TWI393720B - ８-（３-胺基-哌啶-１-基）-黃嘌呤，其製備及作為藥物之用途 - Google Patents

８-（３-胺基-哌啶-１-基）-黃嘌呤，其製備及作為藥物之用途 Download PDF

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TWI393720B
TWI393720B TW095127832A TW95127832A TWI393720B TW I393720 B TWI393720 B TW I393720B TW 095127832 A TW095127832 A TW 095127832A TW 95127832 A TW95127832 A TW 95127832A TW I393720 B TWI393720 B TW I393720B
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methyl
compound
piperidin
amino
cyano
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Waldemar Pfrengle
Peter Sieger
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Boehringer Ingelheim Int
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Description

8－(3－胺基－哌啶－1－基)－黃嘌呤，其製備及作為藥物之用途
本發明係關於下式之新穎經取代之黃嘌呤 其互變異構物、鏡像異構物、其混合物，其鹽及其水合物，尤其係其與無機或有機酸之生理學上可接受之鹽(諸如鹽酸鹽)其具有重要藥理學特性，尤其係對二肽基肽酶－IV(DPP－IV)活性之抑制作用，其製備，其用於預防或治療與增加之DPP－IV活性相關或可藉由降低DPP－IV活性以預防或減輕之疾病或病症(尤其為I型或II型糖尿病)之用途，含有通式(I)之化合物或其生理學上可接受之鹽的醫藥組合物及其製備方法。
對DPP－IV有抑制作用之黃嘌呤衍生物已自WO 02/068420、WO 02/02560、WO 03/004496、WO 03/024965、WO 04/018468、WO 04/048379、JP 2003300977及EP 1 338 595中已知。
本發明之目的在於提供式I之新穎化合物，尤其係具有醫藥用途上有利特性之鹽。
除其用於所需適應症之實際功效以外，一種活性物質亦需滿足其他需求以能夠作為醫藥組合物使用。該等參數在很大程度上與該活性物質之物理化學性質有關。
該等參數之實例(但不受此限制)為起始物質之效用在不同環境條件下的穩定性，在醫藥調配物製備期間之穩定性及在醫藥製劑之最終組合物中之穩定性。因此，用於製備醫藥組合物之醫藥活性物質應具有高穩定性，甚至在不同環境條件下亦應保證其高穩定性。絕對必須防止使用除含有活性物質自身之外，亦含有(例如)其分解產物之醫藥組合物。在該等狀況下，醫藥調配物中所存在之活性物質的含量可能小於所記載之量。
因濕氣吸收會降低醫藥活性物質的含量其乃因水分之吸收造成重量之增加。具有吸收濕氣傾向之醫藥組合物在儲存期間須加以保護，以免受潮，例如藉由添加合適乾燥劑或藉由將藥物儲存於經保護以使其免於受潮之環境中。此外，若將醫藥物質暴露於未以任何方式保護使其免於受潮之環境中，則在製造期間吸收之濕氣可能降低醫藥活性物質之含量。因此，醫藥活性物質較佳應僅具輕微之吸濕性。
由於活性物質之晶體改質對製劑之可再生性活性物質之含量係為重要的，因此需要盡可能地使結晶形活性物質存有多晶形態。若活性物質具有不同之多晶形改質，則須當心以確保該物質之結晶改質在隨後所製備之醫藥製劑中並未變化。否則，此對藥物之可再生效力具有有害作用。與此相反者，特徵為僅具輕微多晶性之活性物質為較佳之活性物質。
