Method of producing derivatives of pyrimidine

专利摘要:
New pyrimidine derivatives of the formula: wherein Z is a group selected from in which R1 and R2 are each hydrogen, alkenyl, ar (lower) alkyl or lower alkyl optionally substituted with epoxy, hydroxy, amino and/or lower alkylamino and R5 is lower alkyl, R' is hydrogen, aryl optionally substituted with lower alkyl, lower alkoxy and/or halogen, or pyridyl optionally substituted with lower alkyl, R4 is hydrogen, lower alkyl or phenyl optionally substituted with lower alkoxy, and Y is =0, =S or =N-R6, in which R6 is lower alkyl; cyclo(lower)alkyl; ar(lower)alkyl optionally substituted with lower alkoxy; N-containing unsaturated heterocyclic group optionally substituted with lower alkyl; or aryl optionally substituted with hydroxy, lower alkyl, halogen or lower alkoxy, in which lower alkoxy substituent may be substituted with epoxy, hydroxy, amino and/or lower alkylamino, provided that Y is =N-R6 when R5 and R4 are each hydrogen, and Y is =S or =N-R6 when R' and R2 are each hyd- rogen or lower alkyl and R5 is phenyl, and pharmaceutically acceptable salts thereof, and processes for preparation thereof nad pharmaceutical composition comprising the same. These derivatives and salts thereof are useful as cardiotonic, antihypertensive agent, cerebrovascularvasodilator and anti-platelet agent.
公开号:SU1436872A3
申请号:SU853892541
申请日:1985-03-28
公开日:1988-11-07
发明作者:Такая Такао；Мурата Масаеси；Ито Киетака
申请人:Фудзисава Фармасьютикал Ко, Лтд (Фирма)；
IPC主号:

专利说明:


This invention relates to a process for the preparation of new pyrimidine derivatives, biologically active compounds that can be used in medicine.
The purpose of the invention is new pyrimidine derivatives with low toxicity and high cardiotonic activity.
Example 1. To a solution of 3,4- -dihydro-6- (3,4-dimethoxyphenyl) -1,3-dimethyl-4-thioxo-2 (1H) -pyrimidinone (1.51 g) in tetrahydrophzfane (150 ml ) methyl iodide (30 ml) is added and the mixture is heated to reflux for 90 minutes. The precipitate is added to 2,4,6-trimethylaniline (6 g) and the mixture is heated at 110-120 ° C for 3 hours. The reaction mixture is washed with a mixture of hexane and diisopropyl ether to remove excess 2,456-trimethylaniline. The resulting precipitate is separated by filtration and then dissolved in chloroform. The solution is washed with an aqueous solution of sodium bicarbonate, dried over magnesium sulphate and evaporated under reduced pressure to give a crude product, which is purified by chromatography on a column of silica gel to obtain 3,4-dihydro-6- (354-dimethoxyphenyl) -1 , 3-dimethyl 4- (2 s, 4,6-three-methylphenyl-amino) -2- (1H) -pyrimindino (1.44 r) i t, pl. 68 - 70 ° C. The resulting compound is recrystallized from a mixture of methanol and water (5: 1) to obtain the target compound in the form of crystals.
T. pl. 96 - 98 ° C.
IR spectrum (Nujol): 1685 ,, 1640, 1590 cm ×
NMR spectrum (CDCl1,}. 6.8 (4H, singlet), 6.7 (1H, singlet), 5.13 (1H, singlet), 3.87 (ZN, singlet), 3.85 (ZN, singlet), 3.57 (ZN, singlet), 3.14 (ZN, singlet), 2.20 (ZN, singlet), 2.00 (6H, singlet).
Example 2. 4- (4-Chloro-2-methyl-phenylimino) 3,4-dihydro-6- (3,4-dimethoxyphenyl) -1, 3-dimethyl-2 (1H) -pyrimidinone (0, 17 g) was prepared according to the procedure of Example 1 from 3,4-dihydro-6 - (3,4-dimethoxyphenyl) -1,3-dimethyl-4 thioxo--2 (1H) -pyrimidinone (g), methyl iodide (4 ml) and 4-chloro-2-methylaniline (0.4 g),
T, pl. 61 IR (Nujol): 1685, 1640,
66 ° C.
1590
cm
0
five
0
five

