CN1055739A - 半水合物 - Google Patents
半水合物 Download PDFInfo
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- CN1055739A CN1055739A CN91101118A CN91101118A CN1055739A CN 1055739 A CN1055739 A CN 1055739A CN 91101118 A CN91101118 A CN 91101118A CN 91101118 A CN91101118 A CN 91101118A CN 1055739 A CN1055739 A CN 1055739A
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- semihydrate
- imidazolidine
- pyridine
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- -1 pyridine-5-yl Chemical group 0.000 claims abstract description 30
- XDFORSMZCYHNBG-UHFFFAOYSA-N benzonitrile;hydrochloride Chemical compound Cl.N#CC1=CC=CC=C1 XDFORSMZCYHNBG-UHFFFAOYSA-N 0.000 claims abstract description 19
- 238000002360 preparation method Methods 0.000 claims abstract description 14
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
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- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Endocrinology (AREA)
- Reproductive Health (AREA)
- Urology & Nephrology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
- Saccharide Compounds (AREA)
- Compounds Of Alkaline-Earth Elements, Aluminum Or Rare-Earth Metals (AREA)
- Lubricants (AREA)
- Liquid Crystal Substances (AREA)
- Pyridine Compounds (AREA)
- Photoreceptors In Electrophotography (AREA)
Abstract
本发明涉及式Ia所示的含结晶水的4-(5,6,7,
8-四氢咪唑并[1,5-a]吡啶-5-基)苄腈盐酸化物的
新晶形
Description
本发明涉及式Ⅰa所示的含结晶水的4-(5,6,7,8-四氢咪唑并[1,5-a]吡啶-5-基)-苄腈盐酸化物的新晶形
其制备方法,含该晶形的药物制剂,并涉及其对人体或动物体的治疗或药物制剂的生产方面的应用。
式Ⅰa化合物,例如已在题为“5-(对-氰基苯基)-5,6,7,8-四氢咪唑并[1,5-a]吡啶盐酸化物”的欧洲专利申请No.165904中公开,并且由于它的抑制芳构化酶的性质,特别建议用于治疗雌激素依赖性疾病,尤其是已绝经妇女的雌激素依赖性乳腺癌。
上面提及的专利申请也描述了式Ⅰa化合物的制备。大多数情况下是将游离碱溶于少量的丙酮中并加入醚的HCL溶液来实现。也有一个例子描述了通过环化溶解于氯仿中的4-[4-氯-4-(对氰基苯基)正丁基]-1H-咪唑而进行的式Ⅰa化合物的直接制备。在所有情况下,式Ⅰa化合物都是以无水形式得到的,即无水合物。
现已发现,式Ⅰa的无水合物晶体至少可以有两种不同的晶型。其中之一后面称作“α-无水合物”,它是以其X-射线粉末花样的下列晶格间距(d值)和相应的线强度(强度)为特征的:
关于测量方法可作下列说明(它们应用类似于下面给出的所有X-射线粉末花样):为了测定晶格间距=面间距(d值),衍射花样记录在胶片上。记录是在传递过程中用一个Guinier照相机(Enraf-Nonius FR 552)和铜-Kα1照射(波长λ=1.54060埃)进行的。为了校准用了一个记录在相同胶片上的石英花样。相应的线强度通过目检来测定。
