Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
  • C07D498/08—Bridged systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/06—Antiarrhythmics

Definitions

• This invention relates to a novel pharmaceutically useful compound, in particular a compound which is useful in the treatment of cardiac arrhythmias.
• Cardiac arrhythmias may be defined as abnormalities in the rate, regularity, or site of origin of the cardiac impulse or as disturbances in conduction which causes an abnormal sequence of activation.
• Arrhythmias may be classified clinically by means of the presumed site of origin (i.e. as supraventricular, including atrial and atrioventricular, arrhythmias and ventricular arrhythmias) and/or by means of rate (i.e. bradyarrhythmias (slow) and tachyarrhythmias (fast)).
• Class III antiarrhythmic drugs may be defined as drugs which prolong the trans-membrane action potential duration (which can be caused by a block of outward K + currents or from an increase of inward ion currents) and refractoriness, without affecting cardiac conduction.
• Antiarrhythmic drugs based on bispidines are known from inter alia international patent applications WO 91/07405, WO 99/31100, WO 00/76997, WO 00/76998, WO 00/76999 and WO 00/77000, European patent applications 306 871, 308 843 and 655 228 and U.S. Pat. Nos. 3,962,449, 4,556,662, 4,550,112, 4,459,301 and 5,468,858, as well as journal articles including inter alia J. Med. Chem. 39, 2559, (1996), Pharmacol. Res., 24, 149 (1991), Circulation, 90, 2032 (1994) and Anal. Sci. 9, 429, (1993). Oxabispidine compounds are neither disclosed nor suggested in any of these documents.
• oxabispidine-based compound exhibits electrophysiological activity, preferably class III electrophysiological activity, and is therefore expected to be useful in the treatment of cardiac arrhythmias.
• Compound A is provided in the form of a monohydrate.
• ambient temperature such as at between room temperature and the reflux temperature of the solvent that is employed (e.g. between 10 and 100° C. in the presence of a suitable solvent system (e.g. DMF, N-methyl-pyrrolidinone or acetonitrile) or preferably, a hydroxylic solvent, such as a lower alkyl alcohol (e.g. a C 1-4 alcohol such as ethanol) and/or water).
• a suitable solvent system e.g. DMF, N-methyl-pyrrolidinone or acetonitrile
• a hydroxylic solvent such as a lower alkyl alcohol (e.g. a C 1-4 alcohol such as ethanol) and/or water).
• L 1 represents a leaving group such as halo, alkanesulfonate (e.g. mesylate), perfluoroalkanesulfonate or arenesulfonate (e.g. 2- or 4-nitrobenzenesulfonate or, particularly, toluenesulfonate) with 3,3-dimethyl-1-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)-2-butanone, for example at elevated temperature (e.g. between 35° C. and reflux temperature) optionally in the presence of a suitable base (e.g. triethylamine or potassium carbonate) and tan appropriate organic solvent (e.g.
• a suitable base e.g. triethylamine or potassium carbonate
• tan appropriate organic solvent e.g.
• L 2 represents a leaving group such as halo (especially chloro), alkanesulfonate, perfluoroalkanesulfonate, arenesulfonate, imidazole or R 23 O- (wherein R 23 represents, for example, C 1-10 alkyl or aryl, which groups are optionally substituted by one or more halo or nitro groups), for example at between room and reflux temperature in the presence of a suitable base (e.g. triethylamine, potassium carbonate or a bicarbonate, such as sodium bicarbonate) and an appropriate solvent (e.g. dichloromethane, chloroform, acetonitrile, N,N-dimethylformamide, THF, toluene, water, a lower alkyl alcohol (e.g. ethanol) or mixtures thereof.
• a suitable base e.g. triethylamine, potassium carbonate or a bicarbonate, such as sodium bicarbonate
• an appropriate solvent e.g. dichlorome
• 4- ⁇ [3-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)propyl]amino ⁇ benzonitrile may be prepared by reaction of a compound of formula I as hereinbefore defined with 9-oxa-3,7-diazabicyclo[3.3.1]nonane or a mono-protected (e.g.
