JQURNAL O F Pharmaceutical
`Sciences
`
`October 1964 volume 53, number 10
`
`Review Article-
`
`Oximes Antagonistic to Inhibitors of Cholinesterase
`Part I1
`
`water solubility, its high o x h e content per mole
`of compound and, most important, its physio-
`logical compatibility, was proposed as the oxime
`of choice. The methanesulfonate of 2-formyl
`N-methyl pyridinium oxime (2FMPOMS), has
`been championed by another group of investi-
`gators (147). The latter contains 56.6% oxime
`per mole of compound and is about as soluble
`as the chloride in water. Equivalent concentra-
`tions of various oxime salts reactivate inhibited
`eel cholinesterase at approximately the same
`rate; that is, there is little or no effect due to
`the anion moiety.
`Aqueous solutions of the chloride can be auto-
`claved without significant breakdown, provided
`that a suitable pH is maintained. Unbuffered
`2.5, 10, and 20% solutions of 2-PAMCl showed
`less than a 4% breakdown when autoclaved at
`120' (15 pounds pressure) for 15 minutes. The
`decomposition of the oxime occurs ui0 two pH-
`TABLE III.-SOLUBILITY AND PER CENT OXIME
`MOIETY IN METHYL PYRIDINIUM ALDOXIME SALTS
`(145)
`
`. Solubility
`mg./d. oi
`Soln. at 2 5 O
`640
`675
`46
`640
`48
`389
`. . .
`565
`1000
`
`Percentage
`Oxime
`79.5
`68.9
`58.6
`58.6
`51.9
`70.6
`69.9
`64.9
`60.6
`
`By ROBERT I. BUIN and J. HENRY WILLS
`PHARMACEUTIC ASPECTS
`Experiments with 2-PAM indicated that the
`iodide form of the o h e would be of little prac-
`tical value because of its comparatively low
`solubility in water. The iodide is approximately
`2% soluble in water at room temperature (144),
`while saturated aqueous solutions at 25' con-
`tain only 4.8%. In View of the fact that 2-PAM
`is efTective in humans in doses of 20 or more
`mg./Kg., a volume of at least 30 ml. would be
`needed for a single injection. Such volumes are
`obviously impractical for intramuscular injection.
`There is an additional inherent disadvantage
`in the use of the iodide form. Large doses of
`2-PAM can, and have, eliated symptoms of
`iodism (145).
`In attempting to find more soluble salts of 2-
`formyl N-methyl pyridinium oxime (PFMPO),
`the nitrate was made by simply adding silver
`nitrate to 2-PAM (146). Fundamental prin-
`ciples of general chemistry tell us that this reac-
`tion should go to completion readily, with the
`formation of insoluble silver iodide and the
`nitrate of the oxime. The resulting nitrate was
`found to be 15 times more soluble than the iodide.
`Other salts were subsequently synthesized.
`Table I11 shows the water solubilities and the
`percentages of oxime in each salt. The chlo-
`ride salt (2-PAMC1) on the basis of its excellent
`Received from the Physiolo Division, Directorate of
`Medid Research U S. Army &ernicd and Research Lnb-
`oratories, Edgewoh ksend. Md..
`EDITOP'S NOTE: Part I of thts review appeared in the
`September issue, THIS JOURNAL, 53, 895(1964).
`
`2-PAM Salt
`Chloride
`Nitrate
`Dihydrogen phosphate
`Hydrogen sulfate
`Iodide
`Fumarate
`Acetate
`Tartrate
`Lactate
`
`1143
`
`Merck Exhibit 2246, Page 1
`Mylan v. Merck, IPR2020-00040
`
`

`

`1144
`
`dependent mechanisms. At pH values below 4,
`the hydrogen ion catalyzes hydrolysis of the acid
`form of the oxime; various states of equilibrium
`between %PAM and its hydrolytic products, py-
`ridine-r carboxaldehyde methiodide and hydroxyl-
`amine, are established in accord with the pH and
`temperature of the reaction mixture. Above pH
`4, the decomposition is due either to hydroxyl ion
`catalysis of breakdown of the acid form of the
`oxime or to noncatalytic, direct attack on the
`oximate ion. Hydroxyl ion attack at the methine
`hydrogen results in the removal of a proton and
`the formation of a carbanion as the rate-controll-
`ing step (134). Subsequent loss of hydroxide
`ion from the oximino nitrogen results in the
`this case the cor-
`formation of a triple bond-in
`responding nitrile
`The nitrile, depending on
`whether there is direct hydroxide ion attack on
`the cyano grouping or addition to the pyridine
`ring, forms carbamidopyridinium or hydroxypy-
`ridinium ions. On further reaction with hy-
`droxide ions, the latter forms a pseudo base which
`loses water to form N-methyl-a-pyridone. Ellin
`(123) showed the presence of 2-cyanopyridinium
`ion. cyanide ion, and N-methyl-pyridone in alka-
`line hydrolysates of 2-PAM. Kosower and
`Patton (148) conclusively showed that 2-carbam.
