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    • 专利摘要:
    Compounds of the formula …<IMAGE>… in which either R1 represents a trifluoromethyl radical, R2 and R3 together with the nitrogen atom to which they are attached form a morpholino radical and R4 represents a 4-methylphenyl, 4-chlorophenyl, 2-, 3- or 4-fluorophenyl, 4-methoxyphenyl, 4-methyl-3-fluorophenyl, 2,4-difluorphenyl or 4-aminophenyl radical, or R1 represents a trifluoromethyl radical, R2 and R3 together with the nitrogen atom to which they are attached form a thiomorpholino radical or R2 represents a methyl radical and R3 represents a 2-methoxyethyl radical, and R4 represents a 4-methylphenyl radical, or R1 represents a chlorine or fluorine atom or a methoxy radical, R2 and R3 together with the nitrogen atom to which they are attached form a morpholino radical and R4 represents a 4-methylphenyl radical, their processes of preparation and the medicaments in which they are present.
    公开号:SU1709911A3
    申请号:SU894614918
    申请日:1989-09-12
    公开日:1992-01-30
    发明作者:Дюброек Мари-Кристин；Пари Жан-Марк；Рено Кристиан
    申请人:Рон-Пуленк Санте (Фирма)；
    IPC主号:
    专利说明:

    The purpose of the invention is to obtain new compounds in the range of quinolines, which in their activity are superior to the structural analogue, using the known method of formation of npoctiix ethers, 1. Meter 1. To a stirred suspension of 2.4 g 2- (4- methylphenyl) -5-trifluoromethyl-4-quinoline and 1.8 g of k - (2-chloromethyl) morpholine in 50 cm of 2-butanone were added 2.2 g of anhydrous potassium carbonate. Heat under reflux for 3 hours, cool to room temperature (about 20 ° C), insoluble materials are removed by filtration, washed with 2-butanone, the organic phases are collected and the solvent is removed under reduced pressure. After recrystallization of the residue and acetonitrile, 2.6 g of 4- (2- (4-methylphenyl) -5-trifluoroethyl-4-quinolyl) oxyacetyl-morpholine is isolated which melts at. 2- (4-Methylphenyl) -B-trifluoromethyl-quinolone can be obtained in the following way. 2.8 g of N- (2-acetyl-3-trifluoromethylphenyl) -4-methyl benzamide and 1.07 g of tertiary butyl potassium in 30 cm of toluene are heated under reflux for 1 h. The mixture is cooled to room temperature (), 0.55 cm of glacial acetic acid is added and diluted with 30 cm of water and 15 cm 3 of ethyl ether. The suspension is stirred for 30 minutes, the precipitate is drained, washed 2 times with ethyl ether, then with water and dried. Melting point above 2 ° C. -N- (2-Acetyl-3 Trifluoromethylphenyl).-T-methylbenzamide was prepared as follows. 2.45 g of 2-amino-6-trifluoro methyl acetophenone, 1.45 cm 47 of methyl benzoyl chloride and 1.7 cm of pyridine in 20 cm of anhydrous toluene are stirred at room temperature (20 ° C) for 45 minutes. Then 20 cm of water and 80 cm of ethyl acetate are added. The aqueous phase is decanted, and the organic phase is washed three times with 25 cm 3 of water, dried over magnesium sulphate and evaporated under reduced pressure. The residue obtained is stirred in 50 cm of petroleum ether, filtered and washed with petroleum ether. This operation is repeated two. 2.5 g of H- (2-acetyl-3-trifluoromethylphenyl) -4-methylbenzamide a, which melts at 171 ° C, are thus isolated. 2-Amino-6-trifluoromethylacetophenone hydrochloride can be prepared by the following method. 