CN1046518C - 新型的带杂环取代基的咪唑并喹喔啉酮及其制备方法和应用 - Google Patents
新型的带杂环取代基的咪唑并喹喔啉酮及其制备方法和应用 Download PDFInfo
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- CN1046518C CN1046518C CN95195396A CN95195396A CN1046518C CN 1046518 C CN1046518 C CN 1046518C CN 95195396 A CN95195396 A CN 95195396A CN 95195396 A CN95195396 A CN 95195396A CN 1046518 C CN1046518 C CN 1046518C
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- Prior art keywords
- alkyl
- nitro
- trifluoromethyl
- gram
- phenyl
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- 238000002360 preparation method Methods 0.000 title abstract description 19
- HOFSPGAYXKNFAM-UHFFFAOYSA-N imidazo[4,5-f]quinoxalin-2-one Chemical class C1=CN=C2C3=NC(=O)N=C3C=CC2=N1 HOFSPGAYXKNFAM-UHFFFAOYSA-N 0.000 title abstract 2
- 125000000623 heterocyclic group Chemical group 0.000 title description 2
- 239000000126 substance Substances 0.000 claims abstract description 10
- 229910052799 carbon Inorganic materials 0.000 claims description 41
- 239000000203 mixture Substances 0.000 claims description 21
- 229910052739 hydrogen Inorganic materials 0.000 claims description 14
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 14
- 239000003814 drug Substances 0.000 claims description 12
- FVGAJEWYPIQRJX-UHFFFAOYSA-N imidazo[4,5-h]quinazolin-2-one Chemical compound N1=CN=C2C3=NC(=O)N=C3C=CC2=C1 FVGAJEWYPIQRJX-UHFFFAOYSA-N 0.000 claims description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 12
- 239000001257 hydrogen Substances 0.000 claims description 10
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 10
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 9
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 9
- 229910052801 chlorine Inorganic materials 0.000 claims description 8
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- 239000005557 antagonist Substances 0.000 description 8
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- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 7
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 238000001704 evaporation Methods 0.000 description 6
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- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 6
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- 238000007074 heterocyclization reaction Methods 0.000 description 5
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Abstract
公开了下式的咪唑并喹喔啉酮及其制备方法
式中，R1～R5、A和B有说明书中的含义。新物质适用于控制各种疾病。
Description
本发明涉及新型的带杂环取代基的咪唑并喹喔啉酮，涉及其制备方法以及涉及它们用于控制各种疾病的应用。
