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Details for Patent: 5,108,912

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Details for Patent: 5,108,912

Title: Antitumor antibiotics (LL-E33288 complex)
Abstract:Antibacterial and antitumor agents designated LL-E33288 complex and their production by new strains of Micromonospora echinospora spp. calichensis NRRL-15839, NRRL-15975 and NRRL-18149, are disclosed.
Inventor(s): Lee; May D. (Monsey, NY), Greenstein; Michael (Suffern, NY), Labeda; David P. (Peoria, IL), Fantini; Amedeo A. (New City, NY)
Assignee: American Cyanamid Company (Stamford, CT)
Filing Date:Sep 10, 1990
Application Number:07/560,415
Claims:1. A process for producing antibiotics LL-E33288.alpha..sub.1 -Br having the following R.sub.f values in the indicated solvent systems on TLC on silica gel sheets:

a) ethyl acetate saturated with 0.1M aqueous potassium dihydrogen phosphate, R.sub.f =0.67;

b) 3% isopropanol in ethyl acetate saturated with 0.1M aqueous potassium dihydrogen phosphate, R.sub.f =0.80; and

c) ethyl acetate: methanol (95:5), R.sub.f =0.79;

LL-E33288.alpha..sub.2 -Br having the following R.sub.f values in the indicated solvent systems on TLC on silica gel sheets:

a) ethyl acetate saturated with 0.1M aqueous potassium dihydrogen phosphate, R.sub.f =0.61;

b) 3% isopropanol in ethyl acetate saturated with 0.1M aqueous potassium dihydrogen phosphate, R.sub.f =0.75; and

c) ethyl acetate: methanol (95:5), R.sub.f =0.73; and having the following structure: ##STR5## LL-E33288.alpha..sub.3 -Br having the following R.sub.f values in the indicated solvent systems on TLC on silica gel sheets:

a) ethyl acetate saturated with 0.1M aqueous potassium dihydrogen phosphate, R.sub.f =0.55;

b) 3% isopropanol in ethyl acetate saturated with 0.1M aqueous potassium dihydrogen phosphate, R.sub.f =0.69; and

c) ethyl acetate: methanol (95:5), R.sub.f =0.61; and having the following structure: ##STR6## LL-E33288.alpha..sub.4 -Br having the following R.sub.f values in the indicated solvent systems on TLC on silica gel sheets:

a) ethyl acetate saturated with 0.1M aqueous potassium dihydrogen phosphate, R.sub.f =0.49;

b) 3% isopropanol in ethyl acetate saturated with 0.1M aqueous potassium dihydrogen phosphate, R.sub.f =0.64; and

c) ethyl acetate: methanol (95:5), R.sub.f =0.54;

LL-E33288.beta..sub.1 -Br

a) having an approximate elemental analysis: C 48.6; H 5.6; N 2.9; S 9.1 and Br 5.5;

b) having a melting point: 146.degree.-150.degree. C. (dec.);

c) having a specific rotation: [.alpha.]D.sup.26 =-49.degree..+-.10.degree. (0.1%, ethanol);

d) having ultraviolet absorption spectra as shown in FIG. I of the drawings;

e) having an infrared absorption spectrum as shown in FIG. II of the drawings;

f) having a proton magnetic resonance spectrum as shown in FIG. III of the drawings;

g) having a carbon-13 magnetic resonance spectrum as shown in FIG. IV of the drawings with significant peaks at:

h) having the following R.sub.f values in the indicated solvent systems on TLC on silica gel sheets:

(i) ethyl acetate saturated with 0.1M potassium dihydrogen phosphate, R.sub.f =0.24;

(ii) 3% isopropanol in ethyl acetate saturated with 0.1M aqueous potassium dihydrogen phosphate, R.sub.f =0.35;

(iii) ethyl acetate: methanol (95:5), R.sub.f =0.36.

