• 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 phosphorus-organic compounds, in particular, a method for the preparation of el (2-chloroethyl-L-nitrosoureido--1-ethylphosphonic acid (EF)) diethyl ester, which has activity against malignant tumors and can be used in medicine. class, ensuring dich better activity and less toxicity. Synthesis of ESP is carried out from 1-amyosylphosphonic acid distil ether and p-chlorostilisocyanate at 0–25 ° C in halocarbon (SNS) with subsequent NaNOj cf. de HCOOL. The EF tests show that, compared with the known N, K-bis- (2-chloroethyl) K-nitrosourea has the best effect on P-388 leukemia, the survival rate is 534 versus 503. Toxicity: em 60.1 vs. 26 mg / kg 4 table CO 00 oo o tsD 4
    公开号:SU1303024A3
    申请号:SU833665922
    申请日:1983-11-16
    公开日:1987-04-07
    发明作者:Лавьелль Жильбер；Кюденнек Клод
    申请人:Адир (Фирма)；
    IPC主号:
    专利说明:

    one
    The invention relates to a process for the preparation of a novel chemical, in particular d (2-chloroethyl-K-nitrosoureido -1-ethylphosphonic acid of the formula


     CHj NO
    V-CH-NH C-N-CH, CH, CE () / IIh
     0 0
    which can be used in medicine,
    The purpose of the invention is to develop a process for the preparation of a compound of formula (I), which, compared with a known compound, has a higher activity and less toxicity.
    Example 1 Preparation of Racemic Diethyl Ester of C. (2-β-chloroethyl) N-nitrosoureido-β-ethylphosphonic acid,
    EXAMPLE 2, Step A, Diethyl ester 1 (2-chloroethyl) -ureido-7-ethylphosphonic acid.
    A solution of 46.65 g (0.26 mol) of diethyl ether cf. α-aminoethylphosphonic acid in 400 ml of chloroform is cooled to O with stirring and a stoichiometric amount of freshly distilled p-chloroethyl isocyanate (22.5 ml or O, 26 mol) is added. The temperature reaches 15 ° C. It is stirred for another 1 hour at room temperature, then the solution is concentrated by evaporation of chloroform, under reduced pressure, without heating.

