CN1504462A - 作为白细胞介素抑制剂的嘧啶基衍生物 - Google Patents
作为白细胞介素抑制剂的嘧啶基衍生物 Download PDFInfo
- Publication number
- CN1504462A CN1504462A CNA031452183A CN03145218A CN1504462A CN 1504462 A CN1504462 A CN 1504462A CN A031452183 A CNA031452183 A CN A031452183A CN 03145218 A CN03145218 A CN 03145218A CN 1504462 A CN1504462 A CN 1504462A
- Authority
- CN
- China
- Prior art keywords
- oxo
- alkyl
- aspartic acid
- pyrimidyl
- ethanoyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
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Abstract
公开了用于抑制白细胞介素－1β(IL－β)蛋白酶活性的化合物、组合物和方法。叙述了具有本文所示的式(I)化合物N－(嘧啶基)－天冬氨酸的α－取代的甲基酮类和天冬氨酸的醛类。这些化合物是1β－转化酶的抑制剂，它们用于要求这种抑制作用的时候。例如，它们可在药理、诊断和有关的研究中用作研究工具；也可用于治疗哺乳动物与IL－β蛋白酶活性有关的疾病。
Description
本申请系1995年3月29日提交的、申请号为95193258.6的、发明名称与本申请相同的申请的分案申请。
发明领域
本发明涉及一系列新颖的天冬氨酸类似物，这些类似物在体外试验和体内试验中显示出对白细胞介素-1β转化酶的选择性抑制作用；还涉及含有这种新颖天冬氨酸类似物的组合物和治疗方法。更具体而言，本发明所述的白细胞介素1β转化酶抑制剂包括新的N-(嘧啶基)-天冬氨酸的醛类和α-取代甲基的酮类，它们在治疗肺部、中枢神经系统和结缔组织的炎症和基于免疫的疾病方面，具有特别的效用。
发明背景
白细胞介素1β(IL-1β)蛋白酶(也称为白细胞介素1β转化酶或ICE)是负责将无生物活性的31kD前体IL-1β加工为有生物活性的17kD型的酶(M.J.科斯图腊，M.J.托西，G.利谬科，J.钦，P.卡麦伦，A.G.希尔曼，N.A.恰特赖因，J.A.施密特，
Proc.Nat.Acad.Sci.，(1989)，86，5227-5231和R.A.布拉克，S.R.克朗海姆，P.R.斯利恩，
FEBS- Let.，(1989)，
247，386-391)。除了作为躯体对损害和传染的早期反应之一以外，有人提出，IL-1β还在多种疾病包括类风湿性关节炎、骨关节炎、肠炎病、败血病、急性和慢性的骨髓性白血病和骨质疏松症中起到介体的作用(C.A.迪纳雷洛，S.M.沃尔夫，
新英格兰医学杂志，(1993)，328，106)。自然存在的IL-1β受体拮抗剂已用来说明在许多人体疾病和动物模型中IL-1β的中介性(C.H.汉农，C.J.威尔科克斯，W.P.阿伦德，G.G.焦斯林，D.J.德里普斯，P.L.海姆达尔，L.G.阿梅斯，A.索默，S.P.艾森伯格，R.C.汤普森，
自然，(1990)，
343，336-340；S.P.艾森伯格，R.J.伊文斯，W.P.阿伦德，E.佛德伯，M.T.布雷沃，C.H.汉农，R.C.汤普森，
自然，(1990)，
343，341-346；K.沃尔森，P.布焦克，M.伯根费尔特，R.哈杰门，R.C.汤普森，
自然，(1990)，
348，550-552；G.瓦卡巴亚希，
FASEB，(1991)，338-343；R.帕西菲西等，
Proc.Natl. Acad.Sci.(1989)，86 2398-2402和I.亚马莫托等，
癌症研究(1989)，
49，4242-4246)。IL-1β在炎症和免疫调节方面的特定作用已由近期的观察结果所证实，这观察结果是牛痘病毒使用ICE抑制剂来阻止其宿主的炎性反应(C.A.赖等，
细胞，(1992)，
69，597-604)。
概而言之，已有一些本领域的工作者提出并用体内试验证明ICE抑制剂对某些由IL-1β传递的疾病状态的改变效用。下列的对ICE研究领域现况的评述进一步为ICE抑制剂的效用提供了证据：
1)1993年5月11日公布的WO 9309135宣称，基于肽的天冬氨酸的芳酰氧基-和芳氧基甲基酮类是体外试验有效的ICE抑制剂。这些化合物还能抑制整个细胞内成熟IL-1β的形成，而使整个细胞内(在体内)的ICE受到特别抑制。这些ICE抑制剂还证明有减轻大鼠发烧和发炎/肿胀的作用。
2)Lyme病的患者有时发展为Lyme关节炎。而Lyme病的病原体，B.burgdorferi，是一种由单核细胞合成IL-1的强有力的诱导剂。米勒等。(L.C.米勒，E.A.伊萨，S.林奇，J.W.洛根，C.A.迪纳雷洛和A.C.斯提尔，“关节液IL-1β和IL-1受体拮抗剂的平衡及从Lyme关节炎的恢复”，
柳叶刀(1993)
341；146-148)指出，在Lyme关节炎恢复快的患者的关节液中，IL-1β和IL-1ra的平衡有利于IL-ra.当该平衡移向有利于IL-1β时，则此病需要更长时间才能恢复。结论是过量的IL-1ra封阻了上述这些患者的IL-1β的影响。
3)IL-1存在于患溃疡性结肠炎的人体受感染的组织中。在有该病的动物模型内，IL-1β的量与疾病严重程度相关。在该模型中，给于IL-1ra可减少组织坏死和结肠中有炎性的细胞数。参见F.科米内利，C.C.纳斯特，B.D.克拉克，R.辛德勒，R.勒伦纳，V.E.埃塞林，R.C.汤普森和C.A.迪纳雷洛，“白细胞介素-1基因表达、合成和其在兔免疫复合物结肠炎中特定IL-1受体封阻的作用”
临床研究杂志(1990)第86卷，第972-980页。
4)IL-Ira可抑制大鼠关节炎的PG-APS模型中的关节肿胀。参见J.H.施瓦布，S.K.安德尔，R.R.布朗，F.G.达尔多夫和R.C.汤普森，“白细胞介素-1在细菌细胞壁引起的大鼠关节炎复发中的促炎和抗炎作用”、
传染免疫(1991)
59；4436-4442。
5)IL-1ra在小开式标记(open-label)的人类类风湿性关节炎试验中显出功效。参见M.E.累布萨克，C.C.波尔，C.C.布洛多，F.X.伯奇，M.A.萨克，W.恰斯和M.A.卡塔伦诺，“类风湿性关节炎患者皮下用的IL-1受体拮抗剂”，
类风湿性关节炎(1991)
34；545。
6)看来IL-1是慢性骨髓性白血病细胞激增的自分泌增长因子。IL-1ra和sIL-1R都能抑制由白血病患者取出的细胞的群体增长。参见Z.埃斯特洛夫，R.克兹罗克，M.韦茨勒，H.肯塔今，M.布拉克，D.哈里斯，J.U.古特曼和M.塔尔帕兹，“用白细胞介素-1(IL-1)受体拮抗剂和可溶性IL-1受体抑制慢性骨髓性白血病的群体增长：IL-1活性抑制剂的新的应用”，
血(1991)
78；1476-1484。
7)如上述6)，但不是针对慢性骨髓性白血病，而是针对急性骨髓性白血病。参见Z.埃斯特洛夫，R.克兹罗克，E.埃斯特，M.韦茨勒，A.弗腊焦利，D.哈里斯，M，布拉克，J.U.古特曼和M.塔尔帕兹，“用白细胞介素-1(IL-1)受体拮抗剂和可溶性IL-1受体抑制急性骨髓性白血病的爆发性激增”，(1992)
血79；1938-1945。
目前还必须充分开发出能商品化的有效疗法来治疗由IL-1β传递的炎性疾病。因此，需要有一些治疗和预防这些疾病的有效药物。
据本申请人所知，本领域叙述过的所有ICE抑制剂都是基于肽的，以利用该基质的酶的特征。在本发明中我们对不基于肽的ICE抑制剂加以叙述，明确地说，在这类抑制剂中嘧啶用作P2和P3氨基酸的识别代替物，至今为止P2和P3氨基酸曾是必须存在的，以产生有效的ICE抑制剂(参见式1)。非肽型抑制剂对它们相对应的肽型抑制剂而言有一熟知的优点，那就是这类非肽型抑制剂在体内的代谢和排泄大大地变小，从而提高了这些化合物在动物和人体内的生物利用率(M.J.亨夫雷和P.S.林格罗斯，“肽和有关的药物：有关它们的吸收、代谢和排泄的评论”，
药物代谢评论，(986)，
17，283-310.还有J.J.普拉特纳和D.W.诺贝克，“由肽前导体开发药物的障碍”，
药物发现技术，(1990)，第5章，92-126，C.R.克拉克和W.H.穆斯编；Horwood：Chichester，U.K.).
