CN101095675A - 二肽基肽酶iv的新效应物 - Google Patents

二肽基肽酶iv的新效应物 Download PDF

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CN101095675A
CN101095675A CNA2007101369808A CN200710136980A CN101095675A CN 101095675 A CN101095675 A CN 101095675A CN A2007101369808 A CNA2007101369808 A CN A2007101369808A CN 200710136980 A CN200710136980 A CN 200710136980A CN 101095675 A CN101095675 A CN 101095675A
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汉斯-乌尔里希·德穆特
康拉德·格隆德
达格玛·施伦齐希
苏珊·克鲁贝尔
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Abstract

本发明提供由氨基酸及噻唑烷或吡咯烷基团形成的二肽模拟物以及它们的盐。本发明还提供包含这些二肽模拟物的药物组合物以及这些二肽模拟物的用途。

Description

二肽基肽酶IV的新效应物
本申请是1999年5月28日提交的，发明名称为“二肽基肽酶IV的新效应物”的中国专利申请99806723.7的分案申请。
技术领域
本发明涉及由一个氨基酸及一个噻唑烷或吡咯烷基团构成的二肽化合物及与二肽化合物类似的化合物，及其盐，下文中称为二肽化合物，也涉及该化合物在治疗哺乳动物葡萄糖耐受不良，糖尿，高脂血症，代谢性酸中毒，糖尿病，糖尿病性神经病和肾病及糖尿病后遗症中的应用。
因此，本发明也涉及在作为如下的酶的活性降低效应物(底物，伪底物，抑制剂，结合蛋白，抗体等等)的二肽化合物的辅助下降低哺乳动物血糖浓度的简便方法，所述的酶具有与二肽基肽酶IV相似或相同的酶活性。
背景技术
DPIV或DPIV类似物(例如胞液性DPII有与DPIV几乎相同的底物特异性)在血循环中具有活性，在血液循环中当脯氨酸或丙氨酸是N末端氨基酸相邻残基时，DPIV或DPIV类似物能够高特异性地从生物学活性肽N末端分解出二肽。
葡萄糖依赖型促胰岛多肽：肠抑胃肽1-2(GIP1-42)及类胰高血糖素肽酰胺-17-36(GLP-17-36)，即通过胰腺刺激葡萄糖诱导型胰岛素分泌的激素(也叫做肠降血糖素)，是DPIV的底物，因为后者在体外及体内能从这些肽的N末端序列上分别分解出酪氨酸-丙氨酸及组氨酸-丙氨酸二肽。
降低在体内分解这些底物的DPIV及类DPIV酶活性能够在实验室及哺乳动物病理条件下有效地抑制不希望的酶活性。例如，II型糖尿病(包括成人型糖尿病)是建立在胰岛素分泌减少或特别是来自蛋白水解的异常肠降血糖素浓度所致的受体功能紊乱的基础上。
依照现有技术，使用胰岛素(例如从牛胰岛分离或基因工程技术得到的物质)来治疗高糖血症及其相应的原因和后遗症(包括糖尿病)。所有已知的方法包括比较先进的手段都需要大量的物质，高额的费用并对患者的生活质量有明显的损害。传统方法(从十九世纪三十年代开始使用的每日静脉注射胰岛素)治疗该疾病的急性症状，但持续使用导致严重的血管变化(动脉硬化)及神经损伤。
最近有建议皮下埋置植入物(胰岛素以计量的方式被释放，不需要日常的注射)及植入(移植)完好的朗罕氏细胞到功能损伤的胰腺或其它器官及组织。这种移植要求有高水平技术。而且，它们涉及对受体生物体的手术介入，这可造成危险，甚至，在细胞移植时需要抑制或干扰免疫系统。
作为DPIV及类DPIV酶活性抑制剂的丙氨酰吡咯烷及异亮氨酰噻唑烷的使用已从PCT/DE 97/00820知道，盐酸异亮氨酰吡咯烷及异亮氨酰噻唑烷的使用已从DD 296075中知道。异亮氨酰噻唑烷，其在后一现有技术中被使用，是天然的，也就是说L-苏型-异亮氨酰噻唑烷，在该两篇说明书的优先权日和申请日时，仅该型，即异亮氨酰噻唑烷天然的形式。
已明确知道这些化合物特别是L-苏型-异亮氨酰噻唑烷是DPIV及类DPIV酶活性的良好效应物，但这些化合物的使用对一些患者及疾病会造成问题。
例如糖尿病时，依赖于症状及严重程度，需要使用与现有已知化合物不同的效应物：如已知为了以优化方式进行疾病的治疗，糖尿病患者的病情必须逐个稳定。在一些时候，例如通过DP IV效应物降低活性应该是足够的。也会出现高水平抑制剂活性及长期同样药物的使用所造成的副作用，特别在长期治疗中。而且，为了增加体内效应物的吸收率需改善某些转运特性。
发明内容
本发明的目的是对例如哺乳动物葡萄糖糖耐受不良，糖尿，高脂血症，代谢性酸中毒，糖尿病，糖尿病性神经病和肾病及糖尿病后遗症的治疗提供一种新的(特别是降低活性的)效应物，及治疗这些疾病的简单方法。
本发明的目的通过提供由一种氨基酸及一种噻唑烷或吡咯烷基团形成的二肽化合物或二肽类似物及其盐来达到。
将这些效应物给予哺乳动物，优选口腔给予时，内源性(或额外外源性给予)的促胰岛肽GIP1-42及GLP-17-36(或GLP-17-37或它的类似物)被DPIV或类DPIV酶分解而减少，因此这些肽激素或其类似物的浓度的降低被减慢或延迟。因此，本发明是建立在血液循环中起作用的DPIV或类DPIV酶活性的降低对血糖水平会造成影响这个发现的基础上。已发现：
1.DPIV或类DPIV酶活性的降低能提高葡萄糖刺激的或外来的肠降血糖素(或其类似物)的相对稳定性，也就是说通过给予DPIV或类DPIV蛋白的效应物，使对血中肠降血糖素分解的控制成为可能；
2.肠降血糖素(或其类似物)的生物学分解稳定性的提高导致内源性胰岛素作用的变化；
3.通过降低血液中DPIV或类DPIV酶活性而提高肠降血糖素的稳定性导致葡萄糖诱导性胰岛素作用的随后变化，因此导致对由DPIV效应物控制的血糖水平的调节。
对本发明的这一目的特别合适的是二肽化合物，其氨基酸选自天然氨基酸，例如亮氨酸，缬氨酸，谷氨酰胺，脯氨酸，异亮氨酸，天冬酰胺及天冬氨酸。
附图说明
图1是毛细管区带电泳(CE)分离异亮氨酰噻唑烷异构体的图，其显示L-苏型-Ile-Thia*延胡索酸盐、L-别-Ile-Thia*延胡索酸盐、D-苏型-Ile-Thia*延胡索酸盐、D-别-Ile-Thia*延胡索酸盐的1∶1∶1∶1的混合物的CE分离结果，方法和测量条件如下：
用来自Beckmann公司的“P/ACE系统MDQ”进行CE研究
物质     CE(min)
 L-threo-IT*F     160
 D-threo-IT*F     158
 L-allo-IT*F     154
 D-allo-IT*F     150
操作条件
缓冲液：20mM磷酸盐，pH 7.0，100mM β-羟基-丙基-环糊精
毛细管：50/60.2cm，25μm内径，用丙烯酰胺包被
电压：10kV
检测：在214nm用光电二极管阵列检测器检测
温度：7℃。
图2是Ile-Thia*延胡索酸盐的CE分离的图，其显示L-苏型-Ile-Thia*延胡索酸盐与D-别-Ile-Thia*延胡索酸盐的1∶1000的混合物的CE分离结果。
图3显示在口服给予各种H-Ile-Thia立体异构体(5μg/300g大鼠)后的血清DP IV活性。酶活性仅受L-别-Ile-Thia和L-苏型-Ile-Thia影响。
图4显示各种氨酰噻唑烷对大鼠葡萄糖耐受的作用(用2g/300gWistar大鼠在0时间点进行口服葡萄糖耐受试验，在口服葡萄糖刺激之前10分钟给予DPIV抑制剂)。
具体实施方式
在本发明中，通过口服给予高亲和性低分子量酶抑制剂相对于在治疗病理症状时广泛使用的外科技术是比较经济的选择。通过针对稳定性，转运及清除特性利用化学方法进行的设计，可调节作用模式及适应不同个体的特性。
如上所说，例如在糖尿病的长期治疗的情况下，可能必须提供具有所述活性的效应物，其可符合患者的不同要求及治疗他们的症状。本发明所说的二肽化合物显示出在(二肽化合物)浓度为10微摩尔，特别在表1所示的条件下，二肽基肽酶IV或类DPIV酶活性至少降低10％，特别是至少降低40％。通常也要求降低至少60％或70％。优选的效应物还可显示最多降低活性20％或30％。而且，本发明化合物的特别是通过转运Pep T1的转运特性显著改善。
特别优选的二肽化合物是L-别-异亮氨酰噻唑烷及其盐类。这些化合物与L-苏型-异亮氨酰噻唑烷相比，经转运肽Pep T1的转运改善高达5倍，同时对于葡萄糖调节具有大致相同的作用程度。
在表1进一步给出优选化合物。
本发明中二肽化合物的盐类可为，例如，有机盐如乙酸盐，琥珀酸盐，酒石酸盐或延胡索酸盐，或无机酸盐如磷酸盐或硫酸盐。最好使用延胡索酸盐，其在对水解作用有高度稳定性及比盐酸盐更不易溶解的同时，有很好的作用。从盖仑制剂的观点来说，这些特点也是有益的。
也优选L-苏型-异亮氨酰吡咯烷及其盐类，特别是延胡索酸盐，及L-别-异亮氨酰吡咯烷及其盐类，特别是延胡索酸盐。
二肽化合物的盐类可以二肽(二肽类似物)组分与盐类组分的摩尔比为1∶1或2∶1存在。例如，(异亮氨酰噻唑烷)2延胡索酸。
特别优选的盐类是L-苏型-异亮氨酰噻唑烷及L-别-异亮氨酰噻唑烷的延胡索酸盐类。
本发明涉及二肽基肽酶IV(DPIV)或类DPIV酶活性的效应物及它们在降低哺乳动物血清中的血糖浓度到高血糖症特征性血糖浓度以下中的应用。本发明特别涉及本发明所述的DPIV或类DPIV酶活性效应物在预防或减轻哺乳动物的病理代谢异常中的应用，所述病理代谢异常为例如，哺乳动物中的葡萄糖耐受不良，糖尿，高脂血症，代谢性酸中毒，糖尿病，糖尿病性神经病和肾病及糖尿病后遗症。在进一步优选的实施方案中，本发明涉及降低哺乳动物血清中的血糖浓度到高血糖症特征性血糖浓度以下的方法，其特征在于给予哺乳动物治疗有效量的本发明所述的至少一种DPIV或类DPIV酶活性效应物。
在进一步优选的实施方案中，本发明涉及药物组合物，也就是说药物，其包括至少一种本发明所述的化合物或其盐类，任选地与一种或多种药物可接受载体及/或溶剂混合。
药物组合物可以是，例如，肠道外或肠道配方的形式并可含有合适载体或它们可以是包括适宜口服给药相应载体的口服配方的形式。
