US3875215A - Substituted phenoxyalkyl quaternary ammonium compounds - Google Patents

Substituted phenoxyalkyl quaternary ammonium compounds Download PDF

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US3875215A
US3875215A US164086A US16408671A US3875215A US 3875215 A US3875215 A US 3875215A US 164086 A US164086 A US 164086A US 16408671 A US16408671 A US 16408671A US 3875215 A US3875215 A US 3875215A
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compound
amino
quaternary ammonium
ethyl
product
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Stanley J Strycker
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Dow Chemical Co
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Dow Chemical Co
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Priority to CA144,364A priority patent/CA948196A/en
Priority to NL7209026A priority patent/NL7209026A/xx
Priority to DE2234080A priority patent/DE2234080A1/de
Priority to GB3285072A priority patent/GB1400173A/en
Priority to FR7225764A priority patent/FR2146325B1/fr
Priority to BE786394A priority patent/BE786394A/xx
Priority to US05/484,525 priority patent/US3932664A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
    • C07D213/16—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom containing only one pyridine ring
    • C07D213/20—Quaternary compounds thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems

Definitions

  • Y represents amino, loweralkylamino or diloweralkylamino
  • R, and R represent lower alkyl
  • R, and R independently taken together represent an aliphatic hydrocarbon moiety of from 4, to 5, to 6 carbon atoms, which can be substituted with zero, one, or two lower alkyl substituents, R R and the quaternary nitrogen forming a 5, 6 or 7-membered ring
  • R represents lower alkenyl, phenacyl, mono-, di or trihalophenacyl, lower alkynyl, substituted lower alkyl, substituted lower alkenyl or substituted lower alkynyl in which such moieties are substituted with one substituent selected from halogen, phenyl, halophenyl, dihalophenyl, trihalophenyl, nitrilo, hydroxy, carboxyalkyl and keto; or R R and R taken together represent a quinuclidine residue; X and X both represent halogen;
  • halogen is employed with respect to the moieties X X and R of the above formula to designate one of the halogens chlorine, bromine and iodine
  • lower alkyl is employed to designate lower alkyl of from 1, to 2, to 3, to 4, to 5, to 6 carbon atoms
  • carboxyalkyl is employed to designate such moieties containing from 2, to 3,'to 4, to 5 carbon atoms
  • lower alkenyl and lower alkynyl are employed to designate such moieties containing from 2, to 3, to 4, to 5, to 6 carbon atoms.
  • pharma- -2 ceutically acceptable anion and pharmaceutically acceptable acid refer to nontoxic anions or 'a'cids employed in quaternary ammo nium salt compounds or acid-addition salts thereof.
  • the terms include the acidic or anionic moieties which have no substantial toxicity or detrimental pharmacological effect when a quaternary ammonium salt compound including such an anion is administered to animals at dosages consistent with good pharmacological activity and acids of such moieties.
  • Such pharmaceutically acceptable anions include non-toxic inorganic anions such as the chloride, bromide, iodide, sulfate, nitrate, bisulfate or phosphate, or organic anions such as the acetate, propionate, succinate, malate, fumarate, glutamate, salicylate, maleate, tartrate or citrate anions, organic sulfonate anions such as the camphorsulfonate, methanesulfonate, benzenesulfonate or toluene sulfonate anions.
  • the methanesulfonate, benzenesulfonate, chloride and bromide anions are particularly useful in the preparation, purification and use of the quaternary ammonium salts of the invention and are preferred pharmaceutically acceptable anions.
  • the compounds of the invention are useful in the study of drug effects upon cardiac activity in animals, and have been found to be particularly useful as antiarrhythmic agents.
  • the compounds can be employed in combatting cardiac arrhythmias in animals by administering an antiarrhythmic amount of one or more of the quaternary ammonium salt compounds to an animal.
  • the compounds are administered internally to the animal to introduce the compound into the animal's cardiovascular system.
  • the compounds can be administered parenterally by intraperitoneal, subcutaneous or intravenous injection, for example, and typically by intravenous injection.
  • the quaternary ammonium salt compounds of the invention can also be administered to animals via the gastrointestinal tract, typically by oral administration.
  • the compounds have excellent antiarryhthmic activity both therapeutically, in administration to an animal suffering from a cardiac arrhythmia, and prophylactically to protect an animal against the occurrence or recurrence of arrhythmias, typically in an animal subject to arrhythmias.
  • arrhythmic, cardiac arrhythmia and arrhythmia as employed herein refer to irregular cardiac activity characterized by irregular beating of the heart, that is, non-rhythmic heart beat. Such arrhythmias involve substantial departure from the regular, substantially sinus (sinusoidal) normal heart beat.
  • arrhythmic animal and arrhythmic mammal, as employed in the present specification and claims, means and refer to animals suffering cardiac arrhythmias. Such arrhythmias can be the result of physiological or pathological conditions.
