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    • 专利摘要:
    (+/-)-4-Substituted-amino-6-substituted-1,3,4,5-tetrahydrobenz[c,d]ino les, or a pharmaceutically-acceptable salt thereof, are central serotonin agonists.
    公开号:SU1375128A3
    申请号:SU853856855
    申请日:1985-02-04
    公开日:1988-02-15
    发明作者:Эдвард Флауф Майкл
    申请人:Эли Лилли Энд Компани (Фирма)；
    IPC主号:
    专利说明:

    The invention relates to heterocyclic nitrogen-containing compounds, in particular to a method for producing (±) -4-di (n-propyl) amino-6-carbamoyl-1-3,4,5-tetrahydrobenz c, d indole of formula 1
    SOMN2
    . (
    sh
    or its pharmaceutically acceptable salt, which are serotonin antagonists of the central nervous system and can be used in the treatment of obesity, old-age dementia, and anti-smoking.
    The aim of the invention is to develop a method for producing new derivatives of general formula 1, which have valuable pharmacological properties.
    The invention is illustrated by the following specific examples of the preparation of the starting material of intermediates and final products (the ratios are voluminous, if the substances are liquid, and by weight, if the substances are solid).
    Example 1. Obtaining (±) -A- -di (n-propyl) amino-6-bromo-1,2,2a, 3, 4,5-hexahydrobenz c, d indole.
    A mixture containing 5.0 g of 5-oxo-1, 2.2a, 3,4,5-hexahydrobenz fc, dj indole in 100 ml of ethanol is treated with 1.63 g of sodium borohydride, administered in individual portions. The resulting mixture is stirred approximately 4 h, then from it. the mass of ethanol is removed in vacuo. The residue obtained is diluted in water and the aqueous mixture is acidified with 3 M hydrochloric acid. The aqueous solution is filtered and the filtrate is treated with a dilute aqueous solution of sodium hydroxide. The (±) -5-hydroxy-1,2,2a, 3, 4,5-benzo c.d obtained in the reaction is indole insoluble in an alkaline medium and precipitated. The precipitate is collected, washed with water and then dried. 4.72 g of (+) - 5-oxide-1,2,2a, 3,4,5-hexahydrobenz c, dj indole are obtained (93% yield). One spot was detected by thin layer chromatography, mp. product 205 C.
    Calculated,%: C 75.83; H 6.94; N 8.04.
    Found,%: C 75.75; H 7.16; N 7.89.
    A solution of 35 g of (±) -5-hydroxy-1,2,2a, -3,4,5-hexahydrobenz c, d indole in 900 ml of cold glacial acetic acid is treated with 22 g of bromine dissolved in 100 ml of glacial acetic acid . After the disappearance of the color of bromine, acetic acid is distilled off in vacuo. The residue comprising a mixture of (±) -5-hydroxy-6-bromo-1,2,2a, 3,4,5-tex-sagidrobenz c, dj indole and the corresponding 6,8-dibromo derivative
    5 is diluted with water and the aqueous mixture is made alkaline with 5 M aqueous sodium hydroxide. Hexahydrobenz c, d) indoles, insoluble at the base, are precipitated and the precipitate is collected. Recrystallization of the precipitate from methanol gives about 3 g of the dibromo derivative plus about 12.5 g of the monobromo derivative and a significant amount of the crystalline fraction, which
    5 is a 1: 1 mixture of the starting material and the monobromo compound. The thus obtained (i) -5- -oxy-6-bromo-1,2,2a, 3,4,5-hexahydrobenz c, d3 indole has mp. approximately (with decomposition). By recrystallization of the various fractions, 24.1 g (yield 47%) of the 6-bromo derivative are obtained. The resulting product still contains a small amount of dibromic impurity.
