CS235968B2 - Method of 2-guanidine-4-imidazolylthiazols production - Google Patents

Description

Accordingly, the present invention provides a process for the preparation of 2-guanidino-4-imidazolylthiazoles of formula I

(I) in which

Y represents a C-CH3 or CH group with f represents a hydrogen atom, a hydroxymethyl group or an alkyl group having from 1 to 6 carbon atoms, and their pharmaceutically acceptable acid addition salts and acids, characterized in that the compound of formula II

O

H in which ·

Bal are as defined above and

B 'represents a halogen atom, reacted with N-aaidinothiourea, in an organic solvent at a temperature of from 0 to 75 ° C, whereupon the resulting compound of formula (I) is converted by treatment with a pharmaceutically acceptable acid to its pharmaceutically acceptable acid addition salt.

A group of compounds of formula I of interest are those wherein Y is CH, i.e. 2-guanidino-4-imidazolylthiazole and derivatives thereof. Preferred are those compounds in which B represents a hydrogen atom, a hydroxymethyl group or a methyl group.

Another preferred group of compounds of formula (I) are those wherein Y is C-CH3, i.e. 2-guanidino-4- (4-methyl-5-imidazolyl) thiazole and derivatives thereof.

Of these compounds, those in which B represents a hydrogen atom or a methyl group are preferred.

The novel compounds of the present invention may be used in the form of a pharmaceutical composition comprising an antisecretorically effective amount of a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof, or a pharmaceutically acceptable carrier or diluent. Preferred are those pharmaceutical compositions which contain the above-described preferred compounds of formula I as active ingredients.

The compounds of formula (I) may be used to treat gastric hyperacidity in animals in need of such treatment by administering to the animal antisecretorically effective amounts of a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof. Preferred substances for this purpose are the preferred compounds of formula I as described above.

The starting materials for the process according to the invention are the compounds of formula (II) in which Y and B are as defined above and B 'is a halogen atom, preferably chlorine or bromine. Preferred starting materials are compounds of formula II wherein B is hydrogen or methyl and B 'is chloro or bromo.

Suitable organic solvents for use in the process of the invention are, for example, tetrahydrofuran, ether or lower alkanols, such as methanol or ethanol.

The starting materials of formula (II) may be prepared by halogenation of the corresponding 2-B -5-B '-4-acetylimidazole in which f 1 represents a hydrogen atom or a methyl group, for example by reaction with halogen in an aqueous hydrogen halide solution and preferably with bromine. aqueous hydrobromic acid.

The 2-H-5-R '-4-acetylimidazole used in this reaction can be prepared by irradiating 1-acetyl-2-K-5-R-imidazole with ultraviolet radiation. Alternatively, the 2-R-4- < / RTI > acetylimidazoles can be prepared by reacting 3-halo-4-n-alkoxy-3-buten-2-one, in particular the corresponding 3-chloro or 3-bromo compound, with the corresponding R-substituted amidine. with a salt thereof in the presence of a base, such as trialkylamine, preferably triethylamine, in an organic solvent such as acetone, tetrahydrofuran, dioxane and the like, at a temperature of from 0 to 100 ° C, preferably refluxing in tetrahydrofuran.

Starting 3-halo-4-n-alkoxy-3-buten-2-ones Can be prepared from the known 3-halo-4-hydroxy-3-buten-2-one by reaction with dialkyl sulfate or diazoalkane, for example in aqueous tetrahydrofuran or dioxane , in the presence of a weak base, such as an alkali metal bicarbonate, at a temperature of from 0 to 60 ° C, preferably from 15 to 30 ° C. Alternative is possible

3-halo-4-n-alkoxy-3-buten-2-one prepared by heating 3-halo-4-hydroxy-3-buten-2-one to reflux with the appropriate n-alkanol, for example in a toluene solution.

The pharmaceutically acceptable acid addition salts of the novel compounds of formula (I) are readily prepared by treating the free base with an appropriate mineral or organic acid either in aqueous solution or in a suitable organic solvent.

