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  • 权利要求
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    • 专利摘要:
    1462095 Triazolobenzodiazepines BOEHRINGER INGELHEIM GmbH 11 April 1974 [13 April 1973] 16334/74 Heading C2C Compounds of the general formula (R 1 = H, C 1-4 alkyl, C 1-2 hydroxyalkyl, C 2-3 alkenyl, C 3-6 cycloalkyl, Ph, piperidyl; R 2 =Ph optionally o-substituted by F, Cl. Br, CF 3 or NO 2 , or α-Py; R 3 =H, F, Cl, Br, CF 3 , NO 2 , Me, OMe, CN, OH) and their acid addition salts are prepared by reacting a compound of the formula (X = removable atom or group) with optionally followed by salt formation. The reaction proceeds via the intermediate 2- acylhydrazino derivative. The above compounds are anticonvulsants, and may be administered in the form of pharmaceutical preparations containing them in association with a carrier.
    公开号:SU730307A3
    申请号:SU742015007
    申请日:1974-04-11
    公开日:1980-04-25
    发明作者:Бауер Адольф；Вебер Карл-Хейнц；Даннеберг Петер；Кун Франц-Иозеф
    申请人:К.Х.Берингер Зон(Фирма)；
    IPC主号:
    专利说明:

    An intermediate of the general formula is first formed.
    k, ss
    (four)
    Rj and R have the indicated
    where r

    meanings
    which, without isolation, can be cyclized into the desired product, which, if necessary, is converted by conventional methods into a physiologically tolerable acid addition salt.
    If a. X is a lower alkoxy group, then an acidic catalyst, such as a Lewis acid (aluminum chloride, zinc chloride, boron fluoride) or trifluoroacetic acid, is advisable to add to the reaction mixture. It is preferable to work at higher temperatures lying approximately between and the temperature of the flags / s of the reaction mixture.
    When performing this method, the compound of formula 2 is reacted preferably with a 2-7 fold excess of acid hydrazide,
    . The use of an inert organic solvent, such as dioxane, toluene, benzene, xylene, acetonitrile, dimethylformamide, or a mixture of these solvents, depends on which bansdiazepine of formula 2 is used; under certain conditions, it is possible to work without solvent. If X denotes a halogen atom, then the addition of these acid catalysts is not needed. The compound of formula 2 (X is a halogen) is preferably reacted between at minus 10 plus 50 ° C with an acyl hydrazide of the formula. Target products of general formula
    It may, if desired, be converted in the usual way into their physiologically tolerable acid addition salts. Suitable for salt formation acids are, for example, hydrohalic acids, sulfuric acid, phosphoric acid, cyclohexyl sulfamic acid, or methanil. Toluene sulfonic acid.
    Source materials of the general formula
    2 mbzhno, for example, to get; in case X is halogen, by the interaction of compounds of the general formula
    about
    Jf (5)
    2
    where Rj and R, have the indicated meanings.
    with an inorganic acid halide, preferably phosphorus pentahalide, in an anhydrous inert organic solvent, such as dioxane, at low temperatures (approximately minus 50 - plus
    if X is an alkoxy group, by reacting a compound of the general formula 5 with a trialkyloxy fluoroborate,
    The proposed method can be synthesized, for example, the following target products, if necessary, in the form of their physiologically tolerable acid additive salts:
    6-phenyl-8-trifluoromethyl-4, b-dihydro-5H-3-triazolo- {4, 3-a) (1,5) -benzdiazepin-5-one;
    8-chloro-6-phenyl-4, b-dihydro-5H-S-triazolo- (4,3-a) (1,5) -benzdiazepin-5-one;
    8-bromo-6-phenyl-4,6-dihydro-5H-8-triazolo- (4,3-a) (1,5) -benzdiazepin-5-one;
    8-nitro-6-phenyl-4, b-dihydro-5H-3-triazolo- (4,3-a) (1,5) -benzdiazepin-5-one.
