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    • 专利摘要:
    Pharmacologically active thiazolo[3,2-a]pyrimidines of the formula <IMAGE> wherein A is a bond between the alpha - and beta -carbon atoms or (-CH2-) group; R1 and R2 represent hydrogen, C1-C4 alkyl, cyano, CF3, thienyl, pyridyl, biphenyl, naphtyl, phenyl optionally substituted, <IMAGE> wherein R' and R'' are hydrogen or alkyl; R3 represents hydrogen, halogen, alkyl, OH, formyloxy, alkanoyloxy, alkenyloxy; R4 represents substituted pyrrole, substituted phenyl or substituted thiazolyl. The compounds have antiinflammatory, antiulcerorgenic and antigastric secretory activity.
    公开号:SU1358786A3
    申请号:SU823466583
    申请日:1982-07-13
    公开日:1987-12-07
    发明作者:Дория Джанфедерико；Пассаротти Карло；Аркари Юлиана；Буттинони Ада
    申请人:Фармиталия Карло Эрба, С.П.А. (Фирма)；
    IPC主号:
    专利说明:

     135
    This invention relates to a process for the preparation of substituted thiazolo (3,2-a) - pyrimidines - new biologically active compounds that can be used in medicine.
    The purpose of the invention is new derivatives in the range of thiazolo, 2-a) pyrimidines of low toxicity and possessing
    higher antiulcer and pro-ethenyl-5H-thiazolo (3,2-a) pyrimidine-inflammatory activity.
    Example 1. 3.06 g of 2-aminothiazole are reacted with 6.4 g of ethyl 2-methyl acetoacetate in 15.3 g of polyphosphoric acid (7.1 g of phosphoric anhydride and 8.2 g of 99% orthophosphoric acid acid) with simultaneous stirring at 100 ° C for 2 hours. After cooling, diluting with ice-water and neutralizing, the precipitate is filtered off, washed with water and recrystallized from isopropyl ether, resulting in 5.04 g of 6.7- dimethyl-5H-thiazolo- (3,2-a) pyrimidin-5-one with so pl. 112- 113 C. The latter is then reacted in the presence of 4. 55 g of sodium methoxide with stirring at reflux temperature for 12 hours from 5.99 g of 3-pyridinecarboxaldehyde in 130 ml of methanol. After cooling, the precipitate is filtered off and washed with water.
    -5-he with m. Pl. 190-191 C,
    6-chloro-7-trans-2- (3-pyridyl) -ethenyl-5H-thiazolo (3,2-a) pyrimidine-5--one, mp, 235-237 ° Ci
    15 Example 2. In 25 g of polyphosphoric acid with stirring and at 100 ° C for 8 hours, 5 g of 2-aminothiazole are reacted with 10.8 g of ethyl 4-chloroacetoacetate.
    20 After cooling, diluting with an ice-water mixture and neutralizing the precipitate, filter and wash with water. Then, at a boiling point under reflux and with simultaneous stirring for 30 hours, 8.8 g of the 7-chloromethyl-5H-thiazolo (3,2-a) pyrimidine-5-one obtained is reacted in 130 ml of acetonitryl. with 12.8 g of trif30 nilphosphine. After cooling, the precipitate is filtered and washed with isopropyl ether, resulting in a yield of 20.6 g of 5H-thiazolo (3; 2-a) - pyrimidin-5-on-7-yl 1-methyltriphenyl-
    25
    30 nilphosphine. After cooling, the precipitate is filtered and washed with isopropyl ether, resulting in a yield of 20.6 g of 5H-thiazolo (3; 2-a) - pyrimidin-5-on-7-yl 1-methyltriphenyl-
    until neutral. The result of phosphonium chloride with m. Pl. 295-299 ° C, 3.2 g of 6-methyl-7 trans-2- (3-pyridyl) -ethenyl-5H-thiazolo (3,2-a) pyrimidin-5-one are obtained by crystallization from methanol with t. pl. 192-194 C. Yield 38.9%.
    4b
    while stirring, they are added to a 50% suspension of sodium hydride (2.61 g) in 300 ml of dimethyl sulfoxide and 200 ml of dichloroethane, and at room temperature for 6 h the 3-pyridine carboxaldehyde is reacted with 7.15 g . After evaporation of dichloroethane in vacuo, the solution is diluted with ice-water mixture to precipitate out
    During similar experiments, the following compounds are obtained:
    6-methyl-7-trans-2- (4-pyridyl) -ethenyl-5H-thiazolo (3,2-a) pyrimidine-5-one with t. Pl. 252-253 ° CV
    6-methyl-7-trans-2- (6-methyl-2-.-Pyridyl) -ethenyl-5H-thiazolo (3,2-a) - pyrimidin-5-one with t. Pl. 198-199 0,
    2,3,6-trimethyl-7-trans-2- (3-pi :: ridyl) -ethenyl-5H-thiazolo (3,2-a) pyri Midin-5-OH, m.p. 193-195 ° C;
    2-chloro-6-methyl-7-trans-G2- (3-pyrid-1x) -ethenyl-5H-thiazolo (3,2-a) pyrimidine-5-one;
    3,6 dimethyl-7-trans-2- (3-pyridyl) -ethenyl-611-thiazolo (3, 2-a) pyri-MCZIN-5-OH, m.p. 211-214 ° Cf
    3- (4-aminophenyl) -7-trans-2- (3-pyridyl) -ethenyl-5H-thiazolo (3,2-a) pyri g1idin-5-one, m.p. 282-284 ° C (decomposition);
    about 6-ethyl-7-trans 2- (3-pyridyl) -zeten-5H-thiazolo (3,2-a) pyrimidine-5-- it is with T .. PL. 176-177 ° C;
    6-prolyl-7-trans-2- (3-pyridyl) -ethenyl-5H-thiazolo (3,2-a) pyrimidine 5-one with m. Pl. 190-191 C,
    6-chloro-7-trans-2- (3-pyridyl) -etheyl-5H-thiazolo (3,2-a) pyrimidine-5-one, m.p., 235-237 ° Ci
    Example 2. In 25 g of polyphosphoric acid, 5 g of 2-aminothiazole are reacted with 10.8 g of ethyl 4-chloroacetoacetate under stirring and at 100 ° C for 8 hours.
    After cooling, diluting with ice-water and neutralizing the precipitate, it is filtered and washed with water. Then, at a boiling point under reflux and with simultaneous stirring for 30 hours, 8.8 g of the 7-chloromethyl-5H-thiazolo (3,2-a) pyrimidine-5-one obtained is reacted in 130 ml of acetonitryl. with 12.8 g of triphenylphosphine. After cooling, the precipitate is filtered and washed with isopropyl ether, resulting in a yield of 20.6 g of 5H-thiazolo (3; 2-a) - pyrimidin-5-on-7-yl 1-methyltriphenyl-
    phosphonium chloride with m. pl. 295-299 ° C,
     phosphonium chloride with m. pl. 295-299 ° C,
    4b
    while stirring, they are added to a 50% suspension of sodium hydride (2.61 g) in 300 ml of dimethyl sulfoxide and 200 ml of dichloroethane, and at room temperature for 6 hours they are reacted with 7.15 g of 3-pyridinecarboxaldehyde. After evaporation of dichloroethane in vacuo, the solution is diluted with ice-water, the precipitate is filtered off and washed with water, after which, by crystallization from isopropyl alcohol, 6.2 g of 7-trans-2- (3-pyridine 1) -ethenyl - are obtained. 5H-thiazolo (3,2-a) 50 pyrimidin-5-one with so pl. 206-207 C. Yield 48.6%;
    In accordance with the foregoing, the following compounds are obtained using suitable aldehydes with a similar yield:
    7-trans-2- (2-pyridyl) -ethJenyl - -5H-thiaz6lo (3,2-a) pyrimidin-5-one with m. Pl. 231-232 seconds;
    7-trans-2- (4-pyridyl) -ethenyl - -5H-thiazolo (3,2-a) pyrimidin-5-one with m. Pl. 246-247 01
    7-trans; - 2- (6-methyl-2-pyridyl) -ethenyl-5H-thiazolo (3,2-a) pyrimidinone with the like. 213-216 ° C {
    7-trans-2- (1-methyl-2-pyrrolyl) -ethenyl-5H-thiazolo (3,2-a) pyrimidin-5-one with m. Pl. 211-212 ° C;
    7-trans-H2- (3-methoxyphenyl-etenyl-5H-thiazolo (3,2-a) pyrimidin-5-one with m. Pl.
