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Патент USA US3093552

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3,093,542
1
United States Patent 0, ice
7 Patented June 11, 1963
1
2
phenylenedimethylene) bis (3-formylpyridinium) halide
3,093,542
dioximes of the formula
BIS QUATERNARY OXIMES
Brennie E. Hackley, Jr., and Edward J. Poziomek, Edge
wood, and George M. Steinherg, Baltimore, Md., as
signors to the United States of America as represented
I CH=NOH
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. 151,127
(IVb)
This invention further relates to unsymmetrical bisqua
10
6 Claims. (Cl. 167-—65)
(Granted under Title 35, US. Code (1952), see. 266)
O H=N O H
ternary 4-tormylpyridiniu-m halide m-onoximes of the for
nm a
.
This invention described herein may be manufactured
and used by or ‘for the Government of the United States
of America for governmental purposes without the pay 15
ment to us of any royalty thereon.
CH=NOH
This is a division of application ‘Serial No. 809,578,
(V)
wherein R" represents either three ‘lower alkyl groups or
liled April 28, 1959, now Patent No. 3,077,476, xgranted
the hydrocarbon portion of the pyridine ring.
March 12, 1963.
This invention is directed to certain diquaternary pyri 20 This invention also relates to the 1,1’ trimethylene bis
(3-arnidooximopyridinium) ' halides
dinium halide oximes which are useful as chemothera
peutic and prophylactic agents for mammals poisoned by
anticholinesterases, particularly the “nerve gas” known
N+——
1 \
( o H93
as GB or sarin, i.e., isopropyl methylphosphono?uoridate.
The invention relates to 1,1’-polymethylene bis (4-for 25
N\+
([l=NOH
mylpyridinium) halide dioximes wherein the polymethyl
o=NoH
NH:
ene group contains from 2 to 6 carbon atoms. These
compounds have the structural formula
'
2X
NH:
(VI)
This invention also relates to the compounds
+
30
+
(02115) aN-(CH!) F'N
‘
2X
\ CH=NOH
(VII)
O H=N O H
This invention also relates to the compounds
(I)
where R is a poly-methylene group having from two to six
carbon atoms and X- is chloride, bromide or iodide.
This invention (further includes compounds of Formula
I, but in which R is a polymethylene group containing
from seven to ten carbon atoms.
N+
\
OH=NOH
40
This invention further includes 1,1'-(2,5-dimethyl-p
CH3
l
.
l
7
- C H-NQ
a
\
H3
2X
7
V
i
_
50
'
CH=NOH
CH=NOH
(VIII)
quite striking di?erences in effectiveness. In all the above
formulas, X- is chloride, bromide or iodide, which appear
45 to be equivalents as to physiological action, except tor
their e?ect on solubility.
Wilson et al., in Patent No. 2,816,113, granted Decem
ber 10, 1957, discloses a group of compounds which are
'dioximes of the formula
/N\1 CH:
‘
While ‘all these compounds are useful in varying degree
for the purposes set out above, the different groups exhibit
phenylenedimethylene) bis (4-formylpyridiniu-m) halide
-
+
(O n 93——N\
2X—
(II)
e?ective as antidotes for treatment of mammals poisoned
by compounds of high anticholinesterase activity, such
as the “nerve igases” diisopropylphosphoro?uoridate
('D‘FP), isopnopyl methylphosphono?uoridate (GB), and
O-ethyl, N,N dimethylphosphoroamidocyanidate (GA),
The invention also relates to l,l’—(2-butenylene) ‘bis
(44formylpyridinium) halide dioximes of the formula
vas well as other related organic phosphorus compounds,
55 includingmany. insecticides. The compound, of the Wil
son et al. group which has received by tar the most atten
tion is Z-formyl-l-methyl pyradinium iodide oxime, com
monly known ‘as Z-pyridine aldoxi-me methiodide or
Z-PAM. This compound is outstanding in its ability to
(III) 60 reactivate, in yitro, acetyl cholinesterase which has been
inhibited by, for example, GB. Thus, even as compared
to the very closely related 4-PAM, disclosed in Example
The invention further relates to 1,1’-polymetl1ylene his
(S-formylpyridinium) halide dioximes of the formula
11 of the Wilson patent, 2-PAM shows much {greater ac
65
CH=NOH
CH=NOH
(IVa)
tivity. With isopropyl methylphosphonylated acetylcho
linesterase the rate constant at pH 7.4 and 25° C. in the
presence of 10-3 M acetylcholine is 2><103 per'lmole per
minute tfor 2-PAM and 1.4)(102 per mole per minute for
4-PAM. The Wilson patent ‘shows a high rate of survival
wherein R is a polymethylene group containing from 2 to 70 in mice which had been poisoned with paraoxon and then
treated with 2-PAM.
