CS241049B2 - Method of pyrimidone derivatives production - Google Patents

Description

The present invention provides certain pyrimidone derivatives, processes for their preparation, compositions containing them and their use as histamine antagonists.

Histamine, which is an endogenous physiologically active compound in mammals, exerts its effects by interacting with certain sites called receptors. One type of such receptor is known as the histamine H 1 -receptor (Ash and Schild, Brit. J. Pharmac. 1966, 27, 427) and the action of histamine on these receptors is inhibited by drugs commonly referred to as "an2 thihistamics" (Hi-antagonists). histamine) and exemplified by mepyramine. The second type of receptor is known as the Hz-receptor (Black et al., Nature 1972, 236, 385).

The action of histamine on these receptors is not inhibited by mepyramine, but is inhibited by burimamide. Compounds that inhibit the effects of histamine on the histamine H 1 -receptors are called histamine H 2 -agonists.

U.S. Pat. No. 4,154,834 discloses compounds of Formula I

(i) in which:

Het represents a 2- or 4-imidazolyl radical optionally substituted by a lower alkyl group (preferably a methyl group), a halogen (preferably chlorine or bromine), a trifluoromethyl group or a hydroxymethyl group, a 2-pyridyl group optionally substituted by one or two identical or different groups selected from the group consisting of lower alkyl groups (preferably methyl), lower alkoxy groups (preferably methoxy), halogen atoms (preferably chlorine or bromine), amino and hydroxyl groups, further being a 2-pyridyl radical to which it is uncondensed

a phenyl ring, a carbocyclic or cyclic ether ring containing two oxygen atoms, furthermore a 2-thiazolyl radical, a 3-isothiazolyl radical optionally substituted by chlorine or bromine, a 3- (1,2,5-thiadiazolyl radical optionally substituted by chlorine or bromine), or a 2- (5-amino-1,3,4-thiadiazolyl) residue,

Y is sulfur or methylene, m is 0, 1 or 2 and n is 2 or 3 such that the sum of these symbols is 3 or 4, or when Y is methylene and Het is not an imidazolyl ring, 2,

Z represents a hydrogen atom or a lower alkyl group (preferably a methyl group),

X represents oxygen or sulfur,

A represents a straight or branched C 1 -C 5 alkylene chain or a radical of the formula

- (CH 2) _p W (CH 2) _q where

W is oxygen or sulfur and p and q are numbers such that their sum is 1 to 4, and. The heme represents a five- or six-membered heteroocyclic ring selected from the group consisting of pyridine, pyridine-N-oxide, furan, thiophene, thiazole, oxazole, isothiazole, imidazole, pyrimidine, pyrazine, pyridazine and thiadiazole ring, which ring is optionally substituted one or two of the same or different substituents selected from the group consisting of lower alkyl, lower alkoxy, halogen atoms, hydroxyl and amino, or Het 1 represents a fused carbocyclic or cyclic ether ring containing two oxygen atoms, or Het 1 represents a pyridine, imidazole or a fused benzene ring thiazole ring, and pharmaceutically acceptable salts thereof.

It is disclosed that these compounds exhibit combined efficacy as histamine H 1 and H 2 -antagonists.

In particular, U.S. Pat. No. 4,154,834 discloses compounds of formula I wherein Het is a 2-pyridyl radical bearing a substituent at the 3-position, Y is a methylene group, and Het is a substituted pyridyl radical. It has now been found that if the Het 2-pyridyl residue contains a second substituent at the 5-position, the relative level of activity from the H 1 -receptors to the H 2 -receptors increases. Furthermore, it has been found that a small number of compounds of formula (I) exhibit efficacy of H 1 -amine histamine antagonists, so that they can be used to treat diseases such as bronchial asthma, rhinitis, hay fever and allergic eczema whose symptoms are mediated by Hi-receptor histamine.

Accordingly, the invention provides a compound of formula II

in which

R ¹ represents a halogen atom or a nitro group,

R ² represents an alkyl group having 1 to 4 carbon atoms,

R ³ represents an alkylene group having 1 to 3 carbon atoms and

R ⁴ represents

3-pyridyl,

N-oxo-3-pyridyl,

6-methyl-3-pyridyl,

N-oxo-6-methyl-3-pyridyl,

4,6-Dimethyl-3-pyridyl,

N-oxo-4,6-dimethyl-3-pyridyl,

5.6-dimethyl-3-pyridyl,

N-oxo-5,6-dimethyl-3-pyridyl,

4-pyridyl or

An N-oxo-4-pyridyl moiety, and pharmaceutically acceptable salts thereof.