此外，药物组合物可包括一种或多种具有低血糖作用的活性成分，其可以是已知的活性成分。
本发明中DPIV或类DPIV酶活性的效应物可用来降低哺乳生物血清中血糖水平到高血糖血症特征性血糖浓度下，或用来生产相应的药物。
本发明中使用的DPIV或类DPIV酶效应物可作为用来降低哺乳动物中DPIV或类DPIV蛋白浓度的抑制剂，底物，伪底物，DPIV表达抑制剂，结合蛋白或这些酶蛋白的抗体或这些不同物质组合的药物可接受配方或配方混合物。本发明的效应物可以是DPIV抑制剂如二肽衍生物或二肽模拟物L-别-异亮氨酰噻唑烷及在表1中提到的效应物及其延胡索酸盐。本发明的效应物能使患者及疾病的治疗依照各自的情况来调整，特别是可以控制个体中发生的不耐受，过敏及副作用。
化合物也显示出不同的时间有效性。医生根据患者的不同情况能采取不同的方法：一方面，他能精确地设置作用的起始速度，另一方面，可控制作用的持续时间，特别是作用的强度。
本发明的方法代表着降低哺乳动物血清中已升高的血糖浓度的一种新的方法。其简单，可经济开发及适应于治疗中使用，特别对建立在高于平均血糖阈值基础上的疾病，适用于哺乳动物，更适用于人类药物。
效应物可以通过药学制剂的形式被给药，该药学制剂包括与现有技术已知的传统载体相结合的活性成分。例如，它们可非肠道给药(如，静脉注射，以生理盐水的形式)或肠道给药(如，口服，与传统的载体如葡萄糖相结合)。
为了使血糖值正常化，依照它们的内源稳定性及生物利用率，效应物需要每天一次或多次给药。例如，人用剂量可在每天0.01毫克到30.0毫克的范围内，优选范围在每千克体重0.01毫克到10毫克的效应物。
已发现哺乳动物的血中二肽基肽酶IV或类DPIV酶效应物给药的直接结果是，由于其活性的暂时降低，内源的(或额外给予的外源的)促胰岛肽肠抑胃肽GIP1-42及胰高血糖素样肽酰胺-17-26(GLP-17-36)(或GLP-17-37或它的类似物)被DPIV或类DPIV酶分解而降低，因此这些肽激素或其类似物的浓度的降低被减慢或延迟。通过DPIV效应物的作用，(内源性或外源性)肠降血糖素或其类似物的稳定性增加，其结果是由于对胰腺内朗罕氏细胞的肠降血糖素受体的促胰岛刺激来说前者的量增加，改变了身体本身胰岛素的有效性，其能刺激被治疗机体碳水化合物的代谢。
结果，被治疗机体血清中的血糖水平降低到高血糖血症特征性血糖浓度以下，因此可预防或减轻代谢异常，如葡萄糖耐受不良，糖尿，高糖血症及严重的代谢酸中毒及糖尿病，它们是长期血液中血糖升高的临床症状。
在现有技术所知的口服有效抗糖尿病药中，如此有效的低分子量物质至今为止是未知的(除了双胍二甲双胍：分子量为130)。氨酰基噻唑烷的分子量在146(甘氨酰噻唑烷)，203(异亮氨酰噻唑烷)到275(色氨酰噻唑烷)的范围内变化。相比之下，磺酰脲(优降糖：494)，糖类(阿卡波糖：630)及噻唑烷二酮(pioglitazon：586)的分子量在500到700Da内变化。体内氨酰噻唑烷被氨基肽酶水解及酸水解形成内源性物质，例如氨基酸及半胱胺，因此本发明化合物作为口服抗糖尿病药的使用丰富了药品。
在小鼠及大鼠中，经口给予本发明中使用的化合物可比平均水平更好地治疗实验诱导的高糖血症(表2及3)。在对小鼠及大鼠所作的三周毒理学实验中，给予有效剂量的500到1000倍不能明显出现病理变化。
表1显示了本发明化合物对DP IV的有益作用。
表1：在30℃，pH 7.6及离子强度为0.125的条件下，不同效应物对于二肽基肽酶IV催化0.4毫摩尔底物H-Gly-Pro-pNA水解反应的作用
效应物 效应物对DPIV的亲和性Ki[nM] 在10微摩尔效应物存在时DPIV的残余活性％
二甲双胍 ＞＞1,000,000  100
优降糖 ＞＞1,000,000  100
阿卡波糖 ＞＞1,000,000  100
H-天冬酰胺-吡咯烷 12,000  83.1
H-天冬酰胺-噻唑烷 3,500  47.2
H-天冬氨酸-吡咯烷 14,000  81.6
H-天冬氨酸-噻唑烷 2,900  45.6
H-天冬氨酸(NHOH)-吡咯烷 13,000  88.2
H-天冬氨酸(NHOH)-噻唑烷 8,800  54.5
H-谷氨酸-吡咯烷 2,200  38.5
H-谷氨酸-酰噻唑烷 610  25.0
H-谷氨酸(NHOH)-吡咯烷 2,800  44.9
H-谷氨酸(NHOH)-噻唑烷 1,700  36.5
H-组氨酸-吡咯烷 3,500  49.7
H-组氨酸-噻唑烷 1,800  35.2
H-脯氨酸-吡咯烷 4,100  50.2
H-脯氨酸-噻唑烷 1,200  27.2
H-异亮氨酸-吡咯烷 3,100  43.8
H-异亮氨酸-噻唑烷 210  12.3
H-L-别-异亮氨酸-噻唑烷 190  10.0
H-缬氨酸-吡咯烷 480  23.3
H-缬氨酸-噻唑烷 270  13.6
已知氨酰吡咯烷及氨酰噻唑烷可被小肠粘膜细胞，血清和肝细胞上的脯氨酸氨基肽酶及氨酰基脯氨酸二肽酶所分解，且噻唑烷环在酸存在时(如胃酸)趋于打开，形成相应的半胱胺衍生物(见US 458407)。因此，当口服给药时，惊奇地发现活性成分具有剂量依赖型有效性。可在下表中看到在对健康的Wistar大鼠经口给予L-别-异亮氨酸-噻唑烷后，L-别-异亮氨酸-噻唑烷对血清DPIV活性的剂量依赖作用。
表2：经口给予及依赖于L-别-异亮氨酸-噻唑烷的剂量后在30℃，pH 7.6及0.125的离子强度的条件下，血清中的DP IV对于0.4毫摩尔的底物H-甘氨酸-脯氨酸-pNA的残余活性，在给予抑制剂30分钟后检测
    每只试验动物的剂量     DPIV的残余活性％
    0毫克     100
    2.5毫克     52
    5.0毫克     40
    10毫克     28
    20毫克     29
在糖尿病动物模型中，经口给予本发明的活性成分L-别-异亮氨酸-噻唑烷并同步口服糖刺激物后，可达到惊奇也是希望看到的结果，就是其具有降糖作用(表3)。
为了加强各种抗糖尿病药的降血糖作用，通常是混合使用不同的口服有效抗糖尿病药。虽然本发明中效应物的抗糖尿病作用是不依赖其它已知口服抗糖尿病药，为了达到理想的正常血糖效果，本发明的活性成分类似地可以合适制剂的形式可适用于组合治疗。
因此，本发明中所使用的化合物可制成传统配方，例如，片剂，胶囊，糖丸，药丸，栓剂，小粒，气雾剂，糖浆，液体，固体及乳剂及悬浮液和溶液，使用惰性，非毒性，药物可接受的载体及添加剂或溶剂。在这样的配方中，每一例子中药物学有效化合物优选以总混合物的约0.1到80％(重量)、优选1-50％(重量)的浓度存在，也就是说足够产生指定范围的剂量的量。
表3：对同步进行糖耐受试验不同的动物模型大鼠经口给予20微摩尔的L-别-异亮氨酸-噻唑烷后，在60分钟期间循环血糖的降低程度
    动物模型 对照组的糖浓度，以％表示 用L-别-异亮氨酸-噻唑烷治疗后的糖浓度，以％表示
Wistar大鼠，健康     100     82
Wistar大鼠(糖尿病2b-模型，肥胖)     100     73
胃肠道粘膜对本发明中所使用化合物的良好吸收使得能够使用大量盖仑制剂：
这些物质作为药物能以糖丸，胶囊，可咬型胶囊，片剂，滴剂，糖浆及栓剂和鼻腔喷雾的形式被使用。
通过使用溶剂及/或载体，任选地使用乳化剂及/或分散剂来扩散活性成分生产配方，任选地，例如水作为稀释剂时有机溶剂可作为助溶剂。
下列的辅助成分可提及：水，非毒性有机溶剂，如石蜡(矿物油部分)，植物油(如油菜籽油，花生油，芝麻油)，醇类(如乙醇，甘油)，乙二醇类(如丙二醇，聚乙二醇)；固体载体，例如粉碎的天然矿物质(高度分散的硅酸，硅酸盐)，糖类(如未加工糖，乳糖，葡萄糖)；乳化剂，如非离子及阴离子乳化剂(如聚氧乙烯脂肪酸酯，聚氧乙烯脂肪醇醚，烷基磺酸盐及芳基磺酸盐)，分散剂(如，木质素，亚硫酸废液，甲基纤维素，淀粉及聚乙烯吡咯酮)及助流剂(如硬脂酸镁，滑石，硬脂酸及十二烷基硫酸钠)及任选地调味剂。
传统的给药方式是有效的，优选肠道或肠道外给药，特别是经口给药。在肠道给药时，除了包括上述的载体，片剂也可包括其它添加剂，如柠檬酸钠，碳酸钙及磷酸钙，也可加入各种辅助成分，如淀粉，特别是土豆淀粉，明胶等。为制成片剂可使用助流剂，如硬脂酸镁，十二烷基硫酸钠，滑石。在为口服使用的水性悬浮液及/或酏剂的情况下，为了各种口味除了上述所提及的添加剂，可在有效成分中加入矫味剂或色素。
对于肠道外给药，可使用活性成分的溶液，其使用了合适的液态载体物质。在静脉给药时，已证明给药剂量大约在0.01到2.0克/千克体重/天的范围内，特别是在0.01到1.0克/千克体重/天的范围内效果较好，在肠道给药时，给药剂量大约在0.01到2.0克/千克体重/天的范围内，特别是在0.01到1.0克/千克体重/天的范围内效果较好。
不过在一些时候，根据试验动物或患者的体重或给药途径，并且以动物的种类及其对药物的个体或给药间隔的不同反应为基础，必须以不同于指示量给药。一些时候例如使用少于上面所提及的最小剂量就够了，而另一些时候需使用超过上述所提及剂量的上限。当使用较大剂量时，最好一天分成几份使用。对于人类也是上述的剂量范围，同时上面的建议也适用。
药物配方的实施例
1.每粒胶囊中含有100毫克的L-别-异亮氨酰噻唑烷：
对于约10,000粒胶囊，需准备下列成分的溶液：
L-别-异亮氨酰噻唑烷盐酸盐    1.0千克
甘油                         0.5千克
聚乙二醇                     3.0千克
水                           0.5千克
                                           
                             5.0千克
溶液以已知方式放入软明胶胶囊中，胶囊适于咀嚼或吞咽。
2.含有100毫克L-别-异亮氨酰噻唑烷的片剂/糖衣片剂或糖丸：
下面是关于制备100,000个片剂所需的量：
L-别-异亮氨酰噻唑烷盐酸盐，细碎    10.0千克
葡萄糖                             4.35千克
乳糖                               4.35千克
