Azole compounds, their production and their use

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

1999-09-20

2002-06-18

Morris, Patricia L. (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C548S253000

Reexamination Certificate

active

06407129

ABSTRACT:

TECNICAL FIELD
The present invention relates to novel azole compounds having an antifungal action, their production and their use.
BACKGROUND ART
Various azole compounds having an antifungal action have hitherto been known. For example, Japanese Patent Kokai Publication No. Hei 6-293740 discloses an azole compound represented by the formula:
(wherein Ar is a substituted phenyl group; R
1
and R
2
independently 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 group bonded through a carbon atom; R
4
is a hydrogen atom or an acyl group; X is a nitrogen atom or a methine group; and Y and Z independently are a nitrogen atom or a methine group which may optionally be substituted with a lower alkyl group) or a salt thereof. Japanese Patent Kokai Publication No. Hei 8-104676 discloses a compound represented by the formula:
(wherein Ar is an optionally substituted phenyl; R
1
and R
2
are, the same or different, 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; Y is a nitrogen atom or a methine group; and A is an optionally-substituted saturated cyclic amide group bonded through a first nitrogen atom) and salts thereof. WO 9625410 A
1
(corresponding to Japanese Patent Kokai Publication No. Hei 9-183769) discloses a compound represented by the formula:
[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 of 0 to 2; and Az is an optionally substituted azolyl group] or a salt thereof.
On the other hand, a series of compounds referred to as a soft drug have hitherto been known as a quaternary ammonium salt type derivative of an azole (imidazole, triazole) compound which is hydrolyzed enzymatically and/or non-enzymatically. For example, quaternary ammonium salt derivatives of 1-methylimidazole are reported in Journal of Medicinal Chemistry, Vol. 23, page 469, 1980 (antibacterial activity), ibid., Vol. 23, 566, 1980 (antitumor activity), ibid., Vol. 23, 474, 1980 (anticholinergic activity) and ibid., Vol. 32, 493, 1989 (acetylcholine esterase reactivation activity), and these quaternary salts themselves have a biological activity and it is one of their features that hydrolysis thereof occurs rapidly. On the other hand, a quaternary ammonium salt type derivative of azole compounds as a kind of prodrug has been reported only in Pharmaceutical Research Vol. 9, page 372, 1992 (antiglaucoma drug) and Entomologia Experimentalis et Aplicata, Vol. 44, page 295, 1987 (insecticide). In addition, an example of use as a synthetic intermediate of a quaternary ammonium type derivative of imidazole, utilizing its easily hydrolysable property, is reported in Journal of Chemical Society Perkin I, page 1341, 1979 and New Journal of Chemistry, Vol. 16, page 107, 1992. Moreover, a series of quaternary ammonium salt type derivatives are described in U.S. Pat. Nos. 4,061,722 and 4,160,099. However, enzymatically and/or non-enzymatically hydrolyzed quaternary salt derivatives of the azole compounds having an antifungal activity have never been disclosed.
Regarding the azole compounds having the above antifungal activity, the solubility in water for use as an injection preparation is not always sufficient, and it is hard to say that internal absorption is sufficient for demonstrating high therapeutic effect. Therefore, an improvement in solubility in water and in internal absorption have been desired.
DISCLOSURE OF INVENTION
Under these circumstances, the present inventors have studied intensively. As a result, the present inventors have found that a derivative prepared by quaternizing nitrogen atoms contained in a 1H-imidazol-1-yl group or 1H-1,2,4-triazol-1-yl group of azole compounds has an improved solubility in water, and is enzymatically and/or non-enzymatically hydrolyzed to produce a compound which has a 1H-imidazol-1-yl group or 1H-1,2,4-triazol-1-yl group and has an antifungal activity. Thus, the present invention has been accomplished based on this finding.
Namely, the present invention relates to a quaternized nitrogen-containing imidazol-1-yl or 1,2,4-triazol-1-yl compound wherein one of nitrogen atoms constituting an azole ring is quaternized with a substituent capable of being eliminated in vivo and the substituent can be eliminated in vivo to be converted into an antifungal azole compound; a method for producing the same; and a pharmaceutical composition containing the compound.
The above “quaternized nitrogen-containing imidazol-1-yl or 1,2,4-triazol-1-yl compound wherein one of nitrogen atoms constituting an azole ring is quaternized with a substituent capable of being eliminated in vivo and the substituent can be eliminated in vivo to be converted into an antifungal azole compound “[hereinafter referred to as a compound (I),]” is a compound having an imidazol-1-yl or 1,2,4-triazol-1-yl group in the molecule, in which the nitrogen atom is quaternized by having a substituent in the nitrogen atom at the 3-position of the imidazol-1-yl group and the nitrogen atom at the 2- or 4-position of the 1,2,4-triazol-1-yl group, and the substituent is hydrolyzed in vivo to eliminate, thereby being converted into a compound which has an imidazol-1-yl group or 1,2,4-triazol-1-yl group having no quaternized nitrogen atom and has an antifungal action.
Examples of such a compound include a compound represented by the formula:
(wherein Q represents an imidazol-1-yl or 1,2,4-triazol-1-yl group in which one of nitrogen atoms constituting an azole ring is quaternized with a substituent capable of being eliminated in vivo; Ar represents an optionally substituted phenyl group; A represents an optionally substituted hydrocarbon or an optionally substituted heterocyclic group; X
1
represents an oxygen atom or a methylene group; X
2
represents an optionally oxidized sulfur atom; m and p respectively represent 0 or 1; Y
−
represents an anion; and {circle around (1)} R
3
, R
4
and R
5
may be the same or different and represent a hydrogen atom or a lower alkyl group, or {circle around (2)} R
3
represents hydrogen atom or a lower alkyl group, and R
4
and R
5
are combined with each other to represent a lower alkylene group, or {circle around (3)} R
5
represents a hydrogen atom or a lower alkyl group, and R
3
and R
4
are combined with each other to represent a lower alkylene group) or a salt thereof [hereinafter referred to as a compound (Ia), sometimes].
“A substituent capable of being eliminated in vivo” in the “imidazol-1-yl or 1,2,4-triazol-1-yl group in which one of nitrogen atoms constituting an azole ring is quaternized with a substituent capable of being eliminated in vivo” represented by Q may be any group which is eliminated in vivo, and the group represented by Q includes those represented by the formula (II):
(wherein R
1
represents an optionally substituted hydrocarbon group or heterocyclic group; R 2represents a hydrogen atom or a lower alkyl group; X represents a nitrogen atom or a methine group; and n represents 0 or 1).
Examples of the “hydrocarbon group” of the “optionally substituted hydrocarbon group” represented by R
1
includes aliphatic hydrocarbon group, aromatic hydrocarbon group and aromatic-aliphatic hydrocarbon group. Examples of the aliphatic hydrocarbon group include alkyl group, cycloalkyl group, cycloalkylalkyl group, alkenyl group and alkynyl group. Examples of the alkyl group include straight-chain or branched alkyl group having 1 to 20 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-b

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