IL34764A - Acid addition salts of n-p-methoxybenzyl-n',n"-dimethyl guanidines,their preparation and pharmaceutical compositions containing them - Google Patents

Description

ηιηρη 'wni on3an (B'j» 3itn *ηο»τ onus D' ^aan Acid addition salts of IT-p-iBetiioxybensyl-Ην,Η*» -dimethyl guanidinee, their preparation and pharmaoe tical compositions containing them fHB WELLCOME KJU DATION LIMITED 0/ 32890 Uhis invention relates to compounds useful in the treatment o arrhythmia.

It has previously been proposed to employ the powerful hypotensive drug bethanidine (H-be z l^^^'^iiae h lguaa di e) sulphate, in the treatment of cardiac arrhythmia* see "Bethanidine: a Hew Antifib¾*illatory Agent" Arch. i t. Pharmacodyn, 1966» Vol. 163, pp- 422-426. the d g has potent antiarrhythmic properties but the hypotensive action attributable to sympathetic blockade causes an undesirable substantial lowering of blood pressure. Thus, it is essential, when the drug is used, for the patients to b© in intensive-care units of hospitals.

It has now been found that S-g-methoxybenzyl-gSH*-dimethylguanidine acid addition s<s, hereinafter referred to as the "Compoundsft possess unexpected advantages over that drug in the treatment of arrhythmia. These Compounds of the invention not only have antiarrhythmic properties comparable to bethanidine, but also significantly less sympathetic blocking action, thus making possible the treatment of heart disorders with little or no adverse effect on blood pressure. the Compounds in the form ©f pharmaceutically acceptable salts are effective in treating and suppressing ventricular fibrillations and atrial fibrillations in mammals, such as humans, dogs an ca s.

Accordingly in one aapect the present invention provides acid adS/tion salts of ,HB-dimethylguanidine.

In another aspect the present invention provide© a pharmaceutical composition comprising an acid addition salt of i association with a pharmaceutically acceptable carrier. he pharmacological activity of the acid addition salts of j^B^e exyhe ayl-H j*^ime ylga nidi e resides in the eation, the nature of the anion only being important for administration requirements when used in medicinal practice* The compounds will of en be administered over a prolonged period and in such cases the anion must be pharmaceutically acceptable, that is, non-toxic, "non-toxic" meaning having no harmful effect on the patient after prolonged treatment, and as used herein the term "non-toxic" has this meaning. Bromide and iodide salts have a pharmacological activity in mammals which may be undesirable especially upon prolonged administration, but such salts are useful intermediates in the preparation of non-toxic salts.

Salts which are especially preferred for therapeutic use are the chlorides, sulphates and sulphonates such as the 3»- oluenesulphonate. ^ 4he point of view o£ s4r therapeutic activity.

The acid addition salts of N-p_-methy3,benzyl- ' "~A* "'"■^^y1 nf -p_-methoxybenzyl-N 1 ,N"-dimethylguanidine may be prepared by any of the known methods for preparing -aralkyl-N * , "-dialkylguanidines .

For example, they may be prepared by the reaction of a guanidine and a compound capable of replacing a guanidine-hydrogen atom by a benzyl or methyl group, as required. This may be represented by the reaction diagram (a) ^^NHMe NHMe (a) A - NH - C + BX > A - NH - C + HX ¾¾S¾¾¾¾-NH NB where one of A and B is the p_-methylbenzyl or the p_-methoxybenzyl group and the other is the methyl group, and X is a proton accepting group or atom such as a sulphonate group or a halogen atom. Such a reaction is usually carried out in a basic medium.

