CS241535B2 - Method of guanidine derivatives production - Google Patents

Description

The present invention provides guanidine 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 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 has been named as the H-1 receptor (see Ash and Schild, Brit. J. Pharmac., 1966, 27, 427) and the effect of histamine on this receptor is blocked (antagonized) by clad "antlhistamines" such as mepyramine.

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

British patent application no

GB 2 052 478 A and Japanese Patent Application No. J 56 108 777 (Derwent Accesion No

736D / 41J discloses histamine H-2 receptor antagonists which are 2-guanidinothiazole derivatives bearing a 4-side chain at the end of which a carbamoyl group is attached. It has now been found that haloalkylguanidinoheterocycles bearing a side chain to which an optionally substituted carbamoyl group is attached are potent antagonists of the H-2 histamine receptors.

The present invention relates to a process for the preparation of guanidine derivatives of the formula I

R.

-ACN _x

N + χ

M / 1 ^N wherein each of R ¹ and R ² , which may be the same or different, represents a hydrogen atom, a branched or unbranched alkyl group having 1 to 10 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms or a cycloalkylalkyl group being Each of these alkyl, cycloalkyl or cycloalkylalkyl groups being optionally substituted with one or more halogen atoms selected from the group consisting of fluorine, chlorine and bromine atoms, with the proviso that at least one of R 1 and R ² is a halogen-substituted alkyl, cycloalkyl or cycloalkylalkyl with the proviso that the carbon atom of the alkyl, cycloalkyl or cycloalkylalkyl which is directly attached to a nitrogen atom is present no halogen substituent, or R ² is hydrogen and R ¹ represents a radical of formula II

R ⁵ —E — W— (II) wherein

W represents an unbranched C 2 -C 6 alkylene chain optionally substituted by one or two C 1 -C 4 alkyl groups,

E represents an oxygen or sulfur atom, a sulfinyl group, a sulfonyl group or a radical of the formula NR ⁶ , wherein R ⁶ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and

R ⁵ represents a hydrogen atom or a straight-chain alkyl group having 1 to 6 carbon atoms, optionally substituted by one or two alkyl groups having 1 to 4 carbon atoms, or are

R ⁵ and R ^6, taken together with the nitrogen atom to which they are attached, form a pyrrolidine, piperidine, morpholine, piperazine or N-methylpiperazine ring, the dotted line in the X ring being a double bond on one side of the nitrogen atom and

Z represents a carbon atom or a nitrogen atom, such that the ring X is a five- or six-membered aromatic heterocyclic ring containing at least one nitrogen atom and optionally containing one or two additional heteroatoms selected from oxygen, nitrogen and sulfur atoms, the heterocyclic ring X there; where appropriate, it may optionally carry one or two substituents selected from the group consisting of fluorine, chlorine and bromine atoms, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, trifluoromethyl, hydroxy and amino,

A represents a phenylene group, a C 5 -C 7 cycloalkylene group or a C 1 -C 8 alkylene radical optionally substituted by one or two C 1 -C 3 alkyl groups and optionally containing one or two groups selected from the group consisting of oxygen and sulfur atoms, NH, N-C 1 -C 6 alkyl, cis- and trans-vinylene, ethinylene, phenylene and cycloalkylene of up to 7 carbon atoms, with the shortest part of the chain between ring X and the C = O group consists of at least 3 atoms, wherein the A-chain may optionally be interrupted by a group directly attached to the C = O group, which is not oxygen, sulfur, NH or N-alkyl, and wherein no two groups optionally, the chain of residue A selected from oxygen and sulfur atoms, NH and N-alkyl groups is interrupted groups are linked together, and the pharmaceutically acceptable acid addition salts.

It will be understood that although in the above general formula I and throughout the double bond in the guanidine moiety bonded to ring X is located at a particular position, there are other tautomeric forms, and the invention, both as to the particular compounds and the method thereof these tautomeric forms are also included.

When A represents or contains a cycloalkylene radical, the groups attached to this radical may be in the cis- or trans-configuration. When A represents or contains a cycloalkylene residue and / or when A represents an alkylene chain substituted by one or two alkyl groups, such compounds of the formula I will in most cases contain at least one center of asymmetry.

Thus, in such cases, the compounds of formula I will exist in at least two enantiomeric forms, the exact number of which is determined by the number of centers of asymmetry. As discussed below, the biological activity of these enantiomeric forms may vary and it should be emphasized that the invention encompasses the racemates of formula I above, including all possible diastereoisomeric forms and all enantiomeric forms exhibiting the desired biological activity, and it is well known how to separate them. diastereoisomeric forms and how racemates can be resolved into individual enantiomers to determine the biological activity of all of these.

Particular halogen-substituted alkyl groups R @ ¹ or R @ ² are 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, -bromo-2,2-difluoroethyl, 2,2-dibromo-2-fluoroethyl, 2-fluoroethyl, 2-chloroethyl, 2,2-difluoroethyl, 2,2-dichloroethyl, 2-chloro-2-fluoroethyl, 2-bromo -2-fluoroethyl, 2,2,3,3-tetrafluoro ₍ propyl, 2,2,3,3,3-pentafluoro-propyl, 1,1,1,3,3,3-hexafluoroisopropyl),

1,3-dichloro-1,1,3,3-tetrafluoroisopropyl, 1-chloro-1,1,3,3,3-pentafluoroisopropyl, 1,3-difluoroisopropyl or 2,2,3,3,4,4,4- a heptafluorobutyl group.

Particular halogen-substituted cycloalkyl groups R 1 or R ² are 2,2,3,3-tetrafluorocyclopropyl, 2-chloro-2,3,3-trifluorocyclopropyl 241535, 2,2-difluorocyclopropyl, 2-chloro-3,3- a difluorocyclopropyl, 2,2,3,3,4,4-hexafluorocyclobutyl or 2-chloro-2,3,3,4,4-pentafluorocyclobutyl group.

Particular halogen-substituted cycloalkylalkyl groups for R ¹ or R ² are (1,2,2,3,3-pentafluorocyclopropyl) methyl, (2-chloro-1,2,3,3-tetrafluorocyclopropyl) methyl, [1, 2,2,3,3,4,4-heptafluorocyclobutyl jmethyl or (2-chloro-1,2,3,3,4,4-hexafluorocyclobutyl) methyl.

Particular alkyl groups for R ¹ and R ² are methyl, ethyl, propyl, isopropyl or butyl.

A particular cycloalkyl group R ¹ or R ² is cyclopropyl or cyclobutyl.

A suitable cycloalkylalkyl group R @ ¹ or R @ ² is cyclopropylmethyl or cyclobutylmethyl.

A preferred optional substituent on W is methyl.

A suitable radical R ⁵ is a hydrogen atom or a methyl group.

A suitable radical R ⁶ is a hydrogen atom or a methyl group.

A suitable radical of formula (II) is a 2-methoxyethyl, 2-hydroxyethyl, 2-methylthloethyl or 2-dimethylaminoethyl group.

Particular values for ring X include oxazole, thiazole, imidazole,

1,2.4-thiadiazole, 1,2,4-oxadiazole, 1,2,3-triazole, 1,2,4-triazole, pyrazole, pyrazine, pyridine, pyrimidine or

A triazine ring, all of which may, where possible, be optionally substituted by one or two substituents selected from the group consisting of fluorine, chlorine and bromine atoms, methyl, methoxy, trifluoromethyl, hydroxy and amino.

A suitable residue in the meaning of the symbol “A” is:

phenylene, cykloipentylenová, cyclohexylene, trimethylene, tetramethylene, pentamethylene, thioethylenová, thiotrimethylenová, thiotetramethylenová, thiopentamethylenová, oxyethylene, oxytrimethylenová, oxytetramethylenová, methylenthiomethylenová, methylenthioethylenová, methylenthiopropylenová, methylenoxymethylenová, methylenoxyethylenová, ethylenoxyethylenová, oxy-2-methylene, thiopropylenthiomethylenová, oxyethylenoxymethylenová, iminoethylenová, iminopropylene, vinylene propylene, oxymethylene vinylene,

1.3- phenylene,

A 1,3-cyclopentylene, methylene-1,4-phenylene, ethyleneoxymethylene-1,4-phenylene, oxy-1,3-phenylenemethylene or thiomethylenethinylenemethylene group.

