Glycopeptide compound or pharmaceutical salt thereof and method for preparing same, and pharmaceutical compositions and applications thereof

Abstract

The present invention provides a glycopeptide compound or pharmaceutically acceptable salt thereof as shown in Formula (I) or (II), and a method for preparing same, and pharmaceutical compositions and applications thereof, wherein the definition of R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5 is the same as that of the specification. The glycopeptide compound of the present invention has in-vitro antibacterial activity and has important significance for development of new antibacterial agents. ##STR00001##

Claims

1. A glycopeptide compound or pharmaceutically acceptable salt thereof of Formula (II), ##STR00035## wherein: R1 is a mono-substituted benzyl substituted by halogen, methoxy or isopropyl; a group of NR4R5 is diethylamino, n-butylamino, or morpholino.

2. The glycopeptide compound or pharmaceutically acceptable salt thereof according to claim 1, wherein the mono-substituted benzyl is 2-bromobenzyl, 3-bromophenyl, 4-bromobenzyl, 4-isopropylbenzyl or 4-methoxybenzyl.

3. The glycopeptide compound or pharmaceutically acceptable salt thereof according to claim 1, wherein a hydroxyl at position 4 of amino acid sugar at position 6 of peptide backbone is a axial bond.

4. A pharmaceutical composition, comprising a therapeutically effective amount of glycopeptide compounds or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable carrier according to claim 1.

5. The pharmaceutical composition according to claim 4, wherein the pharmaceutical composition comprises 0.1 wt. %.Math.99.5 wt. % of the glycopeptide compound or pharmaceutically acceptable salt thereof.

6. The pharmaceutical composition according to claim 5, wherein the pharmaceutical composition comprises, preferably, 0.5 wt. %.Math.90 wt. % of the glycopeptide compound or pharmaceutically acceptable salt thereof.

7. A pharmaceutical composition, comprising a therapeutically effective amount of glycopeptide compounds or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable carrier according to claim 2.

8. The pharmaceutical composition according to claim 7, wherein the pharmaceutical composition comprises 0.1 wt. %.Math.99.5 wt. % of the glycopeptide compound or pharmaceutically acceptable salt thereof.

9. The pharmaceutical composition according to claim 8, wherein the pharmaceutical composition comprises 0.5 wt. %.Math.90 wt. % of the glycopeptide compound or pharmaceutically acceptable salt thereof.

10. A pharmaceutical composition, comprising a therapeutically effective amount of glycopeptide compounds or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable carrier according to claim 3.

11. The pharmaceutical composition according to claim 10, wherein the pharmaceutical composition comprises 0.1 wt. %.Math.99.5 wt. % of the glycopeptide compound or pharmaceutically acceptable salt thereof.

12. The pharmaceutical composition according to claim 11, wherein the pharmaceutical composition comprises 0.5 wt. %.Math.90 wt. % of the glycopeptide compound or pharmaceutically acceptable salt thereof.

Description

DETAILED DESCRIPTION OF THE PRESENT INVENTION AND PREFERRED EMBODIMENTS THEREOF

(1) Hereafter, the present invention will be described specifically with reference to examples. The examples are given only for illustration of the technical solution of the present invention and should not be construed to limit the present invention.

Example 1

Synthesis of Compound I1

(2) In ice-water bath (0 C.), amino methane phosphonic acid (140 mg, 1.26 mmol) is dissolved in 3 ml water, then DIEA (0.2 ml, 1.26 mmol) and 3 ml acetonitrile is added. 37% formaldehyde aqueous solution (15 l, 0.18 mmol) is added into the above solution, and compound (III) (300 mg, 0.18 mmol) (R.sub.1H, R.sub.2H, R.sub.3H, refers to the synthesis method of the Chinese Patent Publication No. CN 101928331 A) and DIEA (0.2 ml, 1.26 mmol) are added for 15 min. The reaction is proceeding at room temperature of 25 C. for 3 h and then stopped. The reaction solution is adjusted to neutral with 20% TFA solution in a ice bath, and an appropriate amount of acetonitrile is added, to produce precipitate and then filtered to obtain a filter cake. A filter cake is washed with acetonitrile for several times, and purified by preparative HPLC by using an aqueous solution containing 0.1% HCOOH and methanol as a mobile phase, to obtain component by distilling off methanol under a reduced pressure, and adjusted pH 6-7 with saturated NaHCO3 aqueous solvent, and separated by gel column by using water as a mobile phase, and then obtain component by distilling off water under a reduced pressure, and dried in vacuum to obtain a solid compound I.sub.1 130 mg, the yield is 42.2%. (refer to Table 1)

(3) Compound I.sub.1: .sup.1H-NMR (400 MHz, DMSO-d.sub.6+D.sub.2O) (ppm): 7.80 (1H), 7.67-7.60 (2H), 7.40 (2H), 7.15-6.98 (4H), 6.50 (2H), 5.61-5.39 (6H), 5.27-5.24 (2H), 5.06 (1H), 4.44-4.41 (3H), 4.30 (2H), 4.07-4.06 (2H), 3.77-3.59 (6H), 3.41 (3H), 2.97-2.94 (2H), 2.64-2.58 (2H), 2.42 (3H), 2.30-2.21 (2H), 2.00 (2H), 1.71-1.60 (5H), 1.35-1.33 (10H), 0.91 (6H).

Example 2

Synthesis of Compound I2

(4) At room temperature 20 C., 10 ml methanol is added into a 100 ml eggplant-shaped flask, then 1 mmol/ml morpholine (0.23 ml, 0.23 mmol) and DIEA (0.1 ml, 0.63 mmol) are added under stirring, and then 1 mmol/ml formaldehyde solution (0.21 ml, 0.21 mmol) is added, then stir for 15 min. compound (III) (300 mg, 0.18 mmol) (R.sub.1H, R.sub.2H, R.sub.3H, refer to the synthesis method of the Chinese Patent Publication No. CN 101928331 A) and DIEA (0.1 ml, 0.63 mmol) are added into the above solution, and stir at room temperature for 3 h when the addition is completed. 70 ml acetone is added under stirring to produce white insoluble precipitate and then filtered to obtain a filter cake. The filter cake is washed with acetone after filtered to obtain a white solid, then purified by preparative HPLC, by using an aqueous solution containing 0.1% HCOOH and methanol as a mobile phase to gradient elution with detection wavelength of 240 nm and 280 nm, a flow rate 22 ml/min. The fractions are concentrated into about 20 ml under a reduced pressure, and then adjusted to pH 6-7 by a saturated sodium bicarbonate solution, and extracted by adding an equal volume of n-butanol, and an organic layer is separated and washed with water (10 ml2), and evaporated to dryness solvent under a reduced pressure to produce a residue, the residue is stirred overnight after adding methylene chloride, and then filtered, and dried at 45 C. to obtain 30 mg compound I.sub.2 (a free base, white powder), and the yield is 9.3%. (refer to Table 1)

