CN1101382C - 10,11－二氢－10－氧－5H－二苯并/b,f/氮杂䓬－5－甲酰胺衍生物 - Google Patents
10,11－二氢－10－氧－5H－二苯并/b,f/氮杂䓬－5－甲酰胺衍生物 Download PDFInfo
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- CN1101382C CN1101382C CN97196803A CN97196803A CN1101382C CN 1101382 C CN1101382 C CN 1101382C CN 97196803 A CN97196803 A CN 97196803A CN 97196803 A CN97196803 A CN 97196803A CN 1101382 C CN1101382 C CN 1101382C
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- Prior art keywords
- alkyl
- dihydro
- azatropylidene
- dibenzo
- formula
- Prior art date
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D223/18—Dibenzazepines; Hydrogenated dibenzazepines
- C07D223/22—Dibenz [b, f] azepines; Hydrogenated dibenz [b, f] azepines
- C07D223/30—Dibenz [b, f] azepines; Hydrogenated dibenz [b, f] azepines with hetero atoms directly attached to the ring nitrogen atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
Landscapes
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Abstract
通式I化合物具有有价值的药理活性，特别是在治疗某些中枢和外周神经系统紊乱方面。可将通式I化合物与药用载体制备成药物组合物。该化合物可以通过以下方法制备：使式II化合物与下列式(III)H<sub>2</sub>NOR<sup>2</sup>的羟胺或其衍生物，或与下列式(IV)H<sub>2</sub>NNR<sup>3</sup>R<sup>4</sup>的氨基脲或硫代氨基脲或其肼衍生物反应，或使其中R是OH的式(I)化合物与下列式(VI)：ACOR<sup>1</sup>或(VII)：ClCOOR<sup>1</sup>的酰化剂反应。
Description
本发明涉及新的10，11-二氢-10-氧-5H-二苯并/b，f/氮杂-5-甲酰胺衍生物，其制备方法和含有它们的药物组合物。该化合物在治疗某些中枢和外周神经系统紊乱方面具有有价值的药理特性。
10，11-二氢-10-氧-5H-二苯并/b，f/氮杂-5-甲酰胺(氧酰胺氮(oxcarbazepine))是已知的癫痫，三叉神经痛和情感紊乱的治疗剂(见药物(Drug)43(6)，873(1992))。但是对某些患者，氧酰胺氮会引起严重的副反应，特别是过敏反应并且可导致血清钠水平的降低。氧酰胺氮的另一个缺点与其快速代谢有关；因此，通常每天需服药三次。
本发明的目的是改进上述特征并且本发明涉及通式I的新化合物
