AU767357B2

AU767357B2 - Cyclic peptide antifungal agents

Info

Publication number: AU767357B2
Application number: AU21892/00A
Authority: AU
Inventors: James Andrew Jamison; John Michael Rodriguez
Original assignee: Eli Lilly and Co
Current assignee: Eli Lilly and Co
Priority date: 1998-12-16
Filing date: 1999-12-15
Publication date: 2003-11-06
Anticipated expiration: 2019-12-15
Also published as: EP1140991A1; AU2189200A; JP2002535248A; WO2000035944A1; CA2354056A1

Description

WO 00/35944 PCT/US99/29914 CYCLIC PEPTIDE ANTIFUNGAL AGENTS FIELD OF THE INVENTION The present invention relates to anti-fungal/anti-parasitic agents, in particular, derivatives of Echinocandin compounds and their use in the treatment of fungal and parasitic infections.

BACKGROUND ART A number of naturally occurring cyclic peptides are known in the art including echinocandin B (A30912A), aculeacin, mulundocandin, sporiofungin, L-671,329, and S31794/F1. In general, these cyclic peptides can be structurally characterized as a cyclic hexapeptide core (or nucleus) with an acylated amino group on one of the core amino acids. This acyl group is typically a fatty acid moiety forming a side chain off the nucleus. For example, echinocandin B has a linoleoyl side chain while aculeacin has a palmitoyl side chain.

These natural products have limited inherent antifungal and antiparasitic properties. The natural compounds can be structurally modified in order to enhance these properties or improve the compound's stability and/or water solubility. Turner et al. Cur.

Pharm. Des. 2:209 (1996). For example, the fatty acid side chain can be removed from the cyclic peptide core to yield an amino nucleus which can be re-acylated to yield semisynthetic compounds.

DISCLOSURE OF THE INVENTION A compound represented by structure I is provided WO 00/35944 WO 0035944PCT/US99/2991 4 where R is an alkyl group, an alkenyl group, an alkynyl group, an aryl group, or heteroaryl group; R' is independently -OH or -O-Pg; R 2 is -CH 3 4-NH21 or -NH-Pg; R 3 is -CH 3 -CH,CONH,, -CH 2 CONH-Pg, -CH.,CHNH,, or -CH 2 CH,NH-Pg; R' is OH, -OSO 3 H, or -OPO,HR', where W~ is hydroxy, C1 -C6 alkyl, C 1

-C

6 alkoxy, phenyl, phenoxy, p-halophenyl, p-halophenoxy, p-nitrophenyl, p-nitrophenoxy, benzyl, benzyloxy, p-halobenzyl, p-halobenzyloxy, p-nitrobenzyl, or p-nitrobenzyloxy; R' is OH, or -OSO 3 H; W 7 is -H or -CH 3

R

4 and R' are independently, hydrogen, or hydroxy and at least one of R' and R' is a sugar moiety of the formula 9 9 R R g where R 9 is independently -OH, -O-Pg, -N-H 2 -NH-Pg. -OPO 2 Ra, or a second sugar moiety containing one to three sugar units of 9

C

0- R 9 b 7 1 and mixtures thereof, where R" 3 is -OH, -N 3 -NH2, -O-Pg, or -N-H-Pg. R 9 b is -OPOR', -OSO 3 H, -H,

-NH

2 -OH, -0-Pg. or -NH-Pg, R 9 C is -CH 3

-CH

2 OH, -CHOSO 3 H, -CH,NH-Pg,

CH

2 O-Pg, -CO.H, or -C0 2 -Pg, where R' is as defined above, and no more than one R 9 is represented by said second sugar moiety; Pg is a protecting group -0-Pg is a hydroxy protecting group, -NIH-Pg is an amino protecting group, -CH,CONH-Pg is an amido protecting groups and -C0 2 -Pg is a carboxy protecting group); and pharmaceutically acceptable salts, esters, hydrates or solvates.

In an aspect, the present invention provides a compound represented by structure I

R

8 wherein R is an alkyl group, an alkenyl group, an alkynyl or heteroaryl group; group, an aryl group,

S.

S. S

S.

