TRIAZOLE ANTIFUNGAL AGENTS

Abstract: Compounds of the formula: where R ist a phenyl group optionally substituted by 1 to 3 substituents each independently selected from F, Cl, Br, I, CF₃, C₁-C₄ alkyl and C₁-C₄ alkoxy, or R is a 5-chloropyrid-­ 2-yl group; X is F, Cl or Br; and n is zero or an integer of from 1 to 5; and their pharmaceutically and agriculturally acceptable salts. The compounds are useful as human and agricultural fungicides.

Description: This invention relates to novel triazole derivatives which have antifungal activity and are useful in the treatment of fungal infections in animals, including humans, and as agricultural fungicides. According to the invention, there are provided compounds of the formula: EMI1.1 where R is phenyl optionally substituted by 1 to 3 substituents each-independently selected from F, Cl, Br, t, CF3, C14 alkyl and C1-C4 alkoxy, or R is a 5-chloropyrid-2-yl group; X is F, C1 or Br; and n is zero or an integer of from 1 vo 5; and their pharmaceutically and agriculturally acceptable salts. C3- and C4 alkyl and alkoxy groups can be straight or branched chain. The invention also provides a pharmaceutical composition comprising a compound of the formula (I)-or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable diluent or carrier. The invention further provides a compound of the formula (I) or a pharmaceutically acceptable salt thereof, for use in medicine, in particular for treating fungal infections in animals, including humans. The invention yet further provides a fungicidal composition for agricultural use, comprising a compound of the formula (I), or an agriculturally acceptable salt thereof, together with an agriculturally acceptable diluent or carrier. The invention yet further provides a method of treating a plant or seed having a fungal infection, which comprises contacting said plant or seed, or the locus of said plant, with an effective amount-of a compound of the formula (I) or an agriculturally acceptable salt thereof. When R is said optionally substituted phenyl group, it is preferably phenyl substituted by I to 3 substituents, more preferably 1 or 2 substituents, each independently selected from F, C1, Br, I and CF3. The more preferred individual groups represented by R are 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-iodophenyl, 4-trifluoromethylphenyl, 2-chlorophenyl, 2-fluorophenyl, 2,4-dichlorophenyl, 2, 4-difluorophenyl, 2, 5-difluorophenyl, 2-fluoro-4-chlorophenyl, 2,4,6-trifluorophenyl and 4-bromo-2,5- difluorophenyl. Most preferably, R is 2,4-difluorophenyl, 4-chlorophenyl or 4-fluorophenyl. "n" is preferably 0, 1 or 2. "n" is most preferably 0. X is preferably Cl. The compounds of the formula (I) can be prepared by the halogenation of the corresponding hydroxy compounds of the formula: - EMI3.1 where R and n are as defined for formula (I). This halogenation is carried out according to conventional procedures, e.g. using SOC12, SOBr2 or diethylaminosulphur trifluoride (Et2NSF3), as appropriate. In a typical procedure utilising thionyl chloride or bromide, the alkanol (11) in a suitable solvent, e.g. dry acetonitrile, is reacted at up to reflux temperature with thionyl chloride or bromide in the presence of a base, e.g. imidazole., The reaction may proceed to completion- at room temperature although in some cases heating at up to reflux temperature may be necessary to accelerate the reaction. The product.can be recovered and purified by conventional procedures. The reaction using diethylaminosulphur trifluoride is typically carried out at about 0 C in-methylene chloride as the solvent. The starting materials of the formula CII) are the subject of our copending UK. patent applications nos. 8223459 and 8231309 filed on, respectively, 14th August and 2nt November, 1982, and can be prepared by the methadsr described. therein. These methods include