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    • 专利摘要:
    This invention provides a benzene-fused hererocyclic compound of the formula: wherein R1 is halogen, nitro, amino, hydroxy, lower alkyl, lower alkoxy substituted by carboxy or protected carboxy, acylamino which may have lower alkyl on the amino moiety, or aryloxy which may have halogen, R2 is hydrogen or halogen, in which R3 is hydrogen, lower alkyl or acyl and A is a group of the formula: in which R4 is hydrogen, lower alkenyl, lower alkynyl or alkyl which may have suitable substituent(s) selected from the groups consisting of hydroxy, acyl, lower alkoxy, di(lower)alkylamino, carboxy, protected carboxy and aryl; or R is hydrogen or lower alkoxy, R2 is hydrogen, X is -N- in which R3 a is lower alkanoyl and R3 A is a group of the formula: and pharmaceutically acceptable salts thereof. This compound possesses diuretic activity, uricosuric activity and vasodilative activity and are useful as a diuretic agent, uricosuric agent and anti-hypertensive agent. The invention further relates to processes for the preparation of this compound and pharmaceutical composition comprising compound of the above formula.
    公开号:SU1375137A3
    申请号:SU853967801
    申请日:1985-10-25
    公开日:1988-02-15
    发明作者:Уеда Икуо；Сиокава Еуити；Манабе Такаси；Кацура Есуке
    申请人:Фудзисава Фармасьютикал Ко.,Лтд (Фирма)；
    IPC主号:
    专利说明:

    eleven
    The invention relates to a process for the preparation of new biologically active chemical compounds, in particular, to a process for the preparation of heterocyclic compounds with condensable benzene, namely, a series of 4,5-dihydropyrazole (4,3-c) quinoline or 1,4-dihydrobenzopyran ( 4,3-c) pyrazole possessing a diuretic with release of uric acid and vasodilator activity, which suggests the possibility of using these compounds in medicine.
    The aim of the invention is to obtain new derivatives of the 4,5-dihydropyrazole (4,3-c) quinoline or 1,4-dihydro (1) -benzopyran (4,3-c) pyrazole derivatives, which have a new type of biological activities - diuretic and / or uric acid release, vasodilator activity.
    The invention is illustrated by the following examples.
    The starting compound II for obtaining the target compound (I) can be obtained using the following procedures:
    Procedure 1. A solution of 6-chloro-3,4-DIHIDRO-4-OXO-2H-1-benzopyran (3.285 g), I, K-dimethylformamide dimethyl acetal (8.568 g) and triethylamine (2.727 g) in benzene (36 ml) is refluxed with stirring for one hour, and then about 3/4 of the solvent is slowly distilled off under atmospheric pressure for one hour. Benzene (36 ml) is added to the residue and the solvent is again distilled off. The residue is dissolved in a mixture of chloroform and ethyl acetate, treated with activated charcoal and evaporated under vacuum. The residual solid is washed with a mixture of diethyl ether and ethyl acetate, whereby 6-chloro-3,4-dihydro-3-dimethylaminomethylene-4-oxo-2H-1-benzopyran (2.73 g
    Procedure 2. A solution of 6-chloro-4-oxo-1-propionyl-1,2,3,4-tetrahydroquinoline (2 g), K, K-dimethylformamide dimethyl acetal (7.009 g) and triethylamine (0 , 87 g) in benzene (50 ml) is refluxed with stirring for an hour, and then about 3/4 of the solvent is slowly distilled off at atmospheric pressure for an hour. Benzene (100 ml) is added to the residue.
    d
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    and again the solvent is distilled off. The resulting solid is collected by filtration, washed with diethylether and dried. B-chloro-3-dimethylaminomethylene-4-oxo-1-propionyl-1,2,3,4-tetrahydroquinoline (2.02 g) is obtained.
    Procedure 3. The following compounds were obtained using procedures similar to 1 and 2:
    (1) 6-chloro-3-dimethylaminomethylene-1-ethylcarbamoyl-4-oxo-1,2,3,4-tetrahydroquinoline;
    IR (Nujol): 3280, 1660, 1655 (bending), 1645 (bending), 1600, 1570, 1540 (wide)
    (2) 6-chloro-3-dimethylaminomethylene-1-ethoxycarbonyl-4-oxo-1,2,3,4-tetrahydroquinoline;
    IR (Nujol): 1700, 1645, 1600, 1580, 1560 cm;
    (3) 6-chloro-3-dimethylaminomethylene-4-oxo-1,2,3,4-tetrahydroquinoline;
    IR (Nujol): 3300, 1640, 1615 cm; NMR (Nujol): 3300, 1640, 1615 cm;
    (4) 3-dimethylaminomethylene-4-ox-1-propionyl-1,2,3,4-tetrahydroquinoline;
    IR (Nujol): 1655, 1650 (bend), 1640, 1600, 1580, 1540 (wide) cm;
    NMR (CBC1e, c /): 1.15 (3N, triplet, Hz); 2.50 (2H, quartet, Hz); 3.23 (6H, singlet); 5.0 (2H, singlet); 7.15-7.5 (3N, multiplet); 7.62 (1H, singlet); 7.99 (W, double doublet, 8 Hz).
    Procedure 4. (l) A solution of cyclopropylcarbonyl chloride (2.09 g) in chloroform (5 ml) is added dropwise to a solution of b-chloro-4-OKco-1, 2,3,4-tetrahydroquinoline (1.815 g) , N, N-dimethylaniline (2.42 g) and 4-dimethyl-amnopyridine (0.488 g) in chloroform (15 ml) with stirring and cooling with ice for 10 minutes. After stirring overnight at ambient temperature, the mixture is sequentially washed with a 10% hydrochloric acid solution, water, an aqueous solution of sodium bicarbonate and water, dried over magnesium sulfate and evaporated under vacuum. The residual solid is washed with diethyl ether and dried. The result is 6-chloro-1-cyclopropyl-carbonyl-4-oxo-1,2,3,4-tetrahydroquinoline (2.14 g).
    IR (Nujol): 1690, 1655, 1595
    (2) a solution of 6-chloro-1-cyclopropyl-carbonyl-4-oxo-1,2,3,4-tetrahydroquinoline (1.996 g), N, N-dimethylformide amide dimethyl acetal (3.808 g) and triethylamine (1.212 g) in benzene (16 ml is refluxed with stirring for 30 minutes and then 3/4 of the solvent is distilled off (slowly, at atmospheric pressure, for about 30 minutes). Benzene is added to the residue (16 ml) and the solvent is again distilled. The residue is dissolved in ethyl acetate, treated with activated carbon and evaporated under vacuum. The residual solid is washed with diethyl ether by growth of ether. As a result, 6-chloro-1-cyclopropylcarbonyl-3-dimethylaminomethylene-4-oxo-1,2,3,4-tetrahydrochioline (2.43 g
    Procedure 5. (1) Using a procedure similar to procedure 4 (D), compound 6 nitro-4-oxo-1-propionyl-1,2,3,4-tetrahydroquinoline (10.66 g) is obtained;
    (2) a mixture of 6-nitro-4-oxo-1-propionyl-I, 2,3,4-tetrahydroquinoline (2.976 g), I, M-dimethylformamide dimethyl acetal (8.568 g) and triethylamine (1.818 g) in benzene (24 ml), refluxed with stirring for 2.5 hours and cooled to room temperature. The resulting precipitates are collected by filtration, washed with cold ethyl acetate and dried. The result is 3-dimethylaminomethylene-6-nitro-4-oxo-1-propionyl-1,2,3,4-tetrahydroquinoline (3.345 g).
    Procedure 6. (1) Propionyl chloride (2.99 ml) is added dropwise to a suspension of 6,7-dichloro-4-oxo-1,2,3,4-tetrahydroquinoline (3.70 g) in pyridine (2, 76 ml) and benzene (40.0 ml). After stirring at room temperature for one hour, water (50 ml)} and ethyl acetate (10 ml) are added to the mixture. The organic layer was diluted with dilute hydrochloric acid, diluted with an aqueous solution of sodium hydrogencarbonate, brine, and dried over magnesium sulfate. The solvent is evaporated under vacuum to give a light brown powder (4.60 g), which is recrystallized from a mixture of ethyl acetate and n-hexane. As a result, b, 7-dichloro-4-oxo-1-pros1Onl1, 2,3,4-tetrahydroquinoline (3.85 g) is obtained in the form of slightly brown prisms. M.p. 135-137 ° C;
    (2) the following compound is prepared according to procedure 1:
    6,7-dichloro-3-dimethylaminomethylene-4-oxo-1-propionyl-1,2,3,4-tetrahydroquinoline. M.p. 182-184 C (after recrystallization from ethanol).
    Procedure 7. (1) The compound 6-methoxy-4-oxo-1-propionyl-1,2,3,4-tetrahydroquinoline is obtained using a procedure analogous to procedure 4 (O;
    IR (Nujol): 1685, 1655 (kink), 1645, 1605, 1575, .1490 cm;
    (2) 3-dimethylaminomethylene-6-methoxy-4-oxo-1-propionyl-1,2,3,4-tetrahydroquinoline compound (2.12 g) is prepared using a procedure similar to procedure 1;
    IR (Nujol): 1655, 1635, 1605, 1580, 1560 (kink), 1550 cm
    Procedure 8. .. (l) Compound 6-chloro-1-myristoc-1-4-oxo-1,2,3,4-tetrahydroquinoline is obtained using a procedure similar to that of 4 (I);
    IR (Nujol): 1690, 1660, 1655 (kink), 1595
    (2) the following compound is obtained using a procedure “similar to procedure 1:
    6-chloro-3-dimethylaminomethylene-1-myristoyl-4-oxo-1,2,3,4-tetrahydroquinoline;
    IR (Nujol): 1665, 1645, 1600, 1570, 1545 (wide) cm
    Procedure 9. (l) According to the procedure similar to procedure 4 (l), 6-chloro-1-methyl-1-sulfonyl-4-oxo-1,2,3,4-tetrahydroquinoline J is obtained.
    IR (Nujol): 1690, 1595 cm
    (2) using a procedure similar to procedure 1, 6-chloro-3-dimethylaminomethylene-1-methyl sulfonyl-4-oxo-1,2,3,4-tetrahydroquinoline is obtained;
    IR (Nujol): 1650 (kink), 1645, 1595, 1670, 1550 cm H
    Procedure 10. (1) Similarly to procedure 4 (1), 5,6-dulsor-4-oxo-1-propionyl-1, 2,3,4-tetrahydroquinoline is obtained. M.p. 122-123 ° C (after recrystallization from a mixture of ethyl acetate and n-hexane);
    (2) 5,6-dichloro-3-dimethylaminomethyl
    flax-4-oxo-1-propionyl-1,2,3, A-tetra hydroquinoline. So pl.219-220 C (after recrystallization from ethanol).
    Procedure 11. (I) In a similar manner to Procedure 4 (1), 6,8-dichloro-4-OKco-1-nponHOHmi-l ,, 4-tetrahydroquinoline is obtained;
    IR (Nujol): 3500, 3275, 1670 cm (2) the compound 6,8-dichloro-3-dimethylaminomethyl-4-oxo-1-propionyl 1,2,3,4-tetrahydroquinoline is obtained in a manner similar to procedure 1. T. square 125-127 C (after recrystallization from ether).
    Procedure 12. (1) 6-metsh4-4-oxo-I-propionyl-1,2,3,4-tetrahydroquinoline is prepared analogously to procedure 4 (1);
    IR (Nujol): 1690, 1655 (wide), 1610 cm;
    (2) Analogously to procedure 1, 3-dimethylpaminomethylene-b-methyl-4-oxo-I-propionyl-1,2,3,4-tetrahydroquinoline is obtained;
    IR (Nujol): 1655, 1635, 1610, 1580, 1550 (wide).
    Procedure 13. (l) In an analogous manner to procedure 4 (l), 6-chloro-1 (2,3-dimethylpentanoyl) -4-oxo-1,2,3,4-tetrahydroquinoline (3.39 g) is obtained;
    IR (film, NaCl): 1680, 1660, 1590 cm;
    (2) 6-chloro-3-dimethylaminomethylene-1- (2,3-dimethylpentanoyl) -4-oxo-1,2,3, 4-tetrahydroquinoline is prepared analogously to procedure 1;
    IR (Nujol): 1660, 1640, 1bOO, 1580, 1555 cm
    Procedure 14. (1) 6- (4-chlorophenoxy) -4-oxog-1-propionyl-1,2,3,4-tetrahydroquinoline is prepared analogously to procedure 4 (1). M.p. 96-98 ° C (after recrystallization from a mixture of ethyl acetate and n-hexane);
    (2) similarly to procedure 1, 6- (4-chlorophenoxy) -3-dimethyl-aminomethylene-4-bKCO-1-propionyl-1,2,3,4 tetrahydroquinoline is obtained. M.p. 146-148 C (after recrystallization from a mixture of ethanol and n-hexane).
