DK147639B - ANALOGY PROCEDURE FOR THE PREPARATION OF BIS-PYRIDINIUM COMPOUNDS - Google Patents

Description

in 147639

The invention relates to an analogous process for the preparation of bis- (4-amino-1-pyridinium) alkanes of the formula I or α, α'-bis- (4-amino-1-pyridinium) xylenes of the invention as claimed in claim 1 formula II, which compounds are useful for controlling bacteria, fungi and Herpes virus.

U.S. Patent No. 3,055,902 discloses a group of bis- (4-amino-1-pyridinium) alkanes as intermediates in the preparation of the corresponding bis- (4-amino-1-piperidino) alkanes which are claimed to have bacteriostatic and bactericidal effects.

W. C. Austin et al., J.Pharm. Pharmacol. 11, 80-93 (1959) disclose 1,10-bis- (4-amino-1-pyridinium) decane diiodide and 1,10-bis- (4-acetamido-1-pyridinium) decane diiodide . It is stated that some species among the large diverse group of indicated quaternary ammonium compounds have amoebicide, antibacterial, antifilarial and trypanocidal activity, but no biological data is provided for any of the above compounds.

The compounds prepared by the method of the invention are useful as antibacterial and antifungal agents and are virucidically active against Herpes virus.

They can be formulated into an antibacterial, antifungal and virucidal agent suitable for topical application, consisting of an effective amount of a compound of formula I or II and a compatible, pharmaceutically acceptable carrier.

The process according to the invention is characterized by the characterizing part of claim 1.

In Formula I, the alkylene group Y is a biv / ally saturated aliphatic hydrocarbon group containing 4 to 18, preferably 8 to 12, carbon atoms arranged in a straight or branched chain separating the two 4- (R-NH) -1 pyridinyl groups having at least 4 and at most 18, preferably at least 8 and at most 12, carbon atoms, for example: 1,4-butylene, 1,5-pentylene, 1,6-hexylene, 1,7-heptylene, 1.8- octylene, 1,9-nonylene, 1,10-decylene, 1,11-undecylene, 1,12-dodecylene, 1,13-tridecylene, 1,14-tetradecylene, 1,15-pentadecylene, 1,16-hexadecylene, 1, 17-heptadecylene, 1,8-octadecylene, 1-methyl-1,4-butylene, 3-methyl-1,5-pentylene, 2-ethyl-1,4-butylene, 3-methyl-1,6-hexylene, 2, 4-dimethyl-1,5-pentylene, 1-methyl-1,7-heptylene, 3-ethyl-1,6-hexylene, 3-propyl-1,5-pentylene, 4,4-dimethyl-1, 7-heptylene, 2,6-dimethyl-1,7-heptylene, 2,4,4-trimethyl-1,6-hexylene, 2,7-dimethyl, 8-octylene, 1-methyl-1,10-decylene, 5- ethyl 1,9-nonylene, 3,3,6,6-tetramethyl-1,8-octylene, 3,8-dimethyl-1,10-decylene, 3-methyl-1,11-undecylene, 6-methyl 1.12- do decylene, 2-methyl-1,3-tridecylene, 4,9-dimethyl-1,12-dodecylene, 4-methyl-1,14-tetradecylene, 2,13-dimethyl-1,14-tetradecylene, 1,4 dipropyl-1,4-butylene, 3- (3-pentyl) -1,5-pentylene, 2- (4,8-dimethylnonyl) -1,4-butylene and 1-heptyl-1,5-pentylene.

It will be appreciated that when Y contains 4 carbon atoms, these must of course be arranged in a straight chain, and similarly, when Y contains 18 carbon atoms and separates the two 4- (R-NH) -1-pyridinyl groups with 18 carbon atoms, also arranged in a straight chain. In all other cases, Y may be either straight-chain or branched.

When R of Formula I is a straight or branched alkyl group having 6-18 carbon atoms, preferably 7-9 carbon atoms, it may e.g. be: 147639 3 · n-hexyl, n-heptyl, n-octyl, n-nonyl-n-decyl, n-undecyl, n-dodecyl, n-tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl , n-heptadecyl, n-octadecyl, 1-methylpentyl, 2,2-dimethylbutyl, 2-methylhexyl, 1,4-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, 2-methylheptyl, 1-ethylhexyl, 2-ethylhexyl , 2-propylpentyl, 2-methyl-3-ethylpenethyl, 1,3,5-trimethylhexyl, 1,5-dimethyl-4-ethylhexyl, 2-propylheptyl, 5-methyl-2-butylhexyl, 2-propylnonyl , 2-butyloctyl, 1,1-dimethylundecyl, 2-pentylnonyl, 1,2-dimethyltetradecyl and 1,1-dimethylpentadecyl.

When R of Formula I is a cycloalkyl group of 5-7 carbon atoms, it may e.g. be cyclopentyl, cyclohexyl and cycloheptyl.

When R of formula I is phenyl substituted with halogen, it may e.g. be: p-chlorophenyl, o-chlorophenyl, m-chlorophenyl, p-bromophenyl, m-fluorophenyl, p-iodophenyl, 2,4-dichlorophenyl, 2,4-difluorophenyl, 2,5-dibromophenyl, 3,5 dichlorophenyl and 3-chloro-4-fluorophenyl.

R 1 of Formula II, which is a straight or branched alkyl group of 1-18 carbon atoms, preferably 6-12 carbon atoms, may be in addition to the above alkyl groups of 6-18 carbon atoms such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, isopropyl, 1-methyl-propyl, isobutyl, tert-butyl, isopentyl, neopentyl and 1-methylpentyl.

R can also be benzyl. If desired, the phenyl portion of the benzyl group may be substituted by halogen.

The two R groups of formula I are the same and the two R 'groups of formula II are the same.

A of formulas I and II may be a pharmaceutically acceptable anion of both inorganic and organic acids, for example: bromide, chloride, fluoride, iodide, sulfate, phosphate, nitrate, sulfamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p toluene sulfonate, naphthalene sulfonate, naphthalene disulfonate, cyclohexyl sulfamate, acetate, trifluoroacetate, malate, fumarate, succinate, tartrate, oxalate, citrate, lactate, gluconate, ascorbate, lactate, phthalate, salicylate, salicylate lauroyl sarcosinate and monofluorophosphate. Bromide and chloride are preferred.

The term "halogen" in this specification shall include fluorine, chlorine, bromine and iodine.

The reaction of the process according to the invention is conveniently carried out by reacting 2 moles of a 4-aminopyridine compound (formula III or III ') with 1 mole of a suitably disubstituted alkane or xylene (formula IV or V) in an inert solvent such as a lower one. alkanol, acetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide, benzene, toluene or xylene, at a temperature of from about 80 to about 150 ° C for a period of 1-24 hours. Usually, the reactants are heated to between 60 and 100 ° C in acetonitrile or N, N-dimethylformamide or a mixture of these solvents or in a lower alkanol for from about 2 to about 20 hours.

Alternatively, the reaction may be carried out in the absence of a solvent by heating stoichiometric amounts of the reactants to 120-150 ° C for from about 2 to about 5 hours.

The resulting bis-pyridinium compounds (formulas I and II) are isolated by conventional methods, e.g. filtration if the product is insoluble in the reaction medium, or dilution of the reaction mixture with a non-polar solvent, such as ether, benzene or hexane, to precipitate the product or evaporation of the reaction medium to obtain the product as a residue.

The isolated crude product may be purified by crystallization from a suitable solvent in the presence of an adsorbent, e.g. activated charcoal or diatomaceous earth.

The bis-pyridinium compounds prepared by the process described above will, of course, contain an anion corresponding to the group leaving the disubstituted alkane or xylene (Z of formula IV and V).

However, if desired, the anion moiety of these compounds can be varied by conventional ion exchange methods, e.g. by passing a solution of a pyridinium compound in a suitable solvent, e.g. methanol, ethanol or water, through a layer of synthetic ion exchange resin containing the desired anion. The solvent is evaporated and the resulting pyridinium compound containing the desired ion is purified by recrystallization from a suitable solvent.

Alternatively, a pyridinium compound can be reacted with a soluble salt containing the desired anion in conjunction with a countercation which joins with the anion of the pyridinium compound to form an insoluble precipitate. The latter is separated leaving a solution of the pyridinium compound containing the desired anion. Eg. for example, a bis- [4- (R-amino) -1-pyridinium] alkane dihalide is reacted with the silver salt of an organic or inorganic acid. The precipitated silver halide is removed leaving a solution of the pyridinium compound containing the desired organic anion.

147639 6

The aforementioned type of metathetic reaction may also be used to prepare insoluble pyridinium compounds. Thus, a soluble bis-pyridinium compound is reacted with a soluble salt containing the desired anion which combines with the pyridinium cation to form the desired product as an insoluble precipitate.

These insoluble pyridinium salts are useful for isolation and purification purposes, and, if appropriately formulated as emulsions, creams, pastes, lotions, gels or powders, may also serve as depot preparations which provide slow, delayed release of the antimicrobial pyridinium compound.

The 4-aminopyridine compounds (Formula III or III ') used as starting materials are generally known, or prepared, if specifically new, by the procedures described for the preparation of the known compounds.

Conveniently, the 4-aminopyridine compounds are prepared by reaction of 4-chloro- or 4-bromopyridine or N- (4-pyridyl) -pyridinium chloride hydrochloride with a suitably substituted amine. The reaction is usually carried out by heating the reactants in the absence of a solvent at 150-225 ° C for from about 1.5 to about 3 hours. The product is isolated in a conventional manner, e.g. by extraction from alkaline aqueous medium into an organic solvent such as ether, methylene chloride or chloroform, evaporation of the organic solvent and crystallization of the residue from a suitable solvent.

Alternatively, the 4-aminopyridine compounds are prepared by catalytic hydrogenation of a mixture containing 4-aminopyridine and a carbonyl compound containing the appropriate number of carbon atoms. The reaction is usually carried out at a temperature of 50-70 ° C in a suitable solvent, e.g. ethanol, under a hydrogen o pressure of 1.4 - 4.2 kg / cm, in the presence of a palladium hydrogenation catalyst. A hydrogenation time of 4-10 hours is generally satisfactory. The use of a large excess of the carbonyl compound, ie. 200 per cent. or more, advantageously results in high yields of pure product within a reaction time of 5 hours or less. After removal of the catalyst, the product is isolated by evaporation of the solvent and either distillation of the residue or crystallization thereof from a suitable solvent.

Reaction of an aldehyde with the appropriate number of carbon atoms with 4-aminopyridine in the presence of formic acid at elevated temperature also yields the desired 4-aminopyridine compounds.

