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    • 专利摘要:
    1. A cephalosporin derivatives of the general formula wherein R1 is an a-, β- or y-amino acid residue (bonded by the ester linkage), which may optionally be substituted by one or two lower alkyl groups at the amino group thereof, R2 is an 1-alkanoyloxyalkyl, 1-alkoxycarbonyloxyalkyl, phthalidyl or 5-methyl-1,3-dioxolen-2-on-4-ylmethyl group, R3 is a carbamoyloxymethyl group, which may optionally be substituted by one or two lower alkyl groups, or a heterocyclothiomethyl group, which may optionally be substituted by one or more appropriate substituents, and R4 is a hydrogen atom or a hydroxy group, or its non- toxic salt are found to be useful as orally administrable antibiotics having broad antimicrobial activities against both gram-positive and gram-negative bacteria.
    公开号:SU1309912A3
    申请号:SU843826171
    申请日:1984-12-24
    公开日:1987-05-07
    发明作者:Какеа Лобухара；Нисизава Сусуми；Тамаки Сатоси；Китао Казухико
    申请人:Киото Фармасьютикал Индастриз,Лтд (Фирма)；
    IPC主号:
    专利说明:

    fO
    The invention relates to a method for the preparation of new antibiotics of the cephalosporic series — derivatives of cephalosporin in the form of their additive salts with hydrohalic acids, which can be used as medicinal substances in medicine.
    The aim of the invention is to obtain new cephalosporins, which have an increased biological effectiveness.
    Example. Synthesis of 1-acetoxy-ethyl (1-alanyl) almond-amido - -3-G (5-methyl-1,3,4-thiadiazol-2-yl) thiomethyl 3-cephem-4-carboxylate hydrochloride (compound 22, Table. one).
    A. 1-Acetoxyethyl 7- (B-almondamino) -3- (5-methyl-1,3,4-thiadiazol-2-yl) thiomethyl 3-cephem-4-carboxylate is dissolved in 30 ml of methylene chloride . With ice-cooling, 210 ml of BOC-alanine, 25 mg of 4-dimethylamino-pyridine and 270 mg of dicyclohexylcar-25 position 7), 6.12 (singlet, 1H, bodiimide, and the resulting mixture are re--CHCONH-) 6.93 are added , 7.02 (quartet, quart5
    The compound obtained in Step A is dissolved in 6 ml of ethyl acetate. To the resulting solution was added 5 ml of 2N hydrochloric acid in isopropyl alcohol, and the mixture was stirred at room temperature for an hour, after which 6 ml of ethyl acetate was added. The resulting white crystals are washed with ether to give 600 mg of the title compound.
    HC (Nujol, cm): 1780, 1755, 1690.
    NMR (CD) SO, values 1.49 (doublet, 6H, J - 6 Hz, 2x CHjCH-), 2.09 (singlet, 3N, CH CO-), 2.70 (singlet, 3N, thiadiazole-CH) , 3.65 (broad, singlet, 2H, H, in position 2) 4.15.4.55 (doublet, doublet, 2H, J 14 Hz, - in position 3), 4.8 (multiplet, 1H,) , 5.08 (doublet, 1H, J 5 Hz, H at position 6), 5.74 (multiplet, 1H,
    stir for an hour. The insoluble material is filtered off and the filtrate is washed with 10% aqueous citric acid solution, an aqueous solution of sodium bicarbonate, an aqueous solution of sodium chloride in this order and dried over anhydrous sodium sulfate. Removal of the solvent by distillation and the subsequent addition of petroleum ether to the obtained residue yields 110 mg of 1-acetoxyethyl (BOC-alanyl) almond-amido-3- (5-methyl-1,3,4-thi. Diazol-2-yl) thiomethyl 3 -3-cephem-4-carboxylate as a yellowish powder.
    IR (nujol, cm): 3350, 1770, 1750 1680,
    NMR (CDj) .O, 0.75-1.92 (multiplet, 15H), (CH,) 00- 2x, 2.07 (singlet, 3H, OHjCG2, 68 (singlet, 3H, thiadiazole-SND), 3.62 (broad, singlet, 2H, N. in position 2), 3.93-4.27 (multiplet, 1H, -CHNH-), 4.14, 4.49 (doublet, doublet, 2H, J 14 Hz, -CH2S in position 3), 5.06 (doublet W, J 5 Hz, H in position 6), 5.35-5.95 (multi
    plet, 2H, H at position 7, BOC-NK-) 6.00 (singlet, 1H, -CHCONH), 6.82, 6.91 (quartet, 1H, J 7 Hz OSNO), 7.40 ( singlet, 5H, phenyl), 9.28 (doublet, W, J 9 Hz, -SON.).
    5 position 7), 6.12 (singlet, 1H, -CHCONH-) 6.93, 7.02 (quartet, quart5
    The compound obtained in Step A is dissolved in 6 ml of ethyl acetate. To the resulting solution was added 5 ml of 2N hydrochloric acid in isopropyl alcohol, and the mixture was stirred at room temperature for an hour, after which 6 ml of ethyl acetate was added. The resulting white crystals are washed with ether to give 600 mg of the desired compound.
    HC (Nujol, cm): 1780, 1755, 1690.
    NMR (CD) SO, values 1.49 (doublet, 6H, J - 6 Hz, 2x CHjCH-), 2.09 (singlet, 3N, CH CO-), 2.70 (singlet, 3N, thiadiazole-CH) , 3.65 (broad, singlet, 2H, H, in position 2) 4.15.4.55 (doublet, doublet, 2H, J 14 Hz, - in position 3), 4.8 (multiplet, 1H,) , 5.08 (doublet, 1H, J 5 Hz, H at position 6), 5.74 (multiplet, 1H,
    tet, 1H, J 6 Hz, CHjCHO-), 7.45 (multiplet, 5H, phenyl), 8.7 (broad, 3N, - NHj) 9.45 (doublet, 1H, J 9 Hz, - CONH-) .
    Similarly to this example, the following compounds of the formula
    -Shch-Sosh-Yr%
    he
    about
    t
    ,
     Br COOR2.
    (I)
    .
    0
    0
    five
    in the D configuration, in the form of their addition salts with hydrochloric acid, where the values of the radicals R 4 are given in Table. 1, which uses the following abbreviations:
    Ala: alanyl;
    Asn: asparaginyl;
    Gly: glypyl;
    Val: poured;
    Ser: series;
    Gin: glutaminyl;
    Phe: phenylalanil;
    oi-asp o (-aspartsh1;
     (s-glutamil;
    Met: methionyl;
    Lys: Lysyl;
    Pro: shed;
    Sar: sarcosyl;
    -Ala: / 4-alanyl;
    GlG 1: glycylglycyl.
    For Rj:
    AOM: acetoxymethyl; ROM: propionyloxynethyl; p BOE: 1-n-butyryloxyethyl; i VOM: isovaleryloxymethyl; i BOE: isobutyryloxyethyl; n VOE: 1-n-valeryloxyethyl; i VOE: isovaleryloxyethyl; AOE: 1-acetoxyethyl; POE: 1-propionyloxyethyl; PVE: 1-pivaloyloxyethyl; PVM: pivaloyloxymethyl; PHT: phthalidyl;
    ALL: 1-ethoxycarbonyloxyethyl DOX: 5-methyl-1,3-dioxolen-2-one-4-ylmethyl. For Rj:
    MTD: C (5-methyl-1,3,4-thiadiazol-2-yl) thiomethyl; TD: (1,3,4-thiadiazol-2-yl)
    thiomethyl; MT: (1-methyl-1H-tetrazol-5yl) thiomethyl; TR: (1H-1,2,3-triazol-5-yl)
    thiomethyl; TZ: G (1, 2,3-thiadiazol-5-yl)
    thiomethyl};
    CM: carbamoyloxymethyl; PD: (3-hydroxypyridazin-6-yl) thiomethyl.
    Acetoxymethyl 7-CO-0- (1-alanyl) almond-amido} -3- (5-methyl-1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylate hydrochloride (compound 15)
    IR (nujol, cm-): 1780, 1760, 1690.
    NMR tCCDj) so, values 1.46 (doublet, 3N, 7 Hz, -CH-CH), 2.08 (singlet, 3N, -CO-CHj), 2.68 (singlet, 3N, thiadiazole-CHj ), 3.65 (broad, singlet, 2H, Ej at position 2), 4.20 (multiplet, 1H, -CH-CHj), 4.17, 4.58 (doublet, doublet, J 14 Hz, 2H, -CHjS - in position H) 5.05 (doublet, 1H J 5 Hz, H in position 6), 5.77 (doublet, doublet, W, J 5 and 9 Hz, H in position 7), 5 , 74 and 5.88 (doublet, doublet, 2H, J 7 Hz), 6.12 (singlet, 1H, - -CH-CONN-), 7.45 multiplet, 5H phenyl), 8.62 (broad, 3N , -NHj) 9.45 (doublet, 1H, J 9 Hz, -CONK-).
    Pivaloyloxymethyl (} -alanyl) almond-amino-3- (5-methyl-1, 3,4-β-thiadiazol-2-yl) thiomethylJ-3-cephem-4-carboxylate hydrochloride (compound 25).
    25
    j 10
    ; f5
    20

    35
     ,,
    e,
    99124
    IR (nujol, cm-): 1785, 1755 and 1690.
    NMR t (CD 3), values (f: 1.16 (singlet, 9H, -CHjX 3), 1.48 (doublet, NN, J 8 Hz, -CH-CHj), 2.68 (singlet, NN: thiadiazole - CH), 3.64 (broad singlet, 2H, H in position 2), 4.20 (multiplet 1H, -CH-CHj), 4.12 and 4.57 (doublet, doublet, 2H, J 14 Hz , -CHj-S- in position 3),
    5.04 (doublet, LN, J 5 Hz, H at position 6), 5.77 (doublet, doublet, 1H,
    J 5 and 9 Hz, in position 7), 5.74 and 5.95 (doublet, doublet, 2H, J 7 Hz, -CHj-OCO-), 6.12 (singlet, 1H, -CH-CONH-) 7.13 (multiplet, 5H, phenyl), 8.63 (broad, KN, -NHj), 9.45 (doublet, 1H, J 9 Hz, -CONH-).
     Pivaloyloxymethyl (1-valyl) almond-amido-3- (5-methyl-1, 3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylate hydrochloride (compound 39).
    IR (nujol, cm-): 3200, 1780, 1750, 1690.
    NMR (CDj) SO, value 0.96 (doublet, 6H, J 7 Hz, -CH (CH3)), 1.18 (singlet, 9H, -C (SI,),), 2.30 (multiplet, W , -CH (CH) 2), 2.68 (singlet, 3N, thiadiazole-SNg), 3.65 (pharoka, singlet, 2H, K in position 2), 4.11 and 4.57 (doublet, doublet, 2H, J 14 Hz,. - in position 3), 4.10 (multiplet, W, -CH-i Pr),
    5.05 (doublet, 1H, J 5 Hz, H at position 6), 5.60-6.05 (multiplet, 3N, H at position 7, -COOCH o-), 6.15 (singlet, 1H-CH-CCA ), 7.25-7.70 (multiplet, 5H, phenyl), 8.63 (broad, 3N, NHj), 9.45 (doublet, W, J 9 Hz, -CONH-).
