WO1991012000A1

WO1991012000A1 - ANILINE DERIVATIVES OF α-STYRYL CARBINOLS AS ANTIFUNGAL AGENTS

Info

Publication number: WO1991012000A1
Application number: PCT/US1991/000193
Authority: WO
Inventors: Chia-Lin Jeffrey Wang
Original assignee: E.I. Du Pont De Nemours And Company
Priority date: 1990-02-13
Filing date: 1991-01-17
Publication date: 1991-08-22
Also published as: NZ237088A; AU7184891A; IL97201A0; IE910456A1

Abstract

There are provided novel aniline derivatives of α-styryl carbinols, pharmaceutical compositions comprising them and methods of using such compounds as antifungal agents.

Description

Title

ANILINE DERIVATIVES OF α-STYRYL

CARBINOLS AS ANTIFUNGAL AGENTS

Field of the Invention

This invention relates to aniline derivatives of α- 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 α-styryl carbinol antifungal agents useful in medicine and/or agriculture. Also described are certain compounds useful as herbicides and plant growth regulants. The compounds described therein have the formula:

wherein:

E is a bond or -O-, provided that when E is -O-, R and R¹ are not halogen;

A is C1-C8 perfluoroalkyl, NMe₂, OH, naphthyl

(optionally substituted by 1-3 of halogen and

CF₃),

optionally substituted by 1 or 2 methyl groups,

phenyl optionally substituted by 1-3

substituents independently selected from:

halogen, C1-C4 alkyl, C1-C4

haloalkyl, C1-C4 alkoxy and

maximally one of the following substituents: C1-C4 haloalkoxy. -S(O)_mR⁵, R⁶, 2-, 3- or 4-pyridyl, imidazol-1-yl, 1, 2, 4-triazol-1-yl and optionally substituted

by 1 or 2 methyl groups,

or a heterocycle selected from imidazol-1-yl, 1,

2, 4-triazol-1-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(O)_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 C1-C4 alkoxy, and maximally one of C1-C4 haloalkoxy and -S(O)_mR⁵,

benzyl optionally substituted on the phenyl ring with halogen or C1-C4 alkyl or α-substituted by

1 or 2 methyl groups, or a heterocycle selected 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(O)_mR⁵;

Q is H, halogen, -S(O)R¹¹, -S-CO-NHR¹², CHO, -CO-Me,

COOR¹³, SCN, SSR¹², or SH or its corresponding disulphide, provided that when Q is not H, then n=O, 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(O)_mR⁵; n is 0-4, provided that when A is

NMe₂ or

OH, then n is not O; 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

-CONR⁸R⁹, -COOR⁷ or C1-C4 haloalkyl;

R³ and R⁴ are H, F or C1-C4 alkyl;

R⁵ is C1-C4 alkyl;

R^e 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;

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-Cl; and

R3 is H. 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 -COY₁, its acetal or ketal derivatives, or

-C(Y₁) = NOY₂;

Y_l 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:

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, haloalkyl, haloalkoxy, haloalkylthio, optionally substituted phenyl, optionally substituted phenoxy, optionally substituted phenylalkyl or optionally substituted phenylalkoxy; and m is 0-3.

EP 129798 describes fungicides active against phytopathogenic fungi. These fungicides have the formula:

wherein:

n is 0-5;

R is H, halogen, alkyl, alkoxy, alkylthio,

alkylsulphonyl, haloalkyl, NO₂, CN, optionally substituted phenyl or optionally substituted phenoxy; R₁ 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)_m; m is 2-7;

Az is 1, 2, 4-triazol-1-yl, 1, 2, 4-triazol-4-yl, 1- imidazolyl, 1-pyrazolyl or 1-benzimidazolyl;

Y is CO or C(R₄)ORs;

R₄ 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:

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 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 described in EP 40345. These compounds are described as being useful as fungicides and as plant grooth

regulators, and have the formula:

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:

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; 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 α-styryl carbinols that are the subject matter of the present application.

