DK147638B - BIS-PYRIDINIUM COMPOUNDS FOR USE AS DISINFECTANT OR TO PREVENT DENTAL PLAQUE - Google Patents

Description

1A7638

The invention relates to novel bis-pyridinium compounds which are useful as disinfectants for removing germs of bacteria, fungi and Herpes virus and in some cases to prevent the formation of dental plaque. The compounds are characterized in that they are bis- (4-amino-1-pyridinium) alkanes having the formula I or the formula (I), or o, ck, '-bis- (4-amino-1-pyridinium) xylenes of claim 1 the formula II of the characterizing part of claim 1.

U.S. Patent No. 3,055,902 discloses a group of bis (4-amino-1-2 147638 pyridinium) alkanes as intermediates in the preparation of the corresponding bis-C4-amino-1-piperidino) alkanes which are reported to have bacteriostatic and bactericidal effects, ¥ .0. Austin et al., J. Pharm. Pharmacol. J, 80-93 (1959) disclose 1,10-bis (4-amino-1-pyridinium) decane diode and 1,10-bis (4-aeetamido-1-pyridinium) decane diode. It is stated that some species among the large diverse group of indicated quaternary ammonium compounds have amoebicidal, antibacterial, anti-filarial and trypanocidal activity, but no biological data is given for any of the above compounds.

As mentioned, the compounds of the invention are useful as disinfectants. Some of the compounds of formula I are also useful as agents for the prevention of dental plaque, for example: 1.6-bis- [4- (octylamino) -1-pyridinium] hexane dibromide and the corresponding dichloride 1.6-bis- [4- (nonylamino) -1-pyridinium] hexane dibromide and the corresponding dichloride 1.6-bis- [4- (decylamino) -1-pyridinium] hexane dibromide 1.6-bis- [4- (dodecylamino) -1-pyridinium] hexane dibromide 1.7-bis- [ 4- (heptylamino) -1-pyridinium] heptanedibromide 1.7-bis- [4- (octylamino) -1-pyridinium] heptanedibromide 1.7-bis- [4- (nonylamino) -1-pyridinium] heptanedibromide 1.7-bis- (decylamino) -1-pyridinium] heptane dibromide 1.7-bis- [4- (dodecylamino) -1-pyridinium] heptane dibromide 1.8-bis- [4- (heptylamino) -1-pyridinium] octane dibromide and the corresponding dichloride 1.8-bis- 4- (octylamino) -1-pyridinium] octane dichloride 1.8-bis- [4- (nonylamino) -1-pyridinium] octane dibromide 1.8-bis- [4- (decylamino) -1-pyridinium] octane dibromide 1.8-bis- (dodecylamino) -1-pyridinium] octane dibromide 1.8-bis [4- (2-ethylhexylamino) -1-pyridinium] octane dibromide 1.9-Bis- [4- (heptylamino) -1-pyridinium] nonanedichloride 1.9-bis- [4- (nonylamino) -1-pyridinium] nonanedibromide 3 1.9-bis- [4- (decylamino) -1-pyridinium] nonanedibromide 1 »9- [4- (dodecylamino) -1-pyridinium] nonandibromide 1.10-bis- [4- (heptylamino) -1-pyridinium] decanedibromide and the corresponding dichloride 1.10- Ms- [4- (nonylamino) -1-pyridinium ] decanedibromide 1.10-bis- [4- (decylamino) -1-pyridinium] decanedibromide 1.10-bis-C 4- (dodecylamino) -1-pyridinium] decanedibromide 1,10- bis- [4- (2-ethylhexylamino) -1- pyridinium] decane dichloride 1.12-bis- [4- (hexylamino) -1-pyridinium] dodecanedibromide and the corresponding dichloride 1.12-bis- [4- (heptylamino) -1-pyridinium] dodecanedibromide 1.12-bis- [4- (octylamino) - 1-pyridinium] dodecanedibromide 1.12-bis- [4- (nonylamino) -1-pyridinium] dodecanedibromide 1.12-bis- [4- (decylamino) -1-pyridinium] dodecanedibromide 1.12-bis- [4- (dodecylamino) -1- pyridinium] dodecane dibromide 1.12-bis- [4- (2-ethylhexylamino) -1-pyridinium] dodecane dibromide and the corresponding dichloride 1f14-bi s- [4- (hexylamino) -1-pyridinium] tetradecanedibromide and the corresponding dichloride 1.14- [4- (heptylamino) -1-pyridinium] tetradecanedibromide and the corresponding dichloride 1.14-bis- [4- (octylamino) -1-pyridinium ] tetradecan dibromide and as particularly preferred compounds: 1,9-bis- [4- (heptylamino) -1-pyridinium] nonandibromide 1,10-bis- [4- (2-ethylhexylamino) -1-pyridinium] decanedibromide 1,10-bis-C4- (octylamino) ) -1-pyridinium] decane dichloride and the corresponding dibromide 1,9-bis- [4- (octylamino) -1-pyridinium] nonandibromide 1.12-bis- [4- (heptylamino) -1-pyridinium] dodecane dichloride and 1.8- bis [4- (octylamino) -1-pyridinium] octandibromid.

4 147638

Thus, some of the compounds of the invention may be included in an oral hygiene agent for the prevention of dental plaque consisting of an effective amount of one of the above compounds and a compatible, pharmaceutically acceptable carrier.

The compounds may also be included in a skin cleanser consisting of an antibacterial, antifungal and virucidically effective amount of a compound of formula I or II, a compatible, pharmaceutically acceptable surfactant and a compatible, pharmaceutically acceptable carrier.

The compounds may further be included in an antibacterial, antifungal and virucidal agent suitable for application to non-living surfaces and consisting of an antibacterial, antifungal and virucidally effective amount of a compound of formula I or II in admixture with hence compatible medium.

In formula I of claim 1, the alkylene group Y is a bivalent saturated aliphatic hydrocarbon group containing 4-18, preferably 8-12, 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-1,8-ethylene, 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-dodecylene, 2- methyl 1,13-tridecylene, 4,9-dimethyl-1,12-dodecylene, 4-methyl-1,14-tetradecylene, 2,13-dimethyl-1,14-tetradecylene, 1,4 dipropyl-1,4-hutylene, 3- (3-pentyl) -1,5-pentylene, 2- (4,8-dimethylnonyl) -1,4-hutylene 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 by 18 carbon atoms, also arranged in a straight chain. In all other cases, Y may be either straight or branched.

