CS240951B2 - Production method of guanidine heterocyclic derivatives - Google Patents

Abstract

Way production heterocyclic derivatives guanidine general formula AND CF, CH, NH ^ _ from - '' N-fc 3 2 C = N-C WITH X , C-A - 7 ~ ch 3 H 2 N Xi / ve which θ X means pyrimidine ring linked in positions 2 and 4 , or pyridine ring and AND represents tetramethylene or thiotrlmethylene residue, and their addition salts with acids, vyzna # cing se by that se compound general formula II CF, CH-NH NH J > C-N-C IN X C-A-C / 11 / h 2 n - '^ ^ NH 2 ve which X and AND they have above said importance, or her addition salt with acid, leave it respond with ethyl 2-formyl propionate, načež se optionally final compound general formula AND, resulting ve form loosely base, reactions with acid providing farmaceutic # ky usable anion Converts on addition salt with acid. Produced compounds they are H-2 antagonists you histamine and they inhibit secretion gastric acid.

Description

The present invention provides a process for the preparation of heterocyclic derivatives which are H-2 histamine antagonists and inhibit gastric acid secretion.

It is believed that the physiologically active substance histamine, which is naturally present in the animal's organism, is capable of binding to certain specific receptors of at least two different and different types when exhibiting its activity.

First J. Pharmac classic

Second 1972, 236, cimetidine.

of these receptors was named as the H-1 receptor (see Ash and Schild, Brit.

, 1966, 27, 427) and the effect of histamine on this receptor is blocked (antagonized) by antihistamines, such as mepyramine.

the histamine receptor has been named as the H-2 receptor (see Black et al., Nature, 385) and the effect of histamine on this receptor is blocked by such agents as

It is known that one of the results of blocking the effect of histamine on the H-2 receptor is the inhibition of gastric acid secretion and that a compound exhibiting this ability is therefore useful in the treatment of gastric ulcers and other conditions caused or re-induced by gastric acidity.

GB2O52478A and GB2O558OOA disclose H-2 histamine receptor antagonists which are 2-guanidinothiazole derivatives bearing a side chain at the 4-position to which a substituted amidino group is attached.

It has now been found that haloalkylguanidinoheterocycles bearing a side chain to which an optionally substituted amidino group is attached are potent antagonists of the H-2 receptors of the histamine.

Accordingly, the present invention provides a process for the preparation of the heterocyclic guanidine derivatives of formula (I)

/ 1 / in which

X represents a pyrimidine ring attached at positions 2 and 4, or a pyridine ring and

A represents a tetramethylene or thiotrimethylene residue, and their acid addition salts, characterized in that the compound of formula II / CF ₃ CH ₂ NH nh

C-N-C

CAC / 11 / h ₂ n

IH in which

X and A are as hereinbefore defined, or an acid addition salt thereof, reacted with ethyl 2-formylpropionate, followed by optionally converting the resulting compound of formula II resulting in the free base into an acid addition salt with a pharmaceutically acceptable anion. with acid.

Specific compounds produced by the process of the invention are described in the Examples. The following compounds are preferably produced:

4-hydroxy-5-methyl-2- [3- [2- [2- (2,2,2-trifluoroethyl) guanidino] pyridin-6-yl] propyl] pyrimidine (Example 1),

4-hydroxy-5-methyl-2- [4- [2- (2,2,2-trifluoroethyl) guanidino] pyrimid-2-yl] butyl] pyrimidine (Example 2) and their pharmaceutically acceptable acid addition salts.

Suitable pharmaceutically acceptable acid addition salts of the guanidine derivatives of the invention are, for example, salts with hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, acetic acid, citric acid or maleic acid.

The process of the invention may be carried out in a diluent or solvent such as methanol or ethanol and may be accelerated or completed by heating, for example by heating to the boiling point of the diluent or solvent.

The starting materials used in the process according to the invention can be prepared by the methods described in the examples.

As mentioned above, guanidine derivatives produced by the method of the invention are H-2 histamine antagonists, inhibit gastric acid secretion in warm-blooded animals and are therefore useful in the treatment of gastric ulcers and other conditions caused or re-induced by gastric acidity including ulcers from stress and gastrointestinal bleeding due to injury.

Efficacy to antaigonize H-2 histamine receptors can be demonstrated by standard assays, such as the ability of compounds of Formula I to inhibit histamine-induced positive chronotropic response in spontaneously beating guinea pig atrium or their ability to inhibit histamine-induced aminopyrine consumption in the acidic area of endothelial cells.

