CN100345866C - 不稳定的dp iv抑制剂的化合物 - Google Patents
不稳定的dp iv抑制剂的化合物 Download PDFInfo
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- CN100345866C CN100345866C CNB998076287A CN99807628A CN100345866C CN 100345866 C CN100345866 C CN 100345866C CN B998076287 A CNB998076287 A CN B998076287A CN 99807628 A CN99807628 A CN 99807628A CN 100345866 C CN100345866 C CN 100345866C
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Abstract
本发明涉及二肽基肽酶IV(DP IV)的不稳定抑制剂的化合物，该化合物具有通式A-B-C，其中A是氨基酸，B是A和C之间的化学键或者是氨基酸，而C是DP IV的不稳定抑制剂。该化合物可用于治疗哺乳动物中受损葡糖耐量、葡糖尿、高脂血、代谢酸中毒、糖尿病、糖尿病性神经病和肾病、以及糖尿病的后遗症。
Description
本发明涉及二肽基肽酶IV(DP IV)的不稳定抑制剂的化合物，该化合物的通式为A-B-C，其中A是氨基酸，B是A和C之间的化学键或者是氨基酸，而C是DP IV的不稳定抑制剂。
已知氨基酰基噻唑化物(thiazolidides)、氨基酰基吡咯烷化物(pyrrolidides)、N-二肽基化物(dipeptididyl)、O-酰基羟胺和其他化合物可作为血清酶二肽基肽酶IV(DP IV)及类似酶的抑制剂(参见DEMUTH，H.-U.，J.Enzyme Inhibition 3，249(1990)；DEMUTH，H.-U.，HEINS，J.，in Dipeptidyl Peptidase IV(B.Fleischer编辑)R.G.Landes，Biomedical Publishers，Georgetown，1995，1-37)。
已经发现T细胞介导的免疫应答，例如移植时的免疫应答，可通过二肽基肽酶IV的稳定抑制剂来影响(参见KOROM，S.，DEMEESTER，I.，STADLBAUER，T.H.W.，CHANDRAKER，A.，SCHAUB，M.，SAYEGH，M.H.，BELYAEV，A.，HAEMERS，A.，SCHARPE，S.，KUPIEC-WEGLINSKI，J.W.，抑制CD26/二肽基肽酶IV的体内活性延长接受大鼠的心脏同种异体移植的存活率(Inhibition of CD26/dipeptidyl peptidase IV activity in vivoprolongs cardiac allograft survival in rat recipients)，Transplantation 63，1495(1997))。还可抑制风湿性关节炎(参见TANAKA，S.，MURAKAMI，T.，HORIKAWA，H.，SUGIURA，M.，KAWASHIMA，K.，SUGITA，T.，二肽基肽酶IV抑制剂对关节炎的抑制(Suppression of arthritis by the inhibitors ofdipeptidyl peptidase IV)，Int.J.Immunopharmacol.19，15(1997))。
还发现，因为酶活性的相关的暂时性下降，给药哺乳动物血液中DP IV或者DP IV类似酶活性的稳定抑制剂(效应物)，可使DP IV和DP IV样酶导致的内源性(或者其他外源性给药的)促胰岛素肽胃抑制剂多肽1-42(GIP1-42)和胰高血糖素样肽酰胺-17-36(GLP-17-36)(或者GLP-17-37或者其类似物)分解的下降，因此减少或延迟了这些肽激素或其类似物浓度的下降。(内源性存在或者外源性引入的)肠降血糖素或其类似物的更高稳定性，由于DP IV效应物的作用，改变了身体本身的胰岛素作用，导致对治疗生物中碳水化合物代谢的刺激作用，而所述DP IV效应物可增加胰腺中Langerhans细胞的肠降血糖素受体的促胰岛素性刺激作用的有效性。其结果是，所治疗生物的血清中的血糖浓度下降至高血糖的特征葡萄糖浓度以下。因此，用DP IV抑制剂可防止或者缓解代谢异常，如过重、葡糖尿、高脂血、以及可能严重的代谢酸中毒和糖尿病，它们是血糖浓度长期升高的结果(参见DE 19616486)。
