CN1079792C - 酶抑制剂 - Google Patents

酶抑制剂 Download PDF

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CN1079792C
CN1079792C CN94194782A CN94194782A CN1079792C CN 1079792 C CN1079792 C CN 1079792C CN 94194782 A CN94194782 A CN 94194782A CN 94194782 A CN94194782 A CN 94194782A CN 1079792 C CN1079792 C CN 1079792C
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pyrrolidines
glutaminyl
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P·D·詹金斯
D·M·琼斯
M·森克
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Abstract

选自下列通式的化合物为DP-Ⅳ介导过程抑制剂。
A选自特定的氨酰基化合物。

Description

酶抑制剂
背景：
DP-IV(EC3.4.14.5)是膜结合性丝氨酸蛋白酶，最初，由于它具有从某种肽的N-端裂解二肽的能力而从鼠的肾脏中鉴定出来(Hopsu-Havu，V.K.和Clenner G.G.，Histochemie，1966，7，197)。二肽必须是x-脯氨酸或x-丙氨酸型的，其中x为任何氨基酸。x-脯氨酸比x-丙氨酸更有效地被断裂。
DP-IV广泛地分布于哺乳动物组织中，并且发现在肾脏、肠上皮和胎盘中含量丰富(Yaron，A.and Naider，F.，Critical Reviews inBiochem.Mol.Biol.1993，28(1)，31)。在人类免疫***中，这种酶几乎全部由激活的CD4+型T-淋巴细胞来表达，其中已显示该酶与细胞表面抗原CD26是同义的。
DP-IV在人类生理学中的确切作用还没有完全弄清楚，但最近的研究表明在人类生理学和病理生理学中，显然，该酶具有重要的作用，例如：
(a)免疫应答：在促***原或抗原刺激的T细胞中，DP-IV表达增加(Mattern，T.等，Scand.J.Immunol，1991，33，737)。曾有报道，DP-IV抑制剂或抗DP-IV抗体以剂量依赖方式抑制促***原或抗原刺激的T细胞的增殖(Sch_n，E等，Biol.Chem.Hopper-Seyler，1991，372，305和其中的参考文献)。
已表明T淋巴细胞的各种其它功能如产生细胞因子、IL-2介导的细胞增殖和B细胞辅助活性都依赖于DP-IV活性(Sch_n，E.等，Scand.J.Immunol，1989，29，127)。最近报道了基于硼脯氨酸(boroproline)的DP-IV抑制剂(Flentke，G.R.等人，Proc.Natl.A-cad.Sci.USA，1991，88，1556)，该DP-IV抑制剂尽管不稳定，但能有效地抑制抗原诱导的淋巴细胞增殖和在鼠CD4+T辅助细胞中产生IL-2。已表明，这种硼酸抑制剂在小鼠体内可有效地抑制由免疫激发引起的抗体产生(Kubota，T.等，Clin.Exp.Immunol，1992，89，192)。近期的其它报道也提供证据表明免疫应答中涉及DP-IV(例如Tanaka，T等人，Proc.Natl.Acad.Sci.NY.1993，90，4586；Hegen，M.等人Cell Immun.1993，146，249；Subramanyan，M.等人J.Immunol.1993，150，25447)。
某些研究者认为DP-IV的重要性在于其细胞表面与跨膜磷酸酯酶CD45缔合(Torimoto，Y等人，J.Immunol，1991，147，2514)。CD45-DP-IV缔合可能被DP-IV抑制剂或非活性位点配体破坏。已知CD45是T细胞信号化的组成性成分。
(b)最近，据巴黎Pasteur Institute发表的报刊(并且接着由A.G.Hovanessian在8th Cent.Gardes Meeting，Paris，25-27th October1993中发表)报道。DP-IV是CD4+T细胞中HIV-1和HIV-2病毒的穿透和感染所必需的。该法国研究组认为DP-IV与病毒gp120外壳糖蛋白的V3环相互作用并且可能裂解V3环。他们也报道了DP-IV抑制剂或抗体有效地抑制病毒进入细胞。过去已知HIV-1感染个体的T细胞中，CD26表达选择性降低(Voll-Blazque，M等，J.Immunol.1992，149，3073)，并且已知HIV-1 Tat蛋白与DP-IV结合(Subramaryam，M等人，J.Immunol，1993，150，2544)。
(c)最近已表明肺内皮DP—IV是肺转移型鼠乳腺和***癌细胞的粘连分子(Johnson，R.C等人，J.Cell，Biol，1993，121，1423)。已知DP-IV与粘连蛋白结合，并且已知某些转移的癌细胞在其表面上携带大量粘连蛋白。
(d)已表明DP-IV与T细胞表面的腺苷脱氨酶(ADA)相结合(Kameoka，J等人，Science，1993，261，466)。ADA缺乏引起人类严重联合免疫缺陷病(SCID)。ADA-CD26相互作用可为SCID的病理生理提供线索。
(e)在患牛皮癣、类风湿性关节炎(RA)和扁平苔癣的病人的人皮肤成纤维细胞中，已发现DP-IV表达水平高(Raynaud，F等，J，Cell.Physiol，1992，151，378)。
(f)在患良性***肥大病人的组织匀浆中和在***体(prostatosome)中，发现DP-IV活性高。这些是***衍化的细胞器，它们对促进***能动性是重要的(Vanhoof，G等人，Eur.J.Clin.Chem.Clin.Biochem，1992，30，333)。
(g)已表明，DP-IV引起在N-端具有次末端脯氨酸或丙氨酸的环状肽(例如P物质，生长激素释放因子和胰高血糖素/血管活性小肠肽族的成员)的降解和灭活(Menthein，R等人，Eur.J.Biochem，1993，214，829)。
(h)在患牙周炎病人的牙龈中，可见DP-IV水平增加(Cox，S.W.等人，Arch.Oral.Biol，1992，37，167)。
(i)也有许多其它的报道表明在各种病理条件下，DP-IV水平增加(或有时降低)。
由上述作用可知，有效的DP-IV抑制剂可作为药物来治疗人类的疾病。这种抑制剂可作为：
(a)免疫抑制剂，例如在器官移植中；细胞因子释放抑制剂，例如在各种自身免疫性疾病如炎症性肠病，多发性硬化病，RA中。
(b)抑制HIV进入T细胞的药物并且因此可用于预防和治疗AIDS。
(c)预防转移癌，尤其是乳腺癌和***癌向肺癌转移的药物。
(d)治疗皮肤病如牛皮癣，扁平苔癣的药物。
(e)抑制***能动力的药物并因此作为男性避孕药。
(f)治疗良性***肥大的药物。DP-IV抑制剂
迄今报道的DP-IV酶活性竞争性抑制剂只有上述提到的不稳定的硼酸衍生物(在PH7时t1/2为30-90分钟)(Bachovchin等，WO91/16339，October 1991)(其对DP-IV的Ki值在纳摩尔范围内)和简单的氨基酸吡咯酰胺(Pyrrolidides)或噻唑酰胺(thiazolides)(Neu-bert等人，DD296075 A5，November 1991)(它们只具有中等的功效(Ki＞0.1μM))。在同一德国专利中公开的氨酰基脯氨酸醛由于易产生N端氨基与醛官能团的分子内缩合而不能被合成。
现在，我们公开高效竞争型DP-IV抑制剂(其Ki值为10-6-10-10)，它们具有化学稳定性(t1/2＞24小时)。它们属于三大组化合物(组I、II和III)。组I
设计了这些与DP-IV活性部位紧密结合并且抑制其蛋白分解活性，但不影响任何可以结合到DP-IV表面(即不在其活性部位)的辅助配位体结合的分子。该组I化合物可用作免疫抑制剂；抗HIV感染剂；抑制激活的T细胞释放某些细胞因子(例如IL-2，IL-6，γ-INF)的试剂。早期提到的硼酸衍生物和吡咯酰胺也属此类。组II
这些是由组I化合物发展而来的；然而它们在通式中称作A的氨基酸的侧链上包含延伸的长链。所得到的化合物紧紧结合到DP-IV的活性部位，但伸长的长链从酶的活性部位伸出并且抑制任何可以结合到DP-IV表面上的其它配位体的结合。该化合物可能具有组I化合物相同的作用，但另外可阻断DP-IV与(i)CD45(ii)HIV-1的gp120V3环(iii)癌细胞表面粘连蛋白(iv)任何对于T细胞激活，病毒进入T细胞或癌细胞粘连重要的其它配位体的相互作用。组III
该组包含新的二聚体，其中两个定向活性位点的DP-IV抑制剂通过通式中称作A的氨基酸残基的侧链结合成长链。该二聚体可同时抑制两种DP-IV分子并且也抑制辅助配位体结合到DP-IV表面，这些二聚体可能具有组II化合物相同的作用但可能是更有效的。
本发明提供DP-IV所介导过程的抑制剂，抑制剂通式为：A-B(细I和II)或
Figure C9419478200141
(组III)其中B为
Figure C9419478200142
n＝1或2；m＝0，1或2；X＝CH2，O， S，SO，SO2，NH或NR1其中R1＝低级烷基C1-C6)；
A与Y接合；
-Y＝-N，-CH或＝C(当A的-CO基由CH＝或CF＝取代时)；
R＝H，CH，CHO，B(OH)2，C≡C-R7或CH＝N-R8；
R7＝H，F，低级烷基(C1-C6)，CN，NO2，OR9，CO2R9或COR9；
R8＝苯基，OH，OR9，OCOR9或OBn；
R9＝低级烷基(C1-C6)；并且可以不含ω或两个ε。
A的结构依赖于B部分中R的性质和化合物所属类别的性质。组I化合物
(a)R＝H
A是由带有环状脂肪族侧链(例如C4-C10，单环或双环)的α-氨基酸衍变的α-氨酰基，其中所述环状脂肪族侧链的环可以含有一个或多个杂原子，例如L-环己基甘氨酸，L-环戊基甘氨酸，L-十氢化萘基甘氨酸，L-哌啶基甘氨酸；
或A为下列通式的β-氨酰基
Figure C9419478200143
其中p＝1-6，并且环也可以含一或多个杂原子代替CH2单元。
上述(a)中α和β-氨酰基都可以在环中含不饱和键，例如
Figure C9419478200151
可以含一个或多个杂原子。
(b)R＝CN；C≡C-R7或CH＝N-R8
A如上(a)中所定义，但另外可以从带有亲脂性侧链的L-α-氨基酸，例如Ile衍化得到。
(c)R＝CHO或B(OH)2
A是上述(a)中所定义的β-氨酰基。得到的A-B化合物是稳定的，不象相同类型的α-氨酰基衍生物容易进行分子内环化。在化合物(c)中，B(OH)2可以以烷基硼酸酯的形式存在，例如
这些化合物在水中是不稳定的，可得到游离烷基硼酸。组II化合物
其中R＝H，CN，C≡C-R7或CH＝N-R8，A是侧链带有官能团的α-氨基酸衍生物，其中可将官能团衍化得到在各种R3基团处终止的长链。A可以是下列三种类型的结构：
Figure C9419478200153
其中a＝1-5；D＝G-(CH2)b-(R4)q-R3；G＝O，NH或NMe；
b＝0-12；q＝0-5；
D1＝D(G≠O)
R4＝Z-NH-(CH2)c-或NH-Z-(CH2)c-其中c＝1-12并且Z＝CO，CH2或SO2；并且
R3＝CO2H或其酯[例如，任何低级烷基，氟烷基或环烷基(C1-C8)或芳族或杂芳族(5或6元环，单或双环)的酯]；CONH2；CONHNH2；CONR5R6；CONHNR5R6；PO3H(或其酯，例如在CO2H下所定义的)；SO3H；SO2NH2；SO2NR5R6；OH；OR5；芳基或杂芳基(例如5或6元环，单环或双环)[包括取代的芳基或杂芳基，其取代基优选选自F，Cl，I，Br，OH，OR5，NO2，SO3H，SO2NH2，SO2NR5R6，NH2，NR5R6，CO2R5，CF3，CN，CONH2，CONR5R6，NHCO2R5，CH(＝NR5)NR5R6，NH-CH(＝NR5)NR5R6和R5]；NH2；NR5R6；NHCO2R5；NHSO2NR5R6；NHCOR5；NH-SO2R5；NH-CH(＝NR5)NR5R6；NHCONR5R6；糖(可以通过醚键或糖苷键与其连接)；CO-氨基糖(通过-NH2连接)例如葡糖胺或半乳糖胺；NHCO-氨基糖，或NHCS-氨基糖。
在上述R3的定义中，“糖”指任何糖类或低聚糖，并且R5和R6独立地选自H和烷基，氟烷基和环烷基(不超过8个原子)，芳基，杂芳基和烷基杂芳基(不超过11个原子)或者R5和R6一起包含一个链(C3-C8)。
其中R1＝H，Me；环也可以含多个杂原子；
E＝J-(CH2)b-(R4)q-R3；J＝CO，CH2或SO2；并且a，b，q，R3和R4如(i)中定义。
Figure C9419478200162
其中R2＝H或Me；环也可以含一个或多个杂原子；
L＝(CH2)d-[CO]r-(CH2)b-(R4)q-R3或(CH2)e-NR1-(CH2)b-(R4)q-R3；
r＝0或1；d＝0-4；e＝2-4；并且b，q，R3和R4如(i)下定义。组III
组III化合物由下列通式定义：
其中ω＝CH2，O，NH，CO，S，SO2，苯基或NMe并且，独立地，
ε＝CH2，O，NH，CO，S，SO2，苯基或NMe。
这些化合物是对称的二聚体。它们可能具有上述定义的任何B结构。A可选自任何组II结构[(i)，(ii)或(iii)]，但在这种情况下，每个A基中都缺少末端基R3并且由连接二聚体两半部分的共享对称基团[ε-ω-ε]代替，可以不含ω，此时，两个ε结合到一起构成连接两个A-B部分的链；或者，可以不含两个ε，此时，ω单独连接两个A-B部分。
当然ε-ω-ε结构必须是在化学上适宜的，例如NH-CO-NH，CO-NH-CO-，SO2-NMe-SO2；对于本领域技术人员而言，不适宜的结构是显然的，例如-NH-NH-NH-。可能的特定实例显示于表7中。
在组II和III所述的这些化合物中，在长链中存在的-CH2-基可以由已知的生物电子等排物，例如-O-代替，并不影响对DP-IV的抑制作用或结合活性。如-CONHCH2CH2NHCO类型的基团(如果存在)也可以由例如下式基团代替：
Figure C9419478200172
进一步讲，对于组I，II和III中的化合物而言，任何连接A和B的酰胺键或任何在A侧链中的酰胺(在组II和III中)都可以由已知的酰胺生物电子等排体代替。例如：
Figure C9419478200181
Figure C9419478200182
代替。
这些替代的实例见表8。生物化学
在体内对纯的人DP-IV(购于M&E，Copenhagen，DenmarK)测定所有的化合物。利用荧光底物Ala-Pro-AFC(Km0.8μM)测定对DP-IV的抑制，每种抑制剂在三种浓度下测定。典型的实验混合物(总体积0.4ml)包含Hepes Na 83.3mM，EDTA 1.67mM，BSA 1.5mg/ml，PH7.8，DP-IV 25μU/ml，抑制剂(在PH4.0的10mM醋酸盐中)。通过加底物开始反应并且每30秒记录一次读数计7.5分钟，激发波长395nm，发射波长450nm。利用Dixon作图法来测定Ki值。化学
表1-8中显示了152种合成化合物的实例，其后有每种不同结构类型制备方法流程式和实验细节。通过FAB质谱来确定所有最终产物的特性，并且通过反相HPLC来测定纯度；通过1HNMR来确定所有中间体的特性。
表9显示对于不同结构类型的抑制剂测定时所得到的对DP-IV的选择性Ki值。
表1组I(a)的实施例
Figure C9419478200191
                                               计算值     FAB质谱No.     A          X       R      n     分子式
                                                Mol.Wt.   [M＋H]+1  
Figure C9419478200192
     CH2    H    1      C11H20N2O   196.2    197.22  
Figure C9419478200193
    CH2    H   1      C12H22N2O    210.2    211.23  
Figure C9419478200194
    CH2    H    1      C10H20N2O   184.2    185.24  
Figure C9419478200195
    CH2    H    1      C12H20N2O   208.2    209.25cis     CH2    H   1      C11H20N2O    196.1    197.2
计算值     FAB质谱No.        A            X      R     n       分子式
                                                       Mol.Wt.    [M＋H]+6trans         CH2    H    1    C11H20N2O    196.1     197.27trans  
Figure C9419478200202
      CH2    H    1    C11H18N2O    194.1     195.28trans  
Figure C9419478200203
      CH2    H    1    C10H18N2O    182.1     183.29     
Figure C9419478200204
      CH2    H    1    C11H14N2O     190.1     191.210trans      CH2    H    1    C13H24N2O     224.2     225.2
表2组I(b)的实施例
                                                          计算值     FAB质谱No.       A           X      n    R1  R     分子式
                                                          Mol.Wt.    [M＋H]+11      H-Ile        CH2    1    H    CN    C11H19N3O     209.3      210.212      H-Lys(Z)     CH2    1    H    CN    C19H26N3O3   358.2      359.213      H-Pro        CH2    1    H    CN    C10H15N3O     193.1      194.114    
Figure C9419478200212
    CH2    1    H    CN    C9H13N3OS     211.1     212.215         CH2    1    H    CN    C9H13N3OS     211.1     212.216       CH2    1    H    CN    C13H21N3O     235.2     236.317    
Figure C9419478200215
   CH2    1    H    CN    C12H19N3O     221.2     222.2
计算值   FAB质谱No.     A            X     n    R1     R      分子式
                                                          Mol.Wt.  [M＋H]+18  
Figure C9419478200221
     CH2   1    H      CN     C11H19N3O     209.2    210.219    H-lle         S      1    H      CN     C10H17N3OS    227.1    228.120    H-lle         S      1    CN     H      C10H17N3OS    227.1    228.121  
Figure C9419478200222
     S      1    H      CN     C12H19N3OS     253.1    254.122    H-Lys(Z)      S      1    H      CN     C18H24N4O3S   376.2    377.223        S     1    H      CN      C11H17N3OS     239.1    240.224    H-lle         O     1    H      CN      C10H17N3O2    211.1    212.225    H-lle         CH2  2    H      CN      C12H21N3O      223.2    224.226    H-lle         S     2    H      CN      C11H19N3OS     241.1    242.127    H-lle         SO2  1    H      CN      C10H17N3O3S   259.1    260.128    H-lle       1    H      CN      C10H17N3O2S   243.1    244.129    H-lle      