    7-trans-p- (4-methylphenyl) -ethenyl-5H-thiazolo- (3.2-a) pyrimidin-5-one with m. Pl. 214-216 Ci
    3- (4-amino-phenyl) -7-trans-2- (3- -pyridyl) -ethenyl-5H-thiazolo (3, 2-a) 282-284 with
    pyrimidine-5 with m.p. (decomposition).
    Example 3. 40 g of polyphosphoric acid at. 110 ° C. With simultaneous stirring for 1 h, 8 g of 2-amino-5-chloroiazol-hydrochloride are reacted with 15.8 g of 4-chloroacetoacetate. After cooling, diluting with water and neutralizing with 35% sodium hydroxide solution, the precipitate is filtered and washed with water. As a result of crystallization from isopropyl ether, 7.45 g of 2-chloro-7-chloromethyl-5H-thiazolo (3,2-a) pyrimidin-5-one with m.p. 123-125 s. Then, with stirring and boiling at reflux temperature, the resulting product is reacted for 10 hours with 9.42 g of triphenylphosphine in 100 ml of acetonitrile. After cooling, the precipitate is filtered and washed with acetone with a yield of 10 g to obtain 10 g of 2-chloro-5H-thiazolo (3,2-a) pyrimidine-3-one-7-sh1-methyltriphenylphosphonium chloride st. square 300-310 ° C (with decomposition), which is further suspended in 40 ml of dimethyl sulfoxide and treated with 2.48 g of potassium t-butoxide dissolved in 40 ml of dimethyl sulfoxide. The operation was carried out at room temperature with stirring for 10 minutes. 2.45 g of 3-pyridinecarboxaldehyde dissolved in 20 ml of dimethyl sulfoxide is added to the solution of the ylide thus obtained, and the reaction mixture is kept at room temperature for 15 minutes with stirring. After diluting the water with ice and neutralizing it with a primary acidic sodium orthophosphate

    20
    25
    thirty
    50 55
    358786
    the precipitate obtained is filtered off and crystallized from a mixture of dichloromethane and isopropyl alcohol, as a result of which 4.3 g of 2-chloro-7-trans-2- (3-pyridyl) -ttenyl) -5H-thiazolo are obtained (3, 2-a) pyrimidine-5-it with so pl. 189-190 C. Exit 31.67.
    In the course of carrying out the process, the following compounds are obtained in a similar way out in a similar way:
    H-methyl-7-trans-2- (3-pyridyl) -ethenyl) -5H-thiazolo (3,2-a) pyrimidin-5-one with m. Pl. 191-193 ° C, 15 2, 3-dimethyl-7-trans-2- (3-pyridyl) -ethenyl-5H-thiazolo (3,2-a) pyri-MIDIN-5-OH with m. Pl. 179-180 ° C;
    H-trifluoromethyl-7-trans-2- (3-pyridyl) -ethenyl-5H-thiazolo (3,2-a) pyrimidin-5-one with m. Pl. 224-226 С,
    2-bromo-7-trans-2- (3-pyridyl) -ethenyl-5H-thiazolo (3,2-a) pyrimidine-5--one with m. Pl. 211-213 ° C-,
    Example 4. In 250 ml of acetonitrile, 7.8 g of 7-chloromethyl-3-phenyl-5H-thiazolo (3,2-a) pyrimidin-5-one was reacted under reflux for 24 hours with stirring. from m.p. 194-195 With obtained in accordance with example 5, with 8 g of triphenylphosphine. After cooling, the solution is concentrated in vacuo to a small residual volume, diluted with isopropyl ether-. rum and the precipitated precipitate is filtered off, resulting in 11 g of 3-fench1-5H — thiazolo (3,2-a) pyrimide in-5-one-7-yl-methyltriphenylphosphonium chloride, which are then suspended in 50 ml of dimethyl sulfoxide and with stirring at-room temperature, 2.46 g of sodium tert-butoxide dissolved in 50 ml of dimethyl sulfoxide are treated. A solution of the ylide obtained in this way is then reacted at room temperature for 60 minutes with 2.36 g of 3-pyridinecarboxaldehyde, followed by diluting the reaction mixture with a mixture of water and ice and neutralizing with sodium hydroxide orthophosphate. The precipitate formed is filtered off and washed with water. As a result of crystallization from a mixture of dichloromethane with methanol, 2.8 g of 3-phenyl-7-trans-f2- (3-pyridyl) -ethenyl-5H-thiazolo (3,2-a) pyrimidin-5-one with t pl. 270-272 C. Yield 30.0%.
    35
    40
    45
    In the course of the experiment in the same way as described above, the following compounds are obtained with a similar yield:
    / - 3- (4-fluorophenyl) -7-trans-G2- (3-pyridyl) -ethenyl-5H-thiazolo (3,2-a) - pyrimidin-5-one with m. Pl. 241-243 CJ 3- (4-chlorophenyl) -6-trans--2 (3-pyridyl) -e tenyl-bH-thiazolo (3,2-a) - pyrimidin-5-one with m. Pl, 282 -283 Cj 3- (4-methylphenyl) -7-trans-2- (3-pyridyl) -ethenyl-5H-thiazolo (3,2-a) - pyrimidin-5-one with t, pl. 254-255 С, 3- (3-methoxyphenyl) -7-trans-2Ш
    The precipitate formed during this process is filtered off and washed with water. As a result of crystallization from a mixture of dichloromethane and methanol, 2.8 g of 3- (3-pyridyl) -7-trans-2- (3-pi dil)-ethensh1 -5H-thiazolo (3, 2-a) pyrim din- 5-she with t. Pl. 270-272 ° C. Exit
    Example 6. In 375 ml of dimethyl acetamide containing 71.5 g of polyphosphoric acid (42.5 g of phosphoric anhydride + 29 g of orthophosphoric acid) under conditions of stirring at 100 ° C for 24 hours, 10 g of 2-aminothiazole is reacted with 37 , 5 g
    cooling, diluting with water and neutralizing with the addition of a secondary acid sodium orthophosphate, the precipitated precipitate is extracted with ethyl acetate.
