Method of producing derivatives of quinazoline or their salts

专利摘要:
A compound of the formula: …<CHEM>… in which… R<1> and R<2> are each hydrogen, halogen, lower alkoxy or halo(lower)alkyl,… R<3> is aryl or ar(lower)alkyl, both of which may have one or more suitable substituent(s), or heterocyclic(lower)alkyl,… R<4> is carboxy or protected carboxy,… A is oxygen or sulfur atom,… Y is carbonyl, thiocarbonyl or sulfonyl and… Z is lower alkylene,… and pharmaceutically acceptable salts thereof, processes for their preparation and pharmaceutical compositions comprising them in admixture with pharmaceutically acceptable carriers.
公开号:SU1588283A3
申请号:SU864028362
申请日:1986-10-03
公开日:1990-08-23
发明作者:Хасимото Масаси；Оку Теруо；Ито Есикуно；Намики Такаюки；Савада Козо；Касахара Чиеси；Баба Юкихиза
申请人:Фудзисава Фармасьютикал Ко, Лтд (Фирма)；
IPC主号:

专利说明:

ethyl acetate. The extract is washed with brine, dried and evaporated. The product thus obtained is purified, recrystallized from diisopropyl ether, to obtain 1.075 g of 2-C3- (3,4-dichlorobenzyl) -1,2,3,4-tetrahydro-2,4-dioxoquinazoline- 1-yl acetic
acid. M.p. 225-227 C.
IR spectrum (nudzhol), cm: 1695, 1650, 1600.
NMR spectrum (DMCO deuterated), m, d: 4.88 (2H, singlet); 5.13 (2H, singlet); 7.17-8.20 (7H, multiplet).
2. (4-Bromo-2-fluorobenzyl) -; 1, 2,3,4-tetrahydro-2,4-dioxo: schnazolin-1-yl acetic acid. M.p. 208210 ° C.
IR spectrum (nujol), cm -1: 1730,
1700, 1660, 1610.
NMR spectrum (DMCO deuterated), MD: 4.90 (2H, singlet); 5.17 (2H, singlet); 6.9-8.1 (7H, multiplet).
3.2- (3-Benzyl-1,2,3,4-tetrahydro2, 4-dioxoquinazolin-1-yl) acetic acid. M.p. 222-223 C.
IR spectrum (nudzhol), cm: 1725, 1700, 1655, 1605, 1480.
NMR spectrum (DMCO deuterated), ppm: 4.87 (2H, singlet); 5.15 (2H, singlet) i 7.17-8.23 (9H, multiplet).
4. (3,4-Dichlorophenyl) -1,2,3,4-tetrahydro-2,4-dioxoquinazolin-1-yl} - acetic acid. M.p. 268 C.
IR spectrum (nudzhol), cm: 1730, 1720, 1670, 1640, 1610. „
NMR spectrum (DMCO-deuterated). M.D.: 4.88 (2H, singlet); 7.18-8.17
(7H, multiplet).
5. 2-СЗ- (3,4-DichlorobenzSH1) -1,2,3, 4-tetrahydro-2,4-dioxoquinazolin-1-yl propionic acid. M.p. 93 C.
IR spectrum (nudzhol), cm: 1700, 1655, 1605.
NMR spectrum (deuterochloroform), MD: 1.70 (3N, doublet, J = 7 Hz); 5.15 (2H, singlet), 5.38 (1Y, quartet, J 7 Hz) 7.00-8.37 (7H, multiplet).
5 (3,4-Dichlorobenzyl) -1, 2.3,
4-tetrahydro-2-oxo-4-thioxoquinazo-LIN-1-IL acetic acid. M.p. 253.5-254.5 S.
IR spectrum (nudzhol), cm: 1705, 1680, 1660, 1600, 1585.
NMR spectrum (DMCO deuterated), M.D .: 4.95 (2H, singlet) i 5.80 (2H, singlet), 7.20-8.70 (7H, multiplet).
0
five
0
five
Q

