DE2643670A1 - PYRIMID-4-ON AND THIONE DERIVATIVES, THEIR SALT WITH ACIDS, PROCESS FOR THEIR PRODUCTION AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS - Google Patents

Description

SMITH KLINE & FRENCH LABORATORIES, LTD. Welwyn Garden City, Hertfordshire, England

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

Priority: October 2, 1975, Great Britain, No.

3 ^ 1/75

In GB-PS 1 419 994 there are pyrimid-4-one and thione derivatives the general formula

R-HH "^ N

■ 1

described, in which X is an oxygen or sulfur atom, Y and

2
Y are hydrogen atoms, lower alkyl, aryl or aralkyl radicals with the same or different meaning, and R is a radical of the general formula

Het-CH ₂ Z (CH ₂ )

709815/1 198

means, in the Het a possibly by lower alkyl «
radicals, halogen atoms, amino or hydroxyl groups substituted, nitrogen atoms containing heterocyclic radical, such as an imidazole, pyridine, thiazole, isothiazole or thiadiazole group,

represents and Z is a sulfur atom or a methylene group

and η is 2 or 3.

tet / Also are tautomers of these compounds and their effectiveness described as histamine Hp antagonists "

It has been found that a certain group of compounds, some of which fall within the definition of the general formula above, has certain advantages over the remainder of the group of compounds of the general formula above. These particular connections have a larger one
Effectiveness as histamine Hp antagonists than the other compounds of the above general formula, and are moreover
in addition to their effectiveness as histamine Hp antagonists also as
Histamine H ^ antagonists effective.

The invention accordingly relates to pyrimid-4-one and -thione derivatives of the general formula I.

(CH ₂ ) _m W (CH ₂ )

". (D

Het'-CH ₂ ZCH ₂ CH ₂ -NH

in the Het 'one optionally by lower alkyl radicals, preferably Methy groups, halogen atoms, preferably chlorine - or Bromine atoms, trifluoromethyl or hydroxymethyl groups substituted 2- or 4-imidazolyl group, an optionally by lower

70981R / 1198

re alkyl radicals, preferably methyl groups, lower alkoxy radicals, preferably methoxy groups, halogen atoms, preferably _{chlorine or bromine atoms, amino or hydroxyl groups substituted 2-pyridyl group 8} a 2-thiazolyl group, a 3-isothiazolyl group optionally substituted by chlorine or bromine atoms, an optionally substituted by chlorine or bromine atoms Bromine atoms is a substituted 3- (1,2,5) -thiadiazolyl group or a 2- (5-amino-1,3,4-thiadiazolyl) group, Z is a sulfur atom or a methylene group, X is an oxygen or sulfur atom, W a methylene group, an oxygen or sulfur atom and Y a hydrogen atom or a lower alkyl radical, the sum of m and η has a value from 1 to 4, if W denotes an oxygen or sulfur atom, or has a value from O to H , when W denotes a methylene group and A denotes a 1- or 2-naphthyl, a 2,3-dihydro-1,4-benzodioxinyl or a 1,3-benzodioxolyl group or a group by at least one lower alkyl, lower alk represents oxy, arylalkoxy, alkoxyalkoxy, di-lower alkylamino, halophenoxy, alkoxyphenoxy, halophenyl or alkoxyphenyl radical or a halogen atom or at least one hydroxyl, trifluoromethyl, phenoxy or phenyl group, which can also be unsubstituted, when the remainder - (CHp) W (CHp) is not a methylene group, and its 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.

The "lower alkyl radicals" contain 1 to H carbon atoms.

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Het is preferably a 2-thiazolyl-, 5-methyl-4-imidazolyl-, S-bromo- ^ - imidazolyl-, 3-bromo-2-pyridyl-, 3-chloro-2-pyridazolyl-, 3-chloro-2-pyridazolyl-, 3-methoxy ~ 2-pyridyl or 3-hydroxy-2-pyridyl group. Z is preferably a sulfur atom, X is an oxygen atom and Y is a hydrogen atom. A preferably denotes a phenyl group substituted by at least one lower alkoxy group, a 2,3-dihydro-l _i ⁱ l-benzodioxinyl or 1,3-benzodioxolyl group, since the compounds of the general formula I in which A has this meaning are present distinguish the remaining compounds of general formula I by advantageous solubility properties.

Preferably m and η have the value 0 and W denotes a methylene group. In a further preferred group, m preferably has the value 0 and η the value 1 and W denotes an oxygen atom,

Particularly preferred compounds of the present invention

2- £ 2- (5-methyl-4-imidazolylmethylthio) -äthylaminoJ-5-C4-chlorobenzyl) -4-pyri: nidon

2- / 2- (2-Thiazolylmethylthio) -äthylaminoJ-5 ~ ⁽ⁱ i-chlorobenzyl) -4-pyrimidone

2-Z2- (3-bromo-2-pyridylmethylthio) -ethylamino_7-5- (4-chlorobenzyl) -4-pyrimidone

2-Z2- (5-Methyl - ^ - imidazolylmethylthio) -äthylamino_7-5 - (^ - chlorbenzyD-6-methyl - ^ - pyrimidone

2-Z2- (5-methyl-1-imidazolylmethylthio) -ethylamino_7-5- (3-chlorobenzyl) - ^ - pyrimidone

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2-Z2- (5-methyl-4-imidazolylmethylthio) -ethylamino7-5- (3,4-dichlorobenzyl) -4-pyrimidone

2- / 2- (5 »methyl-4-imidazolylmethylthio) -ethylamino7-5- (4-methoxybenzyl) -4-pyrimidone

2- £ 2- (5-methyl-4-imidazolylmethylthio) -äthylaminq7-5- (4 -methylbenzyl) -4-pyrimidone

2-Z. "2- (5-Methyl-il-imidazolylmethylthio) -äthylainino7-5- (2-phenyläthy1) -4-pyrimidone

2-Zr2- (5-methyl-i | -imidazolylmethylthio) -ethylamino_7-5- (2-phenylethyl) ~ 6-methyl- ⁱ l-pyrimidone

2 - / "2- (5-Methyl- ^ ~ imidazolylmethylthio) -äthylamino7-5-benzyloxy- ^ -pyrimidone

2-ZJ2- (5-Methyl-i} -imidazolylmethylthio) -äthylamino7-5- (3-methoxybenzyl) - * J-pyrimidone

2-C2 " (5-methyl-4-imidazolylmethylthio) -ethylamino_7-5- (2-chlorobertzyl) -4-pyrimidone

2-Z2- (5-methyl-4-imidazolylmethylthio) -ethylaniine Q7-5- (4-phenylbutyl) -4-pyrimidone

2-Zr2- (5-methyl-4-imidazolylmethylthio) -ethylaminoJ-5-Z5- (1,3-benzodioxolyl) -methyU-4-pyrimidone

2 - /! ^ - (5-Met hy 1-4-imidazolylmethylthio) -äthylamino_7-5- (3-ethoxybenzyl) -4-pyrimidone

2-ZT2- (5-methyl-4-imidazolylmethylthio) -ethylamineq7-5- (3-benzyloxybenzyl) -4-pyrimidone

2-Z'2- (5-methyl-4-imidazolylmethylthio) -ethylamino7-5- (inaphthylmethyl) -4-pyrimidone.