Summary of the Invention

There are provided antifungal compounds having the formula:

or pharmaceutically acceptable salts thereof wherein:

R¹ is H or C1-C4 alkyl;

R² is H, C1-C4 alkyl, R³ C=O, or R¹R²N is

R³ is H, C1-C4 alkyl or CH₂X;

X is Cl or Br;

Ar is 2,4-F₂C₆H₃, 4-ClC₆H₄, 2,4-Cl₂C₆H₃; and

n is 0 or 1. 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 n is 0; and/or

Ar is 2,4-F₂C₆H₃ or 4-CIC₆H₄; and/or

R¹R²N is substituted at the 4-or 5-position; and/or

X is 2-Cl or 2-Br. 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-F₂C₆H₃; and/or

R¹R²N is substituted at the 4-or 5-position; and/or X is 2-Cl.

Specifically preferred compounds of the present invention are those more preferred compounds wherein: a) R¹R²N is 5(CH₃)₂N.

b) R¹R²N 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 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 prepared according to the procedures described in Scheme 1.

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 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 organometallies of

Formula (II) are prepared using standard procedures from the corresponding chlorides, bromides or iodides. The 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 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 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 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.

Finally, reaction of epoxy-olefins of Formula

(VIII) with 1,2,4-triazole in dimethylfuran (DMF) or dimethyl sulfoxide (DMSO) in the presence of potassium carbonate or sodium carbonate at about 50° to 100°C for 1 to 24 hours affords compounds of Formula (I).

When R¹=C1-C4 alkyl, R²=C1-C4 alkyl, or R¹R²N=

and n is 1, compounds of Formula (I) can be prepared from compounds of Formula (I) where n=0 by oxidation 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, phosphoric, methanesulfonic, succinic, fumaric,

ascorbic, and glutaric acids.

Example 1

Preparation of 2- (2 , 4-Difluorophenyl) -3- (2-chloro- 5-dimet-hylaminophenyl) -1- (1H-1 , 2 , 4-triazol-1-yl) - 3-buten-2-ol

(Formula I wherein X=2-Cl, R¹R²N=5-Me₂N, Ar=2,4-F₂C₆H₃, and n=0)

Part A:

Preparation of Methyl 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 saturated aqueous potassium carbonate solution and extracted with 10% MeOH/CH₂Cl₂. The organic layer was washed with brine and dried (Na₂SO₄). Removal of the solvent gave the product (27.8 g, 61%). ¹HNMR (CDCI₃) δ: 7.20 (d, 1H), 7.13 (d, 1H), 6.72 (dd, 1H), 3.90 (s, 3H), 3.73 (bs, 2H, -NH₂). Part B;

Preparation of Methyl 2-chloro-5-dimethyl- aminpbenzoate

A mixture of methyl 2-chloro-5-aminobenzoate from 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, 0.298 mol) was heated at 50° for 2 hours. It was then diluted with ether, washed with water. The ether layer was dried (Na₂SO₄). Removal of the solvent afforded the product (18.54 g, 64%). ¹HNMR (CDCI₃) δ:

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-dimethylaminobenzyl 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 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 give the product (16.28 g, 100%). ¹HNMR (CDCI₃) : δ 7.17

(d, 1H), 6.80 (d, 1H), 6.55 (dd, 1H), 4.70 (d, 2H), 2.93 (s, 6H).

Part D:

Preparation of 2-Chloro-5-dimethylamino- benzaldehyde

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 methylene

chloride (50 mL) at -60°C. The mixture was stirred for 10 minutes and a solution of 2-chloro-5- 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 to room temperature and water (50 mL) was added. The separated methylene chloride layer was washed with brine and dried (Na₂SO₄). Removal of the solvent gave the product (12.6 g, 79%). ¹HNMR (CDCl₃) δ: 10.45 (s, 1H), 7.30 (d, 1H), 7.22 (d, 1H), 6.90 (dd, 1H), 3.00 (s, 6H). Part E:

Preparation of 2-(2 ,4-Difluorophenyl)-3-(2-chloro- 5-dimethylaminophenyl)-1-propene-3-ol

(Formula IV wherein X=2-Cl, R¹R²N=5-Me₂N, Ar=2, 4-F₂C₆H₃) A solution of 1-bromo-1-(2,4-difluorophenyl) 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. 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 (Na₂SO₄). The crude product was purified by flash column

chromatography to give 11.3 g (62%) of the pure product. ¹HNMR (CDCI₃) δ: 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;

Preparation of 2-(2 ,4-Difluorophenyl)-3-(2-chloro- 5-dimethylaminophenyl)-1-propene-3-one

(Formula V wherein X=2-Cl, R¹R²N=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 g of 2-(2,4-difluorophenyl)-3-(2-chloro-5- dimethylaminophenyl)-1-propene-3-ol. The product was directly submitted to the next reaction without

purification.

