EP2227464A1 - Derivatives of 1-[(imidazolidin-2-yl)imino)]indazole - Google Patents
Derivatives of 1-[(imidazolidin-2-yl)imino)]indazoleInfo
- 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- Withdrawn
Links
- 125000004282 imidazolidin-2-yl group Chemical group [H]N1C([H])([H])C([H])([H])N([H])C1([H])* 0.000 title description 73
- 125000001841 imino group Chemical group [H]N=* 0.000 title description 71
- WRSXUNSJGJUKHE-UHFFFAOYSA-N indazole Chemical compound C1=CC=C[C]2C=NN=C21 WRSXUNSJGJUKHE-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 58
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 33
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims abstract description 22
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims abstract description 22
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 18
- 239000001257 hydrogen Substances 0.000 claims abstract description 18
- 150000002431 hydrogen Chemical class 0.000 claims abstract description 16
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 16
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims abstract description 8
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims abstract description 8
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 7
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 7
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 7
- 125000001309 chloro group Chemical group Cl* 0.000 claims abstract description 7
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 7
- 150000002367 halogens Chemical class 0.000 claims abstract description 7
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 claims abstract description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 7
- 229910000042 hydrogen bromide Inorganic materials 0.000 claims abstract description 4
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims abstract description 4
- 229910000043 hydrogen iodide Inorganic materials 0.000 claims abstract description 4
- 229940098779 methanesulfonic acid Drugs 0.000 claims abstract description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 39
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- 238000000034 method Methods 0.000 claims description 30
- 239000008194 pharmaceutical composition Substances 0.000 claims description 14
- XKAUHHTXJNCNME-UHFFFAOYSA-N ditert-butyl 2-sulfanylideneimidazolidine-1,3-dicarboxylate Chemical compound CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)C1=S XKAUHHTXJNCNME-UHFFFAOYSA-N 0.000 claims description 10
- 230000000694 effects Effects 0.000 claims description 10
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
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- SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical compound N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 claims description 2
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 42
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 36
- 229910052757 nitrogen Inorganic materials 0.000 description 34
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- 238000002425 crystallisation Methods 0.000 description 17
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- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 description 16
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- LWJROJCJINYWOX-UHFFFAOYSA-L mercury dichloride Chemical compound Cl[Hg]Cl LWJROJCJINYWOX-UHFFFAOYSA-L 0.000 description 11
- DDLIGBOFAVUZHB-UHFFFAOYSA-N midazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NC=C2CN=C1C1=CC=CC=C1F DDLIGBOFAVUZHB-UHFFFAOYSA-N 0.000 description 10
- 229960003793 midazolam Drugs 0.000 description 10
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- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 5
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- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 3
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- KJOZJSGOIJQCGA-UHFFFAOYSA-N dichloromethane;2,2,2-trifluoroacetic acid Chemical compound ClCCl.OC(=O)C(F)(F)F KJOZJSGOIJQCGA-UHFFFAOYSA-N 0.000 description 1
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- ZOBMUHMHTHUYBX-UHFFFAOYSA-N n-(4,5-dihydro-1h-imidazol-2-yl)-1h-indazol-4-amine Chemical class N1CCN=C1NC1=CC=CC2=C1C=NN2 ZOBMUHMHTHUYBX-UHFFFAOYSA-N 0.000 description 1
- SZQXHDWOBFSIRH-UHFFFAOYSA-N n-(4,5-dihydro-1h-imidazol-2-yl)-1h-indazol-7-amine Chemical class N1CCN=C1NC1=CC=CC2=C1NN=C2 SZQXHDWOBFSIRH-UHFFFAOYSA-N 0.000 description 1
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- YNZAFFFENDLJQG-UHFFFAOYSA-N pyrrol-1-amine Chemical compound NN1C=CC=C1 YNZAFFFENDLJQG-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic 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
- C07D403/12—Heterocyclic 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/06—Anti-spasmodics, e.g. drugs for colics, esophagic dyskinesia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/12—Antidiarrhoeals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
- A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
-
- 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
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
-
- 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
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
- A61P25/32—Alcohol-abuse
-
- 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
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
- A61P25/36—Opioid-abuse
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/06—Antiglaucoma agents or miotics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
-
- 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
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- 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
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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- Neurosurgery (AREA)
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- Pain & Pain Management (AREA)
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- Heart & Thoracic Surgery (AREA)
- Ophthalmology & Optometry (AREA)
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Abstract
The invention provides a compound of formula (I) wherein R1 denotes hydrogen, methyl or phenyl; R2, R3, R4 and R5 denote hydrogen, halogen, preferably a chlorine atom, alkyl, preferably methyl, alkoxyl, preferably methoxyl; m denotes a number 0 or 1; and HX denotes sulfuric, phosphoric, acetic, malonic, fumaric, oxalic, lactic, tartaric, citric, gluconic, p-toluenesulfonic, methanesulfonic acid, hydrogen bromide or hydrogen iodide, preferably hydrogen chloride. The use of the compounds as α2-adrenergic receptor agonists is also provided.
Description
Derivatives of l-[(imidazolidin-2-yl)imino)]indazole
The invention relates to novel derivatives of l-[(imidazolidin-2-yl)imino)]indazole and their use as highly selective agonists of α2/Ii receptors. The compounds find use as antihypertensive agents. In addition, 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 α2- adrenoceptor agonists represent a unique class of compounds due to a wide range of medicinal uses reported in the literature.1"5 For example, activation of central α2- adrenoceptors in the brain stem has been utilized clinically for many years in the treatment of hypertension.2'3 However, 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
Nevertheless, due to some degree of similarity between the two receptor classes and the fact that most α2-adrenoceptor agonists, including prototypical clonidine, also have comparable affinity for Ij imidazoline receptors, it is still difficult to dissociate imidazoline receptors from α2-adrenoceptors both pharmacologically and functionally. Moreover, α2-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. In this context, a comprehensive review by Szabo should be mentioned,11 in which a critical analysis of the above hypotheses led the author to a conclusion that the sympathoinhibitory effects of clonidine-like drugs are best explained by activation of ^-adrenoceptors. On the other hand, Bousquet pointed out that it is possible to produce a hypotensive effect by activating either α2-adrenoceptors or imidazoline receptors within the central nervous system, and a potentiating interaction exists between these two receptor classes.12 Whether the mechanism of this interaction involves molecular receptor-receptor interference on the ventral medullary
cardiovascular neurons or an interaction between receptors located on different neuronal structures but with effects converging to inhibit the vasomotor tone remains to be demonstrated. To achieve this goal, however, new compounds with imidazoline structure and a very high selectivity for α2-adrenoceptors vis a vis imidazoline Ii receptors will be required.
Currently, a growing interest in the field of developing highly selective 012-adrenoceptor agonists has been stimulated by their potential applications as analgesic, sedative, anxiolytic, hemodynamic-stabilizing and organ-protective agents.13'14 Prominent examples of such compounds include imidazole-containing dexmedetomidine 15>1 and spirooxazoline derivative S18616.17 Mivazerol is an example of the imidazole derivative designed for the prevention of myocardial infraction in perioperative patients,18'19 while spiroimidazoline S19014 has been assessed as anti-migraine agent.20'22 Other effects of clonidine-like agents on central noradrenergic transmitter and modulator functions which are not related to hypertension include the stimulation of human growth hormone and decreasing the output of nearly all secretory glands, such as lacrimal, salivary, gastric secretory and sweat glands.23
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 α2- adrenergic receptor agonists, are also known from WO 98/23609.
We have now synthesised new derivatives of l-[(imidazolidin-2-yl)imino)]indazole, which have particular advantages in terms of their selectivity and also have been shown to have additional properties which make them useful in a range of clinical situiations.
Thus, in a first aspect the present invention provides l-[(imidazolidin-2-yl)imino)]indazole compounds of the formula I:
I wherein R1 denotes hydrogen, methyl or phenyl;
R2, R3, R4 and R5 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.
A particularly preferred compound of formula I is one wherein R1, R2, R3, R4 and R5 denote hydrogen, the letter m is the number 1 , and HX denotes hydrogen chloride, which is characterized by high affinity for a2-adrenergic receptors (Kj = 19.4 nM), and when administered intravenously to rats at a dose of 0.1 mg/ kg it lowers arterial blood pressure by 31.99 ± 3.72 mmHg after 35 min. In its turn, a derivative of general formula I, in which R1, R2, R3 and R4 denote hydrogen, R5 denotes methyl, the letter m is the number 1 and HX denotes hydrogen chloride was characterized by potent hypotensive and diuretic action.
In addition, intermediate compounds of l-{[l,3-di(tert-butoxycarbonyl)imidazolidin-2- yl]imino}indazole of general formula II:
II
wherein R1 denotes hydrogen, methyl or phenyl; and
R2, R3, R4 and R5 denote hydrogen, halogen preferably a chlorine atom, alkyl preferably methyl or alkoxyl preferably methoxyl, represent a second aspect of the invention.
A method for the preparation of compounds of formula I is also provided in which a compound of formula III:
III
in which R1 denotes hydrogen, methyl or phenyl; and
R2, R3, R4 and R5 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.
Following addition of ethyl acetate, 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 MgSO4 the ethyl acetate is distilled off under reduced pressure, whereas the oily,
relatively dry residue is separated on silica gel.
