• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    The method of producing pyrido derivatives
    公开号:SU1158045A3
    申请号:SU813308438
    申请日:1981-06-24
    公开日:1985-05-23
    发明作者:Дориа Джанфедерико；Ромео Чириако；Сберзе Пьеро；Тиболья Марчеллино；Луиза Корно Мария
    申请人:Фармиталиа Карло Эрба С.П.А. (Фирма)；
    IPC主号:
    专利说明:

    This invention relates to a process for producing new pyrido derivatives. (1,2-Q) pyrimidine with valuable anti-allergic properties and which can be used in medicine.  The reaction of introducing the cyclopropane ring by reacting with dimethylsulfoxonium methylide in an inert organic solvent at 0-50 ° C 1 is known.  The purpose of the invention is a method of producing new pyrido (1,2-C |) pyrimidine derivatives possessing valuable pharmaceutical properties. The goal is achieved by the method of producing pyrido (1,2-a) pyrimidine of the general formula 1: О RlOOC- | 2 CH-R, where R is hydrogen, C-C-alkyl or (2-di-C4-C4. -alkyamino) ethyl Rj, is hydrogen or C -C-alkyl; Rj - unsubstituted furyl, thienyl.  or pyridyl, or substituted by methyl, unsubstituted phenyl stiphenyl, substituted by halogen, hydroxyl or one of the substituents from the number of C-C-alkyl or C-C alkoxyl or their pharmaceutically acceptable salts with metals, the compound of the general formula 11: O.  RlOOC Y CH CH-CZ "de R, -Rj have the indicated values, are reacted with dimethylsulfoxonium methylide, followed by isolation in free form or as a salt with a metal, or by esterification of a compound of general formula I, where R / I is hydrogen, to obtain the compound by the general formula, where R has the other indicated meanings, or by hydrolysis of a compound of the general formula 1, where R is alkyl, to a compound of the general formula I, where R is hydrogen.  The proposed method is carried out in an inert organic solvent, such as dimethylformamide, dimethyl sulfoxide, dioxane or mixtures thereof, at 0-50 C.  Usually, 1 -3, more often 1-1.5 mol of dimers sulphonium methylide per 1 mol of the compound of the general formula II are used.  The starting compounds of general formula II can be prepared according to a scheme involving the cyclization of a compound of general formula RZ / RiOOC m T  R /, OOC RiOOC YN. , C where R, and R, have the indicated meanings; Rf is hydrogen or alkyl formed by a compound of the general formula.  RjOOC N III, Ri is CHO (V) where R and Ri have the indicated meanings, are treated with an aldehyde of the general formula V / where R has the indicated meanings.  The cyclization of a compound of formula IIJ can be carried out, for example, in the presence of an acidic catalyst, such as polyphosphoric acid (polyphosphoric acid means a mixture of equal amounts of 99% H5P04.  and PtOr) hydrochloric, hydrobromic, hydroiodic, sulfuric acid, para-toluenesulfonic acid at 50-250 C.  This cyclization reaction can occur in an organic solvent medium selected from among solvents, including aliphatic alcohol containing 1-6 carbon atoms, dimethylformamide, dioxane, tetrahydrofuran, benzene, toluene, xylene, acetic acid, ethylene glycol, monomethyl ether and their mixtures, preferably, this reaction proceeds in the absence of a solvent. The compounds obtained by the proposed method have an allergic effect and can be used for the prevention and treatment of allergic diseases, such as asthma, allergic rhinitis, hay fever, urticaria and dermatosis.  The antiallergic effect of the compounds obtained by the proposed method is determined on rats by passive skin anaphylaxis test (PCA).  An important feature of compounds of general formula I is that they exhibit a high antiallergic effect also when administered orally. The table shows the activity indicators obtained when X-ray examination of rats in oral administration of compounds of general formula I obtained by the proposed method designated as K 13808, FCE 20509, K 13830, FCE 20099, FCE 20183, FCE 20461 and FCE 20188, in comparison with the well-known antiallergic drug disodium chromoglycate (DSCG).  Activity values are expressed in terms of K, defined as the dose of the active compound, capable of halving the activity of shorting used for an allergic effect, where B is the dose of the compound that is the antagonist, ug / kg; DR — Dose Ratio: Antilogogram The distance between the logarithmic functions of the serum dose effect with and without antagonist.  In this case, Kg is accepted, since this value does not depend on the dose of the drug, nor on the concentration of antibody used by JtuiH to induce an allergic reaction.  The lower the Kg value, the stronger the antiallergic effect.  