SU1217258A3 - Method of producing derivatives of 2-guanidine-4-heteroarylthiazol or their acid-additive salts which are acceptable in pharmacy - Google Patents

Abstract

The method of producing 2-guanidino-4-heteroaryl thiazole derivatives of the formula NH IJ II A w-w-s C TR Y where Y is a -CH-group or C-R is a hydrogen atom, hydroxymethyl or alkyl with 1-6 carbon atoms, or pharmaceutically acceptable acid addition salts, characterized in that the compound of the formula FI II V, where R and Y have the indicated meanings, R is a bromine atom, is reacted with N-amidinothiourea in an organic solvent, such as acetone, with boiling point of the reaction mass, and the desired product is isolated in free form or as pharmaceutically acceptable acid salt additive. ate you ate oo

Description

The invention relates to a method for producing new biologically active chemical compounds, namely, a method for producing 2-guanidino-4-heteroaryl thiazole derivatives or their pharmaceutically acceptable acid addition salts, which exhibit activity as anti-receptor agents and histamine-antagonists -Ni may be useful in preventing and treating increased gastric acidity and peptic ulcers.

The purpose of the invention is to obtain new derivatives of the heteroarylguanidine series, which have an increased anti-secretory activity and are active histamine -H antagonists.

Example 1. 4-Acetylimidazole.

A mixture of 6.0 g (54 mmol) of 1 - acetyl imidazole in 60 ml of tetrahydrofuran was subjected to photolysis in a Rayonet reactor using a quartz vessel at 30 ° C for 16 h. The mixture was concentrated, the residue was chromatographed on 100 g of silica gel using a mixture of 19 A: 1 chloroform and methanol as eluent. The less polar product is 2-acetylimidazole, m.p. 133-135 ° C (0.32 g 5%). More than half a year the product is 1.1 g (19%) of 4-acetylimidazole. Mp. 165-168 ° C.

Example 2. Hydrobromide 2- -bromo-1 - (4-imidazoi.p) -ethanone.

A solution of 0.50 g (4.5 mmol) of 4-acetylimidazole in 10 MP of methanol is stirred at room temperature and ten drops of 48% hydrogen bromide are added. After stirring at room temperature for 15 minutes, 50 ml of absolute ether are added. The resulting precipitate is collected by filtration and dried to give 0.54 g of hydro-bromide salt, m.p. (dec) This substance was dissolved in 10 ml of 48% hydrogen bromide, warmed to 60 ° C and 0.15 ml (3.0 mmol) of bromine was added. After stirring at 60 ° C for 1 h, the mixture is concentrated, the residue is dissolved with a mixture of isopropanol and ether. The crystalline precipitate is filtered off, washed with ether and dried, yielding 0.42 g (35%)

172582

hydrobromide 2-bromo-1- (4-imidazoyl) - | - ethanone, so pl. 188-192 C.

NMR (DMSO-ab), (): 9.02 (s, 1H), 8.45 (s, 1H); 4.84 (s, 2H). 5 Example 3. 2- -guanidino-4- (4-imidazoyl) -thiazole hydrobromide. A mixture of 0.38 g (1.4 mmol) of 2-bromo-1- (4-imidazoyl) - -ethanone hydrobromide in 10 ml of acetone is heated 10 until it becomes homogeneous, then 0.17 g is added ( 1.4 mmol) amidinothioureas and heated under reflux for 0.5 hours. The mixture is cooled, 15 a white precipitate is collected, washed with ether and dried, yielding 0.24 g (60%) of 2-guanidino-4- hydrobromide (4 -imidazoyl) -thiazole, so pl. 225 ° C (decomp.).

20 NMR (D1-1CO - d), (&): 8.20 (s, 1H), 8.0 fS, 4H), 7.77 (s, 1H); 7.36 (s, 1H) J high resolution mass spectrum:

- Calculated for C HNgS 208.0531; 25 found 208.0517.

Found,%: C 27.23; H 36.57; N 27.64.

