CN86101906A - 制备新的1，2苯并异唑-3-基与1，2苯并异噻唑-3-基衍生物的方法 - Google Patents
制备新的1，2苯并异唑-3-基与1，2苯并异噻唑-3-基衍生物的方法 Download PDFInfo
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- CN86101906A CN86101906A CN86101906.7A CN86101906A CN86101906A CN 86101906 A CN86101906 A CN 86101906A CN 86101906 A CN86101906 A CN 86101906A CN 86101906 A CN86101906 A CN 86101906A
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- -1 1, 2 benzisoxazol-3-yl Chemical class 0.000 title claims description 55
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 19
- 238000000034 method Methods 0.000 claims description 18
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- 238000006243 chemical reaction Methods 0.000 claims description 15
- 125000000217 alkyl group Chemical group 0.000 claims description 13
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Abstract
3-哌啶基-1，2-苯并异噻唑类与3-哌啶基-1，2-苯并异唑类及其可药用的酸加成盐类具有抗精神病作用，并可用于治疗多种疾病，在这些疾病中，血清素的释放是最主要的。
Description
美国专利第4，352，811号和美国专利第4，458，076号叙述了3-
啶基-1，2-苯并异噁唑类和3-
啶基-1，2-苯并异噻唑类化合物，它们具有抗精神病和止痛的作用。
本发明的化合物在
啶部分1-位的取代基与先有技术的化合物不同。
本发明涉及的1，2-吲哚类具有如下的结构式：
及其可药用的酸加成盐类，其中：
R是氢或C1-6烷基
R1和R2为由氢、卤素，羟基，C1-6烷氧基和C1-6烷基所组成的一组基团中各自独立选择的基团;
X是氧或硫;
ALK是C1-4二价烷基;和
Q是具有下式的基团
其中Y1和Y2各是独立的氧或硫;
R3是选自氢，卤素，C1-6烷基，C1-6烷氧三氟甲基，硝基，氰基，羟基，（C1-10烷羰基）氧，氨基，单或双（C1-10烷基）氨基，（C1-10烷羰基）氨基，苯甲氧基和叠氮基等;
R4是氢或卤素;或下式的基团
其中R5是氢或C1-6烷基;
Z是-S-，-CH2-，或-CR6＝CR7-;该R6和R7各是独立的氢或C1-6烷基;和
A是二价官能团-CH2-CH2-，-CH2-CH2-CH2-或-CR8＝CR9-，该R8和R9各是独立的氢，卤素，氨基或C1-6烷基。
在前述定义中卤素一词是氟，氯，溴和碘的总称;“C1-6烷基”是直链和带支链的饱和烃基，具有1-6个碳原子的直链或带支链的饱和烃基，例如，甲基，乙基，1-甲基乙基，1，1-二甲基乙基，丙基，丁基，戊基，己基等;“C1-14二价烷基”包括具有1至4个碳原子的二价直链或带支链的烷基，例如，亚甲基，1，2-亚乙基，1，2-亚丙基，亚丁基等;以及“C1-10烷基”是指如上述定义的C1-6烷基和具有7至10碳原子的较高级的同系物，例如，庚基，壬基等。
本发明中优先选用的化合物是Q为结构式（a）的基团，其中R3是氢，卤素，C1-6烷基，C1-6烷氧基，三氟甲基，羟基，氨基或叠氮基，以及R4是氢;或Q为结构式（b）的基团，其中R5是C1-6烷基和A是二价基团-CH2-CH2-，-CH2-CH2-CH2-，或-CR8＝CR9-，其中R8和R9分别是独立的氢或C1-6烷基。
在优先选用的化合物中，需要特别提出的化合物是R为氢，R1是氢或卤素，R2是氢，卤素，羟基，或C1-6烷氧基。
在特别提出的化合物中较好的化合物是Q为式（a）的基团，其中R3是氢，卤素，或甲基，Y1是氧;或Q是式（b）的基团，其中-Z-A-是-S-CH2-CH2-，-S-（CH2）3-，-S-CR8＝CR9-，其中R8和R9各是独立的氢或甲基，-CH＝CH-CR8＝CR9-其中R8和R9各是独立的氢或甲基，或CH2-CH2-CH2-CH2-。
在较好的化合物中，更好的化合物R1氢，R2是氢，卤素，羟基或甲氧基。
最好的化合物可以从以下一组化合物中选择：3-〔2-〔4-〔6-氟-1，2-苯并异恶唑-3-基）-1-
