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  • 专利说明
  • 权利要求
  • 类似技术
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  • 优先权
    • 专利摘要:
    4,1-Benzoxazepines and thia analogs thereof of the formula: <IMAGE> (wherein -A-B- is the following group: <IMAGE> +TR <IMAGE> (wherein R1 is hydrogen, C1 to C3 alkyl, or C7 to C9 aralkyl; R2 is C1 to C3 alkyl or C1 to C3 alpha -aminoalkyl; R3 is C2 to C6 dialkylamino; R4 is C2 to C6 dialkylamino or C5 to C7 alkylpiperazino; R5 is C1 to C3 alkyl; and Q is oxygen or sulfur); D is oxygen or sulfur; X is halogen or nitro; Y is hydrogen or halogen; and Z is hydrogen, C1 to C3 alkoxy, or C3 to C9 dialkylaminoalkoxy; with the proviso that when -A-B- is <IMAGE> Z is not hydrogen.) useful as novel central nervous system drugs are prepared by various synthetic routes.
    公开号:SU936815A3
    申请号:SU792847003
    申请日:1979-11-27
    公开日:1982-06-15
    发明作者:Хираи Кентаро；Мацутани Сигеру；Исиба Теруюки；Макино Ицуо
    申请人:Сионоги Энд Ко.,Лтд.(Фирма)；
    IPC主号:
    专利说明:

    (54) METHOD FOR OBTAINING 4,1-BENZOXEHEMS OR THEIR TIA ANALOGUES
    one
    The invention relates to the method of obtaining new chemical compounds, specifically to the method of obtaining 4,1-benzoxazepines or ichthyaloganals of the general formula
    AB
    Where AB is one of the following groups:
    Ctt,
    P1
    V /
    about
    and- "c /
    where R is methyl or aminomethyl, X is chlorine or nitro,
    Y z
    - hydrogen, chlorine or f.or,
    hydrogen, ethoxy or dimethylaminoethoxy,
    D is an oxygen or sulfur atom.
    The compounds of formula 1 have an effect on the central nervous system and can be used as sedatives, hypnotics and prophylactic drugs.
    A known method for producing pyrrolo derivatives 2,1-cJ-l, 4-benzoxazepine p of formula
    15
    j / (- hydrogen atom, lower algde, lower alkoxy, trifluoromethyl,
    The 20 nitro or amino group, which is attached in that the pyrryl aminomethanol of the formula where Y has the indicated meanings, is subjected to dehydrohalogenation in the presence of a base in an organic solvent. The pyrrolo f2, benzoxazepine derivatives are bioaogically active. The chain of the invention is the preparation of new derivatives of 4,1-benzo-xazepines or their analogs, which are widely used in a living organism. The goal is achieved by the fact that according to the method of producing compounds of formula 1, a compound of formula A B-CHgE, / C # nH-if cC out. and Bavnz, where X, Y, AB, Z, and D have the indicated meanings, is a halogen atom, is dehydrohalogenated in the presence of a base in a solvent at reflux temperature. Alkali metal or alkaline earth metal hydroxides, as well as alkali metal alkoxides, can be used as the base. Examples of solvents include ethyl alcohol, dioxane, benzene, dimethyl sulfoxide. Example 1. 2- (H, H-dimethylcarbamoyl) -6- (2-chlorophenyl) -8-chloro-4I, 6H- (1,2,4) triazolo 2,3-a G, benzoxazepine (U1). Process diagram: SNZ. CSTP 1tk - c sd) C1CNGCOS1 b) A c It
    1. To a solution of 3.8 g of compound III in 75 ml of tetrahydrofuran, a solution of 0.38 g of sodium borohydride in 6 ml of water is added, and the mixture is stirred for 30 minutes, mixed with water, neutral; and evaporated under reduced pressure. The residue is extracted with chloroform. The extract is washed with water and evaporated under reduced pressure. The residue is subjected to crystallization from sulfuric ether. The result is 3.55 g of compound IV to yield
    92.9%, which is recrystallized from ethyl acetate. Mp. 157-159C.
    NMR spectrum: c (1 (5-DMSO): 3.38, 3.02, 5.90 (doublet, Hz) 6.16 (doublet, Hz); 7.73.
