US 6,586,393 B2Granted

Antibiotics GE 23077, pharmaceutically acceptable salts and compositions, and use thereof

AssigneeBiosearch Italia S.p.A.

InventorsIsmaela Ciciliato, Emiliana Corti, Edoardo Giacomo Sarubbi, Stefania Stefanelli, Nicoletta Montanini, Flavia Marinelli, Michael Kurz, Enrico Selva

Life of this patent

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Abstract

The invention relates to an antibiotic substance of microbial origin, arbitrarily denominated GE23077 complex and the individual factors which constitute it, a mixture of said factors in any proportion, the pharmaceutically acceptable salts and compositions thereof, and their use as an antibacterial agent having a selective inhibitory activity against E. coli RNA polymerase.

Claims17

Dependent claims

Antibiotic GE23077 factor A1 having the following characteristics:

A) Main FAB mass peak, obtained on a Finnigan TSQ700 triple quadrupole mass spectrometer using a xenon atom gun, operating at 8 kV, 0.23 mA current, the sample being mixed with glycerol as ionization matrix, corresponding to (M−H)+ at 804 m/z;
B) 1H-NMR spectrum recorded at 600 MHz in DMSO-d6, exibiting the following signals (in ppm) referenced to the residual peak of DMSO set at 2.5 ppm as internal standard:
the values marked with an asterisk are overlapping of two 1H signals:
8.94;
8.93;
8.93*;
8.04;
7.93;
7.88;
7.68;
7.33/7.27;
7.29;
6.34;
5.97;
5.79;
5.68;
5.00;
4.94;
4.82;
4.65;
4.47;
4.37;
4.31;
4.07;
4.05;
3.90;
3.88;
3.74;
3.59/3.49;
3.53,3.42/3.25;
2.50;
1.74;
1.70;
0.96;
0.94;
0.85;
C) 13C-NMR spectrum, recorded at 150 MHz in DMSO-d6, exibiting the following signals (in ppm) referenced to the residual peak of DMSO set at 39.5 ppm as internal;
standard:
the values marked with an asterisk are overlapping of two 13C signals:
175.6;
171.5;
171.3;
170.7;
170.2;
170.0;
170.0*;
169.6;
169.2;
168.8;
131.6;
129.9;
74.0;
69.9;
69.1;
66.8;
63.1;
60.1;
58.5;
58.2;
57.3;
55.9;
54.3;
43.4;
39.7;
29.8;
19.51;
19.3;
19.2;
13.7;
12.3;
D) Retention time:
14.16 min, determined by HPLC analysis under the following chromatographic conditions:
Instrument:
HP mod. 1090 DAD detector;
Column:
Beckmann ODS C18, 5 μm 250×4.6 mm;
Elution:
Isocratic 15% Phase B;
Phase A:
2.5 g/l Ammonium formiate:
99:1 v/v Methanol;
Phase B:
2.5 g/l Ammonium formiate:
30:70 v/v Methanol;
Flow rate:
1.5 ml/min;
Detector:
UV 230 nm;
and the pharmaceutically acceptable salts thereof.

86 more elements

A process for producing an antibiotic, wherein the antibiotic is selected from the group consisting of antibiotic GE23077 factor A1 having the following characteristics:

