TWI838114B - 黑皮質素-4受體激動劑在預防或治療罕見遺傳性肥胖中的用途 - Google Patents
黑皮質素-4受體激動劑在預防或治療罕見遺傳性肥胖中的用途 Download PDFInfo
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- TWI838114B TWI838114B TW112104117A TW112104117A TWI838114B TW I838114 B TWI838114 B TW I838114B TW 112104117 A TW112104117 A TW 112104117A TW 112104117 A TW112104117 A TW 112104117A TW I838114 B TWI838114 B TW I838114B
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- acid
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- pyrrolidine
- pomc
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Abstract
Description
本發明係關於下式1化合物或其醫藥上可接受的鹽在預防或治療罕見遺傳性肥胖上的用途,特別是與前腦啡黑細胞促素皮促素(proopiomelanocortin,POMC)缺乏相關的罕見遺傳性肥胖:
其中,R1係C2-C5烷基。
黑皮質素受體(MCR)係一種G蛋白耦合受體(GPCR),且G蛋白的主要角色係活化第二信使(secondary messenger)及透過訊號傳遞調節細胞對數種生理刺激的反應。到目前為止,已辨識出黑皮質素受體的五種亞型。MC1R主要
在黑色素細胞及巨噬細胞中表現,並藉由調節黑色素細胞中的黑色素來決定皮膚及毛髮的顏色。MC2R表現於腎上腺及脂肪組織中,且其在腎上腺中藉由腎上腺皮質激素對腎上腺素分泌調節的介導功能係習知的。MC3R、MC4R及MC5R不僅表現於神經末端,亦表現於腦中,且因此了解其係藉由黑皮質素胜肽介導中樞神經作用,其以對行為、學習、記憶、食慾、及神經的產生及再生的影響來表現。到目前為止,已知MC3R涉及勃起功能障礙及發炎反應,及已知MC4R涉及肥胖及糖尿病,且對各受體的作用特定性的研究係積極地進行(MacNeil DJ et al.,Eur J Pharmacol 2002,450,93)。因此,發現MC4R係深度地涉及在患有肥胖者的遺傳性研究中,且藉由顯示移除MC4R之基因剔除小鼠藉由過量進食而發生肥胖來證明此受體在食慾調節中扮演重要角色(Lu D,Willard D et al.,Nature 1994,371(6500),799;Huszar D et al.,Cell 1997,88(1),131;Hinney A et al.,J Clin Endocrinol Metab 1990,84(4),1483)。
同時,作為先前發展的抗肥胖藥物,作用在中樞神經系統的食慾抑止劑係主要的種類。在其中,控制神經傳導物質作用的藥物(例如,芬特明(phentermine)、嗎吲哚(mazindol)、洛卡西林(lorcaserin)、氟西汀(fluoxetine)、及西布曲明(sibutramine))最多地被使用。然而,神經傳導物質調節劑藉由許多亞型受體除了食慾抑止外,還對多種生理作用發揮廣泛的影響。因此,該等調控劑缺乏對各亞型之選擇性,且具有在長期投予的情況下伴隨有多種副作用的巨大缺點。另一方面,黑皮質素激動劑係神經胜肽而非神經傳導物質,且考量到在MC4R基因剔除(KO)小鼠中除了能量代謝以外的所有其他功能皆正常,黑皮質素激動劑因可僅誘發透過食慾抑止的重量減輕而不影響其他生理功能而具有作為作用點的優點。
