TW202225161A - 黑皮質素受體促效劑化合物的晶形ⅲ及其製備方法 - Google Patents
黑皮質素受體促效劑化合物的晶形ⅲ及其製備方法 Download PDFInfo
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Abstract
本發明係關於式1所示之晶形III、製備彼之方法以及包含彼之醫藥組成物。本發明的式1所示之晶形III可由XRD圖案、DSC曲線及/或TGA曲線特徵化。
Description
本發明有關對黑皮質素受體展現優異的促效活性之新穎化合物的晶形III、用於製備彼之方法以及包含彼之醫藥組成物。
相關申請案的交叉參照
本申請案主張基於在2020年10月29日提出申請之韓國專利申請案第10-2020-0142398號之優先權的權益,茲將該案之全部揭示內容納入作為說明書之部分。
瘦素蛋白為脂肪細胞所分泌的一種激素,且其分泌量隨著體脂肪含量的增加而增加。瘦素蛋白調節下視丘產生的各種神經肽的功能,從而調節各種體內功能,包括食慾、體脂肪含量以及能量代謝(Schwartz, et al., Nature 404, 661-671(2000))。用於控制食慾和體重的瘦素蛋白訊號轉導為通過許多下游因子的調節進行,其最具代表性者為黑皮質素、刺鼠相關肽(agouti-related peptide, AgRP)以及神經肽Y(neuropeptide Y, NPY)激素。
當血液中瘦素的濃度由於體內卡路里過剩而增加時,腦下垂體分泌的前腦啡黑細胞促素皮促素(proopiomelanocortin, POMC)蛋白激素增加且AgRP和NPY的產生減少。一種小肽激素,α-黑色素細胞刺激素(alpha-melanocyte-stimulating hormone, MSH),是由POMC神經元所產生。該激素為二級神經元之黑皮質素-4受體(melanocortin-4 receptor, MC4R)的促效劑,且最終誘發食慾下降。同時,當由於卡路里缺乏而減少瘦素濃度時,AgRP(一種MC4R拮抗劑)的表現增加,且NPY的表現也增加,最終促進食慾。亦即,根據瘦素的變化,α-MSH激素和AgRP激素作為MC4R的促效劑和拮抗劑,且因此涉及食慾控制。
除了MC4R以外,α-MSH激素還結合三種MCR亞型以誘發各種生理反應。到目前為止,已識別出五種MCR亞型。其中,MC1R主要在皮膚細胞中表現,且涉及調節黑色素形成(皮膚色素形成)。MC2R主要在腎上腺中表現,且已知涉及糖皮質素激素的產生。其配體僅為衍生自POMC的促腎上腺皮質激素(adrenocorticotropic hormone, ACTH)。MC3R和MC4R主要在中樞神經系統中表現,涉及調節食慾、能量代謝以及體內脂肪儲存效率,而在各種組織中表現的MC5R已知會調節外分泌功能(Wikberg, et al., Pharm Res 42(5)393-420(2000))。特別地,MC4R受體的活化誘發食慾減少和能量代謝增加,且因此具有有效率地減輕體重的效果。因此,MC4R受體已被證明為開發抗肥胖藥物的主要作用點(Review: Wikberg, Eur. J. Pharmacol 375, 295-310(1999));Wikberg, et al., Pharm Res 42(5)393-420(2000);Douglas et al., Eur J Pharm 450, 93-109(2002);O'Rahilly et al., Nature Med 10, 351-352(2004))。
MC4R在控制食慾和體重中的角色主要通過在異常表現刺鼠蛋白的動物模式(刺鼠)中進行的實驗來證明。在刺鼠的情況下,發現了由於基因突變,刺鼠蛋白在中樞神經系統中以高濃度表現,且在下視丘中作為MC4R的拮抗劑而引起肥胖(Yen, TT et al ., FASEB J. 8, 479-488(1994);Lu D., et al. Nature 371, 799-802(1994))。後續研究結果顯示與實際刺鼠蛋白相似的刺鼠相關肽(AgRP)在下視丘神經中表現,且此等也已知為MC4R的拮抗劑並涉及控制食慾(Shutter, et al., Genes Dev., 11, 593-602(1997);Ollman, et al. Science 278, 135-138(1997))。
向動物腦內投藥α-MSH(其為一種體內MC4R促效劑)導致降低食慾的效果。當用SHU9119(肽)或HS014(肽)(其等為MC4R拮抗劑)治療動物時,觀察到食慾再次增加(Kask et al., Biochem. Biophys. Res. Comm. 245, 90-93(1998))。此外,在使用美拉諾坦(Melanotan)II(MTII, Ac-Nle-c[Asp-His-DPhe-Arg-Trp-Lys]-NH2)及其類似促效劑HP228的動物研究中,在腦內、腹膜內或皮下投藥後,發現抑制食慾、降低體重、增加能量代謝等之效率。(Thiele T. E., et al. Am J Physiol 274(1 Pt 2), R248-54(1998);Lee M. D., et al. FASEB J 12, A552(1998);Murphy B., et al. J Appl Physiol 89, 273-82(2000))。相反地,向動物投藥代表性SHU9119顯示顯著且持續的攝食量和體重增加,這為MCR促效劑可能為抗肥胖劑提供了藥理學證據。在MC4R剔除(knock-out, KO)小鼠中未觀察到在投藥MTII後明顯展現的降低食慾的效果。此實驗結果再次證明降低食慾的效果主要通過活化MC4R來達成(Marsh, et al., Nat Genet 21, 119-122(1999))。