    Pivaloyloxymethyl (1-prolyl) almond-amid-3- (methyl, 3,4-β-thiadiazol-2-yl) thiomethyl-3-cefem-4-carboxylate hydrochloride (compound 151).
    IR (Nujol, see b: 1780, 1750, 1685.
    NMR (CDj) SO, values C / J: 1.16 (singlet, 9H, -C (CHj) j), 1.70-2.40 (multiplet, 4H, H, at position 3 and 4 of proline), 2.68 (singlet, 3N, thiadiazole-CHj), 3.05-3.45 (multiplet, 2H, H2 at position 5 of proline), 3.64 (wide, singlet, 2H, H at position 2), 4, 10 and 4.55 (doublet, doublet, 2H, J 14 Hz, - in position 3), 4.35-4.53 (m lightlet, 1H, H in
    thirty
    position 2 of proline), 5.05 (doublet, 1H, J 5 Hz, H at position 6), 5.55 6.05 (multiplet, 3N, H at position 7, -CO-CH -), 6.15 ( singlet, 1H, -CHCONH-), 7.43 (multiplet, 5H, phenyl), 9.30 (broad, 2H, -NH), 9.40 (doublet, 1H, J 9 Gp, -CONH-),
    Pivaloyloxymethyl (capKozyl) almond-amido-3- (5-methyl-1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4 carboxylate hydrochloride (compound 179).
    IR (nujol, cm): 3200, 1780, 1750, 1690.
    NMR (SVS) 280, value 1.17 (singlet, 9H, - € (# 3) 3) 2.60 (singlet, 3N-HCH), 2.68 (singlet, 3N thiadiazole, -CH), 3.65 (broad, singlet, 2H, H in position 2), 4.12 (wide, singlet, 2H, -CONH2-), 4.14, 4.55 (doublet, doublet, 2H, J 14 Hz, .- CHjS - position 3), 5.05 (doublet, 1H, J 5 Hz, H at position 6) 5.60-6.05 (multiplet, 3N, H at position 7, —COjCHj-), 6.15 (singlet, 1H , -CHNOSO-), 7.25-7.75 (multiplet, 5H, phenyl), 9.50 (multiplet, 3N, -CONH, -NH).
    (5-Methyl-1,3-dioxolen-2-one-4-ylmethyl) (1-alanyl) almond-alami- (5-methyl-1,3,4-thiadiazol-2-yl) thiomethyl -3- cephem-4-carboxylate hydrochloride (compound 28).
    IR (nujol, cm): 1815, 1780, 1690.
    NMR (CD,), so, values 1.48 (doublet, GN, J = 7 Hz, -SNCH), 2.18 (singlet, GN, dioxolen-CH3), 2.66 (singlet, GH, thiadiazole, -CHj) , 3.62 (broad, singlet, 2H, H2 at position 2), 4.20 (multiplet, 1H, -CHCHH) 4.07, (doublet, doublet, 2H, J 14 Hz, position 3), 5.05 (doublet, 1H, J 5 Hz, H at position 6) 5.15 (singlet, 2H,), 5.72. (doublet X doublet, 1H, J 5 and 9 Hz, H at position 7), 6.13 (singlet, 1H-CHCONH-), 7.63 (multiplet, 5H, fe-
    Nile), 8.73 (broad, 3N, -Sh), 9.46 (doublet, 1H, J 9 Hz, -WB-).
    (5-Methyl-1,3-dioxolen-2-on-4-yl-methyl) (l -prolyl) -imndalami- (5-methyl-1,3,4-thiazolol-2-CHI) -thiomethyl-3 -cell-4-kabbokkjshatat-hydrokloroid (compound 154).
    IR (nujol, cm): 1820, 1785, 1740, 1680.
    NMR t (CD) ,, SO, values 1.7-2.4 (multiplet, 7H, H at positions 3 and 4 of proline, dioxolen-CHj), 2.70 | (singlet, MN, thiadiazole-CH,), 3.053, 4 (multiplet, 2H, Hj at position 5 of proline) 3.59, 3.97 - (doublet, doublet, 2H, J 18 Hz, H at position 2) 4.07, 4.87 (doublet, doublet, 2H, J 14 Hz, - in position 3),
    4.35-4.53 (multiplet, 1H, H at position 2 of proline), 5.04 (doublet, 1H, J 5 Hz, H at position 6), 5.15 (singlet, 2H, -CO-jCH - ), 5.81 (doublet x doublet, GN, J 9 and 5 Hz, H
    5 at position 7), 7.42 (multiplet, 5H, phenyl), 9.3 (broad, 2H, NH2), 9.40 (doublet, 1H, 9 Hz, -CONH).
    1-Acetoxyztil (glycyl) almond-amido J-3- (5-methyl-1,3,4-thia0 diazol-2-yl) thiomethyl-3-cephem-4-carboxylate hydrochloride (compound
    8) IR (nudzhol, cm): 1780, 1760,
    1685.
    NMR (003) 280, value 1.48 ,; 1.5O (doublet, doublet, ZN, J 6 Hz, -SNCH), 2.03, 2.07 (singlet, singlet, 3H-COOHj), 2.68 (singlet, ZN, thiadiazole-CHj), 3, 65 (broad, singlet, 2H, H in position 2), 3.97 (broad, singlet, 2H, -OSOCN -), 4.13, 4.50 (doublet, doublet, 2H, J 14 Hz, -CHS - in position 3), 5.07 (doublet, 1H, J 5 Hz, H in po5
    0
    0
    Q
    5 positions 6), 5.7 (multiplet, 1Н Н
    in position 7). 6.12 (singlet, 1H-CHCONH-), 6.92, 7.01 (quartet, quartet, W, J - 6 Hz, -SNCH,), 7.43 (multiplet, 5H, phenyl), 8.6 (broad, 3N, -NHj), 9.45 (doublet, 1H, J 9 Hz, -CONH-).
    1-Acetoxyethyl (1-o (-asparagil) almond-amido-3- (5-methyl--1,3,4-thiadiazol-2-yl) thiomethyl-3--cefem-4-carboxylate hydrochloride (compound 106) „
    cm): 1780, 1760,
    IR (Nujol5 1690.
    NMR (CW) 80 values 1.49, 1.52 (doublet, doublet, 3N, 7 Hz, -CHCH), 2.03, 2.07 (singlet, singlet, 3N, -COOHj), 3.05 (doublet, 2H, J 6 Hz,), 2.70 (singlet, GZ, thiadaschazole — CH j), 3.73 (broad, singlet, 2H, H at position 2), 3.90- 4.85 (multiplet , ЗН, -CHNH3 -, - CHjS-) 5.05-5.07 (doublet, doublet, 2H, J 5 Hz, H at position 6), 5.6 (multi713
    tiplet, IH, H at position 7), 6.09 (singlet, 1H, -CHCONH-), 6.85, 6.98 (quartet, quartet, 1H, J 7 Hz, -СНСН), 7.6 (multiplet , 6H, phenyl, -COjH), 8.7 (broad, singlet, 3N, -NHj), 9.48 (doublet, 1H, -CONH-),
     1-Acetsxyethyl (1-glutaminyl) almond-amido-3- (5-methyl-1,3,4-β-thiadiazol-2-yl) -thiomethyl j-3-cephem-4-carboxylate hydrochloride (compound 78) .
    IR (nujol, cm): 3100, 1785, 1720, 1690,
    NMR (SVS) 50, values 1.46, 1.48 (doublet, doublet, 3N, 6 Hz, -CHCHj), 2.03, 2.06 (singlet, singlet, 3N, -COOFj), 2.1- 2.65 (multiplet, 4H,, -), 2.66 (singlet, 3N, thiadiazole-CH j), 3.65 (broad, singlet, 2H, H at position 2), 4.13 4.51 (doublet, doublet, 2H, J 14 Hz, -CH, .S - at position 3), 4.85 (multiplet, 1H, -CHNH), 5.07 (doublet, W, J 5 Hz, H at position 6 ), 5.7 (multiplet, 1H, H at position 7), 6.1 (singlet, 1H- CHCONH-), 6.91, 7.1 (quartet, quartet, W, J 7 Hz, -CHCHj), 7.46 (multiplet ,, 5H, phenyl), 8.7 (wide 5H, NHg, -CONH), 9.20 (doublet, W, J 9 Hz, -CONH).
    1-Acetoxyethyl (1-lysch1) almond-amido-: 3- (5-methyl-1,3,4-thiadiazol-2-yl) thiomethyl} -3-cephem-4-carboxylate hydrochloride (compound 134).
    IR (nujol, cm): 1780, 1750, 1680.
    NMR (, values 1.2-1.93 (broad, 6H, - (CHj)), 1.48, 1.50 (doublet, doublet, NN, J 6 Hz, -CHCHj), 2.06, 2, 08 (singlet, yr, ZN, -COCHj), 2.68 (singlet, ZN, thiadiazole-CHj), 2.75 (broad, 2H, -CHNHj), 4.03 (multiplet, W, -CHNH-), 3.68 (broad, singlet, 2H, HjB position 2), 4.16, 4.56 (doublet doublet, 2H, J 14 Hz, -CHjS at position 3), 5.05 (doublet, 1H, J 5 Hz H at position 6), 5.75 (multiplet, 1H, H at position 7), 6.11 (singlet, W, -CHHCO H-), 6.94, 7.00 (quartet, quartet, W, J 6 Hz, -CHCHj), 7.45 (multiplet, 5H, phenyl), 8.15 (broad, 3N, NHj), 8.83 (wide, 3N, NHp, 9.45 (doublet, W, J 9 Hz, -CONH).
    1-Acetoxyethyl 7-1B-O- (1-methionyl almond-amido-3- (5-methyl-1,3,4-ty28
    adiazol-2-yl) thiomethyl-3-cephem-4-carboxylate hydrochloride (compound
    162).
    IR (nujol, cm): 1780, 1750, 1685.
    NMR of (SVS) SO,. Values of 0 I ,, 1.50 (doublet, doublet, 3N, J 6 Hz, -CHCHj), 2.01 (singlet, 3N, CH3), 2.04, 2.07 (singlet, singlet, 3Hj-CPH3), 2.3 (multiplet, 4H-CH CH5-) 3.68 (broad, singlet, 2H, in position 2), 4.2-4.62 (multiplet, ЗН, - CHjS at position 3, -CHNHp, 5.06 (doublet, H, J 5 Hz, H at position 6), 5.8 (m ultiplet, 1H, H at position 7), 6.03 (singlet, W, - CHCONH-), 6.94, 7.04 (quartet, quartet, 1H, J 4 Hz, -SNSNd), 7.45 (multiplet, 5H, phenyl), 8.6 (broad, 3N, -NHg), 9 , 6 (doublet, 1H, -CONH).
    1-Acetoxyethyl (1-phenyl-alanyl) almond-amido-3- (5-methyl--1,3,4-thiadiazol-2-yl) thiomethyl-3-cefem-4-carboxylate hydrochloride (compound 92).
    IR (nujol, cm): 1780, 1755, 1685.
