CN1306540A - Dpiv抑制剂的前药 - Google Patents

Dpiv抑制剂的前药 Download PDF

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CN1306540A
CN1306540A CN99807629A CN99807629A CN1306540A CN 1306540 A CN1306540 A CN 1306540A CN 99807629 A CN99807629 A CN 99807629A CN 99807629 A CN99807629 A CN 99807629A CN 1306540 A CN1306540 A CN 1306540A
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汉斯-乌尔里希·德穆特
托尔斯滕·霍夫曼
达格玛·施伦齐希
苏珊·曼哈特
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Abstract

本发明涉及二肽基肽酶Ⅳ(DPⅣ)的抑制剂的前药化合物,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DPⅣ的稳定抑制剂。该前药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

DPⅣ抑制剂的前药
本发明涉及二肽基肽酶Ⅳ(DP Ⅳ)抑制剂的前药化合物，该前药化合物的通式为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DPⅣ的稳定抑制剂。
已经发现，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，其是由于DP Ⅳ效应物的作用，增加了胰腺中Langerhans细胞的肠降血糖素的促胰岛素性刺激作用的有效性，并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。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 196 16 486)。
借助于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DPPⅣ活性的强效环肽抑制剂抑制HIV-1对CD 26阳性而不是CD26细胞的感染(Inhibition of HIV-1 infection of CD 26+but not CD 26-cells by apotent cyclopeptidic inhibitor of the DPP Ⅳ activity of CD 26).Abstract P44of the 24th European Pertide 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 of neuropeptideY 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))。
因此，本发明的目的是提供DP Ⅳ的效应物，其与已知的抑制剂相比具有更高的作用，而且可暂时限制作用的启动。
该目的是通过二肽基肽酶Ⅳ(DPⅣ)抑制剂的前药化合物来解决的，该前药化合物具有通式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DPⅣ的稳定抑制剂。
令人惊奇的是，该类掩蔽成前药的抑制剂与未经掩蔽的抑制剂相比具有显著增加的活性：当使用相同量的未掩蔽抑制剂和根据本发明的前药化合物时，如表4所示，在Wistar大鼠中使葡糖耐量提高最多至75％。
鉴于以下事实该提高更是令人惊奇的，即、已经发现100％的DP Ⅳ未掩蔽抑制剂被哺乳动物的胃肠道吸收，并进入身体的血管腔中。因此，人们一直认为仅是用于防止口服给药的化合物在胃肠道中分解的前药化合物不会使抑制剂的活性增加。另外，还应提到的是没有任何原因可以使本领域技术人员在上述事实的基础上寻求改性抑制剂，即使前药化合物本身是已知的；例如参见PCT/US97/09421。
根据本发明的优选实施方案，所用的前药化合物中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。B优选代表在A和C之间的肽键或者通过肽键连接在A和C上。
根据本发明的前药化合物还具有根据个体患者的需要释放DP Ⅳ抑制剂的优点。
当根据本发明的前药化合物与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，前药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，根据本发明的前药化合物再被断裂并由此释放抑制剂。