淀粉                               4.50千克
纤维素，细碎                       4.50千克
上述成分混合后与下面溶液相混，该溶液由以下来制备
聚乙烯吡咯烷酮                  2.0千克
多乙氧基醚                      0.1千克
及水                            大约5.0千克
并用已知的方法将潮湿块磨碎成粒状，随后加入0.2千克的硬脂酸镁，干燥。最后得到30.0千克的片剂混合物，将其制成圆顶样每片300毫克的片剂。该片剂能用已知的方法包衣或糖衣化。
下面是优选化合物的技术数据。
关于Ile-Thia*延胡索酸盐(异构体)及其它盐类的实验
物质  Ki  Mp(℃) CE(min)  MS [α]H20
L-苏型-IT*F  8*10-8  150DSC.  160  203 -10.7(405nm)
D-苏型-IT*F  无抑制  147  158  203 没测
L-别-IT*F  2*10-7  145-6  154  203 -4.58(380nm)
D-别-IT*F  无抑制  144-6  150  203 4.5(380nm)
IT*F＝异亮氨酰噻唑烷延胡索酸盐
核磁共振及高效液相色谱数据证实了实验物质的性质。
测定物质Ki的测量条件
酶：在25毫摩尔Tris pH 7.6，30％硫酸铵，0.5毫摩尔EDTA，
0.5毫摩尔DTE中的DP IV猪肾，0.75毫克/毫升，18单位/毫升(GPpNA)
储存溶液：用测量缓冲液稀释成1∶250
缓冲液：40亳摩尔HEPES pH 7.6，I＝0.125(KCl)
底物：GPpNA*HCl
储存溶液：2.1毫摩尔
测量装置：Perkin-Elmer生物分析读数仪，HTS 7000Plus，T＝30℃λ＝450纳米
测量混合物：100微升缓冲液
100微升 底物(三种不同浓度0.8毫摩尔-0.2毫摩尔)50微升水/抑制剂(七种不同浓度，2.1微摩尔-32.8纳摩尔)
10微升 酶
缓冲液，水/抑制剂及酶预热到30℃，反应在加入如上一样预热的底物后开始。
检测进行四次。
测量时间为10分钟。
熔点测定
使用来自Leica Aktiengesellschaft的Kofler加热平台显微镜或DSC仪器(Heumann-Pharma)来测定熔点，数值未校正。
旋光性
用来自Perkin-Elmer公司的“Polarimeter 341”或更先进的设备记录在不同波长条件下的旋转值。
质谱测量条件
在购自PE Sciex公司的“API165”或“API 365”设备上利用电喷离子化(ESI)来记录质谱。
这个试验中浓度大约为c＝10微克/毫升，物质被MeOH/H2O50∶50，0.1％HCO2H吸收，使用电喷泵(20微升/分钟)灌输。在阳性状态[M+H]+，ESI电压U＝5600V的条件下测量。
盐类有以下数据：
IT*盐类 Ki M(gmol-1) Mp(℃)
琥珀酸盐 5.1e-8  522.73  116
酒石酸盐 8.3e-8  352.41  122
延胡索酸盐 8.3e-8  520.71  156
盐酸盐 7.2e-8  238.77  169
磷酸盐 1.3e-7  300.32  105
检测Ile-Thia的溶解度
Ile-Thia*延胡索酸盐
称量为10.55毫克
相应于0.02毫摩尔(520.72克/摩尔)
加入100微升H2O蒸馏
100微升不溶，目视：对表面不湿润
从200微升开始溶解
一直到400微升才完全溶解
2.63％
因此说这种盐很少潮湿并不易分解
Ile-Thia*琥珀酸盐
称量为16.6毫克
相应于0.031毫摩尔(522.73克/摩尔)
加入16微升H2O蒸馏
16微升不溶，目视：“吸收“水分
从66微升到1.5毫升可观察到物质不完全溶解
Ile-Thia*酒石酸盐
称量为17.3毫克
相应于0.049毫摩尔(352.41克/摩尔)
加入100微升H2O蒸馏
100微升完全溶解
17.3％
Ile-Thia*磷酸盐
称量为15.5毫克
相应于0.051毫摩尔(300.32克/摩尔)
加入100微升H2O蒸馏
可观察到100微升微溶
不断每次加入100微升水
到400微升时完全溶解
3.87％
Ile-Thia*盐酸盐
称量为16.1毫克
相应于0.067毫摩尔(238.77克/摩尔)
加入100微升H2O蒸馏
100微升完全溶解
16.1％
Ile-Thia*盐类的概括分析
Boc保护氨基酸Boc-Ile-OH放入乙酸乙酯中并将混合物冷却到大约零下5℃。逐滴加入N-甲基吗啉，在恒温下逐滴加入氯化新戊酸(试验室规模)或新己酰氯(中试规模)。为了活化，需将反应物搅拌几分钟。  随后依次逐滴加入N-甲基吗啉(试验室规模)及噻唑烷盐酸盐(试验室规模)，加入噻唑烷(中试规模)。实验室中的加工是用传统方法使用盐溶液，中试时混合物用氢氧化钠及醋酸溶液来纯化。
使用盐酸/二恶烷(试验室规模)或硫酸(中试规模)来除去Boc保护基团。
在实验室中从乙醇/乙醚中结晶出盐酸盐。
在中试中，通过加入氢氧化钠/氨来制备游离胺。延胡索酸溶解到热乙醇中，逐滴加入游离胺，出现(Ile-Thia)2延胡索酸盐的沉淀。
电泳分析异构体及对映体。

Claims (18)

1、由氨基酸L-别-异亮氨酸及噻唑烷或吡咯烷基团形成的二肽模拟物，其选自L-别-异亮氨酰噻唑烷、L-别-异亮氨酰吡咯烷及它们的盐。
2、由氨基酸谷氨酰胺及噻唑烷或吡咯烷基团形成的二肽模拟物，其选自谷氨酰胺酰噻唑烷、谷氨酰胺酰吡咯烷及它们的盐。
3、权利要求1的二肽模拟物，其特征在于所述盐是有机盐或无机酸根。
4、权利要求1-3之任一项的二肽模拟物，其中所述盐为乙酸盐、琥珀酸盐、酒石酸盐、延胡索酸盐、磷酸盐或硫酸盐。
5、权利要求1-4之任一项的二肽模拟物的盐，其特征在于它们以二肽组分与盐组分的摩尔比为1∶1或2∶1存在。
6、权利要求1-5之任一项的二肽模拟物的盐，其为延胡索酸盐。
7、权利要求6的二肽模拟物的盐，其为L-别-异亮氨酰噻唑烷的延胡索酸盐。
8、药物组合物，其包含至少一种权利要求1-7之任一项的化合物与一种或多种药学可接受的载体和/或溶剂的组合。
9、权利要求8的药物组合物，其特征在于所述载体是用于肠道外或肠道制剂的载体。
10、权利要求8的药物组合物，其特征在于其以供口服给药的制剂形式存在。
11、权利要求8-10之任一项的药物组合物，其特征在于其包含具有降血糖作用的另一活性成分。
12、至少一种权利要求1-7之任一项的化合物在制备用于降低二肽基肽酶IV活性的药物中的用途。
13、至少一种权利要求1-7之任一项的化合物在制备用于将哺乳动物血清中的血糖水平降低到高血糖症特征性的葡萄糖浓度以下的药物中的用途。
14、至少一种权利要求1-7之任一项的化合物在制备用于口服治疗与糖尿病相关的代谢障碍的药物中的用途。
15、至少一种权利要求1-7之任一项的化合物在制备用于治疗哺乳动物中的葡萄糖耐受不良、糖尿、高脂血症、代谢性酸中毒、糖尿病、糖尿病性神经病和肾病以及糖尿病后遗症的药物中的用途。
16、至少一种由氨基酸及噻唑烷或吡咯烷基团形成的二肽模拟物及其盐在制备用于将哺乳动物血清中的血糖水平降低到高血糖症特征性的葡萄糖浓度以下的药物中的用途，其中所述氨基酸选自亮氨酸、谷氨酰胺、脯氨酸、天冬酰胺和天冬氨酸。
17、至少一种由氨基酸及噻唑烷或吡咯烷基团形成的二肽模拟物及其盐在制备用于口服治疗与糖尿病相关的代谢障碍的药物中的用途，其中所述氨基酸选自亮氨酸、谷氨酰胺、脯氨酸、天冬酰胺和天冬氨酸。
18、至少一种由氨基酸及噻唑烷或吡咯烷基团形成的二肽模拟物及其盐在制备用于治疗哺乳动物中的葡萄糖耐受不良、糖尿、高脂血症、代谢性酸中毒、糖尿病、糖尿病性神经病和肾病以及糖尿病后遗症的药物中的用途，其中所述氨基酸选自亮氨酸、谷氨酰胺、脯氨酸、天冬酰胺和天冬氨酸。
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Families Citing this family (242)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020006899A1 (en) * 1998-10-06 2002-01-17 Pospisilik Andrew J. Use of dipeptidyl peptidase IV effectors for lowering blood pressure in mammals
BR9813233A (pt) * 1997-09-29 2000-08-22 Point Therapeutics Inc Estimulação de células hematopoéticas in vitro
DE19823831A1 (de) * 1998-05-28 1999-12-02 Probiodrug Ges Fuer Arzneim Neue pharmazeutische Verwendung von Isoleucyl Thiazolidid und seinen Salzen
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
US20030176357A1 (en) * 1998-10-06 2003-09-18 Pospisilik Andrew J. Dipeptidyl peptidase IV inhibitors and their uses for lowering blood pressure levels
WO2000053171A1 (en) * 1999-03-05 2000-09-14 Molteni L. E C. Dei Fratelli Alitti Societa' Di Esercizio S.P.A. Use of metformin in the preparation of pharmaceutical compositions capable of inhibiting the enzyme dipeptidyl peptidase iv
US6548529B1 (en) 1999-04-05 2003-04-15 Bristol-Myers Squibb Company Heterocyclic containing biphenyl aP2 inhibitors and method
