IE45336B1 - Usantimicrobial bis pyridinium compounds - Google Patents

Usantimicrobial bis pyridinium compounds

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Publication number
IE45336B1
IE45336B1 IE386/77A IE38677A IE45336B1 IE 45336 B1 IE45336 B1 IE 45336B1 IE 386/77 A IE386/77 A IE 386/77A IE 38677 A IE38677 A IE 38677A IE 45336 B1 IE45336 B1 IE 45336B1
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Ireland
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bis
formula
dibromide
mole
compound
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IE386/77A
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IE45336L (en
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Sterling Drug Inc
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Priority claimed from US05/734,729 external-priority patent/US4107313A/en
Application filed by Sterling Drug Inc filed Critical Sterling Drug Inc
Publication of IE45336L publication Critical patent/IE45336L/en
Publication of IE45336B1 publication Critical patent/IE45336B1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/73—Unsubstituted amino or imino radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A61P31/22—Antivirals for DNA viruses for herpes viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates

Abstract

The compounds of formulae I and II in which the symbols have the meaning given in Claim 1 are prepared by reaction of 2 mole parts of a compound or, respectively, , with one mole part of a compound Z-Y-Z or, respectively, , Z being an atom or radical which splits in the form of an anion which is then the anion A. The latter can be exchanged by metathesis against other anions A. The compounds thus prepared have antibacterial, fungicidal and viricidal properties and can be used, for example, in medicine, as disinfectants and as antimicrobial agents.

Description

The present invention relates to bis-(4~amino-l-pyridinium)alkanes and ajCi'-bis-^-amino-l-pyridiniumJxylenes and the preparation thereof3 said compounds being useful for conI trolling bacteria, fungi and Herpes viruses, and in certain cases! for preventing the formation of dental plaque. ! U.S. Patent 3,055,902 discloses a group of bis-(4amino-l-pyridinium)alkanes as intermediates in the preparation of the corresponding bis-(4-amino-l-piperidino)alkanes stated · to have bacteriostatic and bactericidal effects. ; W.C. Austin et al. , J. Pharm. Pharmacol. 11, 80-93 ' (1959) disclose l,10-bis-(4-amino-l-pyridinium)decane diiodide j ί and l,10-bls-C4-acetamido-l-pyridinium)decane diiodide. It is ! stated that certain species among the large, diverse group of quaternary ammonium compounds disclosed possess amebicidal, 1 antibacterial, anti-filarial and trypanocidal activity, but no biological data are given for either of the above-named compounds, ' The invention relates to biS“[4-(R-amino)-l-pyridinium];alkanes having Formula 1 hereinbelow: j -24 3336 and a,a'-bis-Q-(R-amino)-l-pyridiniumJxylenes having formula II hereinbelow: ...II 1 wherein in Formula I: Y is ss alkylene group containing from 4 to 18 carbon atoms and separating the two 4-(R-NH)-1-pyridinyl groups by from 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, benzyl, substituted benzyl as herein defined or phenyl substituted by methylenedioxy or one or two substituents selected from the group consisting of halogen, lower-alkyl, lower-alkoxy, nitro, cyano and trifluoromethyl; and in Formula II: R is hydrogen, a straight or branched-chain alkyl group containing from 1 to 18 carbon atoms, or benzyl; Q is methyl or chlorine; and V is 0 or an integer 1 to 4; and where in Formulas I and II: A is an anion; m is 1 or 3; n is 1 or 2; and x is i, 2 or 3; and wherein ;m) (2) = (n) (x).
Tnese compounds are useful as antibacterial and antifungal agents and are virucidally active against Herpes viruses. -345336 Certain of the compounds of Formula X are also useful as dental plaque-preventive agents, for example: 1.6- Bis-[4-(octylamino)-1-pyridinium]hexane dibromide and the corresponding dichloride, 1,,6- B i s-[4-(nonylamino)-1-pyridinium]hexane dibromide and the corresponding dichloride, 1.6- Bis-{4-(decylamino)-1-pyridinium]hexane dibromide, 1» β-Sis-[4-(dodecylaa!ino)-l-pyrldinium3hexsne dibromide, l,7“Bis-i4-(hepfcylamiao)-l-pyridinium3heptane dibromide, 1, 7=BiS“[4-(octylamino)-1-pyridiniumJheptsne dibromide, lj7-BiS“[4-(nQnylaKino)“l-pyridlniuia]heptane dibromidef li)7Bis-E4“(dscylamine)-l“pyridiniua3heptane dibromide, 1.7- Bi0-[4“(dodecylsmino5-l-pyridinium3heptane dlbrsmide, X,8-Bis-[4-(heBuyXaminoj-l-pyridinium3oefcsne dibromide and the eorrespohding dichlorids, l,S-Bis-[4-(ectylamino)-l-pyrldiniun}3octane dlehloride, -ft45338 1.8- BiE-[4-(nonylamino)-l-pyrldinium]octane diBromide, 1.8- Bis-[4-(decylamlno)-l”pyridiniuni]octane dibromide, 1.8- BiB-[4-(dodecylamlno)~l-pyrldinium]octane dibromide, 1.8- BiE-[4-(2-ethyIhexylamino)-l-pyridinium]octane dibromide, 1, 9“B1b-[4-(heptylamino)-l-pyridinium]nonane dichloride, 1.9- Bis-[4-(nonylamino)-l-pyridinium]nonane dibromide, 1.9- £is-[4-(decylamino)-l-pyridinium3nonane dibromide, ljg-Bis-L^-dcdecylaminoJ-l-pyridiniumjr.onane dibromide, 1.10- Bis-(4-(heptylamino)-l-pyridlnium]decane dibromide and tne corresponding dichloride, 1,lC-3is-[4-(;;enylamire)-l-pyridinium]decane dibromide, 1.10- Βί s- [4-(dec/lami.nc>‘)-l-pyridinium]decane dibromide, 1.10- Bla-f4-(dodecylamine)-l-pyridinium]decane dibromide, 2, IC-Bis-[4-(2-ethylhexylamino)-l-pyridinium]decane dichloride, 1.12- Bis-[4-(hexylamino)-l-pyridinlum]dodecane dibromide and the corresponding dichloride, 1.12- Bis-[4-(heptylamino)-l”pyridinium3dodecane dibromide, »5dibromide 1.12- Bis-[4-(octylamino)-l-pyridinium3dodecane dibromide, 1.12- Bis-[4-(nonylamino)-1-pyridiniumJdodecane dibromide, l,12-BIs-[4-(deeylamino)-l-pyridinlum]dodecane dibromide, 1.12- Bis-[4-{dodecylamino)-l-pyridinium]dodecane dibromide, 1.12- Bis-[4-(2-ethyIhexylsmlno)-l-pyrldinium]10 dodecane dibromide and the corresponding dichloride, 1,l4-Bis-i4-(hexylamino)-l“pyridinium]tetradecane dibromide and the corresponding dichloride, X,l4-Bis-[4-(heptylamino)-1-pyridinlum]tetradecane dibromide and the corresponding dichloride, l,X4-Bis-[4-(octylamino)-1-pyridinium tetradecane dibromide, and, as particularly preferred species, 1,9—Bis—(4-(heptylamino)-1-pyridinium] nonane dibromide, I 1,IG-Bis-(4-(2-ethylhexylamino)-1-pyridinium]decane dibromide, 1,10“Bis-(4-(octylamino)-1-pyridinium]decane dichloride and the corresponding-dibromide, 1,S—Bis—[4-(octy lamino)-1-pyridinium]nonane dibromide, 1.12- Bis-I4-(heptylamino)-1-pyridinium]dodecane dichloride, and 1,3-3is-[4-(octylamino)-1-pyridinium]octane dibromide. -6«3336 An aspect of the present invention resides in an oral hygiene composition for the prevention of dental plaque comprising an effective amount of one of the above compounds and a compatible, pharmaceutically acceptable c-tUi The invention also relates to an antibacterial, antifungal and virucidal composition suitable for topical administration which comprises an effective amount of a compound havir; Formula I or IX hereinabove and a compatible, pharmaceutically acceptable carrier. The invention further resides in a skin-cleansing composition comprising an antibacterially, antifungally and virucidally effective amount of a compound having Formula I or II hereinabove, a compatible, pharmaceutically acceptable surfactant and a compatible, pharmaceutically acceptable diluent or carrier.
The invent-.ca further relates to an antibacterial, antifungal and 'irucidal composition suitable for application tc inanimate surfaces comprising an antibacterially, •antifungally and virucidally effective amount of a compound having Formula I or II nereinabove in admixture with a compatible vehicle.
The compounds of Formulas I and II can be prepared by reacting a 4-(E-amino)pyridine having Formula III: with a disubstituted alkane having Formula IV: z - y - z ...iv or an u,a’-disubstituted xylene having Formula V: -7-.-t . wherein in Formulas IV and V: Y is an alkylene group containing from 4 to 18 carbon atoms and separating the 2 groups by from 4 to 18 carbon atoms; Z is chloro, bromo, iodo, methanesulfonyloxy, ethanesulfonyloxy, benzenesulfonyloxy or £-toluensulfonyloxy; Q is methyl or chlorine; V is an integer 0 to 4; and wherein: when the 4-(R-amino)pyridine (III) is reacted with a disubstituted alkane (IV), R in Formula III is an alkyl group containing from 5 to 18 carbon atoms, a cyoioalkyl group containing from 5 to 7 carbon atoms, benzyl or phenyl substituted by methylenedioxy or one or two halogen, lower-alkyl, loweralkoxy, nitro, cyano or trifluoromethyl substituents; and when the 4-(R-amino)pyridine (III) is reacted with an α,a‘-disubstituted xylene (V); R in Formula III is hydrogen, a straight or branched-chain alkyl group containing from 1 to 18 carbon atoms, or benzyl.
In formula I herein the alkylene group Y is a bivalent saturated aliphatic hydrocarbon radical containing from 4 to 18, preferably from 8 to 12, carbon atoms arranged in a straight or in a branched chain and separating the two 4-(R-NH)-1-pyridinyl groups from 4 to 18, preferably from 8 to 12, carbon atoms, for example: -81,4-butylene, 1,5-pentylene, 1,6-hexylene, 1,7-hepfcylene, 1,8-oetylene, 1,9-nonylene, 1,10-decylane, 1,11-undecylene, 1,12-dodecylene, 1,13-tridecylene, 1,14-tetradecylene, 1,15pentadecylene, 1,16-hexadecylene, 1,17-heptadecylene, 1,18octadecylene, 1-methy1-1, 4-butylene, 3-methyl-l,5-pentylene, 2-ethyl-l,4-butylene, 3-methyl-l,6-hexylene, 2,4dimethy1-1,5-pentylene, 1-methyl-l,7-heptylene, 3-ethyl-l, 6-hexylene, 3-·ropy.1-1,5-pentylene, 4,4-dimethyl-l,7heptylene, 2,6-dimethyl-l,7-heptylene, 2,4,4-trimethyl-l, 6-hexylene, 2,7-dimethyl-l,8-octylene, 1-methyl-l,10decylene, 5-ethy1-1,9-nonylene, 3,3,6,6-t.etramethyl-l,8octylene, 3,3-dimethyl-l,10-decylene, 3-methyl-l,11undecylene, 6-methyl-l,12-dodecylene, 2-methyl-l,13tridecylene, 4,9-dimethy1-1,12-dodecylene, 4-methy1-1,14tetradecylene, 2,13-dimethy1-1,14-tetradecylene, 1,4dipropyl-1,4-butylei.e, 3-(3-pentyl)-1,5-pentylene, 2-(4,8dimethylnonyl)-1,4-butylene, and 1-hepty1-1,5-pentylene.
It will he appreciated that when Y contains 4 carbon atoms the latter must, of course, be arranged in a straight chain and similarly when Y contains 18 carbon atoms and separates the two 4-(ΐϊ-ΝΗ)-1-pyridinyl groups by 18 carbon atoms said carbon atoms must also be arranged in a straight chain. In all other instances Y can be either straight or branched. -94333® In formula I herein 3 is a straight or branchedchain 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-pentadecyl, n-hexadecyl, n-heptadecyl, n-octadecyl, 1-methylpantyl, 2.2- dimethylbutyl, 2-methylhexyl, 1,4-dimethylpentyl, 2ethylpentyl, 3-ethylpentyl, 2-methylheptyl, 1-ethylhexyl, 2-ethylhsxyl, 2-propylpantyl, 2-methyl-3-ethylpentyl, 3ethylheptyl, 1,3,5-trimethylhexyl, l,5-dimethyl-4-ethyΙΙΟ hexyl, 2-propylheptyl, 5-methyl-2-butylhexyl, 2-propylnonyl. 2-butyloctyl, 1,.1-dimethylundecyi, 2-pentylnonyl, 1.2- dimethyltetradecyl and 1,1-dimethyIpentadecyl.
When R in formula I herein is a cysloalkyl group containing from 5 to 7 carbon atoms, there are included cyclopentyl, cyclohexyl and cycloheptyl.
When R in formula Ϊ herein is phenyl substituted ay methylenedioxy or one or too substituents selected from the group consisting of halogen, lower-alkyl, lower-alkoxy, nitro, cyano and trifIvoromethyl, there are included £2o chlorophenyl, o-chlorophenyl, m-chlorophenyl, g-bromophenyl, m-fluorophsnyl, o-iodophenyl, 2,4-dichlorophenyl, 2,4difluorophenyl, 2,5-dibromophenyl, 3,5-dichlorophenyl, 3ehloro-4-fluorophenyl, 3,4-methylenedioxyphenyl, g-ethylphenyl, g-aethoxyphenyl, m-nitrophenyl, o-cyanophenyl, m-(trifluoromethyl)phenyl and 2-methoxy-5-methyIphenyl. -10Tn formula II herein R is a straight or branchedchain alkyl group containing from 1 tc .:.8, preferably from C to 12 carbon atom.··, and includes, in addition to the aboveinenhinrcd fr'yv & to 73 carbon atoms, such groups as methyl, ethyl, n-propyl, n-butyl, npentyl, isopropyl, 1-methylpropyl, isobutyl, tert-butyl, isopentyl, neopentyl and l-methylpentyl.
In formulas I and 11 herein R can also be benzyl. When R is substituted benzyl, the phenyl moiety of the benzyl group is substituted with from one to two substituents selected from halogen, hydroxy, lower-alxyl, lower-alkoxy, nitro, cyano and trifluoromethyl.
S is the sane in both occurrences in each of formulas I and II.
When Λ in the formulas herein is an anion there are included anions cr both inorganic and organic acids for example: bromide, chloride, fluoride, iodide, sulfate, phosphate, nitrate, sulfamate, methanesulfonate, ethanesulfonate, benzenesulfonate, g-toluenesulfonate, naphthalenesulfonate, naphthalanedxculfonate, cyclohexylsulfamate, acetate, trifluoroacetate, malate, fumarate, succinate, tartrate, oxal*t*, citrate, lactate, gluconate, ascorbate, lactate, phtnalats, '.-aiicylate, benzoate, picrate, methanephosphonata, arseuite, arsenate, thiosulfate, perchlorate, tartronate, sarccsinatc, N-lauroylsarcosinate, monofluorophosphate, hexafluoroaluminate, hexafluorosilicate, hexafluorostannate, fluorozirconate, tetrafluoroborate, hexa-IIchloroplatinate, tetrachloroaluminate,and hexachlorostannate, Bromide and chloride are preferred.
The term halogen as used herein is intended to include fluorine, chlorine, bromine and iodine, In the terms lower-alkyl and lower-alkoxy, lower” denotes an alkyl moiety containing from 1 to 4 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl ana tert-butyl. -1245336 The reaction to prepare the compoundsof FormulasI or II above is conveniently carried out by reacting two moles of a 4-(R-amino)pyridine (Formula (III) with one mole of an appropriately disubstituted alkane or xylene (formula IV or V) in an inert solvent such as a lower-alkanol, acetonitrile, Ν,Ν-dimethylfcrmair.ide, N,Ndimethyl-acetamide, benzene, toluene and xylene at a temperature of from 80°C to 150°C. for a period of from 1 to 24 hours. Usually the reactants are heated at 60°C. to 100°C. in acetonitrile or Ν,Ν-dimethylformamide or a mixture of thes··: solvents or in a lower-alkanol for 2 to 20 hours.
Alternatively the reaction may be carried out in the absence of a solvent by heating stoichiometric quantities of the reactants at 12O°-15O°C. for 2 to 5 hours.
