CN1073996C - 二氢-2,3-苯并二氮杂䓬衍生物的物理形态,制备方法和用途 - Google Patents
二氢-2,3-苯并二氮杂䓬衍生物的物理形态,制备方法和用途 Download PDFInfo
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- CN1073996C CN1073996C CN95109527A CN95109527A CN1073996C CN 1073996 C CN1073996 C CN 1073996C CN 95109527 A CN95109527 A CN 95109527A CN 95109527 A CN95109527 A CN 95109527A CN 1073996 C CN1073996 C CN 1073996C
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Abstract
本发明公开了具有d间距在12.78、9.48、8.99、8.64、8.23、6.39、6.27、5.73、4.01和3.96A的X射线粉末衍射图案的(R)-7-乙酰基-5-(4-氨基苯基)-8,9-二氢-8-甲基-7H-1,3-间二氧杂环戊烯并[4,5-h][2,3]苯并二氮杂䓬的物理形态。该化合物可用作AMPA拮抗剂。
Description
本发明涉及可用作治疗神经系统病症药物的二氢-2,3-苯并二氮杂衍生物的新的物理形态。
欧州专利申请公开第EP-A1-0492485号公开了化合物1-(4-氨基苯基)-3-乙酰基-4-甲基-7,8-亚甲二氧基-3,4-二氢-5H-2,3-苯并二氮杂。该化合物是兴奋性的氨基酸AMPA受体的有效且选择性的拮抗剂,而且据信该化合物能用于治疗各种神经病症。该化合物的(R)对映体,以下称为(R)-7-乙酰基-5-(4-氨基苯基)-8,9-二氢-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,是最有效的对映体。
本发明提供具有d间距在12.78、9.48、8.99、8.64、8.23、6.39、6.27、5.37、4.01和3.96的X射线粉末衍射图案的(R)-7-乙酰基-5-(4-氨基苯基)-8,9-二氢-8-甲基-7H-1,3-间二氧杂环戊烯并[4,5-h][2,3]苯并二氮杂的物理形态。还提供该形态的制备方法及包含该形态的药用组合物及使用方法,
已发现(R)-7-乙酰基-5-(4-氨基苯基)-8,9-二氢-8-甲基-7H-1,3-间二氧杂环戊烯并[4,5-h][2,3]苯并二氮杂是多晶型的(polymorphic)。
据发现(R)-7-乙酰基-5-(4-氨基苯基)-8,9-二氢-8-甲基-7H-1,3-间二氧杂环戊烯并[4,5-h][2,3]苯并二氮杂的第一种物理形态的熔点为约168-172℃,并具有特征性的d间距为6.57和5.24的X射线粉末衍射图案。该物理形态以下称为形态Ⅰ。它是通过以下方法制备的:将(R)-7-乙酰基-8,9-二氢-8-甲基-5-(4-硝基苯基)-7H-1,3-间二氧杂环戊烯并[4,5-h][2,3]苯并二氮杂在乙醇中用氢气还原,并用钯/炭作催化剂,然后过滤除去催化剂,蒸除乙醇,在5.7体积的1∶1水/乙醇中将残余物加热回流,然后将所得溶液放冷。
令人惊讶的是,通过使用甲酸铵和钯/炭代替氢气和钯/炭来改进制备形态Ⅰ的方法能得到(R)-7-乙酰基-5-(4-氨基苯基)-8,9-二氢-8-甲基-7H-1,3-间二氧杂环戊烯并[4,5-h][2,3]苯并二氮杂的新物理形态,以下称为形态Ⅱ。它是通过以下方法制备的:将(R)-7-乙酰基-8,9-二氢-8-甲基-5-(4-硝基苯基)-7H-1,3-间二氧杂环戊烯并[4,5-h][2,3]苯并二氮杂在乙醇中用甲酸铵还原,并用钯/炭作催化剂,然后过滤除去催化剂,蒸除乙醇,在6体积的1∶1水/乙醇中将残余物加热回流,然后将所得溶液放冷。已发现形态Ⅱ具有特征d间距在13.12和5.01的X射线粉末衍射图案。
通过使用甲酸钾和钯/炭代替甲酸铵和钯/炭来改进制备形态Ⅱ的方法还令人惊讶地得到另一种物理形态,以下称为形态Ⅲ。该形态Ⅲ是通过以下方法制备的:将(R)-7-乙酰基-8,9-二氢-8-甲基-5-(4-硝基苯基)-7H-1,3-间二氧杂环戊烯并[4,5-h][2,3]苯并二氮杂在乙醇中用甲酸钾还原,并用钯/炭作催化剂,然后过滤除去催化剂,蒸除乙醇,在6体积的1∶1水/乙醇中将残余物加热回流,然后将所得溶液放冷。已发现形态Ⅲ具有特征d间距在10.61、8.83、6.78、5.83、4.13和3.74A的X射线粉末衍射图案。该物理形态是一个共同未决专利申请(refX9386C)的主题。
令人惊讶的是,还发现另一种物理形态,以下称为形态Ⅳ。最初观察到该形态是在形态Ⅱ被加热后形成的,随后发现形态Ⅳ可通过改进用于制备形态Ⅲ的方法直接制得,特别是通过提高用于结晶步骤的水/乙醇的体积比来制得。该形态Ⅳ是通过以下方法制备的:将(R)-7-乙酰基-8,9-二氢-8-甲基-5-(4-硝基苯基)-7H-1,3-间二氧杂环戊烯并[4,5-h][2,3]苯并二氮杂在乙醇中用甲酸钾还原,并用钯/炭作催化剂,然后过滤除去催化剂,蒸除乙醇,在8体积的5∶3水/乙醇或7体积的4∶3水/乙醇中将残余物加热回流,可选地用形态Ⅳ结晶在70-80℃引晶,并将所得混合物放冷,已发现形态Ⅳ具有特征d间距在12.78、9.48、8.99、8.64、8.23、6.39、6.27、5.73、4.01和3.96的X射线粉末衍射图案。该物理形态为本发明的一个方面。
已发现形态Ⅰ具有几个缺点,特别是,已发现它是以难以搅拌和输送的粘稠浆液的形式结晶出来,已发现过滤时间对于工业生产来说长得令人难以接受,湿滤饼的干燥时间也长,并且,已发现形态Ⅰ是热不稳定的,并已发现形态Ⅰ能转变为形态Ⅳ或有时还能转变为另一种物理形态,以下称为形态Ⅴ。已发现形态Ⅴ具有特征d间距在6.12、5.94和5.48的X射线粉末衍射图案。形态Ⅴ在经示差扫描量热法测定时显示出多相转变。