The 4-aminopyridine compounds can also be prepared by acylating 4-aminopyridine with an acyl halide with the appropriate number of carbon atoms followed by reduction of the resulting amide. Acylation is carried out by well known methods, e.g. by reacting 4-aminopyridine with an acyl halide in an inert solvent such as methylene dichloride or chloroform in the presence of an acid binding agent such as triethylamine.

The amide thus formed is then reduced with a complex metal hydride such as lithium hydride in a suitable solvent such as tetrahydrofuran, ether or dioxane and the amine product is isolated by known procedures.

The disubstituted alkanes of formula IV, also used as starting materials, are generally known compounds or, if specifically new, can be prepared by the procedures used to prepare the known compounds.

147639 8

The ot, os'-disubstituted xylenes of formula III, also used as starting materials, are generally known compounds, or, if specifically new, can be prepared by the procedures used to prepare the known compounds.

Thus, a suitable chlorine or methyl-substituted phthalic, isophthalic or terephthalic acid or ester thereof is reduced to the corresponding xylene-oija'-diol with a metal hydride such as lithium aluminum hydride in a suitable solvent such as tetrahydrofuran, ether or dioxane. The xylene-α, α'-diol thus formed is then converted to an α, θί'-dihalo xylene, e.g. by reaction with hydrogen bromide, phosphorus tribromide, phosphorus oxychloride, thionyl chloride or potassium iodide and orthophosphoric acid, by well known methods. Alternatively, the xylene-α, α'-diol can be converted to a sulfonate ester by reaction with methane, ethane, benzene or p-touenesulfonyl chloride in the presence of an acid-binding agent such as pyridine according to well-known procedures.

As described in more detail below, the compounds of formulas I and II exhibit antimicrobial activity in vitro against several species of microorganisms, including both Gram-positive and Gram-negative bacteria, several species of fungi and Herpes virus.

The compounds can be formulated in suitable pharmaceutical media for the treatment of bacterial, fungal and Herpes virus infections, e.g. as lotions, ointments or creams, by incorporation into conventional lotion, ointment or cream bases such as alkyl polyether alcohols, cetyl alcohol, stearyl alcohol and the like, or as powders by incorporation into conventional powder bases such as starch, talc and the like, or as gels by incorporation into conventional gel bases, such as glycerol and tragacanth. They can also be formulated for use as aerosol sprays or foams.

The molecular structure of the compounds prepared by the process of the invention was determined by examining their infrared and NMR spectra and confirmed by agreement between calculated and found values for elemental assays.

The process according to the invention is further illustrated by the following embodiments.

Example 1 A. A mixture containing 130 g (0.67 mole) of 4-bromo-pyridine hydrochloride and 152 g (1.0 mole) of n-heptylamine hydrochloride was heated in an oil bath. When the bath temperature reached 180 - 185 ° C, the reaction mixture began to melt and stirring was started. At 190 -195 ° C, the melting was complete and the liquid mixture was stirred and heated to 210 - 220 ° C for 2.5 hours. Then, the reaction mixture was cooled to room temperature and the resulting solid was dissolved in water, made alkaline with 35% aqueous sodium hydroxide solution, and the product extracted with chloroform. The chloroform extracts were dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The resulting viscous oil was diluted with a small amount of n-hexane and cooled to give a solid which was collected by filtration and air dried to give 86.6 g of 4- (heptylamino) pyridine, m.p. 51 ° C.

B. Alternatively, 4- (heptylamino) pyridine was prepared as follows: A mixture containing 229 g (1.0 mole) of N- (4-pyridyl) pyridinium chloride hydrochloride and 228 g (1.5 mole) of n-heptylamine hydrochloride was heated for 2 hours with stirring in an oil bath at a bath temperature of 215 ° C. The reaction mixture was cooled to 80 ° C, diluted with ice water, made alkaline with 35% aqueous sodium hydroxide solution and extracted successively with ether and chloroform. The organic extracts were combined and evaporated to dryness under reduced pressure. The remaining viscous oil was dissolved in ether and the ether solution washed with water. The aqueous wash solution was back-extracted with chloroform and the chloroform extracts combined with the ether solution. The combined organic solutions were dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. Cooling of the remaining oil to -78 ° C resulted in partial solidification. The semi-solid was diluted with a small amount of ether and filtered. The solid thus obtained was dissolved in a mixture of acetonitrile and chloroform, the resulting solution treated with decolorizing coal, filtered, and the filtrate evaporated to dryness under reduced pressure. The resulting semi-solid was diluted with a small amount of ether and cooled. The solid thus formed was collected by filtration and washed with a small volume of cold ether to give, after drying, 84.6 g of 4- (heptylamino) pyridine, mp: 50-52 ° C.

C. 4- (Heptylamino) pyridine was also prepared by hydrogenating a mixture containing 4-aminopyridine and heptaldehyde according to the procedure described in Example 9B below.

D. To a stirred hot solution containing 10.0 g (0.052 mol) of 4- (heptylamino) pyridine in 40 ml of acetonitrile was added dropwise a solution containing 9.3 g (0.026 mol) of 1,14-dibromo-tetradecane in 230 ml of acetonitrile, and The resulting mixture was heated at reflux for 20 hours. The product, which was precipitated by cooling the reaction mixture to room temperature, was collected by filtration, washed with cold acetonitrile and dried to give 13.9 g, 14-bis [4- (heptylamino) -1-pyridinium] tetradecane dibromide, mp: 88 - 90 ° C.

EXAMPLE 2

A solution containing 5.0 g of 1,14-bis- [4- (heptylamino) -1-pyridinium] tetradecane dibromide in 5.0 ml of methanol was added to the top of a column of 7.6 cm diameter containing 500 ml of chloride synthetic anion exchange resin (marketed by Rohm and Haas under the name "Amberlite® IRA 400") packed in methanol and eluted with five 125 ml portions of methanol. The combined eluent was evaporated to dryness under reduced pressure and the residual oil was dissolved in ethanol, treated with decolorizing coal and evaporated to dryness. The residual solid was triturated with ether containing a few drops of acetonitrile, collected by filtration and dried over phosphorus pentoxide in vacuo to give 3.94 gl, 14-bis- [4- (heptylamino) -1-pyridinium] tetradecane. dichloride, mp: 113 - 116 ° C.

EXAMPLE 3

A stirred suspension containing 11.54 g (0.06 mol) of 4- (heptylamino) pyridine in 75 ml of acetonitrile was heated at reflux until a clear homogeneous solution was formed. To the clear solution was added dropwise a hot solution containing 9.84 g (0.03 mole) of 1,12-dibromo-dodecane in 75 ml of acetonitrile. After the addition was complete, the refluxing was continued for 18 hours. After cooling to room temperature, the reaction mixture was evaporated to dryness under reduced pressure. The residual solid was slurried in ether, collected by filtration and dried for 48 hours under vacuum at 60 ° C to give 21.1 g of 1,12-bis- [4- (heptylamino) -1-pyridinium iododecane dibromide, mp: 101 - 103 ° C.

EXAMPLE 4 A. A solution containing 6.6 g of 1,12-bis [4- (heptylamino) -1-pyridinium idodecane dibromide in 25 ml of methanol was added to the top of a column of 7.6 cm diameter packed with 1 liter synthetic anion exchange resin in chloride form (marketed by Rohm and Haas under hub / B \ net "Amberlite'0 'IRA 400") in methanol, and slowly eluted with 100 ml portions of methanol until 700 ml eluate was collected . The combined eluate was evaporated to dryness under reduced pressure at below 25 ° C. The remaining gum was repeatedly rubbed off with a 6: 1 mixture of ether and acetonitrile and dried under vacuum to give 5.0 g of 1,12-bis [4- (heptylamino) -1-pyridinium iododecane dichloride, m.p. : 109 - 112 ° C.

B. Alternatively, a mixture containing 76.8 g (0.4 mole) of 4- (heptylamino) pyridine and 47.8 g (0.2 mole) of 1,12-dichlorododecane was heated for 4 hours to 125-130 ° C. After gentle cooling, 300 ml of acetonitrile was added and the resulting mixture was warmed to steam bath temperature to produce complete solution and then stored in a refrigerator overnight. The precipitated product was collected by filtration, washed with cold acetonitrile and ether and the hygroscopic product dried immediately under vacuum to give 112 µl, 12-bis- [4- (heptylamino) -1-pyridinium] dodecane di chloride, mp: 112 - 115 ° C.

EXAMPLE 5 A. A mixture containing 100.0 g (0.51 mole) of 4-bromopyridine hydrochloride and 110 g (0.8 mole) of n-hexylamine hydrochloride was heated in an oil bath. When the bath temperature reached 175 - 180 ° C, the reaction mixture began to melt and stirring was started. The temperature of the bath was then raised to 227 ° C and stirring was continued for 3.5 hours. After cooling to room temperature, the reaction mixture was dissolved in hot water, the resulting solution cooled with ice, made alkaline with dilute aqueous sodium hydroxide solution and extracted with chloroform. The chloroform extracts were dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was triturated with ether and cooled. The resulting solid was collected by filtration and washed with cold ether. Evaporation of the filtrate gave another amount of solid. The amounts were combined, dissolved in chloroform, treated with decolorizing charcoal and filtered. The filtrate was evaporated under reduced pressure and the residue was triturated with cold ether. The product thus obtained was collected by filtration, washed with cold ether and dried to give 63.6 g of 4- (hexylamino) pyridine, mp 66-68 ° C. Evaporation of the filtrate gave an additional 7.0 g, mp 65-67 ° C.

B. Alternatively, 4- (hexylamino) pyridine was prepared as follows: A mixture containing 229 g (1 mole) of N- (4-pyridyl) pyridinium chloride hydrochloride and 207 g (1.5 mole) of n-hexylamine hydrochloride was stirred and heated. to 175 - 185 ° C for 1.75 hours. The reaction mixture was cooled and diluted with 750 ml of ice water. The resulting solution was made alkaline with 35% aqueous sodium hydroxide solution, and after further dilution with 1 liter of water, it was extracted with ether followed by dichloromethane. The organic extracts were combined, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was crystallized from ether, redissolved in chloroform, and the resulting solution treated with decolorizing coal and filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was triturated with a mixture of ether and acetonitrile. The solid thus obtained was again dissolved in chloroform, and the resulting solution treated with decolorizing charcoal and filters straight. The filtrate was evaporated to dryness under reduced pressure and the residue was triturated with cold ether to give 71.0 g of 4- (hexylamino) pyridine, mp: 68-70 ° C.