Calculated,%; C, 27.37; H 3.60, 30 N 27.36,

Example 4. 2-Guanidino-4- - (4-imidazoyl) -thiazole.

A mixture of 42 ml of concentrated sulfuric acid and 21 ml of water is cooled

35 to -10 ° C and 1.56 g added

(22.7 mmol) of sodium nitrate. After stirring at -5 ° C for 10 minutes, 8.1 ml (78 mmol) of cold 50% hypophosphorous is added.

40 acids and continue stirring for another 10 minutes at -5 ° C. Over a period of 0.5 hour, a solution of 2.5 g (8.4 mmol) of 2-guanidino-4- (2-amino acid) dihydrochloride is added dropwise. -445-imidazoyl) -thiazole in 100 ml of water. The reaction mixture was stirred at 50 ° C for 2 hours, then at room temperature for 16 hours. The reaction mixture was diluted with 500 ml.

50 of water, alkalinized with solid sodium carbonate and extracted three times with 150 ml portions of ethyl acetate. The combined ethyl acetate extracts were dried over sodium sulfate, triturated and evaporated to give a solid. This solid is added to boiling methanol, decolorized with activated carbon and

concentrated to a small volume. The resulting solid is collected and dried, thus obtaining 90 mg (5%) of 2-guanidino-4- (4-imidazo-1) -thiazole, similar to that of example 3 according to thin-layer chromatography and mass spectroscopy. .

Example 5. H-Bromo-4-methoxy-3-B-buten-2-one.

5.0 g (30 mmol) of 3-bromo-4-hydroxy-3-butene-2-one is dissolved in a mixture of 100 ml of tetrahydrofuran and 10 ml of water. 8.7 ml (90 mmol) of dimethyl sulfate and 8.3 g (100 mmol) of sodium bicarbonate are added to the solution. The suspension was stirred at 25 ° C for 75 minutes and the solvent was removed in vacuo. The resulting oil and solid are stirred overnight in a mixture of 20 ml of diethyl ether and 150 ml of 0.1N. sodium bicarbonate solution. The aqueous layer is separated and extracted with two 50 ml portions of ether. The combined ether extracts are washed with a saturated solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated in vacuo to a yellow small, which soon solidifies, and 3.21 g (59%) are obtained. bromo-4-label bc-3-buten-2-one, mp. 53-5b with

NMR (LMSO - dg), (): 8.02 (s, 1H) 4.03 (s, 3H) i 2.87 (s, 3N).

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

,

Calculated,%: C 33.55; H 3.94; -. Hr44.64.

Example 6. 1- (2-Methyl-1-imidazolyl) ethanone.

6.3 g (35 mmol) 3-bromo-4-methoxy-3-3-buten-2-one, 16.7 g acetamidine hydrochloride (175 mmol) and 29.2 ml of triethylamine (210 mmol) are combined in 300 ml tetrahydrofuran and refluxed for 6 hours. The solvent is removed in vacuo to a crude orange solid. The crude solid is dissolved in 200 ml of ethyl acetate and concentrated to 25 ml by distilling off the solvent by boiling. Ice-cooling leads to the crystallization of a yellow solid, which is collected by filtration, then first ethyl acetate.

40

45

-50 217258 "

tat, then ether and dried at 25 s under vacuum to obtain 9.995 g (23X) of 1- (2-methyl-1-imidazolyl) -ethane, m.p. 124-127 C.

5 NMR (DMSO-dfi), - (&): 4.61, (s, 1H), 1.41 (s, 3N); 1.39 (s, ZN).

Example 7. 1- (2-Methyl-4-imidazolyl) -ethanone.

5.75 g, (46.3 mmol) 1- (2-methyl 10 -1-imide zolyl) ethanone is dissolved in 600 ml of tetrahydrofuran and subjected to photolysis in a quartz flask using a ultraviolet light source with a short length

15 waves (253 nm) for 18 hours. The tetrahydrofuran solution is concentrated in vacuo to an oil and chromatographed on silica gel using 5% methanol in chloroform.

