EP2227464A1 - Derivate von 1-[(imidazolidin-2-yl)imino]indazol - Google Patents

Derivate von 1-[(imidazolidin-2-yl)imino]indazol

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Publication number
EP2227464A1
EP2227464A1 EP08857024A EP08857024A EP2227464A1 EP 2227464 A1 EP2227464 A1 EP 2227464A1 EP 08857024 A EP08857024 A EP 08857024A EP 08857024 A EP08857024 A EP 08857024A EP 2227464 A1 EP2227464 A1 EP 2227464A1
Authority
EP
European Patent Office
Prior art keywords
compound
hydrogen
imidazolidin
imino
mol
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.)
Withdrawn
Application number
EP08857024A
Other languages
English (en)
French (fr)
Inventor
Franciszek Saczewski
Apolonia Rybczynska
Anita Kornicka
Jaroslaw Saczewski
Daqing Ma
Mervyn Maze
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ip2ipo Innovations Ltd
Medical Uniwersity of Gdansk
Original Assignee
Imperial Innovations Ltd
Medical Uniwersity of Gdansk
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Imperial Innovations Ltd, Medical Uniwersity of Gdansk filed Critical Imperial Innovations Ltd
Publication of EP2227464A1 publication Critical patent/EP2227464A1/de
Withdrawn legal-status Critical Current

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Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D403/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/06Anti-spasmodics, e.g. drugs for colics, esophagic dyskinesia
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/12Antidiarrhoeals
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00Drugs for disorders of the muscular or neuromuscular system
    • A61P21/02Muscle relaxants, e.g. for tetanus or cramps
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/30Drugs for disorders of the nervous system for treating abuse or dependence
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/30Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/32Alcohol-abuse
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/30Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/36Opioid-abuse
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00Drugs for disorders of the senses
    • A61P27/02Ophthalmic agents
    • A61P27/06Antiglaucoma agents or miotics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00Antiparasitic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • A61P9/12Antihypertensives

