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    • 专利摘要:
    Derivatives of formula (I) in which A forms with the pyrrole ring an isoindoline, 6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine, 2,3,6,7- tetrahydro-5H-oxathiinno[1,4][2,3-c]pyrrole or 2,3,6,7-tetrahydro-5H- dithiinno[1,4][2,3-c]pyrrole nucleus, Het = naphthyridinyl, pyridyl or quinolyl which are unsubstituted or substituted by halogen, alkyl (1-4 C), alkoxy (1-4 C), alkylthio (1-4 C) or CF3, Y = CO.C=NOH or CHOH and R = alkenyl (3-10 C), alkyl which is unsubstituted or substituted by OH, alkoxy, alkylthio, cycloalkyl (3 - 6 C), NH2, alkylamino, dialkylamino, alkylcarbonylamino, piperazinyl, piperidyl, 1- azetidinyl, morpholino, pyrrolidinyl, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, (1-piperazinyl)carbonyl, piperidinocarbonyl, pyrrolidinocarbonyl, phenyl, pyridyl or 1-imidazolyl, or else R = 2- or 3-pyrrolidinyl, 2-, 3- or 4-piperidyl, cycloalkyl (3-6 C) or phenyl which is unsubstituted or substituted by halogen, alkyl (1-4 C), alkoxy (1-4 C) or alkylthio (1-4 C), it being understood that the radicals and alkyl portions contain 1 to 10 C unless specially mentioned, and the piperazinyl, piperidino, piperidyl, pyrrolidinyl and azetidinyl radicals may be unsubstituted or substituted in any position by an alkyl, alkylcarbonyl, benzyl or hydroxyalkyl radical or else may form a lactam functional group with the nitrogen atom of the ring. …<??>These products can be used as anxiolytics. …<IMAGE>…
    公开号:SU1577698A3
    申请号:SU874203784
    申请日:1987-12-01
    公开日:1990-07-07
    发明作者:Бурза Жан-Доминик；Капе Марк；Котрель Клод；Лабодиньер Ришар；Пишен Филипп；Руссель Жерар
    申请人:Рон-Пуленк Санте (Фирма)；
    IPC主号:
    专利说明:

    The invention relates to the preparation of new condensed pyrrole derivatives of the general formula
    (ABOUT
    CVh-Y-R
    where Get-1,8-naphthyridine 2 yl, substituted in the 7-position by a bromine or chlorine atom, Cc-C -alkyl radical, kilo-hydroxy group, or Geth-quinolyl, substituted by a chlorine atom;
    Y - CO-group,) C-NOH or
    ) CH-OH groups;
    R - right or branched
    C3-C7 alkenyl, C-Cd-alkyl, possibly substituted cyclohexane, C /) -C-dialkylamino, C ,, dialkylcarbamoyl, or V. - 1-methyl 4-piperidyl, possessing valuable pharmacological properties The purpose of the invention is to obtain new pyrrole derivatives, which have pharmacological advantages in comparison with the known structural analogues of similar effect.
    Example 1. To a solution of 1, 6 g of 3-hydroxy-2- (7-methoxy-1,8-naphthyridin-2-yl) -eioiNdolinona-1, kept in an atmosphere of argon in 20 cm of anhydrous dimethylformamide, is added at a temperature close to -5 ° C, in small portions (0.5 g) of the suspension in oil (50% by weight) of sodium hydride and the resulting suspension is stirred for 30 minutes at a temperature close to -5 ° C. Then add solution 1.2 g 5-methylhexanone-2 in 5 cm of anhydrous dimethylformamide and continue stirring for 5 hours at a temperature of about 20 ° C. Then the reaction mixture is poured into 200 cm of distilled water and extracted 3 times with 100 cm of dichloroethane. The organic phases are combined, washed 5 times with 200 m3 of distilled water, then concentrated to dryness under reduced pressure (2.7 kPa) at
    40 C. The resulting oily residue is purified by chromatography on 15 g of silicon oxide in a column with a diameter of 1.5 cm (eluent-dichloromethane-0
    five
    0
    5 30
    35 40 45, "
    55
    tanol, 99-1 by volume). 30 cm of solvent are eluted first: the corresponding eluate is discarded, then 100 cm 3 of solvent are eluted; the corresponding eluate is concentrated to dryness under reduced pressure (2.7 kPa) at 40 C. The residue obtained is recrystallized from ethyl acetate, thus obtaining 1.3 g of 2- (7-methoxy-1,8-naphthyridin-2-yl) - 3- (5-methyl-2-oxohexyl) -isoindolinone-1, t. Pl. .