The solid salt can then be obtained by precipitation or evaporation of the solvent. The pharmaceutically acceptable acid addition salts of the present invention include, but are not limited to, hydrochlorides, sulfates, hydrogensulfates, mesylates, nitrates, phosphates, acetates, lactates, maleates, fumarates, citrates, tartrates, succinates, and gluconates. Preferred salts are hydrochlorides and dihydrochlorides. If desired, the compounds of formula (I) in the free base form can be obtained from the acid addition salts by treatment with a suitable base followed by extraction of the desired compound in the free base form with a suitable organic solvent.

Compounds of Formula I and theirs; the pharmaceutically acceptable acid addition salts exhibit antisecretory activity. agents and As antagonists of the histamine Hg receptors, and are therefore therapeutically valuable for the treatment of gastric hyperacidity and peptic ulcers. As used herein, treatment of gastric hyperacidity includes treatment of peptic ulcers and other such conditions induced or impaired by gastric acid secretion. The compounds described may be administered to a patient in need of treatment by a variety of conventional routes including oral and parenteral administration. Preferably, the compounds are administered orally.

In general, the compounds of the invention may be administered orally in dosages of from 0.1 to 20 mg / kg body weight of the patient daily, preferably from 0.2 to 2.5 mg / kg daily.

If parenteral administration is desired, the compounds may be administered at dosages of from 0.1 to 1.0 mg / kg of patient body weight per day. It will be understood that, depending on the patient to be treated and the compound selected, deviations from the above dosage will be necessary.

The compounds of the present invention may be administered alone or in admixture with pharmaceutically acceptable carriers or diluents, in single or divided doses. Suitable pharmaceutical carriers include inert diluents or fillers, sterile aqueous solutions and various organic solvents. The pharmaceutical compositions produced by mixing the novel compounds of formula I or salts thereof with pharmaceutically acceptable carriers can conveniently be administered in various dosage forms, such as tablets, powders, capsules, lozenges or syrups.

These pharmaceutical preparations may optionally contain other ingredients such as flavoring agents, binders or other excipients. Thus, tablets containing various excipients such as sodium citrate may be used for oral administration together with various disintegrants such as starch, alginic acid and various more complex silicates, together with 8 binders such as polyvinylpyrrolidone, sucrose, gelatin and acacia. In addition, glidants such as magnesium stearate, sodium lauryl sulfate and talc are often used to prepare tablets. Solid compositions of a similar type may be used to fill soft and hard gelatine capsules. Preferred materials for preparing these compositions include lactose or milk sugar and high molecular weight polyethylene glycols. When aqueous suspensions or elixirs are to be orally administered, the basic active ingredient may be combined with various sweetening or flavoring agents, coloring agents and optionally emulsifying or suspending agents, and mixed with diluents such as water, ethanol, propylene glycol, glycerin or mixtures thereof.

Preferably, the novel compounds of formula (I) are administered orally in unit dosage form, i.e., in single unit doses containing an appropriate amount of the active ingredient in combination with a pharmaceutically acceptable carrier or diluent. Examples of such unit dosage forms are tablets or capsules containing from 5 to 1000 kg of an active ingredient, which is a compound of formula (I), which amounts to 10 to 90% of the total weight of the dosage unit.

For parenteral administration, solutions of the compounds of formula I in sterile aqueous solutions such as aqueous propylene glycol, sodium chloride, dextrose or sodium bicarbonate solutions may be used. These solutions are suitably buffered if necessary and the liquid diluent is first rendered isotonic by addition of an appropriate amount of sodium chloride or glucose. The preparation of suitable sterile liquid media for parenteral administration is well known in the art.

The efficacy of the compounds of formula 1 as antisecretory agents and histamine Hg receptor antagonists can be ascertained by standard pharmacological tests, including, e.g.