作用於中樞神經系統的食欲抑制劑為到目前為止開發的主要類型的抗肥胖藥物。其中,大多數為調節神經傳導物作用的藥物。實例包括正腎上腺素劑(芬特明(phentermine)和馬吲哚(mazindol))、血清基能
(serotonergic)劑、氟西汀(fluoxetine)以及西布曲明
(sibutramine)等。然而,除了食慾抑制以外,神經傳導物調節劑還具有通過眾多亞型受體對各種生理作用有範圍廣泛的效果。據此,調節劑缺乏對各亞型的選擇性,且因此所具主要缺點在於長期投藥時伴隨著各種副作用。
另一方面,黑皮質素促效劑為神經肽,而不為神經傳導物。鑑於在MC4R基因KO小鼠中,能量代謝以外的所有功能均正常,黑皮質素促效劑所具作為作用點的優點在於可僅通過食慾抑制來誘發體重減輕而不影響其他生理功能。特別地,受體為屬於到目前為止開發的最成功的新藥作用點類別之G蛋白偶聯受體(G-protein coupled receptor, GPCR)。因此,該作用點與現有作用點有很大的不同,在於其相對容易確保對亞型受體的選擇性。
至於利用黑皮質素受體作為作用點的實例,國際公開案第WO 2008/007930和WO 2010/056022號揭露作為黑皮質素受體之促效劑的化合物。
此外,本發明的發明人已進行了廣泛的研究,並發明了具有對黑皮質素受體(特別為黑皮質素-4受體(MC4R))有選擇性的優異促效活性的下式1之新穎化合物及用於製備彼之方法(申請案第KR 10-2019-0141649號(在2019年11月7日提出申請)):
其中R
1為C
2-C
5烷基。
同時,醫藥上活性成分之晶體結構經常影響藥物的化學穩定性。不同的結晶條件和儲存條件可導致化合物的晶體結構的變化,且有時伴隨其他晶形的產生。一般來說,非晶形藥品不具有規則的晶體結構,且經常存在,諸如,產品穩定性差、粒徑較小、過濾困難、易結塊、以及流動性差之缺陷。因此,有必要改良產品的各種物理性質。因此,有必要研究單一化合物之具有高純度和良好化學穩定性的晶體結構。
[先前技術文件]
[專利文件]
(專利文件1)國際專利申請公開案第WO 2008/ 007930號
(專利文件2)國際專利申請公開案第WO 2010/ 056022號
技術問題
本發明的一個態樣提供具有對黑皮質素受體(特別為黑皮質素-4受體(MC4R))有選擇性的優異促效活性之新穎化合物的穩定晶形及用於製備彼之方法。
本發明的另一個態樣提供醫藥組成物,其包含新穎化合物的穩定晶形。
技術方案
根據本發明的一個態樣,提供了一種下式1之化合物、其醫藥上可接受之鹽或溶劑化物的晶形III,其中X射線粉末繞射圖案具有3個或更多個、5個或更多個、7個或更多個、9個或更多個、或10個或更多個選自具有以下繞射角(2θ值)之峰中的特徵峰:6.62±0.2°、7.44±0.2°、9.18±0.2°、9.89±0.2°、10.83±0.2°、11.42±0.2°、12.92± 0.2°、14.61±0.2°、15.36±0.2°、15.79±0.2°、15.95±0.2°、17.37±0.2°、18.20±0.2°、18.99±0.2°、19.34±0.2°、19.69±0.2°、20.40±0.2°、21.66±0.2°、21.98±0.2°、22.45±0.2°、22.85±0.2°、24.66±0.2°、25.52±0.2°、26.55±0.2°、28.08±0.2°、29.31±0.2°以及29.54±0.2°,
其中R
1為C
2-C
5烷基。
由於式1之化合物可具有不對稱碳中心和不對稱軸或不對稱平面,其可以順式或反式異構物、R或S異構物、外消旋體、非鏡像異構物混合物以及單個非鏡像異構物存在,其等皆在式1之化合物的範疇內。
在本說明書中,除非為方便起見另有詳細說明,式1之化合物用以包括所有式1之化合物、其醫藥上可接受之鹽、異構物以及溶劑化物。
在根據本發明的一個具體例中,在式1中,R
1為C
2至C
5烷基。在根據本發明的另一個具體例中,在式1中,R
1為直鏈或支鏈C
2至C
5烷基,例如,乙基、正丙基、異丙基、正丁基、異丁基、二級丁基、或三級丁基。
在根據本發明的另一個具體例中,在式1中,R
1為C
2或C
3烷基。在根據本發明的另一個具體例中,式1中,R
1為直鏈或支鏈C
2或C
3烷基,例如,乙基、正丙基或異丙基。
在根據本發明的一個具體例中,醫藥上可接受之鹽包括,但不限於,由無機酸形成之酸加成鹽類,諸如,鹽酸、硫酸、硝酸、磷酸、氫溴酸以及氫碘酸;有機碳酸類,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、富馬酸、馬來酸等;或磺酸類,諸如,甲磺酸、苯磺酸、對甲苯磺酸或萘磺酸。