reacting an oxirane of the formula: EMI4.1 where R is as defined for formula (I), with 1,2,4-triazole, preferably in the presence of a base, e.g. K2CO3. Alternatively an alkali metal salt of 1,2,4-triazole can be used, preparable e.g. from- 1,2,4-triazole and NaH. Typically the reaction is carried out by heating the reactants together at up to 120 C in a suitable organic solvent, e.g. dimethylformamide, for up to about 24 hours. The product can then be isolated and purified conventionally. The oxiranes (III) are obtainable conventionally, generally from the ketones of the formula: EMI4.2 This can be achieved by the reaction of (IV) with dimethyloxo sulphonium methylide prepared from trimethylsulphoxonium iodide - and' either (a) sodium hydride in dimethylsulphoxide, or (b) cetrimide (cetyltrimethylammonium bromide) and sodium hydroxide in a mixture of water and- toluene or water and 1,1,1-trichloroethane. The reaction using sodium hydride is- typically carried out by stirring sodium hydride with trimethylsulphoxonium iodide at, say, room temperature. Dimethylsulphoxide (DMsO) is then added dropwise and the mixture stirred for about 30 minutes, after which time the ketone (IV) is added in DIMS0. The desired product is generally obtained by stirring at room temperature for about an hour. The reaction using cetrimide is typically achieved by stirring the ketone (IV), trimethylsulphoxonium iodide and cetrimide in a mixture of l,l,l-erichloroethane and aqueous sodium hydroxide solution for about 2 hours at, say, 70-lOQ°C. Whilst in either case the oxirane product (III) can be isolated if desired, it is often more convenient to convert this in situ to the desired product. The ketones (IV) are either known compounds or can be prepared conventionally, e.g.: EMI5.1 The compounds of the formula (II) can also be prepared as follows: EMI6.1 <tb> <SEP> Li.R, <SEP> -780C, <SEP> OH <tb> CY3COCH2. <SEP> Hal <SEP> + <SEP> MBrMg.R, <SEP> organic <SEP> solvent <SEP> CF3-C1-CH2.HaI <tb> <SEP> or <SEP> IMg.R <SEP> (e.g. <SEP> Et20). <SEP> R <tb> <SEP> 1,24-triazole, <tb> <SEP> base <SEP> (e.g. <tb> <SEP> K2C 3), <SEP> organic <tb> <SEP> solvent, <SEP> about <tb> <SEP> 7QeC, <SEP> up <SEP> to <SEP> 24 <tb> <SEP> hours. <tb> <SEP> fi <SEP> < <tb> <SEP> OH <tb> <SEP> CF <SEP> -C-CH <SEP> <tb> <SEP> R- <SEP> uZ <tb> <SEP> K <tb> "Hal" = Cl or Br. Again an alkali metal salt of the triazole can be used in place of 1,2,4-triazole/K2CO3. In a typical procedure, the halo-ketone and the lithio or Grignard reagent are stirred together in e.g. diethylether at -78 C for about one hour. The intermediate halo-alkanol can then be recovered conventionally if necessary. The halo-alkanol and 1,2,4-triazole are then heated in e.g. dimethylformamide at, say, 50-130 C, in the presence of a base such as potassium carbonate for up to about 24 hours. The product can then be recovered in a conventional manner. The compounds of the formula (II) in which n is an integer of from I to 5 can be prepared as follows: EMI7.1 [Hal - C1 or Br and n is 1 to 5]. The reaction is typically carried out by heating in dimethylformamide at up to 130 C for up to, say, 24 hours. Again the product can be recovered -in a conventional manner. Again the starting materials are preparable conventionally, e.g., EMI8.1 <tb> <SEP> (a) <SEP> CF3(CF2)nCOCH3 <SEP> Br <SEP> CF3(CF2)nCOCH2Br <tb> <SEP> Concentrated <SEP> H2 <SEP> 504 <tb> <SEP> [see <SEP> J.A.C.S., <SEP> 78, <SEP> 2268-70 <SEP> (1956)J <SEP> R.Li, <tb> <SEP> R.ggBr <SEP> or <tb> <SEP> R.MgI. <tb> <SEP> OH <tb> (n <SEP> = <SEP> O <SEP> to <SEP> 5) <SEP> 3( <SEP> 2)n <SEP> CCF2)nCCH2Br <tb> <SEP> R <tb> <SEP> or <SEP> (b) <SEP> CF(CF)I <SEP> PhMgBr, <tb> <SEP> CF3CCF2)MgBr <tb> <SEP> -78"C <tb> <SEP> -- <SEP> ClCH2COR, <tb> <SEP> - <SEP> / <SEP> -20 C <tb> <SEP> OH <tb> <SEP> ClCH2-C-(CF2)nCF3 <SEP> . <tb> <SEP> R <tb> <SEP> (n <SEP> = <SEP> I <SEP> to <SEP> 5). <tb> All the compounds of the formula (I) contain an optically active centre and the invention includes both the resolved and unresolved forms. Pharmaceutically acceptable acid addition salts of the compounds of the formula (I) are those formed from strong acids which form non-toxic acid addition salts, such as hydrochloric, hydrobromic, sulphuric, oxalic and methanesulphonic acids. The salts may be obtained by conventional procedures, e.g. by mixing solutions containing equimolar amounts of the free base and desired acid, and the required salt is collected by filtration, if insoluble, or by evaporation of the solvent. The compounds of the formula (I) and their pharmaceutically acceptable salts are antifungal agents, useful in combating fungal infections in animals, including humans. For example they are useful in treating topical fungal infections in man caused by, among other organisms, species of Candida, Trichophyton, Microsporum or Epidermophyton, or in mucosal infections caused by Candida albicans (e.g. thrush and vaginal candidiasis). They can also be used in the treatment of systemic fungal infections caused by, for example, Candida albicans, Cryptococcus neoformans, Aspergillus fumigatus, Coccidioides, Paracoccidjoides, Histoplasma or Blastomyces. The in vitro evaluation of the antifungal activity of the compounds can be performed by determining the minimum inhibitory concentration (m.i.c.) which is the concentration of the test compounds in a suitable medium at which growth of the particular micro-organism fails to occur. In practice, a series of agar plates, each having the test compound incorporated at a particular concentration is inoculated with a standard culture of, for example, Candida albicans and each plate is then incubated for 48 hours at 370C. The plates are then examined for the presence or absence of growth of the fungus and the appropriate m.i.c. value is noted. Other micro-organisms used in such tests can include Cryptococcus neoformans, Aspergillus fumigatus, Trichophyton spp; Microsporum spp; Epidermophyton floccosum, Coccidioides immitis and Torulopsis glabrata. The in vivo evaluation of the compounds can be carried out at a series of dose levels by intraperitoneal or intravenous injection or by oral administration, to mice which are inoculated with a strain of Candida albicans. Activity is based on the survival of a treated group of mice after the death of an untreated group of mice following 48 hours observation. The dose level at which the compound provides 50% protection against the lethal effect of the infection (PD50) is noted. For human use, the antifungal compounds of the- formula (I) can be administered alone, but will generally be administered in admixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice. For example, they can be administered orally in the form of tablets containing such excipients as starch or lactose, or in capsules or ovules either alone or in admixture with excipients, or in-the form of elixirs or suspensions containing flavouring or colouring agents. They can be administered parenterally, for example, intravenously, intramuscularly or subcutaneously. For administration by injection, they are best used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood. For oral and parenteral administration to human patients, the daily dosage level of the antifungal compounds of the formula (I) will be from 0.1 to 5 mg/kg (in divided doses) when administered by either the oral or parenteral route. Thus tablets or capsules of the compounds will typically contain from 5 mg to 0.5 g.of active compound for administration singly or two or more at a time as appropriate. The physician in any event will determine the actual dosage which will be most suitable for an individual patient and it will vary with the age, weight and response of the