0
five
0
five
five
NMR spectrum (DMCO-d,} 7.3-6.6 (6H, multiplet), 5.13 (1H, singlet), 3.75 (6H, singlet), 3.22 (ZN, singlet), 3 , 09 (ZN, singlet), 2.05 (ZN, singlet).
Example 3. 3,4-Dihydro-6- - (3,4-dimethoxyphenyl) -1, 3-dimethyl-4- - (-pyridylimine) -2 (1H) -pyrimidinone (i, 1 g) obtained by the method of example t from 3,4-dihydro-6- (3,4-dimethoxyphenyl) -1,3-dimethyl-4-thioxo-2 (1H) -pyrimidinone (1.0 g), methyl iodide (20 ml ) and Z-aG Shnopyridine (4.0 g).
The compound obtained is dissolved in ethyl acetate. A mixture of hydrochloric acid and ethyl acetate is added to the solution. The precipitate is separated by filtration, washed with diisopropyl ether and dried in vacuo to obtain 3,4-dihydro-6- (3,4-dimethoxyphenyl) -1,3-dimethyl-4- (3-pyridylimino) -2 (1H) -pyrimidinone dihydrochloride (1.30 g),
T. pl. 145 - 148 C.
IR (Nujol): 1710, 1610, 1580 cm-.
NMR spectrum (, rf): 9.2-8.6 (ZN, multiplet), 8.30 (1H, double doublet, J 5.5 Hz, 8 Hz), 7.15 (ZN, singlet), 6 , 23 (1H, singlet), 3.93 (3N, singlet), 3.90 (6H, singlet), 3.53 (3N, singlet).
Example 4. 3,4-Dihydro-1,3-dimethyl-6-phenyl-4- (2,4,6-trimethylphenylimino) -2 (1H) -pyrimidinone (0.81 g) obtained by the method of example 1 from 3,4-dihydro-1,3-dimethyl-6-phenyl-4-gioxo-2 (1H) -pyrimide non (1.0 g), methyl iodide (22.7 ml) and 2.4.6 -trimethylaniline (3.6 g).
T. pl. 136 - .139 ° С. ,
IR (Nujol): 1680, 1650.
NMR spectrum (DMCO-dfe, G): 7.40 (5H, multiplet), 6.10 (2H, singlet), 4-, 76 (1H, singlet), 3.46 (ZN, singlet), 3 , 04 (ZN, singlet), 2.13 (ZN, singlet), 1.93 (bN, singlet).
Example 5. 3,4-Dihydro-6- - (3,4-dimethoxyphenyl) -1, 3-dimethyl-4-α-phenylimino-2 (1H) -pyrimidinone (0.64 g) was prepared according to the method of Example 1 of 3 , 4-dihydro-6- (3,4-dimethoxyfennl) -1,3-dimethyl-4-thioxo-2 (1H) -primidinone (1.0 g), - methyl iodide (20 ml) and aniline (3.0 g) 1
T. pl. 60 - 64 ° C
JK-spectrum (Nujol): 1670, 1655, 1590 cm.
NMR (soybean, c): 6.6 - 7.5 (8H, multiplet), 5.50 (1H, singlet), 3.86 (3N, singlet), 3.83 (3N, singlet) , 3.53 (ZN, singlet), 3.16 (ZN, singlet-year),
Example .6. 3,4-Dihydro-6- (3,4-dimethoxyphenyl) -1, 3-dimethyl-4- (3,4,5-trimethoxyphenylimino) -2 (1H) -pyrimidine (0.63 g) was obtained according to the method of example 1 of 3,4-dihydro-6- - (3,4-dimethoxyphenyl) -1, 3-dimethyl-4- -thioxo-2 (1H) -pyrimidinone (1.0 g), methyl iodide (20 ml ) and 3,4,5-trimethoxy-sianiline (3.0 g).
T, pl. 185 - 188 S.. IR spectrum (Nujol): 1680, 1675, 1650 cm- about
NMR spectrum (CDClj, s /): 6.7-6.95 (ZN, multiplet), 6.10 (2H, singlet), 5.60 (1H, singlet), 3.90 (ZN, singlet), 3.87 (ZN, singlet), 3.80 (9H, singlet), 3.52 (ZN, singlet), 3.18 (ZN, singlet).
Example 7. 3,4-Dihydro-6- - (3,4-dimethoxyphenyl) -1, 3-dimesht-4- - (2,4,6-trimethoxyfenstnminko) -2 (1H) - pyrimidinone (1, 19 g) was prepared according to the procedure of Example 1 from 3,4-dihydro-6- - (3,4-dimethoxyphenyl) -1, 3-dimethyl-4- -thioxo-2 (1H) -pyrimidinone (1.0 g), methyl iodide (20 ni) and 2,4,6-trimethoxyaniline (3.20 g). t. Sh1. 173 - 177 ° C.
IR (Nujol): 1680, 1640, 1590.
NMR spectrum (CDC1 J, d): 6.6 - 7.0 (ZN, multiplet), 6.18 (2H5 singlet), 5.26 (1H, singlet), 3.89 (ZN, singlet), 3 , 85 (ZN, singlet), 3.77 (9H, singlet), 3.62 (ZN, singlet).
Example 8. 3,4-Dihydro-6- - (3,4-dimethoxyphenyl) -1, 3-dimethyl-4- - (2,6-dimethylphenylimino) -2 (1 N) -pyrimidinone (0.75 g) obtained according to the method of example 1 from 3,4-dihydro-6- (3,4-dimethoxyphenyl) -1, 3-dimethyl-4-thioxo--2 (1H) -pyrimidinone (1.0 g), methyl iodide (20 ml ) and 2,6-dimethylaniline (2.0 g).
T. Plo 100 - 104 C.
IR spectrum (Nujcl): 1690, 1675, 1640 cm H
NMR spectrum (CDCl1, cf): 6.6 - 7.2, multiplet), 5.15 (1H, singlet) j 3.91 (3N, singlet), 3.88 (3N, si g), 3.65 (ZN, singlet), 3s, 20 (ZN, singlet), 2.10 (6H, singlet).
Example 9. 3,4-Dihydro-6- - (3,4-dimethoxyphensh1) -1, 3-dimethyl-4- - (4-hydroxyphenylimino) -2 (1H) -pyrimidinone (3.05 g) is obtained according to the method of example 1 of 3,4-dihydro-6- (3,4-dimethoxyphenyl) -1, 3-dimethyl-4-thioxo--2 (1H) -pyrimidinone (3.0 g), methyl iodide (60 ml) and 4-hydroxyaniline
0 (5 g).
T. pl. 104 - 108 ° C. IR (Nujol): 1B60, 1640 cm. NMR spectrum (CDC13): 6.82 (3N, singlet), 6.70 (4H, singlet), 3.87
5 (ZN, singlet), 3.84 (ZN, singlet), 3.50 (ZN, singlet), 3.16 (ZN, singlet),
Example 10, 3,4-Digndro-1,3-dimethyl-6- (2,3,4-trimethoxyphenyl) Q -4- (2,4,6-trimethylphenylimino) -2 (1H) - -pyrimidinone (0 , 75 g) obtained by the method of example 1 from 3,4-dihydro-1,3-dimethyl-4-thioxo-6- (2,3,4-trimethoxy-siphenyl) -2 (1H) -pyrimidinone (1, 0 g)
5 methyl iodide (35 ml) and 2,4,6-trimethyl-aniline C, 5 g).
T. nn. 48 - 53 ° C. IR spectrum (Nujol): 1690, 1640, 1600 cm-.
0 NMR spectrum (CDC1 J, f): 6.81 (2H, singlet), 6.73 (1H, doublet, J. 9 Hz), 6.60 (1H, doublet ,. J 9 Hz), 5, 12 (1H, singlet), 3.85 (6H, singlet), 3.80 (ZN, singlet), 3.60 (ZN, singlet), 3.08 (ZN, singlet), 2.22 (ZN, singlet ), 2.04 (6H, singlet),