(1) measuring their ability to antagonize the effects of histamine that are not blocked by antihistamines such as mepyramine, and (2) measuring their ability to inhibit gastric acid secretion in the stomach of dogs with Heidenhain pocket pre-treated with pentagastrin to stimulate gastric acid secretion.

The invention is illustrated by the following non-limiting examples.

He did

4-acetylimidezole

A mixture of 6.0 g (54 mmol) of 1-ethylimidazole and 60 ml of tetrahydrofuran ee in a quartz vessel was photolyzed at 30 ° C for 16 hours in a suitable reactor (Rayonet). The reaction mixture was stirred for 1 h The residue is chromatographed on 100 g of silica gel using chloroform / methanol (19: 1) as the eluent. 0.32 g (5%) of 2-acetylimidazole, m.p. 133-135 ° C, is obtained as the less polar product. As a more polar product, 1.1 g (19%) of 4-acetylimidazole of melting point 165 DEG-168 DEG C. is obtained.

Example 2

2-Bromo-1- (4-imidazolyl) ethanone hydrobromide To a solution of 0.50 g (4.5 mmol) of 4-acetylimidazole in 10 ml of methanol was added 10 drops of 43% hydrogen bromide with stirring at room temperature. The mixture is stirred at room temperature for 15 minutes, then 50 ml of absolute ether is added, the precipitate formed is filtered off and dried. 0.54 g of hydrobromide melting at 214 DEG C. is decomposed. This product was dissolved in 10 mL of 48% hydrogen bromide, the solution was heated to 60 ° C and treated with 0.15 mL (3.0 mmol) of bromine. After stirring at 60 ° C for 1 h, the ams was concentrated and the residue was triturated with a mixture of isopropanol and ether. The white crystalline precipitate formed is filtered off and dried after washing with ether. 0.42 g (35%) of 2-bromo-1- (4-imidazolyl) ethanone hydrobromide is obtained, m.p. 188-192 ° C.

NMR (CDCl 3, δ): 9.02 (singlet, 1 H), 8.45 (singlet, 1 H), 4.84 (singlet, 2 H).

Example a d 3

2-guanidino-4- (4-imidazolyl) thiazole hydrobromide

A mixture of 0.38 g (1.4 mmol) of 2-bromo-1- (4-imidazolyl) ethanone hydrobromide and 10 ml of acetone is heated until homogenization, then 0.17 g (1.4 mmol) is added. amidinothiourea and the resulting mixture was refluxed for 0.5 h. The reaction mixture was cooled, the precipitated white precipitate was filtered off and dried after washing with ether. 0.24 g (60%) of 2-guanidino-4- (4-imidazolyl) thiazole hydrobromide, melting at 225 DEG C., is obtained.

NMR (CDCl 3), 8.20 (singlet, 1 H), 8.0 (broad signal, 4H), 7.77 (singlet, 1 H), 7.36 (singlet, 1 H).

Mass spectrum and high resolution: for ΟγΗ ^ Ν ^ Ξ:

calculated: 208.053 found: 208.051 7.

H, 3.60; N, 27.36. Found: C, 27.23; H, 3.57; N, 27.64.

Example 4

2-guanidino-4- (4-imidazolyl) azzole

A mixture of 42 ml of concentrated sulfuric acid and 21 ml of water was cooled to -10 ° C and 1.56 g (22.7 mmol) of sodium nitrate was added. The resulting mixture was stirred at -5 ° C for 10 minutes, then 8.1 mL (78 mmol) of cold 50% phosphoric acid was added and stirring was continued at -5 ° C for 10 minutes before being added. A solution of 2.5 g (8.4 mmol) of 2-guenidino-4- (2-amino-4-imidazolyl) thiazole dihydrochloride in 100 ml of water is added dropwise over 0.5 h. The reaction mixture was stirred at 50 ° C for 2 hours, then at room temperature for 6 hours, diluted with water (500 mL), basified with solid sodium carbonate and extracted with ethyl acetate (3 x 150 mL).