    g product obtained in butter, used in cheese
    Stage B, Diethyl ether - - - (2-chloroethyl) -K-nitrosoureido - 1 - ethylphosphonic acid ,.
    A solution of 35.4 g (0.12 mol) of the product obtained in stage A in 200 ml of formic acid is cooled to 5 ° C with stirring. Excess sodium nitrite (15 g, 0.22 mol) is added in portions over 30 minutes.
    Stir for another 30 minutes at 10 ° C, then concentrate in vacuo at a temperature below 30-40 ° C. Absorb an oily residue with a mixture of water and methylene chloride in the amount of 400-200 ml. Decant, extract again 200 ml. Wash the organic phase with 100 ml of water saturated with carbon dioxide to a concentration of 10%, then 300 mp of water. The mixture is concentrated. The crystals obtained are thoroughly absorbed in a small amount of isopropyl ether. After drying, 29 g of the expected product are obtained. Recrystallize from 750 ml of ethyl ether at reflux.
    Yield 52%. M.p. 85 ° C.
    IR, cm: (NH) V (CO), respectively, 3220; 1720.
    MI (8): 1.20-1.80, p, 1H; 3.40- 3.70, t, 2H; 3.90-5.00, ta, 5H; 7.40, p, 1H,
    Compound (I) was tested for the ability to lengthen the survival of the smaller, carriers of tumor cells inoculated intraperitoneally (PI) or orally (OP).
    Comparative data on the activity of compound (I) with the known N, N-bis- (2-chloroethyl) -K-nitrosourea (VSSH) for leukemia P 388 in CD25 1 mice (implantation of 10 cells) are presented in Table. one.
    Table I
    Control - untreated animals.
    As can be seen from the table. 1, the survival rate is higher and the ratio of active doses of OP / IL is better for the compound.
    (I).
    The antimetastatic capacity of compound (I) is measured by a coKfianie
    40.5 ± 19.9
    The number of metastases
    N
    thirty
    The first treatment is the day after inoculation.
    As can be seen from the table. 2, compound (I) prevents the formation of metastases.
    The effect of the known compound (BCNH) and compound (I) on the hematopoietic ability in mice relative to untreated animals is estimated by calculating the elements of peripheral blood and bone marrow (femur) and the detection of diluted cells contained in the bone marrow, and is presented in
      Table3
    Control
    11.75 mol / / kg - I 0 (BCNH)
    5-10 100%
    1.55.-10 (-47%) 31% (-69%)
    3030244
    the number and weight of pulmonary metastases, in relation to non-treated animals.
    The antimetastatic activity of compound (I) on the formation of foci of pulmonary metastasis after intramuscular injection of Lewis carcinoma cells is given in Table. 2. Table 2
    ten
    ten
    Continuation of table 3
    7.93 mol / 2, (-7%)
    -S
    / kg-10
    (Compound (I))
    (-58%)
    The results show that 3 days after IP administration the lowest concentration of cancer cells.
    The results were obtained using an effective dose for HSS (11.75 mol / kg-10) and compound (1) (7.93 mol / kg-10.
    The effect of the toxic effect of compound (I) and the known BCNH on the liver is determined by measuring the hepatitis enzyme alanine amino transferase (SGPT) in Long Evans serum.
    The normal concentration in the blood of the indicated enzyme is from 7.5 to I 9 between. unit / l.
    5130302А6
    The results of the action of BCNH and the conjugated hepatitis enzyme in Long neny (I) rats on the circulating level, Evans are given in Table. four.
    Table 4
    all (un)
    14.1 mol / kg
    Compound (I)
    (PI) .5
    9.5 mol / kg -Sh
    Checklists
    the animals
    Average value obtained from 2-4 individual measurements.
    Compound (I) does not have hepatitis toxicity.
    The toxic data LDg of compound (I) and BCNH, respectively (when administered intraperitoneally) is 60.1 and 26 mg / kg.
    These results indicate that Compound (I) is more active and less toxic than known compound VSH.
    权利要求:
    Claims (1)
    [1]
    Invention Formula
    Method for producing (2-chloroethyl) -N-nitrose diethipic ester Compiler S. Polkova Editor M. Blanar Tehred I. Popovich Corrector A. Zimokosov
    Order 1227/57 Circulation 372Subscription
    VNIIPI USSR State Committee
    for inventions and discoveries 113035, Moscow, Zh-35, Raushsk nab., 4/5
    Production and printing company, Uzhgorod, st. Project, 4
    27.3
    10.2 12.6
    22.7
    9,2 10,5
    Ureido - - ethylphosphonic acid 25. formulas
     G-g / P-CH -NH-C-N-CH-SI. Cr X and II g 1 s "n, o about o
     S
    characterized in that 1-aminoethylphosphonic acid diethyl ester is treated with p-chloro ethyl isocyanate at a temperature from 0 to 25 ° C in a halohydrocarbon; sodium nitrite in formic acid.
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    同族专利:
    公开号 | 公开日
    DE3365900D1|1986-10-09|
    ES8501772A1|1984-12-01|
    JPS59106497A|1984-06-20|
    DK524283D0|1983-11-16|
    OA07589A|1985-03-31|
    ZA838558B|1984-07-25|
    IE832680L|1984-05-17|
    NO163409C|1990-05-23|
    MA19952A1|1984-07-01|
    DK524283A|1984-05-18|
    CA1204442A|1986-05-13|
    EP0117959A3|1984-11-14|
    NO834214L|1984-05-18|
    US4567169A|1986-01-28|
    FR2536075A1|1984-05-18|
    IL70253A|1986-10-31|
    NZ206293A|1987-02-20|
    DK169340B1|1994-10-10|
    AU557139B2|1986-12-04|
    FR2536075B1|1985-07-05|
    PT77666A|1983-12-01|
    IL70253D0|1984-02-29|
    PT77666B|1986-05-12|
    ES527353A0|1984-12-01|
    EP0117959A2|1984-09-12|
    AT21905T|1986-09-15|
    EP0117959B1|1986-09-03|
    AU2143683A|1984-05-24|
    JPS6411637B2|1989-02-27|
    NO163409B|1990-02-12|
    IE56259B1|1991-06-05|
    引用文献:
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    US3920733A|1973-08-06|1975-11-18|Monsanto Co|Ureidoalkylphosphonic acids|FR2567129B1|1984-07-06|1986-12-05|Adir|NOVEL OXAAZAPHOSPHORIN DERIVATIVES, THEIR PREPARATION PROCESS AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM|
    IT1246778B|1991-04-12|1994-11-26|Boehringer Mannheim Italia|NITROSOCARBAMOIL GEM-DIPHOSPHONIC ACID DERIVATIVES, A PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM|
    US5298499A|1991-07-05|1994-03-29|Research Triangle Institute|S-2-ethyl phosphorothioates|
    EP0868189A4|1995-11-20|1998-12-23|Sepracor Inc|Antineoplastic methods and compositions employing -fotemustine|
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    US20040072889A1|1997-04-21|2004-04-15|Pharmacia Corporation|Method of using a COX-2 inhibitor and an alkylating-type antineoplastic agent as a combination therapy in the treatment of neoplasia|
    CN100365002C|2004-06-02|2008-01-30|上海医药科技发展有限公司|Process for preparing fotemustine for injection|
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    CN102311456A|2011-07-08|2012-01-11|山东睿鹰先锋制药有限公司|Synthetic method of fotemustine bulk drug|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    FR8219199A|FR2536075B1|1982-11-17|1982-11-17|NOVEL NITROSOUREE DERIVATIVES, THEIR PREPARATION PROCESS AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM|
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