Heterocyclic compounds for therapeutic use

Details Heterocyclic compounds for therapeutic use Heterocyclic compounds for therapeutic use

2001-03-15

2002-06-11

Powers, Fiona T. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C548S377100

Reexamination Certificate

active

06403629

ABSTRACT:

FIELD OF INVENTION
The present invention relates to new heterocyclic compounds of the general formula 1 and 2 for therapeutic use.
The invention further relates to pharmaceutical compositions containing the compounds of the general formula 1 and 2, process for preparing the same and pharmaceutically acceptable salts thereof having a selective action on inflammation and its related disorders.
BACKGROUND OF THE INVENTION
Nonsteroidal anti-inflammatory drugs (NSAIDS) are compounds used mainly in the relief of pain, inflammation, and sometimes fever.
The combined analgesic and antiinflammatory effects of NSAIDS make them particularly useful for the symptomatic relief of painful and/ or inflammatory conditions including musculoskeletal and joint disorders, such as rheumatoid arthritis, osteoarthritis, spondylo arthopathic, peri-articular and soft tissue disorder.
NSAIDS have shown to be useful in alleviating symptoms of inflammation and pain disorders. Prostaglandins (PGs) are ubiquitous fatty acid derivatives that serve as autocrine/paracrine mediators involved in many different physiological processes in addition to their well recognized role in inflammation and immune response modulation. Prostaglandins elicit a variety of important and beneficial responses. Among the undesirable properties of Prostaglandins is their ability to induce pain, fever, and symptoms associated with the inflammatory response.
NSAIDS exert their actions primarily by inhibiting the production of PGs. Recent studies of inflammatory processes has led to the identification of the key enzyme cycloxygenase (Cox) that is expressed in inflammatory conditions. Various studies on the identification of Cox-2 enzyme are reported:-Vane, J. R.; Nature 1994, Made, E. A. ., Smith W. L. ., Dewitt, D. L. J. Biol. Chem. 1993, 268: 6610-14
Cox is the first enzyme in the prostanoid biosynthetc pathway catalyzing the conversion of arachidonic acid to PGH2 as the first step in the synthesis of PGs, Prostacyclins, and Thromboxane, all of which act as important mediators of biological and inflammatory responses. Pairet, M., Engekelhardt,G; Fundam . Clin. Pharmacol 1996, 10, 1-15
The discovery of second inducible isoenzyme has enabled the identification of two major isoforms of COX: the constitutive COX isoform, termed Cox-1 and the inducible isoform, termed the Cox-2 There are now various theories supporting the fact that the inducible Cox-2 enzyme is responsible for the production of inflammatory mediators. Drugs of Future 1998, 23, 598-601.
The commonest side effects occurring during therapy with NSAIDS are generally gastrointestinal disturbances, these are usually mild and reversible but in some patients, peptic ulcer and severe gastrointestinal bleeding have been reported. These adverse effects on the gastrointestinal tract may be associated with the inhibition of the form of cyclooxygenase-1 (Cox-1). NSAIDS that are highly selective inhibitors of the form cycloxygenase-2 ( Cox-2) may have less gastrointestinal toxicity, hence, interest has developed in NSAIDS that are highly selective inhibitors of Cox-2, such as Meloxicam; Nimesulide, Rofecoxib and the like.
Most widely used NSAIDS like Diclofenac, Flufenamic acid, Ibuprofen, Indomethacin and the like, inhibit both the forms of the enzymes (Cox-1 and Cox-2) with many showing selectivity for Cox-1 enzyme.
Inhibition of COX-1 enzyme causes the common gastrointestinal side effects as seen in the known NSAIDS like Diclofenac, Flufenamic acid, Ibuprofen, Indomethacin and the like. All these antiinflammatory agents have shown undesirable side effects.
OBJECT OF THE INVENTION
