HU180946B - Process for producing pyrimidone derivatives - Google Patents

Description

Process for the preparation of pyrime-time derivatives

The present invention relates to a process for the preparation of pharmacologically active pyrimidone derivatives and to pharmaceutical compositions containing such compounds as active ingredients.

The pyrimidone derivatives correspond to formula (1).

These compounds are histamine H ₂ antagonists and additionally have histamine H ₂ antagonist activity, however, they are all particularly active as histamine H ₂ antagonists. They are compared with compounds of similar structure as described in Hungarian Patent Application No. 5,198,198. The reference describes compounds wherein Week ¹ is other than pyridyl substituted with hydroxy or N-oxido.

Seven 5-methylimidazolyl, 2-triazolyl, optionally substituted with halogen (preferably chlorine or bromine), (C 1 -C 4) alkoxy group in the compounds of formula (I),

Y is a sulfur atom or a methylene group,

Z is hydrogen,

A is C 1-4 alkylene, and Sev is ¹ pyridyl substituted with hydroxy or N-oxido and optionally lower alkyl or lower alkoxy.

As used herein, the term "lower alkyl" and "lower alkoxy" refers to C 1-4 alkyl and alkoxy groups which are straight or branched. Such groups include methyl, e'yl, 1-propyl and 2-propyl groups in lower alkyl groups, and methoxy, ethoxy, propoxy and 2-propoxy groups in lower alkoxy groups.

Preferred Seven groups are 5-mecyl-4-imidazolyl, pyridyl, 3-methoxy-2-pyridyl, 3-ethoxy-2-pyridyl, 3,4-dimethoxy-2-pyridyl, 3-fluoro-2 pyridyl, 3-chloro-2-pyridyl, bromo-2-pyridyl, 3-iodo-2-pyridyl, 3-bromo-4-methyl-2-pyridyl or 2-thiazolyl.

Preferably the straight chain α, ω-alkylene, especially methylene.

Week ¹ is especially 4-hydroxy-2-pyridyl, 6-hydroxy-3-pyridyl, 2-hydroxy-4-pyridyl, 4-hydroxy-5-nethyl-2-pyridyl, 6-hydroxy-5-methyl -3-pyridyl, 2-hydroxy-20 -6-methyl-4-pyridyl, 6-hydroxy-5-methoxy-3-pyridyl, N-xido-3-pyridyl, N-oxido-6-methyl-3 pyridyl and N-oxido-4-pyridyl.

Seven ^{1 are} primarily pyridyl substituted with hydroxy and optionally lower alkyl 25 such as in particular 4-hydroxy-2-pyridyl, 6-hydroxy-3-pyridyl or 2-hydroxy-4-pyridyl c.

The compounds of the present invention are described as 4-pinmidone derivatives and are described in equilibrium with the corresponding

-1180946

They exist with 6-pyrimidone derivatives and to some extent in the tautomeric forms shown in equation (A).

The 2-, 4- and 6-hydroxypyridyl groups may exist as 1H-pyridone tautomers and certain Sevic groups may exist in some tautomeric forms. All tautomeric forms of the compounds of formula (1) are within the scope of the invention.

Compounds of formula (1) are prepared by reacting a compound of formula (3) wherein Q is a primary amine-substituted group, preferably nitroamino. Z and A represent the above and Seven 'pyridyl radicals which are hydroxyl. is substituted with a protected hydroxy group or an N-oxo group and optionally a lower alkyl group or a lower alkoxy group, with an amine of formula 2 wherein Sev and Y are as defined above and the protecting groups of the hydroxy group are removed.

The reaction is carried out at elevated temperature in the absence of solvent, for example 80-170 ° C. preferably at 120-140 ° C, or in a solvent at elevated temperature, such as the reflux temperature of the reaction mixture. The choice of solvent will depend upon the solubility characteristics of the materials involved in the reaction and the meaning of the Q group. Preferably the solvent is pyridine. picoline or a mixture of hollens, lower alkanol. preferably an aqueous mixture of ethanol or 1-propanes with lower alkanols. 1,2-octanediol, a ketone such as acetone or 2-butanone. or a non-proton solvent. for example, dimethylformamide, dimethylacetamide, dimethylsulfoxide, hexamethylphosphoramide. sulfolane, acetonitrile or nitromethane, GL is primarily a nitroamino group and the reaction is carried out under reflux in ethanol, 1-propanol or pyridine, or the methylthio group GL and in this case the reaction is carried out under reflux.

Preferably, approximately molar equivalents of the reactants are used, but a small excess, e.g., 1.1 to 1.5 molar equivalents, or greater excess, such as 1.5 to 4 molar equivalents, of each of the reactants may be used. If excess is used. then an amine of formula (2) is preferably used in excess. Any of the materials involved in the reaction may already be in excess at the start of the reaction, but of course, any excess may be used during the reaction.

