WO2002038557A9 - Benzoylbenzofurane derivatives for treatment of cardiac arrhythmia - Google Patents
Benzoylbenzofurane derivatives for treatment of cardiac arrhythmiaInfo
- Publication number
- WO2002038557A9 WO2002038557A9 PCT/US2001/031305 US0131305W WO0238557A9 WO 2002038557 A9 WO2002038557 A9 WO 2002038557A9 US 0131305 W US0131305 W US 0131305W WO 0238557 A9 WO0238557 A9 WO 0238557A9
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- WIPO (PCT)
- Prior art keywords
- alkyl
- compound
- aryl
- group
- heteroaryl
- Prior art date
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
- C07D307/80—Radicals substituted by oxygen atoms
-
- 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
- CHF Congestive heart failure
- a Class-m agent as referred to herein, is an agent which is classified as such in the Naughan- Willia s classification of antiarrhythmic drugs.
- a Class-IH agent exerts its primary antiarrhythmic activity by prolonging cardiac action potential duration (APD), and thereby the effective refractory period (ERP), with no effect on conduction.
- Amiodarone is an antiarrhythmic agent having vasodilator properties that may benefit patients with severe heart failure.
- Amiodarone has been shown to improve survival of post-myocardial infarction patients with asymptomatic high-grade ventricular arrhythmias, and it proved efficacious in patients resistant to other antiarrhythmic drugs without impairing left ventricular function.
- Cardioprotective agents and methods which employ amiodarone in synergistic combination with vasodilators and beta blockers have been described for use in patients with coronary insufficiency (U.S. Patent No. 5,175,187).
- Amiodarone has also been described for reducing arrhythmias associated with CHF as used in combination with antihypertensive agents, e.g., (S)-l-[6-amino-2- [[hydroxy(4-phenylbutyl)phosphinyl]oxyl]-L-proline (U.S. Patent No. 4,962,095) and zofenopril (U.S. Patent No. 4,931,464).
- amiodarone is a difficult drug to manage because of its numerous side effects, some of which are serious.
- amiodarone The most serious long-term toxicity of amiodarone derives from its kinetics of distribution and elimination. It is absorbed slowly, with a low bioavailability and relatively long half-life. These characteristics have clinically important consequences, including the necessity of giving loading doses, a delay in the achievement of full antiarrhythmic effects, and a protracted period of elimination of the drug after its administration has been discontinued. Amiodarone also can interact negatively with numerous drugs including aprindine, digoxin, flecainide, phenytoin, procainamide, quinidine, and warfarin.
- amiodarone Numerous adverse effects limit the clinical applicability of amiodarone. Important side effects can occur including corneal microdeposits, hyperthyroidism, hypothyroidism, hepatic dysfunction, pulmonary alveolitis, photosensitivity, dermatitis, bluish discoloration, and peripheral neuropathy.
- the subject invention pertains to novel compounds, and compositions comprising the compounds, for the treatment of cardiac arrhythmias.
- the subject invention further concerns a method of making the novel compounds.
- the novel compounds are rapidly metabolized analogs of amiodarone, having the distinct and advantageous characteristic of being metabolized to a less lipophilic compound.
- the new compounds can have particular utility for treating life-threatening ventricular tachyarrhythmias, especially in patients with congestive heart failure (CHF).
- CHF congestive heart failure
- the product can also provide effective management for ventricular arrhythmias and supraventricular arrhythmias, including atrial fibrillation and re-entrant tachyarrhythmias involving accessory pathways.
- novel compounds have the particular advantage of reducing the numerous side effects observed with the drugs currently available for treatment of these cardiac arrhythmias.
- the compound of choice currently used for treating cardiac arrhythmias is amiodarone, which has side effects that can be serious.
- novel synthesis procedures for the production of the novel compounds.
- One of the novel synthesis procedures essentially involves acylation of salicylaldehyde followed by cyclization and chain elongation reactions to form methyl-2- benzofuraneacetate. This compound is reacted with p-anisoylchloride involving a Friedel- Crafts type reaction which can use SnCl 4 as a catalyst. The compound resulting from the
- An alternative synthesis procedure which also uses salicylaldehyde as a starting compound, involves a cyclization step to form 2-acetylbenzofuran. This compound is then converted to its thiomorpholide derivative, which can be further converted to 2- benzofurane acetic acid, which is also formed in the other described synthesis procedure.