式Ⅰa的无水合物的第二种晶型后面指作“β-无水合物”是以下列X-射线粉末花样为特征的:
式Ⅰa的α-及β-无水合物晶体均具有吸湿性缺点,也就是说作为环境湿度的函数它们吸收不同量的水。即使在相对干燥的空气,如相对湿度为33%或44%,中也能吸收水份(见表1和2)。表1:式Ⅰa的α-无水合物在44%的相对湿度及T=23℃(在一个气候罐中)下作为时间函数的吸水性:
*)以无水合物的干重为基
表2:式Ⅰa的α-无水合物在33%的相对湿度及T=23℃(在一个气候罐中)下作为时间函数的吸水性
*)以无水合物的干重为基
因为式Ⅰa无水合物晶体是吸湿的,它们的储存稳定性非常不好。因此,将它们制成药物制剂,尤其是制成适合于口服给药的剂型如片剂时较为困难。
进一步说,式Ⅰa的无水合物至少有两种不同的晶型。这就使得药物制剂,尤其是固体制剂的生产变得复杂,因为一直都需要考虑一种晶型到另一种晶型的转换一部分的或完全的,或者采取措施防止这种转换。不同的晶型可以具有不同的性质,例如当注意到它们的微粉化,它们通常的成片性或它们的溶解性时。如果不小心地用自X中形成的不同的晶型Y,或X与Y的混合物代替了所给的晶型X,那么在药物制剂的生产中就会产生严重的问题。
因而本发明要解决的问题是提供一种新的4-(5,6,7,8-四氢咪唑并[1,5-a]吡啶-5-基)苄腈盐酸化物晶形,它不具有上面提及的缺点尤其是即使储存几年也很稳定。
一种4-(5,6,7,8-四氢咪唑并[1,5-a]吡啶-5-基)苄腈盐酸化物新晶形已被发现,它的令人吃惊之处在于不具有这里的式Ⅰa的无水合物的缺点,并且在正常的环境条件下贮存非常稳定。这种新的晶形是4-(5,6,7,8-四氢咪唑并[1,5-a]吡啶-5-基)苄腈盐酸化物的半水合物晶形,它具有式Ⅰ:
令人吃惊的是已经发现无论是在约10%到约75%的范围内改变相对湿度还是在35℃或50℃下加热8天都不会在X-射线粉末花样或式Ⅰ半水合物晶体的水含量方面引起可检测的变化(见表3)。
表3:式Ⅰ的半水合物的水吸收性及水解吸性实验
1)以无水合物的干重为基;式Ⅰ半水合物的理论值3.47%
2)平衡建立后
3)用相应的饱和水溶液调节气候
表3显示了本发明的式Ⅰ半水合物晶体具有无限的储存稳定性。这就意味着它们可以以松散材料(“批料”)储存许多年而没有任何变化。尤其是它们不再吸收更多水份,以致于在储存过程中活性成分的含量保持不变,不象已知的式Ⅰa无水合物那样持续减少,而起始重量保持不变。在考虑到本化合物非常显著的高的有效性及必然的用于人体的低剂量时,通常仅为1或几毫克,这一点是非常重要的(见下)。
式Ⅰ半水合物晶体是以它们的X-射线粉末花样的晶格间距(d值)及相应的线强度(强度)为特征的:
d值[埃(=10-10m)] | 强度 |
13.49.58.27.56.76.55.655.425.345.154.994.844.604.514.204.094.003.833.813.763.74 | 非常强中等弱强非常弱非常强非常强强非常强中等中等强强强强中等强强中等弱中等 |
3.663.623.563.513.403.353.293.253.213.193.153.133.043.01 | 中等强中等中等非常弱中等非常弱强弱弱中等非常弱强弱 |
式Ⅰ的半水合物晶体进一步以其元素分析为特征,该元素分析是与如下分子式的计算值相符的:
C14H13N3·HCL·1/2H2O(MW:268.75):
C62.57%;H5.63%;N15.64%;CL13.19%。
更进一步说,本发明涉及的式Ⅰ的半水合物晶体基本上是纯的。
式Ⅰ的半水合物晶体可以用本质上已知的方法制备,例如
(a)将4-(5,6,7,8-四氢咪唑并[1,5-a]吡啶-5-基)苄腈与氯化氢在水存在下反应,或
(b)用水处理所制备的含水量少于式Ⅰ半水合物的4-(5,6,7,8-四氢咪唑并[1,5-a]吡啶-5-基)苄腈盐酸化物,或
(c)自含水量多于式Ⅰ半水合物的4-(5,6,7,8-四氢咪唑并[1,5-a]吡啶-5-基)苄腈盐酸化物中除去水份,或
(d)将4-(5,6,7,8-四氢咪唑并[1,5-a]吡啶-5-基)苄腈的非盐酸盐在水存在下转化为式Ⅰ半水合物的盐酸盐。
方法(a):反应前,较好将起始原料4-(5,6,7,8-四氢咪唑并[1,5-a]吡啶-5-基)苄腈游离碱溶于有机溶剂中,如乙基甲基酮或特别是丙酮。
较好,用盐酸水溶液将游离碱转化为式Ⅰ半水合物的盐酸盐。盐酸水溶液的浓度本身并不是关键的,但为了提高产率,优选浓盐酸,特别是37%的盐酸。
反应温度如在0°至70℃,优选20°至55℃;反应最好在室温下进行。