称为兴奋性氨基酸的物质，特别是谷氨酸广泛存在于中枢神经系统中。这种兴奋性氨基酸作为谷氨酸受体的传递物质，其中各种亚型是已知的。例如，一种亚型称为特异激动剂N-甲基-D-天冬氨酸NMDA受体。这种NMDA受体对于激动剂和拮抗剂有各种结合位。甘氨酸也可结合到NMDA受体上，并调整天然激动剂谷氨酸的作用。在这一甘氨酸结合位的拮抗药因此可表现出对NMDA受体的拮抗剂作用；并抑制这一受体的过度兴奋。
谷氨酸受体的其他亚型是AMPA受体和红藻氨酸受体，它们以专一激动剂2-氨基-3-羟基-5-甲基-4-异噁唑丙酸(AM-PA)和红藻氨酸命名。这些受体的拮抗物与上述NMDA受体一样，同样抑制过度兴奋。
在许多神经变性疾病或心理紊乱中出现谷氨酸含量升高，并可能产生过度兴奋状态或中枢神经系统(CNS)中毒作用。
谷氨酸受体亚型的拮抗剂因此可用来治疗这些疾病。谷氨酸拮抗剂特别是包括NMDA拮抗剂及其抑扬调节剂(如甘氨酸拮抗剂)和AMPA拮抗剂所以适合于治疗神经变性疾病(享廷顿舞蹈病和帕金森病)、在低氧症、缺氧症或局部缺血后的神经中毒紊乱，如中风后出现的，或者作为镇癫药、抗抑郁药和抗焦虑药(参见Arzneim,Forschung 40(1990)511-514；TIPS,11(1990)334-338和未来的药物14(1989)1059-1071)。
式Ⅱ的许多咪唑并喹喔啉酮已被公开：
Ⅱ
例如，DE-A3004750和DE-A3004751公开了抗过敏作用的物质。此外，在US5166344(=EP400583)中，已要求咪唑并喹喔啉酮作为磷酸二酯酶抑制剂用作心血管剂。
在CNS方面，US-A5182386对咪唑并喹喔啉提出要求，它们是GABA受体的拮抗剂或反激动剂，可用于控制焦虑状态、睡眠紊乱、惊厥状态以及可用于提高记忆。
在许多出版物(如EP374534和EP260467)中公开的谷氨酸拮抗剂主要是喹喔啉-2,3-二酮的衍生物。
例如，WO92/07847涉及在苯型环中有杂环取代基的化合物。US5153196、US5196421和WO93/20077涉及包括咪唑并喹喔啉酮在内的稠合杂环化合物。后者还公开了在环系的苯型部分用有2-4个氮原子的杂环化物取代。
但是，所公开的作为谷氨酸拮抗剂的化合物在稠合咪唑环上只有烷基、三氟甲基或苯基取代基。现已发现，在苯型部分中用杂环化物取代咪唑并喹喔啉酮以及在稠合咪唑环中的羧酸或其酯得到新型的谷氨酸拮抗剂。所以，它们特别适合于治疗神经紊乱。
本发明涉及式Ⅰ的新型咪唑并喹喔啉酮，以及它们的互变异构体和异构体以及生理上允许的盐，
式中，R1为氢、支链或直链C1～C5烷基或苯基，未取代的或被1或2个氯原子、1个三氟甲基、1个硝基或亚甲基二氧基取代的吡啶基或噻吩基；R2为氢、C1～C5烷基或C3～C8二烷氨基烷基，R3为氯或溴原子、三氟甲基、氰基或硝基，A为未取代的或被R4和R5取代的五元杂环，它有1～4个氮原子或有1～2个氮原子和1个氧或硫原子，其中每一R4和R5可为相同的或不同的，为氢、C1～C5烷基、C1～C5羟乙基、苯基、氯原子、三氟甲基或硝基取代的苯基、或-COOH、-COO-C1～C5烷基、-CH2-NR6R7(R6=H、C1～C5烷基、R7=H、C1～C5烷基)、-CH2-NH-CO-R8(R8=C1～C5烷基、苯基、未取代的或被氯原子或硝基或三氟甲基取代的苯基、或杂芳基)或-CH2NHCONHR8以及B为一个键或C1～C5亚烷基链。
优选的式Ⅰ化合物是R1为甲基、乙基或苯基的化合物。R2优选为甲基或乙基，或者氢原子。当R2为氢时，化合物是能与碱金属和碱土金属氢氧化物或有机含氮的碱形成盐的化合物。如果需要，酸可通过如与氢氧化钠或三(羟甲基)甲胺生成盐的方法转变成水溶性形式。对于R3来说，优选的取代基是吸电子基团，如7位的硝基或三氟甲基。
对于A来说，优选的五元杂环是吡咯及其衍生物。优选的吡咯衍生物是3-甲酰基吡咯、3-氨甲基吡咯的酰基衍生物(如苯甲酰基)或吡啶羰基衍生物，或有芳脲基的衍生物，以及特别强调苯甲酰基被硝基或CF3基取代的。在有2个氮原子的五元环系中优选的是咪唑系及其衍生物，还有苯并咪唑和吡唑，有3个和4个氮原子的五元杂环的例子是1,2,3-三唑、1,2,4-三唑及其衍生物，以及四唑系。
B优选为一价键。
令人吃惊的是，与以前公开的咪唑并喹喔啉酮相比，有杂环取代基的本咪唑并喹喔啉酮有许多优点，特别是有更高的活性。
本发明的化合物可用许多种方法制备。
式Ⅲ的8-氨基咪唑并喹喔啉酮与1,4-二羰基化合物或琥珀醛衍生物，或由它们得到的环状或无环缩醛，如式Ⅳ反应，生成比咯，
Ⅲ式中，R1、R3和B有如上规定的含义，R2为烷基，
Ⅳ
式Ⅳ的化合物可购得，或可用通常已知的操作方法制备。
转化成吡咯基化合物用常规的方法，优选在冰醋酸中，在60～120℃下进行，如在C.Ferri，“有机合成反应”，Thieme Verlag 1978,第708页及以下等描述的。本发明的吡咯基化合物Ⅴ可用式Ⅳ适当取代的二酮或缩醛制备
Ⅴ
用这一方法制备的吡咯化合物中的取代基R4或R5可用适合的方法变化，例如，醛基可还原成羟烷基或还原氨化成氨烷基。
还原氨化通常在以下条件下进行：5～80℃，优选10～30℃，在还原剂如氰基氢硼化钠或氢存在下，在加氢催化剂如钯/碳、铂/碳或阮内镍存在下，优选在极性有机溶剂如醇或二甲基甲酰胺中。
醛可用如在R.C.Larock“综合的有机转化”，1989,VCH出版社，第838页以下等描述的常规方法氧化成本发明的羧酸，氧化优选在溶剂如丙酮中，在25℃下，用高锰酸钾进行。
式Ⅵ的起始化合物(其中R3有上规含义，但不是硝基)可用类似EP400583中公开的方法制备，随后硝化和硝基还原，如反应图示1所示：反应图示1
在适合的溶剂如二甲基亚砜、二甲基甲酰胺或乙腈中，在0～140℃下，加入碱如碳酸钾，邻位卤素取代的硝基苯(Ⅵ)可与在N1氮原子上未取代的咪唑Ⅶ反应是已知的。
此外，卤素原子被4-取代的和4,5-二取代的咪唑取代通过对咪唑的最后在空间上受阻的氮原子的亲核攻击来进行，生成单一产物(Ⅷ)也是已知的。