- the synthesis procedures are identical after formation of 2-benzofurane acetic acid.
- the subject invention thus involves the innovative development of a Class-m antiarrhythmic agent having significantly lower toxicity than any currently available compound useful in patients with congestive heart failure (CHF).
- CHF congestive heart failure
- Figures 1A and IB show the step-wise reaction scheme which results in the synthesis of the novel compound, methyl 2-[3-(3,5-diiodo-4- diethylaminoethoxybenzoyl)benzofurane] acetate and its hydrochloride salt form.
- FIG 2 shows an alternative synthetic scheme, where 2-benzofurane acetic acid, compound 7, can be made by synthesizing 2-acetylbenzofuran 13 from salicylaldehyde, followed by a chain elongation procedure known as the Willgerodt-Kindler reaction in order to make the thiomorpholide derivative 14 which is then hydrolyzed to compound 7.
- Figures 3A-3D show the time course of the electrophysiological effects of equimolar concentrations of compound A and amiodarone in spontaneously beating guinea pig hearts.
- Figure 3A is the change in atrial rate versus time plots for equimolar concentrations of amiodarone (v) and compound A (•), versus a control (o).
- Figure 3B is the change in atrioventricular (AN) interval plots for equimolar concentrations of amiodarone (v) and compound A (•), versus a control (o).
- Figure 3C is the change in QRS interval (intraventricular conduction time) plots for equimolar concentrations of amiodarone (v) and compound A (•), versus a control (o).
- Figure 3D is the change in QT interval (repolarization time) plots for equimolar concentrations of amiodarone (v) and compound A (•), versus a control (o).
- Figures 4A-4D show the time course of the electrophysiological effects of equimolar concentrations of compound A and amiodarone in atrially-paced guinea pig hearts.
- Figure 4A is the change in S-H interval (atrioventricular nodal conduction time) plots for equimolar concentrations of amiodarone (•) and compound A (v), versus a control (o).
- Figure 4B is the change in HN interval (His-Purkinje conduction time) plots for equimolar concentrations of amiodarone (•) and compound A (v), versus a control (o).
- Figure 4C is the change in QRS interval (intraventricular conduction time) plots for equimolar concentrations of amiodarone (•) and compound A (v), versus a control (o).
- Figure 4D is the change in QT interval (repolarization time) plots for equimolar concentrations of amiodarone (•) and compound A (v), versus a control (o).
- Figure 5 shows time course of the electrophysiological effects of amiodarone (5 ⁇ M) in atrially-paced guinea pig hearts.
- the subject invention concerns novel compounds which can produce the desired pharmacological properties of amiodarone but, unlike amiodarone, are susceptible to biotransformation by plasma and tissue esterases to give a carboxylic acid metabolite.
- Carboxylic acids can form water-soluble salts at physiological pH, and therefore can undergo renal elimination.
- the novel compounds exemplified herein by compound A, can have shorter elimination half-life. Accordingly, long-term toxicity symptoms (pulmonary fibrosis, corneal microdeposits, etc.) decrease.
- Z, and Z ⁇ may be the same, or different, and are a halogen selected from the group consisting of iodine, fluorine, bromine, and chlorine and X is O, S, or NH; m has a value from 0-10;
- R H, OH, NH 2 , SH, halide, alkyl, O-alkyl, acyl, O-acyl, aryl, O-aryl, substituted amine, or substituted thiol;
- Y OR ! , wherein R x is a straight or branched chain alkyl or hetero alkyl having 1 to 8 carbon atoms, a substituted or unsubstituted aryl or heteroaryl, or
- R 2 , and R 3 are independently selected from H, alkyl or heteroalkyl of 1 to 6 carbon atoms; or m has a value from 0-10;
- R l5 R 2 , and or R 3 may also be a moiety selected from the group consisting of C n . 20 alkyl, C n . 20 heteroalkyl, C 2 . 20 alkenyl, aryl, C 2 alkyl-aryl, C 2 . 20 alkenyl-aryl, heteroaryl, C ⁇ _ 20 alkyl-heteroaryl, C 2 .
