Oidiodendron strain for the production of terpenoid lactone...

Chemistry: molecular biology and microbiology – Micro-organism – per se ; compositions thereof; proces of... – Fungi

Reexamination Certificate

Rate now

  [ 0.00 ] – not rated yet Voters 0   Comments 0

Details

C435S132000

Reexamination Certificate

active

06391616

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 thought 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-1 RA), 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-1 RA. 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's 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
Accordingly, 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
is H;
R
8
is OH; or with proviso that
when X is O and R
2
is absent, the dotted line between the 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.
DETAILED DESCRIPTION OF THE INVENTION
Preferred compounds of this invention include a compound of formula (I) wherein R
1
is O; X is O; R
2
is absent; R
3
is OH; R
4
is H; R
5
and R
6
form, together faith carbon to which they are attached, an oxirane ring; and R
7
and R
8
form, together with carbon to which they are attached, a lactone ring ([5bS-(1aR*,5b&bgr;,8a&agr;,8b&agr;,10a&agr;,10b&bgr;)]-5b,6,7,8,8a,8b,10a,10b-octahydro-2-hydroxy-5b,8a-dimethyl-2H,4H,9H-furo[2′,3′,4′:4,5]oxireno[2,3]naphtho[2,1-c]pyran-4,9-dione);
a compound of formula (I) wherein R
1
is O; X is O; R
2
is absent; R
3
is H; R
4
is H; R
5
and R
6
form, together with carbon to which they are attached, an oxirane ring; and R
7
and R
8
form, together with carbon to which they are attached, a lactone ring ([5bS-(1aR*,5b&bgr;,8a&agr;,8b&agr;,10a&agr;,10b&bgr;)]-5b,6,7,8a,8b,10a,10b-octahydro-5b,8a-dimethyl-2H,4H,9H-furo[2′,3′,4′:4,5]oxireno[2,3]naphtho[2,1-c]pyran-4,9-dione);
a compound of formula (I) wherein R
1
is O; X is O; R
2
is absent; R
3
is methoxycarbonylmethyl; R
4
is H; R
5
and R
6
form, together with carbon to which they are attached, an oxirane ring; and R
7
and R
8
form, together with carbon to which they are attached, a lactone ring ([5bS-(1aR*,5b&bgr;,8a&agr;,8b&agr;,10a&agr;,10b&bgr;)]-5b,6,7,8,8a,8b,10a,10b-octahydro-2-methoxycarbonylmethyl-5b,8a-dimethyl-2H,4H,9H-furo[2′,3′,4′:4,5]oxireno[2,3]naphtho[2,1-c]pyran-4,9-dione);
a compound of formula (I) wherein R
1
is O; X is O; R
2
is absent; R
3
is methoxy; R
4
is H; R
5
and R
6
form, together with carbon to which they are attached, an oxirane ring; and R
7
and R
8
form, together with carbon to which they are attached, a lactone ring ([2R-(1aR*,2&bgr;,5b&bgr;,8a&agr;,8b&agr;,10a&agr;,10b&bgr;)]-5b,6,7,8,8a,

LandOfFree

Say what you really think

Search LandOfFree.com for the USA inventors and patents. Rate them and share your experience with other people.

Rating

Oidiodendron strain for the production of terpenoid lactone... does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Oidiodendron strain for the production of terpenoid lactone..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Oidiodendron strain for the production of terpenoid lactone... will most certainly appreciate the feedback.

Rate now

     

Profile ID: LFUS-PAI-O-2843478

  Search
All data on this website is collected from public sources. Our data reflects the most accurate information available at the time of publication.