Definitions

  • the invention relates to novel derivatives of l-[(imidazolidin-2-yl)imino)]indazole and their use as highly selective agonists of ⁇ 2 /Ii receptors.
  • the compounds find use as antihypertensive agents.
  • they have also been found to have sedative and cytoprotective activity and can be co-administered with drugs such as benzodiazepines allowing lower dosages of the latter to be used to obtain their effect.
  • ⁇ -Adrenoceptors are widely expressed in many tissue types and mediate a multitude of functions in both peripheral organs and within the central nervous system, and the ⁇ 2 - adrenoceptor agonists represent a unique class of compounds due to a wide range of medicinal uses reported in the literature. 1"5
  • activation of central ⁇ 2 - adrenoceptors in the brain stem has been utilized clinically for many years in the treatment of hypertension. 2 ' 3
  • this original explanation has later been challenged by a concurrent 'imidazoline hypothesis' which assumes the existence of the imidazoline receptors and attributes the sympathoinhibition to activation of Ij imidazoline receptors in the medulla oblongata. 6"10
  • ⁇ 2 -adrenoceptor agonists including prototypical clonidine
  • Ij imidazoline receptors it is still difficult to dissociate imidazoline receptors from ⁇ 2 -adrenoceptors both pharmacologically and functionally.
  • ⁇ 2 -adrenoceptors and imidazoline receptors usually co-localize in the central nervous system which raises a question as to whether a link between these two types might exist.
  • Derivatives of 4-(2-imidazolin-2-ylamino)-lH-indazole are known in the art (for example Swiss patent No. 579076, German patent No. 2416024, US patent No. 4036976), derivatives of 6-(imidazolin-2-ylamino)indazole (US patent No. 4436913), derivatives of 6-(imidazolin- 2-ylamino)indazole (patent WO 98/23609) and derivatives of 7-(imidazolin-2- ylamino)indazole (German patent No. 2258318). These compounds are characterized by antihypertensive activity.
  • Derivatives of 6-(imidazolin-2-ylamino)indazole which are ⁇ 2 - adrenergic receptor agonists, are also known from WO 98/23609.
  • the present invention provides l-[(imidazolidin-2-yl)imino)]indazole compounds of the formula I:
  • R 1 denotes hydrogen, methyl or phenyl
  • R 2 , R 3 , R 4 and R 5 denote hydrogen, halogen preferably a chlorine atom, alkyl preferably methyl or alkoxyl preferably methoxyl; m isO or 1 ; and HX denotes sulfuric, phosphoric, acetic, malonic, fumaric, oxalic, lactic, tartaric, citric, gluconic, /Moluenesulfonic, methanesulfonic acid, hydrogen bromide or hydrogen iodide, preferably hydrogen chloride.
  • R 1 denotes hydrogen, methyl or phenyl
  • R 2 , R 3 , R 4 and R 5 denote hydrogen, halogen preferably a chlorine atom, alkyl preferably methyl or alkoxyl preferably methoxyl, represent a second aspect of the invention.
  • R 1 denotes hydrogen, methyl or phenyl
  • R 2 , R 3 , R 4 and R 5 denote hydrogen, halogen preferably a chlorine atom, alkyl preferably methyl or alkoxyl preferably methoxyl is reacted with N,N'-di(tert- butoxycarbonyl)imidazolidine-2-thione in an environment of anhydrous dimethylformamide in the presence of triethylamine and mercury chloride.
  • the precipitate of inorganic salts is filtered and the filtrate is washed with a saturated aqueous solution of sodium chloride and after drying the organic fraction over MgSO 4 the ethyl acetate is distilled off under reduced pressure, whereas the oily, relatively dry residue is separated on silica gel.
  • compounds of formula I can be prepared by reacting corresponding 1-aminoindazoles with tert-butyl 2-(methylthio)-4,5-dihydroimidazole-l-carboxylate using a slightly modified procedure described previously for the synthesis of guanidine derivatives ( S. R. Mundla, L. J. Wilson, S. R. Klopfenstein, W. L. Seibel, N. N. Nikolaides; A novel method for the efficient synthesis of 2-arylamino-2-imidazolines; Tetrahedron Lett., 2000, 41, 6563).
  • the present invention provides a compound of formula I as defined herein for use in medicine.
  • the present invention provides a pharmaceutical formulation comprising at least one compound of formula I or as defined herein and optionally one or more excipients, carriers or diluents.
  • compositions of the invention may be presented in unit dose forms containing a predetermined amount of each active ingredient per dose.
  • a unit may be adapted to provide 5-lOOmg/day of the compound, preferably either 5-15mg/day, 10-30mg/day, 25- 50mg/day 40-80mg/day or 60-100mg/day.
  • doses in the range 100-lOOOmg/day are provided, preferably either 100-400mg/day, 300-600mg/day or 500- lOOOmg/day.
  • Such doses can be provided in a single dose or as a number of discrete doses. The ultimate dose will depend on the condition being treated, the route of administration and the age, weight and condition of the patient and will be at the doctor's discretion.
  • compositions of the invention may be adapted for administration by any appropriate route, for example by the oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) route.
  • oral including buccal or sublingual
  • rectal nasal
  • topical including buccal, sublingual or transdermal
  • vaginal or parenteral including subcutaneous, intramuscular, intravenous or intradermal
  • parenteral including subcutaneous, intramuscular, intravenous or intradermal route.
  • Such formulations may be prepared by any method known in the art of pharmacy, for example by bringing into association the active ingredient with the carrier(s) or excipient(s).
  • compositions adapted for oral administration may be presented as discrete units such as capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or whips; or oil-in-water liquid emulsions or water-in-oil liquid emulsions.
  • compositions adapted for transdermal administration may be presented as discrete patches intended to remain in intimate contact with the epidermis of the recipient for a prolonged period of time.
  • the active ingredient may be delivered from the patch by iontophoresis as generally described in Pharmaceutical Research, 3(6), 318 (1986).
  • compositions adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.
  • the formulations are preferably applied as a topical ointment or cream.
  • the active ingredient may be employed with either a paraff ⁇ nic or a water-miscible ointment base.
  • the active ingredient may be formulated in a cream with an oil- in-water cream base or a water-in-oil base.
  • compositions adapted for topical administration to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent.
  • Pharmaceutical formulations adapted for topical administration in the mouth include lozenges, pastilles and mouth washes.
  • compositions adapted for rectal administration may be presented as suppositories or enemas.
