IL26870A - Imidazoline and tetrahydropyrimidine derivatives,their preparation and use - Google Patents

Description

26870/2 \ ΪΠ3 ©isorn τη33η Imidazoline and tetrahydropyriisidine derivatives, their preparation and use ΗΛ£. , ΡΡΙΖ:Ώ & CO., IHC. 2 26870/2 This invention relates to novel cyclic amidines and their non-toxic acid addition salts which are useful as anthelmintic agents* More particularl , it relates to 1,4,5,6-tetrahydropyriiaidines and 2-imidazolines having at the 2- position a styryl, 2-furylvinyl or a 2-furyl-ethyl group which are of value for the veterinary control of helminthiasis.

Helminthiasis, the infestation of the animal body, and particularly the gastrointestinal tract, by various species of parasitic worms, is perhaps the most common, most serious and most widespread disease in the world today. Although the economic significance of tuis disease lias led to extensive research for new and more effective anthelmintics, the countermeasures developed to date for its treatment and prevention have not been entirely satisfactory. ¾ie present invention has as an object the provision of a group of cyclic and non-cyclic amidines which are effective in the veterinary control of helminthiasis, and which lack many of the objectionable features of the anthelmintics available on the market today.

According to the present invention it has now been unexpectedly found that cyclic amidines having the general formula CH, - 3 - 26870/2 and the non-toxic acid addition salts thereof, wherein E is hydrogen, methyl or halogen; 2 is ethylene or rMethylene; Y is 0 or -HC=CH-; and X is vinylene or when Y is 0 X ciay also be ethylene, are surprisingly effective agents for the veterinary control, e.g. therapeutic and prophylactic, of helminthiasis in animals when administered orally or parenterall . Also included in this invention are the cis- and trans- isomers of those compounds wherein X is vinylene.

In accordance with this invention there is provided a process for making the compounds of formula I which comprises reacting a compound of the general formula R ■wherein R and Y are as defined above in formula I and W is the group in which either X is vinylene and R' is the group -(CH^„-3Q,R, X is ethylene, or, when Y is 0 and/K* is lower alkyl, with a diamine of the formula in which 2 is as defined above or a salt of said amine; and, when required, converting the compound thus produced into an acid addition salt thereof; - 5a - 26870/2 . or reacting a compound of formula III in which W is -CH=0' with a compound of the formula wherein Z is as defined above, and, when required, converting the compound thus produced into an acid addition salt thereof.

By "non-toxic" acid addition salts is meant those salts which 'are non-toxic at the dosages administered. The non-tojxic acid addition salts of the above mentioned bases which may be employed are the water soluble and water insoluble salts such as the hydrochloride, hydrobromide , phosphate, nitrate, sulfate, acetate, hexafluor.ophosphate, citrate, gluconate, benzoate, propionate, butyrate, sulfosalicylate , . maleate, laurate, malate, furaarate, succinate, oxalate, tartrate, amsonate -diaminostilbene-2,2f -disulfonate) , , pamoate (1,1· -methylene -bis -2-hydroxy-3-naphthoate) , stearate, 3-hydroxy-2-naphthoate, p-toluenesulfonate, suramin salt and resin adsorbates. The hexa luorophosphate - 4' - 26870/2 salts are especially valuable as a means for isolating cyclic the novel/amidine products of this invention from aqueous solutions of the free bases or of water soluble acid addi-tion salts. They precipitate out rapidly and quantitatively or almost quantitatively as crystalline products and are easily purified as by washing with water. They thus serve as a means for recovering and purifying these novel ami-dines. The free base is, in turn, easily recovered from the hexafluorophosphate salt by neutralization, j These agents are active against both the mature and immature forms of helminths of the suborders Strongylata and Ascarldata and particularly against the families Strongyloidea and Trichostrongyloidea . Additionally, some of !hese agents are active against Hymenolepsis nana. They are especially effective against the gastrointestinal parasites of ruminants (e.g., sheep, cattle, goats) and of non- I ruminants such as dogs, cats, horses and swine.

