CN101233133A - 1－[(3－氰基－吡啶－2－基)甲基]－3－甲基－7－(2－丁炔－1－基)－8－(3－氨基－哌啶－1－基)－黄嘌呤的盐酸盐及水合物、其制备方法及其作为药物的用途 - Google Patents
1－[(3－氰基－吡啶－2－基)甲基]－3－甲基－7－(2－丁炔－1－基)－8－(3－氨基－哌啶－1－基)－黄嘌呤的盐酸盐及水合物、其制备方法及其作为药物的用途 Download PDFInfo
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Abstract
本发明涉及1－[(3－氰基－吡啶－2－基)甲基]－3－甲基－7－(2－丁炔－1－基)－8－[3－氨基－哌啶－1－基]－黄嘌呤、与盐酸形成的盐，以及其对映体、其混合物及其水合物。
Description
本发明涉及下式的新颖被取代的黄嘌呤
其互变异构体、对映异构体、其混合物，其盐及其水合物，尤其是其与无机或有机酸形成的生理学上可接受的盐(例如盐酸盐)，其具有重要药理学特性，尤其是对二肽基肽酶-IV(DPP-IV)活性的抑制作用，其制备，其用于预防或治疗与增加的DPP-IV活性相关的疾病或病症或可通过降低DPP-IV活性以防止或减轻的疾病或病症(尤其为I型或II型糖尿病)的用途，其含有通式(I)的化合物或其生理学上可接受的盐的药物组合物及其制备方法。
对DPP-IV有抑制作用的黄嘌呤衍生物已自WO 02/068420、WO02/02560、WO 03/004496、WO 03/024965、WO 04/018468、WO 04/048379、JP 2003300977及EP 1 338 595中已知。
本发明的目的在于提供式I的新颖化合物，尤其是具有医药用途上有利特性的盐。
除其用于所需适应症的实际功效以外，活性物质也需满足其他需求以能够作为药物使用。这种参数在很大程度上与该活性物质的物理化学性质有关。
这种参数的实例(但不受此限制)为起始物质在不同环境条件下的活性稳定性，在药用制剂制备期间的稳定性及在药用制剂的最终组合物中的稳定性。因此，用于制备药物组合物所用的医药活性物质应具有高的稳定性，甚至在不同环境条件下必须保证其高稳定性。这是绝对必要的，以防止使用除含有活性物质自身之外，还含有(例如)其分解产物的药物组合物。在这种状况下，药用制剂中所存在的活性物质的含量可能小于所指定的量。
因湿气吸收会降低医药活性物质的含量，这是由于水分吸收所引起的增重。对具有吸湿倾向的药物在储存期间须加以保护，例如通过添加合适干燥剂或通过将药物储存于免于受潮的保护的环境中。此外，若将医药物质放置在未以任何方式保护使其免于受潮的环境中，而且在制造期间吸收的湿气可能降低医药活性物质的含量。因此，医药活性物质优选应仅具有轻微的吸湿性。
由于活性物质的晶体改性对制剂的可重复性的活性物质含量是重要的，因此需要尽可能地明了任何以结晶形式存在的活性物质的多晶形。若活性物质具有不同的多晶形改性，则须确保该物质的结晶改性在随后的药物制备中没有变化。否则，这对药物的可重复的有效性具有有害作用。与此相反者，特征为仅具有数量少的多晶型的活性物质为优选的活性物质。
制剂的选择或制剂制造方法的选择在某些情况下特别重要的另一标准为活性物质溶解度。举例而言，若制备医药溶液(例如输液)，则活性物质在生理学上可接受的溶剂中的可充分溶解性为必要的。对于经口服的药物而言，活性物质的充分可溶性亦极为重要。
本发明的问题在于提供一种医药活性物质，其特征不仅为高药理学有效性而且亦尽可能满足上述物理化学的需求。
令人惊讶地发现式I化合物与盐酸形成的盐，其对映异构体，其混合物及水合物满足此需求。尤其适于本发明的目的的为单盐酸盐及二盐酸盐以及其对映异构体，其混合物及水合物。
下列使用的术语是同义词：
与盐酸形成的盐----盐酸盐。
因此，本发明涉及1-[(3-氰基-吡啶-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-氨基-哌啶-1-基)-黄嘌呤与盐酸形成的盐，以及其对映异构体，其混合物及水合物。为此举例而言，其包括1-[(3-氰基-吡啶-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-[(R)-3-氨基-哌啶-1-基]-黄嘌呤的单盐酸盐及二盐酸盐及其混合物(包括外消旋体)，及1-[(3-氰基-吡啶-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-[(S)-3-氨基-哌啶-1-基]-黄嘌呤的单盐酸盐及二盐酸盐及其混合物(包括外消旋体)。本发明进一步涉及含有至少一种上述盐或水合物的药物组合物及制备药物组合物的方法。
