CN102125560A - Dpp iv抑制剂的用途 - Google Patents

Dpp iv抑制剂的用途 Download PDF

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CN102125560A
CN102125560A CN2011100020035A CN201110002003A CN102125560A CN 102125560 A CN102125560 A CN 102125560A CN 2011100020035 A CN2011100020035 A CN 2011100020035A CN 201110002003 A CN201110002003 A CN 201110002003A CN 102125560 A CN102125560 A CN 102125560A
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methyl
diabetes
inhibitor
treatment
dpp
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克劳斯·达吉
弗兰克·希梅尔斯巴赫
迈克尔·马克
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Abstract

本发明公开了选定DPP IV抑制剂治疗生理功能性病症及降低风险患者群体发展这些功能性病症的风险的用途。此外，本发明还公开了上述DPP IV抑制剂组合其它药物的用途，由此可实现升高的治疗结果。所述用途可用以制备相应的药物。

Description

DPP IV抑制剂的用途
本申请是中国发明申请(发明名称：DPP IV抑制剂的用途；申请日：2007年05月03日；申请号：200780020753.7)的分案申请。 
本说明书描述了选定的DPP IV抑制剂在治疗生理功能性病症及降低处于危险中的患者群出现这些功能性病症的风险的用途。此外，本说明书描述了上述DPP IV抑制剂组合其它活性物质的用途，由此可实习改善的治疗结果。这些应用可用以制备相应药物。
亦称为CD26的酶DPP-IV为促进在N末端具有脯氨酸或丙氨酸基团的蛋白质中二肽裂解的丝氨酸蛋白酶。DPP-IV抑制剂由此影响生物活性肽(包括肽GPG-1)的血浆含量且为用于治疗糖尿病的极具价值的分子。
主要发生在30岁以下的青少年的I型糖尿病归类为自身免疫疾病。在相应遗传因素下及在多种因素影响下，出现胰岛炎，随后破坏B细胞，以使得胰腺不再能产生大量胰岛素(若能产生)。
II型糖尿病并不归类为自身免疫疾病且本身显示空腹血糖含量超过每分升血浆125毫克葡萄糖；血糖值的测量为常规医学分析中的标准程序。若空腹血糖含量超过每分升血浆99毫克葡萄糖的最大正常含量，但不超过每分升血浆125毫克葡萄糖的临限值(其与糖尿病有关)，则疑为前驱糖尿病。此亦称为病理性空腹葡萄糖(空腹葡萄糖异常)。前驱糖尿病的另一指征为葡萄糖耐受性异常，亦即在口服葡萄糖耐受性测试范畴内在空腹摄取75毫克葡萄糖后2小时血糖含量为每分升血浆140-199毫克葡萄糖。
若进行葡萄糖耐受性测试，则空腹摄取75克葡萄糖后2小时，糖尿病患者的血糖含量将超过每分升血浆199毫克葡萄糖。在葡萄糖耐受性测试中，在空腹10-12小时之后向测试患者经口给予75克葡萄糖且在即将摄取葡萄糖之前及在摄取葡萄糖之后1及2小时记录血糖含量。在健康受检者体内，血糖含量在摄取葡萄糖之前应介于每分升血浆60毫克至99毫克之间，在摄取葡萄糖之后1小时小于每分升200毫克且在2小时之后小于每分升140毫克。若在2小时之后，该值介于140毫克至199毫克之间，则将其视 为葡萄糖耐受性异常或在某些状况下视为葡萄糖耐受不良。
在监测糖尿病的治疗时，血红蛋白B链的非酶促糖化产物，HbA1c值尤其重要。由于其形成主要视血糖含量及红血球寿命而定，因此HbA1c在“血糖记忆”意义上反映先前4-12周的平均血糖含量。HbA1c水平已受较强化糖尿病治疗良好控制较长时间(即试样中总血红蛋白＜6.5％)的糖尿病患者受到显著较好的保护而免于糖尿病微血管病。糖尿病的有效治疗可给予糖尿病患者HbA1c水平约1.0％-1.5％的平均改善。此HbA1c水平降低并不足以使所有糖尿病患者处于＜6.5％且优选的＜6％HbA1c的所要目标范围内。
若可检测到胰岛素抵抗，则此为存在前驱糖尿病的复合代谢病症的尤其有力的指征。因此，为维持葡萄糖体内平衡，某人可能需要多达他人2-3倍的胰岛素。测定胰岛素抵抗的最可靠的方法为正常葡萄糖-高血胰岛素钳测试(euglycaemic-hyperinsulinaemic clamp test)。胰岛素与葡萄糖的比率是在经组合的胰岛素-葡萄糖输注技术的范畴内测定。若葡萄糖吸收低于所探查背景群体的25个百分点，则存在胰岛素抵抗(WHO定义)。与钳测试相比较方便的为所谓的最小模型，其中在静脉葡萄糖耐受性测试期间，血液中的胰岛素及葡萄糖浓度是以固定时间间隔测量且由此计算胰岛素抵抗。另一种测量方法为数学HOMA模型。胰岛素抵抗通过空腹血浆血糖浓度及空腹胰岛素浓度来计算。在此方法中，不可能区别肝脏胰岛素抵抗与外周胰岛素抵抗。这些方法并不真正适于在日常实践中评估胰岛素抵抗。通常，日常临床实践中使用其它参数来评估胰岛素抵抗。优选地，例如，使用患者的甘油三酯浓度，这是由于甘油三酯含量增加与存在胰岛素抵抗显著相关。
为略微简化，实务上假定若某人具有以下特征中的至少2个，则其具有胰岛素抵抗：
1)超重或肥胖
2)高血压
3)血脂障碍(血液中总脂质含量改变)
4)至少一位近亲已经确认葡萄糖耐受性异常或II型糖尿病。
超重指体重指数(BMI)介于25kg/m2与30kg/m2之间的情况，BMI为体重(公斤)与身高(米)的平方的商。在显性肥胖症中，BMI为30kg/m2或更高。
根据上述胰岛素抵抗的定义，明显地若发现患者患有高血压，则降血压剂是适合的且表明用于治疗胰岛素抵抗。
前驱糖尿病的类似指征为是否满足代谢综合征的病状，其主要特点为胰岛素抵抗。根据ATP IHINCEP准则(Journal of the American MedicalAssociation 285：2486-2497，2001中的Executive Summary of the Third Reportof the National Cholesterol Education Program(NCEP))，若患者具有以下特征中的至少3个，则存在代谢综合征：
1)腹部肥胖，定义为男性腰围＞40英寸或102厘米且女性＞35英寸或94厘米
2)甘油三酯含量＞150毫克/分升
3)男性的HDL-胆固醇含量＜40毫克/分升
4)高血压＞130/＞85mm Hg
5)空腹血糖＞110毫克/分升。
此代谢综合征的定义直接表明若发现患者患有高血压，则降血压剂适于治疗代谢综合征。
甘油三酯血液含量超过150毫克/分升也表示存在前驱糖尿病。此推测通过HDL胆固醇的低血液含量证实。在女性体内，低于每分升血浆55毫克的含量视为过低，而在男性体内，低于每分升血浆45毫克的含量视为过低。血液中甘油三酯及HDL胆固醇也可通过医学分析中的标准方法来测定且描述于例如Thomas L(编者)：“Labor und Diagnose”，TH-Books mbH，FrankfurtMain 2000中。若空腹血糖含量也超过每分升血浆99毫克葡萄糖，则前驱糖尿病的推测进一步得以证实。
术语妊娠性糖尿病(怀孕糖尿病)表示在妊娠期间发展且通常在分娩之后又立即停止的一种糖疾病形式。妊娠性糖尿病通过在妊娠第24周至第28周之间进行的筛检测试来确认。其通常为在给予50克葡萄糖溶液之后一小时测量血糖含量的简单测试。若此1小时含量超过140毫克/分升，则疑为妊娠性糖尿病。可通过用75克葡萄糖的标准葡萄糖耐受性测试来获得最终确认。
高血糖症描述在空腹状态下(与＜100毫克/分升的正常含量相比，100-125毫克/分升的高葡萄糖含量或＞125毫克/分升的糖尿病-高血糖含量)或在非空腹状态下(＞180毫克/分升的高葡萄糖含量)，在血液中测量到极高葡萄糖含量的功能性病症。
临床医师对于肾上腺素能餐后综合征(反应性低血糖)指不相称的高胰 岛素含量导致由在餐后快速消化的糖类与持续高胰岛素含量之间的不平衡所引起的血糖含量下降(低血糖)的功能性病症。
术语糖尿病足是指由糖尿病引起的足损伤，其主要原因为可归因于不充分代谢控制的多发性神经病。糖尿病足通过在现有糖尿病情况下出现常见损伤(例如溃疡)来确诊。