啶基〕-乙基〕-6，7，8，9-四氢-2-甲基-4H-吡啶并〔1，2-a〕嘧啶-4-酮和3-〔2-〔4-〔6-氟-1，2-苯并异噁唑-3-基）-1-
啶基〕乙基〕-2-甲基-4H-吡啶并（1，2-a）嘧啶-4-酮以及其可药用的酸加成盐。
结构式（Ⅰ）的化合物一般可用具有适当活性的酯（式Ⅱ）与适当取代的
啶（式Ⅲ）反应而制备。在活性酯（Ⅱ）中的W表示活性酯基，例如，卤素（如氯，溴或碘）或磺酰氧基，如甲基碘酰氧基，（4-甲苯基）磺酰氧基等。
（Ⅱ）与（Ⅲ）的反应可便利的在惰性有机溶剂例如，芳香烃（如苯，甲苯，二甲苯等）;低级烷醇（如甲醇，乙醇，1-丁醇等）;酮（如，2-丙酮，4-甲基-2-戊酮等;醚（如1，4-二噁烷，1，1′-氧双乙烷，四氢呋喃等）;N，N-二甲基甲酰胺（DMF）;N，N-二甲基乙酰胺（DMA）;硝基苯;1-甲基-2-吡咯烷酮等中进行，加入适当的碱，例如，碱金属或碱土金属碳酸盐，碳酸氢盐，氢氧化物，醇盐，氢化物，如碳酸钠，碳酸氢钠，碳酸钾，氢氧化钠，甲醇钠，氢化钠等，或有机碱，例如，叔胺，如N，N-二乙基乙胺，N-（1-甲基乙基）-2-丙胺，4-乙基吗啉等可用于中和反应过程中游离出的酸。在某些情况下，加入碘化物（最好是加入碱金属碘化物）是合适的。提高温度可增加反应的速度。
式（Ⅰ）化合物也可以按照制备结构中含有式Q基团化合物的已知方法制备。
例如，式（Ⅰ）中Q是式（a）基团的化合物可用式（Ⅰ-a）表示，该化合物可用尿素或硫脲和适合的2-氨基-苯甲酰胺或2-氨基苯硫代酰胺（式Ⅳ-a）环化而制备。
式（1-a）的化合物也可以用式（Ⅴ）的胺和适合的中间体式（Ⅳ-b）环化而制备。
或使式（Ⅴ）的伯胺和异氰酸酯或异硫氰酸酯（Ⅳ-C）环化制。
该环化反应经搅拌很容易进行，如果需要可将反应物在经选择的沸点较高的适当惰性溶剂中，如脂肪族的或芳香族的烃类（如石油醚，二甲基苯等一起加热。
在上述反应式中，R10和R10-a分别独立表示适当的离去基团，例如C1-6烷氧基，氨基，以及一或二（C1-6烷基）氨基。
式（Ⅰ）中Q是式（b）基团的化合物，可用式（1-b）表示，该化合物可用已知的制备嘧啶-4-酮类的环化法制备，例如，用式（Ⅵ）的胺与式（Ⅶ）的环化剂反应，或用式（Ⅸ）的胺和式（Ⅷ）
该环化反应一般可通过同时搅拌反应物来完成，如果需要，可在有合适的惰性反应溶剂，例如脂肪族烃类，脂环族烃类或芳香族烃类，如乙烷，环己烷，苯等，吡啶;N，N-二甲基甲酰胺和类似的酰胺类存在下进行。提高温度可适当增加反应速度。在某些情况下，最好在反应混合物的回流温度下进行该反应。
在上述反应式中，L和L1分别独立地代表适当的离去基团，例如（C1-6烷基）氧基，羟基，卤素，氨基，一和二（C1-6烷基）氨基等。
按同一环化法，式（Ⅰ-b）的化合物也可以用式（Ⅹ）的试剂和式（Ⅸ）中间产物环化来制备。
式（Ⅰ-b）中的化合物其中Z是硫，可用结构式（Ⅰ-b-l）表示，该化合物也可用式（Ⅻ）的试剂和2-巯基嘧啶酮（式Ⅺ）环化来制备。
在（Ⅻ）中W′与前述W具有相同意义。
式（Ⅰ-b-l）中的A是
的化合物，可用式（Ⅰ-b-l-a）表示该化合物也可用式（ⅫⅠ）试剂和2-巯基嘧啶酮（式Ⅺ）环化来制备。
制备式（Ⅰ-b-l）和（Ⅰ-b-l-a）化合物的环化反应一般可通过同时搅拌反应物来完成，如果需要，可在合适的惰性反应溶剂，例如，脂肪族烃类，脂环族烃类或芳香族烃类，如，己烷，环己烷，等等;吡啶;N，N-二甲基甲酰胺以及类似的酰胺类存在下进行。提高温度可适当地增加反应速度，在某些情况下，在最好反应物混合物的回流温度下进行该反应。
式（Ⅰ）的化合物还可以按已知的官能团转换法互相转变。
例如，式（Ⅰ-a）中R3是氨基的化合物，可按已知的硝基还原为胺的方法，从相应的硝基取代的喹唑啉类衍生中得到。例如，由硝基还原为胺的合适的方法是在相对极性溶剂，例如醇，如甲醇或乙醇中，在有适当的催化剂，如铂-炭存在的情况下进行催化氢化。在某些情况下加入适当的催化剂抑制剂，即噻吩可能是有益的。
式（Ⅰ-a）中R3为苯甲氧基的化合物，可按已知的催化氢解方法转变成式（1-a）中R3为羟基的化合物;式（Ⅰ-a）中R3为氨基式羟基的化合物与适当的酰化剂（例如酰基卤或酸酐）反应，可使式（Ⅰ-a）中R3为氨基或羟基的化合物转变成R3为（C1-10烷羰基）氨基或（C1-10烷羰基）氧基的化合物;式（Ⅰ-a）中R3为氨基的化合物，可用亚硝酸或它的适当碱金属或碱土金属盐使氨基转变成重氮基，然后用叠氮化钠或其它适当的碱金属或碱土金属叠氮化物将该重氮基转变为叠氮基，得到式（Ⅰ-a）中R3成为叠氮基的化合物。式（Ⅰ）化合物具有碱性，因此，经用适当的酸，例如无机酸，如氢卤酸，如盐酸，氢溴酸等，和硫酸，硝酸，磷酸等;或有机酸，例如醋酸，丙酸，羟基乙酸，2-羟基丙酸，2-氧丙酸，乙二酸，丙二酸，丁二酸，（2）-2-丁烯二酸，（E）-2-丁烯二酸，2-羟基丁二酸，2，3-二羟基丁二酸，2-羟基-1，2，3-丙烷三羧酸，甲磺酸，乙磺酸，苯磺酸，4-甲基苯磺酸，环己烷氨基磺酸，2-羟基苯甲酸，4-氨基-2-羟基苯甲酸以及类似的酸处理，可转变成有治疗作用的无毒的酸加成盐。相反，该盐可用碱处理，可转变成游离碱。