    - (3-pyridyl) -ethenyl-5H-thiazolo (3,2-t5 ethyl-2-aCethoxyacetoacetate. After -a) pyrimidin-5-one with m.p. 209-210 С,
    3- (4-methoxyphenyl) -6-trans-2- (3-pyridyl) -ethenyl-5H-thiazolo (3.2-a) pyrimidin-5-one with m.p. 241-242 С
     2-methyl-3-phenyl-7-trans-1 2- (3-pi-20 "0rganic. The solution is evaporated in readl) ethenyl-5H-thiazolo (3,2-a) pyrimidine-5-one with m.p. 234-237 ° C
    3- (4-aminophenyl) -7-trans-L2- (3- -pyridyl) -ethenyl-5H-thiazolo (3.2-a) - 25 pyrimidin-5-one with mp. 282-284 C (with decomposition).
    vacuum to dryness and residue are purified on a silica column using chloroform as eluent.
    As a result of crystallization from isopropyl ether, 8 g of 6-acetoxy-7-methyl-5H-thiazolo are obtained (3,2-a pyrimidin-5-one with mp 118-119 C, which is hydrolyzed by
    Example 5. 5.30 g of 7-chloromethyl-3- (3-pyridyl) -5H-thiazolo (3,2-a) - pyrimidin-5-one with m. Pl. 280-290 0 (with decomposition). prepared in accordance with Example 6 was used to react in 500 ml of acetonitrile with simultaneous stirring and reflux for 40 hours with 5 g of triphenylphosphine. After cooling, the solution is concentrated in vacuo to a small residual volume, diluted with isopropyl ether, and the precipitated precipitate is filtered to obtain 8 g of 3- (3-pyridyl) -5H-thia-Zolo (3,2-a) pyrimidine-5-one-7 -l1-methyltriphenylphosphonium chloride, which is suspended in 100 ml of dimethyl sulfonic acid, and then with stirring at room temperature, the suspension is treated with 1.66 g of tert-potassium botoxide, dissolved in 50 ml of dimethyl sulfoxide. A solution of the ylide obtained in this way was then reacted with 1.74 g of 3-pyridinecarboxaldehyde at room temperature for 30 minutes, after which the reaction mixture was diluted with ice-water and neutralized with sodium acid orthophosphate.
    The precipitate formed is filtered off and washed with water. As a result of crystallization from a mixture of dichloromethane with methanol, 2.8 g of 3- (3-pyridyl) -7-trans-2- (3-pyridyl) -ethane 1 -5H-thiazolo (3, 2-a) pyrimyl are obtained. - din-5-it with t. pl. 270-272 ° C. Exit 44%
    Example 6. In 375 ml of dimethyl-acetamide containing 71.5 g of polyphosphoric acid (42.5 g of phosphoric anhydride + 29 g of orthophosphoric acid) under stirring conditions at 100 ° C for 24 hours, 10 g of 2-aminothiazole are reacted with 37.5 g
    ethyl 2-acetoxyacetoacetate. After
    cooling, diluting with water and neutralizing by adding sodium acid orthophosphate secondary, the precipitated precipitate is extracted with ethyl acetate.
    ethyl 2-acetoxyacetoacetate. After
    rganichesky. the solution is evaporated in
    vacuum to dryness and residue are purified in a silica column using chloroform as eluent.
    As a result of crystallization from isopropyl ether, 8 g of 6-acetoxy-7-methyl-5H-thiazolo (3,2-a) pyrimidin-5-one with m.p. 118-119 C, which is subjected to hydrolysis by
    treating it in 80 ml of methanol with stirring at 60 ° C for 4 hours and 16 g of sodium bicarbonate. After cooling, the solution is evaporated at. vacuum to a slight residual
    volume, and the residue is dissolved in ethyl acetate, followed by repeated extraction treatment with an aqueous solution of sodium hydroxide. The aqueous phase is neutralized by the addition of
    37% hydrochloric acid and the precipitated precipitate is extracted with chloroform. The organic solution is evaporated to dryness in vacuo. Crystallization from ethyl acetate gives 5.3 g.
    6-hydroxy-7-methyl-6H-thiazolo (3,2-a) pyrimidin-5-one with m. Pl. 225-227 ° C, which is then dissolved in 50 ml of dimethylformamide. Further, in the presence of 8.1 g of anhydrous potassium carbonate in
    stirring conditions at room temperature for 16 hours, the product solution is reacted with 8.3 g of methyl iodide. The reaction mixture is diluted with ice water and
    it is subjected to extraction treatment with ethyl acetate, after which the organic solution is treated with gaseous hydrogen chloride. The precipitation is filtered off and washed with ethyl acetate, resulting in a gain of 4.7 g of 6-methoxy-7-methyl-5H-thiazolo (3,2-a) pyrimidine-5-one hydrochloride with so pl. 185-195 ° С (with decomposition). Then, in the presence of 3.3 g of sodium methoxide with stirring and refluxing for 2 hours, 5.4 g of 3-pyridylcarboxaldehyde are reacted. After concentration in vacuo to a small residual volume and dilution with isopropyl ether the precipitation is filtered and washed with isopropyl ether and then with water. As a result of cristianisation, 3, 2 g of 6-methoxy-7-trans-2- (3-pyridyl) ethylene {-5H-thiazolo (3,2-a) pyrimidine-5 are obtained from the 50% ethanol. - it with t. pl. 186 - 187 ° С (yield 11.2%) and 6-methoxy-7- -trans-2- (3-pyridyl) -cyclopropy--5H-thiazolo (3j 2-a) pyrimidin-5-one, t. square 92-95 S.
    In the course of the process, 6-methoxy-7-trans-2- (3-1-tridyl) -ethenyl-5H-thiazolo (3,2-a) -pyrimidin-5-one is obtained in a similar way as described in a similar way out. . 163-165 C.
    formamide, and in the presence of 15 g of potassium carbonate with stirring and at 60 ° C for 3 h, the product solution is reacted with 15.4 g of iodis
    5 of that methyl. After cooling, the reaction mixture is diluted with a mixture of water and ice and neutralized by the addition of primary acidic sodium orthophosphate. The precipitate is filtered off and the aqueous phase is extracted
    ethyl acetate with complete isolation of the product. A total of 5.1 g of 2-chloro-6-methoxy-7-methyl-5H- (3,2-a) pyrimidin-5-one are obtained with
    f5 t. pl. 138-141 ° C, and then, in 40 ml of benzene at reflux temperature, the product is reacted for 40 hours with 17 g of N-bromosuccinimide, which is added in batches in 20 portions. After cooling the reaction mixture, it was diluted with ethyl acetate and treated with an aqueous solution of sodium bicarbonate and then with water. The assigned op
    The 25 solution is evaporated in va-, cuum to dryness and the residue is crystallized from ethyl acetate to give 2.8 g of 7-β-bromomethyl-2-chloro-6-methoxy-5H-thiazolo (3,2-a) pyrimidin-6-one with m.p. Example 7. In 400 ml of dimethyl 160-162 ° C, then in 50 ml of acetocetamide containing 71 g of polyphosphonitrile at the boiling point of hydrochloric acid (29 g of orthophosphoric acid) under reflux for 3 hours + 42 g of phosphoric anhydride) under the conditions of
    the resulting product is reacted with 2.6 g of triphenylphosphine. After
    continuous mixing at 100 ° C
    10 g of 2-ami- cooling and evaporation in vacuo of n-chlorothiazole hydrochloride with 22 g of solvent were purified for 6 hours and the residue was purified from isiol ethyl 2-acetoxy acetoacetate. After calling up ethyl acetate, cooling as a result of dilution with a mixture of water, 3.8 g of 2-chloro-6-methox-ice are obtained and neutralized by adding si-5H-thiazolo (3.2-a) pyrimidine-5-one- 37% sodium hydroxide solution of 0–7-yl-methyltriphenylphosphoniumbromiriya; the precipitated precipitate is extracted with yes, which is suspended in 45 ml
    dimethyl sulfoxide, and at room temperature, with stirring for 10 minutes, 0.75 g of 45 t-butoxide of potassium dissolved in 20 ml of dimethyl sulfoxide is treated.
