IL29176A - Benzylpyridinium compounds,their preparation and pharmaceutical preparations containing them - Google Patents

Description

Benzylpyridinium compounds, their preparation and pharmaceutical preparations containing them CIBA-GEIGY A.G.

C. 27625 29176/2 ^ This invention relates to substituted l-benzy1-2,3»» and 4-acyl pyridinium halide oximes, oxime derivatives and semicarbazones, to processes for their preparation and to their uses* The compounds of this invention can be represented by the following formula% in which , is hydrogen or lower alkyl; hydrogen _alkoxy Rgt independently represent/lower/fluorine* cHorine* bromine or nitro; &2 "^y also represent lower alkyl or hydro¾¾ R^ may also represent lower alkyl, trifluoromethyl or alkoxy""carbonyl and ^ may also represent cyanoj g is hydrogen or, when each of Kg, -j» R^ and ^ is fluorine, fluorine; is hydrogen, lower alkyl, phenyl or lower alkoxycarbonyl; Rg is hydroxy, lower alkoxy, aralkoxy, or -NHGONH^ ; and X is chlorine or bromine; with the proviso that (1) no more than three of 2# -j# R^ and ^ may be hydrogen, (2) when Kg is methyl, no more than two of R^, R^ and (- may be hydrogen, (3) when the group « C is in the 2-position and R, is lower alkoxy, no more than two or > £ (4) when the group in the 2-position and both Rg and are loweralkoxy, no more than one of and may be hydrogen.

The term "lower a kyl" as used herein alone or in "lower alkoxy" means saturated monovalent aliphatic radicals of the general formula wherein m represents an integer of 6 or less, and is inclusive of straight-and branched-chain groups 29176/2 ^ such as methyl, ethyl, n-propyl, isopropyl, n-butyl, etc.

The compounds of this invention are pharmaceutically active agents. They are useful as' cardiovascular agents, particularly for lowering blood pressure. Compounds within the scope of Formula (I) having the following structure in which one of R'3 and R'4 is halogen (particularly fluorine, chlorine and bromine) , the other of R'3 and R'4 is hydrogen or halogen (particularly fluorine, chlorine and bromine), R*Q is hydroxy or -NHCONR^ , and X has the meaning ascribed to it in Formula (I) are particularly useful as sympathetic stimulants. Ά compound of formula I, in which all of R^ to R^ are hydrogen, Rg is hydroxy and X is chlorine, was mentioned in Nature 209. (5020), p.266-271 (1966). No pharmaceutical activity of that compound was disclosed.

Compounds of Formula (I) can be conveniently made from. •starting materials having the following structure: in which R2, R^, R4 , R¾ , RG , and X have the. meaning ascribed to them in Formula (I). known in the art from the corresponding aldehydes, carboxylic acids, esters, and alcohols, or by the known method of halomethylation of the appropriate benzene derivatives.

To produce the compounds of this invention, the starting compound is reacted with a protected pyridine aldehyde or ketone having the following structure: in which R- R^ and Rg have the meanings ascribed to them in formula ( I) .

As an alternative, the compounds of this invention can prepared by reaction of a suitable benzyl halide of Formula a (III) with a pyridinecarbox ldehyde or ketone to give the substituted 1 - benzylpyridinium aldehyde or ketone salt in which R^, R2, 3, R^ , R^, Rg , Ry and X have the meanings ascribed to them in. formula (1). Reaction of appropriately-substituted 1-benzylpyridinium aldehyde or ketone salt with a reagent such as semicarbazide , hydroxylamine, a substituted hydroxylamine etc., gives compounds of Formula (I).

To illustrate this process more specifically, the following is a brief description of the method of preparing l-(4,5-dimethoxy-2-methyl) benzyl-2 -formyl-pyridinium bromide oxime, its 2-benzoylpyridinium oxime, O-ethyloxime and semi-carbazone analogues. The starting material is 3 , 4-dimethoxytoluene which is bromomethylated to give 2-methyl-4 , 5-dimethoxybenzyl bromide To obtain 1- ( 4 , 5-dimethoxy-2-methyl) benzyl-2 -formyl-pyridinium bromide oxime the starting compound is reacted with 2-pyridinealdoxime.

To obtain 1- ( 4 , 5-dimethoxy-2-methyl) benzyl-2-benzoyl-pyridinium bromide oxime (VIII) the starting compound is reacted with 2-benzoylpyridine oxime, To obtain l-( , 5-dimethoxy-2-methyl) benzyl-2-formylpyridinium bromide-0-eth loxime the starting compound is reacted with 2-pyridinealdoxime ethyl ether. And to obtain l-(4 , 5-dimethoxy-2-methyl) benzyl-2-formylpyridinium bromide semicarbazone the starting compound is reacted with 2-pyridinecarboxaldehyde semicarbazone .

The present invention comprehends not only the indicated halide salts, but also other pharmaceutically acceptable nontoxic salts of these compounds formed by using the appropriate acid such as phosphoric or sulfuric.

The compounds of the invention may be used in warmblooded animals, particularly mammals, as medicaments in the form of pharmaceutical compositions containing the compounds in admixture or conjunction with a pharmaceutical organic or inorganic, solid or liquid carrier for oral, rectal, or parenteral administration. The total daily doses can v^r from about 0.1 mg/kg to about 10 mg/kg, preferably about 0.5 mg/kg The preferred route of administration is the oral route. Suitable compositions include, without limitation, tablets, capsules, powders, solutions, suspensions, sustained release formulations and the like.

To produce dosage units for peroral application, the compositions of this invention may be combined, e.g. with solid pharmaceutically acceptable pulverulent carriers such as lactose, saccharose, sorbitol, mannitol; starches such as potato starch, corn starch or amylopectin, also laminaria powder or citrus pulp powder, cellulose derivatives or gelatin, also lubricants such as magnesium or calcium stearate or polyethylene glycols of suitable molecular weights may be added, to form tablets or press coated tablets. The latter are coated for example, with concentrated sugar solutions which can contain e.g. gum arabic, talcum and/or titanium dioxide, or they are coated with lacquer dissolved in easily volatile organic solvents or a mixture of organic solvents. Dyestuffs can be added to these coatings, for example, to distinguish between different contents of active substances .

Hard gelatin capsules contain, for example, granulates of the instant composition with solid pulverulent carrier such as e.g. lactose, saccharose, sorbitol, mannitol and further starches such as potato starch, corn starch or amylopectin, cellulose derivatives or gelatin, as well as magnesium stearate or stearic acid.

Suppositories containing a compound of the present invention are readily obtained by techniques well known to those skilled in the art of compounding dosage forms. A compound of the present invention is dispersed in a carrier such as cocoa The compounds of this invention are more fully illustrated by the following examples, which also show the method of preparing the starting compounds. These examples are included here for the purpose of illustration and are not intended as a limitation. All temperatures are in degrees centigrade.

