US3135761A - Bis quaternary oximes - Google Patents
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- US3135761A US3135761A US151122A US15112261A US3135761A US 3135761 A US3135761 A US 3135761A US 151122 A US151122 A US 151122A US 15112261 A US15112261 A US 15112261A US 3135761 A US3135761 A US 3135761A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
- C07D213/53—Nitrogen atoms
Definitions
- This invention is directed to certain diquaternary pyridinium halide oximes which are useful as chemotherapeutic and prophylactic agents for mammals poisoned by anticholinesterases, particularly the nerve gas known as GB or sarin, i.e., isopropyl methylphosphonofluoridate.
- the invention relates to 1,1'-polymethylene bis (47 formylpyridinium) halide dioximes wherein the polymethylene group contains from 2 to 6 carbon atoms. These compounds have the structural formula N R N 2X- E;
- the invention further relates to 1,l-ploymethylene bis (3-formylpyridinium) halide dioximes of the formula wherein R is a polymethylene group containing from 2 to 6 carbon atoms
- R is a polymethylene group containing from 2 to 6 carbon atoms
- This invention also relates to the compounds (
- Wilson et al. in Patent No. 2,816,113, granted Dec. 10, 1957, disclose a group of compounds which are effective as antidotes for treatment of mammals poisoned by compounds of high anticholinesterase activity, suchfas the nerve gases diisopropylphosphorofluoridate (DFP), iso. propyl methylphosphonofiuoridate (GB), and O-ethyl, N,N-dimethyl phosphoroamidocyanidate (GA), as well as other related organic phosphorus compounds, including many insecticides.
- DFP diisopropylphosphorofluoridate
- GB propyl methylphosphonofiuoridate
- GA O-ethyl, N,N-dimethyl phosphoroamidocyanidate
- 2-formyl-1-methyl pyridinium iodide oxime commonly known as Z-pyridine aldoxime methiodide or Z-PAM.
- Z-PAM Z-pyridine aldoxime methiodide
- Nerve gas poisoning has been treated symptomatically with drugs which are pharmacologically antagonistic to acetyl choline. Such a compound is atropine and it is at present the recommended remedy.
- Z-PAM has been reported to enhance considerablyithe activity of atropine in the chemotherepeusis of poisoning due to organophosphoms compounds.
- mice 0.173mgg/kg.
- LD .Rats '0.'126 mg./kg. (2L-D 'RabbitsL 1 a s -intravenous 0340 mg./kg.v (201413 subcutaneous 0.900 mg./kg;(20LD;-, Dogs and Cats:' V f intravenous; 0.440'mg./kg.' (ZOLD were ordinarily given intravenously.
- the GB was administered subcutaneously, since death from 20 LD intravenous dose of GB occurs so quickly that it is virtually impossible to give timely administration of the antidote.
- Atropine when administered,was included in the fol lowing amounts.
- the prophylactic doses were given within two minutes prior to the injection of the GB, the therapeutic doses so soon as poisoning symptoms were visible.
- the compound When X was chloride the compound had the following Survival properties. (In this and all following tables the survival ratios are those for rats challenged by 2LD doses of GB or (VX) and the oxirne was employed therapeutically.)
- the unsymmetrical quaternary monoximes were obtained by reacting the pyridine oxime with the appropriate omega-halopropyl quaternary salt in a :1 molar ratio. Two procedures were utilized.
- Procedure B A mixture of the oxime and halide was dissolved in about 100 ml. of ethanol and heated in a 200 ml. capped pressure bottle (carbonated beverage type) for the length of time specified. The reaction mixtures were cooled to room temperature and the product removed by filtration. In several instances it was necessary to add absolute ether to eifect complete precipitation. The products were recrystallized from ether. This procedure was usually employed because of its simplicity.
- Table 9 gives the procedure, yields and melting points for representative compounds.
- the compounds of group V were another gr up in tg gg g ggggggggg gwhich the results of therapeutic treatment against GB ring, were better as compared to 2-PAM then the reactiva- B190 16 201%3 tion rate constants would suggest, as shown by the following table, X being bromide.
