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Publication numberUS3385857 A
Publication typeGrant
Publication dateMay 28, 1968
Filing dateNov 7, 1966
Priority dateOct 5, 1965
Also published asDE1670389A1
Publication numberUS 3385857 A, US 3385857A, US-A-3385857, US3385857 A, US3385857A
InventorsStevens George De, Mizzoni Renat Herbert
Original AssigneeCiba Geigy Corp
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Cycloaliphatic pyrimidines
US 3385857 A
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Description  (OCR text may contain errors)

United States Patent 3,385,857 CYCLOALIPHATIC PYRIMIDINES Rcnat Herbert Mizzoni, Long Valley, and George de Stevens, Summit, N.J., assignors to Ciba Corporation, New York, N.Y., a corporation of Delaware No Drawing. Continuation-impart of application Ser. No. $72,671, Aug. 16, 1966. This application Nov. 7, 1966, Ser. No. 592,314

13 Claims. (Cl. 260-2564) This is a continuation-in-part of application Ser. No. 572,671, filed Aug. 16, 1966, which in turn is a continuation-in-part of application Ser. No. 534,666, filed Mar. 16, 1966, which in turn is a continuation-in-part of application Ser. No. 493,233, filed Oct. 5, 1965, now abandoned.

The invention concerns and has for its object the provision of quarternary -ammoniummethyl-4-amino-Z-cycloaliphatic-lower alkyl-pyramidine salts in which the ammonium nitrogen atom is part of a monoor bicyclic heterocyclic radical containing at least one double bond extending from the ammonium nitrogen, as well as methods for their preparation.

More particularly this invention relates to compounds having the formula in which R stands for cycloalkyl or cycloalkenyl, or any such radical substituted by lower alkyl groups, halogen atoms or etherified hydroxy or mercapto groups, alk for lower alkylene, R for an ammonium group of which the nitrogen atom is part of a 5- or 6-ring-membered monocyclic heterocyclic radical or an 8- to -ring-membered bicyclic heterocyclic radical containing up to 3 hetero atoms and at least one double bond extending from the ammonium nitrogen, and X for the anion of an acid, and acid addition salts thereof.

'A cycloalkyl group representing R, more particularly contains 3 to 8 ring-carbon atoms and preferably stands for cycloalkyl or (lower alkyl)-cycloalkyl with 3 to 6 ringcarbon atoms, such as cyclopropyl, Z-methyl-cyclopropyl, 2,2- or 2,3-dimethyl-cyclopropyl, 2,2,3,3-tetramethyl-cyclopropyl, 2-ethyl-cyclopropyl, cyclobutyl, 2,2,3-trimethylcyclobutyl, 3-ethyl-cyclobutyl, cyclopentyl, 2- or 3-methylcyclopentyl, 2,5- or 3,4-dimethyl-cyclopentyl, cyclohexyl, 2-, 3- or 4-methyl-cyclohexyl, 2,3-, 2,4- or 3,5-dimethyl-cyclohexyl, 2,4,6-trimethyl-cyclohexyl, cycloheptyl or cyclooctyl. A cycloalkenyl group R has at most 2 double bonds and, more particularly, contains 3 to 8 ring-carbon atoms. It preferably stands for cycloalkenyl or (lower alkyl)- cycloallienyl wiih S to 6 ringcarbon atoms and represents, for example, 2-cyclopropenyl, 1- or 2-cyclopentenyl, 2,4- cyclopentadienyl, 2- or 3-methyl-2-cyclopentenyl, 4,5-dimethyl-Z-cyclopentenyl, 1-, 2- or 3-cyclohexenyl, 2,5-cycyclohexadienyl, 2-, 3- or 4-methyl-1- or 2-cyclohexenyl, 2,4- or 3,5-dimethyllor 2-cyclohexenyl, 2,4,6-trimethyl- 2,5-cyclohexadienyl, 1-, 2- or 3-cycloheptenyl, 2,6-cycloheptadienyl or Z-cyclooctenyl. The above cycloaliphatic radicals may additionally be substituted by one or more than one halogen atoms, such as fluoro or chloro, or etherified hydroxy or mercapto groups, such as lower alkoxy or lower alkylmercapto, e.g. methoxy, ethoxy, nor i-propoxy, n-, i, sec. or tert.-but0xy, methylor ethylmercapto.

The lower alkylene portion alk separating said cycloaliphatic group from the 2-position of the pyrimidine nucleus preferably has 1 to 4 carbon atoms and especially represents methylene, but also 1,1- or 1,2-ethylene, 1,l,

out-R1 1,2-, 2,2- or 1,3-propylene, 2-methyl-l,3-propylene, 1,1-, 1,2-, 2,2- 1,3- or 1,4-butylene.

The ammonium group R represents, for example a pyridinium, quinolinium, isoquinolinium, pyridazinium, pyrimidinium, pyrazinium, quinazolinium, phthalazinium, 1,5-, 1,6-, 1,7- or 1,8-naphthyridinium, N-lower alkyl-N'- pyrazoli um, N-lower alkyl-N-imidaz-olium, thiazolium, oxazolium, 1,3,5-triazinium, l-lower alkyl-lH-pyrrolo [3,- 2-b pyridinium, 6-lower alkyl-6H-pyrrolo [3 ,4-b pyridinium, thieno[3,2-b]pyridinium, thieno[2,3-b]pyridinium, pyrido[3,2-b] pyrimidinium or pyrido [2,3-b]pyrazinium radical, or a partially hydrogenated derivative thereof, such as pyrazolinium, N-lower alkyl-Npyrazolinium, imidazolinium, N-lower alkyl-N'-imidazolinium, thiazolinium or oxazolinium radical. It may be unsubstituted or substituted by one or more than one of the same or of different substituents, for example, lower alkyl groups, such as those mentioned above, free or functionally converted hydroxy or mercapto groups, such as lower alkoxy or alkylmercapto, e.g. that mentioned above, halogen, e.g. fiuoro, chloro or bromo, trifluoromethyl or amino, especially di-lower alkylamino, e.g. dimethylamino or diethylamino.

The anion X as well as the acid addition salts mentioned in the beginning, are preferably derived from therapeutically useful inorganic or organic acids, such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulfuric, phosphoric, nitric or perchloric acid, aliphatic, alicyclic, aromatic or heterocyclic carboxylic or sulfonic acids, for example, formic, acetic, pripionic, succinic, glycollic, lactic, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, pyroracemic, phenylacetic, benzoic, p-aminobenzoic, anthranilic, p-hydroxybenzoic, salocylic, p-aminosalicylic, embonic, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, ethylenesulfonic, halobenzenesulfonic, toluencsulfonic, naphthalenesulfonic or sulfanilic acid, methionine, tryptophane, lysine or arginine.