The guinea pig atrium test is performed as follows:

The right atrium of the guinea pig is suspended in a 25 ml thermostatically controlled (30 ° C) tissue bath containing oxygenated (95% 0.5%, 5% CO 3) Krebs-Hanseleite buffer (pH 7.4) at a tension of 1 g (isonetrically).

The tissue is allowed to stabilize for 1 hour, during which time it is washed two to four times. Individual contractions are recorded by a force transducer through an extensometric coupler and the instantaneous velocity is monitored with a cardiotachometer.

A control response to 1 µM histamine is observed, and the tissue is washed three times and allowed to re-equilibrate to baseline. After a 15 minute re-calibration, test compound is added until final concentration is reached.

t '·

Ten minutes after the addition of the test compound, histamine (1 JOM) is added again and the response to histamine in the presence of antagonist is compared to the control response to histamine. The results are expressed as a percentage of the control response to histamine. The apparent dissociation constant of the H-2 antagonist is then determined by standard procedures.

The aminopyrine test is performed as follows:

The gastric mucosa of the New Zealand white rabbit is separated from the muscle and washed in buffer 1 / containing 8.007 g of sodium chloride, 0.201 g of potassium chloride in 1 liter,

0.113 g of sodium monohydrogen phosphate, 0.204 g of potassium dihydrogen phosphate, 0.132 g of calcium chloride dihydrate, 0.101 g of magnesium chloride and 1 g of glucose are adjusted to pH 7.4 with sodium hydroxide.

The tissue is finely chopped, suspended in buffer 1 and washed three times with buffer 1. The tissue is then suspended in a dispersant medium (100 mg collagenase (Sigma Chemical Co., type V) and 100 mg bovine serum albumin (Miles Laboratories Ltd., fraction V) in 100 ml buffer 1) 50 ml medium per 10 g net tissue weight (a) incubated at 30 ° C and pH 7.4 under stirring under an oxygen atmosphere (conditions continuously monitored and maintained).

After 30 minutes, the tissue is allowed to settle and the supernatant is separated. Fresh dispersing medium (50 ml per 10 g wet weight) was added and incubation continued. After 40 to 60 minutes, the tissue dispersion consists mainly of glands and whole cells.

All remaining major tissue sections are removed by filtration through a nylon mesh. The gland-cell mixture was isolated by centrifugation at 200 x g and suspended in buffer 1 containing 1% bovine serum albumin (Miles Laboratories Ltd., Fraction V).

Finally, the cells and glands were washed three times with buffer 1 and suspended in buffer 2 / containing 500 ml Eagles medium (MEM), 10 mg aprotinin (Sigma Chemical Co.) and 20 ml (150 mmol).

2- [4- (2-hydroxyethyl) piperazin-1-yl] ethanesulfonic acid, adjusted with sodium hydroxide to pH 7.4 (150 ml per 10 g net tissue weight).

The tissue suspension is stirred at 32 ° C for at least 1 hour before use.

The tissue suspension is incubated for 20 minutes with the test compound and 10 µmol of C ^{X 4} labeled aminopyrine on the 0.37.10 ¹⁰ dimethylamino group with ^-1 ml ^-1 . The consumption of aminopyrine is then stimulated by the addition of histamine and an ICI 63197 / Biochem phosphodiesterase inhibitor. Soc. Special Publi-5 -7 cation 1, 1973, pp. 127-132) to final concentrations of 10 M resp. 5 x 10 M.

After 18 minutes, the cells and glands are separated from the incubation medium by filtering the suspension with glass microfiber filters. The mixture of cells and glands is then washed rapidly (in less than 10 seconds) three times with ice-cold buffer 1.

Scintillation counter is then measured arainopyrin labeled ^C-1, held in the tissue, and comparing konstrolním sample is calculated as the degree of inhibition of aminopyrine consumption caused by the test compound.

From a series of tests performed at different concentrations, the concentrations of the test compound causing 50% inhibition are graphically determined.

All of the compounds exemplified herein were either guinea pig atrial or aminopyrine. All compounds tested in guinea pig atrium are effective at a bath concentration of 10 µM or even lower, with the more active of these compounds showing complete inhibition of responses at that concentration.

All compounds tested by the aminopyrine assay showed a 50% inhibition of aminopyrine consumption at a concentration of 3 ynM or even lower.

