Vancomycin derivative, preparation method, pharmaceutical composition and use thereof

Abstract

Provided are a class of vancomycin derivatives with a structure as shown in the general formula below and pharmaceutically acceptable salts thereof, a preparation method, a pharmaceutical composition containing the compound thereof, and the use of these compounds in preparing drugs for treating and/or preventing bacterial infection diseases, in particular drugs for treating infection diseases caused by Gram-positive bacteria. ##STR00001##

Claims

1. A vancomycin derivative represented by the following Formula I-A or a pharmaceutically acceptable salt thereof: ##STR00099## wherein, R.sub.6 is selected from the group consisting of chlorine and trifluoromethyl, R.sub.2 is selected from the group consisting of OH or the following groups: ##STR00100## n is 2 or 3; X is O, NH, NHC(O) or (CH.sub.2).sub.q, wherein q is an integer between 0 and 2; Y is a selected from the group consisting of: ##STR00101## ##STR00102##

2. A vancomycin derivative represented by the following Formula I-A or pharmaceutically acceptable salt thereof, ##STR00103## wherein, R.sub.6 is selected from the group consisting of chlorine and trifluoromethyl, R.sub.2 is selected from the group consisting of OH or the following groups: ##STR00104## n is 2 or 3; X is O, NH, NHC(O) or (CH.sub.2).sub.q, wherein q is an integer between 0 and 2; Y is selected from the group consisting of: ##STR00105##

3. A vancomycin derivative or pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: TABLE-US-00005 No. Structure Van016 Van037

4. A pharmaceutical composition comprising a therapeutically effective amount of one or more selected from the group consisting of the vancomycin derivative and pharmaceutically acceptable salt thereof according to any one of claims 1, 2 and 3 as an active ingredient, and optionally, a pharmaceutically acceptable carrier, excipient, adjuvant, accessory, and/or diluent, and the said pharmaceutical composition may further comprise other pharmaceutically acceptable therapeutic agents.

5. A method for treatment and/or prevention of a bacterial infectious disease, comprising: administering to a subject in need of such treatment an effective amount of the vancomycin derivative or pharmaceutically acceptable salt thereof according to claim 1.

6. The method according to claim 5, wherein the bacterial infectious disease is caused by a Gram-positive bacterium.

7. The method according to claim 6, wherein the Gram-positive bacterium is selected from the group consisting of Staphylococcus, streptococcus, enterococcus, pneumococcus, Bacillus, Bacillus anthracis, Bacillus diphtherias, tetanus, Clostridium difficile, and Listeria monocytogenes.

8. A method for treatment and/or prevention of a bacterial infectious disease, comprising: administering to a subject in need of such treatment an effective amount of the pharmaceutical composition according to claim 4.

9. The method according to claim 8, wherein the bacterial infectious disease is caused by a Gram-positive bacterium.

10. The method according to claim 9, wherein the Gram-positive bacterium is selected from the group consisting of Staphylococcus, streptococcus, enterococcus, pneumococcus, Bacillus, Bacillus anthracis, Bacillus diphtherias, tetanus, Clostridium difficile, and Listeria monocytogenes.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1 shows the results of a bacterial infection lethal challenge assay of Van016, Van032, Van037 and Van038 in mice;

(2) FIG. 2 shows the results of toxicity tests of Van011 and Van037 as well as vancomycin and telavancin in the HK-2 cell line model;

(3) FIG. 3 shows the results of toxicity tests of Van011 and Van037 as well as vancomycin and telavancin in the HL-7702 cell line model.

DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS

(4) The present invention will be further illustrated based on the following examples. These examples are for illustrative purposes only and are not intended to limit the scope of the invention in any way.

(5) In the following examples, standard procedures and purification methods known to those skilled in the art can be used. Unless otherwise specified, the starting materials are commercially available from, such as Aldrich Chemicals Co. and Acros Organics. The commercially obtained solvents and reagents are generally used as received without further purification. Anhydrous solvents are treated by standard methods, and other reagents are commercially analytical reagents. Unless otherwise stated, all temperatures are expressed in degrees Celsius ( C.). The room temperature or ambient temperature means 2025 C. The structure of a compound was determined by nuclear magnetic resonance spectroscopy (NMR) and/or mass spectrometry (MS).

(6) In nuclear magnetic resonance spectrum, the chemical shift (6) is expressed in parts per million (ppm). .sup.1H-NMR was measured on a Mercury-600 MHz or a Bruker (AV-400) 400 MHz nuclear magnetic resonance instrument with deuterated dimethyl sulfoxide (DMSO-d.sub.6), deuterated chloroform (CDCl.sub.3), deuterated methanol (MeOD-d.sub.4), or deuterated water (D.sub.2O) as a solvent, and tetramethylsilane (TMS) as an internal standard.

(7) High resolution mass spectrometry (HRMS) was measured on an Agilent 6230 Series TOF LC-MS spectrometer. If the intensity of ions containing chlorine or bromine is described, the expected intensity ratio (For ions containing .sup.35Cl/.sup.37Cl, the ratio is about 3:1, and for ions containing .sup.79Br/.sup.81Br, the ratio is about 1:1), and only intensity of the ion with lower mass is given.

(8) HPLC: an Agilent 1260 Analytical High Performance Liquid Chromatography System (Agilent) and a LC3000 Preparative High Performance Liquid Chromatography System (Beijing Innovation Tongheng Technology Co., Ltd.) were used. Analytical reverse-phase HPLC conditions: C18 column (5 m, 4.6250 mm), UV detection band is at 214 nm and 280 nm, elution conditions: a gradient of 0-90% acetonitrile containing 0.1% v/v TFA over 30 min. Preparative High performance liquid chromatography conditions: C18 column (5 m, 19250 mm), UV detection band is at 214 nm and 280 nm, elution conditions: a gradient of 0-90% acetonitrile containing 0.1% v/v TFA over 30 min.

(9) Column chromatography was performed generally using a silica gel of 200-300 mesh as a supporter.

(10) In the above discussion and the examples below, the following abbreviations refer respectively to the definitions herein. If an abbreviation is not defined, it has a generally accepted meaning.

(11) TLC thin layer chromatography;

(12) DIPEA N,N-diisopropylethylamine;

(13) DMF N,N-dimethylformamide;

(14) DMSO dimethyl sulfoxide;

(15) DCM dichloromethane;

(16) EtOAc ethyl acetate;

(17) Hexane hexane;

(18) TfOH trifluoromethanesulfonic acid;

(19) DCC dicyclohexylcarbodiimide;

(20) Fmoc-Cl 9-Fluorenylmethyl chloroformate;

(21) Pd/C palladium on carbon;

(22) HBTU O-(benzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate;

(23) TFA trifluoroacetic acid.

(24) Preparation of starting materials and intermediates

Preparation 1

Preparation of N-(9-fluorenylmethoxycarbonyl)-n-decylaminoacetaldehyde (1)

(25) ##STR00054##

(26) Decyl alcohol 1a (9.5 mL, 50 mmol), 25 mL of dichloromethane, methanesulfonyl chloride (5.4 mL, 70 mmol) in dichloromethane (25 mL) were mixed and stirred at 0 C. for 5 min. Pyridine (5 mL) was added and stirred at room temperature for 24 h. The residue was concentrated to remove solvent and dissolved in hexane (100 mL), washed with water (100 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to give a crude decyl methanesulfonate 1b as a colorless oil, which was directly used in the next step. The crude decyl methanesulfonate 1b was dissolved in 30 mL of ethanol, and a solution of 2-aminoethanol (6.1 g, 100 mmol) in ethanol (30 mL) was added dropwise over 15 min at room temperature. After the addition, the reaction mixture was heated to 90 C. and stirred for 24 h. The residue is concentrated to remove solvents, added with dichloromethane (100 mL) and water (100 mL) and the layers were separated. The combined organic layers were dried over sodium sulfate, filtered and concentrated to give crude 2-(decylamino)ethanol 1c (7.5 g, yield 75%) as a colorless oil, MS (ESI.sup.+): 201.8 [M+H].sup.+.

(27) The crude 2-(decylamino)ethanol 1c (4.15 g). DIPEA (3.6 mL), 30 mL of dichloromethane, and a solution of Fmoc-Cl (4.7 g) in dichloromethane (10 mL) were mixed and stirred at 0 C. for 1 h. TLC showed that the reaction was almost complete. The reaction mixture was washed with saturated aqueous solution of sodium bicarbonate (500 mL) and 0.1 N HCl (200 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give crude N-decyl-N-Fmoc-aminoethanol 1d (8 g) as a colorless oil. MS (ESI.sup.+): 424.3 [M+H].sup.+.

(28) .sup.1H NMR (400 MHz, CDCl.sub.3) (ppm) 7.84 (d, J=7.5 Hz, 2H), 7.66 (d, J=7.4 Hz, 2H), 7.52-7.36 (m, 4H), 4.61 (d, J=5.8 Hz, 2H), 4.31 (t, J=5.7 Hz, 1H), 3.80 (s, 1H), 3.45 (s, 2H), 3.13 (s, 3H), 1.63-1.07 (m, 18H), 0.96 (t, J=6.6 Hz, 3H).

(29) The crude N-decyl-N-Fmoc-aminoethanol 1d (1 g), DIPEA (2 mL), 20 mL of dichloromethane were mixed, and stirred at 5 C. (ice-acetone bath) for 15 min. Then, a solution of pyridine sulfur trioxide (1.88 g) in DMSO (6 mL) was added before stirred at 5 C. for 30 min. TLC showed that the reaction is almost complete. The reaction mixture was poured into a saturated aqueous solution of sodium bicarbonate (50 mL) with crushed ice, and the two phases were separated. The organic layer was washed with 0.1 N HCl (50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to afford crude N-(9-fluorenylmethoxycarbonyl)-n-decylaminoacetaldehyde 1 (0.9 g) as a yellow oil. MS (ESI.sup.+): m/z 422.4 [M+].sup.+.

(30) .sup.1H NMR (400 MHz, CDCl.sub.3): (ppm)=9.38 (d, J=117.7 Hz, 1H), 7.84 (d, J=7.5 Hz, 2H), 7.66 (d, J=7.4 Hz, 2H), 7.52-7.36 (m, 4H), 4.61 (d, J=5.8 Hz, 2H), 4.31 (t, J=5.7 Hz, 1H), 3.80 (s, 1H), 3.33-3.18 (m, 2H), 3.18-3.04 (m, 1H), 1.52-1.36 (m, 1H), 1.37-1.14 (m, 14H), 1.15-1.03 (m, 1H), 0.97-0.79 (m, 3H).

Preparation 2 Preparation of 2-aminoethyl--D-mannopyranoside (2)

(31) ##STR00055##

1,2,3,4,6-O-acetyl-D-mannopyranoside (2a)

(32) D-mannitol (5 g, 27.9 mmol) was dissolved in 25 mL of pyridine, ice-cooled at 0 C., and then 25 mL of acetic anhydride was slowly added. The mixture was stirred at room temperature for 16 h. Solvent was distilled off under reduced pressure. The residue was dissolved in ethyl acetate, washed sequentially with 1N hydrochloric acid, pure water and brine, dried over anhydrous sodium sulfate and filtered. The remaining ethyl acetate was distilled off under reduced pressure to afford a peracetylated mannoside (2a) (10.6 g, 27.1 mmol, yield 97%) as a clear viscous oil. And the product contained two configurations (-isomer/-isomer=33:67, w/w).

(33) .sup.1H NMR (400 MHz, CDCl.sub.3, a mixture of two isomers): NMR data of -isomer (ppm)=1.98 (s, 3H, COCH.sub.3), 2.07 (s, 3H, COCH.sub.3), 2.08 (s, 3H, COCH.sub.3), 2.15 (s, 3H, COCH.sub.3), 2.19 (s, 3H, COCH.sub.3), 3.99-4.05 (m, 1H, 5-H), 4.07 (dd, J=2.4, 12.4 Hz, 1H, 6-H.sub.a), 4.26 (dd, J=4.9, 12.4 Hz, 1H, 6-H.sub.b), 5.23 (dd, J=2.0, 3.1 Hz, 1H, 3-H), 5.31-5.34 (m, 2H, 3-H, 4-H), 6.06 (d, J=2.0 Hz, 1H, 1-H); NMR data of -isomer (ppm)=1.98 (s, 3H, COCH.sub.3), 2.03 (s, 3H, COCH.sub.3), 2.07 (s, 3H, COCH.sub.3), 2.15 (s, 3H, COCH.sub.3), 2.16 (s, 3H, COCH.sub.3), 3.79 (ddd, J=2.4, 5.3, 9.9 Hz, 1H, 5-H), 4.11 (dd, J=2.4, 12.4 Hz, 1H, 6-H.sub.a), 4.28 (dd, J=5.3, 12.4 Hz, 1H, 6-H.sub.b), 5.11 (dd, J=3.3, 10.0 Hz, 1H, 3-H), 5.27 (t, J=10.0 Hz, 1H, 4-H), 5.46 (dd, J=1.2, 3.3 Hz, 1H. 2-H), 5.84 (d, J=1.2 Hz, 1H, 1-H).

Phenyl 2,3,4,6-tetra-O-acetyl-1-sulfo-n-D-mannopyranoside (2b)

(34) The peracetylated mannoside 2a (4.5 g, 12.5 mmol) was added with 10 mL of dichloromethane and thiophenol (1.96 mL, 19.08 mmol), and stirred at room temperature for 20 min. Boron trifluoride etherate (7.8 mL, 63.6 mmol) was added dropwise under ice-bath. The mixture was stirred further for 15 min under ice bath, warmed to room temperature, and stirred for 16 h. The reaction mixture was diluted with dichloromethane (50 mL), added with ice water (100 mL) and stirred. The organic layer was separated, washed with a saturated aqueous solution of sodium bicarbonate and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography (ethyl acetate/hexane 1:5-1:3, v/v) to give phenyl 2,3,4,6-tetra-O-acetyl-1-sulfo--D-mannopyranoside 2b (4.4 g, yield 80%) as a white solid. HRMS (ESI.sup.4): [M+Na].sup.+ calculated for C.sub.20H.sub.24O.sub.9SNa 463.1033, found 463.1039.

(35) .sup.1H NMR (400 MHz, CDCl.sub.3): (ppm)=7.50-5.30 (m, 5H, ArH), 5.50 (dd, J.sub.1,2=1.6 Hz, J.sub.2,3=3.2 Hz, 1H, H-2), 5.50 (d, 1H, H-1), 5.33 (dd, J.sub.4,5=9.8 Hz, J.sub.3,4=9.9 Hz, 1H, H-4), 5.32 (dd, 1H, H-3), 4.55 (ddd, J.sub.5,6a=2.3 Hz, J.sub.5,6b=5.9 Hz, 1H, H-5), 4.31 (dd, J.sub.6a,6b=12.3 Hz, 1H, H-.sub.6b), 4.11 (dd, 1H, H-.sub.6a), 2.16, 2.08, 2.06, 2.02 (s, 12H, 4OCCH.sub.3).

2-(Benzyloxycarbonyl)aminoethyl 2,3,4,6-tetra-O-acetyl--D-mannopyranoside (2c)

(36) Phenyl 2,3,4,6-tetra-O-acetyl-1-sulfo--D-mannopyranoside 2b (2 g, 4.5 mmol) and N-(benzyloxycarbonyl)ethanolamine (1.1 g, 5.4 mmol) were dissolved in anhydrous dichloromethane in the presence of 4 molecular sieve under argon. The mixture was cooled to 0 C., added with N-iodosuccinimide (1.52 g, 6.75 mmol), reacted at 0 C. for 15 min, and then added with trifluoromethanesulfonic acid (80 L, 0.9 mmol). The reaction mixture was stirred overnight at room temperature, quenched by addition of triethylamine, diluted with dichloromethane, and filtered. The resultant organic layer was washed with a saturated aqueous solution of sodium bicarbonate, brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the product was separated by column chromatography (eluting with ethyl acetate/hexane 40:6050:50, v/v) to afford 2-(benzyloxycarbonyl)aminoethyl 2,3,4,6-tetra-O-acetyl--D-mannopyranoside (1.66 g, 3.17 mmol, yield 57%). HRMS (ESI.sup.+): calculated for C.sub.24H.sub.31NO.sub.12 [M+H].sup.+526.1925, found 526.1913.

(37) .sup.1H NMR (400 MHz, CDCl.sub.3): (ppm)=2.00 (s, 3H, COCH.sub.3), 2.04 (s, 3H, COCH.sub.3), 2.09 (s, 3H, COCH.sub.3), 2.16 (s, 3H, COCH.sub.3), 3.36-3.53 (m, 2H, CH.sub.2NH), 3.58 (ddd, J=3.6, 6.8, 10.2 Hz, 1H, CH.sub.aH.sub.bCH.sub.2NH), 3.78 (ddd, J=3.9, 6.2 10.2 Hz, 1H, CH.sub.aH.sub.bCH.sub.2NH), 3.97 (ddd, J=2.3, 5.7 9.5 Hz, 1H, 5-H). 4.08 (dd, J=2.3, 12.2 H 1H, 6-H.sub.a), 4.26 (dd, J=5.7, 12.2 Hz, 1H, 6-H.sub.b), 4.82 (d, J=1.7 Hz, 1H, 1-H), 5.12 (s, 2H, CH.sub.2Ph), 5.20 (bt, J=5.8 Hz, 1H, NH), 5.25 (dd, J=1.7, 3.2 Hz, 1H, 2-H), 5.26 (dd, J=9.5, 10.1 H), 5.31 (dd, J=3.2, 10.0 Hz, 1H, 3-H), 7.29-7.39 (m, 5H, C.sub.6H.sub.5).

2-(Benzyloxycarbonyl)aminomethyl--D-mannopyranoside (2d)

(38) 2-(Benzyloxycarbonyl)aminoethyl 2,3,4,6-tetra-O-acetyl--D-mannopyranoside 2c (466 mg, 0.887 mmol) was dissolved in a solution of 4N sodium methanolate in methanol. The reaction was maintained at pH 10, and reacted at room temperature for 4 h. The reaction mixture was added with a strong acid ion exchange resin, adjusted to pH 7-8, and filtered. The solvent was distilled off under reduced pressure to give 2-(benzyloxycarbonyl)aminomethyl--D-mannopyranoside 2d (301 mg, 0.842 mmol, yield 95%) as a colorless oil. HRMS (ESI.sup.+): calculated for C.sub.16H.sub.23NO.sub.8 [M+Na].sup.+380.1321, found 380.1316.

(39) .sup.1H NMR (400 MHz, MeOD-d.sub.4): (ppm)=3.27-3.39 (m, 2H, CH.sub.2NH), 3.47-3.55 (m, 2H, 5-H, CH.sub.aH.sub.bCH.sub.2NH), 3.60 (t, J=9.5 Hz, 1H, 4-H), 3.68 (dd, J=5.8, 11.7 Hz, 1H, 6-H.sub.a), 3.69 (dd, J=3.4, 9.3 Hz, 1H, 3-H), 3.74 (ddd, J=4.9, 6.4, 10.2 Hz, 1H, CH.sub.aH.sub.bCH.sub.2NH), 3.80 (dd, J=1.7, 3.4 Hz, 1H, 2-H), 3.81 (dd, J=2.3, 11.7 Hz, 1H, 6-H.sub.b). 4.75 (d, J=1.6 Hz, 1H, 1-H), 5.06 (s, 2H, CH.sub.2Ph), 7.24-7.36 (m, 5H, C.sub.6H.sub.5).

2-Aminoethyl--D-mannopyranoside (2)

(40) 2-(Benzyloxycarbonyl)aminomethyl--D-mannopyranoside 2d (285 mg, 0.798 mmol) was dissolved in methanol, and added with PdC (20%) 30 mg. The reaction mixture was charged with hydrogen (at a pressure of 1.5 Pa), stirred at room temperature for 4 hand filtered through a sintered glass funnel to give 2-Aminoethyl--D-mannopyranoside 2 301 mg (0.842 mmol, yield 95%). HRMS (ESI.sup.+): calculated for C.sub.16H.sub.23NO.sub.8 [M+Na].sup.+ 380.1321, found 380.1316.

(41) .sup.1H NMR (400 MHz, MeOD-d.sub.4): (ppm)=2.82-2.86 (m, 2H, CH.sub.2NH.sub.2), 3.48 (ddd, J=4.7, 5.9, 10.2 Hz, 1H, CH.sub.aH.sub.bCH.sub.2NH.sub.2), 3.56 (ddd, J=2.1, 5.8, 9.7 Hz, 1H, 5-H), 3.63 (t, J=9.4 Hz, 1H, 4-H), 3.73 (dd, J=5.8, 11.8 Hz, 1H, 6-H.sub.a), 3.74 (dd, J=3.4, 9.1 Hz, 1H, 3-H), 3.79 (ddd, J=4.7, 5.9, 10.2 Hz, 1H, CH.sub.aH.sub.bCH.sub.2NH.sub.2), 3.86 (dd, J=1.7, 3.4 Hz, 1H, 2-H), 3.86 (dd, J=2.1, 11.8 Hz, 1H, 6-H.sub.b), 4.80 (d, J=1.7 Hz, 1H, 1-H).

Preparation 3 Preparation of 2-aminoethyl--D-glucopyranoside (3)

(42) ##STR00056##

(43) 3a-c and 3 were prepared using the same needed materials, reagents and preparation method as those in preparation 2 except that D-mannitol in preparation 2 was replaced with glucose.

Phenyl 2,3,4,6-tetra-O-acetyl-1-sulfo--D-glucoside (3a)

(44) .sup.1H NMR (400 MHz, CDCl.sub.3): (ppm)=7.55-7.49 (m, 2H), 7.34 (dd, J=5.1, 1.9 Hz, 3H), 5.24 (t, J=9.4 Hz, 1H), 5.03 (d, J=26.5, 9.7 Hz, 2H), 4.73 (d, J=10.1 Hz, 1H). 4.27-4.17 (m, 2H), 3.75 (ddd, J=10.0, 5.0, 2.6 Hz, 1H), 2.10 (d, J=2.9 Hz, 6H), 2.04 (s, 3H), 2.01 (s, 3H).