    with ethyl acetate and the organic layers evaporated to dryness in vacuo. The residue obtained is subjected to hydrolysis by treating it in 100 ml of dioxane at reflux temperature for 2 hours with 50 ml of 35% hydrochloric acid. After cooling, the reaction mixture is diluted with a mixture
    Then, at room temperature iB, the plant is reacted with ice for 1 h and neutralized with the addition of the thief thus obtained or with a 37% aqueous solution of oxide hydrate with 0.9.4 g of 3-pyridinecarboxaldehyde. The reaction mixture is diluted with ice-water, neutralized by the addition of a primary acidic sodium orthophosphate of sodium and the precipitate formed is filtered off. As a result of crystallization from ethanol, 0.96 g-a) pyrimidine-5-one with m.p. 214-217 Cj. 2-hlrr-6-methoxy-7-trans-2- (3-pyri-which is dissolved in 100 ml of dimethyl-; dyl) -ethenyl-3-5H-thiazolo (3,2-a) sodium pyrimis, and the precipitated precipitate is extracted acetylacetate. The organic solution is evaporated to dryness in vacuo, and the resulting residue is crystallized from methanol to give 5.85 g of 2-chloro-6-hydroxy-7-methyl-5H-thiazolo (3.2
    .
    58786 8
    formamide, and in the presence of 15 g of potassium carbonate with stirring and at 60 ° C for 3 hours, the solution of the product is reacted with 15.4 g of methyl iodis. After cooling, the reaction mixture is diluted with a mixture of water and ice and neutralized by the addition of primary acidic sodium orthophosphate. The precipitate is filtered off and the aqueous phase is extracted
    ethyl acetate with complete separation of the product. A total of 5.1 g of 2-chloro-6-methoxy-7-methyl-5H- (3,2-a) pyrimidin-5-one are obtained with
    f5 t. pl. 138-141 ° C, and then, in 40 ml of benzene at reflux temperature, the product is reacted for 40 hours with 17 g of N-bromosuccinimide, which is added in batches in 20 portions. After cooling the reaction mixture, it was diluted with ethyl acetate and treated with an aqueous solution of sodium bicarbonate and then with water. The precipitated organic solution is evaporated in vacuo to dry and the residue is crystallized from ethyl acetate to give 2.8 g of 7-β-bromomethyl-2-chloro-6-methoxy-5H-thiazolo (3,2-a) pyrimidine-6-one with t. pl. 160-162 ° C, then in 50 ml of acetonitrile at reflux temperature for 3 hours
    the resulting product is reacted with 2.6 g of triphenylphosphine. After
    din-5-she with t. pl. 205-207 ° C. Yield 5.4%.
    In the course of the process, 6-methoxy-7-trans-2- (3-pyridyl) -ethenyl-5H-thiazolo (3,2-a) pyrimidin-5-one, m.p. 186-187 ° C.
    Example 8. In 150 ml of dichloroethane with stirring at room temperature for 4 hours, 6.07 g of 2-chloro-7-chloromethyl-5H-thiazolo (3,2-a) pyrimidine-5- it, obtained in accordance with example 5, with 3.8 g of chloride sulphuryl. The reaction mixture is further treated with a 5% aqueous solution of sodium bicarbonate, after which the organic phase is separated and evaporated in vacuo to dryness. Crystallization from methanol yields 5.6 g of 2,6-dichloro-7-chloromethyl-5H-thiazolo (3,2-a) pyrimidin-5-one with m.p. 117-119 C (with decomposition). Then in 115 ml of acetonitrile at a temperature
    135878610
    a) pyrimidine-5-one with m. pl. 226 - 228 ° C;
    6-chloro-3-phenyl-7-trans-2- (3-pyridyl) -3 tenyl-5H-thiaeolo (3,2-a) pyri-pyrimidin-5-one with m. Pl. 203-204 C,
    6-chloro-3- (4-chlorophenyl) -7-trans-.
    (3-Pyridyl) -ethenyl-5H-thiazodo- (3,2-a) pyrimidin-5-one with t. Tsl. 278-280 ° C;
    to 6-chloro-3- (4-methoxyphenyl) -7-trans-. - 2- (3-pyridyl) -ethensh-5H-thiazolo- (3,2-a) pyrimidin-5-one with so pl. 264-265 C,
    6-chloro-3- (4-fluorophenyl) -7-trans-5-2- (3-pyridyl) -ztenyl-5H-thiazolo- (3,2-a) pyrimidin-5-one with m. Pl. 268-269 ° C;
    6-chloro-3- (4-methylphenyl) -7-trans-2- (3-pyridyl) -ethenyl-5H-thiazolo-20 (3,2-a) pyrimidin-5-one with m. Pl. 258259 °;
    6-chloro-3-trifluoromethyl-7-trans-2- (3-Pyridyl) -etheni-5H-thiazolo (3, 2-a) pyri imidin-5-one with so pl. 247 boiling for 20 hours spent reacting 25,249 ° C | The result of the obtained product is 5.95 g of 6-chloro-2-metsh-3-phenyl-7-trans-12-triphenylphosphine. The solution is evaporated; ;-( 3-pyridyl) -ethenyl-5H-thiazolo (3.2- under vacuum to dryness and the residue is pure -a) pyrimidin-5-one with m. Pl. 229-232 C; isopropyl ether, in the result of 6-chloro-7-trans-2- (2-metsh1-5-tiako) get 10.4 g of 2,6-dichloro-5H-30 zolyl) ethenyl 1-5H-thiazolo (3, 2-a) pi-thiazolo (3,2-a) pyrimidin-4-on-7-IJI) - rimidin-5-one, so pl. 230-233 ° C;
    6-chloro-3- (3-pyridyl) -7-trans 2- (3-pyridyl) -ethenyl-5H-thiazolo (3,2-a) pyrimidin-5-one with so pl. 274 - 35 275 ° С.,.
    Example 9. Under stirring conditions at room temperature for 4 hours, 4 g of reaction was carried out for 20 hours and semi-7-methyl-5H-thiazolo (3,2-a) pyrimidine thus obtained was reacted with 2 , 36 g 40 -5-it with t. Pl. 127-129 C, 3-pyridinecarboxaldehyde is obtained. Reaction according to example 1
    using ethyl acetoacetate dissolved in 100 ml of benzene with 4.7 g of N-bromosuccinimide. The precipitated precipitate 45 is dissolved by adding chloroform and the solution is washed with water, evaporated, evaporated to dryness in vacuum and the resulting residue is crystallized from methanol to give 5.1 g of 6-bromo-methyltriphenylphosphonium chloride, which is suspended in 50 ml of dimethyl sulfoxide and at room temperature 2.41 g of potassium t-butoxide dissolved in 45 ml of dimethyl sulfoxide are treated.
    Then at room temperature
    The mixture is diluted with a mixture of water and ice, neutralized with sodium hydroxide orthophosphate and the precipitate formed is filtered off. As a result of crystallization from methanol, 3.45 g of 2,6-dichloro-7-trans-2- (3-pi-pvdyl) -ethenyl-5H-thiazolo (3,2-a) pi-pI midin-5-one is obtained. Art. square 242-243 C. Yield 41.2%.