Compounds As another example, the aolfes of the invention may be produced by the reaction of an appropriate amine or a salt thereof with an S-substituted isothiourea or salt thereof, an O-substituted isourea or salt thereof, an an imidocarbonate or imidothiocarbonate, a diimide, or a formamidine substituted by an unsaturated heterocyclic group containing at least two nitrogen atoms 4 - MEW/RM/1.4.70 in the ring, one of which is attached to the carbon atom of the formamidine structure. These reactions may be illustrated by the following reaction diagrams NB (b) ANH~ + MT - C > A - NH - C NHMe NHMe where one of A and B is the p_-methoxybenzyl group and the other is the methyl group, M is a reactive substituent group in particular a hydrocarbon group, and T is an oxygen or a sulphur atom.

M is preferably an alkyl group of one to four carbon atoms, especially methyl or ethyl, and B is preferably the p_-methoxybenzyl group; either the amino or the urea derivative is advantageously present as an acid addition salt such that during the reaction there is about one molecular equivalent of acid present.

NHMe (c) X - N = C + 2 Me H2 > X - N = C . + 2 Y NHMe Where X is the p_-moth lbon3yl or the. p_-methoxybenzyl group, and Y is a halogen atom or the group TM, where T and M are as defined above; preferably M is an alkyl group of one to: four carbon atoms. When Y is a halogen atom it is preferably a chlorine or bromine atom; this reaction is conveniently carried out in an alcohol, especially preferred being an alcohol such as methanol or ethanol containing an inert solvent such as ether or benzene, and the methylamine is desirably used in excess. When Y is the group TM, then T is preferably oxygen and M preferably an alkyl group of one to six carbon atoms, especially ethyl or methyl; this reaction is normally carried out in an aqueous alcoholic medium, whilst the preferred temperature range is from 10 to 30°C; and the methylamine is advantageously present as a mixture of the base and an acid addition salt thereof, the molecular proportion of the base exceeding that of the salt, (d) NB (i) A - N = C = N - B + BNH — ) A - NH - C NHB (ii) B - N where A is the p_-meth 1 benz l or the p_-methoxybenzyl group and B is the methyl group. These reactions may be carried out in alcoholic solution. (e) ANH2 + QC: (NMe)NHB > A - NH - C: (NMe) .NHN + QH where one of A and B is the ]a-methylfoenzy]—nr t f> p_-methoxybenzyl group and the other is the methyl group, and Q is an optionally substituted unsaturated heterocyclic group containing at least two nitrogen atoms in the ring, one of which is attached to the carbon atom of the -C: (NMe) HB structure. Examples of Q are pyrazolyl, dialkylpyrazolyl, alkyl-arylpyrazolyl, dialkylmonohalo-pyrazolyl, imidazolyl, triazolyl or tetrazolyl; 3,5-di ethylpyrazol - 1 - yl is preferred. 34764/2 Salts of K-2-methoxybenzyl-K' ,N"-dimethylguanidine ,may also be obtained from the appropriate base or other salts. For example, the sulphate may be prepared from the iodide or chloride by reaction with silver sulphate, or from the base by reaction with sulphuric acid. In an analogous manner salts may be converted to the Ν-Ό-methoxybenzyl-N' dimethylguanidine base by treatment with a convenient base, such as sodium hydroxide, and the base converted to another salt.

The present invention also provides the above methods of preparation of acid addition salts of N-b-methoxybenzyl- ' ,N"-dimethylguanidine.

The Compounds, in the present invention may be presented in any acceptable pharmaceutical composition.

Compositions for oral or parenteral administration are preferred. Oral administration is especially preferred.

For oral administration, fine powders or granules of the Compounds may contain diluting, dispersing and/or . surface active agents, and may be presented in a draft in water or in a syrup, in capsules or cachets in the dry state or in a non-aqueous suspension, when suspending agents may be included; in tablets, when binders and lubricants ma be included; or in a suspension in water, . a syrup, an oil or a water/oil emulsion. Where desirable or necessary flavouring, preserving, suspending, thickening or emulsifying agents can be included. Tablets and granules are preferred, and these may be coated.

