• 专利附录
  • 专利说明
  • 权利要求
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    • 专利摘要:
    2-Substituted-5-aryl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indoles of the formula (I): <IMAGE> and the pharmaceutically-acceptable salts thereof, wherein the hydrogen atoms in the 4a position and 9b positions are in a trans relationship to each other and the 5-aryl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole moiety is dextrorotatory; X1 and Y1 are the same or different and are each hydrogen or fluoro; Z1 is hydrogen, fluoro or methoxy; M is a member selected from the group consisting of <IMAGE> a mixture thereof and C=O and n is 3 or 4; their use as tranquilizing agents, pharmaceutical compositions containing them and a process for their production.
    公开号:SU1168094A3
    申请号:SU802865803
    申请日:1980-01-04
    公开日:1985-07-15
    发明作者:МакКован Велч Виллард (младший)
    申请人:Пфайзер Инк (Фирма)；
    IPC主号:
    专利说明:

    4, 4a, 5.9b-hexahydro-1h-pyrido (4,3-b) indole (A) is dextrorotatory, more highly active than the compounds in which the indicated part (A) is levorotatory.
    Example 1. HCl (chloroform) -trans-8-fluoro-5- (p-fluorophenyl) -2- 4-hydroxy-4- (p-fluorophenyl) butyl -2, 3,4,4a, 5,9b-hexahydro 1H-pyrido (4,3-b) indole and hydrochloride trans-8-fluoro-5- (p-fluorophenyl) (p-fluorophenyl) -3-butenyl -2, 3,4,4a, 5,9b-hexahydro 1H-pyrido (4,3-b) indole.
    In a reaction vessel with a capacity of 1000 ml, equipped with a magnetic stirrer and an addition funnel and maintained in a nitrogen atmosphere., Placed 177 ml of 0.94 M borane and in tetrahydrofuran. The solution is cooled in an ice bath, and a solution of 25 g (0.0555 mol) of 8-fluoro-5- (p-fluorophenyl) -2-4-hydroxy-4- (p-fluorophenyl) is added to the cold solution over 30 minutes. ) butyl | -2,3,4,5-tetrahydropyrido (4,3-b) indole in 295 ml of tetrahydrofuran. The resulting mixture was stirred at ambient temperature for 20 minutes, then heated under reflux for 2 hours. The reaction mixture was cooled, evaporated in vacuo to give a liquid residue. To it is added a mixture of 50 ml of acetic acid and 50 ml of 5N. hydrochloric acid, followed by a vigorous introduction of gas. The mixture is heated under reflux for 1 h, cooled to room temperature and filtered. The filtrate is cooled on ice and alkalinized by the addition of a 50% w / w sodium hydroxide solution. The main mixture is extracted twice with 150 ml portions of chloroform, the combined organic layers are dried over magnesium sulphate and evaporated to dryness in vacuo to give a yellow solid foam substance, 25 g. volume) established the presence of two products. The foamed solid is chromatographed on a column of silica gel and eluted with a mixture of
    1680944
    hexane / ethyl acetate 1: 1 (volume) with the control of fractions using -teh. Fractions containing only more mobile products, i.e. 8-fluoro-5- (p-4 / horphenyl) (p-fluorophenyl) -3-butenyl -2, 3,4,4a, 5,9b-hexahydro-1H-pyrido (4,3-b) indole, evaporated dry, dissolve in acetone and convert to hydrochloride O by adding anhydrous hydrogen chloride in acetone. The more solid obtained is separated by filtration, dried, yielding 1.5 g of 3-butenyl. Compounds. M.p. 270 15 273С.
    Fractions containing only less mobile 8-fluoro-5- (p-fluorophenyl) -2- 4-OXI-4- (p-fluorophenyl) butyl -2.3, 4.4a, 5.9b-hexahydro-1H-pyrido20 (4,3-b) indole, evaporated, dissolved in ethyl ether and converted to the hydrochloride salt by the addition of anhydrous hydrogen chloride. 10.8 g of this product are obtained as a mixture of two diastereomers, m.p. 241-245 c.
    The content of the more mobile 3-butenyl compound increases to 100% with a corresponding increase in bone acid30 and an increase in the heating time under reflux in an acetic acid / hydrochloric acid mixture.