.
»6 carbon atoms.
Another class of compounds included are the 1,1'-(p
Nerve gas poisoning has been treated symptomatically
3,093,542
4
with drugs which are pharmacologically antagonistic to
acetyl choline. Such a compound is atropine and it is at
present the recommended remedy. Recently, 2-PAM has
been reported to enhance considerably the activity of atro
pine in the chemotherapeusis of poisoning due to organo
To minimize absorption effects both the GB and
TM'B-4 were ordinarily given intravenously. However,
in the “therapeutic” tests on rabbits, dogs and cats, the
GB was administered subcutaneously, since death from
20 LD50 intravenous dose of GB occurs so quickly that
phosphorus compounds.
it is virtually impossible to give timely administration of
the antidote.
Atropine, when administered, was included in the fol
lowing amounts.
The compounds of Formula I above in which R con
tains from 2 to 6 carbon atoms are appreciably more
effective than 2-PA‘M as reactivators of GB-inhibited
acetylcholinesterase and also in enhancing the activity of 10
Mg./kg.
atropine in both therapy and prophylaxis. When X— is
Rabbits
2
bromide, the variation of the rate constant for the in vitro
reactivation of GB inhibited eel acetylcholinesterase at
Dogs and cats _______________________________ __ 0.5
pH 7.4 and 25° C. was found to be as follows:
The “prophylactic” doses were given within two minutes
15 prior to the injection of the GB, the “therapeutic" doses
TABLE 1
Rats
__________________ __. ________ .__. ________ __
4
as soon as poisoning symptoms were visible.
R
Table 3 shows the results.
Rate constant
(L/moles/minutes)
(CHM
(0112):.
(CH2)4
(CH2)5
(CH2)0
TABLE 3
20
7X10a
6X10a
6x103
1X1O4
6X10a
A. PROPHYLAOTIC
2-PAR
TMB-4
Survival ratio
When administered in combination with atropine to 25
Amalsni
out
atro
pine
pound in which R: (CH-93, i.e., 1,1'etrimethylene bis
(4-formylphyridinium) bromide dioxime also known as
TMB~4, was most effective. In rats challenged with a
2 LD50 dose of GB administered intravenously, all of a
group of six animals survived if the atropine-TM-B-4 com
_
mgjkg. With-
animals poisoned with GB the order of effectiveness was
somewhat different. Under these conditions the com
Survival ratio
Animals
Dose
Mice____
Dose
With
mgJkg. With
atro
With
out
pine
atro
pine
atro
pine
40
40
25
40
40
20
bination was administered intravenously immediately after
poisoning. The atropine-Z-PAM combination saved only 35
two of the group of animals. One lthe 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
treatments, which were given intravenously when symp
Dogs____
toms appeared. However, the recovery time was much 40 Dogs__..
shorter for the surviving animals which received the
The recovery periods, i.e., time for disappearance of
TMB-4, i.e., 2 hours, as against 24 hours for those receiv
symptoms of poisoning, among survivors in the above
ing the 2-PAM.
A summary of the reactivation rates and survival ratios
tests, with atropine, were as follows.
for these compounds when administered therapeutically
to rats together with atropine is as follows:
TABLE 2
R
TABLE 4
Animals
2-PAM
TM 13-4
Prophylactic Therapeutic Prophylactic Therapeutic
Reactivation Survival
rate constant ratio (GB) 50
Rats _______ __
(011m ____________________________________ __
7x103
e><10a
6x103
1x104
e/s
6/6
6/6
6/6
6x103
3/4
These compounds constitute our presently preferred
group.
Rabbits ____ _.
Cats
Done
The compounds of Formula I in which R contains from
7 to 10 carbon atoms are less effective than those of our
preferred group. For these compounds the reactivation
rate constant and the survival ratio for rats (measured as
Our compounds may be'employed prophylactically, i.e.,
injected before exposure to the anticholinesterase agent, 60 given above) were as follows, X- being bromide.
TABLE 5
e.g., GB, or therapeutically, i.e., injected subsequent to
exposure.
The following series of experiments compares the eifec
tiveness of our presently preferred compound, TMB-4,
with Z-PAM applied to various animals by these two
methods. The animals were poisoned by injections of
2X103
(CHaho .................................... -
Rabbits:
Intravenous _________ __ 70.340 mg./kg. (20 LD50).
