CA1073911A - Antimicrobial bis-pyridinium compounds - Google Patents
Antimicrobial bis-pyridinium compoundsInfo
- Publication number
- CA1073911A CA1073911A CA272,596A CA272596A CA1073911A CA 1073911 A CA1073911 A CA 1073911A CA 272596 A CA272596 A CA 272596A CA 1073911 A CA1073911 A CA 1073911A
- Authority
- CA
- Canada
- Prior art keywords
- bis
- formula
- pyridinium
- mole
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
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Classifications
-
- 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
ABSTRACT OF THE DISCLOSURE
Bis-[4-(R-amino)-1-pyridinium]alkanes and .alpha.,.alpha.'-bis-[4-(R-amino)-1-pyridinium]xylenes are prepared by reacting a 4-(R-amino)pyridine with an appropriate disubstituted alkane or .alpha.,.alpha.'-disubstituted xylene. The compounds are useful as antibacterial and antifungal agents. Certain species of the first group are also useful as dental plaque-preventive agents.
Bis-[4-(R-amino)-1-pyridinium]alkanes and .alpha.,.alpha.'-bis-[4-(R-amino)-1-pyridinium]xylenes are prepared by reacting a 4-(R-amino)pyridine with an appropriate disubstituted alkane or .alpha.,.alpha.'-disubstituted xylene. The compounds are useful as antibacterial and antifungal agents. Certain species of the first group are also useful as dental plaque-preventive agents.
Description
~197~
The present invention relates to bis-(4-amino-1-pyri-dinium)alkanes and a,a'-bis-(4-amino-1-pyridinium)xylenes and , :
the preparation thereof. Said compounds being useful for con-~
trolling bacteria, fungi and Herpes viruses, and in certain cases ; 5 for preventing the formation of dental plaque.
U.S. Patent 3,055,902 discloses a group of bis-(4-amino-l-pyridinium)alkanes as intermediates in the preparation of the corresponding bis-(4-amino-1-piperidino)alkanes stated to have bacteriostatic and bactericidal effects.
W.C. Austin et al., J. Pharm. Pharmacol. 11, 80-93 !~
(1959) disclose I,10-bis-(4-amino-1-pyridinium)decane diiodide and 1,10-bis-(4-acetamido-I-pyridinium)decane diiodide. It~is stated that certain species among the large, diverse group o~
quaternary ammonium compounds disclosed possess amebicidal, ;15 ~ antibacterial, anti-filarial and trypanocidal activity, but ~ no biological data are gi~en for either of the above-named f ~ ~ compounds.
i ~ The invention relates to bis-[4-(R-amino)-l-pyridinium]-alkanes having Formula I hereinbelow:
~N~ ~ N _ ~ _ ~ N~ A
f~
~ 2 ', ' ' ; ' . ~ :
'' :
. . .
and a,a'-bis-[4-(R-amino)-l-pyridinium~xylenes having formula II
hereinbelow:
~ CH2-N~--; l RNH _ ~ N-CH2 ~ ~ I A
. ... II
, .
wherein in Formula I:
Y is an alkylene group contalning from 4 to 18 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, ~i a cycloalkyl group containing from 5 to 7 carbon atoms, benzyl, or phenyl substituted by methylenedioxy or one or two substituents . , .
selected from the group consisting of halogen, lower-alkyl, lower-alkoxy, nltro, 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 an integer 0 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 1,
The present invention relates to bis-(4-amino-1-pyri-dinium)alkanes and a,a'-bis-(4-amino-1-pyridinium)xylenes and , :
the preparation thereof. Said compounds being useful for con-~
trolling bacteria, fungi and Herpes viruses, and in certain cases ; 5 for preventing the formation of dental plaque.
U.S. Patent 3,055,902 discloses a group of bis-(4-amino-l-pyridinium)alkanes as intermediates in the preparation of the corresponding bis-(4-amino-1-piperidino)alkanes stated to have bacteriostatic and bactericidal effects.
W.C. Austin et al., J. Pharm. Pharmacol. 11, 80-93 !~
(1959) disclose I,10-bis-(4-amino-1-pyridinium)decane diiodide and 1,10-bis-(4-acetamido-I-pyridinium)decane diiodide. It~is stated that certain species among the large, diverse group o~
quaternary ammonium compounds disclosed possess amebicidal, ;15 ~ antibacterial, anti-filarial and trypanocidal activity, but ~ no biological data are gi~en for either of the above-named f ~ ~ compounds.
i ~ The invention relates to bis-[4-(R-amino)-l-pyridinium]-alkanes having Formula I hereinbelow:
~N~ ~ N _ ~ _ ~ N~ A
f~
~ 2 ', ' ' ; ' . ~ :
'' :
. . .
and a,a'-bis-[4-(R-amino)-l-pyridinium~xylenes having formula II
hereinbelow:
~ CH2-N~--; l RNH _ ~ N-CH2 ~ ~ I A
. ... II
, .
wherein in Formula I:
Y is an alkylene group contalning from 4 to 18 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, ~i a cycloalkyl group containing from 5 to 7 carbon atoms, benzyl, or phenyl substituted by methylenedioxy or one or two substituents . , .
selected from the group consisting of halogen, lower-alkyl, lower-alkoxy, nltro, 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 an integer 0 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 1,
2 or~3; and wherein (m)(2) = (n)(x).~
~: : 20 These compounds are useful as antibacterial and anti-. ; ~ fungal agents and are vlrucidally active against Herpeæ vlruse3.
,:
`''''',~
x' , ,........................................... .
, ~ I
~ q . .:., . .,:
,, ,: .
. ~, . :
.::
.. ' . ~
,: . . ;~ :.
.~ ~ . . . . . .
. " , . .
~. ~ . ~ . . . .
39~1 ..
.
.
Certain of the compounds of Formula I 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 8-[4-(nonylamino)-l-pyridinium~hexane ,......... .
dibromide and the corresponding dichloride, 1,6-Bis-[4-(decylamino)-1-pyridinium]hexane dibromide, .
1,6-Bis-~4-(dodecylamlno)-1-pyrldinlum~hexane dibromlde, -l~ . 1,7-Bis-[4-(heptylamlno)-l-pyridlnlum]heptane dlbromide, : 1,7-Bls-~4-(octylamlno)-1-pyridinlum~heptane dlbromide, 1,7 -~i 8- L4-(nonylamlno)-1-pyrldlnium]heptane dibromlde.
1,7-Bl~-~4-(decylamino)-1-pyrldlnlum]heptane dibromide, 1,7-Bl~-~4-(dodecylamlno)-1-pyridlnlum~heptane ; dlbromideJ
1,8-Bic-[4-(heptylamlno)-1-pyrldlnlum]octane dlbromlde and the correspondlng dlchlorlde, 1,8-B~-[4~(octylamlno)-1-pyrldlnium]octane dlchlorlde, ,......... . . . .
~ _4_ .
' , :, .
'',~ ' ~' ,. , , ~
.
. ., ~ . . .
~: : 20 These compounds are useful as antibacterial and anti-. ; ~ fungal agents and are vlrucidally active against Herpeæ vlruse3.
,:
`''''',~
x' , ,........................................... .
, ~ I
~ q . .:., . .,:
,, ,: .
. ~, . :
.::
.. ' . ~
,: . . ;~ :.
.~ ~ . . . . . .
. " , . .
~. ~ . ~ . . . .
39~1 ..
.
.
Certain of the compounds of Formula I 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 8-[4-(nonylamino)-l-pyridinium~hexane ,......... .
dibromide and the corresponding dichloride, 1,6-Bis-[4-(decylamino)-1-pyridinium]hexane dibromide, .
1,6-Bis-~4-(dodecylamlno)-1-pyrldinlum~hexane dibromlde, -l~ . 1,7-Bis-[4-(heptylamlno)-l-pyridlnlum]heptane dlbromide, : 1,7-Bls-~4-(octylamlno)-1-pyridinlum~heptane dlbromide, 1,7 -~i 8- L4-(nonylamlno)-1-pyrldlnium]heptane dibromlde.
1,7-Bl~-~4-(decylamino)-1-pyrldlnlum]heptane dibromide, 1,7-Bl~-~4-(dodecylamlno)-1-pyridlnlum~heptane ; dlbromideJ
1,8-Bic-[4-(heptylamlno)-1-pyrldlnlum]octane dlbromlde and the correspondlng dlchlorlde, 1,8-B~-[4~(octylamlno)-1-pyrldlnium]octane dlchlorlde, ,......... . . . .
~ _4_ .
' , :, .
'',~ ' ~' ,. , , ~
.
. ., ~ . . .
3~
1, 8-B1B- [4- ( nonylamino)-l-pyridinium~octane . dibromide, 1980~ 4-(decylamino)-1-pyridlnium]octane dibromlde, 1,8-Bi~-[4-(dodecylamlno)-1-pyridinlum]octane dibromlde, 1,8~ 4-(2-ethylhexylamlno)-1-pyrldlnium~-octane dlbromide, 1,9-Bls-[4-(heptylamlno)-1-pyridlnium]non~ne 10 dichloride, 1,9-~ls-[4-(nonylamlno)-1-pyridlnlum~nonane dlbromide, 1,9-Bls-~4-(decylamlno)-1-pyrldinium]nonane dlbromlde, ~;: 15 1,9-Bls-[4-dodecylamino)-1-pyrldinlum~nonane dlbromlde, 1,lO-Bis-[4-(heptylamlno)-1-pyridlnium]decane dlbromlde and the correspondlng dichlorlde, 19 lO-Bi~-[4-(nonylamlno)-1-pyrldlnlum]decane 20 d~bromld~, ~ 0-~i8- t4-(decylamlno)-1-PYridinlum]decane dlbrQmida, 1,lO-Bi8-~4-(dod~cylamino)-1-pyridlnium]decane . dib~omid~, 2S 1,lO-~8-~4-(2-ethylhexylamlno)-1-pyrldlnlum]~
d~oar~e dl~h~ orld~
1,~2-Bi8-14-(hQxylamino)-l-pyrldinlum~dodecane ' ..
dlbromldfi and th~ corresponding dlchloride, : 1,12-~is-~4(heptylamlno)-l-pyridlnlum~dodecane 30 dibro~id~, ..
~' - - ' .
: .
, . , - .
` ~7~3~ ~
2-Bls-[4-(octylamino)-l-pyrldinlum]d~dec~ne dibromide, ; 1,12-Bis [4-(nonylamino)-1-pyridlnlum]dodec~n~
dlbromideJ
1,12-Bi~-[4-(decylamino)-1-pyridinlum]dodecane ~.
: dibromide, :
. 1,12-Bis-[4-(dodecylamino~-1-pyridinium]dodecane dibromide, 1,12-Bis-[4-(2-ethylhexylamino)-1-pyrid~nium~-10 dodecane dibromide and the corresponding dichlorideg ~ 1,14-Bis-[4-(hexylamino)-1-pyridinium]tetradec~ne : : dibromide and the correspondlng dichloride, 1,14-Bis-~4-(heptylamino)-1-pyridinium~tetradecane ~ dlbromlde and the correspondlng dlchloride, .
1,14-Bis-[4-(octylamino)-1-pyridinium tetradecane ::
:~ dibromide, :
and, as particularly preferred species, .
: 1,9-Bis-[4-(heptylamino)-1-pyridinium]nonane , :
dibromide, ~. !
~ 20 1,10-Bis-[4-(2-ethylhexylamino)-1-pyridinium]-... .
. decane dibromide, 1,10-Bis-~4-(octylamino)-1-pyridinium]decane ` dichloride and the corresponding dibromide, '. : . :
;: 1,9-Bis-[4-(octylamino)-1-pyridinium]nonane r ,l '; 25 dibromide, ~l 1,12-Bis [4-(heptylamino)-1-pyridinium]dodecane ,, dichloride, and ,.' 1 .~ 1,8-Bis-[4-(octylamino)-1-pyridinium]octane ~ dibromide.
:, _~
:.
.. ..
.~ , . . . . .
An aspect of the present invention resides in an oral hygiene composition for the prevention of dental plaque com-prising an effective amount of one of the above compounds and a compatible, pharmaceutically acceptable carrier.
The invention also relates to an antibacterial, anti-fungal and virucidal composition suitable for topical administra-tion which comprises an effective amount of a compound having Formula I or II hereinabove and a compatible, pharmaceutically acceptable carrier. The invention further resides in a skin-cleansing composition comprising an antibacterially, anti-fungally and virucidal]y effective amount of a compound having Formula I or II hereinabove, a compatible, pharmaceutically acceptable surfactant and a compatible, pharmaceutically acceptable carrier.
The invention further relates to an antibacterial, - antifungal and virucidal composition suitable for application to inanimate surfaces comprising an antibacterially, anti-fungally and virucidally effective amount of a compound having Formula I or II hereinabove in admixture with a compatible vehicle.
The compounds of Formulas I and II can be prepared by . . , reacting a 4-(R-amlno)pyridine having Formula III:
~ .
RNH ~ N
...III
,1 ; with a disubstituted alkane having Formula IV:
Z - Y - Z ....................... IV
or an ~,~'-disubstituted xylene having Formula V:
.,~ .
.1:
~7--., .
,~ .
,, .
~ ~ -7~
. .
Z-CH2 ~CH2 Z
~: (Q)v wherein in Formulas IV and V: -Y is an alkylene group containing from 4 to 18 carbon atoms and separating the Z groups by from 4 to 18 carbon atoms;
Z is chloro, bromo, iodo, methanesulf'onyloxy, ethane-sulfonyloxy, benzenesulfonyloxy or _-toluenesul~onyloxy;
Q is methyl or chlorine;
v is an integer O 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 6 to 18 carbon atoms, a cycloalkyl group containing from 5 to 7 : : carbon atoms, benzyl or phenyl substituted by methylenedioxy or . 15 one or two halogen, lower-alkyl, lower-alkoxy, nitro, cyano or trifluoromethyl substituents; and whèn the 4-(R-amino)pyridine ~ ! :
(III) is reacted with an ~ disubstituted xylene (V);
R in Formula III is hydrogen, a straight or branched-~ : chain alkyl group containing from 1 to 18 carbon atoms~ or r ' 20 benzyl.
In Formula I herein the alkylene group Y is a bi- .
valent saturated aliphatic hydrooarbon radical containing from .~ ~ 4 to 18, preferably f'rom 8 to 12, carbon atoms arranged in a straight or in a branched chain and separating the two 4-(R-NH)-l-pyrldinyl groups by from 4 to 18, pref'erably from 8 to 12, carbon atoms, f'or example:
.. .
,, . ~ .
' -8-..~, . ~
. ~:
.. .. . .
';
, ~,., , : .
~ a~
1,4-butylene, 1,5-pentylene, 1,6-hexylene, 1,7~
heptylene, 1,8-octylene, l,9-nonylene, l,10-decylene, 1,11-undecylene, 1,12-dodecylene, 1,13-tridecylene, 1,14-tetra-decylene, 1,15-pentadecylene, 1,16-hexadecylene, 1,17-heptadecylene, 1,18-octadecylene, 1-methyl-1,4-butylene, 3-methyl-1,5-pentylene, 2-ethyl-1,4-butylene, 3-methyl-1,6-hexylene, 2,4-dimethyl-1,5-pentylene, 1-methyl-1,7-heptylene, 3-~thyl-1,6-hexylene, 3-propyl-1,5-pentylene,
1, 8-B1B- [4- ( nonylamino)-l-pyridinium~octane . dibromide, 1980~ 4-(decylamino)-1-pyridlnium]octane dibromlde, 1,8-Bi~-[4-(dodecylamlno)-1-pyridinlum]octane dibromlde, 1,8~ 4-(2-ethylhexylamlno)-1-pyrldlnium~-octane dlbromide, 1,9-Bls-[4-(heptylamlno)-1-pyridlnium]non~ne 10 dichloride, 1,9-~ls-[4-(nonylamlno)-1-pyridlnlum~nonane dlbromide, 1,9-Bls-~4-(decylamlno)-1-pyrldinium]nonane dlbromlde, ~;: 15 1,9-Bls-[4-dodecylamino)-1-pyrldinlum~nonane dlbromlde, 1,lO-Bis-[4-(heptylamlno)-1-pyridlnium]decane dlbromlde and the correspondlng dichlorlde, 19 lO-Bi~-[4-(nonylamlno)-1-pyrldlnlum]decane 20 d~bromld~, ~ 0-~i8- t4-(decylamlno)-1-PYridinlum]decane dlbrQmida, 1,lO-Bi8-~4-(dod~cylamino)-1-pyridlnium]decane . dib~omid~, 2S 1,lO-~8-~4-(2-ethylhexylamlno)-1-pyrldlnlum]~
d~oar~e dl~h~ orld~
1,~2-Bi8-14-(hQxylamino)-l-pyrldinlum~dodecane ' ..
dlbromldfi and th~ corresponding dlchloride, : 1,12-~is-~4(heptylamlno)-l-pyridlnlum~dodecane 30 dibro~id~, ..
~' - - ' .
: .
, . , - .
` ~7~3~ ~
2-Bls-[4-(octylamino)-l-pyrldinlum]d~dec~ne dibromide, ; 1,12-Bis [4-(nonylamino)-1-pyridlnlum]dodec~n~
dlbromideJ
1,12-Bi~-[4-(decylamino)-1-pyridinlum]dodecane ~.
: dibromide, :
. 1,12-Bis-[4-(dodecylamino~-1-pyridinium]dodecane dibromide, 1,12-Bis-[4-(2-ethylhexylamino)-1-pyrid~nium~-10 dodecane dibromide and the corresponding dichlorideg ~ 1,14-Bis-[4-(hexylamino)-1-pyridinium]tetradec~ne : : dibromide and the correspondlng dichloride, 1,14-Bis-~4-(heptylamino)-1-pyridinium~tetradecane ~ dlbromlde and the correspondlng dlchloride, .
1,14-Bis-[4-(octylamino)-1-pyridinium tetradecane ::
:~ dibromide, :
and, as particularly preferred species, .
: 1,9-Bis-[4-(heptylamino)-1-pyridinium]nonane , :
dibromide, ~. !
~ 20 1,10-Bis-[4-(2-ethylhexylamino)-1-pyridinium]-... .
. decane dibromide, 1,10-Bis-~4-(octylamino)-1-pyridinium]decane ` dichloride and the corresponding dibromide, '. : . :
;: 1,9-Bis-[4-(octylamino)-1-pyridinium]nonane r ,l '; 25 dibromide, ~l 1,12-Bis [4-(heptylamino)-1-pyridinium]dodecane ,, dichloride, and ,.' 1 .~ 1,8-Bis-[4-(octylamino)-1-pyridinium]octane ~ dibromide.
:, _~
:.
.. ..
.~ , . . . . .
An aspect of the present invention resides in an oral hygiene composition for the prevention of dental plaque com-prising an effective amount of one of the above compounds and a compatible, pharmaceutically acceptable carrier.
The invention also relates to an antibacterial, anti-fungal and virucidal composition suitable for topical administra-tion which comprises an effective amount of a compound having Formula I or II hereinabove and a compatible, pharmaceutically acceptable carrier. The invention further resides in a skin-cleansing composition comprising an antibacterially, anti-fungally and virucidal]y effective amount of a compound having Formula I or II hereinabove, a compatible, pharmaceutically acceptable surfactant and a compatible, pharmaceutically acceptable carrier.
The invention further relates to an antibacterial, - antifungal and virucidal composition suitable for application to inanimate surfaces comprising an antibacterially, anti-fungally and virucidally effective amount of a compound having Formula I or II hereinabove in admixture with a compatible vehicle.
The compounds of Formulas I and II can be prepared by . . , reacting a 4-(R-amlno)pyridine having Formula III:
~ .
RNH ~ N
...III
,1 ; with a disubstituted alkane having Formula IV:
Z - Y - Z ....................... IV
or an ~,~'-disubstituted xylene having Formula V:
.,~ .
.1:
~7--., .
,~ .
,, .
~ ~ -7~
. .
Z-CH2 ~CH2 Z
~: (Q)v wherein in Formulas IV and V: -Y is an alkylene group containing from 4 to 18 carbon atoms and separating the Z groups by from 4 to 18 carbon atoms;
Z is chloro, bromo, iodo, methanesulf'onyloxy, ethane-sulfonyloxy, benzenesulfonyloxy or _-toluenesul~onyloxy;
Q is methyl or chlorine;
v is an integer O 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 6 to 18 carbon atoms, a cycloalkyl group containing from 5 to 7 : : carbon atoms, benzyl or phenyl substituted by methylenedioxy or . 15 one or two halogen, lower-alkyl, lower-alkoxy, nitro, cyano or trifluoromethyl substituents; and whèn the 4-(R-amino)pyridine ~ ! :
(III) is reacted with an ~ disubstituted xylene (V);
R in Formula III is hydrogen, a straight or branched-~ : chain alkyl group containing from 1 to 18 carbon atoms~ or r ' 20 benzyl.
In Formula I herein the alkylene group Y is a bi- .
valent saturated aliphatic hydrooarbon radical containing from .~ ~ 4 to 18, preferably f'rom 8 to 12, carbon atoms arranged in a straight or in a branched chain and separating the two 4-(R-NH)-l-pyrldinyl groups by from 4 to 18, pref'erably from 8 to 12, carbon atoms, f'or example:
.. .
,, . ~ .
' -8-..~, . ~
. ~:
.. .. . .
';
, ~,., , : .
~ a~
1,4-butylene, 1,5-pentylene, 1,6-hexylene, 1,7~
heptylene, 1,8-octylene, l,9-nonylene, l,10-decylene, 1,11-undecylene, 1,12-dodecylene, 1,13-tridecylene, 1,14-tetra-decylene, 1,15-pentadecylene, 1,16-hexadecylene, 1,17-heptadecylene, 1,18-octadecylene, 1-methyl-1,4-butylene, 3-methyl-1,5-pentylene, 2-ethyl-1,4-butylene, 3-methyl-1,6-hexylene, 2,4-dimethyl-1,5-pentylene, 1-methyl-1,7-heptylene, 3-~thyl-1,6-hexylene, 3-propyl-1,5-pentylene,
4,4-dimethyl 1,7-heptylene, 2,6-dimethyl-1,7-heptylene, 2,4,4-trimethyl-1,6-hexylene, 2,7-dimethyl-1,8-octylene, - l-methyl-l,10-decylene, 5-ethyl-1,9-nonylene, 3,3,6,6-tetramethyl-1,8-octylene, 3,8-dimethyl-1,10-decylene, 3-methyl-l,ll-undecylene, 6-methyl-1,12-dodecylene, 2-methyl-1,13-tridecylene, 4,9-dimethyl-1,12-dodecylene, 4-methyl-i 15 1,14-tetradecylene, 2j13-dimethyl-1,14-tetradecylene, 1,4-,l ~ dipropyl-1,4-butylene, 3-(3-pentyl)-1,5-pentylene, 2-(4,8-dimethylnonyl)-1,4-butylene, 1-heptyl-1,5-pentylene, and the ; like.
i~ It will be appreciated that when Y contains 4 20 carbon atoms the latter must, o~ course, be arranged in a straight chain and similarly when Y contains 18 carbon atoms and separates the two 4-(R-NH)-l-pyridinyl groups by 18 carbon atoms said carbon atoms must also be arranged in a ;~ straight chain. In all other instances Y can be either straight or branched.
;~ _9_ ,!i .
``
.
,:
;. _ ,,,,, ,.. , .......... ............... ,... , .. ,... , .... ~ .. ..... ..
j,':
~nl'7~39~
In formula I herein R is a straight or branched-chain alkyl group containing from 6 to 18, preferably from 7 to 9, carbon atoms, for example:
n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-
i~ It will be appreciated that when Y contains 4 20 carbon atoms the latter must, o~ course, be arranged in a straight chain and similarly when Y contains 18 carbon atoms and separates the two 4-(R-NH)-l-pyridinyl groups by 18 carbon atoms said carbon atoms must also be arranged in a ;~ straight chain. In all other instances Y can be either straight or branched.
;~ _9_ ,!i .
``
.
,:
;. _ ,,,,, ,.. , .......... ............... ,... , .. ,... , .... ~ .. ..... ..
j,':
~nl'7~39~
In formula I herein R is a straight or branched-chain alkyl group containing from 6 to 18, preferably from 7 to 9, carbon atoms, for example:
n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-
5 undecyl, n-dodecyl, n-tridecyl, _-tetradecyl, n-pentadecyl, n-hexadecyl, _-heptadecyl, n-octadecyl, l-methylpentyl, 2,2-dimethylbutyl, 2-methylhexyl, 1,4-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, 2-methylheptyl, l-ethylhexyl, 2-ethylhexyl, 2-propylpentyl, 2-methyl-3-ethylpentyl, 3-10 ethylheptyl, 1,3,5-trimethylhexyl, 1,5-dimethyl-4-ethyl-hexyl, 2-propylheptyl, 5-methyl-2-butylhexyl, 2-propyl-nonyl, 2-butyloctyl, l,l-dimethylundecyl, 2-pentylnonyl, : 1,2-dimethyltetradecyl, l,l-dimethylpentadecyl and the like.
:
: When R in formula I herein is a cycloalkyl 1~ group containing from 5 to 7 carbon atoms, there are in- :
cluded cyclopentyl, cyclohexyl, cycloheptyl and the li~e.
" , When R in formula I herein is phenyl substituted by methylenedioxy or one or two substituents selected from ~ .
the group consisting o halogen, lower-alkyl, lower-alkoxy, : 20 nitro, cyano and trifluoromethyl, there are included p-chlorophenyl, o-chlorophenyl, m-chlorophenyl, p-bromophenyl, ; m-fluorophenyl, p-iodophenyl, 2,4-dichlorophenyl, 2,4-difluorophenyl, 2,5-dibromophenyl, 3,5-dichlorophenyl, 3-chloro-4-fluorophenyl, 3,4-methylenedioxyphenyl, p-ethylphenyl, ~5 E~methoxyphenyl, m-nitrophenyl, o-cyanophenyl, m-(trifluoro-~, methyl)phenyl, 2-methoxy-5-methylphenyl, and the like.
. `' ' , ._ :
1'7;~
In formula II herein R is a straight or branched-chain alkyl group containing from 1 to 18, preferably from
:
: When R in formula I herein is a cycloalkyl 1~ group containing from 5 to 7 carbon atoms, there are in- :
cluded cyclopentyl, cyclohexyl, cycloheptyl and the li~e.
" , When R in formula I herein is phenyl substituted by methylenedioxy or one or two substituents selected from ~ .
the group consisting o halogen, lower-alkyl, lower-alkoxy, : 20 nitro, cyano and trifluoromethyl, there are included p-chlorophenyl, o-chlorophenyl, m-chlorophenyl, p-bromophenyl, ; m-fluorophenyl, p-iodophenyl, 2,4-dichlorophenyl, 2,4-difluorophenyl, 2,5-dibromophenyl, 3,5-dichlorophenyl, 3-chloro-4-fluorophenyl, 3,4-methylenedioxyphenyl, p-ethylphenyl, ~5 E~methoxyphenyl, m-nitrophenyl, o-cyanophenyl, m-(trifluoro-~, methyl)phenyl, 2-methoxy-5-methylphenyl, and the like.
. `' ' , ._ :
1'7;~
In formula II herein R is a straight or branched-chain alkyl group containing from 1 to 18, preferably from
6 to 12 carbon atoms, and includes, in addition to the above-mentioned alkyl groups containing from 6 to 18 carbon atoms, 5 such groups as methyl, ethyl _-propyl, _-butyl, n-pentyl, .~ isopropyl, l-methylpropyl, isobutyl, tert-butyl, isopentyl, neopentyl, l-methylpentyl and the like.
In formulas I and II herein R can also be benzyl.
;~
If desired, the phenyl moiety of the benzyl group can be -~ 10 substituted with from one to two substituents such as for .; .
; example, halogen, hydroxy, lower-alkyl, lower-alkoxy, nitro, " : .
cyano, trifluoromethyl, and the like.
R is the same in both occurrences in each of ,:
formulas I and II.
~, ~ 15 When A in the formulas herein is an anion there ,, are included anions of both inorganic and organic acids for example:
: bromide, chloride, fluoride, iodide, sulfate, .Sj i;,~
phosphate, nitrate, sulfamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, naphthalenesulfonate, ~¦ naphthalenedisulfonate, cyclohexylsulfamate, acetate, tri-~. I
i~ fluoroacetate, malate, fumarate, succinate, tartrate, oxalate, citrate, lactate, gluconate, ascorbate, lactate, phthalate, . salicylate, benzoate, picrate, methanephosphonate, arsenite, arsenate, thiosulfate, perchlorate, tartronate, sarcosinate, . i . N-lauroylsarcosinate, monofluorophosphate, hexafluoroaluminate, ',;', .'; hexafluorosilicate, hexafluorostannate, fluorozirconate, i.j~, .
, i", 5,".i ~
, ' I .
,~, ~ ,.. .. .
:' .,'. . . ~: ' . , ' . ' t - .; : . : .. . . : . .. .
tetrafluorobora~e, hexachloroplatinate, tetrachloroaluminate, hexachlorostannate and the like. sromide 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 and tert-butyl..
' ' .
: :
-., : :
,~, :~ :
,~ :
~, r,~
''.1, ~
~ ' , .
1~, ~ ' ~, , : ~ -12-~
:: :
~ .
The reactlon to prepare the compounds o~ Formulas I 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 tformula IV or V) in an inert solvent such as a lower-alkanol, acetonitrile, N,N-dimethylformamide, N,N-dimethyl-acetamide, benzene, toluene, xylene and the like, at a ` temperature of from about 80C. to 150C. for a period of from 1 to 24 hours. Usually the reactants are heated at ~60C. to 100C. in acetonitrile or N,N-dimethylformamide or a mixture of these solvents or in a lower-alkanol for about 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 120-150C. for about 2 to 5 hours.
;, .
The resulting bis-[4-(R-amino)-l-pyridinium~
compounds (formulas I and II) are isolated according to ~ conventional methods, for example by filtration, if the ;~ product is insoluble in the reaction medium, or by dilution ` of the reaction mixture with a non-polar solvent such as ether, benzene or hexane in order to precipitate the product or by evaporation of the reaction medium to leave the product ~l as a residue. The isolated crude product can be purified by j crystallization from a suitable solvent in the presence of , 1 an adsorbent, e.g. charcoal or diatomaceous earth.
The bis-[4-(R-amino)-l-pyridiniu~ compounds produced . ~. .
in accordance with the above-described method, will, of course, contain an anion ~A in formulas I and II) which corresponds to the leaving group of the reactant disubstituted alkane or xylene ~Z in formulas IV and V)~
.
~ : -13-~L~D'7~3~
However, the anionic molety o~ the~e c~mpounds can be variedj ir desired, according to conventional ion exchange me~hods, for example by passlng a ~olutlon 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 of the pyridinium compound con~aining the desired anion. For example a bis-, 15 14-(R-amino)-l-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 2~) be employed to prepare insoluble pyridinium compounds. Thus a soluble bis-[4-(R-amino)-l-pyridinium] c~oundisreacted ! with a soluble salt containing the desired anion which ? combines with the pyridinium cation to afford the desired product as an insoluble precipitate. These insoluble pyridinium ." ~ .
; 25 salts are useful for purposes of isolation and purification and when suitably composited as emulsions, creams, pastes, lotions, jellies or po~Jders also serve as depot preparations providing slow, sustained release of the antimicrobial .
, . . . . . . . .
~`' "' ~'- ' ,'- .'"' ' "' ' ;,' ,. ""' `"' ...... ' ~7~'3~.
pyridinium coi~pound. 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 potential of dental plaque preventive agents.
- 5 Thus, should the anionic portion of a given compound accord to that species characteristics such as solubility, stability, molecular weight, physical appearance toxicity or the like, which render that form of the compound unsuitable for a desired purpose, it can readily be converted to another, ., more suitable form. For use on the skin or other tissues or !
in the oral cavity, pharmaceutically acceptable anions such as, fluoride, chloride, bromide, iodide, methanesulfonate, and the like, are of course employed.
The 4-(R-amino)pyridines (formula III) which are , ~ .
,~ lS used as starting materials generally are known or, if specifically new, are prepared according to the proceudres 'f~l described for preparation of the known compounds.
,' , :: , .
~ Conveniently, the 4-(R-amino)pyridines are prepared f ~ by reacting 4-chloro or 4-bromopyridine or N-(4-pyridyl)-
In formulas I and II herein R can also be benzyl.
;~
If desired, the phenyl moiety of the benzyl group can be -~ 10 substituted with from one to two substituents such as for .; .
; example, halogen, hydroxy, lower-alkyl, lower-alkoxy, nitro, " : .
cyano, trifluoromethyl, and the like.
R is the same in both occurrences in each of ,:
formulas I and II.
~, ~ 15 When A in the formulas herein is an anion there ,, are included anions of both inorganic and organic acids for example:
: bromide, chloride, fluoride, iodide, sulfate, .Sj i;,~
phosphate, nitrate, sulfamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, naphthalenesulfonate, ~¦ naphthalenedisulfonate, cyclohexylsulfamate, acetate, tri-~. I
i~ fluoroacetate, malate, fumarate, succinate, tartrate, oxalate, citrate, lactate, gluconate, ascorbate, lactate, phthalate, . salicylate, benzoate, picrate, methanephosphonate, arsenite, arsenate, thiosulfate, perchlorate, tartronate, sarcosinate, . i . N-lauroylsarcosinate, monofluorophosphate, hexafluoroaluminate, ',;', .'; hexafluorosilicate, hexafluorostannate, fluorozirconate, i.j~, .
