NO146396B - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE PYRIMIDINE DERIVATIVES - Google Patents

Description

This invention relates to an analogue method for the preparation of pharmacologically active compounds that can be used

in pharmaceutical preparations. The compounds produced in . according to the invention, has useful histamine I^-antagonist activity. These compounds can exist as acid addition salts, but for practical reasons they will be referred to here as base compounds. Histamine H^ antagonists can be defined as compounds that block histamine F^ receptors. Histamine H 2 receptors are not blocked by mepyramine and typical "anti-histamines" (histamine H 2 receptor antagonists), but are blocked by burimamide (see Black et al. Nature, 236, 385 (1972)).

Histamine H2 antagonists are useful as inhibitors of gastric acid secretion, as anti-inflammatory agents and as agents acting on the cardiovascular system.

The compounds produced according to the invention

has the general formula 1:

Formula 1

where Het is a 4-imidazolyl ring which is optionally substituted in the 5-position with lower alkyl (preferably methyl), a 2-pyridyl ring which is optionally substituted in the 3-position with lower alkyl (preferably methyl), lower alkoxy (preferably methoxy), halogen (preferably chlorine or bromine) or amino, or a 2-thiazolyl ring;

Y is sulfur or a methylene group;

Z is hydrogen or lower alkyl (preferably methyl);

Het<1>is a pyridine ring which is optionally substituted with

1 or 2 lower alkyl or lower alkoxy groups; a thiophene, thiazole or quinoline ring;

or a pharmaceutically acceptable salt thereof.

Preferably, Z is hydrogen. Particularly preferred is Het' a 3-pyridyl ring. The term "lower alkyl" shall here be understood to mean an alkyl group containing from 1 to 4 carbon atoms, and the term "lower alkoxy" shall be understood to mean an alkoxy group containing from 1 to 4 carbon atoms.

The compounds of Formula 1 are shown and described as 4-pyrimidone derivatives, and these derivatives exist in equilibrium with the corresponding 6-one tautomers. These compounds also exist to a lesser extent as the hydroxy tautomers, and the pyrimidine ring can also exist in the following tautomeric forms:

Certain Het and Het' can also exist in several tautomeric forms, and it will be understood that all these tautomeric forms fall within the scope of the present invention. Hydrates of compounds of Formula 1 and pharmaceutically acceptable hydrated salts of compounds of Formula 1 are also covered by the invention .

According to the invention, the compounds with Formula 1 can be prepared by a method which comprises that an isocytosine with Formula 2

where Z and Het<1> are as indicated under Formula 1, and Q is lower alkylthio, treated with an amine of Formula 3:

where Het and Y are as indicated under Formula 1. This reaction is preferably carried out in the absence of a solvent at an elevated temperature, e.g. 150°C, or in the presence of a solvent such as pyridine under reflux.

The intermediates of Formula 2 where Z is hydrogen

(shown as Formula 6) can be prepared according to Form 1:

Form 1

(where Het<1> is as indicated under Formula 1 and Alk is lower alkyl).

The esters of Formula 4 can be prepared by general methods known in the art, e.g. by condensation of an aldehyde Het<1->CHO with malonic acid in the presence of pyridine and piperidine, and hydrogenation and esterification of the product.

The intermediates of Formula 2 where Z is lower alkyl

(shown as Formula 7) can be prepared according to Form 2:

Form 2

(where Het' is as indicated under Formula 1, Hal is chlorine or bromine, and Alk is lower alkyl).

The amines of Formula 3 can be prepared by methods described in British patents 1305547, 1338169 and 1564502.

The histamine H2~antagonist activity of the compds

with Formula 1 is illustrated by the inhibition of histamine-stimulated secretion of gastric acid from lumen-perfused stomachs in rats anesthetized with urethane, in doses of from 0.5 to 16 micromol per kg intravenously. Many of the compounds with Formula 1 cause at least 50% inhibition in this test in a dose of from 1 to 10 micromoles per kg. Many of the compounds of Formula 1 inhibit histamine-stimulated contraction of guinea pig ileum (histamine H1 antagonist activity) at a dose of 10 molar or more.

Pharmaceutical preparations which can be used as histamine I^ antagonists and histamine H^ and I^ antagonists can be prepared by mixing a compound of formula 1 in base form or in the form of an acid addition salt with a pharmaceutically acceptable acid, with a pharmaceutically acceptable diluent or carrier.