The hydroxyl protecting group is methoxymethyl. methylthiomethyl, tetrahydropyranyl, arylmethyl groups such as benzyl, lower alkyl groups such as methyl and acyl groups. for example, formyl or acetyl.

Compounds of formula (I) wherein Sev 'is 2-, 4- or 6-hydroxypyridyl may conveniently be prepared from compounds of formula (3) wherein Week ^{2 is} a 2-, 4- or 6-hydroxypyridyl group.

Pyridyl substituted at the 4- or 6-position by a lower alkoxy group by acid hydrolysis of the reaction product obtained by reaction of an amine of formula (2).

Compounds of formula (3) wherein G is a nitroamino group can be prepared by reacting a β-oxoester of formula (4) wherein Z is hydrogen, R is lower alkyl, A is as defined above, and Sev ^{3 is} optionally lower. alkyl-substituted pyridyl group or a pyridyl group which is substituted by hydroxyl, a protected hydroxyl group or a lower alkyl N-UXO group and optionally substituted by alkyl or lower alkoxy, is reacted with nitroguanidine, and in cases when Het ³ is optionally substituted by lower alkyl or lower alkoxy the substituted pyridyl group is reacted with an oxidizing agent, the resulting N-oxopyridyl derivative is isolated and optionally the hydroxyl protecting group is removed.

Compounds of formula (3) wherein Q is a lower alkylthio or benzylthio group can be prepared by reacting an O-oxoester of formula (4). wherein Seven ³ pyridyl groups substituted with hydroxy, protected hydroxy or N-oxido and optionally lower alkyl or lower alkoxy are reacted with thiourea, alkylation or benzylation of the resulting 2-thiouracil and optionally .

Compounds of general formula (3). where GL is chlorine or bromine, is prepared by reacting a formula / 3 oxoésztert (4) unk reacted with guanidine, and the product is diazotized kuproklorid presence of HBr HCI or kuprobromid presence of, and in the case where Week ³ where In the case of pyridyl substituted with lower alkyl or lower alkoxy, the product is reacted with an oxidizing agent, the resulting N-oxydopyridyl derivative is isolated and optionally deprotected.

The reaction of the 0-oxoester of formula (4) with nitroguanidine, thiourea and guanidine is a base such as an alkali metal lower alkoxide, preferably sodium methoxide or sodium ethoxide, an alkali metal carbonate or hydroxide, for example sodium hydroxide or potassium hydroxide, , in the presence of. This reaction is preferably carried out at elevated temperature, for example at the reflux temperature of the solvent mixture. Preferably, the solvent is a lower alkanol such as ethanol, a mixture of lower alkanols, a ketone such as 2-butanone, or a polar proton-free solvent such as dimethylformamide. The 3-oxoester of formula 4 can be used in the form of a hemiacetal of a lower alkanol. ·

A peroxycarboxylic acid, preferably, for example, 3-chloroperoxybenzoic acid, peroxybenzoic acid or peracetic acid, may be used as an oxidizing agent to convert a pyridyl group to an N-oxopyridyl group. Preferably, this oxidation is carried out in acetic acid.

Amines of formula 2 wherein Y is sulfur can be prepared by reacting cystamine with a compound of formula Het-CH ₂ L wherein L is a thiol-exchangeable group such as hydroxy, acyloxy (such as acetoxy, methanesulfonyloxy). or p-toluenesulfonyloxy), an alkoxy (e.g., methoxy) moiety of r-2180946, a chlorine or bromine atom, or a triarylphosphonium (e.g. triphenylphosphonium) group. Preferably, the hydroxyl or methoxy group is L and the reaction is carried out under acidic conditions such as hydrochloric acid or hydrobromic acid.

Amines of formula (2) wherein Y is a methylene group and Seven is a 2-pyridyl group containing a lower alkoxy group or a halogen at the 3-position can be prepared by treating 2-halo-3-nitropyridine with diethyl-2- ( 2-cyanoethyl) malonate. The product is then hydrolyzed and decarboxylated and subsequently reduced with palladium and activated carbon to give 3-amino-3- (3-cyanopyridyl) pyridine. This compound is diazotized in 2 M sulfuric acid and alkylated in dimethyl sulfoxide to give 3-alkoxy-2- (3-cyanopropyl) pyridine. The 3-amino-2- (3-cyanopyridyl) -pyridines can be reduced with lithium aluminum hydride to give 4- (3-amino-2-pyridyl) -butylamine, which is diazotized in strong hydrochloric acid in the presence of cupric chloride to give 3-chloramine. diazotized in hydrogen bromide solution in the presence of cuprobromide to give 3-bromamine or diazotized in dilute sulfuric acid in the presence of sodium iodide to give 3-iodamine. The 3-amino-2- (3-cyanopropyl) pyridines can be diazotized in hydroboric acid and reduced with lithium aluminum hydride to give 4- (3-fluoro-2-pyridyl) butylamine.

