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TW201305166A - 對掌性８-（３-胺基六氫吡啶-１-基）-黃嘌呤之製法 - Google Patents

對掌性８-（３-胺基六氫吡啶-１-基）-黃嘌呤之製法 Download PDF

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TW201305166A
TW201305166A TW101117498A TW101117498A TW201305166A TW 201305166 A TW201305166 A TW 201305166A TW 101117498 A TW101117498 A TW 101117498A TW 101117498 A TW101117498 A TW 101117498A TW 201305166 A TW201305166 A TW 201305166A
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Waldemar Pfrengle
Thorsten Pachur
Thomas Nicola
Adil Duran
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Abstract

本發明係關於製備對掌異構性純8-(3-胺基六氫吡啶-1-基)-黃嘌呤之改良方法。

Description

對掌性8-(3-胺基六氫吡啶-1-基)-黃嘌呤之製法
本發明係關於製備對掌性8-(3-胺基六氫吡啶-1-基)-黄嘌呤、其對掌異構物及其生理上可耐受鹽類之改良方法。
下列一般結構之8-(3-胺基六氫吡啶-1-基)-黄嘌呤 其中R1為，例如一視需要經取代之芳基甲基或一視需要經取代之雜芳基甲基，R2為，例如一烷基，及R3為，例如一視需要經取代之苯甲基或一直鏈或支鏈烯基或炔基，已從國際專利申請案WO 02/068420、WO 04/018468、WO 04/018467、WO 2004/041820及WO 2004/046148中得知，其中描述了具有珍貴藥理性質之化合物，其包括，特別是對酵素二肽醯肽酶IV(DPP-IV)活性之抑制作用。因此，此類化合物適合用於預防或治療與增加的DPP-IV活性有關聯之疾病或症狀，或其可藉由降低DPP-IV活性來預防或減輕疾病或症狀，特別是第I型或第II型糖尿病或低葡萄糖耐受。
WO 04/018468揭示了一種製備方法，其中8-(3-胺基六氫吡啶-1-基)-黄嘌呤係藉由將對應的通式(II)之第三-丁氧基羰基-保護衍生物去保護來製備。
在此方法中，雜質很難移除，特別是在工業級製造上會發生，且可歸因於所用的保護基。因此，此方法不適合用於工業上製備8-(3-胺基六氫吡啶-1-基)-黄嘌呤，特別是對純度有嚴格要求之藥品製造業。再者，此方法具有在製造對掌異構性純前驅物3-(第三-丁氧基羰基胺基)六氫吡啶上複雜且昂貴之缺點。然而，由於副作用的風險及將劑量降至最低的考量，對掌異構純活性物質對醫藥的應用係較佳的。這些情況對該現知之工業製備對掌異構性純8-(3-胺基六氫吡啶-1-基)-黄嘌呤之適用性為不利的。.
考慮了上述該現知製備方法之缺點，本發明之目的係提供一種使用現成的高化學及光學純度之起始物質，及無高技術成本及不便性下製備對掌異構性純8-(3-胺基六氫吡啶-1-基)-黄嘌呤之方法。該新穎方法亦適用於工業級合成，因此可作為商業應用。
此目的可藉由以本發明之方法製備對掌性8-(3-胺基六氫吡啶-1-基)-黄嘌呤來達成。除了高產率的工業表現外，絕佳的化學及光學純度為本發明合成路徑之其他的優點。
