Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
2000-08-14
2002-12-17
O'Sullivan, Peter (Department: 1621)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C514S359000, C514S383000, C514S520000, C514S521000, C514S522000, C514S529000, C514S530000, C514S538000, C514S562000, C514S601000, C514S602000, C514S603000, C514S604000, C514S373000, C548S166000, C548S250000, C548S252000, C548S253000, C548S255000, C548S269400, C558S418000, C560S012000, C560S013000, C562S430000, C564S091000, C564S092000
Reexamination Certificate
active
06495604
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a novel cycloalkene derivative which has an inducible nitric oxide (NO) synthetase-derived nitric oxide production-inhibiting effect and/or an inhibitory effect on the production of inflammatory cytokines such as TNF-&agr;, IL-1, IL-6 and the like, and which is useful as a prophylactic and therapeutic agent against diseases including cardiac diseases, autoimmune diseases, inflammatory diseases, central nervous system diseases, infectious diseases, sepsis, septic shock and the like, a method for producing the same and a use of the same.
BACKGROUND
Nitric oxide (NO) is known to have various important in vivo activities in mammals such as a vasodilating factor in the vascular system [Pharmacol. Rev. Vol. 43, p. 109-142 (1991)], a tumoricidal and bactericidal effect in the immune system [Curr. Opin. Immunol., Vol. 3, p. 65-70 (1991)], and a neurotransmitter in the nervous system [Neuron, Vol. 8, p. 3-11 (1992)]. NO is produced principally from L-arginine by NO synthetase (NOS) and currently is known to exist as three inducible isoforms, namely, neuronal NOS, endothelial NOS and an inducible NOS (iNOS) [Cell, Vol. 70, p. 705-707 (1992)], and the former two are referred to also as constitutive NOS (cNOS) in view of their mode of existence, which is in contrast with the latter iNOS.
cNOS occurs in the vascular endothelial cells and neurons, and is calcium calmodulin dependent and activated by various receptor stimulations to produce a small amount of NO, whereby being considered to contribute to the physiological regulatory effects described above. On the other hand, iNOS is induced in macrophages and a neutrophile by various cytokines and bacterial lipopolysaccharides (LPS) to produce a large amount of NO continuously, which makes it to be believed to have not only the pharmacological effects described above but also cell- and tissue-damaging effects at the site of the production [Immunol. Today, Vol.13, p.157-160 (1992)]. Cells known to express iNOS other than those described above may, for example, be hepatocytes, Kupffer cells, glia cells, vascular smooth muscle cells, vascular endothelial cells, myoendocardium, myocardial cells, mesangial cells, chondrocytes, synovial cells, pancreatic &bgr; cells, osteoclasts and the like [FASEB J., Vol.6, p.3051-3064 (1992), Arch. Surg., Vol.128, p.396-401 (1993), J. Biol. Chem., Vol.44, p.27580-27588 (1994), J. Cell. Biochem., Vol.57, p.399-408(1995)], and NO produced in these cells and tissues is known to be involved in various diseases and pathologies. Accordingly, a substance which inhibits the NO production by iNOS inducible cells is considered to be effective as a prophylactic and therapeutic agent against various diseases such as arteriosclerosis, myocarditis, cardiomyopathy, cerebral ischemic failure, Alzheimer's disease, multiple sclerosis, septic shock, chronic rheumatoid arthritis, osteoarthritis, gastric ulcer, duodenal ulcer, ulcerative colitis, diabetes, glomerular nephritis, osteoporosis, pneumonia, hepatitis, psoriasis, graft rejection and pain. From this point of view, several iNOS-inhibiting compounds such as L-arginine analogue [Pharmacol. Rev. Vol.43, p.109-142 (1991)], aminoguanidine [Br. J. Pharmacol., Vol.110, p.963-968 (1993)] and S-ethylisothiourea [J.Biol.Chem., Vol.43, 26669-26676 (1994)] have been reported so far. However, each of these compounds is not satisfactory in terms of it's activity, and has a problematically undesirable inhibitory effect not only on iNOS but also on cNOS which is physiologically active.