Example 1 l-( 3 , 4-Dimethoxy-2-methylbenzyl) -2 -formylpyridinium bromide oxime (a) Monobromomethylmethyl ether. A mixture of methanol (945 and 40% aqueous formaldehyde (500 ml) was cooled to -10° and saturated with hydrogen bromide. The two phases were separated and the lower layer distilled. After a forerun, 242 g of the product, b.p. 86-88°, was collected. (b) 3.4-Dimethoxy-2-methylbenzylbromide (Method A) . A mixture of 2 , 3-dimethoxytoluene (80 g) , monobromomethylmethyl ether (137 g) and glacial acetic acid (88 ml) was maintained at 30° for 8 hours. The reaction mixture was poured into ice-water and the resulting solid filtered off. Recrystallization from hexane gave 73 g of the product as colorless platelets*, m.p. 66-68°.

(Method B) . A mixture of 2 , 3-dimethoxytoluene (91 g) , paraformaldehyde ( 20 g) , 48% hydrobromic acid (68.5 ml), and benzene (300 ml) was cooled to 0° with stirring and was saturated with hydrogen bromide with ice cooling. The organic phase was separated, washed with saturated brine, dried over anhydrous magnesium sulfate and the solvent removed under reduced pressur to give the crude benzylbromide (124 g) . One recrystallization from petroleum ether (b.p. 30-60°) gave the benzyl bromide (95 g.; m.p. 68-70°). A further recrystallization raised the m.p. to 70-72°. (c) l-(3.4-Dimethoxy-2-methyl) benzyl' -2 -formyl-pyridinium bromide oxime (Method A) . 3 , 4-Dimethoxy-2-methylbenzyl bromide (54 g) and 2-pyridinealdoxime (27 g) were dissolved in dimethylformamide (162 ml) and the solution was maintained filtration and the filtrate poured slowly into ethyl acetate (2000 ml) with stirring. The resulting amorphous solid was filtered off and combined with the crystalline material to give a total yield of 74 g of the quaternary salt. Two recrystalliza-tions from methanol gave the pure material as colorless crystals: m.p. 166.5-168°.

(Method B) . A solution of 2-pyridinecarboxaldehyde (5.35 g, freshly redistilled) and 3 , 4-dimethoxy-2-methylbenzyl bromide (12.5 g) , prepared according to the method given in Example 1(b), in dimethylformamide (30 ml) was maintained at room temperature for 18 hours under an atmosphere of nitrogen. The reaction mixture was poured slowly with stirring into ethyl acetate (800 ml) and the resulting yellow precipitate was filtered off to give l-(3 , 4-dimethoxy-2-methyl) benzyl-2-formylpyridinium bromide (13.2 g; m.p. 111-112°) used without purification for the next step .

A solution of l-(3, -dimethoxy-2 -methyl) benzyl -2 -formylpyridinium bromide (9.15 g) in methanol (10 ml) was added to a solution of hydroxylamine in methanol (15 ml; prepared from hydroxylamine hydrochloride (2.4 g) and potassium hydroxide (1.7 g)). The reaction mixture was warmed on the steam bath for 30 minutes and then cooled to 0° and poured into ether (1000 ml) with stirring. The precipitate was filtered off and recrystal-lized from methanol to give l-(3, 4 -dimethoxy-2 -methyl) benzyl^-2 -formylpyridinium bromide oxime m.p. 152-4°.

Example 2 l-(3, 4 -Dimethoxy-2 -methyl benzyl) -6-methyl-2-formylpyridinium bromide oxime 3, 4 -Dimethoxy-2 -methylbenzyl bromide (12.5 g), prepared 2-pyridinealdoxime (7.0 g) were dissolved in dimethylformamide (40 ml) and the solution was maintained at 30° for 18 hours.

The reaction mixture was poured slowly into ethyl acetate (500 ml) with stirring. The resulting product was filtered off and dried.

Example 3 l-(3, 4-Dimethoxy-benzyl) -2 -formylpyridinium bromide oxime (a) 3 , 4-Dimethoxybenzyl bromide. 3 , 4 -Dimethoxybenzyl alcohol (53.2 g) was dissolved in dry benzene (485 ml) and the solution was cooled in an ice/water bath. The solution was saturated with hydrogen bromide while stirring was maintained. The reaction mixture was neutralized with anhydrous potassium carbonate and the solvent removed on the rotary evaporator to give 67.2 g of the crude bromide, used without purification for the next step of the synthesis. (b) 1- ( 3 , 4-Dimethoxy-benzyl) -2 -formylpyridinium bromide oxime 3 , 4-Dimethoxybenzyl bromide (67 g) and 2-pyridinealdoxime (35.5 g) were dissolved in dimethylformamide (153 ml) and the solution was maintained at 30° for 18 hours. The crystalline product was filtered off and the filtrate was poured slowly into ethyl acetate (3000 ml) with stirring. The resulting amorphous precipitate was filtered off and combined with crystalline material to give a yield of 87.5 g of the crude salt. Two recry-stallizations from methanol gave the pure salt, m.p. 168-171.5° as pale yellow crystals.

Example 4 l-( 4 , 5-Dimethoxy-2-methylbenzyl) -2-formylpyridinium bromide oxime (a) 4 , 5-Dimethoxy-2-methylbenzyl bromide (Method A) . - (11 g) and monobromomethylmethyl ether (17 g) was maintained at 30° for 5 hours. The reaction mixture was poured into ice-water, the mixture extracted with ether, and the ether dried over anhydrous magnesium sulfate and evaporated under reduced pressure to give 15 g of the desired product as a straw colored oil, used without purification for the next step of the synthesis. (Method B) . A mixture of 3 , 4 -dimethox toluene (182 g) , paraformaldehyde (40 g) , benzene (600 ml) and -48% hydrobromic acid (137 ml) was cooled to 0° and saturated with hydrogen bromide with ice cooling. he phases were separated and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. On evaporation of the solvent, the product was obtained as a semi-crystalline mass (175 g) . Recrystalliza-tion from hexane gave material of m.p. 31.5-33°. ( b) l-( 4 « 5-Dimethoxy-2-methyl -benzyl) -2 -formylpyridinium bromide oxime . 4 , 5-Dimethoxy-2-methylbenzyl bromide (12.5 g) and 2-pyridinealdoxime (6.3 g) were dissolved in dime hylformamide (32 ml) and the solution was maintained at 30° for 18 hours.

The crystalline product was filtered off and the filtrate poured slowly into ethyl acetate (500 ml) with stirring. The resulting amorphous solid was filtered off and combined with the crystalline material. Two r ecrystallizations from methanol gave the pure material as colorless crystals, m.p. 178,5-181°.