A) Main FAB mass peak, obtained on a Finnigan TSQ700 triple quadrupole mass spectrometer using a xenon atom gun, operating at 8 kV, 0.23 mA current, the sample being mixed with glycerol as ionization matrix, corresponding to (M−H)+ at 804 m/z;
B) 1H-NMR spectrum recorded at 600 MHZ in DMSO-d6, exibiting the following signals (in ppm) referenced to the residual peak of DMSO set at 2.5 ppm as internal standard:
the values marked with an asterisk are overlapping of two 1H signals;:
8.94;
8.93;
8.93*;
8.04;
7.93;
7.88;
7.68;
7.33/7.27;
7.29;
6.34;
5.97;
5.79;
5.68;
5.00;
4.94;
4.82;
4.65;
4.47;
4.37;
4.31;
4.07;
4.05;
3.90;
3.88;
3.74;
3.59/3.49;
3.53,3.42/3.25;
2.50;
1.74;
1.70;
0.96;
0.94;
0.85;
C) 13C-NMR spectrum, recorded at 150 MHZ in DMSO-d6, exibiting the following signals (in ppm) referenced to the residual peak of DMSO set at 39.5 ppm as internal standard:
the values marked with an asterisk are overlapping of two 13C signals:
175.6;
171.5;
171.3;
170.7;
170.2;
170.0;
170.0*;
169.6;
169.2;
168.8;
131.6;
129.9;
74.0;
69.9;
69.1;
66.8;
63.1;
60.1;
58.5;
58.2;
57.3;
55.9;
54.3;
43.4;
39.7;
29.8;
19.9;
19.3;
19.2;
13.7;
12.3;
D) Retention time:
14.16 min, determined by HPLC analysis under the following chromatographic conditions:
Instrument:
HP mod. 1090 DAD detector;
Column:
Beckmann ODS C18, 5 μm 250×4.6 mm;
Elution:
Isocratic 15% Phase B;
Phase A:
2.5 g/l Ammonium formiate:
99:1 v/v Methanol;
Phase B:
2.5 g/l Ammonium formiate:
30:70 v/v Methanol;
Flow rate:
1.5 ml/min;
Detector:
UV 230 nm,
a pharmaceutically acceptable salt of antibiotic GE23077 factor A1, antibiotic GE23077 factor A2 having the following characteristics:
A) Main FAB mass peak, obtained on a Finnigan TSQ700 triple quadrupole mass spectrometer using a xenon atom gun, operating at 8 kV, 0.23 mA current, the sample being mixed with glycerol as ionization matrix, corresponding to (M−H)+ at 804 m/z;
B) Retention time:
20.90 min, determined by HPLC analysis under the following chromatographic conditions:
Instrument:
HP mod. 1090 DAD detector;
Column:
Beckmann ODS C18, 5 μm 250×4.6 mm;
Elution:
Isocratic 15% Phase B;
Phase A:
2.5μl Ammonium formiate:
99:1 v/v Methanol;
Phase B:
2.5 g/l Ammonium formiate:
30:70 v/v Methanol;
Flow rate:
1.5 ml/min;
Detector:
UV 230 nm;
C) 1H-NMR spectrum, recorded after complete conversion of factor A2 into factor A1 was recorded at 600 MHZ in DMSO-d6 and exibits the following signals (in ppm) referenced to the residual peak of DMSO set at 2.5 ppm as internal standard:
the values marked with an asterisk are overlapping of two 1H signals:
8.94;
8.93;
8.93*;
8.04;
7.93;
7.88;
7.68;
7.33/7.27;
7.29;
6.34;
5.97;
5.79;
5.68;
5.00;
4.94;
4.82;
4.65;
4.47;
4.37;
4.31;
4.07;
4.05;
3.90;
3.88;
3.74;
3.59/3.49;
3.53,3.42/3.25;
2.50;
1.74;
1.70;
0.96;
0.94;
0.85;
D) 13C-NMR spectrum, recorded after complete conversion of factor A2 into factor A1 was recorded at 150 MHZ in DMSO-d6 and exibits the following signals (in ppm) referenced to the residual peak of DMSO set at 39.5 ppm as internal standard:
the values marked with an asterisk are overlapping of two 13C signals:
175.6;
171.5;
171.3;
170.7;
170.2;
170.0;
170.0*;
169.6;
169.2;
168.8;
131.6;
129.9;
74.0;
69.9;
69.1;
66.8;
63.1;
60.1;
58.5;
58.2;
57.3;
55.9;
54.3;
43.4;
39.7;
29.8;
19.9;
19.3;
19.2;
13.7;
12.3,
a pharmaceutically acceptable salt of antibiotic GE23077 factor A2, antibiotic GE23077 factor B1 having the following characteristics:
A) Main FAB mass peak, obtained on a Finnigan TSQ700 triple quadrupole. mass spectrometer using a xenon atom gun, operating at 8 kV, 0.23 mA current, the sample being mixed with glycerol as ionization matrix, corresponding to (M−H)+ at 806 m/z;
B) 1H-NMR spectrum, recorded at 600 MHZ in DMSO-d6, exibiting the following signals (in ppm) referenced to the residual peak of DMSO set at 2.5 ppm as internal standard:
the values marked with an asterisk are overlapping of two 1H signals:
9.00;
8.99;
8.94;
8.02;
7.93;
7.88;
7.82;
7.32/7.26;
7.30;
5.90;
5.81;
5.66;
4.99;
4.96;
4.79;
4.65;
4.47;
4.31;
4.31;
4.07;
4.05;
3.88;
3.88*;
3.74;
3.57/3.37;
3.53;
3.47/3.23;
2.49;
1.95;
1.95*;
0.95;
0.94;
0.85;
0.84;
C) 13C-NMR spectrum, recorded at 150 MHZ in DMSO-d6, exibiting the following signals (in ppm) referenced to the residual peak of DMSO set at 39.5 ppm as internal standard:
the values marked with an asterisk are overlapping of two 13C signals:
175.5;
172.3;
171.4;
171.3;
170.7;
170.2;
169.9;
169.9*;
169.5;
169.0;
73.9;
70.0;
69.0;
66.8;
63.1;
60.0;
58.4;
58.3;
57.3;
55.9;
54.5:
44.5;
43.5;
39.4;
29.8;
25.4;
22.3;
19.9;
19.2;
19.2;
D) Retention time:
16.56 min, determined by HPLC analysis under the following chromatographic conditions:
Instrument:
HP mod. 1090 DAD detector;
Column:
Beckmann ODS C18, 5 μm 250×4.6 mm;
Elution:
Isocratic 15% Phase B;
Phase A:
2.5 g/l Ammonium formiate:
99:1 v/v Methanol;
Phase B:
2.5 g/l Ammonium formiate:
30:70 v/v Methanol;
Flow rate:
1.5 ml/min;
Detector:
UV 230 nm,
a pharmaceutically acceptable salt of antibiotic GE23077 factor B1, antibiotic GE23077 factor B2 having the following characteristics;
A) Main FAB mass peak, obtained on a Finnigan TSQ700 triple quadrupole mass spectrometer using a xenon atom gun, operating at 8 kV, 0.23 mA current, the sample being mixed with glycerol as ionization matrix, corresponding to (M−H)+ at 806 m/z;
B) Retention time:
22.71 min, determined by HPLC analysis under the following, chromatographic conditions:
Instrument:
HP mod. 1090 DAD detector;
Column:
Beckmann ODS C18,5 μm 250×4.6 mm;
Elution:
Isocratic 15% Phase B;
Phase A:
2.5 g/l Ammonium formiate:
99:1 v/v Methanol;
Phase B:
2.5 g/l Ammonium formiate:
30:70 v/v Methanol;
Flow rate:
1.5 ml/min;
Detector:
UV 230 nm;
C) The 1H-NMR spectrum, recorded after complete conversion of factor B2 into factor B1 was recorded at 600 MHZ in DMSO-d6 and exibits the following signals (in ppm) referenced to the residual peak of DMSO set at 2.5 ppm as internal standard:
the values marked with an asterisk are overlapping of two 1H signals:
9.00;
8.99;
8.94;
8.02;
7.93;
7.88;
7.82;
7.32/7.26;
7.30;
5.90;
5.81;
5.66;
4.99;
4.96;
4.79;
4.65;
4.47;
4.31;
4.31;
4.07;
4.05;
3.88;
3.88*;
3.74;
3.57/3.37;
3.53;
3.47/3.23;
2.49;
1.95;
1.95*;
0.95;
0.94;
0.85;
0.84;
D) The 13C-NMR spectrum, recorded after complete conversion of factor A2 into factor A1 was recorded at 150 MHZ in DMSO-d6 and exibits the following signals (in ppm) referenced to the residual peak of DMSO set at 39.5 ppm. as internal standard:
the values marked with an asterisk are overlapping of two 13C signals:
175.5;
172.3;
171.4;
171.3;
170.7;
170.2;
169.9;
169.9*;
169.5;
169.0;
73.9;
70.0;
69.0;
66.8;
63.1;
60.0;
58.4;
58.3;
57.3;
55.9;
54.5;
44.5;
43.5;
39.4;
29.8;
25.4;
22.3;
19.9;
19.2;
19.2;
and a pharmaceutically acceptable salt of antibiotic GE23077 factor B2, which comprises:
cultivating Actinomadura sp. DSMZ 13491 or a mutant thereof;
isolating the resulting antibiotic from the mycelium and or the culture broth;
purifying the isolated antibiotic;
and
separating the antibiotic four factors A 1, A2, B 1 and B2 by chromatographic means.