方法(b):用水处理含水量少于本发明的式Ⅰ半水合物的固态4-(5,6,7,8-四氢咪唑并[1,5-a]吡啶-5-基)苄腈盐酸化物,如上面提及的式Ⅰa的α-或β-无水合物,这一反应是按常规的方法用至少为形成半水合物所需量的水作用完成。水最好为液态或气态。
在用液态水进行处理的这种情况下,将含低水量的4-(5,6,7,8-四氢咪唑并[1,5-a]吡啶-5-基)苄腈盐酸化物悬浮于或溶解在水或水溶剂混合物中,然后用常规方法分离出式Ⅰ半水合物晶体。在溶液中,首先必须用常规方法使式Ⅰ半水合物结晶,如浓缩溶液即蒸除部分溶液,加入与水互溶的对式Ⅰ半水合物的溶解性小于水的溶剂,或降低温度。优选的形式,用加入式Ⅰ半水合物晶种来起动或加速式Ⅰ半水合物的结晶。
在用气态水进行处理的情况下,将起始原料暴露于含水汽的大气如湿空气中。且于转化所需的暴露时间随相对湿度的提高而减少。在室温下,相对湿度优选约50到70%。
产品用常规方法分离,如离心,过滤或压力过滤(减压过滤)。产品最好在20°-30℃下干燥,优选20℃下真空干燥。
方法(c):4-(5,6,7,8-四氢咪唑并[1,5-a]吡啶-5-基)苄腈盐酸化物的合适的形式特别是固体或液体,如湿晶体,水悬浮液,水溶液,含水溶剂混合物的悬浮液或含水溶剂混合物的溶液。
用如干燥法除出过量的水,干燥最好在20-30℃下进行,优选20℃真空下进行。
在溶液或悬浮液的情况下,干燥前先分离出式Ⅰ半水合物晶体为好,如方法(b)中描述的采用结晶和/或离心,过滤或压力过滤。然而,溶液或悬浮液也可以在如20-30℃下减压蒸发直接浓缩。
方法(d):盐酸之外的盐,优选药物上可接受的盐。
方法(d)实质上是已知的,例如,将非盐酸的盐溶解于含水溶剂或溶剂混合物中,加入过量的氯化物离子,或特别是氯化氢。优选的是所选的溶剂是一种在其中氯化氢的溶解性小于用作起始原料盐的溶解性的溶剂。
用作起始原料的非盐酸盐例如是由4-(5,6,7,8-四氢咪唑并[1,5-a]吡啶-5-基)苄腈游离碱与相应的酸反应制得的。
本发明也涉及含有作为活性成分的式Ⅰ半水合物晶体的药物制剂。用于肠内特别是口服给药的制剂是特别优选的。制剂可只含活性成分本身,优选与一种或多种药物上可接受的载体同时存在。活性成分的剂量依赖于用于治疗的疾病及种类,年龄,重量,个体条件及给药方式。
药物制剂含约0.1%到约40%的活性成分,单剂量给药形式优选含约0.1%到约20%的活性成分,非单剂量给药形式优选含约0.1%到约10%的活性成分。单位剂型如糖衣丸,片剂或胶囊,含约0.1mg至约20mg,优选约1mg至约4mg的活性成分。
本发明的药物制剂用实质上已知的方法生产,例如常规的混合,成粒,糖膏化,溶解或冻干法。例如,口服给药的药物组合物可通过将活性成分与一种或多种固体载体混合,任意使所得混合物成粒得到,若需要和/或合适,通过加入附加的辅剂处理混合物或成粒以形成片剂或糖衣药丸核。
合适的载体可以是填充剂,如糖,如乳糖,蔗糖,甘露糖醇或山梨糖醇,纤维素制剂和/或磷酸钙,如磷酸三钙或磷酸氢钙及结合剂,如淀粉,如玉米,小麦,米或马铃薯淀粉,甲基纤维素,羟丙基甲基纤维素,羧甲基纤维素钠和/或聚乙烯吡咯烷酮,和/或,如果需要,崩解剂,如上面提及的淀粉,羧甲基淀粉,交联聚乙烯吡咯烷酮,藻酸或其盐,如藻酸钠。
附加辅剂特别是流动调节和润滑剂,如硅酸,滑石,硬脂酸及其盐,如硬脂酸镁或钙,和/或聚乙二醇或其衍生物。
糖衣丸核可用能抵抗胃液的合适的包衣包裹,使用含阿拉伯树胶,滑石,聚乙烯吡咯烷酮,聚乙二醇和/或二氧化钛的特别浓的糖溶液,或溶于合适的有机溶剂或溶剂混合物的硝基纤维素溶液或为制备抗胃液的包衣,使用合适的纤维素制剂溶液如邻苯二甲酸乙酰纤维素或邻苯二甲酸羟丙基甲基纤维素。可以往片剂或糖衣丸中加入着色剂或色素,如为了鉴定或显示不同的活性成分剂量。
用于口服的药物组合物,可以是由凝胶组成的干填充胶囊及由凝胶和成型剂如甘油或山梨糖醇组成的软密封胶囊。干填充胶囊可以含有粒状活性成分,如与填充剂(如玉米淀粉),粘合剂和/或润滑剂(如滑石,或硬脂酸镁)及任意稳定剂的予混合物。在软胶囊中,活性成分优先溶解或悬浮在合适的液态辅剂中,如脂油,石蜡油或液态聚乙二醇,其中也可以加入稳定剂。
合适的可直肠给药的药物组合物可以是如由活性成分与栓剂基础物质结合组成的栓剂。合适的栓剂基础物质可以是如天然或合成的三甘油酯,饱和链烃,聚乙二醇或较高级链烷醇。
本发明也涉及治疗哺乳动物包括人的疾病的方法,它表现为对芳构化酶的抑制活性或对雌激素合成的抑制,如雌激素依赖性疾病,尤其是雌激素依赖性肿瘤,如雌激素依赖性乳腺癌或男子女性型乳房。本发明的半水合物可以预防性或治疗性服药,对一个体重约为70kg的温血动物,日服用本发明半水合物的剂量从约0.1mg至约20mg,优选约1mg至约4mg。