    Example2. To a solution of 8.0 g of 3 hydroxy-2- (7-methoxy 1 yb-naphthyridin-2-yl) -eoindolinone-11 in 125 cm3 of anhydrous dimethylformamide, maintained in an argon atmosphere, is added at a temperature close to -5 ° C, 0.7 g of sodium hydride in small portions. The resulting suspension is stirred for 30 minutes at a temperature close to 5 ° C, then 3.5 g of a solution of 4 dimethylaminobutanol-2 in 5 cm of anhydrous dimethylformamide is added. The mixture is stirred for 3 hours at a temperature of close to 20 ° C, then poured into 500 cm of distilled water and extracted 3 times with 200 cm of dichloromethane. The organic phases are combined, washed 4 times with 25 cm of distilled water, dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. The resulting oily residue was dissolved in 400 cm of ethyl acetate and the resulting solution was extracted with 2 times 100 cm of an aqueous 1N solution. hydrochloric acid. The aqueous phases are combined, washed with 50 cm of ethyl acetate, basified for 10 hours, aqueous sodium hydroxide solution to a pH of about 11 and extracted 2 times with 250 cm of ethyl acetate. The organic phases are combined, washed with 3 times 30 cm of distilled water, dried over magnesium sulfate, filtered, the stream is concentrated to dryness under reduced pressure (2.7 kPa) at 60 ° C. After crystallization from acetonitrile, 2.6 g of 3- (4-dimethylamine, o-2-oxobutyl) -2- (7-methoxy-1,8-naphthyridyl-2-yl) -isoindolonone-1 are obtained, m.p. .140 ° C.
    4-Dimethylaminobutanone-2 can be obtained by a known technique (Mannich S. Arch.Pharm, 1917, 255, 26.1).
    3-Oxy-2- (7-methoxy-1, 8.-naphthyridin-2-yl) -eoindolinone-1 can be obtained by a known method (Belgian Patent No. 815019).
    15
    one
    20
    51577698
    Example To a suspension of 3.0 g of 2- (7-methoxy-1,8-naphthyridin-2-yl) -3- (5-methyl-2-oxohexyl) -isoindolinone-1 in 50 cm of ethanol is added at a temperature of about 20 ° C, 0.41 g of potassium tetrahydroborate as a solution in 12 cm3 of distilled water and stir the suspension for 16 hours at a temperature of about 20 ° C. The reaction mixture is then poured into a mixture of 300 cm of distilled water and 150 cm of dichloromethane, cooled to a temperature of about 0 ° C. The aqueous phase is separated by decantation and re-extracted 2 times with 150 cm of dichloromethane. The organic phases are combined, washed 3 times with 25 cm of distilled water, dried over magnesium sulphate, filtered1, then concentrated to dryness under reduced pressure (2.7 kPa) at 40 C. The product obtained is recrystallized 2 times from isopropyl ether. Thus, 2.0 g of 3- (2-hydroxy-5-methylhexyl) -2- (7-methoxy-1,8-naphthyridin-2-yl) -isoindolinone-1 are obtained, m.p. Software ° C
    PRI me R 4. Work according to the method of example 1, but on the basis of 13.3 g of 3-hydroxy-2- (7-methylthio-1,8-naphthyridin-2-yl) -isoindolinone-1, 4,1 an oil suspension (50 wt.%) of sodium hydride, 9.4 g of 5-methylhexanone-2, the reaction mixture is stirred 4 times at a temperature of about -5 ° C; 4.3 g of 3- (5- methyl 2-oxohexyl) - 2- (7-methylthio-1,8-naphthyridin-2-yl) -eoindolinone-1, so pl. 160 C.
