KR820002137B1 - Process for preparing pyridyl compounds - Google Patents

Abstract

Pyrimidinones (I; Het2=lower alkyl, halogen, or CF3-substituted 4-imidazolyl, 2-pyridyl; Y=S, -CH2-; Z=H, lower alkyl; A=C1-5 alkylene; R=lower alkyl, alkoxy; R1=H, lower alkyl, alkoxy) useful as a histaminic H2 receptor antagonists, were prepd. by reaction of II(Q=-NO2NH2,, lower alkylthio, lenzylthio, Cl, Br) and Het2-CH2Y(CH2)2NH2. Thus, 5.48g 4-(3-methxy-2-pyridyl)butylamine in 500ml pyridine and 7.95g 2-nitroamino-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone reacted for 18hr to give 2-4-(3-methoxy-2-pyridyl) butylamino-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone.

Description

[Name of invention]

Process for preparing pyridyl compound

Detailed description of the invention

The present invention relates to a pharmacologically active pyridylmethylpyrimidone compound and a method for preparing a pharmaceutical composition containing the same.

In German Laid-Open Patent Publication 2658267, the following pyrimidone group (1) is described as having histamine H ₁ -and H ₂ -antagonism.

In the above formula (1), Het is a 2- or 4-imidazolyl group optionally substituted with lower alkyl, halogen, trifluoromethyl or hydroxymethyl, or selected as lower alkyl, lower alkoxy, halogen, amino or hydroxy 3- (1,2,5) -thiazolyl group, which is a substituted 2-pyridyl group, 2-thiazolyl group, 3-isothiazolyl group optionally substituted by chlorine or cancellation, or optionally substituted by chlorine or cancellation, Or a 2- (5-amino-1, 3, 4-thiadiazolyl) group; Y is sulfur or methylene; Z is hydrogen or lower alkyl; X is acid or sulfur; W is methylene, oxygen or sulfur; the sum of p and q is 1-4 and 0-4 when W is methylene; Het is a 5- or 6-ring heterocycle such as pyridine, furan, thiophene, thiazole, oxazole, isothiazole, imidazole, pyrimidine, pyrazine or pyridazine, which is optionally substituted with lower alkyl, lower alkoxy It may contain a benzene ring or a benzene ring fused and substituted therein. The compounds of the above-described classification is a Het ^1, selected lower alkyl or lower alkoxy group, substituted 2-furyl, 2-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-thiazolyl, 2 -A compound of imidazolyl, 2-pyrimidyl, 2-pyrazinyl or 3-pyridazyl group.

A small group of compounds in this total group of compounds improved the therapeutic properties and found less acute toxicity than the other groups of compounds.

According to the present invention, pyrimidone of the following structural formula (2) is provided.

Het ² in the above formula is 4-imidazolyl group optionally substituted with lower alkyl, halogen, or trifluoromethyl or 2-pyridyl optionally substituted with one or more lower alkyl or lower alkoxy groups or halogen elements, or 2- Thiazolyl group; Y is sulfur or methylene; Z is hydrogen or lower alkyl; A is C ₁ -C ₅ alkylene; R is lower alkyl or lower alkoxy; R ¹ is hydrogen, lower alkyl or lower alkoxy.

Throughout this specification, the terms lower alkyl and lower alkoxy refer to alkyl and alkoxy groups which are linear or branched and contain 1-4 carbon atoms. Particular lower alkyl groups are methyl, ethyl, 1-propyl and 2-propyl. Particular lower alkoxy groups are methoxy, ethoxy, 1-propoxy and 2-propoxy.

The compound of formula (2) has particularly good histamine H ₁ -and also-antagonism and exhibits less acute toxicity in mice (when administered intravenously) than the compound of formula (2) wherein R is hydrogen. Reduction of acute toxicity generally does not involve a decrease in histamine H ₁ -antagonism or histamine H ₂ -antagonism.

Examples of the six specific combinations of the formula 1 above:

2- [4- (3-methoxy-2-pyridyl) butylamino] -5- (6-methyl-3-pyridylmethyl) -4-pyrimidone,

2- [4- (3-chloro-2-pyridyl) butylamino] -5- (6-methyl-3-pyridylmethyl) -4-pyrimidone,

2- [2- (5-methyl-4-imidazolylmethylthio) ethylamino] -5- (6-methyl-3-pyridylmethyl) -4-pyrimidone

2- [2- (5-methyl-4-imidazolylmethylthio) ethylamino] -5- (6-methoxy-3-pyridylmethyl) -4-pyrimidone

2- [2- (2-thiazolylmethylthio) ethylamino] -5- (6-methyl-3-pyridylmethyl] -4-pyrimidone and

2- [2- (3-bromo-2-pyridylmethylthio) ethylamino] -5- (5, 6-dimethyl-3-pyridylmethyl) -4-pyrimidone,

The above compounds have approximately the same potency of histamine H ₁ -antagonist and histamine H ₂ as compared to the corresponding 5- (3-pyridylmethyl homologue) lacking the 6-substituent (or 5- and 6-substituent) in the pyridyl group. Although an antagonist, the former compound has at least three times LD ₅₀ inches compared to the latter compound (LD ₅₀ is the minimum dose that kills 50% of mice when bolus intravenous administration of the test compound). ).