Part G:

Preparation of 2-(2,4-Difluorophenyl)-2-(2-chloro-

5-dimethylaminobenzoyl)oxirane

(Formula VII wherein X=2-Cl, R¹R²N=5-Me₂N, Ar=2,4-F₂C₆H₃) To a solution of 2-(2,4-difluorophenyl)-3-(2- chloro-5-dimethylaminophenyl)-1-propene-3-one from Step 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

methylene chloride layer was washed with brine and dried

(Na2SO4). The crude product was purified by flash column chromatography to give 6.75 g (57%) of the pure product.

¹HNMR (CDCI₃) δ: 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, 6H).

Part H:

Preparation of 2-(2,4-Difluorophenyl)-2- [1-(2- chloro-5-dimethylaminophenyl)ethenyl]oxirane

(Formula VIII wherein X=2-C1, R¹R²N=5-Me₂N, Ar=2,4- 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- 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 0°C. The reaction was stirred at room temperature for 1 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 (Na₂SO₄). The crude product was purified by flash column

chromatography to give 2.5 g (37%) of the pure product.

¹HNMR (CDCl₃) δ: 6.93 (m, 1H), 7.15 (d, 1H), 6.80 (m,

2H), 6.50 (m, 2H), 5.40 (s, 1H), 5.27 (s, 1H), 3.03 (s, 2H), 2.85 (s, 6H).

Part I;

Preparation of 2- (2 , 4-Difluorophenyl) -3- (2-chloro-

5-dimethylaminophenyl) -1- (1H-1 , 2 , 4-triazol-1-yl) -3- buten-2-ol

(Formula I wherein X=2-Cl, R¹R²N=5-Me₂N, Ar=2, 4-F₂C₆H₃, n=0)

Treatment of 2- (2,4-difluorophenyl)-2-[1-(2-chloro- 5-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 ether, washed with water. The ether layer was dried (Na₂SO₄). The crude product was purified by flash column chromatography to give 1.1 g (36%) of the pure product, m.p. 147-148°C; ¹HNMR (CDCI₃) δ: 7.93 (s, 1H),

7.73 (s, 1H), 7.53 (q, 1H), 7.23 (d, 1H), 6.83-6.50 (m, 3H), 6.35 (d, 1H), 5.45 (s, 1H), 5.22 (s, 1H), 5.13 (d, 1H), 4.90 (s, 1H), 4.46 (d, 1H), 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 prepared or can be prepared.

Example 15

Preparation of 2- (2.4-Difluorophenyl)-3- (2-chloro-4-acetamidophenyl)-1- (1H-1,2.4-triazol-1-yl)-3-buten-2-ol

(Formula I wherein X=2-Cl, R¹R²N=4-MeC(=0)NH, Ar=2,4- F₂C₆H₃, n=0)

Part A:

Preparation of Methvl 2-chloro-4-aminobenzoate

By following a similar procedure described in 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) δ: 7.77 (d, 1H), 6.67

(d, 1H), 6.50 (dd, 1H), 4.20 (bs, 2H). 3.83 (s, 3H). Part B;

Preparation of Methyl 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 was then washed with 10% aqueous hydrochloric acid, brine, and dried (Na2SO4). Removal of the solvent gave the product (25 g, 100%). ¹HNMR (CDCI₃) δ: 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-acetamidobenzyl 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 t-butyl 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 dried (Na₂SO₄). Removal of the solvent afforded 18.4 g (86%) of the product. ¹HNMR (d₆-DMSO) δ: 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-acetamidobenzaldehyde 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 crude product was purified by flash column

chromatography to give 7.5 g (79%) of the product.

