Antitumor agents LL-D49194.alpha..sub.1, LL-D49194.beta..sub.1, LL-D49194.beta..sub.2, LL-D49194.beta..sub.3, LL-D49194.gamma., LL-D49194.delta., LL-D49194.epsilon., LL-D49194.xi., LL-D49194.eta., LL-D49194.omega..sub.1, LL-D49194.omega..sub.2, and LL-D49194.omega..sub.3

US 4,626,503 A
Filed: 02/14/1985
Issued: 12/02/1986
Est. Priority Date: 04/04/1984
Status: Expired due to Term

First Claim

Patent Images

1. Antitumor agent LL-D49194α

₁, a compositionwhich;

(a) is effective as an antitumor agent;

(b) is effective as an antibacterial agent;

(c) has a molecular weight of 992;

(d) has a molecular formula;

C₄₈ H₆₄ O₂₂ ;

(e) has a melting point of 173°

-176°

C. (with decomposition);

(f) has a specific rotation;

[α

]_D²⁶ =0°

(0.57%, ethanol);

(g) has ultraviolet absorption spectra as shown in FIG. I of the drawings;

(h) has an infrared absorption spectrum as shown in FIG. II of the drawings;

(i) has a proton magnetic resonance spectrum as shown in FIG. III of the drawings;

(j) has a carbon-13 magnetic resonance spectrum as shown in FIG. IV of the drawings with significant peaks at 16.5;

16.9;

17.6;

20.4;

20.9;

25.7;

26.2;

26.7;

35.6;

36.7;

47.8;

52.8;

58.8;

62.7;

62.9;

63.9;

67.4;

67.9;

68.8;

69.0;

69.1;

69.2;

70.1;

71.3;

74.3;

74.4;

83.9;

94.2;

94.8;

97.9;

101.0;

102.3;

104.3;

107.3;

114.8;

114.9;

116.7;

126.5;

135.4;

142.9;

144.8;

151.5;

163.2;

170.3;

202.8; and

(k) releases methyl α

-L-axenoside and methyl β

-L-axemoside upon treatment with dilute methanolic hydrochloric acid.

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Abstract

Antitumor agents LL-D49194α₁, LL-D49194β₁, LL-D49194β₂, LL-D49194β₃, LL-D49194γ, LL-D49194δ, LL-D49194ε, LL-D49194ξ, LL-D49194η, LL-D49194ω, LL-D49194ω₂ and LL-D49194ω₃.

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21 Claims

1. Antitumor agent LL-D49194α
- ₁, a compositionwhich;
  
  (a) is effective as an antitumor agent;
  
  (b) is effective as an antibacterial agent;
  
  (c) has a molecular weight of 992;
  
  (d) has a molecular formula;
  
  C₄₈ H₆₄ O₂₂ ;
  
  (e) has a melting point of 173°
  
  -176°
  
  C. (with decomposition);
  
  (f) has a specific rotation;
  
  [α
  
  ]_D²⁶ =0°
  
  (0.57%, ethanol);
  
  (g) has ultraviolet absorption spectra as shown in FIG. I of the drawings;
  
  (h) has an infrared absorption spectrum as shown in FIG. II of the drawings;
  
  (i) has a proton magnetic resonance spectrum as shown in FIG. III of the drawings;
  
  (j) has a carbon-13 magnetic resonance spectrum as shown in FIG. IV of the drawings with significant peaks at 16.5;
  
  16.9;
  
  17.6;
  
  20.4;
  
  20.9;
  
  25.7;
  
  26.2;
  
  26.7;
  
  35.6;
  
  36.7;
  
  47.8;
  
  52.8;
  
  58.8;
  
  62.7;
  
  62.9;
  
  63.9;
  
  67.4;
  
  67.9;
  
  68.8;
  
  69.0;
  
  69.1;
  
  69.2;
  
  70.1;
  
  71.3;
  
  74.3;
  
  74.4;
  
  83.9;
  
  94.2;
  
  94.8;
  
  97.9;
  
  101.0;
  
  102.3;
  
  104.3;
  
  107.3;
  
  114.8;
  
  114.9;
  
  116.7;
  
  126.5;
  
  135.4;
  
  142.9;
  
  144.8;
  
  151.5;
  
  163.2;
  
  170.3;
  
  202.8; and
  
  (k) releases methyl α
  
  -L-axenoside and methyl β
  
  -L-axemoside upon treatment with dilute methanolic hydrochloric acid.