Example 1

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

(i) Ethyl p-(4-pyridyl)propionate (43.45 g) and ethyl formate (19.6 g) were added over a period of 6 hours to a stirred mixture of sodium wire (5.6 g) and dry ether (150 ml) cooled with an ice-salt bath. The mixture was stirred for 18 h at room temperature, evaporated to dryness, and the residue treated with thiourea (18.45 g) and ethanol (130 mL) and refluxed for 7 h. The mixture was evaporated to dryness and the residue was dissolved in water and the solid product was precipitated by addition of glacial acetic acid to pH 4. The white solid was filtered and washed with ethanol to give 5-(4-pyridylmethyl) -2-thiouracil, m.p. 320-324°C (dec.). (ii) A solution of 5-(4-pyridylmethyl)-2-thiouracil (11.0 g), methyl iodide (7.2 g) and sodium hydroxide (2.1 g) in water (50 ml) and ethanol (100 ml) was stirred at 60°C for 30 minutes, allowed to cool and was filtered to give 5-(4-pyridylmethyl)-2-methylthio-4-pyrimidone, m.p. 179-182°C (ethanol). (iii) An intimate mixture of 5-(4-pyridylmethyl)-2-methylthio-4-pyrimidone (5.9 g) and 2-(5-methyl-4-imidazolylmethylthio)-ethylamine (4.3 g) was heated at 145-150°C for 5 hours and allowed to cool. The residue was triturated with water and treated with ethanolic hydrogen chloride to give the title compound, m.p. 228-233°C.

Example 2

2-[ 2-( 2- thiazolylmethylthio) ethylamino]- 5-( 4- pyridylmethyl)- 4-pyrimidone- trihydrochloride- hemihydrate

An intimate mixture of 5-(4-pyridylmethyl)-2-methylthio-4-pyrimidone (1.55 g) and 2-(2-thiazolylmethylthio)ethylamine (1.16 g) was heated at 135-140°C with frequent stirring. After cooling, the reaction mixture was triturated under water, acidified with dilute ethanolic hydrogen chloride, evaporated to dryness, and the residue recrystallized from methanol to give the title compound, m.p. 190-195°C.

Example 3

2-[ 2-( 3- bromo- 2- pyridylmethylthio) ethylamino]- 5-( 4- pyridylmethyl)-4- pyrimidone- dihydrochloride

5-(4-pyridylmethyl)-2-methylthio-4-pyrimidone (1.1 g) was reacted with 2-(3-bromo-2-pyridylmethylthio)ethylamine (1.15 g) by the method according to example 2. The reaction mixture was triturated with hot water, acidified with dilute ethanolic hydrogen chloride, evaporated to dryness, and the residue recrystallized from ethanol to give the title compound, m.p. 211-215°C (dec.).

Example 4

2- [ 2- ( 5- methyl- 4- imidazolylmethylthio) ethylamino]- 5-( 2- thienyl-methyl)- 4- pyrimidone- dihydrochloride

(i) Ethyl 2-thienyl propionate (33.3 g), ethyl formate (14.1 g)

and sodium (4.2 g) was reacted in ether (120 mL) and the mixture was cooled with an ice-salt bath. The ether was removed by evaporation and the residue was refluxed with thiourea (13.8 g) and ethanol (100 ml). The ethanol was removed by evaporation, and the residue was dissolved in water, and acetic acid was added to precipitate 5-(2-thienylmethyl)-2-thiouracil (38%).

sm.p. 212-215°C (ethanol).