7 g of N- (2-acetyl-3-triphosphoromethylphenyl) -2, 2-dimethyl-propionamide in a mixture of 670 cm of concentrated hydrochloric acid and 670 cm of ethanol are heated under reflux for 5 h 30 min. Cool to room temperature (about). The solvents are evaporated under reduced pressure, the crystalline residue is repeatedly taken up in toluene and each time it is evaporated to remove residual water, washed first with ethyl ether, then with petroleum ether 40-60 ° and dried under reduced pressure. In this way, 50.4 g of 2-amino-6-trifluoromethylacetophenone chlorohydrite is obtained, which is melted at. N- (2-Acetyl-3-trifluoromethylphenyl) -2 j2-dimethyl-prono-amide was prepared as follows. To cooled to a solution, 36 g of N- (2- (oi-hydroxyethyl) -3 trifoftrommethyl-phenyl} -2, 2-dimethylpropionamide in 1000 cm of acetone is added in portions over 20 minutes to 37 g of chromic anhydride. Stir for 15 an additional 19 g of chromic anhydride is added in portions, then stirring is continued for another 15 minutes at 5 ° C, then 120 cm of isopropanol is slowly introduced to destroy the excess of chromic anhydride. The temperature rises to room temperature (about 20 ° C). evaporated under reduced pressure. The residue is treated with 700 cm of water and 1000 cm of ethyl the ether is then stirred for 1 hour, the insoluble matter is filtered off and washed with water and ethyl ether.The aqueous and organic phases are combined, the aqueous phase is decanted and washed twice with 200 cm of ethyl ether.The organic phases are collected, washed with 2 times 100 cm of water, 2 times-100 cm of 5% potassium bicarbonate solution and 2 times 100 cm of water, dried over magnesium sulfate and then evaporated under reduced pressure. Thus, 34.3 g of N- (2-acetyl-3-trifluoromethylphenyl) -2,2-dimethyl-propionamide, which melts at 142 ° C, are obtained. N- (2- (Ob-Hydroxyethyl) -3-trifluoromethyl-phenyl) -2,2-dimethyl-propionamide can be obtained as follows to a solution of 7.7 g. (8-trifluoromethyl-phenyl) -2,2-dimethyl -propionamide in 0 cm3 of dry tetrahydrofuran, placed under nitrogen and cooled to 10 s, is added over 15 min to 5 cm of a solution of 1.37 ML-butyl lithium in hexane, stirred for 2 hours at this temperature. The solution is then cooled to -7 ° C and injected 17.5 cm of acetaldehyde cooled to -78 ° C in 1 time. The temperature quickly rises to 12 ° C, then lowers. When the reaction mixture is at -10 ° C, 150 cm of water are quickly added. After evaporation of the tetrahydrofuranium under reduced pressure, the suspension is dissolved in 200 cm of ethyl ether and stirred to dissolve. The aqueous phase is decanted. The organic phase is washed three times with 20 cm of water, dried over magnesium sulfate and evaporated under reduced pressure. The resulting residue is treated with 1 cm of petroleum ether and decomposed under reflux. The white suspension obtained in this way is cooled, the precipitate is dewatered, transferred to a paste-like state by treatment 2 times with petroleum ether, washed with precooled isopropyl ether and dried under reduced pressure. 6.2 g of N- (2 - ((xi-hydroxyethyl) -3-triphosphoromethyl-feiyl) -2,2-dimethylpropionamide are obtained, which melts at 172 EXAMPLE 2. The operations are carried out as in Example 1 , but they take 2.9 g of 2- (k-chloro-phenyl) -5-trifluoromethyl-quinolo 1.62 g (- (2-chloro-acetyl) -morpholino and 2.5 g of anhydrous potassium carbonate in 60 cm 2 -butanone. After recrystallization in acetonitrile, 3, g of 3- (2- (-chlorophenyl) -5-trifluoromethyiL-xi NOL-yl) KS and acetyl-morpholine, which is melted at 2- (4-Chloro-phenyl ) -5-trifluoromethyl-β-quinoline can be obtained by the following method. The operations are carried out as in Example 1 to obtain 2 - (- M ef: methyl-phenyl) -5-trifluoromethyl-4-quinol-, from N- (2-acetyl-3-trifoptermethyl-phenyl) - -chloro-benzamide (3.5 g) and tertiary potassium butylate (1.24 d) in CC, see toluene, by extending the heating time to 1 h 30 min. The substance has a melting point above 2 W o C. N- (2 Acetyl-3 trifluoromethyl-phenyl) - -chloro-benzamide can be obtained by the following method. as in example 