CH620907A5 - Process for the preparation of antimicrobial bispyridinium derivatives - Google Patents

Description

The present invention relates to the preparation of bis- (4-amino-1-pyridinium) derivatives. The compounds can be used to fight bacteria, fungi and herpes viruses and, in some cases, to prevent the formation of dental plaque.

US Patent No. 3,055,902 describes a group of bis- (4-amino-1-pyridinium) alkanes as intermediates in the preparation of the corresponding bis- (4-amino-1-piperidino) alkanes known to exhibit effects bacteriostats and bactericides.

W.C. Austin et al., "J. Pharm. Pharmacol. ”, 11, 80-93 (1959) describes 1,10-bis- (4-amino-1-pyridinium) -decane diiodide and 1,10-bis- (4-amino-1- diiodide) pyridinium) decane. It is recognized that certain types in the wide and varied group of quaternary ammonium compounds described exhibit an amoeba-destroying activity, an antibacterial, filaricidal and trypanocidal activity, but no biological results are given for any of the above-mentioned compounds. .

The present invention relates to the preparation of bis- [4- (R-amino) -1-pyridinium] alkanes of formula I below:

RNH

- Y -

^ V-NHR

2+

x-

(I)

AT

m

n and a, a'-bis- [4- (R-amino) -1-pyridinium] xylenes of the following formula II:

R'NH

CIv <f, 3 ^

(Q) v

CH2 ^

V

^> - NHR '

2+

AT

m

_ "

x-

not

(he)

3

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formulas in which:

Y is an alkylene group containing from 4 to 18 carbon atoms and which separates the two 4- (R — NH) -1-pyri-dinyl groups by 4 to 18 carbon atoms;

R is an alkyl group containing from 6 to 18 carbon atoms, a cycloalkyl group containing from 5 to 7 carbon atoms, a benzyl group in which the phenyl ring can carry one or two substituents or a phenyl group substituted by the methylenedioxy group or with one or two substituents chosen from halogen, lower alkyl, lower alkoxy, nitro, cyano and trifluoromethyl;

R 'is hydrogen, a straight or branched chain alkyl group containing from 1 to 18 carbon atoms, or a benzyl group in which the phenyl ring can carry one or two substituents; Q is the methyl group or chlorine; and v is an integer from 0 to 4;

A is an anion; m is 1 or 3; n is 1 or 2; x is equal to l, 2 or 3; etm-2 = n-x.

These compounds can be used as antibacterial and antifungal agents and are active on the virulicidal level with regard to herpes viruses.

Some of the compounds of formula I can also be used as agents preventing the formation 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- (decalamino) -1-pyridinium] hexane dibromide, 1,6-bis- [4- (dodecylamino) -1-pyridinium] -hexane dibromide,

1,7-bis- [4- (heptylamino) -1-pyridinium] -heptane dibromide,

1,7-bis- [4- (octylamino) -1-pyridinium] heptane dibromide, 1,7-bis- [4- (nonylamino) -1-pyridinium] heptane dibromide, 1.7 dibromide -bis- [4- (decylamino) -1-pyridinium] heptane, the dibromide of 1,7-bis- [4- (dodecylamino) -1-pyridinium] -heptane,

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 octane dibromide -bis- [4- (decylamino) -l-pyridiniimi] octane, 1,8-bis dibromide- [4- (dodecylamino) -1 -py ridinium] octane, 1,8-bis dibromide [4 - (2-ethylhexy lamino) -1-pyridinium] -octane,

1,9-bis- [4- (heptylamino) -1-pyridinium] -nonane dichloride,

1,9-bis- [4- (nonylamino) -1-pyridinium] nonane dibromide, 1,9-bis- [4- (decylamino) -1-pyridinium] nonane dibromide, 1,9 dibromide -bis- [4- (dodecylamino) -l-pyridinium] -nonane,

1,10-bis- [4- (heptyl ^ mino) -1 -pyridinium] -decane dibromide and the corresponding dichloride,

1,10-bis- [4- (nonylamino) -1-pyridinium] decane dibromide, 1,10-bis- [4- (decylamino) -1-pyridinium] decane dibromide decane, 1,10 dibromide -bis- [4- (dodecylamino) -l-pyridinium] -decane,

1,10-bis- [4- (2-ethylhexylamino) -1-pyridinium] -decane dichloride,

1,12-bis- [4- (hexylamino) -1-pyridinium] -dodecane dibromide and the corresponding dichloride,

1,12-bis- [4- (heptylamino) -1-pyridinium] -dodecane dibromide,

1,12-bis- [4- (octylamino) -1-pyridinium] -dodecane dibromide,

1,12-bis- [4- (nonylamino) -1-pyridinium] -dodecane dibromide,

1,12-bis- [4- (decylamino) -1-pyridinium] -dodecane dibromide,

1,12-bis- [4- (dodecylamino) -1-pyridinium] -dodecane dibromide,

1,12-bis- [4- (2-ethylhexylamino) -1-pyridinium] -dodecane dibromide and the corresponding dichloride,

1,14-bis- [4- (hexylamino) -1-pyridinium] tetra-decane dibromide and the corresponding dichloride,

1,14-bis- [4- (heptylamino) -1-pyridinium] tetra-decane dibromide and the corresponding dichloride,

1,14-bis- [4- (octylamino) -1-pyridinium] tetra-decane dibromide,

and as more particularly preferred species:

1,9-bis- [4- (heptylamino) -1-pyridinium] -nonane dibromide,

1,10-bis- [4- (2-ethylhexylamino) -1-pyridinium] -decane dibromide,

1,10-bis- [4- (octylamino) -1-pyridinium] decane dichloride and the corresponding dibromide,

1,9-bis- [4- (octylamino) -1-pyridinium] nonane dibromide, 1,12-bis- [4- (heptylamino) -1-pyridinium] -dodecane dichloride, and l-dibromide , 8-bis- [4- (octylamino) -1-pyridinium] octane. Using some of these compounds an oral hygiene composition can be prepared to prevent the formation of dental plaque, comprising an effective amount of at least one of the above compounds and a pharmaceutically acceptable compatible carrier.

These compounds can also be used in an antibacterial, antifungal and virulicidal composition suitable for local administration, which comprises an effective amount of a compound of formulas I or II above and a compatible pharmaceutically acceptable carrier. It is also possible to prepare a composition for cleaning the skin, comprising an effective amount, on the antibacterial, antifungal and virulicidal planes, of a compound of formulas I or II above, a compatible surfactant acceptable from the pharmaceutical point of view and a pharmaceutically acceptable compatible carrier.

An antibacterial, antifungal and virulicidal composition suitable for application to inanimate surfaces is also envisaged, comprising an antibacterial, antifungal and virulicidal effective amount of a compound of formulas I or II above in admixture with a compatible vehicle.

The compounds of formulas I and II are prepared by reaction of a 4- (R-amino) pyridine of formula III:

RMH

with a disubstituted alkane of formula IV:

Z-Y-Z IV

or with a xylene a, <x'-disubstituted of formula V:

Z-CH

?

formulas IV and V in which:

Z is chlorine, bromine, iodine, methanesulfonyl-oxy, ethanesulfonyloxy, benzenesulfonyloxy or p-toluene-sulfonyloxy-

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the other symbols having the meaning already given, A in the compound obtained being equal to Z; and, if desired, swap Pennant A = Z for another anion A.

In the preceding formula I, the alkylene group Y is a bivalent saturated aliphatic hydrocarbon radical containing from 4 to 18, preferably from 8 to 12 carbon atoms, in the form of a straight or branched chain and which separates the two groups 4 - (R — NH) -1-pyridinyl by 4 to 18, preferably by 8 to 12 carbon atoms, for example:

the 1,4-butylene, 1,5-pentylene, 1,6-hexylene group,

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, 1,18-octadecylene, 1-methyl-1,4-butylene, 3-methyl-1,5,5-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-l, 7-heptylene, 2,4,4-trimethyl-l, 6-hexylene, 2,7-dimethyl-l, 8- octylene,

1-methyl-l, 10-decylene, 5-ethyl-l, 9-nonylene, 3,3,6,6, -tetramethyl-

1.8-octylene, 3,8-dimethyl-1,10-decylene, 3-methyl-1,11-undecy-lene, 6-methyl-1,12-dodecylene, 2-methyl-1,13-tridecylene,

4.9-dimethyl-1,12-dodecylene, 4-methyl-l, 14-tetradecylene, 2,12-dimethyl-l, 14-tetradecylene, l, 4-dipropyl-l, 4-butylene, 3- (3-pent -yl) -1.5-pentylene, 2- (4,8-dimethylnonyl) -1,4-butylene, l-heptyl-1,5-pentylene and the like.

It will be appreciated that when Y contains 4 carbon atoms, the latter must of course be arranged in the form of a straight chain; similarly, when Y contains 18 carbon atoms and separates the two 4- (R — NH) -l-pyridinyl groups by 18 carbon atoms, said carbon atoms must also be arranged in the form of a straight chain. In all other examples, Y can be in the form of either a straight or branched chain.

In the above formula I, R is a straight or branched chain alkyl group containing from 6 to 18, preferably from 7 to 9 carbon atoms, for example:

n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-tridecyl, n-tetradecyl, n-pen-tadecyl, n-hexadecyl groups heptadecyl, n-octadecyl, 1-methylpen-tyle, 2,2-dimethylbutyl, 2-methylhexyl, 1,4-dimethylpentyl,

2-ethylpentyl, 3-ethylpentyl, 2-methylheptyl, 1-ethylhexyl,

2-ethylhexyl, 2-propylpentyle, 2-methyl-3-ethylpentyle, 3-ethyl-heptyl, 1,3,5-trimethylhexyl, 1,5-dimethyl-4-ethylhexyl, 2-pro-pylheptyl, 5-methyl- 2-butylhexyl, 2-propylnonyl, 2-butyloctyl, 1,1-dimethylundecyl, 2-pentylnonyl, 1,2-dimethyltetradecyl, 1,1-dimethylpentadecyl and the like.

When R, in the preceding formula I, is a cycloalkyl group containing from 5 to 7 carbon atoms, it comprises the cyclopentyl, cyclohexyl and cycloheptyl groups and similar groups.

When R, in the above formula I, is a phenyl group substituted by the methylenedioxy group or by one or two substituents chosen from the group consisting of halogens and lower alkyl, lower alkoxy, nitro, cyano and trifluoromethyl groups, it includes the groups p-chlorophenyl, o-chlorophenyl, m-chlorophenyl, p-bromo-phenyl, m-fluorophenyl, p-iodophenyl, 2,4-dichlorophenyl, 2,4-difluorophenyl, 2,5-dibromophenyl, 3,5-dichlorophenyl,

3-chloro-4-fluorophenyl, 3,4-methylenedioxyphenyl, p-ethylphenyl, p-methoxyphenyl, m-nitrophenyl, o-cyanophé-nyle, m- (trifluoromethyl) phenyl, 2-methoxy-5-methylphenyl and the like .

In the above formula II, R ′ is a straight or branched chain alkyl group containing from 1 to 18, preferably from 6 to 12 carbon atoms, and comprises, in addition to the above-mentioned alkyl groups containing from 6 to 18 carbon atoms, groups such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, isopropyl, 1-methylpropyl, iso-

butyl, t-butyl, isopentyl, neopentyl, 1-methylpentyle and the like.

In the above formulas I and II, R or R ′ may also be the benzyl group. If desired, the phenyl moiety of the benzyl group can be substituted with one or two substituents such as, for example, a halogen, the hydroxyl group, a lower alkyl, lower alkoxy, nitro, cyano, trifluoromethyl and similar groups.

R is preferably identical to R 'in both cases for each formula I and II.

The anion A in the preceding formulas can be an anion of mineral and organic acids, for example: bromide, chloride, fluoride, iodide, sulfate, phosphate, nitrate, sulfamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluene-sulfonate , naphthalenesulfonate, naphthalene disulfonate, cyclohexyl sulfamate, acetate, trifluoroacetate, malate, fumarate, succinate, tartrate, Oxalate, citrate, lactate, gluconate, ascorbate, lactate, phthalate, salicylate, benzoate, picrate, methanephosphonate, methanephosphate, methanephosphate , Perchlorate, tartronate, sarcosinate, N-lauroylsarcosinate, monofluorophosphate, hexafluoroaluminate, hexafluorosilicate, hexafluorostannate, fluorozirconate, tetrafluor-roborate, hexachloroplatinate, tetrachloroaluminate and hexachlo-rost products. Bromide and chloride are preferred.

The term halogen as used in the present description includes fluorine, chlorine, bromine and iodine.

In the terms lower alkyl and lower alkoxy, the lower term means an alkyl moiety containing from 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl and t-butyl groups.

The preparation reaction of the compounds of formulas I and II above can be conveniently carried out by reacting 2 mol of 4- (R-amino) pyridine (formula (III)) with 1 mol of alkane or xylene suitably disubstituted (formulas IV and V) in an inert solvent such as a lower alkanol, acetonitrile, N, N-dimethylformamide, N, N, -dime-thylacetamide, benzene, toluene , xylene and similar products, at a temperature of about 80 to 150 ° C for a period of between 1 and 24 h. Usually, the reagents are heated to between 60 and 100 ° C in acetonitrile or N, N-dimethylformamide or in a mixture of these solvents, or in a lower alkanol, for a period of approximately 2 to 20 h.

In another variant, the reaction can be carried out in the absence of solvent by heating stoichiometric amounts of the reagents between 120 and 150 ° C for about 2 to 5 h.

The resulting compounds of bis- [4- (R-amino) -1-pyridinium] (formulas I and II) can be isolated according to conventional methods, such as by filtration, when the product is insoluble in the reaction medium, or by dilution of the reaction mixture with a non-polar solvent such as ether, benzene or hexane in order to precipitate the product, or by evaporation of the reaction medium to leave the product in the form of a residue. The crude product isolated can be purified by crystallization from a suitable solvent in the presence of an adsorbent, such as, for example, charcoal or diatomaceous earth.

The bis- [4- (R-amino) -1-pyridinium] compounds prepared according to the process described above obviously contain an anion (A in formulas I and II) which corresponds to the remaining group of the alkane or xylene reagent disubstituted (Z in formulas IV and V).

However, the anionic fraction of these compounds can be varied, if desired, by conventional ion exchange methods, for example by passing a solution of a pyridinium compound through a suitable solvent, such as for example methanol, ethanol or water, through a bed of synthetic ion exchange resin containing the desired anion. The solvent is evaporated and the resulting pyridinium compound is purified

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containing the desired anion, by recrystallization from a suitable solvent.

In another alternative, a pyridinium compound can be reacted with a soluble salt containing the desired anion in combination with a counter cation which combines with the anion of the pyridinium compound to obtain an insoluble precipitate. The latter is separated, which leaves 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 mineral anion.

The previous type of metathetic reaction can also be used to prepare insoluble pyridinium compounds. Thus, a soluble bis- [4- (R-amino) -1-pyridinium] compound is reacted with a soluble salt containing the desired anion which combines with the pyridinium cation to provide the desired product in the form of an insoluble precipitate. These insoluble pyridinium salts can be used for isolation and purification purposes and, when they are suitably prepared in the form of emulsions, creams, pastes, lotions, jellies or powders, also serve as storage preparations giving a slow and sustained release of the pyridinium antimicrobial compound. In addition, insoluble salts derived from certain anions, such as those described in US Patent No. 3,937,807 issued February 10, 1976, are effective in decreasing the staining power of teeth from plaque prevention agents.

