NZ237088A - Halogenated phenyltriazoles and antifungal compositions. - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number £37088 237088 FA,. -'/ Ds;_!::: rir>~R: CcrtDSU^ioS;. CcHPMOSbcx^ • > • j fc3»v\ws - BQ.»rPH^WS^........... I .................23 dec f993 Pi!bhc2i:o;'? .2-. >. ...

;J.C\ Journs;, I 'o: . • * H$% -J 5 \* V'I'M ilv » " vv ^ t: ^ u .J .U jj \ j WE, E.I. OU FONT DE NEMOURS AND COMPANY, a corporation organized and existing under the laws of the State of Delaware, U.S.A. of 10th & Market Streets, Wilmington, Delaware 19898, United States of America, hereby declare the invention, for which We pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement: (followed by Page la) 237088 IcA BP-6401 Xitla ANILINE DERIVATIVES OF CX-STYRYL CARBINOLS AS ANTIFUNGAL AGENTS 5 Field of the Invention This invention relates to aniline derivatives of a-styryl carbinols, pharmaceutical compositions containing them and methods of using such compounds for treating fungal infections in a mammal.

Prior Art Commonly assigned EP 251086, describes Ct-styryl carbinol antifungal agents useful in medicine and/or agriculture. Also described are certain compounds useful as herbicides and plant growth regulants. The 15 compounds described therein have the formula: CRR1 P E Q A(CH2)„—C C C—N B R< N 0R*f o wherein: E is a bond or -0-, provided that when E is -0-, R and R1 are not halogen; A is C1-C8 perfluoroalkyl, NMe2/ OH, naphthyl (optionally substituted by 1-3 of halogen and N X CF3), \—-f optionally substituted by 1 or 2 25 methyl groups, phenyl optionally substituted by 1-3 substituents independently selected from: //v halogen, C1-C4 alkyl, C1-C4 !j^ haloalkyl, C1-C4 alkoxy and 3 0 maximally one of the following'^ substituents: C1-C4 haloalkoxy, « (followed by page 2) *1 237088 -S(0)„Ji5, R6, 2-, 3- or 4-pyridyl, imidazol-l-yl, 1, 2, 4-triazol-l-yl N \ and \—/ optionally substituted by 1 or 2 methyl groups, 5 or a heterocycle .selected from imidazol-l-yl, 1/ 2, 4-triazol-l-yl, 2-or 3-thienyl, and 2-, 3- or 4-pyridyl optionally substituted by 1 or 2 of halogen, C1-C4 alkyl, CF3 and S(0)mR5; X is C, NR10 or 0; B is C1-C8 alkyl, naphthyl, biphenylyl, -C(=CH2)-R6, C1-C8 perfluoroalkyl, phenyl optionally substituted by 1-3 substituents independently selected from: halogen, C1-C4 alkyl, C1-C4 haloalkyl or 15 C1-C4 alkoxy, and maximally one of C1-C4 haloalkoxy and -S(0)mR5, benzyl optionally substituted on the phenyl ring with halogen or C1-C4 alkyl or a-substituted by 1 or 2 methyl groups, or a heterocycle selected 20 from 2- or 3-thienyl, and 2-, 3- or 4-pyridyl optionally substituted by 1 or 2 of halogen, Cl-C4 alkyl, CF3 and -S(0)mR5; Q is H, halogen, -SfOJR11, -S-CO-NHR12, CHO, -CO-Me, COOR13, SON, SSR12, or SH or its corresponding 25 disulphide, provided that when Q is not H, then n=0, R, R1 and R4 are independently H or Me, R3=H, and A and B are phenyl optionally substituted by 1-3 of halogen, methyl, CF3, methoxy or -S(0)mR5; / \ N 'X 3 0 n is 0-4, provided that when A is \—/ , NMe2 or OH, then n is not 0; 237088 3 m is 0, 1 or 2; R and R1 independently are H, C1-C4 alkyl, halogen or phenyl, or together form C3-C7 cycloalkyl; R2 is H, allyl, propargyl, C1-C4 alkyl, -CO-R7 5 -CONReR9, -COOR7 or C1-C4 haloalkyl; R3 and R4 are H, F or C1-C4 alkyl; R5 is C1-C4 alkyl; R6 is phenyl optionally substituted by 1-3 of halogen and CF3; R7 is C1-C4 alkyl, phenyl or benzyl; R8 and R9 is H, C1-C4 alkyl, phenyl or benzyl; R10 is H, C1-C4 alkyl or acetyl; R11 is C1-C4 alkyl, C1-C4 haloalkyl, -CH2CN, -CH2SCN, -CH(Me)CN, -CH2COOMe or -CH2COOEt; 1 5 R12 is C1-C4 alkyl, allyl, or phenyl or benzyl both optionally substituted by 1 or 2 of the following halogen, methyl or methoxy; and R13 is H or C1-C4 alkyl.

Fungicides useful in both the medical and veterinary field are described in BE 900063. These compounds have the formula: Specifically claimed are those compounds of the above formula wherein: 1). R1 is BrCH=CH-C(CH3)2 or Cl-CH=CH-C(CH3)2; R2 is 4-C1; and R3 is H. 1 237088 4 2). R1 is BrCH=CH-C(CH3)2; and R2 and R3 are 2,4-di-Cl.

DE 3314548 describes compounds which are useful as antimycotics for treating dermatomycoses and systemic mycoses caused by Candida or Aspergillus. These compounds have the formula: • wherein: R is alkyl, cycloalkyl or Ph, each group optionally substituted; X is -OCH2-, -SCH2-, -(CH2)p- or -CH=CH-; Y is -COYi, its acetal or ketal derivatives, or -C(Yi) « NOY2; Yi is H, alkyl, alkenyl, alkynyl, cycloalkyl, Ph or benzyl, these last 3 groups, being optionally substituted; Y2 is H, alkyl, alkenyl, alkynyl, cycloalkyl or benzyl, these last 2 groups being optionally substituted; Z is halogen, alkyl, alkoxy, alkylthio, haloalkyl, haloalkoxy or haloalkylthio; and m and p are 0, 1 or 2.

Compounds of the following formula, described in DE 3018865, are useful in human and veterinary medicine for the treatment of dermatomycoses and^systemic mycoses due to Trichophyton mentagrophytes: 237088 wherein: R is alkyl, optionally substituted cycloalkyl, or optionally substituted phenyl; X is N or CH; Y is OCH2, -CH2CH2- or CH=CH; Z is halogen, alkyl, cycloalkyl, alkoxy, alkylthio, 10 haloalkyl, haloalkoxy, haloalkylthio, optionally substituted phenyl, optionally substituted phenoxy, optionally substituted phenylalkyl or optionally substituted phenylalkoxy; and m is 0-3.