- a compound of the formula CH NOH wherein R" is selected from the group consisting of three lower alkyl groups and the hydrocarbon portion of the pyridine ring, and where X- is selected fiom the class consisting of chloride, bromide and iodide.
- a compound of the formula 3. A compound of the formula 34. A compound of thelformu la 5. A compound of the formula 6. A compound of the formula 7. A compound of the formula No rferences' cited.
Description
United States Patent 3,135,761 BIS QUATERNARY OXIMES Brennie E. Hackley, Jr., and Edward J. Poziomek, Edgewood, and George M. Steinberg, Baltimore, Md., assignors to the United States of America as represented by the Secretary of the Army No Drawing. Original application Apr. 28, 1959, Ser. No. 869,578, now iatent No. 3,077,476, dated Feb. 12, 1963. Divided and this application Oct. 11, 1961, Ser. No. 151,122
7 Claims. (Cl. 260-296) (Granted under Title 35, US. Code (1952), sec. 266) 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 payment to us of any royalty thereon.
This is a division of application Serial No. 809,578, filed April 28, 1959, now Patent No. 3,077,476, granted February 12, 1963.
This invention is directed to certain diquaternary pyridinium halide oximes which are useful as chemotherapeutic and prophylactic agents for mammals poisoned by anticholinesterases, particularly the nerve gas known as GB or sarin, i.e., isopropyl methylphosphonofluoridate.
The invention relates to 1,1'-polymethylene bis (47 formylpyridinium) halide dioximes wherein the polymethylene group contains from 2 to 6 carbon atoms. These compounds have the structural formula N R N 2X- E;
CH=NOH CH=NOH (I) The invention also relates to 1,1'-(2-butenylene) bis (4-formylpyridinium) halide dioximes of the formula CH=N OH CH=NOH (III) The invention further relates to 1,l-ploymethylene bis (3-formylpyridinium) halide dioximes of the formula wherein R is a polymethylene group containing from 2 to 6 carbon atoms Another class of compounds included are the l,1-(p- (IVa) Patented June 2, 1964 phenylenedimethylene) bis (3-formylpyridinium) halide dioximes of the formula CH=NOH (IVb) This invention furtherv relates to unsymmetrical bisquaternary 4-formylpyridinium halide monoximes of the formula (CHz)3 N\ 2X G=NOH C=NOH NH: NHa This invention also relates to the compounds (VII) The invention also relates to the compounds N:- 0 H2) a N: 2X- U @CH=N OH (V III) appear to be equivalents as to physiological action, eX-' cept for their effect on solubility.
Wilson et al., in Patent No. 2,816,113, granted Dec. 10, 1957, disclose a group of compounds which are effective as antidotes for treatment of mammals poisoned by compounds of high anticholinesterase activity, suchfas the nerve gases diisopropylphosphorofluoridate (DFP), iso. propyl methylphosphonofiuoridate (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 ct al. group which has received by far the most attention is 2-formyl-1-methyl pyridinium iodide oxime, commonly known as Z-pyridine aldoxime methiodide or Z-PAM. This compound is outstanding in its ability to reactivate, in vitro, acetyl cholinesterase which has been inhibited by, for example, GB. Thus, even as compared to the very closely related 4-PAM, disclosed in Example II of the Wilson patent, 2-PAM shows much greater activity. With isopropyl methylphosphonylated acetylcholinesterase the rate constant at pH 7.4 and 25 C. in the presence of 10 M acetylcholine is 2X10 per mole per minute for 2-PAM and 1.4 10 per mole per minute for 4-PAM. The Wilson patent shows a high rate of survival in mice which had been poisoned with paraoxon and then treated with Z-PAM. I
Nerve gas poisoning has been treated symptomatically with drugs which are pharmacologically antagonistic to acetyl choline. Such a compound is atropine and it is at present the recommended remedy. Recently, Z-PAM has been reported to enhance considerablyithe activity of atropine in the chemotherepeusis of poisoning due to organophosphoms compounds.
