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    • 专利摘要:
    The invention relates to substituted fused azo-heterocyclic compounds, in particular, di-benzodiazepinone (DI), the general formula SI CH-C-W-C (O) -C-CHI CH. 1 II L I, -C-NK-C-CH CH, where R, - H, C1; K - group - C (0) - Rj - (1-methyl-4-pyridinyl) methyl;
    公开号:SU1301314A3
    申请号:SU833550248
    申请日:1983-02-04
    公开日:1987-03-30
    发明作者:Труммлитц Гюнтер；Энгель Вольфхард；Эверлейн Вольфганг；Шмидт Гюнтер
    申请人:Рудольф Хаммер (Ат)；Пьеро Дель Солдато (Италия)；
    IPC主号:
    专利说明:

    1130131
    The invention relates to a process for the preparation of new dibenzodiazepinone derivatives of the general formula
    where R is a hydrogen or chlorine atom;
    .R - (1-methyl-4-piperidinyl) -methyl; (1-methyl-1,2,5,6-tetrahydro-4-pyridine) methyl; 1-methyl-1,2,5,6-tetrahydro-4-pyridinyl; (1-methyl-4-piperidinylidene) -methyl} endo- or exo- (8-metsh1-8-azobicyclo (3,2,1) oct-3-yl) -methyl,
    or their acid addition salts, which have an anti-ulcer and inhibitory secretion of gastric juice.
    The purpose of the invention is to obtain new dibenzodiazepine derivatives with improved properties as compared with the known ones.
    Example. 5,1O-dihydro-5-. (1-methyl-1,2,5,6-tetrahydro-4-pyri-dinsh1) acetysh 3-1 1H-dibenzo b, e3 (1,4) - diazepin-11-one.
    With external cooling and maintaining the reaction temperature of +15 C, 14.0 g (0.072 mol) of 1-metsh1-1,2,5,6-tetrahydro-4-pyridine acetic acid potassium salt in 150 ml of anhydrous chloroform are added dropwise to a suspension 5.8 ml (0.081 mol) of thionyl chloride dissolved in 20 ml of chloroform. Additionally stirred for 20 minutes, the mixture is concentrated to dryness in vacuum. The resulting acid chloride 1-methyl-1,2,5,6-tetrahydro-4-pyridineacetic acid is added to a suspension of 8.4 g (0.04 mol) of 5,10-dihydro-1IH-dibenzo fb, e3 (1,4) -diazepin-11-one in a solvent mixture consisting of 300 ml of absolute dioxane and 20 ml of anhydrous pyridine. Intensive
    while stirring, the mixture is heated to 80 ° C for 2 hours, after cooling it is filtered. The filter residue is taken up in water, rendered alkaline with solid sodium carbonate, and the aqueous phase is extracted with chloroform.
    ABOUT
    , P
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    2
    The combined chloroform extracts are dried and evaporated in vacuo. The residue is purified by chromatography on a column of silica gel with the use of a mixture of ethyl ester of acetic acid - methanol (volume ratio 9: 1) as eluent. The target product is injected as an amorphous product. Yield 3.5 g (25% of theoretical).
    Calculated,%: C, 72.6; H 6.09; N 12.09.
    C, Hj, Nj02 (347.42)
    Found,%: C 71.9; H6.31; N 12.14.
    IR (KBG): 1660, shoulder at 1680.
    UV (ethanol): shoulder at 7i 270 nm; (ethanol / KOH): iMoiitc 290 HMJ (, 08), shoulder at L 260 nm (, 105).
     H-NMR (dfi-DMSO., 80 MHz): S 7.1-7.9 (8H-M, aromatic. H); 5.02 wide. (4H, olefin. H); 2.95. Wide. (2H, C C-CHj-N); 2.68 (2H, N-CH); 2.15 to 2.5 (2H-M, CG-CHj); 2.18 (3N-s, NCHg); 1.84 wide. (2H, C C-CH4); 12.00 wide. (1H – C, replaced by H).
    C p and m e r 2. 5,10-Dihydro-5- (1-methyl-1,2,5,6-tetrahydro-4-pyridinip) acetyl-IIH-dibenzo, e (1.4 ) -diazepin-11-one and 5,10-dihydro-5- (I-methyl-4-piperidinylidene) - acetyl} - IH-dibenzo, e (4) -diazepin-1-one.