particular patient. The above dosages are exemplary of the average case; there can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention Alternatively, the antifungal compounds of formula (I) can be administered in the form of a suppository or pessary, or they may be applied topically in the form of a lotion, solution, cream, ointment or dusting powder. For example, they can be incorporated into a cream- consisting of an aqueous emulsion of polyethylene glycols or liquid paraffin; or they can be incorporated, at a concentration between l and 10%, into an- ointment consisting of a white wax or white soft paraffin base together with- such stabilizers and preservatives as may be required. The compounds of the formula (I) and their salts also have activity against a variety of plant pathogenic fungi, including for example various- rusts, mildews and moulds, and the compounds are thus useful for treating plants and seeds to eradicate or prevent such diseases. The in vitro evaluation of the activity of the compounds against plant fungi can be determined by measuring their minimum inhibitory concentrations in the same way as previously described except that the plates are incubated at 3O0C for 48 hours or longer before being examined for the presence or absence of growth. Micro-organisms used in such tests include Cochliobolus carbonum, Pyricularia oryzae, Glomerella cingulata, Penicillium digitatum, Botrytis cinerea and Rhizoctonia solani. For agricultural and horticultural purposes the compounds and their agriculturally acceptable salts are preferably used in the form of a composition formulated as appropriate to the particular use and purpose desired. Thus the compounds may be applied in the form of dusting powders, or granules, seed dressings, aqueous solutions, dispersions or emulsions, dips, sprays, aerosols or smokes Compositions may also be supplied in the form of dispersible powders,. granules or grains, or concentrates for dilution prior to use. Such-compositions-may contain such conventional carriers, diluents or adjuvants as are known and acceptable in agriculture and horticulture and they are manufactured in accordance with conventional procedures. The compositions may also incorporate other active ingredients, for example-, compounds having. herbicidal or insecticidal activity or a further fungicide. The compounds and compositions can be applied in a number of ways, for example they can be applied directly to the plant foliage, stems, branches, seeds or roots or to the soil. The following Examples illustrate the invention. All temperatures are in "C:- EXAMPLE I Preparation of 1-[2-chloro-2-(2,4-difluorophenyl)-3,3,3-trifluoro- propyl]-1H-1,2,4-triazole EMI13.1 Imidazole (0.53 g, 7.8 m.mole) wds dissolved in dry acetonitrile (4 ml) and thionyl chloride (0.3 ml, 4.1 m.mole) was added dropwise over 2 minutes followed by a solution of 2-(2,4-difluorophenyl)-1-(lH-1,2,4-triazol-1-yl)-3,3,3-trifluoro- propan-2-ol (0.389 g, 1.25 m.mole) in dry acetonitrile (12 ml). The mixture was stirred at room temperature for 24 hours and then heated to 700 for h hour. The cooled mixture was then poured into sodium bicarbonate solution and extracted with dichloromethane (3 x 100 ml). The combined dichloromethane extracts were washed once with water, dried over magnesium sulphate and evaporated. Chromatography of the residue on silica (230-400 mesh), eluting with 40:60 (by volume) ethyl acetate:hexane gave, after recrystalisation from ethyl acetate/hexane, the title compound, 170 mg (41%), m.p. 87-88 . Analysis t:- Found: C,42.4; H,2.3; N,13.4. C11H7ClF5N3 requires: C,42.4; H,2.3; N,13.5. EXAMPLES 2 TO 5 The compounds of these Examples were prepared similarly to Example 1 from appropriate starting materials. In Examples 2 and 3, thionyl chloride was added to a solution of the starting alcohol and imidazole, and in Example 2, water