FI66850C - SAOSOM DESINFICERINGSMEDEL OCH TANDPLACKHAEMMARE ANVAENDBARA BIS-PYRIDINIUMALKANER OCH BIS-PYRIDINIUMXYLENER - Google Patents

Description

Ί. . ANNOUNCEMENT, ^ 0 c η 4βΓφ ™ ^ 1) utlAggningsskmft 66850 c ¢ 45) Patent now published 10 12 1924 C 07 D 213 / 7¾ // A 01 N 43 / ^ 0, (51) A 61 K 7/22 ENGLISH —FINLAND (M) 770593 (22) 23.02.77 (23) aMmHM — dUgMadai 23.02.77 (41) TtaltetHUmM — Mlvkcff «ttlg 26.08.77 mvcn * | i rwmMinMiinv ΛΛ ^. __ fWwt · och KglitMityr ·! —i ^ AmBfcn Mtkfiad> «UtoSta · ι ^ αΣμΜ 31-08.8¾ (32) (33) (31)« woik— »> frd prior ** 25.02.76, 25.02.76, 07.09 .76, 22.10.76 USA 661101, 661128, 721315, 73-729 (71) Sterling Drug Inc., 90 Park Avenue, New York, New York, USA (72) Denis Mahlon Bailey, East Greenbush, New York, USA (US) (7¾) Oy Kolster Ab (5¾) Bis-pyridinium alkanes and bis-pyridinium xylenes useful as disinfectants and dental plaque inhibitors - Säsom des inficerings-medel och tandplackhämare användbara bis-pyridiniumalkaner och bis - The present invention relates to bis-pyridinium alkanes and oL'-bis- (4-amino-1-pyridinium) xylenes useful as disinfectants and dental plaque inhibitors.

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

W. C. Austin et al., J. Pharm. Pharmacol., 11 (1959) 80-93 discloses the compounds 1,10-bis- (4-amino-1-pyridinium) decane iodide and 1,10-bis- (4-acetamido-1-pyridinium) decane iodide . Compounds prescribed from a wide and mixed group of these known quaternary ammonium compounds have been shown to have anti-amoebic, bacterial, tapeworm and trypanosomal activity, but no biological values have been shown for either of the above compounds.

66850

The compounds according to the invention are characterized in that they have the formula I or II, Γ ~ +2 Γ Ί-χ / r ~ \ RNH— ('N - Y - N \ NHR, \ _ / \ = j (i) _m wherein in formula IY is an alkylene group of 4 to 18 carbon atoms separating the two 4- (R-NH) -1-pyridinyl groups by 4 to 18 carbon atoms, R is an alkyl group of 6 to 18 carbon atoms, cycl -hexyl or phenyl substituted by one or two halogens;

In formula II, R is hydrogen, a straight or branched alkyl group having 1 to 18 carbon atoms or benzyl; Q is methyl or chlorine; v is an integer from 0 to 4, and in formulas I and II A is an anion; m is 1 or 3; n is 1 or 2; x is 1, 2 or 3 and (m) (2) = (n) (x)

The compounds of formula I are bis- [4- (R-amino) -1-pyridinium] alkanes and the compounds of formula II are <K, «O-bis-Z.4- (R-amino) -1- pyridiniui £ 7-xylenes.

Certain compounds of formula I are also useful as dental plaque inhibitors, for example: 3,668,50,6-bis- [N- (octylamino) -1-pyridinium? -Hexanedibromide and and the corresponding dichloride, 1,6-bis-i (4- (nonylamino) ) -1-pyridinium? -hexanedium dibromide and the corresponding dichloride, 1,6-bis-1- (U- (decylamino) -1-pyridinyl] -hexanedium bromide, 1,6-bis-η 4 - (dodecylamino) -pyridinium / hexane dibromide, 1,7-bis- [4- (heptylamino] pyridinium] -heptane dibromide, 1,7-bis- [4- (octylamino) -1-pyridinium? -Heptanedibromide, 1,7-bis- [4- (nonylamino) -1 -pyridinium 4-heptanediobromide, 1,7-bis-η 4 - (decylamino) -1-pyridinyl-4-heptane dibromide, 1,1-bis-C 1-, - (dodecylamino) -1-pyridinium? -heptanodibromide, 1.8- bis- [4- (heptylamino) -1-pyridinium] -1-octane dibromide and the corresponding dichloride, 1,8-bis-ε- [4- (octylamino) -1-pyridinium] -1-octane dichloride, 1,8-bis- [4- (nonylamino) -1-pyridinium? -Octane idbromide, 1,8-bis- [4- (desylamino) -1-pyridinium] octane dibromide, 1, eb is-N-idodesylamino-1-pyridinyl-4-octane dibromide, 1,8-bis-4- (2-ethylhexylamino) -1-pyridinium? -octane dibromide, 1,9-bis-4- (heptylamino) -1-pyridinyl? nonane dichloride, 1,9-bis - [4- (nonylamino) -1-pyridinium] 7-nonane dibromide, 1,9-bis- [4- (desylamino] pyridinium'-nonane dibromide, 1,9-bis- [4- (dodesylamino] pyridinium] -nonane dibromide , 1.10-bis - / (4- (heptylamino) ** 1-pyridinium) i-decanedibromide and the corresponding dichloride, 1.10-bis- (k- (nonylamino) -1-pyridinyl] -decanedibromide, 1.10-bis- [4- (desylamino) -1-pyridinium-7-decanedibromide, 1,10-bis- [4- (dodecylamino) -1-pyridinium-7-decanedibromide, 1.10-bis- [4- (2-ethylhexylamino) -1-pyridinyl] -decanedichloride, 1.12-bis - E4- (hexylamino) -1-pyridinium-7-dodecane dibromide and the corresponding dichloride, 1.12-bis-E- (heptylamino) -1-pyridine-7-dodecane dibromide, 1.12-bis-Zk- (octylamino) -1-pyridinyl-N-dodecane dibromide 1.12- bis-> C4- (nonylamino N1-pyridine and N-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 β-dodecane dibromide and the corresponding dichloride, * 66850 r 1.14-bis-Z,4- (hexylamino) -1-pyridinium 7-tetradecanedibromide and the corresponding dichloride, 1.14-bis- [4- (heptylamino) -1-pyridinium] -tetradecane dibromide and the corresponding dichloride, 1.14-bis- / 4- (octylamino) -1-pyridinium / -tetradecanedibromide> and especially 1,9-bis- [4- (heptylamino) -1-pyridinium] -nonanedibromide, 1.10-bis- / 4- (2-ethylhexylamino) -1-pyridinium-7-decanedibromide, 1,10-bis-Z,4- (octylamino) -1-pyridinyl-7'-decane dichloride and the corresponding dibromide, 1,9-bis-Z4- (octylamino) -1 -pyridine and β-nonane dibromide, and 1,12-bis-Z4- (heptylamino) -pyridinium 7'-dodecane chloride and 1,8-bis- [4- (octylamino) -1-pyridine] -7-octane dibromide.

The compounds of the invention may be used as an oral hygiene composition for the prevention of dental plaque, the composition comprising an effective amount of one of the above compounds and a compatible, pharmaceutically acceptable carrier.

The compounds of the invention may also be used as disinfectants, and topically as a skin cleanser, wherein the composition comprises an antibacterial and antifungal and antivirally effective amount of a compound of formula I or II above, optionally a compatible pharmaceutically acceptable surfactant and a compatible pharmaceutically acceptable carrier. .

The composition for sterilizing surfaces contains an anti-bacterial and antifungal and antivirally effective amount of a compound of formula I or II above in admixture with a suitable medium.

Compounds of formulas I and II may be prepared by giving formula III

RHH - / "Λ 111 \ = / 5 66850

4- (R-amino) -pyridine of formula IV

Z - Y - Z IV

a disubstituted alkane or formula V

/, Γ \ 'CH ^' Z V

Z-CH2- <) with ot, oi - * - disubstituted xylene, wherein in formulas IV and VY there is an alkylene group having 4 to 18 carbon atoms separating the groups Z with 4 to 18 carbon atoms, Z is chlorine, bromine, iodine, methanesulfonyloxy, ethanesulfonyloxy , benzenesulfonyloxy or p-toluenesulfonyloxy, Q is methyl or chlorine and v is an integer from 0 to 4, and when 4- (R-amino) pyridine (III) is reacted with a disubstituted alkane (IV), R in formula III is 6-18 carbon atoms alkyl group, cyclohexyl group or phenyl substituted by one or two halogens, and when 4- (R-amino) -pyridine (III) is reacted with oC, c <j -disubstituted xylene (V), R in formula III is hydrogen, direct or a branched alkyl group having 1 to 18 carbon atoms or benzyl.

In formula I, the alkylene group Y is a divalent saturated aliphatic hydrocarbon group having 4 to 18, preferably 8 to 12 carbon atoms as a straight or branched chain, separating the two 4- (R-NH) -1-pyridinyl groups to 4 to 18, preferably 8 to 12 carbon atoms. , e.g.

1,4-butylene, 1,5-pentylene, 1,6-hexylene, 1,17-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-pentylene, 2-ethyl-1,4-butylene, 3-methyl-1,6-hexylene, 2,4-dimethyl-6,66850 1,5-pentylene, 1-methyl-1,7-methylene heptylene, 3-ethyl-1,6-hexylene, 3-propyl-1,5-pentylene, 4,4,4-dimethyl-1,7-heptylene, 2,6-dimethyl-1,7-heptylene, 2,4,4, -trimethyl-1,6-hexylene, 2,7-dimethyl-1,8-octylene, 1-methyl-1,10-decylene, 5-ethyl-1,9-nonylene , 3,3,6,6-tetramethyl-1,8-octylene, 3,8-dimethyl-1,10-decylene, 3-methyl-1,11-undecylene, 6-methyl-1,12-dodecylene, 2 -methyl-1,13-tridecylene, 4,9-dimethyl-1,12-dodecylene, 4-methyl-1,14-tetradecylene, 2,13-dimethyl-1,14-tetradecylene, 1,4-dipropyl-1 , 4-butylene, 3- (3-pentyl) -1,5-pentylene, 2- (4,8-dimethyl nonyl) -1,4-butylene, 1-heptyl-1,5-pentylene and others.

It should be noted that when Y contains four carbon atoms, it must of course be straight-chain and just as Y contains 18 carbon atoms and separates both 4- (R-NH) -1-pyridinyl groups at 18 carbon atoms, said carbon atoms must be straight-chain. In all other cases, Y may be straight or branched.

In the formula IR is a straight or branched alkyl group containing 6 to 18, preferably up to nine, carbon atoms, e.g. n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, n-heptadecyl, n-octadecyl, 1-methylpentyl, 2,2-dimethylbutyl, 2-methylhexyl, 1,4-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, 2-methylheptyl, 1-ethylhexyl, 2-ethylhexyl, 2-propylpentyl, 2-methyl-3-ethylpentyl, 3-ethylheptyl, 1,3,5-trimethylhexyl, 1,5-dimethyl- 4-ethylhexyl, 2-propylheptyl, 5-methyl-2-butylhexyl, 2-propylnonyl, 2-butyloctyl, 1,1-dimethylundecyl, 2-pentylononyl, 1,2-dimethyltetradecyl, 1,1-dimethylpentadecyl and other.

In formula II, R is a straight or branched alkyl group having 1 to 18, preferably 6 to 12 carbon atoms, and is, in addition to the above-mentioned alkyl groups having 6 to 18 carbon atoms, e.g., methyl, ethyl, n-propyl, n-butyl, n-pentyl, isopropyl, 1-methyl-propyl, isobutyl, tert-butyl, isopentyl, neopentyl or 1-methylpentyl.

66850

In formula II, R may also be benzyl. In formula I R may also be phenyl substituted by one or two halogens.