`idopyridine methiodide formed when 2-cyano-
`pyridine methiodide was placed in alkaline media.
`One would then expect the formation of this
`amide when 2-PAM is degraded in basic solution;
`its presence among the products of alkaline d e
`gradation of 2-PAM has been confirmed by paper
`chromatographic techniques.
`Because cyanide had been found to be a de-
`composition product of 2-PAM (101, 133), ex-
`periments were run to check for the presence of
`cyanide in aqueous solutions stored over long
`periods of
`time. Accelerated storage-stability
`studies established that the toxicity resulting
`from 10 and 20% concentrations of oxime was
`due only to the initial oxime concentration (145).
`From the established equations for the degrada-
`tion of PAM, the stability of the oxime in aqueous
`solution at any pH and temperature may be
`predicted. Kinetic data show that a solution of
`%PAM, maintained at pH 4.36 at 25O, should
`retain half of its original concentration of oxime
`even after a period of 80 years.
`Other oximes, such as the aforementioned
`TMB-4, show promise as antagonists of
`the
`toxic effects of organophosphorus compounds,
`but have not been investigated so extensively
`as 2-PAM. Experiments concerned with the
`stability of TMB-4 are complete and are being
`prepared for publication (149).
`Although chemicals containing
`
`the o x h e
`
`Journul of Pharmuceutical Sciences
`
`group have been found to possess activity as
`antibacterial, antifungal, antirickettsial,
`try-
`panocidal, tuberculostatic, anticonvulsant, cen-
`trally depressant, antispastic, insecticidal, or
`locally anesthetic agents, probably the most
`striking biological activity of this type of com-
`pound is the ability of some oximes to serve as
`reactivators of cholinesterase inhibited by cer-
`tain organophosphorus and carbamate compounds
`and as antagonists of poisoning by these inhibitors
`of cholinesterases. The oximes that have been
`found to have value in these ways fall in general
`into one of three groups, all mentioned previously.
`R-C( 0)-C( Ri)=NOH
`0x0-Oximes
`I
`
`Q-R
`
`HON=CH
`Monoquaternary Pyridine Aldoxinies
`I1
`
`HON= CH
`~ H = H O N
`Bisquaternary Pyridine Bisoximes
`111
`
`A few oximes antagonistic to organophosphorus
`compounds but having other ring structures,
`including one having the oxime group attached
`directly to a ring carbon, have been described.
`These compounds have not exceeded in activity
`the usual types of oximes.
`TOXICITY OF OXIMES
`The best known members of the 0x0-oxime
`group (I) are MINA, DAM, and DINA; the
`the group of monoquaternaxy
`best known of
`pyridine aldoximes (11) are the chloride, iodide,
`and methanesulfonate salts of 2-formyl N -
`methylpyridinium oxime. Among the bisquat-
`ernary pyridine aldoximes (III), the best known
`is 1,3-bis-(4-formylpyridinium) propane bisoxime
`dibromide (B4FPBOBrz or TMB-4). Table IV
`gives toxicity information about a representative
`group of oximes. It is apparent that DINA is
`the most lethal of the group. O’Leary et al.
`(158) have examined the lethal effectiveness in
`the mouse of i.v. injection of mixtures of equal
`in four cases (2FMPOI +
`parts of pyridinium monoximes and bispyridin-
`B4FPBOBr2, BFMPOL + B4FPBOBr2, 2FM-
`ium bisoximes;
`POCl + B4FPBOC12, and 2FMPOMS +
`B4FPBOBr2), the toxicity of the mixture of
`
`Merck Exhibit 2246, Page 2
`Mylan v. Merck, IPR2020-00040
`
`

`

`Vol. 53, No. 10, October 1964
`TABLE IV.-TOXICITIBS OF SELECTED OXIMES
`
`1145
`
`-
`
`Oximea
`Oximinoacetarnide
`MINA
`
`DINA
`DAM
`2-Oximino-3-pentanone
`2FMPOI( 2-PAM)
`
`Route
`i.p.
`i.p.
`?.P.
`!.P.
`?.P.
`?.P.
`1.p.
`i.v.
`i.p.
`
`Ref.