C. To a stirred hot solution containing 10.7 g (0.06 mole) of 4- (hexylamino) pyridine in 50 ml of acetonitrile was added dropwise a solution containing 10.7 g (0.03 mole) of 1,14-dibromo-tetradecane in 250 ml. ml of acetonitrile, and the resulting mixture was heated at reflux for 22 hours. The reaction mixture was then evaporated to dryness under reduced pressure. The residual solid was dissolved in acetonitrile and the resulting solution treated with decolorizing charcoal and filtered.

The filtrate was evaporated to dryness under reduced pressure and the resulting oil crystallized from acetonitrile. The product was collected by filtration and dried for 48 hours at 70 ° C / 0.1 mmHg to give 13.4 g, 14-bis- [4-] hexylamino] -1-pyridinium] tetradecane dibromide, m.p. : 91 - 93 ° C.

EXAMPLE 6

Following the procedure described in Example 2, but using 5.0 µl, 14-bis- [4- (hexylamino) -1-pyridinium] tetradecane dibromide, 4.33 g of the corresponding dichloride were obtained, m.p. : 94 - 95 ° C.

EXAMPLE 7

By a procedure similar to that described in Example 5C, but using 10.7 g (0.06 mol) of 4- (hexylamino) pyridine and 9.85 g (0.03 mol) 1.12 -dibromo dodecane 17.6 g of 1,12-bis- [4- (hexylamino) -1-pyridinium] dodecane dibromide were obtained. 122 - 124 ° C.

EXAMPLE 8

In a procedure similar to that described in Example 2, but using 5.0 g of 1,12-bis- [4- (hexylamino) -1-pyridinium] dodecane dibromide, 3.69 g of the corresponding dichloride, mp: 86 - 88 ° C.

Example 9 A. A mixture containing 183, 3 g (0.8 mole) of N- (4-pyridyl) pyridinium chloride hydrochloride and 162 g (0.98 mole) of n-octylamine hydrochloride was heated in an oil bath to a bath temperature of 225 - 230 ° C (internal temperature 188 ° C) and the resulting liquid was stirred at that temperature for 2.5 hours. The reaction mixture was then cooled to 70 ° C, diluted with 1 liter of ice and water, made alkaline with 35% aqueous sodium hydroxide solution and extracted with chloroform. The chloroform extracts were dried over anhydrous sodium sulfate, treated with decolorizing coal and evaporated to dryness under vacuum.

The resulting oil was cooled to -78 ° C. The semi-solid formed was triturated with ether and the thus obtained solid collected by filtration, washed with cold ether and dried. The filtrate gave another 10 g. The amounts were combined, dissolved in chloroform, and after treatment with decolorizing charcoal and filtration 16 147fr39 (repeated three times) the chloroform solution was evaporated to dryness under reduced pressure. The resulting solid was triturated with ether, cooled, collected by filtration and washed with cold ether / hexane to give 63.3 g of almost colorless 4- (octylamino) pyridine, m.p .: 62-63 ° C.

B. Alternatively, 4- (octylamino) pyridine was prepared as follows: A mixture containing 94 g (1 mole) of 4-aminopyridine, 384 g (3 mole) of octaldehyde, 7 g of 10% palladium-on-carbon hydrogenation catalyst and sufficient absolute ethanol to give a total volume of 1.2 liters was hydrogenated for 4.5 hours at 70 - 90 ° C under a hydrogen initial pressure of 3.15 kg / cm. After cooling the mixture, the hydrogenation catalyst was removed by filtration and the filtrate was evaporated to dryness under reduced pressure. The residual oil crystallized on standing and the solid product was triturated with hexane, collected by filtration, washed with fresh hexane and dried at 40 ° C under vacuum to give 182 g of 4- (octylamino) pyridine, mp: 70 -73 ° C.

C. To a stirred hot solution containing 10.0 g (0.049 mole) of 4- (octylamino) pyridine in 150 ml of acetonitrile was added dropwise a solution containing 7.4 g (0.0245 mole) of 1,10-dibromo-decane in 50 ml of acetonitrile. and the resulting mixture was heated at reflux for 18 hours. After cooling and stirring for 1 hour at room temperature, the precipitated solid was collected by filtration, washed with acetonitrile and dried for 48 hours at 85 ° C to give 15.6 g, 10-bis- [4- (octylamino) -1-pyridinium] decane dibromide, mp: 163 -164 ° C.

EXAMPLE 10 A. According to a procedure similar to that described in Example 2, but using 5.0 µl, 10-bis- [4- (octylamino) -1-pyridinium] decane dibromide, obtained 4.31 g of the corresponding dichloride, mp: 213 - 214 ° C.

B. Alternatively, a mixture containing 61.8 g of 4- (octylamino) pyridine and 31.5 g of 1,10-dichlorodecane was stirred and heated slowly to 120 ° C. The heat source was removed and the temperature of the now exothermic reaction continued to rise to 180 ° C. As soon as the reaction mixture began to crystallize, 250 ml of Ν, Ν-dimethylformamide was rapidly added and the resulting mixture was heated to form a clear homogeneous solution and then cooled to 0 ° C. The precipitated product was collected by filtration, washed with ether and dried for 24 hours under vacuum to 60 ° C to give 73 g of 1,10-bis- [4- (octylamino) -1-pyridinium] decane dichloro m.p. m.p .: 215 - 217 ° C.

EXAMPLE 11

According to a procedure similar to that described in Example 9C, but using 11.1 g (0.054 mol) of 4- (octylamino) pyridine and 7.34 g (0.027 mol) of 1,8-dibromo-octane and heating of the reaction mixture for 6 hours under reflux, 15.6 g of 8-bis- [4- (octylamino) -1-pyridinium] octane dibromide were obtained, mp: 174 -175 ° C.

EXAMPLE 12

According to a procedure similar to that described in Example 2, but using 5.0 µl, 8-bis- [4- (octylamino) -1-pyridinium] -octane dibromide, 4 was obtained. 30 g of the corresponding dichloride, m.p. 210-211 ° C.

EXAMPLE 13

According to a procedure similar to that described in Example 9C, but using 11.1 g (0.054 mol) of 4- (octylamino) pyridine and 6.6 g (0.027 mol) of 1,6-dibromo-hexane and heating of the reaction mixture for 9 hours under reflux, 15.1 g of 6-bis- [4- (octylamino) -1-pyridinium] hexane dibromide were obtained, mp 136-138 ° C.

EXAMPLE 14

According to a procedure similar to that described in Example 2, but using 5.0 µl, 6-bis- [4- (octylamino) -1-pyridinium] hexane dibromide, 4.23 g of the corresponding dichloride, m.p .: 189 - 191 ° C.

EXAMPLE 15

According to a procedure similar to that described in Example 9C, but using 14.24 g (0.08 mol) of 4- (hexylamino) pyridine and 8.64 g (0.04 mol) of 1,4-dibromobu -tan, after tearing off the crude product with a mixture of acetonitrile and acetone, 20.45 g of 1,4-bis - [4- (hexylamino) -1-pyridinium] butane dibromide was obtained, mp: 199 - 201 ° C.

EXAMPLE 16

According to a procedure similar to that described in Example 9C, but using 10.7 g (0.06 mol) of 4- (hexylamino) pyridine and 7.32 g (0.03 mol) of 1,6-dibromohe -xane, after rubbing off the crude product with a mixture of ether, acetonitrile and acetone, obtained 14.90 g of 1,6-bis - (^ - (3-exylaminoj-1-pyridinium jhexane-dibromide, m.p. : 178 - 179 ° C.

EXAMPLE 17

According to a procedure similar to that described in Example 9C, but using 10.7 g (0.06 mole) of 4- (hexylamino) pyridine and 7.75 g (0.03 mole) of 1,7-dibromo hip -tan, after tearing off the crude product with a mixture of acetonitrile and acetone, 16.4 g of 1,7-bis [4- (hexylamino) -1-pyridinium] heptane dibromide were obtained, mp: 157 - 158 ° C.

EXAMPLE 18

According to a procedure similar to that described in Example 9C, but using 10.7 g (0.06 mol) of 4- (hexylamino) pyridine and 8.6 g (0.03 mol) of 1,9-dibromo -Nan, 17.15 g of 1,9-bis [4- (hexylamino) -1-pyridinium] nonane dibromide was obtained, mp: 114 - 115 ° C.

EXAMPLE 19

According to a procedure similar to that described in Example 9C, but using 15.4 g (0.08 mol) of 4- (heptylamino) pyridine and 8.64 g (0.04 mol) of 1,4-dibromo -butane, 23.1 g of 1,4-bis- [4- (heptylamino) -1-pyridinium] butane dibromide were obtained, mp: 229 - 230 ° C.

EXAMPLE 20

According to a procedure similar to that described in Example 9C, but using 10.0 g (0.052 mol) of 4- (heptylamino) pyridine and 6.7 g (0.026 mol) of 1,7-dibromo-heptane, which obtained 14.05 g of 1,7-bis- [4- (heptylamine) -1- pyridinium jheptane dibromide, mp: 142 - 143 ° C.

EXAMPLE 21

According to a procedure similar to that described in Example 9C, but using 11.6 g (0.06 mol) of 4- (heptylamino) pyridine and 8.2 g (0.03 mol) of 1,8-dibromo -octane, after recrystallization from acetonitrile / ether, 18.6 µl, 8-bis- [4- (heptylamino) -1-pyridinium] octane dibromide was obtained, mp: 161 - 162 ° C.

EXAMPLE 22

According to a procedure similar to that described in Example 2, but using 3.0 g (0.0076 mole) of 1.8-bis- [4- (heptylamino) -1-pyridinium] octane dibromide was obtained. 4.1 g of the corresponding dichloride, mp: 206 - 208 ° C.

EXAMPLE 23

According to a procedure similar to that described in Example 9C, but using 15.4 g (0.09 mol) of 4- (heptylamino) pyridine and 11.44 g of 1,9-dibromnonane, 21 was obtained. 3 g of 1,9-bis- [4- (heptylamino) -1-pyridinium] nonane dibromide, mp: 115 - 116 ° C.

EXAMPLE 24

According to a procedure similar to that described in Example 2, but using 5.0 g (0.075 mole) of 1.9-bis- [4- (heptylamino) -1-pyridinium] nonane dibromide, 4 was obtained. 2 g of the corresponding dichloride, mp: 154 - 155 ° C.