    To a suspension of 16.8 g (0.08 mol) of potassium salt of 3-hydroxy-1-metsh-1-4-pyridine acetic acid in 300 ml of chloroform, while cooling outside, add a solution of 14.2 g (0.12 mol ) thionyl chloride in 50 ml of chloroform at 15 ° C. Stir for 20 minutes and then evaporate in vacuo. The resulting 3-oxy-3-methyl-4-piperidine-acetic acid chloride anhydride added 8.4 g (0.04 mol) of 5,0-dihydro-1 H-dybenzo, f (1 , 4) -diazepin-11-one in a mixture consisting of 400 ml of anhydrous dioxane and 20 ml of dry pyridine. Intensively transferred, the mixture is heated to 80 ° C for 2 hours. After cooling, the precipitate is filtered and taken up in water. The aqueous solution is alkalinized with solid sodium carbonate and extracted with chloroform.
    The combined extracts are dried and evaporated in vacuo. Residue under-
    313
    chromatography over alumina-containing column (degree of activity I) suspended in a mixture of ethyl acetate and methanol (volume ratio 99: 1),
    After being fed to the column, the product was reacted and eluted with a mixture of ethyl acetate and methanol in a volume ratio of 99: 1. In this case, first, 2.5 g (18% of the theoretical) 5, U-dihydro-3- (1-me-, 2,5,6-tetrahydro-4-pyridinip) - acetyl - 1H-dibenzo b, el (1,4) -diaeepin-11-one, which, by thin-layer chromatogram, infrared spectrum and nuclear magnetic resonance spectrum, is completely identical with the product of example 1, and then as the second product 0.2 g (1.4% of theoretical) 5,10-dihydro-5- (1-methyl-4-piperidinylidene) -acetyl I1H-dibenzo b, e3 (1,4) -diazepine-1-it with a melting point of 200- 201 C. C OS "ov product has a value of Rf 0.46, and the second about Duct - R 0.40 (in both cases: silica gel; a mixture of methylene chloride, cyclohexane, methanol, and aqueous ammonia in a volume ratio of 34: 7.5: 7.5: 1).
    Similarly, 6-chloro-5,10-dihydro-5- (1-methyl-1, -2,5,6-tetrahydro-4-pyridinyl) -acetylJ-l1H-dibenzo b, eZ (1, 4) -diazepin-11-one and 6-chloro-5,10-dihydro-5- (I-methyl-4-piperidinylidene) -acetyl-11H-diben, e (1, 4) -diazepin-1 I- he is using 3-hydroxy-α-I-methyl-4-piperidine acetic acid chloride and 6-chloro-5,10-DIHIDRO-11H-dibenzo, e (1, 4) -diazepin-1 1-one. In addition, b-chloro-5,10-dihydro-5- (1-methyl-, 2,5,6-tetrahydro-4-pyridinyl) - acetyl - 1H-dibenzo b, e (1,4) -diazepin -.1 1 -one is obtained in the form of an amorphous powder with so-called diff. 180 C. Yield 31% of theoretical.
    R,: 0.38 (silica gel; a mixture of chloroform, benzene, methanol, and concentrated aqueous ammonia in a volume ratio of 45: 30: 25: 2).
    Calculated,%: C, 66.05; H 5.28; C1 9.28; N 11.01.
    Cj H pClNjO (381.87).
    Found,%: C 66.12; H 5.07; C1 9.00; N 11.20.
    44
    H-NMR (CDCl1, 80 MHz): 7.9 (1H-M, aromatic, H at position I); 6.9-7.6 (6H-M, aromatic. H); 4.9 and 5.15 (1H, olefin. H); 2.8-3.05 (4H-m, 2CH); 2.4-2.65 (2H-m, CHj); 2.3 and 2.35 (3N, N-CH3); 2.05 (2H, CH.,).
    6-Chloro-5,1O-dihydro-5- (-methyl-4-piperidinylidene) -acetyl -1 1H-dibenzo b, e (1,4) -diazepin-11-one is obtained as an amorphous powder with t . 155 C. Output 10% of theoretical.
    Rr: 0.45 - (silica gel; a mixture of chloroform, benzene, methanol and concentrated aqueous ammonia in a volume ratio of 45: 30: 25: 2).
