WO1997015302A1 - Pharmaceutical compositions of levo-enantiomers of medetomidine derivatives and their use - Google Patents
Pharmaceutical compositions of levo-enantiomers of medetomidine derivatives and their use Download PDFInfo
- Publication number
- WO1997015302A1 WO1997015302A1 PCT/FI1996/000560 FI9600560W WO9715302A1 WO 1997015302 A1 WO1997015302 A1 WO 1997015302A1 FI 9600560 W FI9600560 W FI 9600560W WO 9715302 A1 WO9715302 A1 WO 9715302A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- adrenergic
- receptors
- drug
- levo
- treatment
- Prior art date
Links
Classifications
-
- 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
- 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
- A61K31/4164—1,3-Diazoles
-
- 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
-
- 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
- A61P13/08—Drugs for disorders of the urinary system of the prostate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones
-
- 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
-
- 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
- A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
Definitions
- the invention is related to the use of the levo-enantiomers of certain imidazole derivatives in the prevention or treatment of conditions associated with overexpression or hypersensitization of adrenergic ⁇ -2 receptors as well as in the diagnosis of such conditions.
- the invention is also related to pharmaceutical compositions containing such imidazole derivatives.
- the imidazole derivatives used in the invention are either the levo- enantiomers of the compounds of formula I
- is C-
- C NHNH2
- C NHNHCH(C6H6)CH3 or physiologically acceptable esters or salts thereof with the proviso that more than one of the substituents R2 to R4 are not at the same time
- C NHNHCH(C6H6)CH3.
- Preferred compounds are those in which R-j is methyl and R2, R3 and R4 are each independently hydrogen, C *
- the levo-enantiomer of medetomidine is particularly preferred.
- the levo-enantiomers of the imidazole derivative of the formula I are true inverse agonists of adrenergic ⁇ - 2 receptors.
- the compounds of the invention may be used in the prevention or treatment of conditions associated with overexpression or hypersensitization of adrenergic ⁇ -2 receptors.
- an inverse agonist is a drug that by binding to receptors reduces their fraction in active conformation (Jenkins, D.H., et al., 1995, Pharmacol. Rev., 47, 255).
- Inverse agonists may be particularly important in disease states and in pathogenesis which result from mutations in constitutively activated receptors. Inverse agonists, therefore, represent an important and specific therapeutic approach for such disease states.
- a true inverse agonist like a compound of the invention reduces receptor activation state and, therefore, represent the key to the above described targeted agents to diagnose, prevent or treat disease states related to constitutively active receptors.
- Inverse agonists of adrenergic ⁇ -2 receptors can be used in the treatment of disease states associated with increased receptor number or sensitivity either alone or together with adrenergic ⁇ -2 receptor agonists or adrenergic ⁇ -2 receptor antagonists as conventionally defined.
- True inverse agonists of adrenergic ⁇ -2 receptors can be used to treat Raynaud phenomenon (Coffman, J.D. and Cohen, R.A., J. Vase.
- adrenergic ⁇ -2 receptors such as treatment of depression with mianserin or shcizophrenia with olenzapine or clozapine, treatment of rheumathoid arthritis or asthma with dexamethasone or other steroids, or treatment of hypertension with reserpine or other sympatholytics.
- the amount of the corresponding dextro enantiomer i.e. the agonist
- the amount of the corresponding dextro enantiomer is not so high that it interferes with or even neutralises the action of the inverse agonist.
- the maximum amount of the dextro enantiomer depends, of course, on the properties of the two enantiomers in each case and it is believed that the amount can be calculated without undue experimentation by a person having average skill in the art.
- the maximum amount of dexmedetomidine is about 0.3 weight percent of the total amount of both enantiomers, preferably 0.1 percent by weight.