The compounds of this invention possess valuable pharmacological properties. For example, they exhibit antiprotozoal activity, especially against parasites causing coccidiosis, such as Eimeria tenella, acerv'ulina, adenoz'des, agridis, brmzetti, hagani, maxima and necalrix. This can be demonstrated, for example, by the curative effect of a feed, containing about 0.001 to about 0.02% of the compounds of this invention, given to chickens one or two days prior till 8 days after their inoculation with sporulated oocysts of Eimeria tenella, acervulina, maxima or necatrix. The curative effect can also be demonstrated at doses between about 0.001 to 0.02% applied after inoculation with said oocysts. The compounds of this invention are, therefore, useful agents in the control of coccidiosis, which is one of the most important goals in the poultry raising industry. Furthermore, they are useful intermediates in the manufacture of other valuable compounds, especially medicines.

Particularly useful are compounds of the formula in which R stands for cycloalkyl (lower alkyl)-cycloalkyl, (lower alkoxy)-cycloalkyl or (halo)-cycloalkyl with 3 to 6 ring-carbon atoms, alk for alkylene with 1 to 4 carbon atoms, R for pyridinum, quinolinium, isoquinolinium, pyridazinium, pyrimidinium, pyrazinium, thiazolium, thiazolinium, oxazolium, oxazolinium, imidazolium, imidazolinium or such radical substituted by up to 2 lower alkyl groups, and X for the anion of an acid, and acid addition salts thereof.

Of special value are compounds of the formula in which p stands for an integer from 2 to 5, n for an integer from 1 to 2, m for an integer from 1 to 4, q for an integer from to 2, and X for the anion of an acid, and acid addition salts thereof.

Especially mentioned are the -(2,4-dimethylpyridinium)-methyl-4-amino-2-cyclopropylmentylor cyclobutylmethyl-pyrimidine chloride hydrochloride and 5-(2-methyl-pyridinium)-methyl 4-amino-2-cyclopropyl-methylor cyclobutyl methyl pyrimidine chloride hydrochloride which, when given to infected chicken with the feed in an amount between about 0.001 to 0.02%, show an outstanding curative effect.

The compounds of the invention are prepared by methods in themselves known. Advantageously they are obtained by reacting a reactive ester or ether of a S-hydroxymethyl 4-amino-2-cycloaliphatic-lower alkyl-pyrimidine with a monoor bicyclic heterocyclic compound containing at least One ring-nitrogen atom and double bond, and/or converting a quaternary S-ammonium-methyl-4- amino 2-cycloaliphatic-lower alkyl-pyrimidine base or pseudobase into its quaternary salt and/or, if desired, converting a resulting free 4-amino-compound into its acid addition salt or converting a resulting acid addition salt into the free 4-amino-compound or into another salt and/ or converting a resulting quaternary salt into another quaternary salt.

A reactive ester of said S-hydroxymethyl compound is, for example, that of a strong inorganic or organic acid, such as a hydrohalic, sulfuric, sulfonic or carbamic acid, e.g. hydrochloric, hydrobromic, sulfuric or lower alkyl sulfuric acid, a lower alkane or benzene sulfonic acid, e.g. methane, ethane, benzene or p-toluene sulfonic acid, or unsubstituted or N-substituted carbamic acid, e.g. N,N- dimethylor N-phenyl-carbamic acid. An ether of said 5- hydroxymethyl compound is preferably a lower alkyl or phenyl-lower alkyl ether, e.g. the methyl, ethyl, isopropyl or benzyl ether. The quaternary base or pseudobase may contain hydroxy as an anion or as substituent of the heterocyclic ring containing the ammonium nitrogen. Advantageously the esters of the S-hydroxymethyl compound are reacted in the form of their acid addition salts with the free heterocyclic compound, whereas the corresponding ethers are reacted in the free form with an acid addition salt of the heterocyclic reagent.

The compounds of the invention are obtained in the free form, i.e. that having a free 4-amino group, or in the form of their acid addition salts, depending on the conditions under which the process is carried out; these salts are also included in the present invention. Acid addition salts that are obtained can be converted into the free compounds in known manner, for example, with weak alkalies, e.g. alkali metal carbonates or bicarbonates, or into other salts, for example with ion exchangers. Free compounds that are obtained, as well as the quaternary bases or pseudobases, can be converted into acid addition salts or quaternary salts respectively, by reacting them with inorganic or organic acids, especially those that are suitable for the formation of therapeutically useful salts, for example those listed for the anion X The transquaternization is carried out in the usual manner, advantageously with an excess of the corresponding heterocyclic base.

The above reactions are carried out according to stand ard methods, in the presence or absence of diluents, preferably such as are inhert to the reagents and are solvents thereof, of catalysts, condensing agents and/or inert atmospheres, at low temperatures, room temperature or advantageously elevated temperatures, at atmospheric or superatmospheric pressure.

The invention further includes any variant of the present process in which an intermediate product obtainable at any stage of the process is used as starting material and any remaining steps are carried out, or the process is discontinued at any stage thereof, or in which the starting materials are formed under the reaction conditions, or in which the reaction components are used in the form of their salts. For example, the reactive ester ofthe S-hydroxymethyl compounds, e.g. a sulfonic acid ester, is advantageously formed under the reaction conditions, i.e. in the presence of the heterocyclic compound. Mainly those starting materials should be used in the reactions of the invention that lead to the formation of those compounds indicated above as being especially valuable.

The starting materials are known, or if they are new, may be prepared by methods in themselves known. Thus, for example, the 5-hydroxymethyl-4-amino-2-cycloaliph-atic-lower alkyl-pyrimidines may be prepared by reacting a cycloaliphatic-lower alkanoic acid amidine or imido ester with a lower alkoxy-methylidene-malodinitrile, reducing the resulting 5-cyano-4-amino-2-cycloaliphatic-lower alkyl-pyrimidine to the corresponding 5- amino-methyl compound, for example with catalytically activated hydrogen, and converting it into the corresponding S-hydroxymethyl compounds, for example by the reaction of nitrous acid. Said alcohol can be reactively esterified or etherified according to known methods, for example with a thionylh'alide or phosphorus halide, a sulfuric or sulfonic acid halide, e.g. sulfuryl, tosyl or brosyl chloride. A S-halomethyl compound obtained may then be reacted with an anhydrous alcohol or mercaptan in order to obtain the desired ethers. The latter may also be prepared by reacting an acid addition salt of a cyloaliphatic-lower alkanoic acid amidine with an a-alkoxymethylene- 3-alkoxy-propionitrile. The quaternary bases or pseudobases may be obtained by reduction of the corresponding oxo-compounds, i.e. the cyclic amides, for example with the use of complex light metal hydrides, such as lithium aluminum hydride or sodium borohydride.

The compounds of the invention may be used, for example in the form of veterinary compositions, animal feedingstuffs or additives to feedingstutfs, which are a further object of the present invention. The former contain said compounds in admixture with organic or inorganic, solid or liquid pharmaceutical excipients suitable especially for enteral administration. Suitable excipients are substances that do not react with the new compounds, for example water, gelatine, lactose, starch, stearyl alcohol, magnesium stearate, talc, vegetable oils, benzyl alcohol, gums, propylene glycol and other known medicinal excipients. The compositions may be, for example, tablets or pills, e.g. microphills, or in liquid form as solutions, suspensions or emulsions. They may be sterilized and/or contain adjuvants such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure or butters. They are prepared by conventional methods.

