FI60393B - FREQUENCY REQUIREMENT FOR THERAPEUTIC ACTIVATION OF ACTIVE HETEROCYCLISM UREA- ELLER TIOUREAFOERENINGAR - Google Patents

Description

.ir> r i ADVERTISEMENT PUBLICATION £ n 1 Ύ Ύ MA ™ (11) UTLÄGGNINGSSKRIFT 60393 C Patent granted II 01 1982

Patent issued V% siv, “0 07 D 233/64, 213/28. 231/12.

(51) Kv.ik.Vci.3 237/08, 239/26, 241/12, 249/08, 261/08, 263/32, 275/02, 277/22, 285/04 SUO MI — EN N LAN D (21) Rttunttlhakaimit - Patwitanaeknlnf 580/72 (22) Hakmnltpllvt - Ar »öltnlnpdt | 0 3.0 3. 72 "'(23) Home - GIKI (h« t * di | 03.03.72 (41) Interpreters JulklMkal - Bllvlt off «Kll | 10.09.72

National Board of Patents and Registration .... .., ,, ,,,. t. . . ^, (44) Nlhtlvlkalpanoo et al. -

PatMnt · oeh ragittantyralaan v 'Ant «kan utltfd och utJ.tkrlftM publkr.rtd 30.09.8l (32) (33) (31) Pyydatty« Tuoikwi * —B * j »rd prtorlttt 09.03.71 22.07. Tl Great Britain-Great Britain (GB)

6352/71, 3I + 334 / 7I

(71) Smith Kline & French .Laboratories Limited, Mundells, Welwyn Garden City, Hertfordshire, England-England (GB) (72) Graham John Durant, Welwyn Garden City, Herts., John Colin Emmett,

Kimpton, Herts., Charon Robin Ganellin, Welwyn Garden City, Herts.,

The present invention relates to a process for the preparation of therapeutically active heterocyclic urea or thiourea compounds.

Agents acting against histamine have been known since 1937, e.g., D. Bovet, A.M. Staub, C.R. Seanc, Soc. Biol., 124 (1937) 547. These histamine antagonists, or antihistamines, inhibit several of the effects of histamine, such as, for example, bronchoconstriction, the effect of increasing vascular permeability, and the effect of 1 isolated guinea pig ileum. Antihistamines are used therapeutically mainly to block the action of histamine released into the body due to allergic reactions or, for example, hives or insect injections. However, in some cases it has not been possible to therapeutically exploit this histamine inhibitory effect, such as in motion sickness.

The histamine-inducing and antihistamine-blocking receptors found by Bovet and Staub are located primarily in smooth muscle. These receptors are called β-receptors, Ash, Schild, Brit.J.Pharmac.Chemother, 27 (1966) 427, and also have histamine effects that are not affected by conventional antihistamines, e.g., cardiac stimulating effect, gastric secretion stimulating effect, and rat uterine inhibitory effect of electrically stimulated contraction. Compounds that inhibit such effects of histamine are called histamine H2 receptor antagonists, J.W. Black, W.A.M. Duncan, G.J. Durant, C.R. Ganellin, E.M. Parsons, Nature, 236 (1972) 385-390.

According to FI patent applications 2901/70 and 1187/71, certain heterocyclic isothiourea and guanidine compounds have histamine H2 receptor antagonist activity. These compounds are characterized in that a chain of methylene groups connects the heterocyclic ring to an isothiourea or guanidine group. This invention relates to a process for the preparation of similar urea or thiourea compounds, but which compounds have an oxygen or sulfur atom in the methylene group chain attached to the heterocycle. This structural change results in altered histamine Hg receptor antagonist activity.

The present invention relates to an analogous process for the preparation of a therapeutically active heterocyclic urea or thiourea compound of the formula U C- (CH 2) n Y (CH 2 y HCl 1 / NHR 1 in which A together with the indicated carbon atom forms imidazole, pyridine, thiazole, isothiazole, an oxazole, isoxazole, pyrazole, triazole, thiadiazole, pyrimidine, pyrazine or pyridazine ring, X1 bonded to the carbon atom of residue A represents a hydrogen or halogen atom, an alkyl group having 1 to 4 carbon atoms, a hydroxyl or an amino group, X attached to the secondary nitrogen atom of residue A represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, n is 0, 1 or 2, m is 2 or 3 and n + m is 3 or 4, Y is an oxygen or sulfur atom and E is oxygen or a sulfur atom, and R 1 is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms or a dimethylaminoethyl group, and the process is characterized in that the compound of the formula X 1 - CP (CH 2) n Y (CH 2) m NH 2

X ^ 'J

A ---- / 3 1 2 60393 wherein A, X, X, n, m and Υ are as defined above is reacted with a compound of formula R2NCE where E is as defined above and R2 is a sodium or potassium atom , an acyl group, an alkyl group having 1 to 4 carbon atoms or a dimethylaminoethyl group; and when F 2 is an acyl group, the product is finally deacylated to give a compound wherein R 1 is hydrogen. Suitably A in the amine starting material is such that the nitrogen atom is closest to the carbon atom shown, and most preferably such that together with this carbon atom it forms an imidazole, thiazole or pyridine ring. Most preferably it is hydrogen, methyl, bromine, amino or hydroxyl, and X 2 is hydrogen. The process according to the invention is particularly preferred when the starting materials Y and E are sulfur atoms, n is the number 1, m is the number 2 and is methyl. In particular, the following compounds prepared by the process of the invention have been found to be highly preferred: N-methyl-N '- / 2 - ((4-imidazolyl) methylthio) ethyl-7-thiourea, N-methyl-N' - / 2 - ((5 (methyl-4-imidazolyl) methylthio) ethyl] thiourea, N-methyl-N '- [2 - ((5-bromo-4-imidazolyl) methylthio) ethyl] thiourea, N-methyl-N'- [2 - ((1-methyl-2-imidazolyl) methylthio) ethyl] thiourea, N-methyl-N '- [2 - ((2-imidazolyl) methylthio) ethyl] thiourea, N-methyl-N'- [2 - ((2-thiazolyl) methylthio) ethyl] thiourea, N-methyl-N '- [2 - ((3-hydroxy-2-pyridyl) methylthio) ethyl] thiourea, N-methyl-N' - / 2 - (5-amino-2- (1,3,4-thiadiazolyl) methylthio) ethyl7-thiourea, N-methyl-N '- [2- (3- (1,2,4-triazolyl) methylthio) ethyl] thiourea and N-methyl-N '- [3- (2-thiazolyl) thiopropyl] thiourea.

If desired, the products prepared by the process of this invention can also be isolated as their addition salts.

Amine starting materials in which Y is sulfur and n is a number 1 or 2 can be prepared by a process in which a compound of general formula

^ (CH2} nQ

60393 k wherein Q is hydroxyl, halogen or methoxy is reacted with a suitable aminomercaptan of formula.

When Q is halogen, this reaction can be carried out under strongly basic conditions, e.g. in the presence of sodium methoxide or sodium hydroxide. Since the aminomercaptan is a primary amine, it may be necessary to protect the amino group with, for example, a phthalimide group, which can later be removed by acid hydrolysis or hydrazinolysis. When Q is hydroxyl or halogen, the reaction takes place under acidic conditions, e.g. in the presence of a halogen acid such as 88% hydrogen bromide or glacial acetic acid. When Q is methoxy, the reaction also takes place in the presence of 48% hydrobromic acid.

When Y is sulfur and n is 0, the amine starting materials can be prepared by reacting the corresponding heterocyclic thiol compound under acidic conditions with 3-aminopropanol or 4-aminobutanol or under basic conditions with 3 "halopropylamine or 4-halobutylamine, optionally with an protecting group if necessary. a phthalimido group.

The amine starting material prepared using these methods may, of course, also be in the form of an acid addition salt and the free base may be obtained from the acid addition salt by treatment with a suitable base, e.g. an alkali metal alkoxide such as sodium ethoxide or an inorganic base such as potassium carbonate. Amine starting materials can also be prepared by administering a heterocyclic haloalkyl compound of the formula C- (CHn) O (CHO) X 2 n 2 m

X2 A

wherein X is halogen, is reacted with a sodium derivative of the diol HClCl 2) OH followed by treatment of the resulting ether alcohol with thionyl halide, and the resulting product is reacted with an alkali metal azide and then reduced by hydrogenation over a platinum dioxide catalyst.