The compounds 'of Formula I above in which R contains from 2 to 6 carbon atoms are appreciably more effective than Z-PAM as reactivators of GB-inhibited acetylcholinesterase and also in enhancing the activity of atropine 'in both therapy and propylaxis. When X- is bromide,
the variation of the rate constant for the in vitro reactivation of ,GB inhibited eel acetylcholinsterase at pH 7.4 and 25 C. was found to be 'asfollowsz When. administered in combination with atropine to animals poisoned with GE the order of'efiectiveness was somewhat different. Under these conditions the compound in which R: (CH i.e., l,'1'-trimethy1ene bis (4- formylphyridinum) bromide dioxime also known as TMB- 4, was most effective. In rats challenged with a 2LD dose of GB administered intravenously, all ofa group of six animals survived if the atropine-TMB-4 combination was administered intravenously immediately after poisoning. The atropine-2-PAM combination saved only two of TABLE I 1 Rateconstant R (l./moles/minutes) (CH 7 10 .(C glg 6X (CH ..V 6 10 (CH2)5 L. (CH 6 10 the group of animals. Gn the other hand, with dogs which were given a ZOLD dose of GB subcutaneously the survival ratios were the same (4/5 for the two treatments, wln'ch were given intravenously when symptomsappeared. However, the recovery time was much shorter for the surviving animals which received theTMB-4, i.e., 2 hours, as against 24 hours for those receiving the Z-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 I I React iva- Survival R tion rate 1 ratio constant' 7 (GB) 1x10 s/e 6X10 -6/6 6X10 616 1x10 6/6 7 6X10 3/4 These compounds constitute our presently preferred Our compounds may bejemployed.prophylactically; i;e., injected before exposure to the anticholinesterase agent, e.g., GB, or therapeutically, i.e., injected subsequent to exposure. 'j:
7 The following series of experimentscompares the effectivenessof ourpresently preferred compound, TMB-4,
with Z-PAM applied'to various animals by these two To minimize absorption efi' ects both the GB and TMB-4 methods. The animals were poisoned by injections of GBasfolloWs: f l
Mice; 0.173mgg/kg. (LD .Rats '0.'126 mg./kg. (2L-D 'RabbitsL 1 a s -intravenous 0340 mg./kg.v (201413 subcutaneous 0.900 mg./kg;(20LD;-, Dogs and Cats:' V f intravenous; 0.440'mg./kg.' (ZOLD were ordinarily given intravenously. However, in the therapeutic tests on rabbits, dogs and cats, the GB was administered subcutaneously, since death from 20 LD intravenous dose of GB occurs so quickly that it is virtually impossible to give timely administration of the antidote.
Atropine, when administered,was included in the fol lowing amounts.
V Mg./k Rats v Rabbits 2 Dogs and Cats n 0.5
The prophylactic doses were given within two minutes prior to the injection of the GB, the therapeutic doses so soon as poisoning symptoms were visible.
Table 3 shows the results.
TABLE '3 A. PnoPnYLATIo The recovery periods, i.e., timefor disappearance of symptoms of poisoning, among survivors in the above tests, with atropine, were as follows.
TABLE 4 2-PAM TMB-4 Animals Prophy- Thera- Prophy- Theralactic peutic lactic peutic Rats 15 min. Rabbits 3 hr 30 min 2 hr. Oats hr 5 hr 24 hr. Dogs 24 hr 1% hr 3 hr.
The compounds of Formula I in whichR contains from 7 to 10 carbon atoms are less eifective than those'of our preferred group. For these compounds the reactivation rate constant and the survival ratio forrats (measured as given above) were as follows, X being bromide.
TABLE ,5
Rate constant ratio (GB) While these compounds were ineffective in vivo against GB, they were, together with 2-PAM,-very effective against certain other anticholineste'rases, particularly that. designated as VX by the US. Army Chemical Corps. "All 7 these compounds caused survivalof allanimals (survivaltherapeutically rates of 4/4 and 6/6), when administered to rats challenged by2LD doses of VX.