本發明意欲提供下式1化合物或其醫藥上可接受的鹽在預防或治療罕見遺傳性肥胖上的用途,特別是與前腦啡黑細胞促素皮促素(POMC)缺乏相關的罕見遺傳性肥胖:
其中,R1係C2-C5烷基。
本發明提供一種用於預防或治療與前腦啡黑細胞促素皮促素(POMC)缺乏相關的罕見遺傳性肥胖的藥物,其包含一種治療有效量之下式1化合物或其醫藥上可接受的鹽:
其中,R1係C2-C5烷基。
此外,本發明提供一種用於預防或治療與前腦啡黑細胞促素皮促素(POMC)缺乏相關的罕見遺傳性肥胖的醫藥組成物,其包含治療有效量之式1化合物或其醫藥上可接受的鹽、伴隨醫藥上可接受的載體。
此外,本發明提供一種用於預防或治療與前腦啡黑細胞促素皮促素(POMC)缺乏相關的罕見遺傳性肥胖的方法,其包含對有需要的對象投予治療有效量的式1化合物或其醫藥上可接受的鹽。
此外,本發明提供式1化合物或其醫藥上可接受的鹽在預防或治療與前腦啡黑細胞促素皮促素(POMC)缺乏相關的罕見遺傳性肥胖的用途。
本發明係詳述於後。
根據本發明之一態樣,提供一種用於預防或治療與前腦啡黑細胞促素皮促素(POMC)缺乏相關的罕見遺傳性肥胖的藥物,其包含治療有效量之式1化合物或其醫藥上可接受的鹽。
根據本發明之另一態樣,提供一種用於預防或治療與前腦啡黑細胞促素皮促素(POMC)缺乏相關的罕見遺傳性肥胖的醫藥組成物,其包含治療有效量的式1化合物或其醫藥上可接受的鹽、伴隨醫藥上可接受的載體。
在根據本發明之一實施態樣中,式1化合物係下式2之N-((3S,5S)-1-((3S,4R)-1-(第三-丁基)-4-(4-氯苯基)吡咯啶-3-羰基)-5-(嗎啉-4-羰基)吡咯啶-3-基)-N-((1s,4R)-4-甲基環己基)異丁醯胺:
在根據本發明的另一實施態樣中,醫藥上可接受的鹽的例子包括藉由無機酸(諸如鹽酸、硫酸、硝酸、磷酸、氫溴酸、及氫碘酸);有機酸(諸如酒石酸、甲酸、檸檬酸、乙酸、三氯乙酸、三氟乙酸、葡萄糖酸、苯甲酸、乳酸、反丁烯二酸、及順丁烯二酸);及磺酸(諸如甲磺酸、苯磺酸、對甲苯磺酸、及萘磺酸)而形成的酸加成鹽,但不限於此。在根據本發明之另一實施態樣中,醫藥上可接受的鹽可選自由以下所組成之群組:鹽酸、硫酸、硝酸、磷酸、氫溴酸、及氫碘酸。在根據本發明之另一實施態樣中,醫藥上可接受的鹽係鹽酸鹽。
在根據本發明之另一實施態樣中,式1化合物的鹽酸鹽可根據以下反應方案1來製備。然而,所屬技術領域中具通常知識者可基於式1的結構藉由多種方法製備式1化合物。
在反應方案1中,
R2係C1-C5烷基;
R3係未經取代或經1或2個C1-C5烷基取代的C3-C8環烷基;及
R4及R5各獨立地係氫或鹵素。
根據本發明,式1化合物可有效地預防或治療與前腦啡黑細胞促素皮促素(POMC)缺乏相關的罕見遺傳性肥胖。前腦啡黑細胞促素皮促素(POMC)係具有241個胺基酸殘基的前驅物多胜肽,於腦下腺之前葉及中葉中合成,且對數種胜肽荷爾蒙(諸如黑色素細胞刺激素(MSH)、腦內啡、及腎上腺皮質激素(激腎上腺皮質素))扮演前驅物的角色。α-MSH係一種黑皮質素-4受體(MC4R)的配體,其扮演MC4R的上游。當Pomc基因編碼之α-MSH缺乏且α-MSH並未正常表現,其可導致嚴重早發性肥胖。