`(100)
`(100)
`(150)
`(150)
`(100)
`(100, 151,152)
`( 100)
`(157, 158)
`(100,150-154,156,
`(i53: 159)
`16U)
`(156, 160)
`(150)
`(158)
`(156)
`(156)
`(158)
`
`(150)
`
`LDM
`Species
`4200 mg./Kg.
`Mouse
`Mouse
`150
`Rat (M)
`50
`Rat (F)
`74
`Mouse
`20
`51, 85, 900
`Mouse
`350
`Mouse
`140-178
`Mouse
`136-260
`Mouse
`290-340
`Mouse
`S.C.
`1500-4000
`Mouse
`p.0.
`305
`Rat
`i.p.
`Mouse
`115
`1.v.
`Mouse
`205
`i.p.
`Mouse
`4 100
`P.0.
`Rabbit
`95
`1.v.
`121
`i.v.
`Mouse
`118-122
`i.v.
`Mouse
`216
`i.p.
`Mouse
`3700
`Mouse
`p.0.
`109
`i.v.
`Rat
`262
`Rat
`i.D.
`i.m.
`305
`Guinea pig
`147
`i.v.
`Rabbit
`i.m.
`356
`Monkey
`202
`i.p.
`Mouse
`i.v.
`Mouse
`53-89
`i.p.
`130
`Mouse
`i.v.
`57
`Mouse
`44
`i.v.
`Rabbit
`0 2FMPOI P 3-formyl N-methylpyridinium oxime iodide (2-PAM) ; 2FMPOCl
`
`2FMPOCl
`
`2FMPOL
`ZFMPOMSPZS)
`
`2FMPOMS( P2S)
`
`4FPPOBrt
`B4FPBOBrs( TMB-4)
`B4FPBOCIz
`
`chloride. 2FMPOL - 3-formyl N-methylpyridinium odme lactate. 2FMPOMS = 2-formyl N-methylpyridinnnn oxime
`formy1pyridiuium)-propane bisoxime dibromide (TMB-4) ; 4FPBOCL - 1,3-bis(4-formylpyridinium)-propaee bisoxime
`methau&ulfonate; 4FPPOBrr = 1-(4-formylpyridinium)-3-p~dini;m propane odme dibromide; B4FPBOBra - 1,3-bis(4-
`
`2-formyl N-methylpyridin,ium ogme
`
`dichloride.
`
`oximes was between those of the two components
`and close to the value calculated from the toxici-
`ties of the individual components. This last
`finding suggests that there is no potentiation of
`the toxicity of B4FPBOBrl (TMB-4) by either
`the iodide, the lactate, or the methanesulfonate
`of 2-formyl N-methylpyridinium oxime and none
`of that of B4FPBOC12 by the chloride of the
`monoxime.
`EFFECTIVENESS OF OXIMES
`Table V summarizes available information
`about the effectiveness of the same oximes in
`antagonizing the toxic effects of organophos-
`phorus and carbamate inhibitors of cholinester-
`ases. This table shows several things: (a) the
`oxime with which the greatest volume of work
`has been done is 2FMPOI (or 2-PAM), (b) the
`only poisoning of humans in which an oxime has
`been used fairly extensively is that by parathion,
`(c) pyridinium oximes (either mono or bis oximes)
`are more active than the 0x0-oximes, and (d)
`although the oximes are effective antagonists to
`many of the inhibitors of cholinesterase, there
`are some anticholinesterase compounds with
`effects that either are not antagonized by oximes
`or are made worse by administration of an oxime.
`
`In the latter group, Sevin and Diazinon seem to
`be particularly likely to have their toxic effects
`enhanced by administration of oximes. This
`enhancement of toxicity probably occurs through
`the formation of stable phosphorylated (60, 231)
`or carbamylated derivatives of the oximes.
`The only recourse available today as an aid to
`atropine in the treatment of Severe poisonings by
`such compounds as Sevin and Diazinon is arti-
`ficial ventilation.
`In carrying out this form of
`therapy, a first requirement is that the airway
`be rendered patent by removal of secretions and
`other occlusive material from the pharynx. The
`maintenance of a patent airway is aided by
`tilting backwards the head of the supine patient.
`With a patent airway, one must next insure that
`the method of artificial respiration being used
`actually produces effective pulmonary ventila-
`tion.
`Some of the papers from which the data in
`Table V are derived contain other information of
`considerable importance for most effective em-
`ployment of the oximes in therapy of poisonings
`by inhibitors of cholinesterase. One such piece
`of information is that administration of atropine
`along with the oxime increases the antagonistic
`activity of MINA against sarin and tabun
`
`Merck Exhibit 2246, Page 3
`Mylan v. Merck, IPR2020-00040
`
`

`

`Journal of Pharmaceutical Sciences
`1146
`TABLE V.-ACTIVITIES OF OXIMES AND SALTS OF OXIMES AS ANTAGONISTS OF LETHAL AND OTHER EFFECTS
`OF ANTICHOLINES'I~RASE COMPOUNDS
`-
`--
`+
`+
`+ + + +
`- ; +
`+
`- ; +
`
`Antogooismo
`
`Ref.
