CN1030576A - 咪唑衍生物光学异构体 - Google Patents
咪唑衍生物光学异构体 Download PDFInfo
- Publication number
- CN1030576A CN1030576A CN88104440A CN88104440A CN1030576A CN 1030576 A CN1030576 A CN 1030576A CN 88104440 A CN88104440 A CN 88104440A CN 88104440 A CN88104440 A CN 88104440A CN 1030576 A CN1030576 A CN 1030576A
- Authority
- CN
- China
- Prior art keywords
- enantiomorph
- medetomidine
- separation
- acid
- gaonist
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
- C07D233/58—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
-
- 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
- A61P25/20—Hypnotics; Sedatives
-
- 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
- A61P25/22—Anxiolytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/06—Antiarrhythmics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Epidemiology (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Pain & Pain Management (AREA)
- Anesthesiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Optical Fibers, Optical Fiber Cores, And Optical Fiber Bundles (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Optical Record Carriers And Manufacture Thereof (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Saccharide Compounds (AREA)
- Photoreceptors In Electrophotography (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
分离得到Medetomidine的d和l对映体以及
它们的盐是有选择性的和有效的α-受体促效药。
Description
本发明涉及咪唑衍生物的光学异构体及其制备。
具有式Ⅰ的Medetomidine被认为是有选择性的和有效的α2-受体促效药,它已被揭示,如在欧洲专利公开号72615中作为抗高血压剂和在欧洲专利公开号187471中作为兽医的镇静止痛剂。
本发明提供了作为新化合物的Medetomidine的旋光性d-和e-对映体和它们无毒的药物上可接受的酸加成盐。这些化合物可以通过下式来表示:
按照本发明的特点,外消旋的Medetomidine可通过将该外消旋体先转化成非对映异构体混合物,再用分级结晶法将混合物分离成对映体Ⅱ和Ⅲ。由于Medetomidine是碱,因此它可以通过与旋光性酸如酒石酸反应转化成非对映异构体盐混合物。其它有用的旋光性酸例如为(-)-苹果酸,(-)-扁挑酸和(+)-樟脑-10-磺酸,(+)-酒石酸对于拆开外消旋混合物是特别有用的。非对映体的分离是通过从醇例如甲醇或乙醇或它们的混合物中重复结晶来完成的。
在分离非对映体后,该酸加成盐能反转为游离碱,即通过用氢氧化钠制得它碱性水溶液,再用合适的有机溶剂如二氯甲烷萃取已释放的碱。
Medetomidine的d-和l-对映体与有机酸或无机酸反应形成相应的酸加成盐,该盐具有与碱相同的治疗效能,因此它们能形成药物上有效的酸加成盐,例如:氯化物、溴化物、硫酸盐、硝酸盐、磷酸盐、磺酸盐、甲酸盐、酒石酸盐、马来酸盐、枸椽酸盐、萃甲酸盐、水杨酸盐和抗坏血酸盐等。
Medetomidine的d-和l-对映体是有选择性的和有效的α2-受体促效药。
肾上腺素能受体是生理上的重要结合部位,它对去甲肾上腺素和肾上腺素有特异性,它位于细胞膜表面。交感神经系统的肾上腺素能受体分成两类不同的亚型,α-受体和β-受体,它们又进一步划分为两亚组,即是α1和α2以及β1和β2受体。在这些受体类型中,β1、β2和α1主要位于例如平滑肌表面突触后部位并因此传递如平滑肌的收缩或舒张;而α2-受体主要位于去甲肾上腺素能神经末端的突触前部位。如果在生理条件下用去甲肾上腺素刺激α2-受体,则中断了肾上腺素的释放,也就是说这是一种负反馈现象这种负反馈现象还可以通过某些合成的α2-促效药象Medetomidine和某些它的近似衍生物来诱发。
