CS208497B2 - Method of making the pyrimidons - Google Patents

Description

(54) A method for producing pyrimidones

The invention relates to a process for the preparation of pharmacologically active pyrimidone derivatives. According to the invention, pyrimidone derivatives of the general formula I are produced,

CH ₂ Het ^{1 *} (I)

Het-CH ₂ -Y- (CH _{2) 2} NH wherein

Het is 5-methyl-4-imidazolyl, 2-pyridyl, optionally substituted by methoxy, chlorine or bromine, or 2-thiazolyl,

Y represents a sulfur atom or a methylene group and

Het 'means a pyridyl group substituted with a hydroxy group or an N-oxo group and an optionally substituted methyl or methoxy group.

Het is preferably 5-methyl-4-imidazolyl, 2-pyridyl, 3-methoxy-2-pyridyl, 3-chloro-2-pyridyl, 3-bromo-2-pyridyl or 2-thiazolyl .

Het 'is preferably 4-hydroxy-2-pyridyl, 6-hydroxy-3-pyridyl, 2-hydroxy-4-pyridyl, 4-hydroxy-5-methyl-2-pyridyl, 6-hydroxy- 5-methyl-3-pyridyl, 2-hydroxy-6-methyl-4-pyridyl, 6-hydroxy208497

-5-methoxy-3-pyridyl, N-oxo-3-pyridyl, N-oxo-6-methyl-3-pyridyl and N-oxo-4-pyridyl.

Particularly preferred Het 'radicals are pyridyl substituted by hydroxy and optionally substituted by methyl, especially 4-hydroxy-2-pyridyl, 6-hydroxy-3-pyridyl or 2-hydroxy-4-pyridyl.

The compounds of the invention are illustrated and described as 4-pyrimidone derivatives, but these compounds are in equilibrium with the corresponding 6-pyrimidones and, to a lesser extent, with the following tautomeric forms:

2-, 4- and 6-hydroxypyridyl groups may be present as 1H-pyridone tautomers and certain Het radicals may also exist in several tautomeric forms. All such tautomeric forms of the compounds of formula I are within the scope of the invention.

In accordance with the invention, the compounds of formula (1) above are prepared by producing a compound of formula (111),

H

HN-X no ₂ nh ⁿ

CH ₂ -Het ²

III (III) in which 2

Het is a pyridyl group substituted with hydroxy, protected with hydroxy or N-oxo and optionally substituted with methyl or methoxy, with an amine of formula II,

Het-CH ₂ -Y- (CH ₂ ) ₂ NH ₂ (II) wherein

Het and Y are as in formula (I), and any hydroxyl protecting group present is cleaved from the resulting product.

The reaction according to the invention can be carried out at elevated temperature in the absence of a solvent, for example at 80 to 170 ° C, preferably 120 to 140 ° C, or at an elevated temperature in the solvent, for example boiling the reaction mixture. The choice of solvent depends on the solubility of the reactants. A preferred solvent is pyridine, picoline or picoline mixtures, lower alkanol, preferably ethanol or 1-propanol, aqueous lower alkanol, 1,2-ethanediol, a ketone such as acetone or 2-butanone, or a polar aprotic solvent such as dimethylformamide, dimethylacetamide, dimethylsulfoxide, hexamethylphosphoramide, sulfolane, acetonitrile or nitromethane. In accordance with a particularly preferred embodiment, the reaction is carried out under reflux in ethanol, 1-propanol or pyridine.

Preferably, roughly equimolar amounts of reactants are used, although any reactant may be used in excess, for example in a small excess of from 1.1 to 1.5 mol equivalents or in a larger excess of from 1.5 to 4 mol equivalents. When working with an excess of any of the reactants, an excess of the amine of formula (II) above is preferably used. Excess of any of the reactants may be present in the reaction mixture at the start of the reaction or may be introduced during the reaction. Examples of hydroxyl protecting groups include methoxymethyl, methylthiomethyl, tetrahydropyranyl, arylmethyl such as benzyl, lower alkyl such as methyl and acyl such as formyl or acetyl. The compounds of formula (I) in which Het 1 is a 2-, 4- or 6-hydroxypyridyl group may conveniently be prepared by reacting a compound of formula (III) in which Het 1 is a pyridyl group substituted in the 2, 4 or methoxy position with with an amine of formula XI and subsequent acid hydrolysis of the product.

