CH631981A5 - Process for preparing novel derivatives of pyrimid-4-one and pyrimid-4-thione, and their salts with acids - Google Patents

Description

The invention relates to the production of new pyrimide in which Het and Y have the meaning given above, 50 4-one and thione derivatives of the general formula I.

Het-CH2-Y- (CH2) 2-NH

(CH0) -W- (CH9) -Het '2 p 2 q (I)

in which there is a 3- (1,2,5) thia, preferably methyl group, halogen atom, preferably diazolyl group or a 2- (5-amino-1,3, optionally substituted by lower alkyl radicals, preferably 60 substituted by chlorine or bromine atom, or 4-thiadiazolyl) chlorine or bromine atoms, trifluoromethyl or hydroxymeth group, Y denotes a sulfur atom or a 2- or 4-imidazolyl group substituted by methylene-yl groups, a group, Z a hydrogen atom or a lower alkyl, optionally by lower alkyl radicals, preferably meth radical, preferably a methyl group, X represents an oxygen or ylene group, lower alkoxy radicals, preferably methoxy 65 sulfur atom and W represents a methylene group, an oxygen group, halogen atoms, preferably chlorine or bromine or sulfur atom, the sum of p and q has an atom, amino or hydroxyl group-substituted 2-pyri value from 1 to 4 if W is an oxygen or sulfur 1-dyl group, a 2-thiazolyl group, an optionally atom, or a value of 0 to 4 if W is a methyl

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len group means and Het 'is a 5-membered or membered heterocyclic ring which is optionally substituted by lower alkyl or alkoxy radicals or condensed with an optionally substituted benzene ring, preferably a pyridine, furan, thiophene .thiazole, oxazole, isothiazole, imidazole Represents, pyrimidine, pyrazine or pyridazine ring, and their salts with acids.

The salts can be derived from inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid or maleic acid.

Het is preferably 2-thiazolyl-, 5-methyl-4-imidazolyl-, 5-bromo-4-imidazolyl-, 3-bromo-2-pyridyl-, 3-chloro-2-pyridyl-, 3-methoxy-2 -pyridyl or 3-hydroxy-2-pyridyl group. Y is preferably a sulfur atom, X is an oxygen atom and Z is a hydrogen atom. In a preferred group of compounds of the general formula I, W denotes a methylene group and p and q both have the value 0. Het 'preferably denotes a 2-furyl, 2-thienyl, 2-, optionally substituted by lower alkyl or lower alkoxy radicals Pyridyl, 3-pyridyl, 4-pyridyl, 2-thiazolyl, 2-imidazolyl-T 2-pyrimidyl, s 2-pyrazyl or 3-pyrazyl group. More preferably, Het 'means 2-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl or

2-thiazolyl group. Het 'is particularly preferred

3-pyridyl group.

The “lower alkyl” and “lower alkoxy” groups contain 1 to 4 carbon atoms.

The pyrimid-4-one and thione derivatives of the general formula I are in tautomeric equilibrium with the corresponding pyrimid-6-one and 6-thione derivatives. To a lesser extent there are tautomeric equilibrium weights with the corresponding mercapto and hydroxy compounds. The pyrimidine group itself can exist in the following tautomeric forms:

"Ana xh

Certain heterocyclic residues Het and Het 'can also exist in different tautomeric forms. The present invention relates to all possible tautomeric forms as well as to the hydrates and the hydrated salts of the compounds of the general formula I.

Particularly preferred compounds of the present invention are:

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

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

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

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

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

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

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

2- [2- (5-Methyl-4-imidazolylmethylthio) ethylamino] -5- (2-thiazolylmethyl) -4-pyrimidone

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

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

The compounds of the general formula I in which X represents an oxygen atom are obtained by reacting an iso-

cytosine derivatives of the general formula II

30th

.rV ™ »'*

Q

-YT- (CHg) q-Het1

(II)

in which Z, W, p, q and Het 'have the meaning given in the general formula I 3s and Q represents a reactive radical which is displaced in the reaction with an amine, with an amine of the general formula III

Het-CH2 ~ Y- (CH2) 2-NH2 (III)

40 in which Het and Y have the meaning given in the general formula I. The reaction is preferably carried out without a solvent at elevated temperature, for example at 150 ° C., or in the presence of a solvent, such as pyridine, at the reflux temperature. 45 The compounds of general formula I obtained can be converted into a salt by reaction with an inorganic or organic acid. The salts are prepared in a manner known per se by reacting the free base with an acid, for example in an aliphatic alcohol thereof or with an anion exchanger from another salt.

The isocytosine derivatives of the general formula II, in which W is a methylene group, Z is a hydrogen atom and a is a lower alkylthio radical, can be prepared according to reaction scheme 1 below, in which Het 'has the meaning given in general formula I. , a has a value from 0 to 4 and Alk represents a lower alkyl radical.

Reaction scheme 1

1) NaHCOOC2Hs Het '(CH2) aCH2CH2COOC2H5>

(V)

2) Thiourea

| (VL)

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Alk S

Alkyl halide or sulfate

^ 5. CH "(CH") Het

HN ^ V 2 2 a

(VII)

The isocytosine derivatives of the general formula II in which Het 'has the meaning given in the general formula I is a methylene group, Z has a lower alkyl radical and Q tung, a has a value from 0 to 4, Hai is a chlorine or a lower alkylthio radical, can be a lower alkyl radical according to the bromine atom and alk, the following reaction scheme 2 can be prepared, in

ZCOCH2COOC2H5

Reaction scheme 2 NaOC2Hs, HalCH2 (CH2> Het '

CH2 (CH2) aHet 'Z-COCHCOOC2H5

Thiourea

Alk

HN

éSï ^ O

(VIII)

! H2 (CH2) aHet '

Alkyl halide or sulfate ^

ti

HlqA ^ CH2 (CH2> aHet '

H

The isocytosine derivatives of the general formula II, in which Het 'and Z, which in the general Q represent a halogen atom and W represent a methylene group, have the meaning given for formula I, a can have a value of 0 according to the reaction scheme below 3 forth to 4 and shark means a chlorine or bromine atom.

Reaction scheme 3

CH2 (CH2) aHet '

I.

ZCOCHCOOC2H5 sodium salt

(IX)

Guanidine

H,

Z

NA ^ H2 (CH2) aHet '

V

1) HCl, NaN02

2) Cu2Hah

HN

, CH2 (CH2) aHet '

(X)

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The isocytosine derivatives of the general formula II, in which W is an oxygen or sulfur atom according to the reaction schemes below, can be:

a) p has a value of 0

Het '(CH2) qWCH2COOC2H5

1) HCOOC2H5, Na

2) Thiourea

3) alkyl halide or sulfate

HLTV

AlkS 0

W (CH2) Het *

b) p has the value 1. These compounds can be reacted by reacting ethyl 3-benzyloxypropionate or a similar derivative of 3-hydroxypropionate ethyl ether according to reaction scheme 1 above, followed by elimination.

c) p has a value of 2 to 4

0

A

{J

(CH2),

■ H,

sodium

AlkS ^ N - ^ = 0

l) SOCI2 <

2) Het '(CH2) qO-Na + or Het' (CH2) qS-Na +

tion of the protective group, the reaction with thionyl chloride and then with the sodium salt of a compound of the general formula Het (CH2) qOH or Het '(CH2) qSH.

Formic acid ethyl ester

Y

fa

<CVP

CR 0 "Ka +

1) Thiourea

2) alkyl halide or sulfate

AlkS

<* w (cVp0H

HN F

The compounds of general formula I in which X represents a sulfur atom can be prepared by reacting the compounds of general formula I in which X represents an oxygen atom with phosphorus pentasulfide in a solvent such as pyridine. The amines of the general formula III can be prepared by the processes described in GB-PS 1 305 547 and 1 338 169.