When R in Formula I is a straight or branched alkyl group having 6-18 carbon atoms, preferably 7-9 carbon atoms, it may be, for example: 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-dimethylhutyl, 2-methylhexyl, 1.4 -dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, 2-methylheptyl, 1-ethylhexyl, 2-ethylhexyl, 2-propylpentyl, 2-methyl-3-ethylpentyl, 3-ethylheptyl, 1,3,5-trimethylhexyl, 1.5 -dimethyl-4-ethylhexyl, 2-propylheptyl, 5-methyl-2-hutylhexyl, 2-propylnonyl, 2-hutyloctyl, 1,1-dimethylundecyl, 2-pentylnonyl, 1,2-dimethyltetradecyl and 1,1-dimethylpentadecyl .

For example, when R in formula I is a cycloalkyl group of 5-7 carbon atoms, it may be cyclopentyl, cyelohexyl and cycloheptyl.

When R in formula I is phenyl substituted with halogen, it may be, for example: p-chlorophenyl, o-chlorophenyl, m-chlorophenyl, p-homophenyl, m-fluorophenyl, p-iodophenyl, 2,4-dichlorophenyl, 2.4 -difluorophenyl, 2,5-dibromophenyl, 3,5-dichlorophenyl and 3-chloro-4-fluorophenyl.

R '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-hutyl , n-pentyl, isopropyl, 1-methylpropyl, isobutyl, tert-butyl, isopentyl, neopentyl and 1-methylpentyl.

R can also be benzyl. If desired, the phenyl moiety 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 in formulas I and II may be an anion of both inorganic and organic acids, e.g., hromide, chloride, fluoride, iodide, sulfate, phosphate, nitrate, sulfamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-touenesulfonate, naphthalene sulfonate, naphthalene disulfonate, cyclohexyl sulfamate, acetate, trifluoroacetate, malate, fumarate, succinate, tartrate, oxalate, citrate, lactate, gluconate, ascorbate, lactate, phthalate, salicylate, benzoate, benzoate, picrate, methane, picrate tartronate, sarcosinate, N-lauroylsarcosinate, monofluorophosphate, hexafluoroaluminate, hexafluorosilicate, hexafluorostannate, fluorozirconate, tetrafluoroborate, hexachloroplatinate, tetrachloroaluminate and hexachloro Bromide and chloride are preferred.

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

The compounds of the invention are conveniently prepared by reacting 2 moles of a 4-aminopyridine compound of the formula

RNH - V N or R'NH - ('N

Wherein R and R1 are as defined in claim 1, with 1 mole of a suitably disubstituted alkane or xylene of formula 7 respectively.

Z-Y-Z or Z-CH2-V n CH2 ~ Z

(Q) v

IV V

wherein Y, Q and V are as defined in claim 1 and Z is chlorine, bromine, iodine, methanesulfonyloxy, ethanesulfonyloxy, benzenesulfonyloxy or p-toluenesulfonyloxy, in an inert solvent such as a lower alkanol, acetonitrile, Ν, Ν -dimethylformamide, Ν, Ν-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 Ν, Ν-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 Ms 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 nonpolar solvent such as ethylene, 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 into 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 association with a countercation which unites with the anion of the pyridium compound to form an insoluble precipitate. The latter is separated leaving a solution of the pyridinium compound containing the desired anion. 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 or inorganic anion.

The above type of metathetic reaction can 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 suitably 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.

Thus, if the anion moiety of a given compound provides such properties as solubility, stability, molecular weight, physical appearance, toxicity or the like, which render this form of the compound unsuitable for a desired purpose, it can easily be converted into another, more suitable form. Of course, for use on the skin or other tissues or in the oral cavity, pharmaceutically acceptable anions such as fluoride, chloride, bromide, iodide and methanesulfonate are used.

The 4-aminopyridine compounds (Formula III or III1) 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 ° for from about 1.5 to about 5 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, below

ISLAND

a hydrogen pressure of 1.4 - 4.2 kp / 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 earbon atoms with 4-aminopyridine in the presence of formic acid at elevated temperature also gives the desired 4-aminopyridine compounds.

two 4-aminopyridine compounds can also be prepared by acylation of 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 ehloroform, in the presence of an acid inhibitor 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.

The α, α'-disubstituted columns 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, an appropriate chlorine or methyl substituted phthalic, isophthalic or terephthalic acid or ester thereof is reduced to the corresponding xylene-α, α'-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, α'-dihalogenxylene, 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-toluenesulfonyl 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. Therefore, the compounds are thought to be used as antimicrobial or antiseptic agents that can be applied topically to remove microorganisms from human skin and other tissues and to clean and disinfect non-living surfaces. Thus, the compounds can be used in topical antiseptic solutions, in antibacterial cleaners, such as surgeons 'disinfectants, pre-surgery disinfecting patients' skin, soaps and shampoos, or in household and industrial cleaners, disinfectants and protective coatings, such as paints, paints, and paints. wax. The compounds are adapted to the above applications by combining with conventional diluents or carriers, compatible cationic, anionic or non-anionic surfactants, buffering agents, perfumes and colorants, and applied to a surface to be disinfected by conventional methods such as scrubbing, spraying, drying or dipping.

For use as skin cleansers, the bis-pyridinium compounds may be prepared as liquids, or the liquid compositions may, if desired, be thickened with certain additives to a gel or paste or cast into a bar according to well known methods. For example, the compounds may be formulated with any compatible pharmaceutically acceptable surfactant, preferably a nonionic surfactant such as dipolyoxyethylene-polyoxypropylene copolymers disclosed in U.S. Pat.

No. 3,855,140, amine oxides, such as stearyl dimethylamine oxide, disclosed in U.S. Patent No. 3,296,145 and the like or with mixtures thereof. The compositions may contain, in addition to pharmaceutically acceptable diluents such as water, lower alkanols and the like, acids, bases or buffers to maintain a pH of 5.0 - 7.5, and optionally perfumes and colorants. The bis-pyridinium compounds are generally present in such compositions at a concentration of from about 0.5 to about 2.0% by weight, preferably about 1.0% by weight.

When the skin cleansers are prepared as a tincture, the bis-pyridium compounds can be compounded with water, a lower alkanone, e.g. acetone, and a lower alkanol such as ethanol. If desired, the tincture can be colored with a coloring agent. The active ingredient is suitably present at a concentration of from about 0.05 to about 1.0 percent (w / v), preferably 0.1 percent (w / v).

Alternatively, the compounds may be formulated in suitable cosmetic media to remove germs of bacteria, fungal and Herpes viruses, e.g. as lotions, ointments or creams, by incorporation into conventional lotion, ointment or cream bases such as alkyl polyether alcohols, ethyl 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 at incorporation into conventional gel gases such as glycerol and tragacanth. They can also be formulated for use as aerosol sprays or foams.

