5-aryl-1h-1,2,4-triazole compounds as inhibitors of...

Details 5-aryl-1h-1,2,4-triazole compounds as inhibitors of... 5-aryl-1h-1,2,4-triazole compounds as inhibitors of...

2002-05-17

2004-10-12

Morris, Patricia L. (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C548S267200, C548S267400, C548S267600, C548S267800, C548S268600

Reexamination Certificate

active

06803380

ABSTRACT:

The present invention relates to 5-aryl-1H-1,2,4-triazole compounds, to a process for their preparation and to pharmaceutical compositions containing them.
Non-steroidal antiinflammatory drugs (NSAIDs) exert most of their effects through inhibition of prostaglandin H synthase (PGHS), which mediates the conversion of arachidonic acid to prostaglandins. The first committed step in this process is the oxidative cyclisation of arachidonic acid to PGE
2
, which is followed by peroxide reduction to PGH
2
at a second distinct binding site. PGHS, commonly known as cyclooxygenase or COX, exist as two isoforms, each with a distinct physiological role (Hla, T et al, Proc. Natl. Acad. Sci. USA. 1992, 89, 7384, Holtzman, H. J. et al, J. Biol. Chem 1992, 267, 21438; Herschman, H. R., Cancer Metastasis Rev. 1994, 13, 241). One isoform, COX-1, is constitutively produced in a variety of tissues and appears to be important in the maintenance of normal physiological functions including renal blood flow and gastric cytoprotection. The second isoform, COX-2, is induced by a variety of inflammatory stimuli and appears to be largely responsible for the high-level production of prostaglandins that results in inflammation (Masferrer, J. L. et al., Proc. Natl. Acad. Sci. USA 1994, 91, 3228; Vane, J. et al. Proc. Natl. Acad. Sci. USA. 1994, 91, 2046).
WO95/15318, WO95/15316, U.S. Pat. Nos. 5,434,178, 5,466,823, 5,504,215, 5,508,426 and 5,510,496 describe 1,5-diaryl-pyrazoles with in vitro and in vivo activities.
Some 1,5-diphenyl-1H-1,2,4-triazoles such as compound (a), having a moderate Cox-2 inhibitory activity and anti-inflammatory potency, which are not superior to that of known anti-inflammatory agents, have been described in Monatshefte fur Chemie 119, 349-353 (1998).
3-cyano-1,5-diphenyl-1H-1,2,4-triazoles such as compound (b) reported in Chem. Pharm. Bull. 45(6), 987-995 (1997) are weak and non selective inhibitors of cyclooxygenase-1 and cyclooxygenase-2.
It has now been found that some 5-aryl-1H-1,2,4-triazole compounds are surprisingly particularly selective and strong inhibitors of cyclooxygenase-2.
Accordingly one object of this invention is to provide 5-aryl-1H-1,2,4-triazole compounds, which have a potent and selective COX-2 inhibiting activity.
The 5-phenyl-1H-1,2,4-triazole compounds of this invention are represented by the following general formula (I):
in which:
R
1
is hydrogen; a (C
1
-C
6
)alkyl; a halo(C
1
-C
6
)alkyl; or a phenyl optionally substituted by one or several subsdtients selected from the group consisting of a (C
1
-C
4
)alkyl, a halogen, a halo(C
1
-C
4
)alkyl, a hydroxy, a (C
1
-C
4
)alkoxy, an amino, a mono- or di-(C
1
-C
4
)alkylamino, a (C
1
-C
4
)alkylcarbonylamino, a (C
1
-C
4
)alkylthiocarbonylamino, a (C
1
-C
4
)alkoxycarbonylamino, a (C
1
-C
4
)akoxythiocarbonylamino, a (C
1
-C
4
)alkylsulfonyl, a (C
1
-C
4
)alkylsulfonylamino, a methylenedioxy, a nitro and a cyano;
R
2
is a (C
1
-C
6
)alkyl; a (C
3
-C
8
)cycloalkyl; a phenyl or a phenyl(C
1
-C
4
)alkyl in which the phenyl is optionally substituted by one or several substituents selected from the group consisting of a (C
1
-C
6
)alkyl, a halogen, a halo(C
1
-C
4
)alkyl, a hydroxy, a (C
1
-C
4
)alkoxy, an amino, a mono- or di-(C
1
-C
4
)alkylamino, a (C
1
-C
4
)alkylcarbonylamino, a (C
1
-C
4
)alkylthiocarbonylamino, a (C
1
-C
4
)alkoxycarbonylamino, a (C
1
-C
4
)alkoxythiocarbonylamino, a (C
1
-C
4
)alkylsulfonyl, a (C
1
-C
4
)alkylsulfonylamino, a methylenedioxy, a nitro and a cyano; or a heretoaromatic radical;
R
3
is hydrogen; a halogen; a hydroxy; a (C
1
-C
6
)alkoxy; an amino; a mono- or di-(C
1
-C
6
)alkylamino; a (C
1
-C
6
)alkylcarbonylamino; a (C
1
-C
6
)alkylthiocarbonylamino; a (C
1
-C
6
)alkoxycarbonylamino; a (C
1
-C
6
)alkoxythiocarbonylamino; a nitro; or a cyano;
R
4
