CN1283188A - Hiv蛋白酶抑制剂的硫酸氢盐 - Google Patents
Hiv蛋白酶抑制剂的硫酸氢盐 Download PDFInfo
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Abstract
本发明提供下式(Ⅱ)的结晶硫酸氢盐其中发现该化合物比此氮杂肽HIV蛋白酶抑制剂化合物的游离碱形式具有预想不到地高的溶解度/溶解速率和口服生物利用度。
Description
发明背景
1．发明领域
本发明提供了一种新的下式所示的氮杂肽HIV蛋白酶抑制剂的结晶硫酸氢盐：
其比其他盐表现出乎意料外地优越的水溶解度／溶解行为，并且在动物体内比其游离碱具有明显提高了的口服生物利用度。因此，该硫酸氢盐适用于上述蛋白酶抑制剂的药物剂型，特别是口服剂型。
2．现有技术
已公开的PCT专利申请WO 97／40029描述了一系列的氮杂肽HIV蛋白酶抑制剂，据称它们对HIV病毒具有高度的抑制活性。包括在WO97／40029保护范围中的一个化合物是具有下列结构式的化合物：
并且其化学名称为[3S-(3R*，8’R*，9’R*，12R*)]-3，12-双(1，1-二甲基乙基)-8-羟基-4，11-二氧代-9-(苯甲基)-6-[[4-(2-吡啶基)-苯甲基]-2，5，6，10，13-五氮杂十四烷二酸二甲酯，该化合物被评价为一种可能的第二代HIV蛋白酶抑制剂。
WO 97／40029公开了氮杂肽衍生物如化合物Ⅰ的游离碱形式以及多种药学上可接受的酸加成盐。虽然该文献提及了数种有机酸和无机酸，其中包括硫酸，作为可能的盐形成剂，但它未提及作为本申请主题的具体的硫酸氢盐。
发明概述
本发明提供了具有以下结构式的上述化合物Ⅰ的硫酸氢盐：
发明详述
如上公开的化合物Ⅰ是一种弱有机碱，其在水中的溶解度在24±3℃下小于1μg／mL。结晶游离碱形式在水或油中形成动物体内口服生物利用度极低的悬浮液，这可能归因于该化合物在这些载体中溶解性极差。
为了开发药物制剂，特别是口服剂型，活性组分必须具有足够的口服生物利用度。由于化合物Ⅰ的游离碱形式不具备这种生物利用度，本发明人对酸加成盐进行了研究。除了本发明的硫酸氢盐以外，也对许多常用的酸加成盐例如盐酸盐、苯磺酸盐、甲磺酸盐、对甲苯磺酸盐、磷酸盐、硝酸盐、1，2-乙烷二磺酸盐、羟乙基磺酸盐和硫酸盐作出了评估。所有这些盐的结晶形式在水中表现为溶解度较低(在24±3℃下等于或小于1-3mg／ml)，它们的溶解度均小于相同条件下硫酸氢盐约为4-5mg／ml的溶解度。
当将上述其他的酸加成盐悬浮在水中时可以观察到固体状态转变，这可能归因于其解离生成游离碱。在绝大多数情况中，这种转变同时伴随有凝胶形成。与上述其他盐不同的是，硫酸氢盐的额外质子可以阻止向游离碱的转变，正如上面所述，其游离碱极难溶于水且口服生物利用度很低。硫酸氢盐在水中特有的溶解性行为将在下文中作进一步详细说明。
通常，盐向未电离形式的转化或逆向转化均可以基于pH-溶解度原理解释。在水中测定的游离碱的溶解度是24±3℃下pH的函数，如下图所示。化合物具有最高溶解度时的pH被称作pHmax且发现该值约为1．2。文献业已报导，当pH＞弱碱有机化合物的pHmax时，存在于化合物的水悬浮液中的平衡固相为游离碱。当pH＜pHmax时，平衡固体转化为相应盐的形式。术语“平衡固相”是指经过足够的平衡时间之后化合物悬浮液中未溶解或过量的固体。当弱碱的盐以高于其溶解度极限的量在水中保持平衡时(即盐在水中的悬浮液)，所得混悬液的pH可能高于或低于pHmax，这取决于酸在其它因素中的强度。当所得pH高于pHmax时，悬浮固体可转化为游离碱。
对特别是游离碱的甲磺酸盐和盐酸盐研究业已证实了上述文献中报道的一般性发现。这些盐以高于其溶解度的量在24±3℃的水中平衡至少24小时。混悬液在平衡后的pH为2．1±0．1，它大于pHmax。从这些悬浮液中分离出未溶解的固体，风干且定性分析。通过热分析和元素分析，分离自这些悬浮液的未溶解固体被鉴定为游离碱。这种溶解行为是基于由上述曲线图和文献所述研究中显示出的pH-溶解度性能可预期的。
