CN1081671A - 使用已知药治疗糖尿病 - Google Patents
使用已知药治疗糖尿病 Download PDFInfo
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- CN1081671A CN1081671A CN93105195A CN93105195A CN1081671A CN 1081671 A CN1081671 A CN 1081671A CN 93105195 A CN93105195 A CN 93105195A CN 93105195 A CN93105195 A CN 93105195A CN 1081671 A CN1081671 A CN 1081671A
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
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- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
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Abstract
使用包含式Ⅰ结构而且其中所示的氢原子
(H1-9)可以被取代，或不被取代的抗糖尿病的喹啉
-3-甲酰胺化合物或其盐制造用于治疗I型糖尿病
症的组合物。
Description
糖尿病，是因血管异常而以许多器官中的生理学和解剖学异常为特征的疾病。但是，这种病的最显著特征是葡萄糖代谢紊乱，导致血糖过高。糖尿病通常分为两种：胰岛素依赖性糖尿病（Ⅰ型糖尿病）和非胰岛素依赖性糖尿病（Ⅱ型糖尿病）;Ⅰ型糖尿病通常在童年和青春期发生，病人易患酮病和酸中毒;而Ⅱ型糖尿病通常以控制饮食和口服低血糖物治疗的方法解决。就发病率而言，美国每年Ⅰ型糖尿病发病率从每10万名非白种人男性中有10例到每10万名白种人男性中的16例，而两种人种中男性和女性之间的发病率相等。美国人口中各种年令的Ⅰ型糖尿病流行情况为160例/10万人，与男性相比，女性发病的高峰年令（10-12岁）稍早，而男性发病的高峰年令为18岁。遗传背景在这种疾病的发生中起主要作用，同卵挛生者Ⅰ型糖尿病具有40%的一致性，而且家庭成员中发病率高。增加Ⅰ型糖尿病易感性有关的基因存在于副染色体b上的主要的组织相容性染色体组附近，90%以上的Ⅰ型糖尿病患者具有DR3或DR4单倍体或有此二种单倍体特征。共有源于双亲的DR3或DR4单倍体的同胞兄弟姐妹患Ⅰ型糖尿病的发病率，比其它人随机患同样病的发病率更高[1]。
Ⅰ型糖尿病发作的症状，通常是急性的而且常常是跟随在先行的病毒感染之后，这种感染可能引发使β-细胞破坏的过程进而导致自
身免疫胰岛炎。当β-细胞破坏到临界点时，病人的胰岛素水平下降，导致Ⅰ型糖尿病的典型症状的高血糖。诊断时，大约70%的Ⅰ型糖尿病患者，具有对抗岛细胞的细胞浆即抗原的抗体，或对抗岛细胞表面成分的抗体。大约15%的Ⅰ型糖尿病患者也可能显示出其它自体免疫特征，例如甲状腺机能减退、突眼性甲状腺肿、肾上腺性青铜色皮病、重肌无力症和恶性贫血[2]。Ⅰ型糖尿病病例的尸体解剖表明，在胰腺岛中有典型的淋巴细胞浸润[3]。
目前治疗Ⅰ型糖尿病尚不令人满意，这种病会导致只能部分地用适当控制胰岛素水平的方法克服的严重的威胁生命的并发症，而这种控制方法难于用在幼年发作的病人身上。除了急性糖尿病症状之外，慢性糖尿病表现会导致严重的动脉硬化，而细淋巴管病可能造成眼睛早期失明。在20名均患Ⅰ型糖尿病的病人中一人失明，大约40%的Ⅰ型糖尿病发展成肾衰竭，导致慢性血液透析和/或需要作肾移植[4-7]。在Ⅰ型糖尿病患者中出现严重的精神病变化也是典型性的。出现许多与感觉神经、交感神经和副交感神经有关的功能性障碍。除了周围神经之外，脑神经也可能涉及。而神经病的治疗依然不能令人满意只能用适当的胰岛素疗法对葡萄糖作一般性控制。
与非糖尿病患者相比，Ⅰ型糖尿病患者的发病频率更高，中风高两倍，心肌梗塞高2-5倍，心血管意外事故高5-10倍。Ⅰ型糖尿病病人并发急性心肌梗塞症抢救的预后，与抢救急性心肌梗塞的非糖尿病病人的预后相比要重三倍，而且对其它血管并发症的病例相比也是如此。严重而且不能控制的动脉硬化症，也可能与各种病因学因素有关，这些病因学因素涉及血小板、凝固因素和脂载体（如HGL水平）的异常，以及不可控制的糖尿病[1]。