`(59. (100) loo, 102, 120, 144,
`
`163-167)
`(120, 167) '
`(168)
`(59, 163, 166, 169)
`1167. 173. 174)
`
`.-
`Anti-ChE Compouada
`Oxime
`Oxirninoacetamide Sarin
`MINA
`Sarin
`MINA
`Sarin
`MINA
`Tabun
`MINA
`DFP
`MINA
`DFP
`TEPP ~-
`MINA
`MINA
`~ DMNP
`OMPA; Parathion
`MINA
`CHa-Parathion
`MINA
`Diazinon
`MINA
`EPN, Malathion
`MINA
`Dipterex
`MINA
`Ph ysostigmine
`MINA
`DINA
`Sarin
`DFP, TEPP
`DINA
`Sarin
`DAM
`
`Sarin
`DAM
`Tabun
`DAM
`DAM
`DFP
`DFP
`DAM
`TEPP
`DAM
`OMPA
`DAM
`Paraoxon ; Parathion
`DAM
`CHs-Parathion
`DAM
`Diazinon; EPN
`DAM
`Malathion; Dimefox
`DAM
`Dipterex
`DAM
`Physostigrnine
`DAM
`Neostigmine
`DAM
`Bisneostigrnine
`DAM
`Bispyridostigmine
`DAM
`Ambenonium
`DAM
`2-Oximino-3-penta- Sarin
`none
`2-Oximino-3-penta- DFP
`none
`Sarin
`2FMPOI
`2FMPOI
`Sarin
`
`Test Objecth
`m. r
`m, r, gp
`direct reaction
`r
`r, c
`rb eye
`rn; r
`r
`m
`m
`m
`m
`m
`rb eye
`m; r
`r
`m, r, gp, rb, mk;
`man
`direct reaction
`r
`r, c
`rb or human eye
`m, r
`rn, man
`m
`m
`m
`m
`m
`human eye
`c ; man
`man
`man
`man
`m. r
`rb eye
`m, r
`
`0
`-
`0
`
`f +
`f; +
`+ +; f
`+ + + +
`
`+
`f
`0
`-
`- ; f
`- ; 0
`
`f + +; f +
`f + +
`+
`rn, r, rb, c, d, man +
`f
`
`i 175 j
`1175)
`(iiij
`(100; 59, 163)
`(59, 163)
`(59, loo, 102, 120, 144,
`158,164.165,171,172;
`2 18-220)
`(120)
`( 168)
`(59, 165, 169)
`(170, 174)
`(59, 118,127,165,175)
`(175,218-220)
`(118; 175)
`(175)
`(i75j
`(175; 118)
`(175)
`(170)
`(123; 218-220)
`( 218-220)
`(218-220 j
`(218-220)
`(100)
`(174)
`(100)
`(59, 102, 120, 124, 125,
`144,152,158,163,176-
`181. 182, 218-220)
`(60. 120)
`
`155.163. l i .
`(116. 168)
`
`
`
`.
`.
`,
`(21i3-220)
`(81, 82. 116-118, 121,
`122,151,155,178,184,
`188. 189)
`(1%)
`(186)
`(176, 188)
`(122, 129-132. 151, 153,
`175,176,178,184,189-
`209)
`(175, 191, 193,210)
`1191.211.213)
`.
