CS203003B2 - Process for preparing isocytosines - Google Patents

Abstract

There is disclosed the preparation of compounds of the formula wherein Het' is a 2- or 4-imidazolyl ring optionally substituted by lower alkyl (preferably methyl), halogen (preferably chlorine or bromine), trifluoromethyl or hydroxymethyl, a 2-pyridyl ring optionally substituted by lower alkyl {preferably methyl), lower alkoxy (preferably methoxy), halogen (preferably chlorine or bromine), amino or hydroxy, a 2-thiazolyl ring, a 3-isothiazolyl ring optionally substituted by chlorine or bromine, a 3-(1,2,5) thiadiazolyl ring optionally substituted by chlorine or bromine, or a 2-(5-amino-1,3,4-thiadiazolyl) ring; Z is sulphur or a methylene group; X is oxygen or sulphur; W is methylene, oxygen or sulphur; m and n are such that their sum is from 1 to 4 when W is oxygen or sulphur, or from O to 4 when W is methylene; A is a 1- or 2-naphthyl ring, a 2,3-dihydro-1,4-benzodioxinyl or a 1,3-benzodioxolyl ring, a phenyl ring substituted with one or more lower alkyl, lower alkoxy, halogen, arylalkoxy, hydroxy, alkoxyalkoxy, trifluoromethyl, di(loweralkyl)amino, phenoxy, halophenoxy, alkoxyphenoxy, phenyl, halophenyl or alkoxyphenyl group and when is not a methylene group, A may also be phenyl; and Y3 is hydrogen or lower alkyl. The compounds have both histamine H1-antagonist and H2-antagonist activity.

Description

The subject of the invention is a process for the preparation of pharmacologically active substances, as well as pharmaceutical preparations containing them. The compounds prepared by the process of the present invention can be used as H 2 -amine antagonists as well as H-histamine antagonists. The compounds of the present invention may exist in the form of acid addition salts, but to simplify the text, the compounds are referred to as such. Heraamine antagonists can be defined as compounds that block the histamine H 2 receptors. Histamine receptors are not blocked by mepyramines with typical antihisasminics, such as histamine H receptor antagonists, but are blocked by bucinamide, see Black et al., Naura 2 3 6, 385 (1967). Hisaemin antagonists can be used as suitable inhibitors of gastric secretion, anti-inflammatory agents, and cardiovascular agents. syst ^ ^ m.

The present invention relates to a process for the preparation of isocstines of formula (1)

Het-C ^ CC ^ C ^ ³ y -NH

(1), wherein Het is a 4-imidazolyl ring optionally substituted with C 1 -C 4 alkyl, preferably. methyl, a 2-pyridyl ring optionally substituted with a halogen atom, preferably a chlorine or bromine atom, or a 2-thiazole ring,

Z is a sulfur atom or meehylene,

X is an oxygen or sulfur atom,

W is methylene or an oxygen or sulfur atom, and is not an integer from 1 to 4, if W is an aromatic or sulfur atom or an integer of 0 to 4, if W is methylene,

A is 1-naphthyl, 2,3-dihydro-1,4-benzodioxinyl or 1,3-benzodioxolyl, phenyl substituted with one or more C 1 -C 4 alkyl, C 1 -C 4 alkoxy, hydroxy, halogens, trilloimethyl or benzyloxy groups and if U- (SiN) is not methylene group A, it may also be phenyl and y 3 is hydrogen or C 1 -C 4 alkyl.

A preferred group of compounds are those wherein n is 0 and W is methylene. Another preferred group of compounds are those wherein n is 1, wherein W is oxygen.

The compounds of formula I can be expressed and described as 4-ones and 4-thiones, and these derivatives are in equilibrium with the corresponding 6-ones and 6-thions as tautomers. To a lesser extent, these substances may exist as mecaptothutomers or hydroxytautomers, and the pyrimidine ring may also exist in the following tautomeric forms:

2e may also exist in several tautomeric forms and it is intended that all such tautomeric forms are within the scope of the present invention.

The compounds of the invention can be prepared by reacting an amine of formula II

2et-C22ZC22C22NH2 / 11 /, wherein 2e * and Z are as defined above, reacted with a compound of formula III

(III) wherein X, w, A are as defined above and Q is C1-C4 alkylthio, benzylthio or halogen in the absence of a solvent at a temperature of from 100 to 150 ° C or in a solvent such as pyridine at a temperature of boiling.

Intermediates of formula III wherein W is a methylene group

Y 1 is hydrogen and Q is C 1 -C 4 alkyl (see Formula VI) can be prepared according to Reaction Scheme 1.

WITH

Reaction Scheme 1: (A) has the meanings as given in formula (I) and a represents 0 to 4, alkyl represents an alkyl group having 1 to 4 carbon atoms;

A (CH 2) aCH 2 CH 2 COOC 2 H ₅ ^{s =} V °. 4 an alkyl halide or sulfate

1 / Na 2 HCO0C2H5 / thiourea / IV /, / V /, / VI /, ^н н ^/ Ч _сн-2 (сн _{2) п а alkyl-N} 4> «O

Esters of formula IV wherein a is 0 may be prepared by condensing a substituted benzaldehyde derivative with malonic acid followed by hydrogenation and esterification of the product. .

Intermediates of formula III wherein W is methylene, Y ³ is C 1 -C 4 alkyl and Q is C 1 -C 4 alkylthio (see Formula VII) can be prepared according to Scheme 2.