Amines of formula (2) wherein Y is a methylene group and Seven is 2-thiazolyl can be prepared by reacting a thioamide of formula NH ₂ CS (CH ₂ ) ₄ Q, where Q is a protected amino group, with bromoacetaldehyde dialkylacetal. and removing the amino protecting group.

Esters of Formula 4 may be prepared by alkylation of a dialkyl malonate followed by hydrolysis and decarboxylation or condensation of an aldehyde with malonic acid and decarboxylation, esterification and reduction of the product.

The compounds of formula (I) are H ₂ -histamine antagonists, but also have H 1 -histamine antagonists and are particularly effective as H ₂ -histamine antagonists compared to analogous compounds in which Week is hydroxy or N-oxo. other than a pyridyl ring substituted with. The compounds of formula (I) have low fat-binding capacity, as shown by octal-water distribution measurements.

As used herein, H ₂ -receptors are those defined by Black et al. (Naturre, 236, 385, 1972), i.e., histamine receptors that are not blocked by mepiramine but blocked by burimamide, and H 1 -receptors. refers to receptors that have mepyramine-sensitive histamine reactions. Compounds that block H ₂ -histamine receptors as H ₂ -histamine antagonists and compounds that block H 1 -histamine receptors are referred to as 1+ -histamine antagonists.

Blocking of H ₂ -histamine receptors is of great importance in inhibiting the biological effects of histamine that are not inhibited by H1-histamine antagonists. H ₂ -histamine antagonists are active, for example, in inhibiting gastric acid secretion as well as being active as anti-inflammatory agents, and as agents that affect the cardiovascular system, such as inhibiting the effect of histamine on blood pressure.

Under certain physiological conditions, the biological effects of histamine are mediated by both H ₁ and H ₂ histamine receptors, and inhibition of both receptor types is useful. Such conditions include histamine-mediated inflammation, such as dermatitis, and hypersensitivity due to the H 1 and H ₂ receptors, such as allergy.

The activity of the compounds of formula (I) as H 1 -histamine antagonists can be demonstrated by inhibiting histamine-stimulated gastric acid secretion from urethane-anesthetized rats at doses of less than 16 micromoles / kg by intravenous administration. This method was used by Ash and Schild, Brit. J. Pharmac. Chemother. 27, 427 (1966). The H ₂ -histamine antagonist activity of these compounds is also demonstrated by their ability to inhibit other effects of histamine that are not mediated by H 1 -histamine receptors, as mentioned by Ash and Schild. For example, they inhibit the effect of histamine on isolated guinea-pig heart and isolated rat uterus. These agents also inhibit the basal secretion of gastric acid and the stimulation of pentagastrin or food stimulated secretion. These compounds inhibit the vasodilatory effect of histamine in conventional experiments, such as measuring intravenous doses of 0.5 to 256 micromoles / kg in anesthetized cats. The activity of these agents is shown by a 50% inhibition of gastric acid secretion in anesthetized rats and also by a 50% inhibition of histamine-induced tachycardia in isolated teerimal pig heart atria (less than 10 ⁴ moles).

Compounds of formula I such as H _; -histamine antagonists are demonstrated by inhibiting histamine-stimulated isolated guinea-pig gonadal contraction. More preferred is an administration of a compound which is H, - and H ₂ has -hísztamin-antagonist activity than the administration of compounds, one of which only HI-histamine receptor antagonist effect and the other is only -hisztamin _{H2-antagonist} activity, and Thus, difficulties due to different absorption rates and wall macokinetic characteristics can be overcome.

A pharmaceutical composition having an H ₂ -histamine antagonist activity is prepared by mixing a compound of Formula (I) in the form of a free base or a pharmaceutically acceptable acid addition salt thereof with a pharmaceutical carrier or diluent. Such addition salts include salts with hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and maleic acid, which may be prepared by conventional methods from the corresponding compounds of formula (1), for example by treatment with an acid in lower alkanol or the desired ion exchange resins. or they may be formed directly from the base or other addition salt.

The pharmaceutical carrier used may be solid or liquid. Examples of solid carriers are 3

-3180946 include lactose, corn starch, potato starch or modified starches, dicalcium phosphate, square alba, sucrose, cellulose, talc, gelatin, agar, pectin, acacia, magnesium stearate and stearic acid. Liquid vehicles include, for example, syrup, peanut oil, olive oil, alcohol, propylene glycol, polyethylene glycols and water.