    Calculated,%: C, 66.05; H 5.28; C1 9.28; N 11.0.1. C ,, H, C1 N, 0 (381.87)
    Found,%: C 66.15; H 5.32; C1 9.09; N ii .03.
     H-NMR (CDC1,): S 7.9-8.1 (W-m, aromatic. H in position I); 6.9-7.65 (6H-M, aromatic. H); 5.4 and 5.55 (1H, olefin. H); 2.8-3.05 (2H-m, CH,); 1.95-2.55 (6H-M, CHF); 2.2 (3N, N — CHj);
    Example 3. Endo-5,1O-dihydro-5- (8-methyl-8-azobicyclo (3,2,1) oct-3-yl) acetyl-11H-dibenzo b, e (1,4) -diazepine -11-he.
    Example 2 is repeated, with the difference that tropan-3o chloride (acetic acid and 5,10-dihydro-1 111-dibenzo b, e3 (1, 4) -diazepine-11-one) is used. 33% of theoretical Mp 226-227 with (ethyl acetate).
    Endo-6-chloro-5,1O-dihydro-5- (8-methyl-8-azobicyclo 3, 2, l oct-3-yl) acetyl -1 1 H-ibenzo b, e3 (I , 4) -diazepin-11-one (amorphous powder) using propane-Zyg-acetic acid chloride and 6-chloro-5, I0-dihydro-11H-dibenzo b, eZ (1,4) -diazepine 11th Yield 27% of theoretical.
    Calculated,%: C, 67.39; H 5.90; 1 8.65; N 10.25.
    C h24ClN, 02 (409.93)
    Found,%: C 67.42; H 5.85; 1 8.60; N 10.08.
    H-NMR (): S 7.8-8.0 1H-M, aromatic. H in position I); , 0-7.6 (6H-M, aromatic. H); 1.3-3.2 16H-M, CH, CH and N-CH., At 2.2).
    F (KVg): 1665, shoulder at 675 cm-.
    5130
    Example 4. 5, U-Dihydro-Z- - (1-methyl-4-piperi inyl) -acetyl-1IH-dibenzo b, e (1,4) -diazepin-11-one.
    Example 2 is repeated, but using 1-methyl-4-piperidine-acetic acid chloride and 5, IO-dihydro-11H-dibenzo, e (1,4) -diazepin-11-one. Yield 26% of theoretical.
    Waxy substance, t.plav. B: 95 ° C.
    Calculated,%: C, 72.18; H 6.63; N 12.03.
    C. ,, (349.43)
    Found,%: C 71.72; H 7.07; S 14.90.
    MS: - 349 (210; 140; 96). IR (CHjClz): H 3375, CO 1660 and
    1676 cm
    UV (ethanol / con): - (..., ...- 290 nm
    (, 095); band at 7,256 nm (E 0.12). H-NMR (, 80 MHz): 7.7-8.0 (1H-M, aromatic. H); 7.0-7.6 (7H-M, aromatic. H); 2.5-2.9 (2H-m); 0.8-2.4 (12H-m), and at 8 2.12 (3N-s, N-CH ,.
    Exo-5,10-dihydro-5- (8-methyl-8-azobicyclo (3,2,1) oct-3-yl) acetyl - 1 1H-dibenzo b, e3 (1, 4) -diazepin-11 -one is obtained from 5,1O-dihydro-11H-diben-, e (1,4) -diazepin-11-one and chlorine anhydride tropane-3/3-acetic acid Yield 4% of theoretical; t.plavl 148-150 and, and
    Exo-6-chloro-5,10-dihydro-5- (8-methyl-8-azobicyclo (3,2,1) oct-3-yl) ace 1H-dibenzo b, e diazepin-11-one from b-chloro-5,10-dihydro-11H-diben-, eZ (1,4) -diazepin-11-one and chlorine anhydride tropane-3H-acetic acid. Yield 51% of the theoretical.
    Calculated,%: C, 67.39; H 5.90; C1 8.65; N 10.25.
    CjjH ClNjOj (409.93)
    Found,%: C 67.30; H 5.82; C1 8.91; N 10.09.
    IR (KBg): 1665.
    Example 5. 6-Chloro-5,10-di-hydro-5- (1-methyl-4-piperidine) 1-acetyl-11H-dibenzo, e (1,4) -diazepin-11-one.