    8-CHLOR-1-methyl-6-phenyl-4,6-dihydro-5H-3-triazolo- (4,3-a) (1,5-benzodiazepin-5-one;
    1-methyl-6-phenyl trifluoromethyl-4,6-dihydro-5H-3-triazolo- (4, 3-a) (1,5) - -benzdiazepin-5-one;
    1-methyl-8-nitro-b-phenyl-4,6-dihydro-5H-3-triazolo- (4,3-a) (1,5) -: benzdiazepin-5-one; .
    1-methyl-b-phenyl-4, b-dihydro-5H-3-triazolo- (4,3-a) (1,5) -benzdiazepin-5-one;
    1-ethyl-8-chloro b-phenyl-4,6-dihydro-5H-5-triazolo- (4, 3-a) (1, 5) -benzdiazepin-5-one;
    1-n-butyl-8-nitro-b-phenyl-4, b-dihydro-5H-3-triazolo- (4,3-a) -benzdi aze pin-5-one;
    1-allyl-6-fanyl-8-trifluoromethyl-4, b-dihydro-5H-3-triazolo- (4,3-a) (1,5) -benzodiazepin-5-one;
    8-x.nop-l -cyclohexip-b-phenyl-4, b-dihydro-5H-5-triazolo- (4, 3-a) (1,5) -benzodiazepin-5-one;
    1-hydroxymethyl-8-nitro-b-phenyl-4, b-dihydro-5H-3-triazolo- (4,3-a) (1,5) -benzodiazepin-5-one;
    8-chloro-1-hydroxymatyl-b-phenyl-4,6-dihydro-5H-5-triazolo- (4,3-a) (1,5) -benzodiazepin-5-one;
    1-hydroxymethyl-6-fenil-8-trifluorum. Gtil-4, b-dihydro-5H-3-triazolo- (4,3-a) (1,5) -benzodiazepin-5-one;
    1, b-diphenyl-8-trifluoromethyl-4, b-dihydro-5H-3-triazolo- (4, 3-a) (1,5) -benzodg azepin-5-one;
    8-chloro-6- (o-trifluoromethylphenyl) -4, 6-dihydro-5H-3-triazolo- (4,3-a) (1,5) -benzodiazepin-5-one;
    b- (o-chlorophenyl) -8-NITRO-4, b-dihydro-5H-8-triazolo- (4,3-a) (1,5) -benzodiazepin-5-one;
    8-chloro-b- (o-chlorophenyl) -4,6-dihydro-5H-8-triazolo- (4,3-a) (1,5) -benzodiazepin-5-one;
    8-chloro-b- (o-fluorophenyl) -4, b-dihydro-5H-3-triaolo- (4,3-a) (1,5) -benzodiazepin-5-oneJ
    8-chloro-b- (o-nitrophenyl) -4,6-dihydro-5H-8-triazolo- (4, 3-a) (1,5) -benzodiazepin-5-one;
    8-chloro-b- (o-chlorophenyl) -1-methyl-4, b-dihydro-5H-3-triaolo- (4,3-a) (1,5) -benzodiazepin-5-one;
    8-bromo-b- (L-pyridyl) -4, b-dihydro-5H-8-triazolo- (4,3-a) (1,5) -benzodiazpin-5-one. .
    Annulation of a triazole heterocycle to 1,4-benzodiazepines is known to increase the tranquilizing effect of this class of substances. It was unexpectedly found that applying it to the cyclic system of 1,5-benzodiazepines causes a strong differentiation of action.
    So the triazolodiazepines described can be used as highly effective anticonvulsants,
    The anticonvulsant effects of new compounds are close to the magnitude of the anticonvulsant action of Diazepam and are significantly superior to those of Phenobarbital.
    The side effects of the new compounds are significantly lower than those of the two substances indicated for comparison.
    Another significant advantage of new substances is their significantly lower toxicity, allowing the safe use of substances in a wide dose range. Therefore, the novel triazolobenzodiazepines of the general formula 1 and their physiologically tolerable acid addition salts are valuable anti-convulsants with significantly lower toxicity. Particularly suitable are such compounds where R is a hydrogen atom, R is a phenyl radical optionally substituted by chlorine or trifluoromethyl, and R is a chlorine atom, a nitro group, or trifluoromethyl. radical.
    For using the new compounds of general formula 1, a dose of 0.5-50 mg, preferably 1-25 mg as a single dose and 5-150 mg as a daily dose is suggested.
