FI61701B - FOERFARANDE FOER FRAMSTAELLNING AV H2-HISTAMINANTAGONISTISKA 2-AMINO-4-PYRIMIDONDERIVAT - Google Patents

Description

r6l ANNOUNCEMENT t A η f) A

ygar · l »j <11> UTLÄCCN1N <SSSKRIPT 6 i / uic Patent -ny inc · tty 10 09 1932 <49 Patent meddelat ^ (51) Kv.ik.Vci.3 C 07 D 403/12, 401/12, 417/12, 405/14 FINLAND — FINLAND pi) 762803 (22) HtkwnlspUvt - AmMcnlngitag 01.10.76 ^ (23) AlkuplWt — CiMghaodai 01.10.76 (41) Tullut | ulklMlui - Mlvlt offwttlig 03. Ok.77

National Board of Patents and Registration (44) NihavlMpwen | «ku.i4uik.toun ^ - 310582

Patent · och ragistaratyratsan AmMcm utltgd och ucUkrMMo pubiicurad (32) (33) (31) Requested

England-England (GB) U03 ^ 1/75 (71) Smith Kline & French Laboratories Limited, Mundells, Welwyn Garden City, Hertfordshire, England -England (GB) (72) Thomas Henry Brown, Welwyn Garden City, Hertfordshire, Graham John Durant, Welwyn Garden City, Hertfordshire, John Colin Emmett, Codicote,

Hertfordshire, Charon Robin Ganellin, Welwyn Garden City, Hertfordshire,

The present invention relates to an anti-England (GB) (7 * 0 Oy Kolster Ab (5 ^) process for the preparation of 2-amino-U-pyrimidone derivatives of H2-histamine antagonists - Förfarande för framställning av Hg-histaminantagonistiska 2-amino - ^ - pyrimidonderivat process for the preparation of new 2-aramino-U-pyrimidone derivatives of the formula I and their pharmaceutically acceptable acid addition salts, W (CH 2 O 2 "

Het '-CH ZCH CH

wherein Het 'is a k-imidazolyl group optionally substituted by lower alkyl, a 2-pyridyl group or a 2-thiazolyl group optionally substituted by lower alkoxy or halogen, Z is sulfur or methylene, W is methylene, h is n 61701 or oxygen, n is 0 or , when W is oxygen, n may be 1, and A is a 2,3-dihydro-1,1'-benzodioxinyl or 1,3-benzodioxolyl group or a phenyl group substituted by one or more lower alkoxy, halogen, aryloxy, or trifluoromethyl , or when W is oxygen, A may be phenyl. These compounds have an anti-Hg histamine effect.

Histamine Hg antibodies can be defined as compounds that inhibit histamine Hg receptors. Mepyramine and typical antihistamines (antibodies to histamine H 2 receptors) do not inhibit histamine H 2 receptors but burimamide blocks them (see Black et al. Nature, 236, 305 (1972)). Histamine H 2 antibodies are useful in inhibiting gastric acid Hg-histamine antagonists are described in FI patent applications 580/72 and 1261/7 ^ · The compounds of the formula I have advantageous properties compared to them.The new compounds have no side effects and have lower toxicity.

The compounds of formula I have been shown to be H-one derivatives in equilibrium with the corresponding β-one tautomers. To a lesser extent, these compounds are also in the form of hydroxy tautomers and the pyrimidine ring may also exist in the following tautomeric forms: ΗΝ ^^ ϊτ 1] ^ T 1 ^ I 1

-N ^ * ^ N OH -N <si # * SsN /> SsOH

H H

Het 'can also take different tautomeric forms.

Compounds of formula I may be prepared as an amine of formula

Het'-CH2ZCH2CH2NH2 II

wherein Het 'and Z are as defined above are reacted with a compound of formula

m-vw (CHaa

1 J

»* 3 61 701 wherein n, W and A are as defined above and Q is lower alkylthio, and if desired the resulting compound is converted into a pharmaceutically acceptable acid addition salt. The reaction is preferably carried out without solvent at a temperature of about 150 ° C or in the presence of a solvent, e.g. pyridine at reflux temperature.