Example 5 l-(4, 5-Dimethoxy-2 -isopropyl- benzyl) -2-formylpyridinium bromide oxime (a) 3 , 4-Dimethoxycumene . 4-Isopropyl catechol (230 g) was dissolved in a solution of sodium hydroxide (168 g) in water (1210 ml). The solution was cooled to 15° and dimethyl sulfate (325 ml) was added to the stirred and cooled reaction mixture during l-i- hours. The mixture was warmed on the steam bath for one hour and refluxed for 18 hours. After cooling, the organic phase was separated and the aqueous phase extracted with benzene (2 x 250 ml) . The combined organic solutions were washed with $ aqueous sodium hydroxide until no phenolic material remained (ferric chloride test) and then with water. The benzene was removed by distillation through a Vigreux column at atmospheric pressure, and the residue distilled under reduced pressure to yield a pale yellow liquid (223 g), b.p. 123-130°/ 23 mm. (b) 4 , 5-Dimethoxy-2-isopropylbenzyl bromide. (Method A) .

A mixture of 3, 4-dimethoxycumene (41 g) , glacial acetic acid (38 g) and monobromomethylmethyl ether (60 g) was maintained at 30° for 5 hours. The reaction mixture was poured into ice-water, the resulting oil was extracted from the water with ether, the ether dried over anhydrous magnesium sulfate, and exaporated under reduced pressure to give the product as a pale yellow oil (54.7 g) , used without further purification for the next step of the synthesis.

(Method B) . A mixture of 3 , 4-dimethoxycumene (60 g) , paraformaldehyde (11 g) , 48% hydrobromic acid (38 ml), and benzene (166 ml) was cooled to 0° with stirring and was saturated with hydrogen bromide with ice cooling. The organic phase was sep-arated, dried over anhydrous magnesium sulfate, and the solvent-removed under reduced pressure to give the crude benzyl bromide, (86 g) used without purification. ( c) l-(4 , 5-Dimethoxy-2-isopropyl benzyl) -2-formylpyridinium bromide oxime. 4 , 5-Dimethoxy-2-isopropyl-benzyl bromide (54,7 g) formamide (132 ml) and the solution maintained at 30° for 18 hours. The reaction mixture was added slowly to ethyl acetate (3000 ml) and the resulting amorphous product was recrystallized from methanol/ethyl acetate to give the pure product, m.p. 147-148° dec.

Example 6 l-( 3 , 4 , 5 -Trimet oxy- benzyl) -2 -formylpyridinium bromide oxime (a) 3 , 4.5-Trimethoxybenzyl bromide. 3 , 4 , 5-Trimethoxybenzyl alcohol (40.0 g) was dissolved in dry benzene (312 ml) and the solution was cooled to -10°, and saturated with hydrogen bromide with stirring. The reaction mixture was neutralized with anhydrous potassium carbonate, filtered and dried over anhydrous magnesium sulfate. Evaporation of the solvent gave the bromide as an almost colorless oil (43.3 g) used without purification for the next step of the synthesis. ( b) l-( 3.4 , 5-Trimethoxy-benzyl) -2 -formylpyridinium bromide oxime . 3 , , 5-Trimethoxybenzylbromide (43.0.g) and 2-pyridine-aldoxime (32.3 g) were dissolved in dimeth Iformamide (203 ml) and the resulting solution was maintained at 30° for 18 hours. The crystalline product was filtered off and the filtrate poured into ethyl acetate (2000 ml). The resulting amorphous product was filtered off and combined with the crystalline material. Two recrystallizations from methanol gave the pure salt as colorless crystals, m.p. 155-157.5°, Example 7 1- ( 2 , 3-Dimethoxy benzyl) -2 -formylpyridinium bromide oxime (a) 2.3-Dimethoxybenzyl bromide. 2 , 3 -Dimethoxybenzyl alcohol (75.0 g) was dissolved in benzene (683 ml) and the solution cooled to -10°. The solution was saturated with hydrogen bromide, neutralized with anhydrous potassium carbonate, filtered, and dried over anhydrous magnesium sulfate. Evaporation of the solvent gave the bromide as a colorless oil (90.3 g) used without purification for the next step of the synthesis. ( b) 1- ( 2 , 3-Dimethoxybenzyl) -2-formyl-pyridinium bromide oxime . 2 , 3-Dimethoxybenzyl bromide (90.3 g) and 2 -pyridinealdoxime (47.9 g) were dissolved in dimethylformamide (63 ml) and the resulting solution maintained at 30° for 18 hours. The crystalline product was filtered off and the filtrate poured into ethyl acetate (4000 ml). The resulting amorphous precipitate was filtered off and combined with the crystalline material. This is the chemical grade quaternary oxime.

Example 8 l-(3, 4-Diethoxy-2-methyl-benzyl) -2-formylpyridinium bromide oxime (a) 2.3-Diethoxytoluene . 3-Methylcatechol (250 g) was dissolved in a solution of sodium hydroxide (224 g) in water (1600 ml) and the resulting solution was cooled with ice/salt. Diethyl sulfate (600 ml) was slowly added with stirring, the temperature being maintained between 0° and -7°. The reaction mixture was heated on the steam bath for 3 hours, then refluxed for 18 hours and allowed to cool to room temperature. The organic layer was separated and the water layer was extracted thoroughly with benzene.

The combined organic solutions were washed with 10%. sodium hydroxide solution until no phenolic material remained (FeCl^ test) and then with water. The benzene was distilled off at atmospheric pressure through a Vigreux Column and the residue was distilled to give 21904 g of the product, b.p. 123-127°/ (b) 3 , 4-DiethoxY-2-methylbenzyl bromide . A mixture of 2 , 3-diethoxytoluene (213 g), benzene (590 ml), paraformaldehyde (39.4 g) , and 48% hydrobromic acid (135 ml) was cooled to 0° with stirring and saturated with hydrogen bromide. The organic phase was washed with saturated brine (3 x 150 ml), dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The resulting oil was poured into ice-water (1000 ml) and the crystalline product was filtered off and recrystallized from petroleum ether (b.p. 30-60°; charcoal) to give 154 g of the benzyl bromide, m.p. 39-440 o ( c) 1- ( 3.4-Diethoxy-2-methyl-benzyl) -2 -formylpyridinium bromide -oxime . A solution of 12.2 g of 2 -pyridinealdoxime and 27.3 g of 3 , -diethoxy-2-methylbenzylbromide in 30 ml of dimethylformamide was maintained at room temperature for four days. The resulting precipitate was filtered off and the filtrate poured slowly with stirring into 1000 ml of ethyl acetate. The solid which was deposited was filtered off and combined with the material obtained directly from the reaction mixture. Recrystallization from 2B ethanol gave the pure product together with material of technical grade purity.