This is why, when the anionic fraction of a given compound gives this product characteristics such as solubility, stability, molecular weight, physical appearance, toxicity or similar properties which make this form of compound not suitable for a desired use, it can be easily transformed into another more suitable form. For use on the skin or on other tissues or in the oral cavity, use is made of pharmaceutically acceptable anions such as fluoride, chloride, bromide, iodide, methanesulfonate and anions. alike.

The 4- (R-amino) pyridines (formula III) which are used as starting materials are generally known or, if they are specifically new, they can be prepared according to the methods described for the preparation of the known compounds.

Conveniently, 4- (R-amino) -pyridines can be prepared by reacting 4-chloro or 4-bromo-pyridine hydrochloride or N- (4-pyridyl) pyridinium chloride with a substituted amine in an appropriate way. The reaction is usually carried out by heating the reagents in the absence of solvent between 150 and 225 ° C for a time between 1.5 and 3 h. The product is isolated in a usual manner, for example by extraction from the alkaline aqueous medium in an organic solvent such as ether, methylene chloride or chloroform, by evaporation of the organic solvent and crystallization of the residue in a solvent appropriate.

In another variant, 4- (R-amino) -pyridines can be obtained by catalytic hydrogenation of a mixture containing 4-aminopyridine and a carbonyl compound containing the appropriate carbon content. The reaction is usually carried out at a temperature of 50 to 70 ° C in a suitable solvent, for example ethanol, under a hydrogen pressure of 1.4 to 4.2 kg / cm 2, in the presence of a catalyst d hydrogenation with palladium. A hydrogenation time of 4 to 10 hours is generally satisfactory. The use of a large excess of carbonyl compound, for example 200% or more, advantageously results in high yields of pure product for a reaction time of 5 h or less. After removal of the catalyst, the product is isolated by evaporation of the solvent and either by distillation of the residue or crystallization of the product in an appropriate solvent.

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Reaction of an aldehyde with the appropriate carbon content with 4-aminopyridine in the presence of formic acid at elevated temperatures also provides 4- (R-amino) -pyridines.

4- (R-amino) pyridines can also be obtained by acylation of 4-aminopyridine with an acyl halide having the appropriate carbon content, followed by reduction of the resulting amide. Acylation is carried out according to methods known in the art, for example by reaction of 4-amino-pyridine with an acyl halide in an inert solvent such as methylene dichloride or chloroform in the presence of an acceptor d acid such as triethylamine. The amide thus obtained is then reduced using a complex metal hydride such as lithium hydride in an appropriate solvent such as tetrahydrofuran, ether or dioxane, and the amine produced is isolated according to known methods.

The disubstituted alkanes of formula IV also used as starting materials are generally known products; if they are specifically new, they can be prepared according to the methods used for the preparation of the known compounds.

The x, a'-disubstituted xylenes of formula V also used as starting materials are generally known compounds; if they are specifically new, they can be prepared according to the methods used for the preparation of the known compounds.

Thus it is possible to reduce an acid or a suitable chloro or methyl-substituted phthalic, isophthalic or terephthalic ester to xylene-a, a'-diol corresponding using a metal hydride such as hydride aluminum and lithium in a suitable solvent such as tetrahydrofuran, ether or dioxane. The xylene-oc, a'-diol thus prepared is then transformed into an a, a'-dihaloxylene, for example by reaction with hydrobromic acid, phosphorus tribromide, phosphorus oxychloride, chloride of thionyl or potassium iodide and orthophosphoric acid according to methods known in the art. In another variant, the xylene-a, cc'-diol can be transformed into a sulfonate by reaction with methane, ethane, benzene or p-toluenesulfonyl chloride in the presence of an acid acceptor such as pyridine, according to well known methods.

As described more fully below, the compounds of formulas I and II exhibit antimicrobial activity in vitro with respect to different species of microorganisms among which are included Grampositive and Gramnegative bacteria, different species of fungi and herpes viruses. The compounds are therefore indicated for use as antimicrobial agents or antiseptic agents which can be applied locally to disinfect the skin and other human tissues and to sanitize and disinfect inanimate surfaces. Thus, the compounds can be used in local antiseptic solutions for the treatment of wounds, in antibacterial cleaning agents such as solutions for hand cleaning in surgical application, preoperative skin cleaning preparations, soaps and shampoos, and in household and industrial cleaning products, in disinfectant and protective coatings such as paints, varnishes and waxes. The compounds are suitable for the uses indicated above by combining them with traditional diluents or carriers, compatible cationic, anionic or nonionic surfactants, buffering agents, perfumes and coloring agents, and they are applied to a surface to be disinfected by conventional methods such as rubbing, spraying, wiping, immersion and similar methods.

For use as skin disinfectants, the bis- [4- (R-amino) -1-pyridinium] compounds can be prepared in the form of liquids or, if desired, can be prepared. thicken liquid formulations with certain additives in the form of a gel or paste, or they can be molded

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in the form of a bar according to methods known in the art. For example, the compounds may be formulated with any compatible pharmaceutically acceptable surfactant, preferably a nonionic surfactant such as the polyoxyethylene / polyoxypropylene copolymers described in US Patent No. 3,855,140, oxides of amines such as stearyldimethylamine oxide described in US Pat. No. 3,296,145 and similar products or with mixtures of these products. The formulations may contain, in addition to pharmaceutically acceptable diluents such as water, lower alkanols and the like, acids, bases and buffering agents to maintain the pH between 5.0 and 7.5 and , optionally, perfumes and coloring agents. The bis- [4- (R-amino) -1-pyridinium] compounds are generally present in such formulations at a concentration of 0.5 to 2.0% by weight, preferably 1.0% by weight .

If they are prepared in the form of a tincture, the bis- [4- (R-amino) -1-pyridinium] compounds can be formulated with water, a lower alkanone, such as acetone, and a lower alkanol such as ethanol. If desired, the dye can be colored with a coloring agent. The active compound is generally present at a concentration of about 0.05 to 1.0% (weight / volume), preferably 0.1% (weight / volume).

In another variant, the compounds can be formulated in pharmaceutical vehicles suitable for the treatment of bacterial, fungal and viral infections by herpes viruses, for example in the form of lotions, ointments, creams,

by introducing them into traditional bases of lotions, ointments or creams, such as alkylpolyether alcohols, cetyl alcohol, stearyl alcohol and similar products, or in the form of powders by introducing them into conventional bases for powders such as starch, talc and similar products, or in the form of jellies, by introducing them into traditional jelly bases such as glycerol and tragacantha. They can also be formulated for use as aerosol sprays or in the form of foams.

When used to sanitize and disinfect inanimate surfaces, the compounds can be formulated with known detergents and builders such as trisodium phosphate, borax and the like. The bis- [4- (R-amino) -1-pyridinium] compounds are generally present in such formulations 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 plaque. When intended for such use, the compounds can be conveniently applied to the teeth in the form of an oral wash solution or in the form of a toothpaste. The compounds can be formulated with conventional compounds used in formulations of oral solutions and toothpastes, for example water, alcohol, glycerin, buffers, thickening agents, flavoring agents and coloring agents. These formulations can also optionally contain other known compounds, more particularly those which are effective in reducing the staining potential of the teeth, such as the anti-tip agents described in US Patent No. 3,934,002 published January 20, 1976, for example zinc phenolsulfonate, 8-hydroxyquinoline, ethane 1-hydroxy-1, disodium 1-diphosphonate, etc., and the aminocarboxylic compounds described in US Patent No. 3,937,807 issued February 10, 1976, e.g. nitri-lotriacetic acid, 2-hydroxyethylnitrilodiacetic acid or their water-soluble salts. The bis- [4- (R-amino) -l-pyridinium] alkane is usually present in such formulations at a concentration of 0.005 to 0.05% by weight, preferably about 0.01% by weight.

It should of course be understood that the vehicles, diluents, carriers and additives contained in the formulations mentioned above are compatible with the active compound, that is to say that the antimicrobial, antifungal or virulicidal efficacy of the bis- [4- (R-amino) -l-pyridinium] is not compromised by effects attributable to the nature of the vehicle, diluent, carrier or other additive.

The molecular structures of the compounds of the invention are given on the basis of the study of their infrared and NMR spectra, and they are confirmed by the correspondence between the values calculated and found for the elementary analyzes of the elements.

Example 1:

A. A mixture containing 130 g (0.67 mol) of 4-bromopyridine hydrochloride and 152 g (1.0 mol) of n-ethylamine hydrochloride is heated in an oil bath. When the bath temperature has reached 180-185 ° C, the reaction mixture begins to melt and agitation is started. The fusion is complete at 190-195 ° C; the liquid mixture is stirred and heated to 210-220 ° C for 2.5 h. The reaction mixture is then cooled to room temperature and the resulting solid is dissolved in water, which is made alkaline with 35% aqueous sodium hydroxide, and the product is extracted with chloroform. The extracts are dried with chloroform on anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The resulting viscous oil is diluted with a small amount of n-hexane and cooled to obtain a solid which is collected by filtration and air dried to obtain 86.6 g of 4- (heptylamino) -pyridine, mp 49-51 ° C.

B. In another variant, 4- (heptylamino) -pyridine is prepared as follows: a mixture containing 229 g (1.0 mol) of N- (4-pyridyl) pyridinium chloride hydrochloride and 228 g is heated 1.5 mol) of n-heptylamine hydrochloride in 2 h with stirring in an oil bath at a bath temperature of 215 ° C. The reaction mixture is cooled to 80 ° C., diluted with a mixture of ice and water, made alkaline with 35% aqueous sodium hydroxide and extracted successively with ether and chloroform. The organic extracts are combined and evaporated to dryness under reduced pressure. The resulting viscous oil is dissolved in ether and the ethereal solution is washed with water. The aqueous washes are re-extracted with chloroform and the chloroform extracts are combined with the ethereal solution. The combined organic solutions are dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. Cooling the residual oil to -78 ° C gives partial solidification. The semi-solid product is diluted with a small amount of ether and filtered. The solid thus obtained is dissolved in a mixture of acetonitrile and chloroform, the resulting solution is treated with decolorizing carbon, it is filtered and the filtrate is evaporated to dryness under reduced pressure. The resulting semi-solid is diluted with a small amount of ether and cooled. The solid thus prepared is collected by filtration and washed with a small volume of cold ether to obtain, after drying, 84.6 g of 4- (heptylamino) pyridine, m.p. 50-52 ° C.

C. 4- (Heptylamino) pyridine is also prepared by hydrogenation of a mixture containing 4-aminopyridine and heptaldehyde according to the method described in Example 10B below.

D. To a hot stirred solution containing 10.0 g (0.052 mol) of 4- (heptylamino) pyridine in 40 ml of acetonitrile, a solution containing 9.3 g (0.026 mol) of 1.14 is added dropwise -dibromotetradecane in 230 ml of acetonitrile and the mixture is heated for 20 h under reflux. The product which precipitates when the reaction mixture is cooled to room temperature is collected by filtration, washed with cold acetonitrile and dried, which gives 13.9 g of 1,14-bis-dibromide [4- (heptylamino) -1-pyridinium] tetradecane, mp. 88-90 ° C.

Example 2:

A solution containing 5.0 g of 1,14-bis- [4- (heptylamino) -1-pyridinium] tetradecane dibromide is added in 5.0 ml of

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methanol at the top of a 7.62 cm diameter column containing 500 ml of a synthetic anion exchange resin (sold by Rohm and Haas under the trade name Amberlite IRA 400) which has been introduced into methanol and which was eluted with 5 fractions of 25 ml of methanol. The combined eluate is evaporated to dryness under reduced pressure and the residual oil is redissolved in ethanol, it is treated with decolorizing carbon and it is evaporated to dryness. The residual solid is triturated with ether containing a few drops of acetonitrile, it is collected by filtration and dried under vacuum over phosphorus pentoxide to obtain 3.94 g of 1,14-bis-dichloride [4- (heptylamino) -l-pyridinium) tetradecane, 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 is heated under reflux until a clear, homogeneous solution is formed. A hot solution containing 9.84 g (0.03 mol) of 1,12-dibromododecane in 75 ml of acetonitrile is then added dropwise to the clear solution. When the addition is complete, the heating is continued under reflux for 18 h. After cooling to room temperature, the resulting mixture is evaporated to dryness under reduced pressure. The residual solid is suspended in ether, collected by filtration and dried for 48 h under vacuum at 60 ° C to obtain 21.1 g of dibromide I, 12-bis- [4- (heptylamino ) -l-pyridinium] dodecane, mp i01-103 ° C.

Example 4:

A. A solution containing 6.6 g of 1,12-bis- [4- (heptylamino) -1-pyridinium] dodecane dibromide in 25 ml of methanol is added to the top of a column with a diameter of 7, 62 cm filled with 11 of synthetic anion exchange resin in the form of chloride (sold by Rohm and Haas under the trade name Amberlite IRA 400) in methanol and which is eluted slowly with fractions of 100 ml of methanol up to which 700 ml of eluate were collected. The combined eluate is evaporated to dryness under reduced pressure below 25 ° C. The residual gum is triturated several times with a 6 to 1 mixture of ether and acetonitrile and dried under vacuum to obtain 5.0 g 1,12-bis- [4- (heptylamino) -1-pyridinium] dichloride dodloride, mp 109-112 ° C.

B. In another variant, a mixture containing 76.8 g (0.4 mol) of 4- (heptylamino) pyridine and 47.8 g (0.2 mol) is heated for 4 h at 125-130 ° C. ) of 1,12-dichlorododecane. After adding 300 ml of slightly cooled acetonitrile and after heating the resulting mixture to the temperature of the steam bath to make a complete solution, it is kept in a refrigerator overnight. The precipitated product is collected by filtration, washed over acetonitrile and cold ether, and the hygroscopic product is immediately dried under vacuum to obtain 112 g of 1,12-bis- [4- (heptylamino) dichloride. ) -l-pyridinium] dodecane, 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 is heated in an oil bath. When the bath temperature has reached 175-180 ° C, the reaction mixture begins to melt and agitation is started. The temperature of the bath is then brought to 227 ° C. and stirring is continued for a period of 3.5 h. After cooling to room temperature, the reaction mixture is dissolved in hot water, the resulting solution is cooled with ice, made alkaline with dilute aqueous sodium hydroxide and extracted with chloroform . The extracts are dried with chloroform on anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue is triturated with ether and cooled. The resulting solid is collected by filtration and washed with cold ether. Evaporation of the filtrate provides a second crop of solid. The crops are combined, dissolved in chloroform, treated with bleaching carbon and filtered. The filtrate is evaporated under reduced pressure and the residue is triturated with cold ether. The product thus obtained is collected by filtration, washed with cold ether and dried to obtain 63.6 g of 4- (hexylamino) pyridine, m.p. 66-68 ° C. Evaporation of the filtrate provides an additional 7.0 g, m.p. 65-67 ° C.

