DE2658267A1 - PYRIMID-4-ON AND THIONE DERIVATIVES, THEIR SALT WITH ACIDS, PROCESS FOR THEIR PRODUCTION AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS - Google Patents

Description

SMITH KLIME & FRENCH LABORATORIES LIMITED Welwyn. Garden City, Hertfordshire, England

¹¹ Pyrimid-4-one and thione derivatives, their salts with acids, processes for their preparation and medicinal products containing these compounds "

Priority: December 29, 1975, Great Britain, No. 53001/75

The invention relates to pyrimide - ^ - on and -thione derivatives of general formula I.

4 _s ^ < ^CH ₂ V ^w ~ ( ^CH o) _o -Het '(D

Het-CH ₂ -Y- (CHg) ₂ -NH

in the Het a 2- or il-imidazolyl group optionally substituted by lower alkyl groups, preferably methyl groups, halogen atoms, preferably chlorine or bromine atoms, trifluoromethyl or hydroxyraethyl groups, and a lower group optionally substituted by lower alkyl groups, preferably methyl groups

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Alkoxy radicals, preferably methoxy groups, halogen atoms, preferably Chlorine or bromine atoms, amino or hydroxyl groups substituted 2-pyrydyl group, a 2-thiazolyl group, one optionally 3-Isothiazo'lyl group substituted by chlorine or bromine atoms, a 3- (1,2,5) -thiadiazolyl group optionally substituted by chlorine or bromine atoms or a 2- (5-amino-l ^ i ^ -thiadiazolyl-group Y represents a sulfur atom or a methylene group, Z represents a hydrogen atom or a lower one Alkyl radical, preferably a methyl group, X an oxygen or sulfur atom and V / a methylene group, an oxygen or sulfur atom, the sum of ~ p and q represents a Has a value of 1 to 4 when W is an oxygen or sulfur atom,

Has,

or a value from 0 to H / if W is a methylene group and Het 'is a 5- or 6-membered he-

preferably
terocyclic ring, / represents a pyridine, furan, thiophene, thiazole, oxazole, isothiazole, imidazole, pyrimidine, pyrazine or pyridazine ring, and their salts with acids «

The salts can be from inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, hydriodic acid, Sulfuric acid or maleic acid, derive "

Het is preferably a 2-thiazolyl-, 5-methyl- ¹ ! - imidazolyl-, S-bromo - ^ - imidazolyl-, 3-bromo-2-pyridyl-, 3-chloro-2-pyridyl-, 3-methoxy- 2-pyridyl ~ or 3-hydroxy-2-pyri-

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dyl group. Y is preferably a sulfur atom and X is Oxygen atom and Z a hydrogen atom. In a preferred group of compounds of the general formula I denotes W is a methylene group and ρ and q both have the value 0. Het ' preferably means an optionally by lower alkyl or lower alkoxy substituted 2-furyl, 2-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-thiazolyl, 2-imidazolyl, 2-pyrimidyl, 2-pyrazyl or 3-pyrazyl group. More preferred Het 'means a 2-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl or 2-thiazolyl group. Particularly preferred represents Het 'represents the 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 also tautomeric equilibria with the corresponding mercapto and hydroxy compounds. The pyrimidine group itself can exist in the following tautomeric forms:

Certain heterocyclic radicals Het and Het ¹ can also exist in various tautomeric forms. The present invention relates to all possible tautomeric forms

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"as well as the hydrates and the hydrated salts of the Compounds of the general formula I.

Particularly preferred compounds of the present invention

2-ZT2- (5-methyl-4-imidazolylmethylthio) -äthylamina7-5- ( ¹ J-pyridy imethyl) - ^ l-pyrimidone

2 - / "2- (2-thiazolylmethylthio) ethylamino7-5- (4-pyridylmethyl) -4-pyrimidone

2-ZT2- (3-bromo-2-pyridylmethylthio) -äthylamino_7-5- ⁽ⁱ i-pyridylmethyl) -4-pyrimidone

2- ^ 2- (5-methyl-4-imidazolylmethylthio) -äthylamino7-5- (2-thienylmethyl) -4 -pyrimidone

2- ^ 2- (5-methyl-4-imidazolylmethylthio) -ethylamino7-5- (2-pyridylmethyl) -4-pyrimidone

2-Z2- (5-methyl-4-imidazolylmethylthio) -ethylamino7-5- (3-py ridy lmet hy 1) * -4 -pyrimidone

2- ^ 2- (3-bromo-2- pyridylmethylthio) -ethylamino7-5 "(2-pyridylmethyl) -4-pyrimidone

2- ^ 2- (5-methyl- ⁱ l-iniidazolylniethylthio) -ethylamino7-5- (2-thiazolylmethyl) - ^ - pyrimidone

2-ZT2-C 2-thiazolylmethylthio) ethylaminoJ-5- (3-pyridylmethyl) 4-pyrimidone

2- <f2- (3-Bromo-2-pyridylmethylthio) ethylamine Q7-5- (3-pyridylmethyl) -4-pyrimidone.

The compounds of the general formula I according to the invention, in which X is an oxygen atom, can by reaction

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of an isocytosin derivative of the general formula II

in the Z, W, p, q and Het 'those given in general formula I. Have meaning and Q is a lower alkylthio radical, a benzylthio group, a halogen atom or another reactive Represents a remainder which displaces in the reaction with an amine is, with an amine of the general formula III

Het-CH ₂ -Y- (CH ₂ ) ₂ -NH ₂ (III)

in which Het and Y have the meaning given in general formula I, are prepared. The reaction is preferably carried out without solvent at elevated temperature, for example at 150 ⁰ C, or in the presence of a solvent such as pyridine, at reflux temperature.

The compounds of the general formula I in which W is a sulfur atom means, can also by reacting an isocytosine derivative of the general formula IV

/ <- itt Λ _ tr

(IV)

Het-CH ₂ -Y- (CHg) ₂ -NH - ^ S *

in the Het, Y, Z and ρ indicated in the general formula I. Have meaning and V a mercapto group, a chlorine or Bromine atom means having a compound of general

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Formula V

U- (CH ₂ ) _q -yef (V)

q and
in which ^{1 have} the meaning given in general formula I, U is a mercapto group if V is a chlorine or bromine atom and U is a chlorine or bromine atom if V is a mercapto group, with the proviso that q is only has the value 0 if U represents an activated halogen atom (d, hu in o- or p-position to a heterocyclic nitrogen atom).

