CS235970B2 - Method of 2-guanidino-4-triazolylthiazols production - Google Patents

Description

The invention relates to processes for the preparation of novel 2-guanidino-4-triazolylthiazoles. These novel compounds act as antisecretory agents and as antagonists of the Hg-histamine receptors and can therefore be used to prevent and treat gastric hyperacidity and peptic ulcers.

Chronic gastric and duodenal ulcers, which are collectively included under the term peptic ulcers, are a common disease which, depending on the severity and extent of the case, can be treated in a number of ways, including diet, chemotherapy and surgery. Particularly valuable therapeutic agents useful for the treatment of gastric hyperacidity and peptic ulcers are Hg-histamine antagonists which block the action of the physiologically active histamine compound on Hg-receptors in the animal body and thereby inhibit gastric acid secretion.

The present invention provides a process for the production of novel 2-guanidino-4-triazolylthiazoles useful as histamine Hg receptor antagonists and as antisecretory agents which can be used to treat peptic ulcers and other conditions caused or exacerbated by gastric hyperacidity.

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

in which

R represents an amino or C 1 -C 6 alkyl group, and pharmaceutically acceptable acid addition salts thereof, characterized in that the compound of formula (II) oh ₂ n

N (II), in which

R is as defined above, cyclized by heating in an aqueous medium, and the resulting compound of formula (I) is optionally converted by reaction with a pharmaceutically acceptable acid, rather than a pharmaceutically acceptable acid addition salt thereof.

The reaction temperature is from 75 to 110 ° C, preferably boiling.

Preferred are those compounds of formula I wherein R is amino or methyl.

The novel compounds produced by the process of the invention may be used in the form of pharmaceutical compositions comprising an antisecretorically effective amount of a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof together with 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 an antisecretorically effective amount of a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof. Preferred materials for this purpose are the above-described preferred compounds of formula (I) The starting materials of formula (II) above are prepared in two different ways depending on the meaning of R.

In the case where R represents a C 1-6 alkyl group, the starting materials of the formula II are obtained by reacting the compound of the formula II '

CONHR '(II ^Z ) in which

R 'is -NHg, reacted with a compound of formula

R @ ¹ C (NH) OR wherein R @ 1 is an alkyl group having from 1 to 5 carbon atoms and

R is C 1 -C 3 alkyl in the presence of a base

When R is amino, the starting materials of formula II are prepared by reacting the compound of formula II 'with methylisothiourea.

The starting material of formula (II) is prepared by reacting an alkyl halopyruvate, preferably ethyl bromopyruvate, with an N-aminothiourea in an organic solvent such as a lower C 1 -C 4 alkanol, preferably methanol or ethanol, at a temperature of from 0 ° C. to 100 ° C, preferably under reflux of the alcoholic solvent, to give the alkyl ester of 2-guanidino-4-thiazolecarboxylic acid. This ester is then reacted with hydrazine in a lower alcohol solvent, preferably absolute ethanol, at a temperature of from 0 ° C to 00 ° C, preferably under reflux of the alcoholic solvent to give the desired 2-guanidino-4- hydrazide. thiazolecarboxylic acids.

The hydrazide derivative prepared as described above is then reacted with an alkyl carboximidate of the formula RC (NH) OR wherein R is an alkyl group having up to 3 carbon atoms, preferably methyl or ethyl, or an acid addition salt thereof, preferably a hydrohalide such as hydrochloride or hydrobromide to give the corresponding 2-guanidino-4-thiazolecarboxylic acid 2-carboximidohydrazide. The reaction is carried out in an inert organic solvent, preferably a lower alkyl alcohol such as methanol or ethanol, in the presence of a base such as an alkali metal alkoxide, preferably sodium or potassium ethoxide, at a temperature of from 10 ° C to 100 ° C, preferably from 20 ° C to 75 ° C.

Compounds of formula II wherein R is -NHg may be prepared from the 2-guanidino-4-thiazolecarboxylic acid hydrazide described above by reaction with 2-methylisothiourea or an acid addition salt thereof such as a hydrohalide, preferably hydrochloride or hydrobromide. or with hemisulphate to form the corresponding 2-guidinidino-4-thiazolecarboxylic acid 2-amidinohydrazide. The reaction is generally carried out in an organic solvent such as dimethylsulfoxide at a temperature of from 50 ° C to 225 ° C, preferably from 180 ° C to 200 ° C.