US6890904B1 (en) * 1999-05-25 2005-05-10 Point Therapeutics, Inc. Anti-tumor agents
DE19940130A1 (de) 1999-08-24 2001-03-01 Probiodrug Ges Fuer Arzneim Neue Effektoren der Dipeptidyl Peptidase IV zur topischen Anwendung
CA2393825A1 (en) * 1999-12-17 2001-06-21 Versicor, Inc. Novel succinate compounds, compositions and methods of use and preparation
US20080076811A1 (en) * 2000-01-21 2008-03-27 Bork Balkan Combinations comprising depeptidypeptidase-iv inhibitors and antidiabetic agents
ES2433476T3 (es) * 2000-01-21 2013-12-11 Novartis Ag Combinaciones que contienen inhibidores de la dipeptidilpeptidasa-IV y agentes 5 antidiabéticos
AU2001233622A1 (en) * 2000-02-25 2001-09-03 Novo-Nordisk A/S Inhibition of beta cell degeneration
DE60137216D1 (de) * 2000-03-31 2009-02-12 Prosidion Ltd Verbesserung der aktivität der inselzellen bei diabetes mellitus und dessen prävention
GB0010183D0 (en) * 2000-04-26 2000-06-14 Ferring Bv Inhibitors of dipeptidyl peptidase IV
GB0014969D0 (en) 2000-06-19 2000-08-09 Smithkline Beecham Plc Novel method of treatment
US7078397B2 (en) 2000-06-19 2006-07-18 Smithkline Beecham Corporation Combinations of dipeptidyl peptidase IV inhibitors and other antidiabetic agents for the treatment of diabetes mellitus
ATE450504T1 (de) * 2000-08-10 2009-12-15 Mitsubishi Tanabe Pharma Corp Prolinderivative und deren verwendung als medikamente
EP1891948A1 (en) * 2000-10-27 2008-02-27 Probiodrug AG Treatment of neurological and neuropsychological disorders
CA2424475A1 (en) * 2000-10-27 2002-05-02 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
CA2433090A1 (en) * 2000-12-27 2002-07-04 Kyowa Hakko Kogyo Co., Ltd. Dipeptidyl peptidase iv inhibitor
CN100408579C (zh) * 2001-02-24 2008-08-06 贝林格尔英格海姆法玛两合公司 黄嘌呤衍生物,其制法及其作为药物组合物的用途
US20070293426A1 (en) * 2001-04-02 2007-12-20 Hans-Ulrich Demuth Methods for improving islet signaling in diabetes mellitus and for its prevention
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
AU2002254567B2 (en) 2001-04-11 2007-10-11 Bristol-Myers Squibb Company Amino acid complexes of C-aryl glucosides for treatment of diabetes and method
US6944925B2 (en) * 2001-06-13 2005-09-20 Ttx Company Articulated connector reconditioning process and apparatuses
EP1399433B1 (en) 2001-06-27 2007-08-22 Smithkline Beecham Corporation Fluoropyrrolidines as dipeptidyl peptidase inhibitors
KR20040015298A (ko) 2001-06-27 2004-02-18 스미스클라인 비참 코포레이션 디펩티딜 펩티다제 억제제로서의 플루오로피롤리딘
AU2002321135B2 (en) * 2001-06-27 2007-11-08 Probiodrug Ag Dipepitdyl peptidase IV inhibitors and their uses as anti-cancer agents
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
ES2296962T3 (es) 2001-06-27 2008-05-01 Smithkline Beecham Corporation Pirrolidinas como inhibidores de dipeptidil peptidasa.
US20030130199A1 (en) 2001-06-27 2003-07-10 Von Hoersten Stephan Dipeptidyl peptidase IV inhibitors and their uses as anti-cancer agents
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
US20040259883A1 (en) 2001-09-14 2004-12-23 Hiroshi Sakashita Thiazolidine derivative and medicinal use thereof
HUP0700151A2 (en) 2001-10-18 2007-05-29 Bristol Myers Squibb Co Human glucagon-like-peptide-1 mimics and their use in the treatment of diabetes and related conditions
US7238671B2 (en) 2001-10-18 2007-07-03 Bristol-Myers Squibb Company Human glucagon-like-peptide-1 mimics and their use in the treatment of diabetes and related conditions
GB0125446D0 (en) * 2001-10-23 2001-12-12 Ferring Bv Novel anti-diabetic agents
DE60304911D1 (de) 2002-02-25 2006-06-08 Eisai Co Ltd Xanthin-Derivate als DPP-IV-Inhibitoren
DE20220238U1 (de) 2002-02-28 2003-05-08 Probiodrug AG, 06120 Halle Glutaminyl basierte DPIV Inhibitoren
EP1695970A1 (en) * 2002-02-28 2006-08-30 Prosidion Limited Peptides useful for competitive modulation of dipeptidyl peptidase IV catalysis
US20030232761A1 (en) * 2002-03-28 2003-12-18 Hinke Simon A. Novel analogues of glucose-dependent insulinotropic polypeptide
US7057046B2 (en) 2002-05-20 2006-06-06 Bristol-Myers Squibb Company Lactam glycogen phosphorylase inhibitors and method of use
US6710040B1 (en) 2002-06-04 2004-03-23 Pfizer Inc. Fluorinated cyclic amides as dipeptidyl peptidase IV inhibitors
ES2306781T3 (es) * 2002-08-09 2008-11-16 Prosidion Ltd. Inhibidores de la dipeptidil-peptidasa iv para disminucion de la tasa de aumento cronico de peso.
