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US 4,552,867 AGranted
Antibiotic LL-BO1208.alpha. and LL-BO1208.beta., process of preparation, pharmaceutical composition and method of use
AssigneeAmerican Cyanamid Company
InventorsJohn H. E. J. Martin, Jane P. Kirby, Donald B. Borders, Amedeo A. Fantini, Raymond T. Testa
Life of this patent
Estimating the term…
Abstract
This invention relates to two new antibacterial and anti-tumor agents designated LL-BO1208.alpha. and LL-BO1208.beta. produced during microbiological fermentation, under controlled conditions, using the novel microorganism Streptoverticillium stramineum and mutants thereof.
Claims6
The antibiotic LL-BO1208.alpha. wherein the substantially pure form:
- (a) exhibits the following significant carbon-13 nuclear magnetic resonance chemical shifts in parts per million relative to the absorption of tetramethylsilane:
- ______________________________________ 182.3 169.0 126.7 71.5 60.9 38.7 178.8 166.6 119.1 70.4 60.2 37.9 178.6 165.9 113.4 69.6 58.3 34.2 177.5 164.7 99.4 69.2 53.8 34.0 173.3 159.2 98.6 68.5 48.7 24.4 173.1 153.7 76.8 68.3 48.3 20.1 172.7 149.4 75.6 66.0 43.9 16.0 170.4 138.2 74.8 62.2 41.4 13.1 170.2 135.8 74.1 61.5 39.8 12.0 ______________________________________
- (b) has an optical rotation [.alpha]sub.D.sup.25 of +19;
- (c) has an elemental analysis (percent) of about:
- C, 43.18;
- H, 5.74;
- N, 15.47;
- S, 3.39;
- (d) has a characteristic carbon-13 nuclear magnetic resonance spectrum substantially as shown in FIG. V;
- (e) yields, upon hydrolysis, amino acids which include threonine, .beta.-alanine, 4-amino-3-hydroxy-2-methyl valeric acid, 2,3-diaminopropionic acid, and .beta.-amino-.beta.-(4-amino-6-carboxy-5-methylpyrimidin-2-yl) propionic acid;
- and
- (f) yields, upon methanolysis, L-gulose and D-mannose;
- and
- (g) has a characteristic Proton Magnetic Resonance Spectrum substantially as shown in FIG. VI;
- and the pharmaceutically acceptable acid-addition slats thereof.
12 more elements
The antibiotic LL-BO1208.beta. wherein the substantially pure form:
- (a) exhibits the following significant carbon-13 nuclear magnetic resonance chemical shifts in parts per million relative to the absorption of tetramethyl silane:
- ______________________________________ 182.5 159.2 74.7 60.2 37.9 178.8 153.7 74.2 58.3 34.2 178.6 149.3 71.5 53.9 30.3 177.5 138.2 70.4 49.6 24.5 173.5 135.9 69.6 48.6 24.1 173.3 127.1 69.2 45.8 20.1 173.1 119.1 68.5 43.8 16.0 170.3 113.4 68.3 42.0 13.1 169.0 99.4 66.0 41.4 12.0 166.6 98.6 62.2 40.3 165.9 76.7 61.5 39.8 164.6 75.6 60.9 38.7 ______________________________________
- (b) has an optical rotation [.alpha]sub.D.sup.25 of +17+2;
- (c) has an elemental analysis (percent) of about:
- C, 44.82;
- H, 6.50;
- N, 15.41;
- S, 3.94;
- (d) has a characteristic carbon-13 nuclear magnetic resonance spectrum substantially as shown in FIG. III;
- (e) yields, upon hydrolysis, amino acids which include threonine, .beta.-alanine, 4-amino-3-hydroxy-2-methyl valeric acid, 2,3-diaminopropionic acid, .beta.-lysine, and .beta.-amino-.beta.-(4-amino-6-carboxy-5-methylpyrimidine-2-yl)propionic acid;
- (f) yields, upon methanolysis, L-gulose and D-mannose;
- and
- (g) has a characteristic Infrared Absorption Spectrum substantially as shown in FIG. I, a characteristic Ultraviolet Absorption Spectrum substantially shown in FIG. IV, and a characteristic Proton Magnetic Resonance Spectrum substantially as shown in FIG. II;
- and the pharmaceutically acceptable non-toxic salts thereof.
