IL25683A - 2-thienylalkylimidazoline and-tetrahydropyrimidine compounds and their preparation - Google Patents

Description

25683/3 ti PFI SSR C ■:. ϋΌΕΑ'ίϊΟΗ P.O. 476 -4764 UKA-4764B-4764C-4805 Blanket Case II This invention relates to a series of novel cyclic amidines and their non-toxic acid addition salts particularly, it relates to certain nove^-e^3fylrfeh-i derivatives and the non-toxic acid addition salts thereof as agents for the control of helminthiasis in humans and animals.

Helminthiasis, the infestation of the human or animal body 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 this disease has led to extensive research for new and more effective anthelmintics, the counter-measures developed to date have not been entirely satis-factory for one or more reasons; e.g., poor therapeutic index, specificity of action, high cost, low activity, limited anthelmintic spectrum.

The usual method, indeed, the almost universal method for the treatment of helminthic infections, is the oral administration of the drug of choice. The treatment of helminthiasis by the parenteral (e.g., subcutaneous, intramuscular, intracutaneous, intraperitoneal administration of suitable drugs has not been practical in view of the nature and location of the parasites involved and-the poor activity of available drugs by the parenteral route. their action, both with respect to the helminth and to the host. The indiscriminate application of the term "anthelmintic" to drugs which have a toxic action upon parasitic worms belonging to more than one animal phylum erroneously conveys the impression that the organism being acted upon belongs to a biological classification comparable to that which encompasses bacteria or fungi since these organisms are subject to attack by antibacterial and antifungal agents. However, this is not the ease. Roundworms and flatworms belong to different animal phyla and there is no reason to believe that an anthelmintic effective against Aacaris lumbricoides (phylum, Nematoda) will have an effect on Hymenolepsis nana or Taenia saginata (phylum, Platyhelminths) . Indeed, activity against one phylum cannot be extrapolated to another phylum.

The screening procedures employed in the evaluation of potential anthelmintic agents involve in vitro tests with worms of different types with respect to a stimulating, paralyzing or killing effect. The agents selected in this manner are then, if their solubility, toxicity and stability in the animal body warrants, Investigated further in worm-infected humans or animals.

The shortcomings of the in vitro tests become obvious when one considers the following points: the drug may be absorbed or chemically altered before i reaches the helminth; the helminth may be coated with mucous or other substance which serves as a barrier to drug penetration; the physical location of the helminth may be such that the drug does not reach It. The location of the helminth In the host, in fact, constitutes an important reason for the specificity of anthelmintic agents. Moreover, the effectiveness of anthelmintic agents against the same or closely related worm species varies greatly from host to host.

In vivo studies on animal parasites as a means of. determining anthelmintic activity against definite species of human parasites are subject to many of the same objections as in vitro studies. Different species or varieties of parasites, great differences in the anatomy and physiology of the Intestinal tracts of the hosts, varying food habits and different intestinal contents serve to complicate the experiments. The dru must be tested against the particular helminth In the particular host in order to obtain definite results.

There Is at present no broadly effective anthelmintic drug. While more than one roundworm may be susceptible to a given drug, no drug is recommended for therapy against both tapeworms and roundworms.

According to the present invention, it has now been unexpectedly found that certain novel 2-alkylthio-phene derivatives, namely, Λ2" imidazolines, 2-J w-(2-thienyl Jalkyl/- ^2-tetrahydropyri-mldlnes, _their N-.. methyl derivatives (fomula l)j _ naphthoate, suramin salt, resin adsorbates, methiodide, methobromide and methochloride. „ These agents are active against both the mature and immature forms of helminths of the-families Ancylostomidae, Strongylidae and TrichostrongffJtdae .

They are especially effective against the gastrointestinal parasites of humans, ruminants (e.g. sheep, cattle, goats) and of non-ruminants such as dogs, cats, horses and swine.

Methods of studying the sensitivity of this group of parasites to chemotherapeutic agents comprise selecting a laboratory-induced parasitic infestation of a laboratory animal exhibiting a similar host-parasite relationship to that found between such parasites and domestic animals. Such a relationship exists between Nematospiroides dubius and laboratory mice, between Nippostrongylus muris and laboratory rats and mice, and between Syphacia obvelata and laboratory rats and mice. The test with dubius in laboratory mice is carried out by collecting the fecal matter of an infected mouse and suspending it in moist charcoal. Patties are prepared and these are incubated at room temperature for 4 to 5 days until the ova hatch and larvae are produced. The larvae are then collected and used to inoculate healthy mice. It has been found that an inoculum of 40 larvae per mouse yields a flourishing infestation consisting of about 30 adult worms after a 14-day developmental period. Established anthelmintics have been found to be ineffective against an inoculum of this size.

The test with N. muris involves collecting fecal matter of infected rats and setting up fecal cultures in the same way as for dubius, The cultures (charcoal patties) are incubated at 26° C. for 7 days. The larvae are then collected and used to inoculate healthy mice. An inoculum of 500 larvae and 1.25 ∞g. hydrocortisone acetate subcutaneously into young weanling mice produces a flourishing infestation.

S. obvelata, the pin-worm of rats and mice is allowed to maintain itself naturally within the building colony so that practically all mice infected with N. dubius and muris are also infected with E . obvelata.

As noted above, these products are effective to a significant degree in controlling helminthiasis in animals and man, by both the oral and parenteral routes of administration. Subcutaneous and intramuscular injections are the preferred methods of parenteral injection for several reasons; simplicity, convenience and the compounds appear less toxic. According to this method of the present invention, anthelmintic agents described herein or their non-toxic acid addition salts are administered parenterally, e.g., by subcutaneous or intramuscular injection, to humans.or animals suffering from helminthiasis of various types in a dosage equivalent to from about 5 mg. to about 1 0 mg. of the free base/kg. of body weight. A single injection is generally sufficient but, in the event multiple doses are employed, the injection can be repeated at regular, e.g., monthly, intervals, or more frequently if desired. Vehicles suitable for parenteral injection may be 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, com, 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; lycol, 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, ete.j buffering agents, as well as local anesthetics and inorganic salts to afford desirable pharmacological properties..

Administration of these anthelmintic agents in combination with hyaluronidase avoids local irritation. An increase in the rate of absorption of the drug is observed and the pain due to swelling and distentipn is greatly reduced if not completely eliminated. Hyaluronidase levels of at least about 150 (U.S.P.) units are very effective in this respect. Higher or lower levels can, of course, be used but 150 units per dose appears to give consistently good results as evidenced by the absence of edema and the general behavior of the animal following injection of the drug preparation.

When administered by the oral route the novel products of this invention are given in dosages equivalent to from about 1 mg. to about 150 mg. of free base/kg. of body weight. This can be achieved by a number of methods including mixing with the feed, dosage unit formulations such as capsules, tablets, liquid mixtures and solutions including drench solutions, or they can be administered in admixture with minerals such as sodium chloride which are frequently fed to animals as a supplement. Although the dosage specified is based on active ingredient, namely the base form of the cyclic amidine, in practical use the non-toxic acid addition salts specified and the free base can be used interchangeably, except as otherwise noted below.