已发现形态Ⅱ以可容易地过滤的可搅拌悬浮液的形式结晶出来,但已发现干燥缓慢并且残留有结晶溶剂。象形态Ⅰ一样,已发现它向形态Ⅳ的转换,因而是热不稳定的。
已发现形态Ⅲ以可容易地过滤和干燥的可搅拌悬浮液的形式结晶出来。已发现它是热稳定的。
已发现形态Ⅳ以可容易地过滤和干燥的可搅拌悬浮液的形式结晶出来。象形态Ⅲ一样,已发现它是热稳定的。
各形态Ⅰ、Ⅱ、Ⅲ、Ⅳ、和Ⅴ在X射线衍射、13C固态NMR光谱和示差扫描量热法结果方面有明显区别。下面给出所用技术和各形态样品测得的物理特性,同时给出用数个不同样品经示差扫描量热法测得的一般范围(仅对形态Ⅲ和Ⅳ)。
X射线衍射(XRD))图案是以装有在管载50KV和40m下工作的Cukα(λ=1.54056)源的Siemens D5000 X射线衍射仪得到的。用Kevex固态检测器收集数据。将各样品在4和35°2θ之间用步长0.03°、最大扫描速率2秒/步进行扫描。
在Seiko示差扫描量热计上进行示差扫描量热法(DSC)测定。将密封于铝盘中的样品(2-5mg)以10℃/分钟的速率由环境温度(25℃)加热至至少200℃。
13C交叉极化/幻角自旋(13C Cross polarization/magic anglespinning)(CP/MAS)NMR谱是用装有全固体辅助设备(Completesolids accessory)和Varian5或7mm VT CP/MAS探针、在100.577MHZ碳频率下工作的Varian Unity 400MHZ光谱仪得到的,通常测定条件如下:90(deg)质子r.f.脉冲5.0ms,接触时间1-2ms,脉冲重复时间(pulse rcpetitiontime)5s,MAS频率7KHZ,谱宽度50KHZ,探测时间50ms。化学位移位通过样品代换以六甲基苯的CH3基团(δ=17.3ppm)为基准定位。形态ⅠDSC:主吸热在171.5℃,次吸热在207.4℃。
XRD:
间距,d() 相对强度
17.30 100
12.28 34
7.76 71
6.57 37
5.24 35
4.81 94
4.34 30
4.21 29
4.09 19
3.98 14
3.62 18
2.85 12形态ⅡDSC:吸热在85.2℃,放热在91.4℃,吸热在192.3℃。
XRD:
间距,d() 相对强度
13.12 100
9.72 23
6.73 37
6.61 60
5.25 28
5.01 94
4.89 70
4.75 41
4.24 28
3.74 25形态ⅢDSC:该样品吸热在194.7℃,已发现其它样品在192-195℃温度范围内吸热。
XRD:
间距,d() 相对强度
10.61 78
8.83 73
8.33 15
7.85 9
6.78 100
5.83 17
5.68 6
5.31 25
5.11 68
4.94 62
4.78 20
4.55 5
4.41 25
4.13 71
4.07 19
3.90 24
3.74 40
3.53 16
3.42 18
3.37 26
3.28 11
3.21 30
3.02 5
2.85 7
2.78 6形态ⅣDSC:该样品在203.2℃吸热。已发现其它样品在201-207℃温度范围内吸热。
XRD:
间距,d() 相对强度
12.78 100
9.48 29
8.99 17
8.64 23
8.23 59
6.53 58
6.39 13
6.27 20
5.73 33
5.37 44
5.22 14
5.18 11
5.10 15
4.95 32
4.89 61
4.75 12
4.56 10
4.41 29
4.32 20
4.01 53
3.96 35
3.77 22
3.59 31
3.39 15
3.11 19形态ⅤDSC:在170.6℃吸热,在177.3℃放热,在206.2℃吸热。
XRD:
间距,d() 相对强度
17.37 51
12.29 21
7.75 29
6.79 32
6.12 13
5.94 14
5.48 15
5.34 24
4.89 82
4.33 100
4.26 50
4.08 34
4.02 20
3.65 21
2.86 13表Ⅰ:溶液和固态13CNMR化学位移数据形态Ⅰ 形态Ⅱ 形态Ⅲ 形态Ⅳ 形态Ⅴ176.4 173.7 175.4 174.1,176.3 175.3128.6 1269 126.3 127.5,129.4 148.5115.9 150.4 109.4 114.1 149.4148.9 147.6 116.1 116.3 146.7146.3 134.5 149.9 148.0,150.2 135.4136.4 123.3 146.0 146.4 136.7123.9 129.2 135.9 136.1 151.1131.7 135.8 124.3 124.7 154.3154.5 152.1 129.1 131.2,133.6 155.1168.4 170.7 132.8 152.7 163.022.2 22.2 153.5 167.7,169.7 167.218.6 18.3 171.4 23.2,23.7 20.6
24.3 18.5,19.2 19.1
19.4 17.4
根据本发明的另一方面,本发明还提供形态Ⅳ的制备方法,包括
b)在钯/炭催化剂存在下用甲酸钾将式Ⅰ化合物中的对硝基苯基还原成苯胺基团,得到Aryl是对氨基苯基的式Ⅰ化合物;和
c)将Aryl是对氨基苯基的式Ⅰ化合物由水和乙醇的混合物中结晶,其中与每体积乙醇混合的水体积数至少为1.1/1.0。
该方法的步骤(a)宜在0-100℃温度范围内进行。适合的溶剂包括链烷醇例如甲醇或乙醇,和醚例如四氢呋喃。
在步骤(C)中,每体积乙醇的水体积数优选在1.15-2.0范围内,更优选1.2-1.8体积范围内。