- the compounds of the invention may be formulated alone or together with another active ingredient and a pharmaceutically acceptable diluent or carrier to different pharmaceutical unit dosage forms i.e. tablets, capsules, solutions, ointments, emulsions, lotions, gels, creams, patches and powders etc. using conventional techniques. Especially preferable are formulations which may be administered transdermally.
- solid ingredients may include e.g. sugars and sugar alcohols such as lactose, glucose, sucrose, dextrose, mannitol and sorbitol, starch, cellulose and its derivatives, alginates, synthetic polymers such as polyvinylpyrrolidone, talc, stearic acid salts and its derivatives, while liquid ingredients typically include water, polyhydric alcohols such as glycerol, propylene glycol and polyethylene glycols, mineral oil and vegetable oils.
- sugars and sugar alcohols such as lactose, glucose, sucrose, dextrose, mannitol and sorbitol
- starch cellulose and its derivatives
- cellulose and its derivatives alginates
- synthetic polymers such as polyvinylpyrrolidone, talc, stearic acid salts and its derivatives
- liquid ingredients typically include water, polyhydric alcohols such as glycerol, propylene glycol and polyethylene glycols, mineral oil and vegetable oils
- Ingredients for semi-solid products may include above mentioned ingredients and further lanolin, paraffin wax, polyethylene waxes, plant waxes, beeswax, xanthan gum, long-chained alcohols and fatty-acids, carboxyvinyl polymers, sodium lauryl sulphate, sorbitan esters, polyoxyethylene sorbitan esters as well as polyoxyethylene glycol esters.
- the amount of the active ingredient varies from 0.001 to 75 weight %, prefeferably 0.01 to 10 weight % depending on the type of the dosage form.
- Transdermal patches for the compounds of the invention may be prepared, for example, as described in PCT Patent application WO 91/02505 for dexmedetomidine (free base) and in PCT Patent application WO 92/21338 for medetomidine (salt).
- the appropriate dosage for the compounds of the invention depends on several factors such as the compound to be administrated, the species, age and the sex of the subject to be treated, the condition to be treated and on the method of administration. Accordingly, the dosage for parenteral administration is typically from 0.5 ⁇ g/kg to 10 mg/kg per day and that for oral administration is from 5 ⁇ g/kg to 100 mg/kg for an adult male human. Preparation of levomedetomidine
- the (-)-enantiomer of medetomidine can be resolved in the same way as dexmedetomidine (EP 300 652 B1), but instead of using L-(+)-tartaric acid as a resolving agent, D-(-)-tartaric acid can be used to give the D-(-)-tartaric acid adduct of the (-)-enantiomer.
- the purity of the tartrate of the l-enantiomer can be checked e.g. by HPLC so that the recrystallizations are repeated until the content of dexmedetomidine is below 0.3 weight percent of the total amount of both enantiomers.
- the free base and the corresponding hydrochloride can be made using conventional techniques.
- HEL human erythroleukemia
- HEL cells have a adrenergic ⁇ -2 receptor suptype that activate pertussis toxin-sensitive G-protein resulting in Ca 2+ mobilization, via non-selective cation channels, and inhibition of adenylyl cyclase. This system was used to screen different adrenergic ⁇ -2 receptor agonists for functional purposes. Measurement of intracellular Ca 2+
- the intracellular free Ca 2+ concentrations in HEL cells was determined using fura-2 (Grynkiewicz, G. et al, J. biol. Chem. 260, 3440) as described by Kukkonen et al. (1992, J. Pharmacol. Exp. Ther. 263, 1487).
- the cells were loaded with fura-2/AM (Molecular probes, Junction City, USA).
- the cell suspension was then placed in a quartzmicrocuvette and fluorescence measurements were performed with a Hitachi F-2000 fluorescence spectrofotometer at the wavelengths of 340 nm (emission) and 505 nm (excitation).
- the dye responses were calibrated by sequential addition of digitonin and EGTA at the end of the experiment to obtain maximal and minimal fluorescence values, respectively.
