CS235969B2 - Method of 2-guanidine-4-thiazolylthiazols production - Google Patents

Abstract

The present invention relates to a process for the preparation of new 2-guanidino-4-thiazolylthiezoles. These new ones the compounds act as antisecretory agents as histamine Hg-receptor antagonists, and can therefore be used to prevent and treat gastric hyperacidity and peptic ulcers. Chronic gastric and duodenal ulcers, which are collectively encompassed by the term peptic ulcers are a common disease that is possible, depending on severity and the extent in which case, cure by a variety of ways, including dieting, chemotherapy and surgery. Delivered with valuable therapeutic agents useful for treating hyperacidity gastric and peptic ulcers are histamine Hg-receptor antagonists that block the action of the physiologically active histamine compound on the H2-receptors in the animal's body and thereby inhibit gastric acid secretion. The invention provides a process for the preparation of novel 2-guenidino-4-thiazolylthiazoles useful as histamine H 1 -receptor antagonists and as antisecretory agents can be used to treat peptic ulcers and other conditions caused by or exacerbated by hyperacidity stomach. Accordingly, the present invention provides a process for the preparation of 2-guanidino-4-thiazolylthiazoles of formula (I)

Description

The present invention relates to a process for the preparation of novel 2-guanidino-4-thiazolylthiezoles. These novel compounds act as antisecretory agents st 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 that, depending on the severity and extent of each case, can be treated in a variety of ways including diet, chemotherapy and surgery. Especially valuable therapeutic agents useful in the treatment of gastric pre-acidification and peptic ulcers are Hg-histamine antagonists that block the action of the physiologically active histamine compound on the H ₂ -receptors in the animal and thereby inhibit gastric acid secretion.

The present invention provides a process for the production of novel 2-guenidino-4-thiazolylthiazoles useful as histamine H 1 -receptor antagonists and as antisecretory agents that 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-thiazolylthiazoles of formula I

35 9 69 in which

R is hydrogen, -NH ₂ , -NHR 4 or NHCOR, wherein R 1 is C 1 -C 6 alkyl, and pharmaceutically acceptable acid addition salts thereof;

(II) in which

R is halogen, reacted with a compound of formula

RC (S) NH ₂ in which

R is as defined above, whereupon the optionally obtained compound of formula I in which R is -NH ₂ is reacted with the corresponding alkyl halide to give the corresponding compound wherein R is -NHR 3, wherein R 1 is as defined above, or with a halide or anhydride of the appropriate carboxylic acid to form the corresponding compound wherein R is -NHCOR, wherein R, as defined above, and the resulting compound of Formula I is optionally converted by reaction with a pharmaceutically acceptable acid to its pharmaceutically acceptable editing salt. with acid.

Preferred are those compounds of formula I wherein R represents hydrogen, -NH₂, -NHCH _3, or -NHCOCH

The compounds according to the invention can be used in the form of pharmaceutical compositions containing 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 preferred compounds of formula (I) described above as active agents.

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 preferred compounds of formula I described above.

In accordance with the invention, the novel compounds of formula (I) are prepared from the corresponding novel intermediates of formula (II) in which R is a halogen atom, preferably chlorine or bromine, most preferably thunder. The starting materials of formula (II) are prepared from 1,4-dihelogen-2,3-butanedione, preferably 1,4-dihromo-2,3-butanedione, by reaction with an excess of a tri-alkyl orthoformate, preferably triethyl orthoformate, in the presence of a catalytic amount of a strong acid such as concentrated sulfuric acid or p-toluenesulfonic acid, at a temperature of from 0 ° C to 55 ° C, preferably from 15 ° C to 25 ° C.

and

234 9 69

The 4-dihalo-2,2-dialkoxy-3-butane thus formed is then reacted with N-amidinothiourea in an organic solvent such as tetrahydrofuran, dioxene or ether at a temperature of from 0 ° C to 55 ° C, preferably from 20 ° C to 50 ° C, to give 2-guanidino-4- (2-halo-1,1-dialkoxyethyl) thiazole. The latter compound is heated in a solution of hydrogen halide, preferably hydrogen bromide, to a temperature of from 0 ° C to 50 ° C, preferably from 20 ° C to 30 ° C, to give the precipitated 2-halo-1- (2-guanidino-4). (thiazolyl) ethanone, i.e. a compound of formula (II) above wherein R is halogen, preferably bromine.