    3-Oxy-2- (7-methylthio-1,8-naphthyridin-2 yl) -isoindolinone-1 can be obtained by the following procedure. To a suspension of 16.6 g of 2- (7-methylthio-1,8-naphthyridin-2-yl) -isoindolindione-1, 3 in a mixture of 250 cm3 of tetrahydrofuran and 25 cm3 of water is added at a temperature of about 20 ° C in small portions 2.8 g of potassium tetrahydroborate and mix the resulting suspension for 4 hours at a temperature of about 20 ° C. Then the reaction mixture is poured into a mixture of 80 g of ice 160 cm of water and neutralized with 1N. aqueous solution of hydrochloric acid. The insoluble product is filtered off, rummaged 5 times with 50 cm 3 of water and dried in air. Thus, 13 g of 3-hydroxy-2- (7-methylthio-1,8-naphthidin-2-yl) -isoindolinone-1 are obtained, m.p. 210 ° C.
    h n (with m z o
    thirty
    and 1 p about d d
    my di mechi 25 2 gi but cm by 3
    to ve №
    ME 2 of SE 3, according to ri 45 2 TI.
    would (r 16
    ke 3c -2 l to 1pen. desh
    35
    40
    50
    6
    2- (7-Methylthio-1,8-naphthyridin-2-yl) -isoindolindione-1,3 can be obtained as follows. To a suspension of 9.6 g of 2-amino-7-methylthio-1.8-naphthyridine in 275 cm Dauterm A (trade name) was added 7.5 g of phthalic anhydride. The reaction mixture is stirred and heated at a temperature of about 155 ° C for 3 hours, then cooled to a temperature of about 20 ° C and 175 cm of di
    one
    20
    3 th
    thirty
    isopropyl ether and stirred for 1 hour. The insoluble product is filtered and dried in air. Thus, 15.2 g of 2- (7-methylthio-1,8-naphthyridin-2-yl) -isoindolin-dione-1,3 are obtained, mp 235 ° C.
    2-amino-7-methylthio-1,8-naphthyridine can be obtained by a known method (European patent No. 172083). Example 5: Work as in Example 1, but starting from 6.2 g of 2- (7-chloroquinolyl-2) -3-hydroxyisoindolinone-1, 25 2 g of oily suspension (50% by weight) sodium hydride, 4.6 g of 5-methylhexanone-2, the reaction mixture is stirred for 3 hours at a temperature of about -10 ° C; after recrystallization from ethanol, 1.4 g of 2- (7-chloroquinolyl-2) -3 (5 methyl -2-oxohexyl) -isoindolinone-1, so pl. 127 ° C.
     2- (7-Chloroquinolyl-2 -) - 3-hydroxyisoin-dolinone-1 can be obtained by i-. known method (Belgian Patent No. 793851).
    Example 6; The operation is carried out as in example 1, but starting from 6.2 g of 3-hydroxy-2 (7-methoxy-1,8-naphthyridin-2-yl) isoindolinone a-1, 2 g of an oily suspension (60% by weight) of hydride sodium and 3.1 g of 1-cyclohexylpropanone-2; after recrystallization from acetonitrile, 5 g of 3- (3-cyclohexyl- 45 2-oxopropyl) -2- (xy-1, 8-naphthyridine-2- il) -isoindolinone-1, so pl. 139 ° C.
    1-Cyclohexylpropanone-2 can be obtained by a known method (Herbet M. C.R.Acad.Sc, Paris, 1917, 164. 952).
    PRI me R 7 "Work according to the method of example I, but starting from 9.4 g of 3oxy-2- (7-methoxy-1,8-naphthyridin--2-yl) isoindolinone-3, 4.4 g of oil suspension (50% by weight) of sodium hydride and 4.8 g of 4-oxo-M, M-dimethyl-1-pentane, the reaction mixture is exhausted for 4 hours at a temperature of about
    35
    40
    0
    O C, after recrystallization from
    ten
    acetonitrile get 3.1 g of 5 - (7-methoxy-1,8-naphthyridin-2-yl) -3- oxo-isoindolinyl-1} -4-oxo-K, from methylpentane, so pl.184 ° C .