    During the course of the process, the following compounds are obtained in the same way as above:
    6-chloro-3-methyl-7-trans-2- (3-pyridyl) ethenyl 3-5H-thiazolo (3,2-a) pyrimidine-5-one with m. Pl. 219-220 C1
    6-chloro-2,3-dimesh1-7-trans-2- - (3-pyridyl) -ethenyl-5H-thiazolo (3,250 -7-methyl-5H-thiazolo (3,2-a) pyrimidine-5-one mp 233-234 0. Then, in 190 ml of methanol in the presence of 2.2 tons of sodium methoxide under stirring conditions at boiling point
    55 reflux for 2 h
    carried out, the resulting product was reacted with 3.4 h of 3-pyridinecarboxaldehyde. After cooling out
    50 -7-methyl-5H-thiazolo (3,2-a) pyrimidine-5-one with m. Pl. 233-234 0. Then, in 190 ml of methanol in the presence of 2.2 tons of sodium methoxide under stirring conditions at the boiling point with
    55 reflux for 2 h
    carried out, the resulting product was reacted with 3.4 h of 3-pyridinecarboxaldehyde. After cooling out
    111
    the precipitate is filtered and washed with water until neutral. As a result of recrystallization from dichloromethane, 5.18 g of 6-bromo-7-trans-2- (3-pyridix1) -ethenyl-5H-thiazolo (3,2-a) pyrimidin-5-one with t pl. 208-209 s. Yield 64.3%.
    Example 10 In 50 ml of dimethylformamide under stirring conditions at room temperature for 10 hours, 10.4 g of trimethylsulfrxonium iodide were reacted with 50% sodium hydride (2.25 g) and then into the reaction mixture. a solution of 6 g of 7-trans-2- (3-pyridyl) -ethenyl-5H-thiazolo (3,2-a) pyrimidin-5-one in 50 ml of dimethylformamide is added.
    Under stirring conditions at room temperature, this mixture is left in a quiescent state for the reaction to proceed for 20 hours, after which it is diluted with an ice-water mixture, neutralized by the addition20
    . Example. 12. 2.4 g of 6-methyl-7 trans-2- (3-pyridyl) -cyclopropyl-5H-thiazolo (3,2-a) pyrimidine-5-one is dissolved in ethyl acetate and treated with a stoichiometric amount of gaseous HC1 in diethyl ether, the precipitate is filtered off, washed with ethyl acetate, to obtain 2.15 g of 6-methyl-7-trans-2- (3-pyridyl) -cyclopropyl-5H-thiazoate sodium hydrochloride sodium phosphate (3,2-a) pyrimidine hydrochloride 5-she, so pl. and subjected to extraction processing 190 With (decomposition), the output of 79.6%. chloroform. After vacuum evaporation, the crude residue was purified in a silica column using a biological test of the compounds obtained by the proposed procedure.
    Biological tests of the compounds obtained by the proposed
    ethyl acetate as eluent. 30 way.
    As a result of crystallization from ethyl. The proposed compounds are agents that actively affect the gastrointestinal tract, in particular, they have a protonosis and / / gastro-antisecretory effect, in addition, such compounds can be used to alleviate unwanted side effects in the gastrointestinal tract, which are a consequence of
    systematic use of anti-inflammatory prostaglandin MIDIN-5-OH with t. pl. 151-152 C, synthetase inhibitors, due
    6-methyl-7-trans-p- (4-methylphenyl) - which can be used with -cyclopropyl-5H-thiazolo (3,2-a) pyri-45 for this purpose in combination with them. The anti-ulcer effect of the proposed compounds is demonstrated, for example, by the fact that they show activity in the course of testing
    in rats according to the method
    lopropyl-5H-thiazolo (3,2-a) pyrimidine-. Bonfils et al. In the ode of holding -5-on st. square 159-161 C experiments were used six
    6-chloro-3-phenyl-7-trans-2- (3-pi. Male Sprague-Dawley rats (Ridyl weight) cyclopropyl-5H-thiazolo (3.2-55 100-120 g), immobilized during -a) pyrimidin-5-one art. square 136-138 C 24 u. For depriving animals of mobility, 2-chloro-6-methoxy-7-trans-2- (3-pi) square rydyl) cyclopropyl-5H-thiazolo (3,2-. Thick flexible wire nets, -a ) pyrimidine-, 5-he st. square 92-95 C. and, in connection with 4 hours after the two-acetate, 2.35 g of 7-trans-2- (3-pyridgsh) -cyclopropyl-5H-thiazolo (3,2-a) pyrimidine-5-one Art. square 115-117 ° C. Yield 37.3%.
     carrying out the process in the same way as described above, the following compounds are obtained with the same yield:
    b-methyl-7-trans- (3-pyridsh1) -cyclopropsh11-5H-thiazolo (3,2-a) pyrimidin-5-OH st. square 150-155 С,
    2,3,6-trimetsh1-7-trans-2- (3-pyridyl) -cyclopropylT-5H-thiazolo (3,2-a) pyrimidin-5-one with so pl. 120 ° C (melts with decomposition),
    6-chloro-7-trans-2- (3-pyridyl) -CYZ

    12
    Example 11. 2.3 g of 6-methoxy-7-trans-2- (3-pyridyl) -ethenyl-5H-thiazolo (3,2-a) pyrimidine-5-one is dissolved in ethyl acetate and the solution is processed stoichiometrically | m quantitative, aqueous aqueous solution of hydrogen chloride in the environment of diethyl ether. The precipitated precipitate is collected, filtered and washed with ethyl acetate to obtain 2.1 g of 6-methoxy-7-trans- (3-pyridyl) -3 tenyl 3 -5H-thiazolo (3,2-a) pyrimidine-5-one-hydrochloride with t. pl. 2-05-210 C (with decomposition). The output of 80.7%.
    . Example. 12. 2.4 g of 6-methyl-7-trans-2- (3-pyridyl) -cyclopropyl-5H-thiazolo (3,2-a) pyrimidine-5-one is dissolved in ethyl acetate and treated with a stoichiometric amount of gaseous HC1 in diethyl ether, the precipitate is filtered off, washed with ethyl acetate, to obtain 2.15 g of hydrochloride 6-methyl-7-TRANS-2- (3-pyridyl) -cyclopropyl-5H-thiazolo (3,2-a) pyrimidine-5-one, t pl. 190 ° C (with decomposition), yield 79.6%.
    lo (3,2-a) pyrimidine-5-she, so pl. 190 ° C (with decomposition), yield 79.6%.
    Biological tests of the compounds obtained by the proposed
    13, 1358786
    the movements of the rats were euthanized, their stomachs were removed and the number of injuries was calculated using a dissecting magnifier. The test compounds were injected into the animals through the mouth of the animal, 1 hour before immobilization.
    Compound
    7-trans-2- (3-Pyridyl) -ethenyl-5H-thiazolo (3,2-a) pyrimidin-5-one
    2-Chloro-7-trans-2- (3-pyridyl) -ethenyl-5H-thiazolo (3,2-a) pyrimidine 5-one
    The proposed compounds also have gastric antisecretory activity, as evidenced, for example, by the fact that they showed activity after they were introduced into the body through the duodenum, and suppressed the secretion of gastric juice in rats during testing by Method X. Sche et al. Antisecretory activity in the stomach of rats was assessed using a ligature technique. In each group of experimental animals, six Sprague-Dawley rats (weighing 110-130 g) were used. 24 hours before the test, the rats were fed food, but water continued to be given. V. Day of operation under light ether anesthesia transfused with a pilus. Each test compound was injected into the duodenum (E) during the dressing. After 4 hours after the dressing, the rats were killed, the juice secreted in the stomach was collected and subjected to centrifugation at a rotation speed of 3500 rpm for 10 minutes, after which the entire volume of the liquid without sediment was determined. The amount of free hydrochloric acid in the gastric juice was determined by titration with 0.01 n. Oxide 14 Hydrate Solution
    In tab. Figure 1 shows the approximate values of the EDyg (effective dose) of the ulcer activity achieved during the test; the described test in rats after the introduction of two proposed compounds into their bodies.