2-(Benzyloxycarbonyl)aminoethyl 2,3,4,6-tetra-O-acetyl--D-glucoside (3b)

(45) HRMS (ESI.sup.+): calculated for C.sub.24H.sub.31NO.sub.12 [M+H].sup.+526.1925, found 526.1899.

(46) .sup.1H NMR (400 MHz, CDCl.sub.3): (ppm)=2.00 (s, 6H, 2 COCH.sub.3), 2.03 (s, 3H, COCH.sub.3), 2.06 (s, 3H, COCH.sub.3), 3.37-3.41 (m, 2H, CH.sub.2NH), 3.68 (ddd, J=2.5, 4.8, 9.9 Hz, 1H, 5-H), 3.69-3.74 (m, 1H, OCH.sub.aH.sub.bCH.sub.2), 3.87 (ddd, J=4.1, 5.5, 10.0 Hz, 1H, OCH.sub.aH.sub.bCH.sub.2), 4.14 (dd, J=2.4, 12.3 Hz, 6-H.sub.a), 4.14 (dd, J=4.8, 12.4 Hz, 1H, 6-H.sub.b), 4.48 (d, J=8.0 Hz, 1H, 1-H), 4.93 (dd, J=8.0, 9.6 Hz, 1H, 2-H), 5.05 (dd, J=9.4, 9.7 Hz, 1H, 4-H), 5.09 (s, 2H, CH.sub.2Ph), 5.17 (m, 1H, NHCBz), 5.19 (dd, J=9.4, 9.6 Hz, 3-H), 7.33-7.36 (m, 5H, C.sub.6H.sub.5).

2-(Benzyloxycarbonyl)aminomethyl--D-glucopyranoside (3c)

(47) HRMS (ESI.sup.+): calculated for C.sub.16H.sub.23NO.sub.8 [M+Na].sup.+380.1321, found 380.1318.

(48) .sup.1H NMR (400 MHz, MeOD-d.sub.4): (ppm)=3.17 (dd, J=7.9, 9.0 Hz, 1H, 2-H), 3.22-3.29 (m, 3H, 4-H, 5-H, CH.sub.aH.sub.bNH), 3.32-3.38 (m, 1H, CH.sub.aH.sub.bNH), 3.34 (t, J=8.7 Hz, 3-H), 3.58 (ddd, J=4.2, 6.9, 10.4 Hz 1H, CH.sub.aH.sub.bCH.sub.2NH), 3.62 (dd, J=5.2, 12.0 Hz, 1H, 6-H.sub.b), 3.81 (dd, J=2.0, 11.9 Hz, 1H, 6-H.sub.b), 3.86 (ddd, J=5.6, 7.7, 10.2 Hz, 1H, CH.sub.aH.sub.bCH.sub.2NH), 4.22 (d, J=7.8 Hz, 1H, 1-H), 5.02 (s, 2H, CH.sub.2Ph), 7.23-7.29 (m, 5H, C.sub.6H.sub.5).

2-Aminoethyl--D-glucopyranoside (3)

(49) HRMS (ESI.sup.+): calculated for C.sub.8H.sub.17NO.sub.6 [M+H].sup.+224.1134, found 224.1135.

(50) .sup.1H NMR (400 MHz, MeOD-d.sub.4): (ppm)=2.84-2.86 (m, 2H, CH.sub.2NH.sub.2), 3.15 (dd, J=7.8, 9.2 Hz, 1H, 2-H), 3.21-3.24 (m, 2H, 4-H, 5-H), 3.31 (dd, J=9.0, 9.1 Hz, 1H, 3-H), 3.58-3.63 (m, 2H, 6-H.sub.a, CH.sub.aH.sub.bCH.sub.2NH), 3.81 (dd, J=1.3, 11.9 Hz, 1H, 6-H.sub.b), 3.88 (ddd, J=5.0, 7.7, 9.9 Hz, 1H, CH.sub.aH.sub.bCH.sub.2NH), 4.22 (d, J=7.8 Hz, 1H, 1-H).

Preparation 4 Preparation of 2-aminoethyl--D-galactopyranoside (4)

(51) ##STR00057##

(52) 4a-c and 4 were prepared using the same needed materials, reagents and preparation method as those in preparation 2 except that D-mannitol in preparation 2 was replaced with galactose.

Phenyl 2,3,4,6-tetra-O-acetyl-1-sulfo--D-galactoside (4a)

(53) .sup.1H NMR (400 MHz, CDCl.sub.3): (ppm)=7.54 (ddd, J=7.0, 3.8, 2.1 Hz, 2H). 7.37-7.33 (m, 3H), 5.44 (d, J=3.2 Hz, 1H), 5.27 (t, J=9.9 Hz, 1H), 5.07 (dd, J=10.0, 3.4 Hz, 1H), 4.74 (d, J=10.0 Hz, 1H), 4.22 (dd, J=11.3, 7.0 Hz, 1H), 4.17-4.11 (m, 1H), 3.96 (t, J=6.6 Hz, 1H), 2.15 (s, 3H), 2.12 (s, 3H), 2.07 (s, 4H), 2.00 (s, 3H).

2-(Benzyloxycarbonyl)aminoethyl 2,3,4,6-tetra-O-acetyl--D-galactoside (4b)

(54) HRMS (ESI.sup.+): calculated for C.sub.24H.sub.31NO.sub.12 [M+Na].sup.+548.1744, found 548.1747.

(55) .sup.1H NMR (400 MHz, CDCl.sub.3): (ppm)=1.90 (s, 3H, COCH.sub.3), 1.93 (s, 3H, COCH.sub.3), 1.95 (s, 3H, COCH.sub.3), 2.07 (s, 3H, COCH.sub.3), 3.32 (m, 2H, CH.sub.2NH), 3.62 (ddd, J=3.6, 7.1, 10.2 Hz, 1H, CH.sub.aH.sub.bCH.sub.2NH), 3.80-3.82 (m, 2H, 5-H, CH.sub.aH.sub.bCH.sub.2NH), 4.06 (d, J=6.6 Hz, 2H, 6-H.sub.2), 4.38 (d, J=7.9 Hz, 1H, 1-H), 4.93 (dd, J=3.4, 10.5 Hz, 1H, 3-H), 5.02 (s, 2H, CH.sub.2Ph), 5.10 (dd, J=8.0, 10.4 Hz, 1H, 2-H), 5.19 (t, J=5.4 Hz, 1H, NH), 5.31 (dd, J=0.7, 3.4 H, 1H, 4-H), 7.22-7.30 (m, 5H, C.sub.6H.sub.5).

2-(Benzyloxycarbonyl)aminomethyl--D-galactopyranoside (4c)

(56) HRMS (ESI.sup.+): calculated for C.sub.16H.sub.23NO.sub.8 [M+Na].sup.+ 380.1316, found 380.1308.

(57) .sup.1H NMR (400 MHz, MeOD-d.sub.4): (ppm)=3.30 (ddd, J=4.2, 6.8, 14.2 Hz, 1H, CH.sub.aH.sub.bNH), 3.40 (ddd, J=4.1, 6.2, 14.2 Hz, 1H, CH.sub.aH.sub.bNH), 3.46 (dd, J=3.2, 9.7 Hz, 1H, 3-H), 3.50 (ddd, J=1.0, 5.3, 6.8 Hz, 1H, 5-H), 3.52 (dd, J=7.3, 9.8 Hz, 1H, 2-S10H), 3.63 (ddd, J=4.0, 6.8, 10.5 Hz, 1H, CH.sub.aH.sub.bCH.sub.2NH), 3.70 (dd, J=5.3, 11.4 Hz, 1H, 6-H.sub.a), 3.75 (dd, J=6.9, 11.3 Hz, 1H, 6-H.sub.b), 3.82 (dd, J=1.0, 3.2 Hz, 1H, 4-H), 3.91 (ddd, J=4.2, 6.2, 10.4 Hz, 1H, CH.sub.aH.sub.bCH.sub.2NH), 4.22 (d, J=7.3 Hz, 1H, 1-H), 5.06 (s, 2H, CH.sub.2Ph), 7.24-7.37 (m, 5H, C.sub.6H.sub.5).

2-Aminoethyl--D-galactopyranoside (4)

(58) HRMS (ESI.sup.+): calculated for C.sub.8H.sub.17NO.sub.6 [M+H].sup.+224.1134, found 224.1133.

(59) .sup.1H NMR (400 MHz, MeOD-d.sub.4): (ppm)=2.80 (ddd, J=4.2, 6.3, 13.4 Hz, 1H, CH.sub.aH.sub.bNH.sub.2), 2.84 (ddd, J=4.4, 5.5, 13.4 Hz, 1H, CH.sub.aH.sub.bNH.sub.2), 3.45 (dd, J=3.3, 9.7 Hz, 1H, 3-H), 3.49 (ddd, J=1.0, 5.3, 7.0 Hz, 1H, 5-H), 3.52 (dd, J=7.5, 9.7 Hz, 1H, 2-H), 3.61 (ddd, J=4.4, 6.3, 10.5 Hz, 1H, CH.sub.aH.sub.bCH.sub.2NH.sub.2), 3.69 (dd, J=5.3, 11.3 Hz, 1H, 6-H.sub.a), 3.73 (dd, J=7.0, 11.3 Hz, 1H, 6-H.sub.b), 3.80 (dd, J=1.0, 3.3 Hz, 1H, 4-H). 3.91 (ddd, J=4.2, 5.5, 10.3 Hz, 1H, CH.sub.aH.sub.bCH.sub.2NH.sub.2), 4.21 (d, J=7.5 Hz, 1H, 1-H).

Preparation 5 Preparation of 2-aminoethyl-2-acetamido-2-deoxy--D-glucopyranoside (5)

(60) ##STR00058##

(61) 5a, 5b and 5 were prepared using the same needed materials, reagents and preparation method as those in preparation 2 except that D-mannitol in preparation 2 was replaced with N-Acetyl-D-glucosamine.

2-(Benzyloxycarbonyl)aminoethyl 2-acetamido-3,4,6-tri-O-acetyl-2-deoxy--D-glucopyranoside (5a)

(62) HRMS (ESI.sup.): calculated for C.sub.24H.sub.32N.sub.2O.sub.11 [M+H].sup.+525.2084, found 525.2077.

(63) .sup.1H NMR (500 MHz, CDCl.sub.3): (ppm)=1.82 (s, 3H, COCH.sub.3), 1.96 (s, 6H, 2COCH.sub.3), 1.98 (s, 3H, COCH.sub.3), 3.21-3.29 (m, 1H, CH.sub.aH.sub.bNH), 3.33-3.42 (m, 1H, CH.sub.aH.sub.bNH), 3.61 (m, 214, 5-H, CH.sub.aH.sub.bCH.sub.2NH), 3.80 (ddd, J=3.5, 5.9, 9.9 Hz, 1H, CH.sub.aH.sub.bCH.sub.2NH), 3.84 (dt, 1=8.6, 10.2 Hz, 1H, 2-H). 4.06 (dd, J=2.0, 12.3 Hz, 1H, 6-H.sub.a), 4.16 (dd, J=4.8, 12.3 Hz, 1H, 6-H.sub.b), 4.54 (d, J=8.3 Hz, 1H, 1-H), 4.98 (dd, J=9.5, 9.8 Hz, 1H, 4-H), 5.02 (s, 2H, CH.sub.2Ph), 5.12 (dd, J=9.8, 10.2 Hz, 1H, 3-H), 5.31 (t, J=5.2 Hz, 1H, CH.sub.2NH), 5.87 (d, J=8.8 Hz, 1H, 2-NH), 7.23-7.31 (m, 5H, C.sub.6H.sub.5).

2-(Benzyloxycarbonyl)aminoethyl 2-acetylamino-2-deoxy--D-glucopyranoside (5b)

(64) HRMS (ESI.sup.+): calculated for C.sub.18H.sub.26N.sub.2O.sub.8 [M+Na].sup.+ 421.1587, found 421.1570.

(65) .sup.1H NMR (400 MHz, MeOD-d.sub.4): (ppm)=1.93 (s, 3H, COCH.sub.3), 3.23-3.34 (m, 4H, 4-H, 5-H, CH.sub.2NH), 3.43 (dd, J=8.4, 10.3 Hz, 1H, 3-H), 3.58 (ddd, J=5.4, 5.6, 10.6 Hz, 1H, CH.sub.aH.sub.bCH.sub.2NH), 3.65 (dd, J=8.4, 10.3 Hz, 1H, 2-H), 3.66 (dd, J=5.6, 11.9 Hz, 1H, 6-H.sub.a), 3.84 (m, 1H, CH.sub.aH.sub.bCH.sub.2NH), 3.86 (dd, J=2.2, 12.0 Hz, 1H. 6-H.sub.b), 4.38 (d, J=8.4 Hz, 1H, 1-H), 5.05 (s, 2H, CH.sub.2Ph), 7.35-7.25 (m, 5H, C.sub.6H.sub.5).

2-Aminoethyl-2-acetamido-2-deoxy--D-glucopyranoside (5)

(66) HRMS (ESI.sup.+): calculated for C.sub.10H.sub.20N.sub.2O.sub.6 265.1400, found 265.1404 [M+H].sup.+.

(67) .sup.1H NMR (400 MHz, D.sub.2O): (ppm)=2.05 (s, 3H, COCH.sub.3), 2.69-2.85 (m, 2H, CH.sub.2NH.sub.2), 3.34-3.52 (m, 2H, 4-H, 5-H), 3.52-3.59 (m, 1H, 3-H), 3.59-3.67 (m, 1H, CH.sub.aH.sub.bCH.sub.2NH.sub.2), 3.71-3.80 (m, 2H, 2-H, 6-H.sub.a), 3.87-4.01 (m, 2H, 6-H.sub.b, CH.sub.aH.sub.bCH.sub.2NH.sub.2), 4.53 (d, J=8.4 Hz, 1H, 1-H).

Preparation 6 Preparation of Gluconolactone Derivative (6)

(68) ##STR00059##

(69) Gluconolactone (2 g, 11.36 mmol) was dissolved in 12 mL of methanol and added with N-Boc-1,3-propanediamine (2.37 g, 13.63 mmol). The mixture was refluxed for 4 h, and the methanol was distilled off under reduced pressure to give a white solid, which was washed with ethyl acetate and dichloromethane, and vacuumed by an oil pump to afford a white solid 6a (3.6 g, yield 90%). HRMS (ESI.sup.+) calculated for C.sub.14H.sub.28N.sub.2O.sub.8 [M+Na].sup.+375.1743, found 375. 1726.

(70) 6a: .sup.1H NMR (400 MHz, DMSO-d.sub.6) 4.48-3.47 (m, 4H), 4.35-3.57 (m, 2H), 3.92-3.07 (m, 4H), 1.51-1.49 (m, 2H), 1.37 (s, 9H).

(71) 6a was dissolved in 5 mL of methanol, added with 4N hydrochloric acid, stirred at room temperature for 4 h, and distilled off the solvent under reduced pressure to afford a white solid 6.

(72) HRMS (ESI.sup.+) calculated for C.sub.9H.sub.20N.sub.2O.sub.6 253.1400, found 253.1381 [M+H].sup.+.

(73) 6: .sup.1H NMR (400 MHz, DMSO-d.sub.6) 4.23-3.53 (m, 4H), 4.12-3.79 (m, 2H), 2.93-2.87 (t, 4H), 1.92-1.88 (m, 2H).

Preparation 7 Preparation of Lactobionolactone Derivative (7)

(74) ##STR00060##

(75) 7a and 7 were prepared using the same needed materials, reagents and preparation method as those in preparation 6 except that gluconolactone in preparation 6 was replaced with lactobionolactone.

(76) 7a: HRMS (ESI.sup.+) calculated for C.sub.20H.sub.38N.sub.2O.sub.13 515.2452, found 515.2489 [M+H].sup.+.

(77) .sup.1H NMR (400 MHz, D.sub.2O) 4.58-4.56 (d, 1H), 4.41-4.41 (d, 1H), 4.20-4.18 (t, 1H), 4.01-3.55 (m, 10H), 3.31-3.28 (t, 2H), 3.11-3.10 (t, 2H), 1.75-1.68 (n, 2H), 1.44 (s, 9H).

(78) 7: HRMS (ESI) calculated for C.sub.15H.sub.30N.sub.2O.sub.11 415.1928, found 415.1901 [M+H].sup.+.

(79) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 4.58-4.54 (d, 1H), 4.41-4.40 (d, 1H), 4.19-4.19 (t, 1H), 4.0-3.55 (m, 10H), 3.36-3.4 (t, 2H), 3.28-3.30 (t, 2H), 1.69-1.73 (m, 2H).

Example 1

(80) ##STR00061##

(81) Step 1: Commercially available vancomycin (950 mg), N-decyl-N-Fmoc-aminoacetaldehyde 1 (550 mg), DIPEA (0.65 mL), 40 mL of DMF were mixed and stirred at room temperature for 1 h until the solution becomes clear. The mixture was stirred for another 1 h, then added with NaCNBH.sub.3 (80 mg), 10 mL of methanol, 0.25 mL of TFA at room temperature and stirred for 60 min. The reaction mixture was added with diethyl ether (500 mL) to generate precipitates and filtered. The filtered cake was washed with diethyl ether (300 mL) and then with water (300 mL), and dried to give N-decyl-N-Fmoc-aminoethyl-vancomycin (700 mg) as a white solid. HPLC: C18 column (5 m, 4.6250 mm), UV detection at 214 nm, elution conditions: a gradient of 0-90% acetonitrile containing 0.1% v/v TFA over 30 min, retention time (t.sub.R)=22.5 min, purity 95%. MS(ESI.sup.+): 927.7 [M+2H].sup.2+.

(82) N-decyl-N-Fmoc-aminoethyl-vancomycin (550 mg) and a 20% solution (10 mL) of piperidine in DMF was mixed and stirred at room temperature for 30 min. 200 mL of diethyl ether was added to generate precipitates and filtered. The filtered cake was washed with diethyl ether (300 mL) and dried to give N.sup.van-2-(n-decylamino)ethyl-vancomycin Van-a (450 mg) as a white solid. HPLC: C18 column (5 m, 4.6250 mm), UV detection at 214 and 280 nm, elution conditions: a gradient of 0-90% acetonitrile containing 0.1% v/v TFA over 30 min, retention time (t.sub.R)=16.3 min, purity 96%. HRMS (ESI.sup.+) calculated for C.sub.78H.sub.100Cl.sub.2N.sub.10O.sub.24 1630.6289, found 816.3212 [M+2H].sup.2+.

(83) Step 2: 2-aminoethyl--D-mannopyranoside 2 (30 mg) was dissolved in a mixture of water (100 L) and acetonitrile (500 L), added with 30 L of DIPEA, stirred at room temperature until the solid was completely dissolved (10 min). The mixture was added with 2 L of a formaldehyde solution (37 wt %), stirred at room temperature for 15 min, and then cooled to 10 C. and stirred for another 5 min. The reaction mixture was quickly mixed with 1.5 mL of a 80% solution of N.sup.van-2-(n-decylamine)ethyl-vancomycin Van-a (25 mg) in acetonitrile, added with 30 L of DIPEA, and stirred for 8 h at 10 C. The reaction was monitored by HPLC. HPLC: C18 column (5 m, 4.6250 mm), UV detection at 214 nm, elution conditions: a gradient of 2-90% acetonitrile containing 0.1% v/v TFA over 30 min. The crude was purified by reverse-phase C18 HPLC, and lyophilized to give Van001 (15 mg) as a white solid. HRMS (ESI.sup.+) calculated for C.sub.87H.sub.117Cl.sub.2N.sub.11O.sub.30 [M+3H].sup.3+ 1865.7345, found 622.9193.

(84) .sup.1H NMR (600 MHz, DMSO-d.sub.6) 7.79 (d, J=1.9 Hz, 1H), 7.49 (d, J=8.6 Hz, 1H), 7.46-7.43 (m, 1H), 7.41 (t, J=7.9 Hz, 1H), 7.28 (dd, J=8.2, 2.3 Hz, 2H), 7.25 (t, J=7.4 Hz, 1H), 7.20 (d, J=8.4 Hz, 1H), 7.13-7.10 (m, 1H), 6.84 (s, 1H), 6.77 (d, J=8.6 Hz, 1H), 6.51 (s, 1H), 5.71 (s, 1H). 5.66 (s, 1H), 5.28 (d, J=7.7 Hz, 1H), 5.24 (s, 1H), 5.14-5.10 (m, 2H), 5.10-5.07 (m, 1H), 4.81 (s, 1H), 4.65-4.60 (m, 2H), 4.46-4.42 (m, 1H), 4.40 (s, 1H), 4.13-4.06 (m, 3H), 3.84-3.80 (m, 1H), 3.68-3.62 (m, 4H), 3.54 (t, J=8.5 Hz, 3H), 3.44-3.40 (m, 4H), 3.38 (t, J=9.4 Hz, 2H), 3.33 (ddd, J=9.5, 6.2, 2.2 Hz, 2H), 3.25 (d, J=6.4 Hz, 3H), 2.85-2.76 (m, 3H), 2.60 (d, J=3.6 Hz, 1H), 2.54 (s, 2H), 2.37 (d, J=3.2 Hz, 1H), 2.11 (dd, J=16.3, 9.1 Hz, 2H), 1.75 (d, J=19.3 Hz, 2H), 1.67-1.59 (m, 3H), 1.49 (dt, J=14.6, 7.7 Hz, 4H), 1.23 (d, J=9.7 Hz, 16H), 1.06 (d, J=6.3 Hz, 3H), 0.90 (d, J=6.2 Hz, 3H), 0.84 (q, J=6.8 Hz, 6H).