在根據本發明之另一實施態樣中,對各個對象之「治療有效量
(therapeutically effective amount)」意指足以達到上述醫藥功效(即,上述治療功效)的量。化合物的量可依對象的狀況及嚴重性、投予的模式、及將要治療之對象的年齡而變化,但可由所屬技術領域中具通常知識者基於其知識來判定。
在根據本發明之另一實施態樣中,式1化合物之治療有效劑量係例如:根據投予之頻率及強度,一般在每天約0.1至500mg之範圍內。對成人肌肉內或靜脈內投予之一般每日劑量係在每日約0.1至300mg之範圍內,其可以分開之單位劑量投予。一些患者可能需要更高的每日劑量。
在本發明中,「醫藥組成物(pharmaceutical composition)」如果需要可包括除了本發明活性成分以外的其他組分,諸如載體、稀釋劑、賦形劑、或其組合。因此,如果需要,醫藥組成物可包括醫藥上可接受的載體、稀釋劑、賦形劑、或其組合。醫藥組成物促進化合物投予至體內。多種用於投予化合物的方法包括但不限於,口服、注射、氣溶膠、腸胃外、及局部投予。
於本文,「載體(carrier)」意指促進化合物添加進細胞或組織中的化合物。例如,二甲基亞碸(DMSO)係一種促進許多有機化合物投予進活細胞或組織中的習用載體。
於本文,「稀釋劑(diluent)」意指一化合物,其不僅穩定生物活性型態,也稀釋溶解化合物的溶劑。於緩衝液中溶解的鹽在本領域中用作稀釋劑。習用緩衝液係磷酸鹽緩衝鹽水,其模仿體液中的鹽型態。由於緩衝液溶液可以在低濃度下控制溶液的pH,緩衝稀釋劑幾乎不會修改化合物的生物活性。
於本文,「醫藥上可接受的(pharmaceutically acceptable)」意指該等不會妨害化合物之生物活性及物理性質的性質。
根據本發明之化合物可作為多種醫藥投予之劑型來調配。在本發
明之醫藥組成物之製備中,活性組分(特別是式1化合物或其醫藥上可接受的鹽)係與選用的醫藥上可接受之載體混合,該載體係考量所要製備之劑型來選用。例如,本發明之醫藥組成物可視需要調配為注射劑、口服製備品、及諸如此類。
本發明之化合物可藉由習用方法使用已知醫藥載體及賦形劑來調配,並添入一單位或多單位容器中。調配物可係溶液、懸浮液、或於油或水性溶劑中的乳劑,並包括習用分散劑、懸浮劑、或穩定劑。此外,化合物可係例如乾燥粉末形式,其於使用前溶解於滅菌之無熱源水中。本發明之化合物可藉由使用習用栓劑基底(諸如可可脂或其他甘油酯)調配為栓劑。用於口服投予之固體型態包括膠囊、錠劑、丸劑、粉末、及顆粒。較佳係膠囊及錠劑。錠劑及丸劑較佳係經腸衣塗覆。固體型態係藉由混合本發明化合物與至少一選自惰性稀釋劑(諸如蔗糖、乳糖或澱粉)、潤滑劑(諸如硬脂酸鎂)、崩散劑、黏合劑、及諸如此類之載體來製造。此外,其可被調配為經皮劑型,例如,作為洗劑、軟膏、凝膠、乳霜、貼片、或噴劑。
於本文,術語「預防(prevention)」指降低或消除罹患疾病之可能性。
於本文,術語「治療(treatment)」係用於意指於展現疾病症狀的對象中阻止、延緩、或改善疾病的進程。
根據本發明之藥物或醫藥組成物可有效的預防或治療與黑皮質素-4受體(MC4R)路徑相關的罕見遺傳性肥胖,特別是與前腦啡黑細胞促素皮促素(POMC)缺乏相關的罕見遺傳性肥胖。
圖1係表示於高脂飲食(HFD)之POMC異型組合缺失(heterozygous deficient)小鼠模型中測量抗肥胖功效之結果的圖。
圖2係表示於高脂飲食(HFD)之POMC同型組合缺失(homozygous deficient)小鼠模型中測量抗肥胖功效之結果的圖。