在动物实验中,证明了本发明的d-和l-对映体并尤其是d-对映体同外消旋混合物(即Medetomidine)相比较具有高度增强α2-的选择性以及具有更高的效力。d-对映体作为如镇静一止痛、抗忧虑或抗高血压剂的价值是能预期的。另外,在α2-肾上腺受体的生理学和药理学的研究中,d-对映体能用作为药理学工具。
本发明化合物的药理学活性测定如下:
1.在体外的α2-促药效性
通过分离,电刺激老鼠输精管制品来测定α2-促药效性(Marshall et al.,Br.J.Pharmac.62,147,151,1978)。在这个试验物中,α2-促效药可以通过激活突触前α2-肾上腺受体的来阻断因电诱导的平滑肌收缩,并因此减少运动传递质的分泌。已知的α2-促效药如detomidine,Medetomidine和可乐宁是用作参照物。实验结果示于表1,在表中,α2-促效药的作用是用pD2-值表示(即产生最大抑制的50%的试验化合物摩尔浓度的负对数)。
表1
化合物 α2-促效药在体外(老鼠输精管)的pD2
d-对映体 9.3
l-对映体 6.0(部分促药效)
Medetomidine 9.0
detomidine 8.5
可乐宁 8.5
这些结果表明Medetomidine的α2-促效药活性限于d-对映体。同其它研究的试剂相比较表明d-对映体增强α2-促效药活性。
2.在体外α2/α1的选择性
用大鼠的脑膜通过受体结合实验来研究作为α2-促效药的d-对映体选择性。正如Virtanen和Nyman在Eur.J.Pharmac.108,163-9,1985上揭示的那样,d-异构体和这些参照化合物对于同3H-可乐宁(用于α2-受体)和3H-吡唑嗪(用于α1-受体)的竞争能力已作了基本研究、试验结果示于表2,在表中,研究试剂对于同3H-可乐宁和3H-吡唑嗪的结合竞争能力用IC50-值表示(即为对于替换50%放射活性配位体所需的竞争配位体的摩尔浓度)。
表2
化合物3H-可乐宁3H-吡唑嗪 α2/α1-选择性
替换IC50,nM 替换IC50,nM
d-对映体 1.2 55019 45849
l-对映体 46 189975 4129
Medetomidine 3.3 16700 5060
Detomidine 3.7 242 65
可乐宁 6.4 6200 969
上述结果表明d-对映体同Meaetomidine和其它参照化合物比较是一个最有选择性的α2-促效药。
3.镇静止痛作用
通过用小鼠的自发能动性和因剧痛翻试验来研究本发明化合物镇静止痛性能。用Animex活性测定仪测定小鼠和大鼠的自发能动性。在2分钟测定周期前30分钟,试验化合物经腹膜注射给药。
在剧痛翻滚试验中,将研究化合物和食盐水以同样情况给大鼠皮下用药,过45分钟后腹膜注射给于1ml 1%乙酸,接着在25分钟时间记录翻滚的数目(Kosler et al.,Fred.Proc,18:412,1959)。
结果示于表3和表4。
表3:研究化合物在减低小鼠自发能动性的ED50值
化合物 ED50(mg/kg s.c)
d-对映体 0.02
l-对映体 >10
Medetomidine 0.05
Detomidine 0.3
可乐宁 0.3
表4 研究化合物在小鼠以乙酸诱发剧痛翻滚试验中的ED值
化合物 ED50(mg/kg s.c)
d-对映体 0.01
l-对映体 >10
Medetomidine 0.02
Detomidine 0.02
可乐宁 0.03
这些结果表明d-对映体同外消旋混合物(Medetomidine)和其它参照化合物相比较有增强镇静止痛的性能。Medetomidine的镇静止痛作用局限于d-对映体。
4.抗忧虑作用
使用Handley和Mithoni在Naunyn-Schmiedeb,Arch,Pharmacol.237,1-5 1984叙述的方法研究本发明化合物的抗忧虑作用。在本试验中,测定大鼠在升高的t-迷宫中对开口的和闭合的通道的探索方式。表明抗忧虑药增加了对与开口通道相关的探索。在t-迷宫的中央放置一个老鼠并于5分钟内记录老鼠进入开口和闭合通道的次数,得到的结果示于表5。
表5
药物/剂量,mg/kg 进入平均数(n=6)
开口 闭合 总数 开口/总数
NaCl 3.4 8.6 12.0 0.28
d-对映体
0.0003 4.8 10.6 14.0 0.20
0.001 3.2 10.6 13.8 0.23
0.003 4.0 9.5 13.5 0.29
0.01 5.8 8.8 14.6 0.39
0.03 2.5 3.0 5.5 0.45
安定
1 5.2 10.5 15.7 0.33
上述结果表明d-对映体在升高的t-迷宫试验中有抗忧虑的表现。
众所周知对于病症断除的连贯忧虑状态是由于去甲肾上腺素能的机能亢进。因此,用例如可乐宁药物降低去甲肾上腺素的水平,能成功地治疗这些病症。在大鼠实验中表明d-对映体能减抄去甲肾上腺素的释放并因此在中枢神经系统和周围神经系统调和交感神经。通过给大鼠施用d-对映体后,测定MHPG-SO4的CSF浓度(中枢神经去甲肾上腺素的主要代谢产物)已经清楚地证明了上述观点。该结果示于表6。
表6
d-对映体剂量μg/kg CSF MHPG-SO4(%对照)
(在施用d-对映体4小时后)
0 100
3 -10
10 -20
30 -30
100 -65
5.抗高血压作用
本发明化合物的抗高血压性能研究如下:
将标准体重的Sprague-Dawly大鼠首先用氨基甲酸乙酯麻醉,然后将股动脉用聚乙烯管连接到血压传感器上,再将试验物注射入股静脉,用记录器自动记录血压和脉博频率,结果示于表7。
表7:在麻醉大鼠中d-对映体的抗高血压作用
