CN101417987B - 具有磺酰胺甲酰哌嗪结构的dpp-iv抑制剂 - Google Patents
具有磺酰胺甲酰哌嗪结构的dpp-iv抑制剂 Download PDFInfo
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- CN101417987B CN101417987B CN2008101660889A CN200810166088A CN101417987B CN 101417987 B CN101417987 B CN 101417987B CN 2008101660889 A CN2008101660889 A CN 2008101660889A CN 200810166088 A CN200810166088 A CN 200810166088A CN 101417987 B CN101417987 B CN 101417987B
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- phenyl
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Abstract
本发明属于医药技术领域，具体涉及通式(I)所示的具有磺酰胺甲酰哌嗪结构的DPP-IV抑制剂的化合物、其药学上可接受的盐或其异构体：其中R1、Ar、Ar1如说明书中所定义；本发明还涉及这些化合物的制备方法，含有这些化合物的药物组合物，以及这些化合物在制备治疗和/或预防糖尿病、非胰岛素依赖性糖尿病、高血糖、胰岛素抗性的药物中的应用。
Description
1、技术领域
本发明属于医药技术领域，具体涉及具有磺酰胺甲酰哌嗪结构的DPP-IV抑制剂、其药学上可接受的盐或其异构体，这些化合物的制备方法，含有这些化合物的药物组合物，以及这些化合物在制备治疗和/或预防糖尿病及其并发症的药物中的应用。
2、背景技术
糖尿病是一种由于血糖失控高出正常水平所造成的全身慢性代谢性疾病。基本分为四类，包括：I型(胰岛素依赖型)、II型(非胰岛素依赖型)、其它型和妊娠糖尿病。I型和II型糖尿病属于原发性糖尿病，是最常见的两种形式。其中I型糖尿病多发生于青少年，其胰岛素分泌缺乏，必须依赖胰岛素治疗维持生命。II型糖尿病多见于30岁以后中、老年人，其胰岛素的分泌量并不低甚至还偏高，病因主要是机体对胰岛素不敏感(即胰岛素抵抗)。I型和II型糖尿病均会由于糖代谢障碍导致并发症，如心血管疾病、脑血栓、糖尿病性肠病、白内障、感染等。
胰岛素是人体胰腺β细胞分泌的身体内惟一的降血糖激素。胰岛素抵抗是指体内周围组织对胰岛素的敏感性降低，组织对胰岛素不敏感，外周组织如肌肉、脂肪对胰岛素促进葡萄糖摄取的作用发生了抵抗。
研究发现胰岛素抵抗普遍存在于II型糖尿病中，几乎占90％以上，可能是II型糖尿病的主要发病因素之一。因此，糖尿病的药物治疗应针对其病因，注重改善胰岛素抵抗，以及对胰腺β细胞功能的保护，必须选用能改善胰岛素抵抗的药物。这些药物主要是胰岛素增敏剂，使糖尿病患者得到及时有效及根本上的治疗，预防糖尿病慢性并发症的产生和发展。
有研究表明，胰高血糖素样肽-1(GLP-1)在血糖代谢中具有非常重要的作用，例如：(1)GLP-1增加胰岛素分泌；(2)刺激胰岛β-细胞增殖；(3)抑制胰高血糖素的分泌；(4)抑制消化器官分泌和能动性(特别是入动)；(5)抑制食欲。也就是说GLP-1能够抑制食物摄入，延迟其消化吸收过程，并能提高对食物中糖分的利用。
二肽酶-IV(DPP-IV)具有通过裂解端基二肽(His-Ala)而失活胰高血糖素样肽-1(GLP-1)，其生成物肽是GLP-1的受体拮抗剂，并完全降低GLP-1的活性。因此，抑制DPP-IV能增强GLP-1的活性，增加机体对自身胰岛素的敏感性，使糖尿病患者得到及时有效及根本上的治疗，预防糖尿病慢性并发症的产生和发展。
妥拉磺脲是第一代磺酰脲类促胰岛素分泌剂，可降低血糖、明显减少HbA1c，但是有低血糖、过敏反应、体重增加、剂量相关性胃肠道反应的副作用。其结构式如下所示：
目前上市的DPP-IV的抑制剂是sitagliptin phosphate，有较好的安全性和耐受性，目前还没有发现使用的病人有体重增加或者潜在的体重减少以及水肿等症状。然而其疗效差，急需开发更多的DPP-IV的抑制剂的药物来满足临床用药。其结构式如下所示：
sitagliptin
为了解决糖尿病人的痛苦，使其自身的胰岛素得以“复活”而充分发挥作用，使血糖能够重新被机体组织细胞所摄取和利用，使血糖下降，达到长期稳定和全面地控制血糖的目的，本发明人经过长期研究发明了本发明化合物。
3、发明内容
为了解决上述问题，进一步改良和优化DPP-IV的抑制剂，本发明人经过大量的试验研究提供了一类新的DPP-IV的抑制剂。
本发明的技术方案如下：
本发明提供了通式(I)所示的化合物、其药学上可接受的盐或其异构体：
其中：Ar代表被1～5个R2取代或未被取代的苯基，其中R2独立地选自：
(1)卤素原子，
(2)直链或支链的被1～5个卤素原子取代或未被取代的C1-6烷基，
(3)直链或支链的被1～5个卤素原子取代或未被取代的C1-6烷氧基，
(4)氰基，或
(5)羟基；
Ar1代表被1～5个R3取代或未被取代的苯基，其中R3独立地选自：
(1)卤素原子，
(2)直链或支链的被1～5个卤素原子取代或未被取代的C1-6烷基，
(3)直链或支链的被1～5个卤素原子取代或未被取代的C1-6烷氧基，
(4)氰基，或
(5)羟基；
R1代表氢原子、直链或支链的C1-6烷基。
优选的化合物为：
其中：Ar代表被1～5个R2取代或未被取代的苯基，其中R2独立地选自：
(1)卤素原子，