(ii) 5-(2-thienylmethyl)-2-thiouracil (4.5 g) was heated at 65°C with a mixture of methyl iodide (2.8 g), sodium hydroxide (0.8 g) water (75 ml) and ethanol (150 mL) to give 5-(2-thienyl-methyl)-2-methylthio-4-pyrimidone (89%), m.p. 170.5-171.5°C (ethanol). (iii) An intimate mixture of 5-(2-thienylmethyl)-2-methylthio-4-pyrimidone (1.43 g) and 2-(5-methyl-4-imidazolyl-methylthio)ethylamine (1.03 g ) was heated at 140°C for 6 hours. The cooled mixture was washed with water and treated with dilute ethanolic HCl to give the title compound in 40% yield, m.p. 172-176°C (ethanol-acetonitrile). The dihydrochloride was passed down through an ion exchange column of IRA 400 with 1N hydrobromic acid as eluent, and the eluate was evaporated to dryness and recrystallized from ethanol-acetonitrile to give the corresponding dihydrobromide, m.p. 19 9-203°C. Example 5 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(2-pyridyl-methyl)-4-pyrimidone-trihydrochloride-hemihydrate (i) Ethyl-(3-(2-pyridyl)- propionate (19.24 g) and ethyl formate (8.5 g) were added over a period of 1 3/4 hours to a stirred mixture of sodium hydroxide (2.5 g) and dry ether (80 ml) cooled with of a carbon dioxide bath. The mixture was stirred for 21 hours at room temperature, evaporated to dryness, and the residue treated with thiourea (8.2 g) and ethanol (70 mL), and refluxed for 7 1/2 hours. was evaporated to dryness and the residue was dissolved in water and glacial acetic acid was added to pH 5o The white precipitate was filtered off, washed with water and recrystallized from water-acetic acid to give 5-(2-pyridy1-methyl)-2-thiouracil , mp 262-7°C (dec.). (ii) A solution of 5-(2-pyridylmethyl)-2-thiouracil (6.6 g), methyl iodide (4.3 g) and sodium hydroxide (2 .5 g) in water (100 ml) and ethanol (100 ml) was stirred at 70°C for 30 minutes, allowed to cool, and iced k was added to pH 5. The solution was partially evaporated and cooled in an ice bath. The precipitate was filtered off and recrystallized from ethanol to give 5-(2-pyridylmethyl)-2-methylthio-4-pyrimidone, m.p. 195-197.5°C. (iii) An intimate mixture of 5-(2-pyridylmethyl)-2-methylthio-4-pyrimidone (4.7 g) and 2-(5-methyl-4-imidazolylmethylthio)-ethylamine (3.4 g) was heated at 130-135°C for 7 hours. The cooled residue was rubbed with hot water and treated with diluted ethanolic HCl to give the title compound, m.p. 207-210°C (aqueous ethanol). Example 6 2-[ 2-( 5- methyl- 4- imidazolylmethylthio)- ethylamino]- 5-( 3- pyridyl-methyl)- 4- pyrimidone- trihydrochloride (i) Ethyl-P-(3-pyridyl)-propionate (38.9 g) and ethyl formate (17.0 g) were added over a period of 2 1/4 hours to a stirred mixture of sodium hydroxide (5.0 g) and dry ether (150 ml) cooled with an ice bath. The mixture was stirred for 22 h at room temperature, evaporated to dryness, and the residue treated with thiourea (16.5 g) and ethanol (130 mL) and refluxed for 8 h. The mixture was evaporated to dryness and the residue was dissolved in water and acetic acid was added to pH 5 to give 5-(3-pyridylmethyl)-2-thiouracil, m.p. 271-274°C (dec.) (acetic acid-water). (ii) A solution of 5-(3-pyridylmethyl)-2-thiouracil (11.0 g), methyl iodide (7.1 g) and sodium hydroxide (4.2 g) in water (150 ml) and ethanol (150 ml ) was stirred at 65°C for 40 min, allowed to cool, and acetic acid was added to pH 5. The solution was partially evaporated, cooled and filtered to give 5-(3-pyridylmethyl)-2-methylthio-4-pyrimidone , sm.p. 247-9°C (from ethanol-acetic acid). (iii) An intimate mixture of 5-(3-pyridylmethyl)-2-methylthio-4-pyrimidone (6.55 g) and 2-(5-methyl-4-imidazolylmethylthio)-ethylamine (4.8 g) was heated at 130-135°C for 7 hours. The cold mixture was triturated with hot water and treated with dilute ethanolic HCl to give the title compound, m.p.

237-241°C (ethanol-water)„

Example 7

2-[ 2-( 3- bromo- 2- pyridylmethylthio)- ethylamino]- 5-( 2- pyridylmethyl)-4- pyrimidone- trihydrobromide

An intimate mixture of 5-(2-pyridylmethyl)-2-methylthio-4-pyrimidone (1.5 g) and 2-(3-bromo-2-pyridylmethylthio)-ethylamine (1.6 g) was heated at 130° C for 6 hours. After cooling, the residue was triturated with hot water and treated with dilute hydrobromic acid to give the title compound, 44.5% yield,

sm.p. 225-230°C (dec.) (from methanol-water).

Example 8

2-[ 2-( 5- methyl1- 4- imidazolylmethylthio)- ethylamino]- 5-( 2- thiazol-methyl)- 4- pyrimidone- trihydrochloride

(i) A solution of 2-thiazolacrylic acid (26.76 g) and concentrated sulfuric acid (10 ml) in ethanol (150 ml) was refluxed for 18 hours. The solution was partially evaporated and dissolved in water. This solution was extracted with ether, and

the ether extracts were evaporated to give ethyl 2-thiazolacrylate.

(ii) Ethyl 2-thiazoloacrylate (14.8 g) was dissolved in ethanol (170 ml) and hydrogenated at 40°C and a pressure of 3.5 kg/cm2

using 10% palladium-on-charcoal to give ethyl-2-thiazolepropionate. „j£

(iii) Ethyl 2-thiazole propionate (14.2 g) and ethyl formate (5.9 g)

was added over a period of 2 1/4 hours to a stirred mixture of sodium hydroxide (1.8 g) and dry ether (65 ml) cooled by means of an ice bath. The mixture was stirred for 21 h at room temperature, evaporated to dryness, and the residue treated with thiourea (5.8 g) and ethanol (60 mL) and refluxed

treated for 9 hours. The solid product was obtained according to the procedure of Example 5 (i) to give 5-(2-thiazol-methyl)-2-thiouracil, m.p. 275-280°C (dec.) (from acetic acid).