EXAMPLE 25

According to a procedure similar to that described in Example 9C, but using 15.4 g (0.08 mole) of 4- (heptylamino) pyridine and 12.0 g (0.04 mole) of 1,10-dibromo -decane, 25.7 g of 1,10-bis- [4- (heptylamino) -1-pyridinium] decane dibromide were obtained, mp: 163-165 ° C.

EXAMPLE 26

According to a procedure similar to that described in Example 2, but using 5.0 g (0.0073 mol) of 1,10-bis- [4- (heptylamino) -1-pyridinium] decane dibromide, to obtain 4.35 g of the corresponding dichloride, mp: 209 - 210 ° C.

EXAMPLE 27

To a stirred slurry of 30 ml of hydroxide synthetic anion exchange resin (marketed by Rohm and Haas under the trade name "Amberlite® IRA 400") in 150 ml of water was added dropwise 48% aqueous hydrofluoric acid until the mixture was acidic. After stirring for an additional 0.5 hours, the slurry was poured into a column. The column was allowed to drain and the resin was washed with a solution containing 15 ml of 48% aqueous hydrofluoric acid in 185 ml of distilled water. The resin was then washed with distilled water until the eluate was slightly acidic and then successively with 20%, 40% and 50% aqueous methanol and finally with absolute methanol until the eluate was neutral. To the top of this column of ion exchange resin, now in the fluoride form, was added a solution containing 0.25 g (0.000365 mol) of 1,10-bis- [4- (heptylamino) -1-pyridinium] decane dibromide in 1 ml of methanol. Five fractions of 15 ml each were collected. The first three fractions were combined and evaporated to dryness under reduced pressure. The oily residue was dissolved in a mixture of toluene and ethanol and the resulting solution evaporated to dryness under reduced pressure. The remaining oil was redissolved in a mixture of benzene and acetone and the solution concentrated to a small volume. The separated solid was collected by filtration and dried for 24 hours at 24 ° C / 0.1 mmHg to give 0.11 g of crude 1,10-bis- [4- (heptylamino) -1-pyridinium] decane -difluoride, mp: 85 - 90 ° C.

EXAMPLE 28 A. A solid mixture of 115 g (0.5 mole) of N- (4-pyridyl) pyridinium chloride hydrochloride and 119 g (0.66 mole) of n-nonylamine hydrochloride was heated in an oil bath. to a bath temperature of 220 ° C (internal temperature 190 - 194 ° C) and the resulting liquid was stirred at that temperature for 2 hours. The reaction mixture was then cooled to 80 ° C, diluted with 1.2 liters of ice and water, made alkaline with 35% aqueous sodium hydroxide solution and extracted with chloroform. The chloroform extracts were dried over anhydrous sodium sulfate, treated with decolorizing charcoal, filtered and evaporated to dryness under reduced pressure. The remaining viscous oil was cooled to -78 ° C and triturated with ether. The resulting solid was collected by filtration and washed with cold ether. The filtrate gave another amount of solid. The combined amounts were redissolved in chloroform and the resulting solution treated with decolorizing charcoal and filtered. This was repeated again and the filtrate was then evaporated to dryness under reduced pressure. The remaining semi-solid was triturated with ether and cooled to give an almost colorless solid which was collected by filtration and washed with cold ether and dried. The solid was taken up in chloroform and the resulting solution treated with decolorizing charcoal, filtered and evaporated to dryness under reduced pressure. Cooling of the thus obtained semi-solid and rinsing with ether gave a colorless solid which was collected by filtration, washed with cold ether and dried to give 51.7 g of 4- (nonylamino) pyridine, mp: 59 - 60 ° C. The filtrate gave an additional amount of 11.6 g, mp 55-57 ° C.

B. Alternatively, 4- (nonylamino) pyridine was prepared as follows: A mixture of 39.5 g (0.42 mole) of 4-aminopyridine, 175 g (1.24 mole) of nonylaldehyde, 5.0 g of 10% pallet -dium-on-carbon hydrogenation catalyst and sufficient absolute ethanol to give a total volume of 600 ml was heated and hydrogenated under a hydrogen initial pressure of 3.15 kp / cm until the absorption of hydrogen ceased. The reaction mixture was filtered to remove the catalyst and the filtrate was evaporated to dryness under reduced pressure. The remaining oil was then vacuum distilled to remove any amount of nonyl alcohol that may have formed. A fraction boiling at 63 - 64 ° C / 4.5 mmHg was collected and set aside. The residue was triturated with ether and cooled to -78 ° C. The precipitated solid was collected by filtration and washed with cold ether. This product was dissolved in chloroform, the resulting solution treated with decolorizing coal, filtered, and the filtrate evaporated to dryness. The residue was triturated with ether and cooled to -78 ° C. The solid thus obtained was collected by filtration, washed with cold ether and air dried to give 27.0 g of 4- (nonylamino) pyridine, mp: 57-59 ° C.

C. A stirred suspension of 11.0 g (0.05 mole) of 4- (nonylamino) pyridine in 150 ml of acetonitrile was heated until a clear homogeneous solution was obtained. To this clear solution was added dropwise a solution of 6.8 g (0.025 mole) of 1,8-dibromooctane in 50 ml of acetonitrile and the resulting mixture was heated at reflux for a period of time during which a solid precipitated from the solution. . After cooling, the solid was collected by filtration, redissolved in methanol, the resulting solution was treated with decolorizing coal, filtered and evaporated to dryness under reduced pressure. Stripping the residual oil with ether containing a small amount of acetonitrile afforded a colorless crystalline solid which was collected by filtration and dried to give 15.5 gl, 8-bis- [4- (nonylamino) -1-pyridinium] ] octane dibromide, mp: 178 -179 ° C.

EXAMPLE 29

According to a procedure similar to that described in Example 28C, but using 3.54 g (0.026 mol) of 4- (propylamino) pyridine and 3.90 g (0.013 mol) of 1,10-di-bromodecane, to obtain 5.19 g of 1,10-bis- [4- (propylamino) -1-pyridinium] decane dibromide, mp: 206-207 ° C.

EXAMPLE 30

According to a procedure similar to that described in Example 28C, but using 14.24 g (0.08 mol) of 4- (hexylamino) pyridine and 9.20 g (0.04 mol) of 1,5-di -bromopentane, after recrystallization from acetonitrile / acetone, 12.3 g of 1,5-bis- [4- (hexylamino) -1-pyridinium] pentane dibromide were obtained, mp: 155 - 156 ° C.

EXAMPLE 31

According to a procedure similar to that described in Example 28C, but using 10.7 g (0.06 mol) of 4- (hexylamino) pyridine and 8.2 g (0.03 mol) of 1,8-dibromo - U7639 octane, 16.3 g of 1,8-bis [4- (hexylamino) -1-pyridinium] octane dibromide were obtained, mp: 180 - 181 ° C.

EXAMPLE 32

According to a procedure similar to that described in Example 28C, but using 12.5 g (0.07 mol) of 4- (hexylamino) pyridine and 10.5 g (0.035 mol) of 1,10-dibromo-decane , 16.0 g of 1,10-bis- [4- (hexylamino) -1-pyridinium] decane dibromide were obtained, mp: 148 - 149 ° C.

EXAMPLE 33

According to a procedure similar to that described in Example 28C. but using 13.4 g (0.076 mole) of 4- (cyclohexylamino) pyridine and 8.2 g (0.038 mole) of 1,4-dibromobutane, 18.2 g of 1,4-bis- [4- lohexylamino] -1-pyridinium] butane dibromide, mp: 288-290 ° C.

EXAMPLE 34

According to a procedure similar to that described in Example 28C, but using 13.4 g (0.076 mole) of 4- (cyclohexylamino) pyridine and 8.75 g (0.038 mole) of 1.5-dibrompentane, 19 was obtained. 0 g of 1,5-bis- [4- (cyclohexylamino) -1-pyridinium] pentane dibromide, mp: 255 -256 ° C.

EXAMPLE 35

According to a procedure similar to that described in Example 28C, but using 13.4 g (0.076 mole) of 4- (cyclohexylamino) pyridine and 9.3 g (0.038 mole) of 1.6-dibromohexane, 19, 1 g of 1,6-bis [4- (cyclohexylamino) -1-pyridinium] hexane dibromide, mp: 307 - 14 308 ° C.

EXAMPLE 36

According to a procedure similar to that described in Example 28C, but using 13.4 g (0.076 mol) of 4- (cyclohexylamino) pyridine and 9.8 g (0.038 mol) of 1.7-dibromoheptane, 2 was obtained. 01 µl, 7-bis- [4- (cyclohexylamino) -1-pyridinium] heptane dibromide, mp: 311 -313 ° C.

EXAMPLE 37

According to a procedure similar to that described in Example 28C, but using 13.4 g (0.076 mole) of 4- (cyclohexylamino) pyridine and 10.34 g (0.038 mole) of 1.8-dibromooctane, 19 was obtained. 1 g of 1,8-bis- (4- (cyclohexylamino) -1-pyridinium] octane dibromide, mp 270-227 ° C

EXAMPLE 38

According to a procedure similar to that described in Example 28C, but using 13.4 g (0.076 mole) of 4- (cyclohexylamino) pyridine and 10.8 g (0.038 mole) of 1.9-dibromnonane, 16 were obtained. 3 g of 1,9-bis- [4- (cyclohexylamino) -1-pyridinium] nonane dibromide, mp: 149 -151 ° C.

EXAMPLE 39

According to a procedure similar to that described in Example 28C, but using 13.4 g (0.076 mole) of 4- (cyclohexylamino) pyridine and 11.4 g (0.038 mole) of 1.10-dibromodecane, 19 was obtained. 0 g of 1,10-bis- [4- (cyclohexylamino) -1-pyridinium] decane dibromide, mp: 226 - 147639 27 227 ° C.

EXAMPLE 40 A. A mixture of 298.0 g (1.33 mole) of N- (4-pyridyl) pyridinium chloride hydrochloride and 322 g (2 mole) of 2-ethylhexylamine hydrochloride was heated for 2 hours with stirring. in an oil bath at a bath temperature of 213 ° C.

The mixture was cooled to 60 ° C, diluted with 500 ml of water and kept cold by the addition of ice while alkaline with 35% aqueous sodium hydroxide solution. The alkaline mixture was extracted with ether and the ether extracts were dried over anhydrous sodium sulfate and evaporated to dryness. The residual oil was distilled under reduced pressure to give 101.0 g of 4- (2-ethylhexylamino) pyridine, b.p. 145-150 ° C / 0.9 mmHg.