其中R是羟基，烷基，环烷基，烷基环烷基，烷基芳基或烷基杂芳基或R是-O-CO-R1其中R1是氢，烷基，环烷基，烷基环烷基，烷基芳基，芳基或杂芳基或R是-O-CO-OR1其中取代基R1定义如上，或R是-O-R2其中R2是烷基或烷基芳基或R是-NR3R4其中R3是氢，-NH-CO-NH2，NH-CS-NH2，烷基或烷基芳基且R4是氢，烷基，烷基环烷基，烷基芳基，烷基羰基或芳基羰基；术语烷基是指任选被一个或多个烷氧基，卤素，烷氧基羰基或羟基羰基取代的含有一至六个碳原子的直链或支链碳链；术语环烷基代表含有三至六个碳原子的的脂环；术语芳基代表任选被一个或多个烷氧基，卤素或硝基取代的苯基或萘基；术语杂芳基代表含有一个氧原子，硫原子或氮原子的五员或六员环；术语卤素代表氟，氯，溴或碘。
优选的通式I化合物包括：1.10，11-二氢-10-肟基-5H-二苯并/b，f/氮杂-5-甲酰胺2.10，11-苄氧基亚氨基-10，11-二氢-5H-二苯并/b，f/氮杂-5-甲酰胺3.10-乙酰氧基亚氨基-10，11-二氢-5H-二苯并/b，f/氮杂-5-甲酰胺4.10，11-二氢-10-丙酰氧基亚氢基-5H-二苯并/b，f/氮杂-5-甲酰胺5.10-丁酰氧基亚氨基-10，11-二氢-5H-二苯并/b，f/氮杂-5-甲酰胺6.10，11-二氢-10-新戊酰氧基亚氨基-5H-二苯并/b，f/氮杂-5-甲酰胺7.10，11-二氢-10-[(1-萘酰氧基)亚氨基]-5H-二苯并/b，f/氮杂-5-甲酰胺8.10-苄酰氧基亚氨基-10，11-二氢-5H-二苯并/b，f/氮杂-5-甲酰胺9.10，11-二氢-10-琥珀酰氧基亚氨基-5H-二苯并/b，f/氮杂-5-甲酰胺10.10，11-二氢-10-戊二酰氧基亚氨基-5H-二苯并/b，f/氮杂-5-甲酰胺11.10，11-二氢-10-异丁氧基羰氧基亚氨基-5H-二苯并/b，f/氮杂-5-甲酰胺12.10，11-二氢-10-甲氧基亚氨基-5H-二苯并/b，f/氮杂-5-甲酰胺13.10，11-二氢-10-(S)-(-)-莰农酰氧基亚氨基-5H-二苯并/b，f/氮杂-5-甲酰胺14.10，11-二氢-10-[(3-甲氧基苯甲酰氧基亚氨基)]-5H-二苯并/b，f/氮杂-5-甲酰胺15.10，11-二氢-10-烟酰氧基亚氨基-5H-二苯并/b，f/氮杂-5-甲酰胺16.10，11-二氢-10-乙氧基羰氧基亚氨基-5H-二苯并/b，f/氮杂-5-甲酰胺17.10-丁氧羰氧基亚氨基-10，11-二氢-5H-二苯并/b，f/氮杂-5-甲酰胺18.10-苄氧基羰氧基亚氨基-10，11-二氢-5H-二苯并/b，f/氮杂-5-甲酰胺19.10，11-二氢-10-苯基亚肼基-5H-二苯并/b，f/氮杂-5-甲酰胺20.10，11-二氢-10-亚肼基-5H-二苯并/b，f/氮杂-5-甲酰胺21.10，11-二氢-10-(2，4-二硝基苯基亚肼基)-5H-二苯并/b，f/氮杂-5-甲酰胺22.10，11-二氢-10-脲亚氨基-5H-二苯并/b，f/氮杂-5-甲酰胺23.10，11-二氢-10-硫代脲亚氨基-5H-二苯并/b，f/氮杂-5-甲酰胺24.10-(2-氯苯基脲亚氨基)-5H-二苯并/b，f/氮杂-5-甲酰胺25.10，11-二氢-10-甲氧基羰基丙基亚氨基-5H-二苯并/b，f/氮杂-5-甲酰胺
本发明的另一方面涉及式I化合物的制备方法其中取代基R定义如上，该方法包括使式II化合物
与式III的羟胺或其衍生物反应
H2NOR2 III其中取代基R2定义如上，或使式II化合物与式IV的氨基脲，硫代氨基脲或其衍生物反应
H2NNR3R4 IV其中取代基R3和R4定义如上，或者使式V化合物
与式VI的酰化剂反应
A-CO-R1 VI
其中R1定义同通式I中定义，A是羟基，卤素或-O-CO-R’或-O-CO-OR’，其中R’是低级烷基(C1至C4)，或使式V化合物与式VII的酰化剂反应