    five
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    five
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    five
    The reaction mixture is prepared by dissolving 27.43 g of () -5-hydroxy-6-bromo--1,2,2a, 3,4,5-hexahydrobenz s, d indole in, 100 ml of pyridine and then added dropwise 25 ml of ethyl chloroformate for 20 minutes. Approximately 0.5 g of 4- (H, K-dimethylamino) pyridine (DMAP) is added and then the resulting reaction mixture is stirred at room temperature for about 4 hours. The reaction mixture is then cooled by pouring it into 1 liter of a mixture of water and ice. The oil that is separated off almost immediately turns into a crystalline form. The crystals are collected and thoroughly washed with water. The dried amide ester is a solid with a weak pink color, m.p. product about 215 C (with decomposition). The output of 40.48 g (94%). The analysis found that the product as
    impurities contain some amount of 6,8-dibromo compound.
    Pyrolysis of 40.1 g of (±) -1-ethoxycarbonyl-5-ethoxycarbonyloxy-6-bromo-1,2,2a, 3,4,5-hexa-hydrobenbenz, d indole in separate weights (10 g ). The pyrolysis is carried out at 215-220 ° C in a nitrogen atmosphere. Each experiment requires 25 to 30 minutes of heating. Four dark oily residues are combined and diluted in toluene. The toluene solution is passed through a silica gel column chromatography. From the fractions containing the starting material, 1.4 g of this material is extracted, and the main product, 1-ethoxycarbonyl-6-bromo-1,2, 2a, 3ttetragidrobenz c, d indole, is recrystallized from a mixture of hexane-toluene containing predominantly hexane . 19.36 g of the second portion of the product is obtained only from hexane, yield 65%, corrected for the recovered starting material, tm.p. 122-123 s.
    Calculated,%: C 54.56; H 4.58; N 4.55; Br 25.93. Found,%: C 54.59; H 4.61; N 4.41; Вг 25.84.
    The non-cushioned product from the described step is epoxidized as follows.
    A solution of 7.5 1-ethoxycarbonyl-6-bromo-1,2,2a, 3-tetrahydrobenz C, d indole in 250 ml of chloroform is cooled to approximately O With an ice-salt mixture. 6 g of 85% methachloropenzoic acid is added. acid. The reaction mixture is stirred at about 0 ° C. for 1 hour and then maintained at refrigerator temperature overnight. The reaction mixture is washed successively with 1N. aqueous sodium hydroxide, all together; sodium bisulfite aqueous solution; 1 n again. water caustic soda and finally brine. The organic solution is dried and the solvent is removed in vacuo. The resulting solid residue is recrystallized from toluene-hexane. The first portion of the resulting material is 7.33 g, so pl. 126-128 ° C; Total output (two servings) 98%.
    Calculated,%: C, 51.8; H 4.35; N 4.32; Br 24.65.
    Found,%: C, 51.83; H 11.33; N 4.16; Br 24.31.
    A solution of 7.5 g of 1-ethoxycarbonyl-4,5-epoxy-6-bromo-1,2,2a, 3,4,5-hectagidrobenz C, d indole, obtained earlier, in 50 ml of benzene is slowly added to boiling with reflux a solution of 1 g of zinc iodide in 450 ml of benzene, which is dried by distillation with 50 ml of azeotropic mixture of benzene-water. The reflux was continued under nitrogen atmosphere for 1 hour after the addition was stopped. The reaction mixture is cooled. The floating layer is decanted and the decanted solution is washed with water and then brine. The solution is present and the solvent is distilled off in vacuo. The residue, including 1-toxycarbonyl-4-oxo-6-bromo--1,2,2a, 3,4,5-hexahydrobenz-c, is recrystallized from toluene-hexane. Get 5.36 g (71%) of crystalline product, so pl. 186 188 ° С
    Calculated,%: C, 51.87; H 4.35; N 4.32; Br 24.65.
    Found,%: C 51.75; H 4.29; N 4.50; Br 24.80.