The combined ethyl acetate extracts were dried over sodium sulfate, filtered and evaporated to a solid residue which was taken up in boiling methanol. The solution was decolorized with activated carbon and concentrated to a small volume. The resulting solid product was collected and dried to give 9 mg (5%) of 2-gusnidino-4- (4-imidazolyl) thiazole identical to thin layer chromatography and high resolution mass spectrometry with the material prepared in Example 3.

Example 5

3-Bromo-4-methoxy-3-buten-2-one

5.0 g (30 mmol) of 3-bromo-4-hydroxy-3-buten-2-one are dissolved in a solution of 100 ml of tetrahydrofuran and 10 ml of water. To the resulting solution was added 8.7 mL (90 mmol) of dimethyl sulfate and 8.3 g (100 mmol) of sodium bicarbonate, and the resulting suspension was stirred at 25 ° C for 75 minutes, then the solvent was evaporated in vacuo. The residue consisting of a mixture of the oily and solid product was stirred overnight in a mixture of 20 ml of diethyl ether and 150 ml of 0.1N sodium bicarbonate solution.

The aqueous layer was separated, extracted twice with 50 ml of ether each time, the combined ethereal extracts were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated in vacuo to a yellow oily residue which soon solidified. 3.21 g (59%) of 3-bromo-4-methoxy-3-buten-2-one of melting point 53-56 ° C are obtained.

NMR (CDCl 3), δ 8.22 (singlet, 1H), 4.03 (singlet, 3H),

2.37 (singlet, 3H).

H, 3.94; H, 44.64%.

Found: C, 33.27; H, 3.85; Br, 43.46.

Example 6

1- (2-methyl-4-imidazolyl) ethanone

6.3 g (35 mmol) of 3-bromo-4-methoxy-3-buten-2-one, 16.7 g (175 mmol) of acetamidine hydrochloride and 29.2 ml (210 mmol) of triethylemine are combined in 300 ml. tetrahydrofuran and the mixture was refluxed for 6 hours. The solvent was evaporated in vacuo, the crude orange solid was dissolved in 200 mL ethyl acetate and the solution was concentrated to 25 mL by evaporation of the solvent. After cooling the residue in ice, a yellow solid crystallized, which was filtered off, washed first with ethyl acetate and then with ether and then dried in vacuo at 25 ° C. There were obtained 9.995 g (23%) of 1- (2-methyl-4-imidazolyl) ethanone, m.p. 124-127 ° C.

MIR (CDCl 3, delta): 4'ζ61 (singlet, 1H), 1.41 (singlet, 3H),

1.41 (singlet, 3H), 1.39 (signelt, 3H).

Example 7

1- (2-Methyl-4-imidazolyl) ethanone

5.75 g (46.3 mmol) of 1- (2-methyl-1-imidazolyl) ethanone are dissolved in 600 ml of tetrehydrofuran and photolysed in a quartz flask for 18 hours under short wavelength ultraviolet radiation. The tetrahydrofuran solution was concentrated in vacuo to an oily residue which was chromatographed on silica gel using 5% methanol in chloroform as eluent. 2.6 g of (45%) 1- (2-methyl-4-imidazolyl) etenone of melting point 123 DEG-125 DEG C. are obtained.

Example 8

- (2-methyl-4-imidazolyl) -2-bromoethanone hydrobromide

2) 40 g (19.3 mmol) of 1- (2-methyl-4-imidazolyl) ethanone are dissolved in 30 ml of 48% hydrogen bromide and a solution of 3.36 g ( 21 mmol) of bromine dissolved in 5 ml of 48% hydrogen bromide solution. The reaction mixture was heated at 70 ° C for 2.5 hours and then concentrated in vacuo. The dark colored oily residue was triturated with a mixture of isopropyl alcohol and ether. The resulting solid material was filtered off and washed with ether. 2.8 g (51%) of 1- (2-ethyl-4-imidazolyl) -2-bromoethanone hydrobromide, melting at 181 DEG C. with decomposition, are obtained.