For therapeutic use, a dosage equivalent to 1 to 100 mg. of free base/kg. of body weight is recommended. Ordinarily a single dose is sufficient, but in the event multiple doses are employed, this dose is repeated on 2 or 3 consecutive days. Since the present method is effective against not only the mature worms but also against the larval stages, it is not necessary to repeat the dosage after a period of 2 to 3 weeks as is commonly done with prior anthelmintic agents. For administration to sheep, goats, cattle, horses and swine on a therapeutic basis, a drench solution which Is squirted down the animal 's throat by a means of a drenching syringe is convenient. For this purpose an aqueous solution of water soluble non-toxic salt is generally used. From the standpoint of convenience and ease of preparation the hydrochloride salts are favored. Solutions having con-centrations ranging from about 3$ up to the limit of solubility of the salt in water are satisfactory for drench solutions. More dilute solutions, however, can be supplied for drinking purposes. A 0.1 solution is useful.

For prophylactic use, 1 to 50 mg. (calculated as free base), per kg. of body weight daily is administered. 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 1/2 to 45 grams. Boluses of suitable sizes containing these materials can be prepared by con-ventional methods.

Dry mineral mixtures containing the products of this invention are prepared containing from 0.10 to about 10$ of the active ingredient mixed with salt (sodium chloride) and other minerals with which it is desired to treat the animal. This can then be fed 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. If prepared feed supplements are employed, the material can be administered in admixture with the feed. Again, a concentration range of about 0.10 to 1 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. This can be readily deter-mined by simple experimentation. It is generally advisable to mix the daily dose with only a portion of the animal's average daily allotment to insure complete consumption of the dose. The balance of his daily feed supplement can then be fed after consumption of the medicated portion in the usual fashion. These methods 25683/2 are particularly useful for prophylactic treatment, but similar compositions can be employed for therapeutic use. Concentrations of drug in the feed or mineral mixture up to from 2 to depending again upon the palatability of the material, are sometimes useful.

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 significant anthelmintic activity of the compounds of this invention is indeed surprising and unexpected in view of the fact that 2-(2 '-thenyl) imidazoline (the compound of formula I wherein and R2 are hydrogen, y is ethylene and X is methylene), the preparation and antimalarial action of which are described in U.S ..2, 57,0 7, exhibits little or no anthelmintic activity. It was found to be virtually inactive against Nema ospiroides dubius in mice when administered orally on 3 successive days at a dose level of 5OO mg. kg. of body weight. The corresponding 2-( 2 thenyl)tetrahydropyrimidine (formula I wherein ¾ and R2 are hydrogen, Y is trimethylene, and X is methylene) was also found to be virtually inactive at this regimen.

The compounds of this invention, on the other hand, are significantly effective against dubius in mice. 2- 2"-(2-Thienyl)ethyl7~ ^-imidazoline hydrochloride and 2-/2~(2-thienyl)ethyl7- ^2-tetrahydropyri-midine hydrochloride, for example, exhibit high activity against N. dubius at doses of 3 100 mg./kg. 25683/2 The novel products of this invention of formula I wherein X is ethylene or trimethylene can be prepared by known methods, such as the reaction of the appropriate alkylenediamine tosylate with the desired w-(2-thienyl) substituted nitrile, such as w-(2-thlenyl)propionitrile, w-(2-thienyl)acrylonitrile or w-(2-thienyl)butyronitrile to give the tosylate salt of the cyclic amidine. Alternatively, the imino-ether hydrochlorides corresponding to the above mentioned nitriles can be reacted with the appropriate alkylenediamine to give the hydrochloride of the cyclic amidine. In still another modification, an ester of the 2-(2-thienyl)-alkanoic acid, such as methyl-3(2-thienyl)propionate, acrylate or butyrate can be reacted with the desired alkylenediamine to give the cyclic amidine free base. .

The compounds of formula I wherein X is . . vinylene are prepared by reaction of 2-thienylacrylamide with 1,3-propanesultone (Ried and Schmidt, Ann. 676, 114 (1964)) to produce 3-(l »-imino-(3-thienylallyloxy))-propane sulfonic acid, an imino ether in which the newly introduced radical is 3-propylsulfonic acid. The thus-produced iraino ether is then reacted with the appropriate diamine, e.g. ethylenediamine, trimethylenediamine, 2-methyltrimethylenediamine or the N-monomethyl derivatives thereof to give the desired cyclic araidine. The compounds thus produced have the trans configuration. The cis isomers are obtained by irradiation of the trans isomers as described herein.

Those compounds of this Invention wherein X is vinylene (trans) are light sensitive, particularly in solution, and undergo conversion to several products including the cis isomer. They must, therefore, be protected from light by suitable means, e.g. storage in the dark, in brown bottles, dark capsules, etc.

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 recrystalllzation 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 of the herein described compounds can be readily prepared simply by dissolving the free base in a suitable solvent, e.g. acetone, water, 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 lyo-philization. In this manner the sulphate, nitrate, phosphate, acetate, propionate, butyrate, citrate gluconate, benzoate, pamoate, amsonate, tartrate, 3-hydroxy-2-naphtho-ate and the sulphosalicylate and other salts can be prepared. In the case of the dibasic acids, e.g. pamolc, amsonic, a 1 : 2 molar ratio of acid to base is used to give the 1: 2 salt. The inorganic polybasic acids are generally used in a 1 : 1 molar ratio with the desired base.

In still another method, one acid addition salt can be converted to another by an ion exchange process. For example, the tosylate salts 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 compounds of this invention are conveniently prepared by slurrying an aqueous solu-tion of a water soluble salt of the compound 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 C6-120, 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.

The 2-(2-thienyl)propionitriles can be convenient-ly prepared by a novel sequence comprising a Knoevenagel type condensation of the appropriate 2-Thiophenecarboxalde-hyde with cyanoacetic acid in the presence of an appropriate catalyst, e.g. ammonia, primary or secondary amines, pyridine, plperidine, ammonium acetate-pyridine, followed by catalytic hydrogenation of the thus produced w- (2-thienyl)-acrylonitriles. The fact that hydrogenation of the w-(2-thienyl)acrylonitriles can be conducted over a noble metal catalyst, e.g. palladium, platinum, rhenium, rhodium, iridium, osmium, is most unexpected. 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 aqueous dioxane, are satisfactory solvents. The reaction system can be neutral, basic or acidic. A basic system is generally favored since it markedly accelerates the rate of reaction. Bases of particular value in this respect are the inorganic bases, e.g. the alkali metal hydroxides, especially sodium and potassium hydroxide, and the quaternary ammonium hydroxides, e.g.

R1R2R3R4NOH wherein Ηχ, R2, R3 and 4 are alkylj R3 and R are benzyl and alkyl substituted benzyl, such as trimethyl-benzylammonium hydroxide, (p-t-butyl)benzyltrlmethylammonlum 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- (2-thienyl)acrylonitrile 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.

The following examples are provided to illustrate in greater detail the manner of practicing the present invention. They are, however, not to be considered as limiting the scope thereof in any way. (The dosages used in the following examples are calculated as the free base).

