(s,9H),0.89(d,3H)
Ms M+H 407
实施例45:3-[({3-[4-(叔丁基)苯基]-5-乙基-4,5-二氢-5-异噁唑基}羰基)氨基]-5-氟-4-氧戊酸(Iaa3)
1H-NMR(500MHz,DMSO-d6)δ8.52(bs,1H),7.58(m,2H),7.43(dd,2H),5.10(bs,2H),4.71-4.65(m,1H),3.65-3.59(two d,1H),3.40-3.35(two d,1H),2.86-2.60(two m,2H),1.94(m,1H),1.82(m,1H),1.24(s,9H),0.86(m,3H)
Ms M+H 407
实施例46:5-氟-3-({[(5R)-5-异丙基-3-(2-异丙基苯基)-4,5-二氢-5-异噁唑基]羰基}氨基)-4-氧戊酸(Iaa4)
1H-NMR(500MHz,CDCl3)δ7.60-7.53(m,1H),7.41(m,2H),7.27-7.23(m,2H),5.20-4.91(m,1H),4.71(m,1H),4.54-4.42(m,1H),3.69-3.64(two d,1H),3.45-3.38(m,2H),3.12-2.77(m,2H),2.32(m,1H),1.22(d,6H),1.05(d,6H)
Ms M+H 407
实施例47:3-[({(5R)-3-[3-(叔丁基)苯基]-5-异丙基-4,5-二氢-5-异噁唑基}羰基)氨基]-5-氟-4-氧戊酸(Iaa5)
1H-NMR(500MHz,CDCl3)δ7.69(s,1H),7.48(d,1H),7.41(d,1H),7.35(t,1H),4.74-4.50(m,3H),3.69(d,1H),3.40(d,1H),3.06-2.77(m,2H),2.32(m,1H),1.33(s,9H),1.04(m,6H)
Ms M+H 421
实施例48:3-{[(3-[1,1′-联苯]-3-基-5-异丙基-4,5-二氢-5-异噁唑基)羰基]氨基}-5-氟-4-氧戊酸(Iaa6)
将3-联苯甲醛(见Synthesis,2003,337)用作起始材料以生成标题化合物。
1H-NMR(500MHz,DMSO-d6)δ8.42(bs,1H),7.87(d,1H),7.73-7.69(m,4H),7.52(m,1H),7.45(m,2H),7.38(m,1H),5.03(bs,2H),4.63(m,1H),3.73-3.57(m,2H),2.67-2.63(two m,2H),2.22(m,1H),0.89(m,6H)
Ms M+H 441
实施例49-59的制备方法
通过US 6043248,JOC 1982,47,第4315页中已知的方法得到4-取代的吡啶2-甲醛,并依照制剂1、2、和3(或者制剂1和16)的相同流程使它们进行反应。根据需要,通过制备性HPLC使用手性OD柱,将得到的化合物纯化以分离活性手性异构体。依照制剂4的相同流程水解分离的活性手性异构体或无活性手性异构体,并依照实施例1和2的相同流程使得到的化合物与3-氨基-5-氟-4-羟基戊酸叔丁酯进行反应以生成下文实施例49-59的标题化合物。
实施例49:3-({[5-乙基-3-(2-吡啶基)-4,5-二氢-5-异噁唑基]羰基}氨基)-5-氟-4-氧戊酸(Iaa7)
1H-NMR(500MHz,DMSO-d6)δ12.41(bs,1H),8.61(s,1H),8.59-8.53(dd,1H),7.87(m,1H),7.44(m,1H),5.19-5.04(two d,1H),4.70(m,1H),4.45-4.27(m,1H),3.67(m,1H),3.42(m,1H),2.95-2.53(two m,2H),1.96(m,1H),1.86(m,1H),0.85(m,3H)
Ms M+H 352
实施例50:3-[({3-[4-(叔丁基)-2-吡啶基]-5-乙基-4,5-二氢-5-异噁唑基}羰基)氨基]-5-氟-4-氧戊酸(Iaa8)
1H-NMR(400MHz,CDCl3)δ8.58(d,1H),7.90(s,1H),7.65(bs,1H),7.45-7.39(m,1H),4.98-4.68(m,3H),3.92&3.88(two d,1H),3.52 & 3.47(two d,1H),3.05-2.86(m,2H),2.23-2.18(m,1H),2.08-2.00(m,1H),1.38(s,9H),1.05(t,3H)
Ms M+H 408
实施例51:3-[({(5R)-3-[4-(叔丁基)-2-吡啶基]-5-异丙基-4,5-二氢-5-异噁唑基}羰基)氨基]-5-氟-4-氧戊酸(Iaa9)
1H-NMR(400MHz,CDCl3)δ8.58(d,1H),7.88(d,1H),7.61(bs,1H),7.43(m,1H),4.84(m,1H),4.60(bs,2H),3.89-3.82(two d,1H),3.60-3.55(two d,1H),3.04-2.86(m,2H),2.38(m,1H),1.38(s,9H),1.07(m,6H)
Ms M+H 422
实施例52:3-({[5-乙基-3-(4-异丁基-2-吡啶基)-4,5-二氢-5-异噁唑基]羰基}氨基)-5-氟-4-氧戊酸(Iaa10)
1H-NMR(500MHz,DMSO-d6)δ8.58-8.52(dd,1H),8.49(s,1H),7.68(s,1H),7.27(s,1H),5.19-5.04(m,1H),4.69(m,1H),4.46-4.29(m,1H),3.68(m,1H),3.41-3.37(dd,1H),2.93-2.46(m,4H),1.95-1.85(two m,3H),0.86-0.82(m,9H)
Ms M+H 408
实施例53:3-({[3-(4-乙酰基-2-吡啶基)-5-乙基-4,5-二氢-5-异噁唑基]羰基}氨基)-5-氟-4-氧戊酸(Iaa11)
1H-NMR(500MHz,CDCl3)δ8.79(d,1H),8.35(s,1H),7.76(d,1H),7.46(bs,1H),4.84-4.40(m,3H),3.90-3.85(two d,1H),3.51-3.46(two d,1H),3.04-2.84(m,2H),2.65(s,3H),HHHkdkdk2.16(m,1H),2.02(m,1H),1.03(m,3H)
Ms M+H 394
实施例54:3-({[3-(4-环丙基-2-吡啶基)-5-乙基-4,5-二氢-5-异噁唑基]羰基}氨基)-5-氟-4-氧戊酸(Iaa12)
1H-NMR(500MHz,DMSO-d6)δ12.39(b s,1H),8.41(t,1H),7.56(d,1H),7.12(m,1H),5.19-5.04(m,1H),4.72-4.66(m,1H),4.46-4.27(m,1H),3.69-3.63(m,1H),3.39-3.35(two d,1H),2.80-2.74(m,1H),2.63-2.52(m,1H),2.00-1.80(m,3H),1.06(m,2H),0.86-0.80(m,5H)
