• 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 relates to derivatives of nitrogen-containing heterocyclic compounds, in particular 1- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -2- (1,2, 4-triazol-1-yl) -ethane-1-ol (TAL) or its pharmacologically compatible salts, which have biological activity and can be used in medicine. The goal - the creation of active and low-toxic substances of the specified class. Synthesis of TAL is carried out from 1-bromo-4-chlorobenzene, which according to Grignard is subjected to reaction with magnesium chips, and then with squibol, a quantity of 2,2,4-trichloroacetophenone. Next, an aqueous solution is added to the reaction product with & the subsequent isolation, washing, drying and concentration in vacuo of the organic phase. The product obtained is treated with an equimolar amount of 1,2,4-triazole (in the absence of a solvent or in a polar solvent) at 130-150 0 in the presence of an acid acceptor or excess 1,2,4-triazole, followed by separation of TAL into form of pharmacologically compatible salts with acid or in free form. TAL tests show that they have a higher antifungal activity and are less toxic than the known compounds miconazole and clotrimazole. 5 tab. g SO with ate a A yu SG5
    公开号:SU1355126A3
    申请号:SU813254444
    申请日:1981-03-13
    公开日:1987-11-23
    发明作者:Шарвэхтер Петер；Гутше Клаус；Хеберле Вольфганг；Везенберг Вальтер；Кольманн Фридрих-Вильгельм
    申请人:Басф Аг (Фирма)；
    IPC主号:
    专利说明:

    This invention relates to a process for the preparation of 1- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -2- (1,2,4-trnazol-1-yl) -ethane-1 ol or its pharmacologically compatible salt - biologically active compounds that can be used in medicine,
    The purpose of the invention is to obtain new triazole derivatives with high antifungal activity and low toxicity.
    Example 1. 29, 3g of 1-bromo-4-chlorobeneol in 250 ml of diethyl ether is reacted with 4 g of magnesium shavings at boiling point and then 22.4 g of 2.2.4-trichloroacetophenone is added dropwise. After 1 h, an aqueous solution of ammonium chloride is added, the organic phase is washed to neutrality, dried over sodium sulfate and concentrated in vacuo. The oily reaction product was stirred for 2 hours with 20.8 g of 1,2,4-triazole and 3.4 g of sodium bicarbonate at a bath temperature of 130 ° C and after cooling with ice water and chloroform, it was extracted by shaking. The organic phase is dried with sodium sulfate, concentrated and dissolved with diethyl ether. 22.8 g (61.8%) of crystalline 1- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -2- (1,2,4-triazol-1-yl) -ethane-1- are obtained. ol, m.p. 18 ° C, mol. M. 368.67.
    Calculated,%: C 52.13; H 3.28; C1 28.85; N 11.40.
    Found,%: C 52.06; H 3.45; C1 29.4; -N 11.27.
    Example 2, 2.0 g of 1- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -2- (1,2,4-triazol-1-yl} -ethane-I-ol is suspended in 100 ml acetone, then hydrochloric diisopropyl ether is added and heated. 1.7 g (78%) of 1- (4-chlorophenyl) (2,4-dichlorophenyl -) -2- (1,2, 1,2, 4-triazol-1-yl) -etan-ol-hydrochlorohydride, mp: 130 ° C, mol. Mm 405.13.
    Calculated,%: C 47.44; H 3.24; CI 35.01; N 10.37. C, tH „ClvN O
    Found,%: C 47.9i H 3.49; C1 35.5; N 10.3,
    Froze Yun 1- (4-chlorophenyl) (2, 4-dichlorophenyl) -2- (1,2,4-triazol-1-yl) -ethane-1-ol is dissolved
    in 500 ml of chloroform, after which 50 ml of concentrated nitric acid solution are added first
    in diethyl ether and then 3 l of diisopropyl ether. 8 g (73%) of crystalline I- (4-chlorophenyl) (2,4-dichlorophenyl) -2- (1,2,4-triazol-1-yl.) - ethane-1-ol-nitrate are obtained, t. square 176 ° C, C, t H, C1.N40, mol. M. 431.68.
