CN101723947B - 二肽酶-ⅳ抑制剂化合物 - Google Patents
二肽酶-ⅳ抑制剂化合物 Download PDFInfo
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- CN101723947B CN101723947B CN2009101759598A CN200910175959A CN101723947B CN 101723947 B CN101723947 B CN 101723947B CN 2009101759598 A CN2009101759598 A CN 2009101759598A CN 200910175959 A CN200910175959 A CN 200910175959A CN 101723947 B CN101723947 B CN 101723947B
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Abstract
本发明属于医药技术领域，具体涉及通式(I)所示的二肽酶-IV抑制剂化合物、其药学上可接受的盐或其异构体：其中R1、R2、Ar、X、Y和n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，具体涉及二肽酶-IV(DPP-IV)抑制剂化合物、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、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。
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，由遗传和环境因素相互作用而引起。糖尿病的病因十分复杂，但归根到底是由于胰岛素绝对或相对缺乏，或胰岛素抵抗。其特点为由于胰岛素的绝对或相对不足和靶细胞对胰岛素的敏感性降低，引起碳水化合物、蛋白质、脂肪、电解质和水的代谢紊乱。
近年来，由于生活水平的提高、饮食结构的改变、日趋紧张的生活节奏以及少动多坐的生活方式等诸多因素，全球糖尿病发病率增长迅速，糖尿病已经成为继肿瘤、心血管病变之后第三大严重威胁人类健康的慢性疾病。目前全球糖尿病患者已超过1.2亿人，我国患者人群居世界第二。据统计，中国已确诊的糖尿病患者达4000多万，并以每年100万的速度递增。其中，I型糖尿病患者占10％，II型糖尿病患者占90％。糖尿病成了人们日益关注的公共卫生问题。
目前I型糖尿病治疗药物主要是胰岛素制剂及其代用品；对于II型糖尿病的治疗，主要的药物是口服降糖药，大致分为磺脲类、双胍类、中药制剂、其他降糖药及辅助用药。
磺脲类降糖药物是最主要的糖尿病治疗药物，通过刺激β-细胞分泌更多的胰岛素，当它无效时，通过注射胰岛素来增加血浆的胰岛素水平，胰岛素浓度升高可导致刺激高胰岛素抗性组织。双胍类能提高胰岛素的敏感性，使高血糖症有所缓和，但是两种双胍，苯乙双胍和二甲双胍，都可以诱发乳酸中毒和恶心/腹泻。α-葡萄糖苷酶抑制剂类降糖药物，通过抑制小肠粘膜刷状缘α-葡萄糖苷酶的活性，减少低聚糖分解为单糖后再被吸收，可延缓餐后糖分的吸收，抑制饭后血糖高峰，如阿卡波糖、米格列醇，但有肠道胀气、腹泻及其它副作用。其他类降糖药物，如胰岛素增敏剂、胰岛素拮抗激素抑制剂、糖异生抑制剂、胰岛素样生长因子、ISU分泌促进剂等。此外，我国在筛选降血糖中药进行了不少研究，天然药用植物中的萜类、黄酮类、多糖类、多肽氨基酸、不饱和脂肪酸、生物碱、甾体和硫键化合物等成分均具有一定的降血糖作用。Glitazones是最近公开的一类有效改善II型糖尿病多种症状的化合物，是过氧化酶增值剂活化受体的激动剂。目前上市的此类化合物已经表现出严重的副作用。以上大多数糖尿病治疗药物只能从一定程度上控制血糖，不能从根本上驱除病因及防止并发症。
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。表明这种肽酶在人体或其它动物的各种疾病过程中的潜在作用。