R ¹ may be any of halogens, i.e. fluorine, chlorine, bromine or iodine. Preferably R ^{1 is} bromo.

Examples of alkyl groups having 1 to 4 carbon atoms represented by R ² include methyl, ethyl, n-propyl, isopropyl, n-butyl and t-butyl. Preferably R ² represents a methyl group.

Examples of radicals represented by R ³ include methylene, 1,2-ethanediyl or 1,3-propanediyl. Preferably, R ^{3 is} 1,2-ethanediyl or 1,3-propanediyl.

The radical R ^{@ 4} is preferably an optionally substituted 3-pyridyl radical. One of the substituents preferably is 241049 * I has a position of 6 so that the radical R ^{@ 4} is preferably, for example, a 6-methylpyrid-3-yl group.

Examples of compounds falling within the scope of the invention are:

2- [4- (5-nitro-3-methylpyrid-2-yl) butylamino] -5- (6-methylpyrid-3-ylmethyl) -4-pyrimidone,

2- (4- (5-chloro-3-methylpyrid-2-yl) butylamino) -5- (6-methylpyrid-3-ylmethyl) -4-pyrimidone,

2- [4- (5-iodo-3-methylpyrid-2-yl) butylamino] -5- (6-methylpyrid-3-ylmethyl) -4-pyrimidone,

2- (4- (5-fluoro-3-methylpyrid-2-yl) butylamino) -5- (6-methylpyrid-3-ylmethyl) -4-pyrimidone, and is a pharmaceutically acceptable salt thereof. with preferred substituents R ¹ and R ² are:

2- [4- (5-bromo-3-methylpyrid-Z-yl) butylamino] -5- (6-methylpyrid-3-ylmethyl) -4-pyrimidone,

2- (4- (5-bromo-3-methylpyrid-2-yl) butylamino] -5- (pyrid-4-ylmethyl) -4-pyrimidone, and pharmaceutically acceptable salts thereof.

It has been found that 2- [4- (5-bromo-3-methylpyrid-2-yl) butylamino] -5- (6-methylpyrid-3-ylmethyl) -4-pyrimidone is particularly advantageous in that other Hx-histamine antagonists do not enter the central nervous system. This was demonstrated by radiography of the whole rat body.

The compounds of formula II are depicted and described as 4-pyrimidones, which may exist in equilibrium with the corresponding tautomeric 6-ones. These compounds also occur to a lesser extent as tautomeric hydroxy derivatives and the pyrimidine ring may exist in the following tautomeric forms:

ΌΗ

It will be appreciated that all such tautomeric forms are within the scope of the invention.

The compounds of formula (II) form pharmaceutically acceptable salts with pharmaceutically acceptable salt-forming acids. Examples of such acids include hydrochloric acid, sulfuric acid, hydrobromic acid, phosphoric acid, tartaric acid, citric acid, maleic acid, lactic acid, 2-hydroxyethanesulfonic acid, methanesulfonic acid, 4-toluenesulfonic acid, ethanedisulfonic acid, ethanesulfonic acid, ethanesulfonic acid, camphorsulfone.

In accordance with the invention, the compounds of formula (II) above are prepared by guanidine of formula (X)

in which

R ¹ , R ² and R ³ are as in formula II, reacted with a compound of formula XI

in which

R ⁴ is as defined in formula IIa

R ⁸ is C 1 -C 4 alkyl (especially ethyl), benzyl or phenyl.

The reaction may be carried out by heating the guanidine of formula X with a compound of formula XI, optionally in a solvent, for example an alcohol corresponding to an ester function in a compound of formula XI, i.e. an alcohol of formula R ⁸ OH, to elevated temperature, preferably in the presence of a base. in particular sodium alkoxide of the formula NaOR ⁸ , which corresponds to the ester function of the compound of the general formula XI.

The guanidines of formula X can be prepared by reacting a compound of formula XII

AND

Β

Compound corresponding to formula IIIc

ΝΗχ

NH4XiU in which

R ⁹ represents a leaving group, for example methylthio or 3,5-dimethylpyrazolyl, with an amine of formula III

in which

R ² and R ³ are as defined in formula II, and salts thereof may be prepared by reacting a compound of formula IIIb

Compounds of formula III may be prepared by carrying out a Sandmeyer reaction on the corresponding compound of formula IIIa

(HIa) i.e. the amino group R ¹ is diazotized and the palo group is replaced by halogen.