    Prepare a reaction mixture of 14 g of 1-ethoxycarbonyl-4-oxo-6-bromo-1, 2-2a, 3,4,5-hexahydrbenz c, d indole, 28.3 g of n-propylamine, 4.9 ml glacial acetic acid and 300 ml of acetonitrile. The reaction mixture is stirred under nitrogen for about 1 hour. 3A molecular sieves are added to absorb water. Then, 5.6 g of sodium cyanoborohydride and 14 ml of glacial acetic acid are sequentially added. This reaction mixture is stirred for several hours and during this time 7 ml of glacial acetic acid are added. The reaction mixture is stirred for another 2 hours and 7 ml of glacial acetic acid are added again. The layer above the molecular sieves is then decanted and the bulk of the volatile contaminants is stripped off in vacuo. The remaining solution is poured into cold aqueous 2N. caustic soda solution. The alkaline mixture is extracted with methylene chloride. The extract is washed with 0.5 n. aqueous solution of caustic soda, and then brine. The solvent is distilled off in vacuo. The residue obtained is dissolved in 1N. aqueous hydrochloric acid to which methanol has been added. This acidic washing solution
    513
    sulfuric ether and sulfuric ether washing liquid are discarded. The acidic solution is then alkalinized with 5N. an aqueous solution of sodium hydroxide and insoluble in this medium (+) - 1--ethoxycarbonyl-4-propylamino-6-bromo 1,2,2a, 3,4,5-hexahydrobenzo with, d indole, which is obtained by the above reaction, is separated and extracted with methylene chloride. The methyl chloride extract is separated and the solvent is distilled off to obtain 16.7 g of orange oil, which is used in the next step without further purification.
    The resulting crude product is dissolved in 50 ml of acetonitrile, 3 ml of n-propyl iodide and 2 ml of diisopropyl ethylamine. This solution is left in the dark for about three weeks. The solvent is then distilled off under reduced pressure and the residual mixture is partitioned between ethyl ether and 0.5N. water caustic soda. The organic layer is separated and the aqueous alkaline layer is extracted several times with sulfuric ether. The ether extracts are washed with brine and then dried. The sulfuric ester is removed in vacuo. Xylene is added to the residue and evaporated to remove traces of diisopropylethylamine. The crude residue slowly crystallizes. The crystals are dissolved in 20 ml of methylene chloride and 5 ml of acetic anhydride are added. After about 1 hour, the volatile impurities are removed in vacuo and the resulting residue is dissolved in methylene chloride. The methylene chloride solution is mixed with an aqueous solution of sodium carbonate to remove any excess acetic anhydride. Separate the methylene chloride layer and

    The residue is vacuum chromatographed on silica gel using ethyl acetate as an eluting solvent. The fractions containing the target material are combined and the solvent is distilled off in vacuum. The white crystalline residue is transferred onto filter paper using cold isooctane. The total yield of (+) - 1-ethoxycarbonyl-4-di (n-propyl) amino 6-bromo-1,2,2a, 3,4,5-hexahydrobenz s, d indole is 2.39 g and is obtained in two portions, so pl. 90-94 ° C.
    Calculated,%: C 58.68; H 7.14;
    N
    6.84; Br 19.52. Found,%: C 58.98; H 6.88;
    0
    five
    0
    five
    0
    N 6.59; Вг 18,74.
    Alternatively, a solution of 15.7 g of crude secondary amine.
