Oxa(thia)zolidine derivative and anti-inflammatory drug

Details Oxa(thia)zolidine derivative and anti-inflammatory drug Oxa(thia)zolidine derivative and anti-inflammatory drug

2002-09-25

2004-07-13

Desai, Rita (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C548S233000, C546S135000, C514S306000

Reexamination Certificate

active

06762200

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to inhibitor compositions of phospholipase A(2) (hereinafter referred to as PLA (2)) activity characterized by comprising as the active ingredient either an oxa(thia)zolidine derivative or a pharmaceutically acceptable composite thereof, a use of said inhibitor compositions in mammalian which require to relieve sick conditions accompanied by the enhanced PLA(2) activity, and novel oxa(thia)zolidine derivatives which are useful as an active ingredient for said inhibitor compositions.
BACKGROUND OF THE INVENTION
Inflammation is a series of defensive response process caused in the tissues, induced by the applied injurious events (inflammatory stimuli) on any parts of a human body. When the tissues are damaged by inflammatory stimuli that could be caused by bacterial infections, immunological responses or physical injuries, the tissues respond (acute inflammation) to the stimuli, followed by excluding the stimuli to repair the damages. Alternatively, if the exclusion is difficult, the damages are progressed to induce continuously tissue swelling (chronic inflammation). Inflammation is well known to be associated with several diseases, and various mediators are known to be associated with each step during the inflammation process, constituted with activation and interactions of various cells.
PLA(2) is a diverse class of enzymes, catalyzing preferentially the hydrolysis of the sn-2 acyl-ester of glycerophospholipids, that are major components of cell membranes, to liberate fatty acids. It is also well known that the PLA(2)s are responsible for deacylation-reacylation process required for cell membrane repair and maintenance, and the hydrolyzed products, as well as the further metabolites, are lipid mediators with strong diverse physiological activities. The liberated product, arachidonic acid with some activity as mediator, is further metabolized in respective inflammation-associated cells to prostagladins, thromboxanes, lipoxins, leukotrienes, etc., which induce characteristic physiological responses, respectively (Irvine, R.,
Biochemical Journal
204: 3-16 (1982).). The other product, lysophosphatidylcholine not only plays roles as mediator, but also is utilized as a precursor of platelet activating factor (hereinafter referred to as PAF). These lipid mediators play an essential role to maintain homeostasis of living organisms, however, when they produced to excessive amounts under sick conditions associated with inflammation, they could cause adversely effects. In fact, steroidal anti-inflammatory drugs and various non-steroidal anti-inflammatory drugs (hereinafter referred to as NSAID) are known to interfere with the arachidonic acid cascade, have been widely used in clinical therapy. As PLA(2) is positioned at the upstream of the arachidonic acid cascade and is believed to be the rate-limiting step in the generation of these lipid mediators, this enzyme has been expected to be the promising target for research and development of novel anti-inflammatory drugs (Glaser, K. B.,
Advances in Pharmacology
32: 31-66 (1995).).
Recently, numerous PLA(2)s have been identified and rapidly become a large superfamily consisted of more than 15 isozymes are subdivided into four groups, on the basis of the protein structures and the characteristics in the enzymatic activities(Dennis, E. A.,
Trends in Biochemical Science
, 22: 1-2 (1997), and Balsinde, J. et al,
Annual Review of Pharmacology and Toxicology
, 39: 175-189 (1999), etc.). Among them, it is noted that only the particular isozymes are shown high specificity against arachidonyl-phospholipids, as well as the enzymatic activity of the particular isozymes are selectively enhanced in a case of inflammatory disorder. As the examples for such inflammation-associated PLA(2)s, type IV-cytosolic PLA(2) (hereinafter referred to as IV-cPLA(2); molecular weight 85 kDa) and the subtypes IIA, IID, V and X of secretory PLA(2) (hereinafter referred to as sPLA(2); molecular weight 14 kDa) may be exemplified. Among these, IV-cPLA(2) is particularly considered as the responsible isozyme for producing the lipid mediators in the inflammatory diseases, which is supported by findings from the ‘knockout’ (IV-cPLA(2)
−/−
)mice (Uozumi, N. et al,
Nature
390: 619-622 (1997), and Bonventre, J. V. et al,
Nature
390: 622-625 (1997).). Therefore, the enhanced lipid mediators production under sick conditions could be suppressed by inhibiting IV-cPLA(2) activity, thereby facilitating remedy and/or prevention of the inflammatory diseases. Such diseases can be exemplified as following: anaphylaxis induced by various inflammatory stimuli, septic shock, fever and pain; respiratory diseases, such as bronchitis, pneumonia, and adult respiratory distress syndrome; digestive diseases, such as inflammatory intestine disorder, Crohn's disease, ulcerative colitis, hepatitis, and nephritis; cardiovascular diseases, such as vasculitis and arteriosclerosis; allergic inflammatory diseases, such as rhinitis, asthma and atopic syndromes; and auto-immune diseases such as rheumatism; ischemia/reperfusion injuries, such as cerebral infarction and myocardial infarction; nerve degenerative diseases, solar keratosis, psoriasis, and the like.
However, as no drug has been developed yet, which shows remedial effects in the clinical therapies by inhibiting the enzyme activity, it is desired to develop such a new drug that can specifically and comprehensively control the lipid mediators production in inflammatory diseases, with excellent therapeutic and preventive effects.
In WO97/05135, compounds represented by the following general formula;
are disclosed as oxa(thia)zolidine derivatives having activity of inhibiting the PLA (2) activity. However, the compounds which show to have said inhibitory activity are limited to ones wherein the second and the fourth positions are substituted by either oxo or thio. Furthermore, in WO93/10789, 2-imino-4-oxothiazolidine derivative represented by the following chemical formula is disclosed.
It is described in Jpn. Pat. Appln. KOKAI publication No. 63-41471 that the oxa(thia)zolidine derivatives related to the present invention have acaricidal activity. However, it is not known so far that those oxa(thia)zolidine derivatives have PLA(2) inhibitory activity or anti-inflammatory activity.
DISCLOSURE OF THE INVENTION
As described above, it is understood that the enhanced PLA(2) activity plays a major role in the progress of various inflammatory diseases. Therefore, an object of the present invention is to provide medicinal compositions which is effective to remedy the inflammatory sick condition and to cure or prevent the relevant disease, and novel compounds to be used for the medicinal composition.
As a result of the studies by the inventors of the present invention for aiming at achieving the aforementioned object, it is found out that the oxa(thia)zolidine derivatives, which had been known to have acaricidal activity, have been found out also having inhibitory activity on PLA(2), thereby reaching the present invention.
The present invention is constituted with the following aspects (1) through (12).
(1) A medicinal composition characterized by containing as the active ingredient either a compound represented by a general formula (1) or a pharmaceutically acceptable composite thereof;
wherein X represents oxygen or sulfur,
R
1
represents hydrogen, C
1-4
alkyl or C
1-4
haloalkyl,
R
2
represents phenyl optionally substituted by A
1
, naphthyl optionally substituted by A
1
, 5 to 6-membered heterocyclic group optionally substituted by A
1
containing at least one heteroatom selected from a group consisting of oxygen, sulfur and nitrogen, quinolyl optionally substituted by A
1
, or a group represented by a formula (2);
wherein Q represents —(CH
2
)
3
—, —(CH2)
4
— or —OCH
2
O—,
R
3
represents hydrogen, C
1-4
alkyl optionally substituted by A
2
, C
1-4
alkoxy optionally substituted by A
2
, C
1-4
alkylcarbonyl optionally substituted by A
2
, C
1-4
alkoxycarbonyl optional

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