2. Antitumor agent LL-D49194β
- ₁ a compositionwhich;
  
  (a) is effective as an antitumor agent;
  
  (b) is effective as an antibacterial agent;
  
  (c) has a molecular weight of 1010;
  
  (d) has a molecular formula;
  
  C₄₈ H₆₆ O₂₃ ;
  
  (e) has a melting point 163°
  
  -167°
  
  C. (with decomposition);
  
  (f) has specific rotation;
  
  [α
  
  ]_D²⁶ =-51±
  
  10°
  
  (0.137%, ethanol)[α
  
  ]_D²⁶ =-119±
  
  10°
  
  (0.135%, chloroform);
  
  (g) has ultraviolet absortpion spectra as shown in FIG. V of the drawings;
  
  (h) has an infrared absorption spectrum as shown in FIG. VI of the drawings;
  
  (i) has a proton magnetic resonance spectrum as shown in FIG. VII of the drawings;
  
  (j) has a carbon-13 magnetic resonance spectrum as shown in FIG. VIII of the drawings with significant peaks at

3. 16. 5;
- 16.9;
  
  17.6;
  
  20.1;
  
  20.8, 25.8;
  
  26.3;
  
  26.8;
  
  35.7;
  
  35.8;
  
  36.7;
  
  36.8;
  
  53.0;
  
  58.7;
  
  62.3;
  
  62.7;
  
  62.9;
  
  63.9;
  
  67.1;
  
  67.9;
  
  68.8;
  
  69.3;
  
  69.4;
  
  70.1;
  
  70.7;
  
  74.3;
  
  74.5;
  
  84.0;
  
  85.1;
  
  94.9;
  
  95.2;
  
  97.7;
  
  101.0;
  
  106.0;
  
  107.9;
  
  108.3;
  
  113.6;
  
  114.1;
  
  116.8;
  
  126.8;
  
  135.5;
  
  142.4;
  
  145.1;
  
  152.3;
  
  162.4;
  
  170.3;
  
  203.6; and
  
  (k) releases methyl α
  
  -L-axenoside and methyl β
  
  -L-axenoside upon treatment with dilute methanolic hydrochloric acid.

4. Antitumor agent LL-D49194β
- ₂, a compositionwhich;
  
  (a) is effective as an antitumor agent;
  
  (b) is effective as an antibacterial agent;
  
  (c) has a specific rotation;
  
  [α
  
  ]_D²⁶ =+40±
  
  6°
  
  (0.15%, ethanol);
  
  (d) has ultraviolet absorption spectra as shown in FIG. IX of the drawings;
  
  (e) has an infrared absorption spectrum as shown in FIG. X of the drawings;
  
  (f) has a proton magnetic resonance spectrum as shown in FIG. XI of the drawings;
  
  (g) has a carbon-13 magnetic resonance spectrum as shown in FIG. XII of the drawingss with significant peaks at

5. 16. 5;
- 16.9;
  
  17.6;
  
  20.3;
  
  26.1;
  
  26.2;
  
  26.7;
  
  35.6;
  
  35.9;
  
  36.6;
  
  47.9;
  
  52.8;
  
  58.7;
  
  62.7;
  
  63.6;
  
  63.9;
  
  67.6;
  
  68.0;
  
  69.0;
  
  69.1;
  
  69.3;
  
  70.1;
  
  70.2;
  
  71.2;
  
  74.2;
  
  74.4;
  
  83.9;
  
  94.2;
  
  94.8;
  
  98.1;
  
  101.0;
  
  102.3;
  
  104.2;
  
  107.4;
  
  114.8;
  
  114.9;
  
  116.6;
  
  126.6;
  
  135.5;
  
  142.9;
  
  144.7;
  
  151.5;
  
  163.2;
  
  202.9; and
  
  (h) releases methyl α
  
  -L-axenoside and methyl β
  
  -L-axenoside upon treatment with dilute methanolic hydrochloric acid.

