Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-04-14
2002-09-24
Bernhardt, Emily (Department: 1611)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S295000, C544S357000, C544S360000, C544S369000, C544S370000, C544S392000, C544S393000, C514S252110, C514S253120, C514S253010, C514S253130, C514S254020, C514S254050, C514S255030
Reexamination Certificate
active
06455528
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a pharmaceutical agent, particularly, a piperazine compound useful as a TNF-&agr; production inhibitor and/or an IL-10 production promoter, and use thereof as a pharmaceutical agent.
BACKGROUND ART
There are a number of cytokines that have been found as proteins involved in the expression of biological functions, such as biological immune responses, inflammatory reactions and the like. Of such cytokines, tumor necrosis factor alpha (hereinafter to be referred to as TNF-&agr;) was first found as a cytokine having an anti-tumor effect. Subsequent studies have characterized it as a cytokine involved in inflammations. In recent years, TNF-&agr; has been recognized as a cytokine broadly involved in biophylaxis through inflammation and immune responses.
For example, TNF-&agr; has been reported to show a promoting effect on the production of interleukin-1 (hereinafter to be referred to as IL-1), which is an inflammatory cytokine, and the like, an endotoxin shock induction effect, a fibroblast proliferation effect, a bone resorption effect, and an action to cause arthritis, such as cartilage destruction effect and the like [Beutler, B., et al., Nature, 316, 552-554 (1985):Peetre, C., et al., J. Clin. Invest., 78, 1694-1700 (1986):Bevilacqua, M. P., et al., Science, 241, 1160-1165 (1989)].
In rheumatoid arthritis, TNF-&agr; activity has been found in synovial fluid and sera [Macnaul, K. L., et al., J. Immunol., 145, 4154-4166 (1990):Brennan, F. M., et al., J. Immunol., 22, 1907-1912 (1992)]. Since an anti-TNF-&agr; chimera antibody has been recently reported to be effective against rheumatoid arthritis and Crohn's disease, the importance of TNF-&agr; in these diseases has been recognized [Elliott, M. J, et al., Arthritis Rheum., 36, 1681-1690 (1993):VanDullemen, H. M. et al., Gastroenterology 109, 129-135 (1995)].
Increased TNF-&agr; concentrations have been reported in the expectoration of patients with adult respiratory distress syndrome (ARDS), which is a serious respiratory disease, and TNF-&agr; is considered to be involved in ARDS [Marks, J. D. et al., Am. Rev. Respir. Dis. 141, 94-97 (1990), Millar, A. B. et al., Nature, 324, 73 (1986)]. TNF-&agr; is also considered to be involved in viral hepatitis and fulminant viral hepatitis [Sheron, N. et al., Lancet 336, 321-322 (1990), Muto, Y. et al., Lancet, ii, 72-74 (1986)].
In the case of myocardial ischemia, such as acute myocardial infarction, the TNF-&agr; concentration in blood has been reported to increase [Latini, R., et al., J. Cardiovasc. Pharmacol., 23, 1-6 (1990)], thereby suggesting the involvement of TNF-&agr; in such disease state [Squadrito, F. et al., Inflammation Res., 45, 14-19 (1996), Lefer, A. M. et al., Science, 249, 61-64 (1990)]. More recently, TNF-&agr; has been reported to inhibit myocardial contraction [Finkel, M. S., et al., Science, 257, 387-389 (1992); Pagani, D. F., et al., J. Clin. Invest., 90, 389-398 (1992)].
In addition, TNF-&agr; has been found to be equivalent to cachectin which is a cachexia inducer that hypercatabolizes the systemic metabolism in cancer and infectious diseases and causes utmost exhaustion [B. Beutler, D. Greenwald, J. D. Hulmes et al., Nature, 316, 552-554 (1985)].
TNF-&agr; is listed as one of the causes of sepsis [Starnes, H. F. Jr. et al., J. Immunol., 145, 4185-4191 (1990), Lechner, A. J. et al., Am. J. Physiol., 263, 526-535 (1992)], and an inhibitory effect on septic shock has been acknowledged in an experiment using a TNF-&agr; antibody [Starnes, H. F. Jr., et al., J. Immunol., 145, 4185-4191 (1990); Beutler, B., et al., Science, 229, 869-871 (1985)].
