CN111836804A - 用于制备依洛昔巴特的方法 - Google Patents
用于制备依洛昔巴特的方法 Download PDFInfo
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- CN111836804A CN111836804A CN201980018323.4A CN201980018323A CN111836804A CN 111836804 A CN111836804 A CN 111836804A CN 201980018323 A CN201980018323 A CN 201980018323A CN 111836804 A CN111836804 A CN 111836804A
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- C07D281/02—Seven-membered rings
- C07D281/04—Seven-membered rings having the hetero atoms in positions 1 and 4
- C07D281/08—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D281/10—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with one six-membered ring
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- A61K31/554—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
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- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
本发明涉及一种用于制备一些1,5‑苯并硫氮杂
Description
本发明涉及一种用于制备一些1,5-苯并硫氮杂化合物的方法,尤其涉及一种用于制备依洛昔巴特的方法。所述方法可在温和且安全的条件下进行,并可用于以工业规模制备依洛昔巴特。本发明还涉及一种用于制备依洛昔巴特的结晶一水合物的方法。
发明背景
依洛昔巴特(1,1-二氧代-3,3-二丁基-5-苯基-7-甲硫基-8-(N-{(R)-1'-苯基-1'-[N'-(羧甲基)-氨基甲酰基]甲基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,5-苯并硫氮杂,Elobixibat)是回肠胆汁酸转运蛋白(IBAT)抑制剂,可用于治疗或预防血脂异常(WO02/50051)、便秘(WO 2004/089350)和肝病,例如胆汁淤积性肝病和非酒精性脂肪性肝炎(WO 2012/064266)。
回肠胆汁酸转运蛋白位于小肠(尤其是回肠)中,负责调解从小肠摄取胆汁酸到肝脏(该过程为肠肝循环的一部分)。通常,约有95%的胆汁酸通过IBAT再循环到肝脏,其余的5%则分泌到结肠。通过抑制胆汁酸从小肠重吸收到肝脏,增加胆汁酸向结肠分泌。结肠中较高的胆汁酸浓度反过来会导致电解质和水的分泌增加,从而导致粪便软化和大肠蠕动增加。作为回肠胆汁酸转运蛋白的抑制剂,依洛昔巴特可因此用于治疗便秘。
WO 02/50051公开了依洛昔巴特及其相关的几种1,5-苯并硫氮杂化合物的制备。依洛昔巴特的制备包括许多连续步骤,并且涉及几种从环境或安全角度来看不太理想的试剂。最终产物(依洛昔巴特)和几种中间产物的纯化需要制备色谱,这对于小规模的合成有效,但不太适合工业规模的生产。
WO 2014/174066和WO 2016/062848中已经公开了依洛昔巴特的几种稳定的晶型,其中包括依洛昔巴特的晶型IV。但是,这些文献中描述的获得水合物和无水晶型的方法并未针对工业规模的生产进行优化。
因此,需要一种改进的方法来制备依洛昔巴特或其结晶一水合物(例如晶型IV)。这种方法可以使得以工业规模生产依洛昔巴特成为可能,并且比先前描述的方法具有更高的产率和更高的纯度。
发明内容
在第一方面,本发明涉及一种用于制备式(I)化合物或其药学上可接受的盐的方法:
其中
R1和R2各自独立地为C1-4烷基;
R3为C1-4烷基;
R4选自氢、羟基、卤素、硝基、氰基和C1-4烷基;和
R5选自氢、羟基、卤素、硝基、氰基和C1-4烷基;