It is an object of the present invention to provide new pyrazole derivatives and their pharmaceutical compositions as well as their therapeutic uses and the processes for preparing the same. At present there is a pharmacoepial dogma establishing a mandatory connection between anti-inflammatory, antipyretic, other therapeutic uses and the side effects mainly, gastrointestinal disturbances caused by the known NSAIDS. This dogma and the constant need has instigated the inventors to develop a newly synthesized anti-inflammatory compounds showing antimicrobial and antipyretic activity with less side effects. The pyrazole class has shown a promising drug like Celecoxib. The description of various pyrazole derivatives has been disclosed in U.S. Pat. No. 5,521207, J. Med. Chem. 1997, 40, 1347-1365
Pyrazoles have been described for use in the treatment of inflammation U.S. Pat. No. 5,134,142 to Matsuo et al describes 1,5-diaryl pyrzoles and specifically, 1-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3-trifluoromethyl pyrazole, as having anti inflammatory activity.
In view of the extensive studies on the above derivatives, the inventors have discovered new compounds of diarylpyrazole class having more advantageous properties and the manufacturing process for the said new pyrazole derivatives fulfilling the desirable features as described herein under.
DESCRIPTION OF THE INVENTION
The present invention relates to new NSAIDS compounds having Diarylpyrazole ring of the general formula 1 and formula 2, their synthesis and their pharmaceutically acceptable addition salts having a antiinflammatory, antipyrefic, or antibacterial activity.
The present invention also relates to synthesis of the intermediates (substituted diketo compounds ) of the compounds of general formula 1:
where R and R′ represents alkyl, hydrogen, halogens, haloalkyl, cyano, nitro, formyl, carboxyl, alkoxycarbonyl, carboxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, alkylthio, alkylsulfinyl, alkylsulphonyl, N-alkylsulfamyl, N-aryl sulfamyl, cyanoamido, amino, amidino, N-monoalkylamido, N-monoarylamido, N,N-dialkylamido, N-alkyl-N-aryl amido, N,N-dialkylsulfamyl with the alkyl or alkyl part of each such group containing 1-3 carbon atoms.
The following diarylpyrazole compounds of the formula I and their pharmaceutically acceptable salts and the corresponding appropriately substituted intermediates for condensation is given below:
1) N-[4-[5-(4-Methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl]methanesulphonamide prepared by condensation of 4-(methanesulphonamido)phenylhydrazine hydrochloride and 1-(4-Methylphenyl)-4,4,4-trifluorobutane-1,3-dione.
1A) N-[4-[5-(4-Ethylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl]methanesulphonamide prepared by condensation of 4-(methanesulphonamido)phenylhydrazine hydrochloride and 1-(4-Ethylphenyl)-4,4,4-trifluorobutane-1,3-dione
1 B) N-[4-[5-(4-Methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl]methanesulphonamide prepared by condensation of 4-(methanesulphonamido)phenylhydrazine hydrochloride and 1-(4-Methoxyphenyl)-4,4,4-trifluorobutane-1,3-dione
1C) N-[4-[5-(4-Ethoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl]methanesulphonamide prepared by condensation of 4-(methanesulphonamido)phenylhydrazine hydrochloride and 1-(4-Ethoxyphenyl)-4,4,4-trifluorobutane-1,3-dione
1D) N-[4-[5-(3,4-Dichlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl]methanesulphonamide prepared by condensation of 4-(methanesulphonamido)phenylhydrazine hydrochloride and 1-(3,4-Dichlorophenyl)-4,4,4-trifluorobutane-1,3-dione
1E) N-[4-[5-(2,4-Dichlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl]methanesulphonamide prepared by condensation of 4-(methanesulphonamido)phenylhydrazine hydrochloride and 1-(2,4-Dichlorophenyl)-4,4,4-trifluorobutane-1,3-dione
1F) N-[4-[5-(2-Methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl]methanesulphonamide prepared by condensation of 4-(methanesulphonamido)phenylhydrazine hydrochloride and 1-(2-Methylphenyl)-4,4,4-trifluorobutane-1,3-dione
1G) N-[4-[5-(2,4-Dimethylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl]methanesulphonamide prepared by condensation of 4-(methanesulphonamido)phenylhydrazine hydrochloride and 1-(2,4-Dimethylphenyl)-4,4,4-trifluorobutane-1,3-dione 1H) N-[4-[5-(3,4-Dimethylphen

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