    2. Compound IV (2.67 g) is treated by the method as indicated in the Scheme. 0.5 g of compound V is obtained with a yield of 16.2%, which is crystallized from ethyl acetate. M.p. 166-169 p. 5, Calculated,%: C 51.80, H 3.90, N 12.74, C1 24.19, C, Found,%: C 51.95, H 3.82, N 12, 71, C1 23.95. 3. To a solution of 1.4 g of compound V in 140 ml of methyl alcohol is added 6 MP of 10% aqueous sodium hydroxide solution, and the mixture is stirred for 2 hours, neutralized with 10% hydrochloric acid and evaporated. The residue is extracted with ethyl acetate and the extract is washed with water, dried and evaporated. The residue is crystallized from sulfuric ether and 1.1 g of compound VI are obtained with a yield of 84.6%, which is recrystallized from ethyl acetate. M.p. 96 NIE spectrum, cH (CO1): 3.18; 3.3 5.42 + 5.10 (AB q, Hz), 5.93. Calculated,%: C 56.39, H 4.51, N 12.53, C1 15.85. UO a-1/2 CHjCOOC / iH. Found,%: With 56,43; H 4.53; N 12.90; C1 15.98. PRI me R s 2-8. Similarly, the following compounds of Formula 1 can be obtained (see Table 1). Table. 2 shows the physico-chemical characteristics of the compounds of formula 1 according to examples 2-8. In the table below. Table 3 shows the values of the compounds of formula 1 in the anti-pentylenetetrazole experiment and in the rotarod experiment, as well as in the LD. As follows from the table. 3, the compounds of formula 1 have an effect on the central nervous system, and can be used as sedative preparations, hypnotics, muscle relaxants, anti-ailments, vegetative drugs. The compounds of formula 1 may be formulated in various oral or parenteral dosage forms, in pure form or in admixture with other co-active formulations. Pharmaceutical compositions may contain O, U1-99% compound 1 in mixture with a pharmaceutical carrier or carriers, which may be solid materials or liquid substances. Active components 1 may be dissolved, dispersed or suspended in the indicated carriers. S6 They can be in the form of unit dosage forms. Solid compositions can be tablets, powders, dry syrups, grains, capsules, PSH1LULES, suppositories and the like solid forms. Liquid formulations may be used in the form of injections, ointments, dispersions, inhalants, suspensions, solutions, emulsions, syrups or elixirs. All diluents (for example, starch, sugar, milk sugar, calcium carbonate, kaolin), fillers (for example, milk sugar. Sugar, salt, glycocoll, starch, calcium carbonate, calcium phosphate, kaolin, bentonite, talc, sorbitol), binding components ( e.g. starch, gum arabic, gelatin, glucose, sodium arginate, tragacanth, carboxymethylcellulose, sorbitol, polivinilpirropidon), disintegrants (e.g., starch, agar, carbonates, sodium laurylsulfate), lubricants components (e.g. stearic acid, talc, paraffin, boric acid, cree sodium benzene, polyethylene glycol, oil, cocoa, magnesium sulfate), emulsifying agents (for example, lecithin, arabic gum sorbitan monooleate, suspending agents (for example, sorbitol, methylcellulose, glucose, sugar, gelatin, hydroxyethylcellulose, carboxymethyl cellulose cellulose, cellulose cellulose, carboxymethyl cellulose). aluminum, hydrogenated fats), solvents (for example, water, peanut oil, sesame oil, methyl oleate), preservatives (for example methyl or ethyl V-hydroxybenzoate, sorbitol acid), food dyes, aromatic fragrances, solution Gents, buffering agents, stabilizing agents, dispersing agents, wetting agents, antioxidants and the like can be used in a standard way if they do not adversely affect compounds I. Compounds I are usually used as solutions for intravenous, intramuscular or subcutaneous injections. according to the standard way. Compounds 1 may be dissolved in aqueous or oily solvents suitable for ejection to prepare injections in ampoules. To preserve the injectable composition for a long time. 7 9368 It is convenient to formulate the composition in vials that contain crystals, tin, microcrystals or lyophilisate of compounds 1. The composition in the vial can be dissolved or suspended 5 in yka3aH ibix solvents for I1 ections just before using HjieM. The composition may contain specified clamps. 158 Compounds 1 may be administered in daily doses of from about 1 to about 40 mg per adult. The daily dose may be divided into two, three times doses. Depending on the purpose of the treatment, the condition, history and age of the patient, the dosage may increase or decrease,
    it-C
    /
    .N
    1Ш, СН,
    -i
    227-229 2.47 (S, 3N); 4.63-4.97 (AB,, 2H); 5.53 (s, ih).