B. In another variant, 4- (hexylamino) -pyridine is prepared in the following manner. A mixture containing 229 g (1 mol) of N- (4-pyridyl) pyri-dinium chloride hydrochloride and 207 g (1.5 mol) of n-hexylamine hydrochloride is stirred and heated for 1.75 h at 175-185 ° C. The reaction mixture is cooled and diluted with 750 ml of a mixture of water and ice. The resulting solution was basified with 35% aqueous sodium hydroxide and, after further dilution with 11% water, extracted with ether followed by extraction with dichloromethane. The organic extracts are combined, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue is crystallized from ether, redissolved in chloroform, the resulting solution is treated with decolorizing carbon and filtered. The filtrate is evaporated to dryness under reduced pressure and the residue is triturated with a mixture of ether and acetonitrile. The solid thus obtained is again dissolved in chloroform and the resulting solution is treated with decolorizing carbon and filtered. The filtrate is evaporated to dryness under reduced pressure and the residue is triturated with cold ether to obtain 71.0 g of 4- (hexylamino) pyridine, m.p. 68-70 ° C.

C. To a stirred hot solution containing 10.7 g (0.06 mol) of 4- (hexylamino) pyridine in 50 ml of acetonitrile, a solution containing 10.7 g (0.03 mol) is added dropwise of 1,14-dibromotetradecane in 50 ml of acetonitrile and the resulting mixture is heated for 22 h under reflux. The reaction mixture is then evaporated to dryness under reduced pressure. The residual solid is dissolved in acetonitrile, the resulting solution is treated with decolorizing carbon and filtered. The filtrate is evaporated to dryness under reduced pressure and the resulting oil is crystallized from acetonitrile. The product is collected by filtration and dried for 48 h at 70 ° C / 0.1 mm to obtain 13.4 g of 1,14-bis- [4- (hexylamino) -1-pyridinium] tetradecane dibromide, m.p. 91-93 ° C.

Example 6:

Following a process similar to that described in Example 2 but using 5.0 g of 1,14-bis- [4- (hexylamino) -1-pyridinium] tetradecane dibromide, 4.33 g of the dichloride are obtained correspondent, pf 94-95 ° C.

Example 7:

Following a process 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) of 1,12-dibromododecane , 17.6 g of 1,12-bis- [4- (hexylamino) -1-pyridinium] dodecane dibromide are obtained, mp 122-124 ° C.

Example 8:

By following a process 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 dichloride are obtained. correspondent, pf 86-88 ° C.

Example 9:

A. A mixture containing 183.3 g (0.8 mol) of N- (4-pyridyl) pyridinium chloride hydrochloride and 162 g (0.98 mol) of n-octylamine hydrochloride is heated in an oil bath. at a bath temperature of 225-230 ° C (internal temperature 188 ° C) and the resulting mixture is stirred at this temperature for 2.5 h. The reaction mixture is then cooled to 70 ° C, diluted

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with one liter of ice and water, it is made alkaline with 35% aqueous sodium hydroxide and extracted with chloroform. The extracts are dried with chloroform over anhydrous sodium sulfate, treated with bleaching charcoal and evaporated to dryness in vacuo. The resulting oil is cooled to -78 ° C. The semi-solid which forms is triturated with ether and the solid thus obtained is collected by filtration, washed with cold ether and dried. The filtrate provides a second harvest of 10 g. The crops are combined, dissolved in chloroform and, following a treatment with bleaching carbon and filtration (repeated three times), the chloroform solution is evaporated to dryness under vacuum. The resulting solid is triturated with ether, cooled,

it is collected by filtration and washed with a cold ether / hexane mixture to obtain 63.3 g of practically colorless 4- (octyamino) pyridine, m.p. 62-63 ° C.

B. In another variant, 4- (octylamino) -pyridine is prepared as follows: hydrogenation is carried out for 4.5 h

at 70-90 ° C under an initial hydrogen pressure of 3.16 kg / cm2 a mixture containing 94 g (1 mol) of 4-aminopyridine, 384 g (3 mol) of octaldehyde, 7 g of catalyst hydrogenation to 10% palladium on carbon and enough absolute ethanol to give a total volume of 1.21. After cooling the mixture, the hydrogenation catalyst is filtered off and the filtrate is evaporated to dryness under reduced pressure. The residual oil is crystallized on standing and the resulting solid is triturated with hexane, it is collected by filtration, it is washed with fresh hexane and it is dried at 40 ° C. under vacuum to obtain 182 g of 4 - (octylamino) pyridine, pf 70-73 ° C.

C. To a hot stirred solution containing 10.0 g (0.049 mol) of 4- (octylamino) pyridine in 150 ml of acetonitrile, a solution containing 7.4 g (0.0245 mol) of 1 is added dropwise. , 10-dibromodecane in 50 ml of acetonitrile and the resulting mixture is heated for 18 h under reflux. After having cooled it and stirred for 1 h at room temperature, the precipitated solid is collected by filtration, washed with acetonitrile and dried for 48 h at 85 ° C. to obtain 4.6 g of dibromide 1, 10-bis- [4- (octylamino) -l-pyridinium] decane, pf 163-164 ° C.

Example 10:

A. By following a process similar to that described in Example 2 but using 5.0 g of 1,10-bis- [4- (octylamino) -1-pyridinium] decane dibromide, 4.31 g are obtained. corresponding dichloride, mp 213-214 ° C.

B. In another variant, a mixture containing 61.8 g of 4- (octylamino) pyridine and 31.5 g of 1,10-dichlorodecane is stirred and slowly heated to 120 ° C. The heat source is removed and the reaction which becomes exothermic continues to heat and brings the temperature to 180 ° C. As soon as the reaction mixture begins to crystallize, 250 ml of N, N-dimethyl-formamide are rapidly added and the resulting mixture is heated to obtain a homogeneous clear solution and then cooled to 0 ° C. The precipitated product is collected by filtration, washed with ether and dried for 24 h under vacuum at 60 ° C to obtain 73 g of 1,10-bis- [4- (octylamino) -l- dichloride. pyridinium] decane, pf 215-217 ° C.

Example 11:

Following a process similar to that described in Example 9C but using 11.1 g (0.054 mol) of 4- (octylamino) pyridine and 7.39 g (0.027 mol) of 1,8-dibromooctane, and heating the reaction mixture for 6 h under reflux, 15.6 g of 1.8-bis- [4- (octylamino) -1-pyridinium] octane dibromide are obtained, mp 174-175 ° C.

Example 12:

Following a process similar to that described in Example 2 but using 5.0 g of 1,8-bis- [4- (octylamino) -l- dibromide

pyridinium] octane, 4.30 g of the corresponding dichloride are obtained, m.p. 210-211 ° C.

Example 13:

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

Example 14:

Following a process similar to that described in Example 2 but using 5.0 g of 1,6-bis- [4- (octylamino) -1-pyridinium] hexane dibromide, 4.33 g of the dichloride are obtained correspondent, pf 189-19PC.

Example 15:

To a stirred hot solution containing 2.06 g (0.01 mol) of 4- (octylamino) pyridine in 15 ml of acetonitrile, a solution containing 1.37 g (0.005 mol) of dimethyl sulfonate is added dropwise of 1,6-hexanediol in 10 ml of acetonitrile and the resulting mixture is heated under reflux for 20 h. The reaction mixture is evaporated to dryness under reduced pressure and the residual gum is triturated with ether to obtain a colorless hygroscopic solid. This product is redissolved in a mixture of ethanol, benzene and acetonitrile and the resulting solution is evaporated to dryness under reduced pressure. The residue is triturated with ether and the resulting white solid is quickly collected by filtration, washed with anhydrous ether, and dried for 72 h at 28 ° C / 0.1 mm to obtain 2.65 g of 1,6-bis- [4- (octyl-amino) -1 -pyridinium] hexane dimethansulfonate in the form of a waxy white solid.

Example 16:

Following a process 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-dibromobutane , after trituration of the crude product with a mixture of acetonitrile and acetone, 20.45 g of 1,4-bis- [4- (hexylamino) -1-pyridinium] butane, mp dibromide are obtained 199-201 ° C.

Example 17:

Following a process 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- dibromohexane, after trituration of the crude product is obtained with a mixture of ether, acetonitrile and acetone 14.90 g of 1,6-bis- [4- (hexyl-amino) -1-pyridinium] hexane dibromide , pf 178-179 ° C.

Example 18:

Following a process similar to that described in Example 9C but using 10.7 g (0.06 mol) of 4- (hexylamino) pyridine and 7.75 g (0.03 mol) of 1,7-dibromoheptane , after trituration of the crude product is obtained with a mixture of acetonitrile and acetone 16.4 g of l, 7-bis- [4- (hexylamino) -l-pyridiniumjheptane, pf dibromide 157-158 ° C.

Example 19:

Following a process 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-dibromononane , 17.15 g of l, 9-bis- [4- (hexylamino) -1-pyridinium] nonane, mp dibromide are obtained 114-115 ° C.

Example 20:

Following a process 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-dibromobutane , we obtain 23.1 g of

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1,4-bis- [4- (heptylamino) -1-pyridinium] butane dibromide, m.p. 229-230 ° C.

Example 21:

By following a process similar to that described in Example 9C s but using 10.0 g (0.052 mol) of 4- (heptylamino) pyridine and 6.7 g (0.026 mol) of 1,7-dibromoheptane, 14.05 g of 1,7-bis- [4- (heptylamino) -1-pyridinium] dibromide heptane, mp 142-143 ° C.

io

Example 22:

Following a process 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-dibromooctane , after recrystallization from an acetonitrile / ether mixture, 18.6 g of dibromide is l, 8-bis- [4- (heptyIamino) -l-pyridinium] octane, mp are obtained I61-162 ° C.

Example 23:

By following a process similar to that described in Example 2 but using 5.0 g (0.0076 mol) of 1,8-bis- [4- (heptylamino) -1-pyridinium] octane dibromide, obtains 4.1 g of the corresponding dichloride, mp 206-208 ° C.

Example 24:

By following a process similar to that described in Example 9C but using 15.4 g (0.08 mol) of 4- (heptylamino) pyridine and 11.4 g of 1,9-dibromononane, 21 is obtained, 3 g of 1,9-bis- [4- (heptylamino) -1-pyridinium] dibromide nonane, mp 115-116 ° C.

Example 25: 30

By following a process 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, mp 154-155 ° C.

35

Example 26:

Following a process similar to that described in Example 9C but using 15.4 g (0.08 mol) of 4- (heptylamino) pyridine and 12.0 g (0.04 mol) of 1,10-dibromodecane , 25.7 g of l, 10-bis- [4- (heptylamino) -1-pyridinium] decane dibromide are obtained, "> pf 163-165 ° C.

Example 27:

Using a process similar to that described in Example 2 but using 5.0 g (0.0073 mol) of 1,10-bis- [4-45 (heptylamino) -1-pyridinium] decane dibromide, obtains 4.35 g of the corresponding dichloride, mp 209-210 ° C.

Example 28:

To a stirred suspension of 30 ml of synthetic resin 50

anion exchanger in the form of hydroxide (sold by Rohm and Haas under the trade name Amberlite IRA 400) in 150 ml of water, 48% aqueous hydrofluoric acid is added dropwise up to that the mixture becomes acidic. After stirring an additional 0.5 h, the suspension 55 is poured into a column. The column is drained and the resin is washed with a solution containing 15 ml of 48% aqueous hydrofluoric acid in 185 ml of distilled water. The resin is then washed with distilled water until the eluate is weakly acid, then successively with 20, 30 and 50% aqueous methanol, and finally 60 with absolute methanol until the elate be neutral. A solution containing 0.25 g (0.000365 mol) of 1,10-bis- [4- (heptylamino) dibromide is added to the top of this column of ion exchange resin which is now in the form of fluoride. ) -l-pyridinium] decane in 1 ml of methanol. 65 five fractions of 15 ml each are collected. The first three fractions are combined and evaporated to dryness under reduced pressure. The oily residue is dissolved in a mixture of toluene and ethanol and the resulting solution is evaporated to dryness under reduced pressure. The oily residue is redissolved in a mixture of benzene and acetone and the solution is concentrated to a small volume. The solid which separates is collected by filtration and dried for 24 h at 24 ° C / 0.1 mm to obtain 0.11 g of 1,10-bis-difluoride [4- (heptylamino) -l-pyridinium] decane, pf 85-90 ° C.

Example 29:

A. Heating in an oil bath to a bath temperature of 200 ° C (internal temperature of 190-194 ° C) a solid mixture containing 115 g (0.5 mol) of N- chloride hydrochloride ( 4-pyridyl) pyridinium and 119 g (0.66 mol) of n-nonylamine hydrochloride and the resulting mixture is stirred at this temperature for 2 h. The reaction mixture is then cooled to 80 ° C, diluted with 1.21 ice and water, made alkaline with 35% aqueous sodium hydroxide and extracted with chloroform. The extracts are dried with chloroform on anydre sodium sulfate, treated with bleaching carbon, filtered and evaporated to dryness under reduced pressure. The residual viscous oil is cooled to -78 ° C and triturated with ether. The resulting solid is collected by filtration and washed with cold ether. The filtrate provides a second crop of solid. The combined crops are redissolved in chloroform and the resulting solution is treated with bleaching carbon and filtered. This is repeated once more and the filtrate is then evaporated to dryness under reduced pressure. The residual semi-solid is triturated with ether and cooled to obtain an almost colorless solid which is collected by filtration, which is washed with cold ether and which is dried. The solid is taken up in chloroform and the resulting solution is treated with decolorizing carbon, filtered and evaporated to dryness under reduced pressure. The cooling of the semi-solid thus obtained and its trituration with ether provide a colorless solid which is collected by filtration, which is washed with cold ether and which is dried to obtain 51.7 g 4- (nonylamino) pyridine, mp 59-60 ° C. The filtrate provides a second harvest of 11.6 g, m.p. 55-57 ° C.

B. In a variant, 4- (nonylamino) pyridine is prepared as follows: a mixture containing 39.5 g (0.42 mol) of 4-aminopyridine, 175 g (1.24 mol) of nonylaldehyde, is heated, 5 0.0g hydrogenation catalyst 10% palladium on carbon and absolute ethanol in sufficient quantity to give a total volume of 600 ml and hydrogenated under an initial hydrogen pressure of 3.15 kg / cm2 until the absorption of hydrogen is complete. The reaction mixture is filtered to remove the catalyst and the filtrate is evaporated to dryness under reduced pressure. The residual oil is then distilled in vacuo to remove any nonyl alcohol that may have occurred. A fraction of a boiling point of 63-64 ° C / 4.5 mm is collected and set aside. The residue is triturated with ether and cooled to -78 ° C. The solid which precipitates is collected by filtration and washed with cold ether. This product is dissolved in chloroform, the resulting solution is treated with bleaching carbon, filtered and the filtrate is evaporated to dryness. The residue is triturated with ether and cooled to -78 ° C. The solid thus obtained is collected by filtration, washed with cold ether and dried in air to obtain 27.0 g of 4- (nonylamino) pyridine, mp 57-59 ° C.

C. A stirred suspension of 11.0 g (0.05 mol) of 4- (nonylamino) pyridine in 150 ml of acetonitrile is heated until a clear, homogeneous solution is obtained. A solution containing 6.8 g is added dropwise to this clear solution.

(0.25 mol) of 1,8-dibromooctane in 50 ml of acetonitrile and the resulting mixture is heated for 19 h under reflux, during which time it precipitates a solid from the solution. After cooling, the solid is collected by filtration, redissolved in methanol, the resulting solution is treated with decolorizing carbon, filtered and evaporated to dryness under pressure

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scaled down. Trituration of the residual oil with ether containing a small amount of acetonitrile provides a colorless crystalline solid which is collected by filtration and dried to obtain 15.5 g of dibromide of 1.8- bis- [4- (nonylamino) -l-pyridi-niumjoctane, mp 178-179 ° C.