下列实施例用于说明本发明,但无论如何并不限于此范围。温度用摄氏温度。
实施例1:4-(5,6,7,8-四氢咪唑并[1,5-a]吡啶-5-基)-苄腈盐酸化合半水合物。
搅拌下在20-25℃下将33kg4-(5,6,7,8-四氢咪唑并[1,5-a]吡啶-5-基)苄腈引入200升丙酮中。全部溶解后立刻加入1.56升水及1.8kg活性碳的6升丙酮悬浮体。在20-25℃下搅拌45分钟后,分批过滤并用138升丙酮洗涤残余物。在搅拌,20-25°下,往合并的滤液中加入约12.5升盐酸(37%)至PH为2.5-1.0。然后所得的悬浮液在20-25°下搅拌3小时并离心,残余物用80升丙酮分若干次洗涤。20°下真空干燥得到白色晶体粉末的标题化合物。
X-射线粉末花样:晶格间距/强度如上所给;
IR(液体石蜡):3430(强),3375(强),2225(强)cm-1;
元素分析:C14H13N3·HCL·1/2H2O(MW:268.75)
计算值:C62.57%;H5.63%;N15.64%;CL13.19%
实测值:C62.53%;H5.57%;N15.66%;CL13.21%
水含量的检测(按Karl-Fischer):
计算值:3.35%1)
实测值:3.43%。
1)这里所计算的水的理论含量(以式Ⅰ半水合物的分子量为基)是与表3给出的根据无水合物的干重(=分子量)得到的式Ⅰ半水合物的水含量理论值相符的。
用作起始原料的游离碱可根据Ep-A-165904描述的方法制备,尤其是通过用叔丁醇钾的四氢呋喃溶液环合5-(3-氯丙基)-1-(对氰基苯基甲基)-1H-咪唑(见Ep-A-165904之实施例1)。
实施例2:4-(5,6,7,8-四氢咪唑并[1,5-a]吡啶-5-基)苄腈盐酸化合半水合物
将5.3Kg4-(5,6,7,8-四氢咪唑并[1,5-a]吡啶-5-基)苄腈盐酸化物(α-无水合物)引入搅拌过的1.5升水和4.2升丙酮混合物中。混合物加热并在50-55°下搅拌直至得到澄清溶液。然后将溶液冷至30°并用5g4-(5,6,7,8-四氢咪唑并[1,5-a]吡啶-5-基)苄腈盐酸化物半水合物培植。当结晶开始时,在45分钟内将混合物冷至0°。在1小时内,在0-5°下注入35升丙酮。然后悬浮液在0-5°下搅拌2小时并离心,用8升丙酮洗涤晶体残余物。20°下真空干燥得到标题化合物。
X-射线粉末花样:晶格间距/强度如上所给;
IR(液体石蜡):3430(强),3375(强),2225(强)cm-1;
元素分析:C14H13N3·HCL·1/2H2O(MW:268.75)
计算值:C62.57%;H5.63%;N15.64%;CL13.19%
实测值:C62.63%;H5.58%;N15.67%;CL13.25%
水含量检测(按照Karl-Fischer):
计算值:3.35%
实测值:3.46%。
用作起始物质的α-无水合物按Ep-A-165904描述的方法制备,即将游离碱溶解在小量丙酮中并用氯化氢醚溶液中和(见Ep-A-165904之实施例1)。
实施例3:生产10,000 100mg片剂,每片含2mg活性成分:
组成:
4-(5,6,7,8-四氢咪唑并[1,5-a]吡啶-5-基)
苄腈盐酸化物半水合物 20.70g
胶体硅 2.00g
微晶纤维素 100.00g
乳糖,喷雾干燥 817.30g
硬脂酸 10.00g
羧甲基纤维素钠 50.00g
1000.00g
将片剂的所有组分一起混合。当形成了均匀的混合物时,压成片剂。
实施例4:生产10,000 100mg片剂,每片含1mg活性成分:
组成:
4-(5,6,7,8-四氢咪唑并[1,5-a]吡啶
-5-基)苄腈盐酸化物半水合物 10.35g
结晶乳糖 739.65g
微晶纤维素 230.00g
胶体硅 10.00g
硬脂酸镁 10.00g
1000.00g
将片剂所有组成部分一起混合。当形成均匀混合物时,压成片剂。
Claims (7)
1、一种制备4-(5,6,7,8-四氢咪唑并[1,5-a]吡啶-5-基)苄腈盐酸化物的半水合物晶形的方法,它包括:
(a)将4-(5,6,7,8-四氢咪唑并[1,5-a]吡啶-5-基)苄腈与氯化氢在水存在下反应,或
(b)用水处理含水量少于将要制得的式I半水合物的4-(5,6,7,8-四氢咪唑并[1,5-a]吡啶-5-基)苄腈盐酸化物,或,
(c)自含水量多于将要制得的式I半水合物的4-(5,6,7,8-四氢咪唑并[1,5-a]吡啶-5-基)苄腈盐酸化物中除去水分,或
(d)将4-(5,6,7,8-四氢咪唑并[1,5-a]吡啶-5-基)苄腈的非盐酸盐在水存在下转化为式I半水合物的盐酸化物。