The writing of these residues in the meaning of the symbol “A” is done by reading from left to right in formula I, so that the former portion of each residue is bonded to the ring X and the latter portion of each residue is bonded to the group C = O. for example, if —A— is a thiomethylenethinylenemethylene group, then the compound of formula I contains a group of formula III θ

(m)

The following are 6 preferred meanings for the guanidine derivatives of the formula I. If any of these meanings, either singly or in combination, are considered together with the other general or specific meanings given above for the guanidine derivatives of the formula I, subgroups of compounds falling within the above general definition of these compounds.

R ² represents a hydrogen atom and R ¹ represents a 2,2,2-trifluoroethyl, 2-chloro-2,2-difluoroethyl or 2,2,3,3-tetrafluoropropyl group.

2. Ring X bears no optional substituent.

3. Ring X represents a pyrazole, 1,2,3-triazole or 1,2,4-triazole ring to which residue A is attached at position 1, a pyrimidine ring to which residue A is attached at position A, or a thiazole ring, to which symbol A is attached in position 4.

4. Ring X represents a pyrazole, 1,2,3-triazole or 1,2,4-triazole ring to which residue A is attached at the 1-position.

5. Ring X represents a pyrazole ring.

6. —A— means a tetramethylene, pentamethylene, oxytrimethylene, oxytetramethylene, thiatrimethylene or thiatetramethylene residue.

Specific compounds of the invention are shown in the Examples below. The following is a preferred group of these compounds.

4- [4- (2- / 2,2,2-trifluoroethyl / guanidino] pyrimid-2-yl-thio] butyramide (Example 1),

5- [3- (2- / 2,2,2-Trifluoroethyl) guanidinoyl pyrazol-1-yl] valeramide (Example 5),

5- [3- (2- / 2,2,3,3-Tetrafluoropropyl / guanidinoylpyrazol-1-yl) valeramide (Example 8),

5- (3- (2- / 2-chloro-2,2-difluoroethyl / guanidino) pyrazol-1-yl) valeramide (Example 9),

5- (4- (2- (2,2,2-trifluoroethyl) guanidino) -1,2,3-triazol-2-yl) valeramide (Example 10),

5- (4- (2- / 2,2,3,3-tetrafluoropropyl / guanidino) -1,2,3-triazol-2-yl) valeramide (Example 12),

6- (4- (2- / 2,2,2-trifluoroethyl / guanidino) -1,2,3-triazol-2-yl) hexanamide (Example 13),

4- (4- (2- / 2,2,3,3-tetrafluoropropyl) guanidino) pyrimidin-2-yloxy] butyramide (Example 20),

4- (2- (2- / 2,2,3,3-tetrafluoropropyl-1-guanidino) pyrid-6-ylthio) butyramide (Example 29), as well as pharmaceutically acceptable acid addition salts thereof.

From this group of compounds, the compounds of Examples 5, 8 and 20 are preferred, and the compound of Example 5 is particularly preferred.

Suitable pharmaceutically acceptable acid addition salts of guanidine derivatives of the formula I 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 is characterized in that the compound of formula V is hydrolyzed

Z-A-CN (A)

The hydrolysis is preferably carried out by treatment with a strong mineral acid such as concentrated sulfuric acid or with hydrogen peroxide in an alkaline medium, for example in the presence of sodium hydroxide.

When the compounds of formula (I) are obtained in the form of the free bases and the acid addition salts are to be prepared, the compound of formula (I) in the free base form is reacted with an acid to give a pharmaceutically acceptable anion,

The starting materials of formula V used in the process of the invention can be obtained by separately building two side chains on the respective ring X. Thus, the side chain on the left side of the ring can be built by reducing the nitro group to the amino group by reacting the amino group with an isothiocyanate

R ¹ R ² N = C - S and finally the reaction of the resulting thiourea with ammonia in the presence of mercury oxide. The process of constructing the side chain on the right side of the ring may vary depending on the nature of the ring X, the nature of the ring X atom to which the remainder A (carbon or nitrogen) is attached, and the presence or absence of atoms or groups introduced into chains of residue A.

If residue A contains no built-in group, or if the built-in group is a phenylene radical and Z represents a carbon atom, it is preferable to build a ring X with a side chain already present on the right side. When ring X is a pyrimidine ring, it can be built by reacting a suitably substituted imino ether with 2-chloroacrylonitrile, as exemplified in Example 14. If the group introduced into the A chain is a vinylene or ethinylene group, the A residue can be introduced by double or triple bonding by methods such as Example 14.

When the group introduced into the A chain is a cycloalkylene group, the A chain can be built by conjugation addition to the corresponding cycloalk-2-enone. When the built-in group in the A chain is an oxygen or sulfur atom, or an NH or N-alkyl group, the side chain on the right hand side may be constructed in a manner analogous to that illustrated in Examples 1, 17, 23, 26, 27, 28 and 29. nitrogen atom, the right-hand side chain can be built as illustrated in Examples 10 and 25.

As noted above, the guanidine derivatives of the invention are H-2 histamine antagonists that 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 stress ulcers and gastrointestinal bleeding as a result of 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 spontaneously beating guinea pig atrium or their ability to inhibit histamine-induced aminopyrine consumption in the acid endothelial cells.

The guinea pig atrium test is performed as follows:

The fierce anteroom of guinea pigs. strain 1 g (isometrically suspended in 25 ml thermostatically controlled (30 ° C) tissue bath containing oxygenated (95% O 2, 5% CO 2) Krebs-Henseleite buffer (pH 7.4). The tissue is allowed to stabilize for 1 hour, during which time Individual contractions are recorded with a force transducer through an extensometric coupler and the instantaneous velocity is monitored by a cardiotachometer, a control response to 1 μΜ histamine is determined, then the tissue is washed three times and allowed to re-equilibrate to baseline. 10 minutes after the addition of the test compound, histamine (1 μΜ) is added again and the response to histamine in the presence of antagonists is compared to the control response to histamine, and the results are expressed as a percentage of the control response to histamine. Standard procedures then clearly determine dissociation constant of the H-2 antagonist.

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 1 liter of 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 1. The tissue is then suspended in a dispersant medium (100 mg collagenase (Sigma Chemical Co., type B) and 100 mg bovine serum albumin and Miles Laboratories Ltd., fraction V) in 100 ml buffer 1; 50 ml medium per 10 g net tissue weight] is incubated at 30 ° C and pH 7.4 with 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 dispersion medium (50 ml per 10 g wet tissue weight) is added and incubation is 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 20 X g and suspended in buffer 1 containing 1% bovine serum albumin (Miles Laboratories Ltd., fraction VJ). Finally, the cells and glands are washed three times with buffer 1 and suspended in buffer 2 [contains 500 ml Eagles medium (MEM 3, 10 mg aprotinin (Sigma Chemical Co.) and 20 mL (150 mmol) of 2- (4- (2-hydroxyethyl) piperazin-1-yl) ethanesulfonic acid, adjusted to pH 7.4 with sodium hydroxide; 150 ml per 10 g net tissue weight]. The tissue suspension is stirred under an oxygen atmosphere at 32 ° C for at least 1 hour before use.

The tissue suspension was incubated for 20 minutes with test compound and 10 C-labeled aminopyrine Ginola -dimethylamino ¹⁴ (0.1 ^ Ci / MLJ. Consumption of aminopyrine is then stimulated by addition of histamine and the phosphodiesterase inhibitor ICI 63197 (Bioehem. Soc. Special Puhlieatiioin 1, 1973 , pp. 127 to 132) to final concentrations of 10 ^-5 and 5 x X 10 ^-7 M. After 18 minutes, the cells and glands are separated into the incubation medium by filtering the suspension through glass microfiber filters. for less than 10 seconds] three times with ice cold buffer 1. pcčítači scintillation is measured Paik aminpyrin labeled C ¹⁴ detained in the tissue, and comparing with a control sample is calculated as the degree of inhibition of aminopyrine consumption caused by the test compound. from a series of tests carried out with different Concentrations then graphically determine the concentration of test compound causing 50% inhibition.

All of the compounds exemplified herein were subjected to either a guinea pig atrium test or an aminopyrin test. All substances tested in a guinea pig atrium are effective at a bath concentration of 10 μΜ or even lower, with the more active of these compounds showing complete inhibition of responses at that concentration. All compounds tested by the aminopyrine test show a 50% inhibition of aminopyrine consumption at a concentration of 3 μΜ or even lower.

