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    • 专利摘要:
    A substantially (>/=95%) optically pure (5R,6S,1 min R) penem of formula <CHEM> and the pharmaceutically acceptable salts and the ester prodrugs thereof, are endowed with antibacterial activity.
    公开号:SU1586517A3
    申请号:SU884355870
    申请日:1988-06-09
    公开日:1990-08-15
    发明作者:Альпеджиани Марко；Франчески Джованни；Перронэ Этторе；Зарини Франко；Дэлла Бруна Константино
    申请人:Фармиталиа Карло Эрба С.Р.Л.(Фирма)；
    IPC主号:
    专利说明:

    This invention relates to a method for producing new optically pure stereoisomers of penem antibiotics, namely, optically pure (5R, 6S) -6
    s
    - 1 (R) -hydroxyethyl 2-methoxymethyl foam-3-carboxylic acid or its -. esters, or its salts with alkali metals with a basic substance content of not less than 95%, which may be used as anti-bacterial agents in the treatment of infectious diseases in humans and mammals.
    The chain of the invention is the production of new optically pure antibiotics. strap series with higher antibacterial activity.
    Example 1. Allyl (5R, 6S) -6- O (-t-butyldimethylsiloxyethyl J- -2-methoxymethylpenene-3-carboxylate.
    727 mg of (3S, 4R) - 1-C1- (allyloxycarbonyl) -1- (triphenylphosphoranylidene) -megine, 3- Cl (R) -tre. butyldimethylsilyloxy-1sethyl-4- (argentotio) -azetidin-2-one is dissolved in 20 ml of dry and treated with 110 µl of methoxyacetylchloride. After stirring for 10 minutes. At room temperature, the reaction mixture is diluted with ethyl acetate {filtered over celite, washed with 5% aqueous sodium hydrogen carbonate solution, and then twice with brine. After extracting the solvent in vacuo, the residue is dissolved in 150 ml of toluene and maintained at reflux temperature for 90 minutes. The solution is concentrated under reduced pressure as well. then under: they chromatographically treated: on silica gel 230-400 mesh (0.046–0.027 mm) using a mixture of cyclohexane and ethyl acetate in a ratio of 80:20 as eluent, resulting in a yellowish, oil-like appearance. substances receive 360 mg of the product specified in the title of the example (yield 87%).
    IR spectrum (chloroform),): 1785, 1700 cm-.
    NMR spectrum (90 MHz, CBC): 0.09 (6H, s); 0.89 (9H, s.); 1.26 (3N, d, 6.5 Hz); 3.39 (ZN, p.); 3.67 (1H, DD, less than 2 and 7 Hz); 4.23 (1H, m.); 4.5-4.8 (4H, m.); 5.0-5.5 (2H, m.); 5.55-6.05 (1H, m.).
    PRI mme R 2. Allyl (5R, 6S) -6- -D (K) -hydroxyethyl} -2-methoxymethyl- penm-3-carboxylate.
    A solution of 360 mg of allyl (5R, 6S) -6- (I) -treated, butyldimethylsilyloxyethyl -2-methoxymethylpenem-3-carboxylate in 6v ml of dry tetrahydrofuran is treated successively with 0.6 ml of acetic acid and tetrabutyl ammonia trihydrate ammonia ammonia with simultaneous mixing. The solution is allowed to stand overnight at room temperature, then it is concentrated to a small volume and subjected to chromatography on silica gel using a mixture of cyclohexane and ethyl acetate in a ratio of 1: 1 as eluent, resulting in 250 g of product in the form of a white powder, specified in the title of the example.
    UV spectrum (chloroform), (326 nm.
    Example 3. Allyl (5R. 6S) -6- - 1 (K) -hydroxyethyl -2-methoxymethyl- penem-3-carboxylate.