DPP-IV抑制剂是新一代治疗糖尿病的药物。目前上市的DPP-IV的抑制剂是sitagliptinphosphate(磷酸西他列汀)，结构式如下，对DPP-IV具有选择性，不抑制DPP-8和DPP-9的活性，有较好的安全性和可容许性，并且不会引起体重增加、引起水肿和低血糖风险。Vildagliptin(维格列汀)结构式如下，是由诺华开发的口服DPP-IV抑制剂，已在欧洲多个国家上市。
然而这些DPP-IV的抑制剂的药物活性不够理想，并且对DPP家族的其他蛋白选择性不足，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抑制剂。
本发明的技术方案之一是提供了通式(I)所示的化合物、其药学上可接受的盐或其异构体：
其中，
R1、R2分别独立地代表氢原子或C1-6烷基；
Ar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)CN，或
(5)羟基；
X选自：
(1)N，或
(2)C-R4，其中R4选自：氢原子，CN，被1～5个卤素原子取代或未被取代的C1-6烷基，或被1～5个卤素原子取代或未被取代的C1-6烷氧基；
Y选自：
(1)N，或
(2)C-R5，其中R5选自：氢原子，CN，被1～5个卤素原子取代或未被取代的C1-6烷基，或被1～5个卤素原子取代或未被取代的C1-6烷氧基；
n代表0-3的整数。
本发明的另一技术方案是提供了通式(I’)所示的化合物、其药学上可接受的盐或其异构体：
其中，
R1、R2分别独立地代表氢原子，甲基或乙基；
Ar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)氟原子，
(2)溴原子，
(3)CF3，或
(4)CN；
X选自：
(1)N，或
(2)C-R4，其中R4选自：氢原子，或被1～5个卤素原子取代或未被取代的C1-4烷基；
Y选自：
(1)N，或
(2)C-R5，其中R5选自：氢原子，或被1～5个卤素原子取代或未被取代的C1-4烷基；
n代表0-2的整数。
进一步优选的化合物为：
其中，
R1、R2分别独立地代表氢原子或甲基；
Ar选自：
(1)苯基，
(2)3-氟苯基，
(3)3-甲基苯基，
(4)3-三氟甲基苯基，
(5)3-甲氧基苯基，
(6)3，4-二氟苯基，
(7)3，5-二氟苯基，
(8)2，5-二氟苯基，
(9)2，4，5-三氟苯基，
(10)2-氟-4-(三氟甲基)苯基，
(11)4-溴-2，5-二氟苯基，
(12)2-氰基-4，5-二氟苯基，
(13)4-氰基-2，5-二氟苯基，或
(14)5-氰基-2，4-二氟苯基；
X选自：
(1)N，或
(2)C-R4，其中R4选自：氢原子，甲基，乙基，CF3，CH2CF3，或CF2CF3；
Y选自：
(1)N，或
(2)C-R5，其中R5选自：氢原子，甲基，乙基，CF3，CH2CF3，或CF2CF3；
n代表0或者1。
更进一步优选的化合物为：
其中，
R1、R2分别独立地代表氢原子；
Ar选自：
(1)苯基，
(2)3-氟苯基，
(3)3-甲基苯基，
(4)3-三氟甲基苯基，
(5)3-甲氧基苯基，
(6)3，4-二氟苯基，
(7)3，5-二氟苯基，
(8)2，5-二氟苯基，
(9)2，4，5-三氟苯基；
X选自：
(1)N，或
(2)C-R4，其中R4选自：氢原子，甲基，或CF3；
Y选自：
(1)N，或
(2)C-R5，其中R5选自：氢原子，甲基，或CF3；
n代表1。
特别优选的化合物选自：
本发明所述“卤素原子”为氟原子、氯原子、溴原子或碘原子。
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。
本发明还提供了本发明化合物的制备方法，为式(a)所示化合物与式(b)所示化合物在HOBT/DCC下反应后，与三苯基磷/碘化钾反应得磷叶立德(phosphorus ylide)，再与式(c)所示化合物经维狄希(wittig)反应，制得式(I)所示化合物，
式(a)， 式(b)， 式(c)，
其中R1、R2、Ar、X、Y和n代表的基团如前文所定义。
本发明化合物的制备方法还可以用以下详细步骤来论述，反应方程式如下，但不仅限于下列方法：
式(a) 式(b) 化合物A
式(c) 式(I)化合物
反应步骤：
步骤1化合物A的制备