- the value for n maybe from 1 to 19.
- R 2 and R 3 may be the same or different.
- m may have a value from 0 to 10.
- m is 4.
- m is 3.
- m is 2.
- m is 0.
- m is 1.
- the structure includes an iodinated benzene ring moiety.
- C n . 20 alkyl refers to straight or branched chain alkyl moiety having from one to twenty carbon atoms, including for example, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl and the like. In one embodiment, n is at least one, in an alternative embodiment, n is at least 2.
- C 2.20 alkenyl refers to a straight or branched chain alkyl moiety having two to twenty carbon atoms and having at least one double bond. This term would include for example, vinyl, 1-propenyl, 1- and 2-butenyl, 2-methyl-2-propenyl etc.
- cycloalkyl refers to a saturated alicyclic moiety having from three to six carbon atoms and which is optionally benzofiised at any available position. This term includes for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, indanyl and tetrahydronaphthyl.
- heterocycloalkyl refers to a saturated heterocyclic moiety having from three to six atoms. One or more of these atoms maybe heteroatoms selected from N, O, S and oxidized versions thereof, and which is optionally benzofused at any available position. This term includes, for example, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, indolinyl and tetrahydroquinolinyl.
- cycloalkenyl refers to an alicyclic moiety having from three to six carbon atoms and having at least one double bond. This term includes, for example, cyclopentenyl and cyclohexenyl.
- heterocycloalkenyl refers to an alicyclic moiety having from three to six atoms. One, or more, of these atoms maybe heteroatoms selected from N, O, S and oxidized versions thereof, and having in addition one double bond. This term includes, for example, dihydropyranyl.
- aryl refers to an aromatic carbocyclic radical having a single ring or two condensed rings. This term includes, for example phenyl or naphthyl.
- heteroaryl refers to aromatic ring systems of five to ten atoms of which at least one atom is selected from O, N and S, and includes, for example, furanyl, thiophenyl, pyridyl, indolyl, quinolyl and the like.
- the ring may be optionally benzofused at any available position. Examples include succinimidoyl, phthalimidoyl and hydantoinyl.
- benzofused refers to the addition of a benzene ring sharing a common bond with the defined ring system.
- optionally substituted means optionally substituted with one or more of the groups specified, at any available position or positions.
- halogen means fluorine, chlorine, bromine or iodine.
- the novel compounds can also be provided in their salt form.
- the invention includes pharmaceutically acceptable salts, for example acid addition salts derived from inorganic or organic acids, such as hydrohlorides, hydrobromides, p-toluenesulfonates, phosphates, sulfates, perchlorates, acetates, trifluororacetates, proprionates, citrates, malonates, succinates, lactates, oxalates, tartrates, and benzoates.
- inorganic or organic acids such as hydrohlorides, hydrobromides, p-toluenesulfonates, phosphates, sulfates, perchlorates, acetates, trifluororacetates, proprionates, citrates, malonates, succinates, lactates, oxalates, tartrates, and benzoates.
- Salts may also be derived from bases (organic and inorganic), such as alkali metal salts (e.g., magnesium or calcium salts), or organic amine salts, such as morpholine, piperidine, dimethylamine, or diethylamine salts.
- bases organic and inorganic
- alkali metal salts e.g., magnesium or calcium salts
- organic amine salts such as morpholine, piperidine, dimethylamine, or diethylamine salts.
- the ring structure moieties of the novel compounds can be derivatized by methods and procedures well known by those of ordinary skill in the art.
- R-groups can be attached to the six- membered ring of the benzofuran moiety of the subject compound, wherein the R groups can include H, OH, NH 2 , SH, halides, alkyl, O-alkyl, acyl, O-acyl, aryl, O-aryl groups, substituted amines, and substituted thiols.
- R is H and X is O.
- the subject invention encompasses the novel compound A and compositions comprising these compounds.