Example 2

(85) ##STR00062##

(86) Van002 was prepared using the same needed materials, reagents and preparation method as those in example 1 except that 2-aminoethyl--D-mannopyranoside 2 in example 1 was replaced with 2-aminoethyl--D-galactopyranoside 4. HRMS (ESI) calculated for C.sub.87H.sub.117Cl.sub.2N.sub.11O.sub.30 [M+3H].sup.3+ 1865.7345, found 622.9193.

(87) .sup.1H NMR (600 MHz, DMSO-d.sub.6) 7.80-7.77 (m, 1H), 7.49 (d, J=8.5 Hz, 1H), 7.46-7.43 (m, 1H), 7.41 (t, J=7.9 Hz, 1H), 7.28 (dd, J=8.1, 3.5 Hz, 2H), 7.27-7.23 (m, 1H), 7.19 (d, J=8.4 Hz, 1H), 7.13-7.11 (m, 1H), 6.84 (d, J=8.5 Hz, 1H), 6.77 (d, J=8.5 Hz, 1H), 6.52-6.49 (m, 1H), 5.66 (s, 1H), 5.27 (d, J=7.6 Hz, 1H), 5.24 (s, 1H), 5.11 (d, J=7.5 Hz, 2H), 5.09 (s, 1H), 4.83-4.79 (m, 1H), 4.77-4.75 (m, 1H), 4.63 (d, J=7.1 Hz, 1H), 4.44 (s, 1H), 4.40-4.38 (m, 11-1), 4.11 (s, 3H), 3.95 (s, 2H), 3.81 (t, J=15.8 Hz, 3H), 3.65 (d, J=10.7 Hz, 1H), 3.62-3.60 (m, 1H), 3.42-3.40 (m, 2H), 3.37 (d, J=5.9 Hz, 3H), 3.33-3.23 (m, 5H), 3.07 (d, J=21.7 Hz, 3H), 2.85-2.77 (m, 3H), 2.56-2.52 (m, 2H), 2.37 (d, J=3.4 Hz, 1H), 2.15-2.07 (m, 2H), 1.80-1.72 (m, 21-1), 1.67-1.59 (m, 3H), 1.53-1.43 (m, 4H), 1.23 (d, J=9.7 Hz, 16H), 1.10-1.03 (m, 3H), 0.90 (d, J=6.1 Hz, 3H), 0.83 (q, J=6.8 Hz, 6H).

Example 3

(88) ##STR00063##

(89) Van003 was prepared using the same needed materials, reagents and preparation method as those in example 1 except that 2-aminoethyl--D-mannopyranoside 2 in example 1 was replaced with 2-aminoethyl-2-acetamido-2-deoxy--D-glucopyranoside 5. HRMS (ESI.sup.+) calculated for C.sub.89H.sub.120Cl.sub.2N.sub.12O.sub.30 [M+3H].sup.3+ 1906.7610, found 636.5398.

(90) .sup.1H NMR (600 MHz, DMSO-d.sub.6) 7.80 (d, J=5.1 Hz, 1H), 7.50-7.44 (tn. 3H). 7.29 (dd, J=13.6, 8.0 Hz, 2H), 7.22 (d, J=8.3 Hz, 1H), 7.11 (s, 1H), 6.84 (dd, J=8.4, 2.0 Hz, 1H), 6.77 (d, J=8.7 Hz, 1H), 6.51 (s, 1H), 5.64 (d, J=32.6 Hz, 2H), 5.23 (dd, J=15.8, 5.7 Hz, 2H), 5.11 (s, 2H), 4.65 (q, J=6.6 Hz, 1H), 4.42 (d, J=17.0 Hz, 2H), 4.34 (d, J=8.5 Hz, 1H), 4.11 (q, J=11.5, 9.6 Hz, 3H), 3.92-3.80 (m, 3H), 3.74-3.69 (m, 2H), 3.65 (d, J=10.9 Hz, 2H), 3.43 (td, J=8.2, 3.2 Hz, 5H), 3.37 (s, 4H), 3.29 (d, J=9.4 Hz, 1H), 3.27-3.24 (m, 2H), 3.23 (d, J=8.8 Hz, 1H), 3.18-3.14 (m, 3H), 3.07-3.04 (m, 2H), 3.02-2.98 (m, 2H), 2.88 (dd, J=9.4, 6.4 Hz, 214), 2.73 (q, J=7.0, 6.3 Hz, 1H), 2.36 (s, 3H), 1.78 (s, 3H), 1.71 (d, J=13.0 Hz, 1H), 1.54 (dt, J=18.6, 6.1 Hz, 4H), 1.23 (d, J=22.5 Hz, 16H), 1.04 (d, J=6.3 Hz, 3H), 0.87 (d, J=6.2 Hz, 3H), 0.83 (t, J=6.8 Hz, 6H).

Example 4

(91) ##STR00064##

(92) Van004 was prepared using the same needed materials, reagents and preparation method as those in example 1 except that 2-aminoethyl--D-mannopyranoside 2 in example 1 was replaced with 2-aminoethyl--D-galactopyranoside 4. HRMS (ESI.sup.) calculated for C.sub.87H.sub.117Cl.sub.2N.sub.11O.sub.30 [M+3H].sup.3+ 1865.7345, found 622.9195.

(93) .sup.1H NMR (600 MHz, DMSO-d.sub.6) 7.80-7.77 (m, 1H), 7.49 (d, J=8.5 Hz, 1H), 7.46-7.43 (m, 1H), 7.41 (t, J=7.9 Hz, 1H), 7.28 (dd, J=8.1, 3.5 Hz, 2H), 7.27-7.23 (m, 1H), 7.19 (d, J=8.4 Hz, 1H), 7.13-7.11 (m, 1H), 6.84 (d, J=8.5 Hz, 1H), 6.77 (d, J=8.5 Hz, 1H), 6.52-6.49 (m, 1H), 5.66 (s, 1H), 5.27 (d, J=7.6 Hz, 1H), 5.24 (s, 1H), 5.11 (d, J=7.5 Hz, 2H), 5.09 (s, 1H), 4.83-4.79 (m, 1H), 4.77-4.75 (m, 1H), 4.63 (d, J=7.1 Hz, 1H), 4.44 (s, 1H), 4.40-4.38 (m, 1H), 4.11 (s, 3H), 3.95 (s, 2H), 3.81 (t, J=15.8 Hz, 3H), 3.65 (d, J=10.7 Hz, 1H), 3.62-3.60 (m, 1H), 3.42-3.40 (m, 2H), 3.37 (d, J=5.9 Hz, 3H), 3.33-3.23 (m, 5H), 3.07 (d, J=21.7 Hz, 3H), 2.85-2.77 (m, 3H), 2.56-2.52 (m, 2H). 2.37 (d, J=3.4 Hz, 1H), 2.15-2.07 (m, 2H), 1.80-1.72 (m, 2H), 1.67-1.59 (m, 3H), 1.53-1.43 (m, 4H), 1.23 (d, J=9.7 Hz, 16H), 1.10-1.03 (m, 3H), 0.90 (d, J=6.1 Hz, 3H), 0.83 (q, J=6.8 Hz, 6H).

Example 5

(94) ##STR00065##

(95) Van005 was prepared using the same needed materials, reagents and preparation method as those in example 1 except that 2-aminoethyl--D-mannopyranoside 2 in example 1 was replaced with ethanolamine. HRMS (ESI.sup.+) calculated for C.sub.81H.sub.107Cl.sub.2N.sub.11O.sub.25 [M+3H].sup.3+ 1703.6817, found 568.8805.

(96) .sup.1H NMR (600 MHz, DMSO-d.sub.6) 7.79 (d, J=2.0 Hz, 1H), 7.48 (d, J=8.7 Hz, 1H), 7.45 (dd, J=8.3, 1.8 Hz, 1H), 7.30 (d, J=8.4 Hz, 1H), 7.22 (d, J=8.3 Hz, 1H), 7.11-7.09 (m, 1H), 6.84 (dd, J=8.5, 1.9 Hz, 1H), 6.77 (d, J=8.5 Hz, 1H), 6.53 (s, 1H), 5.70-5.61 (m, 3H), 5.23 (dd, J=12.6, 5.9 Hz, 2H), 5.11 (s, 3H), 4.65 (q, J=6.7 Hz, 1H), 4.43 (dd, J=14.7, 5.6 Hz, 2H), 4.12 (dd, J=22.2, 13.0 Hz, 4H), 3.65 (q, J=4.9, 4.1 Hz, 3H), 3.55-3.50 (m, 4H), 3.42 (t, J=5.8 Hz, 3H), 3.28-3.21 (m, 3H), 3.15 (s, 1H), 2.96 (dd, J=6.4, 4.6 Hz, 3H), 2.90 (t, J=7.9 Hz, 3H), 2.14-2.08 (m, 21-1), 1.90-1.86 (m, 1H), 1.71 (d, J=13.1 Hz, 1H), 1.56 (dh, J=12.5, 6.9, 6.5 Hz, 5H), 1.43-1.37 (m, 2H), 1.28-1.18 (m, 16H), 1.04 (d, J=6.3 Hz, 3H), 0.88 (d, J=6.2 Hz, 3H), 0.85-0.81 (m, 6H).

Example 6

(97) ##STR00066##

(98) Van006 was prepared using the same needed materials, reagents and preparation method as those in example 1 except that 2-aminoethyl--D-mannopyranoside 2 in example 1 was replaced with 2-deoxy-2-aminomannose. HRMS (ESI.sup.+) calculated for C.sub.85H.sub.113Cl.sub.2N.sub.11O.sub.29 [M+3H].sup.3+ 1821.7083, found 608.2428.

(99) .sup.1H NMR (600 MHz, DMSO-d.sub.6) 7.79 (d, J=4.9 Hz, 1H), 7.49 (s, 1H), 7.48-7.44 (m, 2H), 7.31 (d, J=8.0 Hz, 1H), 7.22-7.20 (m, 1H). 7.11 (s, 1H), 6.84 (s, 1H), 6.77 (dd, J=8.6, 2.9 Hz, 1H), 6.54-6.52 (m, 1H), 5.70-5.67 (m, 1H), 5.63 (s, 1H), 5.48-5.46 (m, 1H), 5.25 (d, J=7.6 Hz, 1H), 5.22 (d, J=4.0 Hz, 1H), 5.10 (d, J=5.5 Hz, 3H), 4.65 (d, J=6.5 Hz, 2H), 4.47-4.44 (m, 1H), 4.41 (d, J=5.6 Hz, 1H), 4.26-4.24 (m, 1H), 4.10 (s, 2H), 3.69 (d, J=9.7 Hz, 1H), 3.67-3.64 (m, 2H), 3.59 (td, J=8.6, 6.9, 3.5 Hz, 3H), 3.54-3.50 (m, 4H), 3.43-3.40 (m, 3H), 3.28-3.21 (m, 4H), 3.17-3.11 (m, 4H), 2.92-2.88 (m, 3H), 2.60 (s, 1H), 2.38-2.36 (m, 1H), 2.16-2.10 (m, 2H), 1.90-1.87 (m, 1H), 1.72-1.69 (m, 1H), 1.58-1.53 (m, 4H), 1.23 (d, J=9.0 Hz, 16H), 1.04 (d, J=6.4 Hz, 3H), 0.89 (d, J=6.2 Hz, 3H), 0.85-0.83 (m, 4H).

Example 7

(100) ##STR00067##

(101) Van007 was prepared using the same needed materials, reagents and preparation method as those in example 1 except that 2-aminoethyl--D-mannopyranoside 2 in example 1 was replaced with 2-deoxy-2-aminoglucose. HRMS (ESI.sup.+) calculated for C.sub.85H.sub.113Cl.sub.2N.sub.11O.sub.29 [M+3H].sup.3+ 1821.7083, found 608.2418.

(102) .sup.1H NMR (600 MHz, DMSO-d.sub.6) 7.79 (d, J=4.9 Hz, 1H), 7.49 (s, 1H), 7.48-7.44 (m, 2H), 7.31 (d, J=8.0 Hz, 1H), 7.22-7.20 (m, 1H), 7.11 (s, 1H), 6.84 (s, 1H), 6.77 (dd, J=8.6, 2.9 Hz, 1H), 6.54-6.52 (m, 1H), 5.70-5.67 (m, 1H), 5.63 (s, 1H), 5.48-5.46 (m, 1H), 5.25 (d, J=7.6 Hz, 1H), 5.22 (d, I=4.0 Hz, 1H), 5.10 (d, J=5.5 Hz, 3H), 4.65 (d, J=6.5 Hz, 2H), 4.47-4.44 (m, 1H), 4.41 (d, J=5.6 Hz, 1H), 4.26-4.24 (m, 1H), 4.10 (s, 2H), 3.69 (d, J=9.7 Hz, 1H), 3.67-3.64 (m, 2H), 3.59 (td, J=8.6, 6.9, 3.5 Hz, 3H), 3.54-3.50 (m, 4H), 3.43-3.40 (m, 3H), 3.28-3.21 (m, 4H), 3.17-3.11 (m, 4H), 2.92-2.88 (m, 3H), 2.60 (s, 1H), 2.38-2.36 (m, 1H), 2.16-2.10 (m, 2H), 1.90-1.87 (m, 1H), 1.72-1.69 (m, 1H), 1.58-1.53 (m, 4H), 1.23 (d, J=9.0 Hz, 16H), 1.04 (d, J=6.4 Hz, 3H), 0.89 (d, J=6.2 Hz, 3H), 0.85-0.83 (m, 4H).

Example 8

(103) ##STR00068##

(104) Van008 was prepared using the same needed materials, reagents and preparation method as those in example 1 except that 2-aminoethyl--D-mannopyranoside 2 in example 1 was replaced with 2-deoxy-2-aminogalactose. HRMS (ESI.sup.+) calculated for C.sub.85H.sub.113Cl.sub.2N.sub.11O.sub.29 [M+3H].sup.3+ 1821.7083, found 911.8666 [M+2H].sup.2+ 608.2418.

(105) .sup.1H NMR (600 MHz, DMSO-d.sub.6) 7.79 (d, J=4.9 Hz, 1H), 7.49 (s, 1H), 7.48-7.44 (m, 2H), 7.31 (d, J=8.0 Hz, 1H), 7.22-7.20 (m, 1H), 7.11 (s, 1H), 6.84 (s, 1H), 6.77 (dd, J=8.6, 2.9 Hz, 1H), 6.54-6.52 (m, 1H), 5.70-5.67 (m, 1H), 5.63 (s, 1H), 5.48-5.46 (m, 1H), 5.25 (d, J=7.6 Hz, 1H), 5.22 (d, J=4.0 Hz, 1H), 5.10 (d, J=5.5 Hz, 3H), 4.65 (d, J=6.5 Hz, 2H), 4.47-4.44 (m, 1H), 4.41 (d, J=5.6 Hz, 1H), 4.26-4.24 (m, 1H), 4.10 (s, 2H), 3.69 (d, J=9.7 Hz, 1H), 3.67-3.64 (m, 2H), 3.59 (td, J=8.6, 6.9, 3.5 Hz, 3H), 3.54-3.50 (m, 4H), 3.43-3.40 (m, 3H), 3.28-3.21 (m, 4H), 3.17-3.11 (m, 4H), 2.92-2.88 (m, 3H), 2.60 (s, 1H), 2.38-2.36 (m, 1H), 2.16-2.10 (m, 2H), 1.90-1.87 (m, 1H), 1.72-1.69 (m, 1H), 1.58-1.53 (m, 4H), 1.23 (d, J=9.0 Hz, 16H), 1.04 (d, J=6.4 Hz, 3H), 0.89 (d, J=6.2 Hz, 3H), 0.85-0.83 (m, 4H).

Example 9

(106) ##STR00069##

(107) Van009 was prepared using the same needed materials, reagents and preparation method as those in example 1 except that 2-aminoethyl--D-mannopyranoside 2 in example 1 was replaced with the gluconolactone derivative 6. HRMS (ESI.sup.+) calculated for C.sub.88H.sub.120Cl.sub.2N.sub.12O.sub.30 [M+2H].sup.2+ 1894.7610, found 948.3892.

(108) .sup.1H NMR (600 MHz, DMSO-d.sub.6) 7.79 (s, 1H), 7.50-7.47 (m, 1H), 7.45 (dd, J=8.3, 1.8 Hz, 1H), 7.30 (d, J=8.3 Hz, 1H), 7.20 (d, J=8.4 Hz, 1H), 7.10 (s, 1H), 6.84 (dd, J=8.5, 2.0 Hz, 1H), 6.77 (d, J=8.5 Hz, 1H), 6.53 (s, 1H), 5.70 (d, J=21.8 Hz, 2H), 5.29-5.25 (m, 2H), 5.12 (d, J=5.1 Hz, 2H), 5.08 (d, J=2.0 Hz, 1H), 4.80 (s, 1H), 4.65 (d, J=7.1 Hz, 1H), 4.44 (d, J=5.2 Hz, 1H), 4.41 (d, J=6.0 Hz, 1H), 4.09 (d, J=8.4 Hz, 1H), 4.06 (s, 2H), 4.00 (d, J=3.6 Hz, 1H), 3.89 (t, J=2.9 Hz, 1H), 3.65 (d, J=10.7 Hz, 2H), 3.56 (d, J=2.7 Hz, 1H), 3.54 (d, J=2.4 Hz, 2H), 3.37 (d, J=5.3 Hz, 1H), 3.35 (d, J=4.9 Hz, 1H), 3.25 (d, J=5.3 Hz, 3H), 3.16 (ddt, J=19.9, 13.0, 6.6 Hz, 5H), 2.92 (t, J=7.9 Hz, 4H), 2.61-2.59 (m, 1H), 2.56 (s, 2H), 2.50 (d, J=2.0 Hz, 1H), 2.38-2.36 (m, 1H), 2.12-2.05 (m, 2H), 1.95-1.88 (m, 2H), 1.82 (dq, J=14.5, 7.2 Hz, 3H), 1.67-1.60 (m, 3H), 1.51 (t, J=7.8 Hz, 3H), 1.34 (s, 2H), 1.24 (d, J=14.1 Hz, 14H), 1.08 (d, J=6.1 Hz, 3H), 0.90 (d, J=6.0 Hz, 3H), 0.86-0.84 (m, 3H), 0.83 (s, 1H).

Example 10

(109) ##STR00070##

(110) Van010 was prepared using the same needed materials, reagents and preparation method as those in example 1 except that 2-aminoethyl--D-mannopyranoside 2 in example 1 was replaced with the lactobionolactone derivative 7. HRMS (ESI.sup.+) calculated for C.sub.94H.sub.130Cl.sub.2N.sub.12O.sub.35 [M+2H].sup.2+ 2056.8139, found 1029.4148.

(111) .sup.1H NMR (600 MHz, DMSO-d.sub.6) 7.79 (s, 1H), 7.49 (d, J=8.6 Hz, 1H), 7.45 (d, J=9.1 Hz, 1H), 7.30 (d, J=8.3 Hz, 1H), 7.20 (d, J=8.4 Hz, 1H), 7.10 (s, 1H), 6.85-6.83 (m, 1H). 6.77 (d, J=8.5 Hz, 1H), 6.53 (s, 1H), 5.72 (d, J=7.3 Hz, 1H), 5.68 (s, 1H), 5.29 (s, 1H), 5.27 (d, J=7.6 Hz, 1H), 5.11 (s, 2H), 5.08 (s, 1H), 4.80 (s, 1H), 4.65 (d, J=6.5 Hz, 1H), 4.45 (s, 1H), 4.41 (d, J=5.7 Hz, 1H), 4.27 (d, J=7.0 Hz, 1H), 4.11 (d, J=2.3 Hz, 1H), 4.07-4.05 (m, 2H), 4.01-3.99 (m, 2H), 3.90-3.88 (m, 1H), 3.69-3.66 (m. 3H), 3.65 (s, 1H), 3.60-3.59 (m, 1H), 3.58 (d, J=3.6 Hz, 1H), 3.55 (d, J=8.0 Hz, 2H), 3.52 (d, J=5.2 Hz, 2H), 3.50 (d, J=4.4 Hz, 1H), 3.49-3.47 (m, 2H), 3.39 (t, J=6.4 Hz, 2H), 3.30 (d, J=2.2 Hz, 1H), 3.26 (d, J=3.3 Hz, 3H), 3.19-3.11 (m, 6H), 3.05-3.01 (m, 2H), 2.92 (t, J=7.6 Hz, 4H), 2.61-2.59 (m, 1H). 2.56 (s, 21-1), 2.51 (d, J=1.9 Hz, 1H), 2.38-2.36 (m, 1H), 2.04 (s, 1H), 1.93 (s, 2H), 1.85-1.79 (m, 4H), 1.52 (s, 4H), 1.34 (s, 3H), 1.24 (d, J=15.3 Hz, 16H), 1.09 (d, J=6.2 Hz, 3H), 0.91 (d, J=6.0 Hz, 3H), 0.86-0.84 (m, 3H), 0.84 (s, 1H).

Example 11

(112) ##STR00071##

(113) Step 1: commercially available vancomycin (100 mg) and DIPEA (30 L) were dissolved in 3 mL of DMF to give a turbid solution, which was heated to 50 C. to become clear. 4-chlorobiphenyl-4-carboxaldehyde (30 mg) was added, heated and stirred for 4 h. (Aromatic aldehyde has a low reactivity, and therefore, it is necessary to prolong the reaction time and heat up to accelerate the reaction rate. Vancomycin does not have a good solubility in DMF, and the added DIPEA may enhance the dissolution. If there are insolubles, the reaction rate would be affected.) NaCNBH.sub.3 (8 mg), 1 mL of methanol and 30 L of TFA were added at room temperature and stirred overnight. The reaction was monitored by HPLC. Diethyl ether (50 mL) was added to generate precipitates and filtered to give a crude, which was purified by reverse-phase C18 HPLC and lyophilized to give Van-b (60 mg) as a white solid. HPLC: C18 column (5 m, 4.6250 mm), UV detection at 214 nm, elution conditions: a gradient of 2-90% acetonitrile containing 0.1% v/v TFA over 30 min. HRMS (ESI.sup.+) calculated for C.sub.79H.sub.84C.sub.3N.sub.9O.sub.24 [M+2H].sup.2+ 1647.4695, found 824.7489.