Figure C9419478200225
 1    H       CN      C10H17N3O2S   243.1    244.2
计算值    FAB质谱No.    A            X     n      R1     R    分子式
                                                          Mol.Wt.   [M＋H]+30  
Figure C9419478200231
    CH2  1      H       CN    C12H19N3O    221.2     222.231       CH2  1      H       CN    C12H19N3O    221.2     222.232       CH2  1      H       CN    C11H17N3O    207.2     208.233  
Figure C9419478200234
    CH2  1      H       CN    C11H17N3O    207.2     208.234  
Figure C9419478200235
    CH2  1      H       CN    C12H17N3O    219.1     220.135       CH2  1      H       CN    C12H17N3O    219.1     220.1
                                                   计算值      FAB质谱No.    A        X     n     R1   R    分子式
                                                   Mol.Wt.    [M＋H]+36    CH2   1    H    CN    C12H19N3O     221.2    222.237  
Figure C9419478200242
 CH2   1    H    CN    C12H17N3O     219.1    220.1
表3组I(c)的实施例
Figure C9419478200251
                                                       计算值    FAB质谱No.      A          X      R       n      分子式
                                                       Mol.Wt.   [M＋H]+38      CH2  CHO       1     C12H20N2O2    224.2    225.239  
Figure C9419478200253
   CH2  CHO      1     C11H18N2O2    210.2    211.240  
Figure C9419478200254
   CH2  CHO      1     C11H18N2O2    210.2    211.241  
Figure C9419478200255
   CH2  B*      1     C20H33BN2O3   360.3    361.342      CH2   B*      1     C21H35BN2O3   374.3    375.143  
Figure C9419478200257
    CH2   B*      1     C21H35BN2O2   374.3    375.144  
Figure C9419478200258
   CH2   B*      1     C21H33BN2O3   372.3    373.3
                                                  计算值       FAB质谱No.      A          X      R     n     分子式
                                                  Mol.Wt.      [M＋H]+45       CH2   B*  1  C21H33BN2O3    372.3        373.3B*＝  
表4组II(i)的实施例
                                                                  计算值      FAB质谱No.  n         Q                 X    m    R      分子式
                                                                  Mol.Wt.    [M＋H]+46   1   -CONHCH2CO2Bn        CH2   1    H    C17H23N3O4      333.2      334.247   1   -CONHCH2CO2H         CH2   1    H    C10H17N3O4      243.1      244.248   1   -CONH(CH2)3CO2H     CH2   1    H    C12H21N3O4      271.2      272.249   1   -CONH(CH2)2CO2Bn    CH2   1    H    C18H25N3O4      347.2      348.250   1   -CONH(CH2)2CO2H     CH2   1    H    C11H19N3O4      257.1      258.251   1   -CONH(CH2)5CO2Bn    CH2   1    H    C21H31N3O4      389.3      390.352   1   -CONH(CH2)5CO2H     CH2   1    H    C14H25N3O4      299.2      300.253   1   -CONH(CH2)3CO2Bn    CH2   1    H    C19H27N3O4      361.2      362.254   2   -CONHCH2CO2Bn        CH2   1    H    C18H25N3O4      347.2      348.255   2   -CONHCH2CO2H         CH2   1    H    C11H19N3O4      257.1      258.156   2   -CONH(CH2)2CO2Bn    CH2   1    H    C19H27N3O4      361.2      362.357   2   -CONH(CH2)3CO2Bn    CH2   1    H    C20H29N3O4      375.2      376.358   2   -CONH(CH2)3CO2H     CH2   1    H    C13H23N3O4      285.2      286.2
                                                                        计算值      FAB质谱No.   n           Q                  X     m    R      分子式
                                                                        Mol.Wt.    [M＋H]+59    2    -CONH(CH2)5CO2Bn     CH2    1    H    C22H33N3O4        403.3      404.360    2    -CONH(CH2)5CO2H      CH2    1    H    C15H27N3O4        313.2      314.261    2    -CONH(CH2)2CO2H      CH2    1    H    C12H21N3O4        271.2      272.262    2    -CONH(CH2)7CO2Bn     CH2    1    H    C24H37N3O4        431.3      432.463    2    -CONH(CH2)7CO2H      CH2    1    H    C17H31N3O4        341.3      342.564    2    -CONH(CH2)7CONH-      CH2    1    H    C28H45N5O5        531.3      532.3
       (CH2)3NHZ65    2    -CONH(CH2)6CONH-      CH2    1    H    C29H46N4O5        530.4      531.2
       (CH2)5CO2Bn66    2    -CONH(CH2)6CONH-      CH2    1    H    C22H40N4O5        440.3      441.3
       (CH2)5CO2H67    2    -CONH(CH2)7CONH-      CH2    1    H    C20H39N5O3        397.3      398.3
       (CH2)3NH268    2    -CONH(CH2)11CO28n    CH2    1    H    C28H45N3O4        487.3      488.469    2    -CONH(CH2)11CO2H     CH2    1    H    C21H39N3O4        397.3      398.370    2    -CONH(CH2)6CO28n     CH2    1    H    C23H35N3O4        417.3      418.371    2    -CONH(CH2)6CO2H      CH2    1    H    C16H29N3O4        327.2      328.272    2    -CONH(CH2)5CONH-      CH2    1    H    C17H29F3N4O3     394.2      395.3
       CH2CF3
                                                                      计算值    FAB质谱No.   n          Q                  X     m    R       分子式
                                                                      Mol.Wt.   [M＋H]+73    2    -CONH(CH2)5CONH-      CH2   1    H    C19H29F7N4O3    494.2      495.2
       CH2(CF2)2CF374    2    -CONH(CH2)5CONH-      CH2   1    H    C21H40N4O4       412.3      413.2
       (CH2)6OH75    2    -CONH(CH2)5CONH-      CH2   1    H    C24H38N4O3       430.3      431.2
       (CH2)3Ph76    2    -CONH(CH2)5CONH-      CH2   1    H    C25H40N4O3       444.3      445.2
       (CH2)4Ph77    2    -CONH(CH2)5CON-       CH2   1    H    C23H44N4O3       424.3      425.3
       (nBu)278    2    -CONH(CH2)5CON-       CH2   1    H    C27H52N4O3       480.4      481.4
       (nHx)279    2    -CONH(CH2)5CONH-      CH2   1    H    C22H34N4O3       402.3      403.4
       CH2Ph80    2    -CONH(CH2)4CO2Bn     CH2   1    H    C21H31N3O4       389.2      390.381    2    -CONH(CH2)4CO2H      CH2   1    H    C14H25N3O4       299.2      300.382    2    -CONH(CH2)5CONH-      CH2   1    H    C17H32N4O3       340.3      341.3
       CH2CH383    2    -CONH(CH2)6OH         CH2   1    H    C15H29N3O3       299.2      300.384    2    -CONH(CH2)5CO-1-Pip   CH2   1    H    C20H36N4O3       380.3      381.485    2    -CONH(CH2)5CONH2     CH2   1    H    C15H28N4O3       312.2      313.3
                                                                计算值    FAB质谱No.   n           Q                X    m    R      分子式
                                                                Mol.Wt.   [M＋H]+86    2    -CONH(CH2)5CONH-    CH2  1    H    C25H48N4O3    452.4     453.5
       (CH2)9CH387    2    -CONH(CH2)5CONH-    CH2  1    H    C22H42N4O3    410.3     411.4
       (CH2)6CH388    2    -CONH(CH2)5CONH-    CH2  1    H    C22H40N4O3    408.3     409.4
       CH2Ch89    2    -CONH(CH2)5CONH-    CH2  1    H    C26H41N5O5    503.3     504.4
       (CH2)3NHZ90    2    -CONH(CH2)5CONH-    CH2  1    H    C18H35N5O3    369.3     370.3
       (CH2)3NH291    2    -CONH(CH2)5CONH-    CH2  1    H    C19H37N7O3    411.3     412.4
       (CH2)3-Gua92    2    -CONH(CH2)5CONH-    CH2  1    H    C21H32N4O6S   468.2     469.2
       Ph(4-SO3H)93    2    -CONH(CH2)5CONH-4-  CH2  1    H    C27H43N5O3    485.3     486.3
       Pip(1-Bn)94    2    -CONH(CH2)5CONH-    CH2  1    H    C20H37N5O3    395.3     396.3
       4-Pip95    2    -CONH(CH2)4N(Z)-    CH2  1    H    C32H45N5O6    595.3     596.3
       (CH2)3NHZ96    2    -CONH(CH2)4NH-      CH2  1    H    C16H33N5O2    327.2     328.2
       (CH2)3NH2
                                                                         计算值     FAB质谱No.   n           Q                 X       m      R      分子式
                                                                         Mol.Wt.    [M＋H]+97    2    -CONH(CH2)5CO2Bn     CH2    1      CN    C23H32N4O4      428.3      429.398    3    -CONH(CH2)6CONH-      CH2    1      H     C30H48N4O5      544.4      545.2
       (CH2)5CO2Bn99    3    -CONH(CH2)6CONH-      CH2    1      H     C23H42N4O5      454.3      455.3
       (CH2)5CO2H100   3    -CONH(CH2)5CO2Bn     CH2    1      H     C23H35N3O4      417.3      418.2101   3    -CONH(CH2)5CO2H      CH2    1      H     C16H29N3O4      327.2      328.2102   2    -SO2NH(CH2)5CO2H    CH2    1      H     C14H27N3O5S     349.2      350.2103   2    -CONH(CH2)8NH-G        CH2    1      H     C24H45N5O7S     547.4      548.5
Figure C9419478200311
表5组II(ii)的实施例
                                                                       计算值     FAB质谱No.    n          Q                   X     m    R      分子式
                                                                       Mol.Wt.    [M＋H]+104    1    -CO(CH2)6CO2H        CH2   1    H    C15H27N3O4       313.2       314.3105    1    -CO(CH2)6CO2Bn       CH2   1    H    C22H33N3O4       403.3       404.3106    3    -CO(CH2)4CO2H        CH2   1    H    C15H27N3O4       313.2       314.3107    3    -CO(CH2)4CO2Me       CH2   1    H    C16H29N3O4       327.2       328.3108    4    -CO(CH2)5NH2         CH2   1    H    C16H32N4O2       312.3       313.3109    4    -CO(CH2)3NH2         CH2   1    H    C14H28N4O2       284.2       285.2110    1    -CO(CH2)3NHSO2Pfp    CH2   1    H    C20H27F5N4O4S   514.2       515.2111    4    -CO(CH2)3NHCOPfp      CH2   1    H    C21H27F5N4O3    478.2       479.2112    4    -CO(CH2)3NHSO2-      CH2   1    H    C16H29F3N4O4S   430.2       431.3
