CS240952B2 - Production method of guanidine heterocyclic derivatives - Google Patents

Abstract

Process for preparing heterooyclic derivatives guanidine of formula I x ^ - / ch9 /.- c '", / 1 / h '/ nhr2 CF -.ClUNH. J Z = C = N-C H2N ^ in which ring X is 1,2,3-triazole or pyrazole circle a R1 and R2 are taken together to form unsubstituted imidazole or 5-methyl-1,2,4-triazole ring and their pharmaceutically acceptable acid addition salts, characterized by by providing a compound of formula II cf, ch9nh .. "c = N-C." Ν '" > n- / ch 2/4-c "0CH3 X / 11 / N reacted with aminoacetaldehyde dimethyl acetal or with acetohydrazide and the product reaction with acetohydrazide in the case of cyclically, where appropriate, is obtained a compound of formula I in the form of the free base is reacted with an acid providing a pharmaceutically acceptable anion to form an acid addition salt. The compounds produced are H-2 antagonists histamine and inhibit gastric acid secretion.

Description

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

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

The first of these receptors was named as the H-1 receptor (see Ash and Schild, Brit. J. Pharmad., 1966, 27 427) and the effect of histamine on this receptor is blocked / antagonized by classical antihistamines such as mepyramine.

The second histamine receptor has been named as the H-2 receptor (see Black et al. Nature, 1972, 236, 385) and the effect of histamine on this receptor is blocked by such agents as oimetidine.

One result of blocking the effect of histamine on the H-2 receptor is known to inhibit 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.

GB 2O52478A and GB 2O558OOA disclose histamine H-2 receptor antagonists which are 2-guanidinothiazole derivatives bearing a side chain at the 4-position to which a substituted amino 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 histamine receptors.

Accordingly, the invention provides a process for making heterocyclic guanidine derivatives of the formula I, CF ₃ CH ₉ NH, H ₂ NC = n'C "X N / CH _2/4 -C NHR / 1 / in which ring X is 1 , 2,3-triazole or pyrazole ring; and r 2 are joined together to form an unsubstituted iraidazole or 5-methyl-1,2,4-triazole ring, and pharmaceutically acceptable acid addition salts thereof, characterized in that the compound of formula II rNH

CNC, N / CH _2/4 -c;

/ 10 / h ₂ n '

OCH.

wherein ring X is as defined above, is reacted with aminoacetaldehyde dimethylacetal or acetohydrazide, and then optionally obtained compound of formula I in the free base form is reacted with an acid giving a pharmaceutically acceptable anion to form an acid addition salt.

Λ

Specific compounds which can be prepared by the process of the present invention include

3-methyl-5- [4- [3- [2- (2,2,2-trifluoroethyl) guanidino] pyrazol-1-yl] butyl] -1,2,4-triazole (Example 2) a

2- [4- [4- (2- (2,2,2-trifluoroethyl) guanidino] -1,2,3-triazol-2-yl] butyl] imidazole (Example 3), and their 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 solvent or diluent.

The starting materials for the process according to the invention can be prepared as described in the examples. When acetohydrazide is used as the reagent, a compound of the general formula is formed as an intermediate which can be isolated.

CF, CH, NH .. ---- -rNNHCOCH3 2 \ 3 c = nc X _k ^ __ AI- / CH _2/4 -c Η ₂ N s' where hh ₂

X is as defined above.

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 gastric acid, including ulcers from stress and gastrointestinal bleeding due to injury.

The efficacy of antagonizing histamine H-2 receptors can be demonstrated by standard assays, such as the ability of the compounds of formula I to inhibit histamine-induced positive chronotropic response in the spontaneously beating guinea pig atrium or their ability to inhibit histamine-induced aminopyrine consumption in the acid region of endothelial cells.

The guinea pig atrium test is performed as follows:

The right atrium of the guinea pig is suspended at 1 g (isometric) in 25 ml of thermostatically controlled (30 ° C) tissue bath containing oxygenated (95% O 2, 5% CO 3) Krebs-Hanseleite buffer (pH 7.4).

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 re-equilibration for 15 minutes, the test compound is added until final concentration is reached.

Ten minutes after the addition of the test compound, histamine (1 µM) 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 musculature and washed in buffer 1 / containing 8.007 g of sodium chloride, 0.201 g of potassium chloride, 0.113 g of potassium monohydrogen phosphate, 0.204 g of potassium dihydrogen phosphate, 0.132 g of calcium chloride dihydrate. and 1 g glucose, and is adjusted to pH 7.4 with sodium hydroxide.

