CN1160330C - N-取代2-氰基吡咯烷类化合物 - Google Patents
N-取代2-氰基吡咯烷类化合物 Download PDFInfo
- Publication number
- CN1160330C CN1160330C CNB998142026A CN99814202A CN1160330C CN 1160330 C CN1160330 C CN 1160330C CN B998142026 A CNB998142026 A CN B998142026A CN 99814202 A CN99814202 A CN 99814202A CN 1160330 C CN1160330 C CN 1160330C
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- Prior art keywords
- amino
- adamantyl
- group
- ethanoyl
- compound
- Prior art date
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- Expired - Lifetime
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- -1 N-substituted 2-cyanopyrrolidines Chemical class 0.000 title claims description 22
- 150000001875 compounds Chemical class 0.000 claims abstract description 66
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- 101000930822 Giardia intestinalis Dipeptidyl-peptidase 4 Proteins 0.000 claims abstract description 33
- 239000002253 acid Substances 0.000 claims abstract description 30
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 claims abstract description 9
- 239000003814 drug Substances 0.000 claims abstract description 7
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims abstract description 6
- 208000008589 Obesity Diseases 0.000 claims abstract description 5
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 20
- 239000000654 additive Substances 0.000 claims description 18
- 230000000996 additive effect Effects 0.000 claims description 18
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 18
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 18
- 239000001301 oxygen Substances 0.000 claims description 18
- 229910052760 oxygen Inorganic materials 0.000 claims description 18
- 238000002360 preparation method Methods 0.000 claims description 14
- 125000006309 butyl amino group Chemical group 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