Example I 3- (2-Thienyl )Acrylonitrile A solution of 123.4 g. (1.10 moles) of 2-thiophene-carboxaldehyde, 85.0 g. (1.00 mole) cyanoacetic acid, 3 g. of ammonium acetate, 110 ml. of pyridine, and 200 ml. of toluene is heated under reflux in an apparatus which includes a Dean-Stark moisture trap. Heating is continued for 48 hours during which time the solution becomes very dark.

After the heating period is over the solution is allowed to cool and the solvents then evaporated under reduced pressure. The less volatile residue is fractionally distilled through a column packed with Berl saddles to yield the product which is initially a colorless oil: b.p. 154° C. at 30 mm.; yield, 107.4 g. (79$) ¾5 1.6373.

Example II 3- (2-Thlenyl)Propionitrile A pressure bottle is charged with 67.6 g. (0.5 mole) of 3- (2-thienyl)acrylonitrile, 50 cc. of IN sodium hydroxide, 300 cc. of methanol, and 10 g. of $ palladium- on-carbon catalyst. The pressure bottle Is swept free of air by nitrogen and then fitted onto a Paar hydrogenatlon apparatus. Hydrogenatlon is conducted in the normal manner until the theoretical amount (0.5 mole) of hydrogen is ab-sorbed. The catalyst is removed by filtration, and the filtrate concentrated to a mixture of an oil and aqueous sodium hydroxide. Water is added to this mixture and the organic material extracted with ether. The other extract is dried, filtered and evaporated under reduced pressure to give a pale yellow oil which is fractionally distilled through a column packed with Berl saddles to give 3- (2-thienyl)propionitrlle as a colorless oil: b.p. I56-I580 C. at 35 mm.; yield, 9.5 g. (72#); n§5 1.5372.

Example III 2-^-(2-Thienyl)ethyl7-A2_imidazoline Hydrochloride A 00 cc. Erlenmeyer flask is charged with 13.7 g. (0.1 moles) of 3- (2-thienyl)propionitrile, 6.5 g, (0.11 moles) of ethylenediamine, and 19.0 g. (O.l moles) of p-toluenesulfonic acid monohydrate. The mixture is heated at 175° for 8 hours during which time the evolution of ammonia is noted. After cooling, the resulting glass is recrystallized from 2-propanol to yield 9 g, of crystalline material, m.p. 104-106° C. A second crop of 10,5 g. is obtained, melting point 100-104° C.

The first and second crops of the toluenesulfonate salt are dissolved in water and treated with aqueous sodium hydroxide until a strongly basic solution is obtained. The solution is then extracted 3 times with ethyl acetate. The combined extracts are dried, filtered and evaporated under reduced pressure to yield a white solid^material which is recrystallized from acetone and hexane to give colorless platelets of the imidazoline free base, m.p. 99-101° C. The free base is dissolved in methanol and treated with an exact equivalent of hydrogen chloride in methanol. The solvent is then evaporated and the colorless solid recrystallized from 2-propanol/ether to give the desired product. Alternatively, the p-toluenesulfonate salt in methanol may be passed through a chloride anion exchange column to give eventually the hydrochloride.

In like manner, 2-/2:- (2-thienyl)ethyl/-A2-tetra-hydropyrimidine hydrochloride is prepared by substituting trimethylenediamine for ethylenediamine.

Example IV 2-^-(2-Thienyl)ethyl7-A2-Imidazoline Hydrochloride Methyl /^-(2-thienyl)propionimidate hydrochloride (8.5 g.j prepared by conventional procedure from the nitrile of Example II and methanol) is dissolved in dry methanol (40 ml.) and ethylenediamine (2.7 g.) added. The mixture is re-fluxed for one and a half hours, the solvent then evaporated off and the residue recrystallized several times from iso-propyl alcohol-ether to give a white microcrystalllne solid; m.p. 142.5-143.5° C.

Analysis Pound s C, 49.92$ H, 5.95$, CI, 16.43$; N, 12.71$; S, 14.33$ Calcd. for CoH^CD^S: C, 49.86$; H, 6.00$; CI, 16.39$; N, 12.93$; S, 14.78$ Example V 2- 2"- (2-Thienyl )Ethyl7-A2-Tetrahydropyrimldine Hydrochloride Methyl (2-thienyl)propionimidate hydrochloride (8.5 g.) is dissolved in dry methanol (40 ml.) and tri-methylenediamine (3.4 g.) is added. The resultant mixture is refluxed for one and a half hours, the solvent evaporated off and the residue is recrystallized several times from isopropyl alcohol-ether to give a white microcrystalline solid; m.p. 166. -167.5° C.

Analysis Calcd. for C10Hi5Cl 2S: C, 52.020 H, 6.510; CI, 15.400; N, 12.140 S, 13.880 Pound: C, 52.380 H, 6.540; CI, 15.6 N, 12.800 S, 13.570 Example VI 2-/^-(2-Thienyl)Propyl7-^2-Tetrahydro Pyrimidine Hydro- chloride Methyl (2-thienyl )butyrimidate hydrochloride (10.0 g.) is dissolved in dry methanol (25 ml.) and tri-methylenediamine (3.4 g.) added. The mixture is refluxed for one and a half hours. The solvent is evaporated off and the residue recrystallized several times from isopropyl alcohol-ether, the product being obtained as a white micro-crystalline solid; m.p. 138-139° C.

Analysis Found: C, 53.580; H, 6.970; CI, 14.360; H, 11.080; S, 12.930 Calcd. for C11H17CIN2S: C, 53.970; H, 7.000; CI, 14.490; N, 11.450; S, 13.100 Example VII The following compounds can be conveniently prepared by the procedures of Examples III and IV from the appropriate reactants. The necessary 3- (2-thienyl)propio-nitrile can be obtained according to the procedure of Cagniant, et al, Bull. soc. chim. France, 1083-7 (19^8 ) .

This procedure involves the Grignard reaction of 2-iodothio-phene and ethylene oxide to give 2- (2-hydroxyethyl)thio-phene. Treatment of the alcohol with phosphorous tribro-mide and then with sodium cyanide produces the desired 3- (2-thlenyl)propionitrile. 4- (2-Thienyl)butyronitrile can be obtained by dehydration of the corresponding amide as follows. A stirred solution of 18.0 g. of 4- (2-thienyl)bu-tyramide and 60 ml. of pyridine is cooled in an ice-bath. Benzenesulfonyl chloride (l8.5 g.) is then gradually added while maintaining the reaction temperature below 5° C. The mixture is allowed to warm to room temperature, stirred overnight, then poured into 400 ml. of ice water. The aqueous solution is adjusted to pH 1 then extracted with diethyl ether (3 X 100 ml.). The combined extracts are dried over anhydrous MgSO^, filtered and evaporated to give 4- (2-thienyl)butyronitrile. The iminoethers can be prepared according to standard procedures. (-¾> = hydrogen in the following compounds ) .

Procedure Rl X Y* of Example CH3 -CH2-CH2- eth tri IV CH3 -CH2-CH2-CH2 eth tri IV H -CH2-CH2-CH2 tri IV * eth = ethylene; tri = trimethylene Example VIII 2-/2- ( 2-thienyl)ethyl -^2-Imidazoline hydrochloride is dissolved in water (10$ solution) and neutralized by the slow addition of 6N sodium hydroxide with vigorous stir- ring. The insoluble base is collected by filtration, washed with water until free of chloride then dried in air.