    A solution of 6.1 g of (3S, 4H) -1-C1- (allyloxycarbonyl) -1- (triphenylphosphoranylidene) -methyl -3-C1 (R) -hydroxyethyl-4- (argentothio) -azetidin-2-one 250 ml of dry acetonitrile are treated with 1.2 ml of methoxyacetyl chloride at a temperature, and then stirring is continued for 15 minutes at. Ethyl acetate is added and the resulting mixture is filtered through Celite. The organic phase is washed with an aqueous solution of sodium hydrogencarbonate, dried over sodium sulfate and concentrated. As a result of thin-layer chromatographic processing of the residue on silica gel 230-400 mesh (0.046-i, using mixtures of hexane and ethyl acetate as eluent as a yellowish foam-like material, 4.2 g of (3S, 4R) -1-C1- (allyl-oxo-base ) - 1- (triphenylphosphoranylidene) -methyl2-3-C1 (R) -hydroxyethyl 3-4- - (methoxyacetylthio) -azetidin-2-one.
    The product obtained from the above was dissolved in 250 ml of toluene and the solution was heated under reflux for 2 hours. After cooling and removal of the solvent, the residue was purified by chromatography on silica gel using mixtures of cyclohexane and ethyl acetate as eluent, resulting in what get 2.5 g of the product, vvde white powder specified in the title of the example.
    IR spectrum (potassium bromide), -J: 1775, 1705 cm-
    UV spectrum (e-tanol), L „“ ks 326 m.
    EXAMPLE 4. Allyl (5R, 6S) -6- - 1 (R) -hydroxyethyl -2-methoxymethyl-pemen-3-carboxylic acid, sodium salt.
    4.17 (1H, m.); 4.47 and 4.73 (2H, two D., 16 Hz); 5.58 (1H, d., Less than 2 Hz); 5,82 (center LVR).
    II R and measure 6. (5-Methyl-2-oxo-1,
     15865176
    2.3 g allyl (5K, b8) -6-C1 (K) -hydr-Ya-spectrum (CDC1, 90 MHz) with / rox “ethyl 2-megoxymethyl-3-kar-1.33 (ZN, d. 6.5 Hz; 2J2 W with) the boxylate is dissolved in 60. dry 2.3 (1H, s., exch D, 0. 3 Ze sZN tetrahydrofuran, and then the solution last) 3 71 dH pp / g h
    Consequently, 1.05 g of ethyl- / - 2 "6.5 Hz):
    sodium hexane anoate, 300 mg triphenylphosphine and 100 mg tetrakis (triphenylphosphine) palladium (0). Stirring is continued for 30 minutes, after which, ". P p 6. (5-Methyl-2-oxo-1, thin-layer chromatographic ana-3-lyoxolen-4-yl) -methyl (5R, 6S-6lys) showed a complete absence of outcome-1 and K) -hydroxyethyl-2-methoxymethyl material. 40 ml of dipen-3-carboxylate are added.
    ethyl ether and the precipitate is separated
    by centrifugation. Raw material with i sodium salt. (5R,
     J b; -b- | 1 (K) -hydroxyethyl J-2-methoxy-. methylpenem-3-carboxylic acid in 3 MP of dry DMF is treated with 180 mg (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl bromide and stirred at room temperature for 2 hours. The reaction mixture is poured in a mixture of ethyl acetate and water, the organic phase; washed twice with water and then dried and concentrated in vacuo .. As a result of treating the residue with diisoproxy ether, 240 mg of white crystals are obtained
    dissolved in the minimum amount of water and purified back by phase chromatographic processing using a Lichroprep ® K, PC-18 Merck and water, and then a mixture of water and acetone as eluents, the fractions containing the product being collected and subjected to freeze-drying to obtain 1 , 8 g of the product indicated in the title of the example, in the form of a white powder „
    IR spectrum (potassium bromide),%): 1755,
    1600, 1575 CM-V
    UV spectrum (water),.: 258 nm (g 4044); 306 nm (6076).