, i", 5,".i ~
, ' I .
,~, ~ ,.. .. .
:' .,'. . . ~: ' . , ' . ' t - .; : . : .. . . : . .. .
tetrafluorobora~e, hexachloroplatinate, tetrachloroaluminate, hexachlorostannate and the like. sromide 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 and tert-butyl..
' ' .
: :
-., : :
,~, :~ :
,~ :
~, r,~
''.1, ~
~ ' , .
1~, ~ ' ~, , : ~ -12-~
:: :
~ .
The reactlon to prepare the compounds o~ Formulas I 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 tformula IV or V) in an inert solvent such as a lower-alkanol, acetonitrile, N,N-dimethylformamide, N,N-dimethyl-acetamide, benzene, toluene, xylene and the like, at a ` temperature of from about 80C. to 150C. for a period of from 1 to 24 hours. Usually the reactants are heated at ~60C. to 100C. in acetonitrile or N,N-dimethylformamide or a mixture of these solvents or in a lower-alkanol for about 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 120-150C. for about 2 to 5 hours.
;, .
The resulting bis-[4-(R-amino)-l-pyridinium~
compounds (formulas I and II) are isolated according to ~ conventional methods, for example by filtration, if the ;~ product is insoluble in the reaction medium, or by dilution ` of the reaction mixture with a non-polar solvent such as ether, benzene or hexane in order to precipitate the product or by evaporation of the reaction medium to leave the product ~l as a residue. The isolated crude product can be purified by j crystallization from a suitable solvent in the presence of , 1 an adsorbent, e.g. charcoal or diatomaceous earth.
The bis-[4-(R-amino)-l-pyridiniu~ compounds produced . ~. .
in accordance with the above-described method, will, of course, contain an anion ~A in formulas I and II) which corresponds to the leaving group of the reactant disubstituted alkane or xylene ~Z in formulas IV and V)~
.
~ : -13-~L~D'7~3~
However, the anionic molety o~ the~e c~mpounds can be variedj ir desired, according to conventional ion exchange me~hods, for example by passlng a ~olutlon 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 of the pyridinium compound con~aining the desired anion. For example a bis-, 15 14-(R-amino)-l-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 2~) be employed to prepare insoluble pyridinium compounds. Thus a soluble bis-[4-(R-amino)-l-pyridinium] c~oundisreacted ! with a soluble salt containing the desired anion which ? combines with the pyridinium cation to afford the desired product as an insoluble precipitate. These insoluble pyridinium ." ~ .
; 25 salts are useful for purposes of isolation and purification and when suitably composited as emulsions, creams, pastes, lotions, jellies or po~Jders also serve as depot preparations providing slow, sustained release of the antimicrobial .
, . . . . . . . .
~`' "' ~'- ' ,'- .'"' ' "' ' ;,' ,. ""' `"' ...... ' ~7~'3~.
pyridinium coi~pound. 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 potential of dental plaque preventive agents.
- 5 Thus, should the anionic portion of a given compound accord to that species characteristics such as solubility, stability, molecular weight, physical appearance toxicity or the like, which render that form of the compound unsuitable for a desired purpose, it can readily be converted to another, ., more suitable form. For use on the skin or other tissues or !
in the oral cavity, pharmaceutically acceptable anions such as, fluoride, chloride, bromide, iodide, methanesulfonate, and the like, are of course employed.
The 4-(R-amino)pyridines (formula III) which are , ~ .
,~ lS used as starting materials generally are known or, if specifically new, are prepared according to the proceudres 'f~l described for preparation of the known compounds.
,' , :: , .
~ Conveniently, the 4-(R-amino)pyridines are prepared f ~ by reacting 4-chloro or 4-bromopyridine or N-(4-pyridyl)-
7 ~ 20 pyridinium chloride hydrochloride with an appropriately i3 substituted amine. The reaction is usually carried out by 'l ~l~ heating the reactants in the absence of a solvent at 150C.-225C. for about l.S to 3 hours. The product is isolated in a conventional manner, for example by extraction from alkaline !~ 25 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.
:~ -15-~,, .,.
:, , , ,.,- , .. . .
.. ~ .
. . ~ ~ . , ., .
~3'~
Alternatively, the 4-(R-amlno)pyridines are obtained by catalytlc hydrogenation Or a mixture contain-ing 4- a m I` nopyridine and a carbonyl compound contalnlng the appropriate carbon content. The reaction i~ usually carrled out at a temperature Or 50-70C. ln a suitable ~olvent, for example ethanol~ under a hydrogen pressure o~
20-60 psi, in the pre~ence Or a palladium hydrogenatlon catalyst. A hydrogenatlon time of 4-10 hours is generally ~atlsfactory. The use Or a large excess o~ the carbonyl compound, i.e. 200% or greater advantageously results in high yields o~ pure product in a reaction time o~ 5 hours or less. Following removal of the catalyst the product is isolated by evaporation of the solvent and either dlstllling the resldue or cryst~lllzing the latter from a ~ultable solvent.
~".
' Reaction Or an aldehyde having the appropriate ^~ carbon content with 4-amlnopyridine in the presence of ~ormic acid ~t elevated temperatures also provldes the 4-(R-hmino)pyridlnes.
The 4-(R-amlno)pyridines can alio be obtained by acylation o~ 4-~mlnopyridlne with an acyl halide havln~ the appropriate carbon content ~ollowed by reductlon Or the resulting amide. The acylatlon is carried out accordlng to art-recognized methods, for example by reacting 4~amlno-pyrldine with an acyl halide ln an lnert solvent such as methylene dichloride or chloro~orm ln the presence Or an acid acceptor such as triethylamine. The amide so-produced ls then reduced wlth a complex metal hydrlde such as llthlum hydride ln a sultable solvent such as tetrahydroruran ether ; 30 or dloxane and the amine product isolated ln accordance wlth known procedures.
`' .
.. ::~ ....... ....
The disubstituted alkanes having formula IV also used as starting materials generally are known compounds, or if specifically new can be prepared accordiny to ~he procedures ~ used for preparing the known compounds.
.~ . I
The q,~'-disubstituted xylenes having formula V
.
also used as starting materials generally are Xnown compounds, or if specifically new can be prepared according to the procedur~s used for prepâririy ~he kno;:.. ^ompcunds.
. j , .
Thus an appropriate chloro or methyl-substitute~
:
phthalic, isophthalic or terephthalic acid o_ ester is reduced to the corresponding xylene-d,q'-diol with a metal .! ~ ' ' , hydride such as lithium aluminum hydride in a suitable ;~ solvent such as tetrahydrofuran, ether or dioxane. ~The xylene-~,~'-diol so-produced is then converted to an ~,~'-d;.halo~ylene, for example by reaction with hydrogen bromide, ii,, . .
y~ phosphorous tribromide, phosphorus oxychloride, thior.yl chloride or potassium iodide and orthophosphoric acid according .~I , ~ to art-recognized methods. Alternatively, the xylene- a,~' -.",, . ..
diol can be converted to a sulonate ester by reaction ~itn . '~ . ..
; ~ 20 methane-, ethane-, benzene- or p-toluenesulfonyl chloride in the presence of an acid ~cceptor such as pyridine n accordan~e . j, `~ with well kno~!n procedures.
As described more fully hereinbelow the compounds having formulas I and II exhibited in vitro antimicrobial activity against sevexal species of microorganisms among which are in-cluded both gram positive and gram negative bacteria, several .,: . . . .
~l~ species of fungi and Herpes viruses. The compounds are therefore ,~-17-. ~ . . ...
. ~, . . - . . , , , . . . ' indicated 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 ~or 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 ~leaners, disinfectants and protective coverings such as palnts, varnishes and waxes.
The compounds are adapted for ~he above indicated utilities by combining them with conventional diluents or carriers, compa~ible cationic, anionic or non-ionic surfactants, buffering agents, perfumes and coloring agents, and are ~pplied to a surface to be disinfected by conventional methods such as scrubbing, spraying, swabbing, immersion and the like.
For use as skin-cleansing agents the bis-[4-(R-amino)-l-pyridinium~ c ~ ounds 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 kno~n in the art. For example, the compounds can be formulated with any compatible, pharmaceutically acceptable surfactant,preferably a non-ionic surfactant such as the polyoxyethylene polyoxypropylene copolymers described ln U.S. Patent 3,8553140, amine oxlde~ such as stearyl dlmethyl amlne oxlde de cribed ln U.S. Patent 3,29~,14~ and the like or with mlxtures Or the9e. The rormulations may addltionally contaln pharmaceu-tlcally acceptable diluents such as water, lower alkanols -`` 3~ and the llke, aclds, bases, or bur~ering agents so as to ., .
~ ............................................................... ... .................. .. . .. . . . . .
. , , .. . , . . - , .
maintain a pH of 5.0 to 7.5, and, optionally, perfumes and coloring agents. The bis-~4-(R-amino)-l-pyridinium] compounds are generally present in such formulations in a concentration of approximately 0.5 to 2.0 percent by weight, preferably 1.0 percent by weight.
- When prepared as a tincture the bis-[4-(R-amino)-l-pyridinium] 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 about 0.05 to 1.0 percent (w/v) preferably 0.1 percent (w/v).
` Alternatively, the compounds can be formulated in suitable pharmaceutical vehicles for treating bacterial, .i,l ~ 15 fungal and Herpes viral infections for example as lotions, :c~
ointments, or creams by incorporating them in conventional lotion, ointment or cream bases, sach as alkyl polyether alcohols, cetyl alcohol, stearyl alcohol and the like, or as powders by incorporating them in conventional powder bases such as starch, talc and the like, or as jellies, by incorporating them in conventional jelly bases such as glycerol and tragacanth.
They can also be formulated for use as aerosol sprays or foams.
When used for sanitizing and disinfecting inanimate i:~
cl 25 surfaces the compounds can be formulated with known detergents ` and builders such as trisodium phosnhate, borax and the like. The bis-[4-tR-amino)-l-pyridinium compounds are ~; generally present in such formulations in a concentration up to about 10 percent by weight.
~ -19-:''~ .
,' , ; ' .
,~ ' " ~, . . .
,~ , : . ., .
As described in detail h~reinbelow 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 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 anti-calculus agents described in U.S. Patent 3,934,002, issued January 20, 1976, for example zinc phenolsulfonate, 8-hydroxy~uinoline, disodium ethane l-hydroxy-l,l-diphosphonate, etc. and the amino 15 carboxylate compounds disclosed in U.S. Patent 3,937,807, issued February 10, 1976, for example nitrilotriacetic acid, ;l~ 2-hydroxyethylnitrilodiacetic acid or water-soluble salts ~; thereof. The bis-[4-(R-amino)-l-pyridinium]alkane is usually present in such formulations in a concentration of about , ; 20 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 above-, described formulations are compatible with the active ingredient, `l~ 25 i.e. the antibacterial, antifungal and virucidal effectiveness of the bis-[4-(R-amino)-l-pyridinium] compounds is not ., .
-' vitiated by effects ascribable to the nature of the vehicle, ~ diluent, carrier or other additive.
i.' ~; ~he molecular structures of the compounds o the ln~ention were a6signed on the basis of study Or their in-..................... ... .. ........ ... ........ ..
.: . . . , . :: .: : : ,: - . .: . -, ... : - .
7;~'3 1~
fr~red and NMR spectra, and confirmed by the correspondence between calculated and found values ror elemental analyses for the elements.
The invention ls lllustrated by the followlng example~ wlthout, however, being limited thereto.
Example 1 A. A mixture containing 130 g-. (0.67 mole) of 4-bromopyridine hydrochloride and 152 g. (1.0 mole) of n-heptylamine hydrochloride was heated in an oil bath. When the bath temperaturé reached 180-185C. the reaction mixture began to melt and stirrlng was be~un. At 190-195C. melt-lng was complete and the liquld mixture waq stlrred and heated at 210-220C. for 2.5 hours. The reaction mlxture ., .
wa~ then cooled to room temperature and the resulting solid was dissolved in water~ made alkaline with ~5% aqueous sodium ~ hydroxide and the product extracted with chloroform. The J Chlorororm extracts were dried over anhydrous sodium sulrate and evaporated to dryness under reduced pressure. The ~
I resulting viscous oll waq diluted with a small amount of n-Ç~l ~20 hexane and ~ooled to give a solld which was collected by ,riltration and alr-dried to af~ord 86.6 g. Or 4-(heptylamino)-.~ , pyrldlneJ m.p. 49-51C.
B. Alternatively, 4-(hept~lamlno)pyridine was prepared ,as follows: A mixture containing 229 g. (1.0 mole) of N-``25 (4-pyrldyl)pyridlnlum chlorlde hydrochloride and 228 g.
(1.5 moles) of n-heptylamine hydroc~loride was heated 2 hours with stirring in an oil bath at a bath temperature Or 215C. The reaction mixture was cooled to 80C., diluted wlth ice-water, made alkallne wlth 35~ aqueous sodlum hydroxide and extracted successlvely with ether and chloro-;~orm. The organic extracts were combined and evaporated to dryness under reduced pressure. The residual viscous oll ~, ~ -21-' .: .
.~ ~ . . . ..
, .
~ ID7~
was dlssolved in ether and the ethereal solutlon wa~ wa~hed with water. The aqueous wash was back-extracted wlth chloro rorm and the chloroform extracts were combined wlth the ~thereal solution. The combined organlc solutlons were dried over anhydrous sodlum sulfate and evaporated to dryness under reduced pressure. Coollng the resldual oll to -78C. effected partlal solidl~lcatlon~ The seml-solld was dlluted with a small amount of ether and flltered. The solid so-obtalned was dissolved in a mixture of acetonitrlle and chloroform, : 10 the resultlng solution treated wlth decolorlzlng carbon~
flltered, snd the flltrate evaporated to dryness under reduced pressure. The resultlng seml-solid was dlluted wlth a small amount Or ether and cooled. The solld thus-produced was collected by filtratlon and washed wlth a small volume of cold ether to give, after drylng, 84.6 g. of 4-(heptyl-:
amlno)pyridlne, m.p. 50-52C.
C. 4-~Heptylamlno)pyridlne was al80 prepared by hydrogenating a mixture containing 4-aminopyrldlne and heptaldehyde accordlng to the procedure descrlbed in Example IOB herelnbelow.
~i~ D. To a stlrred warm solution contain,lng 10.0 g.
(0.052 mole) o~ 4-(heptylam~no)pyridine ln 40 ml. of acetonitrlle was added dropwlse a solutlon containlng 9.3 g.
(o,026 mole) of 1,14-dibromotetradecane in 230 ml. of aceto-nitrile and the resultlng mixture was heated 20 hours under reflux. The product which preclpitated upon cooling the reaction mlxture to room temperature was collected by filtratlon, washed wlth cold acetonitrlle and dr~ed afford-. . .
lng 13.9 g. of 1,14-bis-[4-(heptylamino)-1-pyrldinium3-.; 30 tetradecane dibromlde, m.p. 88-goc.
; ~ -22-, .
.
.
,., . . , , . -, : . .
~:: . . . . . . . .
., '' ' ~ ' ', ' . .,-~ . . .
~'7~
Example_2 A solution containing 5.0 g. of 1,14-bls-[4 (heptylamino)-l-pyridlnlum]tetradecane dlbromlde ln 5.0 ml.
o~ methanol was added to the top o~ a 3-lnch diameter column containing 500 ml. Or synthetic anion exchange resln ln the chloride ~orm (sold by Rohm and Haas under the tradename Amberlite IRA 400) packed ln methanol and eluted wlth five 125-ml. portions Or methanol. The combined eluate was evaporated to dryness under reduced pressure and the residual oil wa~ redissolved in ethanol, treated with decol~rlzing carbon and evaporated to dryness. ~he resldual solld was triturated w~th ether containing a ~ew drops Or aceto-nltrileJ collected by ~lltration and drled over phos~orus pento~lde under vacuum to give 3.94 g. o~ 1,14-bis-~4-(heptylaminG)-l-pyridinium]tetrade^ane dichlorlde, m.p.
113-116C.
Example 3 A stlrred suspenslon contalnln~ 11.54 g, (o.o6 mole) o~ 4-(heptylamlno~pyrldine ln 75 ml. o~ a¢etonltrlle was heated under reflux untll a clear homogeneous solutlon was ~ormed. To the clear solutlon was then added dropwlse a warm solutlon contalnlng 9.84 g. (0.03 mole) of 1,12-dibromododecann ln 75 ml. o~ acetonitrile. When the addltlon was complete, heating under refIux was continued 18 hours.
Afker coollns to room temperature, the reactlon mixtu~e was evaporated to dryness under reduced pressure. The residual solid was slurried ln ether, collected by rlltration and dried 48 hours under vacuum at 60C. to a~ord 21.1 g. o~
1,12-bis-[4-(heptylamino)-1-pyrldinium]dodecane dlbromlde, m.p. 101-10~C.
:`
., .
:` . . . .
.
... .
~13'73~
Example 4 A. A solution contalnlng 6.6 g. of 1,12-bis-[4-(heptylamino)~ yrldinium]dodecane dlbromide ln 25 ml. of methanol was added to the top of a 3-inch diameter column packed with 1 liter of synthetlc anion exchange resin in the chloride rorm (sold by Rohm and Haas under the trade-name Amberlite IRA 400) in methanol and eluted slowly wlth 100-ml. portions 0r methanol until 700 ml. o~ eluate had been collected. The combined eluate was evaporated to i 10 dryness under reduced pressure below 25C. ~he 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~bls~[4-(heptylamino)-1-pyridinlum]dodecane dichlorlde, m.p. 109-112Co ~15 B. Alternativelyg a mlxture containlng 7~.8 g. (0.4 mole) o~ 4-(heptylamlno)pyridine and 47.8 g. (0.2 mole? of 1,12-dichlorododecane was heated 4 hours at 125-130C.
,. . .
~ After slight cooling 300 ml. of acetonitrile was added and -`~ the re~ulting mixture was heated at steam bath temperature to effect complete solution then stored in a refrigerator overnightO The preclpitated product was collected by filtra-;:;
, tion, washed with cold acetonitrile and ether, and the `~ hygroscoplc product immediately dried under vacuum to glve 112 g. of 1,12-bls-[4-(heptylamino) l-pyridinium]dodecane dichloride, m.p. 112-115C.
Exam~le 5 A. A mIxture containing 100.0 g. (0.51 mole) of 4-bromopyridine hydrochloride and 110 g. (o.8 mole) 0r n-~ ~ hexylamine hydrochloride was heated ln an oil bath. When i -24-',`:
. j .
,.. .
~: `
.~',', .
",.:, ~ . ~ , , . ' ' ~7;~
- the bath temperature resched 175-180C. the reactlon mlxture began to melt and stlrrlng was begun. The temperature of ~the bath was then raised to 227C. and the stirrlng contlnued 3,5 hours. After cooling to room temperature the reaction mlxture was dissolved ln hot water, the resulting solution = cooled wlth lce, made alkallne with dilute aqueous sodium hydroxide and extracted with chloroform. The chloro~orm extracts were drled over anhydrous sodlum sulrate and evaporated to dryness under reduced pressure. The resldue was trlturated wlth ether and cooled, The resultlng solld was collected by rlltratlon and wa~hed with cold ether.
Evaporatlon Or the ~iltrate afforded a second crop of solid.
;~ The crops were combined, dissolved ln chloro~orm, treated wlth decolorizing carbon and filtered. The ~iltrate was evaporated under reduced pressure, and the residue was trl-~!
i turated with cold etherO The product thus-obtalned was collected by flltration, washed wlth cold ether and dried to glve 6306 g. of 4-(hexylamino)pyrldlne, m.p. ~6-68C.
Evaporation of the filtrate afforded an additlonal 7.0 g., m,pO 65-67C.
;~ B. Alternatlvely, 4-(hexylamino)pyridine was prepared as foilows. A mlxture contalnlng 229 g. (1 mole) of N-(4 pyrldyl)pyrldlnium chloride hydrochloride and 207 g.
(1.5 moles) o~ n-hexylamine hydrochlorlde was stlrred and ~5 heated 1.75 hours at 175-185C. The reactlon was cooled and dlluted with 750 ml. o~ ice-water. The resulting solu-tlon wa~ made alkallne with 35~ aqueous sodlum hydroxlde and after further dllutlon wlth 1 1. of water was extracted wlth ether followed by dichloromethane. The organlc extracts were combined, dried over anhydrous sodlum sulfate and , ; ~ ~'7;3~3~l evapo~ated to dryness under reduced pressure. The resldue was crystalllzed from ether, redlssolved in chloroform, the resulting solution treated with decolorlzlng carbon and ~lltered. The ~iltrate was evaporated to dryness under reduced pressure and the residue was triturated with a mix-ture Or ether and acetonitrlle. The solid thus-obtalned I was again dissolved in chloroform and the resulting solu-tion treated with decolorizing carbon and filtered. The ~lltrate was evaporated to dryness under reduced pressure and the resldue was triturated with cold ether to give 71.'0 g.
of 4-(hexylamino)pyridine, mOp. 68-70C.
C. To a slirred warm solution containing 10.7 g.
(o.o6 mole) of 4-(hexylamino)pyridine in 50 ml. of aceto-nitrlle was added dropwise a solution containlng 10.7 g.
(0.03 mole) o~ l,14-dibromotetradecane in 250 ml. of aceto-nltrile and the resulting mixture heated 22 hours under ; re~lux. The reaction was then evaporated to dryne6s under reduced pressure. The resldual solid was dissolved in - acetonitrile and the resulting solution treated with decolorlz-ing carbon and ~iltered. The filtrate was evaporated to dryness under reduced pressure and the resultlng oil crystallized ~rom acetonitrlle. The product was collected by filtration :! and dried 48 hours at 70C./0.1 mm. to give 13.4 g. of 1,14-bls-[4-(hexylamino)-l-pyridinlum]tetradecane dibromide, ., ~5 m.p. 91-93C.
Example 6 Following a procedure slmilar to that described ln Example 2 but employlng 5.0 g. of 1,14-bl8-[4-(hexylamlno)-l-pyrldinium]tetradecane dibromlde there was obtalned 4.33 g.
. . .
of the correspondlng dichloride, m.p. 94-95C.
; -26-.''' ' .
~'7~3 Example 7 Followlng a procedure slmilar to that described in Example 5C but employing 10.7 g. (0. o6 mole) Or 4-(hexylamino)pyridlne and 9.85 g. (0.03 mole) of 1,12-dlbromododecane there was obtained 17.6 g~ of 1,12-bis-~4-(hexylamino)-1-pyrldinlum]dodecane dibromide, m.p.
12~-124C.
Example 8 Following a procedure similar to that descrlbed ln Example 2 but employing 500 g. Or 1,12-bis-~4-(hexyl-~mino)-l-pyridinium]dodecane dibromide there was obtained 3.69 g. of the corresponding dichloride, m.p. 86-88C.
Example 9 A. A mixture containing 183.3 g. (o.8 molej of N-1 15 (4-pyridyl)pyridinium chloride hydrochloride and 162 g.
(o.98 mole) of n-octylamine hydrochlorlde was heated in an , . . .
oil bath to a bath temperature of 225-230C~ (internal temperature of 188C.) and the resultlng llquld was stirred at that temperature ror 2,5 hours. The reaction mixture ~a~ then cooled to 70C., diluted wlth 1 llter of lce and water, made alkallne with 35~ aqueous sodlum hydroxide and ; extracted with chloroform. The chloro~orm extracts were dried over anhydrous sodium sulrate, treated with decolorlz-lng carbon and evaporated to dryness under vacuum. The resultlng oil wa~ cooled to -78C. The seml-solid whlch r~QE~ed was trlturated with ether and the solid thus-obtained collected by ~iltration, washed wlth cold ether and dried. The ~iltrate arforded a second crop o~ 10 g.
':~
. ' .
.... .
,q,3~Y~9~
The crops were ~ombinedJ dis~olved in chloroform and, rollowing treatment with decolorizing carbon and filtra-tion (repeated 3 times)J the chloroform solutlon was evaporated to dryness under reduced pressure. The result-ing solid was trlturated with ether, cooled, collected by flltratlon and washed with cold ether-hexane to give 63.3 g.
of nearly colorless 4-(octylamino)pyridine, m.p. 62-63C.
B. Alternatively 4-(octylamino)pyridine was prepared as follows~ A mixture containing 94 g. (1 mole; of 4-aminopyridine, 384 g. (3 moles) of octaldehyde, 7 g. of 10~ -palladium-on-carbon hydrogenation catalyst and sufficient absolute ethanol to glve a total volume of 1~2 1. was hydro-genated 4.5 hours at 70-90C. under an initial hydrogen pressure of 45 psl, Arter cooling the mlxture the hydro-genatlon cataly~t was removed by filtration and the filtrate was evaporated to dryness under reduced pressure. The re-sidual oil crystallized on standing and the solid product was trlturated wlth hexane, collected by flltration, washed .,~ with ~resh hexane and dried at 40C. under vacuum to give ~I 20 182 g. of 4-(octylamino)pyridine, m.p. 70-73C.
''?.' C~ To a stirred, warm solution containlng 10.0 g (0.049 mole) Or 4-(octylamlno)pyridine in 150 ml. of aceto-!l~ nltrile was added dropwlse a solution containing 7.4 g.
(0,0245 mole) of 1,10 dibromodecane in 50 ml. of aceto-nitrile and the resulting mixture heated 18 hour~ under reflux. After cooling and stirring 1 hour at room tempera-tureD the precipitated solid was collected by filtration, ,',J,'I washed with acetonitrile and dried 48 hour~ at 85C. to give 15.6 g. o~ 1,lO~bis-[4-(octylamino)-1-pyridinium3decane di-bromlde, m.p. 16~-164C.
?.: ',. - .
' ' ". ~ , .. ,,..... .... ,.. , ,,",,,,,,~,, `` : ' , ' ' ' :~ ' , .. , . . . . -: . ' , , .
- ~ ~7~3~
Example 10 A. Followlng a procedure similar to that descrlbed ln Example 2 but employing 5.0 g. of 1,10-bls-~4-(octyl-~mlno)-l-pyrldinium]decane dlbromide there was obtained 4.~1 g.
o~ the corresponding dlchlorlde, m.p. 213-214C.
. Alternatlvely, a mixture containlng 61.8 g. of 4-(octylamlno)pyridine and 310 5 g. Or l,10-dichlorodecane was stirred and heated slowly to 120C. The hest source was removed and the température of the now exothermic reaction lQ contnued to rlse to 180C. As soon as the reactlon mixture began to crystalllze 250 ml. Or N,N-dlmethylrormamide was rapidly added and the resulting mlxture was~heated to give a clear homogeneous solution and then cool~d to 0C. The precipitated product was collected by ~lltratlon, washed wlth ether and dried 24 hours under vacuum at 60C. to give 73 g. of 1,10-bis-[4~(octylamino~-1-pyridinium]decane di-chlorlde, m.p. 215-217C.
Example 11 .
,, Followlng a procedure slmllar to that descrlbed ln Example 9C but employing 11.1 g. (0.054 mole) of 4-(octylamino)pyrldine and 7.34 g. (0.027 mole)'ol 1,8-dibromooctane, and heating the reactlon mlxture 6 hours :~ :
under rerlux there was obtained 15.6 g. Or 1,8-bls-~4-(octylamlno)-lrpyrldlnlum]octane dibromide, m.p. 17~-175C.
Example 12 ; Following a procedure slmllar to that described ~ ln Example 2 but employlng 5.0 g. Or 1,8-bis-[4-(octylamino)-.
.~ .
.. ., . ... , . ... , . . , , ,, ~ ........ ..
:.: .,, .. , _ . . .. .. .
, ,' ~ ' . ' . ,, . ~ . . . ..
l-pyridlnium]octane dlbromide there wa~ obtained 4.30 g. of ; the corresponding dlchloride, m.p. 219-211C.
Example 1~
` Following a procedure similar to that described - 5 in Example 9C but employing llol g. (0.054~mole) of 4-(octylamino)pyridine and 6~6 g. (0.027 mole) of 1,6-dibromo-hexane and heating the reaction mixture 9 hours under reflux there was obtalned 15~1 g. of 1,6-bis-[4-(octylamino)-1-pyridinium]hexane dibromide, m.pO 136-13~C.
..:
,!' lo ' Example 14 . .
Following a procedure similar to that described , ln Example 2 but employing 500 g. of 1,6-bls-[4-(octylamlno)-pyridinium]hexane dibromide there was obtained 4.23 g. Or the corresponding dichloride9 mO p. 189-191Co .,.,~ .
Example 15 To a stirred warm solution containing 2.06 g.
(0.01 mole~ o~ 4-(octylamino)pyridine ln 15 ml. Or aceto-7, nitrile was added dropwlse a s~lution containlng 1.37 g.
~1~ (0.005 mole) o~ 1,6-hexanediol dimethanesulfonate in 10 ml.
~ 20 o~ acetonltrile and the resulting mixture was heated under -; re~lux 20 hours. The reaction mixture was evaporated to dryness under reduced pressure and the residual gum was triturated with ether to give a colorless hygroscoplc solid.
This product was redissolved ln a mixture o~ ethanol, ben-æene and acetonltrile and the resulting solution evaporated to dryness under reduced pressure. The residue was tri-turated with ether and the resultlng whlte solid was quickly collected by ~iltration, washed wlth anhydrous ether, and .: .
_30_ . . .~ .
., . .
.: . : - : . -... ; :
~ ` ~.. t3r7 ~
drled 72 hours at 28C./0.1 mm to give 2.65 g. of 1,6-bls-~4-(octylamino)-1-pyridlnium]hexane dimethanesulfonate as a waxy~ whlte solid.
Example 16 Following a procedure similar to that de~cribed in ; Example 9C but employing 14.24 gO (o.o8 mole) of 4-(hexyl-amino)pyridins and 8.64 g. (0.04 mole) o~ 1,4-dibromobutane there was obtalned following trituration of the crude pro-duct wlth a mixture of acetonitrile and acetone 20.45 g. of 1,4-bis-[4-(hexylamino)-1-pyridinium]butane dibromide, m.p. 199-201C.
,, .
E~ample 17 ~ollowing ~ procedure ~imilar to that described in Example 9C but employlng 10. 7 g ~ ( O ~ o6 mole) of 4-(hexylamino)pyrldine and 7~32 g~ (0.03 mole) of 1,6-dibromo-~` hexane there was obtained ~ollowing trituration o~ the crude product wi~h a mlxture o~ ether, acetonltrile and acetone 14.90 g. of 1,6-bls-[4-(hexylamino)-1-pyrldinlum]-hexane dibromideJ m.p. 178-179~C~
... .
Example 18 ollowing a procedure similar to that described in Example 9C but employing 10. 7 g. (o.o6 mole) of 4-~ (hexylamino)pyridlne and 7.75 g, (0.03 mole) of 1~7-dibromo-: heptane there was obtained following trituratlon of the crude product wlth a mixture o~ acetonltrile and acetone 16.4 g. o~ 1,7-bis-[4-(hexylamino~-1-pyrldinium]heptane .~ .
~ dlbromide, m.p. 157-158Co ., I .
L ~
3~
Example 19 Following a procedure similar to that descrlbed in Example 9C but using 10.7 g. (o.o6 mole) of 4-(hexylamino)-pyrldine and 8.6 gO (0.03 mole) of l,9-dibromononane there was obtained 17015 g. of 1,9-bis-[4-(hexylamino)-1-pyridinlum]-nonane dibromideg m.p. 114-115C~
E m le 20 Following a procedure similar to that described ln Example gc but employing 15.4 g. (0. o8 mole) of-4-(heptylamino)pyrldlne and 8064 gO (0004 mole) of 194-dlbromobutane there was obtained 23.1 g. Or 1J 4-bis-[4-(heptylamino)-l-pyridlniumlbu~ane dibromide, mOp. 229-230C.
Example ?l Following a procedure similar to that described ln Example 9C but employing lOo O g. (0.052 mole) o~ 4-(heptylamlno)pyridine and 6.7 gO (o.026 mole) of 1,7-dibromoheptane there was obtained 14005 gO o~ 1,7-bi~-~4-(heptylamino~ l-pyrldlnium]hepiane dibromide, mOpO 142-143C.
.
` Example 22 .
~ 20 ~ollowing a procedure slmilar to that described ,~ in Example 9C but employing 11.6 g. (o.o6 mole) o~ 4-(heptyl-amino)pyrldine and 8.2 g. (0.03 mole) of 1,8-dibromoctane there was obtained a~ter recrystallizatlon ~rom acetonltrile-ether 1806 gO of 1,8-bis-[4-(heptyl3mino)-l-pyridlnium]-` 25 octane dibromide, m.p. 161-162C.
.;
.,,;
'~' .. . . .. . . .... . .. ..... .. . . ....
. ~ :
o~
Example 23 Followlng a procedure slmilar to that described in Example 2 but employing 5~0 g. (0.0076 mole) o~ lJ8-bis-[4-(heptylamino~-1-pyridlnlum~octane dlbromlde there was obtained 4.1 g. Or the correspondlng dichlorlde, m.p.