20 as eluent to give 2.6 g (45%) of 1- (2-methyl-4-imidazolyl) -ethanon, m.p. 123-125 C.

Example 8. Hydro-bromide 1- (2- -methyl-4-imidazolyl) -2-bromoethanone.

25 2.40 g (19.3 mmol) of 1- (2-methyl-4-imidazolyl) ethanone are dissolved in 30 ml of 48% hydrogen bromide. Over the 5-minute period, 3.36 g (21 mmol) of bromine dissolved in 5 ml of 48% hydrogen bromide are added to the stirred solution at 25 ° C. The reaction mixture is heated to 70 ° C for 2.5 then concentrated in vacuo35 to a dark oil. Add

a mixture of isopropyl alcohol and ether, and trituration of the oil gives a solid. This material was collected by filtration and washed with ether to give 268 g (51%) of 1- (2-methyl-4-imidazylyl) -2-bromoethanone hydrobromide, m.p. 181 C (decomp.).

NMR (DMSO - dg), (): 8.71 (s, 1H) j 4.77 (s, 2H); 2.63 (s, ZN).

Example 9. 2-Guanidino-4- (2-- -methyl-4-ikidazolsh1) -thiazole.

2.8 g (9.86 mmol) of 1- (2-methyl-4-imidazolyl) -2-bromoethanone hydrobromide are dissolved in 10 ml of water, the entire sodium bicarbonate solution is added to pH 10. The resulting solid is collected by filtration and washed with 15 ml of water. The dried free base is heated to reflux in 50 ml of acetone.

To the resulting bright acetone solution was added 1.2 g (9.86 mmol) of amidinothiourea. Immediately dissolves and after 1 minute a solid material begins to form. After one hour of heating under reflux, the suspension is cooled, the solid is collected by filtration and washed with acetone, followed by washing with ether to obtain 2.37 (79%) 2-guanidino-4- - (2-methyl-4-imidazolyl) -thiazole hydrobromide m.p. 158 With (razl).

NMR (DMSO - dg), (6): 6.71, (s, shoulder on broad s, 1H) 7.56 (broad s, 4H), 4.32 (s, IH); 2.51 (s, ZN).

Found,%: C 31.46; - And 4.30; N 27.28.

Calculated,%: C 31.69, H 3.66, N 27.72.

.Hbr

Example 10. 1-Acetyl-4-methylimidazole.

A mixture of 50 g (609 mmol) of 4-metsch1-imidazole in 250 ml of toluene was stirred at room temperature under a nitrogen atmosphere and 239 g (304 mmol) of acetyl chloride were added. The mixture was stirred at room temperature for 5 hours, filtered to remove insoluble substances, and the filtrate was concentrated to give 19 g (50%) of 1-acetyl-4-methylimidazole as a yellow oil, which crystallized on standing.

NMR (SDSg), (): 8.06, (s, 1H), 7.17 (s, 1H); 2.57 (s, ZN), 2.23 (s, ZN).

Example 11. 4-Acetyl-4-methyl imidazole.

A solution of 5.0 g (40.3 mmol) of 1-acetyl-4-methylimidazole in 700 ml of dry tetrahydrofuran is subjected to photolysis in a quartz flask using an ultraviolet: Go source of light with a short wavelength (254 nm) for 24 h. The tetrahydrofuran solution is concentrated in vacuo to give an oil which is chromatographed on a sitchel using 5% methanol in chloroform as eluant. 1.91 g (38%) of 5-acetnl-4-methylimidazole is formed in the form of a white solid, m.p. 140-142 S.%,

NMR (SDS1s7 D4-DMSO), (8): 7.45 (s, 1 2.52 (s, ZN), 2.48 (s, ZN).

Example 12. 1- (4-Methyl-5-them dazolyl) -2-bromoethanone.

