Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1997-11-12
1999-02-23
Trinh, Ba K.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
549343, 549344, C07D30794
Patent
active
058745920
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/JP97/01135 dated Apr. 2, 1997.
TECHNICAL FIELD
The present invention relates to a novel interleukin-1.beta. production inhibiting substance which is produced by a microorganism belonging to the genus Penicillium. The compound has antibacterial activity and interleukin-1 production inhibitory activity and is useful for the treatment of rheumatoid arthritis, gout, osteoarthritis, osteoporosis, periarteritis nodosa, ulcerative colitis, chronic nephritis, active chronic hepatitis, septicemia, endotoxin shock, atherosclerosis, pyrexia of infectious diseases, diffuse scleroderma, and the like.
BACKGROUND ART
Interleukin-1 (hereinafter referred to as IL-1) is a protein having a molecular weight of 17.5 kDa which is produced by a variety of cells in the body such as macrophage, monocyte, neutrophil, fibroblast, skin keratinocyte, hepatic Kupffer cell, renal glomerular mesangial cell, brain astroglia, and angioendothelial cell. IL-1 includes .alpha.-form having an isoelectric point (pI) of 5 and .beta.-form having pI of 7. At present, it is known that the .alpha.-form and the .beta.-form exhibit the same activity.
IL-1 is known to have various biological activities. That is, IL-1 is deemed to act as a factor that enhances multiplicative division of lymphocytes and as a cofactor that enhances multiplication of B cells and production of antibodies. Further, it is considered that IL-1 acts on arachidonic acid cascade in the temperature center of the hypothalamus to increase the synthesis of prostaglandin E.sub.2, thereby causing pyrexia. Furthermore, it is shown that the activity of IL-1 is significantly increased in the serum of patients suffering from septicemia or Crohn's disease and in the cavum articulare of patients who suffer from articular rheumatism. This suggests the participation of IL-1 in the attack and progress of these diseases. Suppression of the production of IL-1 is considered to be effective for alleviating the symptoms that occur through IL-1.
Examples of known compounds having IL-1 production inhibitory activity are synthetic compounds such as naphthalene derivatives (Japanese Published Unexamined Patent Application No. 59743/92), 3-arylisothiazole derivatives (Japanese Published Unexamined Patent Application No. 74121/92), and zingerol derivatives (Japanese Published Unexamined Patent Application No. 202127/92). Japanese Published Unexamined Patent Application No. 157386/91!, and However, the structures of these compounds are different from the structure of the compound represented by formula (I), and there has been no report on IL-1 production inhibition by any of these compounds.
DISCLOSURE OF THE INVENTION
The present invention relates to a compound having IL-1 production inhibitory activity which is represented by formula (I): ##STR2##
The compound represented by formula (I) is hereinafter referred to as EI-2128-1.
The physicochemical properties of EI-2128-1 are shown below.
The data were obtained by using the following instruments.
Melting point: Yanagimoto, Micro melting point apparatus
Mass spectrum: JEOL LTD., JMS HX/HX110A Mass spectrometer
UV absorption spectrum: Shimadzu Corporation, UV-2200 Ultraviolet spectrophotometer
IR absorption spectrum: JEOL LTD., JIR-RFX3001 Infrared spectrophotometer
NMR spectrum: JEOL LTD., .alpha.400 Nuclear magnetic resonance
Specific rotation: Nippon Bunko Kogyo Co., Ltd., DIP-370 Digital polarimeter
Physicochemical Properties of EI-2128-1
Color and form of the substance: White powder
Melting point: 70.degree.-71.degree. C. CHCl.sub.3)
Elementary analysis: Found: C, 63.16; H, 8.44; N, 3.29% Calcd. for C.sub.23 H.sub.35 NO.sub.6.H.sub.2 O: C, 62.85; H, 8.48; N, 3.19% H.sub.36 NO.sub.6 : 422.2542
Molecular formula: C.sub.23 H.sub.35 NO.sub.6
UV absorption spectrum: .lambda..sub.max (CH.sub.3 OH); 220 nm (sh)
IR absorption spectrum: V.sub.max (KBr); 3390, 1668, 1635, 1539, 984, 930 cm.sup.-1
NMR spectrum: .delta. ppm (multiplicity, coupling constant, integration) .sup.1 H-NMR (CDCl.sub.3, 400 MHz) 6.74 (dd, 8.3, 1
REFERENCES:
patent: 5064856 (1991-11-01), Garrity et al.
The Journal of Antibiotics, vol. 41, No. 12 (Dec. 1988) 1780-1784.
The Journal of Antibiotics, vol. 45, No. 10 (Oct. 1992) 1592-1598.
J. Am. Chem. Soc., vol. 110, No. 24 (1988) 8242-8244.
Tetrahedron Letters, vol. 32, No. 45 (1991) 6613-6616.
Tetrahedron Letters, vol. 34, No. 35 (1993) 5519-5522.
J. Chem. Soc., Perkin Trans., vol. 1, No. 12 (1996) 1385-1393.
Agatsuma Tsutomu
Ando Katsuhiko
Koizumi Fumito
Kondo Hidemasa
Matsuda Yuzuru
Kyowa Hakko Kogyo Co. Ltd.
Trinh Ba K.
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