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- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- 125000005466 alkylenyl group Chemical group 0.000 claims description 2
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- 229960003328 benzoyl peroxide Drugs 0.000 claims description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 125000003107 substituted aryl group Chemical group 0.000 claims description 2
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- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 36
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- 239000000203 mixture Substances 0.000 description 19
- 239000000243 solution Substances 0.000 description 18
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 18
- 238000012360 testing method Methods 0.000 description 17
- DKNWSYNQZKUICI-UHFFFAOYSA-N amantadine Chemical class C1C(C2)CC3CC2CC1(N)C3 DKNWSYNQZKUICI-UHFFFAOYSA-N 0.000 description 16
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- 238000002474 experimental method Methods 0.000 description 6
- 238000010189 synthetic method Methods 0.000 description 6
- MGOLNIXAPIAKFM-UHFFFAOYSA-N 2-isocyanato-2-methylpropane Chemical compound CC(C)(C)N=C=O MGOLNIXAPIAKFM-UHFFFAOYSA-N 0.000 description 5
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- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
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- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
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- GLNDAGDHSLMOKX-UHFFFAOYSA-N coumarin 120 Chemical compound C1=C(N)C=CC2=C1OC(=O)C=C2C GLNDAGDHSLMOKX-UHFFFAOYSA-N 0.000 description 3
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- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
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Abstract