    4, -Oxo-Y, M-dimethylpentanamide can be obtained by a known method (Lux P., Collect, czech.Chem, CO 1963, 28 (8), 2182).
    Try on The operation is carried out as in example 1, but starting from 3.11 g of 3-hydroxy--2- (7-methoxy-1, 8-naphthyridin-2 yl) isoindolinone-1, 1 g of an oil suspension (50% by weight) of hydride sodium, 2.6 g 15 6-methylheptanone-2, the reaction mixture is stirred 4-h at a temperature of about -5 ° C, after recrystallization from acetonitrile, 4.4 g of 2- (7-me
    din-2-yl) -ieoindolinone-1 in 195 cm of anhydrous dimethylformamide maintained in a nitrogen atmosphere was added at a temperature of about -5 ° C in small portions of 3.1 g of an oily suspension (50% by weight) of sodium hydride, the suspension is stirred for 30 minutes at a temperature of about -5 ° C. Then a solution of 6.5 g of hexanone-2 in 5 cmu of anhydrous dimethylformamide is added, then restraining is continued for 8 hours at a temperature of about 0 ° C, then 16 at a temperature of about 20 ° WITH. Then the mixture is poured into 1.5 liters of water. The resulting solid was filtered, washed with water and air dried. After recrystallization from ethanol, 3.6 g are obtained.
    toxi-1,8-naphthyridin-3-yl) -3- (6-methyl-20 2- (7-methoxy-1,8-naphthyridin-2-yl) -3-2-oxoheptyl) ieoindolinone-1, t mp.140 ° C.
    6-Methylheptanol-2 can be obtained by the well-known method (J. Bruni, C. and Cologne J. C. R. Acad. Paris, 1962, 15 255. 1621).
    . Example 9: Work as in Example 1, but starting from 3.1 g of 3-hydroxy-2- - (7-methoxy-1,8-naphthyridin-2-yl) -iso-indolinone-1, 1 g of oily suspension (50% by weight) of sodium hydride, 2.4 g of 4-methylhexanone-2, the reaction mixture is stirred for 20 hours at a temperature of about 0 ° C, after recrystallization from acetonitrile, 2.2 g are obtained 2 - (7-methoxy-1,8-naphthyridin-2-yl) - -3 (4 methyl-2-oxohexyl) isoindolinone-1, mp. 120 ° C.
    4-methylhexanone-2 may be semi35
    - (2 oxohexyl) -isoindolinone-1, so pl. .
    EXAMPLE 12: Analogously to Example 13, but starting from 15 g of 3-hydroxy-2- (7-methoxy-1,8-naphthyridin-2-yl) -isoindolinone-1, 4.7 g of oil suspension (50 wt.%) of sodium hydride and 12.4 g of 6-methylhepten-5-one-2, after recrystallization from ethanol, 7.6 g of 2- (7-methoxy -1,8-naphthyridin-2-yl) are obtained -3- (6-methyl-2 - oxohepten-5-yl) -isoindolinone-1, so pl. 160 ° C.
    Example 13. The operation is carried out analogously to Example 11, but starting from 10 g of 3-hydroxy-2 (7-methoxy-1,8-naphthyridin-2-yl) -isoindolinone-1, g of an oily suspension (50% by weight) sodium hydride and 9.2 g of 4-acetyl-1-methylpiperidine; after recrystallization from ethanol, 4.8 g of 2- (7-methoxy-1,8-naphthyridin-2-yl) (1-m tylpiperidyl-4 ) -2-oxo-ethyl-isoindolinone-1, so pl. , 172 ° C.
    chen according to the well-known method (Johnson J.R. and Hager FD Org.Syith coll. T.I, 351).
    PRI me R 10. Work on example 1, but on the basis of 6.2 g of 3-hydroxy--2- (7-methoxy-1,8-naphthyridin-2-yl) - isoindolinone-1, 1.92 g of an oily suspension (50% by weight) of sodium hydride, 4.5 g of 3 methylhexanone-2, after two consecutive recrystallizations from isopropyl ether, 2.1 g of 2- (7-methoxy-1,8-naphthyridine-2 - il) -J3- (3-methyl 2-oxohedsyl) - isoindolinone-1, mp. 86 ° C.