Compounds of formula (III) above may be prepared by reacting the beta-oxoester of formula (IV),

0 = C

CH-CHo-Het ² [

co ₂ r (IV) in which

R is lower alkyl and

Het ³ represents a pyridyl group optionally substituted by a methyl group or a pyridyl group substituted by a hydroxy, protected hydroxy or N-oxo group and an optionally substituted methyl group or a methoxy group, reacted with nitroguanidine, whereupon Het ³ represents a pyridyl group optionally substituted by methyl or a methoxy group, the product obtained is reacted with an oxidizing agent to form the corresponding N-oxopyridyl derivative and any resulting hydroxyl protecting groups are optionally removed from the resulting compound.

Peroxic carboxylic acid, such as 3-chloroperbenzoic acid, perbenzoic acid or peracetic acid, is preferably used as the oxidizing agent to convert the pyridyl group to the N-oxopyridyl group. This oxidation is preferably carried out in acetic acid.

The amines of the above formula (II) in which Y is a sulfur atom may be prepared by reacting cysteamine with a compound of the formula

Het-CH ₂ L wherein L represents a residue exchangeable for a thiol group, for example hydroxyl, acyloxy (such as acetoxy, methanesulfonyloxy or p-toluenesulfonyloxy), lower alkoxy (for example methoxy), chlorine, bromine or triarylphosphonium (for example triphenylphosphonium) . Preferably L is hydroxy or methoxy and the reaction is carried out under acidic conditions, for example in hydrochloric or hydrobromic acid.

The amines of formula II wherein Y is methylene and Het is 2-pyridyl with methoxy or chloro or bromo at the 3-position can be prepared by reacting 2-halo-3-nitropyridine with diethyl 2- (2-cyanethyl) ) malonate. Hydrolysis and decarboxylation of the product followed by reduction in the presence of palladium on carbon gave 3-amino-3- (3-cyanopropyl) pyridine, which could be diazotized in 2M sulfuric acid and methylated in dimethylsulfoxide to give 3-methoxy-2- (3- cyanopropyl) pyridine. 3-Amino-2- (3-cyanopropyl) pyridine can be reduced with lithium aluminum hydride to 4- (3-amino-2-pyridyl) butylsmin, which can be diazotized in strong hydrochloric acid and in the presence of cuprous chloride

208497 4 to give 3-chloramine or in strong hydrobromic acid and in the presence of cuprous bromide to give 3-bromamine.

•

The amines of formula 11 wherein Y is methylene and Het is 2-thiazolyl may be prepared by reacting a thioamide of formula nh ₂ en (ch ₂ ) ₄ q wherein Q is a protected amino group with bromoacetaldehyde dialkyl acetal followed by deprotection amine functions.

Esters of formula (IV) above may be prepared by alkylation of a dialkyl malonate followed by hydrolysis and decarboxylael or condensation of the aldehyde with malonic acid and decarboxylation, esterification and reduction of the product.

The compounds of formula (1) above exhibit activity as histamine H 1 -antagonists and in particular histamine H 3 -antagonists as compared to analogous compounds in which Het 1 represents a residue other than a pyridyl ring substituted by a hydroxy or N-oxo group. The compounds of formula (1) also have a lower lipophilic character as evidenced by the evaluation of their distribution between octanol and water.

The term H ₂ -receptors of the histamine as used herein refers to the reeepers defined by Black et al. (Nature, 236. 385 (1972)) as histamine reeepers, which are not blocked by mepyramine but are blocked by burimamide, and by the term H, histamine free receptors is meant mepyramine-sensitive reeepers. Compounds blocking Hg-histamine histamine receptors are called Hg-histamine antagonists and compounds blocking Hg-histamine histamine receptors are called histamine Hj-antagonists.

Blockade of the H ₂ -receptors of histamine is valuable for inhibiting the biological effects of histamine that are not inhibited by the histamine H-antagonists. Hg-histamine antagonists are effective, for example, as inhibitors of gastric acid secretion, as anti-inflammatory agents and as agents acting on the cardiovascular system, for example as inhibitors of the effects of histamine on blood pressure.

In certain physiological conditions, the biological effects of histamine are mediated by both the H 1 and H ₂ -receptors of the histamine, and therefore blockade of both these types of receptors is useful. These conditions include histamine-mediated inflammatory processes, for example, skin inflammations and manifestations of hypersensitivity, caused by the effect of histamine on H _{1 -} and H ₂ -receptors, such as allergies.