在前述制备过程中的一些中间体和起始原料是已知化合物，它们可根据已知的或类似化合物的方法来制备。例如，式（Ⅱ）中间体和其制备方法已在美国专利第4，335，127号;4，342，870号;4，443，451号和4，485，107号中叙述。其它中间体可根据制备类似化合物已知的方法制备，其中某些中间体的制备方法将在下文叙述。
结构式（Ⅲ）中间体一般可从下式苯甲酰基
啶
其中卤素最好是氟，按已知方法制得，使苯甲酰基
啶（ⅩⅣ）与羟胺反应并环化，得到肟，按照已知方法，于是得到式（Ⅲ）中间体，
其中X是氧，该中间体可以下式表示
式（Ⅲ）中X为硫的中间体可以下式表示
Ⅲ-a和Ⅲ-b可按美国专利第4，458，076号所述的类似的方法制备。
式（1）化合物和其可做药用的酸加成盐是一系列神经递质有力的拮抗剂，因此它们具有有效的药理作用。例如，式（Ⅰ）化合物及其可药用的酸加成盐具有很强的抗精神病作用和抗血清素的作用。
由于其药理学作用，式（Ⅰ）化合物以及其可药用的酸加成盐可用于治疗精神病和各种以释放血清素为主疾病，例如，由血清素导致的支气管组织和血管（动脉和静脉）收缩的阻滞。本化合物还可做为镇静剂，抗焦虑剂，抗紧张剂，肌肉保护剂和心血管保护剂，用于保护温血动物，例如，在激动时的紧张情境以及其它类似的情境。此外，本化合物还可做为内毒素性休克保护剂和止泻药。
鉴于其有效的药理学性质，本化合物可配制不同的药物剂型供服用。为制备本发明的药用配方，以有效量的碱或酸加成盐形式的特定化合物做为有效成分，使之与可药用的赋形剂结合成为紧密的混合物，根据给药所要求的剂型，可采用各种类型的载体作为赋形剂。希望这些药物配方为单次剂量形式，最好能口服经直肠给药，经皮肤给药，或用非经肠胃道的注射方式给药，例如，在制备口服剂型的配方时，任何常用的药用介质都可以应用，例如，在制备口服液体制剂，如悬浮液，糖浆，
剂和溶液剂时，可用水，甘醇，油，醇类等：在制备粉剂，丸剂，胶囊剂和片剂时，可用淀粉，糖，高岭土，润滑剂，粘合剂，崩解剂等固体赋形剂。因为便于服用，片剂和胶囊剂是最方便的口服给药剂型，在这种情况下，显然应使用固体赋形剂。对于非经肠胃道的配方，通常（至少是大部分情况下）用的载体为无菌水，虽然也要用其它的组分，例如，助溶剂。注射液的制备，其赋形剂可包括盐水，葡萄糖溶液或盐水和葡萄糖溶液的混合液。注射用悬浮液也可用适当的液体载体，悬浮剂等来制备。适于经皮肤给药的配方，其载体可选择性地包括渗透促进剂和/或合适的湿润剂，与小比率的适当的任一种类的添加物选择性地结合，该添加剂应对皮肤不会导致明显的毒害作用。该添加剂应有利于皮肤用药和/或应有助于制备所希望的配方。这些配方可以各种方式给药，例如，经皮肤的膏药，Spo-ton，软膏。式（Ⅰ）的酸加成盐由于其水溶性超过其对应的碱，它显然更适于制成液体配方。
以易于服用的剂量单位形式和一致的剂量配成前述药用配方是非常有利的。应用于本说明书和权利要求书中的剂量单位形式涉及到适于作为单位剂量的个别物理单位，每个单位含有预先测定量的有效成分使计算量的有效成分与要求的药用载体结合，以便得到所期望的治疗作用。这些剂量单位形式的实例是片剂（包括模印片或包衣片）胶囊剂，丸剂，粉剂包，干糊片，注射液或悬浮液，一茶匙，一汤匙等以及其分形的倍量。
鉴于本化合物在治疗精神病中的效用，因此本发明提供了一种治疗温血动物精神病的方法，该方法包括系统的服用药用有效量的式（Ⅰ）的化合物或其药用的酸加盐与药用载体的混合物。在精神病治疗中从实验结果很容易测出其有效量。一般认为，其有效量是每公斤体重由0.01毫克到4毫克。最好是由每公斤体重0.04毫克至2毫克。
下列实例的意图是详细说明本发明，并不是限制本发明的范围。除非另有说明否则全部都是按重量计算，所有温度都是摄氏度。
实验部分
A）中间体的制备
实例1
在含有65份1，3-二氟苯，130份氯化铝和195份二氯甲烷的混合物中，在冷却，搅拌下滴入95份1-乙酰基-4-
啶-碳酰氯在65份二氯甲烷中的溶液。全部滴入后，在室温下继续搅拌3小时，将反应混合物注入碎冰和盐酸的混合物中。用二氯甲烷萃取产品。有机层干燥，过滤，蒸发，得残余物48份1-乙酰基-4-（2，4二氟苯甲酰基，
啶，产率为36%（中间体1）。
将含有48份1-乙酰基-4-（2，4-二氟苯甲酰基）
啶和180份6N盐酸溶液的混合物搅拌并加热回流5小时。蒸发反应混合物，搅拌残余物在2-丙醇中的溶液。产品过滤并干燥，得39份（2，4-二氟苯基）（4-
啶基）甲酮盐，盐酸产率为83%（中间体2）。
在室温下搅拌含有12份（2，4-二氟苯基）（4-
啶基）-甲酮盐，盐酸12份盐酸羟胺和120份乙醇的混合物并加入10.5份N，N-二乙基乙胺。搅拌全部溶液并加热回流3小时。冷却后，过滤沉淀并干燥，得11份（2，4-二氟苯基）（4-
啶基）甲酮肟，产率为100%（中间体3）。
搅拌含有11份（2，4二氟苯基）（4-
啶基）甲酮肟，25份氢氧化钾和25份水的混合物，并加热回流2小时。冷却反应混合液，用甲苯萃取干燥，过滤并蒸发萃取液。残余物用石油醚结晶，得6.8份6-氟-3-（4-
啶基）-1.2-苯并异噁唑（中间体4）。
实例2