用DP IV抑制剂还可经验性地防止HIV对CD 26(DP IV)阳性细胞的渗透(参见WAKSELMAN，M.，NGUYEN，C.，MAZALEYRAT，J.-P.，CALLEBAUT，C.，KRUST，B.，HOVANESSIAN，A.G.用CD 26的DPP IV活性的强效环肽抑制剂抑制HIV-1对CD 26阳性而不是CD 26细胞的感染(Inhibition of HIV-1 infection of CD 26+but not CD 26-cells by a potentcyclopeptidic inhibitor of the DPP IV activity of CD 26).Abstract P 44 of the24th European Peptide Symposium 1996)。
还发现DP IV可调节神经活性肽的活性，如神经肽Y和CLIP(参见MENTLEIN，R.，DAHMS，P.，GRANDT，D.，KRUGER，R.，用二肽基肽酶IV对神经肽Y和肽YY的蛋白酶解加工(Proteolytic processing ofneuropeptideY and peptide YY by dipeptidyl peptidase IV).Regul.Pept.49，133(1993)；WETZL，W.，WAGNER，T.，VOGEL，D.，DEMUTH，H.-U.，BALSCHUN，D.，CLIP片段ACTH 20-24对REM睡眠期持续时间的作用(Effects of theCLIP fragment ACTH 20-24 on the duration of REM sleep episodes).Neuropeptides，31，41(1997))。
DP IV抑制剂的这些不同作用表明，当在组织的具体病理生理条件下使用时，它们的作用可对其他正常的生理状态产生作用，例如在其他器官中。这些作用对于目标生物既有正面又有负面的后果。
因此，本发明的目的是提供DP IV的效应物，其具有DP IV抑制剂的高生物利用度，而且在具体的目标组织或者目标生物中具有精确限定的作用时间。
特别是，本发明的目的是提供DP IV抑制剂，其具有精确限定的短作用时间和高生物利用度。
这些目的是通过二肽基肽酶IV(DP IV)的不稳定抑制剂的化合物来解决的，该化合物具有通式A-B-C，其中A是氨基酸，B是A和C之间的化学键或者是氨基酸，而C是DP IV的不稳定抑制剂。
当B代表一个键时，其特别是肽键；当B是氨基酸时，其优选通过肽键连接在A和C上。
根据本发明，这些化合物可用作DP IV的抑制剂，它们的作用部位、作用的起始时间、以及作用的持续时间都可精确地限定。
在给药时，该化合物例如由于合适酶的作用而断裂，由此不稳定的“C”抑制剂通过除去A-B基团而被释放。该抑制剂可通过化学和酶机理释放。例如，酯酶、蛋白酶和肽酶都可用于从根据本发明的化合物中释放活性成分。所述酯酶、蛋白酶等例如公开在WO 97/45117、US5433955、US 5614379和US 5624894中。
所释放的不稳定抑制剂然后可与已经存在的DP IV相互作用并对其进行抑制。其直接结果是，例如上述促胰岛素肽被分解成更小的程度，并由此增加胰岛素的作用。
已证明给药DP IV的不稳定抑制剂本身对于抑制DP IV不是有利的，这是因为它们在体内快速分解，抑制剂的均匀分布、特别是在人体中的均匀分布由此是不可能的。具体而言，在口服给药时，此等抑制剂非常不稳定，使得它们实际上根本没有活性。因此，稳定的抑制剂目前特别是用于糖尿病的治疗。
令人惊奇的是，现已发现不稳定的“C”抑制剂可通过将其掩蔽为式A-B-C的化合物来充分地稳定。
该稳定作用目前也是令人惊奇的，因为具有羰甲基吡啶翁基团的式A-B-C化合物在吡啶翁氮原子处是正电荷的。其结果是，亚甲基对在除去A-B基团后构成抑制剂的活性亲核反应中心的基团产生吸电子作用。在所形成的反应中心活化的基础上，预期其亲核性将增加至亲核基团非特异性地“停留”在化合物A-B-C处的程度，而且抑制剂失活。但令人惊奇地发现，抑制剂的此等失活没有发生。
为通过DP IV抑制剂干扰仅需要对目标酶DP IV产生短期作用的生理控制循环，根据本发明提供例如作为组分C的抑制剂，其仅具有短的作用持续时间，而且在限定的半衰期后变成没有抑制剂活性的化合物。
例如，为增强肠降血糖素在糖尿病中的作用，抑制剂几分钟的持续作用时间就已经足够，而例如抑制移植时的DP IV介导的免疫应答则需要抑制剂的长期作用。
在释放后，根据本发明的不稳定抑制剂环化成例如吡嗪衍生物，并因此失活。该反应同时发生，而且有助于N端氨基氮对二肽衍生物的C端羰基官能团的亲核作用，并可通过氨基酸/酰亚胺键处的cis/trans异构化来促进，该异构化在包含脯氨酸的肽中可特别有利地进行。
而且，在化合物到达所希望的目标腔室例如血液循环并开始所希望的活性前，不会开始分解过程。
本发明化合物的这些性质可根据本发明用于设计不同的DP IV抑制剂，以通过释放后的分子内环化来引发DP IV抑制剂的所希望的暂时性失活。
