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Патент USA US3093551

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United States Patent 0 "
3,093,541
Patented June 11, 1963
2
1
dioximes of the formula
3,093,541
BIS QUATERNARY OXIMES
‘
Brennie E. Hackley, Jr., and Edward J. Poziomek, Edge
wood, and George M. Steinberg, Baltimore, Md, as
i CH==NOH
‘ signors to the United States of America as represented
(IVb)
This invention further relates to unsymmetrical bis
quaternary 4-formylpyridinium halide monoximes of the
formula
by the Secretary of the Army
No Drawing. Original application Apr. 28, 1959, Ser.
No. 809,578, now Patent No. 3,077,476, dated Mar. 12,
1963. Divided and this application Oct. 11, 1961, Ser.
No. 151,126
1 Claim. (Cl. 167-65)
(Granted under Title 35, US. Code (1952.), sec. 266)
This invention described herein may be manufactured
0
and used by or for the Government of the United States
of America for governmental purposes without the pay 15
CH=NOH
ment to us of any royalty thereon.
(V)
wherein R" represents either three lower alkyl groups or
This is a division of application Serial No. 809,578,
?led April 28, 1959, now Patent No. 3,077,476, granted
March 12, 1963.
the hydrocarbon portion of the pyridine ring.
This invention also relates to the 1,1'-trimethylene bis
‘ This invention is directed to certain diquaternary 20
(3-amidooximopyridinium) halides
pyridinium halide oximes which are useful as chemo
therapeutic and prophylactic agents for mammals poisoned
by anticholinesterases, particularly the “nerve gas” known
as GB or sarin, i.e., isopropyl methylphosphono?uoridate.
The invention relates to 1,1'-polymethylene bis(4
formylpyridinium) halide dioximes wherein the poly
(VI)
This invention also relates to the compounds
methylene group contains from 2 to 6 carbon atoms;
These compounds have the structural formula
30
.(vn)
This invention also relates to the compounds
(I)
35
where R is a polymethylene group having from two to six
carbon atoms and Xi is chloride, bromide or iodide.
This invention further includes compounds of Formula
I, but in which R is a polymethylene group containing
CH=NOH
(VIII)
While
all
these
compounds
are
useful
in
varying
degree
40
This invention further includes 1,l'-(2,5-dimethyl-p
for the purposes set out above, the di?erent groups exhibit
phenylenedimethylene) bis (4-formylpridinium) halide
quite striking differences in effectiveness. In all the above
formulas X— is chloride, bromide or iodide, which appear
dioximes of the formula
to be equivalents as to physiological action, except for
from seven to ten carbon atoms.
their effect on solubility.
.
Wilson et -al., in Patent No. 2,816,113, granted Decem
ber 10, 1957, disclose a group of compounds which are ef
fective as antidotes for treatment of mammals poisoned
by compounds of high anticholinesterase activity, such
50 as
The invention also relates to 1,1'-(2-'butenylene) bis
(4-formylpyridinium) halide dioximes of the formula
the “nerve gases” diisopropylphosphoro?uoridate
(DFP), isopropyl methylphosphono?uoridate (GB), and
O-ethyl, N,N dimethyl phosphoroamidocyanidate (GA),
as well as other related organic phosphorus compounds,
including many insecticides. The compound of the Wilson
55 et al. group which has received by far the most attention
is 2-formyl-l-methyl pyridinium iodide oxime, commonly
known as Z-pyridine aldoXime methiodide or 2-PAM. This
compound is outstanding in its ability to reactivate, in
vitro, oholinesterase which has been inhibited by, for ex
60 ample, GB. Thus, even as compared to the very closely
The invention further relates to 1,1'-polymethylene bis
related 4-PAM, disclosed in Example ll of the Wilson pat
0 H=N O H
GH=N O E
(III)
(3-formylpyridinium) halide dioximes of the formula
4.