包括使式(II)化合物与式(III)化合物反应,以获得式(IV)化合物:
其中R1至R4的定义如上所述,
其中
R5的定义如上所述;
R6为合适的保护基;
然后使式(IV)化合物脱保护以获得式(I)化合物。
本文所用术语“卤素”是指氟、氯、溴和碘。
本文所用术语“C1-4烷基”是指具有1-4个碳原子的直链或支链烷基。C1-4烷基的实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基和叔丁基。
本文所用术语“C1-4卤代烷基”是指如上所定义的C1-4烷基,但是其中至少一个氢原子被卤素取代。C1-4卤代烷基的实例包括氟甲基、二氟甲基、三氟甲基。
本文所用术语“保护基”是指临时取代基,其保护潜在的反应性官能团免受不希望的化学变化。这种保护基的实例包括羧酸的酯,例如羧酸的烷基酯和甲硅烷基酯。保护基化学领域已被广泛地综述过。参见例如Wuts P.G.M.和Greene T.W.Greene’s ProtectiveGroups in Organic Synthesis,第4版;John Wiley&Sons,Hoboken,2006。
本文所使用的术语“约”涉及本文中的数值或参数,其包括(和描述)涉及数值或参数本身的实施方案。例如,涉及“约20”的描述包括对“20”本身的描述。数字范围包括定义该范围的端点数字。一般而言,术语“约”涉及变量的指示值,以及指示值在实验误差内(例如,在平均值的95%置信区间内)或不超过指示值±10%的变量的所有值,以两者中的较大范围为准。
在一个优选的实施方案中,本发明涉及一种用于制备式(I)化合物的方法,其中R1和R2各自为正丁基。在另一个优选的实施方案中,一种用于制备式(I)化合物的方法,其中R3是甲基。在另一个优选的实施方案中,一种用于制备式(I)化合物的方法,其中R4是氢。在另一个优选的实施方案中,一种用于制备式(I)化合物的方法,其中R5是氢。在最优选的实施方案中,一种用于制备式(I)化合物的方法,其中R1和R2各自为正丁基,R3为甲基并且R4和R5各自为氢(即依洛昔巴特)。
在所要求保护的方法的第一步中,式(II)的羧酸与式(III)的O-保护的肽进行缩合反应,优选在偶联剂和合适的碱存在下进行。
优选使用相对于式(II)化合物稍微过量的式(III)化合物,更优选使用相对于式(II)化合物约1.0至约1.3当量的式(III)化合物,最优选使用相对于式(II)化合物约1.2当量的式(III)化合物。
式(III)中的R6为合适的保护基,更优选为可以在酸性条件下除去的保护基。在一个优选的实施方案中,R6选自C1-4烷基和三取代的甲硅烷基。更优选地,R6为叔丁基或三甲基甲硅烷基,最优选为叔丁基。
合适的偶联剂的实例包括碳二亚胺(例如二环己基碳二亚胺和二异丙基碳二亚胺),N,N'-羰基二咪唑,O-(苯并三唑-1-基)-N,N,N’,N’-四甲基脲四氟硼酸盐(TBTU),和O-(苯并三唑-1-基)-N,N,N’,N’-四甲基脲六氟磷酸盐(HBTU)。在一个优选的实施方案中,偶联剂是碳二亚胺或O-(苯并三唑-1-基)-N,N,N’,N’-四甲基脲四氟硼酸盐,最优选为O-(苯并三唑-1-基)-N,N,N’,N’-四甲基脲四氟硼酸盐。
可以使用相对于式(II)化合物稍微过量的偶联剂,最优选相对于式(II)化合物约1.0至约1.3当量的偶联剂。
合适的碱的实例包括叔烷基胺(例如三乙胺)和芳香胺(例如吡啶和2,6-二甲基吡啶)。在一个优选的实施方案中,所述碱是2,6-二甲基吡啶。
优选使用相对于式(II)化合物过量的碱,优选相对于式(II)化合物约1.5至约4.0当量的碱,更优选相对于式(II)化合物约2.5至约3.5当量的碱。
用于缩合反应的合适溶剂包括醚(例如四氢呋喃、二烷、环戊基甲基醚和1,2-二甲氧基乙烷),酯(例如乙酸乙酯和乙酸异丙酯),烃(例如己烷和庚烷),芳香烃(例如甲苯和二甲苯),酮(例如丙酮和2-丁酮),卤代烃(例如二氯甲烷和氯仿),卤代芳烃(如氯苯),腈(例如乙腈和丙腈),酰胺(例如N,N-二甲基甲酰胺和N-甲基吡咯烷酮),以及这些溶剂的任意混合溶剂。在一个优选的实施方案中,所述溶剂是卤代烃或腈,更优选卤代烃(例如二氯甲烷或氯仿),最优选二氯甲烷。
反应可以在约0℃至反应溶剂的沸点之间的温度下进行。所述反应优选在约10℃或更高的温度下进行,最优选在约15℃至约35℃的温度下进行。