視調配物之選擇或調配物製造方法之選擇而定，在某些情況下特別重要之另一標準為活性物質之溶解度。舉例而言，若製備醫藥溶液(例如輸液)，則活性物質應以可充分溶於生理學上可接受之溶劑為必要。對於經口服用之藥物而言，活性物質應充分可溶亦極為重要。
本發明之課題在於提供一種不僅特徵為高藥理學效力而且亦盡可能滿足上述物理化學需求之醫藥活性物質。
令人驚訝地發現式I之化合物與鹽酸之鹽，其鏡像異構物，其混合物及水合物滿足此需求。尤其適於本發明之目的的為單鹽酸鹽及二鹽酸鹽及其鏡像異構物，其混合物及水合物。
同義地使用下列術語：
與鹽酸之鹽－鹽酸鹽
因此，本發明係關於1－[(3－氰基－吡啶－2－基)甲基]－3－甲基－7－(2－丁炔－1－基)－8－(3－胺基－哌啶－1－基)－黃嘌呤與鹽酸之鹽，以及其鏡像異構物，其混合物及水合物。舉例而言，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－胺基－哌啶－1－基]－黃嘌呤及1－[(3－氰基－吡啶－2－基)甲基]－3－甲基－7－(2－丁炔－1－基)－8－[(S)－3－胺基－哌啶－1－基]－黃嘌呤之單鹽酸鹽及二鹽酸鹽及其混合物(包括外消旋物)。本發明進一步係關於含有至少一種上述之其鹽或水合物之醫藥組合物及製備醫藥組合物之方法。
由於其抑制DPP－IV活性之能力，因此根據本發明之通式I之化合物及其相應醫藥上可接受之鹽適於影響可受DPP－IV活性之抑制影響之任何病症或疾病。因此，期望根據本發明之化合物將適於預防或治療以下疾病或病症：諸如I型及II型糖尿病、前驅糖尿病、空腹血糖中下降之葡萄糖耐受性或變化、糖尿病性併發症(例如視網膜病、腎病或神經病)、代謝性酸中毒或代謝性酮症、反應性低血糖症、胰島素抗性、代謝症候群、多種起源之高脂血症(dyslipidaemia)、關節炎、動脈粥樣硬化症及相關性疾病、肥胖症、同種異體移植及由降血鈣素所引起之骨質疏鬆症。此外，該等物質適於防止諸如胰腺B－細胞之凋零或壞死之B細胞退化症。該等物質亦適於改善或恢復胰腺細胞之功能，且另外適於增加胰腺B－細胞之大小及數量。此外，基於諸如GLP－1及GLP－2之類升糖素肽的作用及其與DPP－IV抑制相關，期望根據本發明之化合物將適於達到尤其係鎮靜或安定作用，且對手術後之異化狀況或對激素壓力反應具有有利作用，或可能降低心肌梗塞後之死亡率及發病率。此外，其適於治療與上述作用有關且由GLP－1或GLP－2所調節之任何病症。根據本發明之化合物亦可作為利尿劑或抗高血壓藥使用，且適於預防及治療急性腎衰竭。根據本發明之化合物亦可用於治療呼吸道炎性疾患。其亦適於預防及治療諸如大腸急躁症(IBS)、克隆氏病(Crohn's disease)或潰瘍性結腸炎之慢性炎性腸病亦及胰腺炎。亦期望其可用於腸胃道之所有種類的損傷或損害，諸如可在結腸炎及腸炎中發生。此外，期望DPP－IV抑制劑及因此根據本發明之化合物可用於治療不孕症或改善人類或哺乳動物之生育力，尤其係若不孕症與胰島素抗性有關或與多囊性卵巢症有關。另一方面，該等物質適於影響精子活力且因此適於作為男性避孕品使用。此外，該等物質適於治療與受限生長有關之生長激素缺乏，且可合理地用於生長激素可用之所有適應症。基於對DPP－IV之抑制作用，因此根據本發明之化合物亦適於治療諸如類風濕性關節炎、多發性硬化症、甲狀腺炎及巴塞多氏病(Basedow's disease)等多種自體免疫疾病。其亦可用於治療病毒性疾病，且亦可(例如)在HIV感染中用於刺激血液生產，用於良性前列腺肥大、齒齦炎中，以及用於治療諸如阿茲海默氏病(Alzheimer's disease)之神經元缺損及神經退化性疾病。所描述之化合物亦可用於治療腫瘤，尤其係用於限制腫瘤侵入，亦及癌轉移；在此實例為其治療T－細胞淋巴瘤、急性淋巴性白血病、基於細胞之甲狀腺癌、基細胞癌或乳癌的用途。其他適應症為中風，多種起源之局部缺血、帕金森氏病症(Parkinson's disease)及偏頭痛。此外，其他適應症包括濾泡及表皮角化過度症、角質細胞增殖增加、牛皮癬、腦脊髓炎、絲球體腎炎、脂肪營養不良，以及所有種類之心因性生理疾病、抑鬱性疾病及神經精神疾病。