式1
基于肽的ICE抑制剂
(R..多尔等，
药物化学杂志，(1994)，
37，563)
基于嘧啶的ICE抑制剂
(本发明)
应当指出，近期已提到将基于嘧啶的三氟甲基酮类(式2)作为丝氨酸蛋白酶，弹性蛋白酶的抑制剂。由于ICE是一种半胱氨酸蛋白酶而现有技术已知道三氟甲基酮类是相当差的半胱氨酸蛋白酶抑制剂(参见，B.英珀里利厄和R.H.艾布尔斯，
生物化学(1986)，
25.3760-7)，所以预计式2的嘧啶类不是ICE抑制剂。还已经知道，ICE需要在P1处有天冬氨酸支链(-CH2COOH)。抑制弹性蛋白酶的嘧啶类(式2)含有缬氨酸支链(-CHMe2)。此外，正如下文将会指出，本发明所述的基于嘧啶的ICE抑制剂(式1)不抑制人类的白细胞弹性蛋白酶，因此它对ICE有特别的选择性，并与已知的弹性蛋白酶抑制剂明显不同。
式2
基于嘧啶的弹性蛋白酶抑制剂
(Imperical Chemical Industries；
EPO 528 633 A1；1993)
发明概述
根据本发明，提供了式(I)的化合物或其药学上可接受的盐。
式中
-Y是
而当R6是OH，则Y还可以是：
R5是H或氘；
R6是OR8或NHOH
此处R8独立地是H，烷基或芳烷基R3和R4独立地是H，烷基或芳烷基R2＝H、烷基、-(CH2)0-4-环烷基、
芳基、杂芳基、芳烷基、杂芳烷基、-(CH2)2-4-R10；
此处n＝1-3；
此处R10＝烷氧基、CH2F、CHF2、CF3、CF2CF3、OH、COOR11、CONR9R11或NR9R11；
此处R9独立地是H、烷基、芳基、芳烷基、杂芳基、杂芳烷基、-CH2CH2O-烷基和C(O)-R12；
此处R11独立地是H、烷基、芳基、芳烷基、杂芳基和杂芳烷基；
而当R9和R11合在一起，则它们可成为五、六或七元环，其类型是：
而R12是烷基、芳基、芳烷基、杂芳基和杂芳烷基；
R7＝H，CH2F，CHR13O(CO)0-1-芳基，HR13OP(O)(R14)R(15)，
式中：
R13＝H或烷基
R14＝H、烷基或芳基
R15＝H、烷基或芳基
R16＝H、烷基、芳基、杂芳基、芳烷基或杂芳烷基
R17＝H、烷基、CF3、CF2CF3、芳基、杂芳基、芳烷基、杂芳烷基、COOR11或CONR9R11
R18＝H、烷基、CF3、CF2CF3、芳基、杂芳基、芳烷基、杂芳烷基
R1定义为：
R19-R2，R19-R20，R19-R21，R19-NR9R11
此处R19＝(CR3R4)-0-4；
和
此处n-1-3；
R22O-
此处R22是烷基、芳基、杂芳基、芳烷基、杂芳烷基、R19-环烷基、R19-R21、R23-R10、R23-R20；
式中R23＝(CR3R4)-2-4；
R9R11N-和R24R11N-
此处R24＝R19-环烷基、R19-R21、R23-R10、R23-R20、CR3R4COOR11和CR3CR4CONR9R11；
本文所用的术语“药学上可接受的盐”包括酸加成盐和碱加成盐。
术语“酸加成盐”是指那些仍能保持原游离碱生物效力和性质的盐，并且它们并非生物学上或其它方面不需要的盐，它们是用无机酸，诸如盐酸、氢溴酸、硫酸、硝酸、磷酸等，和有机酸，诸如乙酸、丙酸、乙醇酸、丙酮酸、草酸、马来酸、丙二酸、琥珀酸、富马酸、酒石酸、柠檬酸、苯甲酸、肉桂酸、扁桃酸、甲磺酸、乙磺酸、对甲苯磺酸、水杨酸等制成的。
术语“碱加成盐”包括那些由无机碱衍生的盐，诸如钠、钾、锂、铵、钙、镁、铁、锌、铜、锰、铝盐等。特别优选的是铵、钾、钠、钙和镁盐，以及由药学上可接受的有机无毒碱衍生的盐，这包括伯、仲和叔胺、取代胺(包括自然存在的取代胺、环胺和碱性离子交换树脂诸如异丙胺、三甲胺、二乙胺、三乙胺、三丙胺、乙醇胺、2-二甲氨基乙醇、2-二乙氨基乙醇、三甲胺、二(环己基)胺、赖氨酸、精氨酸、组氨酸、咖啡碱、普鲁卡因、哈胺、胆碱、甜菜碱、乙二胺、葡糖胺、甲基葡糖胺、可可碱、嘌呤、哌嗪、哌啶、N-乙基哌定聚胺树脂等)的盐。特别优选的有机无毒碱是异丙胺、二乙胺、乙醇胺、三甲胺、二(环己基)胺、胆碱和咖啡碱。
在上文和全文中所用的下列术语，除非另外注明，都应认为具有下述的含意：
“烷基”定义为直链或支链饱和脂族烃，优选的基团具有不大于约12个碳原子，可以是甲基、乙基、丙基等以及丙基、丁基、戊基、己基、辛基、壬基、癸基、十一烷基、十二烷基的异构体。
“环烷基”定义为含有至少3个到多至8个碳原子的饱和环脂族烃。优选的基团包括环丙基、环丁基、环戊基、环己基、环庚基和环辛基。
“芳基”定义为苯环或萘环或取代苯环或取代萘环，其中有一个或多个氢原子已由相同或不同的取代基所取代，这些取代基选自R1、COR1或R25，此处R25定义为H、OH、卤代、-OC(O)R11、-C(O)R11、-NR11C(O)R1、-NR11C(O)(CR3R4)2-6R1、-COOR11、-COOR11、-CONR9，R11、R11S-、-NR9，R11SO2R8、-SO2NR9，R11、硝基、氰基、-NR11CONR9R11，此处R1、R8、R9、R11和R12如上所定义。
“杂芳基”定义为约5至约12个碳原子的、未取代或任选取代的、单环或二环的环状体系，此处每个单环可具有0至约4个杂原子，而每个二环物可具有0至约5个杂原子，这些杂原子选自N、O和S，但这些杂原子不是相邻的氧和/或硫原子；此处取代基的数目为0至约5个，它们可位于该环状物的任何适当位置，这些取代基可任选地选自已在有关芳基的说明中列出的那些取代基。这种单环或二环的环状体系的实例包括苯并呋喃、苯并噻吩、吲哚、苯并吡唑、香豆素、异喹啉、吡咯、噻吩、呋喃、噻唑、咪唑、吡唑、三唑、喹啉、pyrollidenone、嘧啶、吡啶、吡啶酮、吡嗪、哒嗪、异噻唑、异噁唑和四唑，但这决不意味着限制本发明的范围。
“芳烷基”是指被芳基取代的烷基。例如，苄基。
“杂芳烷基”是指被杂芳基取代的烷基。例如，(4-吡啶基)甲基。
“烷氧基”是指被烷基、芳基或芳烷基取代的氧原子。例如，甲氧基、乙氧基、苯氧基、苄氧基。
“卤代”是指碘代、溴代、氯代和氟代。
“(CR3R4)2-4”这一标示是指至少由2个但不超过4个碳原子组成的烷基键，此处所述的碳原子独立地用以R3和R4表示的基团来代替。这种键的实例包括，但不限于，乙基、丙基、丁基、2-甲基乙基(-(MeHCCH2-)、2，2-二甲基乙基(Me2CCH2-)。
本发明还涉及治疗哺乳动物所需的由IL-1β蛋白酶传递的病症或失调的药用组合物和方法，它包括服用作为活性剂的式(I)的IL-1β蛋白酶抑制剂。这些病症和失调包括：传染病，诸如脑膜炎和输卵管炎之类；败血性休克，呼吸系统疾病；炎症，诸如关节炎、胆管炎、结肠炎、大脑炎、endocerolitis、肝炎、胰腺炎和再灌注损害之类；基于免疫的疾病，诸如过敏性疾病之类；自动免疫性疾病，诸如多发性硬化之类；骨病以及某些肿瘤和白血病。
本发明在调节处理IL-1β以治疗类风湿性关节炎方面有特别的效用。在此病患者的关节液中，IL-1β的水平升高是已知道的。此外，IL-1β能促进合成一些认为与炎症有关的酶，诸如胶原酶和PLA2之类，并能引起关节破坏，这与动物关节内注射后的类风湿性关节炎非常相似。
在实施本发明时，将有效量的本发明化合物或其药用组合物给于需要或希望这种治疗的患者。这些化合物或组合物可经过多种途径中的任一种来给药，这取决于具体使用目的，这些给药途径包括口服的、非经肠道的(包括皮下的、关节内的、肌肉内的和静脉内的给药)、直肠的、口腔的(包括舌下的)、经皮肤的或鼻内的。任一给定情况下最适宜的给药途径取决于用途、具体的有效成分和有关患者的情况。正如本文进一步叙述的那样，这种化合物或组合物还可用控制释放、长效植入物或可注射的配制剂等方式来给药。
一般说来，在本发明所述的用途中，对人的治疗而言，有效成分给药量为约0.1-100mg/kg体重是恰当的，最优选为约0.1-30mg/kg体重，有效成分的给药最好是在约0.1-约20-50mg/kg/日的范围。给药的方式可以一次完成或分成几次或用缓释方式以便达到最有效的结果。当采用一次给药时，给药量最优选为约0.1-约10mg/kg的范围。
这些化合物和组合物的确切给药剂量和给药方式，必须依据待治疗的患者个人的需要、治疗的类型和痛苦程度或需要而定。一般说来，非经肠道给药的所需剂量比其它更依赖于吸收的给药方式所需的低些。
本发明的另一方面涉及药用组合物，该组合物包括作为有效成分的本发明的化合物，并与药学上可接受的无毒载体混合在一起。如上所述，这种组合物可制成非经肠道的(皮下的、关节内的、肌肉内的或静脉内的)用药，特别是制成溶液或悬浮液；或口服的或口腔的用药，特别是制成片剂或胶囊；或鼻内用药，特别是制成粉剂、滴鼻液或烟雾剂。