It is preferred when R is lower alkyl, especially methyl.

Preferred are methoxy groups when R is lower alkoxy

It is preferred that when R ¹ is lower alkyl or lower alkoxy, it is above 5 of the pyridyl group, and particularly preferred when R ¹ is equal to R.

It is preferred when A is linear α, ω-alkylene, in particular methylene.

It is preferred when Z is hydrogen.

As a specific example Het ² is 5-methyl-4-imidazolyl, 5-bromo-4-imidazolyl, 5-trifluoromethyl-4-imidazolyl, 2-pyridyl, 3-methyl-2 -Pyridyl, 3-methoxy-2-pyridyl, 3-ethoxy-2-pyridyl, 3, 4-dimethoxy-2-pyridyl, 3-chloro-2-pyridyl, 3-bromo- 2-pyridyl, 3-bromo-4-methyl-2-pyridyl and 2-thiazolyl.

It is preferable when Y is methylene and Het ² is a 2-pyridyl group optionally substituted with one or more lower alkyl or alkoxy groups or a halogen element, or 2-thiazolyl group. Particular preference is given to Y is methylene, Het ^divalent 2-pyridyl, 3-methoxy-2-pyridyl, 3-ethoxy-2-pyridyl or 3-chloro-2-pyridyl, these compounds being oral or Intravenous administration has particularly good histamine H ₁ -and H ₂ -antagonism.

Compounds of formula 1 have been illustrated and described as 4-pyrimidone derivatives, which are in equilibrium with the corresponding 6-one tautomers. In addition, these compounds are present in a small number as hydroxy tautomers, and the present pyrimidine ring may exist in the following tautomeric forms.

In the production method of the present invention, the compound of formula (2) is prepared by reacting the compound of formula (3) with the compound of formula (4).

Wherein Het ² , Y, Z, A, R and R ¹ are as defined in formula (2), Q is nitroamino (NO ₂ N-) lower alkylthio, benzylthio, chlorine, cancelled or other agents Groups that may be substituted with primary amines.

The reaction can proceed at elevated temperature under solvent exclusion, i.e. 80 ° -170 ° preferably at 120 ° -140 °, and also at elevated temperature in the presence of solvent, i.e. at reflux of the reaction mixture. Can be. The choice of solvent is determined by the solubility characteristics of the reaction fire and the properties of Q. Preferred solvent solvents include pyridine, picolone or a mixture of picolones, lower alkanes where ethanol or 1-propanol is preferred, aqueous lower alkanes, ketones which may be 1, 2-ethanediol, acetone or 2-butanone, Polar aprotic solvents such as dimethylformamide, dimethylacetamide, dimethylsulfoxide, hexamethylphosphoramide, sulfolane, acetonitrile or nitromethane. Particular preference is given when Q is nitroamino and the reaction proceeds under ethanol reflux, 1-propanol reflux or pyridine reflux, or when Q is methylthio and proceeds under pyridine reflux.

It is preferred to use reactants in approximately equal molar concentrations, although both excess amounts of 1.1-1.5 molar equivalents or 1.5-4 molar equivalents can be used as reactants. Preference is given to using excess amines of formula (3) above when excess amines are used. Excess amine may be present at the beginning of the reaction or added during the course of the reaction.

Starting materials of formula (4) can be prepared by reacting β-oxoesters of formula (5), wherein R ² is lower alkyl, with materials (a), (b) and (c), respectively.

(a) reacting with nitroguanidine to obtain a compound of formula (4) wherein Q is nitroamino

(b) reacting with thiouure and alkylating or benzyling to yield a compound of formula (4) wherein Q is lower alkylthio or benzylthio

(c) reacting with guanidine and diazotizing in hydrochloric acid in the presence of cuprous chloride and copper, or diazotizing in briquetting in the presence of copper and copper embrittlement, to obtain a compound of formula (4) wherein Q is chlorine or cancellation. .

