CN1085083A - 药物 - Google Patents
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Abstract
一种用于治疗和/或预防哺乳动物(包括人)焦
虑症的方法,该方法包括给需要作这种治疗和/或预
防的哺乳动物投药有效和/或预防量的5-HT4受体
拮抗剂。
Description
本发明涉及治疗哺乳动物(包括人)焦虑症的方法。
<European Journal of pharmacology>(146,1988年,187-188页)和<Naunyn-Schmiedeberg's Arch.Pharmacol.>(340,1989年,403-410页)上介绍了一种非经典的5-羟基色胺受体,现称作5-HT4受体。
EP-A-501322(Glaxo Group Limited)。WO93/02677、WO93/03725、WO93/05038、WO93/05040和PCT/GB93/00506(Smithkline Beecham plc)介绍了一些具有5-HT4受体拮抗活性的化合物。
据披露,某些5-HT4受体拮抗剂可以用于治疗焦虑症[参见GB2153821A、EP-A-229444(Glaxo Group Ltd.)和EP-A-201165(Beecham Group P.l.C.)]
我们现在发现,以5-HT4受体拮抗剂起作用的化合物,可以用来治疗焦虑症,例如一般焦虑症(GAD)、混合焦虑症/压抑或恐慌症。
在提高的X-迷宫中所观察到的该化合物的抗焦虑作用的条件,不同于就观察5-HT3受体拮抗剂的抗焦虑作用所需的条件。而且,5-HT3受体拮抗剂的作用部位据说是扁桃体[Higgins等,<精神药理学>,104,545-551页,1991年],而5-HT4受体产生的抗焦症作用似乎是通过海马起作用的[Dumuis等,<Mol.Pharmacol.>34,880-887页,1988年]。
因此,本发明提供一种用于治疗和/或预防哺乳动物(包括人)焦虑症的方法,该方法包括给需要作这种治疗和/或预防的哺乳动物施用有效和/或预防量的5-HT4受体拮抗剂。
5-HT4受体拮抗剂可以按例如以下所述的标准方法和在<Naunyn-Schmiedeberg's Arch pharmacol.>(342,619-622页和343,439-446页)和<J.Pharmacol.Exp.Ther.>(252,1378-1386页,1990年)中所述的方法测定。
5-HT4受体拮抗剂的实例包括:R50595(Janssen)(在FR-76530和<Eur.J.Pharmacol.>181,119-125页,1990年之中被描述)、SDZ205-557(在<Naunyn-Schmiedeberg's Arch.Pharmacol.>343(补编),R101,1991年和345,387-393页,1992年内由K.H.Buchheit和R.Gamse撰写的文章中描述)、DAU6215(<Br.J.Pharmacol.>,104,会议文集补编第47页,1991年)、DAU6285(<Naunyn-Schmiedeberg's Arch.Pharmacol.>345,264-269页,1992年)、RS23597-190(Synrex-不列颠药理学会会议,1992年9月)、SC53606(Scarle-第二届国际5-羟基色胺讨论会,美国豪斯顿,1992年9月)和GR113808(Glaxo-EP-A-501322)。
让载于GB2125398A(Sandoz Limited)中的ICS205-930(tropisetron)也是一种5-HT4受体拮抗剂,但是作为5-HT4受体拮抗剂更为有效。
就某个优选方面来说5-HT4受体拮抗剂对5-HT4受体的拮抗比5-HT3受体的拮抗更有效。
所说的5-HT4受体拮抗剂,最好呈基本上纯的药用形式。
5-HT4受体拮抗剂的给药,可以经口、舌下、经皮或非肠道施用。
治疗上述疾病所需的有效剂量,取决于通常诸因素,例如被治疗疾病的种类和严重程度以及哺乳动物的体重。但是,单位剂量通常含0.1-50mg(如0.5-10mg)5-HT4受体拮抗剂,例如式(Ⅰ)化合物或其药用盐。单位剂量通常每日投药一次或多于一次,如每日二、三或四次,通常每日1-3次,以便使每日剂量通常处于(对于70公斤成人来说)0.1-50mg(例如0.1-5mg)范围内,即处于大约0.001-1mg公斤/天范围内,更经常是处于0.005-0.2mg/公斤/天范围内。
对于经口或非肠道投药来说,5-HT4受体拮抗剂最好以单位剂量组合物(例如单位剂量口服中或非肠道组合物)形式投药。
这种组合物用混合法制备成适于口服或非肠道投药使用品,这种药品可以是片剂、胶囊、口服酊剂、粉剂、丸剂、锭剂、可复水的粉剂、注射和可灌注的溶液或悬浮液或栓剂。
经口投药用的片剂和胶囊剂通常以单位剂量制备,而且包含传统的赋形剂,如粘合剂、填充剂、稀释剂、成片剂、滑润剂、崩解剂、着色剂、加香剂和湿润剂。片剂也可以按本领域公知的方法包糖衣。
适于使用的填充剂包括纤维素、甘露醇、乳糖和其它类似的试剂。适用的崩解剂包括淀粉、聚乙烯基吡咯烷酮和例如羟基乙酸淀粉钠之类的淀粉衍生物。适用的润滑剂包括例如硬脂酸镁。适用的药用湿润剂包括十二烷基硫酸钠。
这些固体口服组合物可以用传统的混合、填充或压片法制备。可以采用重复混合操作来将活性成分均匀分布在使用大量填充剂的这些组合物之中。当然,这样的操作是本领域中通用的。
口服液体制剂可以制成例如水或油的悬浮液、溶液、乳液、糖浆或酏剂,也可以制成使用前可以用水或其它适宜的赋形剂重新构成液体制剂的干燥产品。这种液体制剂可以含传统的添加剂,如悬浮剂(如山梨糖醇、糖浆、甲基纤维素、明胶、羟乙基纤维素、羧甲基纤维素、硬脂酸铝凝胶或氢化食用脂),乳化剂(如卵磷酯、脱水山梨糖醇油酸酯或金合欢),非水赋形剂(可以包括食用油),如杏仁油、分馏的椰子油、油的酯类(如甘油、乙二醇或乙醇的酯),防腐剂,如对羟基苯甲酸的甲酯或丙酯或山梨酸;而且必要时还可以含传统的加香剂或着色剂。