根據本發明之化合物亦可結合其他活性物質使用。用於該等組合之合適治療劑包括(例如)抗糖尿劑，諸如二甲雙胍(metformin)、磺脲(例如格列本脲(glibenclamide)、甲苯磺丁脲(tolbutamide)、格列美脲(glimepiride))、那格列奈(nateglinide)、諾和隆(repaglinide)、噻唑烷二酮(例如梵帝雅(rosiglitazone)、吡格列酮(pioglitazone))、PPAR－γ激動劑(例如GI 262570)及拮抗劑、PPAR－γ/α調節劑(例如KRP 297)、PPAR－γ/α/δ調節劑、AMPK活化劑、ACC1及ACC2抑制劑、DGAT－抑制劑、SMT3受體激動劑、11β－HSD抑制劑、FGF19激動劑或模擬劑、α－葡糖苷酶抑制劑(例如醣祿、伏格列波糖(voglibose))、其他DPPIV抑制劑、α2拮抗劑、胰島素及胰島素類似物、GLP－1及GLP－1類似物(例如促胰島素分泌素(exendin－4))或艾汀(amylin)。亦可能為與以下各物質之組合：諸如T－1095或KGT－1251(869682)之SGLT2抑制劑，蛋白酪胺酸磷酸酶1抑制劑，影響肝臟中經解除調控之葡萄糖生產的物質，諸如葡萄糖－6－磷酸酶或果糖－1,6－二磷酸酶、肝糖磷酸化酶之抑制劑、升糖素受體拮抗劑及磷酸烯醇丙酮酸鹽羧基激酶抑制劑、肝糖合成酶激酶或丙酮酸鹽脫氫激酶，降脂劑，諸如HMG－CoA－還原酶抑制劑(例如斯伐他汀(simvastatin)、阿托伐他汀(atorvastatin))、纖維酸酯(例如貝紮貝特(bezafibrate)、非諾貝特(fenofibrate))、菸鹼酸及其衍生物、PPAR－α激動劑、PPAR－δ激動劑、ACAT抑制劑(例如阿伐麥布(avasimibe))或膽固醇吸收抑制劑，諾如依澤替米貝(ezetimibe)、諸如消膽胺(cholestyramine)之膽酸結合物質、回腸膽酸運輸抑制劑、HDL提高化合物，諸如CETP抑制劑或ABC1調節劑或LXRα拮抗劑、LXRβ激動劑或LXRα/β調節劑或治療肥胖症之活性物質，諸如諾美婷(sibutramine)或四氫力普斯坦汀(tetrahydrolipostatin)、右芬氟拉明(dexfenfluramine)、阿索開(axokine)、大麻素1受體拮抗劑、MCH－1受體拮抗劑、MC4受體激動劑、NPY5或NPY2拮抗劑或諸如SB－418790或AD－9677之β3－激動劑以及5HT2c受體激動劑。
亦能夠將該等化合物與諸如AII拮抗劑或ACE抑制劑、利尿劑、β－阻斷劑、Ca－拮抗劑等或其組合之治療高血壓之藥物組合。
便利地達到該作用之所需劑量為經由靜脈內途徑投與1 mg至100 mg，較佳為1 mg至30 mg，且經由口服途徑為1 mg至1000 mg，較佳為1 mg至100 mg，在各種狀況下均為每日1至4次。為達成此目的，根據本發明所製備之式I之化合物(視情況與其他活性物質組合)可與一或多種惰性習知載劑及/或稀釋劑(例如與玉米澱粉、乳糖、葡萄糖、微晶纖維素、硬脂酸鎂、聚乙烯吡咯啶酮、檸檬酸、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、羧甲基纖維素或脂肪物質(諸如硬脂)或其合適混合物)一起併入至習知蓋倫(galenic)製劑中，諸如普通或經塗覆之錠劑、膠囊、粉末、懸浮液或栓劑。
以下實例意欲說明本發明。
