CS241040B2 - Method of pyrimidone derivatives production - Google Patents

Abstract

The invention describes certain pyrimidone derivatives, the method of their manufacture, the compositions comprising the same these compounds and their use as Histamine antagonists.

Description

The present invention provides certain pyrimidone derivatives, a process for their preparation, compositions containing them and their use as histamine β-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 "antihistamines" (Hi-antagonists). histamine) and exemplified by mepyramine. The second type of histamine receptor is known as the H2-receptor (Black et al., Nature 1972, 238, 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 Hs-receptors of histamine are called H2-histamine antagonists.

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

H < 2 > H < 2 >

Het represents a 2- or 4-imidazole radical optionally substituted by a lower alkyl group (preferably methyl), halogen (preferably chlorine or bromine), trifluoromethyl or hydroxymethyl, 2-pyridyl, optionally substituted by one or two of the same 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), aanosulfonyl, and the like. is a 2-pyridyl radical to which a phenyl ring, a carbocyclic or cyclic ether ring containing two oxygen atoms is condensed, furthermore a 2-thiazolyl radical, an SAsothiazole radical optionally substituted by a chloar or bromine A 3- (1,2,5) -thiadiazolyl radical, optionally substituted with chlorine or bromine, or a 2- (5-amino-1,3,4-thiadiazolyl) radical,

Y is a sine or methylene group, m is 0.1 or 2 and n is 2 or 3 such that the sum of these symbols is 3 or 4 or, if Y is an ethylene group and Het is not an imidazole 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 jpWf CH 2 jp where W represents oxygen or sulfur and p and q are numbers of such a value that their sum is 1 to 4, and

Het 1 represents a five- or six-membered heterocyclic ring selected from pyridine, pyridine-N-oxide, furan, thiophene, thiazole, oxazole, isothiazole, imidazole, pyrimidine, pyrazine, pyridazine and thiadiazole ring, which ring is optionally substituted with one or two identical or different substituents selected from the group consisting of lower alkyl, lower alkoxy, halogen atoms, hydroxyl and amino, or Het 1 represents a pyridine ring with a fused carbocyclic or cyclic ether ring containing two oxygen atoms, or Het 1 represents ipyridine, an imidazole or thiazole ring with a fused benzene ring, and? their pharmaceutically acceptable salts.

It is disclosed that these compounds exhibit combined efficacy as histamine H1- and H2- antagonists.

U.S. Pat. No. 4,154,834 discloses, in particular, 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 bypassing the 2-pyridyl residue of Het contains a second substituent at the 5-position, the relative efficacy level of 1: HireeaptOE towards the H 1 -receptors will increase. Furthermore, it has been found that a small number of compounds falling within the scope of the general formula I exhibit the efficacy of histamine H 1 antagonists so that they can be used to treat diseases; ; such as bronchial asthma, rhinitis, hay fever, and allergic eczema, the symptoms of which are mediated by the action of the Hi-histamine receptors.

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 s-1, to-1. 4 carbon atoms,

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

R ⁴ represents a 6-hydroxymethyl-3-pyridyl, 6-hydroxymethyl-4-methyl-3-pyridyl or 6-hydroxymethyl-5-methyl-3-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 sl to 4 carbon atoms in the definition of R 'R ² include methyl, ethyl, n-propyl, isopropyl, n-butyl and t-butyl. Preferably R ² represents a methyl group.

An example of a radical R ³ 'is; mention a methylene, 1,2-ethanediyl or 1,3-propanediyl group. Preferably, R ^{3 is} 1,2-ethanediyl or 1,3-propanediyl.

An example of a compound of the invention with preferred substituents R ¹ and R ² may be mentioned

2- [4- (5-bromo-3-methylpyrid-2-yl) butylamino] -5- (6-hydroxymethylpyrid-3-ylmethyl) -4-pyrimidone, and pharmaceutically acceptable salts thereof. 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, so that the pyrimidine ring may exist in the following tautomeric forms:

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

The compounds of formula (H) 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, ethanesulfonic acid, ethanesulfonic acid, camphorsulfone.