  • They can also be brought about by physical conditions such as electrical stimulation or physical injury or they can result from pharmacological effects such as the administration of compounds such as digitalis or similar compounds such as ouabain, acetyl strophanthidin, deslanoside C or digitoxin; epinephrine; ergot; chloroform; cyclopropane and the like having cardiac stimulant and arrhythmia-inducing activity or side effects.
  • compounds such as digitalis or similar compounds such as ouabain, acetyl strophanthidin, deslanoside C or digitoxin; epinephrine; ergot; chloroform; cyclopropane and the like having cardiac stimulant and arrhythmia-inducing activity or side effects.
  • a quaternary ammonium salt compound is normally incorporated in a pharmaceutical carrier and the resulting composition is administered internally to an animal.
  • pharmaceutical carrier refers to known pharmaceutical excipients which are substantially non-toxic and non-sensitizing at dosage levels consistent with good antiarrhythmic activity.
  • the active ingredient is preferably administered parenterally in the form of liquid injectable solutions or suspensions, and orally in the form of solid compositions which can be prepared by known techniques such as tableting and encapsulation.
  • Suitable pharmaceutical carriers which can be employed for formulating the solid compositions include starch, lactose, glucose, sucrose, gelatin, powdered licorice, malt, rice flour, chalk, silica gel, hydroxyethyl cellulose, hydroxypropyl cellulose, magnesium carbonate, magnesium stearate, carboxymethyl cellulose, and the like and compatible mixtures thereof.
  • the quanterna ry ammonium compounds can also be formulated as liquid compositions including syrups, elixirs, suspensions and emulsions for oral administration.
  • liquid pharmaceutical carriers which can be employed for orally administered compositions are ethanol, water, saline, glucose syrup, syrup of acacia, mucilage of tragacanth, propylene glycol, polyethylene glycols, peanut oil, wheat germ oil, sunflower seed oil or corn oil and the like and compatible mixtures thereof.
  • Orally ingestible compositions can include emulsifying agents such as lecithin, sorbitan trioleate, polyoxyethylene sorbitan monooleate and natural gums such as gum acacia and gum tragacanth, and suspending agents such as polyethylene oxide condensation products of alkylphenols or fatty acids or fatty alcohols, or cellulose derivatives such as carboxymethyl cellulose or hydroxypropylmethyl cellulose.
  • the compositions can also contain sweetening agents such as sucrose, or saccharin, flavoring agents such as caramel, coloring materials, preservatives and the like.
  • injectable compositions adapted for parenteral administration such as intramuscular, subcutaneous or, preferably, intravenous injection can be prepared with pharmaceutical carriers which are liquid parenterally acceptable vehicles, i.e., liquid pharmaceutical carriers which are adapted for use in formulating parenteral preparations and which are substantially non-toxic and non-irritating when administered parenterally at dosages consistent with good antiarrhythmic activity.
  • pharmaceutical carriers which are liquid parenterally acceptable vehicles, i.e., liquid pharmaceutical carriers which are adapted for use in formulating parenteral preparations and which are substantially non-toxic and non-irritating when administered parenterally at dosages consistent with good antiarrhythmic activity.
  • liquid parenterally acceptable vehicles include pyrogen-free water, normal saline solutions,
  • Ringers Injection Lactated. Ringe'rs-lnjectiom,dextrose solutionsgethanol, propylene glycol, liquid polyethylene glycols, fixed vegetable oils such as corn oil, peanut oil or cottonseed oil, ethyl oleate, isopropyl myristate and the like.
  • the injectable compositions can also contain other materials such as preservatives, buffers and the like.
  • Preferred injectable compositions comprise a sterile solution of the quaternary ammonium salt compound in the parenterally acceptable vehicle.
  • the compositions can be formulated by using conventional procedures such as are described in Remingtons Pharmaceutical Sciences, 13th Ed., Chapter 36, Mack Publ. Co., Easton, Pa. (1965).
  • the antiarrhythmic amount of the quaternary ammonium salt compounds to be administered to an animal can vary depending upon such factors as whether or not the animal is suffering from an arrhythmia at the time of administration, the type and severity of arrhythmia exhibited, the method and frequency of administration, the exact antiarrhythmic effect to be produced, the particular quaternary ammonium salt compound employed and the species, size, weight, age and physical condition of the particular animal being treated. In general, when the animal is actively exhibiting arrhythmia, it is preferred to administer the compound at an antiarrhythmic dosage rate sufficient to bring about a complete conversion of the arrhythmia to normal sinus cardiac activity.
  • the active compound is preferably introduced directly into the cardiovascular system of the animal to provide an antiarrhythmic concentration of the quaternary. ammonium salt compound in the cardiovascular system, particularly at the heart.
  • the compound is administered by intravenous injection at an initial antiarrhythmic dosage less than that required to fully convert the arrhythmia to normal rhythm, and the heartbeat of the animal is monitored as the amount of compound administered is gradually increased over a period of minutes until an antiarrhythmic amount sufficient to fully convert the arrhythmia to rhythmic cardiac activity has been administered. It is then preferred to supply the compound in periodic maintenance antiarrhythmic dosages, such administration being either by the same parenteral route, or by administration of larger antiarrhythmic dosages by another route such as orally.