鉴于这种病的自身免疫本质，有人建议用环胞多肽A作为Ⅰ型糖尿病的临床表现出现后立即采用的一种可能的处理方法，获得了一些令人鼓舞的结果[8]。虽然报道了具有完全和部分缓解作用，但是需要采用随机化的双盲临床试验来评价专期的效果以及在IDDM期早期环胞多肽和其它免疫抑制形式的安全性。
本发明用下列实验作进一步说明：
为了研究与糖尿病有关的治疗制度的效果，通常采用非过度肥大的糖尿病（NOD）鼠作实验模型，参见实验部分。能对抗胰岛的淋巴胞性浸润，进而避免胰岛的退化性变化、明显的糖尿病、出现高血糖、糖尿、酮病和体重下降以及在出现高血糖症状后必须使用胰岛素的药物，被本发明定义为抗糖尿病药。
有人提议使用喹啉-3-甲酰胺化合物作为药物。此化合物包括下式Ⅰ给出的结构，所示出的氢原子（H1-9，其中H9是下面（b）中所示出的X1或X2中的一部分）可以有或没有取代基，在适当时还包括此化合物的盐：
此结构式是互变异构Ⅱ-Ⅳ的概括式。
在式Ⅰ-Ⅳ中：
（a）……表示在被虚线连接的原子之间有两个共轭双键（仅式Ⅰ有）;
（b）X1和X2分别选自氧原子或可能被取代的NH9基，所说的X1和X2在连有H7或H8时被单键连接到环上，而且在不连有H7或H8时被双键连接到环上;
（c）H1-9是氢，条件是至少在X1和X2中有一个是NH9基的情况下H9才存在;
（d）H7和H8是连到从X1、X2和喹啉环中氮原子中选出的不同原子上的氢，所说的X1和X2当连有H7或H8时被单键连到环上，在不连有H7或H8时被双键连到环上。
取代H1-9的取代基，根据现有技术可以包含任何使形成的化合
物能够被分离的取代基。例如参见＜印度化学杂志＞第17B卷（1979）488-490页（抗炎性）、US3960868（＝GB1467061，止痛、避孕、抗炎和抗过敏性）、US4547511和4738971（增进细胞传递的免疫性）、WO9015052（＝US申请651234，1990年5月31日提出申请，免疫调节剂）、US4107310（止痛剂）和JP-68023948（杀菌剂）。上述的美国专利和专利申请通过参照结合在本文之中。一般而言，可以确定许多包括结构Ⅰ的化合物，均被归入免疫调节剂之内，它们每个化合物均具有从抑制免疫系统到刺激免疫系统的广谱功能。所达到的具体效果取决于所说的取代基。
具有式Ⅰ结构的最重要的化合物之一是1，2-二氢喹啉-3-甲酰胺，特别是N-苯基-N-甲基-1，2-二氢-4-羟基-1-甲基-2-氧代-喹啉-3-甲酰胺（Linomide
），即H1被等价苯基取代、H2被等价甲基取代、H8被等价甲基取代（被连到喹啉环氮原子上）、H3-7未被取代、H7连到X1上而且X1和X2均是等价氧原子的式Ⅰ和Ⅱ结构的化合物。此化合物在3和4位间以及2位和X2间各有一个双链。
使用Linomide
的科学实验证明，Linomide
有多重的免疫学活性。因此据发现，Linomide
能提高对T细胞和B细胞分裂素的增殖响应[8]，增进抗体的产生[9]和加强NK细胞的活性[10，11]。而且，其免疫刺激性和免疫调节性可以用于治疗肿瘤[12]和系统性红斑狼疮[13，14]，详见美国专利第4547511和4738971。
本发明的一个主要目的在于提供一种用于治疗Ⅰ型糖尿病的方法。第二个主要目的在于提供一种用于制造药物组合物的药品，所说的药物组合物将用于治疗前段中指出的疾病。
其它目的在于提供与治疗上述疾病有关的方法、药品和药物组合物，以减少胰岛的淋巴细胞浸润、高血糖、糖尿、酮病、体重减小或对胰岛素的需求。
在本发明中治疗了能发生Ⅰ型糖尿病的哺乳动物，尤其是人。
在所说的NOD鼠模型中我们研究了所说的免疫调节剂Linomide
，基于这些研究我们发现，与过去基于非特异的免疫抑制作用而采用的治疗对策不同，Linomide
发挥出极有效的抗糖尿病作用。通过研究包含结构Ⅰ的其它化合物，将会找到具有相似作用的进一步候选药。
因此，本发明涉及在上面“发明目的”部分所说的那样治疗糖尿病的方法。此方法是指给病人投药治疗有效量的包含结构Ⅰ的抗糖尿病化合物。本发明方法还包括预防性治疗。本发明也包括该化合物用于制造该治疗方法中使用的药物组合物的用途。
目前人们确信，最优选的那些化合物可以在US4738971和4547511中所描述的化合物中找到。具体说，取代基的组合可以选自：
（ⅰ）H8被从低级烷基（含1-8个碳原子的）中选出的基团取代并且被连接到喹啉环的氮原子上（H8＝低级烷基）;
（ⅱ）X1是其上连有H7的氧（＝-OH基）;
（ⅲ）X2是通过双键连到喹啉环上的氧（由于X2是氧数H9不存在）;
（ⅳ）H1-6均未被取代基取代（H1-6＝H）;和
（ⅴ）H1被芳基尤其是苯基取代（H1＝芳基，尤其是苯基）和/或H2被低级烷基（含1-8个碳原子的）取代。
具体优选的化合物，是Linomide