在口服(或经直肠)给药时，通常将本发明的化合物配成单位剂量的形式，例如片剂、胶囊、栓剂或扁囊剂。这种配制剂通常包括固态、半固态或液态的载体或稀释剂。典型的稀释剂和赋形剂是乳糖、葡萄糖、蔗糖、山梨糖醇、甘露糖醇、淀粉、阿拉伯树胶、磷酸钙、矿物油、可可脂、可可油、aginates、黄蓍胶、明胶、糖浆、甲基纤维素、聚氧乙烯失水山梨糖醇单月桂酸酯、羟基苯甲酸甲酯、羟基苯甲酸丙酯、滑石和硬脂酸镁。
这些组合物可用制药领域熟知的方法，例如
赖明顿的药物科学，第17版，Mack Publishing Company，Easton，PA，1985中所述方法的任一种来制备。非经肠道给药的配制剂中可含有无菌水或盐水、亚烷基二醇诸如丙二醇之类、聚(亚烷基)二醇诸如聚乙二醇之类、植物油、氢化萘等作为通用赋形剂。非经肠道用药的赋形剂实例包括：水；含水赋形剂，诸如盐水、Ringer′s溶液、葡萄糖溶液和Hank′s溶液之类；和非水赋形剂，诸如固定油(如玉米油、棉籽油、花生油和麻油)、油酸乙酯和肉豆蔻酸异丙酯。无菌盐水是优选的赋形剂，且本发明化合物有足够的水溶性以配制所有预先要求的溶液。赋形剂中可含有少量诸如提高溶解度、等渗性和化学稳定性的物质的添加剂，例如抗氧剂、缓冲剂和防腐剂。对口服给药而言，添加胆汁盐，以及添加酰基肉毒碱，可提高配制剂性能(
美国生理学杂志，251：332(1986))。鼻内给药的配制剂可呈固态并含有例如乳糖或葡聚糖作为赋形剂；也可以是水溶液或油溶液，以滴鼻液或定量喷雾剂的形式给药。对口腔给药而言，典型的赋形剂包括糖、硬脂酸钙、硬脂酸镁、预胶凝淀粉等。
当配制鼻内用药时，添加有表面活性的酸诸如甘胆酸、胆酸、牛磺胆酸、ethocholic acid、脱氧胆酸、鹅脱氧胆酸、去氢胆酸、脱氧甘胆酸等，可提高透过鼻粘膜吸收的效果(参见B.H.维克里，“LHRH和其类似物-Contraccption和治疗应用”，第2部分，B.H.维克里和J.S.内斯特编，MTP Press，Lancaster，UK，1987)。
发明详述
本发明的化合物是用一般的在方案1、2、3和4中所述的合成方法来制备的。将Z-天冬氨酸α-溴代甲基酮(方案1；结构式1；Z＝苄氧基羰基)以DMF为溶剂，在KF存在下用醇或羧酸处理，得到α-取代的Z-天冬氨酸甲基酮(结构式2)。制备结构式1的溴化物和将其转变为结构2的化合物，是用A.克兰茨等(生物化学，(1991)，
30，4678-4687)所述的方法来实现的，随后，在氢解条件下将Z-基团除去，以产生N-末端胺(结构式3)。氢解除去Z-基团所用的典型试剂和条件是：氢气；常温和常压；在醇类溶剂例如甲醇中，该甲醇还任选含有2当量的盐酸；以载5％钯的碳为催化剂。没有必要精制这种游离胺中间体或其盐酸盐(如氢解时采用盐酸)，尽管该物料必须干燥而且不含醇，以使随后进行的偶联反应有好的收率。然后将所得的胺(结构式3)与嘧啶羧酸(结构式4)缩合，以产生结构式5的中间体。一般必须将嘧啶羧酸首先活化为酰氯或混合酐，然后在有机碱例如N-甲基吗啉存在下将其与此游离碱(或其盐酸盐)反应。嘧啶羧酸与这种胺中间体的偶联反应也可采用肽偶联化学中所用的酰胺偶联试剂和条件来进行(“肽合成的实践”，M.博丹斯基，Springer-Verlag，NY，1984；肽，第1-3卷，E.格罗斯和J.迈因霍弗编，Academic Press，NY，1981)。制备ICE抑制剂的最后一步合成反应是叔丁基酯官能团的水解。这是将该叔丁基酯(结构式5)在25℃放于25％三氟乙酸(TFA)的二氯甲烷溶液中进行的。通常该脱酯反应可经3小时完成。除去挥发的TFA和有机溶剂后得到这类天冬氨酸(结构式6)。在所提供的叔丁基酯起始物料纯度高时，在大多数实例中该反应的收率是定量的。如果需要，可用重结晶或色谱法进行精制，这些方法都是该领域的技术人员所熟知的。TFA的浓度可为5％-100％，也可采用其它溶剂例如氯仿。用3克分子浓度的无水氯化氢的乙酸乙酯溶液代替TFA-二氯甲烷溶液，也可得相同的效果。
方案2概括了含嘧啶类的天冬氨醛的合成过程。这类合成的起始物料是天冬氨酰缩氨基脲(结构式7)。通过标准的加氢条件将Z-基团除去，以产生相应的胺(结构式8)。然后将其与嘧啶酸(结构式4)相偶联，所用的偶联条件与上文所述的类似。还需要进行双重去保护反应以游离出β位的羧酸基团(用三氟乙酸)和α位的醛基团(用37％多聚甲醛水溶液、乙酸和甲醇)，从而产生结构式10的化合物。
方案3概括了将R1基团引至嘧啶的5-氨基官能团上的另一合成法，该法可进一步增加本发明的范围。含有Z-基团的嘧啶的酸、酯或天冬氨酸酰胺(结构式11)可进行氢解反应(其反应条件与上文所述的类似)以产生相应的5-氨基嘧啶类化合物(结构式12)，胺的部分可与酰氯或活化的羧酸反应(其反应条件与上文方案1中所述用于结构式3和4偶联的条件类似)，以产生含有R1基团的嘧啶类化合物，此处R1具有多种结构。
方案4概括了所需的嘧啶类化合物的合成过程。起始物料是3-羧乙基嘧啶类化合物，其中带有N-烯丙基(结构式13)或N-乙醛缩二甲醇(结构式14)。它们的合成过程可利用本领域已发表在文献中的反应条件等内容方便地演绎而得(C.A.维尔等，
有机化学杂志，(1993)，
58，4490-4493；K.A.古普塔等，
印度化学杂志B，
21B，228；Nemeryuk，M.P.内默留克等，
捷克化学通讯集，(1986)，
51，215-233)。将该乙基酯在含水碱(在H2O-THF中的LiOH或在H2O-THF中的NaOH)存在下水解，以制得相应的酸(结构式15和16)。再将此羧酸进行Curtius重排(J.R.菲斯特等，
合成，(1983)，38；A.S.腊哈克里什纳等，
合成，(1983)，538；K.尼努米亚等，
四面体，(1974)，
30，2151)得到高反应性的异氰酸酯(结构式17和18)，这种异氰酸酯不需分离，可立即与醇或胺反应(参见上述Ninomiya等文献)。全部过程提供了氨基甲酸酯(以醇封端的异氰酸酯)或脲(以胺封端的异氰酸酯)，如结构式19和20所示。此处合成路线分为两路，一路是以N-烯丙基嘧啶为起始物料(结构式19)，该烯烃部分用四氧化锇/N-甲基吗啉N-氧化物(参见V.文伦嫩等，
四面体通信，(1976)，1973-1976；
有机合成第58卷，第43-51页)和高碘酸钠或高碘酸钾(H.O.豪斯；
近代合成反应，W.A.Benjamin Inc.，Menlo Park，CA1972，353-359)来氧化，得到中间体醛(结构式13→结构式19→结构式21)。另一路是以N-乙醛缩二甲醇为起始物料(结构式20)，该二甲基缩醛官能团用稀酸(盐酸水溶液)来处理，得到中间体醛(结构式14→结构式20→结构式21)。结构式4的酸由结构式21的醛经以亚氯酸钠或亚氯酸钾媒介的氧化而制得(B.S.巴尔等，
四面体，(1981)，
37，2091)。应当指出，用苄醇来对异氰酸酯(结构式17和18)封端可得到中间体Z-氨基甲酸酯，该中间体最终可制成结构式11(方案3)的化合物。
方案1
方案2
方案3
方案4
式中：
R1-R4、R9、R11和R24与式(1)中定义相同，Z定义为苄氧基羰基，W定义为OH基、HNC(H)(CH2COOtBu)COCH2R26部分和HNC(H)(CH2COOtBu)C＝NNHCONH2部分。此处R26定义为F、-O(CO)0-1-芳基、-OP(O)(R14)R(15)、**
或
式中R8、R14、R15、R16、R17和R18与以前定义的相同。
下面对本发明的化合物进一步加以阐述。
实施例1
N-[2-(5-苄氧基羰基氨基-6-氧代-2-(4-氟代苯基)-1，6
-二氢-1-嘧啶基)乙酰基(acetoyl)-L-天冬氨酸2，6-二氯苯甲
酰氧基甲基酮
部分A：将N-苄氧基羰基-L-天冬氨酸溴代甲基酮β-叔丁基酯(0.3g；0.76mM)溶于12ml无水DMF中。在此溶液中加粉状氟化钾(0.11g；19mmol)和2，6-二氯苯甲酸(0.17g；0.91mmol)，并将该反应混合物搅拌过夜。将该溶液用Et2O稀释，再用水、饱和NaHCO3水溶液、盐水洗涤，然后干燥(用MgSO4)。所得的酮用硅胶色谱法以乙酸乙酯/己烷为洗脱溶剂来纯化(1H NMR(CDCl3)§7.36(m，9H)，5.90(d，1H)，5.20(m，4H)，4.67(m，1H)，3.00和2.75(doublet of doublets，1H each)，1.42(s，9H))。