        CH2CF3113    4    -CO(CH2)11NHCO-       CH2   1    H    C37H63N5O5        657.5       658.6
        (CH2)6NHZ114    4    -CO(CH2)11NH-         CH2   1    H    C29H57N5O3        523.4       524.4
        CO(CH2)6NH2
                                                                   计算值     FAB质谱No.   n          Q                  X       m    R      分子式
                                                                    Mol.Wt.    [M＋H]+115   4    -CO(CH2)5NHCO-        CH2    1    H    C35H60N5O5    672.5      673.6
       (CH2)5NHCO(CH2)5-
       NHZ116   4    -CO(CH2)5NHCO-        CH2    1    H    C28H54N5O4    538.4      539.4
       (CH2)5NHCO(CH2)5-
       NH2117   4    -CO(CH2)3CO2H       CH2    1    H    C15H27N3O4    313.2      314.3118   4    -CO(CH2)3CO2Bn      CH2    1    H    C22H33N3O4    403.3      404.3119   4    -CO(CH2)6NH2        CH2    1    H    C17H34N4O2    326.3      327.3120   4    -CO(CH2)7NH2        CH2    1    H    C18H36N4O2    340.3      341.3121   4    -CO(CH2)16Me          CH2    1    H    C28H55N3O2    465.4      466.4122   4    -CO(CH2)6-Gua        CH2    1    H    C18H36N5O2    368.3      369.3123   4    -SO2(CH2)7CH3      CH2    1    H    C18H37N3O3S   375.3      376.3124   4    -CO(CH2)11NH2       CH2    1    H    C22H44N4O2    396.4      397.4125   4    -COCH2NHZ             CH2    1    H    C20H30N4O4    390.2      391.3126   4    -CO(CH2)2NHZ         CH2    1    H    C21H32N4O4    404.2      405.3127   4    -CO(CH2)3NHZ         CH2    1    H    C22H34N4O4    418.3      419.3128   4    -CO(CH2)2NH2        CH2    1    H    C12H24N4O2    256.2      257.2
                                                           计算值      FAB质谱No.   n          Q             X     m   R     分子式
                                                            Mol.Wt.    [M＋H]+129   4    -CO(CH2)5NHZ    CH2   1   H   C24H38N4O4    446.3       447.4130   4    -COCH2-Gua       CH2   1   H   C13H25N6O2    298.2       299.3131   4    -CO(CH2)2NH2  CH2   1   H   C13H25N4O2    270.2       271.3132   4    -CO(CH2)2-Gua  CH2   1   H   C14H28N6O2    312.2       313.3133   4    -CO(CH2)3-Gua  CH2   1   H   C15H30N6O2    326.3       327.3134   4    -CO(CH2)5-Gua  CH2   1   H   C17H34N5O2    354.3       355.3135   4    -CO(CH2)6NH2  CH2   1   CN  C18H33N5O2    351.3       352.4136   4    -CO(CH2)7NH2  CH2   1   CN  C19H35N5O2    365.3       366.3
表6  组II(iii)的实施例
                                                                           计算值     FAB质谱No.    R            R1               X      n       Y      分子式
                                                                           Mol.Wt.    [M＋H]+137    H      -OCH2CONH(CH2)5-   CH2     1       H    C15H27N3O5     329.2       330.3
          CO2H138    H      -OCH2CONH(CH2)5-   CH2     1       H    C22H33N3O5     419.3       420.3
          CO2Bn139    H      -OCH2CONH(CH2)4-   CH2     1       H    C21H31N3O5     405.2       406.3
          CO2Bn140    H      -OCH2CONH(CH2)4-   CH2     1       H    C14H25N3O5     315.2       316.3
          CO2H141    CH3   -OCH3                CH2     1       H    C9H18N2O2      186.1       187.2142    CH3   -OC2H5              CH2     1       H    C10H20N2O2     200.1       201.2143    CH3   -O(CH2)5CH3        CH2     1       H    C14H28N2O2     256.2       257.3144    CH3   -OCH2CONH(CH2)5-   CH2     1       H    C23H35N3O5     433.3       434.3
          CO2Bn145    CH3   -OCH2CONH(CH2)5-   CH2     1       H    C16H29N3O5     343.2       344.3
          CO2H
                                                                         计算值    FAB质谱No.     R            R1                X     n      Y     分子式
                                                                         Mol.Wt.   [M＋H]+146    CH3    -OCH2CONH(CH2)4-    CH2    1      H    C22H33N3O5    419.2     420.3
           CO2Bn147    CH3    -OCH2CONH(CH2)4-    CH2    1      H    C15H27N3O5    329.2     330.3
           CO2H
表7   组III的实施例
                                                 计算值    FAB质谱No.        结构                     分子式
                                                 Mol.Wt.   [M＋H]+148
Figure C9419478200371
  C32H54N9O4    614.4    615.4
               表8含酰胺键生物电子等排体的化合物A—B的特定实施例
                                     计算值   FAB质谱No.       A-B             分子式
                                     Mol.Wt.  [M＋H]+149 
Figure C9419478200381
         C11H21N      167.2    168.2150 
Figure C9419478200382
      C12H20N2    192.2    193 2151 
Figure C9419478200383
      C12H20N2    192.2    193.2152          C10H20N2S    200.1    201.2
   表9  对DP-IV的选择性Ki值
    No.             Ki(M)
    2            6.4×10-8
    7            7.6×10-6
    11           2.2×10-9
    20           1.7×10-9
    23           5.0×10-10
    35           3.7×10-8
    38           9.8×10-9
    44           2.0×10-9
    59           1.5×10-7
    66           1.8×10-7
    97           5.0×10-10
    110          2.5×10-7
    136          1.7×10-8
    143          9.4×10-7
    150          1.7×10-6图解表示各类化合物的一般制备方法表1按E.Sch_n等人在Biol.Chem.Hoppe—Seylar，1991，372，305-311中所描述的一般途径，可以制备这些化合物。表2(a)R：-CN
Figure C9419478200401
Figure C9419478200411
表3按W.W.Bachovchin等人在J.Biol.Chem.，1990，265，3738-3743中所描述的方法制备。(b)R＝CHO
Figure C9419478200413
表4(W，P＝保护基；P1，P2＝在相应的表中所述的基团)(a)R＝CN
Figure C9419478200421
按照G.Luisi等人在Tet.Lett.，1993，34，2391-2392中的方法制备(IV)。(c)R＝H，按表1实施例所述对上述方法修改。表5(a)R＝CN
Figure C9419478200431
(b)R＝H，按表1实施例所述对上述方法修改。表6按照表5实施例所描述的方法，由(V)制备(VI)
Figure C9419478200441
表7类似于上述图解的标准偶合，脱水和脱保护系列操作
Figure C9419478200451
表8
Figure C9419478200461
按照K.Clausen等人在Tetrahedron 1981，37，3635-3639中所描述的方法制备硫代酰胺。按照文献先例，可以制备其它酰胺生物电子等排体(A.F.Spatola in“Chemistry and biochemistry of Amino Acids，Pep-tides and proteins”，Vol.III，B.Weinstein Ed.，Marcal Dekker，NewYork，1983，P.267)
特定实施例实验详述实施例1  2-(s)-氰基-1-异亮氨酰基吡咯烷(11)
Figure C9419478200471
将二异丙基乙胺加到H-ProNH2·HCl(225mg，1.5mmol)在无水CH2Cl2(15cm3)的溶液中直到将PH调至9。在氮气氛下，一次加入BocIleONSu并将混合物搅拌16小时。将溶剂蒸发并按标准方法来处理残余物，即将残余物在乙酸乙酯(60cm3)和0.3N KHSO4溶液(10cm3)之间分配。用饱和NaCHO3溶液(10cm3)，水(10cm3)和盐水(5cm3)进一步洗涤有机层。将溶液干燥(Na2SO4)并在减压下蒸发。将粗品经过短的硅胶柱，用己烷∶乙酸乙酯(10∶90-0∶100)洗脱，得到301mg(92％)BocIleProNH2的无色泡沫。1H NMR(CDCl3)，δ(ppm)；6.90(1H，br.s)；5.51(1H，br.s)；5.18(1H，d，J＝9.6Hz)；4.62(1H，dd，J＝2.6，7.0Hz)；4.29(1H，dd，J＝8.4，9.2Hz)；3.79-3.58(2H，m)；2.36(1H，m)；2.09-1.57(5H，m)；1.43(9H，s)；1.17(1H，m)；0.95(3H，d，J＝6.6Hz)；0.90(3H，t，J＝7.3Hz).
在氮气氛下，将咪唑(84mg，1.24mmol)加入BocIleProNH2在无水吡啶(10cm3)的溶液中。在滴加POCl3(0.25cm3，2.48mmol)之前，将溶液冷却至-35℃。在-30℃-20℃之间，将反应搅拌60分钟。然后将溶液蒸发并将粗品残渣进行柱层析(硅胶)，得到180mg(94％)2-(s)-氰基-1-[N-(叔丁氧基羰基)异亮氨酰基]吡咯烷的无色油状物。1H NMR(CDCl3)，δ(ppm)；5.14(1H，d，J＝9.2Hz)；4.80(1H，dd，J＝2.6，7.1Hz)；4.22(1H，dd，J＝7.9，9.1Hz)；3.81(1H，m)，3.71(1H，m)，2.30-2.12(4H，m)；1.75(1H，m)；1.60(1H，m)；1.42(9H，s)；1.19(1H，m)；0.97(3H，d，J＝6.9Hz)；0.91(3H，t，J＝7.3Hz).13C NMR(CDCl3)，δ(ppm)；171.7，155.6，118.0，79.6，56.0，46.5，46.0，37.8，29.6，28.1，25.0，24.2，15.2，10.9.
通过与三氟乙酸一起搅拌60分钟进行脱保护。从水中蒸发并冷冻干燥，得到60mg 2-(s)-氰基-1-异亮氨酰基吡咯烷(11)的白色蓬松固体。
FAB质谱：计算值209.3，实测值(M＋H)+＝210.2。1H NMR(D2O)，δ(ppm)；4.3(1H，m)；3.64(1H，d，J＝5.6Hz)；3.16(2H，m)；1.86-1.48(5H，m)；0.98(1H，m)；0.68(1H，m)；0.51(3H，d，J＝6.9Hz)；0.38(3H，t，J＝7.3Hz).13NMR(D2O)，δ(ppm)；1697，119.7，57.3，48.6，48.1，36.9，30.2，25.8，24.5，15.4，11.5.实施例2  H-Glu[NH(CH2)7CONH(CH2)3NHZ]吡咯烷酰胺(64)
Figure C9419478200481
将二异丙基乙胺加入BocGlu(OH)吡咯烷酰胺(Pyrrolidide)(193mg，0.64mmol)和PyBop(500mg，0.96mmol)在CH2Cl2(6cm3)的溶液中，将混合物的PH调至9。搅拌5分钟后，加入8-氨基-辛酸苄酯(220mg，0.77mmol)在CH2Cl2(5cm3)中的溶液。在室温下，将混合物搅拌16小时。按实施例1所述的标准方法处理反应混合物。将粗品残渣进行柱层析(1％-3％甲醇/乙酸乙酯)，得到344mg(99％)BocGlu[NH(CH2)7CO2Bn]吡咯烷酰胺的无色固体。1H NMR(CDCl3)，δ(ppm)；7.35(5H，s)；6.63(1H，br.t，J＝6.7Hz)；5.65(1H，d，J＝8.3Hz)；5.11(2H，s)；4.36(1H，dt，J＝2.6，8.9Hz)；3.55-3.20(6H，m)；2.34(2H，t，J＝7.3Hz)；2.26(2H，dd，J＝5.6，7.3Hz)；2.11-1.48(10H，m)；1.43(9H，s)；1.32-
1.27(6H，m).
将氢气泡通入BocGlu[NH(CH2)7CO2Bn]吡咯烷酰胺(230mg，0.43mmol)在含10％钯/碳(50mg)的乙酸乙酯(10cm3)中的溶液中。90分钟后，用氮气冲洗反应容器，将溶液通过硅藻土层过滤并将溶剂蒸发，得到187mg(98％)的BocGlu[NH(CH2)7CO2H]吡咯烷酰胺的无色油状物。
将二异丙基乙胺加入BocGlu[NH(CH2)7CO2H]吡咯烷酰胺(125mg，0.28mmol)和PyBop(221mg，0.43mmol)在CH2Cl2(10cm3)的溶液中，将溶液PH调至9。搅拌5分钟后，一次加入ZNH(CH2)3NH2·HCl(90mg，0.37mmol)和二异丙基乙胺(38mg，0.37mmol)的溶液。将溶液搅拌18小时，然后按照实施例1所述的标准方法处理。将粗品残渣进行柱层析(2％-15％甲醇/乙酸乙酯)，得到151mg(85％)BocGlu[NH(CH2)7CONH(CH2)3NHZ]吡咯烷酰胺的无色油状物。1H NMR(CDCl3)，δ(ppm)；7.35(5H，s)；6.60(1H，br,t，J＝7 2Hz)；6.14(1H，br.t，J＝7.2Hz)；5.63(1H，d，J＝8.3Hz)；5.39(1H，br.t，J＝5.6Hz)；5.10(2H，s)；4.38(1H，dt，J＝2.3，9.2Hz)；3.52-3.13(10H，m)；2.26(2H，t，J＝6.9Hz)；2.17(2H，t，J＝7.6Hz)；1.98-1.48(12H，m)；1.44(9H，s)；1.38-1.23(6H，m).
将BocGlu[NH(CH2)7CONH(CH2)3NHZ]吡咯烷酰胺(14mg，0.022mmol)在4N HCl/二噁烷中的溶液搅拌45分钟。将溶剂蒸发并将残渣溶解在水中，过滤并冷冻干燥，得到13mg H-Glu[NH(CH2)7CONH(CH2)3NHZ]吡咯烷酰胺(64)的无色油状物。
FAB质谱：计算值531.3，实测值(M＋H)+＝532.3。实施例3  H-Lys[CO(CH2)3NHSO2Pfp]吡咯烷酰胺(110)
Figure C9419478200501
将ZNH(CH2)3CO2NSu(570mg，1.7mmol)一次加入1-[N-(叔丁氧基羰基)赖氨酰基]吡咯烷(745mg，2.2mmol)在无水CH2Cl2的溶液中。用二异丙基乙胺将PH调至9并将混合物搅拌60分钟。将溶剂蒸发并按实施例1所述的标准方法将残渣处理。柱层析(100％乙酸乙酯-15％甲醇/乙酸乙酯)，得到620mg(68％)BocLys[CO(CH2)3NHZ]吡咯烷酰胺。1H NMR(CDCl3)，δ(ppm)；7.42(5H，s)；6.31(1H，br.t，J＝6.5Hz)；5.58(1H，d，J＝8.9Hz)；5.39(1H，br.t，J＝6.9Hz)；5.17(2H，s)；4.44(1H，m)；3.72-3.20(8H，m)；2.29(2H，t，J＝7.3Hz)；2.14-1.83(8H，m)；1.78-1.41(4H，m)；1.43(9H，s).