Products in which R 1 is hydrogen can be prepared by reacting the amine starting material with an acyl isocyanate or isothiocyanate R 2 NCE, e.g. benzoyl isothiocyanate in a suitable solvent such as chloroform, followed by alkaline hydrolysis with aqueous potassium hydroxide or potassium carbonate.

Products with hydrogen can also be prepared directly from the amine starting material by reacting it with sodium or potassium cyanate or thiocyanate at elevated temperature.

Products in which R 1 is lower alkyl or dialkylamino 1 -yl can be prepared by reacting the amine starting material with isocyanate or isothiocyanate R 1 NCE in a suitable solvent such as chloroform, ethanol, isopropanol, acetonitrile or water.

The compounds prepared by the method of the invention have been found to have pharmacological activity in the body as antibodies against certain effects of histamine which are not inhibited by "antihistamines" such as mepyramine. For example, they have been found to selectively inhibit gastric acid secretion due to histamine stimulation in the stomachs of urethane-anesthetized rats. Similarly, the action of these compounds as antibodies to the effects of histamine can in many cases be demonstrated in other tissues which, according to the aforementioned Ash & Schild paper, are not H-1 receptors. Examples of such tissues are an overgydt, perfused isolated guinea pig heart, an isolated guinea pig heart right atrium, and an isolated rat uterus. The compounds of the invention have also been found to inhibit the secretion of gastric acid caused by pentagastrin or food irritation.

The level of activity achieved with the preparations containing the thiourea derivatives of this invention is described by the dose range for anesthetized rats, which, as mentioned above, 60393, is between 0.5 and 256 micromoles per kilogram. Many of the compounds of this invention provide 50% inhibition in this experiment at a dose of 1-10 micromoles per kilogram. Similar results have been obtained in dogs and humans.

For therapeutic use, the pharmacologically active compounds of this invention are administered to a patient as a pharmaceutical preparation comprising as active ingredient or substantially active ingredient at least one such compound in basic form or in the form of an addition salt with a pharmaceutically acceptable acid and in association with a pharmaceutical carrier.

Other pharmacologically active compounds may in certain cases be included in the preparation. Preferably, the preparation may be presented in unit dosage form suitable for the intended use, e.g. as a tablet, capsule, solution for injection or ointment for topical use.

The invention is further illustrated by the following examples:

Example 1 N-Methyl-N '- [2 - ((4-imidazolyl) methylthio) ethyl] thiourea (1) (a) A solution containing 67 g of 4 (5) -hydroxymethylimidazole hydrochloride and 56.8 g cysteamine hydrochloride in aqueous hydrogen bromide (1 L, 48%) was heated at reflux overnight. After cooling, the solution was evaporated to dryness, the residual solid was washed with ethanol / ether to give 156 g of 4 (5) - ((2-aminoethyl) thiomethyl] imidazole dihydrobromide, m.p. 178-179 ° C.

(b) 2 g of phthalimidoethanethiol were added portionwise while stirring to a solution of sodium ethoxide (prepared from 0.23 g of sodium) in 20 ml of ethanol at 0 ° and under a nitrogen atmosphere.

After further stirring for 2 1/2 hours at 0 °, the resulting yellow solution was cooled in an ice-salt bath, and a solution of 0.76 g of 4 (5) -chloromethylimidazole hydrochloride in 5 ml of methanol was added dropwise over 10 minutes. After this addition, the mixture was stirred at room temperature overnight, after which the mixture was acidified with ethanolic hydrogen chloride and evaporated to dryness. Addition of water precipitated unreacted phthalimidoethanethiol (0.6 g) which was removed by filtration. The filtrate was concentrated and basified with aqueous sodium hydrogencarbonate to give 0.75 g of 7 60393 ((5) - (T2-phthalimidoethyl) thiomethyl / imidazole, m.p. 136-137 ° C, from the white precipitate formed which was recrystallized from aqueous ethanol. A mixture of 0.62 g of this phthalimido derivative in aqueous hydrogen bromide (40 mL, 1W) was heated with stirring and under reflux overnight. After cooling to 0 °, the resulting clear solution was filtered and the filtrate was evaporated to dryness. Recrystallization of the residue from ethanol afforded 0.52 g of 4 (S) - ((2-aminoethyl) thiomethyl) imidazolidine hydrobromide, m.p. 178-179 ° C.

(c) A suspension of cysteamine hydrochloride (118-8 g) in ethanol (200 ml, dried over molecular sieves) was added portionwise at 0 ° to a solution of sodium ethoxide (prepared from 48 g of sodium) in 1 liter of ethanol under a nitrogen atmosphere. After further stirring for 2 hours at 0 °, a solution of 80 g of 4 (5) -chloromethylimidazole hydrochloride in 400 ml of ethanol was added dropwise over 45 minutes, keeping the temperature at -1 ° + 2 ° C. After the addition, the mixture was stirred at room temperature overnight, the mixture was filtered, and the filtrate was acidified with concentrated hydrochloric acid. The solution was then evaporated to dryness, the residue was dissolved in 1 liter of ethanol, and an excess of picric acid in hot ethanol was added to the solution. The resulting crude picrate was dissolved in water (2.7 liters) and after decanting from insoluble oil, the solution was allowed to cool to give 4 (5) - ((2-aminoethyl) thiomethyl) imidazolidipicrate, m.p. 194-195 ° C. Treatment of this picrate with hydrobromic acid followed by extraction with toluene afforded the dihydrobromide, m.p. 178-179 ° C, after evaporation to dryness and recrystallization of the crude residue from ethanol.

(2) A solution of 10 g of 4 (5) - ((2-aminoethyl) thiomethyl) imidazolidine hydrobromide in 25 ml of water was basified to pH 11 by adding a solution containing 8.7 g of potassium carbonate. in ml of water. The resulting solution was evaporated to dryness, the residue was extracted with isopropyl alcohol, and the last aqueous residue was removed by azeotropic distillation using isopropyl alcohol. The residual amine was extracted separately from the inorganic material with isopropyl alcohol, the extracts were concentrated to a volume of about 70 ml, and a solution of 2.3 g of methyl isothiocyanate in 5 ml of isopropyl alcohol was added. The reaction mixture was then heated at reflux for 1 1/2 hours and after cooling the mixture was evaporated to dryness. The residual oil was dissolved in acetone, the solution was filtered to remove residues of inorganic material, and the filtrate was concentrated to give 4.1 g of N-methyl-N '- (2- (4-imidazolyl-diethylthio) ethyl) thiourea. melting point 96-98 ° C. The melting point of the recrystallized test was 98-99 ° C. (Anu.], Y, ys Ί t u was found to be C 41.8, H 6.4, N 24.4, S 27.6, C8H14-44S2 requires: C 41.7, H 6.1; N 24.3; S 27.8).

Example 2 N-Methyl-N '- [2 - ((5-methyl-4-imidazolyl) methylthio) ethyl] thiourea (1) (a) A solution containing 30.0 g of 4-hydroxymethyl-5-methyl -imidazole hydrochloride and 23.0 g of cysteamine hydrochloride in 200 ml of acetic acid were heated at reflux for 10 hours. After cooling to 15-20 ° C, the crystallized solid was separated and washed with isopropyl alcohol to give 45.5 g of 4-methyl-5 - ((2-aminoethyl) thiomethyl) imidazole dihydrochloride, m.p. 189-192 ° C.

(b) A solution of 30.0 g of 4-hydroxymethyl-5-methylimidazole hydrochloride and 23.0 g of cysteamine hydrochloride in 450 ml of concentrated hydrochloric acid was heated under reflux for 17 hours. Concentration following re-evaporation with water gave a residue which was dissolved in isopropyl alcohol, concentrated to a small volume and cooled to give 40.6 g of 4-methyl-5 - [(2-aminoethyl)]] thiomethyl] imidazolidine hydrochloride, melting. 191 ° C.