R1 is independently -OH or -O-Pg; R 2is -CH 3

-NH

2 or -NH- Pg; R 3 is -CH 3

-GH

2

CONH

2

-CH

2 CONH-Pg, -CH 2

CH

2

NH

2 or-

CH

2

CH

2 NH-Pg;

R

5 is -OH, -OSO 3 H, or -OPO 2 HRa, where R a is hydroxy, C 1

-C

6 alkyl,

C

1

-C

6 alkoxy, phenyl, phenoxy, p-halophenyl, p-halophenoxy, p-nitrophenyl, p-nitrophenoxy, benzyl, benzyloxy, p-halobenzyl, p-halobenzyloxy, pnitrobenzyl, orp-nitrobenzyloxy; R 6 is -OH, or -OSO 3 H; R 7 is -H or -CH 3 R 4 and R 8 are independently, hydrogen, or hydroxy and at least one of R 4 and R 8is a sugar moiety of the formula

S.

S

5555

S

5555 5* S S

S

,0 O0 rY where R 9 is independently -OH, -N 3 -O-Pg, -NH 2 -NH-Pg, -OPO 2 Ra, CO 2 Pg, or a second sugar moiety consisting of one to three sugar units selected from the group consisting of R 9b R 9b a.

a.

9* C

C

c.

and mixtures thereof, wherein R 9 a is -OH, -N 3

-NH

2 -O-Pg, or -NH-Pg, R 9 b is -OPO 2

R

8

-OSO

3 H, -NH 2 -OH, -O-Pg, or -NH-Pg, R 9 c is -CH 3

-CH

2 0H,

-CH

2

N

3

-CH

2 0SO 3 H, -CH 2 NH-Pg, -CH 2 0-Pg, -CO 2 H, or -C0 2 -Pg, where Ra is as defined above, and no more than one R 9 is represented by said second sugar moiety; and each Pg is independently a protecting group or a pharmaceutically acceptable salt, ester, hydrate, or solvate thereof.

C.

C

C.

C

In another aspect, the present invention provides a method of inhibiting fungal activity comprising administering to a recipient in need of such inhibition an effective amount of a compound represented by structure I: N 2 N %H O H 0N R7 R 3 N O 0H 0- N R 4 N R 6 wherein R is an alkyl group, an alkenyl group, an alkynyl group, an aryl group, or heteroaryl group; R' is independently -OH or -O-Pg; R 2 is -CH 3

NH-

2 or -NH-Pg; R 3 is -CH 3

-CH

2

CONH

2

-CH

2 CONH-Pg, -CH 2

CH

2

NH

2 or-CH 2

CH

2 NH-Pg; R' is -OH, -OSO 3 H, or -OPO 2 HRa, where Ra is hydroxy, cl-c 6 alkyl, C 1

-C

6 alkoxy, phenyl, phenoxy, p-halophenyl, p-halophenoxy, pnitrophenyl, p-nitrophenoxy, benzyl, benzyloxy, p-halobenzyl, phalobenzyl oxy, p-nitrobenzyl, or p-nitrobenzyloxy; R 6 is -OH, or -OSO 3

H;

R 7 is -H or -CH 3

R

4 and R 8 are independently, hydrogen, or hydroxy and at least one of R 4 and R 8 is a sugar moiety of the formula 9* 9 9 9 R R R 0 0 or R 9 where R 9 is independently -OH, -N 3 -O-Pg, -NH 2 -NH-Pg, -OPO 2 Ra, CO 2 Pg, or a second sugar moiety consisting of one to three sugar units selected from the group consisting of and mixtures thereof, wherein R 9 a is -OH, -N 3

-NH

2 -O-Pg, or -NH-Pg, R 9 b is -OPO 2 Ra, -OSO 3 H, -NH 2 -OH, -O-Pg, or -NH-Pg, R 9 is -CH 3

-CH

2

N

3

-CH

2 0SO 3 H, -CH 2 NH-Pg, -CH20-Pg, -CO 2 H, or -C0 2 -Pg, where Ra is as defined above, and no more than one R 9 is represented by said second sugar moiety; and each Pg is independently a protecting group for a pharmaceutically acceptable salt, ester, hydrate, or solvate thereof.

