Amide-type triazole compounds

Details Amide-type triazole compounds Amide-type triazole compounds

2002-09-27

2003-11-25

Rotman, Alan L. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S367000, C514S371000, C514S377000, C514S380000, C514S383000, C548S163000, C548S195000, C548S233000, C548S246000, C548S268600, C546S272400

Reexamination Certificate

active

06653330

ABSTRACT:

The present invention relates to amide-type triazole compounds which have excellent antifungal activity or pharmacologically acceptable prodrugs thereof or salts thereof; to medicaments (particularly antifungal agents) containing these compounds as active ingredients; to pharmaceutical compositions for treatment of fungal infections which contain these compounds; to the use of these compounds in the manufacture of medicaments (particularly antifungal agents); and to a method for the prevention or treatment of fungal infections which comprises administering these compounds to a warm-blooded animal (particularly a human) in need thereof.
BACKGROUND OF THE INVENTION
A lot of triazole-type compounds have been known as agents for the treatment of fungal infections in a human or animal. One of the most popular triazole-type compounds is fluconazole. However there have been fungal infections which cannot be clinically treated with fluconazole and there is a need for further compounds having more excellent antifungal activity.
Similar compounds to those of the present invention are disclosed in Japanese Patent Application Publication Nos. Hei-8-333350, Hei-10-279567 and Hei-11-80135.
The present inventors have made a great effort to find compounds having an excellent antifungal activity and found that the compounds of formula (I) (hereinafter referred to as compounds (I)) and pharmacologically acceptable prodrugs thereof and salts thereof exhibit excellent antifungal activity. Thereby the present invention has been completed.
SUMMARY OF THE INVENTION
The present invention relates to:
(1) an amide-type triazole compound (I) or a pharmacologically acceptable prodrug thereof or a salt thereof:
 wherein:
Ar
1
represents a phenyl group or a phenyl group substituted with 1 to 3 substituents (said substituents are selected from a halogen atom and a trifluoromethyl group);
Ar
2
represents a phenylene group, a phenylene group substituted with 1 or 2 substituents (said substituents are selected from a fluorine atom and a chlorine atom), a naphthylene group or a naphthylene group substituted with 1 or 2 substituents (said substituents are selected from a fluorine atom and a chlorine atom);
X represents a sulfur atom or a methylene group;
R
1
represents a hydrogen atom or a C
1-3
alkyl group;
R
2
represents a hydrogen atom or a C
1-3
alkyl group;
R
3
represents a C
6-10
aryl group, a C
6-10
aryl group substituted with 1 to 5 substituents selected from substituent group A, a heteroaryl group, a heteroaryl group substituted with 1 or 2 substituents selected from substituent group A, a C
7-14
aralkyl group, and a C
7-14
aralkyl group substituted with 1 to 5 substituents selected from substituent group A;
substituent group A comprises a C
1-6
alkyl group, a C
1-6
alkyl group substituted with 1 to 5 substituents (said substituents are selected from a halogen atom, a hydroxyl group, a cyano group and a C
1-6
alkoxy group), a C
1-6
alkoxy group, a C
1-6
alkoxy group substituted with 1 to 5 substituents (said substituents are selected from a halogen atom, a hydroxyl group, a cyano group and a C
1-6
alkoxy group), a C
1-6
alkanoyl group, a C
2-6
alkanoyl group substituted with 1 to 5 substituents (said substituents are selected from a halogen atom, a hydroxyl group, a cyano group and a C
1-6
alkoxy group), a C
1-6
alkanoyloxy group, a C
2-6
alkanoyloxy group substituted with 1 to 5 substituents (said substituents are selected from a halogen atom, a hydroxyl group, a cyano group and a C
1-6
alkoxy group), a halogen atom, a hydroxyl group, an amino group, a mercapto group, a carbamoyl group, a nitro group, a cyano group, a carboxyl group, a group of formula —S(O)
n
R
4
(wherein R
4
represents a C
1-6
alkyl group or a C
1-6