    Table 1
    Anti-tidal activity when administered through the mouth EDyp, mg / kg.
    ten
    Sodium to pH 7.0 using an electro-pH meter. -One of
    Preferred proposed compounds which have gastric antisecretory action are, for example, 6-methoxy-7-. -trans-2- (3-pyridyl) -ethenyl-5H-thiazolo (3,2-a) pyrimidin-5-one, the value of which was 30 mg / kg, as determined during the described tests on rats after administration of organism through the duodenum.
    The proposed compounds also have an anti-inflammatory effect, since they are active after being introduced into the body through the mouth.
    in suppressing the formation of edema on the hind paw of rats in response to a subplanar injection of carragenin in accordance with the method of K.A. Winter et al. And Artus’s reverse passive reaction
    (OPA) on the paws of rats, which is caused by the interaction of the antigen with the antibody, resulting in the formation of a precipitating immune complex with subsequent fixation of the complement and accumulation of polymorphonuclear leukocytes in the focal point. The proposed compounds also have analgesic activity. Hyalgetic activity
    1513
    For example, they were determined using phenylquinone, which causes painful cramps in mice. in accordance with Zygmund's method. Thus, the compounds of the invention can be used in therapy for the treatment of painful and inflammatory processes, such as rheumatoid arthritis and osteo-arthrosis.

    Compound
    7-: trans- 2- (3-Pyridyl) -ethenyl-5H-thiazolo (3, 2-a) - pyrimidin-5-one
    4-Chloro 7-trans-2- (3-pyridyl) -etenag-3-thiazolo- (3,2-a) pyrimidin-5-one
    6-Methoxy-7-trans | 2- (3-pyridsh1) -ethenyl-5H- -thiazolo (3,) pyrimidin-5-one
    .Compound
    6-Methyl-7-trans-2g- (3-pyridsh1) -ethenylT-5H- -thiazolo (3,2-a) pyrimidin-5-one.
    2-Chloro-7-trans-2- (3-pyridyl) ethenyl-5H-thiazolo (3,2-a) pyrimidin-5-one
    As regards the analgesic effect, for one of the preferred proposed compounds, for example for 2-chloro-7-trans-2- (3-pyridyl) -ethenyl-5H-tnazolo (3,2-a) - pyrimidin-5-one , the approximate value was 25 mg / kg, as determined during the test with painful cramps,
    sixteen
    In tab. Tables 2 and 3 show the approximate ED values obtained in the determination of the anti-inflammatory effect in the course of the test conducted in rats; some proposed compounds were administered through the mouth into KOTOjibDC.
    Table 2
    Anti-inflammatory effect on edema caused by the introduction of carragenin, ED, mg / kg
    sixteen
    15
    Table3
    Anti-inflammatory effect on the reaction of OPRA, mg / kg
    22
    25
    55.
    in rats by means of phenylquinone, after the test compound was injected into the animals' body by means of a mouth sore.
    For comparative purposes, the compounds ENfije are tested together with the known compound 2,3-dihydro-7- (3-pyridyl) thiazole (3,2-a) py19. Continuation of Table 5
    FCE 21601
    23
    FCE 22451
    Known
    20
    FCE codes are given in table. 4 and 5, refer to the following compounds:
    21252 - 7-trans- (2- (3-methoxyphenyl) -VINSH1 -5H-thiazolo (3,2-a) pyrimidine-5-oHt
    21601 - 7-trans-2- (4-pyriddshI) - -volshI-5H-thiazolo (3,2-.a) pyrimidine-5-one,
    21618 - 7-trans-2- (6-metsh1-2-pyrimidesh1) -vinyl - 5H-thiazolo (3,2-a) pyrimidine-5-one;
    22451 - 2,3-dimethyl-7-trans-2- - (3-pyridyl) -vinyl-5N.-thiazolo- (3,2-; -a) pyrimidin-5-one,
    22445 - 3- (3-pyridyl) -7-trans-2- (3-pyridyl) vinyl 3-5H-thiazolo (3, 2-a) pyrimidine-5-oHi
    22591-3- (4-methylphenyl) -7-trans- {2- (3-pyridyl) -vinyl-5H-thiazolo- (3,2-a) pyrimidin-5-one,
    2261.2 .- 2-methyl-3-phenyl-7-trans-2- (3-pyridyl) -vinyl-5H-thiazolo- (3,. 2-a) pyrimidin-5-one J
    22216 - 6-ethoxy-7-trans-2- (3-22005 - 7-trans-2- (4-pyridyl) - 15-jv-5H-thiazolo (3,2-a) pyrimidin-5-one,
    22457 6-methyl-7-trans-2- (3-pyridyl) -cyclopropyl-5H-thiazolo (3,2-a) pyrimidin-5-one
    22460 - 6-chloro-7-trans-2 (3-pyrimyl) -cyclopropyl-5H-thiazolo (3, 2-a) pyrimidin-5-one,
    22452 - 7-trans-2- (4-methylphenyl-vinyl-5H-thiazolo (3,2-a) pyrimidine-5-oHj
    21545 - 7-trans-2- (2-pyridyl) -ethenyl-5H-thiazolo (3,2-a) pyrimidine -5-OHV
    22019 - 3-methyl-7-trans-2- (3-pyridyl) -ethenyl-5H-thiazolo (3,. 2-a) pyrimidine-5-OHi
    22366 - 3-phenyl-7-trans-2- (3-pyridyl) -ethenyl-5H-thiazolo (3,2-a) pyrimidine-5-one;
    22443 - 3-trifluoromethyl-7-trans- (3-pyridyl) -ethenyl-5H-thiazolo (3,2-a) pyrimidin-5-one,
    22592 - 3- (4-fluorophenyl) -7-trans- - 2- (3-pyridsh1 5-ethenyl-5H-thiazolo 30
    -pyridyl) -vinyl-5H-tzazolo (3,2-a) (3,2-a) pyrimidin-5-one, rimidin-5-one; 22595 - 3- (4-hdorfenil) -7-trans 22793 - 7 -trans- 2- (3-pyridyl) -3- (3-pyridyl) -ztenyl-5H-thiazole-cycropyl-5H-thiazolo (3,2-a) pyrimidine-5-oHj
    (3, 2-a) pyrimidine-5-one,
    22604 - 3- (3-methoxyphenyl) -721260 - 7-trans-2- (3-pyridyl) -vi-45-trans-2- (3-pyridyl) -ethenyl-5Nyl-5H-thiazolo (3,2- a) pyrimidine-5-one ,.