d
,
45
50
55
7.2-C3- (4-Chlorobenzyl) -1,2,3,4-tetrahydro-2,4-dioxoquinazolin-1-yl JyK-hydrochloric acid. M.p. 229-230 s.
IR spectrum (nudzhol), cm: 1725, 1705, 1660, 1600, 1480.
NMR spectrum (DMCO deuterated), MD: 4.90 (2H, singlet); 5.13 (2H, singlet) 7.23-8.23 (8H, multiplet).
8. (2,6-Ddchlorobenzyl) -1,2,3, 4-tetrahydro-2,4-dioxoquinazolin-1-yl acetic acid. M.p. 273-275 C.
IR spectrum (nudzhol), cm: 1720, 1660, 1605, 1475.
NMR spectrum (DMCO deuterated), MD: 4.85 (2H, singlet); 5.40 (2H,. Singlet); 7.07-8.13 (7H, multiplet).
9. (3,5-Dlchlorobenzyl) -1, 2,3, 4-tetrahydro-2,4-dioxoquinazolin-1-yl acetic acid. M.p. 212-213 C.
, IR spectrum (nudzhol), cm: 1740, 1720, 1690, 1635, 1605, 1560, 1480.
NMR spectrum (DMCO deuterated), m-d: 4.88 (2H, singlet), 5.13 (2H, singlet); 7.13-8.20 (7H, multiplet).
10. (2,4-D chlorobensyl) -1, 2, 3,4-tetrahydro-2, 4-dioxoquinases olin-1-yl acetic acid. M.p. 223 C.
IR spectrum (nudzhol), cm: 1720, 1675, 1615.
NMR spectrum (DMCO deuterated), M.D .: 4.90 (2H, singlet), 5.18 (2H, singlet) 5 7.00-8.15 (7H, multiplet).
11. (3,5-Dichlorobenzyl) -1,2, 3,4-tetrahydro-2,4-dioxoquinazolin-1-yl-Zacetic acid. M.p. 207 C.
IR spectrum (nudzhol), cm 1710,
1665, 1605.
NMR spectrum (DMCO deuterated), M.D.: 4.90 (2H, singlet), 5.20 (2H, singlet); 7.09-8.17 (7H, singlet).
12., 2,3,4-Tetrahydro-3- (4-methoxybenzyl) -2,4-dioxoquinazolin-1-yl acetic acid. M.p. 213-215 C.
IiK spectrum (nudzhol), cm: 1720, 1700, 1660, 1600, 1480.
 NMR spectrum (DMCO deuterated) M.D.: 3.70 (3N, singlet); 4.88 (2H, singlet) -, 5.08 (2H, singlet); 6.90 (2H, doublet, J 6 Hz); 7.30 (2H, doublet, J 6 Hz); 7.22-8.22 (4H, multiplet).
 13., 2,3,4-Tetrahydro-3- (1-naphthalmethyl) -2,4-dioxoquinazolin-1-yl acetic acid. M.p. 216-218 C.
IR Spectrum (Nujol), 1705, 1660, 1605.
NMR spectrum (DMCO deuterated), MD: 4.93 (2H, singlet), 5.67 (2H,
51588283
singlet); 7.03-8.40 (11H, multiplet), 13.20 (1H, broad singlet).
14. 2,3,3-Tetrahydro-2,4-dioxo-3- (2-pyridylmethyl) quinazolin-1-yl acetic acid. M.p. 220-223 C.
IR spectrum (nudzhol), cm-: 1710, 1660, 1610.
NMR spectrum (DMCO deuterated) M.D.: 4.90 (2H, singlet)} 5.27 (2H, singlet) J 7.15-8.55 (8H, multiplet)
15.2-p- (4-Bromo-2-ftrrbenzyl) 1, 2,3,4-tetrahydro-7-methoxy-2,4-dioxoquinazolin-1-yl acetic acid. M.p. 222-223 0.
IR spectrum (nudzhol), cm -: 1715, 1660, 1620.
NMR spectrum (DMCO deuterated) ppm: 3.88 (EF, singlet); 4.88 (2H, singlet); 5.12 (2H, singlet); 6.83-8.07 SBN, multiplet).
16. (4-Bromo-2-fluorobenzyl) 1, 2,3,4-tetrahydro-6-methoxy-2,4-dioxoquinazolin-1-yl acetic acid. M.p. 224-226.C.
IR (Nujol), 1740, 1690, 1640, 1500, 1480.
NMR spectrum (DMCO deuterated) M.D.: 3.83 (ZN, singlet) -, 4.87 (2H, singlet); 5.17 (2H, singlet), - 6.87 - 7.73 (6H, multiplet).
17. (4-Bromo-2-, fluorobenzyl) -6-chloro-1,2,3,4-tetrahydro-2,4-dioxoquinosin-1-yl acetic acid. M.p. 238-239 ° C.
IR spectrum (nudzhol), cm-: 1725, 1710 (shoulder), 1665, 1605.
NMR spectrum (DMCO deuterated), MD: 4.88 (2H, singlet); 5.15 (2H, singlet) -, 7.05-8.12 (6H, multiplet).
18. (3,4-Dichlorobenzyl) -3,4-DIGIDRO-3-OXO-2H-1,2,4-benzothiadiazin-4-yl acetic acid 1,1-dioxide m.p. 190 C.
IR spectrum (nudzhol), cm: 1720, 1690, 1660.
NMR spectrum (DMCO deuterated), MD: 3.98 (2H, singlet); 4.90 (2H, singlet) 7.20-8.07 (7H, multiplet).
19.2-H- (2-Fluoro-4-iodobenzsh1) 1, 2,3,4-tetrahydro-2,4-dioxoh nasolin-1-yl acetic acid. T. Gsh. 217 ° C.
IR spectrum (nudzhol), cm-: 1765, 1705, 1645, 1605, 1480.
NMR spectrum (DMCO deuterated), MD: 4.87 (2H, singlet); 5.13 (2H, singlet) i 6.77-8.23 (7H, -multiplet).
8283
,
20. (4-Chloro-2-fluorobenzyl) - 1,2,3,4-tetrahydro-2,4-dioxoquinazolin-1-yl acetic acid. M.p.
2.15 ° C.
thirty
0
15
20
NMR spectrum (DMCO deuterated), MD: 4.88 (2H, singlet); 5.18 (2H, singlet); 7.12-8.22 (7H, multiplet).
21. (4-Erom-3-chlorobenzsh1) - 10 1 2,3, 4-heterrahydro-2,4-dioxoquinazolin-1-yl acetic acid. M.p. 233- 234 ° C.
IR spectrum (nudzhol), cm-: 1696, 1680, 1600, 1470.
NMR spectrum (DMCO deuterated), MD: 4.93 (2H, singlet) - 5.17 (2H, singlet), 7.05-8.25 (7H, multiplet) .22. (2.3 -Dichloro-benzyl) -1,2, 3,4-tetrahydro-2,4-dioxoquinazolin-1-yl acetic acid. M.p. .
IR spectrum (nudzhol), cm-: 1720, 1700, 1660, 1600, 1480.
NMR spectrum (DKCO deuterated), MD: 4.93 (2H, singlet), 5.27 (2H, singlet); 6.83-8.23 (7H, multiplet).
23., 2,3,4-Tetrahydro-3- (4-methylbenzyl) -2,4-dioxoquinazolin-1-yl} acetic acid. M.p. 223-224 s.
IR spectrum Snudzhol), cm-: 1725, 1700, 1655, 1605, 1480.
NMR spectrum (DMCO deuterated), MD: 2.27 (3N, singlet); 4.88 (2H, singlet); 5.10 (2H, singlet); 6.97 - 8.20 (8H, multiplet),
24. (4-Chloro-3-methoxybenzyl) - 1,2,3,4-tetrahydro-2,4-dioxoquinazolin-1 -yl acetic acid. M.p.
l g / u l
five
0
5 1
184 C.
IR spectrum (nudzhol), cm-: 1725, 1700, 1650, 1610.
NMR spectrum (DMCO deuterated), MD: 3.81 (G, singlet), 4.92 (2H, singlet); 5.18 (2H, singlet); 6.78 - 8.18 (7H, multiplet).
25. (3-Chloro-4-methoxybenzyl) - 1,2,3,4-tetrahydro-2,4-dioxoquinazolin-1 -yl acetic acid. M.p. 198 C.
IR spectrum (nudzhol), cm-: 1740, 1695, 1640, 1605.
NMR spectrum (DMCO deuterated), MD: 3.83 (EH, singlet) 4.90 (2H, singlet); 5.08 (2H, singlet); 6.99 - 8.15 (7H, multiplet).
26. (4-Bromo-2-fluorobenzyl) -152,3,4-tetrahydro-8-methoxy-2,4-dioxoquinazolin-1 -yl acetic acid. M.p. 204-206 0.
IR spectrum (nudzhol), cm: 1730,; 700, 1660, 1600.
NMR spectrum (DMCO deuterated), D: 3.83 (EF, singlet); 5.00 (2H, inglet) i 5.15 (2H, singlet); 7.13-, 80 (6H, multistit).
27., 2,3,4-Tetrapidpo-2,4-dico-3 (2-thienyl-methyl) -phenazole-1-yl; • acetic acid. M.p. 248-250 С Q
(decomposed). .
IR spectrum (nudzhol), cm-: 1725, 1700, -1655, 1605.
NMR spectrum (DMCO deuterated), MD: 4.88 (2H, singlet); 5.28 (2H, 15 singlet); 6.87-8.23 (7H, multiplet); 12.67 (1H, broad singlet).
28., 2,3,4-Tetrapidpo-3- (2-naphthylmethyl)-2,4-di-toxy-xinazolin-1-yl-cyclic acid. M.p. 183-185 p. 20
NMR spectrum (DMCO deuterated), MD: 4.92 (2H, singlet); 5.33 (2H, singlet); 7.23-8.23 (11H, multiplet).
29.2- 3- (4-Bromo-2-fluorobenzyl) -5-chloro-1,2,3,4-tetrahydro-2,4-dioxoxy-25 nasolin-1-yl acetic acid. M.p.
217-218 C.
IR spectrum (nudzhol), cm: 1725,
1700, 1660, 1590.
30 .. (4-Bromo-2-fluorobenzyl) - 30 1, 2,3,4-tetrahydro-5-methoxy-2,4-dioxoquinazolin-1-yl acetic acid.
M.p. 253-255 ° C.
IR spectrum (nudzhol), cm: 1735, 1700, 1640, 1600.35
NMR spectrum (DMCO deuterium, level), MJ: 3.83 (3N, singlet) j 4.83 (2H, singlet) J 5.08 (2H, singlet); 6.80 - 7.80 (6H, multiplet).
Example 2. A mixture of ethyl Q ester of 2-C3- (4-bromo-2-fluorobenzyl) -7-chloro-1, 2,3,4-tetrahydro-2,4-dioxoquinazin-1-yl acetic acid (249 g), and 795 ml of aqueous 1N. a solution of sodium hydroxide in 1.6 liters of methanol; Kip - 45 tons with reflux for 30 minutes with stirring. The solvent is evaporated, the residue is dissolved in hot water (5 L). The aqueous solution is poured into 3 l of ice-cooled 0.5 n. d of hydrochloric acid. The precipitate is filtered off and recrystallized from a mixture of 6 l of ethanol and 3 l of water; 198 g (4-bromo-2-fluorobenzyl) -7-chloro-1,2,3,4-tetrahydro- 2,4-dioxocinazolin-1-yl acetic acid. M.p. 223-224 S.
IR spectrum (nudzhol) .cm -: 1720, 1700, 1660, 1600.

