CH625801A5 - Process for the preparation of pyrimid-4-one and -thione derivatives and their salts with acids - Google Patents

Description

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

Het • -CH2ZCH2CH2-NH

625 801

(CH2) mW (CH2) nA

(I)

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

2-thiazolyl group, a 3-isothiazolyl group optionally 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, 3,4- thia-diazolyl) group means Z is a sulfur atom or a methylene group, X is an oxygen or sulfur atom, W is a methylene group, an oxygen or sulfur atom and Y3 is a hydrogen atom or a lower alkyl radical, the sum of m and n is a value of 1 to 4 if W represents an oxygen or sulfur atom, or a value of 0 to 4 if W represents a methylene group, and A has a 1- or 2-naphthyl, a 2,3-dihydro-1,4 -benzo-dioxinyl or a 1,3-benzodioxolyl group or one by at least one lower alkyl, lower alkoxy, aryl alkoxy, alkoxyalkoxy, di-lower alkylamino, halophenoxy, alkoxyphenoxy, halophenyl or alkoxy -phenyl radical or a halogen atom or at least one hydroxyl, trifluoromethyl, pheno xy- or phenyl group represents substituted phenyl group, which may also be unsubstituted if the radical— (CH2) mW (CH2) n- is not a methylene group, and their salts with acids.

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

The “lower alkyl residues” contain 1 to 4 carbon atoms.

Het 'is preferably 2-thiazolyl-, 5-methyl-4-imidazolyl-, 5-bromo-4-imidazolyl-, 3-bromo-2-pyridyl-,

3-chloro-2-pyridyl, 3-methoxy-2-pyridyl or 3-hydroxy-2-pyridyl group. Z is preferably a sulfur atom, X is an oxygen atom and Y3 is a hydrogen atom. A is preferably a phenyl group substituted by at least one lower alkoxy radical, a 2,3-dihydro-1,4-benzodioxinyl or 1,3-benzodioxolyl group, since the compounds of the general formula I in which A has this meaning precede the other compounds of general formula I are characterized by advantageous solubility properties.

Preferably m and n are 0 and W is a methylene group. In another preferred group io, m is preferably 0 and n is 1 and W is an oxygen atom.

Particularly preferred compounds of the present invention are:

is 2- [2- (5-methyl-4-imidazolylmethylthio) ethylamino] -5 - (4-chlorobenzyl) -4-pyrimidone 2- [2- (2-thiazolylmethylthio) ethylamino] -5 - (4-chlorobenzyl ) -4-pyrimidone 2- [2- (3-bromo-2-pyridylmethylthio) - ethylamino] -20 5- (4-chlorobenzyl) -4-pyrimidone

2- [2- (5-Methyl-4-imidazolylmethylthio) ethylamino] -5- (4-chlorobenzyl) -6-methyl-4-pyrimidone 2- [2- (5-Methyl-4-imidazolyImethylthio) ethylamino] -5- (3-chlorobenzyl) -4-pyrimidone 25 2- [2- (5-methyl-4-imidazolylmethylthio) ethylamino] -5- (3,4-dichlorobenzyl) -4-pyrimidone 2- [2- ( 5-methyl-4-imidazolylmethylthio) ethylamino] -5 - (4-methoxybenzyl) -4-pyrimidone 2- [2- (5-methyl-4-imidazolylmethylthio) ethylamino] -30 5- (4-methylbenzyl) - 4-pyrimidone

2- [2- (5-methyl-4-imidazolylmethylthio) ethylamino] -5 - (2-phenylethyl) -4-pyrimidone 2- [2- (5-methyl-4-imidazolylmethylthio) ethylamino] -5- ( 2-phenylethyl) -6-methyl-4-pyrimidone 35 2- [2- (5-methyl-4-imidazolylmethylthio) ethylamino] -5-benzyloxy-4-pyrimidone

2- [2- (5-methyl-4-imidazolylmethylthio) ethylamino] -5- (3-methoxybenzyl) -4-pyrimidone 2- [2- (5-methyl-4-imidazolylmethylthio) ethylamino] -40 5- (2-chlorobenzyl) -4-pyrimidone

2- [2- (5-methyl-4-imidazolylmethylthio) ethylamino] -5- (4-phenylbutyl) -4-pyrimidone 2- [2- (5-methyl-4-imidazolylmethylthio) ethylamino] -5- [ 5- (1,3-benzodioxolyl) methyl] -4-pyrimidone 45 2- [2 ~ (5-methyl-4-imidazolylmethylthio) ethylamino] -5- (3-ethoxybenzyl) -4-pyrimidone 2- [2nd - (5-Methyl-4-imidazolylmethylthio) ethylamino] -5 - (3 -benzyloxybenzyl) -4-pyrimidone 2- [2- (5-methyl-4-imidazolylmethylthio) ethylamino] -50 5- (l-naphthylmethyl) ) -4-pyrimidone.