(5) Compound I.sub.2: 1H-NMR (400 MHz, DMSO-d6+D2O) (ppm): 7.90-8.31 (2H), 7.54-7.80 (2H), 7.35-7.11 (4H), 7.12 (2H), 6.75 (2H), 6.47 (1H), 5.68-5.55 (2H), 5.45-4.98 (5H), 4.74 (2H), 4.65-4.43 (3H), 3.76 (2H), 3.64 (4H), 3.45 (2H), 3.00-3.50 (6H), 2.33 (5H), 2.02-1.46 (5H), 1.28-1.02 (10H), 0.94-0.79 (6H).

Example 3

Synthesis of the Compound I3

(6) At room temperature 25 C., 10 ml n-butanol is added into 50 ml eggplant-shaped flask, then 1 mmol/ml n-butylamine solution (0.12 ml, 1.2 mmol) and 1 mmol/ml formaldehyde solution (0.25 ml, 1.0 mmol) are added and stirred for 15 min after the addition is completed. compound (III) (320 mg, 0.2 mmol) (R.sub.1H, R.sub.2H, R.sub.3H, refer to the synthesis method of the Chinese Patent Publication No. CN 101928331 A) is added into the above solution and stirred at room temperature 15-25 C. for 3 h after the addition is completed. 70 ml of acetone is added thereto under stirring, to produce white insoluble precipitate and then filtered to obtain a filter cake., the filter cake is washed with acetone to produce a white solid, then purified by preparative HPLC, using an aqueous solution containing 0.1% HCOOH and methanol as a mobile phase to gradient elution with detection wavelength of 240 nm and 280 nm, a flow rate 22 ml/min. The fractions are concentrated under a reduced pressure to about 20 ml, and then adjusted to pH 6-7 by a saturated sodium bicarbonate solution, then extracted by adding an equal volume of n-butanol, and an organic layer is separated and washed with water (10 ml2), and evaporated to dryness solvent under a reduced pressure to produce a residue, the residue is stirred overnight after adding methylene chloride, after filtering, dried on 45 C. to obtain 35 mg compound I.sub.3, and the yield is 9.8%. (refer to Table 1)

(7) Compound I.sub.3: 1H-NMR (400 MHz, DMSO-d6+D2O) (ppm): 7.90-8.31 (2H), 7.54-7.80 (2H), 7.35-7.11 (4H), 7.12 (2H), 6.75 (2H), 6.47 (1H), 5.68-5.55 (2H), 5.45-4.98 (5H), 4.74 (2H), 4.65-4.43 (3H), 3.76 (2H), 3.64 (4H), 3.45 (2H), 3.00-3.50 (6H), 2.33 (5H), 2.02-1.46 (5H), 1.28-1.02 (10H), 0.94-0.79 (6H).

Example 4

Synthesis of the Compound I4

(8) At room temperature 25 C., n-butylamine (14.1 l, 0.14 mmol) is dissolved in 3 ml water, and DIEA (0.35 ml, 2.10 mmol) and 3 ml acetonitrile are added. 37% formaldehyde aqueous solution (10.5 l, 0.14 mmol) is added by pipette, compound (III) (300 mg, 0.14 mmol) (R.sub.1=n-decyl, R.sub.2=n-decyl, R.sub.3=n-decyl, refers to the synthesis method of the Chinese Patent Application No. 201110070599.2) is added after 15 min, and placed in an oil bath at 30 C. Then the reaction is stopped after 23 h 30 min. The reaction solution is adjusted to neutral with 3 mol/L HCl solution, an appropriate amount of acetone is added, and produce white insoluble precipitate and then filtered to obtain a filter cake, the filter cake is washed with acetone for several times, and purified by preparative HPLC, using the aqueous solution containing 0.1% HCOOH and methanol as the mobile phase, the obtained components is distilled off methanol under a reduced pressure, and then adjusted pH6-7 with a saturated aqueous NaHCO3, then separated by gel column, with water as a mobile phase, and distilled off the water under a reduced pressure, and dried in vacuum to obtain 152 mg solid 14, the yield is 51.9%. (refer to Table 1)

(9) Compound I.sub.4: .sup.1H-NMR (400 MHz, DMSO-d.sub.6+D.sub.2O) (ppm): 9.57 (1H), 8.38 (1H), 8.15 (1H), 7.90-7.84 (2H), 7.65-7.13 (8H), 6.85-6.73 (4H), 6.52 (1H), 6.38 (2H), 5.92 (1H), 5.73 (1H), 5.57 (1H), 5.40-5.18 (7H), 4.95 (1H), 4.80-4.31 (11H), 3.94-3.08 (31H), 2.97 (3H), 2.27-2.16 (6H), 2.00 (1H), 1.69-1.07 (71H), 0.87-0.86 (18H).

Example 5

Synthesis of the Compound I5

(10) At room temperature 35 C., water (5 ml) and acetonitrile (5 ml) are added into 100 ml eggplant-shaped flask, and then 1 mmol/ml morpholine (0.25 ml, 0.25 mmol) and DIEA (0.26 ml, 1.61 mmol) are added and stirred, then 1 mmol/ml formaldehyde solution (0.27 ml, 0.27 mmol) is added, and stirred for 15 min after the addition is completed. Compound (III) (500 mg, 0.23 mmol) (R.sub.1=2-bromobenzyl, R.sub.2H, R.sub.3H, refer to the synthesis method of the Chinese Patent Application No. 201110070598.8) and DIEA (0.26 ml, 1.61 mmol) are added into the above solution, and stirred at room temperature for 3 h after the addition is completed. 70 ml acetone is added thereto under stirring to produce white insoluble precipitate and then filtered to obtain a filter cake, the filter cake is washed with acetone to produce a white solid, and purified by preparative HPLC, using an aqueous solution containing 0.1% HCOOH and methanol as a mobile phase to gradient elution with detection wavelength of 240 nm and 280 nm, a flow rate 22 ml/min. The fractions are concentrated under a reduced pressure to about 20 ml, and then adjusted to pH 6-7 with saturated sodium bicarbonate solution, and extracted by adding an equal volume of n-butanol, and an organic layer is separated and washed with water (10 ml2), and evaporated to dryness solvent under a reduced pressure to produce a residue, the residue is stirred overnight after adding methylene chloride, filtered, and dried to obtain 30 mg compound I.sub.5 at 45 C. (free base, solid brown powder), and the yield is 10.0%. (refer to Table 1)