Many of the substances that are physiologically active in the body combine with certain sites known as receptors during their period of effectiveness. Histamine is one such substance with a number of biological effects. The biological receptors blocked by the compounds commonly known as "antihistamines", such as mepy-ramin, diphenhydramine and chlorpheniramine, are described by Ash and Schild (Brit. J. Pharmac. Chemother., Vol. 27 [1966], p . 427) referred to as histamine hi-receptors. Medicines that block the histamine hi receptors are referred to below as histamine hi antagonists. Another part of the biological effects of histamine is not inhibited by the histamine hi-ant agonists. Effects of this type that are inhibited by a compound by Black and Mitarb. (Nature, Vol. 236 [1972], p. 385) as Burimamid

45 is transmitted through receptors, the Black and Mitarb. Call histamine H2 receptors. Histamine H2 receptors are histamine receptors that are not blocked by mepyramine but by burimamide. Compounds that block histamine H2 receptors are called histamine H2 antagonists. They work e.g. as inhibitors of gastric acid secretion, as anti-inflammatory agents and on the cardiovascular system, e.g. as a blocker of the effect of histamine on blood pressure. A combination of histamine hi and H2 antagonists is useful in treating certain diseases, 55 such as inflammation, and inhibiting the effect of histamine on blood pressure.

The compounds of the general formula I are valuable medicinal substances which have activity both as histamine Hi-Ant-60 agonists and as histamine H2 antagonists. They can therefore be used both in the treatment of diseases in which the administration of histamine H2-antagonists is useful, and in those in which a combination of histamine Hi and H2-Ant-65 agonists is desired.

The compounds of the general formula I are histamine ^ receptor blockers, that is to say they block the biological effects of histamine which are not of

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Histamine hi-antagonists, such as mepyramine, but by example 1

Burimamid can be blocked. They inhibit e.g. by 2- [2- (5-methyl-4-imidazolylmethylthio) ethylamino] -5- (4-

Histamine stimulated acid secretion in perfused stomachs pyridylmethyl) -4-pyrimidone trihydrochloride from urethane-anesthetized rats in intravenous

Doses from 0.5 to 16 micromoles / kg. The test procedure is described in a) A mixture of 5.6 g of sodium wire and 150 ml of the above-cited publication by Ash and Schild serrei diethyl ether is described in an ice-salt bath. Other effects of histamine, which are cooled and stirred with 43.45 g of β- (4-

not caused by histamine Hi receptors, such as ethyl pyridyl) propionate and 19.6 g formic acid - the effect on the isolated right atrium of the sea ethyl ester is offset. The mixture obtained is stirred for 18 hours in pigs and on the isolated rat uterus, stirred at room temperature, then evaporated to dryness by the compounds according to the invention. the residue with 18.45 g of thiourea and 130 ml of ethanol

The compounds of formula I inhibit the normal treated and refluxed for 7 hours. Then

Gastric acid secretion as well as that caused by pentagastrin, the reaction mixture is evaporated to dryness and gastric acid secretion caused by eating. the residue obtained was dissolved in water. By adding

In addition, the compounds have anti-inflammatory is glacial acetic acid up to pH 4, a colorless precipitate effect, as demonstrated in the rat paw test. The one that is filtered off and washed with ethanol. Volume of the rat paw is obtained by subcutaneous administration of a 5- (4-pyridylmethyl) -2-thiouracil of F. 320 to 324 ° C. dose of a compound of the general formula I min.

different. Measurement of anesthetized blood pressure

Katzen shows that the compounds according to the invention inhibit the vasodilatory effect of histamine in a solution of 11.0 g of 5- (pyridylmethyl) -2-thiouracil. 7.2 g methyl iodide and 2.1 g sodium hydroxide in 50 ml

The activity of the compounds of the formula I is shown in water and 100 ml of ethanol is stirred for 30 minutes at 60 ° C., the 50% inhibition of gastric acid secretion and then cooled. The precipitate obtained anesthetized rat, which is filtered off with many of the invention and recrystallized from ethanol. It is the compounds of general formula I is achieved at doses of 1 to 25 5- (4-pyridylmethyl) -2-methylthio-4-pyrimidone of F. 179 10 micromoles / kg, and at the 50% Hem- to 182 ° C obtained.

Tachycardia induced by histamine in the isolated right auricle of the guinea pig. c) A well-stirred mixture of 5.9 g of 5- (4-pyridyl-

The compounds of the general formula I are also methyl) -2-methylthio-4-pyrimidone and 4.3 g of 2- (5-methyl-4-histamine H1 receptor blockers, ie they block the biological 30 imidazolylmethylthio) ethylamine 5 Hours at 145 to see effects of histamine, heated by mepyramine, 150 ° C and then cooled. The product obtained

Diphenhydramine and chlorpheniramine can be blocked. is digested with water and then treated with a solution of, for example, inhibit the compound hydrogen chloride according to the invention in ethanol. It will receive the title of the effects of histamine on the isolated bond from F. 228 to 233 ° C.

Guinea pig's intestine. Many of the 35

compounds of general formula I inhibit in Example 2

Doses from 10 ~ 5 mol / kg the Kon- 2- [2- (2-thiazolylmethylthio) ethylamino] -5- (4-pyridyl tractions of the isolated intestine of guinea pig methyl) -4-pyrimidone trihydrochloride stimulated by histamine - hemihydrate chens. A well-stirred mixture of 1.55g 5- (4-pyridyl-

For therapeutic use, the compounds 40-methyl) -2-methylthio-4-pyrimidone and 1.16 g of 2- (2-thiazolyl dunges of the formula I are administered in customary dosage forms. Methylthio) ethylamine is followed with frequent stirring to 135, which as an active ingredient heats at least one of these compounds up to 140 ° C. After cooling, the reaction mixture is digested in the basic form or in the form of a salt with a mixture with water, acidified with a dilute solution of acid and carriers and / or diluent, de-hydrogen chloride in ethanol and kept dry. The carrier can be solid or liquid. Special 45 evaporated. The residue obtained is recrystallized from methanol. Examples of solid carriers are kaolin, sugar, talc. The title compound from F. 190 to gelatin, agar, pectin, gum arabic, magnesium stearate 195 ° C. is obtained.

and stearic acid. Examples of liquid carriers are

Sugar syrup, peanut oil, olive oil and water. Example 3

The compounds can be made up into a wide variety of forms, such as 50 2- [2- (3-bromo-2-pyridylmethylthio) ethylamino] -5- (4-pyri-forms). When using solid dylmethyl) -4-pyrimidone dihydrochloride carriers the preparations can be tabletted, in powder or according to Example 2 1.1g 5- (4-pyridylmethyl) -2-

Pellet form filled into hard gelatin capsules or to methylthio-4-pyrimidone with 1.15g 2- (3-bromo-2-pyridylmet-

Pastilles or candies can be processed. The amount of hylthio) ethylamine implemented. The reaction carrier obtained can be mixed in a comparatively wide range and digested with hot water, with a ver

Range, preferably about 25 mg to 1 g diluted solution of hydrogen chloride in ethanol is acidified. When using a liquid carrier, the pre- and can be evaporated to dryness. The residue is recrystallized from ready as syrup, emulsion, soft gelatin capsule, injection ethanol. The title compound is obtained from the preparation, administered as an aqueous or non-aqueous suspension, F. 211 to 215 ° C. (dec.).

be enough. 60

The drugs are made according to customary procedures, such as Example 4

Mixing, granulating, pressing or dissolving 2- [2- (5-methyl-4-imidazolylmethylthio) ethylamino] -5- (2-

of the components in the desired shape. You thienylmethyl) -4-pyrimidone dihydrochloride can be given orally or parenterally. The dosage unit preferably contains the drug in a quantity of 65 a). With cooling in an ice-salt bath, 50 to 250 mg are obtained. The daily dose can be 150 to 1500 mg of 33.3 g of 2-thienylpropionate, 14.1 g of formic acid. ethyl ester and 4.2 g sodium in 120 ml diethyl ether

The examples illustrate the invention. puts. The diethyl ether is then distilled off

7

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The residue is dissolved in water and acetic acid is added. The precipitate is recrystallized from ethanol. The 5- (2-thienylmethyl) -2-thiouracil of mp 212 to 215 ° C. is obtained in 38% yield.

b) 4.5 g of 5- (2-thienylmethyl) -2-thiouracil are heated to 65 ° C. with a mixture of 2.8 g of methyl iodide, 0.8 g of sodium hydroxide, 75 ml of water and 150 ml of ethanol. The 5- (2-thienylmethyl) -2-methylthio-4-pyrimidone of mp 170.5 to 171.5 ° C. after recrystallization from ethanol is obtained in 89% yield.

c) A well-stirred mixture of 1.43 g of 5- (2-thienyl-methyl) -2-methylthio-4-pyrimidone and 1.03 g of 2- (5-methyl-4-imidazolylmethylthio) ethylamine is 6 hours Heated 140 ° C. After cooling, the product obtained is washed with water and treated with a dilute solution of hydrogen chloride in ethanol. After recrystallization from a mixture of ethanol and acetonitrile, the title compound of mp 172 to 176 ° C in 40% yield is obtained.

