• 专利附录
  • 专利说明
  • 权利要求
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    • 专利摘要:
    6-Chloro-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, its acid addition salts and its use as an intermediate to prepare mercapto substituted-2,3,4,5-tetrahydro-1H-3-benzazepines as disclosed in European Patent Application No. 79102 279. 1.
    公开号:SU1029827A3
    申请号:SU792783746
    申请日:1979-07-06
    公开日:1983-07-15
    发明作者:Джордж Холден Кеннет；Кайзер Карл
    申请人:Смитклайн Корпорейшн (Фирма)；
    IPC主号:
    专利说明:

    This invention relates to the preparation of novel benzazepine derivatives with an activity to block the dopamine receptor, which can be used as antipsychic and anti-emetic agents. The aim of the invention is to develop a process for the preparation of new compounds with pharmacodynamic activity. This goal is achieved by the method of producing mercapto-substituted 2,3,4,5 tetrahydro-1H-3-benzazepins of the general formula, based on the well-known method 1. . 1 T |. i where R, - is phenyl, m or p-substituted phenyl, where the substituents are trifluoromethyl, chlorine, methyl labels, fluorine, nitro or hydroxy group, cyclohexyl. thienyl, thienylmethyl, furi or furylmethyl, Rj is methoxy, alkanoyloxy, where the alkanoyl has 2-6 C, or the hydroxy group R is hydrogen, bromine, fluorine or trifluoromethyl f or their dione salts of the general formula, -CnS where Ra, has the above Values are reacted with mercaptane with a general formula where RI has the above values, in addition to oxo-substituted phenyl, the resulting 7,8-dioxy derivative is treated with diazomethane or alkanoyl halide if necessary and in free form or as a salt. V Example 1. A mixture of 7,8-dimethoxy-2, 3,4,5-tetrahydro-1H-3-beisazepine (19.5 g, 0.094 mol), 78 ml of formaldehyde and 117 ml of E9-100% formic acid The lots are heated with a refrigerator overnight and then evaporated to dryness. Dilute hydrochloric acid (140 ml) is added to the resulting residue and the residue is evaporated to dryness. The residue is treated with 140 ml of a 10% sodium hydroxide solution and extracted with ethyl acetate. The extract is washed, dried, and the residue is converted to hydrochloride. salt - 7,8-dimethoxy-Zmethyl-2, 3,4,5-tetrahydro-1H-3 benzazepine hydrochloride, so pl. 250254С. The resulting compound (5.2 g, 0.02 mol) is mixed with 100 ml of 48% hydrobromic acid and heated under reflux for 1-1.5 hours. The reaction mixture is evaporated to dryness and converted to azeotropic with toluene to obtain 7,8-hydroxy-3-methyl-2,3,4,5 tetrahydro-1H-3-benzazepine hydrobromide, m.p. 230-233s. (decomposition), To a solution of 16 g (0.0584 mol) of dioxybenzazepine in 300 ml of methanol was added in portions of 14.3 g (, 0.063 mol) of 2, 3-dichloro-5, b-dicyano-1,4-benzoquinone in The mixture is stirred at room temperature for 1 hour. The reaction mixture is cooled in ice-cold E and filtered to give 3-methyl-2,3,4,5-tetrahydro-1H-3 benzazepin-7, 8-dihydrobromide. To a methanol solution (200 ml) of ggiofenol (1.92 g, 0.01775 mol) 2.2 g of 10.0081 mol are added in portions of the indicated dione and the resulting solution is stirred at room temperature under a nitrogen atmosphere. 