(11) Compound I.sub.5: .sup.1H-NMR (400 MHz, DMSO-d.sub.6+D.sub.2O) (ppm): 7.82 (2H), 7.65-7.11 (7H), 6.77 (2H), 6.51-6.47 (1H), 6.32 (2H), 5.61-5.59 (2H), 5.32 (3H), 5.18-5.12 (2H), 4.94 (1H), 4.87 (1H), 4.72-4.60 (3H), 4.48-4.09 (7H), 3.65-2.85 (9H), 2.33-2.00 (6H), 1.93 (2H), 1.77-1.40 (9H), 1.39-1.12 (11H), 1.05-1.03 (6H), 0.96-0.80 (6H).

(12) The synthesis method of compound I.sub.8, compound I.sub.9, compound I.sub.12, compound I.sub.13 is the same as that of Example 5, but each of them selects different compound (III), wherein, R.sub.2, R.sub.3 are hydrogen, R.sub.1 is 3-bromobenzyl, 4-bromobenzyl, 4-methoxybenzyl, or 4-isopropylbenzyl. (refer to Table 1)

(13) Compound I.sub.8: .sup.1H-NMR (400 MHz, DMSO-d.sub.6+D.sub.2O) (ppm): 7.83 (2H), 7.59 (2H), 7.43-7.34 (3H), 7.21 (3H), 6.78 (2H), 6.59 (1H), 6.43 (1H), 5.80-5.54 (2H), 5.32 (3H), 5.18-5.11 (3H), 4.94 (1H), 4.86 (1H), 4.75 (2H), 4.40-3.95 (5H), 3.55-3.38 (5H), 3.37 (4H), 3.12-3.00 (2H), 2.27 (5H), 1.93 (2H), 1.70-1.55 (3H), 1.40 (4H), 1.36-1.04 (10H), 0.87-0.81 (6H).

(14) Compound I.sub.9: .sup.1H-NMR (400 MHz, DMSO-d.sub.6+D.sub.2O) (ppm): 7.83 (2H), 7.59 (2H), 7.37 (3H), 7.20 (3H), 6.78 (3H), 6.59 (1H), 6.33 (2H), 5.54 (1H), 5.37-5.32 (2H), 5.18-5.11 (2H), 4.95 (1H), 4.85 (1H), 4.74 (1H), 4.49-4.26 (5H), 3.60-2.95 (12H), 2.27 (5H), 1.93 (2H), 1.68-1.39 (6H), 1.38-1.04 (10H), 0.87-0.82 (6H).

(15) Compound I.sub.12: .sup.1H-NMR (400 MHz, DMSO-d.sub.6+D.sub.2O) (ppm): 7.81 (2H), 7.59 (2H), 7.39 (2H), 7.20 (3H), 6.78 (3H), 6.54 (1H), 6.32 (2H), 5.53 (2H), 5.32 (3H), 5.17-5.11 (2H), 4.94-4.86 (2H), 4.73-4.48 (2H), 4.37 (1H), 4.36-4.09 (4H), 3.68-3.07 (13H), 2.33 (4H), 2.01 (2H), 1.92 (2H), 1.71-1.50 (4H), 1.44-1.12 (14H), 1.03 (3H), 0.85-0.80 (6H).

(16) Compound I.sub.13: .sup.1H-NMR (400 MHz, DMSO-d.sub.6+D.sub.2O) (ppm): 7.85 (2H), 7.60 (1H), 7.44 (2H), 7.36-7.10 (5H), 6.80 (3H), 6.59 (1H), 6.35 (1H), 5.64 (1H), 5.59 (1H), 5.40-5.33 (3H), 5.18 (2H), 4.95 (1H), 4.86 (1H), 4.76 (2H), 4.60-3.97 (5H), 3.28-2.68 (6H), 2.28 (5H), 1.91 (2H), 1.70-1.61 (4H), 1.48 (3H), 1.24-1.12 (12H), 0.88-0.84 (6H).

Example 6

Synthesis of the Compound I6

(17) At room temperature 20 C., water (5 ml) and acetonitrile (5 ml) are added into 100 ml eggplant-shaped flask, and then 1 mmol/ml diethylamine solution (0.25 ml, 0.25 mmol) and DIEA (0.26 ml, 1.61 mmol) are added under stirring, and afterwards 1 mmol/ml formaldehyde solution (0.25 ml, 0.25 mmol) is added into the solution under stirring for 15 min after the addition is completed. Compound (III) (500 mg, 0.23 mmol) (R.sub.1=2-bromobenzyl, R.sub.2H, R.sub.3H, refer to the synthesis method of the Chinese Patent Application No. 201110070598.8), and DIEA (0.26 ml, 1.61 mmol) are added into the above solution, and stirred for 3 h at room temperature after the addition is completed. 70 ml acetone is added thereto under stirring to produce white insoluble precipitate and then filtered to obtain a filter cake, the filter cake is washed with acetone to obtain a white solid, then purified by preparative HPLC by using an aqueous solution containing 0.1% HCOOH and methanol as a mobile phase to gradient elution with detection wavelength of 240 nm and 280 nm, a flow rate is 22 ml/min. The fractions are concentrated under a reduced pressure to about 20 ml, and then adjusted to pH 6-7 with a saturated sodium bicarbonate solution, and extracted by adding an equal volume of n-butanol, an organic layer is separated and washed with water (10 ml2), and evaporated to dryness solvent under a reduced pressure, the residue is stirred overnight after adding methylene chloride, filtered, and dried at 45 C. to obtain compound I.sub.6 30 mg (free base, white powder), the yield is 10.0%. (refer to Table 1)

(18) Compound I.sub.6: .sup.1H-NMR (400 MHz, DMSO-d.sub.6+D.sub.2O) (ppm): 7.89 (2H), 7.58-7.13 (8H), 6.76-6.69 (2H), 6.54 (1H), 6.40-6.12 (1H), 5.71-5.45 (2H), 5.34-5.11 (6H), 4.94-4.63 (5H), 4.48-4.21 (6H), 3.40-2.83 (9H), 2.33-2.00 (6H), 2.00-1.60 (6H), 1.47-1.20 (10H), 1.17-1.03 (6H), 0.97-0.88 (6H).