(c) A mixture of 15-0 g of 4-hydroxymethyl-5-methylimidazole hydrochloride, 11.5 g of cysteamine hydrochloride and a solution of hydrogen bromide in acetic acid (48¾, 225 ml) was heated under reflux for 7 hours. After cooling, 21.6 g of 4-methyl-5 - [(2-aminoethyl) thiomethyl] imidazole dihydrobromide, m.p. 208-211 ° C, were obtained.

(2) 7.75 g of potassium carbonate was added to a solution of 14.6 g of 4-methyl-5-N- ('2-aminoethyl) thiomethyl] imidazole dihydrochloride in 120 ml of water. The solution was stirred for 15 minutes at room temperature, and 5.15 g of methyl isothiocyanate was added.

After heating at reflux for 30 minutes, the solution was slowly cooled to 5 ° C.

The product (13.1 g) was separated and recrystallized from water to give N-methyl-N '- / - 2 - ((5-methyl-4-imidazolyl) methylthio) ethyl] thiourea, m.p. 150-152 ° C.

9 60393 (Analysis: C 44.5; H 6.7; N 23.0; S 26.2. C 9 H 8 N 2 S requires: C 44.2; H 6.6; N 22.9; S 26, 2).

Examples 3-24

By a two-step method substantially similar to those shown in Examples 1 (1) and (2), thiourea compounds of the following formula were prepared: J1HCH,

Het-CH0SCH0CHoNH-C2 2 2 2 wherein Het is the group indicated in Table 1 below. The melting point and elemental analysis values of the solvent from which the product was crystallized are also given in the table, as is the melting point of the intermediate amine salt of formula

Het CH2SCH2CH2NH2.2HW

wherein W is a picrate anion or a bromide anion as indicated in the table.

Starting materials of formula

Het CH2Q

wherein Q is hydroxyl, halogen or methoxy are all known compounds except those used in Examples 3, 4 and 13, the preparation of which is described after Table 1. In each case, the starting material was reacted with cysteamine hydrochloride in hydrobromic acid as shown in Example 1 (1) (a). When necessary, the resulting amine was purified by conversion to picrate, followed by treatment with hydrochloric acid or hydrobromic acid and removal of picric acid to give the corresponding hydrochloride or hydrobromide (as shown in Example 1 (1) (c)).

Conversion of this hydrochloride or hydrobromide to the free base by the addition of potassium carbonate followed by concentration and extraction with isopropanol or ether / ethanol (3: 1) gave an extract which was reacted with methyl isothiocyanate in a suitable solvent under the same conditions as in Example 1. . The resulting thiourea products that were crystallizable were recrystallized from the solvent listed in Table 1.

Examples 3, 4 j q 1 '] äbt öa i ne i de n va Imi r ·. 1. u: (a) 4-Ethyl-5-hydroxymethylimidazole hydrochloride (Example 3) 60393 286 g of sulfuryl chloride were added at 10-15 ° C to a solution of 300 g of ethyl 3-oxopentanoate in 250 ml. of chloroform. After the addition, the mixture was stirred overnight at room temperature, heated at reflux for 1/2 hour and cooled. After washing with water, sodium hydrogencarbonate solution and water, the solution was dried (sodium sulfate), concentrated and fractionally distilled to give ethyl 2-chloro-3-oxopentanoate, b.p. 94-96 ° C at 14 mmHg.

A mixture of 178 g of ethyl 2-chloro-3-oxo-pentanoate, 450 g of freshly distilled formamide and 38 ml of water was heated at 140-148 ° C, after which the mixture was cooled and added to dilute hydrochloric acid. After decantation from the insoluble matter, the solution was basified with ammonium hydroxide to give a solid which, after recrystallization from aqueous ethanol and ethanol-ethyl acetate, gave 29 g of 4-ethyl-5-carbethoxyimidazole, m.p. 170-172 °.

14.0 g of this ester was reduced with 4.6 g of lithium aluminum hydride in tetrahydrofuran, and the product was treated with hydrogen chloride to give 10.6 g of 4-ethyl-5-hydroxymethylimidazole hydrochloride, m.p. 114-143 ° C (from isopropyl alcohol ether).

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60393 (b) 4-Isopropyl-5-hydroxymethyl-imidazole hydrochloride (Example * 1)

A solution of 43.8 g of sodium nitrite in 92 ml of water was added dropwise at 0 ° to a solution of 100.3 g of ethyl isobutyryl acetate in 80 ml of acetic acid while stirring. After stirring at 0 ° for 30 minutes and then at room temperature for 3 hours, 100 ml of water was added and the mixture was extracted with ether. The extracts were washed with water, saturated sodium bicarbonate solution and water. After drying (CaSO 4), the solution was evaporated to give 112 g of ethyl 2-oximino-4-methyl-3-oxopentanoate as a crude oil.

A solution of 219 g of this oximinoketone in 280 ml of ethanol was added to a suspension of pre-reduced palladium on charcoal (10 g, 10%>) in 1 liter of ethanol and 512 ml of saturated ethanolic hydrogen chloride, and the mixture was hydrogenated at room temperature and pressure until the theoretical amount of hydrogen was bound. The mixture was filtered, the filtrate was concentrated, and ethyl acetate was added thereto to give 230.6 g of 2-amino-4-methyl-3-oxopentanoate hydrochloride, melting point 129-131 ° C (dec.). 50.5 g of this aminoketone was dissolved in 180 ml of redistilled formamide, and the solution was heated at 120 ° C for two hours, at 130 ° C for one hour, and finally at 140 ° C for two hours. After cooling, the mixture was filtered, and the crystalline product was washed with water to give 22 g of ethyl 4-isopropyl-5-carbethoxyimidazole, m.p. 177-178 ° C.

108 g of this ester was introduced into a Soxhlet apparatus and reduced using 34.5 g of lithium aluminum hydride in tetrahydrofuran to give 62.3 g of 4-hydroxymethyl-5-isopropylimidazole, m.p. 121-123 ° C.

c) 4-Methyl-3-hydroxymethyl-1,2,4-triazole (Example 13) 57 g of ethoxyacetyl chloride were slowly added at 0.5 ° C to a solution of 53.5 g of 4-methylthiosemicarbazide in 500 ml of dry pyridine. The mixture was allowed to warm to room temperature and stirring was continued for 18 hours. After concentration under reduced pressure, the residue was treated with a solution of 21.4 g of sodium in 500 ml of ethanol, and the mixture was heated under reflux for 24 hours. After concentration and acidification with hydrochloric acid, a solid formed. After partial concentration, the solid was separated and recrystallized from ethyl acetate to give 53 g of 3-ethoxymethyl-4-methyl-1,2-4-triazoline-5-thione, m.p. 137-138 ° C.

44 g of thione were desulfurized by the slow addition of a solution of 75 ml of hydrochloric acid, 150 ml of water and 1.5 g of sodium nitrite at 15-20 ° C. After basification with sodium carbonate and concentration, the residue was extracted with ethanol-ether (1: 1) and distilled to give 30 g of 3-ethoxymethyl-4-methyl-1,2,4-triazole, b.p. 154-156 ° C. 0.05 mmHg. A solution of 15 g of the above compound in 48% aqueous hydrogen chloride (150 ml) was heated under reflux for 24 hours, the solution was concentrated to dryness, and the residue was immediately used to react with cysteamine hydrochloride and hydrobromic acid.

Examples 25-27

The two-step methods described in Examples 3-24 were used in the following formula NHR-1

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HN

Table 2 shows the values of the symbols m and R 1 as well as the recrystallization solvent, melting point and Elemental analysis for each product.