1 part , get 7, 8-dio.xy-3 - methyl-b-phenylthio 2, 3,4,5-tetragilro-1H-3-benzazepine hydrobromide, so pl. 116-120 0, the free base has so pl. . Following the above procedure and subjecting the interaction of the dion with dicloheximercaptan, m-trifluoromethylthiophenol, p-trifluoromethylthio phenol or p-chlorothiophenol, the corresponding products are obtained: b-cyclohexylthio 7,8-dioxy-3-methyl 2, 3,4,5-tetrahydro-1H-3 - benzazepine, so pl. 148-157 ° C; 7,8-dioxy-3-methyl-6- (m-trifluoromethylphenylthio) -2,3,4,5 tetrahydro-1H-3-benzazepine, m.p. 183-185s, 71,8-dioxy-3-methyl-6- (p-trifluoromethylphenylthio) -2,3,4,5-tetrahydro-1H-3-benzazepine fumarate, m.p. and b- (p-chlorophenylthio 7, 8-dioxy-3-mvtil-2,3,4,5-tetrahydro-1H-3-benzazepine hemifumarate, mp 209-211 C, Example 2 To a methanol suspension of 7,8-dioxy-3-methyl-6-phenylthio-2, 3,4,5-tetrahydro-1H 3-benzazepine (1.0 g, 0.0033 mol, add diazomethane, formed in a known manner using M-methyl-M-nitro-M-nitrosoguanidine. The mixture is stirred at room temperature for 1 hour, the excess diazomethane is removed in a stream of nitrogen and then concentrated,
    The fumaric acid is dissolved in the minimum amount of methanol, added to the mixture, and then the solution is cooled to obtain 7,8-dimethoxy-3-methyl-b-phenylthio-2, 3,4,5-tetrhydro-1H-3-benzazepine fumarate, m.p. 181-184 S.
    Example 3. A solution of 3.2 g of 7,8-dioxy-3-methyl-b-phenylthio-2,3, 4,5-tetrahydro-1H-3-benazepine and about 500 ml of dry benzene per stir at room temperature for 15 minutes and then 4.5 g of triethylamine are added. Acetyl bromide (5.4 g, 0.044 mol) in 20 ml of benzene was added dropwise and the mixture was heated under reflux for 1.5 hours. The reaction mixture was evaporated to dryness and the residue was partitioned with 5% sodium bicarbonate and ethyl acetate. . The ethyl acetate solution is decayed, dried and evaporated. The residue is treated with Fumarc acid, get 7,8 diacetoxy3-methyl-6-phenylthio-2, 3,4,5-tetrahydro-1H-3-phenazepine fumarate, so pl. 15b-1b1s.
    In the same way, b-cyclohexylthio-7, 8-dioxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine is reacted with acetylbromido to obtain 7,8-diacetoxy-b-cyclohexylthio-3-methyl-2 , 3,4,5-tetrahydro-lH-3-benzazepine hydrobromide, so pl. 149-150 0.
    Example 4. A solution of 5 g (0,0166 mol) of 7,8-dioxy-3-methyl-bphenylthio-2, 3,4,5-tetrahydro-1H-3 benzazepine in 250 ml of methanol acidified with ether, hydrogen chloride to obtain hydrochloride. The latter is dissolved in 300 ml of methanol and 4.0, 017b mol) 2,3-dichlorop5, b-dicyano-1, 4-benzoxinonone is added portionwise in nitrogen and the mixture is stirred at room temperature for 20 minutes. Ether and solvents are added to the reaction mixture, decanted to afford 3-methyl-6-phenylthio-2, 3,4,5-tetrahydro-1H-3-benzvazpvin-7, 8-dione hydrochloride. This hydrochloride is dissolved in a minimal amount of methanol and then hydrogen chloride is added in portions to the methanol solution. The mixture is stirred at room temperature for 1 hour, the solvent is evaporated and the residue is triturated with acetonitrile. Separated ochdgy solid by conversion to its free base to give 9-chloro-7,8-dioxy-3-methyl-6-phenylthio-2, 3,4,5-tetrahydro-1H-3-benzazepine, mp. 173-174 s.
    Example 5. To a stirred solution of 2-thiophenothiol (0.9 g, 0.0076 mol) in 200 hp of methanol was added in portions 2 g (0.0074 mol)
    H-methyl-2,3,4,5-tetrahydro-1H-3 benzazepin-7, 8-dione at room temperature in argon. After stirring for 1 hour, the methanol is distilled off in vacuo, the residue is suspended in 30 ml of water and filtered. The filtrate is alkalinized; 7,8-dioxy-3-methyl- (2-thienylthio 2, 3,4, 5-tetrahydro-1H-3-benzazepine, Topl. 189-191 ° C) is obtained. In the same way, the above-mentioned dione (5 g, 0.018 mol) is added by inoculations to a solution of 2.3 g (0.02 mol) of 3-thiophenethiol in 200 ml of methanol; after treatment, 7,8-diox and 3-methyl-6- (3-thienylthio) -2 , 3,4,5-tetragndro-1H-3-benzazepine, mp 189191 ° C.