11 more elements
A method of treating bacterial infections in warm-blooded animals comprising administering to said animals an antibacterially effective amount of an antibiotic selected from the group consisting of:
- (a) the antibiotic LL-BO1208.alpha. wherein the substantially pure form:
- (i) exhibits the following significant carbon-13 nuclear magnetic resonance chemical shifts in parts per million relative to the absorption of tetramethylsilane:
- ______________________________________ 182.3 169.0 126.7 71.5 60.9 38.7 178.8 166.6 119.1 70.4 60.2 37.9 178.6 165.9 113.4 69.6 58.3 34.2 177.5 164.7 99.4 69.2 53.8 34.0 173.3 159.2 98.6 68.5 48.7 24.4 173.1 153.7 76.8 68.3 48.3 20.1 172.7 149.4 75.6 66.0 43.9 16.0 170.4 138.2 74.8 62.2 41.4 13.1 170.2 135.8 74.1 61.5 39.8 12.0 ______________________________________
- (ii) has an optical rotation [.alpha]sub.D.sup.25 of +19;
- (iii) has an elemental analysis (percent) of about:
- C, 43.18;
- H, 5.74;
- N, 15.47;
- S, 3.39;
- (iv) has a characteristic carbon-13 nuclear magnetic resonance spectrum substantially as shown in FIG. V;
- (v) yields, upon hydrolysis, amino acids which include threonine, .alpha.-alanine, 4-amino-3-hydroxy-2-methyl valeric acid, 2,3-diaminopropionic acid, and .beta.-amino-.beta.-(4-amino-6-carboxy-5-methylpyrimidin-2-yl)propionic acid;
- and
- (vi) yields, upon methanolysis, L-gulose and D-mannose;
- and
- (vii) has a characteristic Proton Magnetic Resonance Spectrum substantially as shown in FIG. VI;
- and the pharmaceutically acceptable acid-addition salts thereof;
- (b) the antibiotic LL-BO1208.beta. wherein the substantially pure form:
- (i) exhibits the following significant carbon-13 nuclear magnetic resonance chemical shifts in parts per million relative to the absorption of tetramethyl silane:
- ______________________________________ 182.5 159.2 74.7 60.2 37.9 178.8 153.7 74.2 58.3 34.2 178.6 149.3 71.5 53.9 30.3 177.5 138.2 70.4 49.6 24.5 173.5 135.9 69.6 48.6 24.1 173.3 127.1 69.2 45.8 20.1 173.1 119.1 68.5 43.8 16.0 170.3 113.4 68.3 42.0 13.1 169.0 99.4 66.0 41.4 12.0 166.6 98.6 62.2 40.3 165.9 76.7 61.5 39.8 164.6 75.6 60.9 38.7 ______________________________________
- (ii) has an optical rotation [.alpha]sub.D.sup.25 of +17+2;
- (iii) has an elemental analysis (percent) of about:
- C, 44.82;
- H, 6.50;
- N, 15.41;
- S, 3.94;
- (iv) has a characteristic carbon-13 nuclear magnetic resonance spectrum substantially as shown in FIG. III;
- (v) yields, upon hydrolysis, amino acids which include threonine, .beta.-alanine, 4-amino-3-hydroxy-2-methyl valeric acid, 2,3-diaminopropionic acid, .beta.-lysine, and .beta.-amino-.beta.-(4-amino-6-carboxy-5-methylpyrimidine-2-yl)propionic acid;
- (vi) yields, upon methanolysis, L-gulose and D-mannose;
- and
- (vii) has a characteristic Infrared Absorption Spectrum substantially as shown in FIG. I, a characteristic Ultraviolet Absorption Spectrum substantially as shown in FIG. IV, and a characteristic Proton Magnetic Resonance Spectrum substantially as shown in FIG. II;
- and the pharmaceutically acceptable non-toxic salts thereof;
- (c) and mixtures thereof.