B. Alternatively, 4- (2-ethylhexylamino) pyridine was prepared as follows:

To a stirred solution of 800 g (8.4 mol) of 4-aminopyridine and 1500 ml of triethylamine in 6.4 liters of dichloromethane was added over 3 hours a solution of 1610 g (10.0 mol) of 2-ethylhexanoyl chloride in 1 , 6 liters of dichloromethane.

During the addition, the temperature was maintained at 15 ° C. After the addition was complete, the mixture was heated on a steam bath for 2 hours. After cooling, the reaction mixture was washed thoroughly with water, dried over anhydrous sodium sulfate, treated with decolorizing charcoal and filtered. Evaporation of the filtrate gave 1843 g of N- (4-pyridyl) -2-ethyl-hexanamide.

To a mixture of 100 g (2.63 moles) of lithium aluminum hydride and 2 liters of tetrahydrofuran was added at a sufficient rate to maintain gentle reflux a solution of 570 g (2.62 moles) of N- (4-pyridyl) -2 -ethyl-hexanamide in 4 liters of tetrahydrofuran. After the addition was complete (approximately 3 hours), the reaction mixture was heated under reflux for 7 hours.

After cooling, the mixture was treated successively with 100 ml of water, 100 ml of 15% aqueous sodium hydroxide solution and 300 ml of water. The solid was removed by filtration and the solvent evaporated from the filtrate under reduced pressure. The remaining oil was combined with the product of a similar experiment and vacuum distilled to give 837 g of 4- (2-ethylhexylamino) pyridine, bp: 135-160 ° C / 0.2 mmHg.

C. To a hot solution of 10.3 g (0.05 mole) of 4- (2-ethylhexylamino) pyridine in 50 ml of acetonitrile was added dropwise a solution of 8.2 g (0.025 mole) of 1,12-dibromo-decane in 170 ml of acetonitrile and the resulting mixture was heated at reflux for 20 hours. After cooling to 0 ° C, a first amount of product was collected which was collected by filtration. Evaporation of the filtrate and elution of the residue with ether gave another amount.

The combined amounts were dissolved in methanol, the resulting solution was treated with decolorizing coal, filtered and the filtrate evaporated to dryness under reduced pressure. The remaining oil was cooled and triturated with ether to give a slightly discolored solid. Recrystallization from acetonitrile / ether followed by tearing off the product with ether followed by acetonitrile gave after drying for 72 hours. under vacuum at 60 ° C 14.7 g of 1,12-bis- [4- (2-ethylhexylamine) -1-pyridinium] dodecane dibromide as colorless granules, mp: 146 -147 ° C.

Example 44 A. A mixture of 353.5 g (1.72 mole) of 4- (2-ethylhexylamino) pyridine and 205 g (0.86 mole) of 1,12-dichlorododecane was heated to 120 ° C. The heat source was removed and the temperature of the now exothermic reaction continued to rise to 180 - 190 ° C. After the temperature had dropped to 135 ° C, 1 liter of acetonitrile was gently added and the mixture was heated at reflux to obtain a clear solution. The hot acetonitrile solution was combined with similar solutions from two other experiments, treated with decolorizing charcoal and filtered. The filtrate was cooled and the precipitated product was collected by filtration and washed with cold acetonitrile. Two recrystallizations from acetonitrile gave 970 g of 1,12-bis- [4- (2-ethylhexylamino) -1-pyridinium] dodecane dichloride, mp: 168 - 171 ° C.

B. Alternatively, according to a procedure similar to the one described in Example 2, but using Usage Sw of 3.0 g (0.00405 mol) of 1,12-bis- [4- (2-ethylhexylamino) - 1-pyridinium] dodecane dibromide obtained 2.0 g of the corresponding dichloride, mp: 172 - 173 ° C.

EXAMPLE 42

According to a procedure similar to that described in Example 40C, but using 10.3 g (0.05 mole) of 4- (octylamino) pyridine and 6.45 g (0.025 mole) of 1,7-dibromo-heptane , 14.85 g of 1,7-bis- [4- (octylamino) -1-pyridinium] heptane dibromide, mp: 129-141 ° C, were obtained.

Example 43 A. According to a procedure similar to that described in Example 40C, but using 11.1 g (0.054 mol) of 4- (octylamino) pyridine and 7.72 g (0.027 mol) of 1.9- di-bromnonane, 17.0 g of 1,9-bis- [4- (octylamino) -1-pyridinium] nonane dibromide were obtained, mp: 117 - 119 ° C.

B. The corresponding dichloride prepared according to the procedure of Example 2 had a melting point of 161 - 162 ° C.

EXAMPLE 44

According to a procedure similar to that described in Example 4C, but using 10.3 g (0.05 mole) of 4- (octylamino) pyridine and 8.2 g (0.025 mole) of 1,12-dibromo-dodecane 15.2 g of 1,12-bis- [4- (ethylamino) -1-pyridinium] dodecane dibromide were obtained, mp: 119-120 ° C.

EXAMPLE 45

According to a procedure similar to that described in Example 40C, but using 5.8 g (0.028 mol) of 4- (octylamino) pyridine and 5.0 g (0.014 mol) of 1,14-dibromo-tetradecane, 9.3 g, 14-bis- [4-octylamino) -1-pyridinium] tetradecane dibromide, mp 113-111 ° C.

EXAMPLE 46

According to a procedure similar to that described in Example 40C, but using 11.0 g (0.05 mole) of 4- (nonylamino) pyridine and 6.1 g (0.025 mole) of 1,6-dibromo-hexane 15.2 g of 6-bis- [4- (nonylamino) -1-pyridinium] hexane dibromide were obtained, mp: 152 - 154 ° C.

EXAMPLE 47

According to a procedure similar to that described in Example 4, but using 6.5 g (0.0095 mol) of 1,6-bis- [4- (nonylamino) -1-pyridinium] hexane dibromide, to obtain 4.95 g of the corresponding chloride, mp: 194 - 195 ° C.

EXAMPLE 48

According to a procedure similar to that described in Example 40C, but using 8.8 g (0.04 mole) of 4- (nonylamino) pyridine and 5.2 g (0.02 mole) of 1,7-dibromo hip tan, 12.2 µl, 7-bis- [4- (nonylamino) -1-pyridinium] heptane dibromide, mp 132-134 ° C, were obtained.

EXAMPLE 49

According to a procedure similar to that described in Example 40C, but using 11.0 g (0.05 mole) of 4- (nonylamino) pyridine and 7.15 g (0.025 mole) of 1,9-dibromo-nonane 15.7 g of 9-bis- [4- (nonylamino) -1-pyridinium] nonane dibromide were obtained, mp: 121 - 122 ° C.

EXAMPLE 50

According to a procedure similar to that described in Example 40C, but using 11.0 g (0.05 mole) of 4- (nonylamino) pyridine and 7.5 g (0.025 mole) of 1,10-dibromo-decane 15.63 g of 1,10-bis- [4- (nonylamino) -1-pyridinium] decane dibromide, m.p. 172 - 173 ° C.

EXAMPLE 51

According to a procedure similar to that described in Example 40C, but using 10.12 g (0.046 mole) of 4-nonylamino) pyridine and 7.54 g (0.023 mole) of 1,12-di-bromododecane, to obtain 16.4 g of 1,12-bis- [4- (nonylamino) -1-pyridinium] dodecane dibromide, mp: 105 - 106 ° C.

EXAMPLE 52

To a stirred hot solution of 12.4 g (0.06 mole) of 4- (2-ethylhexylamino) pyridine in 100 ml of acetonitrile was added dropwise a solution of 6.9 g (0.03 mole) of the 1.5-dibromo -tan in 25 ml of acetonitrile and the resulting solution was heated at reflux for 20 hours. The reaction mixture was cooled and diluted with ether until slightly cloudy. Further cooling and stirring afforded a solid precipitate which was collected by filtration and washed with a cold mixture of acetonitrile and ether.

The solid thus obtained was dissolved in ethanol and the resulting solution treated with decolorizing coal and filtered. Evaporation of the filtrate gave a pale yellow viscous oil which was crystallized from acetonitrile / ether. The resulting solid was collected by filtration, washed with cold acetonitrile / ether and dried for 24 hours under vacuum at 90 ° C to give 13.6 g of 5-bis- [4- (2-ethylhexylamino) -1 pyridinium] pentane dibromide, mp: 150 - 151 ° C.

EXAMPLE 53

According to a procedure similar to that described in Example 52, but using 12.4 g (0.06 mole) of 4- (2-ethylhexylamino) pyridine and 7.32 g (0.03 mole) 1.6 -di-bromohexane, 16.1 g of 1,6-bis- [4- (2-ethylamino) -1-pyridinium] hexane dibromide was obtained, mp: 208-209 ° C.

EXAMPLE 54

According to a procedure similar to that described in Example 52, but using 12.4 g (0.06 mole) of 4- (2-ethylhexylamine) pyridine and 7.75 g (0.03 mole) 1.7 -di-bromoheptane, 17.9 g of 1,7-bis- [4- (2-ethylhexylamino) -1-pyridinium] heptane dibromide were obtained, mp 219-220 ° C.

EXAMPLE 35 33

According to a procedure similar to that described in Example 52, but using 12.4 g (0.06 mol) of 4- (2-ethylhexylamino) pyridine and 8.2 g (0.03 mol) of 1.8 -di-bromooctane, 15.9 g of 1,8-bis- [4- (2-ethylhexylamino) -1-pyridinium joctane dibromide were obtained, mp: 160 -161 ° C.

EXAMPLE 56

According to a procedure similar to that described in Example 52, but using 12.4 g (0.06 mole) of 4- (2-ethylhexylamino) pyridine and 8.6 g (0.03 mole) of 1.9 -di-bromnonanone, 15.2 g of 1,9-bis- [4- (2-ethylhexylamino) -1-pyridinium] nonane dibromide were obtained, mp: 158 -159 ° C.

EXAMPLE 57

According to a procedure similar to that described in Example 52, but using 12.4 g (0.06 mole) of 4- (2-ethylhexylamino) pyridine and 9.0 g (0.03 mole) of 1.10 -di-bromnonane, 17.4 g of 1,10-bis- [4- (2-ethylhexylamino) -1-pyridinium] decane dibromide was obtained, mp: 162 -163 ° C.

EXAMPLE 58

According to a procedure similar to that described in Example 2, but using 5.0 g of 1.10 bis- [4- (2-ethylhexylamino) -1-pyridinium] decane dibromide, 4.11 was obtained. g of the corresponding dichloride, mp: 191 - 192 ° C.