NMR spectrum (DMCO deuterated; MD: 4.88 (2H, singlet) 5, 12 (2H, singlet); 7.05-8.12 (6H, multiplet). Example 3. Ethyl ether solution ( 4-bromo-2-fluorobenzyl) -7-chloro-1, 2, 3,4-tetrahydro-2,4-dioxoxy-nazolin-1-yl 3 cyclic acid (69 g) and 191 ml of aqueous 1N hydroxide solution sodium in 350 ml of ethanol is stirred for 3 hours at 60 ° C. After cooling, the precipitate is filtered, washed with water and dried over phosphorus pentoxide. After recrystallization from 39 ml of water, 39.2 g of sodium salt are obtained (4- bromo-2- fluorobenzyl) -7-chloro-1,2,3,4-tetrahydro-2, 4-dioxoquinazolin-1-ylJ acetic acid. Mp above 300 ° C.
IR spectrum (nudzhol), cm-: 3500, 1705, 1670, 1610.
NMR spectrum (in hard water), ppm: 4.66 (2H, singlet); 5.21 (2H, singlet); 7.1-7.4 (6H, multiplet) -, 8.04 (1H, doublet, J 9 Hz).
Example 4 The following compounds were prepared.
one . A solution of bromo-3- (4-bromo-2-fluorobenzyl) -1,2,3,4-tetrahydro-2,4-dioxoquinazolin-1-yl acetic acid ethyl ester (3.0 g) and 5.83 ml of aqueous 1 n. A solution of sodium hydroxide in 69.6 ml of methanol is refluxed for 1 hour with stirring. After cooling, the solvent is evaporated, the resulting residue is acidified with 1N. aqueous hydrochloric acid and extracted with ethyl acetate. The extract is washed with brine and dried. After removing the solvent, the residue is recrystallized from a mixture of ethyl acetate and n-hexane, and 2.36 g of 2-7-bromo-3- (4-bromo-2-fluorobenzyl) -1,2,3,4-tetrahydro-2,4 are obtained. - dioxoquinazolin-1-yl acetic acid. M.p. 217 C.
IR (nujol), 1725, 1710, 1660, 1600, 1580, 1490. NMR spectrum (DMCO deuterated) MD: 4.90 (2H, singlet) j 5, 13 (2H, singlet); 7.14 (1H, double doublet, J 8.8 Hz)} 7.34 (1H, doublet, J - 8 Hz), 7.50-7.58 (2H, multiplet), - 7.78 (1H singlet); 7.99 (1H, doublet
J 8 Hz).
2. 2-, 3- (4-Bromo-2-fluoro benzyl) 1, 2,3,4-tetrahydro-7-iodo-2, 4-dioxoquinazolin-1-yl acetic acid. M.p. 251-252.5 ° C.
IR spectrum (nudzhol), cm-: 1710 1670, 1600, 1580, 1490.
NMR spectrum (DMCO deuterated) M.D.: 4.89 (2H, synglet); 5.13 (2H singlet) 7.13 (1H, double doublet, J 8.8 Hz), 7.34 (1H, doublet, J - 8 Hz) 7.55 (1H, doublet, J 8 Hz) 7 , 75 (2H, multiplet); 7.89 (1H, sin glet).
 2-C3- (4-Brom-2-fluorobenzshl) -7-fluor-1,2,3,4-tetra hydro-2,4-dioxo-hinazolin-1 -yl acetic acid. T. pl. 210-2110С.
IR spectrum (nudzhol), cm: 1710 1660, 1580, 1360.
NMR spectrum (DMCO deuterated) M.D.: 3.50 (1H, sr. Singlet); 4.87 (2H, singlet); 5.14 (2H, singlet); : .. 7, 10-7.56 (5H ,. multiplet); 8.15 (1H in doublet, J 6.6 and 7.5 Hz),
4. -2-C7-ChLOR-3- (2-fluoro-4-iodobenzyl) -1,2,3,4-tetrahydro-2,4-dioxoquinazolin-1-yl acetic acid. T pl 232-233 C.
IR spectrum (nudzhol), cm-: 1730 1710, 1670, 1610.
NMR spectrum (DMCO deuterated) M.D.: 4.90 (2H, singlet); 5.12 (2H singlet) J 6.93-8.10 (6H, multiplet).
5.2-C7-Chloro-3- (2-fluoro-3-iodobenzyl) -1, 2,3,4-tetrahydro-2,4-dioxoquinamin-1-sh1 acetic acid. M.p.
IR Spectrum (Nujol), 1720 1700, 1660, 1600.
6.2-C7-Chloro-3- | (3-chloro-4-iodobenzyl) -1,2,3,4-tetrahydro-2,4-dioxoquinazo-lin-1-shIJyccyclic acid. T np.
40 IR spectrum (nudzhol), cm -: 1725 (shoulder), 1710, 1675, 1600, 1570.
NMR spectrum (DMCO deuterated), ppm:. 4.90 (2H, singlet), 5.12 (2H, singlet) i 6.90-7.70 (3N, multiplet)
Tm / .Tr.
IR spectrum (nudzhol), cm-: 1725 1710, 1665, 1605, 158.0.
7.2- (7-Hpor-3- 4-chloro-3- (trifluoride :: ±:;;: l1 :: & l:, 1 - "- -," "- w1 Acetic acid), - 13 , 30 (1H, shir. Singlet).
14. 2- 7-Bromo-3- (2-fluoro-4-iodobenzyl) -1,2,3,4-tetrahydro-2,4-dioxoquinazolin-1-yl acetic acid. M.p. 252-253 p.
IR spectrum (nudzhol), cm-: 1715,. 1675, 1600.
NMR spectrum (DMCO deuterated), MD: 4.90 (2H, singlet); 5.12 (2H,
55
that M.p. 212-213 ° C.
IR spectrum (nudzhol), cm: 1720 1705, 1660, 1600, 1575.
8.2- {7-Chloro-3-3,5-bis (trifluoro-. G methyl) benz-13-1,2,3,4-tetrahydro-2,4-° dioxoquinazolin-1-yl-acetic acid. M.p. 202-203 S.
IR spectrum (nudzhol), cm: 1740 1700, 1650, 1605, 1590.
9. (4-Bromo-2-fluorobenzyl) -8-chloro-1,2,3,4-tetrahydro-2,4-dioxoquinazoline-1-sh1 acetic acid. M.p. 212-215 0.
singlet), 6.96 (1H, triplet, J 8 Hz), 7.50 (2H, triplet, J 8 Hz); 7.64. (1H, doublet, J 10 Hz); 7.78 (1H, singlet) -, 7.98 (1H, doublet, J - 8 Hz).
1588283
ten