通式Ⅶ化合物可通过多步法制备,由亚甲二氧基苯基酮衍生物出发。该方法包括:
a)提供一定量的式Ⅱ化合物:其中R是甲基;
b)将式Ⅱ化合物不对称还原得到下式化合物:
e)使式Ⅴ化合物与乙酰肼反应得到下式化合物:
f)使式Ⅵ化合物与甲磺酰氯和叔胺反应形成式Ⅶ化合物。
优选的方法包括及早将酮手性还原为醇。在多步方法中引入取代基以关闭苯稠合的吡喃环,然后引入肼试剂以开环并加入需要的氮成分,最后,通过加入强碱关闭第二个环,将该化合物还原为所需化合物。
最优选的是,用手性还原作为由酮合成式(Ⅰ)化合物的第一步,手性还原可采用特定的化学制品或优选用生物制品进行,如下所述。在本方法中早些确立立体化学结构是有益的,可使后面的步骤以相对对映体纯的物料进行。这既提高生产率又提高对映体纯度。
该方法的第一步包括将3,4-亚甲二氧基苯基丙酮手性还原以制备实际上是对映体纯的1,2-亚甲二氧基苯的醇衍生物。所形成的对映体优选是醇的S即(+)立体异构体。
或者,第-步可包括1,2-亚甲二氧基苯的卤代衍生物与富含对映体的环氧化物的化合。这也使得制成高度富含对映体的1,2-亚甲二氧基苯的醇衍生物。
用于进行第一步手性还原的物料可以是化学制品或优选生物制品。若用生物制品,优选的物质是还原酶,最优选接合酵母类的酵母。其它可使用生物制品包括:发酵毕赤酵母、扣囊拟内孢霉、榛针孢酵母、酵母属(Saccharomyces sp)、Candida famata、Saccharomycespastorianus、酿酒酵母、葡萄汁酵母、产朊假丝酵母、球形酵母、多布克鲁维酵母(Kluyveromyces dobzhansk)、乳酸克鲁维酵母、白假丝酵母、面包酵母、Zygosaccharomyces rouxii、Lactobacillus acidophilus、出芽短梗霉,深黄被孢霉、米根霉、爪哇克勒克酵母、法尔皮有孢汉逊酵母、八孢酵母(Octosporomycesoctospori)、季也蒙假丝酵母(Candida guilliermondi)、近平滑假丝酵母、热带假丝酵母、Torulopsis taboadae、Torulopsisethanolitolerans、Torulopsis ptarmiganii、Torulopsissonorensis、三角酵母、Torulopsis enokii、Torulopsismethanothermo、SAF instant yeast、ashtand yeast inact、Candida boidini、Candida blanki和Red Star yeast。
第一步中形成的所需中间体是1,2-亚甲二氧基苯的醇取代同类物,最优选(S)-α-甲基-1,3-苯并间二氧杂环戊烯-5-乙醇的同类物。
然后对第一步形成的所需中间体化合物进行Pictet-Spengler反应,这提供了苯并二氮杂碳组元的会聚稠合。优选的试剂是对硝基苯甲醛,但其它本领域技术人员已知的试剂例如乙缩醛类也可以使用,优选的中间体是二氢苯并吡喃类,最优选的化合物是7,8-二氢-7-甲基-5-(4-硝基苯基)-5H-1,3-间二氧杂环戊烯并-苯并[b]吡喃。
然后将二氢苯并吡喃同类物在C5位氧化得到下式的半缩酮衍生物
优选的氧化剂包括高锰酸钾、DDQ(2,3-二氯-5,6-二氰基-1,4-苯并醌)等,最优选的试剂是氢氧化钠和空气的组合。
然后在酸存在下,使C5半缩酮与乙酰肼反应以形成腙中间体。在该步中,将苯并吡喃环打开,使腙成分连接于C5碳上。反应宜在回流的芳族或质子溶剂中进行,腙具有以下通式:其中R是CH3,X是乙酰基,Aryl是对硝基苯基。
该方法可通过下面反应路线概括:
反应路线(Ⅰ):
在反应路线(Ⅰ)中,该方法的第一步包括加入生物制品,最优选接合酵母属的Zygosaccharomyces rouxii将酮还原为所需醇。合适量的吸附剂树脂(例如AD-7、XAD-7、HP2MGL(RohmδHaas的交联聚甲基丙烯酸酯)、HP20(聚苯乙烯类)或SP207(Mitsubishi的溴化聚苯乙烯)可加入到反应混合物中以防止微生物死亡并在醇形成时将其吸附。也可使用其它的类似树脂。
在反应路线(Ⅱ)中,反应的第一步包括使芳基卤衍生物例如4-溴-1,2-(亚甲二氧基)苯与碱金属烃(优选仲丁基锂)和对映体纯的环氧化物反应。或者,芳基囟可先通过与镁反应被转化成Grignard试剂,然后在氧化亚铜催化剂存在下与对映体纯的环氧化物反应。优选(S)-(-)-1,2-环氧丙烷。在反应路线(Ⅰ)和(Ⅱ)中,目的是尽早确立苯并二氮杂环的C8原子的立体化学结构。已发现这两个反应路线完成了该任务,并已形成纯度98%左右的富含对映体的(ee)醇。
已知(R)-7-乙酰基-5-(4-氨基苯基)-8,9-二氢-8-甲基-7H-1,3-间二氧杂环戊烯并[4,5-h][2,3]苯并二氮杂是AMPA受体的选择性拮抗剂。同时,根据本发明的另一方面,本发明提供形态Ⅳ在生产阻断需要治疗的哺乳动物的AMPA受体用药物方面的用途。
已发现多种生理功能受到兴奋性氨基酸神经传导的过分或不恰当刺激的影响。据信(R)-7-乙酰基-5-(4-氨基苯基)-8,9-二氢-8-甲基-7H-1,3-间二氧杂环戊烯并[4,5-h][2,3]苯并二氮杂能够治疗与此状况相联系的哺乳动物的多种神经病症,包括急性神经疾病如心脏分流手术和移植后的脑缺血、中风、脑局部缺血、脊髓创伤、头部创伤、产期缺氧、心膊停止和低血糖性神经元损伤。据信该化合物能够治疗多种慢性神经病症,如阿尔茨海默氏病,享廷顿氏舞蹈病、肌萎缩性侧索硬化、AIDS引发的痴呆、眼损伤和视网膜病、自发的及药物引起的帕金森氏病。本发明还提供形态Ⅳ在生产治疗这些疾病的药物方面的用途。
据信该化合物还能够治疗多种与谷氨酸机能障碍有关的哺乳动物的其它神经病症,包括肌肉痉挛、惊
、偏头痛、尿失禁、精神病、耐药性和脱瘾性脑综合征、焦虑症、呕吐、脑水肿、慢性疼痛和迟发性运动障碍。该化合物也用作止痛剂。因而,本发明也提供形态Ⅳ在生产治疗这些疾病的药物方面的用途。