EXAMPLE 59

To a stirred hot solution of 12.0 g (0.063 mole) of 4- (hepethylamino) pyridine in 100 ml of acetonitrile was added dropwise a solution of 7.4 g (0.032 mole) of 1,5-dibrompenetane in 25 ml. ml of acetonitrile, and the resulting mixture was heated at reflux for 19 hours. The reaction mixture was cooled in ice and gradual ether was added until a colorless solid precipitated.

The solid was collected by filtration, recrystallized from acetonitrile / ether and dried for 48 hours at 90 ° C / 1 mmHg to give 15.9 g, 5-bis- [4- (heptylamino) -1-pyridinium] pentane dibromide, sm. : 153 - 154 ° C.

EKSE..PEL 60

According to a procedure similar to that described in Example 59, but using 19.2 g (0.1 mole) of 4- (heptylamino) pyridine and 12.2 g (0.05 mole) of 1,6-dibromo -hexane, 27.5 g of crude product was obtained. Recrystallization of a 15 g sample from acetonitrile / ether gave 11.45 g of 1,6-bis- [4- (heptylamino) -1-pyridinium] hexane dibromide, mp: 149-100 ° C.

Example 61 A. A suspension of 24.0 g of crude 1,6-bis [4- (heptylamino) -1-pyridinium] hexane dibromide in 500 ml of water was made alkaline with 3 N aqueous sodium hydroxide solution and extracted with chloroform. The chloroform extracts were dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residual oil was dissolved in methanol and the resulting solution acidified with methanesulfonic acid and evaporated to dryness under reduced pressure. The residue was redissolved in methanol, treated with decolorizing charcoal, filtered and evaporated to dryness in vacuo, leaving an oily residue, which, by rinsing with ether followed by acetonitrile, yielded 18.2 g of gummy solid. The crude material was dissolved in water and the resulting solution made alkaline with 35% aqueous sodium hydroxide solution and extracted with chloroform. The chloroform extracts were dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure.

The resulting solid was successively triturated with ether and acetonitrile, collected by filtration and dried to give 16.3 g of light brown solid, mp: 105 - 108 ° C. The solid thus obtained was dissolved in 100 ml of methanol and the resulting solution acidified with methanesulfonic acid. Evaporation to dryness under reduced pressure gave a viscous oil which was taken up in 20 ml of methanol and treated portionwise with 150 ml of water. The resulting suspension was cooled in ice and the suspended solid was collected by filtration and washed with cold water. The solid was then slurried in hot acetone, cooled, collected by filtration, washed with cold acetone and dried for 48 hours at 95 ° C / 1 mmHg to give 10.8 g of light brown solid, m.p. 163 - 165 ° C.

This product gave a positive chloride ion test with silver nitrate and its NMR spectrum showed the absence of the methane sulfonate group.

B. A suspension of 14.0 g of 1,6-bis [4- (4-heptylamino) -1-pyridinium] hexane dibromide in 500 ml of water was made alkaline with 35% aqueous sodium hydroxide solution and extracted with chloroform. The chloroform extracts were dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The partially solid residue was dissolved in 1 liter of acetonitrile / benzene and the resulting solution evaporated to dryness under vacuum. This process was repeated three times. The final residue was dissolved in 50 ml of acetonitrile and the resulting solution diluted with 50 ml of benzene and cooled in ice to give 5.3 g of light brown solid after filtration and drying. The filtrate gave another 4.8 g. The amounts were combined and dissolved in 50 ml of acetonitrile. Dilution with ether precipitated a solid which was collected by filtration and dried for 48 hours at 95 ° C / 1 mmHg to give 8.85 g of light brown solid, snip: 174 - 176 ° C. This product also gave a positive chloride ion test with silver nitrate.

C. The products from A and B above were combined, mixed with 300 ml of water and heated until a homogeneous solution was obtained. The solution was filtered and the filtrate treated with 50 ml of 12 N hydrochloric acid. The resulting suspension was concentrated under reduced pressure, and the residue was treated with ice. The solid thus formed was collected by filtration, washed with cold water and dried. The product was then dissolved in acetone, the resulting solution diluted with a mixture of benzene and ethanol, and the whole evaporated to dryness under vacuum. The solid residue was slurried in 100 ml of acetone and the slurry was diluted with ether and filtered to give 16 hours after drying at 105 ° C / 1 mmHg and for 72 hours at 115 ° C / 1 mmHg. 3 g of crude 1,6-bis [4-heptylamino) -1-pyridinium hexhexane dichloride as an almost white solid, mp: 176 - 178 ° C.

EXAMPLE 62

According to a procedure similar to that described in Example 59, but using 10.30 g (0.050 mol) of 4- (2-ethylhexylamino) pyridine and 5.4 g (0.025 mol) of 1,4-dibromobutane, 14.9 g of 1,4-bis- [4- (2-ethylhexylamino) -1-pyridinium] butane dibromide, mp: 245 - 246 ° C.

EXAMPLE 63 A. A mixture of 229 g (1.0 mole) of N- (4-pyridyl) pyridinium chloride hydrochloride and 224 g (1.26 mole) of n-decyl amino hydrochloride was stirred and heated for about 2 hours. , 5 hours at 190 - 195 ° C. The reaction mixture was then allowed to cool slowly to 40 ° C and diluted with 2 liters of water. The resulting solution was cooled by the addition of ice and made alkaline with 200 ml of 35 ° A aqueous sodium hydroxide solution. The dark solid which precipitated was collected by filtration and washed with cold water. This material was dissolved in 1 liter of chloroform and the resulting solution was treated with decolorizing charcoal and filtered. The filtrate was evaporated under reduced pressure and the residue was triturated with 150 ml of ether. The solid thus obtained was redissolved in chloroform and the resulting solution treated with decolorizing coal and filtered.

The filtrate was again treated with decolorizing charcoal and filtered. The filtrate was evaporated to dryness under reduced pressure and the residual solid was triturated with ether. Recrystallization from acetonitrile gave, after drying under vacuum, 96.1 g of 4- (decylamino) -pyridine, mp: 71-73 ° C.

B. To a stirred hot solution of 1.2 g (0.052 mol) of 4- (decylamino) pyridine in 150-170 ml of acetonitrile was added dropwise a solution of 6.35 g (0.026 mol) of 1.6-bromohexane in 60 ml of acetonitrile. and the resulting mixture was heated at reflux for about 20 hours. The reaction mixture was then cooled in ice, and the precipitated solid was collected by filtration and washed with cold acetonitrile. The product thus obtained was dissolved in methanol and the resulting solution treated with decolorizing coal and filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was dissolved in 50 ml of cold ether, collected by filtration, and dried for 2 days over phosphorus pentoxide at 70 ° C / 1 mmHg to give 14.6 g. 6- [4- (de-cylamino) -1-pyridinium hexhexane dibromide, m.p .: 138 - 140 ° C.

EXAMPLE 64

According to a procedure similar to that described in Example 63B, but using 12.2 g (0.052 mol) of 4- (decylamino) pyridine and 6.7 g (0.026 mol) of 1,7-dibromoheptane was obtained. 16.0 g of 1,7-bis [4- (decylamino) -1-pyridinium] heptane dibromide, mp 145-147 ° C.

EXAMPLE 65 147639 39

According to a procedure similar to that described in Example 63B, but using 11.7 g (0.050 mole) of 4- (decylamino) pyridine and 6.8 g (0.025 mole) of 1,8-dibromooctane was obtained. 16.9 g of 1,8-bis- [4- (decylamino) -1-pyridinium] octane dibromide, mp: 180 - 182 ° C.

EXAMPLE 66

According to a procedure similar to that described in Example 63B, but using 11.7 g (0.050 mole) of 4- (decylamino) pyridine and 7.15 g (0.025 mole) of 1,9-dibromnonane was obtained. 15.1 g, 9-bis [4- (decylamino) -1-pyridinium nonanone dibromide, mp: 124 - 126 ° C.

EXAMPLE 67

According to a procedure similar to that described in Example 63B, but using 11.2 g (0.048 mole) of 4- (decylamino) pyridine and 7.2 g (0.024 mole) of 1,10-dibromo-decane was obtained. 14.6 g of 1,10-bis- [4- (decylamino) -1-pyridinium] decane dibromide, mp: 173 - 174 ° C.

EXAMPLE 68

According to a procedure similar to that described in Example 63B, but using 11.2 g (0.048 mole) of 4- (decylamino) pyridine and 7.9 g (0.024 mole) of 1,12-dibromo-dodecane was obtained. 16.5 g of 1,12-bis- [4- (decylamino) -1-pyridinium] dodecane dibromide, mp: 102 -106 ° C.

EXAMPLE 69 147639 40

To a stirred hot solution of 13.6 g (0.052 mol) of 4- (dodecylamino) pyridine in 140 ml of acetonitrile was added dropwise a solution of 6.34 g (0.026 mol) of 1,6-dibromohexane in 50 ml of acetonitrile, and the resulting mixture was heated at reflux overnight. The reaction mixture was cooled and the precipitated solid collected by filtration. The solid was dissolved in absolute ethanol and the resulting solution treated with decolorizing charcoal and filtered. The filtrate was evaporated to dryness under reduced pressure to give as a residue a white solid which was slurried in ether, collected by filtration and dried at 60 ° C / 0.1 mmHg to give 17.63 gl, 6-bis - [4- (dodecylamino) -1-pyridinium] hexane dibromide, mp: 164 -165 ° C.

EXAMPLE 70

According to a procedure similar to that described in Example 69, but using 13.6 g (0.052 mol) of 4- (dodecylamino) pyridine and 6.71 g (0.026 mol) of 1,7-dibromo-heptane, to obtain 18.03 g (1,7-bis- [4- (dodecylamino) -1-pyridinium] heptane dibromide, mp: 148-150 ° C.

EXAMPLE 71

According to a procedure similar to that described in Example 69, but using 12.59 g (0.048 mol) of 4- (dodecylamino) pyridine and 6.53 g (0.024 mol) of 1,8-dibromooctane was obtained. 16.18 g of 1,8-bis- [4- (dodecylamino) -1-pyridinium] octane dibromide, mp: 184 -185 ° C.

EXAMPLE 72 147639 41

According to a procedure similar to that described in Example 69, but using 12.59 g (0.048 mole) of 4- (dodecylamino) pyridine and 6.86 g (0.024 mole) of 1,9-dibromnonane was obtained. 19.35 g of 1,9-bis- [4- (do-decylamino) -1-pyridinium] nonane dibromide, mp: 134-135 ° C.