Example 11. 3,4-Dihydro-1,3-dimethyl-6- (4-methoxyphenyl) -4- (2,4, 6-trimethylphenylimino) -2 (1H) -pyrimi- 0 .dinone (2,) obtained according to the method of example 1 from 3,4-dihydro-1,3-dimethyl-6- (4-methoxyphenyl) -4-thioxo-2 (1H) - -pyrimidinone (2.1 g), methyl iodide (40 ml) and 2,4,6-trimethylennlin 5 (9 ml).
T. 50 - 54 ° C., IR spectrum. (Nujol): 1690, 1650, 1610, 1590 cm.
NMR spectrum (DMCO-4, s /): 2.00 Q (6H, singlet), 2, 16 (ZN, singlet), 3.08 (ZN, singlet), 3.60 (ZN, singlet), 3 , 78 (EG, singlet), 4.88 (1H, singlet), 6.84 (2Hs singlet), 7.00 (2H, doublet, J 9 Gd), 7.27 (2H, g doublet, J 9 Hz ).
Example 12. 3,4-Dihydro-1,3-. -dimethyl-6- (4-methoxy-2-methylphenip) - -4- (2, 4 J 6-trimethylphenylimino) -2 (1H) - -pyrimidinone (1.67 g). obtained by ME5
Example 1 of 3,4-dihydro-1,3-dimethyl-6- (4-methoxy-2-methylphenyl) -4-thioxy-2 (1H) -pyrimidinone (1.5 g) methyl iodide (25 ml ) and 2,4,6-trimethylaniline (4.0 g) "
T. pl. 57 -.
IR (Nujol): 1690, 1650, 1610, 1590 cm-.
NMR spectrum (CDClj, s /): 7.1 - 6.6 (5H, multiplet), 5.08 (1H, singlet) 3.80 (ZN, singlet), 3.61 (ZN, singlet), 3 , 01 (ZN, singlet), 2.22 (ZN, singlet), 2.19 (ZN, singlet), 2.03 (ZN, singlet), 2.01 (ZN, singlet).
Example 13. 3.4 ligidro-6- (3,4-dimethoxyphenyl) -3-methyl-4- (2, 4,6-trimethylphenshtamino) (1H) -pyrimidinone (1.71 g) was obtained according to the method of example 1 of 3,4-dihydro-6- (3,4-dimethoxyphenyl) -3-methyl-4-thioxo-2 (1H) -pyrimidinone (1.80 g), methyl iodide (36 ml) and 2, 4,6-trimethylaniline (5.0 g).
T. pl. .
IR (Nujol): 1685, 164 5s 1600 cm.
NMR spectrum (CDCl1 + CD, OD, cG): 6.7 - 7.2 (5H, multiplet), 5.36 (1H singlet), 3.86 (6H, singlet), 3.50 (3N, singlet ), 2.26 (SN, singlet), 2.03 (6H, singlet).
Example 14. 3,4 Dihydro-6-t (3,4-dimethoxyphenyl) -3 methyl-1-n- -propyl-4- (2 J 4,6-trimetnylphenylimino) -2 (1H) -pyrimidine ( 0.5 g) was prepared according to the procedure of Example 1 from 3,4-di-hydro-6- (3,4-dimethoxyphenyl) -3-methyl-1-n-pspyl-4-thioxo-2 (1H) -pyri - midinone (1.0 g), methyl iodide (20 MP) and 2,4,6-trimethylaniline (3.0 g). T. gsh 44 - 48 ° C.
IR (Nujol): 1685, 1640, 1590 cm-H
NMR spectrum (CBC1e, f): 6.65 - 6.9 (5H, multiplet), 5.07 (TH, singlet) 3.67 (ZN, singlet), 3.83 (ZN, singlet), 3, 57 (ZN, singlet), 3.57 (2H, triplet, J 8 Hz), 2.20 (ZN, singlet years), 2.01 (6H, singlet), 1.3 - 1.9 (2H, multiplet), 0.71 (ZN, triplet, J, 8 Hz).
Example 15. 1-Benzsch1-3,4-di-hydro-6- (3,4-dimethoxyphenyl) -3-methyl-4- (2,4,6-trimethyl-1shlimo) -2 (1H) -pyrimidinone ( 0.9 g) obtained by the method of example 1 from 1 benzyl-3,4-dihydr 0-6- (3,4-dimethoxyphenyl)
0
five
-3-methyl-4-thioxo-2 (1H) -pyrimidine (2.8 g), methyl iodide (41.2 ml) and 2,4,6-trimethylaniline (8.5 ml). .T. square 144-145 s.
IR (Nujol): 1695, 1640, 1600, 1590 cm-4
NMR spectrum (DMCO-dfc, cP): 2.02 (6H, singlet), 2.16 (ZN, singlet), 3.44 (ZN, singlet), 3.52 (ZN, singlet), 3.73 (SN, singlet), 4.85 (2H, singlet), 4.95 (1H, singlet), 6.61-7.40 (YUN, multiplet).
Example 16. 3,4-L; ihydro-1,3-dimethyl-4- (2,4, b-trimethylphenyl-yno) -2 (1H) -pyrimidinone (0.74 g) was obtained by the method of example 1 from 3,4-di-hydro-1,3-dimethyl-4-thioxo-2 (1H) -pyrimidinone (0.74 g), methyl iodide (18 mp) and 2,4,6-trimethylaniline (3.9 g d).
T. pl. 91 -.
IR Spectrum (Nujol); 1680, 1655 cm:.
NMR spectrum (DMCO-a, s /): 1.92 (6H, singlet), 2.20 (ZN, singlet), 3.23 (ZN, singlet), 3.40 (ZN, singlet), 5, 00 (1H, doublet, J 8 Hz), 6.82 (2H., Singlet), 7.10 (1H, doublet, J 8 Hz).
Example 17. 3,4-Dihydro-6- - (3,4-dimethoxyphenyl) -1-methyl-4- (2, 4,6-trimethylphenylimino) -2 (1H) -pyrimidinone (0.82 g) obtained according to the method of example 1 from 3,4-dihydro-6- (3,4-dimethoxyphenyl) -1-methyl-4-thioxo-2 (1H) - -pyrimidinone (1.0 g), methyl iodide (3.5 mp ) and 2,4,6-trimethylaniline (1.51 mp).
T. pl. 233 - 236 ° C.
IR (Nujol): 1635.
NMR spectrum (CDC1 3, CDjOD): 6.55 - 6-, 9 (5E, multiplet), 5.08 (1H, singlet), 3.83 (ZN, skglet), 3.80 (ZN, singlet ), 3.23 (AH, singlet), 2.23 (AH, singlet), 2.17 (6H, singlet).
Example 18 To a solution of 3,4-β-dihydro-6- (3,4-dimethoxyLenyl) -2- -isopropoxy-3-methyl-4-thioxypyrimidine (0.80 g) in tetrahydrofuran (40 ml) is added methyl iodide (10 ml) and the mixture is heated under reflux for 1 hour. After cooling, the precipitates are filtered and washed with tetrahydrofuran. Precipitation and 2,4,6-trimethylaniline (2.0 g) are mixed and heated at a temperature of 120 ° C for 1 hour. The mixture obtained is sequentially washed with an aqueous solution of bicarbon0
0
five
0
five
sodium, ethyl acetate and diisopropyl ether to form 3,4-dihydro-6- (3, A-dimethoxyphenyl) -3-methyl-4- (2,4,6-trimethylphenylimino) -2 (1H) - pyrimidinone (0.54 g).
T. pl. .
IR (Nujol): 1685, 1645, 1600 cm-H