(114) Step 2: 2-aminoethyl--D-galactopyranoside 4 (30 mg) was dissolved in a mixture of water (1004) and acetonitrile (500 L), added with 30 L of DIPEA, and stirred at room temperature until the solid was completely dissolved (10 min). The mixture was added with 2 L of a 37 wt % formaldehyde solution, stirred at room temperature for 15 min, and then cooled to 10 C. and stirred for 5 min. The reaction mixture was quickly mixed with 1.5 mL of a 80% solution of N.sup.van-2-(4-chlorobiphenylmethyl)-vancomycin (Van-b) (25 mg) and DIPEA (30 L) in acetonitrile, stirred for 8 h at 10 C. HPLC monitoring (0.1% v/v TFA was separately incorporated in H.sub.2O and acetonitrile, 2-90%, 30 min) showed that the reaction is complete. The crude was purified by reverse-phase C18 HPLC and worked-up to give Van011. HRMS (ESI.sup.+) calculated for C.sub.87H.sub.117Cl.sub.2N.sub.11O.sub.30 [M+3H].sup.3+ 1882.5751, found 628.5331.

(115) .sup.1H NMR (600 MHz, DMSO-d.sub.6) 7.82 (d, J=2.0 Hz, 1H), 7.74-7.70 (m, 4H), 7.69 (s. 1H), 7.56-7.52 (m, 4H), 7.51 (s, 1.1-1), 7.49 (d, J=8.8 Hz, 1H), 7.46 (dd, J=8.3, 1.8 Hz, 1H), 7.31 (d, J=8.4 Hz, 1H), 7.22 (d, J=8.4 Hz, 1H), 7.12 (s, 1H), 6.84 (d, J=8.5 Hz, 1H), 6.77 (d, J=8.6 Hz, 1H), 6.51 (s, 1H), 5.72 (s, 1H), 5.69 (s, 1H), 5.34 (d, J=7.7 Hz, 1H), 5.29-5.27 (m, 1H), 5.11 (d, J=10.2 Hz, 2H), 4.82-4.79 (m, 1H), 4.65 (d, J=6.6 Hz, 1H), 4.46-4.44 (m, 1H), 4.40 (s, 1H), 4.13-4.11 (m, 2H), 4.02 (s, 2H), 3.95 (s, 2H), 3.81-3.77 (m, 1H), 3.66 (d, J=10.6 Hz, 1H), 3.61 (d, J=3.1 Hz, 1H), 3.56 (t, J=8.5 Hz, 1H), 3.50 (ddd, J=12.9, 7.5, 5.1 Hz, 4H), 3.37 (td, J=5.6, 5.1, 3.5 Hz, 4H), 3.31-3.24 (m, 5H), 2.61-2.58 (m, 1H), 2.56-2.52 (m, 2H), 2.37-2.36 (m, 1H), 2.13-2.08 (m, 3H), 1.81 (d, J=13.1 Hz, 2H), 1.68-1.59 (m, 4H), 1.49-1.47 (m, 2H), 1.21 (s, 1H), 1.11 (d, J=6.3 Hz, 3H), 0.90 (d, J=6.3 Hz, 3H), 0.85 (d, J=6.3 Hz, 3H).

Example 12

(116) ##STR00072##

(117) Van012 was prepared using the same needed materials, reagents and preparation method as those in example 11 except that 2-aminoethyl--D-galactopyranoside 4 in example 11 was replaced with (aminomethyl)phosphonic acid. HRMS (ESI.sup.+) calculated for C.sub.81H.sub.90C.sub.13N.sub.10O.sub.27P [M+3H].sup.3+ 1770.4780, found 591.1677.

(118) .sup.1H NMR (600 MHz, DMSO-d.sub.6) 7.86 (s, 1H), 7.73-7.70 (m, 4H), 7.69 (d, J=2.1 Hz, 1H), 7.56-7.52 (m, 4H), 7.52 (d, J=2.2 Hz, 1H), 7.46 (dd, J=8.4, 1.9 Hz, 2H), 7.31 (s, 1H). 7.21 (d, J=8.4 Hz, 1H), 7.13 (s, 1H), 6.79 (dd, J=8.4, 2.0 Hz, 2H), 6.72 (d, J=8.6 Hz. 2H), 6.44 (s, 1H), 5.75 (s, 1H), 5.63 (s, 1H), 5.34 (d, J=7.7 Hz, 1H), 5.28 (s, 1H), 5.14 (s, 2H), 5.10 (s, 1H), 4.86 (s, 1H), 4.66 (d, J=6.6 Hz, 1H), 4.43 (s, 1H), 4.41 (s, 1H), 4.28 (s, 1H), 4.16 (s, 1H), 4.02 (s, 1H), 3.67 (d, J=10.7 Hz, 1H), 3.56 (d, J=8.4 Hz, 2H), 3.28-3.24 (m, 3H), 2.67-2.62 (m, 3H), 2.57-2.54 (m, 2H), 2.38-2.36 (m, 1H), 2.09 (d, J=8.4 Hz, 3H), 1.82 (d, J=13.0 Hz. 2H), 1.66-1.61 (m, 3H), 1.48 (s, 2H), 1.11 (d, J=6.2 Hz, 3H), 0.91-0.89 (m, 3H), 0.85 (d, J=6.0 Hz, 3H).

Example 13

(119) ##STR00073##

(120) Van013 was prepared using the same needed materials, reagents and preparation method as those in example 11 except that 2-aminoethyl--D-galactopyranoside 4 in example 11 was replaced with 2-aminoethyl--D-mannopyranoside 2. HRMS (ESI.sup.+) calculated for C.sub.88H.sub.101C.sub.13N.sub.10O.sub.30 [M+2H].sup.2+ 1882.5751, found 942.2943.

(121) .sup.1H NMR (600 MHz, DMSO-d.sub.6) 7.83 (d, J=2.0 Hz, 1H), 7.73-7.70 (m. 4H), 7.70 (d, J=2.1 Hz, 1H), 7.56-7.52 (m, 4H), 7.52 (d, J=2.0 Hz, 1H). 7.47-7.44 (m, 2H), 7.30 (d, J=8.3 Hz, 1H), 7.19 (d, J=8.5 Hz, 1H), 6.86 (dd, J=8.5, 2.0 Hz, 1H), 6.77 (d, J=8.5 Hz, 1H), 6.54 (s, 1H), 5.87 (d, J=2.0 Hz, 1H), 5.35 (d, J=7.7 Hz, 1H), 5.30 (d, J=4.2 Hz, 1H), 5.13 (s, 1H), 5.11 (s, 1H), 5.07 (d, J=2.0 Hz, 1H), 4.76 (s, 1H), 4.66 (d, J=6.6 Hz, 1H), 4.64 (d, J=1.7 Hz, 1H), 4.46 (s, 1H), 4.41 (d, J=5.8 Hz, 1H), 4.15 (t, J=13.7 Hz, 3H), 4.10 (s, 1H), 4.03 (s, 2H), 3.95 (t, J=6.5 Hz, 1H), 3.86-3.83 (m, 1H), 3.67 (dd, J=3.5, 1.7 Hz, 1H), 3.66-3.64 (m, 1H), 3.63-3.62 (m, 1H), 3.58 (d, J=8.7 Hz, 1H), 3.51 (d, J=3.3 Hz, 1H), 3.49 (d, J=3.5 Hz, 1H), 3.38 (t, J=9.4 Hz, 3H), 3.34 (dd, J=6.3, 2.2 Hz, 2H), 3.26 (d, J=6.2 Hz, 2H), 3.11 (d, J=6.0 Hz, 2H), 2.73 (d, J=15.5 Hz, 2H), 2.10 (d, J=11.5 Hz, 2H), 1.92-1.89 (m, 2H), 1.82 (d, J=13.1 Hz, 2H), 1.51 (s, 3H), 1.10 (d, J=6.2 Hz, 3H), 0.91 (t, J=6.6 Hz, 6H).

Example 14

(122) ##STR00074##

(123) Van014 was prepared using the same needed materials, reagents and preparation method as those in example 11 except that 2-aminoethyl--D-galactopyranoside 4 in example 11 was replaced with the gluconolactone derivative 6. HRMS (ESI.sup.+) calculated for C.sub.89H.sub.104C.sub.13N.sub.11O.sub.30 [M+2H].sup.2+ 1911.6016, found 956.8070.

(124) .sup.1H NMR (600 MHz, DMSO-d.sub.6) 7.82 (s, 1H), 7.74-7.70 (m, 4H), 7.69 (s, 1H), 7.56-7.52 (m, 4H), 7.52 (d, J=1.8 Hz, 1H), 7.50-7.48 (m, 1H), 7.46 (dd, J=8.3, 1.8 Hz, 1H), 7.30 (d, J=8.4 Hz, 1H), 7.22 (d, J=8.4 Hz, 1H), 7.11 (s, 1H), 6.85 (dd, J=8.4, 2.0 Hz, 1H), 6.77 (d, J=8.6 Hz, 1H), 6.52 (s, 1H), 5.71 (d, J=9.9 Hz, 2H), 5.34 (d, J=7.6 Hz, 1H), 5.29 (d, J=4.1 Hz, 1H), 5.12 (d, J=3.8 Hz, 2H), 5.09 (s, 1H), 4.80 (s, 1H), 4.65 (d, J=6.6 Hz, 1H), 4.44 (s, 1H). 4.40 (s, 1H), 4.10 (s, 1H), 4.05 (s, 2H), 4.02 (d, J=6.9 Hz, 2H), 4.00 (d, J=3.6 Hz, 1H), 3.89 (t, J=2.8 Hz, 1H), 3.66 (d, J=10.7 Hz, 2H), 3.58-3.53 (m, 3H), 3.37 (d, J=5.2 Hz, 1H), 3.35-3.34 (m, 1H), 3.28-3.24 (m, 3H), 3.18 (q, J=6.8 Hz, 2H), 3.15-3.12 (m, 2H), 2.91 (s, 3H), 2.55 (s, 2H), 2.10 (d, J=11.2 Hz, 3H), 1.81 (d, J=11.5 Hz, 3H), 1.64 (s, 3H), 1.49 (s, 3H), 1.35 (s, 1H), 1.10 (d, J=6.2 Hz, 3H), 0.91 (d, J=6.2 Hz, 3H), 0.85 (d, J=6.1 Hz, 3H).

Example 15

(125) ##STR00075##

(126) Van015 was prepared using the same needed materials, reagents and preparation method as those in example 11 except that 2-aminoethyl--D-galactopyranoside 4 in example 11 was replaced with the lactobionolactone derivative 7. FIRMS (ESI.sup.+) calculated for C.sub.95H.sub.114C.sub.13N.sub.11O.sub.35 [M+2H].sup.2+ 2073.6544, found 1037.9145.

(127) .sup.1H NMR (600 MHz, DMSO-d.sub.6) 7.82 (d, J=1.9 Hz, 1H), 7.73-7.70 (m, 4H), 7.69 (d, J=2.1 Hz, 1H), 7.56-7.52 (m, 4H), 7.52 (d, J=2.0 Hz, 1H), 7.49 (d, J=8.5 Hz, 1H), 7.47-7.45 (m, 1H), 7.31 (d, J=8.4 Hz, 1H), 7.22 (d, J=8.4 Hz, 1H), 7.10 (s, 1H), 6.85 (dd, J=8.5, 1.8 Hz, 1H), 6.77 (d, J=8.5 Hz, 1H), 6.53 (s, 1H), 5.72 (dd, J=8.5, 4.7 Hz, 2H), 5.34 (d, J=7.6 Hz, 2H), 5.29 (d, J=4.0 Hz, 2H), 5.13 (s, 2H), 5.09 (d, J=1.9 Hz, 1H), 4.81 (s, 2H), 4.66 (t, 1=6.4 Hz, 2H), 4.44 (d, J=5.3 Hz. 1H), 4.41 (d, J=5.7 Hz, 1H). 4.26 (d, J=6.8 Hz, 1H), 4.10 (d, J=2.3 Hz, 2H), 4.06 (s, 2H), 4.02 (d, J=7.5 Hz, 2H), 4.00 (dd, J=4.6, 2.4 Hz, 2H), 3.67 (dq, J=10.3, 6.1 Hz, 4H), 3.59 (d, J=2.7 Hz, 1H), 3.57 (d, J=3.7 Hz, 1H), 3.56 (t, J=3.3 Hz, 1H), 3.52 (d, J=4.8 Hz, 1H), 3.50 (d, J=4.6 Hz, 1H), 3.39 (t, J=6.3 Hz, 2H), 3.32 (d, J=9.5 Hz, 1H), 3.29 (d, J=3.0 Hz, 2H), 3.27 (d, J=6.9 Hz, 1H), 3.25 (s, 1H), 2.92 (t, J=6.6 Hz, 2H), 2.57 (s, 2H), 2.10 (d, J=11.4 Hz, 2H), 2.04 (s, 2H), 1.82 (dd, J=12.9, 6.7 Hz, 3H), 1.65 (d, J=7.4 Hz, 2H), 1.50 (d, J=13.1 Hz, 4H), 1.11 (d, J=6.3 Hz, 3H), 0.91 (d, J=6.1 Hz, 3H), 0.86 (d, J=6.1 Hz, 3H).

Example 16

(128) ##STR00076##

(129) Step 1: commercially available vancomycin (100 mg) and DIPEA (30 L) were dissolved in 3 mL of DMF, to give a turbid solution, which was heated to 50 C. to become clear. 4-trifluoromethyl-biphenyl-4-carboxaldehyde (30 mg) was added, and the reaction mixture was heated under stirring for 4 h. Then, NaCNBH.sub.3 (8 mg), 1 mL of methanol and 30 L of TFA were added at room temperature. The reaction was stirred overnight, and monitored by HPLC. The reaction mixture was added with diethyl ether (50 mL) to generate precipitates, which was filtered to give a crude. The crude was purified by reverse-phase C18 HPLC, and lyophilized to give Van-c (40 mg) as a white solid. HPLC: C18 column (5 m, 4.6250 mm), UV detection at 214 nm, elution conditions: a gradient of 2-90% acetonitrile containing 0.1% v/v TFA over 30 min. HRMS (ESI.sup.+) calculated for C.sub.80H.sub.84Cl.sub.2F.sub.3N.sub.9O.sub.24 1681.4958, found 841.7475 [M+2H].sup.2+.

(130) Step 2: 30 L of DIPEA was added to a mixture of the gluconolactone derivative 6 (40 mg), 500 L of water and 500 L of acetonitrile, and stirred at room temperature until the solid was completely dissolved (10 min). The mixture was added with 2 L of a 37 wt % formaldehyde solution, stirred at room temperature for 15 min, cooled to 10 C. and stirred for 5 min. The mixture was quickly mixed with 1.5 mL of a 80% solution of N.sup.van-2-(4-trifluoromethyl-biphenylmethyl)-vancomycin (Van-c) (25 mg) in acetonitrile, added with 30 L of DIPEA, and stirred at 10 C. for 8 h. The reaction was monitored by HPLC. HPLC: C18 column (5 m, 4.6250 mm), UV detection at 214 nm, elution conditions: a gradient of 2-90% acetonitrile containing 0.1% v/v TFA over 30 min. The crude was purified by reverse-phase C18 HPLC and lyophilized to give Van016 (10 mg) as a white solid. HRMS (ESI.sup.+) calculated for C.sub.90H.sub.104Cl.sub.2F.sub.3N.sub.11O.sub.30 [M+2H].sup.2+ 1945.6280, found 974.8218.

(131) .sup.1H NMR (600 MHz, DMSO-d.sub.6) 7.91 (s, 1H), 7.89 (s, 1H), 7.82 (d, J=8.2 Hz, 3H), 7.80 (d, J=7.9 Hz, 2H), 7.59 (d, J=8.1 Hz, 2H), 7.50-7.45 (m, 3H), 7.31 (d, J=8.4 Hz, 1H), 7.23 (d, J=8.4 Hz, 1H), 7.11 (s, 1H), 6.85 (s, 1H), 6.77 (d, J=8.5 Hz, 1H), 6.52 (s, 1H), 5.72 (d, J=7.3 Hz, 2H), 5.34 (d, J=7.7 Hz, 1H), 5.29 (s, 1H), 5.12 (s, 1H), 5.10 (s, 1H), 4.80 (s, 1H), 4.66 (d, J=6.8 Hz, 1H), 4.45 (s, 1H), 4.41 (s, 1H), 4.11 (s, 2H), 4.07-4.03 (m, 3H), 4.00 (d, J=3.6 Hz, 1H), 3.89 (dd, J=3.7, 2.2 Hz, 1H), 3.67 (d, J=10.6 Hz, 1H), 3.57-3.55 (m, 1H), 3.54-3.53 (m, 1H), 3.51 (d, J=7.1 Hz, 2H), 3.47-3.45 (m, 3H), 3.37 (d, J=5.2 Hz, 1H), 3.35 (d, J=5.0 Hz, 1H), 3.26 (s, 2H), 3.25 (s, 1H), 3.13 (d, J=6.8 Hz, 2H), 2.94-2.89 (m, 3H), 2.60 (d, J=1.8 Hz, 1H), 2.57-2.54 (m, 211), 2.38-2.36 (m, 1H), 2.12-2.09 (m, 2H), 1.84-1.80 (m, 3H), 1.66-1.63 (m, 2H), 1.50 (s, 2H), 1.15 (t, J=7.3 Hz, 1H), 1.13 (s, 1H), 1.11 (d, J=6.2 Hz, 3H), 0.91 (d, J=6.2 Hz, 3H), 0.86 (d, J=6.1 Hz, 3H).

Example 17

(132) ##STR00077##

(133) Step 1: commercially available vancomycin (100 mg), DIPEA (30 L) were dissolved in 3 mL of DMF to give a turbid solution, which was heated to 50 C. to become clear. 3-chloro-4-((2-methyl-[1,1-biphenyl]-3-yl)methoxyl)benzaldehyde (30 mg) was added, and the mixture was heated under stirring for 4 h. Then, NaCNBH.sub.3 (8 mg), 1 mL of methanol and 30 L, of TFA were added, and the reaction was stirred overnight at room temperature, and monitored by HPLC. The reaction mixture was added with diethyl ether (50 mL) to generate precipitates, which was filtered to give a crude. The crude was purified by reverse-phase C18 HPLC and lyophilized to give Van-d (40 mg) as a white solid. HPLC: C18 column (5 m, 4.6250 mm), UV detection at 214 nm, elution conditions: a gradient of 2-90% acetonitrile containing 0.1% v/v TFA over 30 min. HRMS (ESI.sup.+) calculated for C.sub.87H.sub.92C.sub.13N.sub.9O.sub.25 1767.5270, found 884.7633 [M+2H].sup.2+.

(134) Step 2: Van017 was prepared using the same needed materials, reagents and preparation method as those in example 16 except that Van-c in example 16 was replaced with Van-d. HRMS (ESI.sup.+) calculated for C.sub.97H.sub.112C.sub.13N.sub.11O.sub.31 [M+2H].sup.2+ 2031.6591, found 1016.8385.

(135) .sup.1H NMR (600 MHz, DMSO-d.sub.6) 7.83-7.81 (m, 1H), 7.58 (d, J=2.0 Hz, 1H), 7.46 (dd, J=14.4, 6.8 Hz, 6H). 7.43 (d, J=1.7 Hz, 1H), 7.40-7.39 (m, 1H), 7.38-7.35 (m, 3H), 7.30 (d, J=8.4 Hz, 1H), 7.29-7.27 (m, 3H), 7.23-7.19 (m, 3H), 6.86-6.83 (m, 1H), 6.77 (d, J=8.5 Hz, 1H), 6.53 (s, 1H), 5.72 (d, J=10.0 Hz, 2H), 5.33 (d, J=7.6 Hz, 1H), 5.26 (s, 2H), 5.12 (s, 2H), 5.09 (d, J=2.0 Hz, 1H), 4.80 (s, 1H), 4.64 (d, J=6.4 Hz, 1H), 4.45 (d, J=5.6 Hz, 1H), 4.41 (d, J=5.7 Hz, 1H), 4.06 (s, 2H), 4.00 (d, J=3.6 Hz, 2H), 3.93 (s, 1H), 3.89-3.88 (m. 1H), 3.66 (d, J=10.6 Hz, 1H), 3.56-3.53 (m, 2H), 3.47-3.46 (m, 2H), 3.36 (dd, J=10.7, 5.0 Hz, 2H), 3.28-3.24 (m, 2H), 3.21-3.17 (m, 2H), 3.16-3.12 (m, 2H), 2.92 (t, J=7.4 Hz, 3H), 2.57 (s, 3H), 2.19 (s, 3H), 2.12-2.07 (m, 2H), 2.06 (d, J=7.9 Hz, 3H), 1.84-1.77 (m, 4H), 1.67-1.62 (m, 3H), 1.45 (s, 3H), 1.10 (d, J=6.3 Hz, 3H), 0.91 (d, J=6.1 Hz, 3H), 0.86 (d, J=6.2 Hz, 3H).

Example 18

(136) ##STR00078##

(137) Step 1: commercially available vancomycin (100 mg) and DIPEA (30 L) were dissolved in 3 mL of DMF to give an opaque solution, which was heated to 50 C. to become clear. p-ethylbenzaldehyde (30 mg) was added, and the reaction was heated under stirring for 4 h. (Aromatic aldehyde has a low reactivity, and therefore, it is necessary to prolong the reaction time and heat up to accelerate the reaction rate. Vancomycin does not have a good solubility in DMF, and the added DIPEA may enhance the dissolution. If there are insolubles, the reaction rate would be affected.) Then, NaCNBH.sub.3 (8 mg), 1 mL of methanol and 30 L of TFA were added at room temperature, and the reaction was stirred overnight and monitored by HPLC. The reaction mixture was added with diethyl ether (50 mL) to generate precipitates, which was filtered to give a crude. The crude was purified by reverse-phase C18 HPLC and lyophilized to give Van-e (40 mg) as a white solid. HPLC: C18 column (5 m, 4.6250 mm), UV detection at 214 nm, elution conditions: a gradient of 2-90% acetonitrile containing 0.1% v/v TFA over 30 min. HRMS (ESI.sup.+) calculated for C.sub.75H.sub.85Cl.sub.2N.sub.9O.sub.24 [M+2H].sup.2+ 1565.5085, found 783.7540.