- the successful application of the new compounds to the treatment of CHF is evidenced by the evaluation of the thermodynamic properties of the compound, e.g., measuring its partition coefficient between water and octanol, evaluation of its kinetics of elimination by measuring its stability in buffer and in human plasma, and evaluation of its electrophysiological properties in guinea pig heart preparations. See Examples hereinbelow.
- the novel compounds can be used for treating life-threatening ventricular tachyarrhythmias, especially in patients with congestive heart failure.
- This product can provide effective management of not only ventricular tachyarrhythmias and less severe ventricular arrhythmias, but also atrial fibrillation and reentrant tachyarrhythmias involving accessory pathways.
- a composition comprising a novel compound having a rapid elimination rate can offer many advantages over the currently available antiarrhythmic agents such as amiodarone. These advantages include: (i) a shorter onset of action,
- novel compounds can be included in a composition comprising a second active ingredient.
- the second active ingredient can be useful for concurrent or synergistic treatment of arrhythmia or for the treatment of an unrelated condition which can be present with or result from arrhythmia or CHF.
- the subject compounds have thermodynamic properties similar to those of amiodarone, as suggested by log P measurements, but provide the advantageous property of being rapidly metabolized in plasma to a water-soluble metabolite. More specifically, the subject compounds are Class-m agents with electronic, steric, and thermodynamic properties comparable to those of amiodarone, but with an enzymatically labile ester group advantageously built into the structure such that the drug can be readily hydrolyzed in plasma to a polar, water-soluble metabolite. This water-soluble metabolite can be eliminated by the kidneys. This is a definite advantage over amiodarone, which is metabolized primarily in the liver.
- the elimination of the novel compound A is increased and results in a more rapid dissociation of the drug from phospholipid-binding sites.
- the accumulation of the compound which is dependent on the steady-state tissue concentration of the drug, and therefore on the dose, then becomes easily reversible. It follows that, upon discontinuation of a drug comprising one of the novel compounds, clearance from the body is more rapid. This increased elimination makes antiarrhythmic therapy using the subject compounds or compositions comprising the subject compounds easier to manage.
- the compounds of the invention maybe administered in conjunction with other compounds, or compositions thereof.
- These compounds, and compositions thereof may include additional compounds known to be useful for the treatment of cardiac arrhythmias, cardioprotective agents, antibiotics, antiviral agents, or thrombolytic agents (e.g., streptokinase, tissue plasminogen activator, or recombinant tissue plasminogen activator).
- the compounds and compositions of the invention can have particular usefulness for treating life-threatening ventricular tachyarrhythmias, especially in patients with congestive heart failure (CHF).
- CHF congestive heart failure
- Post-myocardial infarction patients can also benefit from the administration of the subject compounds and compositions; thus, methods of treating post-myocardial infarction patients are also provided by the subject invention.
- Cardioprotective agents include vasodilators and beta blockers described for use in patients with coronary insufficiency (such as those of U.S. Patent No. 5,175,187 or others known to the skilled artisan).
- Other cardioprotective agents include known anti- hypertensive agents, e.g., (S)-l-[6-amino-2-[[hydroxy(4-phenylbutyl)phosphinyl]oxyl]-L- proline (U.S. Patent No. 4,962,095) and zofenopril (U.S. Patent No. 4,931,464).
- Additional cardioprotective agents include, but are not limited to, aspirin, heparin, warfarin, digitalis, digitoxin, nitroglycerin, isosorbide dinitrate, hydralazine, nitroprusside, captopril, enalapril, and lisinopril.
- the compounds and compositions also provide effective management for ventricular arrhythmias and supraventricular arrhythmias, including atrial fibrillation and re-entrant tachyarrhythmias involving accessory pathways.
- Compounds and compositions of the invention are also useful for the treatment of ventricular and supra- ventricular arrhythmias, including atrial fibrillation and flutter, paroxysmal supraventricular tachycardia, ventricular premature beats (VPB), sustained and non-sustained ventricular tachycardia (NT), and ventricular fibrillation (NF).
- arrhythmias which may be treated by the compounds of the instant invention include: narrow QRS tachycardia (atrial, intra- /para- A-N node, or accessory pathway),venrricular tachycardia, and ventricular arrhythmias in cardiomyopathy.