部分B：将N-苄氧基羰基-L-天冬氨酸2，6-二氯苯甲酰氧基甲基酮β-叔丁基酯(1.02g，2mmol；上述部分A)溶于绝对乙醇(100ml，4mmol)中，该绝对乙醇还含有2当量的6N HCl水溶液(4mmol)和载10％Pd/C(96mg)。将该反应混合物在氢气气氛中搅拌约1小时(薄层层析[5％MeOH-CH2Cl2]表明，起始物料已消失)。将该溶液过滤，在真空下除去溶剂，得到L-天冬氨酸2，6-二氯苯甲酰氧基甲基酮β-叔丁基酯的HCl盐，这种HCl盐可立即用于下述部分C的反应中。
部分C：将2-(5-苄氧基羰基氨基-6-氧代-2-(4-氟代苯基)-1，6-二氢-1-嘧啶基)乙酸(771mg，2.05mmol)的CH2Cl2(10ml)溶液冷却至-20℃，再依次将氯甲酸异丁酯(0.28ml，2.05mmol)和N-甲基吗啉(0.23ml，2.05mmol)加入。将该反应混合物搅拌15分钟，再将天冬氨酸2，6-二氯苯甲酰氧基甲基酮β-叔丁基酯HCl盐溶液(上述部分B制备的)加入，随后加第二批N-甲基吗啉(0.23ml，2.05mmol)。将反应混合物搅拌30分钟，然后用EtOAc稀释，用水、饱和NaHCO3水溶液和盐水洗涤，随后干燥(用MgSO4)。在真空下除去溶剂，所得产物用硅胶色谱法以40％EtOAc-己烷为洗脱剂纯化，得到N-[2-(5-苄氧基羰基氨基-6-氧代-2-(4-氟代苯基-)1，6-二氢-1-嘧啶基)乙酰基]-L-天冬氨酸2，6-二氯苯甲酰氧基甲基酮β-叔丁基酯(1.2g；80％)。
部分D：将N-[2-(5-苄氧基羰基氨基-6-氧代-2-(4-氟代苯基)-1，6-二氢-1-嘧啶基)乙酰基]-L-天冬氨酸2，6-二氯苯甲酰氧基甲基酮β-叔丁基酯(上述部分C)的含25％(体积/体积)三氟乙酸的二氯甲烷溶液(20ml)在0℃搅拌2小时。在真空下除去溶剂，将残余物用硅胶色谱法纯化得到分析纯的N-[2-(5-苄氧基羰基氨基-6-氧代-2-(4-氟代苯基)-1，6-二氢-1-嘧啶基)乙酰基]-L-天冬氨酸2，6-二氯苯甲酰氧基甲基酮，低分辨率质谱：m/z＝699(M+H)。
实施例2
N-[2-(5-硫代甲基苯甲酰氨基-6-氧代-2-(4-氟代苯基)-
1，6-二氢-1-嘧啶基)乙酰基]L-天冬氨酸2，6-二氯苯甲酰氧
基甲基酮
部分A：将N-[2-(5-苄氧基羰基氨基-6-氧代-2-(4-氟代苯基)-1，6-二氢-1-嘧啶基)乙酰基]-L-天冬氨酸5-(1-(4-氯苯基)-3-三氟甲基)吡唑氧基-甲基酮β-叔丁基酯(2.5g，3.0mmol)溶于绝对乙醇(100ml，4mmol)中，该绝对乙醇还含有2当量的6N HCl水溶液。将该溶液用氮脱气，再加入10％Pd/C(300mg)。将该反应混合物在氢气气氛下搅拌5小时(薄层层析[50％EtOAc-己烷：起始物料的Rf＝0.5；产品的Rf＝0.0]表明，起始物料已消失)。将该溶液过滤，在真空下除去溶剂，以得到N-[2-(5-氨基-6-氧代-2-(4-氟代苯基)-1，6-二氢-1-嘧啶基)乙酰基]-L-天冬氨酸5-(1-(4-氯苯基-3-三氟甲基)吡唑氧基甲基酮β-叔丁基酯，它与甲苯形成共沸混合物，且不须要进一步纯化即可直接用于下一步部分B所述的反应中。
部分B：在N-[2-(5-氨基-6-氧代-2-(4-氟代苯基)-1，6-二氢-1-嘧啶基)-乙酰基]-L-天冬氨酸5-(1-(4-氯苯基)-3-三氟甲基)吡唑氧基甲基酮β-叔丁基酯(713mg，1.0mmol上述部分A制备的)的二氯甲烷(30ml)溶液中，于5℃将4-硫代甲基苯甲酰氯(279mg，1.5mmol)加入，随后再将N-甲基吗啉(0.5ml；4.5mmol)和4-N，N-二甲氨基吡啶(10mg)加入。将该反应混合物于5℃搅拌2小时，然后让其升至室温。将该溶液用EtOAc稀释，再用水、饱和NaHCO3水溶液洗和盐水洗涤，然后干燥(用MgSO4)。在真空下除去溶剂。所得产物用硅胶色谱法以约30％EtOAc-己烷为洗脱剂纯化，得到N-[2-(5-(4-硫代甲基苯甲酰氨基)-6-氧代-2-(4-氟代苯基)-1，6-二氢-1-嘧啶基)乙酰基]-L-天冬氨酸5-(1-(4-氯苯基)-3-三氟甲基)吡唑氧基甲基酮β-叔丁基酯，收率为50％。
部分C：将N-[2-(5-(4-硫代甲基苯甲酰氨基)-6-氧代-2-(4-氟代苯基)-1，6-二氢-1-嘧啶基)乙酰基]-L-天冬氨酸5-(1-(4-氯苯基)-3-三氟甲基)吡唑氧基甲基酮β-叔丁基酯采用上文实施例1中部分D所述的条件转变为与其相对应的酸N-[2-(5-(4-硫代苯甲酰氨基)-6-氧代-2-(4-氟代苯基)-1，6-二氢-1-嘧啶基)乙酰基]-L-天冬氨酸5-(1-(4-氯苯基)-3-三氟甲基)吡唑氧基甲基酮。质谱：m/z＝787(M+H)。
按方案1和2的过程，采用与实施例1和2类似的方法来制备下列化合物。
实施例3
N-[2-(5-苄氧基羰基氨基-6-氧代-2-(4-氟代苯基)-
1，6-二氢-1-嘧啶基)乙酰基]-L-天冬氨酸二苯基膦氧基甲基
酮
质谱：m/z＝727(M+H)
实施例4
N-[2-(5-苄氧基羰基氨基-6-氧代-2-(4-氟代苯基)-
1，6-二氢-1-嘧啶基)乙酰基]-L-天冬氨酸5-(1-(4-氯苯
基)-3-三氟甲基)吡唑氧基甲基酮
质谱：m/z＝771(M+H)
实施例5
N-[2-(5-苄氧基羰基氨基-6-氧代-2-(4-氟代苯基)
-1，6-二氢-1-嘧啶基)乙酰基]-L-天冬氨酸5-(3-苯基)
香豆酰(coumarinyl)氧基甲基酮
质谱：m/z＝747(M+H)
实施例6
N-[2-(5-苄氧基羰基氨基-6-氧代-2-(4-氟代苯基)-
1，6-二氢-1-嘧啶基)乙酰基]-L-天冬氨酸5-(1-苯基-3
-三氟甲基)吡唑氧基甲基酮
质谱：m/z＝737(M+H)
实施例7
N-[2-(5-异丙氧基羰基氨基-6-氧代-2-苯基-1，6-
二氢-1-嘧啶基)乙酰基]-L-天冬氨酸5-(1-苯基-3-三氟甲
基)吡唑氧基甲基酮
质谱：m/z＝671(M+H)
实施例8
N-[2-(5-苄氧基羰基氨基-6-氧代-2-(3-吡啶基)-1，
6-二氢-1-嘧啶基)乙酰基]-L-天冬氨酸5-(1-苯基-3-三
氟甲基)吡唑氧基甲基酮
质谱：m/z＝720(M+H)
实施例9
N-[2-(5-苄氧基羰基氨基-6-氧代-2-(2-噻吩基)-1，
6-二氢-1-嘧啶基)乙酰基]-L-天冬氨酸5-(1-苯基-3-三
氟甲基)吡唑氧基甲基酮
质谱：m/z＝725(M+H)
实施例10
N-{2-(5-苄氧基羰基氨基-6-氧代-2-甲基-1，6-二
氢-1-嘧啶基)乙酰基]-L-天冬氨酸5-(1-苯基-3-三氟甲基)
吡唑氧基甲基酮
质谱：m/z＝657(M+H)
实施例11
N-[2-(5-苄氧基羰基氨基-6-氧代-2-(2-噻吩基)-1，
6-二氢-1-嘧啶基)乙酰基]-L-天冬氨酸5-(1-(2-吡啶基)
-3-三氟甲基)吡唑氧基甲基酮
质谱：m/z＝726(M+H)
实施例12
N-[2-(5-苄氧基羰基氨基-6-氧代-2-(2-噻吩基)-L
-天冬氨酸5-(1-(4-氯苯基)-3-三氟甲基)吡唑氧基甲基酮
质谱：m/z＝759(M+H)
实施例13
N-[2-(5-苄氧基羰基氨基-6-氧代-2-(2-噻吩基)-L
-天冬氨酸2，6-二氯苯甲酰氧基甲基酮
质谱：m/z＝687(M+H)
实施例14
N-[2-(5-苄氧基羰基氨基-6-氧代-2-(2-噻吩基)-1，
6-二氢-1-，嘧啶基)乙酰基]-L-天冬氨酸醛
质谱：m/z＝485(M+H)
按下列模式测试本发明的化合物对IL-1β蛋白酶抑制的活性：
体外试验
去活二级速率常数是采用R.E.多尔等，
药物化学杂志，(1994)，
37，781中所述的酶分析法来求得的。
实施例1-13的化合物具有IL-1β蛋白酶抑制能力(kobs/l大于50,000M-1S-1)。
体内试验
体内抑制(IC50)按如下方法进行测定：
