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    • 专利摘要:
    The invention provides compounds of the formula (I): and their pharmaceutically acceptable acid addition salts a process for their preparation and their use as histamine H2- antagonists. In formula (I) W is a 2-furanyl or 2-thienyl group optionally substituted in the 5-position with a group R1R2N/CH2)m-; a phenyl group substituted in the 3- or 4-position with a group R1R2N(CH2)m-; a 4-imidazolyl group optionally substituted in the 5-position with methyl or bromine; a 2-pyridyl group optionally substituted in the 3-position with C1-4 alkyl, Ci-4 alkoxy, halogen, amino or hydroxy; a 2-thiazolyl group or a 2-guanidino-4-thiezolyl group; X is methylene or sulphur and Y is methylene or, provided X is methylene and W is a substituted phenyl group, oxygen; Z is hydrogen or C1-4 alkyl; and B is a 2-furanyl or 2-thienyl group substituted in the 5-position by a group R1R2N/CH2)m-; a phenyl group substituted in the 3- or 4-position by a group R1R2N(CH2)m-; or a 3-pyridyl group substituted in position 5 or 6 or a 4-pyridyl group substituted in position 2 by a group R1R2N(CH2)m; R1 and R2 are Ci-4 alkyl or together with the nitrogen atom to which they are attached form a pyrrolidino, piperidino or morpholino group; m is 1 to 4.
    公开号:SU1033003A3
    申请号:SU813261944
    申请日:1981-03-27
    公开日:1983-07-30
    发明作者:Генри Браун Томас
    申请人:Смит Клайн Энд Френч Лабораториз Лимитед (Фирма)；
    IPC主号:
    专利说明:

    Isolation refers to a method for the preparation of new k-nvifivt-idione derivatives possessing the properties of H-histamine amtagonists, which can be used in medicine.  The known reaction of replacing the nitroamino group on the α-pyrimido derivatives under the action of amines with the formation of the corresponding amine derivatives WITH The aim of the invention is to obtain the α-pyrimidone gene derivatives with valuable pharmacological properties.  This goal is achieved by the fact that, in the preparation of the -pyri mydon derivatives of the general formula T WCHs GH2CH2 # Jjij A O 2-furanyl or 2 thienyl, optionally substituted in the floor by the group R. ; “5th group of K. ; R and R C, j C 1 -alkyl, phenyl substituted at position 3 or D with the group t-imidazolyl, optionally substituted in residue 5 with methyl 2-guanidino-thiazolyl; B - 2 furanyl or 2-thienyl. substituted with position R 5 of the group R nCHj, phenyl substituted at position 3 or it with the group R R NCH. 2 -; 3-pyridyl substituted at position 6 by the group R R NCH or (-pyridyl substituted at position 2 by the group RR -NCH / - or their pharmaceutically acceptable kinetics additive. The salts derived from 2-alktoethylamine of general formula II, WCH SCH CHjNKj, where W has the indicated meanings, are reacted with γ-pyrimidone of the general formula III where B has the indicated meanings; - L - nitroamino group followed by isolation of the target product as a base or by treatment with Mannich's reagent, when 8 or X - 2-thienyl or unsubstituted. -furanyl, and isolation of the desired product as a base or acid addition salt.  Salts are preferred as pharmaceutically acceptable salts.  32 hydrochloric, hydrobromic, phosphoric, citric and maleic acids.    The interaction of compounds And and GI is usually carried out in an alkanol, for example ethanol, at boiling.  The Mannich reagent can either be obtained directly during the main reaction by adding the amine of the formula and formalin, or it can be prepared in advance, for example, the di I ammonium salt (C – C. -alkyl)} methylene such as dimethylmethylene ammonium chloride, or bis I.  di-C) -C-alkylamino methane, such as bis (dimethylamino) methane.  The starting 2-alkythoethylamines of the general formula are the compounds described above.  Β-pyrimidone derivatives of the formula fTl.  can be obtained by the reaction of nitro guanidine with an oxo ether of the formula B B — CH —CH — COOR HC O; where B has the indicated meanings, R - G "| -Sc. -alkyl   in the presence of a base.  The activity of the compounds of formula 1 as N. -antag Histamine gains are determined by inhibition of histamine-stimulated gastric secretion in rats anesthetized with urethane. Compounds cause 50% inhibition when administered intravenously at a dose of less than 0.5 mmol per kg of animal weight.  Compounds of formula I at a dose of less than 10 mol also cause a 50% inhibition caused by histamine-induced tachycardia of an isolated guinea pig atrium.  The compounds of formula 1 can be used in the treatment of gastric and duodenal ulcers.  Example 1, 5- (Dimethylaminomethyl) thiophene-2-carboxaldehyde II 0.09 g) and piperidine (3 ml) are added to a solution of malonic acid (L, 65 g) in pyridine (150 ml).  The mixture was heated under reflux for 7 hours while stirring.  A solid precipitates during the reaction and then slowly dissolves.  The solution is cooled and poured into a 2 M hydrochloric acid solution (150 ml).  The volume of the solution is reduced by evaporation in vacuo to 120 ml and the solution is extracted with diethyl ether.  Ester exE10 tracts are washed with water.  The aqueous phase is cooled, and the solid product, precipitated: the precipitate is filtered off and washed with ood-isopropanol.  By evaporation of the filtrate to a volume of A ml and addition of isopropanol and subsequent cooling of the mixture in ice for 15 seconds. Additional solid product is obtained.  which is filtered and washed.  isopropanol.  