354 more elements

An antibiotic GE23077 mixture of two or more factors selected from the group consisting of antibiotic GE23077 factor A1 having the following characteristics:

A) Main FAB mass peak, obtained on a Finnigan TSQ700 triple quadrupole mass spectrometer using a xenon atom gun, operating at 8 kV, 0.23 mA current, the sample being mixed with glycerol as ionization matrix, corresponding to (M−H)+ at 804 m/z;
B) 1H-NMR spectrum recorded at 600 MHz in DMSO-d6, exibiting the following signals (in ppm) referenced to the residual peak of DMSO set at 2.5 ppm as internal standard:
the values marked with an asterisk are overlapping of two 1H signals:
8.94;
8.93;
8.93*;
8.04;
7.93;
7.88;
7.68;
7.33/7.27;
7.29;
6.34;
5.97;
5.79;
5.68:
5.00;
4.94;
4.82;
4.65;
4.47;
4.37;
4.31;
4.07;
4.05;
3.90;
3.88;
3.74;
3.59/3.49;
3.53,3.42/3.2:5;
2.50;
1.74;
1.70;
0.96;
0.94;
0.85;
C) 13C-NMR spectrum, recorded at 150 MHz in DMSO-d6, exibiting the following signals (in ppm) referenced to the residual peak of DMSO set at 39.5 ppm as internal standard:
the values marked with an asterisk are overlapping of two 13C signals:
175.6;
171.5;
171.3;
170.7;
170.2;
170.0;
170.0*;
169.6;
169.2;
168.8;
131.6;
129.9;
74.0;
69.9;
69.1;
66.8;
63.1;
60.1;
58.5;
58.2;
57.3;
55.9;
54.3;
43.4;
39.7;
29.8;
19.9;
119.3;
19.2;
13.7;
12.3;
D) Retention time:
14.16 min, determined by HPLC analysis under the following chromatographic conditions:
Instrument:
HP mod. 1090 DAD detector;
Column:
Beckmann ODS C18, 5 μm 250×4.6 mm;
Elution:
Isocratic 15% Phase B;
Phase A:
2.5 g/l Ammonium formiate:
99:1 v/v Methanol;
Phase B:
2.5 g/l Ammonium formiate:
30:70 v/v Methanol;
Flow rate:
1.5 ml/min;
Detector:
UV 230 nm,
a pharmaceutically acceptable salt of antibiotic GE23077 factor A1, antibiotic GE23077 factor A2 having the following characteristics:
A) Main FAB mass peak, obtained on a Finnigan TSQ700 triple quadrupole mass spectrometer using a xenon atom gun, operating at 8 kV, 0.23 mA current, the sample being mixed with glycerol as ionization matrix, corresponding to (M−H)+ at 804 m/z;
B) Retention time:
20.90 min, determined by HPLC analysis under the following chromatographic conditions:
Instrument:
HP mod. 1090 DAD detector;
Column:
Beckmann ODS C18, 5 μm 250×4.6 mm;
Elution:
Isocratic 15% Phase B;
Phase A:
2.5 g/l Ammonium formiate:
99:1 v/v Methanol;
Phase B:
2.5 g/l Ammonium formiate:
30:70 v/v Methanol;
Flow rate:
1.5 ml/min;
Detector:
UV 230 nm;
C) 1H-NMR spectrum, recorded after complete conversion of factor A2 into factor A1 was recorded at 600 MHz in DMSO-d6 and exibits the following signals (in ppm) referenced to the residual peak of DMSO set at 2.5 ppm as internal standard:
the values marked with an asterisk are overlapping of two 1H signals:
8.94;
8.93;
8.93*;
8.04;
7.93;
7.88;
7.68;
7.33/7.27;
7.29;
6.34;
5.97;
5.79;
5.68;
5.00;
4.94;
4.82;
4.65;
4.47;
4.37;
4.31;
4.07;
4.05;
3.90;
3.88;
3.74;
3.59/3.49;
3.53,3.42/3.25;
2.50;
1.74;
1.70;
0.96;
0.94;
0.85;
D) 13C-NMR spectrum, recorded after complete conversion of factor A2 into factor A1 was recorded at 150 MHz in DMSO-d6 and exibits the following signals (in ppm) referenced to the residual peak of DMSO set at 39.5 ppm as internal standard:
the values marked with an asterisk are overlapping of two 13C signals:
175.6;
171.5;
171.3;
170.7;
170.2;
170.0;
170.0*;
169.6;
169.2;
168.8;
131.6;
129.9;
74.0;
69.9;
69.1;
66.8;
63.1;
60.1;
58.5;
58.2;
57.3;
55.9;
54.3;
43.4;
39.7;
29.8;
19.9;
19.3;
19.2;
13.7;
12.3,