The pyrimid-4-one and thio derivatives of the general formula I are in tautomeric equilibrium with the corresponding pyrimid-6-one and 6-thione derivatives. To a lesser extent there are tautomeric equilibria 55 with the corresponding mercapto and hydroxy compounds. The pyrimidine group itself can exist in the following tautomeric forms:

- n ^ n

• -N ^ _N N- ^ NXH

H

The heterocyclic radical Het 'can also exist in various tautomeric forms. The present invention relates to all possible tautomeric forms. The compounds of the

XH

65 general formula I, in which X represents an oxygen atom, can by reacting an amine of the general formula II

625801

4th

Het'-CH2ZCH2CH2NH2

(II)

in which Het 'and Z have the meaning given in the general formula I, with a pyrimid-4-one derivative of the general formula III

* ^ 0

(CH2) fflW (CH2) nA (III)

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15

in which Y3, m, W, n and A have the meaning given in the general formula I and Q represents a lower alkylthio radical, a benzylthio group, a halogen atom or another reactive radical which is displaced in the reaction with an amine, getting produced. The reaction is preferably carried out without a solvent at about 150 ° C. or in the presence of a solvent such as pyridine at the reflux temperature.

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

The pyrimid-4-one intermediates of the general formula III, in which W is a methylene group, Y3 is a hydrogen atom and Q is a lower alkylthio radical, can be prepared according to reaction scheme 1 below, in which A has the meaning given in general formula I. , a has a value from 0 to 4 and Alk represents a lower alkyl radical.

Scheme 1

A (CH2) aCH2CH2COOC2H5 1) Na, HCOOC2H5 IV 2) thiourea

1

Alkyl halide or sulfate

HN '<YCH2 (CH2) aA AlkS ^ N A0

VI

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

The pyrid-4-one intermediates of the general formula III, in which W is a methylene group, Y3 is a lower one

45

Alkyl radical and Q represent a lower alkylthio radical can be prepared according to reaction scheme 2 below, in which A has the meaning given in general formula I, a has a value from 0 to 4, Hai is a chlorine or bromine atom and Alk a lower alkyl radical mean.

Scheme 2

Y3-COCH2COOC2H5 NaOC2H5, HalCH2 (CH2) aA

Y *

VII

Alk

ÙCH2 (CH2) aA O

Alkyl halide or sulfate

CH2 (CH2) aA

I.

Y3-COCHCOOC2H5 thiourea t

3 x

CH2 (CH2) aA

S ^ N Ay.

H 0

5 625 801

The pyrid-4-one intermediates of the general formulas in which A and Y3 have the mei III given in general formula I, in which Q represents a halogen atom, can have the meaning, a has a value from 0 to 4 and a shark the following reaction scheme 3 are prepared, means chlorine or bromine atom.

Scheme 3

VIII

CH2 (CH2) aA

I.

Y3COCHCOOC2Hs

\

Sodium salt \ guanidine

\

Y

N '

V

CH2 <CH2) aA

v- s

1) HCl, NaNCh

2) Cu2 hook

XCH2 (CH2) aA HN ^ |

Xo

The compounds of general formula VIII, in which Y3.

is a hydrogen atom, the pyrimid-4-one intermediates of the general ester of the general formula IV with sodium and formula III in which W is an oxygen or sulfur atom

Formic acid ethyl ester are produced. Compounds 40 indicates can be prepared according to the following reaction schemes of general formula VIII, in which Y3 a lower alkyl:

rest means can be prepared according to reaction scheme 2 a) m has the value 0

I.

Shark

1) HCl, NaNCh

2) Cu2 Hah

V (CH2V

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Another preparation process for these compounds is via the reaction of 4-benzyloxybutyric acid ethyl ester or a similar derivative of the 4-hydroxybutyric acid ethyl ester provided with a protective group in accordance with reaction scheme 1 above, followed by the removal of the protective group, the reaction with thionyl chloride and finally with the Sodium salt of a compound of the general formula A (CH2) nOH or A (CH2) nSH, in which A has the meaning given above.

c) m has a value of 2 to 4 O

O

O-

(CH2) m ^

H2 ethyl formate, sodium ->

o Jy

: CHO ~ Na +

I.

Alk- ^

(CH2) mW (CH2) nA

l) SOCl2

2) A (CH2) nO-Na + or A (CH2) nS ~ Na +

1) Thiourea

2) alkyl halide or sulfate

AlkS ^ N ^,

(CH) OH 2 m

0

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

The amines of the general formula II can be prepared by the processes described in British Patents 1,305,547 and 1,338,169.

Many of the substances 3s that are physiologically active in the body combine with certain points known as receptors during their period of effectiveness. Histamine is one such substance with a number of biological effects. The biological receptors blocked by the compounds commonly known as "antihistamines" such as mepyr-40 amine, diphenhydramine and chlorpheniramine are described by Ash and Schild (Brit. J. Pharmac. Chemother., Vol. 27 [1966], P. 427) referred to as histamine Hi receptors. Drugs that block the histamine Hi receptors are referred to below as histamine Hi antagonists. 45 Another part of the biological effects of histamine is not inhibited by the histamine hi-antagonists. Effects of this type that are inhibited by a compound by Black and Mitarb. (Nature, Vol. 236 [1972], p. 385) as burimamide are transmitted by receptors, which Black and Mitarb. Call histamine ^ receptors. Histamine H2 receptors are histamine receptors that are not blocked by mepyramine, but by burimamide. Compounds that block histamine H2 receptors are called histamine H2 antagonists 55. You 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 effect of histamine on blood pressure. In the treatment of certain diseases, such as inflammation, and the inhibition of the effect of «o

Histamine on blood pressure, a combination of Histamine Hi and H2 antagonists is useful.