Example 30:

Following a process similar to that described in Example 29C but using 14.24 g (0.08 mol) of 4- (hexylamino) pyridine and 9.20 g (0.04 mol) of 1,5-dibromopentane , after recrystallization from an acetonitrile / acetone mixture, 12.3 g of 1,5-bis- [4- (hexylamino) -1-pyridinium] pentane, mp dibromide are obtained 155-156 ° C.

Example 31:

Following a process similar to that described in Example 29C but using 10.7 g (0.06 mol) of 4- (hexyl-amino) pyridine and 8.2 g (0.03 mol) of 1.8 -dibromooctane, 16.3 g of 1,8-bis- [4- (hexylamino) -l-pyridi-nium] octane, mp dibromide are obtained 180-181 ° C.

Example 32:

Following a process similar to that described in Example 29C but using 12.5 g (0.07 mol) of 4- (hexyl-amino) pyridine and 10.5 g (0.035 mol) of 1,10-dibromodecane , 16.0 g of 1,10-bis- [4- (hexylamino) -1-pyridiniumjdecane dibromide, mp are obtained 148-149 ° C.

Example 33:

By following a process similar to that described in Example 29C but using 13.4 g (0.076 mol) of 4- (cyclo-hexylamino) pyridine and 8.2 g (0.038 mol) of 1,4-dibromobutane, obtains 18.2 g of 1,4-bis- [4- (cyclohexylamino) -l-pyridiniumjbutane dibromide, mp 288-290 ° C.

Example 34:

Following a process similar to that described in Example 29C but using 13.4 g (0.076 mol) of 4- (cyclo-hexylamino) pyridine and 8.75 g (0.038 mol) of 1,5-dibromopentane, obtains 19.0 g of 1,5-bis- [4- (cyclohexylamino) -1-pyridinium] dibromide pentane, mp 255-256 ° C.

Example 35:

By following a process similar to that described in Example 29C but using 13.4 g (0.076 mol) of 4- (cyclo-hexylamino) pyridine and 9.3 g (0.038 mol) of 1,6-dibromohexane, obtains 19.1 g of 1,6-bis- [4- (cyclohexylamino) -l-pyridiniumjhexane dibromide, mp 307-308 ° C.

Example 36:

By following a process similar to that described in Example 29C but using 13.4 g (0.076 mol) of 4- (cyclo-hexylamino) pyridine and 9.8 g (0.038 mol) of 1,7-dibromoheptane, obtains 2.01 g of 1,7-bis- [4- (cyclohexyIamino) -1-pyridinium] dibromide heptane, pf 311-313 ° C.

Example 37:

By following a process similar to that described in Example 29C but using 13.4 g (0.076 mol) of 4- (cyclo-hexylamino) pyridine and 10.34 g (0.038 mol) of 1,8-dibromooctane, we obtains 19.1 g of 1,8-bis- [4- (cyclohexylamino) -1-pyridinium] octane dibromide, mp 270-271 ° C.

Example 38:

By following a process similar to that described in Example 29C but using 13.4 g (0.076 mol) of 4- (cyclo-hexylamino) pyridine and 10.8 g (0.038 mol) of 1,9-dibromononane,

16.3 g of 1.9-bis- [4- (cyclohexylamino) -1-pyridiniumjnonane dibromide, m.p. 149-151 ° C.

Example 39:

By following a process similar to that described in Example 29C but using 13.4 g (0.076 mol) of 4- (cyclo-hexylamino) pyridine and 11.4 g (0.038 mol) of 1,10-dibromodecane, obtains 19.0 g of 1,10-bis- [4- (cyclohexylamino) -1-pyridinium] decibromide dibromide 226-227 ° C.

Example 40:

A. A mixture containing 298.0 g (1.33 mol) of N- (4-pyridyl) chloride hydrochloride is heated for 2 h with stirring in an oil bath at a bath temperature of 215 ° C. pyridinium and 322 g (2 mol) of 2-ethylhexyIamine hydrochloride. The mixture is cooled to 60 ° C, diluted with 500 ml of water and kept cold by adding ice while making it alkaline with 35% aqueous sodium hydroxide. The alkaline mixture is extracted with ether and the ethereal extracts are dried over anhydrous sodium sulfate and evaporated to dryness.

The residual oil is distilled under reduced pressure to obtain 101.0 g of 4- (2-ethylhexylamino) pyridine, mp 145-150 ° C / 0.9 mm.

B. In a variant, 4- (2-ethylhexylamino> pyridine) is prepared as follows:

To a stirred solution containing 800 g (8.4 mol) of 4-amino-pyridine and 1500 ml of triethylamine in 6.41 of dichloromethane, a solution containing 16.10 g (10.0 mol) is added for 3 h ) of 2-ethylhexanoyl chloride in 1.6 l of dichloromethane. Throughout the addition, the temperature is maintained at 15 ° C. When the addition is complete, the mixture is heated in a steam bath for 2 h. After cooling, the reaction mixture is washed thoroughly with water, dried over anhydrous sodium sulfate, treated with decolorizing carbon and filtered. Evaporation of the filtrate provides 1843 g of N- (4-pyridyl) -2-ethylhexanamide.

To a mixture containing 100 g (2.63 mol) of aluminum and lithium hydride in 21 of tetrahydrofuran, a solution containing 570 g (2.62 mol) of N is added at a speed sufficient to maintain a slight reflux. - (4-pyridyl) -2-ethylhexanamide in 41 of tetrahydrofuran. When the addition is complete (approximately 3 h), the reaction mixture is heated under reflux for 7 h. After cooling, the mixture is treated successively with 100 ml of water, with 100 ml of 15% aqueous sodium hydroxide and with 300 ml of water. The solids are removed by filtration and the solvent is evaporated from the distillate under reduced pressure. The residual oil is combined with the product from a duplicate test and they are distilled under vacuum to obtain 837 g of 4- (2-ethylhexylamino) pyridine with a boiling point of 135-160 ° C / 0, 2 mm.

C. To a stirred solution containing 10.3 g (0.05 mol) of 4- (2-ethylhexylamino) pyridine in 50 ml of acetonitrile, a solution containing 8.2 g (0.025 mol) of 1,12-dibromodecane in 170 ml of acetonitrile and the resulting mixture is heated for 20 h under reflux. By cooling to 0 ° C., it precipitates a first harvest of product which is collected by filtration. Evaporation of the filtrate and trituration of the residue with ether provides a second harvest. The combined crops are dissolved in methanol, the resulting solution is treated with decolorizing carbon, filtered and the filtrate is evaporated to dryness under reduced pressure. The residual oil is cooled and triturated with ether to obtain a slightly colored solid. Recrystallization from an acetonitrile / ether mixture, followed by trituration of the product with ether, followed by trituration with acetonitrile, provides, after drying for 72 h under vacuum at 100 ° C., 14.7 g of 1,12-bis- [4- (ethylhexylamino) -l-pyridi-niumjdodecane dibromide in the form of colorless granules, mp 146-147 ° C.

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Example 41:

A. A mixture containing 353.5 g (1.72 mol) of 4- (2-ethylhexylamino) pyridine and 205 g (0.86 mol) of 1,12-dichlorododecane is heated to 120 ° C. The heat source is removed, and the temperature of the reaction which becomes exothermic continues to rise to

180-190 ° C. When the temperature has dropped to 135 ° C., 11 acetonitrile are carefully added and the mixture is heated under reflux to obtain a clear solution. The hot acetonitrile solution is combined with similar solutions from two other tests, treated with decolorizing carbon and filtered. The filtrate is cooled, the precipitated product is collected by filtration and washed with cold acetonitrile. Two recrystallizations from acetonitrile provide 970 g of 1,12-bis- [4- (2-ethylhexylamino) -1-pyridinium] -dodecane dichloride, m.p. 168-171 ° C.

B. In a variant, by following a process similar to that described in Example 2 but using 3.0 g (0.00405 mol) of 1,12-bis- [4- (2-ethylhexylamino) dibromide - l-pyridinium] dodé-cane, 2.0 g of the corresponding dichloride are obtained, mp 172-173 ° C.

Example 42:

By following a process similar to that described in Example 41C but using 10.3 g (0.05 mol) of 4- (octylamino) -pyridine and 6.45 g (0.025 mol) of 1,7-dibromoheptane, 14.85 g of 1,7-bis- [4- (octylamino) -1-pyridinium] -heptane dibromide are obtained. 129-131 ° C.

Example 43:

A. By following a process similar to that described in Example 41C but using 11.1 g (0.054 mol) of 4- (octyl-amino) pyridine and 7.72 g (0.027 mol) of 1,9-dibromononane, 17.0 g of l, 9-bis- [4- (octylamino) -1-pyridi-nium] nonane, mp dibromide are obtained 117-119 ° C.

B. The corresponding dichloride prepared according to the method of Example 2 has a m.p. from 161-162 ° C.

Example 44:

Following a process similar to that described in Example 41C but using 10.3 g (0.05 mol) of 4- (octyl-amino) pyridine and 8.2 g (0.025 mol) of 1,12-dibromododecane , 15.2 g of 1,12-bis- [4- (octylamino) -l-pyridiniumjdodecane dibromide, mp are obtained 119-120 ° C.

Example 45:

By following a process similar to that described in Example 41C but using 5.8 g (0.028 mol) of 4- (octyl-amino) pyridine and 5.0 g (0.014 mol) of 1,14-dibromotetradecane, we obtains 9.3 g of 1,14-bis- [4- (octylamino) -1-pyridiniumjtetradecane dibromide, mp 113-115 ° C.

Example 46:

Following a process similar to that described in Example 41C but using 11.0 g (0.05 mol) of 4- (nonyl-amino) pyridine and 6.1 g (0.025 mol) of 1,6-dibromohexane , 15.2 g of 1,6-bis- [4- (nonylamino) -1-pyridiniumjhexane, mp dibromide are obtained 152-154 ° C.

Example 47:

By following a process 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, we obtain 4.95 g of the corresponding dichloride, mp 194-195 ° C.

Example 48:

Following a process similar to that described in Example 41C but using 8.8 g (0.04 mol) of 4- (nonyl-amino) pyridine and 5.2 g (0.02 mol) of 1.7 -dibromoheptane, 12.2 g of 1,7-bis- [4- (nonylamino) -1-pyridinium] heptane dibromide are obtained, mp 132-134 ° C.

Example 49:

Following a process similar to that described in Example 41C but using 11.0 g (0.05 mol) of 4- (nonyl-amino) pyridine and 7.15 g (0.025 mol) of 1,9-dibromononane , 15.7 g of l-9-bis- [4- (nonylamino) -1-pyridi-nium] nonane, mp dibromide are obtained 121-122 ° C.

Example 50:

Following a process similar to that described in Example 41C but using 11.0 g (0.05 mol) of 4- (nonyl-amino) pyridine and 7.5 g (0.025 mol) of 1,10-dibromodecane , 15.63 g of 1,10-bis- [4- (nonylamino) -1-pyridiniumjdecane dibromide, mp are obtained 172-173 ° C.

Example 51:

By following a process similar to that described in Example 41C but using 10.12 g (0.046 mol) of 4- (nonyl-amino) pyridine and 7.54 g (0.023 mol) of 1,12-dibromododecane, obtains 16.4 g of 1,12-bis- [4- (nonylamino) -l-pyridiniumjdodecane dibromide, mp 105-106 ° C.

Example 52:

To a stirred hot solution containing 12.4 g (0.06 mol) of 4- (2-ethylhexylamino) pyridine in 100 ml of acetonitrile, a solution containing 6.9 g (0.03 mol) of 1,5-dibromopentane in 25 ml of acetonitrile and the resulting solution is heated under reflux for 20 h. The reaction mixture is cooled and diluted with ether until it becomes slightly cloudy. Subsequent cooling and stirring provides a solid precipitate which is collected by filtration and washed with a cold mixture of acetonitrile and ether. The solid thus obtained is dissolved in ethanol, the resulting solution is treated with decolorizing carbon and filtered. Evaporation of the filtrate provides a pale yellow viscous oil which is crystallized from an acetonitrile / ether mixture. The resulting solid is collected by filtration, washed with a cold mixture of acetonitrile and ether and dried for 24 h under vacuum at 90 ° C to obtain 13.6 g of 1,5-bis-dibromide [ 4- (2-ethylhexyl-amino) -1-pyridinium] pentane, pf 150-151 ° C.

Example 53:

By following a process 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) of 1, 6-dibromohexane, 16.1 g of 1,6-bis- [4- (2-ethylhexylamino) -l-pyridi-niumjhexane, mp dibromide are obtained 208-209 ° C.

Example 54:

By following a process 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) of 1, 7-dibromoheptane, 17.9 g of dibromide of 1,7-bis- [4- (2-ethylhexylamino) -l-pyridi-nium] heptane are obtained, mp 219-220 ° C.

Example 55:

By following a process 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-ethylhexylamino) -l-pyridi-nium] octane, mp dibromide are obtained 160-161 ° C.

Example 56:

By following a process 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) of 1, 9-dibromononane, we get

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15.2 g of 1,9-bis- [4- (2-ethylhexylamino) -1-dibromide with silver nitrate and its NMR spectrum indicates the absence of pyridinium] nonane, m.p. 158-159 ° C. of the methanesulfonate group.

B. A suspension of 14.0 g of dibromide

Example 57: 1,6-bis- [4- (heptylamino) -1-pyridinium] hexane in 500 ml of water at

Following a process similar to that described in Example 52 s using 35% aqueous sodium hydroxide and extracted with but using 12.4 g (0.06 mol) of 4- (2 -ethylhexylamino) - chloroform. The extracts are dried with chloroform on sulphate

Pyridine and 9.0 g (0.03 mol) of 1,10-dibromodecane, anhydrous sodium is obtained and they are evaporated to dryness under reduced pressure.

17.4 g of 1,10-bis- [4- (2-ethylhexylamino) -l-pyri- dibromide The partially solid residue is dissolved in 11 of diniumjdecane mixture, m.p. 162-163 ° C. acetonitrile / benzene and the resulting solution is evaporated to dryness

io under vacuum. This procedure is repeated three times. We dissolve the

Example 58. final residue in 50 ml of acetonitrile, the solution is diluted

Following a process similar to that described in the resulting example 2 with 50 ml of benzene and cooling with ice for but using 5.0 g of 1,10-bis- [4- (2-ethyl-) dibromide 5.3 g of brownish solid are obtained after filtration and drying. The hexylamino) -1-pyridinium] decane, 4.11 g of the dichloride filtrate is obtained, providing a second harvest of 4.8 g. We combine the correspondents, m.p. 191-192 ° C. 15 harvests and they are dissolved in 50 ml of acetonitrile. The dilution

with ether precipitates a solid which is collected by filtration and

Example 59: that I store 48 h at 95 ° C / 1 mm to obtain 8.85 g of a

To a stirred hot solution containing 12.0 g (0.063 mol) of brownish liquid, m.p. 174-176 ° C. This product also provides

4- (heptylamino) pyridine in 100 ml of acetonitrile, positive test of the chloride ion with silver nitrate is added.

dropwise a solution containing 7.4 g (0.032 mol) of 20 C. The products of parts A and B above are combined,

1.5-dibromopentane in 25 ml of acetonitrile and the mixture is heated with 300 ml of water and heated until the resulting mixture for 19 h under reflux. The mixture is cooled and a homogeneous solution is obtained. The solution is filtered and the reaction is carried out in ice and ether is gradually added. The filtrate is treated and 50 ml of 12N hydrochloric acid are treated. It is concentrated until it precipitates a colorless solid. The resulting solid solution is collected under reduced pressure and the residue is treated by filtration and recrystallized from an acetonitrile / ice ether mixture. The solid thus obtained is collected by filtration, washed and dried for 48 h at 90 ° C / 1 mm to obtain 15.9 g of with cold water and dried. The 1,5-bis- [4- (heptylamino) -1-pyridinium] pentane dibromide product is then dissolved in acetone, the resulting solution is diluted with a mixture of m.p. 153-154 ° C. benzene and ethanol, and the whole is evaporated to dryness under vacuum.