因此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。
另外，根据本发明优选的前药化合物是其中C为氨基酰基吡咯烷化物(pyrrolidide)、氨基酰基噻唑烷化物(thiazolidide)或者N-二肽基、O-酰基羟胺的化合物。这些抑制剂已经表明它们本身是特别有活性的DPⅣ抑制剂。此等抑制剂的例子可以是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。
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抑制剂的新型前药化合物，该前药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。
本发明前药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，从根据本发明的前药化合物中释放基团A-B取决于基团A氨基酸的性质：对于基团A，DP Ⅳ从前药化合物A-B-C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抑制剂的手段：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，通过根据本发明的前药化合物，可特别是几乎没有任何延迟、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。
如果B代表一个键，则其特别是是肽键；如果B代表氨基酸，则其优选通过肽键连接在A和C上。
在分析DP Ⅳ抑制剂异亮氨酰噻唑烷化物作为哺乳动物血糖浓度调节剂的剂量一作用关系时，在向Wistar大鼠口服和非胃肠道给药活性物质之间发现差异：在口服给药时，在摄入活性物质时观察到饱和(根据对血清酶的抑制作用来测量)，而在非胃肠道给药抑制剂时，观察到完全抑制酶。这例如用表1来证实。表1：在i.v.和p.o.给药后在30℃、pH7.6和离子强度为0.125的条件下相对于0.4mM底物H-Gly-Pro-pNA的DP Ⅳ残留活性，其是异亮氨酰噻唑烷化物(Ile-Thia)剂量的函数，而且是在给药抑制剂后30分钟测量的
  非胃肠道给药时的Ile-Thia剂量  DP Ⅳ活性(％) 口服给药时的Ile-Thia剂量   DPⅣ活性(％)
       0mg    100       0mg    100
      0.02mg     80      2.5mg     52
      0.2mg     32      5.0mg     40
       2mg     5      10mg     28
      20mg     0      20mg     29
鉴于肠道中也存在能够断裂前药的可断裂基团并因此释放药物的酶的事实，特别是高浓度的DP Ⅳ，而且如上所述，已经发现DP Ⅳ抑制剂定量地被胃肠道吸收，预期使用DP Ⅳ抑制剂的前药化合物不会在该环境下有任何改进。
因此，非常令人惊奇地发现，与相应的未掩蔽的DP Ⅳ抑制剂相比，根据本发明的DP Ⅳ抑制剂的前药显著增强了葡糖耐量实验中的葡糖耐量。如上所述，因为前药有可能在肠道中被其中存在的酶完全断裂，所述酶例如是二肽基肽酶，并象未掩蔽的抑制剂一样不会再被转运至目标部位处，所以该性质是特别令人惊奇的。
前药化合物被DP Ⅳ或者肠道中存在的其他酶断裂后，立即释放根据本发明的抑制剂，其按照与使用未掩蔽的抑制剂时完全相同的方式对DPⅣ进行抑制。因此，不再发生DP Ⅳ对前药化合物的分解；仍未分解的所有前药化合物或者另外引入的以及过量的(也就是说未结合在DP Ⅳ上的)未掩蔽抑制剂未分解地从胃肠道中通过进入身体的血管腔中。如上所述，在此它们可根据个体需要用作DP Ⅳ抑制剂。但是，在某些时间后，结合在肠道的DP Ⅳ上的抑制剂也被释放，并进入血管腔中。
因此，借助于根据本发明的前药化合物还可得到所希望的体内作用增加。
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。根据本发明的前药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DP Ⅳ抑制剂的前药化合物，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前药化合物中释放抑制剂；
4、控制从前药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前药化合物，并任选与常规载体或赋形剂组合。
根据本发明的前药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，令人人中的代谢紊乱。
