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    • 专利摘要:
    Novel esters of pharmacologically active carboxylic acids, which can be cleaved under physiological conditions, in particular of antibiotically active carboxylic acids from the beta -lactam antibiotic field, are described, which are characterised in that the alcohol component of the ester is a group of the general formula <IMAGE> in which R<1> denotes hydrogen or lower alkyl, R<2> denotes hydrogen, lower alkyl, lower haloalkyl, lower alkenyl, lower alkoxycarbonyl, aryl or heteroaryl or, together with R<1> denotes lower alkylene, R<3> denotes hydrogen, lower alkyl or lower alkoxycarbonyl, R<4> denotes the group -COOR<5>, -COR<6>, -SO2-R<6>, -CONR<7>R<8> or -PO(OR<9>)2, R<5> denotes a saturated or unsaturated hydrocarbon radical having up to 12 carbon atoms, in which up to two methylene groups can be replaced by oxygen atoms, or denotes aryl or aryl-lower alkyl, R<6> denotes lower alkyl or aryl, R<7> and R<8> each denotes hydrogen or lower alkyl or together denotes lower alkylene in which a methylene group can be replaced by an oxygen or sulphur atom or by an imino or lower alkylimino group, and R<9> denotes lower alkyl. If a basic substituent is present, these esters can also be present in the form of pharmaceutically acceptable acid addition salts.
    公开号:SU1598880A3
    申请号:SU884356966
    申请日:1988-11-23
    公开日:1990-10-07
    发明作者:Фурленмейер Андре；ХУБШВЕРЛЕН Кристиан；Монтавон Марк
    申请人:Ф.Хоффманн-Ля Рош Унд Ко.Аг (Фирма)；
    IPC主号:
    专利说明:

    (21) 4356966 / 23-04 1 (22) 11/23/88
    (31) 4570/87; 3165/88
    (32) 11/24/87; 08/25/88
    (33) CH
    (46) 10/07/90. Bul Number 37
    (71) F.Hoffmann-L Rosh und Ko.AH (CH)
    (72) Andre Furlenmeyer (CH), Christian Hubschverlen (pR) and Mark Montavon (CH)
    (53) 547.869.1.07 (088.8)
    (56) Swiss Patent No. 643558, Cl, C 07 D 501/20, published. 1984
    Patent SICHA No. 4427674, cl. 424-246, published. 1984
    Patent CUJA h 4614819, cl. 540-222, pub. 1986
    (54) METHOD FOR OBTAINING COMPLEX ETHERS OF CEFALOSPORINES OR THEIR PHARMACEUTICAL APPLICATIONS OF SALTS WITH ACIDS
    (57) The invention relates to cephalosporin esters, in particular compounds of the general f-ly
    RlNH-C (... H) - (.: (... H) -S-CH2.
    about сNс (: 2
    R R5C CR5 CHR3-0- (
    where R, is H, thienyl-acetyl, 7C (0) -CR N-0-Rj at RT is furyl-2 or 2-aminothiazolyl-4, and Rj is lower alkyl; R is H or, if appropriate, a substituted acetoxy, carbamoyloxy, azido, or 5-methyl-2H-tetrazol-2-yl-methyl group; - H, lower alkyl; R H, lower alkyl, haloalkyl, alkenyl, alkoxycarbonyl or 5-halo-2furyl-2 or (Rj + R) - lower alkylen; R S- H or lower alkyl or alkoxycarbonyl; RgC (0) -ORj, -C (0) -R, o, -C (0) -NR ,, or -Р (О) - () with R 3 - Н- or branched alkyl from C to 10. c to which up to two methylenic groups can be replaced by oxygen, or RJ alkenyl or alkdienyl from C to 10 each, C5-C7-cycloalkyl or. Su-C-cycloalkyl-lower alkyl, nitrophenyl, tetralhydropyranyl or tetrahydropyranyl-lower alkyl; R, 0 is lower alkyl; (R) is lower alkylene; R, 3 lower alkyl, or in the presence of the main substitute of their pharmaceutically applicable salts with acids, which can be used in medicine as antimicrobial substances. The goal is to create new, more active substances of the specified class. Synthesis is carried out by the reaction of etherification of the corresponding acid with a compound of f-ly R5CX-CR CR R J, where X is OH or a leaving group, R is higher. If necessary, the resulting compound, where R, is H, is reacted with acid f-ly R f4 - OH, where Ry R, j except hydrogen, or the resulting ester can be transferred to F1) a macologically applicable salt with an acid. According to this method. predominantly receive (E) -2- (isobutyroxybonyl) -2-pentenyl- (6R, 7R) -7-C (2) -2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetamido3-3- (azidomethyl) -8-oxo-5-thia-1-azabicyclo 4,2,0 JOKT-2-en-2-carboxylate. New compounds have low toxicity (mg / kg). an effective dose of 0.28 mg / kg (oral) for the indicated compound. 3 hp f-ly, 1 tab.
    with "
    cl
    ate
    with
    00 00 X

    cm
    This invention relates to a process for the preparation of new esters of cephalosporins or their pharmaceutically applicable salts with acids, which can be used in medicine as antimicrobial agents.
    The aim of the invention is to obtain new antibiotics of the cephalosporic series, which have lower efficacy due to their ability to decompose under physiological conditions.
