SE452887B - PHOSPHONIUM METHYLIMIDAZOLE SUBSTANCE USED AS INTERMEDIATE IN THE PREPARATION OF CERTAIN PHARMACOLOGICALLY ACTIVE GUANIDINE AND TIOCHARBAMIDE COMPOUNDS - Google Patents

Description

10 15 20 25 452 887 2 phosphonium halide. The formamidine sulfinic acid process uses a base, preferably preferably a non-nucleophilic base, such as a tertiary amine. in To prepare the trisubstituted β-acylvinylphosphonium halides, which are not previously known, a halovinyl alkyl ketone is treated, such as chlorovinyl methyl ketone, with a trialkyl or triphenylphosphine. When RI is hydrogen, the trisubstituted β-formylvinylphosphonium halides are prepared by oxidizing of a B-haloallyl alcohol, such as B-chloroallyl alcohol, and treatment thereof so formed the product with a trialkyl or triphenylphosphine.

In order to produce the above-mentioned pharmacologically valuable guanidine and the thiourea compounds, a compound of formula II is first prepared below by displacing the trisubstituted phosphonium group from a solvent (trisubstituted phosphonium) methylimidazole compound of the formula I as follows reaction scheme: G) l S 1 2 n CHZP (R) 3 R cnzn N N RZH _ + 13015) Y \ § -------> \ \ ° 3 H H RB R3 I II where R 1, R 3 and R 5 have the above definition, R 2 is methoxy, ethoxy, n- NCN propoxy, n-butoxy, i-butoxy, t-butoxy, -SCHZCHZNHT -SCHZCHZNHCá \ NHcH3 6 7 6 7 or -NR R, where R and R are each hydrogen or lower alkyl or together with the nitrogen atom to which they are attached form a piperidine, pyrrolidine or morpholine ring, wherein R 2 is preferably -SCH 2 CH 2 NH 2 or cyNcN ' \ NHCH 3 As used herein, the term "lower alkyl" refers to groups having from one -SCHZCHZNH to four carbon atoms.

According to the above procedure, the displacement of a trisubstituted phosphonium group (-P (R5) 3) in a compound of formula I is carried out by reacting a compound of formula I with R 2 H under basic conditions, i.e. with RZH in the form of its anion 1229. The anion can be formed in situ by reaction between a compound of the formula RZH and a strong base. Bases that can 10 15 20 25 30 35 452 887 3 used in the process are those which can remove the proton from a compound with the formula Rzl-1 to form the anion Rzg, where Rz is as defined above, and which has a pKa greater than 12, e.g. alkali metal alkoxides such as sodium methoxide or ethoxide or metal hydrides, such as sodium hydride, which are preferred. When Rzl-1 itself is sufficiently basic, no additional base needs to be used, e.g. when RZH is piperiain. 1 de fen, where Rzn is extreme: volatile, eåeem when 112 is -NR6R7 and one or both of R 6 and R 7 are hydrogen, it is preferred that R 2 H be in the form of a metallate, e.g. sodium or lithium metallate, such as sodium amide. Suitable is a small excess of R2H present.

The reaction is carried out in an organic solvent, methanol, ethanol, propanol, butanol, acetone, acetonitrile, dimethylformamide and dimethylsulfoxide are preferred. Suitably the reaction is carried out at a temperature ranging from about ambient temperature up to the reflux temperature of the solvent used mr, namely from ee 2s ° c now ce 2oo ° c, where about ss ° c: in a 1oo ° c is suitable, for from about 20 min. to about Z1: h, preferably from about 20 minutes. to about 3 hours.

Preferably, the reaction mixture is worked up by diluting with water and removal of the trialkyl or triphenylphosphine by-product by filtration. Extra- tion of the filtrate, when required, followed by evaporation gives the compounds with formula II. It is often desirable to convert the compounds of formula II to corresponding salts, preferably the hydrochloride salts. Such salts are prepared by treating a solution of the imidazole of formula II with an acid or acid solution, e.g. with an ethereal solution or ethanolic solution of hydrochloric acid, and crystallizes the salt formed from any suitable solvent.

The above procedure is an inexpensive, efficient, high yield process. and the trisubstituted phosphines, P (R5) 3, which are formed during the course of the reaction, can easily removed from the reaction mixture and recycled or reused way.