Inhibition of gastric acid secretion can be demonstrated by standard tests, such as the ability of the compounds of formula I to inhibit acid secretion of gastric juices in intravenous, gastric or oral administration, for example, in rats or dogs with 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 with instrumental injection 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 pylor. The esophagus cannula is washed with saline (9 g sodium chloride / liter) at a dose of 1 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 carried out with 20 mM sodium hydroxide to an end point of pH 6.4. Once the acid secretion has reached uniform values (three consecutive readings are in the range of 5%), the test compound is administered intravenously via a cannula inserted into 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 the 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, following absence of basal secretion within 30 minutes, continuous intravenous infusion of the secretion enhancer (0.5. Mol / kg / h histamine or 2 ₍ µg / kg / h pentagastrin) is initiated. 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 solution until neutrality to determine the acid concentration. (1-2 hours) the test compound is intravenously administered in saline and gastric acid samples are taken for an additional 2-3 hours, continuing to infuse the secretion enhancer.

To determine the effect of the test compound when administered to the stomach, after detecting the absence of basal secretion (within 30 minutes), the test compound contained in 25 ml of 0.5% (w / v) hydroxypropyl methylcellulose and 0.1% (w / w) Tween 80 surfactant in water into the animal's stomach with a fistula cap After 1 hour, the fistula is reopened and an intravenous infusion of the secretion enhancer is started immediately as described above and then collected and monitored as described above. gastric acid samples and the approximation of acid secretion to a stable 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 vesicles in the fundus region were prepared (see Rudick et al., J. Surg. Res. 1967, 7, 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 testing. They are fasted for 23 hours prior to the test (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 a submaximal (60-90% of 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. Dilute a 500 μΐ sample with 5 ml of brine and titrate with 100 mM sodium hydroxide to pH 7.0. 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.

No clear signs of toxicity or side effects were observed during rat and dog tests. 5- (4- (2- / 2,2,2-trifluoroethyl / guanidinyl) pyrimid-2-yl] valeramide, 5- [4- (2- / 2,2,2-trifluoroethyl / guanidino) - 1,2,3-triazol-2-yl] valeramide, 5- [6- (2- / 2,2,3,3-tetrafluoropropyl / guanidino) pyrid-2-yl] valeramide, and 5- (3- ( 2- (2,2,2-trifluoroethyl / guanidino) pyrazol-1-yl] valeramide were administered intravenously to groups of two anesthetized rats and four awake mice at doses corresponding to 10 times or 100 times the dose (in mg / kg) causing approximately 50 % inhibition of gastric acid secretion in anesthetized rats No signs of toxicity were noted in any of the experimental animals receiving these doses.

Many of the compounds disclosed herein inhibit inhibition of gastric acid secretion, which does not deviate from maximum inhibition for a few hours or at all.

The N-methylcyanguanidine moiety in known H-2 receptor antagonists can be converted into a mutagenic N-nitroso-N-methylcyanguanidine moiety in mammalian bodies (see Pool et al., Toxicology, 1979, 15, 69). of the CONHz formula, is not potentially convertible to carcinogenic nitroso derivatives.

The guanidine derivatives produced by the process of the invention may be used in the form of pharmaceutical compositions containing guanidine derivatives 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 can be formulated in known manner, for example, into tablets, capsules, aqueous cell oil solutions or suspensions, emulsions, dispersible powders, suppositories, sterile injectable aqueous or oil solutions or suspensions, gels, creams, ointments or lotions. .

In addition to the guanidine derivative of formula (I), 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, such as pepstatin, other histamine H-2 antagonists such as cimetidine or ranitidine, ulcer healing agents such as carbenoxolone or bismuth salts, anti-inflammatory agents such as ibuprofen, indomethacin, naproxen or aspirin, prosaglandins such as 16,16-dimethylprostaglandin Ez, 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 also contain, in addition to the guanidine derivative of the formula I, one or more classical antihistamines (H-1 histamine antagonists), such as mepyramine or diphenhydramine, and / or one or more steroidal anti-inflammatory agents such as fluocinolone and triamcinolone.

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

A suitable pharmaceutical composition is a formulation suitable for oral administration in unitary 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% (w / w) guanidine derivative.

These pharmaceutical compositions 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 for cimetidine, taking into account the efficacy and duration of action of the guanidine derivative in terms of dose levels. 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, and intravenously, subcutaneously or intramuscularly administered at a dose ranging from 0.5 mg to 50 mg, preferably from mg to 20 mg of the guanidine derivative, wherein the respective composition will be administered one to four times, preferably once a day. 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. NMR spectra are given in terms of δ versus tetramethylsilane (α = OJ as internal standard. Signal forms are designated by the following abbreviations:

s = singlet, d = doublet, t = triplet, q - quartet, m = multiplet, w = broad signal.

The term "ether" refers to diethyl ether.

It should be noted that there is a risk of explosion for 3-nitropyrazole (Example 5) and 4-nitrotriazole (Example 10j). Example 14 describes the preparation of the starting material for the procedure of Example 15 and Example 17 describes the preparation of the starting material for the procedure. of Example 18.

Example 1

A mixture of 0.14 g of 4- [4- (2- / 2,2,2-trifluoroethyl / guanidino) pyrimid-2-lthio] butyrititrile and concentrated sulfuric acid was allowed to react for one hour at room temperature and then diluted with crushed ice and water. The resulting solution was basified with 10N aqueous sodium hydroxide and the mixture was shaken three times with ex241535 ethyl acetate. The combined extracts were dried and evaporated to dryness to give 0.13 g of 4- (4- (2- (2,2,2-trifluoroethyl) guanidino) pyrimid-2-ylthio] hutyramide, characterized as the hydrogen maleate melting after recrystallization from aqueous ethanol at 202-203 ° C.

The starting material used in the above reaction can be prepared as follows.

To a solution of 0.25 g of 2-thiocytosine in 5 ml of 0.5 N aqueous sodium hydroxide was added 0.23 g of 4-chlorobutyronitrile in 2 ml of ethanol, and the mixture was stirred for 18 hours. After an additional 0.23 g of 4-chlorobutyronitrile was added, the mixture was stirred for 24 hours, then concentrated in vacuo to a volume of 2 ml, the residue was cooled and the precipitated crystalline precipitate was filtered off. 0.3 g of 4- (4-aminopyrimid-2-ylthio) butyronitrile is obtained, m.p. 99-100 ° C.

A mixture of 0.25 g of 4- (4-aminopyrimld-2-ylthio) butyronitrile, 3 ml of acetonitrile and 0.21 g of 2,2,2-trifluoroethylisothiocyanate was stirred at 70 ° C for 72 hours and then evaporated to dryness. The residue was crystallized from ether / petroleum ether (b.p. 60-80 ° C) to give 0.37 g of 4- [4- (2- / 2,2,2-trifluoroethyl / thiour eido) pyrimid-2-ylthio]. Buityronitrile, m.p. 125-126 ° C.

A mixture of 0.32 g of 4- [4- (3- / 2,2,2-trifluoroethyl) thioureldo-pyrimidin-2-ylthio-butyroinitrile, ml of ethanol saturated with ammonia and 0.5 g of yellow mercuric oxide is stirred at room temperature for 20 hours, The residue is recrystallized from acetone / petroleum ether (b.p. 60-80 ° C) to give 0.29 g of 4- [4- (2- / 2,2,2-trifluoroethyl) guanidino. M.p. 137 DEG C. Pyrimid-2-ylthio] butyronitrile, m.p.

Examples 2 and 3

In an analogous manner to that described in Example 1, starting from the appropriate nitrile (prepared in an analogous manner to butyronitrile described in Example 1) as starting material,

5- (4- (2- (2,2,2-Trifluoroethyl) guanidino) pyrimid-2-ylthio) valeramide hydrogen maleate, m.p. 184-186 C; and

6- (4- (2- / 2,2,2-Trifluoroethyl) guanidino) pyrimid-2-ylthio] hexanamide hydrogen maleate, m.p. 176-177 ° C.

Example 4

A mixture of 0.16 g of 4- [4- (2- (2-methoxyethyl) guanidino) pyrimidin-2-ylthlo] butyronltril and 2 ml of concentrated sulfuric acid was stirred at room temperature for 5 hours. The reaction mixture was cooled in ice and basified by careful dropwise addition of concentrated aqueous ammonia solution (density 0.880). The white precipitate formed is filtered off, washed with water and then with cold ethanol, the solid material is dissolved in hot ethanol together with maleic acid and the solution is allowed to cool. 0.22 g of 4- (4- (2- (2-methoxyethyl) guanidino) pyrimid-2-ylthio) butyramide maleate is obtained, m.p. 194-195 ° C.

