AZOLE DERIVATIVE AND AZOLE MYCOCIDE

Abstract: A mycocide composition which comprises an azole derivative of formula (II): wherein: each X, which may be identical or different from each other X group if more than one X group is present, represents a halogen, an alkyl group having 1 to 5 carbons atoms, a haloalkyl group, a phenyl group, a cyano group or a nitro group; n represents an integer of from 0 to 5; A represents nitrogen or CH; and R₁ and R₂ each represent hydrogen or an alkyl group having 1 to 5 carbon atoms; or a medically or veterinarily acceptable salt thereof; and a medically or veterinarily acceptable diluent or carrier and an azole derivative of this formula with the provisos that n is not 0 and that, when n is 1 or 2, X does not represent a halogen, an alkyl group having 1 to 5 carbon atoms or a phenyl group.

Description: The present invention relates to azole derivatives and to mycocide compositions suitable for administration to animals and man. EP-A-0052425 discloses compounds of the formula: having pesticidal (especially fungicidal) and plant growth regulating activity, wherein R is a bridging group -(CH₂) n - where n is 0, 1 or 2 or a bridging group -CH=CH-, or is -O-, -S-, -NH- or -C(O)-; X₁ is =N- or =CH-; Y and Z, which may be the same or different, are halogen, alkyl, alkoxy, halo-alkoxy, haloalkyl, nitro, phenyl or phenoxy; m and p are 0, 1, 2 or 3; and salts, metal complexes and functional derivatives thereof. GB-A-2180236 discloses azole derivatives of the formula: which are fungicides and plant growth regulators, wherein n represents an integer of from 1 to 5; X¹ represents a hydrogen atom, a halogen atom, an alkyl group, a haloalkyl group, a phenyl group, a cyano group or a nitro group and when n is greater than 1 each X¹ can be the same or different; and A represents a nitrogen atom or a methine group. The present invention relates to azole derivatives represented by the formula (II): wherein n represents an integer of from 0 to 5; when n represents an integer of from 1 to 5, the or each X, which may be identical or different from each other X group if more than one X group is present, represents a halogen atom, an alkyl group having 1 to 5 carbon atoms, a haloalkyl group, a phenyl group, a cyano group, or a nitro group; A represents a nitrogen atom or CH; and R₁ and R₂ each represent a hydrogen atom or an alkyl group having 1 to 5 carbon atoms, and salts thereof which are medically or veterinarily acceptable. The fact that some of the compounds represented by the formula (II) have activity protecting plants from phytopathogens, growth-regulating effects and herbicidal effects on plants as agricultural and horticultural chemicals has already been reported together with the methods for producing the compounds by the present inventors (Japanese Patent Application No. 60-202431 (1985) from which GB-A-2180236 claims priority and Japanese Patent Application No. 61-265559 (1986) from which EP-A-267778 claims priority). As a result of further studies of the adaptability of the compounds disclosed in Japanese Patent Application Nos. 60-202431 (1985) and 61-265559 (1986) and novel compounds to fields other than the fields of agricultural and horticultural chemicals, the present inventors have found that the known compounds and novel compounds represented by formula (I) have mycocidal effects on animals including man. In a first aspect of the present invention, there is provided an azole derivative represented by the formula (I): wherein n represents an integer of from 1 to 5; the or each X, which may be identical or different from each other X group if more than one X group is present, represents a halogen atom, an alkyl group having 1 to 5 carbon atoms, a haloalkyl group, a phenyl group, a cyano group, or a nitro group; A represents a nitrogen atom or CH; and one of R₁ and R₂ represents an alkyl group having 1 to 5 carbon atoms and the other a hydrogen atom or an alkyl group having 1 to 5 carbon atoms; or a salt thereof; with the proviso that when n is 1 or 2, X does not represent a halogen atom, an alkyl group having 1 to 5 carbon atoms or a phenyl group. In a second aspect of the invention, there is provided a mycocide composition suitable for administration to animals or man, which comprises an azole derivative represented by the formula (II): wherein n represents an integer of from 0 to 5; when n represents an integer of from 1 to 5, the or each X, which may be identical or different from each other X group if more than one X group is present, represents a halogen atom, an alkyl group having 1 to 5 carbon atoms, a haloalkyl group, a phenyl group, a cyano group, or a nitro group; A represents a nitrogen atom or CH; one of R₁ and R₂ represents an alkyl group having 1 to 5 carbon atoms and the other represents hydrogen or an alkyl group having 1 to 5 carbon atoms; or a medically or veterinarily acceptable salt thereof; and a diluent or a carrier which is medically or veterinarily