2、按照权利要求1的制备4-(5,6,7,8-四氢咪唑并[1,5-a]吡啶-5-基)苄腈盐酸化物的半水合物晶形的方法,该化合物的X-射线粉末花样(Guinier照相,铜-Kal照射)显示下列晶格间距(d值)及相对线强度(强度)
3、按照权利要求1的方法制备基本上纯的晶形。
4、按照权利要求2的方法制备基本上纯的晶形。
5、一种制备药物制剂的方法,它包括将按权利要求1至4之任一的方法得到的化合物以0.1至40%的百分比掺入所说制剂中。
6、用按权利要求1至4之任一的方法得到的化合物对人体进行治疗,它包括以0.1至20mg的日剂量服用该化合物。
7、按权利要求6的应用,其特征在于使用所说的化合物作为芳构化酶抑制剂。
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CN91101118A Expired - Lifetime CN1037966C (zh) | 1990-01-12 | 1991-01-11 | 生产4-(5.6.7.8-四氢咪唑并[1.5-a]吡啶-5-基)苄腈盐酸化物半水合物的方法 |
Country Status (33)
Country | Link |
---|---|
US (1) | US5098911A (zh) |
EP (1) | EP0437415B1 (zh) |
JP (1) | JP2694186B2 (zh) |
KR (1) | KR100191360B1 (zh) |
CN (1) | CN1037966C (zh) |
AT (1) | ATE125809T1 (zh) |
AU (1) | AU638085B2 (zh) |
BG (2) | BG60033B2 (zh) |
CA (1) | CA2033937C (zh) |
CZ (1) | CZ279823B6 (zh) |
DE (1) | DE59106101D1 (zh) |
DK (1) | DK0437415T3 (zh) |
DZ (1) | DZ1482A1 (zh) |
ES (1) | ES2075399T3 (zh) |
FI (1) | FI94528C (zh) |
GR (1) | GR3017027T3 (zh) |
HK (1) | HK1000663A1 (zh) |
HU (1) | HU216192B (zh) |
ID (1) | ID964B (zh) |
IE (1) | IE67512B1 (zh) |
IL (1) | IL96879A (zh) |
MA (1) | MA22040A1 (zh) |
MT (1) | MTP1076B (zh) |
NO (1) | NO175747C (zh) |
NZ (1) | NZ236735A (zh) |
PH (1) | PH27601A (zh) |
PL (3) | PL166157B1 (zh) |
PT (1) | PT96447B (zh) |
RO (1) | RO107408B1 (zh) |
RU (2) | RU2021271C1 (zh) |
SA (1) | SA93140021B1 (zh) |
TN (1) | TNSN91001A1 (zh) |
ZA (1) | ZA91229B (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1293055C (zh) * | 1995-10-23 | 2007-01-03 | 味之素株式会社 | 哌啶衍生物晶体、其制备所用的中间体以及其制备方法 |
Families Citing this family (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
TW208013B (zh) * | 1990-03-01 | 1993-06-21 | Daiichi Co Ltd | |
EP0457716A1 (de) * | 1990-04-20 | 1991-11-21 | Ciba-Geigy Ag | Naphthalinderivate |
TW224461B (zh) * | 1990-09-18 | 1994-06-01 | Ciba Geigy Ag | |
CH683151A5 (de) * | 1991-04-24 | 1994-01-31 | Ciba Geigy Ag | Antikonzeption bei weiblichen Primaten ohne Beeinflussung des menstruellen Zyklus. |
