CN106188058A - 黄嘌呤衍生物 - Google Patents
黄嘌呤衍生物 Download PDFInfo
- Publication number
- CN106188058A CN106188058A CN201610356576.0A CN201610356576A CN106188058A CN 106188058 A CN106188058 A CN 106188058A CN 201610356576 A CN201610356576 A CN 201610356576A CN 106188058 A CN106188058 A CN 106188058A
- Authority
- CN
- China
- Prior art keywords
- acid
- pharmaceutically acceptable
- solvate
- xanthine derivative
- methyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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- LRFVTYWOQMYALW-UHFFFAOYSA-N 9H-xanthine Chemical class O=C1NC(=O)NC2=C1NC=N2 LRFVTYWOQMYALW-UHFFFAOYSA-N 0.000 title claims abstract description 28
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 9
- 239000001257 hydrogen Substances 0.000 claims abstract description 9
- 125000005843 halogen group Chemical group 0.000 claims abstract description 6
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 3
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims abstract description 3
- 101000930822 Giardia intestinalis Dipeptidyl-peptidase 4 Proteins 0.000 claims description 30
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 25
- 239000012453 solvate Substances 0.000 claims description 22
- 150000003839 salts Chemical class 0.000 claims description 20
- 238000002360 preparation method Methods 0.000 claims description 18
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 16
- 239000003814 drug Substances 0.000 claims description 15
- 239000000203 mixture Substances 0.000 claims description 15
- 239000008194 pharmaceutical composition Substances 0.000 claims description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
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- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
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- 150000002431 hydrogen Chemical class 0.000 claims description 6
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 6
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- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 4
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- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical group 0.000 claims description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 4
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- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 2
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- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 claims 1
- 125000004429 atom Chemical group 0.000 claims 1
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 claims 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 48
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- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
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- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