(iv) A solution of 5-(2-thiazolmethyl)-2-thiouracil (4.8 g), methyl iodide (3.0 g) and sodium hydroxide (0.9 g) in water (75 ml)

and ethanol (150 mL) was stirred at 70°C for 30 minutes. The solid product was obtained by the method according to example 5 (ii), so that 5-(2-thiazolmethyl)-2-methylthio-4-

pyrimidone, m.p. 181-182.5°C (from ethanol).

(v) An intimate mixture of 5-(2-thiazolmethyl)-2-methylthio-

4-pyrimidone (1.4 g) and 2-(5-methyl-4-imidazolylmethylthio)-

ethylamine (1.0 g) was heated at 145-150°C for 6 hours. The cooled residue was triturated with hot water and treated with dilute ethanolic HCl to give the title compound, m.p. 208-

211°C (from ethanol-water).

Example 9

2-[ 2-( 2- thiazolylmethylthio)- ethylamino]- 5-( 3- pyridylmethyl)-4- pyrimidone- trihydrobromide

5-(3-pyridylmethyl)-2-methylthio-4-pyrimidone (1.74 g)

was reacted with 2-(2-thiazolylmethylthio)-ethylamine (1.30 g) by the method according to example 2. The reaction mixture was

triturated in hot water and treated with dilute hydrobromic acid to give the title compound, m.p. 229-233.5°C (from methanol-water).

Example 10

2-[ 2-( 3- bromo- 2- pyridylmethylthio)- ethylamino]- 5-( 3- pyridylmethyl)-4- pyrimidone- trihydrobromide

5-(3-pyridylmethyl)-2-methylthio-4-pyrimidone (1.27 g) was reacted with 2-(3-bromo-2-pyridylmethylthio)-ethylamine (1.35 g) by the method according to example 2. The reaction mixture was triturated with hot water and treated with dilute hydrobromic acid to give the title compound, m.p. 217-220.5°C (from methanol).

(C18<H>18BrN5OSi3HBr requires: c 32'°»H 3' 1' N 10.4, S 4.8, Br 47.4%;

found: C 32.1, H 3.2, N 10.2, S 4.5, Br 47.5%).

Example 11

Application of:

(a) 2-(3-Methoxy-2-pyridylmethylthio)-ethylamine

(b) 2-(3-Chloro-2-pyridylmethylthio)-ethylamine

(c) 2-(3-Fluoro-2-pyridylmethylthio)-ethylamine

(d) 2-(3-iodo-2-pyridylmethylthio)-ethylamine

instead of 2-(5-methyl-4-imidazolylmethylthio)-ethylamine in the method according to example 6 gave:

(a) 2-[2-(3-methoxy-2-pyridylmethylthio)ethylamino]-5-(3-pyridylmethyl)-4-pyrimidone, m.p. 155-156.5°, (b) 2-[2-(3-chloro-2-pyridylmethylthio)ethylamino]-5-(3-pyridy1-methyl)-4-pyrimidone, m.p. 134-135.5°, (c) 2-[2-(3-fluoro-2-pyridylmethylthio)ethylamino]-5-(3-pyridylmethyl)-4-pyrimidone, m.p. 107.5-109.5°, (d) 2-[2-(3-iodo-2-pyridylmethylthio)ethylamino]-5-(3-pyridylmethyl)-4-pyrimidone, m.p. 118-125.5?.

Example 12

(i) Reaction of 2-chloro-3-nitropyridine with 2-(2-cyanoethyl)-malonic acid diethyl ester and sodium hydride in tetrahydrofuran gave 1-(3-nitro-2-pyridyl)-1,1-bis-(carbethoxy) -butyronitrile,

sm.p. 93.5-94.5°, which after alkaline hydrolysis and acidification gave 2-(3-cyanopropyl)-3-nitropyridine hydrochloride, m.p. 142-in 145.5°. Reduction with hydrogen and palladium-on-charcoal gave 3-amino-2-(3-cyanopropyl)pyridine, and treatment of this compound with sodium nitrite and sulfuric acid and subsequent heating gave 2-(3-cyanopropyl)-3-hydroxypyridine.

Alkylation with methyl iodide and sodium ethoxide in dimethylsulfoxide and subsequent reduction with lithium aluminum hydride gave 4-(3-methoxy-2-pyridyl)butylamine. Alkylation with ethyl iodide and sodium ethoxide in dimethylsulfoxide and subsequent reduction with lithium aluminum hydride gave 4-(3-ethoxy-2-pyridyl)butylamine. Reduction of 3-amino-2-(3-cyanopropyl)pyridine with lithium aluminum hydride gave 4-(3-amino-2-pyridyl)-butylamine.