搅拌含有50份2-噻唑胺，76份3-乙酰基-4，5-二氢-2（3H）-呋喃酮，1.2份浓盐酸和270份甲苯的混合物，并用带有水分离器的装置加热回流2小时。反应混合物经冷却于20°-30℃将340份磷酰氯加入。全部溶液缓缓加热至100～110℃并在温度下继续搅拌2小时。蒸发该反应混合液并将残余物注入碎冰和氢氧化氨的混合物中。用三氯甲烷萃取产品。干燥，过滤和蒸发萃取液。残余物用硅胶柱层析纯化，用三氯甲烷和甲醇（95∶5容积）的混合液做洗提剂，收集含纯品部分并蒸发洗提液。残余物用2-丙醇和1.1′-氧双乙烷的混合液结晶，得36份6-（2-氯乙基）-7-甲基-5H-噻唑并-〔3，2-a〕嘧啶-5-酮（中间体5）。
实例3
在室温下搅拌含有30份4-羟基-2-巯基-6-甲基-5-嘧啶乙醇，25份碳酸钾，270份N，N-二甲基乙酰胺和75份水的混合物，并立即加入36份1，3-二溴丙烷;温度升至50℃。在室温下将全部溶液搅拌过夜。蒸发反应混合液并向残余物中加入水。用水洗涤固体产品，并于100℃真空干燥得21份3，4-二氢-7-（2-羟乙基），-8-甲基-2H，6H-嘧啶并-〔2，1-b〕〔1，3〕噻嗪-6-酮;产率为58%，溶点155℃（中间体6）。
按同一方法并用等量适当的起始原料，还可制得2，3-二氢-6-（2-羟乙基）-7-甲基-5H-噻唑并〔3，2-a〕-嘧啶-5-酮;熔点148.7℃（中间体7）。
实例4
搅拌并加热回流含有20份3，4-二氢-7-（2-羟乙基）-8-甲基-2H，6H-嘧啶并〔2，1-b〕〔1-3〕噻嗪-6-酮，50份醋酸和180份67%氢溴酸醋酸溶液的混合物。在回流温度下继续搅拌过夜。蒸发反应混合物并将固体残余物置于2-丙酮中研碎。过滤并干燥产品，得到24份7-（2-溴乙基）-3，4-二氢-8-甲基-2H，6H-嘧啶并〔2，1-b〕〔1.3〕噻嗪-6-酮单氢溴酸盐;产率为100%溶点215℃（中间体8〕。
按同一方法并用等量适当的起始原料，还可制得6-〔2-溴乙基）2，3-二氢-7-甲基-5H-噻唑并〔3，2-a〕嘧啶-5-酮-单盐酸盐;熔点237.2℃（中间体9）。
B）最终化合物的制备
实例5
在85-90℃将含有5.3份3-（2-氯乙基）-6.7.8.9-四氢-2-甲基-4H吡啶并〔1.2-a〕嘧啶-4-酮-单盐酸盐，4.4份6-氟-3-（4-
啶基）-1，2-苯并异噁唑，8份碳酸钠，0.1份碘化钾和90份N，N-二甲基甲酰胺的混合物搅拌过夜。冷却后，将反应混合液注入水中。过滤收集产品并用N，N-二甲基甲酰胺和2-丙醇混合液结晶。将产品过滤和干燥，得到3.8份3-〔2-〔4-（6-氟-1，2-苯并异噁唑-3-基）-1-
啶基〕乙基-6，7，8，9-四氢-2-甲基-4H-吡啶并〔1，2-a〕-嘧啶-4-酮;产率为46%溶点170.0℃（化合物1）。
按同一方法并用等量适当的起始原料，还可制得6-〔2-〔4-（6-氟-1，2-苯并异噁唑-3-基）-1-
啶基〕乙基〕-7-甲基-5H-噻唑并〔3，2-a〕嘧啶-5-酮;熔点165.1℃（化合物2）;
3-〔2-〔4-（1，2-苯并异噁唑-3-基）-1-
啶基〕乙基〕-2-甲基-4H-吡啶并〔1，2-a〕嘧啶-4-酮;熔点177.9℃（化合物3）;
3-〔2-〔-（6-氟-1，2-苯并异噁唑-3-基）-1-
啶基〕乙基〕-2，7-二甲基-4H-吡啶并〔1，2-a〕嘧啶-4-酮;熔点186.9℃（化合物4）;
3-〔2-〔4-（1，2-苯并异噁唑-3-基）-1-
啶基〕乙基〕6，7，8，9-四氢-2-甲基-4H-吡啶并〔1，2-a〕嘧啶-4-酮;熔点183.1℃（化合物5）;
3-〔2-〔4-（1，2-苯并异噁唑-3-基）-1-
啶基〕乙基〕-2，4-（1H，3H）-喹唑啉二酮单盐酸盐;熔点＞300℃（分解）（化合物6）;
3-〔2-〔4-（1，2-苯并异噻唑-3-基）-1-
啶基〕乙基〕-6，7，8，9-四氢-2-甲基-4H-吡啶并〔1，2-a〕嘧啶-4-酮;熔点145.7℃（化合物7）;
3-〔2-〔4-（6-羟基-1，2-苯并异噁唑-3-基）-1-
啶基〕乙基〕-6，7，8，9-四氢-2-甲基-4H-吡啶并〔1，2-a〕嘧啶-4-酮;熔点213.1℃（化合物8）;
用类似的方法可以制备;
3-〔2-〔4-（5-甲氧基-1，2-苯并异噁唑-3-基）-1-
啶基〕乙基〕-2-甲基-4H-吡啶并〔1，2-a〕嘧啶-4-酮（化合物9）;
3-〔2-〔4-（6-氟-1，2-苯并异噁唑-3-基）-1-
啶基〕乙基〕-2-甲基-4H-吡啶并〔1，2-a〕嘧啶-4-酮（化合物10）。
实例6
搅拌含有3.3份3-（2-氯乙基）-2-甲基-4H-吡啶并〔1，2-a〕嘧啶-4-酮，3.3份6-氟-3-（4-
啶基）-1，2-苯并异噁唑，8份碳酸钠，1份碘化钾和120份4-甲基-2-戊酮的混合物，并加热回流3小时。
反应混合物冷却后，加入水并分层有机相干燥，过滤和蒸发，残余物通过硅胶柱层析纯化，用三氯甲烷和甲醇（95∶5，按容积）的混合液做洗提液，收集含纯品部分并蒸发洗提液，残余物用4-甲基-2-戊酮结晶，得1.2份3-〔2-〔4-（6-氟-1，2-苯并异噁唑-3-基）-1-