口服制剂也包括传统的持续释放型制剂,如有肠溶衣的片剂或丸剂。
对于非肠道给药来说,制备成含5-HT4受体拮抗剂和无菌赋形剂的液体单位剂量。该化合物,根据赋形剂和浓度,可以被悬浮或溶解。非肠道溶液一般的制备方法是:将所说化合物溶解在赋形剂中,灭菌过滤,然后装入适当小瓶或安培之中密封之。最好也将局部麻醉剂,防腐剂和缓冲剂之类佐药溶解在赋形剂中。为了提高其稳定性在将组合物装入小瓶中减压除去水后可以将组合物冷冻。
非肠道悬浮剂按基本上相同的方式制备,只是将所说的化合物悬浮而不是溶解在赋形剂之中,而且在悬浮于灭菌的赋形剂中之前利用曝露在环氧乙烷中的方法赋形剂灭菌。在此组合物中最好还包含表面活性剂或湿润剂以利于本发明化合物的均匀分布。
像普通实践那样,所说的组合物通常伴以书写或印刷的适于有关治疗用途的指示。
本发明还提供使用5-HT4受体拮抗剂制造治疗和/或预防焦虑症用药物的用途。这种治疗和/或预防可以按上述方式进行。
本发明进一步提供一种治疗和/或预防焦虑症用药物组合物,其中含5-HT4受体拮抗剂和药用载体。这种组合物可以按上述同样方式制备。
5-HT4受体拮抗剂的活性
使用重250-400克的雄性几内亚豚鼠。从远侧结肠区取下大约3cm长的纵肌-肠肌丛,在0.5克负荷下将其悬浮于保温在37℃下用含5%CO2的O2鼓泡的含克雷布氏溶液的分离组织浴中。在全部试验中,所说的克雷布氏溶液还含甲硫嗪庚嗪10-7M、二甲麦角新碱2×10-7M和granisetron10-6M。
在30秒接触时间和15分钟给药周期下用5-HT4制出样品浓度-响应曲线之后,选择使所说的肌肉收缩达到最大值的40-70%(10-9M左右)时的浓度。然后每隔15分钟交替地用此浓度的5-HT和大约等效浓度的尼古丁受体***二甲基苯基哌嗪鎓(DMPP)给药。在获得对5-HT和DMPP均一致的响应之后,向所说的浴溶液中加入递增浓度的假定的5-HT4受体拮抗剂。然后按照由5-HT或DMPP引起收缩减少的百分数测定此化合物的作用。由此数据确定IC50值(收缩减少50%所需的拮抗剂浓度)。减少对5-HT的响应而对DMPP响应不减少的化合物被视为以5-HT4受体拮抗剂起作用。
体内试验群体的交互作用
每八只一组物鼠(雄性,查理德Sprague Dawleys鼠,体重250-300克)关在贮藏室中5天,然后在试验前四天将其单个地关在靠近试验室的房间中,试验的当天,从上午10点开始以15分钟的间隔给试验鼠成对(n=8-16)皮下给于赋形剂、试验化合物、或苯并二氮杂草抗焦虑剂、利眠宁,30分钟后将其按重量配对的搭配对(第一次遇到的)放入处于单独房间内的群体交互盒中。此盒用白色有机玻璃制成54cmx37cmx26cmx大小,前面是透明的有机玻璃,无盖。底板被分成24个方块,盒用强光照射(115勒克斯)。用仪表记录主动的群体交互行为(修整、嗅、上下爬、跟随、咬、骑和打斗等行为)15分钟,用透控电视监视得出总的交互点数。每只鼠跨过方格的数目记下并总结之。每次试验结束后仔细擦净试验盒子。
X-迷津试验
X-迷津被提升到底板上方50cm处,该迷宫由两个45cm(长)×10cm(宽)×10cm(高)关闭臂和两个45cm×10cm×10cm的打开的臂组成,四个臂布置得使每种臂的两臂互相相对。将两种典型的臂划成两个相等部分。将试验鼠放入X-迷宫的中心,观察5分钟。观察期间记录下列参数:1,进到(a)开臂(b)闭合臂(c)开臂端和(d)闭合臂端上的次数和所花的时间;2,跨过的区的数目。由开臂所引起的恐惧运动超过闭合臂引起的运动,而且试验鼠通常表现出明显的选择关合的臂。抗焦虑作用的药物增加进行开臂的外半部分上的数目和所花的时间,而且还提高了进到整个开臂上的百分数和所花的时间。对每只试验鼠算出这四项抗焦虑的程度和横跨过诸区的总数。
Claims (8)
1、用于治疗和/或预防哺乳动物(包括人)焦虑症的方法,该方法包括给需要作这种治疗和/或预防的哺乳动物投药有效和/或预防量的5-HT4受体拮抗剂。
2、使用5-HT4受体拮抗剂制造用于治疗和/或预防焦虑症的药物。
3、一种用于治疗和/或预防焦虑症的药物组合物,其中包括5-HT4受体拮抗剂和药学上可接受的载体。
4、权利要求1、2和3所述的方法,用途或组合物,其中所说的5-HT4受体拮抗剂在5-HT4受体上的作用比在5-HT3受体上更有效。
5、用于治疗一般焦虑症(GAD)或混合的焦虑/压抑的权利要求4所述的方法,用途或组合物。
6、用于治疗恐慌症的权利要求5所述的方法,用途或组合物。
7、权利要求1、2或3所述的方法,用途或组合物,其中5-HT4受体拮抗剂是R50595、SDZ205-557、DAU6285、RS23597-190、SC53606或GR113808。
8、权利要求1、2或3所述的方法,用途或组合物,其中5-HT4受体拮抗剂是WO93/02677、WO93/03725、WO93/05038、WO93/05040和PCT/GB93/00506(Smithkline Beecham Plc)中所述的化合物。
Applications Claiming Priority (7)
Application Number | Priority Date | Filing Date | Title |
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GB929205428A GB9205428D0 (en) | 1992-03-12 | 1992-03-12 | Pharmaceuticals |
GB9211082.4 | 1992-05-23 | ||
GB9214399.9 | 1992-07-07 | ||
GB929218846A GB9218846D0 (en) | 1992-09-05 | 1992-09-05 | Pharmaceuticals |
GB9219356.4 | 1992-09-12 | ||
GB9227045.3 | 1992-12-29 | ||