本发明涉及式(I)的化合物，其中R是取代的金刚烷基；和n是0-3；游离形式或其酸加成盐形式。式I的化合物抑制DPP-IV(二肽基肽酶-IV)活性。所以它们可在抑制DPP-IV中和在DPP-IV介导的病症的治疗中用作药物，如非胰岛素依赖型糖尿病、关节炎、肥胖、骨质疏松症和其它葡萄糖耐量异常的病症。
Description
本发明提供新的二肽基肽酶-IV(DPP-IV)抑制剂，其可有效治疗由DPP-IV介导的病症。目前发现，DPP-IV导致I型胰高血糖素样肽(GLP-1)失活。由于GLP-1是胰腺胰岛素分泌的主要刺激物并且对葡萄糖处理具有直接的有益作用，所以DPP-IV的抑制似乎代表了一条治疗疾病如非胰岛素依赖型糖尿病(NIDDM)的令人感兴趣的途径。
本发明涉及新的式I的N-(取代甘氨酰基)-2-氰基吡咯烷类化合物：
其中
R是取代金刚烷基(adamantyl)；和
n是0至3；游离形式或酸加成盐形式。
式1的化合物可以以游离形式或酸加成盐形式存在。优选可药用(即无毒、生理可接受)盐，虽然其他盐也可采用，例如在分离或纯化本发明的化合物中。尽管优选的酸加成盐是盐酸盐，也可以采用甲磺酸、硫酸、磷酸、柠檬酸、乳酸和乙酸的盐。
本发明的化合物可以以旋光异构体或非对应异构体的形式存在，而且可以提供常规技术如色谱法分离和回收。
下列是本发明所用多种术语的的定义。这些定义适用于本申请整个说明书中所用的术语，除非在具体情况中另作说明，或单独或作为较大组的部分。
术语“烷基”是指具有1-10个碳原子，优选1-7个碳原子，首选1-5个碳原子的直链或支链烃基。烷基实例包括甲基、丙基、异丙基、仲丁基、叔丁基、异丁基、戊基、己基等。
术语“烷酰基”是指烷基-C(O)-。
术语“取代金刚烷基”，即被1或多个、如2个取代基取代的金刚烷基，如1-或2-金刚烷基，所述取代基选自烷基、-OR1或-NR2R3；其中R1、R2和R3独立地是氢、烷基、(C1-C8烷酰基)、氨基甲酰基或-CO-NR4R5；其中R4和R5独立地是烷基、未取代或取代芳基和其中R4和R5之一另外是氢，或R4和R5一起代表C2-C7亚烷基；
术语“芳基”优选表示苯基。取代苯基优选是被1或多个，如2个取代取代的苯基，取代基选自如烷基、烷氧基、卤素和三氟甲基。
术语“烷氧基”是指烷基-O-。
术语“卤素”或“卤代”是指氟、氯、溴和碘。
术语“亚烷基”是指含有2-7个碳原子，优选3-6个碳原子，首选5个碳原子的直链桥。
优选组的本发明化合物是式I化合物，其中金刚烷基上的取代基键合在桥头或与桥头相邻的亚甲基。其中甘氨酰基-2-氰基吡咯烷部分键合在桥头的式I化合物中，金刚烷基上的R’取代基优选3-羟基。其中甘氨酰基-2-氰基吡咯烷键合在桥头相邻亚甲基上的式I化合物中，金刚烷基上的R’取代基优选5-羟基。
本发明尤其涉及式(IA)或(IB)的化合物：
其中R’代表羟基、C1-C7烷氧基、C1-C8烷酰氧基或R5R4N-CO-O-，其中R4和R5独立地是C1-C7烷基或苯基，其是未取代或被选自C1-C7烷基、C1-C7烷氧基、卤素和三氟甲基的取代基取代和其中R4另外是氢；或R4和R5一起代表C3-C6亚烷基；和R”代表氢；或R’和R”独立地代表C1-C7烷基；其是游离形式或可药用酸加成盐的形式。
本发明的化合物可以制得，譬如通过一种包括使反应性(2-氰基吡咯烷基)羰基亚甲基化合物与适当的取代胺类化合物偶联的方法；更特别地，为了制备式I的化合物，包括将式II的化合物：
其中Y是反应性基团(优选卤素，如溴、氯或碘)
与式III的化合物反应：
NH2(CH2)n-R III
其中R定义如上，和回收得到的游离形式或酸加成盐形式的式I化合物。
本发明的方法可以以常规方式实现。譬如，式II的化合物与1至3当量，优选3当量的式III的伯胺反应。该反应一般是在惰性有机溶剂如二氯甲烷或环醚如四氢呋喃的存在下进行。反应温度优选约0℃至约35℃，优选约0℃至约25℃。
本发明的化合物可以通过常规方式如色谱法由反应混合物中分离并纯化。
起始原料也可以以普通方式制备。式II的混合物可通过下列的两步反应路线来制得：
步骤1 步骤2
步骤1包括式IV的吡咯烷与摩尔略微过量的卤代乙酰卤化物如溴代乙酰溴或氯代乙酰氯和碱如碳酸钾或三乙胺反应。该反应一般是在惰性有机溶剂(如四氢呋喃)或氯化脂族烃(如二氯甲烷)的存在下进行，反应温度为约0℃至约25℃，优选为约0℃至约15℃。