Diazotization of 4-(3-amino-2-pyridyl)butylamine in hydrochloric acid with copper(I) chloride or in hydrobromic acid with copper(I) bromide gave 4-(3-chloro-2-pyridyl)butylamine and 4-(3 -bromo-2-pyridyl)-butylamine.

(ii) Application of:

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

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

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

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

(e) 4-(3-Bromo-2-pyridyl)butylamine

(f) 4-(3-amino-2-pyridyl)butylamine instead of 2-(5-methyl-4-imidazolylmethylthio)ethylamine by the method according to example 6 gave: (a) 2-[4-(5-methyl-4- imidazolyl)butylamino]-5-(3-pyridymethyl)-4-pyrimidone, isolated as the trihydrochloride, m.p. 242-246°, . (b) 2-[4-(3-methoxy-2-pyridyl)butylamino]-5-(3-pyridylmethyl)-4-pyrimidone, m.p. 117-118°, (c) 2-[4-(3-ethoxy-2-pyridyl)butylamino]-5-(3-pyridylmethyl)-4-pyrimidone, m.p. 135-136°, (d) 2-[4-(3-chloro-2-pyridyl)butylamino]-5-(3-pyridylmethyl)-4-pyrimidone, m.p. 146-147.5°, (e) 2-[4-(3-bromo-2-pyridyl)butylamino]-5-(3-pyridylmethyl)-4-pyrimidone, m.p. 159-162°, (f) 2-[4-(3-amino-2-pyridyl)butylamino]-5-(3-pyridylmethyl)-4-pyrimidone, m.p. 130-131.5°.

Example 13

(i) A solution of 3-quinolyl acrylic acid (6 3.71 g) and concentrated sulfuric acid (25 ml) in ethanol (350 ml) was refluxed for 18 hours. The product was isolated according to the procedure of Example 8 (i) to give ethyl 3-quinolyl acrylate,

sm.p. 86.5-88° (from ethanol-water).

C14H13N02 requires: c 74'0'H 5'8'N 6.2%,

found: C 73.8, H 5.8, N 6.0%.

(ii) Ethyl 3-(3-quinolyl)acrylate (51.68 g) was dissolved in ethanol (170 ml) and hydrogenated at 37 and a pressure of 3.5 kg/cm using 10% palladium-on- charcoal to give ethyl 3-(3-quinolyl)propionate. (iii) Ethyl 3-(3-quinolyl)propionate (47.99 g) and ethyl formate (16.3 g) were added over a period of 3 hours to a stirred mixture of sodium wire (4.8 g) and dry ether (150 ml) cooled in an ice bath. The mixture was stirred for 20 hours at room temperature, evaporated to dryness and the residue treated with thiourea (15.9 g) and ethanol (130 ml) and refluxed for 7 hours. The mixture was evaporated to dryness and the residue was dissolved in water and acetic acid was added to pH 4. The mixture was filtered to give 5-(3-quinolylmethyl)-2-thiouracil, m.p. 281-6° (decomp.) (from acetic acid-water). (iv) A solution of 5-(3-quinolylmethyl)-2-thiouracil (17.51 g), methyl iodide (9.2 g) and sodium hydroxide (5.4 g) in water (200 ml) and ethanol (200 ml ) was stirred at 75° for 1 hour, allowed to cool, and acetic acid was added to pH 4, and the solid was filtered off to give 5-(3-quinolylmethyl)-2-methylthio-4-pyrimidone, m.p. 215.5-218° (from ethanol). (v) An intimate mixture of 5-(3-quinolylmethyl)-2-methylthio-4-pyrimidone (2.1 g) and 2-(5-methyl-4-imidazolylmethylthio)-ethylamine (1.3 g) was heated at 150-5° for 6 hours. The cooled mixture was triturated with hot water and treated with dilute ethanolic HCl to give 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(3-quinolylmethyl)-4-pyrimidone trihydrochloride, m.p. p. 184-9° (from ethanol-water).

Example 14

An intimate mixture of 5-(3-quinolylmethyl)-2-methylthio-4-pyrimidone (2.0 g) and 2-(2-thiazolylmethylthio)ethylamine (1.2 g) was heated at 145° for 4 hours. After cooling, the residue was triturated with hot water and treated with dilute ethanolic HCl to give 2-[2-(2-thiazolylmethylthio)ethylamino]-5-(3-quinolylmethyl)-4-pyrimidone trihydrochloride, m.p. 202-205°

(from ethanol-water).