    The resulting compounds can be used alone or in combination with the active substance agents suggested, if necessary, and in combination with other pharmacologically active active substances as antispasmodic or psychotropic agents. For example, tablets, capsules, suppositories, solutions, syrups, emulsions or dispersible powders.
    Tablets can be made, for example, by mixing the active ingredient or active ingredients with known excipients, for example inert diluents (calcium carbonate, kashti phosphate or milk sugar), corn starch or alginic acid gelling agents, binding agents (starch or gelatin ), lubricants (stearate Mago or talc) and / or means providing an effect of prolonged action (carboxypolymethylene, carboxymethylcellulose, cellulose acetate phthalate or polyvinyl etat)
    five
    Tablets may consist of several layers. Drops can be made if the cores obtained in the same way as tablets are coated, for example, from commonly used for
    These are substances such as kollidone (trade name) or shellac, gum arabic, talc, titanium dioxide or sugar. To achieve a prolonged effect or to avoid incompatibility, a nucleus can also consist of several layers. In order to provide a prolonged effect and the dragee shell consists of several layers ,. moreover, these tablets can be used
    0 excipients.
    Syrups of the proposed active ingredients or combinations of active ingredients may additionally contain a sweet substance saccharin, cycle 5, glycerin or sugar) and a flavor-improving substance, for example, aromatic substances (vanillin or orange extract), and, in addition, suspending agents or
    0 thickeners, such as sodium carboxymethylcellulose, wetting agents, for example, condensation products of fatty alcohols with ethylene oxide, or protective substances such as p-oxy5 benzoates. Injection solutions are made in the usual way, for example with the addition of preservatives, such as p-hydroxybenzoates, or stabilizers (alkaline salts of ethylenediaminetetraacetic acid) and fill them with bottles or ampoules. Capsules containing one or more active substances or combinations of active substances can be obtained, for example, by mixing the active substances with inert fillers (milk sugar or sorbitol) and encapsulating them in gelatin capsules. Southern suppositories can be made, for example, by mixing with prescribed fillers, such as neutral fats or polyethylene glycol or its derivatives.
    Example 1. b-Phenyl-8-trifluoromethyl-4, b-dihydro-5H-5-triazolo5 - (4,3-a) (1,5) benzodiazepin-5-one,
    3 g of 2-ethoxy-5-phenyl-7-trnfluoromethyl-4H-3, 5-DIHYDRO-1,5-benzdiazepin-4-one with 1.8 g of formic hydrazide is heated in an oil bath for 1 h. Then it is allowed to cool to room temperature and the frozen razdlaven is stirred with 100 ml of semi-concentrated hydrochloric acid. The slurries are stirred with ethyl acetate, the aqueous phase is separated, neutralized with concentrated ammonia and extracted several times with methylene chloride. The organic phase is dried with magnesium sulfate and evaporated in vacuo .. The residue is crystallized by the addition of isopropyl ether, and recrystallized from acetone. The output of 2.7 g (91% of theoretical), so pl, 261-263 0.
    Example 2. 1-Methyl-8-nitro-6-phenyl-4, 6-dihydro-5H-3-triazolo- {4, 3-a) (1,5) -benzdiazepin-5-one.
    8.3 g of 7-nitrog-5-phenyl-1H-1, 5-benzdiazepin-2, are added dropwise to a solution of 39.4 tons of phosphorus pentachloride in 250 ml of absolute toluene. 4-ЗН, 5Н -dione, dissolved in 90 ml of absolute dioxane and 15 ml of acetonitrile. The mixture was allowed to react, stirring, for 30 minutes at. The resulting suspension is slowly added to a solution of 70 g of acetylhydrazide in 200 ml of dimethylformamide so that the temperature does not exceed -v 3 C. After 15 minutes, the residue is evaporated in vacuum, stirred with water, shaken, extracted with methylene chloride and then extracted with methylene chloride several times semi concentrated hydrochloric acid. Further processing is carried out as described in Example 1.
    The obtained target product is recrystallized from methylene chloride / isopropyl ether. The output of 5.7 g (63% of theoretical), so pl. 302-305 s.