    Biological trials of triazole derivatives have been carried out. Tests on pseudomycelium and enriching mycelium Candida albicans:
    Candida albicans can form in vivo not only budding cells, but also pseudomycelium and true mycelium (dimorphism). The development of all phases 0 of the growth of this microorganism and the effect of antifungal substances are tested in vitro as follows: Candida albicans (Robin) spores Berkhout N 20 / M (strain of mikoteka, Nordraark5 Werke GmbH) are seeded by sowing from one side to the surface A of the culture medium ( Brain Heart Infusion, Difco), and on the other hand, to the surface B as a culture obtained by an injection.
    In addition, a cover glass C (microaerophilic conditions) is superimposed in the culture zone obtained by the injection. The Petri dish contains in the nutrient medium a series of geometrically decreasing dilutions of the corresponding test substance. After incubation, these test plates (2 days, 37 ° C) were grown in free
    0 from the preparations of the control plates in the aerobic zone A are exclusively budding cells (yeast phase), and in the microasophilic zone B only pseudohyphas and real hyphae.
    {5 Minimum inhibitory concentrations (MIC) denote the degrees of concentration of the test preparation in which 100% inhibition of fungal growth is observed.
    50 This test allows to distinguish between the MIC of the yeast phase and the MIC of the pseudomiceral or mycelial phases of Candida, albicans.
    gg The results are shown in Table 1.
    As follows from the table. 1, the MIC values for the mycelial phase are extremely low, while the MIC values for the yeast phase are more than 128 µg / ml.
    313
    An in vitro antimicrobial effect against dermatophyres is investigated by testing by the method of serial dilutions in agar (lit. R. Klein BELkteriologixhe Griind Lsigen der chemotherapeutischen Laboratorium-spraxis).
    The result of research on the example of the compound (l) is shown in table 2.
    Experimental mouse candidiasis caused by Candida alblcans. To establish the oral action, groups that consist of 10 mice weighing approximately 20 g, 2 days 50 mg / kg intramuscularly with hydrocortisone are pretreated to achieve a good infection. Then the mice are infected with 500,000 Candida albicans embryos intravenously and then orally treated 4 days twice. per day 100 mg / kg of the test substance.
    Along with the infected group and the untreated control group, the microconasol and clotrimazole are treated for comparison in one group with known substances.
    The results are shown in table 3.
    From Table 3 it follows that on the 10th day after infection, up to 100% of the animals treated with the proposed compounds live, while only 30% of the animals in the control group and animals treated with known substances survive (30%). day 100 mg / kg).
    To test the intensity of the action on a living organism, groups of 10 mice are infected, as indicated, with Candida albicjuas glands and then treated for 4 days (twice a day) 46.6 mg / kg (Table 4) and 21.5 µg / k (Table 5) of the selected test substances.
    64
    The results obtained show that the triazole derivatives obtained by the described method have a higher antifungal activity and are less toxic than the known compounds in structure and action by miconazole and clotrimazole.
    权利要求:
    Claims (1)
    [1]
    Invention Formula
    The method of obtaining 1- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -2- (1,2,4-triazol-D-yl) ethane-1-ol of formula
    N OH C1 (O) -CI
    20
    Jq} 5
    five
    0
    five
    0
    or its pharmaceutically compatible salts with an acid, characterized in that the 1-bromo-4-chloro-benzene according to Grignru is reacted with magnesium chips, and then with an equimolar amount of 2,2,4-trichloroacetophenone, to the reaction product aqueous solution of ammonium chloride, they are followed by separation, washing, drying and concentration in vacuo of the organic phase, the resulting product is reacted with an equimolar amount of 1,2,4-triazole in the absence of solvent or in a polar solvent at 130-150 ° C in pr presence of an acid acceptor or an excess of 1,2,4-triazole, followed vvdeleniem title product. form of pharmacologically compatible salts with acid or in free form.