(2)直链或支链的被1～5个卤素原子取代或未被取代的C1-6烷基，
(3)直链或支链的被1～5个卤素原子取代或未被取代的C1-6烷氧基，
(4)氰基，或
(5)羟基；
Ar1代表被1～5个R3取代或未被取代的苯基，其中R3独立地选自：
(1)卤素原子，
(2)直链或支链的被1～5个卤素原子取代或未被取代的C1-6烷基，
(3)直链或支链的被1～5个卤素原子取代或未被取代的C1-6烷氧基，
(4)氰基，或
(5)羟基；
R1代表氢原子、直链或支链的C1-6烷基。
进一步优选的化合物为：
其中：Ar代表被1～5个R2取代或未被取代的苯基，其中R2独立地选自：
(1)氟原子，
(2)溴原子，
(3)三氟甲基，或
(4)氰基；
Ar1代表被1～5个R3取代或未被取代的苯基，其中R3独立地选自：
(1)甲基，
(2)氯原子，
(3)氟原子，
(4)叔丁基，
(5)三氟甲基，或
(6)氰基；
R1代表氢原子、甲基、乙基或异丙基。
再进一步优选的化合物为：
其中，Ar选自：
(1)苯基，
(2)2-氟代苯基，
(3)3，4-二氟苯基，
(4)2，4-二氟苯基，
(5)2，5-二氟苯基，
(6)2，4，5-三氟苯基，
(7)2-氟-4-(三氟甲基)苯基，
(8)4-溴-2，5-二氟苯基，
(9)2-氰基-4，5-二氟苯基，
(10)4-氰基-2，5-二氟苯基，或
(11)5-氰基-2，4-二氟苯基；
Ar1选自：
(1)苯基，
(2)4-甲基苯基，
(3)2-甲基苯基，
(4)4-氯代苯基，
(5)2-氯代苯基，或
(6)4-氟代苯基；
R1代表氢原子或甲基。
本发明所述“卤素原子”为氟原子、氯原子、溴原子或碘原子等。
本发明所述“C1-6烷基”为C1-6直链或支链的烷基，如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、2-甲基丁基、新戊基、3-戊基、正己基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、3，3-二甲基丁基、2，2-二甲基丁基、1，1-二甲基丁基、1，2-二甲基丁基、1，3-二甲基丁基、2，3-二甲基丁基、2-乙基丁基、1，2-二甲基丙基等。
本发明所述“C1-6烷氧基”为甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基、叔丁氧基、正戊氧基、异戊氧基、2-甲基丁氧基、新戊氧基、3-戊氧基、正己氧基、4-甲基戊氧基、3-甲基戊氧基、2-甲基戊氧基、1-甲基戊氧基、3，3-二甲基丁氧基、2，2-二甲基丁氧基、1，1-二甲基丁氧基、1，2-二甲基丁氧基、1，3-二甲基丁氧基、2，3-二甲基丁氧基、2-乙基丁氧基、1-甲基-2-甲基丙氧基、环丙氧基、环丁氧基、1-甲基环丁氧基、环戊氧基、环己氧基等。
更进一步优选的化合物如下：
化学名称：N-[(R)-3-氨基-4-(2，4，5-三氟苯基)-1-丁酰]-N′-(对甲苯磺酰胺)甲酰哌嗪，简称化合物1，结构式如下：
化学名称：N-[(R)-3-氨基-4-(2，4，5-三氟苯基)-1-丁酰]-N′-(对氯苯磺酰胺)甲酰哌嗪，简称化合物2，结构式如下：
本发明还提供了上述化合物的制备方法，反应方程式如下，但不仅限于下列方法：
反应步骤：
步骤1 化合物a的制备
将原料1溶于四氢呋喃中，然后滴加入正丁基锂/正己烷溶液，保温搅拌，然后滴加原料2的四氢呋喃溶液，搅拌反应，加入水淬灭反应，反应液浓缩，剩余物加入乙酸乙酯和盐酸，分出水层，用乙酸乙酯提取三次，合并有机层，盐洗，无水硫酸镁干燥，减压浓缩，硅胶柱纯化(洗脱剂为乙酸乙酯和环己烷的混合液)得化合物a。
步骤2 化合物b的制备
化合物a溶于乙腈中，然后滴加盐酸，反应液搅拌，加入甲醇，浓缩至干，此操作重复三次，然后再用甲苯重复一次，得固体，该固体用二氯甲烷溶解后缓慢加入三乙胺，然后再缓慢滴加入(Boc)2O，反应液室温搅拌，滤除反应生成的固体，滤液用二氯甲烷稀释，分别用HCl溶液和饱和盐水洗涤，无水硫酸镁干燥，硅胶柱纯化，洗脱剂为乙腈和石油醚的混合液，得到化合物b。
步骤3 化合物c的制备
将化合物b加入到四氢呋喃中，冰浴冷却，然后滴加入氢氧化锂的水溶液，反应液室温搅拌，减压浓缩，剩余物用乙酸乙酯溶解，饱和碳酸氢钠和食盐水洗涤，无水硫酸镁干燥，蒸除溶剂得化合物c。
步骤4 化合物d的制备
加入化合物c的乙醚溶液，然后加入三乙胺和氯甲酸异丁酯，加毕，搅拌反应，然后加入重氮甲烷的乙酸乙酯溶液，加入适量的1-甲基-3-硝基-1-亚硝基胍溶于乙醚和氢氧化钠混合溶液，反应液搅拌反应，有机层干燥，混合液用乙酸乙酯稀释，饱和碳酸氢钠和盐水洗涤，无水硫酸镁干燥，减压浓缩至干得化合物d。
步骤5 化合物e的制备
将化合物d溶于甲醇中，降温加入二异丙基乙基胺和苯甲酸银.反应液升温搅拌，反应毕，减压蒸除甲醇，剩余物用二氯甲烷溶解，滤除不溶性固体物，滤液浓缩，硅胶柱纯化得到固体，将此固体溶于四氢呋喃中，然后加入含有氢氧化锂的水中，反应液室温搅拌，浓缩反应液后用乙酸乙酯稀释，饱和碳酸氢钠和盐水洗，无水硫酸镁干燥，浓缩得化合物e。
步骤6 化合物f的制备
于室温下投化合物e于DMF中，然后加入DCC(二环己基碳二亚胺)，室温搅拌反应，过滤除掉反应生成的固体，滤液继续加入反应瓶中，加入哌嗪，升温搅拌，反应毕，加入水，析出固体，以甲醇-乙酸乙酯混合液重结晶，得化合物f。
步骤7 化合物A的制备
在反应瓶中加入化合物f用二氯甲烷溶解后，降低温度，缓慢滴加原料4，升高温度，搅拌反应，再升温至回流，剧烈搅拌下滴加入盐酸，反应后，降温，分出有机层，水层于冰浴下用稀碱液调pH，析出固体过滤，依次用水、乙酸乙酯洗涤，得粗品，用乙醇重结晶得化合物A。
以上反应方程式中的R1、Ar、Ar1代表的基团如前文所述。