20
IR spectrum (nudzhol), cm-: 1730, 1710, 1670, 1605 (shoulder), 1595.
NMR spectrum (DMCO deuterated), 5 MD: 5.03 (2H, singlet); 5.12 (2H, singlet) i 7.10-8.23 (6H, multiplet).
10. (4-Bromo-2-fluorobenzyl) -6,7-dichloro-1,2,3,4-tetrahydro-2,4-dioxoquinazolin-1-yl acetic acid. , 0 m.p.
IR (Nujol), cm-i: 1720, 1675, 1600, 1570, 1485.
NMR spectrum (DMCO deuterated), MD: 4.90 (2H, singlet); 5.13 (2H 15 singlet) ,. 7.17 (1H, double doublet, J 8.8 Hz); 7.34 (1H, doublet, J - 8 Hz), - 7.55 (1H, doublet, J 8 Hz); 7.93 (1H,. Singlet); 8.19 (1H, singlet).
11. (4-Bromo-2-fluorobenzyl) -5,7-DICHLOR-1,2,3,4-tetrahydro-2,4-dioxoquinazolin-1-yl acetic acid m.p. 238-239 C.
IR (Nujol), 3250 1730, 1710, 1670, 1665 (shoulder), 1605, 1590, 1570.
NMR spectrum (DMCO deuterated), MD: 4.92 (2H, singlet); 5.10 (2H, singlet); 7.13-7.63 (5H, multiplet). 30 12. (4-Bromo-2-fluorobenzyl) -7-trifluoromethyl-1,2,3,4-tetrahydro-2, 4-dioxoquinazolin-1-yl acetic acid. M.p. 230-231 s.
IR spectrum (nudzhol), cm-: 1700 5 1660, 1580, 1360.
13., 7-Dichloro-3- (2-fluoro-4-iodobenzyl) -1,2,3,4-tetrahydro-2,4-dioxoquinazolin-1-yl acetic acid. M.p. 255-2574.
0 IR spectrum (nudzhol), cm -: 1725 (shoulder), 1710, 1675, 1600, 1570.
NMR spectrum (DMCO deuterated), ppm:. 4.90 (2H, singlet), 5.12 (2H, singlet) i 6.90-7.70 (3N, multiplet)
Tm / .Tr..h
25
 - -, ““ - NMR spectrum (DMCO deuterated), MD: 4.90 (2H, singlet); 5.12 (2H,
singlet), 6.96 (1H, triplet, J 8 Hz), 7.50 (2H, triplet, J 8 Hz); 7.64. (1H, doublet, J 10 Hz); 7.78 (1H, singlet) -, 7.98 (1H, doublet, J - 8 Hz).
ten
111588283 5. 2- 7-Fluoro-3- (2-fluoro-4-iodobenzyl) -1,2,3,4-tetrahydro-2,4-dioxoxy-: nasolin-1-yl acetic acid. M.p.
: 214-215 p.
: IR spectrum (nudzhol), cm H 3480,
| l710, 1660, 1620, 1600.
NMR spectrum (DMCO deuterated ;, MD: 4.9 (2H, singlet); 5.1 (2H, single.et) 7.0 (1H, doublet, J - 8.8 Hz)} 7.2 (1H, double doublet, J - 8.8 Hz), 7.4-7.7 (3N, multiplet); 8, G (1H, double doublet, J 7.8 Hz, 1.
16. 2-C3- (2-Fluoro-4-iodobenzyl) -7-iodo-1,2,3,4-tetrahydro-2,4-dioxoquinosin-1-yl acetic acid. M.p.
279-28l c.
IR (nujol), cm -1: 171L, 1680, 1600, 1340, 1260, 840.
NMR spectrum (DMCO deuterated), MD: 4.90 (2H, singlet) -, 5.12 (2H, singlet), 6.96 (1H, triplet, J 8 Hz) 7.46-7, 89 (54, multiplet. Example 5. The following compounds are prepared.
1. A mixture of 1.5 g of ethyl 2-G ethyl ester (2-N-benzylcarbamoyl) aniline-cycloxylic acid and 2.85 g of N, K -thiocarbonyldiimidazole is stirred at 120 C for 30 minutes. After cooling, the reaction mixture was diluted with chloroform and separated by chromatography on silica gel. Elution with chloroform gives 2- (3-benzyl-1,2,3,4P) ethyl ether 6. A mixture of ethyl ether (3,4-dichlorobenzyl) -1, 2,3, 4-tetrahydro-2, 4-dithioxoquinazolin-1-yl-acetic acid (85 mg), 0.5 ml of aqueous 1N sodium hydroxide solution and 1 ml of tetrahydrofuran are stirred at room temperature for 20 hours. The reaction mixture is poured into a mixture of ethyl acetate and 0.5N chloride. the organic layer is separated, washed with water and brine and dried over magnesium sulfate. The solvent is removed and 15 residue is subjected to crystallization from chloroform to give 36 mg of (3,4-dichlorobenzyl) -1,2,3,4-tetrahydro-2,4-dithioxoquinazolin-1-yl acetic acid. mp 222-223 s (decomposed). IR- Spectrum (Nujol), 1710,
1685.
Mr spectrum (DMCO deuterated ;, MD: 5.54 (2H, sr. Singlet) 5.75 (2H, singlet) - 7.17-7.60 (5H, multiplet) 7.88 (1H , triplet, J 7 Hz), 8.16 (1H, doublet, J 8 Hz).
Test outside the body.
Enzymatic assay method. The following reagents are used, ml: 0.5 M phosphate buffer (pH 6.2) 0.1; lithium sulfate solution 2.0 M 0.2; the proposed compound (dissolved in physiological saline) 0.1; enzyme solution (aldose solution 20
25
thirty
V / t U Cl i - - - t ----- - 14. tether et al; -4-oxo-2-thioxochnazoline reductase, prepared as a prescription; ; a) sting acid, a mixture of ethyl); 0.5; 60 mM B, L-glyceraldehyde
I gil / jr- -: 7
2- (3-benzyl-1,2,3,4-tetra-hydro-4-oxo-2-thioxoquinazolin-1-yl) acetic acid ester and 2 ml of 1N. A solution of sodium hydroxide in 10 ml of methanol is stirred for 4 hours at room temperature. The reaction mixture was poured into dilute hydrochloric acid and extracted with chloroform. The extract is washed with brine and dried. By removing the solvent, 280 mg of 2- (3-benzyl-1,2,3,4-tetrahydro-4-oxo-2-thioxoquinazolin-1-yl) acetic acid are obtained. M.p. 194-197 C, IR spectrum (nudzhol), cm-: 1720,
1700.
SR spectrum (deuteromethanol), ppm:
4.90 (2H, singlet); 5.20 (2H, singlet); 7.00-7.50 (9H, multiplet).
2. 2-P- (H, 4-Dichlorobenzyl) -1, 2,3, 4-tetrahydro-4-oxo-2-thioxoquinazo-LIN-1-IL and acetic acid. M.p. 105PO C ..,
IR spectrum (chloroform): 1700 cm.
40
pi / vv. J. - - 5 - ---, ..
0.05; 2.5 mM nicotinamide adenine dinucleotide phosphate (NAD.F, reduced form) 0.05.
These reagents are mixed and subjected to interaction at 35 ° C for 2 min, and the decrease in the amount of NADP is measured automatically by a reaction rate analyzer (model 45KB-8600, trademark ElKBB Produter EB) . Per unit of enzymatic activity, a change in the degree of absorption of 0.001 per minute is taken.