    3-Methylhexanone-2- - can be obtained by a known method (Johnson E.J. Arm.chem.pharm. 1884, 226, 87).
    Example 11. To a solution of 10 g of 3-hydroxy-2 (7-methoxy-1,8-naphthyri0
    with
    5,76988
    din-2-yl) -eoindolinone-1 in 195 cm of anhydrous dimethylformamide, maintained in a nitrogen atmosphere, was added at a temperature of about -5 ° C in small portions 3.1 g of an oil suspension (50% by weight) of sodium hydride, suspension stirred for 30 minutes at a temperature of about -5 ° C. Then a solution of 6.5 g of hexanone-2 in 5 cmu of anhydrous dimethylformamide is added, then reshaping is continued for 8 hours at about 0 ° C, then 16 hours at about 20 ° C . Then the reaction mixture is poured into 1.5 liters of water. The resulting solid was filtered, washed with water and air dried. After recrystallization from ethanol, 3.6 g are obtained.
    2- (7-methoxy-1,8-naphthyridin-2-yl) -3
    0
    five
    0
    five
    0
    five
    - (2 oxohexyl) -isoindolinone-1, so pl. .
    EXAMPLE 12: Analogously to Example 13, but starting from 15 g of 3-hydroxy-2- (7-methoxy-1,8-naphthyridin-2-yl) -isoindolinone-1, 4.7 g of oil suspension (50 wt.%) of sodium hydride and 12.4 g of 6-methylhepten-5-one-2, after recrystallization from ethanol, 7.6 g of 2- (7-methoxy -1,8-naphthyridin-2-yl) are obtained -3- (6-methyl-2 - oxohepten-5-yl) -isoindolinone-1, so pl. 160 ° C.
    Example 13. The operation is carried out analogously to Example 11, but starting from 10 g of 3-hydroxy-2 (7-methoxy-1,8-naphthyridin-2-yl) -isoindolinone-1, g of an oily suspension (50% by weight) sodium hydride and 9.2 g of 4-acetyl-1-methylpiperidine; after recrystallization from ethanol, 4.8 g of 2- (7-methoxy-1,8-naphthyridin-2-yl) (1-methylpiperidyl) are obtained. 4) -2-oxo-ethyl-isoindolinone-1, so pl. , 172 ° C.
    4-Acetyl-1-methylpiperidine can be obtained by the following method. At a temperature of about 5 ° C, 3.9 cm of formic acid is added to a solution of 5.2 g of 4-acetylpiperidine in 10 cm3 of distilled water, then 8.2 cm of a 35% formaldehyde aqueous solution. The reaction mixture was heated under reflux for 4 hours. Then, 50 cm of a 1N aqueous solution of sodium hydroxide was added and the resulting aqueous solution was extracted with 3 times 60 cm of methylene chloride. The organic phases are combined and washed with 2 times 40 cm of water, dried over sulfate.
    magnesium and concentrated to dryness under reduced pressure (2.7 kPa). Thus, 1.4 g of 4-acetyl-1-methylpiperidiHa, used without purification in subsequent syntheses, are obtained.
    Example 14. To a suspension of 4.3 g of 2- (7-methoxy-1,8-naphthyridin-2-yl) -3- (2 oxo-5-methylhexyl) -isoindolonone-1 in 100 cm3 of a mixture of water and JQ ethanol (50-50 vol.%) maintained at 0 ° C in an ice bath, 0.9 g of hydroxylamine hydrochloride was added. The resulting suspension is allowed to warm to 20 ° C and a solution of 0.7 g of sodium carbonate in 10 cm of distilled water is added. The suspension obtained is heated under reflux for 22 hours. At this time, 80 cm of ethanol are added 2 times. Continue boiling with reflux for 12 hours, adding 3 times 1.35 g of additional hydroxylamine hydrochloride and 1.05 g of sodium carbonate. Then the reaction mixture was poured into 1 l of water. 25 The aqueous phase is extracted 3 times with 300 cm of methylene chloride. The organic phases are combined, washed 2 times with distilled water, dried over
    5-methylhexanone-2, the reaction mixture is stirred for 3 hours at a temperature of about -5 ° C, then 2 hours at 0 ° C, after recrystallization from ethanol, 1 g of 2- (7-methyl-1,8-naphthyridine-2 -yl) -3- (5 methyl-2-oxohexyl) - isoindolinone-1, so pl. 155 ° C.