(138) Step 2: Van018 was prepared using the same needed materials, reagents and preparation method as those in example 16 except that 4-trifluoromethyl-biphenyl-4-carbaldehyde in example 16 was replaced with p-ethylbenzaldehyde. HRMS (ESI.sup.+) calculated for C.sub.85H.sub.105Cl.sub.2N.sub.11O.sub.30 1829.6406, found 915.8275 [M+2H].sup.2+.

(139) .sup.1H NMR (600 MHz, DMSO-d.sub.6) 7.82 (s, 1H), 7.48 (d, J=8.5 Hz, 2H), 7.47-7.45 (m, 2H), 7.36 (s, 1H), 7.35 (s, 1H), 7.30 (d, J=8.4 Hz, 1H), 7.25 (s, 1H), 7.24 (s, 1H), 7.22 (d, J=8.4 Hz, 1H), 7.10 (s, 1H), 6.84 (d, J=8.6 Hz, 1H), 6.77 (d, J=8.6 Hz, 1H), 6.52 (s, 1H), 5.72 (s, 214), 5.33 (d, J=7.6 Hz, 1H), 5.12 (s, 1H), 5.09 (s, 1H), 4.80 (s, 1H), 4.63 (d, J=6.5 Hz, 1H), 4.45-4.43 (m, 1H), 4.41-4.39 (m, 1H), 4.10 (s, 1H), 4.05 (s, 2H), 4.00 (d, J=3.6 Hz, 2H), 3.97-3.92 (m, 4H), 3.90-3.88 (m, 1H), 3.66 (d, J=10.7 Hz, 2H), 3.57-3.55 (m, 2H), 3.54 (s, 1H), 3.47-3.46 (m, 2H), 3.45 (d, J=2.1 Hz, 1H), 3.36 (dd, J=10.6, 4.9 Hz, 3H), 3.25 (d, J=8.7 Hz, 2H), 3.07 (q, J=7.3 Hz, 3H), 2.58 (s, 1H), 2.37 (d, J=3.6 Hz, 1H), 2.11-2.06 (m, 3H), 1.81-1.76 (m, 3H), 1.67-1.62 (m, 3H), 1.46 (s, 2H), 1.17-1.15 (m, 2H), 1.14 (d, J=1.7 Hz, 2H), 1.13 (d, J=1.9 Hz, 1H), 1.09 (d, J=6.3 Hz, 3H), 0.91 (d, J=6.2 Hz, 3H), 0.86 (d, J=6.2 Hz, 3H).

Example 19

(140) ##STR00079##

(141) Step 1: commercially available vancomycin (100 mg) and DIPEA (30 L) were dissolved in 3 mL of DMF to give an opaque solution, which was heated to 50 C. to become clear. 1-nonanal (30 L) was added, and the reaction was heated and stirred for 4 h. Then, NaCNBH.sub.3 (8 mg), 1 mL of methanol and 30 L of TFA were added at room temperature, and the reaction was stirred overnight and monitored by HPLC. The reaction mixture was added with diethyl ether (50 mL) to generate precipitates, which was filtered to give a crude. The crude was purified by reverse-phase C18 HPLC and lyophilized to give Van-f (40 mg) as a white solid. HPLC: C18 column (5 m, 4.6250 mm), UV detection at 214 nm, elution conditions: a gradient of 2-90% acetonitrile containing 0.1% v/v TFA over 30 min. HRMS (ESI.sup.+) calculated for C.sub.75H.sub.93Cl.sub.2N.sub.9O.sub.24 1573.5711, found 787.7856 [M+2H].sup.2+.

(142) Step 2: Van019 was prepared using the same needed materials, reagents and preparation method as those in example 16 except that Van-c in example 16 was replaced with Van-f. HRMS (ESI.sup.+) calculated for C.sub.78H.sub.100Cl.sub.2N.sub.10O.sub.25 [M+2H].sup.2+ 1646.6238, found 824.3191.

(143) .sup.1H NMR (600 MHz, DMSO-d.sub.6) 7.81 (s, 1H), 7.48 (d, J=8.7 Hz, 1H), 7.46-7.44 (m, 1H), 7.41 (d, J=7.5 Hz, 1H), 7.29 (s, 1H), 7.28 (s, 1H), 7.20 (d, J=8.4 Hz, 1H). 7.10-7.09 (m, 1H), 6.85-6.83 (m, 1H), 6.78 (s, 1H), 6.76 (s, 1H), 6.53 (s, 1H), 5.72 (s, 1H), 5.70 (s, 1H), 5.30 (d, J=7.7 Hz, 1H), 5.27 (s, 1H), 5.12 (s, 2H), 5.08-5.06 (m, 1H), 4.79 (s, 1H), 4.59 (d, J=6.3 Hz, 1H), 4.43 (s, 1H), 4.40 (s, 1H), 4.10-4.08 (m, 1H), 4.06-4.04 (m, 2H), 4.00 (d, J=3.6 Hz, 1H), 3.89 (dd, J=3.7, 2.2 Hz, 1H), 3.66 (d, J=10.9 Hz, 2H), 3.56 (t, J=2.8 Hz, 1H), 3.54 (d, J=2.4 Hz, 1H), 3.53-3.48 (m, 3H), 3.47-3.46 (m, 2H), 3.37 (d, J=5.2 Hz, 1H), 3.35 (d, J=4.8 Hz, 1H), 3.25 (s, 3H), 3.20-3.18 (m, 1H), 3.16-3.12 (m, 2H), 2.94-2.91 (m, 2H), 2.76-2.72 (m, 2H), 2.69-2.65 (m, 2H), 2.59 (s, 1H), 2.57-2.53 (m, 3H), 2.37 (d, J=3.6 Hz, 1H), 2.13-2.08 (m, 2H), 1.97 (d, J=14.5 Hz, 2H), 1.84-1.80 (m, 2H), 1.77 (d, J=13.2 Hz, 2H), 1.66-1.62 (m, 2H), 1.53-1.48 (m, 3H), 1.33 (s, 2H), 1.23 (d, J=11.9 Hz, 14H), 1.06 (d, J=6.3 Hz, 3H), 0.91 (d, J=6.1 Hz, 3H), 0.87-0.84 (m, 3H), 0.83 (d, J=7.1 Hz, 2H).

Example 20

(144) ##STR00080##

(145) Van-b (50 mg, 30 mol) was dissolved in 1 mL of DMF, added with HBTU (O-(benzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate) (21 mg, 45 mol) and DIPEA (25 L, 150 mol), and stirred at room temperature for 15 min. 3-Dimethylaminopropylamine (18 L, 120 mol) was added, and the reaction was stirred at room temperature for 24 h and monitored by HPLC. The reaction mixture was diluted with water, and the crude was purified by reverse-phase C18 HPLC and lyophilized to give Van020 as a white solid. HPLC: C18 column (5 m, 4.6250 mm), UV detection at 214 nm, elution conditions: a gradient of 2-90% acetonitrile containing 0.1% v/v TFA over 30 min. HRMS (ESI.sup.+) calculated for C.sub.84H.sub.96C.sub.13N.sub.11O.sub.23 [M+2H].sup.2+ 1731.5746, found 866.7873.

(146) .sup.1H NMR (600 MHz, DMSO-d.sub.6) 7.84 (d, J=1.9 Hz, 1H), 7.74 (s, 1H), 7.73-7.69 (m, 4H), 7.56 (d, J=8.1 Hz, 4H), 7.53 (d, J=8.3 Hz, 2H), 7.49-7.46 (m, 1H), 7.33 (d, J=8.4 Hz, 1H), 7.26 (s, 1H), 7.22 (d, J=8.3 Hz, 1H), 6.78 (dd, J=8.4, 1.9 Hz, 1H), 6.71 (d, J=8.4 Hz, 1H), 6.39 (d, J=2.3 Hz, 1H), 6.22 (d, J=2.3 Hz, 1H), 5.77-5.74 (m, 1H), 5.36 (d, J=7.7 Hz, 1H), 5.30-5.27 (m, 2H), 4.93 (s, 1H), 4.68 (q, J=6.7 Hz, 1H), 4.48 (d, J=5.1 Hz, 1H), 4.32 (d, J=5.2 Hz, 1H), 4.26 (s, 1H), 4.04 (q, J=12.7 Hz, 3H), 3.96 (d, J=7.3 Hz, 1H), 3.68 (d, 1=10.7 Hz, 1H), 3.58 (t, 1=8.5 Hz, 2H), 3.35 (dt, J=12.9, 6.0 Hz, 2H), 3.31-3.24 (m, 3H), 3.11 (dt, J=20.1, 6.9 Hz, 2H), 3.00-2.96 (m, 2H), 2.75 (d, J=4.0 Hz, 6H), 2.63 (s, 2H), 2.14 (td, J=15.4, 14.1, 6.4 Hz, 3H), 1.87-1.77 (m, 414), 1.71-1.53 (m, 5H), 1.51 (s, 3H), 1.13 (d, J=6.3 Hz, 3H), 0.90 (d, J=6.2 Hz, 3H), 0.85 (d, J=6.3 Hz, 3H).

Example 21

(147) ##STR00081##

(148) 2-Aminoethyl--D-mannopyranoside 2 (30 mg) was dissolved in a mixture of 100 L of water and 500 L of acetonitrile, added with 30 L of DIPEA, and stirred at room temperature until the solid was completely dissolved (10 min). Then, the mixture was added with 2 L of a 37 wt % formaldehyde solution, stirred at room temperature for 15 min, cooled to 10 C. and stirred for 5 min. The mixture was quickly mixed with 1.5 mL of a 80% solution of Van020 (25 mg) in acetonitrile, added with 304, of DIPEA, and stirred at 10 C. for 8 h. The reaction was monitored by HPLC. HPLC: C18 column (5 m, 4.6250 mm), UV detection at 214 nm, elution conditions: a gradient of 2-90% acetonitrile containing 0.1% v/v TFA over 30 min. The crude was purified by reverse-phase C18 HPLC and lyophilized to give Van021 as a white solid. HRMS (ESI.sup.+) calculated for C.sub.93H.sub.13C.sub.13N.sub.12O.sub.29 [M+2H].sup.2+ 1966.6802, found 984.3486.

(149) .sup.1H NMR (600 MHz, DMSO-d.sub.6) 7.83 (s, 1H), 7.74-7.70 (m, 4H), 7.69 (d, J=2.1 Hz, 1H), 7.57 (d, J=8.0 Hz, 2H), 7.52 (dd, J=6.9, 4.9 Hz, 4H), 7.47-7.45 (m, 1H), 7.31 (d, J=8.4 Hz, 1H), 7.23 (d, J=8.4 Hz, 1H), 7.19 (s, 1H), 6.84 (dd, J=8.7, 1.9 Hz, 1H), 6.77 (d, J=8.5 Hz, 1H), 6.49 (s, 1H), 5.73 (d, J=7.3 Hz, 1H), 5.70 (s, 1H), 5.39 (s, 1H), 5.35 (d, J=7.6 Hz, 1H), 5.14 (s, 1H), 5.11 (s, 1H), 4.80 (s, 1H), 4.65 (d, J=6.9 Hz, 1H), 4.64 (d, J=1.7 Hz, 1H), 4.47 (s, 1H), 4.27 (d, J=5.1 Hz, 1H), 4.17 (d, J=7.0 Hz, 1H), 4.11 (d, J=13.2 Hz, 2H), 4.02 (s, 3H), 3.86-3.82 (m, 211), 3.67 (dd, J=3.5, 1.7 Hz, 1H), 3.66-3.64 (m, 1H), 3.63 (d, J=2.3 Hz, 1H), 3.56 (t, J=8.5 Hz, 2H), 3.50 (dd, J=9.0, 3.4 Hz, 2H), 3.38 (dd, J=11.9, 6.8 Hz, 3H), 3.33 (ddd, J=9.2, 6.3, 2.2 Hz, 2H), 3.28-3.24 (m, 2H), 3.11 (s, 3H), 3.01-2.95 (m, 3H), 2.72 (d, J=1.8 Hz, 6H), 2.57 (s, 2H), 2.10 (d, J=10.0 Hz, 3H), 1.83 (d, J=13.6 Hz, 4H), 1.66 (s, 3H), 1.50 (s, 3H), 1.11 (d, J=6.2 Hz, 3H), 0.91 (d, J=6.1 Hz, 3H), 0.86 (d, J=6.2 Hz, 3H).

Example 22

(150) ##STR00082##

(151) Van022 was prepared using the same needed materials, reagents and preparation method as those in example 21 except that 2-aminoethyl--D-mannopyranoside 2 in example 21 was replaced with the gluconolactone derivative 6. HRMS (EST) calculated for C.sub.94H.sub.116C.sub.13N.sub.13O.sub.29 [M+2H].sup.2+ 1995.7067, found 998.8520.

(152) .sup.1H NMR (600 MHz, DMSO-d.sub.6) 7.82-7.81 (m, 1H), 7.75-7.70 (m, 4H), 7.69 (d, J=2.1 Hz, 1H), 7.56-7.52 (m, 4H), 7.52 (d, J=2.0 Hz, 1H), 7.50 (d, J=8.6 Hz, 1H), 7.47-7.45 (m, 1H), 7.30 (d, J=8.4 Hz, 1H), 7.24 (d, J=8.3 Hz, 1H), 7.20 (s, 1H), 6.85 (d, J=9.1 Hz, 1H), 6.77 (d, J=8.5 Hz, 1H), 6.48 (s, 1H), 5.72 (d, J=12.3 Hz, 2H), 5.35 (d, J=7.7 Hz, 1H), 5.30 (s, 1H), 5.13 (s, 1H), 5.11-5.10 (m, 1H), 4.81 (s, 1H), 4.65 (d, J=6.5 Hz, 1H), 4.48-4.46 (m, 1H), 4.29 (d, J=5.4 Hz, 1H), 4.17 (s, 1H), 4.06-4.04 (m, 2H), 4.02 (d, J=11.9 Hz, 2H), 4.00 (d, J=3.6 Hz, 1H), 3.88 (dd, J=3.7, 2.3 Hz, 1H), 3.67 (d, J=10.5 Hz, 1H), 3.56 (d, J=3.3 Hz, 1H), 3.54 (d, J=2.2 Hz, 1H), 3.52-3.49 (m, 2H), 3.36 (dd, J=10.5, 4.9 Hz, 2H), 3.26 (d, J=8.7 Hz, 2H). 3.11 (ddd, J=20.1, 13.4, 6.5 Hz, 4H), 2.99-2.94 (m. 3H), 2.93-2.89 (m. 2H), 2.73 (d, J=4.5 Hz, 6H), 2.61-2.59 (m. 1H), 2.57 (s, 3H), 2.38-2.36 (m, 1H), 2.10 (d, J=11.1 Hz, 3H). 1.84-1.76 (m, 6H), 1.66-1.62 (m, 2H), 1.50 (s, 3H), 1.11 (d, J=6.3 Hz, 3H), 0.91 (d, J=6.1 Hz, 3H), 0.86 (d, J=6.1 Hz, 3H).

Example 23

(153) ##STR00083##

(154) Van-b (50 mg, 30 mol) was dissolved in 1 mL of DMF, added with HBTU (O-(benzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate) (21 mg, 45 mol) and DIPEA (25 L, 150 mol), and stirred at room temperature for 15 min. The gluconolactone derivative 6 (30 mg, 80 mol) was added, and the reaction was stirred at room temperature for 24 h and monitored by HPLC. The reaction mixture was diluted with water, and the crude was purified by reverse-phase C18 HPLC and lyophilized to give Van023 as a white solid. HPLC: C18 column (5 m, 4.6250 mm), UV detection at 214 nm, elution conditions: a gradient of 2-90% acetonitrile containing 0.1% v/v TFA over 30 min. HRMS (ESI.sup.+) calculated for C.sub.88H.sub.102C.sub.13N.sub.11O.sub.29 [M+2H].sup.2+ 1881.5910, found 941.7995.

(155) .sup.1H NMR (600 MHz, DMSO-d.sub.6) 7.84 (s, 1H), 7.75-7.70 (m, 4H), 7.69 (d, J=2.1 Hz, 1H), 7.56-7.52 (m, 4H), 7.52-7.51 (m, 1H), 7.45 (d, J=8.5 Hz, 2H), 7.30 (d, J=8.4 Hz, 2H), 7.20 (q, J=8.4 Hz, 3H), 7.04 (d, J=10.4 Hz, 2H), 6.75 (d, J=9.0 Hz, 1H), 6.69 (d, J=8.5 Hz, 1H), 6.44-6.42 (m, 1H), 6.34 (d, J=2.3 Hz, 1H), 6.29-6.28 (m, 1H), 6.24 (d, J=2.4 Hz, 1H). 5.79 (d, J=6.6 Hz, 1H), 5.74 (d, J=7.2 Hz, 1H), 5.69 (s, 1H), 5.62 (s, 1H), 5.28 (s, 3H), 4.65 (d, J=6.6 Hz, 2H), 4.44 (s, 2H), 4.36 (d, J=5.4 Hz, 1H), 4.33 (d, J=5.7 Hz, 1H), 3.87 (t, J=2.8 Hz, 1H), 3.67 (d, J=10.9 Hz, 1H), 3.56 (d, J=8.4 Hz, 2H), 3.54-3.51 (m, 2H), 3.35-3.32 (m, 2H), 3.27-3.24 (m, 2H), 3.02 (s, 2H), 2.91 (s, 2H), 2.60 (d, J=3.4 Hz, 2H), 2.58 (s, 1H), 2.37 (d, J=3.6 Hz, 1H). 2.12-2.09 (m. 2H), 1.82 (d, J=13.3 Hz, 2H), 1.67-1.63 (m, 2H), 1.55 (d, J=8.8 Hz, 2H), 1.49 (s. 2H), 1.13-1.09 (m, 3H), 0.90 (d, J=6.3 Hz, 3H), 0.85 (t, =5.8 Hz, 3H).

Example 24

(156) ##STR00084##

(157) Step 1: Commercially available vancomycin (100 mg) and DIPEA (30 L) were dissolved in 3 mL of DMF to give an opaque solution, which was heated to 50 C. to become clear. Decanal (30 L) was added, and the mixture was heated under stirring for 4 h. Then, NaCNBH.sub.3 (8 mg), 1 mL of methanol and 30 L of TFA were added at room temperature, and the reaction was stirred overnight and monitored by HPLC. The reaction mixture was added with diethyl ether (50 mL) to generate precipitates, which was filtered to give a crude. The crude was purified by reverse-phase C18 HPLC and lyophilized to give Van-g (40 mg) as a white solid. HPLC: C18 column (5 m, 4.6250 mm), UV detection at 214 nm, elution conditions: a gradient of 2-90% acetonitrile containing 0.1% v/v TFA over 30 min. HRMS (ESI.sup.+) calculated for C.sub.76H.sub.95Cl.sub.2N.sub.9O.sub.24 [M+2H].sup.2+ 1587.5867, found 794.8006.

(158) .sup.1H NMR (600 MHz, DMSO-d.sub.6) 8.70 (s, 1H), 7.81 (d, J=1.9 Hz. 1H), 7.52 (d, J=8.6 Hz, 1H), 7.44 (dd, J=8.3, 1.8 Hz, 1H), 7.29 (d, J=8.4 Hz, 1H), 7.17 (d, J=8.4 Hz, 1H), 7.15-7.11 (m, 1H), 6.76 (dd, J=8.4, 2.0 Hz, 1H), 6.70 (d, J=8.4 Hz, 2H), 6.38 (d, J=2.3 Hz, 1H), 6.23 (d, J=2.3 Hz, 1H), 5.73 (d, J=7.8 Hz, 1H), 5.59 (s, 1H), 5.27 (dd, J=22.9, 6.0 Hz, 2H), 5.14 (dd, J=14.8, 2.8 Hz, 2H), 5.09 (s, 1H), 4.89 (s, 1H), 4.60 (d, J=6.7 Hz, 1H), 4.42 (dd, J=11.8, 5.6 Hz, 2H), 4.17 (s, 2H), 3.94 (s, 1H), 3.65 (d, J=10.8 Hz, 1H), 3.54 (t, J=8.5 Hz, 1H), 3.31-3.22 (m, 3H), 2.74 (s, 1H), 2.67 (d, J=7.2 Hz, 1H), 2.60 (s, 4H), 2.12 (d, J=12.6 Hz, 1H), 1.96 (d, J=11.6 Hz, 1H), 1.77 (d, J=13.1 Hz, 1H), 1.63 (ddd, J=26.5, 12.5, 6.7 Hz, 2H), 1.51 (s, 3H), 1.32 (s, 3H), 1.23 (d, J=18.1 Hz, 16H), 1.06 (d, J=6.3 Hz, 3H), 0.89 (d, J=6.2 Hz, 3H), 0.83 (td, J=7.1, 6.7, 3.6 Hz, 6H).

(159) Step 2: Van024 was prepared using the same needed materials, reagents and preparation method as those in example 16 except that Van-c in example 16 was replaced with Van-g. HRMS (ESI.sup.+) calculated for C.sub.86H.sub.115Cl.sub.2N.sub.11O.sub.30 [M+2H].sup.2+ 1851.7188, found 926.8674.