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- 238000012546 transfer Methods 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229940045136 urea Drugs 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 229960001254 vildagliptin Drugs 0.000 description 1
- SYOKIDBDQMKNDQ-XWTIBIIYSA-N vildagliptin Chemical compound C1C(O)(C2)CC(C3)CC1CC32NCC(=O)N1CCC[C@H]1C#N SYOKIDBDQMKNDQ-XWTIBIIYSA-N 0.000 description 1
- 235000019155 vitamin A Nutrition 0.000 description 1
- 239000011719 vitamin A Substances 0.000 description 1
- 235000019154 vitamin C Nutrition 0.000 description 1
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- 235000019166 vitamin D Nutrition 0.000 description 1
- 239000011710 vitamin D Substances 0.000 description 1
- 150000003710 vitamin D derivatives Chemical class 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
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- 229940045997 vitamin a Drugs 0.000 description 1
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- C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
- C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
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Abstract
本发明涉及一种如式I所示的黄嘌呤衍生物，其中，R选自：R1选自氰基或甲氧羰基；R2选自氢、卤素原子，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、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；X、Y分别独立的选自C或N；n为0、1、2、3或4。
Description
技术领域
本发明属于药物化学领域，具体涉及一类黄嘌呤衍生物及其制备方法，以及该类化合物作为二肽基肽酶IV(DPP-IV)抑制剂的用途。
背景技术
糖尿病是一种多病因的代谢疾病，其特点是慢性高血糖，伴随因胰岛素分泌及/或作用缺陷引起的糖、脂肪和蛋白质代谢紊乱。糖尿病也是一种非常古老的疾病，是由于人体内胰岛素相对或绝对缺乏而引起的血中葡萄糖浓度升高，导致糖大量从尿中排出，并伴随多饮、多尿、多食、消瘦、头晕、乏力等症状。
在糖尿病治疗中，运动疗法和饮食疗法是两种必不可少的糖尿病治疗方法。当这两种疗法不足以控制病情时，可以使用胰岛素或者口服降糖药。但由于这些降糖药物存在很多副作用，开发出一种新型的、低副作用且能够有效治疗糖尿病的药物尤为重要。二肽基肽酶IV(DPP-IV)是一种丝氨酸蛋白酶，它可以在次末端含有一个脯氨酸残基的肽链里裂解N-末端二肽酶，尽管DPP-IV对哺乳动物的生理作用还没有得到完全的证实，但其在神经酶代谢，T-细胞激活，癌细胞转移入内皮以及HIV病毒进入淋巴样细胞过程中都起到非常重要的作用(WO98/19998)。
有研究表明DPP-IV可以阻止胰升糖素样肽(GLP)-1的分泌，裂解(GLP)-1中N-末端的组-丙二肽酶，使其从活性形式的(GLP)-1降解(Endocrinology，1999，140：5356-5363)。在生理情况下，循环血中完整(GLP)-1的半衰期很短，而DPP-IV抑制剂能完全保护内源性甚至外源性的(GLP)-1不被DPP-IV灭活，极大的提高(GLP)-1的生理活性(5-10倍)，由于(GLP)-1对胰腺胰岛素的分泌是一个重要的刺激器并能直接影响葡萄糖的分配，因此DPP-IV抑制剂对非胰岛素依赖型糖尿病例的治疗起到很好的作用(US6110949)。
目前已上市的DPP-IV抑制剂有西格列汀、维格列汀、沙格列汀、阿格列汀以及利格列汀等。其中，利格列汀在肝肾功能损害方面更小。利格列汀结构式如下：
据在利格列汀给FDA的报道中公开利格列汀在鼠以及人体内的生物利用度不高(CD-1 mouse，5mg/kg，F＝18.4％；man，5mg/subject，F＝30％)，因此，提供一种替代利格列汀的化合物是急需解决的问题。
发明内容
为了解决上述问题，本发明是在利格列汀的基础上，对其进行结构改造，以期获得安全、活性更高的、生物利用度更好的化合物。
本发明提供了一类具有抑制DPP-IV活性并且可用于DPP-IV相关疾病的治疗或缓解性药物的化合物。
利格列汀是已上市的DPP-IV抑制剂中活性最高、肝肾毒性最小的药品，由本发明方法得到的化合物具有和利格列汀相近的活性，尤其是化合物I-3的活性比利格列汀更好，将来可以更好的治疗DPP-IV相关的疾病(如糖尿病、高糖血症、肥胖症、或胰岛素抵抗)。
具体来说，本发明提供一种如式I所示的黄嘌呤衍生物及其溶剂合物，或它们药学上可接受的盐，
其中，
R选自：
R1选自氰基或甲氧羰基；
R2选自氢、卤素原子，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、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；
X、Y分别独立的选自C或N；
n为0、1、2、3或4。
优选的，
R2选自氢、氟原子、氯原子、溴原子、甲基、乙基、异丙基、甲氧基、乙氧基、三氟甲基或三氟甲氧基；