The feedingstuffs and additives for feedingstuffs or for the drinking water contain the compounds of the invention together wit-h conventional extenders, diluents and/or nutrients, such as sucrose, glucose, molasses, fermentation residues, cornmeal, ground and rolled oats, wheat shorts and middlings, meat scrap, oil cake, soybean and fish metal, alfalfa, clover, grass clippings and the like, mineral supplements, such as bone meal, calcium carbonate, iodized salt and the like, vitamins, such as vitamins A, B, C and D and other suitable substances, such as preservants, e.g. benzoic acid. The feedingstufis contain the compounds of the invention in an amount ranging between about 0.000l and 0.1% preferably bet-ween about 0.001 and 0.02%, whereas the additives may contain the pure substances, when used, for example, for the drinking water, but usually contain between about 1 and 50% thereof. The amount of the compounds of the invention administered via the veterinary compositions or the drinking water corresponds to that given with the medicated feedingstuffs shown above. The compositions, feedingstufis and additives may contain other therapeutically valuable substances, for example, sulfonamides, such as N'-(6-chloro-2-pyraziny1)-sulfanilamide, N'-(2,6-dimethoxy-4-pyrimidyl)-sulfanilamide, N'- -ethyl- 1 ,3 ,4-thiadiazol-2-yl) -sulfanilarnide, N'-(5-methyl-3-isoxazolyl)-sulfanilamide, N'-( 6-methoxy-3-pyridazinyl) -sulfanilamide and the N-acetyl derivative thereof, N-(4-methyl-2-pyrimidinyl)-sulfanilamide, N'-(2,6-dimethyl-4-pyrimidinyl)-sulfanilamide, N'-(S-methyl-1,3,4'thiadiazol-2-yl)-sulfanilamide, N-(6-chloro-3-pyridiazinyl)-sulfanilamide and the sodium salt thereof, N'- 2-phenyl-3-pyrazolyl) -sulfanilamide, N'-(2-phenyl-5-rnethyl-3-pyrazolyl)-sulfanilamide and the like. Sulfonamides of the type mentioned above can be used in approximately one fifth to one half of the amount effective as an antibacterial. In addition, the compositions, feedingstuffs and additives of the invention may contain antibiotics, e.g. penicillin, streptomycin, aureomyein, Terramycin, tetracycline and the like, antiparasitic agents, e.g. methyl-4-acetamino-Z-ethoxy-benzoate, 2-amino-5- nitro-thiazole or 1-(5-nitro-thiazolyl-2)-2-oxotetrahydroimidazole and/or tranquilizers, such as reserpine, methyl 18-epi-O methyl-reserpate, meprobamate and the like.

The following examples illustrate the invention; temperatures are given in degrees Centigrade and all parts wherever given are parts by weight. The Amberlite IRA- 400 resin, to which reference is made below, is a strong basic quaternary ammonium ion exchange resin of the type covered in US. Patent No. 2,591,573.

Example 1 2.2 g. 5-hydroxymethyl-4-amino-2-cyclopropylmethylpyrimidine are dissolved in ml. of freshly distilled 2,4- lutidine, and to this solution 2.24 g. p-toluenesulfonyl chloride are added. The mixture is allowed to stand at room temperature for 4 days. It is then diluted with diethyl ether to yield a precipitate of which the supernatant solution is decanted. The residue is dissolved in isopropanol and the product 4 times precipitated With diethyl ether until the odor of 2,4-lutidine disappears. The crystalline 5 (2,4-dimethyl-pyridinium)-methyl-4-amino-2- cyclopropylmethyl-pyrimidine salt is dissolved in 100 ml. water and the solution is passed through an Amberlite IRA400 resin column present in the chloride form. The aqueous eluate is concentrated in vacuo and the residue recrystallized from methanol-isopropanol to yield the 5- (2,4 dimethyl pyridinium)-methyl-4-amino-2-cycl0propylmethyl-pyrimidine chloride hydrochloride of the formula The starting material is prepared as follows:

104 g. cyclopropyl-acetonitrile are dissolved in 75 ml. anhydrous ethanol and 300 ml. diethyl ether, and through the solution anhydrous hydrogen chloride is bubbled until the uptake of 46.0 g. thereof is noted. The solid formed is filtered off after cooling and washed with anhydrous diethyl ether. The so-obtained cyclopropyl'acetic acid imino-ethylester hydrochloride is suspended in 75 ml. anhydrous ethanol and the mixture treated with 175 ml. 7.2 N ethanolic ammonia. After stirring at room temperature for 7 hours, the mixture is maintained at this temperature overnight. It is filtered, the filtrate concentrated in vacuo and the residual white crystals filtered off to yield the cyclopropyl-acetic acid amidine hydrochloride.

The solution of 118 g. thereof in 800 ml. anhydrous ethanol is added to a solution of sodium ethylate prepared from 19.9 g. sodium and 850 ml. anhydrous ethanol, whereby the temperature is maintained at 5. The separated salt is removed by filtration and the filtrate is added dropwise within 1 hour to a stirred solution of 112.5 g. ethoxymethylidenemalonodinitrile in 900 ml. anhydrous ethanol at 5 and stirring is continued for additional 2% hours. The product is filtered, washed with ethanol and dried in vacuo at 50 to yield the 5-cyano-4- amino-2-cyclopropylmethyl-pyrimidine.

The suspension of 18.2 g. thereof and 2.0 g. 10% palladium-charcoal in 200 ml. glacial acetic acid is saturated with anhydrous hydrogen chloride and hydrogenated at psi-initial pressure. Three such runs are combined, diluted with water to dissolve separated salts and filtered to remove the catalyst. The filtrate is evaporated in vacuo, to the residue water is added and the distillation is repeated 3 times to remove remaining acetic acid. Finally anhydrous ethanol is added to the residue together with 10 m1. 4 N-ethanolic hydrochloric acid and the distillation is repeated to remove traces of water. The residue is finally boiled with isopropanol and filtered to yield the S-aminomethyl-4-amino-2-cyclopropylmethyl-pyrimidine dihydrochloride.

To a solution of 26.6 g. thereof in 400 ml. water the solution of 7.5 g. sodium nitrite in 400 ml. water is added over a 3 hour period whereby the temperature is maintained at -55. The homogeneous solution is stirred for 17 hours at said temperature, then concentrated by distillation in vacuo and finally adjusted to a pH about 7.5-8 with saturated sodium carbonate solution. The yellow residue extracted with 4 portions of boiling aqueous acetone, the solution concentrated to a small volume and the remaining water is removed azeotropically with ethanol. The solution is filtered, the filtrate acidified to a pH of about 4 with ethanolic hydrochloric acid and then diluted with diethyl ether. After standing for a short time, the precipitated yellow solid is filtered, ground in a mortar with diethyl ether, filtered and vacuum dried at 50 to yield the 5-hydroxymethyl-4-amino-2-cyclopropylmethyl-pyrimidine hydrochloride.

