CN1048728C - 3-取代的3h-2,3-苯并二氮杂䓬衍生物,及其制备和应用 - Google Patents
3-取代的3h-2,3-苯并二氮杂䓬衍生物,及其制备和应用 Download PDFInfo
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- CN1048728C CN1048728C CN95194402A CN95194402A CN1048728C CN 1048728 C CN1048728 C CN 1048728C CN 95194402 A CN95194402 A CN 95194402A CN 95194402 A CN95194402 A CN 95194402A CN 1048728 C CN1048728 C CN 1048728C
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- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- 239000003814 drug Substances 0.000 title claims abstract description 9
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- 150000001875 compounds Chemical class 0.000 claims description 53
- 229910052739 hydrogen Inorganic materials 0.000 claims description 23
- 239000001257 hydrogen Substances 0.000 claims description 23
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- 150000002367 halogens Chemical class 0.000 claims description 13
- 150000003839 salts Chemical class 0.000 claims description 13
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 8
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- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 4
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
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- 125000004185 ester group Chemical group 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
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- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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Abstract
本文描述了通式Ⅰ的新的３－取代的３Ｈ－２，３－苯并二氮杂䓬衍生物 其中 R<sup>1</sup>，R<sup>2</sup>，R<sup>3</sup>，R<sup>4</sup>，R<sup>5</sup>，R<sup>6</sup>，R<sup>7</sup>和ｎ具有在说明书中所说明的意义，它的制备方法及其作为药物的应用。
其中
R1，R2，R3，R4，R5，R6，R7和n具有在说明书中所说明的意义，它的制备方法及其作为药物的应用。
Description
本发明涉及新的3-取代的3H-2，3-苯并二氮杂衍生物，它的制备和作为药物的应用。
众所周知，被选出的2，3-苯并二氮杂草衍生物具有对于Quisqualat-受体调节的效能并且基于这种特性适合作为药物用于治疗中枢神经系统的疾病。
现已发现，通式I的3-取代的3H-2，3-苯并二氮杂草衍生物
其中
R1和R2是相同的或不相同的和是氢，C1-C6-烷基，硝基，卤素，基团-NR8R9，-O-C1-4-烷基或-CF3，R3是基团
R4是任选被取代的C1-6-烷基，
R5是氢或任选被取代的C1-6-烷基，
R6和R7是相同的或不相同的和是氢，任选被取代的C1-6-烷基或任选被取代的芳基，
R8和R9是相同的或不相同的和是氢，C1-6-烷基或是基团
R10是氢，任选被取代的C1-6-烷基，任选被取代的芳基，基团-NR11R12，-O-C1-6-烷基，C3-7-环烷基，C2-6-链烯基或-O-C3-7-环烷基，
R11和R12是相同的或不相同的和是氢，任选被取代的C1-6-烷基或任选被取代的芳基，
R13是C1-6-烷基和
n是1，2或3
及其异构体和生理上可以耐受的盐，同样适合用于中枢神经系统疾病的治疗，这种化合物与所述现有技术相比通过更好的特性而显得突出。因为既不在4-位也不在5-位存在一个光学活性中心，式I化合物也不用对映体分离，容易供使用。