206-208C.
Example 24 Followlng a procedure simllar to that described ~ ln Example 9C but employing 15.4 g. (o.o8 mole) o~ 4-; 10 (heptylamino)pyridine and 11.44 g. o~ l,9-dibromononane there was o~tained 21.3 g. or l,9-bis-[4-(heptylamino)-1-pyridinium]nonane dibromide, m.p. 115-116C.
Example 25 , Following a procedure similar to that described in Example 2 but employing 5.0 g~ (0.0075 mole) of l,9-bis-[4-(heptylamino)-1-pyridinlum]nonane dibromide there was s obtained 4.2 g. Or the corresponding dichloride, m.p.
: .
154-155C.
~e~ .
Followlng a procedure slmilar to that described ! in Example 9C bu~ employing 15.4 g. (o.o8 mole) of 4-(heptyl-amino)pyridine and 12.0 g. (0.04 mole) o~ l,10-dibromodecane there was obtained 25.7 g. Or 1,10-bis-[4-(heptylamino)-1-~ pyridinlum]decane dibromide, m.p. 163-165C.
;; 2~ Example 27 Followlng a procedure similar to that described ln Example 2 but employing 5.0 g. (0.0073 mole) Or 1,10-;3~3~
bis-~4-(heptylamino)-1-pyridinium]decane dibromide there was obtained 4.35 g. Or the correqpond1ng dichloride, m.p. 209-210C.
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 Amberlite IRA 400) in 1~0 ml. of water was added dropwlse 48~ aqueous hydrofluoric acid until the m1xture was acidic. After stirring an additional 0.5 hour the slurry was poured into a column. The column was drained and the resln washed with a solution containing 15 ml. o~ 48% aqueous hydrofluoric acid in 185 ml. of distilled water. The resin was then washed with dlstllled water untll the eluate was weakly acidic, and then successlvely with 20~, 40%, and ~0~ aqueous methanol and ~inally with absolute methanol until the eluate was neutral. To the top of this column o~ ion exchange resln now in the fluoride orm was added a solution containing 0.~5 g. (o.ooo365 mole) :
Or 1,10-bis-[4-heptylamino)-1-pyridinium]decane dibromide ln 1 ml. of methanol. Five fractions of 15 ml. each were i:
collected. The first three ~ractions were comblned and evaporated to dryness under reduced pressure. The oily resldue was dissolved in a mixture of toluene and ethanol and the resulting solutlon evaporated to dryness under reduced pressure. The residual oil was redlssolved in a mixture Or benzene and acetone and the solution concentrated to a small volume. The solid which separated was collected by filtration and dried 24 hours at 24C./0.1 mm. to give 0.11 g. of lmpure 1,10-bis-[4-(heptylamino)-1-pyridinium]-decane dlfluoride, m.p. 85-goc.
:
' '' , ' ' ' ' : :
, ~ :
::
.~ . . . . . . . .
3'~3 Example 29 A. A solld mixture containlng 115 g. (0.5 mole) Or N-(4-pyridyl)pyridinium chloride hydrochloride and 119 g.
(o.6~ mole) Or n-nonylamine hydrochloride wa~ heated in an oil bath up to a bath temperature Or 220C. (internal tem-perature Or 190-194C.) and the resulting liquid was stirred at that temperature ~or 2 hours. The reactlon mixture was then cooled to 80C., 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 sulfate, t~eated wlth decol~riz-ing carbon, ~iltered and evaporated to dryness under reduced pressure. The residual viscous oil was cooled to -78C.
and triturated with ether. The resulting solid was coll,ected by ~iltratlon and wa~hed with cold ether. The filtrate . ~ , sfforded a second crop of solid. The combined crops were redissolved in chloroform and the resulting solution treated wlth decolorlzing carbon and riltered. This was repeated once more and the riltrate was then evaporated to dryness under reduced pressure. The residual semi-solid was tri-, turated with ether and cooled to give a nearly colorless solid which was collected by filtration, washed with cold ether and bried. The solid was taken up ln chloro~orm and the resulting solution treated with decolorizing carbon~
riltered and evaporated to dryness under reduced pressure.
Cooling the seml-solid so-obtained and trituration with ether arforded a colorless solld which was collected by ~lltration, washed with cold ether and drled to glve 51,7 g.
o~ 4-(nonylamlno)pyrldine, m.p. 59-60C. The flltrate ar~orded a second crop of 11.6 g., m.p. ~-57C.
., .
. . _. ... ... _... .
B. Alternatively 4-(nonylsmlno)pyrldine was prepared as ~ollow~': A mixture containlng 39.5 g (o.42 mole) of 4-aminopyrldine, 175 g. ~1,24 moles) o~ nonyl aldehyde, 5.0 g. of 10% palladium-on-carbDn hydrogenation catalyst and sufflcient absolute ethanol to give a total volume Or - 600 ml. was warmed and hydrogenated under an lnltial 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 pres~ure. The resldual oll was then vacuum dlstilled to remove any nonyl alcohol which may ha~e been produced. A
raction boiling at 63-64C./4~5 mm. was collected and ,set ~, aside... The resldue was triturated with ether and cooled at -78C. The solid which precipitated was collected by filtratlon and washed wi~h cold ether. This product was di~solved in chlorofDrm, the resulting solution treated with decolorizing carbon, filtered and the filtrate evaporated `` to d~yness, ~he resldue was triturated with ether and cooled to -78~. The solid thus-obtained was collected by flltration, washed with cold ether and air-dried to glve 27.0 g. of 4-(nonylamino)pyrldlne, m.p. 57-59C.
C. A stiFred suspenslon of 11.0 g. (0.05 mole) of 4-(nonylamlno)pyrldlne ln 150 ml. of acetonltrile was warmed untll a clear homogenous solutlon was obtalned. To this clear ~olutlon was added dropwise a solution contalning 6.8 g, ' !
(0 025 mole) Or 1,8-dibromooctane ln 50 ml. of acetonltrile ;.
; and the resulting mixture heated 19 hours under reflux durlng which time a solld precipltated ~rom solution. After coollng, the solid was collected by rlltration, redissol~ed in methanol, the resulting solutlon treated wlth decolorizlng carbon, , .
.i~ , .: , _ ,, - __._ ,. . . .... ... ... . .
.,',~ .
.. . .
, . .
, . , : .
, t~
filtered and evaporated to dryneas under reduced pressure.
Trlturation o~ the resldual oil wlth ether containing a small amount of acetonltrlte produced a colorlesa crystalllne solld which was collected by filtratlon and drled to glve 15.5 g. of 1,8-bis-[4-(nonylamlno)-I-pyridlnlum~octane dlbromide~ m.p. 178-179C.
Example ~0 Following a procedure similar to that described ln Example 29CIb~t employing ~.54 g. (o.026 mole) o~ 4-(propylamino)pyridlne and 3.90 g. (0.013 mole) of 1,10-dibromodecane there was obtained 5.19 g. of l,10-bls-[4-(propylamino~-1-pyridinium]decane dlbromide, m.p. 206-207C.
Example 31 Followlng a procedure slmilar to that described ln Example Z9C but employlng 14.24 g. (0. o8 mole) of 4-(hexylamino)pyrldlne and 9.20 g. (0.04 mole) of 1,5-dibromopentane there was obtained following recrystall~za-i tion from acetonitrile-acetone 12.3 g. o~ 1,5-bls-[4-(hëxylamino)-l-pyrldinium~pentane dibromlde, m.pO 155-156C.
Example 3?
Following a procedure similar to that descrlbed in Example 29C but employlng 10.7 g. (o.o6 mol~) o~ 4-(hexylamlno)pyrldlne and 8.2 g. (0.03 mole) o~ 1,8-dibromo-octan~ there was obtalned 16.~ g. o~ 1,8-bls-[4-(hexylamino)-l-pyridlnlum~octane dlbromide, m.p. 180-181C.
` ..
_ . _ . _ . ~ ..... . _ ... .. , _ .. , . , .
Example 33 Following a procedure slmllar to that described in Example 29C but employing 12.5 g. (0.07 mole) of 4-~hexylamino)pyrldlne and 10.5 g. (0.035 mole) of 1,10-dlbromodecane there was obtalned 16.0 g. o~ l,10-bl3-[4-(hexylamino)-1-pyridinium~decane dibromide, m.p. 148-49C o Example 34 Following a procedure similar to that described in Example 29C but employing 13.4 g. (o.o76 mole) of 4-(cyclohexylamino)pyrldine and 8.2 g. (0.03~ mole) of 1,4-dibromobutane there wa~ obtained 18.2 g. of 1, 4-bis-[4-(cyclohexylamlno)-l-pyrldlnlum]butane dlbromide, m.p. 288-290C.
, .
Exam~ 3~
Followlng a procedure simllar to that described in Example 29C but employing 13.4 g. (o.o76 mole) of 4-. , .
(cyclohexylamino)pyridine and 8.75 g. (o.038 mole~ Or 1,5-dibromopentane there was obtained 19.0 g, o~ 1,5-bis-[4-(cyclohexylamino)-1-pyridlnium]pentane dibromide, m.p.
255-256C.
Example 36 Following a procedure similar to that descrlbed in Example 29C but employing 13. 4 g. ( O. o76 mole) o~ 4-(cyclohexylamino)pyrldlne and 9.3 g, (o.038 mole) of 1J6 dibromohexane there was obtained 19.1 g. Or l, 6-bis-~4-(cyclohexylamino)-l-pyridlnium]hexane dlbromide, m.p. 307-308C.
. . .
; ' ,.; - . . .
, .
.~ , . .
. . .
~:3L~t';3~3~
~xample ~7 Following a procedure ~imilar to that descrlbed ln Example 29C but employing 13.4 g. (0.076 mole) o~ 4-(cyclohexylamino)pyridine and 9.8 g. of (o.o38 mole) o~
1,7-dibromoheptane there was obtained 2001 ~IOr l~,-bi~4-~clo-hexylamino)-l-pyridinium]heptane dibromide3 m.p. 311-31~C.
Exam~le_38 Following a procedure similar to that described ln Example 29C but employing 13.4 g. (oOo76 mole) o~ 4-(cyclohexylamino)pyridine and 10.~4 g. (o.038 mole) of 1~8-dlbromooctane there was obtained 19.1 g. Or l, 8-bis-[4-(cyclohexylami~o)-l-pyridinium]octane dibromide, m.p. 270-271Co Example ~9 ~ 15 ~ollowing a procedure ~lmilar to that described`~ ~ ln Example 29C but employing 1~.4 g. (o.o76 mole~ o~ 4-~ (cyclohexylamino)pyridine and 10.8 g. (o.o~8 mole) o~ 1,9-- ~ dibromononane there was obtalned 16.3 g. of 1,9-bls-[4-(cyclohexylamino)-l-pyridinium~nonane dlbromide, m.p. 149-151C.
Example 40 Following a procedure simllar to that described i ~ in Example 29C but employing 1~.4 g. (o.076 mole) of 4-(cyclohexylamino)pyridine and 11.4 g. (o.038 mole) Or l,10-di~romodecane there was obtained 19.0 g. of l,10-bis-[4-(cyclohexylamlno)-1-pyridinium]decane dibromlde, m.p.
226-227C.
,................................................................... .
.,',. .
.,.i , , . .
.. ,., .. . . - , --- --~
.. . . . , . ,. : ~, : .
'~7 ~
Example 41 A. A mixture containlng 298.0 g. (1.3~ moles) of N-(4-pyrldyl)pyridlnium chloride hydrochlorlde and 322 g.
(2 moles) of 2 ethylhexylamine hydrochloride wa~ heated 2 hours wlth stirrlng ln an oll bath at a bath temperature of 215Co The mixture wa~ cooled to 60C., dlluted wlth 500 ml~ of water and kept cold by the addltlon of lce while being made alkallne with 35% aqueous sodlum hydroxlde.
~he alkallne mlxture was ex'r~cted wlth ether and the ethereal extracts were dried o~er anhydrous sodium sulfate and evaporated to dryness. ~he resldual oll wa~ dlstilled under reduced pres~ure to give 101.0 gD of 4-(2-athylhexylamlno)pyrldine b.p. 145-150C./0.9 mm.
B. Alternati~ely 4-(2-ethylhexylamlno)pyridlne W8 S
prepared as follows-~o a stirrad solutlon contalnlng 800 g. (8.4 moles) of 4-aminopyridlne and 1500 ml. of trlethylamlne ln 6.4 1.
of dichloromethane there was added ov~r 3 hours a solution containlnz 1610 g. ( lOo O mole~) of 2-~thylhexannyl chlorlde in 1.6 1. of dichloromethane. ~hrou~hout the addition the temperature wa~ malntalned at 15C. When the addltion was compl~e the mlxture was warmed on a steam bath 2 hourn.
After coollng the reactlon mixture was washed thoroughly with water9 dried over anhydrous sodlum sulfate, t~eated wlth decolorizlng carbon and flltered. Evaporation o~ the ril-trate afforded 1843 g. of N-(4-pyrldyl)-2-ethylhexanamide.
To a mixture contalning 100 g. (2.6~ moles) of lithlum aluminum hydrlde ln 2 l. of tetrahydro~uran was added at a sufflcient rate to maintaln gentle reflux a , -`'. , .. . ..
solution contalnlng 570 g. (2.62 moles) Or N-(4-pyrldyl)-?-ethylhexanamide in 4 1. of tetrahydrofuran. When the addl-tion was complete (approximately 3 hours) the reaction mlx-ture was heated under reflux 7 hours. After coollng, the mixture was treated ~uccessively with 100 ml. of water, 100 mlO of 5% aqueous sodlum hydroxide and 300 ml. of waterO The solids were removed by filtratlon and the sol-vent was eva~orated from the filtrate under reduced pressure.
The residual oil wa~ combined with the product of a dupll-cate run ~nd vacuum distllled to glve 837 g. of 4-(2-ethylhexylamlno)pyridine bop~ 135-160Co/0~2 mm.
C0 ~o a stirred, warm solution containlng 1003 gO
, . .
(0005 mole) of 4-(2-ethylhexylamino)pyridlne ln 50 ml.-of acetoni'rlle was added dropwise a solutlon containing 8.2 g.
(00025 mole) of 1312-dibromode^ane in 170 mlO of acetonitrile ;~: and the resulting mlxture was heated 20 hour~ under refluxO
:.
Upon cooling to 0C0 a first crop of product precipltated ;- and ~a~ collected by filtrationO E~aporatlon of the filtrate and trituration of the residue ~ith ether af~orded a second cropD ~h~ combined crops were dissolved in methanolD the result1ng solution treated with decolorizing carbon3 ~iltered , . . .
; and the fiïtrate evaporated to dryness under reduced pressure.
'l The residual oil was cooled and triturated with ether to give a slightly discolored solid. Recrystallization from acetonitrlle-ether followed by trituration of the product with ether rollowed by acetonltrile afforded, after drying '~l 72 hours under ~acuum at 60C., 14D7 gD of 1,1~-bis-[4-~2-~ ethylhex-~lamino)-l-pyridinium]dodecane dibromide as colorless i granules, ~.p. 146-147C.
,...
,...
~ 41-.,j,~ .
~" .
~.-,j, ..
~,,!. ,, ~"~' ' ' - ~ ' ' " "', '7;~1'31~
Example 42 A. A mixture containing 353.5 g. (1.72 mole) of 4-(2-ethylhexylamino)pyridine and 205 g. (o.86 mole) of 1J12 ; dichlorododecane was heated to 120C. The heat source was removed and the temperature of the now exothermic reaction continued to rlse to 180-190Co When the temperature dropped to 1~5~C. one liter of acetonltrile was care~ully added and the mixture heated under reflux to give a clear - solutionO ~he hot acetonitrile solution was comblned wlth similar solutions from two other runs, treated wlth decolorizing carbon and filtered. The flltrate was cooled and the precipltated product was collected by flltratlon and washed with cold acetonltrile. Two recrystallizations from acetonitrile af~orded 970 g, Or 1,12-bis-[4-(2-ethyl-hexylaminG)-l~pyridinium]dodecane dichloride, m.p. 168-171C.
1 Bo Alternatively, by following a procedure slmilar i~ to that described in Example 2 but employing 3.0 g. (0.00405 1 .
mole) of 1912-bis-[4-(2-ethylhexylamino)-l-pyridinium]
~ dodecane dibromide there was obtained 2 0 gO of the corres-;~ 20 ponding dichloride, m.p. 172-17~C.
Example 43 Following a procedure similar to that described in Example 4lC but employing 10.3 g. (0.05 mole) Or 4-(octylamino)pyridlne and 6.45 g. (0.025 ~ole) o~ 1,7-;~ 25 dibromoheptane there was obtalned 14.85 g. of 1,7-bis-[4-(octylamino)-l-pyridlnium]heptane dibromide, m.p. 129-131C.
.
.
.
..... ~,,, Example 44 A. Following a procedure similar to that described in Example 41C but using 11.1 g. (0.054 mole) of 4-(octyl-amino)pyridine and 7.72 g. (0.027 mole) of l,9-dibromononane there was obtained 17.0 g. of 1,9-bis-[4-(octylamino)-1-pyridinium]nonane dibromide, m.p. 117-119C.
B. The corresponding dichloride prepared according to the procedure of Example 2 had a m.p. 161-162C.
Example 45 Following a procedure similar to that ~escribed in ~ 10 Example 41C but employing 10.3 g. (0.05 mole) of 4-(octylamino)-f',' ~ pyridine and 8.2 g. (0.025 mole) of 1,12-dibromododecane there was obtained 15.2 g. of 1-,12-bis-[4-(octylamino)-1-pyridinium]dodecane dibromide, m.p. 119-120C.
Example 46 Following a procedur~e similar to that described in Example 41C but using 5.8 g. (0.028 mole) of 4-(octylamino)-~I pyridine and 5.0 g. (0.014 mole) of 1,14-dibromotetradecane there was obtained 9.3 g. of 1,14-bis-[4-(octylamino)-1-pyridinium]tetradecane dibromide, m.p. 113-115C.
~; 20 Example 47 Follow1ng a procedure simolar to that described in Example 41C but employing 11.0 g. (0.05 mole) of 4-~nonylamino~-pyridine and 6.1 g. (0.025 mole) of 1,6-dibromohexane there was obtained 15.2 g. of 1,6-bis-[4-(nonylamino)-1-pyridinium]-~1 25 hexane dibromide, m.p. 152-154C.
"; ~ ~ ' .
~ -43-,.. :
5'l'~ ~
. .
?
... ~ .
. ' " -~ ' - ~ , .
.. ': ~ . , .
'.-, ' : . ' ' ' ' . ~ .
' ', ~ : ' ' ' . '~ " ; , , ' ' ' ' ' Example 48 .
Following a procedure slmllar to that described in Example 4 but employing 6.5 g. (0.0095 mole) o~ l,6-bls-~4-(nonylamino)-1-pyrldinium]hexane dibromide there was obtained 4095 g. of the correspondlng dichlorlde, m.p. 194-195C.
.
Example 49 Followlng a procedure simllar to that described ln Example 41C but employing 8.8 g. (0Oo4 mole~ Or 4-(nonylamino)pyrldlne and 5.2 g. (0.02 mo'e) o~ 1,7-dibromo-: heptane there W3S obtained 12.2 g. o~ 1,7-bls-[4-(nonyl-~ amlno)-l-pyrldlnium]heptane dlbromide, m.p. 132-134C.
"
Example 50 '?'' Followlng a procedure similar to that described ln Example 41C but employing 11.0 g. (0.05 mole) of 4-(nonylamlno)pyridine and 7.15 g. (0.025 mole) o~ 1,9-dibromoncnane there was obtalned 15.7 g. o~ l,9-b1s-~4-(nonylamlno)-l pyridinium3nonane dibromlde, m.p. 121-122C.
Example 51 ~ollowing a procedure similar to that described ~; in Example 41C but employing 11.0 g. (0.05 mole) of 4-~ (nonylarnlno~pyridine and 7.5 g. (0.025 mole) o~ 1,10-;~ ~ dibromodecane there was obtained 15.63 g. of 1,10-bis-[4-;.. . .
(nonylamlno)-l-pyridlnium]decane dibromide, m.p. 172-173~C.
; 25 Exam~ 52 j~ Following a procedure slmilar to that described ln Example 41C but employing 10.~12 g. (o.o46 mole) o~ 4-, '';
.:
., . ,~ ~.. . .. .. ..
~ " ~
~ 3~ ~
(nonylamino)pyridine snd 7.54 g. (0.023 mole) of 1,12-dibromododecane there was obtained 16.4 g. o~ 1,12-bis-[4-(nonylamino)-1-pyridinlum]dodecane dibromide, m.p.
105-106C.
Example 53 To a stirred, warm solution containing 12.4 g.
; (o.o6 mole) of 4-(2-ethylhexylamino)pyridine ln 100 ml.
Or acetonitrile was added dropwlse-a solution containing 6.9 g. (0003 mole) of 1,5-dibromopentane in 25 ml. o~
10 acetonitrile and the resulting solution heated 20 hours under reflux. The reaction mixture was cooled and diluted wlth ether until slightly cloudy. Further cooling and , ~ stlrring a~rorded a solid precipitate whlch was collected l by flltration and washed wlth~a cold mixture of acetonltrile 15 and ether~ The sslid thus-obtslned was dissolved ln ethanol and the resulting solution treated wlth decolorizing carbon and filtere~. Evaporation o~ the filtrate provided a pale ~ yellow vlscous oll which was crystallized from aceto-3~ nitrile-ether. The resulting solid was collected by 20 ~iltration~ washed with cold acetonitrlle-ether and dried 24 hour~ under vacuum at 90C. to give 13.6 g. or 1,5~bis-4-(2-ethylhexylamino)-1-pyridinium~pentane dibromide, m.p, 150-151C.
;r: Example 54 ,~
`l~ 25 Following a procedure similar to that described ln Example 53 but employing 12.4 g, (o.o6 mole) o~ 4-(2-ethylhexylamlno)pyrldlne and 7.3? g~ ( o. 03 mole) of 1,6-dibromohe~ane there was obtained 16.1 g. of 1,6-bis-[4-(2-ethylhexylamino)-l-pyridlnium]hexane dlbromldeJ m.p. 208-209C.
`` -45-.`"', . . - . ~-.. - .. . - . .. .. ; , - ~ - . :
.: , . .. s...................... . ..
-: . . : : , ";;.. ;, . .
I.07;~9~1 Example 55 Followlng a procedure 61milar to that descrlbed in Example 53 but employlng 12.4 g. (0. o6 mole~ of 4-(2 ethylhexylamlno)pyrldlne and 7.75 g. ~0.03 mole) o~ 1,7-dlbromohept~ne there was obtained 17.9 g. o~ 1,7-bls-~4-(2-ethylhexylamino)-1-pyrldinium]heptane dlbromlde, m.p.
~ 219-220C.
.~,';.
Example 56 Followlng a procedure slmilar to that described ln Example 53 but employing 12.4 g. ( o. o6 mole) of 4-(2-ethylhexylamlno)pyridine and 8.2 g. (0.03 mole) o~ 1,8-dlbromooctane there was obtalned 15.9 g. o~ 1,8-bl~-~4-(2-ethylhexylamlno)-1-pyrldlnium~octane dlbromlde, m.p.
160-161G.
; 15 ExamPle 57 ~, .
Followlng a procedure similar to that descrlbed ln Example 5~ but employlng 12.4 g. (o.o6 mole) o~ 4-(2-. , .
ethylhexylamlno)pyrldine ~nd 8.6 g. (0.03 mole) of 1,9-dibromononane there wa~ obtalned 15.2 g. o~ 1,9-bis-(~-(2-othylhexylamino)-l-pyridlnlum]nonane dibromide, m.p. 158-159C, ; Example 58 Followin~ a procedure slmilar to that described ln Example 53 but employing 12.4 g. (0. o6 mole) o~ 4-(2-` 25 ethylhexylamino)pyrldlne and 9.0 g. (0.03 mole) o~ 1,10-!'`, dlbromodecane there was Gbtained 17.4 g. o~ 1,10-bls-~4-(2-ethylhexylamino)-1-pyridinlum]decane dlbromlde, m.p.
` 162-163C. -46-,' '' ' ''"'.
Example 59 Followlng a procedure slmilar to that de~crlbed ln Example 2 but employlng 5.0 g. of 1,lo-bls-L4-(2-ethyl-hexylamino)-l-pyridinlum]decane dibromlde there was obtained 4.11 g. of the correspondlng dlchlorlde, m.p. 191-192C.
:
Example 60 To a stirred warm solution containlng 12.0 g.
(oOo6} mole) of 4-(heptylamino)pyrldlne in 100 ml. of acetonltrile there was added dropwise a solutlon contalning 7.4 g. (0.032 mole) of 1,5 dlbromopentane ln 25 ml. o~
acetonitrile and the resulting mixture heated 19 hours , . . .
under reflux. The reactlon mlxture was cooled in lce and .: ether was gradually added untll a colorles solid preclpi-~; tated. ~h~ solid was collected by filtratlon recrystallized ~rom acetonitrile-ether and dried 48 hours at 90C./lmm.
~ to give 1509 g. o~ 1,5-bis [4-(heptylamino)-1-pyridlnlum]-; pentane dlbromlde, m.p. 15~-154C.
Example 61 , ;
Following a procedùre slmilar to that descrlbed ln Example 60 but uslng 19.2 g. (0.1 mole) of 4-(heptyl)-amino)pyridine and 12.2 g. (0.05 mole) of 1,6-dlbromohexane there was obtained 27.5 g. of crude product. Recry alllza-t~on of a 15-gram sample from acetonltrlle-eth~r afforded '! 11.45 g. o~ 1,6-bis-~4-(heptylamlno)-1-pyridinium]hexane l 25 dibromlde, m.p. 149-150C.
. . .
!
,,' . .
. .
, . : .
,. . .
~.~'7~
Example 62 ; A~ A suspen~lon Or 24.0 g. o~ crude l,6-bl~-[4-(heptylamlno)-l-pyridinlum]hexane dibromlde in 500 ml. Or water was made alkallne wlth 3N aqueous sodium hydroxide and extracted with chloroform. The chloroform extracts were dr~ed over anhydrous sodium sulfate and evaporated to dryness under reduced presBure. The residual oil was dlssol~ed ln methanol and the resulting solution acldifled wlth methane-sul~onic acid and evaporated to dryness under reduced pressure. The residue was redissolved in methanol, treated with decolorlzlng carbon, filtered and svaporated to dryness under vacuum leaving an oily residue which upon trituration with ether ~ollowed by acetonitrile provlde 18.2 g. of gummy ~olidO The crude solid was dissolved in water and the resulting solution made alkaline with ~5~ aqueou~ sodium hydroxide and extracted wlth chloroform. The chlorororm extracts were dried over anhydrous sodium sulfate and ,, .
evaporated to dryncss under reduced pressure. The resulting solld was triturated successively with ether and scetonitrlle, collected by ~iltration and dried to give 16.~ g. o~ tan solld, m.p, 105-108C. The solid ~o-obtained was dis~olved in lO0 ml. o~ m~thanol and the resulting solutlon acidlfied wlth methanesul~onic acld. Evaporation to dryness under reduced pressure produced a vlscou~ oll which was t~ken up in 20 ml. Or mekhanol and treated portionwlse with 150 ml.
o~ water. ~he resulting suspenslon was cooled ln ice and the suspended solld was collected by filtration and washed wlth cold water. ~he sOlid wa~ then slurried ln hot acetoneJ
cooled, coll~cted by filtrationg washed wlth cold acetone ., .
and dried 48 hours at 95C./1 mm. to glve 10.8 g. Or tan solid, m.p. 163-165C. This product ~ave a posltlve chlorlde .~
lon test wlth sllver nltrate and the nmr spectrum thereof indlcated the absence of the methanesulfonate group.
B. A suspenslon of 14.0 g. of 1,6-bis-~4~(hep'ylamino)-pyrldlnlum]hexane dlbromide ln 500 ml. of water was made alkaline with 35% aqueous sodium hydroxide and extracted wlth chloro~orm. The chloroform extracts were dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The partially solld resldue was dissolved ln 1 lo of acetonitrile-benzene and the resultlng solutlon evaporated to dryness under vacuum. This proce 3 S was :, . i i repeated three tlmes. The ~inal residue was dissolved in 50 ml. o~ acetonitrile and the resulting ~olution diluted ;~
wlth 50 ml. of benzene and cooled in ice to give arter ~lltering and drying 5.3 g. o~ tan solid. The filtrate a~forded a second crop o~ 4.B g. The crops were comblned . ,.
~ and dlssolved ln 50 ml. Or acetonltrlle. Dilu~ion with .
eth@r preclpltated a solld which was collected by flltratlon ' 20 and dried 48 hours at 95C./1 mm. to give 8.85 g. o~ tan solld, m.p. 174-176C. Thls product also gave a posltlve .
chlorlde lon test wlth sllver nitrate.
C. The products o~ parts A and B above were combined, mixed wlth ~00 ml. of water and heated unt~l a homogeneous solution was obtained. The solutlon was ~lltered and the ~i~trate treated wlth 50 ml. o~ 12N hydrochloric acid. The resultlng suspenslon was concentrated under reduced pressure and the resldue was treated with ice. The solld so-produced was collected by riltration, washed wlth cold water and drled. The product was then dissolved ln acetone, the result-lng solutlon diluted wlth a mi~ture o~ benzene and ethanol, . ~ ' . `~
.
, : . '- ~ : -~7 ~
and the whole evaporated to dryne3s under vacuum. The solld residue was slurried in 100 ml. Or acetone and the ~lurry diluted with ether and flltered to glve after drylng 48 hours at 105C./1 mm. and 72 hours at 115C./1 mm. 16 ~ g.
of crude 1,6-bis-[4-(heptylamino)-1-pyridlnlum]hexane dichloride as an or~-white solid, m.p. 176-17!8C.
.
Exam~le 63 Following a procedure slmllar to that descrlbed in Example 50 but employing 10.30 g. ~0.050 mole) of 4-(2-ethylhexylamlno)pyrldlne and 5,4 g. (0.025 mole~ o~ 1,4-dibromobutane there was obtained 1~.9 g. Or 1,4-bls-[4-(2-ethylhexylamino)-1-pyridlnium]butane dibromide, m.p.
245-246C.
Example 64 A. A mixture containing 229 g. (1.0 mole) o~ N-(4-pyridyl)pyridlnium chloride hydrochloride and 244 g. (1.26 moles) of n-decylamine hydrochloride was stirred and heated approximately 2.5 hours at 190-195C. The reaction mixture was then allowed to cool slowly to 40~C. and diluted wlth 2 1. o~ 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 riltration and washed with cold water.
Thls materlal was dissolved in 1 1. Or chloro~orm and the resulting solution was treated with decolorizing carbon and rllt~red. The riltrate was evaporated under reduced pressure and the residue was triturated with 150 ml. Or ether. The solld thus-obtained was redlssolved ln chloroform and the .,;~
~, .
resultlng solutlon treated with decolorlzing carbon and ~lltered. The ~lltrate was agaln treated with decolorizlng carbon and filtered. The ~iltrate was evaporated to dryness under reduced pressure and the resldual sol1d wa~ trlturated wlth ether. Recrystalllzatlon ~rom acetonltrlle af~orded a~ter drying under vacuum 96.~ g. of 4-(decylamino)pyrldlne, ~m.p. 71~73C.
B, To a stlrredl warm solution contalnlng 12.2 g.
(0.052 mole) of 4-(de~ylamlno)pyrldlne ln 150-170 ml. of acetonltrlle was added dropwlse a ~olutlon contalnlng 6c35 g.
(o.026 mole) o~ 1,6-dlbromohexane in 60 ml. of ac~tonltrlle and the resulting mixture heated approximately 20 hours under re~luxc The reactlon mlxture was then cooled ln lce and the precipitated solid was collect~d by flltratlon and wa~hed with cold acetonltrile. The product thus-obtained was dl~solved ln methanol and the resul~lng ~olution treated with decolorizing carbon and ~lltered. The ~lltrate was ~vaporated to drynesa under reduced pres~ure and the residue wa~ triturated with 50 ml. of cold ether, collected by fll-' 20 tratlon and drled 2 days over phosphorus pentoxlde at 70C./
0.1 mm. to glve 14.6 g, o~ 1,6-bis-~4-(decylamino)-1-pyridiniumJ
hexane dlbromlde, m.p. 138-140C.
Example 65 Followlng a procedure ~imilar to that deacrlbed ~ 25 in Example 64B but employlng 12.2 g, (0.052 mole) of 4-- (decylamlno)pyrldine and 6.7 g. (o.026 mole) o~ 1,7-dibromo-hcptane there was obtained 16.0 g. of 1,7-bls-~4-(decylamlno)-l-pyrldlnlumJheptane dibromlde, m.p. 145-147C.
.
;'''' .
."
.',, . ' '. .
o~
Example 66 ~ollowing a procedure similar to that descrlbed in Example 64~ but employing 11.7 g. (0.050 mole) Or 4-(decylamlno)pyridine and 6.8 g. (0.025 mole) Or 1,8-dlbromo-octane there was obtained l~.S g. of 1,8-bis-[4-(decylamino)-l-pyridinium]oct~ne dibromide, m.p. 180-182C~
., .