Ms M+H 392
实施例55:3-({[3-(4-环戊基-2-吡啶基)-5-乙基-4,5-二氢-5-异噁唑基]羰基}氨基)-5-氟-4-氧戊酸(Iaa13)
1H-NMR(500MHz,CDCl3)δ8.50(d,1H),7.67(m,2H),7.26(m,1H),4.88-4.82(m,1H),4.65(bs,2H),3.88-3.81(two d,1H),3.45-3.41(two d,1H),3.05(m,1H),2.96-2.80(m,2H),2.20-2.12(m,3H),2.02-1.96(m,1H),1.83(m,2H),1.72(m,2H),1.60(m,2H),1.01(t,3H)
Ms M+H 420
实施例56:3-({[(5R)-3-(4-环戊基-2-吡啶基)-5-异丙基-4,5-二氢-5-异噁唑基]羰基}氨基)-5-氟-4-氧戊酸(Iaa14)
1H-NMR(400MHz,CDCl3)δ8.58(m,1H),7.74(d,1H),7.63(bs,1H),7.38-7.32(dd,1H),4.88-4.81(m,1H),4.53(bs,2H),3.87-3.79(two d,1H),3.56-3.53(two d,1H),3.12-3.04(m,1H),3.02-2.85(m,2H),2.38(m,1H),2.16(m,2H),1.88(m,2H),1.78(m,2H),1.65(m,2H),1.07(m,6H)
Ms M+H 434
实施例57:3-({[3-(4-环己基-2-吡啶基)-5-乙基-4,5-二氢-5-异噁唑基]羰基}氨基)-5-氟-4-氧戊酸(Iaa15)
1H-NMR(400MHz,CDCl3)δ8.61(m,1H),7.75(d,1H),7.64(bs,1H),7.39-7.33(dd,1H),4.86-4.53(two m,3H),3.87(t,1H),3.50-3.45(dd,1H),3.05-2.85(two m,2H),2.63(m,1H),2.22(m,1H),2.03(m,1H),1.93-1.80(two m,5H),1.44(m,5H),1.05(t,3H)
Ms M+H 434
实施例58:3-({[5-乙基-3-(5,6,7,8-四氢-1-异喹啉基)-4,5-二氢-5-异噁唑基]羰基}氨基)-5-氟-4-氧戊酸(Iaa16)
1H-NMR(500MHz,DMSO-d6)δ8.60-8.53(dd,1H),8.30(d,1H),7.15(d,1H),5.20-5.05(m,1H),4.74-4.66(m,1H),4.45-4.25(m,1H),3.75-3.68(m,1H),3.47-3.41(m,1H),2.94-2.88(m,2H),2.80-2.72(m,3H),2.62-2.53(m,1H),1.99-1.93(m,1H),1.88-1.80(m,1H),1.71-1.69(m,4H),0.88-0.84(m,3H)
Ms M+H 406
实施例59:5-氟-3-({[5-异丙基-3-(4-苯基-2-吡啶基)-4,5-二氢-5-异噁唑基]羰基}氨基)-4-氧戊酸(Iaa17)
1H-NMR(400MHz,CDCl3)δ8.68(d,1H),8.14(s,1H),7.68(m,1H),7.58(m,1H),7.54-7.43(m,5H),4.86-4.60(m,3H),3.92-3.87(two d,1H),3.62(d,1H),3.09-2.86(m,2H),2.39(m,1H),1.11-1.06(m,6H)
Ms M+H 442
实施例60-63的制备方法
依照制剂5的相同流程使(2S)-4-(叔丁氧基)-2-({[(5R)-5-异丙基-3-(1-异喹啉基)-4,5-二氢-5-异噁唑基]羰基}氨基)-4-氧丁酸[通过偶联化合物(VIIf)与Asp(O-t-Bu)-OMe的反应和水解得到的]进行反应以生成溴甲基酮衍生物((3S)-5-溴-3-({[(5R)-5-异丙基-3-(1-异喹啉基)-4,5-二氢-5-异噁唑基]羰基}氨基)-4-氧戊酸叔丁酯)。使此溴甲基酮衍生物与二苯次膦酸在KF/DMF(见制剂5)中进行反应以生成二苯基磷酰氧基甲基酮衍生物,然后依照实施例2的相同流程进行反应以生成标题化合物(实施例60的化合物)。
依照上文所述相同流程由1-苯基-3-(三氟甲基)-1H-吡唑-5-醇、3-苄基-4-羟基-2(5H)-呋喃酮、或异丁酸得到下文实施例61-63的化合物。
实施例60:(3S)-5-[(二苯基磷酰基)氧基]-3-({[(5R)-5-异丙基-3-(1-异喹啉基)-4,5-二氢-5-异噁唑基]羰基}氨基)-4-氧戊酸(Iaa18)
1H-NMR(500MHz,DMSO-d6)δ8.92(m,1H),8.58(m,1H),8.05(m,1H),7.94(m,1H),7.81(m,1H),7.75-7.72(m,3H),7.57(m,3H),7.49(m,4H),7.35(m,2H),4.90-4.65(two m,3H),3.79-3.75(twod,1H),3.69-3.67(two d,1H),2.65(two m,2H),2.22(m,1H),0.84(m,6H)
Ms M+H 614
实施例61:(3S)-3-({[(5R)-5-异丙基-3-(1-异喹啉基)-4,5-二氢-5-异噁唑基]羰基}氨基)-4-氧-5-{[1-苯基-3-(三氟甲基)-1H-吡唑-5-基]氧基}戊酸(Iaa19)
1H-NMR(500MHz,DMSO-d6)δ8.95(m,1H),8.83(d,1H),8.57(m,1H),8.03(d,1H),7.92(d,1H),7.80(m,1H),7.74(m,1H),7.65(d,1H),7.57(m,1H),7.51-7.34(m,3H),6.27(s,1H),5.29-5.15(m,2H),4.76(m,1H),3.92-3.88(m,1H),3.75-3.69(m,1H),2.84-2.60(m,2H),2.33(m,1H),0.96(m,6H)
Ms M+H 624
实施例62:(3S)-5-[(4-苄基-5-氧-2,5-二氢-3-呋喃基)氧基]-3-({[(5R)-5-异丙基-3-(1-异喹啉基)-4,5-二氢-5-异噁唑基]羰基}氨基)-4-氧戊酸(Iaa20)
1H-NMR(500MHz,DMSO-d6)δ8.97(t,1H),8.58(d,1H),8.04(d,1H),7.92(d,1H),7.81(m,1H),7.73(m,1H),7.23-7.07(m,6H),7.51(m,1H),4.79-4.65(m,3H),3.92-3.87(two d,1H),3.74-3.68(two d,1H),2.82-2.58(m,2H),2.31(m,1H),0.95(m,6H)
Ms M+H 586
实施例63:(3S)-5-(异丁酰氧基)-3-({[(5R)-5-异丙基-3-(1-异喹啉基)-4,5-二氢-5-异噁唑基]羰基}氨基)-4-氧戊酸(Iaa21)