• Compound A and intermediates described hereinbefore may be isolated from their reaction mixtures using conventional techniques. Further, Compound A may subsequently be purified by conventional techniques, such as recrystallisation. Suitable solvents for the recrystallisation procedure include lower alkyl alcohols (e.g. C 1-4 alcohols such as ethanol), water and mixtures thereof. The preferred recrystallisation solvent is ethanol/water.
• Functional groups which it is desirable to protect include amino.
• Suitable protecting groups for amino include benzyl, sulfonamido (e.g. benzenesulfonamido), tert-butyloxycarbonyl, 9-fluorenyl-methoxycarbonyl or benzyloxycarbonyl.
• Compound A is useful because it possesses pharmacological activity. It is therefore indicated as a pharmaceutical.
• Compound A exhibits myocardial electrophysiological activity, for example as demonstrated in the tests described below.
• Compound A is thus expected to be useful in both the prophylaxis and the treatment of arrhythmias, and in particular atrial and ventricular arrhythmias.
• Compound A is thus indicated in the treatment or prophylaxis of cardiac diseases, or in indications related to cardiac diseases, in which arrhythmias are believed to play a major role, including ischaemic heart disease, sudden heart attack, myocardial infarction, heart failure, cardiac surgery and thromboembolic events.
• Compound A has been found to selectively delay cardiac repolarization, thus prolonging the QT interval, and, in particular, to exhibit class III activity. Although Compound A has been found to exhibit class III activity in particular, in the treatment of arrhythmias, its mode(s) of activity is/are not necessarily restricted to this class.
• a method of treatment of an arrhythmia which method comprises administration of a therapeutically effective amount of Compound A to a person suffering from, or susceptible to, such a condition.
• Compound A will normally be administered orally, subcutaneously, intravenously, intraarterially, transdermally, intranasally, by inhalation, or by any other parenteral route, in the form of a pharmaceutical preparation comprising the active ingredient, in a pharmaceutically acceptable dosage form. Depending upon the disorder and patient to be treated, as well as the route of administration, Compound A may be administered at varying doses.
• Preferred pharmaceutical formulations include modified release pharmaceutical compositions comprising Compound A and a pharmaceutically-acceptable carrier and/or other means, which carrier or means (as appropriate) gives rise to a modified release of active ingredient, and which is adapted for oral administration.
• Suitable formulations include those in which Compound A is embedded in a polymer matrix. (e.g. in the form of a gelling matrix modified-release system comprising a hydrophilic gelling component and active ingredient).
• Suitable hydrophilic gelling components include xanthan, hydroxypropylcellulose, maltodextrin, scleroglucan, carboxypolymethylene, poly(ethylene oxide), hydroxyethylcellulose and hydroxypropylmethylcellulose. Such formulations may be prepared by way of standard techniques.
• Compound A may also be combined with any other drugs useful in the treatment of arrhythmias and/or other cardiovascular disorders.
• a pharmaceutical formulation including Compound A in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.
• Suitable daily doses of Compound A in the therapeutic treatment of humans are about 0.005 to 25.0 mg/kg body weight at oral administration and about 0.005 to 10.0 mg/kg body weight at parenteral administration.
• Preferable ranges of daily doses of Compound A in the therapeutic treatment of humans are about 0.005 to 10.0 mg/kg body weight at oral administration and about 0.005 to 5.0 mg/kg body weight at parenteral administration.
• Typical daily doses of Compound A are in the range 10 to 2000 mg, e.g. 25, such as 30, to 1200 mg of free base (i.e. excluding any weight resulting from the presence of the counter ion), irrespective of the number of compositions (e.g. tablets) that are administered during the course of that day.
• Preferred daily doses are in the range 50 to 1000 mg, such as 100 to 500 mg.
• Typical doses in individual compositions (e.g. tablets) are thus in the range 15 to 500 mg, for example 40 to 400 mg.
