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Claims for Patent: 4,970,198

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Claims for Patent: 4,970,198

Title: Antitumor antibiotics (LL-E33288 complex)
Abstract:Antibacterial and antitumor agents designated LL-E33288 complex and their production by new strains of Micromonospora echinospora ssp. calichensis NNRL-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)
Application Number:07/009,321
Patent Claims: 1. A LL-E33288.alpha.-Br complex prepared by extracting LL-E33288.alpha..sub.1 -Br, LL-E33288.alpha..sub.2 -Br, LL-E33288.alpha..sub.3 -Br, LL-E33288.alpha..sub.4 -Br, LL-E33288.beta..sub.1 -Br, LL-E33288.beta..sub.2 -Br and LL-E33288.gamma..sub.1 -Br from the fermentation broth of Micromonospora echinospora NRRL-15839, NRRL-15975 or NRRL-18149 with an organic solvent and

purifying the extracted mixture by selective precipitation from lower hydrocarbons,

separating LL-E33288.alpha..sub.1 -Br, LL-E33288.alpha..sub.2 -Br, LL-E33288.alpha..sub.3 -Br and LL-E33288.alpha..sub.4 -Br from LL-E33288.beta..sub.1 -Br, LL-E33288.beta..sub.2 -Br and LL-E33288.gamma..sub.1 -Br by a series of column chromatography and

assaying and analyzing the LL-E33288.alpha.-Br complex by thin layer chromatography.

2. A compound LL-E33288a.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##

3. A compound LL-E33288a.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##

4. A compound 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.].sub.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 ##STR7##

5. A compound 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 prepared by extracting LL-E33288.alpha..sub.1 -Br, LL-E33288.alpha..sub.2 -Br, LL-E33288.alpha..sub.3 -Br, LL-E33288.alpha..sub.4 -Br, LL-E33288.beta..sub.1 -Br, LL-E33288.beta..sub.2 -Br and LL-E33288.gamma..sub.1 -Br from the fermentation broth of Micromonospora echinospora NRRL-15839, NRRL-15975 or NRRL-18149 with an organic solvent and

purifying the extracted mixture by selective precipitation from lower hydrocarbons,

separating LL-E33288.beta..sub.1 -Br, LL-E33288.beta..sub.2 -Br and LL-E33288.gamma..sub.1 -Br from LL-E33288.alpha..sub.1 -Br, LL-E33288.alpha..sub.2 -Br, LL-E33288.alpha..sub.3 -Br, and LL-E33288.alpha..sub.4 -Br by a series of column chromatography,

assaying, analyzing and working up the LL-E33288.beta.-Br complex containing LL-E33288.gamma..sub.1 -Br and

separating LL-E33288.beta..sub.2 -Br from the LL-E33288.beta.-Br complex containing LL-E33288.gamma..sub.1 -Br by column chromatography.

6. A compound 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##

7. A compound 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 0.1 M 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; and

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

(b) having a molecular weight: 1145 prepared by extracting LL-E33288.alpha..sub.1 -I, LL-E33288.alpha..sub.2 -1, LL-E33288.alpha..sub.3 -I, LL-E33288.beta..sub.1 -I, LL-E33288.beta..sub.2 -I, LL-E33288.gamma..sub.1 -I and LL-E33288.delta..sub.1 -I from the fermentation broth of Micromonospora echinospora NRRL-15839, NRRL-15975 and NRRL-18149 with an organic solvent,

purifying the extracted mixture by selective precipitation from lower hydrocarbons,

separating LL-E33288.alpha..sub.1 -I from a complex including LL-E33288.alpha..sub.2 -I, LL-E33288.alpha..sub.3 -I, LL-E33288.beta..sub.1 -I, LL-E33288.beta..sub.2 -I, LL-E33288.gamma..sub.1 -I and LL-E33288.delta..sub.1 -I by a series of column chromatography.

8. A compound 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.sub.9 ;

(i) and having the structure ##STR9##

9. A compound LL-E33288.alpha..sub.3 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;

(h) and having the structure ##STR10##

10. A compound 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;

(g) having a molecular weight: 1381;

(h) and having the structure ##STR11##

11. A compound 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 prepared by

extracting LL-E33288.alpha..sub.1 -I, LL-E33288.alpha..sub.2 -I, LL-E33288.alpha..sub.3 -I, LL-E33288.beta..sub.1 -I, LL-E33288.beta..sub.2 -I, LL-E33288.gamma..sub.1 -I and LL-E33288.delta..sub.1 -I from the fermentation broth of Micromonospora echinospora NRRL-15839, NRRL-15975 and NRRL-18149 with an organic solvent,

purifying the extracted mixture by selective precipitation from lower hydrocarbons; and

separating LL-E33288.beta..sub.2 -I from LL-E33288.alpha..sub.1 -I, LL-E33288.alpha..sub.2 -I, LL-E33288.alpha..sub.3 -I, LL-E33288.beta..sub.1 -I, LL-E33288.gamma..sub.1 -I and LL-E33288.delta..sub.1 -I by a series of column chromatography.

12. A compound LL-E33288.gamma..sub.1 -I

(a) having the following R.sub.f values in the indicated solvent system 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:

(j) and having the structure ##STR12##

13. A compound LL-E33288.delta..sub.1 -I

(a) having the following R.sub.f values in the indicated solvent system 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:

(f) and having the structure ##STR13##

14. A method of treating bacterial infections in warm-blooded animals which comprises administering to said animals an antibacterially effective amount of a compound selected from the group consisting of LL-E33288.alpha..sub.[1] -Br complex; LL-E33288.alpha..sub.2 -Br; LL-E33288.alpha..sub.2 -I; LL-E33288.alpha..sub.3 -Br; LL-E33288.alpha..sub.3 -I; LL-E33288.beta..sub.1 -Br; LL-E33288.beta..sub.1 -I; LL-E33288.beta..sub.2 -Br; LL-E33288.beta..sub.2 -I; LL-E33288.gamma..sub.1 -Br; LL-E33288.gamma..sub.1 -I; and LL-E33288.delta..sub.1 -I.

15. A method of treating the growth of tumors in a mammal comprising administering to said mammal an effective amount of a compound selected from the group consisting of LL-E33288.alpha..sub.[1] -Br complex LL-E33288.alpha..sub.2 -Br; LL-E33288.alpha..sub.2 -I; LL-E33288.alpha..sub.3 -Br; LL-E33288.alpha..sub.3 -I; LL-E33288.beta..sub.1 -Br; LL-E33288.beta..sub.1 -I; LL-E32288.beta..sub.2 -Br; LL-E33288.beta..sub.2 -I; LL-E33288.gamma..sub.1 -Br; LL-E33288.gamma..sub.1 -I; and LL-E33288.delta..sub.1 -I.

16. A method of regressing leukemia in a mammal comprising administering to said mammal an effective amount of a compound selected from the group consisting of LL-E33288.alpha.-Br complex; LL-E33288.alpha..sub.2 -Br; LL-E33288.alpha..sub.2 -I; LL-E33288.alpha..sub.3 -Br; LL-E33288.alpha..sub.3 -I; LL-E33288.beta..sub.1 -Br; LL-E33288.beta..sub.1 -I; LL-E33288.beta..sub.2 -Br; LL-E33288.beta..sub.2 -I; LL-E33288.gamma..sub.1 -Br; LL-E33288.gamma..sub.1 -I; and LL-E33288.delta..sub.1 -I.
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