Compounds of formula III above may also be prepared by halogenation of the corresponding compounds of formula IIIb

CC 3 ^^ čh ₂ r \ h ₂ nh _z (III b) in which

R ² and R ³ have the meanings as in the formula II with a halogen.

in which

R ² and R ³ are as defined in formula II, or a salt thereof with an electrophilic brominating agent.

Examples of electrophilic brominating agents are bromine or dibromocyanuric acid in a polar medium in which Br ⁺ ions are formed. Examples of such media are oleum and fluorosulfonic acid. Br ⁺ ions can also be formed from hydrobromic acid and bromide ions during oxidation in an oxidizing polar environment. For example, hydrobromic acid is oxidized to a bromine with a sulfur trioxide solution to dissociate to form Br ⁺ ions. In the present case, the sulfur trioxide can be dissolved in freon, for example in 1,1,2-trifluorotrichloroethane or sulfuric acid, i.e. the solution is oleum. The hydrobromic acid can be obtained from the dihydrobromide of the compound of formula (IIIb), especially when the reaction is carried out using sulfur trioxide and freon. When the solution of sulfur trioxide is oleum, hydrobromic acid can be obtained from a hydrobromic acid salt, for example an alkali metal hydrobromic acid salt, in particular potassium bromide.

The compounds of formula IIIb form neutral complexes with sulfur trioxide which act by activating the pyridine ring in the compounds of formula IIIb for bromination. Thus, the preferred reaction medium is one that dissolves sulfur trioxide.

Two preferred media for carrying out the bromination reactions are oleum and sulfur trioxide in freon. In practice, at least 20% (w / w) of oleate is used, preferably. at least 65% (w / w) olea. The more concentrated the oleum, the lower the temperature at which the reaction can be carried out. For example, if the reaction medium is 20% oleum, the reaction time should be at elevated temperature to achieve a reasonably short reaction time, and at this oleate concentration the reaction is carried out at a temperature of 100 ° C or higher. When the reaction medium is 65% oleum, the reaction may be carried out at a temperature of from 0 ° C to 100 ° C, preferably from 50 to 60 ° C, and in particular from 55 to 58 ° C.

If the reaction medium is sulfur dioxide in CFC, the reaction is carried out at a temperature from room temperature to the reflux temperature of the solvent.

Compounds of formulas II and IIIa may also be prepared by reduction of the corresponding cyano compound of formula V

R ⁷ represents a halogen atom, a nitro group or an amino group;

R ² and R ³ are as defined in formula II, with a reducing agent which reduces cyano to amino without reducing the radicals represented by R ⁷ in the reaction medium is inert to the reagents and product.

The reducing agent may be, for example, lithium aluminum hydride or diborane. The reaction medium may be a dialkyl ether, for example diethyl ether, or a cyclic ether, for example tetrahydrofuran or dioxane. If the reducing agent is lithium aluminum hydride or diborane, the reaction medium should be anhydrous.

Compounds of formula V wherein R ⁷ is amino may also be prepared by reduction of the corresponding nitro compound of formula V wherein R ⁷ is nitro. The reduction can be carried out by hydrogenation.

Compounds of formula (V) may be prepared by reacting a disubstituted chloropyridine of formula (VI) in which:

R ² has the meaning as in formula II and

R ⁷ represents a halogen atom, a nitro group or an amino group, reacted with a malonic ester of formula VII

ROzC \

CHR ³ CN (Vlij

ROzC

R ³ is as defined above and

R represents an ester-forming residue, in the presence of a strong base in an inert reaction medium, after which the product obtained is de-esterified and decarboxylated.

A particularly suitable radical for R is ethyl.

A particularly suitable strong base is sodium hydride.

Compounds of formula (IIb) may also be prepared by derivatizing a compound of formula (VIII)

(Pour) in which

R ² has the meaning as in formula II, with an alkali metal is reacted with a compound of formula IX

XR ³ NH ₂ (IX) wherein

X represents a halogen atom and

R ³ has the meaning as in formula II, or a salt thereof.

In the compound of formula IX, X may be chlorine, bromine or iodine, especially chlorine.

The alkali metal derivative may be a lithium, sodium or potassium derivative, in particular a sodium derivative.