    Example 1. 1 g of the sodium salt (6R, 7K) -7-G (2) -2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetamido-3-methyl-8-oxo -5-thia-1-azabicyclo C, 2.0 J oct-2-en-2-carboxylic acid is dissolved in 20 ml of dimethylformamide, cooled to and mixed with 0.7 g of methyl bromomethyl acrylic acid. After 2 hours, 80 ml of water was added to the solution and extracted with 200 ml of ethyl acetate. The organic phase is washed three times with water in 50 ml portions, dried over magnesium sulphate and evaporated to a volume of 20 ml. With stirring, 100 mp of ether is added, the precipitated product is filtered off with suction and dried in vacuo at room temperature. 2- (ethoxycarbonyl) allyl- (611, 7R) -7- (7.) - 2- (2-amino-4-thiazol1) -2- (methoxyimino) acetamido 3-3-methyl-8-oxo are obtained. -5-thia-1-azabicyclo C4, 2.0 oct-2-en-2-carboxylate in the form of a white solid (from ethyl acetate / ether mixture).
    Found,%: C 46.82; H 4.64; N 13.50; S 12.38.
    , (509,552)
    Calculated,%: C 47.14; H 4.55; N 13.74; S 12,58.
    2- (ethoxycarbonyl) allyl- (6R, 7R) - .7- (g) -2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetamido -3- (5-methyl-2H tetraz, ol-2-yl) methyl-8-oxo-5-thia-1-azabicyclo 4,2.0 oct-2-en-2-carboxy lat is obtained as a white solid (from ethyl acetate / ether mixture).
    Found,%: 44.39; H 4.45; . N 21.05; S 10.79.
    Ci HjyNgOjS (591.62). , Calculated,%: C 44.66; H 4.26; N 21.31; S 10.84.
    2- (Ethoxycarbonyl) aryl- (6R, 7R) - 3- (carbamoyloxy) methyl-7-C (g) -2- (2 furyl) -2- (methoxyimino) acetamido 3-8-oxo-5-thia- 1-azabicyclo 4,2, 2-en-2-carboxylate as white
    solids (from ethyl acetate / isopropyl ether) -.
    Found,%: C 49.46; H 4.80; N 10.24; S 5.84.
    C2, (536.521).
    Calculated,%: C 49.25; H 4.51; N 10.44; S 5.98.
    Example 2. 2g sodium salt of (6R, 7R) -7- (2) -2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetamido 3-3-methyl-8-oxo-5- thia-1-azabicyclo C4,2,0 oct-2-en-2-carboxylic acid is dissolved in 40 ml of dimethylformamide, cooled to 0 ° C and mixed with 1.58 g (i-bromomethyl acrylic acid with tert-butyl ester After 5 hours, 200 ml of water are added to the solution and extracted with 350 ml of ethyl acetate. The organic phase is washed three times with water in 100 ml portions, dried over magnesium sulfate and evaporated to a volume of 20 ml. With stirring, 250 ml of isopropyl ether are added. The precipitated product is suction. are filtered and dried at room temperature under vacuum to give 2- (tert-butoxycarbonyl) allyl- (6K, 7R) -7- (Z) -2- (2-amino-4-thiazolyl) -2 - (methoxyimino) acetamido J-3-methyl-8-oxo-5-thia-1-azabicyclo 4,2,0 oct-2-en-2-carboxylate as a white solid (from ethyl acetate / isopropyl ether .).
    Found,%: C 48.78; H 5.14; N 13.03; S 12.15.
     (537.61) Calculated,%: C 49, .15; And 5.06; N 13.03; S 11.93.
    2- (tert-Butoxycarbonyl) allyl- (6R, 7R) -7- (g) -2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetamido -3- (azidomethyl) -8- Oxo-5-thia-1-azabicyclo 4,2.0 oct-2-en-2-carboxylate is obtained as a beige solid (from a mixture of ethyl acetate / isopropyl ether).
    Found,%: C 45.87; H 4.63; N 18.93; S 10.83.
    C, H,; jNjO S (578.63)
    Calculated,%: C 45.67; , 52; N 19.36; S 11.08.
    2- (tert-Butoxycarbonyl) allyl- (6R 7R) -7- (g) -2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetamido 3- C (5-methyl-2H-tetrazole- 2-yl) methyl-8-oxo-5-thia-1-azabicyclo 4,2.0 oct-2-en-2-carboxylate is obtained as a white solid (from mixture of ethyl acetate / / isopropyl ether).
    Found%: C 46,33 | H, 20.12; S 10.60. ,, NjO.S 2 (619,683).
    15988
    15
    20
    25
    Calculated,%: C 46.52; H 4.72j N 20.39; S 10,35.5
    2- (tert-Butoxycarbonyl) allyl (6R, 7K) -3-C (carbamoyloxy) methyl-7-G (7) -2- (2-furyl) -2- (methoxyimino) .a1; etamido-8-oxo -5-tna-1-azabicyclo G4,2,0 JoKT-2-1 Q en-2-carboxylate is obtained as a white solid (from ethyl acetate / petroleum ether).
    Found,%: C 51, 19; H 5.16j N 9.55; S 5.47.
     (564,576) (0.25 mol of ethyl acetate).
    Imported,%: C 51.06; H 5.00: N 9.92; S 5.68.
    Froze A solution of 2.5 mmol of an alkali metal salt of an active as an antibiotic carboxylic acid from the group of antibiotics of p-lactam in 20 ml of dry dimethylformamide when cooled with ice water. 2.7 mmol of the corresponding hapogenide in 2 ml of dry dimethylformamide, cooling {{bath) The resulting solution is removed and stirred overnight at approximately. The solution is then diluted with 30 ml of 100 ml of ethyl acetate and extracted three times with water in 50 ml portions and once with 50 ml of sodium chloride solution. The organic phase is dried over magnesium sulphate, filtered, 5 s and evaporated. The residue is quickly chromatographed over a short column of silica gel, eluted with ethyl acetate / hexane (8: 2). The separated fractions are combined and evaporated. A solution of the residue is added in 2 MP of methylene chloride, then added dropwise to 300 ml of a mixture of ethyl acetate and hexane (1: 1). The semi-crystalline α-crystals are filtered and matched under reduced pressure.