The novel products of this invention are prepared by known methods, such as reaction of the appropriate alkyl- enediamine tosylate with an imino-ether hydrochloride corresponding to, e.g. 3-(2-furyl) propionitrile or 3-(3-meth l- 2-furyl)propioni rile to give the hydrochloride of the · corresponding cyclic amidines. . - 5. - f 26870/2 The 3-substituted propionitriles are convenientl prepared from the corresponding 3-substituted acrylonltriles ■ by catalytic hydrogenation over a noble metal catalyst, e.g. I palladium, platinum, rhenium, rhodium, iridium, osmium, j Palladium-on-carbon is especially effective in affording a smooth reaction and satisfactory yields. As solvent system a suitable reaction-inert solvent should be used. Methanol and other alcohols, aqueous tetrahydrofuran and dioxane, are satisfactory solvents. The system can be neutral, basic, or acidic. A slightly basic system is generally favored since it appears to accelerate the rate of reaction. Bases of particular value are the alkali metal hydroxides, especially sodium and potassium hydroxide, and the quaternary ammonium j hydroxides, e.g. R-RgR^R^-NOH, wherein R^, R≥, R^and are alkyl R^ and R^ are benzyl and alkyl substituted benzyl, such as trimethylbenzylammonium hydroxide, (p-t-butyl) benzyltrimethylammonium hydroxide, and di-(p-t-butylbenzyl) dimethylammonium hydroxide. The amount of base used is not critical but in general a molar ratio of from about 0.05 to-, about 0.25 moles of base per mole of w-substituted acrylo- nltrile Is satisfactory. The pressure and temperature appear not to be critical factors. Pressures of up to about 500 psi afford good yields. Reaction temperatures up to .100° C. can be used . The reaction should be stopped when the theoretical amount of hydrogen is taken up. - 6 - 26870/2 The requisite phenyl- and 2-furyl substituted, acrylonitriles are prepared by a Knoevenagel type condensation.of the appropriate aldehyde, e.g. benzaldehyde or 2-furaldehyde, with cyanoacetic acid in the presence of an appropriate catalyst. As catalysts, nitrogen bases, e.g. ammonia, primary and secondary amines, pyridine, piperldine, triethanolamine, can be used. The favored catalyst system is ammonium acetate-pyridine . The reaction is conducted in a reaction-Inert solvent system such as in toluene, benzene, xylene, preferably with continuous removal of by-product water. Additionally, the nitrogenous base can be used as solvent. The reaction is advantageously run at a temperature of from about 80° C. to the reflux temperature of the solvent and preferably at a temperature sufficient to permit simultaneous removal of the by-product water by .azeotropic distillation.

Substituted acrylonitriles and propionitriles are converted by known methods to lmido esters by addition of alcohols under the influence of hydrogen chloride under anhydrous conditions. The usual conditions comprise passing dry hydrogen chloride into an equimolar mixture of the w- substituted acrylonitrile and an alcohol in ether or diox- ane solution. The operative temperature range is from about 0° C. to about 35° C. and preferably from about 0° C. to 15° C. The lmido ester hydrochloride is then ammonolyzed to the desired amidlne by reaction with an alcoholic solution of the appropriate amine. Alternatively, the lmido ester, free base form, is reacted with an alcoholic solution of the amine hydrochloride or other acid addition salt.

Suitable alcohols are methanol, ethanol, butanol, propanol, and 2-propanol. Other solvents such as dioxane, tetrahydro- - 7 - 26870/2 vent of the type mentioned above is" preferred. The ammono-lysis is carried Out at a temperature of from about -5°-C. to about 50° C. and preferably at from about -5° C. to about 30° C. until formation of the product is complete ox* essentially complete. The amidine hydrochloride is recovered, e.g. removal of the solvent, and the residue re-> crystallized from a suitable solvent system.

The novel compounds described herein wherein X is vinylene are also prepared by reaction of the appropriate acrylamide derivative, e.g. 3-phenylacrylamide, with 1,3- propanesuitone (Ried and Schmidt, Ann. 676, 11.4 (1 64) to produce an imino ether in which the newly introduced radical is 3-propylsulfonic acid, e.g. 3-(l '-imino-3-phenylallyloxy) propane sulfonic acid^. The thus produced imino ether isjthen reacted with the N-monomethyl derivatives of the appropriate diamines, i.e. ethylenediamine or trimethylenediamine, to give the desired cyclic amidine. The compounds thus produced have the trans configuration. The cis isomers are obtained by irradiation of the trans isomers as described herein.

In still another method, indeed the preferred method, for making the novel; cyclic amidines described · herein wherein X Is vinylene comprises the direct condensation of the appropriate benzaldehyde or 2-furaldehyde with 1-methyl i-methyl ' a 2-methyl substituted /imidazoline or/tetrahydropyrimidine under conditions which result in the effective removal of by-product water. This is accomplished by conducting the reaction in a reaction-inert solvent which forms an azeo- trope with water, e.g. benzene or toluene, or alternatively, in the absence of a solvent. In either case, the reaction temperature should be sufficient to permit removal of the water. In the former case, when using an azeotropic 110° C. is favored although temperatures of from about 50° C. to 150° C. can be used. Still another method for removing by-product water is by means of molecular sieves (natural and synthetic crystalline aluminosilicates) and a reaction-inert solvent such as benzene, toluene, ethanol, propanol or dimethylsulfoxide .