The compounds of Formula IIexhibite d properties intermediate those-ofthe two subgroups of -FormulaI. 7
When X was chloride the compound had the following Survival properties. (In this and all following tables the survival ratios are those for rats challenged by 2LD doses of GB or (VX) and the oxirne was employed therapeutically.)
Compounds of Formula 111 showed reactivation rates very close to those of our preferred group. Thus when X' in Formula III is bromide the reactivation rate constant was 8X10 as compared to the value for the R=(CH member of our preferred group of 6x10 For the unsaturated member (Formula III) the survival ratio for rats challenged by GB was only A as compared to 6/6 for the saturated analogue (Formula I). Both gave complete survival (ratios of 4/4 and 6/ 6) for animals challenged by VX, however.
Compounds of Formula lVa showed anomalous properties.
They gave reactivation rates which were low, but survival ratios which were high as compared to Z-PAM, as shown by Table 6, X" being bromide.
halide. The unsymmetrical quaternary monoximes were obtained by reacting the pyridine oxime with the appropriate omega-halopropyl quaternary salt in a :1 molar ratio. Two procedures were utilized.
Procedure A.-A mixture of the pyridine oxime and halide was dissolved in sufiicient ethanol and refluxed for the period of time specified in Table 9.
Procedure B.-A mixture of the oxime and halide was dissolved in about 100 ml. of ethanol and heated in a 200 ml. capped pressure bottle (carbonated beverage type) for the length of time specified. The reaction mixtures were cooled to room temperature and the product removed by filtration. In several instances it was necessary to add absolute ether to eifect complete precipitation. The products were recrystallized from ether. This procedure was usually employed because of its simplicity.
Table 9 gives the procedure, yields and melting points for representative compounds.
TABLE 9 TABLE 6 F ul Substituents C (11 Yield (Milt-nag OIHl a. 011 er- I11 0! (3- R-eacmva' sqrvwal No. tions gent composi- R tion rate ratio (GB) Halide R R tion (a) constant point 00 orm um 3.5x10 4/4 (CHM 41x10? 3/4 i:::::::: 331% area. gr 31 .0 233341 3. r 20 210 The compounds of group IVb, wh1ch are closely related I Br 8 219423 to those of Na, were somewhat less effective. When X was bromide the compound had the following prop- 11 70 IVa Br (0112);--- B,6'Jhr- 68 20s-211m. erties. Reactivation Rate Constant 2x10 su al R o (013mm By 60 hr 80 226431 In. (GB)-2/4. B, 20 111;. 83.5 248-2511'11.
The compounds of group V were another gr up in tg gg g ggggggggg gwhich the results of therapeutic treatment against GB ring, were better as compared to 2-PAM then the reactiva- B190 16 201%3 tion rate constants would suggest, as shown by the following table, X being bromide.
TABLE 7 Reactiva- Survival REN+- tion rate ratio (GB) constant (CzH5)3N+ 1. 2X10 4/4 The compounds of Formulas VI, VII and VIII, while being of different structure are alike in exhibiting reactivation rate constants which are very low as compared to Z-PAM but giving high survival ratios as shown by Table 8, X" being bromide in each case.
TABLE 8 Formula No. Reactiva- Survival tion rate ratio (GB) VI 69 4/4 VII Negligible- 4/4 4/4 Preparation 0 Compounds Further details regarding the preparation and properties of certain of our compounds are given in the following publications; by us and our associates.
Pyridine Aldoximes by Edward I. Poziomek, Brennie 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-formyl pyridinium bromide) dioxime in Anticholinestearase 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 1958). These articles are to be considered incorporated by reference in this specification.
While we have shown a number of specific examples of compounds and their use, it will be obvious that various changes can be made without departing from our invention, which is defined by the following claims.
We claim:
1. A compound of the formula CH=NOH wherein R" is selected from the group consisting of three lower alkyl groups and the hydrocarbon portion of the pyridine ring, and where X- is selected fiom the class consisting of chloride, bromide and iodide.
2. A compound of the formula 3. A compound of the formula 34. A compound of thelformu la 5. A compound of the formula 6. A compound of the formula 7. A compound of the formula No rferences' cited.