(19) And the synthesis method of Compound I.sub.10 is the same as that of Example 6, but each of them selects different compounds (III), wherein, R.sub.1 is 4-bromophenyl, R.sub.2 is hydrogen, R.sub.3 is hydrogen. (refer to Table 1)

(20) Compound I.sub.10: .sup.1H-NMR (400 MHz, DMSO-d.sub.6+D.sub.2O) (ppm): 7.91-7.84 (2H), 7.58 (2H), 7.40 (3H), 7.21-7.00 (3H), 6.77 (2H), 6.58 (1H), 6.34 (1H), 5.70-5.55 (2H), 5.38-5.32 (2H), 5.19-5.11 (2H), 4.94 (1H), 4.87 (1H), 4.73 (2H), 4.49-3.95 (7H), 3.46-2.99 (5H), 2.34 (5H), 1.94 (2H), 1.70-1.30 (6H), 1.21 (8H), 1.04-0.98 (6H), 0.88-0.82 (6H).

Example 7

Synthesis of the Compound I7

(21) At room temperature 25 C., water (5 ml) and acetonitrile (5 ml) is added into 100 ml eggplant-shaped flask, n-butylamine solution 1 mmol/ml (0.25 ml, 0.25 mmol) and DIEA (0.26 ml, 1.61 mmol) is added under stirring, and then 1 mmol/ml formaldehyde solution (0.25 ml, 0.25 mmol) is added and stirred for 15 min after the addition is completed. Compound (III) (500 mg, 0.23 mmol) (R.sub.1=2-bromobenzyl, R.sub.2H, R.sub.3H, synthesis refer to the synthesis method of the Chinese Patent Application No. 201110070598.8), and DIEA (0.26 ml, 1.61 mmol) are added, and stirred for 3 h at room temperature after the addition is completed. 70 ml acetone is added thereto with stirring to produce white insoluble precipitate and then filtered to obtain a filter cake, the filter cake is washed with acetone to obtain a white solid, and purified by preparative HPLC by using an aqueous solution containing 0.1% HCOOH and methanol as a mobile phase to gradient elution with detection wavelength of 240 nm and 280 nm, a flow rate is 22 ml/min. The fractions are concentrated under a reduced pressure to about 20 ml, and then adjusted to pH 6-7 with saturated sodium bicarbonate solution, and extracted by adding an equal volume of n-butanol, and an organic layer is separated and then washed with water (10 ml2), and evaporated to dryness solvent under a reduced pressure to produce a residue, the residue is stirred overnight after adding methylene chloride, filtered and dried at 45 C. to obtain compound I.sub.7 27 mg free base (white powder), the yield is 7.0%. (refer to Table 1)

(22) Compound I.sub.7: .sup.1H-NMR (400 MHz, DMSO-d.sub.6+D.sub.2O) (ppm): 7.91 (1H), 7.79-7.11 (9H), 6.86-6.76 (3H), 6.49 (1H), 6.32 (1H), 5.52 (2H), 5.31-5.11 (3H), 5.20-5.00 (3H), 4.94 (1H), 4.85 (1H), 4.74-4.48 (4H), 4.34-4.10 (7H), 3.60-2.70 (9H), 2.33 (5H), 2.02-1.93 (2H), 1.77-1.60 (5H), 1.38 (5H), 1.20 (10H), 1.03 (5H), 0.85-0.80 (9H).

(23) Compound I.sub.11, I.sub.14 is the same as that of Example 7, but each of them selects different compounds (III), wherein, R2, R3 are hydrogen, R1 is 4-bromo benzyl, or 4-isopropylbenzyl. (refer to Table 1)

(24) Compound I.sub.11: .sup.1H-NMR (400 MHz, DMSO-d.sub.6+D.sub.2O) (ppm): 7.90-7.85 (2H), 7.38-7.23 (4H), 7.23-7.13 (3H), 6.76-6.69 (3H), 6.50 (1H), 6.33-6.31 (2H), 5.66 (1H), 5.55 (1H), 5.38-5.19 (5H), 4.84-4.73 (2H), 4.68-4.21 (7H), 3.30-2.94 (8H), 2.33-2.01 (5H), 2.00 (2H), 1.96-1.44 (9H), 1.21 (19H), 1.04-0.88 (6H), 0.88-0.82 (9H).

(25) Compound I.sub.14: .sup.1H-NMR (400 MHz, DMSO-d.sub.6+D.sub.2O) (ppm): 7.89-7.80 (2H), 7.59 (1H), 7.40 (2H), 7.17-7.10 (4H), 6.78 (2H), 6.48 (1H), 6.32 (1H), 5.54 (1H), 5.34-5.19 (3H), 5.13-5.00 (2H), 4.95 (1H), 4.86 (1H), 4.75 (2H), 4.47-4.10 (4H), 3.50-3.00 (9H), 2.28 (5H), 1.94 (2H), 1.74-1.53 (4H), 1.39-1.37 (5H), 1.34-1.12 (16H), 0.85-0.81 (9H).

Example 8

Synthesis of the Compound I15

(26) At room temperature 22 C., water (5 ml) and acetonitrile (5 ml) are added into 100 ml eggplant-shaped flask, a n-butylamine solution 1 mmol/ml (0.22 ml, 0.22 mmol) and DIEA (0.2 ml, 1.26 mmol) are added under stirring, and then 1 mmol/ml formaldehyde solution is added (0.22 ml, 0.22 mmol), and then stirred for 15 min after the addition is completed. Compound (III) (400 mg, 0.20 mmol) (R.sub.1H, R.sub.2=Fmoc-, R.sub.3H, refer to the synthesis method of the Chinese Patent Application No. 201110070598.8), and DIEA (0.2 ml, 1.26 mmol) are added into the flask and then stirred for 3 h at room temperature after the addition is completed. 70 ml acetone is added thereto under stirring to produce white insoluble precipitate and then filtered to obtain a filter cake, the filter cake is washed with acetone to obtain a white solid, then purified by preparative HPLC by using an aqueous solution containing 0.1% HCOOH and methanol as a mobile phase to gradient elution with detection wavelength of 240 nm and 280 nm, a flow rate 22 ml/min. The fractions are concentrated under reduced pressure to about 20 ml, washed with saturated sodium bicarbonate solution and then adjusted to pH 6-7, and extracted by adding an equal volume of n-butanol, and an organic layer is separated and then washed with water (10 ml2), and evaporated to dryness solvent under a reduced pressure to produce a residue, the residue is stirred overnight after adding methylene chloride, filtered, dried at 45 C. to obtain compound I.sub.15 30 mg (free base, white powder), yield 10.0%. (refer to Table 1)

(27) MS (ESI): Compound of formula I.sub.15 is C.sub.93H.sub.109C.sub.12N.sub.11O.sub.28, its calculated molecular weight is 1897. Mass spectrum has m/z 1898.31 (M+H), m/z 1920.28 (M+Na). m/z 1899 (M+2), 1900 (M+2+H), 1901 (M+4), is the isotope peaks.