The tosylate and hydrochloride salts prepared as described above can be readily converted to the free base simply by neutralization of the acid portion of the salt by aqueous sodium or potassium hydroxide and the water insoluble free base recovered by mechanical means or by solvent extraction with a suitable immiscible solvent such as ethyl acetate. The free base, isolated by removal of the solvent, can, if desired, be purified by recrystallization from a suitable solvent system or by vacuum distillation. Alternatively, the free bases are obtained by neutralization of an acid salt with sodium methoxide in methanol and recovery of the base by known methods. Other acid addition salts can be readily prepared simply by dissolving the free base in a suitable solvent, e.g. acetone, a lower aliphatic alcohol (ethanol, isopropanol) containing the desired acid, or to which the desired acid is subsequently added. The salts are recovered by filtration, precipitation with a non-solvent, by evaporation of the solvent or, in the case of aqueous solutions, by lyophilization. In this manner the sulphate, nitrate, phosphate, acetate, propionate, buty-rate, citrate gluconate, benzoate, pamoate, amsonate, the tartrate, 3-hydroxy-2-naphthoate and the sulphosalicylate and other salts can be prepared. In the case of the di-basic acids e.g. pamoic, amsonic, a 1 : 1 molar ratio of acid to base is used to give the l;l salt. The inorganic polybasic acids are generally used in a 1 : 1 molar ratio with the desired base.

The tosylate salts of the amidines produced as described above can be converted to the corresponding hydrochloride salts by percolating a methanolic solution of the tosylate through the chloride form of an anion exchange resin. Other acid addition salts can also be prepared by this method.

Resin adsorbates of the amidines of this invention are conveniently prepared by slurrying an aqueous solution of a water soluble salt of the cyclic amidine of choice with a suspension of the sodium form of a cation exchange resin for a sufficient period to permit adsorption of the compound by the resin. Suitable resins are the strong sulfonic acid type cation resins, such as Dowex 50 , Amberlite CG-120 , Amberlite IR-120 , Zeo-Karb 225 (available from the Dow Chemical Co., Rohm & Haas, and the Permutit Co., Ltd., respectively) , all of which are sulfonated styrene divinyl benzene polymers cross-linked to varying degrees.

As noted above, these products are effective to a significant degree in controlling, that is, in eliminating and preventing, helminthiasis in animals by both the oral and parenteral routes of administration. The terms "controlling" and "control" as used herein are meant to include the treatment of helminthiasis in animals suffering therefrom and the prevention (prophylaxis) of helminthiasis in animals. Subcutaneous and intramuscular injections are the preferred methods of parenteral injection for several reasons; simplicity, convenience and the compounds appear less toxic. Vehicles suitable for parenteral injection maybe either aqueous such as water, isotonic saline, isotonic dextrose, Ringer's solution, or non-aqueous such as fatty oils of vegetable origin (cotton seed, peanut oil, corn, sesame) and other non-aqueous vehicles which will not interfere with the therapeutic efficiency of the preparation and are non-toxic in the volume or proportion used (glycerol, propylene glycol, sorbitol). Additionally, compositions suitable for extemporaneous preparation of solutions prior to administration may advantageously be made.. Such compositions may include liquid diluents, for example, propylene glycol, diethyl carbonate, glycerol, sorbitol, etc.; buffering agents, as well as local anesthetics and inorganic salts to afford desirable pharmacological properties. Administra-tion of these anthelmintic agents in combination with hyal-uronidase avoids local irritation and increases the rate of absorption of the drug. Hyaluronidase levels of at least about 150 (U.S. P.) units are very effective in this respect although higher or lower levels can, of course, be used.

When administered parenterally for therapeutic purpose the anthelmintic agents described herein or their non-toxic acid addition salts are administered in a dosage equivalent to from about 5 mg» "to about 150 mg. of the free base/kg. of body weight.

When administered by the oral route, the preferred route for administering the novel products of this invention, the compounds are given in dosages equivalent to from about 0.5 mg. to about 150 mg. of free base/kg. of body weight. For therapeutic use a dosage equivalent to about 1 mg. to 100 mg. of free base/kg. of body weight is recommended. Oral administration can be accomplished by a number of methods including mixing the feed, unit dosage formulations such as capsules, tablets, liquid mixtures and solutions including drench solutions. Solutions having con-centratlons ranging from about 3$ up to the limit of solubility of the drug in water are satisfactory for drench solutions. More dilute solutions, e.g. 0.005$ solutions can be supplied for drinking purposes. Alternatively, wettable powder containing the active ingredient may be added to the animals' drinking water.

For prophylactic use, 0.5 to 0 mg. (calculated as free base) per kg. of body weight daily is administered. This is the preferred range. Higher dosages can, of course, be used but are not desirable from an economic standpoint. The above methods of administration are suitable although administration in the animal 's food, water, or mineral mixture is more convenient.