The resulting bis-[4-(R-amino)-1-pyridinium] compounds(formulas I ar.d II) are isolated according to conventional methods., ror example by filtration, if the product is insolucle in the reaction medium, or by dilution of the reaction mixture with a non-polar solvent such ether, benzene or hexane in order to precipitate the product or by evaporation of the reaction medium to leave the product as a residue. The isolated crude product can be purified by crystallization from a suitable solvent in the presence of an adsorceut, e.g. charcoal or diatomaceous earth.
The his~[i-(E-amino)-1-pyridiniumj compounds produced in accordance with tae above-described method, will of course, contain an anion (A in formulas I and II) which corresponds to the learing group of the reactant disubstituted alkane or xylene (Z in formulas IV and V). -13However, the anionic moiety of these compounds can be varied; if desired, according to conventional ion exchange methods, for example by passing a solution of a pyridinium compound in a suitable solvent, e.g. 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 containing the desired anion is purified by recrystallization from a suitable solvent.
Alternatively, a pyridinium compound can be reacted with a soluble salt containing the desired anion in association with a counter-cation which combines with the anion of the pyridinium compound to produce an insoluble precipitate.
The latter is separated leaving a solution cf the pyridinium compound containing the desired anion. For example a bis15 [4-(R-amino)-1-pyridinium]alkane dihalide is reacted with the silver salt of an organic or inorganic acid. The precipitated silver halide is removed leaving a solution of the pyridinium compound containing.,the desired organic or inorganic anion.
The above type' of metathetical reaction can also bs employed to prepare Insoluble pyridinium compounds. Thus a soluble bis-(4-(R-amino)-1-pyridinium] compound is reacted with a so.!ubis salt containing the desired anion which combines with the pyridinium cation to afford the desired product as an insoluble precipitate. These insoluble pyridinium salts are useful for purposes of isolation and purification and whan suitably composited as emulsions, creams, pastes, lotions, jellies or powders also serve as depot preparations providing slow, sustained release of the antimicrobial -1443336 pyridinium compound. Moreover, insoluble salts derived from certain anions such as those described in U.S.
Patent 3,937,807, issued February 10, 1976 are effective in reducing the tooth staining pc'en'-^Pl of dental plaque preventive agents.
Thus, should the anionic portion of a given compound accord to that species characteristics such as solubility, stability, molecular weight, physical appearance and toxicity which render that form of the compound unsuitable for a desired purpose, it can readily be converted to another, mere suitable form. For use on the skin or other tissues or in the oral cavity, pharmaceutically acceptable anions, such as fluoride, chloride, bromide, iodide and niethanesulfonate are of course employed.
The I-(R-amino)pyridines (formula III)which are used as starting materials generally are known or, if specifically new, are prepared according to the procedures described for preparation of the known compounds.
Conveniently, the 4- (R-amino)pyridines are prepared by reacting 4-chioro cr 4-brcmopyridine or N(4-pyridyl)-pyridinium chloride hydrochloride with an appropriately substituted amine. The reaction is usually carried out by heating the reactants in the absence of a solvent at 150°C.-225°C. for 1.5 to 3 hours. The product is isolated in a conventional manner, for example by extraction from alkaline aqueous medium into an organic solvent such as ether, methylene chloride or chloroform, evaporation of the organic solvent and crystallization of the residue from an appropriate solvent.
-IS40 «33® Alternatively, the 4-(R-amino)pyridines are obtained by catalytic hydrogenation of a mixture containing 4- aminopyridine and a carbonyl compound containing the appropriate carbon content. The reaction 1b usually carried out at a temperature of 5O-7O°C. in a suitable . solvent, for example ethanol, under a hydrogen pressure of 20-60 psi, in the presence of a palladium hydrogenation catalyst. A hydrogenation time of 4-10 hours is generally satisfactory. The lise of a large excess of the carbonyl 2.0 compound, i.s. 200% or greater advantageously results in high yields of pure product in a reaction time of 5 hours cr less. Following removal of the catalyst the product is isolated by evaporation of the solvent and either distilling the residue or crystallizing the latter from a suitable solvent.
Reaction of an aldehyde having the appropriate carbon content with 4-aminopyridine in the presence of formic acid at elevated temperatures also provides the 4(R-aminoJpyridines.
The 4-(R-araino)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. The acylation is carried out according to art-recognized methods?, for example by reacting 4-amino25 pyridine with an acyl halide in an inert solvent such as methylene dichloride or chloroform in the presence of an acid acceptor such as triethylamine. The amide so-produced 1b than reduced with a complex metal hydride such as lithium hydride in a suitable solvent such as tetrahydrofuran ether or dioxane and the amine product isolated in accordance with known procedures. -l6-3ti33G The disubstituted alkanes having formula IV also used as starting materials generally are known compounds, or if specifically new can be prepared according to the procedures used fcr preparing kno„n compounds.
The α,a’-disubstituted xylenes having formula V, also used as starting materials, generally are known compounds, or if specifically new can be prepared according to the procedures used fc-r preparing the known compounds.
Thus an appropriate chloro or methyl-substituted phthalic, isophthalic or terephthalic acid or ester is reduced to the corresponding xylene-ajoi'-diol with a metal hydride such as lithium aluminum hydride in a suitable solvent such as tetrahydrofuran, ether or dioxane, The xylene-α,α’-diol so-produced is then converted to an α,α'dihaloxylene, for example by reaction with hydrogen bromide, phosphorous tricro/ide, phosphorus oxychloride, thionyl chloride or potassium iodide and orthophosphoric acid according to art-recognized methods. Alternatively, the xyiene-a,u!-diol can be converted to a sulfonate ester by reaction with methane-, ethane, benzene- or £-toluenesulfonyl chloride in the presence of an acid acceptor such as pyridine in accordance with well known procedures.
As described more fully hereinbelow the compounds having formulas I cuid II exhibited in vitro antimicrobial activity against several species of microorganisms among •which are included both gram positive and gram negative bacteria, several species of fungi and Herpes viruses.
The compounds are therefore -17indicated for use as antimicrobial or antiseptic agents which can be applied topically to effect the degerming of human skin and other tissues and to 'sanitize and disinfect inanimate surfaces. Thus the compounds can be used in topical antiseptic solutions for the treatment of wounds, in antibacterial cleansing agents such as surgical hand scrubs, patient pre-operative skin preparations, soaps and shampoos, or in household and industrial cleaners, disinfectants and protective coverings such as paints, varnishes and waxes. The compounds are adapted for the above indicated utilities by combining than with conventional diluents or carriers, compatible cationic, anionic or nonionic surfactants, buffering agents, perfumes and coloring agents, and are applied to a surface to be disinfected by conventional methods such as scrubbing, spraying, swabbing and immersion.
For use as skin-cleansing agents the bis-£4(R-aminoJ-l-pyridiniuml compounds can be prepared as liquids, or, if desired, the liquid formulations can be thickened by certain additives into a gel or paste or molded into a bar according to methods known ir. the art. For example, the ccmpounds can be formulated with any compatible, pharmaceutically acceptable surfactant, preferably a nonionic surfactant, such as the polyoxyethylene polyoxypropy25 lens copolymers described in U.S. Patent 3,855,140, amine oxides, such as stearyl dimethyl amine oxide described in U.S. Patent 3,296,145, or with mixtures of these. The formulations may additionally contain pharmaceutically acceptable diluents, such as water and lower alkanols acids, based or buffering agents so as to -18maintain a pH of 5.0 to 7.5, and, optionally, perfumes and coloring agents. The bis· compounds are generally present in such formulations in a concentration cf 0.5 to 2.0 percent by weight, preferably 1.0 percent by weight.
When prepared as a tincture the bis-|4-(R-amino)1-pyridinium J compounds may be formulated with water, a lower-alkanone, e.g. acetone, and a lower-alkanol such as ethanol. If desired the tincture may be tinted with a coloring agent. The active ingredient is generally present in a concentration of 0.05 to 1.0 percent (w/v) preferably 0.1 percent (w/v).
Alternatively, compounds can be formulated in suitable pharmaceutical vehicles for treating bacterial, fungal and Herpes viral infections for example as lotions, ointments, or creams by incorporating them in conventional lotion, ointment or cream bases, such as alkyl polyethe- alcohols, cetyl alcohol and stearyl alcohol or as powders by Incorporating them in conventional powder bases, such as starch and talc cr as jellies, by incorporating them ir. conventional jelly bases such as glycerol and tragacanth. They can also be formulated for use as aerosal sprays or foams.
When used for sanitizing and disinfecting inanimate surfaces the compounds can be formulated with known detergents and builders such as triso d ium phosphate concentration up to 10 percent by weight.
-IS43336 As described in detail hereinbelow certain of the compounds of formula I are effective in preventing the formation of dental plaque. When intended for such use the compounds can conveniently be applied to the teeth in 5 the form of a mouthwash or a dentifrice. The compounds can be composited with conventional ingredients used in mouthwash or dentifrice formulations, for example water, alcohol, glycerin, buffers, thickeners, flavoring and coloring agents. These formulations,may also optionally contain other known ingredients especially those which are effective in reducing tooth staining potential such as the anticalculus agents described in U.S. Patent 3,934,002, issued January 20, 1976, for example zinc phenolsulfonate, 8hydroxyquinoline and disodium ethane 1-hydroxy-l,1diphosphonate, and the amino carboxylate compounds disclosed in U.S. Patent 3,937,807, issued February 10, 1976, for example nitrilotriacetic acid, 2-hydroxyethylnitrilodiacetic acid or water-soluble salts thereof. The bis-R(R-amino)-l-pyriainiunij alkane is usually present in such 2θ formulations in a concentration of 0.005 to .05 percent by weight preferably about 0.01 percent by weight.
It will of course be appreciated that the vehicles, diluents, carriers.and additives contained in the abovedescribed formulations are compatible with the active ingredient, i.e. the antibacterial, antifungal and virucidal effectiveness of the bis-{4-(R-amino)-1-pyridiniumjcompounds is not vitiated by effects ascribable to the nature of the vehicle, diluent, carrier or other additive.
The molecular structures of the compounds of the □_ invention were assigned on the basis of study of their in-204333 frared and NMR spectra.· snd confirmed by the correspondence between calculated and found values for elemental analyses for the elements.
The invention is illustrated by the following examples without, ,.owever, being limited thereto.
Example 1 A. A mixture containing 130 g. (0.67 mole) of 4bromopyridine hyd..ochlox*ide snd 152 g. (1.0 mole) of nheptylamine hydrochloride was heated in an ell bath. When θ the bath temperature reached 18O-185°C. the reaction mixture began to melt and stirring was begun. At 190-195°C· melting was complete and the liquid mixture was stirred and heated at 2i0-220°C. for 2.5 hours, The reaction mixture was then cooled to room otmperature and the resulting solid was dissolved in water, m-rde alkaline with 32% aqueous sodium hydroxide snd the prediict extracted with chloroform. The chloroform extracts were dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The resulting viscous oil was diluted with a small amount of n2o hexane and cooled to give a solid which was collected by filtration and air-drleo to afford 86.6 g, of 4-fheptylamino)· pyridine, m.p. 49~51°C.
B. Alternatively. 4-(heptylamino)pyridine was prepared as follows : A mixture Containing 229 g. (1.0 mole) of N25 (4-pyridyl)pyrlcinium chloride hydrochloride and 228 g. (1.5 moles) cf h-heptylsmine hydrochloride was heated 2 hours with stirring in an oil bath at a bath temperature of 215eC. The reaction mixture was cooled to 80°C,, diluted with ice-water, made alkaline with 35% aqueous sodium hydroxide and extracted successively with ether and chloroform. The organic extracts were combined and evaporated to dryness under reduced pressure. The residual viscous oil -2133G was dissolved in ether and the ethereal solution was washed with water. The aqueous wash v?as back-extracted with chloroform and the chloroform extracts were combined with the ethereal solution. The combined organic solutions were dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. Cooling the residual oil to -78°C. effected partial solidification. The semisolid was diluted with a small amount of ether and filtered. The solid so-obtained was dissolved in a mixture of acetonitrile and chloroform, the resulting solution treated with decolorizing carbon, filtered, and the filtrate evaporated to dryness under reduced pressure. The resulting semi-solid was diluted with a small amount of ether and cooled. The solid thus-produced was collected by filtration and washed with a small volume of cold ether to give, after drying, 84.6 g. of 4-(heptylamino)pyridine, m.p. 50-52°C.
C. 4-(Heptylamino)pyridine was also prepared by hydrogenating a mixture containing 4-aminopyridine and hepfcaldehyde according to the procedure described in Example 9S hereinbelow.
D. To a stirred warm solution, containing 10.0 g. (0.052 mole) of 4-(heptylamino)pyridine in 40 ml. of acetonitrile was added dropwise a solution containing 9.3 g. (G.O26 mole) of 1,14-dibromotetradecane in 230 ml. of acetonitrile and the resulting mixture was heated 20 hours under reflux. The product which precipitated upon cooling the reaction mixture to room temperature was collected by filtration, washed with cold acetonitrile and dried affording 13.9 g. of 1,14-bis-[4-(heptylamino)l-pyridiniunQ-tetradecane dibromide, m.p. 88-90°C. -224 5 3 3 6 Example 2 A solution containing 5.0 £. of 1,l4-bis-[4(heptylamino)-l-pyridininm?tetradeesne dibromide in 5.0 ml. of methanol was added to the top of a 5-Inch diameter column containing 500 ml. of synthetic anion exchange resin in the chloride form (sold by Rohm and Haas under the tradename Amberlite IRA 400) in methanol and eluted with five 125-ml. portions of methanol. The combined eluate was evaporated to dryness under reduced pressure and the residual oil was redissolved in ethanol, treated with decolorizing carbon and evaporated to dryness. The residual solid was triturated with ether containing a few drops of acetonitrile, collected by filtration and dried over phosphorus pentoxide under vacuum to give 5.94 g. of l,l4-bis-[4(heptylamino)-l-pyr-idiniu,?i j te trade cane dichloride, m, p. 115-ll6°c, Example 5 A stirred suspension containing 11.54 g. (0.06 mole) of 4^(hepty-lamino)pyridine in 75 ml. of acetonitrile was nested under reflux until a clear homogeneous solution was formed. TO the clear solution was then added dropwise a warm solution containing 9.84 g. (0.05 mole) of 1,12dibromododecans in nil. °f acetonitrile. When the addition was complete, heating under reflux was continued 18 hours. After cooling to room temperature, the reaction mixture was evaporated to dryness under reduced pressure. The residual solid was slurried in ether, collected by filtration and dried 48 hours under vacuum at 60cC. to afford 21.1 g. of l, 12-bls-[4~(heptylemino) -1-pyrldlniuraJdodecane dibromide, m. p. 101-105’C.
Example 4 A. A solution containing 6.6 g. of l,12-bis-[4(heptylamino)-l-pyridinium]dodecane dibromide in 25 ml. of methanol was added to the top of a 3-inch diameter column packed with 1 liter of synthetic anion exchange resin in the chloride form (sold by Rohm and Haas under the tradename Amberlite IRA 400) in methanol and eluted slowly with 100-ml. portions of methanol until 700 ml. of eluate had been collected. The combined eluate was evaporated to dryness under reduced pressure below 25°C. The residual gum was triturated repeatedly with a 6 to 1 mixture of ether and acetonitrile and dried under vacuum to afford 5.0 g. of 1,12-bis-[4-(heptylamino)“l-pyridinium3dodecane dichloride, m.p. 109-112°C.
B. Alternatively, a mixture containing 76.8 g. (0.4 mole) of 4-(heptylamino)pyridine and 47.8 g. (0.2 mole) of 1,12-dichlorododecane was heated 4 hours at 125-130°C.
After slight cooling 300 ml. of acetonitrile was added and the resulting mixture was heated at steam bath temperature to effect complete solution then stored in a refrigerator overnight. The precipitated product was collected by filtration, washed with cold acetonitrile and ether, and the hygroscopic product'immediately dried under vacuum to give 112 g. of 1,12-bis-[4-(heptylamino)-l-pyridinium]dodecane dichloride, m.p. 112-115°C.
Example 5 A. A mixture containing 100.0 g. (0.51 mole) of 4bromopyridine hydrochloride and 110 g. (0.8 mole) of nhexylsmlne hydrochloride was heated in an oil bath. When -24•15 3 3 6 the bath temperature reached 175-l8o°C. the reaction mixture began to melt and stirring was begun. The temperature of was triturated with ether end coded. The resulting solid was collected by filtration and washed with cold ether. Evaporation of the filtrate afforded a second crop of solid. The crops were combined, dissolved in chloroform, treated with decolorising carbon ar.d filtered. The filtrate was evaporated under redu pressure, and the residue was triturated with cold -i -r. The product thus-obtained was collected by filt... ,tic-n; washed with cold ether and dried to give 63.6 g. of 4-(hexylamlno)pyrldine, m.p. 66-68°C. Evaporation of the filtrate afforded an additional 7.0 g., m.p. 65-670C.