由于其抑制DPP-IV活性的能力，因此根据本发明的通式I的化合物及其相应可药用盐适于影响可受DPP-IV活性的抑制影响的任何病症或疾病。因此，期望根据本发明的化合物将适于预防或治疗以下疾病或病症：例如I型及II型糖尿病、前驱糖尿病、空腹血糖中下降的葡萄糖耐受性或变化、糖尿病性并发症(例如视网膜病、肾病或神经病)、代谢性酸中毒或代谢性酮症、反应性低血糖症、胰岛素抗性、代谢综合症、不同起源的血脂异常、关节炎、动脉粥样硬化症及相关性疾病、肥胖症、同种异体移植及由降血钙素所引起的骨质疏松症。此外，这种物质适于防止例如胰腺B-细胞细胞凋亡或坏死的B细胞退化症。该物质也适于改善或恢复胰腺细胞的功能，且另外适于提高胰腺B-细胞的大小及数量。此外，并根据通过例如GLP-1及GLP-2的类高糖素肽的作用及其与DPP-IV抑制，期望根据本发明的化合物将适于达到尤其是镇静或安定的作用，且对手术后的代谢状况或对激素应力反应具有有利作用，或可能降低心肌梗塞后的死亡率及发病率。此外，其适于治疗与上述作用有关且由GLP-1或GLP-2所调节的任何病症。根据本发明的化合物也可作为利尿剂或抗高血压药使用，且适于预防及治疗急性肾衰竭。根据本发明的化合物也可用于治疗呼吸道炎性疾病。其也适于预防及治疗例如刺激性大肠综合症(IBS)、节段性回肠炎或溃疡性结肠炎的慢性炎性肠病以及胰腺炎。也期望其可用于肠胃道的各种的损伤或损害，例如在结肠炎及肠炎中发生的。此外，期望DPP-IV抑制剂及因此根据本发明的化合物可用于治疗不孕症或改善人类或哺乳动物的生育力，尤其是在不孕症与胰岛素抗性有关或与多囊性卵巢症有关的情况。另一方面，这些物质适于影响精子活力且因此适于作为男性避孕品使用。此外，该物质适于治疗与侏儒症有关的生长激素缺乏症状，且可合理地用于可用生长激素的所有适应症。基于其对DPP-IV的抑制作用，因此根据本发明的化合物也适于治疗例如类风湿性关节炎、多发性硬化症、甲状腺炎及巴塞多氏病(Basedow’s disease)等多种自体免疫疾病。其也可用于治疗病毒性疾病，且也可(例如)在HIV感染中用于刺激血液形成，用于良性前列腺肥大、牙龈炎中，以及用于治疗例如阿兹海默氏病(Alzheimer’s disease)的神经元缺损及神经退化性疾病。所描述的化合物也可用于治疗肿瘤，尤其用于改变肿瘤侵入，以及癌转移；在此实例为其治疗T-细胞淋巴瘤、急性淋巴性白血病、基于细胞的甲状腺癌、基地细胞癌或乳癌的用途。其他适应症为中风，多种原因的局部缺血、帕金森氏病症(Parkinson’s disease)及偏头痛。此外，其他适应症包括滤泡及表皮角化过度症、增加的角质细胞增殖、牛皮癣、脑脊髓炎、肾小球肾炎、脂肪营养不良，以及不同原因的身心医学的抑郁性疾病及神经性精神病学的疾病。
根据本发明的化合物也可结合其他活性物质使用。用于这些组合的合适治疗剂包括(例如)抗糖尿剂，例如二甲双胍、磺脲(例如格列本脲、甲苯磺丁脲、格列美脲)、那格列奈、瑞格列奈、噻唑烷二酮(例如罗格列酮、吡格列酮)、PPAR-γ激动剂(例如GI 262570)及拮抗剂、PPAR-γ/α调节剂(例如KRP 297)、PPAR-γ/α/δ调节剂、AMPK活化剂、ACCl及ACC2抑制剂、DGAT-抑制剂、SMT3受体激动剂、11β-HSP抑制剂、FGF 19激动剂或模拟剂、α-葡糖苷酶抑制剂(例如醣禄、伏格列波糖)、其他DPPIV抑制剂、α2拮抗剂、胰岛素及胰岛素类似物、GLP-1及GLP-1类似物(例如促胰岛素分泌素(exendin-4))或艾汀(amylin)。亦可以与以下各物质组合：例如T-1095或KGT-1251(869682)的SGLT2抑制剂，蛋白酪氨酸磷酸酶1抑制剂，其影响肝中经脱调控的葡萄糖生产的物质，例如葡萄糖-6-磷酸酶或果糖-1，6-二磷酸酶、糖原磷酸化酶的抑制剂、胰高血糖素受体拮抗剂及磷酸烯醇丙酮酸盐羧基激酶抑制剂、糖原合成酶激酶或丙酮酸盐脱氢激酶，降脂剂，例如HMG-CoA-还原酶抑制剂(例如辛伐他汀、阿托伐他汀)、纤维酸酯(例如苯扎贝特、非诺贝特)、烟碱酸及其衍生物、PPAR-α激动剂、PPAR-δ激动剂、ACAT抑制剂(例如阿伐麦布)或胆固醇吸收抑制剂，例如依泽替米贝，例如考来烯胺的胆酸结合物质、回肠胆酸运输抑制剂、HDL提高化合物，例如CETP抑制剂或ABC1调节剂或LXRα拮抗剂、LXRβ激动剂或LXRα/β调节剂或治疗肥胖症的活性物质，例如西布曲明或四氢力普斯坦汀(tetrahydrolipostatin)、右芬氟拉明、阿索开(axokine)、大麻素1受体拮抗剂、MCH-1受体拮抗剂、MC4受体激动剂、NPY5或NPY2拮抗剂或例如SB-418790或AD-9677的β3-激动剂以及5HT2c受体激动剂。
此外也可与例如AII拮抗剂或ACE抑制剂、利尿剂、β-阻断剂、Ca-拮抗剂等或其组合物的治疗高血压的药物组合。
为达到相应作用所需剂量适宜地经静脉给药为1mg至100mg，优选为1mg至30mg，且经口服给药为1mg至1000mg，优选为1mg至100mg，在各种状况下均为每日1至4次。为此，根据本发明所制备的式I化合物(任选地与其他活性物质组合)可与一种或多种惰性常规的载体及/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/丙三醇、水/山梨糖醇、水/聚乙二醇、丙二醇、十六基硬脂醇、羧甲基纤维素或脂肪物质(例如硬脂)或其合适混合物)一起加工成常规的盖伦制剂中，例如片剂或经包衣片剂、胶囊、粉末、悬浮液或栓剂。