于室温下加入式(a)所示化合物，1-羟基苯并三氮唑(HOBT)，二氯甲烷，然后加入二环己基碳二亚胺(DCC)，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，加入式(b)所示化合物，升温至10～50℃，保温搅拌，反应完毕，减压浓缩反应液，以甲醇和二氯甲烷混合液重结晶，得化合物A。
步骤2式(I)化合物的制备
在反应瓶中，加入上步所得化合物A，以DMF溶解，然后加入三苯基磷/碘化钾得磷叶立德(phosphorus ylide)，于室温搅拌反应，滴加异丙醇，析出固体，过滤，干燥。将固体投入反应瓶中，用二氯甲烷溶解，然后分批加入式(c)所示化合物进行叶立德(wittig)反应，在剧烈搅拌下用饱和的碳酸氢钠溶液调节pH，室温搅拌反应，用浓盐酸调节pH，分出有机层，无水硫酸钠干燥，减压回收溶剂，剩余物中加入丙酮，析出固体，投入反应瓶中，二氯甲烷溶解后，升温至回流，剧烈搅拌下滴加入5N盐酸，反应后，降至室温，分出有机层，水层于冰浴下用稀碱液调pH，析出固体，得式(I)所示化合物。
以上反应方程式中的R1、R2、Ar、X、Y和n代表的基团如前文所定义。
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、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激动剂例如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，例如KRP-297，和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)，(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氨基烷基衍生物)，(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；
(l)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、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1mg～1g，优选25mg～1g，可以为25mg、50mg、75mg、0.1g、0.2g、0.4g、0.5g、0.6g、0.75g、1g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。
本发明还保护本发明化合物、其药学上可接受的盐或其异构体在制备治疗和/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。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、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，(17)肾病，(18)神经病，(19)X综合症，(20)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。
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。
实验例本发明化合物的体外药理活性
供试品：
本发明部分化合物，自制。
对照品：
磷酸西他列汀、维格列汀：自制，其结构式如前文所述。
实验方法：准确称取供试品及对照品，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10μL 100μM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(pH为5.5)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(pH为8.0)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(pH为7.4)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，与磷酸西他列汀及维格列汀相比，本发明供试化合物对DPP-IV的活性较磷酸西他列汀略好，对DPP-7的选择性较维格列汀优秀，对于DPP-8和DPP-9的选择性与磷酸西他列汀、维格列汀相当。因此，本发明化合物具有较强的安全性和有效性。