B. Alternatively, i!-{nexylamlno)pyridine was prepared as I’oilows. A mixture contzthing 2?9 g. (i mole) of N-(4pyridyl)pyridinium chloi'ide hydrochloride end 207 g. (1.5 moles) of n-he'xylamine hydrochloride was stirred and heated 1.75 hour's st i75”lS5uC. The reaction was cooled and diluted with 750 ml. of ice-water. The resulting solution was made alkaline with 35% aqueous sodium hydroxide V and after further dilution with 1 1. of water was extracted with ether followed by dichloromethane. The organic extracts were combined, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was crystallized from ether, redissolved in chloroform, the resulting solution treated Tilth decolorizing carbon and filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was triturated with a mixture of ether and acetonitrile. The solid thus-obtained was again dissolved In chloroform and the resulting solution treated with decolorizing carbon and filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was triturated with cold ether to give 7120 g. of 4-(hexylamino)pyridine, m.p. 68-70°C.
C. To a stirred warm solution containing 10.7 g. (0.06 mole) of 4-(hexylamino)pyrldine In 50 ml. of acetonitrile was added dropwise- a solution containing 10.7 g. (0.03. mole) of 1,14-dibromotetradecane In 250 ml. of acetonitrile and the resulting mixture heated 22 hours under reflux. The reaction was then evaporated to dryness under reduced pressure. The residual solid was dissolved in acetonitrile and the resulting solution ureated with decoloriz20 ing carbon and filtered. The filtrate was evaporated to dryness under reduced pressure and the resulting oil crystallized from acetonitrile. The product was collected by filtration and dried 48 hours at 70°C./0.1 mm. to give 13.4 g. of 1,14biB-(4-(hexylamino)-l-pyridinium]tetradecane dibromide, •25 m.p. 91-93°C.
Example 6 Following a procedure similar to that described in • Example 2 but employing 5.0 g. of 1, l4-bis-[4-(hexylamino)-1pyridiniumltetradeeane dibromide there was obtained 4.33 g. of the corresponding dichloride, m.p. 94-95°C. -26Example 7 Following a procedure similar to that described in Example 60 but employing 10.7 g. (0.06 mole) of 4(hexylsmino)pyridine and 9-85 g. (0.03 mole) cf 1,12dibromodoaecane there was obtained 17.6 g. of 1,12-bis[4-(hexylEmlno)-l-pyrldlniu:;i]dodeeane dibromide, m.p. 122-124°C.
Example 8 Following a procedure similar to that described in Example 2 but employing 5.0 g. of 1.,12-bis-[4-(hexylamincj-l-pyridiniumldodecsne dibromide there was obtained 3.69 g, of the corresponding bichloride, m.p. 86-88’C.
Exjmrlc 9 A. A mixture cint-uning 183.3 g. (0.8 mole) of N(4-pyridyl)pyridiniu:r. chloride hydrochloride and 162 g. (0.98 mole) of n-catylamlne hydrochloride was heated in an oil bath to a bath temperature of 225-230’C, (internal temperature of IftS’C.) and che ”eslilting liquid was stirred at that temperature for 2,5 hours. The reaction mixture was then cooled to 70’C·,, diluted with 1 liter of ice and water, made alkaline with 35)6 aqueous sodium hydroxide and extracted with chloroform, The chloroform extracts were dried over anhydrous sodium sulfate, treated with decolorizing carbon and evaporated to dryness under vacuum. The resulting oil was cooled to -78°C. The semi-solid which ffljnned was triturated wjkh ether and the solid thusobtained collected by filtration, washed with cold ether and dried. The filtrate affoi‘d-?d s second crop of 10 g. -2743336 The crops were combined, dissolved in chloroform and, following treatment with decolorizing carbon and filtration (repeated 5 times), the chloroform solution was evaporated to dryness under reduced pressure. The result5 ing solid was triturated with ether, cooled, collected by filtration and washed with cold ether-hexane to give 63.3 g. of nearly colorless 4-(oetylamino)pyridine, m.p. 62-63°C.
B. Alternatively 4-(oetylamino)pyridine was prepared as follows; A mixture containing 94 g. (1 mole) of 410 aminopyridine, 384 g. (3 moles) of octaldehyde, 7 g. of 10% palladium-on-carbon hydrogenation catalyst and sufficient absolute ethanol to give a total volume of 1.2 1. was hydrogenated 4.5 hours at 70-90eC. under an initial hydrogen pressure of 45 psi. After cooling the mixture the hydro15 genation catalyst -was removed by filtration and the filtrate was evaporated to dryness under reduced pressure. The residual oil crystallised On standing and the solid product was triturated with hexane, collected by filtration, washed xvith fresh hexane and dried at 4o°C, under vacuum to give 182 g, of 4-(ootylamino)'pyridine, m.p. 7O-73°C.
C, To a stirred, warm solution containing 10.0 g. (0.049 mole) of 4-(octvlsraino) pyridine· in 150 ml. of acetonitrile was added dropwi.se a solution containing 7.4 g. (0.0245 mole) of 1,10-dibromedeeane in 50 ml. of aceto25 nitrile and the resulting mixture heated 18 hours under reflux. After cooling and stirring 1 hour at room temperature, the precipitated solid was collected by filtration, washed with acetonitrile and dried 48 hours at 85°C. to give 15.6 g. of 1,10“bis-[4-(oetylamino)-l~pyridinium)decane di30 bromide, m.p. l63-l64°C. -2843336 Example 10 A. Following a procedure similar to that described in Example 2 but employing 5.0 £. of l,10-bis-[4-(octylamino)-l-pyridinium]deeane dibromide there was obtained 4.31 g. of the corresponding dichloride, m.p. 213-2l4°C.
B, Alternatively, a mixture containing 61.8 g. of 4(octylamino)pyrid.·.» snd 21.5 g. of 2., 10-dichlorodeeane was stirred and heateo slowly to 12t)°0. The heat source was removed and the temperature of the now exothermic reaction continued to rise tc 180eC. As soon as the reaction mixture began to crystallize 250 ml. of N,N-dimethylformamide was rapidly added and ths resulting mixture was heated to give a clear homogeneous solution and then cooled to 0*C. The precipitated product wav coxlected by fi?ttration, washed with ether and dried 24 hours under vacuum at 60°C. to give 73 g. of 1,10-bie· ’ ·•••.oetylemino)-l-pyridlnium]decane dichloride, m.p. £15-217/0, Example 11 Foll-hwing & price jure similar to. that described in Example 9C but employing 11,1 g, (0,054 mole) of 4(octylamlno)pyridihQ and 7.24 g. (0.027 mole/of 1,8-, dibromooctane, an-’ writing the reaction mixture 6 hours under reflux there was obtained 15.6 g. of l,8-bis-[4~ (octylanuno)-l-pyridiniumjoctar.e dibromide, m.p. 174-175°C.
Example 12 Following a procedure similar to that described in Example 2 but employing 5.0 g. of l,8-bis-[4“(octylamino) 29i 6 3 3 6 1-pyridinium]octane dibromide there was obtained 4.30 g. of the corresponding dichloride, m.p. 21p-211°C.
Example 13 Following a procedure similar to that described 5 in Example 9C but employing 11.1 g. (0.054'mole) of 4(octylamino)pyridine and 6.6 g. (0.027 mole) of 1,6-dibromohexane and heating the reaction mixture 9 hours under reflux there was obtained 15.1 g. of l,6-bis-[4-(octylamino)-lpyridiniumjhexane dibromide, m.p. 136-13B°C.
· Example l4 Following a procedure similar to that described in Example 2 but employing 5.0 g. of l,6-bls-[4-(octylamino) l-pyridiniumlhexane dibromlde there was obtained 4.23 g. of the corresponding dichloride, m.p, 189-191°C.
Example 15 To a stirred warm solution containing 2.06 g. (0.01 mole) of 4-(octylamino)pyridine in 15 ml, of acetonitrile was added dropwise a solution containing 1.37 g. (0.005 mole) of 1,6-hexanediol diraethane3ulfonate In 10 ml. of acetonitrile and the resulting mixture was heated under reflux 20 hours. ,The reaction mixture was evaporated to dryness under reduced pressure and the residual gum was triturated with ether to give a colorless hygroscopic solid. This product was redissolved in a mixture of ethanol, ben25 sene and acetonitrile and the resulting Solution evaporated to dryness under reduced pressure. The residue was triturated with ether and the resulting white solid was quickly collected by filtration, washed with anhydrous ether, and -304 ίϊ 3 3 ΰ dried 72 hours at 28°C./O.l nun. to give 2.65 g. of 1,6-bis[4-(octylamino)-l-pyridiRium]hexsne dimethanesulfonate as a waxy, white solid.
Example 16 Following a procedure similar to that described in Example $C but employing 24.£4 g. (0.08 mole) of 4-(hexyl8mino)pyridlne an:· 8,64 g. (0.04 mole} of 1,4-dibromobutane there was obtained following trituration of the crude product with a mixture of acetonitrile and acetone 20.45 g. of l, 4-bis-[4-(hexylamino)-i-pyrid:alum]butane dibromide, m. p. 1S9“£O1°C.
Example 17 Following a procedure similar to that described in Example 90 but employing 10.7 g. (Ο.υ6 mole) of 4(hexylamino)pyridin; and 7.32 g. (0,03 mole) of 1,6-dibromohexane there was obtained following trituration of the crude product with 3 mixture of ether, acetonitrile and acetone 14.JO g. of 1,6-ti’-i4-(hexylamino)-l-pyridinium)hexane dibromide, m.p, 178-175pc.
Examtie (¾ Following a procedure similar to that described in Example 9C but employing 10.7 g. (0.06 mole) of 4(hexyiamino)pyridine end 7.75 g. (0.03 mole) of 1,7-dibromoheptane tnere was obtained following trituration of the crude product with a mixture of acetonitrile and acetone 16.4 g. of 1,7-bis-(4-'(hexylamino)-l-pyridlnium]heptane dlbrornicle, m.p. 157-158^0, “314 aJ 3 3 6 Example 19 Following s procedure similar to that described in Example 9C but using 10.7 g. (0.06 mole) of 4-(hexylamino)pyridine and 8.6 g. (0.03 mole) of 1,9-dibromononane there was obtained 17.15 g. of l,9-bis-[4-(hexylamino)-l-pyridinium]nonane dibromide, m.p. 114-115°C.
Example 20 Following a procedure similar to that described in Example 9C but employing 15.4 g. (o.08 mole) of 410 (heptylamino)pyridine and 8.64 g. (0.04 mole) of 1,4dlbromObutane there was obtained 23.1 g. of 1,4-bis-[4(heptylamino)-l-pyridinium]butane dibromide, m.p. 229-230°C.
Example 21 Following a procedure similar to that described in Example 90 but employing 10.0 g. (0*052 mole) of 4(heptylsmino)pyridlne and 6.7 g·. (0.026 mole) of 1,7dibromoheptane there was obtained 14.05 g. of l,7-bis-[4(heptylamino)-l-pyridinium]heptane dibromide, m.p. 142-143°C.
Example 22 Following a procedure similar to that described in Example 90 but employing 11.6 g„ (0.06 mole) of 4-(heptylamino) pyridine and 8.2 g. (0.03 mole) of 1,8-dibromoctane there was obtained after recrystallization from acetonitrileether IS.6 g. of l,8-bis-i4-(heptylamino)-l-pyridlnium325 octane dibromide, m.p. I6l-l62°c. -324 ΐί 3 3 β Following a procedure similar to that described In Example 2 but employing 5.C g. (0.0076 mole) of 1,8-bia[4-(h:?ptylainino)-l-pyrldiniumJoetfine dibromide there was obtained 4.1 g. of the corresponding dichloride, m.p. 20b~20S°C.
Example jd Following a procedure similar to that described in Example 9C but employing 15.4 g. (0.08 mole) of 410 (heptylamino)pyridine and 11.44 g. of 1,9-dibromononane there was obtained 21.3 g. of 1,9-bls-[4-(heptylamitto)-lpyridiniumjnonane dibromids, m.p. 115-ll6eC.
Following « procedure similar tc that described in Example 2 but «a·.]eying «,o g. (0.0075 mole) of 1,9-bisi4-(heptylamino)-i-pyriditiium]nonsise dibromide there was obtained 4.2 g, of the corresponding dichloride, m.p. 154-155’C.
Exafapls 26 Following a procedure similar to that described in Example SC but employing 15-4 g. (0.08 mole) of 4-(heptylamino)pyridine and 12.0 g. (C,06 mole) of 1,10-dibromodecane there was obtained 25.7 g, of 1,10-bis-[4-(heptylamino)-1pyridiniunjdecane dibromide, m.p. 163~165°C.
Following a procedure similar to that described in Example 2 but employing 5-0 g. (0.0073 mole) of 1,10-3343336 bis-[4-(heptylamino)-l-pyridinium]decane dibromide there was obtained 4.35 g· of the corresponding dichloride, m.p. 209210°C.
Example 28 To a stirred slurry of 30 ml. of synthetic anion .exchange resin in the hydroxide form (sold by Rohm and Haas under the tradename Ambsrlite IRA 400) in 150 ml. of water was added dropwise 48% aqueous hydrofluoric acid until the mixture was acidic. After stirring an additional 0.5 hour the slurry was poured into a column. The column was drained and the resin washed with & solution containing 15 ml. of 48% aqueous hydrofluoric acid in 185 ml. of distilled water. The resin was then washed with distilled water until the eluate was weakly acidic, and then successively with 20%, 40%, and 50% aqueous methanol and finally with absolute methanol until the eluate was neutral. To the top of this column of ion exchange resin now in the fluoride form was added a solution containing 0.25 g· (0.000365 mole) of 1,10-bis-[4-heptylamino^-l-pyridinium]decane dibromide in 1 ml. of methanol. Five fractions of 15 ml. each were collected. The first three fractions were combined and evaporated to dryness, under reduced pressure. The oily residue was dissolved in a mixture of toluene and ethanol and the resulting solution evaporated to dryness under reduced pressure. The residual oil was redissolved in a mixture of benzene and acetone and the solution concentrated to a small volume. The solid which separated was collected by filtration and dried 24 hours at 24°C./O.l mm. to give 0.11 g. of impure 1,10-bis-[4-(heptylamino)-l-pyridinium3deeane dlfluoride, m.p. S5-90°0. -344 6 3 3 6 Example 29 A. A solid mixture containing 115 g. {0-5 mole) of N-(4-pyridyl)pyridinium chloride hydrochloride and 119 g. (0.66 mole) of n-nonylamine hydrochloride waa heated in an oil bath up to a bath temperature of 220°C. (internal temperature of 19O-194“g. ) ar.d the resulting liquid was stirred at that temperature for £ hours. The reaction mixture was then cooled to 60sC«, diluted with 1,2 liters of ice and water, made alkaline with 35^ aqueous sodium hydroxide and extracted with chloroform, The chloroform extracts were dried over anhydrous sodium oulfote, treated with decolorizing carbon, filtered and evaporated to dryness under reduced pressure. The residual viscous oil was cooled tc -78°C. arid triturated with ether. The resulting solid was collected by filtration and washed with cold ether. The filtrate afforded a second errp of solid. The combined crops were redissclved in chlox-u orm and the resulting solution treated with decolorizing carbon and filtered. This was repeated once more and the filtrate was then evaporated to dryness under reduced pressure. The residual semi-solid was triturated with ether and cooled to give a nearly colorless solid which was collected by filtration, washed with cold ether and dried. The solid was oaken up in chloroform and the resulting solution treated wish decolorizing carbon, filtered and evaporated to dryness under reduced pressure. Cooling the semi-solid so-obtained and trituration with ether afforded a colorless solid which was collected by filtration, washed with cold ether and dried to give 51.7 g. of 4-(nonylamino)pyrldine, m.p. 59-50*0. The filtrate afforded a second crop of 11.6 g., m.p. 55-57°C.
B. Alternatively 4-(nonylamino)pyridine was prepared as follows1; A mixture containing 39·5 g. (0.42 mole) of 4-aminopyridine, 175 S’ (1,24 moles) of nonyl aldehyde, .0 g. of 10% palladium-on-carbDn hydrogenation catalyst and sufficient absolute ethanol to give a total volume of 600 ml. was warmed and hydrogenated under an initial hydrogen pressure of 45 psi until the absorption of hydrogen ceased.