剂量 mg/kg 血压下降 % 心率下降 %
0.001 -8 -21
0.003 -23 -40
0.01 -43 -47
0.03 -45 -48
0.1 -45 -50
结果表明d-对映体具有明显的抗高血压和心动徐缓作用。
因此d-和l-对映体及它们的无毒性的药物上可接受的酸加成盐或它们的混合物可以肠胃外、静脉注射或口服给药。一般,将有效量的本发明化合物与合适的药物载体结合使用。按本文使用的术语“有效量”是指包括那些能产生所需要的活性但不会发生有害付作用的量。在特定场合时使用的正确量取决于许多因素如:给药方法,哺乳动物种类,为施用本发明衍生物的条件等,自然也取决于衍生物的结构。
同本发明化合物一起使用的具有代表性的药物载体可以是固体或液体,通常以按照愿望给药的具体安排方式来选择。这样,固体载体的实例包括乳糖、蔗糖、明胶和琼脂,液体载体的实例包括水、糖浆、花生油和橄榄油。其它合适的载体是在药剂配方领域中那些技术人员所公知的。本发明的衍生物和载体相结合可以制成许多可接受的形式如:片剂、胶囊、栓剂、溶液、乳剂和粉剂。
以下实例说明本发明新的对映体的制备。
实例
Medetomidine(碱)14g溶于50ml甲醇,10.5g(+)-酒石酸溶于50ml甲醇,将两种溶液混合后,蒸发溶剂至体积为50ml,混合物注入冰浴中得到9g白色沉淀。将沉淀悬浮于25ml乙醇中,混合物置于超声波中14分钟然后过滤,用蒸汽浴加热将沉淀溶于20ml无水乙醇和60ml甲醇的混合物,冷却后得到5g沉淀(旋光度+55°),用60ml甲醇重结晶后得到4.1g产品,旋光度+60°。将产品进行反复重结晶直至旋光度不再增加为止。d-对映体酒石酸盐溶于水中,将溶液配制成硷性,d-对映体溶于有机溶剂如二氯甲烷或乙醚。d-对映体碱的旋光度为+75°。
d-对映体可以从母液中分离得到。
Claims (3)
1、一种分离Medetomidined和1对映体的方法,该方法包括将外消旋的Medetomidine通过与旋光性酸反应转化成非对映异构体盐混合物,然后通过分级结晶分离非对映异构体盐混合物。
2、按照权利要求1的方法,其中使用的旋光性酸是(+)-酒石酸。
3、一种制备药物组合物的方法,包括将Medetomidine的d-或l-对映体或它的无毒的药物上可接受的酸加成盐同药物载体相混合。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB8716803A GB2206880B (en) | 1987-07-16 | 1987-07-16 | Optical isomers of an imidazole derivative |
GB8716803 | 1987-07-16 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1030576A true CN1030576A (zh) | 1989-01-25 |
CN1022323C CN1022323C (zh) | 1993-10-06 |
Family
ID=10620775
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN88104440A Expired - Lifetime CN1022323C (zh) | 1987-07-16 | 1988-07-16 | 从外消旋体中分离咪唑衍生物的d-对映体的方法 |
Country Status (29)
Country | Link |
---|---|
US (1) | US4910214A (zh) |
EP (1) | EP0300652B1 (zh) |
JP (1) | JPH0625138B2 (zh) |
KR (1) | KR940007311B1 (zh) |
CN (1) | CN1022323C (zh) |
AT (1) | ATE71941T1 (zh) |
AU (1) | AU600839B2 (zh) |
BG (1) | BG60473B2 (zh) |
CA (1) | CA1337659C (zh) |
CY (2) | CY1787A (zh) |
DD (1) | DD281807A5 (zh) |
DE (2) | DE3867945D1 (zh) |
DK (1) | DK165788C (zh) |
ES (1) | ES2038757T3 (zh) |
FI (1) | FI95375C (zh) |
GB (1) | GB2206880B (zh) |
GR (1) | GR3003878T3 (zh) |
HK (1) | HK56094A (zh) |
HU (1) | HU198693B (zh) |
IE (1) | IE60456B1 (zh) |
IL (1) | IL87076A0 (zh) |
LU (1) | LU91010I2 (zh) |
NL (1) | NL300117I2 (zh) |
NO (2) | NO170579C (zh) |
NZ (1) | NZ225362A (zh) |
PT (1) | PT88013B (zh) |
SU (1) | SU1648248A3 (zh) |
UA (1) | UA5560A1 (zh) |
ZA (1) | ZA885134B (zh) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101671305A (zh) * | 2009-09-29 | 2010-03-17 | 北京华禧联合科技发展有限公司 | 一种拆分美托咪定的左旋及右旋对映体的方法 |