    Example b. The free base of 7,8-dimethoxy-3-methyl-2,3,4,5 tetrahydro-1H-3-benzazepine (0.075 mol) is dissolved in 170 ml of acetic acid. A thin stream of bromine is added and the mixture is stirred for 2 hours. The precipitate is collected, washed with ether and dissolved in boiling methanol and acetone in order to destroy the excess bromine. 7-Bromo-7,8-dimethoxy-3-methyl-2,3, 4,5-tetrahydro-1H-3-benzazepine-hydrobromide is crystallized from methanol and then transferred to the corresponding free base.
    A mixture of b-bromo compound (0.009 mol), trifluoromethyl iodide (0.036 mol) and 0.0708 mol copper powder in 15 ml dimethylformamide in a pressure reactor is heated at 68 hours. The cooled reaction mixture is diluted with 20 ml dimethylformamide, 200 ml ethyl acetate and then stirred by as 500 ml of water is added.
    The separated organic phase is washed, dried and evaporated to give 7,8-dimethoxy-3-methyl-6-trifluoromethyl-2, 3,4,5-tetrahydro-1H-3 benzazepine, which is dimethylated in methylene chloride with boron tribromide.
    Analogously to Example 2, 7,8-dioxy-3-methyl-6-trifluoromethyl-2, 3, 4,5-tetrahydro-1H-3-benzazepine hydrobromide treated 2,3-dichloro-5,6-dicyano1, 4-benzoquinone, to give 7,8-dione, which is then reacted, for example with thiophenol, 7, 8-dioxy-3-methyl-6-phenylthio-9 trifluoromethyl-2, 3,4,5-tetrahydro 1 H-3-benzazepine hydrobromide is obtained.
    In the same way, after dimethylation of the compound indicated by 6-bromine, which follows the formation of quinone, and after treatment with thiophenol, 9-bromo-7,8-dioxy-3. Methyl-6-phenylthio-2,3,4,5-tetrahydro -lH-3-benzazepine, free base, so pl. 174С (decomposition).
    Approx. 7 / The sulfoxide (8.3 g, 0.024 mol) prepared from above is dissolved in 200 ml of methylene chloride. The solution is cooled to -78 ° C and a solution of 7.9 ml (0.108 mol) of thionyl chloride in 75 ml of methylene chloride is added dropwise in argon. The mixture is stirred in the cold for 4 hours and gradually allowed to warm to room temperature. The reaction mixture is concentrated and the resulting oil is washed with 10% sodium hydroxide solution and then extracted in chloroform. The extract obtained is evaporated in vacuo and the residue is subjected to chromatography on silica using methanol: chloroform: 4.8 g of 9-chloro-7,8-dimethoxy-3-methyl-b-phenylthio-2, 3,4,5-tetrahydro 1H-3 benzazepine hydrochloride, so pl. 209-210С. .
    To a solution of this 9-chlorine compound (3.76 g,: 0.0104 mol) in 120 ml of methanesulfonic acid is added C-methionine (8.6 g, 0.058 mol). The mixture is stirred at room temperature for 18 hours, cooled rapidly with an ice-water system, and horses, centrifuged ammonium hydroxide, are added to a pH of 9.5. The mixture was extracted with ethyl acetate. The extract was dried over sodium sulfate. After evaporation of ethyl acetate, 1.8 g (52%, crude yield) of 9-HLOR-7,8-dioxy-3-methyl-b-phenylthio-2, 3,4,5-tetrahydro-1H-3-benzazepine are obtained, t .pl. 174-17b C, identical to the compound obtained in the example
    Example B. A mixture of 2.6 g of f0.008 mol of 7,8-dimethoxy-Z-methyl6-phenylthio-2, 3,4,5-tetrahydro-1H-3 benzazepine obtained in example 3, and 1.26 g (0 0085 mol) d-methionine in 35 ml of methanesulfonic acid is stirred at room temperature for 3.5 hours. The reaction mixture is cooled with ice water, adjusted to pH 8.5 with 10% sodium hydroxide solution and extracted with chloroform. The extract is washed with a saturated solution of sodium chloride, dried over sodium sulfate and evaporated to give 2.18 g (yield 87%) of 8-hydroxy-7methoxy-3-methyl-b-phenylthio-2, 3,4,5-tetrahydro-1H-3- Benzazepine, m.p. 1b1-162s.