The efficacy of the compounds of Formula 1 as H ₂ -antagonists of histamine can be demonstrated by their ability to inhibit histamine-stimulated gastric acid secretion from washed stomachs of urethane anesthetized rats at intravenous doses of less than 16 µmol / kg. This procedure was described by Ash and Schlld in Brit. J. Pharmac. Chemother. 27, 427 (1966). The efficacy of the disclosed compounds as H ₂ histamine antagonists can also be demonstrated by their ability to inhibit other histamine effects, which, according to Ashe and Schlld, cited above, are not mediated by histamine H-free receptors. For example, these compounds inhibit the effects of histamine on isolated guinea pig atrium and isolated rat uterus. Said substances inhibit the basal secretion of gastric acid as well as the secretion stimulated by pentagastrin or food. In a conventional assay, such as measuring the blood pressure of an anesthetized cat, these compounds inhibit the vasodilating activity of histamine at intravenous doses from 0.5 to 256 µmol / kg. The efficacy of these agents is illustrated by effective dose levels causing 50% inhibition of gastric acid secretion of anesthetized rats and doses causing 50% inhibition of histamine-induced tachycardia in an isolated guinea pig atrium (these doses are less than 10 µmol).

The activity of the compounds of formula I as histamine antagonists can be demonstrated by inhibiting histamine-stimulated contractions of the isolated guinea pig ileum. It is preferable to administer a single compound exhibiting both H1- and Hg-antagonists of histamine rather than individual compounds exhibiting the effects of Η-, histamine-antagonists and Hg-histamine antagonists, as this avoids difficulties arising from different absorption rates and pharmacokinetic characteristics of these individual substances. .

Pharmaceutical compositions which can be used as Hg-antagonists of histamine can be prepared by admixing a compound of formula (I) above either in the form of a base or in the form of an addition salt with a pharmaceutically acceptable acid, pharmaceutically acceptable diluent or carrier. The above addition salts include salts with, for example, hydrochloric, hydrobromic, hydroiodic, sulfuric and maleic acids, and can conveniently be prepared from the corresponding compounds of formula I by standard procedures, for example by reacting a compound of formula I with an acid in lower alkanols or using ion exchangers. In this way, the desired salt can be obtained either directly from the corresponding base compound or from another addition salt.

A useful pharmaceutical carrier can be a solid or a liquid. Examples of solid carriers include lactose, corn starch, potato starch or modified starches, secondary calcium phosphate, kaolin, sucrose, cellulose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Examples of liquid carriers include syrups, peanut oil, olive oil, alcohol, propylene glycol, polyethylene glycols, and water.

When using a solid carrier, the formulations prepared may take the form of tablets, capsules containing powder or pellets, troches or lozenges. The amount of solid carrier in unit dosage form generally ranges from about 25 to 300 mg. When using a liquid carrier, the formulations may be in the form of a syrup, emulsion, multiple emulsion, sterile injectable liquid or an aqueous or non-aqueous solution or liquid suspension. The compositions may contain other ingredients, such as preservatives, for example antioxidants or antibacterial agents and / or flavoring agents or coloring agents. Sterile liquid preparations can be formulated into ampoules, multidose ampoules or unit dosage forms for immediate use. The compositions may also be in semi-solid form, for example, in the form of a cream, paste, ointment or gel, or in liquid or aerosol form for topical administration.

The pharmaceutical compositions are prepared by conventional techniques including such processes as milling, mixing, granulating and compression, spray drying, lyophilizing or dissolving or dispersing, depending on the type of preparation. The active ingredient is present in these compositions in an amount effective to block the histamine Hg receptors. Preferably, each unit dose contains the active ingredient in an amount of about 50 to 250 mg.

The active ingredient is preferably administered one to six times a day. The daily dosage is preferably from about 150 to 1500 mg. The disclosed compounds and preparations can be administered orally or parenterally.

The invention is illustrated by the following non-limiting examples. In the examples, all temperatures are given in degrees Celsius.

t

Example 1

a) A mixture of 61.26 g of 2-methoxy-5-cyanopyridine, 76.4 g of seaicarbazide hydrochloride, 74.92 g of sodium acetate, 1300 ml of ethanol and 400 ml of water is added in the presence of 1.0 g of Raney nickel as a catalyst. , hydrogenated at a pressure of 50 psi. The reaction mixture was concentrated to 500 ml, 1000 ml of water was added to the residue, the mixture was allowed to stand overnight at 0 ° C, then filtered, the solid residue was washed with water and dissolved in 1000 ml of 10% hydrochloric acid. . 450 ml of a 3% (w / v) formaldehyde solution was added to the solution, the mixture was heated for 15 minutes, then allowed to cool and added to a solution of 298.5 g of sodium acetate in 900 ml of water. The resulting mixture was extracted with ether, the combined extracts were washed successively with water, aqueous potassium carbonate solution and again with water, dried and evaporated. 31.5 g (50%) of 6-methoxypyridine-3-carboxaldehyde are obtained, m.p. 48-49 °.