1, to obtain N- (2-acetyl-3-trifto.rmethyl-phenyl) -4-methyl-benzamide, but taking 2-amino-6-trifluorometi-acetophenone hydrochloride {2.7 g), chloride 4-chloro-bvzoyl (1.58 cm) and 2 cm of pyridine in 30 cm of anhydrous toluene, long reaction time up to 2h. The substance has a melting point. The operations are carried out as in Example 1, but they come out of 2.6 g 2 - (-fluorophenyl) -5-trifluoromethyl-4-. -quinolone, 1.53 g - (2-chloro-acetyl) -morpholine and 2.35 g of anhydrous potassium carbonate in 60 cm 2-butanone. After recrystallization in a mixture of isopropyl ether-acetonitrile (37-10 by volume), 3.2 g of 4- (2 - (-fluorophenyl) -5-trift6-rmethyl-quinolyl) -oxy-acetyl-morpholine are obtained, which melt at. 2- (t-Fluorophenyl) -5-trifluoromethyl-quinolone can be obtained in the following way. Operations are carried out as in Example 1 to obtain 2 - (- methylphenyl) -5-trifluoromethyl-4-quinolone, but are derived from N- (2-acethyl-3-trifteropermethyl-phenyl) -4-fluoro- benzamide (8 g) and tertiary potassium butylate (1.18 g) in 40 cm of toluene, extending the reaction time to 2 hours. The substance is obtained with a melting point above. N- (2-Acetyl-3-trifarmethyl-phenyl) -fluorobenzamide can be obtained by the following method. Operations are carried out as in Example 1 to obtain N- (2-acetyl-3 trifluoromethyl-phenyl) -methyl-benzamide, but take 2-amino-6-trifluoromethyl-aceto hydrochloride (phenone (2.7 g), chloride t-fluoro-benzoic (1.49 cm 3) and 2 cm 3 pyridine in 3 cm 3 anhydrous toluene, extending the reaction time to 2 hours. The substance has a melting point. I. Example 4. Operations are performed as in the example t, but taking 2.6 g of 2- (2-fluoro-phenyl) -5-trifluoromethyl-4-quinolone, 1.53 g of 4- (2-chloro-acetyl) -morphine and 2.35 g of anhydrous ali carbonate in 60 cm 3 of 2-butanone, extending the reaction reaction time to 4 hours 30 minutes After recrystallization in the mixture of isopro 17
    Pilot ether, acetonitrile (37-16 in volume; volume), release 3g of g (2 (2-fluoro; -phenyl) -5-trifluoromethyl- -quinolyl) -oxyacetyl3-morpholine, which melts at. 2- (2-Fluoro-phenyl) -5-trifluorometi) 1-4-quinolone can be prepared as follows. The operations are carried out as in Example 1 to obtain 2- (-methyl-phenyl) 5 trifluoromethyl-t-quinolone, but take N- (2-acetyl-3 trifluoromethyl-phenyl) -2-fluoro-benzamide (3.2 d) and tertiary potassium butyllate (1.2 g) in AO cm of toluene, extending the reaction time to 2 hours. The substance has a melting point higher, K- (2-Acetyl-3-trifluoromethyl phenyl) -2-fluoro-benzamide obtained by the following method. Operations are carried out as in Example 1 to obtain N- (2-acetyl-3-trifluoromethyl-phenyl) -methyl-beisamide, but take 2-amino-6-trifluoromethyl-acetophenone hydrochloride (2.7 g), chloride 2 -fluorobenzoyl (1.5 cm3) and 2 cm3 pyridine 30 cm bezvo / g-pure toluene. The substance has a melting point of 100 ° C.
    EXAMPLE 5 Operations are carried out as in Example 1, but 2.9 g of 2- (methoxy-phenyl) -5-trifluoromethyl-quinolone is taken, 1, g 4- (2-chloro-acetyl ). -morpholine and 2.50 g of anhydrous potassium carbonate in 60 cm 2-butanone. After recrystallization in acetonitrile, 3.2 g of - (2- (4g methoxyphenyl) -5-trifluoromethyl-quinolyl) oxyacetyl-morpholine is obtained, which melts at
    2- (if-methoxy-phenyl) -5-trifluoromethyl-quinolone can be obtained by the following method. Operations are carried out as in Example 1 to obtain 2 - (- methyl-phenyl) -5 trifluoromethyl-4-quinolone, but take N- (2-acetyl-3-trifluoromethyl-phenyl) -A-methoxy-benzamide (-3 , 3 g) and tertiary potassium butylate (1.22 g) in lO cm 3 of toluene and the reaction time is extended to 6 hours. The substance has a melting point above 260 ° C.