C For parenteral administration, the compounds may be presented in aqueous injection solutions which may contain antioxidants, buffers, bacteriostatic agents which solubilise a relatively insoluble compound, and solutes which render the salt isotonic with the blood in aqueous suspensions when suspending and thickening agent may also be included; or in non-aqueous solutions and suspensions if the particular compound selected is affected by water.

Dosages are preferably in the range 1 to 10 mg/kg of the base, especially about 4 mg/kg. Desirably the pharmaceutical compositions are presented in unit dosage form, usually containing in the range 100 to 600 mg. of base.

The following examples illustrate the invention.

Example 1 A stirred solution of p_-hydroxybenzonitrile (100 g.) in N-sodium hydroxide (1 litre) was treated at room tempera (I06g) ture with dimethylsulphate /drop by drop. After 24 hours the solid p_-methoxybenzonitrile (93 g.) (m.p. 60°C - 64°C) was collected, washed with water, and dried on a porous plate. This product was dissolved in ethanol (500 ml) and hydrogenated at 100°C and 100 atmospheres in the presence of Raney nickel (5 g.) . The filtrate was neutralised with 2N-HC1, evaporated and the residue crystallised from methanol-ether to give p_-methoxybenzylamine hydrochloride, m.p. 210°C (softens) to 240°C (63 g.). - - - t B 219/B 226 34764/2 A solution of p_-methoxyben_ylamine (23 g.) in ether (150 ml.) was slowly treated with a solution of methyl isothiocyanate (12.4 g.) in ether (200 mis).

The solution was allowed to cool and when cold the precipitated -p_-methoxybenzyl- 1 -methylthiourea (23 g.) (m.p. 100 -104°C) was collected.

A solution of the thiourea (18.5 g.) and methyl iodide (7 ml.) in methanol (75 ml.) was gently refluxed for 2 hours. The product was evaporated to dryness and the residual yellow oil was treated with ethanol-ether to give crystals of the isothiourea hydriodide (25 g.) m.p. 129 - 131°C.

A solution of the isothiourea hydriodide in 33% methanolic methylamine (20 ml.) plus a little water (3 - 5..-ml.) was gently refluxed. for 4½ hours. The product was evapo- \ rated to dryness and the resulting solid crystallised from methanol-ether to give the guanidine hydriodide, m.p. 161 to 164°C.

This salt was reacted with silverkulfate to produce the corresponding "sulfate, m.p. 273°C Example 2 ' A well stirred solution of sodium hydroxide (240 g.) , sodium cyanide (181 g.) and ethanol (480 ml.) in water (1800 ml.), was cooled in a carbon dioxide-ethanol bath and was freely treated with chlorine gas (double-or treble-tube delivery) at such a rate as to maintain the solution at -10°C to 0°C. After about half-an-hour, >diethyliminocarbonate (oil) and diethylchloriminocarbonate (solid) began to separate. Stirring and addition of chlorine was continued until neutrality was approached (pH.8). A white B 219/B 226 crystalline product was collected, ground up, well washed with water, and dried on a porous plate.

Yield 200 - 220 g, m.p. 38 - 41°C.

This product (70 g. ) "was dusted into a solution of arsenious oxide (51 g. ) ,potassium hydroxide (138 g.) in water (580 ml.) and the mixture was shaken vigorously for about 15 minutes. The temperature was maintained at 37° to 42°C by cooling. The resulting oily layer was extracted with ether. Evaporation of the sodium hydroxide-dried extract gave diethyl iminocarbonate (ca. 47 g.) (b.p. 42 - 44°C/15 mm.), which was used in the following stage without distillation. p_-methoxybenzylamine hydrochloride (9.4 g.) in water (100 ml.) was treated with diethyliminocarbonate (5.6 g.). An oil, which separated on warming, was extracted with ether (9 g.).