In accordance with the invention, the compounds of formula (II) above are prepared by preparing a compound of formula (III)

in which

R ¹ , R ² and R ³ are as defined in formula II, or a salt thereof, reacted with a compound of formula IV

in which

R ⁶ represents an amino-exchangeable group, preferably methylthio or nitroamino, and

R ⁴ 'represents an N-oxo-6-methyl-3-pyridyl, N-oxo-4,6-dimethyl-3-pyridyl or N-oxo-5,6-dimethyl-3-pyridyl residue, and the resulting compound of the formula Ha

XX,> 13 ^v

CH ₉ R CH ₂ CH _from NH 4 N 4 _q wherein

R @ ¹ , R @ ² , R @ ³ and R ^{@ 4} as defined above are converted by reaction with an organic acid anhydride, for example trifluoroacetic anhydride, to the corresponding compound of formula II, which is then optionally converted to its pharmaceutically acceptable salt.

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.

(11a)

Preferably R ⁶ is nitroamino.

Reaction of compounds of formulas III and IV may be carried out at elevated temperature in the absence of a solvent, for example at from 80 to 170 ³ C, preferably from 120 to 140 ° C, or in a solvent at elevated temperature, for example the boiling point of the reaction mixture under reflux cooler. The choice of solvent is determined by the solubility of the reactants and the nature of the radical R @ ⁶ . Preferred solvents are pyridine, picoline or mixtures of picolines, alkanols with 1

241414 «

up to 4 carbon atoms, preferably ethanol or 1-propanol, 1,2-ethanedial, ketones such as acgton or 2-butanone, higher boiling alkoxy ethers such as anisole, or polar aprotic solvents such as dimethylformamide, dimethylacetamide, dimethylsulfoxide, hexamethylphosphoramide, sulfclan, acetonitrile or nitromethane.

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

_Of R CH ³ C ^H 2 ^NH Z (Ill), i.e. diazotising the amino group represented by R ¹ and the diazo group is replaced with halo.

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

in which

R ² and R ³ are as in formula (II) by halogen.

Compound corresponding to formula IIIc

(lile). in which

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

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 may be dissolved in freon, for example in 1,1,2-trichlorotrifluoroethane or sulfuric acid, i.e. the solution is oleum. The hydrobromic acid can be obtained from the dihydrobromide of the compound of formula IIIb, particularly 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 environments for carrying out the bromination reactions are oleum and sulfur trioxide in freon. In practice, at least 20% (w / w) oleate, preferably at least 65% (w / w) oleate is used. 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 and above. When the reaction medium is 65% oleum, the reaction can 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.

The compounds of the above formulas III and IIIa can also be prepared by reduction of the corresponding cyano compound

in which

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 substituting a disubstituted chloropyridine of formula (VI)

f yn in which

R ² has the meaning as in formula II and R ⁷ is halogen, nitro or amino.

is reacted with a malonic acid ester. VII

RO.C \

CHR ^J CN /

RO C (VII) in which

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)

(Vlil) in which

R ² has the meaning as in formula I, with an alkali metal is reacted with slou-. 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 the formula VIH with an alkali metal amide (especially sodium amide, in which case the alkali metal is sodium), the solvent preferably being liquid ammonia or an alkali metal alkyl derivative (especially butyllithium, in which case the alkali metal is lithium), the solvent preferably being an ether, for example diethyl ether or tetrahydrofuran.

This reaction is carried out at low temperatures. For example, when the reaction is carried out in liquid ammonia, the reaction temperature is at the boiling point of ammonia, and the derivative of formula VIII is prepared 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.

Compounds of formula IV inert solvent such as an alcohol corresponding to the ester function in the compound of formula XI, i.e. an alcohol of formula R ³ OH at elevated temperature, preferably in the presence of a base in particular the sodium alkoxide of formula NaOR ³ which corresponds to the ester function of the compound of of formula XI.