Example 15

(i) A mixture of pyridine-3-carboxaldehyde (48 g), ethyl acetoacetate (52 g), aqueous piperidine acetate (40%, 4.8 g) and 5% palladium-on-charcoal catalyst (50% wet, 2.48 g) was hydrogenated at 7 kg/cm<2> and 30° for 22 hours. The mixture was diluted with ether and filtered, and the filtrate was evaporated and distilled under reduced pressure to give ethyl 2-(3-pyridy1-methyl)acetoacetate (b.p. 146°/1 mm Hg). This ester was refluxed with thiourea and sodium ethoxide in ethanol and the mixture was then acidified to give

5-(3-pyridylmethyl)-6-methyl-2-thiouracil, m.p. 328-331°.

(ii) Treatment of 5-(3-pyridylmethyl)-6-methyl-2-thiouracil

with methyl iodide and sodium ethoxide in ethanol at 0° followed by acidification gave 2-methylthio-5-(3-pyridylmethyl)-6-methyl-4-

pyrimidone, m.p. 208-211°.

(iii) Melting of 2-methylthio-5-(3-pyridylmethyl)-6-methyl-4-pyrimidone at 160-170° with

(a) 2-(2-thiazolylmethylthio)ethylamine

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

go

(a) 2-[2-(2-thiazolylmethylthio)ethylamino]-5-(3-pyridylmethyl]-6-methyl-4-pyrimidone, mp 118-121° (b) 2-[2-(3 -bromo-2-pyridylmethylthio)ethylamino]-5-(3-pyridy1-methyl)-6-methyl-4-pyrimidone, mp 159-162° (c) Treatment of 2-methylthio-5-(3 -pyridylmethyl)-6-methyl-4-pyrimidone with 2-(5-methyl-4-imidazolylmethylthio)ethylamine in pyridine under reflux for 25 hours, followed by evaporation of the mixture and chromatographic purification of the residue on

silica gel (elution with chloroform/methanol 5:1) gave 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(3-pyridylmethyl)-6-methyl-4-pyrimidone, m.p. 128-131°.

Example 16

(i) 2-(6-methyl-3-pyridyl)acrylic acid, m.p. 213-215.5° was prepared by condensation of 6-methylpyridine-2-carboxaldehyde with malonic acid in pyridine with a piperidine catalyst, and was converted to the corresponding ethyl ester, m.p. 36-37°, which was reduced with hydrogen and palladium-on-charcoal catalyst to give ethyl 3-(6-methyl-3-pyridyl)propionate (oil). (ii) Treatment of ethyl 3-(6-methyl-3-pyridyl)propionate with sodium and ethyl formate by the method according to example 1 (i)

gave 5-(6-methyl-3-pyridylmethyl)-2-thiouracil, m.p. 240-241°C which - was converted to 5-(6-methyl-3-pyridylmethyl)-2-methylthio-4-pyrimidone, m.p. 197-198.5° by the method according to example Kii).

(iii) Treatment of 5-(6-methyl-3-pyridylmethyl-2-methyl-thio-4-pyrimidone with

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

(b) 2-(2-thiazolylmethylthio)ethylamine

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

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

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

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

(g) 4-(2-pyridyl)butylamine

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

by the method according to example 1(iii) respectively gave (a) 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone trihydrochloride, sm. p. 210-214°

(b) 2-[2-(2-thiazolylmethylthio)ethylamino]-5-(6-methyl-3-pyridyl-methyl)-4-pyrimidone trihydrochloride, m.p. 187-190°. (c) 2-[2-(3-bromo-2-pyridylmethylthio)ethylamino]-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone trihydrochloride, m.p. 19 3-196°, (d) 2-[4-(5-methyl-4-imidazolyl)butylamino]-5-(6-methyl-3-pyridyl-methyl)-4-pyrimidone trihydrochloride, m.p. 189-190° (e) 2-[4-(3-methoxy-2-pyridyl)butylamino]-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone trihydrochloride, m.p. 209-210°, (f) 2-[4-(3-chloro-2-pyridyl)butylamino]-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone, isolated as free base, m.p. 132-133° (g) 2-[4-(2-pyridyl)butylamino]-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone isolated as free base, m.p. 156.5-157.5°, (h) 2-[4-(3-ethoxy-2-pyridyl)butylamino]-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone isolated as free base,

sm.p. 104-105°.