本发明上述任一化合物在制备过程中上述通式中的氨基可以被适当的氨基保护基保护，例如叔丁氧羰基、苄氧基羰基或9-芴基甲氧基羰基等。
本发明上述任一化合物药学上可接受的盐是指由药学上可接受的、非毒性碱或酸制备的盐，包括有机酸盐、无机酸盐、有机碱盐、无机碱盐。有机酸包括乙酸、苯磺酸、苯甲酸、对甲苯磺酸、丁烯二酸、(2R，3R)-2，3-二羟基丁二酸、樟脑磺酸、柠檬酸、乙磺酸、富马酸、葡糖酸、谷氨酸、羟乙磺酸、乳酸、马来酸、苹果酸、扁桃酸、甲磺酸、粘酸、硝酸、双羟萘酸、泛酸、琥珀酸、酒石酸等，特别优选苯磺酸、对甲苯磺酸、丁烯二酸、柠檬酸、马来酸、富马酸、酒石酸。无机酸包括氢溴酸、氢氯酸、硝酸、硫酸、磷酸等，特别优选氢溴酸、氢氯酸、硫酸、磷酸。有机碱包括伯、仲和叔胺，被取代胺包括天然存在的取代胺、环胺和碱离子交换树脂，选自精氨酸、甜菜碱、咖啡因、胆碱、N，N’-二苄基乙二胺、二乙胺、2-二乙胺基乙醇、2-二甲胺基乙醇、乙醇胺、乙二胺、N-乙基吗啉、N-乙基哌啶、葡甲胺、氨基葡萄糖、组氨酸、海巴明、异丙基胺、赖氨酸、甲基葡糖胺、吗啉、哌嗪、哌啶、聚酰树酯、普鲁卡因、嘌呤、可可碱、三乙胺、三甲胺、三丙胺、氨丁三醇等。无机碱包括氨以及锂、钠、钾、钙、镁、锌、钡、铝、铁、酮、亚铁、锰、二价锰等的碱性化合物，特别优选氨以及锂、钠、钾、钙、镁、锌、钡的碱性化合物。
本发明化合物含有一个或多个不对称中心，因而可作为外消旋体和外消旋混合物、单一对映异构体、非对映异构体混合物和单一非对映异构体。本发明化合物有不对称中心，这类不对称中心各自会独立的产生两个光学异构体，本发明的范围包括所有可能的光学异构体和非对映异构体混合物和纯的或部分纯的化合物。本发明包括这些化合物的所有异构体形式。本发明所述的部分化合物可以以互变异构体形式存在，其通过一个或多个双键移位而具有不同的氢的连接点。例如，酮和它的烯醇形式是酮-烯醇互变异构体。各互变异构体及其混合物都包括在本发明的化合物中。
本发明的化合物可与一种或多种其它药物联合，比单一药物更安全或者更有效。可将这些其它药物与式(I)化合物同时或相继通过一种途径并以其常用量给药。同时给药时，优选为含所述其它药物和式(I)化合物的单位剂量形式的药用组合物。可与式(I)化合物联合用药及或分别给药或在同一药用组合物中给药的其它活性成分包括，但不限于：
(a)其它二肽酶-IV抑制剂；
(b)胰岛素敏化物包括：(i)PPARγ激动剂，如glitazones(例如曲格列酮、吡格列酮、恩格列酮、MCC-555、罗西格列酮等)和其它PPAR配体，包括PPARα/γ双效激动剂，如KRP-297，和PPARα激动剂如非诺贝酸衍生物(吉非贝齐、氯贝丁酯、非诺贝特和苯扎贝特)，(ii)双胍类，例如二甲双胍和苯乙双胍，和(iii)蛋白络氨酸磷酸酯酶-1B(PTP-1B)抑制剂；
(c)胰岛素或胰岛素模拟物；
(d)磺酰脲类和其它胰岛素促分泌剂，例如甲苯磺丁脲和格列吡嗪、美格列奈和相关药物；
(e)α-葡萄糖苷酶抑制剂(例如acarbose)
(f)高血糖素受体拮抗剂；
(g)GLP-1、GLP-1模拟物和GLP-1受体激动剂；
(h)GLP和GLP模拟物和GLP受体激动剂；
(i)PACAP、PACAP模拟物和PACAP受体3激动剂；
(j)胆固醇降低剂，例如(i)HMG-CoA还原酶抑制剂(洛伐他汀、辛伐他汀、普伐他汀、氟伐他汀、阿妥伐他汀、rivastatin、伊伐他汀、罗苏伐他汀和其它他汀类药物)，(ii)螯合物(考来烯胺、考来替泊和交联右旋糖酐的二烷基胺基烷基衍生物)，(iii)烟醇、烟酸或其它盐，(iv)PPARα激动剂，例如非诺贝酸衍生物(吉非贝齐、氯贝丁酯、非诺贝特和苯扎贝特)，(v)PPARα/γ双效激动剂，例如KRP-297；(vi)胆固醇吸收抑制剂，例如β-谷甾醇和依泽替米贝，(vii)乙酰基CoA，胆固醇酰基转移酶抑制剂，例如阿伐麦布，和(viii)抗氧化剂，例如普罗布考；
(k)PPARδ激动剂；
(1)抗肥胖症化合物，例如芬氟拉明、右芬氟拉明、芬特明、西布曲明、奥利司他、神经肽-Y5抑制剂和β3-肾上腺素能受体激动剂；
(m)回肠胆汁酸转运蛋白抑制剂；和
(n)用于炎症的药物，例如阿司匹林、非类固醇消炎药、糖皮质类固醇、硫氮磺吡啶和环氧酶-2选择抑制剂。
上述联合包括本发明的化合物不仅与一种其它活性化合物而且与两种或多种其它活性化合物的联合。非限定性实例包括具有式(I)的化合物与两种或多种选自双胍类、磺酰脲类、HMG-CoA还原酶抑制剂、PPAR激动剂、PTP-1B抑制剂、其它DPP-IV抑制剂和抗肥胖症化合物的活性化合物的联合。
本发明化合物与第二种活性成分的重量比可以变化，其取决于各种成分的有效剂量。一般来说，将采用各自的有效剂量。因此例如当本发明的化合物与其它药物联合用药时，本发明化合物与其它药物的重量比一般在约200：1到约1：200之间，优选为约20：1到约1：20之间。本发明化合物与其它活性成分的联合用药一般也会在上述范围内，但在每一种情况下，应使用各活性成分的有效剂量。
本发明进一步要求保护包括上面所述的任一化合物、其药学上可接受的盐或其异构体，与一种或多种药用载体和/或稀释剂的药物组合物，为临床上或药学上可接受的任一剂型，优选为口服制剂或注射剂。其中含有生理有效量的通式(I)所示的化合物10mg～10g，优选25mg～5g，可以为25mg、50mg、75mg、0.1g、0.2g、0.4g、0.5g、0.6g、0.75g、1g、2g、3g、5g等所述的活性成分。可按每日1～4次的安排，优选每日1～2次给予所述化合物。
本发明任一化合物、其药学上可接受的盐或其异构体，可以口服或肠胃外给药等方式施用于需要这种治疗的患者。