对于烷基是理解为一个直链的或枝化的烷基例如甲基，乙基，丙基，异丙基，丁基异丁基，仲丁基，戊基，异戊基或己基，它-如芳基残基一样-任选地可以通过C1-6-烷氧基，卤素或C1-6-链烷酰基取代。
如果有一个卤化的烷基，则它可以是多次卤化的或者是全卤化的。
对于卤素是理解为氟，氯，溴和碘。
芳基可以含有6-10个碳原子，在此苯基是优选的。
环烷基是指环丙基，环丁基，环戊基，环己基和环庚基而言，特别是C3-5-环烷基。
链烯基可以是直链的或枝化的。例如它们可以是2-丙烯基，3-甲基-2-丙烯基，2-丁烯基，甲代烯丙基，乙烯基。
链烷酰基是脂肪族羧酸，例如甲酸，乙酸，丙酸，丁酸，己酸，戊酸，三甲基醋酸等的衍生物。
生理上可以耐受的盐是由无机的和有机的酸衍生物出来的。适合的无机酸是例如氢卤酸，如氢氯酸，氢溴酸，磷酸，硫酸或有机酸是例如脂肪族的或芳香族的一元羧酸或二元羧酸如甲酸，乙酸，马来酸，富马酸，丁二酸，乳酸，酒石酸，柠檬酸，草酸，乙醛酸或磺酸，例如C1-4-链烷磺酸如甲磺酸或者是任选地通过卤素或C1-4-烷基取代的苯磺酸如对-甲苯磺酸。
式I化合物也包括E-或Z-异构体或者，如果存在一个手性中心，也包括其外消旋物或对映体。
通式I的优选的化合物是这样的化合物，其中R1是氨基或硝基。
通式I的特别优选的化合物是这样的化合物，其中
R1是硝基或氨基
R2是氢
R3是基团
R4是甲基或乙基
R5，R6和R7是氢
R10是氢，C1-6-烷基，任选地用卤素取代的苯基，基团-NR11R12，C3-7-环烷基，C2-6-链烯基，-O-C1-6-烷基或C1-6-烷基，它是用氟单或多取代的，
R11和R12是相同的或者是不相同的和是氢，C1-4-烷基或苯基和n是1，2或3。
通式I的化合物以及其生理上可以耐受的盐基于它们的AMPA-受体的非竞争性抑制可以作为药物应用。按本发明的化合物基于它们的作用特征适合用于治疗一些疾病，这些疾病是通过兴奋性的氨基酸例如谷氨酸或天冬氨酸活性过强引起。因为新的化合物是作为兴奋性的氨基酸的非竞争性的拮抗剂而起作用，它们特别适合用于治疗这样的疾病，这种疾病通过兴奋性的氨基酸受体，特别是AMPA-受体而受影响。
式I化合物的药理学作用借助下面描述的试验得到确定：
体重18-22g的雄性NMRI小鼠保持在控制的环境下(6°°-18°°点钟明/暗交替，自由通道通向食物和水)和随机分组。每组由5-16个动物组成，对于动物的观察是在8°°-13°°点钟之间进行的。
将AMPA注入自由活动的小鼠的左脑室。给药器是由一个套管针与一个不锈钢的装置组成，它可以将注射深度限制在3.2mm。给药器连接在一个注射泵上。注射针头根据Montemurro和Dukelow的坐标垂直插入头骨的表面。观察动物直至出现阵挛性的或强直性的痉挛直至180秒。阵挛性的运动持续长于5秒的作为痉挛计数，阵挛性痉挛的开始作为确定痉挛阈的终点，为使痉挛阈升高或降低50％的必要的剂量(THRD50)是在4-5个试验中确定的。THRD50和可信限是用一个回归分析确定的。
这些试验的结果表明，式I化合物和它的酸加成盐可以影响AMPA-受体的功能紊乱。因此它们适合用于制备一种用于对一些疾病症状性的和预防性的治疗的药物，这种疾病是由于AMPA-受体-复合物功能改变引起。
用按本发明的化合物治疗可以防止和延缓由于疾病出现的细胞损伤和功能紊乱并可减轻由此产生的症状。
按照本发明化合物可用于治疗由于AMPA-受体过度兴奋引起的神经性的和精神性的紊乱。
属于可以功能性和预防性治疗的神经性疾病例如有神经退化性紊乱如柏金森氏病，阿耳茨海默氏痴呆病，亨延顿氏舞蹈病，肌萎缩性侧索硬化和橄榄脑桥小脑的退化。本发明化合物可用于预防局部缺血后的细胞死亡，在脑外伤后，中风，低氧，缺氧症和低血糖的细胞死亡和用于治疗老年性痴呆，艾滋病痴呆，和HIV(艾滋病病毒)感染有关的神经性症状，多发性梗塞性痴呆以及癫痫和肌肉痉挛状态。属于精神性疾病的有恐怖状态，精神分裂症，偏头疼，疼痛状态，以及睡眠障碍和滥用药物如酒精-，可卡因-，苯杂二氮类-或鸦片制剂后戒除的戒瘾症状的治疗。此外这种化合物可用于预防在长时间应用镇静药例如苯杂二氮类、巴比妥类和吗啡治疗期间耐受量的提高。除此之外这种化合物还可作为麻醉药，止疼药或止吐药来使用。
为了将按本发明的化合物作为药物来应用，将它们制成药物制剂的形式，为了肠内的或不经胃肠的给药，它除了活性物质外还含有适合制药的、有机的或无机的惰性载体材料，例如，水，明胶，阿拉伯胶，乳糖，淀粉，硬脂酸镁，滑石粉，植物油，聚亚烷基二醇等。药物制剂可以以固体的形式，例如片剂，糖衣丸，栓剂，胶囊或者以液体的形式，例如溶液，混悬液或乳剂存在。除此之外可能含有辅助材料如保存剂，稳定剂，湿润剂或乳化剂，用于改变渗透压的盐或缓冲剂。
对于不经胃肠的给药，注射溶液或混悬液，特别是活性化合物在多羟基乙氧基化的蓖麻油中的水溶液是尤其适合的。
作为载体系统也可以利用界面活性辅助材料如胆酸的盐或者是动物的或植物的磷脂，但也可以是它们的混合物以及脂质体或它们的组成成分。
对于经口用药特别适合的是片剂，糖衣丸或胶囊，它们含有滑石粉和/或碳氢化合物载体或粘结剂，例如乳糖，玉米淀粉或马铃薯淀粉。也可以以液体的形式给药，例如糖浆，可以向其中加入甜剂。
活性物质的剂量根据给药途径，病人的年龄和体重，欲治疗疾病的种类和程度和类似的因素来改变。每日的总剂量为0.5-1000mg，优选50-200mg，该剂量可以每日一次给药或每日分两次或多次给药。
