CN1306526A - 具有半胱氨酸蛋白酶抑制作用的新的杂环取代酰胺 - Google Patents

具有半胱氨酸蛋白酶抑制作用的新的杂环取代酰胺 Download PDF

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CN1306526A
CN1306526A CN99807637A CN99807637A CN1306526A CN 1306526 A CN1306526 A CN 1306526A CN 99807637 A CN99807637 A CN 99807637A CN 99807637 A CN99807637 A CN 99807637A CN 1306526 A CN1306526 A CN 1306526A
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phenyl
alkyl
hydrogen
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W·卢比施
A·梅勒
H·J·特雷贝尔
M·克诺普
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BASF SE
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BASF SE
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Abstract

本发明涉及通式(Ⅰ)酰胺,所述化合物是酶抑制剂,尤其是半胱氨酸蛋白酶抑制剂。

Description

具有半胱氨酸蛋白酶抑制作用的新的杂环取代酰胺
本发明涉及新的酰胺，所述化合物是酶抑制剂，尤其是半胱氨酸蛋白酶例如钙蛋白酶(calpain)(即钙依赖性半胱氨酸蛋白酶)及其同工酶和组织蛋白酶例如组织蛋白酶B和L的抑制剂。
钙蛋白酶是属于半胱氨酸蛋白酶类的细胞内蛋白水解酶，并存在于多种细胞内。钙蛋白酶是由钙浓度增加而激活的，其分为由μ摩尔级浓度钙离子激活的钙蛋白酶Ⅰ或μ-钙蛋白酶和由毫摩尔级浓度钙离子激活的钙蛋白酶Ⅱ或m-钙蛋白酶(P.Johnson,Int.J.Biochem.1990,22(8),811-22)。现在有人提出还存在其它钙蛋白酶同工酶的假说(K.Suzuki等人，Biol.Chem.Hoppe-Seyler,1995,376(9),523-9)。
有人怀疑钙蛋白酶在多种生理过程中起重要作用。这些作用包括裂解调控蛋白例如蛋白激酶C、细胞骨架蛋白例如MAP2和血影蛋白、肌肉蛋白、类风湿性关节炎中的蛋白降解、血小板活化中的蛋白、神经肽代谢、有丝分裂中的蛋白、以及在M.J.Barrett等人，Life Sci.1991,48,1659-69和K.K.Wang等人,Trends in Pharmacol.Sci.,1994,15,412-9中列出的蛋白。
已经在多种病生理过程中检测到了钙蛋白酶水平增高，例如：心脏局部缺血(例如心肌梗塞)、肾局部缺血或中枢神经系统局部缺血(例如中风)、炎症、肌肉营养不良、眼睛内障、中枢神经系统损伤(例如创伤)、阿尔茨海默氏病等(参见上述K.K.Wang的文献)。人们怀疑这些疾病与细胞内钙水平持续增高有关。钙水平持续增高导致钙依赖性过程被过度激活，从而不再受生理调控的支配。因此，钙蛋白酶过度活化也可能引起病生理过程。
所以有人提出钙蛋白酶抑制剂可用于治疗这些疾病的假说。各种研究证实了这个假说。Seung-Chyul Hong等人,Stroke 1994,25(3),663-9和R.T.Bartus等人，Neurological Res.1995,17,249-58表明了钙蛋白酶抑制剂在急性神经变性疾病或局部缺血例如中风后发生的局部缺血中的神经保护作用。同样，实验性脑损伤后，钙蛋白酶抑制剂改善了记忆力缺陷以及所发生的神经运动障碍的恢复(K.E.Saatman等人，Proc.Natl.Acad.Sci.USA,1996,93,3428-3433)。C.L.Edelstein等人,Proc.Natl.Acad.Sci.USA,1995,92,7662-6发现了钙蛋白酶抑制剂对由于氧不足导致的肾损伤的保护作用。Yoshida,Ken Ischi等人，Jap.Circ.J.1995,59(1)40-8能表明钙蛋白酶抑制剂对由局部缺血或再灌注引起的心脏损害的有利作用。因为钙蛋白酶抑制剂抑制β-AP4蛋白的释放，所以有人提出其在治疗阿尔茨海默氏病中的潜在治疗应用(J.Higaki等人，Neuron,1995,14,651-59)。钙蛋白酶抑制剂还抑制白细胞介素-1α的释放(N.Watanabe等人，Cytokine 1994,6(6),597-601)。此外，还发现钙蛋白酶抑制剂具有对肿瘤细胞的细胞毒性作用(E.Shiba等人，20th Meeting Int.Ass.Breast Cancer Res.,Sendai Jp,1994,25-28 Sept.,Int.J.Oncol.5(Suppl.),1994,381)。
K.K.Wang,Trends in Pharmacol.Sci.,1994,15,412-8中列出了钙蛋白酶抑制剂的其它可能应用。
文献中已经描述过钙蛋白酶抑制剂。然而，这些抑制剂主要是不可逆抑制剂或肽类抑制剂。不可逆抑制剂通常是烷基化物质，其缺点是在生物体内非选择性地反应，或者不稳定。因此这些抑制剂通常会表现出不利的副作用、例如毒性，从而限制了其应用或者根本不可使用。不可逆抑制剂包括例如环氧化物E 64(E.B.McGowan等人，Biochem.Biophys.Res.Commun.1989,158,432-5)、α-卤代酮(H.Angliker等人，J.Med.Chem.1992,35,216-20)或二硫化物(R.Matsueda等人,Chem.Lett.1990,191-194)。
在半胱氨酸蛋白酶例如钙蛋白酶的已知可逆抑制剂中，有很多是肽醛，尤其是二肽和三肽醛，例如Z-Val-Phe-H(MDL 28170)(S.Mehdi,Trends in Biol.Sci.1991,16,150-3)。在生理条件下，肽醛的缺点是，由于具有高度反应性，它们通常是不稳定的，可迅速代谢，并且倾向于参与可能引起毒性作用的非特异性反应(J.A.Fehrentz和B.Castro,Synthesis 1983,676-78)。
JP 08183771(CA 1996,605307)和EP 520336描述了衍生自4-哌啶酰基酰胺类和1-羰基哌啶-4-基酰胺类、并且是钙蛋白酶抑制剂的醛类化合物。然而，在本申请中要求保护的、并且衍生自具有杂芳族取代基的通式Ⅰ酰胺的醛类化合物在现有技术中没有被公开过。