The alkali metal derivative of the compound of formula VIII may be prepared in situ by reacting the compound of formula VIII with an alkali metal amide (especially sodium amide, in which case the alkali metal is sodium), the solvent being preferably liquid ammonia or an alkali metal alkyl derivative ( in particular butyllithium, in which case the alkali metal is lithium), the solvent being preferably an ether, for example diethyl ether or tetrahydrofuran.

This reaction is carried out at low temperatures. For example, if the reaction is carried out in liquid ammonia, the reaction temperature is

(VIII) at the boiling point of ammonia, and to prepare a derivative of general formula (VIII) in situ from an alkali metal alkyl derivative, the reaction is carried out at the boiling point of liquid nitrogen, preferably under an inert atmosphere.

The compounds of formulas VIII and IX are known or can be prepared by known methods.

Pharmaceutically acceptable salts of the compounds of formula II may be prepared by standard methods, for example by reacting a solution of a compound of formula II with an acid solution.

The activity of the compounds of formula II as Hx-antagonists of histamine can be demonstrated by an in vitro guinea pig ileum assay. In this test, the isolated portion of the guinea pig ileum is fixed under tension of 500 mg between the anchorage and the force transfer transducer in a 10 ml tissue bath and immersed in a magnesium-free Tyrode solution, where it is maintained at 30 ^° C with continuous aeration. The output of the converter is amplified and the amplified signal is sent to the recording device. Measured amounts of histamine are added to the tissue bath such that the histamine concentration increases in steps up to the maximum concentration strength. The tissue bath is washed and filled with fresh magnesium-free Tyrode solution containing the test compound. The solution is left in contact with the tissue for 8 minutes, then measured amounts of histamine are added again until maximum contraction is achieved. The assays are repeated with increasing concentrations of test compound and the dose of histamine exiting the contraction at 50% of the maximal contraction is recorded. The dose ratio (DR) is calculated by comparing the concentrations of histamine required to elicit a response corresponding to 50% of the maximal response both in the absence and antagonist presence. A plot of log DR-1 versus log D (test compound concentration) is plotted and the intersection with the log DR-1 ordinance is taken as a measure of potency (pAzj value). The compounds of Examples 1-12 have pA2 values greater than 8.

The efficacy of the compounds of formula I as histamine H 2 -antagonists can be demonstrated by an in vitro atrial test. In this test, the spontaneously throbbing portion of the right marrow atrium is fixed under tension of 300 mg between the anchorage and the transferor in a 15 ml tissue bath and immersed in McEwens solution, where it is maintained at 37 ° C with continuous aeration. The output of the converter is amplified and the amplified signal is sent to the recording device. Measured amounts of histamine are added to the tissue bath such that the histamine concentration increases gradually to a maximum pulse rate. The tissue bath is washed and filled with fresh McEwens solution containing the test compound. The solution is left in contact with the tissue for 60 minutes, after which time the measured amounts of histamine are added again until the maximum pulse rate is reached. The experiment is repeated with increasing concentrations of the test compound and the dose of histamine inducing a heart rate of 50 θ / o maximum frequency is recorded. Dose ratio (DR) is calculated by comparing the concentrations of histamine required to elicit a response corresponding to 50% of the maximal response both in the absence and in the presence of an antagonist. The plot of log DR-1 versus log D (test compound concentration) is plotted and the intersection with the log DR-1 ordinance is taken as a measure of potency (pA2 value). The compounds of Examples 1-12 have pA 2 values greater than 7.5.

The activity of the compounds of formula II as H 1 -amine histamine antagonists can be demonstrated by the in vivo inhibition of histamine-induced bronchoconstriction. Guinea pigs of both sexes are anesthetized by intraperitoneal injection of natriumpentobarbitone at a dose of 90 mg / kg. A cannula is inserted into the trachea and the animal is converted to artificial respiration using the specified volume of air just needed to expand the lungs. The pressure required to expand the lungs is monitored from the respiratory system using a low pressure transducer. Intravenous injection of histamine causes a dose-dependent increase in the pressure required to expand the lungs as a result of the bronchoconstrictor action of histamine. Histamine responses can be antagonized using histamine β-receptor antagonists.

