IL34765A - Quaternary ammonium compounds,their preparation and pharmaceutical compositions containing them - Google Patents

Description

Quaternary ammonium their preparation and ceutical compositions containing them THE FOUNDATION LIMITED This invention relates to compounds useful in the of has previously been proposed to employ the powerful hypotensive drug bretylium in the treatment of cardiac arrhythmia mic Action of Volume pages July and of cular Fibrillations and other Acute Arrhythmias with Bretylium the American Journal of April Volume 4 pages The drug has potent properties but the hypotensive action attributable to sympathetic blockage causes an undesirable substantial lowering of blood it is when the drug is for the patients to be in units of sulphonate and sulphate It has now been found of the ion or the ammonium hereinafter referred to as the possess unexpected advantages over that drug in the treatment These Compounds not only have properties comparable to but also significantly less sympathetic blocking thus making possible the treatment of heart disorders with little or no adverse effect on blood The Compounds in the form of pharmaceutically acceptable salts are effective in treating and suppressing ventricular fibrillations and fibrillations in mammala such as dogs and one aspect the present invention provides a of the In another aspect the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable eulphonate or sulphate salt of the cation or the in association with a pharmaceutically acceptable pharmacological activity the Compounds resides in the quaternary ammonium the nature of the anion only being important for administration requirements used in medicinal Compounds will often administered over a prolonged period and in such easee the anion toe that in having no harmful effect on the patient after prolonged Bromide and salts of quaternary ammonium compounds have a pharmacological in mammals may be undesirable upon prolonged but such are useful in the preparation of pharmaceutically acceptable in another aspect invention provides salts of the cation or the cation Salts which are especially preferred for therapeutic use are the sulphates and sulphonates such as the The Compounds may be conveniently prepared by quaternization of an appropriate tertiary The quaternization reactions by which they may be produced are set out 4 In these reactions and the symbol R is the ethyl or the the symbol X is the methoxy and the symbol Z represents a chlorine atom or a sulphate or a sulphonate The compounds in the present invention may also be formed by reacting an appropriate secondary amine with two equivalents of a methylating In this the tertiary amine used in reaction is formed in Reactions and may be effected in a for methylethyl ethyl benzene or The reaction is most advantageously effected in the presence of an acid binding for an alkaline salt such as sodium or potassium Compounds The the may also be formed from other salts by double the Compounds toxic oalto of the present invention may be formed thus toxic f om fny i n r The present invention also provides the above methods of preparation of the Compounds of wherein is the group and X is the and the ally acceptable Compounds of formula wherein is the ethyl group and X is the pharmaceutically acceptable Compounds may be presented in any acceptable pharmaceutical Compositions for oral or parenteral administration are Parenteral administration is especially For oral fine powders or granules of the pharmaceutically acceptable Compounds may contain dispersing surface active and may be presented in a draft in water or in a in capsules o cachets in the dr state or in a when suspending agen may be in when binders and lubricants may be or in a suspension i a an oil or Where desirable or necessary thickening or emulsifying agents can be Tablets and granules are and these may be For parenteral the pharmaceutically acceptable Compounds may be presented in aqueous injection solutions which may contain agents which solubilise a relatively insoluble and solutes which render the salt isotonic with the in aqueous suspensions when suspending and thickening agent may also be or in aqueous solutions and suspensions if the particular compound selected is affected by 1 Dosages are preferably in the range 1 to 10 of the Desirably the pharmaceutical compositions are presented in unit dosage usually containing in the range 100 to 600 of The following examples illustrate the Example 1 was combined with acetone and ethyl sulphonate and the mixture fluxed The reaction mixture was then cooled to and the slurry of crystals A crude product was isolated melting at as white needles very soluble in water and and gave the following Calculated Found C H N Example 2 A column of Amberlite resin IRA400 was prepared from resin and It was washed with 2 hydroxide until the elute was alkaline and then with water until the washings were A solution of acid in water was then poured down the when the elute finally became This column was then washed with water until the washings were virtually neutral 300 water was B 224 A solution of ammonium iodide in water was then poured down the column and the solution collected in aliquots of 6 each of which was separately evaporated to dryness in a rotatory After a total of 36 of washing no more product The batches of solid were recrystallised from acetone to give dimethylammonium Example 3 chloride was added slowly to a hot stirred solution of methylaminoethanol in benzene After heating on a bath for 1 the resulting mixture was cooled treated with 5 hydroxide The aqueous layer was separated and extracted with ether The combined organic layers were washed with dried over anhydrous potassium filtered and The residue was distilled in vacuo to give as a colourless Methyl iodide was added to a solution of the above base in ethyl methyl The mixture warmed spontaneously and oil subsequently The resulting was recrystallised from acetone or and subsequently converted to the corresponding sulphonate Β 224 Example 4 Tablets of sulphonate were made by granulating the salt in a fine powder with equal parts of alcohol and Magnesium stearate as a lubricant was and the mixture compressed Example 5 Injection preparations of a solution containing sulphonate in Water for Injection per were made by autoclaving the solution at 15 steam pressure for 30 minutes in unit dose ampoules or in multidose For the the Water for Injection contained benzyl alcohol phenol or cresol Example 6 Tablets and Injection solutions vera prepared in Examples 4 and using insufficientOCRQuality