If used for cleaning and disinfecting non-living surfaces, the compounds can be formulated with known detergents and additives such as trisodium phosphate, borax and the like. The bis-pyridinium compounds are generally present in such compositions at a concentration of up to about 10% by weight.

As described in detail below, some of the compounds of formula I are effective in preventing the formation of dental plaques. For such use, the compounds may conveniently be applied to the teeth in the form of a mouthwash or dental cleanser. The compounds can be formulated with conventional ingredients used in mouthwashes or dental cleansers, e.g. water, alcohol, glycerol, buffering agents, thickeners, flavoring and coloring agents. These compositions may also optionally contain other known ingredients, especially those which are effective in reducing tooth coloring ability, such as the anti-tartar agents disclosed in MS Patent No. 3,934,002 issued January 20, 1976, e.g. zinc phenol sulfonate, 8-hydroxy-guinoline, disodium ethane-1-hydroxy-1,1-diphosphonate, and the amino-carboxylate compounds disclosed in U.S. Pat.

3,937,807, issued February 10, 1976, e.g. nitrilotriacetic acid, 2-hydroxyethylnitrilodiacetic acid or water-soluble salts thereof. The bis [4- (R-amino) -1-pyridinium] alkane is usually present in such compositions at a concentration of from about 0.005 to about 0.05% by weight, preferably about 0.01% by weight.

Of course, it will be appreciated that the media, diluents, carriers and additives contained in the compositions described above must be compatible with the active ingredients, ie. the antibacterial, antifungal and virucidal efficacy of the bis-pyridinium compounds must not be abrogated by effects attributable to the nature of the medium, diluent, carrier or other additive used.

The molecular structure of the compounds 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-bromopyridine 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 percent aqueous sodium hydroxide solution, and the product extracted with chloroform. The chloroform extracts were dried over 147638

Toothless sodium sulfate and evaporated to dryness under reduced pressure. to 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 .: 49 -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 55 percent aqueous sodium hydroxide solution and extracted successively with ether and chloroform. The organic extracts were combined and evaporated to dryness under reduced pressure. residual viscous oil was dissolved in ether and the ether solution washed with water. to 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 residual oil to -78 ° C resulted in partial solidification, the hot semi-solid was diluted with a small amount of ether and filtered, the resulting solid 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. hot resulting semi-solid was diluted with a small amount of ether and cooled, the thus-formed solid was collected by filtration and washed with a small volume of cold ether, whereby, after drying, 84.6 g of 4- (heptylamino) py were obtained. -ridine, 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.

h. 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 for 20 hours under reflux. 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 of 1,14-bis- [4- [(heptylamino) -1-pyr] -dinium] tetradecane dibromide, mp: 88-90 ° C.

EXAMPLE 2

A solution containing 5.0 g of 1,14-his- [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 eluate 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 g of 1,14-his- [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 under 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 h under vacuum at 60 ° C to give 21.1 g of 1,12-bis- [4- (heptylamino) -1-pyrene -dinium] dodecane dibromide, mp: 101-103 ° C.

EXAMPLE 4 A. A solution containing 6.6 g of 1,3-bis-1H-iheptylaminoj-1-pyridinium iododecane dibromide in 25 ml of methanol was added to the top of a column of 7.6 cm diameter packed with 1 per liter of chloride anion synthetic anion resin (marketed by Rohm and Haas under the name "Amberlite®IRA 400") in methanol and slowly eluted with 100 ml portions of methanol until 700 ml eluate was collected. One combined eluate was evaporated to dryness. dryness under reduced pressure at below 25 ° C. One remaining gum was repeatedly rubbed off with a 6: 1 mixture of ether and acetonitrile and dried in vacuo to give 5.0 g of 1,12-bis- [4- (heptylamino) -1-pyridinium] dodecane dichloride mp: 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. One precipitated product was collected by filtration, washed with cold acetonitrile and ether, and the hygroscopic product immediately dried under vacuum to give 112 g of 1,12-bis- [4- (heptylamino) -1-pyridinium] dodecane dichloride mp: 112-115 ° C.

EXAMPLE 5 A. A mixture containing 100.0 g (0.51 mol) of 4-bromopyridine hydrochloride and 110 g (0.8 mol) of n-hexylamine hydrochloride was heated in an oil bath. Once the bath temperature reached 175-180 ° C, the reaction mixture began to melt and stirring was started.

147638 17

The temperature of the bath was then raised to 227 ° 0 and stirring 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 ° 0. 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 pot. 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 coal and filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was triturated with cold ether to give 71.0 g of 4-flux: xylamino) pyridine, mp: 68-70 ° C.

To a stirred hot solution containing 10.7 g (0.06 mol): 4- (hexylamino) pyridine in 50 ml acetonitrile was added dropwise a solution containing 10.7 g (0.05 mol) 1.14 -dibromo-tetradecane in 250 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 cetonitrile. The product was collected by filtration and dried for 48 hours at 70 ° C / 0.1 mmHg to give 13.4 g of 1,14-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 g of 1,14-bis- [4- (hexylamino) -1-pyridinium] tetradecane dibromide, 4 »33 g of the corresponding dichloride was obtained, m.p. .: 94-95 °.

EXAMPLE 7

By a procedure similar to that described in Example 50, but using 10.7 g (0.06 mole) of 4- (hexylamino) pyridine and 9.85 g (0.03 mole) of 1,12-dibromo dodecane 17.6 g of 1,12-bis- [4- (hexylamino) -1-pyridinium] dodecane dibromide, 122-124 ° C were obtained.

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 by 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 (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- (ethylamino) pyridine, mp: 62-63 ° C.

B. Alternatively, 4- (ethylamino) 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 per cent. palladium-on-coal hydrogenation catalyst and sufficient absolute ethanol to give a total volume of 1.2 liters were hydrogenated for 4.5 hours at 70-90 ° C under a hydrogen initial pressure of 3.15 kg / cm 2. 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 ° 0th

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. 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 of 1,10-bis- [4- (octylamino) ) - 1-pyridinium] decane dibromide, mp: 165-164 ° C.

EXAMPLE 10 A. According to a procedure similar to that described in Example 2, but using 5.0 g of 1,10-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- (ethylamino) 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 N, Μ-dimethylformamide was rapidly added and the resulting mixture 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 ° O to give 75 g of 1,10-bis- [4- (octylamino) -1-pyridinium] decane dichloride. mp: 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 7.54 g (0.027 mol) of 1,8-dibromooctane and heating the reaction mixture for 6 hours at reflux, 15.6 g of 1,8-bis [4- (octylamino) -1-pyridinium] octane dibromide were obtained, mp: 174-175 °.