EP 1297 98 describes fungicides active against phytopathogenic fungi. These fungicides have the formula: R? R3 Az -20 wherein: n is 0-5; R is H, halogen, alkyl, alkoxy, alkylthio, alkylsulphonyl, haloalkyl, NO2, CN, optionally substituted phenyl or optionally substituted 2 5 phenoxy; 237088 6 Rl is alkyl, cycloalkyl, cycloalkylalkyl or an optionally substituted aryl, aralkyl, aryloxy, benzyloxyalkyl, alkenyl or alkynyl group; R2 and R3 are alkyl are taken together are (CH2)nu* 5 m is 2-7; Az is 1, 2, 4-triazol-l-yl, 1, 2, 4-triazol-4-yl, 1-imidazolyl, 1-pyrazolyl or 1-benzimidazolyl; Y is CO or C(R<)OR5; R* is H, C1-C4 alkyl, vinyl or allyl; R5 is H, C1-C3 alkyl or optionally substituted alkenyl, alkynyl or benzyl.

EP 117578 describes orally active antimycotic agents as well as fungicides for agricultural use.

These compounds having the formula: or an acid addition salt thereof wherein: 20 A is CO, CHOH or C(C1-C5 alkyl) (OH); Q is imidazolyl or 1-H or 4H-1,2,4-triazol-l-yl; R1 = H, C1-C5 alkyl, or C1-C8 acyl; R2 and R3 are C1-C5 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, benzyl optionally substituted with 1-3 .25 halogens, pyridyl, furyl, thienyl, or phenyl optionally substituted by 1-3 halogens, C1-C3 alkyl or C1-C3 alkoxy.

Azole derivatives and their acid addition salts are 3 0 described in EP 40345. These compounds are described as being useful as fungicides and as plant regulators, and have the formula: 237088 wherein: R is alkyl or optionally substituted cycloalkyl or phenyl; X is N or CH; Y is OCH2, CH2CH2 or CH=CH; Z is halo, alkyl (optionally substituted by halo), cycloalkyl, alkoxy or alkylthio (both optionally substituted by halo), or optionally substandard phenyl, phenoxy, phenylalkyl or phenylalkoxy; and m is 0-3.

GB 2175301 describes triazole and imidazole compounds useful as plant regulating agents. These triazole and imidazole compounds have the formula: Rl R4 Y N X i l rf « N wherein: R1 is alkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl or optionally substituted aryl, aralkyl or heterocyclyl; R2 is alkyl, alkenyl, alkynyl, alkynylalkenyl, alkenyl alkynyl, cycloalkyl, cycloalkenyl or cycloalkylalkyl, all optionally substituted; 2376 8 R3 and R4 are H (but not both H)/ C1-C4 alkyl, C1-C4 alkoxy, OCF3, CF3 or halo; or R3 and R4 taken together are a C3-C6-membered ring; and Y is CH or N; provided that all hydrocarbyl moieties (including cycloalkyl, cycloalkenyl and cycloalkylalkyl) contain up to 8C unless otherwise stated.

None of the prior art references teaches or suggests the antifungal activity of the aniline derivatives of the a-styryl carbinols that are the subject matter of the present application.

Summary of the Invention There are provided antifungal compounds having the 15 formula: <y.

R1R2N(0)n (I) or pharmaceutically acceptable salts thereof wherein: ■ R1 is H or C1-C4 alkyl; „ 3 1 2 t R2 is H, C1-C4 alkyl, or R -OO, or R R N is O - □ ' R3 is H, C1-C4 alkyl or CH2X; X is CI or Br; Ar is 2,4— F2C6H3, 4-CIC6H4, or 2,4—Cl^CgHs; and n is 0 or 1. i/.y Z r- 8 NOV J993 237088 9 Preferred compounds of this invention are those compounds of formula (I) or their pharmaceutically acceptable salts, wherein: R1 and R2 independently are H or C1-C3 alkyl; and/or 5 n is 0; and/or Ar is 2,4-F2CgH3 or 4-ClCgH4; and/or R1R2N is substituted at the 4-or 5-position; and/or X is 2-C1 or 2-Br. 1 0 More preferred compounds of the present invention are those compounds of formula (I) or their pharmaceutically acceptable salts, wherein: R1 and R2 independently are H or C1-C3 alkyl; and/or n is 0; and/or Ar is 2,4-F2CgH3; and/or R*R2N is substituted at the 4-or 5-position; and/or X is 2-CI.

Specifically preferred compounds of the present 2 0 invention are those more preferred compounds wherein: a) RlR2N is 5 (CH3) 2N. b) R*R2N is 4-H2N.

Also provided are pharmaceutical compositions comprising an antifungal effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

Further provided is a method of treating a fungal infection in a mammal comprising administering to the 3 0 mammal an anti-fungal effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.

Synthesis Compounds of Formula (I) where n=0 can be preparec3~"--^ * 3 5 according to the procedures described in Scheme 1. 237088 SCHEME 1 J1 Ar^^M + X OH (II) R1R*/ on) CHO (coa)2j>Mso CH2C12 Et3N \sfsJ Ar R^N (IV) / \ MCPBA CH2C12 W/Sf nt r1r2n OO % H202 aq. NaOH MeOH J=J Ar R1 R2N (V1II) PH3P+CH3Br 237088 11 The allylic alcohols of Formula (IV) can be prepared by reaction of vinyl organometallic reagents of Formula (II), e.g. vinyl Grignard reagents, with aldehydes of Formula (III) in ethereal solvents, such as 5 tetrahydrofuran (THF) or diethyl ether, at a temperature ranging from about -78° to 60°C, preferably 0° to 40°C, for 0.5 to 24 hours. The vinyl organometallics of Formula (II) are prepared using standard procedures from the corresponding chlorides, bromides or iodides. The 10 aldehydes of Formula (III) are known, or can be prepared using methods known to one skilled in the art.

The compounds of Formula (IV) are converted to the keto-oxiranes of Formula (VII) by either (1) Swern oxidation, (2) basic hydrogen peroxide epoxidation of 15 the resulting enones of Formula (V) in an aqueous alcoholic solvent such as methanol or ethanol at 0°C to room temperature for 1 to 24 hours; or (1) m-chloroperbenzoic acid epoxidation in methylene chloride or benzene at 0°C to room temperature for 10 to 30 2 0 hours, (2) Swern oxidation of the resulting epoxy-alcohols of Formula (VI).

Then, keto-oxiranes of Formula (VII) are olefinated with, for example, Wittig reagents, which provide epoxy-olefins of Formula (VIII). Benzene, toluene, THF or 2 5 diethyl ether can be used as a solvent. n-Butyllithium or potassium t-butoxide can be used as a base and the temperature of this reaction can be ranging from about -20° to 80°C. The reaction time is 0.5-10 hours. 3 0 (VIII) with 1,2,4-triazole in dimethylfuran (DMF) or dimethyl sulfoxide (DMSO) in the presence of potassium carbonate or sodium carbonate at about 5|^ to 100°C for 1 to 24 hours affords compounds of Formula (I).

Finally, reaction of epoxy-olefins of Formula When R1=C1-C4 alkyl, R2=C1-C4 alkyl, O - □ ' 237088 and n is 1, compounds of Formula (I) can be prepared from compounds of Formula (I) where n=0 by oxidation 5 methods known to one skilled in the art.

Pharmaceutically suitable salts of compounds of Formula (I) can be prepared in a number of ways known in the art. The salts include those resulting from treatment with hydrochloric, hydrobromic, sulfuric, 10 phosphoric, methanesulfonic, succinic, fumaric, ascorbic, and glutaric acids.