The reaction mixture was filtered to remove the catalyst and the filtrate was evaporated to dryness under reduced pressure. The residual oil was then vacuum distilled to remove any nonyl'alcohol which may have been produced. A fraction boiling at 63-64°c„/4.5 mm. was collected and -set aside.. The residue was triturated with ether and cooled at -78eC. The solid which precipitated was collected by filtration and washed with cold ether. This product was dissolved in chloroform, the resulting solution treated with decolorizing carbon, filtered and the filtrate evaporated to dryness. The residue was triturated with ether and cooled to -78°C. The solid thus-obtained was collected by filtration, washed with cold ether and air-dried to give 27.0 g. of 4-(nonylamlno)pyrldine, m.p. 57-59°C.
G. A stirred suspension of 11.0 g. (0.05 mole) of 4-(nonylamino)pyridine in 150 ml. of acetonitrile was warmed until a clear homogenous solution was obtained. To this clear solution was added dropwise a solution containing 6.8 g, £04025 mole) of 1,8-dibromooctane in 50 ml. of acetonitrile 'and the resulting mixture heated 19 hours under reflux during which time a solid precipitated from solution. After cooling, •the solid was collected by filtration, redissolved in methanol, the resulting solution treated with decolorizing carbon, -36ί> 3 3 3 filtered and evaporated to dryness under reduced pressure. Trituration of the residual oil with ether containing a small amount of acetonitrite produced a colorless crystalline solid which was collected by filtration and dried to give 15.5 g. of 1,8-bis-β-(nonylamino)-1-pyridiniumjoctane dibrcmide, m.p. 178~179°C.
Example·. 30 (comparison Example) Following a procedure similar to that described in Example 29C but employing 3.54 g. (0.026 mole) of 4(propylamino)pyridine and 3.90 g. (0.013 mole) of 1,10dibromodecane there was obtained 5.19 g. of 1,10 -bis- S.·: ample 31 Folic·,-.’ing a procedure similar to that described in Example 2SC but employing 1<·,24 g. (0.08 mole) of 4(hexylamino)pyridine and 5.20 g. (0.04 mole) of 1,5dibromopentane there was obtained following recrystalli.3 g. of 1,5-bis-jjlzation from acetonitrile-acetone 12 (hexylaminoj-l~pyriddniumjpentane dibromide, m.p. 155Example 32 Following a procedure similar to that described in Example 29C but employing 10.7 g. (0.06 mole) of 4(hexylamino)pyridine and 8.2 g. (0.03 mole) of 1,8dibromo-octans there was obtained 16.3 g. of 1,8-bis- -3745336 Example 33 Following a procedure similar to that described in Example 29C but employing 12.5 g. (0.07 mole) of 4(hexylamino)pyridine and 10.5 g. (0.035 mole) of 1,105 dibromodecane there was obtained 16.0 g. of 1,10-bis[4-(hexylamino)-l-pyridinium]decane dibromide, m.p. 148l49eG.
Example 34 Following a procedure similar to that described 10 in Example 29G but employing 13.4 g. (0.076 mole) of 4(cyclohexylaaino)pyridine and 8.2 g. (0.03? mole) of 1,4dibromobutane there was obtained 18.2 g. of l,4-bis-[4(cyclohexylamino)-l-pyridinium]butane dlbroraide, m.p. 288· 290°C, Example 35 Following a procedure similar to that described in Example 290 but employing 13.4 g. (0.076 mole) of 4(eyelehe»yl8Biino)py2ii0ifts and 8.75 6- (0.038 mole) of Ijg-dibramepQntane theae' was obtained 19.0 g. of l,5“bis§0 [4-(eyelQhaxylaaino)-l-pyridiaiUin3p3ntane dibromide, m.p. 255=256°C.
Example 36 Following a procedure similar to that described in Example 290 but employing 13.4 g, (0.076 mole) of 4§5 (cyQlohexylamino)pyridine and 9=3 g. (0.038 mole) of 1,6dibromohsxaaQ there was obtained 19.1 g. of l,6-bis-[4(oyolohaxylamino)-l-pyridlnium3hexane dibromide, m.p. 307· 3os°e.. -38« 5 3 3 (j Example 37 Following a procedure similar to that described in Example 29C but employing 13.4 g. (0.076 mole) of 4(cyclohexylnmino)pyrldine and 9.8 g. of (0.038 mole) of 1,7-dIbromohepi ane there w?s obtained 2,01 g,( of l,7-bis-[4-(cyclohexylamino)-l-pyrldinium]neptane dibromide, m.p. 311-313°C.
Example 38 Following a procedure similar to that described in Example 29C but employing 13.4 g. (0.076 mole) of 4(cyclohexylamlno)pyrldine and 10.34 g. (0.038 mole) of 1,8dibromooctane there was obtsined 19.1 g. of l,8-bis-[4(cyclohexylaminoi-l-pyridinlumloctane dibromide, m.p. 270271%.
Example 39 Follo'-n.r j ε procedure similar to that described in Example 291 but employing 13.4 g. (0.076 mole) of 4(cyelohexylami.no)-pyridine and 10.8 g. (0.038 mole) of 1,9dlbromononane there wic obtainea 16.3 g. of l,9-bis-[4(cyelohexylamiro)-l-pyridiniumjncnane dibromide, m.p. 149151%.
Example 4o Following s procedure similar to that described in Example 29C but employing 1.5.4 g. (0.076 mole) of 4(eyclohexylamino)pyridine and 11.4 g. (0.038 mole) of 1,10-dibromodecsne there was obtained 19.0 g. of 1,10-bisi4-(cyclonexylamino)· l-pyridiniumldecane dibromide, m.p. 226-227°G. 3 3 6 Example 4l A. A mixture containing 298.0 g. (1.33 moles) of N-(4-pyridyl)pyridinium chloride hydrochloride and 322 g. (2 moles) of 2-ethylhexylamine hydrochloride was heated 2 hours with stirring in an oil hath at a bath 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 being made alkaline with 35% aqueous sodium hydroxide.
The alkaline mixture was extracted with ether and the ethereal extracts were dried over anhydrous sodium sulfate and evaporated to drynes3. The residual oil was distilled under reduced pressure to give 101.0 g. of 4-(2-ethylhexylamino)pyrldlne b.p. l45-150°C./0.9 mm.
B. Alternatively 4-(2-ethylhexylamino)pyridine was prepared as follows: To a stirred solution containing 800 g. (8.4 moles) of 4-aminopyridine and 1500 ml. of triethylamine in 6.4 1. of dichloromethane there was added over 3 hours a solution containing 1610 g. (10.0 moles) of 2-ethylhexanoyl chloride in 1.6 1. of dichloromsthane. Throughout the addition the temperature was maintained at 15°0. When the addition was complete the mixture was warmed an ε steam bath 2 hours.
After cooling the react!δη mixture was washed thoroughly with watery dried over anhydrous sodium sulfate, treated with decolorizing carbon and filtered, Evaporation of the filtrate afforded 1843 g. of N-(4-pyridyl)-2-ethylhexanamide.
To a mixture containing 100 g. (2,63 moles) of lithium aluminum hydride in 2 1. of tetrahydrofuran was added at a sufficient rate to maintain gentle reflux a -404 6 3 3 6 solution containing 57ϋ g. (2.62 moles) of Ji-(4-pyridyl)-2ethylhexanamide in 4 1. ci tetrahydrofuren. When the addition was complete (approximately 3 hours) the inaction mixture was heated under reflux 7 hours. After cooling, the mixture was treated successively with 100 ml. of water, 100 ml, of 15% aqueous sodium hydroxide and 300 ml. of water. The solids ’'tre removed by filtration and the solvent was evaporate<‘ from the filtrate under reduced pressure. The residual oil was combined with the product of a duplicate run and vacuum distilled to give 837 g. of 4-(2ethylhsxylaminojpyridins b-p 135-160“0./0.2 mm. 0. To a stirred, warm solution containing 10.3 g. (0.05 mole) of 4-(2-ethyIhexyiBniino)pyridine in 50 ml. of acetonitrile was added dropwise s solution containing 8.2 g. (0,025 mole) of 1,12-di -decane in 170 ml. of acetonitrile and the resulting ?.··* was heated 20 hours under reflux. Open cooling to J·:, a first crop cf product precipitated and was collected by filtration. Evaporation of the filtrate and trituration of tne residue with ether afforded a second crop. The combined crept were dissolved in methanol, the resulting solution treated with decolorizing carbon, filtered and the filtrate evepo;λted to dryness under reduced pressure. The residual oil w«s cooled and tritureted with ether to give a slightly discolored solid. Seerystallization from acetonitrile-ether followed by trituration of the product with ether followed by acetonitrile afforded, after drying 72 hours under yacu>iw at 60“t., 14,7 g. of 1,12-bis-[4-(2ethylhexy2amino)-l-pyridiniv.m]dodeesne dibromide as colorless granules, m.p, l46-l47eC. 41«ΰ330 Example 42 A. A mixture containing 355.5 g. (1-72 mole) of 4(2-ethylhexylamino)pyridine and 205 g· (0.86 mole) of 1,12diehlorododecane was heated to 120°C. The heat source was removed and the temperature of the now exothermic reaction continued to rise to l8o-19OeC. When the temperature dropped to 135°C. one liter of acetonitrile was carefully added and the mixture heated under reflux to give a clear solution. The hot acetonitrile solution was combined with similar solutions from two other runs, treated with decolorizing carbon and filtered. The filtrate was cooled and the precipitated product was collected by filtration and washed with cold acetonitrile. Two recrystallizations from acetonitrile afforded 970 g, of 1,12-bis-[4-(2-ethylhexylamino )-l-pyridinium]dodecane diehloride, m.p. 168-171°C.
B. Alternatively, by following a procedure similar to that described in Example 2 but employing 3,0 g. (0,00405 mole) of 1,12-bis-[4“(2-ethyihexylamino)-l-py£’idinium)dodecane dibromide there was obtained 2,0 g. of the corresponding diehloride, m.p. 172-173°C.
Example 43 Following a procedure similar to that described in Example 4lc but employing 10.3 g. (0.05 mole) of 4(octylamino)pyridine pnd6.45 g, (0.025 mole) of 1,7dibromoheptane there was obtained 14.85 E· of l,7-bis-[4(octylamino)-l-pyridinium]heptane dibromide, m.p. 129-131°0. -42<23336 Example 44 A. Following a procedure similar to that described in Example 41C but using 11.1 g. (0.054 mole) of 4-(octylamino) pyridine and 7.72 g. (0.027 mole) of 1,9-dibromononane there was obtained 17.0 g. of 1,9-bis-[4-(oetylamino)-1pyridinium] nor.ane dibromide, ιρ.,ρ, 1I7~119°C.
B. The corresponding dichloride prepared according to the procedure of s-;ample 2 had a m.p. 161-162’C.
Example 45 Following a procedure similar to that described in Example 41C but employing 10.3 g. (0.05 mole) of 4-(oetylamino)pyridine and 8.2 g. (0.025 t/ia) of 1,12-dibromododecane there was obtained 15.2 g, of 1,12-bis-[4-(oetylamino)-1pyridiniom]dodecane diixrorJde, m.p. 119~120°C.
Example 45 Following . procedure similar to that described in Example 41C but using 5.8 g. (0.028 mole) of 4-(oetylamino)pyridine and 5.0 g. (0.014 mole) of 1,14-dibromotetradecane there was obtained 3.3 g of 1,14-bis-(4-(oetylamino)-1pyridiaiura)tetradecar.e dibroaida, m.p. 113-115°C. i'xampl·; 47.
Following a procedure simolar to that described in Example lie but employing 11.0 g. (0.05 mole) of 4-(nonylamino)pyridine and S.l y. (0.025 mole) of 1,6'dibromohexane there was obtained 15,2 c, of l,6-bis-[4-(nonylamino)-l~pyridinium)hexane dibromide, m.p. 152-154eC. -.43..
Example 48 Following a procedure similar to that described in Example 4 but employing 6.5 g. (0.0095 mole) of 1,6-bis[4-(nonylamino)-l-pyridinlum]hexane dibromide there was obtained 4.95 g» of the corresponding dichloride, m.p. 194195eC.
Example 49 Following a procedure similar to that described in Example 4lC but employing 8.8 g. (0.04 mole) of 410 (nonylamino)pytidine and 5.2 g. (0.02 mole) of 1,7-dibromoheptane there was obtained 12.2 g. of l,7-bis-[4-(nonylamino)-l-pyrldinium]heptane dibibmide, m.p, 132-134°C.
Example 50 Following a procedure similar to that described In Example 4lC but employing 11.0 g. (0.05 mole) of 4(nonylamino/pyridine and 7.15 g» (0.025 mole) of 1,9dibromoncnane there was obtained 15.7 g. of l,9-bis-[4(nonylamino)-l-pyridinium]nonane‘dibromide, m.p. 121-122°C.
Example 51 Following a procedure similar to that described in Example 41C but employing 11»π g. (O.05 mole) of 4(nonylamino)pyridine and 7.5 g. (0.025 mole) of 1,10dibromodecane there was obtained 15.63 g. of l,10-bis-[4(nonylamino)-l-pyridiniumjdecsne dibromide, m.p. 172-173°C.
Example 52 Following a procedure similar to that described in Example 4lC but employing 10.12 g. (0.046 mole) of 4(nonylamlno)pyridine and 7.54 g, (0.023 mole) of 1,12dibromododeoane there was obtained 16Js g. of 1,12-bis[4-(nonylamino)-l-pyridinium jdcdecant· dibromide, m.p. 105-106°c. ΕΧ3πψ1ε__53 To a stirred., warm solution containing 12.4 g. (0.06 mole) of 4-'2~ethylhexylamitso)pyridine in 100 ml. of acetonitrile was added dropwise ε solution containing 6.9 g. (0.0? mole) of 1,5-dibromopentane in 25 ml. of acetonitrile and the resulting solution heated 20 hours under reflux. The reaction mixture «es cooled and diluted with ether until slightly cloudy. Further cooling and stirring afforded a solid precipitate which was collected by filtration and washed ? th a cold mixture of acetonitrile and ether. The solid tnua-obtaineo was dissolved in ethanol and the resulting solution treated with decolorizing carbon and filtered. Evaporation of the filtrate provided a pale yellow viscous oil which was crystallized from acetonitrile-ether. The resulti1'? solid was collected by filtration, wasted with cold scethnitrlle-ether and dried 24 hours under vacuum st 90°C. to give 13.6 g. of 1,5-biB[4-(2-ethylhexylamino)-l-pyridiniumJpentane dibromide, m.p, 150-151’C.
Example 54 Following a procedure similar to that described ir, Example 53 but employing 12.4 g, (0.06 mole) of 4-(2ethylhexylaminc.>)p.yx'idlne snd 7.32 g, (0.03 mole) of 1,6dibromohexane there was obtained 16,1 g. of l,6-bis-f4-(2ethylhexylamlnoj-l-pyrldlnium jhexar.e dibromide, m.p'. 208-209°C. -4 54333s Example 55 Following a procedure similar to that described in Example 5? hut employing 12.4 g. (0.06 mole) of 4-(2ethylhexylamino)pyridine and 7.75 Ε· (0.03 mole) of 1,7-5 dibromoheptane there was obtained 17.9 g. of l,7-bis-[4(2-efchylhexylamino)-l-pyrldinium3heptane dibromide, m.p. 219-2204C.
.Example 56 Following a procedure similar to that described . in Example 53 but employing 12.4 g. (0.06 mole) of 4-(2ethylhexylamino)pyridine and 8.2 g. (0.03 mole) of 1,8dibromooctane there was obtained 15.9 g. of l,8-bis-[4(2-ethylhexylamino)-l-pyridiniUffi]oetsne dibromide, m.p. lSo-i6l°C.
Example 57 Following a procedure similar to that described In Example 55 but employing 12.4 g. (O.Ob mole) of 4-(2sthylhexyiaaino]pyridine and 8.6 g. (0.03 mole)· of 1,9 dibromononane there· was'obtained 15.2.g. of l,9-bis-(4-(2 ©thylhexylemIno)“l“pyridlniumjRonane dibromide, m.p. 158159°Ο.
Example 58.
Following a procedure similar to that described In Example 53 but employing 12.4 g. (0„0β mole) of 4-(225 ethylhexylamino)pyridine and 9.0 g. (0.03 mole) of 1,10dibromodecane there was obtained 17.4 g. of 1,10-bls-[4(2-ethylhexylamino)-l-pyridinium3decane dibromide, m.p. 162-163°C. 45330 Example 59 Following a procedure similar to that described in Example 2 but employing 5-0 g. of 1,10-bis-[4-(2-ethylhexylamino)-l-pyridinium]decane dibromide there was obtained 4.11 g. of the corresponding diehloride, m.p. 191-192°C.