根據本發明之方法，適當的黄嘌呤前驅物(III)係根據流 程1與對掌異構性純的或外消旋之(3-酞醯胺基)-六氫吡啶，在適當的溶劑中於20至160℃、較佳為8至140℃的溫度下反應；所用的溶劑，例如可為四氫呋喃(THF)、二烷、N,N-二甲基甲醯胺(DMF)、二甲基乙醯胺(DMA)、N-甲基-2-吡咯酮(NMP)或二甲基亞碸(DMSO)。較佳的係使用NMP。隨後以本身已知之方法將酞基分開。可能的分開方法係描述於，例如T.W.Greene之"Protective Groups in Organic Synthesis",Wiley 1981，第265頁(例如溶於乙醇中之肼)。
在上述的化學式中，X為離去基，其係選自鹵素之基團，例如氟、氯或溴原子，或磺醯酯之基團，例如苯基磺醯基氧基、對甲苯磺醯基氧基、甲基磺醯基氧基或三氟甲基磺醯基氧基。
R1為苯基羰基甲基、苯甲基、萘基甲基、吡啶基甲基、嘧啶基甲基、喹啉基甲基，異喹啉基甲基、喹唑啉基甲基、喹啉基甲基、萘啶基甲基或啡啶基甲基，其中芳 香或雜芳香基團在各情況下係經Ra單或雙取代，而其取代基可為相同或不同，及Ra為氫、氟、氯或溴原子或氰基、甲基、三氟甲基、乙基、苯基、甲氧基、二氟甲氧基、三氟甲氧基或乙氧基，或二個Ra基，當與相鄰的碳原子鍵結時，亦可為-O-CH2-O-或-O-CH2-CH2-O-基，R2為甲基、乙基、丙基、異丙基、環丙基或苯基及R3為2-丁烯-1-基、3-甲基-2-丁烯-1-基、2-丁炔-1-基、2-氟苯甲基、2-氯苯甲基、2-溴苯甲基、2-碘苯甲基、2-甲基苯甲基、2-(三氟甲基)苯甲基或2-氰基苯甲基。
此方法較佳的係用於該等化合物，其中X為氯或溴原子，R1為苯基羰基甲基、苯甲基、萘基甲基、吡啶基甲基、嘧啶基甲基、喹啉基甲基、異喹啉基甲基、喹唑啉基甲基、喹啉基-甲基或萘啶基甲基，其中芳香或雜芳香基團在各情況下係經Ra單或雙取代，而其取代基可為相同或不同，及Ra為氫、氟或氯原子或氰基、甲基、乙基、甲氧基或乙氧基，R2為甲基、乙基、丙基、異丙基、環丙基或苯基及R3為2-丁烯-1-基、3-甲基-2-丁烯-1-基、2-丁炔-1-基、2-氟苯甲基、2-氯苯甲基、2-溴苯甲基、2-碘苯甲基、2-甲基苯甲基、2-(三氟甲基)苯甲基或2-氰基苯甲基。
此方法更佳的係用於該等化合物，其中X為氯或溴原子
R1為氰基苯甲基、(氰基吡啶基)甲基、喹啉基甲基、(甲基喹啉基)甲基、異喹啉基甲基、(甲基異喹啉基)甲基、喹唑啉基甲基、(甲基喹唑啉基)甲基、喹啉甲基、(甲基喹啉基)甲基、(二甲基喹啉基)甲基或萘啶基甲基，R2為甲基、環丙基或苯基及R3為2-丁烯-1-基、3-甲基-2-丁烯-1-基、2-丁炔-1-基、2-氯苯甲基、2-溴苯甲基或2-氰基苯甲基，但特別是對化合物1-[(4-甲基喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-胺基六氫吡啶-1-基)-黄嘌呤、1-[(3-甲基異喹啉-1-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-((R)-3-胺基六氫吡啶-1-基)-黄嘌呤及1-[(3-氰基六氫吡啶-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-胺基六氫吡啶-1-基)-黄嘌呤，其中X為溴。
在各情況下較佳的係使用(R)-3-(酞醯亞胺基)六氫吡啶作為試劑。式(III)化合物之製備已描述於上述引用之文獻中，且可以本身已知之方法來進行。