The solid residue is suspended in 100 ml of acetone,

Example 60: 30 one djiue ja suspension with ether and one filters to obtain,

By following a process similar to that described in Example 60 after drying for 48 h at 105 ° C / l mm and 72 h at 115 ° C / l mm,

but using 19.2 g (0.1 mol) of 4- (heptylamino) pyridine and 16.3 g of 1,6-bis- [4- (heptylamino) -1-pyridinium dichloride] -

12.2 g (0.05 mol) of 1,6-dibromohexane, 27.5 g of crude hexane are obtained in the form of a perfectly white solid,

gross product. Recrystallization of a 15 g sample from a m.p. 176-178 ° C.

acetonitrile / ether mixture provides 11.45 g of 1,6-bis-35 dibromide

[4- (heptylamino) -1-pyridinium] hexane, m.p. 149-150 ° C. Example 62:

By following a process similar to that described in Example 60

Example 61: but using 10.30 g (0.050 mol) of 4- (2-hexylamino) pyridine

A. A suspension of 24.0 g of dibromide and 5.4 g (0.025 mol) of 1,4-dibromobutane is made alkaline, 14.9 g of

1.6-bis- [4- (heptylamino) -l-pyridinium] crude hexane in 500 ml 40 1,4-bis- [4- (2-ethylhexylamino) -l-pyridinium] dibromide using water 3N aqueous sodium hydroxide and extracted with butane, mp 245-246 ° C.

chloroform. The extracts are dried with chloroform on anhydrous sodium sulfate and evaporated to dryness under reduced pressure. Example 63:

The residual oil is dissolved in methanol, the A is acidified, the mixture is stirred and heated for approximately 2.5 h at 190-195 ° C.

resulting solution using methanesulfonic acid and a mixture containing 229 g (1.0 mol) of hydrochloride of evaporated to dryness under reduced pressure. The N- (4-pyridyl) pyridinium chloride residue and 244 g (1.26 mol) of chlorine are redissolved

in methanol, it is treated with bleaching carbon, n-decylamine hydrate. The mixture is then allowed to cool, it is filtered and evaporated to dryness under vacuum, which leaves a reaction slowly at 40 ° C. and is diluted with 21 of water.

Oily residue which, by trituration with ether followed by The resulting solution is cooled by addition of ice and trituration with acetonitrile, provides 18.2 g of a solid gomso alkalized with using 200 ml of soft aqueous sodium hydroxide. The crude solid is dissolved in water and made alkaline at 35%. The black solid which separates out resulting solution is collected by filtration using 35% aqueous sodium hydroxide and washed with cold water. This product is dissolved in and extracted with chloroform. The chloroform extracts 11 of chloroform are dried, the resulting solution is treated with anhydrous sodium sulfate and evaporated to dryness under decolorization carbon and filtered. The reduced pressure filtrate is evaporated. The resulting product is triturated successively under reduced pressure and the residue is triturated with 150 ml of ether.

with ether and acetonitrile, it is collected by filtration and the solid thus obtained is redissolved in chloroform, dried to obtain 16.3 g of a brownish solid, m.p. 105-108 ° C. treats the resulting solution with discoloration carbon and

The solid thus obtained is dissolved in 100 ml of methanol and filtered. The filtrate is again treated with carbon and the resulting solution is acidified with methanesulfonic acid. discoloration and filtered. The filtrate is evaporated to dryness

Evaporation to dryness under reduced pressure provides an oil under reduced pressure and the residual solid is triturated with queuse which is taken up in 20 ml of methanol and the ether is treated. Recrystallization from acetonitrile provides, after drying in fractions with 150 ml of water. The suspension is cooled in vacuo, 96.1 g of 4- (decylamino) pyridine, m.p. 71-73 ° C. resulting in ice, the solid is collected in suspension by B. A hot stirred solution containing 12.2 g (0.052 mol)

filtration and washed with cold water. The 4- (decylamino) pyridine is then placed in 150-170 ml of acetonitrile, it is suspended in hot acetone, cooled and a solution containing 6.35 g (0.026 mol) is added dropwise. )

collected by filtration, washed with cold acetone and dried 1,6-dibromohexane in 60 ml of acetonitrile and heated

48 h at 95 ° C / 1 mm to obtain 10.8 g of a brownish solid, the resulting mixture under reflux for approximately 20 h. We m.p. 163-165 ° C. This product gives a positive test of the chloride ion then cools the reaction mixture in ice,

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the precipitated solid is collected by filtration and washed with cold acetonitrile. The product thus obtained is dissolved in methanol, the resulting solution is treated with bleaching carbon and filtered. The filtrate is evaporated to dryness under reduced pressure and the residue is triturated with 50 ml of cold ether, it is collected by filtration and dried 2 d over phosphorus pentoxide at 70 ° C / 0.1 mm to obtain 14, 6 g of 1,6-bis- [4- (decylamino) -1-pyridinium] dibromide hexane, mp 138-140 ° C.

Example 64:

By following a process similar to that described in Example 64B but using 12.2 g (0.052 mol) of 4- (decyl-amino) pyridine and 6.7 g (0.026 mol) of 1,7-dibromoheptane, obtains 16.0 g of l, 7-bis- [4- (decylamino) -l-pyridi-niumjheptane dibromide, mp 145-147 ° C.

Example 65:

By following a process similar to that described in Example 64B but using 11.7 g (0.050 mol) of 4- (decyl-amino) pyridine and 6.8 g (0.025 mol) of 1,8-dibromooctane, we obtains 16.9 g of 1,8-bis- [4- (decylamino) -l-pyridi-niumjoctane dibromide, mp 180-182 ° C.

Example 66:

By following a process similar to that described in Example 64B but using 11.7 g (0.050 mol) of 4- (decyl-amino) pyridine and 7.15 g (0.025 mol) of 1,9-dibromononane, obtains 15.1 g of dibromide of 1,9-bis- [4- (decylamino) -l-pyridi-niumjnonane, mp 124-126 ° C.

Example 67:

By following a process similar to that described in Example 64B but using 11.2 g (0.048 mol) of 4- (decyl-amino) pyridine and 7.2 g (0.024 mol) of 1,10-dibromodecane, we obtains 14.6 g of dibromide of l, 10-bis- [4- (decylamino) -l-pyridi-nium] decane, mp 173-174 ° C.

Example 68:

By following a process similar to that described in Example 64B but using 11.2 g (0.048 mol) of 4- (decyl-amino) py ridine and 7.9 g (0.024 mol) of 1,12-dibromododecane, 16.5 g of 1,12-bis- [4- (decylamino) -1-pyridiniumjdodecane dibromide, mp are obtained 102-106 ° C.

Example 69:

To a stirred hot solution containing 13.6 g (0.052 mol) of 4- (dodecylamino) pyridine in 140 ml of acetonitrile, a solution containing 6.34 g (0.026 mol) of 1,6-dibromohexane is added dropwise in 50 ml of acetonitrile and the resulting mixture is heated under reflux overnight. The reaction mixture is cooled and the precipitated solid is collected by filtration. The solid collected is dissolved in absolute ethanol, the resulting solution is treated with decolorizing carbon and filtered. The filtrate is evaporated to dryness under reduced pressure, which gives a white residual solid which is suspended in ether, which is collected by filtration and which is dried at 60 ° C / 0.1 mm to obtain 17.63 g of 1,6-bis- [4- (dodecylamino) -1-pyridinium] hexib, dibromide 164-165 ° C.

Example 70:

By following a process similar to that described in Example 70 but using 13.6 g (0.052 mol) of 4- (dodecylamino) pyridine and 6.71 g (0.026 mol) of 1,7-dibromoheptane, 18 are obtained , 03 g of 1,7-bis- [4- (dodecylamino) -1-pyridinium] dibromide heptane, pf 148-150 ° C.

Example 71:

By following a process similar to that described in Example 70

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 dibromide is obtained [ 4- (dodecylamino) -1-pyridinium] octane, mp 184-185 ° C.

Example 72:

By following a process similar to that described in Example 70 but using 12.59 g (0.048 mol) of 4- (dodecylamino) pyridine and 6.86 g (0.024 mol) of 1,9-dibromononane, 19 are obtained , 35 g of l, 9-bis- [4- (dodecylamino) -1-pyridinium] dibromide nonane, mp 134-135 ° C.

Example 73:

By following a process similar to that described in Example 70 but using 12.59 g (0.048 mol) of 4- (dodecylamino) pyridine and 7.2 g (0.024 mol) of 1,10-dibromodecane, 18 are obtained. .08 g of l, 10-bis- [4- (dodecylamino) -1-pyridinium] decane, pf 178-180 ° C.

Example 74:

By following a process similar to that described in Example 70 but using 11.54 g (0.044 mol) of 4- (dodecylamino) pyridine and 7.22 g (0.022 mol) of 1,12-dibromododecane, 17 are obtained. , 68 g of 1,12-bis- [4- (dodecylamino) -1-pyridinium] -dodecane dibromide, mp 75-77 ° C.

Example 75:

A. To a stirred hot solution containing 21.0 g (0.102 mol) of 4- (p-chlorophenylamino) pyridine in 150 ml of N, N-dimethylformamide, a solution containing is added dropwise

11.02 g (0.051 mol) of 1,4-dibromobutane in 50 ml of acetonitrile and the resulting mixture is heated for 2.5 h in a steam bath. The reaction mixture is cooled to room temperature, diluted with ether and the product is left to crystallize. The precipitated solid is collected by filtration, washed with a mixture of acetonitrile and ether and dried in air to obtain 27.4 g of 1,4-bis-dibromide [4- (p- chlorophenylamino) -l-pyridinium] butane, pf 182-189 ° C.

B. A suspension of the preceding product in 500 ml of water is treated with ice and 2N aqueous sodium hydroxide

and the resulting mixture is completely extracted with chloroform. The chloroform extracts are dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure to obtain 21.0 g of the corresponding anhydrous base in the form of an oil which solidifies on standing.

C. A solution containing the above anhydrous base is acidified in 250 ml of methanol using a solution of methanesulfonic acid in methanol. Evaporation to dryness under reduced pressure provides an oil which is crystallized from a methanol / ether mixture. The solid thus obtained is recrystallized from a methanol / ether mixture to obtain, after drying for 48 h at 92 ° C / 0.1 mm, 18.95 g of 1,4-bis- [4- (p-chlorophenylamino) dimethanesulfonate ) -l-pyridinium] butane, pf 245-247 ° C.

Example 76:

A. To a stirred hot solution containing 21.0 g (0.102 mol) of 4- (p-chlorophenylamino) pyridine in 200 ml of N, N-dimethylformamide, a solution containing 12.45 g (0.051) is added dropwise. mol) of 1,6-dibromohexane in 50 ml of acetonitrile and the resulting mixture is heated for 4 h in a steam bath. Upon cooling to room temperature, a solid begins to precipitate. The reaction mixture is diluted with 150 ml of acetonitrile and then cooled with ice. The precipitated solid is collected by filtration and dried in air to obtain 27.2 g of 1,6-bis- [4- (p-chlorophenylamino) -1-pyridiniumjhexane dibromide, m.p. 148-150 ° C.

B. A methanolic solution of the corresponding anhydrous base is acidified, prepared from the above dibromide according to the

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process of Example 76, using methanesulfonic acid,

and then evaporated to dryness under reduced pressure. The oily residue is crystallized from an acetone / methanol mixture to obtain, after drying for 48 h at 115 ° C / 0.1 mm, 25.2 g of dimethane sulfonate of 1.6-bis- [4- (p- chlorophenylamino) -l-pyridinium] -hexane, pf 108-110 ° C.

Example 77:

A. To a stirred hot solution containing 21.0 g (0.102 mol) of 4- (p-chlorophenylamino) pyridine in 200 ml of N, N-dimethylformamide, a solution containing 13.9 g (0.051) is added dropwise. mol) of 1,8-dibromooctane in 50 ml of acetonitrile and the resulting mixture is heated for 1.5 h in a steam bath. The reaction mixture is then diluted with 100 ml of acetonitrile and heating is continued for an additional 2.5 h, after which time 100 ml of acetonitrile are added. After heating for another 2 hours, the resulting mixture is cooled and the solid which has precipitated is collected by filtration, washed with a mixture of acetonitrile and ether and dried to obtain 30.1 g of l dibromide. , 8-bis- [4- (p-chlorophenylamino) -l-pyridinium] octane, pf 245-247 ° C.

B. A methanolic solution of the corresponding anhydrous base, prepared from the above dibromide according to the method of Example 76B, is acidified with methanesulfonic acid and then evaporated to dryness under reduced pressure. The oily residue is dissolved in acetonitrile, the resulting solution is treated with acetone until the haze is followed by clarification with a small amount of methanol and cooled. The crude solid is collected which crystallizes and it is recrystallized from an acetonitrile / acetone mixture to obtain, after drying for 36 h at 80 ° C / 0.1 mm, 23.5 g of 1,8-bis- [4- dimethanesulfonate (p-chlorophenylamino) -1-pyridinium] octane, pf 164-165 ° C.

Example 78:

A. To a stirred hot solution containing 21.0 g (0.102 mol) of 4- (p-chlorophenylamino) pyridine in 200 ml of N, N-dimethylformamide, a solution containing 15.3 g (0.051) is added dropwise. mol) of 1,10-dibromodecane in 50 ml of acetonitrile and the resulting mixture is heated for 3.5 h in a steam bath. The reaction mixture is then evaporated to dryness under reduced pressure and the residual oil is crystallized from a methanol / acetonitrile mixture. The solid thus produced is collected by filtration and washed with a cold mixture of acetonitrile and ether to obtain 28.0 g of 1,10-bis- [4- (p-chlorophenylamino) -l-pyridinium dibromide ] decane, pf 225-230 ° C.

B. A methanolic solution of the corresponding anhydrous base, prepared from the above dibromide according to the method of Example 76B, is acidified with methanesulfonic acid and then evaporated to dryness under reduced pressure. The residual oil is crystallized from an acetonitrile / ether mixture. The crude solid thus obtained is dissolved in methanol and the resulting solution is treated with decolorizing carbon and filtered. Evaporation of the filtrate provides an oil which is suspended in a mixture of acetonitrile and ether to obtain a crude solid. Recrystallization from a methanol / ether mixture provides, after drying for 48 h at 95 ° C / 0.1 mm, 18.4 g of 1,10-bis- [4- (p-chlorophenylamino) -1 -pyridi dimethanesulfonate -nium] decane, pf 202-204 ° C.