在根據本發明的一個具體例中,溶劑化物可包括水合物;以及與有機溶劑(諸如,甲醇、乙醇、2-丙醇、1,2-丙二醇、1,3-丙二醇、正丁醇、1,4-丁二醇、三級丁醇、乙酸、丙酮、乙酸丁酯、乙酸甲酯、乙酸乙酯、乙酸丙酯、乙酸三級丁酯、乙酸異丁酯、甲基乙基酮、2-戊酮、四氫呋喃、乙腈、氯仿、甲苯及其混合物)之溶劑化物。
在根據本發明的一個具體例中,晶形III可為式1之化合物的醫藥上可接受之鹽的晶形。
式1之化合物的醫藥上可接受之鹽可為下式2之鹽酸鹽化合物:
其中R
2為C
2-C
5烷基。
在根據本發明的另一個具體例中,式1之化合物的醫藥上可接受之鹽可為
N-((3
S,5
S)-1-((3
S,4
R)-1-(三級丁基)-4-(4-氯苯基)吡咯啶-3-羰基)-5-(嗎啉-4-羰基)吡咯啶-3-基)-N-((1
s,4
R)-4-甲基環己基)異丁醯胺鹽酸鹽。
在根據本發明的另一個具體例中,晶形III可為溶劑化物的晶形,具體為式1之化合物的醫藥上可接受之鹽的水合物。
更具體地,晶形III可為式1之化合物的鹽酸鹽(hydrochloride salt)之水合物的晶形。
在根據本發明的一個具體例中,晶形III可為下式4之化合物的晶形。
根據本發明的晶形III顯示3個或更多個、5個或更多個、7個或更多個、9個或更多個、或10個或更多個選自具有以下2θ值的峰中之特徵峰:如藉由X射線粉末繞射(x-ray powder diffraction, XRD)而分析之6.62±0.2°、7.44±0.2°、9.18±0.2°、9.89±0.2°、10.83±0.2°、11.42±0.2°、12.92±0.2°、14.61±0.2°、15.36±0.2°、15.79±0.2°、15.95±0.2°、17.37±0.2°、18.20±0.2°、18.99±0.2°、19.34±0.2°、19.69±0.2°、20.40±0.2°、21.66±0.2°、21.98±0.2°、22.45±0.2°、22.85±0.2°、24.66±0.2°、25.52±0.2°、26.55±0.2°、28.08±0.2°、29.31±0.2°以及29.54±0.2°。
在根據本發明的一個具體例中,晶形III可具有圖4所示之XRD圖案。
在根據本發明的晶形III之差示掃描量熱法(differential scanning calorimetry, DSC)曲線中,兩個吸熱峰出現在40至170℃處,且由於分解引起的吸熱峰出現在220℃或更高處。
在根據本發明的一個具體例中,晶形III可具有圖5所示之DSC曲線。
在熱重分析(thermogravimetric analysis, TGA)曲線中,當根據本發明的晶形III加熱至160℃或更低的溫度時,可具有15%或更低,例如,1%至15%、1%至10%、5%至10%、或7%的重量損失。
在根據本發明的一個具體例中,晶形III可具有圖6所示之TGA曲線。
穩定性測試結果(HPLC)顯示根據本發明的晶形III在加速條件(40℃,75% RH)和苛刻條件(80℃)下展現化學穩定性4週。因此,可看出根據本發明的晶形III對熱和濕氣呈穩定的。
在本說明書中,X射線繞射(XRD)分析顯示了使用PANalytical X' Pert Pro MPD系統(Malvern
Panalytical Ltd.)進行的結果。
差示掃描量熱法(DSC)分析顯示了使用DSC1(Mettler-Toledo AG)進行的結果。
熱重分析(TGA)顯示了使用TGA/DSC 1 (Mettler-Toledo AG)進行的結果。
穩定性分析顯示了使用HPLC(Agilent Technologies,Inc.)進行的結果。
晶形III可具有比式1之粗化合物、式1之非晶形化合物或式1之化合物的其他晶形更高的純度,且可在物理和化學上更穩定。
式1之化合物的晶形III對黑皮質素-4受體的促效能力和對疾病(諸如,肥胖症、糖尿病、炎症、勃起功能障礙等)的預防或治療作用可比彼等已知的黑皮質素-4受體促效劑所具者更好。然而,本發明的效果不限於此。
在另一個態樣中,本發明提供了一種用於製備晶形III之方法,其包括以下步驟:將式1之化合物溶於結晶溶劑以製備混合溶液;以及從該混合溶液獲得晶體。
首先,將式1所示之化合物溶於結晶溶劑。
用於製備晶形III的式1之化合物可為式1之化合物、其鹽、其異構物或其溶劑化物。
式1之化合物可藉由申請案第KR 10-2019-0141649號(在2019年11月7日提出申請)的說明書中描述的製備方法而獲得。
結晶溶劑可以無特別限制地使用,只要其為用於使化合物結晶的合適溶劑。在一個具體例中,結晶溶劑可包括水和極性非質子有機溶劑之混合物。
極性非質子有機溶劑可包括乙酸乙酯、甲基異丁基酮、二甲基亞碸、四氫呋喃、丙酮、二甲基甲醯胺、乙腈或其混合物。
在根據本發明的一個具體例中,極性非質子有機溶劑可包括乙酸乙酯。
在根據本發明的一個具體例中,結晶溶劑可為其中水和極性非質子有機溶劑以15:1至1:15,具體為10:1至1:10、8:1至1:8、1:1至1:10、1:3至1:8、1:5至1:7、1:6.5至1:6.8或1:6.7之體積比混合之混合溶劑。