A solution of 1.57 g (12.6 mmol) of 5- -acetyl-4-methylimidazole, in 15 ml of concentrated hydrobromic acid, is heated to 50 ° C and a solution of 2.01 g (12, 6 mmol) of bromine in 15 ml of concentrated hydrobromic acid. The mixture was stirred at 50 ° C for 1.25 hours, then concentrated. The residue is triturated with isopropyl alcohol, the white solid is collected by filtration to give 2.78 g (78%) of 1- (4-methyl-5-imidazolyl) -2-bromoethanone hydrobromide.

NMR (D TMSO), (): 9.40 (s, 1H); 4.87 (s, 2H), 2.65 (s, MN) ..

This material is converted to its free base by stirring for 15 minutes in 50 ml of all sodium bicarbonate solution, obtained after collecting and (1- (4-methyl-5-imidazolyl) -2-bromoethanone) after filtration and drying 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-α-methyl-5-imidazolyl) -2-bromzthanone in ml of acetate is heated until it becomes homogeneous. 0.96 g (8.13 mmol amidinodiourea) is added and the mixture is heated under reflux for 1 hour. The mixture is then cooled to room temperature, the resulting precipitate is collected by filtration. This substance is 0.98 g (40 %) 2-guanidino-4- (4-methyl-5-imidazolyl) -thiazole hydrobromide, mp. 245 s (decomp.).

NMR (), (S): 8.52 (s, 1H) i 7.67 (5, 4H), 7.20 (s, 1H); 2.49 (s, ZN).

Found: C, 31.80; H, 3.90; N, 26.90.

Calculated,%: C 31.69; H 3.66; N 27.72

C3H, j, rigS.HBr

Example 14. 1-Acetyl-2,4-dimethylimidazole.

A solution of 9.6 g (0.10 mmol) of 2,4-dimethylimidazole in 50 ml of chloroform and 50 ml of toluene is stirred

At room temperature, add 3.6 ml (0.05 mol) of acetyl chloride with a syringe for 1 minute. The mixture was stirred at room temperature for 2 hours, then filtered to remove insoluble solids, and the filtrate was concentrated to give 6.9 g (100%) of 1-acetyl-2,4-dimethyl-imidazole as a white crystalline solid.

NMR (CDSe), (S): 7.00 (s, 1H); 2.68 (s, 3N); 2.57 (s, 3N); 2.21 (s, ZN).

Example 15, 5-Acetyl-2,4-dimethylimidazole.

A solution of 6.9 g (0.05 mol) of 1- -acetyl-2,4-dimethylimidaz ol in 700 ml of dry tetrahydrofuran is subjected to photolysis in a quartz flask using a ultraviolet light source with a short wavelength (254 nm) for 10 hours. The tetrahydrofuran solution is concentrated in vacuo to give an oil which is chromatographed on silica gel using 5% methanol in chloroform as eluant to give 2.8 g (41%) of 5-acetyl--2,4-dimethylimidazole in a white solid, mp. 83-87 s. Recrystallization from isopropyl ether gives analytically pure material, mp. 87-88 ° C.

Mr (sdssez), () 2.53, (s, bn);

2.40 (s, 3N).

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

Calculated,%: C 60.85; H 7.30; N 20.27.

. .

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 is subjected to 50 ° C, 1.16 g is added dropwise within 1 minute (7, 25 mmol of bromine. The mixture is then heated at 50-60 ° C for 1 hour. The mixture is concentrated, the solid residue is triturated with 30 ml of saturated sodium bicarbonate solution. The insoluble matter is collected by filtration, rinsed with water and dried in vacuum, obtaining 1.12 g (71%) 1- ( 2,4-dimethyl-5-imidazolyl) -2-bromoethanone as a white solid, so pl. 128-132 C.

NMR (D DMSO), (S): 4.40 (s, 2H) j 5 2.27 (s, 3N) 2.13 (s, 3N).

Example 17. 2-guanidino-4- (2,4-dimethyl-4-imidazolyl) -thiazole hydrobromide hemihydrate.