啶基〕乙基〕-2-甲基-4H吡啶并〔1，2-a〕嘧啶-4-酮;产率为19%熔点：170.4℃（化合物11）。
实例7
搅拌含有6.75份3-（2-氯乙基）-2，4-（1H，3H）-喹唑啉二酮，6.6份6-氟-3-（4-
啶基）-1，2-苯并异噁唑，10份碳酸氢钠，0.1份碘化钾和90份N，N-二甲基甲酰胺的混合物并于100～110℃加热过夜。冷却后，将反应混合物注入水中，搅拌后过滤收集产品并用N，N-二甲基甲酰胺结晶，得4.8份3-〔2-〔4-（6-氟-1，2-苯并异噁唑-3-基）-1-
啶基〕乙基〕-2，4-（1H，3H）-喹唑啉二酮;产率为39%熔点：253.4℃（化合物12）。
实例8
在80～85℃将含有7.4份6-（2-溴乙基）-3，7-二甲基-5H-噻唑并〔3，2-a〕嘧啶-5-酮单氢溴酸盐，4.4份6-氟-3-（4-
啶基）-1，2-苯并异噁唑，10份碳酸钠和90份N，N-二甲基甲酰胺的混合物搅拌过夜。冷却后，将反应混合物注入水中。过滤收集产品并通过硅胶柱层析纯化，再用三氯甲烷和甲醇（95∶5，容积）的混合液做为洗提液。收集含纯品部分并蒸发洗提液。加2-丙醇于残余物中。过滤收集产品并干燥，得到5.3份6-〔2-〔4-（6-氟-1，2-苯并异噁唑-3-基）-1-
啶基〕乙基〕-3，7-二甲基-5H-噻唑并〔3，2-a〕嘧啶-5-酮;产率为62%熔点：
231.0℃（化合物13）。
用类似的方法可以制备：
6-〔2-〔4-（6-氟-1，2-苯并异噁唑-3-基）-1-
啶基〕乙基〕-2，3-二氢-7-甲基-5H-噻唑并〔3，2-a〕嘧啶-5-酮;熔点：135.0℃（化合物14）;
7-〔2-〔4-（6-氟-1，2-苯并异噁唑-3-基）-1-
啶基〕乙基〕-3，4-二氢-8-甲基-2H，6H-嘧啶并〔2，1-6〕〔1，3〕噻嗪-6-酮;熔点169.3℃（化合物15）;
6-〔2-〔4-（1，2-苯并异噁唑-3-基）-1-
啶基〕乙基〕-2，3-二氢-7-甲基-5H-噻唑并〔3，2-a〕嘧啶-5-酮;熔点：154.5℃（化合物16）;
3-〔2-〔4-（6-氟-1，2-苯并异噻唑-3-基）1-
啶基〕乙基〕-6，7，8，9-四氢-2-甲基-4H-吡啶并〔1，2-a〕嘧啶-4-酮（化合物17）;
3-〔2-〔4-（6-氟-1，2-苯并异噁唑-3-基）-1-
啶基〕乙基〕-2，3-二氢-2-硫代-4（1H）-喹唑啉酮（化合物18）。
C）药理学的实例
本化合物做为治疗精神病药剂使用时的效用，至少由两个不同试验方法之一中得到的数据所证实。即在大白鼠中进行的阿朴吗啡，色胺和去甲肾上腺素结合试验和在狗中进行的阿朴吗啡试验。试验按下述方法进行，实验 据归纳于表1。
实例9
大白鼠中进行的阿朴吗啡（APO）-，色胺（TRY）-，和去甲肾上腺素（NOR）-结合试验。
用于本试验的动物是成年雄性威斯特（Wistar）大白鼠（体重240±10克）。禁食一夜后，给动物皮下注射该化合物的水溶液1毫升/100克，并置于隔离笼内开始观察（时间＝0）。30分钟后（时间＝30分钟）静脉注射盐酸阿朴吗啡（APO），1.25毫克/公斤，以后观察1小时内因阿朴吗啡起的现象存在与否：激动不安和刻板症。在1小时末（时间＝90分钟）给同一动物静脉注射色胺（TRY），40毫克/公斤，并记录色胺引起的典型的身体两侧强直性发作的出现情况。予处置后2小时（时间＝120分钟），最后给同一动物静脉注射去甲肾上腺素（NOR），1.25毫克/公斤，并观察在60分钟后动物的死亡情况。
表1是研究中的一些化合物的ED50值。本文所用的ED50表示保护50%的动物使之不出现因注射阿朴吗啡，色胺或去甲肾上腺素所引起的现象的剂量。
在狗中进行的阿朴吗啡试验（APO-dog）。
应用的方法是P.A.J.Janssen和C.J.E.Niemegeers在Ar3neim-Forsch.（DrugRes.），9，765-767（1959）上发表的。表1中列出的化合物以不同剂量给小猎兔、犬皮下注射，1小时后给动物皮下注射0.31毫克/公斤标准剂量的阿朴吗啡。
表1列出了研究中的一些化合物的ED50值。本表内的ED50值表示保护50%动物不出现呕吐的剂量。
表1中的化合物不是为了限定本发明，只是举例说明式（1）范围内所有的化合物有效的药理作用。
D）配方实例
按照本发明，下述配方举例说明以单位剂量形式表示的典型药用配方，该配方适用于给动物和人全身用药。
用于这些实例的“有效成分”（A.I）与式（1）化合物或其可药用的酸加成盐有关。
实例10 口服滴剂
将500克A.I.在60～80℃溶解于0.5升2-羟基丙酸和1.5升聚乙二醇中。冷却至30～40℃后加入35升聚乙二醇并充分搅拌该混合液。然后加入1750克糖精钠在2.5升纯化水中的溶液，并且在搅拌下加入2.5升可可香精和适量的聚乙二醇至50升，得到每毫升含有A.I.10毫克的。口服滴剂溶液制成的溶液装入合适的容器中。
实例11 口服溶液
