CN112351982A - 制备p300和/或cbp调节剂的方法 - Google Patents
制备p300和/或cbp调节剂的方法 Download PDFInfo
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- CN112351982A CN112351982A CN201980033905.XA CN201980033905A CN112351982A CN 112351982 A CN112351982 A CN 112351982A CN 201980033905 A CN201980033905 A CN 201980033905A CN 112351982 A CN112351982 A CN 112351982A
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- formula
- process according
- following formula
- dichloromethane
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Abstract
制备下式(I)化合物的方法,该方法包括:(a)用下式(6)化合物处理下式(5)化合物以产生下式(7)中间体化合物;(b)用下式(8)化合物处理如前文所定义的式(7)化合物;和(c)回收如前文所定义的式(I)化合物。式(I)化合物是p300/CBP活性的希望调节剂,其在治疗癌症包括***癌、血液学癌、膀胱癌和肺癌中具有潜在效用。
Description
发明领域
本发明涉及制备苯并咪唑化合物,其用作p300和/或CBP活性调节剂和因此能够用作药物物质。
发明背景
进入临床试验阶段和因此可以最终上市为批准药物的药物化合物需要可以以可行的商业规模以高品质获得,具有最大的成本效率。因此,在发现有希望的药物候选者的情况下常常必需重新考虑其合成:在医学化学实验室规模适宜的合成路线并不一定适用于以可靠且成本有效的方式商业放大。
化合物(S)-6-(5-(3,5-二甲基异噁唑-4-基)-1-((1R,4S)-4-甲氧基环己基)-1H-苯并[d]咪唑-2-基)-1-(3,4-二氟苯基)哌啶-2-酮(下文称为化合物(I)或式(I)化合物)是p300/CBP活性的希望调节剂,其具有治疗癌症包括***癌、血液学癌、膀胱癌和肺癌的潜在效用。在实验室规模,该化合物可以根据下述方案A合成:
尽管在实验室中成功,但方案A并不良好地适于以商业规模操作。这存在数个理由。关键的因素是在步骤(i)中引入昂贵的3,5-二甲基异噁唑-4-取代硼酸酯试剂(3,5-二甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)异噁唑),其产生化合物(I)左侧的二甲基异噁唑部分。步骤(i)是六个步骤中的第一步。左侧二甲基异噁唑部分因此在全部五个随后的转化中都存在。作为在那些转化期间由于各阶段不同收率自然产生的损失的结果,给出一定量的最终化合物(I)所需要的取代硼酸酯原料试剂的量不希望地高。又一因素是在步骤(iv)中使用HATU试剂(O-(7-氮杂苯并***-1-基)-N,N,N,N-四甲基脲鎓六氟磷酸盐)使得需要色谱法步骤来分离所希望的产物(D)且导致不希望的玻璃仪器腐蚀。
比如上文提及的那些因素显著降低操作方案A在商业规模的经济可行性。因此需要更佳地适用于商业放大的备择过程来制备式(I)化合物。
发明概要
本发明提供制备下式(I)化合物的方法:
该方法包括:
(a)将下式(5)化合物:
用下式(6)化合物处理:
从而产生下式(7)中间体化合物:
(b)将如前文所定义的式(7)化合物
用下式(8)化合物处理:
(c)回收如前文所定义的式(I)化合物。
所得式(I)化合物可以例如用乙酸乙酯:正庚烷重结晶。通过该手段可以回收热力学上稳定的晶型。
在上述过程中,将3,5-二甲基异噁唑-4-取代硼酸酯试剂加至其中苯并咪唑环、甲氧基环己基和右侧δ-内酰胺环全部已经存在的化合物。一旦3,5-二甲基异噁唑部分已引入,则因此仅需要一个其他过程步骤。作为结果,与上文的方案A方法相比,为了产生一定量的化合物(I)需要显著更少量的3,5-二甲基异噁唑-4-取代硼酸酯试剂。
式(I)化合物具有生物学活性和可以从而用作药物物质。通过如前文所定义的本发明方法制备的化合物可以因此与一种或多种药学上可接受的载体或稀释剂配制以产生药物组合物
附图说明
图1显示式(I)化合物的"形式1"的结晶多晶型物的XRPD衍射图,如下文描述的实施例5获得。
图2是式(I)化合物的"形式1"的单晶结构的ORTEP(Oak Ridge ThermalEllipsoid Plot)图,如下文描述的实施例5获得。
发明详述
在如前文所定义的本发明方法中,步骤(a)一般在四(三苯基膦)钯和碱存在下在非质子溶剂和水中进行。碱可以是例如碳酸钾。非质子溶剂一般是1,4-二噁烷。
步骤(a)中产生的式(7)化合物可以纯化和重结晶,随后在步骤(b)中用式(8)化合物处理。在本发明的一个方面中,该过程因此包括在步骤(b)之前纯化和重结晶式(7)中间体化合物。式(7)化合物可以通过任何适宜手段纯化,例如通过二氧化硅短柱或用适宜螯合剂处理。在待除去的杂质包含硼残余物的情况下,适宜的螯合剂是二乙醇胺。式(7)化合物的重结晶用适宜溶剂进行。适宜溶剂包括乙酸乙酯。
本发明方法的步骤(b)一般在极性溶剂中在吡啶和Cu(OAc)2.H2O存在下进行。在反应期间,可以使空气(一般是过滤空气)从反应混合物上通过。反应混合物一般在空气在其上通过的情况下搅拌。溶剂一般是二氯甲烷(DCM)。
在本发明方法步骤(c)回收的式(I)化合物显示多晶现象,原因是其能够以不同晶型结晶。在本发明方法中一般产生的晶型是热力学上最稳定的形式,称为多晶型物形式1。示于图1和2的X射线数据表征形式1。然而,也能获得亚稳晶型。
所产生的特定多晶型物/晶型取决于各种因素,包括用于重结晶式(I)化合物的溶剂选择。其它有关因素是(a)在结晶期间溶液搅拌/搅动的量和速率,和(b)在结晶期间用希望形式的一个或多个单晶为溶液种晶。使用选自乙酸丁酯、乙酸异丙酯、乙酸乙酯、乙酸乙酯:正庚烷和乙酸乙酯:己烷的重结晶溶剂有利于多晶型物形式1的形成。可以产生形式1的其它溶剂包括DMSO,二甲氧基乙烷和丙酮:水(5%)。多晶型物形式1一般从式(I)化合物在有关溶剂中的悬浮液/溶液中通过缓慢冷却回收。例如,冷却可以进行如下:以0.1℃/min从25℃至5℃随后于5℃保持数小时比如15-20小时、例如16小时的时间段。
本发明方法步骤(a)中所用的式(5)原料化合物可以制备如下:将下式(4)化合物:
用乙酸处理。
乙酸促进环化以形成苯并咪唑环系的"咪唑"部分。在上文方案A的先前过程中,该乙酸介导的环化一般在约80℃的温度进行数小时的时间段。在本发明方法中,反应更一般地在更低的温度例如35℃-55℃、例如40℃-50℃的范围进行多至5天的时间段。这些较温和的条件倾向于有利于在环化步骤期间保持手性完整性。
上文显示的式(4)化合物可以产生如下:将下式(3)化合物
用下式(9)化合物:
将用于上文方案A酰胺偶联中的HATU试剂替换为本发明方法中的避免对式(4)化合物色谱分离的需要。替代地,化合物能够通过浓缩分离。相应地,在发生形成式(5)化合物的乙酸介导的环化之前式(4)化合物一般并不分离。
式(3)化合物可以通过还原下式(2)化合物制备:
还原通过任何适宜手段进行,例如在极性溶剂和水中用Na2S2O4和碱处理式(2)化合物。碱一般是氢氧化铵。极性溶剂可以是极性非质子溶剂例如THF。还原可以另选地用NaBH4和拉尼镍/MeOH进行或者通过用拉尼镍催化氢化进行。
式(2)化合物可以制备如下:将下式(10)化合物:
用下述化合物:
在极性溶剂中在碱存在下处理。极性溶剂可以是极性非质子溶剂比如乙腈。碱可以是例如碳酸钾。
上文描述的本发明单独方法步骤的组合的一个实施方式示于下述
方案B:
(i)K2CO3,MeCN
(ii)Na2S2O4,NH4OH,THF,H2O
(iv)AcOH,40-50℃
(v)Pd(Ph3)4,K2CO3,二噁烷,水
(vi)Cu(OAc)2.H2O,二氯甲烷,吡啶。
应理解在最终式(I)化合物中或在任何中间体或原料化合物中存在的任何原子可以以任何可获得的天然同位素形式存在。例如,碳原子可以是12C或13C。氢原子可以是1H或2H(氘)。式(I)化合物可以从而以氘化形式制备,其中一个或多个氢原子作为2H存在。任何氢原子或其组合可以作为氘存在。
在一种实施方式中式(I)化合物是三氘化的,其中结合至环己基取代基的甲氧基中存在3个2H原子。该三氘化的化合物具有下述结构式(I’):
式(I’)化合物可以制备如下:将上文方案B第一步(i)中所用的试剂替换为下述氘化的类似物:
氘化的化合物比如上述式(I’)化合物能够用作生物分析参比标准。由于氘同位素效果,其还可以具有比非氘化的类似物更高的体内稳定性。从而其在医学领域中可以是非氘化的化合物的有用代替物。氘化的化合物比如上述化合物(I’)可以因此用于式(I)化合物有用的任何治疗方法中。相应地,下文描述式(I)化合物的全部内容应因此理解为包括对式(I’)氘化类似物的描述。
本发明方法制备的式(I)化合物具有作为p300和/或CBP活性调节剂的活性。因此其可以用来治疗癌症或其中表达AR的其它临床病况,或者用于存在CBP和/或p300功能活化的癌症中。能够治疗的癌症包括表达AR或与AR另有关联的那些,包涵CBP或p300功能丢失突变的那些和具有活化的CBP和/或p300的那些。
可以治疗的癌症包括但不限于***癌,乳腺癌,膀胱癌,肺癌,淋巴瘤和白血病。***癌可以是例如对***有抗性的***癌(CRPC)。肺癌可以例如非小细胞肺癌或小细胞肺癌。患癌的人类或动物患者可以从而通过如下方法治疗,其包括对其给药按照本发明制备的式(I)化合物。患者的情况可以由此改善或转好。
式(I)化合物可以从而与放射疗法或又一治疗剂结合给予人类或动物患者用于治疗癌症。因此本文公开联合疗法其中式(I)化合物或包含式(I)化合物的药物组合物与放射疗法同时或依次给予;或者与一种或多种其它治疗剂同时、依次或作为组合制剂给予,用于治疗癌症。
其它或各治疗剂一般是常规用于待治疗癌症类型的试剂。式(I)化合物一般与之组合用于治疗***癌的治疗剂类别包括雄激素受体拮抗剂例如Enzalutamide、Apalutamide,和CYP17A1(17α-羟化酶/C17,20裂合酶)抑制剂例如阿比特龙;用于治疗肺癌的治疗剂类别包括细胞毒性化疗剂例如顺铂、卡铂、多西他赛;和用于治疗膀胱癌的治疗类别包括细胞毒性化疗剂例如吉西他滨、顺铂或免疫疗法例如卡介苗(BCG)。化合物(I)一般与之组合用于治疗血液学癌的治疗剂类别包括下述:
a.AML
i.阿扎胞苷(低甲基化剂)
ii.IDH1/2抑制剂
b.多发性骨髓瘤
i.***
ii.蛋白酶体抑制剂+***
iii.免疫调节剂+***
c.非霍奇金淋巴瘤
i.利妥昔单抗
ii.来那度胺(免疫调节剂)
iii.化学疗法
iv.依罗替尼(BTK抑制剂)
本发明化合物能与之组合的其它试剂类别包括免疫检查点抑制剂例如pembrolizumab、nivolumab、阿特珠单抗、伊匹木单抗;PARP(聚ADP核糖聚合酶)抑制剂比如奥拉帕利;和CDK4/6(细胞周期蛋白-依赖性激酶4和6)抑制剂。
术语"组合"如本文所用是指同时、分别或依次给药。在依次或分别给药的情况下,第二组分的给予延迟不应损失组合的有益效果。
本文也公开产品,其包含
(a)如前文所定义的式(I)化合物;和
(b)一种或多种其它治疗剂;
用于在癌症例如上文提及的特定类型癌症的预防性或治疗性治疗中分别、同时或依次给药。其它治疗剂可以是例如雄激素受体拮抗剂,CYP17A1抑制剂,PARP抑制剂或CDK4/6抑制剂。更特别地,其可以Enzalutamide,Apalutamide,阿比特龙或奥拉帕利。
式(I)化合物能够以各种剂型给予,例如口服给予,比如片剂、胶囊、糖包衣或膜包衣片剂、液体溶液或悬浮液形式,或者经肠胃外例如经肌肉内、经静脉内或经皮下给予。化合物可以因此通过注射或输注给予。
剂量取决于各种因素包括患者的年龄,体重和情况和给药途径。日剂量能够在宽范围内变化和按每个特定情况的单独需要调节。然而一般地,在化合物单独给予成年人类的情况下对于各给药途径采用的剂量是0.0001至50mg/kg体重,最一般为0.001至10mg/kg体重,例如0.01至1mg/kg体重的范围。上述剂量可以例如每日给予1至5次。对于静脉内注射,适宜的日剂量是0.0001至1mg/kg体重,优选0.0001至0.1mg/kg体重。日剂量能够作为单一剂量给予或根据分开给药计划给予。
式(I)化合物配制用作药物或兽医学组合物,其也包含药学上或兽医上可接受的载体或稀释剂。组合物一般按照常规方法制备和以药学上或兽医上适宜的形式给予。化合物可以以任何常规的形式给予,例如下述:
A)口服给予,例如作为片剂,包衣片剂,锭剂,含锭,糖锭,水性或油性悬浮液,液体溶液,可分散粉剂或颗粒剂,乳液,硬或软胶囊,或糖浆剂或酏剂。期望口服使用的组合物可以根据本领域已知用于制备药物组合物的任何方法制备并且所述组合物可以含有选自甜味剂、调味剂、着色剂和防腐剂的一种或多种试剂以便提供药学上美观和适口的制剂。
片剂含有活性成分和与之混合的适于制备片剂的无毒的药学上可接受的赋形剂。这些赋形剂可以是例如惰性稀释剂,比如碳酸钙,碳酸钠,乳糖,右旋糖,蔗糖,纤维素,玉米淀粉,马铃薯淀粉,磷酸钙或磷酸钠;造粒和崩解剂,例如玉米淀粉,藻酸,藻酸盐或淀粉羟乙酸钠;结合剂,例如淀粉,明胶或***胶;润滑剂,例如二氧化硅,硬脂酸镁或钙,硬脂酸或滑石;泡腾混合物;染料,甜味剂,润湿剂比如卵磷脂,聚山梨酸酯,维生素E聚乙二醇琥珀酸酯(也称为维生素E TGPS),聚乙二醇化的甘油酯或月桂基硫酸盐/酯。片剂可以是未经包覆的或它们可以通过已知技术包覆以延缓在胃肠道中的崩解和吸附和由此提供更长时间段的持续作用。例如,可以使用时间延缓物质比如甘油单硬脂酸酯或甘油二硬脂酸酯。所述制剂可以以已知方式制备,例如通过混合,造粒,压片,糖包衣或膜包衣过程制备。
口服使用的配制剂还可以呈现为硬明胶或羟丙基甲基纤维素胶囊,其中活性成分与惰性固体或半固体稀释剂例如碳酸钙、磷酸钙、维生素E聚乙二醇琥珀酸酯(维生素ETGPS)、聚乙二醇化的甘油酯或高岭土混合,或者呈现为软明胶胶囊,其中活性成分原样或者与水或油介质例如花生油、液状石蜡或橄榄油混合存在。
水性悬浮液含有活性物质和与之混合的适于制备水性悬浮液的赋形剂。所述赋形剂是助悬剂,例如羧甲纤维素钠,甲基纤维素,羟基丙基甲基-纤维素,藻酸钠,聚乙烯基吡咯烷酮,黄蓍胶和***胶;分散或润湿剂可以是天然磷脂,例如卵磷脂,或氧化烯烃与脂肪酸的缩合产物例如聚氧乙烯硬脂酸酯,或氧化乙烯与长链脂族醇的缩合产物例如十七乙烯氧基鲸蜡醇,或氧化乙烯与衍生自脂肪酸和己糖醇的偏酯的缩合产物比如聚氧乙烯山梨糖醇单油酸酯,或氧化乙烯与衍生自脂肪酸和己糖醇酐混合物的偏酯的缩合产物例如聚氧乙烯去水山梨糖醇单油酸酯。
所述水性悬浮液还可以含有一种或多种防腐剂例如对羟基苯甲酸乙基或正丙基酯,一种或多种着色剂比如蔗糖或糖精。
油性悬浮液可以配制如下:将活性成分悬浮在植物油例如花生油、橄榄油、芝麻油或椰子油中或者在矿物油比如液状石蜡中。油性悬浮液可以含有增稠剂例如蜂蜡、硬石蜡或鲸蜡醇。
可以加入甜味剂比如上文描述的那些和调味剂以提供适口的口服制剂。这些组合物可以通过加入抗氧化剂比如抗坏血酸来防腐。适于加水制备水性悬浮液的可分散粉剂和颗粒剂提供活性成分和与之混合的分散或润湿剂、助悬剂和一种或多种防腐剂。适宜的分散或润湿剂和助悬剂是诸如上文已提及的那些。还可以存在额外的赋形剂例如甜味剂、调味剂和着色剂。
药物组合物还可以呈水包油乳液形式。油相可以是植物油例如橄榄油或花生油,或矿物油例如液状石蜡或这些的混合物。适宜的乳化剂可以是天然胶例如***胶或黄蓍胶,天然磷脂例如大豆卵磷脂,和衍生自脂肪酸和己糖醇酐混合物的酯或偏酯例如脱水山梨糖醇单油酸酯,和所述偏酯与氧化乙烯的缩合产物例如聚氧乙烯去水山梨糖醇单油酸酯。乳液还可以含有甜味剂和调味剂。糖浆剂和酏剂可以用甜味剂例如甘油,山梨糖醇或蔗糖配制。尤其是用于糖尿病患者的糖浆能够含有仅作为载体的产品例如山梨糖醇,其不代谢为葡萄糖或仅很少量代谢为葡萄糖。
所述配制剂还可以含有缓和剂,防腐剂和调味剂和着色剂。
B)经肠胃外,经皮下或经静脉内或经肌肉内或经胸骨内,或通过输注技术给予,呈无菌可注射水性或油性悬浮液形式。该悬浮液可以根据本领域已知用适宜分散上文已提及的润湿剂和助悬剂的那些配制。无菌可注射制剂还可以是在无毒的经肠胃外可接受的稀释剂或溶剂中的无菌可注射溶液或悬浮液,例如1,3-丁二醇中的溶液。
可以使用的可接受的媒介物和溶剂尤其是水,林格溶液和等渗氯化钠溶液。此外,无菌非挥发油常规用作溶剂或悬浮介质。对于该目的,可以使用任何温和非挥发油包括合成的甘油单酯或二酯。此外脂肪酸比如油酸可用于制备可注射剂。
C)通过吸入给予,呈气雾剂或雾化器用溶液的形式。
D)直肠给予,呈通过将药物与适宜的无刺激性赋形剂混合制备的栓剂形式,所述赋形剂在常温是固体但在直肠温度是液体并将因此在直肠中熔化释放药物。所述物质是可可油和聚乙二醇。
E)局部给予,呈霜剂,软膏剂,胶冻,洗眼剂,溶液或悬浮液形式。
本发明将进一步描述于下文的实施例:
实施例1:制备化合物(5)
将化合物(3)(1002.4g,3.35mol)和化合物(9)(520.7g,3.65mol,1.04当量)溶于二氯甲烷(6840mL)。缓慢加入N,N-二异丙基乙胺(700mL),保持温度在0至5℃,随后用二氯甲烷(300mL)线冲洗。将1-丙基膦酸环状酸酐(50%w/w二氯甲烷溶液)(3304.8g,10.37mol)用二氯甲烷(1000mL)稀释,将溶液加至反应混合物,保持温度在0至15℃。作为线冲洗加入二氯甲烷(700mL)。将反应温度调节至15至25℃,搅拌混合物直至判断反应完成(一般2小时)。
加入Na2CO3水溶液(0.6M,10,000mL),保持温度在0至25℃,分相。水相用二氯甲烷(5000mL)萃取,经合并的有机相用25%w/w氯化铵溶液(3x 5000mL)洗涤。经合并的氯化铵洗涤液用二氯甲烷(5000mL)反萃取,经合并的有机萃取物在硫酸钠上干燥,过滤和浓缩。连续添加冰乙酸替代残余溶剂,随后在不超过50℃的温度减压浓缩。
残余物溶于冰乙酸(15,000mL),温热至40-50℃和在该温度搅拌直至判断形成苯并咪唑(5)的环化完成。浓缩混合物,连续添加甲苯(3x7,500mL)替代残余溶剂,随后在不超过50℃的温度减压浓缩,直至乙酸含量小于20%w/w。残余物溶于甲苯(8,000mL),取样并在该点通过NMR测试。
所含的重量经计算是1240.9g(91%)。
δ(CDCl3;400MHz):1.35-1.55,1.85-2.10,2.16-2.60(m,14H,7x CH2,);3.34(m,1H,CHOMe);3.40(s,3H,CH3O);4.27(m,1H,CH-N);4.98(m,1H,HC-NC=O);6.42(s,1H,N-H);7.12(d,1H,Ar-H),7.57(d,1H,Ar-H);7.63(s,1H,Ar-H)ppm。
化合物(5)的甲苯溶液不加进一步纯化地使用。
实施例2:制备化合物(7)
试剂:Pd(P(Ph3)4,K2CO3,二噁烷,水,85-90℃
在40-50℃减压浓缩含有化合物(5)(818.8g,1.94mol)的甲苯溶液(5807.2g)。加入1,4-二噁烷(4100mL)替换剩余溶剂,在40-50℃减压浓缩。用温和加热(<30℃)将残余物溶于1,4-二噁烷(5700mL),冷却至15至25℃,加至无水碳酸钾(1114.6g,7.96mol)的纯水溶液(1640mL);随后二噁烷(820mL)线冲洗。加入3,5-二甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)异噁唑(630.7g,2.83mol),向混合物通氮大约1小时40分钟,随后快速加入四(三苯基膦)钯(114.3g,0.11mol)。反应加热至85至95℃并搅拌直至判断完成(一般18小时)。冷却至15至25℃之后,于15至30℃用纯水(11,500mL)淬灭反应。混合物用二氯甲烷(3x 3,200mL)萃取,在硫酸钠上干燥和过滤。减压浓缩滤液(<40℃),提供紫色糊状物,和通过1H NMR测试。
在该点化合物(7)的收率经估计是800.7g(94%)。
实施例3:化合物(7)的纯化和重结晶
通过在水浴设置为40至45℃的旋蒸仪上旋转10分钟将化合物(7)(2466.2g,5.84mol)溶于二氯甲烷(9865mL)。然后将溶液冷却至15至25℃,倾倒至二氧化硅短柱(11097.9g)。用5%MeOH/二氯甲烷从短柱洗脱所希望的化合物(7)直至洗脱液中观察不到更多的产物,其通过TLC与2mg/mL参比溶液比较确定;最终25000mL级分显示比参比溶液更弱的斑点指示完全洗脱。需要一共150000mL(60vol)的5%MeOH/二氯甲烷来完全洗脱产物即化合物(7)。
在浴温40至45℃的旋蒸仪上减压蒸发洗脱液直至干燥。将残余物溶于乙酸乙酯(12331mL),在浴温40至45℃的旋蒸仪上减压蒸发直至干燥以替代残余的MeOH/二氯甲烷。将乙酸乙酯(10840mL)加至残余物产生浆液,然后将其加热至70至75℃并保持在该温度40分钟,随后让其缓慢冷却过夜至15至25℃。过滤分离产物,滤饼用乙酸乙酯(5000mL)洗涤两次,然后在氮流下在滤器上干燥过夜达到0.1%w/w的乙酸乙酯含量(通过1H NMR确定)。制得米白色固体(2316.0g,93.9%th)。
δ(CDCl3;400MHz):1.20-1.50,1.80-2.00,2.10-2.45(m,12H,6x CH2,);2.30(s,3H,CH3-het);2.44(s,3H,CH3-het);2.67(m,1H,CH(H)-CO);2.83(m,1H,CH(H)-CO);3.29(m,1H,CHOMe);3.40(s,3H,CH3O);4.04(m,1H,CH-N);5.25(m,1H,HC-NC=O);6.41(s,1H,N-H);7.10(d,1H,Ar-H),7.48(d,1H,Ar-H);7.67(d,1H,Ar-H)ppm
实施例4:制备化合物(I)
试剂:Cu(OAc)2.H2O,空气,二氯甲烷,吡啶
将化合物(7)(975.4g,2.31mol)和3,4-二氟苯取代硼酸(731.7g,4.65mol)加入适宜的反应容器,随后加入二氯甲烷(8800mL),于15至25℃搅拌混合物10分钟。加入吡啶(1800mL),保持温度低于30℃(放热),随后加入二氯甲烷(490mL,线冲洗)和最后加入Cu(OAc)2.H2O(477.8g,1.03当量)。使得过滤空气在反应混合物上通过,于15至25℃将其搅拌至少16小时,直至判断反应完成。在30℃以下加入纯水(9750mL)猝灭反应,搅拌5分钟。分层,水相用二氯甲烷(4920mL)萃取。
经合并的有机萃取物用0.1M Na2EDTA.2H2O溶液(2x 5000ml)和1M盐酸(4x5000mL)洗涤。检查pH(目标<2)确认已除去全部吡啶。有机层然后用1.0M Na2CO3溶液(5020mL&5040mL)和13%w/v盐水(5100mL)洗涤,然后在Na2SO4上干燥,过滤。在45℃以下将有机滤液浓缩至5体积,加入脱色炭(197.6g),于15至25℃搅拌混合物至少45分钟,随后过滤和浓缩。用乙酸乙酯(5000mL)替换溶剂;分批加入,随后蒸发。将残余物溶于乙酸乙酯(2000mL)和加热至回流,然后加入正庚烷(3900mL)并保持至少60℃的温度,在此期间产物结晶。将所得悬浮液在1小时内冷却至15至25℃,并在15至25℃搅拌30分钟。过滤分离产物,滤饼用正庚烷(2x 2000mL)洗涤。固体在滤器上在氮下干燥4小时直至乙酸乙酯和正庚烷含量均低于1.0%w/w。化合物(1)的收率是1073.8g 87%)。
纯化
将粗制化合物(1)(2030.5g)和乙酸乙酯(14250mL)加热至回流(75至82℃),让所得溶液冷却至20℃至40℃然后热过滤。虽然用乙酸乙酯(250mL)线洗涤,将经合并的滤液加热至回流(75至82℃)。在回流下搅拌5分钟之后,在30分钟内加入正庚烷(6000mL);保持至少60℃的温度,然后调节至70℃。加入化合物(1)晶种(20.3g),搅拌混合物5分钟,然后检查确保晶种保持未溶解状态。在30分钟内加入额外的正庚烷(8000mL)并保持至少60℃的温度。再次将混合物加热至70至82℃和搅拌1小时。让所得悬浮液在多至24小时期间内冷却至15至25℃,过滤分离产物。
滤饼用正庚烷(2x 2000mL)洗涤,将滤器上的固体转移至真空炉并减压干燥4小时,直至乙酸乙酯和正庚烷含量均低于0.35%w/w。
所得化合物(1)的重量是1822.4g,(90%)
δ(CDCl3;400MHz):1.25-1.45,1.88-1.89,2.21-2.43(m,12H,6x CH2,);2.30(s,3H,CH3-het);2.43(s,3H,CH3-het);2.67(m,1H,CH(H)-CO);2.83(m,1H,CH(H)-CO);3.29(m,1H,CHOMe);3.39(s,3H,CH3O);4.05(m,1H,CH-N);5.26(m,1H,HC-NC=O);6.95-7.05(m,4H,Ar-H);7.48(d,1H,Ar-H);7.67(m,1H,Ar-H)ppm
实施例5:化合物(I)的X射线分析
X射线粉末衍射(XRPD)
在Bruker D8衍射仪上采集XRPD衍射图:用Cu Kα辐射(40kV,40mA)和配有Ge单色器的θ-2θ测角仪。
在环境条件下作为平板样本分析样品。形式1的XRPD衍射图示于附图1。
标准数据收集方法的细节如下:
·角范围:2至42°2θ
·步长:0.05°2θ
·收集时间:0.5s/步(总收集时间:6.40分钟)
单晶X射线衍射
对于单晶X射线衍射分析有足够尺寸和品质的化合物(I)晶体分离如下:在环境条件下从化合物(I)的乙酸丁酯溶液缓慢蒸发。衍生自单晶研究的结构的椭球图(ORTEP图)示于图2。
实施例6:片剂组合物
各自重0.15g和含有25mg化合物(I)的片剂制备如下:
10,000个片剂的组成
化合物(I)(250g)
乳糖(800g)
玉米淀粉(415g)