CN102464619A (zh) * | 2010-11-17 | 2012-05-23 | 桑迪亚医药技术(上海)有限责任公司 | 一种左旋4-[1-(2,3-二甲基苯基)乙基]-1r-咪唑消旋化方法 |
CN104797252B (zh) * | 2012-10-15 | 2016-09-21 | 奥赖恩公司 | 减轻噪音厌恶的兽医方法 |
CN114671811A (zh) * | 2022-04-14 | 2022-06-28 | 南京正科医药股份有限公司 | 一种右美托咪定拆分副产物的外消旋化回收方法 |
Families Citing this family (33)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2215206B (en) * | 1988-02-29 | 1991-07-03 | Farmos Oy | 4-substituted imidazole derivatives useful in perioperative care |
US5124157A (en) * | 1989-08-18 | 1992-06-23 | Cygnus Therapeutic Systems | Method and device for administering dexmedetomidine transdermally |
US5120713A (en) * | 1990-09-10 | 1992-06-09 | Applied Research Systems Ars Holding N.V. | Treatment of obesity with an alpha-2-adrenergic agonist and a growth hormone releasing peptide |
GB9111732D0 (en) * | 1991-05-31 | 1991-07-24 | Orion Yhtymae Oy | The use of certain salts of medetomidine and its optically active enantiomers to regulate the rate of transdermal administration of the drugs |
GB2281206A (en) * | 1993-08-25 | 1995-03-01 | Orion Yhtymae Oy | Use of dexmedetomidine |
GB9425211D0 (en) * | 1994-12-14 | 1995-02-15 | Ucb Sa | Substituted 1H-imidazoles |
IN187238B (zh) * | 1995-06-30 | 2002-03-09 | Astra Ab | |
GB9521680D0 (en) * | 1995-10-23 | 1996-01-03 | Orion Yhtymo Oy | New use of imidazole derivatives |
US5866579A (en) * | 1997-04-11 | 1999-02-02 | Synaptic Pharmaceutical Corporation | Imidazole and imidazoline derivatives and uses thereof |
US6716867B1 (en) | 1998-04-01 | 2004-04-06 | Orion Corporation | Use of dexmedetomidine for ICU sedation |
AR015744A1 (es) * | 1998-04-01 | 2001-05-16 | Orion Corp | Uso de dexmedetomidina para sedacion en terapia intensiva |
WO2001030347A1 (en) | 1999-10-29 | 2001-05-03 | Orion Corporation | Treatment or prevention of hypotension and shock |
US6388090B2 (en) * | 2000-01-14 | 2002-05-14 | Orion Corporation | Imidazole derivatives |
US7141597B2 (en) * | 2003-09-12 | 2006-11-28 | Allergan, Inc. | Nonsedating α-2 agonists |
EP1956906A4 (en) | 2005-11-09 | 2009-12-30 | Combinatorx Inc | METHODS, COMPOSITIONS AND KITS FOR THE TREATMENT OF PATHOLOGIES |
EP2428205B1 (en) | 2006-03-16 | 2012-10-03 | Tris Pharma, Inc. | Modified release formulations containing drug-ion exchange resin complexes |