When solid carriers are employed, the preparation may be in the form of tablets, powder capsules, pills, or lozenges. The amount of solid carrier in a unit dose will generally range from 25 mg to 300 mg. When a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable liquid in ampoules, or suspension in an aqueous or non-aqueous liquid. The compositions may also contain other additives such as preservatives, for example antioxidants or antibacterial agents, and / or odoriferous or coloring agents. In addition to the ampoules, sterile liquids may also be prepared in multi-dose vials or unit dose forms. The compositions may also be formulated in a semi-solid form, for example, as a cream, paste, ointment or gel, or as a liquid or aerosol for topical use. The pharmaceutical compositions may be prepared by conventional methods such as milling, mixing, granulating and pressing, spray drying, freeze drying, or by dissolving or dispersing the active ingredients in the desired composition. The active ingredients are present in the formulations in amounts that block the H ₂ -receptors. Each unit dose preferably contains from about 50 mg to about 250 mg of the active ingredient.

Preferably, the active pharmaceutical compositions are administered 1 to 6 times daily. The daily dose will generally range from about 150 mg to about 1500 mg of active ingredient. The formulations are administered orally or parenterally.

The process of the invention is also illustrated by the following examples, the temperature values

Give it in C.

Example 1 (a) A mixture of 61.26 g of 2-methoxy-5-cyanopyridine, 76.4 g of semicarbazide hydrochloride, 74.92 g of sodium acetate, 1300 ml of ethanol and 400 ml of water under a pressure of 1.0 g of Raney nickel catalyst is used. hydrogenation. The mixture was then concentrated to a volume of 500 ml, water (1000 ml) was added and the mixture was allowed to stand at 0 ° C overnight. The mixture was filtered and the solid was washed with water and then dissolved in 1000 ml of 10% hydrochloric acid. To the solution was added 450 ml (36% v / v) of formaldehyde solution and the mixture was heated for 15 minutes, then allowed to cool, and 298.5 g of sodium acetate dissolved in 900 ml of water were added. The mixture was extracted with ether and the combined ether extracts washed successively with aqueous potassium carbonate and water, then dried and evaporated. 31.5 g of 50% of 6-methoxy-4-pyridine-3-carboxaldehyde are obtained. 48-49 °.

(b) A mixture of 2.34 g of 6-methoxypyridine-3-carboxaldehyde, 4.51 g of monoethyl malonate, 12 ml of pyridine and 6 drops of piperidine is refluxed for 5 hours and then concentrated. The resulting oil was partitioned between ether and dilute aqueous ammonium hydroxide solution. The ether layer was washed with water and evaporated to give an oil which crystallized on standing. This gave 2.8 g of ethyl 3- (6-methoxy-3-pyridyl) acrylate in 79% yield. 49-52.

(c) 32.33 g of ethyl 3- (6-methoxy-3-pyridyl) acrylate was hydrogenated in 160 ml of ethanol at 344 kPa and 40 ° C over 0.2 g (5%) of palladium on carbon. . The mixture was filtered and the filtrate was evaporated. This gave 32.7 g of ethyl 3- (6-methoxy-3-pyridyl) propionate as an oil.

(d) A mixture of 32.74 g of ethyl 3- (6-methoxy-3-pyridyl) propionate and 17.22 g of ethyl formate is added dropwise over 1.5 hours to an oil suspension of 9.38 g (50%) of sodium hydride which was prepared with 50 ml of 1,2-dimethoxyethane while stirring at -2 °. The reaction mixture was allowed to stand overnight at room temperature, then poured onto ice and extracted with ether. The ethereal phase is discarded and the aqueous phase is adjusted to pH 5 with 2N sulfuric acid. An oil precipitates which crystallizes on standing to give 25.9 g of ethyl 2-formyl-3- (6-methoxy-3-pyridyl) propionate in 70% yield. Mp 91.5-94 °. After recrystallization from aqueous ethanol, the melting point is 93-94 °.

(e) Add 4.7 g of nitroguanidine to a solution of sodium methoxide (1.15 g of sodium) in 50 ml of methanol and reflux for 45 minutes. Subsequently, ethyl 2-formyl-3- (6-methoxy-3-pyridyl) propionate (10.7 g) was added and the mixture heated at reflux for 34 hours and then concentrated. The residue was dissolved in water and the solution was extracted with chloroform (which was discarded). The aqueous solution was adjusted to pH 5 with acetic acid and the precipitate collected by filtration to give 2-nitroamino-5- (6-methoxy-3-pyridylmethyl) -4-pyrimidone. M.p. 183.5-186 °.

(f) A mixture of 2-nitroamino-5- (6-methoxy-3-pyrrolylmethyl) -4-pyrimidone and 2- (5-methyl-4-imidazolylmethylthio) ethylamine in an equal amount was heated at reflux for 18 hours. The mixture was cooled and the material precipitated during cooling was recrystallized from ethanol. This gave 2- [2- (5-methyl-4-imidazolylmethylthio) ethylamino] -5- (6-methoxy-3-pyridylmethyl) -4-pyrimidone in 63% yield. M.p. 197-198.5 °.