    Example 2. The process is carried out 3 as in Example 3, but using 8-fluoro-5- (o-fluorophenyl) (p-fluorophenyl) butyl -2,3,4,5-tetrahydropi) rido (4, 3-b) indole. Quickly moving 4Q through silica gel during chromatography, the component was identified as trans-8-SFtor-5- (o-fluorophenyl) -2С4- (p-fluorophenyl) -3-butenyl -2,3,4,4a, 5.9b-hexahydro-1H-pyrido (4,3-b) 45 indol. T. pl. 141-142 0.
    The slower moving component was identified as trans-8-fluoro-5- (o-fluorophenyl) -2- 4-hydroxy-4- (p-fluorophenyl) butyl-2,4,4,4a, 5,90-hexahydro-1H- pyrido (4,3-b) indole. M.p. 195-197c. Each product is a diastereomer.
    Example 3. HCl a1-trans-5-phenyl-2 3- (p-fluorobenzo5 yl) propyl} -3,4,4a, 5,9b-hexahydro-1H-pyrido (4,3-b) indole.
    In a 25 ml reaction vessel equipped with a magnetic stirrer and maintained under a nitrogen atmosphere, 0.828 ml (8.0 g, 10.3 mmol) of anhydrous pyridine and 10 ml of dichloromethane are placed. 517 mg (5.17 mmol) of chromium trioxide was added to the solution and the resulting dark red suspension was stirred for 15 minutes at room temperature. A solution of 359 mg (0.862 mmol) of the free base of d-trans-5-phenyl-2-4-hydroxy 4- (p-fluorophenyl) butyl -2,3,4,4a, 5,9b-hexahydromate is added in one portion. 1H-pyrido (4,3-b) indole in 5 ml of dichloromethane. The reaction mixture quickly turns into a brown suspension. It is stirred at room temperature for 30 minutes. The insoluble matter is separated by filtration, washed with dichloromethane, and the combined filtrates and washed waters are extracted with 20 ml of 10% sodium hydroxide solution. The organic layer is dried over magnesium sulfate and evaporated to dryness in vacuo to give a gum. The gum is purified by silica gel column chromatography, eluting with 1: 1 (v / v) hexane / ethyl acetate. The fractions containing the desired product are combined, inserted into a yellow resin, the resin is dissolved in ethyl ether and treated without aqueous hydrogen chloride. The resulting suspension is evaporated to dryness, suspended in 3 ml of cold methylene chloride. A colorless solid is formed, which is separated by filtration and dried to give 20 mg of M.P. 244 of the compounds indicated. 246.5 ° C. Example 4. Hydrochloride, ny d5-trans-8-fluorop-5- (p-fluorophenyl) -2-СЗ- (p-fluorobenzoyl) propyl 3-2,3,4, 4 5,9b-hexahydro-1H-pyrido ( 4,3-b) indus A 100 ml flask containing 20 ml of dichloromethane and 1.76 ml (21.9 mmol) of pyridine was added with 1.09 g of chromium trioxide and the resulting dark suspension was stirred for 15 minutes. Then a solution of 824 mg {1.82 mmol) of the free base df-TpaHC-8-fluoro-5- (p-fluorophenyl) -2-4-hydroxy-4- (p-fluorophenyl) butyl -2.3 is added in one portion , 4.4a, 5.9H8Xahydro-1H-pyrido (4,3-b) indole (obtained from hydrochloride salt by alkalizing an aqueous solution with sodium hydroxide, extracting with dichloromethane and evaporating the extract to dryness) in 10 ml of dichloromethane. The resulting red-brown suspension is stirred at room temperature for 1 hour and treated according to the procedure used in Example 10, to obtain 25 mg of the desired product. M.p. 260-263 0. Example 5. Separation of diastereomers df.-TpaHc-8-fluoro-5- (p-fluorophenyl) -2-4-hydroxy-4- (p-fluorophenyl) butyl -2.3,4,4a, 5.9b-hexahydro-1H-pyrido (4,3-b) indole. A. 5 g of a mixture of diastereomers of hydrochloric c1-trans-8-fluoro-5- (p-fluorophenyl) -2-4-hydroxy-4- (p-fluorophenyl) butyl -2.3,4,4a, 5.9b- The hexahydro-1) -pyrido (4,3-b) indole obtained in Example 3 is converted to the free base by distribution between methylene chloride and 1.0% aqueous sodium hydroxide solution. The organic phase is dried (Na2 SO) and evaporated to a foam, which is dissolved in 12.5 ml of ethyl acetate and 45 ml of hexane at the boiling point of the mixture. After cooling overnight, the precipitated product was separated by filtration, and 2.24 g of product