Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-03-15
2004-06-08
Stockton, Laura L. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S240000, C546S146000, C546S169000, C514S307000, C514S314000
Reexamination Certificate
active
06747050
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a novel isoxazoline derivative, pharmaceutically acceptable salts, esters and stereochemically isomeric forms thereof which can serve as an inhibitor for protein caspases (cysteinyl-aspartate proteinases), a process for preparing the same and the use of the derivative as an inhibitor for caspases. The present invention also relates to a pharmaceutical composition for preventing inflammation and apoptosis which comprises the isoxazoline derivative, pharmaceutically acceptable salts, esters and stereochemically isomeric forms thereof and the process for preparing the same. The isoxazoline derivative according to the present invention can effectively be used in treating diseases due to caspases, for example, the disease in which cells are abnormally died, dementia, cerebral stroke, AIDS, diabetes, gastric ulcer, hepatic injure by hepatitis, sepsis, organ transplantation rejection reaction and anti-inflammation.
BACKGROUND ART
All organisms in nature undergo the life cycle consisting of development, differentiation, growth and death. Recently, an extensive research has been made to a mechanism involved in apoptosis which would play a key role in the control of the life cycle and the outbreak of diseases. It has been reported that apoptosis is occurred by a number of factors, but largely due to three kinds of cellular signal transport systems: the first of which is a signal transport system by the protein-protein interaction (See, Muzio M. et al.,
Cell
85, 817, 1996; Humke E. W. et al.,
JBC
273, 15702, 1998), the second, an incorporation of cytochrome C into cytoplasm via mitochondria (See, Liu X. et al.,
Cell
86:147, 1996; Li P. et al.,
Cell
91, 479, 1997), and the third, a cellular signal transport pathway by the SAPK(Stess-activated protein kinases) activation of mitogen-activation protein kinase(MAPK) enzymes. AU the pathways have been known to activate caspases cascade. As such caspases, about 10 kinds of isoenzymes in human and 14 kinds in mouse have been identified (see, Thornberry N. A. et al.,
Science
28, 1312 1998; Green D. R.
Science
28, 1309, 1998; Ahmad A, et al.,
Cancer Res
. 15, 5201 1998). The enzymes exist within the cells in the form of proenzyme which has no enzymatic activity and converted into an activated form if the cells are damaged or are exposed to a substance which leads to cellular necrosis. An activated enzyme has a heterodimer structure in which two polypeptides, i.e. larger subunits with the molecular weight of about 17-20 kDa, and smaller subunits with the molecular weight of about 10 kDa are bound together.
At present, caspases are classified into three (3) groups in view of the genetic identification analysis results and the biochemical characteristics: the first group is caspase-1, 4 and 5 which are responsible for the processing of cytokine activation, the second is caspase-3, 6 and 7 which carry out apoptosis and the third is caspase-8, 9 and 10 which are responsible for enzymatic activation in the upstream of signal transport system of apoptosis.
Among these caspases, Caspase-3 group and Caspase-8, 9, 10 etc. were recently reported to be related to apoptosis, and diseases (see, Thornberry N. A. et al.,
Science
, 28, 1312, 1998).
According to the recent research results, caspases are commonly activated as apoptosis is initiated, even though there is a minor difference depending upon the tissues and cells. The activated caspases then activate intracellular CAD(Caspase-activated DNAse) which finally digests intranuclear DNA to result in cell death (Sakahira H., et al.,
Nature
1 96, 1998; Enari M et al.,
Nature
1 43, 1998). In addition, they promote apoptosis by decomposing substrate such as PARP (Poly-ADP ribose polymerase) which is necessary for the survival of cells.