Example 9 l-( 3 , 4-Dimethoxy-2-methyl benzyl) -5-ethyi-2 -formylpyridinium bromide oxime (a) 5-Ethyl-2 --pyridinealdoxime , A mixture of 5-ethyl-2-methylpyridine (24 g) , glacial acetic acid (80 ml) and 30% hydrogen peroxide (18 ml) was maintained at 80° for three hours. An additional portion of 30% hydrogen peroxide (6 ml) was added and the mixture was maintained at 80° for a further 3-hour period.- The volatile solvents were removed under reduced pressure (water pump) and the residue dissolved in acetic anhydride (50 ml). The mixture was heated to 95°, which initiated an exothermic reaction. The reaction mixture refluxed and refluxing was maintained for a further 2 hours. The solution was distilled under reduced pressure (water pump) and after a forerun, 2-acetoxymethyl-5-ethylpyridine (15.0 g „ , b.p„ 138-140°/12 mm) was obtained.

A mixture of the 2 -acetoxymethyl-5-ethyl -pyridine obtained above, glacial acetic acid (70 ml), and 30% hydrogen peroxide (16 ml) was maintained at 80° for 3 hours. An additional portion of 30% hydrogen peroxide (8 ml) was added and the mixture was maintained at 80° for a further 3-hour period.

The volatile solvents were removed under reduced pressure (water pump) and the residue was dissolved in 6N HC1 (60 ml). The solution was heated on the steam bath for one hour and the bulk of the hydrochloric acid was removed on the rotary evaporator. The residue was dissolved in water, made basic by the addition of aqueous sodium hydroxide, and extracted thor- ougly with ether. The ether was removed on the rotary evaporator and the residue distilled to give 5-ethyl-2 -formyl- pyridine (3.76 g; b.p. 85-106°/12 mm) _ A solution of hydroxylamlne was prepared from hydroxylamlne hydrochloride (1.94 g) , water (10 ml), and sodium bicarbonate (2.35 g) . A solution of the aldehyde obtained above in ethanol (10 ml) was added and the mixture heated on the steam bath for one hour. The reaction mixture was cooled to room temperature, and 5-ethyl-2-pyridinealdoxime (2.99 g: m.p. 148-9°) was obtained . (b) 1- ( 3 , 4 -Dimethoxy-2 -methyl-benzyl) -5-ethyl-2 -formylpyridinium bromide oxime. A solution of 3 , 4 -dimethoxy-2 -methylbenzyl bromide (3.83 g, prepared according to Method A given in Example 1 (b)), and 5-ethyl-2 -pyridinealdoxime (2.34 g) in dimethylformamide (10 ml) was maintained at room temperature for 18 hours and poured slowly with stirring into ethyl acetate (200 ml) . The resulting solid was filtered off. A portion of this material was recrystallized from isopropanol to give the pure quaternary salt m.p. 142-143°, as colorless crystals.

Example 10 3 1- ( 3 , 4 -Dimethoxy-2 -methyl- benzyl) -2-formyl- -methylpyridinium bromide oxime A solution of 3-methyl-2-pyridinealdoxime (6.8 g, prepared by the method of S. Ginsburg and I.B. Wilson, J. Amer . Chem.

Soc, 79., 481 (1957)) and 3 , 4-dimethoxy-2-methylbenzyl bromide (12.2 g, prepared according to Method A given in Example 1 (b)) in dimethylformamide (35 ml) was maintained at room temperature for two hours. The precipitate was filtered off and recrystallized from ethanol to give the pure quaternary salt as colorless crystals, m.p.: 154-155.5°.

Example 11 l-( 3 , 4-Dimethoxy-2-methyl-benzyl) -2-formylpyridinium bromide semicarbazone Semicarbazide hydrochloride (0.8 g) was dissolved in methanol (100 ml) and potassium carbonate (0.5 g) was added.

The solution was filtered and the semicarbazide solution was cooled to room temperature. 1- ( 3 , 4 -Dimethoxy-2-methyl) benzyl-2-formylpyridinium bromide (2.0 g, prepared as described in method B of Example 1 (c)) was dissolved in methanol (50 ml) and added to the methanolic semicarbazide . The reaction mixture was stirred at room temperature for 18 hours and then poured into ether (1000 ml). The resulting precipitate was filtered off and recrystallized from methanol/ethyl acetate to give the quaternary salt, m.p. 178-178.5°, together with material of technical grade purity.

Example 12 1- (2 , 3 , 4-Trimethoxy-benzyl) -2-formylpyridinium bromide oxime (a) 2 , 3 , 4 -Trimethoxybenzyl bromide. A mixture of 48% hydro-bromic acid (3.3 ml), water (1,5 ml) and benzene (500 ml) was saturated with hydrogen bromide. Paraformaldehyde (15 g) was added, followed by 1 , 2 , 3-trimethoxybenzene (84 g)- prepared from pyrogallol by the method of A. Oliviero, G.G. Mauni-Bettolo, and G. Burgellini, Gazz. Chim. Ital., 78, 363 (1948). The reaction mixture was stirred for 18 hours at room temperature, filtered and the filtrate washed with water, saturated aqueous sodium bicarbonate and water. The solution was dried over anhydrous sodium sulfate and the solvent removed to give 98.8 g of crude 2 , 3 , 4 -trimethoxybenzyl bromide, used without purification for the next step of the synthesis. (b) l-(2, 3, 4-Trimethoxy-benzyl) -2-formylpyridinium bromide oxime . 43.3 g of the crude benzyl bromide and 32.25 g of 2-pyridinealdoxime were dissolved in 203 ml of dimethylformamide . The reaction mixture was maintained at 30° for 16-1- hours, then poured into 3 liters of ethyl acetate,, The resulting precipitate was recrystallized three times from methanol to give the pure salt, m.p. 160-161.5°.

- - Example 13 1- ( 3 , 4 -Dimethoxy-2-methyl -benzyl) -3 -formylpyrldinium bromide oxime A solution of 3 , 4 -dimethoxy-2 -methylbenzyl bromide (27 g, prepared as described in Method A of Example 1 (b)) and 3-pyridinealdoxime (13.6 g) in dimethylformamide (81 ml) was maintained at 30° for 18 hours. The reaction mixture was poured slowly into ethyl acetate (1000 ml) with stirring and the resulting precipitate filtered off and recrystalllzed from ethanol to give the pure salt, n.p. 164-165.5°.

Example 14 1- ( 3 , 4-Dimethoxy-2-methyl-benzyl) -4 -formylpyrldinium bromide oxime A solution of 3 , 4-dimethoxy-2-methyl-benzyl bromide (27 g prepared as described in Method A of Example 1 (b)) and 4-pyridinealdoxime (13.6 g) in dimethylformamide (81 ml) was maintained at 30° for 18 hours. The precipitate was filtered off and recrystalllzed from methanol to give the pure salt, m.p. 206.5-207.5°. The mother liquors contained material of technical grade purity.