The imidazole compounds of formula II obtained in the process are useful as intermediates for the preparation of N-cyano-N'-methyl-N "- [2- (S-R1-imidazolylmethylthioctyl] guanidine and N-methyl-N '- [2- (5-R1-imidazolyl- methylthio) ethylthiourea compounds with histamine H 2 antagonist activity. His- thamine HZ antagonists act at the histamine 1-1 receptors, as described by Black et al. [23 238585 (1972)) can be defined as such histamine receptors. that are not blocked by "antihistamines", such as mepyramine, but are blocked of burimamide. Blockade of histamine Hz receptors is useful in inhibition of the biological effects of histamine that are not inhibited by "antihistamines".

Histamine-Antagonists are e.g. useful as inhibitors of gastric acid secretion tion.

Conversion of the compounds of formula II to the pharmacologically active ones 10 15 20 25 30 35 452 887 14 The guanidine and thiourea products can be made in a variety of different ways. When 122 is -SCH 2 CH 2 NH 2 and R B is hydrogen, lower alkyl, trifluoromethyl, benzyl or amino, The 11- (2-aminoethylhiomethylimidazole compound of formula II is treated with methyl isothiocyanate to give the corresponding N-methyl-N '- (Z- (S-R1-imidazolylmethylthiob Ethyutiocarbamides. Reaction between the same lf- (2-aminoethylthiomethylimidazole) and N-cyano-N ', S-dimethylisothiourea give the corresponding N-cyano-N'- methyl-N "- [2- (5-R 1 -imidazolylmethylthioctyl) guanidines. The guanidine products is also prepared by reaction between li- (Z-aminoethylhiomethylimidazole and dimethyl N-cyanoimidodithiocarbonate and subsequent reaction between the resulting N-cyano-N'- [2- (5-R1-imidazolylmethylthioctyl] -S-methylisothiourea and meryiamin. When 122 is -SCHZCHZNHCfNCN, guanidine products are NHCH directly by the procedure described above.

When RZ is -SCHZCHZNHZ and Ra is -SR #, where Ru has the above definition, the compounds of formula II are treated with a reducing agent means, e.g. with Raney nickel, to form the corresponding læ- (1-aminoethystio- methylimidazoles, where RB 3 is hydrogen, which is then converted to guanidine and thiourea products as described above. When R 2 is -SCH 2 CH 2 NHCáNcN \ NHcH3 and RB is -SRLC provides treatment with a reducing agent directly guanidine- the product.

When R 2 is methoxy, ethoxy, n-propoxy, n-butoxy, i-butoxy, t-butoxy or -NR6R7 and RB are -SR1 fl where RI * has the above definition, is removed The SRI group of the compounds of formula II as described above, and thus The products formed are then treated with the cysteamine to give 4- (2-aminoethyl) - the thiomethylimidazole compounds, where Ra is hydrogen, which are converted to guanidine and thiourea products as previously described.

When R 2 is methoxy, ethoxy, n-propoxy, n-butoxy, i-butoxy, t-butoxy or -NR6R7 and Ra are hydrogen, the compounds of formula II are treated with cysteamine to obtain the 4- (2-aminoethyl) thiomethylimidazoles, which are then converted to the guanidine and thiourea products, as previously described.

These thiourea and cyanoguanidine products prepared from The compounds of formula II are described in U.S. Patents 3,950,333 and 3,950,353.

The following examples illustrate the invention but are not intended to limit its scope. Temperatures are in degrees Celsius, if nothing else stated.

EXAMPLE 1 Sodium metal (25.3 g, 1.1 mol) was dissolved in ethanol (21). 2-Mety1pseudo- thiourea sulfate (278.3 g, 1.0 mol) was added and the mixture was stirred under lO 15 20 25 30 35 452 887 5 1/2 hour. Then 411 g (1.0 mol) of triphenyl-β-acetylvinylphosphonium bromide were added, and the mixture was heated at reflux for 18 hours, cooled and filtered.

The filter cake was washed with 200 ml of ethanol. The filtrate and ethanol wash solution were beaten together and evaporated under reduced pressure, leaving a brown residue.

Chloroform (500 ml) was added to the residue, and the mixture was stirred underneath a few minutes, after which it was filtered. The filter cake was washed three times 150 ml portions of chloroform and dried to give 364 g (75,96) of [Q-methylthio- meryizmiaazaiyil-u-meryiJtrifenyifosfaniumbfomia, smäifpunkf 223-229.