- a typical transdermal formulation (a cream) of levomedetomidine may be prepepared as follows:
- emulsifier such as sodium lauryl sulphate, sodium cetostearyl sulphate, polyethylene glycols and glycol stearate, polyethylene glycol glyceryl oleate or laurate or linoleate 0 - 30 w %, preferably 2 - 20 w % of consistency agent, such as cetearyl alcohol, glyceryl stearates
- preservative such as methyl-, ethyl, propyl- and butylparahydroxybenzoate and phenoxyethanol 30 - 90 w %, preferably 60 - 85 w % of purified water
- emulsifiers emollients and consistency agents are melted.
- Preservatives are dissolved by boiling in purified water (a part) in another vessel. Both liquids are adjusted into same temperature (about 80 °C) and combined in a manufacturing vessel. The mixture is homogenized and allowed to cool to 35 °C by continuous mixing under a vacuum. The active ingredient is dissolved in purified water (the rest) and added into the manufacturing vessel. The cream is homogenized and then cooled to room temperature by continuous mixing under a vacuum.
Landscapes
- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Diabetes (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Epidemiology (AREA)
- Obesity (AREA)
- Hematology (AREA)
- Urology & Nephrology (AREA)
- Endocrinology (AREA)
- Emergency Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Saccharide Compounds (AREA)
- Epoxy Resins (AREA)
Abstract
Description
Claims
Priority Applications (13)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
SK486-98A SK48698A3 (en) | 1995-10-23 | 1996-10-23 | Use of imidazole derivative and pharmaceutical composition containing the same |
AT96934847T ATE218340T1 (en) | 1995-10-23 | 1996-10-23 | USE OF LEVO-ENANTIOMERS OF MEDETOMIDINE |
AU73019/96A AU707728B2 (en) | 1995-10-23 | 1996-10-23 | Pharmaceutical compositions of levo-enantiomers of medetomidine derivatives and their use |
JP9516319A JP2000503298A (en) | 1995-10-23 | 1996-10-23 | Pharmaceutical compositions and uses of levoenantiomers of medetomidine derivatives |
EP96934847A EP0858338B1 (en) | 1995-10-23 | 1996-10-23 | Use of levo-enantiomers of medetomidine derivatives |
US09/043,107 US5994384A (en) | 1995-10-23 | 1996-10-23 | Pharmaceutical compositions of levo-enantiomers of medetomidine derivatives and their use |
DE69621633T DE69621633T2 (en) | 1995-10-23 | 1996-10-23 | USE OF LEVO ENANTIOMERS OF MEDETOMIDIN |
NZ320289A NZ320289A (en) | 1995-10-23 | 1996-10-23 | Pharmaceutical compositions of levo-enantiomers of medetomidine derivatives and their use |
EE9800131A EE9800131A (en) | 1995-10-23 | 1996-10-23 | Pharmaceutical compositions of levoenantiomers of medetomidine derivatives and their use |
KR1019980702944A KR19990067008A (en) | 1995-10-23 | 1996-10-23 | Pharmaceutical Compositions Containing Left-Rotational Enantiomers of Medetomidine Derivatives and Uses thereof |
IL12399996A IL123999A (en) | 1995-10-23 | 1996-10-23 | Use of an imidazole derivative in the manufacture of a medicament |
BG102396A BG102396A (en) | 1995-10-23 | 1998-04-21 | Pharmaceutical compositions containing leioenantiomers of medetomidine derivatives, and their application |
NO981799A NO981799L (en) | 1995-10-23 | 1998-04-22 | Pharmaceutical surface mixtures of levo-enantiomers of medetomidine derivatives and their use |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB9521680.0 | 1995-10-23 | ||