Example 15 2-Formyl-l-(3-nitro-benzyl)pyridinium bromide oxime A solution of 2-pyridinealdoxime (6.1 g) and 3 -nitrobenzyl bromide (10.8 g) in dimethylformamide (15 mi) was maintained at room temperature for five days. The resulting precipitate was filtered off and recrystalllzed from methanol to give the pure salt, m.p. 189-90°.

Example 16 1- ( 4-Bromobenzyl) -2-formylpyridinium bromide oxime A solution of 12.5 g of ρ,-bromobenzyl bromide and 6 „ 1 g of 2 -pyridinealdoxime in 15 ml of dimethylformamide was maintained at room temperature for 6 days. The crystalline material was filtered off and recrystallized from isopropanol (charcoal) to give the product, m.p. 167-168°.

Example 17 1- ( 3 , 4 -Dimethoxy-2-methyl -benzyl) -2-acetylpyridinium bromide oxime A solution of 3 , 4 -dimethoxy-2-methylbenzyl bromide (12.25 g, prepared as described in Method A of Example 1 (b)) and 2-acetylpyridine oxime (6.8 g, prepared by the method of S.

Ginsburg and I.B. Wilson, J, Amer. Chem. Soc. 79., 481 (1957)) in dimethylformamide (15 ml) was maintained at room temperature for 18 hours. The crystalline material was filtered from the reaction mixture and identified as 2 -acetylpyridine oxime hydrobromide . The filtrate was poured into ethyl acetate and the resulting precipitate was recrystallized from isopropanol/ethyl acetate to give the pure product, m,p. 128-129.5°.

Example 18 l-(3-Fluoro-benzyl)-2-formylpyridinium bromide oxime A solution of m-fluorobenzyl bromide (9.45 g) and 2-pyridinealdoxime (6.1 g) in tetramethylene sulfone (35 ml) was maintained at room temperature for seven days. The crystalline product was filtered off and recrystallized from isopropanol/methanoL to give the pure salt, m.p. 172-175°.

Example 19 1- ( 3 , 4-Dimethoxy-2-methyl -benzyl) -2 -benzoylpyr idinium bromide oxime.

A solution of 12.25 g of 3 , 4 -dimethoxy-2 -methylbenzyl bromide (prepared as described in Method A of Example 1 (b)), and 9.9 g of 2 -benzoyl-pyridine oxime (prepared by the method of S. Ginsburg and I. B. Wilson, J. Ame . Chem. Soc, 79., 481 (1957)) in 50 ml of tetramethylenesulfone was maintained at room temperature for seven days. The product was filtered off and recrystallized from isopropanol. to give the salt, m.p. 171-3° .

Example 20 l-( 4-Cyano -benzyl) -2-formylpyridinium bromide oxime A solution of p_-cyanobenzyl bromide (9.8 g) and 2-pyridine-aldoxime (6.1 g) in dimethylformamide (60 mi) was maintained at room temperature for 24 days. The resulting precipitate was filtered off and identified as 2-pyridinealdoxime hydrobromide . The filtrate was poured into ethyl acetate (500 ml) with stirring and the precipitated solid was filtered off. One recrystalliza-tion from methanol/ethanol gave a small quantity of 2-pyridinealdoxime hydrobromide. The mother liquors were evaporated and the residue recrystallized three times from methanol/ isopropanol to give the pure salt, map. 169-171°» Example 21 l-( 3-Nitro -benzyl) -3-formylpyridinium bromide oxime A solution of m-nitrobenzyl bromide (10,8 g) and 3-pyridine-aldoxime (6.1 g) in dimethylformamide (30 ml) was maintained at room temperature for 45 minutes. The resulting precipitate was filtered off and recr stallized from methanol ethanol to ive Example 22 l-(2-Hydroxy-5-nitro-benzyl) -2-formyl-pyridinium bromide oxime A solution of 2-hydroxy-5-nitrobenzyl bromide (10.0 g) and 2-pyridinealdoxime (5.65 g) in dimethylformamide (15 ml) was maintained at room temperature for ten days. The crystalline product was filtered off and the filtrate poured slowly into ethyl acetate with stirring. The resulting amorphous material was combined with the crystalline material and recrystallized from methanol to give the pure salt, m.p. 199-200°.

Example 23 1- ( 3-Nitro -benzyl) -2 -formylpyridinium bromide semicarbazone A solution of m-nitrobenzyl bromide (10.8 g) and 2-pyridinecarboxaldehyde semicarbazone (8.2 g, Beilstein 2_1, I, in 45 ml of dimethylformamide 288)/was maintained at room temperature for five days. The resulting crystalline material was filtered off and washed thoroughly with chloroform to give the pure salt, m.p, 214-6°.

Example 24 2-Formyl-l-( 2-nitro-benzyl) pyridinium bromide oxime A solution of 2-pyridinealdoxime (6.1 g) and 2-nitrobenzyl bromide (10. 8 g) in dimethylformamide (15 ml) was maintained at room temperature for 3 days. The crystalline product was filtered off and recrystallized from 2B ethanol (charcoal) to give the quaternary salt, m.p. 177-8°.

Example 25 1- ( 2 , 5-Dimethoxy-benzyl) -3-formylpyridinium bromide oxime (a) 2 , 5-Dimethoxybenzyl alcohol. A solution of t-butyl-aminoborane (9.6 g) in benzene (1100 ml) was added dropwise with stirring to a solution or 2 , 5-dimethoxybenzaldehyde minutes, cooled, and 3N HC1 (250 ml) added dropwise. Stirring was continued for a further hour, the benzene layer was collected, and the aqueous phase washed with benzene (250 ml). The combined benzene solutions were dried over anhydrous sodium sulfate and the solvent removed on the rotary evaporator, to give 2 , 5-dimethoxybenzyl alcohol (36 g) used without purification for the next step of the synthesis. (b) 2 , 5-Dimethoxybenzyl bromide. 35.8 g of the crude alcohol obtained above was dissolved in dry benzene (328 ml) and the solution cooled with an ice/salt bath. The solution was stirred and saturated with hydrogen bromide. The solution was neutralized with anhydrous potassium carbonate, filtered, dried over anhydrous magnesium sulfate and the solvent removed on the rotary evaporator to give 2 , -dimethoxybenzyl bromide (43.6 g) m.p. 68-75°, used without purification for the next step of the synthesis . (c) l-(2.5-Dimethoxy -benzyl) -3- ormylpyridinium bromide oxime. A solution of 2 , 5-dimethoxybenzyl bromide (13.4 g) and 3-pyridinealdoxime (7.1 g) in dimethylformamide (30 ml) was maintained at room temperature for 18 hours.- The precipitate was filtered off and recrystallized from methanol to give the pyridinium salt, m.p. 177-8°.