Cysteamine (12.23 g, 0.13 mol) was dissolved in 100 ml of methanol, and 46.5 ml of 96 (w / v) sodium methoxide solution was added. After stirring at ambient temperature below 10 min. the solid phosphonium salt and the mixture were added refluxed for 20 minutes. The solution was diluted with twice the volume of ice water and stirred. The precipitated triphenylphosene was removed by filtration.

The filtrate was extracted with three 100 ml portions of chloroorm and chloroform extract. The mixture was dried and evaporated to dryness to give 19 g (86 96) of 11- (2-aminoethyl) - thiomethyl-S-methyl-Z-methylthioimidazole as a viscous oil.

Treatment of II- (Z-aminoethylhiomethyl-S-methyl-Z-methylthioimidazole with ethanolic hydrochloric acid gave the corresponding dihydrochloride salt, m.p. (ethanol-ethyl acetate).

EXAMPLE 2 A solution of 48.3 g (0.1 mol) (β-methyl-Z-methylthioimidazolylH1-methyl] - triphenylphosphonium bromide in 250 ml of methanol was added rapidly at ambient temperature. to a stirred solution of 35 ml of 2596 sodium methoxide in methanol in 250 ml methanol. The mixture was refluxed for 20 minutes. and then concentrated to half the volume. After dilution with 900 ml of water, the triphenyl the phosphine by filtration. The aqueous solution was extracted twice with 150 ml of portions of benzene and then three times with 250 ml portions of chloroform. Chloro- the mold extracts were dried (Mg 50g) and evaporated to dryness to give 13g (76 96) 11-Methoxymethyl-S-methyl-2-methylthioimidazole. The melting point of picrate The density of the 11-methoxymethyl-S-methyl-Z-methylthioimidazole was 10-11-11 °.

EXAMPLE 3 Sodium metal (2.3 g, 0.1 mol) was dissolved in ethanol, and 9.5 g (0.1 mol) acetamidine hydrochloride was added with stirring. After 10 min. 41.1 g was added (0.1 mol) of triethylene-S-acetylvinylphosphonium bromide, and the mixture is refluxed. The mixture was boiled for 17 hours. The mixture was filtered, and the filtrate was evaporated to dryness. to give a brown solid which was digested with 300 ml of chloroform.

Ethyl acetate (100 ml) was added, and the precipitate was collected by filtration and was washed with 100 ml of acetone to give 36 g (80,96) ((2,5-dimethylimidazolyD-11 methyl) triphenyltosfonium bromide, m.p. 239-21100. 10 15 20 25 30 35 452 887 6 When an equivalent amount (QJ-dimeryunvidazdlyn-ß-rnaryiJ-triphenyl) phosphonium bromide is used in the procedures of Examples 1 and 2 instead of ((2- methylthio-S-methylimidazolylH1-methyl] triphenylphosphonium bromide, prepared 4- (2- aminoethylhiomethyl-ZJ-dimethylimidazole resp. Zβ-dimethyl-11-methoxymethylimidase zol.

EXAMPLE 4 (a) Trichloroacetamidine (1.62 g, 0.1 mol) was dissolved in 20 ml of dry dimethyl sulfoxide, and 4.1 g (0.1 mol) of triphenyl-β-acetylvinylosophonium bromide in 40 ml of dimethyl sulfoxide was added in one portion while stirring. The exothermic reaction mixture gradually lightened in color and heated at 100 ° for 10 minutes. Evaporation of the solvent gave ((5-methylimidazolyD-11-methylhriphenylphosphonium bromide).

Alternatively, and preferably, the fosionium bromide is prepared using reversal of trichloroacetamidine using the following procedures: Triphenyl-β-acetylvinylphosphonium bromide (8.0 g, 0.019 mol) was dissolved in a minimal amount of dry acetonitrile (about 100 ml), and trichloroacetamidine (4.0 g, 0.25 mol) was added in one portion. The resulting mixture was stirred at room temperature, and the material which crystallized was filtered off to give f (Z-Trichloromethyl-α-methylimidazolyD-11-methyl) -triphenylphosphonium bromide, point rss-isf.