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

Part E:

Preparation of 2-(2,4-Difluorophenyl)-3-(2-chloro- 4-acetamidophenyl)-1-propene-3-ol

(Formula IV wherein X=2-Cl, R¹R²N=4-MeC(=0)NH, Ar=2,4- F₂C₆H₃)

By following a similar procedure described in Example 1, Part E, 8.8 g (69%) of the product was obtained from 18.3 g (83.5 mmol) of 1-bromo-1-(2,4- difluorophenyl) ethylene and 7.5 g (38 mmol) of 2-chloro-

4-acetamidobenzaldehyde from Step D. ¹HNMR (CDCI₃) δ:

8.00-6.73 (m, 7H), 6.02 (d, 1H), 5.60 (s, 1H), 5.38 (s, 1H), 2.17 (s, 3H).

Part F:

Preparation of 2-(2 ,4-Difluorophenyl)-2-[1-(2- chloro-4-acetamidophenyl)methyl-1-ol]oxirane

(Formula VI wherein X=2-Cl, R¹R²N=4-MeC(=0)NH, Ar=2,4- F₂C₆H₃)

A mixture of 2-(2,4-difluorophenyl)-3-(2-chloro-4- acetamidophenyl)-1-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 hours. It was then washed with saturated aqueous sodium bicarbonate solution, brine, and dried (Na₂SO₄). The crude product was purified by flash column

chromatography to give 3.11 g (65%) of the product.

1HNMR (CDCI₃) δ: 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-(2,4-Difluorophenyl)-2-(2-chloro- 4-acetamidobenzoyl)oxirane

(Formula VII wherein X=2-Cl, R¹R²N=4-MeC(=0)NH, Ar=2,4- F₂C₆H₃)

2-(2,4-Difluorophenyl)-2-[1-(2-chloro-4- acetamidophenyl)methyl-1-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.

1HNMR (CDCI₃) δ: 7.70-6.75 (m, 7H). 3.25 (q, 2H). 2.18

(s, 3H).

Part H:

Preparation of 2-(2,4-Difluorophenyl)-2-[1-(2- chloro-4-acetamidophenyl)ethenyl]oxirane

(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- difluorophenyl)-2-(2-chloro-4-acetamidobenzoyl) oxirane from Step G and 19 g (53.2 mmol) of

methyltriphenylphosphonium bromide. ¹HNMR (CDCI₃) δ:

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-Difluorophenyl)-3-(2- chloro- 4-acetamτdophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-buten-2- ol

(Formula I, X=2-Cl, R¹R²N=4-MeC(=0)NH, Ar=2, 4-F₂C₆H₃, n=0) 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 (CDCI₃) δ: 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), 2.17 (s, 3H); HRMS : m/z 418.1001 (M+), calcd. for C₂₀H₁₇F₂CIN₄O₂, 418.1008.

Example 16

Preparation of 2-(2,4-Difluorophenyl)-

3-(2-chloro-4-aminophenyl)-1-

(1H-1,2,4-triazpl-1-yl)-3-buten-2-ol (Formula I wherein X=2-Cl, 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-1-yl)-3-buten-2-ol from Example 15 (450 mg, 1.07 mmol) in ethanol-water (4 mL-2 mL) containing potassium hydroxide (300 mg, 5.35 mmol) was refluxed for 16 hours. The solvent was removed in vacuo, the residue was diluted with ether, washed with brine and dried (Na₂SO₄). Purification by flash column chromatography gave 307 mg (76%) of the product. ¹HNMR (CDCI₃) δ: 7.93 (s, 1H), 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 C₁₈H₁₅F₂CIN₄O, 376.0902. Example 17

Preparation of 2-(2,4-Difluorophenyl-3- (2-chloro-4-dimethylaminophenyl)-1- (1H-1,2,4-triazol-1-yl)-3-buten-2-ol (Formula I wherein X=2-Cl, 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-1-yl)-3-buten-2-ol from Example 16 (1 g, 2.65 mmol), methyl iodide (0.366 mL, 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 (Na₂SO₄). Purification by flash column

chromatography afforded 302 mg (28%) of the product. ¹HNMR (CDCl₃) δ: 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 C₂₀H₁₉F₂CIN₄O, 404.1215.