Intermediates of formula III wherein W is methylene can be prepared according to Scheme 1.

Figure 1

CH -A

A-CHgCHgCOgEt 1) Na, HCOgEt

Formula IV 2) thiourea H

Formula V

alkyl halide or sulfate

Y

AlkS - ^^ N ^^ O Formula VI

Esters of formula IV can be prepared by condensing a substituted benzaldehyde with malonic acid and hydrogenating and esterifying the product.

Intermediates of formula III wherein W is oxygen can be prepared according to Scheme 2.

W (CH_) A

A ^ CH2 ^ nWCH2C02Et ^ HC02Et, Ha i ^ AlkS 0 2) thiourea 3) alkyl halide W is oxygen or sulphate sulfur

The amines of the formula II can be prepared by known methods, for example as described in British Patent Publications GB 13055''7 and GB 1338169.

61 701 u

The histamine H2 response of the compounds of formula I can be demonstrated by inhibition of histamine-stimulated gastric acid secretion by intraperitoneal perfusion in urethane-anesthetized rats at a dose of 0.5 to 16 micromol / kg i.v. In this experiment, many of the compounds of formula I cause at least 50% inhibition at a dose of 1-10 micromoles / kg.

The Hg-histamine antagonist activities of the new compounds are shown in Table 1. Inhibition of histamine-stimulated gastric acid secretion was determined by intraperitoneal perfusion in urethane-anesthetized rats using the modified Ghosh and Schild method described in Brit. J. Pharm. Chemother. 13 51 * (1950).

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6 61 701

Pharmaceutical compositions that can be used as histamine H 2 antibodies can be prepared by mixing a compound of formula T, in base form or as an acid addition salt, with a pharmaceutically acceptable acid, a pharmaceutically acceptable diluent, or a carrier.

The following examples illustrate the invention.

Example 1 2- [2- (5-Methyl-1-imidazolylmethylthio) -ethylamino] -5 '(N-chlorobenzyl) -N-pyrimidone) A solution of 50.5 g of 5- (1 + -chlorobenzyl) -2-thiouracil, 28.1+ g of methyl iodide and 8.2 g of sodium hydroxide in 200 ml of water and 1 + 00 of ethanol were stirred for 30 minutes at 60 ° C and then allowed to cool. The crystalline product was isolated by filtration and washed with water to give 1 + 8.6 g of 5- (1 + -chlorobenzyl) -2-methylthio-1 + -pyrimidone, 193 ° -19l + CO (methanol-ethanol).

II) A well-stirred mixture of 17.7 g of 5- (1 + -chlorobenzyl) -2-methylthio-1 + pyrimidone and 11.1 + g of 2- (5-ethyl-1 + -imidazolylmethylthio) ethylamine was heated for five hours at 11 ° C + 5 ° to 150 ° C. After cooling, the reaction mixture was triturated with water to give the free base, which was isolated by decantation and recrystallized from methanol to give the title compound, m.p. 20l +, 5 ° - 206 ° C.

Example 2 2- [2- (5-Methyl-1 + -imidazolylmethylthio) ethylamino] -5- (3-chlorobenzyl) -1 + pyrimidone dihydrochloride) 39.3 g of ethyl 3- (3-chlorophenyl) were added over six hours. ) -propionate and 11+, 9 g of ethyl formate in a stirred mixture of 1+, 25 g of sodium wire and 110 ml of dry ether cooled in an ice-salt bath. The mixture was stirred for 18 hours at room temperature and evaporated to dryness. From the residue, 11.0 g of thiourea and 100 ml of ethanol were heated under reflux for seven hours. The mixture was evaporated to dryness and the residue was dissolved in water. Acetic acid was added until the pH of the mixture was U. The white precipitate was isolated by filtration and washed to give 5- (3-chlorobenzyl) -2-thiouracil, m.p. 192 ° - 195 ° C (from ethanol).