    Procedure 15. (l) In a manner similar to procedure 4 (l), 6-chloro-1-ethanesulfonyl-4-oxo-1,2,3,4-tetrahydroquinoline is obtained. M.p. 55-68 0;
    (2) analogously to procedure 1, 6-chloro-3-dimethylaminomethylene-1-ethanesulfonyl-4-oxo-1,2,3,4-tetrahydroquinoline is obtained. M.p. 141-143 ° C.
    five
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    Procedure 16. (1) A solution of methanesulfonyl chloride (2.004 g) in methylene chloride (5 ml) is added dropwise to a solution of 6-amino-4-oxo-1-propionyl-1,2,3,4-tetrahydroquinoline. (1.526 g) and triethylamine (2.121 g) in methylene chloride (15 ml) with ice cooling for 15 minutes and stirred for one hour. The mixture was diluted with chloroform, washed successively with a 10% hydrochloric acid solution, water and brine, dried over magnesium sulfate and evaporated under vacuum. The residual solid is washed with methanol and dried. The result is 6- (M, L-dimethylsulfonyl-amino) 4-oxo-1-propionyl-1,2,3,4-tetrahydroquinoline (2.51 g);
    IR (Nujol) ;. 1700, 1670, 1600, 1370, 1160 cm
    (2) similarly to procedure 1, 3-dimethylaminomethylene-6- (K-metsh-1-N-methylsulfonylamino) -4-oxo-1-propionyl-1,2,3,4-tetrahydroquinoline is obtained;
    IR (Nujol): 1655, 1640, 1610 1580, 1550 (wide) cm
    Procedure 17. (1) A mixture of 6-methoxy-4-oxo-1-propionyl-1,2,3,4-tetrahydroquinoline 1: 1.957 g) and aluminum chloride (3.359 g) in benzene (42 ml) is heated to 60-65 C with stirring and incubated for 4 hours. A mixture of crushed ice and 10% hydrochloric acid is added to the aluminum chloride complex and extracted with ethyl acetate. The extract is washed with water, dried over magnesium sulphate and evaporated under vacuum. The residue is purified by chromatography on silica gel (30 g) using a mixture of chloroform and methanol in a ratio of 50, 1 to 10: 1 as eluent. The eluates were evaporated in vacuo to give 6-hydroxy-4-oxo-1-propionyl-1,2,3,4-tetrahydroquinoline (1.52 g).
    IR (Nujol): 3200 (wide), 1690 1635 (kink) / 1620, 1610, 1590
    (2) a mixture of 6-hydroxy 4-goxo-1-propionyl-1,2,3,4-tetrahydroquinoline (1.334 g), methyl bromoacetate (1.01 g) and potassium carbonate (0.828 g) in N, N-dimethylformamide ( 10 ml) is stirred at room temperature for 24 hours, poured into water and extracted with ethyl acetate. The extract is washed with water, dried over magnesium sulphate and evaporated under vacuum. The residue is purified by chromatography on silica gel (15 g) using chloroform as eluent to give 6-methoxycarbonylmetro-OXI-4-OXO-1-propionyl-1,2,3,4-tetrahydroquinoline (2.08 g)
    IR (Nujol): 1740, 1690, 1655 (kink), 1650
    (3) Analogously to procedure 1, 3-dimethylaminomethylene-6-methoxycarbonylmethoxy-4-oxo-1-propionyl 1,2,3,4-tetrahydroquinoline is obtained;
    IR (Nujol): 1735, 1655, 1640 (kink), 1630, 1600, 1580, 1540 cm-.
    Procedure 18. (1) A solution of 6-hydroxy-4-OXI-4-OXO-1-propionyl-1,2,3,4-tetrahydroquinoline (1.643 g) and N-chlorosuccinimide (1.068 i) in K, K-di - methylformamide (10 ml) is stirred at room temperature for 18 hours, poured into water and extracted with ethyl acetate. The extract is washed with water, dried over magnesium sulphate and evaporated under vacuum. The residual solid is recrystallized from chloroform to obtain 5-chloro-6-hydroxy-4-oxo-1-propionyl-1,2,3,4-tetrahydroquinoline (1.74 g).
    IR (Nujol): 3240, 695, 1630, 1565 cm;
    (2) 5-chloro-6-methoxycarbonylmethoxy-4-oxo-1-propionyl-1,2,3,4-tetrahydroquinoline is prepared analogously to procedure 17 (2).
    IR (Nujol): 1765, 1695, 1660, 1600 cm H
    (3) similarly to procedure 1, 5-chloro-3-dimethylamino-methyl-6-methoxy-15-terminyl-methoxy-4-oxo-1-propionyl-1,2,3,4-tetrahydroquinoline is obtained.
    IR (Nujol): 1760, 1660, 1640, 1600, 1550 cm
    Procedure 19. (1) A solution of 6-nitro 4-oxo-1-propionyl-1,2,3,4-tetrahydroquinoline (6.076 g) in methanol (60 ml) is subjected to hydrogenations on 5% palladium on carbon ( 0.5 g) at atmospheric pressure and ambient temperature. After uptake of the theoretical amount of hydrogen, the catalyst was filtered off, and the filtrate was evaporated under vacuum: 5 ohm. Residual solid is washed with diethyl ether and dried.
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    6-amino-4-oxo-1-propionyl-1,2,3,4-tetrahydroquinoline (4.815 g) is obtained.
    IR (Nujol): 3450, 3350, 1690 (kink), 1680, 1650, 1630, 1610
    (2) A solution of acetyl chloride (0.604 g) in methylene chloride (5 ml)
    6-amine-4-OXO-1-propionyl-1,2,3,4-tetrahydroquinoline (1.526 g) and H, N-dimethylaniline (1.016 g) in methylene chloride are added dropwise to the solution. (15 ml) while cooling with ice for 10 minutes and stirred for another 20 minutes. The mixture is diluted with chloroform, washed successively with a 10% solution of hydrochloric acid, water and brine, dried over magnesium sulfate and evaporated under vacuum. The residual solid is recrystallized from methanol. The result is 6-acetamido-4-oxo-1-propionyl-1,2,3,4-tetrahydroquinoline (1.64 g). . .
    IR (Nujol): 3300, 1695, 1640 (wide), 590 cm;
    (3) similarly to procedure 1, 6 acetamido-3-dimethylaminomethylene-4-oxo-1-propionyl-1,2,3,4-tetrahydroquinoline is obtained;
    IR (Nujol): 3250, 1675, 1665, 1640, 1585, 1540 (bend), 1535 cm.
    Procedure 20. (l) A solution of propionyl chloride (1.018 g) in chloroform (5 ml) is added dropwise to a solution of 6-OXO-4-OXO-1-propioyl-1,2,3,4-tetrahydroquinoline (1 , 09 g), and, H-gdi-methylaniline (1.513 g) and 4-dimethyl-aminopyridine (0.061 g) in chloroform (20 ml) while stirring and cooling with ice for 10 minutes. After stirring overnight at ambient temperature, the mixture is evaporated under vacuum and the residue is dissolved in ethyl acetate. The solution is successively washed with a 5% hydrochloric acid solution, water, an aqueous solution of sodium bicarbonate and water, dried over magnesium sulfate and evaporated under vacuum. The result is an oil of 4-oxo-1-pr6pnonsh1-6-propionyloxy-1,2,3,4-tetrahydrohinolin (1.51 g).
    IR (film, NaCl): 1750, 1680 1655, 1600 cm-;
    (2) analogously to procedure 1, receive the compound 3-dimethylamine number
    913
    flax-4-oxo-1-propionyl-6-propionyl si-1,2,3,4-tetrahydroquinoline (1.75 g
    IR (film, NaCl): 1750, 1660, 1620 (wide) cm
    Procedure 21. A solution of 6-oxo-4-oxo-1-propionyl-1,2,3,4-tetrahydroquinoline (0.219 g), H, K-dimethylformamide, dimethyl acetal (0.476 g), triethylamine (0.202 d) in benzene (4 ml), refluxed with stirring for 2.5 hours, and chathen about 3/4 of the solvent is slowly distilled off under atmospheric pressure. A small volume of benzene is added to the residue and the solvent is again distilled off. The resulting solid is collected by filtration and the crude pro duct is obtained.
    The crude product is chromatographed on silica gel (10 g) using chloroform, and then the column is eluted with a mixture of chloroform and methanol (30: 1) in order to obtain two fractions.
    The first fraction is evaporated under vacuum, whereby 3-dimethylaminomethylene-6-methoxy-4-oxo-1-propionyl-1I2,3,4-tetrahydroquinoline (0.09 g) is obtained.
    The physical data of this compound is identical to that of the target compound from procedure 7 (2).
    The second fraction is evaporated under vacuum, whereby 3-dimethylaminomethylene-6-hydroxy-4-oxo-1-propionyl-1,2,3,4-tetrahydroquinoline is obtained (0.19 g).
    IR (Nujol): 3100 (wide) i 1660, 1610, 1540 cm (wide)
    Procedure 22. Similarly to procedures 1-2, compound 6-chloro- is obtained. 3-dimethylaminomethylene-1-methyl-4 -ox-co-1,2,3,4-tetrahydroquinoline. M.p. 122-125 C (after recrystallization from a mixture of benzene and n-hexane). ) Procedure 23. (l) Similarly to procedure 4 (1), the compound 6-chloro-1- (3-methoxypropionyl) -4-oxo-1,2,3,4-tetrahydroquinoline is obtained, m.p. 91-93 ° C (after recrystallization from a mixture of ethyl acetate and n-hexane);
    (2) analogously to procedures 1-2, the compound 6-chloro-3-dimethyl-aminomethylene-1- (3-methoxypropionyl) -4-oxo-1,2,3,4-tetrahydroquinoline is prepared.
    IR (Nujol): 1640 (kink), 1626, 1583, 1559, 1530 ..
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    3710
    Procedure 24. A mixture of 6-chloro-4-oxo-1-propionyl-1,2,3,4-tetrahydroquinoline (200.5 g) and 1,5-diazobicyclo (5.4, 0) undecene-5 ( 384.9 g) in ethyl formate (400.9 g) is heated to with stirring and maintained at this temperature for 7 hours, and then diluted with cold water (450 ml). The mixture was washed successively with diisopropyl ether and ethyl acetate, and then the aqueous layer was acidified with hydrochloric acid under ice-cooling. The resulting precipitate is collected by filtration and dried. As a result, 6-chloro-3-hydroxymethylene-4-oxo-1-propionyl-1,2,3,4-tetrahydroquinoline is obtained (168.29 g).
    IR (Nujol): 3350, 1680 cm.
    The filtrate is extracted with ethyl acetate, the extract is washed with water, dried over magnesium sulphate and evaporated under vacuum. Diisopropyl ether is added to the residue and the mixture is stirred at room temperature for 10 minutes. The resulting powder is collected by filtration and dried. The result is 6-chloro-1-formyl-3-hydroxymethylene-4-oxo-1,2,3,4-tetrahydroquinoline (6 g).
    IR (Nujol): 1690, 1680, 1460, 1200 ,, 830 cm-.
    The examples below illustrate the preparation of target compounds.
    Example 1. A solution of 6-chloro-3,4-dihydro-3-dimethyliminomethyl-4-oxo-2H-1-benzopyran (1.188 g), hydrazine hydrate (0.325 g) and acetic acid (0.39 g) in a mixture of chloroform (10 ml) and methanol (20 ml) is stirred overnight at room temperature, and then evaporated under vacuum. The residual solid is washed with water, dried and recrystallized from ethyl acetate. As a result, 8-chloro-1,4-dihydro (1) -benzopyrano {4,3-c) pyrazole (0.95 g) is obtained. M.p. 175-176 C (after recrystallization from ethyl acetate).