This phosphonium salt (105.0 g, 0.027 mol) was added to 150 ml of methanol, and the resulting mixture was refluxed for 3 hours. The mixture was concentrated to about 15 ml, and the solid was filtered off to give [(2- methoxycarbonyl-β-methylimidazolyl-11-methyl] -triphenylphosphonium bromide, point 168-1700.

The phosphonium salt prepared above was heated to its melting point (about 17 ° C) and chickens at this temperature, when the gas shaking was completed.

After cooling, the solid product was triturated with chloroform to give [(5- methylimidazolyD-1-methylpheniphenylphosphonium bromide, m.p. 238-239 ° - Triphenyl-β-acetylvinylphosphonium chloride (36 g, 0.01) molten molten mol) and trichloro- acetamidine (16.1 g, 0.1 mol) was stirred in 200 ml of methanol for 1 h. Solution was heated to reflux, cooled and the methanol evaporated, leaving [(2-Methoxycarbonyl-5-methylimidazolyl-1β-methyl] -triphenylphosphonium chloride. heating this phosphonium chloride salt at 170 ° until gas evolution is complete, and then cooling and trituration with chloroform gave [β-methylimidazoliz-li- methyl J-rrifenyifasphdnium kidride, srnäirpunkr 22s-227 °. (b) Formamidine sulfinic acid (11.0 g, 0.1 mol) was suspended in 250 ml dry dimethyl sulfoxide, and 2.11 g (0.1 mol) of sodium hydride were added. Then the hydrogen cessation, 36.5 g (0.1 mol) of triphenyl-β-acetylvinylphosphonium chloride, and the mixture was stirred for 1 h at ambient temperature as well 10 l5 20 25 30 35 452 887 7 was heated at 100 ° for 10 minutes. After cooling, the dimethyl sulfoxide was evaporated. and the residue was dissolved in 300 ml of chloroform-methanol 1: 1, after which the solution was filtered. The filtrate was evaporated to dryness, and the residue was recrystallized from chloroform-acetone to give 20 g (50,96) [β-methylimidazolyl-1-methyl] tri- phenylphosphonium chloride, m.p. 223-2250.

Alternatively, and preferably fi ((5-methylimidazolyD-1-methyl) - triphenylphosphonium chloride and bromide using formamidine sulfin acid by the following procedure: Triphenyl-β-acetylvinylphosphonium chloride (3.65 g, 0.01 mol) and formamidine sulfinic acid (1.1 g, 0.01 mol) was dissolved in 50 ml of dimethyl sulfoxide. 1,8-bis (dimethylamino) - naphthalene ("proton fungus") (2.4 g, 0.01 mol) was added and the mixture was heated to 800. After cooling, evaporation of the dimethyl sulphoxide, precipitation of the inorganics the salts with chloroform, filtration, evaporation to dryness and recrystallization of the residue from chloroform-acetone, a mainly quantitative one was obtained yield of f (5-methylimidazolyD-1-methyl] triphenylphosphonium chloride.

Triphenyl-β-acetylvinylphosphonium bromide (20.6 g, 0.05 mol) and formamide dinsulfinic acid (6.0 g, slight excess over 0.05 mol) was dissolved in 100 ml of dimethyl sulfoxide. 1J-Diazabicyclo [5.4.0) undec-5-ene (DBU) (7.6 g, 0.05 mol) was added dropwise while stirring. The mixture was kept at 80 ° for 20 minutes, and the dimethyl sulfoxide evaporated. The residue was taken up in chloroform, and inorganic salts were removed by filtration. The filtrate was evaporated to dryness, and the residue was recrystallized. was prepared from chloroform-acetone to give f (S-methylimidazolyll-11-methyl] triphenyl- phosphonium bromide in 80 96 yield. now a solution of 39.3 g (0.1 mol) of [(s-fneryimidazolyl] -phymyl) - triphenylphosphonium chloride in 200 ml of methanol was added 22 ml of 96% sodium methoxide methanol, and the reaction mixture was refluxed for 1 h. After cooling the solution was diluted with three times its volume of water and filtered for removal of triphenylphosphine. The filtrate was extracted with four 125 ml portions of chloroform. and the extracts were dried (MgSO 4) and evaporated to dryness to give 10.1 g (80 96) 11-methoxymethyl-S-methylimidazole, m.p. 69-70 °, which was converted to corresponding hydrochloride salt as described in Example 1, m.p. 150 °.