Claims (1)

1. method of p eparing a sulphonate or sulphate salt of the cation in which a tertiary amine of the formula wherein E is the is reacted a compound of t formula therein X is methoxy and Z is a chlorine atom or a sulfonate or sulphate a tertiary amine of the formula wherein X is the methoxy is reacted with a compound wherein is the group and Z has the same meaning as a tertiary amine of the formula wherein X is the methoxy group and S is the hydrox ethyl is reacted with a compound wherein Z has the same meaning as or B 224 a secondary amine of the formula X wherein X is the methoxy group and R is the hydroxyethyl is reacted with two equivalents of a methylating wherein Z nuoloophilic has the same meaning as A method of preparing a salt of the cation in which a tertiary amine of the formula wherein R is the ethyl is reacted with a compound of the formula as defined in claim a tertiary amine of the formula as defined in claim is reacted with a compound has the wherein R is the ethyl group and Z same meaning as a tertiary amine of the formula wherein X is the methoxy group and R is the ethyl is reacted with a compound as defined in claim a secondary amine of the formula wherein X is the methoxy group and R is the ethyl is reacted with two equivalents of a ting agent as defined in claim or a toxic salt of the cation is converted by double decomposition into a salt of the B 224 A method as claimed in either of claims and 2 in which the tertiary amines of the formula wherein X is the methoxy group and R is the ethyl or are formed in as mediates in the formation of the cations defined in claims 1 and A method as claimed in any preceding claim wherein the salt is the sulphate or sulphonate salt of the cations defined in claims 1 and A method as claimed in any preceding claim wherein Z is a chlorine atom or a sulphate or sulphonate group A method as claimed in any of claims and in which the reaction is carried out in a A method as claimed in any of claims and in which the reaction is carried out in a solvent selected from ethyl ethylacetate benzene and A method as claimed in either of claims and 2 in which the reaction is effected in the presence of an acid binding A method as claimed in claim 8 in which the acid binding salt is an alkaline A method as claimed in claim 9 in which the alkaline salt is sodium or potassium A method as claimed in any of claims 1 and 3 to 10 in which a salt of the cation defined in claim 1 is a different pharmaceutically acceptable further converted salt of the cation by double B 224 A method as claimed in any of claims 2 to 10 in which a salt of the cation defined in claim 2 is further converted to another salt by double A method as claimed in any of claims 1 to 12 and substantially as herein particularly with reference to any of the Examples 1 to A salt of the cation defined in claim ever prepared by a method as claimed in any of claims 1 3 to and A salt of the cation defined in claim whenever prepared by a method as claimed in any of claims 2 to 12 and 14 B 224 A method of preparing a pharmaceutical tion in which a compound containing either of the cations defined in claims 1 and 2 is admixed with a acceptable carrier A method as claimed in claim 16 and substantially as herein particularly with reference to any of the Examples 4 to A pharmaceutical composition as defined in claim 16 whenever prepared by a method as claimed in either of claims 16 and 15 B 224 A pharmaceutical composition comprising a compound containing either of the cations defined claims 1 and 2 association with a cally acceptable carrier A pharmaceutical composition as claimed in claim 19 in the form of a tablet or A pharmaceutical composition as claimed in claim 19 in the form of an injection A pharmaceutical composition as claimed in any of claims 19 to 21 in the form of a discrete dosage unit containing 100 to 600 of the A pharmaceutical composition as claimed in any of claims 19 to 22 and substantially as herein particularly with reference to any of the Examples 4 to 8 16 17 A sulphoaate or sulphate salt of the sulphonate or sulphate salts of Pharmaceutically acceptable or sulphate salts of the insufficientOCRQuality