rent, 2-PAM ‘shows much greater activity. With isopropyl
methylphosphonylated acetylocholinesterase the rate con
stant at pH 7.4 and 25° C. in the presence of 10-3 M
65 a'cetylocholine is 2x103 per mole per minute for Z-PAM
and 1.4 X102 per mole per minute for 4-PA1M. The
Wilson patent shows a' high rate of survival in mice which
have been poisoned with paraoxon and then treated with
2-PAM.
wherein R is a polymethylene group containing from 2
Nerve gas poisoning has been treated symptomatically
70
to 6 carbon atoms.
with drugs which are pharamacologically antagonistic to
Another class of compounds included are the 1,1’-(p
acetyl choline. Such a compound is atropine and it is at
phenylenedimethylene) bis (3-formy1pridinium) halide
3,093,541
.3
4
a)
present the recommended remedy. Recently, 2-PAM has
been reported to enhance considerably the activity of
atropine in the chemotherapeusis of poisoning due to
organophosphorus compounds.
TMB-4 were ordinarily given intravenously. However,
in the “therapeutic” tests on rabbits, dogs and cats, the GB
was administered subcutaneously, since death vfrom 20
LD50 intravenous dose of GB occurs so quickly that it is
»
The compounds of Formula I above in which R contains
virtually impossible to give timely administration of. the
from 2 to 6 carbon atoms are appreciably more effective
antidote.
Atropine, when administered, was included in the fol
than 2-PAM as reactivators of GB-inhibited acetylcholin
esterase and also in enhancing the activity of atropine in
both therapy and propylaxis. When If is bromide, the
lowing amounts.
variation of the rate constant for the in vitro reactivation 10
of GB inhibited eel acetylcholinesterase at pH 7.4 and 25°
Rats ________________________________ -a ____ __
Rabbits
C. was found to be as follows:
2
_
0.5
The “prophylactic” doses were given within two minutes
prior
to the injection of the GB, the “therapeutic” doses
15
so soon as poisoning symptoms were visible.
Rate constant
Table 3 shows the results.
(l/molcs/minutes)
(cum
(cum
(OHM
(CHM
(cum
4
___________________________________ _ _
Dogs and cats
TABLE 1
R
Mgjkg.
TABLE 3
7><103
6x103
6x103
1x104
6x103
A. PROPHYLAOTIC
20
2—PA M
TM B-4
Survival ratio '
'
Survival ratio
When administered in combination with atropine to
Animals
Animals
animals poisoned with GB the order of effectiveness was 25
DoscDose,
nag/kg. With- With
rug/kg. With- With
somewhat diiferent. Under these conditions the com
pound in which R=\(CH2)3, i.e., 1,1’-trin1ethy1ene bis (4
TMB-4, was most effective.
atro-
out
atro
pine
atro-
pine
pine
In rats challenged with a
Miee_ _ _ _
2 LD50 dose of GB administered intravenously, all of a 30
group of six animals survived if the atropine-TMB-4 com
Rabbits
bina’tion was administered intravenously immediately after
poisoning. The atropine-2—PAM combination saved only
Dogs____
B. THERAPEUTIC
l\/Iice-_-_
treatments, which were given intravenously when symp~
toms appeared. However, the recovery time was much
shorter ‘for the surviving animals which received the
TMB-4, i.e., 2 hours, as against 24 hours for those receiv 40
ing the 2-PAM.
A summary of the reactivation rates and survival ratios
for these compounds when administered therapeutically
to rats together with atropine is as follows:
TABLE 2
______ ._
Rats____
Rabbits
Cats-___
Dogs____
1/6
2/6
5/5
4/5
Miee____
Rats____
Rabbits
Cats.___
D0gs____
The recovery periods, i.e., time for disappearance of
sypmtorns of poisoning, among survivors in the above tests,
with atropine, were as follows.