用于肠胃外给药时，可制成注射剂。注射剂系指药物制成的供注入体内的溶液、乳液或混悬液及供临用前配制或稀释成溶液或混悬液的粉末或浓溶液的无菌制剂，注射剂可分为注射液、注射用无菌粉末与注射用浓溶液。注射液系指药物制成的供注射入体内用的无菌溶液型注射液、乳液型注射液或混悬型注射液，可用于肌内注射、静脉注射、静脉滴注等；其规格有1ml、2ml、5ml、10ml、20ml、50ml、100ml、200ml、250ml、500ml等，其中供静脉滴注用的大体积(一般不小于100ml)注射液也称静脉输液。注射用无菌粉末系指药物制成的供临用前用适宜的无菌溶液配制成澄清溶液或均匀混悬液的无菌粉末或无菌块状物，可用适宜的注射用溶剂配制后注射，也可用静脉输液配制后静脉滴注；无菌粉末用溶媒结晶法、喷雾干燥法或冷冻干燥法等制得。注射用浓溶液系指药物制成的供临用前稀释供静脉滴注用的无菌浓溶液。
制成注射剂时，可采用现有制药领域中的常规方法生产，可选用水性溶剂或非水性溶剂。最常用的水性溶剂为注射用水，也可用0.9％氯化钠溶液或其他适宜的水溶液；常用的非水性溶剂为植物油，主要为供注射用大豆油，其他还有乙醇、丙二醇、聚乙二醇等的水溶液。配制注射剂时，可以不加入附加剂，也可根据药物的性质加入适宜的附加剂，如渗透压调节剂、pH值调节剂、增溶剂、填充剂、抗氧剂、抑菌剂、乳化剂、助悬剂等。常用的渗透压调节剂包括氯化钠、葡萄糖、氯化钾、氯化镁、氯化钙、山梨醇等，优选氯化钠或葡萄糖；常用的pH值调节剂包括醋酸-醋酸钠、乳酸、枸橼酸-枸橼酸钠、碳酸氢钠-碳酸钠等；常用的增溶剂包括聚山梨酯80、丙二醇、卵磷脂、聚氧乙烯蓖麻油等；常用的填充剂包括乳糖、甘露醇、山梨醇、右旋糖酐等；常用的抗氧剂有亚硫酸钠、亚硫酸氢钠、焦亚硫酸钠等；常用抑菌剂为苯酚、甲酚、三氯叔丁醇等。注射剂常用容器有玻璃安瓿、玻璃瓶、塑料安瓿、塑料瓶等。
用于口服时，可制成常规的固体制剂，如片剂、胶囊剂、丸剂、颗粒剂等；也可制成口服液体制剂，如口服溶液剂、口服混悬剂、糖浆剂等。片剂系指药物与适宜的辅料混匀压制而成的圆片状或异形片状的固体制剂，以口服普通片为主，另有含片、舌下片、口腔贴片、咀嚼片、分散片、可溶片、泡腾片、缓释片、控释片与肠溶片等。胶囊剂系指药物或加有辅料充填于空心胶囊或密封于软质囊材中的固体制剂，依据其溶解与释放特性，可分为硬胶囊(通称为胶囊)、软胶囊(胶丸)、缓释胶囊、控释胶囊和肠溶胶囊等。丸剂系指药物与适宜的辅料均匀混合，以适当方法制成的球状或类球状固体制剂，包括滴丸、糖丸、小丸等。颗粒剂系指药物与适宜的辅料制成具有一定粒度的干燥颗粒状制剂，可分为可溶颗粒(通称为颗粒)、混悬颗粒、泡腾颗粒、肠溶颗粒、缓释颗粒和控释颗粒等。口服溶液剂系指药物溶解于适宜溶剂中制成供口服的澄清液体制剂。口服混悬剂系指难溶性固体药物，分散在液体介质中，制成供口服的混悬液体制剂，也包括干混悬剂或浓混悬液。糖浆剂系指含有药物的浓蔗糖水溶液。
制成口服制剂时，可以加入适宜的填充剂、粘合剂、崩解剂、润滑剂等。常用填充剂包括淀粉、糖粉、磷酸钙、硫酸钙二水物、糊精、微晶纤维素、乳糖、预胶化淀粉、甘露醇等；常用粘合剂包括羧甲基纤维素钠、PVP-K30、羟丙基纤维素、淀粉浆、甲基纤维素、乙基纤维素、羟丙甲纤维素、胶化淀粉等；常用崩解剂包括干淀粉、交联聚维酮、交联羧甲基纤维素钠、羧甲基淀粉钠、低取代羟丙基纤维素等；常用润滑剂包括硬脂酸镁、滑石粉、十二烷基硫酸钠、微粉硅胶等。
二肽酶-IV(DPP-IV)是一种涉及多种生物学功能的细胞表面蛋白。它具有广泛的组织分布(肠、肾、肝、胰脏、胎盘、胸腺、脾、上皮细胞、血管内皮、淋巴和髓细胞、血清)和清晰的组织以及细胞类型表达水平。DPP-IV被确定为T型细胞激活标志物CD26，它能在体外裂解大量免疫调节的、内分泌的和神经病学的肽。这表明这种肽酶在人体或其它动物的各种疾病过程中存在潜作用。
药理实验证明，DPP-IV抑制剂可以显著抑制DPP-IV活性，保护GLP-1活性，促进胰岛素分泌，降低餐后胰高血糖素，降低血糖，提高耐糖量；且具有保护GIP活性的作用，可提高GIP的浓度，增强其促胰岛素分泌的效果；DPP-IV抑制剂还可以改善糖脂代谢，防止体重增加。
本发明还提供了新的DPP-IV抑制剂在制备用于治疗和/或预防下列疾病的药物中的用途。
II型糖尿病和相关疾病，现已完全确认GLP-1和GIP可被DPP-IV在体内快速灭活，因此本发明的DPP-IV抑制剂可用于治疗II型糖尿病和治疗和预防伴随II型糖尿病的大量病症，包括代谢综合症X、反应性低血糖和糖尿性异常脂血症。下列疾病、病症和症状与II型糖尿病有关，因此可以通过采用本发明化合物的治疗方法来治疗、控制或在某些情况下预防：(1)高血糖症，(2)低葡萄糖耐受性，(3)抗胰岛素性，(4)肥胖症，(5)质脂疾病，(6)异常脂血症，(7)高脂血症，(8)高甘油三酯血症，(9)高胆固醇血症，(10)低HDL水平，(11)高HDL水平，(12)动脉粥样硬化及其后遗症，(13)血管再狭窄，(14)肠易激惹综合症，(15)肠炎，包括crohn氏病和溃疡性结肠炎，(16)视网膜病，(21)肾病，(22)神经病，(23)X综合症，(24)卵巢的雄激素过多症(多囊性卵巢综合症)及其它具抗胰岛素性的疾病；以及生长素缺乏症，肠损伤，免疫抑制作用，HIV感染，血细胞生成，神经元疾病，脑瘤侵入和转移，良性前列腺肥大，精液能动性，龈炎，骨质疏松症等。
本发明具有磺酰胺甲酰哌嗪结构的DPP-IV抑制剂与现有技术相比，具有以下优点：
(1)本发明化合物可以较好的抑制DPP-IV(负责降解GLP-1的酶)的活性，使体内GLP-1水平更加稳定；疗效确切；
(2)本发明化合物具有高度DPP-IV选择性，因此有很少的不良反应；用药安全；
(3)本发明化合物制备工艺简单，药品纯度高、收率高、质量稳定、可控，易于进行大规模工业生产。