(g) 0.55 g of 2- [2- (5-methyl-4-imidazolylmethylthio) ethylamino] -5- (6-methoxy-3-pyridylmethyl) -4-pyrimidone is refluxed in 2N ethanolic hydrogen chloride. hours. The mixture is then evaporated to dryness and the residue is recrystallized from 2-propanol / ethanol containing hydrogen chloride. 2- [2- (5-Methyl-4-imidazolylmethyl-49-thio) -ethylamino] -5- (6-hydroxy-3-pyridylmethyl) -4-pyrimidone trihydrochloride was obtained in 71% yield. M.p .: 205-209 °.

Example 2 (a) A molar equivalent of 2-nitroamino-5- (6-methoxy-3-pyridylmethyl) -4-pyrimidone and 2- (2-thiazolylmethylthio) ethylamine was refluxed in ethanol for 18 hours. The mixture was cooled and the crystalline material precipitated during cooling was recrystallized from ethanol. 2- [2- (2-Thiazolylmethylthio) ethylamino] -5- (6-methoxy-3-pyridylmethyl) -4-pyrimidone was obtained in 60% yield. 95-97 °.

(b) 2- [2- (2-Thiazolylmethylthio) ethylamino] -5- (6-methoxy-3-pyridylmethyl) -4-pyrimidone is refluxed in 2N ethanolic hydrogen chloride for 24 hours. The mixture is then evaporated to dryness and the residue is recrystallized from 2-propanol / ethanol containing hydrogen chloride. 2- [2- (2-Thiazolylmethylthio) ethylamino] -5- (6-hydroxy-3-pyridylmethyl) -4-pyrimidone trihydrochloride is obtained. M.p. 200-204 °.

Example 3 (a) 20.8 g of sodium are dissolved in 285 ml of methanol and a solution of 115.53 g of 2-chloro-4-cyanopyridine in 850 ml of a 1: 1 mixture of methanol and dioxane is added. Reflux for 1/2 hour, then allow to cool. The mixture was filtered and the filtrate was evaporated to 200 ml with water (400 ml). The precipitated solid was collected by filtration to give 57.2 g (51%) of 2-methoxy-4-cyanopyridine. 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 ml of ethanol and 370 ml of water is hydrogenated over 1.0 g of Raney nickel catalyst. The mixture was concentrated to 450 mL, water (900 mL) was added and the mixture was allowed to stand at 0 overnight. The mixture was filtered and the solid was washed with water and dissolved in 950 mL of 10% hydrochloric acid. To the solution was added 420 ml (36% v / v) of formaldehyde solution and the mixture was heated for 30 minutes, allowed to cool and added to a solution of 280 g of sodium acetate in 840 ml of water. The mixture was extracted with ether (3 x 500 mL) and the combined extracts were washed with water, aqueous potassium carbonate solution and water again, dried and evaporated. 20.53 g of 2-methoxypyridine-4-carboxaldehyde were obtained in 35% yield. Mp: 33-35 °. After recrystallization from petroleum ether, m.p. 33-36 °.

(c) In the general procedure of Example 1 (b, c, d), 6-methoxypyridine-3-carboxaldehyde is replaced by 2-methoxypyridine-4-carboxaldehyde to give ethyl 2-formyl-3- (2-methoxy-4-) pyridyl) propionate as an oil. This oil was treated with nitroguanidine and sodium methoxide according to Method 1 (e) to give 2-nitroamino-5- (2-methoxy-4-pyridylmethyl) -4-pyrimidone in 59% yield.

194-195.5 ° (from aqueous acetic acid).

(c) A molar equivalent of 2-nitroamino-5- (2-methoxy-4-pyridylmethyl) -4-pyrimidine and 2- (5-methyl-4-imidazolylmethylthio) ethylamine is refluxed in ethanol for 18 hours. The solution was cooled to a solid which crystallized from methanol to give 2- [2- (5-methyl-4-imylazolylmethylthio) ethylamino] -5- (2-methoxy-4-pyridylmethyl) -4-pyrimidone With a yield of 51%. M.p. 177-178 °.

The latter compound was heated in 2N ethanolic hydrogen chloride solution for 24 hours and then evaporated to dryness. The residue was recrystallized from 2-propanol / ethanol containing hydrogen chloride to give 2- [2- (5-methyl-4-imidazolylmethylthio) -ethylamino] -5- (2-hydroxy-4-pyridylmethyl) -4-pyrimidone trihydrochloride is obtained. 172-176 °.

Example 4

A molar equivalent of 2-oxoamino-5- (2-methoxy-4-pyridylmethyl) -4-pyrimidone and 2- (2-thiazolylmethylthio) ethylamine was heated at reflux in ethanol for 18 hours. The solid, which crystallizes on cooling, is purified by silica gel column chromatography and recrystallized from 2-propanol-ethanol. 2- [2- (2-Thiazolylmethylthio) -ethylamino] -5- (2-methoxy-4-pyridylmethyl) -4-pyrimidone was obtained in 41% yield. 105.5-106.5 °.