b) A mixture of 2.34 g of 6-methoxy-pyridine-3-carboxaldehyde, 4.51 g of monoethyl malonate, 12 ml of pyridine and 6 drops of piperidine was refluxed for 5 hours and then evaporated to an oily residue. The oil was partitioned between ether and dilute aqueous ammonia, the ether layer was washed with water and evaporated to an oily residue which crystallized on standing. 2.8 g (79%) of ethyl 3- (6-methoxy-3-pyridyl) acrylate are obtained, m.p.

c) 32.33 g of ethyl 3- (6-methoxy-3-pyridyl) acrylate is hydrogenated in 160 ml of ethanol in the presence of 0.2 g of 5% palladium on carbon catalyst at 40 psi. The resulting mixture was filtered and the filtrate was evaporated. 32.7 g of ethyl 3- (6-methoxy-3-pyridyl) propionate are obtained in the form of an oil.

d) To a suspension of 9.38 g of sodium hydride (50% dispersion in oil) in 50 ml of 1,2-dimethoxyethane cooled to -2 °, a mixture of 32.74 g of ethyl-3- ( 6-methoxy-3-pyridyl) propionate and 17.22 g of ethyl formate. The reaction mixture was allowed to stand overnight at room temperature, then poured onto ice, the resulting mixture was extracted with ether (discarded discarded) and the aqueous phase was acidified to pH 5 with 2N sulfuric acid. The precipitated oil crystallized on standing to give 25.9 g (70%) of ethyl 2-formyl-3- (6-methoxy-3-pyridyl) propionate, m.p. 91.5-94 °. A sample of the product melts after recrystallization from ethanol at 93-94 °.

(e) To a solution of sodium methoxide (prepared from 1.15 g of sodium) in 50 ml of methanol, 4.7 g of nitroguanidine are added, and the mixture is refluxed for 45 minutes, then 10.7 g of ethyl-2 is added. of formyl 3- (6-methoxy-3-pyridyl) propionate, the resulting mixture was refluxed for 34 hours, then evaporated. The residue was dissolved in water, the solution was extracted with chloroform and the extract was discarded. The aqueous solution was acidified to pH 5 with acetic acid and the precipitated solid material was filtered off. 2-Nitroamino-5- (6-ethoxy-3-pyridylmethyl) -4-pyrimidone is obtained, m.p. 183.5-186 °.

f) An equimolar mixture of 2-nitroamino-5- (6-methoxy-3-pyridylmethyl) -4-pyrimidone and 2- (5-ethyl-4-imidazolylmethylthio) ethylamine was refluxed in ethanol for 18 hours. Upon cooling, the material crystallized from the reaction mixture to give 2- (2- / 5-methyl-4-imidazolylmethylthio / ethylamino) -5- (6-methoxy-3-pyridylmethyl) -4-pyrimidone in 63% yield after recrystallization from ethanol. mp 197-198.5 °.

g) 0.55 g of 2- (2- / 5-methyl-4-imidazolylmethylthio / ethylanino) -5- (6-methoxy-3-pyridylmethyl) -4-pyrimidone was heated to reflux in 2N ethanolic hydrogen chloride for 24 hours. cooler. The mixture was evaporated to dryness and the residue was recrystallized from a mixture of 2-propanol and ethanol containing hydrogen chloride. Yield: 2- (2- (5-Methyl-4-imidazolylmethylthio) ethylamino) -5- (6-hydroxy-3-pyridylmethyl) -4-pyrimidone trihydrochloride, m.p. 205 DEG-209 DEG.

Example 2

(a) An equimolar mixture of 2-nitroamino-5- (6-methoxy-3-pyridylmethyl) -4-pyrimidone and 2- (2-thiazolylmethylthio) ethylamine was refluxed in ethanol for 18 hours.

After cooling, a solid product crystallizes from the reaction mixture which, after recrystallization from ethanol, yields 2- (2- (thiazolylmethylthio) ethylamino) -5- (6-methoxy-3-pyridylmethyl) -4-pyrimidone in a yield of 60%, m.p. 97 °.

b) 2- (2- (Thiazolylmethylthio) ethylamino) -5- (6-methoxy-3-pyridylmethyl) -4-pyrimidone was heated in reflux in 2N ethanolic hydrogen chloride for 24 hours. The reaction mixture ae is evaporated to dryness and the residue ae is recrystallized from a mixture of 2-propanol and ethanol containing hydrogen chloride. 2- (2- (2-Thiezolylmethylthio / ethylanino) -5- (6-hydroxy-3-pyridylmethyl) -4-pyrimidone trihydrochloride, m.p. 200 DEG-204 DEG.

