Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/16—Amides, e.g. hydroxamic acids
  • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide

Definitions

• antiarrhythmic drugs are available for treating arrhythmias. They have even been classified into four groups or classes based on the dominant electrophysiological property of each drug. The most common of the antiarrhythmic drugs include quihidine, procainamide (The Merck Index, Tenth Edition, Merck & Co., Inc., Rahway, NJ, 1983, Monograph number 7658), disopyramide (number 3378), phenytoin (number 7204), lidocaine (number 5310), mexiletine (number 6047), encainide (US Patent 3,931, 195).
• tocainide (number 9319), lorcainide (number 5401), N-acetylprocainamide (number 14), ethmozin (number 6121), propranolol (number 7740), metoprolol (number 6027), nadolol (number 6195), timolol, atenolol (number 868), bretylium (number 1348), amiodarone (number 491), sotolol (number 8571) flecainide (number 4019) and indecainide and verapamil (number 9747).
• US Patents 4,098,904, 4,145,435 and 4,438,130 claimed benzamide, benzeneacetamide and spirocyclobenzamide and benzeneacetamide type compounds, respectively, which were disclosed as having analgesic utility.
• These compounds as well as other known amides disclosed in US Patents 4,360,531. 4,359,476, 4,466,977, 4,460,600 and in European Patent Applications 84303277.2 and 84303698.9 and US patent application Serial No. 614,408 filed May 25, 1984 have surprisingly and unexpectedly been found to be useful as antiarrhythmic agents. It is known that naloxone, a agonist/antagonist analgesic has antiarrhythmic properties. This was presented by J. W.
• benzamide type antiarrhythmics include encainide hydrochloride, acecainide, capobenate sodium, capobenic acid, flecainide acetate, procainamide hydrochloride, tocainide and tolamolol.
• an arrhythmia which comprises administering an antiarrhythmic effective amount of an aminocycloalkylamide of formula (I) and pharmaceutically acceptable salts thereof.
• a method of preventing sudden cardiac death in a human where the sudden death is precipitated by a disorder of the cardiac rhythm or conduction which comprises administering an antiarrhythmic effective amount of an aminocycloalkylamide of formula (I) or pharmaceutically acceptable salts thereof.
• arrhythmias atrial, ventricular, supraventricular, and junctional.
• the arrhythmias alone are not usually fatal to an individual. It is believed that during a ventricular arrhythmia something will cause a heart to begin to fibrillate which is the immediate cause of sudden cardiac death which claims about 400,000 victims each year in the United States.
• Other types of cardiac arrhythmias have also been associated with sudden cardiac death.
• the method of treatment of the present invention improves the cardiac rhythm of an individual who has arrhythmias by decreasing the frequency of arrhythmic events, thereby decreasing the likelihood of ventricular tachycardia, fibrillation, asystole and/or other rhythm disturbances which in turn prevents an adequate cardiac output, thereby reducing the risk of sudden cardiac death.
• the method also reduces the number and severity of arrhythmic events as well as prevents future arrhythmic events.
• the method of treatment of the present invention would also decrease the number, frequency and/or severity of annoying patient symptoms resulting from arrhythmias such as palpitations, fainting and syncope as well as prevents future symptoms.
• the method of treatment of the present invention is also useful in maintaining the normal rhythm in an individual who previously had an arrhythmia but does not at the present time. It is particularly important to maintain the normal rhythm by preventing recurrence of an arrhythmia that had been treated initially by electrical cardioverslon.
• the method of treatment of the present invention is useful in preventing sudden cardiac death in a human where the sudden cardiac death is precipitated by a disorder of the cardiac rhythm or conduction.
• the disorder of cardiac rhythm is an arrhythmia; and the arrhythmia is usually a ventricular arrhythmia.
• the present invention is useful in preventing arrhythmias in an individual who has never had an arrhythmia but who is at risk of developing an arrhythmia.
• the cardiac risk usually being cardiac disease or one of the many cardiac conditions listed above.
• the aminocycloalkylamldes (I), which are useful as antiarrhythmic agents have two asymmetric centers if R 3 equals R 4 (and three asymmetric centers if R 3 does not equal R 4 ) in the cycloalkyl ring which can independently have R or S configuration (Cahn-Ingold-Prelog). Given that there are two asymmetric centers, two pairs of dlastereolsoraers [RR, SS and RS, SR] or four isomers exist for each compound. The trans and els pairs are readily separable. The enantloraers in each pair of diastereoisomers can be separated as is well known to those skilled in the art, see Example 1. The use of all such stereoisomers in racemic, optically pure or partially resolved form is included within the scope of this invention.