於後文,本發明係以以下實施例更詳盡的說明。然而,應了解本發明之保護範圍不被實施例所限制。
製備實施例:N-((3S,5S)-1-((3S,4R)-1-(第三-丁基)-4-(4-氯苯基)吡咯啶-3-羰基)-5-(嗎啉-4-羰基)吡咯啶-3-基)-N-((1s,4R)-4-甲基環己基)異丁醯胺鹽酸鹽之合成
題述化合物係通過步驟A、B、C、及D來得到。
步驟A:甲基(2S,4S)-1-((3S,4R)-1-(第三-丁基)-4-(4-氯苯基)吡咯啶-3-羰基)-4-(N-((1s,4R)-4-甲基環己基)異丁醯胺)吡咯啶-2-羧酸酯之製備
將甲基(2S,4S)-4-(N-((1s,4R)-4-甲基環己基)異丁醯胺)吡咯啶-2-羧酸酯鹽酸鹽(28.7g,82.73mmol)、(3S,4R)-1-(第三-丁基)-4-(4-氯苯基)吡咯啶-3-羧酸(24.5g,86.87mmol)、1-(3-二甲基胺基丙基)-3-乙基碳二亞胺鹽酸鹽(22.2
g,115.83mmol)、及1-羥基苯并三唑水合物(15.7g,115.83mmol)溶解於N,N’-二甲基甲醯胺(400mL)中,並緩慢地添加N,N'-二異丙基乙基胺(72.0mL,413.66mmol)。於室溫下攪拌16小時後,將反應溶劑在減壓下濃縮,接著添加0.5N水性氫氧化鈉溶液,並以乙酸乙酯進行二次萃取。以水性氯化鈉溶液及水洗滌有機層二次,以無水硫酸鎂乾燥,並過濾。將過濾物在減壓下濃縮,並藉由管柱層析法純化,以得到題述化合物(41.19g,87%)。
MS[M+H]=575(M+1)。
步驟B:(2S,4S)-1-((3S,4R)-1-(第三-丁基)-4-(4-氯苯基)吡咯啶-3-羰基)-4-(N-((1s,4R)-4-甲基環己基)異丁醯胺)吡咯啶-2-羧酸之製備
將得自步驟A之甲基(2S,4S)-1-((3S,4R)-1-(第三-丁基)-4-(4-氯苯基)吡咯啶-3-羰基)-4-(N-((1s,4R)-4-甲基環己基)異丁醯胺)吡咯啶-2-羧酸酯(39.4g,68.62mmol)溶解在甲醇(450mL)中,並添加6N水性氫氧化鈉溶液(57.2mL,343.09mmol)。於室溫下攪拌16小時並以6N水性鹽酸溶液調整pH至約5後,將反應溶液在減壓下濃縮。將濃縮物溶解於二氯甲烷中,接著以濾紙過濾不溶固體。過濾物在減壓下濃縮以獲得粗產物(38.4g,99%),其未經純化即用於下一步驟中。
MS[M+H]=561(M+1)。
步驟C:N-((3S,5S)-1-((3S,4R)-1-(第三-丁基)-4-(4-氯苯基)吡咯啶-3-羰基)-5-(嗎啉-4-羰基)吡咯啶-3-基)-N-((1s,4R)-4-甲基環己基)異丁醯胺之製備
將得自步驟B之(2S,4S)-1-((3S,4R)-1-(第三-丁基)-4-(4-氯苯基)吡咯啶-3-羰基)-4-(N-((1s,4R)-4-甲基環己基)異丁醯胺)吡咯啶-2-羧酸(38.4g,68.60mmol)、1-(3-二甲基胺基丙基)-3-乙基碳二亞胺鹽酸鹽(18.4g,96.04mmol)、及
1-羥基苯并三唑水合物(13.0g,96.04mmol)溶解於N,N'-二甲基甲醯胺(200mL)中,並依序緩慢地添加嗎啉(5.9mL,68.80mmol)及N,N'-二異丙基乙基胺(59.7mL,343.02mmol)。在室溫下攪拌16小時後,將反應溶液在減壓下濃縮,添加0.5N水性氫氧化鈉溶液,並以乙酸乙酯進行二次萃取。以水性氯化鈉溶液及水洗滌有機層二次,以無水硫酸鎂乾燥,並過濾。將過濾物在減壓下濃縮,並藉由管柱層析法純化,以得到題述化合物(37.05g,86%)。