(160) .sup.1H NMR (600 MHz, DMSO-d.sub.6) 8.77 (s, 1H), 8.64 (s, 1H), 7.80 (d, J=1.9 Hz, 1H), 7.60 (s, 1H), 7.48 (d, J=8.5 Hz, 1H), 7.46-7.41 (m, 1H), 7.28 (d, J=8.3 Hz, 1H), 7.20 (d, J=8.3 Hz, 1H), 6.84 (dd, J=8.5, 1.9 Hz, 1H), 6.77 (d, J=8.4 Hz, 1H), 6.53 (s, 1H), 5.73-5.68 (m, 2H), 5.30 (d, J=7.7 Hz, 1H), 5.27 (d, J=4.1 Hz, 1H), 5.12 (s, 2H), 5.07 (d, J=2.0 Hz, 1H), 4.80 (s, 1H), 4.43 (s. 1H), 4.41 (d, J=5.8 Hz, 1H), 4.10-4.04 (m, 3H), 4.00 (d, J=3.6 Hz, 2H), 3.89 (dd, J=3.6, 2.2 Hz, 1H), 3.65 (d, J=10.6 Hz, 1H), 3.57-3.46 (m, 6H), 3.36 (dd, J=10.7, 5.0 Hz, 1H), 3.28-3.22 (m, 3H), 3.21-3.16 (m, 1H), 3.14 (dt, J=13.0, 6.2 Hz, 1H), 2.92 (s, 2H), 2.71 (d, J=39.8 Hz, 3H), 2.56 (s, 3H), 2.11 (s, 1H), 1.96 (d, J=10.7 Hz, 1H), 1.86-1.73 (m, 3H), 1.64 (d, J=9.9 Hz, 2H), 1.50 (s, 3H), 1.33 (s, 3H), 1.22 (s, 16H), 1.06 (d, J=6.3 Hz, 3H), 0.90 (d, J=6.1 Hz, 3H), 0.87-0.81 (m, 6H).

Example 25

(161) ##STR00085##

(162) Step 1: commercially available vancomycin (100 mg) and DIPEA (30 L) were dissolved in 3 mL of DMF. After the solution became clear, 15 L of undecanoyl chloride was added in three portions under ice-water bath, and the reaction was stirred for 2 h under argon. The reaction mixture was added with diethyl ether (50 mL) to generate precipitates, which was filtered to give a crude. The crude was purified by reverse-phase C18 HPLC and lyophilized to give Van-h (40 mg) as a white solid. HPLC: C18 column (5 m, 4.6250 mm), UV detection at 214 nm, elution conditions: a gradient of 2-90% acetonitrile containing 0.1% v/v TFA over 30 min. HRMS (ESI.sup.+) calculated for C.sub.77H.sub.95Cl.sub.2N.sub.9O.sub.25 [M+2H].sup.2+ 1615.5816, found 808.7978.

(163) .sup.1H NMR (600 MHz, DMSO-d.sub.6) 8.63 (s, 1H), 8.46 (d, J=5.7 Hz, 1H), 7.80 (d, J=2.0 Hz, 1H), 7.46 (dd, J=8.4, 1.8 Hz, 1H), 7.43 (dd, J=8.1, 1.9 Hz, 1H), 7.34 (d, J=8.3 Hz, 1H), 7.22 (s, 1H), 7.17-7.15 (m, 1H), 7.00 (d, J=8.3 Hz, 1H), 6.76 (dd, J=8.5, 2.1 Hz, 1H), 6.70 (dd, J=8.5, 3.2 Hz, 2H), 6.39 (d, J=2.3 Hz, 1H), 6.22 (d, J=2.3 Hz, 1H), 5.69 (d, J=8.3 Hz, 1H), 5.48 (d, J=2.1 Hz, 1H), 5.26-5.17 (m, 4H), 5.13 (d, J=4.7 Hz, 1H), 5.08 (s, 1H), 4.77 (dd, J=9.8, 4.5 Hz, 1H), 4.66 (d, J=6.7 Hz, 1H), 4.45 (d, J=5.7 Hz, 2H), 4.41 (d, J=5.7 Hz, 1H), 4.18 (s, 1H), 3.64 (d/=10.8 Hz, 1H). 3.56-3.48 (m, 3H), 3.25 (d, J=5.5 Hz, 2H), 3.13 (s, 1H), 2.82 (s, 3H), 2.41-2.30 (m, 3H), 2.10 (d, J=12.7 Hz, 2H), 1.88 (d, J=11.0 Hz, 1H), 1.71 (d, J=13.1 Hz, 1H), 1.57 (d, J=7.7 Hz, 3H), 1.50-1.42 (m, 2H), 1.36 (d, J=7.3 Hz, 2H), 1.34-1.13 (m, 17H), 1.05 (d, J=6.4 Hz, 3H), 0.85 (dd, J=6.7, 2.4 Hz, 3H), 0.81 (t, J=7.1 Hz, 3H), 0.77 (d, J=6.6 Hz, 3H).

(164) Step 2: Van025 was prepared using the same needed materials, reagents and preparation method as those in example 16 except that N.sup.van-2-(4-trifluoromethyl-biphenylmethyl)-vancomycin (Van-c) in example 16 was replaced with N.sup.van-2-(undecanoyl)-vancomycin (Van-h). HRMS (ESI.sup.+) calculated for C.sub.87H.sub.115C.sub.12N.sub.11O.sub.31 [M+2H].sup.2+ 1879.7138, found 940.8659.

(165) .sup.1H NMR (600 MHz, DMSO-d.sub.6) 8.67 (s, 1H), 7.76 (s, 1H), 7.49-7.45 (m, 1H), 7.43 (d, J=8.7 Hz, 1H), 7.31 (d, J=8.4 Hz, 2H), 7.11 (s, 1H), 7.06 (d, J=8.1 Hz, 1H), 6.84 (dd, J=8.7, 2.1 Hz, 1H), 6.82-6.72 (m, 2H), 6.52 (s, 1H), 5.64 (d, J=7.9 Hz, 1H), 5.57 (s, 1H), 5.22 (dt, J=11.7, 3.6 Hz, 3H), 5.17-5.05 (m, 3H), 4.74 (s, 1H), 4.65 (d, J=6.8 Hz, 1H), 4.44 (dd, J=16.5, 5.8 Hz, 2H), 4.07 (d, J=27.1 Hz, 3H), 4.00 (d, J=3.5 Hz, 1H), 3.92-3.86 (m, 1H), 3.64 (d, J=10.5 Hz, 1H), 3.58-3.50 (m, 4H), 3.36 (dd, J=10.5, 4.5 Hz, 1H), 3.26 (d, J=5.5 Hz, 2H), 3.23-3.08 (m, 3H), 2.92 (s, 2H), 2.42-2.28 (m, 2H), 1.88 (d, J=10.0 Hz, 1H), 1.71 (d, J=13.1 Hz, 1H), 1.54 (q, J=8.0 Hz, 4H), 1.38 (hept, J=6.7 Hz, 1H), 1.28 (d, J=8.2 Hz, 5H), 1.21 (dd, J=14.0, 6.4 Hz, 14H), 1.05 (d, J=6.5 Hz, 3H), 0.87 (d, J=6.5 Hz, 3H). 0.82 (t, J=7.0 Hz, 3H), 0.79 (d, J=6.5 Hz, 3H).

Example 26

(166) ##STR00086##

(167) Step 1: commercially available vancomycin (100 mg) and DIPEA (30 L) were dissolved in 3 mL of DMF. After the solution became clear, 15 L of decanoyl chloride was added in three portions under ice-water bath and the reaction was stirred for 2 h under argon. The reaction mixture was added with diethyl ether (50 mL) to generate precipitates, which was filtered to give a crude. The crude was purified by reverse-phase C18 HPLC and lyophilized to give Van-i (40 mg) as a white solid. HPLC: C18 column (5 m, 4.6250 mm), UV detection at 214 nm, elution conditions: a gradient of 2-90% acetonitrile containing 0.1% v/v TFA over 30 min. HRMS (ESI.sup.+) calculated for C.sub.76H.sub.93Cl.sub.2N.sub.9O.sub.25 [M+2H].sup.2+ 1601.5660, found 801.7908.

(168) .sup.1H NMR (600 MHz, DMSO-d.sub.6) 8.63 (d, J=4.8 Hz, 1H), 7.80 (d, J=2.0 Hz, 1H), 7.49-7.38 (m, 2H), 7.34 (d, J=8.3 Hz, 1H), 7.22 (s, 1H), 7.16 (s, 2H), 7.00 (d, J=8.3 Hz, 1H), 6.76 (dd, J=8.4, 2.2 Hz, 1H), 6.70 (d, J=8.4 Hz, 2H), 6.39 (d, J=2.3 Hz, 1H), 6.22 (d, J=2.3 Hz, 1H), 5.69 (d, J=8.2 Hz, 1H), 5.48 (d, J=2.0 Hz, 1H), 5.29-5.16 (m, 4H), 5.13 (d, J=4.7 Hz, 1H), 5.08 (s, 1H), 4.77 (dd, J=9.5, 4.7 Hz, 1H), 4.66 (q, J=6.5 Hz, 1H), 4.45 (d, J=5.5 Hz, 1H), 4.41 (d, J=5.8 Hz, 1H), 4.18 (s, 1H), 3.64 (d, J=10.9 Hz, 1H), 3.59-3.47 (m, 3H), 3.25 (d, J=5.8 Hz, 2H), 3.13 (s, 1H), 2.82 (s, 3H), 2.42-2.29 (m, 2H), 2.18 (s, 1H), 2.14-2.07 (m, 1H), 1.88 (d, J=10.3 Hz, 1H), 1.70 (d, J=13.1 Hz, 1H), 1.57 (d, J=7.8 Hz, 3H), 1.46 (dt, J=13.7, 7.6 Hz, 1H), 1.42-1.34 (m, 1H), 1.30 (dd, J=9.8, 5.6 Hz, 2H), 1.26 (s, 3H), 1.21 (td, J=14.5, 11.7, 5.6 Hz, 10H), 1.05 (d, J=6.4 Hz, 3H), 0.85 (dd, J=6.7, 2.5 Hz, 3H), 0.84-0.79 (m, 3H), 0.77 (d, J=6.5 Hz, 3H).

(169) Step 2: Van026 was prepared using the same needed materials, reagents and preparation method as those in example 25 except that Van-h in example 25 was replaced with Van-i. HRMS (ESI) calculated for C.sub.86H.sub.113Cl.sub.2N.sub.11O.sub.31 [M+2H].sup.2+ 1865.6931. found 933.8577.

(170) .sup.1H NMR (600 MHz, DMSO-d.sub.6) 8.66 (s, 1H), 7.46 (dd, J=8.3, 1.8 Hz, 1H), 7.45-7.39 (m, 1H), 7.31 (d, J=8.4 Hz, 2H), 7.13-6.98 (m, 2H), 6.84 (dd, J=8.6, 1.8 Hz, 1H), 6.77 (t, J=7.7 Hz, 2H), 6.52 (s, 1H), 5.64 (d, J=7.9 Hz, 1H), 5.57 (s, 1H), 5.22 (dt, J=11.7, 3.8 Hz, 3H), 5.17-5.06 (m, 3H), 4.65 (d, J=6.7 Hz, 1H), 4.44 (dd, J=16.4, 5.7 Hz, 2H), 4.13-4.01 (m, 3H), 4.00 (d, J=3.5 Hz, 1H), 3.89 (t, J=2.8 Hz, 1H), 3.64 (d, J=10.9 Hz, 1H), 3.61-3.48 (m, 4H), 3.36 (dd, J=9.1, 3.5 Hz, 1H), 3.26 (d, J=5.1 Hz, 2H), 3.19 (dt, J=13.4, 6.7 Hz, 1H), 3.14 (d, J=7.7 Hz, 2H), 2.92 (t, J=7.6 Hz, 2H), 2.83 (s, 3H), 2.43-2.27 (m, 2H), 1.88 (d, J=11.4 Hz, 1H), 1.81 (dq, J=14.2, 7.0 Hz, 2H), 1.71 (d, J=13.0 Hz, 1H), 1.54 (q, J=8.4, 7.5 Hz, 4H), 1.38 (dt, J=13.6, 6.6 Hz, 1H), 1.28 (d, J=8.8 Hz, 6H), 1.26-1.15 (m, 12H), 1.05 (d, J=6.3 Hz, 3H), 0.92-0.88 (m, 1H), 0.87 (d, J=6.6 Hz, 3H), 0.82 (t, J=6.8 Hz, 3H), 0.79 (d, J=6.5 Hz. 3H).

Example 27

(171) ##STR00087##

(172) Step 1: Commercially available vancomycin (100 mg) and DIPEA (30 L) were dissolved in 3 mL of DMF to give an opaque solution, which was heated to 50 C. to become clear. 2-naphthaldehyde (21 mg) was added, and the mixture was heated under stirring for 4 h. NaCNBH.sub.3 (8 mg), 1 mL of methanol and 30 L of TFA were added at room temperature, and the reaction was stirred overnight and monitored by HPLC. The reaction mixture was added with diethyl ether (50 mL) to generate precipitates, which was filtered to give a crude. The crude was purified by reverse-phase C18 HPLC and lyophilized to give Van-j (40 mg) as a white solid. HPLC: C18 column (5 m, 4.6250 mm), UV detection at 214 nm, elution conditions: a gradient of 2-90% acetonitrile containing 0.1% v/v TFA over 30 min. HRMS (ESI.sup.+) calculated for C.sub.77H.sub.83Cl.sub.2N.sub.9O.sub.24 [M+2H].sup.2+ 1587.4928, found 794.7548.

(173) .sup.1H NMR (600 MHz, DMSO-d.sub.6) 8.71 (s, 1H), 8.54 (d, J=5.5 Hz, 1H), 7.99 (s, 1H), 7.96 (d, J=8.5 Hz, 1H), 7.93 (dt, J=7.4, 3.1 Hz, 1H), 7.92-7.87 (m, 1H), 7.83 (d, J=1.8 Hz, 1H), 7.59-7.49 (m, 5H), 7.46 (dd, J=8.3, 1.8 Hz, 1H), 7.32 (d, J=8.4 Hz, 1H), 7.19 (d, J=8.4 Hz, 1H), 7.16-7.12 (m, 1H), 6.76 (dd, J=8.4, 2.0 Hz, 1H), 6.70 (d, J=8.5 Hz, 2H), 6.38 (d, J=2.3 Hz, 1H), 6.23 (d, J=2.3 Hz, 1H), 5.74 (d, J=7.8 Hz, 1H), 5.62 (s, 1H), 5.34 (d, J=7.7 Hz, 1H), 5.28 (d, J=4.3 Hz, 1H), 5.16 (dd, J=7.9, 2.8 Hz, 2H), 5.10 (s, 1H), 4.90 (s, 1H), 4.67 (d, J=6.6 Hz, 1H), 4.44 (d, J=5.6 Hz, 1H), 4.41 (d, J=5.7 Hz, 1H), 4.16 (t, J=10.4 Hz, 4H), 3.95 (s, 1H), 3.67 (d, J=10.6 Hz, 1H), 3.57 (t, J=8.5 Hz, 1H), 3.49 (s. 2H), 3.31-3.21 (m, 3H), 2.61 (s, 3H), 2.11 (d, J=11.5 Hz, 2H), 1.83 (d, J=13.2 Hz, 1H), 1.64 (ddd, J=28.9, 13.3, 6.2 Hz, 3H), 1.60-1.52 (m, 2H), 1.50 (s, 3H), 1.12 (d, J=6.2 Hz, 3H), 0.89 (d, J=6.2 Hz, 3H), 0.85 (d, J=6.3 Hz, 3H).

(174) Step 2: Van027 was prepared using the same needed materials, reagents and preparation method as those in example 16 except that Van-c in example 16 was replaced with Van-j. HRMS (ESI.sup.+) calculated for C.sub.87H.sub.103Cl.sub.2N.sub.11O.sub.30 [M+2H].sup.2+ 1851.6249, found 926.8124.

(175) .sup.1H NMR (600 MHz, DMSO-d.sub.6) 8.79 (s, 11-1), 8.65 (d, J=6.0 Hz, 1H), 7.99 (s, 1H), 7.98-7.92 (m, 2H), 7.92-7.87 (m, 1H), 7.60 (s, 1H), 7.59-7.54 (m, 3H), 7.50 (s, 1H), 7.49-7.43 (m, 1H), 7.31 (d, J=8.3 Hz, 1H), 7.22 (d, J=8.4 Hz, 1H), 6.77 (d, J=8.5 Hz, 1H), 6.53 (s, 1H), 5.75-5.70 (m, 2H), 5.34 (d, J=7.7 Hz, 1H), 5.29 (d, J=4.2 Hz, 1H), 5.12 (d, J=4.4 Hz, 2H), 5.09 (d, J 1.9 Hz, 1H), 4.67 (q, J=6.6 Hz, 1H), 4.45 (d, J=5.7 Hz, 1H), 4.41 (d, J=5.7 Hz, 1H), 4.06 (s, 5H), 4.00 (d, J=3.6 Hz, 2H), 3.89 (t, J=2.9 Hz, 1H), 3.66 (d, J=10.7 Hz, 1H), 3.60-3.49 (m, 4H), 3.38-3.33 (m, 1H), 3.31-3.22 (m, 2H), 3.16 (dp, J=26.2, 6.6 Hz, 2H), 2.92 (t, J=7.5 Hz, 2H), 2.57 (s, 3H), 2.11 (d, J=10.9 Hz, 2H), 1.82 (dq, J=14.2, 7.0, 6.1 Hz, 3H), 1.69-1.60 (m, 2H), 1.51 (s, 3H), 1.12 (d, J=6.4 Hz, 3H). 0.91 (d, J=6.1 Hz, 3H), 0.85 (d, J=6.0 Hz, 3H).

Example 28

(176) ##STR00088##

(177) Step 1: Commercially available vancomycin (100 mg) and DIPEA (30 L) were dissolved in 3 mL of DMF to give an opaque solution, which was heated to 50 C. to become clear. 4-((trimethylsilyl)ethynyl)benzaldehyde (27 mg) was added, and the mixture was heated under stirring for 4 h. NaCNBH.sub.3 (8 mg), 1 mL of methanol and 30 L of TFA were added at room temperature, and the reaction was stirred overnight and monitored by HPLC. The reaction mixture was added with diethyl ether (50 mL) to generate precipitates, which was filtered to give a crude. The crude was purified by reverse-phase C18 HPLC and lyophilized to give Van-k (40 mg) as a white solid. HPLC: C18 column (5 m, 4.6250 mm), UV detection at 214 nm, elution conditions: a gradient of 2-90% acetonitrile containing 0.1% v/v TFA over 30 min. HRMS (ESI.sup.+) calculated for C.sub.78H.sub.89Cl.sub.2N.sub.9O.sub.24Si [M+2H].sup.2+ 1633.5167, found 817.7670.

(178) .sup.1H NMR (600 MHz, DMSO-d.sub.6) 8.70 (s, 1H), 7.82 (d, J=1.8 Hz, 1H), 7.51 (dd, J=19.0, 8.3 Hz, 4H), 7.45 (td, J=4.8, 2.1 Hz, 3H), 7.31 (d, J=8.4 Hz, 1H), 7.18 (d, J=8.4 Hz, 1H), 7.16-7.12 (m, 1H), 6.76 (dd, J=8.4, 2.0 Hz, 1H), 6.70 (d, J=8.5 Hz, 2H), 6.38 (d, J=2.3 Hz, 1H), 6.23 (d, J=2.3 Hz, 1H), 5.73 (d, J=7.8 Hz, 1H), 5.61 (s. 1H), 5.32 (d, J=7.6 Hz. 1H), 5.27 (d, J=4.2 Hz, 11-1), 5.15 (dd, J=11.8, 2.8 Hz, 2H), 5.09 (s, 1H), 4.90 (s, 1H), 4.65 (d, J=6.7 Hz, 1H), 4.42 (dd, J=15.8, 5.5 Hz, 2H), 3.96 (d, J=22.9 Hz, 3H), 3.66 (d, J=10.7 Hz, 1H), 3.56 (t, J=8.5 Hz, 1H), 3.30-3.21 (m, 3H), 2.61 (s, 3H), 2.09 (s, 3H), 1.80 (d, J=13.2 Hz, 1H), 1.64 (ddt, J=27.3, 12.8, 6.5 Hz, 3H), 1.54 (dt, J=13.2, 6.9 Hz, 21-1), 1.45 (s, 3H), 1.10 (d, J=6.2 Hz, 3H), 0.89 (d, J=6.2 Hz, 3H), 0.84 (d, J=6.2 Hz, 3H), 0.21 (s, 91-1).

(179) Step 2: Van028 was prepared using the same needed materials, reagents and preparation method as those in example 16 except that Van-c in example 16 was replaced with Van-k. HRMS (ESI.sup.+) calculated for C.sub.88H.sub.109Cl.sub.2N.sub.11O.sub.30Si [M+2H].sup.2+ 1897.6488, found 949.8331.

(180) .sup.1H NMR (600 MHz, DMSO-d.sub.6) 8.78 (s, 1H), 8.65 (s, 1H), 7.61 (s, 1H), 7.50 (d, J=7.9 Hz, 3H), 7.46-7.43 (m, 2H), 7.30 (d, J=8.3 Hz, 1H), 7.21 (d, J=8.4 Hz, 1H), 6.84 (dd, J=8.4, 1.9 Hz, 1H), 6.77 (d, J=8.5 Hz, 2H), 6.53 (s, 1H), 5.72 (d, J=10.8 Hz, 2H), 5.32 (d, J=7.7 Hz, 1H), 5.28 (d, J=4.2 Hz, 1H), 5.12 (s, 2H), 5.08 (d, J=1.9 Hz, 1H), 4.80 (s, 1H), 4.64 (q, J=6.5 Hz, 2H), 4.44 (d, J=5.4 Hz, 1H), 4.41 (d, J=5.7 Hz, 1H), 3.89 (dd, J=3.6, 2.3 Hz, 1H), 3.66 (d, J=10.7 Hz, 1H), 3.59-3.52 (m, 3H), 3.39-3.32 (m, 2H), 3.29-3.22 (m, 3H), 3.16 (dq, J=25.9, 6.8 Hz, 3H), 2.92 (t, J=7.5 Hz, 21-1), 2.56 (s, 3H), 2.09 (s, 3H), 1.82 (td, J=15.9, 14.8, 8.3 Hz, 4H), 1.64 (q, J=6.7, 4.2 Hz, 3H), 1.46 (s, 51-1), 1.09 (d, J=6.3 Hz, 3H), 0.90 (d, J==6.0 Hz, 3H), 0.85 (d, J=6.1 Hz, 3H), 0.21 (s, 9H).