Compounds of formula I may be prepared directly from the corresponding intermediate 2-halo-1- (2-guanidino-4-thiazolyl) alkanone of formula II by reaction with the corresponding compound of formula RC (S) NH ₂ . Thus, for example, reaction of the intermediate 2-halo-1- (2-guanidino-4-thiazolyl) ethanone with thiourea or NR 1 -substituted thiourea affords compounds of formula I wherein R is NHR, while reaction with thioformamide yields a compound wherein R is hydrogen.

The reaction of 2-halo-1- (2-guanidino-4-thiazolyl) alkanone with the corresponding compound of formula RC (S) NH ₂ is generally carried out at a temperature of from 0 ° C to 30 ° C, preferably from 20 ° C to 30 ° C. ° C, in an inert solvent such as dimethylformemide or other polar organic solvents.

Alternatively, compounds of general formula I wherein R is -NHR ,, wherein R represents an alkyl group as defined above, also be prepared by reacting the corresponding compounds of formula I wherein R is _-NH2 with an appropriate alkyl halide in the presence of a base . Similarly, compounds of formula I in which R is -NHCOR may be prepared by reaction of the corresponding compounds of formula I in which R is -NHg with a halide or anhydride of the corresponding carboxylic acid.

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, ipalate, 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 as the free base with a suitable organic solvent.

The compounds of formula (I) and their pharmaceutically acceptable acid addition salts have activity as antisecretory agents and as histamine H ₂ -receptor antagonists and are therefore of therapeutic value 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 caused 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, ubecně _d e compounds may be orally administered in doses from 0.1 to 20 mg / kg of patient body weight per day, preferably from 0.2 to 2.5 mg / kg daily. If parenteral administration is desired, the compounds may be administered at doses of from 0.1 to 1.0 mg / kg of patient body weight per day. It will be understood that variations from the above dosage will necessarily occur depending upon the patient being treated and the compound selected.

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The compounds produced by the method of the 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 the formula I or their salts 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, and 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 in the preparation of 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 divided 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 dosage unit.

For parenteral administration, solutions of the compounds of formula I in sterile aqueous solutions, for example aqueous propylene glycol, sodium chloride, dextrose or sodium bicarbonate solutions, can 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 I as antisecretory agents and H ₂ -receptor histamine antagonists can be determined by standard pharmacological tests, including, for example, (1) measuring their ability to antagonize the effects of histamine not blocked by antihistamines such as mepyramine; the ability to inhibit gastric acid secretion in the stomach of dogs with Heidenhain's pocket that had been previously administered pentagastrin to stimulate gastric acid secretion.

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

EXAMPLE 1 1,4-Dibromo-2,2-diethoxy-3-butanone

A mixture of 1,4-dibromo-2,3-butanedione (40 g, 0.164 mol), triethyl orthoformate (60 ml, 0.36 mol) and concentrated sulfuric acid (2 ml) was stirred at room temperature for 14 hours, then diluted with chloroform (600 ml). Wash with 100 ml of water, 0.5 N hydrochloric acid and 100 ml of saturated sodium chloride solution.

The organic solution was dried over anhydrous sodium sulfate, filtered and evaporated to an oily residue. The oily material is taken up in 300 ml of hexane and the solution is freed from insoluble materials by filtration. The hexane filtrate is cooled in a solid carbon dioxide bath in acetone and the precipitate formed is filtered off. After drying, 44 g (84%) are obtained.

1,4-dihromo-2,2-diethoxy-3-butanone as a white crystalline solid, m.p. 40-41.5 ° C.

NMR (δ '): 4.50 (singlet, 2H), 3.6 to 3.2 (multtplet, 6H),

1.22 (triplet, 6H).

Example 2

2-guanidino-4- (2-bromo-1,1-diethoxyethyl) thiazole

A mixture of 1,4-dibromo-2,2-diethoxy-3-butanone (25.5 g, 80 mmol), N-amidinothiourea (11.8 g, 100 mmol) and tetrahydrofuran (150 ml) was heated at reflux for 3 hours. The reaction mixture was filtered to remove some insoluble solids and the filtrate was concentrated. The residue was triturated with 200 ml of saturated sodium bicarbonate solution and then extracted with a total of 500 ml of ethyl acetate in 4 portions. The combined ethyl acetate extracts were dried over sodium sulphate and evaporated. The solid residue gave 9.7 g (36%) of 2-guanidino-4- (2-bromo-1,1-diethoxyethyl) thiazole as a white solid after recrystallization from 250 ml of acetonitrile with decolorizing charcoal, m.p. 158 ° C.