MS[M+H]=630(M+1)。
步驟D:N-((3S,5S)-1-((3S,4R)-1-(第三-丁基)-4-(4-氯苯基)吡咯啶-3-羰基)-5-(嗎啉-4-羰基)吡咯啶-3-基)-N-((1s,4R)-4-甲基環己基)異丁醯胺鹽酸鹽之製備
將得自步驟C之N-((3S,5S)-1-((3S,4R)-1-(第三-丁基)-4-(4-氯苯基)吡咯啶-3-羰基)-5-(嗎啉-4-羰基)吡咯啶-3-基)-N-((1s,4R)-4-甲基環己基)異丁醯胺(5.0g,7.95mmol)溶解於乙酸乙酯(50mL)中,並緩慢添加2N鹽酸乙酸乙酯溶液(3.97mL,15.89mmol)。在室溫下攪拌30分鐘後,將反應溶劑在減壓下濃縮。將所得粗固體藉由使用己烷及二乙醚研磨來純化,以獲得題述化合物(5.23g,99%)。
MS[M+H]=630(M+1)。
1H NMR(500MHz,CD3OD)δ 7.49-7.44(m,4H),4.83(m,1H),4.23-4.20(m,1H),3.95-3.91(m,2H),3.79-3.47(m,14H),3.03-3.00(m,1H),2.86-2.82(m,1H),2.73-2.67(m,1H),2.20-2.14(m,1H),1.97(m,1H),1.80-1.62(m,5H),1.50(s,9H),1.44-1.27(m,3H),1.06-1.04(m,9H)。
實施例:Pomc剔除小鼠模型實驗
前腦啡黑細胞促素皮促素(POMC)係α-MSH之前驅物多胜肽,其係黑皮質素-4受體(MC4R)的配體,且扮演黑皮質素-4受體的上游。Pomc基因剔除小鼠(於其中此前腦啡黑細胞促素皮促素蛋白質並未適當地表現)係反映POMC缺乏肥胖之模型,該POMC缺乏肥胖係遺傳性肥胖疾病。且此小鼠展現與不正常的代謝疾病相關的表型,諸如過食症及嚴重肥胖。
為了確認抗肥胖功效,將得自製備實施例之N-((3S,5S)-1-((3S,4R)-1-(第三-丁基)-4-(4-氯苯基)吡咯啶-3-羰基)-5-(嗎啉-4-羰基)吡咯啶-3-基)-N-((1s,4R)-4-甲基環己基)異丁醯胺鹽酸鹽(此後稱作「測試化合物」)以10mg/kg或30mg/kg之劑量投予約3週,同時餵食60kcal%之高脂飲食(具有60kcal%之脂肪的飲食)至Pomc異型組合基因剔除小鼠,於該小鼠中編碼前腦啡黑細胞促素皮促素(POMC)之Pomc基因並未正常地表現。結果係顯示於圖1。
為確認抗肥胖功效,將測試化合物以10mg/kg或30mg/kg之劑量投予約10天,同時餵食45kcal%之高脂飲食(具有45kcal%之脂肪的飲食)至Pomc同型組合基因剔除小鼠,於該小鼠中編碼前腦啡黑細胞促素皮促素(POMC)之Pomc基因並未表現。結果係顯示於圖2。
如圖1及2所示,已確認根據本發明之測試化合物顯示優異的抗肥胖效果。
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期刊 Peter Kühnen, M.D., et al., Proopiomelanocortin Deficiency Treated with a Melanocortin-4 Receptor Agonist, N Engl J Med, 375:240-246, 2016/07/21。 |
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