17 60393

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18 60393

Example:? 3 N-methyl-N '- (2- (2- (4-imidazolyl) ethyl) thioethyl) thiourea dihydroiodide (1) A solution containing 13.6 g of 4 (5 ) - (2-chloroethyl) imidazole hydrochloride and 9.3 g of cysteamine hydrochloride in 100 ml of distilled water were added over 30 minutes with stirring to a solution of potassium hydroxide (15.8 g, 85 #) in 40 ml of water at room temperature and in a nitrogen atmosphere. After the addition, the solution was heated at 50 ° C for 4 hours. From time to time it was necessary to add a few drops of potassium hydroxide solution to prevent the pH of the reaction mixture from falling below 11. The reaction mixture was then acidified with 2N hydrochloric acid, evaporated to dryness under reduced pressure and the last aqueous residue removed by azeotropic distillation using n-propanol. The residue was extracted several times with isopropyl alcohol, and the combined extracts were added to a hot solution of picric acid in isopropyl alcohol. After cooling, 42.3 g of 4 (5) - (2- (2-aminoethyl) thioethyl) imidazolide picrate were obtained, m.p. 225-226 ° C.

(2) This dipicrate was converted to the dihydrochloride by adding 200 ml of concentrated hydrochloric acid and then extracting with toluene (5 x 50 ml). The aqueous solution was evaporated to dryness, the residue was dissolved in water and the solution was basified by the addition of aqueous potassium carbonate solution. The leos were evaporated to dryness and the residue was extracted with n-propanol to give 4 (5-) - (2- (2-aminoethyl) thioethyl) imidazole crude base after removal of n-propanol. A solution of 3.3 g of this base and 1.9 g of methyl isothiocyanate in 15 ml of ethanol was heated under reflux for 30 minutes. After cooling, the solution was evaporated to dryness and the residue was chromatographed on silica gel. Elution with ethyl acetate / methanol (3: 2) and evaporation of certain color fractions gave an oily residue which was acidified with aqueous hydrochloric acid (64%).

Decantation several times with ether gave a yellow precipitate which, after washing with acetonitrile followed by ether, gave N-methyl-N * - (2- (2- (4-imidazolyl) ethyl) thioethyl) thiourea dihydroiodide. , melting point 143-145¾. as an off-white solid. (Analysis found: C 21.6; H 3.7; N 11.1; S 12.9; J 50.7. C9H16N4S2 '2HJ requires: C 21.6; H 3.6; N 11.2; S 12.8; J 50.7).

19 60393

Example 20 N- (2- (4-imidazolylmethylthio) ethyl) thiourea (1) A solution containing 6.0 g of 4- (5-) - (2-aminoethyl) thiomethyl) imidazole and 6.0 g of benzoyl isothiocyanate in 150 ml of chloroform was heated at reflux for 1 hour. After concentration and recrystallization from ethyl acetate-isopropyl acetate, 7.5 g of N-benzoyl-N '- (2- (4-imidazolylmethylthio) ethyl) thiourea were obtained. The melting point of the analytically pure test (from aqueous isopropyl alcohol) was 126-128 ° C.

(2) 6.0 g of benzoyl urea was added to a solution of 1.4 g of potassium carbonate in 80 ml of water at a temperature of 60 ° C. The solution was kept at this temperature for 1 hour, concentrated to a small volume and acidified with hydrochloric acid. The benzoic acid was removed by filtration, and the filtrate was basified with potassium carbonate and concentrated under reduced pressure. After extraction and concentration with isopropyl alcohol, the product was crystallized from isopropyl acetate. Recrystallization from water afforded 2.5 g of N- (2- (4-imidazolylmethylthio) ethyl) thiourea, mp 135-137 ° C. Analysis found: C 38.9; H 5.5; N 26.1; S 29.6. C7H12NilS2 requires: C, 38.9; H 5.6; N 25.9; S 29.6.

Example 32 N- [2- (4-Methyl-5-imidazolyl) methylthio) ethyl] thiourea (a) Reaction with 5.0 g of 4-methyl-5 - ((2-aminoethyl) thiomethyl) imidazole and 23, 8 g of benzoyl isothiocyanate were reacted using the procedure described in Example 29 (1) to give 24 g of N-benzoyl-N '- [2- (4-methyl-5-imidazolyl) methylthio) ethyl] thiourea, melting point 138- 140 ° C (from isopropyl alcohol-ethyl acetate-ether). The analytically pure test obtained after recrystallization from aqueous isopropyl alcohol had a melting point of 165-166 °.

(b) 22 g of crude benzoylthiourea was hydrolyzed with potassium carbonate using the method set forth in Example 29 (1) to give 7.5 g of N- [2- (4-methyl-5-imidazolyl) methylthio) ethyl] thiourea. Further recrystallization from water followed by isopropyl alcohol-ether gave pure product (3.8 g), mp 110-112 ° C. Analysis for C 41.9; H 6.3; N 24.5; S 28.0. 08Ηι4Ν ^ 2 requires: C, 41.7; H 6.1; N 24.3; S 27.8.

20 60393

Example 31 N-Methyl-N '- (3- (2-imidazolylthio) propyl) thiourea (1) A solution of 2 g of 2-mercaptoimidazole and 1.14 m] of 3-aminopropanol in hydrobromic acid (48%, 25 ml ) was heated at reflux for 25 hours. The reaction mixture was evaporated to dryness and the residual oily solid was recrystallised twice from ethanol / ether to give 3.55 g of 2- (3-aminopropylmercapto) imidazolidine hydrobromide, m.p. 160-162 ° C.

(2) 7 g of this amine dihydrobromide was converted to the free base, and 1.75 g of methyl isothiocyanate was reacted with this base using the method described in Example 1 (2) to give a crude yellow solid after evaporation of the reaction mixture. This crude product was washed with acetone / isopropyl acetate (1: 1) and recrystallized from water to give 3.46 g of N-methyl-N '- (3- (2-imidazolylthio) propyl) thiourea, melting point 139 -l4l ° C. Analysis found: C 41.5; H 6.1; N 24.1; S 27.7. C 9 H 11 N 2 O 2 requires: C, 41.7; H 6.1; N 24.3; S 27.8.

Examples 32-35

The two-step procedure shown in Examples 31 (1) and (2) was used for the NHCH formula.

/ 3

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22 60393

Example 3 N, N-methyl-N '- (2-oxazolyl) thiopropyl / thiourea (1) 90 ml of hydrochloric acid was added with stirring to a solution of potassium thiocyanate in 1.8 liters of ethanol. After filtration from the inorganic material, 35.9 g of glycol aldehyde was added, and the resulting solution was heated under reflux for 24 hours. Concentration followed by cooling gave a white solid which, after recrystallization from ethanol, gave 30 g of oxazole-2-thiol, m.p. 143-144 ° C.

(2) 13.4 g of 3-bromopropylphthalimide was added to a stirred solution of sodium ethoxide (1.15 g of sodium) and 5.1 g of oxazole-2-thiol in 100 ml of ethanol. The resulting solution was heated at reflux for 2 1/2 hours, after which the solution was concentrated under reduced pressure. The residue was triturated with a 100 ml portion of water to give 14 g of 2- (3-phthalimidopropylthio) oxazole, mp 101¾. Recrystallization from ethanol gave pure oxazole, mp 102-103 ° C.

(3) 5.3 g of hydrazine hydrate was carefully added with stirring to a solution of 10 g of 2- (3-phthalimidopropylthio) oxazole in 173 ml of ethanol. The solution was then heated at reflux for 25 minutes. After cooling and filtration from phthalic hydrazide, the filtrate was concentrated under reduced pressure and the residue was re-evaporated from ethanol to give crude 2- (3-aminopropylthio) oxazole, which was washed twice with ether and dissolved in 60 ml of ethanol. 2.54 g of methyl isothiocyanate was added and the solution was heated at reflux for 30 minutes. After cooling and filtration from insolubles, the filtrate was concentrated to an oil which was chromatographed on a silica gel column with ethyl acetate as eluent. The resulting product crystallized from ethanol-ether-n-hexane to give 2.4 g of N-methyl-N '- [3- (2-oxazolyl) -thiopropyl] thiol urea, m.p. 43-45 °. Analysis found: C 41.7; H 5.9; N 18.3; S 27.5. C 9 H 13 N 3 OS 2 requires: C, 41.5; H 5.7; N 18.2; S 27.7.