The product obtained, being a derivative of l-{[l,3-di(tert-butoxycarbonyl)imidazolidin-2- yl]imino}indazole of general formula II, is reacted with 50% solution of trifluoroacetic acid in methylene chloride, after which the methylene chloride and excess trifluoroacetic acid are distilled off under reduced pressure, whereas water is added to the oily, relatively dry residue, and a product that is a derivative of general formula I, wherein m is 0, is isolated from this solution or mixture by precipitation with 10% aqueous NaOH solution, and is transformed to the corresponding salt of general formula I, in which R1, R2, R3, R4, R5 have the meaning defined above, the letter m is the number 1 , and HX denotes sulfuric, phosphoric, acetic, malonic, fumaric, oxalic, lactic, tartaric, citric, gluconic, p-toluenesulfonic, methanesulfonic acid, hydrogen bromide or hydrogen iodide, preferably hydrogen chloride.
In an alternative method, 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). According to our procedure, the nucleophilic substitution of the methylthio group with 1-aminoazole is accompained by deprotection of the imidazoline nitrogen atom, i.e. the synthesis of l-[(imidazolidin-2-yl)imino]indazole is accomplished in one step"
In a fourth aspect, the present invention provides a compound of formula I as defined herein for use in medicine. In a further aspect 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.
The compositions of the invention may be presented in unit dose forms containing a predetermined amount of each active ingredient per dose. Such 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. For compounds of formula I, 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.
The 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. 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).
Pharmaceutical formulations 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.
Pharmaceutical formulations 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. For example, the active ingredient may be delivered from the patch by iontophoresis as generally described in Pharmaceutical Research, 3(6), 318 (1986).
Pharmaceutical formulations adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.
For applications to the eye or other external tissues, for example the mouth and skin, the formulations are preferably applied as a topical ointment or cream. When formulated in an ointment, the active ingredient may be employed with either a paraffϊnic or a water-miscible ointment base. Alternatively, the active ingredient may be formulated in a cream with an oil- in-water cream base or a water-in-oil base.
Pharmaceutical formulations 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.
Pharmaceutical formulations adapted for rectal administration may be presented as suppositories or enemas.
Pharmaceutical formulations 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.
Pharmaceutical formulations adapted for administration by inhalation include fine particle dusts or mists which may be generated by means of various types of metered dose pressurised aerosols, nebulizers or insufflators.
Pharmaceutical formulations adapted for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations.
Pharmaceutical formulations 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 α2- 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.
So far the results of pharmacological investigations in vitro and in vivo of selected compounds of general formula 1, in which R1, R2, R3, R4, R5 have the meaning defined above, the letter m is the number 1 , and HX denotes hydrogen chloride, showed that as a rule these compounds have high affinity for α2-adrenergic receptors and hypotensive action, examples of which are shown in Table 1, as well as diuretic action, examples of which are shown in Table 2.
As a result these compounds and their analogues of general formula 1 , acting via the α2- 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 α2-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.
In addition, 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.
In further aspects 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 .
The invention will now be described with reference to the following examples, which should not be regarded as in any way limiting the invention.
Example I
1.12 g (0.0037 mol) of N,N -di(tert-butoxycarbonyl)imidazolidine-2-thione and 0.88 g triethylamine (1.21 cm3, 0.0087 mol) are added, while stirring, to a solution of 0.33 g (0.0025 mol) of 1-aminoindazole in 3 cm3 of anhydrous dimethylformamide, after which it is cooled, and 1.0 g HgCl2 (0.0037 mol) is added at a temperature of 00C. Stirring is continued for 20 minutes at a temperature of 00C and for 5 days at ambient temperature (20-220C), after which 40 cm3 ethyl acetate is added. After stirring for 1 hour, the precipitate of inorganic salts is filtered off and washed with three 10 cm3 portions of ethyl acetate. Then the filtrate is washed with three 20 cm3 portions of saturated aqueous NaCl solution and after drying the organic fraction over MgSO4, the solvent is distilled off under reduced pressure. The oily residue is separated on silica gel (MN-kieselgel 60, 0.04-0.063 mm) in ethyl acetatexhloroform mixture, 0.1 : 10 (v/v). We obtain, successively, 0.28 g (25%) of unreacted N,N'-di(tert- butoxycarbonyl)imidazolidine-2-thione and 0.69 g (70%) of raw l-{[l,3-di(tert- butoxycarbonyl)imidazolidin-2-yl]imino}indazole, which is purified by crystallization from n-heptane.
We obtained 0.58 g (59%) of l-{[l,3-di(tert-butoxycarbonyl)imidazolidin-2-yl]- imino}indazole, melting in the range 128-1300C. IRRBΓ spectrum (cm"1): 2980, 2935, 2900 (CH), 1745, 1715 (C=O), 1630, 1610 (C=N). Analysis: Calculated for C20H27N5O4: 17.44% N; Found: 17.32% N.
A solution of 0.8 g (0.002 mol) of the l-{[l,3-di(tert-butoxycarbonyl)imidazolidin-2- yl]imino}indazole obtained in 8 cm3 of 50% solution of trifluoroacetic acid in methylene chloride is stirred for 2 hours at ambient temperature (20-220C), after which the excess trifluoroacetic acid and methylene chloride are distilled off under reduced pressure. 7 cm3 water is added to the oily residue, and while stirring, at a temperature of 0-50C, 10% aqueous NaOH solution is added dropwise to pH 10-10.5. The precipitate is filtered off, washed with
2 cm3 water and is dried at a temperature that is gradually raised to 1000C. The precipitate obtained is purified by crystallization from 2-propanol.
We obtained 0.24 g (60%) of l-[(imidazolidin-2-yl)imino]indazole, melting in the range 172- 1740C. IRKBΓ spectrum (cm"1): 3225, 3160 (NH), 3005, 2945, 2855 (CH), 1630, 1610 (C=N). 1H NMR spectrum (500 MHz, DMSO-d6): δ = 3.01-3.65 (m, 4H, 2xCH2-imidaz.), 6.48 (s, IH, NH), 6.63 (s, IH, NH), 7.05-7.29 (m, 3H, 3xCH-arom.), 7.55-7.79 (m, IH, CH-arom.), 7.85 (s, IH, H-3) ppm.
7 cm3 of anhydrous methanol is added to 0.2 g (0.001 mol) of the l-[(imidazolidin-2- yl)imino]indazole obtained and after cooling, 0.78 cm3 (0.0012 mol) of methanolic solution of hydrogen chloride of density 5.67 g/100 cm3 is added dropwise, while stirring, at a temperature of 0-50C. Stirring is continued for 30 minutes at room temperature (20-220C), after which the methanol is distilled off under reduced pressure from the solution obtained. The dry residue is purified by crystallization from a mixture of anhydrous ethanol and ether (1 :5 v/v).
We obtained 0.18 g (75%) of l-[(imidazolidin-2-yl)imino]indazole hydrochloride, melting in the range 195-196°C. IRKBr spectrum (cm"1): 3275, 3130, 3035, 2980, 2900, 2660 (NH®, CH), 1650, 1625 (C=N). 1H NMR spectrum (200 MHz, DMSOd6): δ = 3.72 (s, 4H, 2xCH2- imidaz.), 7.25-7.33 (m, IH, CH-arom.), 7.54 (d, J = 4.0 Hz, 2H, 2xCH-arom.), 7.86 (d, J = 8.0 Hz, IH, CH-arom.), 8.25 (s, IH, H-3), 8.97 (s, 2H, 2xNH), 12.59 (s broad, IH, NHΦ) ppm.
Example II
1.12 g (0.0037 mol) of N,N'-di(tert-butoxycarbonyl)imidazolidine-2-thione and 0.88 g triethylamine (1.21 cm3, 0.0087 mol) are added, while stirring, to a solution of 0.42 g (0.0025 mol) of l-amino-4-chloroindazole in 3 cm3 of anhydrous dimethylformamide, after which it is cooled and, at a temperature of 00C, 1.0 g HgCl2 (0.0037 mol) is added, then continuing as in Example I. The oily residue is separated on silica gel (MN-kieselgel 60, 0.04-0.063 mm) in ethyl acetate: chloroform mixture, 0.1 :2 (v/v).
We obtained, successively, 0.22 g (20%) of unreacted N,N'-di(tert-butoxycarbony
l)imidazolidine-2-thione and 0.6 g (55%) of raw 4-chloro-l-{[l,3-di(tert-butoxy carbonyl)imidazolidin-2-yl]imino}indazole, which is purified by crystallization from n- heptane.
We obtained 0.39 g (36%) of 4-chloro-l-{[l,3-di(teit-butoxycarbonyl)imidazolidin-2- yl]imino}indazole, melting in the range 122-125°C. IRKBΓ spectrum (cm"1): 2975, 2930, 2910 (CH), 1745, 1710 (C=O), 1640, 1605 (C=N). Analysis: Calculated for C20H26ClN5O4: 16.06% N; Found: 16.32% N.
A solution of 0.87 g (0.002 mol) of the 4-chloro-l-{[l,3-di(tert-butoxycarbonyl)imidazolidin- 2-yl]imino}indazole obtained in 8 cm3 of 50% solution of trifluoroacetic acid in methylene chloride is stirred for 2 hours at room temperature (20-220C), after which the excess trifluoroacetic acid and methylene chloride are distilled off under reduced pressure. 10 cm3 water is added to the oily residue and, after cooling, while stirring at a temperature of 0-5°C, 10% aqueous NaOH solution is added dropwise to pH 10-10.5. The precipitate is filtered off, washed with 2 cm3 water and, after drying, is purified by crystallization from acetonitrile.