In a further aspect, the present invention provides a method of inhibiting parasitic activity comprising administering to a recipient in need of such inhibition an 15 effective amount of a compound represented by structure I: 6* 0*

R

8 R1

R

1 0 0 OH 0N R7 R3 N 0 OH 0- N R 4 N R1 0R R R 6 wherein R is an alkyl group, an alkenyl group, an alkynyl group, an aryl group, or heteroaryl group; R' is independently -OH or -O-Pg; R 2is -CH 3

NH

2 or -NH-Pg; R 3 is -CH 3

-CH

2

CONH

2

-CH

2 CONH-Pg, -CH 2

CH

2

NH

2 or-CH 2

CH

2 NH-Pg; R 5 is -OH1, -OSO 3 H, or -OPO 2 HRa, where R a is hydroxy,

C

1

-C

6 alkyl, C 1

-C

6 alkoxy, phenyl, phenoxy, p-halophenyl, p-halophenoxy, pnitrophenyl, p-nitrophenoxy, benzyl, benzyloxy, p-halobenzyl, phalobenzylIoxy, p-nitrobenzyl, or p-nitrobenzyloxy; R 6 is -OH, or -OSO 3

H;

R 7 is -H or -CH 3

R

4 and R 8 are independently, hydrogen, or hydroxy and at least one of R 4 and R 8 is a sugar moiety of the formula 0 0 0 0 0 0 R* 9

RR

9. 9 R R or .Ro Sa where R 9 is independently -OH, -N 3 -O-Pg, -NH 2 -NH-Pg, -~OPO 2 R G0 2 Pg, or a second sugar moiety consisting of one to three sugar units selected from the group consisting of R 9 b0R 9a 9a R 9aR 9a Ra 0 0 0- R 9C 0 0- R 9b R a R 9a R 9a R9aR 9 a R 9 a and mixtures thereof, wherein R 9 a is -N 3

-NH

2 -O-Pg, or -NH-Pg, R 9 b is -OPO 2 R a, -OSO 3 H, -NH 2 -OH, -O-Pg, or -NH-Pg, R 9 is -CH 3

-CH

2

OH,

-CH

2

N

3

-CH

2

OSO

3 H, -CH 2 NH-Pg, -CH 2 O-Pg, -CO2H, or -C0 2 -Pg, where R a is as defined above, and no more than one R 9 is represented by said second sugar moiety; and each Pg is independently a protecting group for a pharmaceutically acceptable salt, ester, hydrate, or solvate thereof V.040 .0 0S000 The invention encompasses a pharmaceutical formulation is containing one or more pharmaceutical carriers, diluents or excipients and a Compound I described above.

The invention encompasses a method for inhibiting fungal and parasitic activity by administering an effective amount of Compound I to a recipient in-need thereof.

"Alkyl" is a hydrocarbon radical of the general formula containing from 1 to 30 carbon atoms unless otherwise indicated. The alkane radical can be straight, branched, cyclic, or multi-cyclic. The alkane radical can be substituted or unsubstituted.

The alkyl portion of an alkoxy group, alkylthio group or alkanoate have the same definition as above.

"Ci-C12 alkyl" is a straight or branched saturated alkyl chain of from one to twelve carbon atoms. C1-C12 alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, t-butyl, pentyl, 5-methylpentyl, hexyl, heptyl, 3,3dimethylheptyl, octyl, 2-methyl-octyl, nonyl, decyl, undecyl and dodecyl. "C1-C12 alkyl" includes "Cl-C6 alkyl", "C1-C4 alkyl", and "C3-C12 cycloalkyl".

"C3-C12 cycloalkyl" is a cyclic saturated alkyl chain of from 3 to 12 carbon atoms. Moreover, the term "C3-C12 cycloalkyl" includes "C3-C7 cycloalkyl", i.e., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. "C -C12 alkoxy" refers to a C -C12 alkyl group attached through an oxygen atom. Cl-C12 alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, sec-butoxy, n-pentoxy, heptoxy, octyloxy, decyloxy and dodecyloxy. "Cl-C12 alkoxy" includes "C -C6 alkoxy", "C3-C7 alkoxy", and "CI-C4 alkoxy".

"Cl-C 12 alkylthio" is a C1-C12 alkyl group attached through a sulfur atom. C1- C12 alkylthio groups include, but are not limited to, methylthio, ethylthio, propylthio, isopropylthio, butylthio, 3-methyl-heptylthio, octylthio and 5,5-dimethyl-hexylthio. "C1- C12 alkylthio" includes "Cl-C6 alkylthio" and "CI-C4 alkylthio." "Alkenyl" is an acyclic hydrocarbon containing at least one carbon-carbon double bond. The alkene radical can be straight, branched, cyclic, or multi-cyclic, substituted or 30 unsubstituted.