50 Method of preparation of the enzyme solution.
The cores are removed from the eyes of the rabbit and collected. These lenses are homogenized with three volumes of distilled water at (all subsequent; they are also carried out at 4 ° C) and centrifuged at an acceleration of 10,000 G for 60 minutes. The supernatant is dialyzed against 2 liters.
ten
83 -
PRI me R 6. A mixture of ethyl ester (3,4-dichlorobenzyl) -1, 2,3, 4-tetrahydro-2,4-dithioxoquinazolin-1-ylZoacetic acid (85 mg), 0.5 ml of aqueous 1 n . Sodium hydroxide solution and 1 ml of tetrahydrofuran are stirred at room temperature for 20 hours. The reaction mixture is poured into a mixture of ethyl acetate and 0.5N. hydrochloric acid. The organic layer is separated, washed with water and brine, and dried over sulfa-. tom magni The solvent was removed and 15 residue was subjected to crystallization from chloroform, to give 36 mg of (3,4-dichlorobenzyl) -1,2,3,4-tetrahydro-2,4-dithioxoquinazolin-1-yl acetic acid. M.p. 222-223 s (decomposed). IR Spectrum (Nujol), 1710,
1685.
Mr spectrum (DMCO deuterated ;, MD: 5.54 (2H, sr. Singlet) 5.75 (2H, singlet) - 7.17-7.60 (5H, multiplet) 7.88 (1H , triplet, J 7 Hz), 8.16 (1H, doublet, J 8 Hz).
Test outside the body.
Enzymatic assay method. The following reagents are used, ml: 0.5 M phosphate buffer (pH 6.2) 0.1; lithium sulfate solution 2.0 M 0.2; the proposed compound (dissolved in physiological saline) 0.1; enzyme solution (aldose solution 20
25
thirty
V / t U Cl i - - - t ----- - 14. reductase, prepared as prescribed) 0.5; 60 mM B, L-glyceraldehyde
0
pi / vv. J. - - 5 - ---, ..
0.05; 2.5 mM nicotinamide adenine dinucleotide phosphate (NAD.F, reduced form) 0.05.
These reagents are mixed and subjected to interaction at 35 ° C for 2 min, and the decrease in the amount of NADP is measured automatically by a reaction rate analyzer (model 45KB-8600, trademark ElKBB Produter EB) . Per unit of enzymatic activity, a change in the degree of absorption of 0.001 per minute is taken.
50 Method of preparation of the enzyme solution.
The cores are removed from the eyes of the rabbit and collected. These lenses are homogenized with three volumes of distilled water at (all subsequent; s operations are also carried out at 4 ° C) and centrifuged at an acceleration of 10,000 G for 60 minutes. The supernatant is dialyzed against 2 liters.
131588283
0.05 M salt solution, and dialyzed solution is used as an enzyme solution.
The test results are presented in table. 1. Each IR value (M) is the concentration of substances at which aldose reductase activity is inhibited by 50%.
Q L
Tests in the body. The inhibitory effect of the drug on the accumulation of sorbitol in the sciatic nerve is determined.
Sprague-Dowley male rats (6 weeks old) are not given food for 24 hours and then transformed into diabetics by intraperitoneal injection (2 ml / kg) of streptozotocin (75 mg / kg dissolved in 0.002 M citrate buffer solution (pH 4, 5). 7 days after the injection of steptozotocin, blood glucose was determined, blood was taken from the tail vein of Rats with a glucose level in the blood of 300 mg / dl and used as animals with diabetes induced by streptozotocin. Animals with diabetes were randomly divided into two groups A and B.
The drug was suspended in an aqueous 0.5% solution of methylcellulose and administered orally to each rat in group A once a day for 5 days (diabetic rats treated with medication).
Each rat in group B and normal rats are given a vehicle — a 0.5% aqueous solution of methylcellulose (untreated diabetic rats and control rats).
Six hours after the last administration of the drug or vehicle, the animals are killed and the analytical content of sorbitol in the sciatic nerve is determined. The percent inhibition of sorbitol accumulation I in the sciatic nerve for the medicament is calculated as follows:
1 (- | -E-p -). 100,
where S is the content of sorbitol in the sciatic nerve of untreated diabetic rats; 5d - the content of sorbitol in the sciatic nerve of diabetic rats treated with medication;
one
K - content of sorbitol in the sciatic nerve of control rats. The results of the test are presented in Table. 2
Acute toxicity test. (4-Bromo-2-fluorobenzyl) -7-chloro-1 2,3,4-tetrahydro-2-, 4-dioxoquinaz-Q LIN-1-yl acetic acid is used for the test.
After the SD rats (one group of 5 animals) were orally administered a 0.5% methylcellulose suspension containing the test compound, 5 rats were observed for 2 weeks.
The results obtained: LDr-g 1000 mg / kg. The test results show that the test compound is low toxic.
Thus, the compounds proposed are low toxic.
The obtained quinazoline derivatives and their pharmaceutically acceptable salts have inhibitory activity in relation to aldose reductase and are of value, for example, for the therapeutic treatment of diabetic complications such as healing of injuries and corneal wounds, cataracts, neuropathy, retinopathy, nephropathy, especially cataract and neuropathy.
35