步骤2涉及步骤1制得的式V化合物用1至2当量三氟乙酸酐(TFAA)脱水。脱水优选在惰性有机溶剂(如四氢呋喃)或氯化脂族烃(如二氯甲烷)的存在下进行，反应温度为约0℃至约25℃，优选为约0℃至约15℃。
在其制备在本发明中不作特别描述的情况下，用作起始原料的化合物是已知化合物或可以由已知化合物通过已知方法、已知方法的类似方法或实施例所述方法的类似方法来制备。
譬如，式III的伯胺化合物已知并且可以通过文献报导的方法制备，诸如Khin.Farm.Zh.(1986)20(7)，810-15。
最终，获得的本发明的化合物或是游离形式，或是其盐，如成盐基团存在的话。
本发明具有碱性基团的化合物可以转化为酸加成盐，尤其是可药用酸加成盐。这些盐可以与例如无机酸形成，例如矿物酸，如硫酸、磷酸或氢卤酸；或与有机羧酸形成。优选是与盐酸形成的盐。
鉴于游离化合物和盐形式的化合物之间的密切关系，每当本文中提及该化合物时，也是指其相应的盐，条件是这在该情况下是可行或适当的。
包括其盐的化合物也可以以其水合物的形式获得，或含有其结晶所用的其他溶剂。
本发明还包括药物组合物，例如有效抑制DPP-IV的药物组合物，其中含有可药用载体或稀释剂和治疗有效量的式I化合物，或其可药用酸加成盐。
在另一实施方式中，本发明提供一种抑制DPP-IV的方法，包括给需此治疗的哺乳动物施用治疗有效量的式I化合物，或其可药用酸加成盐。特别地，本发明组合物还可以用于治疗肥胖症。
在另外的实施方式中，本发明提供一种治疗由DPP-IV抑制介导的疾病的方法，包括给需此治疗的哺乳动物施用治疗有效量的上述式I化合物，或其可药用酸加成盐。
本发明也涉及本发明化合物或其可药用盐在诸如制备用于预防或治疗与升高水平DPP-IV有关的疾病或病症的药物中的应用。特别地，本发明化合物或其可药用盐还可以用于治疗肥胖症。
如上所述，所有式I化合物及其相应可药用酸加成盐可有效抑制DPP-IV。利用Caco-2 DPP-IV实验可以验证式I化合物及其相应可药用酸加成盐抑制DPP-IV的性能，该实验测定试验化合物抑制由人结肠癌细胞提取物中分离出的DPP-IV的能力。人结肠癌细胞系Caco-2得自美国典型培养物保藏中心(ATCC HTB 37)。这种细胞诱导DPP-IV表达的分化是按照Reisher等人发表在《美国国家科学院院报》第90卷第5757-5761(1993)中的标题为“肠细胞系Caco-2的升高的表达”的文章所述进行。细胞提取物制备自将细胞溶解在10mM Tris HCl，0.15M NaCl，0.04 t.i.u.抑肽酶，0.5％乙基苯基聚乙二醇(nonidet-P40)，pH 8.0，在35000下离心30分钟，4℃下除去细胞碎片。通过加入20μg已溶Caco-2蛋白质进行该实验，试验缓冲液稀释至微量滴定平板孔中的终体积为125μl(25mM Tris Hcl pH 7.4，140mM NaCl，10mM Kcl，1％牛血清白蛋白)。60分钟后，室温下培养，通过加入25μl的1mM底物(H-丙氨酸-脯氨酸-pNA；pNA是对-硝基苯胺)引发反应。该反应在室温下进行10分钟，此后加入19μl体积的25％冰醋酸终止反应。试验化合物-般作为30μl附加物加入并且使试验缓冲液体积减少至95μl。利用0-500μM游离pNA在试验缓冲液中的溶液绘制出游离对硝基丙氨酸的标准曲线。所得曲线为线性，可用于内推的底物消化量(催化活性，nmole裂解底物/分钟)。在MolecularDevices UV Max微量滴定平板读数器中通过测量405nm下的吸收度可测出终点。
用4参数逻辑函数、由8点式剂量—反应曲线计算出试验化合物作为DPP-IV抑制剂的效价，表示为IC50。
获得下列IC50：
| 化合物 | Caco-2 DPP-IV(nM) |
| 实施例1 | 3.5±1.5 |
| 实施例4 | 8 |