将氢气泡通入BocLys[CO(CH2)3NHZ]吡咯烷酰胺(620mg，1.16mmol)和含1分子当量2NHCl的10％钯/碳的甲醇液(10cm3)的混合物中。60分钟后，用氮气冲洗反应混合物并通过硅藻土过滤。将溶剂蒸发得到282mg(49％)BocLys[CO(CH2)3NH2，HCl]吡咯烷酰胺。在氮气氛下，将该产物溶解在CH2Cl2(10cm3)中并搅拌。在引入全氟苯磺酰氯(45mg，0.17mmol)之前，加入二异丙基乙胺，将PH调至9。将该混合物搅拌16小时。蒸发溶剂并按实施例1所述的标准方法将粗品处理。柱层析(100％乙酸乙酯-10％甲醇/乙酸乙酯)，得到33mg(31％)BocLys[CO(CH2)3NHSO2Pfp]吡咯烷酰胺的无色油状物。1H NMR(CDCl3)；δ(ppm)；7.19(1H，br.t，J＝6.3Hz)；6.18(1H，br.t，J＝6.6Hz)；5.50(1H，d，J＝8.4Hz)；4.38(1H，m)；3.65-3.16(8H，m)；2.36(2H，t，J＝6.8Hz)；2.01-1.82(8H，m)；1.69-1.41(4H，m)；1.43(9H，s).
用三氟乙酸(10cm3)将该产品搅拌30分钟。将溶剂蒸发并将粗品溶解在水中，过滤并冷冻干燥，得到30mg H-Lys[CO(CH2)3NHSO2Pfp]Prl(110)的无色油状物。
FAB质谱：计算值514.2；实测值(M＋H)+＝515.2。实施例4  H-Thr[(CH2)5CH3]吡咯烷酰胺(143)
Figure C9419478200511
在氮气氛下，将吡咯烷(0.88g，12.4mmol)加入BocThrONSu(3.0g，9.5mmol)在无水CH2Cl2(30cm3)的溶液中。在室温下，将反应物搅拌60分钟。将溶剂蒸发并按实施例1所述的标准方法将残渣处理。将残渣进行柱层析(己烷∶乙酸乙酯，30∶70)，得到2.50g(96％)1-[N-(叔丁氧基羰基)苏氨酰基]吡咯烷的无色油状物。1H NMR(CDCl3)，δ(ppm)；5.52(1H，d，J＝6.5Hz)；4.30(1H，d，J＝7.4Hz)；4.16(2H，m)；3.72(1H，m)；3.46(3H，m)；1.98-1.82(4H，m)；1.43(9H，s)；1.19(3H，d，J＝7.1Hz).
在0℃、氮气氛下，将氢化钠(17mg，0.70mmol)加入1-[N-(叔丁氧基羰基)苏氨酰基]吡咯烷在无水THF的溶液中。在引入正己基碘(200mg，0.94mmol)之前，在0℃下将混合物搅拌15分钟。然后在室温下，将反应物搅拌16小时。将溶剂蒸发并按实施例1所述的标准方法将残渣处理。将粗品进行柱层析(己烷∶乙酸乙酯，40∶60)，得到25mg(10％)BocThr[CH2)5CH3]吡咯烷酰胺(143)。1H NMR(CDCl3)，δ(ppm)；5.50(1H，d，J＝6.9Hz)；4.48(1H，m)；3.70-3.32(7H，m)；1.92-1.80(6H，m)；1.52(2H，m)；1.42(9H，s)；1.30(6H，m)；1.22(8H，d，J＝6.9Hz)；0.83(3H，t，J＝7.9Hz).
将BocThr[(CH2)5CH3]吡咯烷酰胺(20mg，0.06mmol)在4NHCl/二噁烷(5cm3)中搅拌60分钟。将溶剂蒸发，将残渣溶解在水中，过滤并冷冻干燥，得到H-Thr[(CH2)5CH3]吡咯烷酰胺(20mg)的橙色油状物。通过反相HPLC将产物纯化，得到15mg(143)的无色油状物。
FAB质谱：计算值：256.2，实测值(M＋H)+＝257.3。实施例5  H-Ile-_[CH＝CH]吡咯烷酰胺(149)
在氮气氛下，保持温度在-30℃下，将1.6N正丁基锂(0.50cm3，0.76mmol)加到搅拌的环戊基三苯基溴化鏻(287mg，0.69mmol)在无水THF(6cm3)的溶液中。搅拌60分钟后，将溶液进一步冷却至-50℃，然后滴加N-(叔丁氧基羰基)-L-异亮氨醛(isoleucinal)(125mg，0.58mmol，按Fehrentz and Castro，Synthe-sis，1983，676中的方法制备)在无水THF(4cm3)中的溶液。滴加结束后，反应物经过3.5小时慢慢升至室温。
用饱和氯化铵溶液(2cm3)终止反应。用水(10cm3)将反应物稀释并用***(3×20cm3)萃取。将合并的***层用水(10cm3)洗涤，干燥(Na2SO4)并蒸发，得到187mg(＞100％)粗品，柱层析(90∶10，己烷∶Et2O)得到53mg(34％)Boc-ILe-_[CH＝CH]吡咯烷酰胺的无色油状物。1H NMR(CDCl3)，δ(ppm)；0.84(3H，t，J＝6.9Hz)；0.91(3H，d，J＝7.3Hz)；1.08(1H，m)；1.44(9H，s)；1.48(1H，m)；1.64(5H，m)；2.24-2.45(4H，m)；4.08(1H，br，s)；4.41(1H，br，s)；5.12(1H，dt，J＝2.3，8.9Hz).13C NMR(CDC13)δ(ppm)；155.8，147.4，119.1，79.2，54.8，40.1，34.2，29.6，28.9，26.8，26.6，26.1，15.0，12.1.
  用4N HCl/二噁烷将该产物处理35分钟，除去Boc-保护基。将反应物蒸发，将残渣溶解在水中，过滤并冷冻干燥，得到24mg(63％)H-ILe-_[CH＝CH]吡咯烷酰胺(149)的泡沫状固体。
FAB质谱：计算值：167.2，实测值(M＋H)+＝168.2。
实施例6和7：
H-ILe[(2R)-氰基-_(CH＝CH)吡咯烷酰胺(150)
H-ILe[(2S)-氰基-_(CH＝CH)吡咯烷酰胺(151)
在氮气氛下，在甲苯中将N-(叔-丁氧基羧基)-L-异亮氨醛(2.40g，11.2mmol)和2-氧-1-三苯基正膦环戊烷(4.61g，13.4mmol，按H.O.House and H.Babed，J.Org.Chem.，1963，28，90中所述的方法制备)加热回流。15小时后，将混合物冷却，并将溶剂蒸发。将粗品残渣进行柱层析(80∶20，己烷∶乙酸乙酯)，得到2.33g(74％)BocIle-_[CH＝CH]吡咯烷-2-酮的无色油状物。1H NMR(CDCl3)，δ(ppm)；6.29(1H，dt，J＝2.6，9.2Hz)；4.59(1H，br，d)；4.17(1H，m)，2.82(1H，m)；2.66-2.50(2H，m)；2.34(2H，t，J＝7.8Hz)；1.96(2H，q，J＝7.6Hz)；1.44(1H，m)；1.43(9H，s)；1.12(1H，m)，0.89(3H，d，J＝5.3Hz)；0.88(3H，t，J＝6.9Hz).
在氮气氛下，将二乙基氰基膦酰基乙酸酯(0.30cm3，1.92mmol)加入BocIle-_[CH＝CH]吡咯烷-2-酮(180mg，0.64mmol)和LiCN(0.5M DMF液，3.84cm3，1.92mmol)在无水DMF(2cm3)的溶液中。在室温下将反应物搅拌30分钟。用水(20cm3)将混合物稀释，然后用乙酸乙酯(2×30cm3)萃取。用水(5×10cm3)洗涤合并的有机层，干燥(Na2SO4)并蒸发，得到360mg(＞100％)粗品。将部分该粗品氰基膦酸酯(284mg，0.64mmol)溶解在无水THF中，并在氮气下搅拌。加入叔丁醇(47mg，0.64mmol)再滴加碘化钐(II)(0.1M的THF液，19.2cm3，1.92mmol)。滴加结束后，在加入2N HCl(20cm3)之前，再进一步将反应物搅拌30分钟。用***(3×30cm3)萃取混合物。用10％Na2S2O3溶液(10cm3)、水(2×10cm3)和盐水(2×10cm3)洗涤合并的***层。将溶液干燥(Na2So4)，蒸发并将粗品残渣进行柱层析(90∶10，己烷∶乙酸己脂)，得到122mg(66％)BocILe[2-(RS)-氰基-_(CH＝CH)吡咯烷]非对映体混合物的无色油状物。
1H NMR(CDCl3)，δ(ppm)；5.52(1H，d，J＝9.6Hz)；4.5(1H，br.s)；4.12(1H，m)；
3.35(1H，m)；2.57(1H，m)；2.38(1H，m)；2.17(1H，m)；1.91(2H，m)；1.69(2H，m)；
1.53(1H，m)；1.43(9H，s)；1.12(1H，m)；0.92(1.5H，d，J＝7.3Hz)；0.91(1.5H，d，J
＝7.3Hz)；0.89(1.5H.d，J＝6.6Hz)；0.86(1.5H，t，J＝6.9Hz).
用4N HCl/二噁烷处理该非对映体混合物，除掉保护基。蒸发溶剂并接着将粗品进行反相HPLC得到两种纯的非对映体。
(150)，(47mg，60％)FAB质谱：计算值192.2，实测值(M＋H)+＝193.2
(151)，(28mg，36％)FAB质谱：计算值192.2，实测值(M＋H)+＝193.2
本文参照表1-8和实施例1-7所描述的制备方法构成本发明的一部分。
               缩写
Boc            叔丁氧基羰基
Bn             苄基
BSA            牛血清白蛋白
nBu           正丁基
Ch             环己基
DMF            二甲基甲酰胺
DMP            Dess-Martin Periodane
EDTA           乙二胺四乙酸
FAB            快速原子轰击
Gua            胍基
HPLC           高效液相色谱
nHx           正己基
Mass Spec      质谱
mCPBA          间氯过苯甲酸
Mol Wt         分子量
ONSu           N-O-琥珀酰亚胺
Pfp            五氟苯基
Ph             苯基
Pip            哌啶基Prl              吡咯烷酰胺Py               吡淀PyBop            苯并***-1-基-氧基-三-
             吡咯烷基-鏻的六氟磷酸盐WSCD             水溶性碳化二亚胺Z                苄氧基羰基

Claims (7)

1.选自下列通式的DP-IV介导过程的抑制剂，A-B(组I)其中B为
Figure C9419478200021
n＝1或2；
m＝0，1或2；
X＝CH2，O，S，SO或SO2；
-Y＝-N；
R＝H，CN，CHO或B(OH)2；并且
(a)当R为H时，A为带有4-10个碳原子的环状脂肪族侧链的α-氨酰基或者为下列通式的β-氨酰基其中p为1-6，在任一情况下，环上可任意含有不饱和键和/或杂原子取代；
(b)当R＝CN时，A如(a)中定义并且可以是衍生自异亮氨酸或叔丁基甘氨酸的氨基酰基；
(c)并且当R＝CHO或B(OH)2时，A为(a)中所定义的β-氨酰基。
2.权利要求1的抑制剂，其中B为5元环，n为1；X为CH2或S；并且R为CN。
3.选自下列通式的DP-IV介导过程的抑制剂，A-B(组II)
其中B为
Figure C9419478200031
n＝1或2；
m＝0，1或2；
X＝CH2，O，S，SO或SO2；
-Y＝-N，
R＝H或CN；A与Y连接；并且A为
Figure C9419478200032
其中a＝1-5；
D＝-G-(CH2)b-(R4)q-R3；
G＝NH或NMe；
b＝1-12；q＝0或1；
R4＝Z-NH-(CH2)c-或NH-Z-(CH2)c-，其中c＝1-12，并且Z＝CO或CH2；R3＝CO2H或其酯，CONH2，CONR5R6，SO2NH2，SO2NR5R6，OH，OR5，最多1 1个原子的芳基，NH2，NR5R6，-NHCOR5，NH-SO2R5，NH-CH(：NR5)NR5R6，并且R5和R6独立地选自H和1-6个碳原子的低级烷基和氟烷基或者R5和R6可与它们连结的氮原子一起包含一个链(C3-C8)；或者A为(ii)
Figure C9419478200041
其中R1＝H或Me，E＝J-(CH2)b-(R4)q-R3，J＝CO，并且a，b，q，R3和R4如(i)中定义；或者A为(iii)
Figure C9419478200042
其中R2＝H或Me，L为(CH2)d-[CO]r-(CH2)b-(R4)q-R3，其中r为1，d＝1-4，并且b，q，R3和R4如(i)中定义。
4.根据权利要求1的DP-IV介导过程的抑制剂，其选自：N-(环戊基甘氨酰)吡咯烷，N-(L-环己基甘氨酰)吡咯烷，N-(L-环己-3-烯基甘氨酰)吡咯烷，N-(顺-2-氨基环己基羰基)吡咯烷，N-(反-2-氨基环己基羰基)吡咯烷，N-(反-2-氨基环己-4-烯基羰基)吡咯烷，N-(反-2-氨基环戊基羰基)吡咯烷，N-(反-2-氨基环辛基羰基)吡咯烷，N-异亮氨酰-L-脯氨甲腈，L-(N-苄氧羰基赖氨酰)-L-脯氨甲腈，L-脯氨酰-L-脯氨甲腈，L-4-硫杂脯氨酰-L-脯氨甲腈，3-硫杂脯氨酰-L-脯氨甲腈，L-环己基甘氨酰-L-脯氨甲腈，L-环戊基甘氨酰-L-脯氨甲腈，L-叔丁基甘氨酰-L-脯氨甲腈，L-异亮氨酰-L-4-硫杂脯氨甲腈，L-异亮氨酰-3-硫杂脯氨甲腈，L-环己基甘氨酰-L-4-硫杂脯氨甲腈，L-(N-苄氧羰基赖氨酰)-L-4-硫杂脯氨甲腈，L-异亮氨酰-L-4-氧杂脯氨甲腈，N-(L-异亮氨酰)吡啶甲腈，N-(L-异亮氨酰)-5-硫杂吡啶甲腈，L-异亮氨酰-L-4-硫杂脯氨甲腈-S，S-二氧化，L-异亮氨酰-L-4-硫杂脯氨甲腈-S-氧化，N-(1S，2S-2-氨基环己基羰基)-L-脯氨甲腈，N-(1R，2R-2-氨基环己基羰基)-L-脯氨甲腈，N-(1S，2S-2-氨基环戊基羰基)-L-脯氨甲腈，N-(1R，2R-2-氨基环戊基羰基)-L-脯氨甲腈，N-(1S，2S-2-氨基环己-4-烯基羰基)-L-脯氨甲腈，N-(1R，2R-2-氨基环己-4-烯基羰基)-L-脯氨甲腈，N-(1S，2R-2-氨基环己基羰基)-L-脯氨甲腈，N-(1S，2R-2-氨基环己-4-烯基羰基)-L-脯氨甲腈，N-(反-2-氨基环己基羰基)-L-脯氨甲醛，N-(1S，2S-2-氨基环戊基羰基)-L-脯氨甲醛，N-(1R，2R-2-氨基环戊基羰基)-L-脯氨甲醛，N-(反-2-氨基环戊基羰基)吡咯烷-2-硼酸，N-(1S，2S-2-氨基环己基羰基)吡咯烷-2-硼酸，N-(1R，2R-2-氨基环己基羰基)吡咯烷-2-硼酸，N-(1S，2S-2-氨基环己-4-烯基羰基)吡咯烷-2-硼酸，N-(1R，2R-2-氨基环己-4-烯基羰基)吡咯烷-2-硼酸，及其立体异构体。
5.根据权利要求3的DP-IV介导过程的抑制剂，其选自：N-(Nω-(苄氧羰基甲基)天冬酰胺酰)吡咯烷，N-(Nω-(羧甲基)天冬酰胺酰)吡咯烷，N-(Nω-(3-羧丙基)天冬酰胺酰)吡咯烷，N-(Nω-(2-(苄氧羰基)乙基)天冬酰胺酰)吡咯烷，N-(Nω-(2-羧乙基)天冬酰胺酰)吡咯烷，N-(Nω-(5-(苄氧羰基)戊基)天冬酰胺酰)吡咯烷，N-(Nω-(5-(羧戊基)天冬酰胺酰)吡咯烷，N-(Nω-(3-(苄氧羰基)丙基)天冬酰胺酰)吡咯烷，N-(Nω-(苄氧羰基甲基)谷氨酰胺酰)吡咯烷，N-(Nω-(羧甲基)谷氨酰胺酰)吡咯烷，N-(Nω-(2-(苄氧羰基)乙基)谷氨酰胺酰)吡咯烷，N-(Nω-(3-(苄氧羰基)丙基)谷氨酰胺酰)吡咯烷，N-(Nω-(3-羧丙基)谷氨酰胺酰)吡咯烷，N-(Nω-(5-(苄氧羰基)戊基)谷氨酰胺酰)吡咯烷，N-(Nω-(5-羧戊基)谷氨酰胺酰)吡咯烷，N-(Nω-(2-羧乙基)谷氨酰胺酰)吡咯烷，N-(Nω-(7-(苄氧羰基)庚基)谷氨酰胺酰)吡咯烷，N-(Nω-(7-羧庚基)谷氨酰胺酰)吡咯烷，N-(Nω-(7-(3-(苄氧羰基氨基)丙基氨基羰基)庚基)谷氨酰胺酰)吡咯烷，N-(Nω-(6-(5-(苄氧羰基)戊基氨基羰基)己基)谷氨酰胺酰)吡咯烷，N-(Nω-(6-(5-羧戊基氨基羰基)己基)谷氨酰胺酰)吡咯烷，N-(Nω-(7-(3-氨基丙基氨基羰基)庚基)谷氨酰胺酰)吡咯烷，N-(Nω-(11-(苄氧羰基)十一烷基)谷氨酰胺酰)吡咯烷，N-(Nω-(11-羧基十一烷基)谷氨酰胺酰)吡咯烷，N-(Nω-(6-(苄氧羰基)己基)谷氨酰胺酰)吡咯烷，N-(Nω-(6-羧己基)谷氨酰胺酰)吡咯烷，N-(Nω-(5-(2，2，2-三氟乙基氨基羰基)戊基)谷氨酰胺酰)吡咯烷，N-(Nω-(5-(2，2，3，3，4，4，4-七氟丁基氨基羰基)戊基)谷氨酰胺酰)吡咯烷，N-(Nω-(5-(6-羟基己基氨基羰基)戊基)谷氨酰胺酰)吡咯烷，N-(Nω-(5-(3-苯基丙基氨基羰基)戊基)谷氨酰胺酰)吡咯烷，N-(Nω-(5-(4-苯基丁基氨基羰基)戊基)谷氨酰胺酰)吡咯烷，N-(Nω-(5-(二丁基氨基羰基)戊基)谷氨酰胺酰)吡咯烷，N-(Nω-(5-(二己基氨基羰基)戊基)谷氨酰胺酰)吡咯烷，N-(Nω-(5-(二苄基氨基羰基)戊基)谷氨酰胺酰)吡咯烷，N-(Nω-(4-(苄氧羰基)丁基)谷氨酰胺酰)吡咯烷，N-(Nω-(4-羧丁基)谷氨酰胺酰)吡咯烷，N-(Nω-(5-(乙基氨基羰基)戊基)谷氨酰胺酰)吡咯烷，N-(Nω-(6-羟基己基)谷氨酰胺酰)吡咯烷，N-(Nω-(5-(哌啶-1-羰基)戊基)谷氨酰胺酰)吡咯烷，N-(Nω-(5-氨基甲酰基戊基)谷氨酰胺酰)吡咯烷，N-(Nω-(5-(癸基氨基羰基)戊基)谷氨酰胺酰)吡咯烷，N-(Nω-(5-(庚基氨基羰基)戊基)谷氨酰胺酰)吡咯烷，N-(Nω-(5-(环己基甲基氨基羰基)戊基)谷氨酰胺酰)吡咯烷，N-(Nω-(5-(3-(苄氧羰基氨基)丙基氨基羰基)戊基)谷氨酰胺酰)吡咯烷，N-(Nω-(5-(3-氨基丙基氨基羰基)戊基)谷氨酰胺酰)吡咯烷，N-(Nω-(5-(3-胍基丙基氨基羰基)戊基)谷氨酰胺酰)吡咯烷，N-(Nω-(5-(4-磺基苯基氨基羰基)戊基)谷氨酰胺酰)吡咯烷，N-(Nω-(5-(1-苄基哌啶-4-基氨基羰基)戊基)谷氨酰胺酰)吡咯烷，N-(Nω-(5-(哌啶-4-基氨基羰基)戊基)谷氨酰胺酰)吡咯烷，N-(Nω-(4-(N-苄氧羰基-N-(3-苄氧羰基氨基丙基)氨基羰基)丁基)谷氨酰胺酰)吡咯烷，N-(Nω-(4-(3-氨基丙基氨基羰基)丁基)谷氨酰胺酰)吡咯烷，N-(Nω-(5-(苄氧羰基)戊基)谷氨酰胺酰)脯氨甲腈，N-(Nω-(6-(5-(苄氧羰基)戊基氨基羰基)己基)高谷氨酰胺酰)吡咯烷，N-(Nω-(6-(5-羧戊基氨基羰基)己基)高谷氨酰胺酰)吡咯烷，N-(Nω-(5-(苄氧羰基)戊基)高谷氨酰胺酰)吡咯烷，N-(Nω-(5-羧戊基)高谷氨酰胺酰)吡咯烷，(3S)-3-氨基-N-(5-羧戊基)-4-氧代-4-(1-吡咯烷基)丁磺酰胺，N-(Nω-(8-(葡糖胺基硫代羰基氨基)辛基)谷氨酰胺酰)吡咯烷，N-((2S)-2-氨基-3-(7-羧庚酰基氨基)丙酰基)吡咯烷，N-((2S)-2-氨基-3-(7-(苄氧羰基)庚酰基氨基)丙酰基)吡咯烷，N-(Nω-(5-羧戊酰基)鸟氨酰)吡咯烷，N-(Nω-(5-(甲氧羰基)戊酰基)鸟氨酰)吡咯烷，N-(Nω-(6-氨基己酰基)赖氨酰)吡咯烷，N-(Nω-(4-氨基丁酰基)赖氨酰)吡咯烷，N-(Nω-(4-(五氟苯磺酰氨基)丁酰基)赖氨酰)吡咯烷，N-(Nω-(4-(五氟苯甲酰氨基)丁酰基)赖氨酰)吡咯烷，N-(Nω-(4-(2，2，2-三氟乙磺酰氨基)丁酰基)赖氨酰)吡咯烷，N-(Nω-(12-(7-(苄氧羰基氨基)庚酰氨基)十二烷酰基)赖氨酰)吡咯烷，N-(Nω-(12-(7-氨基庚酰氨基)十二烷酰基)赖氨酰)吡咯烷，N-(Nω-(6-(6-(6-(苄氧羰基氨基)己酰氨基)己酰氨基)己酰基)赖氨酰)吡咯烷，N-(Nω-(6-(6-(6-氨基己酰氨基)己酰氨基)己酰基)赖氨酰)吡咯烷，N-(Nω-(4-羧丁酰基)赖氨酰)吡咯烷，N-(Nω-(4-(苄氧羰基)丁酰基)赖氨酰)吡咯烷，N-(Nω-(7-氨基庚酰基)赖氨酰)吡咯烷，N-(Nω-(8-氨基辛酰基)赖氨酰)吡咯烷，N-(Nω-十八烷酰基赖氨酰)吡咯烷，N-(Nω-(7-胍基庚酰基)赖氨酰)吡咯烷，N-(Nω-辛磺酰基赖氨酰)吡咯烷，N-(Nω-(12-氨基十二烷酰基)赖氨酰)吡咯烷，N-(Nω-(2-(苄氧羰基氨基)乙酰基)赖氨酰)吡咯烷，N-(Nω-(3-(苄氧羰基氨基)丙酰基)赖氨酰)吡咯烷，N-(Nω-(4-(苄氧羰基氨基)丁酰基)赖氨酰)吡咯烷，N-(Nω-(3-氨基丙酰基)赖氨酰)吡咯烷，N-(Nω-(6-(苄氧羰基氨基)己酰基)赖氨酰)吡咯烷，N-(Nω-(2-胍基乙酰基)赖氨酰)吡咯烷，N-(Nω-(3-氨基丙酰基)赖氨酰)吡咯烷，N-(Nω-(3-胍基丙酰基)赖氨酰)吡咯烷，N-(Nω-(4-胍基丁酰基)赖氨酰)吡咯烷，N-(Nω-(6-胍基己酰基)赖氨酰)吡咯烷，N-(Nω-(7-氨基庚酰基)赖氨酰)脯氨甲腈，N-(Nω-(8-氨基辛酰基)赖氨酰)脯氨甲腈，N-(O-(2-(5-羧戊基氨基)-2-氧代乙基)丝氨酰)吡咯烷，N-(O-(2-(5-(苄氧羰基)戊基氨基)-2-氧代乙基)丝氨酰)吡咯烷，N-(O-(2-(4-(苄氧羰基)丁基氨基)-2-氧代乙基)丝氨酰)吡咯烷，N-(O-(2-(4-羧丁基氨基)-2-氧代乙基)丝氨酰)吡咯烷，N-(O-甲基苏氨酰)吡咯烷，N-(O-乙基苏氨酰)吡咯烷，N-(O-己基苏氨酰)吡咯烷，N-(O-(2-(5-羧戊基氨基)-2-氧代乙基)苏氨酰)吡咯烷，N-(O-(2-(5-(苄氧羰基)戊基氨基)-2-氧代乙基)苏氨酰)吡咯烷，N-(O-(2-(4-(苄氧羰基)丁基氨基)-2-氧代乙基)苏氨酰)吡咯烷，和N-(O-(2-(4-羧丁基氨基)-2-氧代乙基)苏氨酰)吡咯烷。