    3-Oxy-2- (7 methyl-1, 8-naphthyridin-2-yl) isoindolinone-1 can be obtained by a known technique (Belgian Patent No. 815019).
    Example 17. To a solution of 3 g of 2- (7-methoxy-1,8-naphthyridin-2-yl) -3- (5-methyl 2-oxohexyl) -eoindolinon-1 in 30 cm of methylene chloride in an atmosphere of argon added At a temperature of about 20 ° C, a solution of 10.8 g of phosphoryl bromide in 30 cm of methylene chloride is heated, the reaction mixture is heated under reflux for 5 hours, then stirred for 16 hours at a temperature of about 20 ° C. The mixture is then poured onto 50 g of ice, 100 cm of water and 200 cm of methylene chloride and is alkalinized with a saturated aqueous solution of sodium carbonate to a pH of about 10. The aqueous phase is decanted and re-extracted with 100 cm of methylene chloride. An organization
    magnesium sulfate, filtered and the concentrated phases are combined, washed
    trite dry. After recrystallization-6 times 50 cm3 of water, dried over sulfate, from propanol-2, 1 g of magnesium is obtained, filtered, then concentrated (2-oxyimino-5-methylhexyl) -2-is evaporated to dryness under reduced pressure (7- methoxy-1,8-naphthyridin-2-yl) isolation (2.7 kPa). After recrystallisation indolinone-1, so pl. 200 ° C. Acetonitrile 2.4 g
    2- (7-Methoxy-1,8-naphthyridin-2-yl) -2- (7-bromo-1,8-naphthyridin-2-yl) 3-3- (5-methyl-2 hydroxyl) -isoindolly- non-can be obtained analogously to example 1.
    PRI me R 15. They work according to Example 1, but starting from 4.5 g of 3-hydroxy-2-0.
    - (I.8-naphthyridin-2-yl) isoindoline-1, 1.2 g of oily suspension
    (50 wt.%) Sodium hydride, 3.7 g of 5-methylhexanone-2, the reaction
    - (5-methyl-2-oxohexyl) -eoindolino-1, m.p. 166 C.
    2- (7-Methoxy-, 8-naphthyridia-2-yl) -3- (5-methyl-2-oxohexyl) -isoindolinone-1 can be prepared in example 1.
    Example 18. A solution of 16.2 g of 2- (7-methoxy-1,8-naphthyridin-2-yl)
    nona-1 in 160 warm when
    cm phosphoryl chloride - 100 C for 6 hours
    the mixture is stirred J at a temperature of -45 3- (5-methyl-2-oxo-hexgly) -isoindolyer at about -10 ° C, after recrystallization from ethanol, 4.1 g of 3- (5-methyl-2-oxohexyl) - 2- (1,8-naphthyridin-2-yl) -isoindolinone-1, m.p. 166 ° C.
    3-Oxy-2- (1,8-naphthyr idin-2-yl) - isoindolinone-1 can be obtained by a known technique (Belgian Patent No. 815019).
    Example 16. Work as in example 1, but starting from 7.9 g of 3-hydroxy-2- - (7-methyl-1,8-naphthyridin-2-yl) -iso-indolinone-1, 2 g of an oily suspension ( 50% by weight sodium hydride and 6.2 g
    55
    the mixture is then cooled to a temperature of about 50 ° C and concentrated to dryness under reduced pressure (2.7 kPa). 150 g of ice and 150 g of water are added to the residue. Then the mixture is alkalinized with an aqueous solution of ammonia () to a pH of about 12, extracted with 3 times 300 cm of ethyl acetate. The organic phases are combined, washed 4 times with 100 cm 3 of water, dried over magnesium sulfate, filtered, then concentrated to dryness under reduced pressure (2.7 kPa).