- Example 67 Following a procedure similar to that described ln Example 64B but employing 11.7 g. (0.050 mole) of 4-(decylamino)pyridine and 7.15 g. (0.025 mole) of 1,9-dlbromononane there was obtained 15.1 g. of 1,9-bis-[4-(decylamino) l-pyridinium]nonane dibromide, m.p. 124-126C.
. , Example 58 ~ Followlng a procedure ~imilsr to that described ;~ 15 in Example 64B but employing 11.2 g. ( o. o48 mole) Or 4-~ (decylamino)pyridine and 7.2 g. (o.024 mole) of 1,10 ;~ dibromodecane there was obtained 14.6 g. of 1,10-bis-~4-~ (decylamino)-l-pyrldinium]decane dibromlde, m.p. 173-174C.
. .:
~ Example 69 , . .
Following a procedure similar to that described ;I ln Example 64B but employing 11.2 g. (o,o48 mole) of 4-(decylamino)pyridine and 7.9 g. (o.024 mole3 of 1,12-!; dibromododecane there was obtained 16.5 g. of 1,12-bis-[4-; (decylamlno)-l-pyridlnium]dodecane dibromide, m.p. 102-106C.
;,,:', ~ ' .,, :
,........................ ..
. . .
~ -52-- .
:, ,.. .
., ~ .
; , : ..
~ . ., ' .
Example 70 To a stirred warm solution contalning 13.6 g.
(0 052 mole) Dr 4-(dodecylamino)pyridine ln 140 ml. of acetonltrlle was added dropwlse a solution contalning 6.34 g. (o.~26 mole) of 1,6 dlbromohexane in 50 ml. Or ; acetonltrile~and the resulting mixture heated under ref-lux overnight. The reaction mixture was cooled and the precl-- pitated solid was collected by filtration. The collected solid was di~solved in absolute ethanol and the resulting ~olution ~reated with decolorizing carbon and ~iltered.
The ~lltrate was evaporated to dryness under reduced pressure a~fording a residual whlte solid which was slurried in , .
ether, collected ~y filtration and drled at 60C./0.1 mm.
to glve 17.63 gO of 1,6-bis-[4-(dodecylamino~-1-pyrldinlum]-;- 15 hex~ne dibromide, m.p. 164-lÇ5C.
Example 71 Following a procedure similar to that described in Example 70 but employing 13.6 g. (0.052 mole) of 4-(dodecylamino)pyridine and 6.71 g. (0.026 mole) Or 1,7-dibromoheptane there was obtained 18.03 g. o~ 1,7-bis-[4-(dodecylamino)-l-pyrldinlum]heptane dibromlde, m.p. 148-150C, ` Example 72 Following a procedure similar to that described ln Example 70 but employing 12.59 g. (o.o48 mole) Or 4-(dodecylamlno)pyrldine and 6.53 g. (0.024 mole) Or 1,8-dibromooctane ~here was obtained 16.18 g. Or l~ 8-bis-[4-(dodecyl8mino)-1-pyridinium]octane dibromide, m.p. 184-185C.
~ . ~ . . , ~ " . - .:
~ ~7;~1R
Example 73 Following a procedure slmllar to that described ln Example 70 but employlng 12~59 gO (o.o48 mole) o~' 4-(dodecylamino)pyridine and 6,86 g. (o.024 moie) of 1,9-dlbromononane there was obtained 19.35 g. o~ 1,9-kls-[4-; (dodecylami~o)-l-pyridinium]nonane dibromlde, m.p. 1~4-135C.
Example 74 ~ollowing a procedure aimilar to that described in Example 70 but employlng 12.59 g. (o.o48 mole) Or 4-~odecylamino~pyridine and 7.2 g. (0.02~ mole) of 1,10-dibromodecane there was obtalned 18.08 g. o~ l,10-bis-[4-(dodecylamino)-1-pyrldinium]decane dlbromlde~ m.p. 178-- 180C.
Example 75 ~ollowlng a procedure simllar to that descrlbed in Example 70 but employlng 11.54 g. (0.044 mole) o~ 4-(dodecylamino)pyridlne and 7.22 g. (0.022 mole) o~ 1,12-dlbromododecane there was obtained 17.68 g. of 1,12-bis-~4-(dodecylamino)-1-pyrldinlum~dodecane dlbromlde, m.p.
75-77C.
. . .
Example 76 A, To a stirred warm solution containing 21.0 gO
(0.102 mole) Or 4-(~-chlorophenylamlno)pyridlne ln 150 ml.
Or N,N-dimekhylrormamide wa~ added dropwise a solution con-~ ?5 tainlng 11.02 g. (0.051 mole) o~ 1,4-dibromobutane in 50 ml.
j o~ acetonltrile and the resultlng mixture was heated 2.5 hourc on a steam bath. The reaction mlxture was cooled to .. ' .
: ~ .
.",,~ , , , ,,,, . - ,....... .
.
,, ., . . ..
.. :
. ~ ~ ' . .-,.. . . . . :
~`-` f~'73~3~i room temperature, dlluted wlth ether and the product allowed to c~ystallize, The preclpltated solld was collected by ~lltration, washed wlth a mlxture of acetonltrlle and ether and alr-drled to glve 27.4 g. of 1,4-bis-[4-(p-chlorophenyl-amlno)-l-pyridinium]butane dlbromide, m.p. 182-189C.
B. A ~uspension of the above product ln 500 ml. o~
water was treated with ice and 2N aqueous sodlum hydroxlde and the resulting mixture extracted thoroughly with chloro-rorm. The chloro~orm extracts were dried over anhydrous sodlum sulfate and evaporated to dryness under reduced pressure to glve 21.0 g. Or the correspondlng anhydro base as an oil ~ich 501idi~ied ~n standing.
C. A solutlon containing the above anhydro base in 2~0 mli o~ methanol was acldi~led wlth a solukion o~ methane-~ - 15 sulfonlc acld in methanol. Evaporatlon to dryness under ; reduced pressure afforded an oil which was crystalllzed from methanol-ether. lThe solid thus-obtalned was recrystalllz-ed ~rom methanol-ether to give a~ter drylng 48 hrs. at 92C./
0.1 mm. 18.95 g. o~ 1,4-bls-[4-(~-chlorophenylamino)-1 pyridinlum]butane dimethanesul~onate, m.p. 245-247C.
- ~ Example 77 A. To a stlrred, warm solutlon contalning 21.0 g.
(0.102 mole) o~ 4-(p-chlorophenylamlno)pyrldlne ln 200 ml.
l Or N,N~dlmethyl~ormamlde was added dropwlse a sol~tlon 1 25 contalning 12.45 g. (0.051 mole) o~ lJ6-dlbromohexane ln 50 ml. o~ acetonitrile and the resultlng mlxture was heated 4 hburs on a steam bath. Upon cooling to room temperature a solid beg~n to preclpitate. The reaction ml~ture was dlluted wlth 150 ml3 o~ acetonltrile and cooled further ln .~ ' .
; ice. The precipitated ~olid was collected by flltratlon and alr-dried to glve 27.2 g. of 1,6-bls [4-(~-chlorophenyl-amino)-l-pyridinium]hexane dlbromide, m.p. 148-150C.
; B. A methanol solution of the corresponding - 5 ;anhydro base prepared from the above dibromide ; according to the procedure of Example 76B wa~ acldlfied with methanesulfonic acld and then evaporated to dryness ; under reduced pressure. The residual oil was crystallized rrom acetone-methanol to give after drying 48 hrs. at 75C./0.1 mm~ 25.2 g. o~ 1,6-bis-[4-(~chlorophenylamino)-l-pyridini~lm]hexane dimethanesulfonate, m.p. 108-110C.
:
Example 78 . , A. To a stirred, warm solution containing 21.0 g.
(0.102 mole) of 4-(p-chlorophenylamino)pyridine in 200 ml.
; 15 o~ N,N-dimethyl~ormamide was added dropwise a solution containing 13.9 g. (0.051 mole) of 1,8-dibromooctane in 50 ml. o~ acetonitrile and the resultlng mixture heated 1.5 hour~ on a steam bath. The reaction mlxture was then diluted with 100 ml. of acetonitrile and heatlng was con-tlnued another 2.5 hours when an addltional 100 ml. o~ aceto-; ' ;l nitrile was added. A~ter heating another 2 hours the re-action mixture was cooled and the solid which had precipitated wa~ collected by ~iltration, washed with a mixture of aceto-nitrile and ether and dried to give ~0.1 g. of 1,8-bls-[4-(~-chlorophenylamino)-l-pyridinium]octane dibromide, m.p.
245-247C~
B. A methanol solution of the corresponding anhydro base prepared ~rom the above dibromlde .
i -56-., ,.;
, j~, . ., ~
,-.. ,........ - . - : :
, . . . . .
. . - .. . - . . . . .. , . . . :, . .
31~
according to the procedure of Example 76B was acldlfled with methanesulronlc acid and then evaporated to dryness under reduced pressure. ~he residual oll was dlssolved in acetonit~lle and the resultlng solutlon treated wlth acetone until cloudy followed by clariricatlon wlth a small amount ~; of methanol and cooled. The crude solld whlch preclpltated - was collected and recrystalllzed from acetonitrlle acetone ; to glve after drying 36 hours at 80C./0.1 mm., 23.5 g. of 1,8-bis-~4~ chlorophenylamino)-1-pyridinlum]octane dime'h~nesul~onate, mOp. 164-165C.
.~
Example 79 A. To a stirred, warm solution containing 21.0 gu (0.102 mole) of 4-(~-chlorophenylamino)pyridine ln 200 ml.
of N,N-dimethylformamide was added drop~ise a solution con-taining 15.3 g. (0.051 mole) of lglO-dibromodecane ln 50 ml.
- of acetonltrile and the resulting mixture W3 S heated 3.5 hours on a steam bath. The reaction mixture was then evaporated to dryness under reduced pressure and the resi-dual oil was crystallized ~rom methanol-acetonitrile. The solld so-produced was collected by filtratlon and washed with a cold mixture of acetonltrile and ether to glve 28.0 g.
of l,10-bis-[4-~p-chlorophenylamino)-1-pyridlnium]decane , dlbromide, m.p. 225-230C.
B. A methanol solution o~ the correspond~ng ~5 anl-l-Jdro base prepared from the above dibromide accordlng to the procedure of Example 76B was acldlfled wlth methanesulronlc acid and then evaporated to dryness under reduced pressure. ~he residual oll was crystallized from "' ' , ' . .
,",,,,1 ' :. ~
.. : ......... .
~cetonitrile-ether. The crude solld thus-obtained was dlssolved ln methanol and the resultlng solutlon was treated with decolorizlng carbon and filtered. Evaporatlon of the flltrate afforded an oil which was suspended ln a mlxture of acetonitrile and acetone to give a crude solid. Recrystalll-zation rrom methanol-ether afforded a~er drylng 48 hours ; - at 95C./0.1 mm. 18.4 g. o~ 1,10-bis-~4-(p-chlorophenyl-~ amino)-l-pyrldlnlum]decane dimethanesul~onate, m.p. 202-; 204C~
Example 80 To a stlrred warm solutlon containlng 10.0 g.
(0.049 mole) of 4-(p-chlorophe~ylamlno)pyrldlne in a mlxture o~ 27~ ml. of acetonitrlle and 100 ml. of N,N-dimethyl-formamlde was add2d dropwlse a solution contalning 5075 g.
(0.025 mole) of 1,5-dlbromopentane ln 25 ml. of acetonitrile and the resulting mlxture heated 24 hours under reflux.
The reaction mlxture was then evaporated to dryne3s under reduced pressure and the resldue triturated with a mixture of ether and acetonltrlle. The pale yellow solld so-obkained was redlssolved ln ethanol and the resulting solution treated with decolorizing carbon and flltered.
,.:, The filltrate was evaporated to dryness under reduced pressure and the resldual oll was crystallized from ether-acetonitrlle.
~;~ The colorless solid was recrystallized from methanol-¢~ 25 acetonitrile and drled 48 hours at 115C./0.1 mm. to glve ;l 8.1 g. o~ 1,5-bis-[4-(~-chlorophenylamlno)-1-pyridinium~-~; pentane dlbromlde, m.p. 166-168C.
.j .
,` . ' .
E~ample 81 To a stlrred, warm solutlon contalnlng 10.0 g.
(0.049 mole) o~ 4~ chlorophenylamino)pyridine in a mix-ture o~ 125 ml~ of N,N-dimethylformamide and 50 ml. Or acetonitrile was added dropwise a solution contalnlng 6.45 g.
; o~ dibromoheptane in 25 ml. of acetonltrile and the resulting mlxture heated 19 hours under re~lux. The reaction mlx~ure was then evaporated to dryness under reduced pressure and the residual oil crystallized from ethanol-acetonitrlle. The solid so-produced was dissolved in methanol and the resulting solution ~re~ted with decoloriz-lng ~arbon:~nd: ~llte.red.:,~ The ~iltr~te was evaporated to ~ryness u~der ~acuu~ and ~he residual Dil agai~ crystallized ~rom ethanol-acetonitrile. The product was collected by ;~ 15 ~lltratlon and-drled 36 hours at 105C.~0.1 mmO to give ~ 10,4 g. o~ 1,7-bls-~4-(p-chlorophenylamino)-1-pyridiniumJ-.
~ h~ptane dibromide, m.p. 202-204C.
.''~ ~ .
Example 82 Following a.procedure slmilar to that described ~0 in ~xample 8} but employlng 10.0 g. (0~049 mole) o~ 4-(p-chlorophenylamlno)pyridine and 7.15 g. (0.025 mole) of 1,9-dlbromononane there was obtalned 11.2 g. o~ 1~9-bis-~4-chlorophenylamino)-l-pyridlnium]nonane dibromide, m.p~
178-179C.
,,~
By ~ollowing procedures simllar to those descrlbed in the ~oregolng e~amples the following bis-[4-(R-amlno)-l-pyrldinium~alkanes are obtained:
; ~
~ ......... . . . .. ... .. .
.~ 3l~
3-~thyl-1,6-bls-[4-(tetradecylamino)-1-pyridinium]-hexane dibromlde by reacting l,6-dlbromo-3-ethylhexane wlth 4-(tetradecylamino)pyridlne whlch ls in turn obtained by reactlng N-(4-pyridyl)pyrldinlum chlorlde hydrochloride with tetradecylamine hydrochloride, 195-bis-L4-(octadecylamlno)-l-pyrldlnium]pentane - dibromlde by reacting 1,5-dibromopentane with 4-(octadecyl-~. amlno)pyridine which in turn ls obtalned by reactlng N-(4-pyridyl)pyrldinlum chloride hydrochloride with octa-` 10 . decylamlne hydrochloride, 1,ll~bis-L4-(2~2-dimethylbutyl~mino)-1-pyrldinlum]-3-methylundecane dibromide by reacting 1,11-dibromo-3-methyl-undecane with 4-(2,2-dimethylbutylamino)pyrldine which ln turn 1B obtalned by reactlng N-(4-pyrldyl)pyrldlnium chlorlde ~:~ 15 hydrochloride with 2,2-dimethylbutylamlne hydrochlorlde, 1918-bl~-[4-(1~4-dimethylpentylamlno?-l-pyridlnium]-octadecane dlbromide by reactlng 1918-dibromooctadecane wl'h 4-(1.94-dim~thylpentylamino)pyridine which in turn ls ~,:
obtained by re~cting N-(4-pyridyl~pyridlnium chlorlde hydro-chloride wlth 194-dimethylpentyl~mlne hydrochlorlde, 4,9-dimethyl-1,12-bls-L4-(1,5-dimethyl-4-ethyl-, . . .
. hexyl~mino)-l-py~ldlnlum]dodecane dibromide by reactlng lJ12-dibromo-4,9~dimethyldodecane with 4~(1,5-dimethyl-4-~i et.hylhexylamino)pyrldine which in turn is obtalned by react-ing N~(4-pyridyl)pyrldinlum chloride hydrochlorlde wlth lg5~
~I dimethyl-4-ethylhexylamlne hydrochlorlde, ,,¦ 1,10-bis-[4-(cyclopentylamino)-1-pyrldinlum~- .
,~, ~i decane dichloride by reacting l,10-dlchlorodecane wlth 4-i ¦cyclopentylamino)pyrldl~e which in turn is obtained by .. . .
O--~, .
~, .
,,, , : ~i ,, .. . ,, ,. . . . . ,, : :. ., . -f~
reacting N-(4-pyrldyl)pyridinium chloride hydrochloride wlth cycl~pentylamine hydrochlorlde, 1,12-bis-[4-(cycloheptylamino)-1-pyridinium]-dodecane dibromlde by reactlng l,12-dibromododecane wlth 4-(cycloheptylamino)pyridine which in turn i9 obtained by reactlng N-(4-pyrldyl)pyridinium chloride hydrochloride with cycloheptylamine hydrochloride, 1,6-bls r [4-(p-bromophenylamino)-1-pyrldinlum]-3-methylhexan.e dibromide by reacting ls 6-dibromo-~-methyl-hexiane wlth 4~ bromophenylamino)pyridine which in turn obtalned ~y reactlng N-(4opyrldy~)pyridlnlun chloride hydrochlo~ide w.th p~bromoaniline hydrochlorlde, l.O10-bi~-[4-(m-fluorophenylamino)-l-pyridinium]-decane dib~omide by reacting l,10-dlbromodecane with 4-(m-~ 15 fluo~opheny-am no)pyridine whlch in turn i~i obtained by r~actlng ~ 54~pyridyl)pyrld~nium chloride hydrochloride with m-~l~oroanlllne hydrochlor de, . 1~4-bis-[4-(~-chloro-4-rluorGphenylamlno)-l-pyridlnlum~-2ethylbutane dlbromlde by reacting 194-dl-bromo-2-ethyibutane with 4-(3-chloro-4-fluorophenylamino)-.:
~ pyridlne which in turn i8 obtained by reacting N-(4-j~ pyridyl)pJridinium chloride hydrochloride wlth ~-chloro-4-. rluoroaniline hydrochloride, lil 1,10bls-[4-(benzylamino)-1-pyridlnium]decane dlchlorlde by reactlng l,10-dichlorodecane with 4-(benzyl-amino)pyridlne, .. 1,8 bi~i~[4-(~4-methylenedioxyphenylamino)-1-pyridiniun]octane dibromide by reacting l,8-dibromooctane . with 4-(~,4-methylenedloxypheny~amino)pyridine which in . -61-. _ . ~ .. .... . . ... ...... . ..
91~
turn ls obtalned by reactlng N-(4-pyridyl)pyridlnium chlorlde hydrochloride with 3J4-methylenedloxyanillne hydrochlorlde, 1,9-bls-[4-(p-ethylphenylamlno)-1-pyrldlnium]nonane dibromlde by reactlng lJg-dlbromononane wlth 4-~p-ethyl-` 5 phenylamino)pyridine which in turn ls obtained by reacting - N-(4-pyr.dyl)pyridinlum chloride hydrochloride with p-` ethylaniline hydrochloride, 1,10-bis-[4-(p-methoxyphenylamino)-1-pyridinium~-decane dichlorlde by reacting lJ10-dichlorodecane wlth : ' 4-(~-methoxyphenylamino)pyridine which is in turn obtainPd , by reacting N-(4-pyridyl)pyridinium chloride hydrochloride ~ . wlth ~-anlsldlne hydrochlorlde, 1911-bis-[4-(m-nitrophenylamino)-l-pyridinium]-undecane dlbromide by reacting lJll-dibromoundecane wlth ~, 4-(m-nitrophenylamino)pyridine whlch in turn is obtained by reacting N-(4-pyridyl)pyridinlum chloride hydrochlorlde wlth m-nitroanlline hydrochlorideJ
~ . 1,12-bis-~4-(o-cyanophenylamino)-1 pyrldlnium]-`~ ~ dodecane dibromide by reacting 1,12-dibromododecane with : 20 4-(o-oyanophenylamino)pyrldine which in turn ls obtained by reacting N-I4-pyrldyl)pyridinium chlorlde hydrochloride , with o-cyanoaniline hydrochlorldeJ
.i 1,16-bis-~4-[m-(trifluoromethyl)phenylamlno]-1-pyrldlniu~hexadecane dibromlde by reacting 1,16-dibromo-hexadecane and 4-Lm-(trlfluoromethyl)phenylamino]pyrldine which in ~urn ls obtained by reacting N-(4-pyrid~l)pyridinium chloride hydrochloride with m-(trifluoromethyl)aniline hydrochloride3 and 1,7-bis-[4-(2-methoxy-~-methylphenylamino)-1-pyridinlum]heptane dlbromlde by reacting 1l7-dibromoheptane ; -~, .. .. .
. ~ ~ . ~, . . . . . . . .
wlth 4-(2-methoxy-5-methylphenylam~no)pyrldlne whtch in turn is obtalned by reacting N-(4-pyrldyl~pyrldlnlum chlorlde hydrochlorlde wlth 2-methoxy-5-methylanlline hydrochlorlde.
The ~ollowing are further illustrative e~amples o~ bls-[4-(R-amlno)-l-pyrldlnium]alkanes o~ fonmula I which are obtalned in accordance wlth the above-de~cribed .
procedures:
3~methyl-1,5-bl~-~4-(undecylamlno)-1-pyridlnlum]-pentane dlbromide, 3-propyl-1,5-bls-[4-(trldecylamlno~
pyridinlum]pentane dichlorlde, 4,4-dimethyl~1,7-~ls-[4-(pen~adecylamino)-l-pyrldlnlum]heptane sul~ate, 2,6-dlmethyl-: 1,7-bis-[4-(hexadecylamino)-1-pyrldlnium~heptane di~ul~a-mate, l-methyl-1,4-bi~-~4-(heptadecylamlno)-1-pyridlnlum-]-butane dlbenzenesulronate, 2~4,4-trimethyl-1,6-bl3-~4-(2-methylhexylamino)-l-pyrldlnium]hexane bls-cyclohexyl~ulfa-mate, l,17-bl6-[4-(3-ethylpentylamlno)-l-pyridlnium]--. heptadecane dlbromlde, 1,16-bis--[4-(1-ethylhe~ylemlno)-1-pyridlnium]hexadecane dlnitr~teJ 1~15-bl~-[4-(heptylamlno)-.
l~pyrl~inlum~pentadecane dibromide, 1,13-bls-C4-(octylamlno)-16pyridinium]trldecane di-2-naphthalenesulfonate, l,ll-bis-~4-(3-ethylheptyl~mino)-1-pyridlnium]undecane 2,.6-; i~
; naphthalenedlsul~onate,-4-me~hyl-1~14-b~s-~4-(2-propylpentyl-` amino)-l-pyridinlum]tetradecane dichlorlde, 5-ethyl-1. 9-bis-: 25 ~4-(1,3,5-trimethylhexylamlno)-1-pyrldinium]nonane dibromlde, ,.
~ 3,3,6,6,-tetramethyl-1,8-bls-~4-(heptylamino)-1-pyridlnium]-octane dlbromide, 2,13-dimethyl-1,14-bis-[4-(1,2-dlmethyl-tetradecylamino)-l-pyrldlnlum]tetradecyl dibromlde, 1,6-bis-~4-(1-methylpentylamlno)-1-pyrldlnlum~hexan~ dl-~-toluene-sulYonate, 1,8-bis~[4-(2-methylheptylamino)-l~pyridinlum]octane ......... , , . ~. .,: .
. . - . . . .
:; - . ' . ' ;. . , ., .. : . ' ~0'~9~ IL
,: , . ..
dliodlde, 1,8-bis-[4-(2-methyl-3-ethylpentylamlno)-1-~ pyrldinium]octane diethanesulronate, 1,9-bis-[4-(o-chloro-; phe~ylamino)-l-pyrldinium]nonane dibromlde, 1,8-bis-[4-(p-lodophenylamlno)-l-pyridlnium]octane dilodlde, 1,12-bis-.: 5 ~4-(2,4 difluorophenylamino)-l-pyridinium]dodecane dibromide, 1,11-bi~-[4-(2,5-dlbromophenylamlno)-1-pyrldlnlum]undecane dlbromide, 1,10-bl~-[4~(3,5-dlchlorophenylamlno)-1-pyrldlnlum]-decane dich'orldeJ 1l8 bis-~4-(2-~luorobenzylamlno)-1-pyrldinium]oe'Giane dichloride, 1,18-bls-[4-(3,4-dichloro-benzylamino)-l-pyridlnlum]octadecane dlbromlde, 1,4~bis-- [4-(4-hydroxy-3-~ethoxybenzylami.no)-1-pyrldlnlum]butane dibromide and 1,12 bis--~4-(4-methylbenzylamino)-1-pyridlnlum]-~ dodecane dibromide.
~ i Example 83 ..,,~:
To a warm, stirred solution containing 11.52 g.
(0.06 mole) of 4-(heptylamino)pyridine in 100 ml. of acetonitrile was added in small portions a solution containing 7.3~ g.
?
: (0.03 mole) of ~ dibromo-~-xylene in 150 ml. of aceto-nitrile. After addition was complete a large mass of ., j . .
j, 20 colorless crystals had separated from solution. The reaction ,ii . mixture was heated under reflux 6 hours. After cooling to ~, roo~. temperature the solid product was collected by filtration, washed with acetonitrile-ether, combined with 3.1 g. of ; product obtained in a pre~lous run and dried 28 hours at ` ~ 25 100C./0.1 mm. to give 22.0 g. of ~,~'-bis-~4-(heptylamino)-pyridinium]-~-xylene dibromide, m.p. 297-298~C.
, . .
.. . ~ -64 ,`
,. . .
.
;.~
.... . .
, ::.. . : .
, j ~ !
.,; i ' . . ' . : .
'. ',' , ~' ~ : ; :
j- ~ ' ' ', ., ' ' '' ~C'~ 311 Example 84 Following a procedure similar to that described in Example 83 but employing 11.6 g. (0.065 mole) of 4-(hexyl-amino)pyridine and 8.7 g. (0.033 mole) of ~,q'-dibromo-p-xylene and refluxing the reaction mixture 20 hours, therewas obtained 19.3 g. of ~,~'-bis-[4-(h~ylamino)pyridinium]-p-xylene dibromide m.p. 313-315C.
E~ample 85 A suspension of 19 g. of 4-aminopyridine and 23 g.
o ~ dichloro-2,3,5,6-tetramethyl-p-xylene in 600 ml. of methanol was heated on a steam bath to effect complete solution. ~.fter filtering from a small amount of insoIuble material the clear solution was warmed gently on the steam bath for 2 hours during which time a white solid began to separate. The mixture was cooled to room temperature and the solid product was collected by filtration, washed ~ successively with methanol and ether and dried 24 hours ; under vacuum at 100C. to give 29 g. of ~,d'-bis-(4-amino-1-pyridinium)-2,3,5,6-tetramethyl-p-xylene dichloride, m.p. >340C.
Example 86 To a hot solution containing 12.5 g. (0.132 mole) of 4-aminopyridine in 100 ml. of 2-propanol was added 11.6 g.
(0.066 mole) of ~,~'-dichloro-~-xylene followed by 400 ml.
of methanol. The mi~ture was heated to effect complete 25 solution. After filtering from a small amount of insoluble material the clear solution was diluted with 500 ml. of , : ~ :
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ethyl acetate and cooled to room temperature. The solld product was collected by fitration, wa~hed with ethylacetate and dried to give 16 g. of q~ bis-(4-amino-l-pyridinium) p=xylene dichloride, m.p. 332-335C.
The following are further illustrative examples of the ~,~'-bis-[4-(R-amino)-l-pyridinium]xylenes of formuia II
which are obtained in accordance with the above-described procedures:
~al-Bis-[4-(ethylamino)-l-pyridinium]-p-xylene dibromide by reacting ~,~'-dibromo-p-xylene with 4-(ethyl-amino)pyridine;
t' . d,~'-Bis-[4-(2-ethylhexylamino)-1-pyridinium]-~-xylene dichloride by reacting ~,a'-dichloro-p-xylene with , ........................................................................... .
4-(2-ethylhexylamino)pyridine (b.p. 145-150C./0.9 mm.) ` 15 which was prepared by reacting N-(4-pyridyl)pyridinium chloride hydrochloride with 2-ethylhexylamine hydrochloride;
'-bis-[4-(decylamino)-l-pyridinium]-p-xylene .,:
dibromide by reacting ~,~'-dibromo-_-xylene with 4-(decylamino)-.,: .
pyridine (m.p. 71-73C.) which was prepared by reacting N-(4-` 20 pyridyl)pyridinium chloride hydrochloride with n-decylamine hydrochloride;
; ~,~'-bis-[4-(dodecylamino)-1-pyridinium]-p-xylene dichloride by reacting ~,~'-dichloro-p-xylene ! with 4-(dodecylamino)pyridine;
:.1 ;~i 2ja,~ -bis-[4-(octadecylamino)-l-pyridinium]-~-li xylene dibromide by reacting ~,~'-dibromo-p-xylene with ,. . .
;, 4-(octadecylamino)pyridine which in turn is obtained by reacting N-(4-pyridyl)pyridinium chloride hydrochloride with octadecylamine hydrochloride;
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a,~ -bis-[4-(tetradecylamino)-1-pyridinium]-m-; xylene dichloride by reacting ~,~'-dichloro-m-xylene with 4-(tetradecylamino)pyridine (m.p. 91-93C.) which was pre-: pared by reacting N-(4-pyridyl)pyridinium chloride hydro-. 5 chloride with tetradecylamine hydrochloride;
bis-[4-(butylamino)-1-pyridinium]-o-xylene dibromide by reacting ~,d'-dibromo-o-xYlene with 4-(butylamino)pyridine;
d,~'-bis-[4-(3-ethylheptylamino)-1-pyridinium]-5-methyl-~. .
IO m-xylene dibromide by reacting a,~'-dibromo-5-methyl-m-xylene with 4-(3-ethylheptylamino)pyridine which in turn is obtained by reacting.N-(4-pyridyl)pyridinium chloride : hydrochloride with 3-ethylheptylamine hydrochloride;
~,~'-bis-[4-(2-methylheptylamino)-1-pyridinium]- ~ -. 15 2,5-dimethyl-_-xylene dibromide by reacting q,~'-dibromo-~ 2,5-dimethyl-p-xylene with 4~(2 methylheptylamino)pyridine : which in turn is obtained by reacting N-(4-pyridyl)pyri-~ dinium chloride hydrochloride with 2-methylheptylamine ;~ hydrochl.oride;
2~ ~,a ~ -bis[4-(octylamino)-1-pyridinium]-2,4,6-trimethyl-m-xylene dichloride by reacting a,a ~ -dichloro-2,4,6-trimethyl-m-xylene with 4-(octylamino)pyridine . IM.P. 62-63~C.) which was prepared by reacting N-(4-pyri.dyl)-pyridin'um chloride hydrochloride with n-octylamine hydro-.~ 25 chloride;
'-bi~-[4-(2,2r-dimethylbutylamino)-1-pyridinium]-2-chloro-p-xylene dichloride by reacting ~,~',2-trichloro-p-xylene with 4-(2,2-.dimethylbutylamino)pyridine ----_._ __ __ ___ .... , . ,.. : .. . .
, . . . . : . . .
,: which in turn ls obtained by reacting N-(4-pyridyl)pyridinium ~ chlori.de hydrochloride with 2,2-dimethylbutylamine hydro-i chloride;
' bis-[4-(methylamino)-1-pyridinium]-4-chloro-o-xylene dibromide by reacting a,~'-dibromo-4-chloro-, o-xylene wi.th 4-(methylamlno)pyridine;
~,4'-bis-[4-(2-propylpentylamino)-1-pyridinium3-; ~,5-dichloro-p-xylene dichloride by reacting ~,a ~, 2, 5-; tetrachloro-p-xylene with 4-(2-propylpentylamino)pyridine " 10 which in turn is obtained by reacting N-(4-pyridyl)pyridiniu~ ' ~' chloride hydrochloride with 2-propylpentylamine hydro-~, chloride;
~; a,d ~ ~~iS- [ 4-(1,1-dimethylundecylamino)-~.-~ pyridinium]-2,3,5-trichloro-p-xylene dlchloride by reacting '' 15 ~,d',2,3,5-pentachloro-~-xylene with 4-(1,1-dimethylundecyl-~: amino)pyridine whi,ch in turn is obtained by reacting N-(4-' pryidyl)pyridinium chloride hydrochloride with 1,1-,.",~ dimethylundecylamine hydrochloride;
.:
~ '-bis-[4-(nonylamino)-1-pyridiniuml-.
2n 2~3~5~6-tetrachloro-p-xylene dichloride by reacting ',2,3,5,6-hexachloro-p-xylene with 4-(nonylamino)pyridin~
... .
.~ (m.p~ 59-60C.) which was prepared by reacting N-(4-pyridyl)-' pyridinium chloride hydrochloride with n-nonylamine hydro--.~ chloride;
: .
~ 25 a,a ' -bi~-[4-(benzylamino)-1-pyridin um~p-xylene ,'u dibromide by reacting ~,~'-dibromo-p-xylene with 4-(benzylamino)-;:' pyridine which in turn is obtained by reacting N-(4-pyridyl)-',' q pyridinium chloride hydrochloride with benzylamine; and, ; .
,' .~ . , ' . .