29 more elements
A therapeutic composition of matter containing as an essential antibacterial agent an antibiotic selected from the group consisting of:
- (a) the antibiotic LL-BO1208.alpha. wherein the substantially pure form:
- (i) exhibits the following significant carbon-13 nuclear magnetic resonance chemical shifts in parts per million relative to the absorption of tetramethylsilane:
- ______________________________________ 182.3 169.0 126.7 71.5 60.9 38.7 178.8 166.6 119.1 70.4 60.2 37.9 178.6 165.9 113.4 69.6 58.3 34.2 177.5 164.7 99.4 69.2 53.8 34.0 173.3 159.2 98.6 68.5 48.7 24.4 173.1 153.7 76.8 68.3 48.3 20.1 172.7 149.4 75.6 66.0 43.9 16.0 170.4 138.2 74.8 62.2 41.4 13.1 170.2 135.8 74.1 61.5 39.8 12.0 ______________________________________
- (ii) has an optical rotation [.alpha]sub.D.sup.25 of +19;
- (iii) has an elemental analysis (percent) of about:
- C, 43.18;
- H, 5.74;
- N, 15.47;
- S, 3.39;
- (iv) has a characteristic carbon-13 nuclear magnetic resonance spectrum substantially as shown in FIG. V;
- (v) yields, upon hydrolysis, amino acids which include threonine, .beta.-alanine, 4-amino-3-hydroxy-2-methyl valeric acid, 2,3-diaminopropionic acid, and .beta.-amino-.beta.-(4-amino-6-carboxy-5-methylpyrimidin-2-yl)propionic acid;
- and
- (vi) yields, upon methanolysis, L-gulose and D-mannose;
- and
- (vii) has a characteristic Proton Magnetic Resonance Spectrum substantially as shown in FIG. VI;
- and the pharmaceutically acceptable acid-addition salts thereof;
- (b) the antibiotic LL-BO1208.beta. wherein the substantially pure form:
- (i) exhibits the following significant carbon-13 nuclear magnetic resonance chemical shifts in parts per million relative to the absorption of tetramethyl silane:
- ______________________________________ 182.5 159.2 74.7 60.2 37.9 178.8 153.7 74.2 58.3 34.2 178.6 149.3 71.5 53.9 30.3 177.5 138.2 70.4 49.6 24.5 173.5 135.9 69.6 48.6 24.1 173.3 127.1 69.2 45.8 20.1 173.1 119.1 68.5 43.8 16.0 170.3 113.4 68.3 42.0 13.1 169.0 99.4 66.0 41.4 12.0 166.6 98.6 62.2 40.3 165.9 76.7 61.5 39.8 164.6 75.6 60.9 38.7 ______________________________________
- (ii) has an optical rotation [.alpha]sub.D.sup.25 of +17+2;
- (iii) has an elemental analysis (percent) of about;
- C, 44.82;
- H, 6.50;
- N, 15.41;
- S, 3.94;
- (iv) has a characteristic carbon-13 nuclear magnetic resonance spectrum substantially as shown in FIG. III;
- (v) yields, upon hydrolysis, amino acids which include threonine, .beta.-alanine, 4-amino-3-hydroxy-2-methyl valeric acid, 2,3-diaminopropionic acid, .beta.-lysine, and .beta.-amino-.beta.-(4-amino-6-carboxy-5-methylpyrimidine-2-yl)propionic acid;
- (vi) yields, upon methanolysis, L-gulose and D-mannose;
- and
- (vii) has a characteristic Infrared Absorption Spectrum substantially as shown in FIG. I, a characteristic Ultraviolet Absorption Spectrum substantially as shown in FIG. IV, and a characteristic Proton Magnetic Resonance Spectrum substantially as shown in FIG. II;
- and the pharmaceutically acceptable non-toxic salts thereof;
- (c) and mixtures thereof. and a pharmaceutical carrier.