When A is an anion in formulas, it may be an anion of both inorganic and organic acids, e.g., bromide, chloride, fluoride, iodide, sulfate, phosphate, nitrate, sulfamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, , naphthalene disulfonate, cyclohexyl sulfamate, acetate, trifluoroacetate, malate, fumarate, succinate, tartrate, oxalate, citrate, lactate, gluconate, ascorbate, lactate, phthalate, salicylate, methionate, picoate, picoate, , perchlorate, tartronate, sarcosinate, N-lauroyl sarcosinate, monofluorophosphate, hexafluoroaluminate, hexafluorosilicate, hexafluorostanate, fluorosirconate, tetrafluoroborate, hexachloroplatinate, tetrachloroaluminate or hexachloroalinate Bromide and chloride are preferred.

As used herein, the term "halogen" means fluorine, chlorine, bromine and iodine.

In the expressions lower alkyl and lower alkoxy "lower" means 1 to 4 carbon atoms containing an alkyl moiety, e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl.

The reaction for the preparation of compounds of formulas I or II is preferably carried out by reacting two moles of 4- (R-amino) -pyridine (formula III) and one mole of an appropriately disubstituted alkane or xylene (formula IV or V) in an unreacted solvent, e.g. in alkanol, acetonitrile, N, N-dimethylformamide. In N, N-dimethylacetamide, benzene, toluene or xylene at a temperature of about 80 ° -150 ° C for 1-24 hours. Usually, the reaction components are heated at 60 to 100 ° C for about 2 to 20 hours in acetonitrile or tai, Ν-dimethylformamide or a mixture thereof or in a lower alkanol.

8 66850

Alternatively, the reaction can be carried out without a solvent by heating stoichiometric amounts of the reaction components at a temperature of 120 to 150 ° C for about 2 to 5 hours.

The resulting bis-η 4 - (R-amino) -1-pyridinium compounds (formulas I and II) are isolated by conventional methods, e.g. by filtration if the product is insoluble in the reaction medium, by diluting the reaction mixture with a non-polar solvent, e.g. ether, benzene. or hexane to precipitate the product or to evaporate the reaction medium to leave the product. The isolated crude product can be purified by crystallization from a suitable solvent in the presence of an adsorbent, activated carbon or diatomaceous earth.

The bis- 3- (R-amino) -1-pyridinium-7 compounds prepared according to the method described above contain an anion (A in formulas I and II) corresponding to the reactive disubstituted alkane. or. a xylene leaving group (Z in formulas IV and V).

But if desired, the anionic moiety of these compounds can be altered by conventional ion exchange methods, e.g., by passing a solution of the Pyridinium Compound in a suitable solvent, e.g., methanol, ethanol, or water, through a layer of synthetic ion exchange resin containing the desired anion. The solvent is evaporated and the pyridine compound containing the desired anion formed is purified by recrystallization from a suitable solvent.

Alternatively, the pyridinium compound can be reacted with a soluble salt containing the desired anion and the corresponding cation to form an insoluble precipitate of the pyridinium compound with the anion. The latter is separated and a solution of the pyridinium compound containing the desired anion remains. For example, bis- (R) - (R-amino) -1-pyridinium-7-alkane dihalide is reacted with a silver salt of an organic or inorganic acid. The precipitated silver halide is removed and a solution of the desired organic or organic anion-containing pyridinium compound remains.

A metathetic reaction of the type described above 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 to form an anion with the pyridinium cation as an insoluble precipitate of the desired product. These insoluble pyridinium salts are

II

9 66850 are suitable for isolation and purification and when incorporated into emulsions, creams, pastes, lotions, gels or powders they also act as long-acting preparations from which the antimicrobial pyridinium compound is slowly excreted. In addition, insoluble salts derived from certain anions, e.g., those described in U.S. Patent No. 3,937,807 (published February 10, 1976), effectively reduce the tooth staining effect of anti-plaque agents.

Thus, if the properties of a particular compound, such as solubility, stability, molecular weight, physical appearance, or toxicity, make the compound unsuitable for the desired purpose, it can be readily converted to another more suitable form. When used on the skin or other tissues or in the oral cavity, pharmaceutically acceptable anions, of course fluoride, chloride, bromide, iodide or methanesulfonate, are of course used.

The 4- (R-amino) pyridines (formula III) used as starting materials are generally known and new ones can be prepared by methods known in the art.

Most conveniently, 4- (R-amino) pyridines are prepared by reacting 4-chloro or 4-bromopyridine or N- (4-pyridyl) pyridinium chloride hydrochloride with an appropriately substituted amine. The reaction is usually carried out by heating the reaction components without solvent at a temperature of 150 to 225 ° C for about 1.5 to 3 hours. The product is isolated in the usual manner, e.g. by extraction from a basic aqueous medium into an organic solvent, e.g. ether, methylene chloride or chloroform, evaporation of the organic solvent and crystallization of the residue from a suitable solvent.

Alternatively, 4- (R-amino) pyridines are obtained by catalytic hydrogenation of a mixture of a carbonyl compound containing 4-aminopyridine and a suitable number of carbon atoms. The reaction is usually carried out at 50 to 70 ° C in a suitable solvent. · · 2 eg in ethanol at a hydrogen pressure of 1.4-4.2 kp / cm in the presence of a palladium hydrogenation catalyst. The hydrogenation time is usually 4-10 hours. When a large excess of carbonyl compound is used, i. 200% or more, results in higher yields of pure product with a reaction time of five hours or less. The catalyst is removed and the product is isolated by evaporating the solvent and either distilling the residue or crystallizing it from a suitable solvent.

_ - r - 10 66850

Reaction of an aldehyde containing a suitable number of carbon atoms with 4-aminopyridine in the presence of formic acid and at elevated temperature also gives U- (R-amino) pyridines.

H- (R-amino) pyridines can also be obtained by acylating 4-aminopyridine with an acyl halide containing an appropriate number of carbon atoms and then reducing the amide formed. The acylation is carried out by methods known in the art by reacting e.g. 4-aminopyridine with an acyl halide in an unreacted solvent, e.g. methylene dichloride or chloroform in the presence of an acid acceptor, e.g. triethylamine. The amide thus formed is then reduced with a metal hydride complex, e.g. lithium hydride, in a suitable solvent, e.g. tetrahydrofuran, ether or dioxane, and the amine product is isolated by known methods.

The disubstituted alkanes of the formula IV used as starting materials are also generally known compounds or new ones can be prepared by methods for the preparation of known compounds.

The disubstituted xylenes of the formula V '*, JL1 also used as starting materials are generally known compounds or new ones can be prepared by methods for the preparation of known compounds.

Thus, the appropriate chlorine- or methyl-substituted phthalic, iso-phthalic or terephthalic acid or ester is reduced to the corresponding xylene-4-diol with a metal hydride such as lithium aluminum hydride in a suitable solvent such as tetrahydrofuran, ether or dioxane. The xylene-o-d'-diol thus formed is then converted to -dihaloxylene, e.g. by reaction with hydrogen bromide, phosphorus tribromide, phosphorus oxychloride, thionyl chloride or potassium iodide and orthophosphoric acid by methods known in the art. Alternatively, the xylene-ε, λ-diol can be converted to the sulfonate ester by reaction with methane, ethane, benzene or p-toluenesulfonyl chloride in the presence of an acid acceptor, e.g. pyridine, according to known methods.

As described in more detail below, the compounds of formulas I and II have in vitro antimicrobial activity against a variety of microorganism species, including both gram-positive and gram-negative bacteria, many fungal species, and Herpes viruses. Thus, the compounds can be used as antiseptics topically on human skin. ! 11 66850 and for sterilizing other tissues and for cleaning and disinfecting inanimate surfaces. Thus, the compounds can be used topically in antiseptic solutions for wound healing, antibacterial cleansers such as operating room hand sanitizers, pre-operative patient skin cleansers, soaps and liquid hair cleansers or household and industrial cleansers and preservatives such as disinfectants, disinfectants. For the above purpose, conventional diluents or carriers, compatible cationic, anionic or nonionic surfactants, buffers, perfumes and coloring agents are added to the compounds. They are applied to the surface to be disinfected in the usual way, e.g. by rubbing, spraying, ossifying or dipping.

When used as skin cleansers, the bis-Z (-CR-amino) -1-pyridinium 7 compounds can be prepared as liquids and, if desired, the liquid compositions can be thickened with certain additives to a gel or paste or cast into a bar by methods known in the art. For example, all compatible pharmaceutically acceptable surfactants may be used in the composition of the compounds, preferably a nonionic surfactant such as the polyoxyethylene polyoxypropylene copolymers described in U.S. Patent No. 3,855,140 or amine oxides such as those described in U.S. Patent 3,296,145. mixtures of these. In addition, the compositions may contain pharmaceutically acceptable diluents, such as water or lower alkanols, acids, bases or buffers to adjust the pH to 5.0 to 7.5, and optionally perfumes and colorants. In such compositions, the amount of bis-η 4 - (R-amino) -1-pyridinium compounds is generally about 0.5 to 2.0% by weight, preferably 1.0% by weight.

As a tincture, compositions of the bis- [4- (R-amino) -1-pyridinium] compounds may contain water, a lower alkanol, e.g. acetone, and a lower alkanol, e.g. ethanol. If desired, the tincture can be colored with a colorant. The amount of active ingredient is generally about 0.05-1.0% (w / v), preferably 0.1% (w / v).

Alternatively, the compounds may be formulated in suitable pharmaceutical media, e.g., lotions, ointments, or creams, by adding them to conventional toner, ointment or cream bases such as alkyl polyether alcohols, cetyl alcohol or stearyl alcohol, or conventional gel bases such as glycerol or tragacanth. They can also be formulated as aerosol sprays or foams.

When used to clean inanimate surfaces. and for disinfection, the compounds may be formulated with known cleaning agents and extenders such as trisodium phosphate or borax. In such compositions, the amount of bis -? - (R-amino) -1-pyridinium compounds is generally up to about 10% by weight.

As described in detail below, some compounds of formula I inhibit the formation of dental plaque. In this case, the compounds can be most conveniently applied to the teeth in the form of a mouthwash or a dentifrice. The compounds may be formulated with conventional ingredients used in mouthwash and dentifrice compositions such as water, alcohol, glycerin, buffers, thickeners, flavoring and coloring agents. In addition, these compositions may contain other known ingredients, and in particular those which reduce the coloring power of teeth, such as the tartar inhibitors described in U.S. Pat. No. 3, No. 202 (published January 20, 1976), e.g. zinc phenol sulfonate, 8-hydroxyquinoline-1-disodium ethane. -1,1-diphosphonate and the aminocarboxylate compounds described in U.S. Pat. No. 3,937,807 (published February 10, 1976), nitrilotriacetic acid, 2-hydroxyethylnitrilodietic acid or water-soluble salts thereof. In these compositions, the bis-ε- (R-amino) -1-pyridinium β-alkane is usually about 0.005 to 0.05% by weight, preferably about 0.01% by weight.

It will, of course, be appreciated that the media, diluents, carriers and excipients of the compositions described above must be compatible with the active ingredient, i. the nature of the medium, diluent, carrier or other additive must not impair the effectiveness of the bis-β- (R-amino) -1-pyridinium-7 compounds as a disinfectant and anti-dental plaque inhibitor.

The molecular structures of the compounds of the invention were determined by IR and NMR spectra and verified by the correspondence between the calculated values of the elements and those given by the elemental analysis.

The following examples illustrate the invention.