We obtained 0.36 g (76%) of 4-chloro-l-[(imidazolidin-2-yl)imino]indazole, melting in the range 194-196°C. IRKBr spectrum (cm"1): 3230, 3175 (NH), 3005, 2945, 2875 (CH), 1625, 1610 (C=N). 1H NMR spectrum (200 MHz, DMSO-d6): δ = 3.37 (s, 4H, 2xCH2-imidaz.), 6.47 (s, IH, NH), 6.74 (s, IH, NH), 7.12 (d, J = 6.3 Hz, IH, H-7), 7.21-7.33 (m, 2H, H-5 and H-6), 7.91 (s, IH, H-3) ppm.
7 cm3 of anhydrous methanol is added to 0.24 g (0.001 mol) of the 4-chloro-l-[(imidazolidin- 2-yl)imino]indazole obtained and after cooling, while stirring at a temperature of 0-5°C, 0.78 cm3 (0.0012 mol) of methanolic solution of hydrogen chloride of density 5.67 g/100 cm3 is added dropwise, after which the same procedure is followed as in Example I.
We obtained 0.18 g (69%) of 4-chloro-l-[(imidazolidin-2-yl)imino]indazole hydrochloride, melting in the range 215-2170C. IRKBΓ spectrum (cm"1): 3140, 3060, 2675 (NH®, CH), 1640, 1610 (C=N). 1H NMR spectrum (500 MHz, DMSO-d6): δ = 3.72 (s, 4H, 2xCH2-imidaz.), 7.38 (d, J = 6.8 Hz, IH, H-7), 7.53-7.55 (m, 2H, H-5 and H-6), 8.33 (s, IH, H-3), 8.94 (s, 2H, 2xNH), 12.73 (s broad, IH, NH®) ppm.
Example HI
1.12 g (0.0037 mol) of N,N -di(tert-butoxycarbonyl)imidazolidine-2-thione and 0.88 g of triethylamine (1.21 cm3, 0.0087 mol) are added, while stirring, to a solution of 0.42 g (0.0025 mol) of l-amino-5-chloroindazole in 3 cm3 of anhydrous dimethylformamide, after which it is cooled and 1.0 g HgCl2 (0.0037 mol) is added at a temperature of 0°C, then continuing as in Example I. The oily residue is separated on silica gel (MN-kieselgel 60, 0.04-0.063 mm) in ethyl acetate: chloroform mixture, 0.1 :2 (v/v).
We obtained, successively, 0.28 g (25%) of unreacted N,N'-di(tert-butoxycarbonyl) imidazolidine-2-thione and 0.81 g (74%) of raw 5-chloro-l-{[l,3-di(tert-butoxycarbonyl) imidazolidin-2-yl]imino}indazole, which is purified by crystallization from n-heptane.
We obtained 0.5 g (46%) of 5-chloro-l-{[l,3-di(tert-butoxycarbonyl)imidazolidin-2- yl]imino}indazole, melting in the range 176-177°C. IRKBr spectrum (cm"1): 2980, 2920, 2910 (CH), 1735, 1710 (C=O), 1630 (C=N). Analysis: Calculated for C20H26ClN5O4: 16.06% N; Found: 16.11% N.
0.87 g (0.002 mol) of the 5-chloro-l-{[l,3-di(tert-butoxycarbonyl)imidazolidin-2- yyll]]iimmiinnoo}}iinnddaazzoollee oobbttaaiinneedd iiss ddiissssoollvveedd iinn 88 ccmm33 ooff 5500^% solution of trifluoroacetic acid, after which the same procedure is followed as in Example II.
We obtained 0.3 g (64%) of 5-chloro-l-[(imidazolidin-2-yl)imino]indazole, melting in the range 159-1600C. IRRBΓ spectrum (cm'1): 3230, 3175 (NH), 2990, 2895 (CH), 1630 (C=N). 1H NMR spectrum (200 MHz, DMSO-d6): δ = 3.37 (s, 4H, 2xCH2-imidaz.), 6.48 (s, IH, NH), 6.69 (s, IH, NH), 7.24 (d, J = 8.8 Hz, IH, H-7), 7.34 (d, J = 8.8 Hz, IH, H-6), 7.76 (s, IH, H- 4), 7.86 (s, IH, H-3) ppm. 13C NMR spectrum (125 MHz, DMSO-d6): δ = 42.3, 43.5 (C-4 and C-5-imidaz.), 112.3, 120.2, 122.8, 124.9, 126.2, 127.9 (6C-arom.), 135.1 (C-3), 164.9 (C-2- imidaz.) ppm.
7 cm3 of anhydrous methanol is added to 0.24 g (0.001 mol) of the 5-chloro-l-[(imidazolidin- 2-yl)imino]indazole obtained and after cooling, while stirring at a temperature of 0-5°C,
0.78 cm3 (0.0012 mol) of methanolic solution of hydrogen chloride of density 5.67 g/100 cm3 is added dropwise, after which the same procedure is followed as in Example I. The dry residue obtained is purified by crystallization from acetonitrile.
We obtained 0.15 g (57%) of 5-chloro-l-[(imidazolidin-2-yl)imino]indazole hydrochloride, melting in the range 181-182°C. IRKBΓ spectrum (cm"1): 3175, 3055, 2880, 2650 (NH®, CH), 1640, 1615 (C=N). 1H NMR spectrum (500 MHz, DMSO-d6): δ = 3.71 (s, 4H, 2xCH2- imidaz.), 7.54 (d, J = 8.8 Hz, IH, H-7), 7.60 (d, J = 8.8 Hz, IH, H-6), 7.97 (s, IH, H-4), 8.23 (s, IH, H-3), 8.93 (s, 2H, 2xNH), 12.72 (s broad, IH, NH®) ppm.
Example IV
1.12 g (0.0037 mol) of N,N-di(tert-butoxycarbonyl)imidazolidine-2-thione and 0.88 g triethylamine (1.21 cm3, 0.0087 mol) are added, while stirring, to a solution of 0.37 g (0.0025 mol) of l-amino-3-methylindazole in 5 cm3 of anhydrous dimethylformamide, after which it is cooled and, at a temperature of 0°C, 1.0 g HgCl2 (0.0037 mol) is added, then continuing as in Example I. The oily residue is separated on silica gel (MN-kieselgel 60, 0.04-0.063 mm) in ethyl acetate: chloroform mixture, 0.1 : 3 (v/v).
We obtained, successively, 0.20 g (18%) of unreacted N,N'-di(tert- butoxycarbonyl)imidazolidine-2-thione and 0.74 g (71%) of raw l-{[l,3-di(tert- butoxycarbonyl)imidazolidin-2-yl]imino}-3-methylindazole, which is purified by crystallization from n-heptane.
We obtained 0.51 g (49%) of l-{[l,3-di(tert-butoxycarbonyl)imidazolidin-2-yl]imino}-3- methylindazole, melting in the range 55-59°C. IRKBΓ spectrum (cm"1): 2980, 2940, 2880 (CH), 1750, 1720 (C=O), 1655, 1615 (C=N). Analysis: Calculated for C21H29N5O4: 16.85% N; Found: 16.52% N.
0.83 g (0.002 mol) of the l-{[l,3-di(tert-butoxycarbonyl)imidazolidin-2-yl]imino}-3- methylindazole obtained is dissolved in 8 cm3 of 50% solution of trifluoroacetic acid in methylene chloride, after which the same procedure is followed as in Example II.
We obtained 0.21 g (50%) of l-[(imidazolidin-2-yl)imino]-3-methylindazole, melting in the range 157-159°C. IRKBΓ spectrum (cm"1): 3220, 3195 (NH), 3050, 2895 (CH), 1635, 1605 (C=N). 1H NMR spectrum (500 MHz, DMSO-d6): δ = 2.48 (s, 3H, CH3-3), 3.38 (s, 4H, 2xCH2-imidaz.), 6.48 (s, IH, NH), 6.59 (s, IH, NH), 6.92-7.05 (m, IH, CH-arom.), 7.19-7.35 (m, 2H, 2xCH-arom.), 7.55-7.70 (m, IH, CH-arom.) ppm. 13C NMR spectrum (50 MHz, DMSOd6): δ = 12.0 (CH3-3), 41.9, 43.0 (C-4 and C-5-imidaz.), 109.9, 119.1, 120.0, 120.7, 125.4, 135.7 (6C-arom.), 137.1 (C-3), 164.0 (C-2-imidaz.) ppm.
7 cm3 of anhydrous methanol is added to 0.21 g (0.001 mol) of the l-[(imidazolidin-2- yl)imino]-3-methylindazole obtained and after cooling, while stirring at a temperature of 0- 5°C, 0.78 cm3 (0.0012 mol) of methanolic solution of hydrogen chloride of density 5.67 g/100 cm3 is added dropwise, after which the same procedure is followed as in
We obtained 0.14 g (60%) of l-[(imidazolidin-2-yl)imino]-3-methylindazole hydrochloride, melting in the range 193-195°C. IRRBΓ spectrum (cm"1): 3140, 2920, 2620 (NH®, CH), 1655, 1615 (C=N). 1H NMR spectrum (200 MHz, DMSO-d6): δ = 2.52 (s, 3H, CH3-3), 3.74 (s, 4H, 2xCH2-imidaz.), 7.25-7.33 (m, IH, CH-arom.), 7.46-7.58 (m, 2H, 2xCH-arom.), 7.82-7.86 (m, IH, CH-arom.), 8.95 (s, 2H, 2xNH), 12.38 (s broad, IH, NH®) ppm.
