• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    The invention provides 3-allyl-7,8-dihydroxy-6-halo-1-(4-hydroxyphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine derivatives, O-alkanoyl esters thereof and pharmaceutically acceptable acid addition salts of these compounds. These compounds have a unique cardiovascular effect in that they are potent renal vasodilators and also induce bradycardia. The invention therefore includes pharmaceutical compositions containing such compounds. The compounds of the invention can be prepared by reacting an appropriate ether of the desired compound in which all three hydroxy groups are etherified, with an ether cleaving agent, with optional subsequent O-acylation and/or salt formation.
    公开号:SU982539A3
    申请号:SU802927002
    申请日:1980-05-23
    公开日:1982-12-15
    发明作者:Вейнсток Джозеф
    申请人:Смитклайн Корпорейшн (Фирма)；
    IPC主号:
    专利说明:

    The invention relates to the preparation of new benzazepine derivatives ryagde X - halo consisting in L that the compound of formula and which possess biological activity and could find application in medicine.
    A known method of producing alcohols by the reaction of cleavage of arylmethyl ethers with boron halides C1J.
    The purpose of the invention is the development, on the basis of the known method, of a method for producing new compounds with valuable pharmacological properties. ..
    The goal is achieved according to the method for producing 3-allyl-7,8-dioxo-6-halogen-1- (4-hydroxy-phenyl -2,3,4,5-tetrahydro-1Н-З-benzazepine of the formula τή
    X | 1 L est b where X - has the indicated value, is treated with boron tribromide and the target product is isolated or in free
    Nom form or transferred to Sol. Salts are prepared using both organic and inorganic acids, for example: maleic, fumaric, benzoic, ascarbinic, pamova, succinic, dimethylene salicylic, methanesulfonic acid, ethanedisulphonic acid, acetic, oxalic, propionic, tartaric, salicylic, lemon, salicylic aspartic "benzenesulfonic acid, hydrochloric, hydrobromic, sulfuric, cyclohexyl sulfamic, phosphoric and nitric acids. Pear base is reacted with an equivalent or excess of the selected acid in an organic solvent. Salt is isolated by filtration or evaporation of the solvent. Salts obtained by the addition of hydrogen halide and especially methane-5 sulfonic acid are of particular interest because of their good solubility and oral activity.
    PRI me R 1.b-chloro-7,8-dimethoxy40 -1— (4-methoxyphenyl) -2,3,4,5-tetrahydro-1H-3-benzazepine mp 140-142.5 ° C, 3.47 g, 0.01 M1 in 50 ml of acetonitrile is mixed with 2.8 mp (0.02 m) of triethylamine and 1.4 ml (0.011'm! 15 allyl bromide. The mixture is heated at 85-95 ° C in for 2-1 / 2 h. The reaction mixture was evaporated. The residue was suspended in water and extracted twice with ethyl acetate. The organic extracts were washed with water, brine and evaporated to give 2.6 g (67.2%) of a yellow oil, 3-allyl-b -chloro-7,8-dimethoxy-1- (4-methoxy-phenyl) -2,3,4,5-tetrahydro-1H-3-benzazepine. 25
    This substance (2.6 g, 0.00 b7 m) is dissolved in 55 ml of methylene chloride and cooled to -1 T5 ° C, while 6.0 ml (0.064 m) of boron tribromide in 40 ml of methylene chloride '0 are slowly added to for 1/2 hour. The reaction mixture was stirred at room temperature for 3 hours, cooled and treated with an excess of methanol slowly and with cooling. Methanol 35 was evaporated to give a foam. This foam is then dissolved in a minimum amount of methanol and cooled. Some acetate was added to isolate 1.85 g (65%) of 3-allyl40 -6-chloro-7,8-dioxo-1- (4-hydroxyphenyl) 2,
    3,4,5-tetrahydro-1H-3-benzazepine hydrobromide, mp 195-199 ° C (with decomposition).