II) 3.1 g of 5- (3-chlorobenzyl) -2-thiouracil were converted into 5- (3-chlorobenzyl) -2-methylthio-1 + pyrimidone (m.p. 178.5 ° -80.5 ° C from ethanol) 1.8 g of the latter compound and 1.1 g of 2- (5-methyl-1 + -imidazolylmethylthio) -1,7,701-ethylamine were reacted according to the procedure described in Example 1 II). to give the title compound as a residue, which was treated with hydrogen chloride-ethanol solution, m.p.

212.5 ° -16 ° C (from ethanol).

Example 3 2- [2- (5-Methyl-N-imidazolylmethylthio) -ethylamino] -5- (3'-dichlorobenzyl) -N-pyrimidone dihydrochloride] 8.8 g of ethyl-3- (3, k- dichlorophenyl) propionate to 5- (3,4-dichlorobenzyl) -2-thiouracil, m.p. 232.5 ° to 233.5 ° C (from methanol-ethanol) by the method described in Example 2 i).

II) 5-7 g of 5- (3, k-dichlorobenzyl) -2-thiouracil were converted into 5- (3, 4-dichlorobenzyl) -2-methylthio-U-pyrimidone, m.p. 216 ° to 218 ° C (from acetic acid) by the method described in Example 1 I).

III) 2.1 g of 5- (3,1 + -dichlorobenzyl) -2-methylthio-U-pyrimidone and 1.2 g of 2- (5-methyl-U-imidazolylmethylthio) ethylamine were reacted in Example a 1 to give the title compound, m.p. 235 → 5 ° to 238.5 ° C (from water-methanol).

Example 1 2- [2- (2-Thioazolylmethylthio) -ethylamino] -5- (1-chlorobenzyl) -1-pyrimidone monohydrochloride

A well-stirred mixture of 1.36 g of 5- (1 + -chlorobenzyl) -2-methylthio-L-pyrimidone and 0.9 g of 2- (2-thiazolylmethylthio) ethylamine was heated at 130 ° to 135 ° C for 2.5 hours. :in. After cooling, the reaction mixture was treated with 2N hydrochloric acid. Evaporation to dryness and recrystallization from isopropanol-methanol gave the title compound, m.p. 172.5 ° - 17.5 ° C. Example 5 2- [2- (5-Methyl-N-imidazolylmethylthio) -ethylamino] -5- (N-methoxybenzyl) -N-pyrimidone dihydrochloride

A well-stirred mixture of 3.0 g of 5- (N-methoxybenzyl) -2-methylthio-H-pyrimidone and 1.95 g of 2- (5-methyl-1 + -imidazolylmethylthio) ethylamine was heated at 135 ° for six hours. At 1 ° C with occasional stirring. After cooling, the reaction mixture was triturated with hot water, filtered, washed with dry ether and dissolved in propan-2-ol. The solution was acidified with dilute hydrogen chloride-ethanol solution, evaporated to dryness and the residue recrystallised from ethanol to give the title compound, m.p. 198 ° - 200 ° C.

β 61 701

Example 6 2- [2- (3-Bromo-2-pyridylmethylthio) -ethylamino] -5- (n-chlorobenzyl) -N-pyrimidone monohydrochloride

1.2 g of 5- (Π-chlorobenzyl) -2-methylthio-β-pyrimidone and 1.1 g of 2- (3-bromo-2-pyridylmethylthio) ethylamine were reacted according to the procedure of Example 1. The reaction mixture was acidified with dilute hydrogen chloride-ethanol solution, evaporated to dryness and the residue recrystallised from ethanol-water to give the title compound, m.p. 215 ° to 218 ° C (decomposes).

Example 7 2- [2- (5-Methyl-5-imidazolylmethylthio) -ethylamino] -7-5-benzyloxy-β-pyrimidone dihydrochloride _________) 60.0 g of ethylbenzyloxyacetate were converted into 5-benzyloxy-2-thiouracil, m.p. 20 ° to 2 ° 0 (acetonitrile-ethyl acetate 1: 1) according to the method of Example 2 I).

T1) 10.0 g of 5-, benzyloxy-2-thiuracil were converted into 5-benzyloxy-2-methylthio-1 + pyrimidone, m.p. 18 ° to 185 ° ® (from methanol) according to the method of Example 1 I).