In the table, compounds corresponding to the proposed method are identified by the following code: K 13830; 2-trans- (2-fensh1Eteni) -3-ethyl-6, 7-methylene-4-oxBo-4H-pyrido (1,2-a) pyrimidine-7-carboxylic acid; FCE 20188: 2-trans (Fensch1Ensh1en) -3-propyl-6, 7-methylene-4-oxo-4H-pyrido (1,2-th) pyrimidine-7-carboxylic acid; FCE 20509: 2-trans-G2- (3-methoxyphenyl) -ethenyl-3-ethyl-6,7-methylene-4-OXO-4H-PYRIDO (1,2-a) pyrimidine-7-carboxylic acid; CE 20461: 2-trans-2- (2,3-dimethoxyphenyl) -thenyl-3-propyl-6,7-methylene-4-oxo-4H-pyrido (1,2-ci) pyrimidine-7-carboxylic acid.  Antiallergic action is determined, for example, by inhibiting JJE-induced anxiety (PCA), using homocytotropic antibodies, to form "cis" in the rat organism.  Test compounds are administered: via. 15 minutes before the injection of the antigen, at least 6 rats are used for each dose.  In addition, connect. The results obtained by the proposed method have an anti-ulcer effect, which is confirmed by inhibition of ulcers in rats caused by stress when immersed in a water bath at a temperature of 25 ° C for 40 minutes.  In addition to the amylergic effect, the compounds of the general formula f, in particular the compounds in which R | represents hydrogen or methyl, possess antidiabetic activity.  The compounds have low toxicity and high therapeutic inex.  For example, the dose of LD50 2-trans- (2-fe1shletenyl) -3-progos-4-oxo-4H-pyrcho (1,2-fct) pyrimidine-7-carboxylic acid, determined by single oral administration in a single dose. Over seven days of increasing doses, it exceeds 800 mg / kg. . Other compounds of the general formula 1, Example 1, have similar toxicity.  Trimethylsulfoxonium iodide (0.7 g) is mixed with 50% sodium hydride (0.15 g) in dimethylformamide (30 ml) with stirring at room temperature, stirring is continued for 1 hour, then a solution of methyl ester 2 is added to the reaction mixture. -trans- (2-phenylethenyl) -3-etsh1-4H pyrido (1,2-) pyrimidine-7-carboxylic acid, c. square  214-216 ° C (0.82 g) in dimethylformamide (20 ml).  The mixture is stirred at room temperature for 3 hours, then it is diluted with ice-water and filtered.  After recrystallization of the precipitate from the filter from acetone, 2-trans- (2-phenylethenyl) -3-ethyl-6,7-methylene-4-oxo-4H-pyrido (1,2-)) pyrimidine-7-carbonyl methyl ester is obtained acids with t. square  194195 G (0.58 g), which is boiled with a 1% solution of potassium hydroxide in 95% ethanol (11 ml) for 15 minutes.  After cooling, the reaction mixture is acidified with acetic acid, evaporated in vacuo and diluted with ice-water, the resulting precipitate is filtered and washed with water until neutral.  After recrystallization from acetone, 0.34 g of 2-trans- (2-phenylethenyl) -3-ethyl-6,7-methylene-4-OXO-4H-PYRIDO (1,2-th |) pyrimidine-7-carboxylic acid is obtained. with t. square  215216 ° C; NMR spectrum (СРзСООВ) (G: 1.22 (multiplet) and 2.93 (multiplet) (6,7-CHt protons), 1.36 (triplet) (), 2.93 (multiplet) (CH, CH 5 , 51 (doublet of doublets) (C-6 protons 7.01 (doublet) (C-9 protons), 7.31 (doublet) (H, vinyl proton), 7.63 (CH-singlet) (phenyl protons), 7.76 (doublet) (HB vinyl proton), (doublet) (C-8 proton).  The following compounds are prepared in a similar manner: 2-trans- (2-fengo1-ethenyl) -3-methyl-6, 7-methylene-4-oxo-4H-pyrido (1, 2-) pyrimidine-7-carboxylic acid with m. square  222-224 C, NMR spectrum (CK5COOV) (Y: 1.18 (triplet) and 2.84 (double).  double ) (6.7 methylene protons), 5.44 (double. double ) (C-6 proton), 6.95 (double. ) (C-9-proton), 8.18 (double. ) (C-8 proton); 2-trans- (2-phenylethenyl) -3-propnp-6, 7-methylene-4-oxo-4H-pyrido (1,2-i. i) pyrimidine-7-carboxylic acid s, t.  square  160 ° C, NMR spectrum (CF, GOOD), ($: 1.13 (triplet) (6,7-methylene proton and -CHiCH CHj), 1.60-2.00 (multiplet) (-CH CH, CH; ), 2.76-3.02 (multiplet) (-CH CHjCHj), 5.47 (doublet doublet) (Cb proton), 6.97 (doublet) (C-9 proton), 7.26 (doublet ) (H, vinyl proton), 7.38-7.80 (multiplet) (H vinyl proton and phenyl protons), 8.20 (doublet) (C-8 proton); 2-trans- (2-fenSh1 ethenyl) - 6,7-methylene-4-oxo-4H-pyrido (1,2 - ") pyrimidine-7-carboxylic acid with t. square  205-210s (decomp. ); 2-trans- (2-phenylethenyl) -3-butyl-6, 7-methylene-4-oxo-4H-pyrido (1,2-0 () pyrimidine-7-carboxylic acid with t. square   (different ), NMR spectrum (CFsCOOD) J: 1.00 (multiplet) (6.7 methylene duct), 2.90 (multiplet) (6.7 methyl proton and -CHj-CHji-CHi CH3), 5.66 ( doublet doublet) (C-8proton), 6.95 (doublet) (C-9 proton), (doublet) (C-8 proton); 2-trans- (2-phenylethenyl). -3-pentyl-6. , 7-methylene-4-oxo-4H-pyrido (1,2-a) 1-irimidine-7-carboxylic acid.  I Example 2.  Trimethylsulfoxonium iodide (1.0 g) is mixed with 50% sodium hydride (0.22 g) in dimethylformamide (30 ml) and stirring is continued at room temperature for 30 minutes, after which a solution of 2-trans methyl ester is added to the reaction mixture. t2- (3-methoxyphenyl) ethenyl-3-these; 1-4-oxo-4H-Pyrido (1,2-0 |) pyrimidine-7-carboxylic acid with m. square - 177-179s (1.27 g) in dimethylformamide (20 ml).  