    L- (2-Acetyl-3-tri (l-fluoromethyl-phenyl) - "- methoxy-benzamide can be obtained in the following way. The operations are carried out as in Example 1 to obtain N- (2-acetyl-3-trifluoromethyl-phenyl) -k-methylbenzamide, but take 2-amino-6-trifluoromethyl-acetophenone hydrochloride (2.7 g), chloride ij-methoxy-benzoyl
    eight
    (1.75 cm) and 2 cm of pyridine in 30 cm of anhydrous toluene, extending the reaction time to 2 hours. The substance has a melting point of 171 ° C,
    EXAMPLE 6 The operations are carried out as in Example 1, but 2.6 g of 2- (4-methyl-3-fluoro-phenyl) -5-trifluoromethyl-t-quinolone are taken, 1.6 g i - (2-chloro-acetyl-morpholine and 2.2 g of anhydrous potassium carbonate in 60 cm 2-butanone. After recrystallization in a mixture of isopropyl ether - acetoiitrile (by volume), 2.7 g of A- (2 - ("- methyl -3-Fluorophenyl) -5-t Pic &lt; RTI ID = 0.0 &gt;pic;
    2- (ij-Methyl-3-fluoro-phenyl) -5-trifluoromethyl-quinolone can be prepared as follows. Operations are carried out as in Example 1 to obtain 2-C-methyl-phenyl) -5-trifluoromethyl-A-quinolone, but take N- (2-acetyl-3-trifluoromethyl-phenyl) - "-methyl-3-fluoride } nzamide (2.9 g) and tertiary potassium butylate (1.06 g) in lO cm3 toluene. The substance has a melting point above 260 ° C.
    N- (2-Acethyl-3-trifopropiamethyl-phenyl) --4 - methyl-3-fluoro-benzamide can be obtained by the following method. Operations are carried out as in Example 1 for the half-body of N- (2-acetyl-3-trifluoromethyl-phenyl) -methyl-benzamide, but taking 2-amino-6-trifluoromethylacetophenone hydrochloride (2.7 g), t-methyl chloride -Z-fluoro-benzoyl (2.82 g) and 2 cm of pyridine in 30 cm3 of anhydrous toluene. The substance has a melting point of 6k ° t.
    EXAMPLE 7 The operations are carried out as in Example 1, but taking 1, 8 g of 2- (3-fluoro-phenyl) -5-trifluoromethyl-4-quinolone, 1, Ob g (2-chloro-1 acetyl) morpholine and 1.60 g of anhydrous potassium carbonate in 36 cm 3 of 2-butanone. The residue (2.85 g) is dissolved by heating in 25 cm 40-60 petroleum ether and the solid precipitate is separated by filtration and dried. 1.77 g of 4-- (2- (3-fluoro-phenyl) -5-trifluoromethyl-quinolyl) oxyacetyl-morLoline is obtained, which is melted at. 2- (3-Fluoro-phenyl) -5-trifluoromethyl-4-quinolone can be obtained as follows. Operations are performed as in Example 1 to obtain 2- (4-methylphenyl) -5-trifluoromethyl-A-quinolone, but take N- (2-acetyl-3-trifluoromethyl-phenyl) -3-ftO-benzomide (2, 5b g.) And tertiary potassium butylate (0.97 g) in 2b cm of toluene, the reaction is extended to 2 hours and 30 minutes. The substance has a melting point greater than 2 ° C. N- (2-Acethyl-3-trifopropylmethyl-phenyl) -3 fluoropropyl benzamide can be prepared as follows. Provoped operations as in Example 1 to produce N- (2-acetyl-3-trifluoromvinyl-phenyl) -methyl-benzamide, but taking 2-amino-6-trifluoromethyl-acetophenone hydrochloride (2.3 g), 3-fluoro benzoyl chloride (1.68 g) and 1.7 cm of pyridine in 26 cm of anhydrous toluene, extending the reaction time to 2 hours. The substance has a melting point of 150 ° C. Example 8: To a stirred suspension, 10 g of a mixture of 5-chloro-2 - (- methyl phenyl) -A-quinolone, 7-chloro-2- (4-methyl-phenyl) -4-quinolone and 10 , 2 g of anhydrous potassium carbonate in 250 cm 2-butanone is added 7.3 g (2-bromo acetyl) -morpholine in 50 cm 2-butanone Heated under reflux for 15 h, cooled to room temperature (about the insoluble substances are filtered off and 2-butanone is evaporated under reduced pressure. The residue is treated with 200 cm of water and the aqueous phase of the extract is washed with T 3 times 100 cm 3 of methylene chloride. The organic phase is decanted, dried and evaporated After two chromium, the first residue on silica gel is chloroform-ethyl acetate (70-30 by volume), the second is using chloroform ethyl acetate (80-20 by volume) as eluent, the resulting solid is recrystallized in ethyl acetate. 