TW200404796A (en) * 2002-08-19 2004-04-01 Ono Pharmaceutical Co Nitrogen-containing compound
US7407955B2 (en) 2002-08-21 2008-08-05 Boehringer Ingelheim Pharma Gmbh & Co., Kg 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions
US7569574B2 (en) 2002-08-22 2009-08-04 Boehringer Ingelheim Pharma Gmbh & Co. Kg Purine derivatives, the preparation thereof and their use as pharmaceutical compositions
US7495005B2 (en) * 2002-08-22 2009-02-24 Boehringer Ingelheim Pharma Gmbh & Co. Kg Xanthine derivatives, their preparation and their use in pharmaceutical compositions
US20040058876A1 (en) * 2002-09-18 2004-03-25 Torsten Hoffmann Secondary binding site of dipeptidyl peptidase IV (DP IV)
EP1543023B1 (en) * 2002-09-18 2010-03-17 Prosidion Limited Secondary binding site of dipeptidyl peptidase iv (dp iv)
ES2344057T3 (es) 2002-10-23 2010-08-17 Bristol-Myers Squibb Company Inhibidores de la dipeptidil peptidasa iv basados en nitrilos de glicina.
US7482337B2 (en) * 2002-11-08 2009-01-27 Boehringer Ingelheim Pharma Gmbh & Co. Kg Xanthine derivatives, the preparation thereof and their use as pharmaceutical compositions
US7098235B2 (en) 2002-11-14 2006-08-29 Bristol-Myers Squibb Co. Triglyceride and triglyceride-like prodrugs of glycogen phosphorylase inhibiting compounds
DE10254304A1 (de) * 2002-11-21 2004-06-03 Boehringer Ingelheim Pharma Gmbh & Co. Kg Neue Xanthinderivate, deren Herstellung und deren Verwendung als Arzneimittel
TW200504021A (en) 2003-01-24 2005-02-01 Bristol Myers Squibb Co Substituted anilide ligands for the thyroid receptor
DE10308355A1 (de) 2003-02-27 2004-12-23 Aventis Pharma Deutschland Gmbh Aryl-cycloalkyl substituierte Alkansäurederivate, Verfahren zu ihrer Herstellung und ihre Anwendung als Arzneimittel
DE10308352A1 (de) 2003-02-27 2004-09-09 Aventis Pharma Deutschland Gmbh Arylcycloalkylderivate mit verzweigten Seitenketten, Verfahren zu ihrer Herstellung und ihre Anwendung als Arzneimittel
DE10308353A1 (de) 2003-02-27 2004-12-02 Aventis Pharma Deutschland Gmbh Diarylcycloalkylderivate, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel
US7148246B2 (en) 2003-02-27 2006-12-12 Sanofi-Aventis Deutschland Gmbh Cycloalkyl derivatives having bioisosteric carboxylic acid groups, processes for their preparation and their use as pharmaceuticals
DE10308351A1 (de) 2003-02-27 2004-11-25 Aventis Pharma Deutschland Gmbh 1,3-substituierte Cycloalkylderivate mit sauren, meist heterocyclischen Gruppen, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel
US7550590B2 (en) 2003-03-25 2009-06-23 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
KR20100106630A (ko) 2003-05-05 2010-10-01 프로비오드룩 아게 글루타미닐 및 글루타메이트 사이클라제의 이펙터의 용도
JP4806628B2 (ja) 2003-05-05 2011-11-02 プロビオドルグ エージー グルタミニルシクラーゼ阻害剤
US20040229848A1 (en) * 2003-05-05 2004-11-18 Hans-Ulrich Demuth Glutaminyl based DP IV-inhibitors
WO2004098625A2 (en) 2003-05-05 2004-11-18 Probiodrug Ag Medical use of inhibitors of glutaminyl and glutamate cyclases
US7638638B2 (en) 2003-05-14 2009-12-29 Takeda San Diego, Inc. Dipeptidyl peptidase inhibitors
US7459474B2 (en) 2003-06-11 2008-12-02 Bristol-Myers Squibb Company Modulators of the glucocorticoid receptor and method
US7566707B2 (en) 2003-06-18 2009-07-28 Boehringer Ingelheim International Gmbh Imidazopyridazinone and imidazopyridone derivatives, the preparation thereof and their use as pharmaceutical compositions
US6995183B2 (en) 2003-08-01 2006-02-07 Bristol Myers Squibb Company Adamantylglycine-based inhibitors of dipeptidyl peptidase IV and methods
ZA200602051B (en) 2003-08-13 2007-10-31 Takeda Pharmaceutical 4-pyrimidone derivatives and their use as peptidyl peptidase inhibitors
US7169926B1 (en) 2003-08-13 2007-01-30 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
US7678909B1 (en) 2003-08-13 2010-03-16 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
JP2007502991A (ja) 2003-08-20 2007-02-15 バイオサイト インコーポレイテッド 生物活性ナトリウム利尿ペプチドを測定するための、およびその治療可能性を向上させるための方法および組成物
AU2004267955A1 (en) * 2003-09-02 2005-03-10 Prosidion Ltd. Combination therapy for glycaemic control
WO2005026148A1 (en) 2003-09-08 2005-03-24 Takeda San Diego, Inc. Dipeptidyl peptidase inhibitors
US7371759B2 (en) 2003-09-25 2008-05-13 Bristol-Myers Squibb Company HMG-CoA reductase inhibitors and method
BRPI0415409A (pt) 2003-10-15 2006-12-05 Probiodrug Ag uso de efetuadores de ciclases de glutaminila e glutamato
DE10348023A1 (de) * 2003-10-15 2005-05-19 Imtm Gmbh Neue Alanyl-Aminopeptidasen-Inhibitoren zur funktionellen Beeinflussung unterschiedlicher Zellen und zur Behandlung immunologischer, entzündlicher, neuronaler und anderer Erkrankungen
EP2338490A3 (en) 2003-11-03 2012-06-06 Probiodrug AG Combinations useful for the treatment of neuronal disorders
KR20170005163A (ko) 2003-11-17 2017-01-11 노파르티스 아게 디펩티딜 펩티다제 ⅳ 억제제의 용도
US7420059B2 (en) 2003-11-20 2008-09-02 Bristol-Myers Squibb Company HMG-CoA reductase inhibitors and method
DE10355304A1 (de) * 2003-11-27 2005-06-23 Boehringer Ingelheim Pharma Gmbh & Co. Kg Neue 8-(Piperazin-1-yl)-und 8-([1,4]Diazepan-1-yl)-xanthine, deren Herstellung und deren Verwendung als Arzneimittel
CA2548918C (en) 2003-12-11 2013-05-21 Mitsubishi Pharma Corporation Alpha-amino acid derivatives and use thereof as medicines
US7326784B2 (en) * 2003-12-19 2008-02-05 Altana Pharma Ag Intermediates for the preparation of tricyclic dihydropyrano-imidazo-pyridines derivatives
CN101618216B (zh) * 2004-01-20 2012-01-04 诺瓦提斯公司 直接压片配方和方法
EP2165703A3 (en) * 2004-01-20 2012-03-28 Novartis Pharma AG Direct compression formulation and process
US7241787B2 (en) 2004-01-25 2007-07-10 Sanofi-Aventis Deutschland Gmbh Substituted N-cycloexylimidazolinones, process for their preparation and their use as medicaments
BRPI0507485A (pt) 2004-02-05 2007-07-10 Probiodrug Ag inibidores novos de glutaminil ciclase
US7501426B2 (en) * 2004-02-18 2009-03-10 Boehringer Ingelheim International Gmbh 8-[3-amino-piperidin-1-yl]-xanthines, their preparation and their use as pharmaceutical compositions
DE102004009039A1 (de) * 2004-02-23 2005-09-08 Boehringer Ingelheim Pharma Gmbh & Co. Kg 8-[3-Amino-piperidin-1-yl]-xanthine, deren Herstellung und Verwendung als Arzneimittel
US7732446B1 (en) 2004-03-11 2010-06-08 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
US7393847B2 (en) * 2004-03-13 2008-07-01 Boehringer Ingleheim International Gmbh Imidazopyridazinediones, their preparation and their use as pharmaceutical compositions
CN102127053A (zh) 2004-03-15 2011-07-20 武田药品工业株式会社 二肽基肽酶抑制剂
DE602004004631D1 (de) 2004-04-01 2007-03-22 Sanofi Aventis Deutschland Oxadiazolone, Verfahren zu ihrer Herstellung sowie ihre Verwendung als Pharmazeutika
US7179809B2 (en) * 2004-04-10 2007-02-20 Boehringer Ingelheim International Gmbh 2-Amino-imidazo[4,5-d]pyridazin-4-ones, their preparation and their use as pharmaceutical compositions
US7439370B2 (en) * 2004-05-10 2008-10-21 Boehringer Ingelheim International Gmbh Imidazole derivatives, their preparation and their use as intermediates for the preparation of pharmaceutical compositions and pesticides
US7687638B2 (en) * 2004-06-04 2010-03-30 Takeda San Diego, Inc. Dipeptidyl peptidase inhibitors
DE102004030502A1 (de) 2004-06-24 2006-01-12 Boehringer Ingelheim Pharma Gmbh & Co. Kg Neue Imidazole und Triazole, deren Herstellung und Verwendung als Arzneimittel
TW200611704A (en) 2004-07-02 2006-04-16 Bristol Myers Squibb Co Human glucagon-like-peptide-1 modulators and their use in the treatment of diabetes and related conditions