肽酮衍生物也是半胱氨酸蛋白酶抑制剂、尤其是钙蛋白酶抑制剂。例如，已知其中酮基是由吸电子基团例如CF3活化的酮衍生物是丝氨酸蛋白酶抑制剂。对于半胱氨酸蛋白酶，具有通过CF3或类似基团活化的酮的衍生物有很小活性或没有任何活性(M.R.Angelastro等人，J.Med.Chem.1990,33,11-13)。令人惊奇的是，迄今为止，人们发现只有其中一方面α-位离去基团引起不可逆抑制作用、并且另一方面羧酸衍生物活化酮基的酮衍生物是有效的钙蛋白酶抑制剂(参见上述M.R.Angelastro等人的文献；WO92/11850；WO92/12140；WO94/00095和WO95/00535)。然而，迄今为止，据报道只有这些酮基酰胺和酮基酯的肽衍生物是有效的(Zhaozhao Li等人，J.Med.Chem.1993,36,3472-80；S.L.Harbenson等人，J.Med.Chem.1994,37,2918-29，以及上述M.R.Angelastro等人的文献)。
酮基苯甲酰胺已经在文献中公开过。因此，WO 91/09801、WO94/00095和WO 92/11850中已经描述了酮基酯PhCO-Abu-COOCH2CH3。然而，在M.R.Angelastro等人.,J.Med.Chem.1990,33,11-13中，发现类似的苯基衍生物Ph-CONH-CH(CH2Ph)-CO-COCOOCH3仅是弱的钙蛋白酶抑制剂。J.P.Burkhardt,Tetrahedron Lett.,1988,3433-36中也描述了该衍生物。然而，鉴于此人们从来没有研究过取代苯甲酰胺的重要性。
在很多治疗中，例如中风的治疗中，活性组分是静脉内给药的，例如以输液形式给药。鉴于此，对于钙蛋白酶抑制剂，需要提供在水中具有适当溶解度的物质来制备输液。然而，许多所描述的钙蛋白酶抑制剂的缺点是在水中的溶解度很小或根本不溶解，因此不适于静脉内给药。这种活性物质只能与可促进其在水中溶解的辅助物质一起给药(参见R.T.Bartus等人,J.Cereb.Blood Flow Metab.1994,14,537-544)。然而，这些辅助物质例如聚乙二醇通常具有副作用，或甚至不能耐受。因此无需辅助物质即可溶于水的非肽类钙蛋白酶抑制剂具有显著优点。迄今为止，这类抑制剂在现有技术中没有描述过，并因此是新的。
本发明描述了取代的非肽醛、酮基羧酸酯和酮基酰胺衍生物。这些化合物是新的，并且通过合并上刚性结构片段而令人惊奇地表现出获得半胱氨酸蛋白酶、例如钙蛋白酶的有效非肽类抑制剂的可能性。此外，所有本发明通式Ⅰ化合物都具有至少一个脂肪胺基团，因此可与酸形成盐。大量这些物质能溶于水以形成pH为0.4-5的0.5％浓度溶液，因此表现出适于静脉内给药、例如中风治疗所需的静脉内给药的必需特征。
本发明涉及通式Ⅰ酰胺、其互变异构体和异构体、可能的对映异构体和非对映异构体、以及可能的生理可接受盐，
Figure A9980763700111
其中各变量具有下述含义：R1可以是氢、直链或支链C1-C6-烷基、苯基、萘基、喹啉基、吡啶基、嘧啶基、吡唑基(pyrazyl)、哒嗪基、喹唑啉基、喹喔啉基、噻吩基、苯并噻吩基、苯并呋喃基、呋喃基、和吲哚基，其中所述环可被最高达3个R6取代，R2是氢、直链或支链C1-C6-烷基、直链或支链O-C1-C6-烷基、C2-C6-链烯基、C2-C6-链炔基、C1-C6-烷基苯基、C2-C6-链烯基苯基、C2-C6-链炔基苯基、OH、Cl、F、Br、I、CF3、NO2、NH2、CN、COOH、COO-C1-C4-烷基、NHCO-C1-C4-烷基、NHCO-苯基、CONHR9、NHSO2-C1-C4-烷基、NHSO2-苯基、SO2-C1-C4-烷基、和SO2-苯基，R3是NR7R8或环例如R4是可携带苯基、吡啶基或萘基环的直链或支链C1-C6-烷基，其中所述环可被最多2个R6取代，R5是氢、COOR11和CO-Z，其中Z是NR12R13和R6是氢、直链或支链C1-C4-烷基、-O-C1-C4-烷基、OH、Cl、F、Br、I、CF3、NO2、NH2、CN、COOH、COO-C1-C4-烷基、-NHCO-C1-C4-烷基、-NHCO-苯基、-NHSO2-C1-C4-烷基、-NHSO2-苯基、-SO2-C1-C4-烷基、和-SO2-苯基，R7是氢、可被苯基环取代的直链或支链C1-C6-烷基，其中所述苯基环可被1个或2个R10取代，R8是氢、可被苯基环取代的直链或支链C1-C6-烷基，其中所述苯基环可被1个或2个R10取代，R9是氢，可携带取代基R16的直链或支链C1-C6-烷基、苯基、吡啶基、嘧啶基、哒嗪基、吡嗪基、吡唑基、萘基、喹啉基、咪唑基，其中所述环可携带1个或2个取代基R14，R10可以是氢、直链或支链C1-C4-烷基、-O-C1-C4-烷基、OH、Cl、F、Br、I、CF3、NO2、NH2、CN、COOH、COO-C1-C4-烷基、-NHCO-C1-C4-烷基、-NHCO-苯基、-NHSO2-C1-C4-烷基、-NHSO2-苯基、-SO2-C1-C4-烷基、和-SO2-苯基，R11是氢、可被苯基环取代的直链或支链C1-C6-烷基，其中所述苯基环可被1个或2个R10取代，R12是氢、直链或支链C1-C6-烷基、和
Figure A9980763700122
R13是氢、可被苯基环取代的直链或支链C1-C6-烷基，其中所述苯基环可携带R10基团，R14是氢、直链或支链C1-C6-烷基、直链或支链O-C1-C6-烷基、OH、Cl、F、Br、I、CF3、NO2、NH2、CN、COOH、COO-C1-C4-烷基，或者两个R14基团可代表桥OC(R15)2O，R15是氢、直链或支链C1-C6-烷基，R16可以是苯基、吡啶基、嘧啶基、哒嗪基、吡嗪基、吡唑基、吡咯基、萘基、喹啉基、咪唑基环，其中所述环可携带1个或2个取代基R6，A是-(CH2)m-、-(CH2)m-O-(CH2)o-、-(CH2)o-S-(CH2)m-、-(CH2)o-SO-(CH2)m-、-(CH2)o-SO2-(CH2)m-、-CH=CH-、-C≡C-、-CO-CH=CH-、-(CH2)o-CO-(CH2)m-、-(CH2)m-NHCO-(CH2)o-、-(CH2)m-CONH-(CH2)o-、-(CH2)m-NHSO2-(CH2)o-、-NH-CO-CH=CH-、-(CH2)m-SO2NH-(CH2)o-、-CH=CH-CONH-和R1-A还可以一起为B是苯基、吡啶、嘧啶、吡嗪、咪唑和噻唑，x是1、2或3，n是0、1或2，且m和o独立地为0、1、2、3或4。
式Ⅰ化合物可以作为外消旋体、对映异构纯化合物或非对映异构体使用。如果需要对映异构纯化合物，可通过例如用适当的旋光性碱或酸将式Ⅰ化合物或其中间体进行常规外消旋体拆分来获得对映异构纯化合物。另一方面，对映异构化合物可通过使用市售化合物例如旋光性氨基酸如苯丙氨酸、色氨酸和酪氨酸来制得。
本发明还涉及式Ⅰ化合物的内消旋体或互变异构体，例如其中式Ⅰ上的醛或酮基呈烯醇互变异构体的式Ⅰ化合物。