    NMR (CDj) SO values 1.48, 1.50 (doublet, doublet, 3N, J 6 Hz, -CHCH), 2.03, 2.06 (singlet, singlet, 3N, -COCH), 2.68 ( singlet, GN, thiadiazole-CHj), 3.22 (doublet, 2H, J 7 Hz, -CHCHj), 3.62 (broad, singlet, 2H, H2 in position 2), 4.18 4.66 (doublet, doublet, 2H, J 14 Hz, -CH2S - in position 3), 4.7 (multiplet, 1H, -CHN), 5.06 (doublet, 1H, J 5 Hz, H in position 6), 5 , 52- 5.89 (multiplet, 1H, Eve position 7), 6.06 (singlet, W, -CHCONH-), 6.75-7.13 (multiplet, 1H, -CHCHN), 7.21 (singlet , 5H, phenyl), 7.37 (singlet, 5H, phenyl), 8.84 (broad, 3N, -NH), 9.42 (doublet, W, J 9 Hz, - CONH-).
    1-Acetoxyethyl (I-prolyl) almond-amido-3- (5-methyl-1,3,4-tn. Adiazol-2-yl) thiomethyl} -3-cephem-4-carboxylate hydrochloride (compound 148).
    IR (nujol, cm): 1785, 1750, 1685
    NMR (003) 280, values 1.48, 1.50 (doublet, doublet, 3N, J 6 Hz, CHjCH-), 1.70, 2.40 (multiplet, 7H, H2 at positions 3 and 4 of proline, CHjCO-), 2.70 (singlet, .ЗН, thiadiazole -Syz), 3.05-3.45 (multiplet.
    2HjH2 at the 5 position of the prelina), 3.64 (broad, singlet, 2N N. in the 2 position), 4.10, 4.55 (doublet, doublet, 2H, J 14 Hz - CHj S - at the 3) position, 4.35-4.53 (multiplet, 1H, H at position 2 of proline), 5.04, 5.06 (doublet, doublet, 1H, J 5 Hz, H at position 6), 5.85 (multiplet, W , H at position 7), 6.12 (singlet, 1H, -CHCONH), 6.94, 7.00 (quartet, quartet, 1H, J 6 Hz, CHjCH-), 7.43 (multiplet, 5H, phenyl ), 9.30 (broad, 2H, -NH-i), 9.46 (doublet, 1H, J 9 Hz, - CONH-).
    1-Acetoxyethyl (a-alanyl) almond-amido J-3- (5-methyl-1,3-tiadi-azol-2-yl) thiomethyl-3-cepheme-4-carton silhydroxloride (compound 190).
    IR (nujol, cm): 1785, 1765, 1690.
    NMR (CDj) 2SO, values 1.46, 1.48 (doublet, doublet, 3N, J 6 Hz, -CHCHj), 2.00, 2.04 (singlet, singlet, 3N, -COCH3), 2.35 . (triplet, 2H, J 6 Hz, -COCH2-), 2.68 (singlet, GN, thiadiazole-SND), 3.1 (multiplet, 2H, -CHNHj), 3.65 (broad, singlet, 2H, Hj, in position 2), 4.12, 4.52 (doublet, doublet, 1H, J 14 Hz, -CHjS - in position 3), 4.15, 4.55 (doublet, doublet, W, J 14 Hz , -CHjS - in position 3), 5.09 (doublet, W, J 5 Hz, H in position 6), 5.7 (doublet to doublet, W, J 9 and 5 Hz, H in position 7), 6 , 15 (singlet5 1H, -CHCONH-), 6.88, 6.96 (quartet, quartet, W, J 6 Hz, -CHCHj), 7.4 (multiplet, 5H, phenyl) 8.73 (wide , ZN, -NHj), 9.46 (doublet, W, J 9 Hz, -CONH-).
    1-Acetoxyethyl (glytsh1) almond-amido} -3- (5-methyl-1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylate hydrochloride (compound 204).
    t (nudzhol, cm): 1780, 1760, 1680., 1630.
     {; (CD,), SO, values 1.50 (doublet, 3N, J 5 Hz, -CHCHj), 2.03 2.06 (singlet, singlet, 3N, -COCH3), 2.68 (singlet, 3N , thiadiazole-CH), 3.63 (broad, singlet, 4H, .H2In position 2, - CHjNHj), 3.85-4.2 (multiplet, 4H, -CHjS in position 3), -CHjNH-), 5.05 (doublet, W, J 5 Hz H in position-6), 5.52-5.93 (multiplet, 1H, H in position 7), 6.04 (singlet, W, -CHCONH-), 6 , 92, 7,, 01
    0
    5 o


    (quartet, quartet, 1H, J 5 Hz, -SNCH,), 7.43 (multiplet, 5H, phenyl) 8.29 (broad, 3N, -NHj), 8.89 (wide, 1H, -CHjNH), 9.40 (doublet, 1H, J 9 Hz, -CONH-).
    1-ethoxycarbonyloxyethyl 7-LD-0- - (1-alanyl) almond-amido J-3- (5-methyl-S--1,3,4-thiadiazol-2-yl) thiomethyl-3-cepheme-4-carboxylate hydrochloride (compound 27) “
    IR (nujol): 17 85, 1765, 1690.
    NMR G (003) 280, values of CG 1, 22 (triplet, ЗН „J 7 Hz,), 1.48 (doublet, ЗН, J 7 Hz, СНСНСНО-), 1.50 (doublet, ЗН, J 4 Hz , -OCHCHj), 2.68 (singlet, GH, thiadiazole-CH3), 3.65 (broad, singlet, 2H, H at position 2), 3.90-4.25 (multiplet, 5H, -CHjS at position 3, -CHNHj), 5.06, 5.08 (doublet, doublet, W, J 5 Hz,, H in position 6), 5.55-5.93 (multiplet, 1H, H in position 7), 6.12 (singlet, 1H, -CHCONH-), 6.82, 6.90 (quartet, quartet, 1H, J 4 Hz, CH CHO-), 7.45 (multiplet, 5H, phenyl), 8.68 ; (broad, 3N, -NHj) 9.46 (doublet, 1H, J 9 Hz, -CONH-).
    Phthalidyl (1-asparaginyl) almond amido; -3- (5-methyl-1, 3,4-thiadiazol-2-yl) thiomethyl -3-cephem-4-carboxylate hydrochloride (compound 68),
    IR (nujol, cm): 1780, 1750, 1675, 1650.
    NMR (CDg) SO, 2.90 (doublet, 2H, J 6 Hz, -CHj, CO-), 2.70 (singlet, 3N, thiadiazole-CHj), 3.72 (broad, singlet, 2H, H in position 2), 4.30 (multiplet, Ш, -CHNHj), 4.20, 4.85 (doublet, doublet, 2Н, J 14 Hz, -CHjS - in position 3), 5.15 (doublet, Ш , J 5 Hz, No position 6), 5.65 (multiplet, 1H, H at position 7), 6.14 (singlet, 1H, -CHCONH-), 7.45 (multiplet, 8H, phenyl, OSNO-, -CONHj), 7.80 (multiplet, 4H, phthalidyl), 8.55 (broad, singlet, 3N, -NHg), 9.45 (doublet,
    1H, J 9 Hz, -CONH-X,
    1-Acetoxyethyl (1-alanyl) almond-amido J-3-C (1H-1,2,3-thiazol-1z-yl) thiomethyl-3-cephem-4-carboxylate hydrochloride (compound 380).
    IR (Nujol): 1785, 1760, 1685.
     {:() j SO, values 1.50 (doublet, 6H, J - 6 Hz, 2 X -CHCHj),
    1113
    2.05, 2.08 (singlet, singlet, —COCH 3.70 (broad, singlet, 2H, H at position 2), 4.15, 4.55 (doublet, doublet, 2H, J 14 Hz - SNGY - in position 3), 4.32 (multiplet, 1H, -CHN3), 5.05 (doublet, 1H, J 5 Hz, H in position 6), 5.51 (broad, 1H, triazole-NH-), 5 , 75 (multiplet, 1H, H at position 7), 6.12 (singlet, 1H CHCONH), 6.92, 7.01 (quartet, quartet, 1H, J 6 Hz, SK CHO-), 7.45 ( multiplet, 5H, phenyl), 7.75 (singlet, 1H, H at position 4 of triazole), 8.72 broad, NN, -NH, 9.50 (dublet, 1H, J 9 Hz, -CONH- ).
    1-Isobutyryloxyethyl 7-D-O- (I- -alanyl) almond amido-3- (1,2,3-thiadiazol-5-yl) thiomethyl-3-cephem-4-carboxylate hydrochloride (compound 399).
    IR (nujol, cm): 3250, 1780, 1740, 1690.
    NMR (CD 3) 2CO, values of / J: 1.16 (doublet, 6H, J 7 Hz, - (CE ,, 1.46 (doublet, GN, J 8 Hz, 1.53, 1.56 (doublet , doublet, 1H, J 6 Hz, CHjCHO-), 2.3-3.0 (multiplet, W, -CH (CHj) 2), 3.7 (wide, singlet, 2H, Hj in position 2), 4.134 , 58 (multiplet, 3N, -CH2S at position 3, -CHNHj), 5.1 (doublet, W, J 5 Hz, H at position 6), 5.7 (multiplet, 1H, H at position 7), 6 , 05 (singlet, Ш, -CHCONH-), 6.9, 7.15 (quartet, quartet, Ш, J 6 Hz-СНСН), 1, (multiplet, 5Н, phenyl), 8.95 (wide, ЗН -NH3), 9.32 (doublet, W, J 9 Hz, -CONH-), 9.57 (singlet, 1H, H at position 4 of the thiadiazole).
    Pivaloyloxymethyl (1-adanyl) -p-hydroximindalamido-3- (5-methyl--1, 3,4-thiadiazol-2-sh1), thiomethyl-3-cephem-4-carboxylate hydrochloride (compound 465).
    IR (nujol, cm): 3350, 1780, 1740, 1685.
    NMR (SVS) 250, values 1.18 (singlet, 9H, -ciiCH,)), 1.46 (ZN doublet, J 7 Hz, CHjCH-), 2.67 (ZN singlet, thiadiazole-CHj), 3 , 65 (broad, singlet, .2H, position 2), 4.25 (multiplet, W, CHjCH-), 4.14, 4.60 (doublet, doublet, 2H, J 14 Hz, in position 3), 5 , 05 (doublet, 1H, J 5 Hz, H at position 6), 5.65-6.00 (multiplet, 4 H-, H at position 7, -OH), 6.10 (singlet, 1H,
    9

    5 - Q
    j
    0 s
    12 12
    -CHCONH-), 6.73, 7.25 (doublet, doublet 4H, J 9 Hz, phenyl), 8.70 (wide, ЗН, -NH,), 9.43 (doublet, 1H, J 9 Hz -CONH-).
    1-Acetoxyethyl 7-CB-0- (1-alanyl) -almond-3-carbamoyloxymethyl-3-cephem-4-carboxylate hydrochloride (compound 410).
    IR (Nujol, CM): 1780, 1750, 1700, 1680.