US7534763B2 (en) 2004-07-02 2009-05-19 Bristol-Myers Squibb Company Sustained release GLP-1 receptor modulators
US7145040B2 (en) 2004-07-02 2006-12-05 Bristol-Myers Squibb Co. Process for the preparation of amino acids useful in the preparation of peptide receptor modulators
WO2006019965A2 (en) 2004-07-16 2006-02-23 Takeda San Diego, Inc. Dipeptidyl peptidase inhibitors
ATE553077T1 (de) * 2004-07-23 2012-04-15 Nuada Llc Peptidaseinhibitoren
US20070259927A1 (en) * 2004-08-26 2007-11-08 Takeda Pharmaceutical Company Limited Remedy for Diabetes
AR050615A1 (es) 2004-08-27 2006-11-08 Novartis Ag Composiciones farmaceuticas para la administracion oral
DE102004043944A1 (de) * 2004-09-11 2006-03-30 Boehringer Ingelheim Pharma Gmbh & Co. Kg Neue 8-(3-Amino-piperidin-1-yl)-7-(but-2-inyl)-xanthine, deren Herstellung und deren Verwendung als Arzneimittel
DE102004044221A1 (de) * 2004-09-14 2006-03-16 Boehringer Ingelheim Pharma Gmbh & Co. Kg Neue 3-Methyl-7-butinyl-xanthine, deren Herstellung und deren Verwendung als Arzneimittel
US20060063719A1 (en) * 2004-09-21 2006-03-23 Point Therapeutics, Inc. Methods for treating diabetes
AR051446A1 (es) 2004-09-23 2007-01-17 Bristol Myers Squibb Co Glucosidos de c-arilo como inhibidores selectivos de transportadores de glucosa (sglt2)
DE102004054054A1 (de) 2004-11-05 2006-05-11 Boehringer Ingelheim Pharma Gmbh & Co. Kg Verfahren zur Herstellung chiraler 8-(3-Amino-piperidin-1-yl)-xanthine
US7872124B2 (en) * 2004-12-21 2011-01-18 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
US7589088B2 (en) 2004-12-29 2009-09-15 Bristol-Myers Squibb Company Pyrimidine-based inhibitors of dipeptidyl peptidase IV and methods
US7635699B2 (en) 2004-12-29 2009-12-22 Bristol-Myers Squibb Company Azolopyrimidine-based inhibitors of dipeptidyl peptidase IV and methods
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
US7317024B2 (en) 2005-01-13 2008-01-08 Bristol-Myers Squibb Co. Heterocyclic modulators of the glucocorticoid receptor, AP-1, and/or NF-κB activity and use thereof
ES2588164T3 (es) 2005-02-18 2016-10-31 Mitsubishi Tanabe Pharma Corporation Sal de un derivado de prolina, solvato del mismo, y método de producción de los mismos
EP1879881A2 (en) 2005-04-14 2008-01-23 Bristol-Myers Squibb Company Inhibitors of 11-beta hydroxysteroid dehydrogenase type i
US7521557B2 (en) 2005-05-20 2009-04-21 Bristol-Myers Squibb Company Pyrrolopyridine-based inhibitors of dipeptidyl peptidase IV and methods
US20090317376A1 (en) 2005-06-06 2009-12-24 Georgetown University Medical School Compositions And Methods For Lipo Modeling
DE102005026762A1 (de) 2005-06-09 2006-12-21 Sanofi-Aventis Deutschland Gmbh Azolopyridin-2-on-derivate als Inhibitoren von Lipasen und Phospholipasen
US7888381B2 (en) 2005-06-14 2011-02-15 Bristol-Myers Squibb Company Modulators of glucocorticoid receptor, AP-1, and/or NF-κB activity, and use thereof
ES2426345T3 (es) 2005-07-20 2013-10-22 Eli Lilly And Company Compuesto unidos en posición 1-amino
DE102005035891A1 (de) 2005-07-30 2007-02-08 Boehringer Ingelheim Pharma Gmbh & Co. Kg 8-(3-Amino-piperidin-1-yl)-xanthine, deren Herstellung und deren Verwendung als Arzneimittel
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
DK1942898T4 (da) 2005-09-14 2014-06-02 Takeda Pharmaceutical Dipeptidylpeptidase-inhibitorer til behandling af diabetes
KR101368988B1 (ko) 2005-09-16 2014-02-28 다케다 야쿠힌 고교 가부시키가이샤 디펩티딜 펩티다제 억제제
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
TW200738266A (en) * 2005-09-29 2007-10-16 Sankyo Co Pharmaceutical agent containing insulin resistance improving agent
JOP20180109A1 (ar) * 2005-09-29 2019-01-30 Novartis Ag تركيبة جديدة
WO2007053819A2 (en) 2005-10-31 2007-05-10 Bristol-Myers Squibb Company Pyrrolidinyl beta-amino amide-based inhibitors of dipeptidyl peptidase iv and methods
WO2007054577A1 (en) 2005-11-14 2007-05-18 Probiodrug Ag Cyclopropyl-fused pyrrolidine derivatives as dipeptidyl peptidase iv inhibitors
CN101365432B (zh) * 2005-12-16 2011-06-22 默沙东公司 二肽基肽酶-4抑制剂与二甲双胍的组合的药物组合物
US7592461B2 (en) 2005-12-21 2009-09-22 Bristol-Myers Squibb Company Indane modulators of glucocorticoid receptor, AP-1, and/or NF-κB activity and use thereof
GB0526291D0 (en) 2005-12-23 2006-02-01 Prosidion Ltd Therapeutic method
WO2007112347A1 (en) 2006-03-28 2007-10-04 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
EP2369341A3 (en) 2006-04-11 2012-01-04 Arena Pharmaceuticals, Inc. Methods of using gpr119 receptor to identify compounds useful for increasing bone mass in an individual
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
EP2007734A1 (en) 2006-04-12 2008-12-31 Probiodrug AG Enzyme inhibitors
US8343531B2 (en) 2006-04-21 2013-01-01 Meiji Co., Ltd. Composition containing peptide as active ingredient
EP1852108A1 (en) * 2006-05-04 2007-11-07 Boehringer Ingelheim Pharma GmbH & Co.KG DPP IV inhibitor formulations
PE20080251A1 (es) 2006-05-04 2008-04-25 Boehringer Ingelheim Int Usos de inhibidores de dpp iv
NO347644B1 (no) 2006-05-04 2024-02-12 Boehringer Ingelheim Int Polymorfer
US20100022457A1 (en) 2006-05-26 2010-01-28 Bristol-Myers Squibb Company Sustained release glp-1 receptor modulators
US7919598B2 (en) 2006-06-28 2011-04-05 Bristol-Myers Squibb Company Crystal structures of SGLT2 inhibitors and processes for preparing same
US7910747B2 (en) 2006-07-06 2011-03-22 Bristol-Myers Squibb Company Phosphonate and phosphinate pyrazolylamide glucokinase activators
US7795291B2 (en) 2006-07-07 2010-09-14 Bristol-Myers Squibb Company Substituted acid derivatives useful as anti-atherosclerotic, anti-dyslipidemic, anti-diabetic and anti-obesity agents and method
JP2010500326A (ja) * 2006-08-08 2010-01-07 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング 糖尿病の治療のためのｄｐｐ−ｉｖ阻害剤としてのピロロ［３，２−ｄ］ピリミジン
NZ574710A (en) 2006-09-07 2012-02-24 Nycomed Gmbh Combination treatment comprising the PDE4 inhibitor Compound A ((2R,4aR, 10bR)6-(2,6-Dimethoxy-pyridin-3-yl)-9-ethoxy-8-methoxy-1 ,2,3,4,4a,10b-hexahydrophenanthridin-2-ol) for diabetes mellitus
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
PE20081150A1 (es) * 2006-09-13 2008-10-03 Takeda Pharmaceutical Inhibidores de dipetidilpeptidasa
EP2099767A1 (en) 2006-11-01 2009-09-16 Brystol-Myers Squibb Company Modulators of glucocorticoid receptor, ap-1, and/or nf- b activity and use thereof
WO2008057862A2 (en) 2006-11-01 2008-05-15 Bristol-Myers Squibb Company MODULATORS OF GLUCOCORTICOID RECEPTOR, AP-1, AND/OR NF-ϰB ACTIVITY AND USE THEREOF
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
ATE554085T1 (de) 2006-11-30 2012-05-15 Probiodrug Ag Neue inhibitoren von glutaminylcyclase
ES2529147T3 (es) 2006-12-26 2015-02-17 Pharmacyclics, Inc. Método para usar los inhibidores de la histona deacetilasa y monitorear biomarcadores en la terapia de combinación
US8093236B2 (en) 2007-03-13 2012-01-10 Takeda Pharmaceuticals Company Limited Weekly administration of dipeptidyl peptidase inhibitors
PE20090185A1 (es) 2007-03-22 2009-02-28 Bristol Myers Squibb Co Formulaciones farmaceuticas que contienen un inhibidor sglt2
WO2008120813A1 (ja) 2007-04-03 2008-10-09 Mitsubishi Tanabe Pharma Corporation ジペプチジルペプチダーゼ４阻害化合物と甘味料との併用
JP5667440B2 (ja) 2007-04-18 2015-02-12 プロビオドルグ エージー グルタミニルシクラーゼ阻害剤としてのチオ尿素誘導体
PE20090696A1 (es) 2007-04-20 2009-06-20 Bristol Myers Squibb Co Formas cristalinas de saxagliptina y procesos para preparar las mismas
MX354786B (es) 2007-06-04 2018-03-21 Synergy Pharmaceuticals Inc Agonistas de guanilato ciclasa utiles para el tratamiento de trastornos gastrointestinales, inflamacion, cancer y otros trastornos.