    (E) -2- (ethoxycarbonyl) -2-butenyl- (6R, 7K) -7-C (g) -2- (2-amino-4-thiazoyl) -2- (methoxyimino) acetamido J-3 -methyl-8-oxo-5-thia-1-azabicyclo 4,2.0 kt-2-en-2-carboxylate is obtained in the form of a colorless solid (from ethylene chloride / ether).
    Found%: c 47i-90: H 4.97: 13.26; S 12.23. , 1 (523.55). Calculated,% :. G 48.17; H 4.81: 13.28; S 12.25.
    (E) -2- (t-Butoxycarbonyl) -2-buenyl- (BK, 7R) -7- (g) -2- (2-amino-4-.
    40
    45
    50
    55 to ka ef
    15
    20
    25
    five
    , - - 2-1 Q -
    - 30, 5
    40
    45
    50
    Thiazolyl) -2- (methoxyimino) acetamido-J-3-methyl-8-oxo-5-thia-1-azabicycloG4, 2.07 oct-2-ene-2-carboxstat, is obtained as a colorless solid,
    Found,%: C 49.89; H 5.39; N 12.60; S 12.69.
    Cjs., (551.61).
    Calculated,%: C 50.08; H 5.30; N 12.70; S 11.62.
    (E) -2 (Isobutoxycarbonsh1) -2-butenyl- (BK, 7K) -7- (g) -2- (2-amcnr-4-thiazolyl) -2- (methoxyimino) acetamidoJ-3- - Methyl-8-oco-5-thia-1-azabicyclo4, 2, oct-2-en-2-carbox1-shat as a colorless solid (ester / methylene chloride).
    Mass spectrum: protonated molecular ion at m / e 552.
    (E) -2- (2-Ethoxyethoxy) carbonyl T-2-butenyl- (BK, 7R) -7-f (Z) -2- (2-aMHHO-4-thiazolyl) -2- (methoxyimino) a e -rat-ai- doZ-3-methyl-8-oxo-5-thia-1-azabicycles) C4,2, -.2-en-2-carboxylate is obtained as a colorless solid.
    Found,%: C 48.37; H 5.41; N 12.57; S 13.31.
     (567.60). Calculated,%: C 48.67; H 5.15; N 12.34; S It, 30.
    (E) -2- (CZ) -2-Etylhexyloxycarbonyl butenyl- (6H, 7R) -7-r (Z) 2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetamido - 3-methyl-8-oxo-5-thia-1-zazibocyclo 4,2.0 lact-2-ene-2-carboxylate is obtained as a solid.
    Mass spectrum: among others, peak at m / e 368.
    (E) -2- G (RS) -2,3-Dimethoxycarbonyl carbonyl -2-butenyl- (6K, 7R) -7-, () 2- (2-amino-4-thiazolyl) -2- ( methoxyimino) acetamone-8-oxo-5-thia-1-aa-bicyclo; 4,2,0 oct-2-en-carboxes1 get in the form of a colorless solid.
    N-found,%: C 48.00; H 5.40 j 11.40; S 10.38.
    N
    C..Hr ;, N.O.S. (597.65).
    N
    .Il3., G0
    Calculated,%: C, 48.23; H 5.23; 11.72; S 10.73.
    (E) -2-Acetyl-2-butensh1- (6K, 7R) -7- (g) -2- (2-amSh1o-4-thiazolyl) -2- (method-. 5 xyimino) acetamido -3- methyl 8-oxo-5-thia-1-azabicyclo C4,2, oct-2-ene-2-carboxylate is obtained as a yellowish solid (from ether / methylene chloride).
    %: C 48.80; H 5.23;
    Found, N.
     (A93.53). Calculated,%: C 48.67; H 4.70; N 14.19.
    (K8) -2- (Methoxycarbon sh) -2-Cyclohexen-1-yl- (6K, 7U-7- (2) -2- (2-amino-4-thiazolyl) -2- (methoxyimino ) acetamido} -3-methyl-8-oxo-5-thia-1-aza-bicyclo 4,2.0 oct-2-en-2-carboxylate is obtained as a colorless solid (rts of methyl methyl chloride / / ether ).
    Found, -%: C 49.35; H 4.90; N 12.67.
     , (535.60). Calculated,%: C 49.34; H 4.71; N 13.08.
     1-Etsh1-4-metsh1 2-rtC (6R, 7R) -7- C (g) -2- (2-amino-4-thiazolyl) -2- (methoxyimimo) adetamido -3-mp. 8-oxo-5-thia-1-azab 4,2,0 JoKT-2-eng 2-yl carbonyl Methoxy fumarate is obtained as a colorless solid (from methylene chloride / ether mixture).
    Mass spectrum: protonated molecular is) at n / e 568.
    权利要求:
    Claims (4)
    [1]
    1-Etsh1-4-methyl 2-tCCC (6R, 7R) -7-C (g) -2- (2-anino-4-thiazolyl) -2- (methoxyimino) acetamido7-3-methyl-8- oxo-5-thia-1-azabicyclo 4,2 O oct-2-en-2-yl carbonyl oxy} methyl maleate is obtained in the form of a colorless solid (from methylene chloride / ether).
    Mass spectrum: protonated molecular ion at m / e 568.