或者具有医疗活性的其生理和药理上可允许的盐，如钠盐或钙盐。
术语“有效量”是指相对于上面给出的效果而言能改善病人的糖尿病状况的量。
给药途径主要是口服，但是也不排除其它途径，例如非肠道、腹膜内、注射、灌输和直肠投药等等。
本发明所说的组合物可以含所说的活性化合物本身，或者适当时还可以包含本领已知的药学上适用的阳离子盐或阴离子盐。可以设想出的剂量范围是0.1-100mg/天，取决于被治疗的具体病情、具体病人的年令和体重以及病人对药物的具体反应而变化。通常情况下，有效剂量为0.01-10（优选0.05-？）mg/Kg体重。
可以使用的制剂，是含或不含但最好是含有药学用载体的粉剂、糖浆、栓剂、软膏、溶液、丸剂、胶囊和颗粒剂等等。详见US4738971和4547511，通过参照特将此二专利内容结合入本文。
实验模型
挑选一些非过度肥大的近交的糖尿病（NOD）鼠，七十天后作为考查导致Ⅰ型糖尿病岛β-细胞破坏的过程和机理用的显著模型，并且用来试验几种预防性措施的可能性。NOD鼠早期出现胰岛的淋巴细胞性浸润，而且在3-4周令时开始出现退化性变化。胰岛炎在13-30周令时导致明显的糖尿病，出现严重的高血糖糖尿、酮病和体重减轻症状，而且在发生高血糖后对胰岛素产生了绝对需要。胰岛类在雌性鼠中（30周令）更普通（雌性与雄性鼠的发病率为85%
比20%）[15]。虽然在雄性和雌性鼠中都出现明显的胰岛炎，但是雌性/雄性患明显糖尿病的比例为85%∶15%，此数值说明在发生糖尿病综合征的致病因素之中，荷尔蒙之类的其它因素在起作用[15]。
NOD鼠的糖尿病显然是免疫调节性的，而且缺乏T-细胞的鼠不出现这种病的全部表现[16-18]。因此，除了辐照和骨髓移植之外，免疫抑制的用药方式，其中包括环胞多肽A、FK-506、抗胸腺细胞球蛋白、单克隆抗胸腺嘧啶（Thy）-1和抗-CD4抗体等，可以阻止或改善（至少是暂时性地）高血糖和胰岛炎[19-25]。
LINOMIDE对NOD鼠发生糖尿病的影响
材料和方法
鼠：全部实验中使用了从丹麦Bomholtgard饲养研究中心（有限公司）买到的雌性NOD鼠。这些鼠在3-5周令时开始发生胰岛炎，26周时患明显症状糖尿病的占55%，28周时占65%，环境温度为21±8℃。根据每隔两周用Labstix检查中连续两次测定出现糖尿，确定糖尿病发生。腹膜内葡萄糖耐受性试验前后测定血液中的葡萄糖水平。试验鼠每两周测体重一次。
葡萄糖耐受试验（GTT）;GTT是按下法完成的：给试验鼠腹膜内注射1克/千克体重的葡萄糖，测定血中葡萄糖底线水平，随后再注射葡萄糖60次并作相应的测定。
病理组织学评定：试验开始后大约八周，将12周令的试验鼠处死，在障眼基础上（blind basis）与对照组比较中评定受试鼠胰腺的病理学组织学组织情况。为了检查与药物相当的可能毒性，还评定了其它器官的病理学情况。
Linomide投药;将Linomde（瑞典赫尔辛堡Kabi Pharmacia Therapeutis AB）溶解在酸化的饮用自来水中，使之浓度为0.5-2.5mg/ml。它仅仅轻度影响（降低）（尤其在使用的剂量高时）水的消耗量。在使用的较低剂量下，每只鼠接受评定量的1.5-2.5mg/Kg/天（60-100mg/Kg）。在3-5周令时开始投药Linomide每10天制备一次该药物的稀释物。而对照用鼠只接受规则量的酸化自来水。
糖尿病和胰岛炎的临床评定
实验鼠分成两组，从第3-5周令开始作Linomide治疗。按常规方法，每两周进行尿糖、体重和流体摄入测定。12周令时处死试验鼠对胰腺和其它器官作病理学组织评价，在16周令时测定GTT。每天测定一次存活率。
糖尿的出现
用Labstix法只有对照鼠出现糖尿，而用Linomide治疗的试验鼠中没有一只有出现糖尿的证据，得到结果如下：
实验1：40周令的试验鼠，对照组5/9有糖尿，而用Linomide（0.5mg/ml）治疗的试验组0/9有糖尿。
实验2：40周令的试验鼠，对照组4/9糖尿，而用Linomide（0.5mg/ml）治疗的试验组0/9有糖尿。
基础血液水平和葡萄糖耐受性试验
腹膜内GTT结果如图1所示：在未治疗的对照鼠中发现了典型的糖尿病模型，即大部分对照鼠在给了葡萄糖后基础血糖水平和葡萄糖水平均增高。与之相反，在用Linomide治疗的NOD鼠中发现血糖水平正常，而且正常的GTT试验与正常的3ALB/C受试者中作的GTT后观察到的GTT水平相当。
病理学