    NMR (SVS) 250, values 1.48 (doublet, 6H, J = 7 Hz, 2 to CHjCH-),
    2.08 (singlet, 3N, CHjCO-), 3.60 (broad, singlet, 2H, H- in position 2), 4.25 (multiplet, W, SNDSOH-), 4.65, 4.90 (doublet , doublet, J 14 Hz, -CHjO - in position 3), 5.08 (doublet, 1H, J 5 Hz, H in position 6), 5.57-5.88 (multiplet, W, H in position 7) , 6.10 (singlet, W-CHCONH-), 6.60 (wide, 2H, - -CONHj), 6.92, 7.00 (quartet, quartet, W, J 7 Hz, CHjCHO-), 7, 40 (multiplet, 5H, phenyl), 8.68 (broad, 3N, -NH), 9.45 (doublet, 1H, J 9 Hz, -CONH).
    1-Ethoxycarbonyloxy is methyl - (prolyl) almond-amido-3- (5-methyl--1,3,4-thiadiazol-2-yl) thiomethyl-3-cephaem-4-carboxylate hydrochloride (compound 1 53).
    IR (nujol, cm): 1780, 1760, 1690.
    NMR (CDj), SO, 1.21 (triplet, 3N, J = 7 Hz), 1.53 (doublet, 3N, J = 5 Hz, -OCHCHj), 1.75-2.38 (multiplet, 4H, CHj at positions 3 and 4 of proline), 2.69 (singlet, GH, thiadiazole CH,), 3.1-3.5 (multiplet, 2H, CH at position 5 of proline), 3.64 (wide, singlet, 2H H at position 2), 3.9-4.8 (multiplet, 5H, at position 3, -CHjCH, CH at position 2 of proline), 5.08 (doublet, W, J 5 Hz, CH at position 6) , 5.56-5.95 (multiplet, W, CH at position 7), 6.12 (singlet, W, -CHCONH-), 6.88 (quartet, quartet, W, J 5 Hz, CHjCHO), 7 , 58 (broad, singlet, 5H, phenyl), 9.5 (doublet, 1H, J 9 Hz, -CONH-), 8.5-10.8 (broad, 2H, -KNg).
    Other compounds of the formula I are prepared analogously, the values of the radicals of which are explained in Table. 1, possessing the following physico-chemical properties.
    1313
    Compound 11.
    IR (Nujol): 3360-3180, 1780, 1760, 1690.
    HMP (CDj) 2 SO, values of / J: 1.16 (singlet, 9H, -CCCHj)), 2.68 (singlet, OG, thiadiazole, -CH), 3.63 (broad singlet, 2H, E in position 2 4.15, 4.54 (doublet, doublet, 2H, J 14 Hz, - in position 3), 5.05 (doublet, 1H, J 5 Hz, H - in position 6), 5.62 6.00 (multiplet, 3N, - H at position 7, -C02CH2-), 6.13 (singlet, 1H, -CH-OCO), 7., 43 (multiplet, 5H, phenyl), 8.54 (wide , singlet, ЗН, -NHj), 9.46 (doublet, 1Н, J 9 Hz, - SOSH-)
    Compound 13.
    IR (nujol, cm): 1780, 1755,
    1690.
    NMR (003) values 1.22
    (triplet, 3N, J 7 Hz, -CHjCH), 1.53 (doublet, 3N, J 6 Hz, -OCHCHj) 2.68 (singlet, 3N, thiadiazole - CHj), 3.64 (wide, singlet, 2H , - Hj in position 2), 3.8-4.7. (Multiplet, 6H,, CHjNHj, -CHjS - in position 3), 5.05 (doublet, W, J - 5 Hz, H in position 6) , 5.5-5.91 (multiplet, 1H, - H in position 7) 6.13 (singlet, Ш, - СИСО), 6.8, 6.89 (quartet, quartet, Ш, J 6.5 Hz, -OCNSS), 7.15-7.78 (multiplet, 5H, phenyl), 8.3-9.1 (wide is 3N, - NHj), 9.46 (doublet, 1H, J 9 Hz, -CONH-) ..
    Compound 14.
    IR (nujol, cm): 1815, 5780,. 1690.
    NMR C (SVS) 2 so, value: 2.18 (singlet, GN, dioxolen, -CH3), 2.70 (singlet, GH, thiadiazole-CH), 3.65 (wide, singlet, 2H, - H in position 2), 4.0 (broad, singlet, 2H, -OCOCHj-), 4.05, 4.72 (doublet, double-year, - 2H, J 14 Hz, -CHS- in position 3), 5, 04 (doublet, W, J 5 Hz, -N at position 6) 5.15 (wide, singlet, 2H, -COjCHj-), 5.72 (multiplet, W, -H at position 7), 6.12 ( singlet, 1Н, -СНСОШ-), 7.43 (multiplet, 5Н, phenyl), 8.75 (broad, ЗН, -Шз), (doublet, Н, J «9 Hz, -CONH-).
    Compound 21.
    IR (nujol, cm): 1780, 1750, 1685..
    NMR (SVS), values 0.9 (yublet, 6H, J 6.5 Hz, - (CH3) 2) 5
    five
    91
    °
    0
    five
    , „
    ;14
    1.5 (doublet, 6H, J 6.5 Hz, CHjCHNHp, 1.7-2.2 (multiplet, 1H, -CH (SND)), 2.18 (broad, singlet, 2H, -), 2, 68 (singlet, 3N, thiadiazole - CHj), 3.84 (broad, singlet, 2H, - position 2), 3.9–4.75 (multiplet, 3N, -CHNH,-at position 3), 5, 06 (doublet, 1H, J 5 Hz, -N - at position 6), 5.53-5.91 (multiplet, 1H, -H at position 7), 6.13 (singlet, 1H, - SNCO-), 6.93, 7.02 (quartet, quartet, W, J 6.5 Hz,), 7.2-7.75 (multiplet, 5H, phenyl), 8.5-9.1 (broad, 3N, - NH), 9.46 (doublet, 1H, J 9 Hz, - CONH).
    Compound 24.
    Cheka (Nujol): 1785, 1745, 1695.
    NMR t (CDj) 2SO, f values: 1.15 (singlet, 9H, -C (CH3) p, 1.49 (doublet, 6H, J 6 Hz, 2 X), 2.68 (singlet, 3N, thiadiazole - CH), 3.65 (broad, singlet, 2H, -H2 in position 2), 3.85-4.75 (multiplet, 3N, -CHjg- in position 3, CHjCHCO-), 5.08 (doublet, 1H, J 5 Hz, -H in position 6), 5.55-5.95 (multillet, W, -H in polo 7), 6.13 (singlet, 1H, -CHCONH- 6.9-7, 05 (multiplet, 1H, -CH-CH,), 7.44 (multiplet, 5H, phenyl), 8.75 (broad, 3N, -NHj), 9.45 (doublet, N, J 9 Hz, - CONH -).
    Compound 26.
    IR (nujol, cm): 3350, 1780, 1740, 1675.
    NMR f (SBz) 2 SO, -values of 1.48 (doublet, J = 7 Hz, LC, CHjCH-), 2.66 (singlet, 3N, thiadiazole-CH3), 3.68 (broad, singlet, 2H in position 2), 4.08-4.60 (multiplet, ЗН, -СН2 S - in position 3, - СНСН 3), 5.04 (doublet, J 5 Hz, 1Н, -Н in position 6), 5 , 70 (multi-bullet, 1H, -H in-position 7), 6.12 (singlet, W, H) SNSO), 7.43 (multiplet, 5H, phenyl), 7.64 (doublet, J 2 Hz, W , —C02CH-), 7.89 multiplet, 4H, ftalid, 8.69 (broad, singlet, 3N, -NH), 9.47. (Multiplet, W, -CONH-).
    1680.
    Connection 42.
    IR (nujol, cm): 1815, 1780,
    I f
     V
    NMR t (CD ,,) 2SO values: 0.97 (doublet, J = 7 Hz, 6H, (CH3) g), 2.17 (singlet, 3N, dioxolen-CHj), 2.2 (multiplet, W, - CH (CH) 2), 2.67
    (singlet, 3N, thiadiazole-CHj), 3.63 (broad, singlet, 2H, -Hj at position 2), 40 (multiplet, 1H, - SNSOg), 4.11, 4.56 (doublet, doublet, J 14 Hz, 2H, -CHj S - in position 3), 5.04 (doublet, J 5 Hz, 1H, -H in position 6), 5.16 (singlet, 2H, -COj-CHj), 5.71 (doublet, doublet, J 5 and 9 Hz H in position 7), 6.15 (singlet, W, -COjCH-), 7.63 (multiplet, 5H, phenyl), 8.8 (broad, 3N, -NH ,), 9.4 (doublet, J 9 Hz, -CONH-),
    Connection 64.
    IR (nujol, cm-): 1780, 1755, 1675.
    NMR f (CDj) 2SO, oCJ values: 1.50 (doublet, 3N, J 6 Hz, -CHCHj), 2.03, 2.05 (-single, singlet, 3N, -COOHj), 2.69 (singlet , ZN, thiadiazole-CHj), 2.91 (doublet, 2H,), 3.65 (broad, singlet, 2H, H2 in positonO
    singlet, 2H, -Hj at position 2), 3.93–4.76 (multiplet, 3N, -GHjS - at position 3, -CHNHj), 5.04 (duplicate 1H, J 5 Hz, -H at position 6 ), 5 5.17 (broad, singlet, 2H, -COjCHj 5.72 (multiplet, 1H, -H in position 7), 6.10 (singlet, 1H, -CNSSO7, 45 (multiplet, 5H, phenyl), 8.76 (broad, singlet, 3N, -NHj), 9.46 (doublet, 1H, J 9 Hz, -CONH-).
    Connection 83.
    IR (nujol, cm): 1780, 1755, 1670.
    NMR C (CD5) jSO, values 1.23 (triplet, 3N, J = 7 Hz, -OCHj - CHj) .1.52 (doublet, 3N, J 6 Hz, -CHCHN) 2.25 (multiplet, 4H ,), 2.68 (singlet, 3N, thiadiazole — CHj), 3.6 (broad, singlet, 2H, —H2 in the position of NII 2), 3.90–4.95 (multiplet, 5H, –OCHjCHj , - at position 3, -CHNHg), 5.05 (doublet, W, J 5 Hz, H at position 6), 5.55-5.93 (cartoon
    thirty
    SRI 2,3,90-4,65) (multiplet, ЗН, -CHiS - in position 3, -CHNHp, 5,06 25 position 7), 6,43- (doublet, Ш, J 5 Hz, -Н in position- (multiplet, 3N, -CH-CH, SRI 6), 5.50-5.95 (multiplet, W, -H in position 7), 6.06 (singlet, W,; -CH-SOSH-) , 6.89, 6.98 (quartet quartet, 1H, J 6 Hz, -CH-CH), 7.05-7.85 (multiplet, 7H, phenyl, -COUR), 8.57 (broad, 3N, NH,), 9.45 (doublet, W, J 9 Hz, -CONH-).
    Connection 69.
    IR (nujol, cm): 1780, 1755, 1675.