In like manner the remaining hydrochloride salt of Example III and those of Examples V, VI, and VII can be converted to their respective free bases.

Example IX A. 2-^-(2-thienyl)ethyl7-A2-imidazoline (0.02 mole) is dissolved with stirring in 300 ml. of warm alcohol containing 0.01 mole of pamoic acid. The mixture is stirred for three hours then filtered to give 61-2-/2- (2-thienyl)ethyl7-A2-imidazoline pamoate is collected and dried.

B. 2- 3-(2-thienyl)propyl)-A2-tetrahydropyrimidine citrate can be prepared by adding 0.01 mole of the free base, 2- J-(2-thienyl)propyl7'-A2-tetrahydropyrimidine, to 25 ml. of a warm aqueous solution of 0.01 mole citric acid. The resulting clear solution is evaporated to give the salt.

By means of these procedures the amsonate, pamoate, 2-hydroxy-3-naphthoate, 2-hydroxy-3-naphthoate, sul-fosalicylate, acetate, propionate butyrate, gluconate, ben-zoate. citrate, stearate, sulfate, phosphate and nitrate salts of the products of Example VIII can be prepared.

Example X 2- 2- (2-Thienyl )ethyl7-A2-tetrahydropyrimidine hydrochloride (5 g.) is dissolved in water (25 ml.), the solution filtered and added to a well-stirred suspension of Amberlite CG-120 (sodium form of a cation exchange resin) (5·9 g.) in 100 ml. water. The mixture is stirred for 3 hours then filtered, washed with water and dried in vacuo. Nitrogen analysis shows approximately 4l# base to be adsorbed.

Resin adsorbants of the products of Examples III, VI, and VII can be prepared in like manner.

Example XI l-Methyl-2-^-(2~Thienyl)Vinyl7-A2-Tetrahydropyrimidine 2-Thienylacrylamide (23.4 g.) and 1,3-propane-sul one (l8.7 g.) are heated at 130-140° G. with rapid stirring. After 0.5 hours the melt solidifies to a hard mass. The mixture is heated for a further 0.5 hours, cooled, crushed to a fine powder then triturated with acetone and filtered. The iminoether is obtained as a pale yellow solid (38.9 &., 92.5 yield); m.p. 198-200° C. The crude product, S-tl'-iminoiS-thienylallyloxylJpropane sul-fonic acid, is used directly for the next stage without further purification. The iminoether (3.2 g.) and N-methyl-trimethylenediamine (1.05 g.) are refluxed together in dry ethanol (50 cc.) for 1.5 hr., the solvent then removed under vacuum, and the residue dissolved in water. The aqueous solution is treated with charcoal and filtered. The filtrate is made alkaline with ΝΑ0Ή, and extracted with chloroform. The organic phase is washed with saturated sodium chloride solution, dried over sodium sulphate, then evaporated to dryness. The residue is dissolved in isopro-panol, acidified with citric acid in the same solvent and the salt precipitated by adding ether. Three recrystal-lizations from methanol provide a pale yellow solid (1.3 g.> 28$ yield); m.p. 178-179° C.

Analysis Found: C, 51.2 $ H, 5.69$J N, 6.88$; S, 7.86$ Calcd. for C, 5L24 H, 5.57 N, 7.03 S, 8.05$ Example XII Methyl ^- (2-thienyl)acrylimidate hydrochloride (10.2 g., prepared in the usual way from the 3- (2-thienyl)-acrylonitrile of Example I and methanol except that the mixture is cooled to -10° C. while saturating with hydrogen chloride) is dissolved in methanol (40 ml.) and added to a solution of N-methyltrimethylenedlamine (44 g.) in methanol (60 ml.) at 5-10° C. The mixture is allowed to warm to room temperature, heated to reflux for three hours then evaporated to dryness. The residue is taken up in water (30 ml.) then poured into an ice-cold stirred mixture of 2N sodium hydroxide (75 ml.) and methylene chloride (75 ml.).

The ether phase is promptly separated, dried ( a2S0_|) and evaporated to give the free base.

The base is dissolved in methanol and treated with a solution of citric acid (8.6 g.) in methanol. The citrate salt is precipitated by the addition of ether and purified by recrystallization from methanol.

Using the appropriate reactants the following compounds are prepared by the above procedures.

H H tri maleate 153-1 4.30 5.21 9.44 10.73# CH3 H eth p-toluene sulfonate 162-164 56.09 5.48 7.59 17.83# H H eth maleate I62-I63 53.46 4.76 9.49 10.90$ CH3 CH3 tri hydrochloride 239-241 55.58 6.8Ο 11.01 chloride (31.8 g., prepared from the corresponding nitrile of Example II and methanol by conventional procedure) is added to a solution of N-methyltrimethylenediamine (l8.5 g.) in methanol (250 ml.) at 0° C. The mixture is refluxed overnight then evaporated to dryness under reduced pressure.

The residue is treated with 100 ml. of 40$ aqueous sodium hydroxide at about 5° C, shaken for several minutes then extracted with ether. The ethereal solution is dried with anhydrous sodium sulfate then evaporated. Extraction of the aqueous solution with chloroform provides an addi-tional quantity of the desired base. The combined bases from the extractions are distilled in vacuo to give the free base.

The hexafluorophosphate salt is obtained by adding the base to an ice-water mixture containing an equimolar proportion of hexafluorophosphoric acid. The salt precipitates, is filtered off and recrystallized from 2-propanol; m.p. 116.5-117.5° C.

Analysis Calcd. for C12H19P6N2PS: C, 39 - 12$; H, 5.19$; N, 7.61$ Pound! C, 39.30$; H, 5.3 $; N, 7.61$ The following compounds are similarly prepared from the appropriate reactants; H -GH2CH2- -CH2CH2- H -CH2CH2- -CH2CH2CH2- H -CH2CH2CH2- -CH2CH2- H -CH2CH2CH2- -CH2CH2CH2- CH3 -CH2CH2- -CH2CH2- CH-a -CH2CH2CH2- -CH2CH2- CH3 -CH2CH2CH2- -CH2CH2CH2- Example XIV l-Methyl-2~^- (2-thienyl)viny ^-^2-tetrahydrc^y lmidine ~" Tartrate" " Trans Isomer The citrate salt of Example XII is added to a cold, stirred aqueous solution (50$) of potassium hydroxide (in a 1:1 molar ratio) 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 and decolorized with charcoal. Removal of the ether affords the base.

The base is taken up in ethanol, stirred and an 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; m.p. 147-148°C.

Analysis Calcd. for C12H20 206Ss C, 50.55; H, 5.76; N, 757; S, 9.00$ Found: C, 50.56; H, 5.66; N, 7.86; S, 9.00# Cis Isomer A stirred solution of trans-l-methyl-2- 2"- (2- 2 thienyl)vinyl7- ^ -tetrahydropyrimidlne tartrate (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 the trans isomer.

The pure cis isomer melts at l60-l6l° C.

The remaining products of Example XII are converted to their respective cis isomers by this procedure.

