U.S. patent application number 12/880591 was filed with the patent office on 2016-09-29 for bis-quaternary ammonium salts as pain modulating agents.
This patent application is currently assigned to University of Kentucky Research Foundation. The applicant listed for this patent is Peter A. Crooks, Linda P. Dwoskin, Joseph R. HOLTMAN, J. Michael McIntosh, Elzbieta Pogonowska Wala. Invention is credited to Peter A. Crooks, Linda P. Dwoskin, Joseph R. HOLTMAN, J. Michael McIntosh, Elzbieta Pogonowska Wala.
Application Number | 20160279119 12/880591 |
Document ID | / |
Family ID | 44225057 |
Filed Date | 2016-09-29 |
United States Patent
Application |
20160279119 |
Kind Code |
A9 |
HOLTMAN; Joseph R. ; et
al. |
September 29, 2016 |
BIS-QUATERNARY AMMONIUM SALTS AS PAIN MODULATING AGENTS
Abstract
Provided are methods for using bis-quaternary ammonium compounds
to treat inflammatory pain, neuropathic pain and nociceptive
pain.
Inventors: |
HOLTMAN; Joseph R.; (Lisle,
IL) ; Crooks; Peter A.; (Little Rock, AR) ;
Dwoskin; Linda P.; (Lexington, KY) ; McIntosh; J.
Michael; (Salt Lake City, UT) ; Wala; Elzbieta
Pogonowska; (Lexington, KY) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
HOLTMAN; Joseph R.
Crooks; Peter A.
Dwoskin; Linda P.
McIntosh; J. Michael
Wala; Elzbieta Pogonowska |
Lisle
Little Rock
Lexington
Salt Lake City
Lexington |
IL
AR
KY
UT
KY |
US
US
US
US
US |
|
|
Assignee: |
University of Kentucky Research
Foundation
Lexington
KY
|
Prior
Publication: |
|
Document Identifier |
Publication Date |
|
US 20110166177 A1 |
July 7, 2011 |
|
|
Family ID: |
44225057 |
Appl. No.: |
12/880591 |
Filed: |
September 13, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
12304948 |
Nov 30, 2009 |
8178678 |
|
|
PCT/US2007/011635 |
May 14, 2007 |
|
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12880591 |
|
|
|
|
61241481 |
Sep 11, 2009 |
|
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60814640 |
Jun 16, 2006 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/47 20130101;
C07D 401/12 20130101; A61K 31/4725 20130101; A61P 29/00 20180101;
A61K 31/4709 20130101; A61K 31/444 20130101; C07D 401/06 20130101;
A61K 31/472 20130101; A61K 31/03 20130101; A61K 31/047 20130101;
C07D 401/14 20130101; A61K 31/4425 20130101; C07D 401/10
20130101 |
International
Class: |
A61K 31/4725 20060101
A61K031/4725; A61P 29/00 20060101 A61P029/00; A61K 31/03 20060101
A61K031/03; A61K 31/047 20060101 A61K031/047; A61K 31/444 20060101
A61K031/444; A61K 31/4709 20060101 A61K031/4709 |
Claims
1. A method of treating inflammatory pain comprising administering
to a mammalian subject in need thereof a pharmaceutically
acceptable amount of a compound of Formula (I)
X.sup.2.crclbar..sym.R.sup.1--H.sub.2C-L.sup.1-Q-L.sup.2-CH.sub.2--R.sup.-
2.sym..crclbar.X.sup.1 (1) wherein X.sup.1.crclbar. and
X.sup.2.crclbar. are each independently an organic or inorganic
anion; wherein Q is selected from phenylene, biphenylene,
--CH.dbd.CH--, --CH.dbd.CH--CH.dbd.CH--, --C.ident.C--,
--C.ident.C--C.ident.C--, --O--(CH.sub.2).sub.2--O--, and
--O--(CH.sub.2).sub.2--O--(CH.sub.2).sub.2--O--; wherein L.sup.1
and L.sup.2 are each independently selected from alkyl, substituted
alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted
alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl,
alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl,
arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted
arylalkynyl, heterocyclic, substituted heterocyclic; SOY.sup.1,
SO.sub.2Y.sup.1, SO.sub.2OY.sup.1 or SO.sub.2NHY.sup.1, where
Y.sup.1 is selected from hydrogen, lower alkyl, alkenyl, alkynyl or
aryl, and where Y.sup.1 is not hydrogen in SOY.sup.1 and if Y.sup.1
is alkenyl or alkynyl, the site of unsaturation is not conjugated
with a heteroatom; COY.sup.2, where Y.sup.2 is selected from
hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted
cycloalkyl, alkoxy, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, aryl, substituted aryl, aryloxy, alkylaryl,
substituted alkylaryl, arylalkyl, substituted arylalkyl,
arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted
arylalkynyl, heterocyclic, or substituted heterocyclic, and where
if Y.sup.2 comprises alkenyl or alkynyl, the site of unsaturation
is not conjugated with the carbonyl group; OY.sup.3, where Y.sup.3
is selected from hydrogen, alkyl, substituted alkyl, cycloalkyl,
substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, aryl, substituted aryl, alkylaryl, substituted
alkylaryl, arylalkyl, substituted arylalkyl, arylalkenyl,
substituted arylalkenyl, arylalkynyl, substituted arylalkynyl,
acyl, alkylsulfonyl, arylsulfonyl, heterocyclic, or substituted
heterocyclic, where if Y.sup.3 comprises alkenyl or alkynyl, the
site of unsaturation is not conjugated with the oxygen;
NY.sup.4Y.sup.5 where Y.sup.4 and Y.sup.5 are each independently
selected from hydrogen, alkyl, substituted alkyl, cycloalkyl,
substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, aryl, substituted aryl, alkylaryl, substituted
alkylaryl, arylalkyl, substituted arylalkyl, arylalkenyl,
substituted arylalkenyl, arylalkynyl, substituted arylalkynyl,
acyl, alkylsulfonyl, arylsulfonyl, heterocyclic, or substituted
heterocyclic, where if Y.sup.4 or Y.sup.5 comprises alkenyl or
alkynyl, the site of unsaturation is not conjugated with the
nitrogen; SY.sup.6, where Y.sup.6 is selected from hydrogen, alkyl,
substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl,
substituted alkenyl, alkynyl, substituted alkynyl, aryl,
substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl,
substituted arylalkyl, arylalkenyl, substituted arylalkenyl,
arylalkynyl, substituted arylalkynyl, heterocyclic, or substituted
heterocyclic, and where if Y.sup.6 comprises alkenyl or alkynyl,
the site of unsaturation is not conjugated with the sulfur; wherein
R.sup.1 and R.sup.2 are each independently five or six membered
nitrogen containing rings as shown in formulas (IIA) and (IIB):
##STR00110## wherein A.sup.1 is carbon, nitrogen, sulfur or oxygen,
provided that when A.sup.1 is a carbon and joins a ring atom with
an unsaturated bond or is a nitrogen, R.sup.3 is absent, and when
A.sup.1 is sulfur or oxygen or joins a ring atom with an
unsaturated bond and is a nitrogen, both R.sup.3 and R.sup.4 are
absent; wherein A.sup.2 is carbon, nitrogen, sulfur or oxygen,
provided that when A.sup.2 is a carbon and joins a ring atom with
an unsaturated bond or is a nitrogen, R.sup.5 is absent, and when
A.sup.2 is sulfur or oxygen or joins a ring atom with an
unsaturated bond and is a nitrogen, both R.sup.5 and R.sup.6 are
absent; wherein A.sup.3 is carbon, nitrogen, sulfur or oxygen,
provided that when A.sup.3 is a carbon and joins a ring atom with
an unsaturated bond or is a nitrogen, R.sup.7 is absent, and when
A.sup.3 is sulfur or oxygen or joins a ring atom with an
unsaturated bond and is a nitrogen, both R.sup.7 and R.sup.8 are
absent; wherein A.sup.4 is carbon, nitrogen, sulfur or oxygen,
provided that when A.sup.4 is a carbon and joins a ring atom with
an unsaturated bond or is a nitrogen, R.sup.9 is absent, and when
A.sup.4 is sulfur or oxygen or joins a ring atom with an
unsaturated bond and is a nitrogen, both R.sup.9 and R.sup.10 are
absent; wherein A.sup.5 is carbon, nitrogen, sulfur or oxygen,
provided that when A.sup.5 is a carbon and joins a ring atom with
an unsaturated bond or is a nitrogen, R.sup.11 is absent, and when
A.sup.5 is sulfur or oxygen or joins a ring atom with an
unsaturated bond and is a nitrogen, both R.sup.11 and R.sup.12 are
absent; wherein A.sup.6 is carbon, nitrogen, sulfur or oxygen,
provided that when A.sup.6 is a carbon and joins a ring atom with
an unsaturated bond or is a nitrogen, R.sup.14 is absent, and when
A.sup.6 is sulfur or oxygen or joins a ring atom with an
unsaturated bond and is a nitrogen, both R.sup.14 and R.sup.15 are
absent; wherein A.sup.7 is carbon, nitrogen, sulfur or oxygen,
provided that when A.sup.7 is a carbon and joins a ring atom with
an unsaturated bond or is a nitrogen, R.sup.16 is absent, and when
A.sup.7 is sulfur or oxygen or joins a ring atom with an
unsaturated bond and is a nitrogen, both R.sup.16 and R.sup.17 are
absent; wherein A.sup.8 is carbon, nitrogen, sulfur or oxygen,
provided that when A.sup.8 is a carbon and joins a ring atom with
an unsaturated bond or is a nitrogen, R.sup.18 is absent, and when
A.sup.8 is sulfur or oxygen or joins a ring atom with an
unsaturated bond and is a nitrogen, both R.sup.18 and R.sup.19 are
absent; wherein A.sup.9 is carbon, nitrogen, sulfur or oxygen,
provided that when A.sup.9 is a carbon and joins a ring atom with
an unsaturated bond or is a nitrogen, R.sup.20 is absent, and when
A.sup.9 is sulfur or oxygen or joins a ring atom with an
unsaturated bond and is a nitrogen, both R.sup.20 and R.sup.21 are
absent; wherein R.sup.13 or R.sup.22 is absent when any of the
bonds to the ammonium nitrogen is unsaturated, and R.sup.13 or
R.sup.22 is a straight chain or branched alkyl group of four
carbons or fewer when all of the bonds to the ammonium nitrogen are
saturated; wherein R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7,
R.sup.8, R.sup.9, R.sup.10, R.sup.11, and R.sup.12, or R.sup.14,
R.sup.15, R.sup.16, R.sup.17, R.sup.18, R.sup.19, R.sup.20, and
R.sup.21, when present, are each independently selected from
hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted
cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted
alkynyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl,
arylalkyl, substituted arylalkyl, arylalkenyl, substituted
arylalkenyl, arylalkynyl, substituted arylalkynyl, heterocyclic,
substituted heterocyclic, halo, cyano, nitro, or R.sup.4 and
R.sup.5 together with A.sup.1 and A.sup.2, or R.sup.5 and R.sup.7
together with A.sup.2 and A.sup.3, or R.sup.15 and R.sup.16
together with A.sup.6 and A.sup.7, or R.sup.16 and R.sup.18
together with A.sup.7 and A.sup.8 independently form a three to
eight member cyclolkane, substituted cycloalkane, cycloalkene,
substituted cycloalkene, aryl, substituted aryl, heterocycle with
one to three hetero atoms of nitrogen, oxygen or sulfur in the
ring, or substituted heterocycle with one to three hetero atoms of
nitrogen, oxygen or sulfur in the ring; and when all of the bonds
to the ring ammonium nitrogen are saturated, then any of R.sup.3,
R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10,
R.sup.11, R.sup.12, R.sup.13, R.sup.14, R.sup.15, R.sup.16,
R.sup.17, R.sup.18, R.sup.19, R.sup.20, R.sup.21 or R.sup.22 which
is attached to the ammonium nitrogen is a straight or branched
alkyl group of four carbons or fewer.
2. The method of claim 1, wherein R.sup.1 and R.sup.2 are
pyridinium rings.
3. The method of claim 1, wherein
-L.sub.1-Q-L.sub.2-is-(CH.sub.2).sub.4-1,2-phenylene-(CH.sub.2).sub.4--,
--(CH.sub.2).sub.4-1,3-phenylene-(CH.sub.2).sub.4--,
--(CH.sub.2).sub.3-1,4-phenylene-(CH.sub.2).sub.3--,
--(CH.sub.2).sub.2-4,4'-biphenylene-(CH.sub.2).sub.2--,
--(CH.sub.2).sub.2--C.ident.C-1,2-phenylene-C.ident.C--(CH.sub.2).sub.2---
,
--(CH.sub.2).sub.2--C.ident.C-1,3-phenylene-C.ident.C--(CH.sub.2).sub.2--
-, --CH.sub.2--C.ident.C-1,4-phenylene-C.ident.C--CH.sub.2--,
--C.ident.C-4,4'-biphenylene-C.ident.C--,
--(CH.sub.2).sub.3--CH.dbd.CH--CH.dbd.CH--(CH.sub.2).sub.3--,
--(CH.sub.2).sub.3--C.ident.C--C.ident.C--(CH.sub.2).sub.3-- or
--CH.sub.2--O--(CH.sub.2).sub.2--O--(CH.sub.2).sub.2--O--CH.sub.2--.
4. The method of claim 3, wherein: R.sup.1 and R.sup.2 are
pyridinium rings; R.sup.3 is hydrogen or methyl; R.sup.5 is
hydrogen, methyl, ethyl, butyl, phenyl, 1-methyl-2-pyrrolidinyl,
bromo, hydroxymethyl or hydroxypropyl; R.sup.7 is hydrogen or
methyl; R.sup.9 is hydrogen or methyl; R.sup.11 is hydrogen; and
X.sup.1 and X.sup.2 are chloride or bromide.
5. The method of claim 3, wherein: R.sup.1 and R.sup.2 are
quinoline, isoquinoline, tetrahydroquinoline or
tetrahydroisoquinoline; and X.sup.1 and X.sup.2 are chloride or
bromide.
6. The method of claim 1, wherein said compound is selected from
the group consisting of:
cis-cis-N,N'-(dodeca-5,7-diene-1,12-diyl)-bis-[3-(2'-5-1-methyl-pyrrolidi-
n-2-yl)-pyridinium]dibromide;
cis-cis-N,N'-(dodeca-5,7-diene-1,12-diyl)-bis-{2-methyl-pyridinium)dibrom-
ide;
cis-cis-N,N'-(dodeca-5,7-diene-1,12-diyl)-bis-(3-methyl-pyridinium)di-
bromide;
cis-cis-N,N'-(dodeca-5,7-diene-1s12-diyl)-bis-(4-methyl-pyridiniu-
m)dibromide;
cis-cis-N,N'-(dodeca-5,7-diene-1,12-diyl)-bis-(5,6,7,8-tetrahydro-quinoli-
nium)dibromide;
cis-cis-N,N'-(dodeca-5,7-diene-1,12-diyl)-bis-(5,6,7,8-tetrahydro-isoquin-
olinium)dibromide;
cis-cis-N,N'-(dodeca-5,7-diene-1,12-diyl)-bis-(2,4-dimethyl-pyridinium)di-
bromide;
cis-cis-N,N'-(dodeca-5,7-diene-1,12-diyl)-bis-(3,4-dimethyl-pyrid-
inium)dibromide;
cis-cis-N,N'-(dodeca-5,7-diene-1,12-diyl)-bis-(3,5-dimethyl-pyridinium)di-
bromide;
N,N'-[1,4-phenylenedi-(4-butanyl)]-bis-[3-(2'-S-1-methyl-pyrrolid-
in-2-yl)-pyridinium]dibromide;
N,N'-[1,4-phenylenedi-(4-butanyl)]-bis-(2-methylpyridinium)dibromide;
N,N'-[1,4-phenylenedi-(4-butanyl)]-bis-(3-methylpyridinium)dibromide;
N,N'-[1,4-phenylenedi-(4-butanyl)]-bis-(4-methylpyridinium)dibromide;
N,N'-[1,4-phenylenedi-(4-butanyl)]-bis-(3-ethylpyridinium)dibromide;
N,N'-[1,4-phenylenedi-(4-butanyl)]-bis-(5,6,7,8-tetrahydroquinolinium)dib-
romide;
N,N'-[1,4-phenylenedi-(4-butanyl)]-bis-(5,6,7,8-tetrahydroisoquino-
linium)dibromide;
N,N'-[1,4-phenylenedi-(4-butanyl)]-bis-[3-(3-hydroxy-propyl)-pyridinium]d-
ibromide;
N,N'-[1,4-phenylenedi-(4-butanyl)]-bis-(2,4-dimethylpyridinium)d-
ibromide;
N,N'-[1,4-phenylenedi-{4-butanyl)]-bis-(3,4-dimethylpyridinium)d-
ibromide;
N,N'-[1,4-phenylenedi-{4-butanyl)]-bis-(3,5-dimethylpyridinium)d-
ibromide; 1,2-bis-[5-(2-methyl-pyridinium)-pent-1-ynyl]-benzene
dibromide; 1,2-bis-[5-(3-methyl-pyridinium)-pent-1-ynyl]-benzene
dibromide; 1,2-bis-[5-(4-methyl-pyridinium)-pent-1-ynyl]-benzene
dibromide;
1,2-bis-[5-(2,4-dimethyl-pyridinium)-pent-1-ynyl]-benzene
dibromide;
1,2-bis-[5-(3,4-dimethyl-pyridinium)-pent-1-ynyl]-benzene
dibromide;
1,2-bis-[5-(3,5-dimethyl-pyridinium)-pent-1-ynyl]-benzene
dibromide; 1,2-bis-(5-quinolinium-pent-1-ynyl)-benzene dibromide;
1,2-bis-(5-isoquinolinium-pent-1-ynyl)-benzene dibromide;
1,2-bis-(5-S-nicotinium-pent-1-ynyl)-benzene dibromide;
1,2-bis-[5-(2-methyl-pyridinium)-pentyl]-benzene dibromide;
1,2-bis-[5-(3-methyl-pyridinium)-pentyl]-benzene dibromide;
1,2-bis-[5-(4-methyl-pyridinium)-pentyl]-benzene dibromide;
1,2-bis-[5-(2,4-dimethyl-pyridinium)-pentyl]-benzene dibromide;
1,2-bis-[5-(3,4-dimethyl-pyridinium)-pentyl]-benzene dibromide;
1,2-bis-[5-(3,5-methyl-pyridinium)-pentyl]-benzene dibromide;
1,2-bis-(5-quinolinium-pentyl)-benzene dibromide;
1,2-bis-(5-isoquinolinium-pentyl)-benzene dibromide;
1,2-bis-(5-S-nicotinium-pentyl)-benzene dibromide;
1,2-bis-[5-(3-n-butyl-pyridinium)-pentyl]-benzene dibromide;
1,2-bis-[5-(3-bromo-pyridinium)-pentyl]-benzene dibromide;
1,2-bis-(5-pyridinium-pentyl)-benzene dibromide;
1,3-bis-[5-(2-methyl-pyridinium)-pent-1-ynyl]-benzene dibromide;
1,3-bis-[5-(3-methyl-pyridinium)-pent-1-ynyl]-benzene dibromide;
1,3-bis-[5-(4-methyl-pyridinium)-pent-1-ynyl]-benzene dibromide;
1,3-bis-[5-(2,4-dimethyl-pyridinium)-pent-1-ynyl]-benzene
dibromide;
1,3-bis-[5-(3,4-dimethyl-pyridinium)-pent-1-ynyl]-benzene
dibromide;
1,3-bis-[5-(3,5-dimethyl-pyridinium)-pent-1-ynyl]-benzene
dibromide; 1,3-bis-(5-quinolinium-pent-1-ynyl)-benzene dibromide;
1,3-bis-(5-isoquinolinium-pent-1-ynyl)-benzene dibromide;
1,3-bis-(5-S-nicotiniuin-pent-1-ynyl)-benzene dibromide;
1,3-bis-[5-(3-n-butyl-pyridinium)-pent-1-ynyl]-benzene dibromide;
1,3-bis-[5-(3-phenyl-pyridinium)-pent-1-ynyl]-benzene dibromide;
1,3-bis-[5-pyridinium-pent-1-ynyl)-benzene dibromide;
1,3-bis-[5-(2-methyl-pyridinium)-pentyl]-benzene dibromide;
1,3-bis-[5-(3-methyl-pyridinium)-pentyl]-benzene dibromide;
1,3-bis-[5-(4-methyl-pyridinium)-pentyl]-benzene dibromide;
1,3-bis-[5-(2,4-dimethyl-pyridinium)-pentyl]-benzene dibromide;
1,3-bis-[5-(3,4-dimethyl-pyridinium)-pentyl]-benzene dibromide;
1,3-bis-[5-(3,5-dimethyl-pyridinium)-pentyl]-benzene dibromide;
1,3-bis-(5-quinolinium-pentyl)-benzene dibromide;
1,3-bis-(5-isoquinolinium-pentyl)-benzene dibromide;
N,N'-[(1,1'-biphenyl)-4,4'-di-(3-propanyl)]-bis-[3-(2'-S-1-methyl-pyrroli-
din-2-yl)-pyridinium]dibromide;
N,N'-[(1,1'-biphenyl)-4,4'-di-(3-propanyl)]-bis-(3,5-dimethylpyridinium)d-
ibromide;
N,N'-[(1,1'-biphenyl)-4,4'-di-(3-propanyl)]-bis-(3,4-dimethylpyr-
idinium)dibromide;
N,N'-[(1,1'-biphenyl)-4,4'-di-(3-propanyl)]-bis-(2,4-dimethylpyridinium)d-
ibromide;
N,N'-[(1,1'-biphenyl)-4,4'-di-(3-propanyl)]-bis-[3-(3-hydroxy-pr-
opyl)-pyridinium]dibromide;
N,N'-[(1,1'-biphenyl)-4,4'-di-(3-propanyl)]-bis-[5,6,7,8-tetrahydroquinol-
inium]dibromide;
N,N'-[(1,1'-biphenyl)-4,4'-di-(3-propanyl)]-bis-[5,6,7,8-tetrahydroisoqui-
nolinium]dibromide;
N,N'-[(1,1'-biphenyl)-4,4'-di-(3-propanyl)]-bis-(4-methylpyridinium)dibro-
mide;
N,N'-[(1,1'-biphenyl)-4,4'-di-(3-propanyl)]-bis-(3-methylpyridinium)-
dibromide;
N,N'-[(1,1'-biphenyl)-4,4'-di-(3-propanyl)]-bis-(2-methylpyridi-
nium)dibromide;
N,N'-{2,2'-[oxybis(2,1-ethandiyloxy)]bis-ethyl}-bis-[3-(2'-S-1-methyl-pyr-
rolidin-2-yl)-pyridinium]dichloride;
N,N'-{2,2'-[oxybis(2,1-ethandiyloxy)]bis-ethyl}-bis(2-methylpyridinium)di-
chloride;
N,N'-{2,2'-[oxybis(2,1-ethandiyloxy)]bis-ethyl}-bis(3-methylpyri-
dinium)dichloride;
N,N'-{2,2'-[oxybis(2,1-ethandiyloxy)]bis-ethyl}-bis(4-methylpyridinium)di-
chloride;
N,N'-{2,2'-[oxybis(2,1-ethandiyloxy)]bis-ethyl}-bis(5,6,7,8-tetr-
ahydroquinolinium)dichloride;
N,N'-{2,2'-[oxybis(2,1-ethandiyloxy)]bis-ethyl}-bis(5,6,7,8-tetrahydroiso-
quinolinium)dichloride;
N,N'-{2,2'-[oxybis(2,1-ethandiyloxy)]bis-ethyl}-bis-[3-(3-hydroxypropyl)--
pyridinium]dichloride;
N,N'-{2,2'-[oxybis(2,1-ethandiyloxy)]bis-ethyl}-bis(3-hydroxymethylpyridi-
nium)dichloride;
N,N'-{2,2'-[oxybis(2,1-ethandiyloxy)]bis-ethyl}-bis(2,4-dimethylpyridiniu-
m)dichloride;
N,N'-{2,2'-[oxybis(2,1-ethandiyloxy)]bis-ethyl}-bis(3,4-dimethylpyridiniu-
m)dichloride;
N,N'-{2,2'-[oxybis(2,1-ethandiyloxy)]bis-ethyl}-bis(3,5-dimethylpyridiniu-
m)dichloride;
N,N'-(5,7-dodecadiyn-1,12-diyl)-bis-(2-methylpyridinium)dichloride;
N,N'-(5,7-dodecadiyn-1,12-diyl)-bis-(3-methylpyridinium)dichloride;
N,N'-(5,7-dodecadiyn-1,12-diyl)-bis-(4-methylpyridinium)dichloride;
N,N'-(5,7-dodecadiyn-1,12-diyl)-bis-(3,4-dimethylpyridinium)dichloride;
N,N'-(5,7-dodecadiyn-1,12-diyl)-bis-(3,5-dimethylpyridinium)dichloride;
N,N'-(5,7-dodecadiyn-1,12-diyl)-bis-(5,6,7,8-tetrahydroisoquinolinium)dic-
hloride;
N,N'-[(1,4-phenylene)-bis-(4-butynyl)]-bis-(3-methyl-pyridinium)d-
ibromide;
N,N'-[(1,4-phenylene)-bis-(4-butynyl)]-bis-(4-methyl-pyridinium)-
dibromide;
N,N'-[(1,4-phenylene)-bis-(4-butynyl)]-bis-(5,6,7,8-tetrahydroi-
soquiolinium)dibromide;
N,N'-[(1,4-phenylene)-bis-(4-butynyl)]-bis-(3,4-dimethyl-pyridinium)dibro-
mide;
N,N'-[(1,4-phenylene)-bis-(4-butynyl)]-bis-(3,5-dimethyl-pyridiniuim-
)dibromide;
N,N'-[(1,1'-biphenyl)-4,4'-di-(1-propyn-3-yl)]-bis-(3-methylpyridinium)di-
bromide;
N,N'-[(1,1'-biphenyl)-4,4'-di-(1-propyn-3-yl)]-bis-(4-methylpyrid-
inium)dibromide;
N,N'-[(1,1'-biphenyl)-4,4'-di-(1-propyn-3-yl)]-bis-(3,4-dimethylpyridiniu-
m)dibromide.
7. The method of claim 1, wherein said compound is
N,N'-[(1,1'-biphenyl)-4,4'-di-(1-propyn-3-yl)]-bis-(3,4-dimethylpyridiniu-
m)dibromide.
8. A method of treating neuropathic pain comprising administering
to a mammalian subject in need thereof a pharmaceutically
acceptable amount of a compound of Formula (I)
X.sup.2.crclbar..sym.R.sup.1--H.sub.2C-L.sup.1-Q-L.sup.2-CH.sub.2--R.sup.-
2.sym..crclbar.X.sup.1 (1) wherein X.sup.1.crclbar. and
X.sup.2.crclbar. are each independently an organic or inorganic
anion; wherein Q is selected from phenylene, biphenylene,
--CH.dbd.CH--, --CH.dbd.CH--CH.dbd.CH--, --C.ident.C--,
--C.ident.C--C.ident.C--, --O--(CH.sub.2).sub.2--O--, and
--O--(CH.sub.2).sub.2--O--(CH.sub.2).sub.2--O--; wherein L.sup.1
and L.sup.2 are each independently selected from alkyl, substituted
alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted
alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl,
alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl,
arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted
arylalkynyl, heterocyclic, substituted heterocyclic; SOY.sup.1,
SO.sub.2Y.sup.1, SO.sub.2OY.sup.1 or SO.sub.2NHY.sup.1, where
Y.sup.1 is selected from hydrogen, lower alkyl, alkenyl, alkynyl or
aryl, and where Y.sup.1 is not hydrogen in SOY.sup.1 and if Y.sup.1
is alkenyl or alkynyl, the site of unsaturation is not conjugated
with a heteroatom; COY.sup.2, where Y.sup.2 is selected from
hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted
cycloalkyl, alkoxy, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, aryl, substituted aryl, aryloxy, alkylaryl,
substituted alkylaryl, arylalkyl, substituted arylalkyl,
arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted
arylalkynyl, heterocyclic, or substituted heterocyclic, and where
if Y.sup.2 comprises alkenyl or alkynyl, the site of unsaturation
is not conjugated with the carbonyl group; OY.sup.3, where Y.sup.3
is selected from hydrogen, alkyl, substituted alkyl, cycloalkyl,
substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, aryl, substituted aryl, alkylaryl, substituted
alkylaryl, arylalkyl, substituted arylalkyl, arylalkenyl,
substituted arylalkenyl, arylalkynyl, substituted arylalkynyl,
acyl, alkylsulfonyl, arylsulfonyl, heterocyclic, or substituted
heterocyclic, where if Y.sup.3 comprises alkenyl or alkynyl, the
site of unsaturation is not conjugated with the oxygen;
NY.sup.4Y.sup.5 where Y.sup.4 and Y.sup.5 are each independently
selected from hydrogen, alkyl, substituted alkyl, cycloalkyl,
substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, aryl, substituted aryl, alkylaryl, substituted
alkylaryl, arylalkyl, substituted arylalkyl, arylalkenyl,
substituted arylalkenyl, arylalkynyl, substituted arylalkynyl,
acyl, alkylsulfonyl, arylsulfonyl, heterocyclic, or substituted
heterocyclic, where if Y.sup.4 or Y.sup.5 comprises alkenyl or
alkynyl, the site of unsaturation is not conjugated with the
nitrogen; SY.sup.6, where Y.sup.6 is selected from hydrogen, alkyl,
substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl,
substituted alkenyl, alkynyl, substituted alkynyl, aryl,
substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl,
substituted arylalkyl, arylalkenyl, substituted arylalkenyl,
arylalkynyl, substituted arylalkynyl, heterocyclic, or substituted
heterocyclic, and where if Y.sup.6 comprises alkenyl or alkynyl,
the site of unsaturation is not conjugated with the sulfur; wherein
R.sup.1 and R.sup.2 are each independently five or six membered
nitrogen containing rings as shown in formulas (IIA) and (IIB):
##STR00111## wherein A.sup.1 is carbon, nitrogen, sulfur or oxygen,
provided that when A.sup.1 is a carbon and joins a ring atom with
an unsaturated bond or is a nitrogen, R.sup.3 is absent, and when
A.sup.1 is sulfur or oxygen or joins a ring atom with an
unsaturated bond and is a nitrogen, both R.sup.3 and R.sup.4 are
absent; wherein A.sup.2 is carbon, nitrogen, sulfur or oxygen,
provided that when A.sup.2 is a carbon and joins a ring atom with
an unsaturated bond or is a nitrogen, R.sup.5 is absent, and when
A.sup.2 is sulfur or oxygen or joins a ring atom with an
unsaturated bond and is a nitrogen, both R.sup.5 and R.sup.6 are
absent; wherein A.sup.3 is carbon, nitrogen, sulfur or oxygen,
provided that when A.sup.3 is a carbon and joins a ring atom with
an unsaturated bond or is a nitrogen, R.sup.7 is absent, and when
A.sup.3 is sulfur or oxygen or joins a ring atom with an
unsaturated bond and is a nitrogen, both R.sup.7 and R.sup.8 are
absent; wherein A.sup.4 is carbon, nitrogen, sulfur or oxygen,
provided that when A.sup.4 is a carbon and joins a ring atom with
an unsaturated bond or is a nitrogen, R.sup.9 is absent, and when
A.sup.4 is sulfur or oxygen or joins a ring atom with an
unsaturated bond and is a nitrogen, both R.sup.9 and R.sup.10 are
absent; wherein A.sup.5 is carbon, nitrogen, sulfur or oxygen,
provided that when A.sup.5 is a carbon and joins a ring atom with
an unsaturated bond or is a nitrogen, R.sup.11 is absent, and when
A.sup.5 is sulfur or oxygen or joins a ring atom with an
unsaturated bond and is a nitrogen, both R.sup.11 and R.sup.12 are
absent; wherein A.sup.6 is carbon, nitrogen, sulfur or oxygen,
provided that when A.sup.6 is a carbon and joins a ring atom with
an unsaturated bond or is a nitrogen, R.sup.14 is absent, and when
A.sup.6 is sulfur or oxygen or joins a ring atom with an
unsaturated bond and is a nitrogen, both R.sup.14 and R.sup.15 are
absent; wherein A.sup.7 is carbon, nitrogen, sulfur or oxygen,
provided that when A.sup.7 is a carbon and joins a ring atom with
an unsaturated bond or is a nitrogen, R.sup.16 is absent, and when
A.sup.7 is sulfur or oxygen or joins a ring atom with an
unsaturated bond and is a nitrogen, both R.sup.16 and R.sup.17 are
absent; wherein A.sup.8 is carbon, nitrogen, sulfur or oxygen,
provided that when A.sup.8 is a carbon and joins a ring atom with
an unsaturated bond or is a nitrogen, R.sup.18 is absent, and when
A.sup.8 is sulfur or oxygen or joins a ring atom with an
unsaturated bond and is a nitrogen, both R.sup.18 and R.sup.19 are
absent; wherein A.sup.9 is carbon, nitrogen, sulfur or oxygen,
provided that when A.sup.9 is a carbon and joins a ring atom with
an unsaturated bond or is a nitrogen, R.sup.20 is absent, and when
A.sup.9 is sulfur or oxygen or joins a ring atom with an
unsaturated bond and is a nitrogen, both R.sup.20 and R.sup.21 are
absent; wherein R.sup.13 or R.sup.22 is absent when any of the
bonds to the ammonium nitrogen is unsaturated, and R.sup.13 or
R.sup.22 is a straight chain or branched alkyl group of four
carbons or fewer when all of the bonds to the ammonium nitrogen are
saturated; wherein R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7,
R.sup.8, R.sup.9, R.sup.10, R.sup.11, and R.sup.12, or R.sup.14,
R.sup.15, R.sup.16, R.sup.17, R.sup.18, R.sup.19, R.sup.20, and
R.sup.21, when present, are each independently selected from
hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted
cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted
alkynyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl,
arylalkyl, substituted arylalkyl, arylalkenyl, substituted
arylalkenyl, arylalkynyl, substituted arylalkynyl, heterocyclic,
substituted heterocyclic, halo, cyano, nitro, or R.sup.4 and
R.sup.5 together with A.sup.1 and A.sup.2, or R.sup.5 and R.sup.7
together with A.sup.2 and A.sup.3, or R.sup.15 and R.sup.16
together with A.sup.6 and A.sup.7, or R.sup.16 and R.sup.18
together with A.sup.7 and A.sup.8 independently form a three to
eight member cyclolkane, substituted cycloalkane, cycloalkene,
substituted cycloalkene, aryl, substituted aryl, heterocycle with
one to three hetero atoms of nitrogen, oxygen or sulfur in the
ring, or substituted heterocycle with one to three hetero atoms of
nitrogen, oxygen or sulfur in the ring; and when all of the bonds
to the ring ammonium nitrogen are saturated, then any of R.sup.3,
R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10,
R.sup.11, R.sup.12, R.sup.13, R.sup.14, R.sup.15, R.sup.16,
R.sup.17, R.sup.18, R.sup.19, R.sup.20, R.sup.21 or R.sup.22 which
is attached to the ammonium nitrogen is a straight or branched
alkyl group of four carbons or fewer.
9. The method of claim 8, wherein R.sup.1 and R.sup.2 are
pyridinium rings.