本发明还涉及式Ⅰ化合物的生理可接受盐，所述盐可通过将通式Ⅰ化合物与适当酸或碱反应来制得。适当酸和碱的实例列在例如Fortschritte der Arzneimittelforschung,1966,BirkhuserVerlag,Vol.10,pp.224-285中。这些酸和碱包括例如盐酸、柠檬酸、酒石酸、乳酸、磷酸、甲磺酸、乙酸、甲酸、马来酸、富马酸等，和氢氧化钠、氢氧化锂、以及氢氧化钾等。
本发明酰胺Ⅰ可依据在合成方案中概述的多种方法制得。合成方案
将杂环羧酸Ⅱ与适当氨基醇Ⅲ连接以生成相应的酰胺Ⅳ。在该反应中使用常规肽偶合方法，例如在C.R.Larock,ComprehensiveOrganic Transformations,VCH Publisher,1989,pages 972 f.，或Houben-Weyl,Methoden der organischen Chemie,4th edition,E5,Chapter V中详细描述的常规肽偶合方法。优选使用其中羧基COOH被转化成COL的Ⅱ的“活化”酸衍生物。L是离去基团例如Cl、咪唑和N-羟基苯并三唑。然后将该活化酸与胺反应以生成酰胺Ⅳ。该反应在无水惰性溶剂例如二氯甲烷、四氢呋喃和二甲基甲酰胺中于-20-+25℃温度下进行。
可将这些醇衍生物Ⅳ氧化以生成本发明醛衍生物Ⅰ。可采用多种常规氧化反应(参见C.R.Larock,Comprehensive OrganicTransformations,VCH Publisher,1989,page 604 f.)，例如Swern氧化和类Swern氧化(T.T.Tidwell,Synthesis,1990,857-70)、使用次氯酸钠/TEMPO进行氧化(上文中S.L.Harbenson等人的文献)、或Dess-Martin氧化(J.Org.Chem.1983,48,4155)。根据所采用的方法(参见上述文献)，优选在惰性非质子传递溶剂例如二甲基甲酰胺、四氢呋喃或二氯甲烷中用氧化剂例如DMSO/吡啶×SO3或DMSO/草酰氯于-50-+25℃温度下进行该氧化反应。
或者，可将羧酸Ⅱ与氨基异羟肟酸衍生物Ⅵ反应以生成苯甲酰胺Ⅶ。用与制备Ⅳ相同的方式进行该反应。异羟肟酸衍生物Ⅵ可通过将保护的氨基酸Ⅴ与羟基胺反应而制得。在该制备中，也使用已经描述过的酰胺制备方法。通过常规方法，例如用三氟乙酸除去保护基Ⅹ、例如Boc。可通过还原将由此获得的酰氨基异羟肟酸Ⅶ转化成本发明醛Ⅰ。在-60-0℃、在惰性溶剂例如四氢呋喃或乙醚中使用例如氢化锂铝作为还原剂来进行还原。
羧酸或羧酸衍生物例如酯Ⅸ(P=COOR’、COSR’)可通过与后一方法类似的方法制得，并且可同样通过还原而转化成本发明醛Ⅰ。R.C.Larock,Comprehensive Organic Transformations,VCH Publisher,1989,page 619-26中描述了这些方法。
具有杂环取代基、并且具有酮基酰胺或酮基酯基团的本发明酰胺Ⅰ可依据在合成方案2和3中概述的多种方法制得。
适当时，可在室温或高温下、例如在25-100℃，在水介质或水与有机溶剂如醇或四氢呋喃的混合物中，用酸或碱例如氢氧化锂、氢氧化钠或氢氧化钾将羧酸酯Ⅱa转化成酸Ⅱ。
采用常规条件，例如在Houben-Weyl,Methoden der organischenChemie,4th edition,E5,Chapter V和C.R.Larock,ComprehensiveOrganic Transformations,VCH Publisher,1989,Ch.9中描述的常规条件，将这些酸Ⅱ与α-氨基酸衍生物连接。
例如，将羧酸Ⅱ转化成“活化的”酸衍生物Ⅱb=Y-COL，其中L是离去基团例如Cl、咪唑和N-羟基苯并三唑，然后通过加入氨基酸衍生物H2N-CH(R3)-COOR将这些活化的酸衍生物转化成衍生物Ⅺ。该反应在无水惰性溶剂例如二氯甲烷、四氢呋喃和二甲基甲酰胺中于-20-+25℃温度下进行。合成方案1
Figure A9980763700151
通过与上述水解类似的水解方法，将通常是酯的衍生物Ⅺ转化成酮基羧酸Ⅻ。酮基酯Ⅰ’是在与Dakin-West反应类似的反应中，使用Zhaozhao Li等人，J.Med.Chem.,1993,36,3472-80的方法制得的。在该方法中，将羧酸例如Ⅻ与草酸单酯酰氯在溶剂例如四氢呋喃中于高温下(50-100℃)反应，然后将所得产物与碱例如乙醇钠在乙醇中于25-80℃温度下反应，以生成本发明酮基酯Ⅰ’。可如上所述将所得酮基酯Ⅰ’例如水解，以生成本发明酮基羧酸。
还可采用类似于Zhaozhao Li等人(参见上文)的方法进行反应以生成酮基苯甲酰胺Ⅰ’。在惰性溶剂例如二氯甲烷中于室温下，使用路易斯酸催化剂例如三氟化硼合乙醚、通过加入1,2-乙烷二硫醇将Ⅰ’中的酮基保护，形成了二噻烷。在极性溶剂例如醇中于0-80℃温度下将这些衍生物与胺R3-H反应，以形成酮基酰胺Ⅰ(R4=Z或NR7R8)。合成方案2
Figure A9980763700161
合成方案2中描述了另一方法。采用常规肽偶合方法(参见上文中的Houben-Wey1)，将酮基羧酸Ⅱ与氨基羟基羧酸衍生物ⅩⅢ反应(对于ⅩⅢ的制备，参见S.L.Harbenson等人，J.Med.Chem.1994,37,2918-29或J.P.Burkhardt等人,Tetrahedron Lett.1988,29,3433-3436)，形成了酰胺ⅩⅣ。可将这些醇衍生物ⅩⅣ氧化，以生成本发明酮基羧酸衍生物Ⅰ。可采用多种常规氧化反应(参见C.R.Larock,Comprehensive Organic Transformations,VCH Publi sher,page 604f.)，例如Swern氧化和类Swern氧化，优选在溶剂例如二氯甲烷或四氢呋喃中、适当时加入二甲亚砜，用二甲亚砜/吡啶×SO3复合物于室温或-50-25℃温度下进行该氧化反应(T.T.Tidwell,Synthesis,1990,857-70)，或用次氯酸钠/TEMPO进行氧化(参见上文中的S.L.Harbenson等人)。
对于α-羟基酯ⅩⅣ(X=O-烷基)，可用与上述方法类似的方法，但是优选在水/四氢呋喃混合物中于室温下用氢氧化锂将这些酯水解，以生成羧酸ⅩⅤ。其它酯或酰胺ⅩⅥ是通过在上述偶合条件下与醇或胺反应而制得的。可将醇衍生物ⅩⅥ氧化，以生成本发明酮基羧酸衍生物Ⅰ。
上文已在一些实例中描述过羧酸酯Ⅱ的制备，或者其是通过化学方法制得的。
其中Ⅹ是一个键的化合物是通过常规芳香偶合制得的，例如采用钯催化的用硼酸衍生物和卤化物进行的Suzuki偶合，或铜催化的芳香卤化物偶合。烷基桥连基团(X=-(CH2)m-)可通过将类似的酮还原，或通过将有机锂化合物例如邻苯基噁唑烷或其它有机金属化合物烷基化而制得(参加I.M.Dordor等人，J.Chem.Soc.Perkins Trans.I,1984,1247-52)。
醚桥连衍生物是通过用卤化物将相应的醇或酚烷基化而制得的。
亚砜和砜可通过将相应的硫醚氧化来制得。
烯和炔桥连化合物是通过例如将芳香卤化物和相应的烯和炔进行Heck反应而制得的(参见I.Sakamoto等人，Chem.Pharm.Bull.,1986,34,2754-59)。