(28) The synthesis of the compound I.sub.16 is the same as that of Example 8, but morpholine is selected instead of n-butylamine solution, and have the same synthetic substrate and method. (refer to Table 1)

(29) Compound I.sub.16:

(30) MS (ESI): Compound of formula I.sub.16 is C.sub.93H.sub.107Cl.sub.2N.sub.11O.sub.29, its calculated molecular weight is 1897. Mass spectrum has m/z 1912.34 (M+H, m/z 1935.31 (M+Na. m/z 1913.32 (M+2, 1914.30 (M+2+H, 1915.31 (M+4) is the isotope peaks.

Example 9

Synthesis of the Compound II1

(31) In an ice-water bath 0 C., water (3 ml) and acetonitrile (3 ml) are added into a 50 ml eggplant-shaped flask, n-butylamine solution 1 mmol/ml (0.12 ml, 1.2 mmol) and 1 mmol/ml formaldehyde solution (0.25 ml, 1.0 mmol) are added, and then stirred for 15 min. Compound (III) (320 mg, 0.2 mmol) (R1=H, R2=H, R3=H, refer to the synthesis method of the Chinese Patent Publication No. CN 101928331 A) is added after the addition is completed, the ice bath is removed and stirred for 3 h at room temperature 15-25 C. 70 ml acetone is added thereto under stirring to produce white insoluble precipitate and then filtered to obtain a filter cake, the filter cake is washed with acetone to obtain a white solid, purified by preparative HPLC, by using an aqueous solution containing 0.1% HCOOH and methanol as a mobile phase to gradient elution with detection wavelength of 240 nm and 280 nm, a flow rate 22 ml/min. The fractions are concentrated under reduced pressure to about 20 ml, and then adjusted to pH 6-7 with saturated sodium bicarbonate solution, and extracted by adding an equal volume n-butanol, and an organic layer is separated and washed with water (10 ml2), and evaporated to dryness solvent under a reduced pressure to produce a residue, the residue is stirred overnight after adding methylene chloride, filtered, and dried at 45 C. to obtain compound II.sub.1 101 mg, the yield is 30.1%. (refer to Table 2)

(32) MS (ESI): Compound of formula II.sub.1 is C.sub.79H.sub.99Cl.sub.2N.sub.11O.sub.26, its calculated molecular weight is 1687. Mass spectrum has m/z 1688 (M+H), m/z 1720 (M+Na. m/z 1,689 (M+2, 1690 (M+2+H, 1691 (M+4) is the isotope peaks.

(33) .sup.1H-NMR (400 MHz, DMSO-d.sub.6+D.sub.2O) (ppm): 7.84-7.56 (3H), 7.42-7.34 (1H), 7.14-7.04 (3H), 6.69-6.45 (3H), 6.04 (1H), 5.67-5.31 (7H), 5.07 (2H), 4.82 (2H), 4.31 (4H), 4.04 (1H), 3.75-3.32 (7H), 3.09-3.00 (3H), 2.58-2.45 (6H), 2.33-2.07 (4H), 1.72-1.10 (19H), 0.97-0.72 (9H).

Example 10

Synthesis of the Compound II2

(34) At room temperature 25 C., water (5 ml) and acetonitrile (5 ml) are added into an 100 ml eggplant-shaped flask, a diethylamine solution 1 mmol/ml (0.23 ml, 0.23 mmol) and DIEA solution (0.26 ml, 1.61 mmol) are added under stirring, and then 1 mmol/ml formaldehyde solution is added (0.23 ml, 0.23 mmol), and stirred for 15 min after the addition is completed. Compound (III) (500 mg, 0.23 mmol) (R.sub.1=2-bromobenzyl, R.sub.2H, R.sub.3H, refer to the synthesis method of the Chinese Patent Application No. 201110070598.8) and DIEA (0.26 ml, 1.61 mmol) are added into the flask, and stirred for 3 h at room temperature after the addition is completed. 70 ml acetone is added thereto under stirring to produce white insoluble precipitate and then filtered to obtain a filter cake, the filter cake is washed with acetone to obtain a white solid, purified by preparative HPLC, by using an aqueous solution containing 0.1% HCOOH and methanol as a mobile phase to gradient elution with detection wavelength of 240 nm and 280 nm, a flow rate is 22 ml/min. The fractions are concentrated under reduced pressure to about 20 ml, and then adjusted to pH 6-7 with saturated sodium bicarbonate solution, and extracted by adding an equal volume n-butanol, and an organic layer is separated and washed with water (10 ml2), and evaporated to dryness solvent under a reduced pressure to produce a residue, the residue is stirred overnight after adding methylene chloride, filtered, then dried at 45 C. to obtain Compound II.sub.2 40 mg (free base, white powder), the yield is 10.0%. (See Table 2)

(35) MS (ESI): Compound of formula II.sub.2 is C.sub.86H.sub.104BrCl.sub.2N.sub.11O.sub.26, its calculated molecular weight is 1855. Mass spectrum has 1657 (M+H), m/z 1778 (M+Na). m/z 1857 (M+2, 1859 (M+4) is the isotope peaks.

(36) .sup.1H-NMR (400 MHz, DMSO-d.sub.6+D.sub.2O) (ppm): 7.89 (2H), 7.58-7.13 (8H), 6.76-6.69 (2H), 6.54 (1H), 6.40-6.12 (1H), 5.71-5.45 (2H), 5.34-5.11 (6H), 4.94-4.63 (5H), 4.48-4.21 (6H), 3.40-2.83 (9H), 2.33-2.00 (6H), 2.00-1.60 (6H), 1.47-1.20 (10H), 1.17-1.03 (6H), 0.97-0.88 (6H).