對於1 g的式1之化合物而言,可使用0.5至5 mL、0.7至3 mL、0.8至2 mL、0.9至1.5 mL、1至1.5 mL、1.0至1.3 mL或1.15 mL的結晶溶劑。
式1之化合物於結晶溶劑之溶解可在不攪拌或攪拌下,在30至85℃,具體為35至80℃、40至75℃、45至70℃、50至65℃、或60℃下進行。
在根據本發明的一個具體例中,可藉由相對於1 g的式1之化合物使用1 mL的EtOAc和0.15 mL的蒸餾水,而獲得其中式1之化合物已在60℃下溶解之混合溶液。
接下來,該方法包括從其中式1之化合物已溶解之混合溶液獲得晶體之步驟。例如,可藉由冷卻溶液、藉由在溶液中滴加酸以形成析出物、藉由蒸發溶劑、藉由添加用於超飽和之反溶劑、或藉由使用方法(諸如,漿液轉化)等而獲得晶體。
在根據本發明的一個具體例中,結晶步驟可包括冷卻混合溶液。可進行冷卻以使得已滴加酸之混合溶液之溫度變成0℃至5℃。具體地,可進行冷卻以使得混合溶液之溫度變成0℃至3℃。
此外,結晶步驟可包括攪拌混合溶液。攪拌可藉由已知的方式進行,且攪拌時間為,例如,但不限於,15小時至50小時(含邊值),具體為15小時至50小時、15小時至45小時、15小時至40小時、15小時至35小時、20小時至30小時、23小時至28小時、或25小時。
在根據本發明的另一個具體例中,可過濾和洗滌藉由冷卻混合溶液且在保持冷卻之混合溶液之溫度的同時攪拌而形成之析出物,以獲得晶體。
在根據本發明的另一個具體例中,該方法可進一步包括在冷卻之前、之後或同時在混合溶液中添加非極性有機溶劑,或在攪拌混合溶液之前、之後或同時在混合溶液中添加非極性有機溶劑之步驟。獲得之晶形III的產率或生產穩定性可藉由添加非極性有機溶劑以增加結晶粒子的生產速率而改良,但本發明不限於此。非極性有機溶劑可以無特別限制地使用,只要其為具有非極性性質之有機溶劑,例如,可使用己烷、庚烷、環己烷、四氯化碳、苯、氯仿等。在根據本發明的一個具體例中,該方法可包括用於在從混合溶液結晶的過程中,在溶液中添加庚烷之步驟。
如上獲得之晶形III可具有比式1之粗化合物、式1之非晶形化合物或式1之任何其他晶形更高的純度,且可在物理和化學上更穩定。然而,本發明的效果不限於此。
在另一個態樣中,本發明提供一種組成物,其包含:(i)晶形III;以及(ii)醫藥上可接受之載劑。
根據本發明的晶形III對黑皮質素受體(特別為黑皮質素-4受體(MC4R))展現優異的促效作用。因此,本發明可提供一種用於促效黑皮質素受體之醫藥組成物,該組成物含有上述晶形III作為活性成分。具體地,該醫藥組成物可為用於促效黑皮質素-4受體之功能的組成物。
此外,由於該醫藥組成物可展現優異的預防或治療肥胖症、糖尿病、炎症以及勃起功能障礙之效果,其可為用於預防或治療肥胖症、糖尿病、炎症或勃起功能障礙之組成物。然而,本發明的用途不限於該等疾病。
如本文中所用,「載劑」是指一種促進化合物引入細胞或組織之化合物。
當本發明的晶形III用於臨床目的而投藥時,欲以單劑量或分劑量向宿主投藥的總每日劑量較佳可為在0.01至10 mg/kg體重之範圍內。然而,個別患者的具體劑量水平可取決於欲使用之具體化合物、患者的體重、性別、健康狀況、飲食、投藥時間、投藥方法、排泄率、藥物組合、疾病的嚴重程度等而異。
本發明的晶形III可如所欲藉由任何途徑投藥。例如,本發明的非晶形化合物可藉由注射或口服而投藥。
本發明的醫藥組成物可為各種口服劑型(諸如,片劑、丸劑、粉劑、膠囊、粒劑、糖漿或乳劑)或腸胃外劑型(諸如,用於肌內、靜脈內或皮下投藥之注射製劑)。
注射製劑可根據已知技術,使用合適的分散劑、潤濕劑、懸浮劑或賦形劑而製備。
可用於本發明的醫藥製劑之賦形劑包括,但不限於,甜味劑、黏合劑、增溶劑(solubilizer)、助溶劑(solubilizing agent)、潤濕劑、乳化劑、等滲劑、吸附劑、崩解劑、抗氧化劑、防腐劑、潤滑劑、填料、香味等。例如,至於賦形劑,可使用乳糖、右旋糖、蔗糖、甘露醇、山梨糖醇、纖維素、甘胺酸、二氧化矽、矽酸鎂鋁、澱粉、明膠、黃蓍膠、精胺酸、海藻酸鈉、甲基纖維素、羧甲基纖維素鈉、水、乙醇、聚乙二醇、聚乙烯吡咯啶酮、氯化鈉、氯化鈣、橙香精、草莓香精、香草香精等。
當本發明的醫藥組成物為口服劑型時,欲使用之載劑的實例包括,但不限於,纖維素、矽酸鈣、玉米澱粉、乳糖、蔗糖、右旋糖、磷酸鈣、硬脂酸、硬脂酸鎂、硬脂酸鈣、明膠、滑石粉等。
當本發明的醫藥組成物為可注射製劑形式時,載劑的實例可包括,但不限於,水、鹽水、葡萄糖水溶液、糖樣(sugar-like)溶液、醇類、二醇類、醚類、油類、脂肪酸類、脂肪酸酯類、甘油酯類等。
在另一個態樣中,提供了用於促效黑皮質素受體(特別為黑皮質素-4受體(MC4R))的功能的上述晶形III。
在一個具體例中,提供了用於治療或預防肥胖症、糖尿病、炎症或勃起功能障礙的上述晶形III。
在另一個態樣中,提供了一種用於促效黑皮質素受體(特別為黑皮質素-4受體(MC4R))的功能之方法,該方法包括向受試者投藥上述晶形III之步驟。
在另一個態樣中,提供了一種用於治療肥胖症、糖尿病、炎症或勃起功能障礙之方法,該方法包括向受試者投藥上述晶形III之步驟。
有利效果