    (E) -2- (Ztoxycarbonyl) -2-pentench1- (6R, 7R) -7- (Z) -2- (2-aNmHo-4-Tna3o-lil) -2- (methoxyimino) acetamido -3-mv - thyl-8-oxo-5-thia-1-azabicyclo 4,2.0 oct-2-en-2-carboxylate is obtained as a colorless solid (from ether).
    C 48.66; H
    Found,%: N 12.82; S 11.60. C,:,
    (537.58) C 49.15;
    5.15;
    H 5.06;
    Calculated,%: N 13.03; S 11.93.
    2- (p-Nitrophenoxycarbonyl) allyl- (6R, 7K) -7-G (g) -2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetamido-3-methyl-8- Oxo-5-thia-1-azabicyclo C4,2,0 oct-2-en-2-carboxylate is obtained as a yellow solid.
    IR spectrum (KBG), cm--: 1778, 1739 1681 and 1615.
    (K) -2-. C (Tetrahydro-2H-pyran-4-yl oxy carbonyl -2-reKcemui- (6R, 7R) -70
    five
    0
    five
    0
    five
    0
    45
    50
    55
    C (2) -2- (2-amino-4-thiazole1) -2- (methoxyimino) acetamido -3-metsh1-8-oxo-5-thia-1-azabicyclo 4,2.0 oct-2- The ene-2-carboxylate is obtained as a colorless solid (from methylene chloride / hexane).
    Mass spectrum: protonated molecular ion at w / e 608.
    (E) (Tetrahydro-2H-pyran-4-yl) oxy-carbonyl -2-pentenyl- (6R, 7R) -7- t. (Z) -2- (2-amino-4-thiazolyl) -2- ( meth- oxymino) acetamido-3-methyl-8-oco-5-thia-1-azabicyclo 4,2.0 oct-2-en-2-carboxylate is obtained as a colorless solid (from methylene chloride / hexane).
    IR spectrum (KBG), cm-: 1781, 1715, 1683, 1619 and 1534.
    (K) -2- (Tetrahydro-2H-pyran-4-yl) - oxy} carbonyl -2-butenyl- (6K, 7R) -7- (g) -2- (2-amino-4-thiazolin) - 2- (met., Oxyimino) acetamidoZ-8-oxo-5-thia-1-azabicyclo 4,2, Ozoct-2-en-2-carboxylate is obtained as a colorless solid (from ethyl acetate / / hexane) .
    Mass spectrum: protonated molecular ion with m / e 580.
    (K) -2- (Isobutoxycarbonyl) -2-pentenyl- (6R, 7H) -7-C (g) -2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetamidoJ-3- methyl 8-oxo-5-thia-1-azabicyclo C4,2.0 oct-2-ene-2-carboxylate is obtained as a colorless solid.
    Mass spectrum: protonated molecular ion with m / e 566.
    (E) -2-CC (J8) - (Tetrahydro-2H-pyran-27-yl) methoxy carbonyl -2-reKcnDi- (6R, 7R) -7- (Z) -2- (2-amino-4- Thiazolyl) -2- (methoxyimino) acetamido-3-methyl-8-oxo-5-thia-1-azabicyclo 4,2,0 Tact-2-en-2-carboxylate is obtained as a colorless solid.
    Mass spectrum: protonated molecular ion at m / e 622.
    (E) -2-C (RS) -Tetrag, shchro-2H-pyran-2-yl methoxy-carbonylj-2-butenyl- (6R, 7Я) -7- (Е) -2- (2-amino-4 -thiazolyl) -2- (methoxyimino) acetamido 3-3-methyl-y-oxo-5-thia-1-azabicyclo-4,2,0 oct-2-en-2-carboxylate is obtained in B1 a colorless solid (from methylene chloride / hexane). .
    Mass spectrum: Drotonated molecule Ion at w / e 594.
    to
    N
    N
    20
    25
    35
    N
    1598880
    (E) -2-HS (K8) -Tetrahydro-2H-pyran-2-yl} methoxy-carbonylZ-2-pentenyl- (6R, 7K) -7- (7.) - 2- (2-ashsho-4 -thiazolyl) -2- (methoxyimino) acetamido J-3-methyl-8-oxo-5-thia-1-azabicyclo 4,2,0} oct-2-en-2-carboxylate is obtained as colorless solid matter (from hexane).
    IR spectrum (KBG), cm-h: 1781, 1718, 1662 and 1620.
    (E) -2- C (Cyclohexyloxy) carbonyl 3 2-butenyl- (6K, 7K) -7 - (; (2) -2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetamido -3- methyl 8-oxo-5-thia-1-azabicyclo C4,2.0 oct-2-ene-2-carboxylate is obtained as a colorless solid (from ether / hexane).
    Found,%: C, 51.95; H 5.96; 12.04.
    is 577.64).
    Calculated,% :, C 51,98; H 5.41; 12.12.
    (E) -2- (Isotsropoxycarbonyl) -2-benzenyl- (6K, 7U-7-C (2) -2- (2-amino-4-. Thiazolyl) -2- (methoxyimino) acetamidoJ-3- methyl 8-oxo-5-thia-1-azabicyclo 4,2, oct-2-ene-2-carboxylate is obtained as a colorless solid (from ether / hexane mixture).
    Mass spectrum: protonated molecular ion at m / e 538.
    (E) -2- (Cyclohexylmethoxy) carbonyl -2-butenyl- (6K, 7R) -7-G (g) -2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetamido} - 3-methyl-8-oxo-5-thia-1-azabicyclo G4.2.0; / oct-2-en-2-carboxylate is obtained as a colorless solid version (from ethyl acetate / hexane). 40
    Mass spectrum: protonated molecular ion with m / e 592.