(37) Synthesis method of the Compound II.sub.7, II.sub.8 is the same as that of Example 10, but each of them selects different compounds (III), wherein, R2, R3 are hydrogen, R1, is 4-bromo benzyl or 4-methoxybenzyl. (refer to Table 2)

(38) Compound II.sub.7: .sup.1H-NMR (400 MHz, DMSO-d.sub.6+D.sub.2O) (ppm): 789 (2H), 7.57 (2H), 7.54-7.50 (3H), 7.26-7.11 (3H), 6.77-6.67 (2H), 6.55 (1H), 5.73 (1H), 5.63 (1H), 5.52 (1H), 5.38-5.11 (5H), 4.86 (1H), 4.72-4.52 (2H), 4.38 (1H), 4.36 (1H), 4.33 (1H), 4.23-4.04 (4H), 3.25-2.67 (7H), 2.34-2.01 (5H), 1.86 (2H), 1.77-1.35 (9H), 1.22 (7H), 1.20-1.00 (8H), 0.89-0.83 (6H).

(39) Compound II.sub.8: .sup.1H-NMR (400 MHz, DMSO-d.sub.6+D.sub.2O) (ppm): 7.90 (2H), 7.59 (2H), 7.36-7.27 (2H), 7.22-7.14 (4H), 6.85-6.68 (4H), 6.56 (1H), 6.34 (1H), 5.74 (1H), 5.65 (1H), 5.55 (1H), 5.40-5.11 (5H), 4.87-4.74 (4H), 4.63 (1H), 4.50 (1H), 4.42 (1H), 4.35 (2H), 4.25-3.75 (4H), 3.65-3.10 (9H), 2.40-2.02 (5H), 1.94-1.60 (5H), 1.50-1.21 (12H), 1.00 (6H), 0.99-0.84 (6H).

Example 11

Synthesis of the Compound II4

(40) At room temperature 25 C., methanol (5 ml) and ethanol (5 ml) are added into a 100 ml eggplant-shaped flask, a diethylamine solution 1 mmol/ml (0.23 ml, 0.23 mmol) and DIEA (0.26 ml, 1.61 mmol) are added under stirring, and then 1 mmol/ml formaldehyde solution (0.69 ml, 0.69 mmol) is added and stirred for 15 min after the addition is completed. Compound (III) (500 mg, 0.23 mmol) (R.sub.1=2-bromobenzyl, R.sub.2H, R.sub.3H, refer to the synthesis method of the Chinese Patent Application No. 201110070598.8), and DIEA (0.26 ml, 1.61 mmol) are added into the flask, and stirred for 3 h at room temperature after the addition is completed. 70 ml acetone is added thereto under stirring to produce white insoluble precipitate and then filtered to obtain a filter cake, the filter cake is washed with acetone to obtain a white solid, purified by preparative HPLC, by using an aqueous solution containing 0.1% HCOOH and methanol as a mobile phase to gradient elution with detection wavelength of 240 nm and 280 nm, a flow rate 22 ml/min. The fractions are concentrated under reduced pressure to about 20 ml, and then adjusted to pH 6-7 with saturated sodium bicarbonate solution, and extracted by adding an equal volume n-butanol, and an organic layer is separated and washed with water (10 ml2), and evaporated to dryness solvent under a reduced pressure to produce a residue, the residue is stirred overnight after adding methylene chloride, filtered, then dried at 45 C. to obtain the compound II.sub.4 40 mg (free base, white powder), yield 10.0%. (refer to Table 2)

(41) Compound II.sub.4: .sup.1H-NMR (400 MHz, DMSO-d.sub.6+D.sub.2O) (ppm): 7.87-7.60 (2H), 7.54-7.11 (6H), 7.12 (2H), 6.75 (2H), 6.50 (1H), 5.68-5.50 (2H), 5.33-5.00 (5H), 4.84-4.62 (4H), 4.47-4.06 (6H), 3.70-3.35 (8H), 3.25-2.84 (4H), 2.33 (5H), 2.02-1.46 (5H), 1.38-1.02 (18H), 0.86-0.80 (9H).

Example 12

Synthesis of the Compound II3

(42) At a temperature 35 C., water (5 ml) and acetonitrile (5 ml) are added into an 100 ml eggplant-shaped flask, a n-butylamine solution 1 mmol/ml (0.28 ml, 0.28 mmol) and DIEA (0.22 ml, 1.38 mmol) are added under stirring, and then 1 mmol/ml formaldehyde solution (1.38 ml, 1.38 mmol) is added, and stirred for 15 min after the addition is completed. Compound (III) (500 mg, 0.23 mmol) (R1=2-bromobenzyl, R2=H, R3=H, refer to the synthesis method of the Chinese Patent Application No. 201110070598.8), and DIEA (0.22 ml, 1.38 mmol) are added into the flask, stirred for 3 h at room temperature after the addition is completed. 70 ml acetone is added thereto under stirring to produce white insoluble precipitate and then filtered to obtain a filter cake, the filter cake is washed with acetone to obtain a white solid, purified by preparative HPLC, by using an aqueous solution containing 0.1% HCOOH and methanol as a mobile phase to gradient elution with detection wavelength of 240 nm and 280 nm, a flow rate 22 ml/min. The fractions are concentrated under reduced pressure to about 20 ml, and then adjusted to pH 6-7 with saturated sodium bicarbonate solution, and extracted by adding an equal volume n-butanol, and an organic layer is separated and washed with water (10 ml2), and evaporated to dryness solvent under a reduced pressure to produce a residue, the residue is stirred overnight after adding methylene chloride, filtered, then dried at 45 C. to obtain the compound II.sub.3 40 mg (free base, white powder), the yield is 10.5%. (refer to Table 2)H-NMR (400 MHz, DMSO-d.sub.6+D.sub.2O) (ppm): 7.88-7.83 (2H), 7.59-7.12 (9H), 6.78 (2H), 6.70-6.53 (2H), 5.73-5.54 (3H), 5.38-5.12 (6H), 4.94-4.63 (5H), 4.49-4.05 (8H), 3.44-2.84 (6H), 2.34 (5H), 2.13-1.68 (3H), 1.61-1.43 (6H), 1.38-1.22 (6H), 1.05-1.04 (7H), 0.99-0.88 (6H).