66850 13

Example 1 A. A mixture of 130 g (0.67 moles) of 4-bromopyridine hydrochloride and 152 g (1.0 mole) of n-heptylamine hydrochloride was heated in an oil bath. When the bath temperature was 180-185 ° C, the reaction mixture began to melt and stirring was started. The melting was complete at 190-195 ° C and the liquid mixture was stirred and heated at 210-220 ° C for 2.5 hours. The reaction mixture was then cooled to room temperature, the solid formed was dissolved in water, basified with 35% aqueous sodium hydroxide solution, and the product was extracted with chloroform. The chloroform extracts were dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. The resulting viscous oil was diluted with a small amount of n-hexane, cooled, the solid formed isolated by filtration and air dried to give 86.6 g of 4- (heptylamino) pyridine, m.p. 49-51 ° C.

B. Alternatively, 4- (heptylamino) pyridine was prepared as follows: A mixture of 229 g (1.0 mol) of N- (4-pyridyl) pyridinium chloride hydrochloride and 228 g (1.5 mol) of n-heptylamine hydrochloride was heated with stirring for two hours. in an oil bath at a bath temperature of 215 ° C. The reaction mixture was cooled to 80 ° C, diluted with ice water, basified with 35% aqueous sodium hydroxide solution and extracted successively with ether and chloroform. The organic extracts were combined and evaporated to dryness in vacuo. The residual viscous oil was dissolved in ether and the ether solution was washed with water. The aqueous washes were re-extracted with chloroform and the chloroform extracts and ether solution were combined. The combined organic solutions were dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. Upon cooling the residual oil to -78 ° C, partial solidification occurred. The semi-solid was diluted with a small amount of ether and filtered. The solid thus obtained was dissolved in a mixture of acetonitrile and chloroform, the resulting solution was treated with activated carbon, filtered and the filtrate was evaporated to dryness in vacuo. The resulting semi-solid was diluted with a small amount of ether and cooled. The solid thus formed was isolated by filtration and washed with a small amount of cold ether to give, after drying, 84.6 g of 4- (heptylamino) pyridine, m.p. 50-52 ° C.

______ - Γ 14 66850 C. 4- (Heptylamino) pyridine was also prepared by hydrogenation of a mixture of 4-aminopyridine and heptaldehyde according to the method of Example 10B described below.

D. To a stirred, warm solution of 10.0 g (0.052 moles) of 4- (heptylamino) pyridine in 40 mL of acetonitrile was added dropwise a solution of 9.3 g (0.026 moles) of 1,14-dibromotetradecane. In 230 ml of acetonitrile and the resulting mixture was heated under reflux for 20 hours. Upon cooling the reaction mixture to room temperature, the precipitated product was isolated by filtration, washed with cold acetonitrile and continued to give 13.9 g of 1,14-bis-β + ((heptylamino) -1-pyridinyl] -tetradecane dibromide, m.p. 88-90 ° C.

Example 2

A solution of 5.0 g of 1,14-bis- [4- (heptylamino) -1-pyridinium] -tetradecane bromide. 5.0. was added to the top of a 3-inch diameter column containing 500 ml of synthetic anion exchange resin in chloride form (manufactured by Rohm & Haas under the tradename Amberlite IRA 400) packed in methanol and eluted with five 125 ml portions of methanol. The combined extracts were evaporated to dryness in vacuo, the oily residue was dissolved in ethanol, treated with activated carbon and evaporated to dryness. The solid residue was triturated with a few drops of ether containing acetonitrile, isolated by filtration and dried over phosphorus pentoxide in vacuo to give 3.94 g of 1,14-bis- [4- (heptylamino) -1-pyridine] -tretradecane dichloride, m.p. 113-116 ° C.

Example 3

A stirred suspension of 11.54 g (0.06 moles) of 4- (heptylamino) pyridine in 75 mL of acetonitrile was heated under reflux until a clear, homogeneous solution formed. A warm solution of 9.84 g (0.03 mol) of 1,12-dibromododecane in 75 ml of acetonitrile was then added dropwise to the clear solution. At the end of the addition, heating under vertical cooling was continued for 18 hours. After cooling to room temperature, the reaction mixture was evaporated to dryness in vacuo. The solid residue was slurried in ether, isolated by filtration and dried under vacuum at 60 ° C for 48 hours to give 21.1 g of 1,12-bis- [4- (heptylamino) -1-pyridinium? -Dodecane dibromide., M.p. 101-103 ° C.

15 66850

Example 4 A. A solution of 6.6 g of 1,12-bis- [4- (heptylamino) -1-pyridinium] -dodecane dibromide in 25 ml of methanol was added to the top of a 3-inch diameter column containing 1 L of synthetic anion exchange resin in chloride form (manufactured by Rohm & Haas under the tradename Amberlite IRA 400) in methanol and slowly extracted with 100 ml portions of methanol until 700 ml of eluate was isolated. The combined eluates were evaporated to dryness in vacuo at a temperature below 25 ° C. The gummy residue was triturated several times with a 6: 1 mixture of ether and acetonitrile and dried in vacuo to give 5.0 g of 1,12-bis- (4- (heptylamino) -1-pyridinium) -1-dodecane dichloride, m.p. 109-112 ° C.

B. Alternatively, a mixture of 76.8 g (0.4 moles) of 4- (heptylamino) pyridine and 47.8 g (0.2 moles) of 1,12-dichloro-decane was heated at 125-130 ° C for four hours. :in. After cooling slightly, 300 ml of acetonitrile were added and the resulting mixture was heated in a water bath to achieve complete dissolution and allowed to stand in the refrigerator overnight. The precipitated product was isolated by filtration, washed with cold acetonitrile and ether and the hygroscopic product was immediately dried in vacuo to give 112 g of 1,12-bis -, [4- (heptylamino) -1-pyridinium] 7-dodecane dichloride, m.p. 112-115 ° C.

Example 5 · A. A mixture of 100.0 g (0.51 moles) of 4-bromopyridine hydrochloride and 110 g (0.8 moles) of n-hexylamine hydrochloride was heated in an oil bath. When the bath temperature was 175-180 ° C, the reaction mixture began to melt and stirring was started. The bath temperature was then raised to 227 ° C and stirring was continued for 3.5 hours. After cooling to room temperature, the reaction mixture was dissolved in hot water, the resulting solution was cooled on ice, basified with dilute aqueous sodium hydroxide solution and extracted with chloroform. The chloroform extracts were dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. The residue was triturated with ether and cooled. The solid formed was isolated by filtration and washed with cold ether. Evaporation of the filtrate gave more solid. The yields were combined, dissolved in chloroform, treated with activated carbon and filtered. The filtrate was evaporated in vacuo and the residue triturated with cold ether. The product thus obtained was isolated by filtration, washed with cold ether and dried to give 63.6 g of 4- (hexylamino) pyridine, m.p. 66-68 ° C. Evaporation of the filtrate gave an additional 7.0 g, m.p. 65-67 ° C.

B. Alternatively, 4- (hexylamino) pyridine was prepared as follows. A mixture of 229 g (1 mol) of N- (4-pyridyl) pyridinium chloride hydrochloride was stirred and heated at 175-185 ° C for 1.75 hours. The reaction mixture was cooled and diluted with 75 ml of ice water. The resulting solution was basified with 35% aqueous sodium hydroxide solution and after further dilution with 1 liter of water was extracted with ether and dichloromethane. The organic extracts were combined, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. The residue was recrystallized from ether, redissolved in chloroform, the resulting solution was treated with activated carbon and filtered. The filtrate was evaporated to dryness in vacuo and the residue triturated with a mixture of ether and acetonitrile. The solid thus obtained was redissolved in chloroform, the resulting solution was treated with activated carbon and filtered. The filtrate was evaporated to dryness in vacuo and the residue triturated with cold ether to give 71.0 g of 4- (hexylamino) pyridine, m.p. 68-70 ° C.

C. To a stirred, warm solution of 10.7 g (0.06 moles) of 4- (hexylamino) pyridine in 50 mL of acetonitrile was added dropwise a solution of 10.7 g (0.03 moles) of 1.14 -dibromotetradecane in 250 ml of acetonitrile and the resulting mixture was heated under reflux for 22 hours. The reaction mixture was evaporated to dryness in vacuo. The solid residue was dissolved in acetonitrile, the resulting solution was treated with activated carbon and filtered. The filtrate was evaporated to dryness in vacuo and the resulting oil was crystallized from acetonitrile. The product was isolated by filtration and dried for 48 hours at 70 ° C / 0.1 mm Hg to give 13.4 g of 1,14-bis- [4- (hexylamino) -1-pyridinyl] -tetradecane dibromide, m.p. 91-93 ° C.

\ 17 66850

Example 6

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

Example 7

Following the procedure 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-bromododecane. 17.6 g of 1,12-bis- [4- (hexylamino) -1-pyridinium] -dodecane dibromide were obtained, m.p. 122-124 ° C.

Example 8

Following the procedure described in Example 2, but using 5.0 g of 1,12-bis- [4- (hexylamino) -1-pyridinium] -dodecanedibromide, 3.69 g of the corresponding dichloride were obtained, m.p. 86-38 ° C.

Example 9 A. A mixture of 183.3 g (0.8 moles) of N- (4-pyridyl) pyridinium chloride hydrochloride and 162 g (0.98 moles) of n-octylamine hydrochloride was heated in an oil bath at a bath temperature of 225-230 ° C. (internal temperature 188 ° C) and the resulting liquid was stirred at this temperature for 2.5 hours. The reaction mixture was then cooled to 70 ° C, diluted with 1 liter of ice water, basified with 35% aqueous sodium hydroxide solution and extracted with chloroform. The chloroform extracts were dried over anhydrous sodium sulfate, treated with activated carbon and evaporated to dryness in vacuo. The resulting oil was cooled to -78 ° C. The resulting semi-solid was triturated with ether and the solid thus obtained was isolated by filtration, washed with cold ether and dried. An additional 10 g of filtrate was obtained. The yields were combined, dissolved in chloroform, treated with activated carbon and filtered (repeated three times) and the chloroform solution evaporated to dryness in vacuo. The solid formed was triturated with ether, cooled, isolated by filtration and washed with cold ether-hexane to give 63.3 g of almost colorless 4- (octylamino) pyridine, m.p. 62-63 ° C.

B. Alternatively, 4- (octylamino) pyridine was prepared as follows. A mixture of 94 g (1 mole) of 4-aminopyridine, 384 g (3 moles) of octaldehyde, 7 g of 10% palladium on hydrocarbon catalyst and enough absolute ethanol to give a final volume of 1.2 66, hydrogenated for 4.5 hours at 70 ° to 90 ° C at an initial hydrogen pressure of 3.15 kp / cm. After cooling, the hydrogenation catalyst was removed by filtration and the filtrate was evaporated to dryness in vacuo. The residual oil crystallized on standing, the solid was triturated in hexane, isolated by filtration, washed with a further amount of hexane and dried at 40 ° C under vacuum to give 182 g of 4- (octylamino) pyridine, mp 70-73 ° C.

C. To a stirred, warm solution of 10.0 g (0.049 moles) of 4- (octylamino) pyridine in 150 mL of acetonitrile was added dropwise a solution of 7.4 g (0.0245 moles) of 1,10-di -bromidecane in 50 ml of acetonitrile and the resulting mixture was heated under reflux for 18 hours. After cooling and stirring at room temperature for 1 hour, the precipitated solid was isolated by filtration, washed with acetonitrile and dried for 48 hours at 85 ° C to give 15.6 g of 10-bis- [4- (octylamino) -1-pyridine] -decanedibromide, m.p. . 163-164 ° C.

Example 10 A. Following the procedure described in Example 2, but using 5.0 g of 1,10-bis-A- (octylamino) -1-pyridinyl-N'-decane dibromide, 4.31 g of the corresponding dichloride were obtained, m.p. 213 - 214 C.