10. The method of claim 8, wherein
-L.sub.1-Q-L.sup.2-is-(CH.sub.2).sub.4-1,2-phenylene-(CH.sub.2).sub.4--,
--(CH.sub.2).sub.4-1,3-phenylene-(CH.sub.2).sub.4--,
--(CH.sub.2).sub.3-1,4-phenylene-(CH.sub.2).sub.3--,
--(CH.sub.2).sub.2-4,4'-biphenylene-(CH.sub.2).sub.2--,
--(CH.sub.2).sub.2--C.ident.C-1,2-phenylene-C.ident.C--(CH.sub.2).sub.2---
,
--(CH.sub.2).sub.2--C.ident.C-1,3-phenylene-C.ident.C--(CH.sub.2).sub.2--
-, --CH.sub.2--C.ident.C-1,4-phenylene-C.ident.C--CH.sub.2--,
--C.ident.C-4,4'-biphenylene-C.ident.C--,
--(CH.sub.2).sub.3--CH.dbd.CH--CH.dbd.CH--(CH.sub.2).sub.3--,
--(CH.sub.2).sub.3--C.ident.C--C.ident.C--(CH.sub.2).sub.3-- or
--CH.sub.2--O--(CH.sub.2).sub.2--O--(CH.sub.2).sub.2--O--CH.sub.2--.
11. The method of claim 10, wherein: R.sup.1 and R.sup.2 are
pyridinium rings; R.sup.3 is hydrogen or methyl; R.sup.5 is
hydrogen, methyl, ethyl, butyl, phenyl, 1-methyl-2-pyrrolidinyl,
bromo, hydroxymethyl or hydroxypropyl; R.sup.7 is hydrogen or
methyl; R.sup.9 is hydrogen or methyl; R.sup.11 is hydrogen; and
X.sup.1 and X.sup.2 are chloride or bromide.
12. The method of claim 10, wherein: R.sup.1 and R.sup.2 are
quinoline, isoquinoline, tetrahydroquinoline or
tetrahydroisoquinoline; and X.sup.1 and X.sup.2 are chloride or
bromide.
13. The method of claim 8, wherein said compound is selected from
the group consisting of
cis-cis-N,N'-(dodeca-5,7-diene-1,12-diyl)-bis-[3-(2'-5-1-methyl-pyrrolidi-
n-2-yl)-pyridinium]dibromide;
cis-cis-N,N'-(dodeca-5,7-diene-1,12-diyl)-bis-{2-methyl-pyridinium)dibrom-
ide;
cis-cis-N,N'-(dodeca-5,7-diene-1,12-diyl)-bis-(3-methyl-pyridinium)di-
bromide;
cis-cis-N,N'-(dodeca-5,7-diene-1s12-diyl)-bis-(4-methyl-pyridiniu-
m)dibromide;
cis-cis-N,N'-(dodeca-5,7-diene-1,12-diyl)-bis-(5,6,7,8-tetrahydro-quinoli-
nium)dibromide;
cis-cis-N,N'-(dodeca-5,7-diene-1,12-diyl)-bis-(5,6,7,8-tetrahydro-isoquin-
olinium)dibromide;
cis-cis-N,N'-(dodeca-5,7-diene-1,12-diyl)-bis-(2,4-dimethyl-pyridinium)di-
bromide;
cis-cis-N,N'-(dodeca-5,7-diene-1,12-diyl)-bis-(3,4-dimethyl-pyrid-
inium)dibromide;
cis-cis-N,N'-(dodeca-5,7-diene-1,12-diyl)-bis-(3,5-dimethyl-pyridinium)di-
bromide;
N,N'-[1,4-phenylenedi-(4-butanyl)]-bis-[3-(2'-S-1-methyl-pyrrolid-
in-2-yl)-pyridinium]dibromide;
N,N'-[1,4-phenylenedi-(4-butanyl)]-bis-(2-methylpyridinium)dibromide;
N,N'-[1,4-phenylenedi-(4-butanyl)]-bis-(3-methylpyridinium)dibromide;
N,N'-[1,4-phenylenedi-(4-butanyl)]-bis-(4-methylpyridinium)dibromide;
N,N'-[1,4-phenylenedi-(4-butanyl)]-bis-(3-ethylpyridinium)dibromide;
N,N'-[1,4-phenylenedi-(4-butanyl)]-bis-(5,6,7,8-tetrahydroquinolinium)dib-
romide;
N,N'-[1,4-phenylenedi-(4-butanyl)]-bis-(5,6,7,8-tetrahydroisoquino-
linium)dibromide;
N,N'-[1,4-phenylenedi-(4-butanyl)]-bis-[3-(3-hydroxy-propyl)-pyridinium]d-
ibromide;
N,N'-[1,4-phenylenedi-(4-butanyl)]-bis-(2,4-dimethylpyridinium)d-
ibromide;
N,N'-[1,4-phenylenedi-{4-butanyl)]-bis-(3,4-dimethylpyridinium)d-
ibromide;
N,N'-[1,4-phenylenedi-{4-butanyl)]-bis-(3,5-dimethylpyridinium)d-
ibromide; 1,2-bis-[5-(2-methyl-pyridinium)-pent-1-ynyl]-benzene
dibromide; 1,2-bis-[5-(3-methyl-pyridinium)-pent-1-ynyl]-benzene
dibromide; 1,2-bis-[5-(4-methyl-pyridinium)-pent-1-ynyl]-benzene
dibromide;
1,2-bis-[5-(2,4-dimethyl-pyridinium)-pent-1-ynyl]-benzene
dibromide;
1,2-bis-[5-(3,4-dimethyl-pyridinium)-pent-1-ynyl]-benzene
dibromide;
1,2-bis-[5-(3,5-dimethyl-pyridinium)-pent-1-ynyl]-benzene
dibromide; 1,2-bis-(5-quinolinium-pent-1-ynyl)-benzene dibromide;
1,2-bis-(5-isoquinolinium-pent-1-ynyl)-benzene dibromide;
1,2-bis-(5-S-nicotinium-pent-1-ynyl)-benzene dibromide;
1,2-bis-[5-(2-methyl-pyridinium)-pentyl]-benzene dibromide;
1,2-bis-[5-(3-methyl-pyridinium)-pentyl]-benzene dibromide;
1,2-bis-[5-(4-methyl-pyridinium)-pentyl]-benzene dibromide;
1,2-bis-[5-(2,4-dimethyl-pyridinium)-pentyl]benzene dibromide;
1,2-bis-[5-(3,4-dimethyl-pyridinium)-pentyl]-benzene dibromide;
1,2-bis-[5-(3,5-methyl-pyridinium)-pentyl]-benzene dibromide;
1,2-bis-(5-quinolinium-pentyl)-benzene dibromide;
1,2-bis-(5-isoquinolinium-pentyl)-benzene dibromide;
1,2-bis-(5-S-nicotinium-pentyl)-benzene dibromide;
1,2-bis-[5-(3-n-butyl-pyridinium)-pentyl]-benzene dibromide;
1,2-bis-[5-(3-bromo-pyridinium)-pentyl]benzene dibromide;
1,2-bis-(5-pyridinium-pentyl)-benzene dibromide;
1,3-bis-[5-(2-methyl-pyridinium)-pent-1-ynyl]benzene dibromide;
1,3-bis-[5-(3-methyl-pyridinium)-pent-1-ynyl]-benzene dibromide;
1,3-bis-[5-(4-methyl-pyridinium)-pent-1-ynyl]benzene dibromide;
1,3-bis-[5-(2,4-dimethyl-pyridinium)-pent-1-ynyl]-benzene
dibromide;
1,3-bis-[5-(3,4-dimethyl-pyridinium)-pent-1-ynyl]-benzene
dibromide;
1,3-bis-[5-(3,5-dimethyl-pyridinium)-pent-1-ynyl]-benzene
dibromide; 1,3-bis-(5-quinolinium-pent-1-ynyl)-benzene dibromide;
1,3-bis-(5-isoquinolinium-pent-1-ynyl)-benzene dibromide;
1,3-bis-(5-S-nicotiniuin-pent-1-ynyl)-benzene dibromide;
1,3-bis-[5-(3-n-butyl-pyridinium)-pent-1-ynyl]-benzene dibromide;
1,3-bis-[5-(3-phenyl-pyridinium)-pent-1-ynyl]-benzene dibromide;
1,3-bis-[5-pyridinium-pent-1-ynyl)-benzene dibromide;
1,3-bis-[5-(2-methyl-pyridinium)-pentyl]-benzene dibromide;
1,3-bis-[5-(3-methyl-pyridinium)-pentyl]-benzene dibromide;
1,3-bis-[5-(4-methyl-pyridinium)-pentyl]-benzene dibromide;
1,3-bis-[5-(2,4-dimethyl-pyridinium)-pentyl]-benzene dibromide;
1,3-bis-[5-(3,4-dimethyl-pyridinium)-pentyl]-benzene dibromide;
1,3-bis-[5-(3,5-dimethyl-pyridinium)-pentyl]-benzene dibromide;
1,3-bis-(5-quinolinium-pentyl)-benzene dibromide;
1,3-bis-(5-isoquinolinium-pentyl)-benzene dibromide;
N,N'-[(1,1'-biphenyl)-4,4'-di-(3-propanyl)]-bis-[3-(2'-S-1-methyl-pyrroli-
din-2-yl)-pyridinium]dibromide;
N,N'-[(1,1'-biphenyl)-4,4'-di-(3-propanyl)]-bis-(3,5-dimethylpyridinium)d-
ibromide;
N,N'-[(1,1'-biphenyl)-4,4'-di-(3-propanyl)]-bis-(3,4-dimethylpyr-
idinium)dibromide;
N,N'-[(1,1'-biphenyl)-4,4'-di-(3-propanyl)]-bis-(2,4-dimethylpyridinium)d-
ibromide;
N,N'-[(1,1'-biphenyl)-4,4'-di-(3-propanyl)]-bis-[3-(3-hydroxy-pr-
opyl)-pyridinium]dibromide;
N,N'-[(1,1'-biphenyl)-4,4'-di-(3-propanyl)]-bis-[5,6,7,8-tetrahydroquinol-
inium]dibromide;
N,N'-[(1,1'-biphenyl)-4,4'-di-(3-propanyl)]-bis-[5,6,7,8-tetrahydroisoqui-
nolinium]dibromide;
N,N'-[(1,1'-biphenyl)-4,4'-di-(3-propanyl)]-bis-(4-methylpyridinium)dibro-
mide;
N,N'-[(1,1'-biphenyl)-4,4'-di-(3-propanyl)]-bis-(3-methylpyridinium)-
dibromide;
N,N'-[1,1'-biphenyl)-4,4'-di-(3-propanyl)]-bis-(2-methylpyridin-
ium)dibromide;
N,N'-{2,2'-[oxybis(2,1-ethandiyloxy)]bis-ethyl}-bis-[3-(2'-S-1-methyl-pyr-
rolidin-2-yl)-pyridinium]dichloride;
N,N'-{2,2'-[oxybis(2,1-ethandiyloxy)]bis-ethyl}-bis(2-methylpyridinium)di-
chloride;
N,N'-{2,2'-[oxybis(2,1-ethandiyloxy)]bis-ethyl}-bis(3-methylpyri-
dinium)dichloride;
N,N'-{2,2'-[oxybis(2,1-ethandiyloxy)]bis-ethyl}-bis(4-methylpyridinium)di-
chloride;
N,N'-{2,2'-[oxybis(2,1-ethandiyloxy)]bis-ethyl}-bis(5,6,7,8-tetr-
ahydroquinolinium)dichloride;
N,N'-{2,2'-[oxybis(2,1-ethandiyloxy)]bis-ethyl}-bis(5,6,7,8-tetrahydroiso-
quinolinium)dichloride;
N,N'-{2,2'-[oxybis(2,1-ethandiyloxy)]bis-ethyl}-bis-[3-(3-hydroxypropyl)--
pyridinium]dichloride;
N,N'-{2,2'-[oxybis(2,1-ethandiyloxy)]bis-ethyl}-bis(3-hydroxymethylpyridi-
nium)dichloride;
N,N'-{2,2'-[oxybis(2,1-ethandiyloxy)]bis-ethyl}-bis(2,4-dimethylpyridiniu-
m)dichloride;
N,N'-{2,2'-[oxybis(2,1-ethandiyloxy)]bis-ethyl}-bis(3,4-dimethylpyridiniu-
m)dichloride;
N,N'-{2,2'-[oxybis(2,1-ethandiyloxy)]bis-ethyl}-bis(3,5-dimethylpyridiniu-
m)dichloride;
N,N'-(5,7-dodecadiyn-1,12-diyl)-bis-(2-methylpyridinium)dichloride;
N,N'-(5,7-dodecadiyn-1,12-diyl)-bis-(3-methylpyridinium)dichloride;
N,N'-(5,7-dodecadiyn-1,12-diyl)-bis-(4-methylpyridinium)dichloride;
N,N'-(5,7-dodecadiyn-1,12-diyl)-bis-(3,4-dimethylpyridinium)dichloride;
N,N'-(5,7-dodecadiyn-1,12-diyl)-bis-(3,5-dimethylpyridinium)dichloride;
N,N'-(5,7-dodecadiyn-1,12-diyl)-bis-(5,6,7,8-tetrahydroisoquinolinium)dic-
hloride;
N,N'-[(1,4-phenylene)-bis-(4-butynyl)]-bis-(3-methyl-pyridinium)d-
ibromide;
N,N'-[(1,4-phenylene)-bis-(4-butynyl)]-bis-(4-methyl-pyridinium)-
dibromide;
N,N'-[(1,4-phenylene)-bis-(4-butynyl)]-bis-(5,6,7,8-tetrahydroi-
soquiolinium)dibromide;
N,N'-[(1,4-phenylene)-bis-(4-butynyl)]-bis-(3,4-dimethyl-pyridinium)dibro-
mide;
N,N'-[(1,4-phenylene)-bis-(4-butynyl)]-bis-(3,5-dimethyl-pyridinium)-
dibromide;
N,N'-[(1,1'-biphenyl)-4,4'-di-(1-propyn-3-yl)]-bis-(3-methylpyr-
idinium)dibromide;
N,N'-[(1,1'-biphenyl)-4,4'-di-(1-propyn-3-yl)]-bis-(4-methylpyridinium)di-
bromide;
N,N'-[(1,1'-biphenyl)-4,4'-di-(1-propyn-3-yl)]-bis-(3,4-dimethylp-
yridinium)dibromide.
14. The method of claim 8, wherein said compound is
N,N'-[(1,1'-biphenyl)-4,4'-di-(1-propyn-3-yl)]-bis-(3,4-dimethylpyridiniu-
m)dibromide.
15. A method of treating nociceptive pain comprising administering
to a mammalian subject in need thereof a pharmaceutically
acceptable amount of a compound of Formula (I)
X.sup.2.crclbar..sym.R.sup.1--H.sub.2C-L.sup.1-Q-L.sup.2-CH.sub.2--R.sup.-
2.sym..crclbar.X.sup.1 (1) wherein X.sup.1.crclbar. and
X.sup.2.crclbar. are each independently an organic or inorganic
anion; wherein Q is selected from phenylene, biphenylene,
--CH.dbd.CH--, --CH.dbd.CH--CH.dbd.CH--, --C.ident.C--,
--C.ident.C--C.ident.C--, --O--(CH.sub.2).sub.2--O--, and
--O--(CH.sub.2).sub.2--O--(CH.sub.2).sub.2--O--; wherein L.sup.1
and L.sup.2 are each independently selected from alkyl, substituted
alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted
alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl,
alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl,
arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted
arylalkynyl, heterocyclic, substituted heterocyclic; SOY.sup.1,
SO.sub.2Y.sup.1, SO.sub.2OY.sup.1 or SO.sub.2NHY.sup.1, where
Y.sup.1 is selected from hydrogen, lower alkyl, alkenyl, alkynyl or
aryl, and where Y.sup.1 is not hydrogen in SOY.sup.1 and if Y.sup.1
is alkenyl or alkynyl, the site of unsaturation is not conjugated
with a heteroatom; COY.sup.2, where Y.sup.2 is selected from
hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted
cycloalkyl, alkoxy, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, aryl, substituted aryl, aryloxy, alkylaryl,
substituted alkylaryl, arylalkyl, substituted arylalkyl,
arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted
arylalkynyl, heterocyclic, or substituted heterocyclic, and where
if Y.sup.2 comprises alkenyl or alkynyl, the site of unsaturation
is not conjugated with the carbonyl group; OY.sup.3, where Y.sup.3
is selected from hydrogen, alkyl, substituted alkyl, cycloalkyl,
substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, aryl, substituted aryl, alkylaryl, substituted
alkylaryl, arylalkyl, substituted arylalkyl, arylalkenyl,
substituted arylalkenyl, arylalkynyl, substituted arylalkynyl,
acyl, alkylsulfonyl, arylsulfonyl, heterocyclic, or substituted
heterocyclic, where if Y.sup.3 comprises alkenyl or alkynyl, the
site of unsaturation is not conjugated with the oxygen;
NY.sup.4Y.sup.5 where Y.sup.4 and Y.sup.5 are each independently
selected from hydrogen, alkyl, substituted alkyl, cycloalkyl,
substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, aryl, substituted aryl, alkylaryl, substituted
alkylaryl, arylalkyl, substituted arylalkyl, arylalkenyl,
substituted arylalkenyl, arylalkynyl, substituted arylalkynyl,
acyl, alkylsulfonyl, arylsulfonyl, heterocyclic, or substituted
heterocyclic, where if Y.sup.4 or Y.sup.5 comprises alkenyl or
alkynyl, the site of unsaturation is not conjugated with the
nitrogen; SY.sup.6, where Y.sup.6 is selected from hydrogen, alkyl,
substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl,
substituted alkenyl, alkynyl, substituted alkynyl, aryl,
substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl,
substituted arylalkyl, arylalkenyl, substituted arylalkenyl,
arylalkynyl, substituted arylalkynyl, heterocyclic, or substituted
heterocyclic, and where if Y.sup.6 comprises alkenyl or alkynyl,
the site of unsaturation is not conjugated with the sulfur; wherein
R.sup.1 and R.sup.2 are each independently five or six membered
nitrogen containing rings as shown in formulas (IIA) and (IIB):
##STR00112## wherein A.sup.1 is carbon, nitrogen, sulfur or oxygen,
provided that when A.sup.1 is a carbon and joins a ring atom with
an unsaturated bond or is a nitrogen, R.sup.3 is absent, and when
A.sup.1 is sulfur or oxygen or joins a ring atom with an
unsaturated bond and is a nitrogen, both R.sup.3 and R.sup.4 are
absent; wherein A.sup.2 is carbon, nitrogen, sulfur or oxygen,
provided that when A.sup.2 is a carbon and joins a ring atom with
an unsaturated bond or is a nitrogen, R.sup.5 is absent, and when
A.sup.2 is sulfur or oxygen or joins a ring atom with an
unsaturated bond and is a nitrogen, both R.sup.5 and R.sup.6 are
absent; wherein A.sup.3 is carbon, nitrogen, sulfur or oxygen,
provided that when A.sup.3 is a carbon and joins a ring atom with
an unsaturated bond or is a nitrogen, R.sup.7 is absent, and when
A.sup.3 is sulfur or oxygen or joins a ring atom with an
unsaturated bond and is a nitrogen, both R.sup.7 and R.sup.8 are
absent; wherein A.sup.4 is carbon, nitrogen, sulfur or oxygen,
provided that when A.sup.4 is a carbon and joins a ring atom with
an unsaturated bond or is a nitrogen, R.sup.9 is absent, and when
A.sup.4 is sulfur or oxygen or joins a ring atom with an
unsaturated bond and is a nitrogen, both R.sup.9 and R.sup.10 are
absent; wherein A.sup.5 is carbon, nitrogen, sulfur or oxygen,
provided that when A.sup.5 is a carbon and joins a ring atom with
an unsaturated bond or is a nitrogen, R.sup.11 is absent, and when
A.sup.5 is sulfur or oxygen or joins a ring atom with an
unsaturated bond and is a nitrogen, both R.sup.11 and R.sup.12 are
absent; wherein A.sup.6 is carbon, nitrogen, sulfur or oxygen,
provided that when A.sup.6 is a carbon and joins a ring atom with
an unsaturated bond or is a nitrogen, R.sup.14 is absent, and when
A.sup.6 is sulfur or oxygen or joins a ring atom with an
unsaturated bond and is a nitrogen, both R.sup.14 and R.sup.15 are
absent; wherein A.sup.7 is carbon, nitrogen, sulfur or oxygen,
provided that when A.sup.7 is a carbon and joins a ring atom with
an unsaturated bond or is a nitrogen, R.sup.16 is absent, and when
A.sup.7 is sulfur or oxygen or joins a ring atom with an
unsaturated bond and is a nitrogen, both R.sup.16 and R.sup.17 are
absent; wherein A.sup.8 is carbon, nitrogen, sulfur or oxygen,
provided that when A.sup.8 is a carbon and joins a ring atom with
an unsaturated bond or is a nitrogen, R.sup.18 is absent, and when
A.sup.8 is sulfur or oxygen or joins a ring atom with an
unsaturated bond and is a nitrogen, both R.sup.18 and R.sup.19 are
absent; wherein A.sup.9 is carbon, nitrogen, sulfur or oxygen,
provided that when A.sup.9 is a carbon and joins a ring atom with
an unsaturated bond or is a nitrogen, R.sup.20 is absent, and when
A.sup.9 is sulfur or oxygen or joins a ring atom with an
unsaturated bond and is a nitrogen, both R.sup.20 and R.sup.21 are
absent; wherein R.sup.13 or R.sup.22 is absent when any of the
bonds to the ammonium nitrogen is unsaturated, and R.sup.13 or
R.sup.22 is a straight chain or branched alkyl group of four
carbons or fewer when all of the bonds to the ammonium nitrogen are
saturated; wherein R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7,
R.sup.8, R.sup.9, R.sup.10, R.sup.11, and R.sup.12, or R.sup.14,
R.sup.15, R.sup.16, R.sup.17, R.sup.18, R.sup.19, R.sup.20, and
R.sup.21, when present, are each independently selected from
hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted
cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted
alkynyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl,
arylalkyl, substituted arylalkyl, arylalkenyl, substituted
arylalkenyl, arylalkynyl, substituted arylalkynyl, heterocyclic,
substituted heterocyclic, halo, cyano, nitro, or R.sup.4 and
R.sup.5 together with A.sup.1 and A.sup.2, or R.sup.5 and R.sup.7
together with A.sup.2 and A.sup.3, or R.sup.15 and R.sup.16
together with A.sup.6 and A.sup.7, or R.sup.16 and R.sup.18
together with A.sup.7 and A.sup.8 independently form a three to
eight member cyclolkane, substituted cycloalkane, cycloalkene,
substituted cycloalkene, aryl, substituted aryl, heterocycle with
one to three hetero atoms of nitrogen, oxygen or sulfur in the
ring, or substituted heterocycle with one to three hetero atoms of
nitrogen, oxygen or sulfur in the ring; and when all of the bonds
to the ring ammonium nitrogen are saturated, then any of R.sup.3,
R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10,
R.sup.11, R.sup.12, R.sup.13, R.sup.14, R.sup.15, R.sup.16,
R.sup.17, R.sup.18, R.sup.19, R.sup.20, R.sup.21 or R.sup.22 which
is attached to the nitrogen is a straight or branched alkyl group
of four carbons or fewer.
16. The method of claim 15, wherein R.sup.1 and R.sup.2 are
pyridinium rings.
17. The method of claim 15, wherein
-L.sub.1-Q-L.sub.2-is-(CH.sub.2).sub.4-1,2-phenylene-(CH.sub.2).sub.4--,
--(CH.sub.2).sub.4-1,3-phenylene-(CH.sub.2).sub.4--,
--(CH.sub.2).sub.3-1,4-phenylene-(CH.sub.2).sub.3--,
--(CH.sub.2).sub.2-4,4'-biphenylene-(CH.sub.2).sub.2--,
--(CH.sub.2).sub.2--C.ident.C-1,2-phenylene-C.ident.C--(CH.sub.2).sub.2---
,
--(CH.sub.2).sub.2--C.ident.C-1,3-phenylene-C.ident.C--(CH.sub.2).sub.2--
-, --CH.sub.2--C.ident.C-1,4-phenylene-C.ident.C--CH.sub.2--,
--C.ident.C-4,4'-biphenylene-C.ident.C--,
--(CH.sub.2).sub.3--CH.dbd.CH--CH.dbd.CH--(CH.sub.2).sub.3--,
--(CH.sub.2).sub.3--C.ident.C--C.ident.C--(CH.sub.2).sub.3-- or
--CH.sub.2--O--(CH.sub.2).sub.2--O--(CH.sub.2).sub.2--O--CH.sub.2--.
18. The method of claim 17, wherein: R.sup.1 and R.sup.2 are
pyridinium rings; R.sup.3 is hydrogen or methyl; R.sup.5 is
hydrogen, methyl, ethyl, butyl, phenyl, 1-methyl-2-pyrrolidinyl,
bromo, hydroxymethyl or hydroxypropyl; R.sup.7 is hydrogen or
methyl; R.sup.9 is hydrogen or methyl; R.sup.11 is hydrogen; and
X.sup.1 and X.sup.2 are chloride or bromide.
19. The method of claim 17, wherein: R.sup.1 and R.sup.2 are
quinoline, isoquinoline, tetrahydroquinoline or
tetrahydroisoquinoline; and X.sup.1 and X.sup.2 are chloride or
bromide.
20. The method of claim 15, wherein said compound is selected from
the group consisting of:
cis-cis-N,N'-(dodeca-5,7-diene-1,12-diyl)-bis-[3-(2'-5-1-methyl-pyrrolidi-
n-2-yl)-pyridinium]dibromide;
cis-cis-N,N'-(dodeca-5,7-diene-1,12-diyl)-bis-{2-methyl-pyridinium)dibrom-
ide;
cis-cis-N,N'-(dodeca-5,7-diene-1,12-diyl)-bis-(3-methyl-pyridinium)di-
bromide;
cis-cis-N,N'-(dodeca-5,7-diene-1s12-diyl)-bis-(4-methyl-pyridiniu-
m)dibromide;
cis-cis-N,N'-(dodeca-5,7-diene-1,12-diyl)-bis-(5,6,7,8-tetrahydro-quinoli-
nium)dibromide;
cis-cis-N,N'-(dodeca-5,7-diene-1,12-diyl)-bis-(5,6,7,8-tetrahydro-isoquin-
olinium)dibromide;
cis-cis-N,N'-(dodeca-5,7-diene-1,12-diyl)-bis-(2,4-dimethyl-pyridinium)di-
bromide;
cis-cis-N,N'-(dodeca-5,7-diene-1,12-diyl)-bis-(3,4-dimethyl-pyrid-
inium)dibromide;
cis-cis-N,N'-(dodeca-5,7-diene-1,12-diyl)-bis-(3,5-dimethyl-pyridinium)di-
bromide;
N,N'-[1,4-phenylenedi-(4-butanyl)]-bis-[3-(2'-S-1-methyl-pyrrolid-
in-2-yl)-pyridinium]dibromide;
N,N'-[1,4-phenylenedi-(4-butanyl)]-bis-(2-methylpyridinium)dibromide;
N,N'-[1,4-phenylenedi-(4-butanyl)]-bis-(3-methylpyridinium)dibromide;
N,N'-[1,4-phenylenedi-(4-butanyl)]-bis-(4-methylpyridinium)dibromide;
N,N'-[1,4-phenylenedi-(4-butanyl)]-bis-(3-ethylpyridinium)dibromide;
N,N'-[1,4-phenylenedi-(4-butanyl)]-bis-(5,6,7,8-tetrahydroquinolinium)dib-
romide;
N,N'-[1,4-phenylenedi-(4-butanyl)]-bis-(5,6,7,8-tetrahydroisoquino-
linium)dibromide;
N,N'-[1,4-phenylenedi-(4-butanyl)]-bis-[3-(3-hydroxy-propyl)-pyridinium]d-
ibromide;
N,N'-[1,4-phenylenedi-(4-butanyl)]-bis-(2,4-dimethylpyridinium)d-
ibromide;
N,N'-[1,4-phenylenedi-{4-butanyl)]-bis-(3,4-dimethylpyridinium)d-
ibromide;
N,N'-[1,4-phenylenedi-{4-butanyl)]-bis-(3,5-dimethylpyridinium)d-
ibromide; 1,2-bis-[5-(2-methyl-pyridinium)-pent-1-ynyl]-benzene
dibromide; 1,2-bis-[5-(3-methyl-pyridinium)-pent-1-ynyl]-benzene
dibromide; 1,2-bis-[5-(4-methyl-pyridinium)-pent-1-ynyl]-benzene
dibromide;
1,2-bis-[5-(2,4-dimethyl-pyridinium)-pent-1-ynyl]-benzene
dibromide;
1,2-bis-[5-(3,4-dimethyl-pyridinium)-pent-1-ynyl]-benzene
dibromide;
1,2-bis-[5-(3,5-dimethyl-pyridinium)-pent-1-ynyl]-benzene
dibromide; 1,2-bis-(5-quinolinium-pent-1-ynyl)-benzene dibromide;
1,2-bis-(5-isoquinolinium-pent-1-ynyl)-benzene dibromide;
1,2-bis-(5-S-nicotinium-pent-1-ynyl)-benzene dibromide;
1,2-bis-[5-(2-methyl-pyridinium)-pentyl]-benzene dibromide;
1,2-bis-[5-(3-methyl-pyridinium)-pentyl]-benzene dibromide;
1,2-bis-[5-(4-methyl-pyridinium)-pentyl]-benzene dibromide;
1,2-bis-[5-(2,4-dimethyl-pyridinium)-pentyl]-benzene dibromide;
1,2-bis-[5-(3,4-dimethyl-pyridinium)-pentyl]-benzene dibromide;
1,2-bis-[5-(3,5-methyl-pyridinium)-pentyl]-benzene dibromide;
1,2-bis-(5-quinolinium-pentyl)-benzene dibromide;
1,2-bis-(5-isoquinolinium-pentyl)-benzene dibromide;
1,2-bis-(5-S-nicotinium-pentyl)-benzene dibromide;
1,2-bis-[5-(3-n-butyl-pyridinium)-pentyl]-benzene dibromide;
1,2-bis-[5-(3-bromo-pyridinium)-pentyl]-benzene dibromide;
1,2-bis-(5-pyridinium-pentyl)-benzene dibromide;
1,3-bis-[5-(2-methyl-pyridinium)-pent-1-ynyl]-benzene dibromide;
1,3-bis-[5-(3-methyl-pyridinium)-pent-1-ynyl]-benzene dibromide;
1,3-bis-[5-(4-methyl-pyridinium)-pent-1-ynyl]-benzene dibromide;
1,3-bis-[5-(2,4-dimethyl-pyridinium)-pent-1-ynyl]-benzene
dibromide;
1,3-bis-[5-(3,4-dimethyl-pyridinium)-pent-1-ynyl]-benzene
dibromide;
1,3-bis-[5-(3,5-dimethyl-pyridinium)-pent-1-ynyl]-benzene
dibromide; 1,3-bis-(5-quinolinium-pent-1-ynyl)-benzene dibromide;
1,3-bis-(5-isoquinolinium-pent-1-ynyl)-benzene dibromide;
1,3-bis-(5-S-nicotiniuin-pent-1-ynyl)-benzene dibromide;
1,3-bis-[5-(3-n-butyl-pyridinium)-pent-1-ynyl]-benzene dibromide;
1,3-bis-[5-(3-phenyl-pyridinium)-pent-1-ynyl]-benzene dibromide;
1,3-bis-[5-pyridinium-pent-1-ynyl)-benzene dibromide;
1,3-bis-[5-(2-methyl-pyridinium)-pentyl]-benzene dibromide;
1,3-bis-[5-(3-methyl-pyridinium)-pentyl]-benzene dibromide;
1,3-bis-[5-(4-methyl-pyridinium)-pentyl]-benzene dibromide;
1,3-bis-[5-(2,4-dimethyl-pyridinium)-pentyl]benzene dibromide;
1,3-bis-[5-(3,4-dimethyl-pyridinium)-pentyl]-benzene dibromide;
1,3-bis-[5-(3,5-dimethyl-pyridinium)-pentyl]-benzene dibromide;
1,3-bis-(5-quinolinium-pentyl)-benzene dibromide;
1,3-bis-(5-isoquinolinium-pentyl)-benzene dibromide;
N,N'-[(1,1'-biphenyl)-4,4'-di-(3-propanyl)]-bis-[3-(2'-S-1-methyl-pyrroli-
din-2-yl)-pyridinium]dibromide;
N,N'-[(1,1'-biphenyl)-4,4'-di-(3-propanyl)]-bis-(3,5-dimethylpyridinium)d-
ibromide;
N,N'-[(1,1'-biphenyl)-4,4'-di-(3-propanyl)]-bis-(3,4-dimethylpyr-
idinium)dibromide;
N,N'-[(1,1'-biphenyl)-4,4'-di-(3-propanyl)]-bis-(2,4-dimethylpyridinium)d-
ibromide;
N,N'-[(1,1'-biphenyl)-4,4'-di-(3-propanyl)]-bis-[3-(3-hydroxy-pr-
opyl)-pyridinium]dibromide;
N,N'-[(1,1'-biphenyl)-4,4'-di-(3-propanyl)]-bis-[5,6,7,8-tetrahydroquinol-
inium]dibromide;
N,N'-[(1,1'-biphenyl)-4,4'-di-(3-propanyl)]-bis-[5,6,7,8-tetrahydroisoqui-
nolinium]dibromide;
N,N'-[(1,1'-biphenyl)-4,4'-di-(3-propanyl)]-bis-(4-methylpyridinium)dibro-
mide;
N,N'-[(1,1'-biphenyl)-4,4'-di-(3-propanyl)]-bis-(3-methylpyridinium)-
dibromide;
N,N'-[(1,1'-biphenyl)-4,4'-di-(3-propanyl)]-bis-(2-methylpyridi-
nium)dibromide;
N,N'-{2,2'-[oxybis(2,1-ethandiyloxy)]bis-ethyl}-bis-[3-(2'-S-1-methyl-pyr-
rolidin-2-yl)-pyridinium]dichloride;
N,N'-{2,2'-[oxybis(2,1-ethandiyloxy)]bis-ethyl}-bis(2-methylpyridinium)di-
chloride;
N,N'-{2,2'-[oxybis(2,1-ethandiyloxy)]bis-ethyl}-bis(3-methylpyri-
dinium)dichloride;
N,N'-{2,2'-[oxybis(2,1-ethandiyloxy)]bis-ethyl}-bis(4-methylpyridinium)di-
chloride;
N,N'-{2,2'-[oxybis(2,1-ethandiyloxy)]bis-ethyl}-bis(5,6,7,8-tetr-
ahydroquinolinium)dichloride;
N,N'-{2,2'-[oxybis(2,1-ethandiyloxy)]bis-ethyl}-bis(5,6,7,8-tetrahydroiso-
quinolinium)dichloride;
N,N'-{2,2'-[oxybis(2,1-ethandiyloxy)]bis-ethyl}-bis-[3-(3-hydroxypropyl)--
pyridinium]dichloride;
N,N'-{2,2'-[oxybis(2,1-ethandiyloxy)]bis-ethyl}-bis(3-hydroxymethylpyridi-
nium)dichloride;
N,N'-{2,2'-[oxybis(2,1-ethandiyloxy)]bis-ethyl}-bis(2,4-dimethylpyridiniu-
m)dichloride;
N,N'-{2,2'-[oxybis(2,1-ethandiyloxy)]bis-ethyl}-bis(3,4-dimethylpyridiniu-
m)dichloride;
N,N'-{2,2'-[oxybis(2,1-ethandiyloxy)]bis-ethyl}-bis(3,5-dimethylpyridiniu-
m)dichloride;
N,N'-(5,7-dodecadiyn-1,12-diyl)-bis-(2-methylpyridinium)dichloride;
N,N'-(5,7-dodecadiyn-1,12-diyl)-bis-(3-methylpyridinium)dichloride;
N,N'-(5,7-dodecadiyn-1,12-diyl)-bis-(4-methylpyridinium)dichloride;
N,N'-(5,7-dodecadiyn-1,12-diyl)-bis-(3,4-dimethylpyridinium)dichloride;
N,N'-(5,7-dodecadiyn-1,12-diyl)-bis-(3,5-dimethylpyridinium)dichloride;
N,N'-(5,7-dodecadiyn-1,12-diyl)-bis-(5,6,7,8-tetrahydroisoquinolinium)dic-
hloride;
N,N'-[(1,4-phenylene)-bis-(4-butynyl)]-bis-(3-methyl-pyridinium)d-
ibromide;
N,N'-[(1,4-phenylene)-bis-(4-butynyl)]-bis-(4-methyl-pyridinium)-
dibromide;
N,N'-[(1,4-phenylene)-bis-(4-butynyl)]-bis-(5,6,7,8-tetrahydroi-
soquiolinium)dibromide;
N,N'-[(1,4-phenylene)-bis-(4-butynyl)]-bis-(3,4-dimethyl-pyridinium)dibro-
mide;
N,N'-[(1,4-phenylene)-bis-(4-butynyl)]-bis-(3,5-dimethyl-pyridiniuim-
)dibromide;
N,N'-[(1,1'-biphenyl)-4,4'-di-(1-propyn-3-yl)]-bis-(3-methylpyridinium)di-
bromide;
N,N'-[(1,1'-biphenyl)-4,4'-di-(1-propyn-3-yl)]-bis-(4-methylpyrid-
inium)dibromide;
N,N'-[(1,1'-biphenyl)-4,4'-di-(1-propyn-3-yl)]-bis-(3,4-dimethylpyridiniu-
m)dibromide.