The starting material can be obtained as follows:

To a mixture of 0.60 g of 4- (4-aminopyrimid-2-ylthio) butyronitrile and 30 ml of tetrahydrofuran was added, under argon atmosphere, with stirring at -78 ° C, 1.9 ml of 1.6 M n-butyllithium in hexane. 0.35 g of 2-methoxyethylisothiocyanate in 5 ml of tetrahydrofuran was added dropwise thereto, and the mixture was allowed to warm to room temperature and stirred for a further 64 hours.

The reaction mixture was poured into water and extracted three times with ethyl acetate. Evaporation of the combined extracts to dryness gave a crude solid material which was purified by medium pressure silica gel chromatography using a chloroform / methanol mixture (9.5: 0.25 v / v) as eluent. 0.25 g of purified product is immediately added to a mixture of 10 ml of ethanol saturated with ammonia and 0.22 g of mercuric oxide, the reaction mixture is stirred for 1.5 hours, then filtered through a pad of diatomaceous earth, the filtrate is evaporated and the residue is purified by medium pressure chromatography on Silica gel using a mixture of chloroform, methanol and aqueous ammonia (density 0.880) (9.5: 0.6: 0.05 v / v / v) as eluent. 0.16 g of 4- [4- (2- (2-methoxyethyl) guanidino) pyrimid-2-ylthio] butyronitrile is obtained as a semi-crystalline solid which is used without further purification.

Example 5

13 g of 5- (3- (2- (2,2,2-trifluoroethyl / guanidino) pyrazol-1-yl) valeronitrile) are added to 65 ml of concentrated sulfuric acid with stirring over a period of 10 minutes and the solution is allowed to react for 18 hours. at 20 ° C, then diluted with 300 ml of ice and basified with 10.8 N sodium hydroxide to pH 9. The mixture is extracted three times with 200 ml of ethyl acetate each time, the extract is dried over magnesium sulphate and evaporated in vacuo to an oily residue. Recrystallization of the crude material from ethyl acetate gave 5- [3- (2- (2,2,2-trifluoroethyl) guanidino) pyrazol-1-yl] valeramide, m.p. 130 [deg.] C. From this base was prepared by treatment with maleic acid in acetone. maleate melting at 183-184 ° C.

The starting material can be prepared as follows.

To a solution of 17.4 g of 2-nitropyrazole in 150 ml of dry dimethylformamide was added portionwise sodium hydride paste [3.16 g of a 61% (w / w) suspension in portions over 30 minutes to maintain the temperature at 20-30 ° C. in liquid paraffin. The resulting mixture was stirred for 45 minutes, to the resulting almost clear solution was added 25 g of 5-bromvaleronitrile at 25-30 ° C over 30 minutes, and the reaction mixture was stirred for 4 hours. After adding 450 ml of water and 450 ml of ethyl acetate upper layer was separated, dried over magnesium sulfate and evaporated in vacuo to an oil which was a mixture of 5- (3-nitro ^j l-yl) valeronitrile and 5- (5-nitro-l- 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) eluted at 0.2 MPa of a mixture of ethyl acetate and petroleum ether (bp 60-80 ° C). in a ratio of 3: 7 (v / v). The 1: 5-isomer is eluted first and then the 1: 3-isomer is eluted. 5- (3-nitropyrazol-1-yl) valeronitrile 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 is added 1.8 g of 5% (w / w) palladium on carbon and the mixture is stirred under a hydrogen atmosphere at 20 ° C. It is taken up in 3.2 liters of hydrogen over 4 hours, the catalyst is filtered off and the filtrate is evaporated in vacuo to give oily 5- (3-aminopyrazol-1-yl) valeronitrile.

To a solution of 7.0 g of 5- (2-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 8 M 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 evaporated in vacuo to give oily 5- (3- (2- (2,2,2-trifluoroethyl / guanidino) pyrazol-1-yl) valeronitrile). of acetone and 5 mol equivalents of maleic acid are added to the solution, and crystalline maleate precipitates from the clear solution obtained by addition of ether, m.p.

Alternatively, 5- (3- (2- (2,2,2-trifluoroethyl) guanidino] pyrazol-1-yl) valeronitrile may be prepared by reaction of 3-amino-pyrazole and 2,2,2-trifluoroethylisothiocyanate, by reaction of the resulting thiourea with ammonia in the presence of mercuric oxide and finally alkylation of the nitrogen atom at the 1-position of the product obtained, which is 3- [2- (2,2,2-trifluoroethyl) guanidino] pyrazole, 5-bromovaleronitrile.

By repeating the procedure described in Example 5 using each of the appropriate starting materials, the following compounds were obtained:

RNH

X

Example R— m number

9

CF3CH2— 3

CF3CH2— 5

CHF2CF2CH2— 4

CCIF2CH2— 4

Comment:

Example 6:

1,25-maleate, m.p. 158-159 ° C (36% yield).

Example 7:

M.p. 130-131 ° C (41% yield).

Example 8:

bis-maleate hemihydrate, m.p. 93-95 ° C (yield 58%).

Example 9:

M.p. 162 DEG-163 DEG C. (yield 86%).

The starting materials can be prepared by repeating the procedures described in the second, third, fourth and fifth sections of Example 5 using 4-bromobutyronitrile, respectively. 6-bromohexanonitrile instead of 5-bromvaleronitrile, and using 2,2,3,3-tetrafluoropropyl isothiocyanate, respectively. 2-chloro-2,2-difluoroethylisothiocyanate instead of 2,2,2-trifluoroethylisothiocyanate.

Example 10

A solution of 0.35 g of 5- [4- (2- / 2,2,2-trifluoroethyl / guanidino) -1,2,3-triazol-2-yl] valeronitrile in 1.0 ml of concentrated sulfuric acid is left for 5 hours The reaction mixture was poured into 5 ml of ice-water, basified with aqueous sodium hydroxide, saturated with sodium chloride and extracted with ethyl acetate. The extract was dried over magnesium sulfate and evaporated to a yellow gummy residue. This resin residue was dissolved in a small volume of ethyl acetate and treated with a solution of 0.14 g of maleic acid in a small volume of acetone to give a solution from which the desired product crystallized. Filtration gave 0.33 g of 5- [4- (2- (2,2,2-trifluoroethyl) guanidino) -1,2,3-triazol-2-yl] valeramide maleate, m.p. 156-157 ° C. .

The starting material can be obtained as follows.

To a solution of 23.0 g of 4-nitro-1,2,3-triazole in 135 ml of dry dimethylformamide was added a dispersion of 4.8 g of sodium hydride in 4.8 g of mineral oil at room temperature. After stirring for 30 minutes, 33.0 g of 5-bromvaleronitrile was added. The reaction 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 silica gel using a mixture of equal volumes of ethyl acetate and petroleum ether (b.p. 60-80 ° C). 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 is stirred in hydrogen to 420 ml of hydrogen. The resulting 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 0.5 g of 2,2,2-trifluoroethylisothiocyanate in 5 ml of acetonitrile was stirred at room temperature overnight. the mixture was evaporated and the residue was recrystallized from toluene / petroleum ether (bp 60-80 ° C) to give 0.5 g of 5- (4- (3- / 2,2,2-trifluoroethyl) thioureido [1,2-a], m.p. 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-trifluoroethyl) thioureidoj-1,2,3-triazol-2-yl] valeronitrile in 10 ml of 6 M ethanolic ammonia was added with stirring The reaction mixture was stirred at room temperature for 2 hours, then filtered and evaporated to give 0.41 g of 5- [4- (2- (2,2,2-trifluoroethyl)]. guanidino) -1,2,3-triazol-2-yl] valeronitrile.

Examples 11 to 13

The procedure described in Example 10 was repeated using the respective starting materials. The following compounds are obtained:

^RN V m

J.C 'N ~~ (r Hg) p ~ CO 1')

Example number R— P 11 CF3CH2— 3 12 CHF2CF2CH2— 4 13 CF3CH2— 5

Comment:

Example 11:

maleate, m.p. 159-161 ° C (53% yield).

Example 12:

maleate, m.p. 141-142 ° C (yield 58%).

Example 13:

maleate, m.p. 146-147 ° C (49% yield).

The starting materials can be prepared by repeating the procedures described in the second, third, fourth and fifth sections of Example 10 using 4-bromobutyronitrile, respectively. 6-bromohexanonitrile instead of 5-bromvaleronitrile and using 2,2,3,3-tetrafluoropropyl isothiocyanate instead of 2,2,2-trifluoromethylisothiocyanate.