acceptable. In a third aspect of the present invention, there is provided an azole derivative represented by the formula (II), or a medically or veterinarily acceptable salt thereof, for use as an active therapeutic substance. The azole derivative of formula (II) or its salts may therefore be provided for use in the treatment of mycosis. In a fourth aspect of the present invention, there is provided use of an azole derivative represented by the formula (II), or a medically or veterinarily acceptable salt thereof, in the manufacture of a medicament for use in the treatment of mycosis. In the accompanying drawings: Figs. 1 to 76 show the infrared absorption spectra of the azole derivatives shown in Table 1, wherein Fig. 1 shows the infrared absorption spectrum of Compound No. 1, Fig. 2 that of Compound No. 2, Fig. 3 that of Compound No. 3 and Figs. 4 to 76 those of Compound Nos. 4 to 76, respectively. Among the compounds of formula (II), X is preferably a halogen atom or a phenyl group, n is preferably 1 or 2, and R₁ and R₂ are preferably alkyl groups having 1 to 3 carbon atoms. Suitable compounds of formula (II) are those wherein: n represents 1 or 2; the or each X, which may be identical or different from each other X group if more than one X group is present, represents a halogen or a phenyl group; and one of R₁ and R₂ represents an alkyl group having 1 to 3 carbon atoms and the other represents hydrogen or an alkyl group having 1 to 3 carbon atoms. Since the compounds used in the present invention have an azolylmethyl group at the 1-position, a hydrogen atom or an alkyl group having 1 to 5 carbon atoms at the 2-position, and a substituted benzyl group at the 5-position, respectively, of a cyclopentane ring, the compounds have geometric isomers and optical isomers. The compounds of the present invention include all these respective isomers and mixtures of any number of isomers in any ratio. Accordingly, the mycocide according to the present invention may contain a single isomer or a mixture of these isomers as an effective ingredient. The compounds of the present invention represented by the formula (I) can be synthesized in accordance with a method described in Japanese Patent Application Nos. 60-202431 (1985) and 61-265559 (1986). The compounds represented by the formula (II) and the physicochemical properties (melting points) thereof are shown in Table 1. "A type" and "B type" in Table 1 represent the following two types: Medicines which contain a compound represented by the general formula (II) or medically or veterinarily acceptable salt thereof, e.g.,a salt of an inorganic acid such as a nitric acid, sulfuric acid and hydrochloric acid and a salt of an organic acid such as a fumaric acid and naphthalene-1,5-disulfonic acid and a diluent or a carrier which is medically or veterinarily acceptable are medicines which show a mycocidal activity and are useful for treating mycosis of animals including man. For example, these medicines are useful for treating a local mycosis of man caused by a fungus belonging to the genus such as Candida, Trichophyton, Microsporum and Epidermophyton or a mucosal mycosis caused by C. albicans, e.g., candidiasis of mouth and candidiasis of vagina. These medicines can also be used for treating a systemic mycosis caused by C. albicans, Cryptococcus neoformans, Aspergillus fumigatus, or a fungus belonging to genus such as Coccidioides, Paracoccidiodes, Histoplasma and Blastomyces. When the compounds represented by the formula (II) is used for man, they may be used singly, but they are generally administered in the form of a mixture with a carrier and/or diluent which is selected in accordance with desired administration route and unit dosage form. For example, these compounds may be orally administered in the form of a tablet containing an excipient such as starch and lactose, in the form of a capsule or ovules in a single state or in a state of being mixed with an excipient, or in the form of an elixir or a suspension containing a flavor or coloring agent. These compounds may also be parenterally administered, for example, by intravenous injection, subcutaneous injection, intramascular injection or the like. In the case of administering such a medicine parenterally, it is most preferable that the medicine is used in the form of a germfree aqueous solution containing a sufficient amount of salt or glucose for making an injection solution isotonic with blood. The compounds represented by the formula (II) may also be administered in the form of a suppository or a vaginal suppository, or applied to the affected part in the form of a lotion, liquid, cream, ointment or dusting powder. For example, these compounds may be added to a cream comprising an aqueous emulsion of polyethylene glycol or liquid paraffin. These compounds may also be added in the range of 1 to 10% concentration to an ointment comprising white Japan wax or white liquid paraffin and necessary stabilizer and