    In suspension 1.8 g (7 mmol) of 6-chloro 5,1O-dihydro-1IN-dibenzo, el (1,4) - diazepin-11-one and 4.92 g (28 mmol) of acid chloride -1 -methyl -4-piperidine-acetic acid in 200 ml of dioxane is added dropwise a mixture of 1.7 g
    five
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    46
    (21 mmol) of pyridine and 30 ml of dioxane at room temperature for 20 minutes and stirred for 7 hours at room temperature, and then the reaction mixture is filtered. The solid components are partitioned between chloroform and a solution of potassium carbonate. The organic phase is dried over magnesium sulphate, treated with charcoal, filtered and evaporated; Os, tatok purified by chromatography on a column of silica gel at. the use of a mixture of chloroform, ethyl acetate and methanol as a solvent in a volume ratio of 1: 1: 1. After trituration with cyclohexane, 0.85 g (32% of the theoretical) of 6-chloro-5,10-dihydro-5- (1-methyl-4-piperidinyl) acetyl-1 H-dibenzo b, e (1 , 4) -diazepine- 11-one.
    Calculated,%: C 65.71; H 5.78; C1 9.24; N 10.95.
    CjlHjjClNjO (383.88) Found,%: C 65.90; H 6.02; C1 8.78; N 10.90.
     H-NMR (CDC1,), 80 MHz): B 7.8-8.0 (1H-M, aromatic. H in position. I); 7.0-7.6 (6H-M, aromatic. H); 2, 5 (ЗН-с, N-CH,); 2.6-2.9 and 1.1-2.3 (11H-M, alifatich. And).
    W (GHjClj): NH 3400 and 3200 cm; 1670 and shoulder 1690 cm.
    UV (ethanol): 270 nm; (ethanol / KOH) 259 and 289 nm.
    6-Chloro-5,1p-dihydro-5- (1-methyl-4-piperidinyl) -acetyl3-IIH-dibenzo (b, e (1, 4) -diazepin-11-one crystallizes from ethyl acetate (1/2 mol of ethyl acetate); melting point.
    Example 6. 5,10-dihydro-5- (1-methyl-1,2,5,6-tetra-hydro-4-pyridiyl) -carbonyl hemihydrate -1 lH-dibenzo, e3 (, 4) - diazepin-11-she.
    A mixture consisting of 10.65 g (0.051 mol) of 5,10-dihydro-11H-dibenzo b, e (1, 4) -diazepin-1 1-one, 16.06 g (0.10 mol) of acid chloride 1 -methyl-1,2,5, b-tetrahydroisonicotinic acid, 20.7 g (0.15 mol) of potassium carbonate and 200 ml of anhydrous toluene, while stirring, are boiled for 24 h.
    After cooling, it is stirred in 500 ml of ice-cold water, the organic layer is separated and the aqueous layer is extracted with ethyl acetate. United organic phases
    7130131
    dried over sodium sulfate and evaporated in vacuo. The residue is subjected to chromatography on a column first with silica gel with a grain size of 0.1-0.4 mm when using as an eluent a mixture of 1,2-dichloroethane and methanol (volume ratio 9: 1) and then with silica gel with a grain size of 0.05 to 0.2 mm when using as a eluent a mixture of 1,2-dichloroethane and methanol (volume ratio 95: 5). Colorless crystals are obtained with melting point. 233-234 ° C (diisopropyl ether / ethyl acetate with acetic acid). Yield 2.4 g (14% of theoretical f5).
    Example 7. 5.10 Dihydro-5- (1-methyl-1,2,5,6-tetrahydro-4-pyridinyl) -acetyl-11H-dibenzo, e (1,4) - diazepin-11- he.20
    A mixture consisting of 0.97 g (6.25 mmol) of 1-methyl-I, 2,5,6-tetrahydro-4-pyridine acetic acid and 0.20 g (6.25 mmol) of 75% sodium hydride in paraffin oil in 25 16 ml of dimethylformamide at 50-80 ° C is heated until the evolution of hydrogen ceases.
    To the sodium acid salt thus obtained, 1.312 g of 30 (6.24 mmol) of 5,10-DIHYDRO-1lH-diben-, e (I, 4) -diazepin-1 1-one were added and drops at -10 C, 0.99 g of 98% phosphorus oxide tri-chloride is added over 10 minutes.