`(190; i g i j
`(161)
`(191, 193)
`(191)
`(175; 191)
`(193; 212)
`
`Sarin
`Soman
`Tabun
`DFP
`DFP
`DFP
`TEPP
`TEPP
`OMPA
`OMPA
`Paraoxon
`
`~
`
`~~~
`
`~
`
`Paraoxon
`Paraoxon
`Parathion
`Parathion
`
`2FMPOI
`2FMPOI
`2FMPOI
`2FMPOl
`2FMPOI
`2FMPOI
`BFMPOI
`_ _ ~
`2FMPOI
`
`_
`_
`-
`2FMPOI
`BFMPOI
`2FMPOI
`
`~
`
`2FMPOI
`2FMPOI
`2FMPOI
`LFMPOI
`
`2FMPOI
`2FMPOl
`LFMPOI
`ZFMPOl
`2FMPOI
`2FMPOI
`2FMP01
`2FMPOI
`
`direct reaction
`rn, rb
`m. r, c. d
`m, r, gp, c, man
`
`f
`0
`
`+
`+
`m, rb or human eye +
`+
`+
`+
`0 ; t
`+
`f
`+
`+
`in, r, gp, rb. c, d, h, +
`
`direct reaction
`m, r, c
`direct reaction
`m
`man
`m. r, gp, rb. c
`
`rn eye
`direct reaction
`r
`
`man
`
`0
`
`+ + + + +
`
`- ; +
`
`0
`f; 0
`
`CH8-Parathion
`Demeton
`CH8-Demeton
`Isosystox
`Phenkaptone
`CHn-Phenkaptone
`Diazinon
`Diazinon
`
`m, r
`m, r
`m, rb
`r
`in. r
`111
`m
`r; ct
`
`Merck Exhibit 2246, Page 4
`Mylan v. Merck, IPR2020-00040
`
`

`

`Antagonisme
`-
`0
`+
`- ; + ; z t
`f; 0
`+
`+
`+
`+
`+
`+ + +
`+ +; 0 + + + +
`
`f
`
`0; + +
`f +; f
`f; +
`-
`f +: f
`O;'+
`0
`+
`
`1147
`
`Rd.
`
`(191)
`i 2 l l
`
`(175)
`(175; 212; 198)
`(211; 193,211)
`(160; 211)
`(190)
`(186)
`(214)
`1170.216)
`(170; 2i5j
`(211,217)
`(117, 154)
`
`(118; 193, 211)
`(211,221,222)
`
`(154,217; 218-220)
`(218-220)
`W 2 2 0 )
`(191.223; 211)
`(223; 211)
`(204,211)
`(217)
`(223)
`(216; 218-220)
`
`i)
`(150; 158; 161, 1
`64, 225,
`226)
`
`Test Objects
`
`m
`r
`r
`m, man
`m; ct; man
`r
`m; r
`m, rb
`direct reaction
`m
`m, rb, c
`rb or human eye
`r, man
`m
`direct reaction
`m; r
`m. r
`m
`gP
`rb or human eye
`m; man
`man
`m
`man
`m; r
`m; r
`r
`m
`m
`m
`m; man
`m
`rb
`rb, d
`m, r. g ~ . rb, d
`
`m, r. g ~ , rb
`m, r, m, rb
`rb eye
`m. r, m. rb
`m. r, m, rb
`m. r. g ~ . rb
`r
`
`~
`
`_
`
`Vol. 53, No. 10, October 1964
`Anti-CHB Compoud'
`&me
`CHI-Diazinon
`2FMPOI
`Guthion
`2FMPOI
`GHs-Guthion
`2FMPOI
`2FMPOI
`EPN
`Malathion
`2FMPOI
`Morphothion; Dimetho-
`2FMPOI
`ate
`DBD; Thimet
`2FMPOI
`Endothion
`2FMPOI
`moo
`2FMPOI
`I, 11, I11
`2FMPOI
`Phospholme
`2FMPOI
`Phospholine
`2FMPOI
`2FMPOI
`PhOsdrin
`~~ W-0340. W-0351,
`2FMPOI
`Ro3-0422
`2FMPOI
`W-0340. Ro3-0422
`2FMPOI
`Dimefox
`Phosphamidon
`2FMPOI
`2FMPOI
`Dipterex
`2FMPOI
`Physostigmine
`2FMPOI
`Physostigmine
`2FMPOI
`Neostigmime
`2FMPOI
`Bisneostigmine
`Mestinon
`2FMPOI
`Bispyridostigmine
`2FMPOI
`Dimetilan
`2FMPOI
`Isolan
`2FMPOI
`SeVin
`2FMPOI
`Humorsol
`2FMPOI
`Pyramat; Pyrolan
`2FMPOI
`2FMPOI
`G23091; Dimetan
`Ambenonium
`2FMPOI
`Edrophonium
`2FMPOI
`Sarin, Tabun
`2FMPOCl
`Sarin
`2FMBOL
`2FMPOMS
`sarii
`Tabun
`2FMPOMS
`DFP
`2FMPOMS
`2FMPOMS
`DFP
`_ _ _ _ _ _ ~ _ _
`TEPP
`2FMPOMS
`OMPA
`2FMPOMS
`Paraoxon
`2FMPOMS
`Demeton
`2FMPOMS
`2FMPOMS
`Isosystox
`_ _ _ _ _ _
`~
`
`2FMPOMS
`Viylphos
`2FMPOMS
`Guthion, CJIrGuthion
`2FMPOMS
`Momhothion: Thimet
`2FMPOMS
`PhoGholine
`Amiton . .~
`2FMPOMS
`2FMPOMS
`S1, Ch-1
`Phosdrin, Phosphamidon r
`2FMPOMS
`2FMPOMS
`Physostigmine
`m, r, g ~ . rb
`Dimetilan
`r
`2FMPOMS
`Isolan; sevin
`2FMPOMS
`r
`Humorsol
`rb eye
`2FMPOMS
`Sarin, DFP
`m
`4FPPOBrs
`TEPP. W-0340
`m
`4FPPOBrz
`m, r, rb, c, d
`B4FPBOBrr
`Sarin
`B4FPBOBr.