EXAMPLE 5 Triphenyl-β-acetylvinylphosphonium bromide (11.1 g, 0.01 mol) was added to a portion to a stirred suspension of 1.1 g (0.01 mol) of formamidine sulfinic acid in 20 ml dimethyl sulfoxide containing 0.25 g of sodium hydride. The mixture was stirred at ambient temperature for 1 hour, and then at 80 ° for a further 1 hour solution of 0.99 g (0.01 mol) of the sodium salt of cysteamine, prepared by addition of two equivalents of sodium methoxide to cysteamine dihydrochloride, in 10 ml methanol was added, and the resulting mixture was heated at 70-800 10 l5 20 25 30 35 452 887 8 for 4 hours. The mixture was diluted twice with its H 2 O volume, and the triphenylphosph the fin was removed by filtration. The filtrate was extracted with 100 ml of toluene and with two 100 ml portions of chloroform. The chloroform extracts were combined, dried (MgSO 4) and evaporated to dryness to give Ål- (Z-aminoethylhiomethyl-5- methylimidazole, the dihydrochloride salt of which has a melting point of 198-192 °.

Alternatively, and preferably, the reaction described above is carried out between triphenyl-β-acetylvinylphosphonium bromide and formamidinesulfinic acid with use of 1,5-bis- (dimethylamino) naphthalene or 1,5-diazabicyclo [5.4.0) -undec- S through the procedures described in Example Mb).

EXAMPLE 6 When an equivalent amount of triphenyl-β-ethylcarbonylvinylphosphonium bromide or triphenyl-β-isopropylcarbonylvinylphosphonium bromide may react with amidine sulfinic acid as described in the procedure of Example 11, is prepared ((5- ethylimidazolylH fl-methyl fi rifenylphosphonium bromide resp. [Ü-isopropylmidazolyl] 11-methyl] triphenylphosphonium bromide.

Reaction of f (5-ethylimidazolyl) -4-methyltriphenylphosphonium bromide or ((S-isopropylimidazolyD-11-methyl] triphenylphosphonium bromide and cysteamine presence of sodium methoxide or sodium hydride as described above gives 4- (2- aminoethylthiomethyl-5-ethylimidazole resp. 4- (2-Aminoethyl) thiomethyl-S-isopropylimino dazol.

Similarly, the triphenylphosphonium group of (5-ethylimine) is displaced dazolyl-11-methylhriphenylphosphonium bromide and f (5-isopropylimidazolylD-11- methyl hryphenylphosphonium bromide by reaction with other nucleophiles through here described procedures.

EXAMPLE 7 When (U-methylimidazolyl-11-methyl] triphenylphosphonium bromide is allowed to react with sodium ethoxide in ethanol, sodium n-propoxide in n-propanol or sodium t butoxide in t-butanol according to the procedure described in Example 11 (b), the following imidazole compounds: 11-ethoxymethyl-1-methylimidazole S-methyl-10-n-propoxymethylimidazole ε-t-butoxymethyl-5-methylimidazole.

EXAMPLE 8 Insertion of a salt of one of the Z-substituted ones listed below the pseudothioureas: Z-ethyl pseudothiourea Z-butyl pseudothiourea Z-benzyl pseudothiourea Z-phenyl pseudothiourea lU l5 20 25 30 35 452 887 9 2- (4-Chlorobenzyl pseudothiourea) in the procedure of Example 1 instead of 2-methylpseudiothiourea the following triphenylphosphonium bromide compounds: f (Z-benzylthio-S-methylimidazolyD-11-methyl] triphenylphosphonium bromide, m.p. 19349190 [(S-methyl-Z-phenylthloimidazolyl-11-methylhriphenylphosphonium bromide f (Z- (Q-chlorobenzylthio-S-methylimidazolyl] -1H-methyl] triphenylphosphonium bromide, m.p. 197-19 ° C.

Reaction between a triphenylphosphonium bromide listed above and cystic acid amine as described in Example 1 gives the imidazole listed below. the compounds: 4- (2-Aminoethylhiomethyl-Z-benzylthio-S-methylimidazole 4- (2-Aminoethyl) thiomethyl-S-methyl-Z-phenylthioimidazole 4- (2-Aminoethylhiomethyl-2- (4-chlorobenzylthio-fi-methylimidazole).