    (±) -1-Ethoxycarbonyl-4- (n-propyl) amino-6-bromo-1,2,2a-3,4,5-hexa-hydrobenzoic, d indole in 80 ml of pyridine is cooled to about 0 ° s 16 ml of propionic anhydride is slowly added. The solution is overclocked overnight at room temperature. The bulk of the pyridine solvent is distilled off in vacuo and the remainder of the solution is stirred with an excess of aqueous sodium carbonate solution for several hours, which ensures the complete removal of unreacted propionic anhydride and some amount of propionic acid, which is by-produced. The aqueous mixture is extracted with methylene chloride, the methylene chloride extract is separated and washed with a 0.5 M aqueous solution of sodium hydroxide, 1N. hydrochloric acid solution and brine. The organic solution is dried, the solvent is distilled off in vacuo and obtained in
    methylene chloride is distilled off. The rest is rast-d5 residue in viscous oil. The oil is dissolved in 50 L of tetrahydrofuran and this solution is added over about 15 minutes to 85 ml of 1N. a solution of diborane in tetrahydrofuran, which is maintained at about 0 ° C. After the addition is complete, the cooling bath is removed and the reaction mixture is heated to reflux for about 1.5 hours. Then the reaction mixture is cooled to about 0 ° C and carefully added 50 ml of methanol. The resulting reaction mass is stirred at room temperature.
    they are stolen in a mixture of dilute hydrochloric acid and methanol. The turbid solution obtained is washed with ether and the ether is discarded. The acidic layer is converted to alkaline, up to 5 n. aqueous solution of caustic soda. The resulting insoluble base, which is separated, is extracted with methylene chloride. After evaporation of the solvent, a wet crystalline residue is obtained. The residue is treated with hexane and the hexane solution is separated from the brown oil insoluble in hexane by decanting. Hexane extracts a viscous oil. Oil solution
    in 50 L of tetrahydrofuran, and this solution is added over about 15 minutes to 85 ml of 1N. a solution of diborane in tetrahydrofuran, which is maintained at about 0 ° C. After the addition is complete, the cooling bath is removed and the reaction mixture is heated to reflux for about 1.5 hours. Then the reaction mixture is cooled to about 0 ° C and carefully added 50 ml of methanol. The resulting reaction mass is stirred at room temperature.
    71
    temperature overnight. The methano is distilled off in vacuo. Methanol is again added and again evaporated. The resulting residue begins to be cured. The semi-solid residue is partitioned between sulfuric ether and 1 M hydrochloric acid containing methanol. As a result of this procedure, a solid is precipitated which is filtered off. The filtrate is alkalinized by the addition of aqueous sodium hydroxide and the alkaline mixture is extracted with methylene chloride. The ether layer obtained, the methylene chloride extract and the separated solid are combined and the solvent is distilled off. The residue is heated with wet dimethyl sulfoxide and this solution is then diluted with water with a sufficient amount of 1 M aqueous sodium hydroxide solution, which provides an alkaline environment. The alkaline mixture is extracted with sulfuric ether. The ether extract, in turn, is extracted with 1 M hydrochloric acid, containing some methanol. The acidic extract is made alkaline again and the alkaline mixture obtained is extracted with methylene chloride-ROD. The methylene chloride extracts are combined. After evaporation of the solvent, 15.49 g of a crude orange-pink compound are obtained. The solid is dissolved in ethyl acetate and the chromatography is carried out on a silica gel. The fractions containing the desired material are combined and the solvent is distilled off in vacuo. Recrystallization of the solid from isooctane gives (+) - 1-ethoxycarbonyl-4-di (n-propyl) amino-6-bromo-1,2,2a, 3,4,5-hexahydro benz c, d indole, mp . 87-89 ° C. The product yield of 14.8 g (94%).
    A solution of 1 g of the indicated solution should be tr.: - of the pure amine in 10 ml of 6 n. hydrochloric acid is maintained at the boiling point under reflux for 8 hours. The method of thin layer chromatography establishes the presence of only residual (traces) quantities of the starting material and it is determined that (±) -4-di (n-propyl) is the main substance amino-6-bromo-1,2,2a, 3,4, Zrhexahydrobenz s, d indol. The acidic solution is poured into a dilute aqueous solution of sodium hydroxide and the resulting alkaline layer is extracted with methyl chloride.
    j 20 5 zo Q
    .
    five
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    288
    no. The methylene chloride extract is separated, washed with brine and then dried. By evaporation of the solvent, a viscous oil is obtained, which crystallizes on cooling. By recrystallization of the precipitate from isoctane, 0.683 g (yield 83%) of (±) - -4-di (n-propyl) amino-6-bromo-1,2,2a, 3,4,5-hexahydrobenz c, d indole, t is obtained .pl. approximately 62-63 ° C.