    NMR spectrum (200 MHz,) cG: 1.30 (d, 6.3 Hz); 3.38 (ZN, p.); 3.91 (1H, d, d, 1.6, and 6.0 Hz); 4.25 (1H, m.); 4.48 and 4.79 (2H, dd, 14.0 Hz); 5.66 (1K, d., 1.6 Hz),
    GG p and m e r 5. Acetoxymethyl (5R, 6S) (K) -hydroxyethyl -2-methoxymethylpenem-3-carboxylate.
    258 mg of sodium salt (5R, 6S) -6lov. |
    thirty
    UV spectrum (chloroform),. ; 326 nm.
    NK-spectrum (KVg), l): 3450, 1820 1780, 1725, 1710 cmЛ
    NMR spectrum (COCl3, 50 MHz), J-1.32 (3N, d, 6.5 Hz); 2.17 (ZN, p.); 2.37 (1H, broadband, exch I), 0); 3.38 (35N); 3.69 (1H, dd, less than 2 .and 6.5 Hz); 4.20 (1H, “.); 4.43 and 4.70 (2H, d two, 16 Hz); 4.93 (2H, s.); 5.60 (1H, d, less than 2 Hz).
    r1CD, Example 7. (5-Methyl-2-oxo-1
    -1and C) -hydroxyethyl 2-methoxymethyl-40H-dioxolen-4-yl) -methyl (5R 6S) -6- penem-3 -carboxylic acid in 3 kp su-1 (U-hydroxyeth. ; simetilpenem-Z-carboxylate,
    Stage A. In a stirred solution
    TeMoeoaTvnP p. - -Z-GCC-trimethylsily
    temperature After separation of Mevda with 45-oxyethyl-4-methoxy-acetylthioazethyl compounds of ethyl acetate and 2% vodnogodin-2-one in 35 ™ dry talgppi
    a solution of sodium bicarbonate organic-C is added 1.8 trieth ° C
    phase two, washed with brine, after which 2–7 g
    vacuum "(5-methyl-2-oxo-1, 3-diox G4-yl) -
    vacuum. As a result of the addition of di-50-methyl oxalylporide in 10 ml of toluene of isopropyl ether to the crude product.
    for 15 min at room temperature, and then washed with water, with a 5% aqueous solution of sodium bicarbonate and again with water. After drying over sodium sulfate, the organic solution is concentrated to a residual volume of 2 MP. Add 4 mp of triethyl phosphite and the solution is boiled with reflux -. Ini l1 I DJ D .J MJ1 L,
    XOHO DMF is treated with 145 mg of acetoxymethyl bromide at and then stirred for 2 hours at room temperature.
     - -j.- - fi. h. f-U -C
    receive thorn precipitate, which is from-. filtered and dried to obtain 220 mg of product.
    IR spectrum (potassium bromide): 3590 1780, 1765, 1715, 1580 cm
    H27 nm °, 17 (1H, m.); 4.47 and 4.73 (2H, two D., 16 Hz); 5.58 (1H, d., Less than 2 Hz); 5,82 (center LVR).
    II R and measure 6. (5-Methyl-2-oxo-1,
     / - 2 „6.5 Hz):
     . P p 6. (5-Methyl-2-oxo-1, 3-lioxolen-4-yl) -methyl (5R, J.
    20
    25
    fishing |
    thirty
    NICOM for 5 hours. The mixture is then cooled to room temperature and then washed three times with water, followed by drying with sodium sulfate. As a result of the removal of the solvent and chromatographic treatment of the residue over silica gel, using a mixture of n-hexane and ethyl acetate as colorless butter material, get 2.9 g of (5-methyl-2- -oxo-1,3-dioxolen-4-yl) -methyl (5R, 6S) -6-.1 (K) -trimethylsilyloxyiztil -2- methoxymethyl) -3-carboxylate.