Example V
1.12 g (0.0037 mol) of N,N -di(tert-butoxycarbonyl)imidazolidine-2-thione and 0.88 g triethylamine (1.21 cm3, 0.0087 mol) are added, while stirring, to a solution of 0.37 g (0.0025 mol) of l-amino-4-methylindazole in 5 cm3 of anhydrous dimethylformamide, after which it is cooled and, at a temperature of O0C, 1.0 g HgCl2 (0.0037 mol) is added, then continuing as in Example I. The oily residue is separated on silica gel (MN-kieselgel 60, 0.04-0.063 mm) in ethyl acetate: chloroform mixture, 0.1 : 3 (v/v).
We obtained, successively, 0.22 g (20%) of unreacted N5N -di(tert-butoxycarbonyl) imidazolidine-2-thione and 0.90 g (87%) of raw l-{[l,3-di(tert-butoxycarbonyl)imidazolidin- 2-yl]imino}-4-methylindazole, which is purified by crystallization from a mixture of ethyl acetate and n-heptane (1: 10 v/v).
We obtained 0.54 g (52%) of l-{[l,3-di(tert-butoxycarbonyl)imidazolidin-2-yl]imino}-4- methylindazole, melting in the range 133-135°C. IRKBΓ spectrum (cm"1): 2975, 2930, 2895 (CH), 1745, 1715 (C=O), 1680, 1605 (C=N). Analysis: Calculated for C21H29N5O4: 16.85% N; Found: 16.89% N.
0.83 g (0.002 mol) of the l-{[l,3-di(tert-butoxycarbonyl)imidazolidin-2-yl]imino}-4- methylindazole obtained is dissolved in 8 cm3 of 50% solution of trifluoroacetic acid in methylene chloride, after which the same procedure is followed as in Example II.
We obtained 0.24 g (56%) of l-[(imidazolidin-2-yl)imino]-4-methylindazole, melting in the range 159-162°C. IRKBr spectrum (cm"1): 3190, 3120 (NH), 3010, 2945, 2920, 2875 (CH), 1630, 1610 (C=N). 1H NMR spectrum (500 MHz, DMSO-d6): δ = 2.52 (s, 3H, CH3-4), 3.37 (s, 4H, 2xCH2-imidaz.), 6.46 (s, IH, NH), 6.63 (s, IH, NH), 6.75-6.89 (m, IH, CH-arom.), 7.02-7.25 (m, 2H, 2xCH-arom.), 7.90 (s, IH, H-3) ppm. 13C NMR spectrum (50 MHz, DMSO-d6): δ = 18.3 (CH3-4), 41.8, 43.1 (C-4 and C-5-imidaz.), 107.7, 119.8, 122.2, 125.5, 126.7, 130.4 (6C-arom.), 135.9 (C-3), 163.9 (C-2-imidaz.) ppm.
7 cm3 of anhydrous methanol is added to 0.21 g (0.001 mol) of the l-[(imidazolidin-2- yl)imino]-4-methylindazole obtained and after cooling, while stirring at a temperature of 0- 5°C, 0.78 cm3 (0.0012 mol) of methanolic solution of hydrogen chloride of density 5.67 g/100 cm3 is added dropwise, after which the same procedure is followed as in Example I.
We obtained 0.15 g (63%) of l-[(imidazolidin-2-yl)imino]-4-methylindazole hydrochloride, melting in the range 194-196°C. IRKBΓ spectrum (cm"1): 3125, 3005, 2910, 2860, 2610 (NH®, CH), 1645, 1615 (C=N). 1H NMR spectrum (500 MHz, DMSO-d6): δ = 2.59 (s, 3H, CH3-4), 3.72 (s, 4H, 2xCH2-imidaz.), 7.07 (d, J = 6.8 Hz, IH, H-5), 7.33 (d, J = 8.3 Hz, IH, H-7), 7.41 (dd, J = 6.8 Hz, J = 8.3 Hz, IH, H-6), 8.32 (s, IH, H-3), 8.93 (s, 2H, 2xNH), 12.59 (s broad, IH, NH®) ppm.
Example VI
1.12 g (0.0037 mol) of N,N -di(tert-butoxycarbonyl)imidazolidine-2-thione and 0.88 g
triethylamine (1.21 cm3, 0.0087 mol) are added, while stirring, to a solution of 0.37 g (0.0025 mol) of l-amino-5-methylindazole in 5 cm3 of anhydrous dimethylformamide, after which it is cooled and, at a temperature of O0C, 1.0 g HgCl2 (0.0037 mol) is added, then continuing as in Example I. The oily residue is separated on silica gel (MN-kieselgel 60, 0.04-0.063 mm) in ethyl acetate: chloroform mixture, 0.1 : 3 (v/v).
We obtained, successively, 0.20 g (18%) of unreacted N,N -di(tert-butoxycarbonyl) imidazolidine-2-thione and 0.70 g (67%) of raw l-{[l,3-di(tert-butoxycarbonyl)imidazolidin- 2-yl]imino}-5-methylindazole, which is purified by crystallization from n-heptane.
We obtained 0.46 g (44%) of l-{[l,3-di(tert-butoxycarbonyl)imidazolidin-2-yl]imino}-5- methylindazole, melting in the range 164-166°C. IRKBΓ spectrum (cm"1): 2975, 2930, 2890 (CH), 1725, 1690 (C=O), 1660, 1620 (C=N). Analysis: Calculated for C21H29N5O4: 16.85% N; Found: 16.63% N.
0.83 g (0.002 mol) of the l-{[l,3-di(tert-butoxycarbonyl)imidazolidin-2-yl]imino}-5- methylindazole obtained is dissolved in 8 cm3 of 50% solution of trifluoroacetic acid in methylene chloride, after which the same procedure is followed as in Example II.
We obtained 0.24 g (56%) of l-[(imidazolidin-2-yl)imino]-5-methylindazole, melting in the range 175-1770C. IRKBΓ spectrum (cm'1): 3215, 3160 (NH), 3005, 2860 (CH), 1620 (C=N). 1H NMR spectrum (200 MHz, DMSO-d6): δ = 2.37 (s, 3H, CH3-5), 3.36 (s, 4H, 2xCH2-imidaz.), 6.47 (s, IH, NH), 6.60 (s, IH, NH), 7.09 (d, J = 8.7 Hz, IH, H-6), 7.24 (d, J = 8.7 Hz, IH, H- 7), 7.42 (s, IH, H-4), 7.74 (s, IH, H-3) ppm. 13C NMR spectrum (50 MHz, DMSO-d6): δ = 21.0 (CH3-5), 41.6, 42.8 (C-4 and C-5-imidaz.), 109.7, 119.2, 121.7, 126.6, 127.2, 128.5 (6C- arom.), 134.7 (C-3), 163.5 (C-2-imidaz.) ppm.
7 cm3 of anhydrous methanol is added to 0.21 g (0.001 mol) of the l-[(imidazolidin-2- yl)imino]-5-methylindazole obtained and after cooling, while stirring at a temperature of 0- 5°C, 0.78 cm3 (0.0012 mol) of methanolic solution of hydrogen chloride of density 5.67 g/100 cm3 is added dropwise, after which the same procedure is followed as in Example I.
We obtained 0.14 g (58%) of l-[(imidazolidin-2-yl)imino]-5-methylindazole hydrochloride, melting in the range 180-183°C. IRKBr spectrum (cm"1): 3165, 3095, 3010, 2950, 2750, 2625 (NH®, CH), 1660, 1635 (C=N). 1H NMR spectrum (200 MHz, DMSOd6): δ = 2.42 (s, 3H, CHs-5), 3.71 (s, 4H, 2xCH2-imidaz.), 7.33-7.45 (m, 2H, H-6 and H-7), 7.61 (s, IH, H-4), 8.14 (s, IH, H-3), 8.92 (s, 2H, 2xNH), 12.45 (s broad, IH, NH®) ppm.
Example VII
1.12 g (0.0037 mol) of N,N -di(tert-butoxycarbonyl)imidazolidine-2-thione and 0.88 g triethylamine (1.21 cm3, 0.0087 mol) are added, while stirring, to a solution of 0.37 g (0.0025 mol) of l-amino-6-methylindazole in 5 cm3 of anhydrous dimethylformamide, after which it is cooled and, at a temperature of 0°C, 1.0 g HgCl2 (0.0037 mol) is added, then continuing as in Example I. The oily residue is separated on silica gel (MN-kieselgel 60, 0.04-0.063 mm) in ethyl acetate: chloroform mixture, 0.1 : 3 (v/v).
We obtained, successively, 0.19 g (17%) of unreacted N,N -di(tert-butoxycarbonyl) imidazolidine-2-thione and 0.58 g (56%) of raw l-{[l,3-di(tert-butoxycarbonyl)imidazolidin- 2-yl]imino}-6-methylindazole, which is purified by crystallization from n-heptane.