Cl-CO-OR1 VII
其中R1定义同通式I中定义；酰化反应可以在缩合剂存在下进行，缩合剂例如可以是二环己基碳二亚胺，羰基二咪唑，氯甲酸乙酯或异丁基酯和/或在有机或无机碱如吡啶，三乙胺或碱性碳酸氢盐存在下在惰性溶剂如烃，氯代烷烃，醚或非质子偶极溶剂中进行，或者反应可以在上述溶剂混合物或没有任何溶剂存在下进行。
上述反应可以在各种温度和压力下进行，如在0℃和在所用压力下的反应混合物的沸点温度之间进行。
化合物II是已知的(如见德国专利2001087)并且化合物III，IV，VI和VII可以用本领域已知的方法如R.C.Larock所著的，VCH于1989年出版的“综合有机转化(comprehensive Organic Transformations)”一书所述的方法制备。
本发明的另一方面包括将式I化合物与药用载体混合后制得的药物组合物。
本发明也包括用于治疗中枢和外周神经系统疾病的含有本发明化合物和药用载体的药物组合物。
本发明进一步包括治疗中枢和外周神经系统疾病的方法，该方法包括服用本发明化合物如本发明的药物组合物。
部分式I化合物可以用于治疗癫痫，三叉神经痛和大脑情感紊乱和在变性和局部缺血后疾病中的神经功能改变。
癫痫是人类最常见的病痛之一，其发病率约为1％。从100多年前的HughlingJakson时代起，对癫痫发作的认识可表达为“偶然的，突然的，过度的，快速的和局部的神经器官的失控”。癫痫发作基本上可以分为两类：局部的和全身性的。局部的癫痫发作是指失控从局部开始，并且通常在局部持续。全身性的癫痫发作涉及整个大脑，包括网状系统，因此导致全部两个半球的异常电活动并立刻失去意识。局部癫痫发作又可分为：(a)局部简单癫痫发作，(b)局部复杂癫痫发作和(c)局部随后全身化的癫痫发作。全身性癫痫发作包括(1)强直—阵挛癫痫发作(癫痫大发作)。(2)失神性癫痫发作(癫痫小发作)。(3)肌阵挛癫痫发作。(4)弛缓癫痫发作。(5)阵挛性癫痫发作和(6)强直癫痫发作。癫痫不同于癫痫发作，它是一种慢性疾病，其特征是反复发作(Gastaut，H：癫痫字典(Dictionary ofepilepsy)，世界卫生组织，日内瓦，1973)。
有两种药物可以消除或减弱癫痫发作的方法：(a)作用于癫痫发作焦点的改变的神经元从而阻止或减弱其过度的失控，和(b)其作用可以减弱来自癫痫发作焦点的兴奋传播从而阻止神经原的正常聚集功能的被阻断。如果不是全部，但这是主要的至少是通过第二机理的可得的抗癫痫病药物，因为它们都能改善大脑对各种癫痫发作刺激反应的能力。对癫痫发作的刺激常用中枢兴奋药，如戊四氮，尤其是在抗惊厥剂试验中，为了相同的目的也可用于电刺激整个大脑导致的癫痫发作中。由经验可知在抑制戊四氮诱导的癫痫发作和在增加电诱导癫痫发作产生的阈值的活性是非常好的有效抗失神性癫痫发作的指数。另一方面，在降低电诱导的惊厥扩散发作期的活性与其它类型癫痫如强直—阵挛癫痫发作的有效控制有关。
式I化合物抗惊厥作用的研究是在电刺激痉挛最大电休克(MES)试验模型，和化学刺激痉挛，如戊四氮试验模型上进行的。MES试验可以评价药物抑制电诱导的大鼠强直后爪延展的能力，其效力可以认为预示着在人体抗全身性强直—阵挛癫痫发作(癫痫大发作)的效力。戊四氮试验预示着有效的抗癫痫剂的抑制阵挛性癫痫发作和有效地抗失神性癫痫发作(小发作)的能力。材料和方法
用从Harlan Interfauna Iberica(Barcelona Spain)动物房得到的体重为180至280g的雄性Wistar大鼠。将动物以每笼两只放置笼中并控制周围的条件(12小时光照/黑暗循环且室温为24℃)无限制地提供食物和水并且试验在日照时进行。I-MES试验