硝基化合物还原成苯胺衍生物Ⅸ可用常规方法进行，如用钯或镍催化剂或用二氯化锡催化加氢。式Ⅵ的邻-卤代硝基苯可购得或可用已知的方法制备。
环闭合生成咪唑并喹喔啉酮X在惰性的非质子传递溶剂中，在150～200℃下，用双活化的碳酸衍生物如光气、碳酸二苯酯或优选N,N′-羰基二咪唑进行。适合的溶剂是十氢萘、四氢萘,1,2-二氯苯或1,3-二甲基亚乙基脲或1,3-二甲基亚丙基脲。一种制备硝基化合物Ⅺ的方法包括用硝酸、硫酸/硝酸或硫酸/硝酸钾，在-10至20℃下使化合物X(R3为上述的，但不是硝基)硝化。
如上所述，硝基的还原得到适合于制备吡咯基化合物Ⅴ的起始化合物Ⅲ。
制备本发明物质的另一方法包括如以前所述首先有两个可交换卤素原子的硝基苯衍生物Ⅻ与咪唑衍生物Ⅶ反应，生成化合物Ⅷb；然后与氮杂环化物ⅩⅢ二次反应，生成化合物ⅪⅤ；再进行硝基还原、环化生成如上所述的化合物：
R1～R5、A和B有上述的含义。
特别优选的式ⅩⅢ杂环化物是有可取代NH基的化合物，它们由氮杂环化物咪唑、吡唑、1,2,3-三唑、1,2,4-三唑和四唑得到。但是，适合的杂环化物还可含有另外的杂原子如氧原子或硫原子。
如果需要，该法也可用以下步骤进行：适合的有两个可交换卤素原子以及在最后环化的合适位置有被护氨基的硝基苯ⅩⅤ首先与所需的杂环化物ⅩⅢ反应，然后与所需的咪唑衍生物Ⅶ反应，生成ⅩⅥ；除去氨基保护基后，得到ⅩⅧ；进行如前所述的环闭合：反应图示3
制备本发明化合物Ⅰ(其中R3为硝基)的另一方法包括化合物ⅩⅧ在B位(ⅪⅩ)首先硝化，然后还原成ⅩⅩⅩⅧR=NO2(ⅩⅨ)R=NH2(ⅩⅩ)氨基的保护，7位重新硝化和释放邻-氨基硝基化合物ⅩⅩ，它们适合通过除去2保护基进一步与如呋喃衍生物Ⅳ反应。ⅩⅪ
式Ⅰ的化合物，其中R1、R2、R3、R4、R5、A和B有上述含义，可通过水解转化成式Ⅰ的酸，其中R1、R3、R4、R5、A和B有所述的含义，而R2为氢。
水解优选在碱性条件下，如在碱金属氢氧化物或碳酸氢钠存在下，在溶剂如水、低碳醇、四氢呋喃或其混合物中进行。如果需要，用这一方法制得的有机酸被转化成生理上允许的胺盐或金属盐。这特别是指碱金属如钠盐和钾盐、碱土金属如钙盐、其他金属如铝盐以及有机碱如吗啉、哌啶、单一、二-和三-乙醇胺或三(羟甲基)氨基甲烷的盐。
本发明的化合物是激动剂氨基酸谷氨酸的拮抗剂，特别是NM-DA受体AMPA受体和红藻氨酸受体的甘氨酸结合位的拮抗剂。
它们适合在人体医学中作药剂，并可用于生产治疗神经变性疾病和中枢神经系统的神经中毒紊乱的药物以及用于生产解痉药、镇癫药、抗焦虑药和抗抑郁药。
化合物Ⅰ的药理学活性在从鼠小脑分离的膜上进行了研究。为此该膜在有放射性标记物质3H-2-氨基-3-羟基-5-甲基-4-异噁唑丙酸(3H-AMPA)、[3H]-甘氨酸和[3H]-红藻氨酸的本发明化合物存在下培养，它们分别专一结合到AMPA、NMDA和红藻氨酸受体上。在这一培养后，用闪烁计数测量的放射性用来确定所述放射性受体配体结合到膜受体上的程度。本发明化合物对相关受体的亲合性由本发明化合物这一结合的浓度有关的替换来计算。离解常数KI(作为亲合性的量度)用统计分析系统(SAS)的迭代非线性回归分析来确定，类似于P.J.Munson和D.Rodbard的配位程序(分析生物化学，107(1980)220，配体：配体结合体系表征的通用计算法)。
进行以下体外试验：
1．3H-2-氨基-3-羟基-5-甲基-4-异噁唑丙酸(3H-AMPA)结合
为了制备膜材料，将新取的大鼠小脑用15倍体积的缓冲溶液A(由30mMα,α,α-三(羟甲基)甲胺盐酸(TRIS-HCl)和0.5mM乙二胺四乙酸(EDTA)组成，PH7.4)用Ultra-Turax均质化。将悬浮液在48000转/分下离心分离20分钟。除去上层清液后，除含在沉积物中的含蛋白质的膜材料用在缓冲溶液A中悬浮的方法洗涤3次，然后每次在48000转/分下离心分离20分钟。然后将膜材料悬浮在15倍体积的缓冲溶液A中，在37℃下培养30分钟。然后用离心分离洗涤蛋白质材料2次，悬浮和在-70℃贮存一直到使用。
对于结合分析，将蛋白质材料在37℃下解冻，在48000转/分下离心分离2次(每次20分钟)，随后悬浮在缓冲溶液B中，缓冲溶液B由50mMTRIS-HCl、0.1M硫氰酸钾和2.5mM氯化钙组成，pH值7.1。随后，将0.25毫克膜材料、0.1微居里3H-AMPA(60居里/毫摩尔)和化合物Ⅰ溶于1毫升缓冲溶液B中，在冰中培养60分钟。将经培养的溶液通过CF/B过滤器(来自Whatman公司)过滤，它先用0.5％聚亚乙基亚胺处理至少2小时。然后用5毫升冷缓冲溶液B洗涤膜残留物，使结合的3H-AMPA与游离的3H-AMPA彼此分离。用闪烁计数法测量在膜材料中结合3H-AMPA的放射性后，用替换曲线的回归分析来确定KI。
2．[3H]-甘氨酸结合
为了制备用于3H-甘氨酸结合分析用的膜；将新取的大鼠海马在10倍体积的制备缓冲溶液(50mM TRIS-HCl,10mM EDTA)中用Potter均质器均质化。均匀液在48000转/分下离心分离20分钟。除去上层清液，通过再悬浮和在48000转/分下(每次20分钟)离心分离的方法洗涤小球中含的膜2次。将再悬浮的膜在液氮中冷冻并在37℃下再融化。在另一洗涤步骤后，将膜悬浮液在振荡水浴中37℃下培养15分钟。在另外4次洗涤步骤(每一情况中48000转/分离心分离20分钟并再悬浮在制备的缓冲溶液中)后，将膜贮存在-70℃下一直到再使用。
将冷冻的膜在37℃下融化，并用48000转/分下离心分离洗涤2次(每次20分钟)，然后再悬浮在结合的缓冲溶液中(50mMTRIS-HCl,pH7.4；10mM MgCl2)。培养混合物含0.25毫克蛋白质(膜)、25nM 3H-甘氨酸(16居里/毫摩尔)和在总计0.5毫升结合的缓冲溶液中的试验物质。加入1mM甘氨酸测定非特异性结合。在4℃下培养60分钟后，通过GF/B过滤器过滤使结合的和游离的配体彼此分离，然后用约5毫升冰冷却的结合缓冲溶液洗涤。用液体闪烁计数法测定过滤器上残留的放射性。用迭代非线性拟合程序或根据Cheng和Prusoff方程由替换曲线计算出离解常数。
