CN1003934B - 生产噻唑烷二酮的方法 - Google Patents

生产噻唑烷二酮的方法 Download PDF

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CN1003934B
CN1003934B CN86100411.6A CN86100411A CN1003934B CN 1003934 B CN1003934 B CN 1003934B CN 86100411 A CN86100411 A CN 86100411A CN 1003934 B CN1003934 B CN 1003934B
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ethyoxyl
pyridine radicals
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目黑宽司
藤田刚
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Takeda Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/30—Oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Abstract

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Description

生产噻唑烷二酮的方法
本发明涉及新颖的噻唑烷二酮衍生物、制备这类衍生物以及用于医药领域的含有这类衍生物的抗糖尿病药剂的方法。
在临床上，使用各种双缩胍和磺酰尿衍生物作为抗糖尿病药剂。
但是，现在很少使用双缩胍类，因为双缩胍往往引起乳酸中毒;而且，虽然磺酰尿类具有很强的降血糖活性，但是使用磺酰尿类时，必须十分小心，因为它们往往造成严重的低血糖。因此，一直期待着一种新型的无这类缺点的抗糖尿病药剂。
在另一方面，在日本特开昭55-22636和特开昭55-64586以及“化学和药物公报”（Chemical ＆ Pharmaceutical Bulletion），第30卷，第3563页（1982），以及同一上述文献，第30卷，第3580页（1982）和第32卷，第2267页（1984）等文献中，提到了具有使血葡萄糖和血脂降低作用的各和噻唑烷二酮类。在“糖尿病”（Diabetes），第32卷，第804页（1983）之中，也报道了西格利塔腙（Ciglitazone）的抗糖尿病活性。但是，这些化合物均未在实践中采用。可以提出的理由是：1）活性不足，或者/和2）有强毒性。
本发明人合成了各种在上面提到的日本特许公开说明书中未具体描述过的各种化合物，而且对其进行了研究，发现这些化合物具有潜在的药理作用，而且毒性较小。
本发明要提出一些在医疗上可以作为抗糖尿病药剂使用的化合物，这些化合物在药理作用和毒性或者不希望有的副反应之间具有很宽的安全范围。
本发明涉及：
1）（Ⅰ）式化合物
Figure 86100411_IMG5
（Ⅰ）
或其药理上可接受的盐，
2）抗糖尿病药剂，其中含有（Ⅰ）式化合物或其药理上可接受的盐作为有效成分，以及
3）制备（Ⅰ）式化合物或其药理上可接受盐的方法，其中包括使下式化合物水解：
Figure 86100411_IMG6
（Ⅱ）
用上面的（Ⅰ）式所表示的化合物，具体地说包括下列物质：
5-〔4-〔2-（3-乙基-2-吡啶基）乙氧基〕苄基〕-2，4-噻唑烷二酮，
5-〔4-〔2-（4-乙基-2-吡啶基）乙氧基〕苄基〕-2，4-噻唑烷二酮，
5-〔4-〔2-（5-乙基-2-吡啶基）乙氧基〕苄基〕-2，4-噻唑烷二酮，
5-〔4-〔2-（6-乙基-2-吡啶基）乙氧基〕苄基〕-2，4-噻唑烷二酮。