EXAMPLE 12 147638

According to a procedure similar to that described in Example 2, but using 5.0 g of 1,8-bis- [4- (octylamino) -1-pyridinium] -octane dibromide, 4 was obtained. 50 g of the corresponding dichloride, m.p .: 210-211 ° C.

EXAMPLE 15

According to a procedure similar to that described in Example 90, but using 11.1 g (0.054 mol) of 4- (octylamino) pyridine and 6.6 g (0.027 mol) of 1,6-dibromohexane and heating the reaction mixture for 9 hours at reflux, 15.1 g of 1,6-bis- [4- (octylamino) -1-pyridinium] hexane dibromide were obtained, mp 136-138 °.

EXAMPLE 14

According to a procedure similar to that described in Example 2, but using 5.0 g of 1,6-bis [4- (octylamino) -1-pyridinium] hexane dibromide, 4.23 g of the corresponding dichloride, mp: 189-191 ° 0.

EXAMPLE 15

According to a procedure similar to that described in Example 9C, but using 14.24 g (0.08 mole) of 4- (hexylamino) pyridine and 8.64 g (0.04 mole) of 1,4-dibromobutane , after tearing off the crude product with a mixture of acetonitrile and acetone, was dissolved. reached 20.45 g of 1,4-bis- [4- (bexylamino) -1-pyridinium] butane dibromide, mp: 199-201 ° 0.

EXAMPLE 16

According to a procedure similar to that described in Example 9C, but using 10.7 g (0.06 mole) of 4- (bexylamino) pyridine 22 and 14.72 g (0.03 mole) 1.6 -dibromohexane, "after tearing off the crude product with a" mixture of ether, acetonitrile and acetone, obtained 14.90 g of 1,6-bis- [4- (kexylamino) -1-pyridinium] hexane dibromide, m.p. : 178-179 ° C.

EXAMPLE 17

According to a procedure similar to that described in Example 90, but using 10.7 g (0.06 mol) of 4- (bexylamino) pyridine and 7.75 g (0.03 mol) of 1,7-dibromoheptane , after tearing off the crude product with a mixture of acetonitrile and acetone, 16.4 g of 1,7-bis- [4- (b.sylamino) -1-pyridinium] heptane dibromide were obtained, mp: 157-158 ° C.

EXAMPLE 18

According to a procedure similar to that described in Example 90, but using 10.7 g (0.06 mole) of 4- (hexylamino) pyridine and 8.6 g (0.03 mole) of 1,9-dibromnonane , 17> 15 g of 1,9-bis- [4- (b.sylamino) -1-pyridinium] nonane dibromide were obtained, mp: 114-115 °.

EXAMPLE 19

According to a procedure similar to that described in Example 90, but using 15.4 g (0.08 mole) of 4- (heptylamino) pyridine and 8.64 g (0.04 mole) of 1,4-dibromobutane , 23.1 g of 1,4-bis- [4- (leptylamino) -1-pyridinium] butane dibromide were obtained, mp: 229 - 230 ° C.

Example 20

According to a procedure similar to that described in Example 90, but using 10.0 g (0.052 mol) of 4- (beptylamino) pyridine and 6.7 g (0.026 mol) of 1,7-dibromoheptane, 14.05 g of 1,7-bis- [4- (heptylamino) -1-pyridinium] heptane dibromide were obtained, mp 142-143 ° C.

EXAMPLE 21

Follow a procedure similar to that described in Example 90, but using 11.6 g (0.06 mole) of 4- (beptylamino) pyridine and 8.2 g (0.03 mole) of 1 , 8-dibromooctane, after recrystallization from acetonitrile / ether, 18.6 g of 1,8-bis- [4 “(heptylamino) -1-pyridinium] octane dibromide were obtained, mp: 161-162 ° C.

EXAMPLE 22

According to a procedure similar to that described in Example 2, but using 5.0 g (0.0076 mole) of 1,8-bis- [4- (lyptylamino) -1-pyridinium] octane dibromide , 4.1 g of the corresponding diciiloride was obtained, mp: 206 - 208 ° C.

EXAMPLE 23

According to a procedure similar to that described in Example 90, but using 15.4 g (0.08 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: 115-111 ° G.

EXAMPLE 24

According to a procedure similar to that described in Example 2, but using 5.0 g (0.0075 mol) of 1,9-bis- [4- (heptylamino) -1-pyridinium] nonane dibromide , 4.2 g of the corresponding dichloride were obtained, mp: 154-155 ° C.

EXAMPLE 25 24 Ϊ47638

According to a procedure similar to that described in Example 90 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

Follow 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 , 4.35 g of the corresponding dichloride was obtained, 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 run off and the resin was washed with a solution containing 15 ml of 48 per cent. aqueous hydrogen fluoric acid in 185 ml of distilled water. The resin was then washed with distilled water until the eluate was slightly acidic, and then successively by 20%, 40%. and 50 per cent. 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- (heptyl) -amino) -1-pyridinium jdecan dibromide in 1 ml of methanol. Eem fractions of each 15 ml were collected. Le first three fractions were combined and evaporated to dryness under reduced pressure. Len oily residue was dissolved in a mixture of toluene and ethanol and the resulting solution evaporated to dryness under reduced pressure. The residual oil was dissolved again 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 gurent 1,10-bis- [4- (heptylamino) -1-pyridinium] dehydrogenase. 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 ° 0 (internal temperature 190-194 ° 0) 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 by 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 coal, 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- (non-nylamino) pyridine, m.p. 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 mol) of 4-aminopyridine, 175 g (1.24 mol) of nonylaldehyde, 5.0 g 10% palladium-on-carbon hydrogenation catalyst and sufficient absolute ethanol to give a total volume of 600 ml was heated and hydrogenated under a heterogeneous initial pressure of 3.15 kp / cm until the absorption of hydrogen ceased. to remove the catalyst and the filtrate was evaporated to dryness under reduced pressure Bone residual oil was then vacuum distilled to remove any amount of nonyl alcohol which had been formed A fraction boiling at 63-64 ° C / 4.5 mmHg The residue was triturated with ether and cooled to -78 ° 0. Bet precipitated solid was collected by filtration and washed with cold ether. Better 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 ° 0. Bet thus obtained solid was collected by filtration, washed with cold ether and air dried to give 27.0 g of 4- (non-nylamino) pyridine, mp: 57-59 ° C.

