Organic compounds -- part of the class 532-570 series – Organic compounds – Four or more ring nitrogens in the bicyclo ring system
Reexamination Certificate
2002-04-29
2003-07-22
Davis, Brian (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Four or more ring nitrogens in the bicyclo ring system
C564S094000, C564S098000, C564S148000, C564S149000, C564S271000, C564S272000, C564S273000, C564S274000, C564S275000, C564S276000, C564S277000, C564S278000, C564S279000, C564S310000, C564S313000, C564S366000, C564S372000, C564S463000, C564S464000, C544S219000, C544S326000, C544S332000, C544S356000, C544S382000, C546S114000, C546S122000, C546S162000, C546S244000, C546S261000, C546S282100, C546S283400, C546S293000, C546S297000, C546S306000, C546S332000, C548S179000, C548S222000, C548S309700, C548S365700, C548S
Reexamination Certificate
active
06596863
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a medical composition containing a nitroetheneamine derivative or a salt thereof as an active constituent.
BACKGROUND ART
The present invention relates to a medical composition containing a nitroetheneamine derivative or a salt thereof as an active constituent, which has excellent matrix metalloproteinase inhibitory activities and which is useful as an angiogenesis inhibitor, an anticancer agent, a tumor cell infiltration inhibitor or a tumor metastasis inhibitor useful for treatment or prevention of cancer or inflammatory diseases, or as a therapeutic or preventive agent for an articular disease such as chronic articular rheumatism, osteoarthritis or rheumatoid arthritis, or as a therapeutic or preventive agent for various diseases such as gingivitis, glomerular nephritis, interstitial nephritis, encephalomyelitis, arterial sclerosis, cirrhosis, restenosis, diabetic retinopathy, neovascular glaucoma, corneal ulcer, epidermolysis bullosa, herniated disk, a bone resorption such as osteoporosis, multiple sclerosis, bronchial asthma, Alzheimer's disease or an autoimmune disorder (such as Crohn's disease or Sjögren's syndrome). Further, some of the nitroetheneamine derivatives and their salts which are active constituents of such medical compositions, are novel compounds, and the present invention relates also to such novel compounds.
Connective tissues of higher organisms are constituted by extracellular matrices. Extracellular matrices maintain homeostatis of biodynamic functions by repeating new formation and degradation (reassembly) depending upon the functions or morphological features of the particular tissues. Matrix metalloproteinases (MMP) are primary enzymes involved in the decomposition of extracellular matrices and characterized in that they have a bivalent zinc ion at the active center. Presence of about 20 types of MMP has been confirmed up to now including a secreted-type and a membrane-anchored-type, and the physiological functions and in-vivo distributions of the respective molecules are being made clear. MMP in a normal living body acts at a site where restructuring of tissues is required, for example, at a fetal development or for wound healing. However, in order to prevent destruction of extracellular matrices more than necessary, a strict regulation mechanism (regulation of expression or feedback regulation) is functioning. Namely, MMP is usually secreted as an inactive substance by external stimulation and then converted to an active substance by various proteases. On the other hand, the decomposition activities by MMP are controlled by TIMP (tissue inhibitor of metalloproteinase) as its endogenous inhibitor. However, if some abnormality occurs in the above control mechanism, and MMP becomes excessive, various tissue diseases will be induced.
For example, {circle around (1)} with respect to MMP-9 (gelatinase B/92 kDa type IV collagenase) having a strong decomposition activity against type IV collagen which is the main constituting component of a basement membrane, no substantial expression is usually observed in human normal tissues. On the other hand, its over expression has been observed in many epithelial cancer cells and hematopoletic cancer cells including cells of breast cancer and lung cancer. {circle around (2)} In carcinoma of the colon and rectum, a positive correlation has been observed between the expression level of MMP-9 and the metastatic nature (M. Nakajima et al, Journal of National Cancer Institute, Vol. 82, 1890, (1990)). {circle around (3)} It has also been experimentally shown with respect to various cancer cells that the metastatic potential or infiltrating potential of cancer cells in which MMP-9 or MMP-2 (gelatinase A/72 kDa type IV collagenase) is highly expressed, is advanced as compared with cells in which such expression is low (D. R. Welch et al, Proceedings of the National Academy of Sciences of the United States of America, Vol. 87, 7687, (1990), S. Yamagata et al, Biochemical and Biophysical Research Communication, Vol. 151, 186-162 (1988)). {circle around (4)} With respect to MMP-13 (collagenase 3), no expression has been observed in normal cells, but its high expression has been observed in breast cancer cells (J. M. Freiji, M. Nakajima et al, Journal of Biological Chemistry, Vol. 269, 16766-76773, (1994)).