这里所用的术语″有效量″指能阻断AMPA兴奋性氨基酸受体的形态Ⅳ的量。根据本发明,具体的化合物使用剂量当然要由该病例的具体情况而定,包括所用化合物、给药途径、治疗的具体病症和其它因素。该形态可通过多种途径给药,包括经口、直肠、经皮、皮下、静脉内、肌内或鼻内途径。或者,该形态可通过连续输注给药,通常日剂量含约0.01mg/kg-30mg/kg本发明活性化合物,优选日剂量为约0.05mg/kg-24mg/kg,更优选约0.1mg/kg-20mg/kg。
形态Ⅳ通常以药用组合物的形式给予病人,根据本发明的另一方面,本发明还提供包含形态Ⅳ和药学上可接受的稀释剂或载体的药用组合物。
在制备本发明的组合物时,通常将活性成分与载体混合或用载体稀释,或封在可以是胶囊、小袋、纸或其它容器的载体中。当载体用作稀释剂时,它可以是固体、半固体或液体物料,它们起到活性成分的载体、赋形剂或介质的作用。所述组合物可以是例如以下形式:片剂、丸剂、粉剂、锭剂、小袋剂(sachcts)、扁囊剂、混悬剂、气雾剂、软和硬明胶胶囊和无菌包装的粉剂。
适合的载体、赋形剂和稀释剂的实例包括:乳糖、葡萄糖、蔗糖、山梨醇、甘露糖醇、淀粉、树胶、阿拉伯胶、磷酸钙、藻酸盐、黄蓍胶、明胶、硅酸钙、微晶纤维素、聚乙烯基吡咯烷酮、纤维素、甲基纤维素、羟基苯甲酸甲酯和丙酯、滑石、硬脂酸镁和矿物油。这些制剂还可包含润滑剂、湿润剂、乳化剂和助悬剂、防腐剂、甜味剂或矫味剂。本发明组合物的配制应使其在通过使用本领域熟知的方法给病人使用后能提供活性成分的快速或慢速释出。
优选将所述组合物配制成单位剂型,每剂含约5-5000mg,优选约25-3000mg活性成分。最优选的单位剂型含约100-2000mg活性成分。术语″单位剂型″指适用作病人和其它哺乳动物的一次剂量的实际上独立的单位,每个单位含有计划产生所需疗效的预定量的活性物质,以及适合的药用载体。
下面的实施例用于说明本发明。
实施例1
(S)-α-甲基-1,3-苯并间二氧杂环戊烯(benzodioxole)-5-乙醇的合成
将1当量3,4-亚甲二氧基苯基丙酮、0.45当量磷酸氢二钠、0.03当量磷酸、12.5体积AD-7树脂和5.8体积水在20-25℃混合在一起并搅拌15-60分钟。加入2.27当量葡萄糖,并以每克酮1.5g湿细胞糊的量(这是0.375g/g干基)加入Z.rouxii ATCC 14462。将该混合物用水稀释至25体积,然后在33-35℃缓慢搅拌8-16小时。将混合物在100筛目(~150微米)不锈钢筛网上过滤,并将滞留在筛子上的树脂用分成4份的25体积水洗涤。然后用25体积丙酮将吸附于树脂上的产物从树脂上解吸。然后在真空下将丙酮/产物溶液汽提至干,得到标题中间体,为黄色、中粘度油状物。现场收率为97-100%,分离收率为85-90%。纯度(potency)为80-95%,EE为100%。
实施例2
(5RS,7S)-7,8-二氢-7-甲基-5-(4-硝基苯基)-5H-1,3-间二氧杂环戊烯并[4,5-G][2]苯并吡喃的合成。
将上述中间体溶于4.64体积甲苯中,用hyflo过滤,并用1.55体积甲苯洗涤。加入1.05当量对硝基苯甲醛和1.05当量浓盐酸,将混合物加热至55-65℃并搅拌1小时。然后在250mmHg进行溶剂交换,用12.4体积93%异丙醇/7%水代替甲苯。在该溶剂交换过程中体积在11-14体积之间变化,最终体积为约11体积。将混合物冷却至0-10℃,并搅拌1小时,将针状产物晶体过滤,并用1.85体积异丙醇洗涤2次,并在50-60℃真空干燥。标题化合物现场收率95+%,分离收率87-93%。纯度99+%,EE为100%。
实施例3
(S)-α-甲基-1,3-苯并间二氧杂环戊烯-5-乙醇的另一种合成方法。
将3.47g 4-溴-1,2(亚甲二氧基)苯在-78℃溶于100ml四氢呋喃中,然后用少于30分钟的时间向其中加入13.9ml 1.3M仲丁基锂环己烷溶液以消耗芳基囟。然后用注射器加入在2ml THF中的1.00g(S)-(-)-1,2-环氧丙烷,并将溶液搅拌45分钟,然后将溶液温热至23℃16小时,将反应混合物倾入到3M氯化铵溶液中,并将产物通过用乙酸乙酯提取进行分离。将合并的提取液滤过florisil用硫酸镁干燥,并用旋转蒸发仪浓缩,将残余油状物通过硅胶色谱,用50∶50的己烷和乙醚混合物洗脱进行纯化,得到1.40g(45%)小标题中间体。物理化学性质:[α]365+117.2°(c1.0,CHCl3)TLC Rf=0.26(50∶50己烷∶乙醚);IR(CHCl3)3598,3012,2973,2887,1490,1249,1041cm-1;13C NMR(CDCl3)d 147.75,146.19,132.26,122.27,109.68,108.30;质谱,m/z(FD,M+)180;元素分析理论值C10H12O3:C,66.65;H,6.71。实测值:C,66.42;H,6.66.实施例4
(5RS,7S)-7,8-二氢-7-甲基-5-(4-硝基苯基)-5H-1,3-间二氧杂环戊烯并[4,5-G][2]苯并吡喃的另一种可供选择的合成方法
将244g对硝基苯甲醛加入到实施例1的生物催化还原步骤中形成的300g中间体的甲苯(4.45L)溶液中。用15-20分钟时间滴加166.5ml浓盐酸,并将所得混合物加热至60℃2.5小时。将混合物冷却至室温,并用旋转蒸发仪浓缩。加入3L乙醇,并将混合物浓缩成固体。加入第二批3L乙醇,并将混合物搅拌1小时,将浆液冷却过夜,真空过滤分离结晶产物。将滤饼用乙醇洗涤并然后在40-60℃在真空干燥箱中干燥,得到450g(86%)灰白色固体,经测定,它是上述小标题中光活性中间体的异构体混合物。物理化学性质[α]365+55℃(c0.4,CHCl3)。
实施例5
(5RS,7S)-7,8-二氢-7-甲基-5-(4-硝基苯基)-5H-1,3-间二氧杂环戊烯并[4,5-G][2]苯并吡喃-5-醇的合成