6. Antitumor agent LL-D49194β
- ₃, a compositionwhich;
  
  (a) is effective as an antitumor agent;
  
  (b) is effective as an antibacterial agent;
  
  (c) has ultraviolet absorption spectra as shown in FIG. XXIV of the drawings;
  
  (d) has a proton magnetic resonance spectrum as shown in FIG. XXV of the drawings; and
  
  (e9 has a carbon-13 magnetic resonance spectrum as shown in FIG. XXVI of the drawings with significant peaks at 16.7;
  
  16.9;
  
  20.3;
  
  26.1;
  
  34.6;
  
  36.0;
  
  36.7;
  
  47.9;
  
  52.8;
  
  58.5;
  
  62.7;
  
  63.6;
  
  67.6;
  
  68.0;
  
  69.0;
  
  69.1;
  
  69.9;
  
  70.1;
  
  71.3;
  
  74.5;
  
  94.3;
  
  94.9;
  
  98.2;
  
  102.3;
  
  104.4;
  
  107.4;
  
  114.9;
  
  116.7;
  
  126.7;
  
  135.5;
  
  142.9;
  
  144.8;
  
  151.6;
  
  163.2;
  
  202.9.

7. Antitumor agent LL-D49194γ
- , a compositionwhich;
  
  (a) is effective as an antitumor agnent;
  
  (b) is effective as an antibacterial agent; and
  
  (c) has ultraviolet absorption spectra as shown in FIG. XIII of the drawings.

8. Antitumor agent LL-D49194δ
- , a compositionwhich;
  
  (a) is effective as an antitumor agent;
  
  (b) is effective as an antibacterial agent; and
  
  (c) has ultraviolet absorption spectra as shown in FIG. XIV of the drawings.

9. Antitumor agent LL-D49194ε
- , a compositionwhich;
  
  (a) is effective as an antitumor agent;
  
  (b) is effective as an antibacterial agent;
  
  (c) has a specific rotation;
  
  [α
  
  ]_D²⁶ =-123±
  
  4°
  
  (0.35%, CHCl₃);
  
  (d) has ultraviolet absorption spectra as shown in FIG. XV of the drawings;
  
  (e) has an infrared absorption spectrum as shown in FIG. XVI of the drawings;
  
  (f) has a proton magnetic resonance spectrum as shown in FIG. XVII of the drawings; and
  
  (g) has a carbon-13 magnetic resonance spectrum as shown in FIG. XVIII of the drawings with significant peaks at 16.5;
  
  16.9;
  
  17.6;
  
  20.2;
  
  20.9;
  
  25.7;
  
  25.9;
  
  26.8;
  
  35.7;
  
  36.4;
  
  36.6;
  
  36.7;
  
  53.0;
  
  59.0;
  
  62.3;
  
  62.8;
  
  62.9;
  
  63.2;
  
  63.8;
  
  66.8;
  
  67.9;
  
  68.8;
  
  69.2;
  
  69.4;
  
  70.5;
  
  74.4;
  
  84.0;
  
  85.0;
  
  94.7;
  
  95.2;
  
  97.6;
  
  101.0;
  
  105.9;
  
  107.8;
  
  108.2;
  
  113.5;
  
  114.1;
  
  16.9;
  
  126.7;
  
  135.5;
  
  142.5;
  
  145.2;
  
  152.3;
  
  162.4;
  
  170.3;
  
  203.4.

10. Antitumor agent LL-D49194ζ
- , a compositionwhich;
  
  (a) is effective as an antitumor agent;
  
  (b) is effective as an antibacterial agent; and
  
  (c) has ultraviolet absorption spectra as shown in FIG. XIX of the drawings.