n为0、1或2。
优选的，
R2选自氢、氯原子、氟原子、甲基或甲氧基。
更优选的，
R2选自氢或氟原子
最优选的，
所述黄嘌呤衍生物选自：
其中，本发明所述的黄嘌呤衍生物及其溶剂合物，或它们药学上可接受的盐，其中所述药学上可接受的盐为黄嘌呤衍生物、或其溶剂合物与选自下列的酸形成的盐：盐酸、对甲苯磺酸、酒石酸、马来酸、乳酸、甲磺酸、硫酸、磷酸、柠檬酸、乙酸或三氟乙酸。优选的，所述的酸为对甲苯磺酸、盐酸、酒石酸或三氟乙酸。
本发明还提供一种含有所述黄嘌呤衍生物及其溶剂合物，或它们药学上可接受的盐的药物组合物。
本发明的黄嘌呤衍生物及其溶剂合物，或它们药学上可接受的盐，可以作为药物组合物的主要活性成分，其重量占药物组合物的0.1-99.9％。
本发明的药物组合物，优选的是单位剂量的药物制剂形式，在制成药物制剂时可以制成任何可药用的剂型，这些剂型选自：片剂、糖衣片剂、薄膜衣片剂、肠溶衣片剂、胶囊剂、硬胶囊剂、软胶囊剂、口服液、口含剂、颗粒剂、混悬剂、溶液剂、注射剂、栓剂、软膏剂、硬膏剂、霜剂、喷雾剂、贴剂。优选的是口服制剂形式，最佳优选的是片剂，胶囊剂。
进一步的，本发明所述药物组合物还含有药学上可接受的载体。
可以采用制剂学常规技术制备该药物制剂，如将本发明的黄嘌呤衍生物及其溶剂合物，或它们药学上可接受的盐，与药学上可接受的载体混合。所述药学上可接受的的载体包括但不限于：甘露醇、山梨醇、山梨酸或钾盐、焦亚硫酸钠、亚硫酸氢钠、硫代硫酸钠、盐酸半胱氨酸、巯基乙酸、蛋氨酸、维生素A、维生素C、维生素E、维生素D、氮酮、EDTA二钠、EDTA钙钠，一价碱金属的碳酸盐、醋酸盐、磷酸盐或其水溶液、盐酸、醋酸、硫酸、磷酸、氨基酸、氯化钠、氯化钾、乳酸钠、木糖醇、麦芽糖、葡萄糖、果糖、右旋糖苷、甘氨酸、淀粉、蔗糖、乳糖、甘露糖醇、硅衍生物、纤维素及其衍生物、藻酸盐、明胶、聚乙烯吡咯烷酮、甘油、丙二醇、乙醇、土温60-80、司班-80、蜂蜡、羊毛脂、液体石蜡、十六醇、没食子酸酯类、琼脂、三乙醇胺、碱性氨基酸、尿素、尿囊素、碳酸钙、碳酸氢钙、表面活性剂、聚乙二醇、环糊精、β－环糊精、磷脂类材料、高岭土、滑石粉、硬脂酸钙、硬脂酸镁等。
本发明的黄嘌呤衍生物及其溶剂合物，或它们药学上可接受的盐，作为药物组合物的有效活性成分，在制成药剂时，单位剂量的药剂可含有本发明的药物活性物质0.1-1000mg，其余为药学上可接受的载体。药学上可接受的载体以重量计可以是制剂总重量的0.1-99.9％。
本发明的药物组合物在使用时根据病人的情况确定用法用量。
本发明还包括所述黄嘌呤衍生物及其溶剂合物，或它们药学上可接受的盐在制备治疗与二肽基肽酶IV相关的疾病的药物中的用途。
所述与二肽基肽酶IV相关的疾病包括但不限于II型糖尿病、葡萄糖耐量异常、高糖血症、肥胖症或胰岛素抵抗等。
附图说明
图1正常鼠的糖耐量实验结果
图2正常鼠的糖耐量实验结果
图3肥胖鼠糖耐量实验结果
图4肥胖鼠糖耐量实验结果
图5糖尿病鼠糖耐量实验结果
图6糖尿病鼠糖耐量实验结果
具体实施方式
实施例1
1-[(6-氟-苯甲腈-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-[(R)-3-氨基-哌啶-1-基]-黄嘌呤的制备
(1)3-甲基-7-(2-丁炔-1-基)-8-溴黄嘌呤的制备
室温条件下，将8-溴-3-甲基黄嘌呤(2.5g，10.2mmol)混悬于15mL N,N-二甲基甲酰胺(缩写为：DMF)中，加入二异丙基乙胺(1.326g，10.2mmol)、1-溴-2-丁炔(1.357g，10.2mmol)，滴加完毕后，室温搅拌12小时。反应完毕，将反应液倒入冰水中，搅拌析出固体，抽滤，真空干燥得淡黄色固体2.57g，产率85％。ES-API(m/z):[M+H]+297.0，299.0。
(2)1-[(6-氟-苯甲腈-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-溴黄嘌呤的制备
将3-甲基-7-(2-丁炔-1-基)-8-溴黄嘌呤(2.9g，9.8mmol)、碳酸钾(2.2g，16mmol)和2-溴甲基-6-氟苯甲腈(2.3g，10.7mmol)加入至100mL的圆底烧瓶中，加入25mLN,N-二甲基甲酰胺，升温至80℃搅拌5小时；反应完毕，将反应液倒入冰水中析出固体，抽滤，固体水洗，干燥得浅黄色固体3.5g，产率84％，ES-API(m/z):[M+H]+430.0。
(3)1-[(6-氟-苯甲腈-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-[(R)-3-叔丁氧羰基氨基-哌啶-1-基]-黄嘌呤的制备
将1-[(6-氟-苯甲腈-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-溴黄嘌呤(3.5g，7.4mmol)、碳酸钾(1.9g，14mmol)和3-(R)-叔丁氧羰基-氨基哌啶(1.6g，8mmol)加入到50mL的圆底烧瓶中，加入25mL N,N-二甲基甲酰胺，升温至80℃搅拌5小时；反应完毕，冷却至室温，将反应液倒入冰水中析出固体，抽滤、真空干燥，得浅黄色固体2.9g，产率72％。ES-API(m/z):[M+H]+550.3。
(4)1-[(6-氟-苯甲腈-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-[(R)-3-氨基-哌啶-1-基]-黄嘌呤的制备
将化合物1-[(6-氟-苯甲腈-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-[(R)-3-叔丁氧羰基氨基-哌啶-1-基]-黄嘌呤(0.4g，0.7mmol)溶于二氯甲烷(8ml)中，室温下滴入三氟醋酸(2ml)，室温反应1小时。加入二氯甲烷(10ml)将反应溶液稀释后，用pH＝10的碳酸钾水溶液洗涤，二氯甲烷萃取，有机相用无水硫酸镁干燥，过滤，浓缩。残留物用薄层色谱(二氯甲烷:甲醇＝20:1)分离纯化，得到化合物1-[(6-氟-苯甲腈-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(0.25g，浅黄色固体)，收率：77％。
ES-API(m/z):[M+H]+450.2。
1H NMR(400MHz,DMSO)δ7.68(m,1H),7.42(m,1H),7.13(m,1H),5.20(s,2H),4.90(s,2H),3.63(m,2H),3.38(s,3H),3.00(m,1H),2.90–2.71(m,2H),1.92–1.72(m,5H),1.62(m,1H),1.34-1.25(m,1H).