GBGB9521680.0A GB9521680D0 (en) | 1995-10-23 | 1995-10-23 | New use of imidazole derivatives |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1997015302A1 true WO1997015302A1 (en) | 1997-05-01 |
Family
ID=10782758
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/FI1996/000560 WO1997015302A1 (en) | 1995-10-23 | 1996-10-23 | Pharmaceutical compositions of levo-enantiomers of medetomidine derivatives and their use |
Country Status (22)
Country | Link |
---|---|
US (1) | US5994384A (en) |
EP (1) | EP0858338B1 (en) |
JP (1) | JP2000503298A (en) |
KR (1) | KR19990067008A (en) |
CN (1) | CN1200035A (en) |
AT (1) | ATE218340T1 (en) |
AU (1) | AU707728B2 (en) |
BG (1) | BG102396A (en) |
CA (1) | CA2232336A1 (en) |
CZ (1) | CZ120498A3 (en) |
DE (1) | DE69621633T2 (en) |
EE (1) | EE9800131A (en) |
ES (1) | ES2178717T3 (en) |
GB (1) | GB9521680D0 (en) |
HU (1) | HUP9900027A3 (en) |
IL (1) | IL123999A (en) |
NO (1) | NO981799L (en) |
NZ (1) | NZ320289A (en) |
PL (1) | PL326562A1 (en) |
RU (1) | RU2193404C2 (en) |
SK (1) | SK48698A3 (en) |
WO (1) | WO1997015302A1 (en) |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6329369B1 (en) | 1997-12-04 | 2001-12-11 | Allergan Sales, Inc. | Methods of treating pain and other conditions |
US6841684B2 (en) | 1997-12-04 | 2005-01-11 | Allergan, Inc. | Imidiazoles having reduced side effects |
US8158668B2 (en) | 2006-01-27 | 2012-04-17 | Hoffmann-La Roche Inc. | Methods for treating CNS disorders with 4-imidazole derivatives |
EP3054934A1 (en) * | 2013-10-07 | 2016-08-17 | Teikoku Pharma USA, Inc. | Methods and compositions for treating withdrawal syndromes using non-sedative dexmedetomidine transdermal compositions |
KR101831536B1 (en) | 2013-07-24 | 2018-04-04 | 아이-테크 에이비 | Use of the enantiomer levomedetomidine as inhibitor for marine biofouling of surfaces |
Families Citing this family (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000076502A1 (en) * | 1999-06-11 | 2000-12-21 | The Ohio State University Research Foundation | Methods and compositions for treating raynaud's phenomenon and scleroderma |
US6444681B1 (en) | 2000-06-09 | 2002-09-03 | The Ohio State University Research Foundation | Methods and compositions for treating Raynaud's Phenomenon and scleroderma |
NZ527142A (en) * | 2003-07-23 | 2006-03-31 | Douglas Pharmaceuticals Ltd | A stable suspension formulation |
CN101671305A (en) * | 2009-09-29 | 2010-03-17 | 北京华禧联合科技发展有限公司 | Method for resolution of levorotatory enantiomer and dexiotropic enantiomer of medetomidine |
WO2013078151A1 (en) | 2011-11-21 | 2013-05-30 | Allergan, Inc. | Pharmaceutical compositions comprising 4-[1-(2,3-dimethylphenyl)ethyl]-3h-imidazole derivatives for treating retinal diseases |
TWI629066B (en) | 2013-10-07 | 2018-07-11 | 帝國製藥美國股份有限公司 | Methods and compositions for treating attention deficit hyperactivity disorder, anxiety and insomnia using dexmedetomidine transdermal compositions |
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 |
EP3054932B1 (en) | 2013-10-07 | 2020-12-09 | Teikoku Pharma USA, Inc. | Dexmedetomidine transdermal delivery devices and methods for using the same |
CN106442765A (en) * | 2016-08-31 | 2017-02-22 | 辰欣药业股份有限公司 | Method for detecting isomers of dexmedetomidine hydrochloride crude product |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0300652A1 (en) * | 1987-07-16 | 1989-01-25 | Orion-Yhtymà Oy | Optical isomer of an imidazole derivative |