Example 14

To 0.3 g of 5- (4- (2- (2,2,2-trifluoroethyl) guanidino) pyrimid-2-yl] valeric acid was added dropwise 1 ml of thionyl chloride and the mixture was gently heated on a steam bath for 5 minutes. The reaction mixture was concentrated in vacuo and the gummy residue was overlayed with 5 mL of dichloromethane, then a solution of 0.105 g of aniline in 0.5 mL of dichloromethane was added, followed by dropwise addition of triethylamine until basic, and the resulting mixture was stirred at room temperature for 30 min. water, the organic phase is separated and dried over magnesium sulphate.

Filtration and evaporation gave an oily material which was dissolved in a small volume of ethanol and excess ethanolic maleic acid was added to the solution.

The precipitate formed is filtered off, washed with ethanol and recrystallized from ethanol. N-phenyl-5- [4- (2- (2,2,2-trifluoroethyl) guanidino) pyrimid-2-yl] valeramide maleate was obtained in 21% yield. 0.25 H2 O, melting at 169-171 ° C.

The starting material can be prepared as follows.

Ethyl 5-cyanvalenamide was stirred in 200 ml of methanol containing 26.4 g of ammonium chloride for 18 hours. The mixture is filtered, the filtrate is evaporated to dryness and the residue is refluxed in 250 ml of ethanol containing 285 ml of triethylamine and 106 g of 2-chloroacrylonitrile. After 2 hours, the reaction mixture was cooled, added to 1 liter of water and adjusted to pH 4 with acetic acid. The aqueous mixture was clarified with charcoal, filtered and the filtrate was extracted with 300 ml of ethyl acetate. The aqueous phase is separated and adjusted to pH 9 with aqueous sodium hydroxide solution. The aqueous mixture is extracted twice with 500 ml of ethyl acetate each time, the combined extracts are evaporated to dryness and the residue is recrystallized from acetonitrile. 16 g of 5- (4-aminopyrimid-2-yl) valeritrile are obtained.

A mixture of 30 g of 5- (4-aminopyrimidin-2-yl) valeronitrile and 30 g of 2,2,2-trifluoroethylisothiocyanate in 50 ml of acetonitrile. The mixture was heated at reflux for 18 hours. The reaction mixture was evaporated to dryness and the residue was dissolved in a saturated methanolic ammonia solution. 48 g of mercuric oxide are added to the resulting solution with stirring, 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) guanidinopyrimid-2-yl] valeronitrile.

To 2 g of 5- [4- (2- (2,2,2-trifluoroethyl) guanidino) pyrimid-2-yl] valeritrile was added 10 ml of concentrated hydrochloric acid and the mixture was heated on a steam bath for 1.75 hours. After cooling the mixture and evaporation in vacuo the residue dissolved in water and basified with aqueous sodium carbonate solution was adjusted to 5. The precipitate was filtered off, washed first with water and then ethanol, and dried in vacuo at 70 C to obtain ^Q with 1.9 g of 5- (4- (2- (2,2,2-trifluoroethyl) guanidino) pyrimid-2-yl) valeric acid which was used without further purification.

Example 15

A mixture of 0.45 g of 5- [4- (2- (2,2,2-trifluoroethyl) guanidino] pyrimid-2-yl] valeronilile hydrogen maleate prepared as described in Example 14 and 4 ml of concentrated sulfuric acid was stirred at room temperature for 4 hours. The reaction mixture is poured onto 15 g of ice and the pH is adjusted to 9 with aqueous sodium hydroxide. The mixture is evaporated to dryness and the solid residue is extracted with 150 ml of methanol / chloroform (1:20 v / v). 0.15 g of 5- [4- (2- (2,2,2-trifluoroethyl) guanidino) pyrimidin-2-yl] valeramide hemihydrate was prepared from the residue by treatment with maleic acid in acetone. m.p. 182-185 ° C.

Example 16

Analogous to Example 15, using the appropriate starting material, 6- (4- (2- (2,2,2-trifluoroethyl) guanidinopyrimidin-2-yl) hexanamide) was obtained in 22% yield, m.p. 179-181 ° C.

The starting material can be prepared by repeating the procedure described in the second and third parts of Example 14, using ethyl 6-cyanohexanimidate instead of ethyl 5-cyanvalerimidate.

Example 17

To a solution of 147 mg of 3- [4- (2- / 2,2,2-trifluoroethyl / guanidino) pyrimid-2-ylthio] propanethiol hydrogen maleate and 70 mg of sodium methoxide in methanol is added 123 mg of 2-iodoacetamide, the resulting solution The mixture was stirred at room temperature for 24 hours and then evaporated to dryness. The residue was partitioned between water and ethyl acetate, the ethyl acetate phase was dried and evaporated to dryness. The residue is purified by preparative thin layer chromatography on silica gel in a solvent system consisting of a mixture of ethyl acetate, methanol and concentrated aqueous ammonia (density 0.880) in a ratio of 6: 1: 0.5 (v / v / v). 50 mg of resinous 2- {3- [4- (2- / 2,2,2-trifluoroethyl / guanidino) pyrimid-2-ylthio] propylthioacetamide are obtained, which crystallizes in the form of hydrogen maleate from ethyl acetate and melts at room temperature. Mp 168-170 ° C.

The starting material can be prepared as follows.

A mixture of 81 mg of sodium methoxide, 10 ml of methanol, 1 ml of 1,3-propanedithiol and 280 mg of 4- (2- (2,2,2-trifluoroethyl) guanidino] -2-ethanesulfinylpyrimidine (see European patent publication no. The residue was partitioned between 2 N aqueous hydrochloric acid and ether, basified with 10 N aqueous sodium hydroxide, and extracted with ethyl acetate. to dryness and the residue was crystallized in the form of hydrogen maleate from acetone to give 260 mg of 3- [4- (2- / 2,2,2-trifluoroethyl / guanidino) pyrimid-2-ylthio] propanethiol hydrogen maleate, m.p. 155 ° C.

Example 18

A mixture of 0.5 g of 5- [4- (2- / 2,2,2-trifluoroethyl / guanidino) pyrimid-2-yloxy] valeronitrile and 3 ml of concentrated sulfuric acid is heated until it reaches a solution which is then treated for 2 hours. Stir at room temperature. The reaction mixture was poured into water and basified with potassium carbonate. Extraction with ethyl acetate yields a yellow gum product which is converted to 5- [4- (2- / 2,2,2-trifluoroethyl / guanidino) pyrimid-2-yloxy] valeramide maleate in acetone, m.p. 192-193 ° C. yielding 0.38 g (54 percent).

The starting material can be prepared as follows.

To 2.75 g of sodium hydride in 95 ml of tert-butanol is added 10 g of 4-cyanobutanol, the solution is heated to 40 ° C and 11.24 g of 4- (2- / 2,2,2,2-g) are added over 10 minutes. (trifluoroethyl / guanidino) -2-methylsulphinylpyrimidine and the reaction solution was first reacted at 40 ° C for 2 hours and then at room temperature for 18 hours. The solvent was evaporated in vacuo and the residue was washed first with water and then with ether. 8.5 g of 5- [4- (2- / 2,2,2-trifluoroethyl) guanidino] pyrimid-2-yloxy] valeronitrile of melting point 134 DEG-136 DEG C. are obtained.

Repeat the procedure described in Example 18 using the appropriate starting materials. The following compounds are obtained:

X N H

\ ^x r * ™ λ, t Example R— number 19 Dec CCIF2CH2— 20 May CHF2CF2CH: 21 CF3CH2—

Comment:

Example 19:

mp 149-153 ° C.

Example 20:

mp 161-162 ° C (yield 38%). Example 21:

mp 189-191 ° C (yield 69%).

The starting materials for the above procedure can be prepared by repeating the second part of Example 18 using 3-cyanopropanol instead of 4-cyanobutanol and using 2-methylsulfinyl-4- [2- (2-chloro-2,2-difluoroethyl) guanidino] pyrimidine, respectively. 2-methylsulfinyl-4- [2- (2,2,3,3-tetrafluoropropyl) guanidino] pyrimidine instead of 2-methylsulfinyl-4- [2- (2,2,2-trifluoroethyl) guanidino] pyrimidine. The pyrimidine derivatives can be prepared by repeating the procedures described in the second, third and fourth parts of Example 34 in European Patent Publication No. 30,092 after poly (CKn) 3-CO using 2-chloro-2,2-difluoroethylisothiocyanate and 2.2, respectively. 3,3,3-tetrafluoropropylisothiocyanate instead of 2,2,2-trifluoroethylisothiocyanate.