The guanidines of formula X can be prepared by reacting an amine of the above formula III with a compound of formula XII

R NH (XH) are either known or can be prepared by processes analogous to known processes, such as described, for example, in U.S. Patent No. 4,154,834 and European Patent No. 17,679.

The compounds of the above formula (IIa) can also be prepared by reacting guanidine of the formula (Xx),

fi. '

3 ",

CH 2 FCH ₂ NH

NH _Z

NH (λ i in which R ^2, R ^2, R ² and R ³ are as defined in formula II) is reacted with a compound of formula XI

R- ‘has the meaning as in formula IV a

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

The reaction may be carried out by heating guanidine of formula X with a compound of formula XI, optionally in a branch

R ⁹ is a leaving group such as methylthio or 3,5-dimethylpyrazolyl.

The activity of the compounds of formula II as HL-histamine antagonists 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 is burnt into magnesium-free Tyrode's 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 concentration. of histamine increases in steps up to maximum contraction 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 inducing a contraction of 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 ordinate is taken as a measure of potency (pAA value). The compounds of Examples 1-12 have pA · values; higher than 8.

The efficacy of the compounds of formula I as histamine H 2 -antagonists can be demonstrated by an in vitro guinea pig atrium test. In this test, the spontaneously throbbing portion of the right guinea pig atrium is fixed under tension of 300 mg between the anchorage and the 241040 girl is transported 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 so that the histamine concentration increases gradually to reach the 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. Repeat the test with increasing concentrations of test compound and record the dose of histamine inducing a heart rate of 50% of the maximum frequency. 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, plotting log DR-1 versus log D (test compound concentration) and intersection with log DR -1 is taken as a measure of potency (pA? Value). The compounds of Examples 1-12 have pAi 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 sodium pentobarbitone 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 iced 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 broncheconstric action of histamine. Histamine responses can be antagonized using histamine H 1 -receptor antagonists.

Histamine dose-response curves are plotted using doses of 20, 40, 80, 160 and 320 nmol / 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 the antagonist to the right so as to coincide with the dose-response curve of histamine in the presence of the antagonist. 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 less than 0.8 µM per kg.

The efficacy of the compounds of formula II as H-histamine antagonists can be demonstrated by the in vivo inhibition of histamine-stimulated gastric acid secretion from the pore 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 a 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 may be formulated 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 administration by spraying or aerosols, or ultrafine powders for inhalation. The active ingredient in the inhalable 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 that 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 capsule formulation comprises a solid granular formulation it · ^1, optionally together with a binder, contained 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 predictors. 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 administered orally between 15 and 400 mg, preferably between 15 and 200 mg, and 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. salts (calculated as the free base), the respective composition being administered one to four times a day.

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

EXAMPLE 1 (a) 148.3 g of 2- (2-cyanethyljmalonic acid diethyl ester) is reacted in tetrahydrofuran at 20 DEG C. with 15.3 g of sodium hydrides, then 100 g of 2-chloro-3-methyl-5-nitropyridine are added and the temperature is The reaction mixture was shaken between water and chloroform, the chloroform extract was dried, clarified with charcoal, filtered through a pad of silica gel and evaporated to dryness. from ethanol afforded 99 g of 4- (3-methyl-5-nitro-pyrid-2-yl-4,4-bis (ethoxycarbonyl jbutyronitrilu mp 64 DEG-65.5 DEG C. ^&

(bj 99 g of 4- (3-methyl-5-nitropyrid-2-yl) -4,4-bis (ethoxycarbonyl) butyronitrile was stirred for 16 hours in a mixture of 1200 ml of ethanol and 1130 ml of 1M sodium hydroxide solution, followed by pH The product was extracted with chloroform to give 57.1 g of an oily material, which was first extracted with 554 ml of 1.5N hydrochloric acid and then diluted with hydrochloric acid, and the combined acid extracts were clarified with activated carbon. 5-nitro-2- (3-cyanopropyl) -3-methylpyridine was obtained in a yield of 49.5 g. The product had a melting point of 51.5-53 ° C.