Thus, highly malignant metastatic cancer cells have abnormal motility, adhesion and tissue invasive potential in addition to abnormal growth nature inherent to neoplasm, and as one of the background factors, excess production of MMP is involved.
Further, it is already known that {circle around (1)} MMP is involved in capillary-like tube formation of cultured vascular endothelial cells (R. Montesano et al, Cell, Vol. 42, 469-477, (1985)), {circle around (2)} MMP acts as one of angiogenesis factors to promote tumor growth (T. Itoh et al, Cancer Research, Vol. 58, 1048-1051, (1998) ), or {circle around (3)} with melanoma cells wherein TIMP-2 is excessively expressed, the tissue-infiltration ability or the angiogenesis inducibility decreases (P. Valente et al, International Journal of Cancer, Vol. 75, 246-253 (1998)).
On the other hand, if inflammatory cytokine is induced by some factor at the joint region, and MMP-1 (interstitial collagenase) or MMP-3 (Stromelysin 1) from synovial cells is excessively produced and stored in a large amount in the joint fluid, it acts on the joint cartilage to destroy the cartilage matrix, thus leading to so-called articular diseases represented by symptoms such as pain, regulation of variable joint region or deformations.
Further, it is known that in a coronary disease, MMP will promote migration of smooth muscle cells from the vascular wall to the intima and will promote formation of atherosclerotic plaques, and further that it is involved in reconstruction after angioplasty in the anginal therapy (D. C. Celentano et al, Journal of Clinical Pharmacology, Vol. 37, 991-1000, (1997)).
Further, in gingivitis, an increase in the production of MMP-1 (interstitial collagenase) is observed.
Thus, MMP is responsible for a wide range of physiological functions in a living body, and its overproduction will upset the homeostasis of the living body and will induce a new disease or aggravation of pathology. Accordingly, a MMP inhibitor is considered to be useful as an angiogenesis inhibitor, an anticancer agent, a tumor cell infiltration inhibitor or a tumor metastasis inhibitor, to be used for treatment or prevention of cancer or inflammatory diseases; a therapeutic or preventive agent for an articular disease such as chronic articular rheumatism, osteoarthritis or rheumatoid arthritis; or as a therapeutic or preventive agent for various diseases such as gingivitis, glomerular nephritis, interstitial nephritis, encephalomyelitis, arterial sclerosis, cirrhosis, restenosis, diabetic retinopathy, neovascular glaucoma, corneal ulcer, epidermolysis bullosa, herniated disk, a bone resorption such as osteoporosis, multiple sclerosis, bronchial asthma, Alzheimer's disease or an autoimmune disorder (such as Crohn's disease or Sjögren's syndrome).
Heretofore, many compounds having MMP inhibition activities have been reported (R. A. Nigel et al, Current Opinion on Therapeutic Patents, Vol. 4, 7-16, (1994), R. P. Beckett et al, Drug Discovery Today, Vol. 1, 16-26, (1996)). However, most of them are peptide derivatives designed based on the amino acid sequence of the enzymatic cleavage site in the collagen molecule constituting the substrate of MMP, including, for example, hydroxamic acid type compounds; thiol type compounds; carboxylic acid type compounds; phosphonate type compounds; and phosphonate type compounds. Among them, with respect to some compounds including hydroxamic acid derivatives, clinical trial have been carried out on diseases such as cancer and arthritis.
It is generally known that a MMP inhibitor having a peptide in the basic structure has a low oral absorbance, and particularly, a hydroxamic acid type MMP inhibitor is
Ikegami Hiroyuki
Kato Fuminori
Kimura Hirohiko
Miyata Keizo
Takeo Hiromi
Davis Brian
Ishihara Sangyo Kaisha Ltd.
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
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