The compounds of the general formula I prepared according to the invention are valuable medicinal substances which have activity both as histamine hi-antagonists and as 65

Histamine H2 antagonists. They can therefore be used both in the treatment of diseases in which administration of histamine H2 antagonists is useful and in those in which a combination of histamine Hi and H2 antagonists is desired.

The compounds of the general formula I are histamine ^ receptor blockers, that is to say they block the biological effects of histamine which are not blocked by histamine hi-antagonists, such as mepyramine, but by burimamide. They inhibit z. B. the histamine-stimulated acid secretion in perfused stomachs of urethane-anesthetized rats at intravenous doses of 0.5 to 16 micro-mol / kg. In this test, many of the compounds produced according to the invention cause at least 50 percent inhibition at doses of 1 to 10 micromoles / kg. The test procedure is described in the Ash and Schild publication cited above. Other effects of histamine that are not caused by histamine Hi receptors, such as the effect on the isolated right auricle of the guinea pig and on the isolated rat uterus, are inhibited by the compounds produced according to the invention.

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

In addition, the compounds produced according to the invention have an anti-inflammatory effect, as was demonstrated in the rat paw test. The volume of the rat paw is reduced by subcutaneous administration of a dose of approximately 500 micromoles / kg of a compound of the general formula I. The measurement of the blood pressure of anesthetized cats shows that the compounds according to the invention inhibit the vasodilatory effect of the histamine.

The activity of the compounds produced according to the invention is shown by the 50 percent inhibition of gastric acid secretion in the anesthetized rat, which is achieved with many of the compounds of general formula I prepared according to the invention at doses of 1 to 10 micromoles / kg, and by the 50 percent inhibition by histamine induced tachycardia in the isolated right auricle of the guinea pig, which is achieved with many of the compounds of general formula I prepared according to the invention at doses lower than 10-5 mol / kg.

The compounds of the general formula T s; nd also

Histamine Hi receptor blockers, i.e. H. they block the biological effects of histamine, which are blocked by mepyramine, diphenhydramine and chlorpheniramine. For example, the compounds produced according to the invention inhibit the action of histamine on the isolated intestine of the guinea pig. Many of the compounds of the general formula I prepared according to the invention inhibit the contractions of the isolated intestine of the guinea pig stimulated by histamine at doses of 10 "mol / kg.

For therapeutic use, the compounds prepared according to the invention are administered in conventional dosage forms which contain at least one of these compounds as the active ingredient in the basic form or in the form of a salt with an acid and carriers and / or diluents. The carrier 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 produced according to the invention can be made up into a wide variety of dosage forms. When using solid carriers, the preparations can be tabletted, filled into hard gelatin capsules in powder or granular form, or processed into pastilles or candies. The amount of solid carrier can be in a relatively wide range, preferably about 25 mg to 1 g are used. When using a liquid carrier, the preparation can be administered as a syrup, emulsion, soft gelatin capsule, injection preparation, as an aqueous or non-aqueous suspension.

The medicaments are produced in the desired form by customary processes, such as mixing, granulating, pressing or by dissolving the constituents. 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.

example 1

2- [2- (5-methyl-4-imidazolylmethylthio) ethylamino] -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 and 400 ml of ethanol are 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, mp 193 to 194 ° C.

b) 17.7 g of 5- (4-chlorobenzyl) -2-methylthio-4-pyrimidone and 11.4 g of 2- (5-methyl-4-imidazolylmethylthio) ethylamine are mixed intimately and 5 hours at 145 to 150 ° 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 of F. 204.5 to 206 ° C is obtained.

Example 2

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

According to Example 1 a), 1.8 g of 5- (2-phenylethyl) -2-thiouracil are converted into 5-phenylethyl-2-methylthio-4-pyrimidone of mp 160 to 161 ° C. after recrystallization from ethanol. According to Example 1 b), the reaction of 1.55 g of 5-phenylethyl-2-methylthio-4-pyrimidone with

625801

1.1 g of 2- (5-methyl-4-imidazolylmethylthio) ethylamine is an oil which is dissolved in 2N hydrochloric acid. The solution obtained is then evaporated to dryness and the residue is recrystallized from methanol. The title compound of mp 214 to 218 ° C. is obtained.

Example 3

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

According to Example 1 a), 4.65 g of 5- (4-methylbenzyl) -2-thiouracil in 5- (4-methylbenzyl) -2-methylthio-4-pyrimidone of mp 208.5 to 211 ° C. after recrystallization converted from a mixture of methanol and ethanol. Then 1.6 g of 5- (4-methylbenzyl) -2-methyl-thio-4-pyrimidone according to Example 1 b) with 1.2 g of 2- (5-methyl-

4-imidazolylmethylthio) ethylamine reacted and then acidified with a dilute solution of hydrogen chloride in ethanol. The solution obtained is evaporated to dryness and the residue is recrystallized from ethanol. The title compound of F. 197 to 198.5 ° C is obtained.