根據本發明的晶形III對黑皮質素受體(特別為黑皮質素-4受體(MC4R))展現優異的促效作用,且因此可有用地用於預防或治療肥胖症、糖尿病、炎症以及勃起功能障礙。
根據本發明的晶形III對黑皮質素-4受體展現靶向效應(on-target effect),從而在不影響焦慮和抑鬱下展現重量損失和飲食減量的效果。此外,其可在無任何安全問題的情況下投藥,諸如,人類ether-a-go-go相關基因(hERG)抑制或誘變的副作用。
此外,根據本發明的晶形III具有比式1之粗化合物、式1之非晶形化合物或式1之任何其他晶形更為優異的純度、產率、物理以及化學穩定性。
具體地,晶形III可具有比式1之粗化合物、式1之非晶形化合物或式1之任何其他晶形更為優異的溶解性、儲存穩定性和生產穩定性。
後文中,將通過製備例和實施例更詳細地描述本發明。然而,此等實施例僅用於闡釋本發明,且本發明的範疇不限於此。
製備例
1
:
(2
S,4
S)-4-(N-((1
s,4
R)-4-
甲基環己基
)
異丁醯胺基
)
吡咯啶
-2-
羧酸甲酯鹽酸鹽之製備
標題化合物通過以下步驟A、B、C、D以及E獲得。
步驟A:(2S,4S)-4-疊氮基吡咯啶-1,2-二羧酸1-(三級丁基)2-甲酯之製備
將(2S,4R)-4-((甲基磺醯基)氧基)吡咯啶-1,2-二羧酸1-(三級丁基)2-甲酯(48.5 g,150 mmol)在氮氣下溶於N,N'-二甲基甲醯胺(250 ml),且添加疊氮化鈉(19.5 g,300 ml)。在80℃下攪拌16小時之後,在減壓下濃縮反應溶劑,添加水,以及用乙酸乙酯進行萃取兩次。將有機層用氯化鈉水溶液和水洗滌,用無水硫酸鎂乾燥,以及過濾。在減壓下濃縮濾液以獲得粗(2S,4S)-4-疊氮基吡咯啶-1,2-二羧酸1-(三級丁基)2-甲酯(39.59 g,98%),其未經純化即用於下一步驟。
MS [M+H] = 271(M+1)
1H NMR(400 MHz, CD3OD)δ 4.43-4.37(m, 1H), 4.35-4.27(br, 1H), 3.77(s, 1.8H), 3.76(s, 1.2H), 3.73-3.66(m, 1H), 3.44-3.38(m, 1H), 2.63-2.49(m, 1H), 2.19-2.11(m, 1H), 1.50(s, 4.5H), 1.44(s, 4.5H)
步驟B:(2S,4S)-4-胺基吡咯啶-1,2-二羧酸1-(三級丁基)2-甲酯之製備
將以上步驟A中獲得之(2S,4S)-4-疊氮基吡咯啶-1,2-二羧酸1-(三級丁基)2-甲酯(24.59 g,91.0 mmol)溶於四氫呋喃(180 ml),且在0℃下緩慢添加1 M三甲基膦四氫溶液(109.2 ml,109.2 mmol)。在相同溫度下攪拌1小時之後,將混合物在室溫下攪拌3小時。在減壓下濃縮反應溶劑之後,添加二氯甲烷(100 ml)和水(150 ml),以及將混合物攪拌約30分鐘。分層並用二氯甲烷再萃取一次,且將有機層用無水硫酸鎂乾燥並過濾。在減壓下濃縮濾液以獲得粗(2S,4S)-4-胺基吡咯啶-1,2-二羧酸1-(三級丁基)2-甲酯(20.62 g,93%),其未經純化即用於下一步驟。
MS [M+H] = 245(M+1)
1H NMR(400 MHz, CD3OD)δ 4.27(m, 1H), 3.77(s, 1.8H), 3.76(s,1.2H), 3.75-3.67(m, 1H), 3.50-3.42(m, 1H), 3.22-3.17(m, 1H), 2.58-2.47(m,1H), 1.82-1.71(m, 1H), 1.48(s, 4.5H), 1.42(s, 4.5H)
步驟C:(2S,4S)-4-(((1s,4R)-4-甲基環己基)胺基)吡咯啶-1,2-二羧酸1-(三級丁基)2-甲酯之製備
將以上步驟B中獲得之(2S,4S)-4-胺基吡咯啶-1,2-二羧酸1-(三級丁基)2-甲酯(20.62 g,84.4 mmol)溶於二氯乙烷(150 ml),且添加4-甲基環己酮(9.5 ml,101.3 mmol)。在0℃下添加三乙醯氧基硼氫化鈉(26.8 g,126.6 mmol),且將混合物在室溫下攪拌16小時。在減壓下濃縮反應溶劑,添加水,以及用乙酸乙酯進行萃取兩次。將有機層用氯化鈉水溶液洗滌,用無水硫酸鎂乾燥,以及過濾。在減壓下濃縮濾液,且藉由管柱層析術純化以獲得(2S,4S)-4-(((1s,4R)-4-甲基環己基)胺基)吡咯啶-1,2-二羧酸1-(三級丁基)2-甲酯(22.9 g,80%)。
MS [M+H] = 341(M+1)
1H NMR(400 MHz, CD3OD)δ 4.26(m, 1H), 3.76(s, 1.8H), 3.75(s, 1.2H), 3.78-3.71(m, 1H), 3.49-3.40(m, 1H), 3.22-3.16(m, 1H), 2.69-2.60(br, 1H), 2.58-2.46(m, 1H), 1.87-1.77(m, 1H), 1.73-1.63(m, 1H), 1.62-1.35(m, 8H), 1.48(s, 4.5H), 1.42(s, 4.5H), 0.96(d, 3H)
步驟D:(2S,4S)-4-(N-((1s,4R)-4-甲基環己基)異丁醯胺基)吡咯啶-1,2-二羧酸1-(三級丁基)2-甲酯之製備