EXAMPLE 9 Insertion of a salt of one of the substituents listed below amidines: guanidine propionamidine valeramidine 2,2,2-trifluoroacetamidine Z-phenylacetamidine in the procedure of Example 3 instead of acetamidine hydrochloride gives the following triphenylphosphonium bromides: [(Z-amino-S-methylimidazolyl-β-methyl] -phenylphosphonium bromide f (2-ethyl-5-methylimidazolyD-11-methyl] triphenylphosphonium bromide f (Z-butyl-fi-methylmidazolyl-11-methyl-riphenylphosphonium bromide [Δ-methyl-Z-trifluoromethylimidazolyl-1β-methylhriphenylphosphonium bromide f (Z-Benzyl-S-methylimidazolyD-11-methyl] triphenylphosphonium bromide.

Reaction between a triphenylphosphonium bromide listed above and cysteamine as described for the procedure of Example 1 gives the following imidazole compounds: Z-amino-11- (Z-aminoethylthiomethyl-5-methylimidazole 4- (2-Aminoethylthiomethyl-Z-ethyl-5-methylimidazole 4- (2-Aminoethyl) thiomethyl-Z-butyl] -methylimidazole 4- (2-aminoethyl) thiomethyl-β-methyl-Z-trifluoromethylimidazole II- (Laminoethylthiomethyl-Z-benzyl-fi-methylimidazole.

EXAMPLE 10 To a solution of 9.25 g (0.1 mol) of B-chloroallyl alcohol in 100 ml of benzene is added 10 15 20 25 30 35 452 887 10 an equivalent amount of an aqueous solution of chromic acid-sulfuric acid (Jones' reagent) and the mixture is stirred at ambient temperature for 1 h. After filtration the layers are separated, and the organic phase is washed with water. Triphenylphosphone (26.2 g, 0.1 mol) is added to the benzene solution, and it is heated to reflux. The precipitates formed on cooling are collected by filtration and dried, yielding B-formylvinylphosphonium chloride.

When an equivalent amount of B-formylvinylphosphonium chloride is allowed to react with formamidine sulfinic acid as described for the procedure of Example 14 is prepared (imidazolyl-β-methyl) triphenylphosphonium chloride.

Reaction between (imidazolyl-1β-methylhriphenylphosphonium chloride and cysteine amine in the presence of sodium methoxide or sodium hydride as described above gives 4- (2-aminoethyl) thiomethylimidazole, the dihydrobromide salt of which has a melting point of 178- 179 ° (Example 1 1 de: British patent 1 sas 169).

Similarly, the triphenylphosphonium group of (imidazolyl-li- methylhryphenylphosphonium chloride by reaction with other nucleophiles through here described procedures.

EXAMPLE ll Tri-n-butylphosphine (20.2 g, 0.1 mol) is added to a solution of 10.4 g (0.1 mol) chlorovinyl methyl ketone in 250 ml of benzene, and the mixture is refluxed for 1 h.

The mixture is cooled, and the precipitated material is collected by filtration and dried to give tri-n-butyl-β-acetylvinylphosphonium chloride.

Triethyl-β-acetylvinylphosphonium chloride is prepared as described above. by using triethylphosphine instead of tri-n-butylphosphine.

Reaction between an equivalent amount of tri-n-butyl-β-acetylvinylphosphonium chloride or triethyl-β-acetylvinylphosphonium chloride and formamidine sulfinic acid such as described for the procedure of Example 4 gives ((5-methylimidazolyD-11-methyl] tri-n- butylphosphonium chloride resp. (β-methylimidazolysis-11-methyl hriethylphosphonium chloride.

Reaction between f (5-methylimidazolyl-1β-methyl hri-n-butylphosphonium chloride) or f (5-methylimidazolyD-11-methylhrietylphosphonium chloride and cysteamine in the presence of sodium methoxide or sodium hydride as described above gives 4- (2- aminoethylhiomethyl-i-methylimidazole, whose dihydrochloride salt has the melting point 1s9-192 °.