ITI) U, 10 g of 5-benzyloxy-2-methylthio-1H-pyrimidone and 2.83 g of 2- (methyl-N-imidazolyl) ethylamine were reacted according to the method of Example 1 to give the title compound, m.p. 161 ° to 162 ° C (from ethanol). Example 8 2- [2- (5-Methyl-1-imidazolylmethylthio) ethylamino] -5- (3-methoxybenzyl) -H-pyrimidone dihydrochloride

16.1 g of 5 '(3-methoxybenzyl) -2-thiouracil were converted into 5- (3-methoxybenzyl) -2-methylthio-U-pyrimidone, m.p. 11 ° to 1 ° C (from ethanol) according to the method of Example 1 I).

3.0 g of 5- (3-methoxybenzyl) -2-methylthio-1-pyrimidone and 2.1 g of 2- (5-methyl-U-imidazolylmethylthio) ethylamine were reacted as described in Example 1 II) to give a residue from which treatment with hydrogen chloride-ethanol solution gave the title compound, m.p. 173 ° to 175 ° C (from ethanol).

Example 9 2- [2- (5-Methyl-N-imidazolylmethylthio) -ethylamino] -5- (2-chlorobenzyl) -p-pyrimidone dihydrochloride ___ I) U8, U g of ethyl 3 '(2-chlorophenyl) propionate was converted 5- (2-chlorobenzyl) -2-thiouracil, m.p. 223 ° to 22 U ° C (from methanol) according to the method described in Example 2 i).

9 61701 II) 5.05 g of 5 '(2-chlorobenzyl) -2-thiouracil were converted into 5- (2-chlorobenzyl) -2-methylthio-4-pyrimidone, m.p. 171 ° to 173 ° C (from ethanol) according to the method of Example 1 I). 1.6 g of 5- (2-chlorobenzyl-2-methylthio-pyrimidone and 1.03 g of 2- (5 "methyl-N-imidazolylmethylthio) ethylamine were reacted as described in Example 1 II) to give a residue which was treated with dilute hydrogen chloride-ethanol solution. the title compound was obtained, m.p.

215 ° to 219 ° C (from methanol-ethanol)

Example 10 2- [2- (5-Methyl-U-imidazolylmethylthio) -ethylamino] -5- (1,3-benzodioxolyl) -methyl) -N-pyrimidone hydrochloride 17.5 g of ethyl-3- (5- (1,3-benzodioxolyl) methyl) propionate to give 5- (5- (1,3-benzodioxolyl) methyl) -2-thiouracil, m.p.

158 ° to 159 ° C (1: 1 ethanol-methanol) according to the procedure described in Example 2 I).

II) Converted to 2.9 g of 5 '(5- (1,3-benzodioxolyl) methyl) -2-methylthio-U-pyrimidone, m.p. 197 ° ~ 198 ° C (from acetonitrile) according to the method described in Example 1 I).

1.2 g of 5- (5 - ((1,3-benzodioxolyl) methyl) -2-methylthio-U-pyrimidone and 0.77 g of 2- (5-methyl-1H-imidazolylmethylthio) ethylamine were reacted to give a residue from which treatment with hydrogen chloride-ethanol solution gave the title compound, m.p. 230 ° to 232 ° C (from ethanol).

Example 11 2- [2- (5-Methyl-N-imidazolylmethylthio) -ethyl-η 5 - (3-ethoxybenzyl) -N-pyrimidone dihydrochloride]

5.0 g of 5- (3-ethoxybenzyl) -2-thiouracil was converted into 5- (3-ethoxybenzyl) -2-methylthio-U-pyrimidone, m.p. 136 ° to 138 ° C (from acetonitrile) according to the method of Example 1 I). 2.0 g of 5- (3-ethoxybenzyl) -2-methylthio-4-pyrimidone a and 1.25 g of 2- (5-methyl-k-imidazolylmethylthio) ethylamine were reacted as described in Example 1 II) to give a residue. , which was treated with a solution of hydrogen chloride in ethanol to give the title compound, m.p. 176 ° - 178 ° C (from ethanol).