当过量的硫酸氢盐在水中达到平衡时，溶液平衡中的固相发生变型。然而，尽管悬浮液的pH(1．9±0．2)大于pHmax且与上述甲磺酸盐和盐酸盐的悬浮液的pH相差不大，在达到平衡后未溶解固相并不是游离碱。利用元素分析来鉴别平衡至少24小时后的固相，该固相为游离碱形式和硫酸的2∶1盐(也称作硫酸盐)的水合形式。硫酸氢盐的这种行为基于pH-溶解度原理是无法预料。
当过量的硫酸盐再在水中达到平衡时，溶液平衡中的固相发生变型。分离出该悬浮液中的未溶解固体，风干且定性。尽管硫酸盐对游离碱的转变不如同甲磺酸盐和盐酸盐般明确，但对这种未溶解固相的热学和元素分析类似于游离碱的。从药学观点看，盐在含水环境中转化为游离碱的倾向是不利的，这是因为游离碱的口服生物利用度很低。所以，硫酸氢盐因其在水中的独特溶解行为而提供了意外的优越性。
硫酸氢盐在水中的溶解行为就在水中化合物Ⅰ游离碱和硫酸相互作用而论也是意外的。例如，用硫酸调节pH为～1．8时游离碱在水中表现为溶解度小于1mg／ml，这可以和在相当的条件下硫酸氢盐的溶解度为4-5mg／m对比。基于pH-溶解度原理，游离碱和盐在指定的pH下应该表现出相似的溶解性。
硫酸氢盐的增高溶解度／溶解形式为其在动物中提供了比游离碱改进的口服生物利用度。当以装在明胶胶囊内的未配制固体形式给药时发现，硫酸氢盐的绝对口服生物利用度在狗中约为20％。与此相比，结晶游离碱在狗中的口服生物利用度极低。
除了最佳溶解度，固态的良好物理稳定性是药用盐形式的另一个理想特性。术语“物理稳定性”是指盐形式在保藏／应力条件下保持其晶体结构(包括结晶的溶剂，如果存在的话)的能力。通过热学方法(例如差示扫描量热法)测定出盐形式的物理特性发生的显著变化是不利的。当在40℃／75℃相对湿度(RH)下保藏时，硫酸氢盐在长达9个月内具有优异的固态物理稳定性，如下图Ⅱa所示。差示扫描量热法表明，硫酸氢盐的受应力样品与未受应力样品(在2-8℃的密闭容器中保藏)相比在热学行为上没有明显的差别。另一方面，当在40℃／75％RH下短期保藏2周时，甲磺酸盐、盐酸盐和硫酸盐在其热学行为上表现有显著的变化，如图Ⅱb、c和d所示。虽然盐形式的物理稳定性的差异是不寻常的，但特定盐形成溶剂化物(或结晶改性(crystal modifications))的倾向及其在保藏／应力条件下保留结晶溶剂的能力(结晶改性的物理稳定性)是事先无法预料的。
Ⅱa．硫酸氢盐的物理稳定性。实线代表未受应力材料。虚线代表在40℃／75％RH受应力9个月的材料。
Ⅱb．盐酸盐的物理稳定性。实线代表未受应力的材料。虚线代表在40℃／75％RH受应力2周的村料。
Ⅱc．甲磺酸盐的物理稳定性。实线代表未受应力材料。虚线代表在40℃／75％RH受应力2周的材料。
Ⅱd．硫酸盐的物理稳定性。实线代表未受应力材料。虚线代表在40℃／75％RH受应力2周的材料。
所述硫酸氢盐的制备可以通过在溶剂如乙腈、异丙醇、乙醇或丙酮中形成化合物Ⅰ游离碱和硫酸的溶液且随后分离出所得的硫酸氢盐。
因其高度的生物利用度及其良好的结晶性和稳定性，硫酸氢盐极其适用于制备化合物Ⅰ的口服剂型。下列实施例举例说明代表性口服制剂的制备。
硫酸氢盐及其制剂如在WO 97／40029中所述被用来治疗病毒，特别是反转录病毒如HIV病毒，所引起的疾病。
具体实施方案的描述
实施例1
由乙醇制备硫酸氢盐
向500ml安装有顶部搅拌器和滴液漏斗的三颈圆底烧瓶中，在搅拌下加入15．013g(0．0213mole)化合物Ⅰ的游离碱和113ml的200标准的乙醇。在约90秒内向此悬浮液中滴加1．28ml的浓硫酸。加入硫酸之后，得到澄清的琥珀色溶液。用#1 Whatman滤纸净化过滤该溶液且用5ml的200标准的乙醇洗涤。向此溶液中加入58ml庚烷和37．5(0．25％重量)式Ⅱ化合物的晶种，随后再另外加入55ml庚烷。所得混合物在300rpm下搅拌6小时。将所得结晶浆液过滤且用50ml乙醇／庚烷(1∶1)溶液洗涤且在60℃的真空下干燥过夜，得到15．11g如上式Ⅱ所示的所需结晶硫酸氢盐(收率为88．4摩尔％)。
硫酸氢盐的特性元素分析：计算值C38H52N6O·1．0H2SO4：C，56．84；H，6．78；N，10．37；S，3．99。实测值：C，56．72；H，6．65；N，10．41；S，3．83．m．p．195．0°H2O=0．28％(KF)
实施例2
由丙酮制备硫酸氢盐