The reaction of the structural formula (5) β-oxoester with nitroguanidine, thiourea and guanidine is preferably carried out in the presence of a base, and the base is preferably an alkali metal lower alkoxide having sodium methoxide, sodium ethoxide, or Examples include potassium carbonate or sodium hydroxide, alkali metal carbonate or alkali metal hydroxides in which sodium hydride is preferred, or quaternary ammonium hydroxides, for example benzyltrimethylammonium hydroxide. This reaction is preferably carried out at elevated temperatures, for example at the reflux temperature of the solvent mixture.

As for this solvent, ethanol which is a lower alkanol, an aqueous lower alkanol, 2-butanone which is a ketone, or dimethylformamide which is a polar aprotic solvent is preferable.

When Z is hydrogen, β-oxoester of formula (5) may be used in the form of hemiacetal of lower alkanol.

Β-oxoesters of formula (5) wherein Z is hydrogen generally use sodium hydrides dissolved in lower alkylformates such as ethyl formate and strong bases such as 1, 2-dimethoxyethane or tetrahydrofuran. By esterification to formyl compounds of formula (6), or by using ether dissolved sodium.

In this reaction, it is preferred to use approximately 2 molar equivalents of ethyl formate and 2 molar equivalents of sodium hydride. Β-oxoesters of formula (5) can be used in unpurified form or in some cases as solids determined separately.

Β-oxoesters of formula (5) wherein Z is lower alkyl can be prepared by alkylating acyl acetate esters. The amine of formula (3) wherein Y is sulfur may be prepared by reacting cysteamine with a compound of the form Het-CH ₂ L, L is a thiol-substitutable group, and examples of L include hydroxy and acyloxy (eg , Acetoxy, methanesulfonyloxy or toluene-p-sulfonyloxy), lower alkoxy (eg methoxy), chlorine, clear or triarylphosphonium (eg triphenylphosphonium). It is preferred that L is hydroxy or methoxy and that the reaction proceeds under acidic conditions, for example under hydrochloric acid or pickling.

Amines of the formula (3) wherein Y is methylene, Het ² is a 2-pyridyl group having a lower alkoxy group and a halogen element at the 3 position are 2-halo-3-nitropyridine and diethyl 2- (2-cyanoethyl) It can be prepared by reacting malonate.

The product was hydrolyzed and decarboxylated and then reduced to palladium and charcoal to afford 3-amino-3- (3-cyanopropyl) pyridane, diazotized in 2 mol sulfuric acid and alkylated in dimethylsulfoxide to 3-alkoxy Obtain 2- (3-cyanopropyl) pyridine. The 3-amino-2- (3-cyanopropyl) pyridine is reduced with lithium aluminum hydride to obtain 4- (3-amino-2-pyridyl) butylamine, which is diazotized in strong hydrochloric acid in the presence of cuprous chloride. 3-chloroamine can be obtained, or diazotized in strong brittle acid in the presence of cuprous emulsifier to obtain 3-bromoamine, and diazotized in sodium iodide containing dilute sulfuric acid to obtain 3-iodoamine.

The 3-amino-2- (3-cyanopropyl) pyridine is diazotized in boric fluoric acid and reduced with lithium aluminum hydride to give 4- (3-fluoro-2-pyridyl) butylamine.

The amine of formula (3), wherein Y is methylene and Het ² is a 2-thiazolyl group, is reacted with a thioamide of NH ₂ CS (CH ₂ ) 4 Q and a dialkylacetalan bromoate aldehyde, wherein Q is a protective amino group. It can be prepared by converting a protective amino group to a free amino group.

Esters of formula (6) can be prepared by alkylating dialkylmalonates followed by hydrolysis and decarbonation or by condensing aldehydes and malonic acid and reducing the product with esterification.

In this specification, the histamine H ₂ -receptor is defined as a histamine receptor blocked by mepamide, such as by Black et al. (Nature, 236,385 (1972)), and the histamine H ₁ -receptor means a receptor that exhibits a histamine response sensitive to mepyramine. . Histamine H ₁ - a compound to block histamine H ₁ receptor-la antagonists and histamine H ₁ - antagonists referred-to compounds which block histamine H ₁ receptors.

Histamine H ₂ -receptor blockers are useful for inhibiting the biological action of histamine that is not inhibited by the histamine H ₁ -receptor. For example, histamine H ₂ -antagonists are active as gastric acid secretion inhibitors and anti-inflammatory agents, and also act as a blocker of the effects of histamine on blood pressure as an example of action on the cardiovascular system.

In some physiological conditions in which the biological action of histamine is regulated through histamine H ₁ -and H ₂ -receptor types, blockers of the type receptor are useful. Today's conditions include inflammation controlled by histamine, such as dermatitis, which is caused by histamine action on H ₁ -and H ₂ -receptors, for example allergic.

