Natural substance cyclamenol and chemical derivatives

Details Natural substance cyclamenol and chemical derivatives Natural substance cyclamenol and chemical derivatives

1995-04-27

1996-10-15

Bond, Robert T.

Organic compounds -- part of the class 532-570 series

Organic compounds

Unsubstituted hydrocarbyl chain between the ring and the -c-...

540452, 540463, 435121, C07D22502, A61K 31395, C12P 1710

Patent

active

055655610

DESCRIPTION:

BRIEF SUMMARY
The invention relates to the new natural substance cyclamenol, a process for its preparation from microorganisms of the order of the Actinomycetales, in particular from the Streptomyces strain MHW 846, chemical derivatives, and their use as medicaments, in particular for acute and chronic inflammatory disorders in human and veterinary medicine.
It is already known that a number of microbially produced macrocyclic lactams, such as, for example, hitachimycin, virginiamycin or myxovirescin have an antibacterial or antitumour action [cf. e.g. J. Antibiotics 34, 261 1981), 37; 13 (1984); Biochim. Biophys. Acta 577, 324 (1975)].
The present invention relates to compounds of the general formula (I) ##STR2## in which A, B, D, E, G, L, M, Q, R, T, U, V, W and X in each case represent the >CH.sub.2 group and case represent the --CH.dbd.CH-group, formula --O--CO--CH.sub.3 or --O--Si(CH.sub.3).sub.3,
Surprisingly, both the new natural substance cyclamenol and its chemical derivatives are distinguished by a strong inhibitory action on central reactions in acute and chronic inflammatory processes.
Processes for the preparation of the compounds of the general formula (I) according to the invention have additionally been found, the production of the natural substance cyclamenol of the formula (Ia) ##STR3## initially being described.
The compound of the general formula (Ia) is produced by culturing the strain Streptomyces spec. MHW 846 in a nutrient medium and then isolating it therefrom.
The compound of the general formula (Ia) according to the invention is produced by the culture of a Streptomyces strain in suitable nutrient solutions under suitable physiological conditions. It is separated off from the culture solution by extraction or by absorption and concentrated by further suitable methods.
The present invention additionally relates to microorganisms of the family Streptomycetaceae which, during culture in a nutrient medium containing carbon and nitrogen sources and also mineral salts, produce a compound which has the properties and parameters shown in the substance characterization in the following under (1) to (6).
The strain Streptomyces spec. HMW 846 from the order of the Actinomycetales, family Streptomycetaceae, genus Streptomyces or variants and mutants derived from it are particularly important for the preparation process. The strain was isolated from a soil sample from Wahuya, Miyagi in Japan. A culture of this strain was deposited in the German Collection of Microorganisms in Brunswick on 14.12.88 under the number DSM 4950.
On the basis of the chemotaxonomic investigations on DL-DAP by C. S. Cummins and H. Harris, J. Gen. Microbiol. 15, 9-10, 1956 and on iso/antiiso fatty acid pattern by R. M. Kroppenstedt in Chemical Methods in Bacterial Systematics (eds. Goodfellow, M.; Minnikin, O. E.) 173-199, 1985, the strain was assigned to the genus Streptomyces. It is a Streptomyces which only poorly forms aerial mycelium on the media according to E. B. Shirling and D. Gottlieb, Int. Journal Syst. Bact. 16, 313-340, 1966, so that the aerial mycelium colour is not clearly ascertainable.
Streptomyces spec. MHW 846 forms melanoid pigment on peptone-iron agar and trypsin agar. Of the C sources supplied, only D-glucose is clearly utilized (Tab. 1). The strain grows in a temperature range from +20.degree. C. to 35.degree. C. At +5.degree. C. and +45.degree. C. no growth is to be observed.


TABLE 1 ______________________________________ C sources utilization of the strain Streptomyces spec. MHW 846 DSM 4950 Utilization of Result: ______________________________________ L-Arabinose - Sucrose - D-Xylose - Inositol - D-Mannitol - D-Fructose - Rhamnose - Raffinose - Cellulose - D-Glucose + ______________________________________ + = Utilization - = No utilization
The concentration and isolation of the strain was carried out by the customary methods of Actinomycetes isolation by plating out soil samples suspensions on Petri dishes, four to six weeks' incubation and repeated s

REFERENCES:
Biochim. Biophys. Acta 577, Seite 324, (1975).
C. S. Cummins and H. Harris, J. Gen. Microbiol. 15, Seiten 9-10, (1956).
R. M. Kroppenstedt, Chemical Methods in Bacterial Systematics, Seiten 173-199, (1985).
E. B. Shirling and D. Gottlieb, Int. Journal Syst. Bact. 16, Seiten 313-340, (1966).
S. T. Williams and T. Cross, (1971), Actinomycetes, Methods in Microbiology, 4, Seiten 295-334.
D. English and B. R. Andersen, Journal of Immunological Methods 5, (1974), Seiten 249-252.
Duling, MVR 5, Seiten 423-429, 1973.
N. Onishi et al.; A macrocyclic antibiotic M-230-B produced by myxococcus xanthus isolation and characterization, Journal of The Journal of Antibiotics, vol. 37, No. 1, Seiten 13-19. (Jan. 1984).

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