按双盲试验法（病理学家E.Rosenmann教授和观测者均不知道用编号标记的载片类型）作了胰腺的病理学检查（每个试验每组三只鼠）。在全部未治疗的NOD鼠中均发现了胰岛炎的典型特征，其中包括在β-细胞中严重的单核细胞浸润。但是在用Linomide治疗的试验鼠中没有一只有出现胰岛类的证据。此关系是绝对的：治疗的鼠中没有一只带胰岛炎特征，反之在全部未治疗的受体中均发现有典型的胰岛炎。
体重
如图2所示，未治疗的对照组在的糖尿出现的同时体重持续平行下降，反之用Linomide治疗的鼠开始增重。
存活率
实验1和2中的治疗鼠除一只之外都继续存活，而未处置的对照鼠中已经发现死亡，情况可以从图3中看出。
我们进行的实验结果表明，口服给药后Linomide能显著地改善自体免疫性胰岛炎，维持正常的葡萄糖的新陈代谢。成功地治疗过的试验鼠没有表现出患病的临床证据，即糖尿阴性、正常的血糖耐受性、没有患自体免疫胰岛炎的病理学踪象和药物毒性证据。反之，未治疗的对照组却出现了糖尿病的典型症状，包括糖尿、高血糖、体重下降和死亡，同时出现无论何时检查均会发现胰腺的β-细胞被单核细胞浸润的典型现象。
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Claims (4)
1、一种抗糖尿病的喹啉-3-甲酰胺化合物或其盐制造用于治疗与Ⅰ型糖尿病有关的病症用组合物的用途，所说的化合物具有式Ⅰ结构，其中所示的氢原子(H1-9)可以被取代基取代或不被取代：
式中：
(a)……表示在被虚线相连的原子间有两个共轭双键：
(b)X1和X2分别选自氧原子或NH9基，所说的X1和X2在连有H7或H8时被单键连到环上而且在不连有H7或H8时被双键连到环上；
(c)H1-9是氢，但是仅在X1和X2中至少一个是NH9基的情况下H9才存在；
(d)H7和H8是连到从X1和X2以及所说喹啉环中的氮原子中选出的不同原子上的氢。
2、按照权利要求1中的抗糖尿病化合物的用途，其特征在于所说的化合物是N-苯基-N-甲基-1，2-二氢-4-羟基-1-甲基-2-氧代-喹啉-3-甲酰胺。
3、治疗与Ⅰ型糖尿病有关病症的方法，其中包括给身患所说病症或有患该病危险的病人施用有效量的抗糖尿病的喹啉-3-甲酰胺化合物或其盐，所说的化合物包含式Ⅰ结构，而且所示出的氢原子可以被取代基选择性地取代：
式中：
（a）……表示在被虚线相连的原子间有两个共轭双键;
（b）X1和X2分别选自氧原子或NH9基，所说的X1和X2在连有H7或H8时被单键连到环上而且在不连有H7或H8时被双键连到环上;
（c）H1-9氢，但是仅在X1和X2中至少一个是NH9基的情况下H9才存在;
（d）H7和H8是连到从X1和X2以及所说喹啉环中的氮原子中选出的不同原子上的氢。
4、按照权利要求3的方法，其中所说的化合物是N-苯基-N-甲基-1，2-二氢-4-羟基-1-甲基-2-氧代-喹啉-3-甲酰胺。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE9201076A SE9201076L (sv) | 1992-04-06 | 1992-04-06 | Användningen av gamla läkemedel för behandling av diabetes |
| SE9201076 | 1992-04-06 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1081671A true CN1081671A (zh) | 1994-02-09 |
Family
ID=20385863
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN93105195A Pending CN1081671A (zh) | 1992-04-06 | 1993-04-05 | 使用已知药治疗糖尿病 |
Country Status (16)
| Country | Link |
|---|---|
| US (1) | US5594005A (zh) |
| EP (1) | EP0634931A1 (zh) |
| JP (1) | JPH07506568A (zh) |
| KR (1) | KR950700738A (zh) |
| CN (1) | CN1081671A (zh) |
| AU (1) | AU667362B2 (zh) |
| CA (1) | CA2131831C (zh) |
| EE (1) | EE03090B1 (zh) |
| HU (1) | HUT69710A (zh) |
| IL (1) | IL105285A0 (zh) |
| NO (1) | NO943723L (zh) |