將以上步驟C中獲得之(2S,4S)-4-(((1s,4R)-4-甲基環己基)胺基)吡咯啶-1,2-二羧酸1-(三級丁基)2-甲酯(37.29 g,109.5 mmol)溶於二氯甲烷(500 ml),添加三乙胺(61.1 ml,438.1 mmol),以及接著在0℃下緩慢添加異丁醯氯(11.7 ml,219 mmol)。在室溫下攪拌16小時之後,在減壓下濃縮反應溶劑,添加碳酸氫鈉水溶液,以及用乙酸乙酯進行萃取兩次。將有機層用氯化鈉水溶液和水洗滌,用無水硫酸鎂乾燥,以及過濾。在減壓下濃縮濾液,且藉由管柱層析術純化以獲得(2S,4S)-4-(N-((1s,4R)-4-甲基環己基)異丁醯胺基)吡咯啶-1,2-二羧酸1-(三級丁基)2-甲酯(38.79 g,86%)。
MS [M+H] = 411(M+1)
1H NMR(400 MHz, CD3OD)δ 4.27(m, 1H), 3.76(s, 1.8H), 3.75(s, 1.2H), 3.78-3.72(m, 1H), 3.50-3.41(m, 1H), 3.33-3.14(m, 1H), 2.69-2.60(m, 2H), 2.57-2.43(m, 1H), 1.87-1.79(m, 1H), 1.70-1.61(m, 1H), 1.60-1.32(m, 8H), 1.47(s, 4.5H), 1.41(s, 4.5H), 1.10(dd, 6H), 0.99(d, 3H)
步驟E:甲基(2S,4S)-4-(N-((1s,4R)-4-甲基環己基)異丁醯胺基)吡咯啶-2-羧酸酯鹽酸鹽之製備
將以上步驟D中獲得之(2S,4S)-4-(N-((1s,4R)-4-甲基環己基)異丁醯胺基)吡咯啶-1,2-二羧酸1-(三級丁基)2-甲酯(34.0 g,82.8 mmol)溶於二氯甲烷(200 ml),且在0℃下添加4 N鹽酸於1,4-二噁烷溶液(82.8 ml,331.3 mmol)之溶液。在室溫下攪拌6小時之後,在減壓下濃縮反應溶劑以獲得粗品(28.7 g,99%),其未經純化即用於下一步驟。
MS[M+H] = 311(M+1)
製備例
2
:
(3S,4R)-1-(
三級丁基
)-4-(4-
氯苯基
)
吡咯啶
-3-
羧酸之製備
標題化合物為根據國際專利公開案第WO 2004/092126號中描述之方法獲得。
MS[ M+H] = 282(M+1)
1 H NMR(400 MHz, CD3OD)δ 7.43-7.33(m, 4H), 3.90-3.69(m, 3H), 3.59(dd, J = 11.2, 10.0 Hz, 1H), 3.29(dd, J = 11.2, 11.2 Hz, 1H), 3.18-3.09(m, 1H), 1.44(s, 9H)
製備例
3
:
N-((3S,5S)-1-((3S,4R)-1-(
三級丁基
)-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
標題化合物通過以下步驟
A
、
B
以及
C
獲得。
步驟 A :(2S,4S)-1-((3S,4R)-1-(三級丁基)-4-(4-氯苯基)吡咯啶-3-羰基)-4-(N-((1s,4R)-4-甲基環己基)異丁醯胺基)吡咯啶-2-羧酸甲酯之製備
將製備例1中獲得之甲基(2S,4S)-4-(N-((1s,4R)-4-甲基環己基)異丁醯胺基)吡咯啶-2-羧酸酯鹽酸鹽(28.7 g,82.73 mmol)、製備例2中獲得之(3S,4R)-1-(三級丁基)-4-(4-氯苯基)吡咯啶-3-羧酸(24.5 g,86.87 mmol)、1-(3-二甲基胺基丙基)-3-乙基碳二亞胺鹽酸鹽(22.2 g,115.83 mmol)以及1-羥基苯并三唑水合物(15.7 g,115.83 mmol)溶於N,N'-二甲基甲醯胺(400 ml)中,且緩慢添加N,N'-二異丙基乙胺(72.0 ml,413.66 mmol)。在室溫下攪拌16小時之後,在減壓下濃縮反應溶劑,添加0.5 N氫氧化鈉水溶液,以及用乙酸乙酯進行萃取兩次。將有機層用氯化鈉水溶液和水洗滌兩次,用無水硫酸鎂乾燥,以及過濾。在減壓下濃縮濾液,且藉由管柱層析術純化以獲得(2S,4S)-1-((3S,4R)-1-(三級丁基)-4-(4-氯苯基)吡咯啶-3-羰基)-4-(N-((1s,4R)-4-甲基環己基)異丁醯胺基)吡咯啶-2-羧酸甲酯(41.19 g,87%)。
MS [M+H] = 575(M+1)
步驟B:(2S,4S)-1-((3S,4R)-1-(三級丁基)-4-(4-氯苯基)吡咯啶-3-羰基)-4-(N-((1s,4R)-4-甲基環己基)異丁醯胺基)吡咯啶-2-羧酸之製備
將以上步驟A中獲得之(2S,4S)-1-((3S,4R)-1-(三級丁基)-4-(4-氯苯基)吡咯啶-3-羰基)-4-(N-((1s,4R)-4-甲基環己基)異丁醯胺基)吡咯啶-2-羧酸甲酯(39.4 g,68.62 mmol)溶於甲醇(450 ml),且接著添加6 N氫氧化鈉水溶液(57.2 ml,343.09 mmol)。在室溫下攪拌16小時且用6 N鹽酸水溶液調節pH至約5之後,在減壓下濃縮反應溶液。在濃縮物溶於二氯甲烷之後,不溶性固體通過濾紙過濾。在減壓下濃縮濾液以獲得粗標題化合物(38.4 g,99%),其未經純化即用於下一步驟。