按本发明的化合物的制备是根据已知的方法来完成，例如式I化合物是通过下述方法获得，将通式II化合物其中R1，R2，R4，R5，R6，R7和n具有在通式I所说明的意义，酰基化和任选地将R1和/或R2上的硝基催化还原和随后任选地酰基化，烷基化，卤化，用有机胺类导入氨基甲酰基或者用醇类导入酯基，分离异构体或者形成盐。
酰基化可以有或者没有溶剂在室温或提高的温度下用普通的酰化剂进行。酐或酰卤作为酰化剂是适合的。作为酐可以使用混合的或者也可以使用对称的酐。如果酰基化用氯甲酸酯如氯甲酸苯酯进行，则可以通过接着与有机的伯胺和仲胺如甲胺反应得到相应的氨基甲酰基化合物或者是可以通过与醇如甲醇、乙醇反应(必要时存在催化量的NaCN)导入相应的酯基。
硝基的还原反应是在极性溶剂中在室温或提高的温度下进行。金属如阮内-镍或贵金属催化剂如钯或铂(任选在载体上)作为还原反应的催化剂是适合的。也可以用已知的方法利用例如甲酸铵或肼代替氢。任选地存在重金属盐的情况下如同配合的金属氢化物一样，也可使用诸如氯化锡(II)或氯化钛(III)的还原剂。铁也可以被用作还原剂。反应是在一种酸例如醋酸或氯化铵的存在下，任选地加入一种溶剂如水或甲醇来进行的。
如果希望氨基烷基化，则可以根据通常的方法-例如用烷基卤-或根据Mitsonubo方法通过与一种醇在三苯膦和偶氮二甲酸酯存在的情况下反应来进行烷基化，或者用醛或酮任选地依次用两种不同的羰基化合物对胺进行还原性的胺化作用。在此得到混合的衍生物[文献例如Verardo等Synthesis(合成)(1993)，121；Synthesis(1991)，447；Kawaguchi，synthesis(1985)，701；Micovic等Synthesis(1991)，1043]。
氨基的酰基化是用普通的方法例如用一种酰卤或酸酐任选地在一种碱如二甲基氨基吡啶的存在下在溶剂如二氯甲烷、四氢呋喃或吡啶中，根据Schotten-Baumann方法在水溶液中弱碱性pH值下或通过与一种酐在冰醋酸中反应来进行。
卤素氯、溴或碘通过氨基的引入也可以例如根据Sandmeyer方法完成，其中将与腈中间形成的重氮盐与氯化铜(I)或溴化铜(I)在相应的酸如盐酸或氢溴酸的存在下反应或者与碘化钾反应。如果使用有机亚硝酸酯，可以例如通过在一种溶剂如二甲基甲酰胺中加入二碘甲烷或四溴甲烷来引入卤素。
氟的导入例如是通过四氟硼酸重氮盐的Balz Schiemann反应完成。
异构体混合物可以根据普通方法如结晶、色谱法或成盐作用被拆分成对映体或E/Z异构体。
盐的制备是用普通的方法进行，其中将式I化合物的溶液与当量的或过量的酸(它可能是在溶液中)混合并将沉淀分离或者用普通的方法处理溶液。
至此尚未说明起始化合物的制备，是由于它们是已知的或者是它们的制备可类似于已知化合物的方法进行(例如DE3527117，Brevetd’invention 879404，EP 0492485，HU 191702，FR 2566774，HU 194550，HU 194529，BP 2034706)。
下列实施例说明本发明化合物的制备。实施例17-乙酰基-5-(4-硝基苯基)-8-甲基-7H-1，3-间二氧杂环戊烯并(dioxolo)[4，5-h][2，3]-苯并二氮杂
1.0g(3.1mmol)5-(4-硝基苯基)-8-甲基-9H-7H-1，3-间二氧杂环戊烯并[4，5-h][2，3]-苯并二氮杂的悬浮液在10ml乙酸酐中在130-140℃加热7小时。溶液倾到在冰上，吸滤沉淀。得到0.99g(理论值的87％)的黄色粉末。将粗产物通过硅胶60用苯/乙酸乙酯(4∶1)作为洗脱剂进行快速色谱法分离，收集相应馏分和浓缩之后得到0.78g(理论值的70％)7-乙酰基-5-(4-硝基苯基)-8-甲基-7H-1，3-间二氧杂环戊烯并[4，5-h][2，3]-苯并二氮杂固体，熔点为200-202℃。将一个样品由乙醇中重结晶，其熔点为205-207℃(轻微的分解)。
以类似的方法制备：
7-乙酰基-5-(4-N-乙酰氨基苯基)-8-甲基-7H-1，3-间二氧杂环戊烯并[4，5-h][2，3]-苯并二氮杂实施例2
7-乙酰基-5-(4-氨基苯基)-8-甲基-7H-1，3-间二氧杂环戊烯并[4，5-h][2，3]-苯并二氮杂
向在40ml甲醇中的0.6(1.64mmol)的7-乙酰基-5-(4-硝基苯基)-8-甲基-7H-1，3-间二氧杂环戊烯并[4，5-h][2，3]-苯并二氮杂的悬浮液加入0.1g阮内镍和0.25ml(4.93mmol)98％的水合肼。将混合物搅拌0.5小时。起始物质在几分钟内溶解。在反应结束后，滤去催化剂。滤出液在真空中浓缩。残留物搅拌入水中，吸滤和用水再洗涤。得到0.49g 7-乙酰基-5-(4-氨基苯基)-8-甲基-7H-1，3-间二氧杂环戊烯并[4，5-h][2，3]-苯并二氮杂，其熔点为175-180℃。粗产品从50％的含水的乙醇中重结晶，得到0.46g(79％)7-乙酰基-5-(4-氨基-苯基)-8-甲基-7H-1，3-间二氧杂环戊烯并[4，5-h][2，3]-苯并二氮杂，其熔点为208-210℃。1H-NMR(CDCl3)：d：2,23(s，3H)，2,26(brs，3H，4,02(brs，2H)，5,97(brs，1H)，6,05(brs，1H)，6,32(brs，1H)，6,64(d，2H)，6,74(s，2H)，7,33(d，2H)：