11. Antitumor agent LL-D49194η
- , a compositionwhich;
  
  (a) is effective as an antitumor agent;
  
  (b) is effective as an antibacterial agent;
  
  (c) has a specific rotation;
  
  [α
  
  ]_D²⁶ =+65±
  
  3°
  
  (0.4%, ethanol);
  
  (d) has ultraviolet absorption spectra as shown in FIG. XX of the drawings;
  
  (e) has an infrared absorption spectrum as shown in FIG. XXI of the drawings;
  
  (f) has a proton magnetic resonance spectrum as shown in FIG. XXII of the drawings; and
  
  (g) has a carbon-13 magnetic resonance spectrum as shown in FIG. XXIII of the drawings with significant peaks at 16.7;
  
  16.9;
  
  20.3;
  
  20.9;
  
  25.7;
  
  26.0;
  
  34.6;
  
  36.7;
  
  47.8;
  
  52.8;
  
  52.8;
  
  58.6;
  
  62.7;
  
  62.9;
  
  63.6;
  
  67.5;
  
  67.9;
  
  68.8;
  
  69.0;
  
  69.1;
  
  69.9;
  
  71.3;
  
  74.4;
  
  94.3;
  
  94.9;
  
  98.0;
  
  102.3;
  
  104.3;
  
  107.3;
  
  114.8;
  
  115.0;
  
  116.7;
  
  126.5;
  
  135.5;
  
  142.9;
  
  144.8;
  
  151.6;
  
  163.2;
  
  170.3;
  
  202.8.

12. Antitumor agent LL-D49194ω
- ₁, a compositionwhich;
  
  (a) is effective as an antitumor agent;
  
  (b) is effective as an antibacterial agent;
  
  (c) has ultraviolet absorption spectra as shown in FIG. XXVII of the drawings;
  
  (d) has a proton magnetic resonance spectrum as shown in FIG. XXVIII of the drawings; and
  
  (e) has a carbon-13 magnetic resonance spectrum as shown in FIG. XXIX of the drawings with significant peaks at 16.5;
  
  16.9;
  
  17.6;
  
  20.1;
  
  26.2;
  
  26.8;
  
  35.7;
  
  35.8;
  
  36.0;
  
  36.7;
  
  53.0;
  
  58.8;
  
  62.2;
  
  62.7;
  
  63.6;
  
  63.9;
  
  67.2;
  
  68.0;
  
  69.3;
  
  69.4;
  
  70.0;
  
  70.1;
  
  70.6;
  
  74.4;
  
  84.0;
  
  85.1;
  
  94.8;
  
  95.2;
  
  98.0;
  
  101.0;
  
  106.0;
  
  107.9;
  
  108.3;
  
  113.5;
  
  114.1;
  
  116.9;
  
  127.1;
  
  135.6;
  
  142.4;
  
  145.2;
  
  152.4;
  
  162.3;
  
  203.5.

13. Antitumor agent LL-D49194ω
- ₂, a compositionwhich;
  
  (a) is effective as an antitumor agent;
  
  (b) is effective as an antibacterial agent; and
  
  (c) has ultraviolet absorption spectra as shown in FIG. XXX of the drawings.

14. Antitumor agent LL-D49194ω
- ₃, a compositionwhich;
  
  (a) is effective as an antitumor agent;
  
  (b) is effective as an antibacterial agent;
  
  (c) has a specific rotation;
  
  [α
  
  ]_D²⁶ =0°
  
  (0.6%, ethanol);
  
  (d) has ultraviolet absorption spectra as shown in FIG. XXXI of the drawings;
  
  (e) has an infrared absorption spectrum as shown in FIG. XXXII of the drawings;
  
  (f) has a proton magnetic resonance spectrum as shown in FIG. XXXIII of the drawings; and
  
  (g) has a carbon-13 magnetic resonance spectrum as shown in FIG. XXXIV of the drawings with significant peaks at 16.7;
  
  16.9;
  
  20.2;
  
  20.9;
  
  25.7;
  