(43) Synthesis method of the compound II.sub.5 is the same as that of Example 12, but each of them selects different compounds (III), wherein, R1 is 3-bromobenzyl, R2 is hydrogen, R3 is hydrogen. (refer to Table 2)

(44) Compound II.sub.5: .sup.1H-NMR (400 MHz, DMSO-d.sub.6+D.sub.2O) (ppm): 7.87-7.60 (2H), 7.54-7.11 (6H), 7.12 (2H), 6.75 (2H), 6.50 (1H), 5.68-5.50 (2H), 5.33-5.00 (5H), 4.84-4.62 (4H), 4.47-4.06 (6H), 3.70-3.35 (8H), 3.25-2.84 (4H), 2.33 (5H), 2.02-1.46 (5H), 1.38-1.02 (18H), 0.86-0.80 (9H).

Example 13

Synthesis of the Compound II6

(45) At room temperature 20 C., methanol (6 ml) and n-butanol (3 ml) are added into an 100 ml eggplant-shaped flask, 1 mmol/ml morpholine (0.46 ml, 0.46 mmol) and DIEA (0.26 ml, 1.61 mmol) are added under stirring, and then 1 mmol/ml formaldehyde solution (2.3 ml, 2.3 mmol) is added, stirred for 15 min after the addition is completed. the compound (III) (500 mg, 0.23 mmol) (R1=3-bromo-benzyl, R2=H, R3=H, refer to the synthesis method of the Chinese Patent Application No. 201110070598.8) and DIEA (0.26 ml, 1.61 mmol) are added, and stirred for 3 h at room temperature after the addition is completed. 70 ml acetone is added thereto under stirring to produce white insoluble precipitate and then filtered to obtain a filter cake, the filter cake is washed with acetone to obtain a white solid, then purified by preparative HPLC, by using an aqueous solution containing 0.1% HCOOH and methanol as a mobile phase to gradient elution with detection wavelength of 240 nm and 280 nm, a flow rate 22 ml/min. The fractions are concentrated under reduced pressure to about 20 ml, and then adjusted to pH 6-7 with saturated sodium bicarbonate solution, and extracted by adding an equal volume n-butanol, and an organic layer is separated and washed with water (10 ml2), and evaporated to dryness solvent under a reduced pressure to produce a residue, the residue is stirred overnight after adding methylene chloride, filtered, then dried at 45 C. to the solution is the compound II.sub.6 40 mg (free base, white powder), the yield is 10.5%. (refer to Table 2)

(46) Compound II.sub.6: .sup.1H-NMR (400 MHz, DMSO-d.sub.6+D.sub.2O) (ppm): 7.89 (2H), 7.57-7.12 (7H), 6.76-6.69 (2H), 6.52 (1H), 6.33 (1H), 5.75-5.54 (2H), 5.37-5.06 (4H), 5.00-4.49 (3H), 4.40-3.90 (5H), 3.25-3.10 (5H), 2.82-2.70 (2H), 2.40-2.00 (6H), 1.85 (2H), 1.67-1.04 (16H), 0.88 (6H).

(47) Synthesis method of compound II.sub.9 is the same as that of Example 13, but each of them selects different compounds (III), wherein, R1 is 4-iso-benzyl, R2 is hydrogen, R3 is hydrogen. (refer to Table 2)

(48) Compound II.sub.9: .sup.1H-NMR (400 MHz, DMSO-d.sub.6+D.sub.2O) (ppm): 7.85-7.79 (2H), 7.54 (4H), 7.30 (4H), 7.00-6.90 (2H), 6.58 (2H), 5.96 (1H), 5.79 (1H), 5.60-5.31 (4H), 5.15 (2H), 5.00-4.79 (4H), 4.66-4.43 (4H), 4.00-3.26 (14H), 2.70-2.02 (10H), 2.00-1.42 (8H), 1.20-1.10 (12H), 0.86 (6H).

(49) In the above Examples 113, the following abbreviations have their respective meanings. Undefined abbreviations have their generally accepted meaning, unless noted otherwise, all room temperature is referred to as 20 C.30 C. DMF N,N-dimethyl-Formamide DIEA N,N-Diisopropylethylamine Fmoc- Fluorenylmethoxycarbonyl TFA Trifluoroacetic acid HPLC High Performance Liquid Chromatography MIC minimum inhibitory concentration
Refer to relevant data of compounds of formula (I) or (III) of some examples in Table 1 and Table 2

(50) Purified condition by preparative HPLC in Example 113 includes Chromatographic Column Sepax BR-C.sub.18 21.2100 mm (5 m), gradient elution, wherein the composition of a mobile phase is as follows.

(51) TABLE-US-00001 Time (min) Methyl Alcohol 0.1% methanoic acid 0 5 95 20 30 70

(52) Detection wavelength is 240 nm and 280 nm. Organic solvents of needed fractions are removed under reduced pressure, and then adjusted to pH 6-7 with saturated aqueous sodium bicarbonate, and extracted with n-butanol, washed with water, and evaporated alcohol under reduced pressure, and dried to obtain the product. The yield of the present invention is referred to as a molar yield.