    IR (Nujol): 3100, 1590, 1460, 1385, 1380, 1360 cm
    Example2. A solution of 6-chloro-3,4-dihydro-3-dimethylaminomethylene-4-OXO-2H-1-benzopyran (1.425 g), methyl hydrazine (0.359 g) and acetic acid (0.468 g) in a mixture of chloroform (10 ml) and methanol (20 ml) stirred overnight at room
    :
    temperature, and then evaporated under vacuum. Ethyl acetate is added to the residue, successively washed with sodium bicarbonate solution, water and hydrochloric acid solution, dried over magnesium sulfate and evaporated under vacuum.
    The residual solid is recrystallized from diisopropyl ether. As a result, 8-chloro-1-methyl-1, A-dihydro- (1) -benzopyrano (4,3-e) pyrazole (0.92 g) was obtained. M.p. AO, 5-81 ° C (after recrystallization from diisopropyl ether).
    IR (Nujol): 1525, 1460, 1420, 1380, 1370, 1330 cm H
    PRI me R 3. A solution of 6-chloro-3-dimethylaminomethylene-4-oxo-1-propio-NIL-1,2,3,4-tetrahydroquinoline (19.0 g), methyl hydrazine (5.13 ml) and acetic acid (11.1 ml) in a mixture of methanol (700 ml) and tetrahydrofuran (700 ml) was stirred for 16 hours at room temperature. Acetic acid (5.0 ml) is then added to the reaction solution, and the solvent is evaporated under vacuum. A saturated aqueous solution of sodium hydrogencarbonate (200 ml) is added to the residue and the mixture is extracted with ethyl acetate (200 ml). The extract was twice washed with water (100 ml), dried over magnesium sulfate, evaporated under vacuum to give a yellow powder (17.8 g), which was subjected to recrystallization from a mixture of ethyl acetate and n-hexane. As a result, 8-chloro-4,5-dihydro-1-methyl-5-propionyl-C-pyrazolo (4,3-c) quinoline 14.7 g is obtained in the form of light yellow prisms, T, mp, 129 -130 s
    IR (Nujol): 1665 cm
    PRI me R 4. A solution of methyl hydrazine (0.331 g) in chloroform (30 ml was added to a mixture of 3-dimeshtamino-methylene-6-nitro-4-oxo-1-propionyl-1, 2,3,4 -tetrahydroquinoline (1.818 g) and acetic acid (0.468 g) in methanol (-30 ml) and stirred at room temperature for 24 hours. Acetic acid (2 ml) is added to this mixture and evaporated with iodine in vacuo. Residual solid the substance is rinsed with ethyl acetate. This gives the desired compound (1.06 g).
    five
    , "
    - 20 - 25 railway - g
    45 l) 50 x 55 The washing liquid is evaporated under vacuum, the residue is purified by chromatography on silica gel (30 g) using chloroform as eluent. The fractions containing the desired compound are obtained.
    These fractions are combined and concentrated under vacuum to give a solid, which is subjected to recrystallization from a mixture of chloroform and ethyl acetate, to obtain 4,5-dihydro-1-methyl-8-nitro-5-propionyl-1H-pyrazolo ( 4,3-e) quinoline (1,395 g), T, Ш1, 180.5-182.5 С
    IR (Nujol): 1665, 1510, 1340 cm-,
    EXAMPLE 5 Chloroform (50 ml) was added to a mixture of 3-dimethylamino-methylene-6-nitro-4-oxo-1-propionyl-1,2,3,4-tetrahydroquinoline (3.03 g) , hydrazine hydrate (0.6 g) and acetic acid (0.78 g) in methanol (50 ml), the mixture is stirred at room temperature for 8 hours, acetic acid (2 ml) is added and evaporated under vacuum. The residual solid is washed with water, dried and recrystallized from a mixture of chloroform and methanol. The result is 4,5-dihydro-8-nitro-5-propionyl-1H-pyrazolo (4,3-e) quinoline (2.53 g) . M.p., 219-22GS.
    IR (Nujol): 3260, 1665, 1615, 1595, 1515, 1340 cm.
    EXAMPLE 6 A mixture of 3-dimethyl-aminomethylene-4-OKCo-l-propionyl-1, 2,3,4-tetrahydroquinoline (2.838 g), hydrazine hydrate (0.66 g) and acetic acid (0.792 g g) in methanol (30 ml) is stirred at room temperature for 3 hours, acetic acid (1 ml) is added and evaporated under vacuum. The residue is dissolved in ethyl acetate, washed successively with an aqueous solution of sodium bicarbonate, water and hydrochloric acid solution, dried over magnesium sulfate and evaporated under vacuum. The residue is subjected to recrystallization from ethyl acetate. The result is 4,5-dihydro-5-propionyl-1H-pyrazolo (4,3-e) quinoline (1.77 g), mp. 129.5-13l c, EXAMPLE 7 The following compounds are prepared as in Examples 1-6: f
    (l) 8-chloro-4,5-dihydro-5-propionyl-1H-pyrazolo (4,3-e) quinoline. T. mp.
    201-203 C (after recrystallization from a mixture of chloroform, methanol and diethyl ether); IR (Nujol): 3280, 1663
    (2) 8-chloro-4,5-dihydro-1-methyl 1H-pyrazolo (4,3-c) quinoline. M.p. 177-180 ° C (after recrystallization from a mixture of ethyl acetate and n-hexane);
    IR (Nujol): 3284, 1619 cm;
    (3) 8-chloro-4,5-dihydro-1-isopropyl-5-propionyl 1H-pyrazolo (4,3-e) quinoline. T. pl. 106-107 ° C (after recrystallization from a mixture of ethyl acetate and n-hexane);
    IR 1; Nujol): 1660, 1650
    (4) 8-chloro-4,5-dihydro-1- (2-di-methylamino-ethyl) -5-propynyl-1H-pyrazolo 4, 3-c) quinoline. M.p. 99-1C1 C (after recrystallization from a mixture of ethyl acetate and n-hexane) ;.
    IR (Nujol): 1650 cm;
    (5) 8-HLOR-4,5-DIHIDRO-5- (2,3-dimethylpentanoyl) -1H-pyrazolo (4,3-e) quinoline. M.p. 169-170.5 ° C after recrystallization from a mixture of ethyladelate and diethyl ether;
    IR (Nujol): 3300, 1655 (kink), 1645 cm;
    (6) 8-chloro-4,5-dihydro-5-ethanesulfonyl-1H-pyrazolo (4,3-e) quinoline. M.p. 159-161 s (after recrystallization from diethyl ether);
    F (Nujol): 3340, 1600, 1350, 1330, 1150, 1145
    (7) 8-chloro-4,5-dihydro-1H-pyrazolo (4, 3-e) quinoline;
    IR (Nujol) G3400, 3370, 3140, 1620 cm;
    (8) 8-chloro-4,5-dihydro-5-myristoyl-1H-pyrazolo (4,3-e) quinoline. M.p. 93-94 ° C;
    IR (Nujol): 3200, 1630, 1600
    (9) 8-chloro-4,5-dihydro-5-methanesulfonyl-1H-pyrazolo (4,3-e) quinoline. M.p. 171.5-172.5 C;
    IR (Nujol): 3350, 3150, 1605 cm
    (10) 8-chloro-4,5-dihydro-5-ethyl-carbamoyl-1H-pyrazolo (4,3-e) quinoline So pl. 2G4-215 ° C (re-peretallization from ethanol and ethyl acetate);
    IR (Nujol): 3150 (wide), 1625 (wide), 1580, 1540 cm;
    (11) 8-HLOR-4,5-DIHIDRO-5-ETOXI carbonyl-1H-pyrazolo (4,3-e) quinoline. M.p. 232-233 C (decomposition) (after
    recrystallization from a mixture of ethanol and ethyl acetate);
    IR (Nujol): 3300, 1695, 1605 cm;
    (12) 8-chloro-5-cyclopropylcarbonyl-4,5-dihydro-1H-pyrazolo (4,3-e) quinoline. M.p. 191-193 ° C (after recrystallization from ethyl acetate);
    IR (Nujol): 3300, 1640, 1600cm; (13) 4,5-dihydro-8-hydroxy-5-propionyl-1H-pyrazolo (4,3-e) quinoline. M.p. 245.5-247 seconds (recrystallization from methanol and chloroform);
    (14) 4,5-DIHIDRO-8- (N-methyl-I-methylsulfonylamino) -5-propioyl-1H-pyrazolo (4,3-e) quinoline. M.p. 216- (after re-recrystallization from a mixture of chloroform and methanol);
    IR (Nujol); 3240, 1625 cm (15) 4,5-dihydro-8-methoxy-5-propionyl-1H-pyrazolo (4,3-e) quinoline. M.p. 132.5-134 ° C;
    IR (Nujol): 3200, 1625, 1495 eat; (16) 8-acetamido-4,5-dihydro-5-propionyl-1H-pyrazolo (4,3-e) quinoline. M.p. 235-237.5 C (decomposition); IR (Nujol): 3200 (wide), 1670, 1640, 1610, 1600 eat-;
    (17) 8,9-dichloro-4,5-dihydro-5-propionyl-1H-pyrazolo (4,3-e) quinoline. M.p. 179-180 ° C (re-recrystallization from ethyl acetate and n-hexane);
    IR (Nujol): 3210, 1660; (18) 6,8-dichloro-4,5-dihydro-5-propionyl-1H-pyrazolo (4,3-e) quinoline. M.p. 221-222 s (after recrystallization from a mixture of ethanol and n-hexane); IR (Nujol): 3250, 1650
    (19) 7,8-DICHLOR-4,5-DIHIDRO-5-propionyl-1H-pyrazolo (4,3-e) quinoline. M.p. 245-246 0 (after recrystallization from tetrahydrofuran);
    IR (Nujol): 3250, 1655cm;
    (20) 9-chloro-4,5-dihydro-8-methyroxycarbonylmethoxy-5-propionyl-1N-pyrazolo (4,3-e) quinoline;
    . I.
    IR (Nujol): 3250, 1765, 1650 cm;
    (21) 4,5-dihydro-8-methoxycarbonylmethoxy-5-propionyl-1H-pyrazolo
    (4,3-e) quinoline;
    IR (Nujol): 3325, 1740, 1640, 1620.
    (22) 4,5-dihydro-8-methyl-5-propionyl-1H-pyrazolo (4,3-e) quinoline. M.p. 164.5-166 ° C (after recrystallization from ethyl acetate);
    (23) 8- (4-chlorophenoxy) -4,5-dihydro-5-propionyl-1H-pyrazolo (4,3-e) quinoline. M.p. 161-162 s (after recrystallization from a mixture of ethyl acetate and n-hexane);
    IR (Nujol): 3280, 1625
    (24) 8-chloro-4,5-dihydro-1-ethyl-5-propionyl-1H-pyrazolo (4,3-e) quinoline. M.p. I2-FR ° C (after recrystallization from a mixture of ethyl acetate and n-hexane);
    IR (Nujol): 1650
    (25) 8-chloro-4,5-dihydro-1- (2-hydroxyethyl) -5-propionyl-IH-pyrazolo
    (4,3-e) quinoline. Mp; 145-147 ° C;
    IR (Nujol): 3325, 1660.
    ExampleB (l) A solution of 6-chloro-β-3-dimethylaminomethylene-4-oxo-1-propionyl-1,2,3,4-tetrahydroquinoline (2.00 g), 1-tert-butoxycarbon-1-1-methyl hydrazine (1.50 g) and acetic acid (1.20 ml) in methanol (100 ml) and tetrahydrofuran (100 ml) are refluxed for 9 hours with stirring. 1-tert-butoxycarbonyl-1-methylhydrazine (1.50 g) is added to the mixture. Stirring is continued for 8 hours under reflux conditions. After evaporation of the solvent under vacuum, a saturated aqueous solution of sodium hydrogencarbonate (15 ml) was added to the mixture and extracted with ethyl acetate (30 ml). The extract is washed with water, dried over.
    ten
    15
    20
    25
    thirty
    Sewing for an additional 1.5 hours. Solvent is added under vacuum, and a saturated aqueous solution of sodium hydrogencarbonate is added to the residue. The mixture is extracted with ethyl acetate, washed with water and dried over magnesium sulfate. The solvent is evaporated under vacuum. A bright brown powder (110 mg) is obtained, which is recrystallized from a mixture of ethyl acetate and n-hexane. As a result, pure 8-chloro-4,5-dihydro-1-methyl-5-propionyl-1H-pyrazolo (4,3-e) quinoline is obtained. M.p. D27-128 ° C.