The latter compound was refluxed in 2N ethanolic hydrogen chloride for 24 hours to give 2- (2- (2-thiazolylmethylthio) ethylamino] -5- (2-hydroxy-4-pyridylmethyl) -4-pyrimidone monohydrochloride. 169-173 °.

Example 5

1.15 moles of 2- (3-bromo-2-pyridylmethylthio) ethylamine are reacted with 2-nitroamino-5- (2-methoxy-4-pyridylmethyl) -4-pyrimidone in ethanol at reflux for 18 hours to give 2- [2- (3-Bromo-2-pyridylmethylthio) ethylamino] -5- (2-methoxy-4-pyridylmethyl) -4-pyrimidone is obtained. which melts at 70-72. This compound is refluxed in ethanol containing hydrogen chloride to give 2- [2- (3-bromo-2-pyridylmethylthio) ethylamino] -5- (2-hydroxy-4-pyridylmethyl) -4-pyrimidone trihydrochloride. 195-198.5 °.

Example 6 (a) In Example 1 (b) - (c), 6-methoxypyridine-3-carbaldehyde is replaced with 4-methoxypyridine-2-carboxaldehyde to give ethyl 3- (4-methoxy-2-pyridyl) Propionate is obtained in the form of an oil. This oil is formylated with ethyl formate and sodium hydride in 1,2-dimethoxyethane and the product is reacted with nitroguanidine and sodium ethoxide to give 2-nitroamino-5- (4-methoxy-2-pyridylmethyl) -4-pyrimidone.

196-198 ° (dec.) (From ethanol / acetic acid).

(b) 2-nitroamino-5- (4-methoxy-2-pyridylmethyl) -4-pyrimidone 1.06 molar equivalent of 2- (5-methyl-4-imidazole)

-5180946 zol ylmethylthio) -ethylamine was reacted with ethanol under reflux for 24 hours. 2- [2- (5-Methyl-4-imidazolyl-ethyl-thio) -ethylamino] -5- (4-methoxy-2-pyridylmethyl) -4-pinmidone is obtained.

128-130 ° (from 2-propanol).

(c) 0.97 g of 2- [2- (5-methyl-4-imidazolylmethylthio) ethylamino] -5- (4-methoxy-2-pyridylmethyl) -4-pyrimidone and 20 ml (48%) of aqueous hydrobromic acid. the solution was heated to reflux for 20 hours and then evaporated to dryness. The residue was recrystallized from a mixture of ethanol and 2-propanol to give 2- [2- (5-methyl-4-imidazolylmethylthio) ethylamine 5- (4-hydroxy-2-pyridylmethyl) -4-pyrimidone trihydrobru. ' ^: we get a dot.

M.p. 167-169 °. After recrystallization from a mixture of ethanol and l-propanol, the melting point of the product is reduced due to the loss of hydrogen bromide.

Examples 7 and 8 (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 under reflux for 45 minutes, ethyl 2-formyl-3- (3-pyridyl) propionate (9.3 g) was added portionwise and the whole was heated under reflux for 45 hours and then evaporated to dryness. Water was added to the residue and the mixture was extracted with chloroform. The residual aqueous phase was adjusted to pH 5 with acetic acid and the resulting solid precipitate was collected by filtration, washed and dried. This gave 2-nitroamino-5- (3-pyridylmethyl) -4-pyrimidone in 38% yield. M.p. 214.5-216 °.

(b) 10.35 g of 3-chloroperoxybenzoic acid are added to 1 2.35 g of 2-nitroamino-5- (3-pyrrolylmethyl) -4-pyrimidone in 300 ml of acetic acid. The mixture was stirred at room temperature for 18 hours and at 60 ° C for 5 hours and then allowed to cool to room temperature. The precipitated solid was collected by filtration and purified by precipitation from dilute sodium hydroxide solution by addition of hydrogen chloride. This gives 2-nitroamino-5- (N-oxido-3-pyridylmethyl) -4-pyrimidone. 271 ° (dec.).

(c) 2-nitroamino-5- (N-cxido-3-pyridylmethyl) -4-pyrimidone with one equivalent of (i) 2- (5-methyl-4-imidazolylmethylthio) ethylamine and (ii) 4- (3-chloro) -2-pyridyl) -butylamine in ethanol at reflux and so on

7. 2- [2- (5-Methyl-4-imidazolylmethylthio) - (ethylamino) -5- (N-oxido-3-pyridylmethyl) -4-pyrimidone, m.p.

8. 2- [4- (3-Chloro-2-pyridyl) -butylamino] -5- (N-oxido-3-pyridylmethyl) -4-pyrimidone, m.p. 84-86 °.