21. The method of claim 15, wherein said compound is
N,N'-[(1,1'-biphenyl)-4,4'-di-(1-propyn-3-yl)]-bis-(3,4-dimethylpyridiniu-
m)dibromide.
Description
FIELD OF THE INVENTION
[0001] The invention relates to bis-quaternary ammonium salts and
their use as agents for pain modulation, treatment, reversal and/or
prevention of inflammatory pain, neuropathic pain or nociceptive
pain.
BACKGROUND OF THE INVENTION
[0002] The treatment of pain is a critical health issue. Acute
(e.g., postoperative pain) and chronic (e.g., arthritis, low back,
cancer) pain affects tens of millions of people annually in the US.
Each year some 30 million people visit a physician with a complaint
of a painful condition. Some 10% of these patients are seen with
chronic pain as their main complaint. The financial loss due to
pain has been estimated to exceed 100 billion dollars a year as a
result of medical fees, decreased productivity, litigation and the
cost of drugs. New therapeutic agents with broader efficacy, for
nociceptive, neuropathic and mixed nociceptive-neuropathic pain
syndromes, and with fewer side effects would result in significant
societal benefit.
[0003] Pain can be broadly divided into two categories: nociceptive
and neuropathic pain. Nociceptive pain occurs as a result of
activation of peripheral nociceptors, actually free nerve endings
by noxious stimuli (heat, pressure, inflammatory mediators).
Examples of nociceptive pain include postsurgical pain,
inflammatory pain (e.g., arthritis) and low back pain. Such a pain
is often described as "a constant, dull, aching pain". Neuropathic
pain occurs as a result of damage to the peripheral or central
nervous system. Examples of neuropathic pain include radiculopathy
(e.g., disc impingement on a nerve), complex regional pain syndrome
(CRPS I, II), diabetic peripheral neuropathy or central pain
(stroke, spinal cord injury, multiple sclerosis). Patients
typically describe neuropathic pain as "burning and tingling" in
nature. It is characterized by hyperalgesia (increased painful
response to a noxious stimulus) and allodynia (pain to a previously
non-noxious stimulus).
[0004] In many pain patients, in particular those with chronic pain
conditions of both malignant (cancer-related pain) and
non-malignant origin, pain is inadequately managed with currently
available drugs. Available drugs are simple modifications (e.g.,
extended release) of drugs from classes which have been available
for decades including the opioids, nonsteroidal anti-inflammatory
agents (NSAID's) or various adjuvants (antidepressants,
anticonvulsants) initially approved for other uses besides pain.
Opioids (e.g., morphine, oxycodone) are often successfully used for
the treatment of moderate to severe nociceptive pain. Chronic
neuropathic pain is much less responsive to opioids. Use of opioid
analgesics is associated with a broad range of significant side
effects including cognitive impairment, respiratory depression and
constipation. In addition, long-term opioid dosing results in the
development of tolerance to the analgesic effect, drug abuse and
dependence. The NSAID's (e.g., ibuprofen) act by inhibition of the
cyclo-oxygenase (Cox-1,2) enzyme. They are especially useful in
nociceptive pain of inflammatory origin (e.g., arthritis). However,
the NSAID's have limited efficacy when compared to the opioids. In
addition, NSAID's have significant side effects (renal,
gastrointestinal, cardiovascular). The discovery of the Cox-2
selective agents (e.g., rofecoxib-Vioxx.RTM.;
celecoxib-Celebrex.RTM.; valdecoxib-Bextra.RTM.) which have far
less gastrointestinal toxicity, was thought to be an advance in
NSAID pharmacology. Nonetheless, these agents still have low
efficacy and evidence is now available linking them to significant
cardiovascular events including stroke and myocardial infarction
following chronic use. This has resulted in the removal of both
rofecoxib and valdecoxib from the market. No truly efficacious
agent exists for the treatment of neuropathic pain. GABA-pentin
(Neurontin.RTM.), an anticonvulsant, has found use for some
neuropathic pain syndromes (e.g., diabetic peripheral neuropathy,
postherpetic neuralgia), but it still has limited efficacy.
Duloxetine (Cymbalta.RTM.), an antidepressant, has recently been
approved for the treatment of diabetic peripheral neuropathy.
However, it has limited efficacy and usefulness for other
neuropathic pain states. The N-methyl-d-aspartate (NMDA) receptor
antagonists (e.g., ketamine) have been proposed for the treatment
of neuropathic pain. Their general use is impractical given the
marked side effects including sedation, psychosis and motor
impairment. The limitations of the currently available therapies
clearly demonstrate the need for a broad spectrum new class of
efficacious and safe analgesic drugs for the treatment of
nociceptive and neuropathic pain.
[0005] Given the need for more effective, less toxic, analgesic
drugs, a great deal of emphasis has been placed on identifying
novel molecular targets that could form the basis for new
analgesics. One of the promising new targets is the neuronal
nicotinic acetylcholine receptor (nAChR). nACHR's play an important
role in the control of pain and thus drugs acting at the nicotinic
receptor, as agonists, partial agonists or antagonists may be
expected to have analgesic properties. The bis-quaternary ammonia
salts of the invention are thought to interact with the nACHR.
Nicotinic receptor drugs have been shown to have a broad spectrum
of analgesic activity in several preclinical models of pain of
nociceptive and neuropathic origin. This includes acute thermal
pain models (tail flick, hot plate), inflammatory pain models
(formalin or carrageenan injection into the paw) and nerve injury
(neuropathic pain) models (spinal or sciatic nerve ligation). Both
anti-hyperalgesic and anti-allodynic effects were observed in the
neuropathic pain models.
[0006] Thus, it appears that nicotine drugs have promise as
analgesic agents for the treatment of several types of clinical
pain, specifically nociceptive, neuropathic and inflammatory
pain.
SUMMARY OF INVENTION
[0007] In one embodiment, compounds corresponding to the following
structure which are useful in treating inflammatory pain,
neuropathic pain or nociceptive pain are provided.
X.sup.2.crclbar..sym.R.sup.1--H.sub.2C-L.sup.1-Q-L.sup.2-CH.sub.2--R.sup-
.2.sym..crclbar.X.sup.1 (1)
[0008] X.sup.1.crclbar. and X.sup.2.crclbar. are each independently
an organic or inorganic anion.
[0009] Q is selected from phenylene, biphenylene, --CH.dbd.CH--,
--CH.dbd.CH--CH.dbd.CH--, --C.ident.C--, --C.ident.C--C.ident.C--,
--O--(CH.sub.2).sub.2--O-- and
--O--(CH.sub.2).sub.2--O--(CH.sub.2).sub.2--O--.
[0010] L.sup.1 and L.sup.2 are each independently selected from
alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl,
alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl,
substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl,
substituted arylalkyl, arylalkenyl, substituted arylalkenyl,
arylalkynyl, substituted arylalkynyl, heterocyclic, substituted
heterocyclic; SOY.sup.1, SO.sub.2Y.sup.1, SO.sub.2OY.sup.1 or
SO.sub.2NHY.sup.1, where Y.sup.1 is selected from hydrogen, lower
alkyl, alkenyl, alkynyl or aryl, and where Y.sup.1 is not hydrogen
in SOY.sup.1 and if Y.sup.1 is alkenyl or alkynyl, the site of
unsaturation is not conjugated with a heteroatom; COY.sup.2, where
Y.sup.2 is selected from hydrogen, alkyl, substituted alkyl,
cycloalkyl, substituted cycloalkyl, alkoxy, alkenyl, substituted
alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl,
aryloxy, alkylaryl, substituted alkylaryl, arylalkyl, substituted
arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl,
substituted arylalkynyl, heterocyclic, or substituted heterocyclic,
and where if Y.sup.2 comprises alkenyl or alkynyl, the site of
unsaturation is not conjugated with the carbonyl group; OY.sup.3,
where Y.sup.3 is selected from hydrogen, alkyl, substituted alkyl,
cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl,
alkynyl, substituted alkynyl, aryl, substituted aryl, alkylaryl,
substituted alkylaryl, arylalkyl, substituted arylalkyl,
arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted
arylalkynyl, acyl, alkylsulfonyl, arylsulfonyl, heterocyclic, or
substituted heterocyclic, where if Y.sup.3 comprises alkenyl or
alkynyl, the site of unsaturation is not conjugated with the
oxygen; NY.sup.4Y.sup.5 where Y.sup.4 and Y.sup.5 are each
independently selected from hydrogen, alkyl, substituted alkyl,
cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl,
alkynyl, substituted alkynyl, aryl, substituted aryl, alkylaryl,
substituted alkylaryl, arylalkyl, substituted arylalkyl,
arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted
arylalkynyl, acyl, alkylsulfonyl, arylsulfonyl, heterocyclic, or
substituted heterocyclic, where if Y.sup.4 or Y.sup.5 comprises
alkenyl or alkynyl, the site of unsaturation is not conjugated with
the nitrogen; SY.sup.6, where Y.sup.6 is selected from hydrogen,
alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl,
alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl,
substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl,
substituted arylalkyl, arylalkenyl, substituted arylalkenyl,
arylalkynyl, substituted arylalkynyl, heterocyclic, or substituted
heterocyclic, and where if Y.sup.6 comprises alkenyl or alkynyl,
the site of unsaturation is not conjugated with the sulfur.
[0011] R.sup.1 and R.sup.2 are each independently five or six
membered nitrogen containing rings as shown in formulas (IIA) and
(IIB).
##STR00001##
[0012] A.sup.1 is carbon, nitrogen, sulfur or oxygen, provided that
when A.sup.1 is a carbon and joins a ring atom with an unsaturated
bond or is a nitrogen, R.sup.3 is absent, and when A.sup.1 is
sulfur or oxygen or joins a ring atom with an unsaturated bond and
is a nitrogen, both R.sup.3 and R.sup.4 are absent.
[0013] A.sup.2 is carbon, nitrogen, sulfur or oxygen, provided that
when A.sup.2 is a carbon and joins a ring atom with an unsaturated
bond or is a nitrogen, R.sup.5 is absent, and when A.sup.2 is
sulfur or oxygen or joins a ring atom with an unsaturated bond and
is a nitrogen, both R.sup.5 and R.sup.6 are absent.
[0014] A.sup.3 is carbon, nitrogen, sulfur or oxygen, provided that
when A.sup.3 is a carbon and joins a ring atom with an unsaturated
bond or is a nitrogen, R.sup.7 is absent, and when A.sup.3 is
sulfur or oxygen or joins a ring atom with an unsaturated bond and
is a nitrogen, both R.sup.7 and R.sup.8 are absent.
[0015] A.sup.4 is carbon, nitrogen, sulfur or oxygen, provided that
when A.sup.4 is a carbon and joins a ring atom with an unsaturated
bond or is a nitrogen, R.sup.9 is absent, and when A.sup.4 is
sulfur or oxygen or joins a ring atom with an unsaturated bond and
is a nitrogen, both R.sup.9 and R.sup.10 are absent.
[0016] A.sup.5 is carbon, nitrogen, sulfur or oxygen, provided that
when A.sup.5 is a carbon and joins a ring atom with an unsaturated
bond or is a nitrogen, R.sup.11 is absent, and when A.sup.5 is
sulfur or oxygen or joins a ring atom with an unsaturated bond and
is a nitrogen, both R.sup.11 and R.sup.12 are absent.
[0017] A.sup.6 is carbon, nitrogen, sulfur or oxygen, provided that
when A.sup.6 is a carbon and joins a ring atom with an unsaturated
bond or is a nitrogen, R.sup.14 is absent, and when A.sup.6 is
sulfur or oxygen or joins a ring atom with an unsaturated bond and
is a nitrogen, both R.sup.14 and R.sup.15 are absent.
[0018] A.sup.7 is carbon, nitrogen, sulfur or oxygen, provided that
when A.sup.7 is a carbon and joins a ring atom with an unsaturated
bond or is a nitrogen, R.sup.16 is absent, and when A.sup.7 is
sulfur or oxygen or joins a ring atom with an unsaturated bond and
is a nitrogen, both R.sup.16 and R.sup.17 are absent.
[0019] A.sup.8 is carbon, nitrogen, sulfur or oxygen, provided that
when A.sup.8 is a carbon and joins a ring atom with an unsaturated
bond or is a nitrogen, R.sup.18 is absent, and when A.sup.8 is
sulfur or oxygen or joins a ring atom with an unsaturated bond and
is a nitrogen, both R.sup.18 and R.sup.19 are absent.
[0020] A.sup.9 is carbon, nitrogen, sulfur or oxygen, provided that
when A.sup.9 is a carbon and joins a ring atom with an unsaturated
bond or is a nitrogen, R.sup.20 is absent, and when A.sup.9 is
sulfur or oxygen or joins a ring atom with an unsaturated bond and
is a nitrogen, both R.sup.20 and R.sup.21 are absent.
[0021] R.sup.13 or R.sup.22 is absent when any of the bonds to the
ammonium nitrogen is unsaturated, and R.sup.13 or R.sup.22 is a
straight chain or branched alkyl group of four carbons or fewer
when all of the bonds to the ammonium nitrogen are saturated.
[0022] R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8,
R.sup.9, R.sup.10, R.sup.11, and R.sup.12, or R.sup.14, R.sup.15,
R.sup.16, R.sup.17, R.sup.18, R.sup.19, R.sup.20, and R.sup.21,
when present, are each independently selected from hydrogen, alkyl,
substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl,
substituted alkenyl, alkynyl, substituted alkynyl, aryl,
substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl,
substituted arylalkyl, arylalkenyl, substituted arylalkenyl,
arylalkynyl, substituted arylalkynyl, heterocyclic, substituted
heterocyclic, halo, cyano, nitro, or R.sup.4 and R.sup.5 together
with A.sup.1 and A.sup.2, or R.sup.5 and R.sup.7 together with
A.sup.2 and A.sup.3, or R.sup.15 and R.sup.16 together with A.sup.6
and A.sup.7, or R.sup.16 and R.sup.18 together with A.sup.7 and
A.sup.8 independently form a three to eight member cyclolkane,
substituted cycloalkane, cycloalkene, substituted cycloalkene,
aryl, substituted aryl, heterocycle with one to three hetero atoms
of nitrogen, oxygen or sulfur in the ring, or substituted
heterocycle with one to three hetero atoms of nitrogen, oxygen or
sulfur in the ring; and when all of the bonds to the ring ammonium
nitrogen are saturated, then any of R.sup.3, R.sup.4, R.sup.5,
R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10, R.sup.11, R.sup.12,
R.sup.13, R.sup.14, R.sup.15, R.sup.16, R.sup.17, R.sup.18,
R.sup.19, R.sup.20, R.sup.21 or R.sup.22 which is attached to the
ammonium nitrogen is a straight or branched alkyl group of four
carbons or fewer.
[0023] In another embodiment, a composition is provided comprising
a pharmaceutically acceptable carrier and a compound as described
above.
[0024] In another embodiment, a method is provided for selectively
modulating the function of a nicotinic acetylcholine receptor
comprising administering a therapeutically effective amount of a
compound as described above to a mammalian subject in need
thereof.
[0025] In another embodiment, a method is provided for modulating,
preventing, treating and/or reversing acute, chronic or cancer pain
of central and/or peripheral origin that is referred to as
nociceptive, neuropathic, visceral, inflammatory or somatic in
nature comprising administering a therapeutically effective amount
of a compound as described above to a mammalian subject in need
thereof.
BRIEF DESCRIPTION OF DRAWINGS
[0026] FIG. 1 shows the time course of the analgesic effects of
ZZ-1-61C in the rodent formalin persistent inflammatory pain model
following intraperitoneal administration. Data are mean.+-.SEM (n=6
rats/dose).
[0027] FIG. 2 shows the dose response of the analgesic effects of
ZZ-1-61C in the rodent persistent inflammatory pain model following
intraperitoneal administration. Data are mean S.E.M. (n=6
rats/dose).
[0028] FIG. 3 provides a graph showing the anti-hyperalgesic
effects of ZZ-1-61C in the paw pressure test.
[0029] FIG. 4 provides a graph showing the anti-allodynic effect of
ZZ-1-61C in a rodent model of chemotherapy-induced pain by
determining paw withdrawal frequency.
[0030] FIG. 5 provides a graph showing the effect of ZZ-1-61C on
the toxicity (body weight loss) of vineristine in a rodent model of
chemotheraopy-induced pain.
DETAILED DESCRIPTION OF INVENTION
[0031] Before the present compositions and methods are described,
it is to be understood that the invention is not limited to the
particular methodologies, protocols, assays, and reagents
described, as these may vary. It is also to be understood that the
terminology used herein is intended to describe particular
embodiments of the present invention, and is in no way intended to
limit the scope of the present invention as set forth in the
appended claims.
[0032] It must be noted that as used herein and in the appended
claims, the singular forms "a," "an," and "the" include plural
references unless the context clearly dictates otherwise.
[0033] Unless defined otherwise, all technical and scientific terms
used herein have the same meanings as commonly understood by one of
ordinary skill in the art to which this invention belongs. All
publications cited herein are incorporated herein by reference in
their entirety for the purpose of describing and disclosing the
methodologies, reagents, and tools reported in the publications
that might be used in connection with the invention. Nothing herein
is to be construed as an admission that the invention is not
entitled to antedate such disclosure by virtue of prior
invention.
[0034] The term "agonist" refers to a substance which interacts
with a receptor and increases or prolongs a physiological response
(i.e. activates the receptor).
[0035] The term "partial agonist" refers to a substance which
interacts with and activates a receptor to a lesser degree than an
agonist.
[0036] The term "antagonist" refers to a substance which interacts
with and decreases the extent or duration of a physiological
response of that receptor.
[0037] The terms "disorder," "disease," and "condition" are used
inclusively and refer to any status deviating from normal.
[0038] The term "lower alkyl" refers to straight or branched chain
alkyl radicals having in the range of 1 to 4 carbon atoms.
[0039] The term "alkyl" refers to straight or branched chain alkyl
radicals having 1 to 19 carbon atoms, and "substituted alkyl"
refers to alkyl radicals further bearing one or more substituents
including, but not limited to, hydroxy, alkoxy (of a lower alkyl
group), mercapto (of a lower alkyl group), aryl, heterocyclic,
halogen, trifluoromethyl, cyano, nitro, amino, carboxyl, carbamate,
sulfonyl, and sulfonamide.
[0040] The term "cycloalkyl" refers to cyclic ring-containing
moieties containing 3 to 8 carbon atoms, and "substituted
cycloalkyl" refers to cycloalkyl moieties further bearing one or
more substituents as set forth above.
[0041] The term "alkenyl" refers to straight or branched chain
hydrocarbyl groups having at least one carbon-carbon double bond
and having 2 to 19 carbon atoms, and "substituted alkenyl" refers
to alkenyl groups further bearing one or more substituents as set
forth above.
[0042] The term "alkynyl" refers to straight or branched chain
hydrocarbyl moieties having at least one carbon-carbon triple bond
and having 2 to 19 carbon atoms, and "substituted alkynyl" refers
to alkynyl moieties further bearing one or more substituents as set
forth above.
[0043] The term "aryl" refers to aromatic groups having 6 to 24
carbon atoms, and "substituted aryl" refers to aryl groups further
bearing one or more substituents as set forth above.
[0044] The term "alkylaryl" refers to alkyl-substituted aryl
groups, and "substituted alkylaryl" refers to alkylaryl groups
further bearing one or more substituents as set forth above.
[0045] The term "arylalkyl" refers to aryl-substituted alkyl
groups, and "substituted arylalkyl" refers to arylalkyl groups
further bearing one or more substituents as set forth above.
[0046] The term "arylalkenyl" refers to aryl-substituted alkenyl
groups, and "substituted arylalkenyl" refers to arylalkenyl groups
further bearing one or more substituents as set forth above.
[0047] The term "arylalkynyl" refers to aryl-substituted alkynyl
groups, and "substituted arylalkynyl" refers to arylalkynyl groups
further bearing one or more substituents as set forth above.
[0048] The term "heterocyclic" refers to cyclic moieties containing
one or more heteroatoms as part of the ring structure and having 3
to 24 carbon atoms, and "substituted heterocyclic" refers to
heterocyclic moieties further bearing one or more substituents as
set forth above.
[0049] The term "acyl" refers to alkyl-carbonyl groups, and
"substituted acyl" refers to acyl groups further bearing one or
more substituents as set forth above.
[0050] The term "halogen" refers to fluoride, chloride, bromide or
iodide groups.
[0051] It is understood that in all substituted groups defined
above, polymers arrived at by defining substituents with further
substituents to themselves (e.g. substituted aryl having a
substituted aryl group as a substituent which is itself substituted
with a substituted aryl group, etc.) are not intended for inclusion
herein. In such cases, the maximum number of such substituents is
three. That is to say that each of the above definitions is
constrained by a limitation that, for example, substituted aryl
groups are limited to -substituted aryl-(substituted
aryl)-substituted aryl.
[0052] Compounds of the present invention are bis-quaternary
ammonium salts disclosed in PCT/US2007/011635, filed May 14, 2007
corresponding to Formula (1):
X.sup.2.crclbar..sym.R.sup.1--H.sub.2C-L.sup.1-Q-L.sup.2-CH.sub.2--R.sup-
.2.sym..crclbar.X.sup.1 (1)
[0053] X.sup.1.crclbar. and X.sup.2.crclbar. are each independently
an organic or inorganic anion.
[0054] Q is selected from phenylene, biphenylene, --CH.dbd.CH--,
--CH.dbd.CH--CH.dbd.CH--, --C.ident.C--, --C.ident.C--C.ident.C--,
--O--(CH.sub.2).sub.2--O--, and
--O--(CH.sub.2).sub.2--O--(CH.sub.2).sub.2--O--.
[0055] L.sup.1 and L.sup.2 are each independently selected from
alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl,
alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl,
substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl,
substituted arylalkyl, arylalkenyl, substituted arylalkenyl,
arylalkynyl, substituted arylalkynyl, heterocyclic, substituted
heterocyclic; SOY.sup.1, SO.sub.2Y.sup.1, SO.sub.2OY.sup.1 or
SO.sub.2NHY.sup.1 where Y.sup.1 is selected from hydrogen, lower
alkyl, alkenyl, alkynyl or aryl, and where Y.sup.1 is not hydrogen
in SOY.sup.1 and if Y.sup.1 is alkenyl or alkynyl, the site of
unsaturation is not conjugated with a heteroatom; COY.sup.2, where
Y.sup.2 is selected from hydrogen, alkyl, substituted alkyl,
cycloalkyl, substituted cycloalkyl, alkoxy, alkenyl, substituted
alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl,
aryloxy, alkylaryl, substituted alkylaryl, arylalkyl, substituted
arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl,
substituted arylalkynyl, heterocyclic, or substituted heterocyclic,
and where if Y.sup.2 comprises alkenyl or alkynyl, the site of
unsaturation is not conjugated with the carbonyl group; OY.sup.3,
where Y.sup.3 is selected from hydrogen, alkyl, substituted alkyl,
cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl,
alkynyl, substituted alkynyl, aryl, substituted aryl, alkylaryl,
substituted alkylaryl, arylalkyl, substituted arylalkyl,
arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted
arylalkynyl, acyl, alkylsulfonyl, arylsulfonyl, heterocyclic, or
substituted heterocyclic, where if Y.sup.3 comprises alkenyl or
alkynyl, the site of unsaturation is not conjugated with the
oxygen; NY.sup.4Y.sup.5, where Y.sup.4 and Y.sup.5 are each
independently selected from hydrogen, alkyl, substituted alkyl,
cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl,
alkynyl, substituted alkynyl, aryl, substituted aryl, alkylaryl,
substituted alkylaryl, arylalkyl, substituted arylalkyl,
arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted
arylalkynyl, acyl, alkylsulfonyl, arylsulfonyl, heterocyclic, or
substituted heterocyclic, where if Y.sup.4 or Y.sup.5 comprises
alkenyl or alkynyl, the site of unsaturation is not conjugated with
the nitrogen; SY.sup.6, where Y.sup.6 is selected from hydrogen,
alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl,
alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl,
substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl,
substituted arylalkyl, arylalkenyl, substituted arylalkenyl,
arylalkynyl, substituted arylalkynyl, heterocyclic, or substituted
heterocyclic, and where if Y.sup.6 comprises alkenyl or alkynyl,
the site of unsaturation is not conjugated with the sulfur.
[0056] R.sup.1 and R.sup.2 are each independently five or six
membered nitrogen containing rings as shown in formulas (IIA) and
(IIB).
##STR00002##
[0057] A.sup.1 is carbon, nitrogen, sulfur or oxygen, provided that
when A.sup.1 is a carbon and joins a ring atom with an unsaturated
bond or is a nitrogen, R.sup.3 is absent, and when A.sup.1 is
sulfur or oxygen or joins a ring atom with an unsaturated bond and
is a nitrogen, both R.sup.3 and R.sup.4 are absent.
[0058] A.sup.2 is carbon, nitrogen, sulfur or oxygen, provided that
when A.sup.2 is a carbon and joins a ring atom with an unsaturated
bond or is a nitrogen, R.sup.5 is absent, and when A.sup.2 is
sulfur or oxygen or joins a ring atom with an unsaturated bond and
is a nitrogen, both R.sup.5 and R.sup.6 are absent.
[0059] A.sup.3 is carbon, nitrogen, sulfur or oxygen, provided that
when A.sup.3 is a carbon and joins a ring atom with an unsaturated
bond or is a nitrogen, R.sup.7 is absent, and when A.sup.3 is
sulfur or oxygen or joins a ring atom with an unsaturated bond and
is a nitrogen, both R.sup.7 and R.sup.8 are absent.
[0060] A.sup.4 is carbon, nitrogen, sulfur or oxygen, provided that
when A.sup.4 is a carbon and joins a ring atom with an unsaturated
bond or is a nitrogen, R.sup.9 is absent, and when A.sup.4 is
sulfur or oxygen or joins a ring atom with an unsaturated bond and
is a nitrogen, both R.sup.9 and R.sup.10 are absent.
[0061] A.sup.5 is carbon, nitrogen, sulfur or oxygen, provided that
when A.sup.5 is a carbon and joins a ring atom with an unsaturated
bond or is a nitrogen, R.sup.11 is absent, and when A.sup.5 is
sulfur or oxygen or joins a ring atom with an unsaturated bond and
is a nitrogen, both R.sup.11 and R.sup.12 are absent.
[0062] A.sup.6 is carbon, nitrogen, sulfur or oxygen, provided that
when A.sup.6 is a carbon and joins a ring atom with an unsaturated
bond or is a nitrogen, R.sup.14 is absent, and when A.sup.6 is
sulfur or oxygen or joins a ring atom with an unsaturated bond and
is a nitrogen, both R.sup.14 and R.sup.15 are absent.
[0063] A.sup.7 is carbon, nitrogen, sulfur or oxygen, provided that
when A.sup.7 is a carbon and joins a ring atom with an unsaturated
bond or is a nitrogen, R.sup.16 is absent, and when A.sup.7 is
sulfur or oxygen or joins a ring atom with an unsaturated bond and
is a nitrogen, both R.sup.16 and R.sup.17 are absent.
[0064] A.sup.8 is carbon, nitrogen, sulfur or oxygen, provided that
when A.sup.8 is a carbon and joins a ring atom with an unsaturated
bond or is a nitrogen, R.sup.18 is absent, and when A.sup.8 is
sulfur or oxygen or joins a ring atom with an unsaturated bond and
is a nitrogen, both R.sup.18 and R.sup.19 are absent.
[0065] A.sup.9 is carbon, nitrogen, sulfur or oxygen, provided that
when A.sup.9 is a carbon and joins a ring atom with an unsaturated
bond or is a nitrogen, R.sup.20 is absent, and when A.sup.9 is
sulfur or oxygen or joins a ring atom with an unsaturated bond and
is a nitrogen, both R.sup.20 and R.sup.21 are absent.
[0066] R.sup.13 or R.sup.22 is absent when any of the bonds to the
ammonium nitrogen is unsaturated, and R.sup.13 or R.sup.22 is a
straight chain or branched alkyl group of four carbons or fewer
when all of the bonds to the ammonium nitrogen are saturated.
[0067] R.sup.3, R.sup.4, R.sup.5R.sup.6, R.sup.7, R.sup.8, R.sup.9,
R.sup.10, R.sup.11, and R.sup.12, or R.sup.14, R.sup.15, R.sup.16,
R.sup.17, R.sup.18, R.sup.19, R.sup.20, and R.sup.21, when present,
are each independently selected from hydrogen, alkyl, substituted
alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted
alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl,
alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl,
arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted
arylalkynyl, heterocyclic, substituted heterocyclic, halo, cyano,
nitro, or R.sup.4 and R.sup.5 together with A.sup.1 and A.sup.2, or
R.sup.5 and R.sup.7 together with A.sup.2 and A.sup.3, or R.sup.15
and R.sup.16 together with A.sup.6 and A.sup.7, or R.sup.16 and
R.sup.18 together with A.sup.7 and A.sup.8 independently form a
three to eight member cyclolkane, substituted cycloalkane,
cycloalkene, substituted cycloalkene, aryl, substituted aryl,
heterocycle with one to three hetero atoms of nitrogen, oxygen or
sulfur in the ring, or substituted heterocycle with one to three
hetero atoms of nitrogen, oxygen or sulfur in the ring; and when
all of the bonds to the ring ammonium nitrogen are saturated, then
any of R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8,
R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14,
R.sup.15, R.sup.16, R.sup.17, R.sup.18, R.sup.19, R.sup.20,
R.sup.21 or R.sup.22 which is attached to the ammonium nitrogen is
a straight or branched alkyl group of four carbons or fewer.
[0068] For example, R.sup.1 and R.sup.2 include pyrrole,
pyrrolidine, pyrazole, imidazole, oxazole, isoxazole, thiazole,
isothiazole, oxadiazole, oxatriazole, dioxazole, 1,2,3-triazole,
1,2,4-triazole, pyridine, pyrimidine, piperidine, quinoline,
tetrahydroquinoline, isoquinoline, tetrahydroisoquinoline,
pyrazine, piperazine, pyridazine, triazine, oxazine, phenazine,
pteridine, benzoxazine, phthalazine, naphthridine, quinoxaline,
quinazoline, cinnoline, quinuclidine, benzothiazole, benzisoxazole,
benzoxazole, indazole, pyranopyrrole, cyclopentapyridine,
benzimidazole, isoindole, 3H-indole, indolene and triazine.
[0069] As another example, R.sup.3, R.sup.4, R.sup.5, R.sup.6,
R.sup.7, R.sup.8, R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.14,
R.sup.15, R.sup.16, R.sup.17, R.sup.18, R.sup.19, R.sup.20, and
R.sup.21, include hydrogen, methyl, ethyl, propyl, butyl,
hydroxymethyl, hydroxyethyl, hydroxypropyl, trifluoromethyl,
chloro, bromo, phenyl, pyrrolidine, N-alkyl pyrrolidine (for
example where the alkyl chain is methyl, ethyl or propyl),
unsaturated pyrrolidine, unsaturated N-alkyl pyrrolidine (for
example where the alkyl chain is methyl, ethyl or propyl),
aziridine, N-methyl aziridine, azetidine, N-methyl azetidine,
unsaturated azetidine, unsaturated N-methyl azetidine, piperidine,
N-methyl piperidine, unsaturated piperidine, unsaturated N-methyl
piperidine, azepane, N-methyl azepane, unsaturated azepane,
unsaturated N-methyl azepane, azocane, N-methyl azocane,
unsaturated azocane, unsaturated N-methyl azocane,
1-aza-bicyclo[3.2.1]octane, 1-aza-bicyclo[2.2.1]heptane,
8-methyl-8-aza-bicyclo[3.2.1]octane,
1-aza-tricyclo[3.3.1.13,7]decane, methyl cycloalkyl, methyl
substituted cycloalkyl, methyl pyrrolidine, methyl N-alkyl
pyrrolidine (for example where the alkyl chain is methyl, ethyl or
propyl), methyl unsaturated pyrrolidine, methyl unsaturated N-alkyl
pyrrolidine (for example where the alkyl chain is methyl, ethyl or
propyl), methyl aziridine, methyl N-methyl aziridine, methyl
azetidine, methyl N-methyl azetidine, methyl unsaturated azetidine,
methyl unsaturated N-methyl azetidine, methyl piperidine, methyl
N-methyl piperidine, methyl unsaturated piperidine, methyl
unsaturated N-methyl piperidine, methyl azepane, methyl N-methyl
azepane, methyl unsaturated azepane, methyl unsaturated N-methyl
azepane, methyl azocane, methyl N-methyl azocane, methyl
unsaturated azocane, methyl unsaturated N-methyl azocane,
methyl-1-aza-bicyclo[3.2.1]octane,
methyl-1-aza-bicyclo[2.2.1]heptane,
8-methyl-8-aza-bicyclo[3.2.1]octane, and
methyl-1-aza-tricyclo[3.3.1.13'7]decane.