(c) 5.9 g of 5-nitro-2- (3-cyanopropyl) -3-methylpyridine was hydrogenated in 150 ml of ethanol using 0.59 g of 10% palladium on carbon catalyst. Hydrogenation was carried out at 140 kPa for 2.5 hours. The reaction mixture was filtered, the filtrate was concentrated to dryness and the residue triturated with ether. 4.70 g of 5-amino-2- (3-cyanopropyl) -3-methylpyridine are obtained, m.p. 103-105 ° C.

(dj 23.0 g of 5-amino-2- (3-cyanopropyl) -3-methylpyridine was reduced in a mixture of 750 ml of tetrahydrofuran and 750 ml of diethyl ether for 3 hours with 12.47 g of lithium aluminum hydride to give 20.8 g of 2- ( 4-Aminobutyl-3-methylpyridine as an amber oil.

NMR (deuterochloroform, values of 5 in ppmj):

1.3-1.9 (multiplet, —CH2CH2CH2NHz),

2.22 (singlet, 3-CH3), 2.6-2.8 [multiplet,

CH 2 (CH 2 CH 2 NH 2), ca. 3.5 (broad signal, 5-NH 2), 6.77 (doublet, proton at position 4 of the pyridyl residue), 7.88 (doublet, proton at position 6 of the pyridyl residue).

(e) 5.11 g of 5-amino-2- (4-aminobutyl) -3-methylpyridine was treated with 4.98 g of cuprous bromide and 0.18 g of copper bronze in 47 ml of 48% hydrobromic acid. A solution of 2.45 g of sodium nitrite in 16 ml of water was added over 45 minutes at 5-8 ° C, the reaction mixture was allowed to stir at 5-8 ° C for an additional hour, then stirred at room temperature for 3.5 hours. . The resulting mixture was diluted with water and hydrogen sulfide gas was added thereto, gradually increasing its pH to 11 by adding sodium hydroxide solution. The precipitated copper salts were filtered from time to time during the above treatment. Extraction of the product at pH 11 with chloroform gave 4.95 g of 5-bromo-2- (4-aminc-butyl] -3-methyl-pyridine, m.p. 35-37 ° C.

(f) Approximately 9 hours of reaction 1.04 g of 5-thromo-2- (4-aminobutyl) -3-methylpyridine [the product of Example 1 (e) is 1.42 g of 2-nitroamino-5- (No.xo-6- methylpyrid-3-ylmethyl) -4-pyrimidone in pyridine at reflux, after the usual working up of the reaction mixture and purification of the crude product by silica gel chromatography and crystallization, 0.48 g of 2- [4- (5-bromo-3-methylpyridine) 2-yl) butylamino-5- (N-oxo-6-methylpyrid-3-ylmethyl) -4-pyrimidone, m.p. 193-194.5 ° C.

410 40

Analysis:

for C21H24BrN5C> 2 calculated: 55.03% C, 5.28% H, 15.28% N,

17.43% Br;

found

% C, 54.67;% H, 5.41;% N / 19.09;

17.60% Br.

(g) 0.9 g of 2- [4- (5-bromo-3-methylpyrid-2-yl) butylamino] -5- (N-oxo-6-methylpyrid-3-ylmethyl) -4-pyrimidone [product from of Example 1 (f)] was treated with 1.65 g of trifluoroacetic anhydride in 6 ml of dichloromethane for 2 days. The solvent was evaporated in vacuo, the residue was dissolved in chloroform, the chloroform solution was washed with 10% sodium bicarbonate solution and concentrated to dryness. 0.42 g of 2- [4- (5'-bromo-3-methylpyrid-2-yl) butylamino-5- (6-hydroxymethylpyrid-3-ylmethyl) -4-pyrimidone is obtained, which melts on heating. 61 to 70 ° C, solidifies again at a temperature of about 120 ° C and then thaws again at 160 to 165 degrees Celsius.