The pyrimid-4-one and thio derivatives of the general formula I.

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are in tautomeric equilibrium with the corresponding pyrimide 6-on and 6-thione derivatives. To a lesser extent, tautomeric equilibria exist with the corresponding mercapto and hydroxy compounds. The pyrimidine group itself can exist in the following tautomeric forms:

The heterocyclic radical Het 'can also be in different tautomeric forms exist. The present invention relates to all possible tautomeric forms

The compounds of the general formula I ₁ according to the invention in which X is an oxygen atom can be prepared by reacting an amine of the general formula II -

Het'-CH ₂ ZCH ₂ CH ₂ NH ₂ (II)

in which Het ¹ and Z have the meaning given in general formula I, with a pyrimid-JJ-one derivative of general formula III

Y ³

in which Y ^, m _# W, η and A have the meaning given in general formula I and Q is a lower alkylthio radical _t a

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Benzylthio group, a halogen atom or another reactive radical which displaces on reaction with an amine will be produced. The reaction is preferably carried out without a solvent at about 150 ° C. or in the presence of a solvent such as pyridine, carried out at the reflux temperature.

The compounds of general formula I obtained can be converted into a by reaction with an inorganic or organic acid Salt to be transferred. The salts are prepared in a manner known per se by reacting the free base with a Acid for example in a lower aliphatic alcohol or with an anion exchanger.

The pyrimid-4-one intermediates of the general formula III, in the W a methylene group, Y a hydrogen atom and Q a lower one Mean alkylthio radical can according to the reaction scheme below 1 are prepared, in which A has the meaning given in general formula I, a has a value from 0 to 4 and Alk is a lower alkyl radical.

Scheme 1.

^: PH

A (CH ₂ ) _a CH ₂ CH ₂ COOC ₂ H ₅ 1) Na, HCOOC ₂ H ₅ P ¹

»^" W ₀ V 2) thiourea ^H

AlkylhÄlogenid ir or sulphate

709815/1198 _VI

The esters of the general formula IV ₁ in which a has the value 0 can be prepared by condensation of an appropriately substituted benzaldehyde with malonic acid and subsequent hydrogenation and esterification of the condensation product.

The pyrid-'l-one intermediates of the general formula III, in the W a methylene group, Y ^ a lower alkyl radical and Q mean a lower alkylthio radical can be prepared according to the following reaction scheme 2, in which A is the in the General formula I has the meaning given, a has a value from 0 to 4, Hal is a chlorine or bromine atom and Alk has a lower one Mean alkyl radical.

Scheme 2

CH ₂ (CH ₂ ) _a A

Y ³ -COCH ₂ XOOC ₂ H ₅ NaOC ₂ H ₅ , HaICH ₂ (CH ₃ ) _& AY ³ -COCHCOOC ₂ H ₅

Thiourea

Ϋ ³

Alkyl halide 1

(CH ₀ ) A or sulfate mf ^ V ^CH 2 ^CCH 2 ^; a ^A

r Δ α s

VII I J ^

AIkS ^ N ^ o _H

The pyrid-JJ-one intermediates of the general formula III, in which Q is a halogenafcom, can be prepared according to reaction scheme 3 below, in which A and Ί / have the meaning given in general formula I, a has a value of 0 to h and Hai means a chlorine or bromine atom.

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VIII
CH ₂ (CH ₂ ) _a A

Y ³ COCHCOOC ₂ H ₅

Nat rl ums al ζ

Scheme 3

guanidine

1) HCl, NaNO _r

2) Cu ₃ HaI ₂

The compounds of the general formula VIII, "in the Y ^ a Wasserst off atom means, can by reacting an ester of the general formula IV can be prepared with sodium and ethyl formate. The compounds of the general formula VIII, in which Y ^ is a lower alkyl radical, according to the reaction scheme 2 can be produced.

The pyrimid-JJ-one intermediates of the general formula III, in the W denotes an oxygen or sulfur atom can be prepared according to the following reaction schemes:

a) m has the value O

7 0 9 815/1 198.

A (CH ₀ ) WCH ₀ COOC ₀ H

1) HCOOC ₀ H ^ -Na

2) Thiourea AIkS

3) alkyl halide or sulfate

W (CH ₉ ) A ^{2 n}

b) m has the value 1

These compounds can be prepared according to the following reaction scheme be asked:

CH ₂ OH

I) SOCl ₂ or HBr

2) A (CH ₂ ) _n 0 ~ Na ⁺ or A (CH ₀ ) S ~ Na ⁺

H,

1)

2) Cu HaI

HH
Λ

Another production process for these compounds is via the implementation of ^ -Benzyloxybuttersaureäthylester or a similar derivative of ethyl 4-hydroxybutyrate provided with a protective group according to the reaction scheme above 1, followed by removal of the protective group, reaction with thionyl chloride and finally with the sodium salt a compound of the general formula A (CHp) OH or A (CHp) SH, in which A has the meaning given above.

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c) m has a value from 2 to

ο ο

P CH ₉ ethyl formate, sodium O
XCH ₀ ^

^CH0 " ^{Na +}

D- thiourea

* Alky! Halide ' or sulfate

(CHo) _1n W (CH ₉ ) A 2 m 2 η

1) SOCl ₂

OH

2YA (CH ₀ ) O Na ⁺ or

A (CH ₂ ) _n S "Na ⁺

The connections of the general. Formula I, in which X is a sulfur atom, can by reacting the compounds of
general formula I, in which X is an oxygen atom, can be prepared with phosphorus pentasulfide in a solvent such as pyridine.

The amines of the general formula II can be according to the in the GB-PSen 1,305,547 and 1,338,169 will,

Many of the substances physiologically active in the body combine with certain as during the period of their effectiveness Receptors known sites .. Histamine is such a sub-

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punch with a number of biological effects. The biological receptors that are blocked by compounds commonly known as "antihistamines" such as mepyramine, diphenhydramine and chlorpheniramine are described by Ash and Schild (Brit. J. Pharmae. Chemother., 27: 427 (1966) ) called histamine H ₁ receptors. Drugs that block the H. histamine receptors are referred to below as H. histamine antagonists. However, another part of the biological effects of histamine is not inhibited by the H. histamine antagonists. Effects of this type, inhibited by a compound, reported by Black et al. (Nature, Vol. 236 (1972), p. 385) is referred to as burimamide, are transmitted by receptors that Black et al. Histamine is called Hp receptors. So histamine Hp receptors are those histamine receptors that are not blocked by mepyramine but by buriramid. Compounds that block histamine Ho receptors are called histamine H ₂ antagonists. They act z. B. as inhibitors of 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. _{A combination of histamine H 1} and H ₂ antagonists is useful in the treatment of certain diseases such as inflammation and in inhibiting the effect of histamine on blood pressure.

The compounds of the general formula I according to the invention are valuable drugs that are effective both as histamine H ^ antagonists and as histamine Hp antagonists. So you can use both in the treatment of diseases

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* where the administration of histamine H ₂ antagonists is useful, as well as those where a combination of histamine H. and Hρ antagonists is desired.