3．[3H]-红藻氨酸的结合
为了制备用于[3H]-红藻氨酸结合分析的膜，将新取的大鼠小脑在15倍体积的制备缓冲溶液(30mM TRIS-HCl,pH7.4,0.5mMEDTA)中，用Ultra-Turrax均质化。将均匀液在48000转/分下离心分离20分钟。除去上层清液，通过再悬浮在制备的缓冲溶液中并在48000转/分下离心分离的方法洗涤3次(每次20分钟)含在小球中的膜。第三次洗涤步骤后，在37℃下培养膜。然后通过离心分离和再悬浮的方法将膜洗涤2次，并贮存在-70℃下一直到再使用。
将冷冻的膜在37℃下解冻，悬浮在结合的缓冲溶液(50mMTRIS-HCl,pH7.4)中，在48000转/分下离心分离20分钟。将存在于小球中的膜再悬浮在结合的缓冲溶液中。培养混合物含有0.25毫克蛋白质(膜)、0.058微居里[3H]-红藻氨酸(58居里/毫摩尔)和在总计1毫升结合缓冲溶液中的试验物质。在0.1mM谷氨酸存在下测定非特异性结合。在冰上培养60分钟后，通过CF/B过滤器过滤的方法使结合的和游离的配体彼此分离，随后用5毫升冰冷却的结合缓冲溶液洗涤。CF/B过滤器预先用0.5％聚亚乙基胺至少处理2小时。用非线性拟合程序或根据Cheng和Prusoff方程分析替换曲线和计算离解常数。
新型化合物很好地进行这些分析。
本发明的药物组合物除常规的药物辅助物质外还含有在治疗上有效数量的化合物Ⅰ。这些药物以常规的浓缩物形式存在，对于局部外用来说，例如可以粉剂和软膏存在。通常，这些物质的用量为0.0001～1％(重量)，优选0.001～0.1％(重量)。
对于内用来说，制剂从单一剂量给药。在单一剂量中，每1千克体重给药0.1～100毫克。该组合物每天可以1次或多次剂量给药，取决于疾病性质和严重程度。
本发明的药物组合物除含有该物质外还含有常规适用于所需的给药方式的赋形剂和稀释剂。可用于局部外用的药物辅助物质例如是乙醇、异丙醇、乙氧基化的蓖麻油、乙氧基化的氢化蓖麻油、聚丙烯酸、聚乙二醇、聚乙二醇硬脂酸酯、乙氧基化脂肪醇、液体石蜡、凡士林和羊毛脂。适合于内用的例子是内酯、聚乙二醇、乙醇、淀粉、滑石和聚乙烯基吡咯烷酮。
此外，抗氧剂(如生育酚和丁基化的羟基苯甲醚)，香料添加剂、稳定剂、乳化剂和润滑剂也可存在。
除了本发明的物质外，在组合物中存在的物质以及用于生产药物组合物的物质在每种情况下都是毒理学上可接受的并与上述物质相容的。药物组合物用常规的方法生产，例如将该物质与常规的赋形剂和稀释剂混合。
该药物组合物可用各种方法给药，如口服、肠胃外、皮下、肠胃内和局部服用。因此，可能的形式是片剂、乳剂、浸剂和注射溶液、糊剂、软膏、凝胶、乳油、洗剂、粉末和喷剂。
实施例1
4,5-二氢-1-甲基-8-(1-吡咯基)-7-三氟甲基-4-氧代咪唑并[1,2-a]喹喔啉-2-羧酸乙酯
a．1-(2-硝基-4-三氟甲基苯基)-4-乙酯基-5-甲基咪唑
将10.45克(0.05摩尔)2-氟-4-三氟甲基硝基苯、7.7克(0.05摩尔)4(5)-乙酯基-5(4)-甲基咪唑和13.8克碳酸钾于100毫升乙腈中的混合物回流4小时。
将1000毫升水加到冷却的反应混合物中，用250毫升二氯甲烷萃取混合物，用硫酸镁干燥二氯甲烷相。蒸发干燥的溶液，用乙醚研制使残留物晶化。
产量：11.4克(理论值的66％)，熔点：142-144℃
b．1-(2-氨基-4-三氟甲基苯基)-4-乙酯基-5-甲基咪唑
用2克钯/碳催化剂(10％Pd)，在100毫升乙醇中，在常压、常温下使11.6克(0.034摩尔)上述化合物a加氢。氢增量停止后，从溶液中除去催化剂，然后在减压下蒸发，用少量乙醚使残留物晶化。
产量：9.8克(理论值的93％)，熔点：189～190℃。
c．4,5-二氢-1-甲基-7-三氟甲基-4-氧代咪唑并[1,2-a]喹喔啉-2-羧酸乙酯
在搅拌下，将上述7.3克(0.0233摩尔)化合物b和4.2克(0.0259摩尔)N,N′-羰基二咪唑于100毫升1,2-二氯苯中煮沸2.5小时。冷却后，用吸滤过滤出固体，用丙酮/乙醚洗涤。
产量：5.1克(理论值的64.5％)，熔点：270～271℃。
d．4.5-二氢-1-甲基-8-硝基-7-三氟甲基-4-氧代咪唑并[1,2-a]喹喔啉-2-羧酸乙酯
用50毫升浓硫酸和50毫升硝酸(d=1.50)的混合物，在室温下使5.0克(0.015摩尔)上述化合物C硝化72小时，然后在60℃硝化1小时。将混合物冷却，然后倒入冰中，用吸滤法过滤出产物并用水洗涤。
产量：3.9克(理论值的70％)，熔点：284-286℃。
e．8-氨基-4,5-二氢-1-甲基-7-三氟甲基-4-氧代咪唑并[1,2-a]喹喔啉-2-羧酸乙酯
将12克(0.031摩尔)上述化合物d溶于200毫升沸腾的冰醋酸中，随后在15分钟内将15克铁粉分份加入。30分钟后，用吸滤法过滤出沉淀，并用乙酸、水和甲醇洗涤。
产量：10克(理论值的91％)，熔点：300℃。
f．将1.5克(0.0042摩尔)上述化合物e吸收在30毫升冰醋酸中，加入1.12克(0.085摩尔)2,5-二甲氧基四氢呋喃，在预热的油浴中将混合物迅速加热到沸点，一直到制得溶液。5分钟后将混合物迅速冷却，用吸滤法过滤出沉淀，并用乙酸和乙醚洗涤。
产量：0.75克(理论值的44％)，熔点：290～295℃。
C19H15F3N4O3
按1f方法，用3位取代的2,5-二甲氧基四氢喃喃衍生物制备另外一些化合物。
2,5-二甲氧基四氢呋喃衍生物：
由它制得的化合物列入表Ⅰ：
实施例9
4,5-二氢-8-(2,5-二甲基-1-吡咯基)-1-甲基-7-三氟甲基-4-氧代咪唑并[1,2-a]喹喔啉-2-羧酸乙酯