0. 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 mol) of 1,8-dibromooctane in 50 ml of acetonitrile and the resulting mixture was heated at reflux for 19 hours during which time 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 gave a colorless crystalline solid which was collected by filtration and dried to give 15.5 g of 1,8-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-dibromodecane, 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- 12.3 g of 1,5-bis- [4- (hexylamino) -1-pyridinium] pentane dibromide, m.p .: 155-155 ° 0 was obtained after recrystallization from acetonitrile / acetone.

EXAMPLE 31

According to a procedure similar to that described in Example 28C, but using 10.7 g (0.06 mole) of 4- (hexylamino) pyridine and 8.2 g (0.03 mole) of 1.8- dibromooctane, 16.3 g of 1,8-bis [4- (bexylamino) -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-besylamino] -1-pyridinium] decane dibromide were obtained, mp: 148-149 ° C.

EXAMPLE 33

According to a procedure similar to that described in Example 28, but using 13.4 g (0.076 mole) of 4- (cyclohexylamino) pyridine and 8.2 g (0.038 mole) of 1,4-dibroinbutane , 18.2 g of 1,4-bis- [4 * (cyclohexylamino) -1-pyridinium] butane dibromide were obtained, 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-yl bromentane, to obtain 19.0 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- (cyclohexyl-amino) pyridine and 9.3 g (0.038 mole) of 1,6-dibromoh In hexane, 19.1 g of 1,6-bis [4- (cyclohexylamino) -1-pyridinium] hexane dibromide were obtained, mp: 307-308 ° 0.

EXAMPLE 36

According to a procedure similar to that described in Example 28C, but using 13.4 g (0.076 mole) of 4- (cyclohexylamino) pyridine and 9.8 g (0.038 mole) of 1,7-dibromoheptane, having obtained 2.01 g of 1.7 "bis- [4" (cyclobexylamino) -1-pyridinium] heptane dibromide, mp: 311-313 ° C.

EXAMPLE 37

Following a procedure similar to that described in Example 28c, but using 13.4 g (0.076 mol) of 4- (cyclohexylamino) pyridine and 10.34 g (0.038 mol) of 1,8-dibromooctane, to obtain 19.1 g of 1,8-bis- [4- (cyclohexylamino) -1-pyridinium] octane dibromide, mp 270-271 ° 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, to obtain 16.3 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-dibromo-dean, to obtain 19.0 g of 1,10-bis- [4- (cyclohexylamino) -1-pyridinium] decane dibromide, mp: 226-227 ° C.

Example 40 1. 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 215 ° C. The mixture was cooled to 60 ° 0, diluted with 500 ml of water and kept cold by the addition of ice while alkaline with 35 per cent. 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 a period of 3 hours. of 1610 g (10.0 mol) of 2-ethylhexanoyl chloride 30 1 47 6 3 8 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-ethylhexanamide.

To a mixture of 100 g (2.63 mol) 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 mol) of N- (4-pyridyl) -2-ethylhexanamide 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 pet. aqueous sodium hydroxide solution and 300 ml of water,. One solid was removed by filtration and the solvent evaporated from the filtrate under reduced pressure. A residual 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 ° / 0.2 mmHg.

C. To a warm 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. One combined amount was dissolved in methanol, the resulting solution was treated with decolorizing coal, filtered and the filtrate evaporated to dryness under reduced pressure. One remaining oil was cooled and etherized to give a slightly discolored solid. Recrystallization from acetonitrile / ether, followed by rinsing the product with ether followed by acetonitrile, after drying for 72 hours under vacuum at 60 ° C gave 14.7 g of 1,12-bis- [4- (2-ethylhexylamino) -1- pyridinium] dodecane dibromide as colorless granules, mp: 146-147 ° 0.

EXAMPLE 41 Å. 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 dropped to 135 ° C, 1 liter of acetonitrile was gently added and the mixture 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 that described in Example 2, but using 3.0 g (0.00405 mol) of 1,12-bis- [4- (2-ethylhexylamino) -1- pyridinium] -dodecane di-bromide 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-dibromoheptane, 14.85 g of 1,7-bis- [4- (octylamino) -1-pyridinium] heptane dibromide, mp: 129-141 ° 0.

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- 17.0 g of 1,9-bis- [4- (octylamino) -1-pyridinium] nonane dibromide, 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 40C, 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- (octylamino) -1-pyridinium] dodececan di-hydride, mp: 119-120 ° C, were obtained.

EXAMPLE · 45

According to a procedure similar to that described "in Example 40c, but using 5> 8 g (0.028 mole) of 4- (octylamino) pyridine and 5.0 g (0.014 mole) of 1,14-dibromo-tetradecane," 9.3 g of 1,14-Ms- [4- (octylamino) -1-pyridinium] tetradecane di-bromide were obtained, mp: 113-115 ° 0.

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-dibromohexane 15.2 g of 1,6-Ms- [4- (nonylamino) -1-pyridinium] hexane di-bromide 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 , 4.95 g of the corresponding dichloride was obtained, 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- dibromoheptane, 12.2 g of 1,7-bis- [4- (nonylamino) -1-pyridinium] leptane dibromide were obtained, mp: 132-134 ° C.

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-dibromnonane, 15.7 g of 1,9-bis- [4- (nonylamino) -1-pyridinium nonanone 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-dibromodecane, 15.63 g of 1,10-bis- [4- (nonylamino) -1-pyridinium] decane dibromide were obtained, mp: 172-173 ° 0.

EXAMPLE 51

According to a procedure similar to that described in Example 40C, but using 10.12 g (0.046 mol) of 4-nonylamino) pyridine and 7 »54 g (0.023 mol) of 1,12-dibromo-dodecane was obtained. 16.4 g of 1,12-bis- [4- (nonylamino) -1-pyridinium] dodecane dibromide, mp: 105-106 ° C.

Example 52 µl a stirred hot solution of 12.4 g (0.06 mole) of 4- (2-ethylhexylamino (pyridine in 100 ml of acetonitrile) was added dropwise to a solution of 6.9 g (0.03 mole) 1,5-dibrompentane in 25 ml aeetonitrile and the resulting solution "was heated at reflux for 20 hours. The reaction mixture was cooled and diluted with ethylene until slightly cloudy. Further cooling and stirring gave a solid precipitate which was collected by stirring. filtration and washed with a cold mixture of aetonitrile 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 1,5-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 mol) of 4- (2-ethylhexylamino) pyridine and 7.32 g (0.03 mol) 1 , 6-dibromohexane, 16.1 g of 1,6-bis- [4- (2-ethylhexylamino) -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 mol) of 4- (2-ethylhexylamino) pyridine and 7.75 g (0.03 mol) 1 , 7-dibromoheptane, 17.9 g of 1,7-bis- [4- (2-ethylhexylamino) -1-pyridinium] heptane dibromide were obtained, mp: 219-220 ° 0.