We obtained 0.4 g (38%) of l-{[l,3-di(tert-butoxycarbonyl)imidazolidin-2-yl]imino}-6- methylindazole, melting in the range 129-131°C. IRKBr spectrum (cm'1): 3000, 2975, 2930 (CH), 1745, 1710 (C=O), 1655, 1620 (C=N). Analysis: Calculated for C21H29N5O4: 16.85% N; Found: 16.82% N.
0.83 g (0.002 mol) of the l-{[l,3-di(tert-butoxycarbonyl)imidazolidin-2-yl]imino}-6- methylindazole obtained is dissolved in 8 cm3 of 50% solution of trifluoroacetic acid in methylene chloride, after which the same procedure is followed as in Example II.
We obtained 0.29 g (67%) of l-[(imidazolidin-2-yl)imino]-6-methylindazole, melting in the range 216-2190C. IRKBr spectrum (cm'1): 3245, 3150 (NH), 2980, 2945, 2885 (CH), 1635 (C=N). 1H NMR spectrum (200 MHz, DMSO-d6): δ = 2.40 (s, 3H, CH3-6), 3.36 (s, 4H, 2xCH2-imidaz.), 6.40 (s, IH, NH), 6.58 (s, IH, NH), 6.84-6.89 (m, IH, H-5), 7.10 (s, IH, H- 7), 7.54 (d, J = 8.4 Hz, IH, H-4), 7.77 (s, IH, H-3) ppm.
7 cm3 of anhydrous methanol is added to 0.21 g (0.001 mol) of the l-[(imidazolidin-2- yl)imino]-6-methylindazole obtained and after cooling, while stirring at a temperature of 0- 5°C, 0.78 cm3 (0.0012 mol) of methanolic solution of hydrogen chloride of density 5.67 g/ 100 cm3 is added dropwise, after which the same procedure is followed as in We obtain 0.15 g (63%) of l-[(imidazolidin-2-yl)imino]-6-methylindazole hydrochloride, melting in the range 197-199°C. IRKBr spectrum (cm"1): 3245, 3075, 2980, 2910, 2700 (NH®, CH), 1635, 1620 (C=N). 1H NMR spectrum (200 MHz, DMSOd6): δ = 2.45 (s, 3H, CH3-6), 3.66 (s, 4H, 2xCH2-imidaz.), 7.08 (d, J = 8.4 Hz, IH, H-5), 7.29 (s, IH, H-7), 7.69 (d, J = 8.4 Hz, IH, H-4), 8.10 (s, IH, H-3), 8.56 (s, 2H, 2xNH), 12.31 (s broad, IH, NHΘ) ppm.
Example VIII
1.12 g (0.0037 mol) of N,N'-di(tert-butoxycarbonyl)imidazolidine-2-thione and 0.88 g triethylamine (1.21 cm3, 0.0087 mol) are added, while stirring, to a solution of 0.37 g (0.0025 mol) of l-amino-7-methylindazole in 5 cm3 of anhydrous dimethylformamide, after which it is cooled and, at a temperature of 0°C, 1.0 g HgCl2 (0.0037 mol) is added. Stirring is continued for 20 minutes at a temperature of 00C and for 3 days at ambient temperature (20- 22°C), after which it is heated for 6 hours at a temperature of 65°C. After cooling to room temperature, 40 cm ethyl acetate is added to the mixture, then continuing as in Example I. The oily residue is separated on silica gel (MN-kieselgel 60, 0.04-0.063 mm) in ethyl acetate: chloroform mixture, 0.1 : 3 (v/v).
We obtained, successively, 0.28 g (25%) of unreacted N,N'-di(tert-butoxycarbonyl) imidazolidine-2-thione and 0.37 g (36%) of raw l-{[l,3-di(tert-butoxycarbonyl)imidazolidin- 2-yl]imino}-7-methylindazole, which is purified by crystallization from n-heptane.
We obtained 0.25 g (24%) of l-{[l,3-di(tert-butoxycarbonyl)imidazolidin-2-yl]imino}-7- methylindazole, melting in the range 160-162°C. IRKBΓ spectrum (cm"1): 3000, 2980, 2930, 2900 (CH), 1715 (C=O), 1650 (C=N). Analysis: Calculated for C2iH29N5O4: 16.85% N; Found: 16.61% N.
0.83 g (0.002 mol) of the l-{[l,3-di(tert-butoxycarbonyl)imidazolidin-2-yl]imino}-7-
methylindazole obtained is dissolved in 8 cm3 of 50% solution of trifluoroacetic acid in methylene chloride, after which the same procedure is followed as in Example II.
We obtained 0.3 g (70%) of l-[(imidazolidin-2-yl)imino]-7-methylindazole, melting in the range 201-2040C. IR (cm"1): 3210, 3170 (NH), 3060, 2950, 2870 (CH), 1635 (C=N). 1H NMR spectrum (500 MHz, DMSOd6): δ = 2.61 (s, 3H, CH3-7), 3.36-3.40 (m, 4H, 2xCH2-imidaz.), 6.20 (s, IH, NH), 6.62 (s, IH, NH), 6.88-6.96 (m, 2H, H-5, H-6), 7.47 (d, J = 7.8 Hz, IH, H- 4), 7.80 (s, lH, H-3) ppm.
7 cm3 of anhydrous methanol is added to 0.21 g (0.001 mol) of the l-[(imidazolidin-2- yl)imino]-7-methylindazole obtained and after cooling, while stirring at a temperature of 0- 5°C, 0.78 cm3 (0.0012 mol) of methanolic solution of hydrogen chloride of density 5.67 g/100 cm3 is added dropwise, after which the same procedure is followed as in Example I.
0.15 g (63%) of l-[(imidazolidin-2-yl)imino]-7-methylindazole hydrochloride is obtained at a temperature of 189-1900C. IRKBr spectrum (cnT1): 3240, 3070, 2975, 2915, 2710 (NH®, CH), 1645, 1625 (C=N). 1H NMR spectrum (200 MHz, DMSOd6): δ = 2.55 (s, 3H, CH3-7), 3.74 (s, 4H, 2xCH2-imidaz.), 7.12-7.29 (m, 2H, H-5, H-6), 7.66 (d, J = 7.7 Hz, IH, H-4), 8.21 (s, IH, H-3), 8.97 (s, 2H, 2xNH), 12.78 (s broad, IH, NH®) ppm.
Example IX
1.12 g (0.0037 mol) of N,N -di(tert-butoxycarbonyl)imidazolidine-2-thione and 0.88 g triethylamine (1.21 cm3, 0.0087 mol) are added, while stirring, to a solution of 0.41 g (0.0025 mol) of l-amino-4-methoxyindazole in 5 cm3 of anhydrous dimethylformamide, after which it is cooled and, at a temperature of 00C, 1.0 g HgCl2 (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).
We obtained, successively, 0.22 g (20%) of unreacted N,N -di(tert- butoxycarbonyl)imidazolidine-2-thione and 0.81 g (75%) of raw l-{[l,3-di(tert- butoxycarbonyl)imidazolidin-2-yl]imino}-4-methoxyindazole, which is purified by
crystallization from n-heptane.
We obtained 0.56 g (51%) of l-{[l,3-di(tert-butoxycarbonyl)imidazolidin-2-yl]imino}-4- methoxyindazole, melting in the range 132-134°C. IRKBr spectrum (cm"1): 3000, 2970, 2930, 2885 (CH), 1715, 1705 (C-O), 1650, 1615 (C=N). Analysis: Calculated for C21H29N5O5: 16.23% N; Found: 15.94% N.
0.86 g (0.002 mol) of the l-{[l,3-di(tert-butoxycarbonyl)imidazolidin-2-yl]imino}-4- methoxyindazole obtained is dissolved in 8 cm3 of 50% solution of trifluoroacetic acid methylene chloride, after which the same procedure is followed as in Example II.
We obtained 0.28 g (61%) of l-[(imidazolidin-2-yl)imino]-4-methoxyindazole, melting in the range 170-1720C. IRKBΓ spectrum (cm"1): 3320, 3250, 3150 (NH), 2990, 2890 (CH), 1635, 1610 (C=N). 1H NMR spectrum (500 MHz, DMSO-d6): δ = 3.37 (s, 4H, 2xCH2-imidaz.), 3.91 (s, 3H, CH3O-4), 6.45 (s, IH, NH), 6.48 (d, J = 7.3 Hz, IH, 5-H), 6.64 (s, IH, NH), 6.91 (d, J = 8.3 Hz, IH, U-T), 7.16-7.19 (m, IH, H-6), 7.82 (s, IH, H-3) ppm. 13C NMR spectrum (125 MHz, DMSO-d6): δ = 42.3, 43.5 (C-4, C-5-imidaz.), 55.9 (CH3O-4), 99.6, 103.5, 113.9, 125.8, 127.0, 138.2 (6C-arom.), 153.5 (C-3), 164.5 (C-2-imidaz.) ppm.
7 cm3 of anhydrous methanol is added to 0.23 g (0.001 mol) of the l-[(imidazolidin-2- yl)imino]-4-methoxyindazole obtained and after cooling, while stirring at a temperature of 0- 5°C, 0.78 cm3 (0.0012 mol) of methanolic solution of hydrogen chloride of density 5.67 g/100 cm is added dropwise, after which the same procedure is followed as in Example I.