Reaction Scheme 2: (wherein up to 4, halogen is chlorine):

Or A has the meanings as given for the shown in formula I, and \ _r bromine and alkyl is an alkyl group having 1-4 carbon is 0 UHL-iγ3 - COCH2COOC2H ₅

NaOC ₂ H ₅ , halogen (1 H) / A

CH 2 (CH 2) aA ₃ I 3 -cOCHCOOC ₂ H ₅

I thi omocov ina y3 s = <J = o

NH alkyl halide or sulfate

Intermediates of general reaction scheme 3.

CH ₂ (CH ₂ ) _n A

O (VII) of formula III, wherein Q is halogen, can be prepared according to

Scheme 3 (where a halogen is chlorine or bromine):

And Y ³ are as defined in formula I, and a is 0-4

CH ₂ (CH _{2) and} A

Y ³ COCHCOOC ₂ H ₅ (as sodium salt)

(VIII) guanidine

Y3

l

1. HCl, NaNO2

2. hal ^ genid has days γ3 halogen

CH2 ^(CH2 ) ^and A

O / ix /

Compounds of formula VIII, wherein Y ³ is hydrogen, can be prepared from compounds of formula IV, sodium and ethyl formate, and compounds of formula VIII, where Y ³ is C 1 -C 4 alkyl, can be prepared using the procedure outlined in Reaction Scheme 2.

Intermediates of formula III wherein W is oxygen or sulfur may be prepared using the following methods:

and / n is 0

A / CH ₂ / _n WCH ₂ COOC ₂ H ₅

1 / HCOOC ₂ H ₅ , Na 2 / thiourea

3) an alkyl halide or alkyl sulfate

HN (R) (CH ₂ ) _n A-alkyl-S-4 _N > = 0

W is oxygen or sulfur b / n is 1

These compounds can be prepared using the procedure of:

N 2 VCH ₂ OH h ₂ nU J = o

1. SOCl 3 or HBr

2. Α (ΟΗ ₂ ) _η Ο ~ Νβ · '· or

AlCHjlnS-Na ·

HN 2 S-CH ₂ W (CH ₂ ) _n A

W represents oxygen or sulfur

1. HCl NaNO ₂

2. copper halide

HN 4 4 -CH ₂ W (CH ₂ ) _n A halogen 4 = 0

N

W represents Oxygen or Sulfur halogen

W represents oxygen or sulfur or otherwise using ethyl 4-benzyloxybutyrate or a similarly protected derivative of ethyl 4-hydroxybutyrate in analogy to the procedure outlined in Scheme 1, followed by sequential removal of the capping group, further treating thionyl chloride and then compound Α / ΟΗ ₂ / _η θ ^Η or A / CH ₂ / _n SH in the form of a sodium derivative.

c / m is 2 to 4

1. Thiourea

2. an alkyl halide or alkyl sulfate

alkyl

First ^SOCl2 | A second _{(CH2) n} ~ ⁺ No ^No BO (CH ₂₎ n ^_ Na ⁺

H N ^{from X - (} R 1 H 2) ^m W (CH 2) ⁿ A and ^alkyl 1 -?

N

W is oxygen or sulfur; m is 2 to 4

Compounds of formula I wherein X is sulfur may be prepared by treating compounds of formula I wherein X is oxygen with phosphorus pentasulfide in a solvent such as pyridine.

The amines of formula (II) may be prepared using the procedures described in British Patent Specifications 1305547 and 1338169.

The anti-hisaamine activity of the compounds of formula I can be demonstrated by inhibiting hisaamine-stimulated gastric acid secretion from the perforated stomachs of rats after urethane anesthesia in doses ranging from 0.5 to 16 micromoles per kg intravenously. For many of the compounds of the invention, at least 50% can be detected in this assay at a dose of from 1 to 10 micromoles per kg.

Many of the compounds of formula (I) inhibit histamine-stimulated ileum of the urine (histamine-stimulated β-antagonistic activity against tistamines) and a dose of 10 µmol.

Pharmaceutical formulations using histamine as well as H 2 and H 2 O-carbohydrate moieties may be prepared by mixing the compound of formula I in base form or in the form of an addition salt with an acid, pharmacologically suitable, pharmacologically acceptable diluent or carrier.

The invention is described in more detail, but not limited, in the form of further examples where all temperature data are in degrees Celsius.

He did

2- [2- / 5-4--mekhtS imiddczlySLtnkhtSthto / kttnlaminč) L-5/4-etllrbečzsl / ^- 4-PDB imídon · I / A solution of 50.5 g of 5- / 4-etllrbknzy1 / -2-ttilujaeclu, 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 DEG C. for 30 minutes, then the reaction mixture is estimated. The crude product is filtered off and 48.6 g are collected by washing with water

5- (4-chlorobenzyl) -2-methylthio-4-pyrimidone, m.p. 193-194 ° C after crystallization from a mixture of methanol and ethanol.

(LL) A finely mixed mixture of 17.7 g of 5- (4-chlorobenzyl) -2-methyltho-4-ylmethylimidone and 11.4 g of 2- (5-methyl-4-imidazolylmethylthio) ethylamine is heated at 145-150 for 5 hours. Deň: 32 ° C. After cooling, the free base is liberated by trituration with water, which is separated by decantary crystallization from methanol to give a compound, the composition of which is given in the specification, m.p. 20-4.5-206 ° C.

Example 2 ..

2- [2- / 5-Methyl-4-imidazolylmethylthio / ethyl amino]] - 5- (phenylethyl) -4-pyrimidone,

Following the procedure described in Example 1, 1.8 g of 5- (2-phenylethyl) was converted to 5-phenylethyl-2-methoxy-4-pyrimidone, m.p. 160 DEG-161 DEG C. (after crystallization from ethanol). Reaction of 1.55 g of the obtained dimerone derivative with 1.1 g of 2- [5-methyl-4-imidazyclylmethyl] using the procedure of Example 1 affords the title product, which is dissolved in 2 N hydrochloric acid, the solution is concentrated to dryness, and crystallization of the residue from methanol to give the title compound, mp 214-218 ° C.