9克4-羟基苯用酸甲酯和1克4-羟基苯甲酸丙酯溶解于4升沸水纯化中。在3升该溶液中首先溶解10克2，3-二羟基丁二酸，然后加入20克A.I.。使后者的溶液与前者的剩余部分合併，并且加入12升1，2，3-丙三醇和3升70%山梨糖醇溶液。将40克糖精钠溶解于0.5升水中，并加入2毫升悬钩子和2毫升鹅莓香精，并与前者溶液混合，加适量的水至体积为20升，得到每茶匙（5毫升）含有20毫克有效成分的口服溶液。制成的溶液装入合适的容器中。
实例12 胶囊剂
将20克A.I.，6克十二烷基硫酸钠56克淀粉，56克乳糖，0.8克胶体二氧化硅和1.2克硬脂酸镁镁放在一起激烈搅拌。得到的混合物然后装入。1000个适当的硬胶囊中，使每粒胶囊含有20毫克有效成分。
实例13 薄膜包衣片剂
片芯的制备
充分混合100克A.I.，570克乳糖和200克淀粉，然后用5克十二烷基硫酸钠和10克聚乙烯吡咯烷酮〔科利当（Kollidon）-K90
〕溶于约200毫升水中的溶液使之湿润。将湿粉过筛，干燥，再过筛。于是加100克微晶纤维素〔阿维塞尔（Avicel
）和15克氢化植物油（斯特罗特克斯（Sterotex
）〕。将全部充分混合后压片，得10，000片，每片含有10毫克有效成分。
包衣
向10克甲基纤维素〔梅托塞路（Methoeel60HG
）的75毫升变性乙醇溶液中加入5克乙基纤维素（埃索塞路Ethocel22CPS
）溶于150毫升二氯甲烷的溶液。然后加入75毫升二氯甲烷和2.5毫升1，2，3-丙三醇。熔化10克聚乙二醇并溶解于75毫升二氯甲烷中。将后者溶液入前者溶液中，然后加入2.5克硬脂酸镁，5克聚乙烯吡咯烷酮和30毫升浓颜料悬浮液（奥普斯雷普Opaspray K-l-2109
）并均化全液。在包衣装置中用此混合液使芯片包衣。
实例14 注射液
将1.8克4-羟基苯甲酸甲酯和0.2克4-羟基苯甲酸丙酯溶于约0.5升注射用沸水中。冷却至约50℃后边搅拌边加入4克乳酸，0.05克丙二醇和4克A.I.。溶液冷却至室温后补充加入适量注射用水至1升，得到每毫升含有A.I.4毫克的溶液。将该溶液过滤灭菌（美国药典ⅩⅦ，第811页）装入灭菌容器中。
例15：栓剂
将3克A.I.溶于含有3克2，3-二羟基丁二酸的25毫升聚乙二醇400溶液中。加入12克表面活性剂（斯潘SPAN）和适量的甘油三酯（维特普斯尔Witepsol 555
）至300克，并且熔化在一起。将后者混合物与前者溶液充分混合。得到的混合物在室温37～38℃注入模具中，制成100粒栓剂，使每粒栓剂中含30毫克有效成分。
Claims (3)
1、制备具有式(Ⅰ)的化合物
或其可药用的酸加成盐的方法
其中
R是氢或C1-6烷基；
R1和R2分别选自一组包括氢，卤素，羟基，
C1-6烷氧基和C1-6烷基的基团；
X是氧或S；
AlK是C1-4二价烷基；和
Q是式(a)基团
其中Y1和Y2分别是独立的氧或硫；
R3是选自一组包括氢，卤素C1-6烷基，C1-6烷氧基，三氟甲基，硝基，氰基，羟基，(C1-10烷基羰基)，氨基，一和二(C1-6烷基)氨基，(C1-10烷基羰基)氨基，苯甲氧基和叠氮基。
R4是氢或卤素，或
式(b)基团
其中R5是氢或C1-6烷基；
Z是-S-，-CH2-，或-CR6=CR7-，该R6和R7分别是独立的氢或C1-6烷基；和
A是二价基团-CH2-CH2-，-CH2-CH2-CH2-或-CR8=CR9-，该R8和R9分别是氢，卤素，氨基，或C1-6烷基其特征在于：
a)在惰性溶剂中使式(Ⅱ)酯
其中W表示活性酯基
与下式的哌啶反应
b)在选择性的惰性溶剂中，使尿素或硫脲与具有下式的中间体环化
于是制得具有下式的化合物
c)在选择性的惰性溶剂中，使具有下式的胺
与具有下式的中间体环化
其中R10和R10-a分别独立表示离去基团，如
C1-6烷氧基，氨基和一和二(C1-6烷基)氨基，于是制得具有结构式(Ⅰ-a)的化合物；
d)在选择性的惰性溶剂中，使具有结构式(Ⅴ)的胺与具有下式的异氰酸酯或异硫氰酸酯环化
于是制得具有结构式(1-a)的化合物；
e)使下式的胺
与α-碳酰羧酸衍生物式Ⅶ反应
其中L表示离去基团，如C1-6烷氧基，羟基，卤素，氨基，一和二(C1-6烷基)氨基，于是制得具有以下结构式的化合物
f)使试剂Ⅷ
与具有下列结构式的β-氨基羧酸衍生物环化
该L和L′分别独立表示离去基团，如C1-6烷氧基，羟基，卤素，氨基，一和二(C1-6烷基)氨基，于是制得结构式(Ⅰ-b)的化合物；
g)使具有以下结构式的腈
与具有下列结构式的β-氨基羧酸衍生物环化
该L表示离去基团如C1-6烷氧基，羟基，卤素，氨基，一和二(C1-6烷基)氨基，于是制得结构式(Ⅰ-b)的化合物；
h)使具有下列结构式的2-巯基嘧啶酮
与具有下列结构式的试剂环化，
于是得到结构式(Ⅰ-b)的化合物，其中Z是硫，该化合物可用以下结构式表示
i)使结构式(Ⅺ)的2-巯基嘧啶酮与具有下列结构式的试剂环化
于是制得结构式(Ⅰ-b)的化合物，其中Z是硫和A是
该化合物可用下列结构式表示：
或按已知的基团转变的方法，将结构式(Ⅰ)的化合物相互转变，并且如果需要，可用适当的酸将结构式(Ⅰ)的化合物转变成具有治疗作用的无毒的酸加成盐，或反过来用碱将酸加成盐转变成为游离碱；和/或制备其立体化学上的异构体。