    NMR (CDj) 2SO, values 1.22 (triplet, 3N, J 7 Hz, -CHjCH), 1.53 (doublet, 3N, J 6Hz, CH: (CHSO-2,69 (singlet, 3N, thiadiazole-CH ), 2.91 (doublet, 2H, -CH2.CO-), 3.66 (broad, singlet, 2H, NH2 in position 2), 3.9-4.78 (multiplet, 3N, -CHjS - in position 3, -СНШ), 5.06
    35
    40
    -CONHj), 7.16-7.80 (multiplet, 5H, phenyl), 8.82 (broad, 3N, -NH), 9.48 (doublet, 1H J 9 Hz, CONH-).
    Connection 84.
    IR (nujol, cm): 1820, 1780, 1760, 1665.
    NMR (C0z) 250, rfj values: 2.17 (singlet, 3N, dioxolen-SNe), 2.3 (multiplet, 4H, - (CH1) -), 2.67 (singlet, 3N, thiadiazole-CHj ), 3.6 (broad, singlet, 2H, -Hj at position 2), 3.9-4.8 (multiplet, 3N, -CHjS at position 3, -CH, Hp, 5.07 (doublet, J 5 Hz, W, –H in position 6), 5.15 (singlet, 2H, -), 5.7–5.92 (multiplet, IH, –H in position 7), 6.11 (singlet, W, - OSSNO), 7.3 (multiplet, 7H,
    (doublet, W, J 5 Hz, -N in position--SON, phenyl), 8.78 (broad, 3N, SRI 6), 5.5-5.94 (multiplet, 1H, -N -NHj), 9.40 (doublet, J 9 Hz, 1H,
    -USH-5.
    Connection 139.
    IR (Nujol, CM -): i780, 1755,
    in position 7), 6.10 (singlet, W, -CHGONfl-) 6.83, 6.90 (quartet, quartet, 1H, J 6 Hz, - CHCH,), 7.40 (multiplet, 5H, phenyl) , 8.52 (shi-p 1680. rock, singlet, 3N-NHS), 9.46 (double-year, 1H, J 9 Gi, -CONH-).
    Connection 70.
    IR (nujol, cm): 1815, 1780, 1675.
    NMR (CPM) 230, meaning “G. 2.16 (singlet, ZN, dioxolen, -CHj), 2.70 (singlet, ZN, thiadiazole - CHj), 2.92 (doublet, 2H, -CHiCO-), 3.66 (broad.
    NMR (CDj) 2SO, starting dJ: 1.20-2.25 (broad, 6H, - (CH);), 1.23 (triplet, 3N, J 7 Hz, -CHjCHj), 1.54 ( doublet, ZN, J 6 Hz, CH, SNOSCO jj 2.68 (singlet, ZN, thiadiazole —CHj), 2.70 (broad, 2H,), 3.68 (broad, singlet, 2H, -H in position 2 ), 3.90-4.85 (multiplet, 5H-CH2S - in position 3,
    singlet, 2H, -Hj in position 2), 3.93-4.76 (multiplet, GN, -GHjS - in position 3, -CHNHj), 5.04 (doublet, 1H, J 5 Hz, -N in position 6), 5.17 (broad, singlet, 2H, -COjCHj), 5.72 (multiplet, 1H, -H in position 7), 6.10 (singlet, 1H, -SHSSOSH) .- 7.45 (multiplet , 5H, phenyl), 8.76 (broad, singlet, 3N, -NHj), 9.46 (doublet, 1H, J 9 Hz, -CONH-).
    Connection 83.
    IR (nujol, cm): 1780, 1755, 1670.
    NMR C (CD5) jSO, 1.23 (triplet, 3N, J = 7 Hz, -OCHj - CHj), 1.52 (doublet, 3N, J 6 Hz, -CHCHN), 2.25 (multiplet, 4H,), 2.68 (singlet, 3N, thiadiazole — CHj), 3.64 (broad, singlet, 2H, —H2 in position 2 II), 3.90–4.95 (multiplet, 5H, -OCHjCHj , - at position 3, -CHNHg), 5.05 (doublet, W, J 5 Hz, -H at position 6), 5.55-5.93 (multi position 7), 6.43- (multiplet, ZN, -CH-CH,
        position 7), 6.43- (multiplet, 3N, -CH-CH,
    -CONHj), 7.16-7.80 (multiplet, 5H, phenyl), 8.82 (broad, 3N, -NH), 9.48 (doublet, 1H J 9 Hz, CONH-).
    Connection 84.
    IR (nujol, cm): 1820, 1780, 1760, 1665.
    NMR (C0z) 250, rfj values: 2.17 (singlet, 3N, dioxolen-SNe), 2.3 (multiplet, 4H, - (CH1) -), 2.67 (singlet, 3N, thiadiazole-CHj ), 3.6 (broad, singlet, 2H, -Hj at position 2), 3.9-4.8 (multiplet, 3N, -CHjS at position 3, -CH, Hp, 5.07 (doublet, J 5 Hz, W, –H in position 6), 5.15 (singlet, 2H, -), 5.7–5.92 (multiplet, IH, –H in position 7), 6.11 (singlet, W, - OSSNO), 7.3 (multiplet, 7H,
    1680.
    NMR (CDj) 2SO, starting dJ: 1.20-2.25 (broad, 6H, - (CH);), 1.23 (triplet, 3N, J 7 Hz, -CHjCHj), 1.54 ( doublet, ZN, J 6 Hz, CH, SNOSO 2.68 (singlet, ZN, thiadiazole —CHj), 2.70 (broad, 2H,), 3.68 (broad, singlet, 2H, -H in position 2) , 3.90-4.85 (multiplet, 5H, -CH2S - at position 3,
    ten
    t5
    -CHNHj), 5.07 (doublet, IH, J 5 Hz, -H in position 6), 5.67-5.93 (multiplet, IH, -H - in position 7), 6.16 (singlet , 1H, -CHCONH-), 6.83, 6.91 (quartet, quartet, 1H, J 6 Hz, -CHCHj), 7.46 (multiplet, 5H, phenyl), 8.15 (wide, 3N, NHj ), 8.81 (broad, 3N, -NHj), 9.48 (doublet, 1H, J 9 Hz, -CONH-).
    Connection 140.
    IR (Nujol): 1820, 1780, 1750, 1680.
    NMR G (SVS) 250, values 1.2-2.2 (broad, 6H, - (CE) -, 2.18 (singlet, 3N, dioxolen-CH3), 2.67 (singlet, 3N, thiadiazole - CHj ), 2.70 (broad, 2H, -CH2NH3), 3.65 (broad, singlet, 2H, - position 2), 4.0-4.7 (multiplet, 3N, -in position 3, -CHNH), 5.06 (doublet, W, J 5 Hz, -N in position 6), 5.14 (singlet, 2H,), 5.75 (multiplet, W, H in position 7), 6.12 (singlet, W , -CHCONH-), 7.44 (multiplet, 5H, phenyl), 8.14 (broad, 3N, NHj), 8.78 (wide, 3N, -NH), 9.43 (doublet, 1H, .J 9 Hz, CONli-).
    Connection 150.
    IR (nujol, cm): 1785, 1745, ° 1695.
    NMR (CDj) 2SO, values 1, 14 (singlet, 9H: -C (CH3) h), 1.50 - (oak-CHjS - in position 3,), 5, (doublet, J 5 Hz, 1H, -H in position 6), 5.15 (singlet, 2H, 5.52-5.9 (multiplet, W, -H in position 7), 6.02 (singlet, W, -COj CH 7.4 ( multiplet, 5H, phenyl), 8.91 (broad, 4H, -CHN, -NHj), 9.38 doublet, J 9 Hz, -SSh-).
    Connection 330,
    IR (nujol, cm): 1780, 1750, 1690.
    NMR C (CDj) jSO, values 1.48 1.50 (doublet, doublet, 3N, J 6 Hz, -CHCHj), 2.03, 2.07 (singlet, singlet, 3N, -COCHj), 3.65 (wide
    20
    25
    singlet, 2H, -Hj in position 2), 3.97 (multiplet, 5H tetrazole-CH CO-), 4.15, 4.32 doublet, doublet, 2H, J 14 Hz, CHjS - in position 3), 5 , 02 (doublet, W, J 5 Hz, - H at position 6), 5.6 (multiplet, W, - H at position 7) 6.13 (singlet, W, -CH-CONH-), 6.92 7.01 (quartet, quartet, 1H, J 6 G -CHCHj), 7.43 (multiplet, 5H, feni 8.55 (wide, 3N, -NHj) -, 9.45 (oak years, W, J 9 Hz, -CONH).
    Connection 332.
    IR (nujol, cm): 1780, 1740, 1690.
    NMR (SVS) hZO, value: 1.15 (singlet, 9H; -C (CH3) h), 1.51 (doublet, NN, J 6 Hz, -O-CH-CHj), 3.66 (broad, singlet, 2H, -Hj in position
    years, 3N, J 5 Hz, CHjCH-), 1.702, 40 (multiplet, 4H, E at position 35 NII 2), 3.70-4.75 (multiplet, 7H,
    3 and position 4 of proline), 2.68 (syntherazole-CHj, CH.CO-, -CHjS -in
    position 3), 4.9–5.25 (multiplet, 1H, –N in a pohuzhzhenii 6), 5.5–5.9
    .gluTu MN, thiadiazole - CH), 3.1-3.5 (multiplet, 2H, -H in position 5 of proline), 3.63 (broad, singlet, 2H, -H in position 2), 4.0- 4.75 (multiplet., ZN, - in position 3, -N in position 2 of proline), 5.06 (doublet, W, TH 5 Hz, -N in position 6),
    40
    "(Multiplet, 1H, -H at position 7), 6.13 (singlet, 1H, -CH-CONH-), 6.65 7.10 (multiplet, 1H, -0-CH-CHj), - 7, 44 (multiplet, 5H, phenyl), 8.75 (broad, 3H, -NHj), 9.45 (doublet.
    5.55-5.90 (multiplet, 1H, -H in polo-W, J 9 Hz, -conH-).
    7), 6.12 (singlet, Ш, -СНСОН- 6.88 ,, 6.96 (quartet, quartet, 1Н, J 5 Hz, -СНСН ,,), 7.44 (multiplet, 5Н, phenyl) , 9.48 (doublet, W, J 9 Hz, -CONH-), 9.0-10.0 (broad, 2H, -NH2).
    Connection 210.
    IR (nujol, cm): 1815, 1780, 1760 ,, 1670, 1630.
    NMR (003) 2 SO, cTj values: 2.18 (singlet, 3N, dioxole, -CH), 2.68 (, 3N, thiadiazole-CH 3, 3.68 (broad, 4H, -Hj, in position 2 ,), 3.8-4.1 (multiplet, 4H.,
    50
    Connection 335. IR (nudzhol, cm): 1780, 1760, 1690.