實例1
3－(酞醯亞胺基)哌啶之R－鏡像異構物的D－酒石酸鹽a.氫化：
將10.00 kg(106.25 mol)3－胺基吡啶、500 g工業級活性炭及65公升乙酸置放於氫化反應器中。添加50 g西村(Nishimura)催化劑(市售之混合銠/鉑催化劑)，懸浮於2.5公升乙酸中，且用2.5公升乙酸沖洗混合物。在50℃及100巴過度氫壓下將其氫化直至氫吸收已停止，且接著於50℃下再氫化30分鐘。濾出催化劑及活性炭且用10公升乙酸洗滌。
在較低劇烈壓力下反應亦可取得成功。
b.醯化：
將15.74 kg(106.25 mol)鄰苯二甲酸酐置放於反應器中，且與來自氫化之濾出液組合。用7.5公升乙酸沖洗混合物，且接著將反應混合物回流，同時在一小時內蒸出約30%之所用乙酸。將反應溶液冷卻至90℃。
c.外消旋物裂解：
將加熱至50℃之11.16 kg D－(－)－酒石酸(74.38 mol)於50公升絕對乙醇中之溶液在90℃下計量供給至醯化反應溶液中。用10公升絕對乙醇將其沖洗且在90℃下攪拌30分鐘，在此時間內產物結晶出。冷卻至5℃後將產物離心分離且用絕對乙醇洗滌。
d.再結晶： 將濕粗產物在50公升丙酮與90公升水之混合物中回流直至已形成溶液。接著將混合物冷卻至5℃，在此時間內產物結晶出。在5℃下將懸浮液攪拌30分鐘，將產物離心分離且最後用20公升丙酮與10公升水之混合物洗滌。將其在乾燥櫃中乾燥，同時在45℃下使之成惰性。
產量：11.7－12.5 kg
實例2
製備1－[(3－氰基－吡啶－2－基)甲基1－3－甲基－7－(2－丁炔－1－基)－8－[( R )－3－胺基－哌啶－1－基]－黃嘌呤鹼a. 3－氰基－2－(氯甲基)－吡啶 在90－100℃下將166.5 g(0.98 mol)2－羥甲基－3－吡啶羧醯胺與270 ml磷醯氯一起加熱1小時。將反應混合物冷卻至周圍溫度，且接著在50－60℃之溫度下逐滴添加至約800 ml水中。磷醯氯水解之後，在冷卻的同時用氫氧化鈉溶液中和混合物，因此產物沉澱。將其濾出，用300 ml水洗滌且接著在35－40℃下乾燥。
產量：122.6 g(理論值之82%)
b. 1－[(3－氰基－吡啶－2－基)甲基]－3－甲基－7－(2－丁炔－1－基)－8－溴－黃嘌呤
將202 g(0.68 mol)3－甲基－7－(2－丁炔－1－基)－8－溴－黃嘌呤、188.5 g(1.36 mol)無水碳酸鉀及1.68公升N－甲基－2－吡咯啶酮置放於反應器中且加熱至70℃。接著逐滴添加於240 ml N－甲基－2－吡咯啶(NMP)中之119 g(0.75 mol)2－氯甲基－3－氰基－吡啶。在70℃下將反應器之內含物攪拌19小時。反應結束後將2.8公升水添加至反應混合物中且冷卻至25℃。濾出產物，用2公升水洗滌且在70℃下於乾燥櫃中乾燥同時使之成惰性。
產量：257.5 g(理論值之91%)
c. 1－[(3－氰基－吡啶－2－基)甲基]－3－甲基－7－(2－丁炔－1－基)－8－(3－( R )－酞醯亞胺基－哌啶－1－基)－黃嘌呤
將230 g(0.557 mol)1－[(3－氰基－吡啶－2－基)甲基]－3－甲基－7－(2－丁炔－1－基)－8－溴－黃嘌呤、318 g(0.835 mol)3－(酞醯亞胺基)哌啶D－酒石酸鹽及1.15公升N－甲基－2－吡咯啶酮置放於反應器中。將反應器之內含物加熱至140℃。達到該溫度後，在20分鐘內計量供給478 ml(2.78 mol)二異丙基乙胺，且接著在140℃下將反應混合物攪拌2小時。接著將反應混合物冷卻至75℃，且用720 ml甲醇稀釋。接著在68－60℃下添加2.7公升水且將混合物冷卻至25℃。濾出產物且用2公升水洗滌。將其在70℃下於乾燥櫃中乾燥，同時使之成惰性。
接著將由此所獲得之粗產物在沸騰溫度下攪拌入1公升甲醇中，趁熱過濾，用200 ml甲醇洗滌且接著在70℃下乾燥，同時使之成惰性。
