• 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:
    Compounds of the formula <IMAGE> wherein R1-is hydrogen, alkyl of 1 to 6 carbon atoms or benzyl; R2-is alkyl of 1 to 6 carbon atoms, cycloalkyl of 5 to 7 carbon atoms or, together with R1 and the adjacent nitrogen atom, pyrrolidino, piperidino, hexamethyleneimino, morpholino or N'-methyl-piperazino, where each of the heterocycles may have one or two alkyl of 1 to 3 carbon atoms or one or two methoxy substituents attached thereto; R3,-R4 and R5 are each hydrogen or methyl; R6-is alkyl of 1 to 4 carbon atoms; and A-is alkylene of 2 to 4 carbon atoms; AND NON-TOXIC, PHARMACOLOGICALLY ACCEPTABLE ACID ADDITION SALTS THEREOF; THE COMPOUNDS AS WELL AS THEIR SALTS ARE USEFUL AS BRONCHOSPASMOLYTICS AND BRONCHOSECRETOLYTICS.
    公开号:SU722486A3
    申请号:SU782624299
    申请日:1978-06-09
    公开日:1980-03-15
    发明作者:Щмидт Гюнтер；Пюшманн Зигфрид；Энгельхардт Гюнтер
    申请人:Др. Карл Томэ Гмбх (Фирма)；
    IPC主号:
    专利说明:

    This invention relates to a process for the preparation of new benzodiazepinone derivatives having valuable pharmacological properties. The purpose of the invention is to obtain new compounds expanding the arsenal of means of action on a living organism, is achieved by synthesizing the latter, based on the well-known thermal decarboxylation reaction 11. The method for producing pyridobenzodia described by the invention, zypons of the general formula G S 3 And, W ( H, (5- N- --N where R is an unbranched or branched alkyl group with 1-3 carbon atoms, the same or different, hydrogen or methyl per group, Kb - C-alkyl groups A - unbranched or branched Cj-C -alkylene g ruppe, or their salts, consisting in that pyridobenzodiazepinone of the general formula II O Tts II I Eb: where RJ-Rg, A - have the indicated values, is subjected to thermal decarboxylation, followed by isolation of the target product in free form or in the form of a salt. Decarboxylation is carried out by conventional methods at 150-250 seconds, if necessary, in the presence of an indifferent solvent such as diethylene glycol, sulfolane, ortho-dichlorobenzene or tetraethylene glycol-dimethyl ether. Compounds of general formula I can be converted by known methods into their physiologically tolerable salts with inorganic or organic acids. Salt, hydrobromic, sulfuric, phosphoric, maleic, fumaric, citric, tartaric, block acids are suitable as the starting material. Original compounds of general form (II) can be obtained by the fact that ribomembodiaeepinone of the general formula eu N where Rj 5 Rg has the indicated values, is reacted with phosgene in toluene or diethyl ketone in the presence of pyridine at SO-IIO C. Semicarmic carboxylic acid chloride They are reacted with gmino alcohol of the general formula 1U X HO-A-WC where RI, RJ and A have the indicated values in an indifferent organic solvent at 100-150 ° C. The pyridobenzodiazepinones of general formula (III) serving as starting compounds can be obtained by reacting 2-halogen nicotinic acid of general formula G1 W, where Rj has the indicated value, Hal is halogen, with orthophenyl diamine of the general formula U1 Ogde R and H have the indicated at a temperature higher, if necessary in the presence of an inert, high boiling solvent, such as tetrahydronaphthalene, dichloro- or trichlorobenzene or glycol, butylglycol or sulfolane and inert gas, and first 6,11-dihydro-5H-pyr 2, 51benzodiazepinon-5-one of formula V1 I I - P C which then via gipkilyodid in ethanol in the presence of sodium hydroxide solution or alkyl iodide in dimethylformamide and sodium hydride in mineral oil by heating to reflux converted to the corresponding piridobenzodiazepinon general formula (111). The starting compounds of general formula (U) can be prepared by saponifying 2-halogen-2-cyanopyridines with concentrated mineral acid, such as sulfuric and nitric acid. Example. 