    Step B, The indicated product is dissolved in 160 ml of 95% ethanol and 2 ml of acetic acid is added to the solution. After stirring for 1 hour at room temperature, the mixture is concentrated in vacuo to dryness. By adding 50 ml of diisopropyl ether, white crystals are obtained which are filtered and dried (20.0 g).
    UV spectrum (chloroform), 326 nm „
    IR (potassium bromide), -0: 3450 1820, 1780, 1725, 1710 and 1580.
    The optical purity of 6- (1-hydroxyethyl) -2-methoxymethylpenem-3-carboxylic acid derivatives, i.e. the content of the isomer (5R, 6S, 1 K) configuration present in the isomeric mixture plays a significant role in the potency, latitude of the spectrum and chemoenzymatic resistance of the product. Thus, when compared with the complex mixture of racemic stereoisomers, sodium salt of an optically pure compound under laboratory conditions is an action that is 8-30 times greater than the effect of the mixture depending on the strain being tested.
    Table 1 shows the antibacterial action in the laboratory of the optical compound (5R, 6S) -6-Cl (R) -hydroxyethyl} -2-methoxymethyl-penem-3-carboxylic acid, sodium salt, and a similar compound as a stereoisomeric mixture, ,
    In comparison with the known racemic mixture, the optically pure compound (5R, 6S, 1 R) configuration obtained by the proposed method also exhibits enhanced stability against bacterial beta-lactamase and renal dehydropeptidases And a significantly higher chemical resistance over the entire range of values pH
    These detected properties were confirmed in vivo experiments.
    In tab. Figure 2 shows the therapeutic effect against experimental infections in mice with optically cleansing (5R, 6S) -6-Cl (R) -hydroxyethyl J-2-methoxymethyl-3-carboxylic acid as sodium salt (compound I) and as (5 -methyl-2-oxo-1,3-dioxolene-4-yl) methyl ester (compound 2).
    Indeed, the sodium salt of the compound of formula (1) is extremely effective in control experiments and in experiments on the treatment of infectious diseases of mice infected by gram-positive and gram-negative bacteria. Under the same experimental conditions, a known racemic mixture does not show any useful therapeutic efficacy.
    Depending on the type of information and the condition of the patient suffering from this infectious disease, the daily dose for treating a warm-blooded adult (a human or other mammal) weighing approximately 70 kg is approximately 125 mg to 5 g. the invention
    The method of obtaining optically pure (5R, 6S) -6-Cl (R) -hydroxyethyl-2-methoxymethyl-3-carbonic acid or its esters or its salts with alkali metals with a basic substance content of at least 95% of the general formula
    СН2-о-сНз
    COOR
    where R is a hydrogen, alkali metal, or etherification group, characterized in that the compound of the general formula
    COOR,
    where A is oxygen or triphenylphosphory-:
    liden; Pg - hydrogen or three (lower alkyl)
    silyl protecting group; the esterifying group or ester protecting group is cyclized at boiling point in an inert organic solvent and, possibly, in the presence of triethyl or trimethylphosphate and, if necessary, removing the ester protecting group with chain product in as a free acid or its alkali metal salt, or the desired product in the form of a free acid or its alkali metal salt is exposed to a compound of the general formula
    R, -Hal,
    where K 2 is etherification carbonic
    acid group; Hal - halogen, to obtain the target product in the form
    its ester.
    Staphylococcus aureus Smith
    S. aureus 39/2 Peh
    S aureus .2MR
    S.aureus 2101 MR
    S.aureus 5635 MR
    S.epidermidis ATCC 122
    Streptococcus pyogenes
    ATCC 12384
    S.salivarius ATCC 9758 S.faecalis ATCC 6057 S.faecalis 55 S.faecium ATCC 8043
    Escherichia coli K12
    E. coli R6K (TEM I)
    E. coli RP1 (TEM 2)
    E. coli P453 (SHV-1)
    E.cfflli R997 (HSM-1)