EXAMPLE · 55

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-dibromooctane, 15.9 g of 1,8-bis- [4- (2-ethylhymylamino) -1-pyridinium] octane 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 mol) of 4- (2-ethylhexylamino) pyridine and 8.6 g (0.03 mol) 1,9-dibromnonone, 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) 1,10-dibromnonane, 17.4 g of 1,10- "bis- [4- (2-ethylhexylamino) -1-pyridinium] decane dibromide, mp: 162-163 ° C was obtained.

EXAMPLE 58

According to a procedure similar to that described "in Example 2, but using 5.0 g of 1,10-bis- [4- (2-ethylxyxylamino) -1-pyridinium] decane-di" bromide, " to obtain 4.11 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- (iieptylamino) pyridine in 100 ml of acetonitrile, a solution of 7.4 g (0.032 mole) was added dropwise. -dibrompentane in 25 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. 147638 stallion from acetonitrile / ether and dried for 48 hours at 90 ° C / 1 mmHg to give 15.9 g of 1,5-bis- [4- (heptylamino) -1-pyridinium] pentane dibromide, m.p. : 153-154 ° G.

EXAMPLE 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-dibromohexane , 27.5 g of crude product was obtained. Recrystallization of a 15 gram sample from acetonitrile / ether yielded 11.45 g of 1, 1-bis-β-iheptylamino-1-pyridinium 1-hexane dibromide, mp: 149-150 ° 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 3N 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, gave 18.2 g of gummy solid. Light crude material was dissolved in water and the resulting solution made alkaline by 35 per cent. aqueous sodium hydroxide solution and extracted with chloroform. The chloroform extracts were dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. Lightly 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. Easily obtained solids were 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. Len resulting 374 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. 165 ° C. This product gave a positive chloride ion test with silver nitrate and its NMR spectrum showed the absence of the methanesulfonate 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 pot. 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 ° / 1 mmHg to give 8.85 g of light brown solid, mp: 174-176 ° C. This product also gave a positive silver nitrate chloride ion test.

C. The products of Å 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 12N 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, after drying, for 48 hours at 105 ° C / 1 mmFFg and for 72 hours at 115 ° C / 1 mmWg 16 3 g of crude 1,6-bis- [4- (heptylamino) -1-pyridinium] hexane 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 mole) of 4- (2-ethylhexylamino) pyridine and 5.4 g (0.025 mole) of 1,4-dibromobutane 14.9 g of 1,4-his- [4- (2-ethylhexylamino) -1-pyridinium] butane dibromide, mp: 245-246 ° C, were obtained.

Example 63 A. A mixture of 229 g (1.0 mole) of N- (4-pyridyl) pyridinium hydrochloride and 244 g (1.26 mole) of n-decylamino hydrochloride was stirred and heated for about 2.5 hours. hours at 190-195 ° C. The reaction mixture was then allowed to cool slowly to 40 ° C and diluted with 2 liters of water. Len resulting solution. was cooled by the addition of ice and made alkaline with 200 ml of 35 $ aqueous sodium hydroxide solution. Light dark solids which precipitated were collected by filtration and washed with cold water. Light material was dissolved in 1 liter of chloroform and the resulting solution was treated with decolorizing coal and filtered. The filtrate was evaporated under reduced pressure and the residue was triturated with 150 ml of ether. Easily obtained solids were again dissolved 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- (acylamino) pyridine, mp: 71-73 ° 0.

B. To a stirred hot solution of 12.2 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-dibromohexane 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 / 0.1 mmHg to give 14.6 g of 1 , 6- [4- (decylamino) -1-pyridinium] hexane-dibromide, mp: 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, obtained 16.0 g of 1,7-bis- [4- (decylamino) -1-pyridinium] heptane dibromide, mp 145-147 ° C.

EXAMPLE · -65

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, 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, obtained 15.1 g of 1,9-bis- [4- (decylamino) -1-pyridinium] nonane 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 mol) of 4- (decylamino) pyridine and 7.2 g (0.024 mol) of 1,10-dibromodecane, 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 mol) of 4- (decylamino) pyridine and 7.9 g (0.024 mol) of 1,12-dibromo-dodecane, obtained 16.5 g of 1,12-bis- [4- (decylamino) -1-pyridinium] dodecane dibromide, mp: 102-106 ° C.

EXAMPLE 69

To a stirred hot solution of 13.6 g (0.052 mol) of 4- (oodecylamino) 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 afford as a residue a white solid which was slurried in ether, collected by filtration and dried at 60 ° / 0.1 mmHg to give 17.63 g of 1.6 g. 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-dibromoheptane), obtained 18.03 g of 1,7-bis- [4- (dodecylamino) -1-pyridinium] heptane dibromide, mp: 148-150 ° C.

41 147638 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, 16.18 g of 1,8-bis- [4- (dodecylamino) -1-pyridinium] octane dibromide, mp; 184-185 ° C.

EXAMPLE · 72

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, obtained 19.35 g of 1,9-bis- [4- (dodecylamino) -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-dibromo-decane, 18 was obtained. 08 g of 1.10-bis- [4- (dodecylamino) -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-dibr oindo de can, 17.68 g of 1,12-bis- [4- (dodecylamino) -1-pyridinium] dodecane dibromide were obtained, mp: 75-77 ° C.

EXAMPLE 75 A. To a stirred hot solution of 21.0 g (0.102 mol) of 4- (p-42-chlorophenylamino) pyridine in 150 ml of Ν, Ν-dimethylformamide was added dropwise a solution of 11.02 g (0.051 mol) 1,4-dibromobutane in 50 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 g. bis- [4- (p-chlorophenylamino) -1-pyridinium] butane dibromide, mp: 182-189 ° C.

B. A suspension of the above product in 500 ml of water was treated with ice and 2N 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 gay an oil which was crystallized from methanol / ether. The solid thus obtained was recrystallized from methanol / ether to give, after drying for 48 hours at 92 ° C / 0.1 mmHg, 18.95 g of 1} 4_ [4_ (p-chlorophenylamino) -1-pyridinium] butane -dimethanesulfonate, mp: 245-247 ° 0.

EXAMPLE · 76 Å. To a stirred hot solution of 21.0 g (0.102 mol) of 4- (p-chloro-phenylamino) pyridine in 200 ml of Ν, Ν-dimethylformamide was added dropwise a solution of 12.45 g (0.051 mol) of 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 * - (p-chlorophenylamino) -1-pyridinium] hexane dibromide, m.p. 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 after drying for 48 hours at 75 ° C / 0.1 mmHg, 25.2 g of 1,6-bis- [4- (p-chlorophenylamino) -1-pyridinium] hexane dimethanesulfonate were obtained, mp: 108-110 ° C.