a pharmaceutically acceptable salt of antibiotic GE23077 factor A2, antibiotic GE23077 factor B1 having the following characteristics:
A) Main FAB mass peak, obtained on a Finnigan TSQ700 triple quadrupole. mass spectrometer using a xenon atom gun, operating at 8 kV, 0.23 mA current, the sample being mixed with glycerol as ionization matrix, corresponding to (M−H)+ at 806 m/z;
B) 1H-NMR spectrum, recorded at 600 MHz in DMSO-d6, exibiting the following signals (in ppm) referenced to the residual peak of DMSO set at 2.5 ppm as internal standard:
the values marked with an asterisk are overlapping of two 1H signals:
9.00;
8.99;
8.94;
8.02;
7.93;
7.88;
7.82;
7.32/7.26;
7.30;
5.90;
5.81;
5.66;
4.99;
4.96;
4.79;
4.65;
4.47;
4.31;
4.31;
4.07;
4.05;
3.88;
3.88*;
3.74;
3.57/3.37;
3.53;
3.47/3.23;
2.49;
1.95;
1.95*;
0.95;
0.94;
0.85;
0.84;
C) 13C-NMR spectrum, recorded at 150 MHz in DMSO-d6, exibiting the following signals (in ppm) referenced to the residual peak of DMSO set at 39.5 ppm as internal standard:
the values marked with an asterisk are overlapping of two 13C signals:
175.5;
172.3;
171.4;
171.3;
170.7;
170.2;
169.9;
169.9*;
169.5;
169.0;
73.9;
70.0;
69.0;
66.8;
63.1;
60.0;
58.4;
58.3;
57.3;
55.9;
54.5:
44.5;
43.5;
39.4;
29.8;
25.4;
22.3;
19.9;
19.2;
19.2;
D) Retention time:
16.56 min, determined by HPLC analysis under the following chromatographic conditions:
Instrument:
HP mod. 1090 DAD detector;
Column:
Beckmann ODS C18, 5 μm 250×4.6 mm;
Elution:
Isocratic 15% Phase B;
Phase A:
2.5 g/l Ammonium formiate:
99:1 v/v Methanol;
Phase B:
2.5 g/l Ammonium formiate:
30:70 v/v Methanol;
Flow rate:
1.5 ml/min;
Detector:
UV 230 nm,
a pharmaceutically acceptable salt of antibiotic GE23077 factor B1, antibiotic GE23077 factor B2 having the following characteristics:
A) Main FAB mass peak, obtained on a Finnigan TSQ700 triple quadrupole mass spectrometer using a xenon atom gun, operating at 8 kV, 0.23 mA current, the sample being mixed with glycerol as ionization matrix, corresponding to (M−H)+ at 806 m/z;
B) Retention time:
22.71 min, determined by HPLC analysis under the following chromatographic conditions:
Instrument:
HP mod. 1090 DAD detector;
Column:
Beckmann ODS C18, 5 μm 250×4.6 mm;
Elution:
Isocratic 15% Phase B;
Phase A:
2.5 g/l Ammonium formiate:
99:1 v/v Methanol;
Phase B:
2.5 g/l Ammonium formiate:
30:70 v/v Methanol;
Flow rate:
1.5 ml/min;
Detector:
UV 230 nm;
C) The 1H-NMR spectrum, recorded after complete conversion of factor B2 into factor B1 was recorded at 600 MHz in DMSO-d6 and exibits the following signals (in rpm) referenced to the residual peak of DMSO set at 2.5 ppm as internal standard:
the values marked with an asterisk are overlapping of two 1H signals:
9.00;
8.99;
8.94;
8.02;
7.93;
7.88;
7.82;
7.32/7.26;
7.30;
5.90;
5.81;
5.66;
4.99;
4.96;
4.79;
4.65;
4.47;
4.31;
4.31;
4.07;
4.05;
3.88;
3.88*;
3.74;
3.57/3.37;
3.53;
3.47/3.23;
2.49;
1.95;
1.95*;
0.95;
0.94;
0.85;
0.84;
D) The 13C-NMR spectrum, recorded after complete conversion of factor B2 into factor B1was recorded at 150 MHz in DMSO-d6 and exibits the following signals (in ppm) referenced to the residual peak of DMSO set at 39.5 ppm as internal standard:
the values marked with an asterisk are overlapping of two 13C signals:
175.5;
172.3;
171.4;
171.3;
170.7;
170.2;
169.9;
169.9*;
169.5;
169.0;
73.9;
70.0;
69.0;
66.8;
63.1;
60.0;
58.4;
58.3;
57.3;
55.9;
54.5;
44.5;
43.5;
39.4;
29.8;
25.4;
22.3;
19.9;
19.2;
19.2;
and a pharmaceutically acceptable salt of antibiotic GE23077 factor B2 in any proportion.

