• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
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  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    Novel-Z-2-Acylamino-3-monosubstituted propenic acids and their esters and salts of the formula <CHEM> wherein R1 is, by preference, hydrogen, lower alkyl or a pharmaceutically acceptable cation, R2 is, by preference, methyl substituted cyclopropyl, (cycloalkyl)alkyl, straight alkyl with more than 4 C-atoms or ramified alkyl and R3 is, by preference, optionally substituted alkyl, are prepared by reacting compounds of the formula R3-CH2-@-COOR1 with compounds of the formula R2CONH2 or by acylation of esters of the formula <CHEM> with an acid chloride R2@CI and treating the obtained acylated esters to the formula <CHEM> with t-butylhypochlorite and sodium methoxide, followed by treatment of the resultant intermediate with anhydrous hydrochloric acid. The novel compounds selectively inhibit the metabolism of dipeptidase (E.C.3.4.13.11) and therefore are useful in combination with antibacterial products, by preference with the thienamycin class of compounds.
    公开号:SU1213983A3
    申请号:SU813444852
    申请日:1981-08-05
    公开日:1986-02-23
    发明作者:В.Грэхэм Дональд；Ф.Роджерс Эдвард；М.Кахан Фредерик
    申请人:Мерк Энд Ко,Инк (Фирма)；
    IPC主号:
    专利说明:

    one
    This invention relates to a process for the preparation of new compounds of the general formula
    .
    X -
    T 2CONH COOpj
    where R is hydrogen
    R - cyclopropane, substitution
    lower alkyl, R lower alkyl,
    which selectively inhibit dipeptidase metabolism.
    The purpose of the invention is to obtain new derivatives of Z-2-acylamino-3 monozyme propenates, which are dipeptidase inhibitors. I Example 1. 2- (2,2-Dimethyl-cyclopropancanoyl IH-d) 2-hexa va acid,
    Stage A: tert-butyl ester of DZ-norleucine.
    To a suspension of 9.82 g (75 mmol) of DZ norleucine in 80 ml of dioxane, placed in a 500 ml autoclave, cooled in an ice bath, 8 ml of concentrated are added slowly (with stirring). After cooling the mixture in an ice bath, add 80 ml of liquid isobutylene. The mixture is allowed to warm to room temperature and is stirred under autogenous pressure for about 23 hours. After the main part of isobutylene is discharged from the autoclave, the slightly turbid solution is cooled in an ice bath and then AGO ml is added to the cooled mixture. n NaOH and 500 from Et20. After shaking in a separate pot, the layers are separated, the aqueous fraction is washed with an additional 100 ml of Etj O, the solution is shaken with 150 ml of n, HCf. The acidic aqueous fraction is treated with 2.5N. NaOH to a strongly alkaline reaction, and then shake with 250 ml of EtgO, the solution is dried (MgSO4), filtered and concentrated on a rotary evaporator. After a long vacuum. NIN under high vacuum on a steam bath, a clear, colorless oily product was obtained in an amount of 9.04 g (65%). The NMR spectrum shows the presence of traces of dioxane. TLC (9: 1 CHCl s MeOH) shows one spot.

    213983
    Stage B: N- (2,2-dimethylcycloproPancarbonyl) TDZ-norleucine tert-butyl ester.
    To a solution of 8.98 g (48 mmol)
    5 tert-butyl ester of DZ- -norleucine and 5.05 g (50 mmol) of triethylamine in 100 ml. stirred in an ice bath under a pipe, a solution is added dropwise (for 75 minutes)
    6.39 g (48 mmol) of 2,2-dimethylcyclopropanecarbonyl chloride in 50 ml of CHjCt. Deposition occurs during the addition of the reactant, especially near the end. As the ice melts, the mixture is warmed to room temperature. After 16 h, the mixture was shaken with 200 ml of 0.5N. NA. The CH.C Pj J fraction is washed with up to 20 ml of 0.5 ml of 0.5 NHC, then 2-200 MP of 0.5 n. NaOH, and finally - 200 ml of HjO CHgCfg. The fraction is dried MgSO 5 is treated with activated carbon and filtered through
    25 (Celite. The filtrate is concentrated on a rotary evaporator (finally under a high vacuum). The yield of the final product, which is a light orange oily substance
    It is 11.93 g (88%), TLC (2. 1 hexane - Et OAc) shows one spot, and the IR spectrum corresponds to the compound of a given structure. After aging for several days, the unused portion of this product crystallizes, mp. 52 - 65 p.
    Stage B; treg-butyl. 2- (252-dimethylcyclopropancano-bromide) -2-methoxyhexanoate.