    Stir for 4 hours at -10 ° C, for 4 hours at 0 ° C and for 20 hours at room temperature. The mixture is mixed with 200 g of crushed ice, the pH is adjusted to 3.5 with sodium hydroxide solution, shaken with methylene chloride, the aqueous phase is adjusted to pH 9 and extracted with methylene chloride. The organic phase is washed with water, dried over sodium sulfate and thicken 45 in vacuums. After xp chromatography on a column of silica gel (eluent: ethyl acetate / methanol in a volume ratio of 9: 1), 0.63 g (29% of the theoretical) of a colorless amorphous product, which, according to elemental analysis, is the spectrum and NMR spectrum is identical with that obtained in Example 1. 55
    Example 8. Example 7 is repeated, but the reaction is carried out at a temp 48
    receive 0.41 g (19% of theoretical) 5,10-dihydro-5- (-methyl-1,2, 5,6-tetrahydro-4-pyridine) acetyl - 11H-dibenzo b, e (1,4) -diazepin-11-it in the form of a colorless amorphous product, which by elemental analysis, infrared spectrum and NMR spectrum is identical with the product of example 1.
    Example 9. 5.1 O-dihydro-5- (1-methyl-1,2,5,6-tetrahydro-4-pyridinyl) acetyl -1 1H-dibenzo bj (1 .4) - diazepin-11- he.
    To a suspension of 1.552 g (10 mmol) of 1-methyl-1,2,5,6-tetrahydro-4-pyridine acetic acid in 20 ml of anhydrous tetrahydrofuran, 1.1 g (10.14 mmol ) ethyl ester of chloroacetic acid. To the mixture was added 2.10 g (10 mmol) of 5,10-dihydro-11H-dibenzo b, e (1 4) -diazepin-1 1-one, stirred for 1 hour at 0 ° C and then for 4 hours. h at room temperature. Then; chill with ice outside. mix with 160 ml of 2N of native liquor, extract with dichloromethane, and evaporate the organic phase in vacuo to dryness. After chromatography on a column of silica gel using a mixture of ethyl acetate and methanol as an eluent in a volume ratio of 9: 1, 0.87 g (25% of the theoretical) of a colorless amorphous product is obtained, which by thin-layer chromatogram, infrared spectrum and nuclear spectrum magnetic resonance is completely identical with the product of example 1.
    Example 10. 6-Chloro-5,10-dihydro-5- (1-methyl-4-pyrididinyl) -acetyl3-11H-dibenzo b, e () -diazepin-11-one hydrochloride.
    734.1 g (3.0 mol) of 6-chloro-5,10-dihydro-1H-dibenzo, e (1,4) -diazepin-11-it is dissolved in 12.0 l of chloroform by heating to boiling points of the reaction mixture together with 639.1 g (3.3 mol) of 1-methyl-4-piperidinyl acetic acid hydrochloride. The mixture is cooled to 50 ° C and at this temperature by adding dropwise for 1.3 h 457.0 ml (6.3 mol) obtained by distilling fresh thionyl chloride. After the reaction, 6 L of chloroform is distilled off. Cool the reaction mixture to O C and filter the precipitate.
    Ratio -10 C for 10 hours. The latter is washed with 1.5 l of chloroform
    48
    receive 0.41 g (19% of theoretical) 5,10-dihydro-5- (-methyl-1,2, 5,6-tetrahydro-4-pyridine) acetyl - 11H-dibenzo b, e (1,4) -diazepin-11-it in the form of a colorless amorphous product, which by elemental analysis, infrared spectrum and NMR spectrum is identical with the product of example 1.
    Example 9. 5.1 O-dihydro-5- (1-methyl-1,2,5,6-tetrahydro-4-pyridinyl) acetyl -1 1H-dibenzo bj (1 .4) - diazepin-11- he.