The compounds of general formula I are histamine Hp receptor blockers, that is, they block the biological effects of histamine, not like those of histamine H. antagonists Mepyramine, however, can be blocked by burinamide. You inhibit z. B. the acid secretion stimulated by histamine in perfused Stomachs of urethane anesthetized rats at intravenous doses of 0.5 to 16 micromoles / kg. Many of the In this test, all compounds cause at least 50 percent inhibition at doses of 1 to 10 micromoles / kg. The test procedure is in the Ash publication cited above and shield. Also other effects of histamine that 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 by the invention Connections inhibited.

■ The compounds of the invention inhibit the normal secretion of Stomach acid as well as that from pentagastrin or food intake caused gastric acid secretion.

In addition, the compounds of the invention have anti-inflammatory properties Effect as demonstrated in the rat paw test. That Volume of the rat paw is determined by subcutaneous administration of a dose of about 500 micromol / kg of a compound of the general formula

7 09815/1198

I diminished. The measurement of the blood pressure of anesthetized cats shows that the compounds of the invention have the vasodilating Inhibit the effects of histamine.

The activity of the compounds according to the invention is shown in the 50 percent inhibition of gastric acid secretion in the anesthetized rat, which is achieved with many of the compounds according to the invention of the general formula I at doses of 1 to 10 micromoles / kg, and in the 50 percent inhibition of histamine-induced tachycardia on the isolated right atrium of the guinea pig, which is achieved with many of the compounds of the general formula I according to ^{the invention at doses lower than ΙΟ "-3} mol / kg.

The compounds of general formula I are also histamine H ^ - Receptor blockers, d. They block the biological effects of histamine caused by mepyrarnine, diphenhydramine and chlorpheniramine blocked. For example, the compounds according to the invention inhibit the action of histamine on the isolated Ileum of the guinea pig. Many of the compounds of the general formula I according to the invention inhibit at doses from 10 mol / kg the histamine-stimulated contractions of the isolated ileum of the guinea pig.

The compounds according to the invention are used in therapy administered in the usual dosage forms, which are called Active ingredient at least one of these compounds in the basic form or in the form of a salt with an acid and carriers

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2843670

and / or contain diluents · The carrier material can be solid or liquid. Specific examples of solid carriers 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 very diverse Dosage forms are packaged. When using solid carriers, the preparations can be made in tablets, in powder or granulate form filled into hard gelatine capsules or processed into lozenges or candies. The amount of solid support can be are in a relatively wide 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, injection preparation, as aqueous or non-aqueous Suspension are 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 1500 mg.

The examples illustrate the invention,

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example 1

2- £ 2- (5-methyl-4-imidazolylmethylthio) -ethylamine7-5- (4-chlorobenzyl) -4-pyrimidone

a) A solution of 50.5 g of 5- (4-chlorobenzyl) -2-thiouracil, 28.4 g of methyl iodide and 8.2 g of sodium hydroxide in 200 ml of water / water and 400 ml of ethanol is stirred at 60 ° C. for 30 minutes and then cooled to room temperature. The precipitated crystalline precipitate is filtered off, washed with water and recrystallized from a mixture of methanol and ethanol. Yield 48.6 g of 5- (4-chlorobenzyl) -2-methylthio-4-pyrimidone from P. 193 to 194 ⁰ C.

b) 17.7 g of 5- (4-chlorobenzyl) -2-methylthio-4-pyrimidone and 11.4 g of 2- (5-methyl-4-imidazoIy! methylthio) ethylamine are intimately mixed and 5 hours to 145 to 150 ⁰ C heated. After cooling, the reaction mixture is digested with water. The free base obtained is then decanted off and recrystallized from methanol. The title compound with a melting point of 204.5 ° to 20 ° C. is obtained.

Example 2

2- £ 2- (5-methyl-4-imidazoIy! Methylthio) -ethylaminoJ-5- (2-phenylethyl) -4-pyrimidone dihydrochloride

According to Example 1 a), 1.8 g of 5- (2-phenylethyl) -2-thiouracil are used converted into 5-phenylethyl-2-methylthio-4-pyrimidone from P. 160 to 16 ° C after recrystallization from ethanol »According to

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Example 1 b) results in the reaction of 1.55 g of 5-phenylethyl-2-methylthio-4-pyrimidone with 1.1 g of 2- (5-methyl-4-imidazolylmethylthio ) -äthylamine an oil that is dissolved in 2 η hydrochloric acid. Thereafter, the resulting solution is evaporated to dryness and the residue recrystallized from methanol. The title compound from P. 214 to 218 ° C is obtained,

Example 3

2-f2- (5-methyl-4-imidazolylmethylthio) -ethylamino7-5- (4-methylbenzyl) -4-pyrimidone dihydrochloride

According to Example 1 a) 4.65 g of 5- (4-methylbenzyl) -2-thio ~ uracil in 5- (4-methylbenzyl) -2-methylthio-4-pyrimidone from P. Converted from 208.5 to 211 ° C after recrystallization from a mixture of methanol and ethanol. Then 1.6 g 5- (4-methylbenzyl) -2-methylthio ~ 4-pyrimidone according to Example 1 b) reacted with 1.2 g of 2- (5-methyl-4-imidazolylmethylthio) ethylamine and then with a dilute solution of hydrogen chloride

in ethanol

/ sour. The resulting solution is evaporated to dryness and the residue recrystallized from ethanol. The title compound of P. 197 to 198.5 ° C. is obtained.

Example 4

2-C2- ( 5-methyl-4-imidazolylmethylthio) -ethylaminoJ-5- (3- chlorobenzyl) "4-pyrimidone dihydrochloride

a) 4.25 g of sodium wire in 110 ml of anhydrous diethyl ether within 6 hours with stirring and cooling with a

70981 5/1198

Ice-salt bath with 39 »3 g of ethyl 3- (3-chlorophenyl) propionate and 14.9 S ethyl formate are added, the mixture is then stirred at room temperature for 18 hours and then evaporated to dryness. The residue obtained is 7 hours with 14.05 g Thiourea and 100 ml of ethanol boiled under reflux and then evaporated to dryness. The residue is taken up in water and mixed with acetic acid up to pH 4 ι the precipitated colorless precipitate is filtered off, washed and recrystallized from ethanol, 5- (3 ~ chlorobenzyl) -2-thiouracil obtained from m.p. 192 to 195 ° C.

b) According to Example 1 a) 3.1 g of 5- (3-chlorobenzyl) -2-thiouracil are used converted into 5- (3-chlorobenzyl) -2-methylthio-4-pyrimidone with a melting point of 178.5 to 130.5 C after recrystallization from ethanol, Then 1.8 g of the compound obtained according to Example 1 b) with 1.14 g of 2- (5-methyl-4-imidazolylmethylthio) -

Hydrogen chloride reacted in ethanol ethylainin, then with a solution of / treated and finally recrystallized from ethanol. The title compound with a melting point of 212.5 to 26 ° C. is obtained.