Meantime, according to the recent disease-related researches, it was reported that the activity of Caspase-3 is increased in the brain of dementia patient which promotes the production of beta-amyloid peptide from beta-amyloid precursor protein that is considered to be a major cause of dementia, thereby accelerating the apoptosis of brain cells (see, Kuida K. et al.,
Nature
28, 368, 1996). Further, it was reported that activation of caspases can be the direct inducer of various diseases such as sepsis (see, Haendeler J. et al.,
Shock
6, 405, 1996; Lenhoff R J. et al., 29, 563, 1999), rheumatoid arthritis (Firestein G. S. et al.,
J. Clin Invest
96(3), 1631, 1995), cerebral stroke (see, Hill I. E. et al.,
Brain Res
. 10, 398, 1995), ALS disease (see, Alexianu M. E. et al.,
J. Neurochem
63, 2365, 1994), autoimmune isease (see, Rieux-Laucat F, et al.,
Science
2, 1347, (1995), diabetes mellitusd(see, Juntti-Berggren et al.,
Science
2, 86, 1993), hepatitis (Haendeler J. et al.,
Shock
6, 405, 1996), organ transplantation rejection reaction (Koglin J. et al.,
Transplantation
, 27, 904, 1999; Bergese S. D. et al.,
Transplantation
27, 904, 1999), gastric ulcer (see, Slomiany B. L. et al.,
J. Physiol. Pharmacol
. 96, 1631, 1995), and the like.
The researches on three dimensional structure of caspase-1 and caspase-3, catalytic mechanism of the enzyme and enzyme-substrate specificity (see, Wilson, K. P et al.,
Nature
370, 270, 1994; Walker, N. P. C. et al.,
Cell
78, 343, 1994
; Nature Struc. Biol
. 3, 619, 1996) revealed that Caspase-1 group has a hydrolase-substrate specificity for the peptide sequence of (P4)-Val-X-Asp(P1) and Caspase-3 group has a hydrolase-substrate specificity for the sequence of (P4)Asp-X-X-Asp(P1).
Z-VAD-fluoromethyl ketone, and Z-DEVD-fluoromethyl ketone which mimics the above amino acid sequence have already been used in the researches on the inhibitors and were proven to have an inhibitory activity on apoptosis of hepatic cells by an activation of caspases (see, Rodriguez I. Et al.,
J. Exp. Med
., 184, 2067, 1996; Rouquet N. et al.,
Curr Biol
. 1, 1192, 1996; Kunstle G. et al.,
Immunol. Lett
55, 5, 1997), and on the apoptosis of brain cells by cerebral ischemias. However, since such peptide derivatives are deficient in drug property for clinical application, they cannot be used as therapeutics.
Fulminant hepatic failure (FHF) is a clinical syndrome resulting from massive death of liver cells or sudden and severe impairment of liver function (See: Trey, C. et al., 1970
, Progress in liver disease
, Popper, H. and F. Schaffner, eds. Grune and stratton, New York, pp282-298). The causes of FHF are diverse: hepatitis virus infection, drugs and toxins, alcohol, ischemia, metabolic disorder, massive malignant infiltration, chronic autoimmune hepatitis, etc. However, these mechanisms are not completely clear. Since the prognosis of FHF is very poor while its progress is very rapid, it is not uncommon that a patient falls in lethal condition in 1-2 weeks from the onset of this syndrome (See, Sherlock, S. 1993
, Adv. Intern. Med
. 38: 245-267). Consequently, the overall mortality in most series is very high. However, the hepatic lesion is potentially reversible, and survivors usually recover completely.
Different therapeutic options that have been tried in FHF include antibiotics, diuretics, corticosteroids, blood transfusion, charcoal haemoperfusion, and plasmaphresis. However, none of these methods have been shown to be effective in controlled studies. In recent years, liver transplantation is generally accepted as the only therapeutic option to actually improve the prognosis of this syndrome. However, liver transplantation cannot be the perfect treatment for FHF because of immune complication, viral or bacterial infection, and graft availability. Thus, a potent therapeutic agent which can protect hepatic cells from massive death during the acute phase is critically desired.
Apoptosis is a type of cell death characterized by a series of distinct morphological and biochemical changes accomplished by specialized cellular machinery. Apoptosis is an essential process to remove excess, unwanted and harmful cells and maintain homeostasis, but inappropriate apoptosis is implicated in many h
Chang Hye-Kyung
Chung Hyun-Ho
Kang Chang-Yuil
Kim Eunice Eun-Kyeong
Kim Young-Myeong
Alexander John B.
LG Chem Investment Ltd.
Stockton Laura L.
LandOfFree
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