NMR (CDCl 3, delta): 8.71 (singlet, 1H), 4.77 (singlet, 2H), 2.63 (singlet, 3H).

Example 9

2-guanldino-4- (2-methyl-4-imidazolyl) thiazole

2.8 g (9.86 mmol) of 1- (2-methyl-4-imidazolyl) -2-bromoethanone hydrobromide are dissolved in 10 ml of water, saturated sodium bicarbonate solution is added to the solution up to pH 10, the precipitated solid product. The mixture is filtered and washed with 15 ml of water. The dried free base was heated to reflux in 50 ml of acetone and 1.2 g (9.86 mmol) of amidinothiourea were added to the clear acetone solution at reflux. It dissolves immediately and solids begin to precipitate within 1 minute. After boiling for 1 hour. The resulting suspension was cooled, the solid material was filtered off and washed first with acetone and then with ether. 2.37 g (79%) of 2-guanidino-4- (2-methyl-4-imidazolyl) thiazole hydrobromide, melting at 158 DEG C., is obtained.

NMR (CDCl3, delta): 7.71 (broad singlet arm, 1H),

7.56 (broad singlet, 4H), 4.32 (siriglet, 1H), 2.51 (singlet, 3H).

H, 3.66; N, 27.72.

Found: C 31.46, H 4.30, N. 27.28%

He did

1-Methyl-4-methylimidazole

To 50 g (609 mmol) of 4-methylimidazole in 250 ml of toluene was added under stirring at nitrogen at room temperature 239 g (304 mmol) of acetyl chloride. The resulting mixture was stirred at room temperature for 5 hours, then filtered to remove insolubles and filtrate. thicken.

19 g (50%) of 1-acetyl-4-methylimidazole are obtained in the form of a yellow oil which crystallizes on standing.

NMR (CDCl 3) 8.06 (singlet, 1 H), 7.17 (singlet, 1 H), 2.57 (singlet, 3H), 2.23 (singlet, 3H).

Example 11

5-ethyl-4-methylimidezole

A solution of 5.0 g (40.3 mmol) of 1-acetyl-4-methyl-imidazole in 700 ml of dry tetrehydrofuran is photolysed in a quartz flask for 24 hours with short wavelength ultraviolet (254 nm). The tetrahydrofuran solution is concentrated in vacuo to an oily residue which is chromatographed on silica gel using 5% methanol in chloroform as the eluent to give 1.91 g (3856) of 5-ethyl-4-methylimidazole as a white solid, m.p. 142 [deg.] C.

NMK (CDCl3 / CDC6), delta: 7.45 (singlet, 1H), 2.52 (singlet, 3H), 2.48 (singlet, 3H).

Example 12

- (4-methyl-5-imidazolyl) -2-bromoethanone

A solution of 1.57 g (12.6 mmol) of 5-ethyl-4-methylimidazole in 15 ml of concentrated hydrobromic acid is heated to 50 ° C and a solution of 2.01 g (1.2.6 mmol) is added over 0.75 hours. of bromine in 15 ml of concentrated hydrobromic acid. The reaction mixture was stirred at 50 ° C for 1.25 hours, then concentrated and the residue was triturated with isopropyl alcohol. The white solid was filtered off. 2.78 g (78%) of 1- (4-methyl-5-imidazolyl) -2-bromoethanone hydrobromide are obtained.

NMK (perdeuterodimethylsulfoxide, delta): 9.40 (singlet, 1H), 4.87 (singlet, 2H),

2.65 (singlet, 3H).

This material was converted to the free base by stirring in 50 mL saturated sodium bicarbonate solution for 15 minutes. Filtration and drying gave 1- (4-methyl-5-imidazolyl) -2-bromoethanone as a white powder.