术语糖尿病相关溃疡是指糖尿病患者的溃疡性发炎性皮肤缺陷。糖尿病相关溃疡通过典型既往病历(anamnesis)及身体检查(例如检查足)来确诊。
若糖尿病患者经受总胆固醇增加或更通常在糖尿病性高脂血症中血浆甘油三酯增加，伴以或不伴以HDL胆固醇降低，则使用术语糖尿病性高脂血症。
若总胆固醇并不升高，但HDL-胆固醇及LDL-胆固醇的分布改变，即患者的HDL胆固醇含量过低(例如女性＜55毫克/分升及男性＜45毫克/分升)，则使用术语糖尿病性血脂障碍。
若主观症状或客观检查表明心脏不能进行必要的射血输出，则使用术语 心力衰竭。主观症状可为例如在应激状态下或在静止状态下呼吸困难。客观检查包括根据超声的心脏的射血输出减少(射血量减少)、根据X射线的肺充血，及/或步行距离减少。
一些选定的DPP IV抑制剂尤其适于制备用于治疗性处理已经确诊患有选自下列病症的医学或生理功能性病症的患者的药物：前驱糖尿病、葡萄糖耐受不良(葡萄糖耐受性异常)、病理性空腹葡萄糖(空腹葡萄糖异常)、糖尿病足、糖尿病相关溃疡、糖尿病性高脂血症、糖尿病性血脂障碍、新诊断的I型糖尿病(以维持胰岛素自胰腺的残余分泌)、妊娠性糖尿病(怀孕糖尿病)、高血糖症、肾上腺素能餐后综合征(反应性低血糖)或心力衰竭。
这些药物也可用于降低如下风险：尽管进行治疗，患者仍经受葡萄糖代谢受损、HbA1c值升高、空腹葡萄糖值异常、显性II型糖尿病(manifest type2diabetes)、糖尿病足、糖尿病相关溃疡、糖尿病性高脂血症或糖尿病性血脂障碍，且尽管治疗，胰岛素治疗仍会变得必需或会出现大血管并发症。
此类大血管并发症的实例为心肌梗塞、急性冠状动脉综合征、不稳定型心绞痛、稳定型心绞痛、出血性中风或缺血性中风、外周动脉阻塞性疾病、心肌病、左心功能不全、右心功能不全、全心衰、心律失常及血管再狭窄。这些大血管并发症为本领域技术人员已知且详细描述于标准教科书中。
此外，这些物质适于在胰岛(islets of Langerhans)或β细胞移植之后增强细胞的生活力及分泌能力，且由此确保移植后的有利结果。这些物质也可用于胰岛或β细胞的分离及移植期间，通过将特定物质以1nmol/l至1μmol/l的合适浓度，优选以1nmol/l至100nmol/l的浓度添加至常规分离或储存培养基中。这使得待移植物质的品质升高。品质升高尤其是与GLP-1(高血糖素样肽1)的量增加(优选的以1-100nmol/l的浓度)组合获得。本发明的另一目标为相应分离或储存培养基及通过将DPP IV抑制剂添加至所用培养基中来增强胰岛或β细胞的生活力及分泌能力的相应方法。
最后，上述抑制剂适于治疗多种形式的关节炎，但尤其为类风湿性关节炎。
本发明选定的DPP IV抑制剂可由式(I)或式(II)来描述
Figure BDA0000042744620000051
其中R1表示([1，5]二氮杂萘-2-基)甲基、(喹唑啉-2-基)甲基、(喹喔啉-6-基)甲基、(4-甲基-喹唑啉-2-基)甲基、2-氰基-苄基、(3-氰基-喹啉-2-基)甲基、(3-氰基-吡啶-2-基)甲基、(4-甲基-嘧啶-2-基)甲基或(4，6-二甲基-嘧啶-2-基)甲基且R2表示3-(R)-氨基-哌啶-1-基、(2-氨基-2-甲基-丙基)-甲基氨基或(2-(S)-氨基-丙基)-甲基氨基。
尤其优选的的DPP IV抑制剂为以下化合物及其治疗活性盐：
1-[(4-甲基-喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-氨基-哌啶-1-基)-黄嘌呤(参看WO 2004/018468，实施例2(142))：
1-[([1，5]二氮杂萘-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-((R)-3-氨基-哌啶-1-基)-黄嘌呤(参看WO 2004/018468，实施例2(252))：
Figure BDA0000042744620000062
1-[(喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-((R)-氨基-哌啶-1-基)-黄嘌呤(参看WO 2004/018468，实施例2(80))：
Figure BDA0000042744620000063
2-((R)-3-氨基-哌啶-1-基)-3-(丁-2-炔基)-5-(4-甲基-喹唑啉-2-基甲基)-3，5-二氢-咪唑并[4，5-d]哒嗪-4-酮(参看WO 2004/050658，实施例136)：
1-[(4-甲基-喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-[(2-氨基-2-甲基-丙基)-甲基氨基]-黄嘌呤(参看WO 2006/029769，实施例2(1))：
Figure BDA0000042744620000071
1-[(3-氰基-喹啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-((R)-3-氨基-哌啶-1-基)-黄嘌呤(参看WO 2005/085246，实施例1(30))：
Figure BDA0000042744620000072
1-(2-氰基-苄基)-3-甲基-7-(2-丁炔-1-基)-8-((R)-3-氨基-哌啶-1-基)-黄嘌呤(参看WO 2005/085246，实施例1(39))：
Figure BDA0000042744620000073
1-[(4-甲基-喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-[(S)-(2-氨基-丙基)-甲基氨基]-黄嘌呤(参看WO 2006/029769，实施例2(4))：
1-[(3-氰基-喹啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-((R)-3-氨基-哌啶-1-基)-黄嘌呤(参看WO 2005/085246，实施例1(52))：
Figure BDA0000042744620000081
1-[(4-甲基-嘧啶-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-((R)-3-氨基-哌啶-1-基)-黄嘌呤(参看WO 2005/085246，实施例1(81))：
Figure BDA0000042744620000082
1-[(4，6-二甲基-嘧啶-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-((R)-3-氨基-哌啶-1-基)-黄嘌呤(参看WO 2005/085246，实施例1(82))：
Figure BDA0000042744620000083
1-[(喹喔啉-6-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-((R)-3-氨基-哌啶-1-基)-黄嘌呤(参看WO 2005/085246，实施例1(83))：
Figure BDA0000042744620000084
这些DPP IV抑制剂不同于结构上类似的DPP IV抑制剂，这是由于当它们与其它医药活性物质组合时，将使特殊效能及持久作用与有利药理特性、受体选择性及有利副作用概况组合，或产生出乎意料的治疗优点或改善。 它们的制备公开于所述的出版物中。
由于不同代谢功能性病症常同时出现，因此往往指定组合许多彼此不同的活性成份。因此，视所确诊的功能性病症而定，若DPP IV抑制剂与选自其它抗糖尿病物质的活性物质，尤其降低血液中血糖含量或脂质含量、升高血液中HDL含量、降低血压或表明用于治疗动脉粥样硬化或肥胖的活性物质组合，则可获得经升高的治疗结果。
当静脉内给药时，DPP IV抑制剂的所需剂量为0.1mg至10mg，优选的0.25mg至5mg，且当经口给药时为0.5mg至100mg，优选的2.5mg至50mg，在各种情况下每天1至4次。为达成此目的，化合物(优选与其它活性物质组合)可与一种或多种常规惰性载体及/或稀释剂(例如与玉米淀粉、乳糖、葡萄糖、微晶纤维素、硬脂酸镁、聚乙烯吡咯烷酮、柠檬酸、酒石酸、水、水/乙醇、水/甘油、水/山梨糖醇、水/聚乙二醇、丙二醇、十六十八醇(cetylstearylalcohol)、羧甲基纤维素或诸如硬脂肪的脂肪物质或其合适混合物)一起配制，以形成常规盖伦制剂(galenic preparation)，例如片剂、包衣片剂、胶囊、散剂、悬浮剂或栓剂。
因此本发明的DPP IV抑制剂是由本领域技术人员使用如现有技术中所述的容许制剂的赋形剂来制备。这些赋形剂的实例为稀释剂、黏合剂、载体、填充剂、润滑剂、助流剂、结晶迟延剂、崩解剂、助溶剂、着色剂、pH值调节剂、表面活性剂及乳化剂。