1H-NMR(500MHz,DMSO-d6)δ12.39(bs,1H),8.96(t,1H),8.73(m,1H),8.58(dd,1H),8.04(d,1H),7.92(d,1H),7.81(t,1H),7.73(m,1H),4.78(m,2H),4.68(m,1H),3.87(t,1H),3.73-3.68(two d,1H),2.79-2.60(two m,2H),2.56(m,1H),2.31(m,1H),1.05(d,3H),0.95(m,9H)
Ms M+H 484
实施例64:(3S)-3-({[(5R)-5-异丙基-3-(1-异喹啉基)-4,5-二氢-5-异噁唑基]羰基}氨基)-4-氧-5-己烯酸(Iaa22)
使(2S)-4-(叔丁氧基)-2-({[(5R)-5-异丙基-3-(1-异喹啉基)-4,5-二氢-5-异噁唑基]羰基}氨基)-4-氧丁酸的weinreb酰胺衍生物(与N,O-二甲基羟胺的缩合衍生物)和乙烯基镁化溴进行反应,并依照实施例2的相同流程使得到的化合物进行反应以生成标题化合物。
1H-NMR(400MHz,DMSO-d6)δ12.27(bs,1H),8.95(t,1H),8.74-8.67(two d,1H),8.58(m,1H),8.04(d,1H),7.92(d,1H),7.83-7.72(m,2H),6.47(m,1H),6.22-6.11(two dd,1H),5.71-5.62(two dd,1H),4.77(m,1H),3.90-3.79(m,1H),3.72-3.64(m,1H),2.82(m,1H),2.62-2.49(m,1H),2.30(m,1H),0.94(m,6H)
Ms M+H 410
制剂22:(3S)-3-氨基-4-羟基-5-(2-吡啶氧基)戊酸叔丁酯(VIIIf)
将溴甲基酮衍生物(X,3.2g,7.93mmol)即制剂5的中间体溶于苯(30ml),添加Ag2CO3(2.62g,1.2Eq)和2-羟基吡啶(0.93g,1.2Eq),并将混合液于80℃在回流下搅动3天。将反应混合液用Celite(硅藻土)过滤,在减压下浓缩,并通过柱层析纯化以生成2-吡啶氧基甲基酮衍生物(XIf)(466mg,收率14%)。
将由此得到的2-吡啶氧基甲基酮衍生物(XIf)(227mg,0.548mmol)溶于四氢呋喃/甲醇(3∶2v/v)的溶剂混合液(10ml),于0℃添加NaBH4(43mg,2.0Eq),并将混合液于室温搅动30分钟。添加饱和氯化铵溶液终止反应,并在减压下浓缩反应溶液。用乙酸乙酯萃取残余物,用水和氯化钠水溶液清洗,干燥(无水Na2SO4),并在减压下浓缩以生成化合物(XIIf)(230mg),其中酮基团还原成羟基。
在氢气环境下(Pd/C)将上文制备的化合物的苄氧基羰基基团去除40分钟以生成标题化合物(155mg,99%)。
实施例65-66的制备方法
依照实施例1和2的相同流程使化合物VIIf(或VIIu)和VIIIf进行反应以生成实施例65-66的标题化合物。在这里,VIIu代表5-乙基-3-(2-异丙基苯基)-4,5-二氢-5-异噁唑羧酸。
实施例65:(3S)-3-({[(5R)-5-异丙基-3-(1-异喹啉基)-4,5-二氢-5-异噁唑基]羰基}氨基)-4-氧-5-(2-吡啶氧基)戊酸(Iaa23)
1H-NMR(500MHz,MeOH-d4)δ9.04(d,1H),8.50(d,1H),7.95(d,1H),7.81(d,1H),7.77(t,1H),7.69(t,1H),7.59(m,1H),6.85-6.80(m,2H),6.67(bs,1H),5.07(bs,1H),4.95(t,1H),4.84(m,1H),3.94-3.79(Abq,2H),2.92-2.80(m,2H),2.39(m,1H),1.09(m,6H)
Ms M+H 491
实施例66:(3S)-3-({[5-乙基-3-(2-异丙基苯基)-4,5-二氢-5-异噁唑基]羰基}氨基)-4-氧-5-(2-吡啶氧基)戊酸(Iaa24)
1H-NMR(500MHz,DMSO-d6)δ8.71(bs,1H),8.02-7.94(two bs,1H),7.71-7.64(m,1H),7.42-7.18(m,4H),6.96-6.90(two t,1H),6.85-6.80(two d,1H),4.99(bs,2H),4.86-4.78(m,1H),3.58(twod,1H),3.48(two d,1H),3.36(m,1H),2.81-2.61(m,2H),2.05-1.80(two m,2H),1.14-1.03(m,6H),0.93-0.88(m,3H)
Ms M+H 468.21
实施例67:2-{[(3S)-4-羧基-3-({[(5R)-5-异丙基-3-(1-异喹啉基)-4,5-二氢-5-异噁唑基]羰基}氨基)-2-氧代丁基]氧基}-1-甲基吡啶鎓三氟甲磺酸盐(Iaa25)
将实施例65中Dess-Martin氧化反应后得到的中间体((3S)-3-({[(5R)-5-异丙基-3-(1-异喹啉基)-4,5-二氢-5-异噁唑基]羰基}氨基)-4-氧-5-(2-吡啶氧基)戊酸叔丁酯(49mg,90μmol)溶于二氯甲烷(2ml),添加三氟甲磺酸甲酯(1.1Eq,10.1μl),并将混合液于室温搅动一天。在减压下浓缩后,将残余物进行实施例2的相同流程以生成标题化合物(60mg)。
1H-NMR(500MHz,DMSO-d6)δ9.00-8.91(m,2H),8.76-8.57(m,2H),8.42(m,1H),8.04(m,1H),7.93(m,1H),7.80(m,1H),7.75(m,1H),7.54(m,1H),5.77-5.48(m,2H),4.85-4.81(m,1H),4.00(s,3H),3.94-3.69(m,2H),2.87-2.60(m,2H),2.33(m,1H),0.98&0.94(two d,6H)
Ms M+505.20
实施例68:2-{[(3S)-4-羧基-3-({[5-乙基-3-(2-异丙基苯基)-4,5-二氢-5-异噁唑基]羰基}氨基)-2-氧代丁基]氧基}-1-甲基吡啶鎓三氟甲磺酸盐(Iaa26)
将实施例66中Dess-Martin氧化反应后得到的中间产物(3S)-3-({[5-乙基-3-(2-异丙基苯基)-4,5-二氢-5-异噁唑基]羰基}氨基)-4-氧-5-(2-吡啶氧基)戊酸叔丁酯(55mg,0.105mmol)溶于二氯甲烷(2ml),添加三氟甲磺酸甲酯(1.1Eq,13μl),并将混合液于室温搅动一天。在减压下浓缩后,将残余物进行实施例2的相同流程以生成标题化合物(59mg,94%)。
1H-NMR(500MHz,DMSO-d6)δ8.80-8.73(two d,1H),8.65(m,1H),8.45-8.38(m,1H),7.56-7.51(m,2H),7.43-7.31(m,3H),7.24-7.12(m,H),5.72-5.48(m,2H),4.91(m,1H),4.01&3.99(twos,3H),3.64(two d,1H),3.48(two d,1H),3.42(m,1H),2.90-2.62(m,2H),2.05-1.80(two m,2H),1.15-1.03(m,6H),0.93-0.88(m,3H)
