• 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:
    20-Amino derivatives of tylosin, and like macrolides, are active against bacteria and Mycoplasma.
    公开号:SU1360588A3
    申请号:SU833555405
    申请日:1983-02-23
    公开日:1987-12-15
    发明作者:Омура Сатоси；Накагава Акира
    申请人:Сатоси Смура (jP)；
    IPC主号:
    专利说明:

    This invention relates to a method for producing new derivatives. 20-amino-desmycosin of general formula
    CH-i CH2CH2N 2
    Ign n 9
    ,
    . sleep
    where R is mycinosyloxy;
    Rj is C-alkyl or, cyclo-pyl,
    with antibacterial action.
    The purpose of the invention is the discovery of new compounds in a series of derivatives of the 20-aminode; zmikosin, which have an increased antibacterial effect.
    Example. 20-fle30Kco-20- (N, N dipropylamino) demicarosyltylosin.
    . Demicarosyltylosin (8.0 g, 10.4 mmol) was dissolved in methanol (80 ml), dipropylamine (2.1 g, 20. 8 mmol) was added. The solution is stirred at room temperature in the presence of 3 A molecular sieve for 15 minutes, sodium cyanobasilide (0.98 g, 15.6 mmol) is added, and stirring is continued for 17 hours. Then the reaction mixture is filtered to remove molecular sieve. The filtrate is evaporated under reduced pressure, and the residue is dissolved in ethyl acetate (400 ml). The ethyl acetate solution is washed with two portions of water (400 and 200 ml). The product is then extracted with two portions (400 and 200 ml) of a 0.5 M buffer solution (pH 6.5), the layers J are separated and the buffer solution is placed on a rotary evaporator to remove the residue of ethyl acetate. Then the buffer solution is rapidly stirred. While slowly adding 5N. sodium hydroxide solution. The addition is stopped after the formation of a thick white precipitate. The solid is filtered on a Buchner funnel, washed with water and dried under vacuum. 5.227% of the desired product is obtained in the form of a white powder (yield 58.7%).
     . . . .
    m "ks. U) 282 nm (22250).
    Mass Spectrum (FDMS) M +. Titration (pKa) 7.7; 9.3.

    15
    0
    25
    thirty
    35 40 45 50 55
    Example2. Under the conditions of Example 1, a desired product is obtained using an appropriate amount of sodium borohydride instead of sodium cyanoborohydride (yield 58%).
    PRI m e r.Z. 20-Deoxo-20- (S, I-diethylamino) demicarosyltylosin.
    Under the conditions of Example 1, using 1.52 g (20.8 mmol) of diethylamine, the expected product is obtained in a yield of 42.3%.
    C1H -) 283 nm (22410).
    Mass Spectrum (FDMS) M.
    Titration (pKa) 7.9; 9.5.
    PRI me R 4. 20-Deoxo-2L- (I, I-dibutylamino) demicarosylthylosin.
    Under the conditions of Example 1, using 2.69 g (20.8 mmol) of dibutylamine, the desired product was obtained in a yield of 56.5%.
    max 282 nm (20160).
    Mass Spectrum (FDMS).
    Titration (pKa) 7.9; 9.5.
    EXAMPLE 5. 20-Deoxo-20- (H, N-Dicyclopentilamino) demicarosyl-tillosin. .
     Under the conditions of Example 1, using 3.19 g (20.8 mmol) of dicyclopentylamine, obtain the desired product in a yield of 15%.
    L 1 "ke) 283 them (21,000). Mass Spectrum (FDMS). Titration (pKa) 7.9; 9.6. : Note E. 6. 20-Deoxo-20- (K, M-dicyclohexylamino) demicarosylthylosin
    Under the conditions of Example 1, using 3.77 g (20.8 mmol) of dicyclohexyl-amine, the expected product is obtained in a yield of 41.3%.
    Sc- () 282 nm (17000).
    , Mass Spectrum (FDMS) 936.
    Titration (pKa) 7.9; 10.0.
    PRI me R 7. 20-Deoxo-20- (I, 11-cyclopropylamino) demicarosylthiolosin.
    Under the conditions of Example 1, using 1.2 g (20.8 mmol) of cyclopropylamine, the expected product is obtained in a yield of 53%.
    currency (&) 282 nm (19500).
    (MS (COP
    Mass spectrum 813; 812. Titration (pKa) 8.9; 7.6.
    31360588
    The study of the antibacterial day-, twi of the proposed compounds is carried out as follows,
    1. The study of the protective effect of g of the compounds against bacteria S. Pyrogenes is carried out on white mice of the I.C.R line of an arbitrarily selected sex weighing 19-21 g. S. Pyrogenes C203 is grown in peptone 10 broth with the addition of 5% defibrinated rabbit blood. Intraperitoneal infusion of 0.5 ml of suspension containing 50-100 LD of bacteria per 0.5 ml is infested. Infected mice are treated 15–5 hours after infection, subcutaneously or orally by injecting 0.25 ml of a solution of the test compound obtained by dissolving it in ethanol (10% of the final volume of solution) and diluting it with a sterile water .. The value of EDJO is calculated in a known manner. The data presented in Table. one. .
    Table 125
    De soi no
    th d s
    TO
    with us
    C 4H g
    25