具体而言，根据本发明优选的化合物是其中C为在C端具有活性羰基的二肽衍生物。C优选为二肽基氯烷基酮、二肽基硼酸或者二肽基氰化物或者二肽基吡啶翁甲基酮化合物。已证明此等抑制剂是特别有效的不稳定DP IV抑制剂。二肽基例如是Ile-Thia、Ile-Pyr、Val-Thia和Val-Pyr。
根据本发明抑制剂(组分C)也可以是盐形式，优选为有机盐，如乙酸盐、琥珀酸盐、酒石酸盐、或富马酸盐，或者优选是无机酸盐如硫酸盐或者磷酸盐。特别优选的是富马酸盐。
根据本发明的优选实施方案，化合物中B是脯氨酸、羟基脯氨酸、噻唑烷羧酸、脱氢脯氨酸、2-哌啶酸、氮杂环丁烷羧酸或者氮丙啶羧酸，其中特别优选脯氨酸和羟基脯氨酸。
具体而言，根据本发明的化合物还具有根据个体患者的需要释放DPIV抑制剂的优点。
当根据本发明的化合物与DP IV分子相互作用时，其被酶断裂为A-B基团和抑制剂C。抑制剂C将抑制DP IV分子，使其不能进一步断裂该化合物。如果还存在DP IV分子，化合物将继续被断裂(如果已给药足够量的相应化合物)，直至抑制最后的DP IV分子。剩余的化合物不再被分解，并由此构成抑制剂储存，直至DP IV分子的浓度又一次升高或者抑制剂分子被DP IV置换或者抑制剂分子被消除或失活，根据本发明的化合物再被断裂并由此释放抑制剂。
本发明的再一个优点是，每种生物将释放抑制已有DP IV所需要的精确量的抑制剂，其在每个情况下都是不同的。例如如果患者具有高浓度的DP IV，则就释放大量的抑制剂；而如果仅有略高浓度的DP IV，则释放少量的抑制剂。
具体而言，特别优选的化合物是其中A-B是式Ile-Pro或者Gly-Pro的二肽。
本发明因此涉及丝氨酸肽酶二肽基肽酶IV的不稳定抑制剂的新型化合物，该化合物可用于治疗各种疾病，特别是治疗与糖尿病有关的代谢紊乱。
令人惊奇的是，此等掩蔽抑制剂比未经掩蔽的抑制更为有效：如果使用相同量的未经掩蔽的DP IV抑制剂和根据本发明的化合物，则根据本发明的化合物在Wistar大鼠中产生显著提高的葡糖耐量。
本发明化合物的再一个优点是，合适地选择基团A-B可以暂时性控制DP IV抑制剂的作用起始和作用持续时间。具体而言，从根据本发明的化合物中释放基团A-B取决于基团A氨基酸的性质：对于基团A，DPIV从化合物中释放基团A-B的速率具体顺序如下：Ile＜Val＜Phe＜Pro＜Ala＜Gly。相应的DP IV催化释放速率常数为1-100s-1。因此就有了以精确暂时性的限定方式释放DP IV抑制剂：如果例如在摄入富葡萄糖的营养物时酶立即作用，所选择的化合物A-B-C中例如具有氨基酸Gly作为A基团；如果延迟抑制剂的作用，则例如选择氨基酸Ile作为基团A。
因此，通过根据本发明的化合物，可特别是实际上没有任何延迟、例如实际上与营养物摄入同时地经由小肠粘膜转运DP IV抑制剂。
而且，DP IV抑制剂释放的部位和它们作用的部位也可以通过基团A-B的性质来控制。
除二肽基肽酶IV以外，各种其他氨基肽酶，如焦谷氨酰基氨基肽酶和脯氨酰基氨基肽酶，也存在于哺乳动物的血液中。合适地选择基团A-B，可根据本发明测定释放DP IV抑制剂的氨基肽酶，并因此确定抑制剂的作用发生在何处。根据本发明的化合物或者相应的药物组合物还因此可用于细胞、组织或者器官特异性DP IV抑制中。基团A-B也可进行选择，使得针对仅在血管中存在并以足够快的速率释放抑制剂的酶。
总之，通过本发明的不稳定DP IV抑制剂的化合物，可完全令人惊奇地实现以下方面：
1、增加抑制剂的作用；
2、根据患者的需要释放抑制剂；
3、以暂时受控的方式从化合物中释放抑制剂；
4、控制从化合物中释放抑制剂的部位；
5、提高DP IV抑制剂的储存；以及
6.从其未掩蔽的时间起精确地限定作用的持续时间或者引发剂作用的结束。
根据本发明还提供特别适用于口服给药的药物组合物，其特征在于包含至少一种根据本发明的化合物，并任选与常规载体或赋形剂组合。
根据本发明的化合物或者包含该化合物的药物组合物可用于治疗或预防哺乳动物中可通过调节哺乳动物的DP IV活性来治疗的疾病，例如人的代谢紊乱。
具体而言，所述化合物可用于治疗哺乳动物中的受损葡糖耐量、葡糖尿、高脂血、代谢酸中毒、糖尿病、糖尿病性神经病和肾病、以及糖尿病的后遗症。因为根据本发明的不稳定抑制优选具有短的作用持续时间，特别有可能最小化或者防止对人或动物体内需要长期DP IV抑制作用的过程的影响。
实施例
不稳定的DP IV抑制剂C以及根据本发明的不稳定DP IV抑制剂的化合物的合成