Example XV Six lambs, naturally infected with gastrointestinal nematodes (Haemonchus, Strongyloides, Nematodirus) and tapeworm are selected at random and divided into 3 pairs. The first pair (I-A and B) received2/?- (2-thienyl)-ethyl7- A -imidazoline hydrochloride, 50$ aqueous solution, as a drench at 40 mg./kg. body weight. The second pair (II-A and B) received 80 mg./kg. body weight of the 50$ aqueous solution (drench), and the third, or control, pair (III-A and B) received only sterile distilled water.

Egg counts are made on the three days preceding the treatment and on the first, fourth and seventh days following treatment. Results are tabulated below in Tables I and II, respectively.

TABLE I Eggs Per Gram of Feces Prior to Medication Animal Day-3 Day-2 Day-1 No. N S 0 Total N S 0 Total «f 5 "0 Total I-A 0 0 420 420 0 0 640 640 0 0 600 600 I-B 0 0 900 900 0 0 720 720 0 0 840 840 II-A 0 0 1400 1400 0 0 1800 l800 0 0 1740 1740 II-B 0 0 2520 2520 0 0 2880 2880 0 0 2640 2640 III-A 20 4660 760 5440 0 736Ο 840 8200 0 5560 680 6240 III-B 0 0 298Ο 298Ο 0 0 236Ο 236Ο 0 0 2520 252Ο TABLE II Eggs Per Gram of Feces After Medication I-A 0 0 200 200 0 0 120 120 0 0 0 0 I-B 0 0 400 400 0 0 120 120 20 0 3 0 36Ο II-A 0 0 120 120 0 0 200 200 0 0 60 60 II-B 0 0 1520 1520 0 0 640 640 0 0 400 400 III-A 0 8040 640 868Ο 0 85 Ο 8OO 932Ο 0 708O 80 788Ο III-B 0 0 I88O I88O 0 0 2120 2120 40 0 2400 2440 N=Nematodirusj S=Strongyloides; 0=0thers, mainly Haemonchus From these data it is seen that 2-^2T-(2-thienyl)-ethyl7- ^-imidazoline hydrochloride is highly effective in reducing the egg counts of Haemonchus and related species.

Similar significant reduction in egg counts can be obtained by administering this agent to cattle, dogs and goats.

Example XVI Repetition of the preceding experiment with 4 other randomly selected, naturally infected lambs, but using -tetrahydropyrimidine hydrochloride as the anthelmintic agent as a 50$ drench solution at 40 mg./kg. and 80 mg./kg. body weight produces the following results. The control lambs of the preceding experiment serve as controls here.

TABLE III Eggs Per Gram of Feces Before Medication Animal Day- 3 Da -2 Day-1 No. N S O Total N" S O Total N S O To^aT IV-A 40 300 240 580" 80 240 320 Μΰ 120 240 360 720 IV-B 20 II60 518O 636Ο 40 160 4120 432O 80 120 5220 6420 V-A 20 38Ο 4660 506O 40 480 6o40 6560 80 400 4700 5l80 V-B 0 40 240 28Ο 40 80 320 440 40 120 36Ο 520 III-A 20 4660 760 5440 0 7360 840 8200 0 5560 68Ο 6240 III-B 0 0 2980 298Ο 0 0 236Ο 2360 0 0 2520 2520 N=Nematodirus; S-Strongyloides j 0=0thers, mainly Haemonchus TABLE IV Eggs Per Gram of Feces After Medication Animal Drug Day + 1 Day * 4 Day + 7 No. mg/kg N S 0 Total N S 0 Total H S 0 Total IV-A 40 kO 80 200 320 0 55 2kO 280 0 60 260 320 iv-B o o i6o 1520 1680 ho 160 ikdo 1680 0 260 10201280 V-A 80 80 2001100 I38O 80 I601000 I2k0 0 0 20 20 V-B 8Ο Ο Ο 8Ο 80 O O 8O 80 O 0 0 0 ill-A 0 03oko 6ho &6ko 08520800 9320 07080 8007880 III-B 0 0 0 I880 I880 0 02120 2120 ko 02k00 2kk0 N s Nematodirus; S = Strongyloides; 0 = Others, mainly Haemonchus Significant reduction in the egg counts are evident particularly at the level of 80 mg./kg. body veight.

Example XVII Oral administration of (I) or of 2-/2-(2-thienylJethyl/- ^-tetrahydropyrimidine (II) as their hydrochloride salts to mice bearing laboratory-induced infestations of Nematospiroides dubius or of Nippostrongylus muris (100 larvae per mouse and 500 larvae per mouse, respectively) at three successive daily doses of 100 mg./kg. body weight produces impressive reductions in the parasite burden.

Compound N. dubius N muris I 97$ reduction 6jf> reduction II 90 reduction 91$ reduction Example XVIII Eighteen sheep naturally infected with gastrointestinal nematodes (Haemonchus, Strongyloides, Trichostrongyles, Nematodirus) are selected at random and divided into six equal groups. One group serves as control and is administered no medication but only sterile distilled water. Four of the remaining five groups are administered l-methyl-2-/2-(2-thienyl)ethyl7- ^-tetrahydropyrimidine (A), dissolved in 0.1 M tartaric acid in a 5$ concentration, at levels equivalent to 12.5, 25, 50, and 100 mg./kg. of body weight, as a drench. The fifth group is drenched with 2-£2-(2-thienyl)ethyl -tetrahydropyrimidine (B), dissolved in 0.1 tartaric acid in a $ concentration, at a level equivalent to 50 mg. of free base per kg. of body weight. The average reductions in the total egg count in each group are tabulated below.

Average Reduction Compound Dosage (mg./kg.) in Egg Count C Example XIX Repetition of the procedure of Example XVII but using l-methyl-2- 2"- (2-thienyl)ethyT7 ^ -imidazoline in place of l-methyl-2- 2 2-thienyl)ethyl7- ^2-tetrahydro- pyrimidine at levels equivalent to 6.25, 12.5* 25 and 50 mg./kg. of body weight produces the following significant reductions in the nematode egg counts.

Average Reduction Dosage (mg./kg. ) in Egg Count ' 6.25 96.46 12.5 98.65$ 99.91$ 50 100.00$ A single dose, 100 mg./kg. body weight, of the resin adsorbate of hydropyrimidine (the product of Example X) reduced the N. dubius and N. muris infestations of mice by 8 $ and 60$, respectively.

Example XX Tablets and Boluses A convenient tablet size is one containing 250 mg, of the drug. Such tablets can be prepared by thoroughly blending 250 g. of 2-^- (2-thienyl)ethyl7- Δ -imidazoline 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 suffi- cient ethanol to make an easily manipulated paste which is extruded through a 10-mesh screen to provide granules which are dried in vacuo until all the solvent is removed. The granules are coated with magnesium stearate by briefly blending with 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 1/2 to 45 g. per day depending again upon the body weight of the animal. Boluses of various sizes can be prepared in the same fashion by simply selecting a die of appropriate size.

Example XXI 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 250 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 prepared by thoroughly blending two parts by weight of (2-thienyl)ethyl7- 2-imidazoline phosphate with one part by weight of 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 XXII Mineral Mixture Such a mixture can be conveniently made by mixing 2- £-(2-thienyl)ethyl7- ^-imidazoline hydrochloride, equivalent to 1 part by weight of free base, with 19 parts by weight 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 animal.