antiseptic. The ordinary dosage of the compound represented by the formula (II) for man is 0.1 to 40 mg/kg per day, whether it is administered orally or parenterally. It is therefore possible to use a tablet or a capsule of this compound which contains 1 mg to 0.5 g of the compound in order to administer one or more of them every time, as occasion demands. The actual optimum dosage is judged by a doctor in accordance with the age, weight, sensitivity, and degree of infection of the patient. The above-described dosage is for an average case, and the effective range of dosage naturally fluctuates depending on cases, such range being included in the present invention. These compounds may be administered to animals other than man by the same administration methods and dosage (0.1 to 40 mg/kg.day) as in the case of man. The mycocidal activity in vitro of the compounds represented by the formula (II) can be evaluated by measuring the minimum inhibitory concentration (hereinunder referred to as "M.I.C.") of the test compounds for inhibiting the growth of a specific fungus in an appropriate culture medium. Actually, standard culture of C. albicans, for example, is inoculated into a series of agar plates containing test compounds in a predetermined concentration. After each agar plate is cultivated at a predetermined temperature for a predetermined time, whether C. albicans has grown or not is examined to determine the M.I.C. of the corresponding compound. Other fungi such as Cryptococcus neoformans, Candida spp., Torulopsis glabrata, Aspergillus spp., Cladosporium carrionii, Fonsecaea pendrosoi, Microsporum spp., E. floccosum, Phialophora verrucosa, C. immitis and Sporothrix schenckii are also usable in this kind of test. The effectiveness of the compounds represented by the formula (II) to fungi will now be shown with reference to the following examples. Example 1 The anti-fungus activities in vitro of the compounds represented by the formula (II) were examined. Testing method: Each of the compounds shown in Table 2 was dissovled in dimethylsulfoxide so as to have a predetermined concentration. In a petri dish, were well mixed 0.1 mℓ of the compound and 9.9 mℓ Sabouraud's agar culture medium of about 60°C to be solidified. The spores of a test fungus which had been cultivated in a plate culture medium at 28°C for 20 to 30 days was suspended in 0.1% Tween 80 solution (Polyoxyethylene Sorbitan Monooleate). The suspension was adjusted by using 0.1% Tween 80 solution so as to have a spore concentration of 10⁵ to 10⁶ spores/mℓ. Into the plate culture medium containing the test compound, 5 µℓ of the fungus suspension was inoculated. After the inoculation, the fungus was cultivated at 28°C. Whether the fungus had grown or not was judged 4 days after the inoculation in the case of Aspergillus, and 7 days after the inoculation in the case of the other fungi to obtain the M.I.C. The degree of growth inhibition was evaluated into 5 stages in accordance with the following standards. The results are shown in Table 2. Growth inhibition 5 M.I.C < 3.13 ppm 4 3.13 ppm ≦ M.I.C. < 12.5 ppm 3 12.5 ppm ≦ M.I.C. < 50 ppm 2 50 ppm ≦ M.I.C. ≦ 100 ppm 1 100 ppm < M.I.C. Compound No. Test fungus A. fla. A. nig. C. car. F. pen. M. gyp. P. ver. T. men. T. rub. 3 5 4 4 5 3 4 4 4 7 5 5 5 5 5 5 5 5 11 5 4 5 5 5 4 5 5 13 4 3 2 3 3 1 3 3 15 5 4 4 4 5 3 5 5 16 5 5 5 5 5 5 5 5 17 5 4 4 5 4 4 5 5 29 4 3 4 4 4 3 4 4 35 5 5 5 5 4 5 5 4 37 5 4 4 4 4 3 4 4 39 5 5 5 5 5 5 5 5 41 4 3 3 3 4 3 5 4 45 5 5 5 5 5 4 5 5 47 5 5 5 5 5 5 5 5 52 5 5 5 5 5 5 5 5 57 5 5 5 5 5 5 5 5 59 5 5 5 5 5 5 5 5 71 5 3 5 5 5 3 4 4 Explanation of Abbreviations: A.fla.; Aspergillus flavus A.nig.; Aspergillus niger C.car.; Cladosporium carrionii F.pen.; Fonsecaea pendrosoi M.gyp.; Microsporium gypseum P.ver.; Phialophora verrucosa T.men.; Trichophyton mentagrophytes T.rub.; Trichophyton rubrum Example 2 The anti-yeast fungal activities in vitro of the compounds represented by the formula (II) were examined. Testing method: Each of the compounds shown in Table 3 was dissolved in dimethylsulfoxide so as to have a predetermined concentration. In a petri dish, were well mixed 0.1 mℓ of the compound and 9.9 mℓ Sabouraud's agar culture medium of about 60°C to be solidified. A test fungus which had been cultivated in a liquid culture medium in advance was suspended in a physiological saline solution so as to have a fungus concentration of 10⁵ to 10⁶ cells/mℓ. Into the plate culture medium containing the test compound shown in Table 3, 5 µℓ of the fungus solution was inoculated. After the inoculation, the fungus was cultivated at 37°C for 2 days. Whether the fungus had grown or not was judged to obtain the M.I.C. The degree of growth inhibition was evaluated into 5 stages in accordance with the following standards. The results are shown in Table 3. Growth inhibition 5 M.I.C. < 3.13 ppm 4 3.13 ppm ≦ M.I.C. < 12.5 ppm 3 12.5 ppm ≦ M.I.C. < 50 ppm 2 50 ppm ≦ M.I.C. ≦ 100 ppm 1 100 ppm < M.I.C.