    Calculated,%: C 60.53; H 7.47; N 8.319; Br 23.69.
    Found,%: C 60.71; H 7.57; N 8.30; Br 23.78.
    Example 2. Synthesis of (+) - 4-di- - (n-propyl) amino-6-bromo-1,2,3,4, - tetrahydrobenz c, and indole.
    Cool down to approximately 0 ° C a suspension of 0.44 g of N-chlorosuccinimide in 16 ml of toluene. 0.3 ml of dimethyl sulfide is added. After 15 minutes, the reaction mixture is cooled in an acetone bath with dry ice to approximately -60 ° C. 0.6 g of (h-) -4- (di-n-propyl) amino-6-bromo-1 is added over 15 minutes 2,2a, 3,4,5-hexahydrobenz c, dj indole prepared according to example 1, and 2 ml of toluene. The reaction was stirred for approximately 2 hours and at the same time 0.8 ml of triethylamine was added. The cooling bath is removed and stirring is continued for about 2.5 hours at ambient temperature. The reaction mixture is then poured into cold aqueous 1N. caustic soda and the resulting alkaline mixture is extracted several times with toluene. The toluene extracts are combined, the combined extracts are washed with brine and then dried. The solvent is distilled off and the resulting residue is chromatographed on 15 g of phlorisyl using an ethyl acetate-toluene mixture (1: 9). The fractions, the content of the desired product, are combined and re-passed through a silica gel chromatography column using the same eluent. The fractions containing the desired product are re-combined and the solvent is distilled off to obtain a greenish oil. This oil is dissolved in about 20 ml of pentane and filtered to remove the colorless precipitate. Then the pentane is removed by evaporation in vacuo. A yellow-green oil (0.303 g, 51%) is obtained, containing (n:) - 4-di (n-propyl) amino-6-bromo-1, J
    3,4,5-tetrahydrobenz c, d indole, which was formed during oxidation. The product crystallizes upon standing. Mp. 72-73 0.
    Calculated,%: C 60.90; H 6.91; N 8.36; Br 23.83.
    Found,%: C 60.77; H 6.87; N 8.28; Br 23.61.
    PRI me R 3. Synthesis of (±) -A-di (n-propyl) amino-6-bromo-1,3,4,5-tetrahydrobenz s, d indol.
    Prepare a solution of 1 g of (+) - 4-di- (n-propyl) amino-6-bromo-1,2,2a, 3,4,5-hexahydrobenz s, e-indole, prepared in accordance with example 1, in 50 ml of hexane. 4 g of activated manganese dioxide is added and the resulting suspension is sonicated at a frequency of 50-55 kHz in a nitrogen atmosphere for about 1 hour. Thin-layer chromatography at this point shows an almost complete absence of starting material. The reaction mixture is filtered under vacuum and the resulting precipitate of manganese dioxide is thoroughly washed with fresh hexane. Hexane is removed from the filtrate and the resulting residue is chromatographed as before. The fractions containing the desired indole are combined and the solvent is removed by evaporation. By recrystallization of the resulting precipitate from isooctane, 0.62 g (yield 62%) of (±) -4-di (n-propyl amino-6-bromo-1,3,4,5-tetrahydrobenz s, d indole, m.p. 73-74 S.
    Example 3. Synthesis of (+) - 4-di (n-propyl) amino-6-cyano-1,3,4,5-tetrahydrobenz c, y indole.