The dihydrochloride is passed through an ion exchanger with 1N hydrobromic acid as the eluent, the eluate is evaporated to dryness and recrystallized from a mixture of ethanol and acetonitrile. The corresponding dihydrobromide of F. 199 to 203 ° C is obtained.

Example 5

2- [2- (5-Methyl-4-imidazolylmethylthio) ethylamino] -5- (2-pyridylmethyl) -4-pyrimidone trihydrochloride hemihydrate a) A mixture of 2.5 g sodium wire and 80 ml anhydrous diethyl ether is added in cooled in a carbon dioxide bath and mixed with stirring in VA hours with 19.24 g of ß- (2-pyridyl) propionic acid ethyl ester and 8.5 g of formic acid ethyl ester. The mixture is stirred at room temperature for 21 hours, evaporated to dryness and the residue with

8.2 g of thiourea and 70 ml of ethanol were added and the mixture was boiled under reflux for 7 hours. The reaction mixture is then evaporated to dryness, the residue is taken up in water and glacial acetic acid is added to a pH of 5. The colorless precipitate obtained is filtered off, washed with water and recrystallized from a mixture of water and acetic acid. The 5- (2-pyridylmethyl) -2-thiouracil of mp 262 to 267 ° C. (dec.) Is obtained.

b) a solution of 6.6 g of 5- (2-pyridylmethyl) -2-thiouracil,

4.3 g of methyl iodide and 2.5 g of sodium hydroxide in 100 ml of water and 100 ml of ethanol are stirred at 70 ° C. for 30 minutes, then cooled and glacial acetic acid is added to a pH of 5. The solvent is then partially distilled off and the residue is cooled in an ice bath. The precipitate obtained is filtered off and recrystallized from ethanol. The 5- (2-pyridyl-methyl) -2-methylthio-4-pyrimidone of mp 195 to 197.5 ° C. is obtained.

c) A well-stirred mixture of 4.7 g of 5- (2-pyridyl-methyl) -2-methylthio-4-pyrimidone and 3.4 g of 2- (5-methyl-4-imidazolylmethylthio) ethylamine is 7 hours Heated from 130 to 135 ° C. The reaction mixture obtained is then cooled, directed with hot water and treated with a dilute solution of hydrogen chloride in ethanol. The title compound of mp 207 to 210 ° C. is obtained after recrystallization from a mixture of water and ethanol.

Example 6

2- [2- (5-Methyl-4-imidazolylmethylthio) ethylamino] -5- (3-pyridylmethyl) -4-pyrimidone trihydrochloride a) A mixture of 5.0 g sodium wire and 150 ml anhydrous diethyl ether is placed in an ice bath cooled and added in 38 mA with 38.9 g of ß- (3-pyridyl) propionic acid ethyl ester and 17.0 g of formic acid ethyl ester. The mixture obtained is stirred for 22 hours at room temperature and then evaporated to dryness. The residue obtained is mixed with 16.5 g of thiourea and 130 ml of ethanol and boiled under reflux for 8 hours. The reaction mixture is then evaporated to dryness, the residue is dissolved in water and acetic acid is added to a pH of 5. The precipitate obtained is filtered off and recrystallized from a mixture of acetic acid and water. The 5- (3-pyridylmethyl) -2-thiouracil of melting point 271 to 274 ° C. (dec.) Is obtained.

b) A solution of 11.0 g of 5- (3-pyridylmethyl) -2-thiou-racil, 7.1 g of methyl iodide and 4.2 g of sodium hydroxide in 150 ml of water and 150 ml of ethanol is stirred at 65 ° C. for 40 minutes , then cooled and mixed with acetic acid to a pH of 5. The solvent is then partially distilled off and the residue is cooled. The precipitate obtained is filtered off and recrystallized from a mixture of ethanol and acetic acid. The 5- (3-pyridylmethyl) -2-methylthio-4-pyrimidone of melting point 247 to 249 ° C. is obtained.

c) A well-stirred mixture of 6.55 g of 5- (3-pyridyl-methyl) ~ 2-methylthio-4-pyrimidone and 4.8 g of 2- (5-methyl-4-imidazolylmethylthio) ethylamine is 7 hours Heated from 130 to 135 ° C. The reaction mixture obtained is cooled, degenerated with hot water and treated with a dilute solution of hydrogen chloride in ethanol. The precipitate obtained is recrystallized from a mixture of ethanol and water. The title compound of F. 237 to 241 ° C is obtained.

Example 7

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

A well-stirred mixture of 1.5 g of 5- (2-pyridylmethyl) -2-methylthio-4-pyrimidone and 1.6 g of 2- (3-bromo-2-pyridylmethylthio) ethylamine is at 130 ° for 6 hours C. heated. After cooling, the reaction mixture is digested with hot water and treated with dilute hydrobromic acid. The precipitate obtained is recrystallized from a mixture of ethanol and water. The title compound of melting point 225 to 230 ° C. (dec.) Is obtained in a 44.5% yield.

Example 8

2- [2- (5-Methyl-4-imidazolylmethylthio) ethylamino] -5- (2-thiazolylmethyl) -4-pyrimidone trihydrochloride a) A solution of 26.76 g 2-thiazolacrylic acid and 10 ml concentrated sulfuric acid in 150 ml of ethanol is refluxed for 18 hours. The solvent is then partially distilled off and the residue is diluted with water. The solution obtained is extracted with diethyl ether. The ether extracts are evaporated. The 2-thiazole acrylic acid ethyl ester is obtained.

b) 14.8 g of 2-thiazolacrylic acid ethyl ester are dissolved in 170 ml of ethanol and hydrogenated at 40 ° C. under a pressure of 3.5 at with 10% palladium-on-carbon to ethyl 2-thiazolopropionate.

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

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c) A mixture of 1.8 g of sodium wire and 65 ml of anhydrous diethyl ether is cooled in an ice bath and 14.2 g of 2-thiazolopropionic acid ethyl ester and 5.9 g of ethyl formate are added in 2 lA hours with stirring. The mixture obtained is stirred for 21 hours at room temperature and then evaporated to dryness. 5.8 g of thiourea and 60 ml of ethanol are added to the residue and the mixture is boiled under reflux for 9 hours. After working up according to Example 5 a), the 5- (2-thiazolmethyl) -2-thiouracil of mp 275 to 280 ° C. (dec.) Is obtained after recrystallization i from acetic acid.

d) A solution of 4.8 g of 5- (2-thiazolmethyl) -2-thiouraciI, 3.0 g of methyl iodide and 0.9 g of sodium hydroxide in 75 ml of water and 150 ml of ethanol is stirred at 70 ° C. for 30 minutes. After working up according to Example 5 b) and recrystallization from ethanol, the 5- (2-thiazolmethyl) -2-methylthio-4-pyrimidone of melting point 181 to 182.5 ° C. is obtained.