The solids are combined and recrystallized from an isopropanol-water mixture, the result is 3- (5-Dimethylaminomethyl-2-thienyl) acrylic acid 27, (5 g) with m „pl.  223.5-225 ° C.  3- (5-Dimethylaminomethyl-2-thienyl) acrylic acid (33.31 g) is dissolved in ethanol (150 ml) and acidified with concentrated sulfuric acid (10 ml) The solution is heated under reflux for 18 h, / cooled and then poured into a mixture of ice and aqueous solutions of ammonia, (0.88 weight / weight, 30 ml).  The resulting aqueous solution is extracted with ether and the combined ether extracts are washed with water and dried over magnesium sulfate.  The ether is evaporated under reduced pressure, the result is ethyl-3 (5-dimethylaminomethyl-2-thienyl) acrylate (30.30 tons) in the form of a light oil; yellow color.  A solution of ethyl-3-f5-dimethylaminomethyl-2-thienyl) acrylpta (30.30 g) in ethanol (U75 ml) is hydrogenated (initial pressure kPa) for 8.5 h at 55-60 0 in the presence of a palladium on carbon catalyst (10 d) made in two steps.  First, the first batch is fed into the reaction mixture, and then after 5.5 hours, the second batch is served.  The catalyst is filtered off and washed with ethanol.  The filtrate is evaporated under reduced pressure, resulting in a floor; 1 ethyl-3- (5-dimethylaminomethyl-2-thienyl) propionate (29.91 g) is obtained as a colorless oil.  A mixture of ethyl 3- (5-dimethylaminomethyl-2-thienyl) propipnate (29.91 g) with ethyl formate (13.77 g 15 ml) is added dropwise with stirring to a suspension of sodium hydride (57% in oil, 6, 52 g) in 1,2-dimethoxyethane (45 ml), which is pre-cooled to -5 ° C.  The temperature of Lod is kept from to during the administration.  Then the mixture slowly 03 is heated to room temperature and incubated for 16 hours  The mixture is poured onto ice, resulting in a brown solution.  When this solution is evaporated to dryness, an oil is formed.  This g (aslo is mixed with acetone, and the mixture is filtered through diatomaceous earth, and the acetone is evaporated, the result is ethyl-3- (5-dimethylaminomethyl-2-thienyl) -2-formylpropionate (32.92 g) in the form of oil, nitroguanidine (16.92 g with 2S% water) and methanol (35 ml) are added to sodium solution (4.7. 1 g) in methanol (95 ml) and mix under reflux with stirring for kS min.  Then, ethyl-3-5-dimethylaminomer is added to this mixture while boiling with a reverse cooler while stirring.  Tyl-2-thienyl -2-formylpropionate.  - -.  .  -.  132.85 g) in methanol (90 ml) for / v1.25 hours  The mixture thus obtained is boiled under reflux with an additional E for 22 hours with stirring.  Methanol is evaporated under reduced pressure, and the residue is dissolved in water.  The resulting solution is extracted with chloroform and the combined extracts are washed with water.  The aqueous phase and the aqueous washes were combined and the water was evaporated under reduced pressure,.  The residue after evaporation. disinfect by assotropic distillation with isopropanol.  The residue of azeotropic drying is mixed with a small amount of water, heated and cooled, the insoluble precipitate is filtered, washed with water, ethanol and dried, the result is 2-nitroamino-5- (5-dimethylamino-2-thienylmethyl) -1-pyrimidone (6.53 d) with t. square  228-232 C (decomp. ).   A mixture of 2- (5-methyl-4-imidazolylmethylthio) ethylamine (1.37 g) and 2-nitroamino-5 (5-dimethylamine-methyl-2-thienyl-methyl} -4-pyrimidone (2.32 g) in ethanol is boiled t under reflux for 48 hours  Ethanol evaporated. t under reduced pressure, as a result, (5-methyl-imidazolyl ethylthio) ethylamino-5- (5-dimethylaminomethyl-2-thienylmvtil) -4-pyrimidine is obtained in the form of a vitreous mass, which is washed with hot water by decantation.  This residue was dissolved in D isopropanol and an ethanolic solution of hydrogen chloride (3 ml) was added.  Excess solvent gogo gl under reduced pressure, half-from crystals of trichloro hydrate 3, 1 g j; After recrystallization of 413 mixtures of methanrl-ethanol, the product is obtained (2.36 g) with m. square  185.5188, 5: с / П р and м and р 2.  A mixture of 2- (5-dimotilaminomethyl-2 furanylmethylthio) ethylamine (1.61 g) and 2-nitroamino5 (5 Limethylaminomethyl-2-thienylmethyl) -A pyrimidone (2.01 g) in ethanol.  (10 ml) is refluxed for 30 h.  Ethanol is evaporated in vacuo to give (5 D methylaminomethyl-I-furanylmethipotyl) methylamino3 5 15-dimethylamine methyl 2-TI8Nylmethyl) -pyrimidone as a brown oil, which is washed with hot water by decanting.  This residue was dissolved in S isopropanol, and an excess of ethanolic hydrogen chloride solution was added to the solution.   the solvent is evaporated in zakuma ,.  and the residue is recaptured from an isopropanol-methanol mixture containing: (-. pts: m ethanol solution of hydrogen chloride, and then trichlorohydrate (2J2 g) with m. is obtained from ethanol-methanol mixture. pl, 197-20-RCh.  Example 3  2- (2-Guanidino-4t-thiazolylmethylthio) ethyl. Mineral dihydrochloride (2.3 g) is dissolved with ethanol solution of ethylate.  sodium (0.37 g) sodium, 15 ml of ethanol).  The solution is peremetio for 1 h, and the precipitated sodium chloride is removed by filtration, 2 nitroamino 5 ($ -Dimethylaminomethyl 2-thienylmethyl) -A-pyrimidone (2.00 g) are added to the solution, and the mixture is boiled under reflux for A8 hours  Ethanol is evaporated. under reduced pressure, and precipitated out from the solution in a minimum amount of ethanol by adding dropwise water, (2-guanidium-thiazolylmethylthio) ethylamino 5- (5 dimethylaminomethyl-2-thienylmethyl) -pyrimidone is obtained as tva dogo oil.  