We obtained 0.16 g (59%) of l-[(imidazolidin-2-yl)imino]-4-methoxyindazole hydrochloride, melting in the range 202-2040C. IRKBr spectrum (cm"1): 3285, 3080, 3005, 2690, 2560 (NH®, CH), 1645, 1610 (C=N). 1H NMR spectrum (200 MHz, DMSO-d6): δ = 3.72 (s, 4H, 2xCH2- imidaz.), 3.96 (s, 3H, CH3O-4), 6.75 (d, J = 7.9 Hz, IH, H-5), 7.07 (d, J = 8.1 Hz, IH, H-7), 7.45 (t, IH, H-6), 8.20 (s, IH, H-3), 8.94 (s, 2H, 2xNH), 12.59 (s broad, IH, NH®) ppm.
Example X
1.12 g (0.0037 mol) of N,N'-di(tert-butoxycarbonyl)imidazolidine-2-thione and 0.88 g triethylamine (1.21 cm3, 0.0087 mol) are added, while stirring, to a solution of 0.41 g (0.0025 mol) of l-amino-6-methoxyindazole in 5 cm3 of anhydrous dimethylformamide, after which it is cooled and, at a temperature of 0°C, 1.0 g HgCl2 (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).
We obtained, successively, 0.24 g (21%) of unreacted N,N -di(tert-butoxycarbonyl) imidazolidine-2-thione and 0.79 g (73%) of raw l-{[l,3-di(tert-butoxycarbonyl)imidazolidin- 2-yl]imino}-6-methoxyindazole, which is purified by crystallization from ethyl acetate.
We obtained 0.6 g (55%) of l-{[l,3-di(tert-butoxycarbonyl)imidazolidin-2-yl]imino}-6- methoxyindazole, melting in the range 178-179°C. IRKBΓ spectrum (cm"1): 2995, 2975, 2930, 2890 (CH), 1715, 1705 (C=O), 1680, 1625 (C=N). Analysis: Calculated for C2iH29N5O5: 16.23% N; Found: 16.21% N.
0.86 g (0.002 mol) of the l-{[l,3-di(tert-butoxycarbonyl)imidazolidin-2-yl]imino}-6- methoxyindazole obtained is dissolved in 8 cm3 of 50% solution of trifluoroacetic acid in methylene chloride, after which the same procedure is followed as in Example II.
We obtained 0.33 g (72%) of l-[(imidazolidin-2-yl)imino]-6-methoxyindazole, melting in the range 178-18O0C. IRKBr spectrum (cπT1): 3295, 3215 (NH), 2965, 2865 (CH), 1635, 1605 (C=N). 1H NMR spectrum (200 MHz, DMSOd6): δ = 3.41 (s, 4H, 2xCH2-imidaz.), 3.81 (s, 3H, CH3O-6), 6.55 (s, IH, NH), 6.61 (s, IH, NH), 6.69-6.72 (m, 2H, H-5, U-T), 7.56 (d, J = 9.2 Hz, IH, H-4), 7.78 (s, IH, H-3) ppm.
7 cm3 of anhydrous methanol is added to 0.23 g (0.001 mol) of the l-[(imidazolidin-2- yl)imino]-6-methoxyindazole obtained and after cooling, while stirring at a temperature of 0-
5°C, 0.78 cm3 (0.0012 mol) of methanolic solution of hydrogen chloride of density
5.67 g/100 cm3 is added dropwise, after which the same procedure is followed as in Example
I.
We obtained 0.17 g (63%) of l-[(imidazolidin-2-yl)imino]-6-methoxyindazole hydrochloride,
melting in the range 193-195°C. IRKBr spectrum (cm'1): 3175, 3080, 2970, 2900, 2780, 2750 (NH®, CH), 1645, 1625 (C=N). 1H NMR spectrum (200 MHz, DMSO-d6): δ = 3.73 (s, 4H, 2xCH2-imidaz.), 3.85 (s, 3H, CH3O-6), 6.89 (dd, J = 8.7 Hz, J = 2.1 Hz, IH, H-5), 6.99 (s, IH, H-7), 7.70 (d, J = 8.7 Hz, IH, H-4), 8.11 (s, IH, H-3), 8.93 (s, 2H, 2xNH), 12.43 (s broad, IH, NH®) ppm.
Example XI
1.12 g (0.0037 mol) of N,N -di(tert-butoxycarbonyl)imidazolidine-2-thione and 0.88 g triethylamine (1.21 cm3, 0.0087 mol) are added, while stirring, to a solution of 0.52 g (0.0025 mol) of l-amino-3-phenylindazole in 5 cm3 of anhydrous dimethylformamide, after which it is cooled and, at a temperature of 0°C, 1.0 g HgCl2 (0.0037 mol) is added, then continuing as in Example I. The oily residue is separated on silica gel (MN-kieselgel 60, 0.04-0.063 mm) in ethyl acetate: chloroform mixture, 0.1 : 7 (v/v).
We obtained, successively, 0.22 g (20%) of unreacted N,N -di(tert- butoxycarbonyl)imidazolidine-2-thione and 0.85 g (71%) of raw l-{[l,3-di(tert- butoxycarbonyl)imidazolidin-2-yl]imino}-3-phenylindazole, which is purified by crystallization from n-heptane.
We obtained 0.6 g (50%) of l-{[l,3-di(tert-butoxycarbonyl)imidazolidin-2-yl]imino}-3- phenylindazole, melting in the range 66-690C. IRKBr spectrum (cm"1): 2980, 2935, 2895 (CH), 1750, 1720 (C=O), 1650, 1615 (C=N). Analysis: Calculated for C26H3 ,N5O4: 14.66% N; Found: 14.32% N.
0.96 g (0.002 mol) of the l-{[l,3-di(tert-butoxycarbonyl)imidazolidin-2-yl]imino}-3- phenylindazole obtained is dissolved in 8 cm3 of 50% solution of trifluoroacetic acid in methylene chloride, after which the same procedure is followed as in Example II. The precipitate is filtered off, washed with 2 cm3 water and is purified by crystallization from ethanol.
We obtained 0.34 g (61%) 3 -phenyl- l-[(imidazolidin-2-yl)imino]indazole, melting in the range 188-1900C. IRKBΓ spectrum (cm'1): 3405, 3210 (NH), 3060, 2980, 2955, 2890 (CH), 1650, 1605 (C=N). 1H NMR spectrum (200 MHz, DMSO-d6): δ = 3.43 (s, 4H, 2xCH2-
imidaz.), 6.69 (s, IH, NH), 6.74 (s, IH, NH), 7.14-7.21 (m, IH, CH-arom.), 7.31-7.55 (m, 5H, Ph), 8.0-8.07 (m, 3H, 3xCH-arom.) ppm.
7 cm3 of anhydrous methanol is added to 0.28 g (0.001 mol) of the 3 -phenyl- 1- [(imidazolidin- 2-yl)imino]indazole obtained and after cooling, while stirring at a temperature of 0-5°C,
1 "X
0.78 cm (0.0012 mol) of methanolic solution of hydrogen chloride of density 5.67 g/100 cm is added dropwise, after which the same procedure is followed as in Example I. The dry residue obtained is purified by crystallization from a mixture of anhydrous ethanol and ether
(1:7 v/v).
We obtained 0.18 g (56%) of 3 -phenyl- l-[(imidazolidin-2-yl)imino]indazole hydrochloride, melting in the range 218-221°C. IRKBΓ spectrum (cm'1): 3265, 3115, 3000, 2910, 2805, 2775 (NH®, CH), 1645, 1615 (C=N). 1H NMR spectrum (200 MHz, DMSOd6): δ = 3.77 (s, 4H, 2xCH2-imidaz.), 7.37-7.47 (m, IH, CH-arom.), 7.51-7.63 (m, 5H, Ph), 8.0-8.04 (m, 2H, 2xCH-arom.), 8.18-8.22 (m, IH, CH-arom.), 9.08 (s, 2H, 2xNH), 12.64 (s broad, IH, NH®) ppm.
Example XII: Preparation of l-[(Imidazolidin-2-yl)imino]indazole
A solution of 1-aminoindazole (0.62 g, 4.6 mmol) and tert-butyl 2-(methylthio)-4,5- dihydroimidazole-1-carboxylate (1.1 g, 5.1 mmol) in acetic acid (2 mL) was stirred at 60-62 0C (oil bath) for 15 hours. Then the solvent was evaporated under reduced pressure. The viscous residue was treated with water (5 mL) and the resulting suspension was made alkaline with 15% aqueous Na2CO3 solution (pH 9) and extracted with dichloromethane (3 x 15 mL). The combined organic phases were dried over anhydrous magnesium sulfate, filtrated and evaporated. The viscous residue was treated with diethyl ether (10 mL) and the solid product thus obtained was filtered off, washed with diethyl ether (4 x 5 mL) and dried. Yield 0.52 g (55%); mp 171-173 °C 1H NMR (200 MHz, DMSO-d6) δ = 3.38 (s, 4H, CH2), 6.47 (s, IH, NH), 6.52 (s, IH, NH), 7.01-7.08 (m, IH, CH), 7.22-7.37 (m, 2H, CH), 7.69 (d, J = 8.1 Hz, IH, CH), 7.87 (s, IH, 3-H); IR (KBr) cm4 3225, 3160, 3005, 2945, 2855, 1630, 1610, 1515, 1405, 1285, 1200, 1055, 905, 835, 735.