一旦反应完成,可用酸的水溶液(例如,盐酸的水溶液),水,碱的水溶液(例如,碳酸氢钠的水溶液)以及水依次洗涤混合物,并且蒸发溶剂。此后可以将产物进一步纯化,例如通过结晶。式(IV)化合物优选从乙腈或庚烷中结晶,最优选从乙腈中结晶。在最优选的实施方案中,将式(IV)化合物从乙腈中重结晶两次。
在第二步中,通过水解基团C(O)OR6,使式(IV)化合物脱保护,优选通过酸水解所述基团。该水解反应可以在合适的酸的存在下进行并获得相应的式(I)的羧酸。
合适的酸的实例包括但不限于盐酸、硫酸、硝酸、甲磺酸、对甲苯磺酸、樟脑磺酸、苯磺酸、甲酸,乙酸和三氟乙酸。在一个优选的实施方案中,所述酸为三氟乙酸。
用于水解反应的合适溶剂包括醚(例如四氢呋喃、二烷、环戊基甲基醚和1,2-二甲氧基乙烷),酯(例如乙酸乙酯和乙酸异丙酯),烃(例如己烷和庚烷),芳香烃(例如甲苯和二甲苯),卤代烃(例如二氯甲烷和氯仿),卤代芳烃(如氯苯),腈(例如乙腈和丙腈),酰胺(例如N,N-二甲基甲酰胺和N-甲基吡咯烷酮),以及这些溶剂的任意混合溶剂。在优选的实施方案中,所述溶剂是芳香烃,更优选的芳香烃为甲苯或二甲苯,最优选甲苯。
所述反应可以在约0℃至反应溶剂的沸点之间的温度下进行。该反应优选在约15℃至约35℃的温度下进行。
一旦水解反应完成,所述的酸可以使用水洗涤除去,并且蒸发有机溶剂。此后可以将产物进一步纯化,例如通过结晶或沉淀。式(I)化合物优选从乙醇中结晶,或通过加入庚烷(特别是正庚烷)从溶液中沉淀出来。
在本发明的另一个实施方案中,式(II)化合物通过烷基化反应制备,所述烷基化反应包括使式(V)化合物与式(VI)化合物反应,以获得式(VII)的中间体化合物:
其中R1至R4的定义如上所述,
其中
R7是合适的保护基;和
X是合适的离去基;
然后水解酯R7O-C(O)-,以获得式(II)化合物。
在式(VI)的烷基化试剂中,R7优选选自C1-4烷基和C1-4卤代烷基。更优选地,R7是C1-4烷基(例如甲基、乙基或叔丁基),最优选地,R7是乙基。X优选选自卤素、三氟甲磺酸酯基、甲磺酰基和对甲苯磺酰基。更优选地,X为卤素,更优选选自氯、溴和碘的卤素。在最优选的实施方案中,式(VI)化合物是溴乙酸乙酯。
相对于式(V)化合物,可以使用稍微过量的式(VI)化合物。如果使用相对于式(V)化合物约1.1至约1.4当量的式(VI)化合物,则可获得最佳产率。
式(V)和(VI)化合物之间的烷基化反应优选在相转移催化剂和碱的存在下进行。合适的相转移催化剂的实例包括四正丁基溴化铵(TBAB)、苄基三甲基氯化铵、苄基三乙基氯化铵、甲基三癸基氯化铵、甲基三丁基氯化铵和甲基三辛基氯化铵。最优选四正丁基溴化铵。合适的碱的实例包括金属氢氧化物(例如氢氧化钠、氢氧化钾和氢氧化锂),金属碳酸盐(例如碳酸钠、碳酸钾和碳酸锂),和金属碳酸氢盐(例如碳酸氢钠、碳酸氢钾和碳酸氢锂)。在一个优选的实施方案中,所述碱是金属碳酸盐,最优选碳酸钠。可以使用相对于式(VI)化合物过量的碱,优选相对于式(VI)化合物约3.0至约6.0当量,更优选约3.5至约4.0当量的碱。
用于烷基化反应的合适的溶剂包括醚(例如四氢呋喃、二烷、环戊基甲基醚和1,2-二甲氧基乙烷),酯(例如乙酸乙酯和乙酸异丙酯),烃(例如己烷和庚烷),芳香烃(例如甲苯和二甲苯),酮(例如丙酮和2-丁酮),卤代烃(例如二氯甲烷和氯仿),卤代芳烃(如氯苯),腈(例如乙腈和丙腈),酰胺(例如N,N-二甲基甲酰胺和N-甲基吡咯烷酮),以及这些溶剂的任意混合溶剂。在一个优选的实施方案中,所述溶剂是芳香烃或卤代烃,更优选甲苯或二甲苯,最优选甲苯。
反应可以在约0℃至反应溶剂的沸点之间的温度下进行。该反应优选在约20℃或更高的温度下进行,最优选在约75℃至约85℃的温度下进行,特别是当使用芳香烃作为溶剂时。
一旦烷基化反应完成,可以加入水,并将相转移催化剂和碱萃取到水层中。然后可以分离出式(VII)的中间体化合物,并进一步纯化。已经发现至少使用芳香烃作为溶剂时,获得高收率和高纯度的式(VII)化合物。在这种情况下,式(VII)的中间体化合物无需进一步分离和纯化即可立即用于下一步。因此,在一个优选的实施方案中,不分离式(VII)的中间体化合物,而是将其立即用于下一步。
在所述下一步中,优选在碱性条件下水解式(VII)化合物,得到式(II)化合物。水解反应可以在添加有碱的水溶液的有机溶剂中进行。
所述的合适的碱的实例包括金属氢氧化物(例如氢氧化钠、氢氧化钾和氢氧化锂),金属碳酸盐(例如碳酸钠、碳酸钾和碳酸锂),和金属碳酸氢盐(例如碳酸氢钠、碳酸氢钾和碳酸氢锂)。在一个优选的实施方案中,所述碱是金属氢氧化物,最优选氢氧化钠。碱优选以相对于式(VII)化合物过量的量使用,优选以约2.0至约6.0当量,更优选以约3.0至约5.0当量,并且更优选以约3.5至约4.5当量的量使用。