Example 37 N-Methyl-N '- β- (4-methyl-2-oxazolyl) thiopropylthiourea (1) Reaction with 5.8 g of 4-methyloxazole-2-thiol and 13.4 g of 60393 23 3- bromopropylphthalimide was reacted with each other using the conditions described in Example 36 to give 1 g of 4-methyl-2- (3-phthalimidopropylthio) oxazole, m.p. 92-93 ° C (ethanol-ether).

(2) Treatment of 3.0 g of the phthalimido compound and 1.53 g of hydrazine together and then reacting the product directly with methyl thioisocyanate (0.73 g) using the conditions of Example 36 gave 1.0 g of the compound N- methyl N'-β- (4-methyl-2-oxazolyl) thiopropylthiourea, m.p. 73-7 ° C (from ethanol-ether-n-hexane). Analysis found C 44.0; H 6.2; N 17.1; S 25.9. C 9 H 18 N 2 O 2 requires: C 44.1 H 6.2; N 17.1; S 26.1.

Example 35 N-Methyl-N '- [2- (4-imidazolylmethoxy) ethyl] thiourea (1) A suspension containing 14.7 g of 4- (2-chloroethoxymethyl) imidazole hydrochloride and 9.8 g of sodium azide in 103 ml of dry dimethylformamide. , was stirred for 5 hours at 95 ° C, after which the mixture was allowed to stand at room temperature overnight. After dilution with water and filtration, the filtrate was concentrated and the residue was purified by chromatography on a dry alumina column using ethanol. The product was basified with a solution of 6.5 g of potassium carbonate in 3 ml of water and the anhydrous residue was extracted with isopropyl alcohol (3 x 50 ml). Concentration of the extracts gave 7.2 g of 4- (2-azidoethoxymethyl) imidazole. Hydrogenation of 7.2 g of the azido compound in 142 ml of isopropyl alcohol over a platinum oxide catalyst (3.0 g) gave 6.48 g of 4- (2-aminoethoxymethyl) imidazole. The melting point of the mono-picrate monohydrochloride test was 139-140 ° C (from nitromethane). Analysis found: C 35.4; H 3.8; N 20.5; Cl 8.8. C 12 H 15 ClN 6 O 8 requires: c 35.4; H 3.7; N 20.7; Cl 8.7.

(2) 2.24 g of 4- (2-aminoethoxymethyl) imidazole were conventionally reacted with a solution of 1.21 g of methyl isothiocyanate in 25 ml of isopropyl alcohol. The crude product was purified by chromatography first on a silica gel column with ethyl acetate as eluent and then on a dry alumina column using chloroform. The final product was recrystallized from ethyl acetate to give 0.80 g of N-methyl-N, - [(4-imidazolylmethoxy) ethyl] thiourea, m.p. 96-98 ° C. Analysis found: C 44.6; H 6.5; N 26.0; S 14.7. CGU ^^ N ^ OS

24 60393 requires: C, 44.8; H 6.6; N 26.2; S 15.0.

Example 39 N-methyl-N '- [2 - ((4-methyl-5-imidazolyl) methylthio) ethyl] urea

A mixture of 5.1 g of 4-methyl-5 - ((2-aminoethyl) thiomethyl) imidazole and 2.0 g of methyl isocyanate in acetonitrile was heated for 18 hours in a pressure vessel at 100 ° G. The solid formed after cooling was separated and recrystallized from isopropyl alcohol-acetonitrile to give 4.0 g of N-methyl-N '- [2 - ((4-methyl-5-imidazolyl) methylthio) ethyl] urea, m.p. 159¾. Analysis found: C 47.4; H 7.1; N 24.5; S 14.4. C 9 H 18 N 2 O 3 requires: C, 47.3; H 7.1; N 24.5; S l4, o.

Example 40 N-Methyl-N * - / T 2- (5-thiazolyl) methylthio) ethyl] thiourea (1) A reaction in which 2.01 g of 5-hydroxymethylthiazole and 1.99 g of cysteamine hydrochloride were reacted with each other in an aqueous solution of hydrogen bromide. The procedure described in Example 1 (1) (a) gave 4.85 g of 5 - ((2-aminoethyl) thiomethyl) -thiazolidine hydrobromide, m.p. 191-194 ° C (from methanol).

(2) A reaction in which 2.24 g of 5 - ((2-aminoethyl) thiomethyl) thiazole and 0.94 g of methyl isothiocyanate were reacted in 10 ml of ethanol gave a thiol urea which was purified by silica gel column chromatography with ethyl acetate. being the eluent. Recrystallization from isopropyl acetate-methyl ethyl ketone ether gave 2.1 g of N-methyl-N '- [72 (5-thiazolyl) methylthio) ethyl] thiol stream, m.p. 86-88 ° C. Analysis found: C 38.6; H 5.4; N 16.9; S 38.6. C 9 H 11 N 2 O requires: C, 38.8; H 5.3; N 17.0; S 38.9-

Example 4l N-Methyl-N '- ([2- (2-pyridyl) methylthio) ethyl] urea

A reaction in which 7.0 g of 2- (12-aminoethyl) thiomethyl] pyridine and 2.7 g of methyl isocyanate were reacted as described in Example 39 gave N-methyl-N '- (72- (2-pyridyl) methylthio). ethyl urea, m.p. 63-66 ° C (from acetonitrile / ether).

25 60393

Example 42 N-Methyl-N '- [2 - ((3-amino-2-pyridyl) methylthio) ethyl] thiourea (1) Lithium aluminum hydride (3.2 g) was added portionwise to a solution of ethyl 3-aminopicolinate (6 , 8 g) in dry ether (150 ml) under a nitrogen atmosphere with stirring and cooling. After the addition, the suspension was heated to reflux for 30 min and diluted with ether (150 mL), then cooled by the addition of water (3.2 mL), dilute sodium hydroxide (3.2 mL) and water (9.6 mL). The slurry was stirred at room temperature for 30 min, magnesium sulfate was added and everything was filtered, the residue was washed well with ether. Concentration and subsequent treatment of the residue with hydrogen chloride in ether gave 3-amino-2-hydroxymethylpyridine hydrochloride (0.2 g), m.p. 292-300 ° C, which was recrystallized from methanol-ether without changing the melting point.

(2) A solution of 3-amino-2-hydroxymethylpyridine hydrochloride (3.4 g) and cysteamine hydrochloride (2.38 g) in aqueous hydrobromic acid (50 ml of 48%) was refluxed for 12 hours. Concentration under reduced pressure and re-evaporation of the residue with ethanol gave a yellow solid (7.5 g) which was recrystallized from methanol-ether to give 3-amino-2-J / T2-aminoethyl) thiomethyl-pyridine dihydrobromide (5.8 g), m.p. 195-196 ° C.

(3) 3-Amino-2- [2-aminoethyl) thiomethyl] pyridine (3.0 g, prepared from an aqueous slurry of dihydrobromide and potassium carbonate by extraction with ethanol-ether 2: 1) was dissolved in ethanol (25 ml), methyl isothiocyanate (1.16 g). ) was added and the solution was then refluxed for 30 min. The residue was triturated with ether to give a solid (3.4 g, mp 98-100 ° C). Recrystallization from isopropyl acetate gave N-methyl-N '- [2 - ((3-amino-2-pyridyl) methylthio) ethyl] thiourea in three fractions, m.p. 99.5-100.5 (1.33 g), m.p. 100-101 ° C (1.04 g) and m.p. 99-100 ° C (1.0 g).

Analysis found: C 47.2; H 6.3; N 21.7; S 24.4; C 10 H 16 N 4 S 2 requires: C, 46.8; H 6.3; N 21.9; S 25.0.

Example 43 N-Methyl-N '-7) 2- (3-isoxazolylmethylthio) ethyl] thiourea a) A solution of 3-chloromethylisoxazole (5.8 g) and cysteamine hydrochloride (6.25 g) in aqueous hydrobromic acid 26 60393 (48%, 100 mL) was refluxed for 6 hours. Concentration in the presence of water followed by n-propanol followed by recrystallization from isopropyl alcohol-ethanol gave 3- (T2-aminoethyl) thiomethyl-isoxazole hydrobromide, m.p. 131-133 ° C.