Example 19. To a solution of 3,4-β-dihydro-b- (3,4-DICHlofenshen1) -1,3-dimethyl-4-thioxo-2 (1H) -pyrimidinone (1.0 g) in toluene (100 ml) methlyl iodide (20 ml) is added and the mixture is heated under reflux for 3 hours. An additional 20 ml of methyl iodide is added to the mixture and the mixture is heated under reflux for an additional 5 hours. After cooling, the mixture is cooled at reduced pressure. To the resulting oily residue was added 2,4,6-trimethylaniline (3.0 g) and the mixture was stirred at 120 ° C for 4 hours. The resulting oil was dissolved in ethyl acetate and washed successively with an aqueous solution of sodium wicarboxylate. After drying over magnesium sulfate, the solution is evaporated under reduced pressure. The residue is chromatographed on a silica gel column eluted with chloroform to give 3, 4-dihydr 0-6- (3,4-dichlorophenyl) -1, 3-dimethyl-4- (2,4,6-trimethylphenylimino) -2 (1H) -pyrimidinone (0.56 g).
T. pl. 194 -.
IR apectrum (Nujol): 1700, 1645, 1600 cm-4
NMR spectrum (COCl3, rf): 7.42 (W, doublet, J 8 Hz), 7.28 (1H, doublet, J 2 Hz), 7.02 (1H, double doublet, J 8 Hz, 2 Hz ), 6.80 (2H, broad singlet), 5.10 (1H, singlet), 3.57 (ZN, singlet), 8.10 (ZN, singlet), 2.20 (ZN, singlet), 2, 02 (6H, singlet).
Example 20. To a solution of 3,4- -dihydro-6- (3,4-dimethoxyphenyl) -1- -ethyl-3-methyl-4-thioxo-2 (1H) -pyrimidinone (0.59 g) in tetragndrofuran; (50 ml) methyl iodide (10 ml) was added and the mixture was heated under reflux for 90 minutes. The precipitate is added to 2,4,6-trimethylanstyne (2 g) and the mixture
and then dissolved in chloroform. The solution is washed with an aqueous solution of sodium bicarbonate, dried over magnesium sulphate and reduced under reduced pressure to obtain an unsized product, which is purified on a chromatographic column with silica gel to obtain 3,4-dihydro-6-10 - (3,4-dimethoxyphenyl ) -1-ethyl-3-methyl -4- (2,4,6-trimethylfengshimino) -2 (1H) - -pyrimidinone (0.29 g); m.p. 57 - 61 ° C.
The compound thus obtained is recrystallized from a mixture of ethanol and water (3: 1) to obtain the target compound in the form of crystals with m.p. 116 - 118 C.
IR (Nujol): 1685, 1660, 20 1600 cm-.
NMR spectrum (CDCl1, f): 6.6 - 6.9 (5H, multiplet), 5.07 ClH, singlet) 3.85 (3N, singlet), 3.83 (3N, singlet), 3.80 (2H, quadruplet, J 7 Hz) 25 3.57 (ZN, singlet), 2.20 (ZN, singlet), 2.02 (6H, singlet), 1.12 (ZN, triplet, J 7 Hz).
Example 21. 1,3-Diethyl-3,4- -dihydr-6- (3,4-dimethoxyphenyl) -4-30 (2,4,6-trimethylphenylimino) -2 (1H) -pyrimidinone (0.69 g ) obtained according to the method of example 20 from 1,3-diethyl-3,4-β-dihydro-6- (3,4 -dimethoxyphenyl) -4-β-thioxo-2 (1H) pyrim-urschinone (1.0 g), 25 methyl iodide (40 ml) and 2,4,6-trimethylaniline (3.0 g), except that toluene was used as a solvent instead of tetrahydrofuran.
T. pl. 122 - 124 ° C.
40 IR spectrum (): 1680, 1650, 1605 cm-H
NMR spectrum (CBC1e): 6.85 - 6.9 (5H, multiplet), 5.06 (1H, singlet), 4.32 (2H, quadruplet, J 7 Hz), 45 3.87 (6H, singlet), 3.68 (2H, quadruplet, J 7 Hz), 2.21 (3N, singlet), 2.03 (6H, singlet), 1.38 (3N, triplet J 7 Hz), 1.12 ( ZN, triplet), J 7 Hz).
5Q Example 22. 3,4-Dihydro-1,3-dimethyl-6- (3,4,5-trimethoxyphenip) -4- - (2,4,6-trimethylphenylimino) -2 (1H) - -pyrimidinone (0 , 39 g) of the proceeds according to the method of Example 20 from 3,4-dihydro-1,3nag ewat at 110-120 C 3 h. Reag-gg -dimethyl-4-thioxo-6- (3,4,5-trimethoxyphenyl) 2 (1H) -pyrimidinone (0.59 g), methyl iodide (2.2 ml) and 2,4,6-trimethylaniline (2.1 g).
The mixture is washed with a mixture of hexane and diisoproxyl ether to remove excess 2,4,6-trimethylaniline. The resulting precipitate is filtered off. square 128 - 13GS.
and then dissolved in chloroform. The solution is washed with an aqueous solution of sodium bicarbonate, dried over magnesium sulphate and extruded under reduced pressure to give a crude product, which is purified on a chromatographic column with silica gel to obtain 3,4-dihydro-6-0 - (3,4-dimethoxyphenyl) - 1-ethyl-3-methyl- -4- (2,4,6-trimethyl-pheneshgimino) -2 (1H) - -pyrimidinone (0.29 g); m.p. 57 - 61 ° C.
The compound thus obtained is recrystallized from a mixture of ethanol and water (3: 1) to obtain the target compound in the form of crystals with m.p. 116 - 118 C.
IR (Nujol): 1685, 1660, 0 1600 cm-.
NMR spectrum (CDCl1, f): 6.6 - 6.9 (5H, multiplet), 5.07 ClH, singlet), 3.85 (3N, singlet), 3.83 (3N, singlet), 3, 80 (2H, quadruplet, J 7 Hz), 5 3.57 (ZN, singlet), 2.20 (ZN, singlet), 2.02 (6H, singlet), 1.12 (ZN, triplet, J 7 Hz ).
Example 21. 1,3-Diethyl-3,4- -dihydr-6- (3,4-dimethoxyphenyl) -4-0 (2,4,6-trimethylphenylimino) -2 (1H) -pyrimidinone (0.69 g ) obtained according to the method of example 20 from 1,3-diethyl-3,4- -dihydro-6- (3,4 -dimethoxyphenyl) -4- -thioxo-2 (1H) -pyrimpechine (1.0 g), 5 methyl iodide (40 ml) and 2,4,6-trimethylf aniline (3.0 g), except that toluene was used as a solvent instead of tetrahydrofuran.
T. pl. 122 - 124 ° C.
0 IR spectrum (): 1680, 1650, 1605 cm-H
NMR spectrum (CBC1e): 6.85 - 6.9 (5H, multiplet), 5.06 (1H, singlet), 4.32 (2H, quadruplet, J 7 Hz), 5 3.87 (6H, singlet), 3.68 (2H, quadruplet, J 7 Hz), 2.21 (3N, singlet), 2.03 (6H, singlet), 1.38 (3N, triplet J 7 Hz), 1.12 ( ZN, triplet), J 7 Hz).
Q Example 22. 3,4-Dihydro-1,3-dimethyl-6- (3,4,5-trimethoxyphenip) -4- - (2,4,6-trimethylphenylimino) -2 (1H) - -pyrimidinone (0 , 39 g) of the receipt according to the method of Example 20 of 3,4-dihydro-1,3T. square 128 - 13GS.