The compounds of the general formula I obtained can be obtained by reaction with an inorganic or organic acid be transferred to a salt. The salts are prepared in a manner known per se by reacting the free base with an acid, for example in a lower aliphatic alcohol 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 is a Value of. O to k and Alk is a lower alkyl radical.

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Reaction scheme 1

BM ■ (CH ₂ ) _a CH ₂ CH ₂ COD0 ₂ H ₅ _

1) NaHCOOC ₂ H ₅

(CH ₂ ) _a Het

(V)

N H

(VI)

Alkyl halide or sulfate

AIkS

(VII)

The esters of the general formula V can be prepared by known processes. For example, the compounds of the general formula V, in which a has the value 0, can through
Condensation of an aldehyde of the general formula Het'-CHO with malonic acid in the presence of pyridine and piperidine and subsequent hydration and esterification of the condensation product can be prepared.

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

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ZCOCH ₂ COOc ₂ H ₅

Reaction scheme 2

CH ₂ (CH ₂ ) _a Yeast, HaICH ₂ (CH ₂ ) _a Het * Z-COCHCOOC ₂ H ₅

Thiourea

HN

H ₂ (CH ₂ ) _a yeast

Alc

, Alky ! Halide -suliate

(VIII)

^(CH 2 ^ a ^Het '

The isocytosine derivatives of the general formula II, in which Q is a Halogen atom and W denote a methylene group can be prepared according to Reaction Scheme 3 below, in which Het 'and Z have the meaning given in general formula I. a has a value from 0 to 4 and Hai is a chlorine or Bromine atom means.

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CH ₂ (CH ₂ ) _a Het »ZCOCHCOOC ₂ H ₅

Sodium salt

(IX) "J. - ■

-ar τ

Reaction scheme

Guanidine

(CH ₂ ) _a Het '

1) HCl, NaNO ₂

2) Cu ₀ HaI,

■ 2

HN

.CH "(CH-) Het '

tj Δα.

The isocytosine derivatives of the general formula II, in the W represents an oxygen or sulfur atom, can be prepared according to the following reaction schemes: a) ρ has the value 0

Het '(CH ₂ ) WCH ₂ COOC ₂ H ₅

HN

1) HCO-OC ₅ H ₁ - ^ Na 2 5

2) Thiourea _AlkS Λ _Ν J ₅ ,

3) alkyl halide _: or sulfate

b) ρ has fourth 1. These compounds can be converted into of 3-benzyloxypropionic acid ethyl esters or a similar one, derivative of 3-hydroxyproplonic acid ether provided with a protective group according to the above reaction scheme 1, followed by the removal of the protective group, the Reaction with thionyl chloride and then with the Na-

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trium salt of a compound of the general formula Het (CH _? ) OH or Het '(CH ₂ ) SH.

c) ρ has a value from 2 to

< ^CH 2> p

Ethyl formate sodium

JL CE 0 "Na ⁺ >

1) thiourea

2) alkyl halide or sulfate

(CH ₂ ) _p W (CH ₂ ) _q Het '1) SOCl ₂

(CH ) OH 2 P

2) Het ' (CH ₂ ) 0 "Na ⁺ or Het ¹ (CH ₂ ) _q S ~ Na ⁺

The compounds of general formula I in which X is a sulfur atom means, can by reacting the compounds of general formula I in which X is an oxygen atom, with phosphorus pentasulfide in a solvent such as pyridine. The amines of the general formula III can according to those described in GB-PSs 13 05 5 ^ 7 and 13 38 169 Process are produced.

Many of the substances physiologically active in the body combine with certain,

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sites known as receptors. Histamine is one such substance with a number of biological effects. The biological Receptors commonly referred to as "antihistamines" known compounds such as mepyramine, diphenhydramine and chlorphenirarnine, are blocked by Ash and Schild (Brit. J. Pharmac. Chemother., Vol. 27 (1966), p. 427) as histamine ^ receptors referred to, drugs that reduce the histamine H. receptors block are hereinafter referred to as histamine H. antagonists designated. Another part of the biological effects of histamine is not inhibited by the histamine H. antagonists, Effects of this type, which are inhibited by a compound described by Black et al., (Nature, Vol. 236 (1972), P. 3 & 5) referred to as burimamide, are through receptors which Black et al. call histamine H ~ receptors. So histamine Hp receptors are those histamine receptors that not be blocked by mepyramine, but by burimamide. Compounds that block histamine Hp receptors will be Called histamine Hp antagonists. They act z. B. as inhibitors gastric acid secretion, as anti-inflammatory drugs and on the cardiovascular system, e.g. B, as a blocker of the effects of Histamine on blood pressure. When treating certain diseases, like inflammation, and inhibiting the effects of histamine on blood pressure, is a combination of histamine H. and Hp antagonists useful «. ·

The compounds of the general formula I according to the invention are valuable drugs that are effective both as histamine IL antagonists al3 and as histamine Hp antagonists

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sit. They can therefore be used both in the treatment of diseases in which administration of histamine H ₂ antagonists is useful, as well as of those in which a combination of histamine IL and Hp antagonists is desired.

The compounds of general formula I are histamine H ₂ receptor blockers, that is to say they block the biological effects of histamine which are not blocked by histamine H. antagonists such as i'lepyramine, but are blocked by burimamide. They inhibit, for example, the acid secretion stimulated by histamine in the perfused stomachs of rats anesthetized with urethane at intravenous doses of 0.5 to 16 micromol / kg. The test procedure is described in the Ash and Schild publication cited above. Other effects of histamine which are not caused by histamine H. receptors, such as the effect on the isolated right atrium of the guinea pig and on the isolated rat uterus, are also inhibited by the compounds according to the invention.

The compounds of the invention inhibit the normal secretion of gastric acid as well as that by pentagastrin or ingestion caused gastric acid secretion.

In addition, the compounds of the invention have anti-inflammatory properties Effect as demonstrated in the rat paw test. The volume of the rat paw is determined by subcutaneous administration of a dose a compound of the general formula T. The measuring

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sung of the blood pressure of anesthetized cats shows that the Compounds according to the invention the vasodilating effect of the Inhibit histamine.

The activity of the compounds according to the invention is indicated the 50 percent inhibition of gastric acid secretion in the anesthetized Rat treated with many of the compounds of general formula I according to the invention at doses of 1 to 10 micromol / kg is achieved, and the 50 percent inhibition of histamine-induced TaGh-y cardia in the isolated right atrium of the guinea pig.