For C ^ HH ^ Íi ^OgSSO: C, 35.62; C, 5.08. N, 16.61; Br, 23.69; S, 9.51;

Found: C, 35.60; H, 4.97; N, 16.99; Br, 23.75; S, 9.59.

Example 3

2-Bromo-1- (2-guanidino-4-thiazolyl) ethanone hydrobromide

A mixture of 9.5 g (28 mmol) of 2-guanidino-4- (2-bromo-1,1-diethoxyethyl) thiazole and 50 ml of 48½ hydrobromic acid was stirred at room temperature for 15 hours. The reaction mixture was evaporated to dryness to give 10.1 g (100%) of 2-bromo-1- (2-guanidino-4-thiazolyl) ethanone hydrobromide, melting at 247 ° C. This material can be converted to the free base by trituration with saturated sodium bicarbonate solution, stirring for 15 minutes, filtering off the solid product and drying under vacuum. In this way, 3.0 g of the hydrobromide was converted to 1.7 g (83%) of the free salt melting at 210 ° C with decomposition.

NMR (DMSO-d 6): 7.84 (singlet, 1H), 6.92 (singlet,

4H), 4.78 (singlet, 2H).

Example 4

2-guanidino-4- (2-amino-4-thiazolyl) thiazole dihydrobromide

Rottok 688 mg (2.0 mmol) of 2-bromo-1- (2-guanidino-4-thiazolyl) ethanone hydrobromide and 183 mg of thiourea in 5 ml of dimethylformamide are stirred at room temperature. After a short time a solid precipitate began to precipitate from the solution. After a total of 4 hours, the solid product was filtered off, washed with ethyl acetate and dried. 595 mg (74%) of 2-guanidino-4- (2-amino-4-thiazolyl) thiazole dihydrobromide are obtained in the form of a white powder, melting with decomposition at 320 ° C. The mass spectrum of the product contains a signal at 240 for the corresponding free base.

234 9 69

The above product can be converted to the free base by trituration with saturated sodium bicarbonate solution, stirring for 15 minutes, filtering off the solid material and drying in vacuo. There was thus obtained 2-guanidino-4- (2-amino-4-thiazolyl) thiazole as a crystalline solid, m.p. 274 ° C.

Analysis: Calculated: C, 34.99; H, 3.36; N, 34.97.

Found: C, 34.94; H, 3.41; N, 34.80.

Example 5

2-guanidino-4- (4-thiazolyl) thiazole

A mixture of thioformamide (1.8 g, 5.2 mmol) (5.5 mmol) was then concentrated and the residue was washed with acetonitrile with thiazole-hydrobromide.

2-bromo-1- (2-guantdino-4-thiazolyl) ethanone hydrobromide, 0.34 g, 0 ml of dimethylformamide was stirred at room temperature for 2 hours, triturated with ecetonitrile. The resulting precipitate was filtered off and dried. This gives 1.74 g (85%) of 2-guenidino-4- (4-thiazolyl). This product is dissolved in 10 ml of water and 1 ml of saturated sodium bicarbonate solution is added to the solution. The precipitate formed is filtered off, washed thoroughly with water and then with acetonitrile and dried under vacuum. 11 g of 2-guan are obtained. di-4- (4-thiazolyl) thiazole as a white solid, m.p. 220-222 ° C.

NMB (Perdeuterodimethylsulfoxide, δ): 8.96 (singlet, 1H), 7.96 (stnglet,, H),

7.18 (singlet, 1H), 7.0 (broad signal, 4H).

H, 3.13; N, 31.09. Found: C, 36.94; H, 3.52; N, 29.74.