Example XIII
Pharmacology. Radioligand Binding Assays. Ii-Binding Site Assay. Kidneys were obtained post-mortem from male Sprague Dawley rats (250-280 g) and crude P2 membranes prepared according to methods of Lione et alP [3H]clonidine (3 nM, Perkin Elmer) was bound in the presence of 10 μM rauwolscine to preclude binding to α2-adrenoceptors, the specific component was defined by 10 μM rilmenidine, under these conditions the site labeled is a model of the central I1 binding site.54 Membrane aliquots (400 μl, 0.2-0.5 mg protein) were incubated with 11 concentrations of the test compound over the range 0.01 μM - 100 mM. Incubations were carried out 50 mM Tris-HCl buffer (pH 7.4) at room temperature for 45 min. Bound ligand and free radioactivity were separated by rapid filtration through pre- soaked (0.5% polyethylamine) glass-fibre filters (Whatman GFB). Trapped ligand was determined by liquid scintillation counting and data analysed by GraphPad Prism version 3.02 for Windows (GraphPad Software, San Diego, California, USA) to yield IC50 values (the concentration of drug that displaces 50% of specifically bound [3H]clonidine).
α2- and ^-Binding Site Assays. Crude P2 brain membranes were prepared as follows. All procedures were carried out at 4 0C 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 MgCl2 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 P2 membrane preparation. This was washed twice in excess buffer (50 mM Tris-HCl, ImM MgCl2) at room temperature, 30 mL were added, the precipitate re- suspended and centrifuged (32000xg for 20 min). The washed membrane preparations were stored at - 70 °C until use. Prior to use they were thawed and washed (as above) a further two times. Membrane aliquots (400 μl, 0.2-0.3 mg protein) were incubated with 11 concentrations of the test compound over the range 0.01 nM - 100 μM in the presence of the selective I2 binding site ligand [3H]2BFI55 (1 nM) or the α2-adrenoceptor antagonist [3H]RX82100244 (1 nM), to final volume of 500 μl. Non-specific binding was determined using 10 μM BU22456, I2 binding and 10 μM rauwolscine, α2-adrenoceptor binding. Each incubation was performed in triplicate, at room temperature and allowed to reach equilibrium (45 min). Bound and free radioactivity were separated by rapid filtration through pre-soaked (0.5% polyethyleimine)
glass-fibre filters (Whatman GF/B). Filters were then washed twice with 5 mL of ice-cold buffer and membrane bound radioactivity remaining on the filters was determined by liquid scintillation counting. Data were analysed by iterative non-linear regression curve fitting procedures in GraphPad Prism version 3.02 for Windows (GraphPad Software, San Diego, California, USA). Each experiment was analysed individually and the equilibrium dissociation constant (K,), determined by the method of Cheng and Prusoff57 and the resulting values are given as means ±SEM for 3-4 separate experiments.
In Vivo Studies: Mean Arterial Blood Pressure (MAP) and Heart Rate (HR) in Rats.
Male Wistar rats, weighing 200-250 g, were purchased from the Animal House of the Polish Academy of Sciences, Warsaw, Poland. All experiments were approved by the Local Ethical Committee on Animal Experiments. The animals were fed a commercial rodent chow (Labofeed-B, Poland) 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 μg/kg/min) during the experiment. The animals were placed on a heated table, and body temperature was maintained between 36 and 37 0C. 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.
After all surgical procedures, a 40 min recovery period was allowed to established steady state. During the whole experiment rats were infused with isotonic saline (Fresenius Kabi, Poland) supplemented with thiopental at the rate of 1.2 mL/h.
After 40 min of saline infusion, the tested compound was administrated as 100 μl bolus through venous catheter at dose 0.1 mg/kg. The antagonist of α2-adrenoceptors (RX821002) was given i.v. at the dose of 5 or 10 μg/kg 5 min. before the tested compound 13k.
Arterial blood pressure and heart rate were monitored directly and sampled continuously at 100 Hz, as we described previously,41 using Biopac Systems, Inc., Model MP 100 (Goleta, CA, USA). The results of measurements were elaborated with the help of the ACQKnowledge (Goleta, CA, USA) measurement system that is selected, scaled and filtered to remove
accidental signal disturbances. The recorded time domain transient data have been presented as a graphs with the help of Excel (Microsoft, USA).
Statistical ANOVAs of mean arterial blood pressure (MAP) and heart rate (HR) were performed for ΔMAP and ΔHR, calculated as the difference in MAP and in HR between sequential measurements and the time of compound application ("time 0") for each group, as we described previously.41 This allowed for direct comparison of responses to treatment between groups when baselines differed. Data were analyzed by ANOVA with repeated measures, using Statistica StatSoft software (StatSoft, Inc., Tulsa, USA), after test compounds or vehicle treatment. When the effect was significant, post hoc comparisons were performed using Duncan and Fisher tests. A value of/? < 0.05 was considered statistically significant.
Table 1. Affinity for α2-adrenergic receptors and maximum hypotensive effect of selected compounds according to formula 1 for m = 1, HX = HCl
*Tests conducted at the University of Alberta, Edmonton (Canada).
** Tests conducted in the Pathophysiology Institute of the Gdansk Medical Academy on rats of the Wistar strain. a) Affinity constant of the test compound for the α2-adrenergic receptors in the rat brain expressed in nM. b) Time after which the maximum drop in arterial blood pressure was observed after intravenous administration of the test compound to rats in a single dose of 0.1 mg/ kg.
c) Maximum drop in arterial blood pressure after intravenous administration of the test compound to rats in a single dose of 0.1 mg/ kg expressed as mean value ± SE.
Table 2. Diuretic activity of selected compounds according to formula 1 for m=l, HX=HCl
* Tests conducted in the Pathophysiology Institute of the Gdansk Medical Academy on rats of the Wistar strain. a) Number of experimental animals used. b) Time of observation of diuresis before (-40 - 0 min) and after (0 - 90 min) intravenous administration of the test compound to rats in a single dose of 0.1 mg/ kg. c) Diuresis after intravenous administration of the test compound to rats in a single dose of 0.1 mg/ kg expressed as mean value ± SE.
Example XIV
Sedative effect of a novel adrenoceptor agonist 7 Cl-Marsanidine (Rl, R2, R3 and R4 are H and R5 is Cl)
Adult Sprague Dawley rats (weight 250-300 g) were used for the following experiments. First, the effect of Midazolam, a benzodiazepine receptor agonist, on sedation measured with the loss righting reflex (LORR) was determined. Midazolam was administered i.p. from doses of 0.5 mg/kg to 40 mg/kg. It revealed that midazolam at the highest dose tested caused LORR in 100% subjects. Second, the combined effect of the compound + midazolam on LORR was investigated. At the fixed dose (500 μg/kg) of the compound followed by variable doses of midazolam, the results showed that the compound remarkably reduced the dose of midazolam required to induce LORR in 100% subjects from 40 mg/kg to 2.5 mg/kg, indicating that the compound synergistically enhanced the sedative effect of midazolam (figure 1)
In addition, facilitation by midazolam of the sedative response of 7-chloro-marsanidine could be blocked by flumazenil, a benzodiazepine antagonist, indicating that this is a general property of benzodiazepines and not restricted to midazolam.
Cytoprotective effect of a novel adrenoceptor agonist 7 Cl-Marsanidine
HK-2 cells, derived from adult human kidney proximal tubular epithelial cells, were used for the cytoprotective experiments. They were cultured at 370C in RPMI 1640 medium supplemented with 10% foetal bovine serum, 2mM L-glutamine, and 100U/mL penicillin streptomycin in a humidified air/ 5% CO2 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. This effect was abolished by an adrenoceptor antagonist of Atipamezole (10 nM). The compound or Atipamezole at the highest studied dose did not cause any cell death. These data suggest that the compound has cytoprotective property and the effect is due to its action on alpha-2 adrenoceptor (figure 2).
References
1. Koblinger, W. Drugs as Tools in Research on Adrenoceptors. Naunyn-Schmied. Arch. Pharmacol. 1986, 332, 113-117.
2. Armach, B. T. Unique Presynaptic oc2-Receptors and Specificity of the Antihypertensive Agent Moxonidine. Arzneim.-Forsch. Drug Res. 1988, 38, 1435-1441.
3. Van Zweiten, P. A. Pharmacology of Alpha2-Adrenoceptor Agonist Rilmenidine. Am. J. Cardiol. 1988, 61, D6-D14.
4. Koblinger, W.; Pichler, L. Centrally Acting Drugs (Clonidine, Methyldopa, Guanfacine). In Handbook of Experimental Pharmacology. Pharmacology of Antihypertensive Therapeutics. Eds Ganten, D. and Murlow, P. J.; Springer- Verlag, Berlin, vol. 93, p.227.
5. Ruffolo Jr., R. R.; Nichols, A. J.; Stadel, J. M.; Hieble, J.P. Pharmacologic and Therapeutic Applications of α2- Adrenoceptor Subtypes. Annu. Rev. Pharmacol. Toxicol. 1993, 32, 243- 279.
6. Verbeuren, T. J.; Yuan, A. T. D., Koenig-Bererd, E.; Viton, P. Rilmenidine. Cardiovascular Drug. Rev. 1990, 8, 56-66.
7. Bousquet, P.; Bricca, G.; Dontenwill, M.; Feldman, J.; Greney, H.; Belcourt, A.; Stutzmann, J.; Tibrica, E. From the α2-Adrenoceptors to the Imidazoline Preferring Receptors. Fundam. Clin. Pharmacol. 1992, <J (Suppl. 1) 15a.