6.权利要求1-5中任一项的化合物在制备抑制DP-IV介导过程的药物中的应用。
7.含DP-IV抑制量的权利要求1-5中任何一项化合物的药物组合物。
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Families Citing this family (254)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6825169B1 (en) 1991-10-22 2004-11-30 Trustees Of Tufts College Inhibitors of dipeptidyl-aminopeptidase type IV
EP0764151A2 (en) * 1994-06-10 1997-03-26 Universitaire Instelling Antwerpen Purification of serine protease and synthetic inhibitors thereof
US20020006899A1 (en) * 1998-10-06 2002-01-17 Pospisilik Andrew J. Use of dipeptidyl peptidase IV effectors for lowering blood pressure in mammals
DE19616486C5 (de) 1996-04-25 2016-06-30 Royalty Pharma Collection Trust Verfahren zur Senkung des Blutglukosespiegels in Säugern
US5965532A (en) 1996-06-28 1999-10-12 Trustees Of Tufts College Multivalent compounds for crosslinking receptors and uses thereof
US6011155A (en) * 1996-11-07 2000-01-04 Novartis Ag N-(substituted glycyl)-2-cyanopyrrolidines, pharmaceutical compositions containing them and their use in inhibiting dipeptidyl peptidase-IV
US6100234A (en) 1997-05-07 2000-08-08 Tufts University Treatment of HIV
US6040145A (en) 1997-05-07 2000-03-21 Tufts University Potentiation of the immune response
KR100458403B1 (ko) 1997-09-29 2004-11-26 포인트 써러퓨틱스, 인크. 생체외 조혈세포의 자극방법
JP2002501889A (ja) * 1998-02-02 2002-01-22 トラスティーズ オブ タフツ カレッジ グルコース代謝を調節する方法、およびそれに関連する試薬
BR9910251A (pt) 1998-05-04 2001-01-02 Point Therapeutics Inc Estimulação hematopoiética
DE19823831A1 (de) * 1998-05-28 1999-12-02 Probiodrug Ges Fuer Arzneim Neue pharmazeutische Verwendung von Isoleucyl Thiazolidid und seinen Salzen
AU765370B2 (en) 1998-06-05 2003-09-18 Point Therapeutics, Inc. Cyclic boroproline compounds
DE19826972A1 (de) * 1998-06-18 1999-12-23 Univ Magdeburg Tech Verwendung von Enzyminhibitoren und pharmazeutische Zubereitung zur Therapie von dermatologischen Erkrankungen mit follikulären und epidermalen Hyperkeratosen und einer verstärkten Keratinozytenproliferation
DE19828114A1 (de) 1998-06-24 2000-01-27 Probiodrug Ges Fuer Arzneim Produgs instabiler Inhibitoren der Dipeptidyl Peptidase IV
DE19828113A1 (de) 1998-06-24 2000-01-05 Probiodrug Ges Fuer Arzneim Prodrugs von Inhibitoren der Dipeptidyl Peptidase IV
DE19834591A1 (de) 1998-07-31 2000-02-03 Probiodrug Ges Fuer Arzneim Verfahren zur Steigerung des Blutglukosespiegels in Säugern
US6979697B1 (en) 1998-08-21 2005-12-27 Point Therapeutics, Inc. Regulation of substrate activity
AU5480199A (en) * 1998-08-21 2000-03-14 Point Therapeutics, Inc. Regulation of substrate activity
US20030176357A1 (en) * 1998-10-06 2003-09-18 Pospisilik Andrew J. Dipeptidyl peptidase IV inhibitors and their uses for lowering blood pressure levels
CO5150173A1 (es) * 1998-12-10 2002-04-29 Novartis Ag Compuestos n-(glicilo sustituido)-2-cianopirrolidinas inhibidores de peptidasa de dipeptidilo-iv (dpp-iv) los cuales son efectivos en el tratamiento de condiciones mediadas por la inhibicion de dpp-iv
WO2000055125A2 (en) 1999-03-15 2000-09-21 Axys Pharmaceuticals, Inc. N-cyanomethyl amides as protease inhibitors
GB9906715D0 (en) * 1999-03-23 1999-05-19 Ferring Bv Compositions for promoting growth
GB9906714D0 (en) * 1999-03-23 1999-05-19 Ferring Bv Compositions for improving fertility
US6890904B1 (en) 1999-05-25 2005-05-10 Point Therapeutics, Inc. Anti-tumor agents
EP1806138A1 (en) * 1999-05-25 2007-07-11 Point Therapeutics, Inc. Anti-tumor agents comprising boroproline compounds
JP2003500360A (ja) * 1999-05-25 2003-01-07 ポイント セラピューティクス， インコーポレイテッド ボロプロリン化合物類を含む抗癌剤
DE19926233C1 (de) 1999-06-10 2000-10-19 Probiodrug Ges Fuer Arzneim Verfahren zur Herstellung von Thiazolidin
US6110949A (en) * 1999-06-24 2000-08-29 Novartis Ag N-(substituted glycyl)-4-cyanothiazolidines, pharmaceutical compositions containing them and their use in inhibiting dipeptidyl peptidase-IV
US6172081B1 (en) 1999-06-24 2001-01-09 Novartis Ag Tetrahydroisoquinoline 3-carboxamide derivatives
US6617340B1 (en) 1999-07-29 2003-09-09 Novartis Ag N-(substituted glycyl)-pyrrolidines, pharmaceutical compositions containing them and their use in inhibiting dipeptidyl peptidase-IV
DE19940130A1 (de) 1999-08-24 2001-03-01 Probiodrug Ges Fuer Arzneim Neue Effektoren der Dipeptidyl Peptidase IV zur topischen Anwendung
JP2003535034A (ja) * 1999-11-12 2003-11-25 ギルフォード ファーマシューティカルズ インコーポレイテッド ジペプチジルペプチダーゼｉｖ阻害剤並びにジペプチジルペプチダーゼｉｖ阻害剤の製造及び使用法
US20040152745A1 (en) * 1999-11-12 2004-08-05 Guilford Pharmaceuticals, Inc. Dipeptidyl peptidase IV inhibitors and methods of making and using dipeptidyl peptidase IV inhibitors
GB9928330D0 (en) * 1999-11-30 2000-01-26 Ferring Bv Novel antidiabetic agents
JP2003520226A (ja) 2000-01-21 2003-07-02 ノバルティス アクチエンゲゼルシャフト ジペプチジルペプチダーゼ−ｉｖ阻害剤および抗糖尿病薬剤を含む組合せ物
JP2003523396A (ja) * 2000-02-25 2003-08-05 ノボ ノルディスク アクティーゼルスカブ ベータ細胞変性の抑制
US6395767B2 (en) 2000-03-10 2002-05-28 Bristol-Myers Squibb Company Cyclopropyl-fused pyrrolidine-based inhibitors of dipeptidyl peptidase IV and method
DK1283735T4 (da) * 2000-03-31 2013-02-04 Royalty Pharma Collection Trust Fremgangsmåde til forbedring signalering af øceller ved diabetes mellitus og til forebyggelse deraf
GB0010183D0 (en) * 2000-04-26 2000-06-14 Ferring Bv Inhibitors of dipeptidyl peptidase IV
US6432969B1 (en) 2000-06-13 2002-08-13 Novartis Ag N-(substituted glycyl)-2 cyanopyrrolidines, pharmaceutical compositions containing them and their use in inhibiting dipeptidyl peptidase-IV
GB0014969D0 (en) 2000-06-19 2000-08-09 Smithkline Beecham Plc Novel method of treatment
ATE556048T1 (de) 2000-08-10 2012-05-15 Mitsubishi Tanabe Pharma Corp Prolinderivate und ihre verwendung als heilmittel
AR033390A1 (es) 2000-08-22 2003-12-17 Novartis Ag Una composicion farmaceutica que comprende un antagonista del receptor at1 y un potenciador de la secrecion de insulina, el uso de dicha composicion para la fabricacion de un medicamento y un kit de partes
AU1313802A (en) 2000-10-12 2002-04-22 Ferring Bv Novel serine protease genes related to dppiv
ZA200302394B (en) * 2000-10-27 2004-03-29 Probiodrug Ag Method for the treatment of neurological and neuropsychological disorders.
US7132104B1 (en) 2000-10-27 2006-11-07 Probiodrug Ag Modulation of central nervous system (CNS) dipeptidyl peptidase IV (DPIV) -like activity for the treatment of neurological and neuropsychological disorders
US6492521B2 (en) * 2000-11-03 2002-12-10 Cytec Technology Corp. Hindered amine light stabilizers based on multi-functional carbonyl compounds and methods of making same
TWI243162B (en) * 2000-11-10 2005-11-11 Taisho Pharmaceutical Co Ltd Cyanopyrrolidine derivatives
US7064123B1 (en) 2000-12-22 2006-06-20 Aventis Pharmaceuticals Inc. Compounds and compositions as cathepsin inhibitors
US7030116B2 (en) 2000-12-22 2006-04-18 Aventis Pharmaceuticals Inc. Compounds and compositions as cathepsin inhibitors
US7026316B2 (en) * 2001-03-27 2006-04-11 Merck & Co., Inc. Dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes
FR2822826B1 (fr) * 2001-03-28 2003-05-09 Servier Lab Nouveaux derives sulfonyles d'alpha-amino-acides, leur procede de preparation et les compositions pharmaceutiques qui les contiennent
US6890905B2 (en) 2001-04-02 2005-05-10 Prosidion Limited Methods for improving islet signaling in diabetes mellitus and for its prevention