从Biological Specialty Corporation(Lansdale，PA)获得的肝素化白细胞电泳单元(heparinized leukopheresis units)分离得到人的单核白细胞。采用Ficoll-Hupaque(Pharmacia Fine Chemicals，Piscataway，NJ)梯度离心来纯化单核白细胞，并用离心淘析得到纯度大于95％的单核白细胞群。该分析是对新鲜分离出来的人的单核白细胞取重复样品进行的，这种单核白细胞是培养在37℃的悬浮液中并盛于圆锥底的聚丙烯试管内(Sardstedt Inc.，Princeton，NJ)加以缓慢旋转。将这种人的单核白细胞以5×106cells/ml的浓度再悬浮于1ml RPMI 1640(一种M.A.Bioproducts，Walkersville，MD的普通组织缓冲液)中，该RPMI1640中含1％胎牛血清(FCS)(HyClone，Logan，UT)和50μg/ml庆大霉素(Gibco，Grand Island，NY)。将这种细胞用本发明的化合物(即需测试的化合物)或非抑制剂(即对照化合物，通常为0.03％DMSO)处理15分钟，然后用0.01％的固定金黄色葡萄球菌(The Enzyme Center，Malden MA)活化1小时。然后将这种细胞进行离心并再悬浮于1ml不含半胱氨酸、蛋氨酸的RPMI介质中，该介质含有1％透析过的FCS(Hyclone)。将这种细胞用需测试的化合物或对照化合物预处理15分钟，然后将0.01％的固定金黄色葡萄球菌和100μCi Tran 35-S标记物(ICN，Irvine，CA)加入，再将这种细胞在37℃培养1小时。然后将这种细胞进行离心，用磷酸盐缓冲盐水洗一次并再悬浮于1ml加有1％胎牛血清的RPMI中。将这种细胞再一次用需测试的化合物或对照化合物预处理15分钟，然后用0.01％金黄色葡萄球菌处理2小时。培养完毕后，将这种细胞进行离心，收集上层清液用于免疫沉淀。将这种细胞再用磷酸盐缓冲盐水洗一次，然后溶解于RIPA中，RIPA是一种含有2mM苯甲磺酰氟、10mM碘代乙酸盐、1μg/ml胃酶抑素A、1μg/ml亮肽菌素和0.5TIU抑肽酶的传代细胞介质缓冲液。
为了进行免疫沉淀，在上述的上层清液中加等体积1％奶粉的RIPA缓冲液和50μl再悬浮的蛋白质A琼脂糖凝胶CL-4B(Pharmacia，Piscataway，New York)，并在上述的细胞溶解液中加1ml含蛋白质A琼脂糖凝胶CL-4B的4％奶粉溶液，再将这些试样在4℃旋转30分钟。此后将小珠体离心沉降，再将试样转移至新的试管中，并与40μg兔的抗人体IL-1β的多克隆抗体(Genzyme，Cambridge，MA)在一起培养过夜。然后用70μl蛋白质A琼脂糖凝胶将IL-1β蛋白质沉淀出来，再悬浮于60μlSDS试样缓冲液中并在15％SGD-PAGE凝胶上进行试验。在干的凝胶上进行放射自显影，并用Betascope 603分析仪定量测定放射性量(每分钟的计数，cpm)。
数据分析
在单核白细胞脉冲追踪测定时，每一测试参数都进行两次测定。用个人计算机将数据从Beta Scope收集起来，然后传至VAX系统以计算平均cpm和该平均值的标准偏差。在对需测试的化合物进行评价时，按如下方式计算成熟IL-1β的释放抑制百分率：
100×[1-(受需测试的化合物刺激处理的细胞-未受刺激的细胞)/(受对照化合物刺激处理的细胞-未受刺激的细胞)]
然后利用这些抑制百分率值来计算每种化合物的IC50值。由于这种人的单核白细胞脉冲追踪测定所用的是来自不同的供血者的原生细胞，因此对每种需测试的化合物是用取自2-3名不同供血者的单核白细胞进行2-3个分别的试验。
对实施例1、6、7和9而言，其体内试验IC50值为约0.1-约10μM的范围。
对弹性蛋白酶的抑制作用(体外试验)
对实施例1、6和7的化合物检验了其抑制弹性蛋白酶的能力。这种体外试验是按恰，
生物化学药理学，(1975)，
24，2177-2185所述方法进行的。实施例1、6和7是这类ICE抑制剂的代表，它们不抑制弹性蛋白酶，其IC50值≥10μM。
Claims (6)
1、一种式(I)的化合物或其药学上可接受的盐：
式中：
Y是
而当R6是OH，则Y还可以是：
R5是H或氘；
R6是OR8或NHOH
此处R8独立地是H、烷基或芳烷基R3和R4独立地是H、烷基或芳烷基R2＝H、烷基、-(CH2)0-4-环烷基、
芳基、杂芳基、芳烷基、杂芳烷基、-(CH2)2-4-R10；
此处n＝1-3；
此处R10＝烷氧基、CH2F、CHF2、CF3、CF2CF3、OH、COOR11、CONR9R11或NR9R11；
此处R9独立地是H、烷基、芳基、芳烷基、杂芳基、杂芳烷基、-CH2CH2O-烷基和C(O)-R12；
此处R11独立地是H、烷基、芳基、芳烷基、杂芳基和杂芳烷基；
而当R9和R11合在一起，则它们可成为五、六或七元环，其类型是：
此处n＝1-3和m＝0-1；
而R12是烷基、芳基、芳烷基、杂芳基和杂芳烷基；
R7＝H，CH2F，CHR13O(CO)0-1-芳基，CHR13OP(O)(R14)R(15)，
或
式中：
R13＝H或烷基
R14＝H、烷基或芳基
R15＝H、烷基或芳基
R16＝H、烷基、芳基、杂芳基、芳烷基或杂芳烷基
R17＝H、烷基、CF3、CF2CF3、芳基、杂芳基、芳烷基、杂芳烷基、COOR11或CONR9R11
R18＝H、烷基、CF3、CF2CF3、芳基、杂芳基、芳烷基、杂芳烷基R1定义为：
R19-R2，R19-R20，R19-R21，R19-NR9R11
此处R19＝(CR3R4)-0-4；
R22O-
此处R22是烷基、芳基、杂芳基、芳烷基、杂芳烷基、R19-环烷基、R19-R21、R23-R10、R23-R20；
式中R23＝(CR3R4)-2-4；
R9R11N-和R24R11N-
此处R24＝R19-环烷基、R19-R21、R23-R10、R23-R20、CR3R4COOR11和CR3CR4CONR9R11。
2、权利要求1的化合物，该化合物选自：
N-[2-(5-苄氧基羰基氨基-6-氧代-2-(4-氟代苯基)-1，6-二氢-1-嘧啶基)乙酰基-L-天冬氨酸2，6-二氯苯甲酰氧基甲基酮、N-[2-(5-硫代甲基苯甲酰氨基-6-氧代-2-(4-氟代苯基)-1，6-二氢-1-嘧啶基)乙酰基]-L-天冬氨酸2，6-二氯苯甲酰氧基甲基酮、N-[2-(5-苄氧基羰基氨基-6-氧代-2-(4-氟代苯基)-1，6-二氢-1-嘧啶基)乙酰基]-L-天冬氨酸二苯基膦氧基甲基酮、N-[2-(5-苄氧基羰基氨基-6-氧代-2-(4-氟代苯基)-1，6-二氢-1-嘧啶基)乙酰基]-L-天冬氨酸5-(1-(4-氯苯基)-3-三氟甲基)吡唑氧基甲基酮、N-[2-(5-苄氧基羰基氨基-6-氧代-2-(4-氟代苯基)-1，6-二氢-1-嘧啶基)乙酰基]-L-天冬氨酸5-(3-苯基)香豆酰氧基甲基酮、N-[2-(5-苄氧基羰基氨基-6-氧代-2-(4-氟代苯基)-1，6-二氢-1-嘧啶基)乙酰基]-L-天冬氨酸5-(1-苯基-3-三氟甲基)吡唑氧基甲基酮、N-[2-(5-异丙氧基羰基氨基-6-氧代-2-苯基-1，6-二氢-1-嘧啶基)乙酰基]-L-天冬氨酸5-(1-苯基-3-三氟甲基)吡唑氧基甲基酮、N-[2-(5-苄氧基羰基氨基-6-氧代-2-(3-吡啶基)-1，6-二氢-1-嘧啶基)乙酰基]-L-天冬氨酸5-(1-苯基-3-三氟甲基)吡唑氧基甲基酮、N-[2-(5-苄氧基羰基氨基-6-氧代-2-(2-噻吩基)-1，6-二氢-1-嘧啶基)乙酰基]-L-天冬氨酸5-(1-苯基-3-三氟甲基)吡唑氧基甲基酮、N-[2-(5-苄氧基羰基氨基-6-氧代-2-甲基-1，6-二氢-1-嘧啶基)乙酰基]-L-天冬氨酸5-(1-苯基-3-三氟甲基)吡唑氧基甲基酮、N-[2-(5-苄氧基羰基氨基-6-氧代-2-(2-噻吩基)-1，6-二氢-1-嘧啶基)乙酰基]-L-天冬氨酸5-(1-(2-吡啶基)-3-三氟甲基)吡唑氧基甲基酮、N-[2-(5-苄氧基羰基氨基-6-氧代-2-(2-噻吩基)-L-天冬氨酸5-(1-(4-氯苯基)-3-三氟甲基)吡唑氧基甲基酮、N-[2-(5-苄氧基羰基氨基-6-氧代-2-(2-噻吩基)-L-天冬氨酸2，6-二氯苯甲酰氧基甲基酮、N-[2-(5-苄氧基羰基氨基-6-氧代-2-(2-噻吩基)-1，6-二氢-1-嘧啶基)乙酰基]-L-天冬氨酸醛。
3、一种抑制白细胞介素-1β蛋白酶的药用组合物，该组合物包括式(I)的化合物或其药学上可接受的盐：
式中：
-Y是
而当R6是OH，则Y还可以是：
R5是H或氘；
R6是OR8或NHOH
此处R8独立地是H、烷基或芳烷基R3和R4独立地是H，烷基或芳烷基R2＝H、烷基、-(CH2)0-4-环烷基，
芳基，杂芳基，芳烷基，杂芳烷基，-(CH2)2-4-R10；
此处n＝1-3；
R2＝H、烷基、-(CH2)0-4-环烷基、
芳基、杂芳基、芳烷基、杂芳烷基、-(CH2)2-4-R10；
此处n＝1-3；
此处R10＝烷氧基、CH2F、CHF2、CF3、CF2CF3、OH、COOR11、CONR9R11或NR9R11；
此处R9独立地是H、烷基、芳基、芳烷基、杂芳基、杂芳烷基、-CH2CH2O-烷基和C(O)-R12；
此处R11独立地是H、烷基、芳基、芳烷基、杂芳基和杂芳烷基；
而当R9和R11合在一起，则它们可成为五、六或七元环，其类型是：
而R12是烷基、芳基、芳烷基、杂芳基和杂芳烷基；
R7＝H，CH2F，CHR13O(CO)0-1-芳基，CHR13OP(O)(R14)R(15)，