在实施例1.1和1.2中显示了不稳定DP IV抑制剂C(相应于通式A-B-C)的制备。根据本发明的不稳定DP IV抑制剂的化合物的合成示于实施例1.3中。根据已知的方法(WEINSTEIN，B.，Chemistry andBiochemistry of Amino Acids，Peptides，and Proteins，Marcel Dekker，NewYork，Basle，1977)制备各种情况下的起始物——相应的肽基氯甲基酮。在实施例1.1和1.2中制得的吡啶翁甲基酮是N-端基保护的二肽衍生物，其极为稳定，并可完全进行表征。在正常的空气湿度时，N-端基解封的二肽衍生物在解封后立即开始分子内分解过程，使得不可能测定熔点。产物通过HPLC和质谱进行表征。
1.1合成H-Val-Pro-CH2-(N+C5H5)/Cl-
a)Z-Val-Pro-CH2-(N+C5H5)/Cl-
结构式：
制备：将10mmol的Z-Val-Pro-氯甲基酮溶解在吡啶中，然后在25℃下搅拌5天。在2mbar的真空下蒸馏掉过量的吡啶。Z-Val-Pro-吡啶翁甲基酮进行HPLC纯制。化合物为油状。
经验式：C24H30N3O4Cl
分子量：459.97Da
产率：理论值的45.8％
HPLC：保留时间：2.3分钟，LiChrosper 100 RP-18(125-4)，λ＝220nm，流速0.5ml/min，非梯度50％乙腈水溶液(0.1％TFA)保留时间：19.3分钟，Nucleosil 7C8，λ＝220nm，流速8ml/min，非梯度50％乙腈水溶液(0.1％TFA)
1H NMR(DMSO-d6)δH：0.8-1.0(6H，m，H12和H13)，1.8-2.1(3H，m，H11和H16)，2.2-2.4(2H，m，H17)，3.4-3.7(2H，m，H15)，3.7-4.1(2H，m，H20和H21)，4.3-4.5(1H，dd，5Hz，8Hz，H9)，4.8-5.1(2H，m，H7)，5.8-6.2(3H，m，H14，H19)，7.2-7.5(5H，m，H2-H6)，8.2-8.3(2H，m，H22和H23)，8.6-8.7(1H，m，H24)，8.8-9.0(1H，d，6Hz，NH)
13C NMR(DMSO-d6)δC：136.8(C1)，127.9(C2，C3)，127.8(C4，C5)，128.4(C6)，66.7(C7)，156.3(C8)，57.9(C9)，170.8(C10)，29.7(C11)，18.5(C12，C13)，63.7(C14)，47.2(C15)，25.1(C16)，27.9(C17)，200.3(C18)，71.1(C19)，146.1(C20，C21)，128.3(C22，C23)，146.4(C24)
MALDI-TOF-MS m/z：424.6Da(M+H+，无氯离子)
b)H-Val-Pro-CH2-(N+C5H5)/Cl-
结构式：
制备：用HBr/冰乙酸从Z-Val-Pro-CH2-(N+C5H5)/Cl-中除去Z保护基，反应时间为5分钟。在1.0mmol的Z-保护肽中添加2ml的HBr/冰乙酸(33％)，混合物在23℃下搅拌约10分钟。然后进行真空浓缩。用乙醚使氢溴酸盐的肽从甲醇中沉淀，抽滤，然后真空干燥。
经验式：C16H24N3O2Cl
分子量：325.84Da
产率：理论值的97.7％
HPLC：保留时间：7.4分钟，LiChrosper 100RP-18(125-4)，λ＝220nm，流速0.5ml/min，非梯度50％乙腈水溶液(0.1％TFA)
MALDI-TOF-MS m/z：291.2Da(M+H+，无氯离子)
1.2合成H-Phe-Pro-CH2-(N+C5H5)/Cl-
a)Z-Phe-Pro-CH2-(N+C5H5)/Cl-
结构式：
制备：将2ml吡啶添加在10mmol的Z-Phe-Pro-氯甲基酮中。该混合物在23℃下搅拌4天。在2mbar的真空下蒸馏掉过量的吡啶。粗产物在60g硅胶上进行纯制。在氯仿/甲醇洗脱液(9∶1体积比)中首先收集产物，然后随着洗脱液的极性增加，收集氯甲基酮。Z-Phe-Pro-吡啶翁甲基酮最后进行HPLC纯制。
经验式：C28H30N3O4Cl
分子量：508.01Da
产率：理论值的69.6％
HPLC：保留时间：17分钟，LiChrosper RP-8(Hibar)，λ＝220nm，流速8.0ml/min，非梯度50％乙腈水溶液(0.1％TFA)保留时间：3.4分钟，LiChrosper RP 8(125*4)，λ＝220nm，流速1.5ml/min，梯度30-80％乙腈水溶液(0.1％TFA)25分钟
保留时间：10.2分钟，Nucleosil 7 C8，λ＝220nm，流速8ml/min，非梯度50％乙腈水溶液(0.1％TFA)
1H NMR(DMSO-d6)δH：1.7-2.1(4H，m，H20和H21)，2.7-3.0(2H，m，H11)，3.4-3.9(2H，m，H19)，4.4-4.6(1H，m，H9)，4.6-4.8(2H，m，H24，H25)，5.0-5.1(2H，dd，H7)，5.7-5.8(1H，d，H18)，5.9-6.1(2H，dd，H23)，7.2-7.4(10H，m，H2-H6，H13-H17)，8.6-8.8(1H，dd，H28)，8.2-8.3(2H，d，H26和H27)，8.8-8.9(1H，d，6Hz，NH)