- narrow QRS tachycardia atrial, intra- /para- A-N node, or accessory pathway
- venrricular tachycardia ventricular arrhythmias in cardiomyopathy.
- novel compounds can be synthesized according to the scheme set out in Figures 1A and IB. Below, the steps of the procedure, as shown in Figures 1A-1B, are described in detail. The primary compounds involved in the synthesis step are numbered corresponding to the numbers provided in Figures 1 A and IB.
- Methyl o-formylphenoxyacetate 2. Approximately 509 g of the starting compound, salicylaldehyde (1) was introduced into a 4-liter Erlenmeyer flask with powdered potassium carbonate (569 g), dimethylformamide (1,000 ml), and methyl chloroacetate (478 g) and mechanically stirred at 65 °C for about 24 hours. The stirring was stopped and the reaction mixture cooled to 25 °C. The mixture was poured into cold water (0°C) while stirring vigorously. An oil separated that suddenly solidified. Stirring was continued for 30 minutes and the solid isolated by filtration. The product was washed with water (2 x 1,000 ml) and pressed dry. The product can also be dried in vacuo at
- Methyl 2-benzofuranecarboxylate 3.
- the crude product 2 was placed into a 5- liter 3-necked round-bottomed flask equipped with a mechanical stirrer and a water trap.
- 2-Benzofuraneacetic acid 7.
- the crude cyanomethylbenzofuran, compound 6, was stirred for 6 hours in boiling water (1,000 ml) containing sodium hydroxide (80 g), cooled to 25 ° C, then washed with methylene chloride (250 ml, then 2 x 100 ml).
- the pH was brought to 2.0 with 6 N HCl.
- the precipitate was extracted with methylene chloride (200 ml, then 100 ml, then 50 ml), dried over magnesium sulfate and the solvent evaporated. The yield was approximately 72 g.
- Methyl 2-benzofuraneacetate 8. Compound 7 (72 g) was dissolved in methanol (200 ml) and the solution saturated with dry HCl. The solution was refluxed for 2 hours and the solvent evaporated. The residue was dissolved in methylene chloride (200 ml) and the solution washed with 5% sodium bicarbonate, and then with water (100 ml). The residue was dried over magnesium sulfate and the solvent was evaporated. The product was distilled in vacuo. The yield was approximately 67.3 g. Methyl 2-(3-anisoylbenzofurane acetate: 9.
- 2-(3-p-hydroxybenzoylbenzofurane)acetic acid 10.
- Aluminum powder (45 g), benzene (900 ml), and iodine crystals (345 g) were introduced in a 2-liter flask with efficient reflux condenser and mechanical stirrer. The solution was placed in a water bath and stirred until most of the heat had dissipated, then stirred at reflux temperature until the red color of iodine disappeared (approx. 30 minutes).
- This mixture was cooled to 25 °C then, while stirring, compound 9 (70 g) and tetrabutylammonium iodide (0.86 g) were added.
- Example 2 Alternative Synthetic Route for the Novel Compounds
- 2-benzofurane acetic acid, compound 7 can be made by an alternative reaction that involves synthesizing 2- acetylbenzofuran 13 from salicylaldehyde 1 reacted with chloroacetone, followed by a chain elongation procedure known as the Willgerodt-Kindler reaction in order to make the thiomorphohde derivative 14 which is then hydrolyzed to compound 7.
- the remainder of the synthetic scheme to the novel compound A is then essentially identical to Example
- the volume of the solution is brought to 6 liters with water. NaOH (40 g) and activated decolorizing charcoal (5 g) are added and the mixture is stirred at reflux temperature for 60 minutes, then filtered through celite. The mixture is then acidified to pH 2 with 12 N HCl, and the product is extracted with ethyl acetate. The extract is dried over sodium sulfate and evaporated, yielding approximately 289 g of a dark solid. The crude product can be used for the next step without further purification. All physical properties of this product are identical to compound 7, and can be used in an identical manner as compound 7 in the synthesis scheme described in Example 1, above.
- thermodynamic properties of the new compound A can be evaluated by measuring its partition coefficient, P, between a pH 7.4 phosphate buffer and octanol.