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。
实施例1、合成根据本发明的前药化合物1.1合成H-Pro-Ile-Thia/HCl
将6.5mM的Boc-Pro-Ile-OH(1当量=1eq.)与N-羟基苯并三唑(1eq.)和噻唑烷(1eq.)悬浮在30ml二氯甲烷(DCM)中。在-10℃下加入等量的1M二环己基碳化二亚胺溶液并搅拌。搅拌在-10℃下进行，然后在室温下过夜。在进行处理时，使溶液完全过滤掉沉淀出的二环己基脲，真空除去DCM，然后将所得残留物溶解在乙酸乙酯中。乙酸乙酯溶液用饱和碳酸氢钠水溶液至少洗涤三次，用饱和氯化钠溶液洗涤一次，用稀释的硫酸氢钾溶液洗涤三次，然后再用氯化钠溶液洗涤。乙酸乙酯相在硫酸钠上干燥，然后使用旋转蒸发器浓缩，剩余的粗产物用乙酸乙酯/戊烷重结晶。在4℃下1-2天内结晶出Boc-Pro-Ile-Thia(产率80％)。在Boc-Pro-Ile-Thia中添加1.1N盐酸/冰乙酸溶液(3ml每mmol肽)。在室温下搅拌2小时，添加无水乙醚，然后使用旋转蒸发器蒸发掉过量的溶液。在4℃下盐酸盐从无水乙醚中定量结晶。用抽滤快速分离晶体，用无水乙醚洗涤几次，然后将产物储存在氢氧化钾或五氧化二磷的干燥器中。1.2合成H-Gly-Pro-Ile-Thia/HCl
将Boc-Gly-OH(1eq.)溶解在20ml四氢呋喃(THF)中，冷却至-10℃，然后在搅拌下顺序添加N-甲基-吗啉(1eq.)和氯甲酸异丁基酯(1eq.)。进行活化约20分钟。同时，将Pro-Ile-Thia.HCl(1eq.)悬浮在10ml的THF中，平衡至-10℃，然后添加N-甲基吗啉(1eq.)进行中和。活化时间完成后，将两种溶液混合在一起，1-2个小时后加热至室温并搅拌过夜。在反应混合物中添加少量的水，然后真空除去THF。残留物溶解在乙酸乙酯中，并用饱和碳酸氢钠水溶液至少洗涤三次，用饱和氯化钠溶液洗涤一次，用稀释的硫酸氢钾溶液洗涤三次，然后再用氯化钠溶液洗涤。乙酸乙酯相在硫酸钠上干燥，使用旋转蒸发器浓缩，产物Boc-Gly-Pro-Ile-噻唑烷化物用乙酸乙酯/戊烷重结晶(产率85％)。类似于H-Pro-Ile-Thia/HCl的合成脱除Boc。
表2：二肽基肽酶Ⅳ抑制剂的前药的分析数据
物质 计算的MW(g/mol)  实测的MWM+H+  CE纯度，保留时间(Rt)  HPLC纯度Rt  熔点℃
pGlu-Ile-Thia*HCl  349.84  314.8  4.2min  10.4min  30-40
Pro-Ile-Thia*HCl  335.90  300.8  4.5min  10.05min  45-69
Gly-Pro-Ile-Thia*HCl  392.94  357.8  4.6min  8.8min  111-121
Ile-Pro-Ile-Thia*HCl  449.05  413.6  5.6min  10.0min  98-107
Pro-Pro-Ile-Thia*HCl  433.01  397.6  5.3min  11.35min  101-118
分析条件：HPLC柱：LiChrospher250-4,100RP-18.5μm，温度25℃
洗脱液：30％ACN、0.1％TFA、等梯度，流速0.5ml/min
检测波长：210nmCE  毛细管：30cm×50μm溶凝硅石，温度25℃
检测波长：200nm
注射：5秒，50mbar
分离：0.1 M磷酸钠缓冲液，pH2.5，在12kV下持续7分钟2、各种肽、DP Ⅳ抑制剂以及前药的转运以及与肽转运蛋白PepT1的亲和性
通过放射活性标记底物D-Phe-Ala的置换分析各种肽、DP Ⅳ抑制剂和DP Ⅳ抑制剂的前药与肽转运蛋白PepT1的亲和性(AMASHEH,S.,WENZEL,U.,WEBER,W.M.,CLAUSS,W.,DANIEL,H.,Electro-physiological analysis of the function of the mammalian renal peptidetransporter expressed in Xenopus laevis oocytes.J.Physiol.504,169-174(1997))。其表明，例如四肽衍生物Ile-Pro-Ile-Thia结合在转运蛋白PepT1上，其方式可以与所选择的氨基酸衍生物相媲美或者更好，而且与所选择的氨基酸和肽类似物相比，其按照类似或更好的方式转运(表3)。
表3：各种氨基酸和肽衍生物在人肽转运蛋白PepT1上的转运性质
氨基酸或肽衍生物 电生理学分析(在卵母细胞中进行的hPEPT1实验)，以Gly-Gln为对照(100％)的通量％ 相对于D-Phe-Ala与PepT1的结合常数mM
    Lys-Phe            95     0.08