CA2690004C (en) 2007-06-04 2018-01-23 Ben-Gurion University Of The Negev Research And Development Authority Tri-aryl compounds and compositions comprising the same
US8969514B2 (en) 2007-06-04 2015-03-03 Synergy Pharmaceuticals, Inc. Agonists of guanylate cyclase useful for the treatment of hypercholesterolemia, atherosclerosis, coronary heart disease, gallstone, obesity and other cardiovascular diseases
JP2010534722A (ja) * 2007-07-27 2010-11-11 ブリストル−マイヤーズ スクイブ カンパニー 新規グルコキナーゼ活性化薬およびその使用方法
WO2009024542A2 (en) * 2007-08-17 2009-02-26 Boehringer Ingelheim International Gmbh Purin derivatives for use in the treatment of fab-related diseases
ES2448839T3 (es) 2007-11-01 2014-03-17 Bristol-Myers Squibb Company Compuestos no esteroideos útiles como moderadores de la actividad del receptor de glucocorticoides AP-1 y/o NF-kappa b y uso de los mismos
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.
AR071175A1 (es) 2008-04-03 2010-06-02 Boehringer Ingelheim Int Composicion farmaceutica que comprende un inhibidor de la dipeptidil-peptidasa-4 (dpp4) y un farmaco acompanante
EP2146210A1 (en) 2008-04-07 2010-01-20 Arena Pharmaceuticals, Inc. Methods of using A G protein-coupled receptor to identify peptide YY (PYY) secretagogues and compounds useful in the treatment of conditions modulated by PYY
PE20100156A1 (es) * 2008-06-03 2010-02-23 Boehringer Ingelheim Int Tratamiento de nafld
CA2726917C (en) 2008-06-04 2018-06-26 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders
CN102149710A (zh) 2008-06-24 2011-08-10 百时美施贵宝公司 糖皮质激素受体、AP-1和/或NF-κB 活性的环戊噻吩调节剂及其用途
WO2010009319A2 (en) 2008-07-16 2010-01-21 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase useful for the treatment of gastrointestinal, inflammation, cancer and other disorders
UY32030A (es) 2008-08-06 2010-03-26 Boehringer Ingelheim Int "tratamiento para diabetes en pacientes inapropiados para terapia con metformina"
KR20200118243A (ko) 2008-08-06 2020-10-14 베링거 인겔하임 인터내셔날 게엠베하 메트포르민 요법이 부적합한 환자에서의 당뇨병 치료
BRPI0917675A2 (pt) * 2008-08-15 2015-12-01 Boehringer Ingelheim Int compostos orgânicos para cura de ferida
MX2011002558A (es) 2008-09-10 2011-04-26 Boehringer Ingelheim Int Terapia de combinacion para el tratamiento de diabetes y estados relacionados.
US20200155558A1 (en) 2018-11-20 2020-05-21 Boehringer Ingelheim International Gmbh Treatment for diabetes in patients with insufficient glycemic control despite therapy with an oral antidiabetic drug
KR101054911B1 (ko) 2008-10-17 2011-08-05 동아제약주식회사 디펩티딜펩티다아제-ⅳ의 활성을 저해하는 화합물 및 다른 항당뇨 또는 항비만 약물을 유효성분으로 함유하는 당뇨 또는 비만의 예방 및 치료용 약학적 조성물
US8865729B2 (en) 2008-12-23 2014-10-21 Boehringer Ingelheim International Gmbh Salt forms of a xanthine compound
TW201036975A (en) 2009-01-07 2010-10-16 Boehringer Ingelheim Int Treatment for diabetes in patients with inadequate glycemic control despite metformin therapy
AR077642A1 (es) 2009-07-09 2011-09-14 Arena Pharm Inc Moduladores del metabolismo y el tratamiento de trastornos relacionados con el mismo
SG178953A1 (en) 2009-09-11 2012-04-27 Probiodrug Ag Heterocylcic derivatives as inhibitors of glutaminyl cyclase
CA2780941C (en) 2009-11-13 2018-06-12 Bristol-Myers Squibb Company Immediate release tablet formulations
PT2498758T (pt) 2009-11-13 2018-10-23 Astrazeneca Uk Ltd Formulações de comprimido bicamada
MX2012005425A (es) 2009-11-13 2012-06-14 Astrazeneca Uk Ltd Formulaciones de metformina de masa reducida.
AU2010323068B2 (en) 2009-11-27 2015-09-03 Boehringer Ingelheim International Gmbh Treatment of genotyped diabetic patients with DPP-IV inhibitors such as linagliptin
TWI562775B (en) 2010-03-02 2016-12-21 Lexicon Pharmaceuticals Inc Methods of using inhibitors of sodium-glucose cotransporters 1 and 2
US9181233B2 (en) 2010-03-03 2015-11-10 Probiodrug Ag Inhibitors of glutaminyl cyclase
AU2011226074B2 (en) 2010-03-10 2015-01-22 Vivoryon Therapeutics N.V. Heterocyclic inhibitors of glutaminyl cyclase (QC, EC 2.3.2.5)
CN102918027A (zh) 2010-04-06 2013-02-06 艾尼纳制药公司 Gpr119受体调节剂和对与所述受体有关的障碍的治疗
US8592396B2 (en) 2010-04-14 2013-11-26 Bristol-Myers Squibb Company Glucokinase activators and methods of using same
US8581001B2 (en) 2010-04-16 2013-11-12 Codman & Shurtleff Metformin-cysteine prodrug
US8541596B2 (en) 2010-04-21 2013-09-24 Probiodrug Ag Inhibitors
WO2011138421A1 (en) 2010-05-05 2011-11-10 Boehringer Ingelheim International Gmbh Combination therapy
KR20190050871A (ko) 2010-06-24 2019-05-13 베링거 인겔하임 인터내셔날 게엠베하 당뇨병 요법
WO2012031124A2 (en) 2010-09-03 2012-03-08 Bristol-Myers Squibb Company Drug formulations using water soluble antioxidants
US9616097B2 (en) 2010-09-15 2017-04-11 Synergy Pharmaceuticals, Inc. Formulations of guanylate cyclase C agonists and methods of use
BR112013008100A2 (pt) 2010-09-22 2016-08-09 Arena Pharm Inc "moduladores do receptor de gpr19 e o tratamento de distúrbios relacionados a eles."
AR083878A1 (es) 2010-11-15 2013-03-27 Boehringer Ingelheim Int Terapia antidiabetica vasoprotectora y cardioprotectora, linagliptina, metodo de tratamiento
TWI631963B (zh) 2011-01-05 2018-08-11 雷西肯製藥股份有限公司 包含鈉－葡萄糖共同輸送體１與２之抑制劑的組合物與應用方法
EP2670397B1 (en) 2011-02-01 2020-05-13 Bristol-Myers Squibb Company Pharmaceutical formulations including an amine compound
US9580471B2 (en) 2011-03-01 2017-02-28 Synergy Pharmaceuticals, Inc. Process of preparing guanylate cyclase C agonists
ES2570167T3 (es) 2011-03-16 2016-05-17 Probiodrug Ag Derivados de benzimidazol como inhibidores de glutaminil ciclasa
WO2012135570A1 (en) 2011-04-01 2012-10-04 Arena Pharmaceuticals, Inc. Modulators of the gpr119 receptor and the treatment of disorders related thereto
US20140066369A1 (en) 2011-04-19 2014-03-06 Arena Pharmaceuticals, Inc. Modulators Of The GPR119 Receptor And The Treatment Of Disorders Related Thereto
US20140051714A1 (en) 2011-04-22 2014-02-20 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
EP2532506A1 (de) 2011-06-06 2012-12-12 Battenfeld-Cincinnati Germany GmbH Abzugsvorrichtung für einen Extruder
WO2012170702A1 (en) 2011-06-08 2012-12-13 Arena Pharmaceuticals, Inc. Modulators of the gpr119 receptor and the treatment of disorders related thereto
KR101985384B1 (ko) 2011-07-15 2019-06-03 베링거 인겔하임 인터내셔날 게엠베하 치환된 퀴나졸린, 이의 제조 및 약제학적 조성물에서의 이의 용도
WO2013055910A1 (en) 2011-10-12 2013-04-18 Arena Pharmaceuticals, Inc. Modulators of the gpr119 receptor and the treatment of disorders related thereto
US9555001B2 (en) 2012-03-07 2017-01-31 Boehringer Ingelheim International Gmbh Pharmaceutical composition and uses thereof
EP2849755A1 (en) 2012-05-14 2015-03-25 Boehringer Ingelheim International GmbH A xanthine derivative as dpp -4 inhibitor for use in the treatment of podocytes related disorders and/or nephrotic syndrome
WO2013174767A1 (en) 2012-05-24 2013-11-28 Boehringer Ingelheim International Gmbh A xanthine derivative as dpp -4 inhibitor for use in modifying food intake and regulating food preference
WO2014074668A1 (en) 2012-11-08 2014-05-15 Arena Pharmaceuticals, Inc. Modulators of gpr119 and the treatment of disorders related thereto
CA2891773C (en) 2012-11-20 2021-01-19 Lexicon Pharmaceuticals, Inc. Inhibitors of sodium glucose cotransporter 1
EP2970384A1 (en) 2013-03-15 2016-01-20 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase and their uses
WO2014151200A2 (en) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Compositions useful for the treatment of gastrointestinal disorders
JP6606491B2 (ja) 2013-06-05 2019-11-13 シナジー ファーマシューティカルズ インコーポレイテッド グアニル酸シクラーゼｃの超高純度アゴニスト、その作成および使用方法
WO2015027021A1 (en) 2013-08-22 2015-02-26 Bristol-Myers Squibb Company Imide and acylurea derivatives as modulators of the glucocorticoid receptor