    NMR t (CD) SO, values 1.21 (triplet, 3N, J 7 Hz, -CHjCHj), 1.53 (doublet, 3N, J 6 Hz, -OCCHH,
    3.64 (broad, singlet, 2H, Hj. At position 2), 3.90-4.90 (multiplet, 9H, tetrazole — CHj, CHjS at position 3,), 5.01 (oak-years, W, J 5 Hz, -N in position 6
    5.65 (multiplet, W, -H in position 7), 6.12 (singlet, 1H, -CHCONH6, 85 (multiplet, W, -OCCHH), 7.4
    -CHjS - in position 3,), 5.04 (doublet, J 5 Hz, 1H, -H in position 6), 5.15 (singlet, 2H,), 5.52-5.9 (multiplet, W, —H at position 7), 6.02 (singlet, W, —COj CH — 7.4 (multiplet, 5H, phenyl), 8.91 (broad, 4H, —CHNH, —NHj), 9.38 doublet, J 9 Hz, -USH-).
    Connection 330,
    IR (nujol, cm): 1780, 1750, 1690.
    NMR C (CDj) jSO, values 1.48, 1.50 (doublet, doublet, 3N, J 6 Hz, -CHCHj), 2.03, 2.07 (singlet, singlet, 3N, -COCHj), 3, 65 (wide)
    singlet, 2H, -Hj in position 2), 3.97 (multiplet, 5H tet, razol-CH CO-), 4.15, 4.32 doublet, doublet, 2H, J 14 Hz, CHjS - in position 3) , 5.02 (doublet, W, J 5 Hz, - H in position 6), 5.6 (multiplet, W, - H in position 7), 6.13 (singlet, W, -CH-CONH-), 6.92, 7.01 (quartet, quartet, 1H, J 6 Hz, -CHCHj), 7.43 (multiplet, 5H, phenyl 8.55 (wide, 3N, -NHj) -, 9.45 (doublet, W, J 9 Hz, -CONH).
    Connection 332.
    IR (nujol, cm): 1780, 1740, 1690.
    NMR (SVS) hZO, value: 1.15 (singlet, 9H; -C (CH3) h), 1.51 (doublet, NN, J 6 Hz, -O-CH-CHj), 3.66 (broad, singlet, 2H, -Hj at position 2), 3.70-4.75 (multiplet, 7H,
    40
    "(Multiplet, 1H, -H in position 7), 6.13 (singlet, 1H, -CH-CONH-), 6.65-7.10 (multiplet, 1H, -0-CH-CHj), - 7 , 44 (multiplet, 5H, phenyl), 8.75 (broad, 3N, -NHj), 9.45 (doublet.
    0
    Connection 335. IR (nudzhol, cm): 1780, 1760, 1690.
    NMR t (CD) SO, values 1.21 (triplet, 3N, J 7 Hz, -CHjCHj), 1.53 (doublet, 3N, J 6 Hz, -OCCHN),
    3.64 (broad, singlet, 2H, Hj. In position 2), 3.90-4.90 (multiplet, 9H, tetrazole — CHj, CHjS in position 3,), 5.01 (oak-years, W, J 5 Hz, -N in position 6),
    5.65 (multiplet, W, -H at position 7), 6.12 (singlet, 1H, -CHCONH, 6.85 (multiplet, W, -OCCHH), 7.40
    (multiplet, 5H, phenyl), 8.68 (broad, singlet, 3N, -NHj), 9.46 (doublet, 1H, J 9 Hz, -CONH-).
    Compound 336
    IR (Nujol): 1815, 1780, 1690.
    NMR (CDj) 2SO, value 2.18 (singlet, 3N, dioxolen-CH), 3.64 (broad, singlet, 2H, -Hj at position 2), 3.95 (multiplet, 5H, tetrazole-CHj , -OCOCHj-), 4.05, 4.72 (doublet, doublet, 2H, J 14 Hz, - - in position 3), 5.04 (doublet, 1H, J 5 Hz, -N in position 6), 5.15 (pshroka singlet, 2H,), 5.72 (multiplet, 1H, -H in position 7), 6.12 (singlet, 1H, -CHCONH-) 7.43 (multiplet, 5H, phenyl), 8 , 75 (broad-a, 3N, -NHj), 9.45 (doublet, W, J 9 Hz, - CONH--).
    Connection 344.
    IR (nudzhol, cm); 1780, 1755, 1690.
    NMR C (SVS) 250, values of / H: 1.49 (doublet, 6H, J 6 Hz, 2 X CHjCH-), 2.09 (singlet, 3N, CHjCO-), 3.65 (wide, singlet, 2H , -K in position 2), 3.92 (singlet, 3N, tetrazole-CH3), 4.0-4.8 (multiplet, 3N, -CH -S - at position 3 /, -CH-NHj), 5, 08 (doublet, 1H, E 5 Hz, - H at position 6), 5.74 (multiplet, 1H, -H at position 7), 6.12 (singlet, W, -CH-CO H-), 6, 95 (multiplet, W, J 6 Hz, SNOOM-), 7.45 (multiplet, 5H, phenyl), 8.7 (wide MN, - t, 9.45 (doublet, 1H, 9 Hz, -CONH-) .
    Compound 346.
    IR (Nujol, see b: 1780, 1740, 1690.
    NMR C (SV3) 280, value 1.14 (singlet, 9H, -C (CH3) h), 1.44, 1.55 (doublet, doublet, 6H, J 6 Hz,. -OCH-CHj, CHj -CH-CO-), 3.65 (broad singlet, 2H, -H in position 2) 3.75-4.7 (multiplet, 6H, tetrazole, -CHgS in position 3), 4.9- 5.2 (multiplet, W, –Iv position 6), 5.5–5.9 (multiplet, 1H, —H at position 7), 6.12 (singlet, 2H, —CH-CONH-), 6, 65-7.10 (multiplet, 16, -OCH-CH3), 7.4 (multgasht, 5H, phenyl), 8.75 (broad, 3N, -NHj), 9.45 (doublet, 1H,. J 9 Hz, -CONH-)
    Connection 347.
    IR (Nujol, cm) :. 1785, 1755, 1690.
    0
    five
    0
    five
    0
    five
    0
    five
    NMK (CDjjSOSO, values 1.16 (singlet, 9H, -C (CH3)), 1.47 (doublet, 3H, J = 7 Hz, -CH-CH3), 3.64 (broad, singlet, 2H, -H in position 2), 3.93 (singlet, 3N, tetrazole —CHj), 4.0–4.7 (multiplet, 3N, –– position 3, –CHNH,), 5.02 (doublet, W, J 5 Hz , -H at position 6), 5.60-6.05 (multiplet, 3N, - H at position 7, -COjCHj-), 6.13 (singlet, 1H, -CH-CONH-), 7.42 ( multiplet, 5H, phenyl), 8.63 (broad, 3N, -Sh), 9.45 (doublet, 1H, J 9 Hz, - CONH-).
    Connection 349.
    IR (nujol, cm): 1785, 1765, 1690.
    NMR (CD3) 2SO, values 1.22 (triplet, 3N, J. 7 Hz, -CHjCHj), 1.48 (doublet, 3N, J 7 Hz, CHjCHCO-),
    1.50 (doublet, 3N, J 4 Hz, -OCHCHj), 3.65 (broad, singlet, 2H, -Hj at position 2), 3.9-4.4 (multiplet,
    8H, tetrazole CHj, - CHjS - at position 3, CHjCHj, -CH-Shr, 5.07 (doublet, 1H, J 5 Hz, - H at position 6 5.7 (multiplet, 1H, - H at position 7), 6.12 (singlet, 1H, -CHCONH), 6.85 (multiplet, 1H, -O-CHCHj), 7.45 (multiplet, 5H, phenyl), 8.68 (broad, 3N, -NH), 9 , 46 (doublet, 1H, J 9 Hz, - CONH-).
    Compound 350.
    IR (Nujol): 1815, 1780, 1690.
    NMR (CD3) 2 SO, values: 1.48 (doublet, 3N, J = 7 Hz, -CHCHj) - 2.18 (singlet, 3N, dioxole - CH.), 3.62 (broad, singlet, 2H, - Hj in position 2), 3.92 (singlet, GH, tetrazole — CH3), 4.20 (multiplet, W, —CH — NHj), 4.07, 4.65 (doublet, doublet, 2H, J 14 Hz, -СНг in position 3), 5.04 (doublet, Ш, J 5 Hz, - Н in position 6), 5.15 (singlet, 2Н, - -COjCH.-), 5.73 (multiplet, Ш - H in position 7), 6.13 (singlet, 1H, -CH-SOSH-), 7.4 (multiplet, 5H, phenyl), 8.73 (broad, 3N, -NH3), 9.46 ( doublet, 1H, J 9 Hz, -CONH).
    Connection 392.
    IR (iujol, cm-): 1780, 1760, 1690.
    NMR (IPS) 80 value 1.48,
    1.51 (doublet, doublet, ZN, J 6 Hz, -CHjCH-), 2.04, 2.07 (singlet, singlet, ZN, CH3SO-), 3.66 (wide, 2H, -N in position 2), 3,96 (wide.
    snnlet, 2H, -CH CO-), 4.13, 4.50 (doublet, doublet, 2H, J 14 Hz, - CHj-, in position 3), 5.06 (doublet, 1H, J .5 Hz, - H in position 6), 5.7 (multiplet, 1H, -H in position 7), 6.11 (singlet, 1H, -CHCSO-), 6.92
    7.01 (quartet, quartet, 1H, J 6 Hz, - CHCHj), 7.42 (multiplet, 5H, phenyl), 8.3 (broad, 3N, -NH), 8.92 (singlet, 1H, tetrazole , -H), 9.48 (doublet, 1H, J 9 Hz, -CONH-).
    Compound 393.
    IR (nujol, cm): 1780, 1750, 1690.
    LMR t (CDj), j so, c / J values: 1.15 (doublet, 6H, J 7 Hz, -CH x 2), Ij54, 1.56 (doublet, doublet, GH, J 6 Hz, SNSNO- ), 2.3-2.0 (multiplet, 1H, -CH (CH3) 2), 3.68 (broad, singlet, 2H, -H in position 2), 3.95 (broad, singlet, 2H, - CH, jCO-) 4.12-4.5 (doublet, doublet, 2H, J 14 Hz, - SNg S - in position 3), 5.10 (doublet, W, J 5 Hz, - H in position 6) , 5.72 (multiplet, Ш, -Н in position 7), 6.12 (singlet, Ш -CHCONH-), 6.93, 7.01 (quartet, quartet, J 6 Hz, -CHCHj), 7, 45 (multiplet, ZN, phenyl), 8.92 (singlet, 1H, thiadiazole - H), 9.5 (multiplet, 4H,
    -t, -cqNH).
    Connection 395.
    IR (Nujol, 1780, 1760, 1690
    NMR G (CO3) 280, values 1.21 (triplet, 3N, J 7 Hz), 1.53 (doublet, 3N, J 6 Hz, -OCHCHj) 3.63 (broad, singlet, 2H, -H in position 2), 3.7-4.8 (mulg tiplet, bN, -CHjCHj, -CHj in position 3), 5.06 (doublet, 1H, J 5 Hz, -N B position 6), 5.45 -5.92 (multiplet, 1H, in position 7), 6.13 (singlet, W, -CHCNO-), 6.81, 6.88 (quartet, - quartet, W, L 6.5 Hz, - OCHCHj 7.5 (multiplet, 5H, phenyl), 8.7 (broad, 3N, - Hj), 8.92 (singlet, IHj, thiadiazole - H), 9.5 (W, doublet, J 9 Hz, - CONH-).
