US3054799A - Bis quaternary osimes - Google Patents
Bis quaternary osimes Download PDFInfo
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- US3054799A US3054799A US3054799DA US3054799A US 3054799 A US3054799 A US 3054799A US 3054799D A US3054799D A US 3054799DA US 3054799 A US3054799 A US 3054799A
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- 150000004820 halides Chemical class 0.000 claims description 20
- 150000001875 compounds Chemical class 0.000 description 58
- 230000004083 survival Effects 0.000 description 30
- -1 pyridinium halide oximes Chemical class 0.000 description 22
- 241001465754 Metazoa Species 0.000 description 20
- 229920002401 polyacrylamide Polymers 0.000 description 18
- 241000700159 Rattus Species 0.000 description 16
- QNBVYCDYFJUNLO-UHDJGPCESA-N [(E)-(1-methylpyridin-2-ylidene)methyl]-oxoazanium;iodide Chemical compound [I-].CN1C=CC=C\C1=C/[NH+]=O QNBVYCDYFJUNLO-UHDJGPCESA-N 0.000 description 16
- 229930006677 A03BA01 - Atropine Natural products 0.000 description 14
- RKUNBYITZUJHSG-SPUOUPEWSA-N Atropine Chemical compound O([C@H]1C[C@H]2CC[C@@H](C1)N2C)C(=O)C(CO)C1=CC=CC=C1 RKUNBYITZUJHSG-SPUOUPEWSA-N 0.000 description 14
- 229960000396 Atropine Drugs 0.000 description 14
- CPELXLSAUQHCOX-UHFFFAOYSA-M bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 14
- 230000000694 effects Effects 0.000 description 10
- 239000000203 mixture Substances 0.000 description 10
- DYAHQFWOVKZOOW-UHFFFAOYSA-N sarin Chemical compound CC(C)OP(C)(F)=O DYAHQFWOVKZOOW-UHFFFAOYSA-N 0.000 description 10
- 102000012440 Acetylcholinesterase Human genes 0.000 description 8
- 108010022752 Acetylcholinesterase Proteins 0.000 description 8
- 229940022698 Acetylcholinesterase Drugs 0.000 description 8
- 241000282326 Felis catus Species 0.000 description 8
- 208000005374 Poisoning Diseases 0.000 description 8
- 125000004432 carbon atoms Chemical group C* 0.000 description 8
- 239000000544 cholinesterase inhibitor Substances 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- 238000000034 method Methods 0.000 description 8
- 150000002923 oximes Chemical class 0.000 description 8
- 230000000607 poisoning Effects 0.000 description 8
- 231100000572 poisoning Toxicity 0.000 description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- 241000282472 Canis lupus familiaris Species 0.000 description 6
- 238000001990 intravenous administration Methods 0.000 description 6
- 230000001225 therapeutic Effects 0.000 description 6
- 229960004373 Acetylcholine Drugs 0.000 description 4
- 229940053514 Anticholinesterase anti-dementia drugs Drugs 0.000 description 4
- 229940055075 Anticholinesterase parasympathomimetics Drugs 0.000 description 4
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 4
- 241000283973 Oryctolagus cuniculus Species 0.000 description 4
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 4
- 230000000973 chemotherapeutic Effects 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 229940079593 drugs Drugs 0.000 description 4
- 230000002708 enhancing Effects 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- 239000003958 nerve gas Substances 0.000 description 4
- 150000002903 organophosphorus compounds Chemical class 0.000 description 4
- JHZHWVQTOXIXIV-UHFFFAOYSA-N oxo-[[1-[3-[4-(oxoazaniumylmethylidene)pyridin-1-yl]propyl]pyridin-4-ylidene]methyl]azanium;dibromide Chemical compound [Br-].[Br-].C1=CC(=C[NH+]=O)C=CN1CCCN1C=CC(=C[NH+]=O)C=C1 JHZHWVQTOXIXIV-UHFFFAOYSA-N 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- QJZUKDFHGGYHMC-UHFFFAOYSA-O pyridin-1-ium-3-carbaldehyde Chemical compound O=CC1=CC=C[NH+]=C1 QJZUKDFHGGYHMC-UHFFFAOYSA-O 0.000 description 4
- BGUWFUQJCDRPTL-UHFFFAOYSA-O pyridin-1-ium-4-carbaldehyde Chemical compound O=CC1=CC=[NH+]C=C1 BGUWFUQJCDRPTL-UHFFFAOYSA-O 0.000 description 4
- 238000011084 recovery Methods 0.000 description 4
- 238000007920 subcutaneous administration Methods 0.000 description 4
- PJOJJDGBJAIPOY-UHFFFAOYSA-M 1-methylpyridin-1-ium-2-carbaldehyde;iodide Chemical compound [I-].C[N+]1=CC=CC=C1C=O PJOJJDGBJAIPOY-UHFFFAOYSA-M 0.000 description 2