The compounds of general formula I are also histamine H. receptor blockers, i. H. they block the biological effects of histamine, by mepyramine, and diphenhydramine Chlorpheniramine blocked «For example, inhibit the invention Compounds the effect of histamine on the isolated ileum of the guinea pig »Many of the invention Compounds of the general formula I inhibit the contractions stimulated by histamine at doses of 10 mol / kg or more of the isolated ileum of the guinea pig.

For therapeutic use, the compounds according to the invention are administered in customary dosage forms, which as Active ingredient at least one of these compounds in the basic form or in the form of a salt with an acid and carriers and / or contain diluents. The carrier material can be solid or liquid. Specific examples of solid carriers

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are kaolin, sugar, talc, gelatin, agar, pectin, gum arabic, Magnesium stearate and stearic acid, examples of liquid Carriers are sugar syrup, peanut oil, olive oil and water.

The compounds according to the invention can be formulated into a wide variety of dosage forms. When using more solid Carriers can take the preparations in tablets, in powder or bulk form filled into hard gelatine capsules or processed into lozenges or candies. The amount of solid support can be lie in a relatively broad range, preferably about 25 mg to 1 g are used. When using a liquid The carrier can be the preparation as a syrup, emulsion, soft gelatin capsule, insect preparation, as aqueous or non-aqueous Suspension to be administered.

The medicaments are by customary methods, such as mixing, granulating, pressing or by dissolving the ingredients in made in the desired shape. They can be given orally or parenterally. The dosage unit preferably contains the Drug in an amount of 50 to 250 mg. The daily dose can be 150 to 15OO mg,

The examples illustrate the invention.

example 1

2-Z ^ - (5-M ethyl-4-imldazolyl methylthio) -ethylamine Q7-5- ( ² pyridy! Methyl) -H -pyrimidone trihydrochloride

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a) A mixture of 5.6 g of sodium wire and 150 ml of anhydrous diethyl ether is cooled in an ice-salt bath and, with stirring, in 6 hours with 43.45 g of ß- (4-pyridyl) propionate and 19.6 g of ethyl formate offset. The resulting mixture is stirred for 18 hours at room temperature, then evaporated to dryness, the residue treated with 18.45 g of thiourea and 130 ml of ethanol and refluxed for 7 hours. The reaction equipment is then evaporated to dryness and the residue obtained is dissolved in water. By adding glacial acetic acid up to pH 4, a colorless precipitate separates out, which is filtered off and washed with ethanol. The 5- (4-pyridylmethyl) ~ 2-thiouracil from P. 320 to 324 ⁰ C (decomp.) Is obtained,

b) A solution of 11.0 g of 5 (4-pyridylmethyl) -2-thiouracil, 7.2 g of methyl iodide and 2.1 g of sodium hydroxide in 50 ml of water and 100 ml of ethanol is stirred for 30 minutes at 60 ° C and then cooled. The precipitate obtained is filtered off and recrystallized from ethanol. It becomes 5 ~ (4-pyridylmethyl) -2-methylthio-4-pyrimidone obtained from P. 179 to 182 ° C.

c) A well-stirred mixture of 5.9 g of 5- (4-pyridylmethyl) -2-methylthio-4-pyrimidone and 4.3 g of 2- (5-methyl-4-imidazolylmethylthio) ethylamine is to 145 to 5 hours 150 ⁰ C. and then cooled, the resulting product is digested with water and then treated with a solution of hydrogen chloride in ethanol. The title compound from P. 228 to 233 ° C. is obtained.

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Example 2

2_-Z2- (2 -ThI azo Iy Ime t hy It hio ) -at hylamino_7-5- (4 -pyrldylme t hy1) .It rPy. ^ Fo A. ^ R "^. ^R A- ^ y tf ^r . ° - Ρ . ^ Λ? ^R ^ - ^ -ft alb hy drat

A well Mulled mixture of 1.55 g of 5 * "(4 ~ pyridylmethyl) -2-methylthio ^ l-pyrimidone and 1.16 g of 2- (2-Thiazolylmethylthio) -ethylamine is with frequent stirring at 135 to 140 ⁰ C. After cooling, the reaction mixture is digested with water, acidified with a dilute solution of hydrogen chloride in ethanol and evaporated to dryness. The residue obtained is recrystallized from methanol. The title compound is obtained with a temperature of 190 ° to 195 ° C. «

Example 3

2 ~ Z2- (3 "3rom-> 2-o, yridylmethylthio) -äth.ylamino7 ^ 5-C ^ -. Pyridyl-meth yl) -4-pyrimidone dihydrochloride

According to Example 2 there are 1.1 g of 5 - (^ - pyridylmethyl) -2-methylthio-4-pyrimidone reacted with 1.15 g of 2- (3-bromo-2 ~ pyridylmethylthio) ~ ethylamine. The reaction mixture obtained is with digested with hot water, acidified with a dilute solution of hydrogen chloride in ethanol and evaporated to dryness. The residue is recrystallized from ethanol. The title compound is obtained with a melting point of 211 to 215 ° C. (decomp.),

Example 4

2 - ^ - (5-Methyl-4-i midazoly lmethylthio) ~ ethylamine p_7-5- (2-thienylmet hyl) ~ ^ -p; / rimidon- dihydrochlo rld

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a) Under cooling in an ice-salt bath 3313 S are 2-Thienylpropionsäureäthylester, 1 * J 1 g of ethyl formate and 2 g of sodium _t K-- reacted in 120 ml Diäthylather. The diethyl ether is then distilled off and the residue is refluxed with 13.8 g of thiourea and 100 ml of ethanol. The ethanol is then distilled off, the residue is dissolved in water and acetic acid is added. The deposited precipitate is recrystallized from ethanol. The 5- (2-thienyl: ethyl) -2-thiouracil from P. 212 to 215 ° C is obtained in 38 percent yield.

b) 5 g of 5- (2-thienylmethyl) -2-thiouracil are heated to 65 ° C. with a mixture of 2.8 g of methyl iodide, 0.3 g of sodium hydroxide, 75 ml of water and 150 ml of ethanol. The 5- (2-thienylmethyl) -2-methylthio- ⁱ l-pyrimidone with a melting point of 170.5 to 171.5 ° C is obtained in 89 percent yield after recrystallization from ethanol,

c) A well-stirred mixture of 1.3 g of 5- (2-thienylmethyl) 2-methylthio-4-pyrimidone and 1.03 g of 2- (5-methyl- ⁱ l ~ imidazolylmethylthio) -ethylamine is brought to 140 for 6 hours ° C heated. 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 is obtained from P. 172-176 ⁰ C in ilOprozentiger yield.