2 g of 4- (5-ChLOR-2 - (- methylphenyl) -4-quinolyl oxyacetyl-morpholine, which is melted at, are obtained. A mixture of 5-ChLOR-2- (4-methyl-phenyl) -quinolone and 7-chloro- 2- (4-methylphenyl) -quinolone May be obtained by the following method. While stirring, 13 g of 3-chloro-aniline and 1.2 g of 4-methylbenzoyl acetate-ethyl and 40 g of polyphosphoric acid are heated under stirring for 20 minutes. Then cooled to, add 10 cm of concentrated hydrochloric acid, then 100 cm of water. The precipitate is dried, washed 3 times with 100 cm of water, 2 times with 50 cm of ethyl ether and 2 times with 50 cm 3 of acetone. A mixture of 5-chloro-2- (A-methyl-phenyl) -4-quinolone and 7 chloro-2- (4-methyl-phenyl) -4-quinrolone is obtained, which is used for subsequent syntheses. PRI me R 9. To a stirred suspension of 2.19 g of 2- (-methyl-pheny / |) -5-methoxy-L-quinolone and 1.62 g of - (i-.-Chloro-acetyl) - morpholine in 76 cm of 2-butanone was added 2.28 g of anhydrous potassium carbonate. Heated under reflux for kh 20 min, cooled to room temperature (about 20 ° C) and the solvent is evaporated under reduced pressure. The residue is treated with water and ethyl acetate, the organic phase is decanted, dried over magnesium sulfate and evaporated under reduced pressure. The residue obtained is chromatographed on silica gel using chloroform-acetone (95 5 by volume) as eluant. The obtained solid product is stirred in 50 cm 40-60 petroleum ether. 2.3 g of 4- (2- (4-methylphenyl) -5-methoxy-quinolyl) oxyacetyl3-morpholine, which melts at 132 ° C, 2- (4-methyl-phenyl) -5-methoxy-4- quinolone can be obtained as follows. 2.27 g of N- (2-acetyl-3-methoxy-phenyl) -4-methy, l-benzamide and 1.36 g of tertiary potassium butylate in 23 cm of toluene are heated under reflux for 1 m. Cool to room temperature (about 20 ° C), add 1.5 cm of glacial acetic acid and dilute with 25 cm of water. The suspension is stirred 15 mI, the precipitate is dried, washed with water, toluene, petroleum ether "0-60, then dried. The substance has a melting point of N- (2-Acetyl-3-methoxy-phenyl) -methyl-benzamide can be obtained as follows. Stir at room temperature (about 20 ° C) for 1 h 20 min. K g of 2-amino-6-methoxy-acetophenone, 3.5 cm-methyl-benzoyl chloride and 2.15 cm of pyridine in 40 cm of anhydrous toluene. Then add 40 cm of water and 60 cm of tolua. The aqueous phase is decanted, the organic phase is washed three times with 25 cm of ode, dried over magnesium sulfate and evaporated under reduced pressure.
    The residue obtained is stirred at 75 cm 3 of CHO-B0 petroleum ether and 25 cm of ethyl acetate, filtered and washed with petroleum ether. 2.4 g of N- (2-Lethyl-3-methoxy-phenyl) - | -methyl-benzamide are obtained, which melt at A8 C.
    2-amino-6-methoxy-acetoLenone can be prepared as follows. 18 g (2-acetyl-3-methoxy-phenyl) -2,2-dimethyl-propionamide in a mixture of 90 cm of concentrated hydrochloric acid and 90 cm of ethanol are heated under reflux for 18 h kG min. Cool to room temperature (about 20 ° C), add 100 cm 3 of ethyl acetate and 250 cm 3 of a saturated potassium carbonate solution. The aqueous phase is extracted with ethyl acetate, and the organic phase is washed with water. The organic phases are collected, dried over magnesium sulphate and evaporated under reduced pressure. The resulting oil is used for further syntheses.
    N- (2-Acetyl-3-methoxy-phenyl) -2,2-dimethyl-propionamide can be obtained by the following method. To cooled to 0 ° C. a solution of 35 g of N- (2- (t-hydroxyethyl) -3 methoxy-phenyl) -2,2-dimethylpropionamide v.525 cm of acetate is added in portions per minute of g of chromic anhydride. Stir for 1 h 51 min at, then add 21 g of additional chromic anhydride in portions. Stirring is continued for another 1 hour at a temperature of 0 ° C, then 1 b O cm 3 of isopropanol is slowly introduced at this temperature to decompose the excess chromic anhydride. The temperature rises to room temperature (about 20 ° C), the solvent is evaporated under reduced pressure. The residue is treated with 500 cm of ethyl acetate and stirred at room temperature. The solid is separated by filtration and washed with 350 cm of ethyl acetate. The organic phase is concentrated under reduced pressure, and the residue is chromatographed on silica gel using methylene chloride - acetone (99-1 p volume). 7.88 g of S (2-acetyl-3-methoxy-phenyl) -2,2-dimethyl-propioamide are obtained, which C melts.