| NZ (1) | NZ251494A (zh) |
| PH (1) | PH30820A (zh) |
| SE (1) | SE9201076L (zh) |
| WO (1) | WO1993019756A1 (zh) |
| ZA (1) | ZA932450B (zh) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102176906B (zh) * | 2008-10-09 | 2014-07-02 | 新树株式会社 | Panduratin衍生物或提琴形凹唇姜提取物的全新用途 |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6133285A (en) * | 1998-07-15 | 2000-10-17 | Active Biotech Ab | Quinoline derivatives |
| SE9802549D0 (sv) * | 1998-07-15 | 1998-07-15 | Active Biotech Ab | Quinoline derivatives |
| SE9802550D0 (sv) * | 1998-07-15 | 1998-07-15 | Active Biotech Ab | Quinoline derivatives |
| FR2827600A1 (fr) * | 2001-07-20 | 2003-01-24 | Lipha | Derives acides de quinolone et leurs applications en therapeutique |
| US8124582B2 (en) * | 2002-12-06 | 2012-02-28 | Fibrogen, Inc. | Treatment of diabetes |
| CN103153959A (zh) | 2010-10-14 | 2013-06-12 | 伊姆纳尔公司 | 作为AhR活化剂的1，2-二氢-4-羟基-2-氧代-喹啉-3-甲酰苯胺类 |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA1034124A (en) * | 1973-05-11 | 1978-07-04 | Ciba-Geigy Ag | Process for the manufacture of new quinolines |
| FR2340735A1 (fr) * | 1976-02-11 | 1977-09-09 | Roussel Uclaf | Nouveaux derives de l'acide 3-quinoleine carboxylique, leur procede de preparation et leur application comme medicament |
| IE52670B1 (en) * | 1981-03-03 | 1988-01-20 | Leo Ab | Heterocyclic carboxamides,compositions containing such compounds,and processes for their preparation |
| DE3134780A1 (de) * | 1981-09-02 | 1983-03-10 | Hoechst Ag, 6000 Frankfurt | "sulfonylharnstoffe, verfahren zu ihrer herstellung, pharmazeutische praeparate auf basis dieser verbindungen und ihre verwendung" |
| US5310913A (en) * | 1989-06-09 | 1994-05-10 | Kabi Pharmacia Aktiebolag | Derivatives of quinoline-3-carboxanilide |
| SE9000624D0 (sv) * | 1990-02-22 | 1990-02-22 | Pharmacia Ab | New use |
| SE9001111D0 (sv) * | 1990-03-27 | 1990-03-27 | Pharmacia Ab | Supportive use |
-
1992