i) having a molecular weight: 1333/1335, respectively for .sup.79 Br/.sup.81 Br;

j) having a molecular formula: C.sub.56 H.sub.76 N.sub.3 O.sub.21 S.sub.4 Br;

k) and having the structure ##STR7## LL-E33288.beta..sub.2 -Br having the following R.sub.f values in the indicated solvent systems on TLC on silica gel sheets:

a) ethyl acetate saturated with 0.1M aqueous potassium dihydrogen phosphate, R.sub.f =0.32;

b) 3% isopropanol in ethyl acetate saturated with 0.1M aqueous potassium dihydrogen phosphate, R.sub.f =0.41; and

c) ethyl acetate: methanol (95:5), R.sub.f =0.45; and LL-E33288.gamma..sub.1 -Br

a) having ultraviolet absorption spectra as shown in FIG. V of the drawings;

b) having an infrared absorption spectrum as shown in FIG. VI of the drawings;

c) having a proton magnetic resonance spectrum as shown in FIG. VII of the drawings; and

d) having the following R.sub.f values in the indicated solvent systems on TLC on silica gel sheets:

(i) ethyl acetate saturated with 0.1M aqueous potassium dihydrogen phosphate, R.sub.f =0.18;

(ii) 3% isopropanol in ethyl acetate saturated with 0.1M aqueous potassium dihydrogen phosphate, R.sub.f =0.28;

(iii) ethyl acetate: methanol (95:5), R.sub.f =0.27,

e) having a carbon-13 magnetic resonance spectrum as shown in FIG. VIII of the drawings with significant peaks at:

f) having a molecular formula: C.sub.55 H.sub.74 N.sub.3 O.sub.21 S.sub.4 Br

g) having a molecular weight: 1319/1321, respectively for .sup.79 Br/.sup.81 Br;

h) and having the structure ##STR8## and which comprises aerobically fermenting the organism Micromonospora echinospora ssp. calichensis NRRL-15839 or mutants thereof including NRRL-15975 and 18149 in a liquid medium containing assimilable sources of carbon, nitrogen, bromine and inorganic salts, until substantial antibiotic activity is imparted to said medium and then recovering the antibiotics therefrom.

2. A process for producing antibiotics LL-E33288.alpha..sub.1 -Br having the following R.sub.f values in the indicated solvent systems on TLC on silica gel sheets:

a) ethyl acetate saturated with 0.1M aqueous potassium dihydrogen phosphate, R.sub.f =0.67;

b) 3% isopropanol in ethyl acetate saturated with 0.1M aqueous potassium dihydrogen phosphate, R.sub.f =0.80; and

c) ethyl acetate: methanol (95:5), R.sub.f =0.79;

LL-E33288.alpha..sub.2 -Br having the following R.sub.f values in the indicated solvent systems on TLC on silica gel sheets:

a) ethyl acetate saturated with 0.1M aqueous potassium dihydrogen phosphate, R.sub.f =0.61;

b) 3% isopropanol in ethyl acetate saturated with 0.1M aqueous potassium dihydrogen phosphate, R.sub.f =0.75; and

c) ethyl acetate: methanol (95:5), R.sub.f =0.73; and having the following structure: ##STR9## LL-E33288.alpha..sub.3 -Br having the following R.sub.f values in the indicated solvent systems on TLC on silica gel sheets:

a) ethyl acetate saturated with 0.1M aqueous potassium dihydrogen phosphate, R.sub.f =0.55;

b) 3% isopropanol in ethyl acetate saturated with 0.1M aqueous potassium dihydrogen phosphate, R.sub.f =0.69; and

c) ethyl acetate:methanol (95:5), R.sub.f =0.61; and having the following structure: ##STR10## LL-E33288.alpha..sub.4 -Br having the following R.sub.f values in the indicated solvent systems on TLC on silica gel sheets:

a) ethyl acetate saturated with 0.1M aqueous potassium dihydrogen phosphate, R.sub.f =0.49;

b) 3% isopropanol in ethyl acetate saturated with 0.1M aqueous potassium dihydrogen phosphate, R.sub.f =0.64; and

c) ethyl acetate:methanol (95:5), R.sub.f =0.54;

LL-E33288.beta..sub.1 -Br

a) having an approximate elemental analysis: 48.6; H 5.6; N 2.9; S 9.1 and Br 5.5;

b) having a melting point: 146.degree.-150.degree. C. (dec.);

c) having a specific rotation: [.alpha.]D.sup.26 =-49.degree..+-.10.degree. (0.1%, ethanol);

d) having ultraviolet absorption spectra as shown in FIG. I of the drawings;

e) having an infrared absorption spectrum as shown in FIG. II of the drawings;

f) having a proton magnetic resonance spectrum as shown in FIG. III of the drawings;

g) having a carbon-13 magnetic resonance spectrum as shown in FIG. IV of the drawings with significant peaks at:

h) having the following R.sub.f values in the indicated solvent systems on TLC on silica gel sheets:

(i) ethyl acetate saturated with 0.1M aqueous potassium dihydrogen phosphate, R.sub.f =0.24;

(ii) 3% isopropanol in ethyl acetate saturated with 0.1M aqueous potassium dihydrogen phosphate, R.sub.f =0.35;

(iii) ethyl acetate:methanol (95:5), R.sub.f =0.36.

i) having a molecular weight: 1333/1335, respectively for .sup.79 Br/.sup.81 Br;

j) having a molecular formula: C.sub.56 H.sub.76 N.sub.3 O.sub.21 S.sub.4 Br;

k) and having the structure ##STR11## LL-E33288.beta..sub.2 -Br having the following R.sub.f values in the indicated solvent systems on TLC on silica gel sheets:

a) ethyl acetate saturated with 0.1M aqueous potassium dihydrogen phosphate, R.sub.f =0.32;

b) 3% isopropanol in ethyl acetate saturated with 0.1M aqueous potassium dihydrogen phosphate, R.sub.f =0.41; and

c) ethyl acetate:methanol (95:5), R.sub.f =0.45, and LL-E33288.gamma..sub.1 -Br

a) having ultraviolet absorption spectra as shown in FIG. V of the drawings;

b) having an infrared absorption spectrum as shown in FIG. VI of the drawings;

c) having a proton magnetic resonance spectrum as shown in FIG. VII of the drawings; and

d) having the following R.sub.f values in the indicated solvent systems on TLC on silica gel sheets:

(i) ethyl acetate saturated with 0.1M aqueous potassium dihydrogen phosphate, R.sub.f =0.18;

(ii) 3% isopropanol in ethyl acetate saturated with 0.1M aqueous potassium dihydrogen phosphate, R.sub.f =0.28;

(iii) ethyl acetate:methanol (95:5), R.sub.f =0.27,

e) having a carbon-13 magnetic resonance spectrum as shown in FIG. VIII of the drawings with significant peaks at:

f) having a molecular formula: C.sub.55 H.sub.74 N.sub.3 O.sub.21 S.sub.4 Br

g) having a molecular weight: 1319/1321, respectively for .sup.79 Br/.sup.81 Br;

h) and having the structure ##STR12## which comprises aerobically fermenting a liquid medium containing assimilable sources of carbon, nitrogen, bromine and inorganic salts; which medium has been inoculated with a viable culture of the organism Micromonospora echinospora ssp. calichensis NRRL-15839 or mutants thereof including NRRL-15975 and 18149 maintaining said fermentation culture at a temperature of about 24.degree.-32.degree. C. for a period of approximately 90-200 hours, harvesting the mash and extracting the antibiotics.

3. A process for producing antibiotics LL-E33288.alpha..sub.1 -I

a) having the following R.sub.f values in the indicated solvent systems on TLC on silica gel sheets:

(i) ethyl acetate saturated with 0.1M aqueous potassium dihydrogen phosphate, R.sub.f =0.67;

(ii) 3% isopropanol in ethyl acetate saturated with 0.1M aqueous potassium dihydrogen phosphate, R.sub.f =0.80;

(iii) ethyl acetate:methanol (95:5), R.sub.f =0.80;

b) having a molecular weight: 1145.

LL-E33288.alpha..sub.2 -I

a) having the following R.sub.f values in the indicated solvent systems on TLC on silica gel sheets:

(i) ethyl acetate saturated with 0.1M aqueous potassium dihydrogen phosphate, R.sub.f =0.61;

(ii) 3% isopropanol in ethyl acetate saturated with 0.1M aqueous potassium dihydrogen phosphate, R.sub.f =0.75; and