本发明的化合物（Ⅰ），在分子中既包含碱性氮也包含酸性氮，而且可以用适当的酸或碱在需要时使之转变成药理上可接受的盐。
这种酸的盐类，例如有无机酸盐（如盐酸盐、氢溴酸盐和硫酸盐等等）、有机酸盐（如丁二酸盐、顺丁烯二酸盐、反丁烯二酸盐、苹果酸盐和酒石酸盐等等）以及磺酸盐（例如甲磺酸盐、苯磺酸盐和甲苯磺酸盐等等）。这种碱的盐，例如有碱金属盐（如钠盐、钾盐）和碱土金属盐（如钙盐等），所有这些盐实际都用已知的方法制备。
本发明的（Ⅰ）式化合物或其药理上可接受的盐，具有降低血葡萄糖和血脂的作用，而且毒性较小;可以直接使用它们，或者以与业已知道的药理上可接受的载体、赋形剂或填料组成混合物的形式使用，以作为哺乳动物（包括人）的抗糖尿病药剂。
这种抗糖尿病药剂，通常以片剂、胶囊（包括软胶囊和微胶囊）剂、粉剂和粒剂等以进行口服投药，而且根据情况，也可以以注射液、栓剂和小丸片等形式进行非肠道投药。成年病人的口服药量最好为0.05-10mg/公斤体重/天，非肠道投药量为0.01-10mg/公斤体重/天，每天一次，或者每周分成2-4次。
由上面提到的通式（Ⅰ）所代表的化合物及其药理上可接受的盐（以下统称“化合物（Ⅰ）”），可由对式（Ⅱ）所代表的化合物进行水解的方法制备。这种水解反应，最好在适当溶剂中用无机酸的条件下进行。所用的溶剂例如有醇类（例如甲醇、乙醇、丙醇、丁醇、异丁醇和2-甲氧基乙醇等）、二甲基亚砜、二氧噻吩烷、二噁烷、四氢呋喃和二甲氧基乙烷等;所用的无机酸例如有盐酸、氢溴酸和硫酸等。水解反应的温度范围从20℃至150℃。反应时间为0.5-20小时。
所制备的上述通式为（Ⅰ）的化合物或其药理上可接受的盐可用传统的浓缩、萃取、重结晶、色层等方法进行分离和纯化。
由上面提到的通式（Ⅱ）所代表的化合物，可以通过下述反应制备：
Figure 86100411_IMG7
其中R代表氢或者低级烷基。
由R所代表的低级烷基，包括甲基、乙基、丙基、异丙基和丁基等类似的C1-C4烷基。
由化合物（Ⅲ）和化合物（Ⅳ）制备化合物（Ⅴ）的反应，是在例如氢化钠存在下进行的。这个反应，可以在-10℃至30℃温度范围内，于某种溶剂中，例如在二甲基甲酰胺和四氢呋喃中进行。由化合物（Ⅴ）生成化合物（Ⅵ）的反应，很容易通过传统的催化还原。采用例如钯-碳作为催化剂来实现，可以以纯产物的形式分离化合物（Ⅵ），也可以使化合物（Ⅵ）在不分离、不提纯的条件下直接进行下一步反应。通过在氢溴酸水溶液存在下，使化合物（Ⅵ）进行重氮化，然后在铜催化剂存在下，例如氧化亚铜、氧化铜、氯化亚铜、氯化铜、溴化亚铜、溴化铜等存在下，使生成物与丙烯酸或者其低级烷基酯（Ⅶ）反应（米尔文芳基化作用，Meerwein arylation），制备化合物（Ⅶ）。化合物（Ⅶ）可以用例如色谱法提纯，而且可以不经分离或者提纯直接进行随后的反应。
然后使化合物（Ⅷ）与硫脲反应生成化合物（Ⅱ）。这个反应通常是在醇类（例如甲醇、乙醇、丙醇、丁醇、异丁醇和α-甲氧基乙醇等）、二甲基亚砜和四氢噻吩砜等之中进行。反应温度通常为20-180℃，最好为60-150℃。所使用的硫脲量，相对于每摩尔化合物（Ⅶ）有1-2摩尔硫脲。
对于这个反应来说，在反应进行时，产生付产物溴化氢，因此为了捕获此付产物，可以在乙酸钠或乙酸钾等存在下进行此反应，其用量相对于每摩尔化合物（Ⅷ）为1-1.5摩尔。可以分离生成的化合物（Ⅱ），但是也可以不经分离直接进行水解。
本发明的化合物（Ⅰ），具有优良的使血葡萄糖和血脂降低的活性，而且毒性很低，这一点可用下列实验数据来证实。
实验例
1.小鼠体内血糖和血脂降低活性
将试验化合物（在三个剂量水平下）以CE-2粉末食物的规定食物混合物形式（CLEA日本）给雄性KKAy鼠（8-10周的鼠，每组5只）喂食，同时使之自由饮水四天。
在第五天，自鼠眼眶静脉中取出血样。