查耳酮类是通过将苯乙酮与醛缩合而形成的,并且在适当时可通过氢化将其转化成类似的烷基衍生物。
酰胺和磺酰胺是通过与上述方法类似的方法由胺和酸衍生物制得的。
二烷基氨基烷基取代基是通过在氢化硼例如BH3/吡啶复合物或NaBH3CN存在下用适当胺将醛衍生物还原胺化而获得的(A.F.Abde1-Magid,C.A.Maryanoff,K.G.Carson,Tetrahedron Lett.10990,31,5595；A.E.Moormann,Synth.Commun.1993,23,789)。
本发明具有杂环取代基的酰胺Ⅰ是半胱氨酸蛋白酶抑制剂，尤其是半胱氨酸蛋白酶例如钙蛋白酶Ⅰ和Ⅱ以及组织蛋白酶B和L的抑制剂。
已经用文献中已知的酶测试法测定了具有杂环取代基的酰胺Ⅰ的抑制作用，以酶活性被抑制50％时所测定的抑制剂浓度(=IC50)作为作用标度。以该方法测定酰胺Ⅰ抑制钙蛋白酶Ⅰ、钙蛋白酶Ⅱ和组织蛋白酶B的作用。
               组织蛋白酶B测试
按照类似于S.Hasnain等人，J.Biol.Chem.1993,268,235-40的方法测定组织蛋白酶B抑制作用。
将用抑制剂和DMSO制得的2μL抑制剂溶液(终浓度：100μM-0.01μM)加到88μL组织蛋白酶B(得自人肝脏的组织蛋白酶B(Calbiochem)，在500μM缓冲液中稀释至5单位)中。将该混合物在室温(25℃)预培养60分钟，然后通过加入10μL 10mM Z-Arg-Arg-pNA(在含有10％DMSO的缓冲液中)来启动反应。用微量滴定板读数计在405nM监视反应30分钟。然后由最大梯度确定IC50。
             钙蛋白酶Ⅰ和Ⅱ测试
在含有50mM tris-HCl、0.1M NaCl、1mM二硫苏糖醇、0.11mMCaCl2、pH为7.5的缓冲液中，用萤光钙蛋白酶底物Suc-Leu-Tyr-AMC(溶于DMSO中，浓度为25mM,Bachem/Switzerland)测定钙蛋白酶抑制剂的抑制特性。从红细胞中分离出人μ-钙蛋白酶，经过几个色谱法纯化步骤(DEAE-琼脂糖，苯基琼脂糖，Superdex 200和BlueSepharose)之后，获得了纯度＞95％的酶，其中该酶的纯度是通过SDS-PAGE、Western印迹分析和N-末端序列分析测定的。在Spex-Fluorolog荧光计中于λex=380nm和λem=460nm处测定裂解产物7-氨基-4-甲基香豆素(AMC)的荧光度。在60分钟的测定期间内，底物的裂解与时间呈线性关系，并且如果测试是在12℃进行的话，钙蛋白酶的自动催化活性很低。将抑制剂和钙蛋白酶底物以DMSO溶液形式加到该测试混合物中，其中DMSO的终浓度不能超过2％。
在测试混合物中，将10μl底物(终浓度为250μM)和10μl μ-钙蛋白酶(终浓度为2μg/ml，即18nM)依次加到含有缓冲液的1ml比色杯中。测定15-20分钟钙蛋白酶介导的底物裂解。然后加入10μl抑制剂(50-100μM的DMSO溶液)，测定40分钟对裂解的抑制。
Ki值是依据可逆抑制的经典公式确定的(酶学中的方法)：Ki=I/(vo/vi)-1；其中I=抑制剂浓度，vo=加入抑制剂前的初速度，vi=平衡中的反应速度。
速度是由v=AMC释放/时间，即高度/时间计算的。
钙蛋白酶是细胞内半胱氨酸蛋白酶。为了阻止细胞内蛋白被钙蛋白酶降解，钙蛋白酶抑制剂必须穿越细胞膜。有些已知的钙蛋白酶抑制剂例如E64和亮抑蛋白酶肽只能非常困难地越过细胞膜，因此，虽然它们是良好的钙蛋白酶抑制剂，但是在细胞内的作用很弱。人们的目标是发现能更好地穿过细胞膜的化合物。我们使用人血小板来确定钙蛋白酶抑制剂穿越细胞膜的能力。
钙蛋白酶介导的血小板中酪氨酸激酶pp60src的断裂
血小板活化后，酪氨酸激酶pp60src被钙蛋白酶裂解。Oda等人在J.Biol.Chem.,1993,Vol.268,12603-12608中描述了对此的详细研究。这表明calpeptin-一种钙蛋白酶抑制剂可阻止pp60src的裂解。我们按照在该出版文章中使用的方法测定了本发明化合物的细胞有效性。将用柠檬酸盐处理的新鲜人血以200g的转速离心15分钟。收集富含血小板的血浆，并用血小板缓冲液(血小板缓冲液：68mM NaCl、2.7mM KCl、0.5mM MgCl2×6H2O、0.24mM NaH2PO4×H2O、12mM NaHCO3、5.6mM葡萄糖、1mM EDTA、pH7.4)进行1∶1稀释。离心并用血小板缓冲液洗涤后，将血小板浓度调节至107个细胞/ml。在室温分离人血小板。
在该测试混合物中，将分离的血小板(2×106)与不同浓度的抑制剂(溶于DMSO中)在37℃预培养5分钟。然后用1μM离子载体A23187和5mM CaCl2将血小板活化。培养5分钟后，以13000rpm转速将血小板短暂离心，把血小板小丸置于SDS样本缓冲液中(SDS样本缓冲液：20mM Tris-HCl、5mM EDTA、5mM EGTA、1mM DTT、0.5mM PMSF、5μg/ml亮抑蛋白酶肽、10μg/ml胃蛋白酶抑制剂、10％甘油和1％SDS)。在12％凝胶中分离蛋白，通过Western印迹法鉴定pp60src及其52kDa和47 kDa裂解产物。所用多克隆兔子抗体-抗-Cys-src(pp60c-src)抗体购自Biomol Feinchemikalien(Hamburg)。用偶合有HRP的山羊第二代抗体(Boehringer Mannheim,FRG)检测该初生抗体。依据已知方法进行Western印迹测定。
通过光密度法定量测定pp60src的裂解，所用对照是未活化血小板(对照1：未裂解)和用离子载体与钙处理的血小板(对照2：相当于100％裂解)。ED50值是颜色反应的强度降低50％时抑制剂的浓度。
皮层神经元中谷氨酸盐诱导的细胞死亡
该测试是按照Choi D.W.,Maulucci-Gedde M.A.和KriegsteinA.R.,“谷氨酸盐在皮层细胞培养物中的神经毒性”.J.Neurosci.1989,7,357-368中描述的方法进行的。
从15天大小的小鼠胚胎中把皮质解剖为两半，通过酶处理(胰蛋白酶)分离到了独立细胞。将这些细胞(神经胶质和皮层神经元)接种到24孔板上。3天(涂布昆布氨酸(laminin)的培养板)或7天(涂布鸟氨酸的培养板)后，用FDU(5-氟-2-去氧尿嘧啶核苷)进行有丝分裂处理。细胞制备15天后，加入谷氨酸盐来诱导细胞死亡(15分钟)。除去谷氨酸盐后，加入钙蛋白酶抑制剂。24小时后，通过测定细胞培养物上清液中的乳酸脱氢酶(LDH)来确定细胞损伤。
有人提出钙蛋白酶也在细胞程序死亡中起作用的假说(M.K.T.Squier等人,J.Cell.Physiol.1994,159,229-237；T.Patel等人,Faseb Journal 1996,590,587-597)。因此，在另一模型中，在钙离子载体存在下用钙诱导人细胞系中的细胞死亡。钙蛋白酶抑制剂必须进入细胞内并抑制其中的钙蛋白酶以阻止所诱导的细胞死亡。