    When reacting 8-hydroxy-7-methoxy-3-methyl-phenylthio-2, 3,4,5-tetrahydro-1H-3-benzazepine with acetyl bromide in trifluoroacetic acid, 8-a1 egoxL5-7-methoxy-3-meth 6 is obtained -phenylthio-2,3,4,5-tetrahydro-1H-3benzazepii hydrochloride, mp, 240241 ° C.
    EXAMPLE 9 To a solution of 1.0 g (0.0078 mol of p-fluorothiophenol in 200 4 liters of methanol, add 2 g (0.0073 mol) of 3-methyl-2,3,4, portions, 5 tetrahydro -1H-3-benzazepin-7, 8-dione of the hydrobromide prepared in Example 2, and the resulting mixture was stirred at room temperature in argon for 1 hour. Methanol was removed from the reaction mixture in vacuo and the residue was partitioned between ether and water.
    the layer is extracted with ether and then made basic with ammonium hydroxide solution. The precipitate is filtered and the dried filtrate is chromatographed on silica using a mixture of methanol and chlorofor. Material Eluted
    , from the column, suspended in ether and filtered. After distillation of the ester, 7,8-dioxy-6- (p-fluorophenylthio) -3-methyl-2,3,4,5-tetrahydro-1H-3-benza-eepin is obtained, m.p. 1b4-16bs. Similarly, the interaction of 1 g (0,0075 mol) of p-toluenethiol and 2 g of dione in 200 ml of methanol get 7,8-dioxy-3-methyl-6- (p-tolylthio) -2,3,4,5-tetrahydro -1H-3-benzazepine, m.p. 105-114 C, by reacting 1.65 g (0.0011 mol of p-nitrothiophenol and 2.3 g of dione in 200 ml of methanol, 7.8 dioxy-3-methyl-b- (p-nitrophenylthio) -2.3.4 are obtained , 5tetrahydro-1H-3-benzazepine, mp 165170С.
    By reacting 7,8-dioxy-b (p-fluorophenylthio-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine with acetyl bromide, as described in Example 4, 7.8-diacetoxy-6- ( p-fluorophenylthio / - 3-methyl-2, 3,4, 5-tetrahydro-1H-3-benzazepine, mp 125-127 ° C
    Example 10. Following the procedure of Example 7, -0.9 g (0.0075 mol) of furfuryl mercaptan and 2 g (0.0073 mol of 3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7 , 8-dione hydrobromide is reacted in 200 ml of methanol; 7.8 dioxyl-6-furfurylthio-3-methyl-2, 3,4,5-tetrahydro-1H-3-benzazepine, free base, mp 162-165 are obtained. WITH.
    The resulting solution is heated to reflux 4.5 g and
    . cool. The reaction mixture is decanted off the red oil, dissolved in 3 ethyl acetate and washed with a saturated solution of sodium chloride and 10% sodium hydroxide solution. The dried ethyl acetate solution is evaporated to give 5.3 g of b - (, p-fluorophenylthio) -3-methyl-9-nitro-2,3,4,5-tetrahydro-1H-3-benzazepine.