Example 9 (a) A mixture of 51.57 g of 6-methylpyridine-3-carboxaldehyde and 44.30 g of malonic acid in 6 ml of piperidine and 300 ml of pyridine was stirred at 100 ° for 3 hours and then allowed to cool. The mixture is evaporated to dryness, water is added to the residue, the precipitated solid is collected by filtration and recrystallized from ethanol / acetic acid. Yield: 41.25 g of 3- (6-methyl-4-pyridyl) acrylic acid, m.p. 213.5-215.5 °.

(b) A mixture of 50.70 g of 3- (6-methyl-3-pyridyl) acrylic acid, 350 µl of dry ethanol and 25 ml of concentrated sulfuric acid was heated at reflux for 18 hours and then the ethanol (about 250 ml) was evaporated. eltávol'tjuk. The residue was poured into ice-aqueous ammonium hydroxide and the mixture was extracted with ether. The ether extracts were washed with water and evaporated. The resulting oily product crystallizes on standing to give ethyl 3- (6-methyl-3-pyridyl) acrylate. M.p. 36-37 °.

(?) Ethyl 3- (6-methyl-3-pyridyl) acrylate (60.36 g) was hydrogenated in ethanol at 35 ° C and 355 kPa over 1.0 g (10%) of palladium on carbon. The mixture was filtered and the filtrate was evaporated to give <: ethyl 3- (6-methyl-3-pyridyl) propionate as an oil.

(d) 1.31 g of ethyl 3- (6-methyl-3-pyridyl) propionate and 7.43 g of ethyl formate are added dropwise to 4.07 g of sodium hydride (as a 50% oil dispersion) in 24 ml of dry 1.2 -dimethoxyethane slurry while stirring and maintaining the temperature at 0 °. The mixture was allowed to warm to room temperature, overnight, and poured into 300 g of ice-water. The mixture is extracted with ether, the aqueous phase is adjusted to pH 5.4 with hydrochloric acid and the precipitated solid is isolated to give 10.5 g of ethyl 2-formyl-3- (6-methyl-3-pyridyl) propionate. In 70% yield. 142-144 °.

(e) A solution of 1.55 g of ethyl 2-formyl-3- (6-methyl-3-pyridyl) propionate in 20 ml of methanol is added with stirring to a solution of sodium methoxide (0.161 g of sodium) in 20 ml of methanol. Dry nitrogen (0.73 g) was added and the mixture was heated to reflux overnight and then evaporated to dryness. The residue was dissolved in water (50 mL) and the solution was extracted with chloroform. The pH of the aqueous phase is adjusted to 5 with acetic acid. The precipitated solid was collected by filtration and recrystallized from methanol / acetic acid. 0.5 g of 2-nitroamino-5- (6-methyl-3-pyridylmethyl) -4-pyrimidinone were obtained in a yield of 27%.

215-216 ° (dec.).

(f) reacting 2-nitroamino-5- (6-methyl-3-pyridylmethyl) -4-pyriridone with 3-chloroperbenzoic acid in acetic acid to give 2-nitroamino-5- (N-oxo-6-methyl-3-pyridylmethyl) - 4-pyrimidone is obtained.

232 ° (dec.).

(g) 2-nitroamino-5- (N-oxido-6-methyl-3-pyridylmethyl) -4-pyrimidone is reacted with one equivalent of 4- (3-chloro-2-pyridyl) butylamine in reflux to give 2- [ 4- (3-Chloro-2-pyridyl) -butylamino] -5- (N-oxido-6-methyl-3-pyridylmethyl) -4-pyrimidone is obtained.

-613

Example 10

In Example 3 (d), 2- (5-methyl-4-imidazolylmethylthio) ethylamine is replaced with 4- (3-methoxy-3-pyridyl) butylamine and 2- [4- (3-methoxy) -2-pyridyl) -butylamino] -5- (2-methoxy-4-pyridylmethyl) -4-pyrimidone is obtained.

72-74 (from aqueous propanol).

This compound was heated at reflux in 2N ethanolic hydrogen chloride to give 2- [4- (3-methoxy-2-pyridyl) butylamino] -5- (2-hydroxy-4-pyridylmethyl) -4-pyrimidone trihydrochloride. we get. 168-170 °.

1-11. The product obtained according to example

Sorbitol solution Β. P.

Citric acid

sodium citrate

methylparaben

propyl paraben

Water

1.0

7.5

0.2

0.05

0.18

0.02 added to 100

The mixture of constituents A is heated to 72 ° and added with stirring to the 70 ° mixture of constituents B and the mixture is stirred until the cream is converted.

Example 11

- nitroamino-5- (N-oxido-6-methyl-3-pyridylmethyl) -4-pyrimidone is reacted with 4- {3-methoxy-2-pyridyl) butylamine in pyridine at reflux to give 2- [4- (3- methoxy-2-pyridyl) butylamino] -5- (N-oxido-6-methyl-3-pyridylmethyl) -4-pyrimidone, m.p. 162-163 °.