           NT2细胞中钙介导的细胞死亡
可在人细胞系NT2中，在离子载体A 23187存在下、用钙诱导细胞死亡。在实验前20小时，将细胞以105个细胞/孔的量置于微量滴定板中。20小时后，在2.5μM离子载体和5mM钙存在下、将细胞与不同浓度的抑制剂培养。5小时后，将0.05ml XTT(细胞增殖试剂盒Ⅱ，Boehringer Mannheim)加到该反应混合物中。约17小时后，依据制造商的使用说明，用SLT Easy Reader EAR 400测定光密度。细胞死亡一半时的光密度是由不使用抑制剂、含有细胞、并且这些细胞是在或不在离子载体存在下培养的两个对照组计算的。
在很多神经性疾病或心理障碍中，都发生谷氨酸盐活性增加，并导致中枢神经系统(CNS)过度兴奋或毒性作用。谷氨酸盐通过多种受体介导其作用。其中有两种受体通过其特异性激动剂被划分为NMDA受体和AMPA受体。因此，这些谷氨酸盐介导作用的拮抗剂可用于治疗这些疾病，尤其是治疗神经变性疾病例如亨廷顿氏舞蹈病和帕金森氏病，低氧、缺氧、局部缺血和损伤后发生的神经毒害疾病，例如中风和创伤后发生的神经毒害，或用作抗癫痫剂(参见Arzneim.Forschung 1990,40,511-514；TIPS,1990,11,334-338；Drugs of the Future 1989,14,1059-1071)。抗兴奋性氨基酸诱导的脑过度兴奋的保护作用(小鼠中的NMDA或AMPA拮抗作用)
脑内给予兴奋性氨基酸EAA，结果诱导了严重的过度兴奋，导致动物(小鼠)在短时间内痉挛和死亡。可通过系统给予例如腹膜内给予中枢活性物质(EAA拮抗剂)来抑制这些症状。因为中枢神经系统中EAA受体的过度激活在多种神经性疾病的发病机制中起重要作用，所以可从已在体内证实的EAA拮抗作用得出这样的结论，即这种物质可用于治疗这些CNS疾病。为了测定这种物质的效力，通过提前腹膜内给予测试物质，确定50％动物的由给予固定剂量NMDA或AMPA引起的症状被消除时的ED50值。
本发明具有杂环取代基的酰胺Ⅰ是半胱氨酸衍生物例如钙蛋白酶Ⅰ和Ⅱ以及组织蛋白酶B和L的抑制剂，因此可用于控制与钙蛋白酶或组织蛋白酶的酶活性增加有关的疾病。因此本发明酰胺Ⅰ可用于治疗局部缺血、创伤、蛛网膜下出血和中风后发生的神经变性疾病，和神经变性疾病例如多发性梗塞性痴呆、阿尔茨海默氏病、亨廷顿氏舞蹈病和癫痫，以及可用于治疗心脏局部缺血后的心脏损伤、肾局部缺血后的肾脏损伤、骨骼肌损伤、肌肉营养不良、由于平滑肌细胞增殖所导致的损伤、冠状血管痉挛、脑血管痉挛、眼睛内障、和血管成形术后的血管再狭窄。此外，本发明酰胺Ⅰ可用于肿瘤和肿瘤转移的化学治疗，并且可用于治疗其中白细胞介素-1水平增加的疾病，例如炎症和风湿性疾病。
除了常规药物辅料以外，本发明药物制剂还含有治疗有效量的化合物Ⅰ。
对于局部外用给药，例如以粉剂、软膏剂或喷雾剂形式给药，制剂中活性组分的浓度可以为常规浓度。按重量计，活性组分的含量一般为0.001-1％，优选为0.001-0.1％。
对于内部给药，制剂以单次剂量给药。每单次剂量为0.1-100mg/kg体重。根据所治疗疾病的类型和严重程度，每天给予一个或多个剂量的制剂。
根据所需的给药方式，本发明药物制剂含有除活性组分以外的常规赋形剂和稀释剂。对于局部外用给药制剂，可使用药物辅料例如乙醇、异丙醇、乙氧基化蓖麻油、乙氧基化氢化蓖麻油、聚丙烯酸、聚乙二醇、聚乙二醇硬脂酸酯、乙氧基化脂肪醇、液状石蜡、凡士林和羊毛脂。对于内部给药制剂，合适辅料的实例是乳糖、丙二醇、乙醇、淀粉、滑石和聚乙烯吡咯烷酮。
本发明药物制剂还可含有抗氧化剂例如生育酚、丁基化甲氧酚以及丁基化羟基甲苯，矫味剂，稳定剂，乳化剂和润滑剂。
本发明药物制剂所含有的除活性组分以外的物质和在药物制剂制备中所使用的物质在毒理学方面是可接受的，并且与活性组分相配伍。本发明药物制剂是以常规方法制得的，例如通过将活性化合物与其它常规赋形剂和稀释剂混合而制得。
本发明药物制剂可以通过多种给药途径给药，例如口服给药，非胃肠道给药例如通过输注的静脉内给药、皮下给药、腹膜内给药，和局部给药。因此可采用的剂型有片剂、乳剂、输液、注射液、糊剂、软膏剂、凝胶剂、霜剂、洗剂、粉剂和喷雾剂。
                    实施例实施例12-((4-苯基哌嗪-1-基)甲基)苯甲酸N-(3-苯基丙-1-醛-2-基)酰胺a)2-(4-苯基哌嗪-1-基甲基)苯甲酸甲酯
将10.0g 2-氯甲基苯甲酸甲酯、15g碳酸钾、8.8g N-苯基哌嗪和一匙尖18-冠-6在200ml DMF中于100℃加热5小时，然后在室温搅拌60小时。滤除过量碳酸钾，将滤液浓缩，把残余物在水和乙酸乙酯之间分配。用硫酸镁将有机相干燥，除去溶剂，获得了16.8g(100％)产物。b)2-(4-苯基哌嗪-1-基甲基)苯甲酸
将16.8g中间体1a置于150ml THF中，在室温加入1.7g LiOH在150ml水中的溶液。加入10ml MeOH将该浑浊溶液变澄清。将该反应混合物在室温搅拌12小时，用等摩尔量的1M盐酸水解。将该反应混合物蒸发至干，把残余物置于甲醇/甲苯中。除去溶剂，获得了15.2g(86％)仍然含有盐的产物。c)2-((4-苯基哌嗪-1-基)甲基)苯甲酸N-(3-苯基丙-1-醇-2-基)酰胺
将3.0g中间体1b和3ml三乙胺置于50ml DMF中。加入5g硫酸钠，将该混合物搅拌30分钟。在0℃依次加入1.5g苯丙氨醇、1.4g HOBT和2.1g EDC，将该混合物在室温搅拌过夜。将该反应混合物倒入蒸馏水中，用碳酸氢钠碱化，用氯化钠饱和，用100ml二氯甲烷萃取3次。将有机相用水洗涤2次，用硫酸镁干燥。除去溶剂，获得了2.5g(59％)产物。d)2-((4-苯基哌嗪-1-基)甲基)苯甲酸N-(3-苯基丙-1-醛-2-基)酰胺
将2.3g中间体1c置于含有2.4g三乙胺的50ml DMSO中，加入2.5g SO3/吡啶复合物。将混合物在室温搅拌过夜。将该混合物倒入250ml蒸馏水中，用碳酸氢钠碱化，用氯化钠饱和，并用100ml二氯甲烷萃取，将有机相用硫酸镁干燥。除去溶剂后，把所得残余物溶于THF中，用在二氧杂环己烷中的HCl沉淀出盐酸盐。抽滤出沉淀，用乙醚洗涤数次，获得了1.9g(71％)产物。1H-NMR(d6-DMSO):δ=2.9(2H),3.0-3.3(8H),4.1-4.5(2H),4.7(1H),6.8-7.7(14H),9.3(1H),9.8(1H)ppm.实施例22-((4-苄基哌嗪-1-基)甲基)苯甲酸N-(3-苯基丙-1-醛-2-基)酰胺a)2-((4-苄基哌嗪-1-基)甲基)苯甲酸甲酯
按照与实施例1a类似的方法，在15g碳酸钾存在下、在100℃下、在200ml DMF中将10.0g 2-氯苯甲酸甲酯和9.6g N-苄基哌嗪反应，获得了17.6g(100％)产物。b)2-((4-苄基哌嗪-1-基)甲基)苯甲酸