EXAMPLE 12 Sodium amide (0.39 g, 0.01 mol) was dissolved in 40 ml of liquid ammonia, and 4.11 g (0.01 mol) of f (5-methylimidazolyD-11-methyl] triphenylphosphonium bromide sat. The suspension was stirred at -UOOC for 1 hour and then allowed to warm room temperature while the ammonia evaporated. The triphenylphosphine was extracted from the residue with benzene, and the remaining solid was taken up in 10 15 20 25 30 35 452 887 ll water and extracted with chloroform. The chloroform extracts were dried and evaporated to give, in 9696 yield, 11-aminomethyl-S-methylimidazole, whose dihydrochloride salt has a melting point of 200-2020 (Sun). This amine reflux was boiled with one molar equivalent of cysteamine in acetic acid and treated with hydrochloric acid to give 4- (2-aminoethyl) thiomethyl-S-methylimidazole dihydrochloride, smänpunm las-isf. ' EXAMPLE 13 Dimethylamine (0.5 g, 0.01 mol) was dissolved in 35 ml of tetrahydrofuran, stirred and cooled in an ice bath while adding 5 ml (0.01 mol) of ZM butyllithium in hexane dropwise with stirring. After stirring the mixture for 15 minutes. in the cold 3.933 (0.01 mol) of [(5-methylimidazolyl) -4-methyltriphenylphosphonium chloride] was added. rid, and the solution was allowed to warm to room temperature. After stirring for 2 hours at room temperature, the solvents were evaporated, and the residue was treated with 50 ml of water. Filtration gave diphenylphosphine. The aqueous filtrate is extracted with chloroform, dried and evaporated to give 4- (N, N-dimethylamino- methyl) -5-methylimidazole, m.p. 92-94 °. This amine was then refluxed with one molar equivalent of cysteamine in acetic acid and treated with hydrochloric acid, which gave 4- (2-aminoethylthiomethyl-5-methylimidazole dihydrochloride.

By the same procedure but using methylamine instead dimethylamine is prepared 11- (N-methylaminomethyl) -5-methylimidazole. In the same way prepared using butylamine and dibutylamine II- (N-butylaminomethyl) 5-methylimidazole and li- (N, N-dibutylaminomethyl-S-methylimidazole. these intermediates with cysteamine by the above procedure and treatment with hydrochloric acid gives 4- (2-aminoethyl) thiomethyl-5-methylimidazole di hydmkiofid, melting point 139-192? EXAMPLE 14 N-cyano-N'-methyl-N "-mercaptoethylguanidine (1.58 g, 0.01 mol) was dissolved in 15 ml of methanol, and 2.3 ml of sodium methoxide in methanol were added. After stirring at room temperature for five minutes a suspension of 3.93 g of [(5- methylimidazolyl-11-methyltriphenylphosphonium chloride in 10 ml of methanol. Solution heated to reflux. An equal volume of water was added and most of it the methanol was removed by evaporation. Filtration and water washing provided triphenylphosphine. The filtrate was treated with charcoal, filtered and concentrated.

Filtration gave N-cyano-N'-methyl-N "- (2- (5-methyl-ε-imidazolylmethylthio) ethyl] nidin.

EXAMPLE 15 A mixture of 6.6 g (0.03 mol) of 4- (2-aminoethyl) thiomethyl-S-methyl-Z- methylthioimidazole and 6.6 g of nickel-aluminum alloy 50:50 in 50 ml of formic acid 10 15 20 25 30 35 452 887 12 refluxed for 3 hours. The metals were removed by filtration, and the filtrate was evaporated to dryness. The residue was dissolved in ethanol, and the ethanol solution saturated with hydrogen sulfide, after which it was filtered. The filtrate was saturated hydrogen chloride. Addition of ethyl acetate caused precipitation of li- (2-aminoethyl) thiomethyl- 5-methylimidazole as the dihydrochloride salt, 189-1920. (British patent 1,338 l69, Example 2.) melting point Similarly, the Z-substituted thio group was removed from the others imidazole compounds, where RB is a substituted thio group, prepared as above.

Potassium carbonate (7.75 g) was added to a solution of 14.6 g of 4- (2-aminoethyl) - thiomethyl-S-methylimidazole dihydrochloride in 120 ml of water. The solution was maintained ambient temperature for 15 minutes, and 1.5 g of methyl isothiocyanate were added.

After heating under reflux for 1 / 2h, the solution was slowly cooled to So.

The product was collected and recrystallized from water to give N-methyl-N'- fZ- (imethyl-1H-imidazolylmethylthio) ethylthiourea, m.p. 150-1520.