Example 22

A solution of 850 mg of 3- [4- (2- / 2,2,2-trifluoroethyl / guanidino) pyrimid-2-ylmethylthio] propionitrile in 4 ml of concentrated sulfuric acid was allowed to react at 20 ° C for 16 hours and then added dropwise to saturated aqueous sodium carbonate solution. The mixture was extracted with ethyl acetate (3.times.20 ml), dried (MgSO4) and evaporated in vacuo. There was thus obtained oily 3- [4- (2- / 2,2,2-trifluoroethyl / guanidino) pyrimid-2-ylmethylthio] propionamide which was treated with maleic acid in acetone to give 720 mg (60%) of the maleate melting at 168-169 with decomposition. Noc: 2 ° C.

The starting material can be prepared as follows.

To a solution of 55 g of chloroacetamidine hydrochloride and 120 ml of triethylamine in 250 ml of ethanol cooled to 10 DEG C., 35 ml of 2-chloroacrylonitrile was added portionwise over 15 minutes. The temperature was allowed to rise to 40 ° C over 1 hour, the mixture was cooled, filtered and the filtrate evaporated in vacuo. The residue is taken up in 600 ml of ethyl acetate from which tar material precipitates. The solution is clarified with activated carbon, filtered and evaporated. 4-Amino-2-chloromethylpyrimidine is obtained as a brown solid.

1.4 g of the pyrimidine prepared above and 0.8 g of thiourea in 40 ml of ethanol were heated under reflux for 20 minutes, whereupon a crystalline precipitate formed. After cooling, S- (4-amimopyrimid-2-ylmethyl) isothiourea hydrochloride was isolated by filtration.

g of the isothiourea derivative prepared above is added to a solution of 1.1 g of potassium hydroxide in 20 ml of water, the resulting solution is stirred under nitrogen for 2 hours, then 1 ml of acrylonitrile is added and the mixture is stirred vigorously for 30 minutes. The reaction solution was extracted with ethyl acetate, the extract was dried over magnesium sulfate and evaporated in vacuo. 3- (4-aminopyrimid-2-ylmethylthio) propionitrile is obtained in the form of a resin which solidifies on standing and melts at 108-109 ° C.

To a solution of 1.7 g of 3- (4-aminopyrimid-2-ylmethylthio) propionitrile in 40 ml of acetonitrile was added 2 ml of 2,2,2-trifluoroethylisothiocyanate, and the resulting solution was heated under reflux for 17 hours. , the residue was dissolved in ethyl acetate, the solution was clarified with charcoal and evaporated after filtration to give 3- [4- (3- / 2,2,2-trifluoroethyl) thioureido] pyrimid-2-ylmethyl-propionitrile as an orange solid melting at 108-110 C. ³

Κ 1 g of the thiourea derivative prepared above in 10 ml of dimethylformamide and 10 ml of 8 M ethanolic ammonia are added 3 g of mercuric oxide. The mixture was stirred for 40 minutes, then diluted with 100 mL of a mixture of equal volumes of ethyl acetate and water, and filtered through a pad of diatomaceous earth. The ethyl acetate extract was dried over magnesium sulfate and evaporated in vacuo to give 3- [4- (2- / 2,2,2-trifluoroethyl) guanidinopyrimidin-2-ylmethylthio] propionitrile as an oil which was used without further purification.

Example 23

The procedure described in Example 22 was repeated using 4- [4- (2- (2,2,2-trifluoroethyl) guanidino) pyrimid-2-ylmethylthio] butyronitrile as starting material. Yield: 4- [4- (2- (2,2,2-trifluoroethyl) guamidino) pyrimid-2-ylmethylthio] butyramide, m.p. 126 DEG-128 DEG.

The starting material can be prepared by repeating the procedure described in the fourth, fifth and sixth parts of Example 22 using 4-bromobutyronitrile instead of acrylonitrile.

Example 24

A solution of 400 mg of trans-6- [4- (2- / 2,2,2-trifluoroethyl / guanidino) pyrimid-2-yl] hex-5-enenitrile in 2 ml of concentrated sulfuric acid was allowed to react at 20 ° for 18 hours. C and then added dropwise to a saturated aqueous solution of sodium carbonate. The mixture was extracted with ethyl acetate (2 x 15 mL each), dried over magnesium sulfate and evaporated in vacuo to give an oily trans-8- [4- (2- / 2,2,2-trifluoroethyl / guanidino) pyrimid-2- yl] hex-5-enamide, from which the maleic acid salt was obtained in acetone, yielding 205 mg (36%) melting at 177-179 ° C.

The starting material can be prepared as follows.

To a solution of 50 ml thiophenol in 400 ml

A 2.5 M aqueous solution of sodium hydroxide was added, while stirring under a nitrogen atmosphere at 20 ° C, 63 g of chloroacetamidine hydrochloride in 250 ml of water. The precipitated solid material was filtered off, squeezed to dryness, suspended in ethyl acetate and the ethyl acetate was evaporated. The solid product was resuspended in ethyl acetate, a saturated solution of hydrochloric acid in ethyl acetate was added thereto, and the mixture was stirred for 30 minutes. The resulting phenylthioacetamidine hydrochloride was filtered off, washed with ether and used directly.

A mixture of 10 g of phenylthioacetamidine hydrochloride, 8.75 g of 2-chloroacrylonitrile, 27.5 ml of trlethylamine and 75 ml of ethanol was heated under reflux for 4 hours. The reaction solution was evaporated in vacuo and the residue was partitioned between ethyl acetate and 1 M aqueous hydrochloric acid. The aqueous extract was basified, extracted with ethyl acetate (3.times.100 ml), dried (MgSO4) and evaporated in vacuo. A red colored oily residue is obtained containing 4-amino-2-phenylthiomethylpyriinidine.

To 15 g of crude 4-amino-2-phenylthiomethylpyrimidine in 150 ml of methanol and 100 ml of water at 60 ° C was added, over 15 minutes, 20 g of sodium metaiodate in 100 ml of water. The methanol was evaporated in vacuo and the clear aqueous solution was decanted from the precipitated red colored resin material. 4-Amino-2-phenylsulfinylmethyl-pyrimidine crystallized from the aqueous solution as a white solid, m.p. 202-204 ° C. Recrystallization from ethanol / ether gave an analytical sample of the product melting at 207-208 ° C.

To a solution of 0.88 g potassium tert-butoxide in 30 ml of dimethylformamide under nitrogen at ^0-C was added with stirring 1.84 g of 4-amino-2-fenylsulfinylmethylpyrimidinu. The resulting solution was stirred for 10 minutes and then 1.3 g of 5-bromo-valeronitrile in 5 ml of DMF was added over 5 minutes. The reaction mixture was stirred at 0 ° C for 30 minutes, then poured into 150 ml of water and extracted four times with 15 ml of ethyl acetate each time. The extract was dried (MgSO4) and evaporated in vacuo to give 1.7 g of a clear resinous material which was dissolved in 40 mL of toluene by refluxing for 30 minutes.

The toluene was evaporated in vacuo and the residue was partitioned between dichloromethane and 1M aqueous hydrochloric acid. The aqueous layer was basified with 4 M aqueous sodium hydroxide and extracted three times with 16 ml dichloromethane each. The extract was dried (MgSO4) and evaporated in vacuo to give a clear gum (900 mg). To this residue is added 500 mg of 2,2,2-trifluoroethylisothiocyanate in 20 ml of acetonitrile and the solution is heated under reflux for 19 hours.

Acetonitrile was evaporated in vacuo and trans-6- [4- (3- / 2,2,2-trifluoromethyl) thioureido] was isolated by evaporation from medium pressure silica gel using ethyl acetate / cyclohexane (3: 7 v / v) as eluent. (Pyrimid-2-yl) hex-5-ene.

350 mg of the thiourea derivative prepared above are dissolved in 8 ml of dimethylformamide and 4 ml of 8 M ethanolic ammonia, 1 g of mercuric oxide is added, the mixture is stirred for 40 minutes, then poured into 100 ml of a mixture of equal portions of water and ethyl acetate. filtered through a pad of diatomaceous earth. The ethyl acetate extract was dried over magnesium sulfate and concentrated in vacuo. There was thus obtained trans-6- [4- (2- (2,2,2-trifluoroethyl) guanidino] pyrimid-2-yl] hex-5-enenitrile gum which was used without further purification.