本發明進一步係提供製備光學活性3-(酞醯亞胺基)六氫吡啶之方法。在此方法中，先將3-胺基吡啶以本身已知之方法氫化。然後將由此得到之外消旋3-胺基六氫吡啶藉由酞酸酐轉變為對應的酞醯亞胺。該(R)對掌異構物可選擇性的從外消旋、粗酞醯亞胺(IV)溶液中藉由D-酒石酸沉澱出。毋須先將原來存在母液中之過量的D-酒石酸移除，以 簡單方法藉由添加L-酒石酸亦可能由鹽類沉澱之母液中得到(IV)之(S)對掌異構物。
此極度簡單的式(IV)化合物進行對掌異構物分離，令熟習本項技術者非常驚訝。由氫化反應得來之外消旋鹼不必預先純化來達到此目的。該等處理工作甚至在工業級製造仍無任何問題。
此外，3-胺基六氫吡啶與酞酸酐之格外完全的反應本身亦令人驚訝，因為根據文獻(例如美國專利4,005,208，特別是實例27)，除了所欲的產物外，混合物中預期會含有環氮經醯化之衍生物。
下列實例將更詳細的說明本發明：
實例1 3-(酞醯亞胺基)六氫吡啶對掌異構物之D-酒石酸鹽 a.氫化作用：
將10.00 kg(106.25 mol)的3-胺基吡啶、500 g技術級的活性碳及65公升醋酸先裝入氫化反應器中。加入50 g的Nishimura催化劑(市售的銠/鉑晃何催化劑)於2.5公升的醋酸中形成漿液及沖入2.5公升的醋酸。於50℃及100 bar的氫氣壓下進行氫化，直到氫氣的吸收停止，及隨後於50℃進行後氫化反應30分鐘。將催化劑及活性碳濾出並以10公升的醋酸沖洗。毋須純化將產物溶液進行進一步的反應。
反應亦可在較不嚴謹的壓力下進行。
b.醯化作用
先將15.74 kg(106.25 mol)的酞酸酐裝入反應器中，並與由氫化反應得來之濾液混合。將其沖入7.5公升的醋酸並隨後將反應混合物加熱回流，在此期間一小時內，約有30%所用的醋酸蒸餾出。將反應溶液冷卻至90℃。毋須純化將產物溶液進行進一步的反應。
c.光學解析
將加熱至50℃、11.16 kg D(-)-酒石酸(74.38 mol)之50公升的無水乙醇溶液於90℃計量加入醯化反應溶液。將其沖入10公升的無水乙醇並於90℃攪拌30分鐘，在此期間有產物結晶出。冷卻至5℃後，將產物離心及以無水乙醇沖洗。毋須純化將產物溶液進行進一步的反應。
d.再結晶作用
將濕的粗產物置於50公升丙酮及90公升水之混合物中加熱回流直到溶液形成。隨後，溶液冷卻至5℃，在此期間有產物結晶出。將懸浮液於5℃攪拌30分鐘，並將產物離心，最後以20公升丙酮及10公升水之混合物沖洗。將混合物置於45℃惰性化乾燥箱中乾燥。
產率：11.7-12.5 kg(29-31%之理論值)
實例2 合成1-[(4-甲基喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-胺基六氫吡啶-1-基)-黄嘌呤 a. 2-氯甲基-4-甲基喹唑啉
先裝入10.00 kg(73.98 mol)的2-胺基苯乙酮及加入24.5公升的1,4-二烷。將溶液冷卻至10℃，與16.72 kg(458.68 mol)的氯化氫覆蓋混合。將反應混合物回溫至22-25℃。於此溫度下另再覆蓋氯化氫。約至總覆蓋量的一半時，混合物冷卻至-10℃並持續覆蓋。隨後，將形成的懸浮液放置於-10℃下至隔夜。於-10℃，一小時內加入6.70 kg(88.78 mol)氯乙腈之2.5公升1,4-二烷溶液。於物料容器中沖入2公升的1,4-二烷。之後，將反應器的內容物加熱至6℃並再攪拌約2小時。
先於另一反應器中裝入122公升水及62.04 kg(775.31 mol)氫氧化鈉溶液(50%)之混合物並冷卻至6℃。分次加入第一反應器之反應混合物。內部的溫度不超過11℃。隨後，首先於第一反應器沖入6公升1,4-二烷，然後沖入6公升的水。將生成的懸浮液於5℃另再攪拌30分鐘。將產物離心，以41公升的水沖洗並於35℃惰性化乾燥箱中乾燥。.