In like manner mineral mixtures of the other products within the ambit of this invention can be prepared.

Example XXIII 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 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, 10 pounds 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 .05$ up to about 10$ on a weight basis.

Example XXIV Lambs naturally infected with gastrointestinal helminths can be cleared to a significant degree by the subcutaneous administration of imidazoline hydrochloride at levels of from about 20 mg./kg. to about 150, mg./kg. The local edema which frequently accompanies the injection can be prevented or at least minimized by the simultaneous administration of about 150 units (U.S.P.) of hyaluronidase. can be used for the control of helminthic infection.

Example XXV l-Methyl-2-^-(2-thlenyl)ethyl7- Imidazoline Methyl w-(2-thienyl)propionimidate hydrochloride (87.3 g.), prepared by the conventional procedure from w-(2-thlenyl)propionitrile, is dissolved in dry methanol (175 ml.)* and to the solution N-methyl ethylene diamine (33.2 g.) is added with cooling. The resulting solution is heated under reflux for 1-1/2 hours, cooled and neutralized with methanolic sodium hydroxide. The solution is concentrated, then cooled, and the precipitated sodium chloride filtered off. The solvent is then distilled off from the filtrate, and the residue distilled in vacuo. The base is obtained as an almost colorless oil, b.p. 134-6° C./l.2mm., n 1.5570.

Analysis Found: C, 62.02; H, 7.12; N, 14.64; S, l6.79# Calcd. for C10Hl 2S: C, 61.83; H, 7.27; N, 14.42; S, 16.48# In like manner, but using methyl w-(2-thienyl)-propionimidate hydrochloride (18.2 g.) dissolved in dry methanol (40 ml.) and N-methyl trimethylene diamine (7.8 g«), l-methyl-2-j^-(2-thienyl)ethyl/- ^2-tetrahydropyrimidine, is produced as an almost colorless oil, b.p. 122-123° C./ 0.4 mm., n24 1.5648.

Alternatively, this product is prepared by bubbling hydrogen sulphide through a mixture of w-(2-thienyl)pro-pionitrile (250 g.) and N-methyltrimethylenediamine (ΐβθ.5 g., 1:1 mole ratio) until 6.1 g. is taken up. The mixture is then heated and stirred at 70-80° C. for two hours. Brisk evolution of ammonia occurs. The temperature is raised and maintained at 95° C. for six hours. The product is recovered by distillation in vacuo; yield - 34.7$, b.p. 145-150° C. at 1.5 mm.

Hydrogen sulphide may be replaced by phosphorous pentasulphide. When used at a level of 0.015 mole per mole of reactants and heated at 70-80° C. for two hours followed by 95° C. for sixteen hours an 82.3$ yield is obtained.

Example XXVI l-Methyl-2-^- (2-thienyl)ethyl7- /^-Imidazoline p-Toluene Sulfonate Method A. The base (5 g.) is dissolved in dry ether (20 ml.), and p-toluene sulphonic acid (4.5 g.) dissolved in a mixture of dry methanol (10 ml.) and ether (100 ml.) is added. The oil which precipitates solidifies on cooling and trituration with ether. After several recrystalliza-tions from isopropanol-ether the p-toluene sulphonate salt is obtained as colorless crystals, m.p. 104-105.5° C.

Analysis Pound: C, 55.91; H, 6.39; N, 7.76; S, 17.35$ Calcd. for c17¾2N2S2°3 i ° > 55 · 75> H> 6 · οβί Ν' 7 · β5' S' 17' . 9$ Method B. This method illustrates the preparation of the p-toluene sulphonate salt direct from w- (2-thienyl)propionitrile, N-methyl ethylene diamine and p-toluene sulphonic acid. w-(2-thienyl)propionitrile (13.7 g.)> N-methyl ethylene diamine (8.15 g«) and p-toluene sulphonic acid (19 g.) are mixed and heated to 175° C. during one hour, this temperature being maintained for a further ten hours.

The reaction mixture is cooled, and the glass that forms dissolved in hot isopropanol. The product is crystallized by addition of warm ether and allowing the mixture to cool. salt Is obtained as colorless crystals, m.p. 104-5° C.

Example XXVII l-Methyl-2i/?-(2-thienyl)ethyl7- /^-Imidazoline Citrate Citric Acid (2.1 g.) is dissolved in dry acetone (50 ml.), and to the solution the base (1.9 g.) dissolved in dry acetone (10 ml.) is added. The precipitated citrate, which solidifies on scratching, is obtained as a colorless crystalline material, m.p. l4l-2° C, after several recrystallizations from methanol-ether.

Analysis Found: C, 9.87; H, 5.86; N, 7.13; S, 8.22$ Calcd. for C, 49.74; H, 5.74; N, 7.25; S, 8.28$ Example XXVIII l-Methyl-2-^-(2-thienyl)ethylJ7- ^-Imidazoline Phosphate The base (1.9 g.) is dissolved in isopropanol (15 ml.) and the solution added to 8 $ phosphoric acid (1.15 g.) dissolved in isopropanol (30 ml.). The colorless solid which precipitates immediately is recrystallized several times from methanol-ether to give the phosphate salt as colorless crystals, m.p. 191-192.5° C, Analysis Pound: C, 41.28; H, 6.03; N, 9.62; P, 10.30; S, 10.93$ Calcd. for C, 41.12; H, 5.86; N, 9.58; P, 10.62; S, 10.95$ Example XXIX l-Methyl-2-^-(2-thienyl)ethy]7- A -Imidazoline Sulfate The base (l g.) is dissolved in ether, and under strong cooling one molecular equivalent of concentrated sulphuric acid is slowly added. The oil which precipitates solidifies on scratching. After several recrystallizations from isopropanol the sulphate Is obtained as colorless plates, m.p. 74.5-75° C.

Analysis Calcd. for C10H1 204S2': C, 41.10; H, 5.51; N, 9-59; S, 21.93# Found: C, 41.05; H, 5.25; N, 10.03; S, 22.03# Example XXX Method A. From lwmethyl-2-/2"- (2-thienyl)ethyl7- tetrahydropyrimidine the p-toluene sulphonate salt is prepared, following essentially the procedure of Example XXVI, Method A.

Purification by repeated recrystallization from isopropanol-ether gives colorless crystals, m.p. 122-123° C.

Analysis Found: C, 57.20; H, 6.47; N, 7.50; S, 16.83# Calcd. for C, 56.84; H, 6.31; N, 7.36; S, l6.85 Method B. The p-toluene sulphonate salt is also prepared from w-(2-thienyl)propionitrile (13.7 g.), N-methyl tri-methylene diamine (9.68 g.) and p-toluene sulphonic acid (19 g.) b following essentially the procedure of Example XXV, Method B, except that heating is continued for sixteen hours. Repeated recrystallization from isopropanol gives the p-toluene sulphonate salt as colorless crystals, m.p. 121.5-122.5° 0.

Example XXXI From 1-methy1-2- 2"- (2-thienyl)ethyl7- ^2-tetrahydropyrimidine a sulphate salt is prepared, following essentially the procedure of Example XXIX.