元素分析：对于C19H17N3O3·H2O(353.36)的计算值：C＝64,68％；H＝5.42％；N＝11.89％；实测值：C＝64.74％；H＝4.89％；N＝11.92％；实施例3-18
类似实施例1得到在表1中说明的式I化合物，
其中R5，R6和R7是氢，n＝1和R4＝甲基
表1
实施例19
| 实施例序号 | R1 | R2 | R3 | 熔点，℃ |
| 3 | 4-NO2 | H | 丙酰基 | 206-208 |
| 4 | 3-NO2 | H | 乙酰基 | 198-200 |
| 5 | 2-NO2 | H | 乙酰基 | 192-194 |
| 6 | 4-NO2 | H | 新戊酰 | 225-227 |
| 7 | 4-NO2 | H | 三氟乙酰 | 213-215 |
| 8 | 2-Cl | H | 乙酰基 | 197-198 |
| 9 | 2-CH3 | H | 乙酰基 | 182-184 |
| 10 | 4-OCH3 | H | 乙酰基 | 173-176 |
| 11 | 3-OCH3 | H | 乙酰基 | 120-122 |
| 12 | 3-Cl | H | 乙酰基 | 130-132 |
| 13 | 4-F | H | 乙酰基 | 208-210 |
| 14 | 4-NO2 | 2-Br | 乙酰基 | 油 |
| 15 | 4-OCH3 | 2-异丙基 | 乙酰基 | 96-98 |
| 16 | 4-OCH3 | 3-F | 乙酰基 | 196-198 |
| 17 | 3-CF3 | H | 乙酰基 | 210-212 |
| 18 | 4-CF3 | H | 乙酰基 | 122-124 |
7-环丙烷羰基-8-甲基-5-苯基-7H-1，3-间二氧杂环戊烯并[4，5-h][2，3]-苯并二氮杂
将0.56g(2.0mmol)8-甲基-5-苯基-9-H-1，3-间二氧杂环戊烯并[4，5-h][2，3]苯并二氮杂和0.41g(3.0mmol)碳酸钾在15ml苯中的悬浮液加热至沸腾，并向其中加入0.31g(3.0mmol)环丙烷碳酰氯。在该温度下再搅拌1.5小时和随后过滤。除去溶剂后将残留物在硅胶60上用己烷/乙酸乙酯2∶1作洗脱剂进行色谱分离。主馏份从乙醇中结晶出来后得到0.35g(50％)的标题化合物，其熔点为165-166℃。实施例20-26
类似于实施例19得到在表2中说明的式I化合物，其中R5，R6和R7是氢，n＝1和R4＝甲基
表2
实施例27
| 实施例序号 | R1 | R2 | R3 | 熔点，℃ |
| 20 | 4-NO2 | H | 苯甲酰基 | ＞212℃ |
| 21 | 4-NO2 | H | 3-氯苯甲酰 | 260-263℃ |
| 22 | 4-NO2 | H | 环丙烷羰基 | 进一步处理 |
| 23 | 4-NO2 | H | 异丁烯酰基 | 进一步处理 |
| 24 | 4-NO2 | H | 异丁酰 | 进一步处理 |
| 25 | 4-NO2 | H | 异戊酰 | 进一步处理 |
| 26 | 4-NO2 | H | 丁酰 | 进一步处理 |
7-甲酰基-5-(4-硝基苯基)-8-甲基-7H-1，3-间二氧杂环戊烯并[4，5-h][2，3]-苯并二氮杂
类似于实施例1得到标题化合物连同由乙酸酐和98％的甲酸(3∶1)组成的混合物。在硅胶上用苯/乙酸乙酯4∶1作洗脱剂色谱分离后得到棕色结晶，熔点123-127℃(36％)实施例28
7-乙氧基羰基-5-(4-硝基苯基)-8-甲基-7H-1，3-间二氧杂环戊烯并[4，5][2，3]-苯并二氮杂
5-(4-硝基苯基)-8-甲基-9H-1，3-间二氧杂环戊烯并[4，5-h][2，3]-苯并二氮杂(0.323g/1.0mmol)、无水碳酸钾(0.28g，2.0mmol)、氯甲酸乙酯(0.12ml，1.2mmol)和无水苯在搅拌下回流加热。分别在1小时和12小时之后添加氯甲酸乙酯(0.12ml)和碳酸钾(0.28g)。18小时后过滤，浓缩和将残留物通过硅胶用苯∶乙酸乙酯作为洗脱剂进行色谱分离。得到92mg黄色无定形的结晶(23％)，无需提纯而用于下一步。实施例29
8-甲基-7-甲基氨基甲酰基-5-(4-硝基苯基)-7H-1，3-间二氧杂环戊烯并[4，5-h][2，3]-苯并二氮杂
A：5-(4-硝基苯基)-8-甲基-9H-1，3-间二氧杂环戊烯并[4，5-h][2，3]-苯并二氮杂(1,61g，5mmol)、氯甲酸苯酯(1.5ml，12.0mmol)、碳酸钾(1.4g，10mmol)和苯(50ml)的混合物在搅拌下回流加热1.5小时。反应混合物趁热过滤，浓缩和残留物用15ml乙酸乙酯充分搅拌。将滤出液浓缩，无需进一步提纯即可以进行下一反应步骤。
B：根据A得到的残留物与10ml DMF和3ml 40％的甲胺水溶液混合，加热至100℃和16小时后加入水中。用氯仿提取后用常用方法处理，得到0.307g标题化合物(16％)。实施例30
8-甲基-7-甲氧羰基-5-(4-硝基苯基)-7H-1，3-间二氧杂环戊烯并[4，5-h][2，3]-苯并二氮杂
将1.85g(3.9mmol)按照例29的反应步骤A得到的产物与90ml无水甲醇和15ml 50％的甲胺的甲醇溶液混合。加入催化量的NaCN和在90℃加热18小时。用普通方法处理。用苯/乙酸乙酯2∶1进行色谱纯化后得到0.44g(30％)的标题化合物。实施例31-47