Inhibition of gastric acid secretion can be demonstrated by standard assays, such as the ability of the compounds of Formula I, by intravenous, gastric or oral administration, to inhibit acid gastric secretion in, for example, rats or dogs with gastric fistula or denervated vesicles in gastric fundus. wherein gastric secretion has been stimulated by administration of a secretion enhancer, such as pentagastrin, histamine, bethanechol or food.

The rat test is performed as follows:

Female rats weighing 200-230 g are anesthetized by intramuscular administration of urethane at a dose of 1.5 g / kg and cannulated into their trachea. A soft tube is inserted through the esophagus into the stomach of the test animal, which is attached to the neck area by a ligature.

A plastic tube (3 mm diameter) with a plurality of holes is inserted into the anterior region of the stomach by incision in the duodenum and secured by a ligature around the pylorus.

The esophagus cannula is washed with saline (9 g sodium chloride / liter) at a dose of 7 ml / min and the liquid collected from the pyloric duct is collected in beakers at 10 minute intervals.

Acid secretion is stimulated by subcutaneous administration of a specific H-2 antagonist dimaprite: at a dose of 10 mg / kg followed by an infusion at a dose of 30 mg / kg / h. Acid secretion is calculated by titrating samples taken after 10 minutes.

Titration is performed with 20 mM sodium hydroxide to an end point of pH 6.4. Once the acid secretion has reached a uniform value (three consecutive readings are in the range of 5%), the test compound is injected intravenously through the left external jugular vein.

Secretion is then measured for an additional 2 hours. A stock solution of each of the test compounds (10 mg / ml in dimethylsulfoxide) was prepared first, and an appropriately diluted solution was prepared from this stock solution by diluting with sodium solution to inject the appropriate dose in a volume of 1 ml / kg (dimethylsulfoxide concentration less than 2%).

The test on dogs with chronic fistula is performed as follows:

A 9 to 12 kg beagle purebred bitch, with a chronic stomach fist, is fasted overnight while not restricting drinking water intake. During the experiment, the dog is slightly tied in the stirrups so that he is forced to stand.

To determine the effect of the test compound on intravenous administration, the fistula is opened and, following absence of basal secretion within 30 minutes, continuous intravenous infusion of a secretion enhancer (0.5 µmol / kg / h histamine or 2 µg / kg / h pentagastrin) is initiated. in brine (15 ml / h).

Gastric acid samples are collected every 15 minutes. The volume of each sample is measured and the 1 ml aliquot is titrated with 100 mM sodium hydroxide until neutrality to determine the acid concentration.

After reaching a stable secretion level (1-2 hours), the test compound is administered intravenously in saline and gastric acid samples are taken for a further 2-3 hours, continuing to infuse the secretion enhancer.

In addition to the determination of the effect of the test compound upon administration to the stomach, after detection of the absence of basal secretion (within 30 minutes), the test compound contained in a medium consisting of 25 ml 0.5% (w / v) hydroxypropyl methylloelulose and 0.1 % (w / v) surfactant / Tween 80 in water into the stomach of the animal through the fistula cap.

After 1 hour, the fistula is reopened and the intravenous infusion of the secretion enhancer is immediately started as described above. Gastric acid samples are then collected and monitored as described above, and the approximation of acid secretion to a stable level is compared to that of a control animal with only the vehicle being introduced into the stomach.

To determine the efficacy of oral administration, the test substance is administered in the form of a gelatin capsule rinsed with 15 ml of water. After one hour, the fistula is opened and the intravenous infusion of the secretion enhancer is immediately started.

Gastric acid samples are collected and monitored as described above, and the approximation of acid secretion to a stable level is compared to that of a control animal to which the test compound has not been administered.

The test on dogs with denervated vesicles in the stomach fund is performed as follows!

Male beagles (14-22 kg) with vague-denerved fundus vesicles were prepared (see Rudick et al., J. Surg. Res. 1967, T, 383]. Animals are allowed to recover for 4 to 6 weeks after surgery, followed by training and standardization of the secretory response for a further 2 to 3 months before dough.

Before the test, dogs are fasted for 23 hours (water intake is not limited). During the experiments, the dogs are slightly suspended on fabric straps. After washing the pouch with warm water, histamine is infused at a dose of 10 µg / min.