Repeated recrystallization from isopropanol gives the sulphate as colorless plates, m.p. 97-99° 0.

Example XXXII 1-Methy1-2-/2- (2-thienyl) ethyl/- A2-Tetrahydropyrimldine Nitrate Neutralization of the base (l g.) with N-aqueous nitric acid, followed by evaporation of the solution to dryness, and repeated recrystallization of the residue from isopropanol-ether gives the nitrate salt as colorless needles, m.p. 108.5-110° C.

Analysis Pound: C, 48.61; H, 6.34; N, 15.34; S, 11.61$ Calcd. for C^-^N^S C, 48.75; H, 6.28; N, 15.51; S, 11.81$ Example XXXIII Method A. l-Methyl-2-/2"- (2-thienyl)ethyl7- pyrimidine Έχχΐΐosalicylate 2.8 g. 5-Sulfosallcylic acid (0.013 mole) is dissolved in 1 ml. water and added to 2.1 g. of l-methyl-2- 2- (2-thienyl)ethyl - (O.Ol mole). A clear solution forms and upon standing, a white solid separates. This is ground up, triturated in a small amount of water, filtered, and air-dried to give 2.6 g. of product. Recrystallization from isopropyl alcohol gives 2.2 g. of a white crystalline solid; m.p. 154-155° C.

Analysis Found: C, 50.82; H, 5.39; N, 6.44 Calcd. for C11Hl6 2S.C?H606S: C, 50.69; H, 5.20; N, 6.57 Method B. l-Methyl-2- 2"- (2-thienyl)ethyl7- £2-Tetrahydro- pyrimidine Citrate To I.92 g. citric acid (O.Ol mole) dissolved in 100 ml. acetone is added dropwise a solution of 2.08 g. 1-methy1-2-^"- (2-thienyl Jethyl/- ^-tetrahydropyrimidine (0.01 mole) in 25 ml. acetone. A white precipitate forms immediately and after stirring 2 hours is filtered off, 3.7 g.J m.p. 142-143.5° C.

Analysis Calcd. for N, 7.00 Pounds N, 7.16 Method C. l-Methyl-2- 2"- (2-thienyl)ethyl/- ^-Tetrahydropyrimidine Phosphate To 4.16 g. 1 methyl-2-^- (2-thienyl)ethyl7- ^2-tetrahydropyrimidine (0.02 mole) dissolved in 25 ml. isopropyl alcohol, there is added a chilled solution of 2.3 g. H3PO (85$, 0.02 mole) in 75 ml. isopropyl alcohol. A gummy white precipitate forms. The solvent is decanted, 100 ml. isopropyl alcohol added, and the mixture scratched until a granular solid forms. This granular solid is filtered off, leaving behind some tacky solid which is discarded. Yield - 4.0 g.; m.p. 202.5-205° C.

Analysis Pounds N, 8.64# Calcd. for Method D. l-Methyl-2 pyrimidine Hydrochloride To 2.08 g. 1-methy 1-2- 2"- (2- hienyljethyl^- ^2-tetrahydropyrimidine (O.Ol mole) dissolved in 75 ml. ether a solution of Ο.365 g. dry HC1 gas in 10 ml. ether is added dropwise with stirring. The oil which forms becomes tacky on standing. The solvent is decanted and more ether added to the tacky mass which is scratched with a glass rod until a solid forms. The solvent is decanted and the light tan residue stripped to dryness on a rotary evaporator to 25683/2 give 2.1 g. of an extremely hygroscopic solid. It sinters about 100° C. and melts at 113-118° C.

Example XXXIV Following the procedures of the preceding example 2 the following salts of l-methyl-2-^/2- (2-thienyl)ethyl/- -tetrahydropyriniidine and of l-methyl-2- 2- (2-thienyl)-ethyl/- ^-imidazoline are prepared, Tables V and VI, respectively. 2 Table V. Salts of l-methyl-2-/2- (2-thienyl )ethyl/- 4 - tetrahydropyrimidine Salt Method .P. Yield pamoate C 137-1^3 41.7 maleate B 78-8Ο 89.5 stearate no solvent) 48-53 100.0 laurate no solvent (oil) 100.0 tartrate B 140-142 38.0 malate B . 99-100 79.0 fumarate B 149-151 95.0 succinate B 85-90 69.0 acetate (no solvent) (oil) 100.0 oxalate B 76-78 47.0 Table VI. Salts of 1-methy1-2-^- (2-thienyl)ethyl/- ^ - imidazoline Salt Method M.P, jo Yield hydrochloride 7Ο-9Ο 68.0 sul osalicylate A I 8-I 9 95.0 pamoate B 166- 168 94.0 stearate .no solvent ) 48-53 100.0 laura e ,no so >lven ) (oil) 100.0 tartrate B 167-I69 58.0 ■ fumarate B I57-I58 80.7 succinate B IO7-IO8 80.O acetate (no solvent) Coll) 100.0 toluene sulphonate salts ( •p-tosylates ) is assessed using; laboratory mice infested with ffematospiroides dubius and laboratory rats Infested with Klpaos rongylus muris.

Results are summarized in fable fable VII Doae (mg./kg.) Given aoval of Comoo nd Helminth Heat Orally Worms Imidazoline base J. dubims Mous 1 x 50 7® Imidazoline base I- ■ Set " 3 x 100 68 Imidazoline p-tosylate i. mum, Mouse t X 25 83 Imidazoline p-tosylate I· Souse 1 x 50 90 Imidazoline p-tosylate I· Eat 1 x 50 ββ Tetrahydropyrimidine base I. Mouse 3 x 100 98 Tetrahydropyrimidine base 1· Hat 3 100 100 ΪΘtranydropyrimidine p-tosylate I· So se 1 x 25 74 Tetrahydropyrimidine p-tosylate J* Mouse 1 x 50 86 Tetrahydropyrimidine p-tosylate 1* muris Eat 1 X 50 77 Setrahyd opyrimidlne Amsonate I· dublus Mouse 2 x 300 96 Tetrahydropyrimidine Amsonate I- muris Sat 1 150 99 - water and dried j ra„p. 300°C0 Analysis Pounds C, 55.171 H, 5.82; N, 10. 1; S, 16. 0$ Calcd. for C36H 6N6S S C, 54.95; H, 5.89; N, 10.68; S, l6.28# -w Example ¾ XXXVII To a solution of Suramin (1.914 g. /equivalent) in 10 ml, of water there is added a solution of 2- ~- (2- thienyl ^2-tetrahydropyrimidine hydrochloride (I.763 g., 6 equivalents) in water (5 ml.). A white gummy oil immediately separated. The supernatant liquors were decanted, the residue. washed free of inorganic salts and dried in vacuo to constant weight. The amorphous solid melts at 145-150° C.

Analysis Founds C, 53.261 H, 5.21; N, 9.61J* Calcd. for C, 54.12; H, 5.07; N, 10.24# Example ¾I XXXVIII 2- 2- (2-Thienyl ) Ethyl/- A2_Tetrahydropyrimidine Amsonate To a solution of amsonic acid (1.9 g.) in 10 ml. water containing 2 equivalents of sodium hydroxide is added a solution of 2-/2"- (2-thienyl) ethyl/- tetrahydro- pyrimidine hydrochloride (2.3 g.) in 10 ml0 water. The creamy solid which forms is filtered off, washed free of chloride ions and dried in vacuo; m.p. > 350° C.