Example 77 A. To a stirred hot solution of 21.0 g (0.102 mole) of 4- (p-chloro-phenylamino) pyridine in 200 ml of Ν, Ν-dimethylformamide was added dropwise a solution of 13.9 g (0.051 mole) 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 50.1 g of 1,8-bis- [4- (p chlorophenylamino) -1-pyridinium joctane 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 75.B 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- ( p-chlorophenylamino) -1-pyridinium ioethane dimethanesulfonate, mp: 164-165 ° C.

Example 78 A. To a stirred hot solution of 21.0 g (0.102 mole) of 4- (p-chloro-phenylamino) pyridine in 200 ml of Ν, Ν-dimethylformamide was added dropwise a solution of 15.3 g (0.051 mole) 1 , 10-dibromo-decane in 50 ml of acetonitrile, and the resulting mixture was heated 5.5 hours on a steam bath. The reaction mixture was then evaporated to dryness under reduced pressure and the residual 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 g of 1,10-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 ° / 0.1 mmHg, 18.4 g of 1,10-bis- [4- (p-chlorophenylamino) -1-pyridinium] decane, dimethanesulfonate, m.p. 202-204 ° C.

this 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 Ν, Ν-dimethylformamide was added dropwise a solution of 5.75 g (0.025 mole) 1,5-dibrompentane in 25 ml of acetonitrile and the resulting mixture was heated at reflux for 24 hours.

45 147638

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 resulting 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-ehlorophenylamino) -1- pyridinium] pentane dibromide, mp: 166-168 ° C.

EXAMPLE · 80 µl of a stirred hot solution of 10.0 g (0.049 mol) of 4- (p-chlorophenylamino) pyridine in a mixture of 125 ml of Ν, Ν-dimethylformamide and 50 ml of acetonitrile was added dropwise to a solution of 6.45 g of 1,7-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 resulting solution 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 105 ° C / 0.1 mmHg to give 10.4 g of 1,7-bis- [4- (p-chlorophenylamino) -1-pyridinium] heptane dibromide mp: 202-204 ° C.

EXAMPLE 81

To a stirred hot solution of 10.0 g (0.049 mol) of 4- (p-chlorophenylamino) pyridine in a mixture of 125 ml of Ν, Ν-dimethylformamide and 50 ml of acetonitrile was added dropwise a solution of 7.15 g (0.025 mole) of 1,9-dibromnonane 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 resulting 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-1,4- (p-chlorophenylamino) -1-pyridinium} nonandibromide, 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 α, α'- dibromo-p-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, O, α, -bis- [4 4 (heptylamino) pyridinium] -β-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 mol) of 4- (hexylamino) pyridine and 8.7 g (0.035 mol) of α, α'-dibromo-β -xylene and refluxing the reaction mixture for 20 hours yielded 19.3 g, a, -bis- [4- (hexylamino) pyridinium] -p-xylene dibromide, mp: 313-315 ° 0.

An 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 _16 (9), 1414-144 (1968). ) to prepare a 1,000 µg / ml solution of the test compound. To the first cup of the autotiter tray, add 0.1 ml of the sample solution. Activation of the autotiter starts a sequence of operations whereby 0.05 ml of the test compound solution is withdrawn from the cup of a Microtiter transfer eye 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 500 to 0.06 µg / ml in double dilutions. The tray is incubated for 18-20 hours at 37 ° C, then 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. Thus, the compounds were tested as solutions to a variety of Gram-positive and Gram-negative bacteria, including Staphylococcus aureus, Proteus mirabilis, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa and Streptococcus pyogenes, and to such fungi as Aspergillus niger, Candida albiger menta-grophytes.

Many of the compounds of formula I were also found to be anti-bacterially 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. Herrmann, Jr., Proc. Soc. Exp. Biol. With.

1071 142 (1961), whereby 2 mg of the test compound was applied to the surface of the growth medium. The compounds of Example 3 »5C, 7, 9C, 10, 11, 13, 16, 17, 20, 21, 23, 30, 32, 34, 35, 36, 52, 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.

48 147638

The tooth plaque-preventing activity of some of the compounds prepared by the process of the invention was determined by measuring the ability of these compounds to inhibit the plaque production of Streptococcus mutans OMZ-61 as follows:

A culture medium for the plaque-producing Streptococcus mutans OMZ-61 containing 1.5 g BBL meat extract, 5 g sodium chloride, 10 g dehydrated trypticase, 5 g sucrose and sufficient distilled water to give a total volume of 1000 ml is adjusted to pH 7.0 and sterilized by membrane filtration. The medium is dispensed aseptically in 10 ml aliquots in 150 x 16 mm test tubes and stored at refrigerator temperature until use.

Two concentrations of the test compound are prepared by dissolving 100 mg of the compound in 1 ml of distilled water using sufficient 0.1 N sodium hydroxide, 10 per cent. dimethyl sulfoxide or 10 per cent. Ν, Ν-dimethylformamide and dilute the resulting solution to 10 ml with distilled water. This 1.0 per cent. solution and 1:10 dilution in distilled water (0.1 per cent) are sterilized by membrane filtration before use.

A sterile piece of plaque-free natural tooth enamel or synthetic hydroxylapatite is suspended in each concentration of the compound for two 1-minute periods, each followed by a 1-minute air drying period. Each piece is then suspended and stirred for 5 minutes in individual test tubes containing sterile distilled water (rinsing). They are then suspended in 10 ml of liquid meat extract medium to which is added 0.3 ml of a 24 hour old anaerobic culture of Streptococcus mutans. The vials containing the "treated" hydroxylapatite and Streptococcus mutans are then anaerobically incubated at 37 ° C for 24 hours. The same process of two 1-minute rinses in the solution of the compound, each followed by 1-minute air drying and finally 5 minutes of rinsing, is repeated before the hydroxyl apatite is again suspended in a fresh tube containing 10 ml of meat extract medium and 0.3 ml of sample material. . At the end of the second 24 hour period, each piece of hydroxylapatite is rinsed for 1 minute in three successive glasses of distilled water. They are then suspended for 1 minute in a solution of F, D & 0 Red No. 3 color. This staining procedure is used to more easily identify the development of plaque after 48 hours of exposure to the plaque-producing organism. The staining period is followed by another 10 seconds of rinsing to remove excess color. Any plaque formation is colored clear pink. Test results are read as plaque inhibition (active) or no plaque inhibition (inactive) at the percent concentration tested. Active compounds are tested at successively lower doses to determine the minimum effective concentration. In some cases, the effect of plaque production is caused by inhibiting the growth of the organism in the culture medium, because the compound has been leached from the hydroxyl apatite to produce an antibacterial level in the medium. When this occurs, the compound is tested at lower concentrations until the growth of the organism in the surrounding medium is as great as in the untreated control culture. Plaque may form at these lower concentrations.