EP2939677A1 (en) | 2010-09-01 | 2015-11-04 | Arena Pharmaceuticals, Inc. | Administration of lorcaserin to indviduals with renal impairment |
ES2704455T3 (es) | 2010-09-01 | 2019-03-18 | Arena Pharm Inc | Formas farmacéuticas de liberación modificada de agonistas de 5-HT2C útiles para la gestión del peso |
JP5749410B2 (ja) | 2012-01-17 | 2015-07-15 | ノバルティス アーゲー | ジヒドロピロロ[1,2−c]イミダゾリルアルドステロンシンターゼまたはアロマターゼ阻害薬の新たな形態および塩 |
WO2018078049A1 (en) | 2016-10-27 | 2018-05-03 | Damian Pharma Ag | Aldosterone synthase inhibitor |
KR20230037680A (ko) * | 2016-10-27 | 2023-03-16 | 다미안 파르마 에이쥐 | 알도스테론 합성효소 저해제 |
IL314302A (en) | 2018-05-03 | 2024-09-01 | Damian Pharma Ag | R-Pedrazole for use in the treatment of aldosteronism |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4617307A (en) * | 1984-06-20 | 1986-10-14 | Ciba-Geigy Corporation | Substituted imidazo[1,5-A]pyridine derivatives as aromatase inhibitors |
US4588732A (en) * | 1982-12-21 | 1986-05-13 | Ciba-Geigy Corporation | Certain imidazo(1,5-a)pyridine derivatives and their use as thromboxane synthetase inhibitors |
-
1990
- 1990-12-14 MT MT1076A patent/MTP1076B/xx unknown
-
1991
- 1991-01-02 PH PH41805A patent/PH27601A/en unknown
- 1991-01-02 US US07/636,816 patent/US5098911A/en not_active Expired - Lifetime
- 1991-01-03 EP EP91810003A patent/EP0437415B1/de not_active Expired - Lifetime
- 1991-01-03 DE DE59106101T patent/DE59106101D1/de not_active Expired - Lifetime
- 1991-01-03 AT AT91810003T patent/ATE125809T1/de not_active IP Right Cessation
- 1991-01-03 ES ES91810003T patent/ES2075399T3/es not_active Expired - Lifetime
- 1991-01-03 DK DK91810003.3T patent/DK0437415T3/da active
- 1991-01-04 IL IL9687991A patent/IL96879A/en not_active IP Right Cessation
- 1991-01-07 MA MA22312A patent/MA22040A1/fr unknown
- 1991-01-09 DZ DZ910008A patent/DZ1482A1/fr active
- 1991-01-09 FI FI910126A patent/FI94528C/fi active
- 1991-01-10 CA CA002033937A patent/CA2033937C/en not_active Expired - Lifetime
- 1991-01-10 PL PL91288653A patent/PL166157B1/pl unknown