The dihydrochloride is with 1 η hydrobromic acid as running.

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medium sent through an ion exchanger, the eluate becomes evaporated to dryness and recrystallized from a mixture of ethanol and acetonitrile. It becomes the corresponding dihydrobromide obtained from P. 199 to 2O3 ° C.

Example 5

2 '- / "2- (5 · - ^' ^ th.yl ~ ^ -imidazolyl · methylthio) ~ cäthylamino7-5- _ι (2-P _M yridy _i lmethy _< l) - ^ - p yrimidone - trihydro _i chlorine id-ha lbhydrate

a) A mixture of 2.5 g of sodium wire and 80 ml of anhydrous diethyl ether is cooled in a carbon dioxide bath and, while stirring, 19.24 g of ß- (2-pyridyl) propionate and 3.5 g of ethyl formate are added over a period of three quarters of an hour. The mixture is stirred for 21 hours at room temperature, evaporated to dryness, and 8.2 g of thiourea and 70 ml of ethanol are added to the residue and the mixture is refluxed for 7 1/2 hours. The reaction mixture is then evaporated to dryness, the residue is taken up in water and glacial acetic acid is added up 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. There is obtained 5- (2-pyridylmethyl) -2-thiouracil from F. to 267 ⁰ C (dec.).

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 is stirred for 30 minutes at 70 ⁰ C, then cooled and mixed with glacial acetic acid up to a pH value of 5.

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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-pyridylmethyl) -2-> methylthio-4-pyrimidone from P. up to 197.5 ° C.

c) A well-stirred mixture of 4.7 g of 5- (2-pyridylmethyl) -2-methylthio-4-pyrimidone and 3.4 g of 2- (5-methyl-4 ~ imidazolyl ~ methylthio) ethylamine is for 7 hours Heated between 130 and 135 ° C. The reaction mixture obtained is then cooled, digested with hot water and treated with a dilute solution of hydrogen chloride in ethanol. The title compound from P. 207 to 210 ⁰ C is obtained after recrystallization from a mixture of water and ethanol,

Example 6

2-Z2- (5-methyl-4-imldazolylmethylthio) -ethylamino7-5- (3-ftyridy-methyl) -4-pyrimidone trihydrochloride

a) A mixture of 5.0 g of sodium wire and 150 ml of anhydrous diethyl ether is cooled in an ice bath and over 2 1/4 hours 33.9 g of ß- (3-pyridyl) propionic acid ethyl ester and 17.0 g formic acid ethyl ester are added Stirred for 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 are added and refluxed for 8 hours, Then the reaction mixture is evaporated to dryness, the residue dissolved in water and with acetic acid up to one

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pH value of 5 added. The precipitate obtained is filtered off and recrystallized from a mixture of acetic acid and water. The 5- (3-pyridylmethyl) -2-thiouracil from P. 271 to 274 ° C (decomp.) Is obtained.

b) A solution of 11.0 g of 5- (3-pyridylmethyl) -2-thiouracll, 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 for 40 minutes at 65 ⁰ C, then cooled and mixed with acetic acid up to a pH value of 5. Some of the solvent is then 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 from P. 247 to 249 ° C is obtained.

c) A well-stirred mixture of 6.55 g of 5- (3-pyridylmethyl) -2-methylthio-4-pyrimidone and 4.8 g of 2- (5-methyl-4-imidazolylmethylthio) -ethylamine is for 7 hours Heated from 130 to 135 ° C. The reaction mixture obtained is cooled, digested 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 from P. 237 to 241 ° C. is obtained.

Example 7

2-Z2- (3-Bromo-2- nyridylmethylthio ) -ethylamine Q7-5- (2-pyridylmethyl ) -4- pyr1mi don-trihydrobromide

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A well-stirred mixture of 1.5 g of 5- (2-pyridylmethyl) -2-methylthio-'l-pyriiiiidon and 1.6 g of 2- (3-B3? Om-2-pyridylmethylthio) ethylamine is for 6 hours on IjJO ⁰ 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 from P, 225 to 23O ⁰ C (ZerSi) is obtained in 1/2 percent yield.

Example 8 2 - ^ '2- (5-methyl - ^ - imidazolyl: iiethylthio) ethylamine Q7-5- (2-thia-

»A» "n> | 1ll | T ■> Il lllllllfc ■ ■ - * —Mr— ■ It ΠΛ ^ * ¹ " * T-Tl <■ 1 IΊ. ! ■ »! ■ Till Hl WH1 I 111 I II * II Hl III» »IW> ■! ΙΙΠ nYn I WII »■■■ -—I — 1 | M— ■ ■» V »! lM ^ - »MI ^ MMMT» ^ IM »I Kl III I Hl ll'W« | H »I | IH> l || IW

Z O lmet hy 1) - * l -py rimidqn-1 r ihy dro chloride

a) A solution of 26.76 g of 2-thiazole acrylic acid and 10 ml of concentrated Sulfuric acid in 150 ml of ethanol is refluxed for 18 hours, whereupon some of the solvent is removed distilled and the residue diluted with water. The solution obtained is extracted with diethyl ether. The ether extracts are evaporated. The ethyl 2-thiazole acrylate is obtained th,

b) 1ί, 3 g of 2-thiazole acrylic acid ethyl ester iferden in 170 ml Ethanol and dissolved at 40 ° C under a pressure of 3.5 at with 10 Palladium-on-activated carbon hydrogenated to ethyl 2-thiazolpropionate.

c) A mixture of 1.8 g of sodium wire and 65 ml of anhydrous Diethyl ether is cooled in an ice bath and in 2 IM hours under

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Stirring is mixed with 14.2 g of ethyl 2-thiazolpropionate and 5.9 g of alkynyl formate. The resulting mixture is stirred for 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 refluxed for 9 hours. After workup according to Example 5 a) 5- (2-Thiazolmethyl) ~ is obtained 2-thiouracil, mp 275 to 28O ⁰ C (dec.) After recrystallization from acetic acid,

A) A solution of 4.8 g of 5- (2-Thiazolmethyl) -2-thiouracil, 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 for 30 minutes at 70 ⁰ C. After working up according to Example 5 b) and recrystallization from ethanol, 5- (2-thiazolmethyl) -2-methylthio-4-pyrimidone from P. 181 to 182.5 ° C. is obtained.

e) A well-stirred mixture of 1.4 g of 5- (2-thiazolmethyl) -2-methylthio-4-pyrimidone and 1.0 g of 2- (5-methyl-4-imidazolylmethylthio) ethylamine is to 145 to 6 hours 150 ⁰ C heated. 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 from F, 208 to 211 ° C. is obtained.