式中：
R13＝H或烷基
R14＝H、烷基或芳基
R15＝H、烷基或芳基
R16＝H、烷基、芳基、杂芳基、芳烷基或杂芳烷基
R17＝H、烷基、CF3、CF2CF3、芳基、杂芳基、芳烷基、杂芳烷基、COOR11或CONR9R11
R18＝H、烷基、CF3、CF2CF3、芳基、杂芳基、芳烷基、杂芳烷基
R1定义为：
R19-R2，R19-R20，R19-R21，R19-NR9R11
此处R19＝(CR3R4)-0-4；
和
此处n-1-3；
R22O-
此处R22是烷基、芳基、杂芳基、芳烷基、杂芳烷基、R19-环烷基、R19-R21、R23-R10、R23-R20；
式中R23＝(CR3R4)-2-4；
R9R11N-和R24R11N-
此处R24＝R19-环烷基、R19-R21、R23-R20、R23-R20、CR3R4COOR11和CR3CR4CONR9R11。
4、权利要求3的药用组合物，其中所述的化合物选自：N-[2-(5-苄氧基羰基氨基-6-氧代-2-(4-氟代苯基)-1，6-二氢-1-嘧啶基)乙酰基-L-天冬氨酸2，6-二氯苯甲酰氧基甲基酮、N-[2-(5-硫代甲基苯甲酰氨基-6-氧代-2-(4-氟代苯基)-1，6-二氢-1-嘧啶基)乙酰基]-L-天冬氨酸2，6-二氯苯甲酰氧基甲基酮、N-[2-(5-苄氧基羰基氨基-6-氧代-2-(4-氟代苯基)-1，6-二氢-1-嘧啶基)乙酰基]-L-天冬氨酸二苯基膦氧基甲基酮、N-[2-(5-苄氧基羰基氨基-6-氧代-2-(4-氟代苯基)-1，6-二氢-1-嘧啶基)乙酰基]-L-天冬氨酸5-(1-(4-氯苯基)-3-三氟甲基)吡唑氧基甲基酮、N-[2-(5-苄氧基羰基氨基-6-氧代-2-(4-氟代苯基)-1，6-二氢-1-嘧啶基)乙酰基]-L-天冬氨酸5-(3-苯基)香豆酰)氧基甲基酮、N-[2-(5-苄氧基羰基氨基-6-氧代-2-(4-氟代苯基)-1，6-二氢-1-嘧啶基)乙酰基]-L-天冬氨酸5-(1-苯基-3-三氟甲基)吡唑氧基甲基酮、N-[2-(5-异丙氧基羰基氨基-6-氧代-2-苯基-1，6-二氢-1-嘧啶基)乙酰基]-L-天冬氨酸5-(1-苯基-3-三氟甲基)吡唑氧基甲基酮、N-[2-(5-苄氧基羰基氨基-6-氧代-2-(3-吡啶基)-1，6-二氢-1-嘧啶基)乙酰基]-L-天冬氨酸5-(1-苯基-3-三氟甲基)吡唑氧基甲基酮、N-[2-(5-苄氧基羰基氨基-6-氧代-2-(2-噻吩基)-1，6-二氢-1-嘧啶基)乙酰基]-L-天冬氨酸5-(1-苯基-3-三氟甲基)吡唑氧基甲基酮、N-[2-(5-苄氧基羰基氨基-6-氧代-2-甲基-1，6-二氢-1-嘧啶基)乙酰基]-L-天冬氨酸5-(1-苯基-3-三氟甲基)吡唑氧基甲基酮、N-[2-(5-苄氧基羰基氨基-6-氧代-2-(2-噻吩基)-1，6-二氢-1-嘧啶基)乙酰基]-L-天冬氨酸5-(1-(2-吡啶基)-3-三氟甲基)吡唑氧基甲基酮、N-[2-(5-苄氧基羰基氨基-6-氧代-2-(2-噻吩基)-L-天冬氨酸5-(1-(4-氯苯基)-3-三氟甲基)吡唑氧基甲基酮、N-[2-(5-苄氧基羰基氨基-6-氧代-2-(2-噻吩基)-L-天冬氨酸2，6-二氯苯甲酰氧基甲基酮、N-[2-(5-苄氧基羰基氨基-6-氧代-2-(2-噻吩基)-1，6-二氢-1-嘧啶基)乙酰基]-L-天冬氨酸醛。
5、一种抑制白细胞介素-1β蛋白酶活性的方法，该法是用于需要对肺部、中枢神经系统和结缔组织的炎症和基于免疫的疾病接受这种治疗的哺乳动物的，该方法包括给该哺乳动物以有效抑制量的药用组合物，该药用组合物包括式(I)的化合物或其药学上可接受的盐：
式中：
Y是
而当R6是OH，则Y还可以是：
R5是H或氘；
R6是OR8或NHOH
此处R8独立地是H、烷基或芳烷基R3和R4独立地是H、烷基或芳烷基
R2＝H、烷基、-(CH2)0-4-环烷基、
芳基、杂芳基、芳烷基、杂芳烷基、-(CH2)2-4-R10；
此处n＝1-3；
此处R10＝烷氧基、CH2F、CHF2、CF3、CF2CF3、OH、COOR11、CONR9R11或NR9R11；
此处R9独立地是H、烷基、芳基、芳烷基、杂芳基、杂芳烷基、-CH2CH2O-烷基和C(O)-R12；
此处R11独立地是H、烷基、芳基、芳烷基、杂芳基和杂芳烷基；
而当R9和R11合在一起，则它们可成为五、六或七元环，其类型是：此处n＝1-3和m＝0-1；
而R12是烷基、芳基、芳烷基、杂芳基和杂芳烷基；
R7＝H，CH2F，CHR13O(CO)0-1-芳基，CHR13OP(O)(R14)R(15)，
式中：
R13＝H或烷基
R14＝H、烷基或芳基
R15＝H、烷基或芳基
R16＝H、烷基、芳基、杂芳基、芳烷基或杂芳烷基
R17＝H、烷基、CF3、CF2CF3、芳基、杂芳基、芳烷基、杂芳烷基、COOR11或CONR9R11
R18＝H、烷基、CF3、CF2CF3、芳基、杂芳基、芳烷基、杂芳烷基R1定义为：
R19-R2，R19-R20，R19-R21，R19-NR9R11
此处R19＝(CR3R4)-0-4；
和
此处X＝O，S，NR9
和
此处n-1-3；
R22O-
此处R22是烷基、芳基、杂芳基、芳烷基、杂芳烷基、R19-环烷基、R19-R21、R23-R10、R23-R20；
式中R23＝(CR3R4)-2-4；
R9R11N-和R24R11N-
此处R24＝R19-环烷基、R19-R21、R23-R10、R23-R20、CR3R4COOR11和CR3CR4CONR9R11。
6、权利要求5的方法，其中所述的化合物选自：N-[2-(5-苄氧基羰基氨基-6-氧代-2-(4-氟代苯基)-1，6-二氢-1-嘧啶基)乙酰基-L-天冬氨酸2，6-二氯苯甲酰氧基甲基酮、N-[2-(5-硫代甲基苯甲酰氨基-6-氧代-2-(4-氟代苯基)-1，6-二氢-1-嘧啶基)乙酰基]-L-天冬氨酸2，6-二氯苯甲酰氧基甲基酮、N-[2-(5-苄氧基羰基氨基-6-氧代-2-(4-氟代苯基)-1，6-二氢-1-嘧啶基)乙酰基]-L-天冬氨酸二苯基膦氧基甲基酮、N-[2-(5-苄氧基羰基氨基-6-氧代-2-(4-氟代苯基)-1，6-二氢-1-嘧啶基)乙酰基]-L-天冬氨酸5-(1-(4-氯苯基)-3-三氟甲基)吡唑氧基甲基酮、N-[2-(5-苄氧基羰基氨基-6-氧代-2-(4-氟代苯基)-1，6-二氢-1-嘧啶基)乙酰基]-L-天冬氨酸5-(3-苯基)香豆酰氧基甲基酮、N-[2-(5-苄氧基羰基氨基-6-氧代-2-(4-氟代苯基)-1，6-二氢-1-嘧啶基)乙酰基]-L-天冬氨酸5-(1-苯基-3-三氟甲基)吡唑氧基甲基酮、N-[2-(5-异丙氧基羰基氨基-6-氧代-2-苯基-1，6-二氢-1-嘧啶基)乙酰基]-L-天冬氨酸5-(1-苯基-3-三氟甲基)吡唑氧基甲基酮、N-[2-(5-苄氧基羰基氨基-6-氧代-2-(3-吡啶基)-1，6-二氢-1-嘧啶基)乙酰基]-L-天冬氨酸5-(1-苯基-3-三氟甲基)吡唑氧基甲基酮、N-[2-(5-苄氧基羰基氨基-6-氧代-2-(2-噻吩基)-1，6-二氢-1-嘧啶基)乙酰基]-L-天冬氨酸5-(1-苯基-3-三氟甲基)吡唑氧基甲基酮、N-[2-(5-苄氧基羰基氨基-6-氧代-2-甲基-1，6-二氢-1-嘧啶基)乙酰基]-L-天冬氨酸5-(1-苯基-3-三氟甲基)吡唑氧基甲基酮、N-[2-(5-苄氧基羰基氨基-6-氧代-2-(2-噻吩基)-1，6-二氢-1-嘧啶基)乙酰基]-L-天冬氨酸5-(1-(2-吡啶基)-3-三氟甲基)吡唑氧基甲基酮、N-[2-(5-苄氧基羰基氨基-6-氧代-2-(2-噻吩基)-L-天冬氨酸5-(1-(4-氯苯基)-3-三氟甲基)吡唑氧基甲基酮、N-[2-(5-苄氧基羰基氨基-6-氧代-2-(2-噻吩基)-L-天冬氨酸2，6-二氯苯甲酰氧基甲基酮、N-[2-(5-苄氧基羰基氨基-6-氧代-2-(2-噻吩基)-1，6-二氢-1-嘧啶基)乙酰基]-L-天冬氨酸醛。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US22171294A | 1994-03-31 | 1994-03-31 | |
| US221712 | 1994-03-31 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN95193258A Division CN1118458C (zh) | 1994-03-31 | 1995-03-29 | 作为白细胞介素抑制剂的嘧啶基衍生物 |
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| Publication Number | Publication Date |