    To a suspension of 1.552 g (10 mmol) of 1-methyl-1,2,5,6-tetrahydro-4-pyridine acetic acid in 20 ml of anhydrous tetrahydrofuran, 1.1 g (10.14 mmol ) ethyl ester of chloroacetic acid. To the mixture was added 2.10 g (10 mmol) of 5,10-dihydro-11H-dibenzo b, e (1 4) -diazepin-1 1-one, stirred for 1 hour at 0 ° C and then for 4 hours. h at room temperature. Then; chill with ice outside. mix with 160 ml of 2N of native liquor, extract with dichloromethane, and evaporate the organic phase in vacuo to dryness. After chromatography on a column of silica gel using a mixture of ethyl acetate and methanol as an eluent in a volume ratio of 9: 1, 0.87 g (25% of the theoretical) of a colorless amorphous product is obtained, which by thin-layer chromatogram, infrared spectrum and nuclear spectrum magnetic resonance is completely identical with the product of example 1.
    Example 10. 6-Chloro-5,10-dihydro-5- (1-methyl-4-pyrididinyl) -acetyl3-11H-dibenzo b, e () -diazepin-11-one hydrochloride.
    734.1 g (3.0 mol) of 6-chloro-5,10-dihydro-1H-dibenzo, e (1,4) -diazepin-11-it is dissolved in 12.0 l of chloroform by heating to boiling points of the reaction mixture together with 639.1 g (3.3 mol) of 1-methyl-4-piperidinyl acetic acid hydrochloride. The mixture is cooled to 50 ° C and at this temperature by adding dropwise for 1.3 h 457.0 ml (6.3 mol) obtained by distilling fresh thionyl chloride. After the reaction, 6 L of chloroform is distilled off. Cool the reaction mixture to O C and filter the precipitate.
    913
    and then dry the crude product. Get 1, 53 kg of crude product. The crude product is recrystallized three times from a solution of 3.5 parts by volume. ethanol, 0.1 ob.h. 10% ethanolic solution of chlorovodotg of the genus, 3.5 parts by vol. diisopropyl ether (per 1 kg of crude product using 7 liters of this solution). Yield 1, 035 kg (82% of theory).
    Calculated,%: C 57.15; H 5.51; C1 16.87; N 10.00.
     (420,338)
    Found,%: C 56.95; H 5.48; C1 16.68; N 9.89.
    Example 11. Hemithartrate 6-chloro-5,1O-dihydro-5- (1-methyl-4-piperidinyl) acetyl -1IP-dibenzo, ej (1,4) -diazepin-11-one.
    To 4.44 g (0,0116 mol) of 6-chloro-5,1O-dihydro-5- (1-methyl-4-piperidinyl) -acetyl -1 1 -dibenzo, e (1,) diazepine- 11-she is added 0.876 g (0.0058 mol) b - (+) - tartaric acid. The mixture is dissolved in 50 ml of ethanol at 45 ° C. The solution is filtered and cooled. 100 ml of diisopropyl ether are added to the solution. The resulting precipitate is filtered and dried. Yield 3 g (58% of theory). M.plavl 165 C (decomposition).
    Calculated,%: C 60.19; H 5.49; N 9.16; C1 7.73.
    C feHsoCl NeOio (916.79)
    Found,%: C 59.09; H 5.50; N 8.59; C1 8.06. .
    Example 12. 6-Chloro-5,1O-dihydro-5- (1-methyl-4-pyrididinyl) -acetylZ-11H-dibenzo b, el (1,4) -diazepin-11 hydrochloride.
    38.83 g (0.1 mol) 6-chloro-5,10-dihydro-5- (1-metip-4-piperidinyl) - acetyl -. 1H-dibenzo b, e (1, 4) -diazepin-11-one is dissolved in 150 ml of absolute ethanol. 100 ml (0.25 mol) of 10% ethanolic hydrogen chloride are added, stirred and mixed with 250 ml of diisopropyl ether. The resulting salt is filtered and recrystallized in absolute ethanol; 3-4 ml of 10% ethanolic hydrochloride solution is added again to the ethanol used (80-100 ml). The product obtained after recrystallization is washed with diisopropyl ether and dried. Yield 40 g (95% of theory). M.plavl (with decomposition).
    0
    15
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    31
    s
    -50 55
    thirty
    35
    40
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    410
    Calculated,%: C 57.15; H 5.51; C1 16.87; N 10.00.
     (420,338)
    Found,%: C 56.95; H 5.43; C1 16.63; N 9.92.
    The biological activity of the novel and known dibenzodiazepinone derivatives is illustrated by the following example, in which the novel compounds A-3 and the known compound 1 are tested.