A solution of 1.0 g (4.6 mmol) of 1- (2,4-0-dimethyl-5-imidazolyl) -2-bromine, the tanonon in 50 ml of acetone is heated and 0.55 g (4.6 g) is added. mmol) amidinothioureas. The mixture was heated under reflux for 5-1 hours, during which time a white solid precipitated. The precipitate is collected, washed with acetone and dried to obtain 1.12 g (77%) of 2-guanium-0-dino-4- (2,4-dimethyl-5-imidazolyl) -thiazole hydrobromide hemihydrate as a white solid, t. square 273 ° C (decomp.)

NMR (), (S): 8.4 - 7.2 (s, 7H) -, 7.00 (s, 1H); 2.50 (s, 3N); 5 2.38 (s, 3N).

Found,%: C 33.47; H 4.19, N 26.93; S 9.91.

Calculated,%: C 33.14; H 4.33; N 25.75; S 9.83. , 2 HBr 1/2

Example 18. 3-Bromo-4-ethoxy-3-butene-2-one.

A mixture of 400 ml of absolute ethanol and 60 ml of toluene is heated to reflux temperature and 20 ml of azeotropic solution. It is removed through a Dean-Stark trap. To the ethanol solution, 33.0 g (0.2 mmol) of 3-bromo-4-6xy-3-buten-0-2-one are added and heating under reflux is continued for 2 hours, during this period the three portions of 20 ml of a mixture of ethanol and toluene through a trap. The solution is concentrated in vacuo to give 38.6 g

(100%) 3-bromo-4-ethoxy-3-butene-2-one in the form of a mobile oil,

NMR (DMSO-D), (8): 8.21 (s, 1H), 4.23 (KB, 2H) -, 2.33 (s, 3N), 1.31 0 (s, 3N).

Example 19. 2-Oxymethyl-4-β-acetylimidazole.

9.7 g (0.05 mol) of 3-bromo-4-ethoxy-3-butene-2-one is mixed with 5.3 g of 5 (0.05 mol) of oxyacetyl-amine hydrochloride in 100 ml of acetone to form - Penza. 11.5 g (0.1 mol) of 1, 1,3,3-tetramethylguanidine was added to the suspension at 25 seconds over a period of 5 minutes. After stirring for 48; The suspension is filtered and the mother liquors are concentrated in vacuo until May, which is chromatographed on silica gel 60 (E. Merk) using chloroform as eluent to obtain 1.48 g (21%) of 2-hydroxymethyl-4-acetylimidazole. mp 147-148 ° C.

NMR (DMSO-Lr, (S): 7.73 (s, 1H); 5.46 (very wide s, 1H); 4.5 (wide s, 2H); 2.4 (s, ZN).

Example 20. 2- oxymethyl-4-bromoacetymimidazole hydrobromide,

1.856 g (0.013 mol) of 2-hydroxymethyl-1-4-acetylimidazole is dissolved in 40 m of 48% hydrobromic acid and 2.1 g (0.013 mol) of bromine is added. The reaction mixture is heated at 80 ° C for 2 hours and then concentrated in vacuo to a solid. This material is triturated with isopropyl ether and the resulting solid is collected by filtration, washed with ether and dried to give 2.2 g (56%) of 2-hydroxymethyl-4-bromoacetylimide ash hydrobromide, i.e. LLO 183 C ( different)

NMR (DMSO-L), (5): 8.8 Lm, 1H); 4.8 (s, 2 X 2H).

Example 21. Hydrobromide 2-gu anidino-4 (2-hydroxymethyl-4-imidazolyl) -thiazole.

1.78 g (0.0059 mol) of 2-hydroxymethyl-4-bromoacetylimidazole hydrobromide is dissolved in water, added sat-. Purified sodium bicarbonate solution to precipitate free base. This material is collected by filtration, dried and combined with 956 mg (0.0081 mol) of amidinothiourea in 60 ml of acetone and heated to 70 ° C. After heating for 15 minutes, a solid is formed. The reaction mixture was cooled and the resulting solid was collected by filtration to obtain 1.65 g (87%) of 2-guanrschino-4- (2-hydroxy-methyl-4-imidazolyl) -thiazole hydrobromide, mp. more A sample of the substance is converted to the free base by dissolving in hot water and adding solid sodium bicarbonate to pH 10 to precipitate 2-guanidino-4- (2-hydroxymethyl-4-imidazolyl) -thiazole as a free base. This substance is dried over toluene

in a high vacuum, obtaining a light reddish-brown solid, so pl. 208-209 0 (decomp.).