Preparation of 2-(2. 4-Difluorophenyl>-3-(2-chloro- 1 5 5-dimethvlaminophenvH -1- (1H-1. 2. 4-triazol-l-vll - 3-buten-2-ol (Formula I wherein X=2-C1, R1R2N=5-Me2N, Ar=2,4-F2C6H3, and n=0) Part ft; 2 0 Preparation of Methvl 2-chloro-5-aminobenzoate A solution of 2-chloro-5-aminobenzoic acid (85%, 50 g, 0.247 mol) in methanol (250 mL) containing concentrated H2SO4 (25 mL) was refluxed for 45 minutes. Methanol was removed, the residue was neutralized with 2 5 saturated aqueous potassium carbonate solution and extracted with 10% MeOH/CH2Cl2« The organic layer was washed with brine and dried (Na2S04). Removal of the solvent gave the product (27.8 g, 61%). ^-HNMR (CDCI3) 8: 7.20 (d, 1H), 7.13 (d, 1H), 6.72 (dd, 1H), 3.90 (s, 3H), 30 3.73 (bs, 2H, -NH2) .

Example 3, b 237088 13 Part B; Preparation of Methvl 2-chloro-5-dimethvl-aminobenzoate A mixture of methyl 2-chloro-5-aminobenzoate from 5 Step A (25.2 g, 0.136 mol) and methyl iodide (18.6 mL, 0.298 mol) in DMF (50 mL) containing potassium carbonate (41.4 g, 0.2 98 mol) was heated at 50° for 2 hours. It was then diluted with ether, washed with water. The ether layer was dried (Na2S04). Removal of the solvent 10 afforded the product (18.54 g, 64%). 1HNMR (CDCI3) 8: 7.28 (d, 1H), 7.13 (d, 1H), 6.77 (dd, 1H), 3.97 (s, 3H), 3.00 (s) 6H) .

Part C;.

Preparation of 2-Chloro-5-dimethvlaminobenzvl 15 alcohol To a solution of methyl 2-chloro-5-dimethylaminobenzoate from Step B (18.5 g, 86.8 mmol) in THF (75 mL) at 0°, was added lithium aluminum hydride (3.95 g, 104.2 mmol) in small portions. The reaction 20 was then stirred at room temperature for 30 minutes and quenched with 4 mL of water, 4 mL of 15% NaOH, and 12 mL of water at 0°. The mixture was stirred at room temperature for 30 minutes and dried over sodium sulfate. It was filtered and the solvent was removed to 25 give the product (16.28 g, 100%). 1HNMR (CDCI3) : 8 7.17 (d, 1H), 6.80 (d, 1H), 6.55 (dd, 1H), 4.70 (d, 2H), 2.93 Is, 6H) .

Part P; Preparation of 2-Chloro-5-dimethvlamino-3 0 benzaldphvde A solution of anhydrous DMSO (18.5 mL, 0.26 mol) in methylene chloride (50 mL) was added to a solution of oxalyl chloride (11.4 mL, 0.13 mol) in me^vlene^ chloride (50 mL) at -60°C. The mixture was stirrecTToir^ 3 5 10 minutes and a solution of 2-chloro-5- 237088 14 dimethylaminobenzyl alcohol from Step C (16.2 g, 0.087 mol) in methylene chloride (50 mL) was added. It was stirred for 1 hour before the addition if triethylamine (60 mL, 0.436 mol). After 15 minutes, it was warmed up 5 to room temperature and water (50 mL) was added. The separated methylene chloride layer was washed with brine and dried (Na2S04) . Removal of the solvent gave the product (12.6 g, 7 9%). *HNMR (CDCI3) 5: 10.45 (s, 1H), 7.30 (d, 1H), 7.22 (d, 1H), 6.90 (dd, 1H), 3.00 (s, 6H) . 10 part E; Preparation of 2-(2.4-Difluorophenvl)-3-(2-chloro-5-dimethvlaminophenvl)-l-propene-3-ol (Formula IV wherein X=2-C1, R1R2N=5-Me2N, Ar=2,4-F2C6H3) A solution of l-bromo-l~(2,4-difluorophenyl) 1 5 ethylene in THF (35 mL) was added to magnesium chips (1.64 g, 67,33 mmol) in THF (30 mL) at room temperature. It was stirred for 1 hour and then cooled to 0°C. A solution of 2-chloro-5-dimethylamino-benzaldehyde from Step D (10.3 g, 56.1 mmol) in THF (50 mL) was added. 20 The mixture was stirred at 0°C for 1 hour, room temperature for 30 minutes and then quenched with ice. THF was removed, the residue was diluted with 10% MeOH/CH2Cl2, washed with brine and dried (Na2S04) . The crude product was purified by flash column 2 5 chromatography to give 11.3 g (62%) of the pure product. iHNMR (CDCI3) 8: 7.20 (m, 2H), 6.83 (m, 3H), 6.62 (dd, 1H), 6.00 (s, 1H), 5.63 (s, 1H), 5.43 (s, 1H) , 2.93 (s, 6H) .

Part F: 3 0 Preparation of 2-(2.4-Difluorophenvl)-3-(2-chloro- -dimethvlaminophenvH-l-propene-3-one (Formula V wherein X=2-C1, RlR2N=5-Me2N, Ar=2,4-F2C6H3) By following a similar procedure described in Part D, 12.5 g (100%) of the product was obtained from 11.29 3 5 g of 2-(2, 4-difluorophenyl)-3-(2-chloro-5- U 237088 dimethylaminophenyl)-l-propene-3-ol. The product was directly submitted to the next reaction without purification.

Part G; Preparation of 2- (2.4-Difluorophenvl)-2-(2-chloro- -dimethvlaTninobenzovH oxjrane (Formula VII wherein X=2-C1, R1R2N-5-Me2N, Ar<=2, 4-F2C6H3) To a solution of 2-(2,4-difluorophenyl)-3-(2-chloro-5-dimethylaminophenyl)-l-propene-3-one from Step 10 F (12.5 g, 34.9 mmol) in methanol-water (25 mL-12.5 mL) at 0°C was added sodium hydroxide (1.55 g, 38.9 mmol) followed by 30% hydrogen peroxide (1.2 mL, 38.9 mmol). The mixture was stirred at 0°C for 1 hour. It was extracted with methylene chloride 3 times. The 15 methylene chloride layer was washed with brine and dried (Na2S04). The crude product was purified by flash column chromatography to give 6.75 g (57%) of the pure product. *HNMR (CDCI3) 8: 7.50 (m, 1H), 7.17 (d, 1H) , 6.87 (m, 2H), 6.67 (m, 2H), 3.35 (d, 1H), 3.23 (d, 1H), 2.92 (s, 20 6H) .