The action of the compound (2) as a histamine H ₂ -antagonist in the lumen-perfused stomachs of rats anesthetized with urethane by intravenous injection of less than 16 micromoles per kilogram It can be suggested by inhibiting gastric acid secretion stimulated with histamine. This method is mentioned by Ash and Schild (Brit. J. Phamac. Chemother., 27, 427 (l966)).

According to Ash and Shield's paper, the action of the compound of formula (2) as a histamine H ₂ -antagonist may be suggested by inhibiting other histamine action which is not regulated by the histamine H ₁ -receptor. As an example, these compounds inhibit histamine action on the extracted guinea pig atrium and the extracted rat uterus. These compounds anf inhibit basal secretion of gastric acid and also secrete gastric acid stimulated by pentagastrin or food.

These combinations inhibit histamine vasodilation when injected intravenously at doses of 0.5-256 micromolar per kilogram in conventional tests, such as blood pressure measurements in anesthetized cats. The efficacy of these compounds is illustrated by an effective amount that inhibits gastric acid secretion by 50% in anesthetized rats and a dose (10 ⁻⁴ mol or less) that inhibits histamine-induced tachycardia by 50% in the extracted guinea atrium. By inhibiting histamine-stimulated contraction on the extracted guinea pig ileum, the incompatibility of structural formula (2) can be suggested as a histamine H ₁ -antagonist. Histamine H ₁ - antagonists and - histamine H ₂ - histamine H than to administer the antagonist individually, compounds having an effect ₁ - and H ₂ - antagonists both to administer a single compound, and glass with which different absorption and drug This is because the difficulties caused by the animal characteristics can be avoided.

Pharmaceutical compositions having utility as a histamine H ₂ -antagonist include a compound of formula (2) with a pharmaceutically acceptable diluent or carrier in the form of a base or as an addition salt with a pharmaceutically acceptable acid. It can be prepared by mixing. These addition salts refer to addition salts with hydrochloric acid, brittle acid, iodide, sulfuric acid and maleic acid. These addition salts can easily be formed from the corresponding compounds of formula (2), which are standard processes, for example by treating these compounds with acids in lower alkanols, or directly from compounds in base form or with different addition salts. It can be formed using an ion exchange resin to obtain the desired salt from.

The pharmaceutical carrier applied may be a solid or a liquid. Examples of solid carriers are lactose, corn starch, potato starch or processed starch, calcium phosphate, white clay, sucrose, cellulose, talc, gelatin, agar, pectin, acacia, magnesium stearate and stearic acid. Examples of liquid carriers are syrup, peanut oil, olive oil, alcohols, propylene glycol, polyethylene glycol and water.

When the solid carrier is used, the composition can be prepared in the form of tablets, powders or pills, capsules, troches or lozenges. The solid carrier amount in a single dosage form is generally about 25 mg to about 300 mg. When a liquid carrier is used, the composition may be prepared in the form of syrups, emulsions, thick emulsions, sterile injections, aqueous or non-aqueous solutions, or fluid suspensions. Additives such as preservatives, for example antioxidants or antimicrobials, and flavoring or coloring agents may be contained. Sterile solutions can be prepared in ampoules, disposable vials, or in single dosage forms. The formulations may also be prepared in semi-solid form of creams, pastas, ointments or gels, or in liquid or spray form for topical administration.

The pharmaceutical compositions can be prepared by conventional methods, which contain methods for grinding, admixing, granulating and compressing, spray drying, freeze drying, or dissolving or dispersing the present ingredients, as appropriate for the intended formulation. The active ingredient is contained in the composition in an effective amount that blocks the histamine H ₂ -receptor. Each dosage form preferably contains about 50 mg-250 mg of active ingredient.

Preferably, the active ingredient is administered 1-6 times daily. Preferably, the daily intake is about 150 mg-1500 mg. Routes of administration may be oral or parenteral.

The preparation of the present starting materials is described in the following preparations and the invention is illustrated by the following examples: The temperature is.

Preparation method 1

(i) A mixture of 6-methylpyrimidine-3-carboxaldehyde (51.57 g), malonic acid (44.30 g), perridine (6 ml) and pyridine (300 ml) is stirred at 100 ° C. for 3 hours and then cooled . The mixture was evaporated to dryness and water was added to the residue and the solid was filtered off and recrystallized from ethanol-acetic acid to give 3- (6-methyl-3-pyridyl) acrylic acid (41.25 g) Melting point: 213.5-215.5.