Ms M+482.17
实施例69-70的制备方法
依照制剂1、17、4和实施例1、2的相同流程使5-氯-1-甲基-1H-吲哚-2-醛或1,5-二甲基-1H-吲哚-2-醛的肟衍生物与3-氨基-5-氟-4-羟基戊酸叔丁酯进行反应以生成实施例69-70的标题化合物。
实施例69:3-({[3-(5-氯-1-甲基-1H-吲哚-2-基)-5-异丙基-4,5-二氢-5-异噁唑基]羰基}氨基)-5-氟-4-氧戊酸(Iaa27)
1H-NMR(500MHz,CDCl3)δ7.59(s,1H),7.46-7.39(two d,1H),7.30-7.23(m,3H),5.01(m,1H),4.75-4.46(m,2H),4.02(d,1H),3.95(s,3H),3.71(d,1H),2.95(m,1H),2.77(m,1H),2.35(m,1H),1.04(m,6H)
Ms M+H 452
实施例70:3-({[3-(1,5-二甲基-1H-吲哚-2-基)-5-异丙基-4,5-二氢-5-异噁唑基]羰基}氨基)-5-氟-4-氧戊酸(Iaa28)
1H-NMR(500MHz,CDCl3)δ7.48(bs,1H),7.39(d,1H),7.23-7.14(m,3H),4.76(m,1H),4.70-4.50(m,2H),4.07-4.02(twod,1H),3.99,3.94&3.93(three s,3H),3.75-3.48(m,1H),2.94-2.82(two m,1H),2.46-2.43(two s,3H),2.34(m,1H),1.05(m,6H)
Ms M+H 432
制剂23:(5R)-5-异丙基-3-(1-异喹啉基)-4,5-二氢-5-异噁唑羧酸的拆分
通过加热至60℃将5-异丙基-3-(1-异喹啉基)-4,5-二氢-5-异噁唑羧酸溶于丙酮(190ml),并添加(S)-α-甲基-苄胺(14.5ml,112mmol)。将反应混合液冷却至室温并搅动4小时。将得到的沉淀过滤并用丙酮(40ml)清洗三次。
通过加热至90℃将由此得到的(5R)-5-异丙基-3-(1-异喹啉基)-4,5-二氢-5-异噁唑羧酸的(S)-α-甲基-苄胺盐溶于丙酮和水(4∶1)的混合液(150ml),冷却至室温,并搅动3小时。将得到的沉淀过滤并用丙酮(40ml)清洗三次以生成纯的(5R)-5-异丙基-3-(1-异喹啉基)-4,5-二氢-5-异噁唑羧酸的(S)-α-甲基-苄胺盐(12.8g,24.3%,99.8%ee)。
使用ChiralCel OD柱(4.6×250mm,5mm)评估(5R)-5-异丙基-3-(1-异喹啉基)-4,5-二氢-5-异噁唑羧酸的光学纯度。使用正己烷/异丙醇/三氟乙酸(92/8/0.1)的混合液作为流动相,流速1ml/分钟,柱温40℃,检测波长225nm。分别在7.8分钟(R异构体)和21.1分钟(S异构体)的保留时间观察到两种光学异构体。
实施例71:化合物(Iii-1)的拆分
1)种子化合物的分离
使用制备性液相层析二氧化硅柱(直径40mm,DYNAMAX-100)分离实施例16的两种非对映异构体。将正己烷/乙醇/三氟乙酸(4000/32/2)的混合液用作流动相,流速50ml/分钟,并于检测波长227nm下,在62-66分钟的保留时间中以比率99∶1收集期望的非对映异构体(两种非对映异构体以连续变化的比率广泛洗脱直至86分钟)。将由此得到的99∶1比率的非对映异构体去保护并作为种子用于拆分。
使用Atlantis C18柱(4.6×250mm,5mm)评估光学纯度。依照如下梯度使用乙腈/水/三氟乙酸的混合液作为流动相,流速1ml/分钟:
t=0分钟, 0∶100∶0.1
3分钟, 20∶80∶0.1
50分钟, 100∶0∶0.1
在检测波长227nm下,分别在36.6分钟(3R,5R异构体)和37.1分钟(3S,5R异构体)的保留时间观察到两种光学异构体。
(3S,5R异构体):(3S)-5-氟-3-({[(5R)-5-异丙基-3-(1-异喹啉基)-4,5-二氢-5-异噁唑基]羰基}氨基)-4-氧戊酸叔丁酯
1H-NMR(500MHz,CDCl3)δ9.13(d,1H),8.55(d,1H),7.85(d,1H),7.78-7.65(m,4H),5.22-5.02(two m,2H),4.90(m,1H),4.02(d,1H),3.80(d,1H),2.92-2.88(dd,1H),2.79-2.75(dd,1H),2.41(m,1H),1.34(s,9H),1.09(m,6H)
Ms M+H 472
(3R,5R异构体):(3R)-5-氟-3-({[(5R)-5-异丙基-3-(1-异喹啉基)-4,5-二氢-5-异噁唑基]羰基}氨基)-4-氧戊酸叔丁酯
1H-NMR(400MHz,CDCl3)δ9.14(d,1H),8.56(d,1H),7.87(d,1H),7.77-7.64(m,4H),5.25-5.00(two q,2H),4.90(m,1H),4.03(d,1H),3.82(d,1H),2.93(dd,1H),2.77(dd,1H),2.42(m,1H),1.35(s,9H),1.11(m,6H)
Ms M+H 472
(3S)-5-氟-3-({[(5R)-5-异丙基-3-(1-异喹啉基)-4,5-二氢-5-异噁唑基]羰基}氨基)-4-氧戊酸(Iii-1)
1H-NMR(400MHz,CDCl3)δ9.07(d,1H),8.57(d,1H),7.89(d,1H),7.78-7.69(m,3H),7.69(d,1H),4.88-4.79(m,2H),4.67(bs,1H),4.07(d,1H),3.81(d,1H),3.08-2.93(m,1H),2.91-2.82(m,1H),2.43(m,1H),1.12(m,6H)
Ms M+H 416
(3R)-5-氟-3-({[(5R)-5-异丙基-3-(1-异喹啉基)-4,5-二氢-5-异噁唑基]羰基}氨基)-4-氧戊酸(Iii-2)
1H-NMR(500MHz,CDCl3)δ9.07(d,1H),8.55(d,1H),7.87(d,1H),7.75-7.68(m,3H),7.52(bs,1H),5.20-4.35(m,3H),4.02(d,1H),3.80(d,1H),3.13-2.90(m,2H),2.39(m,1H),1.08(m,6H)Ms M+H 416
2)再结晶
(3S)-5-氟-3-({[(5R)-5-异丙基-3-(1-异喹啉基)-4,5-二氢-5-异噁唑基]羰基}氨基)-4-氧戊酸(Iii-1)
