CN101384595A - Cd80拮抗剂的盐 - Google Patents

Cd80拮抗剂的盐 Download PDF

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CN101384595A
CN101384595A CNA2007800051162A CN200780005116A CN101384595A CN 101384595 A CN101384595 A CN 101384595A CN A2007800051162 A CNA2007800051162 A CN A2007800051162A CN 200780005116 A CN200780005116 A CN 200780005116A CN 101384595 A CN101384595 A CN 101384595A
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I·R·马修斯
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Abstract

CD80拮抗剂化合物4－(6－氟－3－氧代－1，3－二氢－吡唑并[4，3－c]噌啉－2－基)－N－(2，2－二氟－乙基)－苯甲酰胺的胆碱盐具有良好的水溶性，因此可方便地用于药学应用。

Description

CD80拮抗剂的盐
本发明涉及CD80拮抗剂化合物4-(6-氟-3-氧代-1，3-二氢-吡唑并[4，3-c]噌啉-2-基)-N-(2，2-二氟-乙基)-苯甲酰胺的胆碱盐。
发明背景
国际专利申请号WO 2004/08101涉及一类化合物，包括具有结构式(A)的化合物4-(6-氟-3-氧代-1，3-二氢-吡唑并[4，3-c]噌啉-2-基)-N-(2，2-二氟-乙基)-苯甲酰胺等：
Figure A200780005116D00031
WO 2004/08101所述的化合物是CD80拮抗剂，它能够抑制CD80和CD28的相互作用，因此可用于免疫抑制，例如治疗类风湿性关节炎。游离酸形式的化合物(A)的水溶性差。通常，作为药品口服给药，或在水基载体中胃肠外或局部给药时，需要化合物具有良好的水溶性特征。WO2004/08101也涉及化合物(A)所属化合物类型的盐。然而，并非所有该化合物的盐的水溶性均显著高于其游离酸形式，以便成为该化合物方便的口服给药形式或基于水溶液的形式。
发明概述
本发明基于以下发现：化合物(A)的胆碱盐具有所需的良好水溶性。
发明详述
本发明提供了上式(A)4-(6-氟-3-氧代-1，3-二氢-吡唑并[4，3-c]噌啉-2-基)-N-(2，2-二氟-乙基)-苯甲酰胺的胆碱盐。
含有所述胆碱盐和至少一种药学上可接受载体的口服给药的药物组合物也构成了本发明的一个方面。
所述胆碱盐的可注射水溶液，以及含有所述胆碱盐的局部应用水基液体(aqueous based liquid)或乳膏组合物构成了本发明的另一方面。
口服给药的组合物可以是片剂、胶囊、微型药片、粉末剂、颗粒剂、液体或凝胶制剂形式。口服给药的片剂和胶囊可以是单位剂量形式，并且可含有常用辅料，例如粘合剂，如糖浆、阿拉伯胶、明胶、山梨糖醇、西黄蓍胶或聚乙烯吡咯烷酮；填充剂，如乳糖、糖、玉米淀粉、磷酸钙、山梨糖醇或甘氨酸；压片润滑剂，如硬脂酸镁、滑石粉、聚乙二醇或二氧化硅；崩解剂，如马铃薯淀粉；或者可接受的湿润剂如十二烷基硫酸钠。可按照普通药学实践中熟知的方法对片剂包衣。口服液体制剂可以是(例如)水性或油性混悬剂、溶液剂、乳剂、糖浆剂或酏剂的形式，或者可以是临用前用水或其他合适的载体重建的干燥产品。这类液体制剂可含有常用的添加剂，例如助悬剂，如山梨糖醇、糖浆、甲基纤维素、葡萄糖糖浆、明胶、氢化食用脂肪；乳化剂，如卵磷脂、去水山梨糖醇单油酸酯或阿拉伯胶；非水性载体(可包含食用油)，如杏仁油、分级椰子油，油酯如甘油、丙二醇或乙醇；防腐剂，如对羟基苯甲酸甲酯或对羟基苯甲酸丙酯或山梨酸，如果需要还可含有常用调味剂或着色剂。
局部应用于皮肤时，可将药物制成乳膏剂、洗剂或油膏剂。可用于该药物的乳膏剂或油膏剂是本领域熟知的常规制剂，例如药剂学标准教科书如英国药典(British Pharmacopoeia)中所述。
也可通过注射或输注，以无菌介质经胃肠外途径给予活性成分。根据所用的载体和浓度，药物可悬浮或溶解于该载体中。有利的是，辅助试剂如局部麻醉剂、防腐剂和缓冲剂也可溶解于载体中。
以下实施例中进一步描述了本发明胆碱盐的制备和水溶性。
实施例：
如下所述，制备4-(6-氟-3-氧代-1，3-二氢-吡唑并[4，3-c]噌啉-2-基)-N-(2，2-二氟-乙基)-苯甲酰胺，并形成其胆碱(即(2-羟基-乙基)-三甲基-铵)盐：
N-(2，2-二氟-乙基)-4-(6-氟-3-氧代-1，3-二氢-吡唑并[4，3-c]噌啉-2-基)-苯甲酰胺的制备
将按照WO 2004/08101实施例5所述制备的4-(6-氟-3-氧代-1，3-二氢-吡唑并[4，3-c]噌啉-2-基)-苯甲酸(12.9g)装入装有磁力搅拌器、回流冷凝器和鼓泡器的圆底烧瓶中。缓慢加入亚硫酰氯(65ml)。施加氮气气氛，将该混合物加热至回流。观察到加热气体溢出后，将气体导入洗涤器中。气体发生终止时(约2小时后)，该混合物的颜色由橙红色悬液转变为深红色悬液，冷却至室温。真空去除过量亚硫酰氯，所得红色固体与甲苯(50ml)共沸。获得深红色固体，收集到无水DMA(65ml)中得到深红色溶液。将二异丙基乙胺(12.9g，17.4ml)与2，2-二氟氨基乙烷(3.24g，2.76ml)混合，用4-5分钟逐滴加入上述溶液中。观察到放热。室温下搅拌该混合物。
用0.5M HCl(150ml)终止该反应混合物，得到深红色悬液。过滤收集固体，用水洗涤。在室温下用甲醇(250ml)研磨该固体约1小时，过滤并用甲醇洗涤。在室温下用丙酮(250ml)研磨该固体约1小时，过滤并用丙酮洗涤。最后用乙酸乙酯(250ml)研磨该固体约45分钟，过滤并用乙酸乙酯洗涤。
将产物(约8g)收集到约10ml DMA中得到浓稠的深红色溶液。加入甲醇(150ml)和丙酮(150ml)，过滤收集沉淀。
LC-MS:一个所需产物的峰。该物质的QC分析显示纯度为91.6％。
2-[4-(2，2-二氟-乙基氨甲酰基)-苯基]-6-氟-2H-吡唑并[4，3-c]噌啉-3-酸(2-羟基-乙基)-三甲基-铵的制备
将N-(2，2-二氟-乙基)-4-(6-氟-3-氧代-1，3-二氢-吡唑并[4，3-c]噌啉-2-基)-苯甲酰胺(2.50g)加入装有磁力搅拌器的圆底烧瓶中。将固体悬浮于甲醇(25ml)中，逐滴加入胆碱氢氧化物(782mg，1.74ml 45％ w/w的甲醇溶液)。加入后形成澄清的深褐色溶液。室温下搅拌该溶液2小时。真空浓缩该反应混合物，得到深褐色油状物。加入乙酸乙酯(100ml)，获得两相体系。超声处理后，褐色油状物变得粘稠并开始固化。碾碎该固体，加入异丙醇(30ml)并将该混合物加热到65-70℃。获得悬浮液。将该混合物冷却至室温，用乙酸乙酯(约100ml)稀释。过滤收集固体，用乙酸乙酯(50ml)洗涤。真空干燥该固体。
LC-MS:分离的固体；一个主峰[M+H]+388，纯度95％。
固体盐是褐色粗粉末，2.26g，4.61mmol，71％。
熔点：172-180℃，分解。
如下所述，通过重结晶进一步纯化该产物：将该盐与乙醇混合，加热至回流，搅拌20分钟，趁热过滤。将滤过的乙醇溶液加热至回流，然后冷却至约5℃，搅拌1小时。接着过滤该溶液，用乙醇和庚烷洗涤，干燥至恒重。
用下述实验检测N-(2，2-二氟-乙基)-4-(6-氟-3-氧代-1，3-二氢-吡唑并[4，3-c]噌啉-2-基)-苯甲酰胺的胆碱盐在水和乙醇中的溶解度。也用相同实验检测N-(2，2-二氟-乙基)-4-(6-氟-3-氧代-1，3-二氢-吡唑并[4，3-c]噌啉-2-基)-苯甲酰胺的非盐形式(游离酸)及其一系列其它盐的溶解度。
溶解度实验
称取10mg受试化合物加入一管形瓶中，加入1ml溶剂。如果样品立即溶解形成澄清溶液，则加入更多的受试化合物，并将该管形瓶超声处理15分钟。重复该步骤，直到无法溶解更多的受试化合物(形成悬液)。然后将含有该悬液的管形瓶超声处理15分钟，并放置在振荡器上在25℃/60％相对湿度下振荡24小时。从振荡器中取出后，离心样品，用HPLC分析上清液。结果见表I。
 