将1.0克(0.0028摩尔)实施例1e的化合物与2克乙酰丙酮化物一起在25毫升乙酸中煮沸，在5分钟后得到溶液。再加热10分钟后，将混合物冷却，用吸滤法过滤出沉淀，用乙醚洗涤，在减压下干燥。
产量：0.9克(理论值的75％)，熔点＞300℃,C21H19F3N4O3
实施例10
4,5-二氢-1-甲基-8-(1-吡咯基)-7-三氟甲基-4-氧代咪唑并[1,2-a]喹喔啉-2-羧酸
通过在80℃下短时加热，将0.5克实施例1f中制备的酯溶于1克LiOH于50毫升水中的溶液中。几小时后，用乙酸将混合物酸化到pH值5，用吸滤法过滤出沉淀，在减压下干燥。
产量：0.4克(理论值的86％)，熔点＞300℃,C21H19F3N4O3
用类似的方法，由实施例2-9的醚制得以下的化合物：
20．4,5-二氢-8-(1-咪唑基)-1-甲基-7-三氟甲基-4-氧代咪唑并[1,2-a]喹喔啉-2-羧酸
a．1-(5-氯-2-硝基-4-三氟甲基苯基)-4-乙酯基-5-甲基咪唑
按实施例1a，由2,4-二氯-5-硝基苯并三氟化物和4(5)-乙酯基-5(4)甲基咪唑制备。
熔点：118-119℃,C14H11ClF3N3O4
b．4-(4-乙酯基-5-甲基-1-咪唑基)-2-(1-咪唑基)-5-硝基苯并三氟化物
将5克(0.013摩尔)实施例1a中制得的产物和1.8克(0.026摩尔)咪唑于100毫升乙腈中的溶液回流120小时。然后蒸出溶剂，用乙酸乙酯和水处理残留物，分离出溶剂相，用水洗一次以上，干燥和蒸发。用二异丙醚于四氢呋喃中的99∶1混合物研制残留物后使产物晶化。
熔点：160～162℃,C17H14F3N5O4
c．2-(4-乙酯基-5-甲基-1-咪唑基)-4-(1-咪唑基)-5-三氟甲基苯胺
将3.5克实施例1b的产物于50毫升乙酸中的溶液加热煮沸，然后将5.6克铁粉分份加入。20分钟后，用吸滤法过滤混合物，在减压下蒸发溶液，加入水，用乙酸乙酯萃取混合物2次。然后用碳酸钠洗涤萃取物，一直到不含酸为止，将溶液干燥和蒸发，用乙醚蒸煮残留物。
产量：1.8克(理论值的55％)，熔点：265～266℃。
d．最终产物的制备
将0.7克(0.002摩尔)20c得到的化合物和0.5克1.1′-羰基二咪唑于50毫升1,2-二氯苯中的溶液回流2小时，冷却后用吸滤法过滤出制得的沉淀，用热的甲醇/异丙醇混合物洗涤。
得到以下结果，产量0.2克(理论值的25％)，熔点265～270℃，C18H14F3N5O3。
用类似的方法，由不同的起始化合物得到以下化合物：
21．4,5-二氢-1-甲基-8-(2-甲基-1-咪唑基)-7-三氟甲基-4-氧代咪唑并[1,2-a]喹喔啉-2-羧酸乙酯
熔点＞300℃,C19H15F3N4O3
22．4,5-二氢-1-甲基-8-(1,2,4-三唑-1-基)-7-三氟甲基-4-氧代咪唑并[1,2-a]喹喔啉-2-羧酸乙酯
熔点291-293℃,C17H13F3N6O3
用氢氧化锂如在实施例10中一样水解，由实施例19-21的化合物制得以下化合物：
23．4,5-二氢-8-(1-咪唑基)-1-甲基-7-三氟甲基-4-氧代咪唑并[1,2-a]喹喔啉-2-羧酸
熔点291-293℃,C17H13F3N6O3
24．4,5-二氢-1-甲基-8-(2-甲基-1-咪唑基)-7-三氟甲基-4-氧代咪唑并[1,2-a]喹喔啉-2-羧酸
熔点＞300℃,C17H12F3N5O3
25．4,5-二氢-1-甲基-8-(1,2,4-三唑-1-基)-7-三氟甲基-4-氧代咪唑并[1,2-a]喹喔啉-2-羧酸
熔点＞300℃,C17H12F3N5O3
26．4,5-二氢-1-乙基-8-(1-咪唑基)-7-三氟甲基-4-氧代咪唑并[1,2-a]喹喔啉-2-羧酸
熔点＞300℃,C17H12F3N5O3
27．4,5-二氢-8-(3-甲酰基-1-吡咯基)-1-甲基-7-硝基-4-氧代咪唑并[1,2-a]喹喔啉-2-羧酸乙酯
a．原料的制备
通过2-氟硝基苯与4(5)乙酯基-5(4)甲基-咪唑反应，随后加氢和与N,N′-羰基二咪唑环闭合来制备4,5-二氢-1-甲基-4-氧代咪唑并[1,2-a]喹喔啉-2-羧酸乙酯。
b．4,5-二氢-1-甲基-8-硝基-4-氧代咪唑并[1,2-a]喹喔啉-2-羧酸乙酯
在0-5℃、搅拌下，将25克(0.09摩尔)上述在a)中描述的物质分份加到300毫升100％浓度的硝酸中。15分钟以后，将混合物倒入冰中，用吸滤法过滤，用丙酮处理残留物，得到产物晶体。
产量：26克(理论值的82％)，熔点＞300℃,C14H12N4O5
c．4,5-二氢-8-乙酰氨基-1-甲基-4-氧代咪唑并[1,2-a]喹喔啉-2-羧酸乙酯
上述b)中的化合物在煮沸的乙酸中用铁粉还原。
产量：理论值的66％，熔点＞300℃,C16H16N4O4
d．4,5-二氢-8-乙酰氨基-1-甲基-7-硝基-4-氧代咪唑并[1,2-a]喹喔啉-2-羧酸乙酯
在20℃下，将1克上述d)中的化合物分份加入25毫升100％浓度的硝酸中，随后搅拌5分钟进行硝化。
产量：0.8克(理论值的70％)，熔点＞300℃,C16H15N5O6
e．4,5-二氢-8-氨基-1-甲基-7-硝基-4-氧代咪唑并[1,2-a]喹喔啉-2-羧酸乙酯
通过洗将化合物加热到70℃，然后缓慢冷却到室温的方法，用盐酸选择性水解上述化合物d)。
产量：1.4克(理论值的35％)，熔点＞300℃,C14H13N5O5
f．最终产物的制备
如在实施例1f中那样，将1.0克(0.003摩尔)e)中得到的化合物与1.0克2,5-二甲氧基-3-甲酰基四氢喃喃在煮沸的冰醋酸中反应。
产量：0.3克(理论值的24％)，熔点220～225℃,C19H15N5O6
28．4,5-二氢-1-甲基-8-(2-甲基-1-咪唑基)-7-硝基-4-氧代咪唑并[1,2-a]喹喔啉-2-羧酸乙酯
a．5-乙酰氨基-4-氟-2-(2-甲基-1-咪唑基)硝基苯