The pharmaceutically acceptable acid addition salts of the novel compounds of formula (I) are readily prepared by treating the free base with the 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 free base compounds of formula (I) may be obtained from the acid addition salts by treatment with a suitable base followed by extraction of the desired free base compound with a suitable organic solvent.

The compounds of formula (1) and their pharmaceutically acceptable acid addition salts and acids have activity as antisecretory agents and as histamine Hg receptor antagonists and are therefore therapeutically valuable for the treatment of gastric hyperacidity and peptic ulcers. As used herein, the treatment of gastric hyperacidity includes treatment of peptic ulcers and other such conditions induced or impaired by gastric acid secretion. The disclosed compounds 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 orally administered at dosages of from 0.1 to 20 mg / kg of patient body weight per day, preferably from 0.2 to 2.5 mg / kg per day. If desired, the compounds may be administered at dosages of from 0.1 to 1.0 mg / kg patient body weight per day. It will be understood that, depending on the patient being treated and the compound selected, deviations from the above dosage will necessarily occur.

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 admixing 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 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 gelatin 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 mg 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. If necessary, these solutions are suitably buffered 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 I as antisecretory agents and histamine Hg receptor antagonists can be ascertained by standard pharmacological tests, including, for example, (1) measuring their ability to antagonize the effects of histamine not blocked by antihistamines such as mepyramine; inhibit gastric acid secretion in the stomach of dogs with Heidenhain's pocket that had been previously treated with pentagastrin to stimulate gastric acid secretion.

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

Example 1

2-Guanidino-4-thiazolecarboxylic acid ethyl ester

111.2 g (0.94 mol) of 2-amidinothiourea are dissolved in 1 liter of ethanol under reflux. To the refluxing solution was added 200 g (1.02 mol) of ethyl bromopyruvate rapidly over 10 minutes. After refluxing for 2 hours, an additional 20 g (0.1 mol) of ethyl bromopyruvate was added and heating was continued for 2 hours. The reaction mixture is cooled to 10 ° C and its pH is raised to 10 with concentrated ammonium hydroxide solution. The precipitated solid product is filtered off and, after washing twice with ether, dried in vacuo. 176.4 g (88%) of 2-guanidino-4-thiezolecarboxylic acid ethyl ester, melting at 229 DEG-230 DEG C. with decomposition, is obtained.

Example 2

2-Guanidino-4-thiazolecarboxylic acid hydrazide

16.7 g (0.0779 mol) of 2-guanidino-4-thiazolecarboxylic acid ethyl ester are mixed with 25 ml (0.514 mol) of hydrazine hydrate in 200 ml of absolute ethanol. The suspension is heated to reflux. After refluxing for 1.5 hours, a solid product began to precipitate from the initially clear solution. After refluxing for 2 hours, the reaction mixture was cooled, the solid product was filtered off and washed with isopropyl alcohol and ether. 12.8 g (82%) of 2-guanidino-4-thiazolecarboxylic acid hydrazide, melting at 247 DEG C. with decomposition, is obtained.

Example 3

2-Guanidino-4-thiazolecarboxylic acid 2-amidinohydrazide hemisulfate 7.9 g (0.089 mol) of 2-guanidino-4-thiazolecarboxylic acid hydrazide are mixed with 24.9 g (0.089 mol) of 2-methyl-2-thioisourea sulfate and the mixture was rapidly heated to reflux in 25 ml of dimethyl sulfoxide. The reactants were dissolved and a heavy precipitate formed during the reflux for 5 minutes. The reflux was continued for a total of 30 minutes. The reaction mixture is cooled, the precipitate formed is filtered off, washed first with a small amount of dimethylsulfoxide and then with isopropanol and ether.

After drying the solid material under vacuum, 34.6 g of 2-guanidino-4-thiazolecarboxylic acid 2-amidinohydrezide containing some crystalline dimethyl sulfoxide are obtained.