式I化合物及其相应可药用酸加成盐抑制DPP-IV的能力也可以通过测量试验化合物对人体和大鼠血浆中DPP-IV活性的影响来证实，采用Kubota等人在《临床实验和免疫学》(Clin.Exp.Immunol.)(第89卷，192-197(1992))中发表的标题为“二肽基肽酶IV在体内免疫应答中的参与”所述实验方法的改进版。简单而言，将5μl的血浆加入96孔平底微量滴定平板(Falcon)中，随后加入5μl存在于培养缓冲液(25mMHEPES，140Mm NaCl，1％RIA级BSA，pH 7.8)中的80mMMgCl2。60分钟后，室温下培养，通过加入10μl含有0.1mM底物(H-甘氨酸-脯氨酸-AMC：AMC是7-氨基-4-甲基香豆素)的培养缓冲液引发反应。用铝箔覆盖平板(或保藏在避光条件下)并且在室温下培养20分钟。20分钟后，利用Cytofluor 2350荧光计(激发380nm发射460nm；灵敏度设定4)测量反应的荧光。试验化合物一般加入2μl同时将试验缓冲液体积减少至13μl。利用0-50AMC在试验缓冲液中的溶液得到游离AMC的荧光—浓度曲线。该曲线为线性并且可用于底物消耗量的内推(催化活性，nmole裂解底物/分钟)。如上述实验，用4参数逻辑函数、由8点式剂量—反应曲线计算出试验化合物作为DPP-IV抑制剂的效价，表示为IC50。
获得下列IC50：
| 化合物 | 人血浆DPP-IV(nM) | 大鼠血浆DPP-IV(nM) |
| 实施例1 | 2.7±1.5 | 2.3±0.1 |
| 实施例8 | 6 | 12 |
鉴于其抑制DPP-IV的能力，式1的化合物及其相应可药用酸加成盐可有效治疗由DPP-IV抑制介导的病症。基于上述内容和文献中的发现，可以认为本发明公开的化合物可有效治疗如非胰岛素依赖型糖尿病、关节炎、肥胖、同种异体移植和降钙素-骨质疏松症的病症。此外，基于胰高血糖素样肽酶(如GLP-1和GLP-2)的作用及其与DPP-IV抑制的关系，可预见本发明公开的化合物可有效例如产生镇静或抗焦虑作用，或减弱术后分解代谢变化和对应激的激素反应，或减少心肌梗塞后的死亡率和发病率，或治疗涉及上述可能由GLP-1和/或GLP-2水平介导的作用的病症。
具体而言，譬如，式I化合物及其相应可药用酸加成盐改善早期胰岛素对口服葡萄糖攻击的反应，由此可有效治疗非胰岛素依赖型糖尿病。式I化合物及其相应可药用酸加成盐改善早期胰岛素对口服葡萄糖攻击的反应的能力可以在胰岛素耐受大鼠中按照下列方法测量：
用高脂肪饮食(饱和脂肪＝57％卡路里)饲养2-3周的雄性Sprague-Dawley大鼠在试验当天禁食约2小时，分为每组8-10只，并且用10μmol/kg存在于CMG中的试验化合物口服给药。在试验化合物直接进入试验动物的胃内30分钟后，给予口服葡萄糖丸1g/kg。分析由慢性颈静脉插管在多个时间点或的血样的血浆葡萄糖和免疫反应胰岛素(IRI)浓度，和血浆DPP-IV活性。血浆胰岛素水平是通过双抗体放射免疫测定(RIA)法、利用由Linco Research(St.Louis，MO)获得的特异性抗大鼠胰岛素抗体。RIA的监测下限为0.5μU/ml，同时试验内和试验间的变异性小于5％。数据表示为相对于对照动物的平均百分增量。在口服给药时，各个试验化合物放大早期胰岛素反应，由此改进了胰岛素耐受试验动物中的葡萄糖耐受性。获得下列结果：
| 化合物 | 10μmol/kg下胰岛素反应的增量 |
| 实施例1 | 64％ |
式I的化合物及其相应可药用酸加成盐用于治疗由DPP-IV抑制的病症的精确剂量取决于若干因素，包括宿主、被治疗病症的本质和严重性、给药方式和所用的特定化合物。然而，通常，当式I的化合物或其相应可药用酸加成盐经肠道给药(如口服)或非肠道给药(如静脉内)、优选口服给药且日剂量为0.002-5、优选0.02-2.5mg/kg体重时，或对多数大型灵长类以0.1-250、优选1-100mg的日剂量给药时，可有效治疗由DPP-IV抑制介导的病症。典型的口服剂量动物是0.01-0.75mg/kg，每天1-3次。通常，开始时小剂量给药，逐渐增高剂量直至在监测治疗下达到宿主的最佳剂量。剂量的上限是产生副作用的剂量，可以通过试验测定出被治疗宿主的剂量上限。
式I的化合物及其相应可药用酸加成盐可以和一种或多种可药用载体和任选的一种或多种其它常规药物辅剂合用，并且以片剂、胶囊、囊形片(caplet)等的形式经肠内给药，如口服，或以灭菌可注射溶液或混悬液的形式非肠道给药，如静脉内给药。肠内或非肠道用组合物可以由常规方式制得。
式I的化合物及其相应可药用酸加成盐可以配制为肠内或非肠道药物组合物，组合物含有治疗DPP-IV抑制介导的病症有效量的活性物质，该组合物为单位剂型并且所述组合物含有可药用载体。
式I的化合物(包括它们各自的子集和各自的实施例)可以以对映体纯形式(如ee＞98％，优选＞99％)给药或与
R对映异构体一起给药，例如在外消旋体中。上述剂量范围基于式I化合物计(不包括
R对映异构体的量)。