用Ugo Basile ECT装置7801，频率100Hz，脉冲宽度0.6ms和电流为150mA通过偶极角膜电极进行0.2秒的MES刺激。在置换角膜电极前立即在动物眼中滴入电解质/麻醉剂(盐酸丁氧普鲁卡因)。以后腿强直伸肌的消除作为终点。这些试验条件可导致97％的试验动物产生强直—阵挛惊厥并且仅采用产生典型的强直—阵挛惊厥的大鼠。将所有动物进行三个最大MES期间：在第一个MES期间筛选动物并且选择这些动物代表典型的惊厥行为。第二天，给大鼠试验化合物或载体并且在给试验药物之后的2至4小时进行第二个MES期间。第三个MES期间是在给药后6，8，12小时进行。每一个MES期间的时间间隔至少为4小时(在2小时的大鼠在第6小时进行再试验且在第4小时试验的大鼠在第8小时进行再试验)试验药物抗惊厥参数的评价是以每个大鼠在第一个MES期间获得的对照(内对照)强直相的持续时间(以秒计)为基础的。也对外对照组进行了研究；对于具体的外对照组，给大鼠载体并进行上述的三个MES期间。将所用的所有药物悬浮在0.5％的羧甲基纤维素(4ml/kg)中并通过胃导管给药。2-戊四氮试验
在给戊四氮之前2小时给式I化合物。戊四氮(75mg/kg)在后背通过皮下给药；通过使95％的动物产生惊厥可得到戊四氮的剂量。在戊四氮给药后30分钟的观察期间内观察与癫痫发作持续时间有关的参数，ED50(mg/kg)是癫痫发作持续时间降低50％的剂量。结果1-MES试验
在最高试验剂量(30mg/kg)，式I化合物在对给药2小时后的MES产生了完全的保护作用：在4和8小时的保护作用与对照化合物氨甲酰氮(carbamazepine)类似。在最高试验剂量(30mg/kg)，氨甲酰氮在对给药2小时后的MES产生了完全的保护作用；在给药后4和8小时的保护作用仍然在80％以上。氨甲酰氮在给药后2，4和8小时的ED50值分别为5.6，11.3和20.6mg/kg。式I化合物在给药后2，4和8小时的ED50值分别为6.9，19.8和18.9mg/kg。氧酰胺氮的作用没有氨甲酰氮和式I化合物强。氧酰胺氮在给药后2，4和8小时的ED50值分别为9.7，20.2和22.3mg/kg。2-戊四氮试验
式I化合物对大鼠可以对戊四氮诱导的惊厥产生有效的保护作用。式I化合物的最高有效剂量为30mg/kg并且可使总的癫痫发作时间降低44％。氨甲酰氮在剂量为30和60mg/kg时可分别降低癫痫发作总时间的41％和44％。氧酰胺氮没有氨甲酰氮有效。氧酰胺氮在30和60mg/kg的剂量时可分别降低癫痫发作总时间的3％和32％。结论
在MES和戊四氮试验中，式I化合物显示了有效的抗癫痫活性并且与对照化合物氨甲酰氮和氧酰胺氮相比具有更有效或相似的抗惊厥活性。
式I化合物可以用于治疗人体某些其它中枢和外周神经系统疾病，如三叉神经痛，大脑情感紊乱和变性和后局部缺血疾病中的神经功能改变。
为了从式I化合物制备药物组合物，可以将活性化合物与惰性载体混合。药用载体可以是固体或液体。固体形式的制剂包括粉剂，片剂，可分散颗粒剂和胶囊。固体载体可以是一种或多种可以作稀释剂，调味剂，增溶剂，润滑剂，悬浮剂，粘合剂或片剂崩解剂的物质；也可以是成胶囊材料。
优选地，药物制剂是单位剂量形式，含有单位剂量的小包装制剂如小包装的片剂，胶囊和装在管形瓶中或安瓿中的粉剂。
剂量可以根据患者的要求，疾病的严重性和所用的具体化合物而变化。通常，日剂量可以在一天内分次分批服用。医药领域的普通技术人员可以容易地确定具体情况的适宜剂量。
本发明的公开可以用下列制备实施例举例说明但不应被理解为是对公开范围的限定。变换的方法和类似结构对本领域普通技术人员来说是显而易见的。
实施例实施例1：10，11-二氢-10-肟基-5H-二苯并[b，f]氮杂-5-甲酰胺