was obtained. Mp. 126129 ° C. It was recrystallized three times from a mixture of ethyl acetate / hexane and 1.22 g of one diastereomer were obtained. M.p. 132-134p. This free base is converted to hydrochloride salt by adding an ethereal solution of hydrogen chloride to a solution of the free base in methanol and 1.30 g, m.p. 259-260 ° C. High pressure liquid chromatographic analysis showed that this product is a cC / 3 diastereomer of 99% purity. B. The mother liquor after the first crystallization is evaporated until the resin is obtained, dissolved in ethyl ether and converted into the hydrochloride salt by adding a hydrosulfur solution of hydrogen chloride. The remaining crystalline solid was recrystallized three times from acetonitrile / methanol to give 1.03 g of the second diastereomer, designated as o-diastereomer. M.p. 237-239 ° C. Liquid chromatographic analysis at high pressure showed that this product contains about 95 wt.% Of that y-diastereomer. Example 6. Separation of diast reomers of d -trans-8-fluorop-5- (n-fluorophenyl) -2g 4-hydroxy- „4- (p-fluorophenyl) butylJ-2, 3,4,4a, 5,9b-hexahydro -1H-pi rido (4,3-b) indole. A. OS separation | - diastereomer on c; -enantiomer and | 3-ethantiomer. A solution of 2.40 g (5.3 mmol) of racemic iji, a is a diastereomer, prepared as described, and 2.0 g (7.5 mmol) of N-tert-butoxycarbonyl-L-phenylalanine in 80 ml of chloroform is cooled to ice bath in nitrogen atmosphere. To the stirred solution was added 1.55 g (7.5 mmol) of dicyclohexylcarbodiimide, and the mixture was stirred for 1 at 0 ° C and for an additional hour at room temperature. The precipitated solid (urea) is filtered off and washed with methylene chloride. The filtrate and the washings were vacuum dried and the residue was chromized on silica gel, eluting with a 5: 1 (v / v) mixture of methylene chloride and ethyl acetate. The fractions containing ester N-tert-butoxycarbonyl-1phenylalanine are combined and evaporated in vacuo to give 2.5 g of a white amorphous foam. 30 ml of anhydrous trifluoroacetic acid are added to this foam at and the mixture is stirred in an ice bath for 30 minutes, during which time dissolution occurs. Trifluoroacetic acid is removed by evaporation in a vacuum and a rotary evaporator without external heating of the flask. The remaining solid is dissolved in cold methylene chloride and washed with cold 1% (w / w) aqueous sodium bicarbonate solution until a neutral reaction appears on indicator pH paper. The neutral organic layer is dried (MgSO4, ...), the solvent is scorched and 1.6 g of a pale yellow resin are obtained. The resin is purified by chromatography on 40 g of silica gel Me CK 230-400 mesh, eluting with a 35: 1 mixture (volume) ethyl acetate / methanol. The fractions containing the L-phenylalanine ester of the CC-enantiomer, and the fractions containing the L-phenylalanine ether-ethantimer, are separated, evaporated to dryness in a vacuum, and 636 and 474 mg are obtained, respectively. A stirred solution of 625 mg of L-phenylalanine ester of d, -enantiomer in 10 ml of methanol at room temperature was prepared with a 10% aqueous solution of sodium hydroxide until cloudy, then stirred for 30 minutes at room temperature. Methanol was removed by evaporation under reduced pressure, then 10 ml of water was added. The aqueous suspension is extracted with methylene chloride and the combined organic layers are dried over magnesium sulfate. After evaporation of the solvent, a pale yellow resin is obtained, which is dissolved in acetone (5 ml), treated with an excess of an ethereal solution of hydrogen chloride, from which the hydrochloride salt of the spinning salt of the enantiomer, 380 mg, melts. 251-255 ° C; oi +32.2 (C 1.67 in methanol). As a result of the hydrolysis of the L-phenylalanine ether-ethantiomer (474 mg of the product obtained), a levorotatory / 3-enantiomer of 8-fluoro-5- (p-fluorophenyl) -2-4-hydroxy-4- (p-fluorophenyl) - 2,3,4, 4a, 5,9b-hexahydro-1H-pyrido (4,3-b) indole, T, mp, 252-255s .. 