The mixture was stirred at room temperature for 2 hours, then it was diluted with ice-water mixture, and the resulting precipitate was cleaned to give 1.19 g of methyl 2-trans-2- (3-methoxyphenyl) -ethenip1-E-ethyl-6,7- methylene-4-oxo-4H-pyrido (1,2-) pyrimidine-7-carboxylic acid with m. square  184-188 ° C, which is boiled with a 0.5% potassium hydroxide solution in 95% ethanol (40 ml) for 15 minutes.  After cooling, the reaction mixture is diluted with water, acidified with acetic acid, the resulting precipitate is filtered off, and 2-trans-C2- (3-methoxyphenyl) ethenyl} -3-ethyl-6,7-methylene is obtained after crystallization from methylene chloride-methanol. -4-oxo-4H-PIRIDO 1,2-a pyrimidine-7-carboxylic acid (0.65 g) with t. square  184, 188 С, NMR spectrum (CFj СООО) сГ: 1.22 (double.  double ) (one of the 6.7-methylene protons), 1.36 (triplet) (-CH, -CH), 2.96 (multiplet) (-CHt-CH, and 6.7-methylene proton), 4, 12 (singg years) (UN,), 5.50 (doublet doublet) (C-6 proton), 7.03 (doublet) (C-9 about tone), 7.36 (doublet) (N-vinyl proton) , 7.68 (double-in) (H-vinyl proton), 7.18-7.70 (multiplet) (4-phenyl protons), 8.26 (doublet) (C-8 proton).   16 Hz; , 2-trans-2- (2-methylfensh1) -Etensh1-Z-ethyl-6,7-methylene-4-oxo-4H-pyrid6 (1,2-C () pyrimidine-7-carboxylic acid with t. square  225-227C; 2-trans-C2- (3-metsh1phenyl)-entsh1-3-ETSh1-6,7-metsh-4-oxo-4H-pyrido (1,2-a) pyrimidine-7-carboxylic acid with t. square  165 C (decomp. ); 2-trans-2- (3-methylfensh1) -Etensh1 -3-propyl-6,7-metshёn-4-oxo-4H-pyrido (1,2-a) pyrimidine-7-carboxylic acid with t. square  140s (decomp. ); 2-trans- {1g- (4-fluorophenyl) ethylene-3-3-ethyl-6, 7-methylene-4-oxo-4H-pyrido (1,2-y) pyrimidine-7-carboxylic acid; , 2-trans-2- (4-fluorophenyl) ethensh13-8-propyl-b, 7-methylene-4-oxo-4H-pyrid (1,2-ω) pyrimidine-7-carboxylic acid; 2-trans-112- (4-methylphenyl) ethenyl-3-ETSh1-6, 7-metsh1-4-oxo-4H-Shfi to (1,2-c ") pyrimidine-7-carboxylic acid with tons. square  225-235 ° C (decomp. ); 2-trans-2- (4-methylphenyl) -ethenyl 7 -3-propyl-6,7-methylene-4-oxo-4H-pyr-B-1 (1,2-o) pyrimidine-7-carboxylic acid, c. square  140-150s (decomp. ); 2-trans- 2- (2-methoxyphenyl) -stenyl DZ-з sh1-6, 7-mets-1-4-oxo-4N-pyrido (1,2-)) Pyrimidine-7-carboxylic acid with t. square  208-210s; 2-trans (2- (2-methoxyphenyl) -ethenyl-3-Shch-6,7-methylene-4-oxo-4N-pyrndo (1,2-d) pyrimidine-7-carboxylic acid with t. square  130 C (dec,); 2-trans 2- (2-metsh1fenshg) -ethenyl5-3-prosht-6, 7-metsh1en-4-oxo-4H-py1 rido (1,2-01) pyrimidine-7-carboxylic acid with t. square   (different ), NMR spectrum (CFjCOOD),: 1.12 (multiplet) (6.7 - methylene proton and CHjCH CH. ,) 1.73 (multiplet) (), 2.47 (singlet) (-CH,), 2.87 (multiplet) (6.7 - methylene proton and -CHj CHjCHj), 5.46 (doublet doublet) ( C-6 proton), 6.94 (doublet) (C-9proton), 7.16 (doublet) (H vinyl proton), 7.96 (doublet) (H, (- vinyl proton), 8.19 (doublet ) (C-3 proton) 16 Hz; 2-trans-C2- (3-methoxyphenyl) -ethenyl-3-propyl-b, 7-mets-4-oxo-4H-Pyrido (1,2-a) pyrimidine 7-carboxylic acid with t. square  130 C (decomp.), NMR spectrum (CFgCOOD). ,: 1.13 (multiplet) (6.7-mets1enovy proton and -CH CHj-CHj), 2.83 (multiplet), (6.7-methylene proton and,), 5.46 (doublet doublet) (C 6 proton), 6.97 (doublet) (C-9 proton), 7.18.  (doublet) (N.  vinyl proton), 7.64 I (doublet) (Non vinyl proton), 8.21 (doublet) (C-J5 proton), (, 16 Hz; 2-trans-f2- (3-totoxyphenyl) -tenyl-3 -stil-6, 7-methylene-4-oxo-4H-pyrido (1,2-сО pyrimidine-7-carboxylic acid with t. square  188-190 ° C; 2-trans-2- (3-ethoxyphenyl) -ethenyl} -3-Shch-6,7-methylene-4-oxo-4H-pyrido (1,2-e) pyrimidine-7-carboxylic acid with t. square  97-102 C (decomp. ); 2-trans- {5- (2,3-d1methoxyphenyl) -enten} -3-ethy-1-6, 7-methipen-4-oxo-4H-pyrnzo (1,2-)) pyrimidine -carboxylic acid with m. square  188-190 ° C; 2-trans-H2- (2,3-dimethoxyphenyl) etenip} -3-propyl-6, 7-methylene-4-oxo-4H-pyrido (1,2-61) pyrimidine-7-carboxylic acid with m. square  100-110 ° C (decomp. ); 2-trans-H2- (2,5-dimethoxynphenyl) -ethenyl} -3-propyl-b, 7-methylene-4-oxo-4H-pyrido (1,2-1) pyrimidine-7-carboxylic acid with m. square  170-173s, NMR spectrum (CP4COOB), (Y: 1.20 (multiplet) (6.7 - methylene proton), 2.89 (multiplet) (6.7 - methylene proton and -CHiCfijCHs), 5.48 ( doublet doublet) (C-6 proton), 7.0 (doublet) (C-9 proton), 7.45 (doublet) (H vinyl proton), 7.98 (doublet) (H vinyl proton), 8.22 (doublet) (C-8 proton), JH HP - 16 Hz; 2-trans-p- (2,5-dimethoxyphenyl) -ethenyl-L-3-etype-6, 7-methylene-4-oxo-j-DN- pyrido (1,2-00 pyrimidine-7-carboxylic acid with t. square  192-195 ° C; 2-trans-2 (2-methoxy-3 ethoxyphenyl) -ethenyl-3-eth-1-6,7-methylene-4-oxo-AN-pyrido (1,2-th) pyrimidine-7-carboxylic acid with m. square  180-185 (sect. ); 2-trans-2- (methoxy-3-ethoxyphenyl-etenyl} -3 prop 1-6,7-methylene-4-oxo-4H-pyrido (1,2-a) pyrimidine-T-carboxylic acid with t. square  141 143C;  2-trans- (2-ethoxy-3-methoxyphenyl) -ethenyl-3-eth-1-6,7-methylene-4-OXO-4H-PYRIDO (1,2-e) pyrimidine-7-carboxylic acid; ,  2-trans-2- (2-ethoxy-3-methoxyphenyl) -ethenyl-3-propyl-6,7-methylene-4-oxo-4H-pyrido (1,2-s) pyrimidine-7-carboxylic acid with t . square  181-.  