This product is dissolved in ethanol and decolorized with charcoal.  The solvent is evaporated under reduced pressure, a yellow oil is obtained, which shreds when rubbed, to form a white taerdy product, which is recrystallized from diethyl ether / isopropanol, then from trichloride hydrochloride / isopropanol to give trichlorohydrad (0.59 g) with t . square  l6i | -l66 C.  PRI me R.  A mixture of α-dimethylaminomethylbenzaldehyde (32.6 g), monoethyl malonate (, 29.07 g), pyridine 100 ml) and piperidine (2 ml) was heated under reflux with stirring for 5 hours.  Pyridine is evaporated under reduced pressure, and the oily residue is extracted with diethyl ether.  The combined ether extracts are washed with water and dried over magnesium sulfate.  The ether is evaporated under reduced pressure, the result is ethyl-4- (dimethylaminomethyl) cinnamate in the form of a light yellow oil (ii6,57 g).  PacTDOp ethyl- - Dimethylaminomethyl cinnamate in ethanol (170 ml) is hydrated with palladium on coal (0.5 g) at 36-37 ° C and hydrogen at a pressure of kPa until the theoretically calculated amount of hydrogen is consumed.  The solution is filtered through diatomaceous earth to remove the catalyst and washed on the filter with ethanol.  The combined filtrate and washings were evaporated to give ethyl-3-t-dimethylaminomethylphenyl propionate (t5.97) r in the form of a light yellow oil.  A mixture of ethyl 3 - ((- Dimethylaminomethyl-Ohenyl) propionate (5.97 g) and ethyl Oormiate (21.70 g) was added dropwise with stirring to a suspension of sodium hydride (50 in oil; 11.72 g) in dimethoxyethane (70 ml), which is pre-cooled to -5-FW.  During the whole time of addition, the temperature is maintained below.  After stopping the addition, the mixture gradually. heated to room temperature with stirring and then incubated for. A / 16h.  This mixture is poured onto ice to obtain a brown aqueous solution, which is acidified to pH 6 with glacial acetic acid, as well. the aqueous phase is evaporated.  With ganicheskuyu. the residue phase is extracted with hot acetone and isopropanol, the insoluble inorganic precipitate is filtered off, washed with additional hot acetone and isopropanol.  The filtrate and the washings are evaporated to dryness, and the residue is dissolved in water and the solution is neutralized to pH 7 with sodium bicarbonate.  Water  .  The 7th solution is extracted with ethyl acetate, and the combined organic extracts are washed with water, dried with magnesium sulfate and evaporated under reduced pressure to give ethyl-3 - (1-dimethylaminomethylphenyl) 2-formyl propionate (15j27 g) as a light brown solid with t. square  95.5974.  Nitroguanidine (g with a 25% w / w water content) is washed with methanol (10 ml) and added to sodium methylate sodium solution (from 1, 97 g sodium in methanol (85 ml).  The mixture was stirred and refluxed for 45 minutes, and ethyl-3-t-dimethylaminomethyl-benzyl -2-formyl propionate (g) was added in portions (g) for 1.25 hours.  The mixture was stirred and refluxed for another 22 hours.  Methanol is evaporated under reduced pressure, and the residue is dissolved in de (100 ml) and extracted with chloroform.    The combined chloroform extracts are washed with water. The aqueous layer and the aqueous washes are acidified to pH 5 with glacial acetic acid.  Water is evaporated. isopropanol (80 ml) is added under reduced pressure.  The solid, gradually precipitated out, is filtered off, washed with water and isopropanol and dried in vacuo to give 2-nitroamino-5- (-dimethylaminomethylbenzyl) -pyrimidone (3/90 g) as a white solid with m. pl, 2l4-217 ° C.  Mixture 2- | 5 methyl | -imidazolylmethyl: tylthio) ethylamine (1.37 g) and 2 - nitroamino-5- (4-dimethylaminomethylbenzyl-4-pyrimidone (2.27 g) in ethanol (12 ml)) are refluxed in for 24 hours  Ethanol is evaporated at (Å pressure, to obtain 2-D2-15 methyl-1 "-imidazolylmethyl 6) ethylamino-5- (4-dimethylaminomethylbenzyl) - (- pyrimidone, / which is washed with j.  mixing it with water and heating the mixture, cooling it and decanting the water.  The residue is treated with ethanol: a solution of hydrogen chloride (7 ml); ethanol is distilled off under reduced pressure.  The residue is recrystallized from cmimethanol-ethanol, and trichlorohydrate f2, H pj is obtained in the form of a white solid with t. square  213.5-216 C.  1,038 Example 5.  A mixture of 2- (5 Dimethylaminomethyl-2-furanylmethylthio) ethylamine (1.71 g) and 2-nitroamino-5-dimethylaminomethylbenzyl) -4-pyrimidO (1.97 g) in ethanol (12 ml) is boiled in reverse fridge for 4.  h  The ethanol is evaporated under reduced pressure to give 2-f2-5-dimethylammonium-methyl-2-furanylmethylthioethyl jU-5 C4-dimethylaminomethylbenzylJ-4-pyrimidone as a brown oily residue, which is washed with a hot water, which has been washed with a hot water, which is washed with a white charcoal, and the sample has been removed by means of a palette, and the sample is placed in a brown color, which is washed with a palette, and the sample is placed in a brown liquid that has been applied to a mixture of purity; solution of hydrogen chloride.  The ethanol is evaporated under reduced pressure, and the residue is recrystallized from isopropanol / methanol and ethanol and ethanol to give trichlorohydrate (1.85 g) as a solid with t. square  180-.  iBfOC.  Example 6  A mixture of acetic acid (200 ml), ethyl-3-2-furanyl) propionate (32.2 g), dimethylammonium chloride (17.92 g), and an NDL (weight. /about. ) an aqueous solution of formaldehyde (17.04 g) and slowly heat it up to form a solution.  