349 more elements

A pharmaceutical composition comprising at least one antibiotic selected from the group consisting of antibiotic GE23077 factor A1 having the following characteristics:

A) Main FAB mass peak, obtained on a Finnigan TSQ700 triple quadrupole mass spectrometer using a xenon atom gun, operating at 8 kV, 0.23 mA current, the sample being mixed with glycerol as ionization matrix, corresponding to (M−H)+ at 804 m/z;
B) 1H-NMR spectrum recorded at 600 MHz in DMSO-d6, exibiting the following signals (in ppm) referenced to the residual peak of DMSO set at 2.5 ppm as internal standard:
the values marked with an asterisk are overlapping of two 1H signals:
8.94;
8.93;
8.93*;
8.04;
7.93;
7.88;
7.68;
7.33/7.27;
7.29;
6.34;
5.97;
5.79;
5.68;
5.00;
4.94;
4.82;
4.65;
4.47;
4.37;
4.31;
4.07;
4.05;
3.90;
3.88;
3.74;
3.59/3.49;
3.53,3.42/3.25;
2.50;
1.74;
1.70;
0.96;
0.94;
0.85;
C) 13C-NMR spectrum, recorded at 150 MHz in DMSO-d6, exibiting the following signals (in ppm) referenced to the residual peak of DMSO set at 39.5 ppm as internal standard:
the values marked with an asterisk are overlapping of two 13C signals:
175.6;
171.5;
171.3;
170.7;
170.2;
170.0;
170.0*;
169.6;
169.2;
168.8;
131.6;
129.9;
74.0;
69.9;
69.1;
66.8;
63.1;
60.1;
58.5;
58.2;
57.3;
55.9;
54.3;
43.4;
39.7;
29.8;
19.9;
19.3;
19.2;
13.7;
12.3;
D) Retention time:
14.16 min, determined by HPLC analysis under the following chromatographic conditions:
Instrument:
HP mod. 1090 DAD detector;
Column:
Beckmann ODS C18, 5 μm 250×4.6 mm;
Elution:
Isocratic 15% Phase B;
Phase A:
2.5 g/l Ammonium formiate:
99:1 v/v Methanol;
Phase B:
2.5 g/l Ammonium formiate:
30:70 v/v Methanol;
Flow rate:
1.5 ml/min;
Detector:
UV 230 nm;
a pharmaceutically acceptable salt of antibiotic GE23077 factor A1, antibiotic GE23077 factor A2 having the following characteristics:
A) Main FAB mass peak, obtained on a Finnigan TSQ700 triple quadrupole mass spectrometer using a xenon atom gun, operating at 8 kV, 0.23 mA current, the sample being mixed with glycerol as ionization matrix, corresponding to (M−H)+ at 804 m/z;
B) Retention time:
20.90 min, determined by HPLC analysis under the following chromatographic conditions:
Instrument:
HP mod. 1090 DAD detector;
Column:
Beckmann ODS C18, 5 μm 250×4.6 mm;
Elution:
Isocratic 15% Phase B;
Phase A:
2.5 g/l Ammonium formiate:
99:1 v/v Methanol;
Phase B:
2.5 g/l Ammonium formiate:
30:70 v/v Methanol;
Flow rate:
1.5 ml/min;
Detector:
UV 230 nm;
C) 1H-NMR spectrum, recorded after complete conversion of factor A2 into factor A1 was recorded at 600 MHz in DMSO-d6 and exibits the following signals (in ppm) referenced to the residual peak of DMSO set at 2.5 ppm as internal standard:
the values, marked with an asterisk are overlapping of two 1H signals:
8.94;
8.93;
8.93*;
8.04;
7.93;
7.88;
7.68;
7.33/7.27;
7.29;
6.34;
5.97;
5.79;
5.68;
5.00;
4.94;
4.82;
4.65;
4.47;
4.37;
4.31;
4.07;
4.05;
3.90;
3.88;
3.74;
3.59/3.49;
3.53,3.42/3.25;
2.50;
1.74;
1.70;
0.96;
0.94;
0.85;
D) 13C-NMR spectrum, recorded after complete conversion of factor A2 into factor A1 was recorded at 150 MHz in DMSO-d6 and exibits the following signals (in ppm) referenced to the residual peak of DMSO set at 39.5 ppm as internal standard:
the values marked with an asterisk are overlapping of two 13C signals:
175.6;
171.5;
171.3;
170.7;
170.2;
170.0;
170.0*;
169.6;
169.2;
168.8;
131.6;
129.9;
74.0;
69.9;
69.1;
66.8;
63.1;
60.1;
58.5;
58.2;
57.3;
55.9;
54.3;
43.4;
39.7;
29.8;
19.9;
19.3;
19.2;
13.7;
12.3;
a pharmaceutically acceptable salt of antibiotic GE23077 factor A2, antibiotic GE23077 factor B1 having the following characteristics:
A) Main FAB mass peak, obtained on a Finnigan TSQ700 triple quadrupole. mass spectrometer using a xenon atom gun, operating at 8 kV, 0.23 mA current, the sample being mixed with glycerol as ionization matrix, corresponding to (M−H)+ at 806 m/z;
B) 1H-NMR spectrum, recorded at 600 MHz in DMSO-d6, exibiting the following signals (in ppm) referenced to the residual peak of DMSO set at 2.5 ppm as internal standard:
the values marked with an asterisk are overlapping of two 1H signals:
9.00;
8.99;
8.94;
8.02;
7.93;
7.88;
7.82;
7.32/7.26;
7.30;
5.90;
5.81;
5.66;
4.99;
4.96;
4.79;
4.65;
4.47;
4.31;
4.31;
4.07;
4.05;
3.88;
3.88*;
3.74;
3.57/3.37;
3.53;
3.47/3.23;
2.49;
1.95;
1.95*;
0.95;
0.94;
0.85;
0.84;
C) 13C-NMR spectrum, recorded at 150 MHz in DMSO-d6, exibiting the following signals (in ppm) referenced to the residual peak of DMSO set at 39.5 ppm as internal standard:
the values marked with an asterisk are overlapping of two 13C signals:
175.5;
172.3;
171.4;
171.3;
170.7;
170.2;
169.9;
169.9*;
169.5;
169.0;
73.9;
70.0;
69.0;
66.8;
63.1;
60.0;
58.4;
58.3;
57.3;
55.9;
54.5:
44.5;
43.5;
39.4;
29.8;
25.4;
22.3;
19.9;
19.2;
19.2;
D) Retention time:
16.56 min, determined by HPLC analysis under the following chromatographic conditions:
Instrument:
HP mod. 1090 DAD detector;
Column:
Beckmann ODS C18, 5 μm 250×4.6 mm;
Elution:
Isocratic 15% Phase B;
Phase A:
2.5 g/l Ammonium formiate:
99:1 v/v Methanol;
Phase B:
2.5 g/l Ammonium formiate:
30:70 v/v Methanol;
Flow rate:
1.5 ml/min;
Detector:
UV 230 nm;
a pharmaceutically acceptable salt of antibiotic GE23077 factor B1, antibiotic GE23077 factor B2 having the following characteristics:
A) Main FAB mass peak, obtained on a Finnigan TSQ700 triple quadrupole mass spectrometer using a xenon atom gun, operating at 8 kV, 0.23 mA current, the sample being mixed with glycerol as ionization matrix, corresponding to (M−H)+ at 806 m/z;
B) Retention time:
22.71 min, determined by HPLC analysis under the following chromatographic conditions:
Instrument:
HP mod. 1090 DAD detector;
Column:
Beckmann ODS C18, 5 μm 250×4.6 mm;
Elution:
Isocratic 15% Phase B;
Phase A:
2.5 g/l Ammonium formiate:
99:1 v/v Methanol;
Phase B:
2.5 g/l Ammonium formiate:
30:70 v/v Methanol;
Flow rate:
1.5 ml/min;
Detector:
UV 230 nm;
C) The 1H-NMR spectrum, recorded after complete conversion of factor B2 into factor B1 was recorded at 600 MHz in DMSO-d6 and exibits the following signals (in ppm) referenced to the residual peak of DMSO set at 2.5 ppm as internal standard:
the values marked with an asterisk are overlapping of two 1H signals:
9.00;
8.99;
8.94;
8.02;
7.93;
7.88;
7.82;
7.32/7.26;
7.30;
5.90;
5.81;
5.66;
4.99;
41.96;
4.79;
4.65;
4.47;
4.31;
4.31;
4.07;
4.05;
3.88;
3.88*;
3.74;
3.57/3.37;
3.53;
3.47/3.23;
2.69;
1.95;
1.95*;
0.95;
0.94;
0.85;
0.84;
D) The 13C-NMR spectrum, recorded after complete conversion of factor B2 into factor B1 was recorded at 150 MHz in DMSO-d6 and exibits the following signals (in ppm) referenced to the residual peak of DMSO set at 39.5 ppm as internal standard:
the values marked with an asterisk are overlapping of two 13C signals:
175.5;
172.3;
171.4;
171.3;
170.7;
170.2;
169.9;
169.9*;
169.5;
169.0;
73.9;
70.0;
69.0;
66.8;
63.1;
60.0;
58.4;
58.3;
57.3;
55.9;
54.5;
44.5;
43.5;
39.4;
29.8;
25.4;
22.3;
19.9;
19.2;
19.2;
and a pharmaceutically acceptable salt of antibiotic GE23077 factor B2.