  26.1;
  
  34.7;
  
  36.5;
  
  36.7;
  
  53.0;
  
  58.8;
  
  62.3;
  
  62.8;
  
  62.9;
  
  63.6;
  
  66.8;
  
  67.9;
  
  68.8;
  
  69.4;
  
  69.9;
  
  70.5;
  
  74.4;
  
  85.1;
  
  94.8;
  
  95.3;
  
  97.5;
  
  106.0, 107.9;
  
  108.3;
  
  113.6;
  
  114.0;
  
  116.9;
  
  126.7;
  
  135.5;
  
  142.5;
  
  145.1;
  
  152.3;
  
  162.4;
  
  170.3;
  
  203.5.

15. 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-D49194α
- ₁, LL-D49194β
  
  ₁, LL-D49194β
  
  ₂, LL-D49194β
  
  ₃ ;
  
  LL-D49194ε
  
  ;
  
  LL-D49194δ
  
  ;
  
  LL-D49194ε
  
  ;
  
  LL-D49194ζ
  
  ;
  
  LL-D49194η
  
  ;
  
  LL-D49194ω
  
  ₁ ;
  
  LL-D49194ω
  
  ₃.

16. A method of inducing regression of leukemia and/or inhibiting the growh of tumors in a mammal comprising administering to said mammal an effective amount of a compound selected from the group consisting of LL-D49194α
- ₁ ;
  
  LL-D49194β
  
  ₁ ;
  
  LL-D49194β
  
  ₂ ;
  
  LL-D49194β
  
  ₃ ;
  
  LL-D49194ε
  
  ;
  
  LL-D49194δ
  
  ;
  
  LL-D49194ε
  
  ;
  
  LL-D49194ζ
  
  ;
  
  LL-D49194η
  
  ;
  
  LL-D49194ω
  
  ₁ ;
  
  LL-D49194ω
  
  ₂ and LL-D49194ω
  
  ₃.

17. A process for producing antibiotics LL-D49194α
- ₁ ;
  
  LL-D49194β
  
  ₁ ;
  
  LL-D49194β
  
  ₂ ;
  
  LL-D49194β
  
  ₃ ;
  
  LL-D49194γ
  
  ;
  
  LL-D49194δ
  
  ;
  
  LL-D49194ε
  
  ;
  
  LL-D49194ζ
  
  ;
  
  LL-D49194η
  
  ;
  
  LL-D49194ω
  
  ₁ ;
  
  LL-D49194ω
  
  ₂ and LL-D49194ω
  
  ₃ which comprises aerobically fermenting the organism Streptomyces vinaceus-drappus NRRL 15735 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 antibiotics therefrom.
- View Dependent Claims (20, 21)
- - 20. A biologically pure culture of the microorganism Streptomyces vinaceus-drappus according to claim 17, wherein said microorganism has spontaneously mutated such that the microorganism is genetically altered but still retains the ability to synthesize antibiotics LL-D49194α
    - ₁ ;
      
      LL-D49194β
      
      ₁ ;
      
      LL-D49194β
      
      ₂ ;
      
      LL-D49194β
      
      ₃ ;
      
      LL-D49194γ
      
      ;
      
      LL-D49194δ
      
      ;
      
      LL-D49194ε
      
      ;
      
      LL-DL49194ζ
      
      ;
      
      LLl-D49194η
      
      ;
      
      LL-D49194ω
      
      ₁ ;
      
      LL-D49194ω
      
      ₂ and LL-D49194ω
      
      ₃.
  - 21. A biologically pure culture of the microorganism Streptomyces vinaceus-drappus according to claim 17, wherein said microorganism has been subjected to mutagenic means such that the microorganism is genetically altered but still retains the ability to synthesize antibiotics LL-D49194α
    - ₁ ;
      
      LL-D49194β
      
      ₁ ;
      
      LL-D49194β
      
      ₂ ;
      
      LL-D49194β
      
      ₃ ;
      
      LL-D49194γ
      
      ;
      
      LL-D49194δ
      
      ;
      
      LL-D49194ε
      
      ;
      
      LL-D49194ζ
      
      ;
      
      LL-D49194η
      
      ;
      
      LL-D49194ω
      
      ₁ ;
      
      LL-D49194ω
      
      ₂ and LLl-D49194ω
      
      ₃.