Other than the above-mentioned, possible involvement of TNF-&agr; has been suggested in osteoarthritis [Lewis, A. J. et al., Immunopharm. Immunotoxicol., 17, 607-613 (1995), Venn, G., et al., Arthritis Rheum., 36(6), 819-826 (1993)], multiple sclerosis [Sharief, M. K., etal., Engl. J. Med., 325(7), 467-472 (1991), Beck, J. et al., Acta. Neurol. Scand., 78, 318-323 (1988), Franciotta, D. M. et al., Ann. Neurol., 26, 787-789 (1989), Hofmann, F. M. et al., J. Exp. Med., 170, 607-612 (1989), Gallo, P. et al., J. Neuroimmunol., 23, 41-44 (1989)], Kawasaki disease [Matsubara, T., et al., Clin. Immunol., Immunopathol., 56, 29-36 (1990)], inflammatory bowel diseases such as ulcerative colitis, Crohn's disease and the like [Murch, S. et al., Arch. Dis. Child, 66, 561 (1991), Van Dullemen et al., Gastroenterology, 109, 129-135 (1995)], Behqet's disease [Akoglu, T., et al., J. Rheumatol., 17, 1107-1108(1990)], systemic lupus erythematosus (SLE) [Maury, C. P. J., et al., Arthritis Rheum., 32, 146-150(1989)], graft versus host disease (GvHD) [Piruet et al., J. Exp. Med., 170, 655-663 (1987), Holler et al., Blood, 75, 1011-1016 (1990), Irle et al., Bone Marrow Transplant., 3, 127 (1988), Symington et al., Transplantation, 50, 518-521 (1990), Herve et al., Blood, 79, 3362-3368 (1992), Herve et al., Immunol. Rev., 129, 31-55 (1992), Nestel, F. P., et al., J. Exp. Med., 175, 405-413 (1992)], allograft rejection [Imagawa et al., Transplantation, 50, 189-193 (1990)], malaria [Grau, G. E., et al., Science, 237, 1210-1212 (1987), Grau et al., N. Engl. J. Med., 320, 1586-1591 (1989), Kwiatkowski et al., Q. J. Med., 86, 91-98 (1993)], acquired immunodeficiency syndrome (AIDS) [Lahdevirt et al., Am. J. Med., 85, 289-291 (1988), Tracy, Cancer. Cell, 1, 62-63 (1989), odeh, J. Intern. Med., 228, 549-556 (1990), Bromberg et al., J. Immunol., 148, 3412-3417 (1992), Wllaurie et al., AIDS, 6, 1265-1268 (1992), Ayehunie et al., Clin. Exp. Immunol., 91, 37-42 (1993)], meningitis [Waage, A., et al., Lancet I, 355-357(1987) diabetes [Held, W. et al., Proc. Natl. Acad. Sci. USA, 87, 2239-2243 (1990), Hotamisligil, G. S., et al., Science, 259, 87-91 (1993)], thermal burn [Marano, M. A. et al., Surg. Gynecol. Obstet., 170, 32-38 (1990)], ischemia-reperfusion injury [Squadrito, F. et al., J. Lipid Mediators 8, 53-65 (1993)], chronic heart failure [Levine, B. et al., New Engl. J. Med., 323, 236-241 (1990)], infection [Chang et al., Immunol. Infect. Dis., 2, 61-68 (1992), Harvell, J. Immunol., 143, 2894-2899 (1989), Kindler et al., Cell, 56,731-740 (1989), Liew et al., Immunology, 69, 570-573 (1990), Nakane et al., Infect. Immun., 57, 3331-3337 (1989), Nakano et al., J. Immunol., 144, 1935-1941 (1990), Opal etal., J. Infect. Dis., 161, 1148-1152 (1990)], contact dermatitis [Piguet et al., J. Exp. Med., 173, 673-679 (1991)], bacterial shock [Exley et al., Lancet, 335, 1275-1277 (1990)], endotoxemia [Beutler et al., Science, 229, 860-871 (1985)], demyelinating disease [Probert et al., Proc. Natl. Acad. Sic. U.S.A., 92, 11294-11298 (1995)], fibroid lung [Piguet et al., J. Exp. Med., 170, 655-663 (1989), Piguet et al., Nature, 344, 245-247 (1990)], osteoporosis [Ishimi et al., J. Immunol., 145, 3297-3303 (1990), MacDonald et al., Br. J. Rheumatol., 31, 149-155 (1992)], thrombus due to disseminated intravascular coagulation (DIC) and the like [Tracy et al., Surg. Gen. Obstet., 164, 415-422 (1987), Van et al., N. Engl. J. Med., 322, 1622-1629 (1990)] and the like.
Interleukin-10 (hereinafter to be referred to as IL-10) is a cytokine mainly produced by type 2 helper T cells. IL-10 potentiates activity of B cells and mast cells, but for macrophages, it is one of the inhibitory cytokines that strongly inhibit the function of type 1 helper T cell involved in cellular immunity, because they inhibit antigen presenting ability or cytokine (TNF-&agr;, IL-1 and the like) production capability of macrophages. Thus, IL-10 plays an important role in the immune response system. For example, IL-10 has been reported to inhibit TNF-&agr; production by joint synovial cells in rheumatoid arthritis
Adachi Kunitomo
Aoki Yoshiyuki
Hanano Tokushi
Hisadome Masao
Morimoto Hiroshi
Bernhardt Emily
Crowell & Moring LLP
Mitsubishi Pharma Corporation
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