    E. coli RGN 238 (OXA-1)
    E. coli R46 (OXA-2)
    E. coli R57b (OXA-3) E. coli b
    E.coli B cef R
    Salmonella typhi atcc
    14028
    Shigella flexneri ATCC 11836 Klebsiella aerogenes
    1522E
    K. Aerogenes 1082E. cef.
    Enterobacter cloacae 132
    E.cloacae P99 cef.R
    E.aerogenes F 46
    E.aerogenes 225
    Table 1

    0.78 6.25
    25
    25 3.12 1.56


    6.25 1.56
    3.12 6.25 3, .12 6.25
    12.5
    25
    158651712
    Continued table. one
    Microorganism
    Citrobacter freundii
    ATCC 80900,393,12
    C.freundii 4051 cef.R6, I Serratia marcescens
    I ATCC 2902 .6,25 25 i Acinetobacter ealcolaj ceticus Bg 31,
    I A.calcolaceticus N 4096,
    I Proteus mirabilis FI 74740,7812,5
    I P. rettgeri ATCC 925 1,
    I P.morganii ATCC 258301,
    I P. vulgaris 510,396,25
    i Providencia stuattii Bs 603,; Pseudomonas aeruginosa
     2598. . 25
    : P. aeruginosa ATCC 19660 25 25
    ----- ---. . . ..y, .... , iiu-m
    I.,.:.
    ITABLE2
    Infections; and Terapi U (mg / kg, kuplos mutive dose)
    infection -
    , Connection— Connection 1 2
      - - - ------ - - - - - - --- J ™, ™. "..And, and
    Staphylococcus
    aureus Smith 2 0.21, Eschevichia
    , 5-1,5-6 6,7 13,1
    Subcutaneous administration. . Caroral administration.
    Compiled by 3. Latypova Editor M. Petrova Tehred L. Serdyukova Proofreader T. Malets
    Order 2333 Circulation 325Subscribe
    VNIIPI of the State Committee for Inventions and Discoveries under the State Committee on Science and Technology of the USSR 113035, Moscow, Zh-35, Raushsk nyb., 4/5
    Production and publishing plant Patent, Uzhgorod, st. Gagarin, 101
    Content, mcg / ml

    Stereoisomeric
    mixture
    权利要求:
    Claims (1)
    [1]
    Claim
    A method for the preparation of optically pure (5R, 6S) —6— (1 (R) -hydroxyethylJ-2-methoxymethylpenem-3-carbonic acid or its esters, or its salts with alkali metals with a basic substance content of at least 95% of the general formula where R is hydrogen, an alkali metal or an esterifying group, except that the compound of the general formula
    Org ο Λ-Νψ:
    COOR t where A is oxygen or triphenylphosphorylidene;
    Pg is hydrogen or a tri (lower alkyl) silyl protecting group; $
    R is an esterifying group or an ester protecting group, is subjected to cyclization at the boiling point in an inert organic solvent jq and, possibly, in the presence of triethyl or trimethylphosphate and, if necessary, the ester protecting group is removed with more than 1 ° of the desired product in the form a free acid or an alkali metal salt thereof, or the target product in the form of a free acid or an alkali metal salt thereof is exposed to a compound of the general formula
    R 2 -Hal, where R j is a carboxylic acid esterifying group;
    Hal is a halogen, to obtain the target product in the form of its ester.