Example 26 3-Acetyl-l-( 3 , 4 -dimethoxy-benzyl) -pyridinium bromide oxime A solution of 3 , 4-dimethoxybenzyl bromide (13„4 g, prepared as described in Example 3 (a)), and 3-acetylpyridine oxime (7.9 g, prepared by the method of S. Ginsburg and I.B. Wilson, J. Amer. Chem. Soc. 7_9, 481 (1957)) in dimethylformamide (30 ml) was maintained at room temperature for 18 hours.

The precipitate was filtered off and recrystallized from methanol to give the pure product, m.p. 214-214.5°.

Example 27 1- ( 3 , 4-Dimethoxy-benzyl) -3 -formylpyridinium bromide oxime A solution of 3 , 4 -dimethoxybenzyl bromide (13.4 g, prepared as described in Example 3 (a)) and 3-pyridinealdoxime (7.1 g) in dimethylformamide (30 ml) was maintained at room temperature for 18 hours. The precipitate was filtered off and recrystallized from methanol to give the pure product, m.p. 212-215.5°.

Example 28 1- ( 3-Carbomethoxy-benzyl) -2-formylpyridinium bromide oxime A solution of m-carbomethoxybenzyl bromide (10 g) and 2-pyridinealdoxime (5.2 g) in dimethylformamide (15 ml) was maintained at room temperature for 8 days.' The crystalline material which had formed was filtered off and the filtrate poured slowly with stirring into ethyl acetate (-800 ml) . The solid which formed was filtered off, combined with the crystalline material obtained above, and recrystallized from 2B ethanol to give the pure salt, m.p. 181-5°.

Example 29 1- ( 4-Bromo -benzyl) -3 -formylpyridinium bromide oxime A solution of p_-bromo b e nzy 1 bromide (12,5 g) and 3-pyridinealdoxime (6.1 g) in dimethylformamide (25 ml) was maintained at room temperature for seven days. The precipitate was filtered off and the filtrate poured slowly with stirring into ethyl acetate (800 ml) . The solid which was deposited was filtered off, combined with the material obtained above, and recrystallized from 2B ethanol to give the quaternary salt, m.p. 207-208°.

Example 30 1- ( 4 -Chlorobenzyl) -3-formylpyridinium bromide oxime (a) p-Chlorobenzyl bromide. A solution of ^-chlorobenzyl alcohol (50 g) in benzene (800 ml) was cooled with ice/water then saturated with hydrogen bromide with stirring. The solution was neutralized with excess anhydrous potassium carbonate, the inorganic solid filtered off and the benzene evaporated to give 68.5 g of crude jo-chlorobenzyl bromide. (b) 1- ( -Chlorobenzyl) -3-formylpyridinium bromide oxime. A solution of 20.5 g of crude n-chlorobenzyl bromide and 12 „ 2 g of 3-pyridinealdoxime in 60 ml of dimethylformamide was maintained at room temperature for 18 hours. The precipitate which had formed was filtered off and recrystallized from ethanol (charcoal) to give 9.2 g of the pure salt, m.p. 194.5-196.5°. The reaction mixture filtrate was poured slowly with stirring into ethyl acetate (800 ml) and the resulting solid filtered off and recrystallized from ethanol (charcoal.) to give the pure salt, m.p. 195-196.5°, Example 31 1- ( 4-Chlorobenzyl) -2-formylpyridinium bromide oxime A solution of 20 „ 5 g of the crude pj-chlorobenzyl bromide, prepared as described in Example 3.Ό (a), and 12.2 g of 2-pyridinealdoxime in 30 ml of dimethylformamide was maintained at room temperature for 48 hours. The precipitate which had formed was filtered off, the filtrate poured slowly with stirring into ethyl acetate (800 ml) „ The resulting precipitate was filtered off and combined with the material obtained directly from the reaction mixture. Recrystallization from isopropanol (charcoal) gave the quaternary salt, m.p. 166„5-167o5 Example 32 Ethyl 2-[l-(3, 4-dimethoxy-2-methylbenzyl) ]pyridinium glyoxylate oxime bromide A solution of 12.2 g of 3 , 4 -dimethoxy-2 -methyl-benzyl bromide (prepared as described in Method A of Example 1 (b)) and 9.7 g of ethyl 2 -pyridylglyoxylate oxime in 23 mi of dimethylformamide was maintained at room temperature for four days. The precipitate which had formed was filtered off, and the filtrate was poured slowly with stirring into 800 ml of ethyl acetate. The resulting precipitate was combined with the material obtained directly from the reaction mixture. Two recrystallizations from isopropanol (charcoal) gave the pure salt, m.p. 160-161°.

Example 33 2-Acetyl-l- ( 3-nitrobenzyl) pyridinium bromide oxime A solution of m-nitrobenzyl bromide (10.8 g) and 2-acetylpyridine oxime (6=8 g, prepared by the method of S» Ginsburg and I.B. Wilson, J. Amer . Chem„ Soc 79., 481 (1957)) in dimethylformamide (15 ml) was maintained at room temperature for 17 days. The reaction mixture was poured slowly with stirring into ethyl acetate (1000 ml), the precipitate filtered off and recrystallized from methanol/ethylacetate/petroleum ether to give the quaternary salt, m.p, 181-182° dec.

Example 34 2 -Acetyl -l-( -methoxybenzyl) -pyridinium bromide oxime (a) p-Methoxybenzyl bromide. A solution of 50 g of p_-methoxybenzyl alcohol in 750 ml of benzene was cooled with ice/water and saturated with hydrogen bromide. The solution was neutralized with excess anhydrous potassium carbonate, the inorganic solid filtered off, and the benzene evaporated to give 73 g of crude p_-methoxybenzyl bromide. ( b) 2-Acetyl-l- ( 4-methoxybenzyl) -Tpyridinium bromide oxime. A solution of 18.1 g of crude p_-methoxybenzyl bromide and 12.5 of 2-acetylpyridine oxime (prepared by the method of S. Ginsbur and I.B. Wilson, J. Amer . Chem. Soc. 7_9, 481 (1957)) in 30 ml of dimethylformamide was maintained at room temperature for two days. The precipitate which had formed was filtered off and the filtrate was poured slowly with stirring into 800 ml of ethyl acetate. A gummy solid was deposited^ crystallization occurred on continued stirring. This material was filtered off and recrystallized from isopropanol (charcoal) to give the pure quaternary salt, m,p. 143-145.5°.