将4.0g(15.86mmol)的10，11-二氢-10-氧-5H-二苯并[b，f]氮杂-5-甲酰胺和3.86g(55.49mmol)盐酸羟胺在100mL的绝对乙醇的悬浮液用3.76g(47.57mmol)的吡啶处理。将化合物加热沸腾1小时然后减压蒸发除去乙醇。将残余物分配在150ml水和150ml二氯甲烷中。分离有机层并用50ml1M的HCl，饱和NaHCO3溶液和盐水洗涤，然后用硫酸钠干燥。过滤并减压蒸发溶剂并将所得白色固体用热乙醇研制得到所需化合物，为灰白色粉末，m.p.230.4至231.5℃。实施例2：用与前述实施例相似的方法但用相应的羟胺，制备10-苄氧基亚氨基-10，11-二氢-5H-二苯并[b，f]氮杂-5-甲酰胺。实施例3：10-乙酰氧基亚氨基-10，11-二氢-5H-二苯并[b，f]氮杂-5-甲酰胺
将0.5g(1.87mmol)的10，11-二氢-10-肟基-5H-二苯并[b，f]氮杂-5-甲酰胺的25ml二氯甲烷和0.72g(9.16mmol)吡啶的悬浮液用0.57g(5.61mmol)的乙酸酐处理。将所得混合物在室温搅拌过夜然后用10ml的二氯甲烷稀释。将有机相用20ml 1M的HCl水溶液，饱和NaHCO3溶液和盐水萃取，然后用硫酸钠干燥。减压蒸发溶剂然后将粗产品用二氯甲烷和乙酸乙酯的混合物结晶得到所需产品，为白色晶体，m.p.175.8-176.9℃。实施例4-11：用前述技术但用适宜的酸酐，制备下列化合物：10，11-二氢-10-丙酰氧基亚氨基-5H-二苯并[b，f]氮杂-5-甲酰胺10-丁酰氧基亚氨基-10，11-二氢-5H-二苯并[b，f]氮杂-5-甲酰胺10，11-二氢-10-戊酰氧基亚氨基-5H-二苯并[b，f]氮杂-5-甲酰胺10，11-二氢-10-[(1-萘酰氧基)亚氨基]-5H-二苯并[b，f]氮杂-5-甲酰胺10-苄酰氧基亚氨基-10，11-二氢-5H-二苯并[b，f]氮杂-5-甲酰胺10，11-二氢-10-琥珀酰氧基亚氨基-5H-二苯并[b，f]氮杂-5-甲酰胺10，11-二氢-10-戊二酰氧基亚氨基-5H-二苯并[b，f]氮杂-5-甲酰胺10，11-二氢-10-异丁氧羰氧基基亚氨基-5H-二苯并[b，f]氮杂-5-甲酰胺实施例12：10，11-二氢-10-甲氧基亚氨基-5H-二苯并[b，f]氮杂-5-甲酰胺
将0.2g(0.75mmol)的10，11-二氢-10肟基-5H-二苯并[b，f]氮杂-5-甲酰胺的2ml丙酮悬浮液冷却至0℃然后在其中加入0.065g(1.16mmol)的氢氧化钾的1ml水溶液，接着再加入0.164g(1.16mmol)的碘甲烷。将所得化合物室温搅拌过夜然后加入10ml水。将混合物用乙醚萃取并将有机层用水和盐水洗涤然后用硫酸钠干燥并过滤。减压蒸发除去溶剂并将残余物进行硅胶柱层析并用3％甲醇-二氯甲烷混合物洗脱。将层析相同的部分合并，减压蒸发除去溶剂并将残余物用甲苯结晶得到灰白色产品，m.p.157.9-159.4℃。实施例13：10，11-二氢-10-(S)-(-)-莰农酰氧基亚氨基-5H-二苯并[b，f]氮杂-5-甲酰胺
向0.15g(0.56mmo1)10，11-二氢-10-肟基-5H-二苯并[b，f]氮杂-5-甲酰胺和0.01g(0.08mmol)的4-二甲基氨基吡啶的5ml二氯甲烷及0.22g(2.8mmol)吡啶的悬浮液中分批加入0.15g(0.67mmol)的(S)-(-)-莰农酰氯。将所得混合物室温搅拌2小时后进一步加入0.1g(0.46mmol)的(S)-(-)莰农酰氯。进一步搅拌1.5小时后依次加入5ml二氯甲烷和5ml冰水。分离有机层并用10ml 2M的HCl水溶液，饱和NaHCO3溶液和盐水洗涤，然后用硫酸钠干燥并过滤。减压蒸发除去溶剂并将残余物用乙醚研制并将所得白色固体用二氯甲烷和乙酸乙酯混合物甲基得到所需产品，为白色晶体，m.p.187至187.9℃。实施例14-15：通过上述技术但用适宜的酰卤，制备下列化合物：10，11-二氢-10-[(3-甲氧基苯甲酰氧基)亚氢基]-5H-二苯并[b，f]氮杂-5-甲酰胺10，11-二氢-10-烟酰氧基亚氨基-5H-二苯并[b，f]氮杂-5-甲酰胺实施例16：10，11-二氢-10-乙氧基羰氧基亚氨基-5H-二苯并[b，f]氮杂-5-甲酰胺
