Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2003-05-20
2004-04-06
Davis, Zinna Northington (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C546S160000
Reexamination Certificate
active
06716847
ABSTRACT:
This invention concerns certain amide derivatives and their use as inhibitors of cytokine mediated disease. The invention also concerns processes for the manufacture of said novel amide derivatives, pharmaceutical compositions containing them and their use in therapeutic methods, for example by virtue of inhibition of cytokine mediated disease.
The amide derivatives disclosed in the present invention are inhibitors of the production of cytokines such as Tumour Necrosis Factor (hereinafter TNF), for example TNF&agr;, and various members of the interleukin (hereinafter IL) family, for example IL-1, IL-6 and IL-8. Accordingly the compounds of the invention will be useful in the treatment of diseases or medical conditions in which excessive production of cytokines occurs, for example excessive production of TNF&agr; or IL-1. It is known that cytokines are produced by a wide variety of cells such as monocytes and macrophages and that they give rise to a variety of physiological effects which are believed to be important in disease or medical conditions such as inflammation and immunoregulation. For example, TNF&agr; and IL-1 have been implicated in the cell signalling cascade which is believed to contribute to the pathology of disease states such as inflammatory and allergic diseases and cytokine-induced toxicity. It is also known that, in certain cellular systems, TNF&agr; production precedes and mediates the production of other cytokines such as IL-1.
Abnormal levels of cytokines have also been implicated in, for example, the production of physiologically-active eicosanoids such as the prostaglandins and leukotrienes the stimulation of the release of proteolytic enzymes such as collagenase, the activation of the immune system, for example by stimulation of T-helper cells, the activation of osteoclast activity leading to the resorption of calcium, the stimulation of the release of proteoglycans from, for example, cartilage, the stimulation of cell proliferation and to angiogenesis.
Cytokines are also believed to be implicated in the production and development of disease states such as inflammatory and allergic diseases, for example inflammation of the joints (especially rheumatoid arthritis, osteoarthritis and gout), inflammation of the gastrointestinal tract (especially inflammatory bowel disease, ulcerative colitis, Crohn's disease and gastritis), skin disease (especially psoriasis, eczema and dermatitis) and respiratory disease (especially asthma, bronchitis, allergic rhinitis and adult respiratory distress syndrome), and in the production and development of various cardiovascular and cerebrovascular disorders such as congestive heart disease, myocardial infarction, the formation of atherosclerotic plaques, hypertension, platelet aggregation, angina, stroke, reperfusion injury, vascular injury including restenosis and peripheral vascular disease, and, for example, various disorders of bone metabolism such as osteoporosis (including senile and postmenopausal osteoporosis), Paget's disease, bone metastases, hypercalcaemia, hyperparathyroidism, osteosclerosis, osteoporosis and periodontitis, and the abnormal changes in bone metabolism which may accompany rheumatoid arthritis and osteoarthritis. Excessive cytokine production has also been implicated in mediating certain complications of bacterial, fungal and/or viral infections such as endotoxic shock, septic shock and toxic shock syndrome and in mediating certain complications of CNS surgery or injury such as neurotrauma and ischaemic stroke. Excessive cytokine production has also been implicated in mediating or exacerbating the development of diseases involving cartilage or muscle resorption, pulmonary fibrosis, cirrhosis, renal fibrosis, the cachexia found in certain chronic diseases such as malignant disease and acquired immune deficiency syndrome (AIDS), tumour invasiveness and tumour metastasis and multiple sclerosis.
Evidence of the central role played by TNF&agr; in the cell signalling cascade which gives rise to rheumatoid arthritis is provided by the efficacy in clinical studies of antibodies of TNF&agr; (
The Lancet,
1994, 344, 1125 and
British Journal of Rheumatology,
1995, 34, 334).
Thus cytokines such as TNF&agr; and IL-1 are believed to be important mediators of a considerable range of diseases and medical conditions. Accordingly it is expected that inhibition of the production of and/or effects of these cytokines will be of benefit in the prophylaxis, control or treatment of such diseases and medical conditions.