`m, r
`Soman
`_ _ ~ _ _ ~ _ . _
`r; m
`B4FPBOBrl
`Tabun; DFP
`DFP
`B4FPBOBrr
`TEPP; OMPA
`m
`B4FPBOBrx
`Paraoxon
`m
`B4FPBOBn
`r
`Parathion, CHI-Para-
`BlFPBOBr;
`thion
`m, r
`Armin, Phenkaptone
`B4FPBOBr:
`r
`Dizinon; Dimethoate
`B4FPBOBrt
`m
`B4FPBOBrz
`I, 11, I11
`eospholine, R03-0340
`m
`B4FPBOBri
`Dimefox; Phospbamidon m
`B4FPBOBrz
`Dipterex
`B4FPBOBrr
`m
`rh or human eve
`Physostigmine
`B4FPBOBrz
`m
`Neostigmine; Bisneo-
`B4FPBOBr2
`stigmine
`
`+
`0 ; +
`i 2 i i i
`+
`(Ziij
`+
`(174)
`+
`(161,226)
`+
`( 225
`+
`(211 j
`(162)
`+; - (211)
`(211)
`+
`+
`+
`+
`+
`f
`rb or human eye +
`+; 0
`+
`+
`+.
`+
`f; 0
`+
`0; +
`+
`+
`f ; 0
`
`f
`
`(174)
`(154, 187)
`(154,187)
`(89, 158, 164, 172, 177,
`182, 187,228)
`(182)
`(168; 154, 172,228)
`(170)
`(86,127,154, 187; 229)
`(214)
`(193)
`(193,229)
`(193)
`(214)
`(154,215)
`(193,229; 221,229)
`(229)
`[::!!229;
`
`1541
`
`Merck Exhibit 2246, Page 5
`Mylan v. Merck, IPR2020-00040
`
`

`

`1148
`
`m
`m
`
`Test Objects
`
`Antagonismc
`
`Journal of Pharmaceutical Sciences
`0; +
`Anti-ChE Compoundo
`Oxime
`Ref.
`Mestinon
`B4FPBOBr2
`(229; 216)
`Bispyridostigmine, Iso-
`B4FPBOBrZ
`(154,216,229)
`0
`lan
`Humorsol
`B4FPBOBrp
`0; f (229; 216)
`m
`0; -
`Dimetan ; Ambenonium
`B4FPBOBr2
`(229; 216)
`m
`+; f (158,227; 230)
`Edrophonium
`B4FPBOBrz
`(216)
`m
`0
`+
`rb; c
`Sarin; Soman
`B4FPBOClr
`rb
`Tabun
`B4FPBOClr
`(158)
`a Symbols are: I: Diethyl-P-nitrophenyl phosphonate. II: Methyl-0-ethyl-P-nitrophenyl phosphonate; III: Methyl-0-
`isopropyl-9-nitrophenyl phosphonate; Amiton: O,O-Di~thyl-S-(2-diethylaminoethyl) phosphonothioate; A d n : Ethyl-4-
`nitrophenyl ethylphosphonate; Ch- I : Isopropyl methyl phosphonothiocholinate; D-600 : Diisopropyl-4-nitrophenylphos-
`phate; DBD : O.O-Dtmethyl-S(4-oxo-3-H-1,2.3-benzotriazine-3-methyl) phosphorodithioate; Demeton : O.O-Diethyl-O-(2-
`ethylthioethyl) phosphorothioate; DPP : Diisopropyl phosphorofluoridate; Diuinon : O.O-Dielhyl-O-(2-isopropyl-6-methyl-
`4-pyrimidyl) phosphorothioate; Dimefox : Tetramethyl phosphorodiamidic fluoride; Dimetan : 5,5-Dimethyldihydroresor-
`cinol dimethylcarbamate; Dimethoate: 0,O-Dimethyl-S(N-methyl-carbamylmethyl) phosphorodithioate; Dimetilan: 2-
`Dimeth lcarbamyl-3-methylpyrazolyl-5-dimethylcarbamate; Dipterex: Dimethyl-2.2.2-trichloro-1-hydroxyethyl hos hon
`ate. D d N P : Dimethyl-4-nitrophenylphosphate; Bdrophonium: N-Dimethyl-N-ethyl-m-hydroxyanilinium bromide; &dotLon
`2-(bimethoxy hosphinylthiomethyl)-5-methoxy-4-pyrone; BPN : 0-Ethyl-0-(4-nitrophenyl) phenylphosphonothioate; Ethyl-
`gluthion: O,~-Diethyl-S-(4-oxo-3-H,1,2,3-benzotriazine-3-meth 1) phosphorodithioate; 623091: 2 6-Dimethyl yridyl-4-
