Tetrazole compounds and pharmaceutical agents containing such de

Details Tetrazole compounds and pharmaceutical agents containing such de Tetrazole compounds and pharmaceutical agents containing such de

1998-06-29

2000-10-24

McKane, Joseph

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

514532, 514534, 514542, 514620, 514784, 548250, 548251, 548252, 548253, 548254, 560 19, 560 37, 560 38, 562433, 562442, 562443, 562450, A61K 3141, A61K 4722, C07D25704, C07C22928, C07C22934

Patent

active

061368342

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/JP96/03801 filed Dec. 26, 1996.


FIELD OF THE INVENTION

This invention relates to tetrazole compounds. More particularly, this invention relates to: inhibitory activity of the following formula (I): ##STR6## wherein all of the symbols have the same meanings as described hereinafter, or a non-toxic salt thereof, an acid addition salt thereof or a hydrate thereof; ingredient.


BACKGROUND OF THE INVENTION

Interleukin 1 (IL-1) is a key cytokine that directly or indirectly participates in the regulation of, for example, the immune system, hemopoietic system and neuroendocrine system, and thus, has a crucial physiological role. There are two types of IL-1, which have different isoelectric points (IL-1.alpha.:pl=5, IL-1.beta.:pl=7). Both of these are produced as a precursor having molecular weight of 31 Kd. The IL-1.beta. precursor does not bind to the IL receptor nor exerts a biological function. The IL-1.beta. converting enzyme (ICE) cleaves the precursor protein between Asp 116 and Ala 117 and converts into an active IL-1.beta. mature form having a molecular weight of 17 Kd. Following the cleavage, IL-1.beta. is secreted, binds to the receptor and triggers various biological activities (Ref. The New England Journal of Medicine, 328, 106 (1993)).
The inhibition of ICE enzymatic activity leads to prevention of conversion of the IL-1.beta. precursor into the mature form and hence results in blockage of IL-1 biological activity. There are many possible target diseases for ICE inhibitors, for example, prevention and/or treatment of insulin dependent diabetes (type I), autoimmune diseases, including multiple sclerosis, immune diseases, such as acute or delayed type hypersensitivity, infectious diseases, infection complications, septic shock, acute or chronic inflammatory diseases, such as arthritis, colitis, glomelular nephritis, hepatitis, pancreatitis, reperfusion injury, cholangeitis, encephalitis, endocarditis, myocarditis and vasculitis, neural diseases, such as Alzheimer's disease and Parkinson's disease, bone or cartilage-resorption diseases, Crohn's disease, osteo arthritis etc.
It is believed that ICE and/or ICE-like cystein proteases play important roles in cell death by apoptosis. Therefore it is possible that an ICE inhibitor may be used in the prevention and/or treatment of diseases resulting from apoptosis disorders, such as infection, reduction or enhancement of immune or central nervous system function, neoplasm etc. Diseases associated with apoptosis disorders are as follows; AIDS, ARC (AIDS related complex), adult T cell leukemia, hairy cell (pilocytic) leukemia, myelosis, respiratory dysfunction, arthropathy, HIV or HTLV-I related diseases, such as uveitis, virus related diseases, such as hepatitis C, neoplasm, diffuse collagen diseases, such as systemic lupus erythematosis or rheumatoid arthritis, autoimmune diseases, such as ulcerative colitis, Sjogren's syndrome, primary biliary cirrhosis, idiopathic thrombocytopnic purpura, autoimmonohaemolytic anemia, severe myasthenia, insulin dependent (type I) diabetes, osteodysplasia syndrome, periodic thrombocytopenia, aplastic anemia, idiopathic thrombocytopenia, various diseases which accompany thrombocytopenia, such as disseminated intravascular coagulation, hepatic diseases, including hepatitis (type C, A, B, or F virus borne or drug mediated) and hepatic cirrhosis, Alzheimer's disease, dementia, such as Alzheimer type senile dementia, cerebral vascular disturbance, neuro-degenerative diseases, adult dyspnea syndrome, infection, hyperplasia of the prostate, myoma of the uterus, asthma bronchiole, arteriosclerosis, various kinds of congenital teratoma, nephritis, senile cataract, chronic fatigue syndrome, myodystrophy, peripheral nervous disturbance, and so on (Ref. The New England Journal of Medicine, 328, 106-113 (1993), Arthritis & Rheumatism, 39, 1092 (1996)).


RELATED ARTS

Compounds having an inhibitory activity on IL-1.beta. converting enzyme (ICE) are known. The sequence of the ICE cleavage site of pre-IL-

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