[0070] As a further example, when R.sup.4 and R.sup.5 together with
A.sup.1 and A.sup.2, or R.sup.5 and R.sup.7 together with A.sup.2
and A.sup.3, or R.sup.15 and R.sup.16 together with A.sup.6 and
A.sup.7, or R.sup.16 and R.sup.18 together with A.sup.7 and A.sup.8
independently form a three to eight-membered ring, that ring may be
a heterocycle containing up to three hetero atoms (for example
nitrogen, oxygen or sulfur) in the ring, and further may be
substituted with one or more substituents. For example, possible
rings include benzene, pyridine, pyran, indene, isoindene,
benzofuran, isobenzofuran, benzo[b]thiophene, benzo[c]thiophene,
indole, indolenine, isoindole, cyclopental[b]pyridine,
pyrano[3,4-b]pynrole, indazole, indoxazine, benzoxazole, anthranil,
naphthalene, tetralin, decalin, chromene, coumarin, chroman-4-one,
isocoumarin, isochromen-3-one, quinoline, isoquinoline, cinnoline,
quinazoline, naphthyridine, pyrido[3,4-b]-pyridine,
pyridol[3,2-b]pyridine, pyrido[4,3,-b]-pyridine, benzoxazine,
anthracene, phenanthrene, phenalene, fluorene, carazole, xanthene,
acnidine, octahydro-[1]pyridine, 1-methyloctahydro-[1]pyridine,
octahydroindole, 1-methyloctahydro-indole,
octahydro-cyclopenta[b]pyrrole,
1-methyloctahydro-cyclopenta[b]pyrrole, decahydroquinoline, and
1-methyldecahydroquinoline.
[0071] X.sup.1.crclbar. and X.sup.2.crclbar., for example F.sup.-,
Cl.sup.-, Br.sup.-, I.sup.-, NO.sub.2.sup.-, HSO.sub.4.sup.-,
SO.sub.4.sup.-, HPO.sub.4.sup.-, PO.sub.4.sup.2-, methanesulfonate,
trifluoromethane sulfate, p-toluenesulfonate, benzenesulfonate,
salicylate, proprionate, ascorbate, aspartate, fumarate,
galactarate, maleate, citrate, glutamate, glycolate, lactate,
malate, maleate, tartrate, oxalate, succinate, or similar
pharmaceutically acceptable organic acid addition salts, including
the pharmaceutically acceptable salts listed in the Journal of
Pharmaceutical Sciences volume 66, page 2, 1977, which are hereby
incorporated by reference. The above salt forms may be in some
cases hydrates or solvates with alcohols and other solvents.
[0072] In a compound of Formula (I), preferably R.sup.1 and R.sup.2
are substituted, six-membered, aromatic rings. More preferably,
R.sup.1 and R.sup.2 are substituted pyridinium rings. In other
preferred embodiments, R.sup.1 and R.sup.2 are quinoline,
isoquinoline, tetrahydroquinoline or tetrahydroisoquinoline.
[0073] In a compound of Formula (I), preferably R.sup.13 is
absent.
[0074] In a compound of Formula (I), preferably R.sup.3, R.sup.4,
R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10, R.sup.11 or
R.sup.12 is absent or is hydrogen, alkyl, hydroxyalkyl, halo,
phenyl or 1-alkyl-2-pyrrolidinyl. More preferably, R.sup.3,
R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10,
R.sup.11 or R.sup.12 is absent or is hydrogen, methyl, ethyl,
propyl, butyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, bromo,
phenyl or 1-methyl-2-pyrrolidinyl.
[0075] In a compound of Formula (I), preferably Q is phenylene,
biphenylene, --CH.dbd.CH--CH.dbd.CH--, --C.ident.C--C.ident.C-- and
--O--(CH.sub.2).sub.2--O--(CH.sub.2).sub.2--O--.
[0076] In a compound of Formula (I), preferably L.sup.1 and L.sup.2
are the same and are --CH.sub.2--, --(CH.sub.2).sub.2--,
--(CH.sub.2).sub.3--, --(CH.sub.2).sub.4--, --C.ident.C--,
--CH.sub.2--C.ident.C-- or --(CH.sub.2).sub.2--C.ident.C--.
[0077] In a compound of Formula (I), preferably X.sup.1 SYMBOL and
X.sup.2 SYMBOL are halogens. More preferably, X.sup.1 SYMBOL and
X.sup.2 SYMBOL are chloride or bromide.
[0078] In another embodiment, the compound of Formula (I) is
defined wherein
-L.sub.1-Q-L.sub.2-is-(CH.sub.2).sub.4-1,2-phenylene-(CH.sub.2).s-
ub.4--, --(CH.sub.2).sub.4-1,3-phenylene-(CH.sub.2).sub.4--,
--(CH.sub.2).sub.3-1,4-phenylene-(CH.sub.2).sub.3--,
--(CH.sub.2).sub.2-4,4'-biphenylene-(CH.sub.2).sub.2--,
--(CH.sub.2).sub.2--C.ident.C-1,2-phenylene-C.ident.C--(CH.sub.2).sub.2---
,
--(CH.sub.2).sub.2--C.ident.C-1,3-phenylene-C.ident.C--(CH.sub.2).sub.2--
-, --CH.sub.2--C.ident.C-1,4-phenylene-C.ident.C--CH.sub.2--,
--C.ident.C-4,4'-biphenylene-C.ident.C--,
--(CH.sub.2).sub.3--CH.dbd.CH--CH.dbd.CH--(CH.sub.2).sub.3--,
--(CH.sub.2).sub.3--C.ident.C--C.ident.C--(CH.sub.2).sub.3-- or
--CH.sub.2--O--(CH.sub.2).sub.2--O--(CH.sub.2).sub.2--O--CH.sub.2--,
R.sup.1 and R.sup.2 are pyridinium rings, R.sup.3 is hydrogen or
methyl, R.sup.5 is hydrogen, methyl, ethyl, butyl, phenyl,
1-methyl-2-pyrrolidinyl, bromo, hydroxymethyl or hydroxypropyl,
R.sup.7 is hydrogen or methyl, R.sup.9 is hydrogen or methyl,
R.sup.11 is hydrogen, and X.sup.1 and X.sup.2 are chloride or
bromide.
[0079] In another embodiment, the compound of Formula (I) is
defined wherein
-L.sub.1-Q-L.sub.2-is-(CH.sub.2).sub.4-1,2-phenylene-(CH.sub.2).s-
ub.4--, --(CH.sub.2).sub.4-1,3-phenylene-(CH.sub.2).sub.4--,
--(CH.sub.2).sub.3-1,4-phenylene-(CH.sub.2).sub.3--,
--(CH.sub.2).sub.2-4,4'-biphenylene-(CH.sub.2).sub.2--,
--(CH.sub.2).sub.2--C.ident.C-1,2-phenylene-C.ident.C--(CH.sub.2).sub.2---
,
--(CH.sub.2).sub.2--C.ident.C-1,3-phenylene-C.ident.C--(CH.sub.2).sub.2--
-, --CH.sub.2--C.ident.C-1,4-phenylene-C.ident.C--CH.sub.2--,
--C.ident.C-4,4'-biphenylene-C.ident.C--,
--(CH.sub.2).sub.3--CH.dbd.CH--CH.dbd.CH--(CH.sub.2).sub.3--,
--(CH.sub.2).sub.3.C.ident.C--C.ident.C--(CH.sub.2).sub.3-- or
--CH.sub.2--O--(CH.sub.2).sub.2--O--(CH.sub.2).sub.2--O--CH.sub.2--,
R.sup.1 and R.sup.2 are quinoline, isoquinoline,
tetrahydroquinoline or tetrahydroisoquinoline, and X.sup.1 and
X.sup.2 are chloride or bromide.
[0080] Exemplary compounds of the present invention include: [0081]
cis-cis-N,N'-(dodeca-5,7-diene-1,12-diyl)-bis-[3-(2'-5-1-methyl-pyrrolidi-
n-2-yl)-pyridinium]dibromide; [0082]
cis-cis-N,N'-(dodeca-5,7-diene-1,12-diyl)-bis-{2-methyl-pyridinium)dibrom-
ide; [0083]
cis-cis-N,N'-(dodeca-5,7-diene-1,12-diyl)-bis-(3-methyl-pyridinium)dibrom-
ide; [0084]
cis-cis-N,N'-(dodeca-5,7-diene-1s12-diyl)-bis-(4-methyl-pyridinium)dibrom-
ide; [0085]
cis-cis-N,N'-(dodeca-5,7-diene-1,12-diyl)-bis-(5,6,7,8-tetrahydro-quinoli-
nium)dibromide; [0086]
cis-cis-N,N'-(dodeca-5,7-diene-1,12-diyl)-bis-(5,6,7,8-tetrahydro-isoquin-
olinium)dibromide; [0087]
cis-cis-N,N'-(dodeca-5,7-diene-1,12-diyl)-bis-(2,4-dimethyl-pyridinium)di-
bromide; [0088]
cis-cis-N,N'-(dodeca-5,7-diene-1,12-diyl)-bis-(3,4-dimethyl-pyridinium)di-
bromide; [0089]
cis-cis-N,N'-(dodeca-5,7-diene-1,12-diyl)-bis-(3,5-dimethyl-pyridinium)di-
bromide; [0090]
N,N'-[1,4-phenylenedi-(4-butanyl)]-bis-[3-(2'-S-1-methyl-pyrrolidin-2-yl)-
-pyridinium]dibromide; [0091]
N,N'-[1,4-phenylenedi-(4-butanyl)]-bis-(2-methylpyridinium)dibromide;
[0092]
N,N'-[1,4-phenylenedi-(4-butanyl)]-bis-(3-methylpyridinium)dibromi-
de; [0093]
N,N'-[1,4-phenylenedi-(4-butanyl)]-bis-(4-methylpyridinium)dibr-
omide; [0094]
N,N'-[1,4-phenylenedi-(4-butanyl)]-bis-(3-ethylpyridinium)dibromide;
[0095]
N,N'-[1,4-phenylenedi-(4-butanyl)]-bis-(5,6,7,8-tetrahydroquinolin-
ium)dibromide; [0096]
N,N'-[1,4-phenylenedi-(4-butanyl)]-bis-(5,6,7,8-tetrahydroisoquinolinium)-
dibromide; [0097]
N,N'-[1,4-phenylenedi-(4-butanyl)]-bis-[3-(3-hydroxy-propyl)-pyridinium]d-
ibromide; [0098]
N,N'-[1,4-phenylenedi-(4-butanyl)]-bis-(2,4-dimethylpyridinium)dibromide;
[0099]
N,N'-[1,4-phenylenedi-{4-butanyl)]-bis-(3,4-dimethylpyridinium)dib-
romide; [0100]
N,N'-[1,4-phenylenedi-{4-butanyl)]-bis-(3,5-dimethylpyridinium)dibromide;
[0101] 1,2-bis-[5-(2-methyl-pyridinium)-pent-1-ynyl]-benzene
dibromide; [0102]
1,2-bis-[5-(3-methyl-pyridinium)-pent-1-ynyl]-benzene dibromide;
[0103] 1,2-bis-[5-(4-methyl-pyridinium)-pent-1-ynyl]-benzene
dibromide; [0104]
1,2-bis-[5-(2,4-dimethyl-pyridinium)-pent-1-ynyl]-benzene
dibromide; [0105]
1,2-bis-[5-(3,4-dimethyl-pyridinium)-pent-1-ynyl]-benzene
dibromide; [0106]
1,2-bis-[5-(3,5-dimethyl-pyridinium)-pent-1-ynyl]-benzene
dibromide; [0107] 1,2-bis-(5-quinolinium-pent-1-ynyl)-benzene
dibromide; [0108] 1,2-bis-(5-isoquinolinium-pent-1-ynyl)-benzene
dibromide; [0109] 1,2-bis-(5-S-nicotinium-pent-1-ynyl)-benzene
dibromide; [0110] 1,2-bis-[5-(2-methyl-pyridinium)-pentyl]-benzene
dibromide; [0111] 1,2-bis-[5-(3-methyl-pyridinium)-pentyl]-benzene
dibromide; [0112] 1,2-bis-[5-(4-methyl-pyridinium)-pentyl]-benzene
dibromide; [0113]
1,2-bis-[5-(2,4-dimethyl-pyridinium)-pentyl]-benzene dibromide;
[0114] 1,2-bis-[5-(3,4-dimethyl-pyridinium)-pentyl]benzene
dibromide; [0115] 1,2-bis-[5-(3,5-methyl-pyridinium)-pentyl]benzene
dibromide; [0116] 1,2-bis-(5-quinolinium-pentyl)-benzene dibromide;
[0117] 1,2-bis-(5-isoquinolinium-pentyl)-benzene dibromide; [0118]
1,2-bis-(5-S-nicotinium-pentyl)-benzene dibromide; [0119]
1,2-bis-[5-(3-n-butyl-pyridinium)-pentyl]-benzene dibromide; [0120]
1,2-bis-[5-(3-bromo-pyridinium)-pentyl]-benzene dibromide; [0121]
1,2-bis-(5-pyridinium-pentyl)-benzene dibromide; [0122]
1,3-bis-[5-(2-methyl-pyridinium)-pent-1-ynyl]-benzene dibromide;
[0123] 1,3-bis-[5-(3-methyl-pyridinium)-pent-1-ynyl]-benzene
dibromide; [0124]
1,3-bis-[5-(4-methyl-pyridinium)-pent-1-ynyl]-benzene dibromide;
[0125] 1,3-bis-[5-(2,4-dimethyl-pyridinium)-pent-1-ynyl]-benzene
dibromide; [0126]
1,3-bis-[5-(3,4-dimethyl-pyridinium)-pent-1-ynyl]-benzene
dibromide; [0127]
1,3-bis-[5-(3,5-dimethyl-pyridinium)-pent-1-ynyl]-benzene
dibromide; [0128] 1,3-bis-(5-quinolinium-pent-1-ynyl)-benzene
dibromide; [0129] 1,3-bis-(5-isoquinolinium-pent-1-ynyl)-benzene
dibromide; [0130] 1,3-bis-(5-S-nicotiniuin-pent-1-ynyl)-benzene
dibromide; [0131]
1,3-bis-[5-(3-n-butyl-pyridinium)-pent-1-ynyl]-benzene dibromide;
[0132] 1,3-bis-[5-(3-phenyl-pyridinium)-pent-1-ynyl]-benzene
dibromide; [0133] 1,3-bis-[5-pyridinium-pent-1-ynyl)-benzene
dibromide; [0134] 1,3-bis-[5-(2-methyl-pyridinium)-pentyl]-benzene
dibromide; [0135] 1,3-bis-[5-(3-methyl-pyridinium)-pentyl]-benzene
dibromide; [0136] 1,3-bis-[5-(4-methyl-pyridinium)-pentyl]benzene
dibromide; [0137]
1,3-bis-[5-(2,4-dimethyl-pyridinium)-pentyl]benzene dibromide;
[0138] 1,3-bis-[5-(3,4-dimethyl-pyridinium)-pentyl]-benzene
dibromide; [0139]
1,3-bis-[5-(3,5-dimethyl-pyridinium)-pentyl]-benzene dibromide;
[0140] 1,3-bis-(5-quinolinium-pentyl)-benzene dibromide; [0141]
1,3-bis-(5-isoquinolinium-pentyl)-benzene dibromide; [0142]
N,N'-[(1,1'-biphenyl)-4,4'-di-(3-propanyl)]-bis-[3-(2'-S-1-methyl-pyrroli-
din-2-yl)-pyridinium]dibromide; [0143]
N,N'-[(1,1'-biphenyl)-4,4'-di-(3-propanyl)]-bis-(3,5-dimethylpyridinium)d-
ibromide; [0144]
N,N'-[(1,1'-biphenyl)-4,4'-di-(3-propanyl)]-bis-(3,4-dimethylpyridinium)d-
ibromide; [0145]
N,N'-[(1,1'-biphenyl)-4,4'-di-(3-propanyl)]-bis-(2,4-dimethylpyridinium)d-
ibromide; [0146]
N,N'-[(1,1'-biphenyl)-4,4'-di-(3-propanyl)]-bis-[3-(3-hydroxy-propyl)-pyr-
idinium]dibromide; [0147]
N,N'-[(1,1'-biphenyl)-4,4'-di-(3-propanyl)]-bis-[5,6,7,8-tetrahydroquinol-
inium]dibromide; [0148]
N,N'-[(1,1'-biphenyl)-4,4'-di-(3-propanyl)]-bis-[5,6,7,8-tetrahydroisoqui-
nolinium]dibromide; [0149]
N,N'-[(1,1'-biphenyl)-4,4'-di-(3-propanyl)]-bis-(4-methylpyridinium)dibro-
mide; [0150]
N,N'-[(1,1'-biphenyl)-4,4'-di-(3-propanyl)]-bis-(3-methylpyridinium)dibro-
mide; [0151]
N,N'-[(1,1'-biphenyl)-4,4'-di-(3-propanyl)]-bis-(2-methylpyridinium)dibro-
mide; [0152]
N,N'-{2,2'-[oxybis(2,1-ethandiyloxy)]-bis-ethyl}-bis-[3-(2'-S-1-methyl-py-
rrolidin-2-yl)-pyridinium]dichloride; [0153]
N,N'-{2,2'-[oxybis(2,1-ethandiyloxy)]-bis-ethyl}-bis(2-methylpyridinium)d-
ichloride; [0154]
N,N'-{2,2'-[oxybis(2,1-ethandiyloxy)]-bis-ethyl}-bis(3-methylpyridinium)d-
ichloride; [0155]
N,N'-{2,2'-[oxybis(2,1-ethandiyloxy)]bis-ethyl}-bis(4-methylpyridinium)di-
chloride; [0156]
N,N'-{2,2'-[oxybis(2,1-ethandiyloxy)]bis-ethyl}-bis(5,6,7,8-tetrahydroqui-
nolinium)dichloride; [0157]
N,N'-{2,2'-[oxybis(2,1-ethandiyloxy)]bis-ethyl}-bis(5,6,7,8-tetrahydroiso-
quinolinium)dichloride; [0158]
N,N'-{2,2'-[oxybis(2,1-ethandiyloxy)]bis-ethyl}[3-(3-hydroxypropyl)-pyrid-
inium]dichloride; [0159]
N,N'-{2,2'-[oxybis(2,1-ethandiyloxy)]bis-ethyl}-bis(3-hydroxymethylpyridi-
nium)dichloride; [0160]
N,N'-{2,2'-[oxybis(2,1-ethandiyloxy)]bis-ethyl}-bis(2,4-dimethylpyridiniu-
m)dichloride; [0161]
N,N'-{2,2'-[oxybis(2,1-ethandiyloxy)]bis-ethyl}-bis(3,4-dimethylpyridiniu-
m)dichloride; [0162]
N,N'-{2,2'-[oxybis(2,1-ethandiyloxy)]bis-ethyl}-bis(3,5-dimethylpyridiniu-
m)dichloride; [0163]
N,N'-(5,7-dodecadiyn-1,12-diyl)-bis-(2-methylpyridinium)dichloride;
[0164]
N,N'-(5,7-dodecadiyn-1,12-diyl)-bis-(3-methylpyridinium)dichloride-
; [0165]
N,N'-(5,7-dodecadiyn-1,12-diyl)-bis-(4-methylpyridinium)dichlorid-
e; [0166]
N,N'-(5,7-dodecadiyn-1,12-diyl)-bis-(3,4-dimethylpyridinium)dich-
loride; [0167]
N,N'-(5,7-dodecadiyn-1,12-diyl)-bis-(3,5-dimethylpyridinium)dichloride;
[0168]
N,N'-(5,7-dodecadiyn-1,12-diyl)-bis-(5,6,7,8-tetrahydroisoquinolin-
ium)dichloride; [0169]
N,N'-[(1,4-phenylene)-bis-(4-butynyl)]-bis-(3-methyl-pyridinium)dibromide-
; [0170]
N,N'-[(1,4-phenylene)-bis-(4-butynyl)]-bis-(4-methyl-pyridinium)d-
ibromide; [0171]
N,N'-[(1,4-phenylene)-bis-(4-butynyl)]-bis-(5,6,7,8-tetrahydroisoquiolini-
um)dibromide; [0172]
N,N'-[(1,4-phenylene)-bis-(4-butynyl)]-bis-(3,4-dimethyl-pyridinium)dibro-
mide; [0173]
N,N'-[(1,4-phenylene)-bis-(4-butynyl)]-bis-(3,5-dimethyl-pyridiniuim)dibr-
omide; [0174]
N,N'-[(1,1'-biphenyl)-4,4'-di-(1-propyn-3-yl)]-bis-(3-methylpyridinium)di-
bromide; [0175]
N,N'-[(1,1'-biphenyl)-4,4'-di-(1-propyn-3-yl)]-bis-(4-methylpyridinium)di-
bromide; [0176]
N,N'-[(1,1'-biphenyl)-4,4'-di-(1-propyn-3-yl)]-bis-(3,4-dimethylpyridiniu-
m)dibromide.
[0177] The compounds of the present invention may contain one or
more stereocenters. The invention includes all possible
diastereomers and all enantiomeric forms as well as all
combinations of diastereomers and enantiomers, including racemic
mixtures. The compounds can be separated into substantially
optically pure compounds.
[0178] Pain from nervous system disorders of central and/or
peripheral origin, which may be treated according to the method of
the present invention and includes any disorders involving pain
including those types of pain referred to as nociceptive,
neuropathic (chemical, viral or disease-induced), inflammatory
(arthritis, irritable bowel disease, Crohn's) as well as acute,
chronic, cancer-related, and surgical, as well as pain resulting
from any and all injuries, diseases or toxin induced injuries of
the central or peripheral nervous systems including pain
accompanying stroke, multiple sclerosis, parkinson's disease and
pain from peripheral neuropathy as a result of diabetes, AIDs,
chemotherapeutic drugs, and/or alcohol.
[0179] Pain from cancer which may have its origin at any peripheral
or central site and be caused by tumor invasion of bone, tissue or
nerve.
[0180] In another embodiment, the present invention is directed to
a method for treating and/or preventing neuropathy resulting from a
medication which causes neuropathic pain as a side effect. For
example, the compounds of the present invention may be used to
treat and/or prevent pain associated with chemotherapy drugs such
as vincristine. This is a very serious clinical condition
associated with anticancer drugs.
[0181] In yet another embodiment, the present invention is directed
to a method for preventing and/or treating inflammatory pain
disorders comprising administering to a mammalian subject in need
thereof a therapeutically effective amount of a compound of Formula
(I).
[0182] Inflammatory pain disorders which may be treated according
to the method of the present invention include ankylosing
spondylitis, benign prostatic hyperplasia, cholecystitis,
ulcerative colitis, Crohn's disease, diabetes mellitus, gastritis,
glomerulonephritis, irritable bowel syndrome, multiple sclerosis,
osteoarthritis, pancreatitis, polymyositis, psoriasis and
rheumatoid arthritis.
[0183] The compounds of the present invention can be delivered to a
mammalian organism, including a human, directly or in
pharmaceutical compositions along with suitable carriers or
excipients, as is well known in the art. For example, a
pharmaceutical composition of the invention may include a
conventional additive, such as a stabilizer, buffer, salt,
preservative, filler, flavor enhancer and the like, as known to
those skilled in the art. Exemplary buffers include phosphates,
carbonates, citrates and the like. Exemplary preservatives include
EDTA, EGTA, BHA, BHT and the like.
[0184] An effective amount of such agents can readily be determined
by routine experimentation, as can the most effective and
convenient route of administration and the most appropriate
formulation. Various formulations and drug delivery systems are
available in the art. See, e.g., Gennaro, A. R., ed. (1995)
Remington's Pharmaceutical Sciences.
[0185] Suitable routes of administration may, for example, include
oral, rectal, transmucosal, nasal, or intestinal administration and
parenteral delivery, including intramuscular, subcutaneous,
intramedullary injections, as well as intrathecal, direct
intraventricular, intravenous, intraperitoneal, intranasal, or
intraocular injections. In addition, the agent or composition
thereof may be administered sublingually or via a spray, including
a sublingual tablet or a sublingual spray. The agent or composition
thereof may be administered in a local rather than a systemic
manner. For example, a suitable agent can be delivered via
injection or in a targeted drug delivery system, such as a depot or
sustained release formulation.
[0186] The pharmaceutical compositions of the present invention may
be manufactured by any of the methods well-known in the art, such
as by conventional mixing, dissolving, granulating, dragee-making,
levigating, emulsifying, encapsulating, entrapping, or lyophilizing
processes. As noted above, the compositions of the present
invention can include one or more physiologically acceptable
carriers such as excipients and auxiliaries that facilitate
processing of active molecules into preparations for pharmaceutical
use.
[0187] Proper formulation is dependent upon the route of
administration chosen. For injection, for example, the composition
may be formulated in aqueous solutions, preferably in
physiologically compatible buffers such as Hanks' solution,
Ringer's solution, or physiological saline buffer. For transmucosal
or nasal administration, penetrants appropriate to the barrier to
be permeated are used in the formulation. Such penetrants are
generally known in the art. In a preferred embodiment of the
present invention, the present compounds are prepared in a
formulation intended for oral administration. For oral
administration, the compounds can be formulated readily by
combining the active compounds with pharmaceutically acceptable
carriers well known in the art. Such carriers enable the compounds
of the invention to be formulated as tablets, pills, dragees,
capsules, liquids, gels, syrups, slurries, suspensions and the
like, for oral ingestion by a subject. The compounds may also be
formulated in rectal compositions such as suppositories or
retention enemas, e.g., containing conventional suppository bases
such as cocoa butter or other glycerides.
[0188] Pharmaceutical preparations for oral use can be obtained as
solid excipients, optionally grinding a resulting mixture, and
processing the mixture of granules, after adding suitable
auxiliaries, if desired, to obtain tablets or dragee cores.
Suitable excipients are, in particular, fillers such as sugars,
including lactose, sucrose, mannitol, or sorbitol; cellulose
preparations such as, for example, maize starch, wheat starch, rice
starch, potato starch, gelatin, gum tragacanth, methyl cellulose,
hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose,
and/or polyvinylpyrrolidone (PVP). If desired, disintegrating
agents may be added, such as the cross-linked polyvinyl
pyrrolidone, agar, or alginic acid or a salt thereof such as sodium
alginate. Also, wetting agents such as sodium dodecyl sulfate may
be included.
[0189] Dragee cores are provided with suitable coatings. For this
purpose, concentrated sugar solutions may be used, which may
optionally contain gum arabic, talc, polyvinyl pyrrolidone,
carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer
solutions, and suitable organic solvents or solvent mixtures.
Dyestuffs or pigments may be added to the tablets or dragee
coatings for identification or to characterize different
combinations of active compound doses.
[0190] Pharmaceutical preparations for oral administration include
push-fit capsules made of gelatin, as well as soft, sealed capsules
made of gelatin and a plasticizer, such as glycerol or sorbitol.
The push-fit capsules can contain the active ingredients in
admixture with filler such as lactose, binders such as starches,
and/or lubricants such as talc or magnesium stearate and,
optionally, stabilizers. In soft capsules, the active compounds may
be dissolved or suspended in suitable liquids, such as fatty oils,
liquid paraffin, or liquid polyethylene glycols. In addition,
stabilizers may be added. All formulations for oral administration
should be in dosages suitable for such administration.
[0191] In one embodiment, the compounds of the present invention
can be administered transdermally, such as through a skin patch, or
topically. In one aspect, the transdermal or topical formulations
of the present invention can additionally comprise one or multiple
penetration enhancers or other effectors, including agents that
enhance migration of the delivered compound. Transdermal or topical
administration could be preferred, for example, in situations in
which location specific delivery is desired.
[0192] For administration by inhalation, the compounds for use
according to the present invention are conveniently delivered in
the form of an aerosol spray presentation from pressurized packs or
a nebulizer, with the use of a suitable propellant, e.g.,
dichlorodifluoromethane, trichlorofluoromethane,
dichlorotetrafluoroethane, carbon dioxide, or any other suitable
gas. In the case of a pressurized aerosol, the appropriate dosage
unit may be determined by providing a valve to deliver a metered
amount. Capsules and cartridges of, for example, gelatin, for use
in an inhaler or insufflator may be formulated. These typically
contain a powder mix of the compound and a suitable powder base
such as lactose or starch.
[0193] Compositions formulated for parenteral administration by
injection, e.g., by bolus injection or continuous infusion can be
presented in unit dosage form, e.g., in ampoules or in multi-dose
containers, with an added preservative. The compositions may take
such forms as suspensions, solutions, or emulsions in oily or
aqueous vehicles, and may contain formulatory agents such as
suspending, stabilizing and/or dispersing agents. Formulations for
parenteral administration include aqueous solutions or other
compositions in water-soluble form.
[0194] Suspensions of the active compounds may also be prepared as
appropriate oily injection suspensions. Suitable lipophilic
solvents or vehicles include fatty oils such as sesame oil and
synthetic fatty acid esters, such as ethyl oleate or triglycerides,
or liposomes. Aqueous injection suspensions may contain substances
that increase the viscosity of the suspension, such as sodium
carboxymethyl cellulose, sorbitol, or dextran. Optionally, the
suspension may also contain suitable stabilizers or agents that
increase the solubility of the compounds to allow for the
preparation of highly concentrated solutions. Alternatively, the
active ingredient may be in powder form for constitution with a
suitable vehicle, e.g., sterile pyrogen-free water, before use.
[0195] As mentioned above, the compositions of the present
invention may also be formulated as a depot preparation. Such long
acting formulations may be administered by implantation (for
example, subcutaneously or intramuscularly) or by intramuscular
injection. Thus, for example, the present compounds may be
formulated with suitable polymeric or hydrophobic materials (for
example as an emulsion in an acceptable oil) or ion exchange
resins, or as sparingly soluble derivatives, for example, as a
sparingly soluble salt.
[0196] Suitable carriers for the hydrophobic molecules of the
invention are well known in the art and include co-solvent systems
comprising, for example, benzyl alcohol, a nonpolar surfactant, a
water-miscible organic polymer, and an aqueous phase. The
co-solvent system may be the VPD co-solvent system. VPD is a
solution of 3% w/v benzyl alcohol, 8% w/v of the nonpolar
surfactant polysorbate 80, and 65% w/v polyethylene glycol 300,
made up to volume in absolute ethanol. The VPD co-solvent system
(VPD:5 W) consists of VPD diluted 1:1 with a 5% dextrose in water
solution. This co-solvent system is effective in dissolving
hydrophobic compounds and produces low toxicity upon systemic
administration. Naturally, the proportions of a co-solvent system
may be varied considerably without destroying its solubility and
toxicity characteristics. Furthermore, the identity of the
co-solvent components may be varied. For example, other
low-toxicity nonpolar surfactants may be used instead of
polysorbate 80, the fraction size of polyethylene glycol may be
varied, other biocompatible polymers may replace polyethylene
glycol, e.g., polyvinyl pyrrolidone, and other sugars or
polysaccharides may substitute for dextrose.
[0197] Alternatively, other delivery systems for hydrophobic
molecules may be employed. Liposomes and emulsions are well known
examples of delivery vehicles or carriers for hydrophobic drugs.
Liposomal delivery systems are discussed above in the context of
gene-delivery systems. Certain organic solvents such as
dimethylsulfoxide also may be employed, although usually at the
cost of greater toxicity. Additionally, the compounds may be
delivered using sustained-release systems, such as semi-permeable
matrices of solid hydrophobic polymers containing the effective
amount of the composition to be administered. Various
sustained-release materials are established and available to those
of skill in the art. Sustained-release capsules may, depending on
their chemical nature, release the compounds for a few weeks up to
over 100 days. Depending on the chemical nature and the biological
stability of the therapeutic reagent, additional strategies for
stabilization may be employed.
[0198] For any composition used in the present methods of
treatment, a therapeutically effective dose can be estimated
initially using a variety of techniques well known in the art. For
example, in a cell culture assay, a dose can be formulated in
animal models to achieve a circulating concentration range that
includes the IC.sub.50 as determined in cell culture. Dosage ranges
appropriate for human subjects can be determined, for example,
using data obtained from cell culture assays and other animal
studies.
[0199] A therapeutically effective dose of an agent refers to that
amount of the agent that results in amelioration of symptoms or a
prolongation of survival in a subject. Toxicity and therapeutic
efficacy of such molecules can be determined by standard
pharmaceutical procedures in cell cultures or experimental animals,
e.g., by determining the LD.sub.50 (the dose lethal to 50% of the
population) and the ED.sub.50 (the dose therapeutically effective
in 50% of the population). The dose ratio of toxic to therapeutic
effects is the therapeutic index, which can be expressed as the
ratio LD.sub.50/ED.sub.50. Agents that exhibit high therapeutic
indices are preferred.
[0200] Dosages preferably fall within a range of circulating
concentrations that includes the ED.sub.50 with little or no
toxicity. Dosages may vary within this range depending upon the
dosage form employed and the route of administration utilized. The
exact formulation, route of administration, and dosage should be
chosen, according to methods known in the art, in view of the
specifics of a subject's condition.
[0201] The amount of agent or composition administered will, of
course, be dependent on a variety of factors, including the sex,
age, and weight of the subject being treated, the severity of the
affliction, the manner of administration, and the judgment of the
prescribing physician.
[0202] The present compositions may, if desired, be presented in a
pack or dispenser device containing one or more unit dosage forms
containing the active ingredient. Such a pack or device may, for
example, comprise metal or plastic foil, such as a blister pack.
The pack or dispenser device may be accompanied by instructions for
administration. Compositions comprising a compound of the invention
formulated in a compatible pharmaceutical carrier may also be
prepared, placed in an appropriate container, and labeled for
treatment of an indicated condition.
[0203] These and other embodiments of the present invention will
readily occur to those of ordinary skill in the art in view of the
disclosure herein, and are specifically contemplated.
EXAMPLES
[0204] The invention is further understood by reference to the
following examples, which are intended to be purely exemplary of
the invention. The present invention is not limited in scope by the
exemplified embodiments, which are intended as illustrations of
single aspects of the invention only. Any methods that are
functionally equivalent are within the scope of the invention.
Various modifications of the invention in addition to those
described herein will become apparent to those skilled in the art
from the foregoing description. Such modifications fall within the
scope of the appended claims.
Example 1
Synthesis of compound
cis-cis-N,N'-(dodeca-5,7-diene-1,12-diyl)-bis-[3-(2'-S-1-methyl-pyrrolidi-
n-2-yl)-pyridinium]dibromide
##STR00003##
[0206] cis-cis-1,12-Dibromo-dodeca-5,7-diene (1 mmol) was added to
a solution of S-nicotine (3 mmol) in acetonitrile and the solution
refluxed for 24 hours. The acetonitrile was removed in vacuum and
the resulting residue was partitioned between ether and water. The
aqueous layer was washed extensively with ether until no S-nicotine
left in the aqueous layer. The resulting aqueous solution of the
product was lyophilized to yield the pure product. (70%).
.sup.1HNMR (300 MHZ, D.sub.2O, ppm) 8.60 (s, 2H), 8.59 (d, 2H),
8.32 (d, J=8.4, 2H), 7.88 (t, J=5.7, 2H), 6.12-6.20 (m, 2H),
5.30-5.40 (m, 2H), 4.43 (t, J=7.2, 4H), 3.39 (t, J=8.4, 2H),
3.01-3.06 (m, 2H), 2.16-2.34 (m, 4H), 2.01-2.09 (m, 10H), 1.64-1.88
(m, 10H), 1.25 (p, J=7.5, 4H). .sup.13CNMR, 144.67, 143.35, 132.20,
128.45, 124.12, 67.65, 62.05, 56.65, 39.41, 33.76, 30.32, 26.34,
25.47, 22.36.