Example 4

2- [2- (5-Methyl-4-imidazolylmethylthio) ethylamino] -5- (3-chlorobenzyl) -4-pyrimidone dihydrochloride a) 4.25 g sodium wire in 110 ml anhydrous diethyl ether are added within 6 hours 39.3 g of ethyl 3- (3-chlorophenyl) propionate and 14.9 g of ethyl formate were added to an ice-brine bath while stirring and cooling, then stirred at room temperature for 18 hours and then evaporated to dryness. The residue obtained is boiled under reflux with 14.05 g of thiourea and 100 ml of ethanol for 7 hours and then evaporated to dryness. The residue is taken up in water and acetic acid is added to pH 4. The colorless precipitate which has separated out is filtered off, washed and recrystallized from ethanol. It will

5- (3-Chlorobenzyl) -2-thiouracil of mp 192 to 195 ° C obtained.

b) According to Example 1 a) 3.1 g of 5- (3-chlorobenzyl) -2-thiouracil in 5- (3-chlorobenzyl) -2-methylthio-4-pyrimidone of mp 178.5 to 180.5 ° C converted from ethanol after recrystallization. Thereafter, 1.8 g of the compound obtained in Example 1 b) are reacted with 1.14 g of 2- (5-methyl-4-imidazolylmethylthio) ethylamine, then treated with a solution of hydrogen chloride in ethanol and finally recrystallized from ethanol. The title compound of F. 212.5 to 216 ° C is obtained.

Example 5

2- [2- (5-methyl-4-imidazolylmethylthio) ethylamino] -5- (3,4-dichlorobenzyl) -4-pyrimidone dihydrochloride a) According to Example 4 a), 48.9 g of 3- (3, 4-dichlorophenyl) propionic acid ethyl ester in 5- (3,4-dichlorobenzyl) -2-thiouracil of mp 232.5 to 233.50 C after recrystallization from a mixture of methanol and ethanol converted.

b) According to Example 1 a), 5.7 g of 5- (3,4-dichlorobenzyl) -2-thiouracil in 5- (3,4-dichlorobenzyl) -2-methylthio-4-pyrimido-don from 216 to Converted 218 ° C after recrystallization from acetic acid.

c) The reaction of 2.1 g of 5- (3,4-dichlorobenzyl) -2-methylthio-4-pyrimidone according to Example 3 with 1.2 g of 2- (5-methyl-4-imidazolylmethylthio) ethylamine gives after Recrystallize the title compound of mp 235.5 to 238.5 ° C from a mixture of water and methanol.

7

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625 801

Example 6

2- [2- (2-Thiazolylmethylthio) ethylamino] -5- (4-chlorobenzyl) -4-pyrimidone monohydrochloride 1.36 g of 5- (4-chlorobenzyl) -2-methylthio-4-pyrimidone and 0.9 g of 2- (2-thiazolylmethylthio) ethylamine are mixed intimately and heated at 130 to 135 ° C. for 3 hours. After cooling, the reaction mixture is treated with 2N hydrochloric acid and then evaporated to dryness. The residue is recrystallized from a mixture of isopropanol and methanol. The title compound of F. 172.5 to 174.5 ° C is obtained.

Example 7

2- [2- (5-Methyl-4-imidazolylmethylthio) ethyl jiylamino] -5- (4-methoxybenzyl) -4-pyrimidone dihydrochloride 3.0 g of 5- (4-methoxybenzyl) -2-methylthio-4-pyrimidone and 1.95 g of 2- (5-methyl-4-imidazolylmethylthio) ethylamine are mixed intimately and heated to 135 to 140 ° C. for 6 hours with frequent stirring. After cooling, the reaction mixture is digested with hot water, filtered, washed with anhydrous diethyl ether and dissolved in isopropanol. The solution obtained is acidified with a dilute solution of hydrogen chloride in ethanol, evaporated to dryness and the residue is recrystallized from ethanol. The title compound of F. 198 to 200 ° C is obtained.

Example 8

2- [2- (5-methyl-4-imidazolylmethylthio) ethylamino] -5- (4-chlorobenzyl) -6-methyl-4-pyrimidone dihydrochloride a) According to Example 1 a), 5- (4-chlorobenzyl) -6-methyl-2-thiouracil with methyl iodide to 5 ~ (4-chlorobenzyl) -6-methyl-2-methylthio-4-pyrimidone of melting point 248 to 251 ° C.

b) According to Example 1 b), the reaction of 1.95 g of 5- (4-chlorobenzyl) -6-methyl-2-methylthio-4-pyrimidone with 1.19 g of 2- (5-methyl-4-imidazolylthio) -ethylamine after recrystallization from ethanol, the title compound from

F. 203 to 206.5 ° C.

Example 9

2- [2- (3-bromo-2-pyridylmethylthio) ethylamino] -5- (4-chlorobenzy]) - 4-pyrimidone monohydrochloride According to Example 2, 1.2 g of 5- (4-chlorobenzyl) -2- methylthio-4-pyrimidone reacted with 1.1 g of 2- (3-bromo-2-pyridylmethyl-thio) ethylamine. The reaction mixture obtained is acidified with a dilute solution of hydrogen chloride in ethanol, evaporated to dryness and the residue is recrystallized from a mixture of ethanol and water. The title compound of F. 215 to 218 ° C (dec.) Is obtained.