Example 5

2-Z2- (5-methyl-4- imidazolylmethylthio) -ethylamino7-5- (3,4-dichlorobenzyl) -4-pyrimidon- dlhydroChloride

a) According to Example 4 a) 48.9 g of 3- (3,4-dichlorophenyl) ~ Ethyl propionate in 5- (3,4-dichlorobenzyl) -2-thiouracil from the mp 232.5 to .233.5 ° C after recrystallization from a Converted mixture of methanol and ethanol.

70981 5/1198

b) According to Example 1 a), 5.7 S 5- (3, ¹ J-dichlorobenzyl) ~ 2-thiouracil in 5- (3 | ^ -Dichlorbenzyl) -2-methylthio ~ ⁱ ~ pyrimidone from F. 26 to Converted 218 ° C after recrystallization from acetic acid.

c) The reaction of 2.1 g of 5- (3 » ⁱ J-dichlorobenzyl) ~ 2 ~ methylthio-4-pyrimidone according to Example 3 with 1.2 g of 2- (5-methyl-4-imidazolylmethylthio) ethylamine gives after recrystallization from a mixture of water and methanol, the title compound from F, from 235.5 to 238.5 ⁰ C

Example 6 2- ./^ · · - (^ - Thi azolylme thy l ^ hio) -ät hy lamino7-5- ⁽¹ I- c hlorbenzyl) - ^ - pyr iniidon- monohydr o chloride

1.36 g of 5- ( ⁱ * -chlorobenzyl) -2-methylthio- ¹ } -pyrimidone and 0.9 g of 2- (2-thiazolylmethylthio) ethylamine are intimately mixed for 3 1/2 hours for 130 to 135 ° C heated. After cooling, the reaction mixture is treated with 2 η hydrochloric acid and then evaporated to dryness. The residue is recrystallized from a mixture of isopropanol and methanol. The title compound is obtained from a temperature of 172.5 to 17 * 1.5 ° C.

Example 7

2- / f2- (5-methyl l - ¹ J-imidazolylmethylthio) -äthylamino7-5 ~ ⁽² <-methoxy benzyl) -4-pyrimidone dihydro chloride _j

3.0 g of 5- ( ⁱ l-methoxybenzyl) -2-methylthio- ¹ l-pyriinidone and 1.95 g

709815/1198

2643S70

2- (5-Methyl-4-imidazolylmethylthio) -ethylamine are intimately mixed and heated to 135 to 140 ° C. for 6 hours with frequent stirring. After cooling, the reaction mixture is washed with hot Water digested, filtered, washed with anhydrous diethyl ether and dissolved in isopropanol. The solution obtained is with

a hydrogen chloride in ethanol

/ dilute solution of 7 acidified, evaporated to dryness and the residue recrystallized from ethanol. There is obtained the title compound, melting at I98 to 200 ⁰ C.

Example 8

2- / 2- (5-methyl-4-imidazolylmethylthlo) ~ äthylamino7-5- ^(j l-chlorobenzyl) -6-! Ethyl-4 "p yrimidon-dihyd rochlorid

a) According to Example 1 a), 5- (4-chlorobenzyl) -6-methyl-2-thiouracil is converted with methyl iodide to 5- (4-chlorobenzyl) -6-methyl-2-methylthio-4-pyrimidone with a melting point of 243 bis 251 ⁰ C implemented.

b) According to Example 1 b), the reaction of 1.95 g of 5- (4-chlorobenzyl) -o-methyl-2-methylthio-4-pyrimidone results with 1.19 g of 2- (5-methyl-4-imidazolylmethylthio) ethylamine after recrystallization from ethanol i the title compound from P. 203 to 20 6.5 ° C.

Example 9

2-Z * 2- (5-Bromo-2-pyridylmethylthio) -äthylamino7-5- ( ⁱ t -chlorobenzyl) -4-pyrimidone monohydrochloride

According to Example 2, 1.2 g of 5- (4-chlorobenzyl) -2-methylthio-

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4-pyrimidone with 1.1 g of 2- (3-bromo-2-pyridylmethylthio) ethylamine

one implemented. The reaction mixture obtained is diluted with /

Hydrogen chloride in ethanol
Solution of / acidified, evaporated to dryness and the residue recrystallized from a mixture of ethanol and water. The title compound is obtained with a melting point of 215-218 ° C. (decomp.).

Example 10

2 - ^ - (5-Methyl - ^ - imidazolylmethylthio) -äthylamino7-5- (2 ~ phenyl ethyl) -6-methyl -4 -pyritnidone

a) 6.4 g of sodium are dissolved in 100 ml of ethanol and 23.4 g p <- (PhenyläthyD-Acetessigsäureäthylester and 10.65 g thiourea added, refluxed for 5 1/2 hours and then evaporated to dryness. The solid residue will dissolved in water and mixed with acetic acid up to pH 4. The colorless precipitate obtained is then filtered off and recrystallized from ethanol, it is 5- (2-phenylethyl) -6-methyl-2-thiouracil obtained from P. 210 to 214 ° C.

b) Example 1 is repeated with the change that instead of of 5- (4-chlorobenzyl) -2-thiouracil, the 5- (2-phenylethyl) -6-methyl-2-thiouracil prepared above is used. After this

Recrystallize, from methanol the title compound of P, 222.5 to 224.5 ° C obtained.

Example 11

, 2- / 2- (5-methyl-4-imidazolylmethylthio) -ethylamino7-5-benzyloxy-4-pyrimidone dihydrochloride

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-W-

a) According to Example 4 a) βΟ, Ο g of ethyl benzyloxyacetate in 5-benzyloxy-2-thiouracil from P. 240 to 24l ° C after recrystallization from a mixture of acetonitrile and ethyl acetate converted in a volume ratio of 1: 1.

b) According to Example 1 a) 10.0 g of 5-benzyloxy-2-thiouracil in 5-benzyloxy-2-methylthio-4-pyrimidone from P. 184-185 ⁰ C after recrystallization from methanol converted.

c) The implementation of 4.10 g of 5-benzyloxy-2-methylthio-4-pyrimidone according to Example 3 with 2.83 g of 2- (5-methyl-4-imidazolyl) ethylamine after recrystallization from ethanol gives the title compound with a melting point of 161 to 162 ° C.

Example 12

2- ^ 2- (5-methyl-4-imidazolylmeth.ylthio) -ethylaminoI-5- (3-methoxybenzyl) -4-pyrimidone dihydrochloride

According to Example 1 a) there are 16.1 g of 5- (3-methoxybenzyl) -2-thiouracil converted into 5- (3-methoxybenzyl) -2-methylthio-4-pyrimidone from P. to 14'4 ° G after recrystallization from ethanol.

3 »0 g of 5- (3 ~ methoxybenzyl) -2-methylthio-4-pyrimidone according to Example 1 b) with 2.1 g of 2- ^(5-methyl-1 J-imidazolylmethylthio) ethylamine are reacted and then with a solution treated by hydrogen chloride in ethanol. After recrystallization from ethanol, the title compound of P. 173 to 175.5 ° C. is obtained.