    Connection 396.
    IR (nujol, cm): 1815, 178.0, 1690.
    NMR (SBR) 250, value 2.18 (singlet, GN, dioxole - CHj), 3.65 (broad, singlet, 2H5 - Hj at position 2), 4.0 (broad singlet, 2H, -CH CO-) , 4.04-4.73 (doublet, doublet, 2H, J 14 Hz, in position 3),
    five

    ,

    0
    5.05 (doublet, W, J 5 Hz, -N in position 6), 5.15 (broad, singlet, 2H, -COjCHj-), 5.72 (multiplet,) H, -H in position 7), 6.12 (singlet, W, -CHCONH), 7.45 (multiplet, 5H, phenyl), 8.9 (broad, 3N, -NHj), 8.9 (singlet, H, thiadiazole - H), 9 , 5 (doublet, 1H, J 9 Hz, -CONH-).
    Connection 398.
    IR (Nujol, see b: 1780, 1755, 1685.
    NMR (CDg) 2 SO, value: 1, 48 (doublet, GN, J 7 Hz, CHjCHCO-), 1.48, 1.50 (doublet J doublet, GH, J 6 Hz, CH2CHO-), 2.05, 2.09. (Singlet, singlet, 3N, CHjCO-), 3.65 (broad, singlet, 2H, -H in position 2), 4.14, 4.54 (doublet, doublet, 2H, J 14 Hz, -CHjS - in position 3), 4.81 (multiplet, W, .- CHjCH-), 5.08 (doublet, IH, J 5 Hz, -H in position 6), 5.75 (multiplet, 1H - H in position 7), 6.11 (singlet, 1H, -SHCO-), 7.02 (quartet, quartet, 1H, J 6 Hz, СНзСНО), 7.43 (multiplet, 5H, phenyl), 8.8 ( broad, 3N, NH), 8.93 (singlet, 1H, thiadiazole-H), 9.51 (doublet, 1H, J 9 Hz, -CONH-).
    Compound 401.
    IR (nujol, cm): 1785, 1765, 1690.
    NMR (CDj) 2SO, values of 1.21 (triplet, 3N, J = 7 Hz), 1.46 (doublet, 3N, J = 7 Hz, CH = CH2NO, 1.51 (doublet, 3N, J = 4 Hz, - OCHCH) / 3.64 (broad, singlet, 2H, -H „in position 2), 3.9-4.3 (multiplet, 5H,, CHS -in position 3, - CHNH /), 5.06, 5 , 08 (doublet, doublet, 1Н,, -Н in position 6), 5.7 (multiplet, Ш, - Н in position 7), 6.1 (singlet, Ш, -СНСОШ- 6.82, 6.91 ( quartet, quartet, W, J 4 Hz, CHjCHO-), $ 7.4 (multiplet, 5H, phenyl), 8.7 (broad, 3N, -NH), 8.92 (singlet, W, thiadiazole - H) , 9.56 (doublet, W, J 9 Hz, -CONH-).
    Connection 402.
    IR (nujol, cm): 1815, 1780, 1690.
    NMR (CDj) SO, value: 1.43 (doublet, GN, J = 7 Hz), 2.17 (singlet, GH, dioxole - CHj), 3.63 (broad, singlet, 2H, - H, in the position 2), 4.2 (multiplet, Ш, СНзСН) 4.06, 4.64 (doublet, doublet, 2Н, J «14 Hz, in position 3), 5.06 (doublet, 1Н, J 5 Hz, - H in position 10
    NII 6), 5.15 (singlet, 2H, -CO-CHj- 5.72 (doublet, doublet, 1H, J5, 9 Hz, -H in position 7), 6.13 (singlet, 1H, -CHCONH ), 7.6 (multiplet, 5H, phenyl), 8.6 (broad, 3N, -NHj), 8.92 (singlet, 1H, thiadiazole-H), 9.56 (doublet, 1H, J 9 Hz, -CONH-).
    Connection 402.
    IR (nujol, cm-): 1815, 1780. 1690
    NMR (003) 280, value), 48 (doublet, 3N, J 7 Hz, CHjCH-), 2.17 (singlet, 3N, dioxolen-SND), 3.63 (broad, singlet, 2H, -H in the position 2), 4.2 (multiplet, 1H, CHjCH-), 4.06, 4.64 (doublet, doublet, 2H, J 14 Hz, -CH2 S - in position 3), 5.06 (doublet, W, J 5 Hz, –Iv position 6), 5.15 (singlet, 2H,) 5.72 (doublet, doublet, W, J 5, 9 Hz, –H in position 7), 6.13 (syn- j- rteT, 1H, -CHCONH), 7.6 (multiplet, 5H phenyl), 8.6 (wide ZN, -NHj), 8.92 (singlet, 1H, thiadiazole-H), 9.6 (doublet, W, J 9 Hz, -CONH).
    Connection 464
    IR (nujol, cm): 1830, 1790, 1760, 1695, 1625.
    NMR C (SV3) 2 SO, values 1.45 (doublet, J = 7 Hz, 3N,), 2.18 (singlet, 3N, dioxolen-CHj), 2.66 (singlet, 3N, thiadiazole-CH), 3, 64 (wide, singleton, 2H, -H in position 2), 4.08, .4.66 (doublet, doublet, J 13 Hz, 2Hj -CHjS - in position 3), 4.00-4.3 (multiplet , 1H, CH SI-), 5.12 (doublet, J 5 Hz, 1H, -H in position 6), 5.6, 5.75 (doublet, doublet, J 5.5, 9 Hz, 1H, - H at position 7), 6.00 (singlet, W, -OCNSO-), 6.76, 7.31 (doublet, doublet, J 8.5 Hz, 4H, phenyl), 8.70 (broad, 4H, -OH, -NHj), 9.30 (doublet, J 9 Hz, 1H, -CONH-),
    Connection 466,
    IR (nudzhol, cm: 1785, 1760, 100, 1615.
    5.06, 5, O8 (doublet, 5.5 Hz, -Ive polo 5.90 (multiplet, 1NII 7), 5.99 (single 6.80, 6.88 (quartet, to 5-Hz, - OCHCHj), 6, doublet, 4H, J 8.5 (wide, 4H, -OH-TH, W, J 9 Hz, -CONHA study of antimicros
    Dosage forms tov t sledztash 1m obra
    Dosage forms
    Ready t pills
    tava mg:
    25
    thirty
    40
    45
    Compound
    Polyvinylpyrrolide
    Starch
    Magnesium stearate
    Dosage forms
    Ready t pills
    50
    NMR (003) values of 1.21 (triplet, 3N, J 7 Hz, -CHjCH), 1.45 (doublet, 3N, J 7 Hz, -OCJCHCH), 1.51, 1.53 (doublet, doublet, 3N J 5 Hz, -OCH-CH3), 2.68 (singlet, GH, thiadiazole-CH3), 3.65 (shchiro, singlet, 2H, -H, j in position 2), 3, 97, 4 , 09, 4.50, 4.55 (doublet, double prescription, mg: years, double doublet, 2H, J 13 Hz, Compound 2 - in position 3), 4.17 (quart - Citric acid tetra, 2H, J 7 Hz,) 4.0- Sucrose 4.30 (multiplet, W, C SNCH ,,), SMS-Pa
    stava mg:
    Connection 2
    Citric acid
    Starch
    Magnesium stearate
    Dosage forms
    Prepare tablets VA, mg:
    Connection 3
    Starch
    Hydroxypropylcel
    vine
    Magnesium stearate
    Dosage forms
    Compound 2 is also attached to the resulting capsule. Each of n contains the following and
    Connection 2
    Tartaric acid
    Magnesium stearate
    Starch
    Dosage forms
    Capsules, each and below are listed below and in t, in the same way, form 4, mg:
    Connection example
    Magnesium stearate
    Lactose
    Dosing Lorm
    Dry potion
    5.06, 5, O8 (doublet, doublet, 1H, J 5.5 Hz, –Iv position 6), 5.60–5.90 (multiplet, 1H, –H at position 7), 5.99 (singlet , 1H, -OCNSO-), 6.80, 6.88 (quartet, quartet, W, J 5-Hz, -OCHCHj), 6.78, 7.31 (doublet, doublet, 4H, J 8.5 Hz , phenyl), 8.65 (broad, 4H, -ON-TN3), 9., 31 (doublet, W, J 9 Hz, -CONH).
    Study of antimicrobial activity,
    The dosage forms of the compounds are prepared following the first method.
    Dosage form 1.
    Tablets of the following composition are prepared, mg:
    Compound
    Polyvinylpyrrolidone
    Starch
    Magnesium stearate
    Dosage form 2.
    Preparing the following tablets 125 20 20 2.0

    five
    0
    0
    five
    0
    Shumu recipe mg: Compound 2 Citric acid Sucrose CMC-Pa
    stava mg:
    Compound 2250
    Citric acid 50
    Starch20
    Magnesium Stearate 3.0
    Dosage form 3.
    Prepared tablets of the following composition, mg:
    Compound 3500
    Starch20
    Hydroxypropylcellulose3
    Magnesium stearate 5
    Dosage form 4.
    Compound 2 and tartaric acid are mixed and the resulting mixture is filled into capsules. Each capsule contains the following ingredients, mg:
    Compound 2125
    Wine acid 25
    Magnesium Stearate 1
    Starch Up to 300
    Dosage form 5.
    Capsules, each of which contains the following ingredients, are prepared in the same manner as dosage form 4, mg:
    Connection example 1 125
    Magnesium stearate 2
    Lactose Up to 200
    Dosing Lorma 6 ...
    A dry mixture is prepared as follows.
    62.5 25 70 20
    251309912
    Oral acute toxicity of the proposed cephalosporic derivatives is determined in mice.
    Animals: males of juvenile JCP, age 5 weeks) n 3.
    Method of application: cefgsporin derivatives, prepared according to the presented examples, are dissolved in distilled water and aqueous solutions are used for oral administration. Get the following results
    Compound LD, g / kg
    5.0 5.0 5.0 5.0Application of compounds,.
    In dogs, the dental application of the proposed cephalosporin led to the excretion in urine of the corresponding non-esterified cephalosporins at the excretion rates shown in Table. 2
    20
    where RI and R have the indicated meanings, with a compound of general formula III
    R., COOH,
    where R has the indicated meanings, provided that the band is protected,
    The capsule was introduced stomat- cally in the pre-cooled medium in inert or-20 mg / kg (based on non-esterificant solvent in the present form). The analysis was performed by a microbiologist using the method of Bacillus Subtilis. results
    ze
    the solvent in the presence of an organic base and dicyclohexpcarbodiimide followed by stripping, protecting the amino acid, acid hydrolysis and extracting the desired product as an additive with hydrochloric acid,.
    tests are given in table. 2
    Ph o rmula of the invention
    Method for preparing cephalosporin derivatives of general formula
    -26
    -triazol-5-yl) thiomethyl1 or (1,2, 3-thiadiazol-5-yl) thiomethyl3;
    Kf hydrogen or hydroxy group, in the form of their additive salts with hydrohalic acids,
    about tl and h
    y u and with the fact that the compound of the general formula
    W S
    / L-nn-with n-t-1 he.