GB929227045A GB9227045D0 (en) | 1992-12-29 | 1992-12-29 | Pharmaceuticals |
Publications (1)
Publication Number | Publication Date |
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CN1085083A true CN1085083A (zh) | 1994-04-13 |
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ID=27266092
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Application Number | Title | Priority Date | Filing Date |
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CN93102648A Expired - Fee Related CN1043893C (zh) | 1992-03-12 | 1993-03-11 | 药品 |
CN93107234A Pending CN1085083A (zh) | 1992-03-12 | 1993-05-22 | 药物 |
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Application Number | Title | Priority Date | Filing Date |
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CN93102648A Expired - Fee Related CN1043893C (zh) | 1992-03-12 | 1993-03-11 | 药品 |
Country Status (30)
Country | Link |
---|---|
EP (2) | EP0884319B1 (zh) |
JP (1) | JP2831467B2 (zh) |
KR (1) | KR100282730B1 (zh) |
CN (2) | CN1043893C (zh) |
AP (1) | AP401A (zh) |
AT (2) | ATE180785T1 (zh) |
AU (1) | AU671102B2 (zh) |
CA (1) | CA2131797C (zh) |
CY (1) | CY2510B1 (zh) |
CZ (1) | CZ286194B6 (zh) |
DE (2) | DE69333504T2 (zh) |
DK (2) | DK0630376T3 (zh) |
ES (2) | ES2132223T3 (zh) |
FI (1) | FI107158B (zh) |
GR (1) | GR3030668T3 (zh) |
HK (1) | HK1012352A1 (zh) |
HU (1) | HU219121B (zh) |
IL (1) | IL105003A (zh) |
MA (1) | MA22819A1 (zh) |
MX (1) | MX9301348A (zh) |
MY (1) | MY110110A (zh) |
NO (1) | NO303638B1 (zh) |
NZ (1) | NZ249565A (zh) |
PT (1) | PT884319E (zh) |
RU (1) | RU2104279C1 (zh) |
SG (1) | SG50693A1 (zh) |
SI (1) | SI9300114B (zh) |
SK (1) | SK281423B6 (zh) |
UA (1) | UA41311C2 (zh) |
WO (1) | WO1993018036A1 (zh) |
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US5852014A (en) * | 1992-03-12 | 1998-12-22 | Smithkline Beecham P.L.C. | Condensed indole derivatives as 5HT4 -receptor antagonists |
GB9316195D0 (en) * | 1993-08-05 | 1993-09-22 | Smithkline Beecham Plc | Pharmaceuticals |
US5998409A (en) * | 1992-03-12 | 1999-12-07 | Smithkline Beecham Plc | Condensed indole derivatives as 5HT4 -receptor antagonists |
MX9305947A (es) * | 1992-09-29 | 1994-06-30 | Smithkline Beecham Plc | Compuestos antagonistas del receptor 5-ht4, procedimiento para su preparacion y composiciones farmaceuticas que las contienen. |
JPH08502283A (ja) * | 1992-10-16 | 1996-03-12 | スミスクライン・ビーチャム・パブリック・リミテッド・カンパニー | 5−ht▲下4▼レセプターアンタゴニスト用の縮合環系n−アルキルピペリジニル−4−メチルカルボン酸エステル/アミド |
NZ257545A (en) * | 1992-11-05 | 1997-01-29 | Smithkline Beecham Plc | Heterocyclic (especially piperidine) derivatives and pharmaceutical compositions |