"Alkynyl" is an acyclic hydrocarbon containing at least one carbon-carbon triple bond. The alkync radical can be straight, or branched, substituted or unsubstituted.

"C2-C12 alkynyl" is a straight or branched mono-alkynyl chain having from two to twelve carbon atoms. C2-C12 alkynyl groups include, but are not limited to, ethynyl, ':35 1-propyn-1-yl, l-propyn-2-yl, 1-butyn-1-yl, -butyn-3-yl, 1-pcntyn-3-yl, 4-pcntyn-2-yl, 1- :3 3 •oo°.

WO 00/35944 PCT/US99/29914 reaction solvent can be removed by extraction, evaporation or decantation. The intermediate compound can be further purified, if desired, by common techniques such as crystallization, precipitation, or chromatography over solid supports such as silica gel, alumina and the like, before carrying out the next step of the reaction scheme.

Preferred compounds of the present invention are those compounds represented by structure I wherein R' is hydroxy at each occurrence; R 2

R

3 and R 7 ar-each methyl; R is a moiety of the formula: or

R

4 is hydroxy; and R" is Ci-C 4 .alkyl or C -C 4 alkoxy; or a pharmaceutically acceptable salt or solvate thereof More preferable are those compounds wherein R 5 is hydroxy; R is a moiety of the formula

D

R

8 is a moiety of the formula

R

9 0 0

R

9 9

R

D is hydrogen or C 3

-C

7 alkoxy; R 9 is independently hydrogen, hydroxy, amino, or a moiety of the formula i 9b where R" is -OPOR", -OSO 3 H, -OH, -O-Pg, or -NH-Pg and n is 1, 2, or 3; or a pharmaceutically acceptable salt thereof.

Even more preferable are those compounds wherein D is n-pentoxy; R 9 is independently -OH, -NH, or -OPO,R"; or a pharmaceutical salt or solvate thereof.

16 0 *0o 0 WO 00/35944 PCT/US99/29914 Most preferred are those compounds wherein R 9 is hydroxy at each occurrence; and R 9 b is -OPO,Ra, where R" is methyl or methoxy; or a pharmaceutically acceptable salt or solvate thereof.

The following Preparations and Examples further describe how to synthesize the compounds of the present invention but do not limit the invention. All references cited herein are hereby incorporated by reference. The terms fast atom bombardment mass spectroscopy and high performance liquid chromatography are abbreviated "MS(FAB)" and "HPLC" respectively. The following acronyms represent the corresponding chemical moieties: Ms methanesulfonyl; Ac acetyl; Me methyl; and Tos tosyl (or ptoluenesulfonyl).

Preparation 1 1, 2 ,3,4-Tetra-O-Acetyl-6-Deoxy-6-Methanesulfonyl-P-D-Glucopyranose Ms 0 OAc 9" YAc Ac OAc In a 100 mL round bottom flask containing 50 mL dichloromethane at 0°C was placed 1, 2 ,3, 4 -tetra-O-acetyl-P-D-glucopyranose (4.62 g, 13.26 mmol). To this solution was added triethylamine (2.77 mL, 19.90 mmol) followed by dropwise addition of methanesulfonyl chloride (1.23 mL, 15.9 mmol). The reaction was then warmed to room temperature and stirred for 3 hours at which time the reaction was diluted with 100 mL dichloromethane. The organic layer was then washed two times each with 50 mL of water, IN aqueous hydrochloric acid, saturated aqueous sodium bicarbonate and brine.

The organic layer was dried over magnesium sulfate, filtered and the solvent removed in vacuo to yield 4.45 g of crude title compound as a white solid which was used directly in Preparation 2. Preparation 2 1, 2 3 4 -Tetra-O-Acetyl-6-Azido-6-Deoxy-P3-D-Glucopyranose

N

3 o0 Ac 9"O Ac Ac OAc A 100 mL round bottom flask was charged with 40 mL anhydrous dimethylformamide. sodium azide (2.19 g, 33.6 mmol), and crude 1,2,3,4-tetra-O-acetyl- 6-deoxy-6-methanesulfonyl-p-D-glucopyranose (1.9374 g, 4.54 mmol). The resulting 17 WO 00/35944 PCT/US99/29914 homogeneous solution was heated to 70°C and allowed to react for 10 hours. The reaction was then diluted with 200 mL of ethyl acetate and washed with copious amounts of water. The organic layer was dried over magnesium sulfate, filtered and the solvent removed in vacuo. The resulting brown solid was purified by column chromatography over silica gel to yield 668.3 mg of the title compound MS(FAB) calculated for C14H19N309 (M OCOCH3) 314.1, found 314.1.