    205-207 2.60 (S, 3H), 4.58-5.12 (AB, Hz, 2H), 5.70 (S, JH) 2.53 (S, 3H), 0.83 120-122 (t,, 3H) 4.605, 03 (ABq,, 2H)
    170-173 2,12,2,52,5,05-4,78 (AB q, Hz)
    215-217 2.20 (S, 3N) 4.85
    (AB q, Hz, 2H) 5.70 (S, IH)
    1.75 in g, 5.07-4.80 (AB q)
    33.8 216-219
    ClOC j H.
     (CH)
    NO,
    ° V5
    table 2
    IR spectrum (Nujol), 1620, 1590, 1100, 1090
    , 4 (1L syncgl (Tiuiaiu 1 a I)
    权利要求:
    Claims (1)
    [1]
    Claim
    The method of obtaining 4,1-benzoxazepines or their thiaanalogs of the formula 1
    -Y is hydrogen, chlorine or fluorine, Z is hydrogen, ethoxy or dimethylaminoethoxy,
    D is oxygen or sulfur, characterized in that
    E - halogen, is subjected to dehydrohalogenation in the presence of a base in a solvent at reflux temperature.
    50 Sources of information, ‘where IV is methyl or aminomethyl, X is chlorine or a nitro group taken into account in examination 1. US Patent No. 4045448, cl. C 07 D 498/04. published. 1977.
    VNIIIPI Order 4275/80
    Circulation 445
    Subscription
    Branch of PPP Patent, - Uzhhorod, st. Project, 4
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    RU2163240C2|1994-11-02|2001-02-20|Жансен Фармасетика Н.В.|Derivatives of substituted tetracyclic azepine, method of their synthesis, pharmaceutical composition, intermediate substance and method of its synthesis|
    WO2005105805A1|2004-04-29|2005-11-10|'chemical Diversity Research Institute', Ltd.|Annelated carbamoylase-heterocycles, focused library, pharmaceutical compositions and methods for the production thereof|GB1090611A|1963-05-22|1967-11-08|Lepetit Spa|4,1-benzoxazepine derivatives|
    DE1545639A1|1965-11-19|1969-08-07|Boehringer Sohn Ingelheim|Process for the preparation of derivatives of 3,5-dihydro-4,1-benzothiazepin-2 [1 H] -one|
    BE793629A|1972-01-03|1973-07-03|Upjohn Co|NEW BENZODIAZEPINE DERIVATIVES AND THEIR PREPARATION|
    FR2252103B1|1973-11-28|1977-11-10|Hoffmann La Roche|
    US4000151A|1974-09-11|1976-12-28|The Upjohn Company|Triazolyl benzophenone compounds|
    US3933816A|1974-09-12|1976-01-20|The Upjohn Company|3--7-substituted-3,5-dihydro-as-triazino[4,3-a][1,5]benzodiazepines|
    US3966756A|1975-04-07|1976-06-29|American Cyanamid Company|Substituted dibenzo[b,f]tetrazolo[1,5-d][1,4]-oxazepines|
    US4207322A|1975-11-04|1980-06-10|Deutsche Gold- Und Silber-Scheideanstalt Vormals Roessler|6-Aryl-s-triazolo--pyrido---diazepines|
    US4246270A|1976-05-26|1981-01-20|E. I. Du Pont De Nemours And Company|3-Fluorobenzodiazepines and compositions and uses thereof|
    US4180668A|1977-06-08|1979-12-25|The Upjohn Company|Piperidino-4H-s-triazolo[4,3-a][1,4]benzodiazepines|
    JPS54119499A|1978-03-09|1979-09-17|Shionogi & Co Ltd|Triazolobenzodiazepin derivative|US4374842A|1980-04-18|1983-02-22|Shionogi & Co., Ltd.|4,1-Benzoxazepines and compositions|
    JPH029593B2|1980-09-29|1990-03-02|Shionogi & Co|
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