通过在50℃下搅拌72小时，使3克(0.0138摩尔)5-乙酰氨基-2,4-二氟-1-硝基苯与1.1克(0.0135摩尔)2-甲基咪唑和5克碳酸钾反应。为了处理，用吸滤法过滤反应混合物，在减压下蒸发，用柱色谱法(硅胶，二氯甲烷十5％甲醇)纯化。
产量：1.0克(理论值的26％)，熔点209～210℃(从异丙醇中)，C12H11FN4O3
b．5-氨基-2-(2-甲基-1-咪唑基)-4-(4-乙酯基-5-甲基-1-咪唑基)硝基苯
在100毫升二甲基甲酰胺中，在120℃下搅拌2小时，使6.0克(0.022摩尔)a)所述的化合物与3.4克(0.022摩尔)4(5)-乙酯基-5(4)-甲基咪唑和6克碳酸钾反应。为了处理，用吸滤法过滤混合物，在减压下蒸发溶液，加水，用二氯甲烷萃取混合物。将干燥和蒸发后得到的残留物从异丙醇中结晶(产量3.5克，为理论值的39％)，然后在60℃下与100毫升盐酸搅拌4小时，为了处理，在减压下用蒸馏法基本上除去盐酸，在0℃下用稀氨水中和产物，用二氯甲烷萃取。用柱色谱法纯化残留物。
产量：1克
c．通过在160～170℃搅拌2小时，使1.0克b)所述的化合物与于50毫升1,2-二氯苯中的0.6克N,N′-羰基二咪唑反应。冷却到50℃后，倾倒出溶液，用热丙酮处理残留物，用吸滤法过滤。蒸发滤液得到0.1克所需的化合物。
熔点265～270℃,C18H16N6O5
29．4,5-二氢-1-甲基-8-(1-咪唑基)-7-硝基-4-氧代咪唑并[1,2-a]喹喔啉-2-羧酸乙酯
a．5-氨基-4-氟-2-(1-咪唑基)硝基苯
在0℃下将12克(0.068摩尔)5-氨基-2,4-二氟硝基苯缓慢加到4.7克咪唑(0.069摩尔)和2.1克氢化钠(80％油中；0.07摩尔)的溶液中，然后在这一温度下搅拌数小时。用水稀释混合物，用二氯甲烷萃取几次。干燥和蒸发后，残留物从异丙醇中重结晶。
产量：7.1克(理论值的45％)，熔点211～212℃。
b．5-氨基-2-(1-咪唑基)-4-(4-乙酯基-5-甲基-1-咪唑基)硝基苯
用于30毫升二甲基甲酰胺中的0.82克氢化钠(80％油中；0.027摩尔)预处理4.2克(0.027摩尔)4(5)-乙酯基-5(4)-甲基咪唑1小时，然后加入6.1克(0.027摩尔)上述a)中的化合物，并将混合物搅拌过夜。在处理以前将混合物在50℃下加热1小时。为了处理，加入水，然后加入3毫升乙酸，用乙酸乙酯萃取混合物，随后干燥和蒸发。用乙醚/异丙醇(95+5)处理后，得到化合物晶体。
产量：4.2克(理论值的42％)，熔点213～215℃
c．最终产物的制备
将1.0克b)中描述的化合物按实施例28c反应，得到的本实施例的化合物产量为0.3克(理论值的24％)。
熔点328～330℃,C18H13N5O6
实施例28和29的化合物如在实施例10中描述的用氢氧化锂水解，得到以下化合物：
30．4,5-二氢-1-甲基-8-(1-咪唑基)-7-硝基-4-氧代咪唑并[1,2-a]喹喔啉-2-羧酸
熔点＞300℃,C15H10N6O5
31．4,5-二氢-1-甲基-8(2-甲基-1-咪唑)-7-硝基-4-氧代咪唑并[1,2-a]喹喔啉-2-羧酸
熔点＞300℃,C16H12N6O5
32．4,5-二氢-8-(3-甲酰基-1-吡咯基)-1-甲基-7-硝基-4-氧代咪唑并[1,2-a]喹喔啉-2-羧酸
实施例27的化合物按实施例10描述的用氢氧化锂水解得到上述化合物。
熔点＞300℃,C17H11N5O6
Claims (4)
1．一种式Ⅰ的咪唑并喹喔啉酮，以及它们的互变异构体和异构体以及生理上允许的盐，
式中，R1为氢、支链或直链C1～C5烷基或苯基、未取代的或被1或2个氯原子、1个三氟甲基、1个硝基或亚甲基二氧基取代的吡啶或噻吩基，R2为氢、C1～C5烷基或C3～C8二烷氨基烷基，R3为氯或溴原子、三氟甲基、氰基或硝基，A为未取代的或被R4和R5取代的五元杂环，它有1-4个氮原子或有1-2个氮原子和1个氧或硫原子，其中每一R4和R5可为相同的或不同的，为氢、C1～C5烷基、C1～C5羟乙基、苯基、氯原子、三氟甲基或硝基取代的苯基、或-COOH、-COO-C1～C5烷基、-CH2-NR6R7(R6=H、C1～C5烷基，R7=H、C1～C5烷基)、-CH2-NH-CO-R8(R8=C1～C5烷基、苯基、未取代的或被氯原子或硝基或三氟甲基取代的苯基，或杂芳基)或-CH2NHCONHR8以及B为一个键或C1～C5亚烷基链
2．权利要求1所要求的式Ⅰ咪唑并喹喔啉酮用于生产控制神经变性疾病、中枢神经系统的神经中毒紊乱，特别是用于控制中风、脑和脊柱索创伤性损伤后，以及癫痫、焦虑状态和抑郁的药物的应用。
3．一种口服、肠胃外或肠胃内给药的药物组合物，一次剂量为0.1～100毫克/千克体重，它除含有常规的药物辅助物质外还含有至少一种按权利要求1所述的咪唑并喹喔啉酮Ⅰ。
4．一种静脉注射用药物组合物，它除含有常规的药物辅助物质外还含有0.001～10％(重量)至少一种按权利要求1所述的咪唑并喹喔啉酮Ⅰ。
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| DEP4434941.6 | 1994-09-30 | ||
| DE4434941 | 1994-09-30 | ||
| DE19503825.8 | 1995-02-06 | ||
| DE19503825A DE19503825A1 (de) | 1994-09-30 | 1995-02-06 | Neue heterocyclische substituierte Imidazolo-chinoxalinone, ihre Herstellung und Verwendung |
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| US (1) | US6121265A (zh) |
| EP (1) | EP0783506A1 (zh) |