1A36872
ten
IR Spectrum (Nujol): 16750.1640 cm. NMR spectrum (DMCO-d,): 1.97 (6H, singlet), 2.16 (ZN, singlet), 3.07 (ZN, singlet), 3.46 (ZN, singlet), 3.66 (ZN, singlet), 3.73 (6H,
, singleton), 4.88 (1H, singlet), 6.67
: (2H, singlet), 6.80 (2H, singlet).
Example 23. To a mixture of 3,4-dihydrb-6- (3., 4-dimethoxyphenyl) -3-methyl-Q-4-thioxo-2 (1H) -pyrimidinone (2.7 g) in tetrahydrofuran (24 mp) methyl iodide (12 ml) was added and the mixture was heated under reflux for 3 hours. Precipitate
is filtered off and added to g Fe (Nihonkohden, RIC - 4008). 2,4,6-trimethylaniline (4.1 ml). Mixture Test compounds dissolved
stirred at 5 hours and hexane (10 ml) was added to it. The precipitate is separated by filtration and washed after: with hexane, with an aqueous solution of 2 ° vein. Indicators after administration
: sodium hydroxide, ethanol, and diisosium are compared with
propyl ether to obtain 3,4 before dosing.
: -dihydro-6- (3,4-dimethoxyphenyl) -3-Test results given
-methyl-4- (2,4,6-trimethylphenylimino) -in table. 1, presented in percent
25 maximum change of values
using an analog computer. In order to measure the somatic blood pressure, the left femoral artery is quenched, and the blood pressure pulsation is used to activate a heart rate monitor. Another catheter is inserted into the venous cavity through the right femoral vein and medication is injected through it. Somatic blood pressure, pressure in the left ventricle, dp / dtMWKC values and heart rate are simultaneously recorded in polygon with distilled water (0.2 MPa / kg) or in dimethyl sulfoxide (0.04 ml / kg) and administered as a BI injection into the femoral
-2 (1H) -pyrimidinone (2.75 g).
IR (Nujol): 1685, 1645, 1600 cm-; Example 24. 3,4-Dihydro-6- (3,4-dimethoxyphenyl) -4- (2,456-tri-I methylfenschmNo) -2 (1H) -pyrimidinone I (0.62 g) was prepared by the method of Example I 1 from 354-dihydro-6- (354-dimethoxy-1-nyl) 4-thioxo-2 (1H) -pyrimidinone. (0.6 g), methyl iodide (3 ml) and 2,4,6-trimethylaniline (3 mp), T. pl. 258 - 261 ° С. IR spectrum (Nujol): 1640 cm, NMR spectrum (CDC1.3, cf): 6.5 - (5H, multiplet), 5.32 (1H, singlet), 3.83 (ZN, singlet) e 3 , 77 (ZN, sing-- years), 2.26 (ZN, singlet) ,, 2.14 (6H, singlet).
Biological tests of pyrimidine derivatives obtained under the conditions of the proposed method were carried out.
Test method (cardiotonic activity).
Outbred dogs of both sexes are anesthetized with sodium pentabarbigal (35 mg / kg i.v.) Animals are not stimulated by breathing. The left carotid artery is isolated and a catheter (VSCr, 8F) filled with heparin-containing saline is introduced into the left ventricle. A catheter is connected to a pressure transducer (Nihonkohden, MPVO-5A) for measuring pressure in the left ventricle, from which dp / dt air is obtained.
thirty
dp / dt (mi dp / dt), which is calculated by the following formula:
MI dp / dt (%)
 . after bbefle
R Mikes. Until BbeAvni
0x100.
Determination of acute toxicity with
Test Method
The test solution prepared was described as follows: 1 in the following way, injected 5 female and 5 female mice (1CL5ICR), as well as 5 male and 5 female rats (ICLsSD) regardless of gender for each dosage. After a prescribed dose has been administered, the animals are observed for 14 days. Values are determined using the Litfeld – Wilcoxon method or the Behrens – Corbert method.
45
The test results are given in
tab. one.
Table
50
55
ABOUT,
68
98
1A36872
ten
using an analog computer. In order to measure the somatic blood pressure, the left femoral artery is quenched, and the blood pressure pulsation is used to activate a heart rate monitor. Another catheter is inserted into the venous cavity through the right femoral vein and medication is injected through it. Somatic blood pressure, left ventricular pressure, dp / dtMWKC values and heart rate are simultaneously recorded on a polygraph (Nihonkohden, RIC - 4008). Test compounds are dissolved
in distilled water (0.2 ppm / kg) or dimethyl sulfoxide (0.04 ml / kg) and inject BI in the femoral
maximum change of values
dp / dt (mi dp / dt), which is calculated by the following formula:
MI dp / dt (%)
 . after bbefle
R Mikes. Until BbeAvni
0x100.
Determination of acute toxicity with
Test Method
The test solution prepared was described as follows: 1, in the following way, administered to 5 female and 5 female mice (1CL5ICR), as well as 5 male and 5 female rats (ICLsSD) regardless of gender for each dosage. After a prescribed dose has been administered, the animals are observed for 14 days. Values are determined using the Litfeld – Wilcoxon method or the Behrens – Corbert method.