Example 3

2- [2- [5-Methyl] -4-imidazolylmethylthio / methylthienyl] -5- [4-methyl] methyl] dihydrochloride. -4-pyrimidone.

Following the procedure described in Example 11 (i), 4.65 g of 5- (4-methylbenzyl) -2-thiourea was converted to 5- (4-methylbenzyr) -2-methylthio-4-pyrimidine; mp 208.5 and mp 21 ° C after crystallization from a mixture of methanol and ethanol. Reaction of this pyrimidone derivative in an amount of 1.6 g with 1.2 g of 2- (5-methyl-4-pyrimidazolylmethylthio) -ethylamine using the procedure described in Example II), acidification with ethanolic hydrogen chloride solution yields after concentration to dryness and subsequent crystallization from ethanol. mp 197-198 ° C. .

Example 4.

2- [2- (5-Methyl-4-imidazolylmethylthi) ethhrlamine] -5- (3-chlorobenzyl) -4-pyrimidone (1) A mixture of 39.3 g of 3- (3-chlorophenyl) propyl ester and ethyl ester and 14 9 g of ethyl formate are added with stirring over 6 hours to a suspension of 4.25 sodium wires in 110 ml of dry ether; The reaction mixture was cooled in an ice bath and solA. The reaction mixture is stirred at room temperature for 18 hours, concentrated to dryness, the residue is treated with a solution of 15.04 g of thiourea in 100 ml of ethanol, and the reaction mixture is refluxed for 7 hours. . After concentration to dryness, the residue is dissolved in water and acidified to pH 4 by the addition of acetic acid. The precipitated white precipitate is filtered off and washed with water to give 5- (3-chlorobenzylamino) thiourea which has m.p. 192-195 ° C.

(3.1 g of 5- (3-chlorobenzyl) -2-thicuracil) was converted to 5- (3-chlorobenzyl) -2-methylthio-44-pyrrolidine (m.p. 178.5-180.5 ° C) by crystallization as described in Example 11 above. ethanol; reacting 1.8 g of the compound obtained with 1.14 g of 2- (5-methyl-4-methyl-4-methyl-ethyl-ethyl) -amine as described in Example 1 (ii) to obtain a residue, and adding the ethaned hydrogen chloride solution to the title compound. 212.5-216 ° C (ethanol).

Example 5

Dihydrochloride 2- [2- / 5-те1: “у1. ”4-1 1010а221у1те1: Ьу1К: с1с / е1: Ну1ат £ по] -5“ / 3,4- ^ £ЬооЬЬп2у1-4-pyrimidone.

48.9. g of 3- (3,4-dicylorphenyl) -propionic acid ethyl ester was converted to Example 4 using the procedure described in Example 4 (i). 5- / 3,4-dicyiorbenzyl / -2-tyiouuaaci, mp 232.5 to 33.5 ° C ^{2 / P} o brptaKzaci. 5.7 g of 5 - [(3,4-dicyiorbenzyl) -2-thiouracil] were converted to 5- (3) from a mixture of a mixture of methanol and methyl (ii). 4-Dichlorobenzyl (2-methylmethylthio-4-pyrimidine, m.p. 216-218 ° C (after crystallization from acetic acid)).

(iii) 2.1 g * 5 '(3,4-dicyiorbenzyl) -2-methyl-4-pyridyl-dione is used to react with 2- (5-methyl-4-imidazooyl-methyl-thio-4-yl-amine), 2 g / starting the procedure described in Example 3; 235.5 DEG-238.5 DEG C. (after crystallization from aqueous methylene chloride).

Example 6

2- [2- / 2-r-llyl, h-1-methylthio / ethylamino] -5- (4-cyiorbenzyl) -4-pyrimidone

The finely mixed mixture of 1.36 g of 5-tert-chlorobenzyl-2-ethylthio-4-iyrimirone and 0.9 g of 2- (2-thiazolylmethylthioethyl) amine is heated at 130 ° C to 135 ° C for 3.5 hours. After purification, a 2N hydrochloric acid solution was added to the reaction mixture, and concentrated to dryness followed by crystallization from a mixture of 2-propanol and methanol to give the title compound, mp 17.5.5-174.5 ° C. .

Example 7,

D ^ yc ^^ di yor^{id 2}- [²~^{/ 5-}me t^yy1-4-imi^d azo^ly^lme t^yy l^youi'o Zethy ^ mnol-fj-M-methoxy ^ nzy¹ / -4 -pyr imidone

Finely blended mixture of 3.0 g of 5- / 4-metyoxybenzy1 / metyy1tУio -2-4 ^- idrimirсnu and 1.95 g of 2 * / ** - / 5-imino-metУy1-4 azolylmetУy1tУiс ^d / ^y -etУ Aamin the zayřívá with occasional stirring of 6 hours at 135 and 140 ° C. After cooling, the reaction mixture is triturated with hot water, filtered, washed under ether on filter and washed with anhydrous ether and dissolved in 2-propanol. The solution was ok ^y yseí zředěnéyo adding ethanolic hydrogen chloride solution, and concentrated to Sucy the ^y Cr ^y ytaliiací ZB TKU from etyanolu gave compound the title, m.p., 198 to 200 ° C,

Shit.