采用葡萄糖氧化酶法和使用在市场可买到的分析仪器Cleantech TG-S（Iatron，日本），分别测定血液葡萄糖和血浆甘油三酯（TG）。根据血液葡萄糖和血浆甘油三酯降低活性的剂量响应曲线，计算了每个试验化合物与对照值相比减小25%的有效剂量，作为ED25值（mg/公斤/天）。结果示于表1之中。
2.大鼠体内血脂降低活性
给雄性Sprague-Dawley大鼠（7周的大鼠，每组5只）供给实验室食物（日本，CLEA，CE-2），同时使之自由饮水。让这些鼠强制性经口投药这些试验化合物（三个剂量水平），四天投药的试验化合物均悬浮于5%的阿拉伯胶溶液中。在第五天，自大鼠尾静脉中取出血液样品。使用市场上可以买到的分析仪器Cleantech TG-S（Iatron）测定血浆甘油三酯。根据血脂降低活性的剂量响应曲线，计算了每个试验化合物的血脂减少与对照值相比为25%的有效剂量，作为ED25值（mg/公斤/天）。结果列于表1之中。
3.大鼠的两周毒性研究
给雄性和雌性Sprague-Dawley大鼠（五周的大鼠，每组五只）进食实验室食物（日本，CLEA，CE-2），同时使之自由饮水，给这些大鼠强制地经口投药试验化合物二周，每日一次，所有的试验化合物均悬浮于5%的阿拉伯胶溶液中。每个试验化合物的剂量为100mg/公斤/天。当两周投药结束后，在乙醚麻醉的条件下，使用经肝素化的注射器从腹主动脉中抽取血液样品，经过大约20小时禁食，杀死这些动物，切除肝脏〈＆＆〉，称重。使用自动细胞计数器进行血液分析。这些数据表示相对于对照值增加或者减少的百分数，正如表1中所示的那样。
在表1中，化合物（Ⅰ）是属于本发明范围内的一个化合物，而化合物（a）和（b）是在日本特开昭55-22636中具体提到的已知化合物。
虽然化合物（c）、（d）和（e）未在上面提到的专利申请中具体提过，但是也引证了以便于比较，因为这些化合物在其化学结构上与本发明的化合物（Ⅰ）类似。正如表1中给出的实验结果所表明的那样，本发明的化合物（Ⅰ）在降血糖和降血脂活性方面优于化合物（a）、（c）、（d）和（e），而与化合物（b）相当，和（a）、（b）、（d）和（e）化合物相比，其毒性极低。通过引入乙基所带来的上述效果完全出乎意料。因此，本发明的化合物（Ⅰ）表现有良好的降低血糖和低血脂活性，而且即使连续长时间投药的条件下对内部器官和血液的毒性均极小。所以化合物（Ⅰ）对于哺乳动物（包括人）的Ⅱ型糖尿病及其伴随的肥胖症和血脂过多症是有价值的治疗药剂。
实施例1
a）在冰冷却的条件下，将在油（16.0克）中的60%的氢化钠分批加入2-（5-乙基-2-吡啶基）乙醇（53.0克）和4-氟硝基苯（47.0克）的二甲基甲酰胺（500ml）溶液中，将此混合物在冰冷却的条件下搅拌1小时，然后在室温下搅拌30分钟，倒入水中，用乙醚萃取，用水洗涤乙醚层，经MgSO4干燥，蒸除溶剂，制得晶体状4-〔2-（5-乙基-2-吡啶基）乙氧基〕硝基苯（62.0克，产率62.9%），经乙醚-己烷重结晶后，制成无色的棱晶体，熔点53-54℃。
b）在10%Pd-C催化剂（50%湿品，6.0克）存在下，于室温和1大气压条件下，使溶解在甲醇（500ml）中的4-〔2-（5-乙基-2-吡啶基）乙氧基〕硝基苯（60.0克）的溶液氢化，过滤除去催化剂，在减压下浓缩滤液，将残留的油状物溶解在丙酮（500ml）-甲醇（200ml）之中，在此溶液中加入47%的HB，水溶液（152克），冷却此混合物，在不高于5℃条件下，在此混合物中滴加NaNO2（17.3克）的水（30ml）溶液，5℃下将此全部混合物搅拌20分钟，然后在其中加入丙烯酸甲酯（112克），使温度提高到38℃，剧烈搅拌下，在此混合物中逐渐加入氧化亚铜（2.0克）。搅拌此混合物直至停止产生氮气为止，在减压下加以浓缩，用浓氨水碱化此浓集物，用乙酸乙酯萃取，乙酸乙酯层用水洗涤，干燥（MgSO4）。蒸发除去溶剂，残留下2-溴-3-｛4-〔2-（5-乙基-2-吡啶基）乙氧基〕苯基｝丙酸甲酯，呈原油状物（74.09克，85.7%）。红外光谱（净）Cm-1：1735。核磁共振δ（PPm）（在CDCl3中）：1.21（3H，t，J＝7），2.60（2H，q，J＝7），3.0-3.6（4H，m），3.66（3H，s），4.30（2H，t，J＝7），4.3（1H，m），6.7-7.5（6H，m），8.35（1H，d，J＝2）。