  • the maintenance antiarrhythmic dosage and mode of administration are selected to provide a moreor-less continuous antiarrhythmic concentration of the quaternary ammonium salt compound in'the cardiovascular systemysuch concentration being sufficient to inhibitfurtherarrhythmiaxln general, the quaternary ammonium compound can be-administered intravenously in initial dosages of from about 0.1 or less to about 15 ,or more milligrams per kilogram of animal body istration selected, the type of dosage form employed, the type and cause of the arrhthymia. and the length of time during which a maintenance dose is desired. ln cases in which there is little or no likelihood of recurrence of arrhythmia once conversion has been brought about.
  • the maintenance dosage can comprise a continuation of the initial intravenous antiarrhythmic dosage for a relatively brief period.
  • the maintenance dosage can comprise repeated oral administration of an antiarrhythmic amount of the compounds over extended periods.
  • Maintenance dosages can be administered by single or multiple doses provided that the compounds are administered in an antiarrhythmic amount sufficient substantially to alleviate cardiac arrhythmia.
  • a preferred group of the quaternary ammonium salt compounds comprises the compounds corresponding to the above formula I wherein R and R are both methyl or both ethyl wherein Y is amino and wherein X and X;- are both bromine or both chlorine. It is also generally preferable that the moieties R and R together contain from Z to 6 carbon atoms; that the moiety R contain from 3 to 7 carbon atoms and that R R and R;, together contain from 5 to 9 carbon atoms.
  • Y is amino
  • R is lower alkenyl or lower alkynyl of 3 or 4 carbon atoms or those wherein R is substituted lower alkyl, lower alkenyl or lower alkynyl of from 2 to 4 carbon atoms substituted with a single bromo, ehloro, keto or nitrilo substituent. and those wherein R is benzyl, monohalobenzyl and dihalobenzyl.
  • a further preferred group comprises the compounds corresponding to the above formula wherein n is 2 Y is amino.
  • X and X: are bromine R and R are methyl. and R;, is lower alkenyl or lower alkynyl of 3 or 4 carbon atoms.
  • HX and A have the significance set out above with respect to formula I and R is lower alkenyl or lower alkynyl of 3 or 4 carbon atoms, preferably 2- propynyl. allyl or Z-methylallyl.
  • the preferred compounds of Formula la provide excellent antiarrhythmic results of long duration when administered orally or parenterally in relatively low dosages and are particularly preferred for combatting cardiac arrhythmias.
  • PREPARATION OF THE COMPOUNDS 'lhe quaternary ammonium salt compounds of the invention can be prepared by the reaction of a tertiary amine compound corresponding to the formula ll RI N til H with a substituted organic alkylating agent corresponding to formula lll It] A wherein X X Y and n all have the significance set out above with respect to formula I; and each of the remaining substituent moieties R, R", R' and R" represents a different individual one of the moieties R R and R;, as set out above with respect fo formula I and B represents a pharmaceutically acceptable strongly anionic moiety such as halide, alkyl or aryl sulfonate, sulfate or phosphate.
  • substituted phenoxyalkyl moiety of formula IV can be provided as a substituted phenoxyalkylz'imine or as a substituted phenoxyalkyl halide, and the R R and R moieties similarly can be provided by a tertiary amine compound of formula ll or by a substituted organic compound of formula lV.
  • tertiary amines which can be employed as starting materials include N-methyl-N- ethyl-N(2-propynyl) amine; dimethyl phenethylamine; N,N-diethyl-N-4-chlorobutylamine; N-2-butenyl dimethylamine; N-allyl-pyrrolidine; picoline, lutidine; quinuclidine; 3,5-dibromo-fi-dimethylamino-p- (Z-bromoethane); Propenyl chloride, chlorohexane, methyl bromide, ethylene dibromide, benzyl bromide, 3,4,5-trichlorophenethyl bromide.
  • the reaction proceeds when the reactants are contacted and mixed, preferably in the presence of an inert organic liquid such as acetonitrile or dimethyl formamide as a reaction medium.
  • an inert organic liquid such as acetonitrile or dimethyl formamide as a reaction medium.
  • the substituted halophenoxyalkyl amine compound of formula II and the organic compound of formula III are selected from such compounds in which the R, R", R and R" moieties are such as to provide the R,, R and 11;, moieties desired in the quaternary product.
  • the reaction proceeds readily at temperatures of from about C. to about 100C, and is preferably carried out at a temperature from about C. to about 70C.
  • the reactants to be employed are not critical, however the formation of one molar proportion of the quaternary ammonium salt product requires one molar proportion of each of the tertiary amine and substituted organic reactants, and the reactants are preferably employed in such proportions.
  • the reaction of the tertiary amine and organic compound proceeds with the evolution of heat and the production of a quaternary ammonium salt product wherein the anionic moiety is the anionic moiety B of the organic compound of formula III.
  • the product can be separated by conventional procedures such as filtration. decantation, centrifugation.