EXAMPLE 16 11-Methoxymethyl-5-methyl-Z-methylthioimidazole (13.1 + 6 g, 0.078 mol) and approx. 25 g of Raney nickel was added to 400 ml of ethanol, and the mixture was refluxed for 3 hours. The mixture was filtered, and the filter cake was washed with 25 ml of ethanol.

The filtrate and washings were combined, and hydrogen sulfide gas was introduced into the solution under 10 min. The mixture was filtered, and the filtrate was evaporated to dryness. to give 8.63 g (88,961) of 1-methoxymethyl-5-methylimidazole. 11-Methoxymethyl-5-methylimidazole was converted to the corresponding chloride salt as described above. 1 H-Methoxymethyl-5-methylimidazole hydrochloride (4.9 g, 0.03 mol) and 3.1 μg (0.03 mol) of cysteamine hydrochloride was dissolved in a minimal amount of acetic acid, and the mixture was refluxed for 18 hours. After cooling in an ice bath, it was filtered the mixture to give 5.8 g (80,96) of εβ- (Z-aminoethyl) thiomethyl-fi-methylimidamide zoiaihydrokioridsaif, melting point 1x9-192 °.

(British Patent 1,338,169, Example 2.) Similarly, the other imidazoles prepared above, in which RZ is an alkoxy group and R 3 is a substituted thio group, reacting with Raney nickel followed by treatment of the product thus formed with cysteamine in acetic acid, which gives the corresponding 11- (Z-aminoethylkiomethylimidazoles). (a) A solution of 17.0 g of le- (Z-aminoethylhiomethyl-S-methylimidazole and 1.2 g of N-cyano-N ', S-dimethylisothiourea in 500 ml of acetonitrile were refluxed for 24 h. The mixture was concentrated, and the residue was chromatographed on a silica gel column with acetonitrile as eluent. The product obtained recrystallized from acetonitrile-ether to give N-cyano-N'-methyl-N "- [2- (5- 10 452 887 13 methyl-11-imidazolylmethylthioctyl] guanidine, m.p. 141-1420. (b) A solution of 23.4 g of 41- (2-aminoethylthiomethyl-j-methylimidazole in ethanol was slowly added to a solution of 20.0 g of dimethyl-N-cyanoimidodithiocarbonate in ethanol with stirring at ambient temperature. Filtration gave N-cyano-N- [2- (S-methyl-11-imidazolylmethylthioctyl) -S-methylisothiourea, m.p. 1500. The filtrate was concentrated under reduced pressure, and the mixture was triturated cold water to give a solid which was collected by filtration and was recrystallized twice from isopropanol-ether, m.p. 1148-1500.

A solution of 75 ml of methylamine in ethanol was added to a solution of 1.0 g of N-cyano-N'-[2- (5-methyl-11-imidazolylmethylthio) ethyl] -S-methylisothiocar- bamide in 30 ml of ethanol. The reaction mixture was allowed to stand at ambient temperature for 2 l / 2 h. After concentration under reduced pressure was recrystallized the residue twice from isopropanol-petroleum ether to give N-cyano-N'- methyl-N "- (2- (5-methyl-11-imidazolylmethylthio) ethyl] guanidine, m.p. 141-143 °.

Claims (5)

10 15 452 887 lll- PATEN TK RAV Intermediate for use in the preparation of pharmacologically active N-cyano-N'-methyl-N "- (2- (5-R 1 -imidazolylmethylthioethyl) guanidine and N-methyl-N '- hiocarbamide compounds, wherein R 1 is hydrogen or lower alkyl, characterized by the formula 1s R CH 2 H 2 R 3 wherein R 1 has the above definition, R B is hydrogen, lower alkyl, trifluoromethyl, benzyl, amino or -S where R 1 * is phenyl, benzyl or chlorobenzyl, R 1 is lower alkyl or ethylene, and X is halogen. Compound according to Claim 1, characterized in that methylene. Compound according to Claim 1 or 2, characterized in that R 3 -phenyl. A compound according to claim 1, characterized in that it is (15-methyliryldazolyl-1-methylhrifhenylphosphonium chloride. A compound according to claim 1, characterized in that it is [η] -methylimidazolyl-1H-methylhrifhenylphosphonium bromide.