将350g实施例4的异构中间体加入到731ml二甲亚砜和2923ml二甲基甲酰胺的溶液中。将混合物冷却至8-12℃,并使压缩空气通过该混合物,一次加入117.5ml 50%氢氧化钠水溶液,并将所得混合物搅拌4.5小时。将此反应混合物在用30-60分钟通过套管加入至10-15℃的8.25L搅拌着的1N盐酸溶液中。将所得沉淀过滤并用3L水洗涤,然后风干至恒重(384g),将湿滤饼不经进一步干燥直接用于实施例6。由3∶1异构体混合物记录的物理化学数据如下:
TLC Rf=0.19(75∶25己烷∶乙酸乙酯);IR(CHCl3)3605,3590,3015,3000,2960,2910,1608,1522,1484,1352,1240,1042cm-1;1H NMR(CDCl3,300MHz)d(主要异构体)8.16(d,2H,J=6.9Hz),7.73(d,2H,J=6.9Hz),6.55(s,1H),6.38(s,1H),5.86(s,1H),5.83(s,1H),4.38(M,1H),2.70(m,2H),1.39(d,3H,J=6.3Hz);d(次要异构体)8.27(d,2H,J=8.9Hz),7.90(d,2H,J=8.6Hz),6.87(s,1H),6.73(s,1H),6.03(s,1H),6.02(s,1H),3.95(m,1H),2.7(模糊,m,2H),1.24(d,3H,J=6.1Hz);质谱,m/z(FD,M+)329;元素分析计算值C17H15NO6:C,62.01;H,4.59;N,4.25.实测值C,62.22,H,4.79;N,4.29.
实施例6
(S)-乙酸-[6-(2-羟基丙基)-1,3-苯并间二氧杂环戊烯-5-基](4-硝基苯基)亚甲基]酰肼的合成
向350g实施例5的湿滤饼的乙醇(2300ml)液中加入94.5g乙酰肼和1ml浓盐酸。将所得溶液加热回流2.5小时。并将混合物冷却至室温,并用旋转蒸发仪浓缩得到黄色泡沫状物,将浓缩物溶于4.9L乙酸乙酯中;用1.5L饱和碳酸氢钠洗涤,然后用1.5L盐水洗涤。将有机相用硫酸钠干燥,过滤并浓缩,得到373g黄色泡沫状物(91%)。经鉴定,该物质为1∶1小标题化合物异构体的不可拆分混合物(HPLC测得纯度97%)。由1∶1异构体混合物记录的物理化学数据如下:
mp167.8-169.7℃;TLC Rf=0.55(乙酸乙酯);IR(CHCl3)3590,3485,3310,1694,1673,1520,1485,1346cm-1;1H NMR(CDCl3,300MHz)d 8.64,8.50(s,1H,NH),8.18(d,2H,Ar-H),7.74,7.71(d,2H,J=8,Ar-H),6.99,6.95(s,1H,Ar-H),6.52,6.50(s,1H,Ar-H),6.06,6.05(d,2H,J=5,O2CH2),2.44(s,3H,CH3),3.87(m,1H,CH),2.4-2.2(m,2H,CH2),1.12,1.10(d,3H,CH3);13C NMR(CDCl3,75MHz)d209.94(C),173.38,173.43(C),149.38,149.62(C),148.31,148.58(C),147.90,148.18(C),147.54(C),142.5,143.04(C),132.64(C),127.53,127.61(CH),123.75,123.77(CH),122.86,123.27(C),112.13(CH),110.55(CH),108.03,108.10(CH),108.03,108.10(CH),101.83(CH2),67.51,68.08(CH),42.37,42.97(CH2),23.48,23.83(CH3),23.48,23.83(CH3),20.47,20.55(CH3);[a]589+103.8°(c1,CHCl3);
质谱,m/z(FD,M+)385;元素分析理论值C19H19N3O6:C,59.22;H,4.97;N,10.90.实测值:C,58.99;H,5.04;N,10.68.
实施例7
(S)-乙酸[6-[2-[(甲磺酰基)氧基]丙基]-1,3-苯并间二氧杂环戊烯-5-基](4-硝基苯基)亚甲基]酰肼的合成
将340g实施例6中间体溶于2380ml二氯甲烷中。将溶液冷却至0--10℃,并加入187ml三乙胺。然后加入78.2ml甲磺酰氯,并将所得混合物搅拌15-30分钟。加入510ml水。将分离的有机相用460ml1N盐酸溶液洗涤,然后用500ml盐水洗涤。将二氯甲烷溶液温热至35-45℃,然后用90分钟时间加入4760ml己烷。将混合物缓慢冷却至室温,然后进一步冷却至0-5℃,将产物真空过滤分离并在40-50℃的真空干燥箱中干燥,得到356.2g(87%)小标题化合物的异构体混合物,为黄色固体。由3∶1异构体混合物记录的物理化学数据:mp150.5-152.5℃;TLC Rf=0.80和0.73(乙酸乙酯);IR(CHCl3)1696,1520,1486,1346,1175,1041,923cm-1;1H NMR(CDCl3,300MHz)d8.44(s,1H,NH),8.20(d,2H,J=8.8Hz,Ar-H),7.73(d,2H,J=8.6Hz),6.94(d,1H,J=2.7Hz,Ar-H),6.57(d,1H,2.6Hz,Ar-H)6.08(d,2H,J=5.4Hz),4.77(m,1H,CH),2.90(s,3H,SCH3,主),2.83(s,3H,SCH3,次),2.66-2.57(m,2H,CH2),1.30(d,3H,CH3,次),
1.26(d,3H,CH3,主);质谱m/z(FD,M+)385;
元素分析理论值C20H21N3O8S:C,51.83;H,4.57;N,9.07;S,
6.92.实测值:C,52.05;H,4.53;N,8.84;S,6.96.