- XFNAGAQPPRZSFP-UHFFFAOYSA-N 4-(nitrosomethylidene)-1H-pyridine Chemical compound O=NC=C1C=CNC=C1 XFNAGAQPPRZSFP-UHFFFAOYSA-N 0.000 description 2
- 239000004215 Carbon black (E152) Substances 0.000 description 2
- AAOVKJBEBIDNHE-UHFFFAOYSA-N Diazepam Chemical compound N=1CC(=O)N(C)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 AAOVKJBEBIDNHE-UHFFFAOYSA-N 0.000 description 2
- 206010017740 Gas poisoning Diseases 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- WYMSBXTXOHUIGT-UHFFFAOYSA-N Paraoxon Chemical compound CCOP(=O)(OCC)OC1=CC=C([N+]([O-])=O)C=C1 WYMSBXTXOHUIGT-UHFFFAOYSA-N 0.000 description 2
- 241000018646 Pinus brutia Species 0.000 description 2
- 241001195377 Prorates Species 0.000 description 2
- 241000011102 Thera Species 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 230000002547 anomalous Effects 0.000 description 2
- 230000003042 antagnostic Effects 0.000 description 2
- 230000002605 anti-dotal Effects 0.000 description 2
- 239000000729 antidote Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 235000014171 carbonated beverage Nutrition 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- 230000001747 exhibiting Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 150000002430 hydrocarbons Chemical class 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 230000000749 insecticidal Effects 0.000 description 2
- 239000002917 insecticide Substances 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 229960004623 paraoxon Drugs 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- SLJOWAGYTNTMSC-UHFFFAOYSA-N pyridin-1-ium-4-carbaldehyde;bromide Chemical compound [Br-].O=CC1=CC=[NH+]C=C1 SLJOWAGYTNTMSC-UHFFFAOYSA-N 0.000 description 2
- 238000005956 quaternization reaction Methods 0.000 description 2
- 150000003839 salts Chemical group 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 125000003258 trimethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])[*:1] 0.000 description 2
- 238000010792 warming Methods 0.000 description 2
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Description
United dtares 3,054,799 BIS QUATERNARY GXMS Brennie E. Hackley, Jr., and Edward J. Poziomek, Edgewood, and George M. Steinherg, 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. 809,578. Divided and this appiication Oct. 11, 1961, Ser. No. 151,120
2 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.
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 his (4- formylpyridinium) halide dioximes wherein the polymethylene group contains from 2 to 6 carbon atoms. These compounds have the structural formula CH=NOH CH=NOH r CH=N O H CH=NOH (II) The invention also relates to l,1'-(2-butenylene) bis (4-formylpyridinium) halide dioximes of the formula GH=N O H OH=N O H (III) The invention further relates to 1,1 -polymethylene 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 1,1-(p-.
3,054,799 Patented Sept. 18, 1962 2 phenylenedimethylene) =bis (3-formylpyridinium) halide dioximes of the formula CH=NOH I wherein R" represents eitherthree lower alkyl groups or the hydrocarbon portion of the pyridine ring. a I
This invention also relates to the l,1-trimethylene bis (3-amidooximopyridinium) halides l (IJ=NOH CIJ=NOH N H} N Hz This invention also relates to the compounds (VII) The invention also relates to the compounds (DFP), isopropyl methylphosphonofluoridate (GB), and
O-ethyl, M,N dimethyl phosphoroamidocyanidate (GA), as well as other related organic phosphorus compounds, including many insecticides. The compound of the Wilson et al. group which has received by far the most attention is 2-formyl-1-methyl pyridinium iodide ozime,
commonly known as 2-pyridine aldoxime methiodide or 2-PAM. This compound is outstanding in its ability to reactivate, in vitro, acetyl cholinesterase which has been inihibited 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 2 x 10 per mole per minute for 2-PAM and 1.4 X 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 2-PAM.
