Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2003-06-13
2004-04-27
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...
C548S182000, C548S186000
Reexamination Certificate
active
06727268
ABSTRACT:
BACKGROUND OF THE INVENTION
This U.S. non-provisional application claims priority under 35 U.S.C. §119 to Korean Patent Application No. 2002-35409, filed on Jun. 24, 2002, in the Korean Intellectual Property Office, the contents of which are incorporated herein by reference in its entirety.
1. Field of the Invention
The present invention relates to a 2-thioxothiazole derivative or a non-toxic salt thereof, a method for preparing the same, and a pharmaceutical composition containing the same as an active ingredient.
2. Description of the Related Art
Most nonsteroidal antiinflammatory agents are responsible for blocking enzyme, cyclooxygenase (COX) or prostaglandin G/H synthase, to reduce inflammation, pain, or fever. In addition, they inhibit uterus contraction caused by hormones and also inhibit growth of several cancers. Cyclooxygenase-1 (COX-1) was first discovered in bovine. The COX-1 is constitutively expressed in a variety of cell types. Unlike the COX-1, cyclooxygenase-2 (COX-2) is a recently discovered isoform of cyclooxygenase that can be easily induced by mitogen, endotoxin, hormone, growth factor, or cytokine.
Prostaglandin is a potent mediator for various pathological and physiological processes. The COX-1 plays important physiological roles such as in the release of endogenous prostaglandin, the maintenance of the shape and the function of stomach, and the blood circulation in the kidney. On the other hand, the COX-2 is induced by an inflammatory factor, hormone, a growth factor, or cytokine. Therefore, the COX-2 is involved in pathological processes of prostaglandin, unlike the constitutive COX-1. In this regard, selective inhibitors of the COX-2 produce fewer and less side effects in terms of action mechanism in comparison with conventional nonsteroidal antiinflammatory agents. In addition, they reduce inflammation, pain, and fever and inhibit uterus contraction caused by hormones and growth of several cancers. In particular, they are effective in decreasing side effects such as stomach toxicity and kidney toxicity. Still furthermore, they inhibit the synthesis of contractile prostanoid, thereby leading to suppression of the contraction of smooth muscles. Therefore, they help in preventing premature birth, menstrual irregularity, asthma, and eosinophilic disease.
Recently, it was reported that nonsteroidal antiinflammatory agents are effective in treating large intestine cancer [
European Journal of Cancer
, Vol 37, p2302, 2001], prostate cancer [
Urology
, Vol 58, p127, 2001], and dementia [
Exp. Opin. Invest. Drugs
, Vol 9, p671, 2000].
In addition, it is anticipated that selective inhibitors of the COX-2 would be effective in treating osteoporosis and glaucoma. Utility of selective inhibitors of the COX-2 is well described in publications [John Vane, “Towards a Better Aspirin” in
Nature
, Vol.367, pp215-216, 1994; Bruno Battistini, Regina Botting and Y. S. Bakhle, “COX-1 and COX-2: Toward the Development of More Selective NSAIDs” in
Drug News and Perspectives
, Vol.7, pp501-512, 1994; David B. Reitz and Karen Seibert, “Selective Cyclooxygenase Inhibitors” in
Annual Reports in Medicinal Chemistry
, James A. Bristol, Editor, Vol. 30, pp179-188, 1995].
Various selective COX-2 inhibitors having different structures are known. Among them, a selective COX-2 inhibitor having a diaryl heterocyclic structure, i.e. a tricyclic structure has been widely studied as a potent candidate. The diaryl heterocyclic structure has a central ring and a sulfonamide or methylsulfone group attached to one of the aryl rings. An initial substance having such diaryl heterocyclic structure is Dup697
[Bioorganic
&
Medicinal Chemistry Letters
, Vol 5, p2123, 1995]. Since then, SC-58635 having a pyrazol ring (
Journal of Medicinal Chemistry
, Vol 40, p1347, 1997) and MK-966 having a furanone ring (WO 95/00501) were discovered as derivatives of the Dup697.