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17-[(S)-3-氨基-E-4-烯-5-(2，4，5-三氟基苯基)戊酰基]-3-三氟甲基-5，6，7，8-四氢
-[1，2，4]三唑并[4，3-a]吡嗪的制备
步骤17-[(S)-3-(叔丁氧羰基氨基)-3-氯丁酰基]-3-(三氟甲基)-5，6，7，8-四氢-[1，2，4]三唑并
[4，3-a]吡嗪的制备
于室温下投24g(100mmol)的(S)-3-(叔丁氧羰基氨基)-3-氯丁酸，13.5g(100mmol)HOBT(1-羟基苯并三氮唑)，二氯甲烷100mL，然后加入40g(150mmol)DCC(二环己基碳二亚胺)，室温搅拌反应2h。过滤除掉反应生成的固体，滤液继续加入反应瓶中，加入19.2g(100mmol)3-(三氟甲基)-5，6，7，8-四氢-[1，2，4]三唑并[4，3-a]吡嗪(其制备方法参见J.Med.Chem.2005，48，141-151)，升温至40℃，保温搅拌5h，反应完毕，减压浓缩反应液，以甲醇和二氯甲烷混合液纯化，得目标化合物30.9g，收率：75.1％。
步骤27-[(S)-3-(叔丁氧羰基氨基)-E-4-烯-5-(2，4，5-三氟基苯基)戊酰基]-3-(三氟甲
基)-5，6，7，8-四氢-[1，2，4]-三唑并[4，3-a]吡嗪的制备
在反应瓶中，加入20.6g(50mmol)的上步制备产物7-[(S)-3-(叔丁氧羰基氨基)-3-氯丁酰基]-3-(三氟甲基)-5，6，7，8-四氢-[1，2，4]-三唑并[4，3-a]吡嗪，以100mL DMF溶解。然后加入三苯基磷19.7g(75mmol)、碘化钾7.5g(45mmol)，于室温搅拌反应3h，滴加异丙醇1L，析出固体，过滤，干燥。将固体投入反应瓶中，用100mL二氯甲烷溶解，然后分批加入2，4，5-三氟苯甲醛8g(50mmol)，在剧烈搅拌下用饱和的碳酸氢钠溶液调节pH为9，室温搅拌反应5h，用浓盐酸调节pH为5，分出有机层，无水硫酸钠干燥，减压回收溶剂，剩余物中加入丙酮，析出固体，得产物12.5g，收率：48％。
步骤3化合物1的制备
将步骤2制得的20.8g(40mmol)7-[(S)-3-(叔丁氧羰基氨基)-E-4-烯-5-(2，4，5-三氟基苯基)戊酰基]-3-(三氟甲基)-5，6，7，8-四氢-[1，2，4]-三唑并[4，3-a]吡嗪投入反应瓶中，100mL二氯甲烷溶解后，升温至回流，剧烈搅拌下滴加入5N盐酸50mL，反应1h后，降至室温，分出有机层，水层于冰浴下用稀碱液调pH为9，析出固体，得目标化合物15.4g，收率：92％。
分子式：C17H15F6N5O
分子量：419.32
元素分析：
实测值：C，48.52％；H，3.82％；F，27.05；N，16.45％
理论值：C，48.69％；H，3.61％；F，27.18；N，16.70％
质谱(m/e)：420(M+1)
氢谱(CDCl3，400MHz)：
δ2.34(d，1H)δ2.41(d，1H)δ3.82(q，2H)δ3.96(d，1H)δ4.12(q，4H)δ4.78(d，1H)δ4.95～5.20(d，d，1H)δ6.54(q，1H)δ6.87(m，1H)δ7.09(d，1H)δ7.14(m，1H)
实施例27-[(S)-3-氨基-E-4-烯-5-苯基]戊酰基-3-三氟甲基-5，6，7，8-四氢-[1，2，4]-三唑并
[4，3-a]吡嗪的制备
步骤17-[3-(叔丁氧羰基氨基)-4-氯丁酰基]-3-(三氟甲基)-5，6，7，8-四氢-[1，2，4]-三唑并
[4，3-a]吡嗪的制备
于室温下投14.3g(60mmol)的3-(叔丁氧羰基氨基)-4-氯丁酸，8.8g(65mmol)HOBT(1-羟基苯并三氮唑)，二氯甲烷100mL，然后加入20.6g(100mmol)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11.5g(60mmol)3-(三氟甲基)-5，6，7，8-四氢-[1，2，4]-三唑并[4，3-a]吡嗪(其制备方法参见J.Med.Chem.2005，48，141-151)，升温至50℃，保温搅拌4h，反应完毕，减压浓缩反应液，以甲醇和二氯甲烷混合液重结晶，得目标化合物17.9g，收率：72.5％。