测试的盐 水中的溶解度(mg/ml) 乙醇中的溶解度(mg/ml)
无(游离酸) <0.5 2.1
胆碱 >51 >21
钾 <5 <5
钠 <5 7.1
镁 <5 <5
赖氨酸 <5 <5
精氨酸 <5 <5

Claims (4)

1.式(A)的4-(6-氟-3-氧代-1，3-二氢-吡唑并[4，3-c]噌啉-2-基)-N-(2，2-二氟-乙基)-苯甲酰胺的胆碱盐。
Figure A200780005116C00021
2.一种口服给药的药物组合物，其含有权利要求1所述的胆碱盐和至少一种药学上可接受的载体。
3.如权利要求1所述的胆碱盐的可注射的水溶液。
4.一种局部应用的水基液体或乳膏组合物，其含有权利要求1所述的胆碱盐。
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BRPI0708114B8 (pt) 2021-05-25
JP2009527538A (ja) 2009-07-30
PL1991548T3 (pl) 2014-05-30
EP1991548B1 (en) 2013-12-11
US20180265514A1 (en) 2018-09-20
JP5102785B2 (ja) 2012-12-19
EP1991548A1 (en) 2008-11-19
AU2007217170A1 (en) 2007-08-30
KR101433738B1 (ko) 2014-08-25
DK1991548T3 (en) 2014-03-10
IL192954A (en) 2015-01-29
EA200801875A1 (ru) 2008-12-30
CN101384595B (zh) 2011-02-09
KR20080103523A (ko) 2008-11-27
IL192954A0 (en) 2009-02-11
WO2007096588A1 (en) 2007-08-30
EA014101B1 (ru) 2010-08-30
CA2643668A1 (en) 2007-08-30
BRPI0708114A2 (pt) 2011-05-17
PT1991548E (pt) 2014-03-10
NZ570055A (en) 2011-08-26
US20090221590A1 (en) 2009-09-03
CA2643668C (en) 2014-05-13
AU2007217170B2 (en) 2012-02-02
US20120004237A1 (en) 2012-01-05
ZA200806508B (en) 2009-06-24

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