用于所述水解反应的合适的溶剂包括醇(例如甲醇、乙醇、正丙醇、异丙醇、正丁醇和叔丁醇),醚(例如四氢呋喃、二烷、环戊基甲基醚和1,2-二甲氧基乙烷),脂肪烃(例如己烷和庚烷),芳香烃(例如甲苯和二甲苯),酮(例如丙酮和2-丁酮),卤代烃(例如二氯甲烷和氯仿),卤代芳烃(如氯苯),以及这些溶剂的任意混合溶剂。在优选的实施方案中,所述溶剂是醇或芳香烃,更优选芳香烃,例如甲苯或二甲苯,最优选甲苯。
如果在烷基化反应和随后的水解反应中使用相同的溶剂,则是特别有利的。
反应可以在约0℃至反应溶剂的沸点之间的温度下进行。反应优选在约20℃或更高的温度下进行,最优选在约45℃至约55℃的温度下(当芳香烃用作溶剂时),或当使用醇作为溶剂时反应在约20℃至约30℃的温度下进行。
一旦水解反应完成,就可以通过添加酸(例如甲酸)来酸化反应混合物,并且可以洗涤和浓缩有机层。此后可以将反应产物进一步纯化。式(II)化合物和相应的钠盐均可从有机溶剂中沉淀或结晶。因此,在本发明的一个优选实施方案中,首先将式(II)化合物结晶为相应的钠盐,然后将其质子化并结晶为母体化合物。在一些实施方案中,将式(II)化合物结晶为相应的钠盐可除去任何的非盐类有机杂质。式(II)化合物的钠盐优选从乙酸乙酯和氢氧化钠水溶液的混合物中结晶,而式(II)化合物优选从乙酸乙酯和正庚烷的混合物中结晶。
在本发明的另一个实施方案中,本方法还包括将式(I)化合物转化为稳定的式(I)的结晶水合物。这可以通过从乙醇或包含乙醇和一种或多种其他合适溶剂的混合溶剂中重结晶式(I)化合物来实现。在一个优选的实施方案中,式(I)化合物为依洛昔巴特,并且稳定的式(I)的结晶水合物为依洛昔巴特的结晶一水合物,最优选为依洛昔巴特的晶型IV(也称为依洛昔巴特的晶形IV)。
前面已经公开了可以通过从乙醇或从乙醇和水的混合物中结晶粗品依洛昔巴特来获得晶型IV。在该条件下,首先形成可以分离和干燥的依洛昔巴特的结晶乙醇化物。干燥该结晶乙醇化物产生无水物,其快速吸收空气中的水分,从而变成依洛昔巴特的晶型IV。现已发现,将粗品依洛昔巴特溶于乙醇和乙酸乙酯的混合物中可获得更好的结果。由于依洛昔巴特完全溶于该溶剂混合物中,因此可以对所得溶液进行额外的过滤步骤,以去除任何异物或微生物。如果将正庚烷加入到含有式(I)化合物的乙醇和乙酸乙酯的混合溶液中,也能获得改善的结果。
在第二方面,本发明涉及一种制备依洛昔巴特的晶型IV的方法,该方法包括以下步骤:
(i)在乙醇和乙酸乙酯的混合物中溶解洛昔巴特粗品;
(ii)从步骤(i)中获得的依洛昔巴特粗品在乙醇和乙酸乙酯的混合溶剂中的溶液中结晶出依洛昔巴特的结晶乙醇化物;
(iii)干燥上述依洛昔巴特的结晶乙醇化物以获得依洛昔巴特的结晶无水物;和
(iv)水合该依洛昔巴特的结晶无水物以获得依洛昔巴特的晶型IV。
依洛昔巴特的晶型IV具有通过CuKα1辐射获得的X射线粉末衍射(XRPD)图谱,其至少在位于6.3±0.2和/或19.4±0.2的°2θ位置具有特异峰。
在一个实施方案中,依洛昔巴特的晶型IV具有通过CuKα1辐射获得的X射线粉末衍射(XRPD)图,其在6.3±0.2和19.4±0.2的°2θ位置具有特异峰,并且具有一个或多个以下特征峰:10.2±0.2、10.5±0.2、9.4±0.2、9.5±0.2、12.5±0.2、14.6±0.2、15.6±0.2和23.3±0.2。
在另一个实施方案中,依洛昔巴特的晶型IV具有通过CuKα1辐射获得的X射线粉末衍射(XRPD)图,其在6.3±0.2、19.4±0.2、10.2±0.2、10.5±0.2、9.4±0.2和9.5±0.2的°2θ位置具有特异峰。
在另一个实施方案中,依洛昔巴特的晶型IV具有通过CuKα1辐射获得的X射线粉末衍射(XRPD)图,其在6.3±0.2、19.4±0.2、10.2±0.2、10.5±0.2、9.4±0.2、9.5±0.2、12.5±0.2、14.6±0.2、15.6±0.2和23.3±0.2的°2θ位置具有特征峰,以及在一个或多个以下°2θ位置具有特征峰:8.3±0.2、11.3±0.2、13.4±0.2、13.9±0.2、16.3±0.2、16.6±0.2、18.2±0.2、18.8±0.2、19.1±0.2、19.3±0.2、19.7±0.2、19.8±0.2、20.5±0.2、21.0±0.2、21.3±0.2、21.4±0.2、22.6±0.2、22.9±0.2、23.1±0.2、23.9±0.2、24.5±0.2、24.7±0.2、25.0±0.2、25.2±0.2、25.4±0.2、25.7±0.2、26.7±0.2、26.9±0.2、28.3±0.2和28.9±0.2。