Fart; .H; Preparation of 2- (2.4-Difluorophenvl!-2-fl-(2-chloro-5-dimethvlaminophenyl)ethenvlloxirane (Formula VIII wherein X=2-C1, R1R2N=5-Me2N, Ar=2,4-25 F2C6H3) Methyltriphenylphosphonium bromide (8.57 g, 24 mmol) was heated at 75°C under high vacuum for 1 hour. It was then cooled to room temperature and THF (40 mL) was added. To this mixture at 0°C was added n-3 0 butyllithium (1.6 M, 14.99 mL, 24 mmol) and the resulting dark red solution was stirred at 0°C for 20 minutes before adding to a solution of 2-(2,4-difluorophenyl)-2-(2-chloro-5-dimethylaminobenzoyl)-oxirane from Step G (6.75 g, 20 mmol) in THF (40 mL) at 3 5 0°C. The reaction was stirred at room'te'frtperature for 1 J 237088 16 hour and quenched with ice water. THF was removed, the residue was extracted with methylene chloride and the organic layer was washed with brine and dried (Na2SC>4) . The crude product was purified by flash column 5 chromatography to give 2.5 g (37%) of the pure product. iHNMR (CDCI3) 6: 6.93 (m, 1H), 7.15 (d, 1H), 6.80 (m, 2H), 6.50 (m, 2H), 5.40 (sf 1H), 5.27 (s, 1H), 3.03 (s, 2H) f 2.85 (s, 6H).

Pert I;.

Preparation of 2-(2.4-Difluorophenvl)-3-(2-chloro- -dimethylarnnnophenvl)—1—(1H-l.2.4-triazol-l-vl)-3-buten-2-ol (Formula I wherein X=2-C1, R1R2N=5-Me2N, Ar=2,4-F2C5H3, n=0) Treatment of 2-(2,4-difluorophenyl)-2-[1-(2-chloro- -dimethylaminophenyl)ethenyl]oxirane from Step H (2.5 g, 7.45 mmol) in DMF (20 mL) with 1,2, 4-triazole (1.57 g, 22.35 mmol) and potassium carbonate (3.08 g, 22.35 mmol) at 90°C for 4 hours. It was then diluted with 2 0 ether, washed with water. The ether layer was dried (Na2S04). The crude product was purified by flash column chromatography to give 1.1 g (36%) of the pure product, m.p. 147-148°C; iHNMR (CDCI3) 8: 7.93 (s, 1H), 7.73 (s, 1H), 7.53 (q, 1H), 7.23 (d, 1H), 6.83-6.50 (m, 25 3H), 6.35 (d, 1H), 5.45 (s, 1H), 5.22 (s, 1H), 5.13 (d, 1H), 4.90 (s, 1H), 4.4 6 (d, 1H)f 2.83 (s, 6H); HRMS: m/z 404.1221 (M+), calcd. for C20H19CIF2N4O, 404.1215.

By using the procedures described in Example 1, the following compounds (where n is 0) in Table I were 3 0 prepared or can be prepared.

X. 37088 17 TABLELJ. x Ar in. p. (cC) 1 2 3 4 2-C1 2-CI 2-C1 2-C1 2-C1 -Me*2N 5-Ne2N 5-Et*2N 5-n-Pr*2N -Qn 2,4-F2C6H3 4-CIC6H4 2,4-F2C6H3 2,4-F2C6H3 147-148 122-124 128-123 114-115 2# 4-F2C6H3 118-125 6 7 8 9 11 12 13 14 2-CI 2-Br 2-Br 3-C1 3-C1 3-C1 4-C1 4-C1 4-Br -(H2C=CCH2)2N 3-MeNBu*-i 6-Me2N 2-jq.-BU2N -n I—N 6-Et2N 2-Me2N 3-MeNH 3-EtNPr-i * Me is methyl * Et is ethyl * Pr is propyl * Bu is butyl 2,4-F2C6H3 2,4-F2C6H3 2f4-Cl2C6H3 4-CIC6H4 2/4-F2C6H3 2/4-Cl2C€H3 2,4-F2C6H3 4-ClC6H4 2/4-F2C6H3 122-124 237088 18 Example 15 Preparation of 2- (2.4-Difluorophenvl)-3-(2-chloro-4-acetamidophenvl)-1-(1H-1.2.4-triazol-l-yl)-3-buten-2-ol 5 (Formula I wherein X=2-C1, R1R2N=4-MeC(=0)NH, Ar=2,4-F2C6H3/ n=0) Part A; Preparation of Methyl 2-chlorc>-4-aminpfren?pate By following a similar procedure described in 10 Example 1, Part A, 20.8 g (96%) of the product was obtained from 20 g (0.116 mole) of 2-chloro-4-aminobenzoic acid. 1HNMR (CDCI3) 5: 7.77 (d, 1H), 6.67 (d, 1H), 6.50 (dd, 1H), 4.20 (bs, 2H), 3.83 (s, 3H). Part B; Preparation of Methvl 2-chloro-4-acetamidobenzoate Treatment of methyl 2-chloro-4-aminobenzoate from Step A (20 g, 0.108 mol) with acetic anhydride (11.2 mL, 0.119 mole) and triethylamine (16.5 mL, 0.119 mol) in refluxing methylene chloride (75 mL) for 3 hours. It 20 was then washed with 10% aqueous hydrochloric acid, brine, and dried (Na2S04) . Removal of the solvent gave the product (25 g, 100%). *HNMR (CDCI3) 5: 8.42 (bm, 1H), 7.88 (d, 1H), 7.79 (s, 1H), 7.57 (d, 1H), 3.93 (s, 3H), 2.23 (s, 3H).

Part C; Preparation of 2-Chloro-4-acetamidobenzvl alcohol To a refluxing solution of methyl 2-chloro-4-acetamidobenzoate from Step B (24.3 g, 0.107 mol) and sodium borohydride (12.18 g, 0.32 mol) in £-butyl 3 0 alcohol (200 mL) was added methanol (80 mL) slowly over 1 hour. The mixture was continually refluxed for 16 hours and then quenched with water. The solvent was removed, the residue was diluted with water and extracted with chloroform. The chloroform layer was 3 5 dried (Na2SC>4) . Removal of the solvent affpx^ed^S .4 1 L '6AP*!99i f 237088 19 (86%) of the product. -^HNMR (d6-DMSO) 5: 10.07 (s, 1H) , 7.80 (s, 1H), 7.43 (s, 2H), 5.30 (t, 1H), 4.50 (d, 2H) , 2.03 (s, 3H).

Part D: Preparation of 2-Chloro-4-acetamidobenzaldehvde Treatment of 2-chloro-4-acetamidobenzyl alcohol from Step C (9.6 g, 48 mmol) with manganeous (IV) oxide (20.9 g, 240 mmol) in refluxing chloroform (100 mL) for 16 hours. It was then filtered through Celite®. The 10 crude product was purified by flash column chromatography to give 7.5 g (79%) of the product.

*HNMR (CDCI3) 8: 10.37 (s, 1H), 7.92 (s, 1H), 7.90 (d, 1H), 7.77 (bs, 1H), 7.40 (d, 1H)f 2.23 (s, 1H).