    A mixture of 4.3 g (0.0135 mol of the obtained 9-nitro derivative, dissolved in 100 ml of ethanol, 50 ml of sulfuric acid and 0.4 g of 5% palladium on carbon in 50 ml of ethanol is hydrogenated at 60 psi and for 2 The catalyst is filtered off from the reaction mixture and the filtrate is evaporated. The residue is dissolved in the minimum amount of ethanol to which ethereal hydrogen chloride is added. The solid is filtered to obtain 1.5 g of 9-amino-b (p-fluorophenylthio) -3- methyl 2,3,4,5 tetrahydro-1H-3-benzazepine dihydrochloride. Analogously to Example 9 9-amin6-3 beneazepine dihydrochlori d (1.25 g of diazotizing with sodium nitrite in water and concentrated hydrochloric acid are then treated with copper chloride; after purification with silica, 9-chloro-b- is obtained (p-fluorophenylthio 3-methyl-2,3,4,5-tetrahydro -1H-3benzazepine hydrochloride, mp 212213 C. Example: To a solution of 1.1 (0.00 mol of 2-furantiol in 200 m of methanol, add 2.3 g (0.0084 mol) of 3-methyl-2 , 3,4,5-tetrahydro-1H-3-benzazepin-7, 8-dione hydrobromide After stirring for 1 hour at room temperature, the reaction mixture is filtered and the filtrate is concentrated in vacuo to give 7,8-dioxy-6- (2-furtiltio7 H-methyl-2, 3,4,5-tetrahydro-1H-3 benzazepine hydrobromide. In the same way, by reacting 1.44 g (0.0011 mol of 2-thiophenyl taptiol in 200 ml of methanol and the indicated dione 2.3 g, 0.0084 mol), 7,8-dioxymethyl-6- (2-thienylmethyl-thio) is obtained -2,3,4, -tetrahydro-1H-3-benzazepine hydrochloride. Example 12. Solution 1 of 5.0 g (0.0096 mol) of m-fluoroanisole in 44 MP of dry tetrahydrofuran is treated with 14.5 ml of a 2.6 M solution of n-butyl lithium in hexane at -65 ° C and the resulting mixture is stirred in the cold 2 ± Part of trimethylboronic acid ester (6.41 g, 0.0377 mol in 52 ml of dry ether was added at -65 ° C for 15 minutes. The reaction mixture was heated to room temperature and diluted hydrochloric acid was added. The organic layer was separated. they are heated with water, dried and concentrated; 4.62 g of 3-fluoro-2- (dioxybornyl anisole are obtained (yield 80%). To a solution of the anisole obtained above (4.55 g, 0.0268 mol) in 33 ml of warm toluene is slowly added 12.4 ml of 30% hydrogen peroxide solution and the mixture is heated on a steam bath for 45 minutes. The reaction mixture is cooled, the organic layer is separated and washed with water, 10% ammonium sulfate solution and water. The organic solution is then extracted with 10% sodium hydroxide solution and the basic extract is acidified with concentrated hydrochloric acid to obtain an oil. The oil is extracted with methylene chloride, dried and concentrated to give 2.04 g of 3-fluoro-2-oxyanisole (yield 69%). The oxyanisole derivative (1.77 g, 0.0125 mol) is dissolved in 18 ml of dry acetone and 3.44 g of powdered potassium carbonate and 2.36 ml of methyl sulfate are added. The mixture was stirred and heated under reflux for 30 minutes, diluted with water and extracted with ether. The ether extract is washed with water, stirred for 90 minutes with a dilute solution of ammonium hydroxide and the separated organic layer is washed with water. The dried organic solution is concentrated to 1.64 g (yield 68%) of liquid 3-fluoro-2-methoxyanisole, mp. 93.5-102С at 19-24 mm Hg A 37% formaldehyde solution (26 ml) is added to a solution of the obtained methoxyanisole (25.0 g, 0.16 mol) in 100 ml of glacial acetic acid and hydrogen chloride gas is passed through for 4 ± 1/2 h. support at the level of 20-25 ° С with the help of an ice-water bath The reaction mixture is poured into water, extracted with ether, and the ether extract is washed with water. The dried extract was concentrated at 35 ° C., to obtain 31.63 g (yield 97%) of 3,4-dimethoxy-2-fluorobenzyl chloride, mp. 44, 