步骤27-[3-(叔丁氧羰基氨基)-E-4-烯-5-苯基]戊酰基-3-(三氟甲基)-5，6，7，8-四氢-[1，2，4]-
三唑并[4，3-a]吡嗪的制备
在反应瓶中，加入16.5g(40mmol)的7-[3-(叔丁氧羰基氨基)-4-氯丁酰基]-3-(三氟甲基)-5，6，7，8-四氢-[1，2，4]-三唑并[4，3-a]吡嗪，以100mL DMF溶解。然后加入三苯基磷13.1g(50mmol)、碘化钾6.6g(40mmol)，于室温搅拌反应3h，滴加异丙醇600mL，析出固体，过滤，干燥。将固体投入反应瓶中，用100mL二氯甲烷溶解，然后分批加入苯甲醛4.8g(45mmol)，在剧烈搅拌下用饱和的碳酸氢钠溶液调节pH为10，室温搅拌反应5h，用浓盐酸调节pH为5，分出有机层，无水硫酸钠干燥，减压回收溶剂，剩余物中加入丙酮，析出固体，得产物10.4g，收率：56％。
步骤3化合物2的制备
将步骤2制得的9.3g(20mmol)7-[3-(叔丁氧羰基氨基)-E-4-烯-5-苯基]戊酰基-3-(三氟甲基)-5，6，7，8-四氢-[1，2，4]-三唑并[4，3-a]吡嗪投入反应瓶中，100mL二氯甲烷溶解后，升温至回流，剧烈搅拌下滴加入5N盐酸40mL，反应1h后，降至室温，分出有机层，水层于冰浴下用稀碱液调pH为9，析出固体，得目标化合物6.9g，收率：94.1％。
分子式：C17H18F3N5O
分子量：365.35
元素分析：C，55.65％；H，5.19％；F，15.33％；N，19.05％
(计算：C，55.89％；H，4.97％；F，15.60％；N，19.17％)
质谱(m/e)：366(M+1)
氢谱(CDCl3，400MHz)：
δ2.33(d，1H)δ2.42(d，1H)δ3.81(q，2H)δ3.95(d，1H)δ4.15(q，4H)δ4.76(d，1H)δ4.92～5.190(d，d，1H)δ6.52(q，1H)δ6.84(m，1H)δ7.05(m，1H)δ7.24(m，2H)δ7.39(d，2H)
实施例37-[(S)-3-氨基-E-4-烯-5-(3-甲基苯基)戊酰基]-2-三氟甲基-5，6，7，8-四氢-[1，2，4]三
唑并[1，5-a]吡嗪(化合物10)的制备
步骤17-[(S)-3-(叔丁氧羰基氨基)-3-氯丁酰基]-2-(三氟甲基)-5，6，7，8-四氢-[1，2，4]三唑并
[1，5-a]吡嗪的制备
室温条件下，于250mL三颈瓶中，加入(S)-3-(叔丁氧羰基氨基)-3-氯丁酸(24g，100mmol)，1-羟基苯并三氮唑(13.5g，100mmol)，二氯甲烷100mL，然后加入二环己基碳二亚胺(40g，150mmol)，室温搅拌反应2h。过滤除掉反应生成的固体，滤液加入反应瓶中，加入19.2g(100mmol)2-(三氟甲基)-5，6，7，8-四氢-[1，2，4]三唑并[1，5-a]吡嗪(其制备方法参见J.Med.Chem.2005，48，141-151)，升温至40℃，保温搅拌5h，反应完毕，减压浓缩反应液，以甲醇和二氯甲烷混合液纯化，得目标化合物30.9g，收率：75.1％。
步骤27-[(S)-3-(叔丁氧羰基氨基)-E-4-烯-5-(3-甲基苯基)戊酰基]-2-(三氟甲基)-5，6，7，8-
四氢-[1，2，4]-三唑并[1，5-a]吡嗪的制备
在反应瓶中，加入20.6g(50mmol)的上步制备产物7-[(S)-3-(叔丁氧羰基氨基)-3-氯丁酰基]-2-(三氟甲基)-5，6，7，8-四氢-[1，2，4]-三唑并[1，5-a]吡嗪，以100mLN，N-二甲基甲酰胺溶解。然后加入三苯基磷(19.7g，75mmol)、碘化钾(7.5，45mmol)，于室温搅拌反应3h，滴加异丙醇1L，析出固体，过滤，干燥。将固体投入反应瓶中，用100mL二氯甲烷溶解，然后分批加入3-三甲基苯甲醛6g(50mmol)，在剧烈搅拌下用饱和的碳酸氢钠溶液调节pH为9，室温搅拌反应5h，用浓盐酸调节pH为5，分出有机层，无水硫酸钠干燥，减压回收溶剂，剩余物中加入丙酮，析出固体，得产物9.09g，收率：48％。