DihjyirftccУоrid 2 ^- [2 "/ 5 - eehy11 - imiiraz0l1m-tey l1htiOeehy aminn0-5 1 5/4-chlorobenzyl ^{y 1/4} -O-metУyl- rimiCnnU ^s -ρ) / i / procedure as described in example 1, meeylates 5- (4-cylorbenzyl) -6-methyl- ^2- thiouracil; There was thus obtained 5- [4-cyiorbenzyl] -6-methyl-2-methyl-4-iimidimidone, m.p. 248 DEG-251 DEG.

H, 4.7; H, 10.0; N, 11.4%.

found: 55.3 7. C, 4.67 H, 9.9X N, 11.47 S.

(ii) Reaction of 1.95 g of 5- (4-chlorobenzyl) -6-ethyl-2-methylthin-4-pyrimidone with 1.19 g of 2- (5-methyl-4-imidazolylmethylthio) ethylamine using the procedure described in Example 1 / II / ^s from ská sl.uučei ^Ia _l uvedďná NAT Juseu ^ ^{t. t} . ² ° o6 ^{3-2 5} ° C ^/ s after floes Tali ^Zac and ^{from ethane} ° .u /. Example9 \ '

Monohydro c^hysteed^id ^ [- - ^^ rnm - ^ - ^ yrichlme^thy1^thi O^/e t^{hy y}amino]^{-5- / 4-}C^hlur^bnnzy^h/^-4-pyhi mdonu.

Reaction of 1.2 g of 5-N-chlnrbťtrzy h / -2-methyl-4-thyh.thin pyridinyl imidnnu with 1.1 g of 2- / 3-bromo-2-py yidy 1 'methyhthin / ethyl miiu ^and procedure for poiuití Example 2 yields a reaction mixture which is acidified by adding a dilute solution of hydrogen chloride in ethanol; concentration to dryness and crystallization of the residue from ethanol / water mixtures. to give the title compound, m.p. -15-218 ° C (dec.).

EXAMPLE 10 2- (2- (5-Methyl-4-methyl-4-phenyl-ethylene-ethylamino) -5- (phenylethyl) -2-2-methyl-2,4-pyrimidin-1-ol) 4 g. Of alpha .alpha.-ethyl-ethyl-acetic acid and 10.65 g. Of thiourea are added to a solution of 4.6 g of sodium in 100 ml. Of ethanol, and the reaction mixture is refluxed for 5.5 hours. a residue is obtained which is dissolved in water and adjusted to pH 4 by addition of acetic acid.

The white precipitate was o ^ ffltruje floes and after crystallisation from ethanol to give 5- / 2 ^ ^ ппуУп у У / -6-methy1-2-thinur ^and CC1, mp 210-214 ° C.

/ 2 / Ponuíje When in the general procedure of Example 1 instead of 5- / ^4-b chlnr enizhl 2-ttinuracilu -5- / 2- ^ ппу lethy1 / -6-meehy У ^^ Ьhnuuacc 1, the compound obtained is shown in the title, mp 222.5-224.5 ° C / after crystallization from meΤ.

Example 11

01ЬуУго'С.1Иог1Г 2- (2- / 5-methyl-1-4-imidíazo Пу lmeehhh thi n / ethyl. Amino- 5- enzyyoyy ^{b-4-pyrimidone} / i / 60.0 g ethyl-you-ester with benzhУoxhoctové according to the procedure described in Example 4 (i), to 4-benzyloxy-2-thinuration, m.p. 240 DEG-241 DEG C. (crystallized from mixtures and mixtures of ethyl acetate and ethyl ester). , 11 /.

(ii) 13.0 g of 5-benzyloxy-4-fluoroacil was converted to 5-benzyloxy-2-methoxy-4'-phthiimidine mp 184-185 ° C (crystallized from methanol) using the procedure of Example 1 / i /. .

(iii) 4.10 g of 5-benzyl-oxy-2-methylthio-4-pyrimidine was converted by reaction and 2.83 g of 2- (5-methyl-4-imiryl-ethyl) -amethylamine using the procedure of Example 3 to the title compound, mp 161-162 ° C (from ethanol).

Example 2

2- [2- (5-Methyl-4-imide) azolomethylthio / ethylamino] -5- (3-methylbenzyl) -4-pyrimidone dihydrochloride

16.1 g of 5- (3-methoxybenzyl) -2-thiourea are converted to 5- (3-methoxybenzyl) -2-methylthio-4-pyrimidone, m.p. 144 DEG C. (after crystallization from ethanol) using the procedure of Example 1 (i).

Reaction of 3.0 g of 5- (3-methoxybenzyl) -2-methyl- _1- thio-4-pyrimidone with 2.1 g of 2- (5-methyl-4-imidazolylmethylthio) ethylamine as described in Example 1) ii), to obtain a residue, and further treatment with a solution of hydrogen chloride in ethanol, the title compound, m.p. 173 DEG-175 DEG C. (after crystallization from ethanol).

Example 13

2- [2- (5-Methyl-4-imidazolylmethylthio) ethylamino} -5- (2-chlorobenzyl) -4-pyrimidone dihydrochloride (48) Using the procedure described in Example 4 (i), 48, 4 g of 3- (2-chlorophenyl) propionic acid ethyl ester on 5- (2-chloro-benzoic acid) m.p. 223 DEG-224 DEG C. after crystallization from methanol /.

(ii) 5.05 g of 5- (2-chlorobenzyl) -2-thiouration was converted to 5- (2-chlorobenzyl) -2-methylhio-4-pyrimidone (m.p. 171-173 ° C) after crystallization from ethanol. using the procedure of Example 1 (i). Further reaction of 1.6 g of 5- (2-chlorobenzyl) -2-methylthio-4-pyrimidone with 1.03 g of 2- (5-methyl-4-imidazolylmethylthio) ethylamine according to the procedure described in Example 1 (ii) yields The title compound, m.p. 215-219 ° C (after crystallization from a mixture of methanol and ethanol), was isolated by addition of a dilute solution of hydrogen chloride in ethanol.