183 ° C; 2-trans-C2- (2-ethoxy-5-methoxyphenyl) -ethenyl-3-ethyl-6,7-methylene-4-pkso-4H-pyrido (1,2- (a) pyrimidine-7-carboxylic acid; 2-trans-2- (2-ethoxy-5-methoxyphenide) -ethenyl-1-3-propyl-6,7-methylene-4-oxo-4H-pyrido (1,2-a) pyrimidine-7-carboxylic acid; 2 -trans- 2 (2,3,4-trimethoxyfensch1) -ethenyl: -3-e-il-6,7-methylene-4-OXO-4H-PYRIDO (1) pyrimidine-7 1,. L.  -i  .   - carboxylic acid; 2-trans C2- (2,4,5-trimethoxyphenyl) -ethenyl} -Z-ethyl-6,7-methylene-4-oxo-4H-PIRIDO (1,2-s) pyrimidine-7-Kap6o new acid; 2-trans C2- (2,4,5-trimethoxyphenyl) -ethenyl-3-propyl-6,7-methylene-4-oxo 4H-pyrido (1,2-a) pyrimidine-7-carboxylic acid with t. square  224-226C; 2-trans-2- (3,4,5 trimethoxyphenyl-ztenyl-3-ethyl-6 7-methyl-4-oxo-4H-pyrido (1,2-; ") pyrimidine-7-carboxylic acid; 2- TRANS-12- (3,4 5-trimethoxyphenyl getenyl-3-propyl-6,7-mets-1-4-ok7 co-4H-pyrido (1,2-I) pyrimidine-7-carboxylic acid; 2-trans-2 - (2,4-dimethylphenyl) -ethenyl-3-propyl-6, 7-methyl-4-oxo-4Npyrido (1,2-d) pyrimidine-7-carboxylic acid from T. P. P.  184-186 ° C; 2-trans-2- (3,4-dimethoxyphenip) -ethenyl-3-propyl-b, 7-methylene-4-oxo-4H-pyrido (1,2-d) pyrimidine-7-carboxylic acid with m, pl "208-209 C; 2-trans-t2- (4-metoksifenshI) -ethenyl-3-propyl-6,7-methylene-4-oxo-4H pyrido (1,2-0) pyrimidine-7-carboxylic acid with t. square  180-190 ° C; 2-transX2- (4-methoxyphenyl) -ethenyl-3-ethyl-6,) -methylene-4-oxo-4H-pyrido (1,2-0) pyrimidine-7-carboxylic acid with t. square  235-237 ° C; 2-trans-E2- (2-ethoxyphenyl) -ethenyl-3-propyl-6, 7-methylene-4-oxo-4H-pyrido- (1,2-O) pyrimidine-7-carbonyl acid with t. square  178-180 ° C; 2-trans-2- (3,5-dimethoxyphenyl) -ethenyl-3-propyl-6, 7-methylene-4-oxO-4H-pyrido (1,2-c) pyrimidine-7-carboxylic acid with m. square  170180s (decomp. ); 2-trans-2- (2,5-dimethylphenyl) -ethenyl} -3-prop 1-6, 7-methylene-4-oxo-4N-pyrido C1,2-] pyrimidine-7-carboxylic acid with t. square  150 C (with decomp. ); .  2-trans-2- (2,4-dimethylphenyl) -ethenyl} -Z-ethyl-6, 7-methylene-4-oxo-4Npyrido (1,2-d) pyrimidine-7-carboxylic acid; 2-trans-2- (2,5-dimethylphenyl) -ethenyl-3-3-ethyl-6, 7-methylene-4-oxo-4H-pyrido (1,2-a) pyrimidine-7-carboxylic acid with m. square  205-207С; f 2- (2-methylfensh1) -e tenyl-3-butyl-6, 7-methyl-4-oxo-4H-pyridine (1,2-c |) pyrimidine-7-carboxylic acid with t. square  240 C (rael); 2-trans-2- (3-methoxyphenyl) -ethenyl-3-butyl-6,7-methylene-4-oxo-4H-pyrido (1,2-e) pyrimidine-7-carboxylic acid with m. square  156-158 C; 2-trans-C2- (2,3-dimethoxyphenyl) -ethenyl-3-butyl-6, 7-methylene-4-oxo | -4H-pirido (1,2-0) pyrimidine-7-carboxylic acid with m. square  197-198 ° C; 2-trans-H2- (2-methoxy-3-ethoxyphenyl-5-ethenyl-3-butyl-6, 7-methylene-4-oxo-4H-pyrido-1,2-d) pyrimidine-7-carboxylic acid with m. square  155157С; 2-trays- 2- (2,3-dimethoxyphenyl) -ethenyl-3-propyl-6, 7-methyl-4-oxo-LN-pyrido (1,2-th) pyrimidine-7-carboxylic acid with m. square  177-179 C.  Example 3  Carrying out the process in the same manner as in Example 8, and using the corresponding 2-heteroarnylethenyl derivatives as starting reagents, the following compounds are obtained: 2-trans-p- (2-thienyl) -Ethensh-3ethyl-6 f7-methylvc-4 -oxo-4H-pkrido (1,2-a) pyrimidine-7-carboxylic acid - 11115 2-trans- 2- (2-thienyl) -ethenyl-3-propyl-6, 7-methylene-4-oxo-4H -pyrido (1,2-a) pyrimidine-7 carboxylic acid with t. square  157-162 C (decomp. ); -.  2-trans-C2- (2-pyridyl) -ethenyl-3ethyl-6, 7-methylene-4-oxo-4H-pyridium (1,2-a) pyrimidine-7-carboxylic acid; 2-trans-2- (5-methyl-2-thienyl) -ethyl} -3-ethyl-6,7-methylene-4-oxo-4H-pyridr (1,2-th) pyrimidine-7-carboxylic acid ; 2-trans 2- (5-methyl-2-thiensh:) - ethenyl-3-propyl-6, 7-methylene-4-oxo-4H-pyrido (1,2-Oi) pyrimidine-7-carboxylic acid; .  2-trans-C2- (5-methyl-2-thiens I) -ethenyl-3-propyl-6,7-methylene-4-oxo-4H pyridine (1,2-e) pyrimidine-7-carboxylic acid; 2-trans-2- (5-methyl-2-furyl) -ethenyl-3-ethkl 6, 7-methylene-4-oxo-4H-pyrido (1,2-a) pyrimidine-7-carboxylic acid; 2-trans-2- (5-methyl-2-four-1) -ethenyl-3-propyl-6, 7-methylene-4-oxo-4H-pyrido (1,2-C1) pyrimidine-7-carboxylic acid; 2-trans-2- (6-methyl-2-pyridyl) -ethenyl-3-ethyl-6, 7-methylene-4-oxo-4H-Pyrido (1,2-a) pyrimidine-7-carboxylic acid; 2-trans-2- (6-methyl-2-pyridyl) -ethenyl} -3-propyl-b, 7-methyl-4-oxo-4H-pyrid (1,2-i) pyrimidine-7-carboxylic acid.  