GB0109146D0 (en) * 2001-04-11 2001-05-30 Ferring Bv Treatment of type 2 diabetes
FR2824825B1 (fr) * 2001-05-15 2005-05-06 Servier Lab Nouveaux derives d'alpha-amino-acides, leur procede de preparation et les compositions pharmaceutiques qui les contiennent
ATE318139T1 (de) * 2001-06-20 2006-03-15 Merck & Co Inc Dipeptidylpeptidase-hemmer zur behandlung von diabetes
CA2450579A1 (en) * 2001-06-20 2003-01-03 Merck & Co., Inc. Dipeptidyl peptidase inhibitors for the treatment of diabetes
GB0115517D0 (en) * 2001-06-25 2001-08-15 Ferring Bv Novel antidiabetic agents
DE60223920T2 (de) * 2001-06-27 2008-11-13 Smithkline Beecham Corp. Pyrrolidine als dipeptidyl-peptidase-inhibitoren
CN1321682C (zh) * 2001-06-27 2007-06-20 前体生物药物股份有限公司 新的二肽基肽酶iv抑制剂和它们作为抗癌药的用途
HUP0400321A2 (hu) 2001-06-27 2004-08-30 Smithkline Beecham Corp. Fluorpirrolidin-származékok mint dipeptidil-dipeptidáz inhibitorok és ezeket tartalmazó gyógyszerkészítmények
US20030130199A1 (en) 2001-06-27 2003-07-10 Von Hoersten Stephan Dipeptidyl peptidase IV inhibitors and their uses as anti-cancer agents
US20030135023A1 (en) * 2001-06-27 2003-07-17 Hans-Ulrich Demuth Peptide structures useful for competitive modulation of dipeptidyl peptidase IV catalysis
DE10150203A1 (de) 2001-10-12 2003-04-17 Probiodrug Ag Peptidylketone als Inhibitoren der DPIV
US7368421B2 (en) * 2001-06-27 2008-05-06 Probiodrug Ag Use of dipeptidyl peptidase IV inhibitors in the treatment of multiple sclerosis
UA74912C2 (en) * 2001-07-06 2006-02-15 Merck & Co Inc Beta-aminotetrahydroimidazo-(1,2-a)-pyrazines and tetratriazolo-(4,3-a)-pyrazines as inhibitors of dipeptylpeptidase for the treatment or prevention of diabetes
JP2005504766A (ja) * 2001-08-16 2005-02-17 プロバイオドラッグ アーゲー プロリンエンドペプチダーゼ阻害剤の、細胞内シグナルカスケード依存性イノシトール（１，４，５）トリホスフェート濃度調節への使用。
US6844316B2 (en) * 2001-09-06 2005-01-18 Probiodrug Ag Inhibitors of dipeptidyl peptidase I
WO2003024924A1 (en) 2001-09-14 2003-03-27 Aventis Pharmaceuticals Inc. Novel compounds and compositions as cathepsin inhibitors
KR20040033048A (ko) * 2001-09-14 2004-04-17 미츠비시 웰파마 가부시키가이샤 티아졸리딘 유도체 및 이의 약학적 용도
GB0125446D0 (en) * 2001-10-23 2001-12-12 Ferring Bv Novel anti-diabetic agents
JP2005507261A (ja) * 2001-10-31 2005-03-17 ノバルティス アクチエンゲゼルシャフト Ｔｃｆ１遺伝子における多型に基づく糖尿病および関連状態の治療方法
HUP0401906A3 (en) 2001-11-14 2008-07-28 Aventis Pharma Inc Novel cathepsin s inhibitors, process for their preparation and pharmaceutical compositions containing them
CA2837936A1 (en) 2001-11-26 2003-06-05 Trustees Of Tufts College Peptidomimetic inhibitors of post-proline cleaving enzymes
AU2002360453C1 (en) 2001-11-26 2009-06-18 The Brigham And Women's Hospital, Inc. Methods for treating autoimmune disorders, and reagents related thereto
WO2003057144A2 (en) * 2001-12-26 2003-07-17 Guilford Pharmaceuticals Change inhibitors of dipeptidyl peptidase iv
EP1695970A1 (en) * 2002-02-28 2006-08-30 Prosidion Limited Peptides useful for competitive modulation of dipeptidyl peptidase IV catalysis
SI1480961T1 (sl) 2002-02-28 2007-06-30 Prosidion Ltd Inhibitorji dpiv na osnovi glutaminila
CA2478389A1 (en) * 2002-03-25 2003-10-09 Merck & Co., Inc. Beta-amino heterocyclic dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes
US20030232761A1 (en) * 2002-03-28 2003-12-18 Hinke Simon A. Novel analogues of glucose-dependent insulinotropic polypeptide
KR20040105853A (ko) * 2002-04-08 2004-12-16 토렌트 파마슈티칼스 리미티드 티아졸리딘-4-카르보니트릴 및 유사체와디펩티딜-펩티다아제 억제제로서의 용도
US6710040B1 (en) 2002-06-04 2004-03-23 Pfizer Inc. Fluorinated cyclic amides as dipeptidyl peptidase IV inhibitors
EP1578434A2 (en) * 2002-07-09 2005-09-28 Point Therapeutics, Inc. Methods and compositions relating to isoleucine boroproline compounds
US7208498B2 (en) * 2002-07-15 2007-04-24 Merck & Co., Inc. Piperidino pyrimidine dipeptidyl peptidase inhibitors for the treatment of diabetes
US20040033051A1 (en) * 2002-08-16 2004-02-19 Ip Kiril Kun Wan Method and system for producing and displaying visual presentations which inhibit off-screen duplication
TW200404796A (en) * 2002-08-19 2004-04-01 Ono Pharmaceutical Co Nitrogen-containing compound
US20050176622A1 (en) * 2002-09-18 2005-08-11 Kerstin Kuhn-Wache Secondary binding site of dipeptidyl peptidase IV (DPIV)
US20040058876A1 (en) * 2002-09-18 2004-03-25 Torsten Hoffmann Secondary binding site of dipeptidyl peptidase IV (DP IV)
CA2499586A1 (en) * 2002-10-07 2004-04-22 Merck & Co., Inc. Antidiabetic beta-amino heterocyclic dipeptidyl peptidase inhibitors
CN100383129C (zh) * 2002-10-18 2008-04-23 默克公司 用于治疗或预防糖尿病的β-氨基杂环二肽酰肽酶抑制剂
JP4413863B2 (ja) * 2002-11-07 2010-02-10 メルク エンド カムパニー インコーポレーテッド 糖尿病の治療又は予防のためのジペチジルペプチダーゼ阻害剤としてのフェニルアラニン誘導体
JP2005170792A (ja) * 2002-11-22 2005-06-30 Mitsubishi Pharma Corp Ｌ−プロリン誘導体およびその医薬としての用途。
WO2004050022A2 (en) * 2002-12-04 2004-06-17 Merck & Co., Inc. Phenylalanine derivatives as dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes
US20060052382A1 (en) * 2002-12-20 2006-03-09 Duffy Joseph L 3-Amino-4-phenylbutanoic acid derivatives as dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes
US7265128B2 (en) * 2003-01-17 2007-09-04 Merck & Co., Inc. 3-amino-4-phenylbutanoic acid derivatives as dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes
US7388019B2 (en) * 2003-01-31 2008-06-17 Merck & Co., Inc. 3-amino-4-phenylbutanoic acid derivatives as dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes
US7345180B2 (en) 2003-01-31 2008-03-18 Sanwa Kagaku Kenkyusho Co., Ltd. Compound inhibiting dipeptidyl peptidase IV
EP1608317B1 (en) 2003-03-25 2012-09-26 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
CN101837127A (zh) 2003-05-05 2010-09-22 前体生物药物股份公司 谷氨酰胺酰基和谷氨酸环化酶效应物的应用
PL1620082T3 (pl) 2003-05-05 2010-10-29 Probiodrug Ag Medyczne zastosowanie inhibitorów cyklazy glutaminylowej i glutaminianowej do leczenia choroby Alzheimera i zespołu Downa
US20040229848A1 (en) * 2003-05-05 2004-11-18 Hans-Ulrich Demuth Glutaminyl based DP IV-inhibitors
US7371871B2 (en) 2003-05-05 2008-05-13 Probiodrug Ag Inhibitors of glutaminyl cyclase
US7638638B2 (en) 2003-05-14 2009-12-29 Takeda San Diego, Inc. Dipeptidyl peptidase inhibitors
DE602004023932D1 (de) * 2003-05-14 2009-12-17 Merck & Co Inc 3-amino-4-phenylbutansäurederivate als dipeptidylpeptidase-hemmer zur behandlung oder vorbeugung von diabetes
AU2004247068A1 (en) * 2003-06-06 2004-12-23 Merck & Co., Inc. Fused indoles as dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes
EP1638950A4 (en) * 2003-06-17 2010-06-30 Merck Sharp & Dohme CYCLOHEXYLGLYCIN DERIVATIVES AS INHIBITORS OF DIPEPTIDYL PEPTIDASE FOR THE TREATMENT OR PREVENTION OF DIABETES
DE10330842A1 (de) * 2003-07-08 2005-02-10 Institut für Medizintechnologie Magdeburg GmbH, IMTM Verwendung der Inhibitoren von Enzymen mit Aktivitäten der Aminopeptidase N und/oder der Dipeptidylpeptidase IV und pharmazeutischen Zubereitungen daraus zur Therapie und Prävention dermatologischer Erkrankungen mit Hyperproliferation und veränderten Differenzierungszuständen von Fibroblasten
CN1882551A (zh) * 2003-07-31 2006-12-20 麦克公司 用作用于治疗或预防糖尿病的二肽基肽酶－iv酶抑制剂的六氢二氮杂吖庚因酮
US6995183B2 (en) * 2003-08-01 2006-02-07 Bristol Myers Squibb Company Adamantylglycine-based inhibitors of dipeptidyl peptidase IV and methods
US7169926B1 (en) 2003-08-13 2007-01-30 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
US7470700B2 (en) 2003-08-13 2008-12-30 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
US7678909B1 (en) 2003-08-13 2010-03-16 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
US7205409B2 (en) 2003-09-04 2007-04-17 Abbott Laboratories Pharmaceutical compositions as inhibitors of dipeptidyl peptidase-IV (DPP-IV)
WO2005030751A2 (en) * 2003-09-08 2005-04-07 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
JP2007505121A (ja) 2003-09-08 2007-03-08 武田薬品工業株式会社 ジペプチジルぺプチダーゼ阻害剤
JP2007516154A (ja) * 2003-10-06 2007-06-21 トレント・ファーマシューティカルズ・リミテッド アゾリジンカーボニトリル類及びそれらのｄｐｐ−ｉｖ阻害剤としての用途
CN102302781A (zh) 2003-10-15 2012-01-04 前体生物药物股份公司 谷氨酰胺酰基环化酶效应物和谷氨酸环化酶效应物的应用
US20070123470A1 (en) * 2003-10-24 2007-05-31 Wladimir Hogenhuis Enhancement of growth hormone levels with a dipeptidyl peptidase IV inhibitor and a growth hormone secretagogue
US20100099721A1 (en) * 2003-11-03 2010-04-22 Probiodrug Ag Novel compounds for the treatment of neurological disorders