Example 3

(a) 20.8 g of sodium are dissolved in 285 ml of methanol, a solution of 115.53 g of 2-chloro-4-cyanopyridine in a mixture of equal volumes of methanol and dioxane (850 ml) is added, and the mixture is heated at reflux for 2.5 hours under reflux and then allowed to cool. After filtration, the filtrate is concentrated to a volume of 200 ml and 400 n < l of water is added to the concentrate. Filtration of the precipitated product gave 57.2 g (51%) of 2-methoxy-4-pyridopyridine, m.p. 93-95.5 °.

b) A mixture of 57.2 g of 2-methoxy-4-cyanopyridine, 71.24 g of semicarbazide hydrochloride, 69.86 g of sodium acetate, 1200 of about ethanol and 370 ml of water is hydrogenated in the presence of 1.0 g of Raney-nickel as catalyst. pressure 344 kPa. The reaction mixture is evaporated to a volume of 450 ml, 900 ml of water are added to the residue, the mixture is allowed to stand overnight at 0 ° and then filtered. The solid material was washed with water, dissolved in 950 ml of 10% hydrochloric acid, 420 ml of a 36% w / v formaldehyde solution was added, the mixture was heated for 30 minutes, then allowed to cool and added to a solution of 280 g of sodium acetate. 840 ml of water. The resulting mixture was extracted with ether (3.times.506 ml), the combined extracts washed successively with aqueous potassium carbonate solution and water, dried and evaporated. 20.53% (35%) of 2-methoxy-pyridine-4-kerboxaldehyde, melting at 33-35 °, is obtained. A sample of the product melts after recrystallization from petroleum ether at 33-36 °.

c) Using the general procedure described in Example 1 (b, c, d), using o-ethyl-2-forayl-3- (2-methoxy-4-2-methoxypyridine-4-carboxaldehyde instead of 6-uetoxypyridine-3-carboxaldehyde) (pyridyl) propionate, which reacts with nitroguanidine and sodium ethoxide; using the procedure described in Example 1 (e) gave 2-nitroamino-5- (2-methoxy-4-pyridylmethyl) -4-pyrimidone in a yield of 59%, melting after crystallization from aqueous acetic acid at 194-595.5 °.

d) An equimolar mixture of 2-nitroamino-5- (2-methoxy-4-pyridylaethyl) -4-pyriaidone and 2- (5-methyl-4-fluorazolylmethylthio) 9-thylamine in ethanol was heated under reflux for 18 hours. After cooling, a solid product crystallizes from the reaction mixture, which is recrystallized from methanol. 2- (2- (5-Methyl-4-imidazolylmethylthio / ethylaaino) -5 '(2-methoxy-4-pyridylmethyl) -4-pyrimidone, m.p. 177-178 °, is obtained. Yield: 51%. This compound was heated at reflux in 2N ethanolic hydrogen chloride for 24 hours, the mixture was evaporated to room temperature and the residue was recrystallized from a 2-propanol-ethanol mixture containing hydrogen chloride. 2- (2- (5-methyl-4-imidazolylmethylthio / ethylamino) -5- (2-hydroxy-4-pyridylmethyl) -4-pyrimidone trihydrochloride, m.p. 172-176 °.

Example 4

An equimolar mixture of 2-nitroemino-5- (2-methoxy-4-pyridylmethyl) -4-pyrimidone and 2- (2-thiazolylmethylthio) ethylamine was heated under reflux in ethanol for 18 hours. After cooling, a solid crystallized from the reaction mixture, which was purified by chromatography on silica gel and recrystallized from a mixture of 2-propanol and ethanol. 2- (2- (2-Thiazolylmethylthio) ethylamino) -5- (2-ethoxy-4-pyridyl) ethyl) -4-pyrimidone is obtained in 41% yield, melting at 105.5-106.5 °. This compound gave 2- (2- / 2-thiazolylmethylthio / ethylamino) -5- (2-hydroxy-4 ' -pyridylmethyl) -4-pyrimidone monohydrochloride, refluxing in 2N ethanolic HCl, m.p. 169-173 °.

Example 5

Treatment of 2- (3-bromo-2-pyridylmethylthio) ethylamine with 1.15 mole equivalent of 2-nitroamino-5- (2-methoxy-4-pyridylmethyl) -4-pyrimidone in boiling ethanol for 18 hours affords 2- (2). 70 [deg.] To 72 [deg.] C., which is refluxed in ethanol containing hydrogen chloride to give 2- (2-bromo-2-pyridylaethylthio) aylamino) -5- (2-methoxy-4-pyridylmethyl) -4-pyrimidone. - (3-Bromo-2-pyridylmethylthio) ethylamino) -5- (2-hydroxy-4-pyridylmethyl) -4-pyrimidone trihydrochloride, melting at 195-196.5 °.