将粗制5-氟-3-({[(5R)-5-异丙基-3-(1-异喹啉基)-4,5-二氢-5-异噁唑基]羰基}氨基)-4-氧戊酸叔丁酯(366g)溶于二氯甲烷(1.9kg)并冷却至0℃。添加三乙基硅烷(235g)和三氟乙酸(1.88kg)并于0℃搅动一小时。在减压下蒸馏反应混合液,再溶于乙酸乙酯(2.4kg),并添加2N氢氧化钠水溶液(3.1L)将pH调至5.2。分离有机层,并将水层用乙酸乙酯(2.4kg)萃取一次。将合并的有机层在减压下蒸馏以除去溶剂,将得到的残余物溶于甲基叔丁基醚(530g),并添加少量结晶的(3S)-5-氟-3-({[(5R)-5-异丙基-3-(1-异喹啉基)-4,5-二氢-5-异噁唑基]羰基}氨基)-4-氧戊酸。于室温搅动16小时后,将得到的沉淀过滤并用甲基叔丁基醚和正己烷的9∶1混合液(210ml)清洗。
通过加热至50℃将由此得到的(3S)-5-氟-3-({[(5R)-5-异丙基-3-(1-异喹啉基)-4,5-二氢-5-异噁唑基]羰基}氨基)-4-氧戊酸溶于乙酸乙酯(240ml),缓慢添加正己烷(240ml),并逐渐冷却至室温。于室温搅动24小时后,将得到的沉淀过滤,并用乙酸乙酯和正己烷的1∶1混合液(30ml)清洗以生成标题化合物(Iii-1,46.0g,3S/3R=94/6.0)。使用Luna柱(4.6×250mm,5mm,C18)评估光学纯度。使用乙腈/20mM NH4OAc的混合液(pH 6)(30/70)作为流动相,流速1ml/分钟。在检测波长227nm下,分别在8.0分钟(3R异构体)和9.0分钟(3S异构体)的保留时间观察到两种光学异构体。
实验1:胱天蛋白酶抑制作用的测定
通过修改Thornberry,N.A.等,Nature,1992,356,768;Thornberry,N.A.,Methods in Enzymology,1994,244,615;Walker,N.P.C.等,Cell,1994,78,343中的已知方法,将已知是α2β2形式的半胱氨酸蛋白酶的胱天蛋白酶-1和胱天蛋白酶-8表达、纯化、并激活,还通过类似方法纯化胱天蛋白酶-9,并测试针对它们的抑制活性。简而言之,在大肠杆菌(E.coli)中表达p10和p20亚基(Thornberry,N.A.等,Nature,1992,356,768),并通过镍柱和阴离子交换层析纯化以生成胱天蛋白酶-1、胱天蛋白酶-8、和胱天蛋白酶-9。使用由此得到的胱天蛋白酶-1的荧光底物AcYVAD-AFC、胱天蛋白酶-8的荧光底物AcDEVD-AFC、和胱天蛋白酶-9的荧光底物AcLEHD-AFC来测定合成的抑制物的比活。在含50mM HEPES(pH 7.50)、10%(w/v)蔗糖、0.1%(w/v)CHAPS、100mM NaCl、1mM EDTA、和10mMDTT的缓冲液中,在存在50μM AcYVAD-AFC及相应的10nM胱天蛋白酶-1、50μM AcDEVD-AFC及相应的2.1nM胱天蛋白酶-8、和150μMAcLEHD-AFC及相应的200nM胱天蛋白酶-9时,于25℃以多种抑制物浓度进行酶促反应。通过使用荧光分光光度计随时间流逝测量反应速率并获得初始速率常数来测定抑制物的抑制常数Ki和Kobs。由Lineweaver Burk Plot计算Ki,并由如下方程式1计算Kobs。
方程式1
Kobs=-ln(1-At/Aoo)/t
其中
At指在时间t之时的切割速率(%),和
Aoo指最大切割速率(%)。
使用Molecular Device Co.的Spectra MAX GeminiXS荧光分光光度计,激发波长405nm,发射波长505nm。
通过使用Fas抗体(Upstate Biotech 05-201)使Jurkat细胞(ATCC TIB-152)进行凋亡,并通过在用抑制物处理细胞后,依照Francoeur A.M.和Assalian A.,Biochemica,1996,3,19-25中已知的WST-1法检测颜色变化以观察存活Jurkat细胞的数量,从而测定抑制物的体内抑制活性。使用Molecular Device Co.的Spectra MAX340分光光度计,吸收波长440nm。
表1
化合物编号 | 胱天蛋白酶-1Kobs/[I](M-1min-1) | 胱天蛋白酶-8Kobs/[I](M-1min-1) | 胱天蛋白酶-9Kobs/[I](M-1min-1) | Jurkat细胞IC50(μM) |
Icc | 1.9E5 | 3.3E4 | 22.5 | |
Idd | 3.1E5 | 1.9E5 | 4.25 | |
Iee | 1.8E5 | 32.6 | ||
Iff | 5.0E5 | 1.2 | ||
Igg | 2.7E6 | 1.5E6 | 3.2E5 | 0.17 |
Iii | 1.1E6 | 1.3E7 | 2.0E5 | 0.1 |
Iii-u* | 1.9E5 | 0.71 | ||
III-1 | 2.3E7 | |||
Iii-2 | 4.7E5 | |||
Ijj | 1.9E5 | 4.7 | ||
Ikk | 1.2E5 | 1.1 | ||
Ill | 1.3E5 | 39.2 | ||
Imm | 1.6E5 | 2.0 | ||
Inn | 2.6E5 | 6.5 | ||
Ioo | 2.0E4 | 50 | ||
Ipp | 2.3E6 | 1.7E5 | 3.5 | |
Iqq | 3.3E6 | 1.4E5 | 37 | |
Irr | 无活性 | |||
Iss | 无活性 | |||
Itt | 4.3E5 | 0.16 | ||
Iuu | 2.9E5 | 0.98 | ||
Ivv | 1.5E6 | 0.15 | ||
Iww | 1.1E6 | 1.9 | ||
Ixx | 4.0E4 | 26.5 | ||
Iyy | 3.1E5 | 31.2 | ||
Izz | 4.2E5 | 1.25 | ||
Iaa1 | 1.8E5 | 0.33 | ||
Iaa2 | 3.2E5 | 0.56 | ||
Iaa3 | 1.4E5 | 2.65 | ||
Iaa4 | 5.0E5 | 0.67 | ||
Iaa5 | 3.0E5 | 0.3 | ||
Iaa6 | 2.0E5 | 2.45 | ||
Iaa7 | 4.4E4 | 2.27 | ||
Iaa8 | 4.5E5 | 0.70 | ||
Iaa9 | 2.3E5 | 1.24 | ||
Iaa10 | 1.5E5 | 1.02 | ||
Iaa11 | 6.4E4 | 31 | ||
Iaa12 | 1.9E5 | 0.70 | ||
Iaa13 | 3.1E5 | 0.35 | ||
Iaa14 | 4.1E5 | 0.79 |
Iaa15 | 4.3E5 | 0.72 | ||
Iaa16 | 6.2E5 | 0.73 | ||
Iaa17 | 1.8E5 | 1.14 | ||
Iaa18 | 5.2E5 | 1.5 | ||
Iaa19 | 1.6E4 | 无活性 | ||
Iaa20 | 3.7E4 | 无活性 | ||
Iaa21 | 无活性 | 无活性 | ||
Iaa22 | 无活性 | |||
Iaa23 | 2.9E4 | 无活性 | ||
Iaa24 | 无活性 | |||
Iaa25 | 1.7E5 | 无活性 | ||
Iaa26 | 3.1E4 | 无活性 | ||
Iaa27 | 8.2E5 | 1.3 | ||