By using the procedures described in Examples 15- 17, the following compounds in Table II were prepared or can be prepared.

Example 34

Preparation of 2-(2,4-Difluorophenyl)-3-

(2-chloro-5-dimethylaminooxidephenyl)-1-

(1H-1,2,4-triazol-1-yl)-3-buten-2-ol (Formula I wherein X=2-Cl, R¹R²N=5-Me₂N, Ar=2, 4-F₂C₆H₃, n=1)

A mixture of 2-(2,4-difluorophenyl)-3-(2-chloro-5- dimethylaminophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-buten- 2-ol from Example 1 (270 mg, 0.67 mmol) and MCPBA (170 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) δ: 8.00

(m, 2H), 7.77 (s, 1H), 7.72 (s, 1H), 7.50 (m, 2H), 6.73 (m, 2H), 5.55 (s, 1H), 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.

Example 46

Preparation of Methaneaul fonate salt of

2-(2,4-difluorophenyl)-3-(2-chloro-

5-dimethylaminophenyl)-1- (1H-1,2,4-triazol-1-yl)-3-hnten-2-ol

To a solution of 2-(2,4-difluorophenyl)-3-(2- chloro-5-dimethylaminophenyl)-1-(1H-1,2,4-triazol-1-yl)- 3-buten-2-ol from Example 1 (520 mg, 1.288 mmol) in THF (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. ¹HNMR (d₆-DMSO) δ: 9.08 (s, 1H), 8.23 (s, 1H), 7.50-6.89 (m, 6H & H₂O, -SO₃H). 5.63 (s, 1H), 5.20 (s, 1H), 5.17 (d, 1H), 4.80 (d, 1H), 2.97 (s, 6H).

By using a similar procedure described in Example 46, the following compounds in Table IV were prepared or can be prepared.

Footnotes for Table IV

a ¹HNMR (d₆-DMSO) δ: 9.08 (s, 1H), 8.23 (s, 1H), 7.50-

6.89 (m, 6H & H₂O, -SO₃H), 5.63 (s, 1H), 5.20 (s, 1H), 5.17 (d, 1H), 4.80 (d, 1H), 2.97 (s, 6H).

Pharmaceutical utility

In vitro activity (Table V) is expressed in terms of the minimal inhibitory concentration (MIC) of the 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 concentration of 107 organisms/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 μg/ml. Stock solutions of standard 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,

Mycopathologia, 86, 21-28 (1984)] and C. Hughes, et al. Antimicrob. Ag. and Chemo., 25, 560-562(1984)]. Test compounds are serially diluted in EMEM to give graded concentrations ranging from 100 to 0.4 μg/mL. The appropriate wells are inoculated with the required organism (C. albicans at 1 x 10⁴ organisms/mL and

A. 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 compound which inhibited growth, are determined, [V. Grenta, et al. Antimicrob. Ag. and Chemo., 22, 151-153 (1982)].

The in vivo activity of test compounds is based on the percent (%) survival of infected animals receiving 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, 49 460-467 (1963), and T. Rogers and E. Balish, Infection 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 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 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 C . albicans, and receive test compounds at 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 animals for 14 days at a dose 150 mg/kg/day or less are viewed as active. TABLE V

In Vitro Antifungal Results

MIC values (μg/mL)

Example C . albicans A. fumigatus

(CAND-1) (ASFU-4)

1 ≤0.4 6.3

2 ≤0.4 50

3- ≤0.03 >100

4 0.2 >100

5 ≤0.4 >100

6 0.05 >100

15 0.2 12.5

16 ≤0.03 1.6

17 ≤0.03 0.4

20 0.4 100

21 0.1 1.6

34 0.8 >100

35 ≤0.4 >100

46 ≤0.03 6.3

Amphotericin B* 0.33±0 .2 1.4±0.5

Nystatin* 1.3 ±0 3.0±1.0

5-Fluorocytosine* 0.14+0 .1 5.7+4.0

Ketoconazole* <0.1 11.0±5.0

Miconazole* <0.1 1.3±0

*MIC values of the standard drugs are the mean of five determinations + Standard deviation