alkyl group substituted with 1 to 5 substituents (said substituents are selected from halogen atoms), and n represents 0, 1, or 2), a C
2-6
alkenyl group, a C
2-6
alkynyl group, a C
3-6
cycloalkyl group and a (C
3-6
cycloalkyl)C
1-6
alkyl group; and
(2) a medicament containing an amide-type triazole compound or a pharmacologically acceptable prodrug thereof or a salt thereof described in (1) as an active ingredient.
In the above description:
The “halogen atom” in the definitions of the substituent of Ar
1
and the substituent group A is, for example, a fluorine, chlorine, bromine and iodine atom; preferably a fluorine or chlorine atom; and most preferably a fluorine atom.
The “C
1-3
alkyl group” in the definitions of R
1
and R
2
is a straight or branched chain alkyl group having 1 to 3 carbons, for example, a methyl, ethyl, propyl or isopropyl group; preferably a methyl or ethyl group; and most preferably a methyl group.
The “C
6-10
aryl group” in the definition of R
3
is an aromatic hydrocarbon group having 6 to 10 carbons, for example a phenyl, indenyl or naphthyl group, preferably a phenyl group.
The “heteroaryl group” in the definition of R
3
is a monocyclic aromatic heterocyclyl group or a fused aromatic heterocyclyl group. The “monocyclic aromatic heterocyclyl group” is a 5- or 6-membered aromatic heterocyclyl group containing 1 to 4 nitrogen, oxygen or sulfur atoms, for example, a furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyridazinyl or pyrazyl group; preferably pyridyl or thiazolyl. The “fused aromatic heterocyclyl group” is a 5- or 6-membered aromatic heterocyclyl group which contains 1 to 4 nitrogen, oxygen or sulfur atoms and is fused to 1 or 2 benzene rings or to 5- or 6-membered aromatic heterocyclyl groups containing 1 to 4 nitrogen, oxygen or sulfur atoms. Examples of such a fused heterocyclyl group include isobenzofuranyl, chromenyl, xanthenyl, phenoxathynyl, indolizinyl, isoindolyl, indolyl, indazolyl, purinyl, quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, carbazolyl, carbolinyl, acridinyl, isoindolinyl and benzothiazolyl; preferably benzothiazolyl.
A preferred heteroaryl group is a 5- or 6-membered aromatic heterocyclyl group having 1 or 2 nitrogen, oxygen or sulfur atoms or a bicyclic heterocyclyl group which is a 5- or 6-membered aromatic heterocyclyl group that has 1 or 2 nitrogen, oxygen or sulfur atoms and is fused to a benzene ring. A more preferred heteroaryl group is a furyl, thienyl, pyridyl, isoxazolyl, thiazolyl or benzothiazolyl group; and most preferred is a pyridyl, thiazolyl or benzothiazolyl group.
The “C
7-14
aralkyl group” in the definition of R
3
is a C
1-4
alkyl group substituted with a C
6-10
aryl group. The “C
6-10
aryl group” has the same meaning as described above. The “C
1-4
alkyl group” is a straight or branched chain alkyl group having 1 to 4 carbons, for example, a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or t-butyl group; preferably a methyl or ethyl group and most preferably a methyl group. The “C
7-14
aralkyl group” is, for example, a benzyl, phenethyl, phenylpropyl, phenylbutyl, naphthylmethyl, naphthylethyl, or naphthylbutyl group; preferably a benzyl or phenethyl group and more preferably a benzyl group.
In addition the aryl ring of the “C
6-10
aryl group” and the “C
7-14
aralkyl group” in the definition of R
3
is optionally substituted with 1 to 5 substituents selected from substituent group A and the “heteroaryl group” in the definition of R
3
is optionally substituted with 1 or 2 substituents selected from substituent group A.
The “C
1-6
alkyl group” in the definition of substituent group A (with the proviso that the “C
1-6
alkyl group” in the definition of R
4
is not included) is a straight or branched chain alkyl group having 1 to 6 carbons, for example, a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl or hexyl group; preferably a C
1-3
alkyl group; and more preferably a methyl group.
The “C
1-6
alkyl group substituted with 1 to 5 substituents (said substituents are selected from a halogen atom, a hydroxyl group, a cyano group and a C
1-6
alkoxy group)” in the definition of substituent group A is a strai

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