(ii) A stirred mixture of 3- (6-methyl-3-pyridyl) acrylic acid (50.70 g), dry ethanol (350 ml) and concentrated sulfuric acid was heated under reflux for 18 hours, and ethanol (-250 ml) was removed by evaporation. Let's do it. The residue is poured into ice-ammonia water and the extract extracted with ether is washed with fire and evaporated to an oily phase which is crystallized under standing to give ethyl 3- (6-methyl-3-pyridyl) acrylic acid. Melting Point: 36-37。

(iii) Ethyl 3- (6-methyl-3-pyridyl) acrylic acid (60.36 g) is reduced in ethanol using a palladium catalyst on charcoal (10%, 1.0 g) at 35 °, 355 kPa. The filtrate obtained by filtering the mixture was evaporated to obtain an oily ethyl 3- (6-methyl-3-pyridyl) propionic acid.

(iv) Ethyl-3- (6-methyl-3-pyridyl) propionic acid (57.79 g) wave ethyl formic acid (23.71 g) was added to a stirred mixture of sodium (6.88 g) and ether (200 ml) in an ice-salt bath. Add more than 2.5 hours.

The mixture is stirred for 20 hours and the ether is removed by evaporation. Thiourea (22.76 g) and ethanol (175 ml) were added to the residue, and the mixture was heated under reflux for 7 hours. Water was added to the residue, which was evaporated to dryness, and adjusted to pH 6 with acetic acid. The precipitated solid is filtered off and recrystallized from methanolic acetic acid to give 5- (6-methyl-3-pyridylmethyl) -2-thiouracil (17.24 g). Melting point: 240-1 °

(v) Methyl iodide (l.79 g) was added to a solution of 5- (6-methyl-3-pyridyl) -2-thiouracil (22.66 g) and caustic soda (8.0 g) in agitation (250 ml). The mixed fire is heated at 70 ° for 1 hour and stirred at room temperature overnight. To this was added acetic acid to pH5 and the mixture volume was evaporated to 50 ml. The solid is filtered off and recrystallized from ethanol-acetic acid to give 5- (6-methyl-3-pyridylethyl) -2-methylthio-4-pyrimidone (10.16 g). Melting point-197-7.5.

Preparation method 2

(i) Dry 1, 2-dimethoxyethane (24 ml) and sodium, where a mixture of ethyl 3- (6-methyl-3-pyridyl) propionic acid (1.3 g) and ethyl formate (7.43 g) was kept at 0 °. To the stirred suspension of hydride (50% oil phase dispersion, 4.07 g) is added dropwise. The mixture was warmed to room temperature, stirred overnight, and the mixture added to ice-water (300 g) was extracted with ether, the aqueous layer was adjusted to pH 5.4 with hydrochloric acid, and the precipitated solid was filtered to give ethyl 2-formyl-3-. (6-Methyl-3-pyridyl) propionic acid (10.5 g, 70%) is obtained. Melting Point: 142-4.

(ii) A solution of ethyl 2-formyl-3- (6-methyl-3-pyridyl) propionic acid (1.55 g) and methanol (20 ml) was added sodium methoxide (prepared from 0.161 g sodium) and methanol (20 ml). Is added to the stirred solution. Dry nitroguanidine (0.73 g) was added, the solution was heated overnight under reflux, and the evaporated and dried residue was dissolved in water (50 ml). The solution was extracted with chloroform, the aqueous layer was adjusted to pH 5 with acetic acid, and the precipitated solid was filtered to extract methanol-acetic acid. Recrystallization from 2-nitroamino-5- (6-methyl-3-pyridylmethyl) -4-pyrimidone (0.5 g, 27%) is obtained. Melting Point: 215-6。 (Decomposition)

Preparation method 3

(i) A mixture of ethyl formate (111 g) and 2-butanone (I08 g) was added dropwise to a stirred mixture of oily narcium hydride (50% w / w, 72 g) in dry 1,2-dimethoxyethane. One mixture is left overnight. Ethyl (800 ml) was added and solid (101 g) was filtered to prepare cyanoacetamide (69.5 g) and piperidine acetate (piperidine in acetic acid (7 ml) and water (18 ml) until basic). ) And water were heated under reflux for 2 hours and then cooled. The mixture was acidified with acetic acid and the precipitated solid was recrystallized from aqueous ethanol to give 3-cyano-5, 6-dimethyl-2-hydroxy-pyridine (43.5 g).