Part E; Preparation of 2-(2.4-Difluorophenvl)-3-(2-chloro- 4-acetamidophenvl)-l-propene-3-ol (Formula IV wherein X=2-C1, RlR2N=4-MeC(=0)NH, Ar=2,4-F2C6H3) By following a similar procedure described in 2 0 Example 1, Part E, 8.8 g (69%) of the product was obtained from 18.3 g (83.5 mmol) of 1-bromo-l-(2,4-difluorophenyl)ethylene and 7.5 g (38 mmol) of 2-chloro-4-acetamidobenzaldehyde from Step D. ^•HNMR (CDCI3) 8: 8.00-6.73 (m, 7H), 6.02 (d, 1H)r 5.60 (s, 1H), 5.38 (s, 25 1H), 2.17 (s, 3H) .

Part F: Preparation of 2-(2.4-Difluorophenyl) -7-fl-(7-chloro-4-acetamidophenvl)methvl-1-oiloxirane (Formula VI wherein X=2-C1, R1R2N=4-MeC(=0)NH, Ar=2,4- 3 0 F2C6H3) A mixture of 2-(2,4-difluorophenyl) -3-(2-chloro-4-acetamidophenyl)-l-propene-3-ol from Step E (4.6 g, 13.63 mmol) and MCPBA (3.7 g, 17.72 mmol^ _in methylene chloride (75 mL) was stirred at room temperature for 16 3 5 hours. It was then washed with saturated a«fffSS!S:BsJ5odii 237088 bicarbonate solution, brine, and dried (Na2SC>4) . The crude product was purified by flash column chromatography to give 3.11 g (65%) of the product. 1HNMR (CDCI3) 8: 7.93-6.67 (m, 7H), 5.67 (d, 1H), 3.24 (d, 1H), 2.90 <d, 1H>, 2.17 (s, 3H).

Part G; Preparation of 2-12. 4-Difluorophenvl)-2-(2-chloro- 4-acetamidobenzov3)oxirane (Formula VII wherein X=2~C1, R1R2N=4-MeC(=0)NH, Ar=2,4-10 F2C6H3) 2-(2, 4-Difluorophenyl)-2-[1-(2-chloro-4-acetamidophenyl)methyl-l-ol]oxirane from Step F (15.9 g, 44.98 mmol) was converted to the product (8.5 g, 54%) by a similar procedure described in Example 1, Part D. 15 iHNMR (CDC13) 8: 7.70-6.75 (m, 7H), 3.25 (g, 2H), 2.18 (s, 3H).

Part H: Preparation of 2-12.4-Difluorophenvl)-2-fl-(2-chloro-4-acetamidophenvl)ethenvl1oxirane 20 (Formula VIII wherein X=2-C1, R1R2N=4-MeC(=0)NH, Ar=2,4-F2C6H3) By following a similar procedure described in Example 1, Part H, 4.4 g (52%) of the product was obtained from 8.5 g (24.18 mmol) of 2-(2, 4- 2 5 difluorophenyl) -2- (2-chloro-4-acetamidobenzoyl) oxirane from Step G and 19 g (53.2 mmol) of methyltriphenylphosphonium bromide. ^-HNMR (CDCI3) 8: 7.65-6.70 (m, 7H), 5.46 (s, 1H), 5.28 (s, 1H), 3.04 (ABq, 2H), 2.19 (s, 3H).

Part I: Preparation of 2-(2.4-Difluorophenvl)-3-<2- chloro-4-acetaroidophenvl)-1-<1H-1.2.4-triazol-l-vl)-3-buten-2- el (Formula I, X=2~C1, R1R2N=4-MeC (=0)NH, Ar<=2, 4-F2CgH3, 3 5 n=0) ^ " ....... f v £ : ) 21 2-(2,4-Difluorophenyl)-2-[1-(2-chloro-4- acetamidophenyl)ethenyl]oxirane from Step H (2.7 g, 7.72 mmol) was converted to 0.66 g (20%) of the product by a similar procedure described in Example 1, Part I. 1HNMR 5 (CDCI3) 5: 7.93 (s, 1H), 7.75 (s, 1H), 7.72 (s, 1H), 7.50 (m, 1H), 7.25 (m, 1H), 7.07 (d, 1H), 6.73 (m, 2H), 5.48 <s, 1H), 5.20 (s, 1H), 5.13 (d, 1H), 5.05 (s, 1H), 4.45 (d, 1H)t 2.11 (s, 3H); HRMS: m/z 418.1001 (M+), calcd. for C20H17F2CIN4O2, 418.1008.

(Formula I wherein X=2-C1, R1R2N=4-NH2, Ar=2,4-F2C6H3, n=0) A solution of 2-(2,4-difluorophenyl)-3-(2-chloro-4-acetamidophenyl)-1-(1H-1,2,4-triazol-l-yl)-3-buten-2-ol from Example 15 (450 mg, 1.07 mmol) in ethanol-water (4 2 0 mL-2 mL) containing potassium hydroxide (300 mg, 5.i5 mmol) was refluxed for 16 hours. The solvent was removed in vacuo, the residue was diluted with ether, washed with brine and dried (Na2S04). Purification by flash column chromatography gave 307 mg (76%) of the 2 5 product. 2HNMR (CDCI3) 5: 7.93 (s, 1H) f 7.75 (s, 1H), 7.50 (m, 1H), 6.87 (d, 1H), 6.70 (m, 3H), 6.47 (dd, 1H), 5.45 (s, 1H), 5.20 (s, 1H), 5.13 (d, 1H), 4.87 (s, 1H), 4.45 (d, 1H), 3.75 (bs, 2H); HRMS: m/z 376.0921 (M+), calcd. for C16H15F2CIN4O, 376.0902. ^ Bxemple 1$ Preparation of 2-(2.4-Difluorophenvl)-3-(2-chloro-4-aminophenvl)-1-(1H-1.2.4—triazol-l-vl)—3-buten-2-ol 237088 22 Example 17 Preparation of 2-(2.4-Difluorophenvl-3-f2-chloro-4-dimethvlaminophenvl) -1-(1H-1> 2,-3-bvten-2-ol 5 (Formula I wherein X=2-C1, R1R2N=4-Me2N, Ar=2,4-F2C6H3, n=0) A mixture of 2-(2,4-difluorophenyl)-3-(2-chloro-4-aminophenyl)-1-(1H-1,2,4-triazol-l-yl)-3-buten—2-ol from Example 16 (1 g, 2.65 mmol), methyl iodide (0.366 mL, 10 5.83 mmol) and potassium carbonate (805 mg, 5.83 mmol) was heated at 50°C for 5 hours. It was then diluted with ether and washed with water. The aqueous layer was extracted with ether and the combined ether layer was dried (Na2SC>4) . Purification by flash column 15 chromatography afforded 302 mg (28%) of the product. iHNMR (CDCI3) 8: 7.94 (s, 1H), 7.75 (s, 1H), 7.54 (m, 1H), 6.96 (d, 1H), 6.70 (m, 3H), 6.53 (dd, 1H), 5.45 (s, 1H), 5.23 (s, 1H), 5.13 (d, 1H), 4.84 (s, 1H), 4.46 (d, 1H), 2.95 (s, 6H); HRMS: m/z 404.1218 (M+), calcd. for 20 C20H19F2CIN4O, 404.1215.

By using the procedures described in Examples 15-17, the following compounds in Table II were prepared or can be prepared. 23 TABLE II 237088 \/=J Ar r1r2n Ex.