    SOOVg
    in D - configuration,
    where RI and R have the indicated meanings, with a compound of general formula III
    R., COOH,
    when cooled in an inert organic solvent medium in the presence of
    the solvent in the presence of an organic base and dicyclohexpcarbodiimide followed by stripping, protecting the amino acid, acid hydrolysis and extracting the desired product as an additive with hydrochloric acid,.
    ;Table 1
    COOR
    Gly
    AOM
     MTD
    H
    D - configuration,
    de k :, is an esC, ft or amino acid residue linked through an ester bond, in which the amino group may be replaced by methyl;
    Rj - 1 - (lower alkanoyloxy) -C-Su-alkyl, 1- (lower 5
    carboxycarbonyloxy) -C 2-5Q-apkil, phthalidyl or 5-me 6
    TIL-1, 3-DIOXOL € H-2 OH-4-ylmethyl; 7
    Rj (1-methyl-1H-tetrazol-5-yl)
    thiomethyl, (5-metsh1-1,3,4- 55
    -thiadiazol-2-yl) thiomethyl, (3-hydroxypyridazin-b-yl) thio-; 9
    methyl j. (1,3,4-thiadiazol-1 -2-yl) thiomethyl,. C (1H-, 2,3- Yu
    ROM
    n BOE
    yi
    i VOM
    i BOE
    n VOE
    i VOE
    AOE
    Roe
    PVE
    five
    0
    0
    254 255 256 257 258 259 260 261 262
    5 263 264 265 266 267 268 269 270 271 272 273 274 275 276 277 278
    five
    0
    five
    0
    five
    279 280
    Asn POMTD - H
    n
    i
    i
    n
    i
    AOE
    Roe
    PVE
    PVM
    pHT
    ECE
    Dox
    PheAOMTDH
    POM
    n BOE
    i VOM
    i BOE
    n VOE
    i VOE
    AOE
    9 TlpQg
     PVE Phe PVM XD
     PHT
     ECE
    Dox
    TD I
    It
    H

    Ala





    Ala
    .
    iAsp






    ECE
    Dox
    AOM
    ROM
    n BOE
    i VOM
    i BOE
    n VOE
    i VOE
    AOE
    Roe
    PVE
    PVM
    .PHT
    ECE
    Dox
    AOM
    ROM
    n BOE
    i VOM
    i BOE
    n VOE
    i VOE
    AOE
    Roe
    PVE
    PVM
    Mt
    Mt
    Mt
    H
    H
    five
    0
    five
    0
    five
    0
    five
    0
    five
    362 363 364 365 366 367 368 369 370 371 372 373 374 375 376 377 378 379 38 38 3838 3838 38 38 38 38 38 38
    Pro
    Pro
    Ala
    Gly
    PHT
    ECE
    Dox
    AOM
    POM
    n BOE
    i VOM
    i BOEMT
    n VOE
    i VOE
    AOE
    Roe
    PVE
    PVM
    PHT
    ECE
    Dox
    POMTR
    AOE
    i BOE
    PHT
    ABOUT
    ECE
    Dox
    POETR
    AOE
    i SE
    PHT
    MT H
    H
    H
    41 111rdolgerie
    1309912
    tab. one
    ECE
    Dox
    ROETZ
    GlyAOETZ N
    i BOE
    PHT
    ECE
    Dox
    AlaROE N
    AOE
    i BOE
    PHT
    ECE
    Dox
    GlyROESM H
    AOE
    i- VOE
    PHT
    ECE
    Dox
    Ala roesm H
    . AOE
    i BOE
    PHT
    ECE
    Dox
    Gly AOE PD H
    42:
    Continued table. R
    0
    416 417
    418 419
    420 5
    421 422
    ° 423 424
    5 25 426 427 428 429 430 431 432 433 434 435 436 437 438 439 440 441 442
    35
    40
    45
    50
    55
    Dox
    ECE
    PHT
    PVM
    AlaAOE
    Val
    Asm
    d asp
    d asp
    Lys
    Dox
    ECE
    PHT
    PVM
    AOE
    Dox
    ECE
    PHT
    PVM
    AOE
    Dox
    ECE
    PHT
    PVM
    AOE
    Dox
    ECE
    PHT
    PVM
    AOE
    Dox
    ECE
    ft d II
    PD H
    31309912
    Continued tabl, 1



    RNT.
    PVM

    ProAOE
    Dox
    ECE
    PHT
    PVM
    GinAOE
    pDOX
    tt
    ECE PHT PVMII II
    Non-esterized compound
    8 11 13 14 15 21 22
    24 25
    44 Continuation of table 1
    455 dtGlu AOE
    fO
    }five
    20
    25
    table 2
    H
    ly AGE RUM ECE DOH
    la AOM WOW AOE PVE PVM
    mtd
    H
    1.9 29.3 33.5 36.3

    32.1 30.5 31.8 35.2 33.7 35.2
    45
    130991246
    Continued, table. 2
    47
    Non-esterized compound
    H
    1309912
    48 Continuation of table. 2
    H
    CM
    H
    4.3
    410
    Non-esterized compound
    464 465 466

    MTD ON
    28.4
    3.8 28.9 31.7 37.2
    权利要求:
    Claims (1)
    [1]
    This invention relates to cephalosporin derivatives, in particular compounds I-B n D configuration of the general formula 4 -C 4 H 4 - H ! (S h) -C (O) - "H-X (I), wherein X - group - CH — C — S — CH “R, o = cnc (coorj) = CRj, linked through an ester bond to the residue of a 0-, c> - or ^ -amino acid, where the NH 2 group may be substituted with 'CH 3 ; Rj, - 1- (lower apcanoyloxy) 1 -C, -C 2 -alkyl; 1- (lower carboxycarbonyloxy) -C 1 -C 2 -alkyl; phthalidyl or 5-methyl-1,3, dioxolen-2-one-4-ylmethyl; R 3 - [(1-methyl-1H-tetrazol-5-yl thiomethyl]; [(5-methyl-1,3,4-thiadiazol-2-yl) thiomethyl]; [(3-hydroxypyridazin-6-yl) thiomethyl]; [(1,3,4-thiadiazol-2-yl) thiomethyl J; £ (1H-1,2,3-triazol-5-yl) thiomethyl] or [(1,2,3-thiadiazol-5- il) thiomethyl]; R * - H, 0K, in the form of their additive salts with hydrohalic acids, which can be used in medicine as medicines. To detect β-activity among the derivatives of cephalosporins, new I. were obtained. · "9
    Their synthesis is carried out from the corresponding hydroxy derivative of cephalosporin and an acid of the general formula R 4 -C00H, where the HC values are indicated above, and the DN 2 ~ group is protected by cooling in an inert organic solvent in the presence of an organic base and dicyclohexylcarbodiimide followed by removal of the protective group. Tests I show that they exhibit antimicrobial activity. 2 tab.
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    同族专利:
    公开号 | 公开日
    ES8507150A1|1985-08-16|
    AU2019983A|1984-05-17|
    DE3375787D1|1988-04-07|
    ES8504821A1|1985-04-16|
    JPS59116292A|1984-07-05|
    CY1512A|1990-08-03|
    KR840006667A|1984-12-01|
    AU568094B2|1987-12-17|
    NO833807L|1984-05-11|
    ES532997A0|1985-08-16|
    ES8507151A1|1985-08-16|
    AT32724T|1988-03-15|
    KR900007200B1|1990-10-05|
    HK39390A|1990-06-01|
    SU1322983A3|1987-07-07|
    NZ206019A|1986-06-11|
    NO162240C|1989-11-29|
    CA1239928A|1988-08-02|
    EP0108942B1|1988-03-02|
    FI833839A0|1983-10-20|
    FI833839A|1984-05-11|
    ZA837635B|1984-11-28|
    ES532996A0|1985-08-16|
    ES526561A0|1985-04-16|
    EP0108942A3|1985-05-15|
    NO162240B|1989-08-21|
    US4605651A|1986-08-12|
    EP0108942A2|1984-05-23|
    DK481883A|1984-05-11|
    FI75348C|1988-06-09|
    DK481883D0|1983-10-20|
    FI75348B|1988-02-29|
    WO1984001949A1|1984-05-24|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    GB1229453A|1968-01-30|1971-04-21|
    US3701775A|1970-11-25|1972-10-31|Smith Kline French Lab|Esters of mandeloylaminocephalosporanic acids|
    IL38099A|1970-12-17|1976-01-30|Smith Kline French Lab|3-heterocyclyl thiomethylcephalosporins|
    US3812116A|1971-07-02|1974-05-21|Fujisawa Pharmaceutical Co|7-acylated 3-substituted cephalosporin compounds|
    GB1425933A|1972-03-13|1976-02-25|Astra Laekemedel Ab|Cephalosporins|
    GB1492393A|1974-02-21|1977-11-16|Beecham Group Ltd|Cephalosporin esters|
    US4092476A|1974-02-21|1978-05-30|Beecham Group Limited|Phthalidyl esters of 7-[-3-]cephalosporins|
    CH606001A5|1974-05-13|1978-10-13|Ciba Geigy Ag|
    US3933808A|1974-05-20|1976-01-20|Eli Lilly And Company|Cephalosporin esters|
    US4172196A|1974-09-03|1979-10-23|Bristol-Myers Company|Certain 7-α-substituted-α-hydroxyacetamido-3--3-cephem-4-carboxylic acids|
    JPS5283877A|1976-01-01|1977-07-13|Lilly Co Eli|Cephalospoline esters|
    MA18686A1|1978-07-07|1980-10-01|Ciba Geigy Ag|AMINOTHIAZOLIC COMPOUNDS|
    JPS57193489A|1981-05-21|1982-11-27|Fujisawa Pharmaceut Co Ltd|Syn-isomer of 7-substituted-3-cephem-4-carboxylic acid ester and its preparation|JPS6034978A|1984-03-29|1985-02-22|Kyoto Yakuhin Kogyo Kk|Cephalosporin derivative and its preparation|
    JPS6034975A|1984-03-29|1985-02-22|Kyoto Yakuhin Kogyo Kk|Production of cephalosporin|
    DK401088A|1987-07-21|1989-01-22|Kyoto Pharma Ind|CEPHALOSPOR CONNECTION, PROCEDURES FOR PREPARING THEREOF AND PHARMACEUTICAL PREPARATION CONTAINING IT|
    US7186855B2|2001-06-11|2007-03-06|Xenoport, Inc.|Prodrugs of GABA analogs, compositions and uses thereof|
    JP4323968B2|2004-01-14|2009-09-02|株式会社日立コミュニケーションテクノロジー|Timing adjustment method for wireless communication device|
    US8048917B2|2005-04-06|2011-11-01|Xenoport, Inc.|Prodrugs of GABA analogs, compositions and uses thereof|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    PCT/JP1982/000437|WO1984001949A1|1982-11-10|1982-11-10|Cephalosporin derivatives, process and their preparation, and prophylactic and treating agent against bacterial infection|
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