Example 10

2- [2- (5-methyl-4-imidazolylmethylthio) ethylamino] -5- (2-phenylethyl) -6-methyl-4-pyrimidone a) 6.4 g sodium are dissolved in 100 ml ethanol and mixed with 23, 4 g of ethyl a- (phenylethyl) -acetoacetate and 10.65 g of thiourea are added, the mixture is boiled under reflux for 5 hours and then evaporated to dryness. The solid residue is dissolved in water and acetic acid is added to pH 4. The colorless precipitate obtained is filtered off and recrystallized from ethanol. The 5- (2-phenylethyl) -6-methyl-2-thiouracil of mp 210 to 214 ° C. is obtained.

b) Example 1 is repeated with the change that instead of the 5- (4-chlorobenzyl) -2-thiouracil, the 5- (2-phenylethyl) -6-methyl-2-thiouracil prepared above is used. After recrystallization from methanol, the title compound of mp 222.5 to 224.5 ° C is obtained.

Example 11

2- [2- (5-methyl-4-imidazolylmethylthio) ethylamino] -5-benzyloxy-4-pyrimidone dihydrochloride a) According to Example 4 a), 60.0 g of ethyl benzyloxyacetate in 5-benzyloxy-2-thiouracil from mp 240 to 241 ° C after recrystallization from a mixture of acetonitrile and ethyl acetate in a volume ratio of 1: 1.

b) According to Example 1a), 10.0 g of 5-benzyloxy-2-thiouracil are converted into 5-benzyloxy-2-methylthio-4-pyrimidone of mp 184 to 185 ° C. after recrystallization from methanol.

c) The reaction 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 results in the title compound after recrystallization from ethanol from F. 161 to 162 ° C.

Example 12

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

According to Example 1a), 16.1 g of 5- (3-methoxybenzyl) -2-thiouracil in 5- (3-methoxybenzyl) -2-methylthio-4-pyrimidone of mp 143 to 144 ° C. after recrystallization from ethanol converted.

3.0 g of 5- (3-methoxybenzyl) -2-methylthio-4-pyrimidone are reacted according to Example 1 b) with 2.1 g of 2- (5-methyl-4-imidazolylmethylthio) ethylamine and then with one Solution of hydrogen chloride treated in ethanol. After recrystallization from ethanol, the title compound of mp 173 to 175.5 ° C is obtained.

Example 13

2- [2- (5-methyl-4-imidazolylmethylthio) ethylamino] -5- (2-chlorobenzyl) -4-pyrimidone dihydrochloride a) According to Example 4 a), 48.4 g of 3- (2-chlorophenyl) -propionic acid ethyl ester in 5- (2-chlorobenzyl) -2-thiouracil of mp 223 to 224 ° C after recrystallization from methanol converted.

b) According to Example 1a), 5.05 g of 5- (2-chlorobenzyl) -2-thiouracil in 5- (2-chlorobenzyl) -2-methylthio-4-pyrimidone of melting point 171 to 173 ° C. after recrystallization converted from 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 diluted with one Solution of hydrogen chloride treated in ethanol. After recrystallization from a mixture of methanol and ethanol, the title compound of mp 215 to 219 ° C is obtained.

Example 14

2- [2- (5-Methyl-4-imidazolylmethylthio) ethylamino] -5- (4-phenylbutyl) -4-pyrimidone dihydrochloride a) According to Example 4 a), 43.5 g of 6-phenylhexane-carboxylic acid ethyl ester in 5 - (4-Phenylbutyl) -2-thiouracil of mp 177.5 to 181 ° C after recrystallization from a mixture of ethanol and water converted.

b) According to Example 1a), 3.05 g of 5- (4-phenylbutyl) -2-thiouracil in 5- (4-phenylbutyl) -2-methylthio-4-pyrimidone of melting point 146 to 149 ° C. after recrystallization converted from ethanol. Thereafter, 1.89 g of 5- (4-phenylbutyl) -2-methylthio-4-pyrimidone according to Example 1 b) are reacted with 1.18 g of 2- (5-methyl-4-imidazolylmethylthio) ethylamine and then diluted with one Solution of hydrogen chloride treated in ethanol. After recrystallization from ethanol, the title compound of mp 207 to 209.5 ° C is obtained.

8th

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Example 15 2- [2- (5-methyl-4-imidazolylmethylthio) ethylamino] - 5 - [5 - (1,3-b enzodioxolyl) methyl] -4-pyrimidone dihydrochloride a) According to Example 4 a) 17.5 g of ethyl 3- [5- (1,3-benzodioxolyl)] propionate in 5- [5- (1,3-benzodioxolyl) methyl] -2-thiouracil from F, 158 to 159 ° C. after recrystallization converted from a mixture of ethanol and methanol in a ratio of 1: 1.

b) According to Example 1 a), 2.9 g of 5- [5- (1,3-benzodioxolyl) methyl] -2-thiouracil in 5- [5- (1,3-benzodioxolyl) methyl] - 2-methylthio-4-pyrimidone of mp 197 to 198 ° C after recrystallization from acetonitrile.