Histamine dose-response curves are plotted at doses of 20, 40, 80, 160 and 320 mmol / kg. Antagonist is injected intravenously and histamine dose-response curves are re-constructed after 5 minutes, increasing histamine doses if necessary. The effect of the antagonist can be quantitatively expressed by the so-called dose ratio obtained by shifting the dose-response curve of histamine in the absence of antagonists to the right so as to coincide with the dose-response curve of histamine in the presence of antagonists and determining the magnitude of this shift. A series of antagonist doses can be administered to each animal and the dose ratios for each antagonist dose can then be calculated. The compounds of the examples below cause a shift in the dose-response curves of histamine corresponding to a dose ratio of 10 when administered intravenously at doses below 0.8 µmol / kg.

The efficacy of the compounds of Formula II as H2-antagonists of histamine can be demonstrated in vivo by inhibiting histamine-stimulated gastric acid secretion from the washed stomachs of urethane anesthetized rats. This procedure was described by Ash and Schild in Brit. J. Pharmac. Chemother., 27, 247 (1966). The compounds of the examples below cause 50% inhibition of maximum acid secretion at doses of 0.1 to 30 µmol / kg administered intravenously.

For use as a histamine H 1 antagonist, the compounds of the invention can be formulated into pharmaceutical compositions in accordance with standard pharmaceutical practice.

Accordingly, the invention also provides pharmaceutical compositions comprising a compound of formula (II) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

The compounds of formula II and their pharmaceutically acceptable salts can be administered systemically or topically.

Compositions for topical application to the skin include lotions and creams. Formulations for topical application to the respiratory tract include solutions for application by spraying or aerosols, or ultrafine powders for inhalation. The active ingredient in the inhalation powder has a small particle size, in particular less than 50 µm and preferably less than 10 µm. In addition to the active ingredient, a solid carrier, such as lactose, with particles smaller than 50 µm is present in the composition.

Systemic administration may be achieved by rectal, oral or parenteral administration. A typical suppository composition consists of the active ingredient together with a binder and / or a glidant, for example gelatin or cocoa butter, or other low melting vegetable waxes or fats. Typical compositions for parenteral administration are solutions or suspensions of the active ingredient in a sterile aqueous carrier or parenterally acceptable oil.

The compounds of formula II which are effective when administered orally may be formulated as syrups, tablets, capsules and lozenges.

A syrup composition is generally a suspension or solution of the active ingredient in a liquid carrier, for example, ethanol, glycerin or water, together with a flavoring or coloring agent. The composition in the form of a capsule consists of a solid granular preparation, optionally together with a binder, enclosed in a gelatin capsule. Any suitable pharmaceutical carrier (s) commonly used in the preparation of solid compositions may be used in the manufacture of tablets. Examples of such carriers include magnesium stearate, starch, lactose, glucose, sucrose and cellulose. Preferably, the compositions are in unit dosage forms, for example, in the form of a tablet, capsule, or aerosol, in a metered dose container so that the patient can self-administer the unit dose.

Where appropriate, the compositions of the invention may contain small amounts of bronchodilators and anti-asthma agents, for example sympathomimetically active amines such as isoprenaline, isoetharin, salbutamol, phenylephrine and ephedrine, xanthine derivatives, especially theophylline and aminophylline, and corticosteroids, in particular prednisoleroids. and adrenal stimulants, particularly ACTH. As is customary in practice, these compositions will be provided with written or printed instructions for use in the respective treatment, in this case, as H 1 -amine histamine antagonists for the treatment of, for example, asthma, hay fever or allergic eczema.

Each dosage unit for oral administration preferably contains 1 to 200 mg of the compound of formula II or a pharmaceutically acceptable salt thereof (calculated as the free base).

The pharmaceutical compositions of the invention will normally be administered in human medicine for the treatment of rhinitis, hay fever, bronchial asthma or allergic eczema. An adult patient will be dosed orally between 15 and 400 mg, preferably between 15 and 200 mg, intravenously, subcutaneously or intramuscularly, between 1 and 50 mg, preferably between 1 and 10 mg, of a compound of Formula I or a pharmaceutically acceptable salt thereof. (calculated as the free base), wherein the composition will be administered one to four times daily.

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

EXAMPLE 1 (a) A mixture of 4.06 g of [4- (5-bromo-3-methylpyrid-2-yl)] butylamine and 2.76 g of cyanimide in 50 ml of 1-propanol is acidified to pH 8-9 and heated at room temperature for 24 hours. reflux. The 1-propanol is evaporated under reduced pressure, the residue is dissolved in 50 ml of methanol. the solution is filtered and the filtrate is diluted with 200 ml of 1-propanol. The diluted solution is then cooled in ice. The precipitate formed is filtered off and dried under vacuum at 80 ° C for 3 hours. 3.42 g of 4- (5-bromo-3-methylpyrid-2-yl) butylguanidine hydrogen sulfate are obtained.