(ii) The mixture of 3-cyano-5, 6-dimethyl-2-hydroxy-pyridine (42 g) and phosphorus pentachloride (81 g), which is easy to mix, is heated at 140-160 DEG C for 2 hours. Phosphoryl chloride was removed by distillation under reduced pressure, ice-water (500 g) was added to the residue, and the mixture was adjusted to pH 7 with caustic soda water. The ether extract extracted with ether was evaporated to an oil phase, and ether light petroleum (ether light petroIeum) ( Crystallization at boiling point 60-80 °) to give 2-chloro-3-cyano-5, -dimethylpyrimidine (25.3 g). Melting Point: 83-7。

(iii) 2-chloro-3-cyano-5, 6-dimethylpyridine (21.5 g), semicarbazide hydrochloride (24.0 g), sodium acetate (42.3 g), water (225 ml) and methanol (475 ml) The mixture was reduced using Raney nickel catalyst (5 g) at 344 kPa, 50 ° to fire (750 ml) and filtered. The filtered solid is suspended in water (130 ml) and concentrated hydrochloric acid (70 ml) is heated at 100 ° for 1 hour. The mixture to which formalin (40% w / w, 120 ml) was added was subsequently heated at 100 ° C. for 0.5 hours and then cooled. A mixture of sodium acetate (95 g) and water (250 ml) was added, and the extract extracted with ether was washed with 5% potassium carbonate water and evaporated to give 2-chloro-5, 6-diethyl-3-pyridinecarboxaldehyde (13.24). g, 60%). Melting Point: 69-70。

(iv) heating a mixture of 2-chloro-5, 6-dimethyl-3-pyridinecarboxaldehyde (16.85 g), malonic acid (11.45 g), piperidine (10 ml) and pyridine (100 ml) under reflux for 1 hour. And evaporated to an oil phase. Weaned powder is added to a caustic soda solution, extracted with chloroform, the aqueous layer of the residue is acidified with hydrochloric acid and extracted with chloroform. The combined chloroform extracts were washed with water and evaporated to afford 3- (2-chloro-5, 6-dimethyl-3-pyridyl) acrylic acid (18.3 g, 87%. Melting point: 150-8.

The acid compound is esterified with ethanol and sulfuric acid to obtain an ethyl ester compound. Melting Point 85-8。

(V) The ethyl ester compound (32.7 g) was reduced in ethanol (500 ml) using a palladium catalyst (5% 3 g) on charcoal at 25-30 ° C. and 344 kPa. The filtrate was filtered and the filtrate was evaporated to an oil phase, which was partitioned between chloroform and 2N hydrochloric acid. The aqueous layer is made basic with caustic soda water, and the extract extracted with chloroform is evaporated to give an oily ethyl 3- (5, 6-dimethyl-3-pyridyl) propionic acid (21.8, 80%).

(vii) ethyl 3- (5, 6-dimethyl-3-pyridyl) propionic acid was reacted with ethyl formate and sodium hydride dissolved in dioxymethane at room temperature to yield ethyl-3- (5, 6-dimethyl-3). Pyridyl) -2-formylpropionic acid is obtained.

Melting Point: 148-9。

(vii) Nitroguanidine (6.05 g) was added to a solution of sodium methoxide (prepared from 1.45 g sodium) and dry ethanol (65 mL) under heating at reflux for 45 minutes. The mixture to which ethyl 3- (5, 6-dimethyl-3-pyridyl) -2-formylpropionic acid (14.3 g) was added was heated at reflux for 40 hours and evaporated to dryness. Water (40 ml) was added to the residue and the mixture was extracted with chloroform. The aqueous layer of the residue was adjusted to pH 6 with hydrochloric acid, and the precipitated solid was filtered off and recrystallized from dimethylformamide-ethanol to give 5- (5, 6-dimethyl-3-pyridylmethyl) -2-nitroamino-4-pyridine. Get money Melting Point: 212-3。

Recipe 4

(i) A mixture of 2-methoxy-5-cyanopyridine (61.26 g), semicarbazide hydrochloride (76.4 g), sodium acetate (74.92 g), ethanol (1300 ml) and water (400 ml) was sprayed at 344 kPa. It is reduced using a nickel catalyst (1.0 g). The mixture was evaporated to a volume of 500 ml, and the mixture added with water was allowed to stand overnight at 0 °. The mixture is washed with filtered solids with water and dissolved in 10% hydrochloric acid (1000 ml).

Formaldehyde solution (36% w / v, 450ml) was added and warmed for 15 minutes, then cooled, added to a solution of sodium acetate (298.5g) and water (900ml), followed by ether extraction (3x500ml) and the combined extracts. Then washed with potassium carbonate water and water and evaporated to dryness to afford 6-methoxypyridine-3-carboxaldehyde (31.5 g, 50%). Melting Point: 48-9。

(ii) A mixture of 6-methoxypyridine-3-carboxaldehyde (2.34 g), monoethylmalonic acid (4.51 g), pyridine (12 ml) and piperidine (6 drops) was heated to reflux for 5 hours and evaporated. Let it be paid. This fraction is distributed between the ether and rare ammonia waters. The separated ether layer was washed with water, evaporated to an oil phase and left to crystallize to give ethyl-3- (6-methoxy-3-pyridyl) acrylic acid (2.8 g, 79%). Melting Point: 49-52。

(iii) Ethyl-3- (6-methoxy-3-pyridyl) acrylic acid (32.33 g) was reduced using 344 kPa in ethanol (160 ml), charcoal on a charcoal palladium catalyst (5%, 0.2 g) at 40 °. The filtrate of this mixture was filtered and evaporated to give oily ethyl-3- (6-methoxy-3-pyridyl) propionic acid (32.7 g).