NMR (DMSO - dj), (S): 7.16 (s, 1H), 6.83 (broad s, 4H); 6.68 (s, H) i 4.45 (s, 2H), 3.46 (very wide s, 1H). High Resolution Mass Spectrum: calculated for CgHipNgOS 238.0638, found 238.0654.

New guanidine derivatives and their pharmaceutically acceptable acid addition salts have activity as antisecretory agents and histamine antagonists - H and act in such a way that they block the action of physiologically active histamine at the site of H - receptors and, thus, inhibit the secretion of gastric acid. The novel compounds and their salts may be beneficial in the treatment of increased gastric acidity and peptic ulcers, such as chronic gastric and duodenal ulcers and other painful conditions caused or exacerbated by the secretion of gastric acid.

The activity of new compounds as antisecretory agents and histamine-H antagonists can be determined using standard pharmacological tests, including, for example, measuring their ability to antagonize the action of histamine that is not blocked by an antihistamine like mepyramine, and measuring their ability to inhibit gastric juice in the stomachs of dogs Neidenhain previously treated with pentagastrin to stimulate the secretion of gastric juice

Data on the study of the biological activity of new compounds are presented in examples 22 and 23.

The table presents the data on the biological activity of new guanidine derivatives in comparison with cimetidine (1-cyano-2-methyl-imidazoyl-methylguanidine), which is similar in structure to the new compounds and is used as an anti-sequester and histamine antagonist - Hj.

Example 22. Activity against the inhibition of gastric acid secretion of new derivatives

guanidine is determined on the conscious neidenhain experimental dogs, which are starved during the night.

Pentagastrin (Ayerst pentavalent) is used to stimulate gastric acid by non-continuous administration into the superficial leg vein in doses previously defined as stimulating almost maximum absorption of acid from the gastric pouch. Gastric juice is collected at intervals of 30 minutes after the start of pentagastrin administration and measured with an accuracy of 0.1 ml. Ten samples are taken from each dog during the experiment. The acid concentration is determined by titration with 1.0 ml of gastric juice to a pH of 7.4. Using 0.1 n. sodium hydroxide using an auto burette and a pH meter with a glass electrode (radiometer).

90 minutes after the start of pentagastrin administration, an intravenous drug or carrier is given in a dose of 1 mg / kg. The effect of inhibiting gastric acid secretion is calculated by comparing the lowest acid release after drug administration with the average value of the acid release immediately before the drug.

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

Example 23. The activity of the proposed compound as histamine antagonist - H is determined using the following procedure.

Guinea pigs are quickly slaughtered with a blow to the head, the heart is removed and the right atrium is anatomized for free. The atria are suspended isometrically in a temperature-controlled tissue bath (32 ± 2 ° C) (10 ml) containing oxygen-rich (95% Oj; 5 % CO) is a Krebs Henseleit buffer solution (pH 7.4), and is allowed to stabilize for approximately 1 hour, during which the tissue bath is rinsed several times with water. Individual atrial contractions are monitored with a sensor from

change the power of contractions connected to the cardiotachometer and the IGrass recorder. After obtaining a curve showing doses responding to histamine, a bath containing each atrium is flushed several times with fresh buffer, and the atria return to their original values. After returning to the basic standards, test compounds are added and selected The curve of doses responding to histamine in the presence of an antagonist. The results are expressed as a dose ratio, a ratio of histamine concentrations required to obtain half the maximum stimulation in the presence and absence of an antagonist, and the apparent dissociation constant pA of the antagonist H, the receptor, is determined. The results obtained show that the compounds of examples 3, 9, 13, 17 and 21 have the pA values above ,. than 5.7.