    5,10-Dihydro-5- (1-methyl-1,2,5,6-tetrahydro-5-pyridinyl) -carbonyl - 1 1H-dibenzo Gy, e (1, 4) -diazepin-1 1-one ( BUT).
    6-Chloro-5,1O-dihydro-5- (1-methyl-4-piperidinyl) -acetyl-11H-dibenzo b, e (1,4) -diazepin-1I-OH (B).
    Endo-5,1O-dihydro-5- (8-metsh1-8-azobicyclo (3,2,1) oct-3-yl) acetyl - 11H-dibenzo b, eZ (1,4) -diazepin-11- he is in).
    5,10-Dihydro-5- (1-methyl-1,2,5,6-tetrahydro-4-pyridinyl) -acetyl-11H-dibenzo, e3 (1,4) -diazepin-11-one (G) .
    5,1O-Dihydro-5-G (J methyl-4-piperidinylidene) -acetyl - 1H-dibenzo b, e (1,4) -diazepin-11-one (D).
    6-Chloro-5,10-dihydro-5- (1-methyl-4-piperidinyl) acetone - 1 1H-dibenzo, e (I., 4) -diazepin-11-one (E).
    Hydrochloride 6-chloro-5,1O-dihydro-5- (1-methyl-4-piperidinyl) -acetyl - 11H-diobenzo b, e (1,4) -diazepin-11-one (G).
    Exo-5,1O-dihydro-5- (8-metsh1-azabicyclo (3,2,1) oct-3-yl) acetyl - 1 1 H-dibenzo b, e (1, 4) -diazepin-11 - he (3).
    5,10-Dihydro-5- (4-methyl-1-piperazinyl) - acetyl -1 1H-dibenzo b, e (1,4) -diazepin-11-one (known, I).
    Example 13. Studies on antimuscarinic selectivity.
    Purpose. Oxotremorin, a specific muscarinic receptor agonist, causes lesions of the gastric mucosa in rats and increases the secretion of saliva. This experiment allows to determine the selective effect of the antimuscarinic substance on the stomach.
    The technique. The experiment was conducted on ten rats weighing 120-150 g, which, with free access to drinking water 24 hours before the start of the experiment, were left | without food.
    1113
    The muscarinic effect of oxotremor on each symptom under investigation was determined in preliminary experiments in which at least three doses for each symptom were used to create a curve, dose / action.
    In the study of antimuscarinic substances, this dose of oxotremorin was used, which in preliminary experiments showed a corresponding symptom in 90-100% of animals:
    Defeat
    mucous
    shell
    stomach 0.62 mg / kg intrasecretion of peritoneum saliva 0.083 mg / kg co
    Each antimuscarinic substance was given intravenously in various doses 15 minutes before giving oxremorin. Control animals were given a solvent or suspending agent in an appropriate amount instead of the test substance.
    Immediately after giving oxo-tremorin, animals were observed in a glass cage for 15 minutes.
    The dose was determined to provide a 50% delay in the effect caused by oxotremorine (i.e., the percentage of animals not showing the corresponding symptom). Dose indicated ED
    Effects on damage to the gastric mucosa were determined as follows.
    Damage to the mucosa. The stomach was contracted by intravenous injection of 0.62 mg / kg of oxotremorine 30 minutes after oral administration of 1 mg / kg of neostigmine (cholinesterase inhibitor). 60 minutes after the delivery of neostigmine, the animals were euthanized, the stomachs were enlarged, opened and examined for the presence of an injured mucous membrane. The dose of the test substances was determined, providing a 50% protective effect. Dose indicated
    Studies defining links with muscarinic receptors. KTjo value determination
    Experimental animals are rats weighing 180-220 g. After removing the heart, stomach, and cerebral cortex, all further operations were performed in ice-cold HC1 buffer solution (pH, 7.4; 100 mmol pH. NaClj 10 mmol pH. MgCl ). Smooth
    five
    about
    Q f
    .

    five
    4 12
    the muscles of the bottom of the stomach were freed from the mucous membrane of the stomach and previously homogenized. The heart was crushed with scissors. Then all the organs were subjected to homogenization.