Claims: Claims for the following Contracting States : AT, BE, CH, DE, FR, GB, IT, LI, NL, SE An azole derivative of formula (I): wherein: n represents an integer of from 1 to 5; the or each X, which may be identical or different from each other X group if more than one X group is present, represents a halogen, an alkyl group having 1 to 5 carbon atoms, a haloalkyl group, a phenyl group, a cyano group or a nitro group; A represents nitrogen or CH; and one of R₁ and R₂ represents an alkyl group having 1 to 5 carbon atoms and the other represents hydrogen or an alkyl group having 1 to 5 carbon atoms; or a salt thereof; with the proviso that when n is 1 or 2, the or each X does not represent a halogen, an alkyl group having 1 to 5 carbon atoms or a phenyl group. A mycocide composition suitable for administration to animals or man, which comprises an azole derivative of formula (II): wherein: n represents an integer of from 0 to 5; when n represents an integer of from 1 to 5, the or each X, which may be identical or different from each other X group if more than one X group is present, represents a halogen, an alkyl group having 1 to 5 carbon atoms, a haloalkyl group, a phenyl group, a cyano group or a nitro group; A represents nitrogen or CH; one of R₁ and R₂ represents an alkyl group having 1 to 5 carbon atoms and the other represents hydrogen or an alkyl group having 1 to 5 carbon atoms; or a medically or veterinarily acceptable salt thereof; and a medically or veterinarily acceptable diluent or carrier. A mycocide according to claim 2, wherein the azole derivative of formula (II) is an azole derivative of formula (I) as defined in claim 1. A mycocide according to claim 2 wherein: n represents 1 or 2; the or each X, which may be identical or different from each other X group if more than one X group is present, represents a halogen or a phenyl group; and one of R₁ and R₂ represents an alkyl group having 1 to 3 carbon atoms and the other represents hydrogen or an alkyl group having 1 to 3 carbon atoms. An azole derivative of formula (II), or a medically or veterinarily acceptable salt thereof, as defined in any one of claims 2 to 4 for use as an active therapeutic substance. An azole derivative according to claim 5, for use in the treatment of mycosis. An azole derivative according to claim 6, for use in the treatment of a local mycosis in man caused by a fungus belonging to the genus Candida , Trichophyton , Microsporum and Epidermophyton or of a local mycosis caused by C. albicans . An azole derivative according to claim 6, for use in the treatment of a systemic mycosis caused by C. albicans , Cryptococcus neoformans , Aspergillus fumigatus or a fungus belonging to the genus Coccidioides , Paracoccidiodes , Histoplasma or Blastomyces . Use of an azole derivative of formula (II), or a medically or veterinarily acceptable salt thereof, as defined in any one of claims 2 to 4 in the manufacture of a medicament for use in the treatment of mycosis. Claims for the following Contracting State : ES A process for the preparation of a mycocide composition suitable for administration to animals or man, which process comprises formulating an azole derivative of formula (II): wherein: n represents an integer of from 0 to 5; when n represents an integer of from 1 to 5, the or each X, which may be identical or different from each other X group if more than one X group is present, represents a halogen, an alkyl group having 1 to 5 carbon atoms, a haloalkyl group, a phenyl group, a cyano group or a nitro group; A represents nitrogen or CH; and one of R₁ and R₂ represents an alkyl group having 1 to 5 carbon atoms and the other represents hydrogen or an alkyl group having 1 to 5 carbon atoms; or a medically or veterinarily acceptable salt thereof; with a medically or veterinarily acceptable diluent or carrier. A process according to claim 1, wherein the azole derivative of formula (II) is an azole derivative of formula (I): wherein: n represents an integer of from 1 to 5; the or each X, which may be identical or different from each other X group if more than one X group is present, represents a halogen, an alkyl group having 1 to 5 carbon atoms, a haloalkyl group, a phenyl group, a cyano group or a nitro group; A represents nitrogen or CH; and one of R₁ and R₂ represents an alkyl group having 1 to 5 carbon atoms and the other represents hydrogen or an alkyl group having 1 to 5 carbon atoms; with the proviso that when n is 1 or 2, the or each X does not represent a halogen, an alkyl group having 1 to 5 carbon atoms or a phenyl group. A process according to claim 2, wherein n represents 1 or 2; the or each X, which may be identical or different from each other X group if more than one X group is present, represents a halogen or a phenyl group; and one of R₁ and R₂ represents an alkyl group having 1 to 3 carbon atoms and the other represents hydrogen or an alkyl group having 1 to 3 carbon atoms.

Inventors: ARAHIRA, MASATO, IKEDA, SUSUMU, KUMAZAWA, SATORU, SAISHOJI, TOSHIHIDE
Applicants: KUREHA KAGAKU KOGYO KABUSHIKI KAISHA
Application year: 1988
Main classification: C07D249
IPC codes: A61P31, C07D233, C07D521, A61K31, C07D249