'7~
~ bis-[4-(benzylamino)-1-pyridinium]-2-chlo~o-p-xylene dichloride by reacting ~,~',2-trichloro-p-xylene with 4-(benzylamino)pyridine which in turn is obtained by reacting N-(4-pyridyl)pyridinium chloride hydrochloride with 5 benzylamine.
The an~ibacterial and antifungal acti~ity of representative examples the compounds of Formula I~w~s determlned ualng a modification of the Autot;ter method described by GOSB, et al. Applied Microbiology 16 (9) 1,414-1941O (1968) in which a 1,000 mcg./ml. solution o~ the test compound i8 prepared. To the first cup of the Autotray is added 0.1 ml. of the test solution. Activation Or the Autotiter initiates a sequence o~ operations by which 0.05 ml. Or the test compound solution ls wlthdrawn from the cup 15 by a Microtiter tran3fer loop and dlluted in 0.05 ml. of ;sterile water. Following thls operation, 0.05 ml. of lnoculated double-strength semisynthetic medlum (glucose) ls added automatically to each cup. The overall operation results ln final drug concentratlons ranging from 500 to 20 o.o6 mcg./ml. in twofold decrements. The Autotray is incu--bated ~or 18-20 hours at 37C. at which time the tray~ are examined visu311y for growth as evidenced by turbidity, and the concentration of the last sample ln the serles ~howlng no growth (or no turbidity) is recorded as the mlnimal ;j,~25 lnhibitory concentration (MIC) in mcg./ml. The compounds were thus tested as solutlons against a variety of gram positive and gram negatlve bacteria including Staphylococcus aureus, Proteus mirabilis, Escherichi~ coli, Klebsiells E~ g Pseudomonas ~ E~ , Streptococcus pyogenes, 3~ and against such fungi as Aspergillus niger, Candida alblcans and Trichoph~ton mentagroph~tesD
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Many of the compounds of formula I were also foundto be antibacterially effective against Streptococcus mutans and Actinomyces A-viscosis.
Virucidal activity of representativ~ 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 tl961) wherein 2 mg. of the,test compound was placed on the surface of~
the growth medium. The compounds corresponding to Examples 3, 5C, 7, 9C, 10, 11, 13, 17, 18, 21, 22, 24, 31, 33, 35, 36, 37, 53, 54, 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 ,, 79B were found inactive.
The dental plaque preYentlve activity o~ certain the compounds Or the present invention was determined 'i~ by measuring the ability Or these compounds to inhibit the productlon o~ dental plaque by Streptococcus mutans OMZ-61 as ~ollows~ ' '2Q A culture medium ~or the plaque~producing Strepto- ' ,' occu~ mut~n~ OMZ-61 containlng 1.5 g. of ~BL beef,extract, L
5 g. o~ sodium chloride, 10 g. Or dehydrated tryptlcase, '-5 g. o~ sucrose and su~iclent dlstilled water to give a ' ~otal volume of 1000 ml. is adJusted to pH 7.0 and ~terilized 'I 25 by membrane ~iltratlon. The medlum is dispensed ~septlcally ', ln 10-ml. ~llquot~ into 150 x 16 mm. test tubes and stored '::
~' at re~rlgeration temperature until used.
Two concentrations Or the compound to be tested '; are prepared by dissolving 100 mg. o~ the compound ln 1 ml.
;
,, 30 Or dlstilled water wlth the aid o~ su~iclent O.lN sodium .
' hydroxide, 10% dlmethylsul~oxide or 10% N,N-dimethyl~ormamlde ; and diluting the resu,ltlng solution to 10 ml. wlth distllled ; -70-~ .
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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 ~namel or synthetic hydroxylapatite is suspended in each concentration of compound for two 1 minute periods, each followed by a l-minute air drying period. Each piece is then suspended and agitated for 5 minutes in individual test ,~, . . .
- tubes containing s~erile distilled water (rinse). They are - 10 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 37~C. for 24 hours. The same !il 15 process of two l-minute soaks in the solution of compound, each followed by 1 minute of air drying and the final 5-minute rinse is repeaked before once again suspending the hydroxlapatite in a fresh tube ~ontaining 10 ml. of beef extract medium and 0.3 ml. of inoculum. At the end of the second 24-hour period, each piece o~ 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, D & C Red No. 3 dye. This staining procedure is used in order to identify more easily the development of plaque ~ . .
after the 48-hour period of exposure to the plaque-producing :: .
organism. The staining period is followed by another 10-second 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 ` 71 ~ ~ ~7~3~31~L
the percent concentration tested. Active compounds are tes~ed 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 be formed at these lower concentrations.
Substantivity of the test compound to the tooth surface which is o~ 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 .1 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, ~5 b~illiant 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.
; -72-. . . . . .
' . . . ' .
, .
7;~3~1 Numerical, antibacterial, antifungal, and dental plaque-preventive test data for the compounds are presented in Table A hereinbelow. Corresponding data for two known compounds, viz. 1,8-bis-(4-amino-1-pyridinium)octane dibromide (Reference Compound I) and l,lO-bis-(4-amino-1-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 56C.~ horse serum (40%) in the test medium.
.
The results are expressed as the fold increase in MIC (mcg./ml.) versus Staphyloccocus aureus and Escherichia coli caused by the presence of serum and are presented -n Table B hereinbelow.
Dental plaque-preventive effectiveness in the presence of sterile human saliva (50%) was determined for xepresentative examples. Test results are read as minimum effective concentration and are presented in Table C hereinbelow.
The acute oral toxicity (ALD~o) of several representativ, examples was determined as follows: Groups of 3 young adult male Swiss-Webster strain albino mice were fasted approximately ~25 4 hours before medication and then medicated once orally by ;stomach tube. All mice were observed for 7 days after .
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medication. Autopsy of all mice in the study revealed no gross tissue changes except for the group receiving 1000 mg./kg. of the compound of Example 25 wherein con-gestion of the glandular portion of the stomachs of two of the three mice was observed. The results are presented in Table D herein~elow.
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TABLE ~ ' Ef~ect of Serum on Bacteriostatic Activity ' ' ' ' , . . .
5: MIC (n~/ml) vs. Indlcated Bacterla .
:: S. ~ureus A~CC 6538 E. Co1l ATCC 8739 ." . _ . . .
Cpd. of % 40$ Fold ~ 4~ . Fold Ex. No. Serum Serum Increase Serum Serum Increa~e _ _._ ..... ~
. . 79~ .25 7.8 32 0.5. 15.o 32 22 0.25 3.9 .1~ 0.5 ~.9 8 ~: 33 0.125 1.95 . 1~ 0.25 3.9 ~ 16 ~ 26 0.125 1.95 16 o.5 7.& lo .. ~ 24 0.125 1.95 16 0.25 7.8 32 58 0.25 3.9 16 0.5 15-~ 32 . 3 0.39 3.12 8 0.7825.0 32 lD 0.195 3.12 16 ¦ 1.5525.0 16 7 0.10 1.56 6: 0.3912.5 ~32 ~ 5C 0.10 3.12 32 :0.782~.0 1 32 ,5'j , ~ , " . 13 . 0.25 ~1.2 1~8 1.0 31.2 32 11 0.~ 7.8 16 : o.5 31.2 64 9C 0.5 7.8 16 ~.o 62.5 64 . 29C 0.5 .7.8 16 3.9 62~.5 16 41C 0.2~ 7.8 32 1.0 62.~ 64 ~' ~ : 83 o.i8 6.25 8 0.78 6.25 84 3.12 12.5 4 ~.56 6.25 il . , ."~
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~ABLE C
Staining Potential and Effect of Saliva on Dental Plaque Preventive Activity ~ Dëntal Plaque -1~ Preventi~e Activity in 50~ saliva Staining C~d. of Ex. No. Minimum Effective Conc. (~ Concentration (%) ~ ~ .
27 0.05 24 Ca. 0.005 0.05 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 0.05 0.005 6 0.005 13 0.005 f , 14 0.~1 0.05 11 0.05 0.05 12 Ca. 0.005 0 05 0.005 0.05 44A 0.005 0.05 47 0.004 29C 0.004 ~I 50 0.004 '' 51 0.004 '~' 49 0.005 ,,,:~ --____ ________________ ; 1. No bacterial growth at this concentration, plaque formed at 0.005~
~, i ~
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'7;39~1 Table D
Acube Oral Toxicity ~LD50) Solution or Dose, mg~kg. of Mortality Cpd. of Ex. No. Suspension Total Ma~erial 24 Hrs 7 Dayfs 23 ,~queous125 ` 0/3 0/3 Solution250 0/3 0/3 ~ . 500 1/3 l/3 :~ 1000 3/3 3/3 ~ 7-Day ALD50 = 625 m~kg .: 26 Suspension 125 0/3 0/3 . ir. 1% G.Tl 250 0/3 0/3:
1000 . 0/3 0/~ .
7 Day ALD50 = ~000 ~g,~kg 27 Aqueous125 0/3 V3 .. Solution250 0/3- 0/3 500 .1/3 V3 ~ , 1000 1/3 3/3 ;~ ~ 7-Day ALD50 = 250 mg~kg .. . .
:j 24 Suspension 125 0/3 . 0/3 in 1% G,T. 250 0/3 0/3 , 500 0/3 1/3 ', 1000 0/3~. 0/3 . 7~Day f~LD50 = ~1000 mg~kg A~ueous250 1/3 1/3 .,: . - Solution500 V3 V3 ~, ~7-Day ~LD = 500 mg~k~
3 Suspension 12S 0/3 0/3 in 1~ G.T. 250 0/3 0~
500 0/3 l/3 -Day ALD50 = 1000 mg~kg ~ .
. 4 Susp~nsion 125 0/3 0/3 ~ . : in 1~ G.T. 250 0/3 0/3 .~ A , 0/3 0/3 ,: : 1000 0/3 0/3 7-Day ALD50 = ~1000 mg~kg :
2 Suspension 125 0/3 0/3 r ~ in l~ G.T. .250 0/3 1/3 . 50 ;, 8 Aq~Jw 125 0/3 ~/3 Solution250 1/3 1/3 sno 2/3 3/3 ;~ 1000 3/3 3/3 . 7-Day ~LD50 = 315 mg/kg -83- ~Cont'd.) ., ,~ , . . .
: ~ ;
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Table D (Cont'd.) :~ Solution or Dose, mg/kg of Mortality Cpd. of Ex. ~o. Suspenslon Total Material 24 Hrs æ Suspersion 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 ALD50 = ~1000 mg/kg -. 6 ~gueous 12e 1/3 1/3 Solution 250 0/3 1/3 : 500 2/3 2/3 ; . 1000 3~3 3/3-7-Day ALD50 ~ 315 mg/kg , ID Suspension 125 0/3 0/3 in 1% G.T. 250 0/3 . 0/3 ';, 1000 2/3 V 3 , 7 Day A~D50 = 750 m~/kg 11 Suspension125 0/3 . 0/3 ! . in 1% G.T.250 ~/3 0/3 ~ 500 0/3 1/3 .l . 1000 0/3 0/3 ~ , 7-Day ALD50 ~ ~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 ALD50 = 750 ~g/kg -9C . . Suspension 125 0/3 0/3 in 1~ G.T. 250 0/3 0/3 500 . 0/3 o/3 ~ 1000 0/3 0/3 `~ 7-Day ALD50 - ~1000 m~/kg ,` . 10 Agueous .125 0/3 0/3 ,,~ Solution 250 0/3 0/3 ` ~ 1000 0/3 0/3 7-Day ALD50 = ~1000 mg~kg ::
1~ - . (Cont'd.) ., ~ : ' . :
.. . . .
. ;'~ . ' :
,~ 84 .. , , ':
;', :' .: '` ' :
7 ~t~ ~ ~
Table D tCont'd.) Solution or Dose, mg/kg of Mortality of Ex. No. Suspensi n Total Material 24 Hrs 7 Days 58 Suspension 125 0/3 0/3 in 1% G.T. . 250 0/3 0/3 1000 - 0/3 ` 0~3 ~ 7-Day AI~5~ 1000 mg/kg .~ .
59 A~ueous125 0/3 0/3 Solution 250 0/3 0/3 : . 50~ 1~3 2/3 7-Day ALD50 = 750 mg~kg 56 Suspension 125 0/3 0/3 - in 1~ G.T. 250 0/3 0/3 1000 1/3 1~3 ; . . 7 Day ALD50 = ~lOoo ms/ks 14 ~ Suspension 125 0/3 0/3 . .in 1% G.T. 250 0/3 0/3 500. 0/3 0/3 7-Day ALD50 = ~1000 mg/kg 44~ Susp~nsion125 Oj3 0/3 in 1~ G.T.250 0/3 0/3 . 500 0/3 0/3 1000 0/3 o/3 7-Day ALD50 = ,~1000 mg/kg .~ ~ 29C Suspension125 0/3 0/3 ; :~ in 1% G.T. 250 0/3 0/3 ~ 500 0/3 . 0/3 '~ . I000 0/3 0/3 : 7-Day ALD50 = ;1000 mg/kg .
41CSuspension .125 0/3 0/3 ~ in 1% G.T. 250 0/3 0/3 `:~ 500 0/3 0/3 . - 7-Day ALD50 =;~1000 mg/kg 1. G.T. = Gum Tragacanth '~1 , ~ .
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Alternatively, the 4-(R-amlno)pyridines are obtained by catalytlc hydrogenation Or a mixture contain-ing 4- a m I` nopyridine and a carbonyl compound contalnlng the appropriate carbon content. The reaction i~ usually carrled out at a temperature Or 50-70C. ln a suitable ~olvent, for example ethanol~ under a hydrogen pressure o~
20-60 psi, in the pre~ence Or a palladium hydrogenatlon catalyst. A hydrogenatlon time of 4-10 hours is generally ~atlsfactory. The use Or a large excess o~ the carbonyl compound, i.e. 200% or greater advantageously results in high yields o~ pure product in a reaction time o~ 5 hours or less. Following removal of the catalyst the product is isolated by evaporation of the solvent and either dlstllling the resldue or cryst~lllzing the latter from a ~ultable solvent.
~".
' Reaction Or an aldehyde having the appropriate ^~ carbon content with 4-amlnopyridine in the presence of ~ormic acid ~t elevated temperatures also provldes the 4-(R-hmino)pyridlnes.
The 4-(R-amlno)pyridines can alio be obtained by acylation o~ 4-~mlnopyridlne with an acyl halide havln~ the appropriate carbon content ~ollowed by reductlon Or the resulting amide. The acylatlon is carried out accordlng to art-recognized methods, for example by reacting 4~amlno-pyrldine with an acyl halide ln an lnert solvent such as methylene dichloride or chloro~orm ln the presence Or an acid acceptor such as triethylamine. The amide so-produced ls then reduced wlth a complex metal hydrlde such as llthlum hydride ln a sultable solvent such as tetrahydroruran ether ; 30 or dloxane and the amine product isolated ln accordance wlth known procedures.
`' .
.. ::~ ....... ....
The disubstituted alkanes having formula IV also used as starting materials generally are known compounds, or if specifically new can be prepared accordiny to ~he procedures ~ used for preparing the known compounds.
.~ . I
The q,~'-disubstituted xylenes having formula V
.
also used as starting materials generally are Xnown compounds, or if specifically new can be prepared according to the procedur~s used for prepâririy ~he kno;:.. ^ompcunds.
. j , .
Thus an appropriate chloro or methyl-substitute~
:
phthalic, isophthalic or terephthalic acid o_ ester is reduced to the corresponding xylene-d,q'-diol with a metal .! ~ ' ' , hydride such as lithium aluminum hydride in a suitable ;~ solvent such as tetrahydrofuran, ether or dioxane. ~The xylene-~,~'-diol so-produced is then converted to an ~,~'-d;.halo~ylene, for example by reaction with hydrogen bromide, ii,, . .
y~ phosphorous tribromide, phosphorus oxychloride, thior.yl chloride or potassium iodide and orthophosphoric acid according .~I , ~ to art-recognized methods. Alternatively, the xylene- a,~' -.",, . ..
diol can be converted to a sulonate ester by reaction ~itn . '~ . ..
; ~ 20 methane-, ethane-, benzene- or p-toluenesulfonyl chloride in the presence of an acid ~cceptor such as pyridine n accordan~e . j, `~ with well kno~!n procedures.
As described more fully hereinbelow the compounds having formulas I and II exhibited in vitro antimicrobial activity against sevexal species of microorganisms among which are in-cluded both gram positive and gram negative bacteria, several .,: . . . .
~l~ species of fungi and Herpes viruses. The compounds are therefore ,~-17-. ~ . . ...
. ~, . . - . . , , , . . . ' indicated 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 ~or 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 ~leaners, disinfectants and protective coverings such as palnts, varnishes and waxes.
The compounds are adapted for ~he above indicated utilities by combining them with conventional diluents or carriers, compa~ible cationic, anionic or non-ionic surfactants, buffering agents, perfumes and coloring agents, and are ~pplied to a surface to be disinfected by conventional methods such as scrubbing, spraying, swabbing, immersion and the like.
For use as skin-cleansing agents the bis-[4-(R-amino)-l-pyridinium~ c ~ ounds 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 kno~n in the art. For example, the compounds can be formulated with any compatible, pharmaceutically acceptable surfactant,preferably a non-ionic surfactant such as the polyoxyethylene polyoxypropylene copolymers described ln U.S. Patent 3,8553140, amine oxlde~ such as stearyl dlmethyl amlne oxlde de cribed ln U.S. Patent 3,29~,14~ and the like or with mlxtures Or the9e. The rormulations may addltionally contaln pharmaceu-tlcally acceptable diluents such as water, lower alkanols -`` 3~ and the llke, aclds, bases, or bur~ering agents so as to ., .
~ ............................................................... ... .................. .. . .. . . . . .
. , , .. . , . . - , .
maintain a pH of 5.0 to 7.5, and, optionally, perfumes and coloring agents. The bis-~4-(R-amino)-l-pyridinium] compounds are generally present in such formulations in a concentration of approximately 0.5 to 2.0 percent by weight, preferably 1.0 percent by weight.
- When prepared as a tincture the bis-[4-(R-amino)-l-pyridinium] 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 about 0.05 to 1.0 percent (w/v) preferably 0.1 percent (w/v).
` Alternatively, the compounds can be formulated in suitable pharmaceutical vehicles for treating bacterial, .i,l ~ 15 fungal and Herpes viral infections for example as lotions, :c~
ointments, or creams by incorporating them in conventional lotion, ointment or cream bases, sach as alkyl polyether alcohols, cetyl alcohol, stearyl alcohol and the like, or as powders by incorporating them in conventional powder bases such as starch, talc and the like, or as jellies, by incorporating them in conventional jelly bases such as glycerol and tragacanth.
They can also be formulated for use as aerosol sprays or foams.
When used for sanitizing and disinfecting inanimate i:~
cl 25 surfaces the compounds can be formulated with known detergents ` and builders such as trisodium phosnhate, borax and the like. The bis-[4-tR-amino)-l-pyridinium compounds are ~; generally present in such formulations in a concentration up to about 10 percent by weight.
~ -19-:''~ .
,' , ; ' .
,~ ' " ~, . . .
,~ , : . ., .
As described in detail h~reinbelow 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 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 anti-calculus agents described in U.S. Patent 3,934,002, issued January 20, 1976, for example zinc phenolsulfonate, 8-hydroxy~uinoline, disodium ethane l-hydroxy-l,l-diphosphonate, etc. and the amino 15 carboxylate compounds disclosed in U.S. Patent 3,937,807, issued February 10, 1976, for example nitrilotriacetic acid, ;l~ 2-hydroxyethylnitrilodiacetic acid or water-soluble salts ~; thereof. The bis-[4-(R-amino)-l-pyridinium]alkane is usually present in such formulations in a concentration of about , ; 20 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 above-, described formulations are compatible with the active ingredient, `l~ 25 i.e. the antibacterial, antifungal and virucidal effectiveness of the bis-[4-(R-amino)-l-pyridinium] compounds is not ., .
-' vitiated by effects ascribable to the nature of the vehicle, ~ diluent, carrier or other additive.
i.' ~; ~he molecular structures of the compounds o the ln~ention were a6signed on the basis of study Or their in-..................... ... .. ........ ... ........ ..
.: . . . , . :: .: : : ,: - . .: . -, ... : - .
7;~'3 1~
fr~red and NMR spectra, and confirmed by the correspondence between calculated and found values ror elemental analyses for the elements.
The invention ls lllustrated by the followlng example~ wlthout, however, being limited thereto.
Example 1 A. A mixture containing 130 g-. (0.67 mole) of 4-bromopyridine hydrochloride and 152 g. (1.0 mole) of n-heptylamine hydrochloride was heated in an oil bath. When the bath temperaturé reached 180-185C. the reaction mixture began to melt and stirrlng was be~un. At 190-195C. melt-lng was complete and the liquld mixture waq stlrred and heated at 210-220C. for 2.5 hours. The reaction mlxture ., .
wa~ then cooled to room temperature and the resulting solid was dissolved in water~ made alkaline with ~5% aqueous sodium ~ hydroxide and the product extracted with chloroform. The J Chlorororm extracts were dried over anhydrous sodium sulrate and evaporated to dryness under reduced pressure. The ~
I resulting viscous oll waq diluted with a small amount of n-Ç~l ~20 hexane and ~ooled to give a solld which was collected by ,riltration and alr-dried to af~ord 86.6 g. Or 4-(heptylamino)-.~ , pyrldlneJ m.p. 49-51C.
B. Alternatively, 4-(hept~lamlno)pyridine was prepared ,as follows: A mixture containing 229 g. (1.0 mole) of N-``25 (4-pyrldyl)pyridlnlum chlorlde hydrochloride and 228 g.
(1.5 moles) of n-heptylamine hydroc~loride was heated 2 hours with stirring in an oil bath at a bath temperature Or 215C. The reaction mixture was cooled to 80C., diluted wlth ice-water, made alkallne wlth 35~ aqueous sodlum hydroxide and extracted successlvely with ether and chloro-;~orm. The organic extracts were combined and evaporated to dryness under reduced pressure. The residual viscous oll ~, ~ -21-' .: .
.~ ~ . . . ..
, .
~ ID7~
was dlssolved in ether and the ethereal solutlon wa~ wa~hed with water. The aqueous wash was back-extracted wlth chloro rorm and the chloroform extracts were combined wlth the ~thereal solution. The combined organlc solutlons were dried over anhydrous sodlum sulfate and evaporated to dryness under reduced pressure. Coollng the resldual oll to -78C. effected partlal solidl~lcatlon~ The seml-solld was dlluted with a small amount of ether and flltered. The solid so-obtalned was dissolved in a mixture of acetonitrlle and chloroform, : 10 the resultlng solution treated wlth decolorlzlng carbon~
flltered, snd the flltrate evaporated to dryness under reduced pressure. The resultlng seml-solid was dlluted wlth a small amount Or ether and cooled. The solld thus-produced was collected by filtratlon and washed wlth a small volume of cold ether to give, after drylng, 84.6 g. of 4-(heptyl-:
amlno)pyridlne, m.p. 50-52C.
C. 4-~Heptylamlno)pyridlne was al80 prepared by hydrogenating a mixture containing 4-aminopyrldlne and heptaldehyde accordlng to the procedure descrlbed in Example IOB herelnbelow.
~i~ D. To a stlrred warm solution contain,lng 10.0 g.
(0.052 mole) o~ 4-(heptylam~no)pyridine ln 40 ml. of acetonitrlle was added dropwlse a solutlon containlng 9.3 g.
(o,026 mole) of 1,14-dibromotetradecane in 230 ml. of aceto-nitrile and the resultlng mixture was heated 20 hours under reflux. The product which preclpitated upon cooling the reaction mlxture to room temperature was collected by filtratlon, washed wlth cold acetonitrlle and dr~ed afford-. . .
lng 13.9 g. of 1,14-bis-[4-(heptylamino)-1-pyrldinium3-.; 30 tetradecane dibromlde, m.p. 88-goc.
; ~ -22-, .
.
.
,., . . , , . -, : . .
~:: . . . . . . . .
., '' ' ~ ' ', ' . .,-~ . . .
~'7~
Example_2 A solution containing 5.0 g. of 1,14-bls-[4 (heptylamino)-l-pyridlnlum]tetradecane dlbromlde ln 5.0 ml.
o~ methanol was added to the top o~ a 3-lnch diameter column containing 500 ml. Or synthetic anion exchange resln ln the chloride ~orm (sold by Rohm and Haas under the tradename Amberlite IRA 400) packed ln methanol and eluted wlth five 125-ml. portions Or methanol. The combined eluate was evaporated to dryness under reduced pressure and the residual oil wa~ redissolved in ethanol, treated with decol~rlzing carbon and evaporated to dryness. ~he resldual solld was triturated w~th ether containing a ~ew drops Or aceto-nltrileJ collected by ~lltration and drled over phos~orus pento~lde under vacuum to give 3.94 g. o~ 1,14-bis-~4-(heptylaminG)-l-pyridinium]tetrade^ane dichlorlde, m.p.
113-116C.
Example 3 A stlrred suspenslon contalnln~ 11.54 g, (o.o6 mole) o~ 4-(heptylamlno~pyrldine ln 75 ml. o~ a¢etonltrlle was heated under reflux untll a clear homogeneous solutlon was ~ormed. To the clear solutlon was then added dropwlse a warm solutlon contalnlng 9.84 g. (0.03 mole) of 1,12-dibromododecann ln 75 ml. o~ acetonitrile. When the addltlon was complete, heating under refIux was continued 18 hours.
Afker coollns to room temperature, the reactlon mixtu~e was evaporated to dryness under reduced pressure. The residual solid was slurried ln ether, collected by rlltration and dried 48 hours under vacuum at 60C. to a~ord 21.1 g. o~
1,12-bis-[4-(heptylamino)-1-pyrldinium]dodecane dlbromlde, m.p. 101-10~C.
:`
., .
:` . . . .
.
... .
~13'73~
Example 4 A. A solution contalnlng 6.6 g. of 1,12-bis-[4-(heptylamino)~ yrldinium]dodecane dlbromide ln 25 ml. of methanol was added to the top of a 3-inch diameter column packed with 1 liter of synthetlc anion exchange resin in the chloride rorm (sold by Rohm and Haas under the trade-name Amberlite IRA 400) in methanol and eluted slowly wlth 100-ml. portions 0r methanol until 700 ml. o~ eluate had been collected. The combined eluate was evaporated to i 10 dryness under reduced pressure below 25C. ~he 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~bls~[4-(heptylamino)-1-pyridinlum]dodecane dichlorlde, m.p. 109-112Co ~15 B. Alternativelyg a mlxture containlng 7~.8 g. (0.4 mole) o~ 4-(heptylamlno)pyridine and 47.8 g. (0.2 mole? of 1,12-dichlorododecane was heated 4 hours at 125-130C.
,. . .
~ After slight cooling 300 ml. of acetonitrile was added and -`~ the re~ulting mixture was heated at steam bath temperature to effect complete solution then stored in a refrigerator overnightO The preclpitated product was collected by filtra-;:;
, tion, washed with cold acetonitrile and ether, and the `~ hygroscoplc product immediately dried under vacuum to glve 112 g. of 1,12-bls-[4-(heptylamino) l-pyridinium]dodecane dichloride, m.p. 112-115C.
Exam~le 5 A. A mIxture containing 100.0 g. (0.51 mole) of 4-bromopyridine hydrochloride and 110 g. (o.8 mole) 0r n-~ ~ hexylamine hydrochloride was heated ln an oil bath. When i -24-',`:
. j .
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- the bath temperature resched 175-180C. the reactlon mlxture began to melt and stlrrlng was begun. The temperature of ~the bath was then raised to 227C. and the stirrlng contlnued 3,5 hours. After cooling to room temperature the reaction mlxture was dissolved ln hot water, the resulting solution = cooled wlth lce, made alkallne with dilute aqueous sodium hydroxide and extracted with chloroform. The chloro~orm extracts were drled over anhydrous sodlum sulrate and evaporated to dryness under reduced pressure. The resldue was trlturated wlth ether and cooled, The resultlng solld was collected by rlltratlon and wa~hed with cold ether.
Evaporatlon Or the ~iltrate afforded a second crop of solid.
;~ The crops were combined, dissolved ln chloro~orm, treated wlth decolorizing carbon and filtered. The ~iltrate was evaporated under reduced pressure, and the residue was trl-~!
i turated with cold etherO The product thus-obtalned was collected by flltration, washed wlth cold ether and dried to glve 6306 g. of 4-(hexylamino)pyrldlne, m.p. ~6-68C.
Evaporation of the filtrate afforded an additlonal 7.0 g., m,pO 65-67C.
;~ B. Alternatlvely, 4-(hexylamino)pyridine was prepared as foilows. A mlxture contalnlng 229 g. (1 mole) of N-(4 pyrldyl)pyrldlnium chloride hydrochloride and 207 g.
(1.5 moles) o~ n-hexylamine hydrochlorlde was stlrred and ~5 heated 1.75 hours at 175-185C. The reactlon was cooled and dlluted with 750 ml. o~ ice-water. The resulting solu-tlon wa~ made alkallne with 35~ aqueous sodlum hydroxlde and after further dllutlon wlth 1 1. of water was extracted wlth ether followed by dichloromethane. The organlc extracts were combined, dried over anhydrous sodlum sulfate and , ; ~ ~'7;3~3~l evapo~ated to dryness under reduced pressure. The resldue was crystalllzed from ether, redlssolved in chloroform, the resulting solution treated with decolorlzlng carbon and ~lltered. The ~iltrate was evaporated to dryness under reduced pressure and the residue was triturated with a mix-ture Or ether and acetonitrlle. The solid thus-obtalned I was again dissolved in chloroform and the resulting solu-tion treated with decolorizing carbon and filtered. The ~lltrate was evaporated to dryness under reduced pressure and the resldue was triturated with cold ether to give 71.'0 g.
of 4-(hexylamino)pyridine, mOp. 68-70C.
C. To a slirred warm solution containing 10.7 g.
(o.o6 mole) of 4-(hexylamino)pyridine in 50 ml. of aceto-nitrlle was added dropwise a solution containlng 10.7 g.
(0.03 mole) o~ l,14-dibromotetradecane in 250 ml. of aceto-nltrile and the resulting mixture heated 22 hours under ; re~lux. The reaction was then evaporated to dryne6s under reduced pressure. The resldual solid was dissolved in - acetonitrile and the resulting solution treated with decolorlz-ing carbon and ~iltered. The filtrate was evaporated to dryness under reduced pressure and the resultlng oil crystallized ~rom acetonitrlle. The product was collected by filtration :! and dried 48 hours at 70C./0.1 mm. to give 13.4 g. of 1,14-bls-[4-(hexylamino)-l-pyridinlum]tetradecane dibromide, ., ~5 m.p. 91-93C.
Example 6 Following a procedure slmilar to that described ln Example 2 but employlng 5.0 g. of 1,14-bl8-[4-(hexylamlno)-l-pyrldinium]tetradecane dibromlde there was obtalned 4.33 g.
. . .
of the correspondlng dichloride, m.p. 94-95C.
; -26-.''' ' .
~'7~3 Example 7 Followlng a procedure slmilar to that described in Example 5C but employing 10.7 g. (0. o6 mole) Or 4-(hexylamino)pyridlne and 9.85 g. (0.03 mole) of 1,12-dlbromododecane there was obtained 17.6 g~ of 1,12-bis-~4-(hexylamino)-1-pyrldinlum]dodecane dibromide, m.p.
12~-124C.
Example 8 Following a procedure similar to that descrlbed ln Example 2 but employing 500 g. Or 1,12-bis-~4-(hexyl-~mino)-l-pyridinium]dodecane dibromide there was obtained 3.69 g. of the corresponding dichloride, m.p. 86-88C.
Example 9 A. A mixture containing 183.3 g. (o.8 molej of N-1 15 (4-pyridyl)pyridinium chloride hydrochloride and 162 g.
(o.98 mole) of n-octylamine hydrochlorlde was heated in an , . . .
oil bath to a bath temperature of 225-230C~ (internal temperature of 188C.) and the resultlng llquld was stirred at that temperature ror 2,5 hours. The reaction mixture ~a~ then cooled to 70C., diluted wlth 1 llter of lce and water, made alkallne with 35~ aqueous sodlum hydroxide and ; extracted with chloroform. The chloro~orm extracts were dried over anhydrous sodium sulrate, treated with decolorlz-lng carbon and evaporated to dryness under vacuum. The resultlng oil wa~ cooled to -78C. The seml-solid whlch r~QE~ed was trlturated with ether and the solid thus-obtained collected by ~iltration, washed wlth cold ether and dried. The ~iltrate arforded a second crop o~ 10 g.
':~
. ' .
.... .
,q,3~Y~9~
The crops were ~ombinedJ dis~olved in chloroform and, rollowing treatment with decolorizing carbon and filtra-tion (repeated 3 times)J the chloroform solutlon was evaporated to dryness under reduced pressure. The result-ing solid was trlturated with ether, cooled, collected by flltratlon and washed with cold ether-hexane to give 63.3 g.
of nearly colorless 4-(octylamino)pyridine, m.p. 62-63C.