The data indicate that compounds of this invention have in vitro activity comparable to standard antifungal agents. TABLE VI

In Vivo Antifungal Results

Murine Candidiasis Model

% Survival

Ex. Days

No. 7 14 21

1 100 100 90

2 100 100 90

3 NT NT NT

4 90 80 80

5 100 50 50

6 80 60 60

15 100 70 50

16 100 90 80

17 100 100 90

20 80 40 30

21 70 50 20

34 100 70 60

35 70 30 10

46 NT NT NT

Amphotericin B 100 100 100

Ketoconazole 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 this invention demonstrate in vivo activity comparable to standard antifungal agents.

Dosage Forms

The antifungal agents of this invention can be administered by any means that effects contact of the 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 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.

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 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 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 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, 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 derivatives, magnesium stearate, stearic acid and the 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 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.

The pharmaceutical compositions which are

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

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.

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 or combined, are suitable stabilizing agents.

All the pharmaceutical compositions according to the invention can also contain coloring and flavoring to increase patient acceptance.

Also used are citric acid and its salts and sodium EDTA. In addition, parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl or propyl-paraben, and chlorobutanol.

Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences. (1985) 17th Edition, A. Osol, a standard reference text in this field.

Useful pharmaceutical dosage forms for

administration of the compounds of this invention can be illustrated as follows:

Capsules

A large number of unit capsules are prepared by filling standard two-piece hard gelatin capsules each with 100 milligrams of powdered active ingredient, 150 milligrams of lactose, 50 milligrams of cellulose, and 6 milligrams magnesium stearate.

Soft Gelatin Capsules

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

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 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.

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 water for injection and sterilized. Suspension

An aqueous suspension is prepared for oral

administration so that each 5 milliliters contain 100 administration so that each 5 milliliters contain 100 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

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.

Claims

WHAT IS CLAIMED IS:

1. A compound of the formula:

or pharmaceutically acceptable salts thereof wherein:

R¹ is H or C1-C4 alkyl;

R² is H, C1-C4 alkyl, R³ C=O, or R¹R²N is

R³ is H, C1-C4 alkyl or CH₂X;

X is Cl or Br;

Ar is 2,4-F₂C₆H₃, 4-CIC₆H₄, 2,4-Cl₂C₆H₃; and

n is 0 or 1.

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-F₂C₆H₃ or 4-CIC₆H₄.

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:

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- position; and

X is 2-Cl or 2-Br.

8. A compound of claim 4 wherein Ar is 2,4- F₂C₆H₃.

9. A compound of claim 7 wherein Ar is 2,4- F₂C₆H₃.

10. A compound of claim 6 wherein X is 2-C1.

11. A compound of claim 7 wherein X is 2-C1.

12. A compound of claim 7 wherein:

R¹ and R² independently are H or C1-C3 alkyl; n is 0;

Ar is 2,4-F₂C₆H₃;

R¹R²N is substituted at the 4- or 5- position; and

X is 2-Cl.

13. The compound of claim 12 wherein R¹R²N is 5(CH₃)₂N.

14. The compound of claim 12 wherein R¹R²N is 4- H₂N.

15. The compound of claim 13 wherein the

pharmaceutically acceptable salt thereof is the

methanesulfonate salt.

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

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

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

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

20. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an anti-fungal effective amount of a compound of claim 5.

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

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

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

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

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

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

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

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

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

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

31. A method of treating a fungal infection in a mammal comprising administering to the mammal an anti- fungal effective amount of a compound of claim 1.

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

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

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

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

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

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

38. A method of treating a fungal infection in a mammal comprising administering to the mammal an anti- fungal effective amount of a compound of claim 8.

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

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

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

42. A method of treating a fungal infection in a mammal comprising administering to the mammal an anti- fungal effective amount of a compound of claim 12.

43. A method of treating a fungal infection in a mammal comprising administering to the mammal an antifungal effective amount of the compound of claim 13.

44. A method of treating a fungal infection in a mammal comprising administering to the mammal an antifungal effective amount of the compound of claim 14.

45. A method of treating a fungal infection in a mammal comprising administering to the mammal an antifungal effective amount of the compound of claim 15.