    (E) -2-C (3-Methyl-2-butenyl) oxyJ carbonyl} -2-butenyl (6K, 7R) -7- (Z) -2- (2-amino-4-thiazolyl) -2- (methoxyimino) 45 acetamido 7-3-methyl-8-oxo-5-thia-1-. Azabicyclo 4,2,0 oct-2-en-2-carboxylate is obtained as a colorless solid (from ether / pentane).
    my
    ka am ats bi
    N
    N
    Le C 4
    N
    7R) (me ox entswe ef
    cool
    Sik S (Z xi tia side tve
    those
    7R) (me ox
    2- (GTiperidinocarbonyl) allyl- (6H, 7R) -7-C (Z) -2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetamido} -3-methyl-8-oxo-5- thia-1-azabicyclo 4,2, Q Soct-2 substances (from etip-1779, 1724,
    ... ° 50 en-2-carboxylate is obtained as colorless solid acetate).
    IR spectrum. (KBG), cm H 1677, 1610, 1535 and 1452.
    (E) -2- (Ethoxycarbon®1) -2-buteNyl- (6R, 7R) -7- (Z) -2 (2-amino-4-thiazolyl) -2- (methoxyimimino) acetamido -3- (azi ; housemethyl) -8-oxo-5-thia-1-azabicyclo 14., 2.0 oct-2-en-2-carboxylattane, semicular ion at temperature 564.
    (E) -2- LCC (E / Z) -3,7-Dimethyl-2,6-oxadienyl oxycarbonyl -2-butenyl- (6Я, 7R) -7- (Z) -2- (2 amino-4-thiazolyl) -2- (methoxyimino) acetamido-3-methyl-8-, oxo-5-thia-1-azabicyclo 4,2.0 oct-2-en-2-carboxylate is obtained in the form of a colorless solid substances (from a mixture of ether / hexane).
    to
    0
    N
    98880
    about
    ten
    Shss-spectrum: protonated ion molecular with m / e 632.
    (E) -3- (5-Bromo-2-furyl) -2- (ethoxycarbonyl) (ББ, 7К) -7- (Z) -2- (2-amino-4-thiazolyl) -2- ( methoxyimino) acetamido-3-methyl-8-oxo-5-thia-1-azabicyclo C, 2.0 Doct-2-en-2-carb oxylate is obtained as a colorless solid (from ether / hexane).
    Found,%: C 44.31; H 3.98; N 10.54; S 9.74; Вг 12,09.
    C H BrNfOgS; (654.47).
    Calculated,%: C 44.04; H 3.70; N 10.70; S 9.80; Вг 12,21.
    2- (Ethoxycarbonyl) -2,4-hexadienyl- (6R, 7R) -7-C: (Z) -2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetamido J-3- methyl 8-oxo-5-thia-1-azabicyclo C 4,2,01 oct-2-en-2-carboxylate is obtained as a colorless solid.
    Found,%: C 49.95; H 12.10.
    5.33;
     ., (549.61).
    N
    Calculated,%: C 50.26; H 4.95; 12.74.
    2- (Dimethoxyphosphinip) allyl- (6R ,, 7R) -7-C (Z) -2- (2-amino-4-thiazol) -2- (methoxyimino) acetamyl 3-3-methyl-3-oxo-5 -thia-1-azabicyclo 1 | 4.2.03 oct-2-en2-carboxylate is obtained as a colorless solid (from ether / hexane mixture).
    Mass spectrum: protonated molecule ion at n / e 546.
    (E and / or Z) -4,4,4-TpKxnop-2- (3ToK-sicarbonyl) -2-butenyl (6R, 7R) -7-С (Z) -2- (2-amino-4-thiazol ) -2 (methoxyimino) acetamido} -3-methyl-8-oxo-5 thia-1-isabox 4,2.0 oct-2-en-2 carboxylate is obtained as a colorless solid.
    Mass spectrum: molecular ion at t / e-626.
    2- (GTiperidinocarbonyl) allyl- (6H, 7R) -7-C (Z) -2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetamido} -3-methyl-8-oxo-5- thia-1-azabicyclo 4,2, Q Socto-2-2-carboxylate is obtained as a colorless solid acetate).
    substances (from etip-1779, 1724,
    Receive in the form of a demon, see H 1452.
    Particularly as a colorless solid.
    Found,%: C 44.83; H 4.31; N 19.58; S 11.27.
    C ,, H, Nj07S2 (5.64,57)
    Calculated,%: C 44.67; H 4.28; N 19.85; S 11.36.
    (K) -2- C (Cyclohexylmethoxy) carbonyl -2-butenyl- (6K, 7R) -7- (Z) -2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetamido} - 3- (azidomethyl) -8-oxo-5-thia-1-azabicyclo 4,2, Pzoct-2-en-2-carboxylate is obtained as a colorless solid (from ether / hexane).
    IR spectrum (KBG), cm - 21L4, 1788 1717, 1618 and 1532.
    As a result of treatment of this compound with 4.9 N. hydrochloric acid. isopropanol get hydrochloride (E) -2- C (cyclohexylmethoxy) carbonyl 2-butenyl- (6N, 7R) -7- (7.) - 2- (2-amino 4-thiazolyl) -2- (methoxyimino) acetamido -3 - (Azidomethyl) -8-oxo-5-thia-1-. azabi1Shklo | 4,2, P oct-2-en-2-carboxylate lat in the form of a colorless solid (from isopropanol / hexane mixture)
    Found,%: C 46.28; H 5.10; N 16., 54; C1 5.20; S 9.39.