在0.2g(0.74mmol)10，11-二氢-10-肟基-5H-二苯并[b，f]氮杂-5-甲酰胺和0.01g(0.08mmol)的4-二甲氨基吡啶的10ml二氯甲烷和0.29g(3.7mmol)吡啶的悬浮液中滴加0.28g(2.6mmol)的氯甲酸乙酯。将所得混合物室温搅拌2小时后用20ml 1M的HCl水溶液和饱和NaHCO3溶液洗涤，然后用硫酸钠干燥并过滤。减压蒸发除去溶剂并将残余物用二氯甲烷和乙酸乙酯的混合物结晶得到白色晶体，m.p.188.9-190℃。实施例17-18：通过上述技术但用适宜的氯甲酸酯，制备下列化合物：10-丁氧基羰氧基亚氨基-10，11-二氢-5H-二苯并[b，f]氮杂-5-甲酰胺10-苄氧基羰氧基亚氨基-10，11-二氢-5H-二苯并[b，f]氮杂-5-甲酰胺实施例19：10，11-二氢-10-苯基亚肼基-5H-二苯并[b，f]氮杂-5-甲酰胺
将0.2g(0.8mmol)10，11-二氢-10-氧-5H-二苯并[b，f]氮杂-5-甲酰胺，0.5g(4.6mmol)苯肼和0.5g(6mmol)乙酸钠在5ml水、5ml乙醇和3滴浓盐酸中的混合物在60℃加热30分钟然后冷却至室温。然后将沉淀过滤并用冷水和稀乙醇洗涤得到所需产品，为黄色结晶，m.p.220至220.8℃。实施例20-21：通过上述技术但用适宜的肼，制备下列化合物：10，11-二氢-10-亚肼基-5H-二苯并[b，f]氮杂-5-甲酰胺10，11-二氢-10-(2，4-二硝基苯基亚肼基)-5H-二苯并[b，f]氮杂-5-甲酰胺实施例22：10，11-二氢-10-脲亚氨基-5H-二苯并[b，f]氮杂-5-甲酰胺
搅拌下，在0.4g(3.59mmol)盐酸氨基脲和0.6g(7.32mmol)乙酸钠的4ml溶液中加入0.2g(0.8mmol)的10，11-二氢-10-氧-5H-二苯并[b，f]氮杂-5-甲酰胺。将所得悬浮液水浴加热并加入6ml乙醇直至得到溶液。将溶液在60℃加热1.5小时然后冷却至室温。减压蒸发除去乙醇并将残余物冷却至5℃并保持2小时，将晶体沉淀过滤并用冷水洗涤得到所需产品，为浅黄色结晶，m.p.247.2-248.6℃。实施例23-24：通过上述技术但用适宜的氨基脲。制备下列化合物：10，11-二氢-10-硫代脲亚氨基-5H-二苯并[b，f]氮杂-5-甲酰胺10-(2-氯苯基脲亚氨基)-10，11-二氢-5H-二苯并[b，f]氮杂-5-甲酰胺实施例25：10，11-二氢-10-甲氧基羰基丙基亚氨基-5H-二苯并[b，f]氮杂-5-甲酰胺
在0.2g(0.79mmol)10，11-二氢-10-氧-5H-二苯并[b，f]氮杂-5-甲酰胺和0.1g(0.67mmol)4-氨基丁酸甲酯盐酸盐的5ml二甲苯悬浮液中加入0.07g(0.49mmol)的二乙醚合三氟化硼。将所得混合物在135℃加热7小时然后冷却至室温。将混合物过滤并将残余物用甲苯萃取。将合并的萃取液减压蒸发并残余物用4∶1的石油醚-乙酸乙酯混合物进行硅胶层析。合并层析相同部分并减压蒸发除去溶剂得到所需产品，为黄色油状物并就地结晶得到黄色晶体，该晶体加热分解，没有熔点。
Claims (8)
1.通式I化合物