类似于实施例2得到在表3中说明的式I化合物，其中R4＝甲基，n＝1，R5、R6和R7是氢
表3
实施例48
| 实施例序号 | R1 | R2 | R3 | 熔点，℃ |
| 31 | 4-NH2 | H | 甲酰基 | 用1/2 eq.H2O，141-145无水186 |
| 32 | 4-NH2 | H | 丙酰 | 无水：186，170-172 |
| 33 | 3-NH2 | H | 乙酰 | 196-198 |
| 34 | 4-NH2 | H | 苯甲酰基 | 206-207 |
| 35 | 4-NH2 | H | 3-氯苯甲酰 | 132-134 |
| 36 | 4-NH2 | H | 环丙烷羰基 | 215-217 |
| 37 | 4-NH2 | H | 异丁烯酰基 | 127-132 |
| 38 | 4-NH2 | H | 异丁酰 | 130-135 |
| 39 | 4-NH2 | H | 异戊酰 | 100-103 |
| 40 | 4-NH2 | H | 丁酰 | 114-116 |
| 41 | 4-NH2 | H | 新戊酰 | 206-208 |
| 42 | 4-NH2 | H | 三氟乙酰 | 142-145 |
| 43 | 2-NH2 | H | 乙酰基 | 157-158 |
| 44 | 4-NH2 | 2-Br | 乙酰基 | 250-252 |
| 45 | 4-NH2 | H | 甲基氨基甲酰基 | 157-167 |
| 46 | 4-NH2 | H | 乙氧基羰基 | 142-144 |
| 47 | 4-NH2 | H | 甲氧基羰基 | 144-148 |
7-乙酰基-5-(4-硝基苯基)-8-乙基-7H-1，3-间二氧杂环戊烯并[4，5-h][2，3]-苯并二氮杂
A：7-乙基-5-(4-硝基苯基)-1，3-间二氧杂环戊烯并[4.5g]异苯并二氢吡喃
将1-(3-苯并间二氧杂环戊烯-5-基)-丁烷-2-酮(Nichols等J.Med.Chem.1986，29，2009)还原成为相应的异丁醇并将它与4-硝基苯甲醛根据匈牙利专利HU 194550(C.A.105，1986，226357V)反应成为标题化合物。收率85％，熔点116-118℃(甲醇)。
B：7-乙基-5-(4-硝基苯基)-1，3-间二氧杂环戊烯并[4.5-g][2]苯并吡喃鎓高氯酸盐
将按反应步骤A得到的异苯并二氢吡喃-化合物根据匈牙利专利HU 194529(C.A.105，1986，152712h)氧化成为相应的二酮，用70％的HClO4将其转化为苯并吡喃鎓盐。收率50％，熔点243-245℃(分解)。
C：8-乙基-5-(4-硝基苯基)-9H-1，3-间二氧杂环戊烯并[4，5-h][2，3]苯并二氮杂
按照B得到的吡喃鎓盐与水合肼按照英国专利BP 2034706(C.A.94，1981，103443S)反应成为9-H-2，3-苯并二氮杂。收率88％，熔点218-220℃(DMF)。
D：将反应步骤C得到的产物类似于例1乙酰化。得到标题化合物，其熔点为132-134℃(乙醇)，收率33％。实施例49
7-乙酰基-5-(4-氨基苯基)-8-乙基-7H-1，3-间二氧杂环戊烯并[4，5-h][2，3]苯并二氮杂
将按例48得到的化合物类似于实施例2还原。收率45％，熔点136-138℃(乙醇/水1∶1)。实施例50
8-乙酰基-9-甲基-6-(4-硝基苯基)-8H-2，3-二氢-1，4二噁烷并[2，3-h][2，3]苯并二氮杂
A：6，7-二羟基-3-甲基-1-(4-硝基苯基)-2-苯并吡喃鎓-高氯酸盐
将44.0g 3-甲基-6.7-二甲氧基-1-(4-硝基苯基)-2-苯并吡喃鎓-高氯酸盐(C.A.105，1986，152712h)加入到46.3gAlCl3在170ml的硝基甲烷的溶液中并加热至煮沸4小时。除去溶剂，残留物用500ml冷却的50％的HCl-溶液处理，将得到的产物用冷水洗涤。得到43.5g粗产物，将它与130ml醋酸混合，加热至沸腾和与13.3ml 70％的HClO4混合。冷却后得到30.0g标题化合物(73％)，其熔点为253-255℃(分解乙酸乙酯)。
B：7，8-二羟基-4-甲基-1-(4-硝基苯基)-5H-2，3-苯并二氮杂
将反应步骤A的化合物与水合肼以类似于C.A.94，1981，1034435的方法转化为标题化合物，熔点254-256℃(分解)。
C：9-甲基-6-(4-硝基苯基)-10H-2，3-二氢-1，4-二噁烷并[2，3-h][2，3]苯并二氮杂
向3.0g按反应步骤B得到的化合物在37ml干燥的DMF中的悬浮液加入4.8g KF和1,12ml 1，2-二溴甲烷并将混合物在110-120℃搅拌1小时。冷却后将反应混合物加入250ml水中，滤出产物，用水洗涤并用普通方法处理。得到1.42g(44％)标题化合物，其熔点为228-230℃(分解)。
D：按C得到的化合物按类似于实施例1的方法乙酰化，收率82％，熔点226-228℃(分解)。实施例51
8-乙酰基-9-甲基-6-(4-氨基苯基)-8H-2，3-二氢-1，4-二噁烷并[2，3-h][2，3]-苯并二氮杂
将按例50得到的化合物以类似于例2的方法还原。收率72％，熔点231-233℃(分解)。实施例52
9-乙酰基-10-甲基-7-(4-硝基苯基)-2，3，4，9-四氢-1，5-dioxepino-[2，3-h][2，3]苯并二氮杂