    IR (Nujol): 1665 cm
    EXAMPLE 9 Methyl iodide (1.12 ml is added to a suspension of 8-chloro-4,5-dihydro-5-propion1-1H-pyrazolo (4,3-c) quinoline (4.00 g) and carbonate potassium (2.24 g) in K, I-dimeshm-amide (55 ml). After stirring for 12 hours at room temperature, the mixture was brought to 70 ° C and then stirred for another hour.
    After the solvent was evaporated under vacuo, water (100 ml) was added to the residue and the resulting mixture was extracted with ethyl acetate (40 ml). The extract is washed with water, dried over magnesium sulphate and evaporated under vacuum. A pale yellow powder is obtained which is recrystallized.
    magnesium sulphate and evaporated under w-35 two times from a mixture of ethyl acetate and cuum. The residue (3.90 g) was subjected to n-hexane. As a result, 8-chromatography on silica gel was used with -4,5-dihydro-2-methyl-5-propionyl-2H-pyrazolo (4,3-e) quinoline (1.70 g) in the form of pale yellow prisms. 40
    Chloroform as an eluent. As a result, 3- (2-tretichn. -Butoxycarbonyl 2-methylhydrazino) -metsh-6-chloro-4-oxo-1-propionyl-1,2,3,4-tetrahydroquinoline (2.10 g) in as a yellow amorphous material.
    IR (Nujol): 1720, 1670
    (2) A 36.7% ethanol solution of hydrogen chloride (0.10 ml) is added to a solution of 3- (2-tert-butoxycarbonyl-2-methylhydrazino) methylene-6-. chloro-4-oxo-1-propionyl-1 2,3,4-tetrahydroquinoline (150 mg) in ethanol (3.0 ml) at -4 ° C and stirred for one hour at the same temperature. After stirring at room temperature (te-55 n-hexane);
    M.p. 137-138 C.
    IR (Nujol): 1635 Example 10. The following compounds are obtained in the same manner as in Example 9:
    45 (O 8-chloro-4,5-dihydro-2-ethyl-5-propionic 1-2H-pyrazolo (4,3-e) quinoline. Mp. 115-116 C (after recrystallization from a mixture of ethyl acetate and n- heck sana);
    50 IR (Nujol): 1650
    (2) 8-chloro-4,5-dihydro-2-isopropyl-5-propion1-1H-pyrazolo (4,3-e) quinoline. M.p. 113-114 ° C (after recrystallization from a mixture of ethyl acetate
    IR (Nujol): 1650 cm; (H) 8-chloro 4,5-dihydro-2-all-1-5-propionyl-2H-pyrazolo- (4,3-e) quinoline
    36.7% ethanolic solution of hydrogen chloride (0.50 ml) is added to the mixture for 4 hours and the mixture is continued
    five
    0
    five
    0
    Sewing for an additional 1.5 hours. Solvent is added under vacuum, and a saturated aqueous solution of sodium hydrogencarbonate is added to the residue. The mixture is extracted with ethyl acetate, washed with water and dried over magnesium sulfate. The solvent is evaporated under vacuum. A bright brown powder (110 mg) is obtained, which is recrystallized from a mixture of ethyl acetate and n-hexane. As a result, pure 8-chloro-4,5-dihydro-1-methyl-5-propionyl-1H-pyrazolo (4,3-e) quinoline is obtained. M.p. D27-128 ° C.
    IR (Nujol): 1665 cm
    EXAMPLE 9 Methyl iodide (1.12 ml) was added to a suspension of 8-chloro-4,5-dihydro-5-propion1-1H-pyrazolo (4,3-c) quinoline (4.00 g) and potassium carbonate (2.24 g) in K, I-dimeshm-amide (55 ml). After stirring for 12 hours at room temperature, the mixture is brought to 70 ° C and then stirred for another hour.
    After the solvent was evaporated under vacuo, water (100 ml) was added to the residue and the resulting mixture was extracted with ethyl acetate (40 ml). The extract is washed with water, dried over magnesium sulphate and evaporated under vacuum. A pale yellow powder is obtained which is recrystallized.
    nyl-2H-pyrazolo (4,3-e) quinoline (1.70 g) as pale yellow prisms.
    M.p. 137-138 C.
    IR (Nujol): 1635 Example 10. The following compounds are obtained in the same manner as in Example 9:
    (About 8-chloro-4,5-dihydro-2-ethyl-5-propion1-1H-pyrazolo (4,3-e) quinoline. Mp. 115-116 ° C (after recrystallization from a mixture of ethyl acetate and n-hex - Sana);
    IR (Nujol): 1650
    (2) 8-chloro-4,5-dihydro-2-isopropyl-5-propion1-1H-pyrazolo (4,3-e) quinoline. M.p. 113-114 ° C (after recrystallization from a mixture of ethyl acetate and
    n-hexane);
    IR (Nujol): 1650 cm; (H) 8-chloro 4,5-dihydro-2-all-1-5-propionyl-2H-pyrazolo- (4,3-e) quinoline.
    1713
    M.p. 107-108 C (after recrystallization from a mixture of ethyl acetate and n-hexane);
    IR (Nujol): 1635
    (4) 8-chloro-D, 5-dihydro-2-propane-1-5-propionyl-2H-pyrazolo (4,3-e) quinoline. M.p. 111-112 ° C (after recrystallization from a mixture of ethyl acetate
    and n-hexane);
    IR (Nujol): 3225, 2125, 1631
    (5) 8-chloro-4,5-dihydro-5-propionyl-2- (2-methoxyethyl) -2H-pyrazolo (4,3-e) quinoline. M.p. 88-89 ° C (after recrystallization from a mixture of ethyl acetate and n-hexane);
    IR (Nujol): 1645
    NMR (CDCl},): 1.10 (3N, triplet Hz), 2.40 (2H, quartet, Hz), 3.34 (3N, singlet), 3.78 (2H, triplet, Hz), 4.32 (2H, .plet, Hz), 4.90 (2H, singlet), 7.26 (1H, doublet, 5 Hz), 7.27 (1H, singlet), 7.38 (1H, singlet ), 7.89 (W, doublet, 5 Hz);
    (6) 8-chloro-4,5-dihydro-5-propionyl-2- (2-oxopropyl) -2H-pyrazolo (4,3-с) quinoline. So pl., 131-132 s (after recrystallization from a mixture of ethyl acetate and n-hexane);
    IR (Nujol): 1725., 1645 cm;
    NMR (CDCl, s /): 1.05 (3N, triplet, Hz). 2.13 (ZN, singlet), 2.41 (2H, quartet, Hz), 4.88 (4H, singlet), 7.20 (IH, doublet, 1 1.5 Hz), 7.22 (1H, singlet), 7.25 (1H, singlet), 7.78 (W, doublet, 1 1.5 Hz);
    (7) 8-chloro-4,5-dihydro-2-ethoxycarbonylmethyl-5-propionyl-2H-pyrazolo (4,3-c) quinoline. M.p. 106-107 ° C (after recrystallization from a mixture of ethyl acetate and n-hexane);
    IR (Nujol): 1750, 1635 cm; - NMR (CDC1 J,}: 1.10 (ZN, triplet Hz), 1.28 (ZN, triplet, Hz), 2.44 (2H, quartet, Hz), 4.20 (2H, quartet, Hz) , 4.92 (4H, singlet), 7.22 (1H, doublet, 5 Hz 7.23 (1H, singlet), 7.35 (1H, singlet), 7.85 (1H, doublet, 5 Hz );
    (8) 8-chloro-4,5-dihydro-2- (2) -K, H-dimethylamino (ethyl) -5-propionyl-2H-pyrazolo (4,3-c) quinoline. M.p. 8082 C (after recrystallization from a mixture of ethyl acetate and n-hexane); IR (Nujol): 1655 cm;
    (9) 8-HLOR-4,5-dihydro-5-propionyl-2-n-tetradecyl-2H-pyrazolo (4.3-e

    O 5
    five

    50
    five
    0
    3718
    quinoline. M.p. 65-66 ° C (after recrystallization from diisopropyl ether);
    IR (Nujol): 1650 cm;
    (10) 2-benzyl-8-chloro-4,5-dihydro-5-propionyl-2H-pyrazolo (4,3-e) quinoline. M.p. 115-117 ° C (after recrystallization from a mixture of ethyl acetate and n-hexane);
    IR (Nujol): 1650
    (P) 8-chloro-4,5-dihydro-1-allyl-5-propionyl-1H-pyrazolo (4,3-e) quinoline;
    NMR (CDCl ,, cf): 1.10 (3N, TpHmief, Hz), 2.45 (2H, quartet, Hz), 4.68-5.38 (4H, multiplet), 4.82 (2H, singlet ), 5.77-6.40 (W, multiplet), 7.32 (1H, doublet, 5 Hz), 7.33 (W, singlet), 7.43 (W, singlet), 7.53 ( 1H, doublet, 5 Hz);
    (12) 8-chloro-4,5-dihydro-1-ethoke-carbonylmethyl-5-propionyl-IH-pyrazolo (4,3-e) quinoline;
    NMR (CDCl, f): 1.13 (-ZN, triplet, Hz), 1.28 (ZN, triplet, Hz), 2.44 (2H, quartet, Hz), 4.33 (2H, quartet, Hz ), 4.87 (2H, singlet), 5jl8 (2H, singlet), 7.35 (3N, singleton), 7.47 (1H, singleton);
    (13) 8-chloro-4,5-dihydro-5-propionyl-1 - (2-oceanopropyl) -1H-pyrazolo
    (4,3-e) quinoline;
    NMR (CDC1 ,,). 1.12 (ZN, triplet, Hz), 2.46 (2H, quartet, Hz), 3.35 (ZN, singlet), 3.92 (2H, triplet, Hz), 4.55 (2H, triplet, Hz) 4.80 (2H, singlet), 7.30 (1H, doublet, Hz), 7.32 (1H, singlet), 7.43 (iH, singlet), 7.93 (1H, doublet, Hz) ;
    (14) 8-HLOR-4,5-dihydro-5-propio NIL-1-n-tetradecyl-1H-pyrazolo (4, 3-c) quinoline;
    NMR (CDCl1, s /): 0.73-2.10 (24H, multiplet), 1.13 (ZN, triplet, 1 8 Hz), 2.42 (2H, quartet, Hz), 4.40 (2H , triplet, Hz), 4.82 (2H, singlet), 7.32 (IH, doublet), 7.37 (W, singlet), 7.40 (iH, singlet), 7.55 (1H, doublet) ;
    (15) 8-chloro-4,5-dihydro-1-metsh1-5-propionyl-i H-pyrazolo (4,3-e) quinoline;
    NMR (CDCl1, J): 1.10 (3N, triplet, Hz), 2.44 (2H. Quartet, Hz), 4.13 (3N, singleton), 4.78 (2H, singleton), 7.28 (1H, doublet, Hz),
    7.30 (IH, singlet), 7.33 (IH, singlet), 7.55 (IH, doublet, Hz);
    (16) 8-chloro-4,5-dihydro-l-ethyl-5-propionyl-1H-pyrazolo (4,3-e) quinoline;
    NMR (CDCl, of): 1.10 (3N, triplet, 5 Hz); 1.55 (3N, triplet, 1 6 Hz), 2.44 (2H, quartet,., 5 Hz),
    IR (Nujol): 3380, 3340, 3220, 1650 (kink), 1640, 1615 cm
    Example 13. A solution of sodium hydroxide (0.32 g) in water (4 ml) was added to a mixture of 4,5-dihydro-8-methoxycarbonylmethoxy-5-propionyl-1H-pyrazolo (4,3-c) quinoline (1.26 g) in methanol (20 ml). After stirring with vacuum, the residue is dissolved in an aqueous solution of sodium bicarbonate. The solution is washed with ethyl acetate and acidified.