(iv) A mixture of ethyl-3- (6-methoxy-3-pyridyl) propionic acid (32.74 g) and ethyl formate (17.22 g) was cooled to -2 ° in 1,2-dimethoxyethane (50 ml). To a stirring suspension of sodium hydride (50% oil dispersion, 9.38 g) is added dropwise for 1.5 hours or more, and then left at room temperature overnight and poured on ice. The mixture is extracted with ether and the aqueous layer is adjusted to pH 5 with 2N sulfuric acid. The oil precipitates and crystallizes upon standing to give ethyl-2-3- (6-formyl-3-6) -methoxy-3-pyridyl) propionic acid (25.9 g, 70%), melting point 91.5-94. . Constructions recrystallized from aqueous ethanol have a melting point of 93-4 °.

(v) Nitroguanidine (4.7 g) was added to a solution of sodium methoxide (prepared from 1.15 g sodium) and methanol (50 ml) at reflux for 45 minutes. The mixture to which ethyl 2-formyl-3- (6-methoxy-3-pyridyl) propionic acid (10.7 g) was added was refluxed for 34 hours and evaporated to obtain a residue. The residue was dissolved in water and extracted with chloroform, and the aqueous layer of the residue was adjusted to pH 5 with acetic acid to filter out the precipitated solid, thereby obtaining 2-nitroamino-5- (6-methoxy-3-pyridylmethyl) -4. -Get pyrimidone. Melting Point: 183.5-6。

Example 1

4- (3-methoxy-2-pyridyl) butylamine (5.48 g) and 2-nitroamino-5- (6-methyl-3-pyridylmethyl) -4-pyrimidone dissolved in pyridine (200 ml) 7.95 g) was evaporated to dryness by heating under reflux for 18 hours to give residue 2- [4- (3-methoxy-2-pyridyl) butylamino] -5- (6-methyl-3-pyridylmethyl)- 4-pyrimidone is obtained with an impure free base. The residue extracted with warm propanol (200 ml) was acidified with ethanolic hydrochloric acid to extract a solid (10.83 g, 74%) which precipitated out and recrystallized with 1% 12N hydrochloric acid containing propanol to give a trihydrochloride compound (7.53). g, 51%). Melting Point: 184-8。

Example 2-9

By reacting 5- (6-methyl-3-pyridylmethyl) -2-methylthio-4-pyrimidone in the same molar concentration with the following substances,

2- (5-methyl-4-imidazolylmethylthio) ethylamine

4- (5-methyl-4-imidazolyl) butylamine

4- (2-pyridyl) butalamine

4- (3-methoxy-2-pyridyl) butylamine

4- (3-ethoxy-2-pyridyl) butylamine

4- (3-chloro-2-pyridyl) butylamine

2- (3-bromo-2-pyridylmethylthio) ethylamine and

The reaction was carried out with 2- (2-thiazolylmethylthio) ethylamine at 145-150 ° and the cooled reaction product was purified to obtain the following compound.

Example Number

2. 2- [2- (5-methyl-4-imidazolylmethylxlOH) ethylamino] -5- (6-methyl-3-pyridylmethyl) -4-pyrimidone is a trihydrochloride compound Melting point is 210-4.

3. 2- [4- (5-methyl-4-imidazolyl) butylamino] -5- (6-methyl-3-pyridylmethyl) -4-pyrimidone

It is separated into trihydrochloride compound and has a melting point of 189-190.

4. 2- [4- (2-pyridyl) buxlfamino] -5- (6-methyl-3-pyridyl-methyl) -4-pyrimidone

It is separated into free base compound and has a melting point of 156-7.5.

5. 2- [4- (3-methoxy-2-pyridyl) butylamino] -5- (6-methyl-3-pyridylmethyl) -4-pyrimidone,

It is separated into free base hydrate, melting point 67-9 °, converted to trihydrochloride compound, melting point 209-210 °.

6. 2- [4- (3-ethoxy-2-pyridyl) butylamino] -5- (6-methyl-3-pyridylmethyl (-4-pyrimidone,

It is separated into a free base compound, and the melting point is 104-5.

