Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1987-10-19
1989-12-12
Shah, Mukund J.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C07D49812
Patent
active
048868841
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to novel derivatives of cervinomycin based antibiotics and a process for producing the same.
BACKGROUND TECHNIQUE
Several compounds have been known as antibiotics having xanthone in their basic structure and they include: albofungin (=Kanchanomycin, BA-180265*, P-42-1**) as reported in Tetrahedron Letters, 18, 1751 (1972), Antimicrob. Agent & Chemoth., 767 (1962)*, and J. Antibiotics., 26, 65 (1973)**, lysolipin I as reported in Arch. Microbid., 106, 175 (1975) and Helv. Chim. Acta., 60, 178 (1977); antibiotic AM-5344-A.sub.1 as disclosed in Japanese Patent Application (OPI) No. 9690/1983 (this antibiotic was later designated Cervinomycin A.sub.1); and antibiotic AM-5344-A.sub.2 as disclosed in Japanese Patent Application (OPI) No. 102897/1982 (this antibiotic was later designated Cervinomycin A.sub.2) now U.S. Pat. No. 4,666,715.
The present inventors investigated the solubility and toxicity of the cervinomycin compounds mentioned above and found that they were very poorly soluble in a variety of solvents, had strong toxicity and that they exhibited weak activity against Mycoplasmas and certain Gram-positive bacteria.
Under these circumstances, it is necessary for the purposes of medical treatment of human and animal subjects to develop novel derivatives of cervinomycin that have enhanced solubility, improved antibacterial activity and reduced toxicity.
DISCLOSURE OF THE INVENTION
Therefore, the present invention analyzed the structures of Cervinomycin A.sub.1 and A.sub.2 and undertook synthesis of various derivatives thereof with a view to solving the aforementioned problems of these antibiotics. As a result, the present invention found that novel cervinomycin derivatives of formula [1] noted below exhibit strong activity against Gram-positive and Gram-negative bacteria, as well as pathogenic microorganisms like mycoplasmas. The derivatives exhibit particularly high activity against mycoplasmas that are the causative organism of Mycoplasma pneumonia, and against a variety of anaerobic organisms. The present inventors also found that these derivatives had enhanced solubility in solvents and that yet their toxicity was markedly reduced as compared with cervinomycins and known related antibiotics having xanthone in their basic structure. The present invention has been accomplished on the basis of these findings.
Accordingly, the present invention is to provide a compound represented by formula (1): ##STR3## wherein ring B represents ##STR4## at least one of R.sub.1, R.sub.2 and R.sub.3 is an acyl group or an alkyl group, and the others are a hydrogen atom; and R.sub.4 is a hydrogen atom or an alkyl group. The present invention also provides a process for producing such a compound.
Compound [1] of the present invention can be produced by reacting Cervinomycin A.sub.1 or A.sub.2 with an acylating or alkylating agent in a solvent. According to this reaction, the hydroxyl group in Cervinomycin A.sub.1 or A.sub.2 having the chemical structure shown below is acylated with an acylating agent or O- or C-alkylated with an alkylating agent. ##STR5## wherein ring A represents ##STR6## in Cervinomycin A.sub.1, and ##STR7## in Cervinomycin A.sub.2.
The acylating agent may be selected from among known aliphatic carboxylic acids or reactive derivatives thereof. The term "reactive derivatives" means reactive derivatives of a carboxyl group that are generally used in esterifying a hydroxyl group, and examples of such derivatives include acid halides such as acid chlorides and acid bromides, as well as acid azides, acid anhydrides, mixed acid anhydrides, and active esters. Other acylating agents known in the art may of course be used. If aliphatic carboxylic acids are used as such, condensing agents such as carbodiimides (e.g., N,N'-dicyclohexylcarbodiimide (DCC)) and N,N'-carbonylbisimidazole may be used in combination for achieving acylation.
The alkylating agent may be selected from among known alkylating agents such as alkyl halides (e.g., alkyl iodides and alkyl bromi
REFERENCES:
patent: 4814449 (1989-03-01), Chang-ging et al.
Gurevich et al., "Structure of Albofungin", Tethrahed, Lett. No. 18 pp. 1751-1754, (1972).
Dobler et al., "Metabolites of Microorganisms", Helv. Chim. Acta. vol. 60 No. 19 pp. 178-185 (1977).
Omura et al., "Struct. of Gervinomycin", Chem. Abs. vol. 106: 2725 v, p. 443 (1987).
Qi et al., "Prep. of Antibiotic and Antitumor Subst.", Chem. Abs. vol. 108: 130060d, p. 602 (1988).
Journal of the American Chemical Society, 108:6088-6089 (Sep., 1986).
The Journal of Antibiotics, 39:1636-1638 (Nov. 1986).
Iwai Yuzuru
Nakagawa Akira
Omura Satoshi
Rozycki Andrew C.
Shah Mukund J.
The Kitazato Institute
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