Transformation product of thiosporamicin

Details Transformation product of thiosporamicin Transformation product of thiosporamicin

1986-11-20

1988-11-15

Griffin, Ronald W.

Chemistry: natural resins or derivatives; peptides or proteins;

Peptides of 3 to 100 amino acid residues

Cyclic peptides

424117, C07K 752, A61K 3500

Patent

active

047850787

DESCRIPTION:

BRIEF SUMMARY
TECHNICAL FIELD

This invention is concerned with a new member of the sulfur-containing polypeptide group of antibiotics.


BACKGROUND ART

This family of antibiotics includes thiostrepton (Antibiotics Ann., 1955-1956, 554-559); siomycin (J. Antibiotics, 14:255, 1961): A-59 (J. Antibiotics, A14:194, (1961); thiopeptin (J. Antibiotics, 23:113-119, 1970); sporangiomycin (J. Antibiotics, 21:525-531, 1968); and CP-46, 192, U.S. Pat. No. 4,083,963.


DISCLOSURE OF THE INVENTION

This invention is concerned with a new sulfur-containing polypeptide antibiotic of the formula ##STR1## known as CP-53,648. The present invention also provides a process of preparing CP-53,648 by hydrolyzing thiosporamicin i.e. the compound of the formula ##STR2## under acid conditions.
Additionally the present invention provides for a method of promoting growth of poultry and swine and for increasing the feed utilization efficiency thereof by orally administering a growth and feed utilization efficiency promoting amount of CP-53,648. The invention also embraces feed compositions suitable for ingestion by poultry and swine comprising a nutritionally balanced, growth and feed utilization, efficiency-promoting amount of CP-53,648, together with a physiologically acceptable carrier or diluent.


DETAILED DESCRIPTION

The antibiotic compound of the present invention, CP-53,648, is formed by the acid hydrolysis of thiosporamicin.
The starting material, thiosporamicin was originally isolated from soil samples found in Canada and France, and on examination was found to have the morphological features of a Streptosporangium. This genus is differentiated from others belonging to the group actinomycetes by the production of coiled chains of round elliptical spores contained in sporangia and the production of aerial mycelium on the surface of the culture.
The preparation of the starting material thiosporamicin, also known as Antibiotic Compound 46,192 is described in U.S. Pat. No. 4,083,963.
The novel compound of the present invention is prepared by acid hydrolysis of thiosporamicin. In a preferred embodiment a solution of thiosporamicin is treated with an aqueous solution of either a buffered mineral acid or an acid salt. Suitable mineral acids include hydrochloric acid and phosphoric acid. A suitable acid salt is for example, cobalt chloride. Preferably the thiosporamicin is first dissolved in a solvent such as acetonitrile. Other suitable solvents include dimethyl sulfoxide.
It is important that the required acidic conditions be maintained for the reaction to proceed efficiently. The pH of the reaction mixture is maintained at from about 1.0 to 5.0 preferably from about 3.5 to 4.2. If necessary the pH of the reaction mixture can be maintained by the addition of, for example, phosphoric acid. Other suitable acids include hydrochloric acid.
The mixture of the aqueous acid solution and the thiosporamicin is heated for about 2 to 50 hours, preferably 10 to 48 hours at a temperature from about 40.degree. to 50.degree.. The resulting product can be collected by conventional means, for example extraction with an organic solvent. The product is preferably purified by chromatography.
CP-53,648 is active against a variety of Gram-positive bacteria as illustrated in Table 1.


TABLE I ______________________________________ Minimum Inhibitor Organism Concentration (mcg/ml) ______________________________________ Staphylococcus, aureaus sp. 1.56 Streptococcus equi. .006 Streptococcus agalac. .049 ______________________________________
Significant parenteral protection is afforded to mice experimentally infected with Staphylococcus aureus 01A005 by Compound CP-53,648 at doses of 50 to 200 mg./kg. and an oral dose of 200 mg./kg.
Crude antibiotic mixtures such as those obtained directly from the reaction broth or in any of the intermediate recovery stages as well as purified Compound CP-53,648 may also be employed in the treatment of antibiotic sensitive infections in man and animals at parenteral doses of 200 to 1000 mg., depen

REFERENCES:
patent: 2982689 (1961-05-01), Donovick et al.
patent: 3761587 (1973-09-01), Miyairi et al.
patent: 4083963 (1978-04-01), Celmer et al.
patent: 4175126 (1979-11-01), Lombardi et al.
patent: 4293489 (1981-10-01), Debono
patent: 4320052 (1982-03-01), Abbott et al.
Pagano et al., Antibiotics Annual, pp. 554-559 (1955/6).
Nishimura et al., The Journal of Antibiotics, Ser. A., vol. XIV, No. 5, pp. 255-263 (Sep. 1961).
Miyairi et al., The Journal of Antibiotics, vol. XXIII, No. 3, pp. 113-119 (Jan. 1970).
Thiemann et al., The Journal of Antibiotics, vol. XXI, No. 9, pp. 525-531 (Sep. 1968).
Kondo et al, Studies of a New Antibiotic Produced by Streptomyces Sp. A-59, J. Ant. A14=194-198, 1961.

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