WO1992021338A1 (en) * | 1991-05-31 | 1992-12-10 | Orion-Yhtymä Oy | Medetomidine preparations for transdermal administration |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2101114B (en) * | 1981-07-10 | 1985-05-22 | Farmos Group Ltd | Substituted imidazole derivatives and their preparation and use |
GB8626287D0 (en) * | 1986-11-04 | 1986-12-03 | Ucb Sa | Substituted 1h-imidazoles |
GB8810067D0 (en) * | 1988-04-28 | 1988-06-02 | Ucb Sa | Substituted 1-(1h-imidazol-4-yl)alkyl-benzamides |
US5124157A (en) * | 1989-08-18 | 1992-06-23 | Cygnus Therapeutic Systems | Method and device for administering dexmedetomidine transdermally |
WO1992004054A1 (en) * | 1990-08-30 | 1992-03-19 | STATE OF OREGON, acting by and through THE OREGON STATE BOARD OF HIGHER EDUCATION, acting for and on behalf of THE OREGON HEALTH SCIENCES UNIVERSITY, PORTLAND, OREGON, and THE UNIVERSITY OF OREGON, EUGENE, OREGON, Johnson Hall, University of Oregon | Substituted amidines having high binding to the sigma receptor and the use thereof |
GB9310965D0 (en) * | 1993-05-27 | 1993-07-14 | Ucb Sa | 2-hydroxy-3-(1h-imidazol-4-yl)alkyl)benzenecarboximidamides |
-
1995
- 1995-10-23 GB GBGB9521680.0A patent/GB9521680D0/en active Pending
-
1996
- 1996-10-23 NZ NZ320289A patent/NZ320289A/en unknown
- 1996-10-23 KR KR1019980702944A patent/KR19990067008A/en not_active Application Discontinuation
- 1996-10-23 CZ CZ981204A patent/CZ120498A3/en unknown
- 1996-10-23 CA CA002232336A patent/CA2232336A1/en not_active Abandoned
- 1996-10-23 PL PL96326562A patent/PL326562A1/en unknown
- 1996-10-23 SK SK486-98A patent/SK48698A3/en unknown
- 1996-10-23 JP JP9516319A patent/JP2000503298A/en active Pending
- 1996-10-23 WO PCT/FI1996/000560 patent/WO1997015302A1/en not_active Application Discontinuation
- 1996-10-23 EP EP96934847A patent/EP0858338B1/en not_active Expired - Lifetime
- 1996-10-23 AT AT96934847T patent/ATE218340T1/en not_active IP Right Cessation
- 1996-10-23 DE DE69621633T patent/DE69621633T2/en not_active Expired - Fee Related
- 1996-10-23 HU HU9900027A patent/HUP9900027A3/en unknown
- 1996-10-23 CN CN96197793A patent/CN1200035A/en active Pending
- 1996-10-23 US US09/043,107 patent/US5994384A/en not_active Expired - Fee Related
- 1996-10-23 ES ES96934847T patent/ES2178717T3/en not_active Expired - Lifetime
- 1996-10-23 AU AU73019/96A patent/AU707728B2/en not_active Ceased
- 1996-10-23 IL IL12399996A patent/IL123999A/en not_active IP Right Cessation
- 1996-10-23 EE EE9800131A patent/EE9800131A/en unknown
- 1996-10-23 RU RU98109949/14A patent/RU2193404C2/en not_active IP Right Cessation
-
1998
- 1998-04-21 BG BG102396A patent/BG102396A/en unknown
- 1998-04-22 NO NO981799A patent/NO981799L/en unknown
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0300652A1 (en) * | 1987-07-16 | 1989-01-25 | Orion-Yhtymà Oy | Optical isomer of an imidazole derivative |
WO1992021338A1 (en) * | 1991-05-31 | 1992-12-10 | Orion-Yhtymä Oy | Medetomidine preparations for transdermal administration |
Non-Patent Citations (2)
Title |
---|
J.M. SAVOLA: "Cardiovascular actions of medetomidine and their reversal by atipamezole.", ACTA VET. SCAND.,SUPPL., vol. 85, 1989, pages 39 - 47, XP000618077 * |
M. HONG ET AL: "Stereoselective effects of central alpha2-adrenergic agonist medetomidine on in vivo catechol activity in the rat rostral ventrolateral medulla.", BRAIN RES., vol. 592, no. 1-2, 1992, pages 163 - 169, XP000617961 * |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6329369B1 (en) | 1997-12-04 | 2001-12-11 | Allergan Sales, Inc. | Methods of treating pain and other conditions |