    20
    4.42 (2H, quartet, Hz), 4.77 (2H, io at room temperature to a tsinglet), 7.30 (W, doublet, D, c), for 1.5 hours the solution is evaporated under 7 , 32 (1H, singlet), 7.37 (1H, singlet), 7.50 (1H, doublet, Hz);
    (17) 8-HLOR-4,5-dihydro-1-isopropyl-5-propionyl-1H-pyrazolo (4,3-e) quinoline;
    NMR (CDC1 ,, s /): 1.13 (3N, triplet, Hz), 1.63 (6H, doublet, 1 7 Hz), 2.51 (2H, quartet, Hz), 4.85 (2H, singlet), 4.95 {1H, septet, Hz), 7.40 (1H, doublet, 1 2 Hz), 7.43 (1H, singlet), 7.53 (1H, singlet), 7.62 (1H , doublet, 1 2 Hz);
    (18) 8-HLOR-4,5-dihydro-1- (2) N, H-dimethylamino (ethyl) -5 propionyl-1H-pyrazolo (4,3-c quinoline;
    5ShR (CDC1 ,,, c /): 1.13 (ZN, triplet, Hz), 2.35 {6H, singlet), 2.49 (2H, quartet, Hz), 2.90 (2H, triplet, Hz ), 4.57 (2H, triplet, Hz), 4.87 (2H, singlet), 7.42 (1H, doublet, Hz), 7.43 (1H, singlet), 7.52 (W, singlet) , 7.87
    10% solution of hydrochloric acid under ice cooling and stirring. The resulting precipitate is collected by filtration, washed with water and recrystallized from methanol. The result is: 8-carboxymethoxy-4,5-dihydro-5-propionyl-1H-pyrazolo (4,3-e) quinoline (1.05 g). T.SH1. 207-208.5 C (decomposition);
    IR (Nujol): 3,200, 1730, 1660, 1620 eat.
    Example 14: A solution of an acid sodium hydroxide (5.00 ml) is added to a solution of 8-chloro-4,5-dihydro-2-etkeicarbonylmethyl-5-propionyl-2H-pyrazo (4,3-e) quinoline (1.70 g) in methanol (50.0 ml). The mixture is stirred for 2 hours at room temperature. After evaporation of the solvent under vacuum, the residue is added by adding
    thirty
    40
    (1H, doublet, Hz).
    Example 11. Ratvor 4,5-dihyd-35 of chloro-hydrogenic kiellota ro-8-nitro-5-propionyl-1H-pyrazolo-5.0 ml) and ethyl acetate (5.0 ml). The regenerating reagent is collected by filtration and washed water, get Belsky powder (1.55 g), which is subjected to recrystallization from a mixture of ethanol and n-hexane. As a result. receive 8-chloro-4,5-dihydro-2-car6- .. hydroxymethyl-5-propion1-2H-pyrazolo- (4,3-с) quinoline (1.40 g) as colorless 45 prisms, T .pl. 125 ° C
    IR (Nujol): 3360, 1720, 1630 cm. Example 15. The following compounds are prepared in the same manner as in Examples 1-6:
    50
    (1) 8-chloro-4,5-dihydro-5-metsh1-1H-pyrazolo (4,3-e) quinoline. M.p.
    .148-149 C (after recrystallization from a mixture of ethyl acetate and n-hexane); IR (Nujol): 3145 cm;
    (2) 8-chloro-4,5-dihydro-5- (3-meth (4,3-c) quinoline (1.36 g) in methanol (250 ml) is subjected to hydrogenation over 5% palladium on carbon ( 0.4 g) at atmospheric pressure and ambient temperature. After the theoretical amount of hydrogen is aberated, the catalyst is separated by filtration, the filtrate is evaporated under vacuum. The residual solid is recrystallized from a mixture of methanol and chloroform to give 8-amino-4 , 5-dihydro-5-propionyl-1H-pyrazolo- (4,3-e) quinoline (0.981 g). Mp. 218-220 ° C (after recrystallization from a mixture of chlorofor ma and methanol).
    IR (Nujol): 3310, 3170 (wide), 1625 (wide) eat.
    Example 12. In the same way as in 55 measure 11, 8-amino-4,5-hydroxypropionyl) -1-methyl-1H-pyrazolo (4,3-e) hiiolium is obtained. M.p. 144-146 ° C
    po-1-metsh1-5-propionyl-1H-pyrazolo (4,3-e) quinoline. M.p. 178-179.5 ° C;
    IR (Nujol): 3380, 3340, 3220, 1650 (kink), 1640, 1615 cm
    Example 13. A solution of sodium hydroxide (0.32 g) in water (4 ml) was added to a mixture of 4,5-dihydro-8-methoxycarbonylmethoxy-5-propionyl-1H-pyrazolo (4,3-c) quinoline (1.26 g) in methanol (20 ml). After stirring with vacuum, the residue is dissolved in an aqueous solution of sodium bicarbonate. The solution is washed with ethyl acetate and acidified.
     at room temperature for 1.5 h, the solution is evaporated under
    10% solution of hydrochloric acid under ice cooling and stirring. The resulting precipitate is collected by filtration, washed with water and recrystallized from methanol. The result is: 8-carboxymethoxy-4,5-dihydro-5-propionyl-1H-pyrazolo (4,3-e) quinoline (1.05 g). T.SH1. 207-208.5 C (decomposition);
    IR (Nujol): 3,200, 1730, 1660, 1620 eat.
    Example 14: A solution of an acid sodium hydroxide (5.00 ml) is added to a solution of 8-chloro-4,5-dihydro-2-etkeicarbonylmethyl-5-propionyl-2H-pyrazo (4,3-e) quinoline (1.70 g) in methanol (50.0 ml). The mixture is stirred for 2 hours at room temperature. After evaporation of the solvent under vacuum, the residue is added by stirring
    (2) 8-chloro-4,5-dihydro-5- (3-methoxypropionyl) -1-methyl-1H-pyrazolo (4,3-e) hiiolium. M.p. 144-146 ° C
    211
    (after recrystallization from a mixture of ethyl acetate and n-hexane);
    IR (Nujol): 1647 (kink), 1522 cm;
    (3) 8-chloro-4,5-dihydro-1-propargyl-5-propionyl-1H-pyrazolo (4,3-e) quinoline;
    NMR (CDC1 ,,, J): 1, U (3N, triplet, Hz), 2.46 (2H, quartet, Hz), 2.59 (1H, doublet, Hz), 4.86 (2H, singlet) , 5.18 (2n, doublet, Hz), 7.39 (1H, doublet, 1 1.5 Hz), 7j40 (1H, singlet), 7.47 (IH, singlet), and 7.87 (W, doublet, 5 Hz);
    (4) 8-chloro-5-cyclopropylcarbonyl-4,5-dihydro-1-methyl-1H-pyrazolo
    (4,3-e) quinoline;
    NMR (CBC1e, c): 0.62-1.13 (2H, multiplet), 1.13-1.48 (2H, multiplet), 1.45-2.07 (W, multiplet), 4, .3 (ZN, singlet) 4.82 (2H, singlet), 7.28 (1H, double doublet, 1 2.8 Hz), 7.37 (1H, singlet), 7.43 (1H, doublet, Hz ) and 7.57 (W, doublet, Hz);
    (5) 8-chloro-4,5-dihydro-5-methyl-sulfonyl-1-methyl-1H-pyrazolo (4,3-e)
    quinoline;
    NMR (CDCli,): 2.42 (ZN, syn
    , glat), 4.18 (3N, singlet), 4.85 (2H, singlet), 7.48 (2H, singlet) and 7.73 (2H, broad singlet);
    (6) 8-chloro-4,5-dig1bcd-5-ethoxycarbonyl-1-methyl-1H-pyrazolo (4,3-e) quinoline;
    NMR (CDC1 ,, oR): 1.32 (ZN, triplet, Hz), 4.17 (ZN, singlet), 4.35 (2H, triplet, Hz), 4.87 (2H, singlet), 7, 35 (W, doublet, 1 2 Hz), 7.37 (1H, single -), 7.55 (W, doublet, Hz) and 7.57 (JH, singlet);
    (7) 8-chloro-4,5-dihydro-5-methyl-carbamoyl-1-methyl-1H-pyrazolo (4,3-e) quinoline;
    NMR (CDCl, /): 1.02 (ZN, triplet, Hz), 2.80-3.27 (2H, MULB-tiplet), 4.08 {ZN, singlet), 4.58 (2H, singlet) , 6.73 (IH, broad triplet, Hz), 7.33 (IH, singlet), 7.35 (1H, doublet, Hz), 7.37 (W, singlet) and 7.68 (1H, doublet, Hz).
    Example 16 The following compounds were prepared in the same manner as in Example 9:
    (1) 8-chloro-4,5-dihydro-1-propargyl-5-propionH1-1H-pyrazolo (4,3-e) quinoline. M.p. 148-149 С (after ne37
    22

    0 5
    0
    five
    0
    five
    0
    five
    recrystallization from a mixture of ethyl acetate and n-hexane).
    IR (Nujol): 3246, 2116, 1649
    (2) 2- (2-Butinsh1) -8-chloro-4,5-di hydro-5-propionyl-2H-pyrazolo (4,3-e) quinoline. M.p. 127-129 With (after recrystallization from a mixture of ethyl acetate
    and n-hexane);
    IR (Nujol): 2226, 1641 cm;
    (3) 8-chloro-4,5-dihydro-5- (3-metroxypropionyl) -1-methyl-1H-pyrazolo - (4,3-e) quinoline;
    NMR (CBC1z, “): 2.63 (2H, triplet, Hz), 3.27 (ZN, singlet), 3.50 (2H, triplet, Hz), 4.13 (ZN, singlet), 4.80 (2H, singlet), 7.27 (W, doublet, Hz), 7.28 (iH, singlet), 7.37 (IH, siyglet) and 7.50 (W, doublet, Hz);
    (4) 8-chloro-5-cyclopropylcarboxy-1-4,5-dihydro-1-methyl-1H-pyrazolo - (4,3-с) quinoline;
    NMR (CDCl1, (/): 0.62-1.13 (2H, multiplet), 1.13-1.48 (2H, multiplet), 1.45-2.07 (IH, multiplet), 4.13 (SN, singlet), 4.82 (2H, singlet), 7.28 (1H double doublet, 8 Hz), 7.37 (1H, singlet), 7.43 (W, doublet, Hz) and 7, 57 (W, doublet, Hz);
    (5) 8-chloro-4,5-dihydro-5-methyl-sulfonyl-1-methyl-1H-pyrazolo (4,3-e) quinoline;
    NMR (CDC1 ,,, c /): 2.42 (3N, singlet), 4.18 (3N. Singlet), 4.85 (2H, singlet), 7.48 (2H, singleton) and 7.73 ( 2H, broad singlet);
    (6) 8-chloro-4,5-dihydro-5-ethoxycarbonyl-1-methyl-1H-pyrazolo (4,3-e) quinoline;
    NMR (CDC1 ,, /): 1.32 (ZN, triplet, Hz), 4.17 (ZN, singlet), 4.35 (2H, triplet, Hz), 4.87 (2H, singlet), 7, 35 (W, doublet, Hz), 7.37 (W, singlet), 7.55 (1H, doublet, Hz) and 7.57 (IH, singlet);
    (7) 8-chloro-4,5-dihydro-5-ethyl-1-carbamoyl-1-methyl-1H-pyrazolo (4,3-e) -quinoline;
    NMR (CDCl, cf): 1.02 (ZN, triplet, Hz), 2.80-3.27 (2H, multiplet), 4.08 (ZN, singlet), 4.58 (2H, singlet) , 6.73 (W, broad triplet, Hz), 7.33 (W, singlet), 7.35 (W, doublet, Hz), 7.37 (1H, singlet) and 7.68 (1H, doublet, Hz).
    Example 17. Iiclopropanecarbonyl chloride (1.5 ml) was added in solution to a mixture of H, N-dimethylaniline (2.4 ml), 4-dimethylaminopyridine (5.0 mg) and 8-CHLOR-4,5-DIGIDRO -1-methyl- 1 H-pyrazolo (4, 3-e) quinoline (2.0 g) in chloroform (20 ml) at a temperature and the mixture is stirred at that temperature for 2 hours. After evaporation of the solvent under vacuum, the residue is mixed with A 5% solution of hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over magnesium sulfate. The solvent is evaporated under vacuum. A bright brown powder (2.0 g) is obtained, which is recrystallized from a mixture of n-hexane and ethyl acetate. The result is 8-chloro-5-cyclopropylcarboxy-4,5-di-hydro-1-methyl-1H-pyrazolo (4,3-e) quinoline in the form of colorless prisms. M.p. from 146 to 50 ° C
    IR (Nujol): 1647 cm
    Example 18. The following compounds were prepared as in Example 17:
    (About 8-chloro-4,5-dihydro-5-metsht-sulfonyl-1-methyl-1H-pyrazolo (4,3-e) - quinoline. So pl. 179-183 ° C (after recrystallization from a mixture of ethyl acetate and n-hexane);
    IR (Nujol): 1594, 1340, 1162 cm;
    (2) 8-chloro-4,5-DIHIDRO-5-ETOXI-carbonyl-1-methyl-1H-pyrazolo (4,3-e) quinoline. M.p. 124-125 ° (after recrystallization from a mixture of ethyl acetate and n-hexane);
    IR (Nujol): 1686, 1600, 1523
    (3) 8-chloro-4,5-dihydro-5-ethyl-carbamoyl-1-methyl-1H-pyrazolo (4,3-e) quinoline. M.p. 177-178 s (after recrystallization from a mixture of ethyl acetate and n-hexane);
    IR (Nujol): 3306, 1635, 1598 cm;
    (4) 8-chloro-4,5-dihydro-1-metsh1-5-propionyl-1H-pyrazolo (4,3-e) quinoline;
    NMR (CDC1 ,,, J): 1.10 (3N, triplet, Hz), 2.44 (2H, quartet, Hz), 4.13 (3N, singlet), 4.78 (2H, singlet), 7 , 28 (W, doublet, 1 2 Hz), 7.30 (1H, singlet), 7.33 (W, singlet), 7.55 (1H, doublet,: i 2 Hz);
    (5) 4,5-dihydro-1-methyl-8-nitro-5-propionyl-1H-pyrazolo (4,3-e) quinoline;
    NMR (DMCO-d (, (}: 1.02 (3N, triplet, Hz), 2.57 (2H, quartet.