X Ar HBMS fm/z) 2-C1 4-MeC(~0)NH 2,4-F2C6H3 418.1001(M+) 16 2-C1 4-NH2 2,4-F2C6H3 376.0921(M+) 17 2-C1 4-Me2N 2,4-F2C6H3 404.1218(M+) 18 2-C1 3-MeC<~0)NH 2/4-Cl2C6H3 19 2-C1 3-NH2 4-CIC6H4 2-C1 -MeC (=0) NH 2r 4-F2C6H3 418.1017(M+) 21 2-C1 -NH2 2f4-F2C6H3 376.0902 (M+) 22 2-C1 4-MeNH 2,4-F2C6H3 23 2-C1 ■ 4-i-Pr2N 2,4-F2C6H3 24 2-Br 4-HC(=0)NMe 4-CIC6H4 2-Br 6-NH2 2,4-F2C6H3 26 3-Br 4-EtC(=0)NPr-a 2,4-CI2C6H3 27 3-C1 4-Et2N 2,4-F2C6H3 28 3-C1 -jL-BuC (=0) NH 2r4-Cl2C6H3 29 4-Cl 2-NH2 2/4-F2CgH3 4-Cl 3-MeC(=0)NH 2,4-F2C6H3 31 4-Br 3-NH2 2,4-F2C6H3 32 4-Br 2-ClCH2C(=0)NEt 2/4-F2C6H3 33 4-Br 3-BrCH2C(=0)NH 2r4-Cl2C6H3^ I V* 237088 24 Examp] g> 34 Preparation of 2- (2. 4-Di f luorophenvl) -3-f2-chloro-5-dimethvlamjnor>xirtP>phenvl)-l-(1H-1.2.4-triazol-l-vl)-3-buten-2-ol 5 (Formula I wherein X«=2-C1, R1R2N=5-Me2N/ Ar*^,4-F2C6H3, n=l) A mixture of 2-(2,4-difluorophenyl)-3-(2-chloro-5-dimethylaminophenyl)-1-(1H-1,2,4-triazol-l-yl)-3-buten-2-ol from Example 1 (270 mg, 0.67 mmol) and MCPBA (170 10 mg, 0.8 mmol) in methylene chloride (5 mL) was stirred at room temperature for 30 minutes. The solvent was removed in vacuo and the residue was chromatographed to give 284 mg (100%) of the product. 1HNMR (CDCI3) 8: 8.00 (m, 2H), 7.77 (s, 1H), 7.72 (s, 1H), 7.50 (m, 2H), 6.73 15 <m, 2H), 5.55 (s, 1H) f 5.27 (s, 1H), 5.23 (d, 1H), 4.47 (d, 1H), 3.53 (s, 6H); MS: m/z 421 (M+ +1).

By using the procedure described in Example 34, the following compounds in Table III were prepared or can be prepared. 237088 TABLE III 41 3-C1 42 3-CI •O >-□ 2,4-F2C6H3 2, 4-Cl2C6H3 R1R2N(0)n (D f I2L. Z n Lx.

MS (m/z) 34 2-Cl -Me2N l 2,4-F2C6H3 421 (M++1) 2-Cl -Me2N l 4-ClC6H4 419 (M++1) 36 2-Cl 4-Me2N l 2,4-F2C6H3 37 2-Cl 3-Et2N l 2,4-Cl2C6H3 38 2-Br 3-MeNEt l 2/4-F2C6H3 39 2-Br 6-MeNPr-a l 2# 4-F2C6H3 40 3-C1 2-MeNBu-i l 2,4-Cl2C6H3 43 44 45 3-C1 4-Cl 4-Br 6-Me2N 2-MeNPr-i 3-MeNBu-n 1 2, 4-F2C6H3 1 2,4-F2C6H3 1 2,4-F2CgH3 Example 46 Preparation of Methanesulfonate salt 2-(2 . 4-rUf luorophenyl) -3- (2-chloro-5-ri i methyl ami nophenyl) -1-^ UH-1> 2> 4-t.riazol-l-yl) -3-buten-2-pl' To a solution of 2-(2,4-difluorophenyl)-3-(2-chloro-5-dimethylaminophenyi)-1-(1H-1,2,4-triazol-l-yl) 3-buten-2-ol from Example 1 (520 mg, 1.288 mmol) in THF 237088 26 (3 mL) was added methanesulfonic acid (0.17 mL, 2.576 mmol). The mixture was stirred at room temperature for 15 minutes. Removal of the solvent in vacuo gave 690 mg (90%) of the product. ^HNMR (d6~DMSO) 8: 9.08 (s, 1H), 8.23 (s, 1H), 7.50-6.89 (m, 6H & H20, -SO3H), 5.63 (s, 1H), 5.20 (s, 1H), 5.17 (d, 1H), 4.80 (d, 1H), 2.97 (s, 6H) .

By using a similar procedure described in Example 4 6, the following compounds in Table IV were prepared or can be prepared.

TABLE IV r1r2n EX . hi.

Salt 46a 2 -CI -Me2N 2,4-F2C6H3 2CH3SO3H 47 2 -CI 4-Me2N 2,4-F2C6H3 2CH3SO3H 48 2 -CI -Me2N 4-CIC6H4 2HBr 49 2- -CI 4-Et2N 2,4-Cl2C6H3 2HC1 50 2- -CI 3-MeNEt 2/4-F2C6H3 2H2S04 51 2- -Br 6-MeNPr-n 2,4-F2C6H3 2H3PO4 52 3- -CI 2-Me2N 2,4-F2C6H3 2CH3SO3H 53 3- -CI 4-Me2N 2,4-F2C6H3 2CH3SO3H 54 3- -CI -i-Pr2N 2,4-F2C6H3 2HBr 55 3- -Br 6-Me2N 2,4-Cl2C6H3 2HC1 56 4- -CI 2-Me2N 2, 4-F2C6H3 2CH3SO3H 57 4- -CI 3-MeNBu-a 2,4-F2C6H3 2CH3SO3H 58 4- -CI 3-i-Bu2N 2,4-F2C6H3 2H3PO4 /$ f/'i *T£^>\ « Vi 16 Apr, >? I v «• V" / // e u d 27 937088 o Footnotes for Table IV a iHNMR (d6-DMS0) 8: 9.08 (s, 1H), 8.23 (s, 1H), 7.50-6.89 (m, 6H & H2O, -SO3H), 5.63 (s, 1H), 5.20 (s, 1H), 5 5.17 (d, 1H), 4.80 (d, 1H)r 2.97 (s, 6H).

Pharmaceutical Utility In vitro activity (Table V) is expressed in terms of the minimal inhibitory concentration (MIC) of the 10 test compound which inhibits the growth of yeasts and fungi.

The target organisms, Candida albicans ATCC 11651 and Aspergillus fumigatus ATCC 28214 are standardized, [V. Bezjak, J. Clinical Micro.. 21 509-512 (1984)] to a 1 5 concentration of 107 organisrns/mL and maintained at -70 until use. Test compounds are solubilized in dimethyl sulfoxide (DMSO) and diluted in Eagle's Minimum Essential Medium (EMEM) broth to achieve a final concentration of 200 |i.g/ml. Stock solutions of standard 2 0 antifungal agents are stored at -70° and diluted in EMEM as required.