Example 60 To a stirred warm solution containing 12.0 g. (Ο.Ο63 mole) of 4-(heptylamlno)pyridine in 100 ml. of acetonitrile there was added dropwise a solution containing 7.4 g, (0.032 mole) of 1,5-dibromopentane in 25 ml. of acetonitrile and the resulting mixture heated 19 hours under reflux. The reaction mixture was cooled in ice and ether was gradually added until a colorless solid precipitated. The solid was collected by filtration,recrystallized from acetonitrile-ethei· and dried 48 hours at 90°0./1ιηιη. to give 15.9 g. of 1,5-bis-[4-(heptylamino)-l-pyridiniu>n3pentane dibromide, m.p. 153-154°C.
Example 61 Following a procedure similar to that described in Example 60 but using 19.2 g. (0.1 mole) of 4-(heptyl)8mlno)pyridlne ana 12.2 g. (0,05 mole) of 1,6-dibromohexane there was obtained 27.5 g. of crude product. Recrystalllzatlon of a 15-gram sample from acetonitrile-ether afforded 11.45 g. of l,6-bis-[4-(heptylamino)-l-pyrldinium]hexane dibromide, m.p. 149-15Ο°Ο. -474 5336 Example 62 A. A suspension of 24.0 g. of crude l,6-bis-[4(heptylaminoj-l-pyridinlumlhexane dibromide in 50° ml. of water was made alkaline with 3N aqueous sodium hydroxide and extracted with chloroform. The chloroform extracts were dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residual oil was dissolved in methanol and the resulting solution acidified with methanesulfonic acid and evaporated to dryness under reduced pressure. The residue was redissolved in methanol, treated with decolorizing carbon, filtei'ed and evaporated to dryness under vacuum leaving an oily residue which upon trituration with ether followed by acetonitrile providedlS.2 g. of gummy solid. The crude solid was dissolved in water and the resulting solution made alkaline with 35% aqueous sodium hydroxide and extracted with chloroform. The chloroform extracts were dried over anhydrous sodium sulfate and •evaporated to dryness under reduced pressure. The resulting solid was triturated successively with ether and acetonitrile, collected by filtration and dried to give 16.3 g. of tan solid, m.p. 1O5-1O8°C. The solid so-obtained was dissolved in 100 ml, of methanol and the resulting solution acidified with methanssulfonic acid. Evaporation to dryness under reduced pressure produced a viscous oil which was taken up in 20 ml. of methanol ahd treated portionwise with 150 ml. of water. The resulting suspension was cooled in ice and the suspended solid was collected by filtration and washed with cold water. The solid was then slurried in hot acetone, , cooled, collected by filtration, washed with cold acetone -48£ ίϊ 3 3 6 and dried 48 hours at 95%'·/! mm. to give 10.8 g. of tan solid, m.p. 163-165%. This product gave a positive chloride ion test with silver nitrate and the nmr spectrum thereof Indicated the absence nf the methanesulfonste group.
B. A suspension of 14.0 g. of 1,δ-bis-[4-(heptylamino)l-pyridinium]hexane dibromide in 500 nil. of water was made alkaline with 25% aqueous sodium hydroxide and extx’acted with chloroform. The chloroform extracts were dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The partially solid residue was dissolved in I 1. of acetonitrile-benzene and the resulting solution evaporated to dryness under vacuum. This process was repeated three times. Tne final residue was dissolved in 50 ini β of acetonitrile and the resulting solution diluted with 50 ml. of benzene a, cooled in ice to give after filtering and dryiny 5.3 g. of tan solid. The filtrate afforded a second crop cf 4,8 g. The crops were combined and dissolved in 50 ml. of acetonitrile'; Dilution with ether precipitated a solid which was collected by filtration and dried 48 hours at 95%./1 mm, to give 8.85 g. of tan solid, m.p. 174-176%. This product also .gave a positive chloride ion test with silver nitrate.
C. The products of parts A and B above were combined, mixed with 300 ml. of water and heated until a homogeneous solution was obtained. The solution was filtered and the filtrate treated with 50 ml. of 12N hydrochloric acid. The resulting suspension was concentrated under reduced pressure and the residue was treated with ice. The solid so-produced was collected by filtration, washed with cold wster and dried. The product was then dissolved in acetone, the resulting solution diluted with a mixture Of benzene and ethanol, -494 ο 3 3 6 and the whole evaporated to dryness under vacuum. The solid residue was slurried in 100 ml, of acetone and the slurry diluted with ether and filtered to give after drying 48 hours at 105°C./l mm. and 72 hours at 115°C./1 mm. 16.3 g. of crude l,6-bis-i4-(heptylamino)-l-pyridinium3hexane eichloride as an off-white solid, m.p, 17S=x78°0.
Example 65 Following a procedure similar to that described in Example 60 but employing 10.30 g. (0,050 mole) of 4-(210 sthylhaxylaminojpyridine and 5«4 g. (0.025 mole) of 1,4dibromebutane there was obtained 14,9 g. of l,4-bis-(4(2-ethylhexylamino)-l-pyridiniumjbutane dibromide, m.p. 245-246°C, Example 54 A. A mixture containing 229 E· (l«0 mole) of N-(4pyridyl)pyridinlum chloride hydrochloride and 244 g. (1.26 moles) of n-deeylsmin® nydfochlorlde was., stirred and heated approximately 2,5 hours at 190-195^0« The reaction mixture was then allowed to cool slowly to 40°C. and diluted with 2 1» ef water. The resulting solution was cooled by the addition of ice and made alkaline with 200 ml. of 35$ aqueous sodium hydroxide. The dark solid which separated was collected by filtration and washed with cold water.
This material was dissolved in 1 1. of chloroform and the resulting solution was treated with decolorizing carbon and filtered. The filtrate was evaporated under reduced pressure and the residue was triturated with 150 mi. ef ether. The solid thus-obtained was redissolvsd in chloroform and the -504 5 3 3 6 resulting solution treated with decolorizing carbon and filtered. The filtrate was again treated with decolorizing carbon and filtered. The filtrate was evaporated to dryness under reduced pressure and the residual solid was triturated with ether. Recrystallization from acetonitrile afforded after drying under vacuum 96.1 g. of 4-(decylamino)pyridine, m.p. 71-73’C.
B. To a stirred, warm solution containing 12.2 g. (Ο.Ο52 mole) of 4-(deeylamino)pyridine in 150-170 ml. of acetonitrile was added dropwise a solution containing 6.35 g. (Ο.Ο26 mole) cf 1,6-dibromohexane in 60 ml. of acetonitrile and the resulting mixture heated approximately 20 hours under reflux, The reaction mixture was then cooled in ice and the precipitated solid was collected by filtration and washed with cold acetonitrile. The product thus-obtained was dissolved in methanol and the resulting solution treated with decolorizing carbon and filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was triturated with 50 ml. of cold ether, collected by filtration and dried 2 days over phosphorus pentoxide at 70°C./ 0.1 mm, to give 14.61¾. of 1,6· bis-i4-(decylamino)-l-pyridinium3hexane dibromide, m.p.?138-14O°C.
Example 65 Following a procedure similar to that described in Example 64b but employing 12.2 g. (0.052 mole) of 4(decylamino)pyridine and 6.7 g. (0.026 mole) of 1,7-dibromoheptane there was obtained 16.0 g. of l,7-bis-[4-(decylamino)l-pyridinium]heptane dibromide, m.p. l45-l47*C, -51S 5 3 3 ΰ Example 66 Following a procedure similar to that described in Example 54b but employing 11.7 g. (0.050 mole) of 4(decylamino)pyridine and 6.8 g. (0.025 mole) of 1,8-dibromo5 octane there was obtained 16.9 g. of l,8-bis-[4-(decylamino)l-pyrldinium]oetane dibromide, m.p. 18O-182°G.
Example 67 Following a procedure similar to that described in Example 643 but employing 11.7 g. (0.050 mole) of 410 (decylamino)pyridine and 7.15 S· (0.025 mole) of 1,9dibromononane there was obtained 15.I g. of l,9-bis-[4(decylamino)-l-pyridinium]nonane dibromide, m.p. 124-126°C.
Example 68 Following a procedure similar to that described in Example 64b but employing 11.2 g. (0,048 mole) of 4(decylamino)pyridine and 7.2 g. (0.024 mole) of 1,10dibroiEGdecane there was obtained l4.6 g. of 1,10-bis-[4(decylamino)-l-pyridiniumjdecane dibromids, m.p. 175-174°C.
Example 6g Following a procedure similar to that described in Example 64b but employing 11.2 g. (0.048 mole) of 4(decylamin0)pyridins and 7.9 g. (0.024 mole) of 1,12dibromododecane there was obtained 16.5 g· of l,12-bis-(4(decylamino')-l-pyridinium]dodecane dibromide, m.p. 102-106°C. -524 533 3 Example 70 To a stirred warm solution containing 13,6 g. (0.052 mole) of 4-(dodecylamino)pyridine in 140 ml. of acetonitrile was added dropwise a solution containing 6.34 g. (Ο.Ο26 mole) of 1,6-dlbromohexane in 50 ml. of acetonitrile and the resulting mixture heated under reflux overnight. The reaction mixture was cooled and the precipitated solid was collected by filtration. The collected solid was dissolved in absolute ethanol and the resulting solution treated with decolorizing carbon and filtered.
The filtrate was evaporated to dryness under reduced pressure affording a residual white solid which was slurried in ether, collected by filtration and dried at 60°C./0.1 mm. to give 17.63 g. of l,S-fcis-[4-(dodeeylamino)-l-pyrLdlnium]15 hexane dibromide, m.p. 164-165’O.
Example 71 Following a procedure similar to that described in Example 70 but employing 13.6 g. (0.052 mole) of 4(dodecylaraino)pyridlne and 6.71 g. (0.026 mcle) of 1,720 dlbromoheptane there was obtained 13.03 g. of l,7-bis-[4(dodecylamlno)-l-pyridir!lurajnsptane dibromide, m.p· 148150°C.
Example 72 Following a procedure similar to that described in Example 70 but employing 12.59 g. (0.048 mole) of 4(dodecylamino)pyridlne and 6.53 g. (0.024 mole) of 1,8dibromooctane there was obtained l6.l8 g. of l,8-bis-[4(dodecylamlno)-l-pyridlnium]octane dibromide, m.p. 184-185°C. -534S33G Example 73 Following a procedure similar to that described in Example 70 hut employing 12.59 g. (θ.θ48 mole) of 4(dodecylamlno)pyridine and 6,86 g. (0.024 mole) of 1,95 dibromonohane there was obtained 19.35 g. of l,9-bis-[4~ (dodecylamino)-l-pyridlnium]nonane dibromide, m.p. 134-135%.
Example ?4 Following a procedure similar to that described in Example 70 but employing 12.59 g. (0.048 mole) of 410 (dodecylamino)pyridine and 7.2 g. (0.024 mole) of 1,10dibromodecane there was obtained 18.08 g. of 1,10-bis[4-(dodecylamino)-l-pyridinium]decane dibromide, m.p. 178l80%.
Example 75 Following a procedure similar to that described in Example 70 but employing 11.54 g. (0.044 mole) of 4(dodecylaminojpyrldine and 7.22 g. (0,022 mole) of 1,12dibromododecane there was obtained 17.68 g. of 1,12-bis[4-(dodecylamlno)-l-pyridinTUin3dodecane dibromide, m.p. 75-77%.
Example 76 A, To a stirred warm solution containing 21.0 g. (0.102 mole) of 4-(jx-chlorophenylamino)pyridine in 150 ml. of Η,Κ-dimethylformamide was added dropwise a solution con25 taining 11.02 g. (0.051 mole) of 1,4-dibromobutane in 50 ml. of acetonitrile and the resulting mixture was heated 2,5 hours on a steam bath. The reaction mixture was cooled to -54- 3 3 3 ί. room temperature, diluted with ether end the product allowed to crystallize. The precipitated solid «as collected by filtration, washed with a mixture of acetonitrile and ether and air-dried to give 27.4 g. of l,4-bis-[4-(£-ehlorophenylamino)-l-pyridinium]butane dibromide, m.p. 182-189°C.
B. A suspension of the above product in 500 ml. of water was treated with ice and 2N aqueous sodium hydroxide and the resulting mixture extracted thoroughly with chloroform, The chloroform extracts were dried over anhydrous sodium sulfate and evaporated to dryness under reduced ' pressure to give 21.0 g. of the corresponding anhydro base ss an oil which· solidified cr.· standing.
C, A solution containing the above anhydro base in 250 ml. of methanol was acidified with a solution of methanesulfonic acid in methanol, Evaporation to dryness under reduced pressure afforded an oil which was crystallized from methanol-ethor. .The solid tnuB-obtained was recrystallized from ?nethanol-ether to give after drying 48 hrs. at 92°C./ 0.1 mm. 18.95 g. of 1,4-bis-[4-(£-ch'lorophenylamino)-lpyridinlumlbutane dimethar.s3uXfcnate, m.p, 245-247°C.
Example 77 A. To a stirred, waia solution containing 21.0 g. (0.102 mole) of 4-(£~chlorophenylamino)pyridlne in 200 ml. of N,N-dimethylformamide was added dropwise a solution containing 12.45 g. (0.051 mole) of 1,6-dibromohexane in 50 ml. of acetonitrile and the resulting mixture was heated 4 hours on a steam bath. Upon cooling to room temperature a solid began to precipitate. The reaction mixture was diluted with 150 ml, of acetonitrile and cooled further in -554 5 3 3 6 ice. The precipitated solid was collected by filtration and air-dried to give 27.2 g. of l,6-bis-[4-(£-chlorophenylamino)-l-pyrldinium]hexane dibromide, m.p, l48-15O°C.
B. A methanol solution of the corresponding ;anhydro base prepared from the above dibromide according to the procedure of Example 76b was acidified with methanesulfonic acid and then evaporated to dryneSs under reduced pressure. The residual oil was crystallized from acetone-methanol to give after drying 48 hrs. at 75°C./0.1 mm. 25.2 g. of l,6-bis-[4-(£~chlorophenylamiho)l-pyridiniumjhexane dimethanssulfonate, m.p. 108-110cC.
Example 78 A. To a stirred, warm solution containing 21.0 g. (0.102 mole) of 4-(j3-chlorophenylamino)pyridine in 200 ml. of Ν,Ν-dimethylformamide was added dropwise a solution containing 13· S g. (0.051 mole) of 1,8-dibromooctane In 50 ml. of acetonitrile and the resulting mixture heated 1.5 hours on a steam bath. The reaction mixture was then diluted with 100 ml. of acetonitrile and heating was con20 tinued another 2.5 hours when an additional 100 ml. of acetonitrile was added. After heating another 2 hours the reaction mixture was cooled and the solid which had precipitated was collected by filtration, washed with a mixture of acetonitrile and ether and dried to give 30.1 g. of l,8-bis-[425 (p-chlorophenylamino)-l~pyrldinium]octane dibromide, m.p. 245-247°C.
B. A methanol solution of the corresponding anhydro base prepared from the above dibromide -56a ο 3 3 6 according to the procedure of Example 76B was acidified with methanesulfonic acid and then evaporated to dryness under reduced pressure. The i«esldual oil was dissolved in acetonitrile and the resulting solution treated with acetone until cloudy followed by clarification with a small amount of methanol and cooled. The crude solid which precipitated wee collected and recrystallized from acetonitrile acetone to give after drying 36 hours at 80°C./0.1 mm., 23.5 g. of 1,8-bis-[4-(£~chlcrophenylamlnc)-l-pyridinium]octane dimethanesulfonate, m.p. 164-165°C.
Example.79 A. To a stirred, warm solution containing 21.0 g. (0.102 mole) of 4-(£-chlorophenylamino)pyridine in 200 ml. of Ν,Κ-dimethylformami? s- was added dropwise a solution containing 15.3 g. (0,051 mole) of 1,10-dibromodecane in 50 ml. of acetonitrile rod the. resulting mixture was heated 3.5 hours on a steam bath. The reaction mixture was then evaporated to dryness under reduced pressure and the residual oil was crystallized from methanol-acetonitrile. The solid so-produced was collected by filtration and washed with a cold mixture of acetonitrile and ether to give 28.0 g. of I,10-bis-[4-(£-chlorophenylamino)-l-pyridinium)decane dibromide, m.p. 225-230°C.