• aminocycloalkylamldes (I), and combinations thereof, and pharmaceutically acceptable salts thereof are used to treat and/or prevent arrhythmias, to correct the rhythm of the human heart, to prevent sudden cardiac deaths and to treat the symptoms resulting from arrhythmias generally in the same manner and same way as other antiarrhythmic drugs are used, see US Patent 3,931,195 (encalnlde), Heart Disease, A Textbook of Cardiovascular Medicine, Second Edition, Vol. 1, Edited by E. Braunwald, W. B. Saunders, Philadelphia, 1984 and The Medical Letter, Vol. 25 (Issue 630) March 4, 1983.
• Pharmaceutically acceptable salts include hydrochloride, hydrobromide, hydroiode, sulfate, methanesulfonate, tolunesulfonate, acetate, fumarate, phosphate, lactate, citrate, succinate, benzoate, salicylate, pamoate, cyclohexansulfamate, maleate and the alike.
• Preferred is the methanesulfonate salt.
• These agents may be used in combination with each other and/or in combination with other known antiarrhythmic agents.
• the antiarrhythmic agents (I) may be given by oral or parenteral routes, including intramuscular, intraperltoneal, subcutaneous, transtracheal, transcutaneous, and intravenous administration in appropriate dosage forms.
• oral or intravenous administration is preferred.
• treatment is commenced with a unit dose smaller than anticipated for optimum control of the arrhythmia. Thereafter, the dosage is increased by small increments until the optimal effect is reached. Smaller dosage units are generally required for intravenous treatment than are required for oral treatment.
• the dosage amount administered is preferably at an effective level which is without harmful or deleterious side effect on the patient.
• the antiarrhythmic agents (I) are. generally given in a dosage range of from about 0.1 to about 1000 mg/kg/day, preferably about 1.0 to 500 mg/kg/day, more preferably 10 to 100 mg/kg/day, administered from 1 thru 4 times a day, preferably once or twice a day, more preferably once a day.
• the exact dosage and frequency of administration depends on the particular antiarrhythmic agent (I) used, the particular condition being treated/prevented, the severity of the condition being treate//- prevented, the age, weight, general physical condition of the patient, other medication the individual may be taking as is well known to those skilled in the art and can be more accurately determined by measuring the concentration of the antiarrhythmic agent (I) in the patient's blood.
• TLC thin-layer chromatography
• Saline refers to an aqueous saturated sodium chloride solution.
• Ether refers to diethyl ether.
• Alcohol refers to ethyl alcohol.
• compositions and/or substances which are acceptable to the patient from a pharmacological/- toxicological point of view and to the manufacturing pharmaceutical chemist from a physical-chemical point of view regarding composition, formulation, stability, patient acceptance and bioavailability.
• solvent pairs the ratios of solvents used are volume/volume (v/v).
• alkyl of thru carbon atoms means and includes isomers thereof where such exist.
• A is:
• E is an oxygen atom or bivalent sulfur
• E' is an oxygen atom or bivalent sulfur
• E" is an oxygen atom or bivalent sulfur
• G is: (a) hydroxyl
• M is an oxygen atom or bivalent sulfur
• Q is:
• R is:
• R 1 is:
• R 2 is:
• R f , R g , R h , R i , R j are the same or different and are a hydrogen atom or alkyl group with the proviso that R f + R g + R h + R i + R j is not more than 3 carbon atoms
• R 3 is:
• R 4 is:
• R 3 is a hydrogen atom
• R 4 may form part of a carbon-carbon double bond with an adjacent carbon atom which does not bear the -NR 1 R 2 or -NR moiety of formula (I)
• R 5 is a hydrogen atom or C 1 -C 2 alkyl
• R 6 and R 7 are the same or different and are: (i ) a hydrogen atom or (ii ) C 1 -C 3 alkyl
• R 8 is
• R 9 is a hydrogen atom or C 1 -C 3 alkyl
• R 10 is a hydrogen atom or C 1 -C 3 alkyl
• R a , R b , R c , R d , R e are the same or different and are a hydrogen atom or alkyl group with the proviso that R a + R b + R c + R d + R e is not more than 3 carbon atoms;
• R f , R g , R h , R i , R j are the same or different and are a hydrogen atom or alkyl group with the proviso that R f + R g + R h + R i + R j is not more than 3 carbon atoms;
• R k , R l , R m , R n , R o are the same or different and are a hydrogen atom or alkyl group with the proviso that R k + R l + R m + R n + R o is not more than 3 carbon atoms;
• X and Y are the same or different and are
• R 5 -CO- where R 5 is a hydrogen atom or C 1 -C 2 alkyl
• R 6 and R 7 are the same or different and are:
• sulfinyl (2) bivalent sulfur, (3) sulfinyl; a is 0 or 1 ; b is 1 or 2; m is 3 or 4; n is 0 thru 9; p is 0 thru 9; q is 1, 2, 3 or 4; r is 2 or 3; x is 0 or 1; y is 2, 3 or 4;
• C x -C y alkyl means an alkyl group of x thru y carbon atoms and includes lsomers thereof where such exist.