Boluses and capsules are also used for the therapeutic treatment of animals. For animals weighing from 30 to 1000 pounds the usual dose, calculated as free base, ranges from 0.01 to 4 grams. Boluses of suitable sizes containing these materials can be prepared by conventional method s .

Dry mineral mixtures containing the products of this invention at levels of from 0.001 to about 10$ of the active ingredient mixed with salt (sodium chloride) and other minerals can be fed the animals on an ad libitum basis by adjusting the proportion of active ingredient in the mixture to the average daily consumption per animal so as to provide the proper daily dose as specified above. can be administered in admixture with the feed. Again, a concentration range of about 0.001 to 10$ of the drug in the feed is employed. However, higher proportions can be satisfactorily employed depending upon the palatability of the product to the animal. Additionally, these compounds can be used in micronized form especially when used in emulsions or suspensions by either the oral or parenteral route of administration.

The following examples are given for purposes of illustration and not by way of limitation.

Example I 3-Methyl-2-furanacryllc Acid A solution of 1.0 mole of 3-methyl-2-furaldehyde, 1 .0 mole of malonic acid, 3.0 g. of ammonium acetate, 50 ml. of toluene, and 120 ml. of pyridine is heated under reflux for 48 hours in an apparatus which includes a Dean-Stark moisture trap. The solution is then evaporated under reduced pressure, and the residue triturated under ether. The crystalline product is filtered then recrystalllzed from benzene/hexane to afford pure 3-methyl-2-furanacrylic acid.

Example II 3-Methyl-2-furanacrylamide A stirred solution of 0.5 mole of 3-methyl-2-furanacrylic acid, and 200 ml. of methylene chloride is treated drop-wise with 63.5 S« ( ^2.5 ml., 0.5 mole) of oxalyl chloride. The resulting mixture is allowed to stand at room temperature for two days, then evaporated under reduced pressure. The oily residue is stirred into 600 ml. of ice-chilled concentrated ammonium hydroxide, and the mixture is allowed to stand for an hour before it is filtered. The crystalline product is taken up in 500 ml. of benzene and the mixture heated under reflux in an apparatus which includes a Dean-Stark moisture trap. When water is no longer evolved the hot solution is cooled, and the resulting precipitate filtered. The crystalline residue is recrystalllzed from acetone/hexane to afford pure 3-methyl- 2-furanacrylamide .

Example III 3-Methyl-2-furanacrylonitrile A solution of 1.0 mole of 3-methyl-2-furaldehyde, 1 .0 mole of cyanoacetic acid, 3.0 g. of ammonium acetate, 250 ml. of toluene, and 120 ml. of pyridine is heated under reflux for 48 hours in an apparatus which includes a Dean-Stark moisture trap. The solution is evaporated under re-duced pressure and the residue fractionally distilled in vacuo to afford pure 3-methyl-2-furanacrylonitrile .

Example IV 2-Furanpropionitrile A pressure flask is charged with 132.4 g. (l.l moles) of 2-furanacrylonitrile, 400 ml. of methanol, and 3 g. of 10$ palladium-on-carbon catalyst. The flask is fitted to a Parr hydrogenatlon apparatus, flushed twice with nitrogen, and then three times with hydrogen. The final hydrogen pressure is 45 psi. Shaking is initiated, and hydrogen is allowed to react until 1 .5 moles is absorbed. The reaction is then stopped, the catalyst filtered, and the filtrate is evaporated to an oil . Gas chromatography shows the crude product to consist of approximately 85$ of the desired product, 2-furanpropionitrile. This material is adequate for the preparation of ethyl-2-furanpropionimidate hydro- chloride .

In a like manner, 3-methyl-2-furanpropionitrile is prepared from 3-methyl-2-furanacrylonitrile.

Example V Ethyl 2-Furanpropionimidate Hydrochloride A solution of 30.0 g. (0.248 mole) of 2-furan-propionitrile, 11.5 g„ (l4.6 ml., 0.248 mole) of anhydrous ethanol, and 100 ml. of diethyl ether is saturated with anhydrous hydrogen chloride then stored in a refrigerator for 20 hours. The solution is evaporated under reduced pressure at a temperature not above 25° C Fresh diethyl ether is added to the residue to precipitate an oil which crystallizes on standing. The mixture is placed in the refrigerator for another 20 hours then filtered to afford 38.5 g. (76$) of ethyl 2-furanpropionimidate hydrochloride, a hygroscopic material which is used immediately in subsequent reaction steps.

In a similar way, ethyl 3-methyl-2-furanpropion-imidate hydrochloride is prepared from 3-niethyl-2-furan-propionitrile.