• Compound A has the advantage that it is effective against cardiac arrhythmias.
• Compound A may also have the advantage that it may be more efficacious than, be less toxic than, have a broader range of activity (including exhibiting any combination of class I, class II, class III and/or class IV activity (especially class I and/or class IV activity in addition to class III activity)) than, be more potent than, be longer acting than, produce fewer side effects (including a lower incidence of proarrhythmias such as torsades de pointes) tan, be more easily absorbed than, or that it may have other useful pharmacological properties over, compounds known in the prior art.
• Guinea pigs weighing between 660 and 1100 g were used. The animals were housed for at least one week before the experiment and had free access to food and tap water during that period.
• Anaesthesia was induced by an intraperitoneal injection of pentobarbital (40 to 50 mg/kg) and catheters were introduced into one carotid artery (for blood pressure recording and blood sampling) and into one jugular vein (for drug infusions). Needle electrodes were placed on the limbs for recording of ECGs (lead II). A thermistor was placed in the rectum and the animal was placed on a heating pad, set to a rectal temperature of between 37.5 and 38.5° C.
• a tracheotomy was performed and the animal was artificially ventilated with room air by use of a small animal ventilator, set to keep blood gases within the normal range for the species.
• a small animal ventilator set to keep blood gases within the normal range for the species.
• both vagi were cut in the neck, and 0.5 mg/kg of propranolol was given intravenously, 15 minutes before the start of the experiment.
• the left ventricular epicardium was exposed by a left-sided thoracotomy, and a custom-designed suction electrode for recording of the monophasic action potential (MAP) was applied to the left ventricular free wall.
• the electrode was kept in position as long as an acceptable signal could be recorded, otherwise it was moved to a new position.
• a bipolar electrode for pacing was clipped to the left atrium. Pacing (2 ms duration, twice the diastolic threshold) was performed with a custom-made constant current stimulator.
• the heart was paced at a frequency just above the normal sinus rate during 1 minute every fifth minute throughout the study.
• the blood pressure, the MAP signal and the lead II ECG were recorded on a Mingograph ink-jet recorder (Siemens-Elema, Sweden). All signals were collected (sampling frequency 1000 Hz) on a PC during the last 10 seconds of each pacing sequence and the last 10 seconds of the following minute of sinus rhythm. The signals were processed using a custom-made program developed for acquisition and analysis of physiological signals measured in experimental animals (see Axenborg and Hirsch, Comput. Methods Programs Biomed. 41, 55 (1993)).
• the test procedure consisted of taking two basal control recordings, 5 minutes apart, during both pacing and sinus rhythm. After the second control recording, the first dose of the test substance was infused in a volume of 0.2 mL into the jugular vein catheter for 30 seconds. Three minutes later, pacing was started and a new recording was made. Five minutes after the previous dose, the next dose of test substance was administered. Six to ten consecutive doses were given during each experiment.
• MAP duration at 75 percent repolarization s during pacing
• AV conduction time defined as the interval between the atrial pace pulse and the start of the ventricular MAP
• heart rate defined as the RR interval during sinus rhythm.
• Systolic and diastolic blood pressure were measured in order to judge the haemodynamic status of the anaesthetised animal. Further, the ECG was checked for arrhythmias and/or morphological changes.
• IC50 for K channel blockade was determined using a microtitre plate based screen method, based on membrane potential changes of glucocorticoid-treated mouse fibroblasts.
• the membrane potential of glucocorticoid-treated mouse fibroblasts was measured using fluorescence of the bisoxonol dye DiBac 4(3) , which could be reliably detected using a fluorescence laser imaging plate reader (FLIPR).
• FLIPR fluorescence laser imaging plate reader
• Expression of a delayed rectifier potassium channel was induced in mouse fibroblasts by 24 hours exposure to the glucocorticoide dexamehasone (5 ⁇ M). Blockade of these potassium channels depolarised the fibroblasts, resulting in increased fluorescence of DiBac 4(3) .