The hydrochloride obtained is dissolved in the minimum amount of water and solid potassium carbonate is added while cooling and stirring until an oily layer separates. It is extracted with n-butanol until the last extract is virtually colorless. The combined extracts are dried over potassium carbonate, filtered and evaporated in vacuo. The residue is trituratml with diethyl ether, filtered, washed with ether and dried in vacuo at 50 to yield the 5 hydroxymethyl-4-amino-2-cyclopropylmethyl-pyrimidine.

Example 2 19.0 g. S-hydroxymethyl-4-amino-2-cyclopropylrnethylpyrimidine are dissolved in ml. 2,4-lutidine with warming. Hereupon 20.4 g. p-toluenesulfonyl chloride are added portionwise while cooling, the solution is filtered and allowed to stand at 20 for 18 hours and at room temperature for 5 /2 days. It is then diluted with diethyl ether, the gummy solid triturated with diethyl ether and recrystallized from isopropanol-diethyl ether to yield the 5 -(2,4 dimethyl pyridinium-methyl)-4-amino-2-cyclopropylmethyl-pyrimidine salt melting at 238239.

40.3 g. thereof are dissolved in 300 ml. water containing 5 ml. 0.006 N hydrochloric acid, the solution is treated with charcoal, filtered and the filtrate passed through a column of Amberlite IRA-400 resin column in the chlo ride form. The column is washed with 500 ml. water, the combined eluates treated again with charcoal, filtered and evaporated in vacuo. To the residue isopropanol is added, which is distilled off removing the residual water azeotropically. The dried residue is suspended in acetone, the suspension filtered, the filter cake washed with acetone and recrystallized from methanol-isopropanol (1:1), to yield the 5-(2,4-dimethyl-pyridinium-methyl)-4-amino-2- cyclopropylmethylpyrimidine chloride hydrochloride, melting at 250.5 to 251 with decomposition; it is identical with the product obtained according to Example 1.

The starting material is prepared as follows: To the suspension of 41.1 g. lithium aluminum hydride in 300 ml. anhydrous diethyl ether, the solution of 100 g. cyclopropaue carboxylic acid in 300 ml. diethyl ether is added slowly while stirring. The rate of addition is adjusted to maintain a gentle reflux of the solvent, and stirring and refluxing is continued for 8 hours. Hereupon the mixture is diluted with 500 ml. diethyl ether and 130 ml. aqueous sodium hydroxide are stirred in while chilling. The mixture is filtered, the residue washed with diethyl ether, the filtrate dried, evaporated, the residue distilled and the fraction boiling at 122-126 collected. It represents the cyclopropyl-methanol having an n =1.4299.

89.1 g. thereof are dissolved in 350 ml., anhydrous diethyl ether, the solution cooled to 70 and 40.8 g. phosphorus tribromide are added dropwise with stirring during /2 hour. The reaction mixture is then allowed to warm up gradually to room temperature overnight and is then treated with 12 ml. water. The organic layer is separated, washed with saturated aqueous sodium carbonate and with water, dried, evaporated and the residue distilled to yield the cyclopropylmethyl bromide boiling at 102110, n ==1.4752.

126.5 g. thereof are added to the stirred suspension of 51.9 g. sodium cyanide in 377 ml. dimethylsulfoxide while maintaining the temperature between and Hereupon the reaction mixture is kept at for 2 hours, then cooled, diluted with 500 ml. water and extracted with diethyl ether. The extract is washed with water, 25 ml. 6 N hydrochloric acid, dried and evaporated. The residue is distilled and the fraction boiling at 142-147 collected; it represents the cyclopropylacetonitrile, 11 14218.

The solution of 101 g. thereof in 61.4 g. anhydrous ethanol is gassed with hydrogen chloride until 48.3 g. thereof are consumed. After standing overnight at -20 the precipitate formed is filtered otf, washed with diethyl ether and dried under reduced pressure, to yield the hygroscopic cyclopropylacetimidic acid ethyl ester hydrochloride.

To the solution of 173.1 g. thereof in ml. anhydrous ethanol, ml. 6.3 N ethanolic ammonia are added r rapidly while stirring and cooling. The reaction mixture is allowed to stand at room temperature overnight, whereupon it is filtered, the filtrate concentrated to /2 of its volume and the concentrate chilled until crystallization occurs by scratching. The cyclopropyl-acetamidine hydrochloride formed is filtered off, washed with anhydrous diethyl ether and dried under reduced pressure.

The solution of 136.6 g. thereof in 700 ml. anhyrous ethanol is added to the solution, prepared from 23.6 g. sodium and 950 ml. anhydrous ethanol, at 15 during /2 hour while stirring. Upon addition of Filter-Cel the mixture is filtered through a sintered glass funnel and the filtrate is added to the solution of 130 g. ethoxymethylidene-malonodinitrile in 130 ml. anhydrous ethanol during 1 /4 hours while chilling to 5 to -10". The mixture is stirred for 3 hours at this temperature, then filtered, the residue washed with cold anhydrous ethanol and dried in vacuo at 50, to yield the 5-cyano-4-amino-2- cyclopropylrnethyl-pyrimidine melting at 181-1825.

The suspension of 17.4 g. thereof, 2.5 g. 10% palladium charcoal and 200 ml. glacial acetic acid is saturated with anhydrous hydrogen chloride and hydrogenated at 150 p.s.i. initial pressure. The theoretical hydrogen uptake is noted after about 6 hours. The mixture is diluted with water, filtered and the filtrate evaporated in vacuo. To the residue isopropanol is added and distilled oif, in order to remove water and acetic acid. Finally the residue is heated on a steam bath under vacuum for 1 hour and recrystallized from isopropanol-methanol to yield the 5- aminomethyl 4 amino-2-cyclopropylmethyl-pyrimidine dihydrcchloride melting at 228.5 to 229.

The solution of 75.8 g. thereof in 1.1 liters water is heated to 55 with stirring and the solution of 23.0 g. sodium nitrite in 1 liter water is added dropwise during 2% hours while stirring. The mixture is kept at 54 for 6 hours and overnight at room temperature. Hereupon it is treated with charcoal, filtered with the aid of filter cel and the filtrate concentrated to 500 ml. in vacuo. The concentrate is cooled to 5 and neutralized with saturated sodium carbonate solution to a pH 7.5-8.0. It is extracted with n-butanol, the extract dried and concentrated in vacuo until crystallization occurs. After addition of diethyl ether the mixture is filtered and the residue washed with diethyl ether to yield the 5-hydroxymethyl-4-amino- 2-cyclopropylmethyl-pyrimidine melting at 143146.

EXAMPLE 3 18.5 g. 5-hydroxymethyl-4-amino-2-cyclopropylmethylpyrimidine are dissolved in 100 ml. 2-picoline and to the solution 19.9 g. p-toluenesulfonyl chloride are added. The mixture is worked up as described in Example 1 to yield the 5 (2 methyl-pyridinium-methyl)-4-amino-2cyclopropylmethyl-pyrimidine chloride hydrochloride of the formula Nin J] Ha melting at 225.5 to 226.5.