One selective COX-2 inhibitor, Celecoxib of formula 4 is disclosed in U.S. Pat. No. 5,466,823. The Celecoxib is a substituted pyrazolyl benzenesulfonamide derivative.
Another selective COX-2 inhibitor, Rofecoxib of formula 5 is disclosed in WO 95/00501. The Rofecoxib has a diaryl heterocyclic structure with a central furanone ring.
Valdecoxib of formula 6 as another selective COX-2 inhibitor is disclosed in U.S. Pat. No. 5,633,272. The Valdecoxib has a phenylsulfonamide moiety with a central isoxazole ring.
The selective COX-2 inhibitors of formulas 4 to 6 are effective inflammatory therapeutic agents with fewer and less side effects in comparison with conventional nonsteroidal antiinflammatory agents.
SUMMARY OF THE INVENTION
An aspect of the present invention provides a 2-thioxothiazole derivative of formula 1 or a non-toxic salt thereof.
Another aspect of the present invention provides a method for preparing a 2-thioxothiazole derivative or a non-toxic salt thereof.
Another aspect of the present invention provides a pharmaceutical composition comprising a 2-thioxothiazole derivative or a non-toxic salt thereof as an active ingredient for the treatment of fever, pain, and inflammation.
Yet another aspect of the present invention provides a pharmaceutical composition comprising a 2-thioxothiazole derivative or a non-toxic salt thereof as an active ingredient for the treatment of cancers and dementia.
DETAILED DESCRIPTION OF THE INVENTION
According to an aspect of the present invention, there is provided a 2-thioxothiazole derivative represented by formula 1:
wherein:
R represents hydrogen or methyl;
X represents hydrogen, methyl, halogen, nitro, or methanesulfonyl;
or a non-toxic salt thereof.
The 2-thioxothiazole derivative of formula 1 may be present in a form of a non-toxic salt. The term, “non-toxic salt” as used herein refers to a pharmaceutically acceptable, toxin-free salt, including an organic salt and an inorganic salt.
The Inorganic salt of the 2-thioxothiazole derivative of formula 1 includes an inorganic salt of aluminum, ammonium, calcium, copper, iron, lithium, magnesium, manganese, potassium, sodium, or zinc but is not limited thereto. Preferably, an inorganic salt of ammonium, calcium, potassium, or sodium is used.
The organic salt of the 2-thioxothiazole derivative of formula 1 includes an organic amine salt of primary, secondary, or tertiary amine, substituted amine that is present in nature, or cyclic amine, or a salt of a basic ion exchange resin but is not limited thereto. Examples of the salt of a basic ion exchange resin include, but are not limited to, a salt of arginine, betaine, caffeine, choline, N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpyperidine, N-methylglucamine, glucamine, glucosamine, histidine, hydroamine, N-(2-hydroxyethyl)pyperidine, N-(2-hydroxyethyl)pyrrolidine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, pyperidine, polyamine resin, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, and tromethamine.
The 2-thioxothiazole derivative of formula 1 may be present in a form of an organic acid salt or an inorganic acid salt.
Examples of the organic acid salt or the inorganic acid salt of the 2-thioxothiazole derivative of formula 1 include, but are not limited to, a salt of acetic acid, adipic acid, aspartic acid, 1,5-naphthalene disulfonic acid, benzene sulfonic acid, benzoic acid, camphor sulfonic acid, citric acid, 1,2-ethane disulfonic acid, ethane sulfonic acid, ethylenediaminetetraacetic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, hydroiodic acid, hydrobromic acid, hydrochloric acid, icethionic acid, lactic acid, maleic acid, malic acid, madelic acid, methane sulfonic acid, mucinic acid, 2-naphthalenedisulfonic acid, nitric acid, oxalic acid, pentothenic acid, phosphoric acid, pivalric acid, propionic acid, salicylic acid, stearic acid, succinic acid, sulfuric acid, tartaric acid, p-toluene sulfonic acid, undecanoic acid, and 10-undecenoic acid. Preferably, a salt
Chae Myeong Yun
Cho Il Hwan
Jung Sung Hak
Kang Kyoung Rae
Kim Jong Hoon
CJ Corp.
Stockton Laura L.
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