Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1994-04-08
1996-07-30
Fan, Jane
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514256, 5462724, 5462817, 546298, 546316, 544333, C07D40102, A61K 3144
Patent
active
055412033
DESCRIPTION:
BRIEF SUMMARY
This is a 371 of PCT/EP 92/02278 filed Oct. 1, 1992 now WO 93/07139.
This invention relates to triazole derivatives which have antifungal activity.
More particularly this invention relates to 2-phenyl-3-(pyridinyl or pyrimidinyl)-1-(1H-1,2,4-triazol-1-yl)alkan-2-ol derivatives which are useful in the treatment of fungal infections in animals, particularly human beings.
Cryptococcosis is a severe systemic fungal infection caused by Cryptococcus neoformans with a primary focus in the lung and characteristic spread to the meninges, especially those in the brain, and sometimes to the kidneys, bone and skin. Cryptococcal meningitis is a life-threatening fungal infection in up to 30% of AIDS patients.
The compounds of the present invention are surprisingly active against the clinically important Cryptococcus spp. fungi and in addition have surprisingly reduced liver toxicity.
The present invention provides compounds of the formula: ##STR3## and pharmaceutically acceptable salts thereof, wherein R is phenyl substituted by up to 3 substituents each independently selected from halo and trifluoromethyl; ##STR4## R.sup.3 is --S(O).sub.m R.sup.4 ; R.sup.4 is C.sub.1 -C.sub.4 alkyl; and
The term "halo" means F, Cl, Br or I.
Alkyl groups having three or more carbon atoms may be straight- or branched-chain.
Preferably R is phenyl substituted by 1 or 2 halo substituents.
More preferably R is phenyl substituted by 1 or 2 substituents each independently selected from F and Cl.
Most preferably R is 2,4-difluorophenyl.
Preferably R.sup.1 is methyl.
Preferably R.sup.2 is ##STR5##
Preferably R.sup.4 is methyl.
Preferably m is 2.
The pharmaceutically acceptable salts of the compounds of the formula (I) include acid addition salts formed with acids which form non-toxic salts such as the hydrochloride, hydrobromide, hydroiodide, sulphate, bisulphate, phosphate, hydrogen phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, benzoate, methanesulphonate, benzenesulphonate and para-toluenesulphonate salts. For a review on suitable pharmaceutical salts see Berge et al, J. Pharm. Sci., 66, 1-19 (1977).
The preferred compounds of the formula (I) are 2-(2,4-difluorophenyl)-3-(2-methanesulphonylpyridin-5-yl)-1-(1H-1,2,4-tria zol-1-yl)butan-2-ol and 2-(2,4-difluorophenyl)-3-(5-methanesulphonylpyridin-2-yl)-1-(1H-1,2,4-tria zol-1-yl)butan-2-ol, and the pharmaceutically acceptable salts thereof.
The compounds of the formula (I) contain at least two chiral centres and therefore exist as at least two diastereoisomeric pairs of enantiomers. The invention includes both the individual stereoisomers of the compounds of the formula (I) together with mixtures thereof. Separation of diastereoisomers may be achieved by conventional techniques, e.g. by fractional crystallisation, chromatography or H.P.L.C. of a diastereoisomeric mixture of a compound of the formula (I) or a suitable salt or derivative thereof. An individual enantiomer of a compound of the formula (I) may also be prepared from a corresponding optically pure intermediate or by resolution, either by H.P.L.C. of the racemate using a suitable chiral support or by fractional crystallisation of the diastereoisomeric salts formed by reaction of the racemate with a suitable optically active acid.
The more preferred compounds of the formula (I) are (2R,3S/2S,3R)-2-(2,4-difluorophenyl)-3-(2-methanesulphonylpyridin-5-yl)-1- (1H-1,2,4-triazol-1-yl)butan-2-ol and (2R,3S/2S,3R)-2-(2,4-difluorophenyl)-3-(5-methanesulphonylpyridin-2-yl)-1- (1H-1,2,4-triazol-1-yl)butan-2-ol and the pharmaceutically acceptable salts thereof.
The compounds of the formula (I) preferably have the (2R,3S)- configuration, i.e. ##STR6##
The most preferred compounds of the formula (I) are (2R,3S)-2-(2,4-difluorophenyl)-3-(2-methanesulphonylpyridin-5-yl)-1-(1H-1, 2,4-triazol-1-yl)butan-2-ol and (2R,3S)-2-(2,4-difluorophenyl)-3-(5-methanesulphonylpyridin-2-yl)-1-(1H-1, 2,4-triazol-1-yl)butan-2-ol and the pharmaceutically acceptable salts thereof.
The compounds of the formula (I) provided by the present inve
REFERENCES:
CA 89:43764g (1978). F. Maurer et al.
Bell Andrew S.
Richardson Kenneth
Whittle Peter J.
Fan Jane
Ginsburg Paul H.
Pfizer Inc.
Richardson Peter C.
Zielinski Bryan C.
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