Example 25

A solution of 0.15 g of 5- [3- (2- / 2,2,2-trifluoroethyl / guanidino) -1,2,4-triazol-1-yl] valeronitrile in 3 ml of concentrated sulfuric acid was stirred at room temperature for 1.5 hours. The reaction mixture was poured onto ice and basified with concentrated aqueous ammonia. Extraction with ethyl acetate gave 0.12 g of a white solid which, after trituration with ether, gave 0.085 g (54%) of 5- [3- (2- / 2,2,2-trifluoroethyl) guanidino] -1,2,4 162-164 ° C; triazol-1-yl] valeramide;

The starting material can be prepared as follows.

To a solution of sodium methoxide in methanol (1.2 g of sodium in 30 ml of methanol) was added 4.2 g of 3-amino-1,2,4-triazole, the resulting solution was stirred at room temperature for 0.5 h, then 5-bromvaleronitrile (8.1 g) was added thereto, and the solution was heated to reflux for 12 hours. The reaction solution was evaporated and the residue was partitioned between water and ethyl acetate. The extracts were washed with brine, dried (MgSO4) and evaporated. 6.5 g of a yellowish oily material are obtained, which is purified by medium pressure liquid chromatography using a 6: 1 v / v mixture of ethyl acetate and methanol as eluent. The colorless oily product thus obtained is used without characterization for the following reaction.

To crude 1- (4-cyanbutyl) -3-amino-1,28

Of 4-triazole (5.45 g) in 80 ml of acetonitrile was added 4.4 g of 2,2,2-trifluoroethylisothiocyanate, the resulting solution was heated at reflux for 3.5 hours, then evaporated to a sticky solid residue. The mixture was triturated with a mixture of ether and ethanol. 4.04 g of 5- [343- (2,2,2-trifluoroethyl) thioureido] -1,2,4-triazol-1-yl] valeronitrile are obtained as a white solid, m.p. 136 DEG-138 DEG.

To 3.6 g of this nitrile in 80 ml of methanol and 5 ml of acetonitrile was added 3.06 g of mercuric oxide and 15 ml of methanolic ammonia. The mixture was stirred for 1.5 hours, the resulting black suspension was filtered through a pad of diatomaceous earth, and the filtrate was evaporated to a white solid which was washed with ether and filtered. 2.87 g of 5- [3- (2- / 2,2,2-trifluoroethyl / guanidino) -1,2,4-triazol-1-yl] valeronitrile are obtained as a white solid, m.p. 200 DEG-201 DEG.

Example 26

A solution of 0.25 g of 5- [4- (2- / 2,2,2-trifluoroethyl / guanidino) -1,3,5-triazin-2-ylthio] valeronitrile in 1 ml of concentrated sulfuric acid was allowed to react at room temperature for 4 hours. room temperature. The reaction mixture was diluted with an equal volume of ice, basified with aqueous sodium hydroxide, and filtered. The white solid was dissolved in a small volume of ethanol and acetone, and a solution of 0.09 grams of maleic acid in a small volume of acetone was added. The mixture was allowed to stand overnight and then filtered. 0.15 g of 5- (4- (2- (2,2,2-trifluoroethyl) guanidino) -1,3,5-triazin-2-ylthio) valeramide maleate melting after recrystallization from ethanol at 166-168 ° C is obtained. .

The starting material can be prepared as follows.

A mixture of 5.1 g of 2-mercapto-4-amino-1,3,5-triazine, 16 ml of 10% (w / v) aqueous sodium hydroxide and 5-bromvaleronitrile was allowed to react at room temperature with stirring for 3 hours. The filtrate was allowed to stand overnight at room temperature, then filtered again to isolate the next crop, washed with ether and recrystallized from ethanol to give 6.7 g of 5- (4). amino-1,3,5-triazin-2-ylthio ivaleronitrile, m.p. 123-125 ° C.

To 0.9 g of 5- (4-amino-1,3,5-triazin-2-ylthio) valeronitrile in 30 ml of tetrahydrofuran, under argon at -60 ° C, was added 3.1 ml of a 1.6 M solution of n- butyllithium in hexane. The resulting mixture was stirred at -60 ° C for 30 minutes, then 0.7 g of 2,2,2-trifluoroethylisothiocyanate was added. The reaction mixture was allowed to warm to room temperature, stirred overnight, then poured into water and acidified with a small volume of concentrated hydrochloric acid.

The aqueous and organic phases are separated, the aqueous phase is extracted with ethyl acetate and the extract is combined with the above-mentioned organic phase of the reaction mixture. The combined organics were dried over magnesium sulfate and evaporated to a sticky solid which was triturated with petroleum ether (bp 40-60 ° C and ethyl acetate) to give 1.0 g of 5- [4- (3- / 2,2) 1,2-Trifluoroethyl / thioureido-1,3,5-triazin-2-ylthio] valeronitrile melting after recrystallization from ethanol at 136-137 ° C.

To a suspension of 2.0 g of 5- [4- (3- (2,2,2-trifluoroethyl) thioureido] -1,3,5-triazin-2-ylthio] valeronitrile in 40 ml of 6 M ethanolic ammonia was stirred at a temperature of After about 1 hour, the reaction mixture was diluted with 20 mL of dimethylformamide, allowed to stand overnight, filtered and evaporated.

The nonvolatile residue was dissolved in 40 ml of dimethylformamide and 20 ml of 6M ethanolic ammonia solution, and 1 g of mercuric oxide was added at room temperature. The resulting mixture was stirred for 4 hours, then filtered, the filtrate was evaporated to dryness, redissolved in ethanol and saturated with hydrogen sulfide gas. The mixture is filtered, evaporated to dryness, the residue is dissolved in 15 ml of ethyl acetate, filtered and a solution of 0.66 g of maleic acid in a small volume of acetone is added.

Dilution with petroleum ether (b.p. 60-80 ^° C) gives a solution from which the desired product gradually precipitates. The precipitate is filtered off, washed with a small amount of cold acetone and then with petroleum ether (b.p. 60-80 ° C). 1.6 g of 5- [4- (2- / 2,2,2-trifluoroethyl) guanidino] -1,3,5-triazin-2-ylthio] valeronitrile maleate are obtained, melting after recrystallization from ethanol at 155-156. Deň: 32 ° C.

Example 27

To a solution of 650 mg of 4- {2- [3- (2- / 2,2,2-trifluoroethyl / guanidino] pyrazol-1-yl] ethoxymethyl] benzonitrile in 5 mL of methanol was added first 2 mL of 30% hydrogen peroxide and then 1 mL 1 N aqueous sodium hydroxide was added, the mixture was stirred at room temperature for 2.25 hours, the solvent was evaporated in vacuo, and the yellow gummy residue (700 mg) was purified by medium pressure chromatography using a 96: 3: 1 mixture of ethyl acetate, ethanol and triethylamine. This gave 210 mg (31%) of 4- {2- [3- (2- / 2,2,2-trifluoroethyl) guariidino] pyrazol-1-yl] ethoxymethyl} benzamide.

NMR (perdeuterodimethylsulphide):

7.5 (m, 4H).

7.5 (d, 1H),

5.8 (d, 1H,

5.0 (s, 2H).

4.0 (m, 4H);

3.7 (m, 2 H).

The starting material can be prepared as follows.

To a solution of 13.8 g of potassium carbonate in 40 ml of water was slowly added 7.6 g of 2-hydroxyethylhydrazine. The mixture was cooled to 0 ° C and 8.75 g of 2-chloroacrylonitrile was added slowly with vigorous stirring. Stirring was continued for a further 17 hours and the mixture was continuously extracted with ethyl acetate for 20 hours. Evaporation of the solvent gave 7.7 g (60%) of 3-amino-1- (2-hydroxyethyl) pyrazole, b.p. 170 DEG C./0.7 mbar.

A solution of 13.8 g of 2,2,2-trifluoromethylisothiocyanate and 12.5 g of 3-amino-1- (2-hydroxyethyl) pyrazole in 30 ml of acetonitrile dried over molecular sieves 4.10 ¹⁰ rn is stirred at room temperature for 4 hours. A precipitate began to form for 30 minutes. After filtration, 12.1 g (46%) are obtained.

1- (2-Hydroxyethyl) -3- (3- (2,2,2-trifluoroethyl) thioureido] pyrazole, m.p. 145-146 ° C.