• Mouse ltk fibroblasts were purchased from American Type Culture Collection (ATCC, Manassa, Va.), and were cultured in Dulbeccos modified eagle medium supplemented with fetal calf serum (5 % vol/vol), penicillin (500 units/mL), streptomycin (500 ⁇ g/mL) and L-alanine-L-glutamine (0.862 mg/mL). The cells were passaged every 3-4 days using trypsin (0.5 mg/mL in calcium-free phosphate buffered saline, Gibco BRL). Three days prior to experiments, cell-suspension was pipetted out into clear-bottom, black plastic, 96-well plates (Costar) at 25 000 cells/well.
• DiBac 4(3) (DiBac Molecular probes) was used to measure membrane potential.
• DiBac 4(3) maximally absorbs at 488 nM and emits at 513 nM.
• DiBac 4(3) is a bisoxonol, and thus is negatively charged at pH 7. Due to its negative charge, the distribution of DiBac 4(3) across the membrane is dependent upon the transmembrane potential: if the cell depolarizes (i.e. the cell interior becomes less negative relative to cell exterior), the DiBac 4(3) concentration inside the cell increases, due to electrostatic forces. Once inside the cell, DiBac 4(3) molecules can bind to lipids and proteins, which causes an increase in fluorescence emission. Thus, a depolarization will be reflected by an increase in DiBac 4(3) fluorescence. The change in DiBac 4(3) fluorescence was detected by a FLIPR.
• Test substance was prepared in a second 96 well plate, in PBS containing 5 ⁇ M DiBac 4(3) .
• the concentration of substance prepared was 10 times that of the desired concentration in the experiment as an additional 1:10 dilution occurred during addition of substance during the experiment.
• Dofetilide (10 ⁇ M) was used as a positive control, i.e. to determine the maximum increase in fluorescence.
• the hepatic S-9 fraction from dog, man, rabbit and rat with NADPH as co-factor was used.
• the assay conditions were as follows: S-9 (3 mg/mL), NADPH (0.83 mM), Tris-HCl buffer (50 mM) at pH 7.4 and 10 ⁇ M of test compound.
• test compound was started by addition of test compound and terminated after 0, 1, 5, 15 and 30 minutes by raising the pH in the sample to above 10 (NaOH; 1 mM). After solvent extraction, the concentration of test compound was measured against an internal standard by LC is (fluorescence/UV detection).
• Mass spectra were recorded on one of the following instruments: a Waters ZMD single quad with electrospray (S/N mc350); a Perkin-Elmer SciX API 150ex spectrometer; a VG Quattro II triple quadrupole; a VG Platform II single quadrupole; or a Micromass Platform LCZ single quadrupole mass spectrometer (the latter three instruments were equipped with a pneumatically assisted electrospray interface (LC-MS)).
• LC-MS pneumatically assisted electrospray interface
• 1 H NMR and 13 C NMR measurements were performed on a BRUKER ACP 300 and Varian 300, 400 and 500 spectrometers, operating at 1 H frequencies of 300, 400 and 500 MHz respectively, and at 13 C frequencies of 75.5, 100.6 and 125.7 MHz respectively.
• 13 C NMR measurements were performed on a BRUKER ACE 200 spectrometer at a frequency of 50.3 MHz.
• Rotamers may or may not be denoted in spectra depending upon ease of interpretation of spectra Unless otherwise stated, chemical shifts are given in ppm with the solvent as internal standard.
• IMS (2.5 L, 10 vol) was added to the dichloromethane solution from step (iii) above. The solution was distilled until the internal temperature reached 70° C. Approximately 1250 mL of solvent was collected. More IMS (2.5 L, 10 vol) was added followed by benzylamine (120 mL, 0.7 eq.) in one portion (no exotherm seen), and the reaction was heated at reflux for 6 hours (no change from 2 hour sampling point). More benzylamine was added (15 mL) and the solution was heated for a further 2 hours. The IMS was distilled off (ca. 3.25 L) and toluene was added (2.5 L). More solvent was distilled (ca.