Example 4 melting at 240442".

The starting material is prepared as follows: The solution of 50.0 g. cyclobutylcarboxylic acid in 500 ml. diethyl ether is added to the mixture of 23.6 g. lithium aluminum hydride and 500 ml. diethyl ether while stirring and refluxing. The mixture is refluxed and stirred for 3 hours, then cooled in an ice bath and 71.6 ml. 15% aqueous sodium hydroxide are added under nitrogen. The precipitate formed is filtered off, washed with diethyl ether and the filtrate evaporated. The residue is distilled and the fraction boiling at -143 collected; it represents the cyclobutylmethanol.

36.2 g. thereof are dissolved in 250 ml. anhydrous diethyl ether, the solution chilled to 70, and combined with the solution of 14.8 g. phosphorus tribromide in 20 ml. diethyl ether while maintaining the temperature at 65 to 60. The mixture is stirred for 2 hours and gradually warmed up to room temperature. Hereupon 10 ml. water are added and the organic layer separated. It is washed twice with saturated aqueous sodium carbonate and once with water, dried and evaporated. The residue 9 is distilled and the fraction boiling at 134-136 collected; it represents the cyclobutylmethyl bromide.

28.5 g. thereof are added dropwise to the stirred mixture of 10.5 g. sodium cyanide and 76.4 g. dimethylsulfoxide at 50 within minutes and the resulting mixture is kept for 2 hours at 70. It is then cooled, 150 ml. water are added and extracted with diethyl ether. The extract is washed with cold 6 N hydrochloric acid and water, dried, filtered and evaporated. The residue is distilled and the fraction boiling at 78/ 38 mm. Hg collected; it represents the cyclobutyl-acetonitrile.

To the solution of 11.6 g. thereof in 5.6 g. anhydrous ethanol, 9.9 g. anhydrous hydrogen bromide are added at -30 to 40 and the mixture is allowed to stand overnight at The crystalline material is dried in vacuo over phosphorus pentoxide to yield the cyclobutyl-acetimidic acid ethyl ester hydrobromide melting at 798l.

22.7 g. thereof are dissolved in 10 ml. anhydrous ethanol and the solution treated with an excess of ethanolic ammonia. The mixture is stirred overnight at room temperature, concentrated to a small volume and the precipitate formed filtered off. It is washed with diethyl ether and dried in vacuo to yield the cyclobutyl-acetamidine hydrobromide melting at 152-l56.,

The solution of 18.4 g. thereof in 100 ml. anhydrous ethanol is added to the solution, prepared from 2.3 g. sodium and 100 ml. anhydrous ethanol, at 0 during /z an hour. The mixture is stirred for A1 of an hour in the cold, filtered and the filtrate added to the solution of 12.0 g. ethoxymethylidene-malonodinitrile in 110 ml. ethanol at 0 to 5, during /z an hour. The mixture is stirred for 4 hours at 0, the precipitate formed filtered off, Washed with a little cold anhydrous ethanol and dried in vacuo to yield the 5-cyano-4-amino-2-cyclobutylmethylpyrimidine melting at l79l8l.

The mixture of 18.8 g. thereof, 250 ml. methanol, 50 ml. liquid ammonia and 5 g. Raney nickel is hydrogenated at 3 atm. initial pressure until the theoretical hydrogen uptake is noted. It is then filtered, the filtrate evaporated, the residue dissolved in anhydrous ethanol and the solution acidified against Congo red with ethanolic hydrogen chloride. The precipitate formed is filtered off and washed with anhydrous ethanol to yield the 5-aminomethyl-4- amino-2 cyclobutylmethyl pyrimidine dihydrochloride melting at 259-262.

To the solution of 82.5 g. thereof in 1.1 liters water. the solution of 24.3 g. sodium nitrite in 1 liter Water is added during 2 hours at 50-55 while stirring, and stirring is continued for 6 hours at this temperature. The mixture is filtered, the filtrate concentrated in vacuo and the concentrate made basic with cold saturated aqueous sodium carbonate. The precipitate formed is filtered off, washed with a little cold water, dried and recrystallized from ethyl acetate to yield the 5-hydroxymethyl-4-amino-2- cyclobutylmethyl-pyrimidine melting at 137.

Example 5 the formula NHs ea N I C 112- .2 Cl 1 CH;

CH2-\N/ melting at 220224 10 Example 6 2.7 g. 5-chloromethyl-4-amino-2-cyclopropylmethylpyrimidine hydrochloride are suspended in 20 ml. 2,4- lutidine and the mixture is stirred for 4 hours on the steam bath. Hereupon it is chilled, diluted with diethyl ether, the supernatant liquid decanted and the residue boiled with isopropanol, Upon chilling the suspension is filtered, the residue washed with isopropanol and recrystallized from methanol-isopropanol to yield the 5-(2, 4 dimethyl pyridinium) methyl 4 amino 2 cyclopropylmethyl-pyrimidine chloride hydrochloride melting at 252 with decomposition; it is identical with the product obtained according to Example 1.

The starting material is prepared as follows: To the solution of 5.8 g. 5 hydroxymethyl 4 amino 2 cyclopropylmethyl-pyrimidine in 10 ml. dimethylformamide, 2.45 ml. thionyl chloride are added dropwise while stirring and keeping the temperature below 5. After stirring for 2 hours in the ice bath, the mixture is allowed to stand at 0 for 18 hours. Upon dilution with diethyl ether, the precipitate is filtered off, triturated with diethyl ether and acetone and recrystallized from isopropanoldiethyl ether to yield the 5-chloromethyl-4-amino-2-cyclopropylmethyl-pyrimidine hydrochloride melting at 191l95 with decomposition.

Example 7 The mixture of 6.5 g. 5-chloromethyl-4-amino-2-cyclopropylmethyl-pyrimidine hydrochloride and 30 ml. 2,4- lutidine is heated at the steam cone for 3 hours. It is allowed to stand overnight at room temperature, then diluted with acetone and the precipitate formed filtered off. It is washed with acetone until the odor of 2,4-lutidine disappears and recrystallized from aqueous isopropanol, to yield the 5-(2,4-dimethyl-pyridinium)-methyl-4-amino-2- cyclopropylmethyl pyrimidine chloride hydrochloride melting at 252253 with decomposition; it is identical with the product shown in Example 1.

