Azole compounds, their production and use

Details Azole compounds, their production and use Azole compounds, their production and use

1999-10-07

2002-03-26

Morris, Patricia L. (Department: 1612)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S383000, C548S255000, C548S266600

Reexamination Certificate

active

06362206

ABSTRACT:

TECHNICAL FIELD
The present invention relates to azole compounds useful as antifungal therapeutic agents, methods for producing the same and use thereof.
BACKGROUND ART
A variety of azole compounds have been reported exhibiting antifungal activity (see, for example, EP0122056A1, EP0332387A1, EP0122693A1 and EP0567982A).
None of these azole compounds, however, is satisfactory as a pharmaceutical agent in terms of its antifungal activity, antifungal spectrum, side effect and in vivo pharmacokinetics.
There has been a demand for a safer compound which exhibits better absorption in vivo and higher antifungal activity as an antifungal therapeutic agent.
DISCLOSURE OF INVENTION
The present invention provides
(1) a compound represented by the formula (I):
 wherein Ar is an optionally substituted phenyl group; R
1
and R
2
, the same or different, are a hydrogen atom or a lower alkyl group, or R
1
and R
2
may combine together to form a lower alkylene group; R
3
is a hydrogen atom or an acyl group; X is a nitrogen atom or a methine group; A is Y═Z (Y and Z, the same or different, are a nitrogen atom or a methine group optionally substituted with a lower alkyl group) or an ethylene group optionally substituted with a lower alkyl group; n is an integer from 0 to 2; and Az is an optionally substituted azolyl group, or a salt thereof,
(2) a process for preparing a compound of the formula (I) as defined in claim
1
or a salt thereof which comprises
(i) reacting a compound represented by the formula (II):
 wherein the symbols have the same meanings as defined above; or a salt thereof
with a compound represented by the formula (III):
 wherein the symbols have the same meanings as defined above; or a salt thereof, and, if necessary, followed by an acylation;
(ii) reacting a compound represented by the formula (IV):
 wherein the symbols have the same meanings as defined above; or a salt thereof
with a compound represented by the formula (V′):
 wherein A″ is —N═CH—, —CH═N— or —CH═CH—; the symbols have the same meanings as defined above; or a salt thereof, and, if necessary, followed by an acylation; or
(iii) reducing a compound represented by the formula (I″)
 wherein the symbols have the same meanings as defined above; or a salt thereof, and, if necessary, followed by an acylation,
(3) a pharmaceutical composition to be an antifungal preparation containing a compound represented by the above formula (I) or a salt thereof.
Examples of the substituents for “optionally substituted phenyl group” represented by Ar in the formula (I) include halogen atoms (e.g., fluorine, chlorine, bromide and iodine), lower (C
1-4
) haloalkyl, lower (C
1-4
) haloalkoxy, lower (C
1-4
) alkylsulfonyl, lower (C
1-4
) haloalkylsulfonyl and the like. Preferably, the substituent is halogen atoms (e.g., fluorine, chlorine, bromine and iodine), and more preferably it is fluorine. The number of the substituents is preferably from one to three, more preferably from one to two.
Examples of Ar include halophenyl, lower (C
1-4
) haloalkylphenyl, lower (C
1-4
) haloalkoxyphenyl, lower (C
1-4
) alkylsulfonylphenyl, lower (C
1-4
) haloalkylsulfonylphenyl and the like.
Examples of the halophenyl groups include 2,4-difluorophenyl, 2,4-dichlorophenyl, 4-chlorophenyl, 4-fluorophenyl, 2-chlorophenyl, 2-fluorophenyl, 2-fluoro-4-chlorophenyl, 2-chloro-4-fluorophenyl, 2,4,6-trifluoropheny, 4-bromophenyl and the like.
Examples of the lower (C
1-4
) haloalkylphenyl groups include 4-trifluoromethylphenyl group and the like.
Examples of the lower (C
1-4
) haloalkoxyphenyl groups include 4-trifluoromethoxyphenyl, 4-(1,1,2,2-tetrafluoro-ethoxy)phenyl, 4-(2,2,2-trifluoroethoxy)phenyl, 4-(2,2,3,3-tetrafluoropropoxy)phenyl, 4-(2,2,3,3,3-pentafluoropropoxy)phenyl and the like.
Examples of the lower (C