Example 17

(i) A mixture of ethyl formate (111 g) and 2-butanone (108 g) was added dropwise to a stirred mixture of sodium hydride in oil (50% w/w, 72 g) and the mixture was allowed to stand overnight. Ether (800 mL) was added and the solid (101 g) was filtered off. Cyanoacetamide (69.5 g), piperidine acetate (prepared by adding piperidine to acetic acid (7 mL) and water (18 mL) until the mixture was basic) and water (400 mL) were added to this solid and the mixture was heated under reflux

refrigeration for 2 hours and was 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-hydroxypyridine (43.5 g). (ii) An intimate mixture of 3-cyano-5,6-dimethyl-2-hydroxy-pyridine (42 g) and phosphorus pentachloride (81 g) was heated at 140-160° for 2 hours. Phosphoryl chloride was removed by distillation under reduced pressure, and ice water (500 g) was added to the residue. The mixture was adjusted to pH 7 with aqueous sodium hydroxide and extracted with ether. The ether extracts were evaporated to an oil which was crystallized from petroleum ether (b.p. 60-80°) to give 2-chloro-3-cyano-5,6-dimethylpyridine (25.3 g), m.p. 83-87°. (iii) A mixture of 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) was hydrogenated at 3.5 kg/cm at 50° using Raney nickel catalyst (5 g). The mixture was added to water (750 mL) and filtered. The solid was filtered and suspended in water (130 mL), and concentrated hydrochloric acid (70 mL) was added and the mixture was heated at 100° for 1 hour. Formalin (40% w/w, 120 mL) was added and the mixture was heated at 100° for an additional 1/2 hour and then cooled. Sodium acetate (95 g) and water (250 mL) were added, and the mixture was extracted with ether, and the extracts were washed with 5% aqueous potassium carbonate and evaporated to give 2-chloro-5,6-dimethyl-3-pyridinecarboxaldehyde (13 .24 g, 60%), m.p. 69-70°. (iv) 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) was heated under reflux for 1 hour and evaporated to an oil. This oil was dissolved in 2N sodium hydroxide solution and was extracted with chloroform (discarded). The aqueous phase was acidified with hydrochloric acid and was extracted with chloroform. The chloroform extract was washed with water and evaporated to give 3-(2-chloro-5,6-dimethyl-3-pyridyl)-acrylic acid (18.3 g, 87%), m.p. 150-158°. This acid was esterified using ethanol and sulfuric acid to give the ethyl ester, m.p. 85-88°.

(v) Ethyl 3-(2-chloro-5,6-dimethyl-3-pyridyl)acrylate

(32.7 g) in ethanol (500 mL) was hydrogenated at 25-30° and 3.5 kg/cm 2 using palladium-on-charcoal catalyst (5%, 3 g). The mixture was filtered, and the filtrate was evaporated to an oil which was partitioned between chloroform and 2N hydrochloric acid. The aqueous phase was basified with aqueous sodium hydroxide, extracted with chloroform, and the chloroform extracts were evaporated to give ethyl 3-(5,6-dimethyl-3-pyridyl)propionate (21.8 g,

80%) as an oil.

(vi) Reaction of ethyl 3-(5,6-dimethyl-3-pyridyl)-propionate with ethyl formate and sodium hydride in dimethoxyethane by the method according to example 13(iii) gave 3-(5,6-dimethyl-3-pyridyl) -2-formylpropionate, m.p. 148-149°. Successive treatment of this ester with thiourea and methyl iodide by the method according to example 1 (i) (ii) gave 5-(5,6-dimethyl-3-pyridylmethyl)-2-methyl-thio-4-pyrimidone and reaction of this compound with 2-(3-bromo-2-pyridylmethylthio)ethylamine at 140° for 6 hours gave 2-[2-(3-bromo-2-pyridylmethylthio)ethylamino]-5-(5,6-dimethyl-3-pyridylmethyl)- 4-pyrimidone, m.p. 105-107°.

Example 18

(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 hydrogenated at 3.5 kg/cm<2> using Raney nickel catalyst (1.0 g). The mixture was evaporated to a volume of 500 mL, water (1000 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 10% hydrochloric acid (1000 ml). Formaldehyde solution (36% w/v, 450 ml) was added and the mixture was heated for 15 minutes, cooled and added to a solution of sodium acetate (298.5 g) in water (900 ml). This mixture was extracted with ether (3 x 500 mL) and the combined extracts were washed successively with aqueous potassium carbonate and water and were dried and evaporated to give 6-methoxypyridine-3-carboxaldehyde (31.5 g, 50%), m .p. 48-49°.

(ii) A mixture of 6-methoxypyridine-3-carboxaldehyde

(2.34 g), monoethyl malonate (4.51 g), pyridine (12 mL) and piperidine (6 drops) were heated under reflux for 5 h and evaporated to an oil. This oil was partitioned between ether and dilute aqueous ammonia. The ether layer was washed with water and evaporated to an oil which crystallized on standing to give ethyl 3-(6-methoxy-3-pyridyl)acrylate

(2.8 g, 79%), m.p. 49-52°.