Example 4  Carrying out the process in the same manner as in the example of pax 2 and 3, using the corresponding 2-arSh1ethenes1- and 2-heteroaroetheniphenyl derivatives as the starting products, the following compounds were obtained: 2-trans-C2- (2-metsh1phenyl) - etensh1 | -6,7-methylene-4-oxo-4H-pyrido (1,2-th I pyrimidine-V-carboxylic acid s, t. square  179-182s; 2-trans-C2- (3-mvtsh1phenyl) -enhens9 -t | -6 7-mvtilen-4-oxo-4H-pyrido (t, 2-a acid with T. im / / H XJ 2-trans (4-methyl 1-phenyl) -ethenyl} -6, 7-methylene-4-oxo-4H-pyrido (1,2- "pyrimidine-7-carboxylic acid with t. pl ,, 190-194 ° C; 2-trans-2- (2-methoxyphenyl) -ethenyl} -6, 7-methyl-4-oxo-4H-pyrido (1,2-c |) pyrimidine-7-carbonoBic acid with m. square  150 C (decomp. ); 2-trans-C2- (3-methoxyphenyl) -ethenyl-6, 7-metsten-4-oxo-4H-pyrido (1,2-c) pyrimidine-7-carboxylic acid with t. square  204 C (Rael. ); 2-trans-2- (4-methoxyphenyl) -ethenyl-6, 7-methylene-4-oxo-4H-pyrido (1,2-y) pyrimidine-7-carboxylic acid with m. square  95-110 (decomp. ); 2-trans-2- (3-chlorophenyl) -ethenyl1-6, 7-methylene-4-oxo-4H-pyrido (1,2-a) pyrimidine-7-carboxylic acid with m. square  205-210 ° C (decomp. ); 2-trans-H2- (3-hydroxyphenyl) -ethenyl-6, 7-methyl-4-oxo-4H-pyrido (1,2-0) pyrimidine-7-carboxylic acid; 2-trans-C2- (4-S, H-dimethylaminophenide) -ethenyl 3-6,7-methylene-4-oxo-4H-pyrido (1,2-a) pyrimdine-7-carboxylic acid; 2-trans-C2- (2,4-dimethylphensh1) -ethenyl) -6,7-metsh1-4-oxo-4H-pyrido, (1,) pyrimidine-7-carboxylic acid with t. square  199-202 ° C; 2-trans-2- (2,5-dimethylphenyl) -ethe1 l} -6, 7-methylene-4-oxo-4H-pyrido (1,2-с1) pyrimidine-7-carboxylic acid with t. square  195-200 C; 2-trans - (- (2,3-dimethoxyphenyl) ethenyl5-6, 7-meth- en-4-oxo-4H-pyrido (1,2-a) pyrimidium 1-7-carb, onoic acid; 2-trans-2 - (2,5-dimethoxyphenyl) -ethenyl: -6,7-methylene-4-oxo-4H-pyrido (1,2-a) pyrimidine 7-carboxylic acid; 2-1rans-G2- (2,3,4 -trimethoxyphenyl) -ethenylZ-6,7-methylene-4-oxo-4H-pyrido (1,2-0) pyrimidine-7-. carboxylic acid with t. square  180-182С; 2-trans-C2- (2-thienyl) -ethenylD-6, 7-methyl-4-oxo-4H-pyrido (1,2-c) pyrimdine-7-carboxylic acid; 2-trans-G2- (2-furyl) etenip | -6, 7-methylene-4-oxo-4H-pyrido (1,2-fi) pyrimidine-7-carboxylic acid; 5- (2-methylphenyl) -ethenyl} -3-methyl-6, 7-methylene, 74-oxo-4H-pi-jwciujt-u, / - methylene-n-oxochp-PI- rado (1,2-) pyrimidine -7-carboxylic acid with t. front  240 ° C (decomp. ); 2-trans-C2- (3-meth1phenyl) -ethenyl-3-methyl-6, 7-methylene-4-oxo-4H-pyrido (1,2-a) pyrimidine-7-carboxylic acid with m. pp  190-205s (decomp. ); 2-trans-12- (4-methylphenyl) -z tenyl-3-methyl-6, 7-methylene-4-oxo-4H-pyrido (1,2-ci) pyrimidine-7-carboxylic acid with m. square  260-265 C (decomp. ), 2-trans-2- (2-methoxyphenyl) -ethenyl} -3 methyl-6, 7-methylene-4-oxo-4H-pyrido (1,2-c |) pyrimidine-7-carboxylic acid with t. square  200-205 C (decomp.  2-trans-2- (3-methoxyphenyl) -ethenyl-D-3-methyl-b, 7-methyl-4-oxo-4H-pyrido (1,2-c) pyrimidine-7-carbono-. . - ,.  --gvuyu acid with t. square  200-205 C (decomp.  2-trans-C2- (4-methoxyphensh1) -e. Te nyl-3-methyl-6,7-meth-1-4-oxo-4H-pyrido (1,2-a) pyrimidine-7-carboxylic acid with m. square  234-238 ° C; 2-trans-2- (2-chlorofensh1) -ethenyl-3-methyl-6, 7-methylen-4-oxo-4H-pyrido (1,2-tt) pyrimidine-7-carboxylic acid; 2-trans-C2- (3-chlorophenyl) -ethenyl-3-mets1-6, 7-meTi. pen-4-oxo-4H-pyrid. () pyrimidine-7-carboxylic acid; 2-trans-C2-: (4-chlorophenyl) -ethenyl-3-metsh-6, 7-methylene-4-oxo-4H-pyrido (1,2-) pyrimidine-7-carboxylic acid; 2-trans-2- (3-hydroxyphenyl) -ethenyl-3-methyl-6, 7-methylene-4-oxa-4H-pyrido (1,2-a) pyrimidine-7-carboxylic acid; 2-trans-2- (4-hydroxyphensh1) -tenz1-3-methyl-6, 7-methylene-4-oxo-4H-pyrido (1,2-ci) pyrimidine-7-carboxylic acid;  2-trans-2- (4-N, N-dimethylaminophenyl) -ethenyl-3-metsh-6,7-methylene-4oxo-4H-pyrido (1,2-a) pyrimidine-7-carboxylic acid; 2-trans-2- (4-N, N-diethypaminophenyl) -ethenyl-3-methyl-6,7-methylene-4-OXO-4H-PYRIDO (1,2-nd) 1 Srimidine-7-carboxylic acid; 2-trans-2- (2,4-D1 1-methylphenyl) -ete-nylZ-3-methyl7b, 7-methylene-4-oxo-4H-pyrido (1,2-c () pyrimidine-7-carboxylic acid with m. square  220-223 C (decomp.  2-trans- 2- (2f5-dimesh1phenyl) -enesh13 3-metsht-6, 7-MeTmieH-4-okco-4H-pyrido (T, 2-С |) pyrimidine-7-carboxylic acid with t. square  235-240 C (decomp); 2-trans-12- (2,3-dimethoxyphene J). -ethenylC-3-methyl-b, 7-methyl-4-oxo-4H-pyrido (1,2-o) pyrimidine-7-carboxylic acid with t. square  207-209 C (decomp. ); 2-trans-C2- (2,4-dimethoxyphensh1) -ethenyl7 3-methyl-6, 7-methyl-4-oxo-4H-pyrido (1,2-o) pyrimidine-7-carboxylic acid; 2-trans- 2- (2-, 5-dimethoxyfennl) -ethenyl-3-methyl-6, 7-methylene-4-oxo-4H-pyrido (1,2-ci) pyrimidine-7-carboxylic acid with m. square  171-174 C (decomp. ); 2-trans-12- (3, 4 dimethoxyfensch1) -.  ethylene 13-3-methyl-6,7-methylene-4-oxo 4H-pyrido (1,2-a) pyrimidine-7-carboxylic acid with t. square  207-210 C (decomp. ); 2 trans. 2- (3,5-dimethoxyphenyl) -ethenyl-3-methyl-6, 7-methylene-4-oxo-4H-pyrido (1,2-c) pyrimidine-7-carboxylic acid; 2-trans-f2- (2,3,4-trimethoxyphenyl) -ethenyl} -3-methyl-6, 7-methyl-4-oxo-4H-pyrido (1,2-th) pyrimidine-7-carboxylic acid; 2-trans-2- (2,4,5-trimethoxyphenyl) etheiyl-3-metsh-6,7-meth-Sh1-4-oxo-4H-pyrido (1,2-c) pyrimidine-7-carboxylic acid; 2-tranc-2- (3,4-5-trimethoxyphenyl) -ethenyl 3-methyl-6, 7-methylene-4-oxo-4H-pyrido (1,2-ct) pyrimidine-7-carboxylic acid with t . square  175-180s (decomp. ); 2-trans-G2- (2-thiensh1) -etenSh1} -3-methyl-6, 7-methylene-4-oxo-4H-pyrido (1,2-i) pyrimvdin-7-carboxylic acid with m. square  208-211 ° C (decomp. ); 2-trans-C2- (2-furyl) -ethenyl} -3-methyl-6, 7-methylene-4-o. Kso-4H-pyrido (1,2-ot) pyrimidine-7-carboxylic acid.  