(c) 2- [2- (5-Methyl-4-imidazolylmethylthio) ethylamino] -5-3,4-dimethoxy-2-pyridylmethyl) -4-pyrimidone

(d) 2- [2- (5-methyl-4-imidazolylmethylthio) ethylamino] -5- (3-quinolylmethyl) -4-pyrimidone i (e) 2- [2- (5-methyl-4-imidazolylmethylthio) -ethylamino] -5- (4-isoquinolylmethyl) -4-pyrimidone.

The starting compounds used above can be prepared from the corresponding heterocyclic carboxalides by condensation with malonic acid and subsequent hydrogenation and esterification.

e) A well-stirred mixture of 1.4 g of 5- (2-thiazolyl-20 amine methyl) -2-methylthio-4-pyrimidone and 1.0 g of 2- (5-methyl-4-imidazolylmethylthio) ethylamine becomes 6 Heated to 145 to 150 ° C for hours. The reaction mixture is then cooled, digested with hot water and treated with a dilute solution of hydrogen chloride in ethanol. The precipitate obtained is filtered off and recrystallized from a mixture of ethanol and water. The title compound of F. 208 to 211 ° C is obtained.

Example 12 When using

(a) 2- (2-Imidazolylmethylthio) ethylamine

(b) 2- (4-Imidazolylmethylthio) ethylamine

(c) 2- (5-bromo-4-imidazolylmethylthio) ethylamine

(d) 2- (5-trifluoromethyl-4-imidazolylmethylthio) ethyl

(e) 2- (5-hydroxymethyl-4-imidazolylmethylthio) ethyl

Example 9 30

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

According to Example 2, 1.74 g of 5- (3-pyridylmethyl) -2-methylthio-4-pyrimidone are reacted with 1.30 g of 2- (2-thiazolylmethylthio) ethylamine. The reaction mixture 35 obtained is digested with hot water and treated with dilute hydrobromic acid. The precipitate obtained is filtered off and recrystallized from a mixture of ethanol and water. The title compound of mp 229 to 233.5 ° C. is obtained. 40

Example 10

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

According to Example 2, 1.27 g of 5- (3-pyridylmethyl) -2-methylthio-4-pyrimidone are reacted with 1,35g2- (3-bromo-2-pyridylmethylthio) ethylamine. The reaction mixture obtained is digested with hot water and treated with dilute bromine hydrochloric acid. The precipitate obtained is filtered off and recrystallized from methanol. The title compound of F. 217 to 220.5 ° C is obtained.

Example 11 When using

(a) ethyl ß- (2-methoxy-3-pyridyl) propionate

(b) ethyl ß- (3-methoxy-2-pyridyl) propionate

(c) ethyl ß- (3,4-dimethoxy-2-pyridyl) propionate

(d) ß- (3-QuinoIyl) propionic acid ethyl ester and

(e) ß (4-isoquinolyl) propionic acid ethyl ester instead of ß- (4-pyridyl) propionic acid ethyl ester, the following products are obtained according to example 1:

(a) 2- [2- (5-Methyl-4-imidazolylmethylthio) ethylamino] -5- (2-methoxy-3-pyridylmethyl) -4-pyrimidone

(b) 2- [2- (5-Methyl-4-imidazolylmethylthio) ethylamino] -5- (3-methoxy-2-pyridylmethyl) -4-pyrimidone

45

so

SS

60

65

(f) 2- (2-pyridylmethylthio) ethylamine

(g) 2- (3-methyl-2-pyridylmethylthio) ethylamine

(h) 2- (3-methoxy-2-pyridylmethylthio) ethylamine

(i) 2- (3-chloro-2-pyridylmethylthio) ethylamine (j) 2- (3-amino-2-pyridylmethylthio) ethylamine (k) 2- (3-hydroxy-2-pyridylmethylthio) ethylamine (1 ) 2- (3-isothiazolylmethylthio) ethylamine

(m) 2- (4-bromo-3-isothiazolylmethylthio) ethylamine (n) 2- [3- (1,2,5) thiadiazolylmethylthio] ethylamine

(0) 2- [4-chloro-3- (1,2,5) thiadiazolylmethylthio] ethylamine (p) 2- [5-amino-2- (1,3,4) thiadiazolylmethylthio] ethyl-

amine instead of 2- (5-methyl-4-imidazolylmethylthio) ethylamine, the following products are obtained according to Example 6:

(a) 2- [2- (2-Imidazolylmethylthio) ethylamino] -5- (3-pyridylmethyl) -4-pyrimidone

(b) 2- [2- (4-Imidazolylmethylthio) ethylamino] -5- (3-pyridylmethyl) -4-pyrimidone

(c) 2- [2- (5-bromo-4-imidazolylmethylthio) ethylamino] -5- (3-pyridylmethyl) -4-pyrimidone

(d) 2- [2- (5-Trifluoromethyl-4-imidazolylmethylthio) ethyl amino] -5- (3-pyridylmethyl) -4-pyrimidone

(e) 2- [2- (5-hydroxymethyl-4-imidazolylmethylthio) ethylamino] -5- (3-pyridylmethyl) -4-pyrimidone

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

(g) 2- [2- (3-Methyl-2-pyridylmethylthio) ethylamino] -5- (3-pyridylmethyl) -4-pyrimidone

(h) 2- [2- (3-methoxy-2-pyridylmethylthio) ethylamino] -5- (3-pyridylmethyl) -4-pyrimidone

(1) 2- [2- (3-chloro-2-pyridylmethylthio) ethylamino] -5- (3-pyridylmethyl) -4-pyrimidone

0) 2- [2- (3-Amino-2-pyridylmethylthio) ethylamino] -5- (3-pyridylmethyl) -4-pyrimidone

(k) 2- [2- (3-Hydroxy-2-pyridylmethylthio) ethylamino] -5- (3-pyridylmethyl) -4-pyrimidone

(1) 2- [2- (3-isothiazolylmethylthio) ethylamino] -5- (3-pyridylmethyl) -4-pyrimidone

(m) 2- [2- (4-bromo-3-isothiazolylmethylthio) ethylamino] -5- (3-pyridylmethyl) -4-pyrimidone

(n) 2- {2- [3- (1,2,5) thiadiazolylmethylthio] ethylamino} -5- (3-pyridylmethyl) -4-pyrimidone

(o) 2- {2- [4-chloro-3- (1,2,5) thiadiazolylmethylthio] ethylamino} -5- (3-pyridylmethyl) -4-pyrimidone

(p) 2- {2- [5-Amino-2- (1,3,4) thiadiazolylmethylthio] ethylamino} -5- (3-pyridylmethyl) -4-pyrimidone.

Example 13

a) The reaction of 2-chloro-3-nitropyridine with diethyl 2- (2-cyanoethyl) -malonate and sodium hydride in tetrahydrofuran gives the l- (3-nitro-2-pyridyl) -l, l-bis- (carbäthoxy) - butyronitrile, mp 93.5 to 94.5 ° C. By alkaline hydrolysis and subsequent acidification, the 2- (3-cyanopreopyl) -3-nitropyridine hydrochloride from

F. 142 to 145.5 ° C obtained. This compound is hydrogenated with hydrogen on palladium-on-carbon to 3-amino-2- (3-cyanopropyl) pyridine. The product obtained is treated with sodium nitrite and sulfuric acid and then heated. The 2- (3-cyanopropyl) -3-hydroxypyridine obtained is methylated with methyl iodide and sodium ethylate in dimethyl sulfoxide and then reduced to 4- (3-methoxy-2-pyridyl) butylamine with lithium aluminum hydride. The reduction of 3-amino-2- (3-cyanopropyl) - 3-hydroxypyridine with lithium aluminum hydride gives the 4- (3-amino-2-pyridyl) butylamine. This compound is diazotized at a pH of 1 and then treated with copper (I) chloride or with copper (I) bromide. The 4- (3-chloro-2-pyridyl) butylamine or the 4- (3-bromo-2-pyridyl) butylamine are obtained.

b) The use of

(a) 4- (4-imidazolyl) butylamine

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

(c) 4- (3-Chloro-2-pyridyl) butylamine

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

(e) 4- (3-Amino-2-pyridyl) butylamine instead of 2- (5-methyl-4-imidazolylmethylthio) ethylamine gives the following products according to Example 6:

(a) 2- [4-Imidazolyl) butylamino] -5- (3-pyridylmethyl) -4-pyrimidone

(b) 2- [4- (3-Methoxy-2-pyridyl) butylamino] -5- (3-pyridylmethyl) -4-pyrimidone

(c) 2- [4- (3-Chloro-2-pyridyl) butyl amino] -5- (3-pyridylmethyl) -4-pyrimidone

(d) 2- [4- (3-Bromo-2-pyridyl) butylamino] -5- (3-pyridylmethyl) -4-pyrimidone

(e) 2- [4- (3-Amino-2-pyridyl) butylamino] -5- (3-pyridylmethyl) -4-pyrimidone.