US7795263B2 (en) * | 2008-07-08 | 2010-09-14 | Wildlife Laboratories, Inc. | Pharmaceutical combination for and method of anesthetizing and immobilizing non-domesticated mammals |
EP2370136A4 (en) * | 2008-12-01 | 2015-12-30 | Map Pharmaceuticals Inc | INHALATIVE RELEASE PROCEDURES AND DEVICES |
US8555875B2 (en) * | 2008-12-23 | 2013-10-15 | Map Pharmaceuticals, Inc. | Inhalation devices and related methods for administration of sedative hypnotic compounds |
KR101859486B1 (ko) * | 2009-05-15 | 2018-06-28 | 레크로파마, 인코포레이티드 | 설하용 덱스메데토미딘 조성물과 그의 사용 방법 |
US20130096170A1 (en) | 2011-10-14 | 2013-04-18 | Hospira, Inc. | Methods of treating pediatric patients using dexmedetomidine |
WO2013069025A1 (en) | 2011-11-11 | 2013-05-16 | Neon Laboratories Ltd. | "process for the preparation of dexmedetomidine" |
AU2012352528B9 (en) | 2011-12-11 | 2017-11-02 | Baudax Bio, Inc. | Intranasal dexmedetomidine compositions and methods of use thereof |
US8242158B1 (en) | 2012-01-04 | 2012-08-14 | Hospira, Inc. | Dexmedetomidine premix formulation |
ITMI20120311A1 (it) * | 2012-02-29 | 2013-08-30 | Edmond Pharma Srl | Procedimento per la risoluzione di medetomidina e recupero dell'enantiomero indesiderato |
CA2880456A1 (en) | 2012-08-15 | 2014-02-20 | Tris Pharma, Inc. | Methylphenidate extended release chewable tablet |
TWI709417B (zh) | 2013-10-07 | 2020-11-11 | 美商帝國製藥美國股份有限公司 | 使用右美托咪啶經皮組成物用於治療注意力不足過動症、焦慮及失眠的方法及組成物 |
EP3054930B1 (en) | 2013-10-07 | 2020-12-02 | Teikoku Pharma USA, Inc. | Methods and compositions for transdermal delivery of a non-sedative amount of dexmedetomidine |
US10772871B2 (en) | 2013-10-07 | 2020-09-15 | Teikoku Pharma Usa, Inc. | Dexmedetomidine transdermal delivery devices and methods for using the same |
CN105175339B (zh) * | 2015-10-09 | 2018-01-16 | 辰欣药业股份有限公司 | 一种制备盐酸右美托咪定的方法 |
US9717796B1 (en) | 2016-04-20 | 2017-08-01 | Slypharma, Llc | Heat sterilizeable, premixed, ready to use dexmedetomidine solution packaged in a flexible plastic container |
FR3054218B1 (fr) * | 2016-07-22 | 2020-03-06 | Universite De Rouen | Procede de dedoublement de sels de baclofene |
US11160791B2 (en) | 2018-11-01 | 2021-11-02 | Medefil, Inc. | Dexmedetomidine injection premix formulation in ready to use (RTU) bags |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU518569B2 (en) * | 1979-08-07 | 1981-10-08 | Farmos-Yhtyma Oy | 4-benzyl- and 4-benzoyl imidazole derivatives |