KR20160094956A (ko) 2013-11-05 2016-08-10 벤-구리온 유니버시티 오브 더 네게브 리서치 앤드 디벨럽먼트 어쏘러티 당뇨병 및 당뇨병으로부터 발생하는 합병증 질환의 치료를 위한 화합물
WO2015128453A1 (en) 2014-02-28 2015-09-03 Boehringer Ingelheim International Gmbh Medical use of a dpp-4 inhibitor
GB201415598D0 (en) 2014-09-03 2014-10-15 Univ Birmingham Elavated Itercranial Pressure Treatment
AU2016229982B2 (en) 2015-03-09 2020-06-18 Intekrin Therapeutics, Inc. Methods for the treatment of nonalcoholic fatty liver disease and/or lipodystrophy
US10155000B2 (en) 2016-06-10 2018-12-18 Boehringer Ingelheim International Gmbh Medical use of pharmaceutical combination or composition
JP2018123065A (ja) * 2017-01-30 2018-08-09 株式会社明治 インスリン分泌促進用組成物
WO2018162722A1 (en) 2017-03-09 2018-09-13 Deutsches Institut Für Ernährungsforschung Potsdam-Rehbrücke Dpp-4 inhibitors for use in treating bone fractures
EP3606527A1 (en) 2017-04-03 2020-02-12 Coherus Biosciences, Inc. Ppar-gamma agonist for treatment of progressive supranuclear palsy
ES2812698T3 (es) 2017-09-29 2021-03-18 Probiodrug Ag Inhibidores de glutaminil ciclasa
AU2019304032B2 (en) 2018-07-19 2021-12-09 Astrazeneca Ab Methods of treating HFpEF employing dapagliflozin and compositions comprising the same
BR112021004839A2 (pt) 2018-09-26 2021-06-08 Lexicon Pharmaceuticals, Inc. formas cristalinas de n-(1-((2-(dimetilamino)etil)amino)-2-metil-1-oxopropan-2-il)-4-(4-(2-metil-5-((2s,3r,4r,5s,6r)-3,4,5-triidróxi-6-(metiltio)tetraidro-2h-piran-2-il)benzil)fenil)butanamida e métodos de sua síntese
WO2022022865A1 (en) 2020-07-27 2022-02-03 Astrazeneca Ab Methods of treating chronic kidney disease with dapagliflozin
CN118510504A (zh) 2022-01-26 2024-08-16 阿斯利康(瑞典)有限公司 用于在治疗糖尿病前期或降低发展2型糖尿病的风险中使用的达格列净

Family Cites Families (48)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US25023A (en) * 1859-08-09 Improved device for making electro-magnetic currents, constant or intermittent
US2961377A (en) 1957-08-05 1960-11-22 Us Vitamin Pharm Corp Oral anti-diabetic compositions and methods
US3174901A (en) 1963-01-31 1965-03-23 Jan Marcel Didier Aron Samuel Process for the oral treatment of diabetes
US3879541A (en) 1970-03-03 1975-04-22 Bayer Ag Antihyperglycemic methods and compositions
US3960949A (en) 1971-04-02 1976-06-01 Schering Aktiengesellschaft 1,2-Biguanides
JPS4940442B2 (zh) * 1971-08-30 1974-11-02
CH602612A5 (zh) 1974-10-11 1978-07-31 Hoffmann La Roche
US4935493A (en) 1987-10-06 1990-06-19 E. I. Du Pont De Nemours And Company Protease inhibitors
US5433955A (en) 1989-01-23 1995-07-18 Akzo N.V. Site specific in vivo activation of therapeutic drugs
DD296075A5 (de) * 1989-08-07 1991-11-21 Martin-Luther-Universitaet Halle-Wittenberg,De Verfahren zur herstellung neuer inhibitoren der dipeptidyl peptidase iv
US5258185A (en) * 1989-08-23 1993-11-02 Bauer Kurt H Highly active, rapidly absorbable formulations of glibenclamide, processes for the production thereof and their use
ES2113879T3 (es) 1990-01-24 1998-05-16 Douglas I Buckley Analogos de glp-1 utiles para el tratamiento de diabetes.
US5462928A (en) 1990-04-14 1995-10-31 New England Medical Center Hospitals, Inc. Inhibitors of dipeptidyl-aminopeptidase type IV
ES2099158T3 (es) 1990-04-14 1997-05-16 New England Medical Center Inc Tratamiento del rechazo de trasplantes o de enfermedades autoinmunitarias y complejo de la formula general x-pro-y-boropro asociada al mismo.
WO1991017767A1 (en) 1990-05-21 1991-11-28 New England Medical Center Hospitals, Inc. Method of treating inhibition of dipeptidyl aminopeptidase type iv
JPH0819154B2 (ja) 1991-03-14 1996-02-28 江崎グリコ株式会社 ジペプチジルカルボキシペプチダーゼを阻害するペプチド
JPH04334357A (ja) * 1991-05-02 1992-11-20 Fujirebio Inc 酵素阻害作用を有するアシル誘導体
CA2121369C (en) 1991-10-22 2003-04-29 William W. Bachovchin Inhibitors of dipeptidyl-aminopeptidase type iv
DE4140177C2 (de) * 1991-12-05 1995-12-21 Alfatec Pharma Gmbh Nanosol-Akutform für Glibenclamid
US5614219A (en) * 1991-12-05 1997-03-25 Alfatec-Pharma Gmbh Oral administration form for peptide pharmaceutical substances, in particular insulin
IL106998A0 (en) 1992-09-17 1993-12-28 Univ Florida Brain-enhanced delivery of neuroactive peptides by sequential metabolism
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
IL111785A0 (en) * 1993-12-03 1995-01-24 Ferring Bv Dp-iv inhibitors and pharmaceutical compositions containing them
US5705483A (en) * 1993-12-09 1998-01-06 Eli Lilly And Company Glucagon-like insulinotropic peptides, compositions and methods
US5543396A (en) 1994-04-28 1996-08-06 Georgia Tech Research Corp. Proline phosphonate derivatives
DE4432757A1 (de) * 1994-09-14 1996-03-21 Boehringer Mannheim Gmbh Pharmazeutische Zubereitung enthaltend Metformin und Verfahren zu deren Herstellung
US5512549A (en) 1994-10-18 1996-04-30 Eli Lilly And Company Glucagon-like insulinotropic peptide analogs, compositions, and methods of use
US5614379A (en) 1995-04-26 1997-03-25 Eli Lilly And Company Process for preparing anti-obesity protein
DE19616486C5 (de) * 1996-04-25 2016-06-30 Royalty Pharma Collection Trust Verfahren zur Senkung des Blutglukosespiegels in Säugern
CA2256669A1 (en) 1996-05-29 1997-12-04 Prototek, Inc. Prodrugs of thalidomide and methods for using same as modulators of t-cell function
EP0930882A2 (en) * 1996-08-02 1999-07-28 Institut Pasteur De Lille Prevention or treatment of type 2 diabetes or cardiovascular disease with ppar modulators
US6006753A (en) 1996-08-30 1999-12-28 Eli Lilly And Company Use of GLP-1 or analogs to abolish catabolic changes after surgery
US5827898A (en) * 1996-10-07 1998-10-27 Shaman Pharmaceuticals, Inc. Use of bisphenolic compounds to treat type II diabetes
JPH10182687A (ja) * 1996-10-21 1998-07-07 Bayer Yakuhin Kk アカルボースの貯蔵安定化法
TW492957B (en) * 1996-11-07 2002-07-01 Novartis Ag N-substituted 2-cyanopyrrolidnes
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
AR016751A1 (es) 1996-11-22 2001-08-01 Athena Neurosciences Inc Metodo para inhibir la liberacion del peptido beta-amiloide en una celula, composicion farmaceutica y compuestos utiles en dicho metodo
DE19823831A1 (de) * 1998-05-28 1999-12-02 Probiodrug Ges Fuer Arzneim Neue pharmazeutische Verwendung von Isoleucyl Thiazolidid und seinen Salzen
AU4854999A (en) 1998-07-02 2000-01-24 Invitro Diagnostics, Inc. Methods, compositions and apparatus for making nucleic acid molecules having a selected affinity to a target molecule
DE19834591A1 (de) * 1998-07-31 2000-02-03 Probiodrug Ges Fuer Arzneim Verfahren zur Steigerung des Blutglukosespiegels in Säugern
WO2000053171A1 (en) 1999-03-05 2000-09-14 Molteni L. E C. Dei Fratelli Alitti Societa' Di Esercizio S.P.A. Use of metformin in the preparation of pharmaceutical compositions capable of inhibiting the enzyme dipeptidyl peptidase iv
US6172081B1 (en) * 1999-06-24 2001-01-09 Novartis Ag Tetrahydroisoquinoline 3-carboxamide derivatives
US6107317A (en) * 1999-06-24 2000-08-22 Novartis Ag N-(substituted glycyl)-thiazolidines, pharmaceutical compositions containing them and their use in inhibiting dipeptidyl peptidase-IV
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
AU2001233622A1 (en) 2000-02-25 2001-09-03 Novo-Nordisk A/S Inhibition of beta cell degeneration
US7064145B2 (en) * 2000-02-25 2006-06-20 Novo Nordisk A/S Inhibition of beta cell degeneration
DE60137216D1 (de) * 2000-03-31 2009-02-12 Prosidion Ltd Verbesserung der aktivität der inselzellen bei diabetes mellitus und dessen prävention
DE20220238U1 (de) * 2002-02-28 2003-05-08 Probiodrug AG, 06120 Halle Glutaminyl basierte DPIV Inhibitoren

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