1.2 g of 5- [5- (1,3-benzodioxolyl) methyl] -2-methylthio-4-pyrimidone are mixed in accordance with Example 1b) with 0.77 g of 2- (5-methyl-4-imidazolylmethylthio) - Ethylamine reacted and then treated with a solution of hydrogen chloride in ethanol.

After recrystallization from ethanol, the title compound of mp 230 to 232 ° C. is obtained.

Example 16

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

According to Example 1a), 5.0 g of 5- (3-ethoxybenzyl) -2-thiouracil are converted into 5- (3-ethoxybenzyl) -2-methylthio-4-pyrimidone of mp 136 to 1380 C after recrystallization from acetonitrile . 2.0 g of 5- (3-ethoxybenzyl) -2-methylthio-4-pyrimidone are reacted according to Example 1 b) with 1.25 g of 2- (5-methyl-4-imidazolylmethylthio) ethylamine and then with one Solution of hydrogen chloride treated in ethanol. After recrystallization from ethanol, the title compound of mp 176 to 178 ° C is obtained.

Example 17

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

According to Example 1a), 4.6 g of 5- (3-benzyloxybenzyl) -2-thiouracil in 5- (3-benzyloxybenzyl) -2-methylthio-4-pyrimidone, melting at 176 to 178 ° C, are recrystallized Converted ethyl acetate. 2.0 g of 5- (3-benzyloxy-benzyl) -2-methylthio-4-pyrimidone are reacted according to Example 1 b) with 1.0 g of 2- (5-methyl-4-imidazolylmethylthio) ethylamine and then with one Solution of hydrogen chloride treated in ethanol. After recrystallization from a mixture of ethanol and methanol in a ratio of 1: 1, the title compound of mp 193 to 194 ° C. is obtained.

Example 18

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

According to Example 1 a) 6.7 g of 5- (l-naphthylmethyl) -2-thiouracil in 5- (l-naphthylmethyl) -2-methylthio-4-pyrimidone of mp 178 to 180 ° C. after recrystallization converted from methanol. 0.4 g of 5- (l-naphthylmethyl) -2-methylthio-4-pyrimidone are reacted according to Example 1 b) with 0.25 g of 2- (5-methyl-4-imidazolyl-methylthio) ethylamine and then with one Solution of hydrogen chloride treated in ethanol. After recrystallization from ethanol, the title compound of mp 228 to 230 ° C is obtained.

Example 19

Example 4 is repeated with the change that instead of the 3- (3-chlorophenyl) propionic acid ethyl ester, the 3- (3,4,5-trimethoxyphenyl) propionic acid ethyl ester is used. The 2- [2- (5-methyl-4-imidazolylmethylthio) ethylamino] -5- (3,4,5-trimethoxybenzyl) -4-pyrimidone is obtained.

625 801

Example 20

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

Example 21

Example 7 is repeated with the change that the following amines are used instead of 2- (5-methyl-4-imidazolylmethylthio) ethylamine:

(a) 2- (2-Imidazolylmethylthio) ethylamine

(b) 2- (4-Imidazolylmethylthio) 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- (3-methyl-2-pyridylmethylthio) ethylamine

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

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

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

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

The following connections are obtained:

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

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

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

(d) 2- [2- (5-Trifluoromethyl-4-imidazolylmethylthio) ethylamino] -5- (4-methoxybenzyl) -4-pyrimidone

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

(f) 2- [2- (2-Pyridylmethylthio) ethylamino] -5- (4-methoxybenzyl) -4-pyrimidone

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

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

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

(j) 2- [2- (3-amino-2-pyridylmethylthio) ethylamino] -

5- (4-methoxybenzyl) -4-pyrimidone (k) 2- [2- (3-hydroxy-2-pyridylmethylthio) ethylamino] -

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

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

5- (4-methoxybenzyl) -4-pyrimidone (n) 2- [2- (3- (l, 2,5) -Thiadiazolylmethylthio) ethylaminol-

5- (4-methoxybenzyl) -4-pyrimidone (o) 2- [2- (4-chloro-3- (1,2,5) thiadiazolylmethylthio) -

ethylamino] -5- (4-methoxybenzyl) -4-pyrimidone (p) 2- [2- (5-amino-2- (l, 3,4) -thiadiazolylmethylthio) ethylamino] -5- (4-methoxybenzyl) -4-pyrimidone.

Example 22

Example 12 is repeated with the change that the 4- (4-imidazolyl) butylamine is used instead of the 2- (5-methyl-4-imidazolylmethylthio) ethylamine. It will

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625 801

2- [4- (4-Imidazolyl) butylamino] -5- (3-methoxybenzyl) -4-pyrimidone, mp 193 to 194 ° C.