Example 6

2-guanidino-4- (2-N-methylamino-4-thi-zolyl) thi-zole

A mixture of 2-bromo-1- (2-guanidino-4-thiazolyl) ethanone hydrobromide (1.77 g, 5.14 mmol), N-methylthiourea (0.49 g, 5.5 mmol) and dimethylformamide (10 ml) was stirred for 18 hours. The mixture was stirred at room temperature, then concentrated and the residue triturated with a small amount of acetone / tril. The crude solid was filtered off, dissolved in water, basified with saturated sodium bicarbonate solution and the precipitate was filtered off. Drying and recrystallization from ethanol-water gave 0.70 g (54%) of 2-guanidino-4- (2-N-methylemino-4-thiazolyl) thiazole as a white solid, m.p. 267 ° C.

NMR (CDCl 3 δ): 7.44 (quartet, 1H), 7.0 to 6.9 (singlet + singlet + broad signal, 6H), 2.85 (triplet, 3H).

H, 3.96; N, 33.05 _. Found: C, 37.77; Found: C, 38.01; H, 4.47; N, 32.84.

Example 7

2-guanidino-4- (2-N-8-acetylamino-4-thiazolyl) thiazole

A mixture of 1.77 g (5.14 mmol) of 2-bromo-1- (2-guenidino-4-thiezolyl) ethanone hydrobromide,

0.65 g (5.5 mmol) of N-acetylthiourea and 10 ml of dimethylformamide were stirred at room temperature for 18 hours. The reaction mixture is concentrated, the residue is triturated with scetonitrile, the solid material is filtered off, taken up in 50 ml of saturated sodium bicarbonate solution and stirred for 1 hour. The solid product was filtered off and allowed to dry. Recrystallization from aqueous ethanol gave 1.0 g (68 361 of 2-guanidino-4- (2-N-acetylamino-4-thiazolyl) thiazole) as a white solid, m.p. 288 ° C.

NMR (CDCl 3, δ): 7.40 (singlet, 1H), 7.0 to 6.9 (broad signal, 5H), 3.2 (broad signal, 1H), 2.22 (singlet, 3H).

For C ^ HH ^ NN ^O ^ N requires C, 38.13; H, 3.57;

found. 38.13 56 C, 4.07 H, 29.41 36 N.

Example 8

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 almost maximal acid secretion from the stomach bag. From the beginning of the pentsgastrin infusion, the gastric tendons have been collected at 30 minute intervals, the volume of which varies to within 0.1 ml. 10 samples are taken from each dog during the experiment. The acid concentration was determined by triturating 1.0 ml of gastric glory 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, 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 with the average acid secretion before administration of the test substance.

The results obtained show that the compounds of Examples 4, 5, 6 and 7 generally inhibit gastric acid secretion by at least 15% when administered at a dose of 1 mg / kg.

Example 9

The antagonistic activity of the compounds of the invention to the Hg-histamine receptors is determined as follows.

The guinea pig is quickly killed by a wound to the head and the right atrium is removed from their heart, which is isometrically suspended in a tissue bath of 10 ml oxygenated (95 56 O, 5 36 CO ₉ )

- + * o

Krebs-Henseleit buffer (pH 7.4)], the temperature of which is maintained at 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 shift transducer coupled to a cardlotachometer and a polygraph recording device (Gross). 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 time is re-calibrated to baseline. Upon reaching this baseline rate, the test substance is introduced into the bath at a predetermined final concentration and the response curve of the

235 9 6 9 dose of histamine, this time in the presence of antagonists. 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 antagonists, and reveal the apparent dissociation constant of Hg-receptor antagonists, called pAg.

The results show that the compounds of Examples 4, 5, 6 and 7 have pAg values greater than 5.7.

Claims (1)

Process for the preparation of 2-guanidino-4-thiazolylthiazoles of general formula (I) N = f CD NH N-π ¹¹ II H _Z NCNH in which R represents a hydrogen atom, a group -NHg, -NHR, or -NHCOR ₁ , wherein R ₁ represents an alkyl group having 1 to 1. And pharmaceutically acceptable acid addition salts thereof, characterized in that the compound of formula (II) in which: R is halogen, reacted with a compound of formula RC (S) NHg in which R is as hereinbefore defined, whereupon optionally, a compound of formula I wherein R is -NHg is reacted with an appropriate alkyl halide to give the corresponding compound wherein R is -NHRp wherein R ^ is as defined above, or a halide or anhydride of the appropriate carboxylic acid to give the corresponding compound wherein R is -NHCORp wherein R 1 is as defined above, and the resulting compound of formula I is optionally converted by reaction with a pharmaceutically acceptable acid to its pharmaceutically acceptable acid addition salt.