Preparation of pharmaceutical compositions for oral administration

The following ingredients are used in the preparation of the pharmaceutical composition:

% w / w

1-11. Example 55

Dibasic Calcium Phosphate Dihydrate 20 Proven Coloring 0.5

Polyvinylpyrrolidone 4.0

Microcrystalline cellulose 8.0

Corn starch 8.0

Sodium starch glycolate 4.0

Magnesium stearate 0.5

Components A are mixed (optionally, the dibasic calcium phosphate dihydrate is replaced by lactose or microcrystalline cellulose), concentrated polyvinylpyrrolidone solution is added, the mixture is granulated, dried and the dried granulate is passed through a sieve. Components B are then added to the dry granular product and compressed into tablets containing 100 mg, 150 mg or 200 mg of the active ingredient corresponding to the free base.

Pharmaceutical preparations for topical use

The following substances are used in the preparation of the pharmaceutical composition:

% w / w Stearyl alcohol 15.0 Beeswax 8.0 sorbitan 1.25 Polyoxyethylene sorbitan monooleate 3.75

IS

Claims (7)

Patent claims: A process for the preparation of pyrimidone derivatives of the formula (I) and salts thereof, wherein Hct is 5-methylimidazolyl, 2-pyridyl optionally substituted by lower alkyl or halogen, or 2-thiazolyl, 25 Y sulfur or methylene, Z is hydrogen, A is C 1 -C 4 alkylene and H ^{1 is} pyridyl substituted with hydroxy or N-oxido and optionally lower alkyl or lower alkoxy, characterized in that a compound of formula 3 wherein Q is a primary amine-substituted group, preferably a nitroamine group, Z and A 35 represents the above and Seven ² pyridyl groups substituted with a hydroxy group, a protected hydroxy group or an N-oxide group and optionally a lower alkyl group or a lower alkoxy group, with an amine of formula 2 wherein Sev and Y are as defined above, and the hydroxy protecting groups are removed and, if desired, the resulting compound of formula (1) is converted into a pharmaceutically acceptable acid addition salt thereof in a manner known per se. 2. A process according to claim 1 wherein Q is a nitroamino group and the compound of formula (3) is a compound of formula (2). The amine 50 is reacted with ethanol, 1-propanol or pyridine under reflux. A process for the preparation of a compound of formula (I) according to any one of claims 1 or 2 wherein Week ¹ is a 2-, 455 or 6-hydroxypyridyl group, characterized in that a compound of formula (3) wherein Hct ^{2 is} a pyridyl group substituted at the 2-, 4- or 6-position by a lower alkoxy group, is reacted with an amine of formula 2 and the 60 products were subjected to acid hydrolysis. 4. A process for the preparation of a compound of formula (I) according to any one of claims 1 to 7, wherein Sev is 5-methyl-4-imidazolyl, 2-pyridyl, 3-methoxy-2-pyridyl, 3-ethoxy-265-pyridyl, 3,4-dimethoxy-2-pyridyl, 3-fluoro-2-pyridyl, -7180946 3-chloro-2-pyridyl, 3-ethoxy-2-pyridyl, 3,4-dimethoxy-2-pyridyl. 3-fluoro-2-pyridyl, 3-chloro-2-pyridyl, 3-bromo-2-pyridyl, 3-iodo-2-pyridyl, or 2-thiazolyl, characterized in that ), wherein Sev has the same meaning as above. 5 5. A process for the preparation of a compound of formula (I) according to any one of claims 1 to 3, wherein A is a methylene group, wherein the compound of formula (3) is used as starting material, wherein 10 A represents a ethylene group. Process for the preparation of a compound according to any one of claims 1 to 3 and 5, wherein Week ¹ is 4-hydroxy-2-pyridyl, 6-hydroxy-3-pyridyl, 2-hydroxy- 4 ^PI-15 -pyridyl, 4-hydroxy-5-methyl-2-pyridyl, 6-hydroxy-5-methyl-3-pyridyl, 2-hydroxy-6-methyl-4-pyridyl, 6-hydroxy -5-methoxy-3-pyridyl, N-oxido-3-pyridyl, N-oxido-6-methyl-3-pyridyl or N-oxido-4-pyridyl, characterized in that it is a compound of (3) The starting compounds of formula I are used wherein Week ² has the same meaning as Week ¹ above. 7. A process for the preparation of a H ₂ -histamine antagonist, comprising the steps of 1-6. Claims produced according to any one of (1) a compound of formula wherein as defined in claim 1 and an effective amount of Week, Z, A, Y and Het ¹ is mixed with the base form or in pharmaceutically acceptable acid addition salt, in a pharmaceutically acceptable diluent or carrier and shaped. 1 formula page Responsible for publishing: Director of Economic and Legal Publishing 84.4259 - Zrínyi Printing House. Budapest -8180946 International Classification: C 07 D 403 / 14.4 () 9/14 VI