其中R是羟基，烷基，环烷基，烷基芳基或烷基杂芳基或R是-O-CO-R1其中R1是氢，烷基，环烷基，烷基环烷基，烷基芳基，或杂芳基或R是-O-CO-OR1其中取代基R1定义如上，或R是-O-R2其中R2是烷基或烷基芳基，或R是-NR3R4其中R3是氢，-NH-CO-NH2，-NH-CS-NH2，烷基或烷基芳基且R4是氢，烷基，烷基环烷基，烷基羰基或芳基羰基；术语烷基是指可任选被一个或多个烷氧基，卤素，烷氧基羰基或羟基羰基取代的含有一至六个碳原子的直链或支链碳链；术语环烷基代表含有三至六个碳原子的脂环；术语芳基代表可任选被一个或多个烷氧基，卤素或硝基取代的苯基或萘基；术语杂芳基代表含有氧原子，硫原子或氮原子的五员或六员芳环；术语卤素代表氟，氯，溴或碘。
2.权利要求1定义的化合物，其中化合物是：
10，11-二氢-10-肟基-5H-二苯并/b，f/氮杂-5-甲酰胺，
10-乙酰氧基亚氨基-10，11-二氢-5H-二苯并/b，f/氮杂-5-甲酰胺，
10，11-二氢-10-甲氧基亚氨基-5H-二苯并/b，f/氮杂-5-甲酰胺，
10，11-二氢-10-(S)-(-)-莰农酰氧基亚氨基-5H-二苯并/b，f/氮杂-5-甲酰胺，
10，11-二氢-10-烟酰氧基亚氨基-5H-二苯并/b，f/氮杂-5-甲酰胺，
10，11-二氢-10-苯基亚肼基-5H-二苯并/b，f/氮杂-5-甲酰胺，
10，11-二氢-10-脲亚氨基-5H-二苯并/b，f/氮杂-5-甲酰胺，
10，11-二氢-10-甲氧基羰基丙基亚氨基-5H-二苯并/b，f/氮杂-5-甲酰胺。
3.制备通式I化合物的方法
其中R是羟基，烷基，烷基环烷基，烷基芳基或烷基杂芳基或R是-O-CO-R1其中R1是氢，烷基，环烷基，烷基环烷基，烷基芳基，或杂芳基或R是-O-CO-OR1其中取代基R1定义如上，或R是-O-R2其中R2是烷基或烷基芳基，或R是-NR3R4其中R3是氢，-NH-CO-NH2，-NH-CS-NH2，烷基或烷基芳基且R4是氢，烷基，烷基环烷基，烷基芳基，烷基羰基或芳基羰基，术语烷基是指可任选被烷氧基，卤素，烷氧基羰基或羟基羰基取代的含有一至六个碳原子的直链或支链碳链；术语环烷基代表含有三至六个碳原子的脂环；术语芳基代表可任选被烷氧基，卤素或硝基取代的苯基或萘基；术语杂芳基代表含有氧原子，硫原子或氮原子的五员或六员芳环；术语卤素代表氟，氯，溴或碘，该方法包括使式II化合物
与式III的羟胺或期衍生物反应
H2NOR2 (III)
其中取代基R2定义如上，或使式II化合物与式IV的硫代卡巴肼，硫代氨基脲或其肼衍生物反应
H2NNR3R4 (IV)
其中取代基R3和R4定义如上，或者使式V化合物
与式VI的酰化剂反应
A-CO-R1 VI
其中R1定义同通式I中定义，A是羟基，卤素或-O-CO-R1或-O-CO-OR1，其中R1是低级烷基(C1至C4)，或使式V化合物与式VII的酰化剂反应
Cl-CO-OR1 VII
其中R1定义同通式I中定义。
4.根据权利要求3的方法，其中反应是在缩合剂和/或碱中进行。
5.权利要求1或2要求的化合物用于制备可用于治疗中枢或外周神经系统疾病的药物组合物的用途。
6.根据权利要求5的用途，其中所述疾病为癫痫，三叉神经痛，大脑情感紊乱和在变性及局部缺血后疾病中的神经功能改变。
7.用于治疗中枢和外周神经系统疾病的药物组合物，该组合物含有式I定义的化合物和药用载体。
8.根据权利要求7的药物组合物，其中化合物是权利要求2中要求的化合物。
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| PT101876A PT101876B (pt) | 1996-05-27 | 1996-05-27 | Novos derivados de 10,11-di-hidro-10-oxo-5h-dibenzo(b,f)azepina-5-carboxamida |