按照与实施例1b类似的方法，在150ml THF中、用1.6g LiOH在150ml水中的溶液将17.5g中间体2a水解，获得了9.1g(54％)产物。c)2-((4-苄基哌嗪-1-基)甲基)苯甲酸N-(3-苯基丙-1-醇-2-基)酰胺
按照与实施例1c类似的方法，在60ml DMF中将3.0g中间体2b与3ml三乙胺、1.5g苯丙氨醇、1.3g HOBT和2.0g EDC反应，获得了2.0g(46％)产物。d)2-((4-苄基哌嗪-1-基)甲基)苯甲酸N-(3-苯基丙-1-醛-2-基)酰胺
按照与实施例1d类似的方法，在2.3ml三乙胺存在下、在20mlDMSO中用1.9g SO3/吡啶复合物将1.5g中间体2c在40ml DMSO中氧化，获得了0.4g(21％)富马酸盐形式的产物。1H-NMR(d6-DMsO):δ=2.1-2.3(8H),2.9-3.0(1H),3.3-3.6(6H),4.5(1H),6.6(2H),7.1-7.7(14H),9.7(1H),10.3(1H)ppm.实施例32-((4-苄基哌嗪-1-基)甲基)苯甲酸N-(1-氨基甲酰基-1-氧代-3-苯基丙-2-基)酰胺a)2-((4-苄基哌嗪-1-基)甲基)苯甲酸N-(1-氨基甲酰基-1-醇-3-苯基丙-2-基)酰胺
按照与实施例1c类似的方法，在40ml DMF中将1.5g中间体2b与0.7ml三乙胺、1.0g3-氨基-2-羟基-4-苯基丁酰胺盐酸盐、0.6gHOBT和0.9g EDC反应，获得了0.8g(38％)产物。b)2-((4-苄基哌嗪-1-基)甲基)苯甲酸N-(1-氨基甲酰基-1-氧代-3-苯基丙-2-基)酰胺
按照与实施例1d类似的方法，在0.8g三乙胺存在下、在20ml DMSO中用0.7g SO3/吡啶复合物将0.7g中间体3a氧化，获得了0.1g(18％)游离碱形式的产物。1H-NMR(d6-DMSO):δ=2.3(4H),2.8-3.5(8H),5.3(1H),6.7-7.5(16H),7.8(1H),8.1(1H),10.3(1H)ppm.实施例42-(4-((3-甲基苯基)哌嗪-1-基)甲基)苯甲酸N-(1-氨基甲酰基-1-氧代-3-苯基丙-2-基)酰胺a)2-(4-((3-甲基苯基)哌嗪-1-基)甲基)苯甲酸甲酯
在4.5g碳酸钾存在下、将4.0g 2-氯甲基苯甲酸甲酯和4.4g 3-甲基苯基哌嗪在200ml DMF中于140℃加热3小时。将该反应混合物倒入水中，用乙酸乙酯萃取3次。合并有机相，用饱和盐水洗涤3次，用硫酸镁干燥，浓缩，获得了6.5g(92％)产物。b)2-(4-((3-甲基苯基)哌嗪-1-基)甲基)苯甲酸
按照与实施例1b类似的方法，用0.9g LiOH在75ml水中的溶液将溶于75ml THF中的5.9g中间体4a水解，获得了2.9g(51％)产物。c)2-(4-((3-甲基苯基)哌嗪-1-基)甲基)苯甲酸N-(1-氨基甲酰基-1-醇-3-苯基丙-2-基)酰胺
按照与实施例1c类似的方法，在2.7ml三乙胺存在下、将1.8g中间体4b置于50ml DMF中，依次加入0.8g HOBT、1.3g 3-氨基-2-羟基-4-苯基丁酰胺盐酸盐和1.2g EDC，获得了1.4g(50％)产物。d)2-(4-((3-甲基苯基)哌嗪-1-基)甲基)苯甲酸N-(1-氨基甲酰基-1-氧代-3-苯基丙-2-基)酰胺
按照与实施例1d类似的方法，在1.5ml三乙胺存在下、用1.6gSO3/吡啶复合物将溶于30ml DMSO中的1.2g中间体4c氧化，获得了1.0g(83％)产物。
MS:m/e=484(M+)
实施例5和6是按照与实施例1类似的方法合成的。实施例53-((4-苯基哌嗪-1-基)甲基)苯甲酸N-(3-苯基丙-1-醛-2-基)酰胺富马酸盐1H-NMR(d6-DMSO):δ=2.5(4H),2.9(1H),3.2(4H),3.3(1H),3.7(2H),4.5(1H),6.6(2H),6.75(1H),6.9(2H),7.2(2H),7.2-7.3(5H),7.45(1H),7.55(1H),7.75(1H),7.8(2H),8.9(1H),9.7(1H)ppm.实施例63-((4-(2-叔丁基-4-三氟甲基嘧啶-6-基)高哌嗪-1-基)甲基)苯甲酸N-(3-苯基丙-1-醛-2-基)酰胺MS:m/e=568(M++1)实施例74-(N-(3,4-二氧代亚甲基)苄基-N-甲基氨基甲基)苯甲酸N-(3-苯基丙-1-醛-2-基)酰胺a)4-(N-(3,4-二氧代亚甲基)苄基-N-甲基氨基甲基)苯甲酸
将11.5g N-(3,4-=氧代亚甲基)苄基-N-甲基胺和15.5g三乙胺置于，加入在100ml THF中的15.0g 4-溴甲基苯甲酸。将该反应混合物短暂加热至回流。然后在室温搅拌15小时。滤出盐后，将母液浓缩，把残余物溶于乙酸乙酯中，并用水洗涤。将该水相碱化，用乙酸乙酯萃取数次，获得了6.6g(32％)产物，为白色固体。b)4-(N-(3,4-二氧代亚甲基)苄基-N-甲基氨基甲基)苯甲酸N-(3-苯基丙-1-醇-2-基)酰胺
按照与实施例1c类似的方法，在2.9g三乙胺存在下、将4.4g中间体5a置于50ml DMF中，依次加入1.8g HOBT、2.0g苯丙氨醇和2.8g EDC，获得了2.3g(40％)产物。c)4-(N-(3,4-二氧代亚甲基)苄基-N-甲基氨基甲基)苯甲酸N-(3-苯基丙-1-醛-2-基)酰胺
按照与实施例1d类似的方法，在1.8ml三乙胺存在下、用2.1gSO3/吡啶复合物将溶于60ml DMSO中的2.0g中间体5b氧化，获得了1.3g(68％)产物。1H-NMR(CF3COOD):δ=2.9(3H),3.2(2H),4.3-4.9(5H),6.1(2H),6.6(1H),6.9(3H),7.2-7.4(5H),7.8(2H),8.25(2H)ppm.MS: m/e=430(M+)
实施例8-28是按照与实施例7类似的方法制备的。实施例84-(N-苄基-N-甲基氨基甲基)苯甲酸N-(3-苯基丙-1-醛-2-基)酰胺1H-NMR(CF3COOD):δ=2.9(3H),3.2(2H),4.3-5.0(5H),6.7(1H),7.25-7.5(8H),7.55(2H),7.8(2H),8.2(2H)ppm.MS:m/e = 386(M+)实施例94-(N-(4-甲氧基)苄基-N-甲基氨基甲基)苯甲酸N-(3-苯基丙-1-醛-2-基)酰胺1H-NMR(CF3COOD):δ=2.9(3H),3.3(2H),4.0(3H),4.3-4.9(5H),6.7(1H),7.1-7.4(7H),7.5(2H),7.8(2H),8.2(2H)ppm.MS:m/e=416(M+)实施例104-(N-苄基-N-甲基氨基甲基)苯甲酸N-(3-丁-1-醛-2-基)酰胺1H-NMR(CF3COOD):δ=1.1(3H),1.6(2H),2.0(2H),2.9(3H),4.3-4.5(3H),4.7(1H),4.8(1H),6.6(1H),7.3-7.6(5H),7.8(2H),8.3(2H)ppm.