    - (5-methyl-2-oxohexyl) -eoindolino-1, m.p. 166 C.
    2- (7-Methoxy-, 8-naphthyridia-2-yl) -3- (5-methyl-2-oxohexyl) -isoindolinone-1 can be prepared in example 1.
    Example 18. A solution of 16.2 g of 2- (7-methoxy-1,8-naphthyridin-2-yl)
    nona-1 in 160 warm when
    cm phosphoryl chloride at 100 ° C for 6 hours. (5-methyl-2-oxoheggyl) -isoindo-
    3- (5-methyl-2-oxoheggil) -isoindo-
    the mixture is then cooled to a temperature of about 50 ° C and concentrated to dryness under reduced pressure (2.7 kPa). 150 g of ice and 150 g of water are added to the residue. Then the mixture is alkalinized with an aqueous solution of ammonia () to a pH of about 12, extracted with 3 times 300 cm of ethyl acetate. The organic phases are combined, washed 4 times with 100 cm 3 of water, dried over magnesium sulfate, filtered, then concentrated to dryness under reduced pressure (2.7 kPa).
    The residue obtained is purified by chromatography on 300 g of silica gel placed in a column 4 cm in diameter (eluent: methylene chloride). First 400 ml of solvent are eluted, the corresponding eluate is discarded, then
    I
    1800 cm of solvent are eluted; the corresponding eluate is evaporated to dryness under reduced pressure (2.7 kIa). After recrystallization of the resulting residue from acetonitrile, 6.4 g of 2- (7-chloro-1,8-nftyridin-) -3 (5-methyl-2-oxohexyl) iso-indolinone-1 are obtained, mp. 180 ° C. .
    2- (7-Methoxy-1,8-naphthyridin-2-yl) - -3 (5-methyl-2-oxohexyl) -yzoindolinone-1 can be obtained in example 1
    As can be seen from the results of the comparison, the target products possess, as well as the comparative product, significant activity in the benzodiazepine receptor affinity test. Target products are distinguished by their antagonistic activity in the isoniazid-induced convulsions test (as opposed to a control product that is inactive in this test). The fact that target products at the same time have a strong benzodiazepine receptor activity (receptors that are part of the GABA receptor) and good antagonistic activity with isoniazid-induced convulsions indicate that for these products, unlike the control the in vitro recognition of the receptor with a benzodiazepine is functionally related to the activation of the GABA receptor. Conduct a toxicity test. "- The maximum dose of the product (LD5o) is determined which, when administered by the oral route, causes the death of 50% of the mice.
    Conducted an affinity test for benzodiazepine receptor central sites.
    The technique is based on the SQUI RES and BRAESTRUP described in the journal Nature .. 1977, 266, 732-734 and consists in measuring, in the presence of the test product, the specific fixation of benzodiazepine ligands, fluni razepam.
    If the product has a receptor with a benzodiazepine,

     ,
    -
    0
    specific fixation of the ligands will be reduced.
    The experiment is as follows: mix the washed homogenate (2 centrifugation at 50,000 g) of the male rat brain cortex (CD CODS, Chazles RIVER Franse) in 50 mM Tris-HCl buffer solution with pK 7.4 (final concentration 0.1 mg of protein per 1 ml), test product with various concentrations and flunitrazepas (final concentration 1.5 nM). Non-specific fixation is determined in the presence of diazepam (10 mM). After 120 min of incubation at 0 ° C, each sample is filtered on a glass fiber filter (filter WHATMAN G (B)), and the radioactivity retained on the filter is measured in liquid scintillation.
    Thus, CH50t. E. the concentration of the test product, which slows the specific fixation of the ligands by 50%.
    Conduct convulsions caused by isoniazid.
    All mice receive a dose, by the intraperitoneal route, 200 mg / kg of isoniazid (a single dose containing 25 ml of solution per 1 kg of mouse). The test products are administered orally 2 or 45 minutes before the administration of isoniazid, with single doses contained in a volume of 25 mg per 1 kg of mouse. Use 5 mice per dose and 3 doses per product.