and ethyl acetate were used in the extraction procedure in place of, respectively, sodium bicarbonate and dichloromethane. EMI14.1 EMI14.2 <tb> <SEP> Example <SEP> R <SEP> n <SEP> X <SEP> Yield <SEP> m.p. <SEP> Analysis <SEP> Z <tb> <SEP> No <SEP> ("C) <SEP> (Theoretical <SEP> in <SEP> brackets) <tb> C <SEP> H <SEP> ¯¯e <SEP> N <tb> <SEP> 2 <SEP> < <SEP> O <SEP> 85 <SEP> 62-64 <SEP> 42.7 <SEP> 2.7 <SEP> 13.7 <tb> <SEP> N1 <SEP> (42.6 <SEP> 2.6 <SEP> 13.5) <tb> EMI15.1 <tb> Example <SEP> K <SEP> n <SEP> Z <SEP> Yield <SEP> m.p. <SEP> Analysis <SEP> Z <tb> <SEP> No. <SEP> (OC) <SEP> (Theoretical <SEP> in <SEP> brackets) <tb> <SEP> C <SEP> H <SEP> N <tb> <SEP> 3 <SEP> < <SEP> O <SEP> 42 <SEP> 75-77 <SEP> 44.9 <SEP> 2.6 <SEP> 14.1 <tb> <SEP> 9 <SEP> (45.0 <SEP> 2.7 <SEP> 14.3) <tb> <SEP> 4 <SEP> h <SEP> 1 <SEP> 57 <SEP> 110-113 <SEP> 42.3 <SEP> 2.3 <SEP> 12.3 <tb> <SEP> (41.9 <SEP> 2.4 <SEP> 12.2) <tb> <SEP> 0F <tb> <SEP> 5 <SEP> t <SEP> 2 <SEP> | <SEP> 51 <SEP> 74-76 <SEP> 38.0 <SEP> 1.7 <SEP> 10.0 <tb> <SEP> (37.9 <SEP> 1.7 <SEP> 10.2) <tb> EXAMPLE 6 The following illustrate pharmaceutical compositions for the treatment of fungal infections: (a) Capsule: 71 parts by weight of the compound of Example 1 are granulated with 3 parts maize starch and 22 parts lactose and then a further 3 parts maize starch and I part magnesium stearate are added. The mixture fs regranulated and filled into hard gelatin capsules (b) Cream: 2 parts by weight of the compound of Example 1 are dissolved in 10 parts of propylene glycol and mixed into 88 parts of a vanishing cream base. (c) Pessary: 2 parts by weight of the compound of Example 3 are suspended in 98 parts of a warm liquified suppository base which is poured into moulds and allowed to solidify. The following Preparations illustrate the preparation of certain starting materials. All temperatures are in C:- PREPARATION 1 Preparation of 2-(2,4-difluorophenyl)-1-(lH-1,2,4-triazol-1-yl)- 3,3,3-trifluoropropan-2-ol EMI16.1 A hexane solution of n-butyllithium (1.55 M, 9.6 ml, 14.9 m.mole) was added to diethylether (6 ml) and the solution was cooled to 780 A solution of 2,4-difluorobromobenzene (3.03 g, 15.7 m.mole) in diethylether (100 ml) was added dropwise over 15 minutes and the mixture was stirred at -780 for a further 15 minutes. A solution of l-bromo-3,3,3-trifluoropropan-2-one (2.4 g, 12.6 m.mole) in diethylether (100 ml) was then added dropwise over 15 minutes and the mixture was stirred at -780 for a further 30 minutes. A solution of glacial acetic acid (2 ml) in diethylether (5 ml) was then added, followed by water (15 ml) and the mixture was allowed to warm to 00. The aqueous layer was separated and washed with diethylether (2 x 30 ml). The combined diethylether extracts were dried over magnesium sulphate, evaporated, and the residual oil was dissolved in dimethylformamide (40 ml). 1,2,4-Triazole (2.5 g, 36.2 m.mole) and anhydrous potassium carbonate (10 g, 72.5 m.mole) were then added to this solution and the mixture was stirred and heated at 70 for 18 hours. The mixture was then cooled, poured into water (150 ml) and extracted with ethyl acetate (3 x 100 ml). The combined ethyl acetate extracts were washed with water (100 ml), dried over magnesium sulphate, and evaporated. The residue was chromatographed on silica (230-400 mesh), eluting with ethyl acetate: hexaner 60:40 by volume, to give, after one recrystallisation from ethyl acetate/hexane, the title compound, 1.7 g (47%), m.p. 110-1110. Analysis X: Found: C,45.2; H,2.7; N,14.6. C11H8F5N3O requires: C,45.0; H,2.7; N,14.3 PREPARATIONS 2 AND 3 The following compounds were prepared similarly to Preparation 1 using n-butyllithium, 4-fluorobromobenzene and either l-bromo-3,3,3-trifluoropropan-2-one or 1-bromo-3,3,4,4,4- pentafluorobutan-2-one. EMI18.1 EMI18.2 <tb> Preparation <SEP> n <SEP> m.p. <SEP> ( C) <SEP> Analysis <SEP> Z <tb> <SEP> No. <SEP> (Theoretical <SEP> in <SEP> brackets) <tb> <SEP> C <SEP> H <SEP> N <tb> <SEP> 2 <SEP> 0 <SEP> 134-136 <SEP> 47.8 <SEP> 3.2 <SEP> 15.5 <tb> <SEP> (48:0 <SEP> 3.3 <SEP> 15.3) <tb> <SEP> 3 <SEP> 1 <SEP> 95-97 <SEP> 44.6 <SEP> 2.8 <SEP> 13.3 <tb> <SEP> (44.3 <SEP> 2.8 <tb> <SEP> 12.9) <tb> PREPARATION 4 Preparation of 2-(4-chlorophenyl)-1-(lH-1,2,4-triazol-1-yl)-3,3,3- trifluoropropan-2-o1 EMI19.1 2-Trifluoro-4'-chloroacetophenone (0.8 g, 3.84 m.mole) trimethylsulphoxonium iodide (1.02 g, 4.6 m.mole) and cetyltrimethylammonium bromide (0.1 g, 0.27 m.mole) were stirred in a mixture of 1,1,1-trichloroethane (40 ml) and 18Z sodium hydroxide solution (20 ml) at 750 for 2 hours. The mixture was then allowed to cool, the organic layer was separated, evaporated, and the residue was stirred in dimethylformamide (50 ml) with 1,2,4-triazole (1 g, 14.5 m.mole) and anhydrous potassium carbonate (2 g, 14.5 m.mole) at 90 for 4 hours. The mixture was then allowed to cool, ethyl acetate (100 ml) and water (50 ml) were added and the aqueous layer was separated. The organic layer was washed a further 6 times with water (200 ml in total), dried over magnesium sulphate, and evaporated to give a gum (104 mg) which was chromatographed on silica (230-400 mesh), eluting with ethyl acetate to give as a colourless solid the title compound, 84 mg, (8X), One recrystallisation from dichloromethane/hexane gave colourless crystals, 64 mg, m.p. 117-1184. Analysis Z:- Found: C,45.4; H,3.1; N,14.8. Required for C11H9ClF3N30 : C,45.2; H,3.1; N,14.4. Preparation 5 Preparation of 2-(2,4-difluorophenyl)-3,3,4,4,5,5-heptafluoro1-(1H-1,2,4-triazol-1-yl)-pentan-2-ol EMI20.1 To a solution of heptafluoropropyl iodide (5 g, 0.017 M) in ether (20 ml) cooled to -78 was added phenylmagnesium bromide (5.6 ml. of a 3 molar solution in ether, 0.017 M) dropwise at such a rate that the temperature of the reaction mixture did not exceed -50". When all the phenylmagnesium bromide had been added, the mixture was stirred at -50 for F hour and then cooled again to -78 . A solution of 2-chloro-2',4'-difluoroacetophenone (3.6 g, 0.019 M) in ether (20 ml) was added dropwise at such a rate that the temperature of the reaction mixture did not exceed -50 and, when the addition was complete, the reaction mixture was allowed to warm to -20" and was stirred at this temperature for 2 hours. A solution of glacial acetic acid (3 ml) in ether (5 ml) was then added, followed by water (15 ml) and the mixture was allowed to warm to about 5 . The aqueous phase was separated and extracted with ether (2 x 50 ml) and the. combined ether extracts were dried (MgSO4) and evaporated to give a pale yellow oil (6.7 g). This oil was added to a mixture of 1,2,4-triazole (5.87 g, 0.085 M) and anhydrous potassium carbonate (17.5 g, 0.127 M) in dimethylformamide (60 ml) and this mixture was stirred at a temperature of 800 for 3 hours. The reaction mixture was then cooled, the dimethylformamide was evaporated and the residue was partitioned between water (200 ml) and ethyl acetate (150 ml). The aqueous layer was separated and extracted with ethyl acetate (3 x 150 ml). The combined ethyl acetate extracts were washed successively with aqueous sodium bisulphite and water, dried (MgS04), evaporated and the residue was flash chromatographed on silica (230-400 mesh), eluting with a mixture of hexane: isopropylalcohol:0.88 ammonium hydroxide, 80:20:1.5 by volume, to yield, after one recrystallisatilon from hexane:dichloromethane. the title compound, 1.51 g (23%), m.p. 128-129 . Analysis Z:- Found: C,39.8; H,2.0; N,10.6. Required for C13H8FgN30: C,39.7; H,2.1; N,10.7. Using the test method described previously in the text, the following PD5Û values (mg./kg.) were obtained in mice infected with Candida albicans: Compound PD50 (mg./kg.) Product of Example 1 0.15 2 0.6 3 0.6 4 < 1.0 5 < 1.0.