Analysis showed: Br 33.6; S 13.7; C6H1QN2OSHBr requires: Br 33.4; S 13.4.

b) A solution of 3- (T "2-aminoethyl) thiomethyl / isoxazole (2.44 g, extracted from hydrobromide and potassium carbonate with ether-ethanol 3: 1) and methyl isothiocyanate (1.36 g) in absolute ethanol (40 ml ) was concentrated to reflux for 1.5 hours, followed by concentration and purification by chromatography on a silica gel column using ether as eluent to give N-methyl-N '- [2- (3-isoxazolylmethylthio) ethyl] thiourea as a colorless oil (2.5 g).

Analysis found: C 41.3; H 6.2; N 18.2; S 27.3;

C 9 H 13 N 2 O 2 S requires: C, 4.5; H 5.7; N 18.2; S 27.7.

Example 44 Reaction of N-methyl-N '- [2- (1,4-dimethyl-2-imidazolyl) methylthio) ethyl] thiourea (1) 1,4, dimethylimidazole (5.65 g) with n-butyllithium followed by treatment with formaldehyde to prepare 3-hydroxymethyl-5,6,7,8-tetrahydroimidazo [1,5-a] pyridine gave 1,4-dimethyl-2-hydroxymethylimidiazole (2.71 g). g), m.p. 125-126 ° C (ethyl acetate-petroleum ether).

(2) Reaction of 1,4-dimethyl-2-hydroxymethylimidazole (2.5 g) with cysteamine hydrochloride (2.5 g) in aqueous hydrobromic acid by the method described in Example 1 (1) (a) gave 1,4-dimethyl- 2- (C 2 -aminoethyl) thiomethyl] imidazolidine hydrobromide (6.2 g), m.p. 161-163 ° C (from isopropyl alcohol-methanol).

(3) Reaction of 1,4-dimethyl-2 - [(2-aminoethyl) thiomethyl] imidazole (prepared from 6.2 g of dihydrobromide) with methyl isothiocyanate (1.34 g) in ethanol (50 ml), followed by chromatography on a silica gel column with ethyl acetate. -ethanol (9: 1) as eluent gave N-methyl-N '- [2- (1,4-dimethyl-2-imidazolyl) methylthio) -ethyl] thiourea (2.1 g).

Analysis found: C, 46.8; H 6.9; N 21.5; S 24.9; C 10 H 18 N 2 <S 2 requires: C, 46.5; H 7.0; N 21.7; S 24.8.

60393 27

Example 4 N-Methyl-N '- [2- (trifluoromethyl-5-imidazolyl) methylthio) ethyl] thiourea

A mixture of ethyl 2-chloro-4,4,4-trifluoroacetate (65.7 g), distilled formamide (135 g) and 11 ml of water was heated at 128-130 ° C for 1.5 hours. After cooling, an equal volume of ice-cold water was added to give 4-trifluoromethyl-5-carbethoxyimidazole, m.p. 184-186 ° C (from aqueous methanol).

Reduction of the ester (9.4 g) with 2.4 g of lithium aluminum hydride in tetrahydrofuran gave 5-hydroxymethyl-4-trifluoromethylimidazole, separated as its picrate, m.p. 135.5-137> 5 ° C (from aqueous isopropyl alcohol).

The picrate (5.3 g) was dissolved in $ 48 in aqueous bromic acid and extracted with toluene to remove picric acid.

1.52 g of cysteamine hydrochloride was added to the aqueous phase and the acidic solution was refluxed for 12 hours. Concentration of the residue and trituration with ethanol-ether gave 4-trifluoromethyl-5- (β-aminoethyl) thiomethylimidazolidide hydrobromide (3 g), m.p. 179 "L82 ° C. Basification followed by treatment with methyl isothiocyanate gave N-methyl-N '- [2- (4-trifluoromethyl-5-imidazolyl) methyl] thio) ethyl / thio urea.

Example 46 N-Methyl-N '- [2- (2-pyrimidyl) methylthio) ethyl] thiourea

A mixture of 5.6 g of 5-bromo-2-hydroxymethylpyrimidine and 5.6 g of magnesium oxide in water / ethanol (2: 1) was subjected to hydrogenolysis on 10% palladium on carbon for more than 0.5 hour. Filtration, concentration and extraction with ether from an aqueous solution of the residue gave 1.85 g of 2-hydroxymethylpyrimidine as a liquid.

Reaction of 2-hydroxymethylpyrimidine with cysteamine followed by further reaction of the product with methyl isothiocyanate according to the methods described in Examples 1 and 2 gave N-methyl-N'-12- (2-pyrimidyl) methylthio) ethylthiourea.

Example 47 N-Methyl-N '- [2- (2-pyrazinyl) methylthio) ethyl] thiourea (1) 2-Chloromethylpyrazine (6.4 g) was added over 20 minutes to a solution freshly prepared from 0.23 g. sodium in ethanol (50 ml) to which 5.7 g of cysteamine hydrochloride had been gradually added at 0 ° C and stirred at this temperature for 2 hours.

28 60393

Finally, the resulting suspension was stirred at room temperature overnight, acidified with hydrochloric acid (pH 5) and concentrated under reduced pressure. The dry residue was extracted with ethanol and the extracts were filtered and concentrated to give the crude product. Extraction with isopropyl alcohol, with slight removal of polymeric material and addition of ether, gave 3.5 g of a cream solid which was recrystallized from ethanol-ether to give 2V (2-aminoethyl) thiomethyl / pyrazine hydrochloride, m.p. L44-L46 ° C.

(2) The amine hydrochloride (1.6 g) was reacted to the free base using potassium carbonate and reacted with 0.6 g of methyl isothiocyanate in ethanol in a conventional manner. Recrystallization from ethanol gave 0.88 g of N-methyl-N '- [7- (2-pyrazinyl) methylthio) ethyl] thiourea. 99.5 to 100.5 ° C. Analysis found: C 44.6; H 5.9; N 22.8; S 26.5;

C 9 H 11 N 3 S requires: C, 44.6; H 5.8; N 23.1; S 26.5.

Example 48 N- [2- (4-Methyl-5-imidazolyl) methylthio) ethyl] urea

A solution of 3.33 g of 4-methyl-5- ([2-aminoethyl) thiomethyl] imidazole dihydrobromide, 0.8 g of potassium cyanate and 0.69 g of potassium carbonate in 30 ml of water was heated to 80-90 ° C: in 3 hours. Concentration under reduced pressure and extraction of the residue with n-propanol gave the crude product which was chromatographed on a silica gel column using ethyl acetate-ethanol (5: 1) as eluent. Recrystallization from isopropyl alcohol ether and finally acetonitrile gave 0.8 g of N- [72- (4-methyl-5-imidazolyl) methylthio) ethyl] urea, m.p. L48-L49 ° C.

Analysis found: C 44.6; H 6.5; N 25.7; S 15.0;

C 9 H 18 N 2 O 3 requires: C, 44.8; H 6.6; N 26.1; S 15.0.

Example 49 N-Methyl-N '- [2- (2-amino-4-thiazolyl) methylthio) ethyl] thiourea (1) A mixture of 9.0 g of 2-amino-4-chloromethylthiazole hydrochloride and 55 .3 g of cysteamine hydrochloride in 100 ml of acetic acid were refluxed for 18 hours. The crude product obtained after concentration was treated with picric acid in ethanol to give 2-amino-4- (T2-aminoethyl) thiomethyl] thiazole dipyrate, m.p. approximately 200-210 ° C (from ethanol).

(2) Picrate was reacted to give the free base by adding 29 60393 hydrochloric acid, removing picric acid by toluene extraction, basifying with potassium carbonate and extracting the aqueous residue with ethanol-ether. Reaction of the base (1.89 g) with 0.73 g of methyl isothiocyanate in 10 ml of ethanol gave the crude thiourea as usual. Chromatography on a silica gel column using ethyl acetate as eluent followed by recrystallization from isopropyl alcohol-isopropyl acetate gave N-methyl-N '- [2- (2-amino-4-thiazolyl) methylthio) ethyl] thiourea 1.0 g, m.p. 136-L40 ° C.

