Compounds as PDE IV and TNF inhibitors

Details Compounds as PDE IV and TNF inhibitors Compounds as PDE IV and TNF inhibitors

1996-01-26

2002-10-29

Kifle, Bruck (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C546S296000

Reexamination Certificate

active

06472412

ABSTRACT:

FIELD OF THE INVENTION
This invention is directed to [di(ether or thioether)heteroaryl or fluoro substituted aryl] compounds, their preparation, pharmaceutical compositions containing these compounds, and their pharmaceutical use in the treatment of disease states associated with proteins that mediate cellular activity.
Disease states associated with abnormally high physiological levels of cytokines such as TNF are treatable according to the invention. TNF is an important pro-inflammatory cytokine which causes hemorrhagic necrosis of tumors and possesses other important biological activities. 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 TNF can be broadly classified as inflammatory and catabolic. It has been implicated as a mediator of endotoxic shock, inflammation of joints 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 TNF with poor prognosis in sepsis, graft versus host disease and acute respiratory distress syndrome, and its role in many other immunological processes, this factor is regarded as an important mediator of general inflammation.
TNF primes or activates neutrophils, eosinophils, fibroblasts and endothelial cells to release tissue damaging mediators. TNF also activates monocytes, macrophages and T-lymphocytes to cause the production of colony stimulating factors and other pro-inflammatory cytokines such IL
1
, IL
6
, IL
8
and GM-CSF, which in some case mediate the end effects of TNF. The ability of 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 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 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. TNF also promotes bone resorption and acute phase protein synthesis.
The discussion herein related to disease states associated with TNF include those disease states related to the production of TNF itself, and disease states associated with other cytokines, such as but not limited to IL-1, or IL-6, that are modulated by association with TNF. For example, an IL-1 associated disease state, where IL-1 production or action is exacerbated or secreted in response to TNF, would therefore be considered a disease state associated with TNF. TNF-alpha and TNF-beta are also herein referred to collectively as “TNF” unless specifically delineated otherwise, since there is a close structural homology between TNF-alpha (cachectin) and TNF-beta (lymphotoxin) and each of them has a capacity to induce similar biologic responses and bind to the same cellular receptor.
Disease states associated with pathological conditions that are modulated by inhibiting enzymes, which are associated with secondary cellular messengers, such as cyclic AMP phosphodiesterase, are also treatable according to the invention Cyclic AMP phosphodiesterase is an important enzyme which regulates cyclic AMP levels and in turn thereby regulates other important biological reactions. The ability to regulate cyclic AMP phosphodiesterase, including type IV cyclic AMP phosphodiesterase, therefore, has been implicated as being capable of treating assorted biological conditions.
In particular, inhibitors of type IV cyclic AMP phosphodiesterase have been implicated as being bronchodilators and asthma-prophylactic agents and as agents for inhibiting eosinophil accumulation and of the function of eosinophils, and for treating other diseases and conditions characterized by, or having an etiology involving, morbid eosinophil accumulation. Inhibitors of cyclic AMP phosphodiesterase are also implicated in treating inflammatory diseases, proliferative skin diseases and conditions associated with cerebral metabolic inhibition.
Reported Developments
Chemical Abstracts, 108(15), Apr. 11, 1988, abstract no. 131583p pertains to an abstract of Japanese Patent Application Publication No. JP-A-62 158,253 which discloses that a substituted phenyl compound of formula
is a cardiotonic, but does not disclose or suggest that the compound inhibits cyclic AMP phosphodiesterase or TNF. JP-A-62 158,253 also does not disclose or suggest that the moiety that is ortho to R
1
may be anything other than benzyloxy. JP-A-62 158,253 furthermore does not disclose compounds wherein a methine (═CH—) moiety of the phenyl moiety of the benzamido moiety is substituted by a halomethine (═CX—; wherein X is a halo atom) moiety or an imine (═N—) moiety.
Chemical Abstracts, 99(6), Aug. 8, 1983, abstract no. 43556z pertains to an abstract of Japanese Patent Application Publication No. JP-A-5 869,812 which discloses that a phenyl compound of formula
is a hypoglycemic agent, but does not disclose or suggest that the compound inhibits cyclic AMP phosphodiesterase or TNF. JP-A-5 869,812 also does not disclose or suggest that the benzamido moiety may be substituted by anything other than methoxy.
Panos Grammaticakis,
Bull. Soc. Chim. Fr
., 848-857 (1965) discloses a phenyl compound of the formula
Grammaticakis examines the ultraviolet and visible absorbances of compounds bearing different substituents. Grammaticakis does not disclose or suggest that the compound exhibits any pharmacological activity. JP-A-5 869,812 also does not disclose or suggest that the benzamido moiety may be substituted by anything other than methoxy.
Ian W. Mathison, et al.,
J. Med. Chem
., 16(4), 332-336 (1973), discloses that a phenyl compound of formula
is a hypotensive agent, but do not disclose or suggest that the compound inhibits cyclic AMP phosphodiesterase or TNF. Mathison, et al., also do not disclose or suggest that the benzamido moiety may be substituted by anything other than methoxy.
European Patent Application Publication No. EP 232199 B1 discloses hat phenyl compounds of formula
wherein R
2
is alkyl or mono- or polycyclic cycloalkyl, exhibit anti-inflammatory and/or anti-allergic activity. EP 232199 B1 does not disclose or suggest compounds wherein the R
2
substituent is bonded to the phenyl moiety via an oxygen or sulfur atom. EP 232199 B1 furthermore does not disclose compounds wherein a methine moiety of the phenyl moiety of the benzamido moiety is substituted by a halomethine moiety or an imine moiety.
European Patent Application Publication No. EP 470,805 A1 discloses phenyl compounds of the formula
wherein R may be C
3-7
alkyl, C
3-7
cycloalkyl or
Z may be a bond; o is 1-4; a and b are independently 1-3; and c is 0-2. EP 470,805 A1 discloses that these compounds are useful intermediates for preparing PDE IV inhibitors, but does not disclose or suggest that the compounds have any pharmacological activity. EP 470,805 A1 furthermore does not disclose compounds wherein a methine moiety of the phenyl moiety of the phenylacyl moiety is substituted by a halomethine moiety or an imine moiety.
Japanese Patent Application Publication No. JP-A-0 4360847 discloses compounds of the formula
wherein R
1
, R
2
and R
3
may be the same or different and may be halo or lower alkoxy or lower alkyl both optionally substituted by halo; and A may be optionally substituted aryl or 5-6 membered heterocyclyl group. JP-A-0 4360847 discloses that the compounds are useful intermediates for preparing antimicrobial agents, but does not disclose or suggest that the compounds have any pharmacol

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