Example 14

By reacting ethyl acetoacetate with sodium ethoxide and 3- (chloromethyl) pyridine, the a- (3-pyridylmethyl) -acetoacetic acid ethyl ester is obtained, which in the reaction with thiourea and sodium ethoxide contains 5- (3-pyridylmethyl) -6-methyl-2- thiouracil results. The use of 5- (3-pyridylmethyl) -6-methyl-2-thiouracil instead of 5- (4-pyridylmethyl) -2-thiouracil results in 2- [2- (5-methyl-4-imidazolylmethylthio) according to Example 1 -ethylamino] -5- (3-pyridylmethyl) -6-methyl-4-pyrimidone. Similarly, 2- [2- (5-methyl-4-imidazolylmethylthio) ethylamino] -5- (3-pyridylmethyl) -6-propyl-4-pyrimidone can be prepared by using ethyl butyroacetate.

Example 15

The reaction of 2- [2- (5-methyl-4-imidazolylmethylthio) ethylamino] -5- (3-pyridylmethyl) -4-pyrimidone with phosphorus pentasulfide in hot pyridine gives the 2- [2- (5-methyl -4-imidazolylmethylthio) ethylamino] -5- (3-pyridylmethyl) pyrimid-4-thione.

9 631981

Example 16

a) Butyrolactone is reacted with sodium and ethyl formate, and the product obtained is treated successively with thiourea and with methyl iodide. It

5 5- (2-hydroxyethyl) -2-methylthio-4-pyrimidone is obtained.

b) The 5- (2-hydroxyethyl) -2-methylthio-4-pyrimidone is treated with thionyl chloride. The product obtained

10 is reacted with the sodium derivative of (a) 3- (hydroxymethyl) pyridine and (b) 3- (mercaptomethyl) pyridine. The following products are obtained:

(a) 5- (2- (3-pyridylmethoxy) ethyl) -2-methylthio-4-pyri-

ls midon

(b) 5- (2- (3-Pyridylmethylthio) ethyl) -2-methylthio-4-pyrimidone.

c) The use of

20 (a) 5- (2- (3-Pyridylmethoxy) ethyl) -2-methylthio-4-pyrimidone

(b) 5- (2- (3-Pyridylmethylthio) ethyl) -2-methylthio-4-pyrimidone

25 instead of 5- (3-pyridylmethyl) -2-methylthio-4-pyrimidone gives the following products according to example 6:

(a) 2- [2- (5-Methyl-4-imidazolylmethylthio) ethylamino] -5- (2- (3-pyridylmethoxy) ethyl-4-pyrimidone

30 (b) 2- [2- (5-methyl-4-imidazolylmethylthio) ethylamino] -5- (2- (3-pyridylmethylthio) ethyl) -4-pyrimidone.

d) The use of

35 (a) 3-hydroxypyridine and

(b) 3-Mercaptopyridine instead of 3- (hydroxymethyl) pyridine according to Example 16 b) and c) gives the following products:

40

(a) 2- [2- (5-Methyl-4-imidazolylmethylthio) ethylamino] -5- (2- (3-pyridyloxy) ethyl) -4-pyrimidone

(b) 2- [2- (5-methyl-4-imidazolylmethylthio) ethylamino] -

45 5- (2- (3-pyridylthio) ethyl-4-pyrimidone.

e) The use of

(a) 3- (2-Hydroxyethyl) pyridine and so (b) 3- (2-mercaptoethyl) pyridine instead of 3- (hydroxymethyl) pyridine gives the following products according to Example 16 b) and c):

55 (a) 2- [2- (5-methyl-4-imidazolylmethylthio) ethylamino] -5 - {[2- (3-pyridyl) ethoxy] ethyl} -4-pyrimidone

(b) 2- [2- (5-Methyl-4-imidazolylmethylthio) ethylamino] -5- {2- (3-pyridyl) ethylthio] ethyl} -4-pyrimidone.

60

0 The use of caprolactone instead of butyrolactone results in the following products according to Example 16 a), b) and c):

65 (a) 2- [2- (5-methyl-4-imidazolylmethylthio) ethylamino] -5- [3- (pyridylmethoxy) propyl] -4-pyrimidone

(b) 2- [2- (5-Methyl) -4-imidazolylmethylthio) ethylamino] -5- [3- (3-pyridylmethylthio) propyl] -4-pyrimidone.

631981

10th

Example 17

According to Example 1 a), 5- (3-pyridylmethoxy) -2-thiouracil is prepared from ethyl 3-pyridylmethyl acetate. The use of 5- (3-pyridylmethoxy) -2-thiouracil instead of 5- (4-pyridylmethyl) -2-thiouracil according to Example 1 gives 2- [2- (5-methyl-4-imidazolylmethylthio) ethylamino] - 5- (3-pyridylmethoxy) -4-pyrimidone.

If 3- (3-pyridyl) -propoxyacetic acid ethyl ester or 3- (3-pyridyl) -propylthioglycolic acid ethyl ester are used, 2- [2- (5-methyl-4-imidazolyI-methylthio) ethylamino] -5 - [3- (3-pyridyl) propoxy] -4-pyrimidone or the 2- [2- (5-methyl-4-imidazolylmethylthio) ethylamino] -5- [3- (3-pyridyl) - propylthio] -4-pyrimidone.

for 2- (5-methyl-4-imidazolylmethylthio) ethylamine in Example 6 gave:

(a) 2- [2- (3-methoxy-2-pyridylmethylthio) ethylamino] -5-5 (3-pyridylmethyl) -4-pyrimidone. 155-156.5 °

(b) 2- [2- (3-Chloro-2-pyridylmethylthio) ethylamino] -5- (3-pyridylmethyl) -4-pyrimidone mp 134-135.5 °.

(c) 2- [2- (3-Fluoro-2-pyridylmethylthio) ethylamino] -5- (3-pyridylmethyl) -4-pyrimidone mp 107.5-109.5 °.

io (d) 2- [2- (3-iodo-2-pyridylmethylthio) ethylamino] -5- (3-pyridylmethyl) -4-pyrimidone mp 118-125.5 °.

Example 18

The use of:

(a) Ethyl ß- (2-furyl) propionate

(b) ß- (5-Oxazolyl) -2-propionic acid ethyl ester

(c) ethyl ß- (3-isothiazolyl) propionate

(d) ethyl ß- (2-pyrimidyl) propionate

(e) ethyl ß- (5-pyrimidyl) propionate

(f) ethyl ß- (2-pyrazyl) propionate

(g) ethyl ß- (4-pyridazyl) propionate instead of ß- (4-pyridyl) propionate, the following products are obtained according to example 1:

(a) 2- [2- (5-Methyl-4-imidazolylmethylthio) ethylamino] -5- (2-furylmethyl) -4-pyrimidone

(b) 2- [2- (5-Methyl-4-imidazolylmethylthio) ethylamino] -5- (2-oxazolylmethyl) -4-pyrimidone

(c) 2- [2- (5-Methyl-4-imidazolylmethylthio) ethylamino] -5- (3-isothiazolylmethyl) -4-pyrimidone

(d) 2- [2- (5-Methyl-4-imidazolylmethylthio) ethylamino] -5- (2-pyrimidylmethyl) -4-pyrimidone

(e) 2- [2- (5-Methyl-4-imidazolylmethylthio) ethylamino] -5- (5-pyrimidylmethyl) -4-pyrimidone

(f) 2- [2- (5-Methyl-4-imidazolylmethylthio) ethylamino] -5- (2-pyrazylmethyl) -4-pyrimidone

(g) 2- [2- (5-Methyl-4-imidazolylmethylthio) ethylamino] -5- (4-pyrimidylmethyl) -4-pyrimidone.