合适稀释剂的实例包括纤维素粉末、磷酸氢钙、赤藻糖醇、(低取代)羟丙基纤维素、甘露醇、预胶化淀粉或木糖醇。
合适黏合剂的实例包括乙烯吡咯烷酮与其它乙烯基衍生物的共聚物(共聚乙烯吡咯烷酮)、羟丙基甲基纤维素(HPMC)、羟丙基纤维素(HPC)、聚乙烯吡咯烷酮(聚维酮(povidone))、预胶化淀粉或低取代羟丙基纤维素。
合适润滑剂的实例包括滑石粉、聚乙二醇、山萮酸钙、硬脂酸钙、氢化蓖麻油或硬脂酸镁。
合适崩解剂的实例包括玉米淀粉或交联聚乙烯吡咯烷酮。
制备本发明的DPP IV抑制剂的药物制剂的合适方法为：
●将粉末混合物形式的活性物质与合适的制片赋形剂直接制片；
●与合适的赋形剂一起制粒且随后与合适的赋形剂混合且随后制片以及膜包衣；或
●将粉末混合物或颗粒填充至胶囊中。
合适的制粒方法为：
●在强力混合器中湿式粒化，随后流化床干燥；
●一锅式粒化；
●流化床粒化；或
●与合适的赋形剂一起干式制粒(例如通过滚筒压制)且随后制片或填充至胶囊中。
上述DPP IV抑制剂亦可与其它活性物质组合使用，由此可获得改善的治疗结果。该组合治疗可以以这些物质的自由组合形式或以固定组合形式，例如以片剂或胶囊形式给予。为达成此目的所需的组合搭配物的药物制剂可以以药物组合物形式购得或可由本领域技术人员使用常规方法制备。可以药物组合物形式购得的活性物质于现有技术中多处加以描述，例如每年出版的药物目录，制药工业组合会的“Rote ”中，或每年更新的称为“Physicians’Desk Reference”的处方药物有关制造商资讯的汇编。
抗糖尿病药组合搭配物的实例为二甲双胍；磺酰脲类，诸如格列本脲(glibenclamide)、甲苯磺丁脲(tolbutamide)、格列美脲(glimepiride)、格列吡嗪(glipizide)、格列喹酮(gliquidon)、格列波脲(glibornuride)及格列齐特(gliclazide)；那格列奈(nateglinide)；瑞格列奈(repaglinide)；噻唑烷二酮类，诸如罗格列酮(rosiglitazone)及吡格列酮(pioglitazone)；PPARγ调节剂，诸如美格列德(metaglidase)；PPAR-γ激动剂，诸如GI 262570；PPARγ拮抗剂；PPAR-γ/α调节剂，诸如特沙他唑(tesaglitazar)、莫格他唑(muraglitazar)及KRP297；PPAR-γ/α/δ调节剂；AMPK-活化剂，诸如AICAR；乙酰辅酶A羧化酶(ACC1及ACC2)抑制剂；二酰甘油-乙酰转移酶(DGAT)抑制剂；胰腺β细胞GCRP激动剂，诸如SMT3-受体激动剂及GPR119；11β-HSD抑制剂；FGF19激动剂或类似物；α-葡糖苷酶阻断剂，诸如阿卡波糖(acarbose)、伏格列波糖(voglibose)及米格列醇(miglitol)；α2-拮抗剂；胰岛素及胰岛素类似物，诸如人胰岛素、赖脯胰岛素(insulin lispro)、胰岛素格素林(insulin glusilin)、r-DNA-门冬胰岛素(insulinaspart)、NPH胰岛素、胰岛素迪特美(insulindetemir)、胰岛素锌悬浮液及胰岛素加列金(insulin glargin)；抑胃肽(GIP)；普兰林肽(pramlintide)；淀粉不溶素(amylin)或GLP-1及GPL-1类似物，诸如Exendin-4；SGLT2抑制剂，诸如KGT-1251；蛋白质酪氨酸-磷酸酶的抑制剂； 葡萄糖-6-磷酸酶的抑制剂；果糖-1，6-双磷酸酶调节剂；糖原磷酸酶调节剂(glycogen phosphorylase modulators)；胰高血糖素受体拮抗剂；磷酸烯醇丙酮酸羧基激酶(phosphoenolpyruvatecarboxykinase，PEPCK)抑制剂；丙酮酸脱氢酶激酶(PDK)抑制剂；酪氨酸-激酶的抑制剂(50mg至600mg)，诸如PDGF受体-激酶(参看EP-A-564409、WO 98/35958、US 5093330、WO 2004/005281及WO 2006/041976)；葡糖激酶/调节蛋白调节剂，包括葡糖激酶活化剂；糖原合成酶激酶抑制剂；含有SH2-结构域的2型肌醇5-磷酸酶(SHIP2)；IKK抑制剂，诸如高剂量水杨酸盐；JNK1抑制剂；蛋白激酶C-θ抑制剂；β3激动剂，诸如瑞妥贝隆(ritobegron)、YM 178、索拉贝隆(solabegron)、塔里贝隆(talibegron)、N-5984、GRC-1087、拉法贝隆(rafabegron)、FMP825；醛糖还原酶抑制剂，诸如AS 3201、折那司他(zenarestat)、法地司他(fidarestat)、依帕司他(epalrestat)、阮尼司他(ranirestat)、NZ-314、CP-744809及CT-112；SGLT-1或SGLT-2抑制剂；KV 1.3通道抑制剂；GPR40调节剂；SCD-1抑制剂；CCR-2拮抗剂；及其它DPP IV抑制剂。
11β-HSD1抑制剂的实例描述于：
WO 2007/013929、WO 2007/007688、WO 2007/003521、WO2006/138508、WO 2006/135795、WO 2006/135667、WO 2006/134481、WO2006/134467、WO 2006/132436、WO 2006/132197、WO 2006/113261、WO2006/106423、WO 2006/106052、WO 2006/105127、WO 2006/104280、WO2006/100502、WO 2006/097337、WO 2006/095822、WO 2006/094633、WO2006/080533、WO 2006/074330、WO 2006/074244、WO 2006/068992、WO2006/068991、WO 2006/068199、WO 2006/066109、WO 2006/055752、WO2006/053024、WO 2006/051662、WO 2006/050908、WO 2006/049952、WO2006/048750、WO 2006/048331、WO 2006/048330、WO 2006/040329、WO2006/037501、WO 2006/030805、WO 2006/030804、WO 2006/017542、WO2006/024628、WO 2006/024627、WO 2006/020598、WO 2006/010546、WO2006/002349、WO 2006/002350、WO 2006/012173、WO 2006/012227、WO2006/012226、WO 2006/000371、WO 2005/118538、WO 2005/116002、WO2005/110992、WO 2005/110980、WO 2005/108359、WO 2005/108361、WO2005/108360、WO 2005/108368、WO 2005/103023、WO 2005/097764、WO2005/097759、WO 2005/095350、WO 2005/075471、WO 2005/063247、WO 2005/060963、WO 2005/047250、WO 2005/046685、WO 2005/044192、WO2005/042513、WO 2005/016877、WO 2004/113310、WO 2004/106294、WO2004/103980、WO 2004/089896、WO 2004/089380、WO 2004/089471、WO2004/089470、WO 2004/089367、WO 2004/073200、WO 2004/065351、WO2004/058741、WO 2004/056745、WO 2004/056744、WO 2004/041264、WO2004/037251、WO 2004/033427、WO 2004/011410、WO 2003/104208、WO2003/104207、WO 2003/065983、WO 2003/059267、WO 2003/044009、WO2003/044000、WO 2003/043999、WO 2002/076435、WO 2001/090094、WO2001/090093、WO 2001/090092、WO 2001/090091、WO 2001/090090、US2007/049632、US 2006/148871、US 2006/025445、US 2006/004049、US2005/277647、US 2005/261302、US 2005/245534、US 2005/245532、US2005/245533及JP 2005/170939。11β-HSD1抑制剂的代表性实例为以下化合物：