- 1992-04-06 SE SE9201076A patent/SE9201076L/xx not_active Application Discontinuation
-
1993
- 1993-03-31 WO PCT/SE1993/000272 patent/WO1993019756A1/en not_active Ceased
- 1993-03-31 AU AU39131/93A patent/AU667362B2/en not_active Ceased
- 1993-03-31 CA CA002131831A patent/CA2131831C/en not_active Expired - Fee Related
- 1993-03-31 HU HU9402854A patent/HUT69710A/hu unknown
- 1993-03-31 NZ NZ251494A patent/NZ251494A/en unknown
- 1993-03-31 EP EP93908245A patent/EP0634931A1/en not_active Withdrawn
- 1993-03-31 US US08/313,302 patent/US5594005A/en not_active Expired - Fee Related
- 1993-03-31 JP JP5517372A patent/JPH07506568A/ja active Pending
- 1993-04-02 PH PH45991A patent/PH30820A/en unknown
- 1993-04-02 IL IL105285A patent/IL105285A0/xx unknown
- 1993-04-05 CN CN93105195A patent/CN1081671A/zh active Pending
- 1993-04-05 ZA ZA932450A patent/ZA932450B/xx unknown
-
1994
- 1994-10-05 NO NO943723A patent/NO943723L/no unknown
- 1994-10-06 KR KR1019940703534A patent/KR950700738A/ko not_active Ceased
- 1994-11-17 EE EE9400269A patent/EE03090B1/xx unknown
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102176906B (zh) * | 2008-10-09 | 2014-07-02 | 新树株式会社 | Panduratin衍生物或提琴形凹唇姜提取物的全新用途 |
Also Published As
| Publication number | Publication date |
|---|---|
| KR950700738A (ko) | 1995-02-20 |
| NO943723D0 (no) | 1994-10-05 |
| NO943723L (no) | 1994-10-05 |
| AU667362B2 (en) | 1996-03-21 |
| CA2131831C (en) | 1999-03-09 |
| CA2131831A1 (en) | 1993-10-14 |
| HUT69710A (en) | 1995-09-28 |
| PH30820A (en) | 1997-10-17 |
| HU9402854D0 (en) | 1995-01-30 |
| SE9201076D0 (sv) | 1992-04-06 |
| WO1993019756A1 (en) | 1993-10-14 |
| JPH07506568A (ja) | 1995-07-20 |
| US5594005A (en) | 1997-01-14 |
| SE9201076L (sv) | 1993-10-07 |
| EP0634931A1 (en) | 1995-01-25 |
| ZA932450B (en) | 1993-10-20 |
| NZ251494A (en) | 1997-07-27 |
| EE03090B1 (et) | 1998-06-15 |
| AU3913193A (en) | 1993-11-08 |
| IL105285A0 (en) | 1993-08-18 |
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