  • compositions adapted for nasal administration wherein the carrier is a solid include a coarse powder having a particle size for example in the range 20 to 500 microns which is administered in the manner in which snuff is taken, i.e. by rapid inhalation through the nasal passage from a container of the powder held close up to the nose.
  • Suitable formulations wherein the carrier is a liquid, for administration as a nasal spray or as nasal drops, include aqueous or oil solutions of the active ingredient.
  • Fine particle dusts or mists which may be generated by means of various types of metered dose pressurised aerosols, nebulizers or insufflators.
  • compositions adapted for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations.
  • compositions adapted for parenteral administration include aqueous and nonaqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.
  • Preferred unit dosage formulations are those containing a daily dose or sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient. It should be understood that in addition to the ingredients particularly mentioned above, the formulations may also include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavouring agents.
  • the invention also relates to the use of compounds of formula I, having an effect on ⁇ 2 - adrenergic receptors and hypotensive and diuretic action, for the production of agents used in the treatment of diseases of the circulatory system, especially arterial hypertension in patients with nephropathy, as well as effects of hypopituitarism, glaucoma, spastic states, dependence on opiates and alcohol, diarrhoea and analgesics.
  • these compounds and their analogues of general formula 1 acting via the ⁇ 2 - adrenergic receptors, can find application in medical practice as hypotensive agents, antidiarrheals, analgesics, as well as in therapy of glaucoma, spastic states, effects of hypopituitarism and dependence on opiates and alcohol and as a tool for investigating the function of the ⁇ 2 -adrenergic receptors.
  • These compounds owing to the hypotensive and diuretic action, may also find application in the treatment of arterial hypertension in patients with nephropathy.
  • the compounds allow the use of sub-therapeutic doses of known sedatives, such as benzodiazepines, eg midazolam. This is particularly advantageous when sedating patients in intensive care situations, in view of the potential for CNS damage when using benzodiazepines as a sedative.
  • the present invention provides: i) a compound of formula I for use as a cytoprotective agent or as a sedative; ii) a pharmaceutical composition comprising at least one compound of formula I and a benzodiazepine .
  • Example X 1.12 g (0.0037 mol) of N,N'-di(tert-butoxycarbonyl)imidazolidine-2-thione and 0.88 g triethylamine (1.21 cm 3 , 0.0087 mol) are added, while stirring, to a solution of 0.41 g (0.0025 mol) of l-amino-6-methoxyindazole in 5 cm 3 of anhydrous dimethylformamide, after which it is cooled and, at a temperature of 0°C, 1.0 g HgCl 2 (0.0037 mol) is added, then continuing as in Example I. The dry residue is separated on silica gel (MN-kieselgel 60, 0.04-0.063 mm) in ethyl acetate: chloroform mixture, 0.1:2 (v/v).
  • silica gel MN-kieselgel 60, 0.04-0.063 mm
  • Kidneys were obtained post-mortem from male Sprague Dawley rats (250-280 g) and crude P 2 membranes prepared according to methods of Lione et alP [ 3 H]clonidine (3 nM, Perkin Elmer) was bound in the presence of 10 ⁇ M rauwolscine to preclude binding to ⁇ 2 -adrenoceptors, the specific component was defined by 10 ⁇ M rilmenidine, under these conditions the site labeled is a model of the central I 1 binding site.
  • Crude P 2 brain membranes were prepared as follows. All procedures were carried out at 4 0 C unless otherwise stated, rat brains (male Sprague Dawley rats 250-280 g) were taken and homogenised in 10 vols of ice cold buffer (50 mM Tris-HCl, 1 mM MgCl 2 and 320 mM sucrose, pH 7.4). The homogenate was centrifuged (1000xg for 10 min) and the precipitate discarded. The supernatant was centrifuged a second time (32000xg for 20 min) and the supernatant discarded, with the remaining precipitate making up the crude P 2 membrane preparation.
  • ice cold buffer 50 mM Tris-HCl, 1 mM MgCl 2 and 320 mM sucrose, pH 7.4
  • Membrane aliquots 400 ⁇ l, 0.2-0.3 mg protein were incubated with 11 concentrations of the test compound over the range 0.01 nM - 100 ⁇ M in the presence of the selective I 2 binding site ligand [ 3 H]2BFI 55 (1 nM) or the ⁇ 2 -adrenoceptor antagonist [ 3 H]RX821002 44 (1 nM), to final volume of 500 ⁇ l.
  • Non-specific binding was determined using 10 ⁇ M BU224 56 , I 2 binding and 10 ⁇ M rauwolscine, ⁇ 2 -adrenoceptor binding. Each incubation was performed in triplicate, at room temperature and allowed to reach equilibrium (45 min).
  • MAP Mean Arterial Blood Pressure
  • HR Heart Rate
  • Rats Male Wistar rats, weighing 200-250 g, were purchased from the Animal House of the Polish Academy of Sciences, Warsaw, Tru. All experiments were approved by the Local Ethical Committee on Animal Experiments. The animals were fed a commercial rodent chow (Labofeed-B, Tru) and tap water, available ad libitum. Rats were anaesthetized by i.p. injection of thiopental (Sandoz, Austria) at the dose 70 mg/kg body weight and maintained under anaesthesia by thiopental supplementation (30 ⁇ g/kg/min) during the experiment. The animals were placed on a heated table, and body temperature was maintained between 36 and 37 0 C. Tracheostomy was performed in all experimental groups. Catheters were inserted into the carotid artery for pressure and heart rate monitoring, into a jugular vein for infusions, and into the bladder for free diuresis. Blood pressure and heart rate were constantly monitored to the end of experiment.
  • the tested compound was administrated as 100 ⁇ l bolus through venous catheter at dose 0.1 mg/kg.
  • the antagonist of ⁇ 2 -adrenoceptors (RX821002) was given i.v. at the dose of 5 or 10 ⁇ g/kg 5 min. before the tested compound 13k.
  • MAP mean arterial blood pressure
  • HR heart rate
  • HK-2 cells derived from adult human kidney proximal tubular epithelial cells, were used for the cytoprotective experiments. They were cultured at 37 0 C in RPMI 1640 medium supplemented with 10% foetal bovine serum, 2mM L-glutamine, and 100U/mL penicillin streptomycin in a humidified air/ 5% CO 2 atmosphere. They were treated by depriving the culture medium of glucose and oxygen (OGD) in the absence or presence of the compound at doses ranging from 0.01 to 1 nM after reaching 80% confluence. The cell viability was measured with MTT assay. It can be seen that the cell death was attenuated by the compound in a dose dependent manner.
  • OGD glucose and oxygen