步骤3化合物10的制备
将步骤2制得的15.17g(40mmol)7-[(S)-3-(叔丁氧羰基氨基)-E-4-烯-5-(3-甲基苯基)戊酰基]-2-(三氟甲基)-5，6，7，8-四氢-[1，2，4]-三唑并[1，5-a]吡嗪投入反应瓶中，100mL二氯甲烷溶解后，升温至回流，剧烈搅拌下滴加入5N盐酸50mL，反应1h后，降至室温，分出有机层，水层于冰浴下用稀碱液调pH为9，析出固体，得到目标化合物15.4g，收率：92％。
分子式：C18H20F3N5O
分子量：379.16
元素分析：
实测值：C：56.96％；H：5.29％；F：27.05；N：18.40％
理论值：C：56.99％；H：5.31％；F：15.02；N：18.46％
质谱(m/e)：380(M+1)
氢谱(CDCl3，400MHz)：
δ2.57(m，1H)δ2.32(m，1H)δ3.68(q，2H)δ3.99(d，2H)δ4.46(s，2H)δ3.53(d，1H)δ2.3(s，2H)δ6.19(q，1H)δ6.53(m，1H)δ6.94-7.11(m，4H)δ2.35(s，3H)
制剂实施例本发明化合物片剂的制备
1、处方：
处方1
化合物1 125g
淀粉 180g
羟丙基纤维素 40g
微晶纤维素 45g
1％HPMC的50％乙醇水溶液 105g
微粉硅胶 3g
硬脂酸镁 2g
共制备 1000片
处方2
化合物2 50g
淀粉 200g
羟丙基纤维素 50g
微晶纤维素 55g
1％HPMC的50％乙醇水溶液 140g
微粉硅胶 3g
硬脂酸镁 2g
共制备 1000片
处方3
化合物10 25g
淀粉 225g
羟丙基纤维素 50g
微晶纤维素 55g
1％HPMC的50％乙醇水溶液 140g
微粉硅胶 3g
硬脂酸镁 2g
共制备 1000片
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，
R1、R2分别独立地代表氢原子或C1-6烷基；
Ar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)CN，或
(5)羟基；
X选自：
(1)N，或
(2)C-R4，其中R4选自：氢原子，CN，被1～5个卤素原子取代或未被取代的C1-6烷基，或被1～5个卤素原子取代或未被取代的C1-6烷氧基；
Y选自：
(1)N，或
(2)C-R5，其中R5选自：氢原子，CN，被1～5个卤素原子取代或未被取代的C1-6烷基，或被1～5个卤素原子取代或未被取代的C1-6烷氧基；
n代表0-3的整数。
2.如权利要求1所述的化合物或其药学上可接受的盐，具有下述通式(I’)的结构：
其中，
R1、R2分别独立地代表氢原子，甲基或乙基；
Ar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)氟原子，
(2)溴原子，
(3)CF3，或
(4)CN；
X选自：
(1)N，或
(2)C-R4，其中R4选自：氢原子，或被1～5个卤素原子取代或未被取代的C1-4烷基；
Y选自：
(1)N，或
(2)C-R5，其中R5选自：氢原子，或被1～5个卤素原子取代或未被取代的C1-4烷基；
n代表0-2的整数。
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，
R1、R2分别独立地代表氢原子或甲基；
Ar选自：
(1)苯基，
(2)3，4-二氟苯基，
(3)2，5-二氟苯基，
(4)2，4，5-三氟苯基，
(5)2-氟-4-(三氟甲基)苯基，
(6)4-溴-2，5-二氟苯基，
(7)2-氰基-4，5-二氟苯基，
(8)4-氰基-2，5-二氟苯基，或
(9)5-氰基-2，4-二氟苯基；
X选自：
(1)N，或
(2)C-R4，其中R4选自：氢原子，甲基，乙基，CF3，CH2CF3，或CF2CF3；
Y选自：
(1)N，或
(2)C-R5，其中R5选自：氢原子，甲基，乙基，CF3，CH2CF3，或CF2CF3；
n代表0或者1。
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，