- the buffer solution and octanol are mutually saturated before the experiment.
- the test compounds can be dissolved in the octanol :buffer mixture at such a concentration that neither phase is saturated.
- the volume ratio between buffer and octanol is adjusted so that the concentration of compound in water after equilibrium is measurable.
- the mixture is shaken for 1 hour and centrifuged in order to obtain complete separation of the two phases.
- the concentration of test compound can be measured in the aqueous phase before and after equilibrium, using a UN detection method.
- Analytical method Standard HPLC techniques can be used to determine the concentration of the drug in buffer and in human plasma using standard analytical procedures known in the art. Stability in buffer. A known concentration of the novel compound A can be incubated in a pH 7.4 phosphate buffer at 37°C. Aliquots of the solution can be taken at various recorded intervals and diluted to the appropriate concentration for injection into the HPLC system.
- the hydrolysis rate constant, K, in buffer can be calculated from the plot of drug concentration vs. time. Metabolism rate in human plasma. The same procedure as above can be used with human plasma instead of buffer. The rate constant in plasma can be compared to the rate constant in buffer in order to give an approximated rate of metabolism by plasma enzymes.
- Example 5 Electrophysiological Properties in Guinea Pig Heart Antiarrhythmic activity in guinea pig heart preparations can be tested for the novel compound A by methods and techniques well known by those of ordinary skill in the art. Antiarrhythmic activity in guinea pig heart preparations is accepted in the art as a model for antiarrhythmic activity in humans. Specifically, activity in guinea pig heart preparations is used to show that a compound depresses the spontaneous discharge, slows the sinus node spontaneous firing rate, prolongs the effective refractory period (ERP), slows the intra-atrial conduction, suppresses atrial premature beats, prolongs the ventricular ERP, and decreases ventricular excitability. Microelectrode and pacing techniques can be used as are standard in the art.
- Assays to show such activity can be conducted in the isolated, superfused guinea pig S-A node-right atrial preparation.
- a full dose-response curve for compound A can be calculated in each preparation in order to demonstrate the effects of different doses on S-A node spontaneous rate, atrial action potential duration (APD) and ERP, and on ventricular APD and ERP.
- the EC 50 (the effective concentration that produces 50% of the maximum response), as well as the threshold and maximum doses for the compound can be determined from the full dose- response curve.
- the results of electrophysiological studies carried out in guinea pig isolated hearts using the subject compound, compound A showed that compound A displays electrophysiological properties classically associated with Class m antiarrhythmic agents.
- amiodarone in the clinical setting is its long half- life (> 30 days), which can cause severe life-threatening side effects that are slow to resolve even after discontinuation of drug therapy.
- the advantages of compound A over amiodarone or other currently used antiarrhythmics are that it exhibits more selective antiarrhythmic action, has a potentially shorter half-life, and has cardiac effects which are more easily reversed ("washed") upon cessation of drug treatment.
- Step 4 Synthesis of (3.5-diiodo-4-hydroxybenzoyDbenzofurane-2-propionic acid (6) 3 OOg of compound 5 are dissolved in 200ml of acetic acid and 300ml of 12N HCl.
- Step 5 Synthesis of -sec-butyl 3-(3.5-diiodo-4-hydroxybenzoyl)benzofurane-2- propionate (7)
- Step 6 Synthesis of sec-butyl 3-(3,5-diiodo-4-diethylaminoethoxybenzoyD benzofurane-2-propionate f8)
- Example 7 Uses. Formulations, and Administrations
- compositions containing compounds of the invention as active ingredients are useful in prophylactic or therapeutic treatment of cardiac arrhythmias in humans or other mammals.
- dosage administered will be dependent upon the response desired; the type of host involved; its age, health, weight, kind of concurrent treatment, if any; frequency of treatment; therapeutic ratio and like considerations.
- dosage levels of the adininistered active ingredients can be, for examples, dermal, 1 to about 500 mg/kg; orally, 0.01 to 200 mg/kg; intranasal 0.01 to about 100 mg/kg; and aerosol 0.01 to about 50 mg/kg of animal body weight.