產量：275 g(理論值之88%)
d. 1－[(3－氰基－吡啶－2－基)甲基]－3－甲基－7－(2－丁炔－1－基)－8－(3－( R )－胺基－哌啶－1－基)－黃嘌呤
將412.5 g(0.733 mol)1－[(3－氰基－吡啶－2－基)甲基]－3－甲基－7－(2－丁炔－1－基)－8－(3－(R)－酞醯亞胺基－哌啶－1－基)－黃嘌呤在4125 ml甲苯中加熱至80℃。接著在75－80℃下將445 ml乙醇胺(7.33 mol)添加至懸浮液中。為完成反應，在80－85℃下將混合物再攪拌2小時，在此時間內固體進入溶液。接著分離相。用溫甲苯(在每種狀況下1公升)將乙醇胺相萃取兩次。每次用2公升75－80℃溫水將所組合之甲苯相洗滌兩次。用硫酸鈉乾燥甲苯相，過濾且接著經由在真空中蒸餾降至約430 ml之體積。接著在50－55℃下計量供給1公升第三丁基甲醚，且接著冷卻至0－5℃。經由過濾將產物分離，用第三丁基甲醚洗滌且在60℃下於乾燥櫃中乾燥。
產量：273.25 g(理論值之86.2%)
熔點：188±3℃(無水形式)
如自圖4之吸收圖中清楚可見，1－[(3－氰基－吡啶－2－基)甲基]－3－甲基－7－(2－丁炔－1－基)－8－(3－(R )－胺基－哌啶－1－基)－黃嘌呤之無水形式在高達約50%相對濕度下穩定，超過50%相對濕度時該形式吸收約4%之水且變成單水合物。若隨後使相對濕度返回至50%或更低，則再次形成無水形式，意即轉化成單水合物為完全可逆。
實例3
1－[(3－氰基－吡啶－2－基)甲基]－3－甲基－7－(2－丁炔－1－基)－8－[( R )－3－胺基－哌啶－1－基]－黃嘌呤單鹽酸鹽 將5.00 g 1－[(3－氰基－吡啶－2－基)甲基]－3－甲基－7－(2－丁炔－1－基)－8－[(R )－3－胺基－哌啶－1－基]－黃嘌呤鹼溶解於50 ml甲醇中。接著添加氯化氫於異丙醇中之3.0 ml之3.9莫耳溶液。蒸餾出溶劑，且將殘餘物懸浮於40 ml乙酸乙酯中且回流，在此時間內形成沉澱物。將其冷卻至周圍溫度，濾出沉澱物且用少量乙酸乙酯洗滌且乾燥。接著將產物自絕對乙醇中再結晶。
產量：2.7 g(理論值之50%)
熔點：265±5℃(伴有分解)
單鹽酸鹽顯示較不顯著之吸濕特徵；如在50%相對濕度與60%相對濕度之間以游離鹼所觀測，變成水合物相為不可逆(參看圖7中之單鹽酸鹽的吸收特徵)。單鹽酸鹽亦僅在極高相對濕度(>80%相對濕度)下吸收水。濕度依賴性X射線粉末圖像顯示單鹽酸鹽在超過80%相對濕度下無相變化。
實例4 1-[(3-氰基-吡啶-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-[(R )-3-胺基-哌啶-1-基]-黃嘌呤-二鹽酸鹽
在沸騰溫度下將1-[(3-氰基-吡啶-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-[(R )-3-胺基-哌啶-1-基]-黃嘌呤鹼(1.00 g；2.31 mmol)溶解於9.5 ml絕對乙醇及0.5 ml甲基-第三丁基醚中。接著添加氯化氫於異丙醇中之1.2 ml之3.9莫耳溶液。形成沉澱物。冷卻至周圍溫度後將混合物過濾，用少量MTBE洗滌且乾燥。
產量：1.04 g(理論值之89.0%)
熔點：205±5℃(伴有分解)；超過約150℃放出氣態HCl。
二鹽酸鹽亦顯示不顯著之吸濕特性；如在50%相對濕度與60%相對濕度之間以游離鹼觀測變成水合物相為不可逆(參看圖10中之二鹽酸鹽之吸收特徵)。在全部範圍之相對濕度內二鹽酸鹽連續吸收一定量的水。濕度依賴性X射線粉末圖像顯示在10－90相對濕度之濕度範圍內無相變化。
使用由Mettler－Toledo所供應之裝置(型號：DSC 821)，經由DSC確定熔點。所用之熔化溫度為DSC圖中相應熔融峰之起始溫度。使用10 K/min之加熱速率，且在氮氣氣氛下進行實驗。