实施例2
1-[(4,5-二氟-苯甲腈-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-[(R)-3-氨基-哌啶-1-基]-黄嘌呤的制备
(1)1-[(4,5-二氟-苯甲腈-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-溴黄嘌呤的制备
将3-甲基-7-(2-丁炔-1-基)-8-溴黄嘌呤(2.3g，7.9mmol)、碳酸钾(1.7g，12.6mmol)和2-溴甲基-4,5-二氟苯甲腈(2.0g，8.7mmol)加入至100mL的圆底烧瓶中，加入25mL N,N-二甲基甲酰胺，升温至80℃搅拌5小时；反应完毕，将反应液倒入冰水中析出固体，抽滤，固体水洗，干燥得浅黄色固体3.0g，产率86％，ES-API(m/z):[M+H]+448.0。
(2)1-[(4,5-二氟-苯甲腈-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-[(R)-3-叔丁氧羰基氨基-哌啶-1-基]-黄嘌呤的制备
将1-[(4,5-二氟-苯甲腈-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-溴黄嘌呤(2.3g，5.1mmol)、碳酸钾(1.4g,10.4mmol)和3-(R)-叔丁氧羰基-氨基哌啶(1.1g,5.5mmol)加入到50mL的圆底烧瓶中，加入25mL N,N-二甲基甲酰胺，升温至80℃搅拌5小时；反应完毕，冷却至室温，将反应液倒入冰水中析出固体，抽滤、真空干燥，得浅黄色固体2.2g，产率76％。ES-API(m/z):[M+H]+568.2。
(3)1-[(4,5-二氟-苯甲腈-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-[(R)-3-氨基-哌啶-1-基]-黄嘌呤的制备
将化合物1-[(4,5-二氟-苯甲腈-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-[(R)-3-叔丁氧羰基氨基-哌啶-1-基]-黄嘌呤(0.4g，0.7mmol)溶于二氯甲烷(8ml)中，室温下滴入三氟醋酸(2ml)，室温反应1小时。加入二氯甲烷(10ml)将反应溶液稀释后，用pH＝10的碳酸钾水溶液洗涤，二氯甲烷萃取，有机相用无水硫酸镁干燥，过滤，浓缩。残留物用薄层色谱(二氯甲烷:甲醇＝20:1)分离纯化，得到化合物1-[(4,5-二氟-苯甲腈-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(0.26g，黄色固体)，收率：79％。ES-API(m/z):[M+H]+468.2。
1H NMR(400MHz,DMSO)δ8.18(m,1H),7.42(m,1H),5.16(s,2H),4.89(s,2H),3.62(m,2H),3.38(s,3H),2.99(m,1H),2.90–2.73(m,2H),1.93–1.71(m,5H),1.70–1.53(m,1H),1.35–1.24(m,1H).
实施例3
1-[(3-氰基-吡嗪-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
(1)1-[(3-氰基-吡嗪-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-溴黄嘌呤的制备
将3-甲基-7-(2-丁炔-1-基)-8-溴黄嘌呤(0.71g，2.4mmol)、碳酸钾(0.53g，3.8mmol)和2-溴甲基-3-氰基-吡嗪(0.52g，2.6mmol)加入至50mL的圆底烧瓶中，加入5mLN,N-二甲基甲酰胺，升温至80℃搅拌5小时；反应完毕，将反应液倒入冰水中析出固体，抽滤，固体水洗，干燥得浅黄色固体0.88g，产率89％，ES-API(m/z):[M+H]+414.0。
(2)1-[(3-氰基-吡嗪-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-[(R)-3-叔丁氧羰基氨基-哌啶-1-基]-黄嘌呤的制备
将1-[(3-氰基-吡嗪-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-溴黄嘌呤(0.23g，0.78mmol)、碳酸钾(0.22g,1.6mmol)和3-(R)-叔丁氧羰基-氨基哌啶(0.17g,0.85mmol)加入到10mL的圆底烧瓶中，加入5mL N,N-二甲基甲酰胺，升温至80℃搅拌5小时；反应完毕，冷却至室温，将反应液倒入冰水中析出固体，抽滤、真空干燥，得浅黄色固体0.35g，产率85％。ES-API(m/z):[M+H]+534.3。
(3)1-[(3-氰基-吡嗪-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-[(R)-3-氨基-哌啶-1-基]-黄嘌呤的制备
将化合物1-[(3-氰基-吡嗪-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-[(R)-3-叔丁氧羰基氨基-哌啶-1-基]-黄嘌呤(0.31g，0.6mmol)溶于二氯甲烷(8ml)中，室温下滴入三氟醋酸(2ml)，室温反应1小时。加入二氯甲烷(10ml)将反应溶液稀释后，用pH＝10的碳酸钾水溶液洗涤，二氯甲烷萃取，有机相用无水硫酸镁干燥，过滤，浓缩。残留物用薄层色谱(二氯甲烷:甲醇＝20:1)分离纯化，得到化合物1-[(3-氰基-吡嗪-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(0.19g，黄色固体)，收率：74％。
ES-API(m/z):[M+H]+434.2。
1H NMR(400MHz,DMSO)δ8.84(m,1H),8.75(m,1H),5.38(s,2H),4.89(s,2H),3.71–3.53(m,2H),3.37(s,3H),3.07–2.97(m,1H),2.90(m,1H),2.81(m,1H),1.93–1.73(m,5H),1.70–1.56(m,1H),1.32–1.22(m,1H).