產率：10.5-12.1 kg(74-85%之理論值)
b. 1-[(4-甲基喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-溴黄嘌呤
將10.00 kg(33.66 mol)3-甲基-7-(2-丁炔-1-基)-8-溴黄嘌呤、7.13 kg(37.02 mol)2-氯甲基-4-甲基喹唑啉、3.92 kg (37.02 mol)無水碳酸鈉及30公升N-甲基-2-吡咯酮先裝入反應中。將反應器內容物加熱至140℃並於140℃攪拌2小時。反應結束後，將反應混合物冷卻至80℃並以60公升的96%乙醇稀釋，隨後於70℃以55公升的水稀釋。於60℃，計量加入4.04 kg(67.32 mol)醋酸並沖入5公升的水。將生成的懸浮液於60℃攪拌30分鐘，然後冷卻至23℃並另再攪拌30分鐘。隨後將產物離心並先以20公升96%乙醇及20公升水之混合物沖洗，然後以40公升96%乙醇及40公升水之混合物沖洗。於45℃惰性化乾燥箱中乾燥。
產率：11.6-12.6 kg(76-83%之理論值)
c. 1-[(4-甲基喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-酞醯亞胺基六氫吡啶-1-基)-黄嘌呤
將10.00 kg(22.06 mol)1-[(4-甲基喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-溴黄嘌呤、12.59 kg(33.09 mol)3-(酞醯亞胺基)六氫吡啶D-酒石酸鹽及17.5公升的N-甲基-2-吡咯酮先裝入反應器中。將反應器內容物加熱至140℃。達到此溫度後，於20分鐘內計量加入11.41 kg(88.24 mol)的二異丙基乙基胺。於原料容器中沖入2.5公升的N-甲基-2-吡咯酮及隨後將反應混合物於140℃攪拌2小時。反應結 束後，將反應混合物冷卻至60℃並以80公升的甲醇稀釋。將生成的懸浮液於50℃攪拌30分鐘，然後冷卻至23℃並另再攪拌30分鐘。隨後將產物離心並各以20公升的甲醇沖洗3次。於45℃惰性化乾燥箱中乾燥。
產率：12.0-12.5 kg(90-94%之理論值)
d. 1-[(4-甲基喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-胺基六氫吡啶-1-基)-黄嘌呤
將1800 kg(3 mol)的1-[(4-甲基喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-酞醯亞胺基六氫吡啶-1-基)-黄嘌呤於18公升的甲苯中加熱至80-85℃。隨後，於75-80℃將1.815公升(30 mol)之乙醇胺加到懸浮液中。將混合物於80-85℃攪拌2小時使反應完全，在此期間有固體溶到溶液中。隨後進行相分離。以溫甲苯沖洗乙醇胺層二次(每次4公升)。將組合的甲苯層每次各以8公升的水於75-80℃沖洗二次。由甲苯層，將22公升的甲苯於減壓下蒸餾出。於40-50℃計量4公升的第三-丁基甲基醚加至生成的懸浮液中並隨後冷卻至0-5℃。過濾將產物分離出，以第三丁基甲基醚沖洗並抽氣乾燥。之後以5倍量之無水乙醇將濕的粗物質加熱回流並將該熱溶液經由活性碳過濾淨化。將濾液冷卻至20℃後，結晶作用開始，將其以第三丁基甲基醚稀 釋成二倍體積。將懸浮液冷卻至2℃，另再攪拌2小時，抽氣過濾並於45℃乾燥箱中乾燥。
產率：1174 g(83.2%之理論值)
步驟d之另一種方法：
將1400 g(2.32 mol)的1-[(4-甲基喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-酞醯亞胺基六氫吡啶-1-基)-黄嘌呤先置入4.9 l的四氫呋喃中，隨後加熱至55-65℃。