33.0 ° (C 1.67 in methanol). Analysis by liquid chromatography at high pressure showed that the purity of the oC-enantiomer and the | 3-enantiomer is 99% or more. B. Separation of the YS -diastereomer at the U and 6 -enantiomers, 0 -Diastereomer trans-8-fluoro-5- (p-fluorophenyl) -2-C4-OXI-4- (p-fluorophenyl) butyl -2, 3,4 , 4a, 5.9b-hexahydro-1H- (4,3-b) indole interacts with L-tert-butoxycarbonyl-bphenylalanine, then the ester -but-b-phenylalanine interacts with trifluoroacetic acid to remove the amino-protective (t-side) group The amino acids are then chromatographed for separating the L-phenylalanine esters of the jf-enantiomer and the enantiomer ak as described in part A of Example 6. Then the separated y and S esters are separately hydrolyzed and purified. for the purpose of semi-awn orvraschak tsego U -enantiomer
    Dopamine binding is interrelated with their relative pharmacological ability to act on behavior, probably through dopamine receptors. The best study of the association of neuroleptic receptors was carried out by Leu- sonon using H-spiroperidol (spiperone) as a labeled ligand. The following procedure was applied.
    Male rats, 250-300 g, were decapitated, and the brain was immediately dissected on an ice-cooled glass plate to remove the striped body (L-10 mg / brain). The tissue was homogenized in 40 volumes (1 g + 40 ml) of ice-cold 50 mM Tris (tris-oxymethylaminomethane); buffer pH 4.7. The homogenate was centrifuged twice at 50,000 g (20,000 rpm) for 10 minutes with repeated homogenization of the intermediate precipitate in fresh THAM buffer (same volume). The final precipitate was carefully suspended in 90 volumes of cold cooked (storage period less than one week) 50 mM Tris buffer - pH 7.6, containing 120 mM sodium chloride (7.014 g / l), 5 mM potassium chloride (0.3728 g / l), 2 mM calcium chloride (0.222 g / l), 1 Mm magnesium chloride (0.204 g / l), 0.1% ascorbic acid (1 mg / ml) and 10 μM pargyline (100 μl of the mixture / 100 ml buffer; stock solution 15 mg / 10 ml bidistilled water). Ascorbic acid and pargyline added freshly prepared. The tissue suspension was placed in a water bath at 37 ° C for 5 minutes to ensure the deactivation of the monoamine oxidase tissue and then it was consumed on ice. The incubation mixture consisted of a 0.02 ml solution.
    : inhibitor, 1.0 ml of tissue homogenate and 0.10 ml of labeled indicator (H-spiroperidol. New England nuclear
    23.6 curie / mmol) prepared in this way to obtain 0.5 nM in the final incubation medium (usually diluted with 2.5 μl of the initial solution of 17 ml of bidistilled water). The tubes were incubated for 10 min at 37 ° C in batches of three, after which 0.9 ml from each incubation tube was filtered through Whatman GF / B filters using a high-vacuum pump. Each filter was placed in a scintillation vial. 10 ml of liquid scintillating fluorine was added to it, and each vial was subjected to vigorous vortexing for approximately 5 seconds. The samples were left overnight so that the filters became transparent, then they were again subjected to a vortex, and then radioactivity was calculated for 1.0 min. Binding was calculated as phentamol (10 mol) of H-spiroperidol, bound to 1 mg of protein. Experiments with control solutions (vehicle or 1-butaclamol, M; 4.4 mg were dissolved in 200 µl of glacial acetic acid, then diluted to 2.0 ml with bidistilled water to obtain a UM stock solution and stored in a refrigerator), solutions of blind samples ( d-butaclamol, 10 M; j - per 10 M of the initial solution, as well as for 1-butaclamol, and the inhibitor solutions were repeated three times. The concentration at which binding decreased by 50% () was evaluated on semi-log paper. Insoluble drugs were dissolved in 50% ethanol (incubated in 1% ethanol).