下列实施例表示本发明包括的代表化合物及其合成。然而，应清除理解，它们仅仅是举例说明的目的。
实施例1
1-[(3-羟基-1-金刚烷基)氨基]乙酰基-2-氰基-吡咯烷，(S)
A.1-氨基金刚烷-3-醇：
可以采用略微改进的khim.-Farm.Zh.(1986)，20(7)，810-15所述合成方法。
向快速搅拌、澄清和无色、冰水冷却的96％浓硫酸(210ml；3.943mmol)和65％硝酸(21.0mL；217.0mmol)的混合物中在30分钟内分成小份加入21.0g(112.0mmol)的1-金刚烷基胺HCl(99％)。在加入金刚烷基胺盐酸盐时，出现少量气泡并且该反应轻度放热。将这种出泡、黄色溶液在冰水温度下搅拌约2小时并且在室温下搅拌30分钟。随后将该澄清、略黄的反应倾入约100g的冰中，所得溶液为澄清蓝绿色。
将该反应置于冰水浴中并且令其搅拌30分钟。随后在45分钟内以小份加入约550g的89％纯KOH(8.74mol)。加入期间，反应放热；达到80℃并且产生大量的棕色NO2气。加入完毕后，反应变稠具有白色固体(两种产物和盐)。此后将所得白色糊状物倾在布氏漏斗/硅藻土垫上并且用1.2L的CH2Cl2洗涤。此后由水层提取出CH2Cl2层并且用Na2SO4干燥。随后过滤该溶液并且浓缩(旋转蒸发/泵)提供1-氨基金刚烷-3-醇，其为白色固体。
B.1-氯乙酰基-2-氰基吡咯烷
在45分钟内以滴加方式向20.0g(180.0mmol)氯代乙酰氯和97g(0.70mmol)的碳酸钾在150ml四氢呋喃中的机械搅拌溶液内加入L-脯氨酰氨20.0g(180.0mmol)在500ml四氢呋喃中的溶液。该反应随后在室温下继续机械搅拌2小时。随后过滤该反应除去钾盐并且用Na2SO4干燥滤液。随后经过滤除去Na2SO4并且向这种无色滤液中一次加入三氟乙酸酐(25.0ml，0.180mmol)。该反应在室温下机械搅拌1小时，所得除去黄色/橙色溶液经旋转蒸发器浓缩。通过加入乙酸乙酯除去过量的三氟乙酸酐得到浓油并且经旋转蒸发器再次浓缩。重复3此上述操作。
所得油在乙酸乙酯和水之间分配。随后将产物提取到乙酸乙酯中并且用乙酸乙酯洗涤2次水层。合并的有机层此后连续用水和盐水洗涤，硫酸镁干燥，过滤和浓缩，得到1-氯代乙酰基-2-氰基吡咯烷，其为黄色固体。
C.1-[(3-羟基-1-金刚烷基)氨基]乙酰基-2-氰基-吡咯烷，(S)
向标题A化合物(1-氨基金刚烷-3-醇)(5.80g，34.7mmol)在CH2Cl2(68.0ml)中的非均相溶液内加入9.6g(69mmol)的K2CO3。随后在冰水浴中冷却这种非均相混合物，在30分钟内滴加3.0g(17mmol)标题B化合物(1-氯代乙酰基-2-氰基吡咯烷)溶解在25.0mL的CH2Cl2中的溶液。所得混合物在0℃下搅拌2小时并且在室温下6天。随后浓缩该反应得到黄色糊状物，其在硅胶上用SIMS/Biotage闪式色谱系统纯化，用7％甲醇的二氯甲烷溶液作为洗脱剂，生成游离碱形式的标题化合物，其为白色结晶固体(熔点138℃-140℃，13CNMR(ppm)＝119.59)。
实施例2-12
下列化合物按照硫酸盐实施例1的方法制备(尤其是步骤C)：
(HCl)＝盐酸盐
通过将HCl气通入游离碱在四氢呋喃中0.1摩尔溶液直至溶液明显是酸性的，随后除去溶剂(旋转蒸发/泵)可制得所有终产物的盐酸盐。
氨基-金刚烷起始原料是文献中的已知物质或可以按照下列方法制备：
3，5-二甲基-1-金刚烷基胺的制备如《医学和化学杂志》(J.Med.Chem.)25；1；1982；51-56所述。
3-乙基-1-金刚烷基胺的制备如《医学和化学杂志》(J.Med.Chem.)25；1；1982；51-56所述。
3-甲氧基-1-金刚烷基胺可以制备如下：
向搅拌、冰水冷却的氢化钾(0.680gm，5.95mmol)在15.0ml四氢呋喃中的混悬液内在30分钟内滴加1-氨基金刚烷基-3-醇(1.00g；5.95mmol)和15.0ml四氢呋喃的混合物。随后将所得混合物继续搅拌30分钟，在1分钟内滴加碘甲烷(0.370ml；5.95mmol)。所得不透明白色反应在室温下搅拌18小时。该混合物用50ml的二氯甲烷稀释并且过滤除去无机杂质。浓缩滤液并且在硅胶上采用SIMS/Biotage设备和含19％甲醇和1％氢氧化铵的二氯甲烷溶液作为洗脱剂纯化，生成3-甲氧基-1-金刚烷基胺，为不透明油。