Example 23

The reaction of butyroacetic acid ethyl ester with sodium ethylate and 4-methoxybenzyl chloride gives the a- (4-methoxy-benzyl) -butyroacetic acid ethyl ester, which with refluxing with thiourea and sodium ethylate to give 5- (4-methoxy-benzyl) -6-propyl-2- thiouracil is implemented. The use of 5- (4-methoxybenzyl) -6-propyl-2-thiouracil instead of 5- (4-chlorobenzyl) -2-thiouracil gives 2- [2- (5-methyl-4 -imidazolylmethylthio) ethylamino] -5- (4-methoxybenzyl) -6-propyl-4-pyrimidone.

Example 24

Example 4 is repeated with the change that the following esters are used instead of the 3- (3-chlorophenyl) propionic acid ethyl ester:

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

(b) Ethyl 3- (4-trifluoromethylphenyl) propionate

(c) Ethyl 3- (4-dimethylaminophenyl) propionate

(d) Ethyl 3- (4-phenoxyphenyl) propionate

(e) 3- [4- (4-Chlorophenoxy) phenyl] propionic acid ethyl ester

(f) Ethyl 3- [4- (4-methoxyphenoxy) phenyl] propionate

(g) Ethyl 3- (4-biphenylyl) propionate

(h) Ethyl 3- (4'-chloro-4-biphenylyl) propionate

(i) Ethyl 3- (4'-methoxy-4-biphenylyl) propionate. The following connections are obtained:

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

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

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

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

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

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

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

(h) 2- [2- (5-Methyl-4-imidazolylmethylthio) ethylamino-5- [4- (4-chlorophenyl) benzyl] -4-pyrimidone

(i) 2- [2- (5-Methyl-4-imidazolylmethylthio) ethylamino] -5- [4- (4-methoxyphenyl) benzyl] -4-pyrimidone

Example 25

The reaction of 2- [2- (5-methyl-4-imidazolylmethylthio) ethylamino] -5- (3-benzyloxybenzyl) -4-pyrimidone with hydrogen bromide in acetic acid gives the 2- [2- (5-methyl-4 -imidazolylmethylthio) ethylamino] -5- (3-hydroxybenzyl) -4-pyrimidone.

Example 26

a) Butyrolactone is reacted with sodium and ethyl formate and then in succession with thiourea and methyl iodide to give 5- (2-hydroxyethyl) -2-methylthio-4-pyrimidone.

b) 5- (2-Hydroxyethyl) -2-methylthio-4-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- (4-methoxybenzyloxy) ethyl] -2-methylthio-4-pyrimidone or

2) 5- [2- (4-methoxybenzylthio) ethyl] -2-methylthio-4-pyrimidone reacted.

c) The use of:

1.5- [2- (4-methoxybenzyloxy) ethyl] -2-methylthio-4-pyrimidone

2.5- [2- (4-methoxybenzylthio) ethyl-2-methylthio-4-pyrimidone instead of 5- (4-chlorobenzyl) -2-methylthio-

4-pyrimidone in the reaction according to Example 1 b) gives the following compounds:

1.2- [2- (5-methyl-4-imidazolylmethylthio) ethylamino] -

5- [2- (4-methoxybenzyloxy) ethyl] -4-pyrimidone

2.2- [2- (5-Methyl-4-imidazolylmethylthio) ethylamino] -5- [2- (4-methoxybenzylthio) ethyl] -4-pyrimidone.

d) The use of 1) phenol and 2) thiophenol instead of the 4-methoxybenzyl alcohol in Example 26 b) and c) gives the following compounds:

1.2-f2- (5-methyl-4-imidazolylmethylthio) ethylamino] -5- (2-phenoxyethyl) -4-pyrimidone

2.2- [2- (5-Methyl-4-imidazolylmethylthio) ethylamino] -5- (2-phenylthioethyl) -4-pyrimidone.

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

1.2- [2- (5-Methyl-4-imidazolylmethylthio) ethylamino] -5- [2- (2-phenylethoxy) ethyl] -4-pyrimidone

2.2- [2- (5-Methyl-4-imidazolylmethylthio) ethylamino] -5- [2- (2-phenylethylthio) ethyl] -4-pyrimidone.

f) The use of caprolactone instead of the butyro-lactone in the reaction according to Examples 26 a), b) and c) gives the following compounds:

1.2- [2- (5-Methyl-4-imidazolylmethylthio) ethylamino] -5- [3- (4-methoxybenzyloxy) propyl] -4-pyrimidone

2.2- [2- (5-Methyl-4-imidazolylmethylthio) ethylamino] -5- [3- (4-methoxybenzylthio) propyl] -4-pyrimidone.

Example 27

The use of a) 3-phenylpropoxyacetic acid ethyl ester and b) 3-phenylpropylthioglycolic acid ethyl ester instead of the benzyloxyacetic acid ethyl ester in the reaction according to Example 11 gives the following compounds:

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

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

Example 28

The use of a) 5- {3- [2- (4-methoxyphenyl) ethoxy] benzyl} -2-thiouracil and b) 5- [3- (3-chlorobenzyloxy) benzyl] -2-thiouracil instead of 5- (3-BenzyloxybenzyI) -2-thiouracil in the reaction according to Example 17 gives the following compounds:

(a) 2- [2- (5-Methyl-4-imidazolylmethylthio) ethylamino] -5- {3- [2- (4-methoxyphenyl) ethoxy] benzyl} -4-pyrimidone

(b) 2- [2- (5-Methyl-4-imidazolyImethyIthio) ethylamino] -5 - [3 - (3-chlorobenzyloxy) benzyl] -4-pyrimidone.