    80
    2. The study of the antibacterial activity of the presumed compounds was carried out on a culture of Pasteurella hemolytica 23C in a standard way. The results of determining the minimum .inhibiting concentration (MIC) are given in Table. 2
    Table 2
    Continuation of table 2
    6, Hvn
    (cyclohexyl) desmikosin (known compound)
    Dilution on agar, 24 g,.
    From the data of Tables .. and 2 it follows that the proposed compounds are superior in their antibacterial action to the known compound
    KOZIN
    The acute toxicity of the proposed compounds, determined by intraperitoneal injection in mice, is 42-88 mg / kg.
    权利要求:
    Claims (1)
    [1]
    Invention Formula
    The method of obtaining derivatives of 20-aminodemosicosine General formula
    ABOUT
    sn
    NzS / TcH2CHjl CR2) 2
    RiCH, y with he
    sC. sns he
    where R is mycinosistoxy;
    R is C-C-alkyl or Cd-C-cycloalkyl,
    distinguished by the fact that desmikosine of the general formula
    JLpH HjC | GOS2SNO
    kdaTsnzHo he
    sS2LtLn) 2 ° sns he
    where R., has the indicated value, is reacted with a secondary amine of the general formula
    HN (R) j,
    513605886
    where Rj is as defined, a solvent such as in the presence of a reducing agent, such as methanol, followed by alkaline as cyanrborohydride or boron of the desired product in sodium free hydride, in an inert organic form,
    iJ
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    GB2115813B|1985-09-11|
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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    US3178341A|1960-06-27|1965-04-13|Lilly Co Eli|Antibiotics tylosin and desmycosin and derivatives thereof|
    GB1587685A|1977-03-09|1981-04-08|Microbial Chem Res Found|Macrolactone derivatives and their production|
    JPS53132584A|1977-04-26|1978-11-18|Toyo Jozo Co Ltd|18-cyano-18-substituted amino-18-deoxy-macrolide anibiotic substance derivative|
    NL8004922A|1979-09-19|1981-03-23|Toyo Jozo Kk|DEFORMYLTYLOSINE DERIVATIVES.|
    US4279896A|1980-06-23|1981-07-21|Schering Corporation|Novel 20-imino macrolide antibacterial agents|AU561147B2|1982-09-13|1987-04-30|Eli Lilly And Company|20-amino macrolide antibiotics|
    US4820695A|1982-09-13|1989-04-11|Eli Lilly And Company|C-20-dihydro-deoxy--derivatives of macrolide antibiotics|
    US4443436A|1982-09-13|1984-04-17|Eli Lilly And Company|C-20-Modified macrolide derivatives of the macrolide antibiotics tylosin, desmycosin, macrocin, and lactenocin|
    US4629786A|1983-02-28|1986-12-16|Eli Lilly And Company|C-20- and C-23 modified macrolide derivatives|
    ZA841277B|1983-02-28|1985-09-25|Lilly Co Eli|C-20-and c-23-modified macrolide derivatives|
    IL71032D0|1983-02-28|1984-05-31|Lilly Co Eli|C-20 and c-23-modified macrolide derivatives|
    US4801721A|1984-08-16|1989-01-31|Ryan James W|Stereospecific synthesis of carboxyalkyl peptides|
    US4921947A|1986-03-31|1990-05-01|Eli Lilly And Company|Process for preparing macrolide derivatives|
    FR2638458A1|1988-10-27|1990-05-04|Adir|NOVEL TYLOSIN DERIVATIVES, PROCESS FOR PREPARING THEM AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAME|
    US5354708A|1992-06-04|1994-10-11|Taskar Nikhil R|Method of nitrogen doping of II-VI semiconductor compounds during epitaxial growth using an amine|
    TW309505B|1993-03-31|1997-07-01|Toto Ltd|
    AU3121095A|1994-09-22|1996-04-09|Pfizer Inc.|Antibiotic macrolides|
    EP0778283A3|1995-12-05|1998-01-28|Pfizer Inc.|Antibiotic macrolides|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    JP57029480A|JPH0142277B2|1982-02-25|1982-02-25|
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