以下通过体外药理实验进一步阐述本发明化合物的有益效果，但不应将此理解为本发明化合物仅具有下列有益效果。
实验例1 本发明化合物的体外药理活性
供试品：化合物1、化合物2：自制，其化学名称和结构式如前文所述，制备方法见各化合物的制备实施例；
对照品：磷酸西他列汀：市购；
实验方法：准确称取供试品及对照品磷酸西他列汀，加入DMSO溶解，充分混匀，配成100mM。然后用DMSO将上述母液逐级稀释至10mM、1mM、100μM、10μM。取上述溶液4μl，加入396μl的缓冲液，充分混匀，配成100μM、10μM、1μM、100nM。
1、荧光法检测对DPP-IV的抑制作用：
取5μl正常小鼠血清，加入1μl不同浓度的待测化合物及24μl MgCl2缓冲液，混匀后室温中预孵育5分钟，然后加入10μl100μM反应底物以及20μl缓冲液，避光混匀后进行荧光测定(激发波380nm/发射波460nm)，每隔3分钟测定1次，第20分钟时加入25％乙酸40μl终止反应，室温避光放置5分钟后，再次进行荧光测定。
2、荧光法检测化合物对DPP-7的抑制作用：
以0.1mg/ml的BSA和100mM的二甲胂酸盐的缓冲液(pH5.5)为反应液，5μM的Nle-Pro-AMC为底物与1μl化合物在37℃反应15分钟(激发光和发射光波长分别为360nm和460nm)。
3、荧光法检测化合物对DPP-8的抑制作用：
以0.1mg/ml的BSA和50mM的磷酸钠缓冲液(pH8.0)为反应液，100μM的Ala-Pro-7-amino-4-trifluormethylcoumarin为底物与1μl化合物在37℃反应15分钟(激发光和发射光波长分别为400nm和505nm)。
4、荧光法检测化合物对DPP-9的抑制作用：
以0.1mg/ml的BSA和100mM的Tris/HCl缓冲液(pH7.4)为反应液，100μM的Gly-Pro-AMC为底物与1μl化合物在37℃反应30分钟(激发光和发射光波长分别为360nm和460nm)。
实验结果和结论：
表1 本发明化合物对DPP-IV的活性及选择性
由表1可见，与磷酸西他列汀相比，本发明化合物1、化合物2对DPP-IV的活性较磷酸西他列汀略好，对DPP-7、DPP-8、DPP-9的选择性与磷酸西他列汀相当，因此，化合物1、化合物2既安全又有效。
实验例2 本发明化合物的体内药理活性
供试品：化合物1、化合物2，自制，其化学名称和结构式如前文所述，制备方法见各化合物的制备实施例；；
对照品：妥拉磺脲：市购；
实验方法：
1、造模：选取200g左右体重的大鼠60只，随机分组，一组正常对照组(10只)，给予普通饲料(含脂肪12％，碳水化合物60％，蛋白质28％)；其余50只给予高脂饲料(含脂肪41％，碳水化合物41％，蛋白质18％)，饲养2周后，动物禁食不禁水过夜，按60mg/kg体重腹腔注射STZ，72小时后测动物空腹血糖(fasting blood glucose，FBG)，稳定在13.5mmol/L以上者为造模成功，成膜36只。正常对照组以等剂量的柠檬酸钠-柠檬酸缓冲液尾静脉注射。
2、试验分组及给药方法：将36只成模大鼠按体重和血糖水平随机分为4组，化合物1用药组(简称化合物1组，9只)、化合物2用药组(简称化合物2组，9只)、妥拉磺脲用药组(简称妥拉磺脲组，9只)、病理对照组(简称病理组，9只)。
表2 动物分组及给药
5组大鼠每日灌胃治疗1次，均不限制进食及饮水，治疗周期为8周。
大鼠分别于给药第8周末禁食12小时，从尾静脉采血测空腹血糖(FBG)水平。
3、空腹血糖(FBG)水平测定：取尾静脉血在血糖仪(LifeScan，Milpitas，CA，USA)上测定。
4、统计分析：所有数值均表示为均数士标准差(mean±s)。各计量资料均采用SPSS11.0FOR WINDOWS软件对数据进行统计处理，单因素多个样本均数的比较用方差分析，多样本均数两两比较采用q检验，各组前后比较用配对资料的t检验。P<0.05时，表示在统计上有意义。
5、结果：如表3所示，，病理组和治疗组空腹血糖均明显高于正常组(P<0.01)；治疗组空腹血糖水平显著低于病理组(P<0.01)；各治疗组之间空腹血糖水平无显著差异(P>0.05)，化合物1、化合物2治疗者的血糖水平大大低于妥拉磺脲组，提示化合物1、化合物2能明显降低II型糖尿病大鼠血糖水平，改善II型糖尿病糖代谢紊乱。
表3 各组大鼠FBG水平比较(mean±s)
与正常组相比，*P<0.01；与病理组相比，ΔP<0.01；
结论：本发明化合物1、化合物2对II型糖尿病的效果优于磷酸西他列汀和妥拉磺脲，集两种药物的优点于一体，适用于抗II型糖尿病的临床开发。
4、具体实施方式
以下通过实施例形式的具体实施方式，对本发明的上述内容作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下实施例。凡基于本发明上述内容所实现的技术均属于本发明的范围。以下实施例中各剂型的辅料可以用药学上可接受的辅料替换，或者减少、增加。
实施例 1N-[(R)-3-氨基-4-(2，4，5-三氟苯基)-1-丁酰]-N′-(对甲苯磺酰胺)甲酰哌嗪(化合
物1)的制备
步骤1(2R，5S)-2，5-二氢-3，6-二甲氧基-2-[(2，4，5-三氟苯基)甲基]-5-异丙基吡嗪的制备
将9.2g(50mmol)(2S-(+)-2，5-二氢-3，6-二甲氧基-2-异丙基吡嗪溶于300ml四氢呋喃中，然后于-78℃、30min内滴加入24ml(60mmol，2.5N)的正丁基锂/正己烷溶液，保温搅拌30min，然后滴加入9.9g(55mmol)的2，4，5-三氟基氯苄的50ml四氢呋喃冷溶液，-78℃搅拌反应5h，加入100ml水淬灭反应，反应液浓缩，剩余物加入乙酸乙酯和1N盐酸，分出水层，用乙酸乙酯提取三次，合并有机层，饱和盐水洗，无水硫酸镁干燥，减压浓缩，硅胶柱纯化(洗脱剂为乙酸乙酯和环己烷的混合液)得12g胶状固体目标化合物，收率：73.4％。