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Addiction (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Psychiatry (AREA)
  • Ophthalmology & Optometry (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pain & Pain Management (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Rheumatology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
EP08857024A 2007-12-05 2008-12-05 Derivate von 1-[(imidazolidin-2-yl)imino]indazol Withdrawn EP2227464A1 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
PL383955A PL212581B1 (pl) 2007-12-05 2007-12-05 Nowe pochodne 1-[(imidazolidyn-2-ylo)imino)]indazolu, sposób ich otrzymywania, zastosowanie i zwiazki posrednie
PCT/GB2008/004024 WO2009071906A1 (en) 2007-12-05 2008-12-05 Derivatives of 1-[(imidazolidin-2-yl)imino)]indazole

Publications (1)

Publication Number Publication Date
EP2227464A1 true EP2227464A1 (de) 2010-09-15

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EP08857024A Withdrawn EP2227464A1 (de) 2007-12-05 2008-12-05 Derivate von 1-[(imidazolidin-2-yl)imino]indazol

Country Status (3)

Country Link
EP (1) EP2227464A1 (de)
PL (1) PL212581B1 (de)
WO (1) WO2009071906A1 (de)

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BE792078A (fr) * 1971-12-01 1973-05-29 Wander Ag Dr A Nouveaux derives de l'indazole, leur preparation et leur application comme medicaments
US4036976A (en) * 1973-04-05 1977-07-19 Sandoz, Inc. Substituted imidazolinylamino-indazoles
JPS57501378A (de) * 1980-09-05 1982-08-05

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2009071906A1 *

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PL212581B1 (pl) 2012-10-31
PL383955A1 (pl) 2009-06-08
WO2009071906A1 (en) 2009-06-11

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