29 more elements
A process for preparing an antibiotic selected from the group consisting of:
- (a) the antibiotic LL-BO1208.alpha. wherein the substantially pure form:
- (i) exhibits the following significant carbon-13 nuclear magnetic resonance chemical shifts in parts per million relative to the absorption of tetramethylsilane:
- ______________________________________ 182.3 169.0 126.7 71.5 60.9 38.7 178.8 166.6 119.1 70.4 60.2 37.9 178.6 165.9 113.4 69.6 58.3 34.2 177.5 164.7 99.4 69.2 53.8 34.0 173.3 159.2 98.6 68.5 48.7 24.4 173.1 153.7 76.8 68.3 48.3 20.1 172.7 149.4 75.6 66.0 43.9 16.0 170.4 138.2 74.8 62.2 41.4 13.1 170.2 135.8 74.1 61.5 39.8 12.0 ______________________________________
- (ii) has an optical rotation [.alpha]sub.D.sup.25 of +19;
- (iii) has an elemental analysis (percent) of about;
- C, 43.18;
- H, 5.74;
- N, 15.47;
- S, 3.39;
- (iv) has a characteristic carbon-13 nuclear magnetic resonance spectrum substantially as shown in FIG. V;
- (v) yields, upon hydrolysis, amino acids which include threonine, .beta.-alanine, 4-amino-3-hydroxy-2-methyl valeric acid, 2,3-diaminopropionic acid, and .beta.-amino-62 -(4-amino-6-carboxy-5-methylpyrimidin-2-yl)propionic acid;
- and
- (vi) yields, upon methanolysis, L-gulose and D-mannose;
- and
- (vii) has a characteristic Proton Magnetic Resonance Spectrum substantially as shown in FIG. VI;
- and the pharmaceutically acceptable acid-addition salts thereof;
- (b) the antibiotic LL-BO1208.beta. wherein the substantially pure form:
- (i) exhibits the following significant carbon-13 nuclear magnetic resonance chemical shifts in parts per million relative to the absorption of tetramethyl silane:
- ______________________________________ 182.5 159.2 74.7 60.2 37.9 178.8 153.7 74.2 58.3 34.2 178.6 149.3 71.5 53.9 30.3 177.5 138.2 70.4 49.6 24.5 173.5 135.9 69.6 48.6 24.1 173.3 127.1 69.2 45.8 20.1 173.1 119.1 68.5 43.8 16.0 170.3 113.4 68.3 42.0 13.1 169.0 99.4 66.0 41.4 12.0 166.6 98.6 62.2 40.3 165.9 76.7 61.5 39.8 164.6 75.6 60.9 38.7 ______________________________________
- (ii) has an optical rotation [.alpha]sub.D.sup.25 of +17+2;
- (iii) has an elemental analysis (percent) of about:
- C, 44.82;
- H, 6.50;
- N, 15.41;
- S, 3.94;
- (iv) has a characteristic carbon-13 nuclear magnetic resonance spectrum substantially as shown in FIG. III;
- (v) yields, upon hydrolysis, amino acids which include threonine, .beta.-alanine, 4-amino-3-hydroxy-2-methyl valeric acid, 2,3-diaminopropionic acid, .beta.-lysine, and .beta.-amino-.beta.-(4-amino-6-carboxy-5-methylpyrimidine-2-yl)propionic acid;
- (vi) yields, upon methanolysis, L-gulose and D-mannose;
- and
- (vii) has a characteristic Infrared Absorption Spectrum substantially as shown in FIG. I, a characteristic Ultraviolet Absorption Spectrum substantially as shown in FIG. IV, and a characteristic Proton Magnetic Resonance Spectrum substantially as shown in FIG. II;
- and the pharmaceutically acceptable non-toxic salts thereof;
- (c) and mixtures thereof;
- which comprises aerobically fermenting the organism Streptoverticillium stramineum NRRL 12292 or mutants thereof in a liquid medium containing assimilable sources of carbon, nitrogen, and inorganic salts, until substantial antibiotic activity is imparted to said medium, and then recovering the antibiotic therefrom.