B. Alternatively 4-(octylamino)pyridine was prepared as follows~ A mixture containing 94 g. (1 mole; of 4-aminopyridine, 384 g. (3 moles) of octaldehyde, 7 g. of 10~ -palladium-on-carbon hydrogenation catalyst and sufficient absolute ethanol to glve a total volume of 1~2 1. was hydro-genated 4.5 hours at 70-90C. under an initial hydrogen pressure of 45 psl, Arter cooling the mlxture the hydro-genatlon cataly~t was removed by filtration and the filtrate was evaporated to dryness under reduced pressure. The re-sidual oil crystallized on standing and the solid product was trlturated wlth hexane, collected by flltration, washed .,~ with ~resh hexane and dried at 40C. under vacuum to give ~I 20 182 g. of 4-(octylamino)pyridine, m.p. 70-73C.
''?.' C~ To a stirred, warm solution containlng 10.0 g (0.049 mole) Or 4-(octylamlno)pyridine in 150 ml. of aceto-!l~ nltrile was added dropwlse a solution containing 7.4 g.
(0,0245 mole) of 1,10 dibromodecane in 50 ml. of aceto-nitrile and the resulting mixture heated 18 hour~ under reflux. After cooling and stirring 1 hour at room tempera-tureD the precipitated solid was collected by filtration, ,',J,'I washed with acetonitrile and dried 48 hour~ at 85C. to give 15.6 g. o~ 1,lO~bis-[4-(octylamino)-1-pyridinium3decane di-bromlde, m.p. 16~-164C.
?.: ',. - .
' ' ". ~ , .. ,,..... .... ,.. , ,,",,,,,,~,, `` : ' , ' ' ' :~ ' , .. , . . . . -: . ' , , .
- ~ ~7~3~
Example 10 A. Followlng a procedure similar to that descrlbed ln Example 2 but employing 5.0 g. of 1,10-bls-~4-(octyl-~mlno)-l-pyrldinium]decane dlbromide there was obtained 4.~1 g.
o~ the corresponding dlchlorlde, m.p. 213-214C.
. Alternatlvely, a mixture containlng 61.8 g. of 4-(octylamlno)pyridine and 310 5 g. Or l,10-dichlorodecane was stirred and heated slowly to 120C. The hest source was removed and the température of the now exothermic reaction lQ contnued to rlse to 180C. As soon as the reactlon mixture began to crystalllze 250 ml. Or N,N-dlmethylrormamide was rapidly added and the resulting mlxture was~heated to give a clear homogeneous solution and then cool~d to 0C. The precipitated product was collected by ~lltratlon, washed wlth ether and dried 24 hours under vacuum at 60C. to give 73 g. of 1,10-bis-[4~(octylamino~-1-pyridinium]decane di-chlorlde, m.p. 215-217C.
Example 11 .
,, Followlng a procedure slmllar to that descrlbed ln Example 9C but employing 11.1 g. (0.054 mole) of 4-(octylamino)pyrldine and 7.34 g. (0.027 mole)'ol 1,8-dibromooctane, and heating the reactlon mlxture 6 hours :~ :
under rerlux there was obtained 15.6 g. Or 1,8-bls-~4-(octylamlno)-lrpyrldlnlum]octane dibromide, m.p. 17~-175C.
Example 12 ; Following a procedure slmllar to that described ~ ln Example 2 but employlng 5.0 g. Or 1,8-bis-[4-(octylamino)-.
.~ .
.. ., . ... , . ... , . . , , ,, ~ ........ ..
:.: .,, .. , _ . . .. .. .
, ,' ~ ' . ' . ,, . ~ . . . ..
l-pyridlnium]octane dlbromide there wa~ obtained 4.30 g. of ; the corresponding dlchloride, m.p. 219-211C.
Example 1~
` Following a procedure similar to that described - 5 in Example 9C but employing llol g. (0.054~mole) of 4-(octylamino)pyridine and 6~6 g. (0.027 mole) of 1,6-dibromo-hexane and heating the reaction mixture 9 hours under reflux there was obtalned 15~1 g. of 1,6-bis-[4-(octylamino)-1-pyridinium]hexane dibromide, m.pO 136-13~C.
..:
,!' lo ' Example 14 . .
Following a procedure similar to that described , ln Example 2 but employing 500 g. of 1,6-bls-[4-(octylamlno)-pyridinium]hexane dibromide there was obtained 4.23 g. Or the corresponding dichloride9 mO p. 189-191Co .,.,~ .
Example 15 To a stirred warm solution containing 2.06 g.
(0.01 mole~ o~ 4-(octylamino)pyridine ln 15 ml. Or aceto-7, nitrile was added dropwlse a s~lution containlng 1.37 g.
~1~ (0.005 mole) o~ 1,6-hexanediol dimethanesulfonate in 10 ml.
~ 20 o~ acetonltrile and the resulting mixture was heated under -; re~lux 20 hours. The reaction mixture was evaporated to dryness under reduced pressure and the residual gum was triturated with ether to give a colorless hygroscoplc solid.
This product was redissolved ln a mixture o~ ethanol, ben-æene and acetonltrile and the resulting solution evaporated to dryness under reduced pressure. The residue was tri-turated with ether and the resultlng whlte solid was quickly collected by ~iltration, washed wlth anhydrous ether, and .: .
_30_ . . .~ .
., . .
.: . : - : . -... ; :
~ ` ~.. t3r7 ~
drled 72 hours at 28C./0.1 mm to give 2.65 g. of 1,6-bls-~4-(octylamino)-1-pyridlnium]hexane dimethanesulfonate as a waxy~ whlte solid.
Example 16 Following a procedure similar to that de~cribed in ; Example 9C but employing 14.24 gO (o.o8 mole) of 4-(hexyl-amino)pyridins and 8.64 g. (0.04 mole) o~ 1,4-dibromobutane there was obtalned following trituration of the crude pro-duct wlth a mixture of acetonitrile and acetone 20.45 g. of 1,4-bis-[4-(hexylamino)-1-pyridinium]butane dibromide, m.p. 199-201C.
,, .
E~ample 17 ~ollowing ~ procedure ~imilar to that described in Example 9C but employlng 10. 7 g ~ ( O ~ o6 mole) of 4-(hexylamino)pyrldine and 7~32 g~ (0.03 mole) of 1,6-dibromo-~` hexane there was obtained ~ollowing trituration o~ the crude product wi~h a mlxture o~ ether, acetonltrile and acetone 14.90 g. of 1,6-bls-[4-(hexylamino)-1-pyrldinlum]-hexane dibromideJ m.p. 178-179~C~
... .
Example 18 ollowing a procedure similar to that described in Example 9C but employing 10. 7 g. (o.o6 mole) of 4-~ (hexylamino)pyridlne and 7.75 g, (0.03 mole) of 1~7-dibromo-: heptane there was obtained following trituratlon of the crude product wlth a mixture o~ acetonltrile and acetone 16.4 g. o~ 1,7-bis-[4-(hexylamino~-1-pyrldinium]heptane .~ .
~ dlbromide, m.p. 157-158Co ., I .
L ~
3~
Example 19 Following a procedure similar to that descrlbed in Example 9C but using 10.7 g. (o.o6 mole) of 4-(hexylamino)-pyrldine and 8.6 gO (0.03 mole) of l,9-dibromononane there was obtained 17015 g. of 1,9-bis-[4-(hexylamino)-1-pyridinlum]-nonane dibromideg m.p. 114-115C~
E m le 20 Following a procedure similar to that described ln Example gc but employing 15.4 g. (0. o8 mole) of-4-(heptylamino)pyrldlne and 8064 gO (0004 mole) of 194-dlbromobutane there was obtained 23.1 g. Or 1J 4-bis-[4-(heptylamino)-l-pyridlniumlbu~ane dibromide, mOp. 229-230C.
Example ?l Following a procedure similar to that described ln Example 9C but employing lOo O g. (0.052 mole) o~ 4-(heptylamlno)pyridine and 6.7 gO (o.026 mole) of 1,7-dibromoheptane there was obtained 14005 gO o~ 1,7-bi~-~4-(heptylamino~ l-pyrldlnium]hepiane dibromide, mOpO 142-143C.
.
` Example 22 .
~ 20 ~ollowing a procedure slmilar to that described ,~ in Example 9C but employing 11.6 g. (o.o6 mole) o~ 4-(heptyl-amino)pyrldine and 8.2 g. (0.03 mole) of 1,8-dibromoctane there was obtained a~ter recrystallizatlon ~rom acetonltrile-ether 1806 gO of 1,8-bis-[4-(heptyl3mino)-l-pyridlnium]-` 25 octane dibromide, m.p. 161-162C.
.;
.,,;
'~' .. . . .. . . .... . .. ..... .. . . ....
. ~ :
o~
Example 23 Followlng a procedure slmilar to that described in Example 2 but employing 5~0 g. (0.0076 mole) o~ lJ8-bis-[4-(heptylamino~-1-pyridlnlum~octane dlbromlde there was obtained 4.1 g. Or the correspondlng dichlorlde, m.p.
206-208C.
Example 24 Followlng a procedure simllar to that described ~ ln Example 9C but employing 15.4 g. (o.o8 mole) o~ 4-; 10 (heptylamino)pyridine and 11.44 g. o~ l,9-dibromononane there was o~tained 21.3 g. or l,9-bis-[4-(heptylamino)-1-pyridinium]nonane dibromide, m.p. 115-116C.
Example 25 , Following a procedure similar to that described in Example 2 but employing 5.0 g~ (0.0075 mole) of l,9-bis-[4-(heptylamino)-1-pyridinlum]nonane dibromide there was s obtained 4.2 g. Or the corresponding dichloride, m.p.
: .
154-155C.
~e~ .
Followlng a procedure slmilar to that described ! in Example 9C bu~ employing 15.4 g. (o.o8 mole) of 4-(heptyl-amino)pyridine and 12.0 g. (0.04 mole) o~ l,10-dibromodecane there was obtained 25.7 g. Or 1,10-bis-[4-(heptylamino)-1-~ pyridinlum]decane dibromide, m.p. 163-165C.
;; 2~ Example 27 Followlng a procedure similar to that described ln Example 2 but employing 5.0 g. (0.0073 mole) Or 1,10-;3~3~
bis-~4-(heptylamino)-1-pyridinium]decane dibromide there was obtained 4.35 g. Or the correqpond1ng dichloride, m.p. 209-210C.
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 Amberlite IRA 400) in 1~0 ml. of water was added dropwlse 48~ aqueous hydrofluoric acid until the m1xture was acidic. After stirring an additional 0.5 hour the slurry was poured into a column. The column was drained and the resln washed with a solution containing 15 ml. o~ 48% aqueous hydrofluoric acid in 185 ml. of distilled water. The resin was then washed with dlstllled water untll the eluate was weakly acidic, and then successlvely with 20~, 40%, and ~0~ aqueous methanol and ~inally with absolute methanol until the eluate was neutral. To the top of this column o~ ion exchange resln now in the fluoride orm was added a solution containing 0.~5 g. (o.ooo365 mole) :
Or 1,10-bis-[4-heptylamino)-1-pyridinium]decane dibromide ln 1 ml. of methanol. Five fractions of 15 ml. each were i:
collected. The first three ~ractions were comblned and evaporated to dryness under reduced pressure. The oily resldue was dissolved in a mixture of toluene and ethanol and the resulting solutlon evaporated to dryness under reduced pressure. The residual oil was redlssolved in a mixture Or benzene and acetone and the solution concentrated to a small volume. The solid which separated was collected by filtration and dried 24 hours at 24C./0.1 mm. to give 0.11 g. of lmpure 1,10-bis-[4-(heptylamino)-1-pyridinium]-decane dlfluoride, m.p. 85-goc.
:
' '' , ' ' ' ' : :
, ~ :
::
.~ . . . . . . . .
3'~3 Example 29 A. A solld mixture containlng 115 g. (0.5 mole) Or N-(4-pyridyl)pyridinium chloride hydrochloride and 119 g.
(o.6~ mole) Or n-nonylamine hydrochloride wa~ heated in an oil bath up to a bath temperature Or 220C. (internal tem-perature Or 190-194C.) and the resulting liquid was stirred at that temperature ~or 2 hours. The reactlon mixture was then cooled to 80C., 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 sulfate, t~eated wlth decol~riz-ing carbon, ~iltered and evaporated to dryness under reduced pressure. The residual viscous oil was cooled to -78C.
and triturated with ether. The resulting solid was coll,ected by ~iltratlon and wa~hed with cold ether. The filtrate . ~ , sfforded a second crop of solid. The combined crops were redissolved in chloroform and the resulting solution treated wlth decolorlzing carbon and riltered. This was repeated once more and the riltrate was then evaporated to dryness under reduced pressure. The residual semi-solid was tri-, turated with ether and cooled to give a nearly colorless solid which was collected by filtration, washed with cold ether and bried. The solid was taken up ln chloro~orm and the resulting solution treated with decolorizing carbon~
riltered and evaporated to dryness under reduced pressure.
Cooling the seml-solid so-obtained and trituration with ether arforded a colorless solld which was collected by ~lltration, washed with cold ether and drled to glve 51,7 g.
o~ 4-(nonylamlno)pyrldine, m.p. 59-60C. The flltrate ar~orded a second crop of 11.6 g., m.p. ~-57C.
., .
. . _. ... ... _... .
B. Alternatively 4-(nonylsmlno)pyrldine was prepared as ~ollow~': A mixture containlng 39.5 g (o.42 mole) of 4-aminopyrldine, 175 g. ~1,24 moles) o~ nonyl aldehyde, 5.0 g. of 10% palladium-on-carbDn hydrogenation catalyst and sufflcient absolute ethanol to give a total volume Or - 600 ml. was warmed and hydrogenated under an lnltial 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 pres~ure. The resldual oll was then vacuum dlstilled to remove any nonyl alcohol which may ha~e been produced. A
raction boiling at 63-64C./4~5 mm. was collected and ,set ~, aside... The resldue was triturated with ether and cooled at -78C. The solid which precipitated was collected by filtratlon and washed wi~h cold ether. This product was di~solved in chlorofDrm, the resulting solution treated with decolorizing carbon, filtered and the filtrate evaporated `` to d~yness, ~he resldue was triturated with ether and cooled to -78~. The solid thus-obtained was collected by flltration, washed with cold ether and air-dried to glve 27.0 g. of 4-(nonylamino)pyrldlne, m.p. 57-59C.
C. A stiFred suspenslon of 11.0 g. (0.05 mole) of 4-(nonylamlno)pyrldlne ln 150 ml. of acetonltrile was warmed untll a clear homogenous solutlon was obtalned. To this clear ~olutlon was added dropwise a solution contalning 6.8 g, ' !
(0 025 mole) Or 1,8-dibromooctane ln 50 ml. of acetonltrile ;.
; and the resulting mixture heated 19 hours under reflux durlng which time a solld precipltated ~rom solution. After coollng, the solid was collected by rlltration, redissol~ed in methanol, the resulting solutlon treated wlth decolorizlng carbon, , .
.i~ , .: , _ ,, - __._ ,. . . .... ... ... . .
.,',~ .
.. . .
, . .
, . , : .
, t~
filtered and evaporated to dryneas under reduced pressure.
Trlturation o~ the resldual oil wlth ether containing a small amount of acetonltrlte produced a colorlesa crystalllne solld which was collected by filtratlon and drled to glve 15.5 g. of 1,8-bis-[4-(nonylamlno)-I-pyridlnlum~octane dlbromide~ m.p. 178-179C.
Example ~0 Following a procedure similar to that described ln Example 29CIb~t employing ~.54 g. (o.026 mole) o~ 4-(propylamino)pyridlne and 3.90 g. (0.013 mole) of 1,10-dibromodecane there was obtained 5.19 g. of l,10-bls-[4-(propylamino~-1-pyridinium]decane dlbromide, m.p. 206-207C.
Example 31 Followlng a procedure slmilar to that described ln Example Z9C but employlng 14.24 g. (0. o8 mole) of 4-(hexylamino)pyrldlne and 9.20 g. (0.04 mole) of 1,5-dibromopentane there was obtained following recrystall~za-i tion from acetonitrile-acetone 12.3 g. o~ 1,5-bls-[4-(hëxylamino)-l-pyrldinium~pentane dibromlde, m.pO 155-156C.
Example 3?
Following a procedure similar to that descrlbed in Example 29C but employlng 10.7 g. (o.o6 mol~) o~ 4-(hexylamlno)pyrldlne and 8.2 g. (0.03 mole) o~ 1,8-dibromo-octan~ there was obtalned 16.~ g. o~ 1,8-bls-[4-(hexylamino)-l-pyridlnlum~octane dlbromide, m.p. 180-181C.
` ..
_ . _ . _ . ~ ..... . _ ... .. , _ .. , . , .
Example 33 Following a procedure slmllar to that described in Example 29C but employing 12.5 g. (0.07 mole) of 4-~hexylamino)pyrldlne and 10.5 g. (0.035 mole) of 1,10-dlbromodecane there was obtalned 16.0 g. o~ l,10-bl3-[4-(hexylamino)-1-pyridinium~decane dibromide, m.p. 148-49C o Example 34 Following a procedure similar to that described in Example 29C but employing 13.4 g. (o.o76 mole) of 4-(cyclohexylamino)pyrldine and 8.2 g. (0.03~ mole) of 1,4-dibromobutane there wa~ obtained 18.2 g. of 1, 4-bis-[4-(cyclohexylamlno)-l-pyrldlnlum]butane dlbromide, m.p. 288-290C.
, .
Exam~ 3~
Followlng a procedure simllar to that described in Example 29C but employing 13.4 g. (o.o76 mole) of 4-. , .
(cyclohexylamino)pyridine and 8.75 g. (o.038 mole~ Or 1,5-dibromopentane there was obtained 19.0 g, o~ 1,5-bis-[4-(cyclohexylamino)-1-pyridlnium]pentane dibromide, m.p.
255-256C.
Example 36 Following a procedure similar to that descrlbed in Example 29C but employing 13. 4 g. ( O. o76 mole) o~ 4-(cyclohexylamino)pyrldlne and 9.3 g, (o.038 mole) of 1J6 dibromohexane there was obtained 19.1 g. Or l, 6-bis-~4-(cyclohexylamino)-l-pyridlnium]hexane dlbromide, m.p. 307-308C.
. . .
; ' ,.; - . . .
, .
.~ , . .
. . .
~:3L~t';3~3~
~xample ~7 Following a procedure ~imilar to that descrlbed ln Example 29C but employing 13.4 g. (0.076 mole) o~ 4-(cyclohexylamino)pyridine and 9.8 g. of (o.o38 mole) o~
1,7-dibromoheptane there was obtained 2001 ~IOr l~,-bi~4-~clo-hexylamino)-l-pyridinium]heptane dibromide3 m.p. 311-31~C.
Exam~le_38 Following a procedure similar to that described ln Example 29C but employing 13.4 g. (oOo76 mole) o~ 4-(cyclohexylamino)pyridine and 10.~4 g. (o.038 mole) of 1~8-dlbromooctane there was obtained 19.1 g. Or l, 8-bis-[4-(cyclohexylami~o)-l-pyridinium]octane dibromide, m.p. 270-271Co Example ~9 ~ 15 ~ollowing a procedure ~lmilar to that described`~ ~ ln Example 29C but employing 1~.4 g. (o.o76 mole~ o~ 4-~ (cyclohexylamino)pyridine and 10.8 g. (o.o~8 mole) o~ 1,9-- ~ dibromononane there was obtalned 16.3 g. of 1,9-bls-[4-(cyclohexylamino)-l-pyridinium~nonane dlbromide, m.p. 149-151C.
Example 40 Following a procedure simllar to that described i ~ in Example 29C but employing 1~.4 g. (o.076 mole) of 4-(cyclohexylamino)pyridine and 11.4 g. (o.038 mole) Or l,10-di~romodecane there was obtained 19.0 g. of l,10-bis-[4-(cyclohexylamlno)-1-pyridinium]decane dibromlde, m.p.
226-227C.
,................................................................... .
.,',. .
.,.i , , . .
.. ,., .. . . - , --- --~
.. . . . , . ,. : ~, : .
'~7 ~
Example 41 A. A mixture containlng 298.0 g. (1.3~ moles) of N-(4-pyrldyl)pyridlnium chloride hydrochlorlde and 322 g.
(2 moles) of 2 ethylhexylamine hydrochloride wa~ heated 2 hours wlth stirrlng ln an oll bath at a bath temperature of 215Co The mixture wa~ cooled to 60C., dlluted wlth 500 ml~ of water and kept cold by the addltlon of lce while being made alkallne with 35% aqueous sodlum hydroxlde.
~he alkallne mlxture was ex'r~cted wlth ether and the ethereal extracts were dried o~er anhydrous sodium sulfate and evaporated to dryness. ~he resldual oll wa~ dlstilled under reduced pres~ure to give 101.0 gD of 4-(2-athylhexylamlno)pyrldine b.p. 145-150C./0.9 mm.
B. Alternati~ely 4-(2-ethylhexylamlno)pyridlne W8 S
prepared as follows-~o a stirrad solutlon contalnlng 800 g. (8.4 moles) of 4-aminopyridlne and 1500 ml. of trlethylamlne ln 6.4 1.
of dichloromethane there was added ov~r 3 hours a solution containlnz 1610 g. ( lOo O mole~) of 2-~thylhexannyl chlorlde in 1.6 1. of dichloromethane. ~hrou~hout the addition the temperature wa~ malntalned at 15C. When the addltion was compl~e the mlxture was warmed on a steam bath 2 hourn.
After coollng the reactlon mixture was washed thoroughly with water9 dried over anhydrous sodlum sulfate, t~eated wlth decolorizlng carbon and flltered. Evaporation o~ the ril-trate afforded 1843 g. of N-(4-pyrldyl)-2-ethylhexanamide.
To a mixture contalning 100 g. (2.6~ moles) of lithlum aluminum hydrlde ln 2 l. of tetrahydro~uran was added at a sufflcient rate to maintaln gentle reflux a , -`'. , .. . ..
solution contalnlng 570 g. (2.62 moles) Or N-(4-pyrldyl)-?-ethylhexanamide in 4 1. of tetrahydrofuran. When the addl-tion was complete (approximately 3 hours) the reaction mlx-ture was heated under reflux 7 hours. After coollng, the mixture was treated ~uccessively with 100 ml. of water, 100 mlO of 5% aqueous sodlum hydroxide and 300 ml. of waterO The solids were removed by filtratlon and the sol-vent was eva~orated from the filtrate under reduced pressure.
The residual oil wa~ combined with the product of a dupll-cate run ~nd vacuum distllled to glve 837 g. of 4-(2-ethylhexylamlno)pyridine bop~ 135-160Co/0~2 mm.
C0 ~o a stirred, warm solution containlng 1003 gO
, . .
(0005 mole) of 4-(2-ethylhexylamino)pyridlne ln 50 ml.-of acetoni'rlle was added dropwise a solutlon containing 8.2 g.
(00025 mole) of 1312-dibromode^ane in 170 mlO of acetonitrile ;~: and the resulting mlxture was heated 20 hour~ under refluxO
:.
Upon cooling to 0C0 a first crop of product precipltated ;- and ~a~ collected by filtrationO E~aporatlon of the filtrate and trituration of the residue ~ith ether af~orded a second cropD ~h~ combined crops were dissolved in methanolD the result1ng solution treated with decolorizing carbon3 ~iltered , . . .
; and the fiïtrate evaporated to dryness under reduced pressure.
'l The residual oil was cooled and triturated with ether to give a slightly discolored solid. Recrystallization from acetonitrlle-ether followed by trituration of the product with ether rollowed by acetonltrile afforded, after drying '~l 72 hours under ~acuum at 60C., 14D7 gD of 1,1~-bis-[4-~2-~ ethylhex-~lamino)-l-pyridinium]dodecane dibromide as colorless i granules, ~.p. 146-147C.
,...
,...
~ 41-.,j,~ .
~" .
~.-,j, ..
~,,!. ,, ~"~' ' ' - ~ ' ' " "', '7;~1'31~
Example 42 A. A mixture containing 353.5 g. (1.72 mole) of 4-(2-ethylhexylamino)pyridine and 205 g. (o.86 mole) of 1J12 ; dichlorododecane was heated to 120C. The heat source was removed and the temperature of the now exothermic reaction continued to rlse to 180-190Co When the temperature dropped to 1~5~C. one liter of acetonltrile was care~ully added and the mixture heated under reflux to give a clear - solutionO ~he hot acetonitrile solution was comblned wlth similar solutions from two other runs, treated wlth decolorizing carbon and filtered. The flltrate was cooled and the precipltated product was collected by flltratlon and washed with cold acetonltrile. Two recrystallizations from acetonitrile af~orded 970 g, Or 1,12-bis-[4-(2-ethyl-hexylaminG)-l~pyridinium]dodecane dichloride, m.p. 168-171C.
1 Bo Alternatively, by following a procedure slmilar i~ to that described in Example 2 but employing 3.0 g. (0.00405 1 .
mole) of 1912-bis-[4-(2-ethylhexylamino)-l-pyridinium]
~ dodecane dibromide there was obtained 2 0 gO of the corres-;~ 20 ponding dichloride, m.p. 172-17~C.
Example 43 Following a procedure similar to that described in Example 4lC but employing 10.3 g. (0.05 mole) Or 4-(octylamino)pyridlne and 6.45 g. (0.025 ~ole) o~ 1,7-;~ 25 dibromoheptane there was obtalned 14.85 g. of 1,7-bis-[4-(octylamino)-l-pyridlnium]heptane dibromide, m.p. 129-131C.
.
.
.
..... ~,,, Example 44 A. Following a procedure similar to that described in Example 41C but using 11.1 g. (0.054 mole) of 4-(octyl-amino)pyridine and 7.72 g. (0.027 mole) of l,9-dibromononane there was obtained 17.0 g. of 1,9-bis-[4-(octylamino)-1-pyridinium]nonane dibromide, m.p. 117-119C.
B. The corresponding dichloride prepared according to the procedure of Example 2 had a m.p. 161-162C.
Example 45 Following a procedure similar to that ~escribed in ~ 10 Example 41C but employing 10.3 g. (0.05 mole) of 4-(octylamino)-f',' ~ pyridine and 8.2 g. (0.025 mole) of 1,12-dibromododecane there was obtained 15.2 g. of 1-,12-bis-[4-(octylamino)-1-pyridinium]dodecane dibromide, m.p. 119-120C.
Example 46 Following a procedur~e similar to that described in Example 41C but using 5.8 g. (0.028 mole) of 4-(octylamino)-~I pyridine and 5.0 g. (0.014 mole) of 1,14-dibromotetradecane there was obtained 9.3 g. of 1,14-bis-[4-(octylamino)-1-pyridinium]tetradecane dibromide, m.p. 113-115C.
~; 20 Example 47 Follow1ng a procedure simolar to that described in Example 41C but employing 11.0 g. (0.05 mole) of 4-~nonylamino~-pyridine and 6.1 g. (0.025 mole) of 1,6-dibromohexane there was obtained 15.2 g. of 1,6-bis-[4-(nonylamino)-1-pyridinium]-~1 25 hexane dibromide, m.p. 152-154C.
"; ~ ~ ' .
~ -43-,.. :
5'l'~ ~
. .
?
... ~ .
. ' " -~ ' - ~ , .
.. ': ~ . , .
'.-, ' : . ' ' ' ' . ~ .
' ', ~ : ' ' ' . '~ " ; , , ' ' ' ' ' Example 48 .
Following a procedure slmllar to that described in Example 4 but employing 6.5 g. (0.0095 mole) o~ l,6-bls-~4-(nonylamino)-1-pyrldinium]hexane dibromide there was obtained 4095 g. of the correspondlng dichlorlde, m.p. 194-195C.
.
Example 49 Followlng a procedure simllar to that described ln Example 41C but employing 8.8 g. (0Oo4 mole~ Or 4-(nonylamino)pyrldlne and 5.2 g. (0.02 mo'e) o~ 1,7-dibromo-: heptane there W3S obtained 12.2 g. o~ 1,7-bls-[4-(nonyl-~ amlno)-l-pyrldlnium]heptane dlbromide, m.p. 132-134C.
"
Example 50 '?'' Followlng a procedure similar to that described ln Example 41C but employing 11.0 g. (0.05 mole) of 4-(nonylamlno)pyridine and 7.15 g. (0.025 mole) o~ 1,9-dibromoncnane there was obtalned 15.7 g. o~ l,9-b1s-~4-(nonylamlno)-l pyridinium3nonane dibromlde, m.p. 121-122C.
Example 51 ~ollowing a procedure similar to that described ~; in Example 41C but employing 11.0 g. (0.05 mole) of 4-~ (nonylarnlno~pyridine and 7.5 g. (0.025 mole) o~ 1,10-;~ ~ dibromodecane there was obtained 15.63 g. of 1,10-bis-[4-;.. . .
(nonylamlno)-l-pyridlnium]decane dibromide, m.p. 172-173~C.
; 25 Exam~ 52 j~ Following a procedure slmilar to that described ln Example 41C but employing 10.~12 g. (o.o46 mole) o~ 4-, '';
.:
., . ,~ ~.. . .. .. ..
~ " ~
~ 3~ ~
(nonylamino)pyridine snd 7.54 g. (0.023 mole) of 1,12-dibromododecane there was obtained 16.4 g. o~ 1,12-bis-[4-(nonylamino)-1-pyridinlum]dodecane dibromide, m.p.
105-106C.
Example 53 To a stirred, warm solution containing 12.4 g.
; (o.o6 mole) of 4-(2-ethylhexylamino)pyridine ln 100 ml.
Or acetonitrile was added dropwlse-a solution containing 6.9 g. (0003 mole) of 1,5-dibromopentane in 25 ml. o~
10 acetonitrile and the resulting solution heated 20 hours under reflux. The reaction mixture was cooled and diluted wlth ether until slightly cloudy. Further cooling and , ~ stlrring a~rorded a solid precipitate whlch was collected l by flltration and washed wlth~a cold mixture of acetonltrile 15 and ether~ The sslid thus-obtslned was dissolved ln ethanol and the resulting solution treated wlth decolorizing carbon and filtere~. Evaporation o~ the filtrate provided a pale ~ yellow vlscous oll which was crystallized from aceto-3~ nitrile-ether. The resulting solid was collected by 20 ~iltration~ washed with cold acetonitrlle-ether and dried 24 hour~ under vacuum at 90C. to give 13.6 g. or 1,5~bis-4-(2-ethylhexylamino)-1-pyridinium~pentane dibromide, m.p, 150-151C.
;r: Example 54 ,~
`l~ 25 Following a procedure similar to that described ln Example 53 but employing 12.4 g, (o.o6 mole) o~ 4-(2-ethylhexylamlno)pyrldlne and 7.3? g~ ( o. 03 mole) of 1,6-dibromohe~ane there was obtained 16.1 g. of 1,6-bis-[4-(2-ethylhexylamino)-l-pyridlnium]hexane dlbromldeJ m.p. 208-209C.
`` -45-.`"', . . - . ~-.. - .. . - . .. .. ; , - ~ - . :
.: , . .. s...................... . ..
-: . . : : , ";;.. ;, . .
I.07;~9~1 Example 55 Followlng a procedure 61milar to that descrlbed in Example 53 but employlng 12.4 g. (0. o6 mole~ of 4-(2 ethylhexylamlno)pyrldlne and 7.75 g. ~0.03 mole) o~ 1,7-dlbromohept~ne there was obtained 17.9 g. o~ 1,7-bls-~4-(2-ethylhexylamino)-1-pyrldinium]heptane dlbromlde, m.p.
~ 219-220C.
.~,';.
Example 56 Followlng a procedure slmilar to that described ln Example 53 but employing 12.4 g. ( o. o6 mole) of 4-(2-ethylhexylamlno)pyridine and 8.2 g. (0.03 mole) o~ 1,8-dlbromooctane there was obtalned 15.9 g. o~ 1,8-bl~-~4-(2-ethylhexylamlno)-1-pyrldlnium~octane dlbromlde, m.p.
160-161G.
; 15 ExamPle 57 ~, .
Followlng a procedure similar to that descrlbed ln Example 5~ but employlng 12.4 g. (o.o6 mole) o~ 4-(2-. , .
ethylhexylamlno)pyrldine ~nd 8.6 g. (0.03 mole) of 1,9-dibromononane there wa~ obtalned 15.2 g. o~ 1,9-bis-(~-(2-othylhexylamino)-l-pyridlnlum]nonane dibromide, m.p. 158-159C, ; Example 58 Followin~ a procedure slmilar to that described ln Example 53 but employing 12.4 g. (0. o6 mole) o~ 4-(2-` 25 ethylhexylamino)pyrldlne and 9.0 g. (0.03 mole) o~ 1,10-!'`, dlbromodecane there was Gbtained 17.4 g. o~ 1,10-bls-~4-(2-ethylhexylamino)-1-pyridinlum]decane dlbromlde, m.p.
` 162-163C. -46-,' '' ' ''"'.
Example 59 Followlng a procedure slmilar to that de~crlbed ln Example 2 but employlng 5.0 g. of 1,lo-bls-L4-(2-ethyl-hexylamino)-l-pyridinlum]decane dibromlde there was obtained 4.11 g. of the correspondlng dlchlorlde, m.p. 191-192C.
:
Example 60 To a stirred warm solution containlng 12.0 g.