B. Alternatively, a mixture of 61.8 g of 4- (octylamino) pyridine and 31.5 g of 1,10-dichlorodecane was stirred and slowly heated to 120 ° C. The heater was removed and now the temperature of the exothermic reaction rose to 180 ° C. As soon as the reaction mixture began to crystallize, about 250 ml of N, N-dimethylformamide was added, and the resulting mixture was heated to a clear, homogeneous solution and cooled to 0 ° C. The precipitated product was isolated by filtration, washed with ether and dried under vacuum at 60 ° C for 24 hours to give 73 g of 1,10-bis-4- (octylamino) -1-pyridinium-7-decanedichloride, m.p. 215-217 ° C.

Example 11

Following the procedure described in Example 9C, but using 11.1 g (0.054 mol) of 4- (octylamino) pyridine and 7.34 g (0.027 mol) of 1,8-dibromooctoate and heating the reaction mixture for six hours under vertical cooling, 15.6 g were obtained. (bis-bis-β-toxylamino) -1-pyridine and β-octane dibromide, m.p. 174-17 5 ° C.

Il 19 66850

Example 12

Following the procedure described in Example 2, but using 5.0 g of 1 ', S-bis-N-octylamino-1-pyridinyl] -1'-octane dibromide, 4.30 g of the corresponding dichloride were obtained, m.p. 210 ° -211 ° C.

Example 13

Following the procedure described in Example 9C, but using 11.1 g (0.054 mol) of 4- (octylamino) pyridine and 6.6 g (0.027 mol) of 1,6-dibromohexane and heating the reaction mixture under reflux for nine hours, 15.1 g, 6 -bis- [4- (octylamino) -1-pyridine-p'-hexanedibromide, m.p. 136-138 ° C.

Example 14

Following the procedure described in Example 2, but using 5.0 g of 1,6-bis- [4- (octylamino) -1-pyridinium] -1-hexanedibromide, 4.23 g of the corresponding dichloride were obtained, m.p. 189-191 ° C.

Example 15

To a stirred, warm solution of 2.06 g (0.01 mol) of 4- (octylamino) pyridine in 15 ml of acetonitrile was added dropwise a solution of 1.37 g (0.005 mol) of 1,6-hexanediol. dimethanesulfonate in 10 ml of acetonitrile and the resulting mixture was heated under reflux for 20 hours. The reaction mixture was evaporated to dryness in vacuo and the gummy residue triturated with ether to give a colorless, hygroscopic solid.

This product was dissolved in a mixture of ethanol, benzene and acetonitrile and the resulting solution was evaporated to dryness in vacuo. The residue was triturated with ether and the resulting white solid was isolated by rapid filtration and dried for 72 hours at 28 ° C / 0.1 mm Hg to give 2.65 g of 6-bis - {N- (octylamino) -1-pyridine and 7-hexanedimethanesulfonate as a slurry. as a white solid.

Example 16

Following the procedure described in Example 3C, but using 14.24 g (0.08 moles) of 4- (hexylamino) pyridine and 8.64 g (0.04 moles) of 1,4-dibromobutane, a crude product was obtained in a mixture of acetonitrile and acetone. followed by 20.45 g of 1,4-bis- (b- (hexylamino) -1-pyridinyl] -butane dibromide, mp 199-201 ° C.

20 Γ 6685 0

Example 17

Following the procedure described in Example 9C, but using 10.7 g (0.06 moles) of 4- (hexylamino) pyridine and 7.32 g (0.03 moles) of 1,6-dibromohexane, the crude product ether, acetonitrile and acetone were obtained. after trituration in the mixture, 14.90 g of 1,6-bis-η 4 - (hexylamino-pyridine and β-hexanedibromide, mp 17-117 ° C).

Example 18

Following the procedure described in Example 9C, but using 10.7 g (0.06 mol) of 4- (hexylamino) pyridine and 7.7 g (0.03 mol) of 1,7-dibromoheptane, the crude product was obtained after trituration with a mixture of acetonitrile and acetone. , 4 g of 1,7-bis-N, N-pyridinyl-heptane dibromide, mp 157-158 ° C.

Example 19

Following the procedure described in Example 9C, but using 10.7 g (0.06 moles) of 4- (hexylamino) pyridine and 8.6 g (0.03 moles) of 1,9-dibrominonane, 17.15 g of 1,9-bis- E- (hexylamino) -1-pyridine-n-nonane dibromide, m.p. 114-115 ° C.

Example 20

Following the procedure described in Example 9C, but using 15.4 g (Q, 08 moles) of 4- (heptylamino) pyridine and 8.64 g (0.04 moles) of 1,4-dibromobutane, 23.1 g of 1,4- bis- [4- (heptylamino) -1-pyridine] -7-butanedibromide, m.p. 229-230 ° C.

Example 21

Following the procedure described in Example 9C, but using 10.0 g (0.052 moles) of 4- (heptylamino) pyridine and 6.7 and (0.026 moles) of 1,7-dibromoheptane, 14.05 g of 1,7-bis-β- (heptylamino) -1-pyridinium 2-heptane dibromide, m.p. 142-143 ° C. ;

Example 22

Following the procedure 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, recrystallization from acetonitrile-ether was obtained. then 18.6 g of 1,8-bis- [4- (heptylamino) -1-pyridinyl] octane dibromide, m.p. 161-162 ° C.

21 66850

Example 23

Following the procedure described in Example 2, but using 5.0 g (0.0076 mol) of 1,8-bis-ε-β (heptylamino) -1-pyridinium] -37-octane dibromide, 4.1 g of the corresponding dichloride were obtained, m.p. 206-208 ° C.

Example 2.H

Following the procedure described in Example 9C, but using 15.4 g (0.08 moles) of 4- (heptylamino) pyridine and 11.44 g of 1,9-dibrominonane, 21.3 g of 1,9-bis- {4- ( heptylamino) -1-pyridinium? -nonanedibromide, m.p. 115-116 ° C.

Example 25

Following the procedure described in Example 2, but using 5.0 g (0.0075 moles) of 1,9-bis-N- (heptylamino) -1-pyridinium-7-nonanedibromide, 4.2 g of the corresponding dichloride were obtained, m.p. 154-155 C.

Example 26

Following the procedure described in Example 9C, but using 15.4 g (0.08 moles) of 4- (heptylamino) pyridine and 12.0 g (0.04 moles) of 1,10-dibromidecane, 25.7 g of 1,10-bis- N- (heptylamino) -1-pyridinium? -decanedibromide, m.p. 163-165 ° C.

Example 27

Following the procedure described in Example 2, but using 5.0 g (0.0073 mol) of 1,10-bis- (U- (heptylamino) -1-pyridinium-7-decanedibromide, 4.35 g of the corresponding dichloride were obtained, mp 209-210 ° C.

Example 28

To a stirred suspension of 30 ml of synthetic anion exchange resin in hydroxide form (manufactured by Rohm & Haas under the trade name Amberlite IRA 400) in 150 ml of water was added dropwise a 48% aqueous hydrofluoric acid solution until the mixture became acidic. After stirring for half an hour, the suspension was poured onto a column.

The liquid was drained from the column and the resin was washed with a solution of 15 ml of a 48% aqueous solution of hydrofluoric acid in 185 ml of distilled water. The resin was then washed with distilled water until the eluate was slightly acidic and then successively with 20, 40 and 50% aqueous methanol and finally with absolute methanol until the eluate was neutral. To the upper end of this column, which now contained an ion exchange resin in fluoride form, was added a solution of 0.25 g of 66 "66850 (0.000 365 moles) of 1,10-bis- [4- (heptylamino] -1-pyridyl) decane dibromide. Five 15 ml fractions were collected, the first three fractions were combined and evaporated to dryness in vacuo, the oily residue was dissolved in a mixture of benzene and acetone and the solution was evaporated to a small volume, the separated solid was isolated by filtration and dried for 24 hours at 24 ° C. 0.1 mm Hg to give 0.11 g of crude 1,10-bis- [4- (heptylamino) -1-pyridinium] -decanedifluoride, mp δ 5-90 ° C.

Example 29 A. A solid mixture of 115 g (0.5 moles) of N- (4-pyridyl) pyridinium chloride hydrochloride and 119 g (0.66 moles) of n-nonylamine hydrochloride was heated in an oil bath at a bath temperature of 220 ° C (internal temperature). 190-194 ° C) and the resulting liquid was stirred for two hours at this temperature. The reaction mixture was then cooled to 80 ° C, diluted with 1.2 liters of ice water, basified with 35% aqueous sodium hydroxide solution and extracted with chloroform. The chloroform extracts were dried over anhydrous sodium sulfate, treated with activated carbon, filtered and evaporated to dryness in vacuo. The residual viscous oil was cooled to -78 ° C and triturated with ether. The solid formed was isolated by filtration and washed with cold ether. More solid was obtained from the filtrate. The combined yields were dissolved in chloroform, the resulting solution was treated with activated carbon and filtered. This was repeated once and then the filtrate was evaporated to dryness in vacuo. The remaining semi-solid was triturated with ether and cooled to give an almost colorless solid which was isolated by filtration, washed with cold ether and dried. The solid was dissolved in chloroform, the resulting solution treated with activated carbon, filtered and evaporated to dryness in vacuo. Cooling of the resulting semi-solid and trituration with ether gave a colorless solid which was isolated by filtration, washed with cold ether and dried to give 51.7 g of 4- (nonylamino) pyridine, m.p. 59-60 ° C. An additional 11.6 g of melt was obtained, m.p. 55-57 ° C.

B. Alternatively, 4- (nonylamino) pyridine was prepared as follows. A mixture of 39.5 g (0.42 moles) of 4-aminopyridine, 175 g (1.24 moles) of nonylaldehyde, 5.0 g of 10% palladium on carbon, and sufficient absolute ethanol to give a total volume of To obtain 600 ml, 2 was heated and hydrogenated at an initial pressure of 3.15 kp / cm of hydrogen until hydrogen uptake was complete. The reaction mixture was filtered to remove the catalyst and the filtrate was evaporated to dryness in vacuo. The residual oil was distilled in vacuo to remove any nonyl alcohol in the product. A boiling fraction was isolated at 63-64 ° C / 4.5 mm Hg and set aside. The residue was triturated with ether and cooled to -78 ° C. The precipitated solid was isolated by filtration and washed with cold ether. This product was dissolved in chloroform, the resulting solution was treated with activated carbon, filtered and the filtrate was evaporated to dryness. The residue was triturated with ether and cooled to -78 ° C. The solid thus obtained was isolated by filtration, washed with cold ether and air dried to give 27.0 g of 4- (nonylamino) pyridine, m.p. 57-59 ° C.

C. A stirred suspension of 11.0 g (0.05 moles) of 4- (nonylamino) pyridine in 150 mL of acetonitrile was heated until a clear, homogeneous solution was obtained. To this clear solution was added dropwise a solution of 6.8 g (0.025 moles) of 1,8-dibromooctane in 50 ml of acetonitrile, and the resulting mixture was heated under reflux for 19 hours, during which time a solid precipitated out of solution. After cooling, the solid was isolated by filtration, dissolved in methanol, the resulting solution treated with activated carbon, filtered and evaporated to dryness in vacuo. Trituration of the residual oil in ether containing a little acetonitrile gave a colorless crystalline solid which was isolated by filtration and dried to give 15.5 g of 1,8-bis- [4- (nonylamino) -1-pyridinyl] -octane dibromide, m.p. 178-179 ° C.

Example 30

Following the procedure described in Example 29C, but using 3.54 g (0.026 moles) of 4- (propylamino) pyridine and 3.90 g (0.013 moles), 5.19 g of 1,10-bis- [4- (propylamino) - 1-pyridinedinyl decane dibromide, m.p. 206-207 ° C.

Example 31

Following the procedure described in Example 29C, but using 14.24 g (0.08 moles) of 4- (hexylamino) pyridine and 9.20 g (0.04 moles) of 1,5-dibromopentane, τ ~ 24 66850 was obtained from recrystallization from acetonitrile-acetone. followed by 12.3 g of 1,5-bis- (4- (hexylamino) -1-pyridine urea p-pentane dibromide, mp 155-156 ° C.