13C NMR(DMSO-d6)δC：136.8(C1)，127.9(C2，C3)，127.6(C4，C5)，128.4(C6)，65.5(C7)，156.3(C8)，54.1(C9)，170.9(C10)，36.4(C11)，137.6(C12)，126.6(C13，C14)，128.4(C15，C16)，129.3(C17)，63.1(C18)，46.9(C19)，25.1(C20)，27.6(C21)，200.7(C22)，66.3(C23)，146.2(C24，C25)，128.2(C26，C27)，146.4(C28)
MALDI-TOF-MS m/z：472.8Da(M+H+，无氯离子)
b)H-Phe-Pro-CH2-(N+C5H5)/Cl-
结构：
制备：从Z-Phe-Pro-CH2-(N+C5H5)/Cl-中脱除Z保护基，反应时间为5分钟。在1.0mmol的Z-保护肽中添加2ml的HBr/冰乙酸(33％)，混合物在23℃下搅拌约10分钟。然后进行真空浓缩。用乙醚使氢溴酸盐形式的肽从甲醇中沉淀，抽滤，然后真空干燥。
经验式：C20H24N3O2Cl
分子量：373.88Da
产率：理论值的98％
HPLC：保留时间：6.9分钟，LiChrosper 100RP-18(125-4)，λ＝220nm，流速0.5ml/min，非梯度50％乙腈水溶液(0.1％TFA)
MALDI-TOF-MS m/z：337.2Da(M+H+，无氯离子)
1.3合成H-Gly-Pro-Val-Pro-CH2-(N+C5H5)/Cl-
a)Z-Gly-Pro-Val-Pro-CH2-(N+C5H5)/Cl-
结构式：
制备：将2ml吡啶添加在10mmol的Z-Gly-Pro-Val-Pro-氯甲基酮中。该混合物在23℃下搅拌4天。在2mbar的真空下蒸馏掉过量的吡啶。Z-Gly-Pro-Val-Pro-吡啶翁甲基酮用HPLC进行纯制。
经验式：C31H40N5O6Cl
分子量：614.14Da
产率：理论值的69.6％
HPLC：保留时间：17.4分钟，LiChrosper RP 8 Hibar，λ＝220nm，流速8.0ml/min，非梯度50％乙腈水溶液(0.1％TFA)保留时间：5.4分钟，LiChroCART 100RP-18(125-4)，λ＝220nm，流速0.5ml/min，非梯度50％乙腈水溶液(0.1％TFA)保留时间：17.7分钟，Nucleosil 1007C8，λ＝220nm，流速8ml/min，非梯度50％乙腈水溶液(0.1％TFA)
13C NMR(DMSO-d6)δC：134.4(C1)，128.9(C2，C3)，128.2(C4，C5)，129.8(C6)，65.3(C7)，157.2(C8)，39.0(C9)，165.7(C10)，56.0(C11)，41.6(C12)，24.6(C13)，29.0(C14)，170.5(C15)，52.1(C16)，171.9(C17)，30.3(C18)，18.6，19.3(C19，C20)，58.9(C21)，47.2(C22)，25.0(C23)，29.4(C24)，196.5(C25)，65.8(C26)，137.9(C27，C28)，129.1(C29，C30)，146.5(C31)
MALDI-TOF-MS m/z：579.7Da(M+H+，无氯离子)
b)H-Gly-Pro-Val-Pro-CH2-(N+C5H5)/Cl-
结构：
制备：从Z-Phe-Pro-CH2-(N+C5H5)/Cl-中脱除Z保护基，反应时间为5分钟。在1.O mmol的Z-保护肽中添加2ml的HBr/冰乙酸(33％)，混合物在23℃下搅拌约10分钟。然后进行真空浓缩。用乙醚使氢溴酸盐形式的肽从甲醇中沉淀，抽滤，然后真空干燥。
经验式：C23H34N5O4Cl
分子量：480.0Da
产率：理论值的95％
MALDI-TOF-MS m/z：443.9Da(M+H+，无氯离子)
1、不稳定DP IV抑制剂以及它们掩蔽的形式在水溶液中的分解
为分析在1.1和1.2中制备的抑制剂的稳定性，在缓冲水溶液中温育这些抑制剂，并用MALDI-TOF质谱监测它们的分子内环化(图2和3)。反应产物为相应的吡嗪衍生物(图1)。
分子量为337.2Da的H-Phe-Pro-吡啶翁甲基酮分解为分子量是319.2Da的环状吡嗪衍生物，其中除去水，该反应在30分钟的时间内完全是定量的(图2)。
分子量为291.2Da的H-Val-Pro-吡啶翁甲基酮分解为分子量是273.2Da的环状吡嗪衍生物，其中除去水，该反应在60分钟的时间内完全是定量的(图3)。