    N- (2- (o-hydroxyethyl) -3-methoxy-phenyl) -2,2-dimethyl-propionamide can be obtained by the following method. To a solution of 10 g of N- (3-methoxy-phenyl) -2, 2-dimethyl-propionamide in 150 cm
    dry tetrahydrofuran in an atmosphere of nitrogen cooled before, is added over 25 minutes 90.5 cm of a 1.37M solution of N-butyl lithium in hexane and stirred for 2 hours at this temperature. The solution is then cooled to -78 ° C and 27 cm of acetaldehyde cooled to 1 ° C are introduced at once. The temperature quickly rises to h ° C, then decreases again. When the temperature is below -10 ° C, 57 cm of water and 200 cm of ethyl ether are quickly added. After separation of the phases by decanting, the aqueous phase is extracted with ethyl ether, the organic phases are collected and they are evaporated. To the obtained residue, 100 cm of isopropyl ether are added, the residue is triturated, which crystallizes, then 100 cm of petroleum ether 0-60 is added and stirred for 15 minutes. This treatment is repeated with 50 cm3 of tO-Go petroleum ether and 50 cm of isopropyl ether. After filtration and drying, 9.65 g of N- (2- (-hydroxyethyl) -3-methoxy-phenyl) -2,2-dimethyl-propionamide are obtained. which melts at 159 C.
    N- (3-Methoxy-phenyl) -2,2-dimethyl-propionamide can be obtained as follows. 79.7 cm of pyridine was added to a stirred solution of 110.7 g of 3-methoxyaniline in 1100 cm of toluene, then slowly 120.5 cm of pivaloyl chloride. Stir for 1 h 15 min at a temperature of about, then add 500 cm of water. The precipitate is dried, washed with water and toluene, and dried in a drying cabinet at 70 ° C under reduced pressure in the presence of sodium hydroxide tablets. 137 g of N- (3-methoxy-phenyl) -2,2-dimethyl-propionamide are obtained, which melt at 12b ° C.
    EXAMPLE 10 The operations are carried out as in Example 1, but taking 2.3 g of 2- (2.-difluoro-phenyl) -5 trifluoromethyl-4-quinoline, 1.35 g (2-chloro-acetyl -morpholine and 2.3 g of anhydrous carbonate in 70 cm3 of 2-butanone, extending the reaction time to 5 m. After recrystallization in acetonitrile, 2.3 g of k- (2- (2,4-difluorophenyl) -5- trifluoromethyl-A-) (inolyl) oxyacetyl-morpholine, which is melted at.
    2- (2, -Difluorophenyl) - - triAtoromethyl- | - quinolone can be obtained by the following method 1 1. Operations are carried out as in Example 1 ll to prepare 2- (4-methyl-phenyl) -Trifluoromethyl-quinolone, but 3, g H- (2 acetyl-3 trifluoromethyl-phenyl) -2, A-difluoro-benzamide and 1.3 g of tertiary butyl potassium in AO cm of toluene are taken, extending the reaction time to 2 hours and 30 minutes. The substance has a melting point greater than 260 ° C. N- (2 Acetyl-3 trifluoromethyl-phenyl) -2, + - difluoro-benzamide can be obtained by the following method. Operations are carried out as in Example 1 to obtain N- (2-acetyl-3-trifluoromethyl-phenyl) -methyl-benzamide, but take 3 g of 2-amino-6-trifluoromethyl-acetophenone hydrochloride, which is obtained in Example 1 , 2.29 g 2, A-difluoro-benzoyl chloride and 2.2 cm of pyridine in 35 cm of anhydrous toluene. This compound has R 0.61 (chromatography on a silica gel plate, eluan cyclohexane-ethyl acetate, 50-50 by volume). PRI me R 11. To a stirred suspension of 11.2 g of a mixture of 5-fluoro-2- (-methyl-phenyl) -A-quinolone and 7-fluoro-2- (A-methyl-phenyl) -quinolone and 11.3 g of anhydrous potassium carbonate in 250 CM of 2-butanone was added 7.8 g of (2-brOMO-acetyl) -morpholine in 50 cm of 2-butanone. The mixture is heated under reflux for 15 hours, cooled to room temperature (about 20 ° C), insoluble substances are removed by filtration and 2-butanone is evaporated under reduced pressure. The residue is treated with 200 cm of water, and the aqueous phase is extracted with 3 times 100 cm of methylene chloride. The organic phase is decanted, dried and evaporated under reduced pressure. After chromatography of the residue on silica gel with a mixture of cyclohexane ethyl acetate (7H-30 by volume), the resulting solid is triturated in 100 cm of petroleum ether 40-60. 