Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1996-05-21
1997-06-17
Ramsuer, Robert W.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
5483751, 5483771, A61K 31415, C07D23112, C07D23114
Patent
active
056397771
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
This invention is in the field of anti-inflammatory pharmaceutical agents and specifically relates to compounds, compositions and methods for treating inflammation and inflammation-associated disorders, such as arthritis.
BACKGROUND OF THE INVENTION
Prostaglandins play a major role in the inflammation process and the inhibition of prostaglandin production, especially production of PGG.sub.2, PGH.sub.2 and PGE.sub.2, has been a common target of anti-inflammatory drug discovery. However, common non-steroidal anti-inflammatory drugs (NSAIDs) that are active in reducing the prostaglandin-induced pain and swelling associated with the inflammation process are also active in affecting other prostaglandin-regulated processes not associated with the inflammation process. Thus, use of high doses of most common NSAIDs can produce severe side effects, including life threatening ulcers, that limit their therapeutic potential. A popular current alternative to NSAIDs is the use of corticosteroids, which have even more drastic side effects, especially when long term therapy is involved.
Several families of pyrazole-containing compounds have been described as having anti-inflammatory activity. U.S. Pat. No. 5,134,142 to Matsuo et al describes 1,5-diaryl-pyrazoles, and specifically 1-(4-fluorophenyl)-5-[(4-methylsulfonyl)phenyl]-3-trifluoromethyl-1H-pyraz ole, as having anti-inflammatory activity.
U.S. Pat. No. 3,984,431 to Gueremy et al describes derivatives of pyrazole-5-acetic acid as having anti-inflammatory action. Isofezolac (1,3,4-triphenyl-1H-pyrazole-5-acetic acid) is specifically described. 1,3,4-Triphenyl-5-(chloromethyl)-1H-pyrazole is described as an intermediate in the formation of the above mentioned derivatives. Isofezolac has been found to be as ulcerogenic as other common anti-inflammatory agents [J. Mizoule et al, Arch. int. Pharmacodyn., 238, 305 (1979)].
Little pharmaceutical activity has been described for 1,4,5-triphenyl-1H-pyrazolyl compounds. The rearrangement of epoxyketones has been observed to produce 1,4,5-triphenyl-1H-pyrazole [H. House et al, J. Amer. Chem. Soc., 79, 2490 (1957)]. Photochemical reactions of 4-(2-chlorophenyl)-1,5-diphenyl-1H-pyrazole and of 1,4,5-triphenyl-1H-pyrazole have been described [J. Grimshaw et al, J. Chem. Soc. Perkin. Trans. 1, 2096 (1977)]. The synthesis of a series of 1-aryl-4,5-diphenyl-1H-pyrazoles and a series of 1-aryl-3,4-diphenyl-1H-pyrazoles by reacting 2-phenylacrylophenone and arylhydrazines has been described [J. Wilshire, Aust. J. Chem., 27, 2041 (1974)]. Specifically 1-(4-methylphenyl)-4,5-diphenyl-1H-pyrazole is described. The rearrangement of epoxyphenylpropiophenone has been observed to produce 1-phenyl-4,5-substitutedphenyl-1-H-pyrazoles, and specifically 1-phenyl-4,5-di(chlorophenyl)-1H-pyrazole [H. House et al, J. Amer. Chem. Soc., 83, 979 (1961)]. Triarylpyrazole compounds are prepared by reacting thioketoaldehydes and phenylhydrazines [M. Weissenfels et al, J. Prakt. Chem., 315, 873 (1973)] and specifically 4,5-bis(4-methoxyphenyl)-1-phenyl-1H-pyrazole. The reaction of phenylhydrazines with isoflavonoids to yield pyrazole compounds, such as 2-(1,4-diphenyl-1H-pyrazol-5-yl)-phenol has been described [V. Szabo et al, Acta Chim. Acad. Sci, Hung., 98, 457 (1979)].
The reaction of benzoin phenylhydrazone with aldehydes to produce 3-alkyl-1,4,5-triphenyl-1H-pyrazoles is described [H. Gnichtel et al, Liebigs Ann. Chem., 589 (1989)]. Specifically, 3-methyl-1,4,5-triphenyl-1H-pyrazole is described. The reaction of dinitrophenyl diketone derivatives with hydrazines has been studied, and 4-(2,4-dinitro)phenyl-1-(4-methylphenyl)-5-phenyl-3-methyl-1H-pyrazole has been described [I. Gambhir et al, J. Org. Chem., 27, 1899 (1962)].
1,4,5-Triphenyl-3-bromomethyl-1H-pyrazole is described as an intermediate in the synthesis of 1,4,5-triphenyl-1H-pyrazole-3-ethanoic acid, which is a potential anti-inflammatory agent [H. Biere, Arch, Pharm., 316, 608 (1983)].
DESCRIPTION OF THE INVENTION
A class of compounds useful in treating inflamma
REFERENCES:
patent: 3984431 (1976-10-01), Gueremy et al.
patent: 5134142 (1992-07-01), Matauo et al.
patent: 5466823 (1995-11-01), Talley et al.
J. Mizoule et al, Arch. int. Pharmacodyn., 238, 305-322 (1979).
H. House et al, J. Amer. Chem. Soc., 79, 2490-2495 (1957).
J. Grimshaw et al., J. Chem. Soc. Perkin. Trans. 1, 2096-2099 (1977).
J. Wilshire, Aust. J. Chem., 27, 2041-2045 (1974).
H. House et al, J. Amer. Chem. Soc., 83, 979-983 (1961).
M. Weissenfels et al, J. Prakt. Chem., 315, 873-880 (1973).
V. Szabo et al, Acta Chim. Acad. Sci. Hung., 98, 457-462 (1979).
H. Gnichtel et al, Liebigs Ann. Chem., 589-591 (1989).
I. Gambhir et al., J. Org. Chem., 27, 1899-1901 (1962).
H. Biere, Arch. Pharm., 316, 608-616 (1983).
Bulock Joseph W.
G.D. Searle & Co.
Ramsuer Robert W.
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