Example 32

Following the procedure described in Example 29C, but using 10.7 g (0.06 moles) of 4- (hexylamino) pyridine and 8.2 g (0.03 moles) of 1,8-dibromooctane, 16.3 g were obtained. 8-bis- [4- (hexylamino) -1-pyridinium? -Octane dibromide, m.p. 180-181 ° C.

Example 33,

Following the procedure described in Example 29C, but using 12.5 g (0.07 moles) of 4- (hexylamino) pyridine and 10.5 g (0.035 moles) of 1,10-dibromidecane, 16.0 g of 1,10-bis- 4- (hexylamino) -1-pyridinyl] -β-decane dibromide, m.p. 148-149 ° C.

Example 34

Following the procedure described in Example 29C, but using 13.4 g (0.076 moles) of 4- (cyclohexylamino) pyridine and 8.2 g (0.038 moles) of 1,4-dibromobutane, 18.2 g of 4-bis-η 4 - -lohexylamino-1-pyridinium tert-butane dibromide, mp 288-290 ° C.

Example 35

Following the procedure described in Example 29C, but using 13.4 g (0.076 moles) of 4- (cyclohexylamino) pyridine and 8.75 g (0.038 moles) of 1,5-dibromopentane, 19.0 g of 5-bis- [4- (cyclohexylamino) ) -i-pyridinium-7-pentanedibromide, m.p. 255-256 ° C.

Example 36

Following the procedure described in Example 29C, but using 13.4 g (0.076 moles) of 4- (cyclohexylamino) pyridine and 9.3 g (0.038 moles) of 1,6-dibromohexane, 19.1 g of 6-bis-4- (cyclohexylamino) were obtained. ) -1-pyridinyl] -7-hexanedibromide, m.p. 307-308 ° C.

Example 37

Following the procedure described in Example 29C, but using 13.4 g (0.076 moles) of 4- (cyclohexylamino) pyridine and 9.8 g (0.038 moles) of 1,7-dibromoheptane, 2.01 g of 7-bis-ε- -lohexylamino) -1-pyridinium-7-heptane dibromide, m.p. 311-313 ° C.

Example 38

Following the procedure described in Example 29C, but using 14.4 g (0.076 mol) of 4- (cyclohexylamino) pyridine and 10.34 g of 66850 (0.038 mol) of 1,8-dibromooctane, 19.1 g of 8-bis-octane were obtained. 4- (cyclohexylamino) -1-pyridine and β-octane dibromide, m.p. 270-271 ° C.

Example 39

Following the procedure described in Example 29C, but using 13.4 g (0.076 moles) of 4- (cyclohexylamino) pyridine and 10.8 g (0.038 moles) of 1,9-dibrominonane, 16.3 g of 1,9-bis-β- ( cyclohexylamino) -1-pyridinium-7-nonane dibromide, m.p. 149-151 ° C.

Example 40

Following the procedure described in Example 29C, but using 13.4 g (0.076 moles) of 4- (cyclohexylamino) pyridine and 11.4 g (0.038 moles) of 1,10-dibromidecane, 19.0 g of 1,10-bis-A- (cyclohexylamino) was obtained. ) -1-pyridinium-7-decane dibromide, m.p. 226-2 27 ° C.

Example 41 A. A mixture of 298.0 g (1.33 moles) of N- (4-pyridyl) -pyridinium chloride hydrochloride and 322 g (2 moles) of 2-ethylhexylamine hydrochloride was heated with stirring for two hours in an oil bath at a beef temperature of 215 ° C. . The mixture was cooled to 60 ° C, diluted with 500 mL of water and kept cold by the addition of ice while making basic by the addition of 35% aqueous sodium hydroxide solution. The basic mixture was extracted with ether, the ether extracts dried over anhydrous sodium sulfate and evaporated to dryness. The residual oil was distilled in vacuo to give. 101.0 g of 4- (2-ethylhexylamino) pyridine, b.p. 145-150 ° C / 0.9 mm Hg.

B. Alternatively, 4- (2-ethylhexylamino) pyridine was prepared as follows. To a stirred solution of 800 g (8.4 moles) of 4-aminopyridine and 1500 ml of triethylamine in 6.4 liters of dichloromethane was added over three hours a solution of 1610 g (10.0 moles) of 2-ethylhexanoyl chloride in 1.6 liters of dichloromethane. Throughout the addition, the temperature was maintained at 15 ° C. After the addition was complete, the mixture was heated on a water bath for two hours. After cooling, the reaction mixture was washed thoroughly with water, dried over anhydrous sodium sulfate, treated with activated carbon and filtered. Evaporation of the filtrate gave 1843 g of N- (4-pyridyl) -2-ethylhexanamide.

To a mixture of 100 g (2.63 moles) of lithium aluminum hydride in 2 liters of tetrahydrofuran was added at a suitable rate to maintain a gentle reflux solution of 570 g of 1 - - ----- 26 66850 (2.62 moles} N- (4 -pyridyl) -2-ethylhexanamide in 4 liters of tetrahydrofuran At the end of the addition (after about three hours), the reaction mixture was heated under reflux for seven hours, and after cooling, the mixture was treated successively with 100 ml of water, 100 ml of 15% aqueous sodium hydroxide solution and 11a of water, the solids were removed by filtration and the solvent was evaporated from solution in vacuo The residual oil was combined with the double product and vacuum distilled to give 837 g of 4- (2-ethylhexylamino) pyridine, bp 135-160 ° C / 0.2 mm Hg.

C. To a stirred, warm solution of 10.3 g (0.05 moles) of 4- (2-ethylhexylamino) pyridine in 50 mL of acetonitrile was added dropwise a solution of 8.2 g (0.025 moles) of 1 , 12-dibromodecane in 170 ml of acetonitrile and the resulting mixture was heated under reflux for 20 hours. After cooling to 0 ° C, the first crop of product precipitated and was isolated by filtration. Evaporation of the filtrate and trituration of the residue in ether gave a second crop. The combined yields were dissolved in methanol, the resulting solution was treated with activated carbon, filtered and the filtrate was evaporated to dryness in vacuo. The residual oil was cooled and triturated with ether to give a slightly colored solid. Recrystallization from acetonitrile-ether and trituration of the product with ether and acetonitrile gave 14.7 g of 1,12-bis-4- (2-ethylhexylamino) -1-pyridinium-7-dodecanedibromine after drying for 72 hours under vacuum at 60 ° C. -dia, sp. 146-147 ° C.

Example 42 A. A mixture of 353.5 g (1.72 moles) of 4- (2-ethylhexylamino) pyridine and 205 g (0.86 moles) of 1,12-dichlorodecane was heated to 120 ° C: C. The heating was removed and now the temperature of the exothermic reaction rose to 180,190 ° C. After lowering the temperature to 135 ° C, one liter of acetonitrile was carefully added and the mixture was heated under vertical cooling to a clear solution. The hot acetonitrile solution was combined with the corresponding solutions of the other two runs, treated with activated carbon and filtered. The filtrate was cooled, the precipitate formed was isolated by filtration and washed with cold acetonitrile. Crystallization twice from acetonitrile gave 970 g of 1,12-bis- [1- (2-ethylhexylamino) -1-pyridinium] -dodecanedichloride, m.p. 168-171 ° C.

66850 B. Alternatively, following the procedure described in Example 2, but using 3.0 g (0.00405 moles) of 1,12-bis - N- (2-ethylhexylamino) -1-pyridine and β-dodecane dibromide, 2.0 g of the corresponding dichloride were obtained. , sp. 172-173 ° C.

Example 4 3

Following the procedure described in Example 41C, but using 10.3 g (0.05 moles) of 4- (octylamino) pyridine and 6.45 g (0.025 moles) of 1,7-dibromoheptane, 14.85 μl of 7-bis-4- (octylamino) -1-pyridinium 7-heptane dibromide, m.p. 12-131 ° C.

Example 44 A. Following the procedure described in Example 41C, but using 11.1 g (0.054 mol) of 4- (octylamino) pyridine and 7.72 g (0.027 mol) of 1,9-dibrominonane, 17.0 g of 1.9- bis-N- (octylamino) -1-pyridinyl-4-nonane dibromide, mp 117-119 °.

B. The corresponding dichloride prepared according to the method of Example 2 m.p. was 161-161 ° C.

Example 45

Following the procedure described in Example 41C, but using 10.3 g (0.05 moles) of 4- (octylamino) pyridine and 8.2 g (0.025 moles) of 1,12-dibromidodecane, 15.2 g of 1,12-bis-ε 4 - (octylamino) -1-pyridinium-7-dodecane dibromide, m.p. 119-120 ° C.

Example 46

Following the procedure described in Example 41C, but using 5.8 g (0.028 moles) of 4- (octylamino) pyridine and 5.0 g (0.014 moles) of 1,14-dibromotetradecane, 9.3 g of 1,14-bis- - (octylamino) -1-pyridine and β-tetradecane dibromide, m.p. 113-115 ° C.

Example 47

Following the procedure described in Example 41C, but using 11.0 g (0.05 moles) of 4- (nonylamino) pyridine and 6.1 g (0.025 moles) of 1,6-dibromohexane, 15.2 g of 1,6-bis- N- (nonylamino) -1-pyridinyl-4-hexanedibromide, m.p. 152-154 ° C.

Example 48

Following the procedure described in Example 4, but using 6.5 g (0.0095 mol) of 1,6-bis- (4- (nonylamino) -1-pyridinium) hexane dibromide, 4.95 g of the corresponding dichloride were obtained, m.p. 194-195 ° C.

τ ~ 28 66850

Example 4 9

Following the procedure described in Example 41C, but using 8.8 g (0.04 moles) of 4- (nonylamino) pyridine and 5.2 g (0.02 moles) of 1,7-dibromoheptane, 12.2 g of 1.7- bis- [4- (nonylamino) -1-pyridinium] '- heptane dibromide, m.p. 132-134 ° C.

Example 50

Following the procedure described in Example 41C, but using 11.0 g (0.05 mol) of 4- (nonylamino) pyridine and 7.15 g (0.025 mol) of 1,9-dibrominonane, 15.7 g of 9-bis-5- (nonylamino) -1-pyridinium β-nonanedibromide, m.p. 121-122 ° C.

Example 51

Following the procedure described in Example 41C, but using 11.0 g (0.05 moles) of 4- (nonylamino) pyridine and 7.5 g (0.025 moles) of 1,10-dibromidecane, 15.63 g of 1,10-bis- - (nonylamino) -1-pyridinium-7-decanedibromide, m.p. 172-173 ° C.

Example 52

Following the procedure described in Example 41C, but using 10.12 g (0.046 moles) of 4- (nonylamino) pyridine and 7.54 g (0.023 moles) of 1,12-dibromododecane, 16.4 g of 1,12-bis- - (nonylamino) -1-pyridinium / dodecane dibromide, m.p. 105-106 ° C.

Example 53

To a stirred, warm solution of 12.4 g (0.06 mol) of 4- (2-ethylhexylamino) pyridine in 100 ml of acetonitrile was added dropwise a solution of 6.9 g (0.03 mol) of 1.5 -di-bromopentane in 25 ml of acetonitrile and the resulting solution were heated under reflux for 20 hours. The reaction mixture was cooled and diluted with ether to slightly turbidity. Further cooling and stirring gave a solid precipitate which was isolated by filtration and washed with a cold mixture of acetonitrile and ether. The solid thus obtained was dissolved in ethanol, the resulting solution was treated with activated carbon and filtered. Evaporation of the filtrate gave a pale yellow, viscous oil which was crystallized from acetonitrile-ether. The solid formed was isolated by filtration, washed with cold acetonitrile ether and dried in vacuo at 90 ° C for 24.6 g to give 13.6 g of 5-bis- [4- (2-ethylhexylamino) -1-pyridine] -7-pentanedibromide. mp. 150-151 ° C.