    0
    five
    0
    five
    0
    five
    0
    five
     Hz), 4.21 (ZN, singlet), 4.86 (2H, singlet), 7.50 (1H, singlet), 7.86 (1H, doublet, Hz), 7.23 (1H, double doublet, , 8 Hz), 8.51 (1H, doublet, Hz); ,
    (6) 4,5-dihydro-8-nitro-5-propionyl-IH-pyrazolo (4,3-e) quinoline;
    NMR (DMCO-d, s /): 1.03 (3N, triplet, Hz), 2.58 (2H, quartet, Hz), 4.91 (2H, singlet), 7.72 (W, singlet), 7.80 (1H, doublet,: i 8 Hz) / 8.14 (W, doublet, 8 Hz), 8.47 (1H, doublet, Hz), 13, 14 (W, broad singlet);
    (7) 4,5-dihydro-5-propionyl-1H-pyrazolo (4,3-e) quinoline;
    NMR (DMCO-d, J}: 0.97 (3N, triplet, Hz), 2.45 (2H, quartet, Hz), 4.83 (2H, singlet), 7.17-7.9 (5H, multiplet), 12.95 (1H, broad singlet);
    (8) 8-HLOR-4,5-DIHIDRO-5-PROPIO-NSh1-1H-pyrazolo (4,3-e) quinoline;
    NMR (DMCO-d, V): 0.97 (3N, triplet, 6 Hz), 2.46 (2H, quartet, 6 Hz), 4.85 (2H, singlet), 7.30 (W, double doublet, 8.8.6 Hz), 7.57 (1H, doublet, 6 Hz), 7.71 (1H, singlet), 7.74 (1H, doublet, 1 1.8 Hz), 13, 05 (1H, broad singlet);
    (9) 8-chloro-4,5-dihydro-1-isopropyl-5-propionyl-1H-pyrazolo (4,3-e) quinoline;
    NMR (CDC1 ,,, 1.13 (ZN, triplet, Hz), 1.63 (6H, doublet, Hz), 2.51 (2H, quartet, Hz), 4.85 (2H, singlet), 4, 95 (1H, septet, 1 7 Hz), 7.40 (1H, doublet, Hz), 7.43 (W, singlet), 7.53 (IH, singlet), 7.62 (W, doublet, Hz) ;
    (S) 8-chloro-4,5-dihydro-1- (2-di-methylaminoethyl) -5-propiNYL-1H-pyrazolo (4, 3-e) quinoline;
    NMR (SGS1, cG): 1.13 (3N, triplet, Hz), 2.35 (6H, singlet), 4.57 (2H, triplet, Hz), 4.87 (2H, singlet), 7.42 (W, doublet, Hz), 7.43 (W, singlet), 7.52 (1H, singlet), 7.87 (W, doublet, Hz);
    (Ii) 8-chloro-4,5-dihydro-5- (2,3-dimethylpentanoyl) -H-pyrazolo (4,3-e) quinoline;
    NMR (DMCO-d jd): 0.63 (ZN, triplet, Hz), 0.68 (ZN, doublet, 1 Hz), 1.00 (ZN, doublet, Hz), calculated 0.9-1.8 (MN, multiplet), calculated 2.6-3.1 (IH, multiplet).
    25
    4.41 (IH, doublet, Hz), 5.35 (iH, doublet, Hz), 7.40 (2H, broad singlet), 7.74 (2H, broad singlet);
    (12) 8-chloro-4,5-dihydro-5-ethanesulfonyl, 1H-pyrazolo (4,3-e) quinoline;
    NMR (DMCO-dj,: 0.92 (ZN, triplet, Hz), 2.80 (2H, quartet, Hz), 4.82 (2H, singlet), 7.34 (1H, double doublet, 9 Hz ), 7.58 (1H, doublet, Hz), 7.77 (W, doublet, Hz), 13.13 (1H, broad singlet);
    (13) 8-chloro-4,5-dihydro-5-myristoyl-1H-pyrazo-olo (4,3-e) quinoline;
    NMR (DMSO-d6, t): 0.86 (3N, triplet, Hz), 0.95-1.64 (22H, multiplet); 2.3-2.6 (2H), 4.84 (2H, singleton), 7.32 (iH, double doublet, 8 Hz), 7.53 (1H, doublet, Hz), 7.72 (2H, broad eletlet), 13.02 (Ш, broad eletlet);
    (14) 8-chloro-4,5-dihydro-5-methane-eulfonyl-1H-pyrazolo (4,3-e) quinoline;
    NMR (DMSO- .de, d): 2.61 (3N, eunglet), 4.90 (2H, singleton), 7.45 (W, double doublet, 9 Hz), 7.64 (1H, doublet, Hz), 7.80 (W, singleton), 7.88 (1H, doublet, Hz), it is calculated: 13.0 (1H, wide eletlet);
    (15) 8 Chloro-4,5-dihydro-5-etsh1-carbamoyl-1H-pyrazo-olo (4,3-e) quinoline;
    NMR (DMSO-dg, J): 1.08 (3N, triplet, Hz), 2.86 read: 3.3 (2H., Multiplet), 4.69 (2H, singleton), 6.74 (IH , broad triplet, .Hz) 5 7.23 (1H, double doublet, 8 Hz), 7.43 (1H, doublet, Hz), 7.66 (2H, doublet, Hz), 13.00 (W, ШИРОК1-Ш singlet);
    (16) 8-chloro-4,5-dihydro-5-etkeicarbonyl-1H-pyrazolo (4,3-e) quinoline;
    NMR (DMSO-d, cG): 1, 21 (triplet, 7 Hz), 4jl6 (2H, quartet,), 4.81 (2H, singleton), 7.30 (1H, double doublet, 8 Hz) , 7.61 (1H, double year, Hz), 7.71. (2H, wide net), 13.0 (1H, broad net), 13.0 (1H, broad net);
    (17) 8-chloro-5-cycloprprylcarbonyl 4,5-dihadro-1H-pyrazolo (4,3-e) quinoline I
    NMR (DMCO-d jd): 0.66-1.13 (4H, multiplet), 1.63-21 (W, multiplet 4.87 (2H, singlet), 7.35 (1H, double doublet, , 8 Hz), 7.58 (1H, doublet, Hz), 7.74 (2H, doublet, 1 2 Hz), 12.96 (W, broad singlet


    Yu
    20

    25, „
    35

    ,
    50), j5
    5137 26
    (18) 4,5-dihydro-8-oxy-5-propionyl-1H-pyrazolo (4,3-e) quinoline;
    NMR (DMCO-d, /): 0.93 (3N, triplet, Hz), 2.37 (2H, quartet, Hz), 4.77 (2H, singleton), 6.68 (1H, double doublet, 8 Hz), 7.15 (1H, doublet, Hz), 7.28: (1H, doublet, Hz), 7.63 (1H, broad netlet), 9.56 (iH, broad netlet), 12.83 (W, broad eletlet);
    (19) 4,5-dihydro-8- (M-metsh1-11-methyleulfonylamino) -5-propionyl-HH-pyrazolo (4,3-e) quinoline;
    NMR (DMCO-dg, c /): 1.01 (ZN, triplet, Hz), 2.49 (2H, quartet,. Hz), 3.0 (ZN, singleton), 3.28 (ZN, singlelet) , 4.83 (2H, singlet), 7.29 (W, double doublet, 8 Hz), 7.54 (1H, doublet, Hz), 7.66 (1H, singlet) 7.74 (1H , doublet, Hz), 13.0 (W, broad eletlet);
    (20) 4,5-dihydro-8-methoxy-5-propionyl-1H-pyrazolo (4,3-e) quinoline;
    NMR (DMrO-d,): 0.97 (3N, triplet, Hz), 2.39 (2H, quartet, Hz), 3.85 (3N, singleton), 4.83 (2H, singleton), 6, 88 (W, double doublet, 8 Hz), 7.32 (1H, doublet, 1 2 Hz), 7.42 (W, doublet, Hz), 7.67 (1H, broad eletlet), 12.92 ( W, broad eletlet);
    (21) 8-acetamido-4,5-dihydro-5-propionyl-1H-pyrazolo (4,3-e) quinoline;
    NMR (DMCO-d, s /): 0.97 (3N, 3-plet, Hz), 2.09 (3N, singleton), 2.42 (2H, quartet, Hz), 4.79 (2H, ;; singleton), 7.39 (2H, singleton),
    7.59UH, singlet), 8.02 (IH, doublet, Hz), 9.93 (1H, singlet), 12.93 (1H, broad singlet);
    (22) 8,9-dichloro-4,5-dihydro-5-propionyl-1H-pyrazolo (4,3-e) quinoline;
    NMR (DMCO-dj ,, /): 0.97 (3N, triplet, Hz), .2.43 (2H, quartet, Hz) ,. 4.80 (2H, singlet), 7.53 (2H, singlet), 7.75 (W, singlet), 13.20 (1H, broad singlet);
    (23) 6,8-dichloro-4,5-DIHIDRO-5-. propionyl-1H-piraeolo (4,3-e) quinoline;
    t Р (DNCO-d,}: 0.96 (3N, triplet, Hz), 2.40 (2H, wide e-singlet), 4.04 (1H, wide e-enlet),
    5.60 (1H, broad elett), 7.59 (1H, doublet, Hz), 7.76 (2H, einglet), 13.5 (W, singleton);
    (24) 7,8-dichloro-4,5-dihydro-5-propionyl-3-pyrazolo (4,3-e) quinoline;
    1375137
     t t J k
    NMR (DMCO-d jcy): 1.02 (ZN. Tri-NMR (CDClj,): 1.10 MZN, triplet, plet, Hz), (2H, quartet, Hz), 2.48 (2H, quartet, Hz ), Hz), 4.87 (2H, singlet), 7.73 3.63 (W, broad singlet), 4.08-4.33 (1H, singlet), 7.90 (2H, singlet), ( 2H, multiplet), 4.53 (2H, triplet, 13.11 (W, singlet);
    (25) 9-ChLOR-4,5-dihydro-8-methoxy-carbonylmethoxy-5-propioyl-1H-pyra-3olo (4,3-e) quinoline;
    NMR (DMCO-dg, /): 0.92 (ZN, triplet, Hz), 2.37 (2H, quartet, Hz), 3.73 (ZN, singlet); 4.76 (2H, singlet), 4.97 {2H, singlet), 7.0.3 (W, doublet, Hz), 7.46 (W,
    doublet, Hz), 7.70 (1H, single), - j, yj vJti, singlet ;, 4 ,, 13.1 (W, broad single}); glj), 7.23 (ZN, singLet);
    (26) 4,5-dihydro-8-methoxycarboxy-1 (32) 8-chloro-4,5-dihydro-2-hydroxy-5-propionyl-1H-pyrazole
    three to 10
    methyl-hinoJH, doublet, 5 Hz);
    (31) 8-chloro-4,5-dihydro-2-m 5-propion1-2H-pyrazolo (4,3-e) lin;
    NMR (CDCl, o): 1.08 (ZN, triplet, Hz), 2.43 (2H, quartet, Hz), 3.93 (ZN, singlet), 4.87; (2H, syn 9 G ChN ntrwriYTO t 1
     4, e-dihydro-o-methoxycar methoxy-5-propionyl-1H-pyrazolo- (4,3-e) quinoline;
    NMR (DMCO-d ,.): 0.97 (3N, three lash, Hz), 2.42 (2H, quartet, Hz), 3.76 (3N, singlet), 4.83 (2H, singleton), 4.90 (2H, singlet), 6.62 (1H, double doublet, 9 Hz), 7.30 (1H, doublet, Hz), 7.49 (W, doublet, Hz), 7.68 (1H , singleton): Raschitano: 13.0 (1H, broad singlet);
    (27) 4,5-dihydro-8-methyl-5-l-1H-pipazolo (4.3-e inolin
    20
    propy (32) 8-chloro-4,5-dihydro-2-ethyl-5-propionyl-2H-pyrazolo (4,3-c) quinoline;