Example 6

a) Replacement of 6-methoxy-pyridine-3-carboxaldehyde in Example 1b) and 1c) with 4-methoxy-pyridine-2-carboxaledehyde affords oily ethyl 3- (4-methoxy-2-pyridyl) propionate which is formalized by reaction with with ethyl formate and sodium hydride in 1,2-dimethoxyethane and then reacted with nitroguanidine and sodium ethoxide. 2-Nitroamino-5- (4-methoxy-2-pyridylmethyl) -4-pyrimidone is obtained, melting after crystallization from a mixture of ethanol and acetic acid at 196-198 ° (decomposition).

b) Twenty-four hours' reaction of 2-nitroamino-5- (4-methoxy-2-pyridylmethyl) -4-pyrimidone with 1.06 mol equivalent of 2- (5-methyl-4-imidazolylmethylthio) ethylamine in ethanol at reflux afforded 2 - (2- / 5-methyl-4-imidazolylmethylthio / ethylamino) -5- (4-methoxy-2-pyridylmethyl) -4-pyrimidone, melting after crystallization from 2-propanol at 128-130 °.

(c) A mixture of 0.97 g of 2- (2- / 5-methyl-4-imidazolylmethylthio / ethylamino) -5- (4-methoxy-2-pyridyl-methyl) -4-pyrimidone and 20 ml of 48% aqueous hydrobromic acid is added. The mixture was refluxed for 20 hours and then evaporated to dryness. The residue was recrystallized from ethanol-2-propanol to give 2- (2- (5-methyl-4-imidazolylmethylthio / ethylamino) -5- (4-hydroxy-2-pyridylmethyl) -4-pyrimidin-trihydrobromide, m.p. 167-169). °. After recrystallization from a mixture of ethanol and 2-propanol, the melting point of the sample was lowered due to loss of hydrogen bromide.

Examples 7a8

(a) 1.15 g of sodium are dissolved in 50 ml of methanol and 4.7 g of nitroguanidine are added to the cooled solution. The mixture was heated 45 minutes at reflux, then to it is added portionwise 9.3 g of ethyl 2-formyl-3- (3-pyridyl) propionate _and resulting mixture was heated for 45 minutes under reflux and then evaporate to dryness. Water was added to the residue and the mixture was extracted with chloroform. The remaining aqueous phase was acidified to pH 5 with acetic acid, the precipitated solid product was filtered off and washed after drying. There was obtained 2-nitroamino-5- (3-pyridylmethyl) -4-pyrimidone, m.p. 214.5-216 °. Yield 38%.

b) To 12.35 g of 2-nitroamino-5- (3-pyridylmethyl) -4-pyrimidone in 300 ml of acetic acid is added 10.35 g of 3-chloroperbenzoic acid, the mixture is stirred for 18 hours at room temperature and then for 5 hours. hours at 60 DEG C. and then allowed to cool to room temperature. The precipitated solid material was filtered off and purified by dissolving it in dilute sodium hydroxide and precipitating with hydrochloric acid. There was thus obtained 2-nitroamino-5- (N-oxo-3-pyridylmethyl) -4-pyrimidone, m.p.

c) Reaction of 2-nitroamino-5- (N-oxo-3-pyridylmethyl) -4-pyrimidone with 1 equivalent

i) 2- (5'-methyl-4-imidazolylmethylthio) ethylamine, respectively;

(ii) refluxing 4- (3-chloro-2-pyridyl) butylamine in ethanol yields:

From Example 7: 2- (2- (5-methyl-4-imidazolylmethylthio / ethylamino) -5- (N-oxo-3-pyridylmethyl) -4-pyrimidone, m.p. 95-97 °, and from Example 8: 2- ( 4- (3-chloro-2-pyridyl) butylamino) -5- (N-oxo-3-pyridylmethyl) -4-pyrimidone, m.p. 84-86 °.

Example 9

a) A mixture of 6-methylpyridine-3-carboxaldehyde (51.57 g), malonic acid (44.30 g), piperidine (6 ml) and pyridine (300 ml) was stirred at 100 DEG C. for 3 hours, allowed to cool and evaporated to dryness. Water was added to the residue, the solid product was filtered off and recrystallized from a mixture of ethanol and acetic acid. 41.25 g of 3- (6-methyl-4-pyridyl) acrylic acid, melting at 213.5 to 215.5 °, are obtained.