    C eHjiNaO S -HGl (669,17).
    Calculated,%: C 46.67; H 4.97; N 16.75; C1 5.30; S 9.58.
    , (E) -2- (isobutyrocarbonyl) -2-penta-l- (6R, 7R) -7- (Z) -2- (2-aMHHo-4-thiazolyl) -2- (methoxyimino) acetamide J 3- ( azn7homethyl) -8-oxo-5-thia-1-azabicyclic 14,2, O oct-2-en-2-carboxylate is obtained as a yellowish solid (from ether / hexane mixture)
    Mass spectrum: a protonated molecular ion at temperature 607.
    (E) -2- (1 1 -butoxycarbranyl) -2-bute Hmi- (6R, 7R) -7- (Z) -2- (2-amino-4-thia zolyl) -2- (methoxyimino) acetamido, 0- 3- (azidomethyl) -8-oxo-5-thia-1-azabicyclo 4, 2.0 oct-2-en-2-carboxylate is obtained as a colorless substance.
    Mass spectrum: protonated molecular ion at TP / e 593.
    (E) -2- | X2-Ethoxyethoxy) carbonyl-2-6yTeHmi- (6R, 7R) -7- (g) -2- (2-amino 4-thiazolyl) -2- (methoxyimino) -acetates (azidomethyl) -8-oxo-5-thia-1-azabicyclo 4,2, Ozoct-2-en-2-carboxy lat. Is obtained as a colorless solid.
    G-band: protonated molecule of ion at m / e 609.
    ten
    159888012
    (E) -2- (Ethoxycarbonyl) -2-butensh1- (6R, 7R) -3- (aII; etoksimetil) -8-okso-7-C2- (3-thienyl) acetamido7-5-thia-1-aza - 5 "icyclico 4,2, Oct-2-en-2-carboxylate is obtained as a colorless solid with so pl. (from a mixture of ether / / hexane).
    Found,%: C 52.45; H 4.85; N 5.44.
    C, SIGV / 5 "52 (522.56). Calculated,%: C, 52.86; H 5.02; N 5.36.
    Receive (E) -2- (isobutoxycarbo-5-nyl) -2-pentenyl- (6R, 7R) -3- (acetoxy-methyl) -7 - /: (g) -2- (2-mino-4-thiazolyl ) - 2- (methoxyimino) -acetamido-8-oxo-5 thia-1-azabicyclo 4, 2.03 oct-2-en-2-carboxylate.
    2Q Found: C 50.03; H 5.66; N11.20.
     (623.70). Calculated,%: C 50.07; H 5.33: N 11.23.
    25 (E) -2- (Isobutoxycarbonsh1) -2-pen-TeHKn- (6R, 7R) -7- (Z) -2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetamidoJ-8- oxo-5-thia-1-azabix 4,2, OJOKT-2-en-2-carboxylate is obtained in the form of 30 colorless solid (from methylene chloride / ether mixture).
    Found,%: C 49.85; H 5.41; N 1.46.
    CjjH jjNyO S (551.63).
    Calculated,%: C 50.08; H 5.30; N 12.70. ,
    (E) -2- (isobutoxycarbonyl) -2-pen-TeHmi- (6R, 7R) -3-C (carbamoyloxyl) me- (2) -2- (2-furyl) -2- (methoxy- .4Q imino ) acetamido} -8-oxo-5-thia-1-azabicyclo 4,2.0 oct-2-en-2-carboxylate is obtained as a colorless solid (from methylene chloride / ether mixture).
    45; Found: C, 52.67; H 5.59; N 9.23.
     (592.62). Calculated,%: C, 52.70; H 5.44;
    -N 9.45.
    PRI me R 4. 1 mmol of a carboxylic acid active as an antibiotic from the group of α-lactam type antibiotics, 1 mmol triphenylphosphine and 1.5 mmol of the desired alcohol are dissolved in 5 ml of dimethylacetamide. The resulting solution is treated by adding dropwise a raStor 1.03 mmol diethyl azodicarboxylate c. dimethylacetamide. Stir for 4 h, dilute 35
    50
    55
    131598880
    the reaction mixture is 100 ml of ethyl acetateN
    It is washed and thrice with water in 50 ml portions and twice with 10% aqueous plant salt in 50 ml portions. The organic phase is dried over magnesium sulphate, filtered and evaporated. The residue is then chromatographed over silica gel, eluting with ethyl acetate / hexane (4: 1).
    (RS) -2- (Ethoxycarbonyl) -1,3-dimethyl-2-butenyl- (6K, 7R) -7-C (Z) -2- (2-amino-A-thiazolyl) -2- ( methoxyimino) acetamido-3-methyl-8-oxo-5-thia-1-asa14
    Found,%: C 46.87; And 5.78; N 15.14.
    Cfg (459.95).
    Calculated,%: C 47.00; H 5.70; N 15.23.
    0.32 g of hydrochloride (E) -2- (isobutoxycarbonl) -2-pentenyl- (BK, 7R) -7-amino-3-acidomethyl-8-oxo-5-thia-1-azabicyclo 4,2, 0 oct-2-en-2-carboxylate is dissolved in 15 ml of methylene chloride, then mixed with 0.24 g of S- (2-benzothiazolyl) -2-amino-4-thiazole-glyoxylate- (Z) -O-metshshima. Through
    Bicyclo 4,2,0 oct-2-en-2-carboxylate 6h is reacted: the mixture is evaporated and obtained as a colorless solid.
    Mass spectrum: protonated molecular ion at m / e 552.