(53) TABLE-US-00002 TABLE 1 Compound of formula (I) [].sub.D.sup.25 NO. R.sub.1 R.sub.2 R.sub.3 NR.sub.4R.sub.5 Formula C = 0.1 ESI I.sub.1 H H H C.sub.75H.sub.94Cl.sub.2N.sub.11O.sub.27P 52.sup.a 1714.68 (M + H) I.sub.2 H H H C.sub.78H.sub.97Cl.sub.2N.sub.11O.sub.27 44.sup.a 1712.12 (M + Na) I.sub.3 H H H NHn-C.sub.4H.sub.9 C.sub.75H.sub.94Cl.sub.2N.sub.11O.sub.27 54.sup.a 1700.27 (M + Na) I.sub.4 n-C.sub.10H.sub.21 n-C.sub.10H.sub.21 n-C.sub.10H.sub.21 NHn-C.sub.4H.sub.9 C.sub.108H.sub.159Cl.sub.2N.sub.11O.sub.26 76.sup.a 2097.95 (M + H) I.sub.5 H H 0 C.sub.85H.sub.102BrCl.sub.2N.sub.11O.sub.27 78.sup.b 1858.53 (M + H) I.sub.6 H H N(C.sub.2H.sub.5).sub.2 C.sub.85H.sub.104BrCl.sub.2N.sub.11O.sub.26 58.sup.b 1866.62 (M + Na) I.sub.7 H H NHn-C.sub.4H.sub.9 C.sub.85H.sub.104BrCl.sub.2N.sub.11O.sub.26 41.sup.c 1866.66 (M + Na) I.sub.8 H H C.sub.85H.sub.102BrCl.sub.2N.sub.11O.sub.27 48.sup.c 1880.46 (M + Na) I.sub.9 H H C.sub.85H.sub.102BrCl.sub.2N.sub.11O.sub.27 71.sup.c 1880.55 (M + Na) I.sub.10 H H N(C.sub.2H.sub.5).sub.2 C.sub.85H.sub.104BrCl.sub.2N.sub.11O.sub.26 35.sup.b 1866.61 (M + Na) I.sub.11 H H NHn-C.sub.4H.sub.9 C.sub.85H.sub.104BrCl.sub.2N.sub.11O.sub.26 50.sup.c 1866.54 (M + Na) I.sub.12 H H 0 C.sub.86H.sub.105Cl.sub.2N.sub.11O.sub.28 18.sup.b 1810.72 (M + H) I.sub.13 H H C.sub.88H.sub.109Cl.sub.2N.sub.11O.sub.27 44.sup.c 1822.59 (M + H) I.sub.14 H H NHn-C.sub.4H.sub.9 C.sub.88H.sub.111Cl.sub.2N.sub.11O.sub.26 60.sup.b 1808.80 (M + H) I.sub.15 H Fmoc- H NHn-C.sub.4H.sub.9 C.sub.93H.sub.109Cl.sub.2N.sub.11O.sub.28 50.sup.b 1920.28 (M + Na) I.sub.16 H Fmoc- H C.sub.93H.sub.107Cl.sub.2N.sub.11O.sub.29 55.sup.b 1935.31 (M + Na) Note: .sup.ais a solvent of water, .sup.bis a solvent of DMF, .sup.cis a solvent of methanol

(54) TABLE-US-00003 TABLE 2 Compound of formula (II) [].sub.D.sup.25 NO. R.sub.1 NR.sub.4R.sub.5 Formula C = 0.1 ESI II.sub.1 H NHn-C.sub.4H.sub.9 C.sub.79H.sub.99Cl.sub.2N.sub.11O.sub.26 76.sup.a 1688.67 (M + H) II.sub.2 N(C.sub.2H.sub.5).sub.2 C.sub.86H.sub.104BrCl.sub.2N.sub.11O.sub.26 32.sup.a 1857.61 (M + 2) II.sub.3 NHn-C.sub.4H.sub.9 C.sub.86H.sub.104BrCl.sub.2N.sub.11O.sub.26 47.sup.b 1878.51 (M + Na) II.sub.4 N(C.sub.2H.sub.5).sub.2 C.sub.86H.sub.104BrCl.sub.2N.sub.11O.sub.26 64.sup.a 1856.47 (M + H) II.sub.5 NHn-C.sub.4H.sub.9 C.sub.86H.sub.104BrCl.sub.2N.sub.11O.sub.26 53.sup.b 1856.70 (M + H) II.sub.6 0 C.sub.86H.sub.102BrCl.sub.2N.sub.11O.sub.27 32.sup.b 1893.15 (M + Na) II.sub.7 N(C.sub.2H.sub.5).sub.2 C.sub.86H.sub.104BrCl.sub.2N.sub.11O.sub.26 51.sup.b 1878.62 (M + Na) II.sub.8 N(C.sub.2H.sub.5).sub.2 C.sub.87H.sub.107Cl.sub.2N.sub.11O.sub.27 18.sup.a 1808.64 (M + H) II.sub.9 C.sub.89H.sub.109Cl.sub.2N.sub.11O.sub.27 34.sup.b 1834.70 (M + H) Note: .sup.ais a solvent of water, .sup.bis a solvent of DMF, .sup.cis a solvent of methanol

Effects of Examples

(55) Testing results of in vitro antibacterial activity of some target compounds of the present invention are as follows:

(56) 1. Testing Method:

(57) Drugs: firstly being dissolved in DMSO, and then being diluted to an appropriate concentration with sterile water, and afterwards successively being diluted for twice.

(58) Determination: referencing the standard of CSSI 2008 version, using a agar two times dilution method, determine the minimum inhibitory concentration (MIC values).

(59) 2. Testing Bacterial Strain

(60) Feces enterococci (VSE clinical isolates: MEFA 0039); Streptococcus pneumoniae (PISP: ATCC 49619).

(61) 3. Positive Control Drug is Vancomycin Hydrochloride.

(62) MIC values of some compound are shown in Table 3.

(63) TABLE-US-00004 TABLE 3 MIC Values of Compounds (g/ml) Streptococcus Compound Enterococci pneumoniae vancomycin 0.25 0.125 hydrochloride I.sub.1 0.5 0.125 I.sub.2 0.5 0.063 I.sub.3 0.5 0.25 I.sub.4 >8 >8 I.sub.5 0.25 0.125 I.sub.6 1 0.25 I.sub.7 1 0.5 I.sub.8 0.25 0.063 I.sub.9 0.25 0.031 I.sub.10 2 0.25 I.sub.11 1 0.25 I.sub.12 2 1 I.sub.13 1 0.25 I.sub.14 0.5 0.031 II.sub.1 0.25 0.125 II.sub.2 2 0.5 II.sub.3 2 0.25 II.sub.4 2 0.25 II.sub.5 1 0.25 II.sub.6 2 0.25 II.sub.7 1 0.25 II.sub.8 1 0.25 II.sub.9 1 0.25

(64) It can be seen from Table 3, the activity of series compound I is obviously superior to the activity of series compound II. Compared with the positive control of vancomycin, the activity of series compounds I against enterococci is comparable to vancomycin or is weaker than vancomycin; and the activity against Streptococcus pneumoniae is superior to vancomycin. Wherein, the activity of compounds I.sub.14 and I.sub.9 against streptococcus pneumoniae is more four times than vancomycin. So it is worthy for further modification and pharmacological activity.

(65) Although the present invention has been described in connection with the above embodiments, it should be understood that the present invention is not limited to such preferred embodiments and procedures set forth above. The embodiments and procedures were chosen and described in order to best explain the principles of the invention and its practical application, to thereby enable others skilled in the art to best utilize the invention. It will be apparent to those skilled in the art that various substitution, modifications and changes may be thereto without departing from the scope and spirit of the invention. Therefore, the intention is intended to cover all alternative constructions and equivalents falling within the spirit and scope of the invention as defined only by the appended claims and equivalents thereto.