    21622 - 6-methyl-7-trans-2- (3-pyridyl) -vinyl-5H-thiazolo (3,2-a) pyrimidin-5-ph,
    222.15 - 6-methoxy-7-trans-2- (3-pyridyl) -vinyl-5H-thiazlo (3,2-a) -pyridine-5-one
    21540 - 6-chloro-7-trans-2- (3-pyridyl) -vinyl-5H-thiazolo (3,2-a) pyrimidine-5-one,
    22050 - 2-chloro-7-trans-2- (3-pyridsh1) -vinyl-5H-thiazolo (3, 2-a) -pyrimidin-5-one,
    -thiazolo (3,2-a) pyrimidine-5-one
    22786 - 3- (4-aminophenyl) -7-trans- (3-pyridyl) -ethenyl-5H-thiazolo (3,2-a) pyrimidin-5-one; 5021622 - 6-methyl-7-trans-2- (3-pyridyl) -ztenyl-5H-thiazolo (3,2-a) pyrimidine-5-oHj
    22,215 - 6-methoxy-7-trans-2- (3-55-pyridyl) -ethenyl-5H-thiazolo (3,2-a) - to pyrimidin-5-one;
    2160-1 - 7-trans-2- (4-pyridyl) -ethenyl-5H-thiazolo (3,2-a) -pyrimyl- - din-5-oHJ
    20
    25
    ;
    35878620
    22019 - 3-Netil-7-trans-2- (3-pyridyl) -vinyl-5H-thiazolo (3,2-a) - pyrimidine-5-one;
     22366 - 3-phenyl-7-trans-2- (3-pyridyl) -vinyl-5H-thiazolo (3,2-a) pyri-MIDIN-5-OH}
    225) 7 - 2-chloro-6-methoxy-7-trans-2 (3-pyridyl) -vinyl-5P-thiazolo-Q (3,2-a) pyrimidin-5-one
    22306 - 2-bromo-7-trans-2- (3-pyridyl) -vinyl-5H-thiazolo (3,2-a) pyri-MIDIN-5-OH;
    22005 - 7-trans-2- (4-pyridyl) - 15-vin-5H-thiazolo (3,2-a) pyrimidin-5-one,
    22457 6-methyl-7-trans-2- (3-pyridyl) -cyclopropyl-5H-thiazolo (3,2-a) pyrimidin-5-one
    22460 - 6-chloro-7-trans-2 (3-pyridyl) -cyclopropyl-5H-thiazolo (3, 2-a) - pyrimidin-5-one,
    22452 - 7-trans-2- (4-methylphenyl) - -vinyl-5H-thiazolo (3,2-a) pyrimidine- -5-oHj
    21545 - 7-trans-2- (2-pyridyl) -ethenyl-5H-thiazolo (3,2-a) pyrimidine-5-OHV
    22019 - 3-methyl-7-trans-2- (3-pyridyl) -ethenyl-5H-thiazolo (3,. 2-a) pyrimidine-5-OHi
    22366 - 3-phenyl-7-trans-2- (3-pyridyl) -ethenyl-5H-thiazolo (3,2-a) pyrimidine-5-one;
    22443 - 3-trifluoromethyl-7-trans- (3-pyridyl) -ethenyl-5H-thiazolo (3,2-a) pyrimidin-5-one,
    22592 - 3- (4-fluorophenyl) -7-trans- - 2- (3-pyridsh1 5-ethenyl-5H-thiazolo 30
     4o (3,2-a) pyrimidin-5-one, 22595 - 3- (4-hdorfenyl) -7-trans-3- (3-pyridyl) -ztenyl-5H-thiazole
    (3, 2-a) pyrimidine-5-one,
    22604 - 3- (3-methoxyphenyl) -745-trans-2- (3-pyridyl) -ethenyl-5H-thiazolo (3,2-a) pyrimidin-5-one
    22786 - 3- (4-aminophenyl) -7-trans- (3-pyridyl) -ethenyl-5H-thiazolo (3,2-a) pyrimidin-5-one; 5021622 - 6-methyl-7-trans-2- (3-pyridyl) -ztenyl-5H-thiazolo (3,2-a) pyrimidine-5-oHj
    22,215 - 6-methoxy-7-trans-2- (3-55-pyridyl) -ethenyl-5H-thiazolo (3,2-a) - to pyrimidin-5-one;
    2160-1 - 7-trans-2- (4-pyridyl) -ethenyl-5H-thiazolo (3,2-a) -pyrimyl- - din-5-oHJ
    211358786
    22451 - 2,3-dimethyl-7-trans-2- - (3-pyridyl) -ethenyl-5H-thiazolo (3,2-a) pyrimidine 5-one,
    Taking into account the high therapeutic indicators of the proposed compounds g, they can be safely used in medicine. Thus, for example, the approximate magnitude of acute toxicity is a bond that provides a double bond between pc and ft carbon atoms. Or -CH-group, forming a cycle and with
    so that the connection is common
    ABOUT
    15
    Ri-TT- -V
    Lllr,
    Chester dosage (L5o) compounds
    7-trans-2- (3-pyridyl) -ethenium-5H-thia lopropane ring containing l ash (3,2-a) pyrimidin-5-one and 2-chloro and / carbon atoms, -7-trans-2- (3-pyridsh1) -ethenium G-5H- -thiazolSZ, 2-a) pyrimidin-5-one, determined during testing on mice with a single dose in a constantly increasing dosage with measured on the seventh day after administration, it was in excess of 800 mg / kg (for oral administration). Similar toxico-2 (logical data were also obtained for other proposed compounds.
    The obtained results show that the compounds obtained under the conditions of the proposed method are of low toxicity, show a higher anti-ulcer and anti-inflammatory activity than the known compounds - 2,3-dihydro-7-SZ-pyridyl) -thiazolo. (3,2-a) Pyridimin-5-one.
    25
    S -n
    where R, - R-5 have the indicated values
    Rj - sn, -,
    X is chlorine or bromine,
    introduced into interaction with the aldehyde of the formula
    R-SNO
    thirty
    where R has the indicated meanings, the process is carried out in an organic solvent in the presence of an alkali metal alcoholate, and the compounds thus obtained are isolated or reacted with dimethyl sulfoxoniummethylidide.
    Formula of Invention
    Priority for the Prize Method for Producing Substituted Thiazolo (3,2-a) Pyrimidines of General Formula 35
    D) 07.15.81 when R is hydrogen, (, 1-alkyl, phenyl; unsubstituted or
    Tx
    .-i ALg. -snKg
    S 15
    CH-CH-RH
    /
    40
    substituted in position 3 (,) .- -alkoxy by group or in position 4 by halogen or alxyl (C, -C,), R, is hydrogen, halogen, (,) is alkyl. .
    de R, is hydrogen, halo, C, -C, -alkyl; RJ, is hydrogen, C, -C3-alkyl, trifluoromethyl, 3-pyridyl, phenyl, 45 unsubstituted or substituted in position 3 (Cj-Ce) -alkoxy or in position 4 by halogen, amine or alkyl (C, -C3 ) i-50
    R, is hydrogen, halo, C, -C-alkyl,
    (,) - alkoxy R - unsubstituted 2,3- or 4-pVNIIPI Order 6012/59
    Circulation 372 Subscription
    Random polygons pr-tie, Uzhgorod, st. Project, 4
    2
    Ridyl or 2-pyridyl, substituted in position 6 (C, -C,) - alkyl, or phenyl, substituted in position 3 (C, -Cj) - -alkoxy or in position 4. (C, -C) -alkyl ,
    A is a bond that provides a double bond between pc and ft carbon atoms. Or -CH is a group that forms a cyclopropane ring containing l and / carbon atoms, which is different
    u and with formula
    so that the connection is common
    ABOUT
    Ri-TT- -V
    Lllr,
    a lopropane ring containing l and / carbon atoms, distinguishing
    S -n
    a lopropane ring containing l and / carbon atoms, distinguishing
    where R, - R-5 have the indicated values j
    Rj - sn, -,
    X is chlorine or bromine,
    introduced into interaction with the aldehyde of the formula
    25
    R-SNO
    where R has the indicated meanings, the process is carried out in an organic solvent in the presence of an alkali metal alcoholate, and the compounds thus obtained are isolated or reacted with dimethyl sulfoxoniummethylidide.