709815/1198

Example 13

2 ~ / r2- (5-methyl-4- imidazolyimethylthio ) ~ ethylainino7-5- (2-chlorobenzy1) -4-pyrimidone dihydrochloride

a) According to Example 4 a), 48.4 g of ethyl 3- (2-chlorophenyl) propionate are obtained converted into 5- (2-chlorobenzyl) -2-thiouracil from P. 223 to 224 ° C after recrystallization from methanol.

b) According to Example 1 a), 5.05 g of 5- (2-chlorobenzyl) -2-thiouracil in 5- (2-chlorobenzyl) -2-methylthio-4-pyrimidone from P. 171 to 173 G are obtained after recrystallization Converted to ethanol. Then 1.6 g of 5- (2-chlorobenzyl) -2-methylthio-4-pyrimidone according to Example 1 b) are reacted with 1.03 g of 2- (5-methyl "4 ~ imidazolylmethylthio) ethylamine and then with one 'Treated a dilute solution of hydrogen chloride in ethanol. After recrystallization from a mixture of methanol and ethanol, the title compound with a melting point of 215 to 219 ^° C. is obtained.

Example 14

2 - ^ 2- (5-Methyl-4-i mida zolyl methylthio) -äthylamino7-5- (4-phenyl butyl) -4- pyrimidone dihydrochloride

a) According to Example 4 a), 43.5 g of 6-phenylhexanecarboxylic acid ethyl ester are obtained in 5- (4-phenylbutyl) -2-thiouracil with a melting point of 177.5 to 18 ° C. after recrystallization from a mixture of ethanol and converted to water.

b) According to Example 1 a) 3.05 g of 5- (4-phenylbutyl) ~ 2-thio-

709815/1138

uracil converted into 5- (4-phenylbutyl) -2-methylthio-4-pyrimidone with a melting point of 146 ° to 149 ° C. after recrystallization from ethanol. Then 1.89 g of 5- (4-phenylbutyl) -2-methylthio-4-pyrimidone according to Example 1 b) are reacted with 1.13 g of 2- (5-methyl-4-imidazolylmethylthio) ethylamine and then with a dilute one Treated solution of hydrogen chloride in ethanol. After recrystallization from ethanol, the title compound has a melting point of _{207 to? RiQ t} ^ ^o r. keep

Example 15

2- £ 2- (5-methyl - ^ - imidazolylmeth ylthio) -äthylamino7-5- / 3- (1,3-benzodioxol ioxo lyl) -niethy.l7-4-pyrirnidon-dih \ ^y hydrochloride

a) According to Example 4 a) 17.5 g of 3- / 3- (1,3-benzodioxolyl) _7-propionic acid ethyl ester in 5- / - 3- (l »3-benzodioxolyl) -. * methyl / -2-thiouracil converted from mp 158 to 159 ° C after recrystallization from a mixture of ethanol and methanol in a ratio of 1: 1.

b) According to Example 1 a), 2.9 g of 5-Z ~ 5- (1,3-benzodioxolyl) -methyl_7-2-thiouracil in 5- £ 5- (1,3-benzodioxolyl) -methyl7-2-methylthio -4-pyrimidone converted mp 197-198 ⁰ C after recrystallization from acetonitrile.

1.2 g of 5- / 5- (l, 3 ~ benzodioxolyl) -methyl_7-2-methylthio- ⁱ l-pyrimidone are according to Example 1 b) with 0.77 g of 2- (5-methyl-4-imidazalylmethylthio) - reacted ethylamine and then treated with a solution of hydrogen chloride in ethanol. After recrystallization from ethanol, the title compound with a melting point of 230 to 232 ^° C. is obtained.

709815/1198

Example ί 6

2 - »^ - (, 5" methyl "M-iidazolylmethylthio) -ethylamineQ7-5- (3» ethoxybenzyl) - ^ - pyrimidonyl hydrochloride

According to Example 1 a) 5 * 0 g of 5- (3-ethoxybenzyl) -2-thiouracil in 5- (3-ethoxybenzyl) -2-methylthio- ⁱ l-pyrimidone from P. 136 to 138 ° C after recrystallization converted from acetonitrile. 2.0 g of 5- (3-ethoxybenzyl) -2-methylthio- ¹ i-pyrimidone are reacted according to Example 1 b) with 1.25 g of 2- (5-methyl ⁱ l-imidazolyl · methylthio) ethylamine and then treated with a solution of hydrogen chloride in ethanol. After recrystallization from ethanol the title compound, P is 176 to 17S ^O C hold 5.

Example 17

2- ^ 2- (5 "methyl-4-imidazolylmethylthio) -ethylamino7-5- (3 -benzyl oxybenzyl) -ty-pyrirnidone dihydrochloride

According to Example 1 a), Ί.6 g of 5- (3-benzyloxybenzyl) -2-thiouracil in 5 ^< - (3-benzyloxybenzyl) -2-methylthio-4-pyrimidone from P. 176 to 178 ⁰ C after recrystallization Converted ethyl acetate. 2.0 g of 5- (3-benzyloxybenzyl) -2-methylthio-4-pyrimidone are reacted according to Example 1 b) with 1.0 g of 2- (5-methyl- ^ -imidazolylmethylthio) ethylamine and then with a solution of Treated hydrogen chloride in ethanol.

After recrystallization from a mixture of ethanol and methanol in a ratio of 1.: 1, the tit el compound from P, 19.3 to 19 ' ¹ J ⁰ ? obtain.

709815/1198

Example 1 8

2-Z "2- (5" methyl - ^ - imidazolylmethylthio) ~ ethylamino7-5 ~ (lnaphthy! Methyl) -4-pyrimidone dihydrochloride

According to Example 1 a), 6.7 g of 5- (l-naphthylmethyl) -2-thiouracil in 5- (l-naphthylmethyl) -2-methylthio- ⁱ l-pyrimidone from P. 178 to 180 ° C. after recrystallization Methanol converted »0.4 g of 5- (l-naphthylmethyl) -2-methylthio-4-pyrimidone are according to Example 1 b) with 0.25 g of 2- (5-methyl-4-imidazolyl-

methylthio) ethylamine reacted and then with a Lö-

Hydrogen chloride in ethanol

solution of / treated. After recrystallization from ethanol, the title compound with a melting point of 223 ° to 230 ° C. is obtained.

Example 9

Example 4 is repeated with the change that instead of the ethyl 3- (3-chlorophenyl) propionate, the ethyl 3- (3 »^, 5-trimethoxyphenyl) propionate is used. It becomes 2- £ 2- (5-methyl-4-imidazolylniethylthio) -ät hylaminoJ-5- (3,4,5-trimethoxybsnzyl) -4-pyrimidone obtain,

Example 20

The implementation of 2 - ^ - (5- "4ethyl-4-imidazolylmethylthio) -äthyl-r amino_7-5- (4-methoxybenzyl) -4-pyrimidone with phosphorus pentasulfide in hot pyridine gives 2-Z2- (5-methyl-4-imidazolylmethylthio) -äthylaminoy-S-C ^ -methoxybenzyD-pyrimid - ^ - thione.