(iii) ethyl acetate:methanol (95:5), R.sub.f =0.73;

b) containing only the following elements: C, H, N, O, S and I;

c) having a molecular weight: 1207;

d) having ultraviolet absorption spectra as shown in FIG. IX of the drawings;

e) having an infrared absorption spectrum as shown in FIG. X of the drawings;

f) having a proton magnetic resonance spectrum as shown in FIG. XI of the drawings;

g) having a carbon-13 magnetic resonance spectrum as shown in FIG. XII of the drawings with significant peaks at:

h) having a molecular formula: C.sub.48 H.sub.62 N.sub.3 O.sub.17 S.sub.4 I;

LL-E33288.alpha..sub.3 -I

a) having the following R.sub.f values in the indicated solvent systems on TLC on silica gel sheets:

i) ethyl acetate saturated with 0.1M aqueous potassium dihydrogen phosphate, R.sub.f =0.55;

ii) 3% isopropanol in ethyl acetate saturated with 0.1M aqueous potassium dihydrogen phosphate, R.sub.f =0.69; and

iii) ethyl acetate:methanol (95:5), R.sub.f =0.61;

b) having a molecular weight:1210;

c) having ultraviolet absorption spectra as shown in FIG. XIII of the drawings;

d) having an infrared absorption spectrum as shown in FIG. XIV of the drawings;

e) having a proton magnetic resonance spectrum as shown in FIG. XV of the drawings;

f) having a carbon-13 magnetic resonance spectrum as shown in FIG. XVI of the drawings with significant peaks at:

g) having a molecular formula: C.sub.47 H.sub.59 N.sub.2 O.sub.19 S.sub.4 I; LL-E33288.beta..sub.1 -I

a) having the following R.sub.f values in the indicated solvent systems on TLC on silica gel sheets:

(i) ethyl acetate saturated with 0.1M aqueous potassium dihydrogen phosphate, R.sub.f =0.24;

(ii) 3% isopropanol in ethyl acetate saturated with 0.1M aqueous potassium dihydrogen phosphate, R.sub.f =0.35; and

(iii) ethyl acetate:methanol (95:5), R.sub.f =0.36;

b) having ultraviolet absorption spectra as shown in FIG. XVII of the drawings;

c) having an infrared absorption spectrum as shown in FIG. XVIII of the drawings;

d) having a proton magnetic resonance spectrum as shown in FIG. XIX of the drawings;

e) having a carbon-13 magnetic resonance spectrum as shown in FIG. XX of the drawings with significant peaks at:

f) having a molecular formula: C.sub.56 H.sub.76 N.sub.3 O.sub.21 S.sub.4 I; and

g) having a molecular weight: 1381;

LL-E33288.beta..sub.2 -I having the following R.sub.f values in the indicated solvent systems on TLC on silica gel sheets:

a) ethyl acetate saturated with 0.1M aqueous potassium dihydrogen phosphate, R.sub.f =0.32;

b) 3% isopropanol in ethyl acetate saturated with 0.1M aqueous potassium dihydrogen phosphate, R.sub.f =0.41; and

c) ethyl acetate:methanol (95:5), R.sub.f =0.45;

LL-E33288.gamma..sub.1 -I

a) having the following R.sub.f values in the indicated solvent systems on TLC on silica gel sheets:

(i) ethyl acetate saturated with 0.1M aqueous potassium dihydrogen phosphate, R.sub.f =0.18;

(ii) 3% isopropanol in ethyl acetate saturated with 0.1M aqueous potassium dihydrogen phosphate, R.sub.f =0.28; and

(iii) ethyl acetate:methanol (95:5), R.sub.f =0.27;

b) containing only the following elements: C, H, N, O, S and I;

c) having an approximate elemental analysis: C 48.8; H 5.4; N 2.8; S 9.0; and I 9.2;

d) having a molecular weight: 1367;

e) having a molecular formula: C.sub.55 H.sub.74 N.sub.3 O.sub.21 S.sub.4 I;

f) having an ultraviolet absorption spectra as shown in FIG. XXI of the drawings;

g) having an infrared absorption spectrum as shown in FIG. XXII of the drawings;

h) having a proton magnetic resonance spectrum as shown in FIG. XXIII of the drawings; and

i) having a carbon-13 magnetic resonance spectrum as shown in FIG. XXIV of the drawings, significant peaks as listed below:

and LL-E33288.delta.-I

a) having the following R.sub.f values in the indicated solvent systems on TLC on silica gel sheets:

i) ethyl acetate saturated with 0.1M aqueous potassium dihydrogen phosphate, R.sub.f =0.11; and

ii) 3% isopropanol in ethyl acetate saturated with 0.1M aqueous potassium dihydrogen phosphate, R.sub.f =0.19;

b) having ultraviolet absorption spectra as shown in FIG. XXV of the drawings;

c) having an infrared absorption spectrum as shown in FIG. XXVI of the drawings;

d) having a proton magnetic resonance spectrum as shown in FIG. XXVII of the drawings; and

e) having a carbon-13 magnetic resonance spectrum as shown in FIG. XXVIII of the drawings, significant peaks as listed below:

which comprises aerobically fermenting the organism Micromonospora echinospora ssp. calichensis NRRL-15839 or mutants thereof including NRRL-15975 and 18149, in a liquid medium containing assimilable sources of carbon, nitrogen, iodine and inorganic salts, until substantial antibiotic activity is imparted to said medium and then recovering the antibiotics therefrom.

4. A process for producing antibiotics LL-E33288.alpha..sub.1 -I

a) having the following R.sub.f values in the indicated solvent systems on TLC on silica gel sheets:

(i) ethyl acetate saturated with 0.1M aqueous potassium dihydrogen phosphate, R.sub.f =0.67;

(ii) 3% isopropanol in ethyl acetate saturated with 0.1M aqueous potassium dihydrogen phosphate, R.sub.f =0.80;

(iii) ethyl acetate:methanol (95:5), R.sub.f =0.80;

b) having a molecular weight: 1145;

LL-E33288.alpha..sub.2 -I

a) having the following R.sub.f values in the indicated solvent systems on TLC on silica gel sheets:

(i) ethyl acetate saturated with 0.1M aqueous potassium dihydrogen phosphate, R.sub.f =0.61;

(ii) 3% isopropanol in ethyl acetate saturated with 0.1M aqueous potassium dihydrogen phosphate, R.sub.f =0.75; and

(iii) ethyl acetate:methanol (95:5), R.sub.f =0.73;

b) containing only the following elements: C, H, N, O, S and I;

c) having a molecular weight: 1207;

d) having ultraviolet absorption spectra as shown in FIG. IX of the drawings;

e) having an infrared absorption spectrum as shown in FIG. X of the drawings;

f) having a proton magnetic resonance spectrum as shown in FIG. XI of the drawings;

g) having a carbon-13 magnetic resonance spectrum as shown in FIG. XII of the drawings with significant peaks at:

h) having a molecular formula: C.sub.48 H.sub.62 N.sub.3 O.sub.17 S.sub.4 I;

LL-E33288.alpha..sub.3 -I

a) having the following R.sub.f values in the indicated solvent systems on TLC on silica gel sheets:

i) ethyl acetate saturated with 0.1M aqueous potassium dihydrogen phosphate, R.sub.f =0.55;

ii) 3% isopropanol in ethyl acetate saturated with 0.1M aqueous potassium dihydrogen phosphate, R.sub.f =0.69; and

iii) ethyl acetate:methanol (95:5), R.sub.f =0.61;

b) having a molecular weight: 1210;

c) having ultraviolet absorption spectra as shown in FIG. XIII of the drawings;

d) having an infrared absorption spectrum as shown in FIG. XIV of the drawings;

e) having a proton magnetic resonance spectrum as shown in FIG. XV of the drawings;

f) having a carbon-13 magnetic resonance spectrum as shown in FIG. XVI of the drawings with significant peaks at:

g) having a molecular formula: C.sub.47 H.sub.59 N.sub.2 O.sub.19 S.sub.4 I;

LL-E33288.beta..sub.1 -I

a) having the following R.sub.f values in the indicated solvent systems on TLC on silica gel sheets:

(i) ethyl acetate saturated with 0.1M aqueous potassium dihydrogen phosphate, R.sub.f =0.24;

(ii) 3% isopropanol in ethyl acetate saturated with 0.1M aqueous potassium dihydrogen phosphate, R.sub.f =0.35; and