B. A methanol solution of the corresponding anhydro base prepared from the above dibromide according to the procedure of Example 76s wbs acidified with methanesulfonic acid and then evaporated to dryness under reduced pressure. The residual oil was crystallized from 57acetonitrile-ether. The crude solid thus-obtained was dissolved in methsnoX and the resulting solution was treated with decolorizing carbon and filtered. Evaporation of the filtrate afforded an oil which was suspended in a mixture of acetonitrile and acetone to give a crude solid. Recrystallization from methanol-ether afforded after drying 48 hours ‘ at 95cC./O.l nun. 18.4 g, of 1,10-bis-[4-(jj-chlorophenylamlno)-l~pyridlnium]decane dimethanesulfonate, m.p. 202204°C.
Example 80 To a stirred warm solution containing 10.0 g. (0.049 mole) of 4-(£-chlorophepylamino)pyridine in a mixture of 275 ml. of acetonitrile and 100 ml, of Κ,Η-dimethylformamide was added dropwise a solution containing 5-75 g. (0.025 mole) of 1,5-dibromopentane in 25 ml. of acetonitrile and the resulting mixture heated 24 hours under reflux.
The reaction mixture was then evaporated to dryness under reduced pressure and the residue triturated with a mixture of ether and acetonitrile. The pale yellow solid so20 obtained was redi3solved in;ethanol and the resulting solution treated with decolorizing carbon and filtered.
The filtrate was evaporated to dryness under reduced pressure and the residual oil was crystallized from ether-acetonitrile The colorless solid was recrystallized from methanol25 acetonitrile and dried 48 hours at 115°C./0.1 mm. to give 8.1 g. of 1,5-bis-[4-(£-chlorophenylamlno)-l-pyridinium]pentane dibromide, m.p. ΐββ-ΐ68βΟ. -58<- ΰ 3 3 ο Example 81 To a stirred, warm solution containing 10.0 g. (0.049 mole) of 4-{j3-chlorophenylamino)pyridine in a mixture of 125 ml. of Ν,Ν-dimethylformamide and 50 ml. of acetonitrile was added dropwise a solution containing 6.4g g. of 1,7-dibromoheptane in 25 ml. cf acetonitrile and the resulting mixture heated 19 hours under reflux. The reaction mixture was then evaporated to dryness under reduced pressure and the residual oil crystallized from ethanolacetonitrile. The solid so-produced was dissolved in methanol and the resulting solution treated with decolorizing carbon.arid filtered, Tne filtrate was evaporated to dryness under vacuum and the residual oil’.again crystallized from ethanol-acetonitrile, The product was collected by filtration and dried hours at 105%./0.1' mm. to give 10.4 g. of 1,7-bis-i4·(p-chlerophenylamlno)-l-pyridinium]heptane dibromide, m.p. 202-204%.
Example 82 Following a procedure similar to that described in Example 8l but employing 10.0 g, (0.049 mole) of 4-(pchlorophenylamino)pyridine and 7'.15 g. (0.025 mole) of 1,9dibromononane there was obtained 11,2 g. of 1,9-bis-[4(£-chlorophenylamino)-1-pyridiniumjnonane dibromide, m.p. 178-179%.
By following procedures similar to those described in the foregoing examples the following bls-[4-(R-amino)-lpyridinium]alkanes are obtained: -59463 3 3 3-sthyl-l,6-bis-[4-(tetradecylamino)-l-pyridinium3hexane dibromide by reacting l,6-dibromo-3-ethylhexane with 4-(tetradecylamlno)pyridine which is in turn obtained by reacting N-(4-pyridyl)pyridinium chloride hydrochloride with tetradecylaaiine hydrochloride, l,5-bis-[4-(octadecylamino)-l-pyridinium]pentane dibromide by reacting 1,5-dibromopsntane with 4-(octadecylamlno)pyridine which in turn is obtained by reacting N(4-pyridyl)pyrldinium chloride hydrochloride with octa10 decylamine hydrochloride, 1,11-bis-[4-(2,2-diraethylbu'tylamino)-l-pyridiniumJ-3 methylundecane dibromide by reacting 1,ll-dibromo-J-methylundecane with 4-(2,2-dimethylbutylamlno)pyridine which in turn Is obtained by reacting K-(4-pyridyl)pyridinium chloride hydrochloride with.2,2-dimethylbutylamine hydrochloride, 1,18-bis-[4-(1.4-dimethylpsntylamino)-l-pyrldinium]octadecane dibromide py peacting .1,18-diuromooctadecane with 4-(1,4-dimethvlpentylawino)pyridine which in turn is obtained by reacting. N^{4-pyrldyl)pyrldinium chloride hydro20 chloride with Ii4-dimethylpgntyi3mine hydrochloride, 4.9- dimethyl-l,12-bis-La-(1,5~dimethyl-4-ethylhexylamino)-l-pyridinium]dodecane dibromide by reacting 1,12-dibromo-4,9-dimethyldodecane with 4<-(l,5-dimethyl-4ethylhexylamino)pyridine which in turn is obtained by react25 ing N-(4-pyridyl)pyridinlum chloride hydrochloride with 1,5dimethyl-4-ethylhexylamine hydrochloride, 1.10- bis-[4-(cyelopentylamino)-1-pyridinium]decane dichloride by reacting 1,10-diehlorodecane with 4(cyelopentylamino)pyridine which in turn is obtained by -60< -* 3 3 3 η reacting M-(4-pyridyl)pyridir.ium chloride hydx’ochloride with cyclopentylsmine hydrochloride, 1,12-bis-(4-(eyeloheptylamino)-1-pyridinium]dodecane dlbromide by reacting 1,12-dibromododecane with 4-(cyeloheptyl3mino)pyridine which in turn ia obtained by reacting N-(4-pyridyl)pyridinium chloride hydrochloride with cycloheptylsmine hydrochloride, 1,6-bis [4-(j3-bromopheriylamino)-l-pyridiniumJ~ 3-methylhexane dibremide by reacting 1,6-dibromo-3-methyl-10 hexane with 4-(£-bromophenylamlno)pyrldir:e which in turn is obtained by reacting N-(4~pyridyl)pyridinium chloride hydrochloride with jc-fci’omcrniline hydrochloride, 1.10- bis-[4-(m-fluorophenylamino)-l-pyridinium]decane dibromide by reacting 1,10-dibromodecane with 4-(m15 fluoropheayiaai.uojpyriditr· which in turn is obtained by reacting K-(4-pyridy2’«pyridiniwifi chloride hydrochloride with m-fluoroanil·.:: hydrochloride1,4-biS”[4-{3-chloro-4-fluoroshenylamino)-lpyrldiniwaj-S-ethy.lbutane dihromide by reacting 1,4-di20 bromo-2-ethyibutane with •'i-(3-chloror4-fiuorophenylamino)pyridine which in turn is obtained by reacting N-(4pyridyl)pyridinium chloride hydrochloride with 3-chloro-4fluoroaniline hydrochloride, 1.10- bis-[4-(benzylamine)-l-pyridinium]decane dichloride by reacting I,10-dichlorodecane with 4-(benzylamino;pyridine, 1,8-bis-[4-(3,4-me thylenedioxyphenylamlno)-1-pyridiniunjoctane dibromide by reacting 1,8-dlbromooctane with 4-(3,4-methyienedioxyphenylamino)pyridine which in -614 5 3 3 6 turn is obtained by reacting N-(4-pyridyl)pyridinium chloride hydrochloride with 3,4-methylenedioxyaniline hydrochloride, 1.9- bis-i4-(j3-ethylphenylamino)rl-pyridinium]non'ane dibromide by reacting 1,9-dibromononane with 4-(j)-ethylg phenylamino)pyridine which in turn is obtained by reacting K-(4-pyridyl)pyridinium chloride hydrochloride with £ethylaniline hydrochloride, 1.10- bis-[4-{£-methoxyphenylamino)-l-pyridinium3deeane dichlorlde by reacting 1,10-diehlorodecane with 4-(jc-methoxyphenylamino)pyridine which is in turn obtained by reacting K-(4-pyridyl)pyridiniua chloride hydrochloride with j3-afllsidine hydrochloride, 1.11- bis-[4-(m-nitrcphenylamino)-1-pyridinium3undecane dibromide by reacting 1,11-dibromoundecane with 4-(m-nitrophsnylamino)pyridine which in turn is obtained by reacting K-(4-pyridyl)pyridinium chloride hydrochloride with m-nitroaniline hydrochloride, la12“bis--[4-{o-cyanogher.ylamino)-l-pyridlnium)dodecane dibromide by reacting 1,12-dibromododeeane with 4-(o-cyanophenylamino)pyriditte which in turn is obtained by reacting K=-(4-pyridyi)pyridinium chloride hydrochloride with o-eyanoaniline hydrochloride, 1,l6-bis-<4-fm-(trifluoromethyl)phenylamino3-1pyridlnium^hexadecane dibromide by reacting 1,l6-dibromo25 hexadecane and 4-[m-(trifluoromethyl)phenylamlno3pyridine which In turn is obtained by reacting H-(4-pyrldyl)pyridinium chloride hydrochloride with m-(trifluoromethyl)aniline hydrochloride, and 1,7-bis-[4-(2-methoxy-g-methylphenylamino)-130 pyridiniumjheptane dibromide by reacting 1,7-dibromoheptane -62'ϊ 3 3 3 υ with 4-(£-methoxy-5~methylphenylaEdno)pyrIdine which In turn is obtained by reacting N-(4-pyridyl)pyridinium chloride hydrochloride with 2-methozy-5-methylaniline hydrochloride.
The following are further illustrative examples of bis-[4-(R-amino)-l-pyrldiniumlalkanes of formula I which are obtained in accordance with the above-described . procedures: 3-methyl-l,5-bis-[4-(undecylamino)-l-pyridinium3pentane dibromide, 2-propyl-l,5»bis-[4-(tridecylemino)-l·pyrldiniumlpentane dichloride,. 4;4-dimethyl--l,7“bis-[4(pentadecylaminc)-l-pyridi.fl-umjheptane sulfate, 2,6-dimethyli,7-bta-[4~(hexadecyle.vi no,-l-pyridinlum]heptane dlsulfamate, 1-methyl-l,4-bis- ’> 'neptadeeylaminoj-l-pyridinium·]butane dibenzeneculfonate, 2,4,4-tnmethyl-l,5-bis-[4-(2methylhexylamlno) -1 <.yridir*ium3hexane bis-cyclohexylsulfamate, 1,17-tis- j.4-(3-ethylpentylamino)-l-pyridinium]heptadecane dlbroraide, 1,l6-bis-[4-(1-ethylhexylemino)-1pyridinlumjhaxp.decane s?initrats. 1,15-bis-[4-(heptylamino)lt-pyridinlumjpentadeeane dibromide, 1,13-bie-[4-(ootylamino)li.-pyridinium]tridecsns di-2-naphthalenesulfonate, 1,11-bis[4-(3-£thylheptylsmlno)-i~pyrl.iiiniuni]undecane 2,6- · naphthalenedisulfonate, 4 -methyl,· V l4-bts-[4-( 2-propylpentyl8mInv)-l-pyrldlRiuBi]tetradecane diehlorlde, 5-fethyl-l,9“bls[4-(1,3,5-triraethylhexylamino)-l-pyridlnium]nonane dibromide, 3,3?6,6,-tetramethyl-l,8-bi3-[4-(heptylaimino)-l-pyridinium3octane dibromide, £,13-dlmethyl-l, l4-bls-[4-(1,2-dImethyltetradecylaminc)-l-pyridiniuni3tetradecyl dibromide, 1,6-bis[4-(l-methylpentylamir.o)-l-pyidInium3hexane di-£-toluenesulfonate, l,8-blS“[4-(2-methylheptylamino)-l~pyridinium]oetane -63«2336 diiodide, 1,8-bl3-[4-(2-methyl“3-ethylpGntylamino)-1pyridiniumjoctane diethanesulfonate, 1,9-bis-[4-(o-chlorophenylamino)-i-pyridlniuni]nonane dibromide, l,8-bis-[4(j3-lodophenylamino)-l-pyridinium3cetane diiodide, 1,12-bls5 [4-(2,4-difXuorophenylamino)-l-pyridiniumjdodecane dibromide, 1,11-bis-[4-(2,5-dibr&KOphenylamino)-l-pyrldinium3undecane dibromide, 1,10-bis-[4-(3,5-dichlorophenylamino)-1-pyridinium]decane diehloride, l,8-bis-[4-(2-fluorobenzylamino)-1pyridihiumloefcane diehloride, 1,18-bis-[4-(3,4-dichloro10 benzylamine)-l-pyridinium]octadeeane dibromide, 1,4-bis[4-(4-hydroxy-3-mefchoxybenzylamino)-l-pyridlnium3butane dibbomide and l,12-bis-[4-(4-methylbenzylamino)-l-pyrldinium]dodecane dibromide. I Example 83 To a warm, stirred solution containing 11.52 g. (0.05 mole) of 4-(heptylamino)pyridine in 100 ml. of acetonitrile was added in small portions a solution containing 7.92 g. (0.03 mole) of tfX’-dibromo-o-xylene in 150 ml. of acetonitrile. After addition was complete a large mass of colorless crystals had separated from solution. The reaction mixture was heated under reflux 5 hours. After cooling to room temperature the solid product was collected by filtration, washed with acetonitrile-ether, combined with 3.1 g. of product obtained in a previous run and dried 28 hours at 1 100°C./0.1 mm. to give 22.0 g. of #,i?'-bis-[4-(heptylamino)pyridinium)-js-xylene dibromide, m.p. 297-298°C. “6Λ4 ΰ 3 3 β Example 84 Following a procedure similar to that described in Example S3 but employing 13..6 g. {0.065 raoie) of 4-(hexylamino) pyridine and 8.7 g. (0.033 mole) of cCji/'-dibromo-g^xylene and refluxing the reaction mixture 20 hours, there was obtained 19.3 g. of α,σ'-bis-[4-(hexylamino)pyridinium]j>~xylene dibromidt m.p. 313-315°C.
Example 85 A suspension of 19 g. of 4-aminopyridine and 23 g. of i/X'-dichloro-2r3,5, S-tetramethyi-£-xylene in 600 ml. of methanol was heated on a steam hath to effect complete solution. After filtering from a small amount of insoluble material the clear’solution was warmed gently on the steam hath for 2 hours during which time a white solid began to separate. The mix· ; was cooled tc room temperature and the solid product was collected by filtration, washed successively with methanol ar.d ether and dried 24 hours under vacuum at 100*C. to give 23 g. of Q',c('bis-(4-amino-lpyzidinium)-2,3,5f6-tntramethyl-p-xylene dichloride, m.p. >340°C Example 3b To a hot solution containing 12.5 g. (0.132 mole) of 4-amir.opyridrne in 100 ml. of 2-propanol was added 11.6 g. (0.066 mole) cf <7-<7'-dichloro-p-xylene followed by 400 ml. of methanol. The mixture was heated to effect complete solution. After filtering from a small amount of insoluble material the clear solution was diluted with 500 ml, of -654 5 3 3 3 ethyl acetate and cooled to room temperature. The solid product was collected by fitration, washed with ethylaeetate and dried to give 16 g. of z7,0’,-bis-(4-aminO“l-pyridinium)g-xylene dichloride, m.p. 332-335°C.