11- (3-Diethylaminopropyl) -6,11-DIGIDRO-2,6-dimethyl-5H-pyrido 2, 3-Y I, 5 benzodiazepin-5-one. 2.5 g of (3-dystilaminopropyl) -ether b, 11-dihydro-2, b-dimethyl-5H-pyrido 2, 3-S {1.5 I, benzodiazepin-5-one-carboxylic acid is heated in 1 hour for 1 h up to 225s oil bath. Approximately when the release of COji begins. After cooling, 30 ml of ethyl acetate are added, the mixture is heated to reflux temperature and cooled slowly. The isolated crystals are recrystallized from gasoline (so kip. 100-140 s) and melt at 76-78 ° C. Exit 68% of theory. The hydrochloride obtained from the base of hydrochloric acid in acetonitrile is melted at 274275 ° C during decomposition (recrystallized from ethanol). The same compound is obtained in about the same yield if decarboxylation is carried out in diethylene glycol, sulfolane, ortho-dichlorobenzene or tetraethylene glycol-dimethyl ether. PRI mme R 2. 11- (3-Diethylaminopropyl) -6,11-DIGIDRO-2,4,6-trimethyl-5H-pyrido 2 ,, 5 benzodiazepin-5-one. 2.0 g of (3-diethylaminopropyl) ester b, G1-DIHYDRO-2,4,6-trimethyl-5H-Pyrido 2,3-b 1,5-J benzodiazepin-5-OH-11-carboxylic acid is heated in for 1 h in a heated to oil bath. The selection of SOOD starts at about. After cooling to 60 ° C, 30 ml of ethyl acetate are added, the mixture is heated to reflux temperature and is slowly cooled. Crystals of 11- (3-diethylaminopropyl) -6,11-dihydro-2, 4,6-trimethyl-5H-pyridoA 2,3-1,5 1,5 benzodiazepin-5-one are recovered, which are recrystallized from acetonitrile, m.p. . 149-15 ° C, yield 76% of theory. Calculated,%: C 72.10; H 8.25; N 15.29. SagNzoM O (366.5). Found,% / C 72,12; H 8.10; N 15.08. The same compound is obtained with the same yield if decarboxylation is carried out in diethylene glycol, sulfolane, ortho-dichlorobenzene, or tetraethylene glycol-dimethyl ether.
    Example 3. 11- (3-Diethylamino propyl) -6,11-dihydro-2,6,8,9-tetramethyl-5H-pyrido 2 ,, 5 benzodiazepin-5-one.
    2.0 g (3-diethylaminopropyl) -ether 6,11-DIGIDRO-2, b, 8,9-tetramethyl-5H-pyrido 2, 5 benzodiazepin-5-one-11-carbonic acid in 20 ml of tetraethylene glycol-dimethyl The ether is heated in a 230 ° C oil bath. After about 1 hour, the release of CO is completed. The solvent is distilled off in vacuo, the residue is dissolved in isopropanol and fumaric acid is added to obtain a weak acid reaction. The isolated fumarate is recrystallized from isopropanol, so pl. 1b7-169 ° C, yield 74% of theory.
    Calculated,%: C 65.30; H 7.31; N 11.28.
    Fumarate: Cj, H, N 05 (496.6)
    Found,%: C 65.37; H 7.24; N 11.14.
    In a similar way, the following compounds were obtained:
    . 11- (3-diethylaminopropyl) -6,11-dihydro-2, 4,6,8,9-pentamethyl-5H-pyrido 2, 3-b benzodiazepin-5-one, 104-10 bs, yield 48% of theory;
    6,11-dihydro-2,6-dimethyl-11- (3-dimethylaminopropyl) -5n-pyrido-2 ,, 5 benzodiazepin-5-one, so pl. , yield 16% of theory;
    6,11-dihydro-11- (3-diisopropyl-aminopropl) -2,6-dimethyl-5H- -pyrido 2, 5 benzodiazepin-5-one, so pl. 134-136 0, yield 22% of theory.
    权利要求:
    Claims (1)
    [1]
    1. USSR patent for application number 2461008,
    0 cl. C 07 D 487/04, 1975.
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    引用文献:
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    AT161535T|1989-04-20|1998-01-15|Boehringer Ingelheim Pharma|6,11-DIHYDRO-5H-PYRIDO BENZODIAZEPINE 5-ONE AND THIONE AND THEIR USE FOR THE PREVENTION OR TREATMENT OF AIDS|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    DE19762644121|DE2644121A1|1976-09-30|1976-09-30|NEW PYRIDOBENZODIAZEPINONE, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING IT|
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