Okhlah mix give and maintain it for. A / Zb h at room temperature.  Acetic acid nyteM was removed by evaporation under reduced pressure, an oil was obtained, which was dissolved in water and adjusted to pH 10-11.  The aqueous solution was extracted with ethyl acetate.   The ethyl acetate extracts were combined, dried over magnesium sulfate, and ethyl acetate was evaporated under reduced pressure to give a brown oil, which was distilled to give ethyl 3- (5 -Di. 1-ethyl-aminomethyl-2-foryl) propionate about oida colorless oil (g) with tlsip.  108-П2С / 0.7 mm.  9-3- (5-Diyethylaminomethyl-2-furanyl) propionate (19 g) and ethyl formate (9.33 g) are added dropwise with stirring: a solution to the sodium hydride suspension.  (50 in oil, 4.0 g) in 1,2-dimethoxy-otane (50.  ml) of Kotor is pre-cooled to -40 ° C.  During the - THIS addition process, the temperature is maintained at -30 ° C, and when this addition is completed, the mixture is gradually heated to room temperature over 16 hours.  A solid brown mass is formed which is poured onto ice.  After the ice melts, an aqueous solution is formed which is extracted with ethyl acetate.  The aqueous phase is acidified with acetic acid to a pH of 4.3, evaporated to dryness under reduced pressure and dried aerated with propanol, and a brown oil is obtained.  This oil is extracted with hot acetone, filtered off the insoluble in acetone inorganic substance and washed with hot acetone.  The acetone solution is evaporated to dryness to give ethyl-3-5-Dimethylaminomethyl-2 (|) URANYL) -2-formyl propionate (1 21.22 g), which is used without purification in the next step.   Nitroguanidine 110.85 g with a content of 25% w / w water is added to a solution of sodium (5.75 g) in methanol (100 ml), and the mixture is stirred at reflux for half an hour.  Next, the mixture is chilled.  and a solution of ethyl 3- (5 dimethylaminomethylfuranyl) -2-formylpropionate (21.22 g in methanol (80 ml)) was added dropwise to it.  The resulting mixture was stirred at reflux for 18 hours, the solvent was evaporated under reduced pressure, the residue was mixed with acetone and a solution was formed and a solid precipitate was formed, which was removed by filtration, washed with acetone and acetone washes were combined with the solution.  The combined solution was evaporated under reduced pressure, an oil was obtained which was recrystallized from isopropanol to give 2-nitroamino-5 (5 dimethylaminomethyl 2-furanylmethyl) -pyrimidone (5.2 g) with m. square  210C (with decomp. A) A solution of 2- (3-methyl-amidazolmmethylthio) ethylamine (1.28 g) and -2-nitro amino-5-5-dimethylaminomethyl 2 furanylmethyl-pyrimidone (2.2 g) in pyridine (20 ml) is boiled with reverse chiller for L 16 h  Pyridium is evaporated under reduced pressure, azeotropic distillation with water is carried out to remove pyridine, and water is removed by azeotropic distillation with n.  propanol.  The resulting oily residue was chromatographed on a silica gel column using methanol-ethyl acetate for the elution.  After evaporation of the eluent, a glassy solid is obtained which is dissolved in methanol.  Ether is added to give (5 methyl-α-imid1
    vorona in water and alkalizing an aqueous solution with sodium bicarbonate and extraction with ethyl acetate. Ethyl03 0 azolylmethylthio) ethylamino1-5- (5-Dimethylaminomethyl-2-furanylmethyl / - pyrimidone (1.19 g) as a white solid with mp 108-PO ° C. Ex. 7. Solution 2- (5-Dimethylaminomethyl-2-furanylmethylthio-ethylamine (1.29 g) and 2-nitroamino-5- (5-Dimethylaminomethyl-2-furanylmethyl-pyrimidone in pyridine (15 ml)) is refluxed for - v 20 h. Pyridine is evaporated under reduced pressure. Pyridine residues are removed by azeotrope distillation with water, and water by azeotropic distillation with N. propanol. The oily residue obtained is subjected to romatographic separation in a column of silica gel, eluting with methanol-ethyl acetate 10 (v / v). After evaporation of the eluent, half (5-dimethylaminomethyl-2-furanylmethylthio) ethylamino 3-5 is evaporated; 15 15 DImethyamymethyl-2-furanylmethyl N-pyrimidone in the form of a maspa; into its trichlorohydrate using an excess of ethanolic solution of hydrogen chloride. The resulting salt is recrystallized from isopropanol to give a white solid (OJ2 g) with mp. 181-183 C. Example 8. 2- (2-Guanidine-Thiazolylmethylthio) ethylamine dihydrochloride (2.00 g) was added to a solution of sodium (0.3 g) in ethanol (15 ml). After refluxing the solution for half an hour, ethanol was evaporated under reduced pressure and dry anhydrous pyridine (0 ml) was added. 2-Nitroamio-5 (5-dimethylaminomethyl 2-furanyl) -pyrimidone (1.90 g) was added to the solution, and the mixture was heated under reflux for 20 hours. Pyridine was evaporated under reduced pressure and oil. The pure residue is subjected to azeotropic distillation with water. The residue is further washed with water, and the water is decanted. The residual oil is then subjected to azeotropic distillation with n. Propanol and treated with charcoal to discolor it. The discolored residual product is dissolved in an ethanolic hydrogen chloride solution and evaporated to dryness under reduced pressure. A strongly hygroscopic hydrochloride salt is formed, which is converted into the free base by dissolving it, dried and evaporated to dryness, the result is a solid product of yellow cepe, which is re-crystallized from ethyl acetate, and guanidine-iso-methylmethylthio-ethylamino-5- (5-Dimethylaminomethyl- 2-furanylmethyl) - 4-pyrimidone (0.3 g) with m.p. 113-116С.