(oOo6} mole) of 4-(heptylamino)pyrldlne in 100 ml. of acetonltrile there was added dropwise a solutlon contalning 7.4 g. (0.032 mole) of 1,5 dlbromopentane ln 25 ml. o~
acetonitrile and the resulting mixture heated 19 hours , . . .
under reflux. The reactlon mlxture was cooled in lce and .: ether was gradually added untll a colorles solid preclpi-~; tated. ~h~ solid was collected by filtratlon recrystallized ~rom acetonitrile-ether and dried 48 hours at 90C./lmm.
~ to give 1509 g. o~ 1,5-bis [4-(heptylamino)-1-pyridlnlum]-; pentane dlbromlde, m.p. 15~-154C.
Example 61 , ;
Following a procedùre slmilar to that descrlbed ln Example 60 but uslng 19.2 g. (0.1 mole) of 4-(heptyl)-amino)pyridine and 12.2 g. (0.05 mole) of 1,6-dlbromohexane there was obtained 27.5 g. of crude product. Recry alllza-t~on of a 15-gram sample from acetonltrlle-eth~r afforded '! 11.45 g. o~ 1,6-bis-~4-(heptylamlno)-1-pyridinium]hexane l 25 dibromlde, m.p. 149-150C.
. . .
!
,,' . .
. .
, . : .
,. . .
~.~'7~
Example 62 ; A~ A suspen~lon Or 24.0 g. o~ crude l,6-bl~-[4-(heptylamlno)-l-pyridinlum]hexane dibromlde in 500 ml. Or water was made alkallne wlth 3N aqueous sodium hydroxide and extracted with chloroform. The chloroform extracts were dr~ed over anhydrous sodium sulfate and evaporated to dryness under reduced presBure. The residual oil was dlssol~ed ln methanol and the resulting solution acldifled wlth methane-sul~onic acid and evaporated to dryness under reduced pressure. The residue was redissolved in methanol, treated with decolorlzlng carbon, filtered and svaporated to dryness under vacuum leaving an oily residue which upon trituration with ether ~ollowed by acetonitrile provlde 18.2 g. of gummy ~olidO The crude solid was dissolved in water and the resulting solution made alkaline with ~5~ aqueou~ sodium hydroxide and extracted wlth chloroform. The chlorororm extracts were dried over anhydrous sodium sulfate and ,, .
evaporated to dryncss under reduced pressure. The resulting solld was triturated successively with ether and scetonitrlle, collected by ~iltration and dried to give 16.~ g. o~ tan solld, m.p, 105-108C. The solid ~o-obtained was dis~olved in lO0 ml. o~ m~thanol and the resulting solutlon acidlfied wlth methanesul~onic acld. Evaporation to dryness under reduced pressure produced a vlscou~ oll which was t~ken up in 20 ml. Or mekhanol and treated portionwlse with 150 ml.
o~ water. ~he resulting suspenslon was cooled ln ice and the suspended solld was collected by filtration and washed wlth cold water. ~he sOlid wa~ then slurried ln hot acetoneJ
cooled, coll~cted by filtrationg washed wlth cold acetone ., .
and dried 48 hours at 95C./1 mm. to glve 10.8 g. Or tan solid, m.p. 163-165C. This product ~ave a posltlve chlorlde .~
lon test wlth sllver nltrate and the nmr spectrum thereof indlcated the absence of the methanesulfonate group.
B. A suspenslon of 14.0 g. of 1,6-bis-~4~(hep'ylamino)-pyrldlnlum]hexane dlbromide ln 500 ml. of water was made alkaline with 35% aqueous sodium hydroxide and extracted wlth chloro~orm. The chloroform extracts were dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The partially solld resldue was dissolved ln 1 lo of acetonitrile-benzene and the resultlng solutlon evaporated to dryness under vacuum. This proce 3 S was :, . i i repeated three tlmes. The ~inal residue was dissolved in 50 ml. o~ acetonitrile and the resulting ~olution diluted ;~
wlth 50 ml. of benzene and cooled in ice to give arter ~lltering and drying 5.3 g. o~ tan solid. The filtrate a~forded a second crop o~ 4.B g. The crops were comblned . ,.
~ and dlssolved ln 50 ml. Or acetonltrlle. Dilu~ion with .
eth@r preclpltated a solld which was collected by flltratlon ' 20 and dried 48 hours at 95C./1 mm. to give 8.85 g. o~ tan solld, m.p. 174-176C. Thls product also gave a posltlve .
chlorlde lon test wlth sllver nitrate.
C. The products o~ parts A and B above were combined, mixed wlth ~00 ml. of water and heated unt~l a homogeneous solution was obtained. The solutlon was ~lltered and the ~i~trate treated wlth 50 ml. o~ 12N hydrochloric acid. The resultlng suspenslon was concentrated under reduced pressure and the resldue was treated with ice. The solld so-produced was collected by riltration, washed wlth cold water and drled. The product was then dissolved ln acetone, the result-lng solutlon diluted wlth a mi~ture o~ benzene and ethanol, . ~ ' . `~
.
, : . '- ~ : -~7 ~
and the whole evaporated to dryne3s under vacuum. The solld residue was slurried in 100 ml. Or acetone and the ~lurry diluted with ether and flltered to glve after drylng 48 hours at 105C./1 mm. and 72 hours at 115C./1 mm. 16 ~ g.
of crude 1,6-bis-[4-(heptylamino)-1-pyridlnlum]hexane dichloride as an or~-white solid, m.p. 176-17!8C.
.
Exam~le 63 Following a procedure slmllar to that descrlbed in Example 50 but employing 10.30 g. ~0.050 mole) of 4-(2-ethylhexylamlno)pyrldlne and 5,4 g. (0.025 mole~ o~ 1,4-dibromobutane there was obtained 1~.9 g. Or 1,4-bls-[4-(2-ethylhexylamino)-1-pyridlnium]butane dibromide, m.p.
245-246C.
Example 64 A. A mixture containing 229 g. (1.0 mole) o~ N-(4-pyridyl)pyridlnium chloride hydrochloride and 244 g. (1.26 moles) of n-decylamine hydrochloride was stirred and heated approximately 2.5 hours at 190-195C. The reaction mixture was then allowed to cool slowly to 40~C. and diluted wlth 2 1. o~ 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 riltration and washed with cold water.
Thls materlal was dissolved in 1 1. Or chloro~orm and the resulting solution was treated with decolorizing carbon and rllt~red. The riltrate was evaporated under reduced pressure and the residue was triturated with 150 ml. Or ether. The solld thus-obtained was redlssolved ln chloroform and the .,;~
~, .
resultlng solutlon treated with decolorlzing carbon and ~lltered. The ~lltrate was agaln treated with decolorizlng carbon and filtered. The ~iltrate was evaporated to dryness under reduced pressure and the resldual sol1d wa~ trlturated wlth ether. Recrystalllzatlon ~rom acetonltrlle af~orded a~ter drying under vacuum 96.~ g. of 4-(decylamino)pyrldlne, ~m.p. 71~73C.
B, To a stlrredl warm solution contalnlng 12.2 g.
(0.052 mole) of 4-(de~ylamlno)pyrldlne ln 150-170 ml. of acetonltrlle was added dropwlse a ~olutlon contalnlng 6c35 g.
(o.026 mole) o~ 1,6-dlbromohexane in 60 ml. of ac~tonltrlle and the resulting mixture heated approximately 20 hours under re~luxc The reactlon mlxture was then cooled ln lce and the precipitated solid was collect~d by flltratlon and wa~hed with cold acetonltrile. The product thus-obtained was dl~solved ln methanol and the resul~lng ~olution treated with decolorizing carbon and ~lltered. The ~lltrate was ~vaporated to drynesa under reduced pres~ure and the residue wa~ triturated with 50 ml. of cold ether, collected by fll-' 20 tratlon and drled 2 days over phosphorus pentoxlde at 70C./
0.1 mm. to glve 14.6 g, o~ 1,6-bis-~4-(decylamino)-1-pyridiniumJ
hexane dlbromlde, m.p. 138-140C.
Example 65 Followlng a procedure ~imilar to that deacrlbed ~ 25 in Example 64B but employlng 12.2 g, (0.052 mole) of 4-- (decylamlno)pyrldine and 6.7 g. (o.026 mole) o~ 1,7-dibromo-hcptane there was obtained 16.0 g. of 1,7-bls-~4-(decylamlno)-l-pyrldlnlumJheptane dibromlde, m.p. 145-147C.
.
;'''' .
."
.',, . ' '. .
o~
Example 66 ~ollowing a procedure similar to that descrlbed in Example 64~ but employing 11.7 g. (0.050 mole) Or 4-(decylamlno)pyridine and 6.8 g. (0.025 mole) Or 1,8-dlbromo-octane there was obtained l~.S g. of 1,8-bis-[4-(decylamino)-l-pyridinium]oct~ne dibromide, m.p. 180-182C~
., .
- Example 67 Following a procedure similar to that described ln Example 64B but employing 11.7 g. (0.050 mole) of 4-(decylamino)pyridine and 7.15 g. (0.025 mole) of 1,9-dlbromononane there was obtained 15.1 g. of 1,9-bis-[4-(decylamino) l-pyridinium]nonane dibromide, m.p. 124-126C.
. , Example 58 ~ Followlng a procedure ~imilsr to that described ;~ 15 in Example 64B but employing 11.2 g. ( o. o48 mole) Or 4-~ (decylamino)pyridine and 7.2 g. (o.024 mole) of 1,10 ;~ dibromodecane there was obtained 14.6 g. of 1,10-bis-~4-~ (decylamino)-l-pyrldinium]decane dibromlde, m.p. 173-174C.
. .:
~ Example 69 , . .
Following a procedure similar to that described ;I ln Example 64B but employing 11.2 g. (o,o48 mole) of 4-(decylamino)pyridine and 7.9 g. (o.024 mole3 of 1,12-!; dibromododecane there was obtained 16.5 g. of 1,12-bis-[4-; (decylamlno)-l-pyridlnium]dodecane dibromide, m.p. 102-106C.
;,,:', ~ ' .,, :
,........................ ..
. . .
~ -52-- .
:, ,.. .
., ~ .
; , : ..
~ . ., ' .
Example 70 To a stirred warm solution contalning 13.6 g.
(0 052 mole) Dr 4-(dodecylamino)pyridine ln 140 ml. of acetonltrlle was added dropwlse a solution contalning 6.34 g. (o.~26 mole) of 1,6 dlbromohexane in 50 ml. Or ; acetonltrile~and the resulting mixture heated under ref-lux overnight. The reaction mixture was cooled and the precl-- pitated solid was collected by filtration. The collected solid was di~solved in absolute ethanol and the resulting ~olution ~reated with decolorizing carbon and ~iltered.
The ~lltrate was evaporated to dryness under reduced pressure a~fording a residual whlte solid which was slurried in , .
ether, collected ~y filtration and drled at 60C./0.1 mm.
to glve 17.63 gO of 1,6-bis-[4-(dodecylamino~-1-pyrldinlum]-;- 15 hex~ne dibromide, m.p. 164-lÇ5C.
Example 71 Following a procedure similar to that described in Example 70 but employing 13.6 g. (0.052 mole) of 4-(dodecylamino)pyridine and 6.71 g. (0.026 mole) Or 1,7-dibromoheptane there was obtained 18.03 g. o~ 1,7-bis-[4-(dodecylamino)-l-pyrldinlum]heptane dibromlde, m.p. 148-150C, ` Example 72 Following a procedure similar to that described ln Example 70 but employing 12.59 g. (o.o48 mole) Or 4-(dodecylamlno)pyrldine and 6.53 g. (0.024 mole) Or 1,8-dibromooctane ~here was obtained 16.18 g. Or l~ 8-bis-[4-(dodecyl8mino)-1-pyridinium]octane dibromide, m.p. 184-185C.
~ . ~ . . , ~ " . - .:
~ ~7;~1R
Example 73 Following a procedure slmllar to that described ln Example 70 but employlng 12~59 gO (o.o48 mole) o~' 4-(dodecylamino)pyridine and 6,86 g. (o.024 moie) of 1,9-dlbromononane there was obtained 19.35 g. o~ 1,9-kls-[4-; (dodecylami~o)-l-pyridinium]nonane dibromlde, m.p. 1~4-135C.
Example 74 ~ollowing a procedure aimilar to that described in Example 70 but employlng 12.59 g. (o.o48 mole) Or 4-~odecylamino~pyridine and 7.2 g. (0.02~ mole) of 1,10-dibromodecane there was obtalned 18.08 g. o~ l,10-bis-[4-(dodecylamino)-1-pyrldinium]decane dlbromlde~ m.p. 178-- 180C.
Example 75 ~ollowlng a procedure simllar to that descrlbed in Example 70 but employlng 11.54 g. (0.044 mole) o~ 4-(dodecylamino)pyridlne and 7.22 g. (0.022 mole) o~ 1,12-dlbromododecane there was obtained 17.68 g. of 1,12-bis-~4-(dodecylamino)-1-pyrldinlum~dodecane dlbromlde, m.p.
75-77C.
. . .
Example 76 A, To a stirred warm solution containing 21.0 gO
(0.102 mole) Or 4-(~-chlorophenylamlno)pyridlne ln 150 ml.
Or N,N-dimekhylrormamide wa~ added dropwise a solution con-~ ?5 tainlng 11.02 g. (0.051 mole) o~ 1,4-dibromobutane in 50 ml.
j o~ acetonltrile and the resultlng mixture was heated 2.5 hourc on a steam bath. The reaction mlxture was cooled to .. ' .
: ~ .
.",,~ , , , ,,,, . - ,....... .
.
,, ., . . ..
.. :
. ~ ~ ' . .-,.. . . . . :
~`-` f~'73~3~i room temperature, dlluted wlth ether and the product allowed to c~ystallize, The preclpltated solld was collected by ~lltration, washed wlth a mlxture of acetonltrlle and ether and alr-drled to glve 27.4 g. of 1,4-bis-[4-(p-chlorophenyl-amlno)-l-pyridinium]butane dlbromide, m.p. 182-189C.
B. A ~uspension of the above product ln 500 ml. o~
water was treated with ice and 2N aqueous sodlum hydroxlde and the resulting mixture extracted thoroughly with chloro-rorm. The chloro~orm extracts were dried over anhydrous sodlum sulfate and evaporated to dryness under reduced pressure to glve 21.0 g. Or the correspondlng anhydro base as an oil ~ich 501idi~ied ~n standing.
C. A solutlon containing the above anhydro base in 2~0 mli o~ methanol was acldi~led wlth a solukion o~ methane-~ - 15 sulfonlc acld in methanol. Evaporatlon to dryness under ; reduced pressure afforded an oil which was crystalllzed from methanol-ether. lThe solid thus-obtalned was recrystalllz-ed ~rom methanol-ether to give a~ter drylng 48 hrs. at 92C./
0.1 mm. 18.95 g. o~ 1,4-bls-[4-(~-chlorophenylamino)-1 pyridinlum]butane dimethanesul~onate, m.p. 245-247C.
- ~ Example 77 A. To a stlrred, warm solutlon contalning 21.0 g.
(0.102 mole) o~ 4-(p-chlorophenylamlno)pyrldlne ln 200 ml.
l Or N,N~dlmethyl~ormamlde was added dropwlse a sol~tlon 1 25 contalning 12.45 g. (0.051 mole) o~ lJ6-dlbromohexane ln 50 ml. o~ acetonitrile and the resultlng mlxture was heated 4 hburs on a steam bath. Upon cooling to room temperature a solid beg~n to preclpitate. The reaction ml~ture was dlluted wlth 150 ml3 o~ acetonltrile and cooled further ln .~ ' .
; ice. The precipitated ~olid was collected by flltratlon and alr-dried to glve 27.2 g. of 1,6-bls [4-(~-chlorophenyl-amino)-l-pyridinium]hexane dlbromide, m.p. 148-150C.
; B. A methanol solution of the corresponding - 5 ;anhydro base prepared from the above dibromide ; according to the procedure of Example 76B wa~ acldlfied with methanesulfonic acld and then evaporated to dryness ; under reduced pressure. The residual oil was crystallized rrom acetone-methanol to give after drying 48 hrs. at 75C./0.1 mm~ 25.2 g. o~ 1,6-bis-[4-(~chlorophenylamino)-l-pyridini~lm]hexane dimethanesulfonate, m.p. 108-110C.
:
Example 78 . , A. To a stirred, warm solution containing 21.0 g.
(0.102 mole) of 4-(p-chlorophenylamino)pyridine in 200 ml.
; 15 o~ N,N-dimethyl~ormamide was added dropwise a solution containing 13.9 g. (0.051 mole) of 1,8-dibromooctane in 50 ml. o~ acetonitrile and the resultlng mixture heated 1.5 hour~ on a steam bath. The reaction mlxture was then diluted with 100 ml. of acetonitrile and heatlng was con-tlnued another 2.5 hours when an addltional 100 ml. o~ aceto-; ' ;l nitrile was added. A~ter heating another 2 hours the re-action mixture was cooled and the solid which had precipitated wa~ collected by ~iltration, washed with a mixture of aceto-nitrile and ether and dried to give ~0.1 g. of 1,8-bls-[4-(~-chlorophenylamino)-l-pyridinium]octane dibromide, m.p.
245-247C~
B. A methanol solution of the corresponding anhydro base prepared ~rom the above dibromlde .
i -56-., ,.;
, j~, . ., ~
,-.. ,........ - . - : :
, . . . . .
. . - .. . - . . . . .. , . . . :, . .
31~
according to the procedure of Example 76B was acldlfled with methanesulronlc acid and then evaporated to dryness under reduced pressure. ~he residual oll was dlssolved in acetonit~lle and the resultlng solutlon treated wlth acetone until cloudy followed by clariricatlon wlth a small amount ~; of methanol and cooled. The crude solld whlch preclpltated - was collected and recrystalllzed from acetonitrlle acetone ; to glve after drying 36 hours at 80C./0.1 mm., 23.5 g. of 1,8-bis-~4~ chlorophenylamino)-1-pyridinlum]octane dime'h~nesul~onate, mOp. 164-165C.
.~
Example 79 A. To a stirred, warm solution containing 21.0 gu (0.102 mole) of 4-(~-chlorophenylamino)pyridine ln 200 ml.
of N,N-dimethylformamide was added drop~ise a solution con-taining 15.3 g. (0.051 mole) of lglO-dibromodecane ln 50 ml.
- of acetonltrile and the resulting mixture W3 S heated 3.5 hours on a steam bath. The reaction mixture was then evaporated to dryness under reduced pressure and the resi-dual oil was crystallized ~rom methanol-acetonitrile. The solld so-produced was collected by filtratlon and washed with a cold mixture of acetonltrile and ether to glve 28.0 g.
of l,10-bis-[4-~p-chlorophenylamino)-1-pyridlnium]decane , dlbromide, m.p. 225-230C.
B. A methanol solution o~ the correspond~ng ~5 anl-l-Jdro base prepared from the above dibromide accordlng to the procedure of Example 76B was acldlfled wlth methanesulronlc acid and then evaporated to dryness under reduced pressure. ~he residual oll was crystallized from "' ' , ' . .
,",,,,1 ' :. ~
.. : ......... .
~cetonitrile-ether. The crude solld thus-obtained was dlssolved ln methanol and the resultlng solutlon was treated with decolorizlng carbon and filtered. Evaporatlon of the flltrate afforded an oil which was suspended ln a mlxture of acetonitrile and acetone to give a crude solid. Recrystalll-zation rrom methanol-ether afforded a~er drylng 48 hours ; - at 95C./0.1 mm. 18.4 g. o~ 1,10-bis-~4-(p-chlorophenyl-~ amino)-l-pyrldlnlum]decane dimethanesul~onate, m.p. 202-; 204C~
Example 80 To a stlrred warm solutlon containlng 10.0 g.
(0.049 mole) of 4-(p-chlorophe~ylamlno)pyrldlne in a mlxture o~ 27~ ml. of acetonitrlle and 100 ml. of N,N-dimethyl-formamlde was add2d dropwlse a solution contalning 5075 g.
(0.025 mole) of 1,5-dlbromopentane ln 25 ml. of acetonitrile and the resulting mlxture heated 24 hours under reflux.
The reaction mlxture was then evaporated to dryne3s under reduced pressure and the resldue triturated with a mixture of ether and acetonltrlle. The pale yellow solld so-obkained was redlssolved ln ethanol and the resulting solution treated with decolorizing carbon and flltered.
,.:, The filltrate was evaporated to dryness under reduced pressure and the resldual oll was crystallized from ether-acetonitrlle.
~;~ The colorless solid was recrystallized from methanol-¢~ 25 acetonitrile and drled 48 hours at 115C./0.1 mm. to glve ;l 8.1 g. o~ 1,5-bis-[4-(~-chlorophenylamlno)-1-pyridinium~-~; pentane dlbromlde, m.p. 166-168C.
.j .
,` . ' .
E~ample 81 To a stlrred, warm solutlon contalnlng 10.0 g.
(0.049 mole) o~ 4~ chlorophenylamino)pyridine in a mix-ture o~ 125 ml~ of N,N-dimethylformamide and 50 ml. Or acetonitrile was added dropwise a solution contalnlng 6.45 g.
; o~ dibromoheptane in 25 ml. of acetonltrile and the resulting mlxture heated 19 hours under re~lux. The reaction mlx~ure was then evaporated to dryness under reduced pressure and the residual oil crystallized from ethanol-acetonitrlle. The solid so-produced was dissolved in methanol and the resulting solution ~re~ted with decoloriz-lng ~arbon:~nd: ~llte.red.:,~ The ~iltr~te was evaporated to ~ryness u~der ~acuu~ and ~he residual Dil agai~ crystallized ~rom ethanol-acetonitrile. The product was collected by ;~ 15 ~lltratlon and-drled 36 hours at 105C.~0.1 mmO to give ~ 10,4 g. o~ 1,7-bls-~4-(p-chlorophenylamino)-1-pyridiniumJ-.
~ h~ptane dibromide, m.p. 202-204C.
.''~ ~ .
Example 82 Following a.procedure slmilar to that described ~0 in ~xample 8} but employlng 10.0 g. (0~049 mole) o~ 4-(p-chlorophenylamlno)pyridine and 7.15 g. (0.025 mole) of 1,9-dlbromononane there was obtalned 11.2 g. o~ 1~9-bis-~4-chlorophenylamino)-l-pyridlnium]nonane dibromide, m.p~
178-179C.
,,~
By ~ollowing procedures simllar to those descrlbed in the ~oregolng e~amples the following bis-[4-(R-amlno)-l-pyrldinium~alkanes are obtained:
; ~
~ ......... . . . .. ... .. .
.~ 3l~
3-~thyl-1,6-bls-[4-(tetradecylamino)-1-pyridinium]-hexane dibromlde by reacting l,6-dlbromo-3-ethylhexane wlth 4-(tetradecylamino)pyridlne whlch ls in turn obtained by reactlng N-(4-pyridyl)pyrldinlum chlorlde hydrochloride with tetradecylamine hydrochloride, 195-bis-L4-(octadecylamlno)-l-pyrldlnium]pentane - dibromlde by reacting 1,5-dibromopentane with 4-(octadecyl-~. amlno)pyridine which in turn ls obtalned by reactlng N-(4-pyridyl)pyrldinlum chloride hydrochloride with octa-` 10 . decylamlne hydrochloride, 1,ll~bis-L4-(2~2-dimethylbutyl~mino)-1-pyrldinlum]-3-methylundecane dibromide by reacting 1,11-dibromo-3-methyl-undecane with 4-(2,2-dimethylbutylamino)pyrldine which ln turn 1B obtalned by reactlng N-(4-pyrldyl)pyrldlnium chlorlde ~:~ 15 hydrochloride with 2,2-dimethylbutylamlne hydrochlorlde, 1918-bl~-[4-(1~4-dimethylpentylamlno?-l-pyridlnium]-octadecane dlbromide by reactlng 1918-dibromooctadecane wl'h 4-(1.94-dim~thylpentylamino)pyridine which in turn ls ~,:
obtained by re~cting N-(4-pyridyl~pyridlnium chlorlde hydro-chloride wlth 194-dimethylpentyl~mlne hydrochlorlde, 4,9-dimethyl-1,12-bls-L4-(1,5-dimethyl-4-ethyl-, . . .
. hexyl~mino)-l-py~ldlnlum]dodecane dibromide by reactlng lJ12-dibromo-4,9~dimethyldodecane with 4~(1,5-dimethyl-4-~i et.hylhexylamino)pyrldine which in turn is obtalned by react-ing N~(4-pyridyl)pyrldinlum chloride hydrochlorlde wlth lg5~
~I dimethyl-4-ethylhexylamlne hydrochlorlde, ,,¦ 1,10-bis-[4-(cyclopentylamino)-1-pyrldinlum~- .
,~, ~i decane dichloride by reacting l,10-dlchlorodecane wlth 4-i ¦cyclopentylamino)pyrldl~e which in turn is obtained by .. . .
O--~, .
~, .
,,, , : ~i ,, .. . ,, ,. . . . . ,, : :. ., . -f~
reacting N-(4-pyrldyl)pyridinium chloride hydrochloride wlth cycl~pentylamine hydrochlorlde, 1,12-bis-[4-(cycloheptylamino)-1-pyridinium]-dodecane dibromlde by reactlng l,12-dibromododecane wlth 4-(cycloheptylamino)pyridine which in turn i9 obtained by reactlng N-(4-pyrldyl)pyridinium chloride hydrochloride with cycloheptylamine hydrochloride, 1,6-bls r [4-(p-bromophenylamino)-1-pyrldinlum]-3-methylhexan.e dibromide by reacting ls 6-dibromo-~-methyl-hexiane wlth 4~ bromophenylamino)pyridine which in turn obtalned ~y reactlng N-(4opyrldy~)pyridlnlun chloride hydrochlo~ide w.th p~bromoaniline hydrochlorlde, l.O10-bi~-[4-(m-fluorophenylamino)-l-pyridinium]-decane dib~omide by reacting l,10-dlbromodecane with 4-(m-~ 15 fluo~opheny-am no)pyridine whlch in turn i~i obtained by r~actlng ~ 54~pyridyl)pyrld~nium chloride hydrochloride with m-~l~oroanlllne hydrochlor de, . 1~4-bis-[4-(~-chloro-4-rluorGphenylamlno)-l-pyridlnlum~-2ethylbutane dlbromlde by reacting 194-dl-bromo-2-ethyibutane with 4-(3-chloro-4-fluorophenylamino)-.:
~ pyridlne which in turn i8 obtained by reacting N-(4-j~ pyridyl)pJridinium chloride hydrochloride wlth ~-chloro-4-. rluoroaniline hydrochloride, lil 1,10bls-[4-(benzylamino)-1-pyridlnium]decane dlchlorlde by reactlng l,10-dichlorodecane with 4-(benzyl-amino)pyridlne, .. 1,8 bi~i~[4-(~4-methylenedioxyphenylamino)-1-pyridiniun]octane dibromide by reacting l,8-dibromooctane . with 4-(~,4-methylenedloxypheny~amino)pyridine which in . -61-. _ . ~ .. .... . . ... ...... . ..
91~
turn ls obtalned by reactlng N-(4-pyridyl)pyridlnium chlorlde hydrochloride with 3J4-methylenedloxyanillne hydrochlorlde, 1,9-bls-[4-(p-ethylphenylamlno)-1-pyrldlnium]nonane dibromlde by reactlng lJg-dlbromononane wlth 4-~p-ethyl-` 5 phenylamino)pyridine which in turn ls obtained by reacting - N-(4-pyr.dyl)pyridinlum chloride hydrochloride with p-` ethylaniline hydrochloride, 1,10-bis-[4-(p-methoxyphenylamino)-1-pyridinium~-decane dichlorlde by reacting lJ10-dichlorodecane wlth : ' 4-(~-methoxyphenylamino)pyridine which is in turn obtainPd , by reacting N-(4-pyridyl)pyridinium chloride hydrochloride ~ . wlth ~-anlsldlne hydrochlorlde, 1911-bis-[4-(m-nitrophenylamino)-l-pyridinium]-undecane dlbromide by reacting lJll-dibromoundecane wlth ~, 4-(m-nitrophenylamino)pyridine whlch in turn is obtained by reacting N-(4-pyridyl)pyridinlum chloride hydrochlorlde wlth m-nitroanlline hydrochlorideJ
~ . 1,12-bis-~4-(o-cyanophenylamino)-1 pyrldlnium]-`~ ~ dodecane dibromide by reacting 1,12-dibromododecane with : 20 4-(o-oyanophenylamino)pyrldine which in turn ls obtained by reacting N-I4-pyrldyl)pyridinium chlorlde hydrochloride , with o-cyanoaniline hydrochlorldeJ
.i 1,16-bis-~4-[m-(trifluoromethyl)phenylamlno]-1-pyrldlniu~hexadecane dibromlde by reacting 1,16-dibromo-hexadecane and 4-Lm-(trlfluoromethyl)phenylamino]pyrldine which in ~urn ls obtained by reacting N-(4-pyrid~l)pyridinium chloride hydrochloride with m-(trifluoromethyl)aniline hydrochloride3 and 1,7-bis-[4-(2-methoxy-~-methylphenylamino)-1-pyridinlum]heptane dlbromlde by reacting 1l7-dibromoheptane ; -~, .. .. .
. ~ ~ . ~, . . . . . . . .
wlth 4-(2-methoxy-5-methylphenylam~no)pyrldlne whtch in turn is obtalned by reacting N-(4-pyrldyl~pyrldlnlum chlorlde hydrochlorlde wlth 2-methoxy-5-methylanlline hydrochlorlde.
The ~ollowing are further illustrative e~amples o~ bls-[4-(R-amlno)-l-pyrldlnium]alkanes o~ fonmula I which are obtalned in accordance wlth the above-de~cribed .
procedures:
3~methyl-1,5-bl~-~4-(undecylamlno)-1-pyridlnlum]-pentane dlbromide, 3-propyl-1,5-bls-[4-(trldecylamlno~
pyridinlum]pentane dichlorlde, 4,4-dimethyl~1,7-~ls-[4-(pen~adecylamino)-l-pyrldlnlum]heptane sul~ate, 2,6-dlmethyl-: 1,7-bis-[4-(hexadecylamino)-1-pyrldlnium~heptane di~ul~a-mate, l-methyl-1,4-bi~-~4-(heptadecylamlno)-1-pyridlnlum-]-butane dlbenzenesulronate, 2~4,4-trimethyl-1,6-bl3-~4-(2-methylhexylamino)-l-pyrldlnium]hexane bls-cyclohexyl~ulfa-mate, l,17-bl6-[4-(3-ethylpentylamlno)-l-pyridlnium]--. heptadecane dlbromlde, 1,16-bis--[4-(1-ethylhe~ylemlno)-1-pyridlnium]hexadecane dlnitr~teJ 1~15-bl~-[4-(heptylamlno)-.
l~pyrl~inlum~pentadecane dibromide, 1,13-bls-C4-(octylamlno)-16pyridinium]trldecane di-2-naphthalenesulfonate, l,ll-bis-~4-(3-ethylheptyl~mino)-1-pyridlnium]undecane 2,.6-; i~
; naphthalenedlsul~onate,-4-me~hyl-1~14-b~s-~4-(2-propylpentyl-` amino)-l-pyridinlum]tetradecane dichlorlde, 5-ethyl-1. 9-bis-: 25 ~4-(1,3,5-trimethylhexylamlno)-1-pyrldinium]nonane dibromlde, ,.
~ 3,3,6,6,-tetramethyl-1,8-bls-~4-(heptylamino)-1-pyridlnium]-octane dlbromide, 2,13-dimethyl-1,14-bis-[4-(1,2-dlmethyl-tetradecylamino)-l-pyrldlnlum]tetradecyl dibromlde, 1,6-bis-~4-(1-methylpentylamlno)-1-pyrldlnlum~hexan~ dl-~-toluene-sulYonate, 1,8-bis~[4-(2-methylheptylamino)-l~pyridinlum]octane ......... , , . ~. .,: .
. . - . . . .
:; - . ' . ' ;. . , ., .. : . ' ~0'~9~ IL
,: , . ..
dliodlde, 1,8-bis-[4-(2-methyl-3-ethylpentylamlno)-1-~ pyrldinium]octane diethanesulronate, 1,9-bis-[4-(o-chloro-; phe~ylamino)-l-pyrldinium]nonane dibromlde, 1,8-bis-[4-(p-lodophenylamlno)-l-pyridlnium]octane dilodlde, 1,12-bis-.: 5 ~4-(2,4 difluorophenylamino)-l-pyridinium]dodecane dibromide, 1,11-bi~-[4-(2,5-dlbromophenylamlno)-1-pyrldlnlum]undecane dlbromide, 1,10-bl~-[4~(3,5-dlchlorophenylamlno)-1-pyrldlnlum]-decane dich'orldeJ 1l8 bis-~4-(2-~luorobenzylamlno)-1-pyrldinium]oe'Giane dichloride, 1,18-bls-[4-(3,4-dichloro-benzylamino)-l-pyridlnlum]octadecane dlbromlde, 1,4~bis-- [4-(4-hydroxy-3-~ethoxybenzylami.no)-1-pyrldlnlum]butane dibromide and 1,12 bis--~4-(4-methylbenzylamino)-1-pyridlnlum]-~ dodecane dibromide.