The tissue is finely chopped, suspended in buffer 1 and washed three times with buffer. 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. / stirring in kyslíkové.atmosféře was incubated at 30 C ^U of pH. 7.4 (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 is isolated by centrifugation at 200 x g and suspended in buffer 1 containing 1% bovine serum albumin / Miles Laboratories. 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 µM dimethylamino-labeled aminopyrine (0.1 µCi / ml). The consumption of aminopyrine is then stimulated by the addition of histamine and a phosphodiesterase inhibitor ICX 63197 / Biochem. Soc. Special Publication 1, 1973, pp. 127-132) to final concentrations of 10 µM and 10 µM, respectively. 5 x 10 ^- ? M.

After 18 minutes, the cells and glands are separated into the incubation medium by filtering the suspension through glass microfiber filters. The mixture of cells and glands is then washed quickly (in less than 10 seconds) three times with ice-cold buffer 2.

Scintillation counter is then measured labeled aminopyrine C ¹ ^, retained in the tissue, and comparing with a control sample is calculated consumption degree likely inhibitory aminopyrine 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 exhibiting 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 µM 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 juice secretion in, for example, rats or dogs and gastric fistula or 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 its position 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 dilution with saline to allow an appropriate injection 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, after detection of absence of basal secretion within 30 minutes, continuous intravenous infusion of the secretion enhancer (0.5 µmol / kg / h histamine or 2 yug / kg / h pentagastrin) in saline is initiated. (15 ml / h).

Gastric acid samples are collected every 15 minutes. Measure the volume of each sample and titrate a 1 ml aliquot with 100 ml of sodium hydroxide solution until neutrality to determine the acid concentration.

.s'

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

To determine the effect of the test compound when administered to the stomach, after detection of the absence of basal secretion (within 30 minutes), the test compound contained in 25 ml of 0.5% (w / v) hydroxypropylmethylcellulose and 0.1% (w / w) is introduced. volume / surfactant Tween 80 in water into the stomach of the animal by the fistula cap.

After 1 hour, the fistula is reopened and the intravenous infusion of the secretion enhancer is immediately started as described above. Samples are then taken and monitored as described above

gastric acid and the approximation of acid secretion to a steady state level are compared to that of a control animal that has only been delivered to the stomach by the vehicle.

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]. The 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 testing.

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, the infusion is started at 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.

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 suspensions, emulsions, 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 antacids, such as mixtures of aluminum hydroxide and magnesium hydroxide, antipepsin compounds such as for example pepstatin, other histamine H-2 antagonists such as cimetidine or ranitidine, ulcers healing ulcers such as carbenoxolone or bismuth salts, anti-inflammatory agents such as ibuprofen, indomethacin, naproxen or aspirin, prostaglandins such as 16,16- dimethylprostaglandin E2, classical antihistamines (H1 histamine antagonists) such as mepyramine or diphenhydramine, anticholinergic agents such as atropine or propantheline bromide, anxiolytic agents such as diazepam, chlordiazepoxide or phenobarbital.

The topical pharmaceutical compositions may contain, in addition to the guanidine derivatives of the formula I, one or more classical antihistamines (H-1 histamine antagonists), such as mepyramine or diphenhydramine, and / or one or more steric 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 1%. 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 disclosed compositions may be administered less frequently if they contain an amount of the guanidine derivative that is a multiple of the dose effective when administered one to four times daily.

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

The term ether means diethyl ether. It should be noted that there is a risk of explosion in the case of 3-nitropyrazole (Example 1).

Example 1

A solution of 0.94 g of 5- [3- [2- (2,2,2-trifluoroethyl) guanidino / pyrazol-1-yl] valeronitrile in 10 ml of chloroform and 10 ml of methanol was saturated with hydrogen chloride gas at 0 ° C. The mixture was cooled to 5 ° C for 24 hours, then the volatiles were removed in vacuo at 40 ° C.

The syrupy residue is cooled in ice and 50 ml of ice-cold 10% (w / v) aqueous potassium carbonate solution are added. The resulting oily precipitate was extracted with chloroform, dried over magnesium sulfate and evaporated in vacuo to an oily irainoether.

0.5 g of this imino ether is dissolved in 5 ml of methanol and 0.73 g of acetohydrazide is added. The resulting solution was allowed to react at 20 ° C for 48 hours, after which time the volatiles were removed in vacuo.