实施例4
1-[(3-甲酸甲酯-吡啶-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
(1)1-[(3-甲酸甲酯-吡啶-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-溴黄嘌呤的制备
将3-甲基-7-(2-丁炔-1-基)-8-溴黄嘌呤(2.0g，6.7mmol)、碳酸钾(1.5g，12.6mmol)和2-溴甲基-3-甲酸甲酯-吡啶(1.7g，7.4mmol)加入至100mL的圆底烧瓶中，加入20mL N,N-二甲基甲酰胺，升温至80℃搅拌5小时；反应完毕，将反应液倒入冰水中析出固体，抽滤，固体水洗，干燥得浅黄色固体2.5g，产率83％，ES-API(m/z)：[M+H]+446.0。
(2)1-[(3-甲酸甲酯-吡啶-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-[(R)-3-叔丁氧羰基氨基-哌啶-1-基]-黄嘌呤的制备
将1-[(3-甲酸甲酯-吡啶-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-溴黄嘌呤(1.2g，2.7mmol)、碳酸钾(0.74g,5.4mmol)和3-(R)-叔丁氧羰基-氨基哌啶(0.61g,3.1mmol)加入到50mL的圆底烧瓶中，加入10mL N,N-二甲基甲酰胺，升温至80℃搅拌5小时；反应完毕，冷却至室温，将反应液倒入冰水中析出固体，抽滤、真空干燥，得浅黄色固体1.2g，产率80％。ES-API(m/z):[M+H]+566.3。
(3)1-[(3-甲酸甲酯-吡啶-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-[(R)-3-氨基-哌啶-1-基]-黄嘌呤的制备
将化合物1-[(3-甲酸甲酯-吡啶-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-[(R)-3-叔丁氧羰基氨基-哌啶-1-基]-黄嘌呤(0.4g，0.7mmol)溶于二氯甲烷(8ml)中，室温下滴入三氟醋酸(2ml)，室温反应1小时。加入二氯甲烷(10ml)将反应溶液稀释后，用pH＝10的碳酸钾水溶液洗涤，二氯甲烷萃取，有机相用无水硫酸镁干燥，过滤，浓缩。残留物用薄层色谱(二氯甲烷:甲醇＝20:1)分离纯化，得到化合物1-[(3-甲酸甲酯-吡啶-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(0.25g，浅黄色固体)，收率：77％。ES-API(m/z):[M+H]+466.2。
1H NMR(400MHz,DMSO)δ8.59(m,1H),8.30(m,1H),7.44(m,1H),5.48(s,2H),4.89(s,2H),3.94(s,3H),3.61(m,2H),3.38(s,3H),3.00(m,2H),2.87–2.77(m,1H),1.94–1.72(m,5H),1.71–1.57(m,1H),1.36–1.25(m,1H).