TABLE 4
45
2~PAM
Animals
Reactivation
Survival
rate constant ratio (GB)
_
Rats. _ __
Cats_ _ _ _
two of the group of animals. On the other hand, with
dogs which were given a 20 LD50 dose of GB subcutane
ously the survival ratios were the same (4/5) for the two
(011m ____ ._
out
atro-
pine
formylphyridinurn) bromide dioxime also known as
TMB-4
Prophylactic Therapeutic Prophylactic Therapeutic
7X103
6X103
6X10a
1x104
6x103
These compounds constitute our presently preferred 55
group.
our preferred group. For these compounds the reactiva
tion rate constant and the survival ratio vfor rats (meas
ured as given above) were as follows, X- being bromide.
Our compounds may be employed prophylactically, i.e.,
injected before exposure to the anticholinesterase agent,
e.g., GB, or therapeutically, i.e., injected subsequent to
exposure.
The following series of experiments compares the e?’ec—
tiveness of our presently preferred compound, TMB-4,
with 2-PAM applied to various animals by these two
methods. The animals were poisoned by injections of
GB as follows:
Mice ___________________ __ 0.173 mg./lcg. (LD5O).
Rats ___________________ __ 0.126 trig/kg. (2 LD5Q).
Rabbits:
Intravenous _________ __,_ 0.340 mg./kg. (20 LD50).
Subcutaneous ________ __ 0.900 mg./kg. (20 LD50).
Dogs and cats:
Intravenous __________ __ 0.440 mg/kg. (20 LB“).
Subcutaneous ________ __ 0.900 rug/‘kg. (20 LD50).
To minimize absorption effects both the GB and
The compounds of Formula I in which R contains
from 7 to 10 carbon atoms are less effective than those of
60
TABLE 5
R
Rate
Survival
ratio (GB)
2X10a
1. 2><10a
1. 4X103
0/4
0/4
0/4
0/6
While these compounds were ineffective in vivo against
GB, they were, together with 2-PAM, very e?ective
against certain other anticholinesterases, particularly that
designated as VX by the U.S. Army Chemical Corps.
All these compounds caused survival of all animals (sur~
vival rates of 4/ 4 and 6/6) when administered therapeuti
cally to rats challenged by 2 LD50 doses of VX.
3,093,541
6
ing on a steam bath a neutralized aqueous solution of
The compounds of Formula II exhibited properties
4-pyridinecarboxaldehyde and hydroxylamine hydrochlo
intermediate those of the two subgroups of Formula I.
When X- was chloride the compound had the following
ride. The oxime had a melting point of 130-1305“ C.
The 2- and 3-oximes were produced by similar methods.
The quaternization to produce dioximes was carried
properties. (In this and all following tables the survival
ratios are those for rats challenged by 2 L135“ doses of .
out by reacting the proper oxime with a 1, n dihaloalkane,
(CH2)nX2 employing a 3 :1 molar ratio of oxime to halide.
GB or (VX) and the oxime was employed therapeuti
cally.)
The unsymmetrical quaternary monoximes were obtained
Compounds of Formula III showed reactivation rates
by reacting the pyridine oxime with the appropriate
very close to those of our preferred group. Thus when
X'- in Formula III is bromide the reactivation rate con 10 omega-halopropyl quaternary salt in a 1.5:1 molar ratio.
Two procedures were utilized.
stant was 8><103 as compared to the value ‘for the
Procedure A: A mixture of the pyridine oxime and
R/=(CH2)4 member of our preferred group of 6x103.
halide was dissolved in sufficient ethanol and re?uxed for
For the unsaturated member (Formula III) the survival
the period of time speci?ed in Table 9.
ratio for rats challenged by GB was only 1/ 4 as compared
to 6/6 for the saturated analogue (Formula I). Both 15 Procedure B: A mixture of the oxime and halide was
dissolved in about 100 ml. of ethanol and heated in a 200
gave complete survival (ratios of 4/4 and 6/6) for animals
ml. capped pressure bottle (carbonated beverage type)
challenged by VX, however.
for the length of time speci?ed. The reaction mixtures
Compounds of Formula IVa showed anomalous
were cooled to room temperature and the product re
moved by ?ltration. In several instances it was necessary
20
They gave reactivation rates which were low, but sur
vival ratios which were high as compared to Z-PAM, as ' to add absolute ether to eifect complete precipitation. The
properties.
products were recrystallized from ether. This procedure
was usually employed because of its simplicity.
shown by Table 6, X- being bromide.