EXAMPLE 73

According to a procedure similar to that described in Example 69, but using 1.225 g (0.048 mol) of 4- (dodecylamino) pyridine and 7.2 g (0.024 mol) of 1,10-di-bromodecane were obtained. 18.08 g of 1,10-bis- [4- (dead-cylamino) -1-pyridinium] decane dibromide, mp: 178-180 ° C.

EXAMPLE 74

According to a procedure similar to that described in Example 69, but using 11.54 g (0.044 mol) of 4- (dodecylamino) pyridine and 7.22 g (0.022 mol) of 1,12-dibromo-dodecane was obtained. 17.68 g of 1,12-bis- [4- (do-decylamino) -1-pyridinium] decane dibromide, mp 75-77 ° C.

EXAMPLE 75

To a stirred hot solution of 21.0 g (0.102 mol) of 4- (p-chlorophenylamino) pyridine in 150 ml of N, N-dimethylformamide was added dropwise a solution of 11.02 g (0.051 mol) of 1,4-dibromobutane in 50 ml. ml of acetonitrile, and the resulting mixture was heated for 2.5 hours on a steam bath. The reaction mixture was cooled to room temperature, diluted with ether and the product was allowed to crystallize. The precipitated solid was collected by filtration and washed with a mixture of acetonitrile and ether and air dried to give 27.4 g of 1,4-bis- [4- (p-chlorophenylamino) -1-pyridinium ] butane di-bromide, mp: 182 - 189 ° C

B. A suspension of the above product in 500 ml of water was treated with ice and 2 N aqueous sodium hydroxide solution, and the resulting mixture was extracted thoroughly with chloroform. The chloroform extracts were dried over anhydrous sodium sulfate, evaporated to dryness under reduced pressure to give 21.0 g of the corresponding anhydro base as an oil which solidified on standing.

C. A solution of the above anhydro base in 250 ml of methanol was acidified with a solution of methanesulfonic acid in methanol. Evaporation to dryness under reduced pressure gave an oil which was crystallized from methanol / ether. The solid thus obtained was recrystallized from methanol / ether to give 18.95 g, 4- [4- (p-chlorophenylamino) -1-pyridinium] after drying for 48 hours at 92 ° C / 0.1 mmHg butane di-methanesulfonate, mp: 245 - 247 ° C.

Example 76 A. To a stirred hot solution of 21.0 g (0.102 mol) of 4- (p-chlorophenylamino) pyridine in 200 ml of N, N-dimethylformamide was added dropwise a solution of 12.45 g (0.051 mol) 1 , 6-dibromohexane in 50 ml of acetonitrile, and the resulting mixture was heated for 4 hours on a steam bath. After cooling to room temperature, a solid began to precipitate. The reaction mixture was diluted with 150 ml of acetonitrile and further cooled in ice. The precipitated solid was collected by filtration and air dried to give 27.2 g of 1,6-bis- [4- 1A7639 43 (p-chlorophenylamino) -1-pyridinium] hexane dibromide, mp: 148-150 ° C.

B. A methanol solution of the corresponding anhydro base, prepared from the above dibromide according to the procedure of Example 75B, was acidified with methanesulfonic acid and then evaporated to dryness under reduced pressure. The residual oil was crystallized from acetone / methanol to give 25.2 g, 6-bis- [4- (p-chlorophenylamino) -1-pyridinium] after drying for 48 hours at 75 ° C / 0.1 mmHg hexane-dimethanesulfonate, mp: 108 - 110 ° C.

Example 77 A. To a stirred hot solution of 21.0 g (0.102 mol) of 4- (p-chlorophenylamino) pyridine in 200 ml of N, N-dimethylformamide was added dropwise a solution of 3.9 g (0.051 mol 1,8-dibromooctane in 50 ml of acetonitrile and the resulting mixture was heated for 1.5 hours on a steam bath. The reaction mixture was then diluted with 100 ml of acetonitrile and heating continued for an additional 2.5 hours, after which an additional 100 ml of acetonitrile was added. After heating for a further 2 hours, the reaction mixture was cooled and the precipitated solid collected by filtration, washed with a mixture of acetonitrile and ether and dried to give 30.1 g of 1,8-bis - [4- (p- chlorophenylamino] -1-pyridinium] octane dibromide, mp: 245 - 247 ° C.

B. A methanol solution of the corresponding anhydro base, prepared from the above dibromide according to the procedure of Example 75B, was acidified with methanesulfonic acid and then evaporated to dryness under reduced pressure. The residual oil was dissolved in acetonitrile and the resulting solution treated with acetone until a cloudiness followed by clarification with a small amount of methanol and then cooled.

The precipitated crude solid was collected by filtration and recrystallized from acetonitrile / acetone to give, after drying for 36 hours at 80 ° C / 0.1 mmHg, 23.5 g of 1,8-bis- [4- chlorophenylamino) -1-pyridinium ioctane dimethanesulfonate, mp: 164 - 165 ° C.

EXAMPLE 78 A. To a stirred hot solution of 21.0 g (0.102 mol) of 4- (p-chlorophenylamino) pyridine in 200 ml of N, N-dimethylformamide was added dropwise a solution of 15.3 g (0.051 mol) 1 , 10-dibromo-decane in 50 ml of acetonitrile, and the resulting mixture was heated for 3.5 hours on a steam bath. The reaction mixture was then evaporated to dryness under reduced pressure. The remaining oil was crystallized from methanol / acetonitrile. The solid thus formed was collected by filtration and washed with a cold mixture of acetonitrile and ether to give 28.0 gl, 10-bis- [4- (p-chlorophenylamino) -1-pyridinium] decane. dibromide, mp: 225 - 230 ° C.

B. A methanol solution of the corresponding anhydro base, prepared from the above dibromide according to the procedure of Example 75B, was acidified with methanesulfonic acid and then evaporated to dryness under reduced pressure. The remaining oil was crystallized from acetonitrile / ether. The crude solid thus obtained was dissolved in methanol and the resulting solution treated with decolorizing coal and filtered. Evaporation of the filtrate gave an oil which was suspended in a mixture of acetonitrile and acetone to give a crude solid. Recrystallization from methanol / ether, after drying for 48 hours at 95 ° C / 0.1 mmHg, 18.4 g of 45 147δ39 l, 1Q-bis- [4- (p-chlorophenylamino) -1-pyridinium] decane dimethanesulfonate, m.p. : 202 - 204 ° C.

EXAMPLE 79

To a stirred hot solution of 10.0 g (0.049 mol) of 4- (p-chlorophenylamino) pyridine in a mixture of 275 ml of acetonitrile and 100 ml of N, N-dimethylformamide was added dropwise a solution of 5.75 g (0.025 mol) 1,5-dibromo-pentane in 25 ml of acetonitrile and the resulting mixture was heated at reflux for 24 hours. The reaction mixture was then evaporated to dryness under reduced pressure and the residue triturated with a mixture of ether and acetonitrile. The pale yellow solid thus obtained was redissolved in ethanol and the solution treated with decolorizing coal and filtered.

The filtrate was evaporated to dryness under reduced pressure and the residual oil was crystallized from ether / acetonitrile. The colorless solid was recrystallized from methanol / acetonitrile and dried for 48 hours at 115 ° C / 0.1 mmHg to give 8.1 g of 1,5-bis- [4- (p-chlorophenylamino) -1- pyridinium] pentane dibromide, mp: 166 - 168 ° C.

EXAMPLE 80

To a stirred hot solution of 10.0 g (0.049 mol) of 4- (p-chlorophenylamino) pyridine in a mixture of 125 ml of N, N-dimethylformamide and 50 ml of acetonitrile was added dropwise a solution of 6.45 g of 1.7 g. dibromoheptane in 25 ml of acetonitrile, and the resulting mixture was heated at reflux for 19 hours. The reaction mixture was then evaporated to dryness under reduced pressure and the residual oil was crystallized from ethanol / acetonitrile. The solid thus formed was dissolved in methanol and the solution was treated with staining coal and the filter. The filtrate was evaporated to dryness under vacuum and the residual oil crystallized again from ethanol / acetonitrile. The product was collected by filtration and dried for 36 hours at 105 ° C / 0.1 mmHg to give 10.4 g, 7-bis [4- (p-chlorophenylamino) -1-pyridinium] heptane dibromide, m.p. : 202 - 204 ° C.

EXAMPLE 81

To a stirred hot solution of 10.0 g. (0.049 mole) of 4- (p-chlorophenylamino) pyridine in a solution of 125 ml of N, N-dimethylformamide and 50 ml of acetonitrile was added dropwise a solution of 7.15 g (0.025 mole). 1,9-dibromo-nano in 25 ml of acetonitrile, and the resulting mixture was heated at reflux for 19 hours. The reaction mixture was then evaporated to dryness under reduced pressure and the residual oil crystallized from ethanol / acetonitrile. The solid product formed was dissolved in methanol and the solution was treated with decolorizing coal and filtered. The filtrate was evaporated to dryness under vacuum and the residual oil crystallized again from ethanol / acetonitrile. The product was collected by filtration and dried for 36 hours at 95. ° C / 0.1 mmHg to give 11.2 g of 1,9-bis- [4- (p-chlorophenylamino) -1-pyridinium] nonane dibromide, mp: 178 - 179 ° C.

EXAMPLE 82

To a hot stirred solution of 11.52 g (0.06 mol) of 4- (heptylamino) pyridine in 100 ml of acetonitrile was added in small portions a solution of 7.92 g (0.03 mol) of ajCt'-dibromo-β xylene in 150 ml of acetonitrile. After the addition was complete, a large mass of colorless crystals had separated from the solution. The reaction mixture was heated under reflux for 6 hours. After cooling to room temperature, the solid product was collected by filtration, washed with acetonitrile / ether, combined with 3.1 g of product from a previous experiment and dried for 48 hours at 100 ° C / 0.1 mmHg to give 22, 0 g of α, α'-bis- [4- (heptylamino) pyridinium] -p-xylene dibromide, mp: 297 - 298 ° C.

EXAMPLE 83

According to a procedure similar to that described in Example 82, but using 11.6 g (0.065 mole) of 4- (hexylamino) pyridine and 8.7 g (0.033 mole) of α, α'-dibromo-β- xylene and refluxing the reaction mixture for 20 hours yielded 19.3 g of α, α'-bis- [4- (hexylamino) pyridinium] -p-xylene dibromide, mp: 313 - 315 ° C.

The antibacterial and antifungal activity of representative examples of the compounds of formula I was determined using a modification of the autotiter method described by Goss et al.