滑石粉(30g)
硬脂酸镁(5g)
混合化合物(I)、乳糖和一半的玉米淀粉。然后迫使混合物通过0.5mm目的筛网。将玉米淀粉(10g)悬浮于温水(90ml)中。所得糊状物用来给粉末造粒。在1.4mm目筛网上将颗粒干燥并破开形成小片段。加入剩余量的淀粉、滑石和镁,仔细混合和处理形成片剂。
实施例7:胶囊组合物
各自重0.21g和含有25mg化合物(I)的胶囊制备如下:
10,000个胶囊的组成
化合物(I)(250g)
维生素E聚乙二醇琥珀酸酯(1850g)
10,000个3号尺寸的明胶胶囊
在超过其熔点的温度(40℃)熔化维生素E聚乙二醇琥珀酸酯。然后混合化合物(I)和熔化的维生素E聚乙二醇琥珀酸酯形成无可视结块或聚集的均质混合物。将混合物保持在熔化状态,并将其充入3号尺寸的明胶胶囊。
实施例8:可注射配制剂
将化合物(I)溶于绝大部分的水(35°-40℃)和用盐酸或氢氧化钠酌情将pH调节至4.0至7.0。然后用水将该批料补充至体积,过滤通过无菌微孔滤器进入无菌10mL茶色玻璃小瓶(1型),用无菌封闭装置和顶封装置密封。
实施例9:肌内注射剂
将化合物(I)溶于四氢呋喃聚乙二醇醚。然后加入苄醇和溶解,加水至3ml。然后将混合物过滤通过无菌微孔滤器,密封于无菌3ml玻璃小瓶(类型1)中。
实施例10:糖浆配制剂
将化合物(I)溶于甘油和绝大部分纯水的混合物。然后向该溶液加入苯甲酸钠水溶液,随后加入山梨糖醇溶液和最终调味剂。用纯水补足体积并充分混合。
Claims (14)
2.根据权利要求1的方法,其中步骤(a)在四(三苯基膦)钯和碳酸钾存在下在1,4-二噁烷和水中进行。
3.根据权利要求1或2的方法,其中步骤(b)在二氯甲烷中在吡啶和Cu(OAc)2.H2O存在下进行。
4.根据权利要求1至3中任一项的方法,其还包括在步骤(b)之前纯化和重结晶式(7)中间体化合物。
5.根据权利要求4的方法,其中式(7)化合物借助通过二氧化硅短柱而纯化。
6.根据权利要求4或5的方法,其中式(7)化合物从乙酸乙酯重结晶。
8.根据权利要求7的方法,其中式(4)化合物与乙酸之间的反应在40°-50℃的温度进行。
10.根据前述权利要求中任一项的方法,其还包括从乙酸乙酯:正庚烷重结晶式(I)化合物并回收重结晶的产物。
11.根据前述权利要求中任一项的方法,其还包括将所得式(I)化合物与一种或多种药学上可接受的载体或稀释剂配制以产生药物组合物。
14.药物组合物,包含如权利要求12或13中所定义的化合物和一种或多种药学上可接受的载体或稀释剂。
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PCT/GB2019/051110 WO2019202332A1 (en) | 2018-04-18 | 2019-04-18 | Process for preparing modulators of p300 and/or cbp |
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CN112574189A (zh) * | 2019-09-27 | 2021-03-30 | 海创药业股份有限公司 | 一种ep300/cbp抑制剂 |
CN114989158A (zh) * | 2021-03-02 | 2022-09-02 | 复旦大学 | 组蛋白乙酰转移酶p300溴结构域抑制剂及其药用组合物及其应用 |
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AU2019256788A1 (en) | 2020-10-29 |
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