在另一个实施方案中,依洛昔巴特的晶型IV具有通过CuKα1辐射获得的X射线粉末衍射(XRPD)图,其在6.3±0.2、8.3±0.2、9.4±0.2、9.5±0.2、10.2±0.2、10.5±0.2、11.3±0.2、12.5±0.2、13.4±0.2、13.9±0.2、14.6±0.2、15.6±0.2、16.3±0.2、16.6±0.2、18.2±0.2、18.8±0.2、19.1±0.2、19.3±0.2、19.4±0.2、19.7±0.2、19.8±0.2、20.5±0.2、21.0±0.2、21.3±0.2、21.4±0.2、22.6±0.2、22.9±0.2、23.1±0.2、23.3±0.2、23.9±0.2、24.5±0.2、24.7±0.2、25.0±0.2、25.2±0.2、25.4±0.2、25.7±0.2、26.7±0.2、26.9±0.2、28.3±0.2和28.9±0.2的°2θ位置具有特征峰。
其中溶解有粗品依洛昔巴特的乙醇和乙酸乙酯的混合溶剂中乙醇和乙酸乙酯的质量比(w/w)可以为10:1至0.5:1。在一个优选的实施方案中,粗品依洛昔巴特溶解在约1.85∶1(w/w)的乙醇和乙酸乙酯的混合溶剂中。
在一个实施方案中,步骤(ii)中的结晶是通过将依洛昔巴特的晶型IV的晶种加入到粗品依洛昔巴特在乙醇和乙酸乙酯的混合溶剂中的溶液中引发的。
在另一个实施方案中,在步骤(ii)中将正庚烷添加至粗品依洛昔巴特在乙醇和乙酸乙酯的混合溶剂中的溶液中。
本文公开的发明具有几个优点。较之先前公开的制备方法,本发明所要求保护的制备依洛昔巴特的方法包括更少的合成步骤,因此更有效和更经济。本发明还可以以较高的收率和较低的杂质含量分离出依洛昔巴特。本方法包括改进的纯化步骤,并且不需要不适合大规模合成的几个色谱分离步骤。本方法还涉及依洛昔巴特的晶型IV的制备中的改进。总之,本方法允许以工业规模制备依洛昔巴特(或其稳定的结晶一水合物)。
式(I)化合物是回肠胆汁酸转运蛋白(IBAT)抑制剂。因此,它们可用于治疗或预防需要抑制胆汁酸循环的病症、障碍和疾病,例如脂肪酸代谢和葡萄糖利用障碍,胃肠道疾病和紊乱以及肝脏疾病和紊乱。
脂肪酸代谢和葡萄糖利用障碍包括但不限于高胆固醇血症、血脂异常、代谢综合征、肥胖症、脂肪酸代谢障碍,葡萄糖利用障碍、涉及胰岛素抵抗的紊乱以及1型和2型糖尿病。
胃肠道疾病和紊乱包括便秘(包括慢性便秘,功能性便秘,慢性特发性便秘(CIC)和便秘型肠易激综合征(IBS-C)),克罗恩氏病,初级胆汁酸吸收不良,肠易激综合症(IBS),炎症性肠病(IBD),回肠炎症,和返流疾病及其并发症。
本文所定义的肝脏疾病是肝脏和与其连接的器官(例如胰腺、门静脉、肝实质、肝内胆管树、肝外胆管树和胆囊)中的任何胆汁酸依赖性疾病。肝脏疾病及其紊乱包括但不限于遗传性肝代谢紊乱,胆汁酸合成的先天性异常,先天性胆管异常,胆道闭锁,卡赛病后胆道闭锁,肝移植后胆道闭锁,新生儿肝炎,新生儿胆汁淤积,遗传性胆汁淤积,脑腱黄瘤病,BA合成的二次缺陷,泽尔韦格氏综合症,囊性纤维化(肝脏表现型),α1-抗胰蛋白酶缺乏症,Alagilles综合征(ALGS),拜勒综合征,胆汁酸(BA)合成的原发性缺陷,进行性家族性肝内胆汁淤积症(PFIC,包括PFIC-1、PFIC-2、PFIC-3和未指定的PFIC、胆道转移后PFIC和肝移植后PFIC),良性复发性肝内胆汁淤积症(BRIC,包括BRIC1、BRIC2和未指定的BRIC、胆道转移后BRIC和肝移植后BRIC),自身免疫性肝炎,原发性胆汁性肝硬化(PBC),肝纤维症,非酒精性脂肪肝疾病(NAFLD),非酒精性脂肪性肝炎(NASH),门脉高压,普通胆汁淤积,怀孕期间黄疸,药物导致的黄疸,肝内胆汁淤积,肝外胆汁淤积,原发性硬化性胆管炎(PSC),胆结石和胆总管结石,恶性肿瘤导致的胆道阻塞,胆汁淤积或黄疸引起的瘙痒,胰腺炎,慢性自身免疫性肝病导致的进行性胆汁淤积,肝脂肪变性,酒精性肝炎,急性脂肪肝,妊娠脂肪肝,药物性肝炎,铁超负荷紊乱,肝纤维化,肝硬化,淀粉样变性,病毒性肝炎(包括甲型肝炎、乙型肝炎、丙型肝炎、丁型肝炎和戊型肝炎),肝细胞癌(肝癌),以及由于肝脏、胆道和胰腺的肿瘤和赘生物引起的胆汁淤积问题。