MS [M+H] = 561(M+1)
步驟C:N-((3S,5S)-1-((3S,4R)-1-(三級丁基)-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
將以上步驟B中獲得之(2S,4S)-1-((3S,4R)-1-(三級丁基)-4-(4-氯苯基)吡咯啶-3-羰基)-4-(N-((1s,4R)-4-甲基環己基)異丁醯胺基)吡咯啶-2-羧酸(38.4 g,68.60 mmol)、1-(3-二甲胺基丙基)-3-乙基碳二亞胺鹽酸鹽(18.4 g,96.04 mmol)以及1-羥基苯并三唑水合物(13.0 g,96.04 mmol)溶於N,N'-二甲基甲醯胺(200 ml),且接著依次且緩慢添加嗎啉(5.9 ml,68.80 mmol)和N,N'-二異丙基乙胺(59.7 ml,343.02 mmol)。在室溫下攪拌16小時之後,在減壓下濃縮反應溶液,添加0.5 N氫氧化鈉水溶液,用乙酸乙酯進行萃取兩次。將有機層用氯化鈉水溶液和水洗滌兩次,用無水硫酸鎂乾燥,以及過濾。在減壓下濃縮濾液,且藉由管柱層析術純化以獲得N-((3S,5S)-1-((3S,4R)-1-(三級丁基)-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(37.05 g,86%)。
MS [M+H] = 630(M+1)
製備例
4
:
N
-((3
S,5
S)-1-((3
S,4R)-1-(
三級丁基
)-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
)
異丁醯胺鹽酸鹽之非晶形化合物之製備
基於1 g的以上製備例3中製備之化合物(MC70),在25℃下用19 mL的MBTE溶解化合物(MC70)。在溶解完成之後,添加1 mL的庚烷,且接著將混合物冷卻至-5至0℃。在達到設定溫度之後,滴加1當量的4 M HCl/EtOAc,攪拌混合物約90分鐘,以及過濾以獲得標題化合物(MC71)。(產率:約90%)
製備例4之化合物的XRD(圖1)、DSC(圖2)以及TGA(圖3)分析結果分別於圖1至3所示。分析結果證實其為非晶形化合物。XRD、DSC以及TGA分析方法各自如以下針對實施例1的實驗例中所述。
實施例
1.
N
-((3
S,5
S)-1-((3
S,4
R)-1-(
三級丁基
)-4-(4-
氯苯基
)
吡咯啶
-3-
羰基
)-5-(
嗎啉
-4-
羰基
)
吡咯啶
-3-
基
)-
N-((1s,4
R)-4-
甲基環己基
)
異丁醯胺鹽酸鹽之水合物的晶形
III
之製備
在60℃下,將1 g的以上製備之製備例4之化合物(MC71)溶於1 mL的EtOAc和0.15 mL的蒸餾水。在溶解完成之後,將混合物冷卻至3℃,並在保持溫度的同時用電子攪拌器攪拌25小時,以及接著在氮壓力下過濾以獲得標題晶形III。(產率:約80%)
比較例
1
在室溫下,將1 g的以上製備之製備例4之化合物(MC71)溶於1 mL的EtOAc。在溶解完成之後,將混合物用電子攪拌器攪拌約43小時,但未獲得與實施例1中相同的晶體。
實驗例
1. XRD
評估
藉由以下方法,將作為固態檢測器之配備有單色化輻射源和Ni過濾器之PANalytical X'Pert Pro MPD系統用以獲得粉末XRD繞射圖案。
在玻璃樣本架中壓緊約20至30 mg的樣本以使得該樣本具有平坦的表面,將裝置之產生器設定為45 kV(加速電壓)和40 mA(燈絲發射),以及接著以反射模式(非旋轉)進行測量。以步階大小為0.026°和每步階之時間為51秒的條件測量在4至40°之範圍內的布勒格角(Bragg angle)(2θ)。
獲得之晶形III的XRD測量結果如圖4所示。
從圖4所示之光譜可看出,根據本發明的晶形III在6.62°、7.44°、9.18°、9.89°、10.83°、11.42°、12.92°、14.61°、15.36°、15.79°、15.95°、17.37°、18.20°、18.99°、19.34°、19.69°、20.40°、21.66°、21.98°、22.45°、22.85°、24.66°、25.52°、26.55°、28.08°、29.31°以及29.54°處展現特徵峰(2θ)。XRD之具體值於下表1所示。
實驗例2.差示掃描量熱法(DSC)
將Mettler Toledo DSC1系統用以測量DSC。秤取2至5 mg的樣本並放入40 μL Al坩堝(平底鋁盤,具有一個針孔蓋),且打出1個針孔。接著,在將樣本以10℃/min的速率從25℃加熱至350℃的同時,進行DSC測量。在測量的過程中,將氮氣以70 mL/min的速率供應至儀器內部,以防止氧氣和其他氣體的流入。將軟體STARe用以進行數據收集和評估。
獲得之晶形III的DSC測量結果於圖5所示。
從圖5可看出,針對晶形III,在約42.3℃(開始)處觀察到第一個吸熱峰,且在約124.7℃(開始)處觀察到第二個吸熱峰。在約220℃之後,出現分解引起之吸熱峰。溫度值具有±5℃的誤差。
實驗例
3.