Effect of 2-guanidino-4-heteroaryl-thiazoles as antagonists of hisstamine-Hg and antisecretory agents in comparison with cimetidine

It follows from the table that new guanidine derivatives, like cymetidine, interfere with the secretion of gastric juice, some of which considerably exceed its activity in this activity, and at the same time all these compounds are more active than cimetidine as antagonists of histamine - H.

The compounds of the invention can be used in the form of pharmaceutical compositions comprising an effective gastrointestinal anti-secretory ratio of the compound or its pharmaceutical acceptable acid addition salt, together with a pharmaceutically acceptable carrier or diluent. .

The novel compounds can be used to treat increased gastric acidity in animals in need of treatment by administering to the animal an effective gastro-anti-secretory amount of the compound or its acid additive salt.

The proposed compounds may be administered to a subject in need of treatment using known methods of administration, including oral and parenteral methods. Preferably, the compounds are administered orally. The compounds are administered orally in doses of from 0 to 1 mg / kg of body weight to be treated per subject, preferably 0.2-2.5 mg / day per day. If parenteral administration is required, then these compounds can be given in doses of 0.1-1.0 mg / kg of body weight of the subject being treated per day. However, some variations in dosages will necessarily be in place, depending on the condition of the subject being treated and the specific compound used.

The proposed compound can be administered alone or in a mixture with pharmaceutically acceptable carriers or diluents, in unit or multiple doses. Suitable pharmaceutical carriers include inert diluents or fillers, sterile aqueous solutions and various organic solvents. Pharmaceutical compositions formed by mixing new compounds or their salts with pharmaceutically acceptable carriers are readily prescribed for administration in a variety of dosage forms, such as tablets, powders, capsules, lozenges, or syrups. These pharmaceutical compositions, if necessary, may contain additional ingredients - flavoring and taste flavors.

substances binding or excipients. Thus, for oral administration, tablets containing various excipients, such as sodium citrate, can be used together with various disintegrating agents, such as starch, alginic acid, and some complex silicates, together with binding agents, such as polymers. vinylpyrrolidone, sucrose, gelatin and acacia.

Often lubricating agents are useful for tabletting purposes.

5 you, such as magnesium stearate, sodium lauryl sulfate and talc. Solid compositions of a similar type can also be applied as fillers in soft and hard filled ones.

0 gelatin capsules. Preferred materials for this purpose include lactose or milk sugar and high molecular weight polyethylene glycols. When aqueous suspensions or elixirs are required for oral administration, the main active ingredient in them can be combined with various sweetening or flavoring or flavoring agents; dyes or coloring agents, and, if necessary, emulsifying agents or suspending agents. , along with diluents such as water, ethanol,

5 propylene glycol, glycerin or mixtures thereof.

The proposed compounds are administered orally in the form of a dosage.

Q units, i.e. as the only physically discrete dosage unit containing the appropriate amount of the active compound in combination with a pharmaceutically acceptable carrier or diluent. These dosage unit forms are tablets or capsules containing from 5 to 1000 kg of the active ingredient, compounds

The Q of this invention is from 10 to 90% of the total weight of the dosage unit.

Solutions of new 5 compounds in sterile aqueous solutions, for example aqueous solutions of propylene glycol, sodium chloride, dextrose or sodium bicarbonate, can be used for parenteral administration.

15121725816

Such solutions should be made isotonic by means of a buffered manner, if an adequate amount of saline is used, and the liquid diluent is first solution or glucose.

Claims (2)

The method of obtaining derivatives 2-guanidino-4-heteroarylthiazole of the formula j ϊ ^η Wv ™ where Y is a —CH— group or> C is CH ₃ ; R is a hydrogen atom, oxymethyl or alkyl with 1-6 carbon atoms, or their pharmaceutically acceptable acid additive salts, characterized in that the compound of the formula o <e where R * and Y have the indicated meanings, 2 ’R is a bromine atom, is reacted with N-amidinothiourea in an organic solvent, such as acetone, at the boiling point of the reaction mixture, and the target product is isolated in free form or in the form of a pharmaceutically acceptable acid addition salt.