Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-03-22
2001-11-20
Higel, Floyd D. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S365000, C514S381000, C548S262200, C548S127000, C548S128000, C548S146000, C546S268700
Reexamination Certificate
active
06319933
ABSTRACT:
BACKGROUND OF THE INVENTION
Azole antifungal agents are currently most frequently used for systemic mycosis, but none of them fully fulfil the necessary clinical requirement; such as efficacy against major systemic mycoses including disseminated aspergillosis, safety, and water solubility for parenteral formulation. Although the systematic mycoses caused by Candida, Cryptococcus and Aspergillus spp. are still major infections, there is an increasing medical need for new antifungal agents with broader spectrum that cover not only the above mentioned major pathogens but also emerging pathogens such as mucor spp. Several new azole type agents have been developed to fulfil these unmet medical needs, such as the compounds disclosed in EP 0 667 346 and EP 0 440 372. The present invention intends to provide antifungal agents having broad antifungal spectrum covering Aspergillus as well as mucor spp., their intermediates, a process for their manufacture, an antifungal composition containing them and the use thereof.
SUMMARY OF THE INVENTION
The present invention provides compounds of the general formula
which possess a broad spectrum of antifungal activity. The compounds of the present invention have a surprisingly high level of antifungal activity, in particular against Aspergillus spp., and mucor spp. such as Rhizopus spp., and Absidia spp.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to novel 1-(1H-1,2,4-triazol-1-yl)butan-2-ol derivatives of the formula (I),
wherein
Q is a phenyl ring, optionally substituted by 1 to 3 halogen atom(s);
R is hydrogen, hydroxy, carboxy, carbamoyl, cyano, lower-alkyl, lower-alkoxycarbonyl or lower-alkoxy, whereas lower-alkyl, lower-alkoxycarbonyl and lower-alkoxy may be substituted by one or more halogen, lower-alkyl, di-lower-alkylamino or lower-alkoxy;
X is a 5 or 6 membered hetero-aromatic ring;
Y is phenyl or pyridyl, each of which may be substituted by one or more halogen, cyano, lower-alkyl, di-lower-alkylamino, lower-alkyloxy, acyl, lower-alkoxycarbonyl;
Z is a sulfur and nitrogen containing 5 membered hetero-aromatic ring; and pharmaceutically acceptable salts thereof.
As used above, the following terms have the meanings indicated:
The term “lower” is used to mean a radical consisting of 1 to 5, preferably 1 to 4 carbon atom(s), unless otherwise indicated.
The term “alkyl” refers to a branched or straight chain monovalent saturated aliphatic hydrocarbon radical of one to twenty carbon atoms, preferably of one to sixteen carbon atom(s).
The term “lower alkyl” refers to a branched or straight chain monovalent alkyl radical of one to six carbon atom(s), preferably one to four carbon atom(s). This term is further exemplified by such radicals as methyl, ethyl, n-propyl, isopropyl, n-butyl, i-butyl, tert-butyl and the like.
The term “halogen atom” refers to fluorine, chlorine, bromine and iodine.
The term “heteroatom” refers to N, O and S.
The term “acyl” refers to the group —C(O)—R′, where R′ is a lower alkyl.
The term “lower alkoxycarbonyl” refers to the group —C(O)OR′, where R′ is a lower alkyl.
The term “lower alkoxy” refers to the group —O—R′, where R′ is a lower alkyl.
The term “di-lower alkylamino” refers to two independently selected lower alkyl groups attached to a nitrogen atom, i.e., —N(-lower alkyl)-lower alkyl.
The present invention also relates to pharmaceutical compositions containing above 1-(1H-1,2,4-triazol-1-yl)butan-2-ol derivatives, the use of such derivatives for the prophylaxis or treatment of mycoses as well as to processes for production of such 1-(1H-1,2,4-triazol-1-yl)butan-2-ol derivatives.
Preferable embodiments of the groups for formula I are as follows:
In the definition Z, the term “sulfur and nitrogen containing 5 membered hetero-aromatic ring” preferably means a group selected from the group consisting of the groups represented by the formula,
more preferably
viz. thiazol-2,4-diyl, 1,2,4-thiadiazol-3,5-diyl and 1,2,3-thiadiazol-4,5-diyl.
In the definition X, the term “5 or 6 membered hetero-aromatic ring” preferably means a group selected from the group consisting of the groups represented by the formula:
more preferably
viz. thiazol-2,4-diyl and 1,2,4-thiadiazol-3,5-diyl.
In the definition Y, tie term “phenyl or pyridyl which may be substituted by one or more halogen, cyano, lower-alkyl, di-lower-alkylamino, lower-alkyloxy, acyl, lower-alkoxycarbonyl” preferably means o-phenylene, m-phenylene, p-phenylene, pyridin-2,4-diyl, pyridin-2,5-diyl, pyridin-2,6-diyl and the like. More preferably, Y is m-phenylene, p-phenylene or pyridin-2,5-diyl. The most preferable Y is p-phenylene.
Preferable residues R in accordance with the present invention are hydrogen, hydroxy, lower-alkyl, e.g. methyl or ethyl, lower-alkoxycarbonyl, e.g. ethoxy-carbonyl, and lower-alkyl substituted by one or more halogen, preferably fluoro, e.g. trifluoromethyl or pentafluoroethyl.