Figure BDA0000042744620000121
及其盐。
糖原磷酸酶调节剂的实例描述于：
WO 2006/126695、WO 2006/082401、WO 2006/082400、WO2006/059165、WO 2006/059164、WO 2006/059163、WO 2006/056815、WO2006/055463、WO 2006/055462、WO 2006/055435、WO 2006/053274、WO2006/052722、WO 2005/085245、WO 2005/085194、WO 2005/073231、WO2005/073230、WO 2005/073229、WO 2005/067932、WO 2005/020987、WO2005/020986、WO 2005/020985、WO 2005/019172、WO 2005/018637、WO2005/013981、WO 2005/013975、WO 2005/012244、WO 2004/113345、WO2004/104001、WO 2004/096768、WO 2004/092158、WO 2004/078743、WO2004/072060、WO 2004/065356、WO 2004/041780、WO 2004/037233、WO2004/033416、WO 2004/007455、WO 2004/007437、WO 2003/104188、WO 2003/091213、WO 2003/084923、WO 2003/084922、WO 2003/074532、WO2003/074531、WO 2003/074517、WO 2003/074513、WO 2003/074485、WO2003/074484、WO 2003/072570、WO 2003/059910、WO 2003/037864、WO2002/096864、WO 2002/020530、WO 2001/094300、WO 2000/123347、WO1996/39384、WO 1996/39385、EP 1391460、EP 1136071、EP 1125580、EP1088824、EP 0978279、JP 2004196702、US 2004/002495、US 2003/195243及US 5998463。
葡糖激酶活化剂的实例描述于：WO 2007/017649、WO 2007/007910、WO 2007/007886、WO 2007/007042、WO 2007/007041、WO 2007/007040、WO 2007/006814、WO 2007/006761、WO 2007/006760、WO 2006/125972、WO 2006/125958、WO 2006/112549、WO 2006/059163、WO 2006/058923、WO 2006/049304、WO 2006/040529、WO 2006/040528、WO 2006/016194、WO 2006/016178、WO 2006/016174、WO 2005/121110、WO 2005/103021、WO 2005/095418、WO 2005/095417、WO 2005/090332、WO 2005/080360、WO 2005/080359、WO 2005/066145、WO 2005/063738、WO 2005/056530、WO 2005/054233、WO 2005/054200、WO 2005/049019、WO 2005/046139、WO 2005/045614、WO 2005/044801、WO 2004/081001、WO 2004/076420、WO 2004/072066、WO 2004/072031、WO 2004/063194、WO 2004/063179、WO 2004/052869、WO 2004/050645、WO 2004/031179、WO 2004/002481、WO 2003/095438、WO 2003/080585、WO 2003/055482、WO 2003/047626、WO 2003/015774、WO 2003/000267、WO 2003/000262、WO 2002/048106、WO 2002/046173、WO 2002/014312、WO 2002/008209、WO 2001/085707、WO 2001/085706、WO 2001/083478、WO 2001/083465、WO 2001/044216及WO 2000/058293。
葡糖激酶活化剂的代表性实例为以下化合物：
Figure BDA0000042744620000131
其中G1表示环丙基或环丁基且G2表示5-氟-噻唑-2-基、1-甲基-1H-吡唑-3-基或吡嗪-2-基；及
其中G3表示甲基或乙基且G4表示噻唑-2-基、4-甲基-噻唑-2-基、5-甲基-噻唑-2-基或吡嗪-2-基，及其盐。
SGLT1或SGLT2抑制剂的实例描述于：WO 2006/108842、WO2006/087997、WO 2006/080577、WO 2006/080421、WO 2006/073197、WO2006/064033、WO 2006/062224、WO 2006/054629、WO 2006/037537、WO2006/035796、WO 2006/018150、WO 2006/008038、WO 2006/002912、WO2006/010557、WO 2006/011502、WO 2006/011469、WO 2005/121161、WO2005/012326、WO 2005/095429、WO 2005/095372、WO 2005/095373、WO2005/092877、WO 2005/085267、WO 2005/085265、WO 2005/085237、WO2005/063785、WO 2005/021566、WO 2005/012243、WO 2005/012242、WO2005/012326、WO 2005/012318、WO 2005/011592、WO 2004/113359、WO2004/099230、WO 2004/089967、WO 2004/089966、WO 2004/087727、WO2004/080990、WO 2004/058790、WO 2004/052903、WO 2004/052902、WO2004/019958、WO 2004/018491、WO 2004/014932、WO 2004/014931、WO2004/013118、WO 2003/099836、WO 2003/080635、WO 2003/020737、WO2003/011880、WO 2003/000712、WO 2002/099893、WO 2002/088157、WO2002/083066、WO 2002/068440、WO 2002/068439、WO 2002/064606、WO2002/053573、WO 2002/044192、WO 2002/036602、WO 2002/028872、WO2001/074835、WO 2001/074834、WO 2001/068660、WO 2001/027128、WO2001/016147、JP 2005247834、JP 2004359630、JP 2004196788、JP 2003012686及US 2006/063722。
SGLT1或SGLT2抑制剂的代表性实例为以下化合物及其与天然胺基酸的盐或复合物：
Figure BDA0000042744620000151
其中G5与G8彼此独立地表示氢、氟、氯、溴、氰基、甲基、乙基、异丙基、二氟甲基、三氟甲基、乙炔基、丙-1-炔-1-基、丁-1-炔-1-基、羟基、甲氧基、乙氧基、二氟甲氧基、环丙氧基、环丁氧基、环戊氧基或环己氧基；且
G6表示氟、氯、甲基、乙基、甲氧基、乙氧基、二氟甲氧基、三氟甲氧基、三甲基硅烷基乙基、乙炔基、2-羟基-丙-2-基乙炔基、2-甲氧基丙-2-基乙炔基、3-羟基-1-丙炔-1-基、3-甲氧基-1-丙炔-1-基、环丙基、环丁基、环戊基、环己基、环丙氧基、环丁氧基、环戊氧基、环己氧基、四氢呋喃-3-基氧基、四氢吡喃-4-基氧基、哌啶-4-基氧基、N-甲基哌啶-4-基氧基及N-乙酰基哌啶-4-基氧基；且