    P p i. meper 9. A solution of 2- (5-dimethylaminomethyl- 2-thienylmethylthio) ethyl amine (l, g) and 2-nitroamino 5- (5 DimetiLaminomethyl-2-thienylmethyl) -pyrimidone {2.0 g) in pyridine (10 ml) is refluxed overnight. Pyridine is distilled off under low pressure and traces of pyridine are removed by azeotropic distillation with water to give 2- (5-Dimethylaminomethyl-2-thienylmethylthio) ethylamino-5- (5-Dimethylaminomethyl-2-thienyl methyl) -4-pyrimidone in the form of an oil, which is washed with water. The brown oil is then dissolved in diethyl ether, and this ethyl salt solution of hydrogen chloride is added to the solution. The resulting solution was evaporated, and the solid residue was recrystallized from methanol-ethanol mixture to give the hydrochloride (1.9 O with mp 212-215 ° C.
    Example 10 Cwecb ethyl-3- (6-methyl-3-pyridyl) propionate (38.65 g) / hydrogen peroxide (30%, 25 ml) and glacial acetic acid (100 ml) are stirred at 95 ° C for 5.5 hours. Acetic acid is evaporated under reduced pressure, and the residue is diluted with water (to obtain a volume of 1/100 ml). The pH of the aqueous solution is adjusted to 9 by the addition of an aqueous solution of sodium carbonate, and the solution is extracted with ethyl acetate. The extracts are washed with water, dried with magnesium sulfate, and ethyl acetate is evaporated under reduced pressure to give 3 (6-methyl-3 pyridyl) propionate W-oxide as a brown oil (31.51 g). Distillation of the aqueous layer (until a volume reaches about 100 ml) and continuous extraction for 6 hours with ethyl acetate leads to the formation of an additional amount of this product (3.38 g) also as a brown oil.
    Trifluoroacetic anhydride (100.59 g) is added dropwise over 5 minutes with stirring to a pre-cooled solution of ethyl-3 (b-methyl-3-pyridyl) propionpt-Vl-oxide 59.40 g; 0.28 A mole) in
    dehydrated dichloromethane 500 ml while maintaining the temperature C. Then the mixture is kept for 20 hours at room temperature in the dark. Methanol (" O Ml) was added to the solution, and dichloromethane was removed by distillation. The residue was dissolved in water and the solution was adjusted to pH 6 by the addition of an aqueous solution of sodium bicarbonate. The solution is extracted with chloroform, the chloroform extracts are washed with water, dried with magnesium sulfate, the chloroform is removed by distillation, to obtain a brown oil, which is dissolved in methanol (120 ml) and treated with an ethanolic solution of hydrogen chloride (50 ml). After evaporation of the solvent, ethyl- (6-hydroxymethyl-3-pyridyl) propionate hydrochloride is obtained as a brown oil (66.57 g).
    Thionyl chloride (ml) was added dropwise with stirring over 15 minutes to a pre-cooled solution of () ethyl-3- (6-hydroxymethyl-3-pyridyl) propionate-hydrochloride (66.57 g) in chloroform (300 m while maintaining temperature in the range of 0-2 ° C. After the addition is complete, the reaction mixture is stirred for an additional 2.5 hours, heated to room temperature, and then to A15 minutes. Chloroform and excess thionyl chloride are evaporated under wilted pressure. Residual thionyl chloride is removed by the addition of benzene and evaporation at nQ izhennom pressure to give a brown oil.
    The oil was dissolved in ethanol (300 ml), the solution was cooled to and a solution of dimethylamine DDS wt./about.) In ethanol was added dropwise with stirring over 20 minutes. After stopping the addition, stirring is continued for 1 h, at the same time the reaction mixture is heated to room temperature and allowed to stand overnight.