Example 2 (and 2.1 g of the product of Example 1 (e) and 2.51 g of 2-nitroamino-5- (5,6-dimethyl-N-oxopyrid-3-ylmethyl) -4-pyrimidone in 6 ml of pyridine The mixture was heated under reflux for 13.5 hours, then pyridine was evaporated in vacuo and its last traces removed by azeotropic distillation with n-propanol, the residue was dissolved in 50 ml of hot ethanol and all insoluble matter was filtered off. It is concentrated to a volume of 20 ml and the concentrate is cooled to give crystals which are recrystallized from ethanol and dimethylformamide to give 2.5 g of 2- [4- (5-bromo-3-methylpyrid-2-yl) butylamino]. 204- 206 ° C] -5- (5,6-dimethylpyrid-N-oxo-3-ylmethyl) -4-pyrimidone.

Analysis calculated for C 22 H 26 BrN 5 O 2

H, 5.60; N, 15.00.

17.23% Br; found

% C, 55.93;% H, 5.54;% N, 14.82.

16.92% Br.

(b) A suspension of 1.6 g of the product from paragraph (a) in 10 ml of dry dichloromethane was treated with 1.9 ml of trifluoroacetic anhydride, the mixture was allowed to stand for 2 days, the solvent was evaporated in vacuo. After evaporation of the chloroform, 1.7 g of solid material is obtained, which is crystallized from 10 ml of ethanol with the addition of 20 ml of water, and the solid thus obtained is recrystallized from acetonitrile / water (9: 1: 0). 99 g of 2- [4- (5-bromo-3-methylpyrid-2-yl) butylamino] -5- (5-methyl-6-hydroxymethylpyrid-3-ylmethyl) -4-pyrimidone, m.p. 141 ° C.

Analysis: for CzzHaiBrNsO?

calculated

% C, 55.93;% H, 5.54;% N, 14.82.

16.92% Br;

for C 22 H 28 BrN 5 O 2. 2,0 HO

WDrčteno

% C, 51.97;% H, 5.95;% N, 13.78.

15.72% Br;

riol p7pnn

% C, 51.82;% H, 5.89;% N, 13.83.

15.48% Br.

Example 3

1.06 g of the product of Example 1 (e) and 1.14 g of 2-nitroamino-5- (N-oxopyrid-4-ylmethyl) -4-pyrimidone were heated to reflux in 4 ml of anisole for 7.5 hours. cooler. The anisole was evaporated in vacuo and the residue was chromatographed on silica gel using chloroform / methanol (4: 1) as eluent. The product obtained after crystallization from acetonitrile / water (9 to 1) gave 0.40 g of 2- [4- (5-bromo-3-methylpyrid-2-yl) butylamino] -5- (N-oxopyrid-4-ylmethyl) 4-pyrimidone, m.p. 110-115 ° C.

Analysis calculated for C 20 H 22 BrN 5 O 2

% C, 54.06;% H, 4.99;% N, 15.76.

17.98% Br;

for C 20 H 22 BrN 5 O 2. 0.62 HzO calculated

% C, 52.70;% H, 5.14;% N, 15.37;

17.54% Br;

found

52.68% C. 4.92% H. 15.45% N,

18.26% Br.

Claims (1)

OBJECT OF THE INVENTION A process for the preparation of pyrimidone derivatives of the general formula II nn 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 ¹ represents a 6-hydroxymethyl-3-pyridyl, 6-hydroxymethyl-4-methyl-3-pyridyl or 6-hydroxymethyl-5-methyl-3-pyridyl residue, and pharmaceutically acceptable salts thereof, characterized in that of formula Ha in which R ¹ , R ² and R ³ are as defined in formula II, and R ⁴ 'represents N-oxo-6-methyl-3-pyridyl, N-oxo-4,6-dimethyl-3-pyridyl or N-oxo-5,6-dimethyl-3-pyridyl, reacted with organic anhydride an acid, for example with trifluoroacetic anhydride, and the compound of formula (II) thus obtained is optionally converted into its pharmaceutically acceptable salt.