Example 13

2-guanidino-4- (4-methyl-5-imidazolyl) thiazole hydrobromide

A mixture of 1.65 g (8.13 mmol) of 1- (4-methyl-5-imidazolyl) -2-bromoetone in 165 ml of acetone is heated until homogenization, then 0.96 g / 8.13 mmol is added. The resulting mixture was heated to reflux for 1 hour. The reaction mixture was allowed to cool to room temperature and the precipitate formed was filtered off to give 0.98 g (40%) of 2-guanidino-4- (4-methyl-5-imidazolyl) thiazole hydrobromide, m.p. C.

MMR / Perdeuterodimethylsulfoxide, delph): 8.52 (singlet, 1H), 7.67 (broad signal,

4H), 7.20 (singlet, 1H), 2.49 (singlet, 3H).

Analysis calculated for: C 8 H 8 N 8 S.HBr:

found:

31.69% C, 31.80% Q,

H 3.66, H 3.90,

27.72% N; 26.90% N.

// ......

*

Example 14

1-ethyl-2,4-dimethylimidazole

To a solution of 9.6 g (0.10 mol) of 2,4-dimethylimidazole in 50 ml of chloroform and 50 ml of toluene was added 3.6 ml (0.05 mol) of acetyl chloride with stirring at room temperature over 1 minute. . The reaction mixture was stirred at room temperature for 2 hours then filtered to remove insoluble solids and concentrate the filtrate. 6.9 g (100%) are obtained.

1-acetyl-2,4-dimethylimidazole as a white crystalline solid.

NMR (CDCl3, delta): 7.00 (singlet, 1H), 2.68 (singlet, 3H), 2.57 (singlet, 3H), 2.21 (singlet, 3H).

Example 15

5-acetyl-2,4-dimethylimidazole

A solution of 6.9 g (0.05 mol) of 1-acetyl-2,4-dimethylimidazole in 700 ml of dry tetrahydrofuran is photolysed in a quartz flask for 40 hours under short wavelength ultraviolet radiation (254 nm). The tetrahydrofuran solution was concentrated in vacuo to an oily residue which was chromatographed on silica gel using 5% methanol in chloroform as eluent. 2.8 g (41%) of 5-acetyl-2,4-di-ethylimidazole are obtained as a white solid, m.p. 83-87 ° C. Recrystallization from isopropyl ether gave analytically pure material, m.p. 87-88 ° C.

NMR (CDCl 3): 2.53 (singlet, 6H), 2.40 (singlet, 3H).

For C: HH ^ HN 20O: C, 60.85; H, 7.30; N, 20.27.

Found:% C, 60.66;% H, 7.26;% N, 20.09.

Example 16

1- (2,4-Dimethyl-5-imidazolyl) -2-bromoethanone

A solution of 1.0 g (7.24 mmol) of 5-acetyl-2,4-dimethylimidazole in 15 mL of concentrated hydrobromic acid was heated to 50 ° C and 1.16 g (7.25 mmol) was added dropwise over 1 minute. bromine. The reaction mixture was heated at 50-60 ° C for 1 hour, then concentrated and the solid residue was triturated with 30 mL of saturated sodium bicarbonate solution. The insoluble material was filtered off, washed with water and dried in vacuo. 12 g (71%) of 1- (2,4-dimethyl-5-imidazolyl) -2-bromoethanone are obtained as a white solid, m.p. 128-32 ° C.

NMR (CDCl 3, delta): 4.40 (singlet, 2H), 2.27 (singlet, 3H),

2.13 (singlet, 3H).

Example 17

2-Guanidino-4- (2,4-dimethyl-5-imidazolyl) thiazole hydrobromide hemihydrate

A solution of 1.0 g (4.6 mmol ·) of 1- (2,4-dimethyl-5-imidazolyl) -2-bromoethanone in 50 mL of acetone was heated and 0.55 g (4.6 mmol) was added. amidinothioureas. The reaction mixture was heated under reflux for 1 hour, whereupon a white solid precipitated. The precipitate was filtered off, washed with acetone and dried. 1.12 g (77%) of 2-guanidino-4- (2,4-dimethyl-5-imidazolyl) thiazole hydrobromide hemihydrate are obtained in the form of a white solid, melting with decomposition at 273 ° C.