A：10-甲基-7-(4-硝基苯基)-2，3，4，11-四氢-1，5-dioxepino-[2，3-h][2，3]苯并二氮杂
在例50反应步骤C中所说明的方法中用1，3-二溴丙烷进行，得到标题化合物，收率40％，熔点为204-206℃(DMF/水10∶1)。
B：类似于例1进行乙酰化，得到标题化合物，收率为65％，熔点为202-204℃。实施例53
9-乙酰基-10-甲基-7-(4-氨基苯基)-2，3，4，9-四氢-1，5-dioxepino[2，3-h][2，3]苯并二氮杂
按照例52得到的化合物以类似于例2的方法还原得到标题化合物，收率为66％，熔点为183-184℃。
Claims (5)
1.式1的化合物
其中
R1和R2相同或不同的和是氢，C1-6-烷基，硝基，卤素，基团-NR8R9，或O-C1-4-烷基，或-CF3，R3是基团
R4是C1-6-烷基，R5是氢，R6和R7是氢，R8和R9是相同的或不相同的和是氢，C1-6-烷基或是基团
R10是氢，任选被卤素取代的C1-6-烷基，任选被卤素取代的芳基，基团-NR11R12，-O-C1-6-烷基，C3-7-环烷基，C2-6-链烯基，
R11和R12是相同的或不相同的和是氢，任选被卤素取代的C1-6-烷基或任选被卤素取代的芳基，R13是C1-6-烷基和n是1，2或3及其生理上可以耐受的盐和异构体。
2.按照权利要求1的通式I化合物，其中R1是硝基或氨基R2是氢R3是基团
R4是甲基或乙基
R10是氢，C1-6-烷基，任选用卤素取代的苯基，基团-NR11R12，C3-7-环烷基，C2-6-链烯基，或C1-6-烷基，它是用氟单或多取代的，
R11和R12是相同的或不相同的和是氢，C1-4-烷基或苯基和
n是1，2或3，及其生理上可耐受的盐和异构体。
3.通式I化合物的制备方法，其特征在于，将式II化合物
其中R1，R2，R4，R5，R6，R7和n具有在通式I所说明的意义，酰基化和任选地将R1和/或R2上的硝基催化还原和随后任选地酰基化，烷基化，卤化，用有机胺类导入氨基甲酰基或者用醇类导入酯基，分离异构体或者形成盐。
4.含有按权利要求1或2的通式I化合物的药物。
5.按权利要求1或2的通式I化合物在制备药物中的应用。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP4428835.2 | 1994-08-01 | ||
| DE4428835A DE4428835A1 (de) | 1994-08-01 | 1994-08-01 | Neue 3-substituierte 3H-2,3-Benzodiazepinderivate, deren Herstellung und Verwendung als Arzneimittel |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1155285A CN1155285A (zh) | 1997-07-23 |
| CN1048728C true CN1048728C (zh) | 2000-01-26 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN95194402A Expired - Fee Related CN1048728C (zh) | 1994-08-01 | 1995-07-28 | 3-取代的3h-2,3-苯并二氮杂䓬衍生物,及其制备和应用 |
Country Status (21)
| Country | Link |
|---|---|
| US (1) | US5756495A (zh) |
| EP (1) | EP0775143B1 (zh) |
| JP (1) | JPH10504543A (zh) |
| KR (1) | KR100386709B1 (zh) |
| CN (1) | CN1048728C (zh) |
| AT (1) | ATE223415T1 (zh) |
| AU (1) | AU693241B2 (zh) |
| CA (1) | CA2195747C (zh) |
| CZ (1) | CZ291276B6 (zh) |
| DE (2) | DE4428835A1 (zh) |
| DK (1) | DK0775143T3 (zh) |
| ES (1) | ES2181787T3 (zh) |
| FI (1) | FI113177B (zh) |
| HU (1) | HU225500B1 (zh) |
| MX (1) | MX9700813A (zh) |
| NO (1) | NO319151B1 (zh) |
| NZ (1) | NZ290777A (zh) |
| PT (1) | PT775143E (zh) |
| RU (1) | RU2146678C1 (zh) |
| SK (1) | SK284103B6 (zh) |
| WO (1) | WO1996004283A1 (zh) |
Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
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| HUP9701325A1 (hu) | 1997-07-31 | 2000-08-28 | Gyógyszerkutató Intézet Kft. | Új 2,3-benzodiazepin-származékok |