实施例5
含有5mg TSL-0319化合物的包衣片剂
1个片剂核芯含
TSL-0319 5mg 羟丙甲基纤维素 15mg
磷酸钙 90mg 硬脂酸镁 1.5mg
玉米淀粉 35mg 聚乙烯基吡咯烷酮 10mg
总量 166.5mg
制备：
将TSL-0319化合物与磷酸钙、玉米淀粉、聚乙烯基吡咯烷酮、羟丙甲基纤维素及指定量一半的硬脂酸镁混合。在制片机中制造13毫米直径的片，然后使用适当及其，使其摩擦经过具有筛孔尺寸1.5毫米的筛网，并与其余硬脂酸镁混合。于制片机中压制此颗粒，以形成所要形状的片剂。
核芯重量：166.5mg 冲头：9毫米，凸型
将如此制成的片剂核芯使用基本上由羟丙甲基纤维素构成的薄膜包衣。将最后完成的薄膜包衣以蜂蜡抛光。
包衣片剂的重量：175mg
实施例6 含有5mg TSL-0319化合物的胶囊
化合物TSL-0319 5g
淀粉 400g
微晶纤维素 200g
按常规方法，将所得的药物组合物混合均匀后，装入普通明胶胶囊，得到1000颗胶囊。
按此类方法，得到含有5mg化合物TSL-0319的胶囊。
试验例一体外活性实验
(一)体外DPP-IV活性抑制试验
二肽基肽酶IV(DPP-IV)在室温下可水解Gly-Pro-氨基荧光素(Gly-Pro-Aminoluciferin)，生成氨基荧光素(Aminoluciferin)，该物质在DPPIV-Glo(TM)蛋白酶检测试剂盒提供的荧光素酶反应系统中，可产生“辉光型”发光信号，该发光信号的强弱与DPP-IV酶的活力成正比。
1、实验目的：
观察本发明化合物I-1～I-4对二肽基肽酶IV(DPP-IV)酶的活性抑制，以评价其抑制效果。
2、实验材料：
2.1 人源重组二肽基肽酶IV(DPP-IV)：SIGMA产品，货号D3446-10UG。
2.2 DPPIV-Glo(TM)蛋白酶检测试剂盒：Promega产品，货号G8351。
2.3 Trizma base：Sigma产品，货号 T6066-1KG：配置成10mM Tris-HCl，pH 8.0。
2.4 384孔板(OptiPlate)：PerkinElmer产品，货号6007299。
2.5 液体处理仪器：Bravo(Agilent公司)；Echo(Labcyte公司)
2.6 检测仪器：Envision(PerkinElmer公司)
3、实验方法：
3.1用Bravo将待测样品用DMSO梯度稀释10个浓度，然后用Echo转移250nl样品到384孔板中。
3.2用10mM Tris-HCl(pH 8.0)将二肽基肽酶IV(Sigma)稀释成0.2ng/ml溶液，加入待测样品中，每孔25ul。同时设立空白对照(含底物，不含酶和样品)和阳性对照(含底物，含酶，不含样品)。
3.3每孔加入25ul的DPPIV-GloTM Reagent(按DPPIV-Glo(TM)蛋白酶检测试剂盒说明书配置，含20uMDPP-IV底物Gly-Pro-氨基荧光素和荧光素酶反应体系)。
3.4室温反应60min，用Envision测定发光强度。
3.5根据发光强度计算DPP-IV酶活力，酶活力＝(样品发光强度值-空白对照发光强度值/(阳性对照发光强度值-空白对照发光强度值)X 100。
3.6根据酶活力，应用GraphPad Prism5.0软件计算样品的IC50。
4、实验结果
表1本发明化合物I-1～I-4与利格列汀的IC50值
由以上结果可知，本发明化合物I-3具有比利格列汀更好的活性，其他化合物I-1、I-2、I-4也具有与利格列汀相似的活性。
(二)体外药物选择性实验
1、实验目的：
观察本发明化合物I-3(以下简称TSL-0319)对二肽基肽酶酶的活性抑制作用，与已上市同类药物的选择性比较
2、实验材料：
2.1人源重组二肽基肽酶IV(DPP-IV)、DPP8和DPP9酶，其它实验材料与试验例(一)相同。
3、实验方法：与试验例(一)相同
4、实验结果
表2 本发明化合物I-3与已上市药物的IC50值表
由以上结果可知，本发明化合物TSL-0319只表现出对DPP4有抑制作用，对DPP8、DPP9无抑制作用，同时化合物TSL-0319的选择性要明显优越于所有已上市同类药物的选择性。
试验例二体内实验
1、实验药物：化合物I-3(简称TSL-0319)、利格列汀
2、实验方法：使用了正常鼠、肥胖鼠、糖尿病小鼠进行研究糖耐量实验
OGTT(口服糖耐量实验)实验过程：试验开始前禁食6小时，给药后60min灌胃给予葡萄糖(药物浓度0.6mg/ml，给药体积5ml/kg)(糖尿病鼠给糖2g/kg；肥胖鼠给糖2g/kg；正常鼠给糖5g/kg)，分别测定给予葡萄糖后0min、15min、30min、45min、60min、120min的血糖值。
3、实验结果：
正常鼠的糖耐量实验见表3，附图1-2，本发明化合物I-3(简称TSL-0319)具有很好的降糖效果，尤其是降糖效果优于利格列汀。