Example 79:

To a hot stirred solution containing 10.0 g (0.049 mol) of 4- (p-chlorophenylamino) pyridine in a mixture of 275 ml of acetonitrile and 100 ml of dimethylformamide, a solution containing 5.75 is added dropwise g (0.025 mol) of 1,5-dibromopentane in 25 ml of acetonitrile and the resulting mixture is heated for 24 h under reflux. The reaction mixture is then evaporated to dryness under reduced pressure and the residue is triturated with a mixture of ether and acetonitrile. The pale yellow solid thus obtained is redissolved in ethanol, the resulting solution is treated with bleaching carbon and filtered. The filtrate is evaporated to dryness under reduced pressure and the residual oil is crystallized from an ether / acetonitrile mixture. The colorless solid is recrystallized from a methanol / acetonitrile mixture and dried for 48 h at 115 ° C / 0.1 mm to obtain 8.1 g of the dibromide of 1,5-bis- [4- (p-chlorophenylamino) -l-pyridinium] pen-tane, pf 166-168 ° C.

Example 80:

To a stirred hot solution containing 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, a solution is added dropwise. containing 6.45 g of 1,7-dibromoheptane in 25 ml of acetonitrile and the resulting mixture is heated for 19 h under reflux. The reaction mixture is then evaporated to dryness under reduced pressure and the residual oil is crystallized from an ethanol / acetonitrile mixture. The solid thus obtained is dissolved in methanol, the resulting solution is treated with decolorizing carbon and filtered. The filtrate is evaporated to dryness under reduced pressure and the residual oil is again crystallized from an ethanol / acetonitrile mixture. The solid produced is collected by filtration and dried for 36 h at 105 ° C / 0.1 mm to obtain 10.4 g of 1,7-bis- [4- (p-chlorophenylamino) -l-pyridinium dibromide. ] heptane, pf 202-204 ° C.

Example 81:

By following a process similar to that described in Example 81 but using 10.0 g (0.049 mol) of 4- (p-chlorophenylamino) -pyridine and 7.15 g (0.025 mol) of 1,9-dibromononane, 11.2 g of l, 9-bis- [4- (p-chlorophenylamino) -l-pyri-diniumjnonane, mp dibromide are obtained 178-179 ° C.

By following methods similar to those described in the previous examples, the following bis- [4- (R-amino) -l-pyridi-niumjalcanes are obtained:

3-ethyl-1,6-bis- [4- (tetradecylamino) -1-pyridinium] hexane dibromide hexane by reacting 1,6-dibromo-3-ethylhexane with 4- (tetradecylamino) pyridine which is even obtained by reaction of N- (4-pyridyl) pyridinium chloride hydrochloride with tetradecylamine hydrochloride,

1,5-bis- [4- (octadecylamino) -1-pyridinium] -pentane dibromide by reaction of 1,5-dibromopentane with 4- (octadecyl-amino) pyridine which is itself obtained by reaction of the hydrochloride N- (4-pyridyl) pyridinium chloride with octadecylamine hydrochloride,

1,1 l-bis- [4- (2,2-dimethylbutylamino) -1-pyridinium] -3-methylundecane dibromide by reaction of 1,1 l-dibromo-3-methylundecane with 4- (2,2 -dimethylbutylamino) pyridine which is itself prepared by reaction of N- (4-pyridyl) pyridinium chloride hydrochloride with 2,2-dimethyl-butylamine hydrochloride,

1,18-bis- [4- (1,4-dimethylpentylamino) -1-pyridiniumjoctadecane dibromide by reaction of 1,18-dibromooctadecane with 4- (1,4-dimethylpentylamino) pyridine which is itself obtained by reaction of N- (4-pyridyl) pyridinium chloride hydrochloride with 1,4-dimethylpentylamine hydrochloride,

4,9-dimethyl-1,12-bis- [4- (1,5-dimethyl-4-ethylhexylamino) -l-pyridinium] dodecane dibromide by reacting 1,12-dibromo-4,9-dimethyldodecane with 4- (1,5-dimethyl-4-ethyl-hexylamino) pyridine which is itself obtained by reaction of N- (4-pyridyl) pyridinium chloride hydrochloride with 1,5-dimethyl-4- hydrochloride ethylhexylamine,

1,10-bis- [4- (cyclopentylamino) -1-pyridinium] -decanichloride by reaction of 1,10-dichlorodecane with 4- (cyclopentyl-amino) pyridine which is itself obtained by reaction with chlor5

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N- (4-pyridyl) pyridinium chloride hydrate with cyclopentylamine hydrochloride,

1,12-bis- [4- (cycloheptylamino) -1-pyridinium] -dodecane dibromide by reaction of 1,12-dibromododecane with 4- (cyclo-heptylamino) pyridine which is itself obtained by reaction of the hydrochloride N- (4-pyridyl) pyridinium chloride with cycloheptylamine hydrochloride,

1,6-bis- [4- (p-bromophenylamino) -1-pyridinium] -3-methylhexane dibromide by reaction of 1,6-dibromo-3-methylhexane with 4- (p-bromophenylamino) pyridine which is itself obtained by reaction of N- (4-pyridyl) pyridinium chloride hydrochloride with p-bromoaniline hydrochloride,

1,10-bis- [4- (m-fluorophenylamino) -l-pyridi-nium] -decane dibromide by reaction of 1,10-dibromodecane with 4- (m-fluorophenylamino) pyridine which is itself obtained by reaction of N- (4-pyridyl) pyridinium chloride hydrochloride with m-fluoroaniline hydrochloride,

1,4-bis- [4- (3-chloro-4-fluorophenylamino) -1-pyridinium] -2-ethylbutane dibromide by reaction of 1,4-dibromo-2-ethyl butane with 4- (3- chloro-4-fluorophenylamino) pyridine which is itself obtained by reaction of N- (4-pyridyl) pyridinium chloride hydrochloride with 3-chloro-4-fluoro-aniline hydrochloride,

1,10-bis- [4- (benzylamino) -1-pyridinium] -decane dichloride by reaction of 1,10-dichlorodecane with 4- (benzyl-amino) pyridine,

1,8-bis- [4- (3,4-methylenedioxyphenylamino) -l-pyridinium] octane dibromide octane by reaction of 1,8-dibromooctane with 4- (3,4-methylenedioxyphenylamino) pyridine which is itself obtained by reaction of N- (4-pyridyl) -pyridinium chloride hydrochloride with 3,4-methylenedioxyaniline hydrochloride,

1,9-bis- [4- (p-ethylamino) -1-pyridinium] -nonane dibromide by reaction of 1,9-dibromononane with 4- (p-ethyl-phenylamino) pyridine which is itself obtained by reaction of N- (4-pyridyl) pyridinium chloride hydrochloride with p-ethylaniline hydrochloride,

1,10-bis- [4- (p-methoxyphenylamino) -l-pyri-diniumjdecane dichloride by reaction of 1,10-dichlorodecane with 4- (p-methoxyphenylamino) pyridine which is itself obtained by reaction of N- (4-pyridyl) pyridinium chloride hydrochloride with p-anisidine hydrochloride,

1,1 l-bis- [4- (m-nitrophenylamino) -l-pyridi-nium] undecane dibromide by reaction of 1,11-dibromo-undecane with 4- (m-nitrophenylamino) pyridine which is itself even obtained by reaction of N- (4-pyridyl) pyridinium chloride hydrochloride with m-nitroaniline hydrochloride,

1,12-bis- [4- (o-cyanophenylamino) -l-pyridi-nium] dodecane dibromide by reaction of 1,12-dibromododecane with 4- (o-cyanophenylamino) pyridine which is itself obtained by reaction N- (4-pyridyl) pyridinium chloride hydrochloride with o-cyanoaniline hydrochloride,

1,16-bis- [4-m- (trifluoromethyl) phenylamino-l-pyridinium] hexadecane dibromide by reaction of 1,16-dibromohexadecane with 4- [m- (trifluoromethyl) phenylamino] pyridine which is itself obtained by reaction of N- (4-pyridyl) pyridinium chloride hydrochloride with m- (trifluorome-methyl) aniline hydrochloride, and 1,7-bis- [4- (2-methoxy-5-methylphenylamino) dibromide ) -l-pyridinium] heptane by reaction of 1,7-dibromoheptane with 4- (2-methoxy-5-methylphenylamino) pyridine which is itself obtained by reaction of N- (4-pyridyl) chloride hydrochloride - pyridinium with 2-methoxy-5-methylaniline hydrochloride.

The following examples are additional illustrative examples of bis- [4- (R-amino) -1-pyridinium] alkanes of formula I which are obtained according to the methods described above:

3-methyl-1,5-bis- [4- (undecylamino) -1-pyridinium] pentane dibromide,

3-propyl-1,5-bis- [4- (tridecylamino) -1-pyridi-niumjpentane dichloride,

4,4-dimethyl-1,7-bis- [4- (pentadecylamino) -1-pyridinium] heptane sulfate,

2,6-dimethyl-1,7-bis- [4- (hexadecylamino) -1-pyridinium] heptane disulfamate,

1-methyl-1,4-bis- [4- (heptadecylamino) -1 -pyridinium] butane dibenzenesulfonate,

2,4,4-trimethyl-1,6-bis- [4- (2-methylhexylamino) -1-pyridinium] hexane biscyclohexylsulfamate,

1,17-bis- [4- (3-ethylpentylamino) -l-pyridi-nium] heptadecane dibromide,

1,16-bis- [4- (1-ethylhexylamino) -1-pyridinium] -hexadecane dinitrate,

1,15-bis- [4- (heptylamino) -1-pyridinium] -pentadecane dibromide,

1,13-bis- [4- (octylamino) -1-pyridinium] tridecan di-2-naphthalenesulfonate,

1,1 l-bis- [4- (3-ethylheptyl-amino) -1 -pyridiniumjundecane 2,6-naphthalenedisulfonate,

4-methyl-1,14-bis- [4- (2-propylpentylamino) -1 -pyridiniumjtetradecane dichloride,

5-ethyl-1,9-bis- [4- (1,3,5-trimethylhexyl-amino) -1-pyridinium] nonane dibromide,

3,3,6,6 -tetramethyl-1,8-bis- [4- (heptylamino) -1-pyridinium] octane dibromide,

2,13-dimethyl-1,14-bis- [4- (1,2-dimethyltetra-decylamino) -1 -pyridinium] tetradecane dibromide,

1,6-bis- [4- (1-methylpentylamino) -1-pyridinium] hexane di-p-toluenesulfonate,

1,8-bis- [4- (2-methylheptylamino) -1-pyridinium] -octane diiodide,

1,8-bis- [4- (2-methyl-3-ethylpentyl-amino) -1-pyridinium] octane diethanesulfonate,

1,9-bis- [4- (o-chlorophenylamino) -1-pyridi-niumjnonane dibromide,

1,8-bis- [4- (p-iodophenylamino) -1-pyridinium] -octane diiodide,

1,12-bis- [4- (2,4-difluorophenylamino) -l-pyridiniumjdodecane dibromide,

l, ll-bis- [4- (2,5-dibromophenylamino) -l-pyri-diniumjundecane dibromide,

1,10-bis- [4- (3,5-dichlorophenylamino) -1-pyridinium] decane dichloride,

1,8-bis- [4- (2-fluorobenzylamino) -1-pyridi-niumjoctane dichloride,

1,18-bis- [4- (3,4-dichlorobenzylamino) -1-pyridinium] octadecane dibromide,

1,4-bis- [4- (4-hydroxy-3-methoxybenzyl-amino) -1-pyridinium] butane dibromide and 1,12-bis- [4- (4-methylbenzylamino) -1 dibromide -pyridinium] dodecane.

Example 82:

To a hot stirred solution containing 11.52 g (0.06 mol) of 4- (heptylamino) pyridine in 100 ml of acetonitrile, a solution containing 7.92 g (0.03 mol) of a, a'-dibromo-p-xylene in 150 ml of acetonitrile. After the addition is complete, a large mass of colorless crystals separates from the solution. The reaction mixture is heated under reflux for 6 h. After cooling to room temperature, the solid product is collected by filtration, washed with an acetonitrile / ether mixture, combined with 3.1 g of the product obtained in a preceding test and dried for 28 h at 100 ° C. / 0.1 mm to obtain 22.0 g of oc dibromide, a'-bis- [4- (heptyl-amino) pyridinium] -p-xylene, pf 297-298 ° C.

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16

Example 83:

Following a process similar to that described in Example 83 but using 11.6 g (0.065 mol) of 4- (hexylamino) pyridine and 8.7 g (0.033 mol) of ot, a'-dibromo-p -xylene and by placing the reaction mixture under reflux for 20 h, 19.3 g of a, a'-bis- [4- (hexylamino) pyridinium] -p-xylene, pf dibromide are obtained 313-315 ° C.

Example 84:

Heated in a steam bath to obtain a complete reaction, a suspension of 19 g of 4-aminopyridine and 23 g of a, a'-dichloro-2,3,5,6-tetramethyl-p-xylene in 600 ml of methanol. After filtering a small amount of insoluble product, the clear solution is moderately heated in a steam bath for 2 h, during which time a white solid begins to precipitate. The mixture is cooled to room temperature and the solid product is collected by filtration, washed successively with methanol and ether and dried for 24 h under vacuum at 100 ° C to obtain 29 g of a, a dichloride '-bis- (4-amino-1-pyridinium) -2,3,5,6-tetramethyl-p-xylene, pf > 340 ° C.

Example 85:

To a hot solution containing 12.5 g (0.132 mol) of 4-aminopyridine in 100 ml of 2-propanol, 11.6 g (0.066 mol) of a, a'-dichloro-p-xylene are added, then 400 ml of methanol. The mixture is heated to obtain a perfect solution. After filtration of a small amount of insoluble product, the clear solution is diluted with 500 ml of ethyl acetate and cooled to room temperature. The solid product is collected by filtration, washed with ethyl acetate and dried to obtain 16 g of a, oc'-bis- (4-amino-1-pyridinium) -p-xylene dichloride. , pf 332-335 ° C.