• C x -C y cycloalkyl means a cycloalkyl group of x thru y carbon atoms.
• C x -C y alkoxy or "C x -C y alkylthio” is used, it means an alkoxy or alkylthio group respectively where the alkyl portion is x thru y carbon atoms.
• C x -C y alkanoyloxy it means an alkanoyloxy group where the alkyl portion is x thru y carbon atoms.
• C x -C y alkoxycarbonyl means an alkoxy group where the, alkyl portion is x thru y carbon atoms attached to a carbonyl group.
• ⁇ refers to phenyl (C 6 H 5 ).
• Arrhythmia means a heart beat without any rhythm. It can also mean a single, abnormal heart beat, or groups of abnormal heart beats.
• Dysrhythmla means a rhythmic heart beat with an incorrect rhythm.
• arrhythmia or any. derivative thereof means and includes both arrhythmia and dysrhythmla as defined above, or any disorder of the normal heart rhythm or disorder of normal cardiac conduction.
• Treatment generally means improving, helping or preventing from getting worse an existing undesirable condition more specifically reducing the frequency, number, severity of the arrhythmia, or decreasing the likelihood that the arrhythmia will progress to another and perhaps more dangerous arrhythmia, or decreasing the likelihood that the arrhythmia will stimulate the appearance of another arrhythmia, or reducing the frequency, number or severity of unpleasant symptoms which the patient may experience as a result of the cardiac rhythm, or decreasing the likelihood that the patient will experience sudden cardiac death.
• Prevention generally mean ⁇ stopping or decreasing the likelihood of a cardiac arrhythmia, symptoms related to that arrhythmia, or sudden death in association with arrhythmia in a patient who is judged to be at increased risk for these events.
• Progression of an arrhythmia means that the arrhythmia increases in frequency or severity, or that the arrhythmia predisposes to the development of another type of arrhythmia, or that the arrhythmia converts to another type of arrhythmia.
• the cotton is washed with warm methanol (150 ml)
• the filtrate is placedon a steam bath and treated with ethyl acetate in portions over a few minutes to a volume of 1600 ml.
• a precipitate begins to form and on continued heating the precipitate thickens.
• the mixture is permitted to sit at 20-25° then cooled in an ice bath and filtered.
• the filtrate is concentrated to about 400 ml on the rotary evaporator, giving a residue which is warmed on the steam bath to give a solution.
• the solution is treated with ethyl acetate (200 ml) to give a solid. This solid and the previously obtained solid are combined and recrystallized to give the title compound, rap 279-281
• Example 5 Trans p-bromo-N-[2-(diraethylamlno)cyclohexyl]benzamide maleate (I) Following the general procedure of Example 4 and making noncritl- cal variations but using trans p-bromo-N-[2-(dimethylamino)cyclohexyl]- benzamlde (I, US Patent 4,098,904) and malelc acid, the title compound is obtained.
• Example 7 Trans-(+)-p-brorao-N-[2-(amino)cyclohexyl]benzamlde methanesulfonate (I) and trans-(-)-p-bromo-N-[2-(amino)- cyclohexyl]benzamide methanesulfonate (I) Following, the general procedure of Example 4 and making noncritical variations but starting with trans-(+)-p-bromo-N-[2-(amino)cyclohe- xyl]benzamide (I, Example 6) and trans-(-)-p-bromo-N-[2-(amino)cyclo- hexyl]benzamide (I, Example 6) the title compounds are obtained.