30 more elements
A process for preparing an antibiotic selected from the group consisting of:
- (a) the antibiotic LL-BO1208.alpha. wherein the substantially pure form:
- (i) exhibits the following significant carbon-13 nuclear magnetic resonance chemical shifts in parts per million relative to the absorption of tetramethylsilane:
- ______________________________________ 182.3 169.0 126.7 71.5 60.9 38.7 178.8 166.6 119.1 70.4 60.2 37.9 178.6 165.9 113.4 69.6 58.3 34.2 177.5 164.7 99.4 69.2 53.8 34.0 173.3 159.2 98.6 68.5 48.7 24.4 173.1 153.7 76.8 68.3 48.3 20.1 172.7 149.4 75.6 66.0 43.9 16.0 170.4 138.2 74.8 62.2 41.4 13.1 170.2 135.8 74.1 61.5 39.8 12.0 ______________________________________
- (ii) has an optical rotation [.alpha]sub.D.sup.25 of +19;
- (iii) has an elemental analysis (percent) of about:
- C, 43.18;
- H, 5.74;
- N, 15.47;
- S, 3.39;
- (iv) has a characteristic carbon-13 nuclear magnetic resonance spectrum substantially as shown in FIG. V;
- (v) yields, upon hydrolysis, amino acids which include threonine, .beta.-alanine, 4-amino-3-hydroxy-2-methyl valeric acid, 2,3-diaminopropionic acid, and .beta.-(4-amino-6-carboxy-5-methylpyrimidin-2-yl)propionic acid;
- and
- (vi) yields, upon methanolysis, L-gulose and D-mannose;
- and
- (vii) has a characteristic Proton Magnetic Resonance Spectrum substantially as shown in FIG. VI;
- and the pharmaceutically acceptable acid-addition salts thereof;
- (b) the antibiotic LL-BO1208.beta. wherein the substantially pure form:
- (i) exhibits the following significant carbon-13 nuclear magnetic resonance chemical shifts in parts per million relative to the absorption of tetramethyl silane:
- ______________________________________ 182.5 159.2 74.7 60.2 37.9 178.8 153.7 74.2 58.3 34.2 178.6 149.3 71.5 53.9 30.3 177.5 138.2 70.4 49.6 24.5 173.5 135.9 69.6 48.6 24.1 173.3 127.1 69.2 45.8 20.1 173.1 119.1 68.5 43.8 16.0 170.3 113.4 68.3 42.0 13.1 169.0 99.4 66.0 41.4 12.0 166.6 98.6 62.2 40.3 165.9 76.7 61.5 39.8 164.6 75.6 60.9 38.7 ______________________________________
- (ii) has an optical rotation [.alpha]sub.D.sup.25 of +17+2;
- (iii) has an elemental analysis (percent) of about;
- C, 44.82;
- H, 6.50;
- N, 15.41;
- S, 3.94;
- (iv) has a characteristic carbon-13 nuclear magnetic resonance spectrum substantially as shown in FIG. III;
- (v) yields, upon hydrolysis, amino acids which include threonine, .beta.-alanine, 4-amino-3-hydroxy-2-methyl valeric acid, 2,3-diaminopropionic acid, .beta.-lysine, and .beta.-amino-.beta.-(4-amino-6-carboxy-5-methylpyrimidine-2-yl)propionic acid;
- (vi) yields, upon methanolysis, L-gulose and D-mannose;
- and
- (vii) has a characteristic Infrared Absorption Spectrum substantially as shown in FIG. I, a characteristic Ultraviolet Absorption Spectrum substantially as shown in FIG. IV, and a characteristic Proton Magnetic Resonance Spectrum substantially as shown in FIG. II;
- and the pharmaceutically acceptable non-toxic salts thereof;
- (c) and mixtures thereof, which comprise aerobically fermenting a liquid medium containing assimilable sources of carbon, nitrogen, and inorganic salts, which medium has been inoculated with a viable culture of the organism Streptoverticillium stramineum NRRL 12292 or mutants thereof, maintaining said fermentation culture at a temperature of 24.degree.-35.degree. C. for a period of 80-120 hours, harvesting the mash, and extracting the antibiotics.
29 more elements
Dependencies are inferred from the claim text.