    Prepare a solution, a solvent of 0.7 g of copper (I) cyanide in 10 ml of N-methyl-2-pyrrolidone, pre-vented with nitrogen. 1 g of (+) - 4-di (n-propyl) amino-6-bromo-1,3,4,5-tetrahydrobenz c, d indole is added to a solution of copper cyanide. The solution is kept under nitrogen at 200 ° C. for 1 hour. Then, the reaction mixture is cooled and partitioned between ethyl acetate and dilute aqueous ammonium hydroxide. The alkaline layer is extracted several times with ethyl acetate. The ethyl acetate layers are combined and washed successively with dilute water with ammonium hydroxide, diluted with aqueous ethylenediamine and brine. Then the ethyl acetate layer is dried and the solvent is distilled off. Residual oil
    0
    20
    25
    five
    dd 30
    35
    40
    dissolved in sulfuric ether, the resulting solution was washed twice with brine. The ether layer is separated and the ether is distilled off in vacuo. The residue is then dissolved in ether, the ether is diluted with several volumes of petroleum ether. The supernatant is decanted, the dark residual oil is again treated with a mixture of ether and petroleum ether. The combined supernatant layers are evaporated, leaving a viscous orange oil in the residue. The residue obtained is chromatographed over silica gel using a mixture (1:10) of ethyl acetate and toluene as eluent. Fractions containing the desired (±) 4-di (n-propyl) amino-6-cyano-1, 3,4,5 are obtained. -tetrahydrobenz s, d indole, synthesized in the previous reaction. Recrystallization of the solid from a toluene-hexane mixture gives a crystalline material, mp. 132-133 ° C. Exit 44%.
    Calculated,%: C, 76.83; H 8.24; N 14.83. : Found,%: C 76.56; H 8.09; N 14.86.
    Example 4. Synthesis of () -4- (n- -propyl) amino-6-carbamoyl-1,3, 4-5- -tetrahydrobenz c, d jindole.
    Approximately 1.5 g of powdered potassium hydroxide are suspended in 10 ml of distilled tert-butanol and O, 3 ml of dimethyl sulfoxide. 0.3 g of (±) -4-di (n-propyl) amino-6-cyano-1-, 3,4,5-tetrahydrobenz c, djindole is added. The mixture is heated under reflux in a nitrogen atmosphere in for about 72 hours. At this point, thin layer chromatography shows that the reaction is partially complete. The boiling under reflux is continued for another 24 hours. Then the reaction is stopped by adding cold water and the aqueous mixture is extracted with methylene chloride. The organic layer is separated, washed with brine and then dried. By evaporation of the solvent, a residue is obtained, which is chromatographed through florisil, using ethyl acetate as the eluent with a methanol content of up to 10%. The starting material was eluted with methanol-ethyl acetate (5:95) and the target product was (±) -4-di (n-propyl) amino-6-carbamoyl-1,3,4,5-tetrahydrobenz c, d indol was eluted with methanol - ethyl acetate (10:90). 0.14 g of product and about 0.17 g of starting material are obtained. The recovered starting material is treated as described above, with powdered potassium hydroxide in tert-butanol and dimethyl sulfoxide. The second hydration mixture is heated to reflux for about four days. The reaction is stopped by the addition of cold water, but thin layer chromatography shows that the hydration is not complete. The mass of the 6-carbamoyl derivative obtained from the second experiment is about 0.5 g. The recovered starting material is worked up as before and refluxed with base for about one week. The result is an additional amount of 6-carbamoyl derivative. All fractions containing (±) -4-di (n-propyl) amine 6-6-carbamoyl-1,3,4,5-tetrahydrobenz c, d indole, are combined, chromatographed over Florisil using ethyl acetate, and then a mixture (1: 1) of methanol and ethyl acetate as eluent. The starting material is eluted with ethyl acetate. The (±.) - 4-di (n-propyl) amino-6-carbamoyl-1,3,4,5-tetrahydrobenzo c, d indole is recrystallized, after recrystallization, first from a mixture of toluene and hexa. and then from toluene has so pl. 163-165 ° C. Yield 54%.