349 more elements

A method of treating a bacterial infection comprising administering to a patient in need thereof an effective amount of at least one antibiotic selected from the group consisting of antibiotic GE23077 factor A1 having the following characteristics:

A) Main FAB mass peak, obtained on a Finnigan TSQ700 triple quadrupole mass spectrometer using a xenon atom gun, operating at 8 kV, 0.23 mA current, the sample being mixed with glycerol as ionization matrix, corresponding to (M−H)+ at 804 m/z;
B) 1H-NMR spectrum recorded at 600 MHz in DMSO-d6, exibiting the following signals (in ppm) referenced to the residual peak of DMSO set at 2.5 ppm as internal standard:
the values marked with an asterisk are overlapping of two 1H signals:
8.94;
8.93;
8.93*;
8.04;
7.93;
7.88;
7.68;
7.33/7.27;
7.29;
6.34;
5.97;
5.79;
5.68;
5.00;
4.94;
4.82;
4.65;
4.47;
4.37;
4.31;
4.07;
4.05;
3.90;
3.88;
3.74;
3.59/3.49;
3.53,3.42/3.25;
2.50;
1.74;
1.70;
0.96;
0.94;
0.85;
C) 13C-NMR spectrum, recorded at 150 MHz in DMSO-d6, exibiting the following signals (in ppm) referenced to the residual peak of DMSO set at 39.5 ppm as internal standard:
the values marked with an asterisk are overlapping of two 13C signals:
175.6;
171.5;
171.3;
170.7;
170.2;
170.0;
170.0*;
169.6;
169.2;
168.8;
131.6;
12.9.9;
74.0;
69.9;
69.1;
66.8;
63.1;
60.1;
58.5;
58.2;
57.3;
55.9;
54.3;
43.4;
39.7;
29.8;
19.9;
19.3;
19.2;
13.7;
12.3;
D) Retention time:
14.16 min, determined by HPLC analysis under the following chromatographic conditions:
Instrument:
HP mod. 1090 DAD detector;
Column:
Beckmann ODS C18, 5 μm 250×4.6 mm;
Elution:
Isocratic 15% Phase B;
Phase A:
2.5 g/l Ammonium formiate:
99:1 v/v Methanol;
Phase B:
2.5 g/l Ammonium formiate:
30:70 v/v Methanol;
Flow rate:
1.5 ml/min;
Detector:
UV 230 nm;
a pharmaceutically acceptable salt of antibiotic GE23077 factor A1, antibiotic GE23077 factor A2 having the following characteristics:
A) Main FAB mass peak, obtained on a Finnigan TSQ700 triple quadrupole mass spectrometer using a xenon atom gun, operating at 8 kV, 0.23 mA current, the sample being mixed with glycerol as ionization matrix, corresponding to (M−H)+ at 804 m/z;
B) Retention time:
20.90 min, determined by HPLC analysis under the following chromatographic conditions:
Instrument:
HP mod. 1090 DAD detector;
Column:
Beckmann ODS C18, 5 μm 250×4.6 mm;
Elution:
Isocratic 15% Phase B;
Phase A:
2.5 g/l Ammonium formiate:
99:1 v/v Methanol;
Phase B:
2.5 g/l Ammonium formiate:
30:70 v/v Methanol;
Flow rate:
1.5 ml/min;
Detector:
UV 230 nm;
C) 1H-NMR spectrum, recorded after complete conversion of factor A2 into factor A1 was recorded at 600 MHz in DMSO-d6 and exibits the following signals (in ppm) referenced to the residual peak of DMSO set at 2.5 ppm as internal standard:
the values marked with an asterisk are overlapping of two 1H signals:
8.94;
8.93;
8.93*;
8.04;
7.93;
7.88;
7.68;
7.33/7.27;
7.29;
6.34;
5.97;
5.79;
5.68;
5.00;
4.94;
4.82;
4.65;
4.47;
4.37;
4.31;
4.07;
4.05;
3.90;
3.88;
3.74;
3.59/3.49;
3.53,3.42/3.25;
2.50;
1.74;
1.70;
0.96;
0.94;
0.85;
D) 13C-NMR spectrum, recorded after complete conversion of factor A2 into factor A1 was recorded at 150 MHz in DMSO-d6 and exibits the following signals (in ppm) referenced to the residual peak of DMSO set at 39.5 ppm as internal standard:
the values marked with an asterisk are overlapping of two 13C signals:
175.6;
171.5;
171.3;
170.7;
170.2;
170.0;
170.0*;
169.6;
169.2;
168.8;
131.6;
129.9;
74.0;
69.9;
69.1;
66.8;
63.1;
60.1;
58.5;
58.2;
57.3;
55.9;
54.3;
43.4;
39.7;
29.8;
19.9;
15.3;
19.2;
13.7;
12.3;
a pharmaceutically acceptable salt of antibiotic GE23077 factor A2, antibiotic GE23077 factor B1 having the following characteristics:
A) Main FAB mass peak, obtained on a Finnigan TSQ700 triple quadrupole. mass spectrometer using a xenon atom gun, operating at 8 kV, 0.23 mA current, the sample being mixed with glycerol as ionization matrix, corresponding to (M−H)+ at 806 m/z;
B) 1H-NMR spectrum, recorded at 600 MHz in DMSO-d6, exibiting the following signals (in ppm) referenced to the residual peak of DMSO set at 2.5 ppm as internal standard:
the values marked with an asterisk are overlapping of two 1H signals:
9.00;
8.99;
8.94;
8.02;