Example VI 3-(2-Furanacrylimidoyloxy)propanesulfonic Acid A solution of 13.7 g. (0,1 mole) of 2-furanacryl-amide and 12.2 g. (0.1 mole) of 1,3-propanesul one is heated at 130-140° C. with occasional stirring by a glass rod.

After a short time the solution solidifies. Heating is continued for 3 minutes, and the mixture then allowed to cool to room temperature. The solid mass is ground in a mortar then triturated under acetone. The crude product weighs about 21.6 g. (83$) and is used in subsequent - 15 - 26870/2 preparations without further purification.

In like manner, 3-(3-methyl-2-furanacrylimidoy- loxy)propanesulfonic acid is prepared from 3-methyl-2- furanacrylamido .

Example VII 2- 2"-(2-Furyl)vinyl7-l, J5,6-tetrahydro-l-methylpyrimldine Dihydrogen Citrate A solution of 21.6 g. (0.0834 mole) of 3-(2-furanacrylimidoyloxy) propanesulfonic acid, 8.8 g. (0.1 mole) of N-methyl-l,3-propanediamine, and 100 ml. of methanol is heated under reflux for 5 hours. After coolin to room temperature the solution is evaporated under reduced pressure to furnish a dark oil which is taken up in 200 ml. of water. The aqueous solution is washed with ethylacetate and then stirred under 100 ml. of ether while sodium hydroxide pellets are added to raise the pH to 14. The' ether phase is then separated and the aqueous , phase . - . extracted three times with 50 ml. portions of ether. The combined ether extracts are dried, filtered, and evaporated to afford 7.6 g. of an oil, which is taken up in 50 ml. of acetone and poured into a solution of 8.36 g. (0.0398 mole) of citric acid monohydrate in 50 ml. of acetone. A thick gum precipitates. The mixture is heated and enough methanol added to effect solution. Upon cooling, the crystalline product precipitates: yield 13.6 g. ( 3 ) , m.p. 157-158° C. The product is recrystallized from methanol/acetone (includ-ing an activated carbon treatment) to afford analytically pure 2- 2"- ( 2-furyl ) vinylj-l , 4, 5 , 6-tetrahydro-l-methyl-pyrimidine dihydrogen citrate: yield, 7. 5 g., m.p. 157-158° C, max (H20) 306 mu. ( , 31,400).

Analysis: Calcd . for C-^H^NgOg: C, 53.41 ; H, 5.80 ; N, 7.3 $ Pound: C, 53.21; H, 5.74; N, 7.34$ In like manner, -compounds of the formula: CH. 3 are prepared, as their dihydrogen citrate salts, from the appropriate N-methyl alkylenediamine and the proper acryl-imidoyloxypropane sulfonic acids wherein R has the values shown below: R Z 3-methyl-2-furyl trimethylene 3-methyl-2-furyl ethylene phenyl trimethylene o-tolyl trimethylene phenyl ethylene o-tolyl ethylene Example VIII 2- 2- ( 2-furyl ) ethylj-l , , 5 , 6-tetrahydro-l-methylpyrimidine Hydrogen Maleate A solution of 0.15 moles of N-methyl-1, 3-propane-dlamlne and 75 ml. of methanol Is treated portlonwlse with 20.4 g. (0.1 mole) of ethyl .2-furanpropionlmldate hydrochloride. The resulting solution is heated under reflux overnight then allowed to cool. The volatiles are evaporated under reduced pressure , and the residue is taken up in 150 ml. of water. The aqueous phase is stirred under 100 ml. of ether and the pH raised to 14 by addition of sodium hydroxide pellets. The ether phase is separated, dried, filtered and evaporated. The oily residue is taken up in 75 ml. of acetone then poured into acetone containing 0.1 mole of maleic acid. The resulting precipitate is isolated, and crystallized for analysis.

In a like manner l,4, 5i 6-tetrahydro-l-methyl-2-^-( 3-methyl-2-furyl)ethyl7pyrimidine is prepared from ethyl 3-methyl-2-furanpropionimidate hydrochloride. By substituting N-methylethylenediamine for N-methyl-l, 3-propanediamine in these reactions, 2- 2"- ( 2-furyl )ethyl7-l-methyl-2-imlda-zoline and l-methyl-2-/2"-( 3-methyl-2-furyl)ethyl7-2-imidazoline are prepared.