Example 21 Example 7 is repeated with the change that instead of the

70981 5/1198

2- (5-methyl-4-imidazolylmethylthio) ethylamine the following Amines are used:

(a) 2- (2-Imidazolylmethylthio) ethylamine

(b) 2- (4-imidazolylraethylthio) ethylamine

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

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

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

(f) 2- (2 ~ pyridylmethylthio) ethylamine

(g) 2- O-methyl-pyridylmethylthio.) -ethylamine-(h) 2- (3-methoxy-2-pyridy lniethy It hio) -ethylamine

(i) 2- (3-chloro-2-pyridylmethylthio) ethylamine

U) 2- (3-A: iiino-2-pyridylmethylthio) ethylamine

(k) 2- (3-Hydroxy-2-pyridylmethylthio) ethylamine

(1) 2- (3-isothiazolylmethylthio) ethylamine

(m) 2- (4-3rom-3-isothiazolylme'thylthio) ethylamine

(n) 2- (3- (1,2,5) -thiadiazolylmethylthio) -ethylamine

(o) 2- (4-Chloro-3- (1,2,5) -thiadiazolylmethylthio) -ethylamine

(p) 2- (5-Amino-2- (1,3,4) thiadiazolylmethylthio) ethylamine

The following connections are obtained:

(a) 2- / r2- (2-imidazolylmethylthio) ethylamino7-5- (4-methoxybenzyl) -4-pyrimidone

(b) 2 - / "2- (4-imidazolylraethylthio) ethylamine Q7-5 - (^ - methoxybenzyl) -4-pyrimidone

(c) 2-A2- (5-Bromo-4-imidazolylmethylthio) -ethylamino7-5- (4-methoxybenzyl) -4-pyrimidone

7098 15/1 198

(d) 2-Z ~ 2- (5-trifluoromethyl-4-imidazolylmethylthio) -ethylaraino7-5- (4-methoxybenzyl) -4-pyrimidone

(e) 2-ZT2- (5-hydroxymethyl-4-imidazolylmethylthio) -ethylamine7-5- (4-methoxybenzyl) -4-pyrimidone

(f) 2-Z2- (2-pyridylmethylthio) ethylamine Q7-5- ( ² l -niethoxybenzyl) -4-pyrimidone

(g) 2-Z "2- (3-methyl-2-pyridylmethylthio) ethylamino.7-5- ( ^i- methoxybenzyl) -4-pyrimidone

(h) 2- _i r2- (3-methoxy-2-pyridylmethyrthio) -äthylamino7-5- ( ⁱ <-

methoxybenzy1) -4-pyrimidone (i) 2-Z ~ 2- (3-chloro -2-pyridylmethylthio) -äthylarainQ7-5 - (^ -

methoxybenzyD - ^ - pyrimidon (j) 2-Z "2- (3-Amino-2-pyridylniethylthio) -äthylaTnino7-5- ( ¹ {-

methoxybenzyl) -4-pyrimidone (k) 2-Z2- (3-hydroxy-2-pyridylmethylthio) -ethylaraino7-5 ~ ( ^/ l-

methoxybenzyD- ^ l-pyriniidön (1) 2-Z.'2- (3-isothiazolylmethylthio) ~ ethylamino7-5- ( ¹ l-

methoxybenzyl) -4-pyrimidone (m) 2- / 2- (4-Bromo -3-isothiazolylmethylthio) -ethylamino7-5- (4-methoxybenzyl) -4-pyrimidone

(n) 2-Z2- (3- (l, 2,5) -Thiadiazolylmethylthio) -äthylamino7-5-

(4-methoxybenzyl) -4-pyrimidone (o) 2- / 2- (4-chloro -3- (l, 2,5) -thiadiazolyLnethylthio) -ethyl-

aminoT ^ -S-C 4-methoxybenzyl) -4-pyrimidone (p) 2-ZT2- (5-Amino-2- (1,3,4) -thiadiazolylmethylthio) -ethylamino7-5- (4-methoxybenzyl) -4-pyrimidone.

709815/1198

Example 22

Example 12 is repeated with the modification that is used instead of 2- (5-methyl-4-imidazolylmethylthio) -äthylamins the ¹ J- (4-imidazo lyl) butylamine "It is the 2- / ¹ J- ⁽ⁱ l-imidazolyl) butylaminoJ-SO-methoxybenzyD - ^ - pyrimidone from F. 193 to 19 ¹ J ⁰ obtained.

Example 23

The reaction of ethyl butyroacetate with sodium ethylate and ^ -Methoxybenzylchlorid gives the o (- (4-methoxybenzyl) -butyroacetic acid ethyl ester, which is reacted with thiourea and sodium ethylate under reflux to 5 - (^ - methoxybenzyl) -6-propyl-2-thiouracil Use of the 5-Ot-methoxybenzyl) -6-propyl-2-thiouracil instead of the 5- ( ¹ -chlorobenzyl) -2-thiouracil results in the reaction according to Example 1, the '2-Z "2- (5-methyl -i | -imidazol'ylmethylthio) -äthylamino7-5- ( ^i- methoxybenzyl) -6-propyl-4-pyrimidone.

Example 24

Example 4 is repeated with the change that instead of the Ethyl 3- (3-chlorophenyl) propionate the following esters are used:

(a) Ethyl 3- (2-naphthyl) propionate

(b) Ethyl 3- ( ⁱ l-trifluoromethylphenyl) propionate

(c) 3- ^(i-i Dimethylami'nophenyl) -propionsäureäthylester

(d) Ethyl 3- ( ^f l-phenoxyphenyl) propionate

(e) 3- ^ l | - (4-chlorophenoxy) -phenyl? -propionic acid ethyl ester

709815/1 198

(f) 3 - ^ - (4-Methoxyphenoxy) ~ phenyl7-propionic acid ethyl ester

(g) Ethyl 3- (4-biphenyty] X-propionate

(h) ethyl 3- (4'-chloro- ^ l-biphenyly ^ -propionate

(i) 3- ⁽¹ J '-methoxy-4-biphenyly: i) -propionsäureäthylester.

The following connections are obtained:

(a) 2-Z2- (5-methyl-4-imidazolylmethylthio) -äthylamino_7-5- (2-naphthy ! methyl) -4-pyriTiidone

(b) 2- / 2- (5-Methyl - ^ - imidazolylmethylthio) -äthylamino7-5 ~ (^ -trifluoromethylbenzylJ - ^ - pyrimidone

(c) 2-Z ~ 2- (5-- ^/ Iethyl- ⁱ ) -imidazolylmethylthio) -äthylaniino7-5 - (^ - dimethyla ^ inobenzyl) -4-pyrimidone

(d) 2-ZT2- (5-methyl- ^ - imidazolyl: -nethylthio) -äthylaminoy-S - (^ - phenoxybenzyl) -4-pyri.-nidone

(e) 2 ~ Z ^ - (5 -. "3thyl-4-iiaidazo'lyi; nethylthio) ethylamine Q7-5-Z ^ i-C ^ l-chlorphenoxyJ-behzyU - ^ - pyrirnidon

(f) 2-Z2- (5-I-ethyl- ⁱ 4-imidazolylmethylthio) ethylamine Q7 »5- £ 4- (4-methoxyphenoxy) -benzylj- ^ - pyriniidone

(g) 2-Z. "2- (5-I'lethyl-4-imidazolylmethylthio) -äthylaTiino.7-5- (4-phenylbenzyl) -4-pyrimidone

(h) 2- / 2- (5 -: - lethyl-4-imidazolylmethylthio) -äthylamino_7-5-Z ^ - (4-chlorophenyl) -benzyiy - ^ - pyrimidone

(i) 2- / f2 (5- ^r 'lethyl-4 - imidazolylmethylthio) -äthylamino7 "5- ß \ ~ (4-metho xyphe ny1) -benzyl-Ij -4-pyrimidone

• Example 25
The conversion of 2 - // 2 ~ (5-i'1ethyl-4-i-nidazolylmethylthio) ~

70981 5/1198

. 3 ^

äthylaraino7-5- (3 ~ benzyloxybenzyl) - ⁱ l-pyriinidon with hydrogen bromide in acetic acid gives the 2- / i2- ^(5-methyl-1 J.-imidazolylmethylthio) -äthylamino_7-5- (3-hydroxybenzyl) -4 ~ pyrimidone .

