2,859,217 United ‘States Patent O? ice ‘ Patented Nov. 4, 1958 1. 2 Ordinarily, if a particular halide ion is desired in the 2,859,217 ?nal bis-quaternary ammonium compound, the prepara ACETYLCHOLINE ESTERASE INHIBITORS tion of the compound is carried ‘outwith the speci?c halide Quentin F. Super, Indianapolis, Ind., assignor to Eli Lilly initially present in the bis-(phenacyl-halide) reactant. and Company, Indianapolis, Ind., a corporation , of However, if for some reason ‘this method of preparation Indiana . is not desirable, itis possible to ‘interchange the halide ions in the ?nal bisjquaternary ammonium compound by No Drawing. Application September 28, 1956 , methods well knownrzto. the ‘art. For example,~a ‘bis Serial No. 612,575 quaternary ammonium bromidelcan be reacted with vsilver 5 Claims. (Cl. 260-296) 10 chloride to yieldthe ‘less‘soluble silver bromide and the bis-quaternary vammonium chloride. Other methods such My invention relates to certain ‘novel bis-quaternary as theuse of ion :exchange ~resins and simple lmetathetic ammonium compounds. processes can be employed. Thecompounds provided by my .inventionycan'be rep The method of halide ‘interchange can be used also to resented by the following formula: prepare the bis-(phenacylihalide) starting material. For in which X is an oxygen or a sulphur atom; Hal is a example, 4,4’-oxy-‘bis-'(phenacyl-chloride) and excess so halogen atom having an atomic numbergreater than 16, dium iodide reacted together in acetone solution give, for example, chlorine, bromine‘or iodine; and Aml and 4,4'-oxy-bis-_(phenacyl-iodide) . Amz represent tertiary amines, such as tri-lower alkyl 20 The compounds provided by this invention .are useful amines, as for example, triethylamine, trimethylamine, pharmaceuticalagents. They ?nd particular use as in tripropylamine, diethylmethylamine [and dimethylpropyl hibitors of acetylcholine Yesterasean'd as such, their chief amine, and aromatic-type heterocyclic amines, as for ex application lies in the treatment of the congenital disorder ample, pyridine, picoline, ethylpyridine,propylpyridine, known as Myasthenia gravis. . The compounds, being oral quinoline, isoquinoline and solubility, they can also be ‘administered orally as solu line salts. They are quitie-solubleinwater and are some tions in water _or.as elixirs inlalcohol and water. ‘In pre what less soluble in the more polar. ‘organic. solvents. paring capsules, the dose of-v-theltherapeutically active They are substantially :insoluble in ;the nonpo'lar organic 30 compound, for example, 50, 100 or 200 mgs. of 4,4’-oxy solvents. :Illustrative compounds coming ‘within the pur bis-(phen'acyl-pyridiniumchloride), ‘is mixed with a solid view of the :above formula are the following: ' pharmaceutical extending medium such as starch and the 4,4’-oxy-bis-(phenacyl-pyridinium chloride) mixture ‘is'then ?lled ‘into anjempty capsule. However, 4,4’-thio-bis-(phenacyl-pyridinium bromide) cross scored “tablets, which can be broken into two or 4,4’-oxy-bis-(phenacyl-triethylammonium iodide) 35 four sections, are thew-preferred mode of administration 4,4’-thio-bis-(phenacyl-trimethylammonium bromide) of one of 'my novel compoundssince the dosage level 4,4’-oxy-'bis-(phenacyl-isoquinolinium chloride) must be tailor-made to suit the needs of the individual 4,4’-oxy-bis-(phenacyl-pyridinium bromide) Myasthenia gravis patient. Such ‘tablets are prepared 4,4’-thio-bis-(phenacyl-?-picolinium iodide) as follows using 4,4'-oxy-bis-(phenacyl-pyridinium chlo 4,4'-oxy-bis-(phenacyl-quinaldinium‘ chloride) 40 ride) ‘as exemplary of one-of my active compounds: 240 g. of 4,4’-oxy-bis-(phenacyl-pyridinium chloride), 120 g. 4-(4-quinolinium acetylphenylmercapto). - phenacyl PY ridinium dichloride of starch and 2 g. of magnesium‘stearate are granulated 4- (4-triethylammonium .acetylphenylmercapto) -phenacyl and, then compressed into, tablets such that each tablet oc-picolinium dibromide contains '200 ‘mg. ‘of ‘the ‘active compound. Other ?llers 4,4’-oxy-bis-(phenacylediethylmethylammonium bromide) 45 or binders can, of course, be ‘used in place of the starch and magnesium stearatespeci?ed above. The preparation of compounds represented by the above This invention is further illustrated by ‘the following formula can be accomplished by reacting a 4,4'-oxy7bis speci?c, examples: (phenacylhalide) or 4,4"-thio-bis-(phenacyl-halide) with a EXAMPLE 1 suitable tertiary amine. symmetrically substituted com 50 Preparation of 4,4’-oxy-bis- (phenacyl-pyridinium pounds are prepared by using a molar excess ofjthe chloride) tertiary amine Whereas unsymmetrically substituted'com A reaction mixture was prepared containing 72 g. of pounds are prepared by using less than one equivalent of 4,4’-oxy-bis-.