    For the experiment, organ homogenates were diluted as follows:
    Smooth muscle
    bottom of the stomach: 1 00
    Heart1: 250
    The cerebral cortex1: 3000 Incubation of homogenates of organs was carried out at a certain concentration of radio adrende and a series of concentrations of non-radioactive test substances in an Eppendorfer centrifuge tube at 30 C. The incubation period was 45 minutes. As
    This radioaddende was applied with 0.3N H-Nmethylscopolamine (11-NMC). At the end of the incubation, the radioactivity in the granules was determined by centrifugation at 14,000 g. It is the Sum of specific and non-specific binding, defined as the radioactivity that was bound in the presence of 1 µm quinuclide-dinyl benzylate. Each experiment was conducted 4 times. The CT values of unlabelled test substances were determined graphically. They represent the concentration of the test substance, providing a 50% delay in the specific binding of H-NMC to muscarinic receptors in various organs.
    Determination of toxicity.
    Each of the studied compounds was given orally at a dose of 500 mg / kg in five doses. After 14 days, animal mortality was determined.
    The results of the experiments are summarized in the table (as it was not determined).
    Comparison of the data on the ED of new compounds A-3 with the corresponding data of the known compound 1 indicates a higher activity of the new compounds, since their effective dose is significantly lower than the effective dose of the known compound.
    The coefficient f is the ratio between the values of the cerebral cortex and the mean values obtained from the values of
    13
    smooth muscles of the stomach and heart. The higher this ratio, the better the selectivity of action. ,
    F o rmula of the invention
    The method of obtaining dibenzodiazepinone derivatives of the general formula
    where RJ is a hydrogen or chlorine atom;
    RJ is (1-methyl-4-piperidinyl) methyl; (1-methyl-1,2,5,6-tetrahydro-4-pyridinesh1) methyl; 1-metsh1-1,2,5,6-tetrahydro-4-pyridinyl; (1-methyl-4-piperidinylidene) -methyl; and- or exo- (8-methyl-8-azobidiclo (3,2,1) oct-3-yl) methyl,
    1301314
    or their acid addition salts (possessing an anti-ulcer and inhibiting gastric acid secretion), characterized in that the compound of the general formula
    RI n
    where R has the indicated meanings, is reacted with an acid derivative of the general formula
    , ABOUT
    where Z is a chlorine atom or lower alkoxy;
    Rj has the indicated values in an inert organic solvent at a temperature of from -10 ° C to the boiling point of the reaction mixture.
    thirty
    100
    250
    3.1
    80
    500
    权利要求:
    Claims (1)
    [1]
    Formula of the invention
    1301314 14 or their acid addition salts (having antiulcer and inhibitory secretion of gastric juice) action, characterized in that the compound of the general formula
    A method of obtaining derivatives of di ~ benzodiazepinone of the general formula a hydrogen atom or chlorine;
    (1-methyl-4-piperidinyl) -megda R (
    R, tyl; (1-methyl-1,2,5,6-tetrahydro-4pyridinyl) methyl; 1-metip-1,2,5,6tetrahydro-4-pyridinip; (1-methyl-4piperidinipide) methyl; endo- or exo- (8-methyl-8-azobicyclo (3.2.1) oct20
    Ri Η where R ^ has the indicated meanings, is reacted with an acid derivative of the general formula where Ζ is a chlorine atom or lower alkoxy;
    has the indicated values, inert organic
    R z in the solvent medium at a temperature of from -10 C to the boiling point of the reaction
    3-yl) methyl tion mixture. Test compound Studies by definition with CT 5 receptors ( , / n mol L andconnections Test with oxotremonin, mcg / kg (intravenous antiulcer effect) Toxicity Vduo "mg / kg (oral) Cortex Smooth muscles, bottom of the stomach Heart Coefficient E D 5 about Delay of secretion of saliva ED 50 A thirty 100 250 6 3,1 80 > 500 B 28 170 200 6.5 4.4 230 > 500 IN fifteen 200 55 5.5 G, 1 105 > 500 G 5 20 20 4 fifteen 350 > 500 D 10 20 thirty 3 20 400 > 500 E but. but. but. but. 2,8 80 > 500 F n about. but. but. but. 3.0 100 > 500 31 (known) but. but. but. but. 16 400 > 500 23 70 60 3 fifty* **400 > 500
    At 50 μg, the protective effect is 15%.
    At 400 mcg, the protective effect is 10%.
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