FR2699921B1 (fr) * | 1992-12-30 | 1995-02-10 | Synthelabo | Dérivés d'acide 2-(thien-2-yl)imidazo[2,1-b]benzothiazole-3-acétique, leur préparation et leur application en thérapeutique. |
GB9303340D0 (en) * | 1993-02-19 | 1993-04-07 | Smithkline Beecham Plc | Pharmaceuticals |
GB9310582D0 (en) * | 1993-05-22 | 1993-07-07 | Smithkline Beecham Plc | Pharmaceuticals |
GB9312348D0 (en) * | 1993-06-16 | 1993-07-28 | Smithkline Beecham Plc | Pharmaceuticals |
KR100219922B1 (ko) * | 1996-05-16 | 1999-09-01 | 이서봉 | 신규한 항바이러스성 6-아릴옥시 및 6-아릴카르보닐 2,4-피리미딘디온 유도체 및 그의 제조 방법 |
AU3464397A (en) * | 1996-07-02 | 1998-01-21 | Sang Sup Jew | Oxirane carboxylic acid derivative and its manufacturing method |
TR199900321T2 (xx) * | 1996-08-16 | 1999-04-21 | Smithkline Beecham P.L.C. | N-(1-nbutil - 4 - piperidil)metil) -3,4-dihidro -2H- (1,3) oksazino (3.2A) indol-10- Karboksamit haz�rlama prosesi ve prosesteki tuzlar ve ara �r�nler. |
US6100397A (en) * | 1996-08-16 | 2000-08-08 | Smithkline Beecham Plc | Process for the preparation of N-[(1-n butyl-4-piperidyl)methyl]-3,4-dihydro-2H-[1,3]oxazino[3,2-a] indole-10-carboxamide and salts and intermediates in the process |
GB9618967D0 (en) * | 1996-09-11 | 1996-10-23 | Smithkline Beecham Plc | Pharmaceuticals |
GB9725933D0 (en) * | 1997-12-05 | 1998-02-04 | Smithkline Beecham Plc | Pharmaceuticals |
US6251893B1 (en) * | 1998-06-15 | 2001-06-26 | Nps Allelix Corp. | Bicyclic piperidine and piperazine compounds having 5-HT6 receptor affinity |
US20020091271A1 (en) | 1998-07-16 | 2002-07-11 | Smithkline Beecham Plc | Process for the preparation of an indole derivative |
GB9819035D0 (en) * | 1998-09-01 | 1998-10-28 | Cerebrus Res Ltd | Chemical compounds VII |
DE69935600T2 (de) * | 1998-09-10 | 2007-12-06 | F. Hoffmann-La Roche Ag | Dihydrobenzodioxincarbonsäureamid- und ketonderivate als 5-ht4-rezeptorantagonisten |
GB9820294D0 (en) * | 1998-09-17 | 1998-11-11 | Smithkline Beecham Plc | Pharmaceuticals |
US6545004B1 (en) | 1999-10-27 | 2003-04-08 | Cytokinetics, Inc. | Methods and compositions utilizing quinazolinones |
AU782870C (en) * | 2000-08-07 | 2007-03-15 | Glaxo Group Limited | The use of 5HT4 receptor antagonists in the prophylaxis or treatment of certain cardiovascular conditions |
AU2005203196B9 (en) * | 2000-08-07 | 2009-04-09 | Glaxo Group Limited | The use of 5HT4 receptor antagonists in the prophylaxis or treatment of certain cardiovascular conditions |
KR20030027010A (ko) * | 2000-08-07 | 2003-04-03 | 라보라뜨와르 글락소스미스클라인 | 심방 세동 예방 또는 치료용 의약의 제조에서의 5ht4수용체 길항제의 용도 |