Analysis found: C 37.1; H 5.5; N 20.8; S 36.3; C 8 H 11 N 3 O 3 requires: C, 36.6; H 5.4; N 21.3; S 36.7-

Example 50 N-Methyl-N '- [3- (4-imidazolylmethoxy) propyl] thiourea (1) 13.5 g of sodium were added over 3 hours to 450 ml of propane-1,3-diol under a nitrogen atmosphere at 70 ° C. with stirring. This solution was added over 20 minutes to a stirred solution of 4-chloromethylimidazole hydrochloride (50.0 g) under a nitrogen atmosphere at 40-60 ° C. Thereafter heating at 60-65 ° C for 3 hours and then cooling overnight, filtering and concentrating gave 4- (3-hydroxypropoxy) methylimidazole. Subsequent reaction with thienyl chloride gave 4- (3-chloropropoxy) methylimidazole hydrochloride (38.3 g).

(2) Reaction of this chloride (36.2 g) with 22.4 g of sodium azide in dry dimethylformamide at 95 ° C for 3 hours and dry column chromatography on aluminum using ethanol as eluent gave 4- (3-azidopropoxy) methylimidazole , which was further purified by the same method using chloroform as the eluent. 2.95 g of azide in 200 ml of ethanol was hydrogenated over a platinum oxide catalyst to give 2.42 g of 4- (3-aminopropoxy) methylimidazole.

(3) Reaction of 2.42 g of amine with 1.25 g of methyl isothiocyanate in ethanol at room temperature for 65 hours and subsequent chromatography of the product on a silica gel column using ethyl acetate as eluent gave N-methyl-N'-β- (4-imidazo). lyylmethoxy) propylthiourea 0.49 g as a low melting solid.

Example 51 N-Methyl-N '- [2- (3-isothiazolylmethylthio) ethyl] thiourea 60393 30

A solution was prepared by gradually adding 2.03 g of cysteamine hydrochloride to 0.83 g of sodium dissolved in 50 g of ethanol with stirring at 0 ° C under a nitrogen atmosphere. After stirring for 2 hours at 0 ° C, 3 * 2 g of 3-bromomethylisothiazole was added dropwise over 15 minutes at 0 ° C, after which the reaction mixture was set aside overnight at room temperature. After acidification to pH 3.5 with hydrochloric acid, concentration and re-evaporation with ethanol, the residue was dissolved in ethanol, filtered and concentrated to give 3.5 g of 3- (T2-aminoethyl) thiomethyl] isothiazole hydrochloride. This was converted directly to the free base by treatment with aqueous potassium carbonate and extraction with ether. The extracts were dried over magnesium sulfate, filtered and concentrated to give the amine base as an oil (1.56 g). The amine was dissolved in 10 ml of ethanol, 0.66 g of methyl isothiocyanate was added and the solution was refluxed for 30 min. Concentration and subsequent purification of the crude product by chromatography on a silica gel column using ethyl acetate as eluent and then chromatography on an alumina column using benzene / ethyl acetate as eluent gave N-methyl-N '- [7- (3' isothiazolylmethylthio] thio) ethyl / ethylthio) ethyl.

Analysis found: C38.9; H 5.4; N 16.5; S 38.3; C8H13N3S3 requires: 038.8; H 5.3; N 17.0; S 38.9-

Example 52 Reaction of N-methyl-N '- / 2 - ((4-bromo-3-isothiazolyl) methylthio) ethylthio-urea 4-Bromo-3- (bromomethyl) isothiazole (8.5 g) 3.76 g with cysteamine (from cysteamine hydrochloride) was carried out under the same conditions as described in Example 51. The reaction gave 4-bromo-3- (T2-aminoethyl) thiomethyl] isothiazole hydrobromide, which, after recrystallization from ethanol-ether and acetonitrile, gave 4.0 g. 111-112 ° C. 2.73 g of the amine base were separated by basification with sodium hydroxide and extraction with chloroform, followed by dissolution in ethanol and treatment with 0.78 g of methyl isothiocyanate. The solution was refluxed for 30 min, concentrated and the residue triturated with ether to give 2.9 g of crystalline thiourea, m.p. 60-6l ° C. Recrystallization from isopropyl acetate gave N-methyl-N '- [2 - ((4-bromo-3-isopropyl) methyl] thio) ethyl urea (2.3 g) as needles, m.p. 62-63 ° C.

31 60393

Analysis found: C 29.5; H 3.8; N 12.9; Br 24.6; S 29.3; C 9 H 12 BrN 3 S 3 requires: C, 29.5; H 3.7; N 12.9; Br'24,5; S 29.5-

Example 53 N-Methyl-N '- [2 - ((5-hydroxy-2-pyridyl) methylthio) ethyl] thiourea (a) A mixture of 16.2 g of 2-hydroxymethyl-5-hydroxypyridine hydrochloride and 11.4 g of cysteamine hydrochloride in refluxing 48 hydrobromic acid gave 23 g of 2 - ((2-aminoethyl) thiomethyl) -5-hydroxypyridine dihydrobromide, m.p. 210-212 ° C (methanol).

(b) Reaction of 2 - ((2-aminoethyl) thiomethyl-5-hydroxypyridine (13.5 g from dihydrobromide) with methyl isothiocyanate (2.84 g) gave 7.5 g of N-methyl-NT-12- ( (5-hydroxy-2-pyridyl) methylthio) ethyl / thiourea, mp 130-132 ° C (water).

Analysis found: C, 46.9; H 5.7; N 16.5; S 24.9%; C10H15N3OS2 requires: C, 46.7; H 5.9; N 16.3; S 24.9%.

Example 54 N-Methyl-N'-12- (3-bromo-2-pyridyl) methylthio) ethyl / thiourea (a) A solution of 2.38 g of sodium nitrite in 10 ml of water was added dropwise to a stirred mixture of was 4.8 g of 3-amino-2-hydroxymethylpyridine in aqueous hydrobromic acid (48% t 10 ml) and water (5 ml) at 0-5 ° C. A solution of the diazonium salt was added to a hot solution of copper (I) bromide (2.5 g) in $ 60 hydrobromic acid and upon completion of nitrogen evolution the mixture was heated on a steam bath for 1/2 hour, diluted with water and saturated with hydrogen sulfide. Filtration, concentration to low volume and extraction with chloroform gave 4.8 g of 3-bromo-2-hydroxymethyl-pyridine. This was dissolved in aqueous hydrobromic acid (48%, 50 ml), 3.22 g of cysteamine hydrochloride was added and the resulting solution was refluxed for 6 hours. Concentration and then recrystallization from aqueous ethanol gave 6.1 g of 2 - ((2-aminoethyl) thiomethyl) -3-bromopyridine dihydrobromide, m.p. 252-254 ° C.

Analysis found: C 23.7; H 3.4; N 6.7; S 7.9; C8Hi; LBrN2S.2HBr requires: C, 23.5; H 3.2; N 6.9; S 7.8.

(b) Reaction of 3.48 g of 2 - ((2-aminoethyl) thiomethyl) -3-bromopyridine with 1.23 g of methyl isothiocyanate 32 60393 in 60 ml of ethanol gave 1.4 g of N-methyl -N * -_ / 2 - ((3'-bromo-2-pyridyl) methylthio) ethyl / thiourea as a low melting solid after chromatography on a silica gel column eluting with ethyl acetate.

Analysis found: C 37.1; H 4.7; N 13.2; Br 25.1; S 19.9% C 10 H 11 + BrN 3 S 2 requires: C 37.5; H 4.4; N 13.1; Br 25.0; S 20.0%.

Example 55 N-Methyl-N '- (3- (2-pyrimidyl) thiopropyl) thiourea (1) A mixture of 5.6 g of pyrimidine-2-thiol and 13.4 g of 3-bromopropylphthalimide in 100 ml of ethanol containing 1.15 g of sodium was refluxed for 20 hours to give 2- (3-phthalimidopropylthio) pyrimidine, m.p. 81.5-82.5 (ethanol-water).

Analysis found: C 60.1; H 4.6; N 13.9; S 10.6%> C 15 H 13 N 3 O 2 S requires: C 60.2; H 4.4; N 14.0; S 10.7%.