The syrupy residue crystallized upon trituration with a mixture of ether and ethanol (9: 1, v / v). N-acetylamino-5- [3- (2- (2,2,2-trifluoroethyl) guanidino) pyrazol-1-yl] valeramidine is obtained, m.p. 142-144 ° C.

The starting material can be prepared as follows:

To a solution of 17.4 g of 3-nitropyrazole in 150 ml of dry dimethylformamide was added portionwise over 30 minutes 6.16 g of sodium hydride paste (61% (w / w) / suspension in liquid) while maintaining the temperature by external cooling on ice at 20-30 ° C. paraffin.

The mixture was stirred for 45 minutes, to the resulting almost clear solution at 25-30 ° C over 30 minutes was added 25 g of 5-bromovaleronitrile, and the resulting mixture was stirred for 4 hours. After addition of 450 ml of water and 450 ml of ethyl acetate, the upper layer is separated, dried over magnesium sulphate and evaporated in vacuo to an oily residue consisting of a mixture of 5- (3-nitropyrazol-1-yl) valeronitrile ^and 5- (5-nitropyrazole-1-). yl / valeronitrile.

The oily material was separated into two 15 g portions which were fractionated on a silica gel column (3.5 cm diameter, 100 cm length) eluting at 0.2 MPa with ethyl acetate / petroleum ether (b.p. 60-80 ° C). in a ratio of 3: 7 (v / v).

First, the 1,5-isomer is eluted followed by the 1,3-isomer. 5- (3-nitropyrazol-1-yl) valeronltril melts at 32-33 ° C.

To a solution of 9.16 g of 5- (3-nitropyrazol-1-yl) valeronitrile in 200 ml of dry tetrahydrofuran was added 1.8 g of 5% (w / w) palladium on carbon and the mixture was stirred at 20 ° under a hydrogen atmosphere. C.

3.2 liters of hydrogen are absorbed in 4 hours. The catalyst was filtered off and the filtrate was evaporated in vacuo to give oily 5- (3-aminopyrazol-1-yl) valeronitrile.

To a solution of 7.0 g of 5- (3-aminopyrazol-1-yl) valeronitrile in 25 ml of acetonitrile was added 6.02 g of 2,2,2-trifluoroethylisothiocyanate. After 15 minutes, the solvent was evaporated in vacuo to give 5- (3- (3- (2,2,2-trifluoroethyl) thioureido / pyrazol-1-yl) valeronitrile as a white crystalline solid, m.p. 96-98 ° C. C.

12.5 g of the thiourea prepared above were dissolved in 120 ml of 8M ammonia in ethanol, 12.8 g of mercury oxide were added and the mixture was stirred at 20 ° C for 30 minutes. The reaction mixture was filtered and the filtrate was evaporated in vacuo to give oily 5- [3- [2- (2,2,2-trifluoroethyl) guanidino] pyrazol-1-yl] valeronitrile.

A sample of this oily material was dissolved in acetone and 5 mol equivalents of maleic acid were added to the solution. Addition of ether to the clear solution thus formed precipitated crystalline maleate melting at 123-125 ° C.

Example 2

N-acetylamino-5- (3- (2- (2,2,2-trifluoroethyl) guanidino / pyrazol-1-yl) valeramidine (0.141 g) was heated at 160 ° C for 12 minutes, and the resulting glass mass was dissolved in ml of acetone containing 0.056 g maleic acid.

After addition of ether, the 3-methyl-5- [4- [3- / 2-, 2-dimethylate] dimalate crystallizes out. trifluoroethyl (guanidino) pyrazol-1-yl] butyl] -1,2,4-triazole, m.p. 125-130 ° C.

Example 3

A solution of 0.5 g of unpurified methyl 5- [4- [2- (2,2,2-trifluoromethyl) guanidino] -1,2,3-triazol-2-yl] valerimidate and 0.2 ml of aminoacetal dimethylacetal * - of ldehyde in 10 ml of methanol was stirred at room temperature overnight.

The resulting mixture was evaporated to dryness, the residue was dissolved in 10 ml of concentrated aqueous hydrochloric acid and heated on a steam bath for 10 minutes. The reaction mixture was evaporated, the residue basified with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate.