3-[[(叔丁基氨基)羰基]氧基]-1-氨基金刚烷的合成：
向1-氨基金刚烷基-3-醇(5.00g；30.0mmol)和碳酸钾96.20g；45mmol)在150ml四氢呋喃中的混合物内在10分钟内滴加氯甲酸苄酯(4.70g，33.0mmol)。随后该混合物在室温下搅拌2小时，此后在乙酸乙酯和水之间分配。将产物提取到乙酸乙酯中并且用乙酸乙酯(100ml)洗涤水层2次。合并的有机层再连续用100ml的2N氢氧化钠水溶液、水和盐水洗涤，硫酸钠干燥，过滤和浓缩(旋转蒸发/泵)，提供1-苄基氨基甲酰基金刚烷-3-醇，为白色固体，收率85％。
用注射器向1-苄基氨基甲酰基金刚烷-3-醇(1.00g：3.22mmol)和异氰酸叔丁酯(380μl，3.32mmol)在30ml二氯甲烷中的澄清溶液内加入三甲基硅烷基氯(20.0μl，0.17mmol)。该反应随后在室温下搅拌18小时，浓缩(旋转蒸发)，在硅胶上采用SIMS/Biotage设备和含20％乙酸乙酯的己烷溶液作为洗脱剂纯化，得到3-[[(叔丁基氨基)羰基]氧基]-1-苄基氨基甲酰基金刚烷，其为白色固体，收率定量。
向存在于1L帕尔氏氢化瓶中的3-[[(叔丁基氨基)羰基]氧基]-1-苄基氨基甲酰基金刚烷(1.50g，3.75mmol)和10％炭载钯(400mg)在乙醇(150ml)中的混合物内加入氢(50psi)。将该不透明黑色混合物随后振摇24小时。经硅藻土过滤该反应，除去钯催化剂，浓缩(旋转蒸发/泵)，得到3-[[(叔丁基氨基)羰基]氧基]-1-氨基金刚烷，其为澄清油，收率99％。
4-[[[(甲氧基苯基)氨基]羰基]氧基]-1-氨基金刚烷的合成方法基本上是3-[[(叔丁基氨基)羰基]氧基]-1-氨基金刚烷的制备方法，除了第二步中用当量的异氰酸4-甲氧基苯基酯代替异氰酸叔丁酯，用1，2-二氯乙烷作为溶剂代替二氯甲烷并且反应在50℃下搅拌18小时以外。最终的胺中间体呈油提供。
3-[[(苯基氨基)羰基]氧基]-1-氨基金刚烷的合成方法基本上是3-[[(叔丁基氨基)羰基]氧基]-1-氨基金刚烷的制备方法，除了第二步中用当量的异氰酸苯基酯代替异氰酸叔丁酯，用1，2-二氯乙烷作为溶剂代替二氯甲烷并且反应在50℃下搅拌18小时以外。最终的胺中间体呈油提供。
制备2-氨基金刚烷-5-醇的方法与实施例1相同，但除了起始原料为2-氨基金刚烷而不是1-氨基金刚烷。
3-乙酰氧基-1-氨基金刚烷基的合成方法基本上是3-[[(叔丁基氨基)羰基]氧基]-1-氨基金刚烷的制备方法，除了用1.2当量的乙酰氯、3.0当量的吡啶、0.1当量的4-二甲基氨基吡啶和1，2-二氯乙烷使1-苄基氨基甲酰基金刚烷-3-醇标准乙酰化并且全部物质在室温下搅拌24小时以外。最终的胺中间体呈稠油提供。
3-[[[(二异丙基)氨基]羰基]氧基]-1-氨基金刚烷的合成方法基本上是3-[[(叔丁基氨基)羰基]氧基]-1-氨基金刚烷的制备方法，除了第二步中用当量的二异丙基氨基甲酰氯代替异氰酸叔丁酯，用1，2-二氯乙烷作为溶剂代替二氯甲烷并且反应在85℃下搅拌18小时以外。最终的胺中间体呈灰色固体提供。
3-[[[(环己基)氨基]羰基]氧基]-1-氨基金刚烷的合成方法基本上是3-[[(叔丁基氨基)羰基]氧基]-1-氨基金刚烷的制备方法，除了第二步中用当量的异氰酸环己基酯代替异氰酸叔丁酯，用1，2-二氯乙烷作为溶剂代替二氯甲烷并且反应在50℃下搅拌18小时以外。最终的胺中间体呈澄清稠油提供。
3-乙氧基-1-金刚烷基胺(澄清油)的制备方法与3-甲氧基-1-金刚烷基胺相同，除了用碘乙烷(1.3当量)代替碘甲烷以外。
制剂实施例
各含50mg活性成分(如(S)1-[(3-羟基-1-金刚烷基)氨基]乙酰基-2-氰基-吡咯烷)的片剂可制备如下：
组成(10 000片)
活性成分 500.0g
乳糖 500.0g
土豆淀粉 352.0g
明胶 8.0g
滑石 60.0g
硬脂酸镁 10.0g
二氧化硅(高分散) 20.0g
乙醇 适量
将活性成分与乳糖和292g的土豆淀粉混合，将该混合物用明胶的醇溶液湿润并且通过筛分方式制粒。干燥后，与剩余的土豆淀粉、滑石、硬脂酸镁和高分散二氧化硅混合并且将混合物压缩为片剂，片重分别为145.0mg，活性成分含量50.0mg，如果希望，可以提供裂痕用于剂量的更精细调节。
Claims (9)
1.式I的化合物：
其中