熱重分析
(TGA)
將Mettler Toledo TGA/DSC 1模組用以測量TGA。秤取約4至8 mg的樣本並放入100 μL鋁坩堝(平底鋁坩堝)。接著,在將以10℃/min的速率從30℃加熱至350℃的同時,進行TGA測量。在測量的過程中,將氮氣以80 mL/min的速率供應至儀器內部,以防止氧氣和其他氣體的流入。將軟體STARe用以進行數據收集和評估。
獲得之晶形III的TGA測量結果於圖6所示。
從圖6可看出,針對晶形III,在低於100℃的溫度下觀察到約2.4%的重量損失。之後,在110至150℃下發生約4.8%之重量損失。在約220℃之後,發生分解引起之重量損失。溫度值具有±5℃的誤差。
實驗例
4.
穩定性評估
將約10至30 mg的樣本在加速條件(40℃,75% RH)下的開放狀態中或在80℃的烘箱中之苛刻條件下的密封狀態中儲存4週。為了將該樣本與在室溫下儲存的樣本進行比較,藉由於下表2所示之方法進行HPLC分析。
獲得之晶形III的穩定性評估結果於下表所示。
從上表3可看出,根據本發明的晶形III在加速條件(40℃,75% RH)和苛刻條件(80℃)下顯示化學穩定性4週。因此,證實根據本發明的晶形III顯示對熱和濕氣之優異穩定性。
[圖1]為製備例4之XRD結果圖。
[圖2]為製備例4之DSC結果圖。
[圖3]為製備例4之TGA結果圖。
[圖4]為實施例1之XRD結果圖。
[圖5]為實施例1之DSC結果圖。
[圖6]為實施例1之TGA結果圖。
Claims (13)
- 一種下式1之化合物、其醫藥上可接受之鹽或其溶劑化物之晶形III, 其中X射線粉末繞射圖案具有3個或更多個選自具有以下繞射角(2θ值)之峰中的特徵峰:6.62±0.2°、7.44±0.2°、9.18±0.2°、9.89±0.2°、10.83±0.2°、11.42±0.2°、12.92±0.2°、14.61±0.2°、15.36±0.2°、15.79±0.2°、15.95±0.2°、17.37±0.2°、18.20±0.2°、18.99±0.2°、19.34±0.2°、19.69±0.2°、20.40±0.2°、21.66±0.2°、21.98±0.2°、22.45±0.2°、22.85±0.2°、24.66±0.2°、25.52±0.2°、26.55±0.2°、28.08±0.2°、29.31±0.2°以及29.54±0.2°, [式1] 其中R 1為C 2-C 5烷基。
- 如請求項1之晶形III,其中該式1之化合物的該醫藥上可接受之鹽為選自由以下所組成之群組:該化合物之鹽酸、硫酸、硝酸、磷酸、氫溴酸以及氫碘酸。
- 如請求項1之晶形III,其為該式1之化合物的溶劑化物的晶形。
- 如請求項3之晶形III,其中該溶劑化物為水合物。
- 一種用於製備如請求項1至5中任一項之晶形III之方法,該方法包含以下步驟:將該式1之化合物溶於結晶溶劑以製備混合溶液;以及從該混合溶液獲得晶體。
- 如請求項6之用於製備晶形III之方法,其中該結晶溶劑包括水、極性非質子有機溶劑或其混合物。
- 如請求項7之用於製備晶形III之方法,其中該極性非質子有機溶劑包括乙酸乙酯、甲基異丁基酮、二甲基亞碸、四氫呋喃、丙酮、二甲基甲醯胺、乙腈或其混合物。
- 如請求項7之用於製備晶形III之方法,其中該結晶溶劑為其中水和該極性非質子溶劑以15:1至1:15之體積比混合之混合溶劑。
- 如請求項6之用於製備晶形III之方法,其中該結晶步驟包括用於冷卻該混合溶液之步驟。
- 一種醫藥組成物,其包含如請求項1至5中任一項之晶形III以及醫藥上可接受之載劑。
- 一種用於促效黑皮質素-4受體的功能之醫藥組成物,該組成物包含如請求項1至5中任一項之晶形III以及醫藥上可接受之載劑。
- 如請求項12之醫藥組成物,其為用於預防或治療肥胖症、糖尿病、炎症或勃起功能障礙。
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JP2024500966A (ja) * | 2020-12-22 | 2024-01-10 | エルジー・ケム・リミテッド | メラノコルチン受容体アゴニスト化合物の結晶形iおよびその製造方法 |
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CA2433025A1 (en) * | 2001-01-23 | 2002-08-01 | Chaoyu Xie | Substituted piperidines/piperazines as melanocortin receptor agonists |
AR044510A1 (es) | 2003-04-14 | 2005-09-14 | Merck & Co Inc | Procedimiento e intermedios para preparar acidos carboxilicos de pirrolidina |
KR100661118B1 (ko) * | 2003-11-12 | 2006-12-26 | 주식회사 엘지생명과학 | 멜라노코틴 수용체의 항진제 |
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UA99555C2 (en) * | 2008-11-12 | 2012-08-27 | Элджи Лайф Саенсез Лтд. | Melanocortin receptor agonists |
BR112019016488B1 (pt) | 2017-02-08 | 2022-11-16 | Tilray, Inc | Método e aparato para processamento de cannabis com energia radiante de baixa pressão |
SG11202112163XA (en) * | 2019-11-07 | 2021-12-30 | Lg Chemical Ltd | Melanocortin-4 receptor agonists |
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US20230382895A1 (en) | 2023-11-30 |
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TWI823169B (zh) | 2023-11-21 |
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AU2021370072A1 (en) | 2023-06-01 |
ZA202305593B (en) | 2024-09-25 |
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