之後，將350 ml的水及1433 g(2.32 mol)的乙醇胺加到懸浮液中。將混合物於60-63℃再攪拌3小時使反應完全。之後，加入619 ml 45%的氫氧化鈉溶液及3.85 l的水，並將混合物於55-65℃攪拌30分鐘。然後於反應混合物中加入5.6 l的甲苯，將混合物攪拌15分鐘，之後進行相分離。以2.8 l的水於55-65℃沖洗有機層，之後移出。從有機層，減壓下蒸餾出4.2 l。之後，於65-75℃加入1.4 l的甲基環己烷，在此期間產物結晶出。將懸浮液於15-25℃攪拌8-16小時，然後冷卻至0-5℃。將產物過濾分離，以4.2 l的甲基環己烷沖洗，抽氣乾燥並於35℃減壓乾燥。隨後將乾燥的粗物質(991 g)以5倍量之甲醇加熱回流，加入活性碳及過濾混合物。將甲醇蒸餾出使濾液體積降至1.5 l。將濾液冷卻至45-55℃，以第三丁基甲基醚稀釋成四倍體積。懸浮液冷卻至0-5℃，攪拌2小時，抽氣過濾、以第三丁基甲基醚沖洗並於35℃真空乾燥箱中乾燥。
產率：899 g(81.9%理論值)
實例3 1-[(3-氰基吡啶-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-胺基六氫吡啶-1-基)-黄嘌呤 a. 3-氰基-2-(氯甲基)-吡啶
將165.5 g(0.98 mol)的2-羥基甲基-3-吡啶甲醯胺與270 ml的氧氯化磷共同加熱至90-100℃歷經1小時。將反應混合物冷卻至室溫及隨後於50-60℃逐滴加入約800 ml的水。待氧氯化磷水解後，以氫氧化鈉溶液冷卻中和，在此期間有產物沉澱出。將其過濾，以300 ml的水沖洗及隨後於35-40℃下乾燥。
產率：122.6 g(82%之理論值)
步驟a之變化：3-氰基-2-(氯甲基)吡啶
將20.0 g(131.45 mmol)的2-羥基甲基-3-吡啶甲醯胺懸浮於110 ml的乙腈中並加熱至78℃。逾15分鐘內，量取60.65 g(395.52 mmol)的氧氯化磷至混合物中並將混合物加熱至81℃歷經2小時。於22℃冷卻後，將反應混合物置於200 ml的水中於40℃下攪拌。加入100 ml的甲苯後，以氫氧化鈉溶液冷卻中和。進行相分離後，以100 ml的水沖洗有機層。移出有機層並減壓蒸發溶劑得到起初生成的油狀物，將其靜置使其結晶。
產率：16.66 g(83%之理論值)
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
將202 g(0.68 mol)的3-甲基-7-(2-丁炔-1-基)-8-溴黄嘌呤、188.5 g(1.36 mol)的無水碳酸鉀及1.68公升的N-甲基-2-吡咯酮先裝入反應器中並加熱至70℃。隨後，逐滴加入119 g(0.75 mol)的2-氯甲基-3-氰基吡啶之240 ml的N-甲基-2-吡咯酮(NMP)溶液。將反應內容物於70℃下攪拌19小時。待反應結束後，將2.8公升的水加到反應混合物中並冷卻至25℃。將產物過濾出，以2公升的水沖洗並於70℃惰性化乾燥箱中乾燥。
產率：257.5 g(91%之理論值)
c. 1-[(3-氰基吡啶-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-酞醯亞胺基六氫吡啶-1-基)-黄嘌呤
將230 g(0.557 mol)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、318 g(0.835 mol)的3-(酞醯亞胺基)六氫吡啶D-酒石酸鹽及1.15公升的N-甲基-2-吡咯酮先裝入反應器中。將反應器加熱至140℃。待達到此溫度後，逾20分鐘內計量加入478 ml(2.78 mol)的二異丙基乙基胺，隨後並將反應混合物140℃攪拌2小時。之後， 將反應混合物冷卻至75℃並以720 ml的甲醇稀釋，之後，於68-60℃加入2.7公升水並將混合物冷卻至25℃。將產物過濾出並以2公升的水沖洗。於70℃惰性化乾燥箱中進行乾燥。
之後將得到的粗產物置於1公升的甲醇中煮沸，熱過濾，以200 ml的甲醇沖洗，隨後於70℃惰性化條件下乾燥。
產率：275 g(88%之理論值)
d. 1-[(3-氰基吡啶-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-胺基六氫吡啶-1-基)-黄嘌呤