`dimethylcarbamate; Guthion: O,O-Dimethyl-S(4-oxo-3-H,1.~3-beo~otriazine-3-methyl) phos hoiodithioate; &unorrol:
`Decamethylene bis IN-methylcarbamic acid m-dimethylaminophenyl ester] bromoethylate. Isofan: 1-Isopro yl 3 methyl-
`5-pyrazolyl dimethylcarbamate; Iso-Syltox : O,O-Diethyl-S(2-ethylthioethyl)phosphorothibate; Malathion : dl0;Gmethyl-
`S( 1,2-dicarbethoxyethyl) thiothionophosphatc; Mestinon:
`I-Methyl-3-h drox yridinium bromide dimethylcarhamate;
`Methyldemeton: 0 0-Dimethyl-0-(2-eth lthioethyl) phosphorothioate. dethyl);EPtinon: 0 O-Dimethyl-O-(2-iso rop 1 6
`kaptone : 8 O-Dimethyl-S(methylthio~2,5-dichlorophenyl) ph&phorodithioate; MorpEothion : O,O-Dimethyl-S-(N-morpholino
`methyl-4- yrimidyl) 'phosphorothioate. dethylparathion : 0 O-Dimeth;l-O-(4-nitro henyl) phbsphorothioate; Me&ylpgen:
`carbamylmhhyl) phosphorodithioate; OMPA : Tetramonoisopropyl pyro hosphortetramide; Paraoxon : Diethyl-4-nitrophenyl-
`phosphate; Parathion : 0.0-Diethyl-O-(+nitrophenyl) phosphorothioate; gheukaptone : O.O-Diethyl-S(methylthio-2,5-dichlor-
`ophenyl) phosphorodithioate; Phosdrm : Dimethyl-1-meth 1 2 carbomethox vinyl phosphate; P h o r p h m d o n : Dimethyl-
`l-methyl-2-chloro-2-N,N-dicthylcarbamylvinyl hosphate. Jho;pholine : 0,8-Diethyl-S-2-trimethyIammonium-ethyl phos-
`phonothiolate iodide; Pyramat : l-Propyl-l-me& lpyrimdyl-6-dimethylcarbamate; Pyrolan : 3-Meth 1 1 phenyl 5 pyrazolyl
`dimethylcarhamate; Ro3-0340 : 3-( Diethy1phosptato)-N-trimethylanilinium-methyl sulfate; RoJ-OJd 3-(Diisipiopylphos-
`phato) pyridme. Ro3-0422 : 3-(Diethylphosphato)-N-methyl-quinolinum methyl sulfate; S-1: Isopropylmethyl-S-dimethyl-
`aminoethyl phoi honothiolate; Sarin : Isopropyl methylphosphonofluoridate; Sevin : 1-Naphthyl-N-methylcabamate; Soman :
`Pinacol yl-methyrphosphonolluoridate. Tabun : Ethyl-N-dimethyl phosphoramido cyanidate; TEPP : Tetraethyl pyrc-
`phosphate; T k m e t : 0,O-Diethyl-S;thylthio-methyl phosphorodithioate; Vinylphor: Diethyl-2chlorovinylphosphate.
`
`b Symbols are: m = mouse, r - rat, gp = guinea pig. r b = rabbit, c = cat, d - dog, mk - monkey, h = horse, and c t -
`c Symbols are: - = administration of oxime increases severity of toxic or other effect of the anti-ChE compound: 0 -
`administration of oxime has no eflect on the toxicity or other action of the =ti-ChE compound; rt - administration of oxime
`may decrease toxicity or other effect of the anti-ChE compound; + = administration of oxime decreases toxicity or other
`action of the anti-ChE compound. The semicolon is used to separate entries including disparate or qualitatively different
`eKects.
`
`cattle.