c）将在b）中得到的2-溴-3-｛4-〔2-（5-乙基-2-吡啶基）乙氧基〕苯基｝丙酸甲酯（73.0克）、硫脲（14.2克）、乙酸钠（15.3克）和乙醇（500ml）的混合物，迴流下搅拌3小时，减压下浓缩此反应混合物，用碳酸氢钠饱和水溶液中和得到的浓集物，在其中加入水（200ml）和乙醚（100ml）。将全部混合物搅拌10分钟，生成5-｛4-〔2-（5-乙基-2-吡啶基）乙氧基〕苯基｝-2-亚胺基-4-噻唑烷二酮晶体（0.3克，52.30%）。经甲醇重结晶后，得到无色棱晶体，熔点187-188℃（分解）。C19H21N3O2S的元素分析结果：
计算值：C，64.20;H，5.95;N，11.82。
测得值：C，64.20;H，5.84;N，11.73。
d）将5-｛4-〔2-（5-乙基-2-吡啶基）乙氧基〕苄基｝-2-亚胺基-4-噻唑烷二酮（23.5克）的2NHCl（200ml）溶液迴流6小时。减压下蒸除溶剂，用碳酸氢钠饱和水溶液中和此残余物。过滤收集沉淀出的晶体（23.5克，97.5%），用二甲基甲酰胺-水重结晶，制得无色针状的5-｛4-〔2-（5-乙基-2-吡啶基）乙氧基〕苄基｝-2，4-噻唑烷二酮（20.5克，86.9%），熔点为183-184℃。C19H20N2O3S的元素分析结果：
计算值：C，64.02;H，5.66;N，7.86。
测得值：C，63.70;H，5.88;N，8.01。
e）在5-｛4-〔2-（5-乙基-2-吡啶基）乙氧基〕苄基｝-2，4-噻唑烷二酮（356mg）的甲醇（10ml）的悬浮液中，加入28%甲醇钠-甲醇溶液（0.2克）以制备溶液。浓缩此溶液，用乙醚稀释至生成晶体。过滤收集这些晶体，用甲醇-乙醇重结晶，制成5-｛4-〔2-（5-乙基-2-吡啶基）乙氧基〕苄基｝-2，4-噻唑烷二酮的钠盐，是无色晶体（298mg，78.8%），熔点262-263℃（分解）。
C19H19N2O3SNa的元素分析结果：
计算值：C，60.31;H，5.06;N，7.40。
测得值：C，60.20;H，5.07;N，7.52。
参 照 例 1
按照实施例1-a）的步骤，制备表2中列出的化合物。
Figure 86100411_IMG10
参 照 例 2
按照实施例1-b）制备下列化合物。
2-溴-3-｛4-〔2-（3-甲基-2-吡啶基）乙氧基〕苯基｝丙酸甲酯。红外光谱（净）Cm-1：1735。核磁共振δ（PPm，CDCl2）：2.34（3H，s），3.10（1H，dd，J＝14和7），3.25（2H，t，J＝6），3.38（1H，dd，J＝14和7），3.67（3H，s），4.29（1H，t，J＝7），4.37（2H，t，J＝6），6.8-7.5（6H，m），8.35（1H，dd，J＝5和2）。
2-溴-3-｛4-〔2-（4-甲基-2-吡啶基）乙氧基〕苯基｝-丙酸甲酯。红外光谱（净）Cm-1：1735。核磁共振δ（PPm，CDCl3）：2.30（3H，s），3.10（1H，dd，J＝14和7），3.26（3H，t，J＝7），3.37（1H，dd，J＝14和7），3.67（3H，s），4.30（3H，t，J＝7），6.7-7.36（6H，m），8.37（1H，d，J＝6）。
参 照 例 3