| ATE255112T1 (de) * | 1997-08-12 | 2003-12-15 | Egyt Gyogyszervegyeszeti Gyar | 1-3 dioxolo/4.5-h//2,3-benzodiazepin derivate als ampa/kainate-rezeptor-hemmer |
| UA67749C2 (uk) * | 1997-08-12 | 2004-07-15 | Егіш Дьйодьсердьяр Рт. | Похідна 8-заміщеного-9н-1,3-діоксол/4,5-h//2,3/бензодіазепіну з властивостями амра/каїнатного антагоніста, спосіб одержання похідних, фармацевтична композиція (варіанти), спосіб її одержання та спосіб лікування |
| HU227128B1 (en) * | 1999-07-07 | 2010-07-28 | Egyt Gyogyszervegyeszeti Gyar | New 2,3-benzodiazepine derivatives |
| NO320473B1 (no) * | 2002-09-09 | 2005-12-12 | Norsk Hydro As | Anordning ved separator for separasjon av flerfasefluid. |
| US6858605B2 (en) * | 2003-02-04 | 2005-02-22 | Ivax Drug Research Institute, Ltd. | Substituted 2,3-benzodiazepine derivatives |
| GB0405034D0 (en) * | 2004-03-05 | 2004-04-07 | Novartis Ag | Organic compounds |
| ME01224B (me) * | 2005-04-04 | 2013-06-20 | Eisai R&D Man Co Ltd | Jedinjenja dihidropiridina za liječenje neurodegenerativnih bolesti i demencije |
| DK1926483T3 (da) * | 2005-09-09 | 2011-03-14 | Novartis Ag | Behandling af autoimmune sygdomme |
| WO2015121268A1 (de) * | 2014-02-14 | 2015-08-20 | Bayer Pharma Aktiengesellschaft | 1-phenyl-3h-2,3-benzodiazepine und ihre verwendung als bromodomänen-inhibitoren |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0492485A1 (en) * | 1990-12-21 | 1992-07-01 | Gyogyszerkutato Intezet | N-Acyl-2,3-benzodiazepine derivatives, pharmaceutical compositions containing them and process for preparing same |
-
1994
- 1994-08-01 DE DE4428835A patent/DE4428835A1/de not_active Withdrawn
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1995
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- 1995-07-28 DK DK95927636T patent/DK0775143T3/da active
- 1995-07-28 EP EP95927636A patent/EP0775143B1/de not_active Expired - Lifetime
- 1995-07-28 CA CA002195747A patent/CA2195747C/en not_active Expired - Fee Related
- 1995-07-28 RU RU97103140A patent/RU2146678C1/ru not_active IP Right Cessation
- 1995-07-28 SK SK135-97A patent/SK284103B6/sk unknown
- 1995-07-28 PT PT95927636T patent/PT775143E/pt unknown
- 1995-07-28 CZ CZ1997159A patent/CZ291276B6/cs not_active IP Right Cessation