Example 35 l-(4-Fluorobenzyl) -2-formylpyridinium bromide oxime A solution of 10.5 g of p_-fluorobenzyl bromide and 6 7 g of 2-pyridinealdoxime in 15 ml of dimethylformamide was maintained at room temperature for 18 hours „ The precipitate which had formed was filtered off and the filtrate was poured slowly with stirring into 800 ml of ethyl acetate. The solid which was deposited was filtered off and combined with the material obtained directly from the reaction mixture. One recrystallization from 2B ethanol (charcoal) gave the pure salt, m.p. 181-182.5°, Example 36 2-Formyl-l-( 4 -methoxybenzyl) -pyrldlnlum bromide oxime A solution. , of 20.1 g of crude jo-methoxybenzyl bromide, prepared as described in Example 34 (a), and 12.2 g of 2 -pyridinealdoxime in 30 ml of dimethylformamide was maintained at room temperature for 14 days. The precipitate which had formed was filtered off and the filtrate was poured slowly with stirring into 800 ml of ethyl acetate. The solid which was deposited was filtered off and combined with the material obtained directly from the reaction mixture. Two recrystallizations from 2B ethanol (charcoal) gave the quaternary salt, m.p. 150-150.5° .

Example 37 2 -Acetyl-l-( -chlorobenzyl) -pyridinium bromide oxime A solution of 20.5 g of crude p-chlorobenzyl bromide (prepared as described in Example 30 (a)) and 13.6 g of 2-acetylpyridine oxime (prepared by the method of S„ Ginsburg and I.B. Wilson, J„ Amer. Chem-.- Soc. 79., 481 (1957)) in dimethyIformamide (30 ml) was maintained at room temperature for 15 days. The reaction mixture was poured slowly with stirring into 800 ml of ethyl acetate and the resulting solid was filtered off and recrystallized from isopropanol (charcoal) to give the pure quaternary salt, m.p. 149.5-150.5°.

Example 38 l-( 4-bromobenzyl) -2-formylpyridinlum bromide semicarbazone A solution of 1215 g of jo-bromobenzyl bromide, and 8.2 g of 2-pyridinecarboxaldehyde semicarbazone (Beilstein 2_1, I, 288) in 50 ml of dimethylformamide was maintained at room temperature for 56 days. The precipitate which had formed was filtered off and recrystallized from methanol to give the pure salt, m.p. 178.5-180°.

Example 39 2-Formyl-l-pentafluorobenzy])pyridinium bromide oxime A solution of 6.53 g of pentafluorobenzyl bromide and 3.1 g of 2-pyridinealdoxime in 15 ml of dimethylformamide was maintained at room temperature for 42 days. The reaction mixture was poured slowly with stirring into 900 ml of ethyl acetate. A gummy material was deposited, which crystallized on continued stirring. The product was filtered off and recrystallized from isopropanol to give the quaternary salt, m.p. 170-172°.

Example 40 1- (2-Bromobenzyl) -2-formylpyridinium bromide oxime A solution of 12.5 g of o_-bromobenzyl bromide and 6.1 g of 2-pyridinealdoxime in 15 ml of dimethylformamide was maintained at room temperature for 42 hours. The crystalline product was filtered and recrystallized once from isopropanol and twice from isopropanol/dilute HBr to give the quaternary salt, m.p. 170.5-171°.

Example 41 3-Formyl-l-(4-methoxybenzyi)pyridinium bromide oxime A solution of 20. Ig of p_-methoxybenzyl bromide (prepared as described in Example 34 (a)) and 12.2 g of 3-pyridinealdoxime in 60 ml of dimethylformamide was maintained at room temperature for 35 days. The reaction mixture was poured slowly with stirring into 800 ml of ethylacetate; the resulting solid was filtered off and recrystallized once from isopropanol (charcoal) and once from 2B ethanol (charcoal) to give the pure product, m. .146-1470 » Example 42 1- ( 3 , 4-Dimethoxy-2-methyl enzyl) -2-formylpyridinium bromide -0-propyloxime A solution of 12.25 g of 3 , 4-dimethoxy-2-methylbenzyl bromide (prepared as described in Method A of 1(b)) and 8.21 g in 35 ml of tetramethylene sulfone of 2-pyridinealdoxime-0-propyl ether/was maintained at room temperature for 127 days. The reaction mixture was poured slowly with stirring into 800 ml of ethyl acetate and the precipitate which formed was filtered off and recrystallized from ethyl acetate/isopropanol to give the quaternary salt, m.p. 108-110° .

Example 43 2 -Formyl-1- iaitrobenzyl) pyridinium bromide oxime A solution of 10.7 g of p_-nitrobenzyl bromide and 6.1 g of 2-pyridinealdoxime in 30 ml of dimethylformamide was maintained at room temperature for 17 days. The reaction mixture was poured into 800 ml of ethyl acetate with stirring: a tarry substance was deposited which solidified on continued stirring. The product was recrystallized twice from methanol (charcoal) to give the pure salt, m,p„ 169.5-171.5°.

Example 44 1- ( 3-Bromobenzyl) -3-formylpyridinium bromide oxime A solution of 12.5 g of m-bromobenzyi bromide and 6„1 g of 3-pyridinealdoxime in 30 ml of dimethyl ormamide was maintained at room temperature for 48 hours. The resulting crystalline material was filtered off and the filtrate poured with stirring into 800 ml of ethyl acetate. The precipitate which formed was filtered off, combined with the material obtained directly from the reaction mixture and recrystallized from methanol to give the quaternary salt, m.p. 110-111.5°.

Example 45 1- ( 2-Bromobenzyl) -3 -formylpyridinium bromide oxime A solution of 12.5 g of p_-bromobenzyl bromide and 6.1 g of 3-pyridinealdoxime in 30 ml of dimethylformamide was maintained at room temperature for 48 hours. The resulting crystalline material was .filtered off and the filtrate poured slowly with stirring into 800 ml of ethyl acetate. The precipitate which formed was filtered off, combined with the material obtained directly from the reaction mixture and recrystalllzed from 2B ethanol to give the quaternary salt, m,p. 145 „ 5-146 °» Example 46 3 -Acetyl-1- ( 3 , 4 -dimethoxy-2 -methylbenzyl) -pyridinium bromide oxime A solution of 12.2 g of 3.4-dimethoxy-2 -methylbenzyl bromide •(prepared as described in Method A of Example 1(b)) and 6.8 g of 3-acetylpyridine oxime (prepared by the method of S. Ginsburg and LB.Wilson, J. Amer. Chern-.- Soc. 79., 481 (1957)) in 23 ml of dimethylformamide was maintained at room temperature for 98 days. The product was induced to crystallize by scratching and was filtered off. The filtrate was poured slowly with stirring into 800 ml of ethyl acetate. The precipitate which formed was filtered off, combined with the material obtained directly from the reaction mixture and recrystalllzed from 2B ethanol to give the pure quaternary salt, m.p. 200-200.5° .