However, the adhesion of the test compound to the tooth surface, which of course is necessary to prevent the formation of dental plaque thereon, may enhance the adhesion of coloring agents, e.g. coffee, tobacco, food dyes, etc., on the tooth surface. Therefore, the above procedure was also used to determine the coloring ability, ie. the ability of the test compound to promote adhesion of coloring agents to the tooth surface.

Thus, a residual uniform pale pink color on the tooth surface after the last rinse indicates staining ability at the percent concentration tested and is reported as staining concentration. The uniform pale pink color produced by the test compound is easily distinguished from the localized clear pink color caused by plaque formation. In general, the preferred compounds advantageously have a staining concentration which is significantly higher than the minimally effective plaque preventing concentration.

Numerical antibacterial, antifungal and dental plaque prevention 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 1,1O-bis- (4-amino-1-pyridinium) deeandibromide ( reference compound II), is also included in Table A for comparison purposes. Staining concentrations for representative examples are reported in Table B below.

Tooth plaque preventive efficacy in the presence of sterile human saliva (50 per cent) was determined for representative examples. The test results are read as minimal effective concentration and are listed in Table B below.

The acute oral toxicity (ALD ^ q) 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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55 147638

Color ability and effect of saliva on dental plaque-preventing activity

Fort). Tooth plaque-preventing from activity in $ 50 saliva ex Minimum effective conc. ($) Coloring concentration ($) 26 0.05 23 Oa. 0.005 0.05 24 0.05 57 Approx. 0.005 0.05 58 0.05 55 0.1. 0.05 3 0.1 0.05 4 Approx. 0.005 0.005 50 0.051 ^ 0.005 6 0.005 13 0.005 14 0.1 0.05 11 0.05 0.05 12 0.05 9C Approx. 0.005 0.05 10 0.005 0.05 43A 0.005 0.05 46 0.004 28C 0.004 49 0.004 50 0.004 48 0.005 ^ No bacterial growth at this concentration, plaque formed at $ 0.005.

56

TABLE C

147638

Acute oral toxicity (ALD

Eorb. Solution from or Dose, mg / kg, of Mortality excluding suspension total material 24 hours 7 days 22 Aqueous 125 0.5 0.3 solution 250 0/3 0/3 500 1/3 1/3 1000 3/3 3 / 3 7 days ALD ^ Q = 625 mg / kg 25 Suspension 125 0/3 0/3 in 1 $ GT1) 250 0/3 0/3 500 0/3 0/3 1000 0/3 0/3 7 days ALD ^ q => 1000 mg / kg 26 Aqueous 125 0/3 1/3 solution 250 0/3 0/3 500 1/3 1/3 1000 1/3 3/3 7 days ALD ^ Q = 250 mg / kg 23 Suspension 125 0/3 0/3 in Af> GT 250 0/3 0/3 500 0/3 1/3 1000 0/3 0/3 7 days ALD ^ 0 => 100 mg / kg 24 Aqueous 250 1/3 1/3 solution 500 1/3 1/3 1000 3/3 3/3 7 days AID ^ q = 500 mg / kg 3 Suspension 125 0/3 0/3 in Ί? Ο GT 250 0/3 0/3 500 0/3 1/3 1000 1/3 1/3 7 days ALD ^ Q = 1000 mg / kg 4 Suspension 125 0/3 0/3 in 158 G.T. 250 0/3 0/3 500 0/3 0/3 1000 0/3 0/3 7 days ALD ^ Q => 1000 mg / kg 2 Suspension 125 0/3 0/3 in 158 G.T. 250 0/3 1/3 500 0/3 0/3 1000 0/3 1/3 7 days ALD ^ q = 1000 mg / kg TABLE C (cont.) 147638 57

Eorb. 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 ^ q = 315 mg / kg 50 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 ^ q => 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 ^ Q = 315 mg / kg 1D Suspension 125 0/3 0/3 in 1 $ GT 250 0/3 0/3 500 1/3 1/3 1000 2/3 2/3 7 days A1D50 = 750 mg / kg 11 Suspension 125 033 0/3 in 1J6 G-.T. 250 0/3 0/3 500 0/3 1/3 1000 0/3 0/3 7 days ALD ^ q => 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 ^ q = 750 mg / kg 90 Suspension 125 0/3 0/3 in 1 $ GT 250 0/3 0/3 500 0/3 0/3 1000 0/3 0/3 7 days ALD ^ q => 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 ^ q => 1000 mg / kg TABLE · C (contd.) 58 147638 from ^ or * 16 Dose, play Ag, of Mortality ex. suspension total material 24 hours 7 days 57 Suspension 125 0/3 0/3 in 1% GT 250 0/3 0/3 500 0/3 0/3 1000 0/3 0/3 7 days ALD ^ 0 => 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 ADD ^ q = 750 mg / kg 55 Suspension 125 0/3 0/3 i 1 $ GI 250 0/3 0/3 500 0/3 0 / 3 1000 1/3 1/3 7 days AID ^ q => 1000 mg / kg 14 Suspension 125 0/3 0/3 in ΐβ GT 250 0/3 0/3 500 0/3 0/3 1000 0/3 1 / 3 7 days ALD ^ Q => 1000 mg / kg 43A Suspension 125 0/3 0/3 in 1 # GT 250 0/3 0/3 500 0/3 0/3 1000 0/3 0/3 7 days ALD ^ q => 1000 mg / kg 28C Suspension 125 0/3 0/3 in 1J6 GF 250 0/3 0/3 500 0/3 0/3 1000 0/3 0/3 7 days AID ^ q = > 1000 mg / kg 40C Suspension 125 0/3 0/3 in GT 250 0/3 0/3 500 0/3 0/3 1000 0/3 0/3 7 days ALD ^ q => 1000 mg / kg 1) 'GT = Tragaeanth rubber

Claims (2)

147639 P_a_t_e_n_t_k_r_a_v_j. 1. Bis-pyridinium compounds for use as disinfectants or dental plaque prevention agents, characterized in that they have the general formulas: 2+ x- -0-0 NHR I mn LJ ... I or 2+ x- _ AR 'NH- ^ / CH2- ~ ^ j ^^ € H2 ~ N ^^ -NHR' (Q) T m _ Jn .. .11 wherein Y means a straight-chain 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 of 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 chloro,