附图说明
图1、图3、图5及图8表示实施例2(无水形式及单水合物)、实施例3及实施例4的X射线粉末图；图2、图6及图9表示实施例2、实施例3及实施例4的热分析；且图4、图7及图10表示1-[(3-氰基-吡啶-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-3-氨基-哌啶-1-基)-黄嘌呤的游离碱及单盐酸盐及二盐酸盐(实施例2、实施例3及实施例4)的吸收特性。
以下实例用来说明本发明。
实施例1
3-(邻苯二甲酰亚胺基)哌啶的R-对映异构体的D-酒石酸盐
a.氢化：
将10.00kg(106.25mol)的3-氨基吡啶、500g工业级活性炭及65升乙酸置于氢化反应器中。添加50g西村催化剂(Nishimura catalyst，市售得到的铑/铂混合催化剂)，悬浮于2.5升乙酸中，并用2.5升乙酸冲洗混合物。在50℃及超过100巴氢压下将其氢化直至氢吸收停止，且接着于50℃下再氢化30分钟。滤出催化剂及活性炭并用10升乙酸洗涤。
在较低的剧烈压力下反应也可取得成功。
b.酰化：
将15.74kg(106.25mol)邻苯二甲酸酐置于反应器中，且与氢化后的滤液混合。用7.5升乙酸冲洗混合物，且接着将反应混合物加热回流，同时在1小时内蒸出约30％的所用乙酸。将反应溶液冷却至90℃。
c.外消旋体拆分：
将加热至50℃的11.16kg的D-(-)-酒石酸(74.38mol)于50公升无水乙醇中的溶液在90℃下计量加入至酰化反应溶液中。用10升无水乙醇将其冲洗且在90℃下搅拌30分钟，在此时间内结晶出产物。冷却至5℃后，将产物离心分离并用无水乙醇洗涤。
d.重结晶：
将湿粗产物在50公升丙酮与90公升水的混合物中加热回流直至形成溶液。接着将混合物冷却至5℃，这时结晶出产物。在5℃下将悬浮液搅拌30分钟，将产物离心分离且最后用20升丙酮与10公升水的混合物洗涤。将其在干燥箱中在45℃下惰性气氛下干燥。
产量：11.7-12.5kg
实施例2
1-[(3-氰基-吡啶-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-[(R)-3-氨基-哌啶-1-基]-黄嘌呤碱的制备
a.3-氰基-2-(氯甲基)-吡啶
将165.5g(0.98mol)的2-羟甲基-3-吡啶羧酰胺与270ml磷酰氯在90-100℃下加热1小时。将反应混合物冷却至周围温度，且接着在50-60℃的温度下滴加至约800ml水中。磷酰氯水解后，在冷却下用氢氧化钠溶液中和混合物，由此产物沉淀。将其滤出，用300ml水洗涤且接着在35-40℃下干燥。
产量：122.6g(理论值的82％)
b.1-[(3-氰基-吡啶-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-溴-黄嘌呤
将202g(0.68mol)的3-甲基-7-(2-乙炔-1-基)-8-溴-黄嘌呤、188.5g(1.36mol)无水碳酸钾及1.68升N-甲基-2-吡咯烷酮置于反应器中且加热至70℃。接着滴加于240ml N-甲基-2-吡咯烷酮(NMP)中的119g(0.75mol)的2-氯甲基-3-氰基-吡啶。在70℃下将反应器的内含物搅拌19小时。反应结束后，将2.8升水添加至反应混合物中且冷却至25℃。滤出产物，用2升水洗涤且在70℃惰性气氛下于干燥箱中干燥。
产量：257.5g(理论值的91％)
c.1-[(3-氰基-吡啶-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-邻苯二甲酰亚氨基-哌啶-1-基)-黄嘌呤
将230g(0.557mol)的1-[(3-氰基-吡啶-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-溴-黄嘌呤、318g(0.835mol)的3-(邻苯二甲酰亚胺基)哌啶D-酒石酸盐及1.15升N-甲基-2-吡咯烷酮置于反应器中。将反应器内含物加热至140℃。达到该温度后，在20分钟内计量加入478ml(2.78mol)二异丙基乙胺，且接着在140℃下将反应混合物搅拌2小时。接着将反应混合物冷却至75℃，并用720ml甲醇稀释。之后在68-60℃下添加2.7升水且将混合物冷却至25℃。滤出产物并用2升水洗涤。将其在70℃惰性气氛下于干燥箱中干燥。
接着将由此获得的粗产物在沸腾温度下搅拌到1升甲醇中，趁热过滤，用200ml甲醇洗涤且接着在70℃惰性气氛下干燥。
产量：275g(理论值的88％)
d.1-[(3-氰基-吡啶-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
将412.5g(0.733mol)的1-[(3-氰基-吡啶-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-邻苯二甲酰亚胺基-哌啶-1-基)-黄嘌呤在4125ml甲苯中加热至80℃。接着在75-80℃下将445ml乙醇胺(7.33mol)添加至悬浮液中。为完成反应，在80-85℃下将混合物再搅拌2小时，这时溶液中产生固体。接着分离相。用温热甲苯(每次1升)萃取乙醇胺相两次。合并的甲苯相用每次2升的75-80℃温水洗涤两次。用硫酸钠干燥甲苯相，过滤且接着经在真空中蒸馏使体积降至约430ml。接着在50-55℃下计量加入1升叔丁基甲醚，且接着冷却至0-5℃。经过滤将产物分离，用叔丁基甲醚洗涤且在60℃下于干燥箱中干燥。
产量：273.25g(理论值的86.2％)
熔点：188±3℃(无水形式)
如自图4的吸收图中清楚可见，1-[(3-氰基-吡啶-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-氨基-哌啶-1-基)-黄嘌呤的无水形式在高达约50％相对湿度下是稳定的；超过50％相对湿度时，该形式吸收约4％的水且转化成单水合物。若随后使相对湿度返回至50％或更低，则再次形成无水形式，即转化成单水合物是完全可逆的。
表1：1-[(3-氰基-吡啶-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-氨基-哌啶-1-基)-黄嘌呤的无水形式的X射线衍射强度(标准化)
| 2Θ[°] | dhkl[] | 强度I/I0[％] |
| 8.17 | 10.81 | 22 |
| 8.37 | 10.56 | 19 |
| 10.29 | 8.59 | 100 |
| 11.40 | 7.76 | 14 |
| 11.70 | 7.56 | 6 |
| 12.48 | 7.09 | 9 |
| 14.86 | 5.96 | 1 |
| 15.49 | 5.72 | 2 |
| 16.26 | 5.45 | 7 |
| 16.75 | 5.29 | 18 |
| 18.38 | 4.82 | 11 |
| 18.60 | 4.77 | 7 |
| 18.92 | 4.69 | 3 |
| 19.35 | 4.58 | 3 |
| 19.55 | 4.54 | 2 |
| 20.73 | 4.28 | 24 |
| 21.34 | 4.16 | 1 |
| 21.77 | 4.08 | 4 |
| 22.10 | 4.02 | 7 |
| 22.60 | 3.93 | 4 |
| 22.86 | 3.89 | 5 |
| 23.09 | 3.85 | 5 |
| 23.47 | 3.79 | 11 |
| 24.30 | 3.66 | 12 |
| 24.66 | 3.61 | 5 |
| 25.58 | 3.48 | 2 |
| 26.02 | 3.42 | 2 |
| 26.52 | 3.36 | 13 |
| 27.15 | 3.28 | 3 |
| 27.60 | 3.23 | 2 |
| 28.22 | 3.16 | 4 |
| 28.60 | 3.12 | 2 |
| 28.84 | 3.09 | 3 |
| 29.80 | 3.00 | 5 |
| 30.02 | 2.97 | 8 |
表2：1-[(3-氰基-吡啶-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-氨基-哌啶-1-基)-黄嘌呤单水合物的X射线衍射强度(标准化)
| 2Θ[°] | dhkl[] | 强度I/I0[％] |
| 8.00 | 11.05 | 12 |
| 8.45 | 10.46 | 26 |
| 9.27 | 9.54 | 5 |
| 10.43 | 8.48 | 100 |
| 11.45 | 7.72 | 23 |
| 11.74 | 7.53 | 4 |
| 12.53 | 7.06 | 6 |
| 15.91 | 5.57 | 8 |
| 16.01 | 5.53 | 7 |
| 16.73 | 5.30 | 29 |
| 16.94 | 5.23 | 17 |
| 17.99 | 4.93 | 11 |
| 18.43 | 4.81 | 15 |
| 18.95 | 4.68 | 7 |
| 19.31 | 4.59 | 2 |
| 20.54 | 4.32 | 36 |
| 20.85 | 4.26 | 30 |
| 21.86 | 4.06 | 19 |
| 22.13 | 4.01 | 8 |
| 22.70 | 3.91 | 7 |
| 22.96 | 3.87 | 15 |
| 23.43 | 3.79 | 8 |
| 24.56 | 3.62 | 18 |
| 25.45 | 3.50 | 2 |
| 25.84 | 3.44 | 14 |
| 25.99 | 3.43 | 14 |
| 26.58 | 3.35 | 6 |
| 26.88 | 3.31 | 4 |
| 28.06 | 3.18 | 3 |
| 29.04 | 3.07 | 4 |
| 29.29 | 3.05 | 9 |
| 30.22 | 2.96 | 6 |
实施例3
1-[(3-氰基-吡啶-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-[(R)-3-氨基-哌啶-1-基]-黄嘌呤单盐酸盐
将5.00g的1-[(3-氰基-吡啶-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-[(R)-3-氨基-哌啶-1-基]-黄嘌呤碱溶解于50ml甲醇中。接着添加3.0ml氯化氢于异丙醇中的3.9摩尔溶液。蒸馏出溶剂，且将残余物悬浮于40ml乙酸乙酯中且加热回流，这时形成沉淀物。将其冷却至周围温度，滤出沉淀物并用少量乙酸乙酯洗涤且干燥。
产量：2.7g(理论值的50％)
熔点：265±5℃(分解)
单盐酸盐显示较弱的吸湿特征；不存在如游离碱在50％相对湿度与60％相对湿度之间发生的转化为水合物相的可逆变化(参看图7中的单盐酸盐的吸收特征)。单盐酸盐也仅在极高的相对湿度(＞80％相对湿度)下吸收水。湿度依赖性X射线粉末图像显示单盐酸盐在超过80％相对湿度下无相变。
表3：1-[(3-氰基-吡啶-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-[(R)-3-氨基-哌啶-1-基]-黄嘌呤单盐酸盐的无水形式的X射线衍射强度(标准化)
| 2Θ[°] | dhkl[] | 强度I/I0[％] |
| 17.95 | 4.92 | 5 |
| 10.38 | 8.51 | 100 |
| 8.99 | 9.83 | 22 |
| 6.80 | 13.01 | 26 |
| 5.97 | 14.82 | 1 |
| 5.19 | 17.07 | 12 |
| 4.99 | 17.78 | 5 |
| 4.74 | 18.72 | 8 |
| 4.44 | 20.00 | 10 |
| 4.31 | 20.60 | 13 |
| 3.98 | 22.33 | 10 |
| 3.93 | 22.61 | 11 |
| 3.80 | 23.38 | 4 |
| 3.57 | 24.91 | 11 |
| 3.50 | 25.43 | 11 |
| 3.32 | 26.87 | 4 |
| 3.15 | 28.35 | 2 |
| 2.96 | 30.20 | 1 |
| 2.89 | 30.97 | 2 |
| 2.80 | 31.92 | 5 |
| 2.74 | 32.63 | 2 |
| 2.57 | 34.89 | 2 |
实施例4
1-[(3-氰基-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-二盐酸盐
在沸腾温度下，将1-[(3-氰基-吡啶-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-[(R)-3-氨基-哌啶-1-基]-黄嘌呤碱(1.00g；2.31mmol)溶解于9.5ml无水乙醇及0.5ml甲基-叔丁基醚中。接着添加1.2ml氯化氢于异丙醇中的3.9摩尔溶液。形成沉淀物。冷却至周围温度后，将混合物过滤，用少量MTBE洗涤且干燥。
产量：1.04g(理论值的89.0％)
熔点：205±5℃(分解)；超过约150℃放出气态HCl。
二盐酸盐也显示寻常的吸湿特征；不存在如游离碱在50％相对湿度与60％相对湿度之间所观察到的转化为水合物相的可逆变化(参看图10中的二盐酸盐的吸收特征)。在全部范围的相对湿度内，二盐酸盐连续吸收一定量的水。湿度依赖性X射线粉末图像显示在10-90％相对湿度的湿度范围内无相变。
表4：1-[(3-氰基-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-二盐酸盐的无水形式的X射线衍射强度(标准化)
| 2Θ[°] | dhkl[] | 强度I/I0[％] |
| 7.20 | 12.26 | 3 |
| 7.86 | 11.24 | 27 |
| 9.34 | 9.46 | 3 |
| 10.04 | 8.81 | 54 |
| 11.53 | 7.67 | 100 |
| 11.87 | 7.45 | 5 |
| 12.20 | 7.25 | 19 |
| 13.25 | 6.68 | 2 |
| 13.97 | 6.33 | 5 |
| 14.47 | 6.12 | 15 |
| 15.77 | 5.61 | 18 |
| 16.65 | 5.32 | 4 |
| 17.15 | 5.17 | 2 |
| 18.05 | 4.91 | 11 |
| 18.50 | 4.79 | 37 |
| 18.80 | 4.72 | 14 |
| 20.16 | 4.40 | 15 |
| 20.46 | 4.34 | 2 |
| 21.03 | 4.22 | 3 |
| 21.36 | 4.16 | 10 |
| 21.64 | 4.10 | 18 |
| 22.54 | 3.94 | 9 |
| 23.17 | 3.84 | 13 |
| 23.90 | 3.72 | 15 |
| 24.57 | 3.62 | 7 |
| 24.86 | 3.58 | 9 |
| 25.06 | 3.55 | 11 |
| 25.39 | 3.50 | 13 |
| 25.95 | 3.43 | 6 |
| 26.14 | 3.41 | 13 |
| 26.52 | 3.36 | 12 |
| 26.79 | 3.32 | 43 |
| 27.24 | 3.27 | 4 |
| 27.66 | 3.22 | 3 |
| 28.15 | 3.17 | 6 |
| 29.22 | 3.05 | 3 |
| 29.48 | 3.03 | 23 |
| 30.16 | 2.96 | 18 |
使用由Mettler-Toledo所提供的装置(型号：DSC 821)，经DSC确定熔点。使用DSC图中相应熔融峰的起始温度作为熔化温度。使用10K/分钟的加热速率，且在氮气气氛下进行实验。
X射线粉末图(除一种情形外)是使用STOE Stadi P X射线粉末衍射仪记录。该衍射仪使用CuKα1辐射(λ＝1.5406)及位置敏感性检测器进行。X射线发生器在40mA及40kV下运行。
使用Bruker D8 Advance X射线粉末衍射仪(其上置有由MRI所制的专用空气湿度元件)记录游离碱的单水合物的X射线粉末图。在约72％相对湿度下记录。该Bruker D8 Advance使用使用CuKα辐射(λ＝1.5418)以及位置敏感性检测器进行。X射线发生器在30mA及40kV下运行。
实施例5
含有75mg活性物质的包衣片剂
1片剂片芯含有：
活性物质 75.0mg
磷酸钙 93.0mg
玉米淀粉 35.5mg
聚乙烯吡咯烷酮 10.0mg
羟丙基甲基纤维素 15.0mg
硬脂酸镁 1.5mg
230.0mg
制备：
将活性物质与磷酸钙、玉米淀粉、聚乙烯吡咯烷酮、羟丙基甲基纤维素及半数指定量的硬脂酸镁混合。在制片机中制造直径约13mm的压制品，且接着使用合适机器将其经1.5mm筛孔尺寸的筛子摩擦且与剩余硬脂酸镁混合。在制片机中该颗粒压制成所需形状的片剂。
片芯重：230mg
模具：9mm，凸面
用基本上由羟丙基甲基纤维素组成的薄膜涂覆由此所制的片剂片芯。用峰蜡抛光所完成的包衣片剂。
包衣片剂重量：245mg
实施例6
含有100mg活性物质的片剂
组成：
1片剂含有：
活性物质 100.0mg
乳糖 80.0mg
玉米淀粉 34.0mg
聚乙烯吡咯烷酮 4.0mg
硬脂酸镁 2.0mg
220.0mg
制备方法：
将活性物质、乳糖及淀粉一起混合，并用聚乙烯吡咯烷酮水溶液均匀湿润。潮湿组合物经筛选(2.0mm筛孔尺寸)且在50℃下在托架型干燥器中干燥之后，对其再次筛选(1.5mm筛孔尺寸)并添加润滑剂。压制所完成的混合物以形成片剂。
片剂重量：220mg
直径：10mm，双面，在两面上均有刻面且在一面有凹槽。
实施例7
含有150mg活性物质的片剂
组成：
1片剂含有：
活性物质 150.0mg
粉末状乳糖 89.0mg
玉米淀粉 40.0mg
硅胶 10.0mg
聚乙烯吡咯烷酮 10.0mg
硬脂酸镁 1.0mg
300.0mg
制备：
用20％聚乙烯吡咯烷酮水溶液湿润与乳糖、玉米淀粉及硅胶混合的活性物质，并经具有1.5mm筛孔尺寸的筛子。
将在45℃下干燥的颗粒再次经相同筛子，且与指定量的硬脂酸镁混合。自混合物压制片剂。
片剂重量：300mg
模具：10mm，平面
实施例8
含有150mg活性物质的硬明胶胶囊
1胶囊含有：
活性物质 150.0mg
玉米淀粉(干燥) 约180.0mg
乳糖(粉末状) 约87.0mg
硬脂酸镁 3.0mg
约420.0mg
制备：
将活性物质与赋形剂混合，通过具有0.75mm筛孔尺寸的筛子，且在合适装置均匀混合。将所完成的混合物装入1号硬明胶胶囊中。
胶囊填充物：约320mg
胶囊外壳：1号硬明胶胶囊
实施例9
含有150mg活性物质的栓剂
1栓剂含有：
活性物质 150.0mg
聚乙二醇1500 550.0mg
聚乙二醇6000 460.0mg
聚氧乙烯脱水山梨糖醇单硬脂酸酯 840.0mg
2,000.0mg
制备：
在栓剂块熔化后，将活性物质均匀分布于其中，且将熔融体倒入经冷却的模具中。
实施例10
含有50mg活性物质的悬浮液
100ml悬浮液含有：
活性物质 1.00g
羧甲基纤维素-Na-盐 0.10g
对羟基苯甲酸甲酯 0.05g
对羟基苯甲酸丙酯 0.01g
葡萄糖 10.00g
丙三醇 5.00g
70％的山梨糖醇溶液 20.00g
芳香剂 0.30g
蒸馏水 补足100ml
制备：
将蒸馏水加热至70℃。在搅拌下，将对羟基苯甲酸甲酯及对羟基苯甲酸丙酯与丙三醇及羧甲基纤维素钠盐溶解于其中。将溶液冷却至周围温度，且在搅拌下添加活性物质并使其均匀分散于其中。加入并溶解糖、山梨糖醇溶液及芳香剂之后，在搅拌下抽真空悬浮液以排除空气。
5ml悬浮液含有50mg活性物质。
实施例11
含有10mg活性物质的安瓶
组成：
活性物质 10.0mg
0.01N盐酸 适量
双蒸水 补足2.0ml
制备：
将活性物质溶解于必要量的0.01N HCl中，用食盐使其等张，无菌过滤且转移至2ml安瓶中。
实施例12
含有50mg活性物质的安瓶
组成：
活性物质 50.0mg
0.01N盐酸 适量
双蒸水 补足10.0ml
制备：
将活性物质溶解于必要量的0.01N HCl中，用食盐使其等张，无菌过滤且转移至10ml安瓶中。
Claims (14)
1.1-[(3-氰基-吡啶-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-氨基-哌啶-1-基)-黄嘌呤的盐酸盐及其水合物。
2.1-[(3-氰基-吡啶-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-[(R)-3-氨基-哌啶-1-基]-黄嘌呤的盐酸盐及其水合物。
3.1-[(3-氰基-吡啶-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-[(S)-3-氨基-哌啶-1-基]-黄嘌呤的盐酸盐及其水合物。
4.1-[(3-氰基-吡啶-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-氨基-哌啶-1-基)-黄嘌呤单盐酸盐及其水合物。
5.1-[(3-氰基-吡啶-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-氨基-哌啶-1-基)-黄嘌呤二盐酸盐及其水合物。
6.1-[(3-氰基-吡啶-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-[(R)-3-氨基-哌啶-1-基]-黄嘌呤单盐酸盐及其水合物。
7.1-[(3-氰基-吡啶-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-[(R)-3-氨基-哌啶-1-基]-黄嘌呤二盐酸盐及其水合物。
8.1-[(3-氰基-吡啶-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-[(S)-3-氨基-哌啶-1-基]-黄嘌呤单盐酸盐及其水合物。
9.1-[(3-氰基-吡啶-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-[(S)-3-氨基-哌啶-1-基]-黄嘌呤二盐酸盐及其水合物。
10.1-[(3-氰基-吡啶-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-氨基-哌啶-1-基)-黄嘌呤单水合物。
11.1-[(3-氰基-吡啶-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-[(R)-3-氨基-哌啶-1-基]-黄嘌呤单水合物。
12.1-[(3-氰基-吡啶-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-[(S)-3-氨基-哌啶-1-基]-黄嘌呤单水合物。
13.如权利要求1至12中任一项所述的化合物在制备用于治疗I型及II型糖尿病、关节炎、肥胖症、同种异体移植及由降钙素所引起的骨质疏松症的药物组合物中的用途。
14.药物组合物，其含有如权利要求1至12中任一项所述的盐及任选地一种或多种惰性载体及/或稀释剂。
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| DE102005035891A DE102005035891A1 (de) | 2005-07-30 | 2005-07-30 | 8-(3-Amino-piperidin-1-yl)-xanthine, deren Herstellung und deren Verwendung als Arzneimittel |
| DE102005035891.8 | 2005-07-30 | ||
| PCT/EP2006/064657 WO2007014886A1 (de) | 2005-07-30 | 2006-07-26 | Hydrochloride und hydrate von 1-[(3-cyano-pyridin-2-yl) methyl]-3-methyl-7-(2-butin-1-yl)-8-(3-amino-piperidin-1-yl)-xanthin, deren herstellung und deren verwendung als arzneimittel |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102372691A (zh) * | 2011-11-15 | 2012-03-14 | 海门慧聚药业有限公司 | (r)-3-苯二甲酰亚胺哌啶酒石酸盐的制备工艺 |