权利要求:
Claims (1)
[1]
The invention The method for producing quinazoline derivatives of the general formula
0
five
0
five
where r
is attached to the quinazoline ring in position 7 or 8 and means a hydrogen atom, halogen, lower alkoxy, and R is attached to the quinazoline ring in position 5 or 6 and means a hydrogen atom, halogen, lower alkoxy group; RJ is naphthyl (lower) alkyl or phenyl (lower) alkyl, substituted by one or two substituents selected from halogen, lower alkoxy group, or CFj;
A is an oxygen or sulfur atom;
Y is carbonyl, thiocarbonyl or sulfonyl; lower alkylene.
Z or their salts, about tl and h and the fact that the connection
u u and u
Z-R:
15882831
where R ,,, Rj, A, Y and Z have Ack, are common values;
H
ean values;
R, l is a protected carboxy group, is subjected to hydrolysis with the release of the target product in free form or as a salt.
Table 1 Test Results
CHj-COOH
.
CNG
C1
, -soon
CH2- "
-Wg
BUT ABOUT F
CH2-COOH
SNP
SNZ-Soon
about .C1
-But
CHj-COOH, oh
.
C1
CHj-COOH
.0-C1.
SNS;
оС1
CHj-COOH
n soooooo
UVN tn
about f
CHj-COOH
Vg
NZS-0
sn
2 F
5.4 "10-1-1
4.8 10-51-2
1,1x10- "1-6
2.8MO-11-7
8.2 "10
-9
1-9
1.9, 1-10
5,4x10-91-15
6.2K10 1-16
CH,
Continuation of table 1
6,8x10-91-29
CHg-COOH
CHj-COOH
7,6к10-91-30
3.7 and 0-9
3.1x10-9A-1
4,0x10-94-2
2.6 10-54-3
2,3x10-9А-4
4,5x10-94-5
2.5 10-94-6
5,0x10-94-7
3, Oh10- "4-9
CH, -COOH
I
S1SNO-COOH
I
Siz-SOOTs
 about .1
"T
SI
about
CHj-COOH
S C1
CH,
CIlj-COOH
CHj-Cl
Continuation of table 1
T P
i.Bj-V ..
3,4x10-A-10
2.9MO-EA-11
5,1x10-94-12
3.5.10-4-13
1-9
3.140 4-14
2,8x10-54-15
3.2MO-54-16
.five,
, C1
one,
23
1588283Table 2
1-19
4-1
2
24
32 32 32
101
103
99