1-4
) alkylsulfonylphenyl groups include 4-methanesulfonylphenyl and the like.
Examples of the lower (C
1-4
) haloalkylsulfonylphenyl groups include 4-(2,2,2-trifluoroethanesulfonyl)phenyl, 4-(2,2,3,3-tetrafluoropropanesulfonyl)phenyl, 4-(2,2,3,3,3-pentafluoropropanesulfonyl)phenyl and the like.
Specific examples of the phenyl groups of Ar are phenyl groups substituted with one to two halogen atoms such as 2,4-difluorophenyl, 2,4-dichlorophenyl, 4-chlorophenyl, 4-fluorophenyl, 2-chlorophenyl, 2-fluorophenyl, 2-fluoro-4-chlorophenyl, 2-chloro-4-fluorophenyl, 4-bromophenyl and the like, among which phenyl groups substituted with one or two fluorine atoms such as 4-fluorophenyl, 2-fluorophenyl and 2,4-difluorophenyl are more preferable and 2-fluorophenyl and 2,4-difluorophenyl are most preferable.
Examples of the lower alkyl groups represented by R
1
or R
2
in the formula (I) include straight or branched C
1-4
alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl and the like, among which methyl is more preferable. It is particularly preferable that both of R
1
and R
2
are hydrogen atoms or methyl groups, or one of R
1
and R
2
is a hydrogen atom and the other is a methyl group.
Examples of the lower alkylene groups formed by the combination of R
1
and R
2
include straight lower (C
2-4
) alkylene groups such as ethylene, propylene, butylene and the like, among which ethylene is preferred.
Among them, it is preferable that one of R
1
and R
2
is a hydrogen atom and the other is a C
1-4
alkyl group such as a methyl group and the like.
Examples of the acyl groups represented by R
3
in the formula (I) include acyl groups derived from organic carboxylic acids such as alkanoyl, preferably C
1-7
alkanoyl (e.g., formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, hexanoyl and heptanoyl), more preferably C
1-3
alkanoyl; arylcarbonyl, preferably C
7-15
arylcarbonyl (e.g., benzoyl and naphtalenecarbonyl), more preferably C
7-11
arylcarbonyl group; alkoxycarbonyl, preferably C
2-7
alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonnyl, sec-bu-toxycarbonyl and tert-butoxycarbonyl), more preferably C
2-4
alkoxycarbonyl; aryloxycarbonyl, preferably C
7-15
aryloxy-carbonyl (e.g., phenoxycarbonyl), more preferably C
7-11
aryloxycarbonyl; aralkylcarbonyl group, preferably C
8-20
aralkylcarbonyl (e.g., benzylcarbonyl, phenetylcarbonyl, phenylpropylcarbonyl and naphthylethylcarbonyl), more preferably C
8-14
aralkylcarbonyl; and the like.
Preferably, the above acyl groups are those being capable of hydrolyzing in vivo. Examples thereof are formyl, acetyl, benzoyl, benzylcarbonyl and the like. Preferred R
3
is a hydrogen atom.
X in the general formula (I) is preferably a nitrogen atom.
Examples of the lower alkyl groups for “a methine group optionally substituted by a lower alkyl group” represented by Y or Z when A is Y═Z in the formula (I) include straight or branched C
1-4
alkyl groups (methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl), among which methyl is preferred.
Examples for the methine group optionally substituted with a lower alkyl group represented by Y or Z include methine, ethylidyne (—C(CH
3
)═), propylidyne (—C(CH
2
CH
3
)═), butylidyne (—C(CH
2
CH
2
CH
3
)═) and the like, among which methine, ethylidyne and the like are preferable, and methine and the like are more preferable.
It is preferable that one of Y and Z is a nitrogen atom and the other is methine; that both are methine; that both are nitrogen atoms; and one is a nitrogen atom and the other is ethylidyne. It is particularly preferable that one of Y and Z is a nitrogen atom and the other is methine or both of Y and Z are methine.
When A is “an ethylene group optionally substituted with a lower alkyl group” in the formula (I), examples of the lower alkyl groups include straight or branched C
1-4
alkyl groups (methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl), among which methyl, ethyl and the like are preferable, and methyl and the like are more preferable.
Examples of the ethylene groups optionally subst

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