Example 2
Synthesis of compound
cis-cis-N,N'-(dodeca-5,7-diene-1,12-diyl)-bis-(2-methyl-pyridinium)dibrom-
ide
##STR00004##
[0208] cis-cis-1,12-Dibromo-dodeca-5,7-diene was added to a
solution of 2-picoline (3 mmol) in acetonitrile and the solution
refluxed for 24 hours. The acetonitrile was removed in vacuum and
the resulting residue was partitioned between ether and water. The
aqueous layer was washed extensively with ether until no picoline
left in the aqueous layer. The resulting aqueous solution of the
product was lyophilized to yield the pure product. (76%).
.sup.1HNMR (300 MHz, D.sub.2O, ppm) 8.52 (dd, J=6.3, 2H), 8.17 (dt,
J=7.8, J=1.5, 2H), 732 (d, J=7.8, 2H), 7.64 (t, J=6.3, 2H),
6.18-6.23 (m, 2H), 5.33-5.41 (m, 2H), 4.37 (t, J=7.1, 4H), 2.66 (s,
6H), 2.09 (q, J=7.5, 4H), 1.72-1.82 (m, 4H), 1.36 (p, J=7.5, 4H).
.sup.13CNMR, 155.26, 145.01, 144.73, 132.25, 130.23, 125.64,
124.15, 58.06, 29.10, 26.38, 25.61, 19.73.
Example 3
Synthesis of compound
cis-cis-N,N'-(dodeca-5,7-diene-1,12-diyl)-bis-(3-methyl-pyridinium)dibrom-
ide
##STR00005##
[0210] cis-cis-1,12-Dibromo-dodeca-5,7-diene was added to a
solution of 3-picoline (3 mmol) in acetonitrile and the solution
refluxed for 24 hours. The acetonitrile was removed in vacuum and
the resulting residue was partitioned between ether and water. The
aqueous layer was washed extensively with ether until no picoline
left in the aqueous layer. The resulting aqueous solution of the
product was lyophilized to yield the pure product. (76%).
.sup.1HNMR (300 MHZ, D.sub.2O, ppm) 8.50 (s, 2H), 8.44 (d, J=6.3,
2H), 8.16 (d, J=7.8, 2H), 7.74 (dd, J=7.8, J=6.3, 2H), 6.15-6.18
(m, 2H), 5.38-5.38 (m, 2H), 4.38 (t, J=5.7, 4H), 2.35 (s, 6H), 2.06
(q, J=7.5, 4H), 1.83 (p, J=7.5, 4H), 1.25 (p, J=7.5, 4H).
.sup.13CNMR, 145.99, 143.71, 141.30, 139.95, 132.19, 127.46,
124.06, 61.69, 30.27, 26.35, 25.44, 17.93.
Example 4
Synthesis of compound
cis-cis-N,N'-(dodeca-5,7-diene-1,12-diyl)-bis-(4-methyl-pyridinium)dibrom-
ide
##STR00006##
[0212] cis-cis-1,12-Dibromo-dodeca-5,7-diene was added to a
solution of 4-picoline (3 mmol) in acetonitrile and the solution
refluxed for 24 hours. The acetonitrile was removed in vacuum and
the resulting residue was partitioned between ether and water. The
aqueous layer was washed extensively with ether until no picoline
left in the aqueous layer. The resulting aqueous solution of the
product was lyophilized to yield the pure product. (75%).
.sup.1HNMR (300 MHZ, D.sub.2O, ppm), 8.45 (d, J=6.9, 4H), 7.68 (d,
J=6.9, 4H), 6.14-6.19 (m, 2H), 5.31-5.39 (m, 2H), 4.35 (t, J=7.2,
4H), 2.47 (s, 6H), 2.07 (q, J=7.2, 4H), 1.83 (p, J=7.5, 4H), 1.25
(p, J=7.5, 4H).
Example 5
Synthesis of compound
cis-cis-N,N'-(dodeca-5,7-diene-1,12-diyl)-bis-(5,6,7,8-tetrahydro-quinoli-
nium)dibromide
##STR00007##
[0214] cis-cis-1,12-Dibromo-dodeca-5,7-diene was added to a
solution of 5,6,7,8-tetrahydro-quinoline (3 mmol) in acetonitrile
and the solution refluxed for 24 hours. The acetonitrile was
removed in vacuum and the resulting residue was partitioned between
ether and water. The aqueous layer was washed extensively with
ether until no quinoline left in the aqueous layer. The resulting
aqueous solution of the product was lyophilized to yield the pure
product. (75%). .sup.1HNMR (300 MHz, D.sub.2O, ppm) 8.35 (d, J=6.3,
2H), 7.97 (d, J=8.1, 2H), 7.52 (dd, J=8.1, J=6.3, 2H), 6.16-6.22
(m, 2H), 5.32-5.42 (m, 2H), 4.30 (t, J=7.8, 4H), 2.92 (t, J=6.2,
4H), 2.79 (t, J=6.2, 4H), 2.09 (q, J=7.2, 4H), 1.60-1.83 (m, 12H),
1.36 (p, J=7.5S 4H).
Example 6
Synthesis of compound
cis-cis-N,N'-(dodeca-5,7-diene-1,12-diyl)-bis-(5,6,7,8-tetrahydro-isoquin-
olinium)dibromide
##STR00008##
[0216] cis-cis-1,12-Dibromo-dodeca-5,7-diene was added to a
solution of 5,6,7,8-tetrahydro-isoquinoline (3 mmol) in
acetonitrile and the solution refluxed for 24 hours. The
acetonitrile was removed in vacuum and the resulting residue was
partitioned between ether and water. The aqueous layer was washed
extensively with ether until no isoquinoline left in the aqueous
layer. The resulting aqueous solution of the product was
lyophilized to yield the pure product. (75%). .sup.1HNMR (300 MHz,
D.sub.2O, ppm) 8.30 (s, 2H), 8.19 (d, J=6.6, 2H), 7.50 (d, J=6.3,
2H), 6.09-6.16 (m, 2H), 5.28-5.36 (m, 2H), 4.27 (t, J=7.2, 4H),
2.29-2.82 (br, 4H), 2.67-2.74 (br, 4H), 2.02 (q, J=7.2, 4H), 1.81
(p, J=7.2, 4H), 1.62-1.69 (m, 8H), 1.22 (p, J=7.2, 4H). CNMR158.82,
143.10, 139.60, 138.96, 132.28, 127.92, 124.09, 60.82, 49.13,
30.07, 29.35, 26.32, 26.20, 25.43, 21.01.
Example 7
Synthesis of compound
cis-cis-N,N'-(dodeca-5,7-diene-1,12-diyl)-bis-(2,4-dimethyl-pyridinium)di-
bromide
##STR00009##
[0218] cis-cis-1,12-Dibromo-dodeca-5,7-diene was added to a
solution of 2,4-lutidine {3 mmol) in acetonitrile and the solution
refluxed for 24 hours. The acetonitrile was removed in vacuum and
the resulting residue was partitioned between ether and water. The
aqueous layer was washed extensively with ether until no
2,4-lutidine left in the aqueous layer. The resulting aqueous
solution of the product was lyophilized to yield the pure product.
(75%). .sup.1HNMR (300 MHZ, D.sub.2O, ppm) 8.31 (d, J=6.3, 2H),
7.53 (s, 2H), 7.46 (d, J=6.9, 2H), 6.16-6.22 (m, 2H), 5.32-5.40 (m,
2H), 4.28 (t, J=8.1, 4H), 2.58 (s, 3H), 2.38 (s, 3H), 2.07 (q,
J=7.2, 4H), 1.74 (p, J=7.5, 4H), 1.33 (p, J=7.5, 4H). CNMR, 159.20,
153.87, 143.69, 132.32, 130.44, 126.34, 124.18, 57.19, 29.10,
26.41, 25.63, 21.19, 19.46.
Example 8
Synthesis of compound
cis-cis-N,N'-(dodeca-5,7-diene-1,12-diyl)-bis-(3,4-dimethyl-pyridinium)di-
bromide
##STR00010##
[0220] cis-cis-1,12-Dibromo-dodeca-5,7-diene was added to a
solution of 3,4-lutidine (3 mmol) in acetonitrile and the solution
refluxed for 24 hours. The acetonitrile was removed in vacuum and
the resulting residue was partitioned between ether and water. The
aqueous layer was washed extensively with ether until no
3,4-lutidine left in the aqueous layer. The resulting aqueous
solution of the product was lyophilized to yield the pure product.
(75%). .sup.1HNMR (300 MHZ, D.sub.2O, ppm) 8.34 (s, 1H), 8.29 (d,
J=6.3, 1H), 7.60 (d, J=6.3, 1H), 6.13-6.18 (m, 2H), 5.30-5.38 (m,
2H), 4.31 (t, J=7.2, 4H), 2.37 (s, 3H), 2.25 (s, 3H), 2.05 (q,
J=7.2, 4H), 1.81 (p, J=7.5, 4H), 1.24 (p, J=7.5, 4H). CNMR, 158.66,
142.37, 140.71, 138.65, 132.25, 128.23, 124.07, 60.80, 30.11,
26.31, 25.42, 19.69, 16.34.
Example 9
Synthesis of compound
cis-cis-N,N'-(dodeca-5,7-diene-1,12-diyl)-bis-(3,5-dimethyl-pyridinium)di-
bromide
##STR00011##
[0222] cis-cis-1,12-Dibromo-dodeca-5,7-diene was added to a
solution of 3,5-lutidine (3 mmol) in acetonitrile and the solution
refluxed for 24 hours. The acetonitrile was removed in vacuum and
the resulting residue was partitioned between ether and water. The
aqueous layer was washed extensively with ether until no
3,5-lutidine left in the aqueous layer. The resulting aqueous
solution of the product was lyophilized to yield the pure product.
(75%). .sup.1HNMR (300 MHZ, D.sub.2O, ppm) 8.29 (s, 4H), 7.99 (s,
2H), 6.12-6.18 (m, 2H), 5.30-5.38 (m, 2H), 4.31 (t, J=7.5, 4H),
2.30 (s, 6H), 2.05 (q, J=7.2, 4H), 1.81 (p, J=7.5, 4H), 1.24 (p,
J-7.5, 4H). CNMR, 146.56, 140.96, 139.11, 132.28, 124.09, 61.49,
30.21, 26.34, 25.43, 17.73.
Example 10
Synthesis of compound
N,N'[1,4-phenylenedi-(4-butanyl)]bis-[3-(2'-S-1-methyl-pyrrolidin-2-yl)-p-
yridinium]dibromide
##STR00012##
[0224] 1,4-Bis-(4-bromo-butyl)-benzene was added to a solution of
S-nicotine (3 mmol) in acetonitrile and the solution refluxed for
24 hours. The acetonitrile was removed in vacuum and the resulting
residue was partitioned between ether and water. The aqueous layer
was washed extensively with ether until no S-nicotine left in the
aqueous layer. The resulting aqueous solution of the product was
lyophilized to yield the pure product.
[0225] (75%). .sup.1HNMR (300 MHZ, D.sub.2O, ppm) 8.57-8.59 (m,
4H), 8.35 (d, J=8.1, 2H), 7.88 (dd, J=7.8, J=6.6, 2H), 7.01 (s,
4H), 4.45 (t, J=7.5, 4H), 3.40 (t, 2H), 3.04-3.10 (m, 2H), 2.49 (t,
J=7.5, 4H), 2.30-2.40 (m, 2H), 2.18-2.29 (m, 2H), 2.03 (s, 6H),
1.80-1.90 (m, 8H), 1.40-1.55 (m, 4H). CNMR, 144.65, 143.48, 143.30,
139.76, 128.74, 128.42, 67.61, 61.99, 56.62, 39.37, 33.96, 33.73,
30.17, 27.28, 22.33.
Example 11
Synthesis of compound
N,N'[1,4-phenylenedi-(4-butanyl)]-bis-(2-methylpyridinium)dibromide
##STR00013##
[0227] 1,4-Bis-(4-bromo-butyl)-benzene was added to a solution of
2-picoline (3 mmol) in acetonitrile and the solution refluxed for
24 hours. The acetonitrile was removed in vacuum and the resulting
residue was partitioned between ether and water. The aqueous layer
was washed extensively with ether until no 2-picoline left in the
aqueous layer. The resulting aqueous solution of the product was
lyophilized to yield the pure product.
[0228] (75%). .sup.1HNMR (300 MHZ, D.sub.2O, ppm) 8.49 (dd, J=6.0,
1.2, 2H), 8.17 (dt, J=8.1, J=1.5, 2H), 7.70 (d, J=8.1, 2H), 7.65
(dt, J=8.1, J=1.2, 2H), 7.04 (s, 4H), 4.37 (t, J=7.2, 4H), 2.62 (s,
6H), 2.51 (t, J=7.2, 4H), 1.77 (p, J=7.8, 4H), 1.57 (p, J=7.8, 4H).
CNMR. 145.05, 144.73, 139.79, 130.24, 128.78, 125.64, 58.02, 34.11,
29.01, 27.49, 19.70.
Example 12
Synthesis of compound
N,N'[1,4-phenylenedi-(4-butanyl)]-bis-(3-methylpyridinium)dibromide
##STR00014##
[0230] 1,4-Bis-(4-bromo-butyl)-benzene was added to a solution of
3-picoline (3 mmol) in acetonitrile and the solution refluxed for
24 hours. The acetonitrile was removed in vacuum and the resulting
residue was partitioned between ether and water. The aqueous layer
was washed extensively with ether until no 3-picoline left in the
aqueous layer. The resulting aqueous solution of the product was
lyophilized to yield the pure product.
[0231] (75%). .sup.1HNMR (300 MHZ, D.sub.2O, ppm) 8.45 (s, 2H),
8.40 (d, J=6.6, 2H), 8.16 (d, J=8.1, 2H), 7.72 (dd, J=8.1, J=6.0,
2H), 7.00 (s, 4H), 4.37 (t, J=7.5, 4H), 2.47 (t, J=7.5, 4H), 2.34
(s, 6H), 1.82 (p, J=7.5, 4H), 1.46 (p, J=7.5, 4H). CNMR. 146.02,
143.68, 141.68, 139.96, 139.79, 128.75, 127.46, 61.69, 34.04,
30.14, 27.28, 17.90.
Example 13
Synthesis of compound
N,N'[1,4-phenylenedi-(4-butanyl)]-bis-(4-methylpyridinium)dibromide
##STR00015##
[0233] 1,4-Bis-(4-bromo-butyl)-benzene was added to a solution of
4-picoline (3 mmol) in acetonitrile and the solution refluxed for
24 hours. The acetonitrile was removed in vacuum and the resulting
residue was partitioned between ether and water. The aqueous layer
was washed extensively with ether until no 4-picoline left in the
aqueous layer. The resulting aqueous solution of the product was
lyophilized to yield the pure product.
[0234] (75%). .sup.1HNMR (300 MHZ, D.sub.2O, ppm) 8.38 (d, J=6.9,
4H), 7.64 (d, J=6.9, 4H), 6.98 (s, 4H), 4.33 (t, J=7.2, 4H), 2.46
(t, J=7.2, 4H), 2.44 (s, 6H), 1.81 (p, J=7.5, 4H), 1.45 (p, J=7.5,
4H). CNMR. 159.99, 143.04, 139.79, 128.74, 128.65, 60.99, 34.02,
30.03, 27.26, 21.50.
Example 14
Synthesis of compound
N,N'[1,4-phenylenedi-(4-butanyl)]bis-(3-ethylpyridinium)dibromide
##STR00016##
[0236] 1,4-Bis-(4-bromo-butyl)-benzene was added to a solution of
3-ethylpyridine (3 mmol) in acetonitrile and the solution refluxed
for 24 hours. The acetonitrile was removed in vacuum and the
resulting residue was partitioned between ether and water. The
aqueous layer was washed extensively with ether until no
3-ethylpyridine left in the aqueous layer. The resulting aqueous
solution of the product was lyophilized to yield the pure product.
(75%). .sup.1HNMR (300 MHZ, D.sub.2O, ppm) 8.45 (s, 2H), 8.41 (d,
J=6.0, 2H), 8.19 (d, J=8.4, 2H), 7.73 (dd, J=8.1, J=6.0, 2H), 6.97
(s, 4H), 4.37 (t, J=7.2, 4H), 2.66 (q, 7.8, 2H), 2.49 (t, J=7.2,
1.83 (p, J=7.5, 4H), 1.45 (p, J-1.5, 4H), 1.09 (t, J=7.8, 6H).
CNMR. 145.61, 145.08, 143.09, 141.51, 139.78, 128.75, 127.68,
61.70, 34.01, 30.13, 27.24, 25.70, 13.92.
Example 15
Synthesis of compound
N,N'[1,4-phenylenedi-(4-butanyl)]-bis-(5,6,7,8-tetrahydroquinolinium)dibr-
omide
##STR00017##
[0238] 1,4-Bis-(4-bromo-butyl)-benzene was added to a solution of
tetrahydroquinoline (3 mmol) in acetonitrile and the solution
refluxed for 24 hours. The acetonitrile was removed in vacuum and
the resulting residue was partitioned between ether and water. The
aqueous layer was washed extensively with ether until no
tetrahydroquinoline left in the aqueous layer. The resulting
aqueous solution of the product was lyophilized to yield the pure
product. (75%). .sup.1HNMR (300 MHZ, D.sub.2O, ppm) 8.30 (d, J=6.3,
2H), 7.95 (d, J=7.8, 2H), 7.49 (dd, J=8.1, J=6.3, 2H), 7.02 (s,
4H), 4.28 (t, 7.5, 4H), 2.83 (t, J=7.5, 4H), 2.77 (t, J=7.5, 4H),
2.49 (t, J=7.5, 4H), 1.66-1.80 (m, 8H), 1.35-1.63 (m, 8H).
Example 16
Synthesis of compound
N,N'[1,4-phenylenedi-(4-butanyl)]-bis-(5,6,7,8-tetrahydroisoquinolinium)d-
ibromide
##STR00018##
[0240] 1,4-Bis-(4-bromo-butyl)-benzene was added to a solution of
tetrahydroisoquinoline (3 mmol) in acetonitrile and the solution
refluxed for 24 hours. The acetonitrile was removed in vacuum and
the resulting residue was partitioned between ether and water. The
aqueous layer was washed extensively with ether until no
tetrahydroisoquinoline left in the aqueous layer. The resulting
aqueous solution of the product was lyophilized to yield the pure
product. (75%). .sup.1HNMR (300 MHZ, D.sub.2O, ppm) 8.21 (s, 2H),
8.13 (d, J=6.3, 2H), 7.46 (d, J=6.3, 2H), 6.96 (s, 4H), 4.25 (t,
J=7.2, 4H), 2.2.78-2.84 (br, 4H), 2.63-2.70 (br, 4H), 2.44 (t,
J=7.2, 4H), 1.78 (p, J=7.5, 4H), 1.64-1.70 (m, 8H), 1.42 (p, J=7.5,
4H). CNMR, 158.77, 143.03, 139.78, 139.56, 138.88, 128.72, 127.84,
60.79, 49.11, 34.01, 29.91, 29.31, 27.16, 26.16, 20.99.
Example 17
Synthesis of compound
N,N'[1,4-phenylenedi-(4-butanyl)]-bis-[3-(3-hydroxy-propyl)-pyridinium]di-
bromide
##STR00019##
[0242] 1,4-Bis-(4-bromo-butyl)-benzene was added to a solution of
{3-hydroxy-propyl)-pyridine (3 mmol) in acetonitrile and the
solution refluxed for 24 hours. The acetonitrile was removed in
vacuum and the resulting residue was partitioned between ether and
water. The aqueous layer was washed extensively with ether until no
(3-hydroxy-propyl)-pyridine left in the aqueous layer. The
resulting aqueous solution of the product was lyophilized to yield
the pure product. (75%). .sup.1HNMR (300 MHZ, D.sub.2O, ppm) 8.49
(s, 2H), 8.43 (d, J=6.0, 2H), 8.22 (d, J=8.1, 2H), 7.75 (dd, J=7.8,
J=6.0, 2H), 6.98 (s, 4H), 4.38 (t, J=7.2, 4H), 3.45 (t, J=6.6, 4H),
2.72 (t, J=7.8, 4H), 2.46 (t, J=7.5, 4H), 1.83 (p, J-7.5, 4H),
1.70-1.75)m, 4H), 1.44 (p, J-7.5, 4H). CNMR, 145.53, 143.51,
141.78, 139.78, 128.75, 127.78, 61.75, 60.67, 34.01, 32.17, 30.13,
28.81, 27.24.
Example 18
Synthesis of compound
N,N'[1,4-phenylenedi-(4-butanyl)]-bis-(2,4-dimethylpyridinium)dibromide
##STR00020##
[0244] 1,4-Bis-(4-bromo-butyl)-benzene was added to a solution of
2,4-lutidine (3 mmol) in acetonitrile and the solution refluxed for
24 hours. The acetonitrile was removed in vacuum and the resulting
residue was partitioned between ether and water. The aqueous layer
was washed extensively with ether until no 2,4-lutidine left in the
aqueous layer. The resulting aqueous solution of the product was
lyophilized to yield the pure product.
[0245] (75%). .sup.1HNMR (300 MHZ, D.sub.2O, ppm) 8.27 (d, J=6.6,
2H), 7.50 (s, 2H), 7.45 (d, J=6.6, 2H), 7.02 (s, 4H), 4.28 (t,
J=7.2, 4H), 2.52 (s, 6H), 2.48 (t, J=7.2, 4H), 2.38 (s, 6H), 2.20
(s, 3H), 1.79 (p, J=7.5, 4H), 1.42 (p, J=7.5, 4H).
Example 19
Synthesis of compound
N,N'[1,4-phenylenedi-(4-butanyl)]-bis-(3,4-dimethylpyridinium)dibromide
[ZZ 1 81]
##STR00021##
[0247] 1,4-Bis-(4-bromo-butyl)-benzene was added to a solution of
3,4-Iutidine (3 mmol) in acetonitrile and the solution refluxed for
24 hours. The acetonitrile was removed in vacuum and the resulting
residue was partitioned between ether and water. The aqueous layer
was washed extensively with ether until no 3,4-lutidine left in the
aqueous layer. The resulting aqueous solution of the product was
lyophilized to yield the pure product.
[0248] (75%). .sup.1HNMR (300 MHZ, D.sub.2O, ppm) 8.25 (s, 2H),
8.22 (d, J=6.0, 2H), 7.55 (d, J=6.0, 2H), 6.96 (s, 4H), 4.27 (t,
J=7.2, 4H), 2.45 (t, J=7.2, 4H), 2.34 (s, 6H), 2.21 (s, 6H), 1.79
(p, J=7.5, 4H), 1.42 (p, J=7.5, 4H). CNMR, 158.64, 142.28, 140.66,
139.78, 138.61, 128.72, 128.18, 34.02, 29.94, 27.20, 19.67,
16.29.
Example 20
Synthesis of compound
N,N'[1,4-phenylenedi-(4-butanyl)]-bis-(3,5-dimethylpyridinium)dibromide
[ZZ 1 82]
##STR00022##
[0250] 1,4-Bis-(4-bromo-butyl)-benzene was added to a solution of
3,5-lutidine (3 mmol) in acetonitrile and the solution refluxed for
24 hours. The acetonitrile was removed in vacuum and the resulting
residue was partitioned between ether and water. The aqueous layer
was washed extensively with ether until no 3,5-lutidine left in the
aqueous layer. The resulting aqueous solution of the product was
lyophilized to yield the pure product.
[0251] (75%). .sup.1HNMR (300 MHZ, D.sub.2O, ppm) 8.23 (s, 4H),
7.97 (s, 2H), 6.97 (s, 4H), 4.29 (t, J=7.2, 4H), 2.45 (t, J=7.2,
4H), 2.27 (s, 12H), 1.81 (p, J=7.5, 4H), 1.45 (p, J=7.5, CNMR,
146.50, 140.89, 139.79, 139.04, 128.74, 63.46, 34.04, 30.03, 27.22,
17.70.
Example 21
Synthesis of compound
5-[2-(5-hydroxy-pent-1-ynyl)-phenyl]-pent-4-yn-1-ol
##STR00023##
[0253] 1,2-Dibromobenzene (10.94 g, 46.37 mmol), 4-pentyn-1-ol
(9.36 g, 111.30 mmol), and bis(triphenylphosphine)palladium(II)
dichloride (650 mg, 0.93 mmol) was stirred in triethylamine (150
mL) under nitrogen for 5 min. Copper(I) iodide (88 mg, 0.46 mmol)
was added and the mixture was stirred for 4 hrs at 85.degree. C.
for 6 days. The mixture was cooled to room temperature and filtered
through a celite pad, rinsed with ethylacetate. The combined
filtrate was evaporated to dryness under reduced pressure. The
resulting residue was purified by column chromatography
(chloroform:methanol 30:1) to afford 5.33 g of the title compound.
Yield: 47%. .sup.1H NMR (300 MHZ, D.sub.2O, ppm) .delta. 1.85 (m,
4H), 2.58 (t, J=6.6 Hz, 4H), 3.82 (t, J=6.0 Hz, 4H), 7.18 (m, 2H),
7.36 (m, 2H) ppm; .sup.13C NMR (75 MHz, CDCl.sub.3) .delta. 16.3,
31.4, 62.4, 80.2, 93.3, 126.0, 127.4, 131.8 ppm.
Example 22
Synthesis of compound 1,2-bis-(5-bromo-pent-1-ynyl)-benzene
##STR00024##
[0255] 5-[2-(5-Hydroxy-pent-1-ynyl)-phenyl]-pent-4-yn-1-ol (2.40 g,
9.90 mmol) and carbon tetrabromide (8.21 g, 24.75 mmol) were
dissolved in dry methylene chloride (30 mL) and cooled to 0.degree.
C. Triphenyl phosphine (6.82 g, 25.99 mmol) in methylene chloride
(15 mL) was added dropwise and the mixture was stirred for 1 h at
0.degree. C. The mixture was poured into hexanes (200 mL) and then
filtered through a short silica gel column, washed with
ethylacetate/hexanes (1/4). The combined organic solvents were
evaporated to dryness under reduced pressure. The resulting residue
was purified by column chromatography (hexanes:ethylacetate 30:1)
to afford 2.48 g of the title compound. Yield: 68%. .sup.1H NMR
(300 MHz, CDCl.sub.3) .delta. 2.16 (m, 4H), 2.68 (t, J=6.6 Hz, 4H),
3.65 (dt, J=6.6, 0.6 Hz, 4H), 7.20 (m, 2H), 7.38 (m, 2H) ppm;
.sup.13C NMR (75 MHz, CDCl.sub.3) .delta. 18.6, 31.8, 32.7, 80.7,
91.8, 125.9, 127.6, 131.9 ppm.
Example 23
Synthesis of compound
1,2-bis-[5-(2-methyl-pyridinium)-pent-1-ynyl]-benzene dibromide
##STR00025##
[0257] A mixture of 1,2-bis-(5-bromo-pent-1-ynyl)-benzene (264 mg,
0.72 mmol) and 2-picoline (1 mL) was heated at 60-70.degree. C. for
12 hrs. The resulted mixture was washed with diethyl ether and then
dissolved in water (15 mL), the aqueous solution was extracted with
diethyl ether (30 mL.times.3). Water was removed by lyophilization
to afford 327 mg of the title compound. Yield: 82%. .sup.1H NMR
(300 MHz, CD.sub.3OD) .delta. 2.35 (m, 4H), 2.81 (t, J=6.6 Hz, 4H),
3.02 (s, 6H), 4.91 (t, J=7.5 Hz, 4H), "7.27-7.50 (m, 4H), 7.92-8.15
(m, 4H), 8.45 (t, J=7.8 Hz, 2H), 9.11 (d, J=6.3 Hz, 2H) ppm;
.sup.13C NMR (75 MHz, CD.sub.3OD) .delta. 17.6, 21.1, 30.1, 58.2,
81.9, 92.9, 126.4, 127.0, 129.2, 129.3, 131.5, 133.1, 146.4, 156.7
ppm.
Example 24
Synthesis of compound
1,2-bis-[5-(3-methyl-pyridinium)-pent-1-ynyl]-benzene dibromide
##STR00026##
[0259] A mixture of 1,2-bis-(5-bromo-pent-1-ynyl)-benzene (270 mg,
0.73 mmol) and 3-picoline (1 mL) was heated at 60-70.degree. C. for
12 hrs. The resulted mixture was washed with diethyl ether and then
dissolved in water (15 mL), the aqueous solution was extracted with
diethyl ether (30 mL.times.3). Water was removed by lyophilization
to afford 350 mg of the title compound. Yield: 86%. .sup.1H NMR
(300 MHz, CD.sub.3OD) .delta. 2.45 (m, 4H), 2.56 (s, 6H) 2.78 (t,
J=6.6 Hz, 4H), 4.95 (t, J=7.2 Hz, 4H), 7.22-7.42 (m, 4H), 8.05 (dd,
J=8.1, 6.0 Hz, 2H), 8.39 (d, J=7.8 Hz, 2H), 9.10 (d, J=6.0 Hz, 2H),
9.19 (s, 2H) ppm; .sup.13C NMR (75 MHz, CD.sub.3OD) .delta. 17.6,
18.9, 31.2, 61.9, 81.6, 92.8, 126.4, 128.7, 129.0, 132.9, 140.9,
143.1, 145.6, 147.3 ppm.
Example 25
Synthesis of compound
1,2-bis-[5-(4-methyl-pyridinium)-pent-1-ynyl]-benzene dibromide
##STR00027##
[0261] A mixture of 1,2-bis-(5-bromo-pent.about.1-ynyl)-benzene
(268 mg, 0.73 mmol) and 4-picoline (1 mL) was heated at
60-70.degree. C. for 12 hrs. The resulted mixture was washed with
diethyl ether and then dissolved in water (15 mL), the aqueous
solution was extracted with diethyl ether (30 mL.times.3). Water
was removed by lyophilization to afford 435 mg of the title
compound. Yield: 86%. .sup.1H NMR (300 MHz, CD.sub.3OD) .delta.
2.41 (m, 4H), 2.51 (s, 6H), 2.78 (t, J=6.6 Hz, 4H), 4.91 (t, J=6.6
Hz, 4H), 7.30 (s, 4H), 7.92 (d, J=6.3 Hz, 4H), 9.05 (d, J=6.3 Hz,
4H) ppm; .sup.13C NMR (75 MHz, CD.sub.3OD) .delta. 17.5, 22.3,
31.0, 61.4, 81.5, 92.8, 126.4, 129.0, 129.8, 132.9, 144.9, 161.1
ppm.
Example 26
Synthesis of compound
1,2-bis-[5-(2,4-dimethyl-pyridinium)-pent-1-ynyl]-benzene
dibromide
##STR00028##
[0263] A mixture of 1,2-bis-(5-bromo-pent-1-ynyl)-benzene (268 mg,
0.73 mmol) and 2,4-lutidine (1 mL) was heated at 60-70.degree. C.
for 12 hrs. The resulted mixture was washed with diethyl ether and
then dissolved in water (15 mL), the aqueous solution was extracted
with diethyl ether (30 mL.times.3). Water was removed by
lyophilization to afford 343 mg of the title compound. Yield: 81%.
.sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 2.34 (m, 4H), 2.52 (s,
3H), 2.84 (t, J-6.6 Hz, 4H), 2.97 (s, 3H), 4.87 (t, J=7.5 Hz, 4H),
7.27-7.45 (m, 4H), 7.80 (d, J=6.3 Hz, 2H), 7.87 (s, 2H), 8.99 (d,
J=6.3 Hz, 2H) ppm; .sup.13C NMR (75 MHz, CD.sub.3OD) .delta. 17.6,
20.9, 22.0, 30.1, 57.5, 81.6, 93.0, 126.4, 127.6, 129.1, 131.7,
133.0, 145.5, 155.5, 160.3 ppm.
Example 27
Synthesis of compound
1,2-bis-[5-(3,4-dimethyl-pyridinium)-pent-1-ynyl]-benzene dibromide
[GZ 581 B]
##STR00029##
[0265] A mixture of 1,2-bis-(5-bromo-pent-1-ynyl)-benzene (276 mg,
0.75 mmol) and 3,4-lutidine (1 mL) was heated at 60-70.degree. C.
for 12 hrs. The resulted mixture was washed with diethyl ether and
then dissolved in water (15 mL), the aqueous solution was extracted
with diethyl ether (30 mL.times.3). Water was removed by
lyophilization to afford 355 mg of the title compound. Yield: 81%.
.sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 2.37 (s, 3H), 2.40 (s,
3H), 2.44 (m, 4H), 2.79 (t, J=6.6 Hz, 4H), 4.88 (t, J=6.6 Hz, 4H),
7.29 (s, 4H), 7.86 (d, J=6.3 Hz, 2H), 8.95 (d, J=6.3 Hz, 2H), 9.06
(s, 2H), ppm; .sup.13C NMR (75 MHz, CD.sub.3OD) .delta. 17.3, 17.7,
20.4, 31.1, 61.2, 81.3, 93.0, 126.5, 129.0, 129.4, 132.8, 139.5,
142.7, 144.3, 159.8 ppm.
Example 28
Synthesis of compound
1,2-bis-[5-(3,5-dimethyl-pyridinium)-pent-1-ynyl]-benzene dibromide
[GZ 581 A]
##STR00030##
[0267] A mixture of 1,2-bis-(5-bromo-pent-1-ynyl)-benzene (280 mg,
0.76 mmol) and 3,5-lutidine (1 mL) was heated at 60-70.degree. C.
for 12 hrs. The resulted mixture was washed with diethyl ether and
then dissolved in water (15 mL), the aqueous solution was extracted
with diethyl ether (30 mL.times.3). Water was removed by
lyophilization to afford 363 mg of the title compound. Yield: 82%.
.sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 2.42 (m, 4H), 2.51 (s,
6H), 2.76 (t, J-6.9 Hz, 4H), 4.86 (t, J=6.9 Hz, 4H), 7.30 (m, 4H),
8.13 (s, 2H), 8.95 (s, 4H) ppm; .sup.13C NMR (75 MHz, CD.sub.3OD)
.delta. 17.7, 18.7, 31.2, 61.9, 81.6, 92.9, 126.6, 129.0, 132.8,
140.2, 142.9, 147.9 ppm.
Example 29
Synthesis of compound 1,2-bis-[5-quinolinium-pent-1-ynyl)-benzene
dibromide
##STR00031##
[0269] A mixture of 1,2-bis-(5-bromo-pent-1-ynyl)-benzene (249 mg,
0.68 mmol) and quinoline (1 mL) was heated at 60-70.degree. C. for
12 hrs. The resulted mixture was washed with diethyl ether and then
dissolved in water (30 mL), the aqueous solution was extracted with
chloroform (20 mL.times.3). Water was removed by lyophilization to
afford 317 mg of the title compound. Yield: 75%. .sup.1H NMR (300
MHz, CD.sub.3OD) .delta. 2.42 (m, 4H), 2.78 (t, J=6.6 Hz, 4H), 5.36
(t, J=6.9 Hz, 4H), 7.02-7.28 (m, 4H), 7.97 (t, J=7.5 Hz, 2H),
8.07-8.40 (m, 4H), 8.67 (d, J=9.0 Hz, 2H), 9.15 (d, J=8.4 Hz, 2H),
9.15 (d, J=8.4 Hz, 2H), 9.70 (d, J=5.7 Hz, 2H) ppm; .sup.13C NMR
(75 MHz, CD.sub.3OD) .delta. 17.8, 29.8, 58.5, 81.6, 92.9, 119.7,
123.2, 126.2, 129.0, 130.5, 131.3, 132.0, 132.7, 137.2, 139.0,
149.0, 150.6 ppm.