    Table 1
    MicroorganismContent, mcg / ml5R, 6S, 1 'R-isomer Stereoisomeric mixture
    Staphylococcus aureus Smith 0.09 0.78 S. aureus 39/2 Peh ' 1 ' 0.09 6.25 S.aureus 2MR 3, 12 > 25 S.aureus 2101 MR 3.12. > 25 S.aureus 5635 MR 0.19 3, 12 S.epitiermidis ATCC 12228 0.09 1,56 Streptococcus pyogenesATCC 12384 0,022 0.39 S. salivarius ATCC 9758 0,022 0.19 S.faecalis ATCC 6057 1,56 > 25 S.faecalis 55 3.12 > 25 S.faecium ATCC 8043 3.12 > 25 Escherichia coli K12 0.39 6.25 E.coli R6K (TEM I) 0.39 12.5 E.coli RP1 (TEM 2) 0.78 25 E.coli P453 (SHV-1) 0.39 6.25 E.coli R997 (HSM-1) 0.39 6.25 E.coli RGN 238 (0XA-1) 0.78 12.5 E.coli R46 (OXA-2) 0.39 12.5 E.coli R57b (OXA-3) 0.39 6.25 E.coli B 0.39 6.25 E.coli B cef R 0.78 > 25 Salmonella typhi ATCC14028 0.39 6.25 Shigella flexneriATCC 11836 0.19 1,56 Klebsiella aerogenes1522E 0.39 3.12 K. Aerogenes 1082E. cef.R 0.39 6.25 Enterobacter cloacae'1321E 0.39 3.12 E.cloacae P99 cef.R 0.39 6.25 E.aerogenes F 46 0.78 12.5 E.aerogenes 225 0.78 25
    - eleven
    Continuation of the table. 1
    Microorganismh Content, mcg / ml 5R, 6S, 1 'R-isomer Stereoisomeric mixture Citrobacter freundii- ATCC 8090 0.39 3.12 C.freundii 4051 cef.R 6.25 > 25 Serratia marcescensATCC 2902 6.25 > 25 Acinetobacter ealcola-ceticus bg 3 1,56 > 25 A.calcolaceticus N 409 6.25 > 25. Proteus mirabilis FI 7474 0.78 12.5 P. rettgeri ATCC 925  1,56 > 25 P.morganii ATCC 25830 1,56 > 25 P. vulgaris 51 0.39 6.25 Providencia stuattii bs 60 3.12 > 25 Pseudomonas aeruginosa2598 > 25 > 25 P. aeruginosa ATCC 19660 > 25 > 25
    table 2
    Infection Therapy after infection, h IU 5c (mg / kg, cumulative dose) Connection 1 * Connection 2 * * Staphylococcus aureus Smith 2 0.21 - Eshevichia coli g 0.5-1.5-6 6.7 13.1
    Subcutaneous administration. Oral administration.
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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
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    EP0233155A1|1986-02-14|1987-08-19|Ciba-Geigy Ag|Aminoacyloxymethyl compounds|
    GB8624686D0|1986-10-15|1986-11-19|Erba Farmitalia|Preparing penems|
    JPH01207387A|1988-02-15|1989-08-21|Res Assoc Util Of Light Oil|Production of hydrocarbon|US5416208A|1989-07-05|1995-05-16|Farmitalia Carlo Erba S R L|Process for penems|
    GB8915392D0|1989-07-05|1989-08-23|Erba Carlo Spa|Process for penems|
    PL169584B1|1990-08-20|1996-08-30|Suntory Ltd|Method of obtaining novel penemic esters|
    DE69131774T2|1990-08-20|2000-06-21|Suntory Limited Osaka|ANTIBACTERIAL PENEM ESTER DERIVATIVES|
    JP3148235B2|1990-08-20|2001-03-19|サントリー株式会社|Antibacterial penem compounds|
    GB9210371D0|1992-05-14|1992-07-01|Erba Carlo Spa|Hydroxy protecting group removal in penems|
    US5399679A|1992-06-16|1995-03-21|Farmitalia Carlo Erba S.R.L.|4-acylthio azetidinones|
    GB9216102D0|1992-07-29|1992-09-09|Smithkline Beecham Plc|Pharmaceutical substances|
    PE20080940A1|2006-06-28|2008-07-09|Pfizer Prod Inc|PENEM DRUGS|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    GB878713515A|GB8713515D0|1987-06-10|1987-06-10|Methoxymethyl compounds|
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