Example 29

(181) ##STR00089##

(182) Step 1: Commercially available vancomycin (100 mg) and DIPEA (30 L) were dissolved in 3 mL of DMF to give an opaque solution, which was heated to 50 C. to become clear. 4-ethynylbenzaldehyde (24 mg) was added, and the mixture was heated under stirring for 4 h. NaCNBH.sub.3 (8 mg), 1 mL of methanol and 30 L of TFA were added at room temperature, and the reaction was stirred overnight and monitored by HPLC. The reaction mixture was added with diethyl ether (50 mL) to generate precipitates, which was filtered to give a crude. The crude was purified by reverse-phase C18 HPLC and lyophilized to give Van-1 (40 mg) as a white solid. HPLC: C18 column (5 m, 4.6250 mm), UV detection at 214 nm, elution conditions: a gradient of 2-90% acetonitrile containing 0.1% v/v TFA over 30 min. HRMS (ESI.sup.+) calculated for C.sub.75H.sub.81Cl.sub.2N.sub.9O.sub.24 [M+2H].sup.2+ 1561.4771, found 781.7473.

(183) .sup.1H NMR (600 MHz, DMSO-d.sub.6) 7.57-7.51 (m, 3H), 7.48 (dd, J=9.2, 4.0 Hz, 3H), 7.33 (d, J=8.4 Hz, 1H), 7.21 (d, J=8.3 Hz. 1H), 7.16 (s, 1H), 6.78 (dd, J=8.5, 2.0 Hz, 1H), 6.72 (d, J=8.7 Hz, 1H), 5.76 (d, J=7.3 Hz, 1H), 5.66-5.59 (m, 1H), 5.34 (d, J=7.7 Hz, 1H), 5.29 (d, J=4.4 Hz, 1H), 5.20-5.13 (m, 2H), 5.11 (s, 1H), 4.92 (s, 1H). 4.67 (t, J=6.6 Hz, 1H), 4.44 (dd, J=15.6, 5.6 Hz, 1H), 4.25 (d, J=2.9 Hz, 1H), 4.19 (s, 1H). 3.68 (d, J=10.7 Hz, 1H), 3.58 (t, J=8.5 Hz, 1H), 3.55-3.49 (m. 1H), 3.31-3.23 (m, 2H), 2.62 (s, 3H), 2.19-2.05 (m, 2H), 1.82 (d, J=13.3 Hz, 1H), 1.72-1.60 (m, 2H), 1.57 (dd, J=12.7, 6.3 Hz, 1H), 1.48 (d, J=8.6 Hz, 3H), 1.28-1.21 (m, 1H), 1.12 (d, J=6.4 Hz, 3H), 0.92 (d, J=6.2 Hz, 3H), 0.87 (d, J=6.2 Hz, 3H).

(184) Step 2: Van029 was prepared using the same needed materials, reagents and preparation method as those in example 16 except that Van-c in example 16 was replaced with Van-1. HRMS (ESI.sup.+) calculated for C.sub.85H.sub.101Cl.sub.2N.sub.11O.sub.30 [M+2H].sup.2+ 1825.6093, found 913.8131.

(185) .sup.1H NMR (600 MHz, DMSO-d.sub.6) 8.79 (s, 1H), 8.65 (s, 1H), 7.61 (s, 1H), 7.52 (d, J=7.8 Hz, 2H), 7.50-7.42 (m, 4H), 7.30 (d, J=8.3 Hz, 1H), 7.21 (d, J=8.4 Hz, 1H), 6.84 (dd, J=8.4, 1.9 Hz, 1H), 6.77 (d, J=8.5 Hz, 1H), 6.53 (s, 1H), 5.72 (d, J=10.5 Hz, 2H), 5.32 (d, J=7.7 Hz, 1H), 5.28 (d, J=4.1 Hz, 1H), 5.12 (d, J=3.5 Hz, 2H), 5.08 (d, J=2.0 Hz, 1H), 4.64 (d, J=6.7 Hz, 1H), 4.44 (d, J=5.4 Hz, 1H), 4.41 (d, J=5.7 Hz, 1H), 4.25-4.21 (m, 1H), 4.07 (d, J=16.7 Hz, 4H), 4.02-3.94 (m, 4H), 3.89 (t, J=2.8 Hz, 1H), 3.66 (d, J=10.6 Hz, 1H), 3.58-3.51 (m, 3H), 3.36 (dd, J=10.8, 5.3 Hz, 1H), 3.26 (s, 2H), 3.16 (dq, J=26.0, 6.8 Hz, 2H), 2.92 (t, J=7.3 Hz, 2H), 2.56 (s, 3H), 2.08 (s, 2H), 1.82 (td, J=14.1, 7.6 Hz, 3H), 1.69-1.60 (m, 2H), 1.45 (s, 4H), 1.09 (d, J=6.3 Hz, 3H), 0.91 (d, J=6.0 Hz, 3H), 0.85 (d, J=6.0 Hz, 3H).

Example 30

(186) ##STR00090##

(187) Step 1: commercially available vancomycin (100 mg) and DIPEA (30 L) were dissolved in 3 mL of DMF to give an opaque solution, which was heated to 50 C. to become clear. 4-butoxybenzaldehyde (24 L) was added and the mixture was heated under stirring for 4 h. NaCNBH.sub.3 (8 mg), 1 mL of methanol and 30 L of TFA were added at room temperature, and the reaction was stirred overnight and monitored by HPLC. The reaction mixture was added with diethyl ether (50 mL) to generate precipitates, which was filtered to give a crude. The crude was purified by reverse-phase C18 HPLC, lyophilized to give Van-m (40 mg) as a white solid. HPLC: C18 column (5 m, 4.6250 mm), UV detection at 214 nm, elution conditions: a gradient of 2-90% acetonitrile containing 0.1% v/v TFA over 30 min. HRMS (ESI.sup.+) calculated for C.sub.77H.sub.88Cl.sub.2N.sub.9O.sub.25 [M+2H].sup.2+ 1609.5347, found 805.7758.

(188) .sup.1H NMR (600 MHz, DMSO-d.sub.6) 8.72 (s. 1H), 7.85 (d, J=1.9 Hz, 1H), 7.47 (dd, J=8.3, 1.8 Hz, 1H), 7.38-7.34 (m, 2H), 7.33 (d, J=8.4 Hz, 1H), 7.22 (d, J=8.3 Hz, 1H), 6.96 (d, J=8.6 Hz, 2H), 6.78 (dd, J=8.4, 2.0 Hz, 1H), 6.72 (d, J=8.6 Hz, 2H), 6.40 (d, J=2.3 Hz, 1H), 6.25 (d, J=2.3 Hz, 1H), 5.76 (d, J=5.2 Hz, 1H), 5.62 (s, 1H), 5.35 (d, J=7.8 Hz, 1H), 5.28 (d, J=4.3 Hz, 1H), 5.18 (dd, J=7.4, 2.9 Hz, 2H), 5.11 (s, 1H), 4.92 (s, 1H), 4.66 (q, 1=6.5 Hz, 1H), 4.45 (d, J=5.5 Hz, 1H), 4.43 (d, J=5.8 Hz, 1H), 4.19 (s, 1H), 3.97 (t, J=6.5 Hz, 2H), 3.92 (q, J=12.6 Hz, 3H), 3.68 (d, J=10.7 Hz, 1H), 3.58 (t, J=8.5 Hz, 1H), 3.52 (dd, J=11.0, 4.3 Hz, 1H), 3.32-3.23 (m, 3H), 3.09 (q, J=7.3 Hz, 2H), 2.59 (s, 3H), 2.11 (s, 3H), 1.80 (d, J=13.2 Hz, 1H), 1.71-1.62 (m, 4H), 1.54 (s, 2H), 1.47 (s, 2H), 1.45-1.38 (m, 3H), 1.17 (t, J=7.3 Hz, 3H), 1.12 (d, J=6.2 Hz, 3H), 0.96-0.89 (m, 6H), 0.86 (d, J=6.0 Hz, 3H).

(189) Step 2: Van030 was prepared using the same needed materials, reagents and preparation method as those in example 16 except that Van-c in example 16 was replaced with Van-m. HRMS (ESI.sup.) calculated for C.sub.87H.sub.109Cl.sub.2N.sub.11O.sub.31 [M+2H].sup.2+ 1873.6668, found 937.8422.

(190) .sup.1H NMR (600 MHz, DMSO-d.sub.6) 7.84 (s, 1H), 7.61 (s, 1H), 7.52-7.49 (m, 1H), 7.48 (dd, J=8.3, 1.8 Hz, 1H), 7.36 (d, J=8.4 Hz, 2H), 7.32 (d, J=8.4 Hz, 1H), 7.23 (d, J=8.4 Hz, 1H), 7.12 (s, 1H), 6.96 (d, J=8.5 Hz, 2H), 6.86 (dd, J=8.5, 2.0 Hz, 1H). 6.79 (d, J=8.5 Hz, 1H), 6.54 (s, 1H), 5.72 (d, J=12.4 Hz, 2H), 5.35 (d, J=7.6 Hz, 1H), 5.29 (d, J=4.2 Hz, 1H), 5.14 (s, 2H), 5.11 (d, J=2.0 Hz, 1H), 4.82 (s, 1H), 4.66 (q, J=6.6 Hz, 1H), 4.46 (d, J=5.5 Hz, 1H), 4.43 (d, J=6.1 Hz, 1H), 4.10 (d, J=28.9 Hz, 3H), 4.02 (d, J=3.6 Hz, 1H), 3.97 (t, J=6.5 Hz, 3H), 3.91 (dd, J=8.5, 6.0 Hz, 3H), 3.68 (d, J=10.6 Hz, 1H), 3.60-3.55 (m, 2H), 3.55-3.50 (m, 2H), 3.44 (s, 2H), 3.40-3.36 (m, 1H), 3.31-3.24 (m, 2H), 3.18 (ddq, J=31.3, 13.3, 6.4 Hz, 3H), 2.92 (s, 2H), 2.56 (s, 2H), 2.16-2.07 (m, 2H), 1.83 (tt, J=13.7, 6.9 Hz, 3H), 1.67 (td, J=12.1, 10.5, 6.1 Hz, 4H), 1.47 (s, 3H), 1.41 (dt, J=14.7, 7.5 Hz, 3H), 1.11 (d, J=6.3 Hz, 3H), 0.94-0.90 (m, 6H), 0.87 (d, J=6.2 Hz, 3H).

Example 31

(191) ##STR00091##

(192) Step 1: Commercially available vancomycin (100 mg) and DIPEA (30 L) were dissolved in 3 mL of DMF to give an opaque solution, which was heated to 50 C. to become clear. 4-pentylbenzaldehyde (24 L) was added, and the mixture was heated under stirring for 4 h. NaCNBH.sub.3 (8 mg), 1 mL of methanol and 30 L of TFA were added at room temperature, and the reaction was stirred overnight and monitored by HPLC. The reaction mixture was added with diethyl ether (50 mL) to generate precipitates, which was filtered to give a crude. The crude was purified by reverse-phase C18 HPLC and lyophilized to give Van-n (40 mg) as a white solid. HPLC: C18 column (5 m, 4.6250 mm), UV detection at 214 nm, elution conditions: a gradient of 2-90% acetonitrile containing 0.1% v/v TFA over 30 min. HRMS (ESI.sup.+) calculated for C.sub.78H.sub.91Cl.sub.2N.sub.9O.sub.24 [M+2H].sup.2+ 1607.5554, found 804.7777.

(193) .sup.1H NMR (600 MHz, DMSO-d.sub.6) 8.56 (d, J=5.8 Hz, 1H), 7.85 (d, J=1.9 Hz, 1H), 7.57-7.53 (m, 1H), 7.47 (dd, J=8.3, 1.8 Hz, 1H), 7.36 (d, J=7.8 Hz, 2H), 7.33 (d, J=8.3 Hz, 1H), 7.24 (d, J=8.1 Hz, 2H), 7.20 (d, J=8.4 Hz, 1H), 7.16 (s, 1H), 6.78 (dd, J=8.4, 2.0 Hz, 1H), 6.72 (d, J=8.5 Hz, 2H), 6.40 (d, J=2.3 Hz, 1H), 6.25 (d, J=2.3 Hz, 1H), 5.76 (d, J=7.9 Hz, 1H), 5.63 (s, 1H), 5.35 (d, J=7.8 Hz, 1H), 5.28 (d, J=4.2 Hz, 1H), 5.19 (d, J=3.6 Hz, 1H), 5.17 (d, J=2.0 Hz, 1H), 5.11 (s, 1H), 4.92 (s, 1H), 4.66 (d, J=6.6 Hz, 1H), 4.45 (d, J=5.4 Hz, 1H), 4.43 (d, J=5.7 Hz, 1H), 4.20 (s, 2H), 3.96 (s, 4H), 3.68 (d, J=10.7 Hz, 1H), 3.58 (t, J=8.5 Hz, 1H), 3.28 (h, J=7.9, 7.4 Hz, 2H), 2.63 (s, 3H), 2.57 (t, J=7.6 Hz, 2H), 2.11 (d, J=11.1 Hz, 2H), 1.81 (d, J=13.2 Hz, 1H), 1.71-1.60 (m, 3H), 1.55 (h, J=7.5 Hz, 4H), 1.47 (s, 3H), 1.32-1.19 (m, 5H), 1.12 (d, J=6.3 Hz, 3H), 0.91 (d, J=6.2 Hz, 3H), 0.86 (d, J=6.9 Hz, 3H), 0.84 (d, J=7.2 Hz, 3H).

(194) Step 2: Van031 was prepared using the same needed materials, reagents and preparation method as those in example 16 except that Van-c in example 16 was replaced with Van-n. HRMS (ESI.sup.+) calculated for C.sub.89H.sub.111Cl.sub.2N.sub.11O.sub.30 [M+2H].sup.2+1871.6875, found 936.8522.

(195) .sup.1H NMR (600 MHz, DMSO-d.sub.6) 8.80 (s, 1H), 8.67 (s, 1H), 7.85-7.83 (m, 1H), 7.62 (s, 1H), 7.52-7.49 (m, 1H), 7.48 (dd, J=8.3, 1.7 Hz, 1H), 7.36 (d, J=8.0 Hz, 2H), 7.32 (d, J=8.3 Hz, 1H), 7.24 (d, J=7.7 Hz, 3H), 7.12 (s, 1H), 6.86 (dd, J=8.6, 1.8 Hz, 1H), 6.79 (d, J=8.6 Hz, 1H), 6.54 (s, 1H), 5.75-5.71 (m, 2H), 5.35 (d, J=7.7 Hz, 1H), 5.30 (d, J=4.1 Hz, 1H), 5.14 (s, 2H), 5.11 (d, J=2.0 Hz, 1H), 4.82 (s, 1H), 4.66 (t, J=6.5 Hz, 1H), 4.46 (d, J=5.7 Hz, 1H), 4.43 (d, J=5.9 Hz, 1H), 4.07 (s, 4H), 4.02 (d, J=3.6 Hz, 1H), 3.98-3.93 (m, 21-1), 3.92-3.90 (m, 1H), 3.68 (d, J=10.5 Hz, 1H), 3.59-3.55 (m, 3H), 3.54-3.49 (m, 3H), 3.40-3.36 (m, 1H), 3.30-3.23 (m, 2H), 3.18 (dq, I=25.5, 6.9 Hz, 211), 2.93 (s, 1H), 2.57 (d, J=7.1 Hz, 5H), 2.12 (d, J=20.5 Hz, 2H), 1.86-1.78 (m, 3H), 1.66 (s, 2H), 1.55 (p, J=7.5 Hz, 3H), 1.48 (s, 3H), 1.31-1.22 (m, 5H), 1.11 (d, J=6.3 Hz, 3H), 0.92 (d, J=6.1 Hz, 3H), 0.87 (d, j=6.1 Hz, 3H), 0.85 (t, J=7.1 Hz, 3H).

Example 32

(196) ##STR00092##

(197) Van032 was prepared using the same needed materials, reagents and preparation method as those in example 8 except that N.sup.van-2-(n-decylamine)ethyl-vancomycin (Van-a) in example 8 was replaced with N.sup.van-2-(4-trifluoromethyl-biphenylmethyl)-vancomycin (Van-c). HRMS (ESI) calculated for C.sub.87H.sub.97Cl.sub.2F.sub.3N.sub.10O.sub.29 [M+2H].sup.2+ 1872.5752, found 937.2960.

(198) .sup.1H NMR (600 MHz, DMSO-d.sub.6) 8.83 (s, 1H), 7.92 (d, J=8.1 Hz, 2H), 7.84 (d, J=8.5 Hz, 3H), 7.84-7.79 (m, 2H), 7.62 (t, J=10.7 Hz, 3H), 7.54-7.44 (m, 2H), 7.33 (d, J=8.3 Hz, 1H), 7.23 (dd, J=8.4, 3.1 Hz, 1H), 7.16 (s, 1H), 6.90-6.85 (m, 1H), 6.79 (t, J=9.0 Hz, 1H). 6.55 (d, J=4.7 Hz, 1H), 5.74 (d, J=9.7 Hz, 2H), 5.53 (d, J=3.5 Hz, 1H), 5.36 (d, J=7.7 Hz, 1H), 5.31 (s, 1H), 5.19-5.07 (m, 3H), 4.83 (s, 1H), 4.68 (d, J=6.9 Hz, 1H), 4.50 (s, 1H), 4.43 (t, J=5.8 Hz. 1H), 4.27 (d, J=15.9 Hz, 1H), 4.08 (d, J=14.2 Hz, 2H), 4.03 (d, J=8.3 Hz, 1H), 3.90-3.83 (m, 1H), 3.82 (t, J=6.5 Hz, 1H), 3.58 (t, J=8.5 Hz, 2H), 3.53 (dt, J=10.6, 4.4 Hz, 3H), 3.29 (s, 2H), 2.75 (s, 1H). 2.59 (s, 3H), 2.13 (d, J=13.0 Hz. 2H), 1.84 (d, J=13.2 Hz, 1H), 1.51 (s, 4H), 1.13 (d, J=6.3 Hz, 3H), 0.93 (d, J=6.0 Hz, 3H), 0.88 (d, J=6.1 Hz, 3H).

Example 33

(199) ##STR00093##

(200) Van033 was prepared using the same needed materials, reagents and preparation method as those in example 8 except that N.sup.van-2-(n-decylamine)ethyl-vancomycin (Van-a) in example 8 was replaced with N.sup.van-2-(4-((trimethylsilyl)ethynyl)benzyl)-vancomycin (Van-k). FIRMS (ESI.sup.+) calculated for C.sub.85H.sub.102Cl.sub.2N.sub.10O.sub.29Si [M+2H].sup.2+ 1824.5960. found 913.3060.

(201) .sup.1H NMR (600 MHz, DMSO-d.sub.6) 8.80 (s, 1H), 8.71 (s, 1H), 7.82 (d, J=8.1 Hz, 1H), 7.62 (s, 1H), 7.53-7.47 (m, 3H), 7.45 (d, J=7.7 Hz, 3H), 7.30 (d, J=8.3 Hz, 1H), 7.19 (d, J=8.3 Hz, 1H), 7.13 (s, 1H), 6.86 (d, J=8.9 Hz, 1H), 6.76 (d, J=8.5 Hz, 2H), 6.53 (d, J=4.6 Hz, 1H), 5.71 (s, 2H), 5.33 (d, J=7.7 Hz, 1H), 5.28 (s, 1H), 5.16-5.06 (m, 3H), 4.80 (s, 1H), 4.65 (d, J=6.8 Hz, 1H), 4.48 (s, 1H), 4.40 (t, J=5.9 Hz, 1H), 4.23 (s, 1H), 4.16-3.91 (m, 5H), 3.84 (d, J=10.9 Hz, OH), 3.80 (t, J=6.5 Hz, 1H), 3.73-3.63 (m, 1H), 3.55 (t, J=8.5 Hz, 1H), 3.50 (d, J=10.0 Hz, 2H), 3.26 (s, 2H), 2.72 (s, 1H), 2.57 (s, 3H), 2.17-2.03 (m, 2H), 1.80 (d, J=13.2 Hz, 1H), 1.64 (d, J=9.8 Hz, 2H), 1.46 (s, 3H), 1.21 (s, 1H), 1.09 (d, J=6.3 Hz, 3H), 0.91 (d, J=6.0 Hz, 3H), 0.86 (d, J=6.1 Hz, 3H), 0.21 (s, 9H).

Example 34

(202) ##STR00094##

(203) Van034 was prepared using the same needed materials, reagents and preparation method as those in example 8 except that N.sup.van-2-(n-decylamine)ethyl-vancomycin (Van-a) in example 8 was replaced with N.sup.van-2-(decyl)-vancomycin (Van-g). HRMS (ESI.sup.+) calculated for C.sub.83H.sub.108Cl.sub.2N.sub.10O.sub.29 [M+2H].sup.2+ 1778.6661, found 890.3400.