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| GB0112812D0 (en) * | 2001-05-25 | 2001-07-18 | Portela & Ca Sa | Mthd for preparation of 10, 11-dihydro-10-hydroxy-5H-dibenz/B,F/azepine-5-c arboxamide and 10,11-dihydro-10-oxo-5H-dibenz/B,F/azepine-5-carb oxamide therefrom |
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| CH649080A5 (de) * | 1981-04-16 | 1985-04-30 | Ciba Geigy Ag | 5h-dibenz(b,f)azepin-5-carboxamide als mittel zur prophylaxe und behandlung von zerebraler leistungsinsuffizienz. |
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| GR3035910T3 (en) | 2001-08-31 |
| AU2974097A (en) | 1998-01-05 |
| SI0810216T1 (zh) | 2001-08-31 |
| CA2206172C (en) | 2002-07-16 |
| BR9703403A (pt) | 1998-09-15 |
| CN1226234A (zh) | 1999-08-18 |
| ES2156319T3 (es) | 2001-06-16 |
| TR199802462T2 (xx) | 2000-07-21 |
| AU713807B2 (en) | 1999-12-09 |
| AR007291A1 (es) | 1999-10-27 |
| PT101876A (pt) | 1997-12-31 |
| JP3592892B2 (ja) | 2004-11-24 |
| EP0810216B1 (en) | 2001-03-21 |
| DE69704297D1 (de) | 2001-04-26 |
| DK0810216T3 (da) | 2001-07-23 |
| EP0810216A1 (en) | 1997-12-03 |
| ATE199901T1 (de) | 2001-04-15 |
| PL189298B1 (pl) | 2005-07-29 |
| JPH1081669A (ja) | 1998-03-31 |
| RU2187503C2 (ru) | 2002-08-20 |
| MX9703846A (es) | 1998-06-30 |
| WO1997045416A1 (en) | 1997-12-04 |
| US5866566A (en) | 1999-02-02 |
| BR9703403B1 (pt) | 2010-06-29 |
| DE69704297T2 (de) | 2001-09-20 |
| PL330141A1 (en) | 1999-04-26 |
| PT101876B (pt) | 1999-09-30 |
| CA2206172A1 (en) | 1997-11-27 |
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