Example 9

2-Z.2- (2-Thiazolylmethylthlo) -ethylamino7-5-C3-pyridy / methyl) -4-pyrimldon-trihydrobromide "_j

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According to Example 2, 1.7 g of 5- (3-pyridylmethyl) -2-methylthio - ^ - pyrimidone with 1.30 g of 2- (2-thiazolylmethylthio) ethylamine implemented. The resulting reaction mixture 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. It becomes the title compound obtained from P. 229 to 233.5 ° C.

Example 10

2-Z "2- (3-3rom-2-pyridylmethylthib) - ethylamino7" 5 - (3-pyyi dyl m ethyD - ^ - pyrimidone trihydrobromide

According to Example 2, 1.27 g of 5- (3-pyridylmethyl) -2-methylthio- ^ - pyrimidone are reacted with 1.35 g of 2- (3-bromo-2-pyridylmethylthio) ethylamine. The resulting reaction mixture is digested with hot water and treated with dilute hydrobromic acid. The precipitate obtained is filtered off and recrystallized from methanol. There is obtained the title compound, P. 217 to 220.5 ⁰ C.

Example 11 Using

(a) β- (2-Methoxy-3-pyridyl) -propionic acid ethyl ester

(b) β- (3-Methoxy-2-pyridyl) propionic acid ethyl ester

(c) .beta. (3, ¹ J-dimethoxy-2-pyridyl) -propionsäureathylester

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

(e) β- (4-Isoquinolyl) propionic acid ethyl ester

instead of ß- (4-pyridyl) propionic acid ethyl ester are according to

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Example 1 obtained the following products:

(a) 2- ^ 2- (5-methyl-4-imida2olylraethylthio) -ethylamino7-5- (2-methoxy-3-pyridylmethyl) -4-pyrimidone

(b) 2-ZT2- (5-methyl-4-imidazolylmethylthio) -ethylaminoJ-5- (3-methoxy-2-pyridylmethyl) -4-pyrimidone

(c) 2-Z2- (5 ^ ethyl-4-imidazolylmethylthio) -äthylamino7-5-3, ⁱ i-dimethoxy-2-pyridy! methyl) -4-pyrimidone

(d) 2-r2- (5-methyl-4-imidazolylmethylthio) -ethylamino7-5 ~ (3-quinolylmethyl) -4-pyrimidone

(e) 2-Z2- (5-methyl-4-dmidazolylmethylthio) -äthylamino7-5 - (^ -isoquinolylmethyD - ^ - pyrimidone.

The starting compounds used above can be obtained from the corresponding heterocyclic carboxaldehydes by condensation with malonic acid and subsequent hydrogenation and "esterification getting produced.

Example 1 12
When using

(a) 2- (2-Imidazolylmethylthio) ethylamine

(b) 2- (4-imidazolylmethylthio) ethylamine

(c) 2- (5- ^Bromo-i l-imidazolylinethylthio) -ethylamine

(d) 2- (5-Trifluoromethyl-4-imidazolylmethylthio) -ethylamine

(e) 2- (5-Hydroxymethyl-4-imidazolylmethylthio) ethylamine

(f) 2- (2-pyridylmethylthio) ethylamine

(ε) 2- (3-Hethyl-2-pyridylmethylthio) ethylamine
(h) 2- (3-methoxy-2-pyridylmethylthio) ethylamine
(i) 2- (3-chloro-2-pyridylmethylthio) ethylamine

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Cj) 2- (5-amino-2-pyridylmethylthio) ethylamine

(k) 2- (3-Hydroxy-2 "pyridylinethylthio) ethylamine

(1) 2- (3-isothiazolylmethylthio) ethylamine

(m) 2- (4-Bromo-3-isothiazolylmethylthio) ~ ethylamine

Cn) 2- .β- (1,2,5) -thiadiazolylmethylthio_7-ethylaniine

(0) 2- £ i-chloro-3- (1,2,5) -thiadiazolylmethy lthioj-ethylamine * Cp) 2-Z5-aniino-2- (1,3, ^J! ») -ThiadiazolylraethylthiQ7-ethylamine

instead of 2- (5-methyl - ^ - i: nida2olyl: nethylthio) -ethylamine according to example 6 the following products are obtained:

Ca) 2- £ 2- (2-IraidazolyL-nethylthio) -ethylamine Q7-5- (3-pyridylmethyl) -H -pyrimidone

(b) 2-Zr2- (M "imidazolylmethylthio) ethylaTTiino7-5 ~ (3-pyridylmethyl") ^-1 I -pyrimidone

(c) 2-Z2- (5-3rom-4-iniidazoly'lmethylthio) -äthylaniinq7-5- (3-pyridylmethyl) - ¹ J-pyrimidone

(d) 2- / T2- (5-trifluoromethyl-i | -imidazolylmethylthio) -ethylaminoJ-5-C 3-pyridylmethy 1) - ^ -pyrimidone

(e) 2-ZT2- (5-hydroxymethyl- ⁱ l-iniidazolylmethylthio) -ethylamino7-5- (3-pyridylinethyl) -4-pyrimidone

Cf) 2- / 2- (2-pyridylmethylthio) ethylamino7-5- (3-pyridylmethyl) -4-pyrimidone

(g) 2- / 2- (3-Methyi_2-pyridylmethylthio) -äthylamino7-5- (3-pyridylmethyl) -4-pyrimidone

(h) 2- / r2- (3-methoxy-2-pyridylmethylthio) -ethylamino7-5- (3-pyridylmethyl) -4-pyrimidone

(1) 2- ^ 2- (3-chloro-2-pyridylmethylthio) ethylamino7-5- (3-pyridy! Methyl) -4-pyrimidone

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(j) 2-ZT2- (3-amino-2-pyridylmethylthio) -äthylamino7-5- (3-pyridylmethyl) - ⁱ l-pyrimidone