US20050171112A1 (en) * 2003-11-03 2005-08-04 Probiodrug Ag Combinations useful for the treatment of neuronal disorders
CA2544573A1 (en) 2003-11-03 2005-06-02 Probiodrug Ag Combinations useful for the treatment of neuronal disorders
CA2541212A1 (en) * 2003-11-04 2005-05-19 Wallace T. Ashton Fused phenylalanine derivatives as dipeptidyl peptidase-iv inhibitors for the treatment or prevention of diabetes
CN1894261B (zh) * 2003-11-12 2012-12-05 芬诺密克斯公司 杂环硼酸化合物
US7317109B2 (en) 2003-11-12 2008-01-08 Phenomix Corporation Pyrrolidine compounds and methods for selective inhibition of dipeptidyl peptidase-IV
US7767828B2 (en) 2003-11-12 2010-08-03 Phenomix Corporation Methyl and ethyl substituted pyrrolidine compounds and methods for selective inhibition of dipeptidyl peptidase-IV
US7576121B2 (en) 2003-11-12 2009-08-18 Phenomix Corporation Pyrrolidine compounds and methods for selective inhibition of dipeptidyl peptidase-IV
ES2524916T3 (es) 2003-11-12 2014-12-15 Sino-Med International Alliance, Inc. Compuestos heterocíclicos de ácido borónico
CN1905876B (zh) 2003-11-17 2010-06-09 诺瓦提斯公司 二肽基肽酶iv抑制剂的用途
EP1715893B8 (en) 2004-01-20 2009-12-16 Novartis Ag Direct compression formulation and process
US7230002B2 (en) * 2004-02-03 2007-06-12 Glenmark Pharmaceuticals Ltd. Dipeptidyl peptidase IV inhibitors; processes for their preparation and compositions thereof
CA2554809C (en) 2004-02-05 2014-04-29 Probiodrug Ag Novel n-alkyl thiourea- and thioamide-substituted imidazolyl inhibitors of glutaminyl cyclase
EP1712547B1 (en) 2004-02-05 2011-12-14 Kyorin Pharmaceutical Co., Ltd. Bicycloester derivative
WO2005077900A1 (ja) * 2004-02-18 2005-08-25 Kyorin Pharmaceutical Co., Ltd. ビシクロアミド誘導体
EP1719757B1 (en) * 2004-02-27 2013-10-09 Kyorin Pharmaceutical Co., Ltd. Bicyclo derivative
US7348346B2 (en) 2004-03-08 2008-03-25 Abbott Laboratories Pharmaceutical compositions as inhibitors of dipeptidyl peptidase-IV (DPP-IV)
US7732446B1 (en) 2004-03-11 2010-06-08 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
AU2004318013B8 (en) 2004-03-15 2011-10-06 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
CN1950349A (zh) * 2004-05-04 2007-04-18 默克公司 作为用于治疗或预防糖尿病的二肽基肽酶－ⅳ抑制剂的1,2,4－噁二唑衍生物
CA2564884A1 (en) * 2004-05-18 2005-12-08 Merck & Co., Inc. Cyclohexylalanine derivatives as dipeptidyl peptidase-iv inhibitors for the treatment or prevention of diabetes
JP2008501714A (ja) 2004-06-04 2008-01-24 武田薬品工業株式会社 ジペプチジルペプチダーゼインヒビター
US20110104186A1 (en) 2004-06-24 2011-05-05 Nicholas Valiante Small molecule immunopotentiators and assays for their detection
WO2006019965A2 (en) 2004-07-16 2006-02-23 Takeda San Diego, Inc. Dipeptidyl peptidase inhibitors
AU2005267093B2 (en) 2004-07-23 2009-10-01 Nuada Llc Peptidase inhibitors
PE20060652A1 (es) 2004-08-27 2006-08-11 Novartis Ag Composiciones farmaceuticas de liberacion inmediata que comprenden granulos de fusion
US20060063719A1 (en) * 2004-09-21 2006-03-23 Point Therapeutics, Inc. Methods for treating diabetes
EP1799639B1 (en) * 2004-10-12 2013-09-04 Glenmark Pharmaceuticals S.A. Novel dipeptidyl peptidase iv inhibitors, pharmaceutical compositions containing them, and process for their preparation
JP2008524331A (ja) * 2004-12-21 2008-07-10 武田薬品工業株式会社 ジペプチジルペプチダーゼ阻害剤
DOP2006000008A (es) 2005-01-10 2006-08-31 Arena Pharm Inc Terapia combinada para el tratamiento de la diabetes y afecciones relacionadas y para el tratamiento de afecciones que mejoran mediante un incremento de la concentración sanguínea de glp-1
CN102372704B (zh) 2005-02-18 2014-10-08 田边三菱制药株式会社 脯氨酸衍生物的盐，其溶剂合物，及其生产方法
CN101277949A (zh) 2005-04-22 2008-10-01 阿兰托斯制药控股公司 二肽基肽酶-ⅳ抑制剂
US7825139B2 (en) 2005-05-25 2010-11-02 Forest Laboratories Holdings Limited (BM) Compounds and methods for selective inhibition of dipeptidyl peptidase-IV
MY152185A (en) 2005-06-10 2014-08-29 Novartis Ag Modified release 1-[(3-hydroxy-adamant-1-ylamino)-acetyl]-pyrrolidine-2(s)-carbonitrile formulation
CN101232873A (zh) * 2005-08-11 2008-07-30 霍夫曼-拉罗奇有限公司 含有dpp-iv抑制剂的药物组合物
GT200600381A (es) 2005-08-25 2007-03-28 Compuestos organicos
PE20070622A1 (es) * 2005-09-14 2007-08-22 Takeda Pharmaceutical Administracion de inhibidores de dipeptidil peptidasa
US20070060528A1 (en) * 2005-09-14 2007-03-15 Christopher Ronald J Administration of dipeptidyl peptidase inhibitors
CA2622472C (en) * 2005-09-14 2013-11-19 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors for treating diabetes
TW200745079A (en) * 2005-09-16 2007-12-16 Takeda Pharmaceuticals Co Polymorphs of benzoate salt of 2-[[6-[(3R)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl]methyl]-benzonitrile and methods of use therefor
TW200745080A (en) * 2005-09-16 2007-12-16 Takeda Pharmaceuticals Co Polymorphs of tartrate salt of 2-[2-(3-(R)-amino-piperidin-1-yl)-5-fluoro-6-oxo-6H-pyrimidin-1-ylmethyl]-benzonitrile and methods of use therefor
CN101360723A (zh) 2005-09-16 2009-02-04 武田药品工业株式会社 制备嘧啶二酮衍生物的方法
US20100048450A1 (en) * 2005-10-07 2010-02-25 Klinken S Peter Sumoylation Control Agent and Uses Thereof
DE102005054700B4 (de) * 2005-11-16 2009-01-08 Imtm Gmbh Neue duale Peptidase-Inhibitoren als Prodrugs zur Therapie von entzündlichen und anderen Erkrankungen
CN101379069A (zh) * 2005-12-19 2009-03-04 塔夫茨大学信托人 软蛋白酶抑制剂及其前软形式
GB0526291D0 (en) 2005-12-23 2006-02-01 Prosidion Ltd Therapeutic method
EP1995237A4 (en) 2006-03-08 2011-07-06 Kyorin Seiyaku Kk PROCESS FOR PREPARING AN AMINOACETYLPYRROLIDINCARBONITRILE DERIVATIVE AND PRODUCTION PRODUCT THEREOF
JP2009536611A (ja) * 2006-03-28 2009-10-15 バイオファルミカ リミテッド ホルモン依存性障害の処置のための作用物質及びその使用
WO2007112368A1 (en) * 2006-03-28 2007-10-04 Takeda Pharmaceutical Company Limited Preparation of (r)-3-aminopiperidine dihydrochloride
WO2007112347A1 (en) 2006-03-28 2007-10-04 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
JP2009532038A (ja) * 2006-04-07 2009-09-10 バイオファルミカ リミテッド 転写因子モジュレーター
PE20071221A1 (es) 2006-04-11 2007-12-14 Arena Pharm Inc Agonistas del receptor gpr119 en metodos para aumentar la masa osea y para tratar la osteoporosis y otras afecciones caracterizadas por masa osea baja, y la terapia combinada relacionada a estos agonistas
EA200802054A1 (ru) 2006-04-12 2009-04-28 Пробиодруг Аг Ингибиторы фермента
US8324383B2 (en) 2006-09-13 2012-12-04 Takeda Pharmaceutical Company Limited Methods of making polymorphs of benzoate salt of 2-[[6-[(3R)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl]methyl]-benzonitrile
AU2007296556B2 (en) * 2006-09-13 2013-09-19 Takeda Pharmaceutical Company Limited Use of 2-6- (3-Amino-piperidin-1-yl) -3-methyl-2, 4-dioxo-3, 4-dihydro-2H-pyrimidin-1-ylmethyl-4-fluoro-benzonitrile
WO2008055945A1 (en) 2006-11-09 2008-05-15 Probiodrug Ag 3-hydr0xy-1,5-dihydr0-pyrr0l-2-one derivatives as inhibitors of glutaminyl cyclase for the treatment of ulcer, cancer and other diseases
TW200838536A (en) * 2006-11-29 2008-10-01 Takeda Pharmaceutical Polymorphs of succinate salt of 2-[6-(3-amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethy]-4-fluor-benzonitrile and methods of use therefor
SI2091948T1 (sl) 2006-11-30 2012-07-31 Probiodrug Ag Novi inhibitorji glutaminil ciklaze
KR100848491B1 (ko) * 2007-01-16 2008-07-28 영진약품공업주식회사 베타아미노기를 갖는 2-싸이아졸리딘 유도체, 이의약학적으로 허용 가능한 염 및 이의 제조 방법
KR100913495B1 (ko) * 2007-01-16 2009-08-25 영진약품공업주식회사 베타아미노기를 갖는 1,4-디아제펜 유도체, 이의약학적으로 허용 가능한 염 및 이의 제조 방법
JP2010120851A (ja) * 2007-02-09 2010-06-03 Kyorin Pharmaceut Co Ltd 二量化シクロ誘導体
US8093236B2 (en) 2007-03-13 2012-01-10 Takeda Pharmaceuticals Company Limited Weekly administration of dipeptidyl peptidase inhibitors
US8143427B2 (en) 2007-03-22 2012-03-27 Kyorin Pharmaceutical Co., Ltd. Method for producing aminoacetylpyrrolidinecarbonitrile derivative
ES2529149T3 (es) 2007-04-03 2015-02-17 Mitsubishi Tanabe Pharma Corporation Una combinación de inhibidor de dipeptidil peptidasa IV y edulcorante para uso en el tratamiento de la obesidad
EP2142514B1 (en) 2007-04-18 2014-12-24 Probiodrug AG Thiourea derivatives as glutaminyl cyclase inhibitors
US8338450B2 (en) * 2007-09-21 2012-12-25 Lupin Limited Compounds as dipeptidyl peptidase IV (DPP IV) inhibitors
CN101468988A (zh) 2007-12-26 2009-07-01 上海恒瑞医药有限公司 哌嗪类衍生物,其制备方法及其在医药上的应用
CL2008003653A1 (es) 2008-01-17 2010-03-05 Mitsubishi Tanabe Pharma Corp Uso de un inhibidor de sglt derivado de glucopiranosilo y un inhibidor de dppiv seleccionado para tratar la diabetes; y composicion farmaceutica.