Example 30
Synthesis of compound
1,2-bis-[5-isoquinolinium-pent-1-ynyl)-benzene dibromide [GZ 582
B]
##STR00032##
[0271] A mixture of 1,2-bis-(5-bromo-pent-1-ynyl)-benzene (252 mg,
0.68 mmol) and isoquinoline (1 mL) was heated at 60-70.degree. C.
for 12 hrs. The resulted mixture was washed with diethy! ether and
then dissolved in water (30 mL), the aqueous solution was extracted
with chloroform (20 mL.times.3). Water was removed by
lyophilization to afford 319 mg of the title compound. Yield: 74%.
.sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 2.46 (m, 4H), 2.77 (t,
J=6.3 Hz, 4H), 5.01 (t, J=6.6 Hz, 4H), 6.91 (m, 2H), 7.04 (m, 2H),
7.90-8.50 (m, 10H), 8.78 (d, J=6.9 Hz, 2H), 10.10 (s, 2H) ppm;
.sup.13C NMR (75 MHz, CD.sub.3OD) .delta. 17.8, 30.8, 62.1, 81.3,
92.7, 125.7, 127.3, 128.1, 128.5, 131.2, 131.4, 132.1, 132.2,
135.6, 137.9, 138.4, 150.8 ppm.
Example 31
Synthesis of compound
1,2-bis-[5-(2'-S-nicotinium-pent-1-ynyl)]benzene dibromide
##STR00033##
[0273] A mixture of 1,2-bis-(5-bromo-pent-1-ynyl)-benzene (330 mg,
0.90 mmol) and S-nicotine (1 mL) was heated at 60-70.degree. C. for
12 hrs. The resulted mixture was washed with diethyl ether and then
dissolved in water (20 mL), the aqueous solution was extracted with
chloroform (20 mL.times.3). Water was removed by lyophilization to
afford 340 mg of the title compound. Yield: 55%. .sup.1H NMR (300
MHz, CD.sub.3OD) .delta. 2.00-2.82 (m, 16H), 2.55 (s, 6H), 2.90 (m,
2H), 3.55 (m, 2H), 4.17 (m, 2H), 4.95 (t, J=6.9 Hz, 4H), 7.27 (m,
2H), 7.37 (m, 2H), 8.17 (dd, J=7.8, 6.3 Hz, 2H), 8.69 (d, J=8.4 Hz,
2H), 9.15 (d, J=6.0 Hz, 2H), 9.40 (s, 2H) ppm; .sup.13C NMR (75
MHz, CD.sub.3OD) .delta. 17.5, 23.5, 30.9, 34.1, 40.3, 57.6, 62.4,
68.7, 81.9, 92.7, 126.4, 129.1, 129.6, 133.0, 141.1, 145.8, 146.0,
146.5 ppm.
Example 32
Synthesis of compound
5-[2-(5-hydroxy-pentyl)-phenyl]-pentan-1-ol
##STR00034##
[0275] 5-[2-(5-Hydroxy-pent-1-ynyl)-phenyl]-pent-4-yn-1-ol (2.70 g,
11.14 mmol) was dissolved in ethanol (30 mL) and 10% Pd/C (2.5%
w/w) was added. The resulting mixture was hydrogenated on a Parr
hydrogenation apparatus (45 psi) for 4 hrs. The catalyst was
removed by filtration through a Celite pad. The filter cake was
rinsed with methanol, and the combined organic liquors were
concentrated under reduced pressure. The crude product was purified
by column chromatography (chloroform:methanol 20:1) to afford 2.55
g of the title compound. Yield: 91%. .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 1.38-1.67 (m, 12H), 2.60 (t, J=7.8 Hz, 4H),
3.59 (t, J=6.6 Hz, 4H), 7.11 (m, 4H) ppm; .sup.13C NMR (75 MHz,
CDCl.sub.3) .delta. 26.0, 31.3, 32.6, 32.8, 62.6, 125.8, 129.1,
140.2 ppm.
Example 33
Synthesis of compound 1,2-bis-[5-bromo-pentyl)-benzene
##STR00035##
[0277] 5-[2-(5-Hydroxy-pentyl])-phenyl]-pentan-1-ol (2.50 g, 10.00
mmol) and carbon tetrabromide (8.29 g, 25.00 mmol) were dissolved
in dry methylene chloride (30 mL) and cooled to 0.degree. C.
Triphenyl phosphine (6.88 g, 26.25 mmol) in methylene chloride (15
mL) was added dropwise and the mixture was stirred for 1 h at
0.degree. C. The mixture was poured into hexanes (200 mL) and then
filtered through a short silica gel column, washed with
ethylacetate/hexanes (3/4). The combined organic solvents were
evaporated to dryness under reduced pressure. The resulting residue
was purified by column chromatography (hexanes:ethylacetate 30:1)
to afford 3.76 g of the title compound. Yield: 99%. .sup.1H NMR
(300 MHz, CDCl.sub.3) .delta. 1.47-1.73 (m, 8H), 1.91 (m, 4H), 2.63
(t, J=7.8 Hz, 4H), 3.42 (t, J=6.9 Hz, 4H), 7.15 (s, 4H) ppm;
.sup.13C NMR (75 MHz, CDCl.sub.3) .delta. 28.5, 30.6, 32.7, 32.9,
34.0, 126.0, 129.2, 139.9 ppm.
Example 34
Synthesis of compound
1,2-bis-[5-(2-methyl-pyridinium)-pentyl]-benzene dibromide
##STR00036##
[0279] A mixture of 1,2-bis-(5-bromo-pentyl)-benzene (280 mg, 0.74
mmol) and 2-picoline (1 mL) was heated at 60-70.degree. C. for 12
hrs. The resulted mixture was washed with diethyl ether and then
dissolved in water (15 mL), the aqueous solution was extracted with
diethyl ether (30 mL.times.3). Water was removed by lyophilization
to afford 400 mg of the title compound. Yield: 95%. .sup.1H NMR
(300 MHz, CD.sub.3OD) .delta. 1.54 (m, 4H), 1.68 (m, 4H), 2.01 (m,
4H), 2.69 (t, J=7.5 Hz, 4H), 2.90 (s, 6H), 4.61 (t, J=7.8 Hz, 4H),
7.02-7.19 (m, 4H), 7.92 (t, J=6.6 Hz, 2H), 8.00 (d, J=7.8 Hz, 2H),
8.44 (dt, J=7.8, 1.2 Hz, 2H), 8.93 (dd, J=6.3, 1.2 Hz, 2H) ppm;
.sup.13C NMR (75 MHz, CD.sub.3OD) .delta. 20.8, 27.4, 31.2, 32.0,
33.4, 59.3, 126.9, 127.0, 130.3, 131.5, 141.0, 146.3, 146.4, 156.6
ppm.
Example 35
Synthesis of compound
1,2-bis-[5-(3-methyl-pyridinium)-pentyl]-benzene dibromide
##STR00037##
[0281] A mixture of 1,2-bis-(5-bromo-pentyl)-benzene (296 mg, 0.79
mmol) and 3-picoline (1 mL) was heated at 60-70.degree. C. for 12
hrs. The resulted mixture was washed with diethyl ether and then
dissolved in water (15 mL), the aqueous solution was extracted with
diethyl ether (30 mL.times.3). Water was removed by lyophilization
to afford 382 mg of the title compound. Yield: 86%. .sup.1H NMR
(300 MHz, CD.sub.3OD) .delta. 1.47 (m, 4H), 1.66 (m, 4H), 2.08 (m,
4H), 2.59 (s, 6H), 2.65 (t, J=7.5 Hz, 4H), 4.64 (t, J=7.5 Hz, 4H),
7.01-7.19 (m, 4H), 7.99 (d, J=7.5, 6.0 Hz, 2H), 8.43 (dd, J=8.1,
0.6 Hz, 2H), 8.86 (d, J=6.0 Hz, 2H), 8.96 (s, 2H) ppm; .sup.13C NMR
(75 MHz, CD.sub.3OD) .delta. 18.7, 27.2, 32.0, 32.6, 33.5, 62.9,
127.1, 128.7, 130.3, 141.0, 141.2, 143.1, 145.5, 147.2 ppm.
Example 36
Synthesis of compound
1,2-bis-[5-(4-methyl-pyridinium)-pentyl]-benzene dibromide
##STR00038##
[0283] A mixture of 1,2-bis-(5-bromo-pentyl)-benzene (290 mg, 0.77
mmol) and 4-picoline (1 mL) was heated at 60-70.degree. C. for 12
hrs. The resulted mixture was washed with diethyl ether and then
dissolved in water (15 mL), the aqueous solution was extracted with
diethyl ether (30 mL.times.3). Water was removed by lyophilization
to afford 387 mg of the title compound. Yield: 89%. .sup.1H NMR
(300 MHz, CD.sub.3OD) .delta. 1.44 (m, 4H), 1.65 (m, 4H), 2.04 (m,
4H), 2.64 (t, J=7.5 Hz, 4H), 2.68 (s, 6H), 4.58 (t, J=7.5 Hz, 4H),
7.02-7.15 (m, 4H), 7.92 (d, J=6.3 Hz, 4H), 8.83 (dd, J=5.1, 1.8 Hz,
4H) ppm; .sup.13C NMR (75 MHz, CD.sub.3OD) .delta. 22.3, 27.0,
31.9, 32.3, 33.3, 62.0, 127.0, 129.8, 130.2, 140.9, 144.7, 160.8
ppm.
Example 37
Synthesis of compound
1,2-bis-[5-(2,4-dimethyl-pyridinium)-pentyl]-benzene dibromide
##STR00039##
[0285] A mixture of 1,2-bis-(5-bromo-pentyl)-benzene (270 mg, 0.72
mmol) and 2,4-lutidine (1 mL) was heated at 60-70.degree. C. for 12
hrs. The resulted mixture was washed with diethyl ether and then
dissolved in water (15 mL), the aqueous solution was extracted with
diethyl ether (30 mL.times.3). Water was removed by lyophilization
to afford 355 mg of the title compound. Yield: 84%. .sup.1H NMR
(300 MHz, CD.sub.3OD) .delta. 1.52 (m, 4H), 1.68 (m, 4H), 2.01 (m,
4H), 2.61 (s, 6H), 2.68 (t, J=7.5 Hz, 4H), 2.82 (s, 6H), 4.53 (t,
J=7.8 Hz, 4H), 7.02-7.19 (m, 4H), 7.73 (dd, J=6.3, 1.2 Hz, 2H),
7.82 (d, J-1.5 Hz, 2H), 8.72 (d, J=6.3 Hz, 2H) ppm; .sup.13C NMR
(75 MHz, CD.sub.3OD) .delta. 20.5, 22.0, 27.4, 31.2, 32.0, 33.4,
58.4, 127.0, 127.6, 130.3, 131.6, 141.0, 145.4, 155.2, 160.2
ppm.
Example 38
Synthesis of compound
1,2-bis-[5-(3,4-dimethyl-pyridinium)-pentyl]-benzene dibromide [GZ
584 B]
##STR00040##
[0287] A mixture of 1,2-bis-(5-bromo-pentyl)-benzene (270 mg, 0.72
mmol) and 3,4-lutidine (1 mL) was heated at 60-70.degree. C. for 12
hrs. The resulted mixture was washed with diethyl ether and then
dissolved in water (15 mL), the aqueous solution was extracted with
diethyl ether (30 mL.times.3). Water was removed by lyophilization
to afford 329 mg of the title compound. Yield: 78 .sup.1H NMR (300
MHz, CD.sub.3OD) .delta. 1.43 (m, 4H), 1.65 (m, 4H), 2.03 (m, 4H),
2.48 (s, 6H), 2.59 (s, 6H), 2.64 (t, J=7.5 Hz, 4H), 4.54 (t, J=7.5
Hz, 4H), 7.02-7.17 (m, 4H), 7.85 (d, J=6.3 Hz, 2H), 8.67 (d, J=4.8
Hz, 2H), 8.77 (s, 2H) ppm; .sup.13C NMR (75 MHz, CD.sub.3OD)
.delta. 17.3, 20.6, 27.1, 31.9, 32.4, 33.3, 61.8, 126.9, 129.4,
130.2, 139.7, 140.9, 142.4, 144.0, 159.5 ppm.
Example 39
Synthesis of compound
1,2-bis-[5-(3,5-dimethyl-pyridinium)-pentyl]-benzene dibromide [GZ
584 A]
##STR00041##
[0289] A mixture of 1,2-bis-(5-bromo-pentyl)-benzene (290 mg, 0.77
mmol) and 3,5-lutidine (1 mL) was heated at 60-70.degree. C. for 12
hrs. The resulted mixture was washed with diethyl ether and then
dissolved in water (15 mL), the aqueous solution was extracted with
diethyl ether (30 mL.times.3). Water was removed by lyophilization
to afford 321 mg of the title compound. Yield: 71%. .sup.1H NMR
(300 MHz, CD.sub.3OD) .delta. 1.50 (m, 4H), 1.65 (m, 4H), 2.12 (m,
4H), 2.58 (s, 12H), 2.64 (t, J=6.3 Hz, 4H), 4.68 (t, J=7.5 Hz, 4H),
7.02-7.19 (m, 4H), 8.33 (s, 2H), 8.91 (s, 4H) ppm; .sup.13C NMR (75
MHz, CD.sub.3OD) .delta. 18.7, 27.2, 31.9, 32.5, 33.4, 62.5, 126.9,
130.2, 140.0, 140.9, 142.6, 147.7 ppm.
Example 40
Synthesis of compound 1,2-bis-[5-quinolinium-pentyl)-benzene
dibromide
##STR00042##
[0291] A mixture of 1,2-bis-(5-bromo-pentyl)-benzene (282 mg, 0.75
mmol) and quinoline (1 mL) was heated at 60-70.degree. C. for 12
hrs. The resulted mixture was washed with diethyl ether and then
dissolved in water (20 mL), the aqueous solution was extracted with
chloroform (20 mL*3). Water was removed by lyophilization to afford
411 mg of the title compound. Yield: 86%. .sup.1H NMR (300 MHz,
CD.sub.3OD) .delta. 1.41-1.73 (m, 8H), 2.13 (m, 4H), 2.47 (t, J=6.6
Hz, 4H), 5.22 (t, J=7.5 Hz, 4H), 6.91 (m, 4H), 8.00 (t, J=7.8 Hz,
2H), 8.16 (m, 2H), 8.31 (t, J-7.2 Hz, 2H), 8.44 (d, J-7.8 Hz, 2H),
8.65 (d, J=8.7 Hz, 2H), 9.30 (d, J=8.1 Hz, 2H), 9.70 (d, J=5.4 Hz,
2H) ppm; .sup.13C NMR (75 MHz, CD.sub.3OD) .delta. 27.3, 30.9,
31.6, 33.1, 59.2, 119.8, 123.0, 126.7, 129.8, 131.0, 131.1, 131.8,
137.1, 138.6, 140.6, 148.6, 150.2 ppm.
Example 41
Synthesis of compound 1,2-bis-[5-isoquinolinium-pentyl)-benzene
dibromide [GZ 585 B]
##STR00043##
[0293] A mixture of 1,2-bis-(5-bromo-pentyl)-benzene (271 mg, 0.72
mmol) and isoquinoline (1 mL) was heated at 60-70.degree. C. for 12
hrs. The resulted mixture was washed with diethyl ether and then
dissolved in water (20 mL), the aqueous solution was extracted with
chloroform (20 mL.times.3). Water was removed by lyophilization to
afford 392 mg of the title compound. Yield: 86%. .sup.1H NMR (300
MHz, CD.sub.3OD) .delta. 1.38-1.70 (m, 8H), 2.20 (m, 4H), 2.52 (t,
J=7.2 Hz, 4H), 4.92 (t, J=7.5 Hz, 4H), 6.83-7.05 (m, 4H), 7.99 (dd,
J=6.9, 1.2 Hz, 2H), 8.18 (dt, J=8.1, 0.9, 2H), 8.28 (d, J-8.4 Hz,
2H), 8.45-8.60 (m, 4H), 8.84 (dd, J=6.9, 1.2 Hz, 2H), 10.21 (s, 2H)
ppm; .sup.13C NMR (75 MHz, CD.sub.3OD) .delta. 27.0, 31.6, 32.2,
33.1, 62.5, 126.7, 127.2, 128.2, 128.5, 129.9, 131.2, 132.2, 135.6,
137.9, 138.3, 140.6, 150.3 ppm.
Example 42
Synthesis of compound 1,2-bis-[5-(2'-S-nicotinium-pentyl)]benzene
dibromide
##STR00044##
[0295] A mixture of 1,2-bis-(5-bromo-pentyl)-benzene (278 mg, 0.74
mmol) and S-nicotine (1 mL) was heated at 60-70.degree. C. for 12
hrs. The resulted mixture was washed with diethyl ether and then
dissolved in water (20 mL), the aqueous solution was extracted with
chloroform (20 mL.times.3), Water was removed by lyophilization to
afford 390 mg of the title compound. Yield: 75%. .sup.1H NMR (300
MHz, CD.sub.3OD) .delta. 1.40-1.75 (m, 8H), 2.08-2.45 (m, 10H),
2.67 (s, 6H), 2.55-2.75 (m, 8H), 3.07 (m, 2H), 3.67 (m, 2H), 4.43
(t, J=6.9 Hz, 4H), 7.02-7.22 (m, 4H), 8.24 (dd, J=7.8, 6.3 Hz, 2H),
8.85 (d, J=8.1 Hz, 2H), 9.17 (d, J=6.0 Hz, 2H), 9.39 (s, 2H) ppm;
.sup.13C NMR (75 MHz, CD.sub.3OD) .delta. 23.4, 27.1, 31.8, 32.2,
33.2, 33.7, 40.2, 57.6, 63.2, 68.9, 126.9, 129.6, 130.2, 139.8,
140.9, 145.8, 146.4 ppm.
Example 43
Synthesis of compound
1,2-bis-[5-(3-n-butyl-pyridinium)-pentyl]-benzene dibromide
##STR00045##
[0297] A mixture of 1,2-bis-(5-bromo-pentyl)-benzene (232 mg, 0.62
mmol) and 4-n-butylpyridine (0.5 mL) was heated at 60-70.degree. C.
for 12 hrs. The resulted mixture was washed with diethyl ether and
then dissolved in water (20 mL), the aqueous solution was extracted
with chloroform (20 mL.times.3). Water was removed by
lyophilization to afford 154 mg of the title compound. Yield: 39%.
.sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 0.98 (t, J=7.2 Hz, 6H),
1.30-1.87 (m, 16H), 2.09 (m, 4H), 2.64 (t, J=7.5 Hz, 4H), 2.92 (t,
J-7.2 Hz, 4H), 4.70 (t, J=6.6 Hz, 4H), 6.98-7.18 (m, 4H), 8.05 (dd,
J=8.1, 5.4 Hz, 2H), 8.49 (d, J=8.1 Hz, 2H), 9.95 (d, J=5.7 Hz, 2H),
10.08 (s, 2H) ppm; .sup.13C NMR (75 MHz, CD.sub.3OD) .delta. 14.4,
23.3, 27.2, 31.9, 32.6, 33.3, 33.4, 33.8, 62.8, 127.0, 128.9,
130.3, 140.9, 143.3, 145.2, 145.5, 146.5 ppm.
Example 44
Synthesis of compound
1,2-bis-[5-(3-bromo-pyridinium)-pentyl]-benzene dibromide
##STR00046##
[0299] A mixture of 1,2-bis-(5.about.bromo-pentyl)-benzene (235 mg,
0.72 mmol) and 3-bromopyridine (1 mL) was heated at 60-70.degree.
C. for 12 hrs. The resulted mixture was washed with diethyl ether
and then dissolved in water (15 mL), the aqueous solution was
extracted with diethyl ether (30 mL.times.3). Water was removed by
lyophilization to afford 410 mg of the title compound. Yield: 95%.
.sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 1.30-1.75 (m, 8H), 2.13
(m, 4H), 2.63 (t, J=7.5 Hz, 4H), 4.79 (t, J=7.5 Hz, 4H), 7.00-7.21
(m, 4H), 8.12 (dd, J-8.1, 6.0 Hz, 2H), 8.84 (d, J=7.8 Hz, 2H), 9.24
(d, J=5.7 Hz, 2H), 9.58 (s, 2H) ppm; .sup.13C NMR (75 MHz,
CD.sub.3OD) .delta. 27.2, 31.9, 32.5, 33.4, 63.2, 124.0, 127.0,
130.2, 140.9, 144.9, 147.1, 149.4 ppm.
Example 45
Synthesis of compound 1,2-bis[5-pyridinium-pentyl)-benzene
dibromide
##STR00047##
[0301] A mixture of 1,2-bis-(5-bromo-pentyl)-benzene (244 mg, 0.65
mmol) and pyridine (1 mL) was heated at 60-70.degree. C. for 12
hrs. The resulted mixture was washed with diethyl ether and then
dissolved in water (15 mL), the aqueous solution was extracted with
diethyl ether (30 mL.times.3). Water was removed by lyophilization
to afford 317 mg of the title compound. Yield: 92%. .sup.1HNMR (300
MHz, CD.sub.3OD) .delta. 1.48 (m, 4H), 1.65 (m, 4H), 2.10 (m, 4H),
2.63 (t, J-7.5 Hz, 4H), 4.74 (t, J=7.5 Hz, 4H), 7.02-7.20 (m, 4H),
8.16 (t, J=6.9 Hz, 4H), 8.64 (t, J=7.8 Hz, 2H), 9.13 (d, J=5.4 Hz,
4H) ppm; .sup.13C NMR (75 MHz, CD.sub.3OD) .delta. 27.1, 31.9,
32.5, 33.3, 62.9, 127.0, 129.4, 130.3, 140.9, 145.8, 146.7 ppm.
Example 46
Synthesis of compound
5-[3-(5-hydroxy-pent-1-ynyl)-phenyl]pent-4-yn-1-ol
##STR00048##
[0303] 1,3-Dibromobenzene (7.48 g, 31.71 mmol), 4-pentyn-1-ol (6.40
g, 76.10 mmol), and &M(triphenylphosphine)palladium(II)
dichloride (445 mg, 0.63 mmol) was stirred in triethylamine (150
mL) under nitrogen for 5 min. Copper(I) iodide (61 mg, 0.32 mmol)
was added and the mixture was stirred for 18 hrs at 75.degree. C.
The mixture was cooled to room temperature and filtered through a
celite pad, rinsed with ethylacetate. The combined filtrate was
evaporated to dryness under reduced pressure. The resulting residue
was purified by column chromatography (chloroform:methanol 20:1) to
afford 7.24 g of the title compound. Yield: 94%. .sup.1H NMR (300
MHz, CDCl.sub.3) .delta. 1.85 (m, 4H), 2.53 (t, J=6.9 Hz, 4H), 3.81
(t, J=6.0 Hz, 4H), 7.16-7.31 (m, 3H), 7.42 (t, J=1.2 Hz, 1H) ppm;
.sup.13C NMR (75 MHz, CDCl.sub.3) .delta. 16.2, 31.6, 61.9, 80.6,
90.0, 124.0, 128.3, 130.8, 134.7 ppm.
Example 47
Synthesis of compound 1,3-bis-(5-bromo-pent-1-ynyl)-benzene
##STR00049##
[0305] 5-[3-(5-Hydroxy-pent-1-ynyl)-phenyl]-pent-4-yn-1-ol (2.86 g,
11.80 mmol) and carbon tetrabromide (9.78 g, 29.50 mmol) were
dissolved in dry methylene chloride (30 mL) and cooled to 0.degree.
C. Triphenyl phosphine (8.13 g, 30.98 mmol) in methylene chloride
(20 mL) was added dropwise and the mixture was stirred for 1 h at
0.degree. C. The mixture was poured into hexanes (200 mL) and then
filtered through a short silica gel column, washed with
ethylacetate/hexanes (1/4). The combined organic solvents were
evaporated to dryness under reduced pressure. The resulting residue
was purified by column chromatography (hexanes:ethylacetate 30:1)
to afford 3.64 g of the title compound. Yield: 84%. .sup.1H NMR
(300 MHz, CDCl.sub.3) .delta. 2.13 (m, 4H), 2.60 (t, J=6.6 Hz, 4H),
3.58 (dt, J=6.6 Hz, 4H), 7.18-7.32 (m, 3H), 7.43 (t, J=1.5 Hz, 1H)
ppm; .sup.13C NMR (75 MHz, CDCl.sub.3) .delta. 18.4, 31.7, 32.7,
81.1, 88.7, 123.8, 128.4, 131.0, 134.8 ppm.
Example 48
Synthesis of compound
1,3-bis-[5-(2-methyl-pyridinium)-pent-1-ynyl]-benzene dibromide
##STR00050##
[0307] A mixture of 1,3-bis-(5-bromo-pent-1-ynyl)-benzene (368 mg,
1.00 mmol) and 2-picoline (1.5 mL) was heated at 60-70.degree. C.
for 12 hrs. The resulted mixture was washed with diethyl ether and
then dissolved in water (20 mL), the aqueous solution was extracted
with diethyl ether (30 mL.times.3). Water was removed by
lyophilization to afford 472 mg of the title compound. Yield: 84%.
.sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 2.29 (m, 4H), 2.69 (t,
J=6.6 Hz, 4H), 2.97 (s, 6H), 4.81 (t, J=7.5 Hz, 4H), 7.23-7.38 (m,
3H), 7.43 (d, J=1.5 Hz, 1H), 7.95 (t, J=6.9 Hz, 2H), 8.01 (d, J=7.8
Hz, 2H), 8.43 (dt, J=7.8, 1.5 Hz, 2H), 8.99 (dd, J=6.3, 1.5 Hz, 2H)
ppm; .sup.13C NMR (75 MHz, CD.sub.3OD) .delta. 17.4, 20.9, 29.9,
58.3, 82.1, 89.6, 124.7, 127.0, 129.8, 131.5, 132.2, 135.2, 146.5,
146.6, 156.8 ppm.
Example 49
Synthesis of compound
1,3-bis-[5-(3-methyl-pyridinium)-pent-1-ynyl]-benzene dibromide
##STR00051##
[0309] A mixture of 1,3-bis-(5-bromo-pent-1-ynyl)-benzene (348 mg,
0.94 mmol) and 3-picoline (1.5 mL) was heated at 60-70.degree. C.
for 12 hrs. The resulted mixture was washed with diethyl ether and
then dissolved in water (20 mL), the aqueous solution was extracted
with diethyl ether (30 mL.times.3). Water was removed by
lyophilization to afford 469 mg of the title compound. Yield: 90%.
.sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 2.35 (m, 4H), 2.56 (s,
6H) 2.63 (t, J=6.6 Hz, 4H), 4.80 (t, J=7.2 Hz, 4H), 7.22-7.33 (m,
3H), 7.37 (s, 1H), 8.00 (dd, J=8.1, 6.3 Hz, 2H), 8.39 (d, J=7.8 Hz,
2H), 8.91 (d, J-6.3 Hz, 2H), 9.00 (s, 2H) ppm; .sup.13C NMR (75
MHz, CD.sub.3OD) .delta. 17.3, 18.8, 31.0, 62.1, 82.1, 89.4, 124.7,
128.7, 129.7, 132.1, 135.4, 141.1, 143.3, 145.7, 147.4 ppm.
Example 50
Synthesis of compound
1,3-bis-[5-(4-methyl-pyridinium)-pent-1-ynyl]-benzene dibromide
##STR00052##
[0311] A mixture of 1,3-bis-(5-bromo-pent-1-ynyl)-benzene (350 mg,
0.94 mmol) and 4-picoline (1.5 mL) was heated at 60-70.degree. C.
for 12 hrs. The resulted mixture was washed with diethyl ether and
then dissolved in water (20 mL), the aqueous solution was extracted
with diethyl ether (30 mL.times.3). Water was removed by
lyophilization to afford 478 mg of the title compound. Yield: 92%.
.sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 2.33 (m, 4H), 2.58 (s,
6H), 2.63 (t, J=6.6 Hz, 4H), 4.77 (t, J=6.9 Hz, 4H), 7.28 (s, 4H),
7.93 (d, J=6.3 Hz, 4H), 8.90 (d, J=6.6 Hz, 4H) ppm; .sup.13C NMR
(75 MHz, CD.sub.3OD) .delta. 17.3, 22.3, 30.8, 61.4, 81.9, 89.5,
124.7, 129.9, 132.1, 135.2, 145.0, 161.2 ppm.
Example 51
Synthesis of compound
1,3-bis-[5-(2,4-dimethyl-pyridinium)-pent-1-ynyl]-benzene
dibromide
##STR00053##
[0313] A mixture of 1,3-bis-(5-bromo-pent-1-ynyl)-benzene (249 mg,
0.68 mmol) and 2,4-lutidine (1 mL) was heated at 60-70.degree. C.
for 12 hrs. The resulted mixture was washed with diethyl ether and
then dissolved in water (15 mL), the aqueous solution was extracted
with diethyl ether (30 mL.times.3). Water was removed by
lyophilization to afford 357 mg of the title compound. Yield: 91%.
.sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 2.29 (m, 4H), 2.51 (s,
3H), 2.73 (t, J=6.6 Hz, 4H), 2.94 (s, 3H), 4.79 (t, J=7.5 Hz, 4H),
7.33 (d, J=0.9 Hz, 4H), 7.78 (dd, J=6.6, 2.1 Hz, 2H), 7.85 (s, 2H),
8.89 (d, J=6.6 Hz, 2H) ppm; .sup.13C NMR (75 MHz, CD.sub.3OD)
.delta. 17.4, 20.6, 22.0, 29.9, 57.6, 82.0, 89.7, 124.8, 127.6,
129.9, 131.7, 132.1, 135.1, 145.6, 155.5, 160.5 ppm.
Example 52
Synthesis of compound
1,3-bis-[5-(3,4-dimethyl-pyridinium)-pent-1-ynyl]-benzene dibromide
[GZ 570 B]
##STR00054##
[0315] A mixture of 1,3-bis-(5-bromo-pent-1-ynyl)-benzene (253 mg,
0.69 mmol) and 3,4-lutidine (1 mL) was heated at 60-70.degree. C.
for 12 hrs. The resulted mixture was washed with diethyl ether and
then dissolved in water (15 mL), the aqueous solution was extracted
with diethyl ether (30 mL.times.3). Water was removed by
lyophilization to afford 261 mg of the title compound. Yield: 65%.
.sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 2.36 (s, 3H), 2.43 (s,
3H), 2.47 (m, 4H), 2.66 (t, J=6.6 Hz, 4H), 4.77 (t, J=6.9 Hz, 4H),
7.18-7.36 (m, 4H), 7.87 (d, J=6.3 Hz, 2H), 8.82 (d, J=6.3 Hz, 2H),
8.92 (s, 2H), ppm; .sup.13C NMR (75 MHz, CD.sub.3OD) .delta. 17.2,
17.4, 20.4, 30.8, 61.5, 81.9, 89.5, 124.9, 129.5, 129.8, 132.0,
135.3, 139.8, 142.9, 144.5, 160.0 ppm.
Example 53
Synthesis of compound
1,3-bis-[5-(3,5-dimethyl-pyridinium)-pent-1-ynyl]-benzene
dibromide
##STR00055##
[0317] A mixture of 1,3-bis-(5-bromo-pent-1-ynyl)-benzene (249 mg,
0.68 mmol) and 3,5-lutidine (1 mL) was heated at 60-70.degree. C.
for 12 hrs. The resulted mixture was washed with diethyl ether and
then dissolved in water (15 mL), the aqueous solution was extracted
with diethyl ether (30 mL*3). Water was removed by lyophilization
to afford 356 mg of the title compound. Yield: 90%. .sup.1HNMR (300
MHz, CD.sub.3OD) .delta. 2.35 (m, 4H), 2.51 (s, 6H), 2.64 (t, J=6.3
Hz, 4H), 4.75 (t, J=7.2 Hz, 4H), 7.28 (d, J=1.2 Hz, 3H), 7.33 (s,
1H), 8.19 (s, 2H), 8.82 (s, 4H) ppm; .sup.13C NMR (75 MHz,
CD.sub.3OD) .delta. 17.4, 18.7, 31.0, 61.8, 81.9, 89.7, 124.6,
129.7, 132.0, 135.2, 140.1, 142.8, 147.9 ppm.
Example 54
Synthesis of compound 1,3-bis-(5-quinolinium-pent-1-ynyl)-benzene
dibromide [GZ571A]
##STR00056##
[0319] A mixture of 1,3-bis-(5-bromo-pent-1-ynyl)-benzene (253 mg,
0.69 mmol) and quinoline (1 mL) was heated at 60-70.degree. C. for
12 hrs. The resulted mixture was washed with diethyl ether and then
dissolved in water (30 mL), the aqueous solution was extracted with
chloroform (20 mL.times.3). Water was removed by lyophilization to
afford 271 mg of the title compound. Yield: 63%. .sup.1H NMR (300
MHz, CD.sub.3OD) .delta. 2.45 (m, 4H), 2.73 (t, J=6.6 Hz, 4H), 5.31
(t, J=7.5 Hz, 4H), 7.14 (d, J-1.2 Hz, 1H), 7.20-7.30 (m, 3H),
8.02-8.17 (m, 4H), 8.31 (dt, J=7.2, 1.2 Hz, 2H), 8.41 (dd, J=8.4,
1.5 Hz, 2H), 8.67 (d, J=9.0 Hz, 2H), 9.17 (d, J=8.7 Hz, 2H), 9.54
(dd, J=5.7, 1.5 Hz, 2H) ppm; .sup.13C NMR (75 MHz, CD.sub.3OD)
.delta. 17.5, 29.6, 58.7, 81.8, 89.8, 119.7, 123.1, 124.4, 129.6,
131.2, 131.4, 131.9, 132.1, 135.0, 137.3, 139.1, 149.1, 150.6
ppm.
Example 55
Synthesis of compound
1,3-bis-(5-isoquinolinium-pent-1-ynyl)-benzene dibromide
##STR00057##
[0321] A mixture of 1,3-&.English
Pound.s-(5-bromo-pent-1-ynyl)-benzene (257 mg, 0.70 mmol) and
isoquinoline (1 mL) was heated at 60-70.degree. C. for 12 hrs. The
resulted mixture was washed with diethyl ether and then dissolved
in water (30 mL), the aqueous solution was extracted with
chloroform (20 mL.times.3). Water was removed by lyophilization to
afford 316 mg of the title compound. Yield: 72%. .sup.1H NMR (300
MHz, CD.sub.3OD) .delta. 2.47 (m, 4H), 2.74 (t, J=6.3 Hz, 4H), 5.01
(t, J=6.9 Hz, 4H), 6.54 (s, 1H), 6.85-7.03 (m, 3H), 8.01 (dt,
J=6.0, 1.5 Hz, 2H), 8.11-8.22 (m, 4H), 8.40-8.57 (m, 4H), 8.79 (dd,
J=6.9, 1.2 Hz, 2H), 10.15 (s, 2H) ppm; .sup.13C NMR (75 MHz,
CD.sub.3OD) .delta. 17.6, 30.6, 62.6, 82.0, 89.2, 124.4, 127.5,
128.4, 129.2, 129.3, 131.5, 131.7, 132.5, 134.7, 136.0, 138.4,
139.1, 151.5 ppm.