The starting compounds (b) to (g) used above can be prepared by condensing the corresponding heterocyclic carboxaldehyde with malonic acid and then hydrogenating and esterifying the product obtained.

Example 19

The 2- [l- (4-methoxybenzyl) imidazolyl] acrylic acid is obtained by reacting l- (4-methoxybenzyl) -2-imidazole-carboxaldehyde with malonic acid in the presence of pyridine and piperidine. The use of 2- [l - (4-methoxy-benzyl) imidazolyl] acrylic acid instead of 2-thiazolacrylic acid gives, according to Example 8, after splitting off the protective group with anisole and hydrogen bromide in acetic acid Methyl-4-imidazolylmethylthio) ethylamino] -5- (2-imidazolylmethyl) -4-pyrimidone.

Example 21

is (i) The reaction of 2-chloro-3-nitropyridine with diethyl 2- (2-cyanoethyl) -malonic acid and sodium hydride in tetrahydrofuran gave 1 - (3-nitro-2-pyridyl / -1,1-bis (carbeth -oxy) -butyronitrile, mp. 93.5-94.5 °, which after alkaline hydrolysis and acidification gave 2- (3-cyanopropyl) -3-nitropy-20 ridine hydrochloride, mp. 142-145.5 °. Reduction with hydrogen and cardboard on activated carbon gave 3-amino-2- (3-cyanopropyl) pyridine, which was treated with sodium nitrite and sulfuric acid and then warmed up to give 2- (3-cyanopropyl) -3-hydroxypyridine.25 Alkylation with methyl iodide and sodium methoxide in dimethylsulphoxide and subsequent reduction with lithium aluminum hydride gave 4- (3-methoxy-2-pyridyl) butylamine. Alkylation with ethyl iodide and sodium ethoxide in dimethylsulphoxide and subsequent reduction 30 with lithium aluminum hydride gave 4- (3-ethoxy-2- pyridyl) butylamine Reduction of 3-amino-2- (3-cyano-propyl) pyridine with lithium aluminum hydride gave 4- (3-amino-2-pyridyl) -b utylamine. Diazotization of 4- (3-amino-2-pyridyl) butylamine in hydrochloric acid with copper chloride or in 35 hydrobromic acid with copper bromide gave 4- (3-chloro-2-pyridyl) butylamine and 4- (3-bromo-2-pyridyl) - butylamine.

(ii) Substitution of:

40

45

(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 for 2- (5-methyl-4-imidazolylmethylthio) ethylamine in the process according to Example 6 gave:

Substitution of:

Example 20

(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

(a) 2- [4- (5-Methyl-4-imidazolyl) butylamino] -5- (3-pyridyl-50 methyl-4-pyrimidone, isolated as trihydrochloride, mp.

242-246 °

(b) 2- [4- (3-methoxy-2-pyridyl) butylamino] -5- (3-pyridyl-methyl) -4-pyrimidone, mp 117-118 °

(c) 2- [4- (3-Ethoxy-2-pyridyl) butylamino] -5- (3-pyridyl-55 methyl) -4-pyrimidone, mp 135-136 °

(d) 2- [4- (3-Chloro-2-pyridyl) butylamino] -5- (3-pyridyl-methyl) -4-pyrimidone, mp 146-147.5 °

(e) 2- [4- (Bromo-2-pyridyl) butylamino] -5- (3-pyridyl-methyl) -4-pyrimidone, mp 159-162 °.

eo

Example 22

(i) A solution of 3-quinolylacrylic acid (63.71 g) and concentrated sulfuric acid (25 ml) in ethanol (350 ml) 65 was refluxed for 18 hours. The product was isolated according to the procedure of Example 8 (i) and gave ethyl 3-quinolylacrylate, mp. 86.5-88 ° (from ethanol-water).

11 631981

Analysis: C14H13NO2 (wt%) (a) 2- (2-thiazolylmethylthio) ethylamine

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

Calc .: C 74.0; H 5.8; N 6.2

Found: C 73.8; H 5.8; N 6.0. revealed

5

(ii) Ethyl 3- (3-quinolyl) acrylate (51.68 g) was dissolved in ethanol (a) 2- [2- (2-thiazolylmethylthio) ethylamino] -5- (3-pyridyl- (170 ml) and at 37 ° and a pressure of 3.5 kg / cm 2 of methyl] -6-methyl-4-pyrimidone, mp. 118-121 °.

hydrated with 10% palladium on activated carbon. Obtained (b) 2- [2- (3-bromo-2-pyridylmethylthio) ethylamino] -5- (3-

was ethyl 3 (3-quinolyl) propionate. pyridylmethyl) -6-methyl-4-pyrimidone mp 159-162 °.

(iii) Ethyl 3- (3-quinolyl) propionate (47.99 g) and Ethyl 10 (c) Treating 2-methylthio-5- (3-pyridylmethyl) -6-format (16.3 g) for 3 hours with stirring methyl-4-pyrimidone with 2- (5-methyl-4-imidazolylmethyl-a mixture of sodium wires (4.8 g) and dry thio) ethylamine at reflux with pyridine while 25 ether (150 ml) with cooling by means of an ice bath, evaporate the mixture and chromatograph. The mixture was purified over silica gel for 20 hours at room temperature (eluting with stirred, evaporated to dryness, and the residue with 15 chloroform / methanol 5: 1) to give 2- [2- (5-methyl-4-imidazo-thiourea ( 15.9 g) and ethanol (130 ml) during 7 lylmethylthio) ethylamino] -5- (3-pyridylmethyl) -6-methyl-4 hours treated at reflux. The mixture became a pyrimidone mp. 128-121 °.

Evaporates and the residue is evaporated in water and

Acetic acid (pH4) dissolved. After filtration, this solution gave Example 25

5- (3-Quinolylmethyl) -2-thiouracil, mp 281-6 ° (decomp. 20 (i) 2- (6-methyl-3-pyridyl) acrylic acid, mp. 213-215.5 °

tongue) (from acetic acid / water). was by condensation of 6-methylpyridine-2-carbox-

(iv) A solution of 5- (3-quinolylmethyl) -2-thiouracil aldehyde with malonic acid in pyridine with piperidine as catalyst (17.51 g), methyl iodide (9.2 g) and sodium hydroxide (5.4 g) produced, and to the corresponding ethyl ester,

in water (200 ml) and ethanol (200 ml) was converted at 75 ° C. mp. 36-37 °, which with hydrogen and palladium

Stirred for one hour, allowed to cool, after which acetic acid was reduced to activated carbon. Ethyl 3 was obtained.