• ENUMERATED EMBODIMENTS 1. A method of maintaining the normal rhythm in an individual who has had an arrhythmia which comprises administering an antiarrhythmic effective amount of an aminocycloalkylamide of the formula
• R e , R f , R g , R h , R i , R j , R k , R l , R m , R n , R o , X, Y, Z, a, b, m, n, p, q, r, x, y and - are defined in the specification.
• Embodiment 2 A method according to Enumerated Embodiment 1 where the method of maintaining the normal rhythm is preventing the recurrence of an arrhythmia that had been treated Initially by electrical cardioversion.
• a method according to Claim 1 where the pharmaceutically acceptable salt is selected from the group consisting of hydrochloride , hydrobro- raide , hydroiode , sulfate, methanesulfonate, tolunesulfonate, acetate, fumarate , phosphate , lactate , citrate , succinate , benzoate , salicylate , pamoate, cyclohexansulfamate and maleate.
• a method according to Enumerated Embodiment 1 where the antiarrhythmic effective amount is from about 10 to 100 mg/kg/day.
• a method of preventing arrhythmias in an individual who is at risk of developing an arrhythmia which comprises administering an antiarrhythmic effective amount of an aminocycloalkylamide of the formula (I)
• a cardiac disease or condition selected from the group consisting of coronary artery disease, rayocardial infarction, Ischemic disease , congestive heart failure , congenital heart disease , valvular heart disease, cardlorayopathy, pericardial disease, myocarditis , or drug induced arrhythmias.
• aminocycloalkylamide (I) is selected from the group consisting of trans-(+)- p-bromo-N-[2-(dlmethylamlno)cyclohexyl]benzamide, trans-(+)-p-bromo-N- [2-(amino)cyclohexyl]-benzamlde , trans-( + )-p-bromo-N-[2- ( dimethyl- amino )cyclohexyl]benzamide , trans-(+)-p-bromo-N-[2-(amlno)cyclohexyl]- benzamide , trans- (- )-p-bromo-N-[2- (amino )cyclohexyl]benzamlde and pharmaceutically acceptable salts thereof .
• a method according to Claim 1 where the pharmaceutically acceptable salt is selected from the group consisting of hydrochloride , hydrobromide , hydroiode , sulfate, methanesulfonate, tolunesulfonate, acetate , fumarate , phosphate , lactate , citrate , succinate , benzoate , salicylate, pamoate, cyclohexansulfamate and maleate.
• a method of preventing sudden cardiac death in a human where the sudden death is precipitated by a disorder of the cardiac rhythm or conduction which comprises administering an antiarrhythmic effective amount of an aminocycloalkylamide of the formula (I)
• R e , R f , R g , R h , R i , R j , R k , R l , R m , R n , R o , X, Y, Z, a, b, m, n, p, q, r, x, y and - are defined In the specification.
• aminocycloalkylamide (I) is selected from the group consisting of trans-(+)- p-bromo-N-[2-(dlmethylamino)cyclohexyl]benzamide, trans-(+)-p-bromo-N- [2-(araino)cyclohexyl]-benzamlde, trans-(+)-p-bromo-N-[2-(dimethyl- amino)cyclohexyl]benzamlde, trans-(+)-p-bromo-N-[2-(amino)cyclohexyl]- benzamide, trans-(-)-p-bromo-N-[2-(amino)cyclohexyl]benzamide and pharmaceutically acceptable salts thereof.
• the pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, hydrobromide , hydroiode , sulfate , methanesulfonate , tolunesulfonate , acetate , fumarate , phosphate , lactate, citrate, succlnate, benzoate, sallcylate , pamoate , cyclohexansulfamate and maleate.

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• 1986
  • 1986-05-22 WO PCT/US1986/001111 patent/WO1986007257A2/fr not_active Application Discontinuation
  • 1986-05-22 JP JP61503195A patent/JPS63500796A/ja active Pending
  • 1986-05-22 EP EP86903872A patent/EP0224566A1/fr not_active Withdrawn
  • 1986-10-08 EP EP86307770A patent/EP0263208A2/fr not_active Withdrawn

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