在分子内反应期间形成吡嗪的双键系统，使得能够通过UV光谱计定量分析环化过程(图4)。在0.1M HEPES缓冲液pH＝7.6和25℃下由其中测定的不稳定DP IV抑制剂的分子内环化反应速率常数见以下表1所示。
表1：不稳定DP IV抑制剂的环化反应参数
| 化合物 | kmin-1 | 半衰期(分钟) |
| H-Val-Pro-CH2-(N+C5H5) | 8.7×10-4(±4×10-5) | 13.3 |
| H-Phe-Pro-CH2-(N+C5H5) | 1.2×10-3(±3.9×10-5) | 9.6 |
与此相反的是，证明根据本发明的H-Val-Pro-CH2-(N+C5H5)和H-Gly-Pro-Val-Pro-CH2-(N+C5H5)化合物在相同条件下于24小时的时间中是完全稳定的。
2、不稳定DP IV抑制剂或者根据本发明的包含二肽基肽酶IV的化合物在水溶液中的相互作用
在存在底物时DP IV目标酶与不稳定抑制剂温育，首先观察酶的抑制；由于平行地发生抑制剂的分子内环化，抑制作用随实验时间的发展开始下降，这是因为反应溶液中的抑制剂浓度由于同时发生的化学反应而降低。该作用见图5和6所示。因为抑制剂浓度的时间依赖性降低，底物的酶催化水解的速率随时间增加。
与未掩蔽的DP IV抑制剂相反，已证明在没有酶存在时根据本发明的化合物H-Gly-Pro-Val-Pro-CH2-(N+C5H5)在缓冲水溶液中于24小时的时间内都是稳定的。仅在添加DP IV酶时释放活性DP IV抑制剂H-Val-Pro-CH2-(N+C5H5)(在此也称为释放DP IV抑制剂)，其中除去N端二肽H-Gly-Pro-OH。因此，在质谱(图7)中，即使在温育60分钟后，根据本发明的温育化合物中仍有50％以上可以被检测出来。由于延迟释放，还令人惊奇地发现除所希望地有效抑制目标酶外，与不稳定DP IV抑制剂相比，明显地延长了活性而且显著降低根据本发明的化合物的浓度(图8)。
图1：H-Phe-Pro-吡啶翁甲基酮的分子内环化产物的结构式。对相应的原子给出用13C NMR和1H NMR测定的特征化学位移(ppm)。
图2：H-Phe-Pro-吡啶翁甲基酮在pH＝7.6的缓冲水溶液中的分子内环化反应的MALDI-TOF质谱，其是根据温育时间来记录的。
图3：H-Val-Pro-吡啶翁甲基酮在pH＝7.6的缓冲水溶液中的分子内环化反应的MALDI-TOF质谱，其是根据温育时间来记录的。
图4：在0.1M HEPES缓冲液pH＝7.6中于30℃下温育的H-Phe-Pro-吡啶翁甲基酮水溶液的UV光谱。环化反应的监测时间为40分钟。
图5：在0.1M HEPES缓冲液pH＝7.6、30℃中有2.8×10-3M的H-Val-Pro-吡啶翁甲基酮、0.06μg/ml的DP IV、4×10-4M的H-Gly-Pro-pNA存在时DP IV对底物H-Gly-Pro-pNA的催化水解反应曲线。
图6：在0.1M HEPES缓冲液pH＝7.6、30℃中有2.1×10-4M的H-Phe-Pro-吡啶翁甲基酮、0.06μg/ml的DP IV、1.0×10-3mol/l的H-Gly-Pro-pNA存在时DP IV对底物H-Gly-Pro-pNA的催化水解反应曲线。
图7：在有2.6×10-5mol/l的H-Gly-Pro-Val-Pro-吡啶翁甲基酮、0.06μg/ml的DP IV、2.0×10-4M的H-Gly-Pro-pNA、0.1M HEPES缓冲液pH＝7.6存在时在30℃下DP IV对H-Gly-Pro-pNA的催化水解的温育浴的MALDI-TOF质谱。
图8：在0.1M HEPES缓冲液pH＝7.6、30℃中有2.6×10-5mol/l的H-Gly-Pro-Val-Pro-吡啶翁甲基酮、0.06μg/ml的DP IV、2.0×10-4M的H-Gly-Pro-pNA存在时DP IV对H-Gly-Pro-pNA的催化水解的反应曲线。
Claims (14)
1、二肽基肽酶IV的抑制剂的化合物，该化合物具有通式A-B-C，其中
A是氨基酸，
B是A和C之间的肽键或者通过肽键与A和C连接的氨基酸，以及
C是二肽基肽酶IV的不稳定抑制剂二肽基吡啶鎓甲基酮基团。
2、如权利要求1所述的化合物，其特征在于，B是脯氨酸、羟基脯氨酸、噻唑烷羧酸、脱氢脯氨酸、2-哌啶酸、氮杂环丁烷羧酸或者氮丙啶羧酸。
3、如权利要求1或2所述的化合物，其特征在于，B是脯氨酸或羟基脯氨酸。
4、如权利要求1所述的化合物，其特征在于，二肽基是Ile-Thia、Ile-Pyr、Val-Thia或Val-Pyr。
5、如权利要求1所述的化合物，其特征在于，所述抑制剂为盐的形式。
6、如权利要求5所述的化合物，其特征在于，抑制剂是有机盐或者是无机酸盐。