Acid was added to a pH4, the solid substance (6-methyl-3-pyridyl) propionate (oil).

was filtered to give 5- (3-quinolylmethyl) -2-methylthio-

4-pyrimidone, mp. 215.5-218 ° (from ethanol). (ii) Treating ethyl 3- (6-methyl-3-pyridyl) propionate

(v) An intimate mixture of 5- (3-quinolylmethyl) -2- with sodium and ethyl format according to the method of methylthio-4-pyrimidone (1.3 g) and 2- (5-methyl-4-imida- 30 example) 1 (i) gave 5- (6-methyl-3-pyridylmethyl) -2-thio-zolyl-methylthio) ethylamine (1.3 g) was warmed to 150-5 ° uracil mp. 240-241 °, which in 5- (6-Methyl-3-pyridylmethyl) -rend warmed for 6 hours. The cooled mixture was converted to 2-methylthio-4-pyrimidone, mp. 197-198.5 ° by driving with hot water and then with dilute HCl of Example 1 (ii).

treated in ethanol. 2- [2- (5-Methyl-4-imidazo-

lylmethylthio) ethylamino] -5- (3-quinolylmethyl) -4-pyrimi- 35 (iii) treating 5- (6-methyl-3-pyridylmethyl) -2-me-

dontrihydrochloride, mp. 184-9 ° (from ethanol-water). thylthio-4-pyrimidone with

Example 23 (a) 2- (5-Methyl-4-imidazolylmethylthio) ethylamine

An intimate mixture of 5- (3-quinolylmethyl) -2-methyl- (b) 2- (2-thiazolylmethylthio) ethylamine thio-4-pyrimidone (2.0 g) and 2- (2-thiazolylmethylthio) ethyl 40 ( c) 2- (3-Bromo-2-pyridylmethylthio) ethylamine amine (1.2 g) was heated to 145 ° C over 4 hours. (d) 4- (5-methyl-4-imidazolyl) butylamine

After cooling, the residue was treated with warm water (e) 4- (3-methoxy-2-pyridyl) butylamine and then with dilute alcoholic HCl (f) 4- (3-chloro-2-pyridyl) butylamine. 2- [2- (2-Thiazolylmethylthio) ethyl- (g) 4- (2-pyridyl) butylamine amino] -5- (3-quinolylmethyl) -4-pyrimidone-trihydrochloride, 45 (h) 4- (3 -Athoxy-2-pyridyl) butylamine mp 202-205 ° (from ethanol-water).

according to the general procedure of Example 1 (iii) gave Example 24

(i) a mixture of pyridine-3-carboxaldehyde (48 g),

Ethyl acetoacetate (52 g), aqueous piperidine acetate (40%, 50 (a) 2- [2- (5-methyl-4-imidazolylmethylthio) ethylamino] -5-4.8 g) and 5% palladium catalytic on activated carbon ( 50% moist, (6-methyl-3-pyridylmethyl) -4-pyrimidone trihydrochloride (2.48 g) was under a pressure of 7 kg / cm 2 for 22 mp 210-214 °.

Hydrogenated at 31 ° C for hours. The mixture was diluted with (b) 2- [2- (2-thiazolylmethylthio) ethylamino] -5- (6-methyl-

Diluted ether, filtered, the filtrate evaporated and in 3-pyridylmethyl-4-pyrimidone trihydrochloride mp.

Vacuum distilled. Ethyl 2- (3-pyridyl-55 187-190 ° was obtained.

methyl) acetoacetate (boiling point 146 ° / 1 mmHg). This ester (c) 2- [2- (3-bromo-2-pyridylmethylthio) ethylamino] -5- (6-

was refluxed with thiourea and sodium ethoxide in ethanol on methyl-3-pyridylmethyl) -4-pyrimidone trihydrochloride, and the mixture was then acidified. Man mp. 193-196 °.

received 5- (3-pyridylmethyl) -6-methyl-2-thiouracil mp (d) 2- [4- (5-methyl-4-imidazolyl) butylamino] -5- (6-methyl-

328-331 °. a »3-pyridylmethyl) -4-pyrimidone trihydrochloride mp.

189-190 °.

(ii) Treat 5- (3-pyridylmethyl) -6-methyl-2-thio- (e) 2- [4- (3-methoxy-2-pyridyl) butylamino] -5- (6-methyl-3- uracil with methyl iodide and sodium ethoxide in ethanol at 0 ° pyridylmethyl) -4-pyrimidone trihydrochloride mp.

and acidification gave 2-methylthio-5- (3-pyridylmethyl) -6- 209-210 °.

methyl-4-pyrimidone mp 208-211 °. 65 (f) 2- [4- (3-chloro-2-pyridyl) butylamino] -5- (6-methyl-3-

pyridylmethyl) -4-pyrimidone, isolated as free base, mp.

(iii) Melt 2-methylthio-5- (3-pyridylmethyl) -6- 132-133 °.

methyl-4-pyrimidone at 160-170 ° with (g) 2- [4-3-ethoxy-2-pyridyl) butylamino] -5- (6-methyl-3-

631981

12

pyridylmethyl) -4-pyrimidone, isolated as a free base. Mp 156.5-157.5 °.

(h) 2- [4- (3-Ethoxy-2-pyridyl) butylamino] -5- (6-methyl-3-pyridylmethyl) -4-pyrimidone, isolated as free base, mp. 104-105 °.

Example 26

(i) A mixture of ethyl format (111 g) and 2-butanone (108 g) was added dropwise to a mixture of sodium hydride in oil (50%, 72 g) and the mixture was left 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 and the mixture was refluxed for 2 hours and then cooled. The mixture was then acidified with acetic acid, the solid precipitated and 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-hydroxypyridine (42 g) and phosphorus pentachloride (81 g) was heated to 140-160 ° for 2 hours. The phosphoryl chloride was evaporated by distillation under reduced pressure and ice water (500 g) was added to the residue. The pH of the mixture was adjusted to 7 with aqueous sodium hydroxide and extracted with ether. The ether extract was evaporated to an oil and crystallized in petroleum ether (column 60-80 °). 2-chloro

3-cyano-5,6-dimethylpyridine (25.3 g) mp 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) were hydrogenated in the presence of Raney nickel catalyst (5 g) at 50 ° C. under 3.5 kg / cm 2. The mixture was poured into water (750 ml) and filtered. The residual substance was suspended in water (130 ml) and 70 ml conc. Hydrochloric acid was added. The mixture was heated at 100 ° for 1 hour; Formalin (40% w / w, 120 ml) was added and the mixture was heated at 100 ° C for a further half hour and finally cooled. Sodium acetate (95 g) and water (250 ml) were added and the mixture extracted with ether. The extracts were washed with 5% aqueous potassium carbonate and evaporated. 2-Chloro-5,6-dimethyl-3-pyridine car-boxaldehyde (13.24 g, 60%) was obtained, mp 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 refluxed during

Heated for 1 hour and evaporated to an oil. This oil was dissolved in 2N sodium hydroxide and extracted (discarded) with chloroform. The aqueous phase was acidified with hydrochloric acid and extracted with chloroform. The chloroform extracts were washed with water and evaporated. 3- (2-Chloro-5,6-dimethyl-3-pyridyl) acrylic acid (18.3 g, 87%) mp 150-158 ° was obtained. This acid was esterified with ethanol and sulfuric acid. The ethyl ester had a melting point of 85-88 °.

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

(32.7 g) in ethanol (500 ml) were in the presence of a palladium catalyst on activated carbon (5%, 3 g), at 25-50 ° C

and 3.5 kg / cm2 hydrogenated. The mixture was filtered and the filtrate evaporated to oil which was between chloroform and

2 N hydrochloric acid was divided. The aqueous phase was made alkaline with aqueous sodium hydroxide and extracted with chloroform. The chloroform extracts were evaporated to give ethyl 3- (5,6-midethyl-3-pyridyl) propionate (21.8 g, 80%) as an oil.

s

(vi) Reaction of ethyl 3- (5,6-dimethyl-3-pyridyl) propionate with ethyl format and sodium hydrad in dimethoxyethane according to the general procedure of Example 24 (iii) gave 3- (5,6-dimethyl) -3-pyridyl) -2-formylpropionate, io mp 148-149 °. Successive treatment of this ester with thiourea and methyl iodide according to the general procedure of Example 1 (i) (ii) gave 5- (5,6-dimethyl-3-pyridylmethyl) -2-methylthio-4-pyrimidone and reaction of this compound with 2- (3-Bromo-2-pyridylmethyl-15 thio) ethylamine at 140 ° for 6 hours gave 2- [2- (3-bromo-2-pyridylmethylthio) ethylamino] -5- (5,6-dimethyl-3-pyridylmethyl) -4-pyrimidone, mp 105-107 °.