(iii) Ethyl 3-(6-methoxy-3-pyridyl)acrylate (32.33 g) in ethanol (160 mL) was hydrogenated at 3.5 kg/cm<2>at 40° using palladium-on -charcoal catalyst (5%, 0.2 g). The mixture was filtered and the filtrate was evaporated to give ethyl 3-(6-methoxy-3-pyridyl)propionate (32.7 g) as an oil. (iv) A mixture of ethyl 3-(6-methoxy-3-pyridyl)propionate (32.74 g) and ethyl formate (17.22 g) was added dropwise over 1 1/2 hours to a stirred suspension of sodium hydride in oil (50%, 9.38 g) in 1,2-dimethoxyethane (50 mL) cooled to -2°,

allowed to stand overnight at room temperature and poured onto ice. The mixture was extracted with ether (discarded), and the aqueous phase was adjusted to pH 5 with 2N sulfuric acid. An oil precipitated and crystallized on standing to give ethyl 2-formyl-3-(6-methoxy-3-pyridyl)propionate (25.9 g, 70%), m.p. 91.5-94°. A sample recrystallized from aqueous ethanol had m.p. 93-94°.

Successive treatment of this ester with thiourea and methyl iodide by the method according to example 1 (i) (ii) gives 5-(6-methoxy-3-pyridylmethyl)-2-methylthio-4-pyrimidone and reaction of this compound at 140° in 6 hours with

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

(b) 2-(2-thiazolylmethylthio)ethylamine

gives

(a) 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(6-methoxy-3-pyridylmethyl)-4-pyrimidone trihydrochloride, m.p. 205-209°. (b) 2-[2-(2-thiazolylmethylthio)ethylamino]-5-(6-methoxy-3-pyridyl-methyl)-4-pyrimidone, m.p. 95-97°.

Example 19

(i) Sodium (20.8 g) was dissolved in methanol (285 ml), a solution of 2-chloro-4-cyanopyridine (115.5 g) in methanol/dioxane

(1:1, 850 mL) was added and the mixture was refluxed for 2 1/2 hours and allowed to cool. The mixture was filtered, and the volume of the filtrate was reduced by evaporation to 200 ml, and water (400 ml) was added. The solid that precipitated was filtered off to give 2-methoxy-4-cyanopyridine (57.2 g, 51%), m.p. 93-95.5°. (ii) A mixture of 2-methoxy-4-cyanopyridine (57.2 g), semicarbazide hydrochloride (71.25 g), sodium acetate (69.86 g), ethanol (1200 ml) and water (370 ml) was hydrogenated at 3.5 kg/cm<2> using Raney nickel catalyst (1.0 g). The mixture was evaporated to a volume of 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 10% hydrochloric acid (950 mL). Formaldehyde solution (36% w/v, 420 ml) was added and the mixture was heated for 30 minutes, allowed to cool and added to a solution of sodium acetate (280 g) in water (840 ml). The mixture was extracted with ether (3 x 500 mL) and the combined extracts were washed successively with aqueous potassium carbonate and water and were dried and evaporated to give 2-methoxypyridine-4-carboxaldehyde (20.53 g, 35%), sm . 33-5°. A sample recrystallized from petroleum ether had m.p. 33-36°. (iii) Use of 2-methoxypyridine-4-carboxaldehyde instead of 6-methoxypyridine-3-carboxaldehyde in the general procedure according to example 18 (ii-iv) gave ethyl 2-formyl-(2-methoxy-4-pyridyl)propionate which an oil.

Successive treatment of this ester with thiourea and methyl iodide by the general procedure according to example 1 (i)

(ii) gives 5-(2-methoxy-4-pyridylmethyl)-2-methylthio-4-pyrimidone,

and reaction of this compound at 140° for 6 hours with

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

b) 2-(2-thiazolylmethylthio)ethylamine

gives respectively

a) 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(2-methoxy-4-pyridylmethyl)-4-pyrimidone, m.p. 177-178°, b) 2-[2-(2-thiazolylmethylthio)ethylamino]-5-(2-methoxy-4-pyridylmethyl)-4-pyrimidone, m.p. 105.5-106.5°.

Claims (1)

Analogous method for the preparation of therapeutically active pyrimidine derivatives with the formula: Formula 1 where Het is a 4-imidazolyl ring which is optionally substituted in the 5-position with lower alkyl, a 2-pyridyl ring which is optionally substituted in the 3-position with lower alkyl, lower alkoxy, halogen or amino, or a 2-thiazolyl ring; Y is sulfur or a methylene group; Z is hydrogen or lower alkyl; Het' is a pyridine ring which is optionally substituted with 1 or 2 lower alkyl or lower alkoxy groups; a thiophene, thiazole or quinoline ring, or a pharmaceutically acceptable salt thereof, characterized in that an isocytosine of the formula Formula 2 where Z and Het<1> are as indicated above, and Q is lower alkylthio, is reacted with an amine of the formula: Het-CH2-Y-(CH2)2"NH2 Formula 3 where Het and Y are as above, and the product is optionally converted into a pharmaceutically acceptable salt.