  • the quaternary ammonium salt can be separated by other conventional procedures such as evaporation under reduced pressure, cooling of the reaction mixture and scratching or seeding to induce crystallization, dilution with organic liquids such as ethyl acetate, benzene or butyl acetate or the like.
  • the product can be purified by conventional procedures such as recrystallization and washing.
  • the anionic moiety A of the quaternary ammonium salts corresponding to formula I can be varied by conversion of one salt to another by conventional procedures for anion exchange.
  • the exchange can be carried out, for example. by the methathetic reaction ofone of the quaternary ammonium salts of the invention with the desired anion in the presence of a cation which forms a methathesis reaction product with the anionic moiety to be replaced. said methathesis reaction prod uct being soluble in the reaction medium employed for the methathetic reaction.
  • a quaternary ammonium halide of the invention is prepared as described above using a reactant corresponding to formula III wherein A is halogen. such as chlorine or bromine.
  • the quaternary ammonium halide is dissolved in aqueous ethanol at room temperature and the solution is mixed with an aqueous solution of an acid supplying the desired anion. e.g.. sulfuric acid.
  • the halide is removed as hydrogen halide by fractional distillation and the methathesis quaternary ammonium salt product is separated and purified by conventional procedures.
  • different anionic moieties can be introduced into the quaternary ammonium salt compounds offormula l by passing an aqueous solution ota compound offormula 1 through an anion-exchange resin saturated with the anion desired in the product.
  • the pharmaceutically acceptable acid addition salt form of the quaternary ammonium compounds that is, those quaternary ammonium salts of formula I wherein m is one, are prepared according to conventional pro cedures for forming acid addition salts of primary, secondary or tertiary amines.
  • a quaternary ammonium salt corresponding to formula I wherein m is zero is taken up in a minimal amount of a lower alkanol and the mixture is treated with an excess of the desired pharmaceutically acceptable acid in ether or dioxane.
  • the salt is separated and purified by conventional procedures.
  • the tertiary amine reactant employed is a substituted 3,5-dihalophenoxy alkylamine corresponding to the above formula 11 wherein R and R" represent the R and R lower alkyl moieties as described above with respect to formula I and R' represents a substituted phenoxyalkyl moiety corresponding to the above formula IV.
  • Such tertiary amine starting materials can be prepared readily by the reaction of a substituted phenoxyalkyl halide with a dialkyl amine by the procedures described in U.S. Pat.
  • the substituted organic compound reactant employed is a compound of formula 11 above wherein R" represents R as described with respect to formula I and B represents 40 halo, alkyl sulfonyl or aryl sulfonyl.
  • R" represents R as described with respect to formula I
  • B represents 40 halo, alkyl sulfonyl or aryl sulfonyl.
  • the substituted halophenoxyalkylamine is dispersed in an inert organic liquid such as dimethylformamide or acetonitrile. and an equimolar proportion of the organic compound of formula III is added gradually and mixed therewith.
  • the reaction mixture is maintained at a temperature within the reaction temperature range for a period of l to 36 hours.
  • the product can be conveniently separated by diluting the reaction mixture with several volumes of ethyl acetate.
  • the product can be conveniently separated by diluting the reaction mixture with several volumes of ethyl acetate.
  • product can be crystallized by treating the ethyl acetate mixture with excess pharmaceutically acceptable acid.
  • the product can be purified by conventional procedures such as recrystallization and washing.
  • EXAMPLE 1 the solution with stirring, during which time a temperature rise of 34 C. is observed.
  • the reaction mixture is heated at a temperature of 5565C. forfour hours with continued stirring. Formation of a precipitate is observed in the mixture, beginning about 15 minutes after addition of the 2-methallyl chloride and continuing through the heating period.
  • the reaction mixture is then cooled in an ice bath and filtered.
  • the [2-(4- amino-2,6-dibromophenoxy)ethyl]dimethyl-(2- methylallyl)ammonium chloride product is collected as a filter cake, dried in air and found to melt at l85186C.
  • the product is dissolved in hot isopropanol and the solution treated with activated carbon and filtered.
  • the crystalline solid product is collected as a filter cake by suction filtration of the mixture and the filter cake is recrystallized from boiling ethanol.
  • the [2-(4-amino- 2,6-dibromophenoxy)ethyl]dimethyl(ethyl carboxymethyl) ammonium bromide is obtained as a light tan crystalline solid, melting at l87-188C.
  • the product is found by combustion analysis to have carbon, hydrogen and nitrogen contents of 33.5,43 and 5.6 percent, respectively, as compared with the theoretical contents of 33.3, 4.2 and 5.6 percent, respectively, calculated for the named structure.
  • the structure of the product is confirmed by infrared spectroscopy and nuclear magnetic resonance analysis.
  • a second crop of the product is obtained by diluting the dimethyl formamide reaction mixture filtrate with excess ethyl acetate, and collecting the resulting precipitate by filtration. This crop of the product is dried,
  • the reaction mixture is filtered, and the [2-(4- amino-2,6-dibromophenoxy)ethyl]dimethyl(2- chlorobenzyl)ammonium chloride product is collected as a filter cake, dried'in air, and recrystallized from isopropanol.