b) A mixture of 50.70 g of 3- (6-methyl-3-pyridyl) acrylic acid, 350 ml of dry ethanol and 25 ml of concentrated sulfuric acid was heated at reflux for 18 hours, after which about 250 ml of ethanol were evaporated. . The residue was poured into ice / aqueous ammonia, extracted with ether, washed with water and evaporated to an oily residue which crystallized on standing. There was obtained ethyl 3- (6-methyl-3-pyridyl) acrylate, m.p. 36-37 °.

c) 60.36 g of ethyl 3- (6-methyl-3-pyridyl) acrylate is hydrogenated in ethanol at 35 DEG under 35 mm Hg in the presence of 1.0 g of 10% palladium on carbon catalyst. The reaction mixture is filtered and the filtrate is evaporated to give oily ethyl 3- (6-methyl-3-pyridyl) propionate,

d) A mixture of 1.31 g of ethyl 3- (6-methyl-3-pyridyl) propionate and 7.43 g of ethyl formate was added dropwise to a suspension of 4.07 g of sodium hydride (50% dispersion in oil) with stirring at 0 °. in 24 ml dry 1,2-dimethoxyethane. The resulting mixture was allowed to warm to room temperature, stirred overnight and then poured into 300 g of ice water. The aqueous mixture is extracted with ether, the aqueous phase is acidified to pH 5.4 with hydrochloric acid and the precipitated solid is filtered off. 10.5 g (70%) of ethyl 2-formyl-3- (6-methyl-3-pyridyl) propionate, m.p.

142-144 °.

e) To a solution of sodium methoxide (prepared from 0.161 g of sodium) in 20 ml of methanol was added with stirring a solution of 1.55 g of ethyl 2-formyl-3- (6-methyl-4-pyridyl) propionate in 20 ml of methanol. After the addition of 0.73 g dry nitroguanidine, the mixture was refluxed overnight and then evaporated to dryness. The residue 3e is dissolved in 50 ml of water, the solution is extracted with chloroform and the aqueous phase is acidified with acetic acid to pH 5. The precipitated solid product is filtered off and recrystallized from methanol-acetic acid to give 0.5 g (27%) of 2-nitroamino- 5- (6-methyl-3-pyridylmethyl) -4-pyrimidine, m.p. 215 DEG-216 DEG.

f) Reaction of 2-nitroamino-5- (6-methyl-3-pyridylmethyl) -4-pyrimidone 3 with 3-chloroperbenzoic acid in acetic acid affords 2-nitroamino-5- (N-oxo-6-methyl-3-pyridylmethyl) -4-pyrimidone, melting at 232 ° with decomposition.

g) Reaction of 2-nitroamino-5- (N-oxo-6-methyl-3-pyridylmethyl) -4-pyrimidone with one equivalent of 4- (3-chloro-2-pyridyl) butylamine in ethanol affords refluxing. 2- (4- (3-chloro-2-pyridyl) butylamino) -5- (N-oxo-6-methyl-3-pyridylmethyl) -4-pyrimidone.

Example 10

Using the procedure of Example 3d) substituting 4- (3-aetoxy-2-pyridyl) butylamine for 2- (5-methyl-4-imidazolylmethylthio) ethylamine, 2- (4- / 3-methoxy) was obtained. -2-pyridyl / butylamino) -5- (2-aetoxy-4-pyridylaethyl) -4-pyrimidone, melting after crystallization from aqueous 2-propanol at 72-74 ° C This product affords refluxing in 2N ethanolic hydrogen chloride 2- (4- (3-methoxy-2-pyridyl) butylamino) -5- (2-hydroxy-4-pyridylmethyl) -4-pyrimidone trihydrochloride, m.p. 168-171 °.

Examples 11 to 13

Replacing 2- (5-methyl-4-imidazolylmethylthio) ethylamine in the procedure of Example 3d)

(i) 4- (2-pyridyl) butylamine;

11) 4- (3-chloro-2-pyridyl) butylamine, respectively. iii) 4- (3-bromo-2-pyridyl) butylamine ee obtained:

from the example, 1: 2- (4- / 2-pyridyl / butylamino) -5- (2-hydroxy-4-pyridylmethyl) -4-pyrimidone from Example 12: 2- (4- / 3-chloro-2-pyridyl) (butylamino) -5- (2-hydroxy-4-pyridylmethyl) -4-pyrimidone and from Example 13: 2- (4- / 3-bromo-2-pyridyl) butylamino) -5- (2-hydroxy-4-pyrldylmethyl) -4-pyrimidone.