在机械搅拌下，将5M H2SO4(8．52ml，42．6mM)滴加至处于50℃油浴中的式Ⅰ游离碱化合物(30．0g，42．6mM)的丙酮(213mL)悬浮液中。几乎立刻得到澄清溶液。在该溶液内加入式Ⅱ游离碱化合物的晶种。2分钟后，形成沉淀，溶液变为糊状物。将该混合物在50℃下搅拌1小时，在25℃下搅拌30分钟且在0℃下搅拌2小时。过滤固体并且利用第一批滤液将烧瓶内的残余物转移到过滤漏斗中。产物用依次用丙酮、庚烷洗涤并且在真空下干燥过夜，得到31．48g(校正收率92％)的式Ⅱ硫酸氢盐，m．p．198-199℃，分解。元素分析：计算值C38H52N6O7·1．0 H2SO4·0．2 H2O：C，56．59；H，6．80；N，10．42；S，3．98；H2O，0．45。实测值：C，56．66；H，6．78；N，10．50；S，4．20；H2O，0．45(KF)。
实施例3
由异丙醇制备硫酸氢盐
将硫酸水溶液(5．0M，0．20mL，1mM)加入到冰浴中冷却的式Ⅰ化合物游离碱(0．704g，1．00mM)的异丙醇(4．0ml)悬浮液中。除去冰浴且在室温下搅拌该混合物。15分钟后悬浮液溶解。在该溶液内放入实施例1或2制备的晶种且搅拌5小时。过滤固体且用滤液将烧瓶内的固体转移到漏斗中。用庚烷洗涤产物且在真空下干燥，得到0．752g的式Ⅱ硫酸氢盐结晶，收率90％，m．p．160-190℃，分解。元素分析：计算值C38H52N6O7·1．0 H2SO4·2．0 H2O：C，54．40；H，6．97；N，10．02；S，3．82；H2O，4．29。实测值：C，54．25；H，6．73；N，10．02；S，3．67；H2O，4．53(KF)。
由异丙醇得到的结晶在粉末X射线衍射图谱上表现出不同于由乙腈、乙醇-庚烷或丙酮得到的结晶。它们现在称为Ⅱ型晶体。Ⅰ型晶体似乎是无水／去溶剂化结晶物，而Ⅱ型晶体是水合、吸湿性晶型。
实施例4
硫酸氢盐的胶囊制剂的制备
A．胶囊(50和200mg游离碱当量)
提供的胶囊适于口服给药，其中该胶囊是#0大小、灰色、不透明的硬明胶胶囊，其中含有利用湿法制粒与乳糖、聚乙烯聚吡咯烷酮和硬脂酸镁一起配制的式Ⅱ化合物的硫酸氢盐。
B．胶囊(100mg游离碱当量)
提供的胶囊适于口服给药，其中该胶囊为#0大小、灰色、不透明的硬明胶胶囊，该胶囊内含有悬浮在Gelucire 44／14中的式Ⅱ化合物的硫酸氢盐。Gelucire 44／14是饱和聚乙二醇化甘油酯，它由甘油一酯、二酯和三酯和聚乙二醇的一和二脂肪酸酯组成。胶囊的制备是通过将Gelucire44／14在45-70℃下熔融，随后在搅拌下加入硫酸氢盐。将熔融的混合物填充到硬明胶胶囊中且令其冷却且固化。
Claims (2)
1．具有下式的硫酸氢盐
2．一种药物剂型，含有权利要求1所述的硫酸氢盐和药学上可接受的载体。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US7196898P | 1998-01-20 | 1998-01-20 | |
| US60/071,968 | 1998-01-20 |
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| Publication Number | Publication Date |
|---|---|
| CN1283188A true CN1283188A (zh) | 2001-02-07 |
| CN1116282C CN1116282C (zh) | 2003-07-30 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN98812741A Expired - Lifetime CN1116282C (zh) | 1998-01-20 | 1998-12-22 | Hiv蛋白酶抑制剂的硫酸氢盐 |
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| Country | Link |
|---|---|
| US (1) | US6087383A (zh) |
| EP (1) | EP1056722B1 (zh) |