The test results are given in
tab. one.
Table
ABOUT,
68
98
111436872
Continuation of table 1
12 Continuation of table 1
13
1436872
14 Continued tabl. 2
At this dosage level, deaths are not
marked.
I The tests carried out show that the compounds obtained under the conditions of the proposed method have low toxicity and higher cardiotonic activity than amrinone and phenoximone.

权利要求:
Claims (1)
[1]
 Claim I Investigation method of pyri-midin derivatives of general formula
° R,
where Rj has the specified s
   - RI-N-N-RI
or
R
where R, is hydrogen or C -C-alkyl; RJ - hydroxy, -alkyl or
benzyl;
RJ-phenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, 4-ztoxy-3-methoxyphenyl, 3,4,5-trimethoxyphenyl, 283,4-trimethoxyphenyl, 3,4-dichlorophenyl, 4 -methoxy-2-methylphenyl or 2-FTOR-4,5-dimethoxyphenylJR / - pyridyl, phenyl, 4-hydroxyphenyl, 2,4,6-trimethylphenyl, 2,4,6-trimethoxyphenyl, 3,4,5 -tri-methyloxyphenyl, 2,6-dimethylphenyl or 4-chloro-2-mettsphenyl,
or their salts, distinguished by the fact that compounds of general formula Z X.
ORs
T 7J-Ri
where R ,, and Rx have j specified
RJ-C-Cj-alkyl,
35 mi general formulas are introduced
R - NH,
where R takes the indicated or their salts, the process in rahidrofuran., toluene in methyl iodide with 90 division products in its own or in the form of salt.
45
Priority to m
by
R
U,
25.03.83 when RI is C, gQ R1 is Ci-Cj alkyl, RI is f-dimethoxyphenyl; Rt pi-trimethylphenyl, 4-chloro-2
06.06.83 with R - j - C - C} alkyl; R 3 3 gg siphenyl, 3,4J5-trimethox 2,4,6-trimethylphenyl
10/18/83 when RI is hydrogen, C, -C3-alkyl RJ-4-methoxyphenyl, 3.4
where Rj has the indicated meanings
   - RI-N-N-RI
whether
ORs
T 7J-Ri
where R ,, and Rx have the indicated values j
RJ-C-Cj-alkyl,
enter into interaction with compounds of the general formula
R - NH,
where R takes the indicated values, or their salts, the process is carried out in tetrahydrofuran., toluene in the presence of methyl iodide at 90120 ° C with the release of products in free form or in the form of a salt.
Priority to m
by recognition 25, 03.83 with RI - C, C-alkyl; R1 is Ci-Cj-alkyl, RI phenyl 3,4-. dimethoxyphenyl; Rt pyridyl, 2,456-trimethylphenyl, 4-chloro-2-methylphenyl;
06/07/83 with R - C C-alkyl; R j - C —C} alkyl; R 3 3,4-dimethoxyphenyl, 3,4J5-trimethoxyphenyl; R 2,4,6-trimethylphenyl
10/18/83 with RI - C C-alkyl; R is hydrogen, C, -Cz-alkyl5 benzyl RJ-4-methoxyphenyl, 3,4-dimethoxy. With 1436872
15.6
phenyl, 2,3,4-trimethoxyphenyl, 2,4-trimethylphenyl, 2,4,6-trimethoxyphe-α-dichloroyl, 4-methoxy-2-methylphenyl, 3,4,5-trimethoxyphenyl, 2,6- dinyl; Rt is phenyl, 4-oxyphenyl, 2,4,6-methylphenyl.