Subcutaneous ________ -. 0.900 mg./kg. (20 LB“).
Dogs and cats:
Intravenous _________ __ 0.440 nag/kg. (20 LD50).
Subcutaneous ________ ... 0.900 mg./kg. (20 LDEO).
Survival
ratio (GB)
1. 2X103
GB as follows.
Mice ___________________ __ 0.173 mg./kg. (LD59).
Rats ___________________ __ 0.126 mg./kg. (2 LD50).
Rate
constant
1. 4X103
0/4
0/4
0/4
0/0
While these compounds were ineffective in vivo against
GB, they were, together with 2-PAM, very effective
against certain other anticholinestenases, particularly that
designated ‘as VX by the US. Army Chemical Corps.
All these compounds caused survival of all animals (sur
‘vival rates of 4/4 and 6/6), when administered thera
peutically to rats challenged by 2 LD50 doses of VX.
3,093,542
out by reacting the proper oxime with a 1, n dihaloal-hane
(CH2)nX2 employing a 3:1 molar ratio of oxime to
halide. The unsymmetrical quaternary monoximes were
obtained by reacting the pyridine oxime with the appro
priate omega-halopropyl quaternary salt in a 1.5:1 molar
ratio. 'Fwo procedures were utilized.
Procedure A: A mixture of the pyridine oxime and
halide was dissolved in su?icient ethanol and re?uxed for
the period of time speci?ed in Table9.
The compounds of Formula II exhibited properties
intermediate those of the two subgroups of Formula I.
When X- was chloride ‘the compound had the following
properties. (In this and tall following tables the survival
ratios are those for rats challenged by 2 LD50 doses of
GB or (VX) and the oxime was employed therapeuti
callly.)
"Compounds of Formula 111 showed reactivation rates
very close to those of our preferred group. Thus when
Procedure B: A mixture of the oxime and halide was
X- in Formula III is bromide the ‘reactivation rate con 10
dissolved in about :100 ml. of ethanol and heated in a
stant was 8X103 as compared to the value for the
200 ml. capped pressure bottle (carbonated beverage type)
R=(CH2)4 member of our preferred group of 6x103.
for the length of time speci?ed. The reaction mixtures
For the unsaturated member (Formula III) the survival
were cooled to room temperature and the product re
ratio for rats challenged by GB was only 1/4 as compared
to 6/6 for the saturated analogue (Formula I). Both 15 moved by ?ltration. In several instances it was necessary
to add absolute ether to effect complete precipitation.
gave complete survival (ratios of 4/4 and 16/ 6) for ani
The products were recrystallized from ether. This pro
cedure was usually employed because of its simplicity.
mals challenged by VX,_‘however.
Compounds of Formula IVa showed anomalous prop
erties.
Table 9 gives the procedure, yields and melting points
They gave reactivation rates which were low, but sur 20 for representative compounds.
vival ratios which were high as compared to 2-PAM, as
TABLE 9
shown by Table 6, X- being bromide.
TABLE 6
For-
Substituents
mula
25
R
(CHM ____________________________________ -(01195 ____________________________________ __
Halide
Reactivation Survival
rate constant ratio (GB)
3. 5X102
‘12x102
4/4
3/4
30
The compounds of group IVb, which are closely related
I ____ __
I ____ __
I ____ -_
I ____ __
-
Melting (m)
__
No.
I ____ __
Br
Br
B1‘
B!‘
Br
II_____
CI
R
Condi-
ticns
Yield
or decom
percent position (d)
R”
point, ° C.
8h
___________________ __ B, 68 hr__
35. 0
88. 2
81. 0
95.0
>300 111.
238-241 (1.
239-241 (1.
208-210 (1.
85.0
219-223 (1.
70
>300 m.
to those of IVa, were somewhat less e?ective. When X
Iva...
Br
(CH2);
_________ __
, 60
r__
68
208-211 In.
was bromide the compound had the following proper
ties: Reactivation rate constant 2x102, survival ratio
IVa___
Br
(@1195
_________ __
, 60 hr__
80
226-231 m.
1%.. -
B1‘
___________________ __
, 20 hr__
83.5
248-251 in.
V ____ __
V .... __
Br
Br
________ _-
(CzH5)a__
________ __
pyridine
B, 69 111:, 64 hr__
43
10
230-231 (1.
223-226 (1.
ring.
___________________ __ B, 90 hr__
16
201-203 d.
(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 2-PAM than the reactivation rate
VIII--. Br
Further details regarding the preparation and proper
ties of certain of our compounds are given in the follow
constants would suggest, as shown by the following table,
40
ing publications by us and our associates:
X- being bromide.
