Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-07-20
2001-10-23
Richter, Johann (Department: 1621)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C560S013000, C560S017000, C560S032000, C560S033000, C562S429000, C562S431000, C562S621000, C514S340000, C514S347000, C514S357000, C514S364000, C514S394000, C514S418000, C514S423000, C514S424000, C514S438000, C514S464000, C514S506000, C514S530000, C514S562000, C514S563000, C514S570000, C546S166000, C546S269400, C546S294000, C546S337000, C548S131000, C548S309700, C548S477000, C548S531000, C548S556000, C549S077000, C549S441000
Reexamination Certificate
active
06306873
ABSTRACT:
This invention is directed to substituted, thiocarboxylic acids and their bioisosteres, their preparation, pharmaceutical compositions containing these compounds, and their pharmaceutical use in the treatment of disease states associated with proteins that mediate cellular activity. This invention is also directed to intermediates useful in preparing the substituted, thiocarboxylic acids and their bioisosteres.
Tumour necrosis factor (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 adult respiratory distress syndrome, and its role in many other immunologic 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 relates to disease states associated with TNF including 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 associated with TNF. For example, a 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 ccollectively 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 biological responses and bind to the same cellular receptor.
Cyclic AMP phosphodiesterases are important enzymes which regulate cyclic AMP levels and in turn thereby regulate other important biological reactions. The ability to regulate cyclic AMP phosphodiesterases 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 agents, prophylactic agents useful against asthma 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.
We have now found a novel group of compounds which have valuable pharmaceutical properties, in particular the ability to regulate proteins that mediate cellular activity, for example, cyclic AMP phosphodiesterases (in particular type IV) and/or TNF. Compounds structurally similar to those of the present invention have been described in EP 0 780 386 and WO 97/24117 as inhibitors of matrix metalloproteinases. We have surprisingly found that the compounds of the present invention inhibit AMP phosphodiesterases (in particular type IV) and/or TNF without concomitant activity against matrix metalloproteinases.
Thus, in one aspect, the present invention is directed to compounds of general formula (I):
wherein
R
1
and R
3
may be the same or different and each independently represents a group —L
1
—R
5
[where L
1
is a direct bond, a straight or branched C
1-6
alkylene chain, a straight or branched C
2-6
alkenylene chain, a straight or branched C
2-6
alkynylene chain or a straight or branched C
1-6
alkylene chain containing an oxygen or sulfur atom, a phenylene, imino (—NH—) or alkylimino linkage, or a sulfinyl or sulfonyl group, in which each of the alkylene, alkenylene and alkynylene chains may be optionally substituted, the substituents chosen from alkoxy, aryl, carboxy, cyano, cycloalkyl, halogen, heteroaryl, hydroxyl, or oxo; and R
5
represents hydrogen, aryl, aroyl, carboxy or an acid bioisostere, cyano, cycloalkyl, cycloalkenyl, heterocycloalkyl, heteroaryl, arylalkoxycarbonyl, —NH—C(═O)—NH
2
, —C═N—O—C(═O)—NH
2
, —C(═O)—NY
1
Y
2
, (where Y
1
and Y
2
are independently hydrogen, alkyl, arylalkyl, and aryl, or the group NY
1
Y
2
may form a 4-6 membered cyclic amine {which may optionally contain a further heteroatom selected from O, S, or NR
6
in which R
6
is hydrogen, alkyl, aryl or arylalkyl, or which may be fused to an additional aromatic ring}), —NY
1
SO
2
aryl, —NHR
6
, —SR
6
, or —OR
6
];
R
2
and R
4
may be the same or different and are each independently hydrogen or alkyl; or
R
2
and R
4
together form a bond; or
R
1
and R
2
, or R
1
and R
3
, or R
3
and R
4
together with the carbon atom(s) to which they are attached form a 3 to 8 membered cycloalkyl or cycloalkenyl ring, optionally substituted by alkyl, arylalkyl, or heteroarylalkyl, and which may optionally contain a heteroatom selected from O, S or NR
6
; or
R
1
and R
3
together with the carbon atoms to which they are attached form a heteroaryl ring;
Y represents carboxy or an acid bioisostere;
A
1
represents a direct bond, a straight or branched C
1-4
alkylene chain or a NR
6
group; and
Ar is a group chosen from
where the dotted lines indicate optional bonds between B-C, and /or C-D, and/or D-E;
R
7
represents a straight- or branched-chain alkyl group of 1 to about 6 carbon atoms, optionally substituted by one or more halogen atoms, or when Z
1
represents a direct bond R
7
may also represent a hydrogen atom or a lower alkenyl or lower alkynyl group;
R
8
represents an optionally substituted cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl or partially saturated bicycloaryl group;
R
9
represents R
10
, —OR
10
, —SR
10
, —SOR
12
, —SO
2
R
12
, —SO
2
NR
10
R
11
, —NR
10
SO
2
R
12
, —NR
10
R
11
, —O(C═O)NR
10
R
11
, NR
10
C(═O)R
12
, —N(OH)C(═O)R
12
, or —C(═O)N(OH)R
12
(where R
10
and R
11
, which may be the same or different, each represent a hydrogen atom, or an alkyl, alkenyl, heterocycloalkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl group, or the group NR
10
R
12
may also represents a 3 to 7 membered cyclic amine optionally containing one or more additional heteroatom selected from O, NR
6
, or S, and
R
12
represents an alkyl, alkenyl, heterocycloalkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, arylalkyl or heteroaryla
Burns Christopher J.
Condon Stephen
Groneberg Robert D.
Labaudiniere Richard
Mathew Rose M.
Aventis Pharmaceuticals Products Inc.
Davis Brian J.
Newman Irving
Richter Johann
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