IX Example J 4, 5, 6-Tetrahydro-l-methyl-2-styrylpyrimidine Hexafluoro-phosphate A solution of 10.6 g. (0.1 mole) of benzaldehyde, 11 .2 g. ( 0.1 mole) of 1 ,4,5,6-tetrahydro-l , 2-dimethyl-pyrimidine, and 25 ml. of toluene is heated under reflux in an apparatus which includes a Dean-Stark moisture trap. When approximately 1 .2 ml. of water is collected, the re- action mixture is allowed to cool and the volatiles then evaporated under reduced pressure. The residue is taken up in ether, treated with activated carbon, filtered, and evaporated to afford a light brown oil. The oil is stirred rapidly into a mixture of 25 g. of 6 $ hexafluorophosphoric acid and 75 g. of ice. A yellow gum forms which crystallizes on scratching. , The product is filtered and recyrstallized twice from ethanol to furnish colorless needles of 1,4,5^6-tetrahydro-l-methyl-2-styrylpyrimidine hexafluorophosphate : yield, 6.4 g. (19 ); m.p. l47- l48° c.

Analysis: Calcd, for C ^Ε γΈ ^ '· C, 4 .09; H, 4 .95 ; N, 8.09$ Found: C, 45.14; H, 4.83; N, 7.89$ Example X¾£ A. 1,4,5,6-Tetrahydro-1-methyl-2- (2-methylstyryl ) pyrimidlne Hexafluorophosphate In a manner analogous to that of the previous example, the subject compound is prepared from 12.0 g. (0.1 mole) of o-tolualdehyde, 11.2 g. (0.1 mole) of 1,4,5,6-tetrahydro~l,2-dimethylpyrimidine, and 65$ hexafluorophos-phoric acid; yield, 5.2 g. (l4$); m.p. 158-158.50 C.

Analysis; Calcd. for Cli+HigFgN2P: C, 46.66; H, 5-32; N, 7.78$ Pound: C, 46.71; H, 5- 58; N, 7.72$ B. 1,4,5,6-Tetrahydro-l»methyl-2-(2-methylstyryl pyrimidine Tartrate Trans Isomer The hexafluorophosphate salt of Example XII is added to a cold, stirred aqueous solution (50$) of potassium hydroxide (equivalent amount) and 3 volumes of ether. After stirring a few minutes the ether layer is separated and the aqueous phase extracted again with ether. The ether layers are combined, dried over anhydrous magnesium sulfate - 19 - ' , 26870/2 and decolorized with charcoal. Removal of the ether affords the base.

The base is taken up in ethanol, stirred, and aa ethanolic solution of tartaric acid added slowly (1:1 molar ratio) . The tartrate salt crystallizes and is recovered by filtration. It is purified by dissolution in methanol, decolorization, and dilution with 2.5 volumes of ethanol. Concentration of the clear solution to, small volume yields the pure, crystalline product.

Cis Isomer A stirred solution of the trans isomer (3.0 g.) in methanol (300 ml.) is irradiated under an atmosphere of nitrogen by a.550-watt Hanovia high pressure quartz lamp "for 15 hours. Evaporation of the solvent under reduced pressure affords the cis isomer. Purification is accomplished as described above for trans isomer. '" " " I . The products of Examples VII,V.III,311 and.XIHare converted to their respective cis isomers-by this procedure.

I Example XI 1.4.5.6-Tetrahydro-l-methyl-2-( 2-methylstyryl)pyrimldine Sequihydrochloride With ice-bath cooling 112.1 g (l.O mole) of 1,4,5,6- I teJtrahydro-l,2-dimethylpyrimidine was treated with 120.1 g (1.0 mole) of o-tolualdehyde. After standing overnight in a refrigerator, the mixture was nearly, completely crystallized, aJd consisted almost entirely of the adduct; With ice-bath cooling, the unrefined adduct was treated with 359 ml- of Ac20. Upon removing the ice bath the temperature rose spontaneously to about 50°C. Most of the excess Ac20 was ·/ - 20 - 26870/2 solution of 80 g of dry HC1 in 550 ml of MeOH. .After 15 minutes, the alcoholic solution was evaporated, and the thick oily residue was treated with benzene. Evaporation was continued, and a solid residue was obtained. This material was triturated under i-PrOH and filtered to afford 1,4,5,6-tetrahydro-l-methyl-2-(2-methylstyryl)pyrimidine Sequihydro-chloride, yield 62.0 g (23$), mp 184-188°C.

Example XII ' 2- 2-(2-Furyl)vinyl7-l--methyl--2-lniida2oline Hydrochloride In a manner analogous to that of the previous example, 0.1'mole of 2-furaldehyde, and 0.1 mole of 1,2-. dimethyl-2-imidazoline are condensed to afford 2-^2~-(2- furyl)vinyl7-l-methyl-2-imidazoline. The residue remaining after removal of the solvent is taken up in methanolic hydrogen chloride, the solution evaporated, and the crystalline hydrochloride salt recrystalllzed from 2-propanol/ isopropyl ether to give 0.92 g. of pure material: m.p. 93-94° C.