Example 2 β

a) Butyrolactone is treated with sodium and ethyl formate and

then successively with thiourea and methyl iodide 5- (2-hydroxyethyl) -2-methylthio - ^ - pyrimidone implemented.

b) 5- (2-Hydroxyethyl) -2-methylthio- ⁱ l-pyrimidone is added with thionyl chloride and then with the sodium salt of 1) .4-methoxybenzyl alcohol and 2) "4-methoxybenzyl mercaptan

1) 5- ^ 2- ( ² l-methoxybenzyloxy) -ethyl7-2-methylthio- ⁱ l-pyrimidone b zvj «

2) 5-Z "2- (4-methoxybenzylthio) ethyl7-2-methylthio-i | -pyrimidone implemented.

c) The use of:

1. 5-Z2- ( ⁱ J-methoxybenzyloxy) -ethyl7-2-methylthio-4-pyrimidone

2. 5-Zr2- (4-methoxybenzylthio) "ethyl7-2-methylthio-4-pyrimidone

instead of 5- (iJ-chlorobenzyl) -2-methylthio- ⁱ J ~ pyrimidone in the reaction according to Example 1 b) results in the following compounds:

1. 2- / T2-C 5-methyl-ii ~ imidazolylmethylthio) -ä / C2- (4-methoxybenzyloxy) -ethyl7 - ^ - pyr'iraidon

2. * 2 ~ ZT2- (5-methyl - ^ - imidazolylmethylthio) ethylamine Q7-5

^ - (^ - methoxybenzylthioJ-äthyiy-iJ-pyrimidon.

709815/1198

d) The use of 1) phenol and 2) thiophenol instead of dos 4-Methoxybenzyl alcohol in Example 26 b) and c) gives the fol connections:

1. 2-Z ~ 2- (5-methyl-4-imidazolylmethylthio) -äthylamino7-5- (2-phenoxyethyl) -'J-pyrimidone

2. 2-Z2- (5-methyl- ⁱ J-imidazolylmethylthio) -ethylamine Q7-5- (2-phenylthioethy1) -4 -pyrimidone.

e) The use of 1) 2-phenylethanol and 2) 2-phenylethyl mercaptan instead of 4-methoxybenzyl alcohol in the implementation according to Example 26 b) and c) results in the following compounds:

1. 2Tf2- (5-Methyl-il-i.Tiidazolylmethylthio) -äthylaniinQ7-5- / 2- (2-phenylethoxy) -äthy 17 - ^ - PyX ¹ ImIdOn

2. 2- £ 2- (5-3tethyl-1-iaiidazolyimethylthio) -ethylamino7-5- £ 2- (2-phenylethylthio) -ethyl7- ⁱ ) -pyrimidone.

f) The use of caprolactone instead of butyrolactone in the reaction according to Examples 26 a), b) and c) results the following connections:

1. 2-Z2- (5-methyl-4-imidazolylmethylthio) -ethylamino7-5-Z3 - (^ - raethoxybenzyloxyi-propyiy - ^ - pyrimidone

2. 2- / 2- (5 ^ ethyl-4-iraidazolylmethylthio) -äthylamino7-5-Z3- ⁽ⁱ i-methoxybenzylthio) -propyl7-4-pyrimidone.

709815/1198

Example 27

The use of a) 3-Phenylpropoxyessigsäureäthylester and b) ethyl 3-phenylpropylthioglycolate instead of ethyl benzyloxyacetate the reaction according to Example 11 gives the following compounds:

(a) 2-r2- (5-methyl-4-imidazolylmethylthio) -ethylamino7-5- (3-phenylpropoxy) -4-pyrimidone

(b) 2- / 2- (5-: iethyl-4-imidazolylmethylthio) -ethylamino7-5- (3-phenylpropylthio) -4-pyrimidone.

Example 28

The use of a) 5- ^ 3-A2 "(^ - ^ ethoxyphenyl) ~ ethoxyJ ~ benzylj · 2-thiouracil and b) 5- / 3- (3-chlorobenzyloxy) benzyl7-2-thiouracil instead of 5- (3-benzyloxybenzyl) -2-thiouracil in the reaction according to Example 17 results in the following compounds:

a) 2-Z "2- (5-Methyl-i | -iinidazolylmethylthio) -äthylamino7-5- {3- ^{Z- 2- (i} } -methoxyphenyl) -ethoxy7-benzyl ^ -4-pyrimidone

b) 2-A2 - (^ - methyl-1-imidazolylmethylthio) -äthylaTiinQ7-5- / 3- (3-chlorobenzyloxy) -benzy] 7 "-4-pyri: nidone.

Example 29

The use of a) 3-Z £ - (2,3 ~ dihydro-l, ⁱ J-benzodioxinyl7-propionic acid ethyl ester and b) 3- (3-bromophenyl) -propionic acid ethyl ester instead of 3- (3-chlorophenyl) -propionic acid ethyl ester in the Implementation according to Example ¹ I results in the following compounds:

70981 5/1198

a) 2- / 2 - ^ - Methyl- ² ! -imidazolylmethylthio) -äthylamino7-5-Zi-2,3-dihydro-lj4-benzodioxinyl) -methyl? - ^ - pyriraidon

b) 2-Z2- (5-methyl-4-iiaidazolylmethylthio) -äthylamino7-5- (3-bronibenzyl) - ⁱ l-pyriinidone,

Example 3 0

The reaction of ethyl 3- (3-hydroxyphenyl) propionate with dimethoxymethane and the use of the product obtained instead of the ethyl 3- (3-chlorophenyl) propionate in the reaction according to Example ¹ I gives the 2- / 2- (5-methyl 1) - ² I-imidazolylmethylthio) -äthylamino7-5-Z3- (methoxymethoxy) -benzyl_7- ² ipyrimidon from which after reaction with hydrochloric acid, the 2-C2 ~ (5-methyl -. ^ - imidazolyl lmethylthio) -äthylaminoJ'-S - (3-hydroxyben- ² n is obtained.