Example 5  Trimethylsulfoxonium iodide (2.3 g) is mixed with 50% sodium hydride (0.5 g) in dimethylformamide (30 ml) and stirring is continued at room temperature for 1 h, then a solution of 2- (diethylamino) is added to the reaction mixture ethyl ester 2 trans | 2 (2,3-dimethoxyphenyl) ethyl-3-ethyl-4-OXO-4H-PNRIDO (1,2-a) pyrimidine-7-carboxylic acid (3.5 g) in dimethylpyrmide (20 ml), Stirring at room temperature the temperature is continued for 90 minutes, then the mixture is diluted with water and extracted with ethyl acetate, the organic layer is washed with water and evaporated to dryness in vacuo.  The residue (2.9 g) was purified on a silica gel column using acetone as the solvent, 1.9 g of 2- (2-diethylamino) ethyl ether 2-trans-2- (2,3-cimethoxynphenyl) ethenyl-3-ethyl 6,7-methylene-4-oxo-AN-pyrido (1,2-cr) pyrimidine-7-carboxylic acid in the form of oil, NMR spectrum (DMSOd,), S :.  (triplet) fn, - fn.  SNg - SNz 1, 30 (multip. ) (6,7-methylene | proton and -), 2.54 (qyCHj-pH, tet) (-H. , „. .  , 2.70 (triplet) CHj-GHj (-O-CH-CH iN), 2.4-2.8 (multiplet (6.7-methylene proton-CH-CH), 3.81 (single) (- DOS,), 3.83 (single. ) (-OCH,), 4.2 (triplet) (O-CH -CHi-N 4.78 (double, double. ) (C-6 proton), 6.38 (double. ) (C-9 proton), 7.18 (double. ) (C-8 proton), 7.39 (double) (Hp-vinyl, proton), 8.07 (H-vinyl, proton), 7.18-7.46 (multiplet) (phenyl protons).  Example 6  2 trans. 2- (3-methoxyphenyl) ethenyl-3-ethyl-6,7-methylene-4-oxo-4H-py5ido (1,2-ci) pyrimidine-7-carboxylic acid (|, 2g mixed with thionyl chloride (0, 6 ml) in dioxane (12 ml), and then boil for 1 h, after which the mixture is evaporated to dryness in vacuum.  The residue is treated with excess methanol at 50 C for 30 minutes, after which the solution is evaporated in vacuo, the residue is diluted with ice-water.  After filtration of the precipitate, 1.2 g of methyl 2-trans-2- (3-methoxy phenyl) ethenyl-3-ethyl-b, 7-methylene-4-OXO-4H-PIR1THO (1,2-ct) pyrimidine 7-carboxylic acid with t. yl  14314bH.  Example 7  2-trans- (2-phenyl ethenyl) -3-methyl-6,7-methylene-4-oxo-4H-Pyrido (1,2-a) pyridine-7-carboxylic acid (0.8 g) is mixed with methyl iodide (0.55 g) and anhydrous KjCGj (0.65 g) in dimethylformamide (7 ml) with stirring at room temperature for 4 hours.  After dilution with ice-water mixture, the precipitate formed is filtered and recrystallized from acetone to obtain 0.5 g of 2-trans (2-phenyl-1-methyl-3-methyl-4-oxo-4H-pyrido-1-methyl ester (1 , 2-) pyrimidush-7-carboxylic acid with m. square  164-165p.  The following compounds are obtained analogously: 2-trans- (2-phenyl-.  ethenyl) -3-ethyl-6,7-methylene-4-oxo-4H-pyrido (1,2-o |) pyrimidine-7-carboxylic acid with m. square  194-195 С; 2-trans- (2-phenyl 1-phenyl) -3-butyl-6,7-methylene-4-oxot-4H-PYRIDO (1,2-c |) pyrimidine-7-carboxylic acid venomous ester with m. square  112-113C; 2-trans-f2- (2,5-dimethoxyphenyl) ethenyl-3-propyl-6, 7-methylene-4-oxo-4H-pyrido (1,2-e) pyrimidine-7-carboxylic acid methyl ester with m. square  117-120С; 2-trans-C2- (3-methItoxyphenyl) ethene-3-methyl-6,7-methylene-4-oxo-4H-pyrido (1,2-ci) pyrimidine-7-carboxylic acid methyl ester with m. square  143-146 C.  Example 8  Analogously to Examples 6 and 7 and using respectively ethanol or ethyl iodide, the following compounds are obtained: 2-trans (2-phenylethenyl) -3-ethyl-6,7-methylene-4-oxo-4HPyrido (1,2-e . a) pyrimidine-7-carboxylic acid; acids; 2-trans-2- (2-methyl-phenyl) -ethenyl-3-ethyl-6,7-methylene-4-OXO-4H-PYRIDO (1,2-a) pyrimidine-7-carboxylic acid ethyl ester; 2-trans-2- (3-methoxyphenyl) -ethenyl-3-ethyl-6,7-methylene-4-OXO-4H-PYRIDO (1,2-c) pyrimidine-7-carboxylic acid ethyl ester with m. square  123125 ° C; ethyl) 1Y 2-trans-C2- (2-methylphenyl) ethylene-3-3-propyl-6,7-methylene-4-oxo-4H-pyrido (1,2-cl) pyrimidine-7-carboxylic acid ester.  Example 9  Analogously to examples 6 and 7, eopropyl is obtained.  The n-hexyl and n-rctyl esters of the following compounds: 2-trans (2-phenylethenyl) -3-ethyl-6, 7-methylene-4-oxo-4H-pyrido (1,) pyrimidine-7-carboxylic acid; 2-trans-f2- (2-methylphenyl) -ethenyl-3-ztil-b, 7-methylene-4-oxo-4H-pyrido (1,2-a) pyrimidine-7-carboxylic acid; 2-trans-2- (2-methylfensh1) -ethenyl-3-prop 1-6, 7-methylene-4-ox. o-4H-pyrido (1,2-a) pyrimidine-7-ka carboxylic acid; 2-trans-C2- (3-methoxyphenyl) -ethenyl} -3-ethyl-6, 7-methylene 4-oco-4J-pyrido 1, pyrimidine-7-carboxylic acid.  Example 10  2-trans-C2- (2-methylphenyl) -ethenyl} -3-propyl-4-ox-4I-PYRIDO (1,2-a) Pyrimidine-7-carboxylic acid (3.6 g) is mixed with 1-chloro -2- (diethylamine) ethane (2.7 t and anhydrous K200-} (2.8 g) in dimethyl formamide (40 ml) with stirring at 50 ° C and held for 8 hours under stirring at the same temperature.  