66850 29

Example 54

Following the procedure described in Example 53, but using 12.4 g (0.06 moles) of 4- (2-ethylhexylamino) pyridine and 7.32 g (0.03 moles) of 1,6-dibromohexane, 16.1 g, 6 -bis- [4- (2-ethylhexylamino) -1-pyridinyl] hexane dibromide, m.p. 208-209 ° C.

Example 55

Following the procedure described in Example 53, but using 12.4 g (0.06 moles) of 4- (2-ethylhexylamino) pyridine and 7.75 g (0.03 moles) of 1,8-dibromooctane, 15.9 g, 8 -bis-1- (14- (2-ethylhexylamino) -1-pyridinium] -7-heptane dibromide, mp 219-220 ° C.

Example 56

Following the procedure described in Example 53, but using 12.4 g (0.06 moles) of 4- (2-ethylhexylamino) pyridine and 8.2 g (0.03 moles) of 1,8-dibromooctane, 15.9 g of 1, 8-bis- [4- (2-ethylhexylamino) -1-pyridinyl] -4-octane dibromide, m.p. 160-161 ° C.

Example 57

Following the procedure described in Example 53, but using 12.4 g (0.06 moles) of 4- (2-ethylhexylamino) pyridine and 8.6 g (0.03 moles) of 1,9-dibrominonane, 15.2 g, 9-bis - E4- (2-ethylhexylamino) -1-pyridinium p-nonane dibromide, m.p. 158-159 ° C.

Example 5 8

Following the procedure described in Example 53, but using 12.4 g (0.06 moles) of 4- (2-ethylhexylamino) pyridine and 9.0 g (0.03 moles) of 1,10-dibromidecane, 17.4 g, 10-bis - E 4- (2-ethylhexylamino) -1-pyridinium-7-decanedibromide, m.p. 162-163 ° C.

Example 59

Following the procedure described in Example 2, but using 5.0 g of 1,1'-bis-η 4 - (2-ethylhexylamino) -1-pyridinium-7-decanedibromide, 4.11 g of the corresponding dichloride were obtained, m.p. 191-192 ° C.

Example 60

To a stirred, warm solution of 12.0 g (0.063 mol) of 4- (heptylamino) pyridine in 100 ml of acetonitrile was added dropwise a solution of 7.4 g (0.032 mol) of 1,5-dibromopentane in 25 ml. in acetonitrile and the resulting mixture was heated under reflux for 19 hours. The reaction mixture was cooled! 66850 30 was placed on ice and ether was gradually added until a colorless solid precipitated. The solid was isolated by filtration, recrystallized from acetonitrile-ether and dried for 48 hours at 90 ° C / 1 mm Hg to give 15.9 μl of 5-bis- [4- (heptylamino) -1-pyridinium] -pentanedibromide. mp. 153-154 ° C.

Example 61

Following the procedure described in Example 60, but using 19.2 g (0.1 mol) of 4- (heptylamino) pyridine and 12.2 g (0.05 mol) of 1,6-dibromohexane, 27.5 g of crude product were obtained. Recrystallization of a 15 g sample from acetonitrile ether gave 11.45 g of 1,6-bis - β - (heptylamino] -1-pyridine and β-hexane di-bromide, mp 149-150 ° C.

Example 62 A. A suspension of 24.0 g of crude 1,6-bis- [4- (heptylamino) -1-pyridinyl] -hexanedibromide in 500 ml of water was basified with 3N aqueous sodium hydroxide solution and extracted with chloroform. The chloroform extracts were dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. The residual oil was dissolved in methanol, the resulting solution was acidified with methanesulfonic acid and evaporated to dryness in vacuo. The residue was redissolved in methanol, treated with activated carbon, filtered and evaporated to dryness in vacuo. The residual oil was triturated with ether and acetonitrile to give 18.2 g of a gummy solid. The crude solid was dissolved in water, the resulting solution was basified with 35% aqueous sodium hydroxide solution and extracted with chloroform. The chloroform extracts were dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. The solid formed was triturated with ether and acetonitrile, isolated by filtration and dried to give 16.3 g of a tan solid, m.p. 105-108 ° C. The solid thus obtained was dissolved in 100 ml of methanol, and the resulting solution was acidified with methanesulfonic acid. Evaporation to dryness in vacuo gave a viscous oil which was dissolved in 20 ml of methanol and treated portionwise with 150 ml of water. The resulting suspension was cooled on ice, the suspended solid was isolated by filtration and washed with cold water. The solid was slurried in hot acetone, cooled, isolated by filtration, I! 66850 31 was washed with cold acetone and dried for 48 hours at 95 ° C / 1 mm Hg to give 10.8 g of a tan solid, m.p. 163-165 ° C. This product gave a positive chloride reaction with silver nitrate and its NMR spectrum showed the absence of a methanesulfonate group.

B. A suspension of 14.0 g of 1,6-bis-β- (neptylamino) -1-pyridinium? -Hexanedibromide in 500 ml of water was basified with 35% aqueous sodium hydroxide solution and extracted with chloroform. The chloroform extracts were dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. The partially solid residue was dissolved in 1 liter of acetonitrile-benzene and the resulting solution was evaporated to dryness in vacuo. This was repeated three times. The final residue was dissolved in 50 ml of acetonitrile, the resulting solution was diluted with 50 ml of benzene, cooled in ice and, after filtration and drying, 5.3 g of a tan solid were obtained. An additional 4.8 g was obtained from the filtrate. The yields were combined and dissolved in 50 ml of acetonitrile. Dilution with ether precipitated a solid which was isolated by filtration and dried for 48 hours at 95 ° C / 1 mm Hg to give 8.85 g of a tan solid, m.p. 174-176 ° C. This product also gave a positive chloride reaction with silver nitrate.

C. The products of parts A and B above were combined, mixed with 300 ml of water and heated to a homogeneous solution. The solution was filtered and the filtrate was treated with 50 mL of 12 N hydrochloric acid. The resulting suspension was evaporated in vacuo and the residue was treated with ice. The solid thus formed was isolated by filtration, washed with cold water and dried. The product was dissolved in acetone, the resulting solution was diluted with a mixture of benzene and ethanol and evaporated to dryness in vacuo. The solid residue was slurried in 100 mL of acetone, the suspension was diluted with ether, filtered and dried at 105 ° C / 1 mm Hg for 48 hours and 115 ° C / 1 mm Hg for 72 hours to give 16.3 g of crude 1,6-bis- 4- (heptylamino) -1-pyridinium} -hexanedichloride as an off-white solid, m.p. 176-178 C.

Example 63

Following the procedure described in Example 60, but using 10.30 g (0.050 moles) of 4- (2-ethylhexylamino) pyridine and TT-66850, 5.4 g (0.025 moles) of 1,4-dibromobutane gave 14.9 g of 1.4 -bis- (4- (2-ethylhexylamino) -1-pyridino-tert-butane dibromide, mp 245-246 ° C.

Example 64.

A. A mixture of 229 g (1.0 mol) of N- (4-pyridyl) -pyridinium chloride hydrochloride and 244 g (1.26 mol) of n-decylamine hydrochloride was stirred and heated .n. 2.5 hours at 190 ° -195 ° 195 ° C. The reaction mixture was allowed to cool slowly to 40 ° C and diluted with 2 liters of water. The resulting solution was cooled by the addition of ice and basified with 200 ml of 35% aqueous sodium hydroxide solution. The dark solid was isolated by filtration and washed with cold water. This material was dissolved in 1 liter of chloroform, the resulting solution was treated with activated carbon and filtered. The filtrate was evaporated to dryness in vacuo and the residue was triturated with 150 ml of ether. The solid thus obtained was redissolved in chloroform, the resulting solution was treated with activated carbon and filtered. The filtrate was re-treated with activated carbon and filtered. The filtrate was evaporated to dryness in vacuo and the solid residue was triturated with ether. Recrystallization from acetonitrile, after drying in vacuo, gave 96.1 g of 4- (desylamino) pyridine, m.p. 71-73 ° C.

B. To a stirred, warm solution of 12.2 g (0.052 moles) of 4- (decylamino) pyridine in 150-170 mL of acetonitrile was added dropwise a solution of 6.35 g (0.026 moles) of 1,6-di -bromohexane in 60 ml of acetonitrile and the resulting mixture was heated under reflux for about 20 hours. The reaction mixture was cooled on ice, the precipitated solid was isolated by filtration and washed with cold acetonitrile. The product thus obtained was dissolved in methanol, the resulting solution was treated with activated carbon and filtered. The filtrate was evaporated to dryness in vacuo, the residue triturated in 50 ml of cold ether, isolated by filtration and dried over phosphorus pentoxide at 70 ° C / 0.1 mm Hg for 2 days to give 14.6 g of 1,6-bis- [4- (desylamino) ) -1-pyridinium-4-hexanedibromide, m.p. 138-140 ° C.

I.

66850 33

Example 65 Following the procedure described in Example 64B, but using 12.2 g (0.052 moles) of 4- (decylamino) pyridine and 6.7 g (0.026 moles) of 1,7-dibromoheptane, 16.0 was obtained. g of 1,7-bis- [4- (desylamino) -1-pyridinyl] -heptanedibromide, m.p. 145-147 ° C.

Example 66

Following the procedure described in Example 64 B, but using 11.7 g (0.050 moles) of 4- (desylamino) pyridine and 6.8 g (0.025 moles) of 1,8-dibromooctane, 16.9 g of 8-bis- / 4 - (desylamino) -1-pyridinium-4-octane dibromide, m.p. 180-182 ° C.

Example 67

Following the procedure described in Example 64B, but using 11.7 g (0.050 moles) of 4- (decylamino) pyridine and 7.15 g (0.025 moles) of 1,9-dibrominonane, 15.1 g of 9-bis-4 - ( desylamino) -1-pyridinium n-nonane dibromide, m.p. 124-126 ° C.

Example 68

Following the procedure described in Example 64B, but using 11.2 g (0.048 moles) of 4- (decylamino) pyridine and 7.2 g (0.024 moles) of 1,10-dibromidecane, 14.6 g of 1,10-bis- [4- (desylamino-pyridinium] -decane dibromide, mp 173-174 ° C.

Example 69

Following the procedure described in Example 64B, but using 11.2 g (0.048 moles) of 4- (decylamino) pyridine and 7.9 g (0.024 moles) of 1,12-dibromododecane, 16.5 g of 1,12-bis-4 - ( desylamino) -1-pyridinyl-4-dodecane dibromide, m.p. 102-106 ° C.

Example 70

To a stirred, warm solution of 13.6 g (0.052 mol) of 4- (dodesylamino) pyridine in 140 ml of acetonitrile was added dropwise a solution of 6.34 g (0.026 mol) of 1,6-dibromohexane in 50 ml. in acetonitrile and the resulting mixture was heated under reflux overnight. The reaction mixture was cooled and the precipitated solid was isolated by filtration. The isolated solid was dissolved in absolute ethanol, the resulting solution was treated with activated carbon and filtered. The filtrate was evaporated to dryness in vacuo to a white residue which was slurried in ether, isolated by filtration and dried at -6 DEG-346.850 60 ° C / 0.1 nun Hg to give 17.63 g of 1,6-bis- (4- (dodesylamino)). -1-pyridinyl-7-hexanedibromide, mp 164-165 ° C.

Example 71

Following the procedure described in Example 70, but using 13.6 g (0.052 moles) of 4- (dodecylamino) pyridine and 6.71 g (0.026 moles) of 1,7-dibromoheptane, 18.03 g of 7-bis- / “4- (Dodesylamino) -1-pyridinium? -Heptanedibroinide, m.p. 148-150 ° C.