    Ethanol is evaporated under reduced pressure, the residue is dissolved in water and the pH is adjusted to 9 with added. a sodium bicarbonate aqueous solution. The aqueous solution is extracted with ethyl acetate, washed with water, dried with magnesium sulfate and evaporated under reduced pressure to give ethyl - (- (6-dimethylaminomethyl-3 pyridyl) propionate (55.01 g) as a brown oil. This oil is dissolved in ethanol and treated with "a large ethanol solution of hydrogen chloride. Evaporation of the solvent under an understood pressure yields an oil, which is recrystallized from a mixture of isrpropanol-ethyl acetate, 3-6-dimethylaminomethyl-3-pyridyl) propionate-dichlorohydrate (6.85 g ) in the form of light After solidification of the mother liquor, a residue is obtained, which is recrystallized from isopropanol-ethyl acetate, and additionally (1.55 g) of the desired product is obtained. A mixture of ethyl-3 dried over a vacuum ( -pyridyl) aropionate (28.02 g), obtained by neutralizing the dichlorohydrate of this compound with sodium bicarbonate, and ethyl formate (13.18 g) are added dropwise with stirring to the cooled to a suspension of sodium hydride 50 in oil, 7.12 g ) in 1,2-dimethoxyethane (sO ml) for 30 minutes while maintaining Peru the reaction mixture. Stirring is continued by heating the reaction mixture to room temperature, then it is incubated overnight. j The reaction mixture was poured onto ice and the resulting brown solution was extracted with petroleum ether b.p. OH — C) and diethyl ether. The extracts are combined and washed with water. The aqueous washes were combined with the aqueous solution, and the water was evaporated, and the last traces were removed by distillation with n-propanol, to obtain 2-formyl-3- (6-dimethylaminomethyl-3-pyridyl) propionate (22.81 g in the form of a brown oil. Nitroguanidine (11.96 g, containing 25% w / w water) is washed with methanol (15 ml) and introduced into a solution of sodium methylate in methanol (based on 2.97 g of sodium and 55 ml of methanol). Mixture is stirred for 5 minutes under reflux with a reverse chiller and then a solution of ethyl 2-formyl-3 - (b-dimethylaminomethyl-3- iridyl propionate (22.78 g) in methanol (50 ml) D for 1.25 h, then the mixture was kept under reflux for 19 h. The methanol was evaporated under reduced pressure, and the residue was dissolved in water (100 The aqueous solution is extracted with chloroform, and the chloroform extracts are washed with water.The aqueous phase is combined with a water wash and the pH is adjusted to 5 by adding acetic acid. The solvent is evaporated under reduced pressure and dehydrated by azeotropic distillation with isopropanol. The residue is extracted twice with boiling acetone / n. propanol, and recrystallized from water, get 2-nitroamino-5- (6-dimethylaminomethyl-3-pyrimidylmethyl) - -pyrimidone (9.31 g) in the form of a pale green solid with so pl. . A mixture of 2- (5-methyl-A-imidazolylmethylthio) ethylamine (1.37 g), 2-nitroamino-5- (6-dimethylaminomethyl-3-pyridylmethyl) -4-pyrimidone (2.28 g) in pyridine is boiled with 22 hours under reflux. Pyridine (12 ml) is evaporated under reduced pressure to give 2- (5-methyl-imidazolyl-methylthio ethylamino-5- {6-dimethylaminomethyl-3-pyridyl methyl) -f-pyrimidone as a brown oil which is washed with water by decanting. It is then dissolved in a dilute ethanolic solution of hydrogen chloride, and the excess solvent is evaporated under reduced pressure. The residue is recrystallized from methanol / dil. Ethanolic hydrogen chloride solution and then recrystallized twice from methanol / ethanol, tetrachlorohydrate (0.82 g) is emitted as a light brown solid with mp. 1b71 70 ° C. Example 11. A mixture of 2- (5-Dimethylaminomethyl-2-furanylmethylthio) ethylamine (1.71 g) and 2-nitroamino-5 b-dimethylaminomethyl-3 pyridylmethyl) -4-pyrimidone (1.98 g) in pyridine (12 ml are boiled under reflux for 22 hours, the reaction mixture is cooled, and pyridine is evaporated under reduced pressure. The residue is washed by decanting with hot water, dissolved in dilute ethanol and hydrogen chloride, the solvent is evaporated, receive (5-dimethylaminomethyl-2-furanylmethylthio ethylamino 5 6-dimethylaminomethyl-Zpyridylmethyl - - pyrimidone The residue is recrystallized from methanol / diluted ethanol solution of hydrogen chloride and from methanol-ethanol to give the desired dihydrochloride (0.85 g) as a light brown solid with mp H2. As a result of evaporation of the mother liquors and recrystallization evaporation from methanol / ethanol was discharged to give an additional amount of product (0.62 g) with a mp. Example 12. Raney nickel (g) was added to a solution of 3 dimethylaminomethylbenzonitrile (78.30 rj and sodium hypophosphate monohydrate (170.0 g) in water - acetic acid - pyridine in the ratio of 1: 1: 2 (1600 ml). The mixture is stirred for 3 hours at and then cooled. Rene nickel is removed by filtration through diatomaceous earth, and the filter bed is washed with ethanol. The combined washes and filtrate were concentrated under reduced pressure to a volume of 600 ml. And diluted with water (250 ml). The volume of the resulting solution is again reduced (600 ml), the pH of the solution is adjusted to 8 by the addition of an aqueous solution of potassium carbonate and extracted with ethyl acetate. The extract is washed with water, dried over magnesium sulfate and the solvent is evaporated, to give 3-dimethylaminomethylbenzaldehyde (62.88 g) as a light yellow liquid. A mixture of 3 dimethylaminomethylbenzaldehyde (32.6 g), monomethylmalonate (29.07 t), pyridine (100 ml) and piperidine (2 ml) was heated under reflux with stirring for 5 hours. The reaction mixture was cooled and the pyridine was removed under reduced pressure. pressure. The residue is dissolved in diethyl ether, the ethereal solution is washed with water, dried with sulphate and evaporated under reduced pressure, and then dried to obtain ethyl 3- (dimethylaminomethyl) cinnamo Ho, 39 g as a light yellow oil. A mixture of ethyl 3- (dimethylaminomethyl) cinnamate (0, ZE g7 and palladium on coal (10, -0.3 g) in ethanol (170 ml is hydrogenated at a pressure of 3 kPa until the theoretical calculated amount of water is consumed The catalyst was removed by filtration through diatomaceous earth, washed with ethanol, and the combined filters and washes were evaporated under reduced pressure to give ethyl-3-f3-dimethyl amiomethylphenyl) propionate (38.63 g) as a yellowish liquid. 