(b) To a mixture of 1.50 g of 4- (5-bromo-3-methylpyrid-2-yl) butylguanidine hydrogen sulfate and 0.65 g of sodium methoxide in 50 ml of methanol was added 0.89 g of 2-formyl-4- (2). Methyl 5-pyridyl] propionate is added and the mixture is heated under reflux for 24 hours with stirring, the methanol is evaporated off under reduced pressure, the residue is stirred with water, the aqueous mixture is extracted with methylene chloride, the extract is dried and evaporated. silica gel column using 5% (v / v) methanol in chloroform as eluent.

The eluate was collected and the solvent was evaporated, yielding 1.32 g of 2- [4- (5-bromo-3-methylpyrid-2-yl) butylamino] -5- (6-methylpyrid-3-ylmethyl) -4- 156 DEG-157 DEG C. (uncorrected).

Example 2

To a solution of 20 g of 2- (4- (5-bromo-3-methylpyrid-2-yl) butylamino) -5- (6-methylpyrid-3-ylmethyl) -4-pyrimidone in 67 ml of methanol is added a solution of 15.3 g of 1,2-ethanedisulfonic acid in 48 ml of methanol, upon cooling, a solid crystallized out, which was filtered off, washed with cold methanol and dried to give 2- [4- (5-bromo-3-methylpyrid-2-) -ethanesulfonate neutral ethanesulfonate. yl) butylamino] -5- (6-methylpyrid-3-ylmethyl) -4-pyrimidone, m.p. 182 DEG-185 DEG C. Yield: 31 g.

Analysis: for C 21 H 21 N 4OBr. 1.5C2H6O6S2. H2O calculated:

% C, 37.75;% H, 4.88;% N / 9.17;

12.60% S, 10.46% Br, found:

37.60% C, 4.78% H, 9.10% N,

12.30% S, 10.71% Br.

Example 3

Pharmaceutical composition for oral administration comprising the following components% by weight

2- (4- (5-bromo-3-methylpyrid-2-yl) butylamino) -5- (6-methylpyrid-3-ylmethyl) -4-pyrimidone 55 calcium monohydrogen phosphate dihydrate 20 approved dye 0,5 polyvinylpyrrolidone

4.0

microcrystalline cellulose 8.0 cornstarch 8.0 sodium glycolate 4.0 magnesium stearate 0.5

is prepared by mixing component A (if desired, lactose or microcrystalline cellulose may be used instead of calcium monohydrogen phosphate dihydrate), a concentrated solution of polyvinylpyrrolidone is added, the mixture is granulated, the wet granulate is dried and sieved, to the dried granulate components B are added and tablets containing 5 mg, 15 mg or 50 mg of the free base are compressed from the mixture.

Example 4

Pharmacically, an injectable preparation is prepared by 2- [4- (5-bromo-3-methylpyrid-2-yl) -butylamino] -5- (6-methylpyrid-3-ylmethyl) -4-pyrimidone hydrochloride. dissolve in sterile water to a 1-5% (w / w) solution, which is clarified by filtration, then filled with ampoules, sealed and sterilized, and a suitable ampoule containing 2 ml of solution.

Claims (4)

SUBJECT Process for preparing pyrimidone derivatives OF THE INVENTION of the general formula II in which R ¹ represents a halogen atom or a nitro group, R ² represents an alkyl group having 1 to 4 carbon atoms, R ³ represents an alkylene group having 1 to 3 carbon atoms and R ⁴ represents 3-pyridyl, N-oxo-3-pyridyl, 6-methyl-3-pyridyl, N-oxo-6-methyl-3-pyridyl, 4,6-dimethyl-3-pyridyl, N-oxo-4,6-dimethyl-3-pyridyl, 5.6-dimethyl-3-pyridyl, N-oxo-5,6-dimethyl-3-pyridyl, 4-pyridyl or N-oxo-4-pyridyl, and pharmaceutically acceptable salts thereof, characterized in that the guanidine of the formula R ¹ , R ² and R ³ are as defined in formula (II), reacting with a compound of formula (XI) wherein: R @ ¹ is as defined in formula (II) and R @ ⁸ represents an alkyl group having from 1 to 2 The compound of formula (II) is optionally converted into its pharmaceutically acceptable salt.