(phenacyl chloride), 50.5 ,ml. of pyridine, 2 two different tertiary amines in each of two successive 55 ml. of 12 N hydrochloric acid and 2250 ml. of 95 percent reactions. A mono-halo, mono-quaternary ammonium ethanol. The mixture was heated to re?uxing tempera salt is of necessity an intermediate in the latter method ture for about 2 days, thus forming 4,4'-oxy-bis-(phen of preparation. When a symmetrical compoundisto acyl~pyridinium chloride). The volume of solution was be ‘prepared, the excess of ‘the particular amine which is decreased to about 15001111. by evaporation of the reac present can also be used as a solvent provided the amine tion mixture in vacuo. Su?icient anhydrous diethyl ether is a liquid at reaction temperatures. A preferable method was then added to bring the volume of solution up to of preparation, however, is one employing an inert solvent about 3 l. whereupon the 4,4’=oxy-bis-'(phenacyl-pyridin such as a low molecular weight alcohol. The use of a ium chloride) precipitated from solution. The precipi solvent or diluent is, of course, ‘necessary when the re tated material .was collected by I?ltration, and was recrys acting tertiary amine is a solid or When a compound with tallized :twice .from .95 ‘percent ethanol after ‘a decolori unsymmetrical amine substituents is to be prepared. vIn zation with activated'charco'al. Seventy-three ‘and two carrying out the reaction, the reaction mixture is simply tenths grams of puri?ed 4,4'éoxy-bis4(phenacyl-pyridin heated, usually at the re?ux temperature of the system, ium chloride) .meltingat about 169° C. ‘were obtained. until the reaction issubstantially complete. The compound analysed for atrihydrate as follows. 2,859,217 4 . Analysis.—Calc’d (after drying): Cl=14.70. Found: product.v The resulting mixture was ?ltered. The ?ltrate ‘ ' Cl_=14.45. Wt. loss on drying=9.78. Theoretical wt. separated into a water layer and an organic layer con loss for three molecules of water=10.09. taining the 4,4’-thio-bis-(phenacyl chloride). The organic . layer was separated, and evaporated to dryness in vacuo. , EXAMPLE 2 The resulting residue comprising crystalline 4,4’-thio-bis Preparation of 4,4’-thio-bis-(phenacyl-pyridinium (phcnacyl chloride), was twice decolorized with activated ‘ chloride) charcoal and was then recrystallized from anhydrous A~ A mixture of 10 g. of 4,4’-thio-bis-(phenacyl chloride) ethanol. 4,4’-thio-bis-(phenacyl chloride) thus obtained . and 75 ml. of pyridine were re?uxed for about 16 hrs., melted at about l05-106° C. thus forming 4,4’-thio-bis-(phenacyl-pyridinium chloride). 10 Analysis. —— Calc’d: C=56.65; H=3.57. Found: 7, The compound was isolated by- treating the reaction mix C=56.45; H=3.46. ture with acetone, and separating the resulting solid by EXAMPLE 7 ?ltration. The ?lter cake was puri?ed by several recrys- ' tallizations from an acetone-ethanol solvent mixture. Preparation of 4 - (4 - chloroacetylphenoxy) - phenacyl- 1 15 4,4’-thio-bis-(phenacyl-pyridinium chloride) melted at . - pyridinium chloride ’ about 163° C. with some early softening. A solution was prepared containing 0.1 mol. of 4,4'-. oxy-bis-(phenacyl chloride), 250 ml. of benzene and 250 - EXAMPLE‘ 3 ml. of acetone. This solution was stirred and was heated Preparation of 4,4’-thio - bis - (phenacyl - trimethylam - to re?uxing temperature during the addition of 0.075 monium chloride) - , mol of pyridine dissolved in 100 ml. of benzene. The stir ring and re?uxing were continued for about 16 hours after A reaction’ similar to that of Example 2 was carried the addition of the pyridine had been completed in order out except that a solution of trimethylamine in acetone to give a maximum yield of 4-(4-chloroacetylphenoxy) was used in place of pyridine. 