1 3 A mixture of ethyl 3- (3-dimethylaminomethylphenyl propionate (38.63 g) and ethyl porter (18.25 g / was added dropwise at the stirring to a pre-cooled (-5 ° C) suspension of sodium hydride (50% in oil, 9.85 g) in 1,2-dimethoxyethane (60 ml) for 1.75 h, while maintaining the temperature of the reaction mixture below OS. The mixture is heated to room temperature with continuous stirring, and then vydernya {overnight. The mixture is poured on ice, you get a brown aqueous solution, which is extracted with petroleum ether (so kip. t0-60 C) and diethyl ether. The extracts are washed with water and the combined aqueous washes and water (the acid is acidified to pi 6. The aqueous phase is evaporated under reduced pressure, a brown oil is obtained, which is dehydrated by azeotropic distillation with isopropanol. The dried residue is extracted with hot isopropanol / acetone, non-solvent. We remove inorganic solids by filtration through diatomaceous earth and rinse with additional isopropanol / acetone mixture. The combined Ti wash filtrate is suspended in water, the pH of which is adjusted to S by adding an aqueous solution of sodium bicarbonate. The aqueous phase is extracted with ethyl acetate. The extract is washed with water, dried with magnesium sulfate, evaporated under reduced pressure, to give ethyl 2-formyl-3- (3 dimethylpminomethylphenyl) propionate (20, g) as a light brown oil colors. Nitroguanidine (10.56 g, with a content of 25 (o / w) water) is washed with methanol (10 ml) and introduced into a solution of sodium methylate in methanol (2.62 g of sodium in 50 ... ml of methanol). The mixture was stirred and refluxed for 0.75 - and then a solution of 2 formyl-3- (3-dimethylaminomethylphenyl) propionate (20.0 (g) in methanol (50 ml) was added with stirring for 1 hour). ) The mixture was stirred and boiled / refluxed for 22 hours. The methanol was evaporated under reduced pressure, and the residue was dissolved in water (100 ml), extracted with chloroform, and the chloroform extracts were washed with water. The aqueous phase was acidified to pH 5 by adding glacial acetic acid. The mapopo which precipitated upon cooling was separated by separation, to give 2-nitroamide no-5 .. (3 dimethylaminomethylbenzyl - - pyrimmdon (8.79 g) as a solid Dii of pale cream color with mp.232 .. After evaporation of the mother solution, an oily residue is obtained, which is washed with water and boiled t with propanol, an additional amount (1.57 g) of a pale cream solid is obtained with a melting point of 225226 ° C. A mixture of 2- (5-methyl-imidazolylmethylthio) ethylamine (1.37 g) and 2 nitroamino -5- (3 Diethylpminomethylbenzyl - (-pyrimidone (2.27 f) in pyridine (12 ml)) is refluxed for 18 hours. The solvent is evaporated under reduced pressure. enii, the residue washed with water by decantation, dried, dried produk treated with maleic acid in acetone. The solvent is evaporated and the resulting 2-1 5-methyl-4-imidazolylmethylthio) ethylamino-5- (3-dimethylaminomethylbenzyl) -pyrimidone is recrystallized from a mixture of isopropanol-tanol, the trimaleate of compound d is isolated as a light brown solid with t .pl. , 5 1t2,5 ° C. Example 13. A mixture of 2- {5-Dimethylaminomethyl-2-Oranylmethylthio) ethyl amine (1.71 g) and 2-nitroamino-5- (3-dimethylaminomethylbenzyl) -pyrimido per (1.97 g) in pyridine (12 ml D was refluxed for 23 hours. Excess pyridine was evaporated to give (5-Dimethylaminomethyl-2-furanylmethylthio) ethylamino-5 - (3 Dimethylaminobenzyl) - -pyrimidone as an oily product, which was washed with water by decantation. This product then dissolved in a dilute ethanolic solution of hydrogen chloride, and the excess solvent is removed. The catalyst is recrystallized from isopropanol / ethanol and then trichlorohydrate (2.51 g) is obtained from ethanol as a light brown solid with mp 182.5-185 ° C. Example 1 (+. Diethyl sulfate mixture ( 57.1 g) and tri-n-propylamine is added dropwise with stirring to a solution of furanyl acrylic acid (g) in acetone (15 mL). After the addition is stopped, the mixture is boiled under reflux for 6 hours. The acetone is evaporated under reduced pressure. The resulting residue is dissolved in ethyl acetate, washed with an aqueous solution of sodium bicarbonate, dried over magnesium sulfate (the solvent is evaporated) to give ethyl 3- (2-furanyl) acrylate (6.7 g) as a brown oil. Ethyl 3- (2-furanyl) acrylate (46.7 g) in a concentrated solution of ammonium hydroxide (25 ml) is hydrogenated in the presence of a catalyst Rane's nickel (500 g) at 35 ° C until consumed. theoretically calculated amount of hydrogen. Nicene, Rene is removed by filtration through diatomaceous earth, and the filtrate is evaporated under reduced pressure to give a brown oil. This oil was dissolved in ethyl acetate, washed with distilled water, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to give ethyl 3- (2-furan 1 / (l) propionate (33.77 g) as a brown oil. Ethyl 3 mixture - (2-furanyl) propionate (33.77 g) and ethyl formate (22.22 g) to be added dropwise with stirring to a pre-cooled suspension (0 ° C) of sodium hydride (50 in oil, (8.45 g ) in dimethoxyethane (70 ml), maintaining the temperature / ru below O C during this addition. The reaction mixture is heated to room temperature, then It is taken up in ice and the water is extracted with ethyl acetate. The aqueous layer is acidified to pH and extracted again with ethyl acetate. The ethyl acetate extracts (second) are combined, dried with ammonium sulfate and evaporated under reduced pressure to give ethyl 3- (2-oranyl) -2-frrmylpropionate (19.0 g). Nitroguanidine (l2.59 g, containing 25 (w / w) waterJ) is added to a solution of sodium methoxide in methanol from 6.25 g sodium and 100 ml methanol and the mixture is boiled with reflux. The mixture is chilled and ethyl-3 (2-furanyl) -2-formylpropionate (l9 g) is added to it. The mixture is then heated under reflux for an hour. The methanol is evaporated under reduced pressure to give an oil, which is mixed with water and acidified to pH by the addition of glacial acetic acid. After cooling the aqueous mixture, a solid is obtained.