X射線粉末圖(有一例外)係使用STOE Stadi P X射線粉末繞射儀記錄。該繞射儀使用CuKα 1 輻射(λ＝1.5406)及位置敏感性偵測器運作。X射線產生器在40 mA及40 kV下運作。
使用Bruker D8 Advance X射線粉末繞射儀(其上置有由MRI所製之專用空氣濕度元件)記錄游離鹼之單水合物之X射線粉末圖。在約72%相對濕度下記錄圖。該Bruker D8 Advance使用CuKα 輻射(λ＝1.5418)亦及位置敏感性偵測器運作。X射線產生器在30 mA及40 kV下運作。
實例5
含有75 mg活性物質之經塗覆錠劑 1錠劑核心含有：
製備： 將活性物質與磷酸鈣、玉米澱粉、聚乙烯吡咯啶酮、羥丙基甲基纖維素及半數所指定量之硬脂酸鎂混合。在錠劑製造機中製造直徑約13 mm之半成品，且接著使用合適機器將其經由1.5 mm篩孔尺寸之篩子摩擦且與剩餘硬脂酸鎂混合。在錠劑製造機中擠壓此顆粒以形成所需形狀之錠劑。
核心重量：230 mg模具：9 mm，凸面
用基本上由羥丙基甲基纖維素組成之薄膜塗覆由此所製之錠劑核心。用蜂蠟拋光所完成之經薄膜塗覆之錠劑。
經塗覆之錠劑重量：245 mg
實例6
含有100 mg活性物質之錠劑 組成：1錠劑含有：
製備方法： 將活性物質、乳糖及澱粉一起混合，且用聚乙烯吡咯啶酮水溶液均勻濕潤。潮濕組合物經篩選(2.0 mm篩孔尺寸)且在50℃下在托架型乾燥器中乾燥之後，對其再次篩選(1.5 mm篩孔尺寸)並添加潤滑劑。擠壓所完成之混合物以形成錠劑。
錠劑重量：220 mg直徑：10 mm，雙面，在兩面上均有小刻面且在一面上有凹口
實例7
含有150 mg活性物質之錠劑 組成：1錠劑含有：
製備： 用20%聚乙烯吡咯啶酮水溶液濕潤與乳糖、玉米澱粉及矽膠混合之活性物質，並經由具有1.5 mm篩孔尺寸之篩子。
將在45℃下乾燥之顆粒再次經由相同篩子，且與指定量之硬脂酸鎂混合。自混合物壓製錠劑。
錠劑重量：300 mg模具：10 mm，平面
實例8
含有150 mg活性物質之硬明膠膠囊 1膠囊含有：
製備： 將活性物質與賦形劑混合，經由具有0.75 mm篩孔尺寸之篩子，且使用合適裝置均勻混合。將所完成之混合物裝入尺寸1之硬明膠膠囊中。
膠囊填充物：大約320 mg膠囊外殼：尺寸1之硬明膠膠囊
實例9
含有150 mg活性物質之栓劑 1栓劑含有：
製備： 在栓劑塊熔化後，將活性物質均勻分佈於其中，且將熔融體倒入經冷卻之模具中。
實例10
含有50 mg活性物質之懸浮液 100 ml懸浮液含有：活性物質 1.00 g羧甲基纖維素－Na－鹽 0.10 g對羥基苯甲酸甲酯 0.05 g對羥基苯甲酸丙酯 0.01 g葡萄糖 10.00 g丙三醇 5.00 g 70%之山梨糖醇溶液 20.00 g芳香劑 0.30 g蒸餾水 補足100 ml
製備： 將蒸餾水加熱至70℃。在攪拌的同時，將對羥基苯甲酸甲酯及對羥基苯甲酸丙酯與丙三醇及羧甲基纖維素之鈉鹽溶解於其中。將溶液冷卻至周圍溫度，且在攪拌的同時添加活性物質並使其均勻分散於其中。加入並溶解糖、山梨糖醇溶液及芳香劑之後，在攪拌的同時抽空懸浮液以排除空氣。
5 ml懸浮液含有50 mg活性物質。
實例11
含有10 mg活性物質之安瓶 組成：活性物質 10.0 mg 0.01 N鹽酸 適量雙蒸水 補足2.0 ml
製備： 將活性物質溶解於必要量之0.01 N HCl中，用食鹽使其等張，無菌過濾且轉移至2 ml安瓶中。
實例12
含有50 mg活性物質之安瓶 組成：活性物質 50.0 mg0.01 N鹽酸 適量雙蒸水 補足10.0 ml
製備： 將活性物質溶解於必要量之0.01 N HCl中，用食鹽使其等張，無菌過濾且轉移至10 ml安瓶中。