G7表示氢或氟；
Figure BDA0000042744620000161
其中G表示氟、氯、甲基、乙基、乙炔基、甲氧基、乙氧基、二氟甲氧基、三氟甲氧基、环丁氧基、环戊氧基、3-四氢呋喃基氧基或4-四氢吡喃基氧基；
Figure BDA0000042744620000162
其中G表示氟、氯、甲基、乙基、乙炔基、甲氧基、乙氧基、二氟甲氧基、三氟甲氧基、环丁氧基、环戊氧基、3-四氢呋喃基氧基或4-四氢吡喃基氧基；
Figure BDA0000042744620000163
其中G8表示氢、甲氧基羰基或乙氧基羰基，且
G9表示氟、氯、甲基、乙基、乙炔基、甲氧基、乙氧基、二氟甲氧基、三氟甲氧基、环丁氧基、环戊氧基、3-四氢呋喃基氧基或4-四氢吡喃基氧基；及
Figure BDA0000042744620000171
其中：
G10表示C1-3烷基或全氟-C1-3烷基；
G11表示氢、C1-3烷基或全氟-C1-3烷基；
G12表示氟、氯、溴、C1-6烷基、被1至3个氟原子取代的C1-6烷基、C1-6烷氧基、被1至3个氟原子取代的C1-6烷氧基、C1-6烷硫基、C2-6烯基、C2-6炔基、全氟-C1-3烷基、环丁氧基、环戊氧基、环己氧基、四氢呋喃基氧基或4-四氢吡喃基氧基；且
G13与G14彼此独立地表示氢、氟、氯、溴、C1-6烷基、被1至3个氟原子取代的C1-6烷基、C1-6烷氧基、被1至3个氟原子取代的C1-6烷氧基、C1-6烷硫基、C2-6烯基、C2-6炔基、全氟-C1-3烷基；且
G15表示氢、C2-20烷酰基、C1-6烷氧基羰基或苯甲酰基。
抗糖尿病药组合搭配物尤其优选的实例为二甲双胍，其剂量为约100mg至500mg或200mg至850mg(一天一至三次)，或约300mg至1000mg一天一次或两次；或缓释(delayed-release)二甲双胍，其剂量为约100mg至1000mg或优选的500mg至1000mg一天一或两次或约500mg至2000mg一天一次。另一尤其优选的实例为吡格列酮，其剂量为约1-10mg、15mg、30mg或45mg一天一次。另一尤其优选的实例为米格列醇，其剂量为约10mg至50mg或至多100mg一天一至三次。
降低血液中脂质含量的组合搭配物的实例为HMG-CoA还原酶抑制剂，诸如辛伐他汀(simvastatin)、阿托伐他汀(atorvastatin)、洛伐他汀(lovastatin)、氟伐他汀(fluvastatin)、普伐他汀(pravastatin)及罗苏伐他汀(rosuvastatin)；贝特类(fibrates)，诸如苯札贝特(bezafibrate)、非诺贝特(fenofibrate)、氯贝丁酯(clofibrate)、吉非贝齐(gemfibrozil)、依托贝特(etofibrate)及乙羟茶碱氯贝丁酯(etofyllinclofibrate)；烟酸及其衍生物，诸如阿昔莫司(acipimox)；PPAR-α 激动剂；PPAR-δ激动剂；酰基辅酶A：胆固醇酰基转移酶(ACAT；EC 2.3.1.26)抑制剂，诸如阿伐麦布(avasimibe)；胆固醇再吸收抑制剂，诸如依泽替米贝(ezetimib)；与胆汁酸结合的物质，诸如消胆胺(cholestyramine)、考来替泊(colestipol)及考来维仑(colesevelam)；胆汁酸转移抑制剂；HDL调节活性物质，诸如D4F、逆向D4F、LXR调节活性物质及FXR调节活性物质；CETP抑制剂，诸如托彻普(torcetrapib)、JTT-705或来自WO 2007/005572的化合物12；LDL受体调节剂；及ApoB100反义RNA。尤其优选的实例为阿托伐他汀，其剂量为约1mg至40mg或10mg至80mg一天一次。
降血压的组合搭配物的实例为β-阻断剂，诸如阿替洛尔(atenolol)、比索洛尔(bisoprolol)、塞利洛尔(celiprolol)、美托洛尔(metoprolol)及卡维地洛(carvedilol)；利尿剂，诸如氢氯噻嗪、氯噻酮(chlortalidon)、希帕胺(xipamide)、呋塞米(furosemide)、吡咯他尼(piretanide)、托拉塞米(torasemide)、螺内酯(spironolactone)、依普利酮(eplerenone)、阿米洛利(amiloride)及氨苯蝶啶(triamterene)；钙通道阻断剂，诸如氨氯地平(amlodipine)、硝苯地平(nifedipine)、尼群地平(nitrendipine)、尼索地平(nisoldipine)、尼卡地平(nicardipine)、非洛地平(felodipine)、拉西地平(lacidipine)、乐卡地平(lercanipidine)、马尼地平(manidipine)、伊拉地平(isradipine)、尼伐地平(nilvadipine)、维拉帕米(verapamil)、加洛帕米(gallopamil)及地尔硫卓(diltiazem)；ACE抑制剂，诸如雷米普利(ramipril)、赖诺普利(lisinopril)、西拉普利(cilazapril)、喹那普利(quinapril)、卡托普利(captopril)、依那普利(enalapril)、贝那普利(benazepril)、培哚普利(perindopril)、福辛普利(fosinopril)及群多普利(trandolapril)；以及血管紧张素II受体阻断剂(ARB)，诸如替米沙坦(telmisartan)、坎地沙坦(candesartan)、缬沙坦(valsartan)、氯沙坦(losartan)、厄贝沙坦(irbesartan)、奥美沙坦(olmesartan)及依普罗沙坦(eprosartan)。尤其优选的的实例为每天50mg至200mg剂量的美托洛尔、每天2.5mg至10mg剂量氨氯地平、每天2.5mg至15mg剂量的雷米普利、每天80mg至160mg剂量的缬沙坦及每天20mg至320mg或40mg至160mg剂量的替米沙坦。
增加血液中HDL含量的组合搭配物的实例为胆固醇酯转移蛋白(CETP)抑制剂；内皮脂肪酶抑制剂；ABC1调节剂；LXRα拮抗剂；LXRβ激动剂；PPAR-δ激动剂；LXRα/β调节剂，及增加载酯蛋白A-I的表达及/或血浆浓度的物质。
用于治疗肥胖的组合搭配物的实例为西布曲明(sibutramine)；四氢利普司他汀(tetrahydrolipstatin)(奥利司他(orlistat))；艾利沙美(alizyme)；右芬氟拉明(dexfenfluramine)；阿索开(axokine)；大麻素受体1拮抗剂，诸如CB1拮抗剂利蒙本特(rimonobant)；MCH-1受体拮抗剂；MC4受体激动剂；NPY5以及NPY2拮抗剂；β3-AR激动剂，诸如SB-418790及AD-9677；5HT2c受体激动剂，诸如APD 356；筒箭毒碱(myostatin)抑制剂；Acrp30及脂缔素(adiponectin)；硬脂酰辅酶A去饱和酶(SCD1)抑制剂；脂肪酸合成酶(FAS)抑制剂；CCK受体激动剂；胃内激素(Ghrelin)受体调节剂；Pyy3-36；阿立新(orexin)受体拮抗剂；及特索芬辛(tesofensine)。
用于治疗动脉粥样硬化的组合搭配物的实例为磷脂酶A2抑制剂；酪氨酸-激酶的抑制剂(50mg至600mg)，诸如PDGF-受体-激酶抑制剂(参看EP-A-564409、WO 98/35958、US 5093330、WO 2004/005281及WO2006/041976)；oxLDL抗体及oxLDL疫苗；apoA-1Milano；ASA；及VCAM-1抑制剂。
用于治疗心力衰竭的组合搭配物的实例为β-阻断剂，诸如阿替洛尔、比索洛尔、塞利洛尔及美托洛尔；利尿剂，诸如氢氯噻嗪、氯噻酮、希帕胺、呋塞米、吡咯他尼、托拉塞米、螺内酯、依普利酮、阿米洛利及氨苯蝶啶；ACE抑制剂，诸如雷米普利、赖诺普利、西拉普利、喹那普利、卡托普利、依那普利、贝那普利、培哚普利、福辛普利及群多普利；以及血管紧张素II受体阻断剂(ARB)，诸如替米沙坦、坎地沙坦、缬沙坦、氯沙坦、厄贝沙坦、奥美沙坦及依普罗沙坦；心糖苷，诸如地高辛(digoxin)及洋地黄毒苷(digitoxin)；组合α/β阻断剂，诸如卡维地洛(carvedilol)；B-型利钠肽(BNP)及BNP-衍生的肽及BNP-融合产物。尤其优选的的实例为每天50mg至200mg剂量的美托洛尔、每天2.5mg至15mg剂量的雷米普利、每天80mg至160mg剂量的缬沙坦、每天20mg至320mg或40mg至160mg剂量的替米沙坦、25-100mg剂量的依普利酮(eplereron)、每天0.25mg至0.6mg剂量的地高辛、3.25mg至100mg剂量的卡维地洛、快速注射2μg/kg随后0.01μg/kg/min剂量的BNP(例如奈西立肽(nesiritide))。