This agonist dose induces submaximal (60-90% of the maximum) increase in acid secretion in all experimental dogs. The secretions from the sac are collected at fifteen minute intervals in calibrated glass tubes and measured to the nearest 0.1 ml volume.

A 500 µL sample was diluted with 5 mL of brine and titrated with 100 mM sodium hydroxide to pH 7.0. The total acid production is calculated from the acid concentration in the secretion and the secretion volume.

Test compounds are administered intravenously at a dose of 0.1 ml / kg to the vein of cephalica or orally in the form of a gelatin capsule while the secretion has stabilized (three consecutive readings are in the range of 10%). Secretion is measured for 3 hours after administration of the test substance.

The results obtained in the guinea pig atrium test and the aminopyrine test indicate the efficacy in the rat and dog tests.

The compounds produced by the process of the invention may be used in the form of pharmaceutical compositions containing the guanidine derivatives of the invention in combination with non-toxic, pharmaceutically acceptable diluents or carriers.

i>

For example, the pharmaceutical compositions may be in a form suitable for oral, rectal, parenteral or topical administration. For this purpose, the compositions may be formulated in known manner, for example into tablets, capsules, aqueous or oily solutions or emulsion suspensions, dispersible powders, suppositories, sterile injectable aqueous or oily solutions or suspensions, gels, creams, ointments or lotions.

In addition to the guanidine derivative of the invention, these pharmaceutical compositions for oral, rectal or parenteral administration may contain or be co-administered with one or more known drugs selected from the group consisting of antacidics, such as aluminum hydroxide and magnesium hydroxide, antipepsin compounds, such as pepstatin, other histamine H-2 antagonists such as cimetidine or ranitidine, ulcers healing agents such as carbenoxolone or vizraut salts, anti-inflammatory agents such as ibuprofen, indomethacin, naproxen or aspirin, prostaglandins such as 16,16-dimethylprostaglandin E ₂ , classical antihistarainics (H1 histamine antagonists), such as mepyramine or diphenhydramine, anticholinergic agents such as atropine or propantheline bromide, anxiolytics such as diazepam, chlordiazepoxide or phenobarbital.

Pharmaceutical compositions for topical application may contain, in addition to the guanidine derivative of the formula I, one or more classical antihistamines (H1 histamine antagonists), such as mepyramine or diphenhydramine, and / or one or more steroidal anti-inflammatory agents such as fluocinolone or triamcinolone. .

Topical compositions may contain 1 to 10% (w / w) guanidine derivative of the invention.

A preferred pharmaceutical composition is a formulation suitable for oral administration in unit dosage form, for example a tablet or capsule containing 5 to 500 mg of a guanidine derivative, or a formulation suitable for intravenous, subcutaneous or intramuscular injection, for example a sterile injection formulation containing 0.1 to 10%. weight / weight / guanidine derivative.

The pharmaceutical compositions described above are normally administered to humans for the treatment of gastric ulcers and other conditions caused or re-induced by gastric acidity in the same general manner as when administering cimetidine, taking into account the potency and duration of action of the derivative in terms of dose levels. guanidine according to the invention as compared to cimetidine.

Thus, for oral administration, each patient will be administered a dose ranging from 5 mg to 500 mg, preferably from 10 mg to 100 mg of the guanidine derivative of the invention, or intravenously, subcutaneously or intramuscularly, from 0.5 to 50 mg preferably from 2 mg to 20 mg of a guanidine derivative according to the invention, wherein the respective composition will be administered one to four times, preferably once, daily.

The rectally administered dose will be approximately equal to the orally administered dose. The compositions may be administered less frequently if they contain an amount of the guanidine derivative which is a multiple of the dose effective when administered once to four times daily.

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

He did

A mixture of 22.2 g of ethyl formate, 15.3 g of ethyl propionate, 1 ml of ethanol, 15 g of a 50% (w / w) sodium hydride dispersion in mineral oil and 300 ml of ether was stirred at room temperature for 18 hours, then filtered. Dissolve in 150 ml of methanol and add 38 g of 4- (2- (2- / 2,2,2-trifluoroethyl) guanidinyl) pyrid-5-ylthio butanimidine hydrochloride.

The reaction mixture was stirred under reflux for 5 hours, then evaporated to dryness and the residue was partitioned between ether and water. The aqueous phase was acidified to pH 1, washed with ether and then neutralized with saturated aqueous sodium bicarbonate.