|---|---|
| CN1504462A true CN1504462A (zh) | 2004-06-16 |
Family
ID=22829018
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA031452183A Pending CN1504462A (zh) | 1994-03-31 | 1995-03-29 | 作为白细胞介素抑制剂的嘧啶基衍生物 |
| CN95193258A Expired - Fee Related CN1118458C (zh) | 1994-03-31 | 1995-03-29 | 作为白细胞介素抑制剂的嘧啶基衍生物 |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN95193258A Expired - Fee Related CN1118458C (zh) | 1994-03-31 | 1995-03-29 | 作为白细胞介素抑制剂的嘧啶基衍生物 |
Country Status (18)
| Country | Link |
|---|---|
| US (3) | US5670494A (zh) |
| EP (1) | EP0752987B1 (zh) |
| JP (1) | JP3703836B2 (zh) |
| CN (2) | CN1504462A (zh) |
| AT (1) | ATE254111T1 (zh) |
| AU (1) | AU703451B2 (zh) |
| CA (1) | CA2186511C (zh) |
| DE (1) | DE69532113T2 (zh) |
| DK (1) | DK0752987T3 (zh) |
| ES (1) | ES2210289T3 (zh) |
| FI (1) | FI112943B (zh) |
| HK (1) | HK1012623A1 (zh) |
| HU (1) | HU224731B1 (zh) |
| MX (1) | MX9604420A (zh) |
| NO (1) | NO308603B1 (zh) |
| NZ (1) | NZ283876A (zh) |
| PT (1) | PT752987E (zh) |
| WO (1) | WO1995026958A1 (zh) |
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| US5847135A (en) * | 1994-06-17 | 1998-12-08 | Vertex Pharmaceuticals, Incorporated | Inhibitors of interleukin-1β converting enzyme |
| US6420522B1 (en) | 1995-06-05 | 2002-07-16 | Vertex Pharmaceuticals Incorporated | Inhibitors of interleukin-1β converting enzyme |
| US5716929A (en) * | 1994-06-17 | 1998-02-10 | Vertex Pharmaceuticals, Inc. | Inhibitors of interleukin-1β converting enzyme |
| US5756466A (en) * | 1994-06-17 | 1998-05-26 | Vertex Pharmaceuticals, Inc. | Inhibitors of interleukin-1β converting enzyme |
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| US5843904A (en) * | 1995-12-20 | 1998-12-01 | Vertex Pharmaceuticals, Inc. | Inhibitors of interleukin-1βconverting enzyme |
| WO1997024339A1 (fr) * | 1995-12-27 | 1997-07-10 | Ono Pharmaceutical Co., Ltd. | Derives de tetrazole et medicaments les contenant a titre d'ingredients actifs |
| KR20000049050A (ko) * | 1996-10-11 | 2000-07-25 | 로즈 암스트롱, 크리스틴 에이. 트러트웨인 | 술폰아미드 치환된 아스파르트산 인터루킨-1β 전환 효소 억제제 |
| JP2001508404A (ja) | 1996-10-11 | 2001-06-26 | ワーナー―ランバート・コンパニー | スルホンアミドインターロイキン―１β変換酵素阻害剤 |
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| DE69925581T2 (de) | 1998-03-09 | 2006-04-27 | Vertex Pharmaceuticals Inc., Cambridge | 1,2-diazepanderivate als inhibitoren des interleukin-1beta umwandelnden enzyms |
| KR100928878B1 (ko) | 1998-03-19 | 2009-11-30 | 버텍스 파마슈티칼스 인코포레이티드 | 카스파제의 억제제 |
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| WO2002076503A1 (en) * | 2000-06-20 | 2002-10-03 | Mayo Foundation For Medical Education And Research | Treatment of central nervous system diseases by antibodies against glatiramer acetate |
| WO2002006242A2 (en) * | 2000-07-18 | 2002-01-24 | Neurogen Corporation | 5-substituted 2-aryl-4-pyrimidinones |
| US7429374B2 (en) * | 2001-12-04 | 2008-09-30 | Teva Pharmaceutical Industries, Ltd. | Process for the measurement of the potency of glatiramer acetate |
| US7410956B2 (en) * | 2002-02-11 | 2008-08-12 | Vertex Pharmaceuticals Incorporated | Caspase inhibitor prodrugs |
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| AU2003242270A1 (en) * | 2002-06-14 | 2003-12-31 | Ajinomoto Co., Inc. | Process for producing pyrimidine compound |
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| EP1778221A2 (en) | 2004-05-27 | 2007-05-02 | Vertex Pharmaceuticals Incorporated | Ice inhibitors for the treatment of autoinflammatory diseases |
| EP1833794B1 (en) * | 2004-11-24 | 2012-02-01 | Vertex Pharmceuticals Incorporated | 3-[2-(3-acylamino-2-oxo-2h-pyridin-1-yl)-acetylamino]-4-oxo-pentanoic acid derivatives and their use as caspase inhibitors |