包含选定DPP IV抑制剂的药物组合含有例如1.75mg至10.5mg格列本脲、500mg至3000mg甲苯磺丁脲、0.5-6g格列美脲、2.5mg至40mg格列吡嗪、1-4×30mg格列喹酮、至3×25mg格列波脲、80mg至160mg格列齐特； 500mg至1000mg，优选的500mg、850mg或1000mg二甲双胍；60mg至180mg那格列奈；0.25mg至4mg瑞格列奈；2mg至45mg噻唑烷二酮；200mg至600mg美格列德；2.5mg至5mg PPARγ/α调节剂；0.1mg至100mgα葡糖苷酶阻断剂；1-250IU胰岛素；15μg至120μg普兰林肽；5mg至80mg他汀类(statin)；50mg至1000mg贝特类(fibrate)；1000mg至3000mg烟酸或衍生物；约250mg阿昔莫司(acipimox)；约10mg胆固醇再吸收抑制剂；0.5g至30g胆汁酸结合物质；10mg至600mg且优选的10mg至120mg CETP抑制剂；2.5mg至100mgβ-阻断剂；3mg至200mg利尿剂；2.5mg至500mg钙通道阻断剂；1mg至4mg ACE抑制剂；5mg至600mg血管紧张素II受体阻断剂；10mg至15mg西布曲明；约120mg奥利司他；15mg至30mg右芬氟拉明；或5mg至20mg大麻素受体拮抗剂，25mg至100mg剂量的依普利酮；每天0.25mg至0.6mg剂量的地高辛；3.25mg至100mg剂量的卡维地洛；快速注射2μg/kg随后0.01μg/kg/min剂量的BNP(例如奈西立肽)。
实施例
实施例1：前驱糖尿病的治疗
本发明的DPP IV抑制剂对治疗特征为病理性空腹葡萄糖及/或葡萄糖耐受性异常的前驱糖尿病的功效使用临床研究来测试。在历经较短时期(例如2-4周)的研究中，通过在研究治疗期结束后测定空腹葡萄糖值及/或餐后或负荷测试(口服葡萄糖耐受性测试或接受指定餐后的食物耐受性测试)后的葡萄糖值，且将其与开始研究之前的值比较及/或与安慰剂组的那些值比较来检验治疗的成功性。此外，在治疗前后测定果糖胺值且与初始值及/或安慰剂值相比较。空腹葡萄糖水平或非空腹葡萄糖水平显著下降证明了治疗的功效。在历经较长时期(12周或更长时间)的研究中，通过测定HbA1c值，与初始值及/或与安慰剂组的值比较来测试治疗的成功性。与初始值及/或安慰剂值相比，HbA1c值的显著变化证明DPP IV抑制剂对治疗前驱糖尿病的功效。
实施例2：预防显性II型糖尿病
治疗患有病理性空腹葡萄糖及/或葡萄糖耐受性异常(前驱糖尿病)的患者也是为了预防转变成显性II型糖尿病。治疗的功效可在前驱糖尿病患者经 活性物质或活性物质的组合，或安慰剂或非药物治疗或其它药物治疗较长时期(例如1-5年)的比较临床研究中考察。在治疗期间及在治疗结束时，通过测定空腹葡萄糖及/或负荷测试(loading test)(例如，oGTT)检测多少患者出现显性II型糖尿病，即空腹葡萄糖含量＞125mg/dl及/或根据oGTT的2小时值＞199mg/dl。与其它形式治疗中之一比较，当以活性物质或活性物质的组合治疗，出现显性II型糖尿病的患者数目显著减少，证明了活性物质或活性物质的组合对预防前驱糖尿病转变为显性糖尿病的功效。
实施例3：II型糖尿病的治疗
用本发明的活性物质治疗II型糖尿病患者，除产生葡萄糖代谢状况立即的改善以外，从长远上还预防代谢状况恶化。患者经本发明的活性物质或活性物质的组合治疗较长时期，例如1-6年，与用其它抗糖尿病药物治疗的患者相比较能够观察到此结果。若未观察到空腹葡萄糖及/或HbA1c值增加或仅观察到其略有增加，则证明与用其它抗糖尿病药物治疗的患者相比的治疗成功。若与用其它药物治疗的患者相比，用本发明的活性物质或本发明的活性物质的组合治疗的患者在葡萄糖代谢上产生恶化(例如HbA1c值增加至＞6.5％或＞7％)，显著较少百分比地达到用另外口服抗糖尿病药物或用胰岛素或用胰岛素类似物或用其它抗糖尿病剂(例如GLP-1类似物)治疗的程度，则进一步证明治疗成功。
实施例4：胰岛素抵抗的治疗
在进行不同持续时间(例如2周至12个月)的临床研究中，使用高胰岛素正常血糖钳研究来检查治疗成功。在研究结束时，与初始值相比或与安慰剂组合或给予不同治疗的组相比，葡萄糖输注速率的显著升高证明了活性物质或活性物质的组合对治疗胰岛素抵抗的功效。
实施例5：糖尿病性高脂血症或血脂障碍的治疗
在对II型糖尿病患者进行不同持续时间(例如2周至60个月)的临床研究中，通过测定总胆固醇、LDL-胆固醇、HDL-胆固醇及血浆甘油三酯来检查治疗成功。在研究期间或在研究结束时，与初始值相比或与安慰剂组或给予不同治疗的组相比，总胆固醇、LDL-胆固醇或血浆甘油三酯显著下降及/ 或HDL-胆固醇含量升高，证明了活性物质或活性物质的组合对治疗糖尿病性血脂障碍或高脂血症的功效。
实施例6：高血糖症的治疗
在进行不同持续时间(例如1天至24个月)的临床研究中，通过测定空腹葡萄糖或非空腹葡萄糖(例如在餐后或在oGTT或确定餐的负荷测试之后)来检查高血糖症患者的治疗成功。在研究期间或在研究结束时，与初始值相比或与安慰剂组或给予不同治疗的组相比，这些葡萄糖值的显著下降证明了活性物质或活性物质的组合对治疗高血糖症的功效。
实施例7：妊娠性糖尿病的治疗
在进行较短时期(例如2-4周)的临床研究中，通过在研究的治疗时期结束时测定空腹葡萄糖值及/或在餐后或在负荷测试(确定餐后的口服葡萄糖耐受性测试或食物耐受性测试)之后的葡萄糖值且将其与开始研究之前的值比较及/或与安慰剂组的值比较来检查治疗成功。此外，果糖胺值可在治疗前后测定且与初始值及/或安慰剂值相比较。空腹葡萄糖含量或非空腹葡萄糖含量显著下降，证明了活性物质或活性物质的组合的功效。
在进行较长时间的研究(12周或更长时间)中，通过测定HbA1c值(与初始值及安慰剂组相比)来检查治疗成功。与起始值及/或安慰剂值相比，HbA1c值的显著变化，证明了活性物质或活性物质的组合对治疗妊娠性糖尿病的功效。
实施例8：已患有妊娠性糖尿病的女性的治疗
妊娠性糖尿病患者在怀孕之后产生显性II型糖尿病的风险显著增加。治疗可预防向显性II型糖尿病的转变。为达成此目的，有妊娠性糖尿病史的女性经本发明的活性物质或本发明的活性物质的组合或经安慰剂或经非药物治疗或经其它药物治疗较长时期(例如1-4年)。在治疗期间及在治疗结束时，通过测定空腹葡萄糖及/或通过负荷测试(例如，oGTT)来进行检查以确定多少患者已发展为显性II型糖尿病(空腹葡萄糖含量＞125mg/dl及/或oGTT后的2小时值＞199mg/dl)。与不同类型的治疗相比，当以本发明的活性物质或本发明的活性物质的组合治疗，发展为显性II型糖尿病的患者的数目显著 减少，证明了活性物质或活性物质的组合对预防有妊娠性糖尿病史的女性的显性糖尿病的功效。
实施例9：微血管或大血管并发症的预防
用本发明的活性物质或本发明的活性物质的组合对II型糖尿病或前驱糖尿病患者的治疗预防或减少了微血管并发症(例如糖尿病性神经病、糖尿病性视网膜病、糖尿病性肾病、糖尿病足、糖尿病性溃疡)或大血管并发症(例如心肌梗塞、急性冠状动脉综合征、不稳定型心绞痛、稳定型心绞痛、中风、外周动脉阻塞性疾病、心肌病、心力衰竭、心律失常、血管再狭窄)。II型糖尿病或前驱糖尿病患者经本发明的活性物质或本发明的活性物质的组合长期治疗，例如历时1-6年，且将其与用其它抗糖尿病药物或用安慰剂治疗的患者相比较。与用其它抗糖尿病药物或用安慰剂治疗的患者相比，较少数目的单一并发症或多个并发症证明治疗成功。在大血管事件、糖尿病足及/或糖尿病性溃疡的情况下，通过既往病历及多种测试方法来计数。在糖尿病性视网膜病的情况下，通过电脑控制照明及评估眼睛背景或其它眼科方法来测定治疗成功。在糖尿病性神经病的情况下，除既往病历及临床检查以外，神经传导率例如使用校准音叉来测量。对于糖尿病性肾病，在研究开始之前、在研究期间及在研究结束时探查以下参数：白蛋白的分泌、肌酸酐清除率、血清肌酸酐值、血清肌酸酐值倍增所历经的时间、直至需要透析所历经的时间。
实施例10：代谢综合征的治疗