7. 2- [4- (3-chloro-2-pyridyl) butylamino] -5- (6-methyl-3-pyridylmetal) -4-pyrimidone,

It is separated into a free base compound, with a melting point of 132-3 °

8. 2- [2- (3-bromo-2-pyridylmethylthio) ethylamino] -5- (6-methyl-3-pyridylether) -4-pyrimidone,

It is separated into trihydrochloride compound, melting point is 193-6 °

9. 2- [2- (2-thiazolylmethylthio) ethylamino] -5- (6-methyl-3-pyridylmethyl) -4-pyrimidone,

It is separated into trihydrochloride compound, melting point is 187-190 °

Example 10

A mixture of 5- (5, 6-dimethyl-3-pyridylmethyl) -2-nitroamino-4-pyrimidone and 1.1 equivalents of 2- (5-methyl-4-imidazolylmethylthio) ethylamine was added. Heated at reflux for 5 hours, then heated at reflux in ethanol for 12 hours and evaporated to dryness to separate product. 2- [2- (5-methyl-4-imidazolyl ylthio) ethylamino] -5- (5 , 6-dimethyl-3-pyridylmethyl) -4-pyrimidone monohydrate is obtained. Melting Point: 115。 (softened at 98。)

Example 11

A mixture of 5- (5, 6-dimethyl-3-pyridylmethyl) -2-nitroamino-4-pyrimidone and 1.2 molar equivalents of 2- (3-bromo-2-pyridylmethylthio) ethylamine Heated under reflux of ethanol for 48 hours, evaporated to dryness and the product was isolated to afford 2- [2- (3-bromo-2-pyridyl methylthio) ethylamino] -5- (5, 6-dimethyl-3-pyridyl Obtain methyl) -4-pyrimidone. Melting point 105-7。

Example 12

Equal molar concentrations of 5- (5, 6-dimethyl-3-pyridylmethyl) -2-nitroamino-4-pyrimidone and 4- (3-methoxy-2-ferridyl) -butylamine together in ethanol Reflux for 24 hours. The mixture to which 0.1 molar equivalent of this amine was added was refluxed for 24 hours, evaporated to dryness and purified to give 2- [4- (3-methoxy-2-pyridyl) butylamino) -5- (5, 6-dimethyl-3 Pyridylmethyl) -4-pyrimidone dihydrate is obtained. Melting Point 93-94.5。

Example 13

Equal molar concentrations of 2-nitroamino-5- (6-methoxy-3-pyridylmethyl) -4-pyrimidone and 2- (5-methyl-4-imidazolylmethylthio) ethylamine in reflux in ethanol Under heating for 18 hours. The solid precipitated upon cooling is obtained by recrystallization from ethanol. Melting point 197-8.5 °, yield 63%

[Example 14]

5, 6-dimethoxypyridine-3-carboxaldehyde to 2-nitroamino-5- (5, 6-dimethoxy-3-pyridylmethyl) -4-pyrimidone by the procedure of Preparation 1 and Preparation 2 Convert and react bonpyrimidone with 4- (3-methoxy-2-pyridyl) -butylamine to yield 2- [4- (3-methoxy-2-pyridyl) -butylamino] -5- (5 , 6-dimethoxy-3-pyridylmethyl) -4-pyrimidone is obtained.

Preparation of pharmaceutical composition for oral administration

Pharmaceutical compositions containing the following composition,

Component A above is mixed together (if necessary, substituted by lactose or microcrystalline cellulose instead of dicalcium phosphate dihydrate), and concentrated polyvinylpyrrolidone solution is added, and the granules, dried and dried granules are screened. And a mixture of component B added to the dried granules, which can be compressed into tablets, containing an amount corresponding to 100 mg 150 mg or 200 mg free base compound.

Preparation of pharmaceutical composition for topical administration

Pharmaceutical compositions containing the following compositions are prepared.

The above mixture of component A is heated to 72 °, added to the mixture of component B with stirring at 70 ° and stirring continued until it forms a creamy form.

Claims (1)

A method for producing pyrimidone of formula (2), wherein the compound of formula (3) is reacted with an amine of formula Het ² CH ₂ Y (CH ₂ ) ₂ NH ₂ .

Wherein Het ² is a 4-imidazolyl group optionally substituted with lower alkyl, halogen or trifluoro methyl, at least one lower alkyl or lower alkoxy group or 2-pyridyl group optionally substituted with halogen element: Y is sulfur or Methylene: Z is hydrogen or lower alkyl: A is C ₁ -C ₅ alkylene: R is lower alkyl or lower alkoxy: R ¹ is hydrogen, lower alkyl or lower alkoxy. In the above formula (3), Z, A, R ¹ are as defined in the above formula (2), Q is nitroamino (NO ₂ NH-), lower alkylthio, benzylthio, chlorine, cancelled, or primary amine And other groups which may be substituted with.