US6841684B2 (en) | 1997-12-04 | 2005-01-11 | Allergan, Inc. | Imidiazoles having reduced side effects |
US8158668B2 (en) | 2006-01-27 | 2012-04-17 | Hoffmann-La Roche Inc. | Methods for treating CNS disorders with 4-imidazole derivatives |
KR101831536B1 (en) | 2013-07-24 | 2018-04-04 | 아이-테크 에이비 | Use of the enantiomer levomedetomidine as inhibitor for marine biofouling of surfaces |
EP3054934A1 (en) * | 2013-10-07 | 2016-08-17 | Teikoku Pharma USA, Inc. | Methods and compositions for treating withdrawal syndromes using non-sedative dexmedetomidine transdermal compositions |
EP3054934A4 (en) * | 2013-10-07 | 2017-04-05 | Teikoku Pharma USA, Inc. | Methods and compositions for treating withdrawal syndromes using non-sedative dexmedetomidine transdermal compositions |
Also Published As
Publication number | Publication date |
---|---|
NO981799D0 (en) | 1998-04-22 |
HUP9900027A2 (en) | 1999-04-28 |
EP0858338A1 (en) | 1998-08-19 |
SK48698A3 (en) | 1999-03-12 |
EP0858338B1 (en) | 2002-06-05 |
US5994384A (en) | 1999-11-30 |
RU2193404C2 (en) | 2002-11-27 |
PL326562A1 (en) | 1998-09-28 |
ES2178717T3 (en) | 2003-01-01 |
CN1200035A (en) | 1998-11-25 |
CA2232336A1 (en) | 1997-05-01 |
BG102396A (en) | 1999-01-29 |
HUP9900027A3 (en) | 1999-11-29 |
IL123999A (en) | 2002-09-12 |
EE9800131A (en) | 1998-10-15 |
GB9521680D0 (en) | 1996-01-03 |
NO981799L (en) | 1998-04-22 |
DE69621633D1 (en) | 2002-07-11 |
AU707728B2 (en) | 1999-07-15 |
JP2000503298A (en) | 2000-03-21 |
KR19990067008A (en) | 1999-08-16 |
CZ120498A3 (en) | 1998-09-16 |
ATE218340T1 (en) | 2002-06-15 |
DE69621633T2 (en) | 2003-02-06 |
NZ320289A (en) | 1999-08-30 |
AU7301996A (en) | 1997-05-15 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US5994384A (en) | Pharmaceutical compositions of levo-enantiomers of medetomidine derivatives and their use | |
Ameri | The effects of Aconitum alkaloids on the central nervous system | |
LESCH et al. | Corticotropin and cortisol secretion after central 5-hydroxytryptamine-1A (5-HT1A) receptor activation: effects of 5-HT receptor and β-adrenoceptor antagonists | |
JPH0625138B2 (en) | Optical isomers of imidazole derivatives | |
KR19990067527A (en) | Use of efinastin for the treatment of pain | |
AU2009219546A1 (en) | Kit, composition, product or medicament for treating cognitive impairment | |
US20020045566A1 (en) | Selective maxi-K potassium channel openers functional under conditions of high intracellular calcium concentration, methods and uses thereof | |
JP3464230B2 (en) | Pyridazinedione compound, pharmaceutical composition for treating neuropathy containing the compound, method for treating animal neuropathy, and method for producing the compound | |
JP2007502297A (en) | Treatment of sleep disorders with cholinesterase inhibitors | |
WO2001012195A2 (en) | Use of morphine derivatives as medicaments for the treatment of neuropathic problems | |
KR20150115809A (en) | Isometheptene isomer | |
HRP20010403A2 (en) | Composition containing an analgesic and a xanthine or a xanthine derivative | |
EP3849976B1 (en) | A gaba a receptor ligand | |
Routledge et al. | In vivo characterization of the putative 5-HT1A receptor antagonist SDZ 216,525 using two models of somatodendritic 5-HT1A receptor function | |