Iaa28 | 1.8E6 | 0.6 |
*化合物Iii-u是化合物Iii的(5S)形式。
实验2:在小鼠中对LPS诱导的急性肝炎的治疗效果
第一步:制备血样
将雌性Balb/c小鼠(6周龄,Charles River Laboratory,大阪,日本)置于如下条件:22℃,55%相对湿度,和12小时的光照-黑暗循环。随意供应食物和水。分别将LPS(脂多糖)和D-半乳糖胺溶于不含热原的盐水,浓度分别为0.4mg/ml和280mg/ml,并给小鼠注射它们的1∶1混合液,数量为5ml/kg。注射LPS和D-半乳糖胺后立即给小鼠腹膜内注射溶解了待测化合物的载体(将PEG400∶乙醇∶Tween80=15∶7.5∶2.5的混合液用盐水稀释五倍)或载体本身。注射药物后8小时,由它们的心脏采集血样。
第二步:测定血浆氨基转移酶的活性
使用ALT测定试剂盒(Asan Pharm.Co.,汉城,韩国)依照制造商的说明书对第一步中得到的血样测定血浆ALT活性。结果是,看来注射LPS和D-半乳糖胺陡然提高血浆中的ALT活性,而待测化合物以剂量依赖方式抑制升高的酶活性。根据这些结果,使用GraphPad公司的Prism软件计算待测化合物的ED50值,为0.01-10mg/kg。
实验3:在SD大鼠中对肝纤维化的抑制作用
第一步:诱导肝纤维化和施药
将雄性Spargue-Dawley大鼠(6周龄,Korea Biolink)置于如下条件:22℃,55%相对湿度,和12小时的光照-黑暗周期。随意供应食物和水。为了结扎胆管,通过吸入1%氟烷麻醉大鼠,切开大鼠的腹部,结扎远端和近端胆管,切割两个结扎部位中间的部分,注射2ml盐水,并缝合。
口服施用待测化合物(Iii),剂量为3mg/kg或10mg/kg,每天两次。即,将该化合物溶于共溶剂(PEG400∶乙醇∶Tween 80=15∶7.5∶2.5),用磷酸盐缓冲液(pH 7.4)稀释五倍,并施用。给对照组施用不含待测化合物的溶液。自结扎胆管1周后开始施药1周。
第二步:制备组织切片和Sirius红染色
施药后,处死大鼠。用10%中性福尔马林固定肝,制备5μm厚的石蜡切片,并用0.1%Sirius红(Direct red 80,Sigma)染色。用光学显微镜检查组织切片以观察染成红色的胶原纤维,结果如图1所示。
实验4:在SD大鼠中的胆汁停滞过程之中对凋亡的抑制作用
依照实验3第一步的流程给胆管被结扎的SD大鼠施用待测化合物(Iii)。手术后2周,处死大鼠。用10%中性福尔马林固定肝,并制备5μm厚的石蜡切片。使用ApopTag过氧化物酶原位凋亡检测试剂盒(Chemicom)依照制造商的说明书进行TUNEL染色。在放大倍数为200,拍照观察到超过10处TUNEL染色的肝组织且没有任何交叠,结果如图2所示。对每个测试组中对遭受凋亡的细胞数进行计数,结果如下文表2所示。在下表中,假手术指胆管暴露但未结扎的情况,而BDL手术指结扎胆管后只施用载体的情况。
表2
胆汁停滞过程中化合物(Iii)对肝细胞凋亡的抑制作用(单位:TUNEL阳性细胞/视野)
假手术 | BDL手术 | BDL+化合物(Iii)3mg/kg | BDL+化合物(Iii)10mg/kg |
0.76±0.15 | 16.7±2.75 | 4.12±1.3 | 5.66±1.34 |
结论
在通过胆汁停滞诱导肝纤维化而建立的模型中,经TUNEL染色显示了化合物(Iii)对凋亡的有效抑制(75%抑制)。另外,在对照组中Sirius红染色显示了严重的纤维化,但是在化合物(Iii)处理组中几乎不显示纤维化。该结果证明了化合物(Iii)对大鼠中的肝纤维化的抑制作用,因而预期化合物(Iii)能够在临床应用中通过抑制肝细胞凋亡而展示抑制肝硬化的药理学活性。其应用不仅可以扩展至由胆汁停滞引起的肝硬化,还可扩展至多种肝病,其中包括由凋亡引起的肝纤维化。
实验5:在大鼠中的消炎作用
将雄性SD大鼠(6周龄,Orient)置于如下条件:22℃,55%相对湿度,和12小时的光照-黑暗周期。随意供应食物和水。在诱导水肿前,用体积测量器测量每只大鼠的足部体积。在诱导水肿前,给大鼠口服施用溶解了待测化合物的载体(PEG400∶乙醇∶Tween80=15∶7.5∶2.5的混合液用磷酸盐缓冲液稀释十倍)或载体本身。将角叉菜聚糖(gamma)以浓度1%溶于盐水,并皮下注射到大鼠的右后足中,剂量100μl。3小时后,再次用体积测量器测量右足体积。以水肿抑制(%)显示待测化合物的效果(见表3)。水肿抑制(%)是依照下文方程式2计算的。
方程式2
水肿抑制(%)=100×(载体施用组的平均足部体积增量-待测化合物施用组的足部体积增量)/载体施用组的平均足部体积增量
表3
化合物(Iii)的水肿抑制作用
实验6:在大鼠中对风湿性关节炎的治疗效果
将雌性Lewis大鼠(7周龄,Charles River,日本)置于如下条件:22℃,55%相对湿度,和12小时的光照-黑暗周期。随意供应食物和水。于4℃将II型胶原(牛)以浓度2mg/ml溶于0.05M乙酸,并于4℃添加相同数量的完全弗氏佐剂以乳化溶液。将0.1ml如此乳化的溶液皮下注射到Lewis大鼠的鼠尾中。7天后,以相同方式再次注射乳化的溶液。自第二次注射乳化的溶液的日子开始,每天给大鼠口服施用溶解了待测化合物的载体(将PEG400∶乙醇∶Tween80=15∶7.5∶2.5的混合液用磷酸盐缓冲液稀释十倍)或载体自身。自第一次注射含胶原的乳化溶液算起的第14天,再次用体积测量器测量右后足体积(见表4)。依照下文方程式3测定水肿抑制(%)。
方程式3
水肿抑制(%)=100×(第14天载体施用组的平均足部体积增量-第14天待测化合物施用组的足部体积增量)/第14天载体施用组的平均足部体积增量
另外,通过Student t-检验由第14天的足部体积增量计算p值以确认显著性。
表4
足部水肿抑制作用
*p值=0.032
在大鼠足部水肿测试中,化合物(Iii)在剂量为3、30、和100mg/kg时分别显示大约2、21、和23%的剂量依赖性水肿抑制作用。在风湿性关节炎模型中,在阴性对照组显示最大水肿的第14天,化合物(Iii)施用组的足部水肿显著减轻(大约减轻70%)。因此,认为化合物(Iii)在炎性疾病模型中对炎症发展具有抑制作用,因而能够治疗自身免疫炎性疾病。
实验7:与已知化合物的效果比较
测试依照本发明的化合物(Iii)和PCT/KR00/01047(WO 01/21600)中已知的LB84068MP(化合物68),并将结果显示于下文表5。
表5
LB84068MP | Iii | |
对胱天蛋白酶-8的Kobs/[I] | 1.02E6(M-1min-1) | 1.30E7(M-1min-1) |
IC50(Jurkat细胞) | 1.6μM | 0.1μM或更低 |
ED50(LPS+Gal) | 0.99mg/kg | 0.01mg/kg |
溶解度(pH=7.44磷酸盐) | 0.93mg/ml或更低 | 7.8g/ml |