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| CN (1) | CN1046518C (zh) |
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| DE19611476A1 (de) * | 1996-03-22 | 1997-09-25 | Basf Ag | Neue heterocyclische substituierte Imidazolo-chinoxalinone, ihre Herstellung und Verwendung |
| US6555564B1 (en) * | 1999-03-04 | 2003-04-29 | The Board Of Trustees Of The University Of Illinois | Neuropharmacological treatments of sleep-related breathing disorders |
| US7542773B2 (en) * | 2002-03-29 | 2009-06-02 | At&T Intellectual Property I, L.P. | Customized alerts for incoming data messages |
| CN100386326C (zh) * | 2003-10-22 | 2008-05-07 | 中国人民解放军军事医学科学院毒物药物研究所 | 1-羟甲基咪唑并[1，2-a]喹喔啉化合物及其应用 |
| WO2007087250A2 (en) * | 2006-01-23 | 2007-08-02 | Amira Pharmaceuticals, Inc. | Tricyclic inhibitors of 5-lipoxygenase |
| EP2666775A1 (en) * | 2012-05-21 | 2013-11-27 | Domain Therapeutics | Substituted pyrazoloquinazolinones and pyrroloquinazolinones as allosteric modulators of group II metabotropic glutamate receptors |
| FR3031105B1 (fr) * | 2014-12-31 | 2018-04-06 | Universite De Montpellier | Nouveaux imidazo[1,2-a]quinoxalines et derives pour le traitement des cancers |
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| WO1993020077A1 (en) * | 1992-04-03 | 1993-10-14 | Yamanouchi Pharmaceutical Co., Ltd. | Fused quinoxalinone derivative and pharmaceutical composition containing the same |
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| IL59104A (en) * | 1979-02-09 | 1984-02-29 | Roussel Uclaf | Heterotricyclic derivatives,process for their preparation and pharmaceutical compositions incorporating them |
| FR2448541A1 (fr) * | 1979-02-09 | 1980-09-05 | Roussel Uclaf | Nouveaux derives de l'oxoimidazoquinoxaline et leurs sels, leur procede de preparation, leur application comme medicaments et les compositions pharmaceutiques les renfermant |
| SE462338B (sv) * | 1982-04-28 | 1990-06-11 | Roussel Uclaf | Nya imidazo /1,2-a/ kinoxaliner och deras salter, foerfarande foer framstaellning daerav samt farmaceutiska kompositioner innehaallande densamma |
| IE66149B1 (en) * | 1986-09-16 | 1995-12-13 | Novo Nordisk As | Quinoxaline compounds and their preparation and use |
| DK716188D0 (da) * | 1988-12-22 | 1988-12-22 | Ferrosan As | Quinoxalinforbindelser, deres fremstilling og anvendelse |
| US5055465A (en) * | 1989-05-31 | 1991-10-08 | Berlex Laboratories, Inc. | Imidazoquinoxalinones, their aza analogs and process for their preparation |