After dilution with water, the precipitate formed is filtered and washed with water until neutral, and after recrystallization from isopropyl ether, 2.1 g of 2-diethylaminoethyl 2-trans-2- (2-metsh1 Fensch-1) ethylene 1 -3-propyl-4-oxo are obtained. -4Hpyrido (1) pyrimidine-7-carboxylic acid.  The following compounds are prepared in a similar manner: 2- (diethylamino) ethyl 2-trans-2- (2-methylphenyl) ethenyl-3-propyl-6, 7-methylene-4-6 x-4-x-4H-pyrido (1.2-0 a) pyrimidine-7-carboxylic acid; 2- (diethylamino) ethyl ester 2-trans-2- (2-methylphensh1) ethen1-3-ethyl-6, 7-methy-4-oxo-4H-pyrido (1,2-a) pyrimidine-U-carboxylic acids; 2 (diethylamino) ethyl ester 2-trans-2- (3-methoxyphenyl) -ethenyl} -Z-ethyl-6, 7-me; shlen-4-oxo-4H-pyrid (1,2-a), pyrimidine 7-carboxylic acid; 2- (2-trans-2- (2,3-dimethoxyphenyl) ethenesh1 -3-ethyl-6,7-methylene-4-oxo-4H-pyrido (1,2-a) pyrimidine-7- carboxylic acid.  NMR (DMSO, 97 (triple. ).  CH - CH, N. .  CH - CHj, 0.95-1.30 (multip. ) (6.7 methylene.  proton and -CHi-CHj), 2.54 (quartet) (P, 2.70 (triple. ) CHj (-O-CH -CH. , -N), 2.4-2.8 (multip. ) (6,7-methylene.  proton i), 3.81 (singlet) (-OCH,), 3.88 (single) (-OCH), 4.22 (triple) (0-CH4 -CHi-Ji 4.78 (double).  double ) (C-6 proton), 6.38 (double. ) (C-9 proton), 7.18 (double. ) (C-8 proton), 7.39 (double ) (H „-vinyl proton),, 07 (1 -vinyl, proton), 7.18 - 7.46 (cartoon. ) (phenyl, protons).  Example 11  2-trans-2- (2,3-dimethoxyphenyl) -ethenyl | -3-ethyl-4-OXO-4H-Pyrido (1,2-a) pyrimidine-7-carboxylic acid (1.2 g) is mixed with chloride thionyl (0.6 ml) in dioxane (20 ml) and then boiled for 3 hours, after which the mixture was evaporated in vacuo.  The residue was dissolved in dioxane (60 ml), and 2- (diethylamino) ethanol (1.2 g) was added to this solution and stirred for 20 hours at room temperature. .  After dilution with water, the precipitate is filtered off, dissolved in acetone (100 ml) and treated with a stoichiometric amount of a solution of hydrogen chloride in ether, the precipitate formed is filtered off, washed with ethyl ether and dissolved in water.  After alkalinization with potassium carbonate, filter. and acetone crystallization, 0.6 g of 2- (diethylamino) ethyl 2-trans-C2- (2,3-dimethoxyphenyl) ethylene 1 | -3-ethyl 1-4-oxo-4H-pyrido (1,2- C () pyrimidine-7-carboxylic acid with m. ll  148-150s.  In a similar manner, 2- (diethylamino) ethyl ester of 2-trans-2- (2,3-dimethoxyfennl) ethylene 1 / -3-ethyl-6, 7-methylene-4-oxo-4H-pyrido (1,2-a) is obtained irimIdin-7-carboxylic acid, MP spectrum (DMSO d6): 0.97 (triplet) CHj-CHj 0.95-1.30 (multipl. ), (6.7-mets1enovy. proton i),, 54 (quartet). - / CHi-chji o -, p. -CHjv (triplet) (0-CH4 -CH7, -N. ), 2.4-2.8 (multiplet) (6,7-methylene pbp and -CH5. -СНз), 3.81 (single) (-ОСНз), 3.88 (single. ), (OSI,).  22 (triple. ) (-O-CHj-CHi-NX), 4.78 (double  ubl ) (C-6 proton), 6.38 (double. ) With 9-proton), 7.18 (double ) (C-8 UNDP), 7.39 (double ) (N-vinyl proon), 8.07 (N-vinyl proton), 18 - 7.46 (multiplet) (phenyl rotons).  , Pr and m and p 12.  2-trans-C2- (2methylphenyl) ethenyl-3-propnl-4-oxo-4H-pyrido- (1,2-m) pyrimidine-7-car19 115804520
    boom acid (5 g) is treated with D-3-propyl-A-oxo-4H-pyrido
    a solution of sodium bicarbonate (1.25 g) (1,2-a) pyrimidine-7-carboxylic acid in water (15 ml) with up to one-half hammer (3.9 g) with m.p. 300 C.
    dissolving the precipitate. After cooling, the sodium is obtained analogously.
    Neither to 5 ° C a precipitate is formed, which is 5-salt of 2-trans-2- (3-methoxyphenyl) -et "
    Filtered and washed with a 1-3-ethyl-6,7-methylene-4-oxo-dn mixture with an ice-water mixture. Sodium pyrido (1,2-c) pyrimidine-7-carbosol 2-trans-C2- (2-methylphenyl) -ethyl acid is obtained, m.p. (different).
    权利要求:
    Claims (1)
    [1]
    The method of obtaining derivatives of pyrido (1,2-a) pyrimidine of General formula I:
    wherein R, - hydrogen, C 1 _ alkyl or -Sa (2-di-C 1 -S4.-alkylamino) ethyl; R z is hydrogen or C., is C5 ~ alkyl; R ·} - unsubstituted furyl, thienyl or pyridyl or substituted with methyl, unsubstituted phenyl or phenyl substituted with halogen, hydroxyl or one to three substituents from among C ^ -Cj-alkyl or C ^ -Cy alkoxyl pharmaceutically acceptable or their salts with metals ^ characterized in that the compound of general formula II:
    r 2
    Cho.
    CH = CH-R 3 where R 1 - R 5 have the indicated meanings, are reacted with dimethyl sulfoxonium methylide, followed by isolation in the form of a salt or a metal or etherification of a compound of the general formula I, where Rj is hydrogen, to obtain a compound of the general formula I, where R 1 has the other indicated meanings, or by hydrolysis of a compound of general formula I, where R is alkyl, into a compound of general formula T, where R is hydrogen.