    Prize priority

    substituted in position 3 (,) .- -alkoxy by group or in position 4 by halogen or alxyl (C, -C,), R, is hydrogen, halogen, (,) is alkyl. .
    01/20/82 when R is hydrogen, (C) -alkyl-phenyl, unsubstituted or substituted in position 4 by halogen or (C4-C,) - alkyt1, R, - (C, -C,) - alkoxy.
    04/29/82 when .R is hydrogen, (-C.) Is alkyl, trifluoromethyl, 3-pyridyl, or phenyl, unsubstituted or substituted in position 3 () - -alkoxy or in position 4 by halogen or (C4-Cj) - alkyl.
    Circulation 372 Subscription
    权利要求:
    Claims (1)
    [1]
    Claim
    The method of obtaining the 'substituted thiazolo (3,2-a) pyrimidines of the general formula K1 S to where R, is hydrogen, halogen, C, -0, -alkyl;
    R a is hydrogen, C ( -Se alkyl, trifluoromethyl, 3-pyridyl, phenyl, 45 unsubstituted or substituted at position 3 (C ^ -C,) - alkoxy or at position 4 with halogen, amine or alkyl (C, -C e ); '50
    R - hydrogen, halogen, C ( -C e -alkyl, (C <-C,) - alkoxy R 4 - unsubstituted 2,3- or 4-piR 4 -CHO where R 4 has the indicated meanings, the process is carried out in an organic solvent in the presence of an alkali metal alcoholate and the resulting compounds are isolated or reacted with d'methylsulfoxoniummethylidide.
    Priority by signs:
    07/15/81 at R 4 - hydrogen, (C-C-alkyl, phenyl, 'unsubstituted or substituted at position 3 (C ^ -C,). - alkoxy group or at position 4 with halogen or alkoxy (C 4 -C 3 ) ', R, - hydrogen, halogen, (C, -C 3 ) -alkyl.
    20 ^ 01.82 when R 2 is hydrogen, (C <C 3 ) -alkyl-phenyl unsubstituted or substituted in position 4 by halogen or (C 4 -C e ) -alkyl, * R, - (C ( -C 3 ) -alkoxy .
    04/29/82 at, R 2 is hydrogen, (C 4 —Cj) -alkyl, trifluoromethyl, 3-pyridyl or phenyl, unsubstituted or substituted at position 3 (C 4 -C 3 ) -alkoxy or at position 4 with halogen or ( C <-C 3 ) -alkyl.
    VNIIIPI Order 6012/59 _______ Circulation 372 - Subscription
    Custom polygr. ave, city of Uzhhorod, st. Project, 4
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    FI63031B|1982-12-31|PROCEDURE FOR THERAPEUTIC ADMINISTRATION OF THERAPEUTIC TINO | PYRIMIDIN-4-ONER
    KR830000711B1|1983-04-06|Method for preparing 5- | -6- | -2,3-dihydroimidazo- [2, 1-b] thiazole
    同族专利:
    公开号 | 公开日
    FI822468A0|1982-07-12|
    FR2509734B1|1985-07-19|
    NO822441L|1983-01-17|
    YU151582A|1985-04-30|
    IE53426B1|1988-11-09|
    AU8564882A|1983-01-20|
    DK156222B|1989-07-10|
    SE453295B|1988-01-25|
    US4444773A|1984-04-24|
    KR880002301B1|1988-10-22|
    SE8204292D0|1982-07-12|
    GB2103608A|1983-02-23|
    NZ201194A|1985-02-28|
    DE3226516A1|1983-02-03|
    IT1190914B|1988-02-24|
    FI71940B|1986-11-28|
    IL66316D0|1982-11-30|
    IE821692L|1983-01-15|
    CH653036A5|1985-12-13|
    CA1208635A|1986-07-29|
    IL66316A|1986-04-29|
    US4551457A|1985-11-05|
    SE8204292L|1983-03-14|
    AT384614B|1987-12-10|
    ES513808A0|1983-08-01|
    ATA266182A|1987-05-15|
    FR2509734A1|1983-01-21|
    HU186951B|1985-10-28|
    LU84262A1|1983-02-07|
    IT8222353D0|1982-07-12|
    PT75240B|1984-07-23|
    KR840000569A|1984-02-25|
    FI822468L|1983-01-16|
    GB2103608B|1985-01-30|
    ES8404363A1|1984-05-01|
    DK156222C|1989-12-04|
    ES8307827A1|1983-08-01|
    DK314682A|1983-01-16|
    PT75240A|1982-08-01|
    AU551718B2|1986-05-08|
    NL8202706A|1983-02-01|
    GR76208B|1984-08-03|
    FI71940C|1987-03-09|
    ES520642A0|1984-05-01|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    US3594378A|1969-10-24|1971-07-20|Ayerst Mckenna & Harrison|Thiazolopyrimidine derivatives and preparation thereof|
    US3888983A|1970-08-14|1975-06-10|Seperic|Derivatives of thiazolino-pyrimidin-6-ones, in inducing analgesia|
    GB2084568A|1980-08-16|1982-04-15|Beecham Group Ltd|Imidazothiazole derivatives|
    NL8202706A|1981-07-15|1983-02-01|Erba Farmitalia|SUBSTITUTED THIAZOLO3,2-APYRIMIDINES AND METHODS FOR PREPARING THE SAME|
    KR20070085048A|2004-12-03|2007-08-27|로무 가부시키가이샤|Drive circuit of charge pump circuit, power supply and light emitting device|NL8202706A|1981-07-15|1983-02-01|Erba Farmitalia|SUBSTITUTED THIAZOLO3,2-APYRIMIDINES AND METHODS FOR PREPARING THE SAME|
    US4537962A|1982-02-04|1985-08-27|Farmitalia Carlo Erba, S.P.A.|Substituted 1,3,4-thiadiazolo[3,2-A]pyrimidines and compositions containing them|
    US4546101A|1982-09-10|1985-10-08|Fujisawa Pharmaceutical Co., Ltd.|New cephem compounds useful for treating infectious diseases in human being and animals and processes for preparation thereof|
    GB8300728D0|1983-01-12|1983-02-16|Erba Farmitalia|Substituted carboxy-thiazolo / 3 2 - a / pyrimidine derivatives|
    DE10112197A1|2001-03-14|2002-09-19|Gruenenthal Gmbh|Medicaments for treating e.g. epilepsy, schizophrenia, neurodegenerative diseases or especially pain, comprising new or known pyrazolo-pyrimidine or thiazolo-pyrimidine compounds|
    WO2009109987A2|2008-01-11|2009-09-11|Glenmark Pharmaceuticals, S.A.|Fused pyrimidine derivatives as trpv3 modulators|
    US8119647B2|2008-04-23|2012-02-21|Glenmark Pharmaceuticals S.A.|Fused pyrimidineone compounds as TRPV3 modulators|
    EP2247601B1|2008-07-02|2013-04-10|Avexa Limited|Thiazopyrimidinones and uses thereof|
    CN106916168B|2017-03-13|2019-08-27|牡丹江医学院|A kind of compound and preparation method thereof for treating severe pancreatitis|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    GB8121979|1981-07-15|
    GB8201621|1982-01-20|
    GB8212430|1982-04-29|
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