Applied Microbiology IJj (9), 1414 - 1415 (1968) to prepare a 1000 µg / ml solution of the sample compound. To the first cup in the autotiter tray, add 0.1 ml of the sample solution. Activation of the auto-titre starts an operation sequence whereby 0.05 ml of the sample compound solution is withdrawn from the cup of a Microtiter transfer bed and diluted in 0.05 ml of sterile water. After this operation, 0.05 ml of grafted double-strength semi-synthetic medium (glucose) is automatically added to each cup. The overall operation results in final concentrations of the compound of from 500 to 0.06 µg / ml in double dilutions. The tray is incubated for 18-20 hours at 37 ° C, after which the trays are visually examined for growth, as shown by turbidity, and the concentration of the last sample in each row showing no growth (or turbidity) is recorded as the minimum inhibition concentration. (MIC) in µg / ml. The compounds were thus tested as solutions against a variety of Gram-positive and Gram-negative bacteria, including Staphylococcus aureus, Proteus mirabilis,

Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa and Streptococcus pyogenes and against such fungi as Aspergillus niger, Candida albicans and Trichophyton mentagrophytes.

Many of the compounds of formula I were also found to be antibacterially effective against Streptococcus mutans and Actinomyces A viscosis.

Virucid activity of representative examples of Herpes simplex type 2 virus was determined in vitro using a procedure similar to the plaque inhibition assay to determine specific inhibitors of DNA-containing viruses published by E.C.

Herrman, Jr., Proc. Soc. Exp. Biol. With. 107, 142 (1961), whereby 2 mg of the test compound was applied to the surface of the growth medium. The compounds of Examples 3, 5C, 7, 9C, 10, 11, 13, 16, 17, 20, 21, 23, 30, 32, 34, 35, 36, 51, 53, 54, 55, 56, 57, 59 , 60, 62, 80, 81, 82 and 83 were found to be active and the compounds of Examples 15, 33, 38, 39 and 78B were found to be inactive.

Numerical antibacterial and antifungal test data for the compounds are listed in Table A below.

Corresponding data for two known compounds, namely 1,8-bis (4-amino-1-pyridinium) octane dibromide (reference compound I) and 1,10-bis- (4-amino-1-pyridinium) decane dibromide (reference compound II), are also included in Table A for comparison purposes.

147639 49

Antibacterial efficacy in the presence of serum was determined for representative examples of the standard row dilution test, whereby paired comparisons of minimum inhibitory concentrations (MIC) were determined in the absence and in the presence of heat-inactivated (30 min at 56 ° C) horse serum (40% ) in the sample medium. The results are expressed as increases in MIC (µg / ml) against Staphylococcus aureus and Escherichia coli, caused by the presence of serum, and are listed in Table B below.

The acute oral toxicity (ALD µg) of several representative examples was determined as follows: Groups of three young adult albino male mice of the Swiss-Webster strain were fasted for about 4 hours prior to administration of the agent and then administered the compound once orally. through stomach tubes. All mice were observed for 7 days after administration. Autopsy of all mice in the study revealed no major tissue changes, except in the group receiving 1000 mg / kg of the compound of Example 24, where congestion of the glandular portion of the gastric sacs was observed in two of the three mice. The results are listed in Table C below.

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147639 55

Effect of serum on bacteriostatic activity MIC (yug / ml) against specified bacteria 5. aureus ATTC 6558_E. coli ATCC 8739 F orb.

from 0¾ 40¾ Ganges 0¾ 40¾ Ganges ex serum serum increase serum serum increase 78B 0.25 7.8 32 0.5 15.6 32 21 0.25 3.9 16 0.5 3.9 8 32 0.125 1.95 16 0.25 3.9 16 25 0.125 1.95 16 0.5 7.8 16 23 0.125 1.95 16 0.25 7.8 32 57 0.25 3.9 16 0.5 15.6 32 3 0.39 3.12 8 0.78 25.0 32 ID 0.195 3.12 16 1.56 25.0 16 7 0.10 1.56 16 0.39 12.5 32 5C 0.10 3.12 32 0.78 25.0 32 13 0.25 31.2 128 1.0 31.2 32 11 0.5 7.8 16 0.5 31.2 64 9C 0.5 7.8 16 1.0 62, 5 64 28C 0.5 7.8 16 3.9 62.5 16 40C 0.25 7.8 32 1.0 62.5 64 82 0.78 6.25 8 0.78 6.25 8 83 3, 12 12.5 4 1.56 6.25 4

TABLE C

147639 56

Acute oral toxicity (ALD µg)

Conn. Solution from or Dose, mg / kg, of Mortality excluding suspension total material 24 hours 7 days 22 Aqueous 125 0.3 0.3 solution 250 0/3 0/3 500 1/3 1/3 1000 3/3 3 / 3 7 days ALD, -g = 625 mg / kg 25 Suspension 125 0/3 0/3 in 1¾ GTl) 250 0/3 0/3 500 0/3 0/3 1000 0/3 0/3 7 days ALD, .g = ^ 1000 mg / kg 26 Aqueous 125 0/3 1/3 solution 250 0/3 0/3 500 1/3 1000 1/3 3/3 7 days ALD ^ g = 250 mg / kg 23 Suspension 125 0 / 3 0/3 in 1¾ GT 250 0/3 500 0/3 1/3 1000 0/3 0/3 7 days ALD, -g => 100 mg / kg 24 Aqueous 250 1/3 1/3 solution 500 1/3 1/3 1000 3 / 3 3/3 7 days ALD ^ g = 500 mg / kg 3 Suspension 125 0/3 0/3 in 1¾ GT 250 0/3 0/3 500 0/3 1/3 1000 1/3 1/3 7 days ALD ^ g = 1000 mg / kg 4 Suspension 125 0/3 0/3 in IS G.T. 250 0/3 0/3 500 0/3 0/3 1000 0/3 0/3 7 days ALD ^ -g => 1000 mg / kg 2 Suspension 125 0/3 0/3 in 1K G.T. 250 0/3 1/3 500 0/3 0/3 1000 0/3 1/3 7 days ALD ^ g = 1000 mg / kg TABLE C (continued)

Conn. Solution from or Dose, mg / kg, of Mortality excluding suspension total material 24 hours 7 days 8 Aqueous 125 0/3 0/3 solution 250 1/3 1/3 500 2/3 3/3 1000 3/3 3 / 3 7 days ALD, -g = 315 mg / kg 5C Suspension 125 0/3 0/3 in 1% GT 250 0/3 0/3 500 0/3 0/3 1000 1/3 1/3 7 days ALD ^ g => 1000 mg / kg 6 Aqueous 125 1/3 1/3 solution 250 0/3 1/3 500 2/3 2/3 1000 3/3 3/3 7 days ALD, -g = 315 mg / kg ID Suspension 125 0/3 0/3 in 1¾ GT 250 0/3 0/3 500 1/3 1/3 1000 2/3 2/3 7 days ALD, -g = 750 mg / kg 11 Suspension 125 033 0/3 in 1¾ G.T. 250 0/3 0/3 500 0/3 1/3 1000 0/3 0/3 7 days ALD, -g => 1000 mg / kg 12 Aqueous 125 0/3 0/3 solution 250 0/3 0/3 500 1/3 1/3 1000 2/3 2/3 7 days ALD, .g = 750 mg / kg 9C Suspension 125 0/3 0/3 in 1¾ GT 250 0/3 0/3 500 0/3 0/3 1000 0/3 0/3 7 days ALD ^ g => 1000 mg / kg 10 Aqueous 125 0/3 0/3 solution 250 0/3 0/3 500 0/3 0/3 1000 0/3 0/3 7 days ALD ^ g => 1000 mg / kg TABLE C (continued)

Conn. Solution from or Dose, mg / kg, of Mortality excluding suspension total material 24 hours 7 days 57 Suspension 125 0/3 0/3 in 1¾ G.T. 250 0/3 0/3 500 0/3 0/3 1000 0/3 0/3 7 days ALD, g = 1000 mg / kg 58 Aqueous 125 0/3 0/3 solution 250 0/3 0/3 500 1/3 2/3 1000 1/3 1/3 7 days ALD, -g = 750 mg / kg 55 Suspension 125 0/3 0/3 in 18 GT 250 0/3 0/3 500 0/3 0/3 1000 1/3 1/3 7 days ALD ^ g = 1000 mg / kg 14 Suspension 125 0/3 0/3 in 1% G.T. 250 0/3 0/3 500 0/3 0/3 1000 0/3 0/3 7 days ALD ^ g = 1000 mg / kg 43A Suspension 125 0/3 0/3 in 18 G.T. 250 0/3 0/3 500 0/3 0/3 1000 0/3 0/3 7 days ALD ^ g = 1000 mg / kg 28C Suspension 125 0/3 0/3 in 18 G.T. 250 0/3 0/3 500 0/3 0/3 1000 0/3 0/3 7 days ALD ^ g = 1000 mg / kg 40C Suspension 125 0/3 0/3 in 18 G.T. 250 0/3 0/3 500 0/3 0/3 1000 0/3 0/3 7 days ALD ^ g = 1000 mg / kg ^ G.T. = Tragacanth rubber

Claims (2)

147839 1. Analogous process for the preparation of bis-pyridinium compounds of the general formulas: "Π2 + Γ ~ I * ~ RNH _ Y N \ ^ ^ —NHR A m n i or .-. t-1 2+ x- // \ J / \ JT \ R'NH U N-CH2 — V) —CH2-N \ Y_NHR 'V = / \ * = s \ = / a (e) v Jm L Jn wherein Y is a straight or branched alkylene group of 4-18 carbon atoms separating the two 4- (R-NH) -1-pyridinyl groups of at least 4 carbon atoms, R means an alkyl group of 3 or of 6-18 carbon atoms, a cycloalkyl group with 5-7 carbon atoms or an optionally halogen substituted benzyl or phenyl group, R 'means a straight or branched alkyl group having 1-18 carbon atoms, Q means methyl or chlorine, 147639 v is an integer from 0 to 4, A represents a pharmaceutically acceptable anion, m is 1 or 3, n is 1 or 2, x is 1, 2 or 3, and (m) (2) = (n) (x), characterized by two moles of a 4-aminopyridine compound of formula: RNH-C N 1 - / 111 huori R has the above meaning, is reacted with a mole of a disubstituted alkane of formula Z - Y - Z IV wherein Y has the above meaning and Z is chlorine, bromine, iodine, methanesulfonyloxy, ethanesulfonyloxy, benzenesulfonyloxy or p-toluenesulfonyloxy, or two moles of a 4-aminopyridine compound of the formula: R'NH- \ - / III 'wherein R' is as defined above, is reacted with one mole of an a, a ' -disubstituted xylene of the formula: