Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Preparing heterocyclic carbon compound having only o – n – s,...
Reexamination Certificate
2000-09-08
2002-07-09
Saucier, Sandra E. (Department: 1651)
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Preparing heterocyclic carbon compound having only o, n, s,...
Reexamination Certificate
active
06416979
ABSTRACT:
TECHNICAL FIELD
This invention relates to novel 5-substituted picolinic acid compounds, and particularly to novel 5-substituted picolinic acid compounds produced by fermentation of a fungus Marasmiellus sp., which has been deposited as FERM BP-5735. This invention also relates to processes for producing the 5-substituted picolinic acid compounds, and a pharmaceutical composition comprising the same, which is usefull in the treatment of IL-1 and TNF mediated diseases.
BACKGROUND ART
Interleukin-l (IL-1) and tumor necrosis factor (TNF) are biological substances produced by a variety of cells, such as monocytes or macrophages. 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, osteoartbritis, 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, mbella arthritis, and acute synovitis. Recent evidence also links IL-1 activity to diabetes (T. Mandrup-Poulsen et al., Allergy, 1985, 40, 424). The only IL-1 blocker available today is the natural IL-1 receptor antagonist (IL-1RA), which is easily metabolized in the bloodstream with a very short halfAife (E. V. Granowitz et al., Cytokine, 1992, 4, 353). 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 known (C. C. George et al., Exp. Opin. Ther. Paten, 1996, 6 (1), 41).
Excessive or unregulated TNF production has also 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 receptor 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 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 may be necessary for normal host defense mechanisms. This finding has added to the excitement concerning the identification of a unique metalloproteinase enyyme 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).
Inhibitors of interleukin 1, 6 and 8 and TNF are described in PCT application US94/07969 which was published on Jan. 26 1995. The inhibitors of TNF are also described in PCT application US94/04950 which was published on Nov. 24 1994. Substituted picolinic acid compounds have been known to be produced by fungus. These include phenopicolinic acid (5-(4-hydroxylbenzyl)picolinic acid) (T. Nakamura et al., J. Antibiotics, 27:477-, 1975), fusaric acid (5-butylpicolinic acid)( H. Hidaka et al., J.Antibiotics, 22:228-, 1969), and fusarinolic acid (K. Steiner et al., Helv. Chim. Acta, 54:845-, 1971).
The object of the present invention is to provide novel 5-substituted picolinic acid compounds having an excellent activities for TNF and/or IL-1 biosynthesis inhibition and a pharmaceutically composition comprising the same. Another object is to provide processes for producing the novel 5-substituted picolinic acid compounds.
BRIEF DISCLOSURE OF THE INVENTION
Accordingly, the present invention provides novel 5-substituted picolinic acid compounds of formula (I):
or a pharmaceutically acceptable salt thereof,
wherein R
1
and R
2
are independently H, C
2
-C
6
acyl or halo-substituted benzoyl; and R
3
is —C(O)O—C
1
-C
6
alkyl, C(O)OH, CN, CONH
2
, CONHCH
3
,° CON(CH
3
)2, 1-methyltetrazole or 2-methyltetrazole, with the proviso that when R
1
is acetyl and R
3
is methoxycarbonyl, R
1
is not H; and that when R
3
is CN, CONH
2
, CONHCH
3
, CON(CH
3
)
2
, 1-methyltetrazole or 2-methyltetrazole, R
1
and R
2
are H.
Preferred compounds of this invention are those of formula (I) shown above, wherein R
3
is —C(O)O—C
1
-C
6
alkyl or C(O)OH, with the proviso that when R
2
is acetyl and R
3
is methoxycarbonyl, R
1
is not H.
The present invention also provides a culture of Marasmiellus sp. FERM BP-5735, which is capable of producing the 5-substituted picolinic acid compounds, especially those of formula (I) wherein wherein R
1
and R
2
are H, and R
3
is methoxycarbonyl (methyl 5-(1,2-dihydroxypropyl)-2-pyridinecarboxylate), or R
1
is acetyl, R
2
is H, and R
3
is methoxycarbonyl (methyl 5-(1-acetoxy-2-hydroxypropyl)2-pyridinecarboxylate).
Further, the present invention provides a process for producing the 5-substituted picolinic acid compounds of formula (X), which comprises cultivating a microorganism having identifying characteristics of Morasmiellus sp., FERM BP-5735, or a mutant or recombinant form thereof.
The present invention further provides a process comprising additional steps of isolating the 5-substituted picolinic acid compounds from the fermentation broth and chemically modifying the isolated compounds.
Also, the present invention provides a pharmaceutical composition for use in the treatment of IL-1 and/or TNF mediated diseases, which comprises the 5-substituted picolinic acid compounds of formula (1) wherein R
1
and R
2
are H; and R
3
is methoxycarbonyl (methyl 5-(1,2-dihydroxypropyl)-2-pyridinecrbo xylate); R
1
is acetyl; R
2
is H; and R
3
is methoxycarbonyl (methyl 5-(1-acetoxy-2-hydroxypropyl)-2-pyridinecarboxylate); R
1
and R
2
are H; and R
3
is C(O)OH (5-(1,2-dihydroxypropyl)-2-pyridinecarboxylic acid); or R
1
and R
2
are acetyl; and R
3
is methoxycarbonyl (methyl 5-(1,2-diacetoxypropyl)-2-pyridinecarboxylate); or pharmaceutically acceptable salt thereof in an amount effective in such treatments, and a pharmaceutically acceptable carrier.
Also, the present invention provides a method for the.treatment of IL-1 and/or TNF mediated diseases, which comprises administering to said subject an antinflammation amount of the compound of formula (1) wherein R
1
and R
2
are H; and R
3
is methoxycarbonyl (methyl 5-(1,2-dihydroxypropyl)-2-pyridinecarboxylate); R
1
is acetyl; R
2
is H; and R
3
is methoxycarbonyl (methyl 5-(1-acetoxy-2-hydroxypropyl)-2-pyridinecarboxylate); R
1
and R
2
are H; and R
3
is C(O)OH (5-(1,2-dihydroxypropyl)-2-pyridinecarboxylic acid); or R
1
and R
2
are acetyl; and R
3
is methoxyca
Hirai Hideo
Ichikawa Katsuomi
Kojima Nakao
Nishida Hiroyuki
Satake Kunio
Benson Gregg C.
Kleiman Gabriel L.
Pfizer Inc.
Richardson Peter C.
Saucier Sandra E.
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