(k) 2- / 2- (3-Hydroxy-2-pyridylmethylthio) -äthylaminoJ-5-

(3-pyridylmethyl) -H -pyrimidone
(1) 2-ZT2-C 3-isothiazolylmethylthio) -äthylamino7-5- (3-pyridyl-

methyl) - ² J-pyrimidone
(m) 2-ZT2- (4-bromo-3-isothiazolylmethylthio) -ethyla: ninq7-5- (3-pyridylmet hy 1) - ^! - pyrimidone

(n) 2- [2-Z3- (1,2 _i 5) -thiadiazolylmethylthio7 ~ ethylamino] -5-

(3-pyridylmethyl) -JJ-pyrimi'don
(o) 2- [2-A-chloro-3- (l _i 2,5) -thiadiazolylmethylthioJ-ethyl-

aminq3 ~ 5- (3-pyridylmethyl) - ^ - pyrimidone (p) 2- {2 - ^ - Amino-2- (1,3, ^) -thiadiazolylmethylthioj-ethylamino \ -5 - "(3-pyridylmethyl) ~ 4-pyrimidone.

Example 13

a) The reaction of 2-chloro-3-nitropyridine with 2- (2-cyanoethyl) malonic acid diethyl ester and sodium hydride in tetrahydrofuran gives the l- (3-nitro-2-pyridyl) -l _> l-bis- (carbethoxy) - butyronitrile from F, 93.5 to 9.5 ° C. The 2- (3-cyanopropyl) -3-nitropyridine hydrochloride with a temperature of 1 ^ 2 to 1 ^ 5.5 ° C. is obtained therefrom by alkaline hydrolysis and subsequent acidification. This compound is hydrogenated with hydrogen on palladium-on-charcoal to give 3-amino-2- (3-cyanopropyl) pyridine. The product obtained is treated with sodium nitrite and sulfuric acid and then heated. The obtained 2- (3-cyanopropyl) -3-hydroxypyridine is methylated with methyl iodide and sodium ethylate in dimethyl sulfoxide and then with lithium aluminum

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hydride reduced to 4- (3-methoxy ~ -2-pyridyl) butylamine. The reduction of 3-amino-2- (3-cyanopropyl) -3-hydroxypyridine with lithium aluminum hydride gives the ^ - (3-amino-2-pyridyl) butylarain. This compound is diazotized at pH 1 and then treated with copper (I) chloride or with copper (I) bromide. The ⁱ l- (3-chloro-2-pyridyl) butylamine or 4- (3-bromo-2-pyridyl) butylamine are obtained.

b) The use of

(a) h - ( ¹ J -imidazo IyI) -butylamine

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

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

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

(e) ^ - (3-Amino-2-pyridyl) butylamine

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

(a) 2-Z3- ( ⁱ <-imidazolyl) -butylamino_7-5- (3-pyridylmethyl) -4-pyrimidone

(b) 2-Z ⁷ l- (3-methoxy-2-pyridyl) -butylamino _? - 5- (3-pyridylmethyl)

4-pyrimidone

(c) 2-Z? * - (3-chloro-2-pyridyl) -butylamino7-5- (3-pyridylmethyl) -

^ -pyrimidone

(d) 2-Z7 »- (3-Bromo-2-pyridyl) -butylamino7-5- (3-pyridylmethyl) 4-pyrimidone

(e) 2-Z? l- (3-Amino-2-pyridyl) -butylamino7-5- (3-pyridylmethyl) -4-pyrimidone.

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Example 14

By reacting ethyl acetoacetate with sodium ethoxide and 3- (chloromethyl) pyridine, the o (- (3-pyridylmethyl) -acetoacetic acid ethyl ester is obtained, which in the reaction with thiourea and sodium ethoxide gives 5- (3-pyridylmethyl) -6-methyl -2-thiouracil, the use of 5 ~ (3-pyridylmethyl) -6-methyl-2-thiouracil in place of 5- ⁽ⁱ * ~ pyridylmethyl) -2-thioura ~ eil obtained according to example 1, the 2 -. / "2 - (5-Methyl- ⁱ -imidazolylmethylthio) -äthylamino7-5- (3-pyridy! Methyl) -6-methyl- ⁱ J-pyriniidont By using iithylbutyroate, the 2-Z2- (5- Methyl-4-imidazolylmethylthio) -äthylamino_7-5 - (3-pyridylmethyD-o-propyl-Ji-pyrimidon are produced.

Example 15

The reaction of 2-ZT2- (5-Methyi- ⁱ f-imidazolylmethylthio) ethyl ~ amino7-5- (3-pyridylniethyl) - ⁱ l-pyrimidone with PhosphGrpentasulfid in hot pyridine gives 2- / f2- (5-methyl - ⁱ l-imidazolylmethyl-thio) -äthylamino7-5- (3-pyridylmethyl) -pyrimid- ⁱ i "thione.

Example 16

a) Butyrolactone is reacted with sodium and ethyl formate, and the product obtained is treated successively with thiourea and with methyl iodide. The 5- (2-hydroxyethyl) -2-methylthio- ² i-pyrimidone is obtained.

b) The 5- (2-hydroxyethyl) -2-methylthio-4-pyrimidone is with Thionyl chloride treated. The product obtained is treated with the sodium derivative of (a) 3- (hydroxymethyl) pyridine and (b) 3-

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(Mercaptomethyl) ~ pyridine reacted, P ^ s are ate the following products obtain:

(a) 5- (2- (3-pyridylmethoxy) -ethyl) -2 -: methylthio-4-pyrimidone

(b) 5- (2- (3-pyridylmethylthio) ethyl) -2-methylthio-i) pyrimidone.

c) The use of

(a) 5- (2- (3-Pyridylmethoxy) ethyl) -2-methylthiü-1-pyrimidone

(b) 5- (2- (3-pyridylmethylthio) ethyl) »^ -methylthio-iJ-pyrimidone instead of 5- (3-pyridylmethyl) -2-methylthio- ⁱ l - pyrimidone gives according to example ο the following ' nd products:

(a) 2-Γ2- (5-methyl-il »imidazolylmethylthio) -ethylarainQ7-5 ··· (2- (3-pyridylinethoxy) ethyl) -4-pyrimidone