Analysis Founds C, 54.07; H, 5.32; N, 10.44; S, 16.52# Calcd. for C^H^NgO^ s C, 53.70; H, 5.58; N, 11.07; S, 16.89* >t Example -¾¾H XXXIX Repetition of the procedures of Examples XI, XII and XIV but using the proper acid in place of citric, maleic and p-toluene sulfonic acids permits preparation the following salts of compounds having formula I wherein is vinylene.

R2 Y Salt CH3 H tri Hydrochloride CH3 H tri Pamoate CH3 H tri Acetate CH3 H eth Tartrate CH3 H eth Laura te CH3 H tri Sulfate H H tri Amsonate H H eth Phosphate H H eth 3-Hydroxy-2-Naphthoate CH3 CH3 tri Citrate CH3 CH3 tri Tartrate CH3 CH3 tri Sulphosalicylate CH3 CH3 tri Gluconate Example XLHE-I-l-Methyl-2 2~-(3-methyl-2-thienyl) vinyl/- ^2-tetrahydro-pyrimldine Hydrochloride ' A mixture of 12.6 g. (0.10 mole) of 3-methylthio-phene-2-carboxaldehyde, 11„2 g. (0„10 mole) of 1,2-dlmethyl- 1, ,5,6-tetrahydropyrimidine, 1.5 ml, of piperidine and 25 ml, of benzene is refluxed under an atmosphere of nitrogen in an apparatus equipped with a Dean-Stark apparatus for four hours. The mixture is concentrated in vacuo to remove benzene and piperidine. The residue is taken up in 150 ml. of IN hydrochloric acid and the solution washed with ether. The aqueous acid solution is then extracted with chloroform and the chloroform solution decolorized and dried over anhydrous sodium sulfate. Evaporation of the chloroform yields the product as a yellow solid which is recrystallized twice from chloroform/benzene j m.p. 239-241° C.

Analysis Calcd. for C12H17 2SCls C, 56. 12 ; H, 6.67 ; N, 10.91$ Pounds C, 55.58 ; H, 6.80; N, 11 .01$ Repetition of this procedure but using the appropriate reactants produces the following compounds as their hydrochloride salts; Ri Y H H eth H H tri H CH3 eth H CH3 tri CH3 CH3 eth Example XL V- The anthelmintic activity of l-methyl-2/2""- (2-thienyljethyl/- ^-imidazoline and l-methyl-2- 2~- (2-thienyl)-ethyl/- ^ -tetrahydropyrimidine and their amsonate and p-toluene sulphonate salts ( 'p-tosylates 1 ) is assessed using laboratory mice Infested with Nematospiroides dubius and laboratory rats infested with Nippostrongylus muris . Results are summarized in Table VIII.

TABLE VIII Dose $> Removal Compound Helminth Host (Given Orally) of Worms Imidazoline base o dubius Mouse 1 X 50 mg./kg. 78 Imidazoline base ΪΤ7 muris Rat 3 X 100 mg./kg. 88 Imidazoline p- tosylate N, dubius Mouse 1 X 25 mg,/kg. 83 Imidazoline p- tosylate o dubius Mouse 1 X 50 mg./kg. 90 Imidazoline p- tosylate N. muris Rat 1 X 50 mg./kg. 88 Tetrahydrop rimi- dine base o dubius Mouse 3 X 100 mg./kg. 98 Tetrahydropyrimi- dine base N. muris Rat 3 X 100 mg./kg. 100 Tetrahydropyrimi- dine p-tosylate N0 dubius Mouse 1 X 25 mg./kg. 74 Tetrahydropyrimi- dine p-tosylate No dubius Mouse 1 X 50 mg./kg. 86 Tetrahydropyrimi- dine p-tosylate N. muris Rat 1 X 50 mg./kg. 77 Tetrahydropyrimidine amsonate N. dubius Mouse 2 X 300 mg./kg. 96 Tetrahydropyrimidine amsonate No muris Rat 1 X 150 mg./kg. 99 2-/2"- (2-Thienyl) ethyl/- -tetrahydropyrimidine amsonate and suramin salts are active against N. dubius and No muris as the following data shows.

Amsonate N. dubius Mouse 3 x 500 mg./kg. 99 Amsonate N\ muris Rat 3 x 250 mg./kg. 84 Suramin salt ΈΌ dubius Mouse 3 x 250 mg./kg. 99 Suramin salt \ muris Rat 3 x 250 mg./kg. 80 Example XL¥ II Repetition of the procedure of Example XLI-H- but using l-methyl-2-/2- (3-methyl-2-thienyl)vinyl/- ^ -tetrahydropyrimidine hydrochloride as the drug gives the following results demonstrative of the efficacy of this drug as an anthelmintic .

Helminth Dose Removal of Worms N° dubius 1 x 250 mg./kg. 100 dubius 1 x 125 mg./kg. 100 E° dubius 1 x 62.5 mg./kg. 100 N. dubius 1 x 31 = 25 mg./kg. 100 T. dubius 1 x 7.8 mgo/kg, 100 TT. dubius 1 x 3.5 mgo/kg 0 100 F. dubius 1 x 1.25 mg./kg. 93 Example XlflEHI The effect of l-methyl-2-/2~- (2-thlenyl )ethyl7- -tetrahydropyrimidine tartrate against the migratory phases of Ascarls 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 ration of Group 3 at a level of 50 g. of drug per ton of ration beginning two days before infectio . The pigs are artifically infected on the third and fourth day by provid ing 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 character istic lesions and the number of larvae present.

The drug is thus found to be highly effective 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 patachial 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

Claims (3)

1. 25683/2 P.C. i .76i4.-l4.76i4- UKA-I4.76.4B i4-76l4.C-i4.805 Blanket Case II 2-thienyialkyl - imidazoline- and tetruhydropyrimidine I, A process for the preparation of -2-«a4cyl«a. -fefctephene compoundsof the formula wherein and R2 are eac^ hydrogen or methyl, Y is ethylene or trimethylene and X is ethylene, trimethylene or vinylene, which comprises (a) reacting an alkylene diamine tosylate of the formula HpN-Y-NH tosylate with a tt-(2-thienyl)substituted nitrile of the formula or (b) reacting the hydrochloride of an imino ether of the formula or an ester of the formula 25683/2 * with an alkylene diamine of the formula H2N-Y-NH wherein R^ is lower alkyl or (c) reacting a mixture containing a w-(2-thienyl )nitrile and an alkylene diamine with hydrogen sulphide or phosphorus pentasulphide.

2. A process according to claim 1, wherein the vinylene compound is obtained by reacting an imino ether of the formula with a diamine of the formula H2 -Y-NHR1

3. A process according to claim 1, wherein the nitrile compound and alkylene diamine are present in a ratio of about 1:1. I4.. A process according to claim 1 or 3» wherein 1-methyl-2- 2- (2-thienyl)ethyl/-