The following are further illustrative examples of the a, z/'-bis-{4-(R-amino)-1-pyridinium]xylenes of formula II which are obtained in accordance with the above-described procedures: chd' -Bis-[4-(ethylamino)-1-pyridinium]-p-xylene XO dibromide by reacting tf,£7'-dibromo-g-xylene with 4- (ethylamino )pyridine; a,C('-Bis-[4-(2-ethylhexylamino)-l-pvridinium]n-xylene dichloride by reacting c/,iZ'-dichloro-£-xylene with 4-(2-ethylhexylamino)pyridine (b.p. 145-150®C./0.9 mm.) which was prepared by reacting N-(4-pyridyl)pyridinium chloride hydrochloride with 2-e^hylhaxylamine hydrochloride? Q',£?'-bis-[4- (decylamino)-1-pyridinium] -p-xylene dibromide by reacting <9',i,'-dibromo-£-xylene with 4-(decylamino) pyridine (m.p. 71-73°C.) which was prepared by reacting M-(420 pyridyl)pyridinium chloride hydrochloride with ndecylaraine hydrochloride; dW’-bis-[4-(dodesylamino)-1-pyridinium] xylene dichloride by reacting i^z/'-dichloro-p-xylene with 4-(dodecylamino) pyridine; 2 j £?,«?-bis-[4- (octadecylamino) -1-pyridinium] -pxylene dibromide by reacting Q^’-dibromo-p-xylene with 4-(octadecylamino)pyridine which in turn is obtained by reacting N-(4-pyridyl)pyridinium chloride hydrochloride with octadecylamine hydrochloride; -66α,ΰ'-bis-[4-(tetradecylamino;-1-pyridinium]-mxylene dichloride by reacting c^'-dichlo :o~in-xylene with 4-(tetradecylamino)pyridine (m.p. 91-93^0.) which was prepared by reacting N-(4-pyridyl)pyridinium chloride hydro5 chloride with tetradecylamine hydrochloride; a,O' -bis- [4- ibutylamino) -1-pyridinium) -oxylene dibromide ;:Λ reacting cf,O' -fiibromo-o-xylene with 4-(butylamino)pyridine; (/,£/'-bis-[4-(3-ethylheptylamino)-1-pyridinium]-5-methy1 10 m-xylene dibromide by reacting G,tt'-dibromo-5-methy1-mxylene with 4-(3-ethylheptylamino)pyridine which in turn is obtained by reacting N-(4-pyridyl)pyridinium chloride hydrochloride with 3-etbylbeptylamine hydrochloride; 0,0'-bis-[4-'2-methylheptylamino)-1-pyridinium]15 2,5-dimethyl-g~xylene dibromide by reacting a,a1-dibromo2,5-dimethyl-g-: ylene with 4-(2--mefehylheptylamino)pyridine which in turn is obtained by reacting N-(4-pyridyl)pyridinium chloride hydrochloride with 2-methylheptylamine hydrochloride; a,ff'bis'4-(octylamino)-1-pyridinium]-2,4,6trimethyl-m-xylene dicnloride by reacting i7,tf'-dichloro2,4,6-trimethyl-m-xylene with 4-(octylamino)pyridine (M.P. S2-63°C.) which was prepared by reacting N-(4-pyridyl)pyridinium chroride hydrochloride with n-octylamine hydro25 chloride; iZ, Ο,ΰί' -bis- [4- (methylamino)-1-pyridinium]-45 ehloro-o-xylene dibromide by reacting a, <7,-dibromo-4-chloroo-xylene with 4-(methylamino5pyridine; <7,-bis-[4-<2-propylpentylamino)-1-pyridinium] 2,5~dichloro-g-xylene dichloride by reacting ,2,5tetrachloro-g-xylene with 4-(2-propylpentylamino)pyridine which in turn is obtained by reacting N-(4-pyridyl)pyridinium chloride hydrochloride with 2-propylpentylamine hydrochloride ; ^7,ar,-bis-[4-(l,l-dimethylundecylamino)-lpyridiniuml-2,3,5-trichlores-g-xylene dichloride by reacting -58 w 3 3 β α,ϋ'-αία-ί 4~(benzylamino)-l-pyridinium]-2-chlcro£-xylene dichloride by reacting J,ci1,2--trichloro-£-xylene with 4-(benzylamine)pyridine which in turn is obtained by reacting N-(4-pyridyl)pyridinium chloride hydrochloride with benzylamine.
The antibacterial and antifungal activity of representative examples tine compounds of Formula I was determined using a modification of the Autotiter method described by Goss, et al. Applied Microbiology 16 (9) 1,414-1,415 (1968) in which a 1,000 mcg/ml. solution of the test compound is prepared. To the first cup of the Autotray is added 0.1 ml. of the test solution. Activation of the Autotiter initiates a sequence of operations by which 0.05 ml. of the test compound solution is withdrawn from the cup by a Microtiter fransf'’r .*.·-.ορ and diluted in 0.05 ml. of sterile water. Fclowing this operation, 0.05 ml. of inoculated double -/ vrength semisynthetic medium (glucose) is added automatically to each cup, The overall operation results in final drug concentrations ranging from 500 to 2Q 0.06 meg./ml. in twofold decrements, The Autotray is incubated for 18-20 hours at 37cc. at which time the trays are examined visually for growth as evidenced by turbidity, and the concentration of the last sample in the aeries showing no growth (or no turbidity) is recorded as the minimal 2g inhibitory concentration (MIC) in meg./ml. The compounds were thus tested as solutions against a variety of gram positive and gram negative bacteria including Staphylococcus aureus, Proteus mirabilis, Escherichia coll, Klebsiella pneumoniae, Pseudomonas aeruginosa, S t r s1.1oc o ccus pyogenes, and against such fungi as Aspergillus nlger, Candida albicans snd Trichophyton mentagrophytes. -69______ Many of the compounds of formula I were al9O found to he antibacterially effective against Streptococcus autans and Actinomyces A-viscosis.
Virucidal activity of representative examples against Herpes simplex type 2 virus was determined in vitro employing a procedure similar to the plaque inhibition test for detection of specific inhibitors of DNA-containing viruses published by E.C. Herrmann, Jr., Proc. Soc. Exp. Biol. Med. 107, 142 (1961) wherein 2 mg. of the. test compound was placed on the surface of the growth medium. The compounds corresponding to Examples 3, SC, 7, 9C, 10, 11, 13, 17, IS, 21, 22, 24, 31, 33, 35, 36, 37, 53, 54, 55, 56, 57, 58, 60, 61, 63, 81, 82, 83 and 84 were found active and the compounds of Examples 16, 34, 39, 40 and. 793 V7ere found inactive.
The dental plaque preventive activity of certain of the compounds of the present invention was determined by measuring the ability of these compounds to inhibit the production of dental plaque by Streptococcus mutans 0MZ-61 as follows s A culture medium for the-.plaque-produelng Streptococcus mutans OMZ-61 containing 1.5 g. of BBL beef extract, g. of sodium chloride, 10 g. of dehydrated tryptiease, g. of sucrose and sufficient distilled water to give a total volume of 1000 ml. is adjusted to pH 7.0 and sterilized by membrane filtration. The medium Is dispensed aseptically in 10-ral4 aliquots Into 150 s 16 mm. test tubes and stored at refrigeration temperature until used.
Two concentrations of the compound to be tested are prepared by dissolving 100 mg. of the compound in 1 ml. of distilled water with the aid of sufficient 0.1N sodium hydroxide, 10% dimethylsulfoxide or 10% Ν,Ν-dimethylformamide and diluting the resulting solution to 10 ml. with distilled -70'ζ ί> 3 3 G water. This 1.0% solution and a 1:10 dilution in distilled water (0.1%) are sterilized by membrane filtration before use.
A sterile piece of plaque-free natural tooth 5 enamel or synthetic hydroxylapatite is suspended in each concentration of compound fcr two 1-minute periods, each followed by a 1-minute air drying period. Each piece is then suspended ar.d agitated for 5 minutes in individual test tubes containing sterile distilled water (rinse). They are then suspended in 10 ml. of liquid beef extract medium to which has been added 0.3 ml. of a 24-hr. anaerobic culture of Streptococcus mutans. The tubes containing the ’’treated hydroxylapatite and the Streptococcus mutans are then incubated anaerobically at 37C. for 24 hours. The same process of two l-minate soaks in the solution of compound, each followed by 1 minute of air drying and the final 5minute rinse is repeated before once again suspending the hydroxlapatite in a fresh tube Containinc 10 ml. of beef extract medium and 0.3 ml. of inoculum. At the end of the second 24-hour period, each piece of hydroxylapatite is rinsed for 1 minute in 3 successive tubes of distilled water. These are then suspended for 1 minute in a solution of F, DiC Red No. 3 dye. This staining procedure is used in order to identify more easily the development of plague after the 48-hour period of exposure tc the plague-producing organism. The staining period is followed by another 10second rinse to remove excess dye. Any plaque formation stains a brilliant pink. Test results are read as plaque inhibition (active) or no plaque inhibition (inactive) at -7145336 the percent concentration tested. Active compounds are tested at successively lower doses in order to determine the minimum effective concentration. On some occasions, the interference of plaque production is caused by the inhibition of growth of the organism in the culture medium because the compound has been leached from the hydroxylapatite to produce an antibacterial level in the medium. When this occurs, the compound is tested at lower concentrations until the growth of the organism in the surrounding medium is equal to that in the nonmedicated control culture. Plaque may or may not se formed at these lower concentrations.
Substantivity of the test compound to the tooth surface which is of course necessary to prevent the formation of dental plaque thereon, may, however, potentiate the accumulation of staining agents, e.g., coffee, tobacco, food colorants, etc., on the tooth surface. Therefore the above procedure was also utilized to estimate staining potential, i.e,, the ability of the test compound,to promote adherence of staining agents to the tooth surface. Thus, a residual, uniform pale pink color adhering to the test surface following the final rinse is indicative of staining potential at the precent concentration tested and is reported as staining concentration« The uniform pale pink color caused by the test compound is readily distinguished from the localized, brilliant pink color caused by plaque formation. In general the preferred species advantageously have a staining concentration considerably higher than the minimum effective plaque-preventive concentration. s-72' «ί 3 3 a Numerical, antibacterial, antifungal, and dental plaque-preventive test data for the compounds are presented in Table A hereinbelow. Corresponding data for twc known compounds, viz. l,8-bis-(4-amino-l-pyridinium)octane dibromide (Reference Compound ΐ'ί and 1,10-bis- (4-amino-l-pyridinium)decane dibromide (Reference Compound II) are also included in Table A for purposes of comparison. Staining concentrations for representative examples are reported in Table C hereinbelow.
Antibacterial effectiveness in the presence of serum was determined for representative examples by the standard serial tube dilution test wherein paired comparisons of minimum inhibitory concentrations (MIC) were determined in the absence and in the presence of heat inactivated (30 min. at 56aC.) horse serum (40¾) in the test medium.
The results are expressed as the fold increase in MIC (meg./ml.) versus Staphyloccocus aureus and Escherichia coli caused by tiie presence of serum and are presented in Table B hereinbelow.
Dental plague-preventive effectiveness in the presence of sterile human saliva f50%) was determined for representative examples, Tc't results are read as minimum effective concentration and are presented in Table C hereinbelow.
The acute oral toxicity (ALD.„) of several representativ· examples was determined as follows; Groups of 3 young adult male Swiss-Webster strain albino mice were fasted approximately 4 hours before medication and then medicated once orally by stomach tube. All mice were observed for 7 days after -7345336 medication. Autopsy of all mice in the study revealed no gross tissue changes except for the group receiving 1Q00 mg./kg. of the compound of Example 25 wherein congestion of the glandular portion of the stomachs of two of the three mice was observed. The results are presented in Table D hereinbelow. -74j <5330 In Vitro Antibacterial and Antifungal Activity p A ,.-S! 4J i. .Ή S>i o -V H o o Ο O o -3 O O o O $ & 4J n S35 c ωυ Φ ·)> -4 -H H <—4 f-i ,-i ~4 r-4 'OnΓίΰ. t'J F-iH <0 C -P o o O <~4 rH ftr_> fi. .-4 6 d 3 \O ιη tO ;*> in cn ιΛ to tO n ιΛ CM H OS OS CO OS in «-4 n r-4 os E rH OS CM f—i -.n H η’ sC in r4 in Ό ·. -n m :4 r-I r-4 »H U3 74 iri η *n Lfi ΠΊ CO tn to CO n n lO s CM CM os OS • OS in i-4 OS .£ w * rH T- υ nj s CM H 14 '•j? κ m to so O cn m m i~4 H r- r-4 ίβ S tn n ιΛ m cn CO co n 3 H in η H CM os Os » m OS 00 CM O CM CM CM cm CM d d • jO f\ SO γΗ \D O cn o m 1—i • H O □ « m cn Ό •O £ to 00 n cm tn £ ·. j in ?n co in in in n rH τ-d Cd ό Ci CM ?*· p-l Hd i-t CM r4 Γ* ’ \D m; ή Α A β s ιη •n co co m os CO OS o cn o m CO 3S xr «3· OS o. os Γ- *i* 0 s ofe r4 <*> i-> r-i O C ύ d d .-4 d o d r-4 υ H £ -4 cm 8I £ CM Hi CM ιΛ f-l d \£S 1-4 X> rH in os H in Os r-4 co r- ce os d 00 r- CO r- n os r-4 Μ rP 1—! •H 1 Ή CM 0 cn a cn co tn tn co co S, CO OS ό co co os Os OS os co o -«-i f J rH H cn CO --4 0 Ή rH r4 m d r* r-I ίΗ < 3N 4 ,¾ 8 8 tn 8 US us CM n />1 UStn CM m CM n rH in CM n CM m r-I s .--4 ii ,-4 rH 43 f-4 i-4 n rH r4 cn a. A A Λ A A us 7 8 X 0 tn 04 n ,¾ LO in tn iM £ n CM CM η Λ Ci ;Λ —4 -4 r-4 tO CM t-4 to d-gg Λ Λ A ./ A A Λ A Λ 5 ‘r: ,n in tn cO n o ο C) S —> CO Os os • Os in n r4 OS ί ΓΜ £ r-4 •n *n ’J cn m rH m r4 Pl r4 - *%. 1 -AAki •r<) η η iiS m tn cn to n .tig1 US r-4 M? rH os O\ • OS • US r-4 OS CM rH CM >4? tn -4 η r-| -*> r—Ί cn cn r4 r4 m r4 r-4 m H cn •Ί1 os OS OS os n •3 X CO co σι M* CM CM CM ςρ m rO D 4- H m d r-- d d d d d d d d o o W 3? ί °£ ill ca CQ rj (O 1_. rs. co CTI rH CM s CM r- cn 3a i-H Ι—ί c>. CO o CM CM r-4 rH CM -75¢5336 * # 3 3 6 TABLE A(Cont’d) ί 77· £ *o 3 3 G •P c u -7843336 TABLE A(COnt'd) In Vitro Antibacterial and Antifungai Activity -7945336 80· 3 3β TABLE Ε Effect of Serum on Bacteriostatic Activity MIC (mcg/ntl) vs. Indicated Bacteria '7·»·1· ' ................... S. Aureus ATCC 653 8 £. Coli ATCC 8739 Cpd. of 0% 40% Fold 40% Fold Ex. No. Serum Lerum Increase Serum Serum Increase 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 26 0.25 3.9 16 26 0.125 1.95 x6 0.5 7.8 16 24 0.125 1.95 16 0.25 7.8 32 53 0.25 3 s s; IS 0. 5 15.6 32 3 0.39 ., o 1, 2. 8 0.78 25.0 32 IE 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 - 'S iJ 0.25 31,2 128 1.0 31.2 32 ϋ 0.5 7.3 16 0.5 31.2 64 3C 0,5 7.8 .16 1.0 62.5 64 290 0=5 7.8 16 3.S 62.5 16 41C 0.25 7.8 32 1.0 62.5 64 33 0.78 6,25 8 0.78 6.25 8 64 3.12 12.5 4 •-81 1.56 6.25 4 S3 3 6 TABLE C Staining Potential and Effect of Saliva on Dental Plaque Preventive Activity Cpd. of Ex. No. Dental Plaque Preventive Activity in 50% saliva Minimum Effective Cone. (%) Staining Concentration (%) 27 0.05 24 Ca. 0.005 0.05 25 0.05 58 Ca. 0.005 0.05 59. 0.05 56.- 0.1 0.05 3 0.1 0.05 4 Ca. 0.005 0.005 5C 0.051 0.005 6 0.005 13 0.005 14 0.1 0.05 11 0.05 0.Ό5 12 0.05 SC Ca. 0.005 0.05 10 0.005 0.05 44Ά 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% -824 ο 3 3 ο A-.ble D Acute Oral Toxicity (ALDCq'j Solution or : Ex. No. Suspension Dose, mg/kg, of Total Material Mortality 24 Hrs 7 Days 23 Aqueous 125 0/3 0/3 Solution 250 0/3 0/3 500 1/3 1/3 1000 3/3 3/3 7-Oay ALDj-q = 625 mg/kg 26 .uspension 125 0/3 0/3 in 1% G.T, 250 0/3 0/3 500 0/3 0/3 1000 0/3 0/3 7“Day ALD^n =>1000 mg/kg 27 Aqueous Solution 125 250 500 1000 0/3 0/3 1/3 1/3 1/3 0/3 1/3 3/3 7-Day ALD5Q = 250 mg/kg 24 Suspension 125 0/3 0/3 in 13 O.T. 250 0/3 0/3 500 0/3 1/3 1000 0/3 0/3 7-Day .¾ =>1000 mg/kg 25 Aqueous 250 1/3 1/3 Solution 500 1/3 1/3 1000 3/3 3/3 7-Day ΑΜ,-θ = 500 mg/kg 3 Suspension 125 0/3 0/3 in 1% G.T, 250 0/3 0/3 5C0 0/3 1/3 1000 1/3 1/3 7-Day ALl>50 =>1000 mg/kg 4 Suspension 125 0/3 0/3 in 1¾ G.T, 250 0/3 0/3 500 0/3 0/3 1000 0/3 0/3 7-Day ALD^q = >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 7-Day ΑΕΟ^θ =>1000 mq/kg 8 Aqueous 125 0/3 0/3 Solution 250 1/3 1/3 500 2/3 3/3 1000 3/3 3/3 7-Day ALD5Q = 315 mg/kg •8342336 Table D (Confc'd) Cpd. of Ex. Ko. Solution car Suspension Doss, mg/kg of Total Material 24Hrs Mortality 7 Days 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 7-Day ALD5Q =>1000 mg/kg 6 Aqueous Solution 125 250 1/3 0/3 1/3 1/3 500 2/3 2/3 1000 3/3 3/3 7-Day ALDgQ = 315 mg/kg ID Suspension 125 0/3 0/3 in 1% G.T. 250 0/3 1/3 500 1/3 1/3 1000 2/3 2/3 7-Day ALD^^ = 750 mg/kg 11 Suspension in 1% G.T. 125 250 500 1000 0/3 0/3 0/3 0/3 0/3 0/3 1/3 0/3 7-Day ALDgQ =>1000 mg/kg 12 Aqueous 125 0/3 0/3 Solution 250 0/3 0/3 500 1/3 1/3 1000 2/3 2/3 7-Day ΑΜ^θ =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 7-Day ALD5Q =>1000 mg/kg 10 Aqueous 125 0/3 0/3 Solution 250 0/3 0/3 500 0/3 0/3 1000 0/3 0/3 7-Day ALDj-θ =>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 7-Day ALDgQ = >1000 mg/kg Aqueous 125 0/3 0/3 Solution 250 0/3 0/3 500 1/3 2/3 1000 1/3 1/3 7-Day ALD5Q = 750 mg/kg -84-4 5 3 3 ϋ Table D (cant'd) Cpd. of Solution ar Dose, ng/kg of Mbrtality Hz. No. Suspension Total Material 24Hrs 7 Days 56 Suspension in 125 0/3 0/3 1% G.T. 250 0/3 0/3 500 0/3 0/3 1000 1/3 1/3 7-Day ALD-n =71000 mg/kg ** L)U 14 Suspension in .1¾ G.T. 125 250 500 1000 0/3 0/3 0/3 0/3 0/3 0/3 0/3 1/3 7-Dav Al.-Πύο =>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 7-Day ALDjq =71000 mg/kg 29C Suspension in 1% G.T- 125 250 500 1000 0/3 0/3 0/3 0/3 0/3 0/3 0/3 0/3 7-Day ΛΑΠ,-θ =>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 7-Day ALD^^ =>1000 mg/kg 1. G.T. = Gum Tragacar.th

Claims (31)

1. A compound having the Formula I or II (herein) where in Formula I: ϊ is an alkylene group containing from 4 to 18 5 carbon atoms and separating the two 4-(R-NH)-l-pyridinyl groups by from 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, benzyl, substituted benzyl as herein defined, or 10 phenyl substituted by methylenedioxy or one or two halogen, lower-alkyl, lower alkoxy, nitro, cyano or trifluoromethyl substituents; and in Formula II R is hydrogen, a straight or branched-chain alkyl group containing from 1 to 18 carbon atoms, or benzyl; 15 Q is methyl or chlorine; V is 0 or an integer 1 to 4; and where in Formulae I and II: A is ari anion; m is 1 or 3; 20 n is 1 or 2; x is 1, 2 or 3; and wherein (m) (2) = (n) (x).