Claims (1)
1. A COMPOUND OF THE FORMULA
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US151122A US3135761A (en) | 1959-04-28 | 1961-10-11 | Bis quaternary oximes |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US809578A US3077476A (en) | 1959-04-28 | 1959-04-28 | Bis quaternary oximes |
| US151122A US3135761A (en) | 1959-04-28 | 1961-10-11 | Bis quaternary oximes |
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| US3135761A true US3135761A (en) | 1964-06-02 |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2571053A1 (en) * | 1984-08-28 | 1986-04-04 | Israel Inst Biolog Res | New quaternary ammonium compounds, their preparation and applications |
| EP0906773A1 (en) * | 1997-10-02 | 1999-04-07 | Etat-Francais représenté par le Délégué Général pour L'Armement | Decontaminating composition |
| US20080107736A1 (en) * | 2006-11-02 | 2008-05-08 | Mcdonough Joseph A | Pharmaceutically Active Nanosuspensions |
| US20090281144A1 (en) * | 2008-03-13 | 2009-11-12 | Southwest Research Institute | Bis-quaternary pyridinium-aldoxime salts and treatment of exposure to cholinesterase inhibitors |
| US20100040692A1 (en) * | 2008-08-15 | 2010-02-18 | Southwest Research Institute | Two phase bioactive formulations |
| US20100086601A1 (en) * | 2008-10-03 | 2010-04-08 | Southwest Research Institute | Modified Calcium Phosphate Nanoparticle Formation |
| US20110195125A1 (en) * | 2010-02-08 | 2011-08-11 | Southwest Research Institute | Nanoparticles For Drug Delivery To The Central Nervous System |
-
1961
- 1961-10-11 US US151122A patent/US3135761A/en not_active Expired - Lifetime
Non-Patent Citations (1)
| Title |
|---|
| None * |
Cited By (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2571053A1 (en) * | 1984-08-28 | 1986-04-04 | Israel Inst Biolog Res | New quaternary ammonium compounds, their preparation and applications |
| EP0906773A1 (en) * | 1997-10-02 | 1999-04-07 | Etat-Francais représenté par le Délégué Général pour L'Armement | Decontaminating composition |
| FR2769234A1 (en) * | 1997-10-02 | 1999-04-09 | France Etat | DECONTAMINATION COMPOSITION |
| US20080107736A1 (en) * | 2006-11-02 | 2008-05-08 | Mcdonough Joseph A | Pharmaceutically Active Nanosuspensions |
| US8946200B2 (en) | 2006-11-02 | 2015-02-03 | Southwest Research Institute | Pharmaceutically active nanosuspensions |
| US8404850B2 (en) | 2008-03-13 | 2013-03-26 | Southwest Research Institute | Bis-quaternary pyridinium-aldoxime salts and treatment of exposure to cholinesterase inhibitors |
| US20090281144A1 (en) * | 2008-03-13 | 2009-11-12 | Southwest Research Institute | Bis-quaternary pyridinium-aldoxime salts and treatment of exposure to cholinesterase inhibitors |
| US20100040692A1 (en) * | 2008-08-15 | 2010-02-18 | Southwest Research Institute | Two phase bioactive formulations |
| US8722706B2 (en) * | 2008-08-15 | 2014-05-13 | Southwest Research Institute | Two phase bioactive formulations of bis-quaternary pyridinium oxime sulfonate salts |
| US20100086601A1 (en) * | 2008-10-03 | 2010-04-08 | Southwest Research Institute | Modified Calcium Phosphate Nanoparticle Formation |
| US8309134B2 (en) | 2008-10-03 | 2012-11-13 | Southwest Research Institute | Modified calcium phosphate nanoparticle formation |
| US20110195125A1 (en) * | 2010-02-08 | 2011-08-11 | Southwest Research Institute | Nanoparticles For Drug Delivery To The Central Nervous System |
| US9028873B2 (en) | 2010-02-08 | 2015-05-12 | Southwest Research Institute | Nanoparticles for drug delivery to the central nervous system |
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