    Results obtained with various forms of trans-8-fluoro-5- (p-fluorophenyl) -2- 4-hydroxy-4- (p-fluorophenyl) butsh1 -1,3,3,4, 4, a, 5.9b hydrochloride hexahydro-1H-pyrido (4,3-b) indole, are presented in table 5
    Table 1
    S, N. CH- (CH,), O 5 TL
    oi
    n-FCjH 9 OH
    n-CHjOC H CH-CCH;), - h
    he
    n-FCgH C-CCHj), 0
    (CH2) ZON
    n-FC l CH-CCHj), Oh (|; H- (CH2) s OH n-CHjOC H CH-CCHj,) OH n-FCj H C - (C%) s
    H / b) H
    C.Hj H / b / H
    , H / b / HC HjCCHj), CYC-9-z- (4-methyl-1-piperazinyl) propylidene -2- (dimethyl sconamido) -thioxanthene
     HaifeeHO, that for an appropriate observation time of 1 hour. . U.S. Patent 3,991,199 U.S. Patent 3,310,553.
    0.032-0.10.1-0.32
    0.1-0.320.1-0.32
    0.1-0.32 lGO
    0.1-0,, 32
    0.1-0,, 32
    0,0.32 0.32
    0.32, 032-0.1, 0.032-0.1, 0.032-0.1
    0.1-0.32 0.1 0.32 1.0 1.0
    1.0 3.2
    3.2-32 32 3.2, 0
    Not tested l.10 3.2-10 3.2-32 3.2
    3.2-10
    ten
    0.32-1.0
    ten
    32
    analog 4a, 9b-cis ED 56 mg / kg with
    Compound
    Suppression of the binding of H-spiroperiodol, MP (HKjj)
    Smashed in with / 1 - and about the diastereomers in example 1
    ", Th-diastereomer in example 5
    Right-handed o-enantiomer in Example 6
    Left rotatory / 3-enantiomer according to example 6
    Diastereomer in example 5
    Right rotation | -enantiomer - for example 6
    Levorotatory & - jK enantiomers example 6
    T a b
    faces. five
    21
    23
    22 1800
    23 25 30
    权利要求:
    Claims (3)
    [1]
    1. METHOD FOR PRODUCING TRANS-2-SUBSTITUTED 5-ARIL-2,3,4,4a,
    5,9b-hexahydro-1H-pyrido (4,3-b) indoles of the general formula or a mixture thereof, or (3 - j part of 5-aryl-2,3,4,4a, 5,9b-hexahydro-1H-pyrido (4,3-b) indole is dextrorotatory, characterized in that a compound of general formula (II) wherein the hydrogen atoms in the 4a and 9b positions are in transsootnoshenii Dru g _ to .dr y y;
    X and Y are the same or different and mean hydrogen or fluorine;
    Z is hydrogen, fluorine or methoxy;
    η - 3 illn 4;
    m - Н ОН. * it is esterified with optically active acid - tert-side-L-phenylalanine in an inert solvent at a temperature from 0 С to room temperature in the presence of dicyclohexylcarbodiimide, distereomeric esters are separated, the dextrorotatory isomers are recovered, hydrolyzed and, in the case of necessary, to obtain the compounds of formula (D), when M -6 = 0, oxidized with chromic acid.
    [2]
    2. The method of Pop. 1, characterized in that the 2-butoxycarbonyl-protecting group with trifluoroacetic acid is removed before the diastereomeric esters are separated.
    [3]
    3. The method according to PP. 1 and 2, characterized in that; separation of diastereomeric isomers is carried out by column chromatography. ·
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US06/005,698|US4224329A|1979-01-23|1979-01-23|2-Substituted-trans-5-aryl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indoles|
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