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, 2-PAM has been reported to enhance considerably the activity of atropine in the chemotherapeusis of poisoning due to organophosphorus 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 acetylcholinesterase at pH.74 and 25 C. was found to be as: follows:
When administered in combination with atropine to animals poisoned with GB the order of eflfectiveness was somewhat difierent. Under these conditions the compound in which R: (CH i.e., 1,1'-trimethylene bis (4- iormylpyridinium) bromide dioxime also known as TMB- 4, was most effective. In rats challenged with a 2 LD dose of GB administered intravenously, all of a group of six animals survived if the atropine-TMB-4 combination was administered intravenously immediately after poisoning. The atropine-2PAM combination saved only two of the group of animals. On the other hand, with dogs which were given a 20 LD dose of GB subcutaneously the survival ratios were the same (4/5) for the two treatments, which were given intravenously when symptoms 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 receiving the Z-PAM.
A summary of the reactivation rates and survival ratios 4 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 5 impossible to give timely administration of the antidote.
Atropine, when administered, was included in the following amounts.
The propyhylactic doses were given within two minutes prior to the injection of the GB, the therapeutic doses so soon as poisoning symptoms were visible.
v Table 3 shows the results.
Table 3 A. PROPHYLACTIC 2-PAM TMB-4 Survival ratio Survival ratio Animals Animals Dose Dose mg./kg. With- With 131g./kg. with With out atroout atroatropine etropine pine pine Mice 40 0/10 12 (1/10 Rats 40 0/6 25 0/6 Rabbits 5 015 5 2/5 Cats 40 2/5 20 5/5 Dogs 40 5/5 20 5/5 B THEE The recovery periods, i.e., time for disappearance of symptoms of poisoning, among survivors in the above tests, with atropine, were as follows.
for these compounds when administered therapeutically Table 4 to rats together with atropine is as follows:
Table 2 Animals Z-PAM TMB-4 Pro h lactic There eutic Pro h lactic Thera eutic B Reactivation Survival p y p p y p rate constant ratio (GB) Rats 60 min- 15 min. Rabbits- 3 hr 30 min 2 hr. 2): 7X103 6/6 Cats 5 hr 5 hr 5 hr 24 m (CH2)s---- 6X103 6/6 Dogs- 24 hr 24 hr 1% hr 3 hr.
CH2 6X10 6/6 (CH2)5 1X10 6/6 I I I (CHM 6x103 3/4 The compounds of Formula I m wh1ch R contams from These compounds constitute our presently preferred group.
Our compounds may be employed prophy-lactically, 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 effectiveness 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 GB as follows.
Mice 0.173 rug/kg. (LD Rats 0.126 mgjkg. (2 LD Rabbits:
Intravenous 0.340 mg./ kg. (20 LD Subcutaneous 0.900 mg./kg. (20 LD Dogs and cats:
Intravenous 0.440 mg./ kg. (20 LD Subcutaneous 0.900 mg/kg. (20 LD To minimize absorption effects both the GB and TMB- 75 7 to 10 carbon atoms are less effective than those of our preferred group. For these compounds the reactivation Table 5 R Rate constant Survival ratio (13G) 2x10 O/4 1. 2x10 014 0/4 1. 4x10 (1/6 While these compounds were ineffective in vivo against GB, they were, together with Z-PAM, very efiective against certain other anticholinesterases, particularly that designated as VX by the Us. Army Chemical Corps. All
these compounds caused survival of all animals (survival rates of 4/4 and 6/6) when administered therapeutically to rats challenged by 2 LD doses of VX.
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 all following tables the survival ratios are those for rats challenged by 2 LD doses of GB or (VX) and the oxime was employed therapeutically.)
6 warming on a steam bath a neutralized aqueous solution of 4-py1idinecarboxaldehyde and hydroxylamine hydrochloride. The oxime had "a melting point of 1:30130.5 1C. The 2- and 3-oximes were produced by similar 5 methods.