將412.5 g(0.733 mol)的1-[(3-氰基吡啶-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-酞醯亞胺基六氫吡啶-1-基)-黄嘌呤溶於4125 ml的甲苯中加熱至80℃。隨後於75-80℃將445 ml的乙醇胺(7.33 mol)加到懸浮液中。將混合物於80-85℃再攪拌2小時，使反應完全，在此期間有固體進入溶液中。之後，進行相分離。將乙醇胺層以溫甲苯萃取二次(每次1公升)。將組合的甲苯層於75-80℃以每次2公升的水沖洗二次。硫酸鈉乾燥甲苯層，過濾並隨後於減壓下蒸餾將體積降至約430 ml。之後於50-55℃計量加入1公升的第 三丁基甲醚，然後將混合物冷卻至0-5℃。將產物過濾分離，以第三丁基甲基醚沖洗並於60℃乾燥箱中乾燥。
產率：273 g(86%之理論值)
熔點：188±3℃
類似實例2及3，製備出1-[(3-甲基異喹啉-1-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-((R)-3-胺基六氫吡啶-1-基)-黄嘌呤。

Claims (7)

  1. 一種下列通式之化合物或其對掌異構物或鹽類， 其中R1為苯基羰基甲基、苯甲基、萘基甲基、吡啶基甲基、嘧啶基甲基、喹啉基甲基、異喹啉基甲基、喹唑啉基甲基、喹啉基甲基、萘啶基甲基或啡啶基甲基，其中芳香或雜芳香基團係各自經Ra單或雙取代，而其取代基可為相同或不同，及Ra為氫、氟、氯或溴原子或氰基、甲基、三氟甲基、乙基、苯基、甲氧基、二氟甲氧基、三氟甲氧基或乙氧基，或二個Ra基，當與相鄰的碳原子鍵結時，亦可為-O-CH2-O-或-O-CH2-CH2-O-基，R2為甲基、乙基、丙基、異丙基、環丙基或苯基及R3為2-丁烯-1-基、3-甲基-2-丁烯-1-基、2-丁炔-1-基、2-氟苯甲基、2-氯苯甲基、2-溴苯甲基、2-碘苯甲基、2-甲基苯甲基、2-(三氟甲基)苯甲基或2-氰基苯甲基，該化合物係藉由下列合成步驟獲得：a)將通式(III)之化合物 其中X為離去基，其係選自鹵素或磺醯酯，及R1至R3各係如上述之定義，與3-(酞醯亞胺基)六氫吡啶或其對掌異構物反應，b)將得到的通式(II)化合物去保護 其中R1至R3各係如上述之定義，及c)視需要轉變為生理上可耐受之鹽類。
  2. 如請求項1之化合物，其中X為氯或溴原子，R1為苯基羰基甲基、苯甲基、萘基甲基、吡啶基甲基、嘧啶基甲基、喹啉基甲基、異喹啉基甲基、喹唑啉基甲基、喹啉基甲基或萘啶基甲基，其中芳香或雜芳香基團係各自經Ra單或雙取代，而其取代基可為相同或不同，及 Ra為氫、氟或氯原子或氰基、甲基、乙基、甲氧基或乙氧基，R2為甲基、乙基、丙基、異丙基、環丙基或苯基及R3為2-丁烯-1-基、3-甲基-2-丁烯-1-基、2-丁炔-1-基、2-氟苯甲基、2-氯苯甲基、2-溴苯甲基、2-碘苯甲基、2-甲基苯甲基、2-(三氟甲基)苯甲基或2-氰基苯甲基。
  3. 如請求項2之化合物，其中X為氯或溴原子R1為氰基苯甲基、(氰基吡啶基)甲基、喹啉基甲基、(甲基喹啉基)甲基、異喹啉基甲基、(甲基異喹啉基)甲基、喹唑啉基甲基、(甲基喹唑啉基)甲基、喹啉甲基、(甲基喹啉基)甲基、(二甲基喹啉基)甲基或萘啶基甲基，R2為甲基、環丙基或苯基及R3為2-丁烯-1-基、3-甲基-2-丁烯-1-基、2-丁炔-1-基、2-氯苯甲基、2-溴苯甲基或2-氰基苯甲基。
  4. 如請求項3之化合物，其中X為溴原子，R1為(4-甲基喹唑啉-2-基)甲基、(3-甲基異喹啉-1-基)甲基或(3-氰基吡啶-2-基)甲基，R2為甲基及R3為2-丁炔-1-基。
  5. 如請求項1至4中任一項之化合物，其中(R)-3-(酞醯亞胺 基)六氫吡啶係用於步驟a)中作為反應物。
  6. 一種醫藥品，其係包含如請求項1至5中任一項之化合物及視需要一或多種惰性載劑及/或稀釋劑。
  7. 一種如請求項1至5中任一項之化合物之用途，其係用於製造適合供治療第I型及第II型糖尿病、前糖尿病癥兆或低葡萄糖耐受、關節炎、肥胖症、同種異體移植及降鈣素引起的骨質疏鬆症之醫藥品。
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