~ i Example 83 ..,,~:
To a warm, stirred solution containing 11.52 g.
(0.06 mole) of 4-(heptylamino)pyridine in 100 ml. of acetonitrile was added in small portions a solution containing 7.3~ g.
?
: (0.03 mole) of ~ dibromo-~-xylene in 150 ml. of aceto-nitrile. After addition was complete a large mass of ., j . .
j, 20 colorless crystals had separated from solution. The reaction ,ii . mixture was heated under reflux 6 hours. After cooling to ~, roo~. temperature the solid product was collected by filtration, washed with acetonitrile-ether, combined with 3.1 g. of ; product obtained in a pre~lous run and dried 28 hours at ` ~ 25 100C./0.1 mm. to give 22.0 g. of ~,~'-bis-~4-(heptylamino)-pyridinium]-~-xylene dibromide, m.p. 297-298~C.
, . .
.. . ~ -64 ,`
,. . .
.
;.~
.... . .
, ::.. . : .
, j ~ !
.,; i ' . . ' . : .
'. ',' , ~' ~ : ; :
j- ~ ' ' ', ., ' ' '' ~C'~ 311 Example 84 Following a procedure similar to that described in Example 83 but employing 11.6 g. (0.065 mole) of 4-(hexyl-amino)pyridine and 8.7 g. (0.033 mole) of ~,q'-dibromo-p-xylene and refluxing the reaction mixture 20 hours, therewas obtained 19.3 g. of ~,~'-bis-[4-(h~ylamino)pyridinium]-p-xylene dibromide m.p. 313-315C.
E~ample 85 A suspension of 19 g. of 4-aminopyridine and 23 g.
o ~ dichloro-2,3,5,6-tetramethyl-p-xylene in 600 ml. of methanol was heated on a steam bath to effect complete solution. ~.fter filtering from a small amount of insoIuble material the clear solution was warmed gently on the steam bath for 2 hours during which time a white solid began to separate. The mixture was cooled to room temperature and the solid product was collected by filtration, washed ~ successively with methanol and ether and dried 24 hours ; under vacuum at 100C. to give 29 g. of ~,d'-bis-(4-amino-1-pyridinium)-2,3,5,6-tetramethyl-p-xylene dichloride, m.p. >340C.
Example 86 To a hot solution containing 12.5 g. (0.132 mole) of 4-aminopyridine in 100 ml. of 2-propanol was added 11.6 g.
(0.066 mole) of ~,~'-dichloro-~-xylene followed by 400 ml.
of methanol. The mi~ture was heated to effect complete 25 solution. After filtering from a small amount of insoluble material the clear solution was diluted with 500 ml. of , : ~ :
~' .
,..
.
~ .
.
.' ~. ' " ' - . ' : .',, , ', ' , IL~D7~31i.
ethyl acetate and cooled to room temperature. The solld product was collected by fitration, wa~hed with ethylacetate and dried to give 16 g. of q~ bis-(4-amino-l-pyridinium) p=xylene dichloride, m.p. 332-335C.
The following are further illustrative examples of the ~,~'-bis-[4-(R-amino)-l-pyridinium]xylenes of formuia II
which are obtained in accordance with the above-described procedures:
~al-Bis-[4-(ethylamino)-l-pyridinium]-p-xylene dibromide by reacting ~,~'-dibromo-p-xylene with 4-(ethyl-amino)pyridine;
t' . d,~'-Bis-[4-(2-ethylhexylamino)-1-pyridinium]-~-xylene dichloride by reacting ~,a'-dichloro-p-xylene with , ........................................................................... .
4-(2-ethylhexylamino)pyridine (b.p. 145-150C./0.9 mm.) ` 15 which was prepared by reacting N-(4-pyridyl)pyridinium chloride hydrochloride with 2-ethylhexylamine hydrochloride;
'-bis-[4-(decylamino)-l-pyridinium]-p-xylene .,:
dibromide by reacting ~,~'-dibromo-_-xylene with 4-(decylamino)-.,: .
pyridine (m.p. 71-73C.) which was prepared by reacting N-(4-` 20 pyridyl)pyridinium chloride hydrochloride with n-decylamine hydrochloride;
; ~,~'-bis-[4-(dodecylamino)-1-pyridinium]-p-xylene dichloride by reacting ~,~'-dichloro-p-xylene ! with 4-(dodecylamino)pyridine;
:.1 ;~i 2ja,~ -bis-[4-(octadecylamino)-l-pyridinium]-~-li xylene dibromide by reacting ~,~'-dibromo-p-xylene with ,. . .
;, 4-(octadecylamino)pyridine which in turn is obtained by reacting N-(4-pyridyl)pyridinium chloride hydrochloride with octadecylamine hydrochloride;
:i~
c,:
: ` ' ' ., ,., .. ~.. ... ~.... ,.. ,,.. ~ ..... .. . ..
~;`' . ~ , ;," ,,, . . :
. ,. - .
: , , , ~3~
a,~ -bis-[4-(tetradecylamino)-1-pyridinium]-m-; xylene dichloride by reacting ~,~'-dichloro-m-xylene with 4-(tetradecylamino)pyridine (m.p. 91-93C.) which was pre-: pared by reacting N-(4-pyridyl)pyridinium chloride hydro-. 5 chloride with tetradecylamine hydrochloride;
bis-[4-(butylamino)-1-pyridinium]-o-xylene dibromide by reacting ~,d'-dibromo-o-xYlene with 4-(butylamino)pyridine;
d,~'-bis-[4-(3-ethylheptylamino)-1-pyridinium]-5-methyl-~. .
IO m-xylene dibromide by reacting a,~'-dibromo-5-methyl-m-xylene with 4-(3-ethylheptylamino)pyridine which in turn is obtained by reacting.N-(4-pyridyl)pyridinium chloride : hydrochloride with 3-ethylheptylamine hydrochloride;
~,~'-bis-[4-(2-methylheptylamino)-1-pyridinium]- ~ -. 15 2,5-dimethyl-_-xylene dibromide by reacting q,~'-dibromo-~ 2,5-dimethyl-p-xylene with 4~(2 methylheptylamino)pyridine : which in turn is obtained by reacting N-(4-pyridyl)pyri-~ dinium chloride hydrochloride with 2-methylheptylamine ;~ hydrochl.oride;
2~ ~,a ~ -bis[4-(octylamino)-1-pyridinium]-2,4,6-trimethyl-m-xylene dichloride by reacting a,a ~ -dichloro-2,4,6-trimethyl-m-xylene with 4-(octylamino)pyridine . IM.P. 62-63~C.) which was prepared by reacting N-(4-pyri.dyl)-pyridin'um chloride hydrochloride with n-octylamine hydro-.~ 25 chloride;
'-bi~-[4-(2,2r-dimethylbutylamino)-1-pyridinium]-2-chloro-p-xylene dichloride by reacting ~,~',2-trichloro-p-xylene with 4-(2,2-.dimethylbutylamino)pyridine ----_._ __ __ ___ .... , . ,.. : .. . .
, . . . . : . . .
,: which in turn ls obtained by reacting N-(4-pyridyl)pyridinium ~ chlori.de hydrochloride with 2,2-dimethylbutylamine hydro-i chloride;
' bis-[4-(methylamino)-1-pyridinium]-4-chloro-o-xylene dibromide by reacting a,~'-dibromo-4-chloro-, o-xylene wi.th 4-(methylamlno)pyridine;
~,4'-bis-[4-(2-propylpentylamino)-1-pyridinium3-; ~,5-dichloro-p-xylene dichloride by reacting ~,a ~, 2, 5-; tetrachloro-p-xylene with 4-(2-propylpentylamino)pyridine " 10 which in turn is obtained by reacting N-(4-pyridyl)pyridiniu~ ' ~' chloride hydrochloride with 2-propylpentylamine hydro-~, chloride;
~; a,d ~ ~~iS- [ 4-(1,1-dimethylundecylamino)-~.-~ pyridinium]-2,3,5-trichloro-p-xylene dlchloride by reacting '' 15 ~,d',2,3,5-pentachloro-~-xylene with 4-(1,1-dimethylundecyl-~: amino)pyridine whi,ch in turn is obtained by reacting N-(4-' pryidyl)pyridinium chloride hydrochloride with 1,1-,.",~ dimethylundecylamine hydrochloride;
.:
~ '-bis-[4-(nonylamino)-1-pyridiniuml-.
2n 2~3~5~6-tetrachloro-p-xylene dichloride by reacting ',2,3,5,6-hexachloro-p-xylene with 4-(nonylamino)pyridin~
... .
.~ (m.p~ 59-60C.) which was prepared by reacting N-(4-pyridyl)-' pyridinium chloride hydrochloride with n-nonylamine hydro--.~ chloride;
: .
~ 25 a,a ' -bi~-[4-(benzylamino)-1-pyridin um~p-xylene ,'u dibromide by reacting ~,~'-dibromo-p-xylene with 4-(benzylamino)-;:' pyridine which in turn is obtained by reacting N-(4-pyridyl)-',' q pyridinium chloride hydrochloride with benzylamine; and, ; .
,' .~ . , ' . .
'7~
~ bis-[4-(benzylamino)-1-pyridinium]-2-chlo~o-p-xylene dichloride by reacting ~,~',2-trichloro-p-xylene with 4-(benzylamino)pyridine which in turn is obtained by reacting N-(4-pyridyl)pyridinium chloride hydrochloride with 5 benzylamine.
The an~ibacterial and antifungal acti~ity of representative examples the compounds of Formula I~w~s determlned ualng a modification of the Autot;ter method described by GOSB, et al. Applied Microbiology 16 (9) 1,414-1941O (1968) in which a 1,000 mcg./ml. solution o~ the test compound i8 prepared. To the first cup of the Autotray is added 0.1 ml. of the test solution. Activation Or the Autotiter initiates a sequence o~ operations by which 0.05 ml. Or the test compound solution ls wlthdrawn from the cup 15 by a Microtiter tran3fer loop and dlluted in 0.05 ml. of ;sterile water. Following thls operation, 0.05 ml. of lnoculated double-strength semisynthetic medlum (glucose) ls added automatically to each cup. The overall operation results ln final drug concentratlons ranging from 500 to 20 o.o6 mcg./ml. in twofold decrements. The Autotray is incu--bated ~or 18-20 hours at 37C. at which time the tray~ are examined visu311y for growth as evidenced by turbidity, and the concentration of the last sample ln the serles ~howlng no growth (or no turbidity) is recorded as the mlnimal ;j,~25 lnhibitory concentration (MIC) in mcg./ml. The compounds were thus tested as solutlons against a variety of gram positive and gram negatlve bacteria including Staphylococcus aureus, Proteus mirabilis, Escherichi~ coli, Klebsiells E~ g Pseudomonas ~ E~ , Streptococcus pyogenes, 3~ and against such fungi as Aspergillus niger, Candida alblcans and Trichoph~ton mentagroph~tesD
,.,~
,'~ .
'73~13L
,, .
Many of the compounds of formula I were also foundto be antibacterially effective against Streptococcus mutans and Actinomyces A-viscosis.
Virucidal activity of representativ~ 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 tl961) wherein 2 mg. of the,test compound was placed on the surface of~
the growth medium. The compounds corresponding to Examples 3, 5C, 7, 9C, 10, 11, 13, 17, 18, 21, 22, 24, 31, 33, 35, 36, 37, 53, 54, 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 ,, 79B were found inactive.
The dental plaque preYentlve activity o~ certain the compounds Or the present invention was determined 'i~ by measuring the ability Or these compounds to inhibit the productlon o~ dental plaque by Streptococcus mutans OMZ-61 as ~ollows~ ' '2Q A culture medium ~or the plaque~producing Strepto- ' ,' occu~ mut~n~ OMZ-61 containlng 1.5 g. of ~BL beef,extract, L
5 g. o~ sodium chloride, 10 g. Or dehydrated tryptlcase, '-5 g. o~ sucrose and su~iclent dlstilled water to give a ' ~otal volume of 1000 ml. is adJusted to pH 7.0 and ~terilized 'I 25 by membrane ~iltratlon. The medlum is dispensed ~septlcally ', ln 10-ml. ~llquot~ into 150 x 16 mm. test tubes and stored '::
~' at re~rlgeration temperature until used.
Two concentrations Or the compound to be tested '; are prepared by dissolving 100 mg. o~ the compound ln 1 ml.
;
,, 30 Or dlstilled water wlth the aid o~ su~iclent O.lN sodium .
' hydroxide, 10% dlmethylsul~oxide or 10% N,N-dimethyl~ormamlde ; and diluting the resu,ltlng solution to 10 ml. wlth distllled ; -70-~ .
.. :, , ., : :
~- ' ` , ' ' . ~: .
- : , . : -1~)7;~
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 ~namel or synthetic hydroxylapatite is suspended in each concentration of compound for two 1 minute periods, each followed by a l-minute air drying period. Each piece is then suspended and agitated for 5 minutes in individual test ,~, . . .
- tubes containing s~erile distilled water (rinse). They are - 10 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 37~C. for 24 hours. The same !il 15 process of two l-minute soaks in the solution of compound, each followed by 1 minute of air drying and the final 5-minute rinse is repeaked before once again suspending the hydroxlapatite in a fresh tube ~ontaining 10 ml. of beef extract medium and 0.3 ml. of inoculum. At the end of the second 24-hour period, each piece o~ 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, D & C Red No. 3 dye. This staining procedure is used in order to identify more easily the development of plaque ~ . .
after the 48-hour period of exposure to the plaque-producing :: .
organism. The staining period is followed by another 10-second 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 ` 71 ~ ~ ~7~3~31~L
the percent concentration tested. Active compounds are tes~ed 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 be formed at these lower concentrations.
Substantivity of the test compound to the tooth surface which is o~ 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 .1 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, ~5 b~illiant 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.
; -72-. . . . . .
' . . . ' .
, .
7;~3~1 Numerical, antibacterial, antifungal, and dental plaque-preventive test data for the compounds are presented in Table A hereinbelow. Corresponding data for two known compounds, viz. 1,8-bis-(4-amino-1-pyridinium)octane dibromide (Reference Compound I) and l,lO-bis-(4-amino-1-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 56C.~ horse serum (40%) in the test medium.
.
The results are expressed as the fold increase in MIC (mcg./ml.) versus Staphyloccocus aureus and Escherichia coli caused by the presence of serum and are presented -n Table B hereinbelow.
Dental plaque-preventive effectiveness in the presence of sterile human saliva (50%) was determined for xepresentative examples. Test results are read as minimum effective concentration and are presented in Table C hereinbelow.
The acute oral toxicity (ALD~o) of several representativ, examples was determined as follows: Groups of 3 young adult male Swiss-Webster strain albino mice were fasted approximately ~25 4 hours before medication and then medicated once orally by ;stomach tube. All mice were observed for 7 days after .
''''`
.'' '.' 'I , . . .
... , . - ': ., . ' . ' ~''. .'~ '' . '' ~0'7~
. . , ~ ~ .
medication. Autopsy of all mice in the study revealed no gross tissue changes except for the group receiving 1000 mg./kg. of the compound of Example 25 wherein con-gestion of the glandular portion of the stomachs of two of the three mice was observed. The results are presented in Table D herein~elow.
. ., . : ' ". .
; , ; , ,' ~ .
. :
.,. ~: .
:~ `
. .
., ~, .
. ~ .
.
~v c ~
~ c v- v o o o o o o o o o o o p~ ~ ~ ~ ~
, C V O O, o . o -- ~ - .~
c cO ~ cn ~ ~ O ~ co ~ O~ 0 o 6 ~ ~ m ~ o o ~ 0 _~
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TABLE ~ ' Ef~ect of Serum on Bacteriostatic Activity ' ' ' ' , . . .
5: MIC (n~/ml) vs. Indlcated Bacterla .
:: S. ~ureus A~CC 6538 E. Co1l ATCC 8739 ." . _ . . .
Cpd. of % 40$ Fold ~ 4~ . Fold Ex. No. Serum Serum Increase Serum Serum Increa~e _ _._ ..... ~
. . 79~ .25 7.8 32 0.5. 15.o 32 22 0.25 3.9 .1~ 0.5 ~.9 8 ~: 33 0.125 1.95 . 1~ 0.25 3.9 ~ 16 ~ 26 0.125 1.95 16 o.5 7.& lo .. ~ 24 0.125 1.95 16 0.25 7.8 32 58 0.25 3.9 16 0.5 15-~ 32 . 3 0.39 3.12 8 0.7825.0 32 lD 0.195 3.12 16 ¦ 1.5525.0 16 7 0.10 1.56 6: 0.3912.5 ~32 ~ 5C 0.10 3.12 32 :0.782~.0 1 32 ,5'j , ~ , " . 13 . 0.25 ~1.2 1~8 1.0 31.2 32 11 0.~ 7.8 16 : o.5 31.2 64 9C 0.5 7.8 16 ~.o 62.5 64 . 29C 0.5 .7.8 16 3.9 62~.5 16 41C 0.2~ 7.8 32 1.0 62.~ 64 ~' ~ : 83 o.i8 6.25 8 0.78 6.25 84 3.12 12.5 4 ~.56 6.25 il . , ."~
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~ABLE C
Staining Potential and Effect of Saliva on Dental Plaque Preventive Activity ~ Dëntal Plaque -1~ Preventi~e Activity in 50~ saliva Staining C~d. of Ex. No. Minimum Effective Conc. (~ Concentration (%) ~ ~ .
27 0.05 24 Ca. 0.005 0.05 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 0.05 0.005 6 0.005 13 0.005 f , 14 0.~1 0.05 11 0.05 0.05 12 Ca. 0.005 0 05 0.005 0.05 44A 0.005 0.05 47 0.004 29C 0.004 ~I 50 0.004 '' 51 0.004 '~' 49 0.005 ,,,:~ --____ ________________ ; 1. No bacterial growth at this concentration, plaque formed at 0.005~
~, i ~
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'7;39~1 Table D
Acube Oral Toxicity ~LD50) Solution or Dose, mg~kg. of Mortality Cpd. of Ex. No. Suspension Total Ma~erial 24 Hrs 7 Dayfs 23 ,~queous125 ` 0/3 0/3 Solution250 0/3 0/3 ~ . 500 1/3 l/3 :~ 1000 3/3 3/3 ~ 7-Day ALD50 = 625 m~kg .: 26 Suspension 125 0/3 0/3 . ir. 1% G.Tl 250 0/3 0/3:
1000 . 0/3 0/~ .
7 Day ALD50 = ~000 ~g,~kg 27 Aqueous125 0/3 V3 .. Solution250 0/3- 0/3 500 .1/3 V3 ~ , 1000 1/3 3/3 ;~ ~ 7-Day ALD50 = 250 mg~kg .. . .
:j 24 Suspension 125 0/3 . 0/3 in 1% G,T. 250 0/3 0/3 , 500 0/3 1/3 ', 1000 0/3~. 0/3 . 7~Day f~LD50 = ~1000 mg~kg A~ueous250 1/3 1/3 .,: . - Solution500 V3 V3 ~, ~7-Day ~LD = 500 mg~k~
3 Suspension 12S 0/3 0/3 in 1~ G.T. 250 0/3 0~
500 0/3 l/3 -Day ALD50 = 1000 mg~kg ~ .
. 4 Susp~nsion 125 0/3 0/3 ~ . : in 1~ G.T. 250 0/3 0/3 .~ A , 0/3 0/3 ,: : 1000 0/3 0/3 7-Day ALD50 = ~1000 mg~kg :
2 Suspension 125 0/3 0/3 r ~ in l~ G.T. .250 0/3 1/3 . 50 ;, 8 Aq~Jw 125 0/3 ~/3 Solution250 1/3 1/3 sno 2/3 3/3 ;~ 1000 3/3 3/3 . 7-Day ~LD50 = 315 mg/kg -83- ~Cont'd.) ., ,~ , . . .
: ~ ;
~ , . .
.. , A
Table D (Cont'd.) :~ Solution or Dose, mg/kg of Mortality Cpd. of Ex. ~o. Suspenslon Total Material 24 Hrs æ Suspersion 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 ALD50 = ~1000 mg/kg -. 6 ~gueous 12e 1/3 1/3 Solution 250 0/3 1/3 : 500 2/3 2/3 ; . 1000 3~3 3/3-7-Day ALD50 ~ 315 mg/kg , ID Suspension 125 0/3 0/3 in 1% G.T. 250 0/3 . 0/3 ';, 1000 2/3 V 3 , 7 Day A~D50 = 750 m~/kg 11 Suspension125 0/3 . 0/3 ! . in 1% G.T.250 ~/3 0/3 ~ 500 0/3 1/3 .l . 1000 0/3 0/3 ~ , 7-Day ALD50 ~ ~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 ALD50 = 750 ~g/kg -9C . . Suspension 125 0/3 0/3 in 1~ G.T. 250 0/3 0/3 500 . 0/3 o/3 ~ 1000 0/3 0/3 `~ 7-Day ALD50 - ~1000 m~/kg ,` . 10 Agueous .125 0/3 0/3 ,,~ Solution 250 0/3 0/3 ` ~ 1000 0/3 0/3 7-Day ALD50 = ~1000 mg~kg ::
1~ - . (Cont'd.) ., ~ : ' . :
.. . . .
. ;'~ . ' :
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Table D tCont'd.) Solution or Dose, mg/kg of Mortality of Ex. No. Suspensi n Total Material 24 Hrs 7 Days 58 Suspension 125 0/3 0/3 in 1% G.T. . 250 0/3 0/3 1000 - 0/3 ` 0~3 ~ 7-Day AI~5~ 1000 mg/kg .~ .
59 A~ueous125 0/3 0/3 Solution 250 0/3 0/3 : . 50~ 1~3 2/3 7-Day ALD50 = 750 mg~kg 56 Suspension 125 0/3 0/3 - in 1~ G.T. 250 0/3 0/3 1000 1/3 1~3 ; . . 7 Day ALD50 = ~lOoo ms/ks 14 ~ Suspension 125 0/3 0/3 . .in 1% G.T. 250 0/3 0/3 500. 0/3 0/3 7-Day ALD50 = ~1000 mg/kg 44~ Susp~nsion125 Oj3 0/3 in 1~ G.T.250 0/3 0/3 . 500 0/3 0/3 1000 0/3 o/3 7-Day ALD50 = ,~1000 mg/kg .~ ~ 29C Suspension125 0/3 0/3 ; :~ in 1% G.T. 250 0/3 0/3 ~ 500 0/3 . 0/3 '~ . I000 0/3 0/3 : 7-Day ALD50 = ;1000 mg/kg .
41CSuspension .125 0/3 0/3 ~ in 1% G.T. 250 0/3 0/3 `:~ 500 0/3 0/3 . - 7-Day ALD50 =;~1000 mg/kg 1. G.T. = Gum Tragacanth '~1 , ~ .
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Claims (13)
1. A process for preparing a bis-pyridinium alkane hav-ing the Formula ...I
or ...II
where in Formula I:
Y is an 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, or phenyl substituted by methylene dioxy or one or two halogen, lower-alkyl, lower alkoxy, nitro, cyano, or tri-fluoromethyl substituents; 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;
V is an integer 0 to 4; and where in Formulas I and II:
A is an anion;
m is 1 or 3;
n is 1 or 2;
x is 1, 2 or 3; and wherein (m) (2) = (n) (x);
characterized by reacting two moles of a 4-(R-amino)pyridine having the Formula ...III
with one mole of a disubstituted alkane having the Formula Z-Y-Z (IV) or with one mole of an .alpha.,.alpha.'-disubstituted xylene having the Formula ...V
wherein R in Formula III corresponds to R in Formula I when producing a compound of Formula I and R in Formula III corres-ponds to R in Formula II when producing a compound of Formula II, and Z is chloro, bromo, iodo, methanesulfonyloxy, ethanesulfonyloxy, -86a-benzenesulfonyloxy, or p-toluenesulfonyloxy, A in the result-ing compound of Formula I or II corresponding to Z, and, if desired, replacing A with another desired anion.
or ...II
where in Formula I:
Y is an 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, or phenyl substituted by methylene dioxy or one or two halogen, lower-alkyl, lower alkoxy, nitro, cyano, or tri-fluoromethyl substituents; 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;
V is an integer 0 to 4; and where in Formulas I and II:
A is an anion;
m is 1 or 3;
n is 1 or 2;
x is 1, 2 or 3; and wherein (m) (2) = (n) (x);
characterized by reacting two moles of a 4-(R-amino)pyridine having the Formula ...III
with one mole of a disubstituted alkane having the Formula Z-Y-Z (IV) or with one mole of an .alpha.,.alpha.'-disubstituted xylene having the Formula ...V
wherein R in Formula III corresponds to R in Formula I when producing a compound of Formula I and R in Formula III corres-ponds to R in Formula II when producing a compound of Formula II, and Z is chloro, bromo, iodo, methanesulfonyloxy, ethanesulfonyloxy, -86a-benzenesulfonyloxy, or p-toluenesulfonyloxy, A in the result-ing compound of Formula I or II corresponding to Z, and, if desired, replacing A with another desired anion.
2. A process according to claim 1, characterized by preparing a compound of the Formula I wherein R is an alkyl group containing from 6 to 18 carbon atoms, 7 to 9 carbon atoms.
3. A process according to claim 2, characterized by preparing a compound of the Formula I wherein R is an alkyl group containing from 7 to 9 carbon atoms.
4. A process according to claim 1, characterized by the fact that 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. A process according to claim 1, characterized by the fact that a compound of the Formula II is prepared by the reaction of the compound of Formula III with a compound of the Formula V.
6. A process according to claim 1, for preparing 1,10-bis-[4-(octylamino)-1-pyridinium]decane dichloride in which 4-(octylamino)pyridine is reacted with 1,10-dichloro-decane.
7. A process according to claim 1, for preparing 1,12-bis-[4-(heptylamino)-1-pyridinium]dodecane dibromide, in which 4-(heptylamino)pyridine is reacted with 1,12-dibromo-dodecane.
8. A process according to claim 1, for preparing 1,12-bis-[4-(heptylamino)-1-pyridinium]dodecane dichloride in which 4-(heptylamino)pyridine is reacted with 1,12-dichloro-dodecane.
9. A process according to claim 1, for preparing .alpha.,.alpha.'-bis-(4-amino-1-pyridinium)-p-xylene dichloride in which 4-aminopyridine and .alpha.,.alpha.'-dichloro-p-xylene are reacted.
10. A compound of the Formula I or II when prepared by the process according to claim 1 or by an obvious chemical equivalent thereof.
11. A compound of the Formula I or II as defined in claim 2, 4 or 5, when prepared by the process according to claim 2, 4 or 5, respectively, or by an obvious chemical equivalent thereof.
12, 1,10-Bis-[4-(octylamino)-1-pyridinium]decane di-chloride, l,12-bis-]4-(heptylamino)-1-puridinium]dodecane dibromide or 1,12-bis-]4-(heptylamino)-1-pyridinium]dodecane dichloride when prepared by the process according to claim 6, 7 or 8, respectively, or by an obvious chemical equivalent thereof.
13. .alpha.,.alpha.'-Bis-(4-amino-1-pyridinium)-p-xylene dichloride when prepared by the process according to claim 9 or by an obvious chemical equivalent thereof.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US66112876A | 1976-02-25 | 1976-02-25 | |
| US66110176A | 1976-02-25 | 1976-02-25 | |
| US72131576A | 1976-09-07 | 1976-09-07 | |
| US05/734,729 US4107313A (en) | 1976-02-25 | 1976-10-22 | α,α-Bis-[4-(R-amino)-1-pyridinium]xylenes and antibacterial and antifungal uses |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1073911A true CA1073911A (en) | 1980-03-18 |
Family
ID=27505307
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA272,596A Expired CA1073911A (en) | 1976-02-25 | 1977-02-24 | Antimicrobial bis-pyridinium compounds |
Country Status (23)
| Country | Link |
|---|---|
| JP (1) | JPS6033108B2 (en) |
| AR (2) | AR214876A1 (en) |
| AT (1) | AT355571B (en) |
| AU (1) | AU510149B2 (en) |
| BE (1) | BE851807A (en) |
| CA (1) | CA1073911A (en) |
| CH (1) | CH620907A5 (en) |
| DE (1) | DE2708331A1 (en) |
| DK (1) | DK147638C (en) |
| ES (1) | ES456252A1 (en) |
| FI (1) | FI66850C (en) |
| FR (1) | FR2342286A1 (en) |
| GB (1) | GB1533952A (en) |
| HK (1) | HK67484A (en) |
| IE (1) | IE45336B1 (en) |
| IL (1) | IL51520A (en) |
| LU (1) | LU76837A1 (en) |
| MX (1) | MX5132E (en) |
| NL (1) | NL186086C (en) |
| NO (2) | NO148779C (en) |
| PH (2) | PH22315A (en) |
| PT (1) | PT66224B (en) |
| SE (1) | SE432421B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9770019B2 (en) | 2013-11-20 | 2017-09-26 | L'air Liquide, Societe Anonyme Pour L'etude Et L'exploitation Des Procedes Georges Claude | Kit for producing foams containing bispyridinium alkane |
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| 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 |
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| DE19647402A1 (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 |
| DE19647413A1 (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 |
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| DE102005002643B4 (en) * | 2005-01-19 | 2007-11-22 | Schülke & Mayr GmbH | Compositions for hygienic hand disinfection and disinfecting hand washing |
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| DE102005002644A1 (en) * | 2005-01-19 | 2006-07-20 | Schülke & Mayr GmbH | Compositions for hygienic hand disinfection and disinfecting hand washing |
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| DE102005063375A1 (en) * | 2005-09-15 | 2007-04-19 | Schülke & Mayr GmbH | Antimicrobial preparations containing octenidine dihydrochloride encapsulated in liposomes |
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| DE102006051891A1 (en) * | 2006-10-31 | 2008-05-08 | Schülke & Mayr GmbH | Antimicrobial composition containing Bispyridiniumalkan |
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| DE102014107413A1 (en) | 2014-05-26 | 2015-11-26 | Schülke & Mayr GmbH | Kit for coloring of disinfected areas of a surface |
| 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 |
| US11014907B2 (en) * | 2017-08-21 | 2021-05-25 | Dishman Carbogen Amcis Ltd. | Octendidine based compounds |
| EP3771338A1 (en) | 2019-07-29 | 2021-02-03 | The Procter & Gamble Company | Acidic antimicrobial composition |
| EP3771339A1 (en) | 2019-07-29 | 2021-02-03 | The Procter & Gamble Company | Disinfectant composition |
| EP3771770A1 (en) | 2019-07-29 | 2021-02-03 | The Procter & Gamble Company | Antimicrobial freshening compositions |
| EP3771741A1 (en) | 2019-07-29 | 2021-02-03 | The Procter & Gamble Company | Fabric treatment |
| EP3771337A1 (en) | 2019-07-29 | 2021-02-03 | The Procter & Gamble Company | Antimicrobial composition |
| 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 |
-
1977
- 1977-02-11 GB GB5784/77A patent/GB1533952A/en not_active Expired
- 1977-02-21 PH PH19473A patent/PH22315A/en unknown
- 1977-02-22 IL IL51520A patent/IL51520A/en unknown
- 1977-02-23 IE IE386/77A patent/IE45336B1/en unknown
- 1977-02-23 NL NLAANVRAGE7701965,A patent/NL186086C/en not_active IP Right Cessation
- 1977-02-23 AU AU22582/77A patent/AU510149B2/en not_active Expired
- 1977-02-23 FI FI770593A patent/FI66850C/en not_active IP Right Cessation
- 1977-02-23 MX MX775459U patent/MX5132E/en unknown
- 1977-02-23 PT PT66224A patent/PT66224B/en unknown
- 1977-02-24 ES ES456252A patent/ES456252A1/en not_active Expired
- 1977-02-24 NO NO770631A patent/NO148779C/en unknown
- 1977-02-24 CA CA272,596A patent/CA1073911A/en not_active Expired
- 1977-02-24 LU LU76837A patent/LU76837A1/xx unknown
- 1977-02-24 SE SE7702072A patent/SE432421B/en not_active IP Right Cessation
- 1977-02-24 DK DK81277A patent/DK147638C/en not_active IP Right Cessation
- 1977-02-24 CH CH233677A patent/CH620907A5/en not_active IP Right Cessation
- 1977-02-24 AR AR266668A patent/AR214876A1/en active
- 1977-02-25 FR FR7705621A patent/FR2342286A1/en active Granted
- 1977-02-25 AT AT129777A patent/AT355571B/en not_active IP Right Cessation
- 1977-02-25 JP JP52020130A patent/JPS6033108B2/en not_active Expired
- 1977-02-25 DE DE19772708331 patent/DE2708331A1/en active Granted
- 1977-02-25 BE BE1007973A patent/BE851807A/en not_active IP Right Cessation
- 1977-11-11 PH PH20428A patent/PH25097A/en unknown
-
1978
- 1978-01-04 AR AR270629A patent/AR218052A1/en active
-
1982
- 1982-09-28 NO NO823274A patent/NO150758C/en unknown
-
1984
- 1984-08-30 HK HK674/84A patent/HK67484A/en unknown
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9770019B2 (en) | 2013-11-20 | 2017-09-26 | L'air Liquide, Societe Anonyme Pour L'etude Et L'exploitation Des Procedes Georges Claude | Kit for producing foams containing bispyridinium alkane |
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