NMR (CDCl3, delta): 8.4-7.2 (broad signal, 7H), 7.00 (singlet, 1H), 2.50 (singlet, 3H), 2.38 (singlet, 3H).

Analysis: gNgS.HBr.1 / 2H ₂ O Calculated: 33.14% C, 4.33% H, 25.76% N, 9.83% Si Found: 33.47% C, 4.19% H N, 9.91% S.

Example 18

3-Bromo-4-ethoxy-3-buten-2-one

A mixture of 400 ml of absolute ethanol and 60 ml of toluene is heated to reflux and 20 ml of the azeotropic mixture are removed by means of a Deen-Stark well. 33.0 g (0.2 mol) of 3-bromo-4-hydroxy-3-buten-2-one are then added to the ethanol-toluene mixture and heating at reflux is continued for 2 hours, while stirring at room temperature. three aliquots of 20 ml of ethanol / toluene were removed with a Dean-Stark trap. The resulting solution was concentrated in vacuo to give 38.6 g (100%) of 3-bromo-4-ethoxy-3-buten-2-one as a mobile oil.

NMR (CDCl3, delta): 8.21 (singlet, 1H), 4.23 (quartet, 2H),

2.33 (singlet, 3H), 1.31 (singlet, 3H).

Example 19)

2-hydroxymethyl-4-acetylimidazole

9.7 g (0.05 mol) of 3-bromo-4-ethoxy-3-buten-2-one are mixed with 5.53 g (0.05 mol) of hydroacetamidine hydrochloride in 00 ml of acetone to form a suspension, to which ae at 25 ° C add 11 over 5 minutes _; Β 5 (0 ¹ mol) of 1,1,3,3-tetramethylguanidine. After stirring for forty-eight hours, the suspension was filtered and the filtrate was concentrated in vacuo to an oily residue which was chromatographed on silica gel using chloroform as eluent. 1.48 g (21%) of 2-hydroxymethyl-4-acetylimidazole of melting point 147 DEG-148 DEG C. are obtained.

NMR (CDCl3, delta): 7.73 (singlet, 1H), 5.46 (very broad singlet, 1H), 4.5 (broad singlet, 2H),

2.4 (singlet, 3H).

Example 20

2-hydroxymethyl-4-bromoacatylimidazole hydrobromide

1.826 g (0.013 mol) of 2-hydroxymethyl-4-acetylimidazole are dissolved in 40 ml of 48% hydrobromic acid and 2.1 g (0.013 mol) of bromine are added. The reaction mixture was heated at 80 ° C for 2 hours, then concentrated in vacuo to a solid residue which was triturated with isopropyl ether. The solid product was filtered off, washed with ether and dried to give 2.2 g (56%) of 2-hydroxymethyl-4-bromoacetylimidazole hydrobroinide, melting at 183 ° C with decomposition.

NMR (CDCl 3, delta): 8.8 (singlet, 1H), 4.8 (singlet, 2 2H),

1

Example 21

2-guanidino-4- (2-hydroxymethyl-4-imidazolyl) thiazole hydrobromide

1.78 g (0.005 9 mol) of 2-hydroxymethyl-4-bromoacetylimidazole hydrobromide are dissolved in water and the free base is precipitated by the addition of saturated sodium bicarbonate solution. This material was filtered off, dried, treated with 956 mg (0.008 1 mol) of amidinothiourea in 60 ml of acetone and heated to 70 ° C. Upon heating for 15 minutes, a solid formed. The reaction mixture was debugged and the solid product was filtered off. 1.65 g (87%) of 2-guanidino-4- (2-hydroxymethyl-4-imidazolyl) thiazole hydrobromide, m.p. A sample of this product is converted into the free base by dissolving in hot water and adding solid sodium bicarbonate up to pH 10 to precipitate 2-guanidino-4- (2-hydroxymethyl-4-imidazolyl) thiazole as the free base. base. This material, after drying over toluene under high vacuum, gave a slightly reddish brown solid, m.p. 208 DEG-209 DEG C. with decomposition.