Example 1 ε. d 14

2- [2- (5-Methyl-4-imidazolylmethylthio) ethylamino] -5- (4-phenylbutyl) -4-pyrimidone] 43.5 g of ethyl 6-phenylhexanoate were converted using the procedure of EXAMPLE 4 (i) to 5- (4-phenylbutyl) -2-1-thiouration 1. After crystallization from a mixture of ethanol and water, the compound has a melting point of 177.5 to 181 ° C.

(ii) Using the procedure of Example 1 (i), 3.05 g of 5- (4-phenylbutyl) -2-thiouration of 5- (4-phenylbutyl) -2-methylthio-4-pyrimidone of m.p. m.p. 146-149 ° C (after crystallization from ethanol).

Reaction of 1.89 g of 5- (4-methylbutylbutyl) -1H-4-pyrimidine with 1.18 g of 2- (5-methyl-4-imidazolyl) methylthio (Ethylamine according to the procedure of Example 1 (ii)) gave a residue and further treatment with a dilute solution of hydrogen chloride in ethanol to give the title compound, mp 207-209.5 ° C (after crystallization from ethanol).

Example 15

2- (2- (5-Methyl-4-imidoylmethylmethylthio) ethylamino) -5- [5- (1,3-benzodioxolyl) -4-pyrimidone] dihydrochloride. 17.5 g of ethyl 3- [5- (1,3-benzoyl-ol / propionic acid) ethyl ester were converted to 5- [5- (1,3-benzodioxolyl) methyl] -2-thiouracyl [eta] mp 158-159 ° C. C) after crystallization from a 1: 1 mixture of ethanol and methanol using the procedure described in Example 4 (i).

2.9 g of 5- [5- (13-benzyloxyolyl) thiophene-2-thiouryl] was converted using the procedure described in Example 1 (i) to 5- [5- (1,3-benzodioxolyl) methyl] -2-methylthio-4-pyrimidone, mp 197-198 ° C (after crystallization from acetonitrile).

Reaction 1.2 g of 5- [5- / 1,3-benzodioxolyll] methyl] -2-methylthio-4-pyrimidone 8 0.77 g of 2- (5-methyl) 4-Imidazolylmethylthio (ethylamine as described in Example 1 (ii)) yielded a residue, followed by treatment with a solution of hydrogen chloride in ethanol, the title compound, mp 230-232 ° C (after crystallization from ethanol).

Př.íkl. ad16 ¹

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

5.0 g of 5- (3-ethoxybenzyl) -2-thiouracil was converted to 5- (3-ethoxybenzyl) -2-methylthio-4-pyrimidone, mp 136-138 ° C (after crystallization from acetonitrile) using the procedure described in of Example 1 (i). Reaction of 2.0 g of 5- (3-ethoxybenzyl) -2-methylthio-4-pyrimidone with 1.25 g of 2- (5-methyl-4-imidazolylmethylthio) ethylamine, as described in Example 1 (ii), The residue is treated with a solution of hydrogen chloride in ethanol to give the title compound, mp 176-178 ° C (from ethanol).

Example17

2- [2- (5-methyl-4-imidazolylmethylthib) ethylamino] -5- (3-benzoxyoxybenzyl) -4-pyrimidone dihydrochloride. . »

4.6 g of 5- (3-benzyloxybenzyl) -2-thiouracil were converted according to the procedure described in Example 1 (i) to 5- (3-benzyloxybenzyl) -2-methylthio-4-pyrimidone, mp 176-178 ° C (after crystallization from ethyl acetate). Reaction of 2.0 g of 5- (3-benzyloxybenzyl) -2-methylthio-4'-pyrimidone with 1.0 g of 2- (5-methyl-4-imidazolylmethylthio) ethylamine as described in Example 1 (ii). The residue was treated with a solution of hydrogen chloride in ethanol to give the title compound, mp 193-194 ° C (after crystallization from methanol / ethanol).

Example 1 a d 18

2- [2- (5-Methyl-4-imidazolylmethylthio) -ethylamino] -5- (1-naphthylmethyl) -4-pyrimidone dihydrochloride

Using the procedure described in Example 1 (i), 6.7 g of 5- (1 ^{w of} naphthylmethyl) -2-thiouracil are converted to 5- (1-naphthylmethyl) -2-methylthio-4-pyrimidone, m.p. 178 DEG-180 DEG C. (after crystallization from methanol). Reaction of 0.4 g of 5- (1-naphthylmethyl) -2-methylthio-4-pyrimidone with 0.25 g of 2- (5-methyl-4-imidazolylmethylthio) ethylamine as described in Example 1 (ii). to give a residue, and further reaction with a solution of hydrogen chloride in ethanol, the title compound, mp 22.7-230 ° C (after crystallization from ethanol).

Example 1 a d 19

When 3- (3,4-trimethoxyphenyl) propionic acid ethyl ester is used in the general procedure as described in Example 4, instead of 3- (3-chlorophenyl) propionate, ethyl 2- (2) is obtained as the reaction product. - (5-methyl-4-imidazolylmethylthio) ethylamino] -5- (3,4,5-tri methoxybenzyl) -4-pyrimidone.

1

Example 20

Treatment of 2- [2- / 5-methyl-4-imidazolylmethylthio] -5- (4-methoxybenzyl) -4-pyrimidine in pyridine by warming the phosphorus sulfide affords 2- (2- / 5-methyl-4-). imidazolylmethylthio (ethylamino) -5- [4-methoxybenzyl] pyrimidin-4-thione.