在另一方面,本发明涉及药物组合物,其包含通过本文公开的方法制备的式(I)化合物,以及一种或多种药学上可接受的辅料。辅料可包括填充剂、粘合剂、崩解剂、助流剂和润滑剂。在一个优选的实施方案中,通过本文公开的方法制备的式(I)化合物是依洛昔巴特。
本文所用的术语“药学上可接受的”是指适合于人类药用并且通常是安全的、无毒的并且在生物学上或其他方面都不是不良的那些化合物和材料。
药物组合物可以是适合于口服给药、肠胃外注射(包括静脉内,皮下,肌内和血管内注射)、局部给药或直肠给药的形式。在一个优选的实施方案中,药物组合物为适合口服给药的形式,例如片剂或胶囊剂。
合适的填充剂的实例包括但不限于:磷酸二钙二水合物、硫酸钙、乳糖(例如乳糖一水合物)、蔗糖、甘露醇、山梨糖醇、纤维素、微晶纤维素、干淀粉、水解淀粉和预胶化淀粉。在某些实施方案中,填充剂是甘露醇和/或微晶纤维素。
合适的粘合剂的实例包括但不限于淀粉,预胶化淀粉,明胶,糖类(例如蔗糖、葡萄糖、右旋糖、乳糖和山梨醇),聚乙二醇,蜡剂,天然和合成树胶(例如阿拉伯胶和紫云英胶),海藻酸钠,纤维素衍生物(例如羟丙基甲基纤维素(或羟丙甲纤维素)、羟丙基纤维素和乙基纤维素)和合成聚合物(例如丙烯酸和甲基丙烯酸共聚物、甲基丙烯酸共聚物、甲基丙烯酸甲酯共聚物、甲基丙烯酸氨基烷基酯共聚物、聚丙烯酸/聚甲基丙烯酸的共聚物和聚乙烯吡咯烷酮(聚维酮))。在某些实施方案中,粘合剂是羟丙基甲基纤维素(羟丙甲纤维素)。
合适的崩解剂的实例包括但不限于干淀粉,改性淀粉(例如(部分)预胶化淀粉、羟乙酸淀粉钠和羧甲基淀粉钠),海藻酸,纤维素衍生物(例如羧甲基纤维素钠、羟丙基纤维素和低取代的羟丙基纤维素(L-HPC))和交联的聚合物(如羧甲基纤维素、交联羧甲基纤维素钠、羧甲基纤维素钙和交联的PVP(交联聚维酮))。在某些实施方案中,崩解剂是交联羧甲基纤维素钠。
合适的助流剂和润滑剂的实例包括但不限于滑石粉、硬脂酸镁、硬脂酸钙、硬脂酸、二十二烷酸甘油酯、胶体二氧化硅、二氧化硅水分散液、合成硅酸镁、细粉氧化硅、淀粉、十二烷基硫酸钠、硼酸、氧化镁、蜡(如巴西棕榈蜡)、氢化油、聚乙二醇、苯甲酸钠、聚乙二醇和矿物油。在某些实施方案中,助流剂或润滑剂是硬脂酸镁或胶体二氧化硅。
本发明药物组合物可以常规地用一层或多层包衣层包衣。本发明也包括了肠溶衣层或用于延迟或靶向释放式(I)化合物的包衣层。包衣层可以包含一种或多种包衣剂,并且可以任选地包含增塑剂和/或颜料(或着色剂)。
合适的包衣剂的实例包括但不限于基于纤维素的聚合物(例如乙基纤维素、羟丙基甲基纤维素(或羟丙甲纤维素)、羟丙基纤维素、邻苯二甲酸乙酸纤维素、乙酸琥珀酸酯纤维素、羟丙基甲基纤维素乙酸琥珀酸酯和羟丙基甲基纤维素邻苯二甲酸酯),基于乙烯基的聚合物(例如聚乙烯醇)和基于丙烯酸及其衍生物的聚合物(例如丙烯酸和甲基丙烯酸共聚物、甲基丙烯酸共聚物、甲基丙烯酸甲酯共聚物、甲基丙烯酸氨基烷基酯共聚物、聚丙烯酸/聚甲基丙烯酸共聚物)。在某些实施方案中,所述包衣剂是羟丙基甲基纤维素。在其他实施方案中,所述包衣剂是聚乙烯醇。
合适的增塑剂的实例包括但不限于柠檬酸三乙酯、甘油三乙酸酯、柠檬酸三丁酯、邻苯二甲酸二乙酯、乙酰基柠檬酸三丁酯、邻苯二甲酸二丁酯、癸二酸二丁酯和聚乙二醇。在某些实施方案中,所述增塑剂是聚乙二醇。
合适的色素的例子包括但不限于二氧化钛,氧化铁(例如黄色、棕色、红色或黑色的氧化铁)和硫酸钡。
包含式(I)化合物(尤其是依洛昔巴特)的药物组合物的实例公开于例如WO 2014/174066,US 2017/0143738和US 2017/0143783中,将其全部内容引入本文作为参考。
治疗或预防本文所述的病症所需的剂量取决于给药途径、疾病的严重程度、患者的年龄和体重,以及主治医师在为特定患者确定适当的方案和剂量水平时通常考虑的其他因素。
所述化合物的给药量因所治疗的患者而异,其范围可从每日约1μg/kg体重到约50mg/kg体重。单位剂型(例如片剂或胶囊剂)通常包含约1至约250mg的活性成分(例如约1至约100mg,或如约1至约50mg,或如约1至约20mg——比如约2.5mg,或约5mg,或约10mg,或约15mg)。每日剂量可以单次剂量给药,也可以分为一、二、三或更多单位剂量给药。IBAT抑制剂的口服给药日剂量优选在约0.1至约250mg之内,更优选在约1至约100mg之内,例如在约1至约5mg之内,例如在约1至约10mg之内,例如在约1至约15mg之内,或例如在约1至约20mg之内。