    N
    C, 72.21; H 8.42; 8.27;
    H
    40
    Calculated 14.03.
    Found,%: C 72.23; N 13.57.
    Both p and MER 5. Preparation of 4-dimethylamino-6-carbamoyl-1,3, 4,5 tetra-hydrobenzoic s, d indole citrate.
    100 mg 4-dimethylamino-6-carbamoyl-1, 3,4,5-tetrahydrobenz c,., The following: serotonin (Amersham, 11
    Kyu / mmol), 2-3 nM; LSD (Amersham, 1.8 Kyu / mmol), 1.8-2.6 nM; spiperone (Amersham, 20 Kyu / mmol), 0.6-0.7 nM.
    and N-spiperon in 10 M LSD. The specific binder is calculated as the difference between the amount of the binder without the added non-radioactive compound and the non-specific binder. ICJg is determined, i.e. the amount of substance causing 50% inhibition of a specific binder using 12 concentrations in the range of 10. Concentrations of N-ligands
    The fraction is dissolved in a small amount of ethyl acetate and slowly added at. stirring a solution of 71 mg of citric acid (monohydrate) in 10 ml of ethyl acetate. The resulting precipitate is separated and dried at 50 ° C at a pressure of 0.07 mm Hg. during the night.
    Yield 151 mg (92%) ..
    Calculated,%: C 58.64; H 6.77; N 8.55.
    Found,%: C 58., 50; H 6.94; N 8.34.
    The central serotonergic effect of compound I.
    50
    55
    The results are summarized in table. 1 I,
    Determine the activity of the central serotonin agonist, as well as the dopamine agonist by changing the number of serotonium metabolites in the brain and dopamine metabolites, respectively.
    Wistar rats weighing 150-200 g are injected subcutaneously with (±) -4-di (and 20 5 o
    Suppression of labeled serotonin uptake.
    The brain substance is taken from male Wistar rats weighing 150-200 g. The cortex is excised and then homogenized and centrifuged using pre-incubation in a buffer without the addition of an inhibitor of the enzyme monoamine oxidase, in order to suppress endogenous serotonin. For receptor binding, each sample contains 300-400 µg of membrane protein and 10 µg of pargyline per dobayok per H-ligand in 1 ml of 0.05 M Tris buffer, pH 7.4. The serotonin binder is analyzed according to the Bennett method and Snyder, analysis of labeled spiperone in accordance with the Perout and Sneider method. Samples were incubated for 15 minutes at 37 ° C and then filtered through a GF / C glass fiber filter pad using a Vrendel M-24 cell apparatus modified for a binder receptor. After two rinses (5 ml each), the filter disks are placed in scintillation vials and measurements are made in 10 MP scintillation medium with Amersam PCS. Nonspecific H-serotonin binder (n-5HT) is determined by the presence of 10 M serotonin
    five
    0
    , the following: serotonin (Amersham, 11
    l am
    and N-spiperon in 10 M LSD. The specific binder is calculated as the difference between the amount of binder without the added non-radioactive compound added and the non-specific binder. ICJg is determined, i.e. the amount of substance causing 50% inhibition of a specific binder using 12 concentrations in the range of 10. Concentrations of N-ligands
    The results are summarized in table. 1 I,
    Determination of central serotonin agonist activity, as well as dopamine agonist by changing the number of serotonin metabolites in the brain and dopamine metabolites, respectively.
    Wistar rats weighing 150-200 g were injected subcutaneously with (±) -4-di (i1313
    -propyl) amino-6-substituted tetrahydrobenz c, e indole (0.3 mg / kg). Then, after 60 minutes, each rat is decapitated and the hypothalamus and striatum are dissected out and extracted. The amount of homovanilic acid (HVA) and 3,4-dioxyphenylacetic acid (DOPUK) in the striatum and 5-hydroxyindole-acetic acid (5 (CCIA) in the hypothalamus, using electrochemical detection. Serum corticosteroids are also measured.