- the active ingredient of the invention can be present in the new compositions for use dermally, intranasally, bronchially, intramuscularly, intravaginally, intravenously, or orally in a concentration of from about 0.01 to about 50% w/w of the composition, and especially from about 0.1 to about 30% w/w of the composition.
- the novel compound is present in a composition from about 1 to about 10% and, most preferably, the novel composition comprises about 5% novel compound.
- compositions of the invention are advantageously used in a variety of forms, e.g., tablets, ointments, capsules, pills, powders, aerosols, granules, and oral solutions or suspensions and the like containing the indicated suitable quantities of the active ingredient.
- Such compositions are referred to herein and in the accompanying claims generically as "pharmaceutical compositions.”
- they can be in unit dosage form, namely, in physically discrete units suitable as unitary dosages for human or animal subjects, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic or prophylactic effect in association with one or more pharmaceutically acceptable other ingredients, e.g., diluent or carrier.
- the active ingredients can be packaged in pressurized aerosol containers with a propellant, e.g., carbon dioxide, nitrogen, propane, etc. with the usual adjuvants such as cosolvents, wetting agents, etc.
- a propellant e.g., carbon dioxide, nitrogen, propane, etc.
- adjuvants such as cosolvents, wetting agents, etc.
- the active ingredient can be mixed with a diluent vehicle such as cocoa butter, viscous polyethylene glycols, hydrogenated oils, and such mixtures can be emulsified if desired.
- a diluent vehicle such as cocoa butter, viscous polyethylene glycols, hydrogenated oils, and such mixtures can be emulsified if desired.
- compositions comprise, as an inactive ingredient, an effective amount of one or more non-toxic, pharmaceutically acceptable ingredient(s).
- ingredients for use in the compositions include ethanol, dimethyl sulfoxide, glycerol, silica, alumina, starch, calcium carbonate, talc, flour, and equivalent non-toxic carriers and diluents.
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Abstract
Description
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Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
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AU1147902A AU1147902A (en) | 2000-10-06 | 2001-10-04 | Novel compound for treatment of cardiac arrhythmia, synthesis and methods of use |
EP01979531A EP1322630A2 (en) | 2000-10-06 | 2001-10-04 | Benzoylbenzofurane derivatives for treatment of cardiac arrhythmia |
AU2002211479A AU2002211479B2 (en) | 2000-10-06 | 2001-10-04 | Benzoylbenzofurane derivatives for treatment of cardiac arrhythmia |
CA002425245A CA2425245A1 (en) | 2000-10-06 | 2001-10-04 | Novel compounds for treatment of cardiac arrhythmia synthesis, and methods of use |
JP2002541092A JP2004513167A (en) | 2000-10-06 | 2001-10-04 | Benzoylbenzofuran derivatives for treating cardiac arrhythmias |
Applications Claiming Priority (6)
Application Number | Priority Date | Filing Date | Title |
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US08/078,371 US5364880A (en) | 1993-06-16 | 1993-06-16 | Compound for treatment of cardiac arrhythmia, synthesis, and methods of use |
US08/260,869 US5440054A (en) | 1993-06-16 | 1994-06-16 | Compound for treatment of cardiac arrhythmia, synthesis, and methods of use |
US08/468,602 US5849788A (en) | 1993-06-16 | 1995-06-06 | Compound for treatment of cardiac arphythmia, synthesis, and methods of use |
US09/211,246 US6130240A (en) | 1993-06-16 | 1998-12-14 | Compound for treatment of cardiac arrhythmia, synthesis, and methods of use |
US09/680,880 | 2000-10-06 | ||
US09/680,880 US6316487B1 (en) | 1993-06-16 | 2000-10-06 | Compounds for treatment of cardiac arrhythmia synthesis, and methods of use |
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US5364880A (en) * | 1993-06-16 | 1994-11-15 | Advanced Therapies, Inc. | Compound for treatment of cardiac arrhythmia, synthesis, and methods of use |
DK1222180T3 (en) * | 1999-10-15 | 2007-12-27 | Aryx Therapeutics | Enantiomeric compounds for the treatment of cardiac arrhythmias and methods of use |
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WO2002038557A2 (en) | 2002-05-16 |
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