Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-03-19
2003-06-24
Peselev, Elli (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S023000, C514S053000, C548S253000
Reexamination Certificate
active
06583164
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a composition comprising a novel azole-based compound having an anti-fungal action and a saccharide, which is used in the fields of medicine etc.
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 a salt 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 known.
These azole-based compounds having an anti-fungal action are neither necessarily sufficient in respect of their solubility in e.g. water for use as injection nor sufficiently satisfactory in respect of the absorption thereof into a living body for demonstrating a high therapeutic effect, and thus there is a need for improvements in the solubility thereof in water and for improvements in the absorption thereof into a living body. Further, there is a need for a pharmaceutical preparation for injection stably containing an azole compound having an anti-fungal action.
DISCLOSURE OF INVENTION
As a result of their extensive study under the circumstances described above, the present inventors found that those derivatives derived from azole-based compounds by quaternarizing nitrogen atoms contained in 1H-imidazole-1-yl group or 1H-1,2,4-triazole-1-yl group thereof have improved solubility in water and are hydrolyzed enzymatically and/or non-enzymatically in vivo to form those compounds having 1H-imidazole-1-yl group or 1H-1,2,4-triazole-1-yl group and having an anti-fungal activity, that the stability of said compounds is improved by adding saccharides to said compounds, and that lyophilization of compositions containing said compounds and saccharides can give rise to further stable lyophilized products, and on the basis of these findings, the present invention was completed.
That is, the present invention relates to:
(1) A composition comprising a quaternized nitrogen-containing imidazole-1-yl or 1,2,4-triazole-1-yl compound wherein one of the nitrogen atoms constituting the azole ring is quaternized with a group eliminating in vivo and represented by the formula:
wherein R
1
represents a hydrocarbon or heterocyclic group which may be substituted, R
2
represents a hydrogen atom or a lower alkyl group, and n is 0 or 1, and a saccharide, said compound being capable of being converted into an anti-fungal azole compound upon elimination of said group in vivo;
(2) The composition according to item (1) above, which is a lyophilized product;
(3) The composition according to item (1) or (2) above, wherein the quaternized nitrogen-containing imidazole-1-yl or 1,2,4-triazole-1-yl compound is a compound represented by the formula:
wherein X represents a nitrogen atom or a methine group, Ar represents a phenyl group which may be substituted, A represents a hydrocarbon or heterocyclic group which may be substituted, X
1
represents an oxygen atom or a methylene group, X
2
represents a sulfur atom which may be oxidized, m and p each represents 0 or 1, and Y
−
represents an anion, (1) R
3
, R
4
and R
5
are the same or different and each represents a hydrogen atom or a lower alkyl group, (2) R
3
represents a hydrogen atom or a lower alkyl group, and R
4
and R
5
are combined to form a lower alkylene group, or (3) R
5
represents a hydrogen atom or a lower alkyl group, and R
3
and R
4
are combined to form a lower alkylene group, and other symbols have the same meanings as defined above;
(4) The composition according to item (1) or (2) above, wherein the quaternized nitrogen-containing imidazole-1-yl or 1,2,4-triazole-1-yl compound is 4-acetoxymethyl-1-[(2R,3R)-2-(2,4-difluorophenyl)-2-hydroxy-3-[2-oxo-3-[4-(1H-tetrazol-1-yl)phenyl]-1-imidazolydinyl]butyl]-1H-1,2,4-triazolium chloride;
(5) The composition according to item (1) or (2) above, which is an anti-fungal agent;
(6) The composition according to item (1) or (2) above, wherein the saccharide is a monosaccharide, a disaccharide or sugar alcohol;
(7) The composition according to item (1) or (2) above, wherein the saccharide is fructose, glucose, maltose, cellobiose, gentiobiose, melibiose, lactose, turanose, sophorose, trehalose, isotrehalose, isosaccharose, white sugar, mannitol, sorbitol, xylitol or inositol;
(8) The composition according to item (1) or (2) above, wherein the saccharide is maltose, lactose, white sugar, mannitol, trehalose or inositol;
(9) The composition according to item (1) or (2) above, wherein the saccharide is inositol or trehalose;
(10) The composition according to item (1) or (2) above, wherein the saccharide is contained in an amount of 0.001 to 1000 parts by weight per 1 part by weight of the quaternized nitrogen-containing imidazole-1-yl or 1,2,4-triazole-1-yl compound;
(11) The composition according to item (1) or (2) above, wherein the saccharide is conta
Horibe Hidetoshi
Nagao Masao
Nishida Yoko
Chao Mark
Peselev Elli
Ramesh Elaine M.
Takeda Chemical Industries Ltd.
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