Claims: CLAIMS EMI23.1 1. A compound of the formula: EMI23.2 where R is a phenyl group optionally substituted by l to 3 substituents each independently selected from F, Cl, Br, I, CF3, C1-C4 alkyl and C1-C4 alkoxy, or R is a 5-chloropyrid-2-yl group; X is F, Cl or Br; and n is zero or an integer of from 1 to 5; or a pharmaceutically or agriculturally acceptable salt thereof. 2. A compound as claimed in claim 1, wherein R is 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-iodophenyl, 4-trifluoromethylphenyl, 2-chlorophenyls 2-fluorophenyl, 2,4-dichlorophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 2-fluoro-4-chlorophenyl, 2,4,6-trifluorophenyl or 4-bromo-2,5-difluorophenyl. 3. A compound as claimed in claim 2, wherein R is 2, 4-difluorophenyl, 4-chlorophenyl or 4-fluorophenyl. 4. A compound as claimed in any one of the preceding claims, wherein X is Cl. 5. A compound as claimed in any one of the preceding claims, wherein n is 0, 1 or 2. 6. A compound as claimed in claim 5, wherein n is O. 7. A pharmaceutical composition comprising a compound of the formula (I) as claimed in any one of the preceding claims, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable diluent or carrier. 8. A compound of the formula (I) as claimed in any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, for use in medicine, in particular for use in treating a fungal infection in a human being. 9. A fungicidal composition for use in agriculture, comprising a compound of the formula (I) as claimed in any one of claims l to 6, or- an agriculturally acceptable diluent or carrier. 10. A method of treating a plant or seed having a fungal infection, which comprises contacting said plant or seed, or- the locus of said plant, with an antifungally effective amount of a compound as claimed in any one of claims I to 6 or agriculturally acceptable salt thereof, or with a composition as claimed in claim 9. CLAIMS FOR THE CONTRACTING STATE AT 1. Process for preparing a compound of the formula: EMI25.1 or a pharmaceutically or agriculturaily acceptable acid addition salt thereof, wherein R is phenyl optionally substituted by l to 3 substituents each independently selected from F, Cl, Br, I, CF3, C1-C4 alkyl and Cl-C4 alkoxy, or R is a 5-chloropyrid-2-yl group; X is F, C1 or Br; and n is zero or an integer of from I to 5; characterised by halogenating a compound of the formula EMI25.2 where R and n are as defined above, so as to produce a product of the formula (I) in which X is F, Cl or Br; followed by, optionally, conversion of the product into a pharmaceutically or agriculturally acceptable acid addition salt by reaction with a suitable acid. 2. A process as claimed in claim 1, characterised in that R is 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-iodophenyl, 4-trifluoromethylphenyl, 2-chlorophenyl, 2-fluorophenyl, 2,4-dichlorophenyl, 2 ,4-difluorophenyl, 2,5-difluorophenyl, 2-fluoro-4-chlorophenyl, 2,4,6-trifluorophenyl or 4-bromo-2,5-difluorophenyl. 3. A process as claimed in claim 2, characterised in that R is 2,4-difluorophenyl, 4-chlorophenyl or 4-fluorophenyl 4. A process as claimed in any one of the preceding claims, characterised in that n is 0, 1 or 2. 5. A process as claimed in claim 4, characterised in that n is 0. 6. A process according to any one of the preceding claims, characterised in that the halogenation is carried out with, as appropriate, diethylaminosulphur trifluoride, thionyl chloride or thionyl bromide. 7. A process according to claim 6, characterised in that the halogenation is carried out with thionyl chloride or bromide in the presence of a base. 8. A process according to claim 7, characterised in that the base is imidazole. 9. The use of a compound of the formula (I) as defined in claim l, or an agriculturally acceptable salt thereof, as an agricultural fungicide.

Inventors: RICHARDSON, KENNETH, DR., WHITTLE, PETER JOHN, DR.
Applicants: PFIZER CORPORATION, PFIZER LIMITED
Application year: 1983
Main classification: C07D249
IPC codes: A61P31, C07D249, A61K31, A01N43, C07D521