| JP (2) | JP4860037B2 (zh) |
| KR (1) | KR100559283B1 (zh) |
| CN (1) | CN1116282C (zh) |
| AR (1) | AR014417A1 (zh) |
| AT (1) | ATE219057T1 (zh) |
| AU (1) | AU735875B2 (zh) |
| BG (1) | BG64774B1 (zh) |
| BR (1) | BR9814736A (zh) |
| CA (1) | CA2317736C (zh) |
| CO (1) | CO4970820A1 (zh) |
| CZ (1) | CZ293507B6 (zh) |
| DE (1) | DE69806067T2 (zh) |
| DK (1) | DK1056722T3 (zh) |
| EE (1) | EE04434B1 (zh) |
| EG (1) | EG23936A (zh) |
| ES (1) | ES2178300T3 (zh) |
| GE (1) | GEP20033026B (zh) |
| HK (2) | HK1033667A1 (zh) |
| HU (1) | HU227196B1 (zh) |
| IL (2) | IL137384A0 (zh) |
| LT (1) | LT4780B (zh) |
| LV (1) | LV12522B (zh) |
| MY (1) | MY114838A (zh) |
| NO (1) | NO315605B1 (zh) |
| NZ (1) | NZ504417A (zh) |
| PE (1) | PE20000185A1 (zh) |
| PL (1) | PL190744B1 (zh) |
| PT (1) | PT1056722E (zh) |
| RO (1) | RO118869B1 (zh) |
| RU (1) | RU2186070C2 (zh) |
| SK (1) | SK283975B6 (zh) |
| TR (1) | TR200001876T2 (zh) |
| TW (1) | TW531531B (zh) |
| UA (1) | UA59432C2 (zh) |
| UY (1) | UY25345A1 (zh) |
| WO (1) | WO1999036404A1 (zh) |
| ZA (1) | ZA9956B (zh) |
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| CN104250223A (zh) * | 2013-06-28 | 2014-12-31 | 上海威智医药科技有限公司 | 阿扎那韦氢溴酸盐及其制备和应用 |
| CN104250225A (zh) * | 2013-06-28 | 2014-12-31 | 上海威智医药科技有限公司 | 阿扎那韦磷酸盐及其制备和应用 |
| CN105596356A (zh) * | 2003-01-14 | 2016-05-25 | 吉里德科学公司 | 用于联合抗病毒治疗的组合物和方法 |
| CN109251165A (zh) * | 2018-10-02 | 2019-01-22 | 黄胜利 | 阿扎那韦达二4-氨基苯磺酸盐及其制备方法 |
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| BG66056B1 (bg) * | 2006-10-05 | 2010-12-30 | Красимир ДЕЧЕВ | Метод и инсталация за производство на трисезонна добавка към дизелово гориво |
| BRPI0823520A2 (pt) | 2007-06-12 | 2013-12-17 | Concert Pharmaceuticals Inc | Composto derivado de azapeptídeos e composição farmacêutica contendo o mesmo |