    To a solution of 6.37 g (22.5 mmol) of N- (2, 2 dimethylcyclopropanacarbonyl) -DZ-: -norleucine t-butyl ester) in 35 ml, stirred at room temperature under a nitrogen atmosphere in the absence of light, add 2 , 69 t-tn (2.45 g, 22.5 mmol) of tr8T-butyl 1 hypochlorite.
    After 15 minutes, a solution of sodium methoxide was added, obtained by dissolving 0.52 g (22.6 mmol) of sodium in 35 MP MeOI. Stirring is continued at room temperature under a nitrogen atmosphere, in the absence of light. After 16.5 hours, the sodium chloride quenched in sediment is filtered off. The filtrate is diluted and washed successively with 3-50 ml, 0, 5 Houns B, 50 ml of saturated NajCOj
    312
    and 2-50 ml of water. dried over MgSO4. and filtered. The filtrate is evaporated on a rotary evaporator. A pale, golden yellow oil (6.45 g) was subjected to high pressure preparative liquid chromatography, with the result that two diastereomers of 273 each were isolated and 496 mg of tert-butyl were isolated; 2- - (2,2-dimethylcyclopropanecarboxamo-) -2-methoxyhexanoate (corresponding to mp. 114-118 and 124-125.5 ° C), and also 1.97 g of the independent isomer Z-frpeT-butyl 2 - (2,2-dimethyl-c13-klopropan-carboxamido / -2-hexanoate (colorless oil).
    Stage G: 2- (2,2-dimethylcyclopropanecarboxamido) -2-hexenoic acid.
    A solution of 0.84 g (3.0 mmol) of t-butyl 2- (2,2-dimethylcyclopropane-carboxamido) -2-hexenoate in 10 ml of Et20, saturated with anhydrous HC1, is kept at room temperature under a drying tube. After 17 hours, the solution is evaporated and the remaining mass is dissolved in 10 ml of saturated .NaHCO. This solution is washed with an additional 15 ml of 0.5 H.HCt, then dried (MgSO4), filtered and evaporated, resulting in a viscous oil, which is recrystallized from toluene. The yield of white crystals is 0.32 g (47%). M.p. 119-122 ° C, TEX (4: 1 toluene - AcOH) shows one spot. The NMR spectrum confirms the formation of practically pure Z-isomer (with
    ,
    z
    sn
    CH,
    sn.
    CH,
    :
    SNG
    sn
    ..,
    CH
    CHj
    834
    treating the methanol adduct with tert-butyl 2- (2,2-dimethylcycloprocar-carboxamido) -2-methoxyhexenoate with anhydrous HCf in EtjO medium in the same way, the same product is formed.
    Example 2 (illustrates the activity). . The results of the experiment in vitro.
    Use 1 ml of the system 50 pM MOPS buffer, pH 7.1. To this is added 5 g of porcine renal enzyme and such an amount of the compound tested that its final concentration is 0.1 mM. After 5 min of thermostating at 37 ° C, such an amount of GDF (glycerol hydrophenylalanine) is added) such that its final concentration is 0.05 mM. The system is again thermostatic at 37 ° C for 10 minutes. Hydrolysis of HDP is determined by the change in its optical density with time at 275 nm. Enzyme inhibition is determined by comparison with the results of a control experiment conducted in the absence of an inhibitor, and expressed as a percentage of inhibition. TO; is a value indicating the inhibitor concentration necessary to achieve 50% inhibition of the enzyme. This is a calculated value resulting from several tests carried out as described above, at concentrations leading to inhibition below or above the 50% inhibition point. The results obtained are presented in tabl; c.
    0.18 0.89 0.12 19.8
    Table continuation
    权利要求:
    Claims (1)
    [1]
    METHOD FOR PRODUCING-Z-2-Acyl-
    Amino-3-monosubstituted propenoates of the general formula
    P
    C / h R 2 CONH COORi where R, is hydrogen;
    R 2 is cyclopropane substituted with lower alkyl;
    R - lower alkyl, characterized in that the acid chloride of the General formula
    ABOUT
    B 2 -C-C1.
    react with tert-butyl ester of << · -amino acid
    H I
    In 3- CH , -C-COO-C (CH3) s nh 2 where R 2 and R 3 have the indicated meanings, © in the presence of a base followed by oxidative addition of sodium methoxide and treatment of the resulting intermediate with anhydrous hydrochloric acid.
    Priority by signs:
    07.24.78 when R <is hydrogen, R 2 cyclopropane substituted by lower alkyl, R lower alkyl;
    06/22/79 at R ( is hydrogen, R a is cyclopropane substituted with lower alkyl, Rj is lower alkyl.
    996SHG , 10 ^>.
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