    Using a solution of sodium carbonate-45, they neutralize an aliquot of hydrobromide (1 g) in aqueous methanol. The base (500 mg) reacts with a weak excess of methanesulfonic acid in methanol to give methyl sulfonate (550 ml), __
    The use of 6-fluoro-7,8-dimethoxy 3 1— (4-methoxy-phenyl 2,3,4,5-tettahydro-1H-3-benzazepine for N-allylation followed by dimethylation with boron trichromide, as described above, gives 3 -allyl-b-fluoro-7,8-dioxo-55 -1- (4-hydroxyphenyl) -2,3,4,5-tetrahydro-1H-3-benzazepine bromohydrate Substitution 6-bromo 1 -7,8-dimethoxy -1- (4-methoxyphenyl) -2,3,4,5-tetrahydro-1H-3-benzazepine in the described manner using 60 using N-allylation and dealkylation with boron bromide gives 3-allyl-6-bromo-7,8- daoxy-1- (4-hydroxyphenyl) -2,3,4,5-tetrahydro-1H-3-benzazepine bromide. 65
    PRI me R 2. The starting material for b-bromo-trimethoxybenzazepine in Example 1 (7.8 g 0.018 m) in 300 ml of methylene chloride and an excess of trifluoroacetic anhydride was stirred for 2 hours. Then the solvent was evaporated and toluene was added. The mixture was stirred again to give 3-amide. A mixture of 25 ml of lithium butyl (2.5 M 0.65 m) in 200 mp ether is cooled to -78 ° C and 3-amide (8.7 g) in 60 mp toluene is added. After 15 minutes of stirring, a mixture of 9.1 g of iodine (0.038 m) and 60 ml of ethyl ether is added. After stirring for the time required to warm to room temperature, the mixture was reacted with 200 ml of 10% hydrochloric acid at 0 ° C. The mixture was stirred. The collected solid was taken up in methylene chloride methanol, washed / brine, dried and evaporated to give b-iodo-7,8-dimethoxy-1- (4-methoxy-phenyl) -2,3,4,5-tetrahydro-1H- 3 benz azepine hydrochloride, mp 273 ~ 239 ° C. Allylation of 2 g of a trimethoxy compound using allyl iodide followed by demethylation of 1.25 g of the N-allyl compound in the same manner as in Example 1 gives 450 mg of 3-allyl-7,8-dioxi-b-iodo-1- (4-hydroxyphenyl) -2, 3,4,5-tetrahydro-1H-3-beneazepine bromide hydrate.
    权利要求:
    Claims (1)
    [1]
    1. Weigand Hilgetag Experimental methods in organic chemistry. Chemistry, M, 1968, p. 361-363.
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    同族专利:
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    AT1448T|1982-08-15|
    DD151162A5|1981-10-08|
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    NO146025B|1982-04-05|
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    KR840001212B1|1984-08-21|
    EP0020107A1|1980-12-10|
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    FI66599C|1984-11-12|
    IL60144D0|1980-07-31|
    HU180582B|1983-03-28|
    NO146025C|1982-07-14|
    NZ193767A|1982-12-21|
    GR68523B|1982-01-11|
    DK154833C|1989-05-16|
    AU5852080A|1980-11-27|
    PL124374B1|1983-01-31|
    KR830002715A|1983-05-30|
    DE3060753D1|1982-10-07|
    IL60144A|1984-09-30|
    NO801497L|1980-11-26|
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    YU140580A|1983-02-28|
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    PT71262A|1980-06-01|
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    JPS55157569A|1980-12-08|
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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    US4160765A|1976-11-17|1979-07-10|Smithkline Corporation|Method for 6-bromination of 1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine compounds|
    US4104379A|1977-01-19|1978-08-01|Smithkline Corporation|Substituted 1-alkylthiophenyl-2,3,4,5-tetrahydro-1H-3-benzazepine compounds|
    ZA777444B|1977-01-19|1978-10-25|Smithkline Corp|Alkylthio-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1h-3-benzazepines having dopaminergic activity|
    US4108989A|1977-04-01|1978-08-22|Smithkline Corporation|2,3,4,5-tetrahydro-1h-3-benzazepine-7,8-diones|
    US4171359A|1978-04-12|1979-10-16|Smithkline Corporation|Benz-tetrasubstituted 1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepines|US4340601A|1980-07-08|1982-07-20|Smithkline Corporation|Dopaminergic isoquinolines|
    US4328153A|1980-07-17|1982-05-04|Smith Kline Corporation|Dopaminergic benzazepines|
    CA2098446A1|1992-09-30|1994-03-31|Eckard Weber|2,5-dihydro-2,5-dioxo-1h-azepines and 2,5-dihydro-2-oxo-1h-azepines and the use thereof as excitatory amino acid and glycine receptor antagonists|
    US20070122353A1|2001-05-24|2007-05-31|Hale Ron L|Drug condensation aerosols and kits|
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    US7540286B2|2004-06-03|2009-06-02|Alexza Pharmaceuticals, Inc.|Multiple dose condensation aerosol devices and methods of forming condensation aerosols|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US06/042,680|US4251525A|1979-05-25|1979-05-25|3-Allyl-7,8-dihydroxy-6-halo-1--2,3,4,5-tetrahydro-1H-3-benzazepine derivatives|
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