    The results are shown in Table. 2
    Compound I does not show significant activity as a dopamine agonist, however, unlike the cyano compound, it exhibits significant activity as a serotonin agonist at the same dosage.
    Compound 1 may be administered parenterally as an isotonic solution of a pharmaceutically acceptable salt. Preferably, oral administration in each treatment regimen of the drug is mixed with one or more pharmaceutical excipients and loaded into empty gelatin capsules or compressed into tablets, each tablet or capsule containing a single dose of antidepressant.
    权利要求:
    Claims (1)
    [1]
    Formula of the invention
    The method of obtaining (+) - 4-di (n-propyl) amino-6-carbamoyl-1,3,4,5-tetrahydrobenzo c, d of formula 1
    .
    .1 (СН2СН2.СН5
    14
    or a pharmaceutically acceptable salt thereof, characterized in that (+) - 4-di (n-propyl) amino-6-cyano--1,3,4,5-tetrahydrobenz c, d indol of the formula
    .Cn
    .KSNgSN2SNz)
    HN
    hydrolyzed with potassium hydroxide in tert-butanol medium under nitrogen in the presence of dimethyl sulfoxide. to isolate the target product by chromatographic separation and, if necessary, be converted to a pharmaceutically acceptable salt of the acid.
    Table 1
    (±) -4-Di (n-propyl) amino-6-aminocarbonyl-1,3,4,5-tetrahydrobenz c, d indol 60 4980
    (+) - 4-Di (n-propyl) amino-6-cyano-1, 3,4,5-tetrahydrobenz
    c, d indol 90 390
    (±) -4-Dimethylamino-1, 3,4,5-tetrahydrobenz
    c, d ind120730
    15
    II
    2.34 + 0.07 A, 25 + 0.25 2.27 ± 0.16 47 t 4
     I 1.58 + 0.03 6.23 ± 0.56 4.12 + 0.27 49 + 2
    Control 2.59 + 0.11
    5.58 + 0.38 4.24 + 0.27
    Static values
    1375128
    16 Table2
    7 + 1
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    同族专利:
    公开号 | 公开日
    DE3577848D1|1990-06-28|
    EP0153083A3|1987-01-14|
    CY1657A|1993-05-14|
    PT79925A|1985-03-01|
    ES8704894A1|1987-04-16|
    HU193941B|1987-12-28|
    ES8605236A1|1986-03-16|
    AR240641A1|1990-07-31|
    DK167572B1|1993-11-22|
    DK48785A|1985-09-03|
    IL74222A|1988-07-31|
    PH20490A|1987-01-21|
    IE850263L|1985-08-06|
    JPS60208959A|1985-10-21|
    SG66992G|1992-09-04|
    AT53021T|1990-06-15|
    CA1291484C|1991-10-29|
    JPH06279406A|1994-10-04|
    MY102763A|1992-10-31|
    ZA85916B|1986-09-24|
    DK48785D0|1985-02-04|
    KR860001892B1|1986-10-24|
    JPH0699388B2|1994-12-07|
    GR850313B|1985-06-05|
    EP0153083A2|1985-08-28|
    AU572258B2|1988-05-05|
    EP0153083B1|1990-05-23|
    HUT37121A|1985-11-28|
    AU3841985A|1985-08-15|
    IE57916B1|1993-05-19|
    ES540151A0|1986-03-16|
    KR850005825A|1985-09-26|
    IL74222D0|1985-05-31|
    PT79925B|1987-02-05|
    ES548942A0|1987-04-16|
    NZ211031A|1989-08-29|
    HK63792A|1992-08-28|
    UA5954A1|1994-12-29|
    JPH0745470B2|1995-05-17|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US57709684A| true| 1984-02-06|1984-02-06|
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