Examples 14 to 17

While using

1) 4- (2-pyridyl) butylamine; ii) 4- (3-methoxy-2-pyridyl) butylamine; iii) 4- (3-chloro-2-pyridyl) butylamine respectively;

iv) 4- (3-bromo-2-pyridyl) butylamine instead of 2- (5-methyl-4-imidazolylmethylthio) ethylamine were obtained

a) working according to the procedure of example 1f), 1g)

(i) 2- (4- / 2-pyridyl / butylamino) -5- (6-hydroxy-3-pyridylmethyl) -4-pyrimidone; ii) 2- (4- (3-methoxy-2-pyridyl) butylamino) -5- (6-hydroxy-3-pyridylmethyl) -4-pyrimidone, iii) 2- (4- (3-chloro-2-pyridyl) butylamino) -5- (6-hydroxy-3-pyridylmethyl) -4- and iv) 2- (4- (3-bromo-2-pyridyl) butylamino) -5- (6-hydroxy-3-pyridylmethyl) -4-pyrimidone; and

b) working according to the procedure of example 6b), 6c)

Example 14: 2- (4- (2-pyridyl) butylamino) -5- (4-hydroxy-2-pyridylmethyl) -4-pyrimidone,

Example 15: 2- (4- (3-Methoxy-2-pyridyl) butylamino) -5- (4-hydroxy-2-pyrldylmethyl) -4-pyrimidone;

Example 16: 2- (4- (3-chloro-2-pyridyl) butylaaino) -5- (4-hydroxy-2-pyridylmethyl) -4-pyrimidone and

Example 17: 2- (4- (3-bromo-2-pyridyl) butylamino) -5- (4-hydroxy-2-pyridylmethyl) -4-pyrimidone.

Examples 18 and 19

Replacement of 6-methoxypyridine-3-carboxyldehyde using Example 1b) to le) 5.6 dimethoxypyridine-3-carboxaldehyde affords 2-nitroamino-5- (5,6-dimethoxy-3-pyridylmethyl) -4-pyrimidone, which is reacted with 2- (5-methyl-4-iidazolylmethylthio) ethylamine or 4- (3-chloro-2-pyridyl) butylamine and the resulting product is heated to reflux in 2N ethanolic hydrogen chloride. The following compounds are obtained:

Example 18: 2- (2- (5-Methyl-4-imidazolylmethylthio / ethylamino) -5- (6-hydroxy-5-methoxy-3-pyridylmethyl) -4-pyrimidone and

Example 19: 2- (4- (3-chloro-2-pyridyl) butylamino) -5- (6-hydroxy-5-methoxy-3-pyridylmethyl)

-4-pyrimidone.

Example 20: Reaction of 2-nitroamino-5- (N-oxo-6-methyl-3-pyridylmethyl) -4-pyrimidone with 4- (3-methoxy-2-pyridyl) butylamine in pyridine at reflux. 2- (4- (3-methoxy-2-pyridyl) butylamino) -5- (N-oxo-6-methyl-3-pyridylmethyl) -4-pyrimidone, m.p. 162-163 °.

Claims (4)

SUBJECT OF THE INVENTION A process for the preparation of pyrimidones of the general formula I, Het-CH-Y- (CH _{2) 2} NH CH ₂ ~ Het ¹ Ό (I) in which Het is 5-methyl-4-imidazolyl, 2-pyridyl, optionally substituted with methoxy, chlorine or bromine, or 2-thiazolyl, Ϊ represents a sulfur atom or a methylene group; and Het 'is a pyridyl group substituted with hydroxy or N-oxo and optionally substituted with methyl or methoxy, characterized in that the compound of formula III, HN '% ·' ΝΟ, ΝΗ N ^x 0 in which (III) Het ² is a hydroxy-substituted, hydroxy-protected or N-oxo-substituted pyridyl group and optionally substituted by a methyl or methoxy group, is reacted with an amine of formula 11, Het-CH ₂ -Y- (CH ₂ ) ₂ H ₂ (IX) in which Het and Y are as in formula I, and any hydroxyl protecting group present is removed from the resulting product. 2. A process according to claim 1, wherein the reaction is carried out under reflux in ethanol, 1-propanol or pyridine. 3. A process according to any one of items 1 and 2 for the preparation of compounds of the above formula I, wherein Het * is 2-, 4- or 6-hydroxypyridyl and Het and ϊ are as defined in item 1, A compound of formula 111 wherein Het ² is a pyridyl group substituted at the 2, 4 or 6 position by methoxy is reacted with an amine of formula 11, wherein Het and Y are as in 1, and the resulting the product is subjected to acid hydrolysis. 4. A process according to any one of claims 1 to 3, wherein the starting materials of the above general formula (II) are used in which Het is 5-methyl-4-imidazolyl, 2-pyridyl, 3-methoxy-2- pyridyl, 3-chloro-2-pyridyl, 3-bromo-2-pyridyl or 2-thiazolyl and Y is as in 1.