在另一方面,本发明涉及在受试者(例如男人)中治疗或预防本文所述的任何疾病的方法,其包括向需要该治疗或预防的受试者给药有效量的药物组合物,所述药物组合物包括通过本文公开的方法制备的式(I)化合物。本发明还涉及包含通过本文公开的方法制备的式(I)化合物的药物组合物,其用于治疗或预防本文所述的任何疾病。本发明还涉及通过本文公开的方法制备的式(I)化合物在制备用于治疗或预防本文所述的任何疾病的药物中的用途。在该方面的优选实施方案中,通过本文公开的方法制备的式(I)化合物是依洛昔巴特。
通过以下实施例进一步说明本发明,这些实施例在任何方面均不限制本发明。
实验方法
一般方法
用于以下实施例的试剂和起始原料均是商业化产品,或者可以通过本领域已知的标准方法制备。起始原料3,3-二丁基-7-(甲基硫烷基)-1,1-二氧代-5-苯基-2,3,4,5-四氢-1H-1,5-苯并硫氮杂-8-醇和2-[((2R)-2-苄氧羰基氨基-2-苯基乙酰氨基]乙酸1,1-二甲基乙基酯可以如WO 02/50051中所述制备(分别参见方法26和85)。
高分辨率质谱(HRMS)测试通过Waters Acquity H Class UPLC/Xevo G2-XS QTof进行。
实施例
实施例1
在反应器中,将3,3-二丁基-7-(甲基硫烷基)-1,1-二氧代-5-苯基-2,3,4,5-四氢-1H-1,5-苯并硫氮杂-8-醇(70.00kg)、碳酸钠(69.30kg)、四丁基溴化铵(4.55kg)、甲苯(606.20kg)和溴乙酸乙酯(30.10kg)混合并在80℃下搅拌4小时。冷却后,将反应物用水(1680kg)洗涤,并丢弃水层。
将氢氧化钠溶液(25.04kg氢氧化钠和225.4kg水的混合物)加入上述甲苯层中,在47℃下搅拌所得混合物3.5小时。冷却后,向该反应溶液中加入乙酸乙酯(374.74kg),然后搅拌并加入甲酸直至pH为3.6。弃去水层,并且用水(2×333.84kg)洗涤有机层。
真空下浓缩有机层,并将乙酸乙酯(599.24kg)加入到浓缩的残余物中。冷却后,搅拌并缓慢加入氢氧化钠溶液(125.19kg氢氧化钠和709.41kg水的混合物)。沉淀出钠盐的晶体,通过离心将其分离。
将所述钠盐、乙酸乙酯(599.24kg)和水(333.8kg)混合。在搅拌的同时加入甲酸直到pH变为3.5。用水(333.8kg×2)洗涤有机层,并在真空下将其浓缩。将正庚烷(228.68kg)加入到浓缩的残余物中,搅拌混合物。过滤沉淀的晶体,并在真空下干燥,得到目标化合物的干晶体,为灰白色固体(65.38kg)。
HRMS(ESI,m/z),计算值C26H34NO5S2[M-H]-:504.1880,实测值:504.1832。
实施例2
N-[(2R)-2-氨基-2-苯基乙酰基]甘氨酸叔丁酯的制备
在反应器中,加入无水乙醇(266.30kg)、2-[(2R)-2-苄氧羰基氨基-2-苯基乙酰氨基]乙酸叔丁酯(33.75kg)、10%钯碳(含50%水)(4.05kg)和甲苯(87.75kg)。所得混合物在3.5kg/cm2压力的氢气中在18℃搅拌3小时。
过滤所述反应物,并用无水乙醇(106.65kg)洗涤滤床。真空浓缩滤液,得到目标化合物,为无色粘稠液体(21.70kg)。
HRMS(ESI,m/z),计算值C14H21N2O3[M+H]+:265.1553,实测值:265.1452。
实施例3
在反应器中,将实施例1的化合物(65.00kg)、实施例2的化合物(40.95kg)和二氯甲烷(864.50kg)混合。加入2,6-二甲基吡啶(37.05kg),然后在5℃下加入O-(苯并三唑-1-基)-N,N,N′,N′-四甲基脲四氟硼酸盐(46.15kg)。将该混合物在25℃下搅拌15小时。加入二氯甲烷(1037.40kg),所得有机层依次用以下液体洗涤:(1)稀盐酸(74.10kg盐酸和667.55kg水的混合物);(2)水(260.00kg);(3)碳酸氢钠溶液(26.00kg碳酸氢钠和260.00kg水的混合物);(4)水(260.00kg)。
所得有机层在真空下浓缩。加入乙腈(306.80kg)后,将混合物加热至溶解,然后冷却至13℃。沉淀出晶体,然后将其离心并用乙腈(51.35kg)洗涤。
加入乙腈(606.45kg)至所得的全部粗晶体中。加热该混合物直至其溶解,然后冷却至0℃。沉淀出晶体,将其离心并用乙腈(51.35kg)洗涤。将所得的湿晶体真空干燥,得到目标化合物,为白色粉末(81.20kg)。
HRMS(ESI,m/z),计算值C40H52N3O7S2[M-H]-:750.3250,实测值:750.3164。