R1、R2分别独立地代表氢原子；
Ar选自：
(1)苯基，
(2)3，4-二氟苯基，
(3)2，5-二氟苯基，
(4)2，4，5-三氟苯基；
X选自：
(1)N，或
(2)C-R4，其中R4选自：氢原子，甲基，或CF3；
Y选自：
(1)N，或
(2)C-R5，其中R5选自：氢原子，甲基，或CF3；
n代表1。
5.如权利要求1所述的化合物或其药学上可接受的盐，其中化合物选自：
7-[(S)-3-氨基-E-4-烯-5-(2，4，5-三氟基苯基)戊酰基]-3-三氟甲基-5，6，7，8-四氢-[1，2，4]-三唑并[4，3-a]吡嗪，
7-[(S)-3-氨基-E-4-烯-5-苯基]戊酰基-3-三氟甲基-5，6，7，8-四氢-[1，2，4]-三唑并[4，3-a]吡嗪，
或7-[(S)-3-氨基-E-4-烯-5-[3-甲基苯基]戊酰基]-2-三氟甲基-5，6，7，8-四氢-[1，2，4]三唑并[1，5-a]吡嗪。
6.一种制备权利要求1通式(I)所述的化合物的制备方法，所述方法为式(a)所示化合物与式(b)所示化合物在HOBT/DCC下反应后，与三苯基磷/碘化钾反应得磷叶立德，再与式(c)所示化合物经维狄希反应制得制得式(I)所示化合物，
其中R1、R2、Ar、X、Y和n代表的基团如权利要求1所定义。
7.如权利要求1～5任一项所述的化合物或其药学上可接受的盐制成药学上可接受的任一剂型，其特征在于包括一种或多种药用载体和/或稀释剂。
8.如权利要求7所述的制剂，其特征在于单位制剂含有通式(I)所示的化合物1mg～1g作为必需的活性成分。
9.如权利要求1～5任一项所述的化合物或其药学上可接受的盐在制备治疗和/或预防糖尿病、高血糖、胰岛素抗性的药物中的应用。
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1571667A (zh) * | 2001-10-23 | 2005-01-26 | 凡林有限公司 | 二肽基肽酶ⅳ的抑制剂 |
| US20060154866A1 (en) * | 2005-01-10 | 2006-07-13 | Zhi-Liang Chu | Combination therapy for the treatment of diabetes and conditions related thereto and for the treatment of conditions ameliorated by increasing a blood GLP-1 level |
| CN1803797A (zh) * | 2000-04-26 | 2006-07-19 | 费林股份公司 | 二肽基肽酶iv抑制剂 |
| CN101357921A (zh) * | 2007-08-02 | 2009-02-04 | 山东轩竹医药科技有限公司 | 新的二肽酶-iv抑制剂化合物 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1803797A (zh) * | 2000-04-26 | 2006-07-19 | 费林股份公司 | 二肽基肽酶iv抑制剂 |
| CN1571667A (zh) * | 2001-10-23 | 2005-01-26 | 凡林有限公司 | 二肽基肽酶ⅳ的抑制剂 |
| US20060154866A1 (en) * | 2005-01-10 | 2006-07-13 | Zhi-Liang Chu | Combination therapy for the treatment of diabetes and conditions related thereto and for the treatment of conditions ameliorated by increasing a blood GLP-1 level |
| CN101357921A (zh) * | 2007-08-02 | 2009-02-04 | 山东轩竹医药科技有限公司 | 新的二肽酶-iv抑制剂化合物 |
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