Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Reexamination Certificate
2000-09-28
2003-03-04
Morris, Patricia L. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
C514S383000, C548S112000, C548S268600
Reexamination Certificate
active
06528500
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to azole derivatives and salts thereof each having excellent antimycotic action and good aqueous solubility, and medicaments containing the derivatives or salts as an effective ingredient, respectively.
2. Description of the Related Art
A number of azole compounds having antimycotic action have already been known. Although the conventional azole compounds can be used as a dermatologic preparation for external use, their low solubility in an aqueous solvent disturbs formulation of them into an aqueous preparation such as orally administrable preparation or intravenously administrable preparation without any treatment.
It is therefore proposed to add a complex forming agent or a cyclodextrin derivative in order to obtain an aqueous preparation (European Patent Application Laid-Open No. 0440372).
Use of such an additive is however not preferred for suppressing the side effect to the minimum level and to make the azole derivative itself soluble in an aqueous solvent is desired.
SUMMARY OF THE INVENTION
An object of the present invention is therefore to provide a novel compound having both strong antimycotic action and excellent solubility in an aqueous solvent.
With the foregoing in view, the present inventors have synthesized a variety of novel azole derivatives and carried out an extensive investigation on their antimycotic action and solubility in an aqueous solvent. As a result, it has been found that the compounds represented by the below-described formula (1) satisfy both, leading to the completion of the present invention.
In one aspect of the present invention, there is thus provided an azole derivative represented by the following formula (1):
wherein, R
1
represents a phenyl group substituted with one or more than one halogen atom or a phenyl group substituted with a trifluoromethyl group; R
2
and R
3
each represents a fluorine atom or an alkyl group, or may be coupled together to form a lower alkylene group; and R
4
represents an alkyl group, or salt thereof; and a medicament comprising the derivative or salt as an effective ingredient.
In another aspect of the present invention, there is also provided a pharmaceutical composition comprising an azole derivative represented by the above-described formula (1) or salt thereof; and a pharmaceutically acceptable carrier.
In a further aspect of the present invention, there is also provided use, as a medicament, of an azole derivative represented by the above-described formula (1) or salt thereof.
In a still further aspect of the present invention, there is also provided a method for treating infectious diseases, which comprises administering an azole derivative represented by the above-described formula (1) or salt thereof.
Since the azole derivatives or salts thereof according to the present invention exhibit excellent antimycotic action and at the same time, good solubility in an aqueous solvent, they are suited for an intravenously administrable preparation and orally administrable preparation.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
In the azole derivative (1) of the present invention, examples of the halogen atom which is substituted for the phenyl group of R
1
include fluorine, chlorine, bromine and iodine atoms, with fluorine atom being particularly preferred. As R
1
, a difluorophenyl or (trifluoromethyl)phenyl, particularly 2,4-difluorophenyl or 4-(trifluoromethyl)phenyl group is desired.
As the alkyl group of R
2
or R
3
, linear or branched C
1-5
alkyl groups are preferred and specific examples include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, tert-butyl and n-pentyl groups. As R
2
and R
3
, fluorine atom and methyl group are preferred. It is more preferred that R
2
and R
3
represent the same group.
Preferred examples of the alkylene group formed through coupling of R
2
and R
3
include C
2-5
alkylene groups and specific examples include ethylene, trimethylene, tetramethylene and pentamethylene, with an ethylene group (—CH
2
CH
2
—) being particularly preferred. When R
2
and R
3
are coupled into the alkylene group, they form a saturated cyclic hydrocarbon with the adjacent carbon atom.
Preferred examples of the alkyl group represented by R
4
include linear, branched or cyclic C
1-10
alkyl groups, with linear or branched C
1-4
alkyl or C
3-6
cycloalkyl groups being particularly preferred. Specific examples include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups, of which methyl, ethyl and cyclopropyl groups are most preferred.
Any pharmaceutically acceptable salt can be used as the salt of the azole derivative (1) of the present invention. Examples include hydrochloride, nitrate, hydrobromide, p-toluenesulfonate, methanesulfonate, fumarate, succinate and lactate.
The azole derivatives (1) of the present invention include those containing an asymmetric carbon atom so that they can exist as optically active substances. The racemic mixtures and optically active substances are all embraced in them. In addition, their solvates such as hydrates are also embraced in them.
The azole derivatives (1) or salts thereof can each be prepared, for example, in accordance with the following reaction scheme.
wherein, R
a
and R
b
each independently represents a C
1-6
alkyl group or a phenyl group which may contain a substituent, or R
a
and R
b
may form, together with a nitrogen atom bonded thereto, a ring such as morpholine ring, R
c
and R
d
each independently represents a hydroxy protecting group and R
1
to R
4
have the same meanings as described above.
Described specifically, the target azole derivative (1) can be prepared by reacting Compound (2) with Compound (3) to obtain Compound (4), oxidizing the resulting Compound (4) into Compound (5) and then, hydrogenating the resulting Compound (5).
This preparation process will next be described more specifically.
Compound (2) serving as a raw material is available, for example, by the process described in Japanese Patent Application Laid-Open No. Hei 3-223266, 9-227531, 11-240871 and 11-279160.
First, Compound (4) is prepared by reacting Compound (2) with Compound (3). Examples of the hydroxy protecting group of R
c
or R
d
of Compound (3) used here include a benzyl group which may be substituted with a halogen atom and C
1-6
alkyl groups such as t-butyl. The benzyl group can be removed later by catalytic hydrogenation, while the C
1-6
alkyl group can be removed under hydrolysis conditions. As a preferred example of Compound (3), dibenzyl diisopropylphosphoramidite (R
a
, R
b
=isopropyl, R
c
, R
d
=benzyl) commercially available from Sigma-Aldrich can be mentioned.
In the reaction between Compound (2) and Compound (3), a reaction solvent which does not adversely affect the reaction such as methylene chloride, chloroform or ethyl acetate can be used, with methylene chloride being particularly preferred.
Examples of the additive include 1H-tetrazole, 4-dimethylaminopyridine, tetrazole hydrobromide, 5-methyltetrazole hydrobromide and pyridinium hydrobromide.
The reaction is desirably conducted at room temperature or greater, of which the room temperature is more desired.
Compound (4) can be converted into Compound (5) by oxidation. Examples of the oxidizing agent usable here include m-chloroperbenzoic acid, aqueous hydrogen peroxide, peracetic acid, potassium permanganate and oxone. As the reaction solvent, a solvent not adversely affecting the reaction such as methylene chloride, chloroform or ethyl acetate is preferred, with methylene chloride being particularly preferred. The reaction is preferably conducted at temperature less than room temperature, with 0° C. being more preferred.
The hydroxy-protected phosphate ester represented by the formula (5) is then hydrogenated in the presence of a catalyst, whereby the compound represented by the formula (1) can be obtained.
Examples of the catalyst in the reaction solvent include palladium carbon
Asaoka Takemitsu
Eto Hiromichi
Ishida Kazuya
Maebashi Kazunori
Matsumoto Masaru
Morris Patricia L.
SSP Co. Ltd.
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