(b) 2-ZT2- (5-methyl- ' ⁱ i-iiiiidazolylmethylthio) -äthyla2nino7 ~ 5 ~ (2- (3-pyridylmethylthio) ethyl) - ^ - pyrimidone »

d) The use of

(a) 3-hydroxypyridine and

(b) 3-mercaptopyridine

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

(a) 2 - ^ - (5-Methyl ~ 1-imidazolylmethylthio) -äthylaminoJ-5- (2 - (3-pyr ^> ldyloxy) -ethyl) ~ 4-pyrimidone

(b) 2 - / "2- (5-Methyl-i | -imidazolylmethylthio) -äthylaraino7-5 · ' (2- (3-pyridylthio) -ethyl-4-pyrimidone,

e) The use of

(A) 3- (2-hydroxyethyl) pyridine and

(b) 3- (2-mercaptoethyl) pyridine

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* ob ^

instead of 5- (hydroxymethyl) pyridine gives according to Example 16 b) and c) the following products:

(a) 2-ZT2- (5-methyl-4-imidazolylmethylthio) -äthylaminq7-5- \ 2-r2- ( 3 ~ pyridyl) -ethoxy_7-ethy 1} -Ί -pyrimidone

(b) 2- £ 2- (5-Methyl-i | -iraIdazolylmethylthio) -äthylaniinci7-5-

[2- £ 2- (3-pyridyl) ethylthio / ethyl / -4 ~ pyrimidone.

f) The use of caprolactone instead of butyrolactone gives the following products according to Example 16 a), b) and c)

(a) 2- / 2- (5-Methyl- ^ l-Iniidazolylniethylthio) -äthylarainQ7-5-Z3- (3-pyridylinethoxy) -propyl7- '<- pyrimidone

(b) 2-Z ~ 2- (5-Methyl-i) -imidazolylmethylthio) -äthylamino7-5- / 3- (3-PyTiUyIrHCtIIyItIIiO) -PrOPyI ₁ ? - ^ - pyrimidone.

Example 17

According to Example 1 a) is from 3 ~ pyridylmethoxyacetic acid ethyl ~ ester the 5- (3-pyridylmethoxy) -2-thiouracil prepared. the Using 5- (3-pyridylmethoxy) -2-thiouracil instead of 5 - (^ - pyridylmethyl) -2-thiouracil gives according to Example 1 that 2-zT2- (5-methyl-4-imidazolylmethylthio) -ethylamino7-5-5 (3-pyridyl methoxy) -4-pyrimidone 4

When using 3- (3 ~ pyridyl) -propoxyessigsäureäthylester or 3- (3-pyridyl) -propylthioglykolsäureäthylester can similarly 2- _<f2- ^(5-methyl-i i-imidazolylmethylthio) -äthylaminQ7-5-iT3- (3-pyridyl) -propoxy7-4-pyrimidone or the 2-Z ^ - (5-methyl - ^ - imidazolylmethylthio) -. EthylamineQ7-5 ~ yT3- (3-pyri-

- ^ - pyrimidone are produced,

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Example 1 8 The use of:

(a) ß- (2 ~ Furyl) -propionic acid ethyl ester

(b) ß- (5 ~ oxazolyl) -propionic acid ethyl ester

(c) ß- (3-Isothiazolyl) propionic acid ethyl ester

(d) ß- (2-Pyriraidyl) -propionic acid ethyl ester

(e) ß- (5-Pyrimidyl) ~ propionic acid ethyl ester

(f) ß- (2-pyrazyl) propionic acid ethyl ester

(g) ß- (4-Pyridazyl) ~ propionic acid ethyl ester

instead of ß ~ (4-pyridyl) propionic acid ethyl ester is obtained according to example 1 the following products:

(a) 2-Z2- (5-methyl-4 ^ imidazolylmethylthio) -ethylamino7-5- (2-furylmethyl) -4-pyrimidone ·

(b) 2-Z2- (5-methyl-i | -imidazolylmethylthio) -äthylamino7-5 - (2-oxazolylmethyl) - f ^i-pyriraidon

(c) 2-ZT2- ^(5-methyl-i} -imidazolylmethylthio) -äthylamino7-5- (3-isothiazolylmethyl) - ⁱ l-pyriniidon

(d) 2- ^ 2- (5-methyl-i) -imidazolylmethylthio) -ethylarainoJ-5- (2-pyrimldylmethyl) -4-pyrimidone

(e) 2-Z2- (5-methyl- ^ - imidazolylmethylthio) -äthylaminq_7-5- (5-pyrimidylmethyl) - ^ -pyrimidone

(f) 2- _/ r2- (5 ~? 4ethyl- ⁱ l-iniidazolylmethylthio) -ethylamino7-5-C2-pyrazylmethyl) -4-pyrimidone

(g) 2- / 2- (5-methyl-il-iraidazolylmethylthio) -äthylamino7-5- (4-pyridazylmethyl) - '{- pyrimidone.

The output connections (b) to (g) used above can by condensing the corresponding heterocyclic

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Carboxaldehydes are prepared with malonic acid and subsequent hydrogenation and esterification of the product obtained.

Example 19

Reaction of 1- ( ⁱ -methoxybenzyl) -2-imidazole-carboxaldehyde with malonic acid in the presence of pyridine and piperidine gives 2 ~ £ L ~ (4-methoxybenzyl) -imidazolyl7 ~ acrylic acid. The use of 2- / Ί - ('I-jiethoxybenzyl) -imidazolylT-acrylic acid instead of 2-thiazole acrylic acid gives, according to Example 8, after cleavage of the protective group with anisole and hydrogen bromide in acetic acid, the 2-Z2- (5-methyl-4 -iraidazolylmethylthio) -äthylarninoJ'-5- (2 - imidazolylTiethyl) - ⁱ l-pyrimidon «

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Claims (1)