Example 47 l-(3, 4 -Dimethoxy-2 -methylbenzyl) -3-formylpyridinium bromide-0-benzyloxime To a solution of 6.1 g of 3, 4-dimethoxy-2-methylbenzyl bromide ( re ared as described i Method A of Exam le 1 (b)) in ml of dimethylformamide was added 5.3 g of 3-pyridinealdoxime- 0-benzyl ether. After 15 minutes at room temperature, the product was filtered off and recrystalllzed from isopropanol to give the pure quaternary salt, m.p. 150-151° „ Example 48 1- (3, -Dimethoxy-2-methylbenzyl) -3-formylpyridinium bromide-O-phenethyloxime A solution of 6.1 g of 3 , 4 -dimethoxy-2 -methylbenzyl bromide (prepared as described in Method A of Example 1 (b)) and 5.65 g of 3-pyridinealdoxime-0-phenethyl ether in 5 ml of dimethylformamide was maintained at room temperature for 10 minutes „ The product was filtered off and recrystalllzed from isopropanol to give the pure quaternary salt, m„p. 167-167 „ 5° , Example 49 "benzyl 2-Formyl-l- ( 3-trifluoromethylifpyridinium chloride oxime A solution of 9„8 g of m-trifluoromethylbenzyi chloride and 6.1 g of 2 -pyridinealdoxime in 15 ml of dimethylformamide was maintained at room temperature for 65 days. The reactio mixture was poured slowly with stirring into 800 ml of ethyl acetate and the resulting precipitate was filtered off and recrystalllzed from isopropanol/ethyl acetate to give the pure quaternary salt, m»p, 192.5-193CO 29176/2

Claims (1)

CLAIMS 1 * Comp in which is hydrogen or lower alkyl; . hydrogei^lkox , R2, R^t R^,and R^ independently represent/lower/fluorine, chlorine, bromine or nitro; R^ may also represent lower alkyl or hydros; R^ may also represent lower alkyl, trifluoromethyl or alkoxy~carbonyl and may also represent cyanoj Rg is hydrogen or, when each of is fluorine, fluorine; Ry is hydrogen, lower alkyl, phenyl or lower alkoxycarbonyl; RQ is hydroxy, lower alkoxy, aralkoxy, or -iiHCOHH^ » X is chlorine or bromine; with the proviso that (1) no mcae than three of , R^ ? R4 and may be hydrogen (2) when Rg is methyl, nor more than two of R^, R^ and ^ may be hydrog (3) when the group is in the 2-position and R is lower alkoxy, no more than two of R2 , ^ and R^ may be hydrogen, and (4) when the group -C is in the 2-position and both R2 and R^ are lower alkoxy, no more than one of R^ and R4 may be hydrogen. 2. A compound according to Claim 1 in which the group is in the 2-position. 3. A compound according to Claim 2 which is 1- ( 3 , 4-dimet Qxy~ 2 -methylbenzyl) -2 -formylpyridlnium bromide oxiine. 4. A compound according to Claim 2 which is l-( 4 , 5-dimethoxy-2 -methylbenzyl) -2 -forinylpyridinium bromide oxime. 5. A compound according to Claim 2 which is 2-formyi-l-( 3-nitrobenzyl) -pyridinium bromide oxime. 6. A compound according to Claim 2 which is 2-acetyl-l-( 3-nitrobenzyl) -pyridinium bromide oxime. 7. A compound according to Claim 2 which is ethyl 2-[l-(3,4-dimethoxy-2-methyibenzyl) ]-pyridinium glyoxylate oxime bromide, 8. A compound according to Claim 2 which is 2-acetyl-l-(4-methoxybenzyl) -pyridinium bromide oxime, 9. A compound according to Claim 2 which is 2-acetyl-l-(4-chlorobenzyl) -pyridinium bromide oxime. 10. A compound according to Claim 2 which is l-( 3 , 4-dimethoxy-2-methylbenzyl) -2 -formylpyridinium bromide-O-propyloxime . 11. A compound according to Claim 1 in which the group -C is in the 3-position. 12. A compound according to Claim 11 which is l-(3, 4-dimethoxy- 2 -methylbenzyl) -3 -formylpyridinium bromide oxime. 13. A compound according to Claim 11 which is l-(3, 4-dimethoxy-benzyl) -3 -formylpyridinium bromide oxime. 14. A compound according to Claim 11 which is l-( 2 , 5-dimethoxy-benzyl) -3 -formylpyridinium bromide oxime „ 15. A compound according to Claim 11 which is 1- ( 2-bromobenzyl) 3 -formylpy idinium bromide oxime „ 16. A compound according to Claim 1 in which the group is in the 4-position. 17. A compound according to Claim 2 in which each of -R^, Rg and R^ is hydrogen; one of ^ and R^ is fluorine, chlorine, or bromine; the other of R^ and R^ is hydrogen, fluorine, chlorine or bromine; and Rg is hydroxy or -NHCONR^ . 18. A compound according to Claim 17 which is l-( 4 -bromobenzyl) 2 -formylpyridinium bromide oxime. 19. A compound according to Claim 17 which is l-(3-fluoro- 20. A compound according to Claim 17 which is l-(4-chlorobenzyl) 2-formylpyridinium "bromide oxime. 21. A compound according to Claim 17 which is 1- ( 4 -fluorobenzyl) 2-formylpyridinium bromide oxime. 22. A compound according to Claim 17 which is 1- ( 4 -bromobenzyi) -2-formylpyridinium bromide semicarbazone . 23. Process for the production of compounds defined in Claim 1. characterized by reacting in the known way a compound of the formula in which 2 , R3 , R4 , R^, Rg and X have the meanings defined in Claim 1, and a compound of the formula NR in which R^, R^ and Rg have the meanings defined in. Claim 1, and isolating the benzylpyridinium compound formed. 24. Process for the production of compounds defined in Claim 1, characterized by reacting in the known way a compound of the formula in which , 2» ^# R^, ^, Rg, R^ and X have the meanings defined in Claim 1, and a compound in which Kg has the meaning defined in Claim 1, and isolating the benzylpyridinium compound formed« 25· A therapeutic composition for producing cardiovascular effects comprising a pharmaceutical carrier and a therapeutically effective amount of a compound as defined in Claim

1. 26« A method for treating a non-human mammal suffering from cardiovascular disorders comprising administering to said mammal a therapeutically effective amount of a compound as defined in Claim 1« 27· Processes according to Claim 23 or 24, substantially as hereinbefore described with reference to any of the foregoing Examples· For the applicants DR. REimOLD GOHN .