  Lys-Phe-Pro            10     0.19
    Asn-Pyr            30     3.01
    Asn-Thia            83     0.50
    His-Pry             7     5.34
    His-Thia            12     0.57
    Ile-Pyr            14     2.66
    Ile-Thia            25     0.98
 Ile-Pro-Ile-Thia            44     0.61
在人全血中活性DP Ⅳ抑制剂Ile-Thia从根据本发明的前药中的释放
根据本发明的DP Ⅳ抑制剂的前药，还可使DP Ⅳ抑制剂在目标腔室例如在血液循环中延迟释放。
例如图1所示，从根据本发明的前药化合物中释放抑制剂异亮氨酰噻唑烷化物可导致对人血DP Ⅳ的抑制，该抑制作用作为时间的函数经历了不同的过程。在例如DP Ⅳ本身(Pro-Pro-Ile-Thia=PPIThia,Gly-Pro-Ile-Thia=GPIThia)或者氨基肽酶(pGlu-Ile-Thia=pEIThia,Pro-Ile-Thia=PIThia)的实施例(图1)中，可在血液中释放掩蔽的DP Ⅳ抑制剂。当使用相同浓度的前药化合物时，在血液中从前药化合物中释放DP Ⅳ抑制剂异亮氨酰噻唑烷化物的效率有差异，与Pro-Ile-Thia(PI Thia)和Gly-Pro-Ile-Thia(GPI Thia)相比，Pro-Pro-Ile-Thia(PPIThia)和pGlu-Ile-Thia
(pEIThia)时显示活性物质的释放显著延迟。3、使用前药增加DPⅣ抑制剂赋予的葡糖耐量
将活性物质异亮氨酰噻唑烷化物转化为根据本发明的前药，其结果是在口服给药后在Wistar大鼠中观察到明显改善的作用曲线(图2)。与未掩蔽的活性物质Ile-Thia相比，根据本发明的前药化合物使得在检查期间DPⅣ抑制剂所导致的血糖浓度下降增加约30％(表4)。
表4：在p.o.血糖刺激期间和向Wistar大鼠p.o.给药Ile-Thia或者根据本
发明的前药(剂量：2.5μM活性物质/300g动物)的血糖浓度关系
 活性物质/前药  ％血糖浓度
 对照  100
 Ile-Thia  74.4
 Gly-Pro-Ile-Thia  57.1
 Pro-Ile-Thia  56.1

Claims (12)

1、二肽基肽酶Ⅳ(DP Ⅳ)的抑制剂的前药化合物，该前药化合物具有通式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的稳定抑制剂。
2、如权利要求1所述的前药化合物，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所述的前药化合物，其特征在于，B是脯氨酸和羟基脯酸。
4、如任一前述权利要求所述的前药化合物，其特征在于，C是氨基酰基吡咯烷化物、氨基酰基噻唑烷化物或者N-二肽基、O-酰基羟胺。
5、如任一前述权利要求所述的前药化合物，其特征在于，所述抑制剂为盐的形式。
6、如任一前述权利要求所述的前药化合物，其特征在于，A-B是式Ile-Pro或Gly-Pro的二肽。
7、特别是用于口服给药的药物组合物，其特征在于包括至少一种如任一前述权利要求所述的前药化合物以及任选的常规载体或赋形剂。
8、如任一前述权利要求所述的前药化合物或者药物组合物在制备用于暂时性受控体内抑制DP Ⅳ的药物中的应用。
9、如权利要求1-6之一所述的前药化合物或药物组合物在细胞、组织或器官特异性抑制DP Ⅳ中的应用。
10、如权利要求1-6之一所述的化合物或药物组合物在治疗哺乳动物中可通过调节哺乳动物的DP Ⅳ活性来治疗的疾病中的应用。
11、如权利要求9所述的应用，其是用于治疗人的代谢紊乱。
12、如权利要求9所述的应用，其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。
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CN1245417C (zh) 2006-03-15
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US20040171555A1 (en) 2004-09-02
US20020049164A1 (en) 2002-04-25
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HUP0102281A2 (hu) 2001-11-28
RU2226533C2 (ru) 2004-04-10
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