is a (C
1
-C
6
)alkyl; an amino; a mono- or di-(C
1
-C
6
)alkylamino; a (C
1
-C
6
)alkylcarbonylamino; a (C
1
-C
6
)alkylthiocarbonylamino; a (C
1
-C
6
)alkoxycarbonylamino; or a (C
1
-C
6
)alkoxythiocarbonylamino; and its pharmaceutical acceptable salts.
The term “(C
1
-C
4
)alkyl” or “(C
1
-C
6
)alkyl” is understood as meaning a linear or branched hydrocarbon chain having 1 to 4 (respectively 6) carbon atoms such as for example a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl or hexyl radical.
The term “halo(C
1
-C
4
)- or (C
1
-C
6
)alkyl” is understood as meaning a (C
1
-C
4
) or (C
1
-C
6
)alkyl radical in which 1 to 7 hydrogen atoms have been substituted with 1 to 7 halogen atoms such as for example a trifluoromethyl, a 2,2,2-trifluoroethyl, a pentafluoroethyl, a chloromethyl or a bromomethyl radical.
The term “halogen” is understood as meaning a chlorine, bromine, iodine or fluorine atom.
The term “(C
3
-C
8
)cycloalkyl” is understood as meaning a saturated monocyclic hydrocarbon having 3 to 8 carbon atoms such as for example a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl radical.
The term “heteroaromatic radical” is understood as meaning a 5 or 6-membered monocyclic or 9 or 10-membered bicyclic aromatic heterocycles containing one or two heteroatoms chosen from N, S and O, such as for example a pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyrazolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, indolyl or indazolyl radical.
Preferred compounds of formula (I) are those in which
R
1
is hydrogen, a (C
1
-C
6
)alkyl, a halo(C
1
-C
6
)alkyl or a phenyl;
R
2
is a (C
3
-C
8
)cycloalkyl; a phenyl optionally substituted by one or several substituents selected from the group consisting of a halogen, a (C
1
-C
4
)alkyl, a (C
1
-C
4
)alkoxy, a hydroxy, a nitro, a di(C
1
-C
4
)alkylamino, a (C
1
-C
4
)alkylsulfonylamino, a (C
1
-C
4
)alkylsulfonyl and a methylenedioxy; a phenyl(C
1
-C
4
)alkyl in which the phenyl is substituted by one or several substituents selected from the group consisting of a hydroxy, a (C
1
-C
4
)alkyl and a (C
1
-C
4
)alkoxy; or a 5- or 6-membered monocyclic aromatic heterocycle containing one or two nitrogen, sulfur and/or oxygen atoms;
R
3
is hydrogen or a halogen;
R
4
is a (C
1
-C
6
)alkyl, a (C
1
-C
4
)alkylcarbonylamino or an amino.
Especially preferred are the compounds of formula (I) in which R
1
is a (C
1
-C
4
)alkyl or a halo(C
1
-C
4
)alkyl such as trifluoromethyl.
Also especially preferred are the compounds of formula (I) in which R
2
is a phenyl optionally substituted by one or several substituents selected from the group consisting of a halogen, a (C
1
-C
4
)alkyl, a (C
1
-C
4
)alkoxy, a hydroxy, a nitro, a di(C
1
-C
4
)alkylamino, a (C
1
-C
4
)alkylsulfonylamino, a (C
1
-C
4
)alkylsulfonyl and a methylenedioxy.
Further especially preferred compounds of formula (I) are those in which R
3
is hydrogen and those in which R
4
is a (C
1
-C
6
)alkyl or an amino.
The following compounds are especially valuable:
1-(4-methoxy-phenyl)-3-methyl-5-(4-methylsulfonyl-phenyl)-1H-1,2,4-triazole
1-(4-methoxy-phenyl)-5-(4-methylsulfonyl-phenyl)-3-trifluoromethyl-1H-1,2,4-triazole
1-(4-bromo-phenyl)-5-(4-methylsulfonyl-phenyl)-3-trifluoromethyl-1H-1,2,4-triazole
1-(4-methylsulfonylamino-phenyl)-5-(4-methylsulfonyl-phenyl)-3-trifluoromethyl-1H-1,2,4-triazole
1-(4-methoxy-phenyl)-5-(4-aminosulfonyl-phenyl)-3-trifluoromethyl-1H-1,2,4-triazole.
The pharmaceutically acceptable salts of the compounds of formula (I) are non-toxic salts including (i) salts of compounds of formula (I) containing acidic groups, for example alkali metal salts or alkaline earth metal salts such as sodium salts, potassium salts, magnesium salts and calcium salts, and also salts with pharmaceutically acceptable quaternary ammonium ions or organic amines such as triethylamine, ethanolamine or tris-(2-hydroxyethyl)amine and the like, and (ii). salts of compounds of the formula (I) which contain basic groups, for example, salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like or with organic carboxylic acids such as acetic acid, propionic acid, glycolic acid, pyruvic aci

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