| US5196421A (en) * | 1991-06-05 | 1993-03-23 | Eli Lilly And Company | Excitatory amino acid receptor antagonists in methods for the use thereof |
| US5153196A (en) * | 1991-06-05 | 1992-10-06 | Eli Lilly And Company | Excitatory amino acid receptor antagonists and methods for the use thereof |
| US5182386A (en) * | 1991-08-27 | 1993-01-26 | Neurogen Corporation | Certain imidazoquinoxalinones; a new class of gaba brain receptor ligands |
| US5306819A (en) * | 1992-08-27 | 1994-04-26 | Neurogen Corporation | Certain aryl a cycloalkyl fused imidazopyrazinols; and new class of GABA brain receptor ligands |
| DE4310523A1 (de) * | 1993-03-31 | 1994-10-06 | Basf Ag | Imidazolo-chinoxalinone zur Behandlung zentralnervöser Erkrankungen |
| ATE214069T1 (de) * | 1994-02-11 | 2002-03-15 | Novo Nordisk As | Heterocyclische verbindungen und ihre herstellung und verwendung |
| US5536718A (en) * | 1995-01-17 | 1996-07-16 | American Cyanamid Company | Tricyclic benzazepine vasopressin antagonists |
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- 1995-09-19 BR BR9509055A patent/BR9509055A/pt not_active Application Discontinuation
- 1995-09-19 AU AU36506/95A patent/AU3650695A/en not_active Abandoned
- 1995-09-19 US US08/809,170 patent/US6121265A/en not_active Expired - Fee Related
- 1995-09-19 EP EP95934074A patent/EP0783506A1/de not_active Withdrawn
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- 1995-09-19 SI SI9520108A patent/SI9520108A/sl unknown
- 1995-09-19 JP JP8511334A patent/JPH10513435A/ja active Pending
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| WO1993020077A1 (en) * | 1992-04-03 | 1993-10-14 | Yamanouchi Pharmaceutical Co., Ltd. | Fused quinoxalinone derivative and pharmaceutical composition containing the same |
Also Published As
| Publication number | Publication date |
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| NO971424L (no) | 1997-05-22 |
| PL319406A1 (en) | 1997-08-04 |
| FI971317A0 (fi) | 1997-03-27 |
| WO1996010572A1 (de) | 1996-04-11 |
| CA2200358A1 (en) | 1996-04-11 |
| CZ94297A3 (en) | 1997-08-13 |
| IL115444A0 (en) | 1995-12-31 |
| JPH10513435A (ja) | 1998-12-22 |
| US6121265A (en) | 2000-09-19 |
| BR9509055A (pt) | 1998-06-23 |
| AU3650695A (en) | 1996-04-26 |
| BG101328A (en) | 1997-08-29 |
| HU9502847D0 (en) | 1995-11-28 |
| FI971317A (fi) | 1997-03-27 |
| NO971424D0 (no) | 1997-03-25 |
| HUT73969A (en) | 1996-10-28 |
| SI9520108A (en) | 1997-10-31 |
| EP0783506A1 (de) | 1997-07-16 |
| CN1159807A (zh) | 1997-09-17 |
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