This product (4.5 g.) and methylamine sulphate (1.48 g.) in water (2 ml.) were mixed with 33% ethanolic methylamine (15 ml.) and the mixture was shaken to a homogeneous solution and then left 3 days at room temperature. The product was evaporated to dryness and the residual solid dissolved in water (10 ml.) , treated with excess of lO -sodium hydroxide solution and the resulting oily layer well extracted with ether. The extract, dried over solid sodium hydroxide, on evaporation gave the guanidine base as a syrup. From this, the sulphate was obtained by neutralisation with dilute sulphuric acid and evaporation. The sulphate was crystallised from methanol-ether to give a white solid, m.p. 273°C.

B 219/B 226 Example 3 Diethyliminocarbonate was prepared in essentially the same manner as in Example 2 except that in the first stage the temperature was -20°C and bromine was used diethyl instead of chlorine to give/bromoiminocarbonate, and in the second stage sodium thiosulphate was used instead of arsenious oxide. p_-Methoxybenzylamine (95.4 g.) in water (360 ml.) was treated at less than 20°C with hydrochloric acid (58 mis of concentrated acid in 90 mis of water) so that the resultant mixture had a pH. of 4.7. A solution of diethyliminocarbonate (75.9 g) in toluene (540 ml.) was added and the. whole stirred for 22 hours. The toluene layer was separated/washed with water and evaporated to N-give an oily residue of p_-methoxybenzyl diethyliminocarbonate .

This product (145 g.) was added to a methylamine solution at 20°C obtained by mixing water (30 ml.) and sulphuric acid (27.2 g.) and adding them to methylamine (255 g.) of a 10 per cent aqueous solution. Industrial (ethanol containing 5$ methanol) alcohol/was added and the whole stirred overnight/ the excess amine and solvent were evaporated off and the solid dissolved in water (about 300 ml.). Extraction with toluene, then water, followed by evaporation resulted in a solid which was disolved in methanol (about 200 ml.) at 60°C. Acetone (320 ml.) was added and the precipitate collected, washed with ethanol and in vacuo at 80°C to give N-p_-methoxybenzyl-N 1 , "-dimethylguanidine sulphate (m.p. 273 - 274°C) . 34764/2 - 12 - Example ■ 4 Tablets (0.55 g) of -£-methoxy¾enzyl-N« .^"-dimethylguanidine sulfate were made by mixing, the salt (0.25 g).in a fine powder with lactose (0.25 g) and starch (0.05 g) , granulating the mixture with alcohol or alcoholic polyvinyl pyrrolidone or a mixture of equal parts of alcohol and water, drying. the granules at 40°, adding magnesium stearate (0.010 g) as a lubricant and compressing the mixture.

Example 5 Tablets (0.208 g.) of -p_-meth lbenzyl-N ' , "- dimethylguanidine hydriodide were made by granulating the salt (0.1 g.) in a fine powder and lactose (0.1 g.) with gelatin (0.005 g.) in equal parts of alcohol and water. Magnesium stearate (0.003 g.) as a lubricant was added, and the mixture compressed directly.

Example 6 ' . Injection solutions containing -p_-methylbenzyl- N' ,N" -dimethylguanidine hydriodide in Water for Injection (0.2 g. per ml.) were made by autoclaving the solution at 15 lb. steam pressure for 30 minutes in until dose ampoules of multidose. containers. For the latter, the Water for Injection contained benzyl alcohol (1.0%), phenol (0.5%) or chlorocresol (0.1%).

Claims (1)