Example 21

When 4- (4-imidazolyl) butylamine is used instead of 2- (5-methyl-4-imidazolylmethylthio) ethylamine in the procedure of Example 7, 2- [4- / 4-imidazolylbutyl] is obtained as the product. 1-amino] -5- (4-methoxybenzyl) -4-pyrimidone, mp 193-194 ° C.

.

filled hard gelatin capsules.

Example 22

Pharmaceutical preparation:

Amounts in mg 2- [2- / 5-methyl-4-imidazolylmethylthio] -ethylamino] -5- (3-methoxybenzyl) -4-pyrimidone dihydrochloride sucrose

Starch talc stearic acid

The ingredients are passed through a sieve, mixed and blended

Example 23

Pharmaceutical preparation:

Dichlorohydrochloride 2- [2- (5-methyl-1-4-imidazolylmethylthio) -ethylamino] -5- (3-methoxybenzyl) -4-pyrimidone lactose

The ingredients are passed through a sieve, and the mixture is filled with hard gelatin capsules.

EXAMPLE 24 (i) Ethyl 3- (2-methoxyphenyl) propionate (65.0 g) was converted to 5- (2-methoxybenzyl) -2-thiouracil, m.p. 1: 1 (by the procedure of Example 1 (i)).

amount in mg

100 ALIGN!

100% of 5- (2-methoxybenzyl) -2-thiouracyl (9.0 g) was converted to 5- (2-methoxybenzyl) -2-methylthio-4-pyrimidone, m.p. 163 DEG-166 DEG C. (from ethanol) according to the procedure of Example 1 (i).

(iii) 5- (2-Methoxybenzyl) -2-methylthio-4-pyrimidone (2.00 g) was treated with 2- (5-methyl-4-imidazolylmethylthio) ethylamine (1.37 g) according to the procedure of Example 1 (ii) to give 2- (2- (5-methyl-4-imidazolylmethylthio-ethylamino) -5- (2-methoxybenzyl) -4-pyrimidone, mp 163-167 ° C (from ethanol).

For C ₁₉ H ₂₃ N ₅ O ₂ S calculated: 59.2% C, 6.0. ZH, 18.2 ZN, 8.3 ZS; found: 58.4 ZC,

6.1 Z Η, 17.6 Z N, 8.2 Z S.

Example 25 (i) Ethyl 3- (3,4-dimethoxyphenyl) propionate (37.5 g) was converted to 5- (3,4-dimethoxybenzyl) -2-thiouration, mp 236-237 ° C (from ethanol) by the procedure according to Example 4 (i.).

(ii) 5- (3,4-dimethoxybenzyl) -2-thiouration (7.3 g) was converted to 5- (3,4-dimethoxybenzyl) -2-methylthio-4-pyrimidone, mp 199-200 ° C (from ethanol) according to the procedure of Example 1 (i).

(iii) 5- (3, 6-thioxybenzyl) -2-caethylthio-4-pyrimidone (1.3 g) was reacted with 2- (5-methyl-4-imidazol-1-ol) line methylthio / ethyl amine (0.76 g) according to the procedure of Example 3 to give 2- (2- (5-methyl-4-iidazolylmethylthio / ethylamino) -5- / 3). 4-dimethoxybenzyl (4-pyrimidone dihydrochloride, mp 226-230 ° C) (from methanol).

For C _{2 0} H _2? C 1 ₂ N ₅ 0 ₃ S _calculated . _{δ> 2.} 7. C, 5.6 ZH, 14.3 ZN, 6.6 ZS, 14.5 Z Cl; found:

48.1 Z C, 5.5 Z / / 14.0 Z N, 6.4 Z S, 14.2 7, Cl.

EXAMPLE 26 (i) Ethyl 3- (3-difluoromethylphenyl) pentohalide (90.0 g) was converted to 5- (3-trifluoromethyl-benzyl) -2-thiouracyl, mp 217-219 [deg.] C. (from ethanol) to methanol. (Example 4) (ii) 5- (3-Trifluoromethylbenzyl) -2-thiouration 1 (40.13 g) was converted to 5- (3-trifluoromethylbenzyl) -2-methylthio-4-pyrimidone, m.p. 187-189 ° C (from ethanol) according to the procedure of Example 1 (i).

(iii) 5- (3-Trifluoromethylbenzyl) -2-methylthio-4-pyrimidone (2.5 g) was treated with 2- (5-methyl-4-imidazolylmethylthio) ethylamine (1.43 g) according to the procedure of of Example 3 to give 2- (2- (5-methyl-4-imidazolylmethylthio) ethylamino] -5- (3-trifluoromethylbenzyl) -4-pyrimidone dichloride mp 174-176 ° C (from 2-propanol).

For C _g H ₂₂ C1 ₂ F ₃ N ₅ ^° Calculated: 46.0 ZC 4.5 ZH, Z 4 14.1 6.5 14.3 S. Z Cl ,; found: 45.8 ZC, 4.4 ZH, 14.0 ZN, 6.6 ZS, 13.9 Z Cl.

Example 1 a d 27.

2- [2- (5-Methyl-4-imidazolylmethylthio) -thylamino] -5- (3-ethoxybenzyl) -4-pyrimidine (2.35 g) was suspended in anhydrous dichloromethane (30 ml) and bromide was carefully added. boron (6.49 g). The mixture was stirred in a dry atmosphere overnight. Water (30 ml) was then added cautiously to separate into two phases. The aqueous phase is treated with sodium bicarbonate to precipitate a greasy solid, which is repeatedly washed with water until the solid is filtered off and dried. Treatment with ethanolic HCl gave 2- [2- (5-methyl-4-imidazolylmethylthio) ethylamino] -5- (3-hydroxybenzyl) -4-pyrimidone dihydrochloride, m.p. 142-144 ° C (from ethanol).