TABLE 6
Table 9 gives the procedure, yields and melting points
25
Reactivation Survival
rate constant ratio (GB)
(CH2): ------------------------------------ -
(CHM ------------------------------------ -
a. 5x101
4. 2x102
for representative compounds.
TABLE 9
4/4
3/4
For-
Substituents
- Melting (n1)
mula
30
The compounds of group IVb, which are closely related
to those of IVa, were somewhat less effective. When X"
was bromide the ‘compound had the following proper
ties: Reactivation rate constant 2x102, survival ratio
(GB)--2/4.
35
The compounds of group V were another group in
which the results of therapeutic treatment against GB
were better as compared to Z-PAM than the reactivation
rate constants would suggest, as shown by the following
table, X- being bromide.
TABLE 7
40
Gondi-
No.
tions
Halide
R
Yield
or decom
percent position (d)
R”
point, ° C.
I ____ _- Br
I ____ __ Br
I ____ __ Br
I ____ __ Br
I ____ __ Br
35. 0
88. 2
81.0
95. 0
85. 0
>300 m.
238-241 (I.
239-241 (I.
208-210 (1.
219-223 6.
II“... 01
IVa__
Br
IVai.
Br
___________________ __ B, as hr__
(011m _________ ._ B, 60 r__
(Slim _________ __ B, 60 hr__
70
68
80
1%... Br
___________________ __ B, 20 111:.
83.5
>300 m.
208-211 m.
226-231 m.
248-251 in.
V .... __ Br
V ____ ._ Br
________ _- (021393“
________ __ pyridine
B, 69 11LB, 64 11L-
43
10
230-231 (1.
223-226 (1.
VIII." Br
rmg.
___________________ __ B, 90 hr__
16
201-203 (1.
Further details regarding the preparation and properties
+
R"EN-—
Reactivation Survival
rate constant ratio (GB)
of certain of our compounds are given in the following
45 publications by us and our associates:
50
“Pyridine Alcloximes,” by Edward J. Poziomek, Bernnie
E. Hackley, Jr., and George M. Steinberg, “Journal of
Organic Chemistry,” vol. 23, pp. 714-717 (May 1958);
and “Chemotherapeutic Effectiveness of Trimethylene Bis
(4-Formy1 Pyridinium Bromide) Dioxime in Anticholin
esterase Poisoning,” by Edmund Bay, S. Kropp and L. F.
Yates, Proceedings of the Society for Experimental Biol
+
(0,115) iN1. 2x101
4/4
ogy and Medicine, vol. 98, pages 107-109 (May 1958).
These articles are to be considered incorporated by refer
The compounds of Formulas VI, VII and VIII, while 55 ence in this speci?cation.
being of di?erent structure are alike in exhibiting reactiva
While we have shown a number of speci?c examples of
tion rate constants which are very low as compared to
compounds and their use, it will be obvious that various
Z-PAM but giving high survival ratios as shown by Table
changes can be made without ‘departing from our inven
8, X- being bromide in each case.
tion, which is de?ned by the following claim.
60
TABLE 8
We claim:
A method of therapeutically treating a mammal which
has been poisoned by a compound having high anticho
Formula No.
Reactivation Survival
ratio (GB)
rate
linesterase activity which comprises injecting a composi
69
4/ 465
67
4/4
Negligible
4/4
tion comprising atropine and 1,1'-(2-butenylene) bis(4
formylpyridinium) halide dioxime.
' References Cited in the ?le of this patent
Preparation of Compounds
Poziomek: Am. Chem. Soc. Abst. of Papers, 132nd
4-pyridinecarboxaldehyde oxime was prepared by war-m 70 Meeting, 1957, pages 16-0.
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