| EP2185721B1 (en) * | 2007-08-03 | 2014-04-02 | Sanofi | Caspase imaging probes |
| EP2262783A2 (en) * | 2008-02-21 | 2010-12-22 | Sanofi-Aventis | Covalently binding imaging probes |
| EP2635906A4 (en) | 2010-11-05 | 2014-04-02 | Univ Brandeis | ICE INHIBITING COMPOUNDS AND USES THEREOF |
| US9956260B1 (en) | 2011-07-22 | 2018-05-01 | The J. David Gladstone Institutes | Treatment of HIV-1 infection and AIDS |
| EP2848696A1 (en) | 2013-09-13 | 2015-03-18 | Sanofi-Aventis Deutschland GmbH | Caspase-1 imaging probes |
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| US5441960A (en) * | 1992-04-16 | 1995-08-15 | Zeneca Limited | 1-pyrimidinylacetamide human leukocyte elastate inhibitors |
| CA2186511C (en) * | 1994-03-31 | 2009-02-10 | Roland E. Dolle | Pyrimidinyl derivatives as interleukin inhibitors |
-
1995
- 1995-03-29 CA CA002186511A patent/CA2186511C/en not_active Expired - Fee Related
- 1995-03-29 NZ NZ283876A patent/NZ283876A/en not_active IP Right Cessation
- 1995-03-29 AU AU22323/95A patent/AU703451B2/en not_active Ceased
- 1995-03-29 AT AT95915448T patent/ATE254111T1/de not_active IP Right Cessation
- 1995-03-29 JP JP52582195A patent/JP3703836B2/ja not_active Expired - Fee Related
- 1995-03-29 CN CNA031452183A patent/CN1504462A/zh active Pending
- 1995-03-29 CN CN95193258A patent/CN1118458C/zh not_active Expired - Fee Related
- 1995-03-29 MX MX9604420A patent/MX9604420A/es active IP Right Grant
- 1995-03-29 HU HU9602664A patent/HU224731B1/hu not_active IP Right Cessation
- 1995-03-29 DE DE69532113T patent/DE69532113T2/de not_active Expired - Lifetime
- 1995-03-29 DK DK95915448T patent/DK0752987T3/da active
- 1995-03-29 EP EP95915448A patent/EP0752987B1/en not_active Expired - Lifetime
- 1995-03-29 ES ES95915448T patent/ES2210289T3/es not_active Expired - Lifetime
- 1995-03-29 WO PCT/US1995/003909 patent/WO1995026958A1/en active IP Right Grant
- 1995-03-29 PT PT95915448T patent/PT752987E/pt unknown
- 1995-11-20 US US08/559,870 patent/US5670494A/en not_active Expired - Lifetime
-
1996
- 1996-09-26 NO NO964058A patent/NO308603B1/no unknown
- 1996-09-27 FI FI963897A patent/FI112943B/fi not_active IP Right Cessation
-
1997
- 1997-06-17 US US08/877,380 patent/US6162800A/en not_active Expired - Lifetime
-
1998
- 1998-12-16 HK HK98113788A patent/HK1012623A1/xx not_active IP Right Cessation
-
2000
- 2000-12-19 US US09/740,623 patent/US6407080B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| NO308603B1 (no) | 2000-10-02 |
| US20010003750A1 (en) | 2001-06-14 |
| HU224731B1 (en) | 2006-01-30 |
| FI963897A (fi) | 1996-09-27 |
| JP3703836B2 (ja) | 2005-10-05 |
| HUT75715A (en) | 1997-05-28 |
| AU703451B2 (en) | 1999-03-25 |
| CN1118458C (zh) | 2003-08-20 |
| AU2232395A (en) | 1995-10-23 |
| HU9602664D0 (en) | 1996-11-28 |
| MX9604420A (es) | 1997-12-31 |
| US6407080B2 (en) | 2002-06-18 |
| DE69532113T2 (de) | 2004-07-29 |
| CN1149292A (zh) | 1997-05-07 |
| NZ283876A (en) | 2001-03-30 |
| NO964058D0 (no) | 1996-09-26 |
| EP0752987B1 (en) | 2003-11-12 |
| WO1995026958A1 (en) | 1995-10-12 |
| FI963897A0 (fi) | 1996-09-27 |
| CA2186511A1 (en) | 1995-10-12 |
| EP0752987A1 (en) | 1997-01-15 |
| FI112943B (fi) | 2004-02-13 |
| HK1012623A1 (en) | 1999-08-06 |
| DK0752987T3 (da) | 2004-03-15 |
| NO964058L (no) | 1996-09-26 |
| ATE254111T1 (de) | 2003-11-15 |
| EP0752987A4 (en) | 1997-04-09 |
| JPH09511249A (ja) | 1997-11-11 |
| PT752987E (pt) | 2004-03-31 |
| DE69532113D1 (de) | 2003-12-18 |
| US5670494A (en) | 1997-09-23 |
| US6162800A (en) | 2000-12-19 |
| ES2210289T3 (es) | 2004-07-01 |
| CA2186511C (en) | 2009-02-10 |
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