    After isoniazid injection, the mice are placed in a box divided into 15 compartments with a side of 13 cm, so that each mouse remains isolated during the entire observation time. These boxes are covered with a transparent plate. All control mice that received a dose of 200 mg / kg i.p. isoniazid, already after 80 minutes, have more or less severe convulsions, which quickly become fatal. Mice are monitored for 150 min after injection of isoniazid. In this case, any mouse is considered protected from convulsions, which has no convulsions during these 1.50 minutes. product is the dose that, at the culmination of its effect, relieves spasms caused by isoniazid in 50% of animals.
    The results obtained are tabulated.
    45
    l Nontoxic.
    The products of general formula (I) have interesting pharmacological 35 properties, which are manifested in anxiolytic activity, hypnotic, anticonvulsant antiepileptic and muscle relaxant activity. They also have good in vitro affinity for the benzodiazepine receptor centers. Target products have low toxicity (more than 300 mg / kg) when administered orally to mice.
    Thus, the proposed method allows to obtain new pyrrole derivatives with a broad spectrum of pharmacological activity, which distinguishes them favorably from structures,. tour an anlo ga.50
    权利要求:
    Claims (1)
    [1]
    Invention Formula
    The method of obtaining condensed pyrrole derivatives of the general formula
    From
    a 55 N-Gy
    H2-Y-R
     to obtain the desired product of formula (I), where Y is CO, in di- media. methylformamide in the presence of an alkali metal hydride at a temperature of from -5 ° C to ambient temperature, followed, if necessary, by transferring the obtained target product to the compound of formula (I),
    where Y C NOH by reacting
    with hydroxylamine in a water-alcohol alkaline medium at reflux or in a compound of the formula (I), where Y is CH — OH,
    by reacting with a borohydride alkaline metal in an alcohol medium at 20 ° C, or the resulting product mules (I), where the geth is 7-C -C-alkyl-oxy-naphthyridin-2-yl, is converted to the compound of formula (I), where Get-naphthyridin-2-yl, substituted in the 7-position by a chlorine or bromine atom, it is possible to react with halo-phosphorylr in the presence of methylene chloride while boiling the reaction mixture with a reverse fridge.
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    同族专利:
    公开号 | 公开日
    SU1630612A3|1991-02-23|
    PT86260A|1988-01-01|
    ES2029282T3|1992-08-01|
    FI875298A|1988-06-03|
    IE61088B1|1994-09-21|
    FI875298A0|1987-12-01|
    IL84657D0|1988-04-29|
    HUT46001A|1988-09-28|
    GR3002576T3|1993-01-25|
    FI84722B|1991-09-30|
    NO166036C|1991-05-22|
    EP0274930B1|1991-08-21|
    US4960779A|1990-10-02|
    AU600776B2|1990-08-23|
    CA1298296C|1992-03-31|
    MA21117A1|1988-07-01|
    NO166036B|1991-02-11|
    ZA879000B|1988-06-01|
    MX9560A|1993-11-01|
    DE3772369D1|1991-09-26|
    NO875011D0|1987-12-01|
    FR2607503A1|1988-06-03|
    KR960011775B1|1996-08-30|
    DK630687D0|1987-12-01|
    HU198047B|1989-07-28|
    AU8191187A|1988-06-02|
    KR880007516A|1988-08-27|
    FI84722C|1992-01-10|
    PT86260B|1990-11-07|
    AT66480T|1991-09-15|
    NO875011L|1988-06-03|
    NZ222751A|1989-10-27|
    IE873251L|1988-06-02|
    DK630687A|1988-06-03|
    DK168383B1|1994-03-21|
    JP2531710B2|1996-09-04|
    IL84657A|1991-09-16|
    FR2607503B1|1989-02-24|
    JPS63154681A|1988-06-27|
    EP0274930A1|1988-07-20|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    FR8616795A|FR2607503B1|1986-12-02|1986-12-02|NOVEL ISOINDOLINONE DERIVATIVES, THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM|
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