2, g of (5-Ator-2- (4-methylphenyl) -quinolyl) oxy-Cetyl-morpholine, which is melted at k2 C, is obtained. A mixture of 5-fluoro-2- (A-methyl-phenyl) -t-quinolone and 7 α-fluoro-2 (4-methyl-phenyl-α-quinolone can be obtained by the following method. Heated at 150 ° C for 30 minutes with active stirring 7.8 g of 3-fluoro-aniline and, 2b, 7 g-methyl benzoyl ethyl acetate in 27 g of polyphosphoric acid. Then 111 is cooled before and 60 cm of normal hydrochloric acid is added and the precipitate is dried, washed 3 times with 60 cm of water, then three times with 60 cm of ethyl ether and finally two times with 50 cm of acetone. with mixing 5-fluoro-2- (A-methyl-phenyl) - "- quinolone, which is used in the next step. Example 12. Work as in example 1, but take 2 - (+ - methyl-phenyl) -5-trifluoromethyl - -quinolone and (2-chloro-acetyl) -thiomorpholine; get- (2- (A-methylphenyl) -5-trifluoromethyl-α-quinolyl) oxyacylJ-thiomorpholine, melting at 13 o. mimer 13 They work as in measure 1, but they take 2 - (- methyl-phenyl) -5-trifluoromethyl-4-quinolone and N-methyl- (2-chloroacetyl) -H- (2-methoxyethyl) -5-trifluoromethyl- - quinolyl-oxiacetamide melting at 11 ° C. New products were investigated for pharmacological activity. The test results are summarized in table. The pharmacological activity of the proposed compounds was compared with the biological activity of the compound corresponding to formula R. 0-eH, -CO-NR, R, | 1 1 i to where R is hydrogen; - morpholino; R is -methylphenyl (product A) and R is hydrogen, morpholino; - 4-methoxyphenyl (product B) 1. Test for affinity for central benzodiazepine receptors. A known technique is that, in the presence of a test product, the specific ixation of benzodicepine receptor ligands — tritiated flunitrase — is measured. The specific fixation ligand is reduced when the product is related to benodiazepine receptor sites. The experiment is as follows. The washed homogenate 2 centrifugation was mixed with 50,000 g of the whole ode of the male rat brain (DM, COBS, Charles Ruver, France) in Tris-HCl buffer 50 mmol, pH 7, (final, O concentration, 1 mg of protein per ml), the test product is in various concentrations, the final concentration of tritiated flunitrazepam is 1.5 nM. Non-specific fixation was determined in the presence of diazepam (Yu nM). After 120 minutes of incubation with O, each sample was filtered on a glass fiber filter (WHATMAN GF / B filter) and the radioactivity retained on the filter was measured by liquid scintillation. The value of Clg, t, e, e, the concentration of the test product, which inhibits 50 specific fixatives + 1 and ligands, is determined. 2. Test for chemical convulsions caused by pentetrazol. USES mice weighing 18–22 g. Use a subcutaneously fixed dose of 150 mg / kg of pentetrazole to mice (a single dose containing 25 ml of solution per 1 kg of mouse). The test products were administered orally for 5 minutes or 1 hour and 30 minutes before administration of pentetrazo, with single doses being contained in a volume of 25 ml per 1 kg of mouse. Use 5 mice per dose and 3 doses for the test product. After the introduction of pentrazole, the mice are placed in boxes, divided into 15 compartments 15 cm long so that each mouse is isolated during the whole experiment. The boxes. Cover with a transparent plastic plate. Control mice receive a dose of 150 mg / kg of pentetrazole for no more than 15 minutes. They have more or less severe convulsions that quickly end with the death of the animal. Mice were observed for 30 minutes after administration of penteralol. The mouse is considered to be protected from convulsions during this period (30 minutes) if it does not have any convulsions. The dose of the DA – j product is the dose of J, which, at its maximum effect, eliminates pentetrazole convulsions in 50 animals. Equivalent data show that lagged compounds are more active in vivo than known products. Rumula was invented and allowed to obtain derivatives of the quinine of the formula R 0-CH, -CO-NR, R. R4 is a trifluoromethyl radical and, together with nitrogen, with which they are bonded, form a morpholino radical; 4-methyl-phenyl, A-chloro-phenyl, 2,3-or-fluoro-phenyl, -methoxy-phenyl, -methyl-3-fluoro-phenyl or 2, -difluorophenyl radical, R (is trifluoromethyl) , cal; and Rj form together with nitrogen with which they are bound, a thiomorpholino radical, Rj is a methyl radical; R, a 2-methoxy-ethyl radical; a-methyl-phenyl radical; R4; R {chlorine or fluorine methoxy 1 3 together with the nitrogen to which they are bonded, the morpholino radical; R4 is a methyl-phenyl radical, characterized in that one reaction of the quinolone of the formula R and R have the indicated meanings with a derivative of the formula Gal - CHg - CO - NRjjRj, 2 have associated meanings, Hal halogen.