  • the purified [2-(4-amino-2,6- dibromophenoxy)-ethyl]dimethyl(2-chlorobenzyl)ammonium chloride product is found to melt at l72-l 73C.
  • the structure of the product is confirmed by infrared and nuclear magnetic resonance spectroscopy.
  • the product is found by combustion analysis to have carbon, hydrogen and nitrogen contents of 41.3,
  • the [2-(4- amino-2,6-dibromophenoxy)ethyl]dimethyl(2- propynyl)ammonium bromide product is obtained as a yellow crystalline solid melting at l66168C.
  • the product is found by combustion analysis to have carbon, hydrogen and bromide contents of 34.5, 3.8 and 52 percent, respectively, as compared with the theoretical contents of 34.2, 3.8 and 52.5 percent, respec- 60 tively, calculated for the named structure.
  • the structure of the product is confirmed by infrared spectroscopy and nuclear magnetic resonance analysis.
  • the EXAMPLE l5 [2-(4-amino-2,6-dibromophenoxy)ethyl]dimethyl- (acetonyl)ammonium chloride product is collected as a filter cake, dried in air, and recrystallized from isopropanol.
  • the purified [2-(4-amino-2,6- dibromophenoxy)ethyl]dimethyl(acetonyl)ammonium chloride product is obtained as a tan crystalline solid melting at 18 l-l82C.
  • the structure of the product is confirmed by infrared and nuclear magnetic resonance spectroscopy.
  • the product is found by combustion analysis to have carbon, hydrogen and nitrogen contents of 36.1, 4.6 and 6.4 percent, respectively, as compared with the theoretical contents of 36.3, 4.5 and 6.5 percent, respectively, calculated for the named structure.
  • the product is recrystallized once from hot isopropanol and a second time from an ethanol-ethyl acetate mixture.
  • the [2-(4-amino-2,6- dibromophenoxy)ethyl]dimethyl(allyl)ammonium bromide product is obtained as a yellow crystalline solid melting at l57.5-159C.
  • the product is found by combustion analysis to have carbon, hydrogen and bromine contents of 33.8, 4.2 and 52.0 percent, respectively, as compared with the theoretical contents of 34.0, 4.2 and 52.2 percent, respectively, calculated for the named structure.
  • the structure of the product is confirmed by infrared spectroscopy and nuclear magnetic resonance analysis.
  • the mixture is heated with stirring at a temperature of 6065C. for 4 hours, stirred at room temperature overnight, then heated at 6065C. for about 18 hours and cooled.
  • the crystalline product is separated by filtration of the mixture and the [2-(4-amino-2,6- dibromophenoxy)ethyl]diethyl(allyl)ammonium bromide product is obtained as a crystalline solid melting at 205207C.
  • the product is taken up in hot acetonitrile and the solution is filtered; The hot filtrate is Cooled, whereupon a crystalline solid precipitate forms, and filtered.
  • the purified [2-( 4-amino-2 ,6- dibromophenoxy )ethyl]dimethyl[ 2-nitriloethyl1ammonium benzenesulfonate product is collected as a filter cake, air dried, and found to melt at l73.5l75C.
  • the structure of the product is confirmed by infrared and nuclear magnetic resonance spectroscopy.
  • the product is found by combustion analysis to have carbon, hydrogen and nitrogen contents of 40.6, 3.93 and 7.87 percent, respectively, as compared with the theoretical contents of 40.39, 3.96 and 7.85 percent, respectively, calculated for the named structure.
  • the [2-(4-amino-2,6-dibromophenoxy)- ethyl]dimethyl(allyl)ammonium methanesulfonate product is collected as a filter cake, dried, andrecrystallized from n-propanol.
  • the product is found to melt at 202203C.
  • the structure of the product is confirmed by infrared and nuclear magnetic resonance spectroscopy.
  • the product is found by combustion analysis to have carbon, hydrogen and nitrogen contents of 35.35, 4.65 and 6.13 percent, respectively, as compared with the theoretical contents of 35.45, 4.68 and 5.91 percent, respectively, calculated for the named structure.
  • EXAMPLE 01,3,5-Tribromo-p-phenetidine (20.2 grams) is dissolved in 150 milliliters of acetonitrile, then mixed with a solution of 6 grams of quinuclidine in 100 milliliters of acetonitrile.
  • the reaction mixture is heated at a temperature of about C. for 4 hours and then cooled, and held for 48 hours at ambient temperature.
  • the reaction mixture is filtered, and the [2-(4-amino-2,6- dichlorophenoxy)-ethyl] quinuclidinium bromide product is collected as a filter cake, washed with acetonitrile and dried.
  • EXAMPLE 22 In a procedure similar to that described in Example 21, l-[2-(4-amino-2,6-dibromophenoxy)ethyl]-l-allyl piperidinium bromide hydrobromide, melting at 207209C., is prepared by reacting 17 grams of 3,5- dibromo-B-piperidino-p-phenetidine and 5.75 grams of allyl bromide in 50 milliliters of acetonitrile.