实施例8
(R)-7-乙酰基-8,9-二氢-8-甲基-5-(4-硝基苯基)-7H-1,3-间二氧杂环戊烯并[4,5-h][2,3]苯并二氮杂的合成
将325g实施例7中间体溶于3174ml甲醇中,向该搅拌着的溶液中加入38.1ml 50%苛性苏打溶液,将所得混合物搅拌4小时。向混合物中加入6348ml水,并将混合物搅拌3小时,然后真空过滤分离所得沉淀。将该物质在45-55℃真空干燥箱中干燥,得到255g(97%)小标题化合物,通过HPLC面积%测得其纯度为97.6%。将221g该干燥物质通过在1105ml加热回流的乙醇中再变成浆液而将其进一步纯化。将所得混合物冷却至室温,并通过真空过滤分离沉淀。将分离物在45-55℃真空干燥箱中干燥,得到199g(90%)小标题化合物,HPLC强度分析(HPLC potency assay)其纯度为100%。
实施例9
(R)-7-乙酰基-5-(4-氨基苯基)-8,9-二氢-8-甲基-7H-1,3-间二氧杂环戊烯并[4,5-h][2,3]苯并二氮杂的形态Ⅳ的合成
向5g实施例8中间体的乙醇(50ml)液中加入0.5g用水湿润的10%Pd/C。将该搅拌着的浆液用4g甲酸钾的水(4ml)溶液处理,将所得混合物搅拌2.5小时,然后滤过Hyflo。将滤液蒸馏浓缩至10-20ml,并缓慢向该热(78℃)溶液中加入22ml水。将所得混合物加热至90℃,然后缓慢冷却至室温。将产物真空过滤分离,并用10-20ml水洗涤。将分离的固体在50℃真空干燥,得到4.17g(93%)小标题目标化合物,HPLC强度分析其纯度为100%。[α]365=-303.7(c=1,甲醇)
发现结晶产物是形态Ⅳ。
实施例10
(5RS,7S)-7,8-二氢-7-甲基-5-(4-硝基苯基)-5H-1,3-间二氧杂戊烯并[4,5-G][2]苯并吡喃-5-醇的合成
将15g实施例4中间体(衍生自Z.rouxi为媒介的酮还原)溶于75ml二甲亚砜和75ml二甲基甲酰胺的溶液中。将该溶液冷却至7-9℃,然后通入含40%氧的氮气。加入7.62g 50%氢氧化钠水溶液,并将所得混合物搅拌3-4小时。终止反应,同时将温度保持在≤12℃,加入120ml甲苯,接着加入45ml水和10ml盐酸的混合物。发生相分离,有机层用75ml 10%硫代硫酸钠水溶液洗涤。将含有小标题中间体的有机层直接用于进行下一步骤。
实施例11
(S)-乙酸-[6-(2-羟基丙基)-1,3-苯并间二氧杂环戊烯-5-基](4-硝基苯基)亚甲基酰肼的合成
向实施例10的中间体的甲苯溶液中加入4.26g乙酰肼和(0.01体积)盐酸。将所得混合物加热回流3.5小时并用Dean-Stark分水器除去水。真空蒸馏将反应混合物浓缩至1体积。将浓缩物用105ml二氯甲烷稀释,并用饱和碳酸氢钠溶液和盐水各50-55ml洗涤。将有机溶液用硫酸镁(0.25wt%)干燥,并滤过hyflo滤垫。将滤器用1体积二氯甲烷漂洗。将含小标题中间体的合并的有机相直接用于进行下一步骤。
实施例12
(S)-乙酸[6-[2-[(甲磺酰基)氧基]丙基]-1,3-苯并间二氧杂环戊烯-5-基](4-硝基苯基)亚甲基]酰肼的合成
将含实施例11中间体的二氯甲烷溶液冷却至0--5℃,并加入10ml三乙胺。缓慢加入4.1ml甲磺酰氯以将反应温度保持在≤0℃。向所得溶液中加入1.5体积水。分离有机相,用2.5体积1N盐酸溶液洗涤。分离有机相,并通过常压蒸馏浓缩至原始体积的一半。通过在45℃向溶液中滴加庚烷(2∶1体积庚烷:有机浓缩液)将产物沉淀。将混合物搅拌下冷却至20-25℃1小时,然后冷却至0-5℃1-2小时。真空过滤分离沉淀,并用3体积4∶1庚烷:二氯甲烷洗涤,然后在45-50℃真空干燥箱中干燥。得到17.43g小标题中间产物(78%),为光活性腙异构体混合物,HPLC强度分析纯度为97.7%。
实施例13
(R)-7-乙酰基-8,9-二氢-8-甲基-5-(4-硝基苯基)-7H-1,3-间二氧杂环戊烯并[4,5-h][2,3]苯并二氮杂的合成
将17.5g实施例12中间体悬浮在175ml乙醇中。向搅拌着的混合物中加入1.7g粉末状氢氧化钠。将所得混合物搅拌1小时。向混合物中加入88ml水,并将混合物搅拌1小时,然后真空过滤分离所得沉淀,用175ml水洗涤。将该物质在70℃真空干燥箱中干燥,得到12.2g(86%)小标题化合物,HPLC强度分析纯度为99.9%。
实施例14
(R)-7-乙酰基-5-(4-氨基苯基)-8,9-二氢-8-甲基-7H-1,3-间二氧杂环戊烯并[4,5-h][2,3]苯并二氮杂的合成
用实施例13的产物,采用与实施例9所述相同的实验方法得到标题化合物。
实施例15
(R)-7-乙酰基-8,9-二氢-8-甲基-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1.05g(S)-乙酸[6-[2-羟基丙基]-1,3-苯并间二氧杂环戊烯-5-基](4-硝基苯基)亚甲基酰肼和0.78g三苯基膦的四氢呋喃(70ml)液冷却至0℃。用15分钟时间滴加0.57g偶氮二甲酸二乙酯的四氢呋喃(5ml)溶液。将所得混合物搅拌2小时,然后温热至室温2小时。将混合物转移至分液漏斗中,并将溶液用1N HCl、水和盐水洗涤。将有机相用硫酸镁干燥,过滤,并用旋转蒸发仪浓缩。将残余物通过硅胶柱洗脱(1∶1乙酸乙酯:己烷)。将含所需化合物的流份浓缩成黄色油状物,放置固化。使黄色结晶物在0℃在30ml二氯甲烷和己烷(3∶7)中成为浆液。过滤除去沉淀,并将滤液浓缩得到黄色泡沫状物。将残余物悬浮于10ml乙醇中,先将该悬浮液加热至回流,尔后缓慢冷却至室温。过滤收集沉淀,并在60℃真空干燥箱中干燥。得到0.51g(50%)小标题产物(100%ee),HPLC强度分析纯度为98.3%。
实施例16-18
将0.5ml含表1微生物的冻酵母悬浮液加至在250ml烧瓶中的50ml酵母-麦芽(yeast-malt)培养基中。摇动48小时后,将1.0ml培养液加入到另外50ml培养基中并再摇动48小时,加入3,4-亚甲二氧基苯基丙酮,直至最终浓度为10g/升,同时加入1ml 10%葡萄糖,将培养物培养,并摇动24小时,然后用HPLC分析实施例1的手性醇中间体的存在。
表1
%实施例号 微生物 源 转化率 %EE16 Candida famata (C.f.) A.T.C.C. 0.0 ----
2641817 Zygosaccharomyces (Z.r.) A.T.C.C. 77.8 99.5
rouxi 1446218 Mortierrela (M.i.) N.R.R.L. 1.7 94.3
isobellina 1557
实施例19