Example 12 2- [2- (5-Methyl-U-imidazolylmethylthio) -ethylamino] -5- (3-benzyloxybenzyl) -U-pyrimidone dihydrochloride ______

0.6 g of 5- (3-benzyloxybenzyl) -2-thiouracil was converted into 5- (3-benzyloxybenzyl) -2-methylthio-U-pyrimidone, m.p. 176 ° to 178 ° C (from ethyl acetate) as described in Example 1 II). 2.0 g of 5- (3-benzyloxybenzyl) -2-methylthio-1H-pyrimidone and 1.0 g of 2- (5-methyl-1H-imidazolylmethylthio) ethylamine were reacted as described in Example 1 II): <·. . *! / 'V>' - · 61 701 ίο to a residue which was treated with a solution of hydrogen chloride in ethanol to give the title compound, m.p. 193 DEG-19 DEG C. (from methanol-ethanol).

Example 13 2- [2- (5-Methyl-U-imidazolylmethylthio) -ethylamino] -5- (3,5 *, 5-trimethoxybenzyl) -N-pyrimidone dihydrochloride) By the method described in Example 2 I), ethyl 3- ( 3,5-Trimethoxyphenyl) propionate (82, g) to 5- (3,5,5-trimethoxybenzyl) -2-thiouracil, m.p. 211-215 ° C (from ethanol).

II) By the method described in Example 1 I), 5- (3,5-trimethoxybenzyl) -2-thiouracil (12.9 g) was converted to 5- (3,5-trimethoxybenzyl) -2-methylthio- To U-pyrimidone, m.p. 158-159 ° C (from ethanol).

III) As described in Example 1, 5- (3,5-trimethoxy-benzyl) -2-methylthio-1H-pyrimidone (2.39 g) was reacted with 2-5-methyl-U-imidazolylthio) ethylamine (1 , 3T g) to give 2- [2- (5-methyl-U-imidazolylmethylthio) ethylamino] -5- (3,5,5-trimethoxybenzyl) -N-pyrimidone hydrochloride, m.p. 17 DEG-17 DEG C. (from ethanol).

Example lU

2- [N- (1-imidazolyl) -butylamino] -5- (3-methoxybenzyl) -U-pyrimidone___

Example 8 was repeated, replacing 2- (5-methyl-U-imidazolylmethylthio) ethylamine with U- (i + -imidazolyl) butylamine. There was thus obtained 2- [N- (U-imidazolyl) -butylamino] -5- (3-methoxybenzyl) -1 + -pyrimidone, m.p. ^ 193-199 ° C.

Example 15 2- [2- (5-Methyl-1H-imidazolylmethylthio) ethylamino] -5- (3,3-dimethoxybenzyl) -4-pyrimidone dihydrochloride) By the method described in Example 21), ethyl 3- (3,3 * + -dimethoxyphenyl) propionate (37.5 g) to 5- (3, U-dimethoxybenzyl) -2-thiouracil, m.p. 236-237 ° C (from ethanol).

II) By the method described in Example 1 i), 5- (3,6-dimethoxybenzyl) -2-thiouracil (7.3 g) was converted into 5- (3,1 + -dimethoxybenzyl) -2-methylthio-1 + pyrimidone, m.p. 199-200 ° C (from ethanol).

III) 5- (3,5-Dimethoxy-benzyl) -2-methylthio-β-pyrimidone (1.3 g) was reacted as described in Example 1 with 2- (5-methyl-h-imidazolylmethylthio) ethylamine (0, 76 g) to give 2- [2- (5-methyl-1-imidazolylmethylthio) ethylamino] -5- (3,5-dimethoxybenzyl) -N-pyrimidone dihydrochloride, m.p. 226-230 ° C (from ethanol).

: .'t, f \. r · f '· 11 61 701

Example 16 2- [2- (5-Methyl-U-imidazolylmethylthio) -ethylamino] -5- (3-trifluoromethylbenzyl) -N-pyrimidone dihydrochloride) By the method described in Example 2 I), ethyl 3- (3-tri- fluoromethylphenyl) propionate (90.0 g) to 5- (3-trifluoromethylbenzyl) -2-thiouracil, m.p. 217-219 ° C (from ethanol-methanol).