(2) Reaction of 3.7 g of the phthalimido compound with 1.86 g of hydrazine and subsequent direct reaction of the product with 0.83 g of methyl isothiocyanate gave 1.9 g of N-methyl-N '- Β- (2-pyrimidyl) thiopropyl] urea, m.p. 120-121 ° C (from ethanol-ether).

Analysis found: C 44.7; H 5.8; N 22.8; S 26.1%; c 9 H 14 N 4 S 2 requires: C, 44.6; H 5.8; N 23.1; S 26.5%.

Example 56

Reaction of 3.0 g of 4-hydroxymethyl-3-methylisothiazole with 2.8 g of cysteamine hydrochloride in 50 ml of a 48% aqueous solution of hydrobromic acid according to Example 1 (1) (a) gave 3-methyl-4- [2]. -aminoethyl) thiomethyl7isothiazole hydrobromide. The base is obtained by basifying with aqueous potassium carbonate solution, extracting with chloroform, drying the extracts over magnesium sulfate and concentrating. Reaction of 5.0 g of amine with 1.94 g of methyl isothiocyanate in 25 ml of ethanol at reflux for 30 min and purification of the product on an alumina column using benzene as eluent gives N-methyl-N * - £ 2- ( 3-methyl-4-isothioazolylmethylthio) ethyl / thiourea as a yellow oil.

Analysis found: C 40.8; H 5.9; N 16.1; S 36.4; C9H15U-S3 requires: C, 41.3; H 5.8; N 16.1; S 36.8.

33 60393 N.M.R. (60 mHz DMSO-Dgrssa)

CH

ΝίΛ. f2 CH2SCH2CH2NH-C - NHCH2

Delta value Peak type Corresponding protons Number of protons detected 8.80 singlet S— ^ 1

B

II

7.5 multiplet NH - C - NH 2 3.83 singlet> -CH2s -)) 3.62 multiplet CH2CH2NH j 2.83 doublet NHCH,) _3)) 2.6 multiplet SCH-CH-) - 2)) 2.43 singlet = ^ Η3)

Example 57 N- [2- (3-Bromo-2-pyridylmethyl) thioethyl / urea 0.4 g of potassium cyanate and 0.34 g of potassium carbonate were added to a solution of 2.0 g of 2- (3-bromo-2- pyridylmethyl) thioethylamine dihydrobromide in 10 ml of water and the mixture was heated at 80-85 ° C for 3 hours and evaporated to dryness. The residue was extracted with n-propanol and this material was purified by chromatography on silica gel eluting with ethyl acetate / isopropanol (10: 1) and recrystallization from ethanol to give the title compound, m.p. 125 ° C.

Example 58 N-Methyl-N * - [2- (2,5-dimethyl-4-imidazolylmethylthio) ethyl] -thiourea

A mixture of 1.85 g of 2- (2,5-dimethyl-4-imidazolylmethylthio) ethylamine, 0.803 g of methyl isothiocyanate and 60 ml of absolute ethanol was refluxed for 8 hours at 60393 and evaporated to dryness. The residue was recrystallized 3 times from isopropanol and purified by chromatography on silica gel eluting with ethyl acetate / methanol (2: 1) to give the title compound (0.6 g) which, after recrystallization from isopropanol, gave a melting point of 119-121 ° C.

Analysis found: C, 46.6; H 7.3; N 21.2; C 10 H 18 N 4 S 2 requires: c 46.5; H 7.0; N 21.7%.

Example 5? N-methyl-N '- [2 - (- 3-chloro-2-pyridylmethylthio) ethyl] thiourea 2- (3-chloro-2-pyridylmethylthio) ethylamine dihydrobromide, m.p. 250-255 ° C, prepared in the same manner as described in Example 1 (1) a, and converted to the free base by treatment with aqueous potassium carbonate solution and extraction with ether / ethanol (3: 1). This free base was treated with methyl isothiocyanate under the general conditions of Example 1 (2) to give the title compound as a low melting solid.

35 60393 N.M.R. (60 mHz in DMSO-D 6) \ CH 2 SCH 2 CH 2 NH - (Γ ^ NHCH 3

Delta value Peak type Corresponding protons Number of protons detected 2.61 multiplet SCH2CH2) ~) 5 2.84 doublet NHCH-,)) 3.62 multiplet CH2CH2NH 2 3.99 singlet Λ CH2S 2 7.2-7.7 multiplet NH-15- NH) H /> 3 "multiplets - '" "' p)

B

7.94 doublets Λ- Cl 1 8.48 doublets r / n. 1

Example 60 N-methyl-NT-λ2- (3-fluoro-2-pyridylmethylthio) ethyl] thiourea-2 cm -thionyl chloride was added over 15 minutes to a stirred solution of 1.015 g of 3-fluoro-2-hydroxymethylpyridine in 25 cm3: in ethanol-free chloroform at room temperature, and the mixture was stirred for another hour. The solution was then evaporated to dryness to give 1.54 g of 3 'fluoro-2-chloromethylpyridine hydrochloride, m.p. 95-98 ° C (closed test tube).

36 60393 1.023 g of cysteamine hydrochloride was added to a solution of 0.621 g of sodium in 40 parent ethanol and the mixture was stirred, cooled to 7 ° C, 1.49 g of 3-fluoro-2-chloromethylpyridine hydrochloride in 30 parent ethanol was added over 30 minutes and the mixture was left stand overnight at room temperature. The mixture is filtered and the filtrate is evaporated to give a residue which is triturated with 50 cm3 of sodium-dried ether and the filtrate is evaporated to give 1.085 g of 2- (2 * -aminoethylthiomethyl) -3-fluoropyridine as an amber oil.

500 mg of N-methyl isothiocyanate was mixed with a solution of 196 mg of 2- (2T-aminoethylthiomethyl) -3-fluoropyridine in 5 ml of ethanol at room temperature and left overnight. The solvent was evaporated to give a residue which was chromatographed on silica gel using 10% methanol / chloroform as eluent and evaporated to dryness in vacuo at 55 ° C to give the title compound as a colorless oil (485 mg).

Analysis found: C, 46.11; H 5.66; N 16.40; S 22.50; C 10 H 14 N 3 F ° 2 requires: C, 46.31; H 5.44; N 16.20; S 24.72%.

37 60393 The N.M.R. spectrum in CDCl 3 at 100 MHz showed the following resonances:

fT

^ ch0sch9ch0nh-c ^ 2 \ nhc „3

Delta value Peak type Corresponding protons Number of protons detected (TY '8.33 multiplet N ^ \ 1

B

H F

7.35 multiplet ~ 2 6.87 multiplet?

HN- NH

3.92 doublets> - ch2s)) 3.75 multiplets SCH2CH2N j 2.93 doublets NHCH ^ 3 2.79 multiplets SCH2CH2N 2

Claims (2)

38 60393 An analogous process for the preparation of a therapeutically active heterocyclic urea or thiourea compound of the formula IU-CCH 1 Y 2 CH 2 NHC , X1 attached to a carbon atom of a pyrazole, triazole, thiadiazole, pyrimidine, pyrazine or pyridazine ring, residue A represents a hydrogen or halogen atom, an alkyl group having 1 to 4 carbon atoms, a hydroxyl or amino group, X attached to a secondary nitrogen atom means a residue a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, n is 0, 1 or 2, m is 2 or 3 and n + m is 3 or 4, Y is an oxygen or sulfur atom and E is an oxygen or sulfur atom, and R 1 is a hydrogen atom, Alkyl group or dimethylaminoethyl group having 1 to 4 carbon atoms, characterized in that the compound of formula J, C- (CVnnCH3) raNHs X2 'A ___J2 in which A, Χ, Χ, η, m and Y have the same meaning as above is reacted compound with the formula RgNCE, wherein E is as defined above and R e is a sodium or potassium atom, an acyl group, an alkyl group having 1 to 4 carbon atoms, or a dimethylaminoethyl group; and when R 1 is an acyl group the product is finally deacylated to give a compound wherein R 2 is hydrogen. 2 Process according to Claim 1, characterized in that Y and E represent sulfur, n is 1, m is 2 and R 1 is methyl.