This extract was extracted with 2N aqueous hydrochloric acid, the acidic extract was basified with 2.5N aqueous sodium hydroxide and extracted with ethyl acetate. The latter extract was dried over magnesium sulfate, concentrated to a small volume, and a solution of 0.36 g of maleic acid in a small volume of acetone was added to the residue.

0.35 g of 2- [4- [4- (2- (2,2,2-trifluoroethyl) guanidino] -1,2,3-triazol-2-yl] butyl] imidazole dihydrogen maleate is obtained, m.p. 137 to 139 ° C.

The starting material can be obtained as follows:

and a solution of 23.0 g of 4-nitro-1,2,3-triazole in 135 ml of dry dimethylformamide was added with stirring at room temperature a dispersion of 4.8 g of sodium hydride in 4.8 g of mineral oil.

After stirring for 30 minutes, 33.0 g of 5-bromvaleronltril was added, the resulting mixture was stirred at room temperature overnight, then poured into water.

The product was extracted with ethyl acetate and purified by column chromatography on 1 kg of silica gel using a mixture of equal volumes of ethyl acetate and petroleum ether (bp 60-80 ° C) as eluent. 22.3 g of oily 5- (4-nitro-1,2,3-triazol-2-yl) valeronitrile are obtained.

A suspension of 0.5 g of 5% (w / w) palladium on carbon in a solution of 1.0 g of 5- (4-nitro-1,2,3-triazol-2-yl) valeronitrile in 20 ml of acetic acid at a pressure of 0 The hydrogen was stirred until 420 ml of hydrogen were taken up.

The mixture was filtered and evaporated to give 0.85 g of oily 5- (4-amino-1,2,3-triazol-2-yl) valeronitrile.

A solution of 0.35 g of 5- (4-amino-1,2,3-triazol-2-yl) valeronitrile and 0.50 g of 2,2,2-trifluoroethylisothiocyanate in 5 ml of acetonitrile was stirred at room temperature overnight. The reaction mixture is evaporated and the residue is recrystallized from toluene / petroleum ether (b.p. 60 ° C) to give 0.50 g of 5- [4- (3- (2,2,2-trifluoroethyl) thioureido) - 1,2,3-triazol-2-yl] valeronitrile melting after recrystallization from toluene at 86-88 ° C.

To a solution of 0.45 g of 5- [4- (3- (2,2,2-trifluoromethyl) thioureido) -1,2,3-triazol-2-yl] valeronitrile in 10 ml of 6M ethanolic ammonia solution was added with stirring at room temperature 0.6 g of mercuric oxide.

The mixture was stirred at room temperature for 2 hours, then filtered and evaporated. 0.41 g of 5- [4- [2- (2,2,2-trifluoroethyl) guanidino] -1,2,3-triazol-2-yl] valeronitrile is obtained.

A solution of 1.0 g of unpurified 5- [4- (2- (2,2,2-trifluoroethyl) guanidino] -1,2,3-triazol-2-yl] valeronitrile in a mixture of 15 ml of chloroform and 10 ml of methanol at 0 ° C saturated with hydrogen chloride gas. The mixture was allowed to react at 5 ° C in a sealed flask for 2 days and then evaporated to dryness to give the product as an ol with hydrochloric acid.

This hydrochloride was basified with saturated aqueous sodium bicarbonate and the mixture was extracted with dichloromethane. The extract was dried (MgSO4) and evaporated to give 1.0 g of methyl 5- [4- (2- (2,2,2-trifluoromethyl) guanidino] -1,2,3-triazol-2-yl] valerimidate as an oil which is used without further purification.

Claims (1)

SUBJECT OF THE INVENTION A process for the preparation of heterocyclic guanidine derivatives of the general formula I CF.CH.NH, - - -, NR ^{1 3 2} z> J / CNC _ ^ X N / CH _2/4 C / 1 / H ₂ N ^^ '^''' N '^' NHR ² in which ring X is a 1,2,3-triazole or pyrazole ring, 1 2 R and R are joined together to form an unsubstituted imidazole or 5-methyl-2,4 -triazolového ring and pharmaceutically acceptable acid addition salts, characterized in that a compound cf the formula II CH ₂ NH _3-m CNC. ^ X _of ^ N- (CH2 _{) 4} -C ^ / 11 / HJN Ό0Η ^ ₃ in which the ring X has the above meanings, is reacted with aminoacetaldehyde dimethylacetal or with acetohydrazide and then optionally obtained compound of formula I in free base form is reacted with an acid affording a pharmaceutically acceptable anion to form an addition salt with an acid.