EP2108960A1 (en) 2008-04-07 2009-10-14 Arena Pharmaceuticals, Inc. Methods of using A G protein-coupled receptor to identify peptide YY (PYY) secretagogues and compounds useful in the treatment of conditons modulated by PYY
WO2010016584A1 (ja) 2008-08-07 2010-02-11 杏林製薬株式会社 ビシクロ[２．２．２]オクチルアミン誘導体の製造方法
CA2733778A1 (en) * 2008-08-14 2010-02-18 Hiroshi Uchida Stabilized pharmaceutical composition
WO2010029422A1 (en) * 2008-09-12 2010-03-18 Cadila Pharmaceuticals Ltd. Novel dipeptidyl peptidase (dp-iv) compounds
JO2870B1 (en) 2008-11-13 2015-03-15 ميرك شارب اند دوهم كورب Amino Tetra Hydro Pirans as Inhibitors of Peptide Dipeptide IV for the Treatment or Prevention of Diabetes
US20100144140A1 (en) * 2008-12-10 2010-06-10 Novellus Systems, Inc. Methods for depositing tungsten films having low resistivity for gapfill applications
WO2010079433A2 (en) * 2009-01-07 2010-07-15 Glenmark Pharmaceuticals, S.A. Pharmaceutical composition that includes a dipeptidyl peptidase-iv inhibitor
JP5654572B2 (ja) 2009-05-15 2015-01-14 ノバルティス アーゲー アルドステロンシンターゼ阻害剤としてのベンズオキサゾロン誘導体
MA33358B1 (fr) 2009-05-15 2012-06-01 Novartis Ag Arylpyridine en tant qu'inhibiteurs de l'aldostérone synthase
CN101899048B (zh) 2009-05-27 2013-04-17 上海恒瑞医药有限公司 (R)-7-[3-氨基-4-(2,4,5-三氟-苯基)-丁酰]-3-三氟甲基-5,6,7,8-四氢-咪唑并[1,5-a]吡嗪-1-羧酸甲酯的盐
ES2602826T3 (es) 2009-05-28 2017-02-22 Novartis Ag Derivados aminobutíricos sustituidos como inhibidores de neprilisina
MA33364B1 (fr) 2009-05-28 2012-06-01 Novartis Ag Dérivés aminobutyriques substitués en tant qu'inhibiteurs de néprilysine
WO2010146597A1 (en) 2009-06-18 2010-12-23 Lupin Limited 2-amino-2- [8-(dimethyl carbamoyl)- 8-aza- bicyclo [3.2.1] oct-3-yl]-exo- ethanoyl derivatives as potent dpp-iv inhibitors
AR077642A1 (es) 2009-07-09 2011-09-14 Arena Pharm Inc Moduladores del metabolismo y el tratamiento de trastornos relacionados con el mismo
RU2550508C2 (ru) 2009-09-02 2015-05-10 Мерк Шарп И Доум Корп. Аминотетрагидропираны в качестве ингибиторов дипептидилпептидазы-iv для лечения или предупреждения диабета
ES2548913T3 (es) 2009-09-11 2015-10-21 Probiodrug Ag Derivados heterocíclicos como inhibidores de glutaminil ciclasa
EP2477985B1 (en) 2009-09-15 2018-11-07 BlueLink Pharmaceuticals, Inc. Crlx101 for use in the treatment of cancer
US8519134B2 (en) 2009-11-17 2013-08-27 Novartis Ag Aryl-pyridine derivatives as aldosterone synthase inhibitors
JO2967B1 (en) 2009-11-20 2016-03-15 نوفارتس ايه جي Acetic acid derivatives of carbamoyl methyl amino are substituted as new NEP inhibitors
US20110237540A1 (en) 2009-11-23 2011-09-29 Crawford Thomas C Cyclodextrin-based polymers for therapeutic delivery
EP2507234B1 (en) 2009-11-30 2014-03-12 Novartis AG Imidazole derivatives as aldosterone synthase inhibitors
US20110178287A1 (en) 2010-01-19 2011-07-21 Cerulean Pharma Inc. Cyclodextrin-based polymers for therapeutic delivery
WO2011103256A1 (en) 2010-02-22 2011-08-25 Merck Sharp & Dohme Corp. Substituted aminotetrahydrothiopyrans and derivatives thereof as dipeptidyl peptidase-iv inhibitors for the treatment of diabetes
JP6026284B2 (ja) 2010-03-03 2016-11-16 プロビオドルグ エージー グルタミニルシクラーゼの阻害剤
JP5688745B2 (ja) 2010-03-10 2015-03-25 プロビオドルグ エージー グルタミニルシクラーゼ（ｑｃ、ｅｃ２．３．２．５）の複素環阻害剤
JP2013523819A (ja) 2010-04-06 2013-06-17 アリーナ ファーマシューティカルズ， インコーポレイテッド Ｇｐｒ１１９レセプターのモジュレーターおよびそれに関連する障害の処置
US8581001B2 (en) 2010-04-16 2013-11-12 Codman & Shurtleff Metformin-cysteine prodrug
WO2011131748A2 (en) 2010-04-21 2011-10-27 Probiodrug Ag Novel inhibitors
US8980929B2 (en) 2010-05-21 2015-03-17 Merck Sharp & Dohme Corp. Substituted seven-membered heterocyclic compounds as dipeptidyl peptidase-iv inhibitors for the treatment of diabetes
KR101871011B1 (ko) 2010-09-22 2018-06-25 아레나 파마슈티칼스, 인크. Ｇｐｒ１１９ 수용체의 조절제 및 그와 관련된 장애의 치료
WO2012049566A1 (en) 2010-10-14 2012-04-19 Japan Tobacco Inc. Combination therapy for use in treating diabetes
US8673974B2 (en) 2010-11-16 2014-03-18 Novartis Ag Substituted amino bisphenyl pentanoic acid derivatives as NEP inhibitors
US8877815B2 (en) 2010-11-16 2014-11-04 Novartis Ag Substituted carbamoylcycloalkyl acetic acid derivatives as NEP
WO2012123563A1 (en) 2011-03-16 2012-09-20 Probiodrug Ag Benz imidazole derivatives as inhibitors of glutaminyl cyclase
WO2012135570A1 (en) 2011-04-01 2012-10-04 Arena Pharmaceuticals, Inc. Modulators of the gpr119 receptor and the treatment of disorders related thereto
WO2012145361A1 (en) 2011-04-19 2012-10-26 Arena Pharmaceuticals, Inc. Modulators of the gpr119 receptor and the treatment of disorders related thereto
US20140038889A1 (en) 2011-04-22 2014-02-06 Arena Pharmaceuticals, Inc. Modulators Of The GPR119 Receptor And The Treatment Of Disorders Related Thereto
WO2012145604A1 (en) 2011-04-22 2012-10-26 Arena Pharmaceuticals, Inc. Modulators of the gpr119 receptor and the treatment of disorders related thereto
WO2012170702A1 (en) 2011-06-08 2012-12-13 Arena Pharmaceuticals, Inc. Modulators of the gpr119 receptor and the treatment of disorders related thereto
US9051329B2 (en) 2011-07-05 2015-06-09 Merck Sharp & Dohme Corp. Tricyclic heterocycles useful as dipeptidyl peptidase-IV inhibitors
WO2013055910A1 (en) 2011-10-12 2013-04-18 Arena Pharmaceuticals, Inc. Modulators of the gpr119 receptor and the treatment of disorders related thereto
US9115082B2 (en) 2012-01-18 2015-08-25 Catherine Yang Dipeptidyl-peptidase-IV inhibitors for treatment of type 2 diabetes complex with hypertension
WO2013122920A1 (en) 2012-02-17 2013-08-22 Merck Sharp & Dohme Corp. Dipeptidyl peptidase-iv inhibitors for the treatment or prevention of diabetes
WO2014018350A1 (en) 2012-07-23 2014-01-30 Merck Sharp & Dohme Corp. Treating diabetes with dipeptidyl peptidase-iv inhibitors
TWI500613B (zh) 2012-10-17 2015-09-21 Cadila Healthcare Ltd 新穎之雜環化合物
WO2014074668A1 (en) 2012-11-08 2014-05-15 Arena Pharmaceuticals, Inc. Modulators of gpr119 and the treatment of disorders related thereto
UY35144A (es) 2012-11-20 2014-06-30 Novartis Ag Miméticos lineales sintéticos de apelina para el tratamiento de insuficiencia cardiaca
AP2015008621A0 (en) 2013-02-14 2015-07-31 Novartis Ag Substituted bisphenyl butanoic nep 'neutral endopeptidase' inhibitors
JP2016527249A (ja) 2013-07-25 2016-09-08 ノバルティス アーゲー 合成アペリンポリペプチドのバイオコンジュゲート
UY35670A (es) 2013-07-25 2015-02-27 Novartis Ag Polipéptidos cíclicos para el tratamiento de insuficiencia cardíaca
KR20170103970A (ko) 2015-01-23 2017-09-13 노파르티스 아게 개선된 반감기를 갖는 합성 아펠린 지방산 접합체
CA2979033A1 (en) 2015-03-09 2016-09-15 Intekrin Therapeutics, Inc. Methods for the treatment of nonalcoholic fatty liver disease and/or lipodystrophy
US11583516B2 (en) * 2016-09-07 2023-02-21 Trustees Of Tufts College Dash inhibitors, and uses related thereto
JOP20190086A1 (ar) 2016-10-21 2019-04-18 Novartis Ag مشتقات نافثيريدينون جديدة واستخدامها في معالجة عدم انتظام ضربات القلب
WO2018162722A1 (en) 2017-03-09 2018-09-13 Deutsches Institut Für Ernährungsforschung Potsdam-Rehbrücke Dpp-4 inhibitors for use in treating bone fractures
US11253508B2 (en) 2017-04-03 2022-02-22 Coherus Biosciences, Inc. PPARy agonist for treatment of progressive supranuclear palsy
EP3424927B1 (en) 2017-07-04 2019-04-17 F.I.S.- Fabbrica Italiana Sintetici S.p.A. Efficient process for the preparation of sitagliptin through a very effective preparation of the intermediate 2,4,5-trifluorophenylacetic acid
EP3461819B1 (en) 2017-09-29 2020-05-27 Probiodrug AG Inhibitors of glutaminyl cyclase
CN108003080A (zh) * 2017-12-12 2018-05-08 湖北科技学院 一种n-氨基酸氰基吡咯烷类衍生物及其制备方法
UY38072A (es) 2018-02-07 2019-10-01 Novartis Ag Compuestos derivados de éster butanoico sustituido con bisfenilo como inhibidores de nep, composiciones y combinaciones de los mismos
ES2770143T3 (es) 2018-02-13 2020-06-30 Fis Fabbrica Italiana Sintetici Spa Nuevo procedimiento eficiente para la preparación de sitagliptina
JP2022509184A (ja) 2018-11-27 2022-01-20 ノバルティス アーゲー 代謝性障害の処置のためのプロタンパク質コンバターゼスブチリシン／ケキシン９型（ｐｃｓｋ９）阻害剤としての環状ペプチド
UY38485A (es) 2018-11-27 2020-06-30 Novartis Ag Compuestos tetrámeros cíclicos como inhibidores de proproteína convertasa subtilisina/kexina tipo 9 (pcsk9), método de tratamiento, uso y su preparación
CN113166101A (zh) 2018-11-27 2021-07-23 诺华股份有限公司 作为治疗代谢障碍的蛋白质原转换酶枯草杆菌蛋白酶/kexin 9型（PCSK9）抑制剂的环状五聚体化合物
US20230285576A1 (en) 2020-08-05 2023-09-14 Ellipses Pharma Ltd Treatment of cancer using a cyclodextrin-containing polymer-topoisomerase inhibitor conjugate and a parp inhibitor
TW202333563A (zh) 2021-11-12 2023-09-01 瑞士商諾華公司 用於治療疾病或障礙之二胺基環戊基吡啶衍生物
AR127698A1 (es) 2021-11-23 2024-02-21 Novartis Ag Derivados de naftiridinona para el tratamiento de una enfermedad o un trastorno

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5283749A (en) * 1976-01-01 1977-07-12 Shionogi & Co Ltd Novel polypeptide
DD158109A1 (de) * 1981-04-10 1982-12-29 Gunter Fischer Verfahren zur hemmung der katalytischen aktivitaet von peptidhydrolasen
WO1991016339A1 (en) * 1990-04-14 1991-10-31 New England Medical Center Hospitals, Inc. Inhibitors of dipeptidyl-aminopeptidase type iv
WO1993008259A2 (en) * 1991-10-22 1993-04-29 New England Medical Center Hospitals, Inc. Inhibitors of dipeptidyl-aminopeptidase type iv

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3639382A (en) * 1967-12-22 1972-02-01 Merck & Co Inc O-ethyl threonine derivatives
DD296075A5 (de) * 1989-08-07 1991-11-21 Martin-Luther-Universitaet Halle-Wittenberg,De Verfahren zur herstellung neuer inhibitoren der dipeptidyl peptidase iv
IE912874A1 (en) * 1990-08-15 1992-02-26 British Bio Technology Compounds

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5283749A (en) * 1976-01-01 1977-07-12 Shionogi & Co Ltd Novel polypeptide
DD158109A1 (de) * 1981-04-10 1982-12-29 Gunter Fischer Verfahren zur hemmung der katalytischen aktivitaet von peptidhydrolasen
WO1991016339A1 (en) * 1990-04-14 1991-10-31 New England Medical Center Hospitals, Inc. Inhibitors of dipeptidyl-aminopeptidase type iv
WO1993008259A2 (en) * 1991-10-22 1993-04-29 New England Medical Center Hospitals, Inc. Inhibitors of dipeptidyl-aminopeptidase type iv

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