Example 72

Following the procedure described in Example 70, but using 12.59 g (0.048 moles) of 4- (dodecylamino) pyridine and 6.53 g (0.024 moles) of 1,8-dibromooctane, 16.18 g of 8-bis- [4- (dodesylamino) -1-pyridinyl] octane dibromide, m.p. 184-185 C.

Example 73

Following the procedure described in Example 70, but using 12.59 g (0.048 moles) of 4- (dodesylamino) pyridine and 6.86 g (0.024 moles) of 1,9-dibrominonane, 19.35 g of 9-bis-4- (dodesylamino) was obtained. ) -1-pyridinyl-4-nonane dibromide, m.p. 134-135 ° C.

Example 74

Following the procedure described in Example 70, but using 12.59 g (0.048 moles) of 4- (dodesylamino) pyridine and 7.2 g (0.024 moles) of 1,10-dibromidecane, 18.08 g of 10-bis-4- (dodesylamino) was obtained. ) -1-pyridine and 4-decane dibromide, m.p. 178-180 ° C.

Example 75

Following the procedure described in Example 70, but using 11.54 g (0.044 moles) of 4- (dodesylamino) pyridine and 7.22 g (0.022 moles) of 1,12-dibromododecane, 17.68 g of 1,12-bis- - (dodesylamino) -1-pyridinium-7-dodecane dibromide, m.p. 75-77 ° C.

Example 76 A. To a stirred, warm solution of i.e. 21.0 g (0.102 moles) of 4- (p-chlorophenylamino) pyridine in 150 mL of N, N-dimethylformamide was added dropwise a solution of 11.02 g ( 0.051 mol) of 1,4-dibromobutane in 50 ml of acetonitrile and the resulting mixture was heated on a water bath for 2.5 hours. The reaction mixture was cooled to room temperature, diluted with ether and the product was allowed to crystallize. The precipitated solid was isolated by filtration, washed with a mixture of acetonitrile and ether and air dried to give 27.4 g of 1,4-bis - {4- (p-chlorophenylamino) -1-pyridinyl] -butane dibromide, m.p. 182-189 ° C.

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

C. A solution of the anhydro base described above in 250 ml of methanol was acidified with a methanolic solution of methanesulfonic acid. Evaporation to dryness in vacuo gave an oil which was crystallized from methanol-ether. The solid thus obtained was recrystallized from methanol-ether, dried for 48 hours at 92 ° C / 0.1 mm Hg to give 18.95 g of 1,4-bis-β- (p-chlorophenylamino) -1-pyridinyl] -butanedimethanesulfonate. , sp. 245-247 ° C.

Example 77 A. To a stirred, warm solution of 21.0 g (0.102 moles) of 4- (p-chlorophenylamino) pyridine in 200 mL of N, N-dimethylformamide was added dropwise a solution of 12.45 g ( 0.051 mol) of 1,6-dibromohexane in 50 ml of acetonitrile and the resulting mixture was heated on a water bath for four hours. As it cooled to room temperature, a precipitate began to form. The reaction mixture was diluted with 150 mL of acetonitrile and further cooled on ice. The precipitated solid was isolated by filtration and air dried to give 27.2 g of 1,6-bis - N- (p-chlorophenylamino) -1-pyridinium-7-hexanedibromide, m.p. 148-150 ° C.

B. A methanol solution of the corresponding anhydro base prepared from the dibromide described above according to the method of Example 76B was acidified with methanesulfonic acid and evaporated to dryness in vacuo. The residual oil was crystallized from acetone-methanol and dried for 48 hours at 75 ° C / 0.1 mm Hg to give 25.2 g of 1,6-bis- [4- (p-chlorophenylamino) -1-pyridine] hexane dimethanesulfonate. , sp. 108-110 ° C.

Example 78 A. To a stirred, warm solution of 21.0 g (0.102 moles) of 4- (p-chlorophenylamino) pyridine in 200 mL of N, N-dimethylformamide was added dropwise a solution of. 13.9 g (0.051 mol) of 36,66850 1,8-dibromooctane in 50 ml of acetonitrile and the resulting mixture were heated in a water bath for 1.5 hours. The reaction mixture was then diluted with 100 mL of acetonitrile and heated for an additional 2.5 h while adding 100 mL of acetonitrile. After heating for an additional two hours, the reaction mixture was cooled, the precipitated solid was isolated by filtration, washed with a mixture of acetonitrile and ether and dried to give 30.1 g of 1,8-bis- (p-chlorophenylamino] -1-pyridine-4-octane dibromide, mp 245 247 ° C.

B. A methanol solution of the corresponding anhydro base prepared from the dibromide described above according to the method of Example 76B was acidified with methanesulfonic acid and evaporated to dryness in vacuo. The residual oil was dissolved in acetonitrile, the resulting solution was treated with acetone to cloudy, clarified with a small amount of methanol and cooled. The precipitated crude solid was isolated, recrystallized from acetonitrile-acetone and dried for 36 hours at 80 ° C / 0.1 mm Hg to give 23.5 g of 1,8-bis- [4- (p-chlorophenylamino) -1-pyridinium] 7-octate. -nimethanesulfonate, m.p. 164-165 ° C.

Example 79 A. To a stirred, warm solution of 21.0 g (0.10 moles) of 4- (p-chlorophenylamino) pyridine in 200 mL of N, N-dimethylformamide was added dropwise a solution of 15.3 g (0.051 moles) of 1,10-dibromidecane in 50 ml of acetonitrile and the resulting mixture was heated on a water bath for 3.5 hours. The reaction mixture was evaporated to dryness in vacuo and the residual oil was crystallized from methanol-1-acetonitrile. The solid thus formed was isolated by filtration and washed with a cold mixture of acetonitrile and ether to give 28.0 g of 1,10-bis- [4- (p-chlorophenylamino) -1-pyridine] -decanedibromide, m.p. 225-230 ° C.

B. A methanol solution of the corresponding anhydro base prepared from the dibromide described above according to the method of Example 76B was acidified with methanesulfonic acid and evaporated to dryness in vacuo. The residual oil was crystallized from acetonitrile ether. The crude solid thus obtained was dissolved in methanol, the resulting solution was treated with activated carbon and filtered. Evaporation of the filtrate gave an oil which was suspended in acetonitrile

II

a7 to a mixture of 66850 and acetone and an impure solid was obtained. Recrystallization from methanol-ether gave, after drying for 48 hours at 95 ° C / 0.1 mm Hg, 18.4 g of 1,10-bis - [+ - (p-chlorophenylamino) -1-pyridinium] -decanedimethanesulfonate, m.p. 202-204 ° C.

Example 80

To a stirred, warm solution of 10.0 g (0.049 moles) of 4- (p-chlorophenylamino) pyridine in a mixture of 275 ml of acetonitrile and 100 ml of N, N-dimethylformamide was added dropwise a solution of 5.75 g (0.025 mol) of 1,5-dibromopentane in 25 ml of acetonitrile and the resulting mixture were heated under reflux for 24 hours. The reaction mixture was then evaporated to dryness in vacuo and the residue triturated with a mixture of ether and acetonitrile. The pale yellow solid thus obtained was dissolved in ethanol, the resulting solution was treated with activated carbon and filtered. The filtrate was evaporated to dryness in vacuo and the residual oil was crystallized from ether-acetonitrile. The colorless solid was recrystallized from methanol-acetonitrile, dried for 48 hours at 115 ° C / 0.1 mm Hg to give 8.1 g of 5-bis- [4- (p-chlorophenylamino) -1-pyridinium] -pentane dibromide, m.p. . 166-16 ° C.

Example 81

To a stirred, warm solution of 10.0 g (0.049 moles) of 4- (p-chlorophenylamino) pyridine in a mixture of 125 ml of N, N-dimethylformamide and 50 ml of acetonitrile was added dropwise a solution of 6.45 g 1,7-Dibromoheptane in 25 ml of acetonitrile and the resulting mixture were heated under reflux for 19 hours. The reaction mixture was evaporated to dryness in vacuo and the residual oil was crystallized from ethanol-acetonitrile. The solid thus formed was dissolved in methanol, the resulting solution was treated with activated carbon and filtered. The filtrate was evaporated to dryness in vacuo and the residual oil was recrystallized from ethanol-acetonitrile. The product was filtered off and dried for 36 hours at 105 ° C / 0.1 mm Hg to give 10.4 g of 1,7-bis- [4- (p-chlorophenylamino) -1-pyridinium] -7-heptane dibromide, m.p. 202-204 ° C.

38 66850

Example 82

Following the procedure described in Example 81, but using 10.0 g (0.0 * 19 moles) of 4- (p-chlorophenylamino) pyridine and 7.15 g (0.025 moles) of 1,9-dibrominonane, 11.2 g of 1.9- bis - [(1- (p-chlorophenylamino) -1-pyridine] -7-nonane dibromide, m.p. 178-179 ° C.

Example 83 To a warm, stirred solution of 11.52 g (0.06 mol) of * + - (heptylamino) pyridine in 100 ml of acetone-tril was added in small portions a solution of 7.92 g (0.03 mol) of ) </ α, β-Dibromo-β-xylene in 150 ml of acetonitrile. At the end of the addition, a large amount of colorless crystals had precipitated from the solution. The reaction mixture was heated under reflux for six hours. After cooling to room temperature, the solid was isolated by filtration, washed with acetonitrile-ether, combined with 3.1 g of the product from the previous run and dried for 28 hours at 100 ° C / 0.1 mm Hg to give 22.0 g of -bis - / ^ 4- ( heptylamino) -pyridinium β-p-xylene dibromide, m.p. 297-298 ° C.

Example 8 * +

Following the procedure described in Example 83, but using 11.6 g (0.065 moles) of * + - (hexylamino) pyridine and 8.7 g (0.033 moles) of dibromo-p-xylene and heating under reflux for 20 hours, the reaction mixture was obtained. 19.3 g of β'-bis-4- (hexylamino) -pyridinium-7-p-xylene dibromide, m.p. 313-315 ° C.

Example 85

A suspension of 19 g of * + - aminopyridine and 23 g of oO-dichloro-2,3,5,6-tetramethyl-p-xylene in 600 ml of methanol was heated on a water bath to complete dissolution. After a small amount of insoluble matter was removed by filtration, the clear solution was gently heated on a water bath for two hours, at which time a white solid began to precipitate. The mixture was cooled to room temperature, the solid isolated by filtration, washed successively with methanol and ether and dried overnight in vacuo at 100 ° C to give 29 g of * ;, <** - bis- (4-amino- 1-pyridinium) -2,3,5,6-tetramethyl-p-xylene dichloride, m.p. above 340 ° C.

Example 86

To a hot solution of 12.5 g (0.132 moles of 4-aminopyridine in 100 ml of 2-propanol) were added 11.6 g (0.066 moles) of oC 2 -C'-dichloro-p-xylene and 400 ml of methanol. After removal of a small amount of insolubles by filtration, the clear solution was diluted with 500 mL of ethyl acetate and cooled to room temperature, and the solid was isolated by filtration, washed with ethyl acetate and dried to give 16 g of (fioObis-14-amino-1-pyridinium). -xylene dichloride, m.p. 332-335 ° C.

The antibacterial and antifungal potency of the representative examples of the compounds of formula I and II was determined using the modified Auto-titer method described by Oss et al., Aplied Microbiology, 16, (9) 1414-1415 (1968), in which 1000 micrograms / ml of active ingredient was prepared. 0.1 ml of test solution was added to the first cup of Autotray, and when the Autotiter was started, the Microtiter transfer loop begins a series of steps in which the Microtiter transfer loop takes 0.05 ml of test compound solution from the cup and dilutes it to 0.05 ml of sterile water. 0.05 ml of inoculated, doubly concentrated, semi-synthetic medium (glucose) is automatically added, after which the final concentration of the solution was 500-0.06 micrograms / ml in two-fold increments.The autotray is incubated for 18-20 hours at 37 ° C. The last sample in the series with no growth (or turbidity) is called the minimum entraxia (MEK) micrograms / ml. In this way, the compounds were tested as solutions against various gram-positive and gram-negative bacteria, including Staphylococcus aureus, Proteus mirabilis, Escherichia coli, Klebsiella pneumoniae, 40 66850

Pseudomonas aeruginosa, Streptococcus pyogenes, and fungi such as Aspergillus niger, Candida albicans, and Trichophyton mentagrophytes.