1. 3 A method of preparing acid addition salts of in which a guanidine is reacted with a compound in accordance with the following reactio diagram wherein one of A and B the group and the other is the methyl and X is a proton accepting group or an appropriate amine o a salt thereof reacted with substit ted isothiourea or salt or with an isourea or salt in accordance with the following reaction diagram wherein one of A and 1 is the group and the other is the is a reactive substituent and is an oxygen or a sulphur an appropriate amine or a sal thereof is reacted with an isoeyanodihalide or with an imidocarbonate or accordance the following reactio wherein X is the group and 14 Y is a halogen atom or the group TM in which M is a reactive substituent group and T is an oxygen or sulphur an appropriate amine or a salt thereof is reacted with a diimide in accordance with either of the following reaction diagrams A N C N B A NH C NHB NA B N C N B B NH wherein A is the and B is the methyl an appropriate amine or a salt thereof is reacted with an unsaturated heterocyclic compound in accordance with the following reaction diagram A H2 QC NHB A NH C NHB wherein one of A and B is the group and the other is the methyl and Q is an optionally substituted unsaturated clic group containing at least two nitrogen atoms in the one of which is attached to the carbon atom of the or the base is reacted with the appropriate and the resulting guanidine product isolated from the reaction mixture as an acid tion salt B 226 A method as claimed in claim 1 wherein the acid addition salts are the sulphate or sulphonate A method as claimed in either of claims and 2 wherein X is a sulphonate group or a halogen A method as claimed in any of claims 2 and 3 in which the reaction is carried out in a basic A method as claimed in either of claims and 2 wherein is a hydrocarbon A method as claimed in claim 5 wherein the carbon group is an alkyl group having 1 to 4 carbon A method as claimed in claim 6 wherein the alkyl group is methyl or A method as claimed in any of claims and 7 wherein B is the or benzyl A method as claimed in any of claims 2 and 5 to 8 wherein the amino or the urea derivative is present as an acid addition salt such that during the reaction there is about one molecular equivalent of acid A method as claimed in either of claims or 2 wherein M is an alkyl group of one to four carbon atoms A method as claimed in either of claims and wherein Y is a chlorine or bromine A method as claimed in claim 11 in which the action is carried out in an A method as claimed in claim 12 in which the alcohol is methanol or ethanol containing an inert A method as claimed in claim 13 in which the inert solvent is ether or B 226 A method as claimed in any of claims 11 to 14 in which the methylamine is in excess A method as claimed in either of claims and 2 wherein T is A method as claimed in either of claims wherein M is an alkyl group of one to six carbon atoms and T is A method as claimed in claim 17 wherein M is ethyl or A method as claimed in any of claims 16 to 18 in which the reaction is carried out in an aqueous alcoholic medium and at a temperature from 10 to A method as claimed in any of claims 16 to in which the methylamine is present as a mixture of the base and an acid addition salt the molecular proportion of the base exceeding that of the A method as claimed in either of claims and 2 in which the reaction is carried out in alcoholic A method as claimed in either of claims and 2 wherein Q is dialkylpyrazolyl triazolyl or A method as claimed in claim 22 wherein Q is A method as claimed in either of claims and wherein the acid is sulphuric A method as claimed in any preceding claim in which or a acid addition salt product is further converted to another salt 17 A method as claimed in wherein the hydrogen iodide or chloride salts of g anidine are reacted with silver sulphate to produce the sulphate addition method as in any of Claims 1 to 26 and substantially as herein described particularly with re to any of the Examples 1 to An acid addition salt whenever prepared by a method as claimed in any of Claims 1 to A method preparing a pharmaceutical composition in which a pharmaceutically acceptable acid addition salt of is with a therapeutically acceptable carrier A method as claimed in Claim 29 and substantially as herei particularly with reference to any of the to A pharmaceutical composition comprising a pharmaceutically acceptable acid addition salt of whenever prepared by a method as claimed in either of 29 and A pharmaceutical composition comprising a pharmaceutically acceptable acid addition of in association with a therapeutically acceptable carrier pharmaceutical composition as claimed in Claim the form of a tablet or A pharmaceutical composition as claimed in Claim 32 in the of an injection pharmaceutical composition as claimed i y of Claims 32 to 34 in the form of a discrete dosage unit containing 200 to of A pharmaceutical composition of a pharmaceutically acceptable acid addition salt of h claimed in any of Claims to 35 and substantially as particularly with reference to any of the o acid addition salt of A acid addition salt as claimed in Claim 37 wherein the anion h For Applicants A D insufficientOCRQuality