TABLE 7
“Pyridine Aldoximes,” by Edward J. Poziomek, Brennie
E. Hackley, Jr., and George M. Steinberg, “Journal of
Organic Chemistry,” vol. 23, pp. 714-717 (May 1958);
+
Reactivation Survival
R”EN—rate constant ratio (GB)
and “Chemotherapeutic Eifectiveness of Trimethylene
45
Bis (4-Formyl Pyrid-inium Bromide) Dioxime in Anti
cholinesterase Poisoning,” by Edmund Bay, S. Kropp and
L. F. Yates, Proceedings of the Society for Experimental
Biology and Medicine, vol. 98, pages 107-109 (May
+
N(
1.3><103
4/4
50
While we have shown a number of speci?c ‘examples
of compounds and their use, it will be obvious that various
changes can be made without departing from our inven
+
(OrHmN-
1. 2x103
1958). These articles are to be considered incorporated
by reference in this speci?cation.
4/4
The compounds of :Formulas VI, VII and VIII, while
tion, which is de?ned by the following claims.
being of different structure are alike in exhibiting reacti 55 We claim:
vation rate constants which are very low as compared to
1. A method of therapeutically treating a mammal
Z-PAM but giving high survival ratios as shown by Table
which has been poisoned by a compound having high
8, X- being bromide in each case.
anticholinesterase activity which comprises injecting a
composition consisting of atropine and a 1,1’ polymethyl
TABLE 8
60
ene bis(4-formyl pyridinium) oxide halide compound of
the formula
Formula No.
Reactivation
rate
Survival 1
ratio (GB)
VI ________________________________________ __
69
4/4
VII _______________________________________ _VIII ______________________________________ -_
Negligible
67
4/4
4/4
Preparation of Compounds
+
65
+
EN)“BT13 2X
CH=NOH
0 H=NOH
wherein R is a polymethylene group containing from two
4-pyridinecarboxaldehyde ox'ime was prepared by 70 to six carbon atoms and X'- is selected from the class con
warming on a steam bath a neutralized aqueous solution
of 4-pyridinecarboxaldehyde and hydroxylamine hydro
sisting of chloride, bromide and iodide.
2. A method of therapeutic-ally treating a mammal
which has been poisoned by a compound of high anti
cholinesterase activity, comprising injecting a composition
chloride. The oxime had a melting point of 130-130.5°
C. The 2- and 3-oximes were produced by similar
5 consisting of atropine and 1,1’-trimethylene bis (4-formy1
methods.
The qua-ternization to produce dioximes was carried
pyridinium) bromide dioxime.
3,093,542
7
8
3. A method of protecting 1a mammal against poison
ing by a compound of high anticholinesterase activity
comprising injecting, prior to said poisoning, Ia composi
tion consisting of atropine and {a 1,1’ polymethylene
1bis(4-formyl pyridinium) oxime halide compound of the
the formula
1'
N
O
R——N
2X
0 O
formula
wherein R is a polymethylene group containing from 7 to
10 carbon atoms and X~ is selected from the class con
10 sisting of chloride, bromide and iodide.
6. A method of therapeutically treating 1a mammal
CHrzNOH
which vhas been ‘poisoned by a compound having high
*anticholinesterase activity which compnises injecting a
composition consisting of atropine and a 1,1'-polymethyl
OH=NOH
15 ene bis-(3-formyl pyridinium) halide dioxime of the
wherein R is 1a polymethylene group containing from 2
to 6 carbon atoms and X- is selected from the class con
sisting of chloride, bromide ‘and iodide.
4. A method of protecting a mammal against poison
ing by a compound of high anticholinestepase activity, 20
comprising injecting a composition consisting of atropine
and 1,1’-trimethylene bis-(4-formylpyridinium) bromide
dioxime prior to said poisoning.
5. A method of thenapeutically treating a mammal
which has been poisoned by a compound having high
anticholinestemse activity which ‘comprises injecting a
composition consisting of atropine and a 1,1’-po1ymethy1
ene bis(4-formyl pyridinium) oxime halide compound of
formula
+
N\
i?
_
R--————N\ 2X
CH=NOH
CH=NOH
wherein R is a polymethylene group containing from 2
to 6 carbon atoms and X— is selected from the class
consisting of chloride, bromide and iodide.
References Cited in the ?le of this patent
Poziomek: Am. Chem. Soc. Abst. of Papers, 132nd
Meeting, 1957, pages 16-0.
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