7、如权利要求6所述的化合物，其特征在于，所述有机盐是乙酸盐、琥珀酸盐、酒石酸盐、或富马酸盐，而所述无机酸盐是硫酸盐或者磷酸盐。
8、如权利要求1所述的化合物，其特征在于，A-B是式Ile-Pro或Gly-Pro的二肽。
9、用于口服给药的药物组合物，其特征在于包括至少一种如权利要求1-8之一所述的化合物以及任选的常规载体或赋形剂。
10、如权利要求1-8之一所述的化合物在制备用于暂时性受控体内抑制二肽基肽酶IV的药物中的应用。
11、如权利要求1-8之一所述的化合物在制备用于细胞、组织或器官特异性抑制二肽基肽酶IV的药物中的应用。
12、如权利要求1-8之一所述的化合物在制备用于治疗哺乳动物中可通过调节哺乳动物的二肽基肽酶IV活性来治疗的疾病的药物中的应用。
13、如权利要求12所述的应用，其中所述药物是用于治疗人的代谢紊乱。
14、如权利要求12所述的应用，其中所述药物是用于治疗哺乳动物中受损葡糖耐量、葡糖尿、高脂血、代谢酸中毒、糖尿病、糖尿病性神经病和肾病、以及糖尿病的后遗症。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19828114A DE19828114A1 (de) | 1998-06-24 | 1998-06-24 | Produgs instabiler Inhibitoren der Dipeptidyl Peptidase IV |
| DE19828114.5 | 1998-06-24 |
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| Publication Number | Publication Date |
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| CN1306541A CN1306541A (zh) | 2001-08-01 |
| CN100345866C true CN100345866C (zh) | 2007-10-31 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB998076287A Expired - Fee Related CN100345866C (zh) | 1998-06-24 | 1999-06-24 | 不稳定的dp iv抑制剂的化合物 |
Country Status (17)
| Country | Link |
|---|---|
| US (1) | US7053055B2 (zh) |
| EP (1) | EP1090030A1 (zh) |
| JP (1) | JP3761781B2 (zh) |
| KR (1) | KR100630254B1 (zh) |
| CN (1) | CN100345866C (zh) |
| AU (1) | AU758843B2 (zh) |
| BR (1) | BR9911415A (zh) |
| CA (1) | CA2335978A1 (zh) |
| DE (1) | DE19828114A1 (zh) |
| HU (1) | HUP0102250A3 (zh) |
| IL (1) | IL140338A0 (zh) |
| IS (1) | IS5739A (zh) |
| NO (1) | NO20006483D0 (zh) |
| NZ (1) | NZ508721A (zh) |
| PL (1) | PL345060A1 (zh) |
| RU (1) | RU2226195C2 (zh) |
| WO (1) | WO1999067279A1 (zh) |
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- 1999-06-24 EP EP99931163A patent/EP1090030A1/de not_active Withdrawn
- 1999-06-24 BR BR9911415-1A patent/BR9911415A/pt not_active IP Right Cessation
- 1999-06-24 CN CNB998076287A patent/CN100345866C/zh not_active Expired - Fee Related
- 1999-06-24 NZ NZ508721A patent/NZ508721A/xx unknown
- 1999-06-24 AU AU47772/99A patent/AU758843B2/en not_active Ceased
- 1999-06-24 RU RU2001102057/04A patent/RU2226195C2/ru not_active IP Right Cessation