圖1、圖3、圖5及圖8展示實例2(無水形式及單水合物)、實例3及實例4之X射線粉末圖；圖2、圖6及圖9展示實例2、實例3及實例4之熱分析；且圖4、圖7及圖10展示游離鹼及1－[(3－氰基－吡啶－2－基)甲基]－3－甲基－7－(2－丁炔－1－基)－8－(3－(R )－胺基－哌啶－1－基)－黃嘌呤之單鹽酸鹽及二鹽酸鹽(實例2、實例3及實例4)的吸收特徵。

Claims (21)

  1. 一種化合物，其係結晶無水形式之1-[(3-氰基-吡啶-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-[3-(R)-胺基-哌啶-1-基]-黃嘌呤之單鹽酸鹽或二鹽酸鹽。
  2. 一種化合物，其係1-[(3-氰基-吡啶-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-[3-(R) -胺基-哌啶-1-基]-黃嘌呤之單鹽酸鹽，該化合物具有260℃至270℃之熔點。
  3. 一種化合物，其係1-[(3-氰基-吡啶-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-[3-(R)-胺基-哌啶-1-基]-黃嘌呤之單鹽酸鹽，且其中該單鹽酸鹽之X射線粉末圖像包含下列具有至少約10%強度之特徵值2θ：8.51°、9.83°、13.01°、17.07°、20.00°、20.60°、22.33°、22.61°、24.91°及25.43°。
  4. 一種化合物，其係1-[(3-氰基-吡啶-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-[3-(R)-胺基-哌啶-1-基]-黃嘌呤之二鹽酸鹽，該化合物具有200℃至210℃之熔點。
  5. 一種化合物，其係1-[(3-氰基-吡啶-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-[3-(R)-胺基-哌啶-1-基]-黃嘌呤之二鹽酸鹽，且其中該二鹽酸鹽之X射線粉末圖像包含下列具有至少約18%強度之特徵值2θ：7.86°、10.04°、11.53°、12.20°、15.77°、18.50°、21.64°、26.79°、29.48°及30.16°。
  6. 一種醫藥組合物，其包含賦形劑及結晶無水形式之1-[(3-氰基-吡啶-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-[3- (R)-胺基-哌啶-1-基]-黃嘌呤之單鹽酸鹽或二鹽酸鹽化合物。
  7. 一種醫藥組合物，其包含賦形劑及1-[(3-氰基-吡啶-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-[3-(R) -胺基-哌啶-1-基]-黃嘌呤之單鹽酸鹽化合物，該化合物具有260℃至270℃之熔點。
  8. 一種醫藥組合物，其包含賦形劑及1-[(3-氰基-吡啶-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-[3-(R)-胺基-哌啶-1-基]-黃嘌呤之單鹽酸鹽，且其中該單鹽酸鹽之X射線粉末圖像包含下列具有至少約10%強度之特徵值2θ：8.51°、9.83°、13.01°、17.07°、20.00°、20.60°、22.33°、22.61°、24.91°及25.43°。
  9. 一種醫藥組合物，其包含賦形劑及1-[(3-氰基-吡啶-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-[3-(R)-胺基-哌啶-1-基]-黃嘌呤之二鹽酸鹽化合物，該化合物具有200℃至210℃之熔點。