(204) .sup.1H NMR (600 MHz, DMSO-d.sub.6) 8.81 (s, 1H), 8.73 (s, OH), 7.83 (d, J=7.7 Hz, 1H), 7.62 (s, 1H), 7.50 (d, J=8.7 Hz, 1H), 7.47 (d, J=8.4 Hz, 1H), 7.31 (d, J=8.3 Hz, 1H), 7.20 (d, J=7.9 Hz, 1H), 7.15 (s, 1H), 6.87 (d, J=8.7 Hz, 1H), 6.78 (dd, J=8.5, 2.5 Hz, 1H), 6.55 (s, 1H), 5.76-5.68 (m, 1H), 5.32 (d, J=7.7 Hz, 1H), 5.29 (d, J=4.1 Hz, 1H), 5.17-5.05 (m, 2H), 4.82 (s, 1H), 4.61 (d, J=6.9 Hz, 1H), 4.42 (t, J=6.0 Hz, 1H), 4.25 (s, 1H), 4.18-3.94 (m, 3H), 3.86 (d, J=10.3 Hz, 0H), 3.82 (t, J=6.5 Hz, 0H), 3.67 (d, J=10.9 Hz, 1H), 3.56 (t, J=8.5 Hz, 1H), 3.52 (d, J=9.6 Hz, 2H), 3.44 (d, J=8.4 Hz, 3H), 3.27 (d, J=9.8 Hz, 3H), 2.73 (d, J=38.7 Hz, 2H), 2.58 (s, 2H), 2.14 (s, 1H), 1.98 (d, J=11.8 Hz, 1H), 1.79 (d, J=13.1 Hz, 1H), 1.66 (s, 2H), 1.35 (s, 3H), 1.24 (s, 15H), 1.08 (d, J=6.2 Hz, 3H), 0.93 (d, J=6.0 Hz, 3H), 0.89-0.83 (m, 6H).

Example 35

(205) ##STR00095##

(206) Van035 was prepared using the same needed materials, reagents and preparation method as those in example 8 except that N.sup.van-2-(n-decylamine)ethyl-vancomycin (Van-a) in example 8 was replaced with N.sup.van-2-(4-ethynylbenzyl)-vancomycin (Van-l). FIRMS (ESI) calculated for C.sub.82H.sub.94Cl.sub.2N.sub.10O.sub.29 [M+2H].sup.2+ 1752.5565, found 877.2869.

(207) .sup.1H NMR (600 MHz, DMSO-d.sub.6) 8.81 (s, 1H), 7.85 (d, J=8.0 Hz, 1H), 7.63 (s, 1H). 7.55 (d, J=8.0 Hz, 2H), 7.50 (t, J=11.3 Hz, 4H), 7.33 (d, J=8.3 Hz, 1H), 7.22 (dd, J=8.6, 3.8 Hz, 1H), 6.87 (s, 1H), 6.79 (dd, I=10.3, 6.2 Hz, 1H), 5.74 (d, J=9.4 Hz, 2H), 5.35 (d, J=7.6 Hz, 1H), 5.30 (d, J=4.2 Hz, 1H), 5.19-5.06 (m, 3H), 4.83 (s, 1H), 4.67 (d, J=7.0 Hz, 1H), 4.43 (q, J=6.1 Hz, 1H), 4.27 (d, J=1.9 Hz, 2H), 3.69 (d, J=10.7 Hz, 1H), 3.58 (t, J=8.5 Hz, 1H), 3.55-3.49 (m, 2H), 3.47 (d, J=8.6 Hz, 1H), 3.37 (d, J=8.9 Hz, 2H), 3.32-3.22 (m, 3H), 2.59 (s, 3H), 2.20-2.05 (m, 2H), 1.82 (d, J=13.2 Hz, 1H), 1.67 (d, J=9.3 Hz, 2H), 1.48 (s, 3H), 1.12 (d, J=6.3 Hz, 3H), 0.93 (d, J=6.0 Hz, 3H), 0.88 (d, J=6.1 Hz, 3H).

Example 36

(208) ##STR00096##

(209) Van036 was prepared using the same needed materials, reagents and preparation method as those in example 8 except that N.sup.van-2-(n-decylamine)ethyl-vancomycin (Van-a) in example 8 was replaced with N.sup.van-2-(4-pentylbenzyl)-vancomycin (Van-n). HRMS (ESI.sup.+) calculated for C.sub.85H.sub.104Cl.sub.2N.sub.10O.sub.29 [M+2H].sup.2+ 1798.6348, found 900.3265.

(210) .sup.1H NMR (600 MHz, DMSO-d.sub.6) 8.80 (s, 1H), 8.72 (s, 1H), 7.82 (d, J=7.5 Hz, 1H), 7.61 (s, 1H), 7.49 (d, J=8.8 Hz, 1H), 7.46 (d, J=8.4 Hz, 1H), 7.34 (d, J=7.8 Hz, 2H), 7.30 (d, J=8.3 Hz, 1H), 7.21 (dd, J=15.1, 8.1 Hz, 3H), 6.85 (d, J=8.3 Hz, 1H), 6.77 (dd, J=10.3, 6.2 Hz, 1H), 6.53 (d, J=4.5 Hz, 1H), 6.45 (s, 0H), 5.72 (d, J=9.0 Hz, 2H), 5.51 (d, J=3.5 Hz, 0H), 5.33 (d, J=7.6 Hz, 1H), 5.28 (s, 1H), 5.16-5.07 (m, 3H). 4.80 (s, 1H). 4.64 (d, J=6.6 Hz, 1H), 4.48 (s, 1H), 4.40 (t, J=5.9 Hz, 1H), 4.23 (s, 1H), 4.09 (d, J=41.4 Hz, 2H), 4.00 (s, 1H), 3.93 (q, J=12.7 Hz, 2H), 3.84 (d, J=11.7 Hz, 0H), 3.80 (t, J=6.5 Hz, 1H), 3.72-3.64 (m, 1H), 3.55 (t, J=8.5 Hz, 1H), 3.53-3.46 (m, 3H), 3.25 (d, J=9.5 Hz, 2H), 2.73 (s, 1H), 2.56 (dd, J=10.3, 4.8 Hz, 4H), 2.09 (d, J=12.0 Hz, 2H), 1.79 (d, J=13.2 Hz, 1H), 1.53 (p, J=7.5 Hz, 3H), 1.46 (s, 3H), 1.30-1.18 (m, 4H), 1.09 (d, J=6.3 Hz, 3H). 0.91 (d, J=6.1 Hz, 3H), 0.86 (d, J=6.1 Hz, 3H), 0.83 (t, J=7.1 Hz, 3H).

Example 37

(211) ##STR00097##

(212) Van037 was prepared using the same needed materials, reagents and preparation method as those in example 2 except that N.sup.van-2-(n-decylamine)ethyl-vancomycin (Van-a) in example 2 was replaced with N.sup.van-2-(4-trifluoromethyl-biphenylmethyl)-vancomycin (Van-c). HRMS (ESI.sup.+) calculated for C.sub.89H.sub.101Cl.sub.2F.sub.3N.sub.10O.sub.30 [M+2H].sup.2+ 1916.6014, found 959.3086.

(213) .sup.1H NMR (600 MHz, DMSO-d.sub.6) 8.79 (s, 1H), 7.92 (d, J=8.1 Hz, 2H), 7.84 (d, J=8.7 Hz, 3H), 7.82 (d, J=7.8 Hz, 2H), 7.61 (d, J=7.9 Hz, 3H), 7.52 (d, J=8.6 Hz, 1H), 7.49 (d, J=8.4 Hz, 1H), 7.33 (d, J=8.4 Hz, 1H), 7.25 (d, J=8.4 Hz, 1H), 7.15 (s, 1H), 6.86 (d, J=8.6 Hz, 1H), 6.78 (d, J=8.5 Hz, 1H), 6.51 (s, 1H), 5.75 (s, 1H), 5.70 (s, 1H), 5.37 (d, J=7.6 Hz, 1H), 5.31 (d, J=4.2 Hz, 1H), 5.14 (d, J=6.1 Hz, 3H), 4.83 (d, J=15.8 Hz, 1H), 4.69 (q, J=6.6 Hz, 1H), 4.47 (d, J=5.3 Hz, 1H), 4.43 (d, J=6.0 Hz, 1H), 4.14 (p, J=10.0, 7.2 Hz, 4H), 4.06 (s, 3H), 3.95 (s, 2H), 3.69 (d, J=10.7 Hz, 2H), 3.63 (d, J=3.0 Hz, 1H), 3.59 (t, J=8.5 Hz, 2H), 3.55-3.49 (m, 5H), 3.35-3.22 (m, 5H), 2.54 (d, J=5.7 Hz, 2H), 2.14 (d, J=16.3 Hz, 2H), 1.84 (d, J=13.2 Hz, 1H), 1.71-1.58 (m, 3H), 1.51 (s, 4H), 1.17 (t, J=7.3 Hz, 1H), 1.13 (d, J=6.2 Hz, 3H), 0.92 (d, J=6.2 Hz, 3H), 0.87 (d, J=6.3 Hz, 3H).

Example 38

(214) ##STR00098##

(215) Van038 was prepared using the same needed materials, reagents and preparation method as those in example 8 except that N.sup.van-2-(n-decylamine)ethyl-vancomycin (Van-a) in example 8 was replaced with N.sup.van-2-(4-chlorobiphenylmethyl)-vancomycin (Van-b). HRMS (ESI.sup.+) calculated for C.sub.86H.sub.97Cl.sub.2N.sub.10O.sub.29 [M+2H].sup.2 1838.5489, found 920.2862.

(216) .sup.1H NMR (600 MHz, DMSO-d.sub.6) 8.80 (s, 21-1), 8.72 (s, 2H), 7.85-7.81 (m, 1H), 7.75-7.67 (m, 4H), 7.61 (s, 2H), 7.58-7.53 (m, 3H), 7.52 (d, J=4.4 Hz, 2H), 7.51 (d, J=8.4 Hz, 1H), 7.46 (d, J=8.6 Hz, 2H), 7.31 (d, J=8.3 Hz, 1H), 7.20 (dd, J=8.4, 3.4 Hz, 1H), 6.86 (dd, J=8.4, 2.1 Hz, 1H), 6.77 (t, J=8.6 Hz, 2H), 6.53 (d, J=4.7 Hz, 1H), 5.72 (d, J=11.0 Hz, 2H), 5.51 (d, J=3.6 Hz, 1H), 5.33 (d, J=7.7 Hz, 1H), 5.29 (d, J=4.2 Hz, 1H), 5.16-5.07 (m, 3H), 4.80 (s, 1H), 4.66 (d, J=6.8 Hz, 2H), 4.48 (s, 1H), 4.40 (t, J=5.8 Hz, 2H), 4.23 (s, 1H), 4.05-3.97 (m, 3H), 3.86-3.81 (m, 1H), 3.79 (d, J=6.5 Hz, 1H), 3.75 (d, J=3.2 Hz, 1H), 3.66 (d, J=10.8 Hz, 2H), 3.56 (t, J=8.5 Hz, 2H), 3.42-3.37 (m, 2H), 3.29-3.23 (m, 2H), 3.15 (dd, J=10.5, 3.5 Hz, 1H), 2.71 (s, 214), 2.57 (s, 3H), 2.10 (d, J=12.8 Hz, 3H), 1.82 (d, J=13.2 Hz, 1H), 1.65 (s, 3H), 1.49 (s, 4H), 1.26-1.19 (m, 2H), 1.10 (d, J=6.3 Hz, 3H), 0.91 (d, J=6.0 Hz, 3H), 0.86 (d, J=6.1 Hz, 3H).

(217) Activity Assay:

Biological Test Example 1 In Vitro Antibacterial Activity Assay

(218) 38 compounds of the present invention were subjected to in vitro antibacterial activity assay. The antimicrobial concentrations (Minimal Inhibitory concentration, MIC) of the vancomycin derivatives were measured according to the Clinical Laboratory Standardization Association (CLSI) 2006 reference method for dilution, and the results were shown in Table 1.

(219) The vancomycin-sensitive Staphylococcus aureus Newman strain (Newman) and vancomycin-middle resistant Staphylococcus aureus Mu50 strain (Mu50) were selected as the strains to perform the assay.

(220) Vancomycin was purchased from Wuhan Dahua Pharmaceutical Co., Ltd., batch number DH20160105, and telavancin was prepared according to the method described in US20020022590 A1.

(221) Test method: The compounds to be tested were dissolved in DMSO to prepare a stock solution at 1.28 mg/mL, which was then diluted with DMSO to an initial concentration of 128 g/mL. Further 1:2 serial dilutions were performed. On a 96-well cell culture plate, each row was added with 100 L of a corresponding drug solution in an order from a low concentration of 0.125 g/mL to a high concentration of 128 g/mL. In the meantime, sterile control (no drugs and bacteria were added and only the culture was added), growth control (DMSO was added in the culture broth of the well without adding the drug), and positive control group (vancomycin) were set. Each test and growth control well was inoculated with 5 L of bacterial suspension (100 L of bacterial solution at a concentration of 10.sup.5 CFU/mL). The 96-well cell culture plate was incubated at 37 C. for 16 h. The lowest concentration to inhibit bacterial growth completely was considered as the MIC value of the compound.

(222) TABLE-US-00003 TABLE 1 Test results of In vitro antibacterial activities of the inventive compounds MIC (g/mL) Compd. Newman Mu50 Vanco. 2 8 Tela. <0.0625 1 Van001 1 2 Van002 0.5 2 Van003 4 16 Van004 1 4 Van005 1 4 Van006 8 32 Van007 4 8 Van008 0.0625 0.25 Van009 0.5 1 Van010 0.25 1 Van011 0.0625 1 Van012 0.5 0.5 Van013 2 4 Van014 0.25 0.125 Van015 0.25 0.5 Van016 0.0625 0.25 Van017 0.5 1 Van018 4 8 Van019 0.5 2 Van020 1 1 Van021 2 4 Van022 1 2 Van023 2 4 Van024 0.125 0.5 Van025 16 32 Van026 32 64 Van027 1 4 Van028 1 2 Van029 4 8 Van030 1 2 Van031 0.125 0.5 Van032 0.0625 0.0625 Van033 0.5 2 Van034 0.0625 0.25 Van035 2 8 Van036 0.25 0.5 Van037 0.0625 0.25 Van038 0.0625 0.125

(223) The above in vitro antibacterial activity studies showed that most of the vancomycin analogues of the present invention represented by the examples have more active antibacterial activities against vancomycin-resistant Staphylococcus aureus than vancomycin. The antibacterial activity of some preferred compounds was 10-100 times higher than vancomycin, and 4-10 times higher than telavancin that was marketed in 2009. Antibacterial experiments show that the modification strategies for the novel vancomycin analogs involved in the present invention can significantly enhance antibacterial activity.

Biological Test Example 2 In Vivo Antibacterial Assay in Mice

(224) Van016, Van032, Van037, Van038 of the present invention, vancomycin and telavancin were dissolved in sterile re-distilled water (ddH.sub.2O) to prepare a solution in which the concentration of each compound was about 2 mg/mL.

(225) SPF female BALB/c mice were purchased from the Shanghai Lab. Animal Research Center and housed under environment free of specific microorganisms. Overnight cultured Staphylococcus aureus USA300 LAC strain (Community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA)) was transferred into a fresh tryptic soy broth (TSB) medium at 1:100, and further cultivated for 3 h to reach the exponential growth phase. The collected strains were washed twice with sterile PBS buffer and suspended in the same buffer.

(226) 105 BALB/c mice were randomly divided into 7 groups, namely, negative control group, Van016 group, Van032 group, Van037 group, Van038 group, vancomycin group and telavancin group, with 15 mice in each experimental group, and each mice weighed approximately 18 grams.

(227) Six to eight week old female BALB/c mice were anesthetized with pentobarbital sodium (80 mg/kg, intraperitoneally), and infected by retro-orbital injection with a suspension of 2.3510.sup.8 colony-forming units (CFUs) of USA300 LAC. One hour after infection, the mice in the six groups other than the negative control group were administered intraperitoneally with a single dose of 7 mg/kg of the selected compounds and the positive control compounds, respectively. At the same time, mice in the negative control group were injected with the same amount of sterile ddH.sub.2O. The numbers of dead mice were recorded for the next 10 consecutive days, and the survival percentage of mice was calculated. The results were shown in FIG. 1.

(228) As shown in FIG. 1, after 10 days, the survival rate of the Van038 group was 93.3%, the survival rate of the Van037 group was 86.6%, the survival rate of the Van032 group was 73.3%, and the survival rate of the Van016 group was 60.0%. In the positive control groups, the survival rate of the telavancin group was 93.3% while that of the vancomycin group was 6.6%. All the mice in the negative control group died after 6 days, and the survival rate was 0%.

(229) The above in vivo pharmacodynamic studies showed that all of the said four vancomycin analogs of the present invention showed antibacterial activity against methicillin-resistant Staphylococcus aureus higher than vancomycin, indicating that Van016, Van032, Van037, Van038 have obvious protective effects on Methicillin-resistant Staphylococcus aureus and have better activity than vancomycin. Among these compounds, Van038 and Van037 achieved comparable activities with telavancin.

Biological Test Example 3 In Vivo Pharmacokinetic Assay in Mice

(230) Van016, Van032, Van037, Van038 prepared by the present invention and the positive compounds vancomycin and telavancin were selected to perform the in vivo pharmacokinetic assay in mice. CD-1 mice used in this assay were purchased from Shanghai Lingchang Biotechnology co., LTD, and grown to 18-22 g at 18-29 C. and a relative humidity of 30-70%.

(231) Eighteen male CD-1 normal mice were randomly divided into 6 groups, namely, Van016 group, Van032 group, Van037 group, Van038 group, vancomycin group and telavancin group, with 3 in each group. The mice in each group were injected intravenously a single dose of 5 mg/kg with the corresponding compound solutions prepared in Biological Test Example 2. Blood samples were collected (from the femoral vein) at 0.05 h, 0.25 h, 0.75 h, 2 h, 4 h, 8 h, 24 h, 7 time points in total, after the injection. LC-MS/MS was used to detect the plasma concentration (ng/mL) of the drug in the 6 groups of mice at different times. The pharmacokinetic software WinNonlin 6.4 was used to obtain the corresponding half-life (T.sub.1/2), the area under the drug concentration-time curve (AUC), the plasma clearance rate (CL), the mean residence time (MRT), and the volume of distribution calculated when the drug reaches steady state in vivo (V.sub.SS). The specific results are shown in Table 2 below.

(232) From the results of Table 2, it can be seen that the four compounds of the present invention showed a half-life (T.sub.1/2) longer than vancomycin and telavancin, and an area under the drug concentration-time curve (AUC) 10-20 times larger than vancomycin and comparable to telavancin. In terms of plasma clearance (CL), all of the four compounds showed clearance rates slower than vancomycin and comparable to telavancin, and thus have good druggability parameters superior to the positive compound.

(233) TABLE-US-00004 TABLE 2 In vivo pharmacokinetic test results in mice of representative compounds of the invention T.sub.1/2 AUC.sub.last AUC.sub.INF_obs CL_obs MRT.sub.INF_obs V.sub.SS_obs Compd. (h) (h*ng/mL) (h*ng/mL) (mL/min/kg) (h) (mL/kg) Van016 3.72 0.70 10666 2063 13450 12725 6.4 1.39 4.79 0.24 1826 334 Van032 3.45 1.26 20105 1714 24345 2804 3.45 0.40 4.41 1.23 900 180 Van037 2.94 1.39 16631 4960 20047 5489 4.42 1.42 4.21 2.08 1077 449 Van038 3.81 0.31 12112 2483 12238 2486 7.0 1.38 4.18 0.34 1754 380 Vanco. 0.597 0.208 1242 335 1271 347 68.7 18 0.790 0.26 3076 175 Tela. 1.13 0.13 17143 5611 17304 5745 5.1 1.5 1.71 0.13 520 121 Note: AUC.sub.last: area under the drug concentration-time curve of the measured time period; AUC.sub.INF_obs: measured value of the area under the drug concentration-time curve of the theoretical full time period; CL_obs: measured value of the plasma clearance; MRT.sub.INF_obs: measured value of the mean retention time of the theoretical full time period; VSS_obs: measured value of the volume of drug distribution at steady-state. The subscript of obs is an abbreviation of observed, indicating the measured value observed. The subscript of INF is an abbreviation of infinity, and refers to the infinite time range, that is, the theoretical full time period. The subscript of last refers to the time range from the start point to the end point of the measured time, that is, the measured time period.

Biological Test Example 4 Liver and Kidney Cytotoxicity Assays

(234) Van011, Van037, vancomycin and telavancin were used to perform the liver and kidney cytotoxicity experiments. Liver and kidney cell viability assays were performed using the Cell Activity Assay Kit CCK8 (Cell Counting Kit-8) method.

(235) HK-2 cells (human renal proximal tubular epithelial cells) and HL-7702 cells (human liver cells) in logarithmic growth phase were inoculated to a 96-well culture plate at a suitable density (about 5000 cells), at 100 L per well. After overnight incubation, different concentrations (10 M, 50 M, 100 M) of vancomycin, telavancin, Van011 or Van037 were added to treat for 72 h. Three replicate wells were set for each concentration, and the physiological saline vehicle control well corresponding to each concentration and a well for cell-free zero-adjustment were set. After the treatment, 10 L of CCK8 detection solution was added into each well, the incubation was performed at 37 C. for about 1.5 h. The optical density (OD value) at 450 nm was measured on a VERSMax microplate reader. The OD value was converted to cell viability value according to the following equation:
Cell viability value=OD.sub.C/OD.sub.C=0100,

(236) wherein, OD.sub.C represents the optical density obtained by different concentrations of the compounds to be tested, C represents the concentration of the compound, and OD.sub.C=0 represents the optical density obtained without addition of the compound to be tested. And the results were shown in FIGS. 2 and 3.

(237) The results showed that Van011 and Van037 of the present invention have less toxicity in liver cells than vancomycin and telavancin, and thus have better safety, while in kidney cells, they have toxicity less than vancomycin and comparable to telavancin.

(238) The above is only a schematic description of the present invention, and those skilled in the art should understand that various modifications can be made to the present invention without departing from the working principle of the present invention, and thus fall in the protective scope of the present invention.