    Table 1
    -N
    HE
     Jri
     Ni M-CH2-C- 5
    Ri
    HE
    2-C1 4-C1 A-G1
    Kikonazol Clotrimazole
    Genus Microsporowi:
    M. audoiiinii M. ferrugineum M. canis M. canis M. canis
    Trichophyton genus: T. schoenleinii T. violaceum T. mentagroph T. menta roph T. mentagroph
    Genus Epedermophyten: E. floccosum
    Continuation of table 1
    , 125 1000 0.125 578 microns 0.15 750-800
    Table 2
    0.25
    9 10
    159 172 173
    157
    0.25 1
    0.125
    0.25
    0.25
    sixteen
    1.28
    0.32
    0.5
    0.32
    110 10 10 10. 10 10. 10 10 10 10
    210 10 10 10 10 10 10 10 10
    Table 3
    1355126
    10 10
    1010 1010 10 10 1010
    Clot-rimazole 10 10
    553220
    Control
    10 10
    53111О
    Editor N.Rogulich
    Compiled by V. Volkov
    Tehred K. KhodanychKorregorM.Maksimishinets
    Order 5719/57
    Circulation 372Subscribe
    VNIIPI USSR State Committee
    for inventions and discoveries 113035, Moscow, Zh-35, Raushsk nab., 4/5
    Production and printing company, Uzhgorod, Proektna St., 4
    10 Continuation of table 5
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    同族专利:
    公开号 | 公开日
    IL62332D0|1981-05-20|
    DE3010093A1|1981-10-01|
    NO810878L|1981-09-16|
    IL62332A|1984-08-31|
    IE51146B1|1986-10-15|
    DD156808A5|1982-09-22|
    GR73187B|1984-02-14|
    EP0036153B1|1983-11-02|
    NO155692B|1987-02-02|
    YU65081A|1983-09-30|
    AU6835581A|1981-09-24|
    DE3161300D1|1983-12-08|
    ES8201554A1|1981-12-16|
    CS221824B2|1983-04-29|
    FI810743L|1981-09-16|
    DK114181A|1981-09-16|
    EP0036153A1|1981-09-23|
    JPS56142273A|1981-11-06|
    NO155692C|1987-05-13|
    IE810533L|1981-09-15|
    PT72574B|1982-02-12|
    PT72574A|1981-03-01|
    AT5190T|1983-11-15|
    ZA811664B|1982-11-24|
    IN152638B|1984-02-25|
    FI70578B|1986-06-06|
    AU544076B2|1985-05-16|
    FI70578C|1986-09-24|
    ES500334A0|1981-12-16|
    HU180630B|1983-03-28|
    引用文献:
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    DE2324010C3|1973-05-12|1981-10-08|Bayer Ag, 5090 Leverkusen|1-Substituted 2-triazolyl-2-phenoxyethanol compounds, process for their preparation and their use for combating fungi|
    DE2431407C2|1974-06-29|1982-12-02|Bayer Ag, 5090 Leverkusen|1,2,4-Triazol-1-yl-alkanones and alkanols, processes for their preparation and their use as fungicides|
    DE2547954C2|1975-10-27|1989-02-16|Bayer Ag, 5090 Leverkusen, De|
    IE44186B1|1975-12-03|1981-09-09|Ici Ltd|1,2,4-triazolyl alkanols and their use as pesticides|
    IE45765B1|1976-08-19|1982-11-17|Ici Ltd|Triazoles and imidazoles useful as plant fungicides and growth regulating agents|US4654332A|1979-03-07|1987-03-31|Imperial Chemical Industries Plc|Heterocyclic compounds|
    US4927839A|1979-03-07|1990-05-22|Imperial Chemical Industries Plc|Method of preventing fungal attack on wood, hides, leather or paint films using a triazole|
    AT73293T|1980-08-18|1992-03-15|Ici Plc|USE OF TRIAZOLYLAETHANOL DERIVATIVES AND THEIR COMPOSITIONS AS NON-AGRICULTURAL FUNGICIDES.|
    JPS5764614A|1980-08-28|1982-04-19|Ici Ltd|Pharmaceutically or veterinarily antibacterial composition and method of controlling or sterilizing microbes of candida or trichophyton genus|
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    PH20855A|1984-01-24|1987-05-19|Pfizer|Antifungal agents|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    DE19803010093|DE3010093A1|1980-03-15|1980-03-15|1,1-DIPHENYL-2--ETHANE-1-OLE, METHOD FOR THE PRODUCTION THEREOF AND THERAPEUTIC AGENTS CONTAINING THEM|
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