步骤2(R)-N-2-(叔丁氧羰基)-3-(2，4，5-三氟苯基)丙氨酸甲酯的制备
16.4g(50mmol)的(2R，5S)-2，5-二氢-3，6-二甲氧基-2-[(2，4，5-三氟苯基)甲基]-5-异丙基吡嗪溶于100ml乙腈中，然后滴加100ml1N的盐酸，反应液室温搅拌24h.加入甲醇，浓缩至干，此操作重复三次，然后再用甲苯重复一次，得固体，该固体用400ml二氯甲烷溶解后缓慢加入50g的三乙胺，然后再缓慢滴加入24g(110mmol)(Boc)2O，反应液室温搅拌8h，滤除反应生成的固体，滤液用二氯甲烷稀释，分别用1N的HCl溶液和饱和盐水洗涤，无水硫酸镁干燥，硅胶柱纯化，洗脱剂为乙腈-石油醚的混合液，得到10.5g固体目标化合物，收率：63.3％。
步骤3(R)-N-2-(叔丁氧羰基)-3-(2，4，5-三氟苯基)丙氨酸的制备
将10g(30mmol)的(R)-N-2-(叔丁氧羰基)-3-(2，4，5-三氟苯基)丙氨酸甲酯中加入200ml四氢呋喃，冰浴冷却，然后滴加入2.15g(90mmol)氢氧化锂的200ml水溶液，反应液室温搅拌15h，减压浓缩，剩余物用乙酸乙酯溶解，饱和碳酸氢钠和食盐水洗涤，无水硫酸镁干燥，蒸除溶剂得7.7g固体，收率：80.3％。
步骤4(R)-3-[(叔丁氧羰基)胺基]-1-重氮-4-(2，4，5-三氟苯基)丁基-2-酮的制备
加入8g(25mmol)的(R)-N-2-(叔丁氧羰基)-3-(2，4，5-三氟苯基)丙氨酸，150ml乙醚，然后于-30℃下加入3g(30mmol)的三乙胺和4ml氯甲酸异丁酯，加毕，-30℃搅拌反应30min，然后加入含5.3g重氮甲烷的乙酸乙酯溶液，于0℃下加入适量的1-甲基-3-硝基-1-亚硝基胍溶于乙醚和40％氢氧化钠混合溶液，反应液0℃下搅拌反应20min，有机层干燥，混合液用乙酸乙酯稀释，饱和碳酸氢钠和盐水洗涤，无水硫酸镁干燥，减压浓缩至干得7.6g固体目标化合物，收率：88.2％。
步骤5(R)-3-[(叔丁氧羰基)胺基]-4-(2，4，5-三氟苯基)丁酸的制备
加入13.7g(40mmol)(R)-3-[(叔丁氧羰基)胺基]-1-重氮-4-(2，4，5-三氟苯基)丁基-2-酮溶于300ml甲醇中，降温至-30℃加入18.9g(120mmol)二异丙基乙基胺和2.3g(10mmol)的苯甲酸银，反应液升至室温搅拌3h，反应毕，减压蒸除甲醇，剩余物用200ml二氯甲烷溶解，滤除不溶性固体物，滤液浓缩，硅胶柱纯化得到固体，将此固体溶于100ml四氢呋喃中，然后加入含有1.8g(75mmol)氢氧化锂的100ml的水中，反应液室温搅拌16h，浓缩反应液后用乙酸乙酯稀释，饱和碳酸氢钠和盐水洗，用无水硫酸镁干燥，浓缩得7.2g白色固体化合物，收率：54.2％。
步骤6(R)-3-(叔丁氧羰基)胺基-4-(2，4，5-三氟苯基)-1-丁酰哌嗪的制备
于室温下投16.7g(50mmol)的(R)-3-[(叔丁氧羰基)胺基]-4-(2，4，5-三氟苯基)丁酸，6.8g(50mmol)HOBT(1-羟基苯并三氮唑)，DMF100ml，然后加入20g(75mmol)DCC(二环己基碳二亚胺)，室温搅拌反应1h。过滤除掉反应生成的固体，滤液继续加入反应瓶中，加入8.6g(100mmol)哌嗪，升温60℃搅拌3h，反应毕，加入300ml水，析出固体，以甲醇-乙酸乙酯混合液重结晶，得产物14.5g，收率：72.1％。
步骤7N-[(R)-3-氨基-4-(2，4，5-三氟苯基)-1-丁酰]-N′-(对甲苯磺酰胺)甲酰哌嗪的制备
在反应瓶中加入(R)-3-(叔丁氧羰基)胺基-4-(2，4，5-三氟苯基)-1-丁酰哌嗪18.1g(45mmol)，用100ml二氯甲烷溶解后，降低温度至0～5℃，缓慢滴加对甲苯磺酰胺基甲酰氯10.5g(45mmol)，升高温度至40℃，搅拌反应6h，再升温至回流，剧烈搅拌下滴加入40ml5N盐酸，反应1h后，降至室温，分出有机层，水层于冰浴下用稀碱液调pH9，析出固体过滤，依次用水、乙酸乙酯洗涤，得粗品，用乙醇重结晶得产物16.9g，收率：75.3％。
分子式：C22H25F3N4O4S
分子量：498.52
氢谱(CDCl3，400MHz)：
δ/ppm：2.31(q，1H)，2.37(s，3H)，2.55(q，1H)，2.71(q，1H)，2.97(q，1H)，3.29(m，1H)，3.58(m，4H)，3.65(m，4H)，5.17(br，2H)，6.04(br，1H)，6.67(m，2H)，6.84(m，2H)，7.45(d，2H)，7.79(d，2H)
质谱(m/z)：499(M+1)
元素分析：
实测值：C，53.15％；H，5.26％；F，11.22％；N，11.08％；S，6.22％
理论值：C，53.00％；H，5.05％；F，11.43％；N，11.24％；S，6.43％
实施例2N-[(R)-3-氨基-4-(2，4，5-三氟苯基)-1-丁酰]-N′-(对氯苯磺酰
胺)甲酰哌嗪(化合
物2)的制备
制备方法参考实施例1步骤7，投(R)-3-(叔丁氧羰基)胺基-4-(2，4，5-三氟苯基)-1-丁酰哌嗪18.1g(45mmol)，对氯苯磺酰胺基甲酰氯11.4g(45mmol)，得产物18g，收率：77.2％。
分子式：C21H22F3N4O4S
分子量：518.94
氢谱(CDCl3，400MHz)：
