Organic compounds -- part of the class 532-570 series – Organic compounds – Sulfur containing
Reexamination Certificate
2002-10-03
2003-06-24
Vollano, Jean F. (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Sulfur containing
C568S032000
Reexamination Certificate
active
06583321
ABSTRACT:
TECHNICAL FIELD
The present invention relates to 4′-methanesulfonyl-biphenyl derivatives as a highly selective cyclooxygenase-2 inhibitor.
BACKGROUND
Most of non-steroid anti-inflammatory drugs represent actions such as anti-inflammation, analgesic, and antipyretic activity by inhibiting the enzymatic activity of cyclooxygenase or prostaglandin G/H synthase. In addition, they can suppress the uterine contraction induced by hormones and the cell proliferation in several kinds of cancers. First, only cyclooxygenase-1 was known to be found in cow as a constitutional enzyme. But recently, cyclooxygenase-2 is elucidated as an induced form. Cyclooxygenase-2 is identified to be discriminated clearly from cyclooxygenase-1 and can be provoked easily by mitogen, endotoxin, hormones, growth factors, cytokines and the like.
Prostaglandins have various pathological and physiological functions. Precisely, cyclooxygenase-1 as a constitutional enzyme participates in the secretion of basic endogenous prostaglandin and plays an important role in physiological aspects such as stomach homeostasis, renal blood circulation and so on. On the other hand, cyclooxygenase-2 is induced by inflammatory factors, hormones, growth factors, cytokines and the like and thus plays an important role in pathological effects of prostaglandins. Therefore, selective inhibitors against cyclooxygenase-2 are expected to have no side effect on account of the functional mechanism compared with the anti-inflammatory drugs such as conventional non-steroid agents and to represent actions such as anti-inflammation, analgesic, and antipyretic activity. Furthermore, it is estimated to suppress the uterine contraction induced by hormones and the cell proliferation in several kinds of cancers. Especially, it probably has less side effects such as gastrointestinal toxicity, renal toxicity and the like. Also, it is assumed to prevent the synthesis of contractive prostanoids and thus inhibit the contraction of smooth muscle induced by the prostanoid. Hence, it can be applied usefully to treat a premature birth, dysmenorrhea, asthma and several diseases associated with eosinophilic leukocytes. Besides, it can be exploited widely to cure osteoporosis, glaucoma and athymia, which has been disclosed in a lot of references, especially the usefulness of selective inhibitors against cyclooxygenase-2 (References: John Vane, “Towards a better aspirin” in
Nature
, Vol. 367, pp 215-216, 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, pp 501-512, 1994; David B. Reitz and Karen Seibert, “Selective Cyclooxygenase Inhibitors” in
Annual Reports in Medicinal Chemistry
, James A. Bristol, Editor, Vol. 30, pp 179-188, 1995).
The selective inhibitors against cyclooxygenase-2 have been reported to have various structural forms. Among these, the diaryl heterocycle structure, namely a tricyclic system, has been studied most frequently and exploited to construct a lot of candidate substances. In this structure, it is essential that sulfonamide or methanesulfone group exist onto one phenyl group. The initial substance of such a structure is identified to be Dup697 (Bioorganic and Medicinal Chemistry Letters, Vol. 5, No. 18, p 2123, 1995). Then, as a derivative, SC-58635 (Journal of Medicinal Chemistry, Vol. 40, p 1347, 1997) having a pyrrazole structure, MK-966 (WO 95/00501) having a furanone structure and the like are disclosed.
DISCLOSURE OF INVENTION
Based upon the above technical backgrounds, the inventors of the present invention have tried a lot in order to develop novel compounds as a highly selective cyclooxygenase-2 inhibitor. As a result, we have found that 4′-methanesulfonyl-biphenyl derivatives of formula 1 satisfied such a purpose and completed the present invention successfully.
Therefore, the object of the present invention is to provide 4′-methanesulfonyl-biphenyl derivatives of formula 1 and its pharmaceutically acceptable salts as depicted below.
Hereinafter, the present invention will be described more clearly.
