Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Preparing heterocyclic carbon compound having only o – n – s,...
Patent
1998-03-20
1999-03-02
Richter, Johann
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Preparing heterocyclic carbon compound having only o, n, s,...
435171, 514280, 548418, 549382, A61K 0000, C07D20956, C07D31179, C12P 102
Patent
active
058769846
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to novel compounds having antiviral activities. In particular, the invention relates to sesquiterpene derivatives having inhibitory activities against influenza A and B, a process for preparing the same and pharmaceutical compositions containing such derivatives.
BACKGROUND ART
The development of effective therapeutic agents for viral disease is one of the most important subject matters in the field of medicine and pharmacy. As in the case of other virus diseases, there have been no established method for treating the commonest viral disease, influenza. Human influenza viruses are classified into types A, B and C, depending on their internal antigens, among which types A and B are known to cause intensive symptoms. Amantadine has been known for more than 20 years as a chemotherapeutic agent though, efficiency thereof has not been evaluated yet. Accordingly, there has been a strong demand for the development of novel and effective anti-influenza agents.
It has been known that microorganisms can produce various useful compounds. For example, Stachybotrys, a fungus, was known to produce compounds having Japanese Patent Publication (KOKAI) 128266/1994; (3) Japanese Patent Publication (KOKAI) 239869/1994; (4) Japanese Patent Publication (KOKAI) 256350 1994; (5) J. Org. Chem. 57 6700-03 (1992)!.
These references, however, merely describe that such compounds have nerve growth factor (NGF) activating effects and are useful for treatment of Alzheimer's disease (References 1-4) or that such compounds have antibacterial and antifungal effects (Reference 5). Thus, it has not been known that Stachybotrys produces compounds having antiviral activities.
Further, the following references describe compounds having spiro-type fused ring of tetrahydrofuran ring: (6) Japanese Patent Publication (KOKOKU) 11634/1982 (U.S. Pat. No. 4,229,466); (7) Japanese Patent Publication (KOKOKU) 32170/1987 (U.S. Pat. No. 4,831,053); (8) Japanese Patent Publication (KOKAI) 145161/1995; (9) WO 95 26344. Among these references, References (6), (7) and (9) merely show that their compounds are useful in the testament of anti-complement activity
ephritis, hepatitis, and depression/mania, respectively, and Reference (8) merely shows that the compounds have retrovirus protease inhibitory effects. Although a neuraminic acid derivative (4-guanidino-Neu5Ac2en; a neuraminidase inhibitor) (Japan Glaxo) has been proposed as a compound having an antiviral activity so far, the said compound, when administered orally or intraperitoneally, has not a satisfactory activity against influenza A and B (Antimicrob. Agent Chemother. 37 (7) 1473-1479 (93.7); Antimicrob. Agent Chemother. 38(10) 2270-2275 (91.10); ICAAC (34th) 265 (94.10). Therefore, the development of novel and effective antivirus agents, in particular, those effective against influenza orally or parenterally has long been demanded.
The present inventors have found that, when cultivated in an appropriate medium, fungus strains belonging to the Stachybotrys genus produce a substance(s) having a strong inhibitory activity against virus. The substance has been isolated, purified, structurally elucidated, and characterized. As a result, the substance was revealed that it is a sesquiterpene derivative having a novel structure containing a fused ring with a 5-membered ring and a pyran ring and that it has remarkable activity against virus, in particular, influenza A and B viruses. Furthermore, the present inventors have succeeded in preparing a series of useful compounds having an antiviral activity through the chemical modification of the compound derived from microorganisms.
DISCLOSURE OF INVENTION
Thus, the present invention provides a compound of the formula (I): ##STR2## wherein
R.sup.1 is hydrogen; and R.sup.2 is hydrogen, a halogen, azido, an optionally substituted lower alkyl, an optionally substituted lower alkylcarbonyl, an optionally substituted arylcarbonyl, an optionally substituted heteroarylcarbonyl, --OR.sup.7 (wherein R.sup.7 is hydroge
Fujiwara Tamio
Horibe Isao
Kamigauchi Toshiyuki
Kawamura Yoshimi
Tani Hiroyoshi
Richter Johann
Shionogi & Co., Ltd
Solola Taofiq A.
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