Meyer et al. | Pharmacokinetics and first clinical experiences with an antihypertensive dopamine (DA2) agonist | |
Segura et al. | The influence of structure on the accumulation of caffeine induced by methyl xanthine derivatives | |
Pozza et al. | Electrophysiological characterization of CGP6873OA a N-methyl-D-aspartate antagonist acting at the strychnine-insensitive glycine site | |
EP1303277B1 (en) | Pharmaceutical composition based on cocaethylene and use thereof for treating psychoactive substance dependence | |
ES2532479T3 (en) | Agents for the treatment of migraine | |
Górska et al. | Influence of mianserin on the activity of some hypotensive drugs in spontaneously hypertensive rats | |
DE2518677A1 (en) | NEW PHARMACEUTICAL PREPARATIONS | |
WO1997047293A1 (en) | Use of preparations containing opiate antagonists and agonists for the prevention and therapeutic treatment of migraines | |
EA042675B1 (en) | GABA-A RECEPTOR LIGAND | |
Kar | Indian Pharmacological Society | |
AU2014200818A1 (en) | Kit, composition, product or medicament for treating cognitive impairment |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
WWE | Wipo information: entry into national phase |
Ref document number: 96197793.0 Country of ref document: CN |
|
AK | Designated states |
Kind code of ref document: A1 Designated state(s): AL AM AT AU AZ BA BB BG BR BY CA CH CN CZ DE DK EE ES FI GB GE HU IL IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK TJ TM TR TT UA UG US UZ VN AM AZ BY KG KZ MD RU TJ TM |
|
AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): KE LS MW SD SZ UG AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI |
|
DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
ENP | Entry into the national phase |
Ref document number: 2232336 Country of ref document: CA Ref document number: 2232336 Country of ref document: CA Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: 320289 Country of ref document: NZ Ref document number: 48698 Country of ref document: SK |
|
WWE | Wipo information: entry into national phase |
Ref document number: PV1998-1204 Country of ref document: CZ |
|
WWE | Wipo information: entry into national phase |
Ref document number: 1996934847 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 98-00886 Country of ref document: RO |
|
WWE | Wipo information: entry into national phase |
Ref document number: 1019980702944 Country of ref document: KR Ref document number: PA/A/1998/003176 Country of ref document: MX |
|
WWP | Wipo information: published in national office |
Ref document number: 1996934847 Country of ref document: EP |
|
REG | Reference to national code |
Ref country code: DE Ref legal event code: 8642 |
|
WWE | Wipo information: entry into national phase |
Ref document number: 09043107 Country of ref document: US |
|
WWP | Wipo information: published in national office |
Ref document number: PV1998-1204 Country of ref document: CZ |
|
WWP | Wipo information: published in national office |
Ref document number: 1019980702944 Country of ref document: KR |
|
WWG | Wipo information: grant in national office |
Ref document number: 1996934847 Country of ref document: EP |
|
WWR | Wipo information: refused in national office |
Ref document number: 1019980702944 Country of ref document: KR |
|
WWR | Wipo information: refused in national office |
Ref document number: PV1998-1204 Country of ref document: CZ |