  • EXAMPLE 24 In a procedure similar to that described above in Example 20, B,3,5-tribromo-p-phenetidine and 3-picoline are reacted together to prepare l-[ 2-(4-amin0-2.6- dibromophenoxy)ethyl]-3-picolinium bromide, melting at 2l8220C.
  • Ventricular tachycardia is produced in dogs in a method similar to the method of Lucchesi and Hardman (J. Pharmacol. Exptl. Therap., 132, 372, 1961) by the administration of ouabain.
  • a dog is anesthetized by the intravenous administration of pentobarbital sodium at a dosage rate of 30 milligrams per kilogram.
  • a femoral artery is cannulated with polyethylene tubing for measurements of blood pressure.
  • a femoral vein is similarly cannulated for administration of ouabain and administration of the test compound.
  • Hypodermic needle electrodes are employed for recording electrocardiograms.
  • ouabain is administered intravenously by infusion at a constant rate via the cannulated femoral vein.
  • the infusion rate is 35 micrograms of ouabain per kilogram of animal body weight per hour.
  • a ventricular tachycardia is seen to develop.
  • a test compound is administered intravenously by administration of varying amounts of a composition comprising 50 milligrams of the test compound as a sterile solution in milliliters of water containing 0.9 percent sodium chloride. Each dose is administered slowly over a period of to 30 seconds. The compound is administered at an initial dosage rate of 0.25 milligram of test compound per kilogram of animal body weight. Blood pressure and electrocardiogram are observed for 5 minutes after administration. When a complete conversion from the arrhythmic condition to normal sinus rhythm is not observed Within the 5 minute period, a second dose of 0.50 milligram of the test compound per kilogram is administered by a similar procedure and blood pressure and heartbeat are similarly observed for 5 minutes.
  • the dosage is increased two-fold every 5 minutes until complete conversion is obtained.
  • the animal is then observed and the duration of the period of normal cardiac rhythm produced by administration of the test compound is recorded as the duration of antiarrhythmic activity.
  • the termination of the period of normal activity is marked by the reappearance of ventricular tachycardia or fibrillation as indicated by the electrocardiogram observations.
  • the antiarrhythmic dosage of test compound sufficient to bring about a complete conversion of the ouabain-induced tachycardia, and the duration of the period of normal cardiac activity are set out below.
  • EXAMPLE 28 [2-(4-amino-2,6-dibromophenoxy)ethyl]dimethyl- (2-methylallyl)ammonium chloride is employed to alleviate multifocal ventricular arrhythmias induced by administration of n-hexane and epinephrine. In these operations, dogs are anesthetized by intravenous administration of 30 milligrams of pentobarbital sodium per kilogram. Transient ventricular arrhythmias are induced by a modification of the method of Garb and Chenowith, J. Pharmacol. Exp. Ther.
  • the above-named quaternary ammonium compound is found to give excellent protection against the arrhythmias when administered intravenously at a dosage rate of one milligram per kilogram, the duration of antiarrhythmic effect lasting about one hour.
  • the duration of protection is found to be greater than 2 hours.
  • EXAMPLE 29 An experimental occlusion of the anterior descending coronary artery is produced in dogs according to the method of Harris, Circulation 1, 1318 (1950). Following surgery the animals are given a penicillinstreptomycin preparation and allowed to recover for 18-24 hours. The animals are given 3 milligrams per kilogram of morphine sulfate as an analgetic and sedative to allow handling. Electrocardiograms are recorded both before and after administration of [2-(2- amino-2,6-dibromophenoxy)ethyl]dimethyl-(2- methylallyl)ammonium chloride to the test animals.
  • the incidence of abnormal complexes is recorded as a percentage of total beats per minute.
  • the test compound is administered by intravenous infusion at rates of l, 2, 2 and 2 milligrams per kilogram at intervals of 10 to minutes.
  • a marked decrease in heart beat rate is observed with a concomitant decrease in percentage of abnormal beats per minute following the first infusion.
  • the heartbeat rate is observed to have decreased from a rate of over 160 beats per minute prior to the first infusion to about 90-100 beats per minute.
  • the incidence of ectopic beats at this time has decreased from a pretreatment level of 100 percent abnormal beats per minute to below 60 percent, reaching zero (100 percent normal beats) within about 10 minutes after the last infusion.
  • the lower heartbeat rate and low incidence of abnormal beats (generally 0 to 20 percent of the total beats per minute are abnormal) is found to persist for 2 hours following the last infusion of test compound at which time the experiment is terminated.
  • test compound is infused at dosages of l, 2 and 4 milligrams per kilogram at intervals over a forty minute period.
  • incidence of abnormal beats Prior to infusion the incidence of abnormal beats is 100 percent. Within about eight minutes following the last infusion, a substantially complete conversion to sinus rhythm is obtained. The incidence of abnormal beats is found to remain at zero with occasional brief periods of slight arrhythmia (2-5 percent abnormal beats) for 2.5 hours following the last dosage of the test compound, when recordingjs terminated. Resumption of recording 215 minutes later indicates that significant antiarrhythmic effects are still exhibited.