(iii) ethyl acetate:methanol (95:5), R.sub.f =0.36;

b) having ultraviolet absorption spectra as shown in FIG. XVII of the drawings;

c) having an infrared absorption spectrum as shown in FIG. XVIII of the drawings;

d) having a proton magnetic resonance spectrum as shown in FIG. XIX of the drawings;

e) having a carbon-13 magnetic resonance spectrum as shown in FIG. XX of the drawings with significant peaks at:

f) having a molecular formula: C.sub.56 H.sub.76 N.sub.3 O.sub.21 S.sub.4 I; and

g) having a molecular weight: 1381;

LL-E33288.beta..sub.2 -I having the following R.sub.f values in the indicated solvent systems on TLC on silica gel sheets:

a) ethyl acetate saturated with 0.1M aqueous potassium dihydrogen phosphate, R.sub.f =0.32;

b) 3% isopropanol in ethyl acetate saturated with 0.1M aqueous potassium dihydrogen phosphate, R.sub.f =0.41; and

c) ethyl acetate:methanol (95:5), R.sub.f =0.45;

LL-E33288.gamma..sub.1 -I

a) having the following R.sub.f values in the indicated solvent systems on TLC on silica gel sheets:

(i) ethyl acetate saturated with 0.1M aqueous potassium dihydrogen phosphate, R.sub.f =0.18;

(ii) 3% isopropanol in ethyl acetate saturated with 0.1M aqueous potassium dihydrogen phosphate, R.sub.f =0.28; and

(iii) ethyl acetate:methanol (95:5), R.sub.f =0.27;

b) containing only the following elements: C, H, N, O, S and I;

c) having an approximate elemental analysis: C 48.8; H 5.4; N 2.8; S 9.0; and I 9.2;

d) having a molecular weight: 1367;

e) having a molecular formula: C.sub.55 H.sub.74 N.sub.3 O.sub.21 S.sub.4 I;

f) having an ultraviolet absorption spectra as shown in FIG. XXI of the drawings;

g) having an infrared absorption spectrum as shown in FIG. XXII of the drawings;

h) having a proton magnetic resonance spectrum as shown in FIG. XXIII of the drawings; and

i) having a carbon-13 magnetic resonance spectrum as shown in FIG. XXIV of the drawings, significant peaks as listed below:

LL-E33288.delta.-I

a) having the following R.sub.f values in the indicated solvent systems on TLC on silica gel sheets;

(i) ethyl acetate saturated with 0.1M aqueous potassium dihydrogen phosphate, R.sub.f =0.11; and

(ii) 3% isopropanol in ethyl acetate saturated with 0.1M aqueous potassium dihydrogen phosphate, R.sub.f =0.19;

b) having ultraviolet absorption spectra as shown in FIG. XXV of the drawings;

c) having an infrared absorption spectrum as shown in FIG. XXVI of the drawings;

d) having a proton magnetic resonance spectrum as shown in FIG. XXVII of the drawings; and

e) having a carbon-13 magnetic resonance spectrum as shown in FIG. XXVIII of the drawings, significant peaks as listed below:

which comprises aerobically fermenting a liquid medium containing assimilable sources of carbon, nitrogen, iodine and inorganic salts, which medium has been inoculated with a viable culture of the microorganism Micromonospora echinospora ssp. calichensis NRRL-15839 or mutants thereof including NRRL-15975 and 18149, maintaining said fermentation culture at a temperature of about 24.degree.-32.degree. C. for a period of approximately 90-200 hours, harvesting the mash and extracting the antibiotics.

5. A biologically pure culture containing the microorganism Micromonospora echinospora ssp. calichensis NRRL-15839, said culture being capable of producing the LL-E33288 complex in recoverable quantity upon aerobic fermentation in an aqueous medium containing assimilable sources of carbon nitrogen, inorganic salts, and either iodine or bromine or both.

6. A biologically pure culture containing the microorganism Micromonospora echinospora ssp. calichensis NRRL-15975, said culture being capable of producing the LL-E33288 complex in recoverable quantity upon aerobic fermentation in an aqueous medium containing assimilable sources of carbon nitrogen, inorganic salts, and either iodine or bromine or both.

7. A biologically pure culture containing the microorganism Micromonospora echinospora ssp. calichensis NRRL-18149, said culture being capable of producing the LL-E33288 complex in recoverable quantity upon aerobic fermentation in an aqueous medium containing assimilable sources of carbon nitrogen, inorganic salts, and either iodine or bromine or both.
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