5-47,. Sodium cyanide (9.19 g, 0.087 mol) is added to a solution of this benzyl chloride (30.7 g, 0.15 mol) in 530 ml of dimethyl sulfoxide. After about 45 minutes, the reaction mixture is poured into 1 l of ice-water and extracted with ether . The ether extract is washed with water, dried and concentrated at, to obtain 26.9 g (yield 92%) of 3,4-dimethoxy-2-fluorobenzyl nitrile. Benzylnitrile (3.9 g, 0.02 mol is dissolved in equal volumes of ethanol and ION aqueous solution of sodium hydroxide (50 ml each) and heated under reflux for 24 hours. The reaction mixture is poured into about 200 ml of hot water, filtered and chii filtrate was acidified with concentrated hydrochloric acid. After cooling, 2-ftorgomoveratrovuyu acid. Analogously to examples 1 and 2 ftorgomoveratrovuyu 2-carboxylic acid is reacted with the dimethylacetal to form aminoatsetaldegiom N12,2-dimethoxyethyl) -3,4-dimethoxy-2-fluorophenylacetamide. ring which is sealed with hydrochloric acid and acetic acid, to give 2, 3-dihydro-7,8-dimethoxy-6-fluoro-2OKCo-1H-3-benzazepine. Dihydrobenzazepine is first reduced by hydrogen and palladium on carbon, and then diborane, to obtain 7,8-dimethoxy-b-fluoro-2, 3,4,5-tetrahydro 1 H-3-ben-aeepin. The latter is treated with a mixture of formaldehyde and formic acid to obtain the corresponding 3-b} ethyl derivative, which is dimethylated with 48% hydrobromic acid. The resulting catechin is oxidized with 2, 3-dichloro-5,6 Yacyano-1, 4-benzoquinone and the dione is treated with a methanol solution of thiophenol, to obtain 7,8-dioxy-9-fluoro-3-methyl-6-phenylthio-2, 3,4,5 -tetrahydro-1H-3-benzazepine.
    Example 13. Following the procedure described in Example 2, a methanol solution of p-methoxythiophenol is reacted with 3-methyl-2,3, 4,5-tetrahydro-1H-3-benzazepin-7,8-dione hydrobromide to obtain 7,8-dioxy-b - {p-methoxyphenylthio} -3-methyl2, 3,4,5-tetrahydro-1H-3-benzazepine: as a free base. After treatment with boron tribromide in a solution of methylene chloride, 7.8 dioxy-b- (p-hydroxyphenylthio / -3-methyl2, 3,4,5-tetrahydro-1H-3-benzazepine) are obtained.
    In order to block the dopamine receptor, a compound of formula 1 or a pharmaceutically acceptable addition salt thereof is usually combined with a pharmaceutical carrier and administered to an animal or person in a non-toxic amount sufficient to make the JVIH of this property. The route of administration may be oral or parenteral. Preferably, equal doses are administered until the desired effect is obtained, for example, two or three times a day with a daily dosage selected from 2-900 mg of the active ingredient.
    权利要求:
    Claims (1)
    [1]
    A method for producing mercapto-substituted 2,3,4,5-tetrahydro-1H-3benzazepines of the general formula where is phenyl, m- or p-substituted phenyl, where the substituents are trifluoromethyl, chlorine, methoxy,. methyl, fluoronitro or hydroxy group, cyclohexyl, thienyl, thienyl-, methyl, furyl or furylmethyl)
    R a is methoxy, alkanoyloxy, where alkanoyl has 2-6 C, or hydroxy)
    R 3 is hydrogen, bromine, fluorine or trifluoromethyl, or their salts, characterized in that it is a dione of the general formula
    SU 1029827 And where R ^ has the above meanings, is reacted with mercaptan of the general formula
    R <SH where has the above meanings, in addition to hydroxy substituted phenyl, the obtained 7,8-dioxo derivative is treated, if necessary, with diazomethane or alkanoyl halide and the target product is isolated in free form or in the form of a salt.
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    DK156001B|1989-06-12|
    NO152213B|1985-05-13|
    DK156001C|1989-11-06|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US92261378A| true| 1978-07-07|1978-07-07|
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