R是在3位和/或5位被一个或多个取代基取代的金刚烷基；其中所述取代基选自C1-C10烷基、-OR1或-NR2R3；其中R1、R2和R3独立地是氢、烷基、C1-C8烷酰基、氨基甲酰基或-CO-NR4R5；其中R4和R5独立地是C1-C10烷基、未取代或取代芳基，其中所述取代的芳基是被一个或多个选自下列的基团取代的苯基：C1-C10烷基、C1-C10烷氧基、卤素和三氟甲基，并且其中R4和R5之一还可以是氢，或R4和R5一起代表C2-C7亚烷基；而
n是0-3；其呈游离形式或酸加成盐的形式。
2.式(IA)或(IB)的按照权利要求1的化合物：
其中R’代表羟基、C1-C7烷氧基、C1-C8烷酰氧基或R5R4N-CO-O-，其中R4和R5独立地是C1-C7烷基或苯基，其是未取代的或被选自C1-C7烷基、C1-C7烷氧基、卤素和三氟甲基的取代基取代和其中R4还可以是氢；或R4和R5一起代表C3-C6亚烷基；和R”代表氢；或R’和R”独立地代表C1-C7烷基；其呈游离形式或可药用酸加成盐的形式。
3.按照权利要求1的式I化合物，选自：
(S)1-[[(3，5-二甲基-1-金刚烷基)氨基]-乙酰基]-2-氰基-吡咯烷；
(S)1-[[(3-乙基-1-金刚烷基)氨基]乙酰基]-2-氰基-吡咯烷；
(S)1-[[(3-甲氧基-1-金刚烷基)氨基]-乙酰基]-2-氰基-吡咯烷；
(S)1-[[[3-[[(叔丁基氨基)羰基]氧基]-1-金刚烷基]氨基]乙酰基]-2-氰基-吡咯烷；
(S)1-[[[3-[[[(4-甲氧基苯基)氨基]羰基]氧基]-1-金刚烷基]氨基]乙酰基]-2-氰基-吡咯烷；
(S)1-[[[(3-[[(苯基氨基)羰基]氧基]-1-金刚烷基)氨基)乙酰基]-2-氰基-吡咯烷；
(S)1-[[(5-羟基-2-金刚烷基)氨基]-乙酰基]-2-氰基-吡咯烷；
(S)1-[[(3-乙酰氧基-1-金刚烷基)氨基]乙酰基]-2-氰基-吡咯烷；
(S)1-[[[3-[[[(二异丙基)氨基]羰基]氧基]-1-金刚烷基]氨基]乙酰基]-2-氰基-吡咯烷；
(S)1-[[[3-[[[(环己基)氨基]羰基]氧基]-1-金刚烷基]氨基]乙酰基]-2-氰基-吡咯烷；和
(S)1-[[(3-乙氧基-1-金刚烷基)氨基]乙酰基]-2-氰基-吡咯烷；或，在各种情况下，其可药用的酸加成盐。
4.按照权利要求1的化合物，其中(S)1-[(3-羟基-1-金刚烷基)氨基]乙酰基-2-氰基吡咯烷或其可药用盐。
5.一种药物组合物，含有游离形式或其可药用酸加成盐形式的权利要求1所述化合物，以及至少一种可药用载体或稀释剂。
6.权利要求1的化合物或其可药用酸加成盐在制备用于抑制二肽基肽酶-IV的药物中的用途。
7.权利要求6的用途，其中所述药物用于治疗二肽基肽酶-IV抑制介导的疾病。
8.按照权利要求7的用途，其中所述药物用于治疗非胰岛素依赖型糖尿病。
9.按照权利要求7的用途，其中所述药物用于治疗肥胖症。
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| US20906898A | 1998-12-10 | 1998-12-10 | |
| US09/209,068 | 1998-12-10 |
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Cited By (4)
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| CN103641761A (zh) * | 2013-11-22 | 2014-03-19 | 沈阳化工大学 | 一种维格利汀的制备方法 |
| CN105439873A (zh) * | 2014-08-20 | 2016-03-30 | 天津药物研究院 | 3-羟基-1-金刚烷胺的制备方法 |
| CN104817482A (zh) * | 2015-03-17 | 2015-08-05 | 宁波百思佳医药科技有限公司 | 2-取代吡咯烷类化合物、制备方法及其在制备维格列汀中的应用 |
| CN104817482B (zh) * | 2015-03-17 | 2017-05-10 | 宁波百思佳医药科技有限公司 | 2‑取代吡咯烷类化合物、制备方法及其在制备维格列汀中的应用 |
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