(R)-7-乙酰基-5-(4-氨基苯基)-8,9-二氢-8-甲基-7H-1,3-间二氧杂环戊烯并[4,5-h][2,3]苯并二氮杂卓的形态Ⅰ的合成
将(R)-7-乙酰基-8,9-二氢-8-甲基-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(38.93g)用7.79g 10%钯/炭和1个大气压氢气在730ml(19体积)2B-3乙醇中氢化。当HPLC分析表明原料已被耗尽时,过滤除去催化剂,蒸发滤液,得到38.7g粗产物。将该粗产物通过加热至回流溶于220ml(5.7体积)1∶1水/乙醇中。将混合物放冷,产物在室温左右沉淀。将所得粘稠的不易搅拌的浆液在室温搅拌,然后在冰/水浴中冷却。过滤分离固体,在55℃真空干燥箱中干燥过液,得到31.6g纯产物。用同样条件进行第二次重结晶,在65℃真空干燥3天,并在室温真空干燥3天后得到28.7g(80%)产物。将产物非常缓慢地干燥,此时样品中仍留有1.6%乙醇。X射线衍射(XRD)分析,固态NMR(SSNMR)分析和示差扫描量热法(DSC)分析表明形成了形态Ⅰ多晶型物。
实施例20
(R)-7-乙酰基-5-(4-氨基苯基)-8,9-二氢-8-甲基-7H-1,3-间二氧杂环戊烯并[4,5-H][2,3]苯并二氮杂的形态Ⅱ的合成
将(R)-7-乙酰基-8,9-二氢-8-甲基-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(8.63g)用0.86g 10%钯/炭和作为氢气转换源的4.59g碳酸铵的水(5ml)液在170ml(19体积)2B-3乙醇中氢化。当HPLC分析表明原料已被耗尽时,过滤除去催化剂,蒸发滤液,得到8.19g粗产物。将该粗产物通过加热至回流溶于50ml(6.0体积)1∶1水/乙醇中。将混合物放冷至室温然后在冰/水浴中冷却。过滤分离固体,在60℃真空干燥箱中干燥过液,得到7.41g(93%)纯产物。大结晶含5.0%乙醇(GC)和4.2%水(KF)。XRD、SSNMR和DSC分析表明形态Ⅱ多晶型物形成。
实施例21
(R)-7-乙酰基-5-(4-氨基苯基)-8,9-二氢-8-甲基-7H-1,3-间二氧杂环戊烯并[4,5-H][2,3]苯并二氮杂的形态Ⅲ的合成
将(R)-7-乙酰基-8,9-二氢-8-甲基-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(2.04g)用0.20g 10%钯/炭和作为氢气转换源的1.47g在4ml水中的甲酸钾在20ml(10体积)2B-3乙醇中氢化。当HPLC分析表明原料已被耗尽时,过滤除去催化剂,蒸发滤液,得到2.09g粗产物。将该粗产物通过加热至回流溶于12ml(6.0体积)1∶1水/乙醇中。将混合物放冷,并在约40℃用形态Ⅱ结晶引晶,达到室温后,将混合物在冰/水浴中冷却。过滤分离固体,并在50℃真空干燥箱中干燥24小时,得到1.45g(77%)纯产物。分析表明含0.05%乙醇(GC)和0.75%水(KF)。尽管使用了形态Ⅱ多晶型晶种,但XRD、SSNMR和DSC分析表明,形成了形态Ⅲ多晶型物。
实施例22
(R)-7-乙酰基-5-(4-氨基苯基)-8,9-二氢-8-甲基-7H-1,3-间二氧杂环戊烯并[4,5-h][2,3]苯并二氮杂的形态Ⅳ的合成
将(R)-7-乙酰基-8,9-二氢-8-甲基-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(25.2g)用2.0g10%钯/炭和作为氢气转换源的18.0g甲酸钾的水(20ml)液在250ml(10体积)2B-3乙醇中氢化。当HPLC分析表明原料已被耗尽时,过滤除去催化剂。将滤液蒸馏浓缩,直至剩余约70ml(3体积)乙醇。回流下向溶液中加入水(93ml,4体积)。将混合物放冷,并在80℃用实施例9的结晶产物引晶。将所得浆液放冷至室温并搅拌过夜。过滤分离固体,并在50℃真空干燥箱中干燥24小时,得到19.8g(85%)纯产物,分析表明无可检测级乙醇(GC),水含量1.0%(KF)。
XRD、SSNMR和DSC分析表明形成了形态Ⅳ多晶型物。
实施例23
(S)-α-甲基-1,3-苯并间二氧杂环戊烯-5-乙醇的另一种可供选择的合成方法
向镁屑(17g)的四氢呋喃(50ml)悬浮液中滴加5-溴-1,3-苯并间二氧杂环戊烯(93.6g)溶液。完全加入后,将混合物用250ml四氢呋喃稀释,并将所得混合物搅拌过夜。将13ml该溶液(0.78M)转移至含碘化亚铜(0.12g)的圆底烧瓶中。将所得混合物冷却至-50℃,并缓慢加入(s)-(-)-1,2-环氧丙烷的四氢呋喃(3ml)溶液,然后搅拌10分钟。将混合物用乙醚稀释。将分离的有机相用水和盐水洗涤。将水洗涤液用乙醚提取两次,将合并的有机溶液用硫酸镁干燥,过滤并浓缩。将残余物用硅胶色谱(含50%乙醚的戊烷溶液)纯化,得到1.66g所需产物(91%)。手性HPLC分析表明,该物质旋光纯度为98.3%。
实施例24
药物制剂活性成分 1mg 10 50 100淀粉 444.5mg 435.8 396.2 346.6硅氧烷液 4.49mg 4.22 3.84 3.36
将各成份混合,装入零号硬胶囊,装入量为450mg。
Claims (4)
2.如权利要求1所述的(R)-7-乙酰基-5-(4-氨基苯基)-8,9-二氢-8-甲基-7H-1,3-间二氧杂环戊烯并[4,5-h][2,3]苯并二氮杂的物理形态的制备方法,包括:
b)在钯/炭催化剂存在下用甲酸钾将式Ⅰ化合物中的对硝基苯基还原成苯胺基团,得到Aryl是对氨基苯基的式Ⅰ化合物;和
c)将Aryl是对氨基苯基的式Ⅰ化合物在8体积的5∶3水/乙醇或7体积的4∶3水/乙醇中将残余物加热回流,可选地用形态Ⅳ的结晶在70-80℃引晶,并将所得混合物放冷结晶。
3.一种药用组合物,它包含具有d间距在12.78、9.48、8.99、8.64、8.23、6.39、6.27、5.73、4.01和3.96的X射线粉末衍射图案的(R)-7-乙酰基-5-(4-氨基苯基)-8,9-二氢-8-甲基-7H-1,3-间二氧杂环戊烯并[4,5-h][2,3]苯并二氮杂的物理形态和药学上可接受的稀释剂或载体。
4.具有d间距在12.78、9.48、8.99、8.64、8.23、6.39、6.27、5.73、4.01和3.96的X射线粉末衍射图案的(R)-7-乙酰基-5-(4-氨基苯基)-8,9-二氢-8-甲基-7H-1,3-间二氧杂环戊烯并[4,5-h][2,3]苯并二氮杂的物理形态在生产用作AMPA受体拮抗剂的药物方面的应用。
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US29864594A | 1994-08-31 | 1994-08-31 | |