Example 56
Synthesis of compound
1,3-bis-[5-(2'-S-nicotinium-pent-1-ynyl)]benzene dibromide
##STR00058##
[0323] A mixture of 1,3-bis-(5-bromo-pent-1-ynyl)-benzene (244 mg,
0.66 mmol) and S-nicotine (1 mL) was heated at 60-70.degree. C. for
12 hrs. The resulted mixture was washed with diethyl ether and then
dissolved in water (20 mL), the aqueous solution was extracted with
chloroform (20 mL.times.3). Water was removed by lyophilization to
afford 388 mg of the title compound. Yield: 85%. .sup.1H NMR (300
MHz, CD.sub.3OD) .delta. 1.75-2.15 (m, 6H), 2.35 (s, 6H), 2.33-2.50
(m, 6H), 2.63 (t, J=6.6 Hz, 4H), 3.37 (m, 2H), 3.74 (m, 2H), 4.87
(t, J=6.9 Hz, 4H), 7.23-7.35 (m, 3H), 7.41 (s, 1H), 8.12 (dd,
J-8.1, 6.0 Hz, 2H), 8.61 (dd, J=7.8, 0.9 Hz, 2H), 9.03 (dd, J=6.0,
0.9 Hz, 2H), 9.18 (s, 2H) ppm; .sup.13C NMR (75 MHz, CD.sub.3OD)
.delta. 17.2, 23.9, 30.8, 35.5, 40.7, 57.8, 62.3, 68.5, 82.2, 89.3,
124.7, 129.4, 129.7, 132.2, 135.4, 144.9, 145.1, 145.4, 146.1
ppm.
Example 57
Synthesis of compound
1,3-bis-[5-(3-n-butyl-pyridinium)-pent-1-ynyl]-benzene
dibromide
##STR00059##
[0325] A mixture of 1,3-bis-(5-bromo-pent-1-ynyl)-benzene (242 mg,
0.66 mmol) and 4-n-butylpyridine (0.5 mL) was heated at
60-70.degree. C. for 12 hrs. The resulted mixture was washed with
diethyl ether and then dissolved in water (30 mL), the aqueous
solution was extracted with chloroform (20 mL.times.3). Water was
removed by lyophilization to afford 347 mg of the title compound.
Yield: 83%. .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 0.98 (t,
J=7.2 Hz, 6H), 0.95 (t, J=7.2 Hz, 6H), 1.40 (m, 4H), 1.67 (m, 4H),
2.39 (m, 4H), 2.67 (t, J=6.6 Hz, 4H), 2.88 (t, J=7.8 Hz, 4H), 4.90
(t, J=6.9 Hz, 4H), 7.29 (d, J=1.2 Hz, 3H), 7.33 (s, 1H), 8.07 (dd,
J=7.8, 6.0 Hz, 2H), 8.45 (d, J=8.1 Hz, 2H), 9.04 (d, J-6.3 Hz, 2H),
9.14 (s, 2H) ppm; .sup.13C NMR (75 MHz, CD.sub.3OD) .delta. 14.4,
17.3, 23.3, 31.0, 33.3, 33.6, 62.1, 82.1, 89.4, 124.7, 129.0,
129.7, 132.2, 135.4, 143.5, 145.4, 145.5, 146.8 ppm.
Example 58
Synthesis of compound
1,3-bis-[5-(3-phenyl-pyridinium)-pent-1-ynyl]-benzene dibromide
##STR00060##
[0327] A mixture of 1,3-bis-(5-bromo-pent-1-ynyl)-benzene (243 mg,
0.66 mmol) and 3-bromopyridine (0.5 mL) was heated at 60-70.degree.
C. for 12 hrs. The resulted mixture was washed with diethyl ether
and then dissolved in water (30 mL), the aqueous solution was
extracted with chloroform (20 mL.times.3). Water was removed by
lyophilization to afford 390 mg of the title compound. Yield: 87%.
.sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 2.41 (m, 4H), 2.70 (t,
J=6.6 Hz, 4H), 5.00 (t, J=6.9 Hz, 4H), 7.15 (d, ''J=1.2 Hz, 1H),
7.18 (m, 3H), 7.45-7.58 (m, 6H), 7.77-7.87 (m, 4H), 8.14 (dd,
J-8.1, 6.0 Hz, 2H), 8.74 (ddd, J=8.1, 1.5, 1.2 Hz, 2H), 9.13 (d,
J=6.0 Hz, 2H), 9.56 (s, 2H) ppm; .sup.13C NMR (75 MHz, CD.sub.3OD)
.delta. 17.4, 30.9, 62.4, 82.0, 89.5, 124.5, 128.6, 129.5, 129.6,
130.6, 131.4, 132.0, 134.1, 135.3, 142.1, 143.9, 144.0, 144.2
ppm.
Example 59
Synthesis of compound 1,3-bis-(5-pyridinium-pent-1-ynyl)-benzene
dibromide
##STR00061##
[0329] A mixture of 1,3-bis-(5-bromo-pent-1-ynyl)-benzene (240 mg,
0.65 mmol) and pyridine (1 mL) was heated at 60-70.degree. C. for
12 hrs. The resulted mixture was washed with diethyl ether and then
dissolved in water (15 mL), the aqueous solution was extracted with
diethyl ether (30 mL.times.3). Water was removed by lyophilization
to afford 322 mg of the title compound. Yield: 94%. .sup.1H NMR
(300 MHz, CD.sub.3OD) .delta. 2.40 (m, 4H), 2.68 (t, J=6.9 Hz, 4H),
4.94 (t, J=7.5 Hz, 4H), 7.32 (m, 3H), 7.39 (d, J=1.2 Hz, 1H), 8.19
(dd, J=7.8, 6.9 Hz, 4H), 8.63 (m, 2H), 9.23 (dd, J=7.2, 1.2 Hz, 4H)
ppm; .sup.13C NMR (75 MHz, CD.sub.3OD) .delta. 17.2, 31.0, 62.1,
82.1, 89.4, 124.6, 129.4, 129.7, 132.2, 135.3, 146.0, 146.9
ppm.
Example 60
Synthesis of compound
5-[3-(5-hydroxy-pentyl)-phenyl]-pentan-1-ol
##STR00062##
[0331] 5-[3-(5-Hydroxy-pent-1-ynyl)-phenyl]-pent-4-yn-1-ol (3.40 g,
14.03 mmol) was dissolved in methanol (60 mL) and 10% Pd/C (2.5%
w/w) was added. The resulting mixture was hydrogenated on a Parr
hydrogenation apparatus (45 psi) for 12 hrs. The catalyst was
removed by filtration through a Celite pad. The filter cake was
rinsed with methanol, and the combined organic liquors were
concentrated under reduced pressure. The crude product was purified
by column chromatography (chloroform:methanol 20:1) to afford 3.12
g of the title compound. Yield: 89%. .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 1.30-1.45 (m, 4H), 1.50-1.72 (m, 8H), 2.59 (t,
J=7.8 Hz, 4H), 3.62 (t, J=6.6 Hz, 4H), 6.99 (m, 3H), 7.18 (m, 1H)
ppm; .sup.13C NMR (75 MHz, CDCl.sub.3) .delta. 25.7, 31.5, 32.8,
36.1, 63.0, 125.8, 128.3, 128.7, 142.5 ppm.
Example 61
Synthesis of compound 1,3-bis-(5-bromo-pentyl)-benzene
##STR00063##
[0333] 5-[3-(5-Hydroxy-pentyl)-phenyl]-pentan-1-ol (2.26 g, 9.03
mmol) and carbon tetrabromide (7.49 g, 22.58 mmol) were dissolved
in dry methylene chloride (20 mL) and cooled to 0.degree. C.
Triphenyl phosphine (6.22 g, 23.70 mmol) in methylene chloride (15
mL) was added dropwise and the mixture was stirred for 1 h at
0.degree. C. The mixture was poured into hexanes (200 mL) and then
filtered through a short silica gel column, washed with
ethylacetate/hexanes (1/4). The combined organic solvents were
evaporated to dryness under reduced pressure. The resulting residue
was purified by column chromatography (hexanes:ethylacetate 30:1)
to afford 2.80 g of the title compound. Yield: 82%. .sup.1H NMR
(300 MHz, CDCl.sub.3) .delta. 1.46 (m, 4H), 1.61 (m, 4H), 1.88 (m,
4H), 2.59 (t, J=7.8 Hz, 4H), 3.40 (t, J=6.9 Hz, 4H), 7.00 (m, 3H),
7.19 (m, 1H) ppm; .sup.13C NMR (75 MHz, CDCl.sub.3) .delta. 28.1,
30.9, 32.9, 34.1, 36.0, 125.9, 128.3, 128.6, 142.4 ppm.
Example 62
Synthesis of compound
1,3-bis-[5-(2-methyl-pyridinium)-pentyl]benzene dibromide
##STR00064##
[0335] A mixture of 1,3-bis-(5-bromo-pentyl)-benzene (240 mg, 0.64
mmol) and 2-picoline (1 mL) was heated at 60-70.degree. C. for 12
hrs. The resulted mixture was washed with diethyl ether and then
dissolved in water (15 mL), the aqueous solution was extracted with
diethyl ether (30 mL.times.3). Water was removed by lyophilization
to afford 328 mg of the title compound. Yield: 91%. .sup.1HNMR (300
MHz, CD.sub.3OD) .delta. 1.54 (m, 4H), 1.73 (m, 4H), 2.02 (m, 4H),
2.63 (t, J=7.5 Hz, 4H), 2.95 (s, 6H), 4.67 (t, J-7.5 Hz, 4H),
6.98-7.22 (m, 4H), 7.97 (t, J=6.9 Hz, 2H), 8.07 (d, J=8.1 Hz, 2H),
8.49 (t, J=7.8 Hz, 2H), 9.05 (d, J=6.3 Hz, 2H) ppm; .sup.13C NMR
(75 MHz, CD.sub.3OD) .delta. 20.9, 26.9, 31:0, 32.0, 36.5, 59.2,
126.85, 126.88, 129.3, 129.6, 131.4, 143.3, 146.2, 146.3, 156.4
ppm.
Example 63
Synthesis of compound
1,3-bis-[5-(3-methyl-pyridinium)-pentyl]-benzene dibromide
##STR00065##
[0337] A mixture of 1,3-bis-(5-bromo-pentyl)-benzene (265 mg, 0.70
mmol) and 3-picoline (1 ml) was heated at 60-70.degree. C. for 12
hrs. The resulted mixture was washed with diethyl ether and then
dissolved in water (15 mL), the aqueous solution was extracted with
diethyl ether (30 mL.times.3). Water was removed by lyophilization
to afford 362 mg of the title compound. Yield: 91%. .sup.1H NMR
(300 MHz, CD.sub.3OD) .delta. 1.44 (m, 4H), 1.69 (m, 4H), 2.10 (m,
4H), 2.59 (t, J=7.8 Hz, 4H), 2.62 (s, 6H), 4.70 (t, J=7.5 Hz, 4H),
6.94-7.09 (m, 3H), 7.16 (t, J=1.5 Hz, 1H), 8.03 (dd, J=8.1, 6.0 Hz,
2H), 8.48 (d, J=8.1 Hz, 2H), 8.96 (d, J=6.0 Hz, 2H), 9.08 (s, 2H)
ppm; .sup.13C NMR (75 MHz, CD.sub.3OD) .delta. 18.9, 26.6, 31.9,
32.3, 36.5, 62.6, 126.9, 128.6, 129.3, 129.6, 140.9, 142.9, 143.3,
145.3, 147.1 ppm.
Example 64
Synthesis of compound
1,3-bis-[5-(4-methyl-pyridinium)-pentyl]-benzene dibromide
##STR00066##
[0339] A mixture of 1,3-bis-(5-bromo-pentyl)-benzene (240 mg, 0.64
mmol) and 4-picoline (1 mL) was heated at 60-70.degree. C. for 12
hrs. The resulted mixture was washed with diethyl ether and then
dissolved in water (15 mL), the aqueous solution was extracted with
diethyl ether (30 mL.times.3). Water was removed by lyophilization
to afford 332 mg of the title compound. Yield: 92%. .sup.1H NMR
(300 MHz, CD.sub.3OD) .delta. 1.42 (m, 4H), 1.67 (m, 4H), 2.06 (m,
4H), 2.59 (t, J-7.5 Hz, 4H), 2.69 (s, 6H), 4.66 (t, J=7.5 Hz, 4H),
6.95-7.08 (m, 3H), 7.16 (t, J=7.5 Hz, 1H), 7.97 (d, J=6.3 Hz, 4H),
8.94 {d, J=6.3 Hz, 4H) ppm; .sup.13C NMR (75 MHz, CD.sub.3OD)
.delta. 22.4, 26.6, 31.9, 32.2, 36.5, 61.9, 126.9, 129.3, 129.6,
129.8, 143.3, 144.7, 160.7 ppm.
Example 65
Synthesis of compound
1,3-bis-[5-(2,4-dimethyl-pyridinium)-pentyl]-benzene dibromide
##STR00067##
[0341] A mixture of 1,3-bis-(5-bromo-pentyl)-benzene (237 mg, 0.63
mmol) and 2,4-lutidine (1 mL) was heated at 60-70.degree. C. for 12
hrs. The resulted mixture was washed with diethyl ether and then
dissolved in water (15 mL), the aqueous solution was extracted with
diethyl ether (30 mL.times.3). Water was removed by lyophilization
to afford 323 mg of the title compound. Yield: 87%. .sup.1H NMR
(300 MHz, CD.sub.3OD) .delta. 1.51 (m, 4H), 1.71 (m, 4H), 1.99 (m,
4H), 2.62 (t, J=7.5 Hz, 4H), 2.64 (s, 6H), 2.87 (s, 6H), 4.58 (t,
J=7.5 Hz, 4H), 6.96-7.12 (m, 3H), 7.17 (t, J-7.5 Hz, 1H), 7.78 (dd,
J=6.6, 1.5 Hz, 2H), 7.89 (d, J=1.5 Hz, 2H), 8.82 (d, J=6.6 Hz, 2H)
ppm; .sup.13C NMR (75 MHz, CD.sub.3OD) .delta. 20.5, 22.1, 26.9,
31.1, 32.1, 36.6, 58.4, 126.9, 127.5, 129.3, 129.6, 131.6, 143.3,
145.3, 155.1, 160.1 ppm.
Example 66
Synthesis of compound
1,3-bis-[5-(3,4-dimethyl-pyridinium)-pentyl]-benzene dibromide [GZ
578 B]
##STR00068##
[0343] A mixture of 1,3-bis-(5-bromo-pentyl)-benzene (235 mg, 0.62
mmol) and 3,4-lutidine (1 mL) was heated at 60-70.degree. C. for 12
hrs. The resulted mixture was washed with diethyl ether and then
dissolved in water (15 mL), the aqueous solution was extracted with
diethyl ether (30 mL.times.3). Water was removed by lyophilization
to afford 350 mg of the title compound. Yield: 97%. .sup.1H NMR
(300 MHz, CD.sub.3OD) .delta. 1.44 (m, 4H), 1.68 (m, 4H), 2.09 (m,
4H), 2.51 (s, 6H), 2.59 (t, J=7.8 Hz, 4H), 2.60 (s, 6H), 4.65 (t,
J-7.5 Hz, 4H), 6.96-7.20 (m, 4H), 7.92 (d, J=6.3 Hz, 2H), 8.82 (d,
J=6.3 Hz, 2H), 8.96 (s, 2H) ppm; .sup.13C NMR (75 MHz, CD.sub.3OD)
.delta. 17.3, 20.7, 26.6, 31.9, 32.2, 36.5, 61.7, 126.8, 129.2,
129.3, 129.5, 139.6, 142.3, 143.2, 143.9, 159.4 ppm.
Example 67
Synthesis of compound
1,3-bis-[5-(3,5-dimethyl-pyridinium)-pentyl]-benzene dibromide
##STR00069##
[0345] A mixture of 1,3-bis-(5-bromo-pentyl)-benzene (246 mg, 0.65
mmol) and 3,5-lutidine (1 mL) was heated at 60-70.degree. C. for 12
hrs. The resulted mixture was washed with diethyl ether and then
dissolved in water (15 mL), the aqueous solution was extracted with
diethyl ether (30 mL.times.3). Water was removed by lyophilization
to afford 371 mg of the title compound. Yield: 96%. .sup.1H NMR
(300 MHz, CD.sub.3OD) .delta. 1.46 (m, 4H), 1.68 (m, 4H), 2.11 (m,
4H), 2.58 (s, 12H), 2.63 (t, J=6.6 Hz, 4H), 4.66 (t, J=7.5 Hz, 4H),
6.95-7.20 (m, 4H), 8.34 (s, 2H), 8.92 (s, 4H) ppm; .sup.13C NMR (75
MHz, CD.sub.3OD) .delta. 18.7, 26.7, 32.0, 32.4, 36.5, 62.3, 126.8,
129.2, 129.5, 140.0, 142.6, 143.3, 147.6 ppm.
Example 68
Synthesis of compound 1,3-bis-(5-quinolinium-pentyl)-benzene
dibromide
##STR00070##
[0347] A mixture of 1,3-bis-(5-bromo-pentyl)-benzene (253 mg, 0.67
mmol) and quinoline (1 mL) was heated at 60-70.degree. C. for 12
hrs. The resulted mixture was washed with diethyl ether and then
dissolved in water (30 mL), the aqueous solution was extracted with
chloroform (20 mL.times.3). Water was removed by lyophilization to
afford 383 mg of the title compound. Yield: 90%. .sup.1H NMR (300
MHz, CD.sub.3OD) .delta. 1.52 (m, 4H), 1.64 (m, 4H), 2.13 (m, 4H),
2.51 (t, J=7.5 Hz, 4H), 5.17 (t, J=7.5 Hz, 4H), 6.81-7.06 (m, 4H),
8.03 (t, J=7.8 Hz, 2H), 8.12 (dd, J=8.4, 6.0 Hz, 2H), 8.31 (dt,
J-6.0, 1.5 Hz, 2H), 8.45 (dd, J=8.4, 0.9 Hz, 2H), 8.61 (d, J=9.0
Hz, 2H), 9.27 (d, J=8.4 Hz, 2H), 9.59 (d, J=5.7 Hz, 2H) ppm;
.sup.13C NMR (75 MHz, CD.sub.3OD) .delta. 27.0, 30.9, 31.9, 36.4,
59.3, 119.8, 123.0, 126.8, 129.1, 129.4, 131.2, 131.3, 132.0,
137.2, 138.9, 143.1, 148.7, 150.2 ppm.
Example 69
Synthesis of compound 1,3-bis-(5-isoquinolinium-pentyl)-benzene
dibromide [GZ 579 B]
##STR00071##
[0349] A mixture of 1,3-bis-(5-bromo-pentyl)-benzene (278 mg, 0.74
mmol) and isoquinoline (1 mL) was heated at 60-70.degree. C. for 12
hrs. The resulted mixture was washed with diethyl ether and then
dissolved in water (30 mL), the aqueous solution was extracted with
chloroform (20 mL.times.3). Water was removed by lyophilization to
afford 391 mg of the title compound. Yield: 83%. .sup.1H NMR (300
MHz, CD.sub.3OD) .delta. 1.43 (m, 4H), 1.64 (m, 4H), 2.17 (m, 4H),
2.49 (t, J=7.5 Hz, 4H), 4.88 (t, J=7.5 Hz, 4H), 6.81-7.06 (m, 4H),
8.01 (t, J=7.8 Hz, 2H), 8.19 (t, J-7.5 Hz, 2H), 8.28 (d, J=8.4 Hz,
2H), 8.53 (t, J=6.9 Hz, 4H), 8.79 (dd, J=6.9, 0.9 Hz, 2H), 10.16
(s, 2H) ppm; .sup.13C NMR (75 MHz, CD.sub.3OD) .delta. 26.6, 31.8,
32.2, 36.3, 62.6, 126.7, 127.4, 128.3, 128.7, 129.1, 129.4, 131.4,
132.3, 135.7, 138.1, 138.5, 143.1, 150.4 ppm.
Example 70
Synthesis of compound
N,N'-[(1,1'-biphenyl)-4,4'-di-(3-propanyl)]-bis-[3-(2'-S-1-methyl-pyrroli-
din-2-yl)-pyridinium]dibromide
##STR00072##
[0351] 4,4'-Bis-(3-bromo-propyl)-biphenyl was added to a solution
of 5-nicotine (3 mmol) in acetonitrile and the solution refluxed
for 24 hours. The acetonitrile was removed in vacuum and the
resulting residue was partitioned between ether and water. The
aqueous layer was washed extensively with ether until no S-nicotine
left in the aqueous layer. The resulting aqueous solution of the
product was lyophilized to yield the pure product. (75%). .sup.1H
NMR (300 MHz, D.sub.2O, ppm), 9.10 (s, 2H), 9.01 (d, J=6.0, 2H),
8.52 (d, J=7.8, 2H), 8.05 (dd, 2H), 7.49 (d, J=8.1, 4H), 7.33 (d,
J=8.1, 4H), 4.79 (t, J=7.5, 4H), 3.53 (t, J=8.1, 2H), 3.23 (m, 2H),
2.83 (t, J=7.5, 4H), 2.30-2.45 (m, 6H), 2.20 (s, 6H), 1.85-1.97 (m,
4H). CNMR, 145.85, 144.42, 143.74, 143.54, 139.48, 138.65, 129.07,
128.23, 126.81, 67.32, 61.64, 56.83, 39.90, 35.21, 32.87, 31.99,
23.09.
Example 71
Synthesis of compound
N,N'-[(1,1'-biphenyl)-4,4'-di-(3-propanyl)]-bis-(3,5-dimethylpyridinium)d-
ibromide [ZZ 1 55 D]
##STR00073##
[0353] 4,4'-Bis-(3-bromo-propyl)-biphenyl was added to a solution
of 3,5-lutidine (3 mmol) in acetonitrile and the solution refluxed
for 24 hours. The acetonitrile was removed in vacuum and the
resulting residue was partitioned between ether and water. The
aqueous layer was washed extensively with ether until no
3,5-lutidine left in the aqueous layer. The resulting aqueous
solution of the product was lyophilized to yield the pure product.
(75%). .sup.1H NMR (300 MHZ, D.sub.2O, ppm), 8.79 (s, 4H), 8.15 (s,
2H), 7.46 (d, J=8.1, 4H), 7.31 (d, J=8.1, 4H), 4.66 (t, J=7.5, 4H),
2.81 (t, J=7.5, 2.46 (s, 12H), 2.34-2.39 (m, 4H). CNMR, 146.52,
141.58, 139.58, 139.00, 138.36, 129.05, 126.55, 61.28, 32.58,
32.05, 17.58.
Example 72
Synthesis of compound
N,N'-[(1,1'-biphenyl)-4,4'-di-(3-propanyl)]-bis-(3,4-dimethylpyridinium)d-
ibromide [ZZ 55 C]
##STR00074##
[0355] 4,4'-Bis-(3-bromo-propyl)-biphenyl was added to a solution
of 3,4-lutidine (3 mmol) in acetonitrile and the solution refluxed
for 24 hours. The acetonitrile was removed in vacuum and the
resulting residue was partitioned between ether and water. The
aqueous layer was washed extensively with ether until no
3,4-lutidine left in the aqueous layer. The resulting aqueous
solution of the product was lyophilized to yield the pure product.
(75%). .sup.1H NMR (300 MHz, D.sub.2O, ppm), 8.82 (s, 2H), 8.73 (d,
J=6.3, 2H), 7.78 (d, J=63, 2H), 7.47 (d, J=8.4, 4H), 7.29 (d,
J=8.4, 4H), 4.64 (t, J=7.2, 4H), 2.79 (t, J=7.2, 4H), 2.470 (s,
6H), 2.32-2.42 (m, 10H). CNMR, 158.42, 143.02, 141.37, 139.56,
138.50, 138.32, 129.04, 128.32, 126.56, 60.61, 32.56, 31.97, 19.44,
16.12.
Example 73
Synthesis of compound
N,N'-[(1,1'-biphenyl)-4,4'-di-(3-propanyl)]-bis-(2,4-dimethylpyridinium)d-
ibromide
##STR00075##
[0357] 4,4'-Bis-(3-bromo-propyl)-biphenyl was added to a solution
of 2,4-lutidine (3 mmol) in acetonitrile and the solution refluxed
for 24 hours. The acetonitrile was removed in vacuum and the
resulting residue was partitioned between ether and water. The
aqueous layer was washed extensively with ether until no
2,4-lutidine left in the aqueous layer. The resulting aqueous
solution of the product was lyophilized to yield the pure product.
(75%). .sup.1H NMR (300 MHZ, D.sub.2O, ppm), 8.83 (d, J=6.3, 2H),
7.79 (d, J=1.5, 2H), 7.68 (dd, J=7.8, J=1.5, 2H), 7.52 (d, J=8.4,
4H), 7.37 (d, J=8.4, 4H), 4.58 (t, J=7.5, 4H), 3.60 (t, J=7.2, 4H),
2.85 (t, J=7.2, 4H), 2.75 (s, 6H), 2.54 (s, 6H), 2.22-2.27 (m, 4H).
CNMR, 159.10, 154.11, 144.30, 139.67, 138.39, 130.59, 129.22,
126.70, 126.55, 56.89, 31.94, 31.73, 31.02, 19.51.
Example 74
Synthesis of compound
N,N'-[(1,1'-biphenyl)-4,4'-di-(3-propanyl)]-bis-[3-(3-hydroxy-propyl)-pyr-
idinium]dibromide [ZZ 55 G]
##STR00076##
[0359] 4,4'-Bis-(3-bromo-propyl)-biphenyl was added to a solution
of 3-(3-hydroxypropyl)-pyridine (3 mmol) in acetonitrile and the
solution refluxed for 24 hours. The acetonitrile was removed in
vacuum and the resulting residue was partitioned between ether and
water. The aqueous layer was washed extensively with ether until no
3-(3-Hydroxypropyl)-pyridine left in the aqueous layer. The
resulting aqueous solution of the product was lyophilized to yield
the pure product. (75%). .sup.1H NMR (300 MHz, D.sub.2O, ppm), 8.96
(s, 2H), 8.87 (d, J=6.0, 2H), 8.42 (d, J=7.8, 2H), 7.96 (dd, J=6.0,
J=7.8, 2H), 7.48 (d, J=8.1, 4H) .delta. 7.29 (d, J=8.1, 4H), 4.70
(t, J=7.5, 4H), 3.60 (t, J=6.3, 4H), 2.92 (t, J=6.3, 4H), 2.81 (t,
J=7.5, 4H), 2.41 (p, J=72, 4H), 1.87-1.95 (m, 4H). CNMR, 145.47,
144.22, 143.95, 142.22, 139.27, 138.77, 128.87, 127.75, 126.76,
61.55, 60.46, 32.94, 32.56, 31.96, 29.09.
Example 75
Synthesis of compound
N,N'-[(1,1'-biphenyl)-4,4'-di-(3-propanyl)]-bis-[5,6,7,8-tetrahydroquinol-
inium]dibromide
##STR00077##
[0361] 4,4'-Bis-(3-bromo-propyl)-biphenyl was added to a solution
of 5,6,7,8-tetrahydroquinoline (3 mmol) in acetonitrile and the
solution refluxed for 24 hours. The acetonitrile was removed in
vacuum and the resulting residue was partitioned between ether and
water. The aqueous layer was washed extensively with ether until no
5,6,7,8-tetrahydroquinoline left in the aqueous layer. The
resulting aqueous solution of the product was lyophilized to yield
the pure product. (75%). .sup.1H NMR (300 MHz, D.sub.2O, ppm), 8.79
(d, J=6.3, 2H), 8.19 (d, J=7.2, 2H), 7.77 (dd, J=6.3, J=7.8, 2H),
7.54 (d, J=7.8, 4H), 7.36 (d, J=7.8, 4H), 4.59 (t, J=7.8, 4H), 3.07
(t, J=6.3, 4H), 2.97 (t, J=6.0, 4H), 2.87 (t, J=7.5, 4H), 2.30 (p,
J=7.5, 4H), 1.93-1.99 (m, 4H), 1.81-1.87 (m, 4H). CNMR, 154.12,
145.55, 143.40, 139.94, 139.38, 138.83, 128.99, 126.66, 124.51,
56.85, 31.93, 31.52, 28.77, 26.88, 21.54, 20.63.
Example 76
Synthesis of compound
N,N'-[(1,1'-biphenyl)-4,4'-di-(3-propanyl)]-bis-[5,6,7,8-tetrahydroisoqui-
nolinium]dibromide
##STR00078##
[0363] 4,4'-Bis-(3-bromo-propyl)-biphenyl was added to a solution
of 5,6,7,8-tetrahydroisoquinoline (3 mmol) in acetonitrile and the
solution refluxed for 24 hours. The acetonitrile was removed in
vacuum and the resulting residue was partitioned between ether and
water. The aqueous layer was washed extensively with ether until no
5,6,7,8-tetrahydroisoquinoline left in the aqueous layer. The
resulting aqueous solution of the product was lyophilized to yield
the pure product. (75%). .sup.1H NMR (300 MHz, D.sub.2O, ppm), 8.67
(s, 2H), 8.60 (d, J=6.3, 2H), 7.68 (d, J=6.3, 2H), 7.48 (d, J=8.4,
4H), 7.29 (d, J=8.4, 4H), 4.59 (t, J=7.2, 4H), 2.94 (br, 4H), 2.86
(br, 4H), 2.81 (t, J=7.2, 4H), 2.39 (p, J-7.5, 4H), 1.74-1.85 (m,
10H), CNMR, 158.38, 143.86, 140.21, 139.39, 138.64, 138.48, 128.86,
127.91, 126.56, 60.78, 21.12, 32.00, 29.31, 26.22, 21.11.
Example 77
Synthesis of compound
N,N'-[(1,1'-biphenyl)-4,4'-di-(3-propanyl)]-bis-(4-methylpyridinium)dibro-
mide
##STR00079##
[0365] 4,4'-Bis-(3-bromo-propyl)-biphenyl was added to a solution
of 4-picoline (3 mmol) in acetonitrile and the solution refluxed
for 24 hours. The acetonitrile was removed in vacuum and the
resulting residue was partitioned between ether and water. The
aqueous layer was washed extensively with ether until no 4-picoline
left in the aqueous layer. The resulting aqueous solution of the
product was lyophilized to yield the pure product. (75%). .sup.1H
NMR (300 MHz, D.sub.2O, ppm), 8.90 (d, J=6.6, 4H), 7.85 (d, J=6.3,
4H), 7.48 (d, J=8.4, 4H), 7.32 (d, J=8.4, 4H), 4.68 (t, J=7.5, 4H),
2.78 (t, J=7.8, 2.58 (s, 6H), 2.34 (m, 4H). CNMR, 159.77, 143.71,
139.52, 138.51, 129.08, 128.73, 126.76, 60.72, 32.76, 31.91,
21.27.
Example 78
Synthesis of compound
N,N'-[(1,1'-biphenyl)-4,4'-di-(3-propanyl)]-bis-(3-methylpyridinium)dibro-
mide
##STR00080##
[0367] 4,4'-Bis-(3-bromo-propyl)-biphenyl was added to a solution
of 3-picoline (3 mmol) in acetonitrile and the solution refluxed
for 24 hours. The acetonitrile was removed in vacuum and the
resulting residue was partitioned between ether and water. The
aqueous layer was washed extensively with ether until no 3-picoline
left in the aqueous layer. The resulting aqueous solution of the
product was lyophilized to yield the pure product. (75%). .sup.1H
NMR (300 MHz, D.sub.2O, ppm), 9.00 (s, 2H), 8.92 (d, J=6.3, 2H),
8.35 (d, J=7.8, 2H), 7.93 (dd, J=6.0, J=8.1, 2H), 7.46 (d, J=8.4,
4H), 7.32 (d, J=8.4, 4H), 4.72 (t, J=7.5, 4H), 2.80 (t, J=7.5, 4H),
2.50 (s, 6H), 2.35-2.44 (m, 4H). CNMR, 146.06, 144.41, 141.92,
139.82, 139.55, 138.42, 129.11, 127.61, 126.70, 61.45, 32.76,
31.99, 17.80.
Example 79
Synthesis of compound
N,N'-[(1,1'-biphenyl)-4,4'-di-(3-propanyl)]-bis-(2-methylpyridinium)dibro-
mide
##STR00081##
[0369] 4,4'-Bis-(3-bromo-propyl)-biphenyl was added to a solution
of 2-picoline (3 mmol) in acetonitrile and the solution refluxed
for 24 hours. The acetonitrile was removed in vacuum and the
resulting residue was partitioned between ether and water. The
aqueous layer was washed extensively with ether until no 2-picoline
left in the aqueous layer. The resulting aqueous solution of the
product was lyophilized to yield the pure product. (75%). .sup.1H
NMR (300 MHz, D.sub.2O, ppm), 9.02 (d, J=6.3, 2H), 8.40 (dt, J=1.5,
J=7.8, 2H), 7.97 (d, J=7.8, 2H), 7.90 (t, J=6.3, 2H), 7.53 (d,
J=8.1, 4H), 7.38 (d, J=8.1, 4H), 4.65 (t, J=7.8, 4H), 2.86 (t,
J=7.8, 4H), 2.82 (s, 6H), 2.24-2.32 (m, 4H) CNMR, 155.49, 145.33,
145.23, 139.56, 138.54, 130.41, 129.21, 126.78, 125.89, 57.71,
31.93, 31.71, 19.75.
Example 80
Synthesis of compound
N,N'-{2,2'-[oxybis-(2,1-ethandiyloxy)]bis-ethyl}-bis-[3-(2'-S-1-methyl-py-
rrolidin-2-yl)-pyridinium]dichloride
##STR00082##
[0371] 1-Chloro-2-{2-[2-(2-chloro-ethoxy)-ethoxy]-ethoxy}-ethane
was added to a solution of S-nicotine (3 mmol) in acetonitrile and
the solution refluxed for 24 hours. The acetonitrile was removed in
vacuum and the resulting residue was partitioned between ether and
water. The aqueous layer was washed extensively with ether until no
S-nicotine left in the aqueous layer. The resulting aqueous
solution of the product was lyophilized to yield the pure product.
(75%). .sup.1H NMR (300 MHZ, D.sub.2O, ppm), 8.63-6.64 (m, 4H),
8.38 (d, J=8.1, 2H), 7.90 (dd, J=7.8, d=6.6, 2H), 2.61-2.63 (m,
4H), 3.85 (t, J=4.8, 4H), 3.36-3.47 (m, 10H), 3.04-3.04 (m, 2H),
2.20-2.38 (m, 4H), 2.04 (s, 6H), 1.60-1.84 6H).
Example 81
Synthesis of compound
N,N'-{2,2'-[oxybis-(2,1-ethandiyloxy)]bis-ethyl}-bis(2-methylpyridinium)d-
ichloride
##STR00083##
[0373] 1-Chloro-2-{2-[2-(2-chloro-ethoxy)-ethoxy]-ethoxy}-ethane
was added to a solution of 2-picoline (3 mmol) in acetonitrile and
the solution refluxed for 24 hours. The acetonitrile was removed in
vacuum and the resulting residue was partitioned between ether and
water. The aqueous layer was washed extensively with ether until no
2-picoline left in the aqueous layer. The resulting aqueous
solution of the product was lyophilized to yield the pure product.