           MS:m/e=338(M+)实施例114-(N-(3,4-二氧代亚甲基)苄基-N-甲基氨基甲基)苯甲酸N-(3-丁-1-醛-2-基)酰胺1H-NMR(CF3COOD):δ=1.1(3H),1.6(2H),1.9(2H),2.9(3H),4.25-4.6(4H),4.75(1H),6.1(2H),6.6(1H),6.9(3H),7.8(2H),8.3(2H)ppm.MS:m/e=382(M+)实施例124-(N-(4-甲氧基)苄基-N-甲基氨基甲基)苯甲酸N-(3-丁-1-醛-2-基)酰胺MS:m/e=368(M+)实施例134-(N-(3,4-二氧代亚甲基)苄基-N-甲基氨基甲基)苯甲酸N-(3-环己基丙-1-醛-2-基)酰胺1H-NMR(CF3COOD):δ=1.0-2.0(13H),2.9(3H),4.3-4.9(4H),6.1(2H),6.6(1H),6.9(3H),7.8(2M),8.3(2H)ppm.MS:m/e=436(M+)实施例144-(N-(4-苄基-N-甲基氨基甲基)苯甲酸N-(3-环已基丙-1-醛-2-基)酰胺1H-NMR(d6-DMSO):δ=1.0-1.8(13H),2.1(3H),3.4(2H),3.5(2H),4.3(1H),7.1-7.4(5H),7.5(2H),7.8(2H),8.8(1H),9.5(1H)ppm.实施例154-(N-(4-甲氧基)苄基-N-甲基氨基甲基)苯甲酸N-(3-环己基丙-1-醛-2-基)酰胺1H-NMR(CDCl3):δ=1.0-1.8(13H),2.1(3H),3.4(2H),3.5(2H),3.7(3H),4.3(1H),6.8(2H),7.25(2H),7.5(2H),7.9(2H),8.8(1H),9.5(1H)ppm.实施例164-((2-苯基吡咯烷-1-基)甲基)苯甲酸N-(3-环己基丙-1-醛-2-基)酰胺MS:m/e=420(M+)实施例174-((2-苯基吡咯烷-1-基)甲基)苯甲酸N-(3-丁-1-醛-2-基)酰胺MS:m/e=364(M+)实施例184-((2-苯基吡咯烷-1-基)甲基)苯甲酸N-(3-苯基丙-1-醛-2-基)酰胺MS:m/e=412(M+)实施例194-((1,2,3,4-二氢喹啉-1-基)甲基)苯甲酸N-(3-环己基丙-1-醛-2-基)酰胺1H-NMR(CDCl3):δ=1.0-1.9(13H),2.0(2H),2.8(2H),3.3(2H),4.5(2H),4.8(1H),6.4(1H),6.5(2H),7.0(2H),7.4(2H),7.8(2H),9.7(1H)ppm.MS:m/e=404(M+)实施例204-((1,2,3,4-二氢喹啉-1-基)甲基)苯甲酸N-(3-苯基丙-1-醛-2-基)酰胺1H-NMR(d6-DMSO):δ=1.9(2H),2.75(2H),2.9(1H),3.3(1H),3.4(2H),4.4(1H),4.5(2H),6.3(2H),6.8(2H),7.1-7.25(5H),7.3(2H),7.7(2H),8.8(1H),9.5(1H)ppm.MS:m/e=398(M+)实施例214-((1,2,3,4-二氢喹啉-1-基)甲基)苯甲酸N-(3-丁-1-醛-2-基)酰胺1H-NMR(d6-DMSO):δ=0.9(3H),1.2-2.0(6H),2.7(2H),3.3(2H),4.2(1H),4.5(2H),6.4(2H),6.8(2H),7.3(2H),7.8(2H),8.8(1H),9.5(1H)ppm.MS:m/e=350(M+)实施例224-((1,2,3,4-二氢异喹啉-2-基)甲基)苯甲酸N-(3-环己基丙-1-醛-2-基)酰胺1H-NMR(d6-DMSO):δ=0.9-1.8(13H),2.7-2.9(4H),3.6(2H),3.75(2H),4.4(1H),6.9-7.1(4H),7.4(2H),7.8(2H),8.8(1H),9.5(1H)ppm.MS:m/e=404(M+)实施例234-((1,2,3,4-二氢异喹啉-2-基)甲基)苯甲酸N-(3-苯基丙-1-醛-2-基)酰胺1H-NMR(d6-DMSO):δ=2.7(2H),2.8(2H),2.9(1H),3.2(1H),3.5(2H),3.7(2H),4.5(1H),6.9-7.1(4M),7.2-7.3(5H),7.5(2H),7.75(2H),8.8(1H),9.5(1H)ppm.MS:m/e=398(M+)实施例244-((1,2,3,4-二氢异喹啉-2-基)甲基)苯甲酸N-(3-丁-1-醛-2-基)酰胺盐酸盐1H-NMR(d6-DMSO):δ=0.9(3H),1.2-2.0(4H),3.0(1H),3.3(2H),3.6(1H),4.1-4.6(5H),7.2(4H),7.8(2H),8.0(2H),9.0(1H),9.5(1H),11.75(1H)ppm.实施例254-((6,7-二甲氧基-1,2,3,4-二氢异喹啉-2-基)甲基)苯甲酸N-(3-环己基丙-1-醛-2-基)酰胺1H-NMR(d6-DMSO):δ=0.9-1.9(13H),2.7(4H),3.4(2H),3.6(3H),3.65(2H),3.7(3H),4.3(1H),6.5(1H),6.6(1H),7.5(2H),7.8(2H),8.8(1H),9.5(1H)ppm.MS:m/e=464(M+)实施例264-((6,7-二甲氧基-1,2,3,4-二氢异喹啉-2-基)甲基)苯甲酸N-(3-苯基丙-1-醛-2-基)酰胺1H-NMR(d6-DMSO):δ=2.7(4N),2.9(1H),3.25(1H),3.6(6H),3.7(2H),4.5(1H),6.6(1H),6.7(1H),7.2-7.3(5H),7.4(2H),7.8(2H),8.9(1H),9.6(1H)ppm.MS:m/e=458(M+)实施例274-((6,7-二甲氧基-1,2,3,4-二氢异喹啉-2-基)甲基)苯甲酸N-(3-丁-1-醛-2-基)酰胺1H-NMR(d6-DMSO):δ=0.9(3H),1.4(2H),1.5-1.8(2H),2.7(4H),3.4(2H),3.7(3H),3.75(3H),3.8(2H),4.3(1H),6.6(1H),6.7(1H),7.4(2H),7.8(2H),8.8(1H),9.5(1H)ppm.MS:m/e=410(M+)实施例282-((1,2,3,4-二氢喹啉-1-基)甲基)苯甲酸N-(3-丁-1-醛-2-基)酰胺MS:m/e=441(M+)
         表
Figure A9980763700331
Figure A9980763700351
Figure A9980763700371
Figure A9980763700381
Figure A9980763700391
Figure A9980763700421
Figure A9980763700431
Figure A9980763700441
Figure A9980763700451
Figure A9980763700481
Figure A9980763700491
Figure A9980763700511
Figure A9980763700531
Figure A9980763700541
Figure A9980763700551
Figure A9980763700561
Figure A9980763700571
Figure A9980763700591
Figure A9980763700611
Figure A9980763700621
Figure A9980763700631
Figure A9980763700641
Figure A9980763700671
Figure A9980763700691
Figure A9980763700721
Figure A9980763700751
Figure A9980763700761
Figure A9980763700781
Figure A9980763700791
Figure A9980763700811
Figure A9980763700821
Figure A9980763700831
Figure A9980763700841