| CN102617566A (zh) * | 2011-01-30 | 2012-08-01 | 山东轩竹医药科技有限公司 | 吡啶并咪唑烷衍生物 |
| CN107011345A (zh) * | 2008-12-23 | 2017-08-04 | 勃林格殷格翰国际有限公司 | 有机化合物的盐形式 |
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| HU230382B1 (hu) * | 2001-02-24 | 2016-03-29 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Xantinszármazékok, előállításuk és alkalmazásuk gyógyszerként |
| CN100497336C (zh) * | 2002-05-31 | 2009-06-10 | 先灵公司 | 制备黄嘌呤磷酸二酯酶v抑制剂及其前体的方法 |
| US7407955B2 (en) | 2002-08-21 | 2008-08-05 | Boehringer Ingelheim Pharma Gmbh & Co., Kg | 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions |
| US7569574B2 (en) | 2002-08-22 | 2009-08-04 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Purine derivatives, the preparation thereof and their use as pharmaceutical compositions |
| US7495005B2 (en) * | 2002-08-22 | 2009-02-24 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Xanthine derivatives, their preparation and their use in pharmaceutical compositions |
| US7482337B2 (en) | 2002-11-08 | 2009-01-27 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Xanthine derivatives, the preparation thereof and their use as pharmaceutical compositions |
| DE10254304A1 (de) * | 2002-11-21 | 2004-06-03 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Neue Xanthinderivate, deren Herstellung und deren Verwendung als Arzneimittel |
| US7566707B2 (en) * | 2003-06-18 | 2009-07-28 | Boehringer Ingelheim International Gmbh | Imidazopyridazinone and imidazopyridone derivatives, the preparation thereof and their use as pharmaceutical compositions |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107011345A (zh) * | 2008-12-23 | 2017-08-04 | 勃林格殷格翰国际有限公司 | 有机化合物的盐形式 |
| CN102617566A (zh) * | 2011-01-30 | 2012-08-01 | 山东轩竹医药科技有限公司 | 吡啶并咪唑烷衍生物 |
| CN102617566B (zh) * | 2011-01-30 | 2015-03-04 | 山东轩竹医药科技有限公司 | 吡啶并咪唑烷衍生物 |
| CN102372691A (zh) * | 2011-11-15 | 2012-03-14 | 海门慧聚药业有限公司 | (r)-3-苯二甲酰亚胺哌啶酒石酸盐的制备工艺 |
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