Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1994-11-03
1996-07-30
Dees, Jos e G.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514446, 514445, 514438, 514431, 549 28, 549 13, 549 62, 549 66, 549 67, 549 9, 549 78, A61K 3138, C07D33502, C07D33302, C07D33332
Patent
active
055412190
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/GB93/00445, filed on Mar. 4, 1993.
FIELD OF THE INVENTION
This invention is directed to sulfur-containing aromatic compounds which are useful in inhibiting cyclic AMP phosphodiesterase or tumor necrosis factor. The invention is also directed to the preparation of these compounds, pharmaceutical compositions containing these compounds and methods for their pharmaceutical use.
.alpha.-TNF is an important pro-inflammatory glycoprotein cytokine which causes hemorrhagic necrosis of tumors and possesses other important biological activities. .alpha.-TNF is released by activated macrophages, activated T-lymphocytes, natural killer cells, mast cells and basophils, fibroblasts, endothelial cells and brain astrocytes among other cells.
The principal in vivo actions of .alpha.-TNF can be broadiy classified as inflammatory and catabolic. It has been implicated as a mediator of endotoxic shock, inflammation of ioints and of the airways, immune deficiency states, allograft rejection, and in the cachexia associated with malignant disease and some parasitic infections. In view of the association of high serum levels of .alpha.-TNF with poor prognosis in sepsis, graft versus host disease and acute respiratory distress syndrome, and its role in many other immunologic processes, this factor is regarded as an important mediator of general inflammation.
.alpha.-TNF activates neutrophils, eosinophils and endothelial cells to inflammation where they release tissue damaging mediators. .alpha.-TNF also activates monocytes, macrophages and T-lymphocytes to cause the production IL.sub.8 and GM-CSF, which mediate the end effects of .alpha.-TNF. The ability of .alpha.-TNF to activate T-lymphocytes, monocytes, macrophages and related cells has been implicated in the progression of Human Immunodeficiency Virus (HIV) infection. In order for these cells to become infected with HIV and for HIV replication to take place the cells must be maintained in an activated state. Cytokines such as .alpha.-TNF have been shown to activate HIV replication in monocytes and macrophages. Features of endotoxic shock such as fever, metabolic acidosis, hypotension and intravascular coagulation are thought to be mediated through the actions of .alpha.-TNF on the hypothalamus and in reducing the anti-coagulant activity of vascular endothelial cells. The cachexia associated with certain disease states is mediated through indirect effects on protein catabolism. .alpha.-TNF also promotes bone resorption and acute phase protein synthesis.
Reported Developments
WO Patent Application No. 92/12961 discloses that a compound of formula ##STR1## is a cyclic AMP phosphodiesterase inhibitor, but does not disclose or suggest that the compound inhibits TNF.
The object of the present invention is directed to a compound that inhibits TNF and cyclic AMP phosphodiesterase.
SUMMARY OF THE INVENTION
This invention is directed to a novel class of 1-alkoxy-2-(alkoxy- or cycloalkyloxy-)-4-(cyclothioalkyl- or cyclothioalkenyl-)benzene compounds. Compounds within the scope of the present invention inhibit cyclic AMP phosphodiesterase and tumor necrosis factor (TNF) and are useful in treating disease states involving a physiologically detrimental excess of cyclic AMP phosphodiesterase or TNF.
Disease states sought to be treated in accordance with the present invention include inflammatory and autoimmune diseases, pathological conditions attributable to increases in cyclic AMP phophodiesterase (in particular type IV cyclic AMP phosphodiesterase), eosinophil accumulation and the function of eosinophils.
DETAILED DESCRIPTION OF THE INVENTION
As used above, and throughout the description of the invention, the following terms, unless otherwise indicated, shall be understood to have the following meanings:
"Patient" embraces both human and other mammals.
The "*" designation on the carbons in the compound according to the invention represents that the carbons are chiral.
"Alkyl" means an aliphatic hydrocarbon group which may be straight or branched
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Fenton Garry
Mason Jonathan S.
Palfreyman Malcolm N.
Ratcliffe Andrew J.
Dees Jos e G.
Lambkin Deborah
Nicholson James A.
Parker III Raymond S.
Rhone-Poulenc Rorer Limited
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