  10. 一種醫藥組合物，其包含賦形劑及1-[(3-氰基-吡啶-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-[3-(R)-胺基-哌啶-1-基]-黃嘌呤之二鹽酸鹽，且其中該二鹽酸鹽之X射線粉末圖像包含下列具有至少約18%強度之特徵值2θ：7.86°、10.04°、11.53°、12.20°、15.77°、18.50°、21.64°、26.79°、29.48°及30.16°。
  11. 一種結晶無水形式之1-[(3-氰基-吡啶-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-[3-(R)-胺基-哌啶-1-基]-黃嘌呤之單鹽 酸鹽或二鹽酸鹽之用途，其係製備用於治療II型糖尿病或肥胖症之藥劑。
  12. 一種1-[(3-氰基-吡啶-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-[3-(R) -胺基-哌啶-1-基]-黃嘌呤之單鹽酸鹽之用途，其係製備用於治療II型糖尿病或肥胖症之藥劑，其中該單鹽酸鹽具有260℃至270℃之熔點。
  13. 一種1-[(3-氰基-吡啶-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-[3-(R)-胺基-哌啶-1-基]-黃嘌呤之單鹽酸鹽之用途，其係製備用於治療II型糖尿病或肥胖症之藥劑，其中該單鹽酸鹽之X射線粉末圖像包含下列具有至少約10%強度之特徵值2θ：8.51°、9.83°、13.01°、17.07°、20.00°、20.60°、22.33°、22.61°、24.91°及25.43°。
  14. 一種1-[(3-氰基-吡啶-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-[3-(R)-胺基-哌啶-1-基]-黃嘌呤之二鹽酸鹽之用途，其係製備用於治療II型糖尿病或肥胖症之藥劑，其中該二鹽酸鹽具有200℃至210℃之熔點。
  15. 一種1-[(3-氰基-吡啶-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-[3-(R)-胺基-哌啶-1-基]-黃嘌呤之二鹽酸鹽之用途，其係製備用於治療II型糖尿病或肥胖症之藥劑，其中該二鹽酸鹽之X射線粉末圖像包含下列具有至少約18%強度之特徵值2θ：7.86°、10.04°、11.53°、12.20°、15.77°、18.50°、21.64°、26.79°、29.48°及30.16°。
  16. 如請求項2之化合物，其中該(R)構形化合物係自對應的(S)構形化合物離析出來。
  17. 如請求項3之化合物，其中該(R)構形化合物係自對應的(S)構形化合物離析出來。
  18. 如請求項4之化合物，其中該(R)構形化合物係自對應的(S)構形化合物離析出來。
  19. 如請求項5之化合物，其中該(R)構形化合物係自對應的(S)構形化合物離析出來。
  20. 如請求項2之化合物，其中該單鹽酸鹽化合物之X射線粉末圖像包含下列具有至少約10%強度之特徵值2θ：8.51°、9.83°、13.01°、17.07°、20.00°、20.60°、22.33°、22.61°、24.91°及25.43°。
  21. 如請求項4之化合物，其中該二鹽酸鹽之X射線粉末圖像包含下列具有至少約18%強度之特徵值2θ：7.86°、10.04°、11.53°、12.20°、15.77°、18.50°、21.64°、26.79°、29.48°及30.16°。
TW095127832A 2005-07-30 2006-07-28 ８-（３-胺基-哌啶-１-基）-黃嘌呤，其製備及作為藥物之用途 TWI393720B (zh)

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