AU782863C (en) * | 2000-08-07 | 2006-08-31 | Glaxo Group Limited | The use of 5HT4 receptor antagonists in the prophylaxis or treatment of certain cardiovascular conditions |
AU7655801A (en) * | 2000-08-08 | 2002-02-18 | Smithkline Beecham Plc | Pharmaceutical composition comprising condensed indole compound |
NZ535261A (en) * | 2000-08-08 | 2004-12-24 | Smithkline Beecham P | A tablet comprising the hydrochloride salt of N-(1-nbutyl-4-piperidinyl)methyl]-3,4-[1,3]oxazino[3,2-a] indole-10-carboxamide |
ATE329581T1 (de) * | 2002-02-14 | 2006-07-15 | Glaxo Group Ltd | Pharmazeutische formulierung, die n-((1-n-butyl-4-piperidinyl)menthyl)-3,4-dihydr -2h-(1, 3)oxazino(3,2-a)indol-10-carboxamid oder ein entsprechendes salz hiervon enthält, sowie deren herstellungsprozess, welcher trockengranulierung beinhaltet |
GB0211230D0 (en) | 2002-05-16 | 2002-06-26 | Medinnova Sf | Treatment of heart failure |
ITMI20031468A1 (it) | 2003-07-18 | 2005-01-19 | Acraf | Farmaco ativo nel dolore neuropatico |
ITMI20031467A1 (it) * | 2003-07-18 | 2005-01-19 | Acraf | Farmaco attivo nel dolore neuropatico |
CA2551171C (en) | 2003-12-23 | 2012-07-10 | Bio-Medisinsk Innovasjon As | Modulators of peripheral 5-ht receptors |
JP4612301B2 (ja) * | 2003-12-26 | 2011-01-12 | 広栄化学工業株式会社 | 1−アルキル−4−アミノメチルピペリジンの製造法 |
MX2009013815A (es) | 2007-06-22 | 2010-03-01 | Arqule Inc | Compuestos de quinazolinona y metodos de uso para los mismos. |
GB0905641D0 (en) * | 2009-04-01 | 2009-05-13 | Serodus As | Compounds |
WO2021116487A1 (en) | 2019-12-13 | 2021-06-17 | Som Innovation Biotech, S.A. | Compounds for use in the treatment of niemann-pick c disease |
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DE2557342A1 (de) * | 1975-12-19 | 1977-06-30 | Hoechst Ag | Basisch substituierte indolderivate und verfahren zu ihrer herstellung |
AU622330B2 (en) * | 1989-06-23 | 1992-04-02 | Takeda Chemical Industries Ltd. | Condensed heterocyclic compounds having a nitrogen atom in the bridgehead for use as fungicides |
CA2030051C (en) * | 1989-11-17 | 2001-08-07 | Haruhiko Kikuchi | Indole derivatives |
US5189041A (en) * | 1990-11-16 | 1993-02-23 | Syntex (U.S.A.) Inc. | Tricyclic 5-ht3 receptor antagonists |
GB9103862D0 (en) * | 1991-02-25 | 1991-04-10 | Glaxo Group Ltd | Chemical compounds |
US5206382A (en) * | 1991-06-27 | 1993-04-27 | Fidia Georgetown Institute For The Neurosciences | Indole derivatives, pharmaceutical compositions and methods of treating neurological and psychiatric disorders |
-
1993
- 1993-03-10 AP APAP/P/1993/000494A patent/AP401A/en active
