Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Preparing heterocyclic carbon compound having only o – n – s,...
Patent
1997-08-14
2000-06-13
Witz, Jean C.
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Preparing heterocyclic carbon compound having only o, n, s,...
4352541, 514451, 549297, C12P 1704, C12N 114, A01N 4316, C07D30777
Patent
active
060748559
DESCRIPTION:
BRIEF SUMMARY
CROSS-REFERENCE TO RELATED APPLICATIONS
This application is the National Stage of copending International Application PCT/IB95/00217, filed Mar. 30, 1995, entitled "Process for Preparing Spirolaxine and Spirolaxine Methyl Ether".
BACKGROUND OF THE INVENTION
This invention relates to processes for producing the compound of formula (I) ##STR2## (hereinafter referred to as spirolaxine); and to processes for producing the compound of formula (II) ##STR3## (hereinafter referred to as spirolaxine methyl ether).
Spirolaxine is a known antibiotic which can be isolated from the fungus Chrysosporium pruinosum ATCC 15155. Spirolaxine is reported to have weak bacteriostatic activity against Bacillus cereus, Bacillus subtillis and Escherichia coli. Arnone et al., Phytochemistry, 1990, 29, 613-616. Further, spirolaxine is reported to have no antifungal activity against Aspergillus niger, Botrytis cinerea, Cladosporium, cucumerinum, Ophiostoma ulmi and Saccharomyces cerevisiae. Arnone et al., Phytochemistry, 1990, 29, 613-616.
Gastric and duodenal ulcers affect a significant portion of the human population worldwide. Currently, the usual treatment for both gastric and duodenal ulcers involves treatment of the patient with H.sub.2 blockers. While generally effective in healing ulcers, ulcer relapse occurs in up to 90% of patients within a year of discontinuing H.sub.2 blocker therapy. O'Connor, H. J., Postgraduate Medical Journal, 1992, 68, 549-57. Thus, patients must continue the treatment for many years or risk a recurrence of the ulcer. It is now known that ulcer healing drugs such as colloidal bismuth subcitrate (CBS) are helicobactericidal and as such CBS is used in combination with H.sub.2 blockers to treat ulcers. O'Connor, ibid. Additionally, CBS, an H.sub.2 blocker and amoxicillin have been used in combination to treat ulcer patients. O'Connor, ibid.
Helicobacter pylori has recently been demonstrated to be a major causative agent in gastric and duodenal ulcers and other gastroduodenal disorders, diseases and adverse conditions. Thus, antibiotic therapy to eliminate Helicobacter pylori from the gastroduodenal tract would remove the root cause of said gastroduodenal disorders, diseases and adverse conditions and eliminate the need for an ulcer patient to continue long and costly treatment with H.sub.2 blockers and the like. None of the foregoing treatments are capable of 100% eradication of Helicobacter pylori.
Spirolaxine and spirolaxine methyl ether are potent helicobactericidal compounds, as disclosed hereinbelow. A helicobactericidal compound is a compound which kills Helicobacter pylori. Therefore spirolaxine and spirolaxine methyl ether possess utility in treating gastroduodenal disorders, diseases and adverse conditions and particularly in treating gastric and duodenal ulcer and preventing gastric cancer.
It has now been found that spirolaxine and spirolaxine methyl ether are produced by various strains of fungi belonging to the genera Sporotrichum and Phanerochaete.
SUMMARY OF THE INVENTION
This invention is directed to a process for preparing the compound of formula (I) ##STR4## comprising fermenting a culture of a fungus selected from the group consisting of Sporotrichum pruinosum FD 29585, ATCC 74327; Sporotrichum pruinosum FD 29454, ATCC 74329; Sporotrichum pruinosum FD 29586, ATCC 74328; Sporotrichum pruinosum FD 29458, ATCC 74330; and Phanerochaete chrysosporium LN 3576, ATCC 74326; and isolating said compound of formula (I).
This invention is also directed to a process for preparing the compound of formula (II) ##STR5## comprising fermenting a culture of a fungus selected from the group consisting of Sporotrichum pruinosum FD 29585, ATCC 74327; Sporotrichum pruinosum FD 29454, ATCC 74329; Sporotrichum pruinosum FD 29586, ATCC 74328; and Phanerochaete chrysosporium LN 3576, ATCC74326; and isolating said compound of formula (II).
With respect to the compounds of formula (I) and (II) prepared by the process of this invention, it is to be understood that there are numerous stereoisomeric forms of
REFERENCES:
ATCC Catalogue of Filamentous Fungi (1991) 18th edition, pp. 105, 303, 304, 392.
Arnone et al., Phytochemistry, 1990, 29, No. 2, pp. 613-616.
Centraalbureau Voor Schimmelcultures, Delft `List of Cultures 1987`, 1987, Institute of the Royal Netherlands Academy of Arts and Sciences, Baarn, NL see pp. 76, 238, and 301.
O'Conner, H.J., Postgraduate Medical Journal, 1992, 68, 549-57.
Guadliana Mark A.
Huang Liang H.
Kaneko Takushi
Benson Gregg C.
Hanley Susan
Pfizer Inc.
Richardson Peter C.
Ronau Robert T.
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