2、制备选自一组包括3-〔2-〔4-〔6-氟-1，2-苯并异噁唑-3-基）-1-哌啶基〕乙基〕-6，7，8，9-四氢-2-甲基-4H-吡啶并-〔1，2-a〕嘧啶-4-酮或其可药用的酸加成盐的方法，其特征在于使3-（2-氯乙基）-6，7，8，9-四氢-2-甲基-4H-吡啶并〔1，2-a〕嘧啶-4-酮或其酸加成盐在合适的惰性溶剂中与6-氟-3-（4-哌啶基）-1，2-苯并异噁唑或其酸加成盐反应;并且如果需要，可用适当的酸处理，使得到的化合物转变成具有治疗活性并且无毒的酸加成盐，或相反，用碱将酸加成盐转变成游离碱。
3、制备选自一组包括3-〔2-〔4-〔6-氟-1，2苯并异噁唑-3-基）-1-哌啶基〕乙基〕-2-甲基-4H-吡啶并〔1，2-a〕嘧啶-4-酮，或其可药用的酸加成盐的方法，其特征在于使3-（2氯乙基）-2-甲基-4H-吡啶并〔1，2-a〕嘧啶-4-酮或其酸加成盐与6-氟-3-（4-哌啶基）-1，2-苯并异噁唑或其酸加成盐在适当的惰性溶剂中反应;并且如果需要，可用适当的酸处理，使得到的化合物转变成具有治疗活性并且无毒的酸加成盐，或相反，用碱将酸加成盐转变成游离碱。
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US71706785A | 1985-03-27 | 1985-03-27 | |
| US717,067 | 1985-03-27 | ||
| SG119294A SG119294G (en) | 1985-03-27 | 1994-08-20 | 1,2-benzisoxazol-3-yl and 1,2-benzisothiazol-3-yl derivatives |
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| Publication Number | Publication Date |
|---|---|
| CN86101906A true CN86101906A (zh) | 1986-10-01 |
| CN1022566C CN1022566C (zh) | 1993-10-27 |
Family
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN86101906A Expired - Lifetime CN1022566C (zh) | 1985-03-27 | 1986-03-24 | 制备新的取代的1-哌啶亚烷基-吡啶并嘧啶酮或噻唑并嘧啶酮的方法 |
Country Status (15)
| Country | Link |
|---|---|
| US (1) | US4804663A (zh) |
| EP (1) | EP0196132B1 (zh) |
| JP (1) | JPH0613511B2 (zh) |
| CN (1) | CN1022566C (zh) |
| AU (1) | AU579232B2 (zh) |
| BG (1) | BG60432B2 (zh) |
| CA (1) | CA1256867A (zh) |
| CY (1) | CY1801A (zh) |
| DK (1) | DK168537B1 (zh) |
| HK (1) | HK108794A (zh) |
| IE (1) | IE58388B1 (zh) |
| LU (1) | LU88576I2 (zh) |
| NL (1) | NL940006I2 (zh) |
| SG (1) | SG119294G (zh) |
| SU (1) | SU1468419A3 (zh) |
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| PH23995A (en) * | 1984-01-09 | 1990-02-09 | Janssen Pharmaceutica Nv | 4((bicycle heterocyclyl)-methyl and hetero)piperidines |
| US4665075A (en) * | 1984-12-05 | 1987-05-12 | Janssen Pharmaceutica N.V. | Derivatives of hydroxy- or amino-substituted (piperidinylalkyl)quinazolines |
| US4689330A (en) * | 1985-04-15 | 1987-08-25 | Janssen Pharmaceutica N.V. | Antidepressive substituted N-[(4-piperidinyl)alkyl] bicyclic condensed oxazol- and thiazolamines |
| HUT43600A (en) * | 1985-06-22 | 1987-11-30 | Sandoz Ag | Process for production of new thiazole derivatives and medical compound containing those |