8. Chrisp, P.; Faulds, D. Moxonidine. Drugs 1992, 44, 993-995.
9. Molderings, G. J.; Gothert, M. Imidazoline Binding Sites and Receptors in Cardiovascular Tissue. Gen. Pharmac. 1999, 32, 17-22.
10. Ernsberger, P.; Damon, T. H.; Graff, L. M.; Schafer, S. G., Christen, M. O. Moxonidine a Centrally Acting Antihypertensive Agent is a Selective Ligand for I [-Imidazoline Sites. J. Pharmacol. Exp. Ther. 1993, 264, 172-176.
11. Szabo, B. Imidazoline Antihypertensive Drugs: a Critical Review on Their Mechanism of
Action. Pharmacol. Ther. 2002, 93, 1-35.
12. Bousquet, P. Identification and Characterization Of I1 Imidazoline Receptors. Their Role in Blood Pressure Regulation. Am. J. Hypertension 2000, 13, 845-848.
13. Sanders, R. D.; Maze, M. α- Adrenoceptor Agonists. Curr. Opinion Invest. Drugs. 2007, 8, 25-33.
14. Mantz, J. Alpha2- Adrenoceptor Agonists: Analgesia, Sedation, Anxiolysis, Haemodynamics, Respiratory Function and Weaning. Bailliere 's Clinical Anesthesiology 2000, 14, 433-448.
15. Gerlah, A. T. Dexmedetomidine: An Updated Review. Ann. Pharmacother. 2007, 41, 245-252.
16. Pandharipande, P. P.; Pun B. T.; Herr, D. L.; Maze, M.; Girard, T. D.; Miller, R. R.; Shintani, A. K.; Thompson, J. L.; Jackson, J. C; Deppen, S. A.; Stiles, R. A.; Dittus, R. S.; Bernard, G. R.; Ely, E. W. Effect of Sedation with Dexmedetomidine vs Lorazepam on Acute Brain Dysfunction in Mechanically Ventilated Patients: The Mends Randomized Controlled Trial. JAMA. 2007, 298, 2644-2653.
17. Millan, M. J.; Dekeyne, A.; Newman-Tancredi, A.; Cussac, D.; Audinot, V.; Milligan, G.; Duqueyroix, D.; Girardon, S.; Mullot, J.; Boutin, J. A.; Nicolas, J.-P.; Renouard-Try, A.; Lacoste, J.-M.; Cordi, A.A. S18613 a Highly Potent, Spiroimidazoline Agonist at α2- Adrenoceptors: I. Receptor Profile, Antinociceptive and Hypothermic Actions in Comparison with Dexmedetomidine and Clonidine. J. Pharmacol. Exp. Ther. 2000, 295, 1192-1205.
18. Richer, C; Gober, J.; Noyer, M.; Wulfert, E.; Giudicelli, J. F. Peripheral Alpha2- Adrenoceptor-Mediated Sympathoinhibitory Effects of Mivazerol. Fundam. Clin. Pharmacol. 1996, 10, 529-537.
19. Priebe, H. -J. Perioperative Myocardial Infraction - Aetiology and Prevention. Br. J. Anaesth. 2005, 95, 3-19.
20. Cordi, A. A.; Lacoste, J. M.; Descombes, J.-J.; Courchay, Ch.; Vanhautte, P. M.; Laubie, M.; Verbeuren, T. J. Design, Synthesis and Structure - Activity Relationships of a New Series of α2-Adrenergic Agonists : Spiro [( 1 ,3-Diazacyclopent- 1 -ene)-5 ,2'-( 1 ' ,2',3 ',4'- tetrahydronaphthalene)]. J. Med. Chem. 1995, 38, 4056-4069.
21. Cordi, A. A.; Lacoste, J. M.; Le Borgne, F.; Herve, Y.; Vaysse-Ludot, L.; Descombes, J.- J.; Courchay, Ch.; Laubie, M.; Verbeuren, T. J. (S)-Spiro[(l,3-Diazacyclopent-l-ene)-5,2'- (7'-methyl-l',2',3',4'-tetrahydronaphthalene)]: Resolution, Stereospecific Synthesis and Preliminary Pharmacological Characterization as a Potential α- Adrenergic Agonist. J. Med. Chem. 1997, 40, 2931-2935.
22. Kapoor, K.; Willems, E. W.; Maassen VanDenBrink, A.; Hillgers, J. P. C; Cordi, A. A.; Vaysettes-Courchay, C. Assessment of Anti-Migraine Potential of a Novel α- Adrenoceptor Agonist S 19014: Effects on Porcine Carotid and Regional Haemodynamics and Human Coronary Artery. Cephalalgia 2004, 24, 425-438.
23. Stahle, H. A Historical Perspective: Development of Clonidine. Bailliere 's Clinical Anesthesiology 2007, 14, 237-246.
Claims
1. A compound of the formula I:
I wherein R1 denotes hydrogen, methyl or phenyl;
R2, R3, R4 and R5 denote hydrogen, halogen, preferably a chlorine atom, alkyl, preferably methyl, alkoxyl, preferably methoxyl; m denotes a number 0 or 1 ; and
HX denotes sulfuric, phosphoric, acetic, malonic, fumaric, oxalic, lactic, tartaric, citric, gluconic, /7-toluenesulfonic, methanesulfonic acid, hydrogen bromide or hydrogen iodide, preferably hydrogen chloride.
2. A compound as claimed in claim 1 wherein R1, R2, R3, R4 and R5 denote hydrogen; m is 1 ; and
HX denotes hydrogen chloride.
3. A compound as claimed in claim 1 wherein R1, R2, R3 and R4 denote hydrogen; R5 denotes methyl; m is 1 ; and HX denotes hydrogen chloride.
4. A compound of general formula II:
II
wherein R1 denotes hydrogen, methyl or phenyl;
R2, R3, R4 and R5 denote hydrogen, halogen preferably a chlorine atom, alkyl preferably methyl or alkoxyl preferably methoxyl.
5. A method for the preparation of a compound as defined in claim 1, comprising reacting a compound of formula III:
III
wherein R1 denotes hydrogen, methyl or phenyl;
R2, R3, R4 and R5 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.
6. A compound as claimed in any one of claims 1 to 3 for use in medicine.
7. A pharmaceutical formulation comprising at least one compound as claimed in claim 1 and optionally one or more excipients, carriers or diluents.
8. A compound as claimed in any one of claims 1 to 3 for use as a α2-adrenergic receptor agonist.
9. A compound as claimed in claim 8 for use as a hypotensive or diuretic agent.
10. A compound as claimed in claim 8 which is for use in treating diseases of the circulatory system, such as arterial hypertension in patients with nephropathy, as well as effects of hypopituitarism, glaucoma, spastic states, dependence on opiates and alcohol, diarrhoea and analgesics.
11. A compound as claimed in any one of claims 1 to 3 for use as a sedative or anaesthetic.
12. A compound as claimed in any one of claims 1 to 3 for use as a cytoprotective agent.
13. A pharmaceutical composition comprising at least one compound as claimed in claim 1 and a benzodiazepine .
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PL383955A PL212581B1 (en) | 2007-12-05 | 2007-12-05 | New derivatives ofe 1-[(imidazolidine-2-ilo)imino)]indazol and the manner of obtaining them |
| PCT/GB2008/004024 WO2009071906A1 (en) | 2007-12-05 | 2008-12-05 | Derivatives of 1-[(imidazolidin-2-yl)imino)]indazole |
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| Publication Number | Publication Date |
|---|---|
| EP2227464A1 true EP2227464A1 (en) | 2010-09-15 |
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ID=40282302
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP08857024A Withdrawn EP2227464A1 (en) | 2007-12-05 | 2008-12-05 | Derivatives of 1-[(imidazolidin-2-yl)imino)]indazole |
Country Status (3)
| Country | Link |
|---|---|
| EP (1) | EP2227464A1 (en) |
| PL (1) | PL212581B1 (en) |
| WO (1) | WO2009071906A1 (en) |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BE792078A (en) * | 1971-12-01 | 1973-05-29 | Wander Ag Dr A | NEW INDAZOLE DERIVATIVES, THEIR PREPARATION AND THEIR APPLICATION AS MEDICINAL PRODUCTS |
| US4036976A (en) * | 1973-04-05 | 1977-07-19 | Sandoz, Inc. | Substituted imidazolinylamino-indazoles |
| WO1982000824A1 (en) * | 1980-09-05 | 1982-03-18 | Geissmann F | 1h and 2h indazol derivatives and medicaments containing them |
-
2007
- 2007-12-05 PL PL383955A patent/PL212581B1/en not_active IP Right Cessation
-
2008
- 2008-12-05 EP EP08857024A patent/EP2227464A1/en not_active Withdrawn
- 2008-12-05 WO PCT/GB2008/004024 patent/WO2009071906A1/en not_active Ceased
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| Title |
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| See references of WO2009071906A1 * |
Also Published As
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| PL383955A1 (en) | 2009-06-08 |
| WO2009071906A1 (en) | 2009-06-11 |
| PL212581B1 (en) | 2012-10-31 |
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