The in vitro assay utilizes a microtiter broth dilution technique [L. Polonelli and G. Morace, Mvcopathologia. 86, 21-28 (1984)] and C. Hughes, et al. 25 Antimicrob. Aa. andChemo.. 560-562 (1984)]. Test compounds are serially diluted in EMEM to give graded concentrations ranging from 100 to 0.4 Jig/mL. The appropriate wells are inoculated with the required organism (£j. albicans at 1 x 104 organisms/mL and 3 0 2L. fumigatus at 5 x 105 organisms/mL) and the assay incubated at 30° for 24 hours. The extent of fungal growth is determined at an optical density equal to 540 nm using a scanning spectrophotometer (Flow® MCC) and MIC values, representing the minimal concentration of a 3 5 compound which inhibited growth, are determined, [ ) V*. ^ 237088 28 Grenta, et al. Antimicrob. Aq. and Chemo.. 22, 151-153 (1982)].

The in vivo activity of test compounds is based on the percent (%) survival of infected animals receiving 5 test or standard agent compared to that in an infected untreated group (Table VI). The in vivo assays are chronic systemic infections lethal to mice within 7 days post infection, [J. Barnes, et al. Lab investigation. £2. 460-467 (1963), and T. Rogers and E. Balish, Infection 10 and Immunity, 14 33-38 (1976)].

Candida albicans ATCC 11651, from a frozen stock culture (109 organisms/mL) maintained at -70°, is diluted in saline to 1 x 107 organisms/mL and 0.2 mL inoculated intravenously (caudal vein) into 20.0 gm CF-1 15 female mice (Charles River).

Test compounds are routinely solubilized in 0.25% (w/v) methylcellulose (Methocel®) but for those compounds difficult to solubilize 10% (w/v) Emulophor® (EL620 GAF Corp.) is used. The standard antifungal 20 agents, amphotericin B (Fungizone®) in water and ketoconazole (Nizoral®) in Methocel®, are administered at 1.0 mg/kg/day and 150 mg/kg/day, respectively.

In a primary assay, mice (10 per group) are infected with albicans,, and receive test compounds at 2 5 50 or 150 mg/kg/day via the subcutaneous route. Animals are dosed with the test compound at 1 and 6 hour postinfection and then once daily for the next three days. Survival of mice in each group is recorded for 21 days. Compounds which protect >70% of the infected 3 0 animals for 14 days at a dose 150 mg/kg/day or less are viewed as active. ~ r~ 29 TABLE V la Vitro Antifungal Results MIC values (jig/mL) Example 1 2 3' 4 6 16 17 21 34 46 Amphotericin B* Nystatin* -Fluorocytosine* Ketoconazole* Miconazole* C. albicans (CAND-1) <0.4 <0.4 <0.03 0.2 <0.4 0.05 0.2 <0.03 <0.03 0.4 0.1 0.8 <0.4 <0.03 0.33+0.2 1.3 ±0 0.14+0.1 <0.1 <0.1 A. fumioatus (ASFU-4) 6.3 50 >100 >100 >100 >100 12.5 1.6 0.4 100 1.6 >100 >100 6.3 1. 4±0.5 3.0+1.0 5.7+4.0 11.0+5.0 1.3+0 O c 137088 *MIC values of the standard drugs are the mean of five determinations + Standard deviation 3 0 The data indicate that compounds of this invention have in vitro activity comparable to standard antifungal agents. 237088 TABLE VI In Vivo Antifungal Results Murine Candidiasis Model % Survival Ex.

Days HSL. 1 11 21 1 100 100 90 2 100 100 90 3 NT NT NT 4 90 80 80 100 50 50 6 80 60 60 100 70 50 16 100 90 80 17 100 100 90 80 40 21. 70 50 34 100 70 60 34 100 70 60 70 46 NT NT NT ricin B 100 100 100 izole 100 80 50 NT= not tested Compounds which protect >70% of the infected animals for 14 days at a dose of <150 mg/kg/day are active. Therefore the data indicate the compounds of 3 0 this invention demonstrate in vivo activity comparable to standard antifungal agents.

Dosaoe Forms The antifungal agents of this invention 3 5 administered by any means that effects conta 237088 31 active ingredient with the agent's site of action in the body. The compounds can be administered by any conventional means available for use in conjunction with pharmaceuticals, either as individual therapeutic agents 5 or in a combination of therapeutic agents. They can be administered alone, but are generally administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice. 1 0 The dosage administered will, of course, vary depending on the use and known factors such as the pharmacodynamic characteristics of the particular agent, and its mode and route of administration: age, health, and weight of the recipient; nature and extent of 15 symptoms, kind of concurrent treatment, frequency of treatment, and the effect desired.

Dosage forms (compositions) suitable for administration contain from about 200 milligram to about 2000 milligrams of active ingredient per unit. In these 20 pharmaceutical compositions, the active ingredient will ordinarily be present in an amount of about 0.5-95% by weight based on the total weight of the composition. For use in the treatment of said diseases, a daily dose of active ingredient can be about 10 to 50 milligrams per 2 5 kilogram of body weight.

The composition of the invention may be in a conventional pharmaceutical form suitable for oral administration, for example a tablet, a capsule, an emulsion or an aqueous or oily solution or suspension, 3 0 or suitable for topical application, for example a cream, ointment or gel. It can also be administered parenterally in sterile liquid dosage forms.

Gelatin capsules contain the active ingredient and powdered carriers, such as lactose, starch, cellulose 3 5 derivatives, magnesium stearate, stearic acid and V. 237088 32 like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed 5 tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract. ointments, creams and gels can, for example, contain the usual diluents, e.g. animal and vegetable fats, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide or mixtures of these 15 substances.

In general, water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions. 20 Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents and if necessary, buffer substances. Antioxidizing agents such as sodium bisulfite, sodium sulfite or ascorbic acid, either alone 2 5 or combined, are suitable stabilizing agents.

All the pharmaceutical compositions according to the invention can also contain coloring and flavoring to increase patient acceptance. 3 0 EDTA. In addition, parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl or propyl-paraben, and chlorobutanol.

The pharmaceutical compositions which are Also used are citric acid and its salts and sodium Suitable pharmaceutical carriers are'gwiescribed in Remington's Pharmaceutical Sciences. (1985) 17th * L- 1/ 237088 33 Edition, A. Osol, a standard reference text in this field.

Useful pharmaceutical dosage forms for administration of the compounds of this invention can be 5 illustrated as follows: Capsules A large number of unit capsules are prepared by filling standard two-piece hard gelatin capsules each 10 with 100 milligrams of powdered active ingredient, 150 milligrams of lactose, 50 milligrams of cellulose, and 6 milligrams magnesium stearate.

Soft Gelatin Capsules 15 A mixture of active ingredient in a digestable oil such as soybean oil, cottonseed oil or olive oil is prepared and injected by means of a positive displacement pump into gelatin to form soft gelatin capsules containing 100 milligrams of the active 20 ingredient. The capsules are washed and dried.

