Organic compounds -- part of the class 532-570 series – Organic compounds – Oxygen containing
Patent
1997-06-23
1998-03-03
Lambkin, Deborah
Organic compounds -- part of the class 532-570 series
Organic compounds
Oxygen containing
560 43, 564163, 564167, 549 13, 549 74, 549 78, 549 79, 549426, 549427, 549428, 549496, 549497, 549498, 549499, 5483361, 5483674, 5483164, 5483265, 548541, 548557, 548127, 548128, 548134, 548136, 548146, 548215, 548240, 548250, 548255, 546290, 546304, 546242, 546244, 546153, 546159, 544298, 544322, 544383, 544402, 544158, 544162, 544170, C07D33312, C07D31704, C07D23366, C07D21172, C07C 43205, C07C22938, C07C23364, C07C33502
Patent
active
057236810
DESCRIPTION:
BRIEF SUMMARY
FIELD OF INVENTION
The present invention relates to novel 3,3-(disubstituted)cyclohexan-1-ol dimers and related compounds, pharmaceutical compositions containing these compounds, and their use in treating allergic and inflammatory diseases and for inhibiting the production of Tumor Necrosis Factor (TNF).
BACKGROUND OF THE INVENTION
Bronchial asthma is a complex, multifactorial disease characterized by reversible narrowing of the airway and hyperreactivity of the respiratory tract to external stimuli.
Identification of novel therapeutic agents for asthma is made difficult by the fact that multiple mediators are responsible for the development of the disease. Thus, it seems unlikely that eliminating the effects of a single mediator will have a substantial effect on all three components of chronic asthma. An alternative to the "mediator approach" is to regulate the activity of the cells responsible for the pathophysiology of the disease.
One such way is by elevating levels of cAMP (adenosine cyclic 3',5'-monophosphate). Cyclic AMP has been shown to be a second messenger mediating the biologic responses to a wide range of hormones, International Congress Excerpta Medica, 17-29, 1973!. When the appropriate agonist binds to specific cell surface receptors, adenylate cyclase is activated, which converts Mg.sup.+2 -ATP to cAMP at an accelerated rate.
Cyclic AMP modulates the activity of most, if not all, of the cells that contribute to the pathophysiology of extrinsic (allergic) asthma. As such, an elevation of cAMP would produce beneficial effects including: 1) airway smooth muscle relaxation, 2) inhibition of mast cell mediator release, 3) suppression of neutrophil degranulation, 4) inhibition of basophil degranulation, and 5) inhibition of monocyte and macrophage activation. Hence, compounds that activate adenylate cyclase or inhibit phosphodiesterase should be effective in suppressing the inappropriate activation of airway smooth muscle and a wide variety of inflammatory cells. The principal cellular mechanism for the inactivation of cAMP is hydrolysis of the 3'-phosphodiester bond by one or more of a family of isozymes referred to as cyclic nucleotide phosphodiesterases (PDEs).
It has now been shown that a distinct cyclic nucleotide phosphodiesterase (PDE) isozyme, PDE IV, is responsible for cAMP breakdown in airway smooth Potential Targets for Novel Anti-asthmatic Agents" in New Drugs for Asthma, Barnes, ed. IBC Technical Services Ltd., 1989!. Research indicates that inhibition of this enzyme not only produces airway smooth muscle relaxation, but also suppresses degranulation of mast cells, basophils and neutrophils along with inhibiting the activation of monocytes and neutrophils. Moreover, the beneficial effects of PDE IV inhibitors are markedly potentiated when adenylate cyclase activity of target cells is elevated by appropriate hormones or autocoids, as would be the case in vivo. Thus PDE IV inhibitors would be effective in the asthmatic lung, where levels of prostaglandin E.sub.2 and prostacyclin (activators of adenylate cyclase) are elevated. Such compounds would offer a unique approach toward the pharmacotherapy of bronchial asthma and possess significant therapeutic advantages over agents currently on the market.
The compounds of this invention also inhibit the production of Tumor Necrosis Factor (TNF), a serum glycoprotein. 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 sarcoidosis, bone resorption diseases, reperfusion injury, graft vs. host reaction, allograft rejections, fever and myalgias due to infection, such as influenza, cachexia secondary to infection or malignancy, cachexia secondary to human acquired immune d
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Christensen, IV Siegfried B.
Karpinski Joseph M.
Kanagy James M.
Lambkin Deborah
Lentz Edward T.
SmithKline Beecham Corporation
Venetianer Stephen
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