    (J8) -2- (Ethoxycarbonyl) -1-methyl-aplyl) - (HB, 7H) -7-C (7.) - 2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetamidoJ- 3-methyl-8-oxo-5-thia-1-azabicyclo 4,2.0 oct-2-en-2-carboxylate as
    20
    the current is then rapidly chromatographed over a short column of silica gel, eluted with ethyl acetate / hexane (1: 1) and then with ethyl acetate. The collected fractions are combined and evaporated. The residue is dissolved in 20 mp etthatatate, then mixed with 5 ml of 4N. hydrochloric acid in ethyl acetate. The crystals obtained are filtered off with suction on a colorless solid (from a mixture of ether and hexane is recrystallized from isopropane). 0.2 g of (E) -2- is obtained (isobuMass-spectrum. Tr: protonated molecular ion at mp / e 524.
    toxycarbonyl) -2-pentenyl- (6H ,, 7R) -7-C (Z) -2- (2-amino-4-thiazolyl) -2- (metG-Ciimino) acetamido-3-azidomethyl-8-oxo- 5-thia-1-azabicyclo 4,2.0 oct-2-en-2-carboxylate.
    Example5. 0.51 g of (6R, 7R) -7-30 amino-3-azidomethyl-8-oxo-5-thia-1-azabicycl 4, 2.0 oct-2-en-2-carboxylic acid are dissolved in 50 ml of acetone, then cooled to and mixed with 0.29 ml of dibutyl urea. After 15 minutes, this solution is mixed with 0.54 g of isobutyl- (g) -2- (methyl bromide) -2-pentenoate and stirred overnight at 0 ° C. The solution is then diluted with 50 ml of acetic acid butyl ester and the crystals are filtered on a filter. The filtrate is mixed with 30 ml of common salt and the mixture is filtered with suction. Organic phase
    toxycarbonyl) -2-pentenyl- (6H ,, 7R) -7-C (Z) -2- (2-amino-4-thiazolyl) -2- (metG-Ciimino) acetamido-3-azidomethyl-8-oxo- 5-thia-1-azabicyclo 4,2.0 oct-2-en-2-carboxylate.
    Found,%: C 43.41; And 4.72; N16.0.
    C.H oClNgOS (693.13)
    Calculated,%: C 44.82; H 4.86; N 17.42. .
    The resulting new esters have valuable pharmacological properties. They are particularly suitable for enteral, in particular oral, administration for the treatment of diseases.
    The oral antimicrobial activity according to the invention of anti-ester active antibiotics
    Separate, dry, filter, and isoparboxylic acids can be added. The residue is quickly chromatographed over a short column of silica gel, eluting with ethyl acetate / hexane (6: 4). The resulting fractions are combined and evaporated. The residue is added to JQ with 20 ml of ethyl acetate and mixed with 4N. hydrochloric acid in ethyl acetate. After 24 hours at 0 ° C, the crystals are filtered and dried under reduced pressure. 0.38 g of hydrochloride (E) -2- (isobutoxycarbonyl) -2-pentenyl (6R, 7H) -7-amino-3-azidomethyl-8-oxo-5-thia-1-azabicyclo 4,2 is obtained, 0 oct-2-ene-carboxylate.
    55
    zana, for example, experiences on animals. In white mice weighing 16–20 g, experimental septicemia was caused by the fact that the test animals intraintestinally infected themselves with a sample of a diluted culture of an experienced organism of Escherichia coli 25922, which was grown overnight. The dose set was measured in such a way that the dose was 10–20 times the required dose to kill untreated test animals within 48 hours. The bacteria were injected as a suspension in the culture broth. As for control animals, so
    0
    the current is then rapidly chromatographed over a short column of silica gel, eluted with ethyl acetate / hexane (1: 1) and then with ethyl acetate. The collected fractions are combined and evaporated. The residue is dissolved in 20 mp etthatatate, then mixed with 5 ml of 4N. hydrochloric acid in ethyl acetate. The resulting crystals are filtered off with suction on filtoxycarbonyl) -2-pentenyl- (6H ,, 7R) -7-C (Z) -2- (2-amino-4-thiazolyl) -2- (metG-Ciimino) acetamido-3-azidomethyl- 8-oxo-5-thia-1-azabicyclo 4,2.0 oct-2-en-2-carboxylate.
    Found,%: C 43.41; And 4.72; N16.0.
    C.H oClNgOS (693.13)
    Calculated,%: C 44.82; H 4.86; N 17.42. .
    The resulting new esters have valuable pharmacological properties. They are particularly suitable for enteral, in particular oral, administration for the treatment of diseases.
    The oral antimicrobial activity according to the invention of anti-ester active antibiotics
    Moat-carboxylic acids can be dock
    zana, for example, experiences on animals. In white mice weighing 16–20 g, experimental septicemia was caused by the fact that the test animals intraintestinally infected themselves with a sample of a diluted culture of an experienced organism of Escherichia coli 25922, which was grown overnight. The dose set was measured in such a way that the dose was 10–20 times the required dose to kill untreated test animals within 48 hours. The bacteria were injected as a suspension in the culture broth. As for control animals, so
    The products according to the invention can be used as pharmaceuticals, for example, in the form of pharmaceutical preparations for enteral administration. Products according to the invention
    but administered orally, for example, in the form of tablets, tablets with shells, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions, or rectally, for example, in the form of suppositories.