The precipitate formed is filtered off, dissolved in methanol, acidified with ethereal hydrogen chloride solution, the precipitated hydrochloride is filtered off and recrystallized from methanol. There was obtained 4-hydroxy-5-methyl-2- [3- [2- / 2- (2,2,2-trifluoroethyl) guanidino] pyrid-6-ylthio] propyl] pyrimidine dihydrochloride, m.p. Deň: 32 ° C.

The starting material can be obtained as follows:

To a solution of 83.7 ml of benzyl mercaptan and 16.4 g of sodium in ethanol was added 40 g of 2-amino-6-bromopyridine, and the mixture was heated under reflux for 72 hours with stirring. The reaction mixture is evaporated to dryness, the residue is stirred with a mixture of 1.4 l of water and 700 ml of ethyl acetate and acidified to pH 1 with concentrated aqueous hydrochloric acid.

The precipitated solid was filtered off to give 30 g of 2-amino-6-benzylthiopyridine hydrochloride, m.p. 189-191 ° C.

To a solution of 47.2 g of 2-amino-6-benzylthiopyridine hydrochloride in 700 ml of liquid ammonia is added, in small portions, 17.0 g of sodium. After the sodium addition is complete, 21.9 g of ammonium chloride are added and the mixture is evaporated to dryness.

The residue was dissolved in a mixture of 100 ml of ethanol and 100 ml of water, 23 ml of 4-bromobutyronitrile was added, and the mixture was stirred at room temperature for 18 hours. The reaction solution was evaporated to dryness and the residue was partitioned between 2N aqueous hydrochloric acid and ether.

The aqueous phase was basified with 10 N aqueous sodium hydroxide and extracted with ethyl acetate. The extract was dried over sodium sulfate and evaporated to dryness to give 36.1 g of 4- (2-aminopyrid-6-ylthio) butyronitrile which was used without further purification.

A solution of 4- (2-aminopyrid-6-ylthio) butyronitrile (36 g) and 2,2,2-trifluoroethylisothiocyanate (22 ml) in acetonitrile (100 ml) was allowed to stand at room temperature for 18 hours. Filtration of the crystalline precipitate and washing with cold ethanol gave 4- (2- [3- (2,2,2-trifluoroethyl) thioureido] pyrid-6-ylthio] butyronitrile, m.p. 131-133 ° C.

A mixture of 29 g of 4- (2- (3- (2,2,2-trifluoroethyl) thioureido) pyrid-6-ylthio butyronitrile, 29 g of yellow mercuric oxide and 100 ml of saturated ethanolic ammonia solution is stirred at room temperature for 24 hours and then is filtered.

The filtrate is evaporated to dryness, the residue is triturated with petroleum ether (b.p. 60-80 ° C) and filtered off. 24 g of 4- (2- [2- (2,2,2-trifluoroethyl) guanidino] pyrid-6-ylthio butyronitrile, m.p. 89 DEG-91 DEG C., are obtained.

A solution of 36.5 g of 4- (2- / 2- / 2,2,2-trifluoroethyl-guanidino / pyrid-5-ylthio) butyronitrile in 150 ml of chloroform and 150 ml of methanol at 0 ° C is saturated with hydrogen chloride gas and then was allowed to react at 0 ° C for 72 hours.

The reaction mixture was evaporated to dryness and the residue was partitioned between aqueous potassium carbonate solution and chloroform. The aqueous phase is extracted twice more with chloroform, the chloroform extracts are combined and, after drying, evaporated to dryness.

The residue is dissolved in 200 ml of methanol, 8.6 g of ammonium chloride are added, the mixture is stirred at room temperature for 2 hours and then evaporated to dryness. The residue was triturated with acetonitrile and the insoluble material was filtered off to give 38 g of 4- (2- / 2- / 2,2,2-trifluoroethyl) guanidino / pyrid-6-ylthio] butanamidine hydrochloride which was used without further purification. A sample of the product characterized as the dihydrochloride melts at 118-120 ° C

 . , 240951

Example 2

A mixture of 0.37 g of ethyl formate, 0.6 g of ethyl propionate and 0.5 g of a 50% (w / v) sodium hydride dispersion in mineral oil was heated to reflux in 15 ml of ether containing 1 drop of ethanol. After 2 hours, the precipitated white precipitate was filtered off with exclusion of moisture and heated at reflux for 24 hours. 0.75 g of 5- [4- / 2- / 2,2,2-trifluoroethyl] guanidino / pyriraid- 2-yl] valeramidine hydrochloride in 10 mL of methanol.