MKR (perdeuterodimethylsulfoxide, delta): 7.16 (singlet, 1H), 6.83 (broad singlet,

4H), 6.68 (singlet, 1 H), 4.45 (singlet, 2 H), 3.46 (very broad singlet, 1 H).

High resolution mass spectrum:

for C _S H, ₀ H _Ď OS:

calculated: 238.063 8 found: 238.065 4.

Example 22

The efficacy of the compounds of the invention to suppress gastric acid secretion is assured in waking dogs with a Heidenhain pocket who have been left fasting overnight.

To stimulate acid secretion, pentagastrin (Pentavlon-Ayerst) is applied by continuous infusion into the superficial vein of the paw of the dog at doses previously found to stimulate near maximal acid secretion from the gastric sac. From the beginning of the infusion of pentagastrin, gastric juice was collected at 30 minute intervals and measured to within 0.1 ml. 10 samples are taken from each dog during the experiment. The acid concentration was determined by titrating 1.0 ml of gastric juice to pH 7.4 with 0.1 N sodium hydroxide using an automatic burette and a glass electrode pH meter (Radiometer).

90 minutes after the initiation of the pentagastrin infusion, either the test substance or vehicle is administered intravenously at a dose of 1 mg / kg. Antisecretory efficacy for gastric acid secretion is calculated by comparing the lowest acid secretion after administration of the test substance to the average acid secretion before administration of the test substance.

The results obtained show that the compounds of Examples 3, 9, 13, 17 and 21 all inhibit gastric acid secretion by at least 15% when administered at a dose of 1 mg / kg.

Example 23

The antagonist activity of the compounds of the invention on histamine Hg receptors is determined as follows.

The guinea pigs are quickly killed by a wound to the head and the right atrium is removed from their hearts, which is isometrically suspended in a tissue bath of 10 ml of oxygenated (95% 0, 5% COg) Krebs-Henseleit buffer (pH 7.4) maintained. to 32 ± 2 ° C, where it is allowed to stabilize for about 1 hour, during which time the tissue bath is changed several times. Individual atrial contractions are monitored using a force transducer associated with a cardiotachometer and a grass printing device. After obtaining a dose-response curve of histamine, the bath with each atrium is flushed several times with fresh buffer and the number of atrial contractions per unit is re-equilibrated to baseline.

Upon reaching this baseline rate, the test substance is introduced into the bath at a predetermined final concentration and the histamine dose-response curve is again determined, this time in the presence of the antegonist. The results are expressed as dose ratios, i.e. the ratio of histamine concentrations required to achieve half maximal stimulation in the presence and absence of antagonist, and the apparent dissociation constant of the Hg-receptor entagonist, called pAg, is determined.

The results show that the compounds of Examples 3, 9, 13, 7 and 21 do not have pAg values greater than 5.7.

Claims (1)

A process for the preparation of 2-guanidino-4-imidazolylthiazoles of the general formula 1 in which Y is C-CH3 or CHa R represents a hydrogen atom, a hydroxymethyl group or a C1-C6 alkyl group, and pharmaceutically acceptable acid addition salts thereof, characterized in that the compound of formula (II) O H in which R 'and Y' are as defined above; er 'represents a halogen atom, reacted with N-amidinothiourea, in an organic solvent at a temperature of 0 to 75 ° C, optionally converting the resulting compound of formula I into a pharmaceutically acceptable acid by reaction with a pharmaceutically acceptable acid. acid addition salt.