US298,645 | 1994-08-31 | ||
US298645 | 1994-08-31 | ||
US08/412,242 US6329364B1 (en) | 1994-08-31 | 1995-03-28 | Crystalline form of dihydro-2,3-benzodiazepine derivative |
US412,242 | 1995-03-28 | ||
US412242 | 1995-03-28 |
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US5824662A (en) | 1996-09-27 | 1998-10-20 | Guilford Pharmaceuticals Inc. | Treatment of global and focal ischemia using naaladase inhibitors |
US6017903A (en) | 1996-09-27 | 2000-01-25 | Guilford Pharmaceuticals Inc. | Pharmaceutical compositions and methods of treating a glutamate abnormality and effecting a neuronal activity in an animal using NAALADase inhibitors |
CA2264043A1 (en) | 1996-09-27 | 1998-04-02 | Guilford Pharmaceuticals Inc. | Naaladase compositions and methods for treating glutamate abnormality and effecting neuronal activity in animals |
CN1271360A (zh) * | 1997-08-12 | 2000-10-25 | 埃吉斯药物工厂 | 作为ampa/红藻氨酸受体抑制剂的1,3-二氧杂环戊烷并/4,5-h//2,3/苯并-二氮杂䓬衍生物 |
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 |
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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 |
WO1995001357A1 (en) * | 1993-07-02 | 1995-01-12 | Gyógyszerkutató Intézet Kft. | Optically active 1-(4-nitrophenyl)-4-methyl-7,8-methylenedioxy-3,4-dihydro-5h-2,3-benzodiazepine and process for preparing same |
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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 |
WO1995001357A1 (en) * | 1993-07-02 | 1995-01-12 | Gyógyszerkutató Intézet Kft. | Optically active 1-(4-nitrophenyl)-4-methyl-7,8-methylenedioxy-3,4-dihydro-5h-2,3-benzodiazepine and process for preparing same |
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EP0699678B1 (en) | 2004-03-24 |
NO953394L (no) | 1996-03-01 |
FI954066A0 (fi) | 1995-08-30 |
DE69532739T2 (de) | 2005-03-17 |
ATE262531T1 (de) | 2004-04-15 |
CZ222195A3 (en) | 1996-03-13 |
FI954066A (fi) | 1996-03-01 |
BR9503843A (pt) | 1996-09-10 |
PT699678E (pt) | 2004-07-30 |
DE69532739D1 (de) | 2004-04-29 |
JPH0881469A (ja) | 1996-03-26 |
PL181086B1 (pl) | 2001-05-31 |
TR199501070A2 (tr) | 1996-06-21 |
PL310228A1 (en) | 1996-03-04 |
NO309192B1 (no) | 2000-12-27 |
AU695424B2 (en) | 1998-08-13 |
CA2157248A1 (en) | 1996-03-01 |
NZ272898A (en) | 1996-12-20 |
EP0699678A1 (en) | 1996-03-06 |
IL115102A (en) | 1998-12-27 |
NO953394D0 (no) | 1995-08-30 |
HU9502549D0 (en) | 1995-10-30 |
ES2214491T3 (es) | 2004-09-16 |
DK0699678T3 (da) | 2004-06-28 |
CN1128264A (zh) | 1996-08-07 |
JP3449835B2 (ja) | 2003-09-22 |
HUT72675A (en) | 1996-05-28 |
IL115102A0 (en) | 1995-12-08 |
FI112489B (fi) | 2003-12-15 |
HU223843B1 (hu) | 2005-02-28 |
AU3035795A (en) | 1996-03-14 |
CA2157248C (en) | 2000-02-22 |
CZ288679B6 (cs) | 2001-08-15 |
HK1013820A1 (en) | 1999-09-10 |
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