    类似技术:
    公开号 | 公开日 | 专利标题
    EP0299470B1|1996-12-04|Imidazo[1,2-a]pyridines
    SU1158045A3|1985-05-23|Method of obtaining pyrido | pyrimidine derivatives or their pharmaceutically acceptable salts with metals
    SU980627A3|1982-12-07|Process for producing n-desmethylvinblastine, vincristine, n-desmethylleurosine, h-dimethyl-n-formylleurosine, n-dismethyl-n-|-vinblastine, n-desmethyl-n-|-leurosine or their salts
    IL34897A|1973-08-29|Tetrahydropyrido-thioxanthene derivatives,compositions containing them,and the preparation thereof
    US3941782A|1976-03-02|Heterocyclic esters of benzopyrans
    US4239887A|1980-12-16|Pyridothienotriazines
    CA1140928A|1983-02-08|Aldose reductase inhibiting quinolylhydantions
    US4623725A|1986-11-18|[1,2,4]Triazolo[4,3-a]quinoxaline-4-amine derivatives
    US3801597A|1974-04-02|2,3-dihydro-4h-thieno|benzopyran-4-ones
    SU1017170A3|1983-05-07|Process for preparing derivatives of 3-amino-1-benzoxepine or their stereoisomers or their salts
    SU1138027A3|1985-01-30|Method of obtaining substituted aurons
    EP0150966B1|1989-07-12|Benzopyran derivatives, compositions containing them and processes for their preparation
    EP0481243A1|1992-04-22|Tricyclic heterocyclic compounds, their production and use
    US2767191A|1956-10-16|Dihydropyrrolo-pyridines
    EP0107455B1|1986-07-09|Triazoloquinoxalines as antidepressants and antifatigue agents
    US3470165A|1969-09-30|Furochromone derivatives
    US3567716A|1971-03-02|1,8-naphthyridine derivatives and intermediates thereof
    Sasaki et al.1992|The synthesis of novel polycyclic heterocyclic ring systems via photocyclization. 7.[1] Benzothieno [2, 3‐c] naphtho [2, 1‐h] quinoline and [1] benzothieno [2, 3‐c] naphtho [2, 1‐h][1, 2, 4] triazolo [4, 3‐a] quinoline
    US3542796A|1970-11-24|Certain hexahydro-1,12-trimethylene-indolo|quinolizines
    PL101181B1|1978-12-30|METHOD OF MAKING NEW DERIVATIVES OF TRIAMINOANDROSTANE
    GB2103207A|1983-02-16|Substituted pyrrolo]2,1-bquinazolines and pyrido]2,1-bquinazolines and process for their prepara
    EP0026675B1|1984-03-14|1-azaxanthone-3-carboxylic acids, their preparation and pharmaceutical compositions containing them
    NZ205986A|1986-06-11|triazolo|quinoxaline-4-amine derivatives and pharmaceutical compositions
    Moore et al.1964|Heterocyclic Studies. XII. The Base-Catalyzed Deuterium Exchange and Rearrangement of 2, 3-Dihydro-5-methyl-6-phenyl-4H-1, 2-diazepin-4-one to α-Aminopyridines1, 2
    US4085116A|1978-04-18|Novel chromone derivatives
    同族专利:
    公开号 | 公开日
    NO153137B|1985-10-14|
    GR68075B|1981-10-30|
    NO153137C|1986-01-22|
    FI801464A|1980-11-09|
    LU82419A1|1980-07-31|
    ES491238A0|1981-04-01|
    IE800945L|1980-11-08|
    CS528780A2|1985-09-17|
    SU1217259A3|1986-03-07|
    SE437158B|1985-02-11|
    FR2456093A1|1980-12-05|
    NO801342L|1980-11-10|
    HU181778B|1983-11-28|
    ZA802390B|1981-04-29|
    JPS562983A|1981-01-13|
    AU5731980A|1980-11-13|
    CH647777A5|1985-02-15|
    CA1134359A|1982-10-26|
    FI68824B|1985-07-31|
    PT71197A|1980-06-01|
    CS244107B2|1986-07-17|
    IE49787B1|1985-12-11|
    FR2456093B1|1984-02-03|
    NL8002656A|1980-11-11|
    AU527931B2|1983-03-31|
    ATA245680A|1983-12-15|
    CS321380A2|1984-12-14|
    US4341780A|1982-07-27|
    BE883150A|1980-11-07|
    IT1209326B|1989-07-16|
    AT375370B|1984-07-25|
    ES8104287A1|1981-04-01|
    US4310526A|1982-01-12|
    DK200280A|1980-11-09|
    IT8021821D0|1980-05-06|
    IL59802A|1983-07-31|
    GB2050353B|1983-04-27|
    DE3015738A1|1980-11-13|
    IL59802D0|1980-06-30|
    NZ193579A|1982-09-07|
    FI68824C|1985-11-11|
    SE8003433L|1980-11-09|
    GB2050353A|1981-01-07|
    PH16695A|1984-01-06|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    US4209622A|1973-03-30|1980-06-24|Chinoin Gygyszer es Vegyeszeti Termekek Gyara Rt.|3--6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine|
    US3935197A|1975-05-16|1976-01-27|E. R. Squibb & Sons, Inc.|2-Styryl-4H-pyridopyrimidin-4-ones|
    HU178910B|1977-08-19|1982-07-28|Chinoin Gyogyszer Es Vegyeszet|Process for preparing 2,3-disubstituted-4-oxo-4h-pyrido/1,2-a/-pyrimidines|
    HU180701B|1977-12-29|1983-04-29|Chinoin Gyogyszer Es Vegyeszet|Process for preparing pyrido-/1,2-a/pyrimidines containing a carboxylic or ester group on the pirimidimering|
    HU184058B|1977-12-29|1984-06-28|Chinoin Gyogyszer Es Vegyeszet|Process for preparing new compounds with nitrogen bridge head|AT377586B|1981-06-30|1985-04-10|Erba Farmitalia|METHOD FOR PRODUCING SUBSTITUTED PYRROLO--QUINAZOLINES AND PYRIDO-QUINAZOLINES|
    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|
    CA1211111A|1982-02-15|1986-09-09|Isao Yanagisawa|Process for preparing novel pyrimidone compounds|
    ES8406476A1|1982-04-29|1984-07-01|Erba Farmitalia|Condensed cycloaliphatic derivatives of substituted pyrido[1,2-a]pyrimidines and methods of treating allergic conditions, peptic ulcers and inhibiting gastric acid secretion with them|
    ES524262A0|1982-08-05|1984-11-16|Erba Farmitalia|"PROCEDURE FOR PREPARING QUINAZOLINE DERIVATIVES"|
    GB8300728D0|1983-01-12|1983-02-16|Erba Farmitalia|Substituted carboxy-thiazolo / 3 2 - a / pyrimidine derivatives|
    US4457932A|1983-07-22|1984-07-03|Bristol-Myers Company|Anti-ulcer agents|
    GB8501015D0|1985-01-16|1985-02-20|Riker Laboratories Inc|Drug|
    JP2668259B2|1988-02-18|1997-10-27|塩野義製薬株式会社|Heterocyclic compounds and anti-ulcer agents|
    WO2009109987A2|2008-01-11|2009-09-11|Glenmark Pharmaceuticals, S.A.|Fused pyrimidine derivatives as trpv3 modulators|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    GB7915810|1979-05-08|
    [返回顶部]