    Example 3. 8-Bromo-6-phenyl-4, 6-dihydro-5H-3-triazolo (4,3-a) (1,5) -benzdiazepin-5-one.
    - 6 g of 2-ethoxy-7-bromo-5-phenyl-4H-3, 5-DIHYDRO-1,5-benzodiazepin-4-one and 4.8 g of formic hydrazide slightly heated, dissolved in 150 ml of absolute dioxane and heated with 2 ml of trifluoroacetic acid to flow for 1 h under reflux. Then the solution is evaporated and then treated as in example 1. The target product is recrystallized from methylene chloride / isopropyl ether. The output of 5.9 g (96% of theoretical), so pl. 282-284 S.
    Similarly to Examples 1-3, the compounds of general formula 1 are given in the table.
    权利要求:
    Claims (3)
    [1]
    1. A method for producing substituted triazolo-1,5-benzodiazepines of the general formula
    O (11
    where R means hydrogen, unbranched or branched alkyl radical with 1-4 carbon atoms, 65 oxyalkyl radical with 1-2 atoms
    carbon, cycloalkyl radical with B-6 carbon atoms, phenyl or piperidyl radical;
    RJ is unsubstituted or substituted. ortho-positioned by a fluorine, chlorine or bromine atom, trifluoromethyl or a nit {ogroup; a phenyl radical or an o1-pyridyl radical;
    R, is hydrogen, fluorine, chlorine or bromine atom, trifluoromethyl, nitro, methyl, methoxy, cyano or hydroxy group,
    or their salts, characterized in that the compound of the general formula
    X
    Rg have indicated
    where Rg and value.
    X means a halogen atom or a lower alkoxy group, condenses with
    monoacyl hydrazide of the general formula
    HgU-NH-C-K, O)
    where R - has the specified values, with the subsequent selection of the target
    product in free form or as
    salt.
    [2]
    2. Method POP.1, about tl and tea and with the fact that condensation
    0 compounds of general formula 2, where X is an alkoxy group, are carried out
    in the presence of an acid catalyst.
    [3]
    3. Method according to paragraphs. 1 and 2, characterized in that the acid catalyst of Lewis is used, such as aluminum chloride, zinc chloride or boron fluoride or fluoroacetic acid.
    Information sources,
    0 taken into account in the examination
    1. USSR patent in application 2005609 / 23-04, cl. C 07 D 487/04, 03/09/73 ..
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    同族专利:
    公开号 | 公开日
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    CH591486A5|1977-09-30|
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    FI56837B|1979-12-31|
    GB1462095A|1977-01-19|
    AT336025B|1977-04-12|
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    BE813677A|1974-10-14|
    SE419989B|1981-09-07|
    FR2225164B1|1977-05-06|
    DE2318673A1|1974-11-07|
    NO741351L|1974-10-15|
    FR2225164A1|1974-11-08|
    NL7404884A|1974-10-15|
    DK136821B|1977-11-28|
    ATA248274A|1976-08-15|
    ES425216A1|1976-05-16|
    FI56837C|1980-04-10|
    DK136821C|1978-05-08|
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    引用文献:
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    US4080323A|1977-03-07|1978-03-21|Hoffmann-La Roche Inc.|Imidazo [1,5-a][1,5] benzodiazepines|
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    DE3435972A1|1984-10-01|1986-04-10|Boehringer Ingelheim KG, 6507 Ingelheim|PHARMACEUTICAL COMPOSITIONS CONTAINING DIAZEPINE WITH PAF-ANTAGONISTIC EFFECT|
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    DE102005061840A1|2005-12-23|2007-06-28|Merck Patent Gmbh|New polyaza-benzo-azulene compounds are transforming growth factor-beta receptor kinase inhibitors used for treating e.g. cancer, HIV infection and Alzheimer's disease|
    DE102006051796A1|2006-11-03|2008-05-08|Merck Patent Gmbh|Triaza-benzo [e] azulene derivatives|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    DE2318673A|DE2318673A1|1973-04-13|1973-04-13|NEW SUBSTITUTED TRIAZOLO-1,5BENZODIAZEPINE|
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