    NMR (): 1.08 (ZN, triplet, Hz), 1.50 (5H, triplet, Hz), 2.42 (2H, quartet, 7 Hz), 4.18 (2H,
    H, doublet, 11 L, 5 Hz);
    (33) 8-chloro-4,5-dihydro-2-isopropyl-5-propion-2H-pyrazolo (4,3-e) quinoline;
    NMR (CDCl1, c /): 1.11 (3N, triplet, 5 Hz), 2.46 (2H, quartet, 1 7.5 Hz), 4.94 (2H, singleton), 6.87-7 , 48 (8H, multiplet), 12.0 (1H, broad elett);
    (29) 8-chloro-4,5-dihydro-1-ethyl-5-propionyl-1H-pyrazolo (4,3-e) quinoline;
    NMR (CDCljjc /): 1.10 (3N, triplet, 5 Hz), 1.55 (3N, triplet, 1 6 Hz), 2.44 (2H, quartet, 7.5 Hz), 4.42 ( 2H, quartet, Hz), 4.77
    1375137
    t t J k I
    j, yj vJti, singlet ;, 4 ,, glat), 7.23 (3N, singlet);
    methyl-hinoJH, doublet, 5 Hz);
    (31) 8-chloro-4,5-dihydro-2-m 5-propion1-2H-pyrazolo (4,3-e) lin;
    NMR (CDCl, o): 1.08 (ZN, triplet, Hz), 2.43 (2H, quartet, Hz), 3.93 (ZN, singlet), 4.87; (2H, syn 9 G ChN ntrwriYTO t 1
    - j, yj vJti, singlet ;, 4 ,, glat), 7.23 (3N, singlet);
    (32) 8-chloro-4,5-dihydro-2-
    0
    (32) 8-chloro-4,5-dihydro-2-ethyl-5-propionyl-2H-pyrazolo (4,3-c) quinoline;
    NMR (): 1.08 (ZN, triplet, Hz), 1.50 (5H, triplet, Hz), 2.42 (2H, quartet, 7 Hz), 4.18 (2H,
    H, doublet, 11 L, 5 Hz);
    (33) 8-chloro-4,5-dihydro-2-isopropyl-5-propion-2H-pyrazolo (4,3-e) quinoline;
    2ui
    NMR (CDCl.c /): 1.10 (ZN, triplet, Hz), 2, AO; (2H, .quartet, Hz), 3.34 (ZN, singlet), 3.78 (2H, triplet, Hz ), 4.32 (2H, trig 5 Hz} doublet
    7.38 (W, singlet ,,. ,, ,,, ...,,
    5 Hz);
    {37) 8-HLOR-4,5-dihydro-5-propio-tO nyl-2- (2-oxopropyl) -2H-pyrazolo (4,3-e) quinoline;
    NMR (CDCljjC /): 1.05 (3N, triplet, Hz), 2.13 (3N, singlet), 2.41 (2H, quartet, Hz), 4.88 (4H, gl), 7.20 ( 1H, doublet, 5 Hz), 7.22 (1H, singlet), 7.25 (1H,. Singlet) 7.78 (1H, doublet, 5 Hz);
    (38) 8-HLOR-4,5-dihydro-2 ethoxycarbonylmethyl-5-propion1-2H-pyrazo-20o (4,3-c) quinoline;
    NMR (CDCl ,,): 1.10 (3Hi triplet, Hz), 1.28 (3N, triplet, Hz), 2.44 (2H, quartet, Hz), 4.20 (2H
    -t- - - "N / lo / / n
    137513730
    (42) 8-chloro-4,5-dihydro-1-allyl-5-propionyl-1H-pyrazolo (4,3-e) hino
    l o t, J-C J quinoline;
    NMR (CDC1, s): 1.13 (ZN, triplet, Hz), 1.28 (ZN, triplet, Hz); 2.44 (2H, quartet, Hz), 4.33 (2H quartet, Hz), 4.87 (2H, singlet) 5.18 (2H. Singlet). 7.35 (3N. Syn 4D; -chloro, 5-dihydro-propionyl-1-n-tetradecyl-1H-pyrazolo (4,3-e quinoline;
    NMR (CDCl, c): 0.73-2.10 (2 4NG multiplet), 1.13 (3N, triplet, 1 8 Hz), 2.42 (2H, quartet, Hz),
    quartet, 0. / 1 c ;, h, s / UH, p 5.18 (2H, singlet), 7.35 (3N, gl), 7.47 (1H, singlet);
    (44) 8-chloro-4,5-dihydro-5-propionyl-1- (2-oxopropyl) -1H-pyrazolo
     ,. ,,., - - .., -r-- - -., (4,3-е) quinoline;
    2.44 (2H, quartet, Hz), 4.20 (2H, NMR (ODCl, o): 1.12 (ZN, triplet, quartet, Hz), 4.92 (4H, singlet), 25 Hz), 2.4L (2H. Quartet, Hz), 7.22 (1H, doublet, 5 Hz), 7.23 3.35 (ZN, singleton), 3.92 (2H, three- (1H, singlet), 7.35 (W, singleton), plet, Hz.), 4.55 (2H, triplet, 7.85 (1H, doublet, 5 Hz);
    (39) 8-chloro-4,5-dihydro-2- (2) -K, N-dimethylaminoethyl-5-propion1-2H-pi-JQ has been broken (4,3-e) quinoline;
    NMR (CDCl, oP): 1.10 (3N, triplet, 5 Hz), 2.32 (6H, singlet), 2.43 (2H, quartet, 5 Hz), 2.78 (2H, triplet, Hz), 4.23 (2H, triplet, Hz), 4.89 (2H, singlet), 7.21 (1H, doublet, 5 Hz), 7.23. (W, singlet), 7.35 ( 1H, singlet), 7.85 (W, doublet, 5 Hz);
    (40) 8-chloro-4,5-dihydro-5-propio .. nyl-2-n-tetradecyl-2H-pyrazolo (4,3-c) quinoline;
    NMR (CDCljX): 0.74-2.0 (24H, multiplet), 1.10 (3N, triplet, 18 Hz), 2.39 (2H, quartet, Hz), 4.15 (2H, triplet, Hz), D, 92 (2H, singlet), 7.26 (1H, doublet, 1 1.5 Hz), 7.27 (2H, singlet); 7.91 (W, doublet, 5 Hz);
    (41) 2-benzyl-8-chloro-4,5-dihydro-5-propion1-1H-pyrazolo (4,3-e) quinho-50 lin;
    NMR (CDCl ,,,): 1.10 (3N, triplet, 5 Hz), 2.44 (2H, quartet, 1 7.5 Hz), 4.88 (2H, singleton), 5.33 (2H singlet), 7.25 (IH, doublet, I 1.5 Hz), 7.27 (2H, singlet), 7.35 (7H, singlet), 7.93 (W, doublet, .5 Hz);
    and
    t,)
    137513730
    (42) 8-chloro-4,5-dihydro-1-allyl-5-propionyl-1H-pyrazolo (4,3-e) hino
    l o t, J-C J quinoline;
    NMR (CDC1, s): 1.13 (ZN, triplet, Hz), 1.28 (ZN, triplet, Hz); 2.44 (2H, quartet, Hz), 4.33 (2H, quartet, Hz), 4.87 (2H, singlet), 5.18 (2H. Singlet). 7.35 (ЗН. Synquartet, 0. / 1 с ;, ч, Ь / UH, с 5.18 (2Н, singlet), 7.35 (ЗН, глт), 7.47 (1Н, singlet);
     4D; -chloro, 5-dihydro-propionyl-1-n-tetradecyl-1H-pyrazolo (4,3-e) quinoline;
    NMR (CDCl, c): 0.73-2.10 (2 4NG multiplet), 1.13 (3N, triplet, 1 8 Hz), 2.42 (2H, quartet, Hz),
    doublet, Hz), 7.69 (1H, doublet, Hz), 7.74 (1H, singlet), 11.33 (IH, broad singlet);
    (48) 8-chloro-4,5-dihydro-5- (3-methoxypropionyl) -1-methyl-1H-pyrazolo (4,3-c) quinolium;
    NMR (CDCl1, /): 2.63 (2H, triplet, Hz), 3.27 (3N, singlet), 3.50 (2H, triplet, Hz), 4.13 (3N, singlet), 4.80 (2H, singlet), 7.27 (1H, doublet, Hz), 7.28 (1H,. Singlet), 7.37 (1H, singlet) and 7.50 (W, doublet, Hz);
    ten
    and then ethanol. The result is 8-chloro-4,5-dihydro-1-methyl-5-propionyl-1H-pyrazole 6 (4,3-e) quinoline (65.84 g). The physical data for this compound is identical to the physical data for the target compound of Example 3.
    PRI me R 20 276 and acetic acid (13 ml) in methanol (2.76 l) at a temperature of 10 Or
    (49) 8-HLOR-4,5-dihydro-1-propar-5 to 2 ° C for 10 minutes. After peGSh1-5-PROPIONIL-IH-pyrazolo (4,3-e) quinoline;
    NMR (CDClI,. /): 1.14 (3N, triplet, Hz), 2.46 (2H, quartet, Hz), 2.59 (W, doublet, Hz), 4.86 (2H, singlet), 5.18 (2H, doublet, Hz) 7.39 (1H, doublet, 5 Hz), 7.40 (W, singlet), 7.47 (W, singleton) and 7.87 (1H, doublet, 5 Hz);
    20
    stirring for 1.5 hours at the same temperature, the resulting precipitate is collected by filtration, washed with methanol and dried. The result is 8-chloro-4,5-dihydro-5-formyl-1-methyl-1H-pyrazolo (4,3-e) quinoline (174 g).
    The filtrate is dried overnight at room temperature
    (50) 2- (2-Butinsh1) -8-chloro-4,5-di-25% precipitate is collected by filtration.
    hydro-5-propionyl-2H-pyrazolo (4,3-e) quinoline;
    NMR (CDCl3, f): 1.10 (3N, triplet, Hz), 1.90 (3N, doublet, Hz), 2.44 2H, quartet, Hz), 4.90 (2H, singleton), 4, 92 J2H, quartet, Hz), 7.18 (W, s inglet), 7.20 (W, doublet, HzT, 7.45 (W, singlet) and 7.83 (W, doublet, Hz);
    (51) 8-chloro-4,5-DIHIDRO-5-FORMIL-1-methyl-1H-pyrazolo (4,3-e) quinoline;
    NMR (CDCls, -): 4.20 (3N, singlet), 4.86 (2H, singlet), 7.36 (W, singlet), 7.03-7.46 (2H, multiplet) ,. 7.62 He, doublet, Hz) 7 8.47 CN, singlet).
    Example 19: Netilhydrazine (30.56 g) was added dropwise to a mixture of 6-chloro-3-hydroxymethylene-4-oxo-1-propionyl-1,2,3,4-tetrahydroquinoline (160.3 g) and acetic acid (75.8 ml) in methanol (1.6 l) with stirring and cooling for 10 minutes. After stirring for one hour at room temperature, the mixture is filtered with suction, the filtrate is evaporated under vacuum after the addition of uceuic acid (160 ml). The reactor is neutralized with an aqueous solution of sodium hydroxide with ice-cooling. The resulting precipitate is collected by filtration, washed with water and recrystallized from aqueous ethanol35
    40
    washed with methanol and dried. The result is 8-chloro-4,5-dihydro-gO-5-formyl-1-methyl-1 H-pyrazolo. (4,3-e) quinoline (22.9 g).