Analysis: Calcd. for C10H13C1N20: C, H, β.ΐβ; N, 13* Found: C, 56.62; H, 6.18; N, 13.14$ In a like manner but using the appropriate aldehyde in place of 2-furaldehyde, l-methyl-2-styryl-2-imidazoline and l-methyl-2-(2-methylstyryl) -2-imidazoline are prepared as their hydrochloride and hexafluorophosphate salts.

Example Kit XII 1>4} 5> 6-Tetrahydro-l-methyl-2-( 2-chlorostyryl ) yrimidine Tartrate A solution of 14.0 g. o-chlorobenzaldehyde (0.1 mole), 11.2 g. (0.1 mole), 1,4,5,6-tetrahydro-l ,2-dimethyl-pyrimidine and 25 ml. of benzene is heated under reflux in an apparatus which includes a Dean-Stark moisture trap for three hours. Approximately 1.1 ml. of water is collected. The benzene solution is extracted with a solution of 15.0 g. (0.1 mole) of tartaric acid in 100 ml. water.

The product, recovered by evaporation of the solvent, is a yellow solid. It is purified by recrystallization from ethanol/methanol (1:1) j m.p. 178.5-18O.50 c.

Analysis: Calcd. for C17H21C106N2: C, 53.06; H, 5-50; N, 7.28 Found: C, 52.93; H, 5.59; N, 7. 1$ Similarly, but using the appropriate aldehyde in place of o-chlorobenzaldehyde and the proper N-methylalkyl-enediamine, the following compounds are prepared as their tartrate salts. chloro ethylene bromo ethylene bromo trime h lene iodo ethylene iodo trimethylene fluoro ethylene fluoro trimethylene Example W XIV The acid addition salts of the products of Examples VII-XIV are neutralized to their free bases according to the procedure set forth in Example IX and the resulting bases converted to acid addition salts by treatment with an equimolar proportion of the appropriate acid in methanol as solvent. The salts are recovered by precipitation with a non-solvent, e.g. ether, hexane, or alternatively, if desired, by evaporation of the solvent. Acid addition salts are thus prepared with the following acids: sulfonic, pamoic, am-sonic, 3-hydroxy-2-naphthoic, stearic, citric, gluconic, benzoic, acetic, propionic, butyric, sulfuric, nitric, phosphoric, hydrobromic, t-butylacetic, trimethylacetic, oxalic, succinic, malic, tartaric, p-toluenesulfonic, maleic and fumaric acids.

Example XV A. Tablets and Boluses A convenient tablet size is one containing 20 mg. of the drug. Such tablets can be prepared by thoroughly blending 250 g. of l,4,5,6-tetrahydro-l-methyl-2-(2-methyl-styryl)pyrimidine hydrochloride or the equivalent weight of other compound within the scope of this invention and 50 g. of starch in a twin "shell blender. The blended powders are then mixed with sufficient ethanol to make an easily manipulated paste which is extruded ' through a 10-mesh screen to provide granules which are dried in vacuo until - 23 - 26870/2 all the solvent is removed. The granules are coated with magnesium stearate by briefly blending with 2$ the total weight of granules of that substance. This mixture is then fed to a tableting press to produce tablets containing 250 mg. of anthelmintic agent. in addition to proportionate quantities of the carriers and excipients listed above. For animals, the daily dose varies from 0.01 to g..per day depending again upon the body weight of the animal. Boluses of various sizes can be prepared in the same fashion by 1 simply selecting a die of appropriate Size.

B. Capsules The products of this invention and their acid addition salts can be conveniently encapsulated in hard gelatin capsules. For therapeutic and prophylactic purposes, from | about 10 mg. to 1 gram of these agents can be contained in a single capsule. It is convenient to mix the active ingredient with a solid diluent, for instance calcium phosphate. From about 15 to 50 the weight of drug of tricalcium phosphate is employed. Thus, a hard gelatin capsule can be pre-| pared by thoroughly blending two parts by weight, of 1,4,5,6- tetrahydro-l-methyl-2-^-( 3-methyl-2-furyl)vinyl/pyrimidine citrate and calcium phosphate in. a twin shell blender. .The powder is then subdivided, and loaded into hard gelatin capsules in such a fashion that each capsule contains 250 | mg. active ingredient.