Figure A9980763700851
Figure A9980763700861
Figure A9980763700881
Figure A9980763700901

Claims (23)

1．式Ⅰ酰胺、其互变异构体和异构体、可能的对映异构体和非对映异构体、以及可能的生理可接受盐，
Figure A9980763700021
其中各变量具有下述含义：R1可以是氢、直链或支链C1-C6-烷基、苯基、萘基、喹啉基、吡啶基、嘧啶基、吡唑基、哒嗪基、喹唑啉基、喹喔啉基、噻吩基、苯并噻吩基、苯并呋喃基、呋喃基、和吲哚基，其中所述环可被最高达3个R6取代，R2是氢、直链或支链C1-C6-烷基、直链或支链O-C1-C6-烷基、C2-C6-链烯基、C2-C6-链炔基、C1-C6-烷基苯基、C2-C6-链烯基苯基、C2-C6-链炔基苯基、OH、Cl、F、Br、I、CF3、NO2、NH2、CN、COOH、COO-C1-C4-烷基、NHCO-C1-C4-烷基、NHCO-苯基、CONHR9、NHSO2-C1-C4-烷基、NHSO2-苯基、SO2-C1-C4-烷基、和SO2-苯基，R3可以是NR7R8或环例如R4是可携带苯基、吡啶基、噻吩基、环己基、吲哚基或萘基环的直链或支链C1-C6-烷基，其中所述环可被最多2个R6取代，R5是氢、COOR11和CO-Z，其中Z是NR12R13和
Figure A9980763700031
R6是氢、直链或支链C1-C4-烷基、-O-C1-C4-烷基、OH、Cl、F、Br、I、CF3、NO2、NH2、CN、COOH、COO-C1-C4-烷基、-NHCO-C1-C4-烷基、-NHCO-苯基、-NHSO2-C1-C4-烷基、-NHSO2-苯基、-SO2-C1-C4-烷基、和-SO2-苯基，R7是氢、可被苯基环取代的直链或支链C1-C6-烷基，其中所述苯基环可被1个或2个R10取代，R8是氢、可被苯基环取代的直链或支链C1-C6-烷基，其中所述苯基环可被1个或2个R10取代，R9是氢，可携带取代基R16的直链或支链C1-C6-烷基、苯基、吡啶基、嘧啶基、哒嗪基、吡嗪基、吡唑基、萘基、喹啉基、咪唑基，其中所述环可携带1个或2个取代基R14，R10可以是氢、直链或支链C1-C4-烷基、-O-C1-C4-烷基、OH、Cl、F、Br、I、CF3、NO2、NH2、CN、COOH、COO-C1-C4-烷基、-NHCO-C1-C4-烷基、-NHCO-苯基、-NHSO2-C1-C4-烷基、-NHSO2-苯基、-SO2-C1-C4-烷基、和-SO2-苯基，R11是氢、可被苯基环取代的直链或支链C1-C6-烷基，其中所述苯基环可被1个或2个R10取代，R12是氢、直链或支链C1-C6-烷基、和
Figure A9980763700032
R13是氢、可被苯基环取代的直链或支链C1-C6-烷基，其中所述苯基环可携带R10基团，R14是氢、直链或支链C1-C6-烷基、直链或支链O-C1-C6-烷基、OH、Cl、F、Br、I、CF3、NO2、NH2、CN、COOH、COO-C1-C4-烷基，或者两个R14基团可代表桥OC(R15)2O，R15是氢、直链或支链C1-C6-烷基，R16可以是苯基、吡啶基、嘧啶基、哒嗪基、吡嗪基、吡唑基、吡咯基、萘基、喹啉基、咪唑基环，其中所述环可携带1个或2个取代基R6，A是-(CH2)m-、-(CH2)m-O-(CH2)o-、-(CH2)o-S-(CH2)m-、-(CH2)o-SO-(CH2)m-、-(CH2)o-SO2-(CH2)m-、-CH=CH-、-C≡C-、-CO-CH=CH-、-(CH2)o-CO-(CH2)m-、-(CH2)m-NHCO-(CH2)o-、-(CH2)m-CONH-(CH2)o-、-(CH2)m-NHSO2-(CH2)o-、-NH-CO-CH=CH-、-(CH2)m-SO2NH-(CH2)o-、-CH=CH-CONH-和R1-A还可以一起为B是苯基、吡啶、嘧啶、吡嗪、咪唑和噻唑，x是1、2或3，n是0、1或2，且m和o独立地为0、1、2、3或4。
2．权利要求1的具有杂环取代基的式Ⅰ酰胺，其中B是吡啶或苯基，R5是氢，R9是氢、可携带取代基R16的直链或支链C1-C6-烷基，R16是可携带1个或2个取代基R14的苯基，n为0和1，且x为1。
3．权利要求1的具有杂环取代基的式Ⅰ酰胺，其中B是吡啶或苯基，R5是CONR12R13，R9是氢、可携带取代基R16的直链或支链C1-C6-烷基，R16是可携带1个或2个取代基R14的苯基，n为0和1，且x为1。
4．权利要求1的具有杂环取代基的式Ⅰ酰胺，其中B是吡啶或苯基，R2是氢，R5是氢，R9是氢、可携带取代基R16的直链或支链C1-C6-烷基，R16是可携带1个或2个取代基R14的苯基，n为0和1，且x为1。
5．权利要求1的具有杂环取代基的式Ⅰ酰胺，其中B是吡啶或苯基，R2是氢，R5是CONR12R13,R9是氢、可携带取代基R16的直链或支链C1-C6-烷基，R16是可携带1个或2个取代基R14的苯基，n为0和1，且x为1。
6．权利要求1的具有杂环取代基的式Ⅰ酰胺，其中A是-(CH2)m-、-(CH2)m-O-(CH2)o-、-(CH2)o-S-(CH2)m-、-CH=CH-、-C≡C-、-(CH2)m-CONH-(CH2)o-、-(CH2)m-SO2NH-(CH2)o-，B是吡啶或苯基，R2是氢，R5是氢，R9是氢、可携带取代基R16的直链或支链C1-C6-烷基，R16是苯基，m、n、o为0和1，且x为1。
7．权利要求1的具有杂环取代基的式Ⅰ酰胺，其中A是-(CH2)m-、-(CH2)m-O-(CH2)o-、-(CH2)o-S-(CH2)m-、-CH=CH-、-C≡C-、-(CH2)m-CONH-(CH2)o-、-(CH2)m-SO2NH-(CH2)o-，B是吡啶或苯基，R2是氢，R5是CONR12R13,R9是氢、可携带取代基R16的直链或支链C1-C6-烷基，R16是苯基，m、n、o为0和1，且x为1。
8．权利要求1的具有杂环取代基的式Ⅰ酰胺，其中B是吡啶或苯基，R1、R2是氢，R5是氢，R9是氢、可携带取代基R16的直链或支链C1-C6-烷基，R16是苯基，m、n、o为0，且x为1。
9．权利要求1的具有杂环取代基的式Ⅰ酰胺，其中B是吡啶或苯基，R1、R2是氢，R5是CONR12R13，R9是氢、可携带取代基R16的直链或支链C1-C6-烷基，R16是苯基，m、n、o为0，且x为1。
10．权利要求1-5任一项的式Ⅰ酰胺在治疗疾病中的应用。
11．权利要求1-5任一项的式Ⅰ酰胺作为半胱氨酸蛋白酶抑制剂的应用。
12．权利要求6的应用，其中所述应用是作为半胱氨酸蛋白酶抑制剂，例如钙蛋白酶和组织蛋白酶、尤其是钙蛋白酶Ⅰ和Ⅱ以及组织蛋白酶B和L的抑制剂的应用。
13．权利要求1-5任一项的式Ⅰ酰胺在制备用于治疗其中钙蛋白酶活性增加的疾病的药物中的应用。
14．权利要求1-5任一项的式Ⅰ酰胺在制备用于治疗神经变性疾病和神经元损伤的药物中的应用。
15．权利要求9的应用，其中所述应用是在治疗由局部缺血、创伤或大出血引起的神经变性疾病和神经元损伤中的应用。
16．权利要求10的应用，其中所述应用是在治疗中风和颅脑创伤中的应用。
17．权利要求10的应用，其中所述应用是在治疗阿尔茨海默氏病和亨廷顿氏舞蹈病中的应用。
18．权利要求10的应用，其中所述应用是在治疗癫痫中的应用。
19．权利要求1-5任一项的式Ⅰ化合物在制备用于治疗下述疾病的药物中的应用：心脏局部缺血后的心脏损伤、肾局部缺血后的肾脏损伤、骨骼肌损伤、肌肉营养不良、由于平滑肌细胞增殖所导致的损伤、冠状血管痉挛、脑血管痉挛、眼睛内障、和血管成形术后的血管再狭窄。
20．权利要求1-5任一项的式Ⅰ酰胺在制备用于治疗肿瘤以及肿瘤转移的药物中的应用。
21．权利要求1-5任一项的式Ⅰ酰胺在制备用于治疗其中白细胞介素-1水平增加的疾病的药物中的应用。
22．权利要求1-5任一项的酰胺在治疗免疫性疾病例如炎症和风湿性疾病中的应用。
23．口服、非胃肠道和腹膜内给药的药物制剂，其中每一单位制剂包含至少一种权利要求1-5任一项的式Ⅰ酰胺和常规药物辅料。
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