709815/1198

Claims (1)

Pyrimid-4-one and thione derivatives of the general formula I. Het ^f -CH ₂ ZCH ₂ CH ₂ -NH Het ^f an optionally te by lower Alkylre &, preferably. "/ iethy! groups, halogen atoms, preferably chlorine or bromine atoms, trifluoromethyl or hydroxymethyl groups, substituted 2- or 'I-imidazolyl optionally substituted by lower alkyl groups, preferably methyl groups, _t lower alkoxy _t preferably methoxy groups, halogen atoms _s preferably chlorine or 3ro: n atoms _f 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-isothiazolyl group optionally substituted by chlorine or bromine atoms - (l, 2 _i 5) -thiadiazolyl group or a 2- (5-amino-l _> 3 _l ^ -thiadiazolyl) group, Z is a sulfur atom or a methylene group, X is an oxygen or sulfur atom, W is a methylene group Oxygen or sulfur atom and Y is a hydrogen atom or a lower alkyl radical, _{s is} the sum of m and η has a value from 1 to H , when W is acid substance «or sulfur atom or has a value from 0 to 4, 'if W is a methylene group and A is a 1- or 2-naphtha ethyl, a 2,3 "dihydro ~ 1,4rbenzodioxinyl or a 1,3-benzodioxolyl group or one by at least one lower 709815/1198 ORIGINAL INSPECTED Alkyl, lower alkoxy, arylalkoxy, alkoxyalkoxy, di-lower alkylamino, halophenoxy, alkoxyphenoxy, halophenyl or alkoxyphenyl radical or a halogen atom or at least one hydroxyl, trifluoromethyl, phenoxy or phenyl group substituted phenyl, which also represents can be unsubstituted if the radical - (CH ₂ ) W (CH ₂ ) - is not a methylene group, and its salts with acids, 2, compounds according to claim 1 of the general formula I, in which A is one by at least one lower alkyl, lower alkoxy, di-lower alkylamino, halophenoxy or halophyl radical or a halogen atom or at least one hydroxyl, trifluoromethyl, phenoxy or Phenyl group represents a substituted phenyl group, which can also be unsubstituted if the radical - (CH ₉ ) VZ (CH ₉ ) - is not a? 4ethylene group. 3. Compounds according to claim 1 or 2 of the general formula I, in which Het 'a 2-thiazolyl, 5-methyl ⁱ l-imidazolyl, 5-bromo-4-imidazolyl, 3-bromo-2-pyridyl , 3-chloro-2-pyridyl, 3-methoxy-2-pyridyl or 3-hydroxy-2-pyridyl group means » 4. Compounds according to claim 1 to 3 of the general formula I, in which Z is a sulfur atom, 5, compounds according to claim 1 to 4 of the general Forarel I, in which X means an oxygen atom " 6 «compounds according to claim 1 to 5 of the general formula I, in which Y is a hydrogen atom . 3. 7. Compounds according to claim i to 6 of the general formula I, in which A is a phenyl group substituted by at least one lower alkoxy radical. 8. Compounds according to claim 1 to 6 of the general formula I, in which A is a 2,3-dihydro-1,4-benzodioxinyl or a 1,3-benzodioxolyl group means. 9 «Compounds according to claims 1 to 8 of the general formula I, in which m and η are 0 and W is a methylene group means. 10. Compounds according to claim 1 to 8 of the general formula I, in which m is 0 and η is 1 and W is an oxygen atom means, 11. 2 - /: 2- (5-Methyl-4-imidazolylmethylthio ')' - ethylamino7-5- (4-chlorobenzyl) -4-pyrimidone. 12. 2-Z2- (2-thiazolylniethylthio) ~ ethylamino7-5- (4-chlorobenzyl) -4-pyrimidone « 13. 2-Z72- (3-bromo-2-pyridylmethylthio) -äthylaminq7-5 ~ (4-chlorobenzyl) -4-pyrimidone, 14. 2-Zr2- (5-Methyr-4-imidazolylmetbylthio) -ethylamino7-5 (4-chlorobenzyl ) -6 ~ methyl-4-pyriniidone. 709815/1198 2643U7Ö - jer - - • Ϋ. 15. 2-Z2- (5-Methyl-4-imidazolylmethylthio) -äthylamino7-5- (3-chlorbenzy1) -4 -pyrimidone. 16. 2-ZT2- (5-methyl-4-imidazolyl lmethy It hio) ~ äthylaminq7-5- (3 ^'i i-dlchlorbenzyl) - ⁱ l-pyrimldon. 17. 2 ~ ZT2- (5-methyl - ^ - imldazolylm8thylthio) -äthylamino_7-i5 · (^ -methoxybenzyl) - ^ - pyrimidone. 18. 2-Z2- (5-Methyl-il-iniidazolylmethylthio) -äthylaniino7-5 - (^ l-methylbenzyD-A-pyriniidone. 19. 2- / 2- (5-methyl-il-imidazolylmethylthio) -ethylamino7-5- (2-phenylethyl) -4-pyrimidone " 20. 2- / 2- (5-Methyl-4-imldazolylmethylthio) -ethylamino7-5- (2-phenylethyl) -6-methyl ^J i-pyri. ^v nidon. 21. 2-Z2- (5-methyl-4-imidazolyImethylthio) -ethylaminoJ-S -benzyloxy- ^ - pyrimidone. 22. 2- / T2- (5-methyl-4-imidazolylmethylthio) -ethylamino7-5- (3-methoxybenzyl) -4-pyrimidone. 23. 2-Z2- (5-Methy1-4-imidazolyImethylthio) -äthylamino7-5- (2-chlorobenzy1) -4-pyrimidone. 2k . 2 - / "2- (5-Methyl-l | -imidazoly Imethylthio) -äthylamino7-5 · (Ί-phenylbuty] J - ^ - pyrimidone. 70981 5/1198 • sr- 25. 2 - /? - (5-Methyl-4-imidazolylmethylthio) -ethylamino.7-5- (5- (1,3-benzodioxolyl) -methyl) -4-pyrimldone. 26. 2-Z2 ~ (5-methyl-4-imidazolylmethylthio) -äthylaTninq7-5- (3-ethoxybenzyl) -4-pyrimldone. 27. 2-C2. "{ 5-Methyl-4 -imidazolylmethylthio) -ethylamino.7-5- (3-benzyloxybenzyl) -4-pyrimidones 28. 2- / j2- (5-Methyl-4-imidazolylmethylthio) -äthylamino_7-5- (l-naphthylmethylJ - ^ - pyrimidone, 29 »Process for the preparation of the compounds of the general formula I, characterized in that one a) for the preparation of the compounds of the general formula I in which X is an oxygen atom, an amine of the general formula Formula II Het ¹ - CH ₂ ZCH ₂ CH ₂ NH ₂ (II) in which Het 'and Z have the meaning given above, with a] ^ rdinid - ^ - one derivative of the general formula III Y ³ (CH ₂ ) _m W (CH ₂ ) _n A _(m) Q N ^ o in which Y, m, η and A have the meanings given above and Q is a lower alkylthio radical, a benzylthio group, represents a halogen atom or another reactive radical, 709815/1198 2643170 which is displaced during the reaction with an amine, b) for the preparation of the compounds of general formula I, in X denotes a sulfur atom, the compound of the general formula I obtained in which X denotes an oxygen atom with Phosphorus pentasulfide converts and optionally converting the compound obtained according to a) or b) into a salt with an inorganic or organic acid. 30 «Medicines with histamine H ^ and Hp receptor blocker effect, characterized by a content of a compound according to Claims 1 to 28. 709 8 15/1198