Without wishing to imply that the compounds disclosed in the present invention possess pharmacological activity only by virtue of an effect on a single biological process, it is believed that the compounds inhibit the effects of cytokines by virtue of inhibition of the enzyme p38 kinase. p38 kinase, otherwise known as cytokine suppressive binding protein (hereinafter CSBP) and reactivating kinase (hereinafter RK), is a member of the mitogen-activated protein (hereinafter MAP) kinase family of enzymes which is known to be activated by physiological stress such as that induced by ionising radiation, cytotoxic agents, and toxins for example endotoxins such as bacterial lipopolysaccharide, and by a variety of agents such as the cytokines, for example TNF&agr; and IL-1. It is known that p38 kinase phosphorylates certain intracellular proteins which are involved in the cascade of enzymatic steps which leads to the biosynthesis and excretion of cytokines such as TNF&agr; and IL-1. Known inhibitors of p38 kinase have been reviewed by G J Hanson in
Expert Opinions on Therapeutic Patents.
1997 7, 729-733. p38 kinase is known to exist in isoforms identified as p38&agr; and p38&bgr;.
European Patent Application No. 0 566 226, discloses certain quinazoline compounds as tyrosine kinase-inhibiting anticancer agents including the compounds:
4-(3-acetamidoanilino)-6,7-dimethoxyquinazoline and
4-(3-benzamidoanilino)-6,7-dimethoxyquinazoline.
The compounds disclosed in the present invention are inhibitors of the production of cytokines such as TNF, in particular of TNF&agr;, and various interleukins, in particular IL-1.
According to one aspect of the present invention there is provided a compound of the Formula (I):
wherein:
G is N or CH;
R
1
is hydroxy, halo, trifluoromethyl, cyano, mercapto, nitro, amino, carboxy, carbamoyl, formyl, sulphamoyl, C
1-6
alkyl, C
2-6
alkenyl, C
2-6
alkynyl, C
1-6
alkoxy, —O-(C
1-3
alkyl)-O—, C
1-6
alkylS(O)
n
- (wherein n is 0-2), N-C
1-6
alkylamino, N,N-(C
1-6
alkyl)
2
amino, C
1-6
alkoxycarbonyl, N-C
1-6
alkylcarbamoyl, N,N-(C
1-6
alkyl)
2
carbamoyl, C
2-6
alkanoyl, C
1-6
alkanoyloxy, C
1-6
alkanoylamino, N-C
1-6
alkylsulphamoyl, N,N-(C
1-6
alkyl)
2
sulphamoyl, C
1-6
alkylsulphonylamino, C
1-6
alkylsulphonyl-N-(C
1-6
alkyl)amino, or R
1
is of the Formula (IA):
A—(CH
2
)
p
—B— (IA)
wherein A is halo, hydroxy, C
1-6
alkoxy, C
1-6
alkylS(O)
n
- (wherein n is 0-2), cyano, amino, N-C
1-6
alkylamino, N,N-(C
1-6
alkyl)
2
amino, carboxy, C
1-6
alkoxycarbonyl, carbamoyl, N-C
1-6
alkylcarbamoyl or N,N-(C
1-6
alkyl)
2
carbamoyl, p is 1-6, and B is a bond, oxy, imino, N-(C
1-6
alkyl)imino or —C(O)NH—, with the proviso that p is 2 or more unless B is a bond or —C(O)NH—,
or R
1
is of the Formula (IB):
D—E— (IB)
wherein D is aryl, heteroaryl or heterocyclyl and E is a bond, C
1-6
alkylene, C
1-6
alkeneoxy, oxy, imino, N-(C
1-6
alkyl)imino, C
1-6
alkyleneimino, N-(C
1-6
alkyl)-C
1-6
alkyleneimino, C
1-6
alkyleneoxy-C
1-6
alkylene, C
1-6
alkyleneimino-C
1-6
alkylene, N-(C
1-6
alkyl)-C
1-6
alkyleneimino-C
1-6
alkylene, —C(O)NH—, —SO
2
NH—, —NHSO
2
— or C
2-6
alkanoylimino, and any aryl, heteroaryl or heterocyclyl group in a R
1
group may be optionally substituted with one or more groups selected from hydroxy, halo, C
1-6
alkyl, C
1-6
alkoxy, carboxy, C
1-6
alkoxycarbonyl, carbamoyl, N-C
1-6
alkylcarbamoyl, N,N-(C
1-6
alkyl)
2
carbamoyl, C
2-6
alkanoyl, amino, N-C
1-6
alkylamino and N,N-(C
1-6
alkyl)
2
amino,
and any heterocyclyl group in a R
1
group may be optionally
AstraZeneca AB
Davis Zinna Northington
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