δ/ppm：2.32(q，1H)，2.53(q，1H)，2.70(q，1H)，2.96(q，1H)，3.27(m，1H)，3.57(m，4H)，3.64(m，4H)，5.16(br，2H)，6.03(br，1H)，6.66(m，2H)，6.82(m，2H)，7.65(d，2H)，7.86(d，2H)
质谱(m/z)：519(M+1)
元素分析：
实测值：C，48.41％；H，4.54％；Cl，6.70％；F，10.69％；N，10.92％；S，6.29％
理论值：C，48.60％；H，4.27％；Cl，6.83％；F，10.98％；N，10.80％；S，6.18％
参照以上制备方法，还可以制备以下化合物
| 名称 | 分子式 | 分子量 | 质谱(m/z) |
| N-[(R)-3-氨基-4-(2-氟苯基)-1-丁酰]-N’-(4-氯苯磺酰胺基)甲酰哌嗪 | C21H24ClFN4O4S | 482.96 | 483 |
| N-[(R)-3-氨基-4-(3，4-二氟苯基)-1-丁酰]-N’-(4-氯苯磺酰胺基)甲酰哌嗪 | C21H23ClF2N4O4S | 500.95 | 501 |
| N-[(R)-3-氨基-4-(2，5-二氟苯基)-1-丁酰]-N’-(4-氯苯磺酰胺基)甲酰哌嗪 | C21H23ClF2N4O4S | 500.95 | 501 |
| N-[(R)-3-氨基-4-(2-氟-4-三氟甲基苯基)-1-丁酰]-N’-(4-氯苯磺酰胺基)甲酰哌嗪 | C22H23ClF4N4O4S | 550.95 | 551 |
| N-[(R)-3-氨基-4-(3，4-二氟苯基)-1-丁酰]-N’-(4-氟苯磺酰胺基)甲酰哌嗪 | C21H23F3N4O4S | 484.49 | 485 |
| N-[(R)-3-氨基-4-(2，4-二氟苯基)-1-丁酰]-N’-(4-甲基苯磺酰胺基)甲酰哌嗪 | C22H26F2N4O4S | 480.53 | 481 |
| N-[(R)-3-氨基-4-苯基-1-丁酰]-N’-(4-甲基苯磺酰胺基)甲酰哌嗪 | C22H28N4O４S | 444.55 | 445 |
| N-[(R)-3-氨基-4-(2，4，5-三氟苯基)-1-丁酰]-N’-(2-氯苯磺酰胺基)甲酰哌嗪 | C21H22ClF3N4O4S | 518.94 | 519 |
| N-[(R)-3-氨基-4-(2，5-二氟-4-溴苯基)-1-丁酰]-N’-(4-氯苯磺酰胺基)甲酰哌嗪 | C21H22BrClF2N4O4S | 579.84 | 579 |
| N-[(R)-3-氨基-4-(2，5-二氟-4-氰基苯基)-1-丁酰]-N’-(4-氯苯磺酰胺基)甲酰哌嗪 | C22H22ClF2N5O4S | 525.96 | 526 |
| N-[(R)-3-氨基-4-(4，5-二氟-2-氰基苯基)-1-丁酰]-N’-(4-甲基苯磺酰胺基)甲酰哌嗪 | C23H25F2N5O4S | 505.54 | 506 |
| 名称 | 分子式 | 分子量 | 质谱(m/z) |
| N-[(R)-3-氨基-4-(4，6-二氟-3-氰基苯基)-1-丁酰]-N’-(4-氯苯磺酰胺基)甲酰哌嗪 | C22H22ClF2N5O4S | 525.96 | 526 |
制剂实施例 本发明化合物片剂的制备
1、处方：
处方1
处方2
处方3
2、制备工艺：按照处方称取原料和辅料，将原料粉碎过100目筛，其余辅料分别过100目筛；将原料、淀粉、羟丙基纤维素和微晶纤维素混合均匀，加入混合制粒机，加入1％HPMC的50％乙醇水溶液，搅拌15分钟，制成颗粒；颗粒在低于60℃的条件下烘干；干燥好的颗粒加入微粉硅胶和硬脂酸镁，整粒，混合均匀；取样，半成品化验；按照化验确定的片重压片；成品全检，包装入库。
Claims (9)
1.通式(I)所示的化合物或其药学上可接受的盐：
其中：Ar代表被1～5个R2取代或未被取代的苯基，其中R2独立地选自：
(1)卤素原子，
(2)直链或支链的被1～5个卤素原子取代或未被取代的C1-6烷基，
(3)直链或支链的被1～5个卤素原子取代或未被取代的C1-6烷氧基，
(4)氰基，或
(5)羟基；
Ar1代表被1～5个R3取代或未被取代的苯基，其中R3独立地选自：
(1)卤素原子，
(2)直链或支链的被1～5个卤素原子取代或未被取代的C1-6烷基，
(3)直链或支链的被1～5个卤素原子取代或未被取代的C1-6烷氧基，
(4)氰基，或
(5)羟基；
R1代表氢原子、直链或支链的C1-6烷基。
2.式(Ia)所示的权利要求1的化合物或其药学上可接受的盐：
其中：Ar代表被1～5个R2取代或未被取代的苯基，其中R2独立地选自：
(1)卤素原子，
(2)直链或支链的被1～5个卤素原子取代或未被取代的C1-6烷基，
(3)直链或支链的被1～5个卤素原子取代或未被取代的C1-6烷氧基，
(4)氰基，或
(5)羟基；
Ar1代表被1～5个R3取代或未被取代的苯基，其中R3独立地选自：
(1)卤素原子，
(2)直链或支链的被1～5个卤素原子取代或未被取代的C1-6烷基，
(3)直链或支链的被1～5个卤素原子取代或未被取代的C1-6烷氧基，
(4)氰基，或
(5)羟基；
R1代表氢原子、直链或支链的C1-6烷基。
3.如权利要求2所述的化合物或其药学上可接受的盐：
其中：Ar代表被1～5个R2取代或未被取代的苯基，其中R2独立地选自：
(1)氟原子，
(2)溴原子，
(3)三氟甲基，或
(4)氰基；
Ar1代表被1～5个R3取代或未被取代的苯基，其中R3独立地选自：
(1)甲基，
(2)氯原子，
(3)氟原子，
(4)叔丁基，
(5)三氟甲基，或
(6)氰基；
R1代表氢原子、甲基、乙基或异丙基。
4.如权利要求3所述的化合物或其药学上可接受的盐：
其中，Ar选自：
(1)苯基，
(2)2-氟代苯基，
(3)3，4-二氟苯基，