The reaction mixture is evaporated to dryness and the residue is partitioned between 20 ml of dilute aqueous acetic acid and 10 ml of ethyl acetate. The aqueous layer was separated and the pH adjusted to about 7 with aqueous sodium bicarbonate solution.

The aqueous mixture was extracted twice with 20 ml of ethyl acetate (ethyl acetate) and the layers were combined, evaporated to dryness and the residue purified by preparative thin layer chromatography using a mixture of chloroform, methanol and aqueous ammonia / density 0; 88 (in a ratio of S: 2: δ, v / v / v) as eluent. . "

The appropriate material isolated from the plates, after trituration with acetonitrile, yields 0.1 g of 4-hydroxy-5-methyl-2- [4- / 4- [2- / 2,2,2-trifluoroethyl] guanidinopyrimid-2-yl] butyl ] pyrimidine, m.p. 210-212 ° C,

The starting material can be prepared as follows:

Ethyl 5-cyanvalerimidate (g) was stirred with 200 ml of methanol containing 2 * 6.4 g of ammonium chloride for 18 hours, then the mixture was filtered and the filtrate was evaporated to dryness. The residue is refluxed in 250 ml of ethanol containing 285 ml of triethylamine and 106 g of 2-chloroacrylonitrile. _t

After 2 hours, the reaction mixture was cooled, added to 1 liter of water, adjusted to pH 4 with acetic acid, charcoal was added to the aqueous mixture, the mixture was filtered and the filtrate was extracted with 300 ml of ethyl acetate.

The aqueous layer was separated, adjusted to pH 9 with aqueous sodium hydroxide solution, and extracted with ethyl acetate (2 x 50 mL). The combined extracts were evaporated to dryness and the residue was recrystallized from acetonitrile to give 16 g of 5- (4-aminopyrimid-2-yl) valeronitrile.

A mixture of 5- (4-aminopyrimidin-2-yl) valeronitrile (30 g) and 2,2,2-trifluoroethylisothiocyanate (30 g) in acetonitrile (50 ml) was heated at reflux for 18 h, then evaporated to dryness. methanolic ammonia solution.

48 g of mercuric oxide are added to the resulting solution, after 2 hours the mixture is filtered through a pad of diatomaceous earth and the filtrate is evaporated to dryness. The residue was triturated with ether and the solid product was filtered off to give 39 g of 5- [4- [2- (2,2,2-trifluoroethyl) guanidino] pyrimid-2-yl valeronitrile.

A solution of 39 g of 5- [4- [2- (2,2,2-trifluoroethyl) guanidino] pyrimid-2-yl] valeronitrile. in a mixture of 250 ml of chloroform and 150 ml of methanol is cooled to -10 DEG C. and saturated with hydrogen chloride gas. The mixture is allowed to stand at 0 ° C for 60 hours, then evaporated to dryness and a mixture of 100 g of potassium carbonate and 300 ml of water, cooled to 5 ° C, is added to the residue.

The resulting mixture was extracted twice with 200 ml of chloroform each, the combined organic extracts were dried over magnesium sulfate and evaporated to dryness. The residue is stirred in 150 ml of methanol with 7 g of ammonium chloride, the mixture is filtered for 3 hours and 500 ml of ether are added to the filtrate.

After filtering off the precipitated solid, 30 g of 5- (4- / 2- / 2,2,2-trifluoro π · ^{t 'in,'} '

240951 '10; '*.

ethyl (guanidino) pyrimidin-2-yl] valeramidine hydrogen chloride, which was used without further purification.

Claims (1)

P YES X) MEASURING NXLEZ _f Process for the production of heterocyclic derivatives of guanidine (1) in which: X stands for pyrrolidine crimped at positions 2 and 4, or pyramid. circle á '• i · * ’·. ·' ·. · '·. And represents a "tetraffiethylene" or "thiothimethylene" residue, and their acid addition salts, indicating! se. by 'compound of formula II' c ' CF, CH_NH. with 3 2. of C 6 = E-Cl <. η, ν <: 7 li> in which (i X and A find the abovementioned ₄ or an acid addition salt thereof, react with ethyl 2-formylpropionate, and optionally, the resulting compound of formula (I), resulting in the free base, by reaction with an acid affording converting a pharmaceutically acceptable anion into an acid addition salt.