The following examples are additional illustrative examples of the a, a'-bis- [4- (R-amino) -1-pyridinium] xylenes of formula II which can be obtained according to the methods described above:

a, a'-bis- [4- (ethylamino) -1-pyridinium] -p-xylene dibromide by reaction of a, a'-dibromo-p-xylene with 4- (ethyl-amino) pyridine;

a, a'-bis- [4- (2-ethylhexylamino) -l-pyridi-nium] -p-xylene dichloride by Foc reaction, a'-dichloro-p-xylene with

4- (2-ethylhexylamino) pyridine (boiling point 145-150 ° C / 0.9 mm) which was prepared by reaction of N- (4-pyridyl) pyridinium chloride hydrochloride with 2 hydrochloride -ethylhexylamine;

a, a'-bis- [4- (decylamino) -1-pyridinium] -p-xylene dibromide by reaction of a, a'-dibromo-p-xylene with 4- (decylamino) -pyridine (mp 71-73 'C) which was prepared by reaction of N- (4-pyridyl) pyridinium chloride hydrochloride with n-decylamine hydrochloride;

a, a'-bis- [4- (dodecylamino) -l-pyridinium] -p-xylene dichloride by reaction of a.a'-dichloro-p-xylene with 4- (dodé-cylamino) pyridine;

a, a'-bis- [4- (octadecylamino) -l-pyridinium] -p-xylene dibromide by reacting Fa, ct'-dibromo-p-xylene with 4- (octa-decylamino) pyridine which is itself obtained by reaction of N- (4-pyridyl) pyridinium chloride hydrochloride with octadecylamine hydrochloride;

a, a'-bis- [4- (tetradecylamino) -l-pyridinium] -m-xylene dichloride by reaction of Fa, a'-dichloro-m-xylene with 4- (tetradecylamino) pyridine (pf 91 -93 ° C) which is prepared by reaction of N- (4-pyridyl) pyridinium chloride hydrochloride with tetradecylamine hydrochloride;

a, a'-bis- [4- (butylamino) -1-pyridinium] -o-xylene dibromide by reaction of a, a'-dibromo-o-xylene with 4- (butyl-amino) pyridine;

a, a'-bis- [4- (3-ethylheptylamino) -1-pyridinium dibromide] -

5-methyl-m-xylene by reaction of a, a'-dibromo-5-methyl-m-

xylene with 4- (3-ethylheptylamino) pyridine which is itself obtained by reaction of N- (4-pyridyl) -pyridinium chloride hydrochloride with 3-ethylheptylamine hydrochloride;

o, a'-bis- [4- (2-methylheptylamino) -1-pyridinium] -2,5-dimethyl-p-xylene dibromide by reaction of a, oc'-dibromo-2,5- dimethyl-p-xylene with 4- (2-methylheptylamino) pyridine which is itself obtained by reaction of N- (4-pyridyl) pyridinium chloride hydrochloride with 2-methylheptylamine hydrochloride;

a, a'-bis- [4- (octylamino) -1-pyridinium] -2,4,6-trimethyl-m-xylene dichloride by reaction of a, a'-dichloro-2,4,6 -trimethyl-m-xylene with 4- (octylamino) pyridine (mp 62-63 ° C) which is prepared by reaction of N- (4-pyridyl) -pyridinium chloride hydrochloride with n-octylamine hydrochloride ;

a, a'-bis- [4- (2,2-dimethylbutylamino) -1-pyridinium] -2-chloro-p-xylene dichloride by reaction of a, oc'-2-trichloro-p-xylene with 4- (2,2-dimethylbutylamino) pyridine which is itself prepared by reaction of N- (4-pyridyl) pyridinium chloride hydrochloride with 2,2-dimethylbutylamine hydrochloride;

a, a'-bis- [4- (methylamino) -1-pyridinium] -4-chloro-o-xylene dibromide by reaction of a, oc'-dibromo-4-chloro-o-xylene with 4- (methylamino) pyridine;

oc dichloride, a'-bis- [4- (2-propylpentylamino) -l-pyridi-nium] -2,5-dichloro-p-xylene by reaction of oc, oc'-2,5-tetrachloro -p-xylene with 4- (2-propylpentylamino) pyridine which is itself prepared by reaction of N- (4-pyridyl) -pyridinium chloride hydrochloride with 2-propylpentylamine hydrochloride;

tx, a'-bis- [4- (1,1-dimethylundecylamino) -1-pyridinium] -2,3,5-trichloro-p-xylene dichloride by reaction of a, a'-2,3 , 5-pentachloro-p-xylene with 4- (1,1-dimethylundecylamino) -pyridine which is itself prepared by reaction of N- (4-pyridyl) pyridinium chloride hydrochloride with 1,1 hydrochloride - dimethylundecylamine;

a, a'-bis- [4- (nonylamino) -1-pyridinium] -2,3,5,6-tetrachloro-p-xylene dichloride by reaction of oc, a'-2,3,5 , 6-hexachloro-p-xylene with 4- (nonylamino) pyridine (mp 59-60 ° C) which is prepared by reaction of N- (4-pyridyl) -pyridinium chloride hydrochloride with n hydrochloride -nonylamine;

a, a'-bis- [4- (benzylamino) -1-pyridinium] -p-xylene dibromide by reaction of oc, a'-dibromo-p-xylene with 4- (benzyl-amino) pyridine which is itself prepared by reaction of N- (4-pyridyl) pyridinium chloride hydrochloride with benzylamine; and a, a'-bis- [4- (benzylamino) -1-pyridinium] -2-chloro-p-xylene dichloride by reaction of a, a'-2-trichloro-p-xylene with 4 - (benzylamino) pyridine which is itself prepared by reaction of N- (4-pyridyl) pyridinium chloride hydrochloride with benzylamine.

Antibacterial and antifungal activity is determined from representative examples of the compounds of formulas I and II using a modification of the Autotiter method described by Goss et al., "Applied Microbiology", 16 (9), 1414-1416 (1968), in which a solution of 1000 jig / ml of the test compound is prepared. To the first cup of the Autotray, 0.1 ml of the test solution is added. Activation of the Autotiter triggers a sequence of operations in which 0.05 ml of the test compound solution is drawn off from the cup using a transfer loop of the Microtiter and which is diluted in 0.05 ml of sterile water. After this operation, 0.05 ml of a semi-synthetic inoculated medium of double intensity (glucose) is automatically added to each cup. The total operation results in final drug concentrations ranging from 500 to 0.06 mg / ml in decreases of two. The Autotray is incubated for 18 to 20 h at 37 ° C., at the end of which the plates are visually examined from the point of view of growth, which is highlighted by turbidity, and the concentration of the last sample of the series showing no growth

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(or no turbidity) as the minimum inhibitory concentration (MIC) in ng / ml. This is how the compounds are examined in the form of solutions with regard to a certain number of Gram positive and Gram negative bacteria including Staphylo-coccus aureus, Proteus mirabilis, Escherichia coli, Klebsiella-pneumoniae, Pseudomonas aeruginosa , Streptococcus pyogenes, and vis-à-vis fungi such as Aspergillus niger, Candida albicans and Trichophyton mentagrophytes.

It is also found that many compounds of formula I are effective on the antibacterial level with regard to Streptococcus mutans and Actinomyces A-viscosis.

The virulicidal activity of the representative examples with respect to the herpes simplex virus type 2 is determined in vitro using a method similar to that of the plaque inhibition test for the detection of specific inhibitors of viruses containing DNA, process published by EC Herrmann, Jr., "Proc. Soc. Exp. Biol. Med. ”, 107.142 (1961), in which 2 mg of the test compound is placed on the surface of a growth medium. The compounds corresponding to examples 3, 5C, 7, 9C, 10, 11, 13, 17, 18, 21, 22, 24, 31, 33, 35, 36, 37, 53, 54, 56, 57 are found to be 58, 60, 61, 63, 81, 82, 83 and 84 are active and the compounds of Examples 16, 34, 39, 40 and 79B are found to be inactive.

The prevention activity of dental plaque of certain of the compounds of the present invention is determined by measuring the attitude of these compounds to inhibit the production of dental plaque by Streptococcus mutans OMZ-61, as follows:

Adjusted to pH 7.0 and sterilized by membrane filtration a culture medium for the production of plate of Streptococcus mutans OMZ-61 containing 1.5 g of BBL beef extract, 5 g of sodium chloride, 10 g dehydrated trypticase, 5 g of sucrose and enough distilled water to have a total volume of 1000 ml. The medium is distributed under asepsis in the form of 10 ml aliquots in test tubes of dimension 150 × 16 mm and they are kept at refrigerator temperature until use.

Two concentrations of the compound to be examined are prepared by dissolving 100 mg of the compound in 1 ml of distilled water using sufficient 0.1N sodium hydroxide, 10% dimethyl sulphoxide or N, N-dimethylformamide to 10% and diluting the resulting solution to 10 ml with distilled water. This solution is sterilized to 1.0% and a solution obtained by dilution to 1/10 in distilled water (0.1%) by membrane filtration before use.

A sterile sample of natural tooth enamel without plaque or synthetic hydroxylapatite is suspended in each concentration of the compound for two periods of 1 min, each followed by a period of air drying of 1 min. Each sample is then suspended and stirred for 5 min in sterile distilled water (rinsing). They are then suspended in 10 ml of a medium of liquid beef extract to which 0.3 ml of an anaerobic culture has been added for 24 h of Streptococcus mutans. The tubes containing the treated hydroxylapatite and Streptococcus mutans are then incubated anaerobically at 37 ° C. for 24 h. The same process is repeated of two soaking for 1 min in the solution of the compound, each followed by 1 min in the solution of the compound, each followed by 1 min of air drying and the final rinsing of 5 min before suspending at again the hydroxylapatite in a new tube containing 10 ml of the beef extract medium and 0.3 ml of the inoculum. At the end of the second 24 h period, each hydroxylapatite sample is rinsed for 1 min in three successive tubes of distilled water. They are then suspended for 1 min in a solution of red dye No. 3 F, D and C. The stain procedure is used to more easily identify the development of the plaque after the 48 h period of exposure to the organism that produces plaque. The stain period is followed by another rinse for 10 s to remove excess dye. Any plaque formation is colored in brilliant pink. The test results are read in the form of inhibition of plaque (active) and in the form of non-inhibition of plaque (inactive) at the concentration examined in percent. Active compounds are examined at successively lower doses to determine the minimum effective concentration. In some cases, interference from the production of plaque is caused by the inhibition of organism growth in the culture medium, given that the compound is extracted from hydroxylapatite to give an antibacterial level in the medium. . When this occurs, the compound is examined at lower concentrations until the growth of the organism in the surrounding medium is equal to that of the control culture not treated with the drug. A plaque may or may not form at these lower concentrations.

The substantivity of the test compound vis-à-vis the dental surface, which is of course necessary to avoid the formation of dental plaque on its surface, can however make possible the accumulation of agents giving stains on the tooth surface, such as coffee, tobacco, food colors, etc. This is why the preceding method is also used to estimate the potential for creating stains, that is to say the ability of the test compound to contribute to adhering agents giving stains to the surface of the teeth. . Therefore, a uniform pale pink residual color adhering to the test surface after the final rinse is indicative of the stainability at the actual concentration tested and is called the stain concentration. The uniform pale pink coloration caused by the test compound is easily distinguished from the localized bright pink coloration caused by plaque formation. In general, the preferred types of compounds advantageously have a concentration of stain formation considerably higher than the minimum effective concentration preventing the formation of plaque.

Table A presents the results of digital antibacterial, antifungal tests and tests to inhibit the formation of dental plaque. Also shown in Table A for comparison purposes are the corresponding results for two known compounds, i.e., 1,8-bis- (4-amino-1-pyridinium) octane dibromide (compound I) and 1,10-bis- (4-amino-1-pyridinium) decane dibromide (reference compound II). The concentrations of stain formation are reported in Table C for representative examples.

The antibacterial efficacy in the presence of serum is determined for the representative examples by the normal serial tube dilution test, in which coupled comparisons of minimum inhibitory concentrations (MIC) are determined in the absence or in the presence of horse (40%) heat inactivated (30 min at 56 ° C) in the test medium. The results are expressed in the form of an increase in number of times of the ICD value (mcg / ml) vis-à-vis Staphyloccocus aureus and Escherichia coli caused by the presence of serum, and the results are presented in the table. B.

The prevention efficacy of dental plaque in the presence of sterile human saliva (at 50%) is determined for representative examples. The test results are read as the minimum effective concentrations and are presented in Table C.

The acute oral toxicity (ALD50) of a few representative examples is determined as follows: groups of 3 young adult male albino mice of Swiss-Webster race are fasted for approximately 4 h before drug treatment and the drug is then administered orally using a stomach tube. All mice are observed for 7 days after administration of the drug. The autopsy of all the mice under study did not show any significant tissue changes, except for the group receiving 1000 mg / kg of the compound of Example 25 for which congestion was observed in the glandular part of the stomach. two and three mice. The results are presented in Table D.

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I

II

76i

771

781

791

61

621

21

60

22

17

18

23

32

19

33

31

16

20

26

24

25

63

53

54

55

57

27

58

59

56

81

82

34

35

36

37

Table A

Antibacterial and antifungal activity in vitro ICD (n / ml)

Plaque prevention activity

S. E. K. P. Ps. S. C. C. Concentration aureus coli pneum. mirab. aerug. E. coli E. coli pyogen. A. niger albicans albicans T. menta, examined (%)

Smith Vogel 39645 MGH-1 MGH-2 AB1932-1 100 / B22 C203 16404 10231 Wisc. 9129 Active Inactive

31.3

125

> 500

> 500

> 500

125

250

31.3

125

125

125

125

1.0

7.8

62.5

250

> 500

500

31.3

62.5

7.8

125

62.5

62.5

15.6

1.0

7.8

15.6

> 250

> 250

> 125

7.8

15.6

1.95

> 250

125

12.5

62.5

1.0

3.9

15.6

500

500

500

3.9

15.6

1.95

62.5

62.5

125

15.6

1.0

0.4

3.1

31.3

125

125

1.6

3.1

0.2

31.3

62.5

62.5

31.3

1.0

0.4

1.6

3.1

> 125

62.5

0.8

1.6

0.4

25

3.13

6.25

6.25

1.0

0.2

3.1

6.3

> 250

125

1.6

1.6

0.4

25

6.25

6.25

3.13

1.0

0.24

3.9

3.9

> 125

> 62.5

1.95

1.95

0.98

7.8

3.9

3.9

3.9

1.0

0.24

1.95

3.9

125

125

1.95

1.95

0.98

15.6

3.9

3.9

3.9

1.0

0.49

31.3

31.3

> 125

125

3.9

7.8

1.95

15.6

15.6

15.6

7.8

1.0

0.39

1.95

1.95

62.5

313

0.98

0.98

0.49

15.6

0.98

1.95

1.95

0.1

0.49

31.3

125

> 250

> 125

7.8

7.8

0.78

> 250

7.8

15.6

15.6

1.0

0.39

15.6

15.6

> 125

> 125

7.8

7.8

0.49

15.6

6.25

7.8

15.6

1.0

0.5

1.95

1.95

62.6

31.3

1.0

1.95

1.0

7.8

1.0

1.95

1.95

0.1

0.24

3.9

7.8

> 250

125

1.95

3.9

0.49

7.8

3.9

3.9

7.8

1.0

0.39

1.95

3.9

125

125

1.95

1.95

0.49

15.6

1.95

3.9

3.9

1.0

0.195

1.95

3.9

31.3

31.3

0.98

1.95

0.49

3.9

1.95

3.9

1.95

1.0

1.95

125

> 125

> 250

> 125

31.3

62.5

0.98

31.3

31.3

62.5

31.3

1.0

7.8

125

> 125

> 125

> 250

62.5

125

1.95

125

125

125

15.6

1.0

0.98

31.3

> 125

> 250

> 250

7.8

15.6

0.49

15.6

15.6

15.6

3.9

1.0

0.37

0.75

1.49

6.0

11.9

0.75

0.75

1.95

2.98

0.75

1.49

0.75

0.01

0.25

1.0

1.95

15.6

62.5

1.0

1.95

0.5

3.9

1.0

1.0

0.5

0.003

0.25

1.0

1.95

31.3

31.3

1.0

1.0

0.5

1.95

1.0

1.0

1.0

0.004

0.98

62.5

> 125

> 125

125

7.8

31.3

1.25

31.3

31.3

31.3

15.6

1.0

0.49

15.6

> 125

> 125

125

7.8

15.6

0.625

31.3

31.3

15.6

7.8

1.0

0.49

7.8

125

> 125

> 250

1.95

3.9

0.625

15.6

7.8

7.8

1.95

1.0

0.49

3.9

7.8

> 125

125

3.9

3.9

0.49

15.6

7.8

7.8

1.95

1.0

0.31

0.98

7.8

125

125

0.98

0.98

0.625

15.6

3.9

3.9

0.98

1.0

0.25

0.5

1.0

7.8

7.8

1.0

0.5

0.5

3.9

1.96

1.0

1.0

0.004

0.24

1.5

3.0

12.1

48.4

0.37

0.76

1.95

6.0

3.0

1.5

0.76

0.003

0.25

1.0

1.95

7.8

31.3

1.0

0.5

1.0

15.6

1.95

1.95

1.0

0.003

0.31

3.9

7.8

125

125

0.98

1.95

0.16

15.6

3.9

3.9

1.95

0.004

0.98

3.9

> 125

> 125

> 125

125

3.9

0.49

31.3

31.3

31.3

7.8

1.0

0.625

0.98

7.8

> 125

125

0.98

1.95

0.24

15.6

3.9

3.9

3.9

1.0

125

125

> 500

> 500

> 500

125

125

31.3

500

500

500

125

1.0

125

> 500

> 500

> 500

> 500

> 500

> 500

15.6

500

500

500

125

1.0

15.6

> 125

> 125

> 125

> 125

125

> 125

15.6

125

125

125

15.6

1.0

7.8

> 125

> 125

> 125

125

125

> 125

7.8

> 125

125

125

15.6

1.0

Table A (continued)

Comp.