    30 IR (Nujol): 1675 (kink), 1665 1470, 1460 (kink) cm;
    NMR (CDClj.cn): 4.20 (3N, singlet 4.86 (2H, singleton), 7.36 (IH, eiglet), 7.03-7.46 (2H, multiplet), 7.62 (W, doublet, Hz), 8.47 (iH singlet).
    Example 21 A solution of 6-chloro-3-dimethylaminomethylene-4-oxo-1-propionyl-1,2,3,4-tetrahydroquinoline (2.02 g) is dissolved in methanol (30 m hydrate hydrazine (0.37 ml; the mixture is stirred overnight at room temperature and digested under vacuum conditions. The residue is separated by chromatography on silica gel columns. The column is eluted with a mixture of chloroform and methanol (50: 1), after which the fractions containing target compound, collect and
    50 is evaporated under vacuum under the formation of 8-chloro-4,5-dihydro-5-pro pionyl-1H-pyrazole (4,3-e) quinoline (0.5 g). The physicochemical properties of the compound obtained are identical.
    55 properties of the compound described in Example 7 (1).
    Heterocyclic compounds with condensed benzene have
    45
    and then ethanol. The result is 8-chloro-4,5-dihydro-1-methyl-5-propionyl-1H-pyrazole 6 (4,3-e) quinoline (65.84 g). The physical data for this compound is identical to the physical data for the target compound of Example 3.
    EXAMPLE 20 Methylhydrazine (52.5 g) was added dropwise to a mixture of 6-chloro-1-forma-3-hydroxymethylene-4-ox-1,2,3,4-tetrahydroquinoline ( 276 g) and acetic acid (13 ml) in methanol (2.76 l) at a temperature of 10 Or
    TO 2 ° C for 10 min. After 2 ° C for 10 min. After ne
    stirring for 1.5 hours at the same temperature, the resulting precipitate is collected by filtration, washed with methanol and dried. The result is 8-chloro-4,5-dihydro-5-formyl-1-methyl-1H-pyrazolo (4,3-e) quinoline (174 g).
    The filtrate was removed overnight at room temperature, the semi-dried precipitate was collected by filtration.
    washed with methanol and dried. The result is 8-chloro-4,5-dihydro-gO-5-formyl-1-methyl-1 H-pyrazolo (4,3-e) quinoline (22.9 g).
    IR (Nujol): 1675 (kink), 1665, 1470, 1460 (kink) cm;
    NMR (CDClj.cn): 4.20 (EH, singlet); 4.86 (2H, singleton), 7.36 (IH, e-glet), 7.03-7.46 (2H, multiplet), 7.62 (W, doublet, Hz), 8.47 (iH singlet)
    Example 21: Solution of 6-chloro-3-dimethylaminomethylene-4-oxo-1-propionyl-1,2,3,4-tetrahydroquinoline (2.02 g) is dissolved in methanol (30 ml) , hydrazine hydrate (0.37 ml) is added, the mixture is stirred overnight at room temperature, and ryparivat under vacuum. The residue is separated by chromatography on silica gel columns. The column was eluted with a mixture of chloroform and methanol (50: 1), after which the fractions containing the desired compound were collected and
    evaporated under vacuum conditions to form 8-chloro-4,5-dihydro-5-propionyl-1H-pyrazole (4,3-e) quinoline (0.5 g). The physicochemical properties of the compound obtained are identical.
    properties of the compound described in Example 7 (1).
    Heterocyclic compounds with condensed benzene have
    331375137
    diuretic, urinary and vasodilating activity.
    The following pharmacological test data (Table O. (I) test compound: (a) a compound of the formula
    Table 1
    (b) a compound of the formula
    SNGS "SI
    SOS
    (c) test procedure:
    Male rats of the SD strain at the age of 6 weeks were used after holocadenis for 18 hours. The test compound was administered to the rats by mouth (dose: 320 mg / kg). Immediately after administration (20 mp / kg of physiological saline solution is used), the animals
    The cell is placed in the cage to observe ANIMAL metabolism} urine is collected every 3 hours for 6 hours. Experiments were performed using 3 groups (3 rats per group) for each compound. The volume of urine is measured using a measuring cylinder; urinary electrolytes (Na and K) - using the state / iron system (Technicon), and the amount of urinary
    acid in urine - modified
    Makino's method, using the device (measuring instrument MK), produced by the company Kiowa Medeks Co. All parameters are expressed in the amount of leaching (%) per kg
    animal weights compared to the same values for control rats;
    (g) the test results are given in table 2.

    Volume of urine,%
    Similarly, other targets of its compounds are tested.
    Pharmacological test results for compounds in which
    table 2
    Allocation,%
    On
    TO
    uric acid
    -N-, are given in table. 3
    R,
    35
    1375137
    36 Table 3
    37
    137513738
    Continuation of table 3
    R. - lower quinil
    R - lower quinil
    R - C, - C 4 alkyl
    R - lower alknl
    replacement hydro
    to a strong group
    R 4 - the lowest al
    kil, substituted
    lower alkoxy
    Noah group
    R - lower al-: kil, substituted by carboxyl group
    R is lower alkyl substituted by dimethylamino group
    (Dose; 32 kg / mg)
    B - lower alkyl, substituted by benzyl group



    10 (6) 286
    Table 4 summarizes the results of fission, in which X is an oxygen atom, the macroscopic tests of target compounds4


    170 163
    123
    141
    135
    134
    226
    458
    The test data for acute toxicity of a typical target compound is given below.
    1. Test compound
    CHy-nn
    ,
    20
    2. Test Method:
    After the ICR strain infected male mice (average weight 29 g, one group - ten animals), a 0.5% methylcellulose suspension containing the test compound was administered through the mouth, mice were observed for a week .
    3.Result test:
    权利要求:
    Claims (1)
    [1]
    average lethal dose 1000 mg / kg Formula of the invention
    thirty
    The method of obtaining heterocyclic compounds with condensed beisol of formula 1
    (I)
    where A is a group of the formula
    W; -P-
    T or Y
    - oxygen atom or group forTD
    - Nt. ;
    at X - oxygen atom R - 50 chlorine atom; R., j is a hydrogen atom; E is hydrogen or methyl; when X is the group N; s
    R is a hydrogen or chlorine atom.
    55
    a nitro, amino, or hydroxy group, methyl, methoxy, carboxymethoxy, or acetamido; R - hydrogen or chlorine atom: R atom in
    ten
    15
    20
    g
    dorodol, methyl, propionyl, methoxypropionyl, cyclopropylcarbonyl, methanesulfonyl, ethip-carbamoyl, or ethoxycarbonyl; R is an oxygen atom, lower alkenyl, lower apkyl, C, - C1 alkyl, or lower alkyl, substituted by hydroxy group, lower alkoxy group, carboxy-group, lower alkanoyl group, dimethylamino group, or benzyl,
    about that with the fact that
    compound of formula II
    snv
    thirty
    where R, R and X have the indicated meanings;
    .T -R J
    B - hydroxy group or group
    -N R ,. and R is lower apkyl, I
    subjected to interaction with the compound of the formula III
    40
    one
    five
    0
    five
    where R. has the indicated values, in an environment of an organic solvent, such as chloroform, methanol, tetrahydrofuran, or their mixture, and if R in the resulting compound of the general formula I is a hydrogen atom, it is alklylated, if get a compound of General formula I, containing the nitrogroup, the latter; reduced to an amino group, if in the resulting compound of the formula IR is methoxycarbonylmethoxy or R4 is lower alkyl substituted by (lower alkoxy) carbonyl group, carboxy-protecting groups are removed, and in the resulting compound of the general formula IR - hydrogen atom, it is acylated.
    according to p and 3 41
    Priority n and m:
    10.26.84 at X - oxygen atom R,
    13
    or group - w, with X - atom. oxygen RI - chlorine atom, R -, atom
    hydrogen, R4 is a hydrogen atom or methyl, at X - the group is NC B, is an atom
    hydrogen or chlorine, nitro, amino, or hydroxy, methyl, methoxy, carboxymethoxy, or adhetamido; H is a hydrogen or chlorine atom; R3 is a hydrogen atom, propionyl, methoxypropionyl, cyclopropylcarbonyl, methane sulfonyl, ethylcarbamoyl or ethoxycarbonyl {R4 is a hydrogen atom, lower al 1375137
    42
    five
    keNIL, lower quinil. C, - C is an apkyl or isopic alkyl, substituted by a hydroxy group, a lower alkoxy group, a carboxy group, a lower alkanoyl group, a dimethylamino group, or a benzyl group;
    08.05,85 with X - group -NSI h
    RI is a hydrogen or chlorine atom, a nitro, amino, or hydroxy group, methyl, methoxy, carboxymethox w: shG acetamido; R is a hydrogen or chlorine atom; R is a hydrogen atom, lower alkenyl, lower alkyl, C - C, - alkyl or lower alkyl substituted by hydroxy group, lower alkoxy group, carboxy group, 1 lower alkanoyl group, dimethylamino group, or benzyl.
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    CN85108618A|1986-08-27|
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    GR852593B|1985-12-24|
    US4767780A|1988-08-30|
    AU4855185A|1986-05-01|
    JPH0649702B2|1994-06-29|
    ES548205A0|1986-12-16|
    KR860003259A|1986-05-21|
    NO854275L|1986-04-28|
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    ES8801266A1|1987-12-16|
    DE3587362T2|1993-09-09|
    HUT40124A|1986-11-28|
    EP0180352B1|1993-05-26|
    FI853757A0|1985-09-30|
    JPS61112076A|1986-05-30|
    PH21213A|1987-08-21|
    EP0180352A2|1986-05-07|
    AT89825T|1993-06-15|
    ES557041A0|1987-12-16|
    DE3587362D1|1993-07-01|
    ES8702139A1|1986-12-16|
    EP0180352A3|1988-03-30|
    US4675324A|1987-06-23|
    引用文献:
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    FR2009079A1|1968-05-22|1970-01-30|Sandoz Sa|
    US3624102A|1969-05-21|1971-11-30|Warner Lambert Co|Substituted benzopyranopyrazoles|
    EP0022078B1|1979-06-21|1984-07-25|Ciba-Geigy Ag|Pyrazolo-quinolines, processes for their production, and pharmaceutical compositions containing them|
    US4524146A|1982-12-08|1985-06-18|Ciba-Geigy Corporation|Certain -2-heterocycle substituted pyrazoloquinolines|US4839368A|1986-05-02|1989-06-13|Mochida Pharmaceutical Co., Ltd.|1-acyl-2,3-dihydro-4-quinolinone-4-oxime derivatives|
    US4816467A|1987-01-09|1989-03-28|Farmitalia Carlo Erba S.R.L|Heteroaryl 3-oxo-propanenitrile derivatives, pharmaceutical compositions and use|
    CA1311761C|1987-04-09|1992-12-22|E.I. Du Pont De Nemours And Company|Insecticidal substituted indazoles|
    JP2602037B2|1987-10-31|1997-04-23|持田製薬株式会社|1-acyl-2,3-dihydro-4-quinolinone-4-oxime derivatives, process for preparing the same, and pharmaceutical compositions containing diuretic, antihypertensive, anti-edema and ascites removal based on them|
    US5192768A|1990-09-14|1993-03-09|Kyowa Hakko Kogyo Co., Ltd.|Pyrazoloquinoline derivatives|
    DK1221440T3|1994-06-15|2007-09-17|Otsuka Pharma Co Ltd|Benzoheterocyclic derivatives useful as vasopressin or oxytocin modulators|
    US5865170A|1997-07-23|1999-02-02|Moles; Randall C.|Customizable mouthpiece for scuba-divers|
    ES2282693T3|2002-11-22|2007-10-16|Active Biotech Ab|PIRAZOLOQUINOLINAS WITH IMMUNOMODULATING ACTIVITY.|
    US20070238740A1|2003-08-28|2007-10-11|Nitromed, Inc.|Nitrosated And Nitrosylated Cardiovascular Compounds, Compositions And Methods Of Use|
    AU2006216665A1|2005-02-24|2006-08-31|Nicox S.A.|Nitric oxide enhancing diuretic compounds, compositions and methods of use|
    UA100501C2|2006-12-29|2013-01-10|Ебботт Гмбх Унд Ко. Кг|Carboxamide compounds and their use as calpain inhibitors|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    GB848427124A|GB8427124D0|1984-10-26|1984-10-26|Benzene-fused heterocyclic compound|
    GB858513399A|GB8513399D0|1985-05-28|1985-05-28|Heterocyclic compound|
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