For ^C ₁₈ ^H 23 ^Cl 2 ^N 5 ° 2 ^S calculated: 48.7 ZC, 5.2 ZH, 15.8 ZN, 7.2 ZS, 16.0 Z Cl; found: 48.5 7. C *, 5.2 7. H, 15.7 ZN, 7.3 ZS, 15.8 Z Cl.

Example 2 8

2- [2- (5-Methyl-4-imidazolylmethylthio) ethylamino] -5- (4-methoxybenzyl) -4-pyrimidone (5.66 g) was reacted with boron tribromide (14.73 g) according to the procedure of Example 27 to give 2- [2- (5-methyl-4-imidazolylmethylthio) ethylamino] -5- (4-hydroxybenzyl) -4-pyrimidone dihydrochloride, mp 207-210 ° C (from ethanol).

3

For ^C 18 ^H 23 ^Cl 2 ^N 5 ° 2 ^S ^ calculated: 48.7% С, 5.2% H, 15.8% Ν, 7.2% S, 16.0% Cl; found: 48.4% С, 5.1% Η, 15.5% Ν, 7.2% S, 15.4% Cl.

EXAMPLE 29 (a) Ethyl 3- [6- (2,3-dihydro-1,4-benzodioxins)] - propionate was prepared by esterification of 3- [6-

(2,3-dihydro-1,4-benzodioxino) -1 H-2-oxoic acid with ethanol in the presence of toluene and sulfuric acid and hydrogenation of the product using palladium on carbon catalyst.

(b) Ethyl 3- {N - (2,3-dihydro-1,4-benzodioxinyl)] - propionate was converted to 5- [6- / 2,3-dihydro-

- 1,4-benzodioxinyl (tetraethyl) -2-thiouracyl, m.p. 294-296 ° C (from 2-methoxyethanol / ethanol),

2: 1) according to the procedure of Example 4 (i) and this was converted to 5- [6- (2,3-dihydro-1,4-benzodioxinyl) methyl] -2-methylthio-4-pyrimidone, mp 200-201 ° C (from methanol) according to the procedure of Example 1 (i). 5- [6- (2,3-Dihydro-1,4-benzodioxinyl) methyl] -2-methylthio-4-pyrimidone (1.50 g) was reacted with 2- (5-methyl-4-). imidazolylmethylthio (ethylamine) (0.94 g) according to the procedure of Example 3 to give 2- [2- (5-methyl-4-imide) and zolylmethylthio / ethylamino] -5- [6- / 2,3-dihydro-1,4] 4-pyrimidone, which is dissolved in dilute hydrobromic acid to give the dihydrobromide, mp 210-214 ° C (from ethanol).

from _T to C _2O ^H 25 ^Br 2 ^N 3 ^S 5 ° C ⁱⁿ yP ^ten0: 41.8% C, 4.4% H, 12.2% N 5.6% S, 27.8% Br; Found: C 41.9%, H 4.4%, N 11.9%, S 5.3%, Br 27.5%.

Example. 30

5- (3-Methoxybenzyl) -2-methylthio-4-pyrimidone (2.79 g) was treated with 2- (2-thiazolylethylthio) ethylamine (1.86 g) according to the procedure of Example 6 to give 2 - 2- (2-thiazolylmethylthio) ethylamino} -5- (3-methoxybenzyl) -4-pyrimidone-hemihydrochloride, mp 104-106 ° C (from 2-propanol).

For ^C ₁₈ ^H 20 ^N 4 ^S 2 ° 2 ^{1/2 HC1} Calculated: 53.2% C, 5.1% H, 1-3,8% N, 15.8% S, 4.4% Cl; Found: C 52.9, H 5.2, N 13.6, S 15.5, Cl 4.6.

EXAMPLE 31 (i) Ethyl 3- (3-trifluoromethylphenyl) propionate (90.0 g) was converted to 5- (3-trifluoromethylbenzyl) -2-thi-aci 1 mp 217-219 [deg.] C. phthalone (1) by the procedure of Example 1 (i).

(ii) 5- (3-Trifluoromethylbenzyl) -2-thiouration (40.13 g) was converted to 5- (3-trifluoromethylbenzyl) -2-methylthio-4-pyrimidone, mp 187-189 ° C (ethanol) according to the procedure described in of Example 1 (i).

(iii) 5- (3-Trifluoromethylbenzyl) -2-methylthio-4-pyrimidone (2.5 g) was reacted with 2- (5-methyl-4-imidazolylmethylthio) ethylamine (1.43 g) according to the procedure according to Example 3 to give 2- [2- (5-methyl-4-imidazolylmethylthio) ethylamino] -5- (3-trifluoromethylbenzyl) -4-pyrimidone dihydrochloride, mp 174-176 ° C (2-propanol). For C ₁₉ H ₂₂ C1 ₂ F ₃ N ₅ OS

Calculated: 46.0% c / 4.5% H, 14.1% N, 6.5% S, 14.3% Cl; Found: 45.8% C, 4.4% H,

N, 14.0; S, 6.6; Cl, 13.9.