18. A process for producing antibiotics LL-D49194α
- ₁ ;
  
  LL-D49194β
  
  ₁ ;
  
  LL-D49194β
  
  ₂ ;
  
  LL-D49194β
  
  ₃ ;
  
  LL-D49194.sub.γ
  
  ;
  
  LL-D49194δ
  
  ;
  
  LL-D49194ε
  
  ;
  
  LL-D4194ζ
  
  ;
  
  LL-D49194η
  
  ;
  
  LL-D49194ω
  
  ₁ ;
  
  LL-D49194ω
  
  ₂ and LL-D49194ω
  
  ₃ which comprises 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 Streptomyces vinaceus-drappus NRRL 15735 or mutants thereof, maintaining said fermentation culture at a temperature of 24°
  
  -32°
  
  C. for a period of 90-200 hours, harvesting the mesh and extracting the antibiotics.

19. A biologically pure culture of the microorganism Streptomyces vinaceus-drappus having the identifying characteristics of NRRL 15735, said culture being capable of producing antibiotics LL-D49194α
- ₁ ;
  
  LL-D49194β
  
  ₁ ;
  
  LL-D49194β
  
  ₂ ;
  
  LL-D49194β
  
  ₃ ;
  
  LL-D49194γ
  
  ;
  
  LL-D49194δ
  
  ;
  
  LL-D49194ε
  
  ;
  
  LL-D49194ζ
  
  ;
  
  LL-D49194η
  
  ;
  
  LL-D49194ω
  
  ₁ ;
  
  LL-D49194ω
  
  ₂ and LL-D49194ω
  
  ₃ in recoverable quantities upon fermentation in an aqueous nutrient medium containing assimilable sources of carbon, nitrogen and inorganic substances.

Specification

Resources

Litigation Campaign Assessment

Current Assignee
America Cyanamid Company
Original Assignee
American Colloid Company (Minerals Technologies Incorporated)
Inventors
Borders, Donald B., Labeda, David P., Fantini, Amedeo A., Lee, May D., Testa, Raymond T., Maiese, William M.
Primary Examiner(s)
NOT, DEFINED

Application Number

US06/701,831
Time in Patent Office

656 Days
Field of Search

435/75, 435/253, 424/116, 424/117, 424/118, 424/119, 536/16.8, 514/33
US Class Current

424/116
CPC Class Codes

C07H 17/04   Heterocyclic radicals conta...

C12N 1/205   Bacterial isolates

C12P 1/06   by using actinomycetales

C12P 19/60   having an oxygen of the sac...

C12R 2001/465   Streptomyces

Antitumor agents LL-D49194.alpha..sub.1, LL-D49194.beta..sub.1, LL-D49194.beta..sub.2, LL-D49194.beta..sub.3, LL-D49194.gamma., LL-D49194.delta., LL-D49194.epsilon., LL-D49194.xi., LL-D49194.eta., LL-D49194.omega..sub.1, LL-D49194.omega..sub.2, and LL-D49194.omega..sub.3

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Abstract

9 Citations

21 Claims

Specification

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Antitumor agents LL-D49194.alpha..sub.1, LL-D49194.beta..sub.1, LL-D49194.beta..sub.2, LL-D49194.beta..sub.3, LL-D49194.gamma., LL-D49194.delta., LL-D49194.epsilon., LL-D49194.xi., LL-D49194.eta., LL-D49194.omega..sub.1, LL-D49194.omega..sub.2, and LL-D49194.omega..sub.3

First Claim

1 Assignment

Subscription Required

Subscription Required

0 Petitions

Subscription Required

Accused Products

Subscription Required

Abstract

9 Citations

21 Claims

Specification

Subscription Required

Solutions

Use Cases

Quick Links