    权利要求:
    Claims (1)
    [1]
    METHOD OF PRODUCING DERIVATIVES OF 4-pyrimidone or a pharmaceutically acceptable acid addition salts (57) A method for the preparation of 4-pyrimidone derivatives of general formula CH ~ ~ nr 2 i WCH 2 gCH 2 CH 2 NHA N X Q where W -2-furanyl or 2 -thienyl optionally substituted at position 4 by a group R 1 to HCH-2 .;
    R and R are C., C4 alkyl, phenyl substituted at the 3 or 4 position by R 1 R 2 NCH 2 ~; 4-imidazolyl optionally substituted at 5-methyl; 2-guanitol dino-4-thiazolyl;
    L-2-furanyl or 2-thienyl substituted at position 5 with the group R 1 R ^ NCH ^ -; phenyl substituted at position 3 or 4 with the group r'r ^ HCH ^ - ·, 3-pyridyl, substituted at position 6 with the group 'K 1 R ilCHj.- or 4-pyridyl, za- ·. placed in flaxen. 2 group of R 1 , or their pharmaceutically acceptable acid addition salts, with the exception of the fact that the derivative of the '2-alkioethylamine of the general formula.
    WCH ^ SCH ^ H ^ NH ^, (P) where W has the indicated meanings, is reacted with a 4-pyrimidone derivative of the general formula wherein B has the indicated meanings;
    A - nitroamino group g with the subsequent isolation of the target product in the form of a base or treatment with Mannich's reagent K, when B or Y / are unsubstituted 2-thienyl or 2-furanyl, and the isolation of the target product in the form of a base of a kiblot additive salt,
    Priority by signs: 03/29/80 with W - all values;
    R ^ and R i are all values; B is 2-furanyl or 2-thienyl substituted at position 5 with the group R ^ R 2 NCHt .; phenyl substituted at position 3 or 4 with a group R 4 R ^ HCHz;
    01/21/81 at B - 3 “pyridyl substituted at position 6 with the group R 1 R 2 NCH2 or 4-pyridyl substituted at position 2 with the group R ^ R ^ NCH ^.
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    同族专利:
    公开号 | 公开日
    EP0039989A1|1981-11-18|
    NZ196640A|1983-11-18|
    RO81930A|1983-06-01|
    EP0039989B1|1984-08-29|
    RO81930B|1983-05-30|
    GR74841B|1984-07-12|
    ES500796A0|1982-01-01|
    PT72752A|1981-04-01|
    YU81181A|1983-12-31|
    DE3165733D1|1984-10-04|
    AR225955A1|1982-05-14|
    NO811065L|1981-09-30|
    FI810961L|1981-09-30|
    AU6885881A|1981-10-08|
    ZW6581A1|1981-07-01|
    ES8201982A1|1982-01-01|
    US4388317A|1983-06-14|
    DK140281A|1981-09-30|
    CA1155842A|1983-10-25|
    AU541724B2|1985-01-17|
    JO1164B1|1983-11-30|
    PL230363A1|1981-11-27|
    DD157703A5|1982-12-01|
    PT72752B|1982-03-23|
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    US4218452A|1975-10-02|1980-08-19|Smith Kline & French Laboratories Limited|Substituted 4-pyrimidone compounds, compositions and methods of use|
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    IN151188B|1978-02-13|1983-03-05|Smith Kline French Lab|
    PH16240A|1978-04-11|1983-08-11|Smith Kline French Lab|Process for making histamine antagonist|
    ZA793443B|1978-07-26|1980-12-31|Glaxo Group Ltd|Heterocyclic derivatives|US4808589A|1982-02-20|1989-02-28|Smith Kline & French Laboratories Limited|Pyrimidone derivatives|
    JO1274B1|1982-12-03|1985-04-20|سيدني ساخ جورج|Puridone derivatives|
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    CA1275097A|1984-10-02|1990-10-09|Fujio Nohara|Pyridyloxy derivatives|
    EP2054386B1|2006-08-03|2014-10-08|Trustees Of Tufts College|Non-flushing niacin analogues, and methods of use thereof|
    US20100137388A1|2007-04-19|2010-06-03|Barden Christopher J|Therapeutic Pro-Antibiotic Agents and Methods of Use Thereof|
    WO2022034121A1|2020-08-11|2022-02-17|Université De Strasbourg|H2 blockers targeting liver macrophages for the prevention and treatment of liver disease and cancer|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    GB8010663|1980-03-29|
    GB8101705|1981-01-21|
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