The starting material is prepared as follows: To the solution prepared from 7.6 g. sodium and 200 ml. anhydrous ethanol, 61.2 g. cyclopropyl-acetamidine hydrobromide are added while stirring at 0l0. Stirring is continued for /2 an hour and hereupon 53.0 g. oc-IllB'tllOXY- methylidene-fi-isopropoxy-proponitrile (containing about 71% of the cis-isomer) are added in one portion and the mixture is stirred for 20 hours at room temperature. The precipitate formed is filtered olf, the filtrate evaporated in vacuo and the residue dissolved in methylene chloride. The solution is washed with water, the aqueous layer extracted with methylene chloride, the combined organic solutions dried, filtered and evaporated. The residue is dried in vacuo at room temperature and recrystallized from cyclohexane to yield the 5-isopropoxymethyl-4- amino-2-cyclopropylmethyl-pyrimidine melting at 107.5- 108.5

10.0 g. thereof are dissolved in 50 ml. anhydrous ethanol and the solution refluxed while being gassed with anhydrous hydrogen chloride for 2 hours. The mixture is cooled, concentrated with hydrogen chloride and allowed to stand for 24 hours at room temperature. It is then filtered, the residue triturated with diethyl ether and recrystallized from acetone-diethyl ether to yield the 5- chloromethyl 4 amino-2-cyclopropylmethyl-pyrimidine hydrochloride melting at l93-195 Example 8 2.2 g. S-hydroxymethyl-4-amino-2-(2-chloro-cycloproyD-methyl-pyrimidine are dissolved in 12 ml. 2,4-lutidine with warming. Hereupon 2.0 g. p-toluenesulfonyl chloride are added while cooling. The mixture is then filtered and the filtrate allowed to stand at 20 for 2 days and at room temperature for 4 days. It is then diluted with acetone, the precipitate formed filtered off, washed with acetone and recrystallized from isopropanoldiethyl ether to yield the 5-(2,4-dimethyl-pyridinium)- 1 1 methyl 4 amino-2-(2-chloro-cyclopropyl)methyl-pyridine chloride hydrochloride of the formula The starting material is prepared as follows: The stirred mixture of 35.64 g. phenyl-(trichlorornethyl)-rnercury, 21 ml. allylcyanide and 100 ml. dry benzene is refluxed for 137 hours under nitrogen. At this time the mercury com pound is completely used up. The mixture is filtered, the filtrate evaporated in vacuo and the residue triturated with diethyl ether. The precipitate formed is filtered off, the residue washed with diethyl ether, the filtrate evaporated in vacuo, the residue distilled and the fraction boiling at 100107/ 11 mm. Hg. collected; it represents the 2,Z-dichloro-cyclopropyl-acetonitrile.

15.0 g. thereof are dissolved in 60 ml. anhydrous ethanol and through the cooled solution hydrogen chloride is bubbled until 3.7 g. thereof are consumed. After standing overnight in the refrigerator the precipitate formed is filtered off, washed with diethyl ether and dried to yield the 2,2-dichloro-cyclopropyl-acetimidic acid ethyl ester hydrochloride.

97.5 g. thereof are suspended in 75 ml. anhydrous ethanol and 100 ml. 6.3 N ethanolic ammonia are added rapidly while stirring and cooling. The reaction mixture is allowed to stand at room temperature overnight. It is filtered, the filtrate evaporated and the residue recrystallized from ethanol to yield the 2,2-dichloro-cyclopropylacetic acid amidine hydrochloride.

68.5 g. thereof are dissolved in 350 ml. anhydrous ethanol and the solution combined with that prepared from 2.4 g. sodium and 95 m1. anhydrous ethanol. The mixture obtained is stirred for /2 hour at room temperature, then filtered through a glass funnel and the filtrate added dropwise to the solution of 13.0 g. ethoxymethylidene-malonodinitrile in 13 ml. anhydrous ethanol while keeping the temperature below The mixture is stirred for 3 hours at this temperature, then filtered, the residue washed with a little cold ethanol and dried in vacuo to yield the 5-cyano-4-amino 2 (2,2-dichloro-cyclopropyl)-methylpyrimidine.

15.0 g. thereof are hydrogenated in 100 ml. 2 N ethanolic ammonia over 15.0 g. Raney nickel for 2 days at 47 p.s.i. and room temperature. The mixture is then filtered, the filtrate evaporated and the residue acidified with ethanolic hydrochloric acid. The precipitate formed is filtered ofl? to yield the S-aminomethyl-4-amino-2-(2- chloro-cyclopropyl)-methyl-pyrimidine dihydrochloride.

The solution of 8.6 g. thereof in 115 ml. water is heated to 55 and the solution of 2.3 g. sodium nitrite in 100 ml. water is added dropwise while stirring. The mixture is kept at this temperature for 6 hours and stirred overnight at room temperature. Hereupon it is treated with charcoal, filtered and the filtrate concentrated to about 50 ml. in vacuo. The concentrate is cooled, neutralized with saturated aqueous sodium carbonate and extracted with nbutanol. The extract is dried and evaporated in vacuo. The residue is triturated with diethyl ether and the precipitate formed filtered off to yield the S-hydroxymethyl- 4-amino-2-(Z-chloro-cyclopropyl)-methyl-pyrimidine.

Example 9 In the manner described in the previous examples, the following compounds are prepared by using the equivalent amounts of the corresponding starting materials: 5-quinoliniummethyl-4-amino-2-cyclopropylmethylpyrimidine, S-isoquinoliniummethyl-4-amino-2-cyclopentylmethyl pyrimidine,

12 S-pyridaziniummethyl-4-amino-Zcyclopentylmethylpyrimidine, 5-pyrimidiniummethyl-4-amino-2-cyclohexylmethylpyrimidine, 5-pyraziniummethyl-4-amino-2-cyelopentylmethylpyrimidine, S-thiazoliniummethyl-4-amino-2-(2-cyclopentenyl)- methyl-pyrimidine, 5-oxazoliniummethyl-4-amino-2-(2-cyclopropylethyl)- pyrimidine, 5-(5,6-dimethoxy-quinolinium)-methyl-4-amino-2- cyclobutylmethyl-pyrimidine, S-quinaldiniummethyl-4-amino-2-cyclohexylmethylpyrimidine, 5-lepidiniummethyl-4-amino-2- (Z-cyclopentenyl) -methylpyrimidine, 5 1-methyl-isoquino1inium)-methyl-4-amino-2-(2- cyclohexenyl) methyl-pyrimidine, 5-(2,6-di-methyl-4-methoxy-pyridinium)-methyl-4-amino- 2-cyclopentylmethyl-pyrimidine, 5-(2,4-dimethyl-oxazolinium)-methyl-4-amino-2- cyclopropylmethyl-pyrimidine, 5- 3-chloro-pyridinium) -methy1'4-amino-2-( l-cyclopropylethyl) -pyrimidine, 5-(3-dimethylamino-pyridinium)-methyl-4-amino-2-cyclopentylmethyl-pyrimidine and the 2-(2-methyl-cyc1opropylmethyl) -2- 2,3-dimethyl-cyclopropylmethyl) 2-(2-methoxy-cyclopropylmethyl)-, 2-(2,2,3-trimethylcyclobutyl)-methyl-, 2-cyclopentylmethyl, 2-(2-cyclopropyl-ethyl)- and 2-(2-cyclopropenylmethyl)-4-amino- 5-(2-methy1- or 2,4-dimethyl-pyridinium-methyl)-pyrimidine salts, particularly the corresponding chloride hydrochlorides.