(75%). .sup.1H NMR (300 MHz, D.sub.2O, ppm), 8.55 (dd, J=6.3,
J=1.2, 2H), 8.23 (dt, J=7.8, J-1.5, 2H), 7.75 (d, J=7.8, 2H), 7.68
(dt, J=7.8, J=1.5, 2H), 4.62 (t, 4H), 3.82 (t, 4H), 3.40-3.44 (m,
4H), 3.35-3.39 (m, 4H), 2.36 (s, 6H).
Example 82
Synthesis of compound
N,N'-{2,2'-[oxybis-(2,1-ethandiyloxy)]bis-ethyl}-bis(3-methylpyridinium)d-
ichloride
##STR00084##
[0375] 1-Chloro-2-{2-[2-(2-chloro-ethoxy)-ethoxy]-ethoxy}-ethane
was added to a solution of 3-picoline (3 mmol) in acetonitrile and
the solution refluxed for 24 hours. The acetonitrile was removed in
vacuum and the resulting residue was partitioned between ether and
water. The aqueous layer was washed extensively with ether until no
3-picoline left in the aqueous layer. The resulting aqueous
solution of the product was lyophilized to yield the pure product.
(75%). .sup.1H NMR (300 MHZ, D.sub.2O, ppm), 8.54 (s, 2H), 8.49 (d,
J=6.0, 8.22 (d, J=8.1, 2H), 8.76 (dd, J=8.1, J=6.0, 2H), 4.57 (t,
J=4.8, 4H), 3.84 (t, J=5.1, 4H), 3.43-3.48 (m, 4H), 3.35-3.39 (m,
4H), 2.69 (s, 6H). CNMR, 146.48, 144.22, 141.89, 139.81, 127.33,
69.93, 69.60, 68.95, 60.97, 17.89.
Example 83
Synthesis of compound
N,N'-{2,2'-[oxybis-(2,1-ethandiyloxy)]bis-ethyl}-bis(4-methylpyridinium)d-
ichloride
##STR00085##
[0377] 1-Chloro-2-{2-[2-(2-chloro-ethoxy)-ethoxy]-ethoxy}-ethane
was added to a solution of 4-picoline (3 mmol) in acetonitrile and
the solution refluxed for 24 hours. The acetonitrile was removed in
vacuum and the resulting residue was partitioned between ether and
water. The aqueous layer was washed extensively with ether until no
4-picoline left in the aqueous layer. The resulting aqueous
solution of the product was lyophilized to yield the pure product.
(75%). .sup.1H NMR (300 MHz, D.sub.2O, ppm), 8.47 (d, J=6.9, 4H),
7.70 (d, J=6.3, 4H), 4.54 (t, J=4.8, 4H), 3.83 (t, J=4.8, 4H),
3.43-3.47 (m, 4H), 3.35-3.38 (m, 4H), 2.47 (s, 6H). CNMR, 160.56,
143.63, 128.52, 69.92, 69.57, 68.95, 60.27, 21.58.
Example 84
Synthesis of compound
N,N'-{2,2'-[oxybis-(2,1-ethandiyloxy)]bis-ethyl}-bis(5,6,7,8-tetrahydroqu-
inolinium)dichloride
##STR00086##
[0379] 1-Chloro-2-{2-[2-(2-chloro-ethoxy)-ethoxy]-ethoxy}-ethane
was added to a solution of tetrahydroquinoline (3 mmol) in
acetonitrile and the solution refluxed for 24 hours. The
acetonitrile was removed in vacuum and the resulting residue was
partitioned between ether and water. The aqueous layer was washed
extensively with ether until no tetrahydroquinoline left in the
aqueous layer. The resulting aqueous solution of the product was
lyophilized to yield the pure product. (75%). .sup.1H NMR (300 MHZ,
D.sub.2O, ppm), 8.39 (d, J=6.3, 2H), 8.04 (d, J=8.1, 2H), 7.55 (dd,
J=8.1, J=6.3, 2H), 4.57 (t, J=4.5, 4H), 3.83 (t, J=4.5, 4H),
4.43-3.49 (m, 4H), 3.36-3.38 (m 4H), 2.98 (t, 6.3, 4H), 2.82 (t,
J=6.3, 4H), 1.79-1.83 (m, 4H), 1.63-1.69 (m, 4H). CNMR, 154.58,
145.92, 143.59, 139.99, 123.92, 70.19, 69.74, 68.40, 56.28, 49.10,
28.72, 27.26, 21.40, 20.45.
Example 85
Synthesis of compound
N,N'-{2,2'-[oxybis-(2,1-ethandiyloxy)]bis-ethyl}-bis(5,6,7,8-tetrahydrois-
oquinolinium)dichloride
##STR00087##
[0381] 1-Chloro-2-{2-[2-(2-chloro-ethoxy)-ethoxy]-ethoxy}-ethane
was added to a solution of tetrahydroisoquinoline (3 mmol) in
acetonitrile and the solution refluxed for 24 hours. The
acetonitrile was removed in vacuum and the resulting residue was
partitioned between ether and water. The aqueous layer was washed
extensively with ether until no tetrahydroisoquinoline left in the
aqueous layer. The resulting aqueous solution of the product was
lyophilized to yield the pure product. (75%). .sup.1H NMR (300 MHz,
D.sub.2O, ppm), 8.33 (s, 2H), 8.24 (d, J=6.3, 2H), 7.52 (d, J=6.3,
2H), 4.47 (t, J=4.8, 4H), 3.81 (t, J=4.8, 4H), 3.42-3.45 (m, 4H),
3.33-3.37 (m, 4H), 2.81-2.84 (br, 4H), 2.70-2.74 (br, 4H),
1.63-1.70 (m, 8H). CNMR, 159.33, 143.61, 140.12, 138.77, 127.74,
69.96, 69.60, 69.02, 60.12, 29.40, 26.18, 20.98, 20.95.
Example 86
Synthesis of compound
N,N'-{2,2'-[oxybis-(2,1-ethandiyloxy)]bis-ethyl}-bis-[3-(3-hydroxypropyl)-
-pyridinium]dichloride
##STR00088##
[0383] 1-Chloro-2-{2-[2-(2-chloro-ethoxy)-ethoxy]-ethoxy}-ethane
was added to a solution of 3-(3-hydroxypropyl)-pyridine (3 mmol) in
acetonitrile and the solution refluxed for 24 hours. The
acetonitrile was removed in vacuum and the resulting residue was
partitioned between ether and water. The aqueous layer was washed
extensively with ether until no 3-(3-hydroxypropyl)-pyridine left
in the aqueous layer. The resulting aqueous solution of the product
was lyophilized to yield the pure product. (75%). .sup.1H NMR (300
MHz, D.sub.2O, ppm), 8.59 (s, 2H), 8.53 (d, J=6.0, 8.29 (d, J=8.4,
2H), 7.81 (dd, J=8.4, J=6.0, 2H), 4.60 (t, J=4.8, 4H), 3.85 (t,
J=4.5, 4H), 3.44-3.49 (m, 8H), 3.36-3.39 (m, 4H), 2.76 (t, J=7.8,
4H), 1.74-1.80 (m, 4H). CNMR, 145.99, 144.09, 143.35, 142.35,
127.64, 69.96, 69.64, 68.96, 61.06, 60.60, 31.21, 28.81.
Example 87
Synthesis of compound
N,N'-{2,2'-[oxybis-(2,1-ethandiyloxy)]bis-ethyl}-bis-(3-hydroxymethylpyri-
dinium)dichloride
##STR00089##
[0385] 1-Chloro-2-{2-[2-(2-chloro-ethoxy)-ethoxy]-ethoxy}-ethane
was added to a solution of 3-hydroxymethylpyridine (3 mmol) in
acetonitrile and the solution refluxed for 24 hours. The
acetonitrile was removed in vacuum and the resulting residue was
partitioned between ether and water. The aqueous layer was washed
extensively with ether until no 3-hydroxymethylpyridine left in the
aqueous layer. The resulting aqueous solution of the product was
lyophilized to yield the pure product. (75%). .sup.1H NMR (300 MHZ,
D.sub.2O, ppm), 8.72 (s, 2H), 8.65 (d, J=6.0, 8.39 (d, J=7.8, 2H),
7.91 (t, J=6.9, 2H), 4.69 (t, J=4.8, 4H), 4.64 (s, 4H), 3.89 (t,
J=4.2, 4H), 3.41-3.49 (m, 8H).
Example 88
Synthesis of compound
N,N'-{2,2'-[oxybis-(2,1-ethandiyloxy)]bis-ethyl}-bis-(2,4-dimethylpyridin-
ium)dichloride
##STR00090##
[0387] 1-Chloro-2-{2-[2-(2-chloro-ethoxy)-ethoxy]-ethoxy}-ethane
was added to a solution of 2,4-dimethylpyridine (3 mmol) in
acetonitrile and the solution refluxed for 24 hours. The
acetonitrile was removed in vacuum and the resulting residue was
partitioned between ether and water. The aqueous layer was washed
extensively with ether until no 2,4-dimethylpyridine left in the
aqueous layer. The resulting aqueous solution of the product was
lyophilized to yield the pure product. (75%). .sup.1H NMR (300 MHZ,
D.sub.2O, ppm), 3.35 (d, J=6.6, 2H), 7.58 (s, 2H), 7.50 (d, J=6.6,
2H), 4.54 (t, J=4.8, 4H), 3.82 (t, J=4.8, 4H), 3.41-3.45 (m, 4H),
3.34-3.36 (m, 4H), 2.62 (s, 6H). 2.40 (s, 6H). CNMR, 159.76,
154.44, 144.47, 130.31, 126.00, 70.16, 69.66, 68.42, 56.36, 49.10,
21.27, 19.90.
Example 89
Synthesis of compound
N,N'-{2,2'-[oxybis-(2,1-ethandiyloxy)]bis-ethyl}-bis-(3,4-dimethylpyridin-
ium)dichloride
##STR00091##
[0389] 1-Chloro-2-{2-[2-(2-chloro-ethoxy)-ethoxy]-ethoxy}-ethane
was added to a solution of 3,4-dimethylpyridine (3 mmol) in
acetonitrile and the solution refluxed for 24 hours. The
acetonitrile was removed in vacuum and the resulting residue was
partitioned between ether and water. The aqueous layer was washed
extensively with ether until no 3,4-dimethylpyridine left in the
aqueous layer. The resulting aqueous solution of the product was
lyophilized to yield the pure product. (75%). .sup.1H NMR (300 MHZ,
D.sub.2O, ppm), 8.36 (s, 2H), 8.30 (d, J=6.3, 2H), 7.61 (d, J=6.3,
2H), 4.49 (t, J=4.8, 4H), 3.81 (t, J=4.8, 4H), 3.42-3.45 (m, 4H),
3.34-3.37 (m, 4H), 2.37 (s, 6H). 2.25 (s, 6H). CNMR, 159.23,
142.79, 141.27, 138.49, 128.06, 69.92, 69.58, 69.01, 60.08, 49.07,
19.75, 16.32.
Example 90
Synthesis of compound
N,N'-{2,2'-[oxybis-(2,1-ethandiyloxy)]bis-ethyl}-bis-(3,5-dimethylpyridin-
ium)dichloride
##STR00092##
[0391] 1-Chloro-2-{2-[2-(2-chloro-ethoxy)-ethoxy]-ethoxy}-ethane
was added to a solution of 3,5-dimethylpyridine (3 mmol) in
acetonitrile and the solution refluxed for 24 hours. The
acetonitrile was removed in vacuum and the resulting residue was
partitioned between ether and water. The aqueous layer was washed
extensively with ether until no 3,5-dimethylpyridine left in the
aqueous layer. The resulting aqueous solution of the product was
lyophilized to yield the pure product. (75%). .sup.1H NMR (300 MHz,
D.sub.2O, ppm), 8.34 (s, 4H), 8.06 (s, 2H), 4.52 (t, J=4.8, 4H),
3.83 (t, J=4.8, 4H), 3.42-3.46 (m, 4H), 3.35-3.38 (m, 4H), 2.31 (s,
12H). CNMR, 146.98, 141.42, 138.93, 69.95, 69.61, 69.01, 60.75,
49.08, 17.68.
Example 91
Synthesis of compound
N,N'-(5,7-dodecadiyn-1,12-diyl)-bis-(2-methylpyridinium)dichloride
##STR00093##
[0393] 1,12-Dibromo-dodeca-5,7-diyne was added to a solution of
2-picoline (3 mmol) in acetonitrile and the solution refluxed for
24 hours. The acetonitrile was removed in vacuum and the resulting
residue was partitioned between ether and water. The aqueous layer
was washed extensively with ether until no 2-picoline left in the
aqueous layer. The resulting aqueous solution of the product was
lyophilized to yield the pure product.
[0394] (75%). .sup.1H NMR (300 MHz, D.sub.2O, ppm), 8.58 (d, 2H),
8.18-8.24 (m, 2H), 7.65-7.74 (m 4H), 4.40 (t, 4H), 2.68 (s, 6H),
2.21 (t, 4H), 1.84-1.94 (m, 4H), 1.46-1.54 (m, 4H). CNMR, 155.29,
145.16, 144.78, 130.32, 125.75, 77.89, 65.52, 57.61, 28.78, 24.44,
18.19.
Example 92
Synthesis of compound
N,N'-(5,7-dodecadiyn-1,12-diyl)-bis-(3-methylpyridinium)dichloride
##STR00094##
[0396] 1,12-Dibromo-dodeca-5,7-diyne was added to a solution of
3-picoline (3 mmol) in acetonitrile and the solution refluxed for
24 hours. The acetonitrile was removed in vacuum and the resulting
residue was partitioned between ether and water. The aqueous layer
was washed extensively with ether until no 3-picoline left in the
aqueous layer. The resulting aqueous solution of the product was
lyophilized to yield the pure product.
[0397] (75%). .sup.1H NMR (300 MHz, D.sub.2O, ppm), 8.72 (s, 2H),
8.66 (d, 2H), 8.38 (d, 2H), 7.94 (dd, 2H). 4.59 (t, 4H), 2.58 (s,
6H), 2.32 (t, 4H), 2.28 (p, 4H), 1.59 (p, 4H). CNMR, 146.17,
143.83, 141.40, 140.11, 127.60, 77.95, 65.54, 61.35, 30.00, 24.36,
18.22, 18.00.
Example 93
Synthesis of compound
N,N'-(5,7-dodecadiyn-1,12-diyl)-bis-(4-methylpyridinium)dichloride
##STR00095##
[0399] 1,12-Dibromo-dodeca-5,7-diyne was added to a solution of
4-picoline (3 mmol) in acetonitrile and the solution refluxed for
24 hours. The acetonitrile was removed in vacuum and the resulting
residue was partitioned between ether and water. The aqueous layer
was washed extensively with ether until no 4-picoline left in the
aqueous layer. The resulting aqueous solution of the product was
lyophilized to yield the pure product.
[0400] (75%). .sup.1H NMR (300 MHz, D.sub.2O, ppm), 8.48 (d, 4H),
7.68 (d, 4H), 4.38 (t, 4H), 2.46 (s, 6H), 2.18 (t, 4H), 1.86-1.98
(m, 4H), 1.34-1.44 (m, 4H). CNMR, 160.12, 143.13, 128.77, 77.87,
65.47, 60.61, 29.86, 24.30, 21.56, 18.17.
Example 94
Synthesis of compound
N,N'-(5,7-dodecadiyn-1,12-diyl)-bis-(3,4-dimethylpyridinium)dichloride
##STR00096##
[0402] 1,12-Dibromo-dodeca-5,7-diyne was added to a solution of
3,4-Iutidine (3 mmol) in acetonitrile and the solution refluxed for
24 hours. The acetonitrile was removed in vacuum and the resulting
residue was partitioned between ether and water. The aqueous layer
was washed extensively with ether until no 3,4-lutidine left in the
aqueous layer. The resulting aqueous solution of the product was
lyophilized to yield the pure product.
[0403] (75%). .sup.1H NMR (300 MHz, D.sub.2O, ppm), 8.35 (s, 2H),
8.29 (d, 2H), 7.60 (d, 2H), 4.32 (t, 4H), 2.38 (s, 6H), 2.24 (s,
6H), 2.16 (t, 4H), 1.86-1.94 (m, 4H), 1.30-1.42 (m 4H).
Example 95
Synthesis of compound
N,N'(5,7-dodecadiyn-1,12-diyl)-bis-(3,5-dimethylpyridinium)dichloride
##STR00097##
[0405] 1,12-Dibromo-dodeca-5,7-diyne was added to a solution of
3,5-lutidine (3 mmol) in acetonitrile and the solution refluxed for
24 hours. The acetonitrile was removed in vacuum and the resulting
residue was partitioned between ether and water. The aqueous layer
was washed extensively with ether until no 3,5-lutidine left in the
aqueous layer. The resulting aqueous solution of the product was
lyophilized to yield the pure product.
[0406] (75%). .sup.1H NMR (300 MHz, D.sub.2O, ppm), 8.32 (s, 4H),
8.00 (s, 2H), 4.36 (t, 4H), 2.34 (s, 12H), 2.18 (t, 4H), 1.86-1.94
(m, 4H), 1.34-1.44 (m, 4H). CNMR, 146.62, 140.97, 139.15, 77.88,
65.41, 61.05, 29.88, 24.28, 18.14, 17.70.
Example 96
Synthesis of compound
N,N'-(5,7-dodecadiyn-1,12-diyl)-bis-(5,6,7,8-tetrahydroisoquinolinium)dic-
hloride
##STR00098##
[0408] 1,12-Dibromo-dodeca-5,7-diyne was added to a solution of
tetrahydroisoquinoline (3 mmol) in acetonitrile and the solution
refluxed for 24 hours. The acetonitrile was removed in vacuum and
the resulting residue was partitioned between ether and water. The
aqueous layer was washed extensively with ether until no
tetrahydroisoquinoline left in the aqueous layer. The resulting
aqueous solution of the product was lyophilized to yield the pure
product. (75%). .sup.1H NMR (300 MHZ, D.sub.2O, ppm), 8.34 (s, 2H),
8.22 {d, J=6.3, 2H), 7.54 (d, J=6.3, 2H), 4.31 (t, J=7.2, 4H),
2.82-2.84 (br, 4H), 2.71-2.73 (br, 4H), 2.12 (t, J=6.6, 4H),
1.81-1.91 (m, 4H), 1.64-1.69 (m, 8H), 1.29-1.38 (m, 4H). CNMR,
158.94, 143.15, 139.67, 139.05, 128.01, 77.81, 65.50, 60.46, 29.92,
29.41, 26.26, 24.38, 21.02, 21.05, 18.20.
Example 97
Synthesis of compound
N,N'-[(1,4-phenylene)-bis-(4-butynyl)]-bis-(3-methyl-pyridinium)dibromide
##STR00099##
[0410] 1,4-Bis-(4-bromo-but-1-ynyl)-benzene was added to a solution
of 3-picoline (3 mmol) in acetonitrile and the solution refluxed
for 24 hours. The acetonitrile was removed in vacuum and the
resulting residue was partitioned between ether and water. The
aqueous layer was washed extensively with ether until no 3-picoline
left in the aqueous layer. The resulting aqueous solution of the
product was lyophilized to yield the pure product. (75%). .sup.1H
NMR (300 MHz, D.sub.2O, ppm), 8.67 (s, 2H), 8.60 (d, J=6.0 Hz, 2H),
8.25 (d, J=8.0 Hz, 2H), 7.80 (dd, J=6.0 Hz, J=8.0 Hz, 2H), 7.14 (s,
4H), 4.63 (m, 4H), 3.02 (t, J=6.3 Hz, 4H), 2.36 (s, 6H). CNMR,
146.68, 144.11, 141.66, 139.87, 131.59, 127.39, 122.22, 86.10,
84.40, 59.68, 21.95, 17.90.
Example 98
Synthesis of compound
N,N'-[(1,4-phenylene)-bis-(4-butynyl)]-bis-(4-methyl-pyridinium)dibromide
##STR00100##
[0412] 1,4-Bis-(4-bromo-but-1-ynyl)-benzene was added to a solution
of 4-picoline (3 mmol) in acetonitrile and the solution refluxed
for 24 hours. The acetonitrile was removed in vacuum and the
resulting residue was partitioned between ether and water. The
aqueous layer was washed extensively with ether until no 4-picoline
left in the aqueous layer. The resulting aqueous solution of the
product was lyophilized to yield the pure product. (75%). .sup.1H
NMR (300 MHz, D.sub.2O, ppm), 8.60 (d, J=6.6 Hz, 4H), 7.73 (d,
J=6.6 Hz, 4H), 7.15 (s, 4H), 4.60 (t, J=6 Hz, 4H), 3.01 (t, J=6.0
Hz, 2.49 (s, 61-1). CNMR, 160.87, 143.41, 131.58, 128.57, 122.26,
86.16, 84.25, 59.03, 21.87, 21.68.
Example 99
Synthesis of compound
N,N'-[(1,4-phenylene)-bis-(4-butynyl)]-bis-(5,6,7,8-tetrahydroisoquiolini-
um)dibromide
##STR00101##
[0414] 1,4-Bis-(4-bromo-but-1-ynyl)-benzene was added to a solution
of tetrahydroisoquinoline (3 mmol) in acetonitrile and the solution
refluxed for 24 hours. The acetonitrile was removed in vacuum and
the resulting residue was partitioned between ether and water. The
aqueous layer was washed extensively with ether until no
tetrahydroisoquinoline left in the aqueous layer. The resulting
aqueous solution of the product was lyophilized to yield the pure
product. (75%). .sup.1H NMR (300 MHz, D.sub.2O, ppm), 8.46 (s, 2H),
8.35 (d, J=6.6 Hz, 2H), 7.56 (d, J=6.6 Hz, 2H), 7.09 (s, 4H), 4.54
(t, J=6.3 Hz, 4H), 2.98 (t, J=6.3 Hz, 4H), 2.83 (t, J=6.0 Hz, 4H),
2.66 (t, J=5.4 Hz, 4H), 1.64-1.68 (m, 8H).
Example 100
Synthesis of compound
N,N'-[(1,4-phenylene)-bis-(4-butynyl)]-bis-(3,4-dimethyl-pyridinium)dibro-
mide [ZZ-1-110]
##STR00102##
[0416] 1,4-Bis-(4-bromo-but-1-ynyl)-benzene was added to a solution
of 3,4-lutidine (3 mmol) in acetonitrile and the solution refluxed
for 24 hours. The acetonitrile was removed in vacuum and the
resulting residue was partitioned between ether and water. The
aqueous layer was washed extensively with ether until no
3,4-lutidine left in the aqueous layer. The resulting aqueous
solution of the product was lyophilized to yield the pure product.
(75%). .sup.1H NMR (300 MHZ, D.sub.2O, ppm), 8.50 (s, 2H), 8.44 (d,
J=6.3 Hz, 2H), 7.65 (d, J=6.3 Hz, 2H), 7.13 (s, 4H), 4.57 (t, J=6.3
Hz, 4H), 2.99 (t, J=6.3 Hz, 4H), 2.38 (s, 6H), 2.24 (s, 6H).
Example 101
Synthesis of compound
N,N'-[(1,4-phenylene)-bis-(4-butynyl)]-bis-(3,5-dimethylpyridinium)dibrom-
ide [ZZ 1 111]
##STR00103##
[0418] 1,4-Bis-(4-bromo-but-1-ynyl)-benzene was added to a solution
of 3,5-lutidine (3 mmol) in acetonitrile and the solution refluxed
for 24 hours. The acetonitrile was removed in vacuum and the
resulting residue was partitioned between ether and water. The
aqueous layer was washed extensively with ether until no
3,5-lutidine left in the aqueous layer. The resulting aqueous
solution of the product was lyophilized to yield the pure product.
(75%). .sup.1H NMR (300 MHZ, D.sub.2O, ppm), 8.46 (s, 4H), 8.04 (s,
2H), 7.11 (s, 4H), 4.59 (t, J=6.3 Hz, 4H), 2.99 (t, J=6.3 Hz, 4H),
2.29 (s, 12H). CNMR, 147.17, 141.31, 138.96, 131.59, 122.24, 86.31,
84.46, 59.45, 21.99, 17.73.
Example 102
Synthesis of compound
N,N'-[(1,1'-biphenyl)-4,4'-di-(1-propyn-3-yl)]-bis-(3-methylpyridinium)di-
bromide
##STR00104##
[0420] 4,4'-Bis-(3-bromo-prop-1-ynyl)-biphenyl (1 mmol) was added
to a solution of 3-picoline (3 mmol) in acetonitrile and the
solution refluxed for 24 hours. The acetonitrile was removed in
vacuum and the resulting residue was partitioned between ether and
water. The aqueous layer was washed extensively with ether until no
3-picoline left in the aqueous layer. The resulting aqueous
solution of the product was lyophilized to yield the pure product.
(75%). .sup.1H NMR (300 MHz, d.sub.6-DMSO, ppm), 9.16 (s, 2H), 9.12
(s, 2H), 8.54 (d, 2H), 8.22 (dd, 2H), 7.8 (d, 4H), 7.62 (d, 4H),
5.8 (s, 4H), 2.4 (s, 6H). CNMR, 147.52, 144.53, 142.46, 140.44,
139.73, 133.14, 128.36, 127.69, 120.85, 89.16, 82.81, 51.19,
18.79.
Example 103
Synthesis of compound
N,N'-[(1,1'-biphenyl)-4,4'-di-(1-propyn-3-yl)]-bis-(4-methylpyridinium)di-
bromide
##STR00105##
[0422] 4,4'-Bis-(3-bromo-prop-1-ynyl)-biphenyl (1 mmol) was added
to a solution of 4-picoline (3 mmol) in acetonitrile and the
solution refluxed for 24 hours. The acetonitrile was removed in
vacuum and the resulting residue was partitioned between ether and
water. The aqueous layer was washed extensively with ether until no
4-picoline left in the aqueous layer. The resulting aqueous
solution of the product was lyophilized to yield the pure product.
(75%). .sup.1H NMR (300 MHZ, d.sub.6-DMSO, ppm), 9.05 (d, 4H), 8.06
(d, 4H), 7.78 (d, 4H), 7.62 (d, 4H), 5.8 (s, 4H), 2.62 (s, 6H).
CNMR, 160.67, 144.10, 140.41, 133.11, 129.27, 127.69, 120.85,
89.06, 82.97, 50.56, 22.39.
Example 104
Synthesis of compound
N,N'-[(1,1'-biphenyl)-4,4'-di-(1-propyn-3-yl)]-bis-(3,4-dimethylpyridiniu-
m)dibromide [ZZ-1-61 C]
##STR00106##
[0424] 4,4'-Bis-(3-bromo-prop-1-ynyl)-biphenyl (1 mmol) was added
to a solution of 3,4-lutidine (3 mmol) in acetonitrile and the
solution refluxed for 24 hours. The acetonitrile was removed in
vacuum and the resulting residue was partitioned between ether and
water. The aqueous layer was washed extensively with ether until no
3,4-lutidine left in the aqueous layer. The resulting aqueous
solution of the product was lyophilized to yield the pure product.
(75%). .sup.1H NMR (300 MHz, d.sub.6-DMSO, ppm), 9.02 (s, 2H), 8.88
(d, 2H), 8.0 (d, 2H), 7.8 (d, 4H), 7.6 (d, 4H), 5.9 (s, 4H), 2.46
(s, 6H), 2.40 (s, 6H). CNMR, 159.64, 143.10, 141.96, 140.39,
138.65, 133.12, 128.88, 127.68, 120.88, 88.83, 83.08, 50.41, 20.66,
17.19.
[0425] It will be appreciated that, although specific embodiments
of the invention have been described herein for purposes of
illustration, various modifications may be made without departing
from the spirit and scope of the invention. All such modifications
and variations are intended to be included herein within the scope
of this disclosure and the present invention and protected by the
following claims.
Example 105
Persistent Inflammatory Pain Model
[0426] A rat model of tonic inflammatory pain (the formalin test)
was used in this study (Wheeler-Aceto and Cowan, 1991). Fifty ul of
formalin (5%) was injected subcutaneously (SC) into the dorsal
surface of the left hind paw. This procedure typically produces a
biphasic behavioral response consisting of flinching, lifting and
licking. The first phase (0-10 min) is thought to result from
direct stimulation of nociceptors (nociceptive pain) whereas the
second phase (20-60 min) is thought to involve central
sensitization resulting from continued activation of receptors
(TRPA1) with an important role in inflammatory pain. Rats were
pretreated 15 min prior to formalin (SC) injection with ZZ-16-1C as
synthesized in Example 104 and administered by the I.P. route.
Saline served as control. Incidences of formalin-induced flinching
were counted continuously in 5 min intervals for 60 min. Each rat
received only one treatment. The results are presented in FIGS. 1
and 2. FIG. 1 shows the time course of the effect of
intraperitoneal administration of varying doses of ZZ-16-1C in the
rodent model of tonic inflammatory pain. The drug produced a
decrease in the number of twitches in both phases of the formalin
test indicating it's a analgesic effect in this. The effect of the
drug remained significant even at 60 min. FIG. 2 shows the dose
response effect of ZZ-16-1C following intraperitoneal
administration in the rodent model of tonic inflammatory pain. The
effect of the drug was dose-related. Both phases of the formalin
test were affected, however, ZZ-6-1C was more effective in phase 2
than phase 1.
Example 106
Study of the Anti-Hyperalgesic Effects of ZZ-1-61C Following
Intraperitoneal Administration in a Rodent Model of
Chemotherapy-Induced Pain
[0427] A study was performed to screen the analgesic activity of
ZZ-1-61C following administration by the intraperitoneal (IP) route
in the rodent model of chemotherapy-induced pain. A well accepted
preclinical model of neuropathic pain that produced enhanced pain
sensitivity similar to that observed as a result of chemotherapy
administration in humans was employed (Polomano and Bennett, 2001).
Rats were injected (IP) with vincristine, a vinca alkaloid
anti-tumor agent, using two 5-day cycles (100 ug/kg/day). Rats
typically develop a neuropathic pain state with hypersensitivity to
pain as a result of nerve damage induced by the vincristine. The
ability of ZZ-1-61C to prevent chemotherapy-induced neuropathic
pain was determined as follows. Male rats (N=6) were given 100
ug/kg of ZZ-1-61C in combination with vincristine. The control
group (N=6) was given vincristine alone. Mechanical hyperalgesia
was assessed employing the paw pressure test (32 g/sec, 300 g
cut-off) as described by Randal and Selitto (1957) using a Basile
Analgesimeter (UGO Basile, Italy) with vocalization as an
end-point. The results are presented in FIG. 3. The ZZ-1-61C was
effective in blocking the development of chemotherapy-induced
neuropathic pain (anti-hyperalgesic effect) by the vincristine.
Example 107
Study of the Anti-Allodynic Effect of ZZ-1-61 C Following
Intraperitoneal Administration in a Rodent Model of
Chemotherapy-Induced Pain
[0428] A study was performed to screen the analgesic activity of
ZZ-1-61C following administration by the intraperitoneal (IP) route
in the rodent model of chemotherapy-induced pain. A well accepted
preclinical model of neuropathic pain that produced enhanced pain
sensitivity similar to that observed as a result of chemotherapy
administration in humans was employed (Polomano and Bennett, 2001).
Rats were injected (IP) with vincristine, a vinca alkaloid
anti-tumor agent, using two 5-day cycles (100 ug/kg/day). Rats
typically develop a neuropathic pain state with hypersensitivity to
pain as a result of nerve damage induced by the vincristine. The
ability of ZZ-1-61C to prevent chemotherapy-induced neuropathic
pain was determined as follows. Male rats (N=6) were injected with
vincristine as describe above. The rats were then given ZZ-1-61C at
a dose of 100 ug/kg following completion of the chemotherapy
regimen A second group of rats (N=6) was given vincristine alone.
The control group received saline. Rats were placed on an elevated
mesh floor and von Frey Filaments (Stoelting, Wood Dale, Ill.) with
bending forces of 4 g and 15 gm were applied to the plantar
surfaces of both hind paws. A positive response was regarded as a
sharp withdrawal of the paw. The results are presented in FIG. 4.
The ZZ-1-61C was effective in reducing the allodynia
(anti-allodynic effect) produced by vincristine.
Example 108
Study of the Effect of ZZ-1-61C on the Toxicity (Body Weight Loss)
of Vincristine in a Rodent Model of Chemotherapy-Induced Pain
[0429] A study was performed to assess the ability of ZZ-1-61C to
prevent loss of body weight typically induced by vincristine follow
administration in a rodent model of chemotherapy-induced pain. A
well accepted preclinical model of neuropathic pain that produced
enhanced pain sensitivity similar to that observed as a result of
chemotherapy administration in humans was employed (Polomano and
Bennett, 2001). Rats were injected (IP) with vincristine, a vinca
alkaloid anti-tumor agent, using two 5-day cycles (100 ug/kg/day).
Rats typically develop a neuropathic pain state with
hypersensitivity to pain as a result of nerve damage induced by the
vincristine accompanied by weight loss. The ability of ZZ-1-61C to
prevent chemotherapy-induced toxicity manifested as weight loss was
determined as follows. Male rats (N=6) were given 100 ug/kg of
ZZ-1-61C in combination with vincristine. The control group (N=6)
was given vincristine alone. Body weight was assessed on a daily
basis. The results are presented in FIG. 5. The ZZ-1-61C was able
to obtund the weight loss in the rats normally seen as a result of
vincristine administration in the chemotherapy-induced pain
model.
Example 109
Bis Analogs Ability to Block .alpha.9.alpha.10 nAChR
[0430] Bis analogs were tested for their ability to block
.alpha.9.alpha.10 nAChRs. Cloned nAChR subunits were heterologously
expressed in Xenopus oocytes, voltage-clamped and exposed to ACh
and compounds as previously described in Vincler, M. et al.,
Molecular mechanism for analgesia involving specific antagonism of
alpha9alpha10 nicotinic acetylcholine receptors, Proc Natl Acad Sci
USA 2006, 103: 17880-17884 and Cartier G E et al., A new
alpha-Conotoxin which targets alpha3best2Nicotinic Acetylcholine
Receptors, J. Biol. Chem. 1996, 271:7522-7528. Briefly, the oocyte
chamber consisting of a cylindrical well (.about.30 .mu.l in
volume) was gravity perfused at a rate of .about.2 ml/min with ND96
containing 0.01% (wt/vol) BSA. Oocytes were exposed once a minute
to 1 sec pulses of ACh. The ACh concentration was 10 .mu.M.
Compounds were applied at the beginning of a 5 min static bath
incubation. The % block was calculated as a % of ND96 control (no
compound) response.
[0431] Results are shown in Table I. SEM represents the standard
error of the mean. The results indicate that bis compounds
consisting of a variety of different structures are activity at
blocking .alpha.9.alpha.10 nAChRs, the therapeutic target.
TABLE-US-00001 TABLE I % Block Compound at 100 nM SEM GZ 585 B 68.9
8.6 GZ 582 B 72.0 3.9 GZ 581 B 68.7 5.8 GZ 584 B 28.0 6.9 GZ 581 A
32.4 16.9 GZ 584 A -24.4 10.2 GZ 578 B 37.3 7.7 GZ 570 B 23.1 11.9
GZ 571 A 58.4 6.7 GZ 579 B 62.5 6.6 ZZ 1 81 63.3 11.3 ZZ 1 82 2.9
9.9 ZZ 1 110 89.4 4.6 ZZ 1 111 23.8 8.3 ZZ 55 G 65.4 9.8 ZZ 55 C
10.7 10.8 ZZ 1 55 D -13.8 4.6 ZZ 161 C 91.9 6.1
##STR00107## ##STR00108## ##STR00109##
* * * * *