Organic compounds -- part of the class 532-570 series – Organic compounds – Sulfur containing
Reexamination Certificate
1999-12-23
2001-01-09
Morris, Patricia L. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Sulfur containing
Reexamination Certificate
active
06172266
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to a triazole derivative or salt thereof which has excellent antimycotic action and high safety, an intermediate for preparing said compound and a pharmaceutical comprising said compound as an effective ingredient.
2. Description of the Related Art
Mycosis can be classified into two types, that is, superficial mycosis represented by various trichophytosis, marginated eczema, psoriasis, cutaneous candidiasis or the like and deep seated mycosis represented by mycotic meningitis, mycotic infectious disease of respiratory organ, fungemia, mycosis of urinary tract or the like. Of these, deep seated mycosis such as candidiasis or aspergillosis tends to show a marked increase in recent days owing to the frequent use of an anticancer chemotherapeutic agent or immunosuppressive agent or lowering in the bioimmunology due to HIV infection or the like. There is accordingly a demand for a pharmaceutical efficacious against fungi causing such diseases.
As pharmaceuticals effective against Aspergillus spp. and Candida spp., Amphotericin B and azole base compounds such as Fluconazole and Itraconazole are conventionally known, but not so many pharmaceuticals have been commercially available yet. In addition, the above-exemplified pharmaceuticals involve problems in safety and antimycotic action. There is accordingly a demand for an antimycotic effective against Aspergillus spp. and Candida spp. Now, more effective azole base compounds are under development. For example, as a compound having a difluoromethylene group, those described in Japanese Patent Application Laid-Open Nos. 163374/1984, 163269/1993 and 227531/1997 are known. As an azole base compound having a substituted ter-tiary hydroxyl group, cyclic compounds as described in Japanese Patent Application Laid-Open Nos. 217778/1996 and 333367/1996, acyl compounds as described in Japanese Patent Application Laid-Open Nos. 104676/1996 and 183769/1997, and the like are known but they are not fully satisfactory.
SUMMARY OF THE INVENTION
Accordingly, an object of the present invention is to provide a compound which has high safety and has antimycotic activity effective against Aspergillus spp. and Candida spp.
With the forgoing in view, the present inventors synthesized a number of triazole derivatives and salts thereof and carried out an investigation on their antimycotic activity effective against Aspergillus spp. and Candida spp. As a result, it has been found that a cyclopropylthio- or cyclopropylsulfonyl-containing triazole derivative represented by the below-described formula (1) and a salt thereof are superior in antimycotic activity against fungi including Aspergillus spp. and Candida spp. and also in safety to the analogous compounds which have been known to date, leading to the completion of the present invention. In one aspect of the present invention, there are thus provided a triazole derivative represented by the following formula (1):
wherein R
1
represents a hydrogen atom, lower alkyl group or aralkyl group, X
1
and X
2
are the same or different and each independently represents a hydrogen atom, a halogen atom or a halogenoalkyl group and n stands for an integer of 0 to 2, or salt thereof; an intermediate for preparing said compound; and a preparation process of these compounds.
In another aspect of the present invention, there is also provided a pharmaceutical comprising as an effective ingredient the triazole derivative represented by the formula (1) or salt thereof.
In a further aspect of the present invention, there is also provided a pharmaceutical composition comprising the triazole derivative represented by the formula (1) or salt thereof and a pharmacologically acceptable carrier.
In a still further aspect of the present invention, there is also provided the use of the triazole derivative represented by the formula (1) or salt thereof as a pharmaceutical.
In a still further aspect of the present invention, there is also provided a treating method of mycotic infections, which comprises administering to a patient a pharmacologically effective amount of the triazole derivative represented by the formula (1) or salt thereof.
The triazole derivative or salt thereof according to the present invention has strong antimycotic activity, and an antimycotic comprising such compound as an effective ingredient is useful for the prevention and treatment of mycotic infections of mammary animals including humans.
BRIEF DESCRIPTION OF THE PREFERRED EMBODIMENTS
In the triazole derivative of the present invention, examples of the lower alkyl group represented by R
1
in the formula (1) include linear or branched C
1-6
alkyl groups. Specific examples include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, n-pentyl, i-pentyl and n-hexyl. As the aralkyl group represented by R
1
, C
7-10
aralkyl groups are preferred, with phenyl-C
1-4
alkyl groups being more preferred. Specific examples include benzyl, phenethyl and phenylpropyl. As R
1
, methyl and benzyl groups are preferred. In X
1
or X
2
, examples of the halogen atom include fluorine, chlorine, bromine and iodine atoms, with the fluorine and chlorine atoms being particularly preferred. Examples of the halogenoalkyl group include the above-exemplified C
1-6
alkyl groups each substituted by the above-exemplified halogen atom. Among them, perfluoro-C
1-6
alkyl groups are preferred, with trifluoromethyl and pentafluoroethyl groups being particularly preferred and trifluoromethyl group being more preferred. The number n of oxygen atoms stands for an integer of 0 to 2, with 0 or 2 being preferred.
No particular limitation is imposed on the salt of the triazole derivative (1) of the present invention insofar as it is a pharmacologically acceptable salt. Examples include acid addition salts such as hydrochlorides, nitrates, hydrobromides, p-toluenesulfonates, methanesulfonates, fumarates, succinates and lactates.
The triazole derivative (1) or salt thereof according to the present invention has stereoisomers based on its asymmetric carbon and sulfoxide. The present invention embraces any one of such isomers and isomer mixtures such as racemic modifications. The triazole derivative (1) or salt thereof may exist in the form of a solvate typified by a hydrate. The present invention also embraces solvates of these compounds.
The triazole derivative (1) of the present invention can be prepared, for example, in accordance with the reaction scheme described below:
wherein R
1
, X
1
and X
2
have the same meanings as defined above and X
3
represents a halogen atom.
Described specifically, Compound (1a), that is, a compound of the formula (1) wherein n stands for 0 can be prepared by introducing a cyclopropylthio group into a 2-haloacetophenone derivative (5) which is a known compound; difluorinating the resulting cyclopropylthio compound (4) into Compound (2); and directly introducing a triazolemethyl group into Compound (2) or first introducing an epoxymethylene group into Compound (2) to obtain Compound (3) and then introducing a triazole group into Compound (3). The R
1
of the resulting Compound (1a) can be alkylated or aralkylated as desired. By the oxidation of Compound (1a), Compound (1b), that is, a compound of the formula (1) wherein n stands for 1 or Compound (1c), that is, a compound of the formula (1) wherein n stands for 2 can be prepared. Alternatively, Compound (1c) can be prepared by the oxidation of Compound (1b).
In the above preparation process, the 2,2-difluoro-2-cyclopropylthioacetophenone derivative represented by the formula (2) and oxirane derivative represented by the formula (3) are novel compounds synthesized by the present inventors and are useful as an intermediate for the synthesis of a triazole derivative (1).
The present invention will hereinafter be described in accordance with the above steps.
Step (5-4):
Compound (4) can be prepared by introducing a cyclopropylthio group into Compound (5).
In Compound (5) employed as a starting material, examples of X
3
i
Asaoka Takemitsu
Eto Hiromichi
Ishida Kazuya
Kaneko Yasushi
Maebashi Kazunori
Morris Patricia L.
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
SSP Co. Ltd.
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