(4)2，4-二氟苯基，
(5)2，5-二氟苯基，
(6)2，4，5-三氟苯基，
(7)2-氟-4-(三氟甲基)苯基，
(8)4-溴-2，5-二氟苯基，
(9)2-氰基-4，5-二氟苯基，
(10)4-氰基-2，5-二氟苯基，或
(11)5-氰基-2，4-二氟苯基；
Ar1选自：
(1)苯基，
(2)4-甲基苯基，
(3)2-甲基苯基，
(4)4-氯代苯基，
(5)2-氯代苯基，或
(6)4-氟代苯基；
R1代表氢原子或甲基。
5.如权利要求4所述的化合物或其药学上可接受的盐，其中所述化合物为：
N-[(R)-3-氨基-4-(2，4，5-三氟苯基)-1-丁酰]-N′-(对甲苯磺酰胺)甲酰哌嗪，或
N-[(R)-3-氨基-4-(2，4，5-三氟苯基)-1-丁酰]-N′-(对氯苯磺酰胺)甲酰哌嗪，
6.如权利要求1～5任一权利要求所述的化合物或其药学上可接受的盐，其药学上可接受的盐选自有机酸盐、无机酸盐、有机碱盐或无机碱盐。
7.包括权利要求1～5任一权利要求所述的化合物或其药学上可接受的盐与一种或多种药用载体和/或稀释剂的药物组合物，为药学上可接受的任一剂型。
8.如权利要求7所述的药物组合物，含有权利要求1～5任一权利要求所述的化合物或其药学上可接受的盐10mg～10g作为必需的活性成分。
9.权利要求1～5任一权利要求所述的化合物或其药学上可接受的盐在用于制备治疗和/或预防非胰岛素依赖性糖尿病、高血糖、胰岛素抗性的药物中的应用。
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002100822A1 (en) * | 2001-06-11 | 2002-12-19 | Biovitrum Ab | Substituted sulfonamide compounds, process for their use as medicament for the treatment of cns disorders, obesity and type ii diabetes |
| WO2005095418A1 (en) * | 2004-04-02 | 2005-10-13 | Novartis Ag | Sulfonamide-thiazolpyridine derivatives as glucokinase activators useful the treatment of type 2 diabetes |
| US20050277649A1 (en) * | 2003-12-22 | 2005-12-15 | Amgen Sf, Llc | Aryl sulfonamide compounds and uses related thereto |
| WO2007041365A3 (en) * | 2005-09-30 | 2007-06-21 | Novartis Ag | 3-cyclyl-2- (4-sulfamo yl-phenyl) -n-cyclyl-propionamide derivatives useful in the treatment of impaired glucose tolerance and diabetes |
| WO2007070506A3 (en) * | 2005-12-14 | 2007-12-13 | Amgen Inc | Diaza heterocyclic sulfonamide derivatives and their uses |
-
2008
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002100822A1 (en) * | 2001-06-11 | 2002-12-19 | Biovitrum Ab | Substituted sulfonamide compounds, process for their use as medicament for the treatment of cns disorders, obesity and type ii diabetes |
| US20050277649A1 (en) * | 2003-12-22 | 2005-12-15 | Amgen Sf, Llc | Aryl sulfonamide compounds and uses related thereto |
| WO2005095418A1 (en) * | 2004-04-02 | 2005-10-13 | Novartis Ag | Sulfonamide-thiazolpyridine derivatives as glucokinase activators useful the treatment of type 2 diabetes |
| WO2007041365A3 (en) * | 2005-09-30 | 2007-06-21 | Novartis Ag | 3-cyclyl-2- (4-sulfamo yl-phenyl) -n-cyclyl-propionamide derivatives useful in the treatment of impaired glucose tolerance and diabetes |
| WO2007070506A3 (en) * | 2005-12-14 | 2007-12-13 | Amgen Inc | Diaza heterocyclic sulfonamide derivatives and their uses |
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