Example 4

2-guanidino-4- (3-amino-5,1,2,4-triazolyl) thiezole

29.1 g (0.1 mol) of 2-guanidino-4-thiazolecarboxylic acid 2-amidinohydrazide hemisulphate are heated to boiling with 250 ml of concentrated ammonium hydroxide. The volume drop caused by the loss of ammonia is compensated by the addition of additional ammonium hydroxide. After heating for 8 hours, boiling is continued until the pH drops below 8.0 and the reaction mixture is allowed to cool. The precipitated solid material was filtered off, washed with a small amount of water, clarified with activated charcoal, recrystallized from water and dried in vacuo. 10.8 g (48%) of 2-guanidino-4- (3-amino-5,1,2,4-triezolyl) thiazole of melting point 173-175 ° C are obtained.

NMR (CDCl3): 7.07 (singlet, 1H), 6.93 (broad singlet, 4H), 5.53 (broad singlet, 2H),

For C ₆ H ₈ N _and S calculated: 32.14% C, 3.60% H, 49.97% N;

Found: C, 32%; H, 3.70; N, 50.15.

Example 5

2-Guanidino-4-thiezolecarboxylic acid 2-ecetiminohydrazide

37.1 g (0.3 mol) of ethyl acetimidate hydrochloride are dissolved in 200 ml of absolute ethanol and to this solution is added a solution of sodium ethoxide prepared from 6.9 g (0.3 mol) of sodium in 300 ml of absolute ethanol. The precipitated sodium chloride was filtered off and 20.0 g (0.1 mol) of 2-guanidino-4-thiazolecarboxylic acid hydrazide was added to the clear filtrate. The resulting slurry was stirred at 25 ° C for 60 hours to completely dissolve all solids. The clear, light orange solution was concentrated in vacuo to a soft solid residue, which upon trituration with ethyl acetate / ethanol (10: 1) gave 24.0 g (88) of 2-guenidino-4-thiazole-11-arboxylic acid crude 2-acetiminohydrazide melting with decomposition. in a wide range of 150-178 ° C.

Example 6

2-guanidino-4- (3-methyl-5-1,2,4-triazolyl) thiazole hemihydrate

2-Guanidino-4-thiazolecarboxylic acid 2-acetiminohydrazide (23.0 g, 0.095 mol) was heated to boiling with 200 ml of concentrated ammonium hydroxide solution. The drop in volume due to ammonia losses is compensated by the addition of additional ammonium hydroxide. After heating for 7 hours, the boiling was continued until the pH dropped below 8.0 before allowing the mixture to cool. The solid product was filtered off, washed with a small amount of water and dried at 110 ° G / 13 Pa for 24 hours. 8.6 g (39%) of 2-guanidino-4- (3-methyl-5-1,2,4-triazolyl) thiazole hemihydrate are obtained, melting at 185 ° C (loss of water) and then decomposing at 260 ° C. Deň: 32 ° C.

NMR (CDCl 3) 7.22 (singlet, 1H), 6.90 (broad singlet, 4H), 3.50 (broad singlet, 1H-HgO), 2.32 (singlet, 3H).

For G ₇ H ₉ N ₇ Sl / 2 HgO calculated: 36 '9% C, 4.34% H, 42.22% N;

Found: C, 36.43; H, 4.29; N, 42.17.

Example 7

2-Guanidino-4-thiazolecarboxylic acid 2-butyriminohydrazide

To 2.90 g (14.48 mol) of 2-guanidino-4-thiazolecarboxylic acid hydrazide in 50 ml of dry ethanol is added 29.1 mmol of ethyl butyrimidate prepared from 4.41 g (29.1 mmol) of ethylbutyrimidate hydrochloride, the resulting suspension was stirred at 25 ° C for 5 days, then filtered. The solid product was washed with ethanol and ether, and dried. 3.071 g (78%) of 2-guenidino-4-thiazolecarboxylic acid 2-butyriminohydrazide are obtained.

Example 8

2-guanidino-4- (3-propyl-5, 1,2-triazolyl) thlazole hemihydrate

2.547 g (9.5 mmol) of 2-guanidino-4-thiazolecarboxylic acid 2-butyriminohydrazide were heated at reflux for 2 hours in 50 ml of water. The reaction mixture was cooled and the solid product was recrystallized from 150 ml of a 4: 1 mixture of water and ethanol. There was obtained 1.119 g (47%) of 2-guanidino-4- (3-propyl-5-1,2,4-thiazolyl) thiazole hemihydrate, melting at 268-270 ° C with decomposition.

NMR (CDCl 3): 13.68 (broad singlet, 1H), 7.18 (singlet, 1H), 6.90 (broad singlet, 4H), 2.64 (triplet, 2H), 1.70 (multiplet, 2H1, 0.90 (triplet, 3H)).