On the other hand, cytokines such as TNF-&agr;, IL-1 and IL-6 are secreted from various cells such as monocyte, macrophage, lymphocyte, neutrophile, fibroblast and vascular endothelial cells, and involved widely in inflammation-related biological defense and immune mechanisms [The Cytokine Handbook, 2nd ed., Academic Press Limited (1994), Advances Immunol., Vol.62, p.257-304 (1996)], and thus are referred to as inflammatory cytokines. Since the cells targeted by these cytokines range widely over the inflammatory system, vascular system, central nervous system, hematopoietic system and endocrine system, their biological activities are considered to be diverse, including representative biological activities of TNF-&agr; and IL-1 which were reported to be (1) a pyrogenic activity, (2) an activation and chemotaxis promotion of inflammatory cells such as macrophage and neutrophile, (3) an induction of inflammatory cytokines and acute phase proteins including IL-1, IL-6, IL-8, TNF-&agr; and CSF and (4) an enhancement of the production of various chemical mediators such as NO, O
2
−
, PAF, prostaglandin, leukotriene and protease as well as those of IL-6 which were reported to be (1) an induction of acute phase proteins, (2) a thrombocyte-increasing activity, (3) a differentiation and an activation of lymphocytes and NK cells and (4) a osteoclast-increasing activity. However, these cytokines, once produced excessively or produced in a wrong site or at a wrong time, exhibit undesirable biological effects, and are proven to be involved in various diseases such as cachexia due to protozoa, bacteria, fungi, viruses and cancers, allergic diseases, chronic rheumatoid arthritis, abscess, graft rejection, anemia, arteriosclerosis, autoimmune disease, diabetes, central nervous system diseases, inflammatory bowel diseases, cardiac failure, hepatitis, hepatocirrhosis, nephritis, osteoporosis, psoriasis, septic shock and the like. From this point of view, substances which have inhibitory effects or antagonistic effects on the production of TNF-&agr;, IL-1 and IL-6 and the like [Eur. J. Immunol., Vol.18, p.951-956 (1991), Immunol., Vol.83, p.262-267 (1994), Proc. Natl. Acad. Sci., Vol.93, p.3967-3971 (1997), J. Immunol., Vol.147, p.1530-1536 (1991), Immunol. Today, Vol.12, p.404-410 (1991)] were reported to be expected to serve as the therapeutic agents against diseases listed above.
DISCLOSURE OF INVENTION
While several therapeutic agents for treating cardiac failure, autoimmune diseases, inflammatory diseases and septic shock have been known, each of them was not excellent in pharmaceutical properties such as efficacy and safety, and thus an objective of the invention is to provide a prophylactic and therapeutic agent against cardiac failure, autoimmune diseases, inflammatory diseases and septic shock which is further improved with regard to the pharmaceutical properties mentioned above.
In view of such circumstances, we made an effort to obtain a prophylactic and therapeutic agent against the diseases listed above which has an inhibitory effect on the NO production and/or the inflammatory cytokine production by an iNOS-inducible cell, and finally have succeeded to synthesize a novel compound represented by the formula:
wherein R represents an aliphatic hydrocarbon group optionally having substituents, an aromatic hydrocarbon group optionally having substituents, a heterocyclic group optionally having substituents, a group represented by the formula: OR
1
(wherein R
1
represents a hydrogen atom or an aliphatic hydrocarbon group optionally having substituents) or a group represented by the formula:
(wherein R
1b
represents a hydrogen atom or an aliphatic hydrocarbon group optionally having substituents, R
1c
is, same with or different from R
1b
, a hydrogen atom or an aliphatic hydrocarbon group optionally having substituents, ring A is a cycloalkene substituted by 1 to 4 substituents selected from (i) an aliphatic hydrocarbon group optionally having substituents, (ii) an aromatic hydrocarbon group optionally having substituents, (iii) a group represented by the formula: OR
1
(wherein R
1
represents the same meaning as mentioned above) and (iv) a halogen atom, R
0
represents a hydrogen atom or an aliphatic hydrocarbon group, or R and R
0
represent a bond with each other, Ar represents an aromatic hydrocarbon group optionally having substituents
Ichimori Yuzo
Ii Masayuki
Itoh Katsumi
Kitazaki Tomoyuki
Yamada Junji
Chao Mark
O'Sullivan Peter
Ramesh Elaine M.
Takeda Chemical Industries Ltd.
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