在10%Pd-c催化剂（50%湿品，2.0克）存在下，1大气压下使溶有4-〔2-（5-甲基-2-吡啶基）乙氧基〕硝基苯（15.0克）的甲醇（150ml）溶液催化还原，滤除催化剂，浓缩滤液制得4-〔2-（5-甲基-2-吡啶基）乙氧基〕苯胺晶体（12.3克，92.5%），用乙酸乙酯-己烷重结晶，制得无色棱晶体，熔点74-75℃。
C14H16N2O的元素分析。
计算值：C，73.66;H，7.06;N，12.27。
测得值：C，73.84;H，7.17;N，12.06。
参 照 例 4
在4-〔2-（5-甲基-2-吡啶基）乙氧基〕苯胺（12.0克）、47%的HBr水溶液（36.5克）和甲醇（40ml）-丙酮（80ml）的混合物中，在5℃或低于5℃下滴加NaNO2（4.0克）水（10ml）溶液。5℃下将全部混合物搅拌20分钟，然后在其中加入丙烯酸甲酯（27.0克），将温度提高到38℃。剧烈搅拌下，逐渐在此混合物中加入氧化亚铜（1.0克），停止产生氮气后，在减压下浓缩此反应混合物，用浓氨水碱化此浓集物，然后用乙酸乙酯萃取，用水洗涤乙酸乙酯层，干燥（MgSO4），蒸除溶剂后，残留下2-溴-3-｛4-〔2-（5-甲基-2-吡啶基）乙氧基〕苯基｝-丙酸甲酯（17.5克，87.5%），呈原油状物。红外光谱（净）Cm-1：1735。核磁共振δ（PPm，CDCl3）：2.27（3H，s），3.10（1H，dd，J＝14和7），3.22（2H，t，J＝6），3.38（1H，dd，J＝14和7），3.66（3H，s），4.29（2H，t，J＝6），4.32（1H，t，J＝7），6.7-7.5（6H，m），8.34（1H，d，J＝2）。
参 照 例 5
按照实施例1-C）制备表3所列的化合物
Figure 86100411_IMG11
参 照 例 6
按照实施例1-d）制备表4中所列的化合物。
Figure 86100411_IMG13
参 照 例 7
将2-亚胺基-5-｛4-〔2-（5-甲基-2-吡啶基）乙氧基〕苄基｝-4-噻唑烷二酮（8.0克）、2NHCl（80ml）和乙醇（80ml）的混合物迴流16小时。用碳酸氢钠饱和水溶液中和此反应溶液以生成晶体，过滤收集这些晶体，用乙醇重结晶后得出5-｛4-〔2-（5-甲基-2-吡啶基）乙氧基〕苄基｝-2.4-噻唑烷二酮（7.0克，87.5%），为无色棱晶体，熔点192-193℃。
C16H18N2O3的元素分析：
计算值：C，63.14;H，5.30;N，8.18。
测得值：C，63.22;H，5.40;N，8.11。

Claims (8)

1、一种制备式（Ⅰ）的化合物或其药理上可接受盐的方法，
Figure 86100411_IMG2
　（Ⅰ）
其特征在于在醇类、二甲基亚砜、四氢噻吩砜等溶剂存在下以及20℃到180℃的反应条件下，将化合物（Ⅷ）与硫脲反应得到化合物（Ⅱ），
其中式（Ⅷ）为
Figure 86100411_IMG4
在无机酸的存在下，将式（Ⅱ）的化合物在有机溶剂中进行水解反应，并维持该反应在20℃到150℃的温度范围及0.5到20小时。
2、根据权利要求1所述的方法，其中所述的有机溶剂选自醇类、二甲基亚砜、二氧噻吩烷、二噁烷、四氢呋喃或二甲氧基乙烷。
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HK3692A (en) 1992-01-17
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IE58928B1 (en) 1993-12-01
LV5779B4 (lv) 1997-04-20
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AR240698A1 (es) 1990-09-28
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