Example 10 A poultry feed containing 0.005% of the active ingredient may be prepared as follows.

Premix: G.

5-(2,4-dimethyl-pyridinium) methy1-4-arrn'no-2- cyclo-propylmethyl-pyrimidine chloride hydrochloride 5.00

Wheat standard middlings (30-80 mesh) 9,995.00

The ingredients are mixed thoroughly until uniformity is obtained.

Feed formula: Grams Corn meal 1,062.875 Fat 80.000 Fish meal, 60% protein 100.000 Soybean meal, 50% protein 500.000 Corn gluten meal 100.000 Dehydrated alfalfa meal 50.000 Corn distillers solubles 40.000 Dicalcium phosphate 28.000 Calcium carbonate 20.000 Iodized salt 10.000 Vitamins A and D (1,000,000 Int. units A and 250,000 D/pound 4.000 Calcium pantothenate 0.250 Butylated hydroxytoluene 0.250 Choline chloride, 25% 2.500 Riboflavin conc. (24 g. per pound) 0.125 Vitamin B (0.02 g. per pound) 1.000 Methionine 0.500 Manganese sulfate 0.500

Total weight 2,000.000

The feed formula is prepared as follows: A portion of the corn meal is introduced into the blending machine (about half of the amount to be added). The remaining corn meal, previously blended with the pre-heated, liquified fat, is added thereto and mixing is continued until uniformity is obtained. The maganese sulfate, dicalcium phosphate, calcium carbone and iodized salt are then added with mixing, followed by the addition of the fish,

soybean, corn gluten and alfalfa meal and the corn distiller solubles. After a uniform mixture has been obtained, vitamins A and D, calcium pantothenate, choline chloride, riboflavin, vitamin B and methionine are added in that order. Mixing is continued after the addition of butylated hydroxytoluene, and maintained until a uniform product is obtained.

The premix is added to the feed formula prepared as described above in an amount sufiicient to provide a concentration of 0.005 g. of the active ingredient per 100 g. of feed in the uniformly blended mix.

Another premix which may be used accordingly is the following An aqueous solution containing 0.01% of the active ingredient may be prepared from said additive.

Example 12 A poultry feed containing 0.0005 of the active ingredient is prepared as follows.

Feed formula:

(2,4 dimethyl pyridinium methyl)- 4-amino-2-cyolopropylmethyl pyrimidine chloride hydrochloride grams 5.0

Corn meal pounds 1103.0 Soybean meal, 44% protein ..do 660.0 Alfalfa meal do 30.0 Dicalcium phosphate do 40.0 Limestone meal do 10.0 Salt do 5.0 Fish meal, 60% protein do 40.0 Stabilized fat do 60.0 Dried whey do 40.0 Manganese sulfate do 0.5 Zinc oxide do 0.3 d,l-Methionine do 1.5 Vitamin premix do 10.0

lb. of the vitamin composition contain: 16,000,000 I.U. vit. A, 1,000,000 I.U. vit. D 5,000 I.U. vit. E acetate, 6 g. vit. K 6 mg. vit. B 3 g. riboflavin, 30 g. niacin, 5 g. calcium pantothenate and 100 g. ethoxyquin, made up to 10 lb. with corn meal.

The 5 (2,4-dimethyl-pyridiniurn-methyl)-4-amino-2- cyclopropylmethyl-pyrimidine chloride hydrochloride is first premixed with about 1 kg. of the finely ground feed mixture (which is supplied as such by the manufacturer). The premix is increased to about 25 kg. with the feed and then thoroughly mixed with the main batch in a horizontal mixer.

Example 13 A poultry feed, containing 0.003% each of two active ingredients, is prepared as follows.

14 Premix: G. I. 5 (2,3 dimethyl pyridinium) methyl-4- amino-Z cyclopropylmethyl pyrimidine chloride hydrochloride 3.0 II. N-(6-chloro-2-pyrazinyl)sulfanilamide 3.0

III. Wheat standard middlings (30-80 mesh) 9,994.0

The thoroughly mixed ingredients are added to 99 kg. of the feed formula shown in Example 10 and the whole is homogenized in a horizontal mixer.

Example 14 A poultry feed is prepared as follows.

Premix: G. I. 5 (2,4 dimethyl pyridinium) methyl 4- amino 2 cyclopropylmethyl pyrimidine chloride hydrochloride 115.0

II. N'(6-chloro-2-pyrazinyl)-sulfanilamide 45.0 III. Confectioners sugar 45.0

IV. Soybean feed, solvent extracted 250.0

The premix is prepared by t-riturating I and II with III and the mixture is then screened through a 30 mesh screen, U.S. standard sieze size; the screened material is then blended with IV in a mixer and the thoroughly mixed ingredients are added to 910 kg. of the feed formula shown in Example 10 and the whole is homogenized in a horizontal mixer.

Example 15 A poultry feed is prepared as follows:

Premix:

I. 5 (2,4 dimethyl pyridinium) methyl-4- amino- 2 cyclopropylmethyl pyrimidine chloride hydrochloride 105.0

II. N'-(6-chloro-2-pyrazinyl)-sulfanilamide 34.0 III. Soybean oil 18.0 IV. Corn gluten feed 298.0

About one third of the amount of IV is combined with I and II, mixed and then screened through a 30 mesh screen, U.S. standard sieve. The remainder of IV is then put into a mixer, III is added and the materials mixed to form a uniform dispersion to which the screened material is added and then mixed until uniformity is obtained. The resulting mixture is then added to 910 kg. of the feed formula shown in Example 8 and the whole is homogenized in a horizontal mixer.

In preparing the premix materials in the above-identified examples one may, of course, substitute an equivalent amount of a sulfanilamide for the sulfanil-amide shown and one may substitute other equivalent materials, such as cottonseed meal, cottonseed oil, linseed meal, oatmeal, etc., in place of the carriers shown. In these examples, it is shown that the sulfanilamide may be present in the final composition in an amount of about 0.0003 to 0.005% per 0.0125 of the quaternary component. Actually, one can utilize an amount of sulfanilamide in the range of 0.001 to 0.010% for the intended purposes.

What is claimed is:

1. Quaternary 5 ammoniummethyl-4-amino-2-cyclo aliphatic-lower alkyl-pyrimidine salts having the formula in which R is a member selected from the group consisting of 3 to 8 ring membered cycloalkyl, cycloalkenyl, and any such radical substituted by a member selected from the group consisting of lower alkyl, halogen, lower alkoxy and lower alkylmercapto, alk is lower alkylene, R is pyridinium, quinolinium, isoquinolinium, pyridazinium, pyrimidinium, pyrazinium, quinazolinium, phthalazinium, 1,5-naphthyridinium, 1,6-naphthyridinium, 1,7-

naphthy-ridinium, 1,8-naphthyridinium, N-lower alkyl-N'- pyrazol-iurn, N-lower alkyl-N-imidazolium, thiazol ium, oxazolium, 1,3,5-triaziniurn, l-lower alkyl-lH-pyrrolo- [3,2 b]pyridinium, 6-1ower alkyl-6H-pyrrolo[3,4b]pyridinium, thieno 3,2-b pyridinium, thieno 2,3-b] pyridiniurn, pyrido[3,2-b]pyrimidinium, pyrido[2,3-b]pyrazinium, pyrazolinium, N-lower alkyl-N -pyrazolinium, imidazolinium, N-lower alkyl-Ndmidazolinium, thiazolinium, oxazolinium and each of said groups substituted by a member selected from the group consisting of lower alkyl, hydroxy, lower alkoxy, mercapto, lower alkylmercapto, halogen, trifluoromethyl and di-lower alkylamino and X is the anion of a therapeutically useful acid, and a therapeutically useful acid addition salt thereof.