- 1991-01-10 KR KR1019910000244A patent/KR100191360B1/ko not_active IP Right Cessation
- 1991-01-10 PT PT96447A patent/PT96447B/pt not_active IP Right Cessation
- 1991-01-10 PL PL91304087A patent/PL166500B1/pl unknown
- 1991-01-10 AU AU69280/91A patent/AU638085B2/en not_active Expired
- 1991-01-10 PL PL91304084A patent/PL167164B1/pl unknown
- 1991-01-10 RO RO146713A patent/RO107408B1/ro unknown
- 1991-01-10 NZ NZ236735A patent/NZ236735A/xx unknown
- 1991-01-11 NO NO910137A patent/NO175747C/no not_active IP Right Cessation
- 1991-01-11 ZA ZA91229A patent/ZA91229B/xx unknown
- 1991-01-11 CZ CS9155A patent/CZ279823B6/cs not_active IP Right Cessation
- 1991-01-11 TN TNTNSN91001A patent/TNSN91001A1/fr unknown
- 1991-01-11 RU SU914894233A patent/RU2021271C1/ru active
- 1991-01-11 JP JP3065711A patent/JP2694186B2/ja not_active Expired - Lifetime
- 1991-01-11 HU HU4/91A patent/HU216192B/hu unknown
- 1991-01-11 IE IE10391A patent/IE67512B1/en not_active IP Right Cessation
- 1991-01-11 CN CN91101118A patent/CN1037966C/zh not_active Expired - Lifetime
- 1991-01-14 BG BG093623A patent/BG60033B2/xx unknown
-
1992
- 1992-01-30 ID IDP190792A patent/ID964B/id unknown
- 1992-04-07 RU SU925011257A patent/RU2088584C1/ru active
- 1992-08-18 BG BG096793A patent/BG61489B2/bg unknown
-
1993
- 1993-06-29 SA SA93140021A patent/SA93140021B1/ar unknown
-
1995
- 1995-08-03 GR GR950401945T patent/GR3017027T3/el unknown
-
1997
- 1997-11-24 HK HK97102235A patent/HK1000663A1/xx not_active IP Right Cessation
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1293055C (zh) * | 1995-10-23 | 2007-01-03 | 味之素株式会社 | 哌啶衍生物晶体、其制备所用的中间体以及其制备方法 |
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C15 | Extension of patent right duration from 15 to 20 years for appl. with date before 31.12.1992 and still valid on 11.12.2001 (patent law change 1993) | ||
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Expiration termination date: 20110111 Granted publication date: 19980408 |