Example 29

The use of a) 3- [6- (2,3-dihydro-l, 4-benzo-dioxinylj-propionic acid ethyl ester and b) 3- (3-bromophenyl) propionic acid ethyl ester instead of 3- (3-chlorophenyl) - Ethyl propionate in the reaction according to Example 4 gives the following compounds:

a) 2- [2- (5-Methyl-4-imidazolylmethylthio) ethylamino] -5- [6-2,3-dihydro-l, 4-benzodioxinyl) methyl] -4-pyrimidone b) 2- [2 - (5-Methyl-4-imidazolylmethylthio) ethylamino] -5- (3-bromobenzyl) -4-pyrimidone.

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Example 30

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 4 results

625 801

the 2- [2- (5-methyl-4-imidazolylmethylthio) ethylamino] -5- [3- (methoxymethoxy) benzyl] -4-pyrimidone, from which after the reaction with hydrochloric acid the 2- [2- (5 -Methyl-4-imidazolyl-methylthio) ethylamino] -5- (3-hydroxybenzyl) -4-pyrimidone is obtained.

B

Claims (3)

625 801 2 PATENT CLAIMS I. Process for the preparation of pyrimid-4-one derivatives of the general formula I Het'-CHgZCHgCHg ffifL / <CH2) mW (CH2) nA -NH- ^ SÎ (I) 15 in the Het 'a 2- or 4-imidazolyl group optionally substituted by lower alkyl radicals, halogen atoms, trifluoromethyl or hydroxymethyl groups, a 2-pyridyl group optionally substituted by lower alkyl radicals, lower alkoxy radicals, halogen atoms, amino or hydroxyl groups, a 2-thiazolyl group, a 3-isothiazolyl group optionally substituted by chlorine or bromine atoms, a 3- (1, 2,5) -thiadiazolyl group optionally substituted by chlorine or bromine atoms or a 2- (5-amino-l, 3,4-thiadiazolyl group means Z is a sulfur atom or a methylene group, X is an oxygen atom, W is a methylene group, an oxygen or sulfur atom and Y3 is a hydrogen atom 2s or a lower alkyl radical, the sum of m and n is a value of 1 to 4 if W is an oxygen or sulfur atom, or has a value of 0 to 4 if W is a methylene group and A is a 1- or 2-naphthyl, a 2,3-dihydro-1,4 -benzodioxinyl or a 1,3-benzodioxolyl group or one by at least one lower alkyl, lower alkoxy, arylalkoxy, alkoxyalkoxy, di-lower alkylamino, halophenoxy, alkoxyphenoxy, halophenyl or alkoxyphenyl radical or at least one halogen atom or at least one a hydroxyl, trifluoromethyl, 35 Phenoxy or phenyl group is substituted phenyl group, which can also be unsubstituted if the radical - (CH2) mW (CH2) n- does not mean a methylene group, and their salts with acids, characterized in that an amine of the general formula II 40 that one carries out the reaction in a solvent. 4. The method according to claim 1, characterized in that one carries out the reaction in pyridine. 5. Use of the compounds of the formula I obtained by the process according to claim 1 for the preparation of the corresponding compounds in which X is sulfur, characterized in that the compound obtained is reacted with phosphorus pentasulfide. In GB-PS 1419 994 are pyrimid-4-one and -thione derivatives of the general formula 30th R-NH AA H Het'-CH2ZCH2CH2NH2 (II) described in which X represents an oxygen or sulfur atom, Y1 and Y2, with the same or different meaning, represent hydrogen atoms, lower alkyl, aryl or aralkyl radicals, and R represents a radical of the general formula in which Het 'and Z have the meaning given above, with a pyrimid-4-one derivative of the general formula III 45 Het-CH2Z (CH2) n-reacted , ((M2)! NW (CH2) nA (III) in which W, Y3, m, n and A have the meaning given above and Q represents a reactive radical which is displaced in the reaction with an amine, and in that the compound of the formula I obtained is optionally reacted with an inorganic or organic acid transferred a salt. 2. The method according to claim 1, characterized in that that a pyrimid-4-one derivative of the general formula III is used in which Q denotes a methylthio group. 3. The method according to claim 1, characterized in means in which Het is a heterocyclic radical which is optionally substituted by lower alkyl radicals, halogen atoms, amino or hydroxyl groups and contains nitrogen atoms, such as an imidazole, pyridine, thiazole, isothiazole or thiadiazole group, and Z is a Is a sulfur atom or a methylene group and n is 2 or 3. Tautomers of these compounds and their activity as histamine Hz antagonists are also described. It has been found that a particular group of compounds, some of which fall within the definition of the general formula above, have certain advantages over the remaining group of compounds of the above-60 general formula. These certain compounds have a greater activity than histamine H2 antagonists than the other compounds of the above general formula and, in addition to their activity as histamine H2 antagonists, are also effective as histamine Hi-65 antagonists.