To a solution of 20.0 g of 1- (2-hydroxyethyl) -3- (3- (2,2,2-trifluoroethyl) thioureido) pyrazole in 700 ml of 5N ethanolic ammonia solution was added with stirring 64.8 g of yellow oxide. Stirring is continued for a further 2 hours, then the mixture is filtered through diatomaceous earth and the solvent is evaporated to dryness in vacuo to give 18.5 g (99%) of 1- (2-hydroxyethyl) -3- [2- (2,2,2-Trifluoroethyl) guanidino] pyrazole, m.p. 82 ° C.

A mixture of 2.51 g of 1- (2-hydroxyethyl) -3- [2- (2,2,2-trifluoroethyl) guanidino] pyrazole and 1.96 g of p-cyanobenzyl bromide was heated at 140 ° C for 10 minutes. after cooling, it was dissolved in 5 ml of methanol and purified by chromatography on silica gel using a mixture of ethyl acetate, ethanol and triethylamine (9: 1: 1, v / v / v) as eluent to give 700 mg (19%) of 4- ( 2- (3- (2- / 2,2,2-trifluoroethyl / guanidino) pyrazol-1-yl) ethoxymethylbenzonitrile.

Example 28

A solution of 0.2 g of 4- [6- (2- / 2,2,2-trifluoroethyl / guanidino) pyrid-2-yloxy] butyronitrile in concentrated sulfuric acid was allowed to react at room temperature for 6 hours, then diluted with water and basified. with 10N aqueous sodium hydroxide. The resulting solution was extracted three times with ethyl acetate, the combined extracts were dried and evaporated to dryness. The residue was dissolved in acetone and added to an acetone solution of maleic acid. Filtration of the crystalline precipitate affords 0.14 g of 4- [6- (2- (2,2,2-trifluoroethyl) guanidino] pyridin-2-yloxy) butyramidohydride maleate, m.p. 176-177 ° C.

The starting nitrile can be prepared as follows.

A mixture of 0.85 g of 4-hydroxybutyronitrile, 0.48 g of a 50% (w / w) sodium hydride dispersion in mineral oil and 5 ml of sulfola241535 nu is stirred at room temperature for 1 hour, then 0.87 g of 2-amino is added. Of 6-bromopyridine, the resulting mixture was heated to 130 ° C with stirring for 18 hours, then cooled, diluted with 20 mL of water, acidified with concentrated aqueous hydrochloric acid and washed with ether. The aqueous phase was basified with 10 N aqueous sodium hydroxide, extracted three times with ethyl acetate, the combined extracts were dried and evaporated to dryness.

A solution of the residue obtained above in 5 ml of acetonitrile was treated with 2,2,2-trifluoroethylisothiocyanate, heated at reflux for 1 hour, and evaporated to dryness. The residue is stirred with 20 ml of 2N aqueous hydrochloric acid and 20 ml of ether, and the insoluble material is filtered off.

This solid was dissolved in methanolic ammonia solution, 2 g of yellow mercury oxide was added, the mixture was stirred at room temperature for 18 hours, then filtered and the filtrate was evaporated to dryness. 1.0 g of 4- [6- (2- (2,2,2-trifluoroethyl) guanidino) pyrid-2-yloxy] butyronitrile is obtained, which is used without further purification.

Example 29

In analogy to Example 28, using 4- [2- (2- / 2,2,3,3-tetrafluoropropyl / guanidino) pyrid-6-ylthio] butyronitrile as the starting material, the yield was 58% of 4- [2- (2- / 2,2,3,3-Tetrafluoropropyl / guanidino) pyrid-6-ylthio] butyramide maleate, m.p. 173-174 ° C.

Examples 30 to 36

Using the procedure described in Example 1, the following compounds can be prepared:

: ON-C

V-4-C0NH,

ZZ example circle —X — A—

Legend:

Example 30:

maleate, m.p. 143-146 ° C. Example 31:

maleate, mp 199-201 ° C. Example 32:

maleate, m.p. 171-172 C. Example 33:

168 DEG-170 DEG.

Example 34:

hydrogen maleate, mp 192 ° C. Example 35:

mp-maleate, m.p. 138-141 ° C.

Example 36:

maleate, m.p. 138-139 ° C. Examples 37 to 40

Using the procedure described in Example 1, the following compounds can be prepared:

CF ₃ CW ₂ NM.

CN - C ₂ n

Legend:

Example 37:

NMR (per deuterodiinethylsulfoxide):

7.5 (m, 5H);

5.73 (d, 1H),

4.06 (q, 2H);

5.22 (s, 2H).

Example 38:

NMR (Perdenterodimethylsulfoxide):

7.7 (s, 1 H),

3.92 (m, 4H);

2.06 (t, 2 H),

1.5 (m, 4H).

Example 39:

the maleate melts at 143-146 ° C.

Example 40:

NMR dimalate (perdeuterodimethylsulfoxide):

8.4 - 6.4 (broad m, 10H including 7.7 [s, 1H]),

5.04 (quintet, 1H),

4.35 (q, 2H);

2.85 (quintet, 1H),

2.45-1.9 (m, 6Ή).

Claims (2)

SUBJECT VYNALEZ U A process for the preparation of guanidine derivatives of the general formula I (X 1) CNC (f) wherein each of R ¹ and R ² , which may be the same or different, represents a hydrogen atom, a branched or unbranched alkyl group having 1 to 10 carbon atoms, (C 3 -C 8) cycloalkyl or (C 4 -C 14) cycloalkyl group, each of which is alkyl, cycloalkyl or cycloalkylalkyl optionally substituted by one or more halogen atoms selected from the group consisting of fluorine, chlorine and bromine, that at least one of R ¹ and R ² represents a halogen-substituted alkyl, cycloalkyl or cycloalkylalkyl group and with the proviso that no halogen substituent is present on the carbon atom of the alkyl, cycloalkyl or cycloalkylalkyl group directly connected to the nitrogen atom, or R ² is hydrogen and R ¹ is b ytek II R5- _e __ _ _W (II) wherein W represents an unbranched C 2 -C 6 alkylene chain optionally substituted by one or two C 1 -C 4 alkyl groups, E represents an oxygen or sulfur atom, a sulfinyl group, a sulfonyl group or a radical of the formula NR ⁶ , wherein R ⁸ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and R ⁵ represents a hydrogen atom or a straight-chain alkyl group having 1 to 6 carbon atoms, optionally substituted by one or two alkyl groups having 1 to 4 carbon atoms, or are R ⁵ and R ^6, taken together with the nitrogen atom to which they are attached, form a pyrrolidine, piperidine, morpholine, piperazine or N-methylpiperazine ring, the dotted line in the X ring being a double bond on one side of the nitrogen atom and Z represents a carbon atom or a nitrogen atom, such that the ring X is a five- or six -241535 membered aromatic heterocyclic ring containing at least one nitrogen atom and optionally containing one or two additional heteroatoms selected from oxygen, nitrogen and sulfur atoms, the heterocyclic ring X there where appropriate, it may optionally carry one or two substituents selected from the group consisting of chlorine, chlorine and bromine atoms, alkyl groups of 1 to 6 carbon atoms, alkoxy groups of 1 to 6 carbon atoms, trifluoromethyl, hydroxy and amino, A represents a phenylene group, a C 5 -C 7 cycloalkylene group or a C 1 -C 8 alkylene radical optionally substituted by one or two C 1 -C 3 alkyl groups and optionally containing one or two groups selected from the group consisting of oxygen and sulfur atoms, NH, N-C 1 -C 6 alkyl, cis- and trans-vinylene, ethinylene, phenylene and cycloalkylene of 5 to 7 carbon atoms, with the shortest part of the chain between the rings X and C = O consists of at least 3 atoms, wherein the A chain may optionally be interrupted by a group directly attached to C = O, which is not oxygen, sulfur, NH or N-alkyl, and wherein no two groups are present, optionally interrupting the chain of residue A selected from oxygen and sulfur atoms, NH and N-alkyl groups and pharmaceutically acceptable acid addition salts thereof, characterized in that a compound of formula V 'from -A-CN (V) in which: R ^1, R ^2, A, X and Z have the above meanings, and the resulting compound of formula I, resulting in the free base form, optionally converted by reaction with an acid affording a pharmaceutically acceptable anion to its acid addition salt. 2. The process according to claim 1, wherein the starting materials of the general formula V are used in which: R ¹ represents a 2,2,2-trifluoroethyl group, R ² is hydrogen, ring X is a pyrazole ring, A represents a tetramethylene group.