类似技术:

---

公开号 | 公开日 | 专利标题

---

SU1436872A3|1988-11-07|Method of producing derivatives of pyrimidine

---

SU1396963A3|1988-05-15|Method of producing derivatives of dihydropyridazinone

---

EP1102768B1|2005-12-21|Substituted pyrazole derivatives condensed with six-membered heterocyclic rings

---

EP1102767B1|2005-11-02|Substituted pyrazole derivatives

---

EP1339714B1|2006-10-18|Novel sulfonamide-substituted pyrazolopyridine derivatives

---

US3995039A|1976-11-30|Pyrazolo [1,5-a] [1,3,5] triazines

---

DE19834045A1|2000-02-03| -1- | -1H-pyrazolo [3,4-b] pyridine

---

US4501745A|1985-02-26|Anxiolytic imidazo[1,2-a]pyridine derivatives

---

US4613603A|1986-09-23|Compounds with a nitrogen-containing heterocyclic nucleus, and drugs in which they are present

---

EP0096517A2|1983-12-21|Aryl pyrazinones

---

IE55904B1|1991-02-14|Dihydropyridines

---

US4937242A|1990-06-26|1,4-dihydropyridine derivatives and pharmaceutical composition thereof

---

JP2544183B2|1996-10-16|Novel parabanic acid derivative and pharmaceutical composition containing the compound as an active ingredient

---

US4508718A|1985-04-02|Cardiotonic and antihypertensive oxadiazinone compounds

---

US4661484A|1987-04-28|Pyridazinone derivatives and salts thereof as cardiac stimulants

---

FR2631827A1|1989-12-01|NOVEL | ARYL-5 TETRAZOLE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND THERAPEUTIC USE THEREOF

---

EP0145019B1|1990-11-07|Pyridazinone derivatives and salts thereof

---

EP0134928A1|1985-03-27|Imidazo[1,5-a]pyrimidine derivatives and process for their preparation

---

EP0124090A1|1984-11-07|5-Acyl-2-|-pyridinones

---

EP0132817B1|1988-09-21|Benzothiazolone derivatives, processes for preparation thereof and pharmaceutical compositions comprising the same

---

EP0139993A2|1985-05-08|Quinazoline derivatives, process for their preparation, and medicaments containing these compounds

---

ES2519441T3|2014-11-07|Compounds to treat impotence

---

US4822797A|1989-04-18|Piperazinyl carbonyl phenyl pyridazinone derivatives useful as cardiotonics

---

US4430342A|1984-02-07|N-Acyl-3-[4-|piperazin-1-yl]-sydnonimine compound, process for prodction thereof, and use thereof

---

US5215987A|1993-06-01|Substituted benzhydryl 2-hydroxypropyl piperazine derivatives

同族专利:

---

公开号 | 公开日

---

US4746664A|1988-05-24|

---

EP0123402A3|1985-09-18|

---

US4824851A|1989-04-25|

---

KR840008333A|1984-12-14|

---

NO841168L|1984-09-26|

---

DK160492B|1991-03-18|

---

FI841128A0|1984-03-21|

---

CA1256107A|1989-06-20|

---

GR81758B|1984-12-12|

---

US4612376A|1986-09-16|

---

SU1349698A3|1987-10-30|

---

ES538190A0|1985-11-01|

---

FI841128A|1984-09-26|

---

DE3473875D1|1988-10-13|

---

EP0123402A2|1984-10-31|

---

PH22022A|1988-05-13|

---

HU195195B|1988-04-28|

---

ES8601922A1|1985-11-01|

---

DK166884A|1984-09-26|

---

EP0123402B1|1988-09-07|

---

ES530916A0|1985-06-16|

---

ES8505972A1|1985-06-16|

---

DK166884D0|1984-03-23|

---

DK160492C|1991-08-26|

引用文献:

---

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

---

---

GB1296371A|1969-02-26|1972-11-15|

---

AU1108070A|1969-03-06|1971-08-12|Imperial Chemical Industries Limited|Pyrimidine derivatives|

---

GB1336138A|1969-12-10|1973-11-07|Ici Ltd|Process for the production of pyrimidine derivatives|

---

US3923807A|1973-09-10|1975-12-02|Takeda Chemical Industries Ltd|6-Aminouracil derivatives|

---

JPS5053381A|1973-09-20|1975-05-12|

---

US4208366A|1978-10-31|1980-06-17|E. I. Du Pont De Nemours And Company|Process for preparing a nonwoven web|

---

DE2847693A1|1978-11-03|1980-05-22|Hoechst Ag|METHOD FOR PRODUCING PYRIMIDO- -ISOCHINOLIN-2-ONES|

---

US4612376A|1983-03-25|1986-09-16|Fujisawa Pharmaceutical Co., Ltd.|Substituted-3,4-dihydro-4--2-pyrimidones useful as cardiotonic, antihypertensive, cerebrovascular vasodilator and anti-platelet agent|US4612376A|1983-03-25|1986-09-16|Fujisawa Pharmaceutical Co., Ltd.|Substituted-3,4-dihydro-4--2-pyrimidones useful as cardiotonic, antihypertensive, cerebrovascular vasodilator and anti-platelet agent|

---

US4598149A|1984-03-02|1986-07-01|Merck & Co., Inc.|3-amino-2-hydroxypropyl of pyrimidin-4-one useful as antihypertensive, cardioprotective, antiarrythmic, and antianginal agents|

---

US4649142A|1984-06-25|1987-03-10|Fujisawa Pharmaceutical Co., Ltd.|3,4-dihydro-1,3-disubstituted-6--2-pyrimidinone useful as cardiotonic agent and anti-allergic agent|

---

US4708958A|1986-09-24|1987-11-24|G. D. Searle & Co.|6--4-iminopyrimidinones useful as hypotensive agents|

---

US5521315A|1993-01-12|1996-05-28|Cell Therapeutics, Inc.|Olefin substituted long chain compounds|

---

IT1270122B|1994-10-04|1997-04-28|Ist Superiore Sanita|6-BENZYL-4-OXYPYRIMIDIN REPLACED, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM|

---

US6244121B1|1998-03-06|2001-06-12|Applied Materials, Inc.|Sensor device for non-intrusive diagnosis of a semiconductor processing system|

---

MXPA05007485A|2003-01-14|2006-01-30|Arena Pharm Inc|1,2,3-trisubstituted aryl and heteroaryl derivatives as modulators of metabolism and the prpphylaxis and treatment of disorders related thereto such as diabetes and hyperglycemia.|

---

AR045697A1|2003-07-14|2005-11-09|Arena Pharm Inc|ARIL AND HETEROARIL FUSIONATED DERIVATIVES AS MODULATORS OF METABOLISM AND THE PREVENTION AND TREATMENT OF DISORDERS RELATED TO THE SAME|

---

DOP2006000009A|2005-01-13|2006-08-15|Arena Pharm Inc|PROCEDURE TO PREPARE ETERES OF PIRAZOLO [3,4-D] PYRIMIDINE|

---

JP5113752B2|2005-08-22|2013-01-09|メリオール・ファーマスーティカルズ・ワン・インコーポレイテッド|Methods and formulations for modulating the activity of LYN kinase and treating related diseases|

---

NZ579227A|2007-02-20|2012-11-30|Melior Pharmaceuticals I Inc|Methods of identifying activators of lyn kinase|

---

CA2693809A1|2007-07-23|2009-01-29|Melior Discovery, Inc.|Methods of activating irs-1 and akt|

---

US8552184B2|2008-07-03|2013-10-08|Melior Pharmaceuticals I, Inc.|Compounds and methods for treating disorders related to glucose metabolism|

---

EP2462123B1|2009-08-04|2013-10-02|Merck Sharp & Dohme Corp.|4,5,6-trisubstituted pyrimidine derivatives as factor ixa inhibitors|

---

CN103539791B|2010-09-22|2017-01-11|艾尼纳制药公司|Modulators of the GPR119 receptor and the treatment of disorders related thereto|

---

US10183949B2|2014-08-29|2019-01-22|The University Of Tokyo|Pyrimidinone derivative having autotaxin-inhibitory activity|

---

WO2016031987A1|2014-08-29|2016-03-03|国立大学法人東京大学|Pyrimidinone derivative having autotaxin-inhibitory activity|

---

CN107405332A|2015-01-06|2017-11-28|艾尼纳制药公司|Treatment and S1P1The method of receptor related illness|

---

CA3059432A1|2017-04-10|2018-10-18|Melior Pharmaceuticals I, Inc.|Treatment of adipocytes|

---

CN109053589A|2018-09-30|2018-12-21|浙江师范大学|The preparation method of 4- imido grpup tetrahydropyrimidin-2-ones class compound|

法律状态:

优先权:

---

申请号 | 申请日 | 专利标题

---

GB838308290A|GB8308290D0|1983-03-25|1983-03-25|Pyrimidinone derivatives|

---

GB838315542A|GB8315542D0|1983-06-07|1983-06-07|Pyrimidinone derivatives|

---

GB838327859A|GB8327859D0|1983-10-18|1983-10-18|Pyrimidine derivatives|

---