GB2092569B (en) * | 1981-02-05 | 1984-09-19 | Farmos Oy | Substituted imidazole derivatives and their preparation and use |
GB2101114B (en) * | 1981-07-10 | 1985-05-22 | Farmos Group Ltd | Substituted imidazole derivatives and their preparation and use |
FI844786A0 (fi) | 1984-12-04 | 1984-12-04 | Farmos Oy | Terapeutiskt utnyttjbar foerening. |
DE3531682A1 (de) * | 1985-09-05 | 1987-03-12 | Thomae Gmbh Dr K | (+)-6-chlor-5,10-dihydro-5-((1-methyl-4- piperidinyl)acetyl)-11h-dibenzo(b,e)(1,4) diazepin-11-on, seine isolierung und verwendung als arzneimittel |
-
1987
- 1987-07-16 GB GB8716803A patent/GB2206880B/en not_active Expired - Lifetime
-
1988
- 1988-06-14 FI FI882819A patent/FI95375C/fi active Protection Beyond IP Right Term
- 1988-06-28 UA UA4356076A patent/UA5560A1/uk unknown
- 1988-06-28 SU SU884356076A patent/SU1648248A3/ru active
- 1988-07-08 DE DE8888306250T patent/DE3867945D1/de not_active Expired - Lifetime
- 1988-07-08 DE DE2003199005 patent/DE10399005I2/de active Active
- 1988-07-08 ES ES198888306250T patent/ES2038757T3/es not_active Expired - Lifetime
- 1988-07-08 EP EP88306250A patent/EP0300652B1/en not_active Expired - Lifetime
- 1988-07-08 AT AT88306250T patent/ATE71941T1/de active
- 1988-07-11 DK DK386288A patent/DK165788C/da not_active IP Right Cessation
- 1988-07-11 NZ NZ225362A patent/NZ225362A/xx unknown
- 1988-07-11 AU AU18941/88A patent/AU600839B2/en not_active Expired
- 1988-07-12 IL IL87076A patent/IL87076A0/xx not_active IP Right Cessation
- 1988-07-14 CA CA000572086A patent/CA1337659C/en not_active Expired - Lifetime
- 1988-07-14 DD DD88317936A patent/DD281807A5/de not_active IP Right Cessation
- 1988-07-15 IE IE217488A patent/IE60456B1/en not_active IP Right Cessation
- 1988-07-15 ZA ZA885134A patent/ZA885134B/xx unknown
- 1988-07-15 NO NO883155A patent/NO170579C/no not_active IP Right Cessation
- 1988-07-15 HU HU883708A patent/HU198693B/hu unknown
- 1988-07-15 KR KR1019880008937A patent/KR940007311B1/ko not_active IP Right Cessation
- 1988-07-15 PT PT88013A patent/PT88013B/pt not_active IP Right Cessation
- 1988-07-15 US US07/219,637 patent/US4910214A/en not_active Expired - Lifetime
- 1988-07-16 CN CN88104440A patent/CN1022323C/zh not_active Expired - Lifetime
- 1988-07-16 JP JP63177959A patent/JPH0625138B2/ja not_active Expired - Lifetime
-
1992