II) By the method described in Example 1 I), 5- (3-trifluoromethylbenzyl) -2-thiouracil (± 0.13 g) was converted into 5- (3-trifluoromethylbenzyl) -2-methylthio-1 + pyrimidone, m.p. 187-189 ° C (from ethanol).

III) As described in Example 1, 5- (3-trifluoromethyl-benzyl) -2-methylthio-1 + -pyrimidone (2.5 g) was reacted with 2- (5-methyl-U-imidazolylmethylthio) ethylamine (1.03 g). ) to give 2- [5- (5-methyl-U-imidazolylmethylthio) ethylamino] -5- (3-trifluoromethylbenzyl) -U-pyrimidone dihydrochloride, m.p. 17 DEG-176 DEG C. (from 2-propanol).

Example 17 2- [2- (5-Methyl-U-imidazolylmethylthio) ethylamino] -5 '[6- (2,3-dihydro-1,1'-benzodioxinyl) methyl] -5-pyrimidone dihydrobromide I) Prepared ethyl 3- [6 - (2,3-dihydro-1,1-benzodioxinyl] -propionate by esterification with 3- [5- (2,3-dihydro-1,1'-benzodioxinyl] -prop-2-enoic acid ethanol in the presence of toluene and sulfuric acid, and the product was hydrogenated using a palladium / carbon catalyst.

II) By the method described in Example 2 i), 3- [6- (2,3-dihydro-1,1'-benzodioxinyl) 7-propionate was converted into 5- [6- (2,3-dihydro-1,1'-benzodioxinyl) methyl, 7-2-thiouracil m.p. 29 DEG-296 DEG C. (from methoxyethanol-ethanol, 2: 1), and the obtained compound was modified as described in Example 1 I) 5- [6- (2,3-dihydro-1,1'-benzodioxinyl) methyl] -2-methylthio -U-pyrimidone, m.p.

200-201 ° C (from methanol).

III) As described in Example 1, 5- [6- (2,3-dihydro-1,1 * -benzodioxinyl) methyl] -2-methylthio] -pyrimidone (1.50 g) was reacted with 2- (5-methylthio) pyrimidone (1.50 g). -imidazolylmethylthio) ethylamine (0.9 g) to give 2- [2- (5-methyl-U-imidazolylmethylthio) ethylamino] -5- [6- (2,3-dihydro-1,1H-benzodioxinyl) ethyl] -1 + -pyrimidone dissolved in dilute hydrobromic acid to give the dihydrobromide, m.p. 210-215 ° C (from methanol).

Example 18 2- [2- (2-Thiazolylmethylthio) -ethylamino] -5- (3-methoxybenzyl) -N-pyrimidone hemihydrochloride

As described in Example H, 5- (3-methoxybenzyl) -2-methylthio-yl-pyrimidone (2.79 g) was reacted with 2- (2-thiazolylmethylthio) ethylamine (1.86 g) to give 2- / 2- (2-thiazolylmethylthio) ethylamino / -5-1216701 (3-methoxybenzyl) -U-pyrimidone hemihydrochloride, m.p. 10U-106 ° C (from 2-propanol).

Example 19 2- [2- (5-Methyl-1H-imidazolylmethylthio) ethylamino] -5- (fluorobenzyl) -4-pyrimidone dihydrochloride) Ethyl 3- (1H-fluorophenyl) propionate was reacted with ethyl formate and sodium hydride from dimethoxyethane. to give phenyl 3- (h-fluorophenyl) propionate (oil) which was heated to reflux with thiourea and sodium ethoxide in ethanol to give 5- (H-fluorobenzyl) thiouracil, m.p. 22H-226 ° C.

II) 5- (1 + -fluorobenzyl) thiouracil was reacted with methyl iodide and sodium hydroxide in aqueous ethanol to give 2-methylthio-5 '(N-fluorobenzyl) -1,4-pyrimidone, m.p. L60 ~ 159 ° C.