4,4’-thio-bis-(phenacyl phenacyl-pyridinium chloride. Upon cooling the reaction trimethylammonium chloride) thus formed, was puri?ed 25 by threefold recrystallization from a solvent mixture , mixture, crystals of 4-(4-chloroacetylphenoxy)4phenacy1 containing diethyl ether and 95 percent ethanol followed’ pyridinium chloride precipitated. These were collected by a recrystallization from a solvent mixture containing by ?ltration. Recrystallization of the ?ltered materials methanol and ethyl acetate. 4,4’-thio-b'is-(phenacyl from anhydrous ethanol yielded crystals of 4-(4-chloro acetylphenoxy) - phenacyl .- pyridinium chloride melting trimethylammonium chloride) did not melt even when with decomposition at about 198-199" C. heated above 320° C. ' Analysis.'—Calc’d: C=62.70; H=4.20; N=3.4s. EXAMPLE 4 Found: C=62.49; H=4.25; N=3.21. p 7 Other half-quaternary ammonium salt half-halide com Preparation of 4,4’ - oxy-bis - (phenacyl - trimethylam pounds can be prepared by using other tertiary amines monium chloride) . such as a-picoline, quinoline, trimethylamine and the like ‘A preparation similar to that of Example 3 was carried in place of pyridine in the above example, and by using . out using 4,4’-oxy-bis-(phenacy1 chloride) in place of the appropriate 4,4’-oxy-bis-(phenacyl halide). the corresponding thio compound. 4,4'-oxy-bis-(phenacyl-r trimethylammonium chloride) prepared and isolated by EXAMPLE 8 the above procedure, was puri?ed by one recrystallization 40 Preparation of ‘4-(7-picolinium acetylphenoxy)-phenacyl? ' from 95 percent ethanol followed by two recrystalliza pyridinium dichloride >7 tions' from a methanol-ethyl acetate solvent mixture. The Following the procedure of Example 7, 4-(4-chloro compound did not melt even when heated to above acetyl-phenoxy)-phenacylpyridinium chloride was reacted, , about 380° C. with a solution of 'y-picoline and alcohol to yield 4-(4-7 Analysis. —— Calc’d: C=59.86; H=6.85. Found: 45 picolinium acetylphenoxy) -phenacylpyridinium dichlo (1:60.04; H=7.54. ride. This compound melted at about 179-180° C. with.} EXAMPLE 5 _ decomposition after recrystallization from an alcohol ether solvent mixture. , ' Preparation of 4,4'-oxyi-bis-(phenacyl-u-picolinium chlo Analysis.--Ca'.lc’d: N=5.66. Found: N=5.41.. ride) 59. EXAMPLE 9 A reaction was carried out following the procedure of Example 2 but employing a-picoline in place of pyridine Preparation of 4,4’-oxy-bis-phenacyl quaternary and 4,4’-oxy-bis-(phenacyl chloride) in place of 4,4’-thie ammonium bromides or iodides ' . bis-(phenacyl chloride). .4,4’-oxy-bis-(phenacyl-a-pico Following the method of Example 1 but employing‘ linium chloride) prepared in this way melted at about .. 4,4'-oxy-bis-(phenacyl bromide) in place of 4,4’-oxy-bis-, 250-252“ C. after being recrystallized three times from (phenacyl chloride), 4,4’-oxy-bis-(phenacyl pyridinium a mixture of 95 percent ethanol and ether. Similar re bromide) can be prepared. The corresponding thio com actions were carried out using ?-picoline, 'y-picoline, and pound can be prepared by, using the 4,4’-thid-bis4 quinoline in place of' a-picoline to give 4,4’-oxy-bis (phenacyl bromide). Other tertiary amines can be used (phenacyl-B-picolinium chloride), 4,4’-oxy-bis-(phenacyl 6.0 in place of pyridine to yield different bis phenacyl 'y-picolinium chloride), and 4,4’-oxy-bis-(phenacyl-quin quaternary ammonium bromides. The corresponding olinium chloride), respectively. > iodides can also be prepared by the same method, using thev appropriate phenacyl iodide as a starting material. ' EXAMPLE 6 ’ I claim: ' ‘ i Preparation of 4,4’-thio-bis-(phenacyl chloride) ' 1. 4,4’-oxy-bis-(phenacyl-pyridinium chloride). ‘ ' 2. 4,4’-thio-bis-(phenacyl-pyridinium chloride). One mol of diphenyl ‘sul?de was dissolved in 1 1. of . 3. 4,4’ - oxy-bis - (phenacyl - trimethylammonium chlo carbon disul?de in which had been suspended 275 g.’ ride); . _ ‘ of anhydrous aluminum chloride. To this stirred mix-1 4. 4,4’-oxy-bis-(phenacyl-a-picolinium chloride). ture was added 339 g. of chloracetylchloride. After‘ the 70, 5. 4-(4Jy-picolinium acety1phenoxy)—phenacyl pyridini addition had been completed, the reaction mixture was. um dichloride. ‘ ‘ f ' stirred for one-half hour further to insure more nearly‘ complete formation of of 4,4’-thio-_bis-(pheriacyl chlo.-3 7 References Cited in the ?le of this patent ride) and was then poured over 2 kg. of ‘ice to decompose! Bahner et al.: J. Am. Chem. Soc.,- vol. 75, pagesv organoaluminium complexes and free the desired reaction 75 1472-3 (l953).