- 1992-02-21 GR GR920400299T patent/GR3003878T3/el unknown
-
1994
- 1994-01-18 BG BG98380A patent/BG60473B2/bg unknown
- 1994-05-24 HK HK56094A patent/HK56094A/xx not_active IP Right Cessation
-
1995
- 1995-10-20 CY CY178795A patent/CY1787A/xx unknown
-
2003
- 2003-02-14 LU LU91010C patent/LU91010I2/fr unknown
- 2003-03-03 NL NL300117C patent/NL300117I2/nl unknown
- 2003-07-01 NO NO2003004C patent/NO2003004I2/no unknown
-
2004
- 2004-10-27 CY CY200400006C patent/CY2004006I1/el unknown
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101671305A (zh) * | 2009-09-29 | 2010-03-17 | 北京华禧联合科技发展有限公司 | 一种拆分美托咪定的左旋及右旋对映体的方法 |
CN102464619A (zh) * | 2010-11-17 | 2012-05-23 | 桑迪亚医药技术(上海)有限责任公司 | 一种左旋4-[1-(2,3-二甲基苯基)乙基]-1r-咪唑消旋化方法 |
CN104797252B (zh) * | 2012-10-15 | 2016-09-21 | 奥赖恩公司 | 减轻噪音厌恶的兽医方法 |
CN114671811A (zh) * | 2022-04-14 | 2022-06-28 | 南京正科医药股份有限公司 | 一种右美托咪定拆分副产物的外消旋化回收方法 |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1022323C (zh) | 从外消旋体中分离咪唑衍生物的d-对映体的方法 | |
CN1102388C (zh) | 用羟基咔唑化合物抑制平滑肌的移行与增生 | |
CN1081460C (zh) | 醛糖还原酶抑制剂用于制备减少与非心脏局部缺血有关的组织损伤的药物的用途 | |
CN1622805A (zh) | 包含止泻药和埃坡霉素或埃坡霉素衍生物的组合 | |
CN1048385A (zh) | 四唑类兴奋性氨基酸受体拮抗剂 | |
CN1543344A (zh) | 治疗尿失禁的芳基(或杂芳基)氮杂茂甲醇衍生物 | |
CN1161041A (zh) | 杂环稠合的类吗啡衍生物 | |
US20200215068A1 (en) | Treatment of type i and type ii diabetes | |
CN1226175A (zh) | 吸收促进剂 | |
CN1085979C (zh) | 麻药型镇痛剂依赖性/抗性形成抑制剂 | |
CN1077790C (zh) | 青光眼治疗剂及眼压降低剂 | |
CN1253151C (zh) | mGluR5拮抗剂用于治疗瘙痒症的用途 | |
CN1249682A (zh) | 用于治疗有症状的心力哀竭的血管紧张素ⅱ拮抗剂 | |
AU2001256685A1 (en) | Pharmaceutical compositions containing aminothiazole derivatives for the treatment of colonic motor dysfunctions | |
CN86100749A (zh) | 制备改进的抗炎药剂的方法 | |
CN1052305A (zh) | 新吡啶衍生物、含它们的药物组合物及其制备方法 | |
CN1434724A (zh) | 用于神经系统疾病的治疗和/或预防药物 | |
CN1033809A (zh) | 6-氯-4-羟基-2-甲基-N-(2-吡啶基)-2H-噻吩并(2,3-e)-1,2-噻嗪-3-羧基酰胺1,1-二氧化物烯醇醚类化合物,其制备方法及应用 | |
CA2264101A1 (en) | Preventives/remedies for muscle tissue degenerations | |
CN1031998C (zh) | [α-(叔丁基氨基甲基)-3,4-二氯苄基]硫代乙酰胺,其制备方法及应用 | |
CN1241558C (zh) | 阿替洛尔滴丸及其制备方法 | |
CN1262099A (zh) | 阿苯达唑乳剂 | |
CN1268395C (zh) | 慢性肾脏疾病治疗药物 | |
CN1079395C (zh) | N-乙酰-5,6-二甲氧基色胺的生产方法 | |
CN1589154A (zh) | 含有血管紧张肽ii受体拮抗剂的药用组合物 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
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) | ||
OR01 | Other related matters | ||
C17 | Cessation of patent right | ||
CX01 | Expiry of patent term |