Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-12-08
2003-08-05
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C544S333000
Reexamination Certificate
active
06602877
ABSTRACT:
This invention is directed to imidazolyl-cyclic acetals, their preparation, pharmaceutical compositions containing these compounds, and their pharmaceutical use in the treatment of disease states capable of being modulated by the inhibition of TNF.
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, and endothelial cells to release tissue damaging mediators and increase the expression of adhesion molecules. In fibroblasts, TNF stimulates the production of collagenase, an enzyme implicated in the joint destruction in rheumatoid arthritis. 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 cases 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. 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.
TNF-alpha inhibits surfactant protein C gene transcription, which may contribute to abnormalities of surfactant homeostasis associated with pulmonary injury and infection, induces mucin hypersecretion and mediates the recruitment of neutrophils and eosinophils during airway inflammation. Although TNF-alpha inhibits collagen synthesis in fibroblasts, a number of studies point to it being pro-fibrotic in vivo. Thus, by inhibiting TNF-alpha production, the compounds of the invention have potential in suppressing the inflammation and airways remodelling that occurs in asthma.
TNF-alpha inhibits the ability of insulin to stimulate glucose uptake in adipose tissue. In obesity the overproduction of TNF is thought to cause an insulin-resistant state. Thus, by blocking TNF release the compounds of the invention have anti-diabetic potential.
TNF-alpha can induce angiogenesis in normally avascular tissue, possibly through upregulation of other pro-inflammatory cytokines, upregulation of adhesion molecules, stimulation of matrix mettalloproteinase expression and increased prostaglandin production. Thus, inhibition of TNF-alpha release by compounds of the invention will have benefit in angiogenesis dependent diseases including arthritis, diabetic retinopathies and ischemia induced diseases (myocardial infarction) and cancer.
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 association 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 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 biological responses and bind to the same cellular receptor.
We have now found a novel group of imidazolyl-cyclic acetals which have valuable pharmaceutical properties, in particular the ability to regulate proteins that mediate cellular activity, for example TNF.
Thus, in one aspect, the present invention is directed to compounds of general formula (I):
wherein:
R
1
is optionally substituted heteroaryl;
R
2
is optionally substituted aryl or optionally substituted heteroaryl;
R
3
represents a group —L
1
—R
7
or —L
2
—R
8
[where L
1
represents a straight- or branched-chain alkylene linkage containing from 1 to about 6 carbon atoms optionally substituted by halogen or oxo; R
7
is hydrogen, aryl, cyano, cycloalkyl, heteroaryl, heterocycloalkyl, nitro, —S(O)
n
R
9
, (where R
9
is alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, heteroarylalkyl, or heterocycloalkyl and n is zero or an integer 1 or 2), —NHSO
2
R
9
, —C(═Z)OR
10
(where Z is an oxygen or sulphur atom and R
10
is hydrogen or R
9
), —C(═Z)R
10
, —OR
10
, —N(R
11
)—C(═Z)R
9
(where R
11
is hydrogen or alkyl), —NY
1
Y
2
{where Y
1
and Y
2
are independently hydrogen, alkenyl, alkyl, alkynyl, aryl, arylalkyl, cycloalkenyl, cycloalkyl, heteroaryl or heteroarylalkyl, or the group —NY
1
Y
2
may form a 5-7 membered cyclic amine which may optionally contain a further heteroatom selected from O, S, or NY
3
(where Y
3
is hydrogen, alkyl, aryl, arylalkyl, —CHO, —C(═Z)R
9
or —SO
2
R
9
), or which may also be fused to additional aryl, heteroaryl, heterocycloalkyl or cycloalkyl rings to form a bicyclic or tricyclic ring system}, —SO
2
—NY
1
Y
2
, —C(═Z)—NY
1
Y
2
, —N(R
11
)—C(═Z)—NY
1
Y
2
, —N(OR
10
)—C(═Z)—NY
1
Y
2
, —N(OR
10
)—C(═Z)R
10
, —C(═NOR
10
)R
10
, —C(═Z)NR
10
OR
12
(where R
12
is hydrogen, alkyl, aryl or arylalkyl), —N(R
11
)—C(═NR
13
)—NY
1
Y
2
(where R
13
is hydrogen, cyano, alkyl, cycloalkyl or aryl), or —N(R
11
)—C(═Z)OR
11
; L
2
represents a direct bond or a straight- or branched-carbon chain comprising from 2 to about 6 carbon atoms and contains a double or triple carbon-carbon bond; and R
8
is hydrogen, aryl, cycloalkenyl, cycloalkyl, heteroaryl or heterocycloalkyl];
R
4
represents a group —L
3
—R
14
[where L
3
represents a direct bond or a straight- or branched-chain alkylene linkage containing from 1 to about 6 carbon atoms (optionally substituted by halogen, hydroxy, alkoxy or oxo); and R
14
is hydrogen, alkyl, azido, hydroxy, alkoxy, aryl, arylalkyloxy, aryloxy, carboxy (or an acid bioisostere), cycloalkyloxy, heteroaryl, heteroarylalkyloxy, heteroaryloxy, heterocycloalkyl, heterocycloalkyloxy, nitro, —NY
4
Y
5
, {where Y
4
and Y
5
are independently hydrogen, aryl, cycloalkyl, heterocycloalkyl, heteroaryl or alkyl optionally substituted by alkoxy, aryl, cyano, cycloalkyl, heteroaryl, heterocycloalkyl, hydroxy, oxo, —CO
2
R
10
, —CONY
1
Y
2
or —NY
1
Y
2
, or the group —NY
4
Y
5
may form a 5-7 membered cyclic amine which (i) may be optionally substituted with one or more substituents selected from alkoxy, carboxamido, carboxy, hydroxy, oxo (or a 5, 6,or 7 membered cyclic acetal derivative thereof), R
9
or alkyl substituted by carboxy, carboxamido or hydroxy (ii) may also contain a further heteroatom selected from O, S, SO
2
or NY
6
(where Y
6
is hydrogen, alkyl, aryl, arylalkyl, —C(═Z)R
9
, —C(═Z)OR
9
or —SO
2
R
9
) and (iii) may also be fused to additional aryl, heteroaryl, heterocycloalkyl or cycloalkyl r
Bamborough Paul L.
Collis Alan J.
Halley Frank
Lewis Richard A.
Lythgoe David J.
Aventis Pharma Limited
Balasubramanian Venkataraman
Darkes Paul R.
Newman Irving
Raymond Richard L.
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