    Example 6. Gelatin capsules of the following composition are obtained, mg: (E) -2- (Nbutoxycarbonyl) -2-pentenyl- (BK, 7R) -7- (Z) where R. (i: hydrogen, thienyl-acetyl or residue of formula
    R7-C-CO
    II
    N I 0-R
    at
    where R, is furyl-2 or 2-aminothiazolyl-4; nizhj al kil;
    R. 17
    - hydrogen or in the corresponding case; measured by an aceto-XI-, carbamoyloxy-, azido-, or 5-methyl-2H-tetrazol-2-yl-methyl group; hydrogen or N31 alkyl;
    ten
    t5
    your halogenoalkyl, lower alkenyl, lower alkoxycarbonyl or 5-halogen (Buryl-2 or R and R together - lower alkylene |
    hydrogen, lower alkyl or lower alkoxycarbonyl; rpynna-COORg, -COR ,,, -CONR R f2 or -PO (OR, straight or branched alkyl containing up to 10 carbon atoms, in which up to two methylene groups. can be replaced by oxygen atom, alkenyl or alkynyl each containing up to 10 atoms of synol, 7-Diclo-25 alkyl, C C -dikloalkyl-lower, alkyl, nitrophenyl, tetrahydropyranyl or tetrahydropyranyl-lower alkyl, - lower alkyl;
    YU
     ,
    - lower alkylene;
    - lower alkyl,
    the presence of a basic substitute for pharmaceutically applicable groups distinguishing d- that the corresponding compound of formula (I) carboxylic acid
    X (II)
    thirty
    35
    40
    R R,
    9888P 8.
    where X is a hydroxy or leaving group;
    3 4
    ten
    t5
    25
    YU
    thirty
    35
    40
    Ri and R have the indicated meanings
    and, if necessary, the resulting compound of formula (I), where R j is hydrogen, is reacted with a carboxylic acid of general formula R, —OH, where R is as indicated for R; values other than hydrogen and, if necessary, the resulting ester is converted to a pharmaceutically acceptable salt with an acid.
    [2]
    2. A method according to claim 1, characterized in that the carboxylic acid corresponding to a compound of formula (I) is taken as a salt and is reacted with a compound of formula (II) in which X is a leaving group.
    [3]
    3. The method according to claim 1, characterized by the fact that the carboxylic acid corresponding to the compound of formula (I) is reacted in the presence of a condensing agent
    with a compound of the formula (11) in which X is a hydroxyl group.
    [4]
    4. Method according to paragraphs. 1 to 3, of which it is obtained in order to obtain (E) -2- (isobutoxycarbonyl) -2-pentenyl- (6R, 7R) -7- (Z) -2- (2-amine- 4-thiazolyl) -2- (methoxyimino) acetamido-3- (azidomethyl) -8-oxo-5-thia-T-azabicyclic C4,2, Octoct-2-en-2-carboxylate.
    Prioritized by points
    11/24/87 to paragraphs 2 and 3
    08.25.88 pp. 1 and 4
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    同族专利:
    公开号 | 公开日
    YU191589A|1991-02-28|
    MC1991A1|1989-11-30|
    EP0318767A2|1989-06-07|
    NZ226989A|1992-05-26|
    DK637888A|1989-05-25|
    PT89080A|1988-12-01|
    FI885330A|1989-05-25|
    HU207522B|1993-04-28|
    YU216188A|1990-04-30|
    HUT48895A|1989-07-28|
    KR890008082A|1989-07-08|
    DK637888D0|1988-11-15|
    PT89080B|1993-04-30|
    AU2578588A|1989-05-25|
    EP0318767A3|1991-03-20|
    NO885221L|1989-05-25|
    NO885221D0|1988-11-23|
    IL88403D0|1989-06-30|
    JPH01165585A|1989-06-29|
    FI885330A0|1988-11-17|
    AU614793B2|1991-09-12|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    FR2476087B1|1980-02-18|1983-07-18|Roussel Uclaf|
    JPS5984889A|1982-11-05|1984-05-16|Sumitomo Chem Co Ltd|Cephalosporin derivative and its preparation|IL99898A|1990-11-09|1996-10-31|Eisai Co Ltd|7-Acyl-3-substituted carbamoyloxy cephem compounds their preparation and antibacterial compositions containing them|
    KR19990008354A|1995-05-03|1999-01-25|페터 죤 기딩스|Ester of carbapenem|
    KR20140064917A|2011-08-31|2014-05-28|말린크로트 엘엘씨|Remote assembly of targeted nanoparticles using h-phosphonate-ene/-yne hydrophosphonylation reactions|
    EA028342B1|2011-09-09|2017-11-30|Мерк Шарп И Доум Корп.|Methods for treating pneumonia|
    US8809314B1|2012-09-07|2014-08-19|Cubist Pharmacueticals, Inc.|Cephalosporin compound|
    US8476425B1|2012-09-27|2013-07-02|Cubist Pharmaceuticals, Inc.|Tazobactam arginine compositions|
    KR102226197B1|2013-03-15|2021-03-11|머크 샤프 앤드 돔 코포레이션|Ceftolozane antibiotic compositions|
    US20140275000A1|2013-03-15|2014-09-18|Cubist Pharmaceuticals, Inc.|Ceftolozane pharmaceutical compositions|
    US9872906B2|2013-03-15|2018-01-23|Merck Sharp & Dohme Corp.|Ceftolozane antibiotic compositions|
    ES2800603T3|2013-09-09|2021-01-04|Merck Sharp & Dohme|Treatment of infections with ceftolozane / tazobactam in patients with renal impairment|
    US8906898B1|2013-09-27|2014-12-09|Calixa Therapeutics, Inc.|Solid forms of ceftolozane|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    CH457087|1987-11-24|
    CH316588|1988-08-25|
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