Pa t e η ta η S ₁ ρ rü che 1, pyrimid-4-one and -thiön derivatives of the general formula I. (CH ₂ ) _p -W- (CH ₂ ) _q -Het ' (D He t-CH _o -Y- (CH, in the Het a 2- or k -imidazole group optionally substituted by lower alkyl groups, preferably methyl groups, halogen atoms, preferably chlorine or bromine atoms, trifluoromethyl or hydroxymethyl groups, an optionally substituted by lower alkyl groups, preferably methyl groups, lower alkoxy groups, preferably methoxy groups, halogen atoms , preferably chlorine or bromine atoms, amino or hydroxyl groups substituted 2-pyridyl group, a 2-thiazolyl group, a 3-isothiazolyl group optionally substituted by chlorine or bromine atoms, a 3- (l, 2,5) optionally substituted by chlorine or bromine atoms ~ Thiadiazolyl group or a 2- (5 ~ amino-l, 3i ^ -thiadiazolyl) group, Y is a sulfur atom or a methyl group, Z is a hydrogen atom or a lower alkyl radical, preferably a methyl group, X is an oxygen or sulfur atom and W is Represents a methylene group, an oxygen or sulfur atom, the sum of ρ and q has a value from 1 to k , we nn W is an oxygen or sulfur atom, or a value Has,
from 0 to 4 / if W denotes a methylene group and Het ¹ denotes a 5- or 6-membered heterocyclic ring which is optionally substituted by lower alkyl or alkoxy groups or condensed with an optionally substituted benzene ring, preferably 709827/1085 ORIGINAL INSPECTED a pyridine, furan, thiophene, thiazole, oxazole, isothiazole, Represents imidazole, pyrimidine, pyrazine or pyridazine ring, so; ie their salts with · acids » 2, pyrimidone derivatives according to claim 1 of the general formula I, in the Het 'an optionally by lower alkyl or alkoxy radicals substituted or with an optionally substituted benzene ring fused pyridine, furan, thiophene », Thiazole, oxazole, isothiazole, imidazole or pyrimidine group means. 3. Compounds according to claim 1 or 2 of the general formula I, in which Het is a 2-thiazolyl, 5- " ^v iethyl- ⁱ J-imidazolyl-, 5-bromo - ^ - imidazolyl-, 3-bromo-2-pyridyi -, 3-chloro-2-pyridyl, 3-methoxy-2-pyridyl or 3-hydroxy-2-pyridyl group. 4, compounds according to claims 1 to 3 of the general formula I, in which Y is a sulfur atom. 5. Compounds according to claim 1 to H of the general formula I, in which X is an oxygen atom. 6, compounds according to claims 1 to 5 of the general formula I ₁ in which Z is a hydrogen atom. 7. Compounds according to claim 1 to 6 of the general formula I, in which W is a .Methylene group and ρ and q both have the value 0. J 709827/1085 8, compounds according to claims 1 to 7 of the general formula I, in which "a possibly by lower alkyl or alkoxy substituted 2-furyl, 2-thienyl, 2-pyridyl, 3-pyridyl-, ^ -pyridyl-, 2-thiazolyl-, 2-imidazolyl-, 2-pyri'nidyl-, 2-pyrazyl or 4-pyridazyl group means « 91 Compounds according to claim 8 of the general formula 1, in yeast is a 2-thienyl, 2-pyridyl, 3-pyridyl, ii-pyridyl or 2-thiazolyl group. 10. Compounds according to claim 9 of the general formula I in the yeast is a 3-pyridyl group, 11. 2-ZT2- (5-methyl - ^ - imidazolylmethylthio) -äthylaminoJ-5 - (^ l -py ridylmct hy 1) -M -py rimidon « 12. 2-Z ^ - (2-Thiazolylmethylthio) -äthylamino_7-5 - ('4-pyridylmethyl) ^-1 I -py rimidon « 13. 2-A2- (3-bromo ~ 2 ~ pyridylmethylthio) -äthylamino7-5- ( ¹ l-pyridylmethyl) - ^ - pyrimidone, IiJ. 2- / r2- (5-Methyl-4-imidazolylTiiethylthio) -äthylamino_7-5- (2-thienylrnGt hy 1) -4 ~ py rimidon, 15. 2-Z2- (5-methyl-4-imidazolylmethylthio) -ethylamine7-5- (2 "pyridy! Methyl) -4-pyri 709827 / 10.8S 16 2- / 2- (5-methyl-4-imidazolylmethylthio) -äthylamino7-5- ^(3-pyi> idylmethyl) - ⁱ i-pyriniidon. 2- / 2- (3-bromo-2-pyr ± dylraethylthio) -äthylamino7-5- (2- -4-pyrimidone. 18. 2-Z72- (5-> iethyl-4-imidazolylmethylthio) -ethylamino7-5- (2-thiazolylmethyl) - ⁱ l-pyriniidone. 19. 2- £ 2- (2-Thiazolylmethyltftio) -äthylamino7-5- (3-pyrIdylmethyl) -4-pyrimidone, 20. 2- / 2- (3-Bromo-2-pyridylmethylthio) -äthylaraino7-5- (3-pyridylmethyl) -4-pyrimidone " 21. A process for the preparation of the compounds according to claim 1, characterized in that. man a) for the preparation of the compounds of general formula I, in which X is an oxygen atom, an isocytosine derivative of the general formula II ^(CH 2 y ^w - ^(CH 2 V ^Het ' in the Z, W, p, q and Het 'the meaning given above and Q represents a lower alkylthio radical, a benzylthio group, a halogen atom or another reactive radical, which is displaced during the reaction with an amine, 709827/1085 with an amine of the general formula III ... Het-CH ₂ -Y- (CH ₂ ) ₂ -NH ₂ . ... (III) in which Het and Y have the meaning given above, b) for the preparation of the compounds of the general formula I ₁ in which X is a sulfur atom, the compound of the general formula I in which X is an oxygen atom is reacted with phosphorus pentasulfide and optionally the compound obtained according to a) or b) converted into a salt with an inorganic or organic acid. 22 *. Method according to claim 21, characterized in that an isocytosine derivative of the general formula II is used, in which Q is a methylthio group. 23 «Process for the preparation of the compounds according to claim 1 of the general formula I, in which W is a sulfur atom and X is Oxygen atom means, characterized in that either a) an isocytosine derivative of the general formula IV P HetCH ₂ Y (CH ₂ ) ₂ NH 709827/1085 in which Het, Y, Z and ρ is as defined above and have V represents a mercapto group, ^w ith a compound of general Foriael V is reacted U (CH ₂ ) _q Het '(V) in which q and Het 'have the meanings given above and U represents a chlorine or bromine atom, with the proviso that q only has the value 0 if U is an active halogen atom or / b) an isocytosine derivative of the general formula IV, in which Het, Y, Z and ρ have the meanings given above and V represents a chloro- or bromatoin, is reacted with a compound of the general formula V in which q and Het ¹ die have the meaning given above and U represents a mercapto group. 24. Medicines with histamine H and H ^ receptor blocker effects, characterized by a content of a compound according to Claims 1 to 20. 709827 / 108S