7.93;
7.88;
7.82;
7.32/7.26;
7.30;
5.90;
5.81;
5.66;
4.99;
4.96;
4.79;
4.65;
4.47;
4.31;
4.31;
4.07;
4.05;
3.88;
3.88*;
3.74;
3.57/3.37;
3.53;
3.47/3.23;
2.49;
1.95;
1.95*;
0.95;
0.94;
0.85;
0.84;
C) 13C-NMR spectrum, recorded at 150 MHz in DMSO-d6, exibiting the following signals (in ppm) referenced to the residual peak of DMSO set at 39.5 ppm as internal standard:
the values marked with an asterisk are overlapping of two 13C signals:
175.5;
172.3;
171.4;
171.3;
170.7;
170.2;
169.9;
169.9*;
169.5;
169.0;
73.9;
70.0;
69.0;
66.8;
63.1;
60.0;
58.4;
58.3;
57.3;
55.9;
54.5:
44.5;
43.5;
39.4;
29.8;
25.4;
22.3;
19.9;
19.2;
19.2;
D) Retention time:
16.56 min, determined by HPLC analysis under the following chromatographic conditions:
Instrument:
HP mod. 1090 DAD detector;
Column:
Beckmann ODS C18, 5 μm 250×4.6 mm;
Elution:
Isocratic 15% Phase B;
Phase A:
2.5 g/l Ammonium formiate:
99:1 v/v Methanol;
Phase B:
2.5 g/l Ammonium formiate:
30:70 v/v Methanol;
Flow rate:
1.5 ml/min;
Detector:
UV 230 nm;
a pharmaceutically acceptable salt of antibiotic GE23077 factor B1, antibiotic GE23077 factor B2 having the following characteristics:
A) Main FAB mass peak, obtained on a Finnigan TSQ700 triple quadrupole miss spectrometer using a xenon atom gun, operating at 8 kV, 0.23 mA current, the sample being mixed with glycerol as ionization matrix, corresponding to (M−H)+ at 806 m/z;
B) Retention time:
22.71 min, determined by HPLC analysis under the following chromatographic conditions:
Instrument:
HP mod. 1090 DAD detector;
Column:
Beckmann ODS C18, 5 μm 250×4.6 mm;
Elution:
Isocratic 15% Phase B;
Phase A:
2.5 g/l Ammonium formiate:
99:1 v/v Methanol;
Phase B:
2.5 g/l Ammonium formiate:
30:70 v/v Methanol;
Flow rate:
1.5 ml/min;
Detector:
UV 230 nm;
C) The 1H-NMR spectrum, recorded after complete conversion of factor B2 into factor B1 was recorded at 600 MHz in DMSO-d6 and exibits the following signals (in ppm) referenced to the residual peak of DMSO set at 2.5 ppm as internal standard:
the values marked with an asterisk are overlapping of two 1H signals:
9.00;
8.99;
8.94;
8.02;
7.93;
7.88;
7.82;
7.32/7.26;
7.30;
5.90;
5.81;
5.66;
4.99;
4.96;
4.79;
4.65;
4.47;
4.31;
4.31;
4.07;
4.05;
3.88;
3.88*;
3.74;
3.57/3.37;
3.53;
3.47/3.23;
2.49;
1.95;
1.95*;
0.95;
0.94;
0.85;
0.84;
D) The 13C-NMR spectrum, recorded after complete conversion of factor B2 into factor B1 was recorded at 150 MHz in DMSO-d6 and exibits the following signals (in ppm) referenced to the residual peak of DMSO set at 39.5 ppm as internal standard:
the values marked with an asterisk are overlapping of two 13C signals:
175.5;
172.3;
171.4;
171.3;
170.7;
170.2;
169.9;
169.9*;
169.5;
169.0;
73.9;
70.0;
69.0;
66.8;
63.1;
60.0;
58.4;
58.3;
57.3;
55.9;
54.5;
44.5;
43.5;
39.4;
29.8;
25.4;
22.3;
19.9;
19.2;
19.2;
and a pharmaceutically acceptable salt of antibiotic GE23077 factor B2.

349 more elements

Dependencies are inferred from the claim text.

Facts

Application: 09/986,540Filed 9 Nov 2001
Priority: EP 001266184 Dec 2000
Published: US 2002/0115597 A122 Aug 2002
Granted: 1 Jul 2003
Term ends: Not estimatedThe source records don’t support an estimate.

Classification9 codes

C07K 7/56
With at least one abnormal peptide link in the ring: the cyclisation not occurring through 2,4-diamino-butanoic acid
A61P 31/00
Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
A61P 31/04
Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics: antibacterial agents
A61K 38/00
Medicinal preparations containing peptides

Family

US 2002/0115597 A1Pre-grant publication · published 22 Aug 2002
US 6,586,393 B2This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

Facts

Application

09/986,540Filed 9 Nov 2001

Priority

EP 001266184 Dec 2000

Published

US 2002/0115597 A122 Aug 2002

Granted

1 Jul 2003

Term ends

Not estimatedThe source records don’t support an estimate.

Classification9 codes

C07K 7/56
With at least one abnormal peptide link in the ring: the cyclisation not occurring through 2,4-diamino-butanoic acid
A61P 31/00
Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
A61P 31/04
Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics: antibacterial agents
A61K 38/00
Medicinal preparations containing peptides