  • the [2-(2-amino-2,6- dibromophenoxy)ethyl]dimethyl(2-methylallyl)ammonium chloride is administered orally in gelatin capsules.
  • the test compound is administered in multiple dosages of 30, 30 and 50 milligrams perkilogram over a period of 150 minutes. Periods of reduced frequency of abnormal heart beats are noted beginning 10 minutes after administration of the first dosage of test compound, the second and third doses providing further and more consistent antiarrhythmic effects. Beginning about 25 minutes after the last dose of the test compound is administered the electrocardiogram shows periods in which less than 10 percent of the beats are abnormal interspersed with occasional periods of arrhythmia. Antiarrhythmic effects continue to be observed until the recording is terminated minutes after the last dose of test compound.
  • EXAMPLE 3O [2-(4-amino-2,6-dibromophenoxy)ethyl]dimethyl- (allyl)ammonium bromide is administered to mice intravenously and orally. The animals are thereafter sacrificed and blood and heart tissue analyses are carried out to ascertain the concentration of test compound present. In such operations mice intravenously administered the test compound at a rate of 6 milligrams per kilogram are found to have blood levels of 27 micrograms of test compound per milliliter 10 seconds after injection, 2.1 micrograms per milliliter 3 minutes after injection. Analysis of heart tissue indicates a concentration of 5.5 micrograms of test compound per gram of tissue 10 minutes after injection. Similar analyses are carried out with animals administered 6 milligrams of test compound per kilogram orally. Thirty minutes after oral administration, blood and heart levels of 1.1 and 5.1 micrograms, respectively, of test compound per milliliter of blood or gram of heart tissue, respectively, are found.
  • EXAMPLE 31 An aqueous solution of [2-(4-amino-2,6- dibromophenoxy)ethylldimethyl (2-methylallyl)ammonium chloride is administered orally to several groups of male and female Sprague-Dawley derived rats and male and female Swiss mice (Cox strain). The compound is administered as single oral doses in varying amounts, and the animals are held to assess toxicity 24 hours after administration of the compound. In such operations, the quaternary ammonium compound is found to have an LD,-, of 758 milligrams per kilogram (mg/kg) in the male rats; 725 mg/kg in the female rats, 560 mg/kg in the male mice, and 550 mg/kg in the female mice.
  • LD,- of 758 milligrams per kilogram (mg/kg) in the male rats; 725 mg/kg in the female rats, 560 mg/kg in the male mice, and 550 mg/kg in the female mice.
  • EXAMPLE 32 35 Grams of [2-(4-amino-2,6-dibromophenoxy)ethyl-dimethyl (2-methylallyl)ammonium bromide is dissolved in 2 liters of sterile normal physiological saline solution. The solution is filtered and filled into cubic centimeter (cc) syringes calibrated to permit injection of the parenteral preparation in 0.5 cc increments. The syringes are individually packaged in containers adapted to maintain sterility and sterilized. The parenteral dosage units are each adapted for parenteral administration of the active compound in increments of about 8.75 milligrams each to a total of 175 milligrams.
  • EXAMPLE 33 100 Parts of [3-(4-amino-2,b-dichlorophenoxy)- propyl]dibutyl(3-butynyl)ammonium methanesulfonate and 35 parts of lactose are mixed well with 751 parts of starch. The mixture is filled with gelatin capsules in the amount of 0.4 grams per capsules are suitable for oral administration.
  • EXAMPLE 34 Tablets are prepared from a granulation comprising 50 parts by weight of [2-(4-amino-2,6- dibromophenoxy)ethyl]dimethyl(2-methylallyl)ammonium chloride, 100 parts lactose, 3.5 parts magnesium stearate, 170 parts starch, 50 parts microcrystalline cellulose, one part of a polyoxyethylene sorbitan monooleate surface active dispersing agent and 0.4 part of F.D.&C. approved color.
  • the granulation is screened and compressed into tablets weighing about 0.287 grams each to prepare a composition in dosage unit form adapted for oral administration to animals.
  • the dosage units are adapted to be employed in maintenance antiarrhythmic therapy to inhibit recurrence of arrhythmias in animals subject thereto, and prophylactically to animals in preparation for exposure to physical or chemical conditions creating a risk of cardiac arrhythmia.
  • the tablets are administered to animals at the rate of one or two tablets (containing 50 milligrams of active antiarrhythmic agent) per day.
  • a compound of claim 6 wherein the compound is [2-(4-amino-2,6-dibromophenoxy)ethyl]dimethyl (2- methylallyl)-ammonium chloride.
  • a compound of claim 3 wherein the compound is [2-(4-amino-2,6-dibromophenoxy)ethylldimethyl (allyl)ammonium methane sulfonate.
  • a compound of claim 3 wherein the compound is a [4-(4-amino-2,6- dibromophenoxy)butyl]dimethyl(allyl)ammonium halide.