Example XVI Mineral Mixture Such a mixture can be conveniently made by mixing an amount of the hydrochloride of a compound according to the - 24 - 26870/2 of the usual granular stock of salt (sodium chloride). The mixture is thoroughly blended and fed .to the. animals in such quantities as to provide the recommended daily .dose? ' ■ . Such salt mixtures can also be incorporated into block form but this is not preferred due to lack of control of the dosage size received by the animals. / Example XVIL Feed Mixture Prophylactic use of these products can be properly accomplished by adding the agent to a feed mixture. The usual prophylactic dose is -from about 2.5 to 25 g. (calculated as free base) daily for 1000 pound cattle. Assuming such animal consumes 10 lbs. of feed supplement per day, at least 10 lbs. of the chosen agent per ton would be incorporated. Depending upon- the feed consumption of the animal and the dosage employed, the proportion of agent in the feed varies from 0.001$ p to about 10$. on a weight basis.

Example X.yjn .

Lambs naturally infected with gastrointestinal helminths, can be cleared to a significant degree by the subcutaneous administration of l,4,5j6-tetrahydro-l-methyl- 2-(2-methylstyryl)pyrimidine hydrochloride at levels of from about 5 mg./kg. to about 150 mg./kg. The local edema which frequently accompanies the infection can be prevented, or at least minimized by the simultaneous administration of about 150 units (U.S. P.) of hyaluronidase .

Similarly, the other products of this invention can be used for the control of helminthic infections.

Example i#f χιχ A pen previously occupied for two weeks by two sheep naturally infested with digestive Strongyles is sprayed with a 20$ aqueous solution of 1,4,5j6-tetrahydro-l-methyl-2-(2-methylstyryl)pyrimidine hydrochloride at the rate of 0.5 gallon per 1000 square feet after removal of the infected sheep. The following day two nematode-free sheep are placed in the enclosure. Daily checks of their feces for two weeks followed by post-mortem examination show no nematode infestation.

Example X The effect of l, ,5,6-tetrahydro-l-methyl-2-(2-methylstyryl)pyrimidine citrate against the migratory phases of Ascaris suum in pigs is determined as follows: Nine four-week-old pigs are divided into three groups of three and treated in the: following manner.

Group 1 - Non—infected , non-medicated Group 2 - Infected, non-medicated Group 3 - Infected, medicated The above drug is administered in the basal ration of Group 3 at a level of 50 g. of drug per ton of ration beginning two days before infection. The pigs are artificially infected on the third and fourth days by providing them with 100,000 embryonated ova (per pig) in wet feed each day. The Group 2 pigs are infected in like manner.

The Group 3 pigs receive the medicated feed ad_ libitum as during the pre-infection period for a total of ten days treatment .

All animals are sacrificed seven days after the infection and the livers and lungs inspected for charac- teristic lesions and the number of larvae present.

The drug is thus found to "be highly effective in protecting pigs against Ascaris suum infection. The infected, non-medicated animals developed thumping, coughing, anorexia and prostration and their livers and lungs were covered with innumerable mottling lesions and petochial hemorrhages. The infected, medicated animals showed no abnormal signs during the experiment. Their livers showed some lesions. However, similar mottling lesions appeared in the non-infected, non-medicated animals indicating they contained some natural Ascaris suum infection.

Additionally, reduction in the number of larvae in the lungs of up to 98 is observed. This is determined by removing a 10 g. sample from both lungs, digesting the samples in acidified pepsin at 37° C . overnight and examining the fluid thus produced for the presence of larvae with the aid of a binocular microscope.

The other products described herein behave similarly. / · ·

Claims (1)

1. CLAIMS Cyclic amidines of the general and the acid additio salts wherein R is methyl or Z is ethylene or Y is 0 or and X is vinylene or when Y is 0 X may also he ethylene The hydrochloride salt of the compound of formula I in Claim in which R is Y is and Z is A process preparing cyclic amidines of the formula I in Claim 1 in which X is which comprises reacting a compound of the general wherein R and Y are as defined in Claim with a diamine the in which Z is as defined in Claim 1 or a salt of said diamine if converting the compound obtained into an acid addition salt process preparing cyclic of the formula I 1 in which I is 0 and is reacting a compound of the in which E is as defined in 1 and is a diamine of the in which 2 is ao defined in Claim 1 or a salt of said diamine if converting the compound thus obtained into an acid addition salt A process for preparing cyclic of the formula I in Claim 1 in which is comprises reacting a compound of the general which and Y have the meaning as in with a compound of the wherein is as defined in Claim 1 if converting compound thus obtained into an acid addition salt A process to Claim in which the or are condensed a substituted or totrahydropyrimidine under conditions result the effective of product in Claim A process for producing cyclic amidines of formula substantially as amidines of formula I in 1 whenever prepared by the as A method for the veterinary control of which the administration to an animal of an effective amount of a compound of the I in Claim 1 or an acid addition salt A method according to Claim in which an amount of from to 150 of the compound of formula I in Claim 1 or of an acid addition salt thereof on the free is administered per of body weight the For the Applicants MBred insufficientOCRQuality