Organic compounds -- part of the class 532-570 series – Organic compounds – Nitriles
Patent
1996-07-11
2000-01-11
Killos, Paul J.
Organic compounds -- part of the class 532-570 series
Organic compounds
Nitriles
514520, 514521, 514523, 560 21, 560 27, 560 59, 562469, 564171, C07C25500
Patent
active
060138270
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to novel phenylcyclohexan-1-ylcarboxylic acids, pharmaceutical compositions containing these compounds, the use of these compounds in treating allergic and inflammatory diseases and to the use of these compounds to inhibit 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 components of chronic bronchial asthma.
An alternative to the "mediator approach" is to regulate the activity of cells responsible for the pathophysiology of asthma. Cyclic AMP (cAMP, adenosine cyclic 3',5'-monophosphate) modulates the activity of most, if not all, of the cells that contribute to the pathophysiology of extrinsic (allergic) asthma. 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. Cyclic AMP has been shown to mediate cellular responses to a wide range of hormones, neurotransmitters and drugs; [Krebs Endocrinology Proceedings of the 4th International Congress Excerpta Medica, 17-29, 1973].
One potential means to regulate the activity of cells responsible for the pathophysiology of asthma is to control the intracellular levels of cyclic AMP. Cellular cAMP levels are elevated when an appropriate agonist binds to particular cell surface receptors, thereby activating adenylate cyclase to convert Mg.sup.+2 -ATP to cAMP at an accelerated rate. 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 (cyclic nucleotide phosphodiesterase hereinafter "PDE"s). 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.
It has been shown that a distinct PDE isozyme, PDE IV, is responsible for cAMP breakdown in airway smooth muscle and inflammatory cells. [Torphy, "Phosphodiesterase Isozymes: 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. The beneficial effects of PDE IV inhibition are markedly potentiated when adenylate cyclase activity of target cells is elevated by appropriate hormones or autocoids. Thus, PDE IV inhibitors would be effective in the asthmatic lung, where levels of prostaglandin E.sub.2 and prostacyclin (both activators of adenylate cyclase) are elevated. PDE IV inhibitors offer a unique approach to the pharmacotherapy of bronchial asthma, and possess significant therapeutic advantages over agents currently on the market The compounds of this invention have the ability to inhibit PDE IV.
The compounds of this invention also inhibit the production of TNF, a serum glycoprotein. Excessive or unregulated TNF production has been implicated in mediating or exacerbating a number of undesirable physiological conditions, such as diseases , and 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 syndrom
REFERENCES:
patent: 4065573 (1977-12-01), Lednicer
Chemical Abstracts, vol. 120, Issued 1994, Christensen, Cyclohexylbenzene . . . No. 120: 134020m.
Chemical Abstracts, vol. 120, Issued 1994, Christensen, Preparation of . . . No. 120: 163532k.
Chemical Abstracts, vol. 120, Issued 1994, Christensen, Cyclohexylbenzones . . . No. 120: 191326q.
Bordas-Nagy Joseph
Gorycki Peter
Webb Kevin Scott
Kanagy James M.
Killos Paul J.
Kinzig Charles M.
SmithKline Beecham Corporation
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