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引用文献:

---

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

---

---

US4016166A|1973-12-14|1977-04-05|Hisamitsu Pharmaceutical Co., Inc.|1-Nitrophenylquinazoline-2,4-diones|

---

DE2652144A1|1976-11-16|1978-05-18|Merck Patent Gmbh|Quinazoline:di:one derivs. - useful as analgesics, antiinflammatory agents and sedatives|

---

CA1161036A|1980-05-15|1984-01-24|Masayuki Ishikawa|Quinazoline-dione compounds, process for productionthereof and pharmaceutical use thereof|

---

DE3172006D1|1980-05-22|1985-10-03|Masayuki Ishikawa|Novel quinazoline-dione compounds, process for production thereof and pharmaceutical use thereof|

---

JPH033669B2|1982-03-17|1991-01-21|Chugai Pharmaceutical Co Ltd|

---

DD232702A1|1982-09-20|1986-02-05|Adw Ddr|PROCESS FOR THE PREPARATION OF 1,2,3,4-TETRAHYDROCHINAZOLIN-2,4-DION VINEGARES, THEIR SALTS AND ESTERS|

---

US4490374A|1982-09-30|1984-12-25|Ortho Pharmaceutical Corporation|5,6-Dialkoxy-3,4-optionally substituted-2quinazolinones, composition and method of use|

---

JPH0358343B2|1983-04-08|1991-09-05|Chugai Pharmaceutical Co Ltd|

---

GB8524663D0|1985-10-07|1985-11-13|Fujisawa Pharmaceutical Co|Quinazoline derivatives|GB8524663D0|1985-10-07|1985-11-13|Fujisawa Pharmaceutical Co|Quinazoline derivatives|

---

MX7829A|1986-08-21|1993-08-01|Pfizer|QUINAZOLINDIONAS AND PIRIDOPIRIMINDIONAS AND THE PROCEDURE FOR THEIR PREPARATION|

---

US4889851A|1986-11-21|1989-12-26|Fujisawa Pharmaceutical Co, Ltd.|Benzothiadiazine compounds, and pharmaceutical composition comprising the same|

---

US4931440A|1987-07-29|1990-06-05|Fujisawa Pharmaceutical Company, Ltd.|Uricosuric composition|

---

WO1989002432A1|1987-09-16|1989-03-23|Taiho Pharmaceutical Company, Limited|Thienopyrimidine derivatives|

---

JP2621460B2|1988-02-29|1997-06-18|藤沢薬品工業株式会社|Diuretics or antihypertensives|

---

US5324747A|1992-07-15|1994-06-28|Hoffmann-La Roche Inc.|N-substituted anilines, inhibitors of phospholipases A2|

---

JP2789134B2|1992-09-28|1998-08-20|ファイザー・インク．|Substituted pyrimidines control diabetic complications|

---

EP0847382B1|1995-08-31|2000-12-20|Clariant GmbH|Monoesters of carboxymethylene anthranilic acids and process for preparing the same|

---

DE19532052C2|1995-08-31|1998-11-19|Clariant Gmbh|Process for the preparation of quinazoline derivatives|

---

DE69614986T2|1995-12-26|2002-04-25|Sumitomo Chemical Co|Process for the preparation of isatoic anhydrides|

---

EP0896961A4|1995-12-28|1999-04-07|Fuji Chem Ind Co Ltd|Process for the preparation of 3-dihalobenzyl-2,4-quinazolinedione derivatives|

---

US5780628A|1996-02-01|1998-07-14|Sumitomo Chemical Company, Limited|Process for producing dioxoquinazolines|

---

DE19650975A1|1996-12-09|1998-06-10|Basf Ag|New heterocyclically substituted benzamides and their application|