Many compounds of formula I were also found to be antibacterial against Streptococcus mutans and Actinomyces A-viscosis.

The antiviral efficacy of representative examples against Herpes simplex type 2 virus was determined in vitro using a method similar to that used to study plaque inhibition in determining inhibitors of DNA-containing viruses, published by E. C.

Herrmann Jr., Proc. Soc. Exp. Biol. Med. , 107, 142 (1961), in which 2 mg of the test compound was placed on the surface of the medium. Examples 3, 5C, 7, 9C, 10, 11, 13, 17, 18, 21, 22, 24, 31, 33, 35, 36, 37, 53, 54, 55, 56, 57, 58, 60, 61 , 63, 81, 82, 82 and 84 were found to be effective and the compounds of Examples 16, 34, 39, 40 and 79B were found to be ineffective.

The dental plaque inhibitory efficacy of some of the compounds of the present invention was tested by determining the ability of these compounds to inhibit dental plaque caused by Streptococcus mutans OMZ-61 as follows:

The culture medium of the plaque-causing species Streptococcus mutans OMZ-61 containing 1.5 g of BBL beef extract, 5 g of sodium chloride, 10 g of dehydrated trypticase, 5 g of sucrose and distilled water to a total volume of 1000 ml was adjusted to pH 7.0 and sterilized. membrane filtration. The culture medium was dispensed in 10 ml aliquots into 15 x 16 mm test tubes and stored at refrigerator temperature until use.

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

A sterile piece of plaque-free natural tooth enamel or synthetic hydroxylapatite was suspended at each compound concentration for two one-minute periods, drying after each.

II

66850 in the air for one minute. Each piece was then suspended and mixed for five minutes in different test tubes with sterile distilled water (rinsing). The pieces were then suspended in 10 ml of liquid bull extract medium supplemented with 0.3 ml of an anaerobic culture of Streptococcus mutans. Tubes containing "treated" hydroxylapatite and Streptococcus mutanis were incubated anaerobically for 24 hours at 37 ° C. The same procedure was repeated by dipping twice in the compound solution for one minute, drying in air for one minute after each time and finally rinsing for five minutes, and resuspending the hydroxylapatite in a new test tube containing 10 ml of beef extract medium and 0.3 ml of graft. At the end of the second 24 hour period, each piece of hydroxylapatite was rinsed for one minute in three consecutive test tubes containing distilled water. The pieces were then suspended for one minute at F. D&C Red No. To a solution containing 3 colors. This staining method was used to facilitate the identification of plaque development after exposure to the plaque-forming organism for 48 hours. After staining, rinse for 10 seconds to remove excess dye. The plaque turns pink on the fitting. Test results are graded as plaque inhibition (effective) or non-plaque inhibition (ineffective) as a percentage of test concentration. The active compounds were tested in gradually decreasing doses to determine the minimum inhibitory effect. In some cases, inhibition of culture medium growth affects plaque formation because the compound is extracted from hydroxylapatite to form an inhibitory concentration of the bacterium in the medium. In such cases, the compound is tested at lower concentrations until the growth of the organism in the medium is the same as in the untreated control culture. At these lower concentrations, plaque is formed or not.

However, the presence of a test compound on the tooth surface, which is, of course, necessary to prevent plaque formation on the tooth, may enhance the adhesion of colorants such as coffee, tobacco, nutrients and dyes to the tooth surface.

Therefore, the method described above was also used to determine the staining ability, i. how the test compound is able to prevent the adherence of colorants to the tooth surface. Thus, the remaining uniform pink color adhering to the test surface after the last rinse indicates the staining ability at the percentage test concentration of 42 66850 and is expressed as the staining concentration. The uniform pink color produced by the test compound is readily distinguishable from the local pink color caused by plaque formation. In general, the staining concentration of the preferred compounds is significantly higher than the lowest effective anti-plaque concentration.

Table A below shows the experimental values of the antibacterial and antifungal and anti-plaque properties of the compounds. For comparison, the corresponding values for two known compounds, e.g. For 1,8-bis- (4-amino-1-pyridinium) -octane dibromide (Reference Compound I) and 1,10-bis- (4-amino-1-pyridinium) -decanedibromide (Reference Compound II). The staining concentrations of the representative examples are shown in Table B below.

The inhibitory effect of dental plaque in the presence of sterile human saliva (50%) was determined for representative examples. The test results are reported as mini-inhibitory concentrations and are shown in Table B below.

The acute oral toxicity of some representative examples was determined as follows. Groups of three young, adult Swiss-Webster male albino mice were fasted for approximately four hours prior to treatment and then administered orally once by gavage. All mice were observed for seven days after treatment. No significant tissue changes were observed at necropsy in all experimental mice except for the group receiving 1000 mg / kg of the compound of Example 25. In this case, two blood clots in the abdominal gland were observed in two mice. The results are shown in Table C below.

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Table Β Staining power and the effect of saliva on dental plaque inhibition power _ - - .. I "-" - - «

Example No. Dental plaque inhibitory potency at 50% Stain compound in saliva minimum inhibitory concentration _ thio (%) __ (_%) _ 27 0.05 24 N. 0.005 0.05 25 0.05 58 N. 0.005 0.05 59 0.05 56 0.1 0.05 3 0.1 0.05 4 N. 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 N. 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

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

Table C

Acute oral toxicity (ALDj-g) 50 6 6 8 5 0

Example Solution or Dose mg / kg Mortality No. compound suspension total 1 day 7 days substance 23 Aqueous solution 125 0/3 0/3 250 0/3 0/3 500 1/3 1/3 1000 3/3 3/3

7 days. ALDC = o U

625 mg / kg 26 suspension 125 0/3 0/3 in 1% GT ^ 250 0/3 0/3 500 0/3 0/3 1000 0/3 0/3 7 days · ALD50 => 1000 mg / kg 27 Aqueous solution 125 0/3 1/3 25Q 0/3 0/3 500 1/3 1/3 1000 1/3 3/3 7 days. ALDC _ =

D U

250 mg / kg 24 Suspension 125 0/3 0/3 in 1% GT 250 0/3 0/3 500 0/3 1/3 1000 0/3 0/3 7 days. ALDj-q => 1000 mg / kg 25 Aqueous solution 250 1/3 1/3 500 1/3 1/3 1000 3/3 3/3 7 days. ALDC =

o U

500 mg / kg 3 Suspension 125 0/3 0/3 in 1% GT 250 0/3 0/3 500 0/3 1/3 1000 1/3 1/3 I!

Table C (continued)

Acute oral toxicity (ALD ^ g) 51 66850

Example Solution or Dose mg / kg Mortality No. Compound suspension total 1 day 7 days substance_ 7 days. ALD50 = 1000 mg / kg 4 Suspension 125 0/3 0/3 in 1% GT 250 0/3 0/3 500 0/3 0/3 1000 0/3 0/3 7 days. ALDC = 50 0> 1000 mg / kg 2 Suspension 125 0/3 0/3 in 1% GT 250 0/3 2/3 500 0/3 0/3 1000 0/3 1/3 7 days. ALD ^ q = 1000 mg / kg 8 Aqueous solution 125 0/3 0/3 250 1/3 1/3 500 2/3 3/3 1000 3/3 3/3

7 days. ALD n o U

5C Suspension 125 0/3 0/3 1% s a in GT 250 0/3 0/3 500 0/3 0/3 1000 1/3 1/3 7 days. ALD50 => 1000 mg / kg 6 Aqueous solution 125 1/3 1/3 250 0/3 1/3 500 2/3 2/3 1000 3/3 3/3 7 days. ALDg0 = 315 mg / kg _ "Γ" 52 66850

Table C (continued)

Acute oral toxicity (ALD ^ q)

Example Solution or Dose mg / kg Mortality No. compound suspension total 1 day 7 days substance ID Suspension 125 0/3 0/3 in 1% GT 250 0/3 0/3 500 1/3 1/3 1000 2/3 2/3 7 days ALDcn = bu 750 mg / kg 11 Suspension 125 0/3 0/3 in 1% GT 250 0/3 0/3 500 0/3 1/3 1000 0/3 0/3 7 days. ALDrn = bu> 1000 mg / kg 12 Aqueous solution 125 0/3 0/3 250 0/3 0/3 500 1/3 1/3 1000 2/3 2/3

7 days. ALD = o U

750 mg / kg 9C Suspension 125 0/3 0/3 in 1% GT 250 0/3 0/3 500 0/3 0/3 1000 0/3 0/3 7 days ALDj.q => 1000 mg / kg 10 Aqueous solution 125 0/3 0/3 250 0/3 0/3 500 0/3 0/3 1000 0/3 0/3 7 days. ALD5q => 1000 mg / kg

Table C (continued)

Acute oral toxicity (ALD ^ g) 53 66850

Example Solution or Dose mg / kg Mortality No. compound suspension of total matter 1 day 7 days 58 Suspension 125 0/3 0/3 in 1% GTr 250 0/3 0/3 500 0/3 0/3 1000 0/3 0/3 7 days. ALDC =

• o U

> 1000 mg / kg 59 Aqueous solution 125 0/3 0/3 250 0/3 0/3 500 1/3 2/3 1000 1/3 1/3 7 days. ALDr = bu 750 mg / kg 56 Suspension 125 0/3 0/3 in 1% GT 250 0/3 0/3 500 0/3 0/3 1000 1/3 1/3 7 days. ALD5q => 1000 mg / kg 14 Suspension 125 0/3 0/3 in 1% 250 0/3 0/3 in GT 500 0/3 C / 3 1000 0/3 1/3 7 days. ALDgQ => 1000 mg / kg 4 4A Suspension 125 0/3 0/3 in 1% GT 250 0/3 0/3 500 0/3 0/3 1000 0/3 0/3 7 days. ALDj-q => 1000 mg / kg

Table C (continued) 6685 0

Acute oral toxicity (ALDj-q) 54

Example Solution or Dose mg / kg Mortality No. compound suspension of total matter 1 day 7 days 29C Suspension 125 0/3 0/3 in 1% GT 250 0/3 0/3 500 0/3 0/3 1000 0 / 3 0/3 7 days. ALDj-q => 1000 mg / kg 41C Suspension 125 0/3 0/3 in 1% GT 250 0/3 0/3 500 0/3 0/3 1000 0/3 0/3 7 days. ALDj.q => 1000 mg / kg 1. GT = tragacanth • * I!

Claims (2)

66850 5 5 Bis-pyridinural uranes and bis-pyridinium xylenes, known for use as disinfectants and anti-fouling plaque inhibitors, characterized in that they have the formula I or II, I1 mn Q -, - φτ-Ο-Τ Γ.Τ ^ v ti __ n wherein in formula IY is an alkylene group having 4 to 18 carbon atoms which separates both 4- (R-NH) -1-pyridinyl groups by 4 to 18 carbon atoms; R is an alkyl group having 6 to 18 carbon atoms, cyclohexyl or phenyl substituted by one or two halogens, and in formula II R is hydrogen, a straight-chain or branched alkyl group having 1 to 38 carbon atoms or benzyl, Q is methyl or chlorine; is an integer from 0 to 4, and in formulas I and II A is an anion, m is 1 or 3, n is 1 or 2, x is 1, 2 or 3 and (m) (2) = (n) (x). Compound according to Claim 1, characterized in that in the formula I R is an alkyl group having 6 to 18, preferably 7 to 9, carbon atoms.