- 1993-03-10 DK DK93905561T patent/DK0630376T3/da active
- 1993-03-10 SI SI9300114A patent/SI9300114B/sl active Search and Examination
- 1993-03-10 JP JP5515490A patent/JP2831467B2/ja not_active Expired - Lifetime
- 1993-03-10 UA UA94095780A patent/UA41311C2/uk unknown
- 1993-03-10 SG SG1996008846A patent/SG50693A1/en unknown
- 1993-03-10 CZ CZ19942210A patent/CZ286194B6/cs not_active IP Right Cessation
- 1993-03-10 MY MYPI93000436A patent/MY110110A/en unknown
- 1993-03-10 EP EP98114130A patent/EP0884319B1/en not_active Expired - Lifetime
- 1993-03-10 PT PT98114130T patent/PT884319E/pt unknown
- 1993-03-10 CA CA2131797A patent/CA2131797C/en not_active Expired - Fee Related
- 1993-03-10 ES ES93905561T patent/ES2132223T3/es not_active Expired - Lifetime
- 1993-03-10 AT AT93905561T patent/ATE180785T1/de active
- 1993-03-10 EP EP93905561A patent/EP0630376B1/en not_active Expired - Lifetime
- 1993-03-10 ES ES98114130T patent/ES2219813T3/es not_active Expired - Lifetime
- 1993-03-10 NZ NZ249565A patent/NZ249565A/en not_active IP Right Cessation
- 1993-03-10 AT AT98114130T patent/ATE266033T1/de active
- 1993-03-10 DE DE69333504T patent/DE69333504T2/de not_active Expired - Lifetime
- 1993-03-10 WO PCT/GB1993/000506 patent/WO1993018036A1/en active IP Right Grant
- 1993-03-10 RU RU94040864A patent/RU2104279C1/ru not_active IP Right Cessation
- 1993-03-10 SK SK1078-94A patent/SK281423B6/sk not_active IP Right Cessation
- 1993-03-10 DK DK98114130T patent/DK0884319T3/da active
- 1993-03-10 HU HU9402601A patent/HU219121B/hu unknown
- 1993-03-10 DE DE69325167T patent/DE69325167T2/de not_active Expired - Lifetime
- 1993-03-10 KR KR1019940703167A patent/KR100282730B1/ko not_active IP Right Cessation
- 1993-03-10 IL IL10500393A patent/IL105003A/en not_active IP Right Cessation
- 1993-03-10 AU AU36448/93A patent/AU671102B2/en not_active Expired
- 1993-03-10 MA MA23113A patent/MA22819A1/fr unknown
- 1993-03-11 MX MX9301348A patent/MX9301348A/es not_active IP Right Cessation
- 1993-03-11 CN CN93102648A patent/CN1043893C/zh not_active Expired - Fee Related
- 1993-05-22 CN CN93107234A patent/CN1085083A/zh active Pending
-
1994
- 1994-09-09 NO NO943348A patent/NO303638B1/no not_active IP Right Cessation
- 1994-09-12 FI FI944204A patent/FI107158B/fi not_active IP Right Cessation
-
1998
- 1998-12-15 HK HK98113467A patent/HK1012352A1/xx not_active IP Right Cessation
-
1999
- 1999-06-30 GR GR990401755T patent/GR3030668T3/el unknown
-
2005
- 2005-04-12 CY CY0500021A patent/CY2510B1/xx unknown
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