实施例4
粗品依洛昔巴特的制备
在反应器中,将甲苯(1331.10kg)和实施例3的化合物(76.50kg)混合。在3℃下加入三氟乙酸(341.95kg),所得混合物在25℃下搅拌29小时。用水(306.00kg)重复洗涤该反应混合物,直到水层的pH变为3.4。
过滤有机层后,将滤液在真空下浓缩。将正庚烷(520.20kg)加入到浓缩的残余物中,搅拌该混合物。离心沉淀的晶体并用正庚烷(104.04kg)洗涤。将所得晶体真空干燥,得到粗品依洛昔巴特,为灰白色固体(64.34kg)。
HRMS(ESI,m/z),计算值C36H44N3O7S2[M-H]-:694.2623,实测值:694.2553。
实施例5
依洛昔巴特晶型IV的制备
在反应器中混合粗品依洛昔巴特(64.00kg)、乙酸乙酯(154.88kg)和无水乙醇(288.00kg),所得混合物在40℃下搅拌直至溶解。将溶液过滤后,其滤液用乙酸乙酯(17.28kg)和无水乙醇(15.36kg)的混合物洗涤。
所述滤液冷却后,在25℃下加入依洛昔巴特的晶型IV的晶种(0.032kg),搅拌该混合物2小时。加入正庚烷(832.00kg),所得混合物在23℃继续搅拌。沉淀出晶体,将其离心并用正庚烷(43.52kg)洗涤。所得的湿晶体在真空下干燥以获得干晶体。
然后通过将所得的干燥晶体在25℃下暴露于潮湿条件(40±25%RH)来水化(润湿),直到其达到2.4%至3.4%的水含量(通过卡尔·费休滴定法测定)。所得的依洛昔巴特的晶型IV为白色粉末(50.64kg)。
Claims (20)
2.根据权利要求1的方法,其中R6选自C1-4烷基和三取代的甲硅烷基。
3.根据权利要求1或2的方法,其中R6是叔丁基。
4.根据权利要求1-3中任一项的方法,其中式(II)和(III)化合物之间的反应在2,6-二甲基吡啶存在下进行。
5.根据权利要求1-4中任一项的方法,其中式(IV)化合物从乙腈中重结晶。
6.根据权利要求1-5中任一项的方法,其中式(IV)化合物的水解反应在甲苯中进行。
7.根据权利要求1-6中任一项的方法,其中通过加入庚烷使式(I)化合物从溶液中沉淀。
9.根据权利要求8的方法,其中R7选自C1-4烷基和C1-4卤代烷基。
10.根据权利要求8或9的方法,其中X选自卤素、三氟甲磺酸酯基、甲磺酰基和对甲苯磺酰基。
11.根据权利要求8-10中任一项的方法,其中式(II)化合物先以相应的钠盐沉淀,再质子化和结晶。
12.根据权利要求8-11中任一项的方法,其中式(VII)的中间体化合物的制备在甲苯中进行。
13.根据权利要求8-12中任一项的方法,其中式(VII)的中间体化合物不进行分离,而是立即用于下一步反应。
14.根据权利要求8-13中任一项的方法,其中所述烷基化反应和随后的水解反应在相同的溶剂中进行。
15.根据权利要求1-14中任一项的方法,进一步包括将式(I)化合物转化成式(I)的稳定的结晶水合物。
16.根据权利要求15的方法,其中将式(I)化合物溶解在乙醇和乙酸乙酯的混合溶剂中。
17.根据权利要求15或16所述的方法,其中将正庚烷加入到式(I)化合物在乙醇和乙酸乙酯的混合溶剂中的溶液中。
18.根据权利要求15-17中任一项所述的方法,其中所述稳定的结晶水合物是结晶一水合物。
19.一种制备依洛昔巴特的晶型IV的方法,包括以下步骤:
(i)在乙醇和乙酸乙酯的混合溶剂中溶解依洛昔巴特粗品;
(ii)自步骤(i)获得的依洛昔巴特粗品在乙醇和乙酸乙酯的混合溶剂中的溶液中结晶依洛昔巴特的结晶乙醇化物;
(iii)干燥所得的依洛昔巴特的结晶乙醇化物以获得依洛昔巴特的结晶无水物;和
(iv)水合依洛昔巴特的结晶无水物以获得依洛昔巴特的晶型IV。
20.根据权利要求19的方法,其中在步骤(ii)中,将正庚烷加入到粗品依洛昔巴特在乙醇和乙酸乙酯的混合溶剂中的溶液中。
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TWI823573B (zh) | 2023-11-21 |
JP2021515023A (ja) | 2021-06-17 |
TW202302546A (zh) | 2023-01-16 |
BR112020017353A2 (pt) | 2020-12-15 |
KR20230159639A (ko) | 2023-11-21 |
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