正如上文表5所示,与LB84068MP相比,依照本发明的化合物(Iii)显示的对胱天蛋白酶-8和Jurkat细胞的抑制活性提高10倍或更多,对LPS诱导的急性肝炎模型(小鼠)的抑制活性提高大约100倍。同样,对于物理-化学特性而言,该化合物也显示改进的溶解度,因而能够容易的用作注射剂。即,与对比化合物LB84068MP相比,本发明的化合物在活性和物理-化学特性两个方面都显示高度改进的效果。
Claims (20)
1.符合如下通式(1)的化合物、或其盐或立体异构体:
其中
I)R代表H、简单烷基链即-SAC、简单环烷基链即-SCAC、芳香基或杂环芳香基即-Ar、或用芳香基或杂环芳香基取代的简单烷基链即-SAC-Ar,
II)R1代表-SAC、-SCAC、-Ar、-SAC-Ar、或所有天然氨基酸的侧链残基;且当R1所附着的碳由于R1基团而变成立构中心时,符合通式(1)的化合物以特定非对映形或其混合物存在;或者,当R1是含羧基部分的氨基酸的侧链残基时,符合通式(1)的化合物具有酯形式即其中R3是-SAC的-CO2R3或磺酰胺形式即其中R4是-SAC的-CONHSO2R4的保护基团,或以制药学可接受盐的形式存在;或者当R1是含碱部分的氨基酸的侧链残基时,符合通式(1)的化合物也以制药学可接受盐的形式存在,
III)R2代表-SAC、-SCAC、-Ar、-SAC-Ar、或天然氨基酸的侧链残基;且当R2所附着的碳由于R2基团而变成立构中心时,符合通式(1)的化合物以特定非对映形或其混合物存在;当R2是含羧基部分的氨基酸的侧链残基时,符合通式(1)的化合物具有酯形式即其中R5是-SAC的-CO2R5或磺酰胺形式即其中R6是-SAC的-CONHSO2R6的保护基团,或以制药学可接受盐的形式存在;或者,当R2是含碱部分的氨基酸的侧链残基时,符合通式(1)的化合物也以制药学可接受盐的形式存在,或者
R2进一步代表H;-(CH2)mOR7,其中R7是-SAC、-SCAC、-Ar、或-SAC-Ar,且n=1或2;或-(CH2)mOC(=O)R8,其中R8是-SAC、-SCAC、-Ar、或-SAC-Ar,且n=1或2,
IV)A代表-(CH2)n-,其中n=0,
V)B代表-Ar,或者
VI)R和R1与它们所附着的碳原子一起形成环,其中-R-R1-是-(CH2)n-、-(CH2)n-O-(CH2)m-、或-(CH2)n-NR10-(CH2)m-,其中n+m<9且R10是-SAC、-SCAC、-Ar、-SAC-Ar、-C(=O)-SAC、-C(=O)-SCAC、-C(=O)-Ar、或-C(=O)-SAC-Ar,
VII)X代表-C(=O)CH2OR11,其中R11是-SAC、-SCAC、-Ar、或-SAC-Ar;-C(=O)CH2OC(=O)R12,其中R12是-SAC、-SCAC、-Ar、或-SAC-Ar;-CH=CH-CO2R13,其中R13是-SAC、-SCAC、-Ar、或-SAC-Ar;-CHCH-SO2R14,其中R14是-SAC、-SCAC、-Ar、或-SAC-Ar;-C(=O)CH=CH2;或-COCH2-W,其中W是-N2、-F、-Cl、-Br、-I、-NR15R16、-SR17,其中R15和R16各自是-SAC、-SCAC、-Ar、或-SAC-Ar,或者一起形成3至6元饱和或不饱和环状基团,R17是-SAC、-SCAC、-Ar、或-SAC-Ar,或W是下列通式:
其中
Y是H、-OH、-OR18、-C(=O)R19、-F、-Cl、-Br、-I、-CN、-NC、-N3、-CO2H、-CF3、-CO2R20、-C(=O)NHR21、或-C(=O)NR22R23,其中R18=-SAC或-SCAC,R19=-H、-SAC、或-SCAC,R20=-SAC或-SCAC,R21=-SAC或-SCAC,
R22和R23各自是-SAC、-SCAC、-Ar、或-SAC-Ar,
R24是H、-SAC、-SAC-Ar、或-Ar,
VIII)SAC指线性或支化异构体形式的具有1-8个碳原子的烃,SCAC指具有3-10个碳原子的环状基团,
IX)所述芳香基指联苯基,或指5至15元单个或稠合的不饱和环,并且所述环未取代或用一个或多个选自卤素和烷基的基团取代,
X)所述杂环芳香基指含有1-5个选自氧、硫和氮的杂原子的芳香基,其未取代或用一个或多个选自酰基、卤素、烷基、环烷基和苯基的基团取代,
2.依照权利要求1的化合物,其中R代表H。
3.依照权利要求1的化合物,其中R1代表-CH2COOH、-CH2COOR3、或-CH2CONHSO2R4,其中R3=SAC,R4=SAC。
4.依照权利要求1的化合物,其中R2代表H、-SAC、-Ar、或-(CH2)nOR7,其中R7=-SAC、-SCAC、-Ar、或-SAC-Ar,且n=1或2。
5.依照权利要求1的化合物,其中X代表-C(=O)CH2OAr、-C(=O)CH2OC(=O)Ar、或-COCH2-W,其中W是-N2、-F、-Cl、-Br、-I、-NR15R16、或-SR17,其中R15和R16各自是-SAC、-SCAC、-Ar、或-SAC-Ar,或者一起形成3至6元饱和或不饱和环状基团,R17是-SAC、-SCAC、-Ar、或-SAC-Ar。
6.依照权利要求1的化合物,其中
I)R代表H,
II)R1代表-CH2COOH、-CH2COOR3、或-CH2CONHSO2R4,其中R3=SAC,R4=SAC,
III)R2代表H、-SAC、-Ar、或-(CH2)nOR7,其中R7=-SAC、-SCAC、-Ar、或-SAC-Ar,且n=1或2,
IV)A代表-(CH2)n-,其中n=0,
V)B代表-Ar,
VI)X代表-COCH2N2、-COCH2F、-COCH2Cl、-COCH2Br、-COCH2I、-COCH2OAr、-COCH2OCOAr、或-COCH2SR17,其中R17是-SAC、-SCAC、-Ar、或-SAC-Ar。
7.依照权利要求1的化合物,其选自下组:
(1)(3S)-5-[(2,6-二氯苯甲酰)氧基]-3-({[5-甲基-3-苯基-4,5-二氢-5-异唑基]羰基}氨基)-4-氧戊酸(Iaa);
(5)(3S)-3-({[5-乙基-3-(2-萘基)-4,5-二氢-5-异唑基]羰基}氨基)-4-氧-5-(2,3,5,6-四氟苯氧基)戊酸(Iee);
(8)3-({[5-乙基-3-(1-异喹啉基)-4,5-二氢-5-异唑基]羰基}氨基)-5-氟-4-氧戊酸乙酯(Ihh);
(20)5-氟-3-({[(5S)-3-(1-异喹啉基)-5-丙基-4,5-二氢-5-异唑基]羰基}氨基)-4-氧戊酸(Itt);
(30)5-氟-3-({[(5R)-5-异丙基-3-(2-异丙基苯基)-4,5-二氢-5-异唑基]羰基}氨基)-4-氧戊酸(Iaa4);
(38)3-({[3-(4-环丙基-2-吡啶基)-5-乙基-4,5-二氢-5-异唑基]羰基}氨基)-5-氟-4-氧戊酸(Iaa12);
(39)3-({[3-(4-环戊基-2-吡啶基)-5-乙基-4,5-二氢-5-异唑基]羰基}氨基)-5-氟-4-氧戊酸(Iaa13);
(40)3-({[(5R)-3-(4-环戊基-2-吡啶基)-5-异丙基-4,5-二氢-5-异唑基]羰基}氨基)-5-氟-4-氧戊酸(Iaa14);