S.

E.

K.

P.

Ps.

from the ex.

aureus coli pneum.

mirab.

aerug.

E. coli

E. coli

No.

Smith

Vogel

39645

MGH-1

MGH-2

AB1932-1

100 / B 22

80

7.8

125

> 125

> 125

> 125

31.3

125

38

3.9

62.5

> 125

> 125

250

31.3

62.5

40

0.24

15.6

> 125

> 125

> 125

7.8

15.6

39

0.98

31.3

125

> 500

500

31.3

31.3

3

0.39

1.56

3.13

3.13

6.25

6.25

3.13

2

1.0

1.95

3.9

3.9

1.95

1.0

1.0

4

0.25

0.5

1.95

1.95

3.9

1.0

0.5

8

0.25

1.0

1.0

7.8

15.6

1.0

0.5

1D

0.77

1.54

0.77

1.54

3.0

3.0

0.77

10

0.5

1.95

1.95

3.9

3.9

1.0

1.0

7

0.15

0.37

1.5

6.0

23.8

0.37

0.37

5C

0.38

0.76

0.76

1.5

6.0

0.76

0.76

6

0.5

1.0

1.0

3.9

3.9

0.5

0.5

13

0.5

1.95

3.9

31.3

31.3

1.0

1.95

14

0.25

1.0

1.95

15.6

31.3

0.5

0.5

11

0.25

1.0

1.95

7.8

15.6

1.0

1.95

12

0.25

1.0

1.0

3.9

7.8

1.0

0.5

9C

0.5

1.95

3.9

3.9

3.9

1.0

1.95

45

0.5

1.95

1.0

1.95

1.95

1.95

1.95

43

0.5

1.95

1.0

7.8

31.3

1.0

1.0

46

1.0

7.8

7.8

3.9

3.9

3.9

3.9

44A

1.0

1.0

1.95

15.6

3.9

1.0

1.0

47

0.5

1.0

3.9

3.9

15.6

1.95

1.95

48

1.0

1.95

3.9

7.8

15.6

1.95

1.95

29C

1.0

3.9

1.95

3.9

7.8

1.95

1.95

50

1.95

1.95

3.9

3.9

3.9

3.9

1.95

51

1.95

1.95

3.9

3.9

3.9

3.9

3.9

52

1.95

3.9

3.9

3.9

3.9

7.8

3.9

72

7.8

31.3

> 62.5

62.5

> 62.5

62.5

> 62.5

73

7.8

62.5

> 62.5

62.5

> 62.5

> 62.5

62.5

70

7.8

31.3

> 62.5

> 62.5

> 62.5

> 62.5

62.5

71

3.9

62.5

> 62.5

62.5

62.5

62.5

62.5

74

15.6

> 62.5

> 62.5

> 62.5

> 62.5

> 62.5

> 62.5

75

31.3

> 62.5

> 62.5

> 62.5

> 62.5

> 62.5

> 62.5

65

1.0

3.9

7.8

3.9

7.8

3.9

3.9

66

1.0

1.95

3.9

7.8

7.8

7.8

3.9

67

1.0

1.95

15.6

7.8

7.8

7.8

3.9

68

1.95

7.8

31.3

7.8

15.6

15.6

15.6

69

1.95

7.8

31.3

15.6

15.6

31.3

15.6

49

0.5

1.0

1.95

3.9

15.6

1.95

1.95

Plaque prevention activity S. C. C. Pyogen concentration. A. niger albicans albicans T. menta, examined (%) • C203 16404 10231 Wisc. 9129 Active Inactive

1.95

62.5

62.5

62.5

15.6

1.0

0.93

15.6

31.3

31.3

3.9

1.0

3.9

7.8

3.9

7.8

1.95

1.0

3.9

7.8

15.6

15.6

3.9

1.0

0.39

3.13

1.56

3.13

1.56

0.004

1.0

7.8

3.9

7.8

1.0

0.01

1.0

7.8

1.95

1.95

0.5

0.003

1.0

7.8

1.0

1.0

1.0

0.01

1.95

3.0

1.54

1.54

0.77

0.1

1.0

7.8

1.95

1.95

1.95

0.005

1.0

3.0

0.74

0.74

0.37

0.01

1.0

3.0

1.5

0.76

0.76

0.005

1.95

3.9

1.0

1.95

0.5

0.004

0.5

3.9

1.95

1.95

0.5

0.004

0.5

15.6

1.95

1.95

1.0

0.004

1.0

3.9

1.0

1.0

0.5

0.004

0.5

7.8

1.0

1.0

1.0

0.005

0.5

1.95

1.0

1.0

1.0

0.004

1.0

7.8

1.0

3.9

1.0

0.005

1.0

7.8

1.95

1.95

1.0

0.005

1.95

15.6

7.8

7.8

1.95

0.005

0.5

3.9

1.0

1.95

1.0

0.003

1.0

15.6

3.9

1.95

1.0

0.004

1.0

3.9

1.95

1.95

1.0

0.01

1.95

7.8

3.9

3.9

1.95

0.004

1.95

7.8

3.9

3.9

1.95

0.004

1.95

7.8

3.9

3.9

1.95

0.004

1.95

15.6

7.8

7.8

1.95

0.01

15.6

> 62.5

31.3

31.3

7.8

0.1

15.6

> 62.5

> 62.5

31.3

7.8

0.1

7.8

62.5

15.6

31.3

7.8

0.1

7.0

62.5

62.5

62.5

7.8

0.1

15.6

> 62.5

> 62.5

> 62.5

15.6

0.1

15.6

> 62.5

> 62.5

> 62.5

15.6

1.0

1.0

7.8

15.6

15.6

1.95

0.01

1.95

15.6

7.8

15.6

1.95

0.01

1.95

31.3

31.3

15.6

3.9

0.01

3.9

15.6

15.6

15.6

3.9

0.01

3.9

15.6

15.6

15.6

3.9

0.1

1.0

7.8

1.95

1.95

1.0

0.004

Table A (continued)

Comp, from the ex. No.

S.

aureus Smith

E.

coli

Vogel

K.

pneum. 39645

P.

mirab. MGH-1

Ps.

aerug. MGH-2

E. coli AB1932-1

E. coli 100 / B22

S.

pyogen. C203

A. niger 16404

vs.

albicans 10231

vs.

Wisc albicans.

Plaque prevention activity Concentration T. menta, examined (%) 9129 Active Inactive

64B

1.0

1.95

3.9

1.95

7.8

1.95

7.8

1.0

7.8

1.95

3.9

1.0

0.01

41C

0.5

1.0

1.95

3.9

3.9

1.0

1.0

0.5

3.9

1.0

1.0

1.0

0.1

83

1.95

15.6

125

125

125

7.8

15.6

3.9

125

125

125

125

84

1.44

23.2

92.6

92.6

92.6

5.8

11.6

1.0

23.2

23.2

46.3

5.8

85

31.3

500

500

500

500

• -

• -

-

500

500

-

250

86

250

500

500

500

500

-

-

-

31.3

500

-

-

Table B

Influence of the serum on the bacteriostatic activity CIM ((ig / ml) vis-à-vis the bacteria indicated

S. aureus ATCC 6538 E. coli ATCC 8739

Compound

0% of

40% of

Increase

% of

40% of

Increase in ex. No.

serum serum number of times serum serum number of times

79B

0.25

7.8

32

0.5

15.6

32

22

0.25

3.9

16

0.5

3.9

8

33

0.125

1.95

16

0.25

3.9

16

26

0.125

1.95

16

0.5

7.8

16

24

0.125

1.95

16

0.25

7.8

32

58

0.25

3.9

16

0.5

15.6

32

3

0.39

3.12

8

0.78

25.0

32

1D

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

29C

0.5

7.8

16

3.9

62.5

16

41C

0.25

7.8

32

1.0

62.5

64

83

0.78

6.25

8

0.78

6.25

8

84

3.12

12.5

4

1.56

6.25

4

21

620 907

Table C

Potential for stain formation and influence of saliva on the prevention activity of dental plaque

Prevention activity

Compound

dental plaque in

Concentration of the example saliva at 50%. Concentration spot formation

No.

minimum effective (%)

(%)

27

0.05

24

about

0.005

0.05

25

0.05

58

about

0.005

0.05

59

0.05

56

0.1

0.05

3

0.1

0.05

4

about

0.005

0.005

5C

0.051

0.005

6

0.005

13

0.005

14

0.1

0.05

11

0.05

0.05

12

0.05

9C

about

0.005

0.05

10

0.005

0.05

44A

0.005

0.05

47

0.004

29C

0.004

50

0.004

51

0.004

49

0.005

1. No bacterial growth at this concentration, plaque formed at 0.005%.

Table D Acute oral toxicity (ADL50)

Compound of Solution or Dose, mg / kg Mortality example No. suspension of total product 24 h 7d

23 Solution 125 0/3 0/3 aqueous 250 0/3 0/3

500 1/3 1/3

1000 3/3 3/3 ALD50 at 7 days = 625 mg / kg

26 Suspension 125 0/3 0/3 in 1% G.T.i 250 0/3 0/3

500 0/3 0/3

1000 0/3 0/3

ALD50 at 7 days = 1000 mg / kg

27 Solution 125 0/3 1/3 aqueous 250 0/3 0/3

500 1/3 1/3

^ 1000 1/3 3/3

ALD50 at 7 days = 250 mg / kg

24 Suspension 125 0/3 0/3 in 1% G.T. 250 0/3 0/3

500 0/3 1/3

1000 0/3 0/3

ALD50 at 7 days = 1000 mg / kg

25 Solution 250 1/3 1/3 aqueous 500 1/3 1/3

1000 3/3 3/3

ALD50 at 7 days = 500 mg / kg

Composed of

Solution or Dose, mg / kg Mortality

Example No.

24 h total product suspension

7d

3

Suspension 125

0/3

0/3

in 1% G.T. 250

0/3

0/3

500

0/3

1/3

1000

1/3

1/3

ALD50 at 7 d =

1000 mg / kg

4

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

ALD50 at 7 d =

1000 mg / kg

2

Suspension 125

0/3

0/3

in 1% G.T. 250

0/3

1/3

500

0/3

0/3

1000

0/3

1/3

ALD50 at 7 d =

1000 mg / kg

8

Solution 125

0/3

0/3

aqueous 250

1/3

1/3

500

2/3

3/3

1000

3/3

3/3

ALD50 at 7 d =

315 mg / kg

5C

Suspension 125

0/3

0/3

in 1% G.T. 250

0/3

0/3

500

0/3

0/3

1000

1/3

1/3

ALD50 at 7 d =

1000 mg / kg

6

Solution 125

1/3

1/3

aqueous 250

0/3

1/3

500

2/3

2/3

1000

3/3

3/3

ALD50 at 7 d =

315 mg / kg

1D

Suspension 125

0/3

0/3

in 1% G.T. 250

0/3

0/3

500

1/3

1/3

1000

2/3

2/3

ALD50 at 7 d =

750 mg / kg

11

Suspension 125

0/3

0/3

in 1% G.T. 250

0/3

0/3

500

0/3

1/3

1000

0/3

0/3

ALD50 at 7 d =

1000 mg / kg

12

Solution 125

0/3

0/3

aqueous 250

0/3

0/3

500

1/3

1/3

1000

2/3

2/3

ALD50 at 7 d =

750 mg / kg

9C

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

ALD50 at 7 d =

1000 mg / kg

10

Solution 125

0/3

0/3

aqueous 250

0/3

0/3

500

0/3

0/3

1000

0/3

0/3

ALD50 at 7 d =

1000 mg / kg

58

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

ALD50 at 7 days = 1000 mg / kg

5

10

15

20

25

30

35

40

45

50

55

60

65

620 907

22

Compound of Solution or Dose, mg / kg, Mortality example No. suspension of total product 24 h 7d

59

Solution 125

0/3

0/3

aqueous 250

0/3

0/3

500

1/3

2/3

1000

1/3

1/3

ALD50 at 7 d =

: 750 mg / kg

56

Suspension 125

0/3

0/3

in 1% G.T. 250

0/3

0/3

500

0/3

0/3

1000

1/3

1/3

ALD5oà7j =

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

1/3

ALD50 at 7 d =

1000 mg / kg

44A

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

ALD50 at 7 d =

1000 mg / kg

29C

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

ALD50 at 7 d =

1000 mg / kg

41C

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

ALD50 at 7 d =

1000 mg / kg

1 G.T. = tragacanth.

Claims (2)

620 907 2 1. Process for the preparation of a compound of formula RNH - Y - NHR R'NH- ^ ^ - CH „- 2+ x- AT m - not S-NHR ' (I) or * (Q) v 2+ AT m - • X- not (he) in which: Y is a C4 to Cis alkylene group, separating the two nitrogen atoms connecting the pyridinio rings with 4 to 18 carbon atoms, R represents a C 1 to C 6 alkyl group, C 5 to C 7 cycloalkyl, benzyl optionally mono- or disubstituted on the phenyl ring, or phenyl substituted by methylenedioxy or one or two substituents chosen from halogen, lower alkyl, lower alkoxy, nitro, cyano and trifluoromethyl, R ′ is hydrogen, a C1-C6 alkyl group with a straight or branched chain, or benzyl optionally mono- or disubstituted on the phenyl ring, Q represents — CH3 or — Cl, m v is an integer from 0 to 4, n A is an anion, x Z representing chlorine, bromine, iodine, methane-sulfonyloxy, ethanesulfonyloxy, benzenesulfonyloxy or p-toluenesulfonyloxy radical, A in the compound obtained being identical to Z; and, if desired, we replace the anion A = Z with another anion. 2. Method according to claim 1, characterized in that a compound of formula I is prepared in which R is an alkyl group containing from 6 to 18 carbon atoms, preferably from 7 to 9 carbon atoms. = 1 or 3, = 1 or 2, = 1, 2 or 3, m-2 being equal to n • x, characterized in that 2 mol of a compound of formula is reacted RNH ^ with 1 mol of a compound of formula Z - Y - Z or 2 mol of a compound of formula R'NH (III) (IV) (IIIA) 40 with 1 mol of a compound of formula ZCH0 ^ 5T "CH2Z = h (Q) v (V)