本发明的活性物质或活性物质的组合的功效可在具有不同进行时间(例如12周至6年)的临床研究中通过测定空腹葡萄糖或非空腹葡萄糖(例如在餐后或在oGTT或确定餐的负荷测试之后)或HbA1c值来测试。在研究期间或在研究结束时，与初始值相比或与安慰剂组或给予不同治疗的组相比，这些葡萄糖值或HbA1c值的显著下降证明活性物质或活性物质的组合对治疗代谢综合征的功效。与在研究开始时的起始值相比或与经安慰剂或不同疗法治疗的患者组相比，收缩压及/或舒张压降低、血浆甘油三酯下降、总胆固醇或LDL胆固醇减少、HDL胆固醇增加或体重减轻。
实施例11：DPP IV抑制剂膜包衣片剂
为制备制粒溶液，在周围温度下将共聚乙烯吡咯烷酮(copovidone)溶解于纯水中。将DPP IV抑制剂、甘露醇、预胶化淀粉及玉米淀粉在合适的混合器中混合以制备预混物。将该预混物用制粒溶液润湿且随后在混合器中以高切应速率制粒。将湿颗粒通过筛孔尺寸为1.6mm的筛进行筛检。将这些颗粒在约60℃下在流化床干燥器中干燥直至获得2-4％的干燥失重值。压制加工过的混合物以形成片芯。
在合适的混合器中，在周围温度下将羟丙基甲基纤维素、聚乙二醇、滑石粉、二氧化钛及氧化铁悬浮于纯水中以制备片剂包衣用悬浮液。将片芯用此悬浮液包衣直至获得3％的重量增加。举例而言，以下片剂组合物可以用此方式获得：
  成份   mg   mg   mg   mg   mg
  DPP IV抑制剂   0.500   1.000   2.500   5.000   10.000
  甘露醇   67.450   66.950   65.450   130.900   125.900
  预胶化淀粉   9.000   9.000   9.000   18.000   18.000
  玉米淀粉   9.000   9.000   9.000   18.000   18.000
  共聚乙烯吡咯烷酮   2.700   2.700   2.700   5.400   5.400
  硬脂酸镁   1.350   1.350   1.350   2.700   2.700
  总质量(片芯)   90.000   90.000   90.000   180.000   180.000
  HPMC   1.500   1.500   1.500   2.500   2.500
  PEG   0.150   0.150   0.150   0.250   0.250
  二氧化钛   0.750   0.750   0.750   1.250   1.250
  滑石粉   0.525   0.525   0.525   0.875   0.875
  黄氧化铁   0.075   0.075   0.075   0.125   0.125
  总质量(膜包衣片剂)   93.000   93.000   93.000   185.000   185.000
实施例12：增强胰岛或β细胞的生活力及分泌能力
此实验是在成功分离胰岛或胰腺β细胞之后，通过将其在含有1nmol/l至1μmol/l浓度，优选1nmol/l至100nmol/l浓度的DPP IV抑制剂的培养基中储存、转移或培养以供将来移植。
此外，在胰岛或胰腺β细胞移植之后，患者(且这些也可为动物)用DPPIV抑制剂以介于1mg至200mg之间的日剂量，优选以5mg至100mg剂量的DPP IV抑制剂治疗以增强这些移植物的生活力及分泌能力。这通过在用葡萄糖或增加胰岛素分泌的其它药物刺激之后分析胰岛素分泌来测试。此外，品质改善也可在活体外或动物模型中使用Diabetologia 42：566，1999或Diabetes 48：738 1999(investigation of apoptosis and inhibition thereof)中所述的TUNEL技术来检查。
实施例13：DPP IV抑制剂-二甲双胍的组合治疗
对于治疗II型糖尿病或前驱糖尿病而言，本发明的DPP IV抑制剂可与抗糖尿病活性物质二甲双胍以自由组合或固定组合形式组合于片剂中。治疗有效剂量的DPP IV抑制剂(例如介于0.1mg至100mg之间的剂量)可与不同剂量的二甲双胍，例如与单次剂量为500mg、850mg或1000mg的二甲双胍，总日剂量为500-2850mg的二甲双胍，或与500mg、1000mg、1500mg或2000mg缓释形式的二甲双胍组合。与二甲双胍的该组合的临床功效可在临床研究中进行测试。对此，II型糖尿病或前驱糖尿病患者经单独DPP IV抑制剂或经单独二甲双胍或经DPP IV抑制剂与二甲双胍的组合治疗。治疗持续介于2周至6年之间的时间。DPP-IV抑制剂与二甲双胍的组合引起空腹葡萄糖及/或非空腹葡萄糖及/或HbA1c值与单独DPP IV抑制剂或单独二甲双胍相比显著更大程度减少证明了该组合适当且有效。
实施例14：DPP IV抑制剂-格列酮(glitazone)的组合治疗
对于治疗II型糖尿病或前驱糖尿病而言，本发明的DPP IV抑制剂可与包含格列酮类或噻唑烷二酮类(例如吡格列酮或罗格列酮)的抗糖尿病活性物质以自由组合或固定组合形式组合于片剂中。治疗有效剂量的DPP IV抑制剂(例如介于0.1mg至100mg之间剂量)可与不同剂量的吡格列酮(15mg、30mg或45mg)或罗格列酮(2mg、4mg或8mg，一天给予一或两次)组合。与罗格列酮或吡格列酮的该组合的临床功效可在临床研究中进行测试。对此，II型糖尿病或前驱糖尿病患者经单独DPP IV抑制剂或经单独罗格列酮或吡格列酮或经DPP IV抑制剂与罗格列酮或吡格列酮的组合治疗。治疗持续介于2周至6年之间的时间。DPP-IV抑制剂与罗格列酮或吡格列酮的组合引 起空腹葡萄糖及/或非空腹葡萄糖及/或HbA1c值与单独DPP IV抑制剂或单独罗格列酮或吡格列酮相比显著更大程度减少证明了该组合适当且有效。
实施例15：DPP IV抑制剂-SGLT2抑制剂的组合治疗
对于治疗II型糖尿病或前驱糖尿病而言，本发明的DPP IV抑制剂可与包含SGLT-2抑制剂的抗糖尿病活性物质以自由组合或固定组合形式组合于片剂中。治疗有效剂量的DPP IV抑制剂(例如介于0.1mg至100mg之间的剂量)可与不同剂量的SGLT-2抑制剂(0.5mg至1000mg)组合。与SGLT-2抑制剂的该组合的临床功效可在临床研究中进行测试。对此，II型糖尿病或前驱糖尿病患者经单独DPP IV抑制剂或经单独SGLT-2抑制剂或经DPP IV抑制剂与SGLT-2抑制剂的组合治疗。治疗持续介于2周至6年之间的时间。DPP-IV抑制剂与SGLT-2抑制剂的组合引起空腹葡萄糖及/或非空腹葡萄糖及/或HbA1c值与单独DPP IV抑制剂或单独SGLT-2抑制剂相比显著更大程度减少证明了该组合适当且有效。
实施例16：DPP IV抑制剂-抗高血压剂的组合治疗
对于治疗II型糖尿病或前驱糖尿病或代谢综合征患者而言，本发明的DPP IV抑制剂可与抗高血压活性物质以自由组合或固定组合形式组合于片剂中。治疗有效剂量的DPP IV抑制剂(例如介于0.1mg至100mg之间的剂量)可与不同剂量的ACE-抑制剂(例如2.5mg至15mg雷米普利)、AT1-受体拮抗剂(例如20mg至160mg替米沙坦)、β-阻断剂(例如50mg至200mg美托洛尔)或利尿剂(例如12.5mg至25mg氢氯噻嗪)组合。与抗高血压剂的该组合的临床功效可在临床研究中进行测试。对此，II型糖尿病或前驱糖尿病或代谢综合征患者经单独DPP IV抑制剂或经单独抗高血压剂或经DPP IV抑制剂与抗高血压剂的组合治疗。治疗持续介于2周至6年之间的时间。DPP-IV抑制剂与抗高血压剂的组合降低空腹葡萄糖及/或非空腹葡萄糖及/或HbA1c值的程度至少与单独DPP IV抑制剂差不多，且DPP-IV抑制剂与抗高血压剂的组合降低收缩压及/或舒张压的程度至少与单独抗高血压剂差不多，证明了该组合适当且有效。
实施例17：DPP IV抑制剂-降脂剂的组合治疗
对于治疗II型糖尿病或前驱糖尿病或代谢综合征或糖尿病性血脂障碍或高脂血症患者而言，本发明的DPP IV抑制剂可与降脂剂/HDL-升高剂以自由组合或固定组合形式组合于片剂中。治疗有效剂量的DPP IV抑制剂(例如介于0.1mg至100mg之间的剂量)可与不同剂量的他汀(例如10mg至80mg阿托伐他汀或10mg至80mg辛伐他汀)、贝特(例如非诺贝特)、胆固醇吸收抑制剂或与诸如CETP-抑制剂(例如托彻普10mg至120mg一天一次或120mg每天两次)的HDL-升高物质组合。与降脂剂/HDL-升高剂的该组合的临床功效可在临床研究中进行测试。对此，II型糖尿病或前驱糖尿病或代谢综合征或糖尿病性血脂障碍或高脂血症患者经单独DPP IV抑制剂或经单独降脂剂/HDL-升高剂或经DPP IV抑制剂与降脂剂/HDL-升高剂的组合治疗。治疗持续介于2周至6年之间的时间。DPP-IV抑制剂与降脂剂/HDL-升高剂的组合降低空腹葡萄糖及/或非空腹葡萄糖及/或HbA1c值的程度至少与单独DPPIV抑制剂差不多，且DPP-IV抑制剂与降脂剂/HDL-升高剂的组合降低总胆固醇或LDL-胆固醇或血浆甘油三酯的程度或增加HDL-胆固醇值的程度至少与单独降脂剂/HDL-升高剂差不多，证明了该组合适当且有效。
实施例18：DPP IV抑制剂-BNP/BNP衍生的肽或BNP-融合肽对心力衰竭患者的组合治疗
对于治疗急性心力衰竭患者而言，本发明DPP IV抑制剂可与有利影响心力衰竭的物质以自由组合或固定组合形式组合于片剂中。治疗有效剂量的DPP IV抑制剂(例如介于0.1mg至100mg之间的剂量)可与不同剂量的ACE-抑制剂(例如2.5mg至15mg雷米普利)、AT1-受体拮抗剂(例如20mg至160mg替米沙坦)、β-阻断剂(例如50mg至200mg美托洛尔)、组合α/β-阻断剂(例如3.25mg至100mg卡维地洛)、利尿剂(例如12.5mg至25mg氢氯噻嗪)、盐皮质激素受体拮抗剂(例如25mg至100mg依普利酮；及/或B-型利钠肽(BNP))(例如快速注射2μg/kg随后0.01μg/kg/min奈西立肽)、BNP衍生的肽或BNP-融合产物组合。BNP与DPP-IV抑制剂的组合在活体内产生较高浓度的全长BNP(1-32)。特定组合的临床功效可在临床研究中进行测试。治疗持续介于1天至6年之间的时间。与其它疗法相比，该组合引起临床状况显著改善(较高心脏射血输出及/或肺充血逆转、及/或肺楔压逆转、及/或由急性心力衰竭引起的死亡率降低)证明了该组合有效治疗急性心力衰竭。
实施例19：DPP-IV抑制剂治疗心力衰竭患者
本发明的DPP IV抑制剂可用以治疗慢性心力衰竭患者。此治疗在活体内产生较高浓度的内源性全长BNP(1-32)。此治疗的临床功效可在临床研究中进行测试。治疗持续介于2周至6年之间的时间。与不同治疗或安慰剂相比，本发明的DPP-IV抑制剂引起临床状况显著改善(归因于急性心力衰竭的住院治疗频率较低、行走较长距离的能力、较高人体功率(ergometrics)负荷能力、较高心脏射血输出及/或肺充血逆转、及/或由心力衰竭引起的死亡率降低)证明了该组合有效治疗慢性心力衰竭。

Claims (19)

1.式(I)或式(II)的DPP IV抑制剂及其盐之一在制备用于治疗性处理已经确诊患有选自前驱糖尿病、葡萄糖耐受不良、病理性空腹葡萄糖、糖尿病足、糖尿病相关溃疡、糖尿病性高脂血症、糖尿病性血脂障碍、新诊断的I型糖尿病、妊娠性糖尿病、高血糖症、肾上腺素能餐后综合征及心力衰竭的生理功能性病症的患者，或用于治疗性处理移植胰岛或β细胞的患者的药物中的用途，
其特征在于
R1表示([1，5]二氮杂萘-2-基)甲基、(喹唑啉-2-基)甲基、(喹喔啉-6-基)甲基、(4-甲基-喹唑啉-2-基)甲基、2-氰基-苄基、(3-氰基-喹啉-2-基)甲基、(3-氰基-吡啶-2-基)甲基、(4-甲基-嘧啶-2-基)甲基或(4，6-二甲基-嘧啶-2-基)甲基，且
R2表示3-(R)-氨基-哌啶-1-基、(2-氨基-2-甲基-丙基)-甲基氨基或(2-(S)-氨基-丙基)-甲基氨基。
2.式(I)或式(II)的DPP IV抑制剂及盐之一在制备用于治疗已经确诊患有前驱糖尿病或显性II型糖尿病的患者的药物中的用途，其特征在于通过使用该药物，降低如下的风险：尽管治疗仍存在的葡萄糖代谢受损、尽管治疗仍存在的HbA1c值升高、尽管治疗仍存在的空腹葡萄糖值损害、胰岛素治疗的需求、显性II型糖尿病、糖尿病足、糖尿病相关溃疡、糖尿病性高脂血症、糖尿病性血脂障碍或大血管并发症，
Figure FDA0000042744610000021
其特征在于
R1表示([1，5]二氮杂萘-2-基)甲基、(喹唑啉-2-基)甲基、(喹喔啉-6-基)甲基、(4-甲基-喹唑啉-2-基)甲基、2-氰基-苄基、(3-氰基-喹啉-2-基)甲基、(3-氰基-吡啶-2-基)甲基、(4-甲基-嘧啶-2-基)甲基或(4，6-二甲基-嘧啶-2-基)甲基，且
R2表示3-(R)-氨基-哌啶-1-基、(2-氨基-2-甲基-丙基)-甲基氨基或(2-(S)-氨基-丙基)-甲基氨基。
3.如权利要求2所述的用途，其特征在于该大血管并发症选自心肌梗塞、急性冠状动脉综合征、不稳定型心绞痛、稳定型心绞痛、出血性中风或缺血性中风、外周动脉阻塞性疾病、心肌病、左心功能不全、右心功能不全、全心衰、心律失常及血管再狭窄。
4.如权利要求1所述的用途，其特征在于该药物组合物用于治疗性处理已经确诊前驱糖尿病、葡萄糖耐受不良或病理性空腹葡萄糖的患者。
5.如权利要求1所述的用途，其特征在于该药物组合物是用于治疗性处理已经确诊糖尿病性高脂血症或糖尿病性血脂障碍的患者。
6.如权利要求1所述的用途，其特征在于该药物组合物是用于治疗性处理妊娠性糖尿病。
7.如权利要求1所述的用途，其特征在于该药物组合物是用于治疗性处理高血糖症或肾上腺素能餐后综合征。
8.如权利要求1所述的用途，其特征在于该药物组合物是用于治疗性处理心力衰竭。
9.如权利要求2所述的用途，其特征在于通过使用药物组合物，降低了HbA1c值进一步升高、空腹葡萄糖恶化及对胰岛素治疗的需求的风险。
10.式(I)或式(II)的DPP IV抑制剂及其盐之一在制备与选自下列的活性物质的药物组合中的用途：其它的抗糖尿病的活性物质；降低血糖水平的活性物质；降低血液中脂质水平的活性物质；升高血液中HDL水平的活性物质；降低血压的活性物质；及用于治疗动脉粥样硬化或肥胖的活性物质，
其特征在于
R1表示([1，5]二氮杂萘-2-基)甲基、(喹唑啉-2-基)甲基、(喹喔啉-6-基)甲基、(4-甲基-喹唑啉-2-基)甲基、2-氰基-苄基、(3-氰基-喹啉-2-基)甲基、(3-氰基-吡啶-2-基)甲基、(4-甲基-嘧啶-2-基)甲基或(4，6-二甲基-嘧啶-2-基)甲基，且
R2表示3-(R)-氨基-哌啶-1-基、(2-氨基-2-甲基-丙基)-甲基氨基或(2-(S)-氨基-丙基)-甲基氨基。
11.如权利要求10所述的用途，其特征在于制备DPP IV抑制剂与其它抗糖尿病活性物质或降血压活性物质的药物组合。
12.如权利要求10所述的用途，其特征在于制备DPP IV抑制剂与二甲双胍、米格列醇、阿托伐他汀、缬沙坦或替米沙坦的药物组合。
13.如权利要求10所述的用途，其特征在于该药物组合用于治疗性处理已经确诊生理功能性病症的患者，所述的生理功能性病症选自前驱糖尿病、葡萄糖耐受不良、病理性空腹葡萄糖、糖尿病足、糖尿病相关溃疡、糖尿病性高脂血症、糖尿病性血脂障碍、新诊断的I型糖尿病、妊娠性糖尿病、心力衰竭、高血糖症及肾上腺素能餐后综合征。
14.用于胰岛或β细胞的分离或储存的培养基，其特征在于该培养基含有1nmol/l至1μmol/l的DPP IV抑制剂以用于增强这些细胞的生活力及分泌能力。
15.如权利要求14所述的培养基，其特征在于该DPP IV抑制剂的结构为式(I)或式(II)所示及其盐之一，
Figure FDA0000042744610000041
其特征在于
R1表示([1，5]二氮杂萘-2-基)甲基、(喹唑啉-2-基)甲基、(喹喔啉-6-基)甲基、(4-甲基-喹唑啉-2-基)甲基、2-氰基-苄基、(3-氰基-喹啉-2-基)甲基、(3-氰基-吡啶-2-基)甲基、(4-甲基-嘧啶-2-基)甲基或(4，6-二甲基-嘧啶-2-基)甲基，且
R2表示3-(R)-氨基-哌啶-1-基、(2-氨基-2-甲基-丙基)-甲基氨基或(2-(S)-氨基-丙基)-甲基氨基。
16.增强胰岛或β细胞的生活力及分泌能力的方法，其特征在于这些胰岛或β细胞的分离和移植期间，将DPP IV抑制剂以1nmol/l至1μmol/l的浓度添加至该分离及储存培养基中。
17.使用DPP IV抑制剂治疗患者的方法，其特征在于所述患者诊断为生理功能病症，所述病症选自前驱糖尿病、葡萄糖耐受不良、病理性空腹葡萄糖、糖尿病足、糖尿病相关溃疡、糖尿病性高脂血症、糖尿病性血脂障碍、新诊断的I型糖尿病、妊娠性糖尿病、心力衰竭、高血糖症和肾上腺素能餐后综合征，或治疗移植胰岛或β细胞的患者。
18.使用DPP IV抑制剂治疗前驱糖尿病或II型糖尿病患者的方法，其特征在于所述治疗降低了尽管治疗但葡萄糖代谢仍受损的风险、尽管治疗但HbA1c值仍升高的风险、尽管治疗但空腹葡萄糖值仍损害的风险、对胰岛素治疗的需求、显性II型糖尿病、糖尿病足、糖尿病相关的溃疡、糖尿病性高脂血症、糖尿病性血脂障碍或大血管并发症。
19.使用DPP IV抑制剂治疗患者的方法，其特征在于所述患者患有心力衰竭。
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