The present invention relates to 4′-methanesulfonyl-biphenyl derivatives of formula 1 and its pharmaceutically acceptable salts.
<Formula 1>
Wherein, R
1
and R
2
are respectively a hydrogen;
C
1
-C
4
-alkyl substituted or not substituted by halogens;
C
3
-C
7
-cycloalkyl;
C
1
-C
5
-alkyl containing 1~3 ether bonds and/or an aryl substitute;
substituted or not substituted phenyl;
or substituted or not substituted five or six ring-cycled heteroaryl containing more than one hetero atoms selected from a group consisting of nitrogen, sulfur and oxygen (wherein, phenyl or heteroaryl can be one- or multi-substituted by a substituent selected from a group consisting of hydrogen, methyl, ethyl and isopropyl).
The compound of the present invention can exist as a pharmaceutically acceptable salt form, wherein the pharmaceutically acceptable salt means a nontoxic salt containing organic salt and inorganic salt and accepted pharmaceutically. The inorganic salt consists of aluminum, ammonium, calcium, copper, iron, lithium, magnesium, manganese, potassium, sodium, zinc and the like and preferably, ammonium, calcium, magnesium, potassium, sodium. The organic salt consists of primary-, secondary- or tertiary-amines, naturally substituted amines, cyclic amines, modified salts prepared through basic ion exchange resin and the like. Preferably, the organic salt can be selected among arginine, betain, caffeine, colin, N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholin, N-ethylpiperidine, N-methylglucamine, glucamine, glucosamine, histidine, hydrapamine, N-(2-hydroxyethyl)piperidine, N-(2-hydroxyethyl)pyrrolidine, isopropylamine, lysine, methylglucamine, morpholin, piperazine, piperidine, polyamine resin, procain, purine, teobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.
Besides, the compound of the present invention can be a salt form of nontoxic acids containing the organic acid and the inorganic acid and accepted pharmaceutically, in case that it be basic. Preferably, the acid can be adopted among acetic acid, adipic acid, aspartic acid, 1,5-naphthalenedisulfonic acid, benzenesufonic acid, benzo acid, camposulfonic acid, citric acid, 1,2-ethanedisulfonic acid, ethanesulfonic acid, ethylendiaminetetraacetic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, hydriodic acid, hydrobromic acid, hydrochloric acid, icethionic acid, lactic acid, maleic acid, malic acid, manderic acid, methanesulfonic acid, music acid, 2-naphthalene disulfonic acid, nitric acid, oxalic acid, parnoic acid, pantothenic acid, phosphoric acid, pivalic acid, propionic acid, salicylic acid, stearic acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid, undecanoic acid, 10-undecenoic acid and the like and more preferably, among succinic acid, hydrobromic acid, hydrochloric acid, maleic acid, methanesulfonic acid, phosphoric acid, sulfuric acid, tartaric acid and the like.
Preferably, the compound of the present invention of formula 1 as a selective inhibitor against cyclooxygenase-2 is that R
1
and R
2
are separately methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclopentyl, or benzyl.
For preferred embodiments of the present invention, the compounds of formula 1 will be described more clearly as follows:
4′-methanesulfonyl-3,4-dimethoxy-biphenyl;
4′-methanesulfonyl-3,4-diethoxy-biphenyl;
4′-methanesulfonyl-3,4-dipropyloxy-biphenyl;
4′-methanesulfonyl-3,4-diisopropyloxy-biphenyl;
4′-methanesulfonyl-3,4-dicyclopropyloxy-biphenyl;
4′-methanesulfonyl-3,4-dibutyloxy-biphenyl;
4′-methanesulfonyl-3,4-dibenzyloxy-biphenyl;
4′-methanesulfonyl-3,4-dicyclopentyloxy-biphenyl; and
3-butoxy-4-isopropoxy-4′-methanesulfonyl-biphenyl
On the other hand, the compounds of formula 1 in the present invention can be prepared by perf
Cho Il Hwan
Chun Hyung Ok
Kim Je Hak
Kim Jong Hoon
Lee Eun Young
Cheil Jedang Corporation
Swanson & Bratschun L.L.C.
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