Compounds of Formula III showed reactivation rates The quaternization to produce dioximes was carried very close to those of our preferred group. Thus when out by reacting the proper oxirne with a 1, n dihaloalkane X- in Formula III is bromide the reactivation rate (CH X employing a 3:1 molar ratio of oxime to constant was 8x10 as compared to the value for the halide. T-he unsymmetrical quaternary monoximes were R=(CH member of our preferred group of 6x10 10 obtained by reacting the pyridine oxime with the ap- For the unsaturated member (Formula III) the survival propriate omega-halopropyl quaternary salt in a -1.5 :1 ratio for rats challenged by GB was only 1/4 as commolar ratio. Two procedures were utilized. pared to 6/6 for the saturated analogue (Formula 1). Procedure A:A mixture of the pyridine oXime and Both gave complete survival (ratios of 4/4 and 6/6) for halide was dissolved in sufiicient ethanol and refluxed for animals challenged by VX, however. the period of time specified in Table 9.
Compounds of Formula We: showed anomalous prop- Procedure B:A mixture of the oxime and halide was erties. dissolved in about 100 m1. of ethanol and heated in a They gave reactivation rates which were low, but sur- 200 ml. capped pressure bottle (carbonated beverage vival ratios which were high as compared to Z-PAM, as type)for the length of time specified. The reaction mixshown by Table 6, X- being bromide. tures were cooled to room temperature and the product Tab 1e 6 removed by filtration. In sevegal instances it was necessary to add absolute ether to effect complete precipitation. R Reactivation Survival The products were recrystalized from ether This prorate constant ratio (GB) cedure was usually employed because of its simplicity.
Table 9 gives the procedure, yields and melting points (CH2)3 5x102 4/4 for representative compounds. (CHM 4-2X102 Table 9 The compounds of group IV 17, which are closely related to those of Wu, were somewhat less eifective. When X- FOP Substituents Gown yield @3 was bromide the compound had the following properties: 1111112 tions D 9 D Reactivation rate constant 2x10 survival ratio (GB)- Halide R cent 5319}; 2/4.
The compounds of group V were another group in 58%;, 350 300 which the results of therapeutic treatment against GB 2 a 238-241 6 were better as compared to 2-PAM than the reactivation g: 2 5: SE18 233% 3 rate constants would suggest, as shown by the following (OHM 2 ?8- 219923 (1 300m table, X- being bromide. (CH2); B, 60 hr 68 208-211m (C1195 B, 60 hr 80 226-231 In Table 7 B, 20 hr 83.5 248-251m B, 69h 43 230-231 d. B, 64 hr 10 223-226 (1. II: R ifii iiiiii r iifi Zdii 16 0 -203 a.
45 Further details regarding the preparation and proper- 1'3X103 4/4 ties 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 (CEHQBNL 11x10; 4/4 Organic Chemistry, vol. 23, pp. 714-717 (May 1958);
The compounds of Formulas VI, VII and VIII, while being of difierent 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.
PREPARATION OF COMPOUNDS 4-pyridinecarboxaldehyde oxime was prepared by and Chemotherapeutic Eifectiveness of Trimethylene Bis (4-Formyl Pyridinium Bromide) Dioxime in Anticholinesterase Poisioning, 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 1,1'-(2,5 dimethyl-p-phenylmethylene) bis-(4- formylpyridinium) halide dioxime.
2. A 1,1'-(p-phenylene dimethylene) bis (3-formyl pyridinium) halide dioxime.
No references cited.
Claims (1)
1. A 1,1''-(2,5 DIMETHYL-P-PHENYLMETHYLENE) BIS-(4FORMYLPYRIDINIUM) HALIDE DIOXIME.
Publications (1)
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US3054799A true US3054799A (en) | 1962-09-18 |
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US3054799D Expired - Lifetime US3054799A (en) | Bis quaternary osimes |
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3137702A (en) * | 1960-08-13 | 1964-06-16 | Merck E | Preparation of bis-quaternary pyridinium salts |
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0
- US US3054799D patent/US3054799A/en not_active Expired - Lifetime
Non-Patent Citations (1)
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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US3137702A (en) * | 1960-08-13 | 1964-06-16 | Merck E | Preparation of bis-quaternary pyridinium salts |
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