The preferable embodiments of —Z—R in the formula (I) are thiazole-2-yl, 4-methyl-thiazol-2-yl, 4-isopropyl-thiazol-2-yl, 4-ethyl-thiazol-2-yl, 4-trifluoromethyl-thiazol-2-yl, 4-pentafluoroethyl-thiazol-2-yl, 4-acetyl-thiazol-2-yl, 4-carboxy-thiazol-2-yl, 4-cyano-thiazol-2-yl, 4-methoxy-thiazol-2-yl, 4-ethoxycarbonyl-thiazol-2-yl, 4-chloro-thiazol-2-yl, 4-hydroxy-thiazol-2-yl, 1,2,4-thiadiazol-3-yl, 5-methyl-1,2,4-thiadiazol-3-yl, 5-ethyl-1,2,4-thiadiazol-3-yl, 5-isopropyl-1,2,4-thiadiazol-3-yl, 5-trifluoromethyl-1,2,4-thiadiazol-3-yl, 5-pentafluoroethyl-1,2,4-thiadiazol-3-yl, 5-acetyl-1,2,4-thiadiazol-3-yl, 5-carboxy-1,2,4-thiadiazol-3-yl, 5-cyano-1,2,4-thiadiazol-3-yl, 5-methoxy-1,2,4-thiadiazol-3-yl, 5-ethoxycarbonyl-1,2,4-thiadiazol-3-yl, 5-chloro-1,2,4-thiadiazol-3-yl, 1,3,4-thiadiazol-5-yl, 2-methyl-1,3,4-thiadiazol-5-yl, 2-ethyl-1,3,4-thiadiazol-5-yl, 2-isopropyl-1,3,4-thiadiazol-5-yl, 2-trifluoromethyl-1,3,4-thiadiazol-5-yl, 2-pentafluoroethyl-1,3,4-thiadiazol-5-yl, 2-acetyl-1,3,4-thiadiazol-5-yl, 2-carboxy-1,3,4-thiadiazol-5-yl, 2-cyano-1,3,4-thiadiazol-5-yl, 2-methoxy-1,3,4-thiadiazol-5-yl, 2-ethoxycarbonyl-1,3,4-thiadiazol-5-yl, 2-chloro-1,3,4-thiadiazol-5-yl, 1,2,3-thiadiazol-4-yl, 5-methyl-1,2,3-thiadiazol-4-yl, 5-ethyl-1,2,3-thiadiazol-4-yl, 5-isopropyl-1,2,3-thiadiazol-4-yl, 5-trifluoromethyl-1,2,3-thiadiazol-4-yl, 5-pentafluoroethyl-1,2,3-thiadiazol-4-yl, 5-acetyl-1,2,3-thiadiazol-4-yl, 5-carboxy-1,2,3-thiadiazol-4-yl, 5-cyano-1,2,3-thiadiazol-4-yl, 5-methoxy-1,2,3-thiadiazol-4-yl, 5-ethoxycarbonyl-1,2,3-thiadiazol-4-yl, 5-chloro-1,2,3-thiadiazol-4-yl and the like, more preferably, thiazole-2-yl, 4-methyl-thiazol-2-yl, 4-ethyl-thiazol-2-yl, 4-trifluoromethyl-thiazol-2-yl, 4-pentafluoroethyl-thiazol-2-yl, 4-ethoxycarbonyl-thiazol-2-yl, 4-chloro-thiazol-2-yl, 4-hydroxy-thiazol-2-yl, 1,2,4-thiadiazol-3-yl, 5-methyl-1,2,4-thiadiazol-3-yl, 5-ethyl-1,2,4-thiadiazol-3-yl. The most preferable residues —Z—R are 1,2,3-thiadiazol-4-yl and thiazole-2-yl.
In the definition of Q, the term “phenyl ring optionally substituted by 1 to 3 halogen atom(s)” preferably means 2-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 4-chlorophenyl, 2-bromophenyl, 2,4-dichlorophenyl, 2,4-difluorophenyl, 2-chloro-4-fluorophenyl, 2-fluoro-4-chlorophenyl, 2,5-difluorophenyl, 2,4,6-trifluorophenyl, 4-bromo-2,5-difluorophenyl and the like; more preferably 2-fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 2,4,6-trifluorophenyl, 4-bromo-2,5-difluorophenyl. The most preferable residues Q are 2,4-difluorophenyl and 2,5-difluorophenyl.
In a preferred embodiment, the present invention relates to 1-(1H-1,2,4-triazol-1-yl)butan-2-ol derivatives of the above formula (I) wherein Q is a radical selected from the group consisting of 2,4-difluorophenyl and 2,5-difluorophenyl; X is a radical selected from the group consisting of 1,2,4-thiadiazol-3,5-diyl and thiazol-2,4-diyl; Y is p-phenylene; Q is 2,4-difluorophenyl or 2,5-difluorophenyl; and —Z—R is a radical selected from the group consisting of 1,2,3-thiadiazol-4-yl and thiazole-2-yl.
Preferred 1-(1H-1,2,4-triazol-1-yl)butan-2-ol derivatives in accordance with the pr
Komiyama Susumu
Shimma Nobuo
Tsukuda Takuo
Basilea Pharmaceutica AG
Higel Floyd D.
Johnston George W.
Saeed Kamal
Tramaloni Dennis P.
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