Ui) Equimolar amounts of 2- (5-methyl-1H-imidazolylmethylthio) -ethylamine and 2-methylthio-5- (U-fluorobenzyl) -U-pyrimidone were melted together at 160 ° C (bath temperature) for 1+ hours and the residue purified by treatment with hydrogen chloride in ethanol and crystallization from ethanol to give 2- [2- (5'-ethyl-U-imidazolylmethylthio) ethylamine] -5- (U-fluorobenzyl) -U-pyrimidone hydrochloride, m.p. ^ 191-199 ° C.

Example 20 2- [1- (3-Methoxy-2-pyridyl) benzylamino] -5- (3-methoxybenzyl) -1-pyrimidone

Reaction of 2-chloro-3-nitropyridine with 2- (2-cyanoethyl) -malonic acid diethyl ester and sodium hydride in tetrahydrofuran gave 1- (3-nitro-2-pyridyl) -1,1-bis- (carbethoxy) -butyronitrile, m.p. 93 , 1 + -91 +> 5 ° C, and after alkaline hydrolysis and acidification gave 2- (3-cyanopropyl) -3-nitropyridine hydrochloride, mp lU2-1l + 5.5 ° C. Reduction with hydrogen and palladium on carbon gave 3- amino-2- (3-cyanopropyl) pyridine and treatment of this compound with sodium nitrile and sulfuric acid followed by heating to give 2- (3-cyanopropyl) -3-hydroxypyridine. 2-pyridyl) butylamine.

II) A mixture of 1- + (3-methoxy-2-pyridyl) butylamine (1.1 g) and 2-methylthio-5- (3-methoxybenzyl) -N-pyrimidone (1.1 + 5 g) was melted under nitrogen at 160 ° C. at 5.5 hours. The residue was purified by silica gel column elution with 10 μl of methanol-chloroform and recrystallization from ethanol to give 2- [N- (3-methoxy-2-pyridyl) -butylamino] -5- (3-methoxybenzyl) -1 + -pyriridone, m.p. 135-136 ° C.

Γ .; ί · It V.

13 61 701

Example 21 2 - /% - (3-methoxy-2-pyridyl) butylamino] -5- [5- (1,3-benzodioxolyl] -N-pyrimidone dihydrochloride _____.____ U- (3-methoxy-2-pyridyl) butylamine (1, A mixture of 0 g) and 2-methylthio-5- [5- (1,3-benzodioxolyl) methyl] -1'-pyrimidone (1.39 g) was melted under nitrogen at 10 ° C for 1 hour. column with 10% methanol-chloroform to give 2- [5 + - (3-methoxy-2-pyridyl) butylamino] -5- [5- (1,3-benzodioxolyl) methyl] -1'-pyrimidone, which was treated hydrogen chloride in ethanol to give the dihydrochloride, m.p.

19 ^ -195.5 ° C.

i «• v. · * -

Claims (2)

61 701 Il * 1 I Het '-CH 2 ZCH 2 CH 2 -NH' / ^ N '' '^ 0 wherein Het' is a U-imidazolyl group optionally substituted by lower alkyl, a 2-pyridyl group or a 2-thiazolyl group optionally substituted by lower alkoxy or halogen, Z is sulfur (-S-) or methylene (-CH 2 -), W is methylene or oxygen (-O-), n is 0 or, when W is oxygen, n may be 1, and A is 2,3-dihydro-1, A U-benzodioxinyl or 1,3-benzodioxolyl group or a phenyl group substituted by one or more lower alkoxy, halogen, arylalkoxy or trifluoromethyl or, when W is oxygen, A may be phenyl, characterized in that the amine of the formula Het ' -CH 2 ZCH 2 CH 2 NH 2 II wherein Het 'and Z are as defined above is reacted with a compound of formula IT III wherein n, W and A are as defined above and Q is lower alkylthio, and if desired the resulting compound is converted into a pharmaceutically acceptable acid addition salt. A process for the preparation of Hg-histamine antagonist 2-amino-U-pyrimidone derivatives of formula I and their pharmaceutically acceptable acid addition salts ffl-Vw (CHA-A Process according to Claim 1, characterized in that 2- [2- (5-methyl-1-imidazolylmethyl) ethylamino] -5- (1,3-benzodioxolyl) methyl) is prepared. I * -pyrimidone. > Λ