(42)3-({[5-乙基-3-(5,6,7,8-四氢-1-异喹啉基)-4,5-二氢-5-异唑基]羰基}氨基)-5-氟-4-氧戊酸(Iaa16);
(43)5-氟-3-({[5-异丙基-3-(4-苯基-2-吡啶基)-4,5-二氢-5-异唑基]羰基}氨基)-4-氧戊酸(Iaa17);
(45)(3S)-3-({[(5R)-5-异丙基-3-(1-异喹啉基)-4,5-二氢-5-异唑基]羰基}氨基)-4-氧-5-{[1-苯基-3-(三氟甲基)-1H-吡唑-5-基]氧基}戊酸(Iaa 19);
(47)(3S)-5-(异丁酰氧基)-3-({[(5R)-5-异丙基-3-(1-异喹啉基)-4,5-二氢-5-异唑基]羰基}氨基)-4-氧戊酸(Iaa21);
(52)2-{[(3S)-4-羧基-3-({[5-乙基-3-(2-异丙基苯基)-4,5-二氢-5-异唑基]羰基}氨基)-2-氧代丁基]氧基}-1-甲基吡啶三氟甲磺酸盐(Iaa26);
(55)(3S)-5-氟-3-({[(5R)-5-异丙基-3-(1-异喹啉基)-4,5-二氢-5-异唑基]羰基}氨基)-4-氧戊酸(Iii-1)。
12.包含权利要求1中定义的符合通式(1)的胱天蛋白酶抑制物化合物、其盐或立体异构体作为活性成分以及制药学可接受载体且用于预防炎症和凋亡的治疗性组合物。
13.依照权利要求12的组合物,用于治疗痴呆、脑中风、由AIDS引起的脑损伤、糖尿病、胃溃疡、由肝炎引起的脑损伤、由肝炎诱导的肝病、急性肝炎、暴发性肝功能衰竭、肝硬化、败血症、器官移植排斥、风湿性关节炎、或由缺血性心脏病引起的心脏细胞凋亡。
14.依照权利要求12的组合物,用于治疗急性肝炎或肝硬化。
15.依照权利要求12的组合物,用于治疗风湿性关节炎。
16.依照权利要求12的组合物,其配制成口服制剂、注射液、或贴剂。
17.依照权利要求12的组合物,包含权利要求8中定义的化合物(Iii)作为活性成分。
18.依照权利要求12的化合物,包含权利要求10中定义的化合物(Iii-1)作为活性成分。
19.制备权利要求12中定义的用于预防炎症和凋亡的治疗性组合物的方法,包括将权利要求1中定义的符合通式(1)的胱天蛋白酶抑制物化合物、其盐或立体异构体与制药学可接受载体混合。
20.权利要求1中定义的符合通式(1)的胱天蛋白酶抑制物化合物、其盐或立体异构体在制备用于预防炎症和凋亡的药物中的用途。
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CN105753853B (zh) | 2014-12-16 | 2020-08-04 | 沈阳中化农药化工研发有限公司 | 一种含异恶唑啉的脲嘧啶类化合物及其用途 |
WO2017079566A1 (en) | 2015-11-05 | 2017-05-11 | Conatus Pharmaceuticals, Inc. | Caspase inhibitors for use in the treatment of liver cancer |
SG11201805480TA (en) | 2015-12-31 | 2018-07-30 | Conatus Pharmaceuticals Inc | Methods of using caspase inhibitors in treatment of liver disease |
MX2019003889A (es) | 2016-10-05 | 2019-08-12 | Novartis Ag | Composiciones de combinacion que comprenden agonistas de fxr para tratar o prevenir una enfermedad o trastorno fibrotico o cirrotico. |
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CN110770232B (zh) | 2017-06-13 | 2023-08-15 | 拜耳公司 | 除草活性的四氢和二氢呋喃羧酸和酯的3-苯基异噁唑啉-5-甲酰胺 |
AU2018285213B2 (en) | 2017-06-13 | 2022-05-19 | Bayer Aktiengesellschaft | Herbicidally active 3-phenylisoxazoline-5-carboxamides of tetrahydro and dihydrofuran carboxamides |
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US20220306591A1 (en) | 2018-01-25 | 2022-09-29 | Bayer Aktiengesellschaft | Herbicidally active 3-phenylisoxazoline-5-carboxamides of cyclopentenylcarboxylic acid derivatives |
DK3937637T3 (da) | 2019-03-12 | 2023-07-24 | Bayer Ag | Herbicidt virksomme 3-phenylisoxazolin-5-carboxamider af s-holdige cyclopentenylcarbonsyreestere |
WO2020213970A1 (ko) * | 2019-04-19 | 2020-10-22 | 주식회사 엘지화학 | 캐스파제 저해제의 프로드럭 |
KR102442103B1 (ko) * | 2019-04-30 | 2022-09-08 | 주식회사 엘지화학 | 캐스파제 저해제의 프로드럭 |
JP7301448B2 (ja) * | 2019-05-31 | 2023-07-03 | エルジー・ケム・リミテッド | カスパーゼ阻害剤プロドラッグを含有する注射用組成物及びその調製方法 |
TW202237143A (zh) | 2020-12-10 | 2022-10-01 | 南韓商Lg化學股份有限公司 | 酸(Boronic Acid)化合物 |
WO2022123062A1 (en) | 2020-12-11 | 2022-06-16 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Blocking caspase and/or fasl for preventing fatal outcome in covid-19 patients |
CN114908028B (zh) * | 2022-04-19 | 2024-05-31 | 杭州师范大学 | 一种双相体系下化学酶法级联催化腈类化合物的一锅法合成工艺 |
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