肥胖鼠糖耐量实验见表4，附图3-4，本发明化合物I-3(简称TSL-0319)具有很好的降糖效果，尤其是降糖效果优于利格列汀
糖尿病鼠糖耐量实验见表5，附图5-6，本发明化合物I-3(简称TSL-0319)具有很好的降糖效果，尤其是降糖效果优于利格列汀
表3 正常鼠口服糖耐量实验(鼠种：C57BL/6J)(-60min给药，0min给葡萄糖)：
*：P<0.05vs空白组；**：P<0.01vs空白组；***：P<0.001vs空白组
表4 肥胖鼠糖耐量实验(鼠种：B6.Cg-Lepob/JNju)(-60min给药，0min给葡萄糖)：
*：P<0.05vs模型组；**：P<0.01vs模型组
表5 糖尿病鼠糖耐量实验(鼠种：B6.BKS(D)-Leprdb/JNju)(-60min给药，0min给葡萄糖)：
*：P<0.05vs模型组；**：P<0.01vs模型组；***：P<0.001vs模型组
4、结论：
在体内糖代谢试验中，使用了正常鼠、肥胖鼠、糖尿病小鼠进行研究，本发明化合物I-3(简称TSL-0319)对三种小鼠都具有降糖作用且降糖效果优于利格列汀。
试验例三、hERG毒性研究
1.测试方法：应用手动膜片钳的方法在转染hERG钠通道的稳定细胞株CHO上测试化合物对hERG钠电流的作用，进而计算化合物对hERG的IC50值。
膜片钳技术(Conventional Patch-Clamp)是已公开技术，是研究离子通道最重要的技术手段，被公认为是离子通道研究的“黄金标准”，是最精确的测量离子通道的实验方法，适用于研究化合物与离子通道作用的作用机制，亦可用于新药申报过程中候选药物的毒性评价和先导化合物的结构优化。
在心肌细胞中，human Ether-a-go-go Related Gene(hERG)编码的钾通道介导一种延迟整流钾电流(IKr)，IKr抑制是药物导致QT间期延长最重要的机制。hERG因其特殊的分子结构，使其可被结构多样化的化合物抑制。目前，检测化合物对hERG钾通道的作用已是临床前评价化合物心脏安全性的关键步骤，也是FDA要求的新药报批必备资料。
使用稳定转染hERG钾通道的CHO细胞系，通过膜片钳技术，可以测试化合物对hERG的影响并测定相应的IC50。
2.实验结果：进行的hERG实验中，TSL-0319对hERG的IC50＝79.80μM。(利格列汀没有报道对hERG的IC50，只提及：在1μM浓度下，对hERG的抑制率为3％；TSL-0319在1μM浓度下，对hERG的抑制率为0％。)
按照大于Cmax 20倍的要求计算，TSL-0319在5mg/kg剂量下，小鼠体内Cmax为200-500nM，对hERG的IC50应大于20μM，因此TSL-0319在hERG毒性方面是安全的，要明显优于利格列汀。
试验例四、药-药相互作用研究(DDI)
1、测试方法：使用人肝微粒体进行化合物对CYP酶的抑制活性测试。
利用体外人肝微粒体孵育体系，通过cocktail探针药物法(已公开技术)，同时测定人肝微粒体CYP1A2、CYP2C9、CYP2C19、CYP2D6、CYP3A4底物非那西丁、双氯芬酸、S-美芬妥英、美沙芬、咪达唑仑的含量变化，评价不同浓度下TSL-0319对人肝微粒体CYP1A2、CYP2C9、CYP2C19、CYP2D6、CYP3A4亚型活性的影响并测定相应的IC50。
实验结果：
表6 TSL-0319不用浓度对CYP酶抑制率
| TSL-0319浓度μM | 0 | 0.05 | 0.15 | 0.5 | 1.5 | 5 | 15 | 50 |
| 对CYP1A2抑制率(％) | 0 | 0 | 0 | 2.2 | 4.2 | 6.6 | 20.8 | 41.8 |
| 对CYP2C9抑制率(％) | 0 | 0 | 0 | 3.2 | 5.7 | 10.5 | 12.1 | 13.9 |
| 对CYP2C19抑制率(％) | 0 | 0 | 3.3 | 8.2 | 14 | 2.9 | ||
| 对CYP2D6抑制率(％) | 0 | 0 | 0 | 0 | 0 | 0 | 3 | 14.6 |
| 对CYP3A4抑制率(％) | 0 | 0 | 0 | 4 | 4.4 | 8.7 | 17.9 | 44.6 |
2、结论：TSL-0319对CYP1A2、CYP2C9、CYP2C19、CYP2D6、CYP3A4五种代谢酶的IC50都大于50μM，因此TSL-0319的使用不会影响其他药物的代谢，可与其他药物联用。
试验例五、化合物TSL-0319小鼠药代动力学实验
1、给药方案：
7-10周健康CD-1鼠6只，随机分为两组。分别静脉注射以及灌胃给予2mg/kg、5mg/kg的TSL-0319(静脉注射，2mg/ml，以DMSO/PEG400/H2O＝20/60/20的溶液制成透明溶液；灌胃，5mg/ml；以PEG400/Tween80/H20＝40/10/50的溶液制成透明溶液)；给药前禁食12小时，自由饮水；于给药前和给药后按时间点在大隐静脉或颌下静脉取血(静脉注射取血时间点：0h、0.0833h、0.250h、0.500h、1.00h、2.00h、4.00h、8.00h、12.00h、24.00h；灌胃取血时间点：0h、0.250h、0.500h、1.00h、2.00h、4.00h、8.00h、12.00h、24.00h)，最低定量浓度(lowerlimit of quantitation，LLOQ)设为3ng/ml。