- 1995-07-28 HU HU9700320A patent/HU225500B1/hu unknown
- 1995-07-28 US US08/776,536 patent/US5756495A/en not_active Expired - Fee Related
- 1995-07-28 MX MX9700813A patent/MX9700813A/es unknown
- 1995-07-28 WO PCT/DE1995/001029 patent/WO1996004283A1/de active IP Right Grant
- 1995-07-28 JP JP8506095A patent/JPH10504543A/ja not_active Ceased
- 1995-07-28 AU AU31609/95A patent/AU693241B2/en not_active Ceased
- 1995-07-28 AT AT95927636T patent/ATE223415T1/de not_active IP Right Cessation
- 1995-07-28 CN CN95194402A patent/CN1048728C/zh not_active Expired - Fee Related
- 1995-07-28 KR KR1019970700650A patent/KR100386709B1/ko not_active IP Right Cessation
- 1995-07-28 DE DE59510364T patent/DE59510364D1/de not_active Expired - Fee Related
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1997
- 1997-01-31 FI FI970434A patent/FI113177B/fi active
- 1997-01-31 NO NO19970435A patent/NO319151B1/no unknown
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0492485A1 (en) * | 1990-12-21 | 1992-07-01 | Gyogyszerkutato Intezet | N-Acyl-2,3-benzodiazepine derivatives, pharmaceutical compositions containing them and process for preparing same |
Also Published As
| Publication number | Publication date |
|---|---|
| AU3160995A (en) | 1996-03-04 |
| CA2195747C (en) | 2006-01-24 |
| ATE223415T1 (de) | 2002-09-15 |
| HUT76801A (en) | 1997-11-28 |
| SK284103B6 (sk) | 2004-09-08 |
| MX9700813A (es) | 1997-05-31 |
| FI970434A0 (fi) | 1997-01-31 |
| DE59510364D1 (de) | 2002-10-10 |
| DK0775143T3 (da) | 2002-12-02 |
| ES2181787T3 (es) | 2003-03-01 |
| EP0775143B1 (de) | 2002-09-04 |
| FI970434A (fi) | 1997-01-31 |
| CZ15997A3 (en) | 1997-06-11 |
| CA2195747A1 (en) | 1996-02-15 |
| CN1155285A (zh) | 1997-07-23 |
| NO319151B1 (no) | 2005-06-27 |
| PT775143E (pt) | 2003-01-31 |
| NO970435D0 (no) | 1997-01-31 |
| NZ290777A (en) | 1998-07-28 |
| SK13597A3 (en) | 1997-07-09 |
| DE4428835A1 (de) | 1996-02-08 |
| CZ291276B6 (cs) | 2003-01-15 |
| WO1996004283A1 (de) | 1996-02-15 |
| HU225500B1 (en) | 2007-01-29 |
| US5756495A (en) | 1998-05-26 |
| KR100386709B1 (ko) | 2003-08-19 |
| FI113177B (fi) | 2004-03-15 |
| AU693241B2 (en) | 1998-06-25 |
| NO970435L (no) | 1997-01-31 |
| JPH10504543A (ja) | 1998-05-06 |
| RU2146678C1 (ru) | 2000-03-20 |
| EP0775143A1 (de) | 1997-05-28 |
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