`
`(167, 168), of DAM against sarin and tabun
`(144, 164, 168), of 2FMPOI or 2FMPOMS
`against sarin, tabun, DFP, TEPP, OMPA, para-
`oxon, parathion (- 176, +190). CHa-Demeton,
`endothion, S-1, CH-1, Ro3-0340, Ro3-0351, Ro3-
`0422 and phosphamidon (89, 116, 117, 124, 154,
`164, 176, 177, 183, 184, 190, 222, 225), of 4FP-
`POBr2 against DFP and TEPP (154), and of
`B4FPBOBrz against sarin, tabun, DFP, TEPP
`and Ro3-0340 (89, 154, 164, 168, 177). On the
`other hand, the mixture of atropine and oxime has
`no significant advantage against guthion, C~HI-
`guthion, Demeton, and rnorphothion
`(211).
`Still, it appears that, as a general rule, the oxime
`should be used along with atropine sulfate. The
`necessity for large doses of atropine in treating
`poisoning by cholinesterase inhibitors has been
`pointed out many times (130, 131, 196, 218,
`232-235).
`The dosages for the only oximes used so far to
`treat intoxication by inhibitors of cholinesterase
`in man, DAM and 2FMPOI appear to be quite
`similar (218). Grob and Johns (218) recommend
`total intravenous doses of 2000 mg. of either
`oxime, given at rates not greater than 500 mg./
`minute for 2FMPOI or 200 mg./minute for DAM,
`in severe intoxication with cholinesterase in-
`
`hibitors. This dose may be repeated if muscular
`weakness is not relieved or recurs. In less severe
`intoxication, total doses of 1000 mg. of either
`oxime may be used similarly. Durham and
`Hayes (236) recommend total intravenous doses
`of 1000 mg. of 2FMPOI in either severe or mod-
`erate poisoning by anticholinesterase compounds.
`Other salts of 2FMPO may be used similarly.
`The finding of Crook et al. (224) that salts of
`2FMPO administered orally prior to exposure to
`lethal concentrations of sarin vapor are effective
`in protecting dogs subsequently exposed to sarin
`and then treated by intramuscular injection of
`5 mg./Kg. of atropine sulfate, suggests that
`prophylactic employment of such salts may be
`useful in cases of possible exposures to cholin-
`esterase inhibitors. This possibility has not been
`reduced to practice, however.
`Certain of the references in Table V compare
`B4FPBOBr2 with 2FMPOI and conclude that
`the former compound is the more active and the
`more rapidly effective against poisoning by sarin,
`tabun, TEPP, paraoxon, I, 11, 111, and phos-
`phamidon (86, 127, 154, 168, 177, 187, 214, 221,
`228). Despite these apparently advantageous
`properties, no salt of B4FPBO has been used to
`treat intoxications of men by inhibitors of cholin-
`
`Merck Exhibit 2246, Page 6
`Mylan v. Merck, IPR2020-00040
`
`

`

`VoZ. 53, No. 10, October 1964
`esterase. The lack of interest in the bis-quat-
`ernary type of oxime for therapy may be due to
`the increased lethality of this type of oxime
`(Table IV) as well as to the toxic actions of the
`compound.
`The principal toxic effects of B4FPBO are
`related to its being a bis-quaternary compound:
`they are a curariform block of neuromuscular
`transmission and a hexamethonium-like depres-
`sion of blood pressure (237). This oxime recently
`has been found to be imtating to the human
`stomach when daily oral doses were given (238).
`2FMPOMS has been reported (239) to produce
`fibrosis of the mucous membrane of the stomach
`in dogs given the material by mouth on 5 days a
`week for 17 weeks. The most striking toxic
`effects of 2FMPOI are (a) the production of
`pharyngeal pain and enlargement of the parotid
`glands in some men-effects that seem to be
`related to the iodide ion and that are absent from
`(a) the produc-
`2FMPOCl and 2FMPOM-d
`tion by large doses of block of neuromuscular
`transmission (123,163,218). Other toxic effects
`of DAM and 2FMPOI in mau have been re-
`ported by Jager and Stagg (240). Daily doses of
`as much as 6 Gm. of 2FMPOCl have been given
`by mouth to humans for many weeks without
`signs of gastric discomfort or of any other sort
`of toxicity (238).
`Salts of 2FMPO increase the pressor response
`to injections of catecholamines (238, 241). This
`pressor-sensitizing effect of salts of 2FMPO
`enables single doses of mixtures of these com-
`pounds and of salts of B4FPBO to be admin-
`istered parenterally to experimental animals
`without marked deleterious effect on blood pres-
`sure and with excellent therapeutic activity
`against poisonings by sarin or tabun (158).
`
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`_,
`
`Merck Exhibit 2246, Page 7
`Mylan v. Merck, IPR2020-00040
`
`

`

`1150
`
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`, - "__,
`.
`f l Q R f l )
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