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  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
US164086A 1971-07-19 1971-07-19 Substituted phenoxyalkyl quaternary ammonium compounds Expired - Lifetime US3875215A (en)

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US164086A US3875215A (en) 1971-07-19 1971-07-19 Substituted phenoxyalkyl quaternary ammonium compounds
CA144,364A CA948196A (en) 1971-07-19 1972-06-09 Substituted phenoxyalkyl quaternary ammonium compounds
NL7209026A NL7209026A (OSRAM) 1971-07-19 1972-06-29
DE2234080A DE2234080A1 (de) 1971-07-19 1972-07-11 Quaternaere ammoniumverbindungen mit substituiertem phenoxyalkylrest
GB3285072A GB1400173A (en) 1971-07-19 1972-07-13 Substituted phenoxyalkyl quaternary ammonium compounds
FR7225764A FR2146325B1 (OSRAM) 1971-07-19 1972-07-17
BE786394A BE786394A (fr) 1971-07-19 1972-07-18 Composes d'ammonium quaternaire
US05/484,525 US3932664A (en) 1971-07-19 1974-07-01 Substituted phenoxyalkyl quaternary ammonium compounds as antiarrhythemic agents
US05/648,547 US4066771A (en) 1971-07-19 1976-01-12 Substituted phenoxyalkyl quaternary ammonium compounds as antiarrhythemic agents

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3917679A (en) * 1974-04-12 1975-11-04 Lilly Co Eli Quaternary ammonium salts of N-dialkylaminoalkyl-N-(2-indanyl)anilines
US4146558A (en) * 1966-05-23 1979-03-27 Sterling Drug Inc. Azo dyestuff intermediate nitro- or aminobenzenes ring-substituted by a quaternized amine alkyl or amino-alkoxy group
US4206144A (en) * 1971-11-22 1980-06-03 Sterling Drug Inc. N,N-Dialkyl-N-aminoalkyl-N-(amino or nitro)phenylalkyl- and N-methyl-N-[3-(amino or nitro)phenoxy-2-hydroxy-1-propyl]-N,N-bis(3-aminopropyl)quaternary ammonium salts
US4327214A (en) * 1979-10-08 1982-04-27 Basf Aktiengesellschaft Substituted alkylammonium salts, the manufacture thereof, the use thereof for regulating plant growth, and agents therefor
US20040170583A1 (en) * 2000-05-12 2004-09-02 Tim Heeg Cranberry seed oil, cranberry seed flour and a method for making
US6794543B2 (en) * 2000-05-16 2004-09-21 Clariant Gmbh Method for producing arylpoly(oxalkyl)-benzyldimethyl-ammonium derivatives
US20080199547A1 (en) * 2004-05-03 2008-08-21 Timothy Heeg Berry Oils and Products

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9012001D0 (en) * 1990-05-30 1990-07-18 Unilever Plc Bleaching composition

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2017497A1 (OSRAM) * 1969-04-22 1970-11-05

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2017497A1 (OSRAM) * 1969-04-22 1970-11-05

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4146558A (en) * 1966-05-23 1979-03-27 Sterling Drug Inc. Azo dyestuff intermediate nitro- or aminobenzenes ring-substituted by a quaternized amine alkyl or amino-alkoxy group
US4206144A (en) * 1971-11-22 1980-06-03 Sterling Drug Inc. N,N-Dialkyl-N-aminoalkyl-N-(amino or nitro)phenylalkyl- and N-methyl-N-[3-(amino or nitro)phenoxy-2-hydroxy-1-propyl]-N,N-bis(3-aminopropyl)quaternary ammonium salts
US3917679A (en) * 1974-04-12 1975-11-04 Lilly Co Eli Quaternary ammonium salts of N-dialkylaminoalkyl-N-(2-indanyl)anilines
US4327214A (en) * 1979-10-08 1982-04-27 Basf Aktiengesellschaft Substituted alkylammonium salts, the manufacture thereof, the use thereof for regulating plant growth, and agents therefor
US20040170583A1 (en) * 2000-05-12 2004-09-02 Tim Heeg Cranberry seed oil, cranberry seed flour and a method for making
US8124142B2 (en) * 2000-05-12 2012-02-28 Tim Heeg Cranberry seed oil, cranberry seed flour and a method for making
US20120148687A1 (en) * 2000-05-12 2012-06-14 Timothy Heeg Cranberry seed oil, cranberry seed flour and a method for making
US6794543B2 (en) * 2000-05-16 2004-09-21 Clariant Gmbh Method for producing arylpoly(oxalkyl)-benzyldimethyl-ammonium derivatives
US20080199547A1 (en) * 2004-05-03 2008-08-21 Timothy Heeg Berry Oils and Products
US7943182B2 (en) 2004-05-03 2011-05-17 Timothy Heeg Berry oils and products

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CA948196A (en) 1974-05-28
DE2234080A1 (de) 1973-02-01
NL7209026A (OSRAM) 1973-01-23
GB1400173A (en) 1975-07-16
BE786394A (fr) 1973-01-18
FR2146325A1 (OSRAM) 1973-03-02
FR2146325B1 (OSRAM) 1975-11-28

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