-
1986
- 1986-02-05 US US06/826,517 patent/US4804663A/en not_active Expired - Lifetime
- 1986-03-05 SU SU864027047A patent/SU1468419A3/ru active
- 1986-03-13 EP EP86200400A patent/EP0196132B1/en not_active Expired - Lifetime
- 1986-03-13 LU LU88576C patent/LU88576I2/fr unknown
- 1986-03-18 CA CA000504409A patent/CA1256867A/en not_active Expired
- 1986-03-24 CN CN86101906A patent/CN1022566C/zh not_active Expired - Lifetime
- 1986-03-26 JP JP61066108A patent/JPH0613511B2/ja not_active Expired - Lifetime
- 1986-03-26 DK DK143986A patent/DK168537B1/da not_active IP Right Cessation
- 1986-03-26 IE IE80186A patent/IE58388B1/en not_active IP Right Cessation
- 1986-03-26 AU AU55297/86A patent/AU579232B2/en not_active Expired
-
1993
- 1993-06-16 BG BG97873A patent/BG60432B2/bg unknown
-
1994
- 1994-04-11 NL NL940006C patent/NL940006I2/nl unknown
- 1994-08-20 SG SG119294A patent/SG119294G/en unknown
- 1994-10-06 HK HK108794A patent/HK108794A/xx not_active IP Right Cessation
-
1995
- 1995-02-17 CY CY180195A patent/CY1801A/xx unknown
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1315826C (zh) * | 2002-03-05 | 2007-05-16 | 菲尔若国际公司 | 用于制备3－(2－(4－(6－氟苯并(d)异噁唑－3－基)－哌啶－1－基)－乙基)－2－甲基－6,7,8,9－四氢－4h－吡啶并－(1,2－a)嘧啶－4－酮的方法 |
Also Published As
| Publication number | Publication date |
|---|---|
| NL940006I2 (nl) | 1999-09-01 |
| US4804663A (en) | 1989-02-14 |
| NL940006I1 (nl) | 1994-05-16 |
| DK168537B1 (da) | 1994-04-18 |
| DK143986D0 (da) | 1986-03-26 |
| BG60432B2 (bg) | 1995-03-31 |
| EP0196132A3 (en) | 1988-01-20 |
| CA1256867A (en) | 1989-07-04 |
| CY1801A (en) | 1995-02-17 |
| HK108794A (en) | 1994-10-14 |
| EP0196132A2 (en) | 1986-10-01 |
| DK143986A (da) | 1986-09-28 |
| LU88576I2 (fr) | 1995-03-21 |
| AU5529786A (en) | 1986-10-02 |
| EP0196132B1 (en) | 1992-08-12 |
| AU579232B2 (en) | 1988-11-17 |
| IE58388B1 (en) | 1993-09-08 |
| CN1022566C (zh) | 1993-10-27 |
| JPH0613511B2 (ja) | 1994-02-23 |
| JPS61221186A (ja) | 1986-10-01 |
| SU1468419A3 (ru) | 1989-03-23 |
| IE860801L (en) | 1986-09-27 |
| SG119294G (en) | 1995-03-17 |
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