H, 5.42; N, 37.66.

Found: 41.81% G, 5.50% H, 38.10% N.

Example 9

2-Guanidino-4-thiazolecarboxylic acid 2-propioniminohydrezide

2.90 g (14.48 mmol) of 2-guanidino-4-thiazolecarboxylic acid hydrazide in 50 ml of dry ethanol were stirred at 25 ° C for 5 days with 29.1 mmol of ethyl propionimidate prepared from 4.0 g (29 g). , 1 mmol) of ethyl propionimidate hydrochloride. The resulting suspension was filtered and the solid product was dried under vacuum at 60 ° C for 2 hours to give 2.802 g (75%) of 2-guanidino-4-thiazolecarboxylic acid 2-propioniminohydrazide.

Example 10

2-guanidino-4- (3-ethyl-5-1,2,4-triazolyl) thiazole

2.72 g (10.7 mmol) of 2-guanidino-4-thiazolecarboxylic acid 2-propionimino-anhydride were heated to reflux in 50 ml of water for 2 hours. After cooling the reaction mixture, a solid precipitated which was stirred with 200 ml of boiling water. A small amount of insoluble material was filtered off and the solution was cooled to give a white solid. Subsequent recrystallization twice from water gave 1.048 g (41%) of 2-guanidino-4- (3-ethyl-5-1,2,4-triazolyl) thiazole, melting at 251-257 ° C with decomposition.

NMR (δ): 13.80 (broad singlet, 1H), 7.27 (singlet, 1H), 6.95 (broad singlet, 4H), 2.70 (quartet, 2H), 1.25 ( triplet, 3H).

H, 4.67; N, 41.32.

Found:% C, 40.61;% H, 4.60;% N, 40.50.

They did

The efficacy of the compounds of the invention for inhibiting gastric acid secretion is revealed in the waking pseoh with a Heidenhain pocket who were left fasting overnight. To stimulate acid secretion, pentagastrin (Pentavlon-Ayerst) is applied by continuous infusion into the superficial vein of the dog's paw at doses previously found to stimulate near maximal acid secretion from the stomach bag. From the beginning of the pentagastrin infusion, gastric glory has been collected at three minute intervals and measured to within 0.1 ml. 10 samples are taken from each dog during the experiment. The acid concentration was measured by titration with 1.0 ml of gastric glory to pH 7.4 with 0.1 N sodium hydroxide using an automatic burette and a pH electrode with a glass electrode (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. The 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 4, 6, 8 and 10 generally inhibit gastric acid secretion by at least 15% when administered at a dose of 1 mg / kg.

Example 12

The antagonist activity of the compounds of the invention on the 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 and isometrically suspended in a tissue bath (10 ml oxygenated (95% Og, 5% Krebs-Henseleit buffer (pH 7.4)) maintained at 32 ° C. + 2 ° C, where it is allowed to stabilize for about 1 hour, during which time the tissue bath is replaced several times, and individual atrial contractions are monitored using a force transducer coupled to a cardiotachometer and a grass printing device. response to the applied histamine dose, the bath with each atrium is flushed several times with fresh buffer, and the number of atrial contractions per unit of time is re-equilibrated to baseline, after reaching this baseline the test substance is introduced at a predetermined final concentration. on the histamine dose, this time in the presence The results are expressed as dose ratios, i.e. the ratio of the concentrations of histamine required to achieve half maximal stimulation in the presence and absence of the antagonist, and the apparent dissociation constant of the Hg-receptor antagonist, called pAg, is determined.

The results show that the compounds of Examples 4, 6, 8 and 10 have pAg values greater than 5.7.

Claims (1)

SUBJECT OF THE INVENTION A process for the preparation of 2-guanidino-4-triazolylthiazoles of the formula I N = r a) r h ₂ ncnh— in which. R represents araino or C 1 -C 6 alkyl group and pharmaceutically acceptable acid addition salts thereof, characterized in that the compound of formula (II) NH *, _ H ₂ NCNH-ol HjN R In (II), in which R is as defined above, heated to boiling in an aqueous medium, whereupon the resulting compound is optionally converted into a pharmaceutically acceptable acid addition salt by reaction with a pharmaceutically acceptable acid. Severography, n. P., Mos Price 2,40 Kčs