• the reaction was then left to cool to 30° C. and deionised water (250 mL) was added. This caused the temperature to rise from 30° C. to 45° C. More water (2.15 L) was added over a total time of 30 minutes such that the temperature was less than 54° C.
• the solution was cooled to 30° C. and then dichloromethane (2 L) was added.
• the reaction mixture was basified by adding aqueous sodium hydroxide (10 M, 2 L) at a rate that kept the internal temperature below 38° C. This took 80 minutes. The stirring was stopped and the phases separated in 3 minutes.
• the toluene phase was discarded along with a small amount of interfacial material.
• the acidic phase was returned to the original reaction vessel and sodium hydroxide (10 M, 1.4 L, 3.5 rel. vol.) was added in one portion. The internal temperature rose from 30° C. to.80° C. The pH was checked to ensure it was >14. Toluene (1.6 L, 4 rel. vol.) was added and the temperature fell from 80° C. to 60° C. After vigorous stirring for 30 minutes, the phases were partitioned. The aqueous layer was discarded along with a small amount of interfacial material. The toluene phase was returned to the original reaction vessel, and 2-propanol (4 L, 10 rel. vol.) was added.
• the temperature was adjusted to between 40° C. and 45° C. Concentrated hydrochloric acid (200 mL) was added over 45 minutes such that the temperature remained at between 40° C. and 45° C. A white precipitate formed. The mixture was stirred for 30 minutes and then cooled to 7° C. The product was collected by filtration, washed with 2-propanol (0.8 L, 2 rel vol.), dried by suction and then further dried in a vacuum oven at 40° C.
• This reaction may also be performed using a lower weight ratio of catalyst to benzylated starting material.
• This may be achieved in several different ways, for example by using different catalysts (such as Pd/C with a metal loading different from that in the Type 440L catalyst employed above, or Rh/C) and/or by improving the mass transfer properties of the reaction mixture (the skilled person will appreciate that improved mass transfer may be obtained, for example, by performing the hydrogenation on a scale larger than that described in the above reaction).
• the weight ratio of catalyst to starting material may be reduced below 4:10 (e.g. between 4:10 and 1:20.).
• the crude benzenesulfonate salt was alternatively prepared by the addition of a 70% (w/w) aqueous solution of benzenesulfonic acid to an ethanolic solution of the free base.
• the organic layer (volume 570 mL) was collected and distilled at atmospheric pressure to remove DCM (450 mL, pot temperature 40-42° C., still-head temperature 38-39° C.). Ethanol (250 mL) was added, and the solution was allowed to cool to below 30° C. before turning on the vacuum. More solvent was removed (40 mL was collected, pressure 5.2 kPa (52 mbar), pot and still-head temperatures were 21-23° C.), and the product gradually came out of solution. The distillation was stopped at this point, and more ethanol (50 mL) was added. The mixture was warmed (hot water bath at 50° C.) to 40° C.
• Ethanol 160 mL, 8 vols was added to the crude product (20.00 g, 63.22 mmol, 1.0 eq). The mixture was stirred under nitrogen and warmed to 40° C. using a hot water bath. On reaching this temperature, all of the solid had dissolved to give a clear, yellow solution. Water (60 mL, 3 vols) was added dropwise over a period of 10 minutes, whilst the internal temperature was maintained in the range 38-41° C. The water bath was removed, and the solution was allowed to cool to 25° C. over 40 minutes, by which time crystallisation had begun. The mixture was cooled to ⁇ 5° C. over 10 minutes, then held at this temperature for a further 10 minutes.
• the pale yellow solid was collected by filtration, suction dried for 10 minutes, then dried to constant weight in a vacuum oven (40° C., 15 hours).
• the mass of title compound obtained was 18.51 g (58.51 mmol, 93% (from the crude product)).
• API atmospheric pressure ionisation (in relation to MS)
• NADPH nicotinamide adenine dinucleotide phosphate
• n-, s-, i-, t- and tert- have their usual meanings: normal, secondary, iso, and tertiary.

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