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| PT2170292E (pt) * | 2007-06-22 | 2014-03-06 | Bristol Myers Squibb Holdings Ireland | Composições de comprimido contendo atazanavir |
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| DE602008005316D1 (de) * | 2007-06-22 | 2011-04-14 | Bristol Myers Squibb Co | Tablettierte atazanavirhaltige zusammensetzungen |
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| PL2493312T3 (pl) | 2009-10-26 | 2022-01-03 | Merck Sharp & Dohme Corp. | Kompozycje farmaceutyczne w postaci ciała stałego zawierające inhibitor integrazy |
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| CN105859611A (zh) * | 2016-04-18 | 2016-08-17 | 上海现代制药海门有限公司 | 一种阿扎那韦硫酸氢盐a型结晶的制备方法 |
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| US5849911A (en) * | 1996-04-22 | 1998-12-15 | Novartis Finance Corporation | Antivirally active heterocyclic azahexane derivatives |
| TW409125B (en) * | 1996-04-22 | 2000-10-21 | Novartis Ag | Antivirally active heterocyclic azahexane derivatives |
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105596356A (zh) * | 2003-01-14 | 2016-05-25 | 吉里德科学公司 | 用于联合抗病毒治疗的组合物和方法 |
| CN1980666B (zh) * | 2004-05-04 | 2011-03-30 | 布里斯托尔-迈尔斯斯奎布公司 | 制备阿扎那韦硫酸氢盐的方法和新的形式 |
| CN101565398B (zh) * | 2004-05-04 | 2011-12-14 | 布里斯托尔-迈尔斯斯奎布公司 | 制备阿扎那韦硫酸氢盐的方法和新的形式 |
| CN104250223A (zh) * | 2013-06-28 | 2014-12-31 | 上海威智医药科技有限公司 | 阿扎那韦氢溴酸盐及其制备和应用 |
| CN104250225A (zh) * | 2013-06-28 | 2014-12-31 | 上海威智医药科技有限公司 | 阿扎那韦磷酸盐及其制备和应用 |
| CN104250223B (zh) * | 2013-06-28 | 2017-04-12 | 上海威智医药科技有限公司 | 阿扎那韦氢溴酸盐及其制备和应用 |
| CN109251165A (zh) * | 2018-10-02 | 2019-01-22 | 黄胜利 | 阿扎那韦达二4-氨基苯磺酸盐及其制备方法 |
| CN109251165B (zh) * | 2018-10-02 | 2022-09-23 | 国药集团川抗制药有限公司 | 阿扎那韦达二4-氨基苯磺酸盐及其制备方法 |
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