Example 32

2- (2- (5-Methyl-4-imidazolylmethylthio) ethylamino] -5- (3-methoxybenzyl) -4-pyrimidone (2.35 g) was suspended in anhydrous dichloromethane (30 mL) and boron tribromide was carefully added. (6.49 g) The mixture was stirred overnight in an anhydrous atmosphere, after careful addition of water (30 ml), the two phases were separated and the aqueous phase was treated with sodium bicarbonate to precipitate a greasy solid which was repeatedly washed with water. The product thus obtained was filtered and dried, and treated with ethanolic hydrochloric acid to give 2- [2- (5-methyl-4-methyl-4-methyl-thiazol-4-yl) -thio] -ethylamino] -5- (3-carboxylic acid). oxybenzyl 1-pyrimidone dihydric acid, m.p. 142-144 ° C;

For ^ ι ^ 2 ₈ Η23 5 ^{Ν Ο δ} 2 Calculated: 48.7 ZC, 5.2% H, 15.8 ZN 7.2% .With, 16.0 Z-Cl; found:. 48.5-ZC, 5.2 ZH, 15.7 ZN, 7.3 ZS, 15.8 Z Cl.

Example d 33

2- [2- (5-Methyl-4-imidazoryl-methylphenyl) - (methylamino) -5-44-methylbenzyl] -4-pyrimidine (5.66 g) was reacted with boron tribromide (14.73 g) according to the procedure of Example 32 to give . 2- (2- (5-methyl-4-imidazrlylmethylmethyl) -1H-methylamino] -5-4-hydroxybenzyl) -4-pyrimidine (m.p. 207-210 ° C) ethanoH

For gH C ₂₃ Cl ₂ N ₅ O ₂ S Calculated: C 48.7 7th, 5,2 ZH ZN 15.8, 48.4 ZC ZH 5.1, 15, ZN 5, 7, 2 W, 15.4 W Cl.

EXAMPLE 1 ad also 34 'and' Et ^{hyl 3} - ^F6 '- / ^{2,3-d i} h ^y dr o-1, ^{4-benzo di} ox ^{y 1 and} n ^{/ p} ro ^ sulfonates ^t] -dilydro- 1,4 &apos; -benzoic acid-1-prop-2-enoic acid in the presence and hydrogenation of the product on palladium to carbon.

72, Z S, 16.0 Z Cl; found:

pnpraví es i i t or c ^{and also} 3- (6- / 2,3toluenu and sulfuric acid is converted to 5- (6 / 2,3-dihydro- / b / Ethyl 3- [6- / 2,3-dihydro o-1,4-benzodioxinyl 1-propyl, i.e. -1,4-benzodioxinyl 1-methyl-4-thiourea, mp 294-296 ° C; Ethyl 1-ethanol, 2: as described in Example 4 (i), and this compound was converted to 5- [6- (3-dihydro-1,4-benzodioxinyl) methyl] -2-methylthio-4-pyrimidone, mp 200-201 ° C (methanol) according to the procedure of Example 1 (i).

(c) 5- [6- (2,3-Dihydro-1,4-benzodioxinyl) -methyl-2-methylthio] -4-pyrimidone (1.50 g) was reacted with 2- (5) 4-Methyl-4-imidazolylmethyl-hexylaluminum (0.14 g) according to the procedure of Example 3 to give 2- [2- (5-methyl-4-imidazolylmethyl) ethyl] -O-5-p- 2,3-oxo-1,4-benzodoxiayl (methyl) -4-pyrimido, which is dissolved in dilute hydrobromic acid to give the dihydrobromide, mp 210-214 ° C (methanone). '

For C2O ^H 25 ^B * 2 ^N 5 ⁽ ° 3 ^S calculated: 4 ', 9 ZC, 4.4 ZH, 11.9 ZN, 5.3 Z

41.8 Z C, 4.4 Z H, 12.2 Z N S, 2 7.5 Z Br.

5.6 W, 27.8 W; naleženo:

Claims (3)

1. A method for preparing isocytosines in general 1 V3 / 1 /, ^h áS xW (CH ₂ ) n A where ¹ Hec is a 4-imidazolyl ring optionally substituted with C 1 -C 4 alkyl, preferably 15 is methyl, a 2-sulfide ring optionally supported by a halogen atom, preferably a chlorine or bromine atom, or a 2-thiazolyl ring; sulfur atom or methylene; is an oxygen or sulfur atom, is methylene or an atom of oxygen or sis and is an integer from 1 to 4 if W is an oxygen or sulfur atom or a total number from 0 to 4 if W 'is (ле ^ уии,. < is 1-nnyl, 2,3-diSO5-1,4-benzodioxinyl. or 1,3-benzoyl, phenyl substituted with one or more C 1 -C 4 alkyls, C 1 -C 4 alkoxy groups, oxides, halogens, trifluoromethyls or benzyloxy groups, and when W-C 1-6 alkyls; is not methylene. A may also be phenyl and is hydrogen or (C1-C4) -alkyl, characterized in that the amine of formula (II) Hee ', -CH ₂ ZCH ₂ CH ₂ NH _2/11 / where He and Z is as defined above-is reacted with a SL-učeaia under formula III γ3 ^И г 1 X, ^yj W to A M ^Al importance Uve ^ Nu above, and Q is - Al ^ thiosb ^ to ¹ and ^{f 2 3 4} atom ^y k ^u l ^{Cart U} benzyStUi-skkpiaa or halogen-free přítomnoosi solvent at a temperature of from 100 to 150 ° C or in a solvent such as pyridine at the boiling point, 2. A process as claimed in claim 1, wherein the starting material is a compound of formula (II), wherein O is phenyl containing one or more C1-C4 alkyls, alkoxy groups having 1 to 4 carbon atoms, And 1-4 is not methyl, and A is also phenyl and the others. skbstitueats maaí - meaning above. , Ж. ' 3. A process as claimed in claim 1 or 2, wherein the starting material is a compound of both zirconium oxides, wherein Q is molybdenum and others. . suSstikeenSy have the above mentioned challenges.