Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-01-15
2001-05-01
Owens, Amelia (Department: 1651)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S285000, C514S468000, C549S276000, C549S298000, C546S062000
Reexamination Certificate
active
06225339
ABSTRACT:
TECHNICAL FIELD
This invention relates to terpenoid lactone compounds and particularly to terpenoid lactone compounds produced by fermentation of an fungus
Oidiodendron griseum
, which has been deposited as FERM BP-5778. This invention also relates to processes for producing the terpenoid lactone compounds, and a pharmaceutical composition comprising the same, which is useful in the treatment of IL-1 and TNF mediated diseases.
BACKGROUND ART
Interleukin-1 (IL-1) and tumor necrosis factor (TNF) are biological substances produced by a variety of cells, such as monocytes or macrophages. The IL-1 and TNF have been demonstrated to mediate a variety of biological activities though to be important in immunoregulation and other physiological conditions such as inflammation.
There are many disease states in which excessive or unregulated IL-1 production is implicated in exacerbating and/or causing the disease. These include rheumatoid arthritis, osteoarthritis, endotoxemia and/or toxic shock syndrome, other acute or chronic inflammatory disease states such as the inflammatory reaction induced by endotoxin or inflammatory bowel disease; tuberculosis, atherosclerosis, muscle degeneration, cachexia, psoriatic arthritis, Reiter's syndrome, rheumatoid arthritis, gout, traumatic arthritis, rubella arthritis, and acute synovitis. Recent evidence also links IL-1 activity to diabetes and pancreatic b cells. The only IL-1 blocker available today is the natural IL-1 receptor antagonist (IL-1RA), a polypeptide which is easily metabolized in the bloodstream with a very short half-life. Thus, active research has been carried out to develop stable, long-acting agents which can be taken by oral administration or by parenteral injections rather than by intravenous infusion, which is required for IL-1RA. A number of compounds as IL-1 receptor antagonists, IL-1 biosynthesis inhibitors, and IL-1 converting enzyme inhibitors have been claimed.
Excessive or unregulated TNF production has been implicated in mediating or exacerbating a number of diseases including rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions; sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoisosis, bone resorption diseases, reperfusion injury, acquired immunodeficiency syndrome (AIDS), AIDS related complex (ARC), keloid formation, scar tissue formation, Crohn'disease, ulcerative colitis, or pyresis. Although significant progress in developing potent TNF modulators has been achieved through the use of recombinantly derived proteins including monoclonal antibodies and soluble receptors, the development of biosynthesis inhibitors and antagonists has been less successful. Recently a number of small molecule TNF modulators have been claimed. Most of them which specifically inhibit TNF production do so by increasing intracellular cyclic adenosine monophosphate (cAMP) which ultimately blocks TNF gene expression (Y. KATAKAMI et al.,
Immunology
, 1988, 64, 719). The most important of these compounds are the rolipram and pentoxifylline-related phosphodiesterase IV (PDE IV) inhibitors which are being activity pursued by a number of pharmaceutical companies (A. BADGER et al.,
Circul. Shock,
1994, 44, 188). The ability of thalidomide to block TNF production contributes to its therapeutic properties in humans (E. P. SAMPAIO et al.,
J. Exp. Med.,
1991, 73, 699). Recent studies suggest that cell-associated TNF may be necessary for normal host defense mechanisms. This finding has added to the excitement concerning the identification of a unique metalloproteinase enzyme which is responsible for the proteolytic processing of TNF. Inhibitors of matrix metalloproteinase-related enzyme have appeared (K. M. MOHLER et al.,
Nature,
1994, 370, 218).
The object of the present invention is to provide the terpenoid compounds having an excellent activities for TNF and/or IL-1 biosynthesis inhibition and a pharmaceutical composition comprising the same. Another object is to provide processes for producing the terpenoid compounds.
BRIEF DISCLOSURE OF THE INVENTION
According, the present invention provides novel terpenoid compounds of the following formula:
wherein the dotted line is an optional bond;
R
1
is O or OH;
X is O or N, or absent;
R
2
is H, C
1
-C
5
alkyl, or benzyl or absent;
R
3
is H, OH, C
1
-C
4
alkoxycarbonyl-C
1
-C
3
alkyl, C
1
-C
4
alkoxycarbonyl-C
1
-C
3
alkenyl, C
1
-C
4
alkoxy or C
1
-C
4
alkylthio;
R
4
is H or C
1
-C
5
alkoxy;
R
5
is H, C
1
-C
4
alkylthio or C
1
-C
4
alkoxycarbonyl-C
1
-C
4
alkylthio or absent;
R
6
is H or OH; or
R
5
and R
6
form, together with the carbon atom to which they are attached, an oxirane ring;
R
7
and R
8
form, together with the carbon to which they are attached, a lactone ring;
with proviso that
when X is O and R
2
is absent, the dotted line between 3- and 4-positions is a single bond;
when R
5
is absent, R
7
is H and R
8
is OH; and
when R
1
is O; and R
5
and R
6
form, together with the carbon atom to which they are attached, an oxirane ring; R
3
is not methoxy.
The present invention also provides a culture of
Oidiodedron griseum
which is capable of producing the terpenoid compounds.
Further, the present invention provides a process for producing the terpenoid compounds of formulas (I) which comprises cultivating a microorganism having identifying characteristics of FERM BP-5778; or a mutant or recombinant form thereof, and, if required, isolating terpenoid lactone compounds from the fermentation broth.
Also, the present invention provides a pharmaceutical composition for use in the treatment of IL-1 and TNF mediated diseases, which comprises the terpenoid compounds of formulas (I) and a pharmaceutically acceptable carrier.
Also, the present invention provides a method for the treatment of IL-1 and TNF mediated diseases, which comprises administering to said subject an antiinflammation amount of the compounds of formulas (I) and a pharmaceutically acceptable carrier.
REFERENCES:
Tetrahedron Let. 36, pp. 5255.
Tetrahedron Let., vol. 25, No. 4 pp. 469-472, 1984.
Katakami et al., Immunology, 1988, 64, 719.
Badger et al., Circul. Shock, 1994, 44, 188.
Mohler et al., Nature, 1994, 370, 219.
Sampaio et al., J. Exp. Med, 1991, 73, 699.
Ichikawa Katsuomi
Ikunaka Masaya
Kojima Nakao
Nishida Hiroyuki
Yoshikawa Nobuji
Benson Gregg C.
Kleiman Gabriel L.
Owens Amelia
Pfizer Inc.
Richardson Peter C.
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