    权利要求:
    Claims (1)
    [1]
    SUMMARY OF THE INVENTION Method for the Preparation of Quinoline Derivatives of the Formula ________ 'Rj 0-CH 2 -C0-NR 2 R 3 or R (or R z
    R
    K 4 or R <
    K 5, and R 3 B 4
    - trifluoromethyl radical, form, together with the nitrogen with which they are bound, a morpholino radical;
    - the radical 4-methyl-phenyl, 4-chloro-phenyl, .2,3- or 4-fluoro-phenyl, 4-methoxy-phenyl, 4-methyl-3-fluoro-
    phenyl or 2,4-difluorophenyl,
    - trifluoromethyl radio, feces;
    together with the nitrogen with which they are bound, form a thiomorpholino radical,
    - methyl radical;
    - the radical 2-methoxy-ethyl *,
    - 4-methyl-phenyl radical; chlorine or fluorine or ': the methoxy radical together with the nitrogen to which they are attached form a morpholino radical;
    - the radical 4-methyl-phenyl, in that the quinolone of the formula
    R c.
    smoldering carry out the reaction where R, with a derivative of the formula
    Gal - CH Z - CO - NR z R 5 , where R z and Rj have the indicated meanings, Gal is halogen.
    1 7 1709911
    Example Affinity of receptors with benzodiazepine I.K. PM Pentetrazole, Toxicity by mouth, mg / kg mg / h 1 1.8 1,60 netoke. 900 2 3.9 7.15 netox. 900 3 0.7 1,50 netox. 900 4 1.6 ’ 11.00 netox. 900 5 16.0 7.0 netox. 900 6 4.0 2.60 netox. 900 7 m 22.00 netox. 300 8 2.9 '10.00 netox. 300 9 100.0 22.50 netox. zoo 12 41.0 19.00 > 300 thirteen 8.0 16.50 netox. 300 10 2.0 2.10 netox. 300 eleven 1.3 2,50 300 - 900
    Product
    A £ 100.
    Product
    At £ 100
    Editor M. Tsitkina Compiled by G. ZhukovTehred m. Didyk Corrector. M. Pozho - Order Circulation Subscribed
    VNIIIPI of the State Committee for Inventions and Discoveries at the State Committee for Science and Technology of the USSR 113035, Moscow, Zh-35, Raushskaya nab., 4/5
    Production and Publishing Plant Patent ”, Uzhgorod, st. Gagarina, 101
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    NO893653L|1990-03-14|
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    DK449989A|1990-03-14|
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    DK449989D0|1989-09-12|
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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    FR2582514B1|1985-05-30|1988-02-19|Rhone Poulenc Sante|AMIDE DRUGS, NEW AMIDES AND THEIR PREPARATION|US5493027A|1993-01-22|1996-02-20|Board Of Regents, The University Of Texas System|Anticonvulsive agents and uses thereof|
    US5783700A|1997-07-03|1998-07-21|Nichols; Alfred C.|Quinolic acid derivatives|
    EP1110552A1|1999-12-22|2001-06-27|Aventis Pharma S.A.|Use of a compound with affinity for the mitochondrial benzodiazepine receptor in cancer therapy|
    WO2002000623A2|2000-06-26|2002-01-03|Neurogen Corporation|Aryl fused substituted 4-oxy-pyridines|
    SE528638C2|2005-04-08|2007-01-09|Boule Medical Ab|Device for filling a unit for determining a sample volume|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    FR8811903A|FR2636327A1|1988-09-13|1988-09-13|QUINOLINE DERIVATIVES, PROCESSES FOR THEIR PREPARATION AND MEDICAMENTS CONTAINING SAME|
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