---

EP0973534B1|1997-04-15|2006-11-02|Csir|Plant extracts having appetite suppressant activity|

---

US6444816B1|1997-10-27|2002-09-03|Dr. Reddy's Research Foundation|Fused 7-oxo-pyrimidinyl compounds, preparation, composition and use thereof|

---

EP1004307B1|1998-01-30|2002-09-04|R-Tech Ueno, Ltd.|Ophthalmic composition|

---

AU2129500A|1999-01-25|2000-08-07|Fujisawa Pharmaceutical Co., Ltd.|Eye drops|

---

WO2000048447A2|1999-02-18|2000-08-24|R-Tech Ueno, Ltd.|Composition for treatment of external secretion disorders except hypolacrimation|

---

IL145114D0|1999-03-09|2002-06-30|Fujisawa Pharmaceutical Co|A process for preparing a quinazoline derivative|

---

JP4625637B2|2002-02-22|2011-02-02|シャイアエルエルシー|Active substance delivery system and method for protecting and administering an active substance|

---

US6545004B1|1999-10-27|2003-04-08|Cytokinetics, Inc.|Methods and compositions utilizing quinazolinones|

---

US7230000B1|1999-10-27|2007-06-12|Cytokinetics, Incorporated|Methods and compositions utilizing quinazolinones|

---

GB2355657B|1999-10-27|2004-07-28|Phytopharm Plc|Inhibitors Of Gastric Acid Secretion|

---

US6380200B1|1999-12-07|2002-04-30|Pfizer, Inc.|Combination of aldose reductase inhibitors and selective serotonin reuptake inhibitors for the treatment of diabetic complications|

---

GB2363985B|2000-06-30|2004-09-29|Phytopharm Plc|Extracts,compounds & pharmaceutical compositions having anti-diabetic activity and their use|

---

SK6092003A3|2000-11-30|2004-07-07|Pfizer Prod Inc|Combination of GABA agonists and aldosereductase inhibitors|

---

WO2002098462A1|2001-06-01|2002-12-12|Ono Pharmaceutical Co., Ltd.|Remedies containing aldose reductase inhibitor as the active ingredient for demyelinating diseases or diseases associated with demyelination|

---

US7009049B2|2002-02-15|2006-03-07|Cytokinetics, Inc.|Syntheses of quinazolinones|

---

AU2003270015A1|2002-05-09|2003-12-02|Cytokinetics, Inc.|Compounds, compositions, and methods|

---

JP2006508030A|2002-05-09|2006-03-09|サイトキネティクス・インコーポレーテッド|Pyrimidinone compounds, compositions and methods|

---

AU2003290507A1|2002-05-10|2004-04-08|Cytokinetics, Inc.|Compounds, compositions and methods|

---

JP2005536475A|2002-05-23|2005-12-02|サイトキネティクス・インコーポレーテッド|Compounds, compositions and methods|

---

EP1556357A4|2002-06-14|2006-09-13|Cytokinetics Inc|Compounds, compositions, and methods|

---

JP2006501201A|2002-07-23|2006-01-12|サイトキネティクス・インコーポレーテッド|Compounds, compositions and methods|

---

US20040048853A1|2002-08-21|2004-03-11|Gustave Bergnes|Compounds, compositions, and methods|

---

US7557115B2|2002-09-30|2009-07-07|Cytokinetics, Inc.|Compounds, compositions, and methods|

---

US20070010537A1|2004-08-20|2007-01-11|Kazumasa Hamamura|Fused pyramidine derivative and use thereof|

---

EP1682534A2|2003-11-03|2006-07-26|Cytokinetics, Inc.|Pyrimidin-4-one compounds, compositions, and methods|

---

WO2005046588A2|2003-11-07|2005-05-26|Cytokinetics, Inc.|Compounds, compositions, and methods|

---

JP2007513154A|2003-12-08|2007-05-24|サイトキネティクス・インコーポレーテッド|Compounds, compositions and methods|

---

US20110092566A1|2004-11-19|2011-04-21|Srivastava Satish K|Treatment of cancer with aldose reductase inhibitors|

---

JP2009543861A|2006-07-19|2009-12-10|イー・アイ・デュポン・ドウ・ヌムール・アンド・カンパニー|Method for producing 3-substituted 2-amino-5-halobenzamide|

---

AT518544T|2007-03-12|2011-08-15|Zadec Aps|REDBUSCH EXTRACT AGAINST DIABETES|

---

EP2139330B1|2007-03-23|2014-09-24|The Board of Regents of The University of Texas System|Methods involving aldose reductase inhibitors|

---

KR101167773B1|2007-08-03|2012-07-24|에프. 호프만-라 로슈 아게|Pyridinecarboxamide and benzamide derivatives as taar1 ligands|

---

US20090270490A1|2008-04-24|2009-10-29|The Board Of Regents Of The University Of Texas System|Methods involving aldose reductase inhibition|

---

CN102219759B|2010-04-16|2013-07-24|中国科学院上海药物研究所|Aryl methanamide compounds and preparation method, medicinal compositions and application thereof|

---

CA2822672C|2010-12-23|2018-06-05|The Board Of Regents Of The University Of Texas System|Methods for treating copd|

---

KR20160007598A|2013-05-10|2016-01-20|님버스 아폴로, 인코포레이티드|Acc inhibitors and uses thereof|

---

CN105358155A|2013-05-10|2016-02-24|尼普斯阿波罗有限公司|Acc inhibitors and uses thereof|

---

US10208063B2|2013-05-10|2019-02-19|Gilead Apollo, Llc|ACC inhibitors and uses thereof|

---

TW201623257A|2014-05-09|2016-07-01|奧利安公司|Pharmacologically active quinazolinedione derivatives|

法律状态:

优先权:

---

申请号 | 申请日 | 专利标题

---

GB858524663A|GB8524663D0|1985-10-07|1985-10-07|Quinazoline derivatives|

---