2. A compound according to claim 1, of the Formula I wherein R is an alkyl group containing from 6 to 18 carbon 25 atoms.
3. A compound according to claim 2, wherein R is an alkyl group containing from 7 to 9 carbon atoms. -863 333 6
4. A compound according to claim 1, of the Formula I wherein R is eyclonexyl.
5. A compound according to claim 1, of the Formula I wherein R is p-chlorophenyl.
6. A compound according to any one of claims 1 to 5, of Formula I wherein Y ia (CH-} and w is from 4 to 18. £ w
7. A compound according to claim 6, wherein w is from 8 to 12.
8. A compound according to claim 1, of the Formula II wherein the (C) -xylene group linking the 4-(R-amino)-1pyridinium groups is (Q) -p-xviene.
9. A compound according to any one of the preceding claims, wherein A is chloride or bromide.
10. 1,12-Bis- (heptylamino) -l~pyridinium]dodecane dibromide.
11. 1,12-Bis-(4-(heptylamino)-1-pyridiniumjdodecane dichloride.
12. 10 -Bis-[4-(Octylamino)-1-pyridiniumjdecane dibromide.
13. 1,iO-Bis J4-(octylamino)-l-pyridiniumjdecane dichloride.
14. 1,12-Bis- f~4- (2-ethylhexy lamino) -1-pyridiniumj dodecane dibromide. -874S336
15. 1,12-Bis- ^4-(2-ethylhexylamino)-1-pyridiniumj dodecane dichloride.
16. 1,9-Bis f 4-(heptylamino)-l-pyridinium]nonane dibromide. 5
17. 1,10-Bis-[4-(2-ethylhexylamino)-1-pyridinium]decane dibromide.
18. a,u'-Bis-(4-amino-l-pyridinium)-p-xylene dichloride.
19. α,a 1 -Bis-(4-amino-l-pyridinium)-2 ,-3,5,6-tetramethyl10 p-xylene dichloride.
20. a,
21. A,os'-Bis-jji-(heptylamino) -1-pyridinium]-p-xylene dibromide. Lg 22. A precess for preparing a compound according to claim 1, which comprises reacting two moles of a 4-(Ramino)pyridine having the Formula III (herein) with one mole of a disubstituted alkane having the Formula IV (herein) or with one mole of an a,a'-disubstituted xylene 20 having the Formula V (herein) wherein R in Formula III corresponds to R in Formula I when producing a compound of Formula I and R in Formula III corresponds to R in Formula II when producing a compound of Formula II, and Z is chloro, bromo, iodo, methanesulfonyloxy, ethanesulfony25 loxy, benzenesulfonyloxy, or p-toluenesulfonyloxy, A in the resulting compound of Formula I or II corresponding to -88ϊ, and, if desired,- replacing A with another desired anion. V3. A process according to claim 22, wherein a compound of the Formula I is prepared by the reaction of the compound of Formula III with a compound of the Formula IV. 5 24. A process according to claim 22, wherein a compound of the Formula /?. is prepared by the reaction of the coinpound of Formula III with a compound of the Formula V.
22. 25, A process for preparing a compound of the Formula I according to claim 1, substantially as herein described 10 with reference to any one of Examples 1 to 29 and 31 to 821 25. A process for preparing a compound of the Formula ii according to claim 1, substantially as herein described with rafcrence to any one of Examples 83 to 86. i~ 27. A compound as defined in claim 1 when prepared by the process according co any one of claims 22 to 26.
23. 28. A compound of the Formula 1 according to claim 1, substantially as herein described with reference to any one of Examples 1 to 29 and 31 tc; 82. 20 29. A compound of the Formula II according to claim 1, substantially as herein described with reference to Examples 83 tc 86, A compound according to claim 1, of the Formula I. 30. -8931. A compound according to claim 1, of the Formula IX.
24. 32. An antibacterial and antifungal composition suitable for topical administration comprising an effective amount of a compound according to any one of claims 1 to 21 and 27 to 31 and a pharmaceutically acceptable carrier.
25. 33. A skin-cleansing composition comprising an antibacterially and antifungally effective amount of a compound according to any one of claims 1 to 21 and 27 to 31 and a pharmaceutically acceptable surfactant and a compatible pharmaceutically acceptable diluent or carrier.
26. 34. An oral hygiene composition for the prevention of dental plaque comprising an effective amount of 1,9-bis {Ϊ-(heptylamino)-1-pyridiniumJnonane dibromide, 1,10-bis Jj(2-ethylhexylamino)-l-pyridiniumjdecane dibromide, 1,10Bis-{4-(oetylamino)1-pyridiniumjdeeane dichloride, 1,9-bis j,4-(oetylamino)-1-pyridiniumJnonane dibromide,,1,12-bisJ4-(heptylamino)-1-pyridiniumjdcdecane dichloride, 1,8bis- (4- (oetylamino) -1-pyridiniuiil octane dibromide, or 1, 10-bis-j^4-(oetylamino)-l-pyridinium]decane dibromide and a compatible, pharmaceutically acceptable carrier.
27. 35. An antibacterial and antifungal composition suitable for application to inanimate surfaces comprising an effective amount of a compound according to any one of claims 1 to 21 and 27 to 31 in admixture with a compatible vehicle.
28. 36. A composition according to any one of claims 32 to 35, substantially as herein described with reference to -90*4·ϋ 3 3 6 the Examples.
29. 37. An antiviral composition suitable for topical administration comprising an effective amount of a compound according to claim 1, and a pharmaceutically acceptable carrier. 3rf. An antiviral composition suitable for application to inanimate surfaces comprising an effective amount of a compound according to claim 1, in admixture with a compatible vehicle.
30. 39. A skin-cleansing composition comprising a virucidally effective amount of a compound according to claim 1 and a pnarmacetitically acceptable surfactant and a compatible pharmaceutically acceptable diluent or carrier.
31. 40, A composition according to any one of claims .37-39, substantially as herein described with reference to the Examples.
IE386/77A 1976-02-25 1977-02-23 Usantimicrobial bis pyridinium compounds IE45336B1 (en)

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Families Citing this family (37)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4420484A (en) 1979-08-13 1983-12-13 Sterling Drug Inc. Basic amino or ammonium antimicrobial agent-polyethylene glycol ester surfactant-betaine and/or amine oxide surfactant compositions and method of use therof
USRE32300E (en) * 1979-08-13 1986-12-02 Sterling Drug Inc. Basic amino or ammonium antimicrobial agent-polyethylene glycol ester surfactant-betaine and/or amine oxide surfactant compositions and method of use thereof
DE19647413A1 (en) * 1996-11-15 1998-05-20 Hoechst Schering Agrevo Gmbh Substituted nitrogen heterocycles, processes for their preparation and their use as pesticides
DE19647317A1 (en) * 1996-11-15 1998-05-20 Hoechst Schering Agrevo Gmbh Substituted nitrogen heterocycles, processes for their preparation and their use as pesticides
DE19647402A1 (en) * 1996-11-15 1998-05-20 Hoechst Schering Agrevo Gmbh Substituted nitrogen heterocycles, processes for their preparation and their use as pesticides
DE10005853C1 (en) * 2000-02-10 2002-02-07 Schuelke & Mayr Gmbh Process for the preparation of bis- (4-amino-1-pyridinium) alkanes
DE10205883A1 (en) * 2002-02-13 2003-08-21 Schuelke & Mayr Gmbh Aqueous antiseptic based on bispyridiniumalkanes
TWI278315B (en) * 2003-06-13 2007-04-11 Ind Tech Res Inst A compound having anti-virus activity
ES2237332B1 (en) * 2004-01-14 2006-11-01 Consejo Sup. Investig. Cientificas DERIVATIVES OF PIRIDINIO AND QUINOLINIO.
DE102005002643B4 (en) * 2005-01-19 2007-11-22 Schülke & Mayr GmbH Compositions for hygienic hand disinfection and disinfecting hand washing
DE102005002645A1 (en) * 2005-01-19 2006-07-20 Schülke & Mayr GmbH Alcoholic compositions for disinfection
DE102005002644A1 (en) * 2005-01-19 2006-07-20 Schülke & Mayr GmbH Compositions for hygienic hand disinfection and disinfecting hand washing
DE102005063375A1 (en) 2005-09-15 2007-04-19 Schülke & Mayr GmbH Antimicrobial preparations containing octenidine dihydrochloride encapsulated in liposomes
DE102005045145A1 (en) 2005-09-15 2007-03-29 Schülke & Mayr GmbH Use of octenidine dihydrochloride in semisolid preparations
DE102005048131A1 (en) * 2005-10-06 2007-04-12 Bayer Innovation Gmbh Antimicrobial plastic composition with low elution rate and long efficacy
DE102005048132A1 (en) * 2005-10-06 2007-04-12 Bayer Innovation Gmbh Process for producing antimicrobial plastic compositions
DE102006012991A1 (en) 2006-03-22 2007-10-11 Bayer Innovation Gmbh Method and device for optically reading information
DE102006051891A1 (en) * 2006-10-31 2008-05-08 Schülke & Mayr GmbH Antimicrobial composition containing Bispyridiniumalkan
DE102008011691A1 (en) 2008-02-28 2009-09-10 Schülke & Mayr GmbH Stabilized antimicrobial composition containing bispyridiniumalkane
DE102009049504A1 (en) 2009-10-15 2011-04-21 Schülke & Mayr GmbH Wound and mucous membrane antiseptic based on bispyridiniumalkanes
DE102010022367A1 (en) 2010-04-20 2011-10-20 Klosterfrau Berlin Gmbh Pharmaceutical composition in form of lubricating agent or gel used for treating and preventing infections and pain associated with catheterization comprises octenidine or its salts and local anesthetic
EP2384733B1 (en) * 2010-05-07 2016-07-27 Ivoclar Vivadent AG Antimicrobial dental materials
DE102010025932A1 (en) 2010-07-02 2012-01-05 Schülke & Mayr GmbH Antiseptic based on bispyridiniumalkanes
DE102011077432A1 (en) * 2011-06-10 2012-12-13 Schülke & Mayr GmbH Use of bispyridiniumalkanes to kill spores
DE102012215511A1 (en) 2012-08-31 2014-06-12 Schülke & Mayr GmbH Process for the preparation of a semi-solid preparation containing bispyridiniumalkane
DE102013223657A1 (en) 2013-11-20 2015-05-21 Schülke & Mayr GmbH Kit for the production of Bispyridiniumalkan containing foams
DE102014107413A1 (en) 2014-05-26 2015-11-26 Schülke & Mayr GmbH Kit for coloring of disinfected areas of a surface
DE102014107412A1 (en) 2014-05-26 2015-12-17 Schülke & Mayr GmbH Colored disinfecting preparation based on bispyridiniumalkane
DE102014115080A1 (en) 2014-10-16 2016-04-21 Schülke & Mayr GmbH Use of fatty acid esters to improve the antimicrobial effectiveness of an alcoholic disinfectant
KR20200044872A (en) * 2017-08-21 2020-04-29 디쉬맨 카보젠 아믹스 리미티드 Octenidine-based compounds
EP3771338A1 (en) 2019-07-29 2021-02-03 The Procter & Gamble Company Acidic antimicrobial composition
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EP3816272B1 (en) 2019-10-31 2023-11-01 The Procter & Gamble Company Fabric care composition
CN114989076A (en) * 2022-06-07 2022-09-02 八叶草健康产业研究院(厦门)有限公司 Preparation method of octenidine base

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AU2258277A (en) 1978-08-31
NO770631L (en) 1977-08-26
FI66850B (en) 1984-08-31
CA1073911A (en) 1980-03-18
JPS6033108B2 (en) 1985-08-01
FR2342286A1 (en) 1977-09-23
AR218052A1 (en) 1980-05-15
PH25097A (en) 1991-02-19
ATA129777A (en) 1979-08-15
IE45336L (en) 1977-08-25
AT355571B (en) 1980-03-10
DE2708331A1 (en) 1977-09-08
BE851807A (en) 1977-08-25
DE2708331C2 (en) 1991-03-21
JPS52105228A (en) 1977-09-03
DK147638C (en) 1985-07-15
IL51520A0 (en) 1977-04-29
FR2342286B1 (en) 1979-03-09
DK147638B (en) 1984-10-29
NL186086C (en) 1990-09-17
NO150758C (en) 1984-12-12
NL7701965A (en) 1977-08-29
AU510149B2 (en) 1980-06-12
FI66850C (en) 1984-12-10
ES456252A1 (en) 1978-02-01
PH22315A (en) 1988-07-29
LU76837A1 (en) 1977-09-12
PT66224B (en) 1978-07-14
IL51520A (en) 1980-12-31
DK81277A (en) 1977-08-26
NO148779C (en) 1983-12-14
CH620907A5 (en) 1980-12-31
NO823274L (en) 1977-08-26
NL186086B (en) 1990-04-17
NO148779B (en) 1983-09-05
MX5132E (en) 1983-03-28
HK67484A (en) 1984-09-07
FI770593A (en) 1977-08-26
SE432421B (en) 1984-04-02
SE7702072L (en) 1977-10-10
PT66224A (en) 1977-03-01

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