2. A compound as claimed in claim 1 and being a member selected from the group consisting of the compound having the formula GE -R3 N wl Xe Braw -k in which R is a member selected from the group consisting of 3 to 6 ring-membered cycloalkyl, (lower alkyl)- cycloalkyl, (lower alkoxy)-cycloalkyl and (halo)-cycloalkyl with a-lk is alkylene with 1 to 4 carbon atoms, R is a member selected from the group consisting of pyridinium, quinolinium, isoquinolinium, pyridazinium, pyrimidiniurn, pyrazinium, thiazolium, thiazolinium, oxazolium, oxazolinium, imidazolium, imidazolinium and each of such groups substituted by lower alkyl and X is the anion of a therapeutically useful acid, and a therapeutically useful acid addition salt thereof.

3. A compound as claimed in claim 1 and being a member selected from the group consisting of the compound h-aving the formula CHP Q N Xe (C H:) p H-C nHhiNy 16 in which p is an integer from 2 to 5, n is an integer from 1 to 2, m is an integer from 1 to 4, q is an integer from 0 to 2, and X is the anion of a therapeutically useful acid, and a therapeutically useful acid addition salt thereof.

4. A compound as claimed in claim 1 and being a therapeutically useful 5-(2,4 dimethyl pyridinium)- methyl-4-amino-2-cyclopropylmethylpyrimidine salt.

5. A compound as claimed in claim 4 and being the 5 (2,4 dimethyl pyridinium) methyl 4 amino 2- cyclopropylmethyl-pynimidine chloride hydrochloride.

6. A compound as claimed in claim 1 and being a therapeutically useful S-(Z-methyl-pyridinium)-methyl-4- amino-2-cyclopropylmethyl-pyrimidine salt.

7. A compound as claimed in claim 6 and being the 5 (2 methyl pyridinium) methyl 4 amino 2- cyc-lopropylmethyl-pyrimidine chloride hydrochloride.

8. A compound as claimed in claim 1 and being a therapeutically useful 5 (2,4-dimethyl pyridinium)- methyl-4-amino-2-cyclobutylmethylpyrimidine salt.

9. A compound as claimed in claim 8 and being the 5 (2,4 dimethyl pyridinium) methyl 4 amino 2- cyclobutylmethyl-pyrimidine chloride hydrochloride.

10. A compound as claimed [in claim 1 and being a therapeutically useful 5-(2-methyl-pyridinium)-methyl-4- amino-2-cyclobutylmethyl-pyrimidine salt.

11. A compound as claimed in claim 10 and being the 5 (2 methyl pyridinium) methyl 4 amino 2- cyclobutyl-methyl-pyrimidine chloride hydrochloride.

12. A compound as claimed in claim 1 and being a therapeutically useful 5-(2,4-dimethyl-pyridinium)-methyl- 4 amino 2 (2 chloro cyclopropyl) methyl pyrimidine salt.

13. A compound as claimed in claim 12 and being the 5 (2,4 dimethyl pyridinium) methyl 4 amino- 2 (2 chloro cyclopropyl) methyl pyrimidine chloride hydrochloride.

References Cited UNITED STATES PATENTS 3,042,676- 7/ 1962..-Rogers et a1. 260256.4

ALEX MAZEL, Primary Examiner.

R. J. GALLAGHER, Assistant Examiner.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,385,857 May 28, 1968 Renat Herbert Mizzoni et a1.

It is certified that error appears in the above identified patent and that said Letters Patent are hereby corrected as shown below:

Column 1, line 57, "2,5cy-" should read 2,5- line 66, "tert.-" should read tert. Column 2, line 2, after "2,2-" insert a comma; line 13, after "as" insert a line 44, "0.001" should read 0.0001 Column 4, line 56, "microphills" should read micropills line 68, "metal" should read meal Column 5, lines 59 to 65, the portion of the formula reading "-CHZ-" should read -CH Column 9, lines 69 to 75, at the right-hand side of the formu1a,.ZCl" should read .2Cl Column 11, lines 3 to 9, the righthand portion of the formula should appear as shown below:

CH3 .2c1

Column 12, line 1, "2cyclopentylmethyl-" should read Z-cyclopentylmethylline 27, "propylmethylj-2-(2,3-dimethyl cyclopropylmethyl)-" should read propylmethyl)-, 2(2,3-

dimethylcyclopropylmethyl), line 74, "carbone" should read carbonate Column 14, line 23, "sieze" should read sieve Column 15, line 28, cancel "with", first occurrence.

Signed and sealed this 31st day of March 1970.

(SEAL) Attest:

EDWARD M.FLETCHER,JR. WILLIAM E. SCHUYLER, JR. Attesting Officer Commissioner of Patents

Patent Citations
Cited PatentFiling datePublication dateApplicantTitle
US3042676 *Feb 2, 1960Jul 3, 1962Merck & Co IncPyridinium quaternary salts and methods of preparing the same
Referenced by
Citing PatentFiling datePublication dateApplicantTitle
US3454575 *Mar 6, 1967Jul 8, 1969Ciba Geigy CorpQuaternary 5-ammonium-methyl-4-amino-2 cycloaliphatylpyrimidine salts
US4006143 *Oct 16, 1975Feb 1, 1977Merck & Co., Inc.Heterocyclic substituted pyrimidine compounds
US4044133 *Oct 16, 1975Aug 23, 1977Merck & Co., Inc.Anticoccidial compositions
US6077981 *Aug 28, 1998Jun 20, 2000Eastman Chemical CompanyProcess for the production of cyclopropylmethyl halides
US6118032 *Aug 3, 1999Sep 12, 2000Eastman Chemical CompanyProcess for the production of cyclopropylmethyl halides
WO2002066029A2 *Feb 21, 2002Aug 29, 2002Remon Jean PaulAntiprotozoal methods, compositions and feedstuffs
Classifications
U.S. Classification544/328, 544/238, 544/327, 544/296, 544/295
International ClassificationA23K1/16, C07D307/54, C07C17/16, A61K31/505, C07D277/66, C07D239/42, A61K31/635
Cooperative ClassificationA61K31/505, C07D307/54, A61K31/635, C07D239/42, C07D277/66, A23K1/1615, C07C17/16
European ClassificationA61K31/635, C07C17/16, A61K31/505, C07D239/42, C07D277/66, C07D307/54, A23K1/16F