- 1999-06-24 CA CA002335978A patent/CA2335978A1/en not_active Abandoned
- 1999-06-24 WO PCT/EP1999/004381 patent/WO1999067279A1/de active IP Right Grant
- 1999-06-24 JP JP2000555930A patent/JP3761781B2/ja not_active Expired - Fee Related
- 1999-06-24 HU HU0102250A patent/HUP0102250A3/hu unknown
- 1999-06-24 KR KR1020007014586A patent/KR100630254B1/ko not_active IP Right Cessation
- 1999-06-24 PL PL99345060A patent/PL345060A1/xx not_active Application Discontinuation
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2000
- 2000-11-28 IS IS5739A patent/IS5739A/is unknown
- 2000-12-19 NO NO20006483A patent/NO20006483D0/no not_active Application Discontinuation
- 2000-12-21 US US09/745,883 patent/US7053055B2/en not_active Expired - Lifetime
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| WO1993008259A2 (en) * | 1991-10-22 | 1993-04-29 | New England Medical Center Hospitals, Inc. | Inhibitors of dipeptidyl-aminopeptidase type iv |
| WO1995011689A1 (en) * | 1993-10-29 | 1995-05-04 | Trustees Of Tufts College | Use of inhibitors of dipeptidyl-aminopeptidase to block entry of hiv into cells |
Also Published As
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| BR9911415A (pt) | 2001-03-20 |
| NO20006483L (no) | 2000-12-19 |
| HUP0102250A2 (hu) | 2001-11-28 |
| WO1999067279A1 (de) | 1999-12-29 |
| RU2226195C2 (ru) | 2004-03-27 |
| CN1306541A (zh) | 2001-08-01 |
| IS5739A (is) | 2000-11-28 |
| AU4777299A (en) | 2000-01-10 |
| NZ508721A (en) | 2003-06-30 |
| IL140338A0 (en) | 2002-02-10 |
| PL345060A1 (en) | 2001-11-19 |
| EP1090030A1 (de) | 2001-04-11 |
| AU758843B2 (en) | 2003-04-03 |
| US20010020006A1 (en) | 2001-09-06 |
| KR100630254B1 (ko) | 2006-10-02 |
| HUP0102250A3 (en) | 2001-12-28 |
| NO20006483D0 (no) | 2000-12-19 |
| JP3761781B2 (ja) | 2006-03-29 |
| DE19828114A1 (de) | 2000-01-27 |
| KR20010071563A (ko) | 2001-07-28 |
| JP2002518518A (ja) | 2002-06-25 |
| US7053055B2 (en) | 2006-05-30 |
| CA2335978A1 (en) | 1999-12-29 |
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