Example 27

20 (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) were pressurized under 3 kg / cm2 in the presence of Raney nickel catalyst ( 1.0 g) hydrogenated. The mixture was evaporated to a volume of 500 ml, water was added and the mixture was stored at 0 ° C. overnight. The mixture was filtered, the solid washed with water and dissolved in 10% hydrochloric acid (1000 ml). Formaldehyde solution (36% by weight, 450 ml) was added and the mixture heated for 15 minutes, then allowed to cool 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, dried and evaporated. 6-methoxy-pyridine-3-carboxaldehyde (31.5 g, 50%), mp. 48-49 °, was obtained.

(ii) A mixture of 6-methoxypyridine-3-carboxaldehyde (2.34 g), monoethyl malonate (4.51 g), pyridine (12 ml)

40 and piperidine (6 drops) was heated under reflux for 5 hours and evaporated to an oil. This oil was partitioned between ether and dilute aqueous ammonia. The ethereal layer was washed with water and evaporated. The remaining oil crystallized on standing and gave ethyl (3- (6-methoxy-3-pyridyl) acrylate (2.8 g, 79%), mp. 49-52 °.

(iii) Ethyl 3- (6-methoxy-3-pyridyl) acrylate (32.33 g) in ethanol (160 ml) was in the presence of a palladium catalyst.

50 lysators on activated carbon (5%, 0.2 g) at 3.5 kg / cm2 pressure and 40 ° C hydrogenated. The mixture was filtered, the filtrate evaporated. Ethyl 3- (6-methoxy-3-pyridyl) propionate (32.7 g) was obtained as an oily substance.

55 (iv) A mixture of ethyl 3- (6-methoxy-3-pyridyl) propionate (32.74 g) and ethyl format (17.22 g) was added dropwise during 1 x hour with stirring a suspension of sodium hydride in oil (50% , 9.38 g) in 1,2-dimethoxyethane (50 ml) cooled to -2 °, added. After standing overnight at room temperature, the mixture was poured onto ice, extracted with ether (discarded) and the aqueous phase with 2 N acidified to pH 5. An oily substance precipitated and crystallized on standing to form ethyl 2-formyl-3- (6-methoxy-3-65 pyridyl) propionate (25.9 g, 70%), mp. 91.5-94 °. A sample which was recrystallized from aqueous ethanol had a melting point of 93-94 °.

Successive treatment of this ester with thiourea

13

631981

and methyl iodide according to the general procedure of Example 1 (i) (ii) gave 5- (6-methoxy-3-pyridylmethyl) -2-methylthio-4-pyrimidone and the reaction of this compound with at 140 ° C for 6 hours :

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

(b) 2- (2-Thiazolylmethylthio) ethylamine

(a) 2- [2- (5-Methyl-4-imidazolylmethylthio) ethylamino] -5- (6-methoxy-3-pyridylmethyl) -4-pyrimidone trihydrochloride, mp. 205-209 °.

(b) 2- [2- (2-thiazolylmethylthio) ethylamino] -5- (6-methoxy-3-poyridylmethyl) -4-pyrimidone, mp 95-97 °.

io

IS

Example 28

(i) Sodium (20.8 g) was dissolved in methanol (285 ml);

a solution of 2-chloro-4-cyanopyridine (115.53 g) in methanol / dioxane (1: 1.850 ml) was added to this mixture, heated under reflux for 2 VI hours and then cooled. The mixture was filtered and the volume of the filtrate was reduced to 200 ml by evaporation, after which 400 ml of water were added. The precipitated solid was filtered off and gave 2-methoxy-25 4-cyanopyridine (67.2 g, 51%), mp. 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 (3701) was in the presence hydrogenated by Raney nickel (1.0 g) under 3.5 kg / cm 2. The mixture was evaporated to a volume of 450 ml, 900 ml of water were added and over

Let stand at 0 ° overnight. The mixture was filtered and the solid washed with water and dissolved in 10% hydrochloric acid (950 ml). Formaldehyde (36% w / v, 420 ml) was added and the mixture warmed for 30 minutes, allowed to cool and added to an aqueous solution of sodium acetate (280 g in 840 ml). The mixture was extracted with ether (3 x 500 ml) and the combined extracts washed successively with aqueous potassium carbonate and water, dried and evaporated.

This gave 2-methoxypyridine-4-carboxaldehyde (20.53 g, 35%), mp. 3-5 °. A sample was recrystallized in petroleum ether and had a melting point of 33-36 °.

(iii) Substitution of 2-methoxypyridine-4-carboxaldehyde in place of 6-methoxypyridine-3-carboxaldehyde in the process according to Example 29 (ii-iv) gave ethyl 2-formyl (2-methoxy-4-pyridyl) propionate as oily Substance.

Successive treatment of this ester with thione urea and methyl iodide according to the general procedure of Example 1 (i) (ii) gave 5- (2-methoxy-4-pyridylmethyl) -2-methyl-thio-4-pyrimidone and the reaction of this compound at 140 ° for 6 hours with

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

(b) 2- (2-Thiazolalmethylthio) ethylamine

(a) 2- [2- (5-Methyl-4-imidazolylmethylthio) ethylamino] -5- (2-methoxy-4-pyridylmethyl) -4-pyrimidone, mp 177-178 °

(b) 2- [2- (2-Thiazolylmethylthio) ethylamino] -5- (2-metoxy-4-pyridylmethyl) -4-pyrimidone, m.p. 105.5-106.5 °.

B

Claims (10)

631981 2 PATENT CLAIMS 1. Process for the preparation of new compounds of general formula I Het-CH2-Y- (CH2) 2-NH (CII9) ~ tt ~ (CH0) -Het '£ p / J q (I) in which a 2- or 4-imidazolyl group optionally substituted by lower alkyl radicals, halogen atoms, trifluoromethyl or hydroxymethyl groups, a 2-pyridyl group optionally substituted by lower alkyl radicals, lower alkoxy radicals, amino or hydroxyl groups, a 2-thiazolyl group, a 3-isothiazolyl group optionally substituted by chlorine or bromine atoms, a 3- (1,2,5) thiadiazolyl group or a 2- (5-amino-1,3,4-thiadiazolyl) group optionally substituted by chlorine or bromine atoms, Y represents a sulfur atom or a methylene group, Z represents a hydrogen atom or a lower alkyl radical, X represents an oxygen atom and W represents a methylene group, an oxygen or sulfur atom, the sum of p and q has a value from 1 to 4 when W has an oxygen or sulfur atom, or a value from 0 to 4 , when W represents a methylene group and Het 'represents a 5- or o-membered heterocyclic ring 30 which is optionally substituted by lower alkyl or alkoxy radicals or condensed with an optionally substituted benzene ring, and their salts with acids, characterized in that an isocytosine derivative of general formula II IS 20th 25th 35 (CH2> p-lf- (CH2) q-HOt ' (II) 40 in which Z, W, p, q and Het 'have the meaning given above and Q represents a reactive radical which is displaced in the reaction with an amine, have reacted with an amine 45 of the general formula III, and optionally converting the obtained compound into a salt with an inorganic or organic acid. 2. Use of a compound of general formula I in which X represents an oxygen atom for the preparation of a corresponding compound of general formula I in which X represents a sulfur atom, characterized in that the starting material is reacted with phosphorus pentasulfide. 3. The method according to claim 1, characterized in that one uses an isocytosine derivative of the general formula II in which Q represents a methylthio group. 4. The method according to claim 1, characterized in that Het represents a methyl or 2- or 4-imidazolyl group. 5. The method according to claim 1, characterized in that Het is a chloro or bromine substituted 2- or 4-imidazolyl group. 6. The method according to claim 1, characterized in that Het is a 2-pyridyl group substituted by a methyl group. 7. The method according to claim 1, characterized in that Het means a 2-pyridyl group substituted by a methoxy group. 8. The method according to claim 1, characterized in that Het means a 2-pyridyl group substituted by a chlorine or bromine atom. 9. The method according to claim 1, characterized in that Z represents a methyl group. 10. The method according to claim 1, characterized in that Het 'represents an optionally substituted or fused furan, thiophene, thiazole, oxazole, isothiazole or imidazole ring. Het-CH2-Y- (CH2) 2-NH2 (III)