2、实验结果：见表7
表7 TSL-0319药代动力学实验数据
3、结论
TSL-0319使用CD-1小鼠做药代动力学实验，由于取血点以及LLOQ的设定，其T1/2与linagliptin的公开数据相比有较大差别，但是60.5％的生物利用度远高于同等条件下linagliptin的生物利用度(linagliptin使用CD-1小鼠做药代动力学实验，5mg/kg，口服，生物利用度为18.4％)。
本发明化合物I-1～I-2、1-4结构与I-3类似，因此化合物I-1～I-2、1-4都具有与化合物I-3相同的药效作用。
Claims (10)
1.如式I所示的黄嘌呤衍生物及其溶剂合物，或它们药学上可接受的盐，
其中，
R选自：
R1选自氰基或甲氧羰基；
R2选自氢、卤素原子，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、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；
X、Y分别独立的选自C或N；
n为0、1、2、3或4。
2.根据权利要求1所述的黄嘌呤衍生物及其溶剂合物，或它们药学上可接受的盐，其中，
R2选自氢、卤素原子、甲基、乙基、异丙基、甲氧基、乙氧基、三氟甲基或三氟甲氧基；
n为0、1或2。
3.根据权利要求2所述的黄嘌呤衍生物及其溶剂合物，或它们药学上可接受的盐，其中，
R2选自氢、氯原子、氟原子、嗅原子、甲基或甲氧基。
4.根据权利要求3所述的黄嘌呤衍生物及其溶剂合物，或它们药学上可接受的盐，其中，
R2选自氢或氟原子。
5.根据权利要求4所述的黄嘌呤衍生物及其溶剂合物，或它们药学上可接受的盐，其中，所述黄嘌呤衍生物选自：
6.根据权利要求1～5任一所述的黄嘌呤衍生物及其溶剂合物，或它们药学上可接受的盐，其中所述药学上可接受的盐为黄嘌呤衍生物、或其溶剂合物与选自下列的酸形成的盐：盐酸、对甲苯磺酸、酒石酸、马来酸、乳酸、甲磺酸、硫酸、磷酸、柠檬酸、乙酸或三氟乙酸；优选中所述药学上可接受的盐为黄嘌呤衍生物、或其溶剂合物与选自下列的酸形成的盐：甲苯磺酸、盐酸、酒石酸或三氟乙酸。
7.含有权利要求1～5任一项所述的黄嘌呤衍生物及其溶剂合物，或它们药学上可接受的盐为活性成分的药物组合物，其中活性成分占药物组合物的总重量的0.1-99.9％。
8.权利要求1～5任一项所述的黄嘌呤衍生物及其溶剂合物，或它们药学上可接受的盐与药学上可接受的载体制成制剂，其中药学上可接受的载体以重量计可以是制剂总重量的0.1-99.9％。
9.权利要求1～5任一所述的黄嘌呤衍生物及其溶剂合物，或它们药学上可接受的盐在制备治疗与二肽基肽酶IV相关的疾病的药物中的应用。
10.根据权利要求9所述的应用，所述与二肽基肽酶IV相关的疾病选自：II型糖尿病或葡萄糖耐量异常。
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| TW201643166A (zh) | 2016-12-16 |
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| HK1245796A1 (zh) | 2018-08-31 |
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| EP3305787B1 (en) | 2022-02-16 |
| SG11201709782SA (en) | 2017-12-28 |
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| AU2016270100A1 (en) | 2017-12-14 |
| RU2709348C2 (ru) | 2019-12-18 |
| US10358449B2 (en) | 2019-07-23 |
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| AU2016270100B2 (en) | 2020-02-13 |
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| CA2987697A1 (en) | 2016-12-08 |
| KR20180011270A (ko) | 2018-01-31 |
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