Tablets A large number of tablets are prepared by conventional procedures so that the dosage unit is 100 milligrams of active ingredient, 0.2 milligrams of 2 5 colloidal silicon dioxide, 5 milligrams of magnesium stearate, 275 milligrams of microcrystalline cellulose, 11 milligrams of starch and 98.8 milligrams of lactose. Appropriate coatings may be applied to increase palatability or delay absorption. 3 0 Injectable A parenteral composition suitable for administration by injection is prepared by stirring 1.5% by weight of active ingredient in 10% by volume propylene glycol. The solution is made to volume with 3 5 water for injection and sterilized'.

Lj*

Claims (47)

V 237088 34 Suspension An aqueous suspension is prepared for oral administration so that each 5 milliliters contain 100 administration so that each 5 milliliters contain 100 5 milligrams of finely divided active ingredient, 100 milligrams of sodium carboxymethyl cellulose, 5 milligrams of sodium benzoate, 1.0 grams of sorbitol solution, U.S.P., and 0.025 milliliters of vanillin. Cream 10 A cream for topical application is prepared by incorporating 100 milligrams of the finely pulverized active ingredient in 5 grams of a cream base which comprises 40% white petrolatum, 3% microcrystalline wax, 10% lanolin, 5% Span®20, 0.3% Tween®20 and 41.7% water. 10 u WHATf/WE CLAIM IS; . . . . . i 35 ■WHAT IS CLAIMED IC.—

1. A compound of the formula: /AX OH N V=/ - w R1 R2N(0)n (I) 5 or pharmaceutically acceptable salts thereof wherein: R1 is H or C1-C4 alkyl; R2 is H, C1-C4 alkyl,or R3-G=0, or R1R2N is O - □1 R3 is H, C1-C4 alkyl or CH2X; X is CI or Br; Ar is 2,4-F2C6H3, 4-C1C6H4, or 2,4-Cl2C6H3; and n is 0 or 1. 15

2. A compound of claim 1 wherein R1 and R2 independently are H or C1-C3 alkyl.

3. A compound of claim 1 wherein n is 0.

4. A compound of claim 1 wherein Ar is 2,4-F2CgH3 or 4-CIC6H4. 20

5. A compound of claim 1 wherein R1R2N is substituted at the 4- or 5- position.

6. A compound of claim 1 wherein X is 2-Cl or 2- Br.

7. A compound of claim 1 wherein: 2 5 R1 and R2 independently are H or C1-C3 alkyl; n is 0; Ar is 2/4-F2C6H3 or 4-CIC6H4; R1R2N is substituted at the 4- or 5- p<?sition; and 3 0 X is 2-Cl or 2-Br. 237088 36

8. A compound of claim 4 wherein Ar is 2,4- f2c6h3.

9. A compound of claim 7 wherein Ar is 2,4- f2c6h3. 5

10. A compound of claim 6 wherein X is 2-Cl.

11. A compound of claim 7 wherein X is 2-Cl.

12. A compound of claim 7 wherein: R1 and R2 independently are H or C1-C3 alkyl; n is 0; 10 Ar is 2,4-F2CgH3; R^-RZN is substituted at the 4- or 5- position; and X is 2-Cl.

13. The compound of claim 12 wherein RXRZN is 15 5-(CH3)2N.

14. The compound of claim 12 wherein RXR2N is 4- h2n.

15. The compound of claim 13 wherein the pharmaceutically acceptable salt thereof is the 20 methanesulfonate salt.

16. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an anti-fung.ally effective amount of a compound of claim 1.

17. A pharmaceutical composition comprising a 25 pharmaceutically acceptable carrier and an anti-fungally effective amount of a compound of claim 2.

18. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an anti-fungally effective amount of a compound of claim 3. 3 0

19. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an anti-fungally effective amount of a compound of claim 4.

20. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an anti-fungally 3 5 effective amount of a compound of claim 5. •;>, • u » L / V 12 " AUG |p9j 237 AP o 37

21. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an anti-fungally effective amount of a compound of claim 6.

22. A pharmaceutical composition comprising a 5 pharmaceutically acceptable carrier and an anti-fungally effective amount of a compound of claim 7.

23. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an anti-fungally effective amount of a compound of claim 8. 10

24. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an anti-fungally effective amount of a compound of claim 9.

25. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an anti-fungally 15 effective amount of a compound of claim 10.

26. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an anti-fungally effective amount of a compound of claim 11.

27. A pharmaceutical composition comprising a 2 0 pharmaceutically acceptable carrier and an anti-fungally effective amount of a compound of claim 12.

28. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an anti-fungally effective amount of the compound of claim 13. 25

29. A pharmaceutical composition comprising a pharmaceutically acceptable' carrier and an anti-fungally effective amount of the compound of.claim 14.

30. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an anti-fungally 3 0 effective amount of the compound of claim 15.

31. A method of treating a fungal infection in a non^-human mammal comprising administering to the mammal an anti- fungally effective amount of a compound of claim 1. ®a '•v v\ ol - 8 NOV 1993 / G. U 237n«»

32. A method of - treating a fungal infection in a nonr-human mammal comprising administering to the mammal an anti- fungally effective amount of a compound of claim 2.

33. A method of treating a fungal infection in a non-human 5 mammal comprising administering to the mammal an anti- fungally effective amount of a compound of claim 3.

34. A method of treating a fungal infection in anon-human mammal comprising administering to the mammal an anti- fungally effective amount of a compound of claim 4. 1 0

35. A method of treating a fungal infection in anon-human. mammal comprising administering to the mammal an anti- fungally effective amount of a compound of claim 5.

36. A method of treating a fungal infection in anon-human mammal comprising administering to the mammal an anti- 15 fungally effective amount of a compound of claim 6.

37. A method of treating a fungal infection in anon-human mammal comprising administering to the mammal an anti- fungally effective amount of a compound of claim 7.

38. A method of treating a fungal infection in anon-human, 2 0 mammal comprising administering to the mammal an anti- fungally effective amount of a compound of claim 8.

39. A method of treating a fungal infection in anon-human mammal comprising administering to the mammal an anti- fungally effective amount of a compound of claim 9. 25

40. A method of treating a fungal infection in anon*-human mammal comprising administering to the mammal an anti- fungally effective amount of a compound of claim 10.

41. A method of treating a fungal infection in anon-human mammal comprising administering to the mammal an anti- 3 0 fungally effective amount of a compound of claim 11.

42. A method of treating a fungal infection in a non-human mammal comprising administering to the mammal an anti- fungally effective amount of a compound of claim 12. \ 37088 39

43. A method of treating a fungal infection in anon-human mammal comprising administering to the mammal an anti- fungally effective amount of the compound of claim 13.

44. A method of treating a fungal infection in anon-human 5 mammal comprising administering to the mammal an anti- fungally effective amount of the compound of claim 14.

45. A method of treating a fungal infection in anon-human mammal comprising administering to the mammal an anti- fungally effective amount of the compound of claim 15.

46. A compound as claimed in claim 1 as specifically set forth herein.

47. A process for producing a compound as claimed in claim 1 substantially as herein described with reference to any one of the Examples. E.I. DU PONT DE NEMOURS AND COMPANY By their/ attorneys BALDWIN, SON & CAREY