Preparation 3 1,2,3,4-Tetra-O-Acetyl-6-Deoxy-6-Iodo- P-D-glucopyranose 0 OAc -,OAc Ac OAc A 1 L round bottom flask containing 500 mL of methyl ethyl ketone was charged with 1,2,3, 4 -tetra-O-acetyl-6-deoxy-6-methanesulfonyl- P-D-glucopyranose (4.45 g, 10.44 mmol) and sodium iodide (15.73 g, 104.9 mmol). The reaction was heated at reflux for 24 hours. The solvent was removed in vacuo and the resulting residue was taken up in 250 mL dichloromethane. The organic layer was washed with sodium thiosulfate (2 x 100 mL), water (2 x 100 mL) and once with 100 mL of brine. The organic layer was dried over magnesium sulfate, filtered and the solvent removed in vacuo to yield crude 1,2,3,4-tetra-O-acetyl-6-deoxy-6-iodo-p-D-glucopyranose as a white solid (4.99 g) which was used directly in Preparation 4.

Preparation 4 1, 2 3 4 -Tetra-O-Acetyl-6-Deoxy--D-Glucopyranose Me 0 ,OAc 9" Y "OAc Ac OAc 1,2,3,4-Tetra-O-acetyl-6-deoxy-6-iodo--D-glucopyranose (251.6 mg, 0.549 mmol) was dissolved in 20 mL of ethanol. To this solution was added 1 mL of triethylamine and 5% palladium on carbon (50.0 mg). The reaction mixture was exposed to 60 psi of hydrogen in a Parr apparatus at room temperature for 5 hours. The palladium on carbon was filtered off and the ethanol was removed in vacuo to yield a white solid.

Purification via column chromatography over silica gel yielded 82.3 mg of the title compound as a white solid. MS(FAB) calculated for C14H2009 332.1.

Found: 331.1.

WO 00/35944 PCT/US99/29914 Preparation 1,2,5,6-Diacetone-4-p-Toluenesulfonyl-D-Allofuranose 0 TosO" A 500 mL round bottom flask containing 160 mL ofpyridine was charged with 1,2,5,6-diacetone-D-allofuranose (40.72 g, 156.44 mmol) and p-toluenesulfonyl chloride (45.67 g, 239.53 mmol). The reaction was allowed to stir at room temperature for 27 hours. The reaction mixture was poured into 1.5 L of ice water and, upon melting, was filtered and dried in a vacuum oven at 30 0 C to yield 56.74 g of the title compound which was used crude in Preparation 6.

Preparation 6 1,2,5,6-Diacetone-4-p-Azido-D-Allofuranose 0'0 In a 2 L round bottom flask containing 1 L ofdimethylformamide was added 1,2,5,6-diacetone-4-p-toluenesulfonyl-D-allofuranose (56.44 g, 136.17 mmol) and sodium azide (142.12 g, 2.186 mol). The reaction mixture was heated to reflux and allowed to react for 20 hours. The reaction was cooled to room temperature and the dimethylformamide was removed in vacuo. The resulting residue was partitioned between 250 mL ethyl acetate and 250 mL water. The organic layer was washed with 300 of water and brine. The organic layer was dried over magnesium sulfate, filtered and the solvent removed in vauco to obtain a crude brown oil. Purification via column chromatography over silica gel (10% ethyl acetate/hexanes) yielded the title compound.

Preparation 7

HO

O

.OH

HO" ""OH

N

3 1,2,5,6-Diacetone-4-p-azido-D-allofuranose was suspended in 50 mL of water in a 500 mL round bottom flask. To this suspension was added Dowex 50 X 8-100 acidic resin (20 the reaction mixture was heated at 60 0 C for 16 hours. The resin was filtered and the filtrate was lyophilized to yield 9.92 g of the title compound as a white solid.

WO 00/35944 PCT/US99/29914 Preparation 8 a-D-Acetochlororhamnose Me,,0O Cl 9 OAc Ac OAc In a 25 mL round bottom flask containing 10 mL of acetyl chloride was placed 1.0117 g of L-rhamnose. The reaction was stirred for 48 h at room temperature. The reaction was diluted with 100 mL of dichloromethane and washed with 50 mL ice water and then 50 mL of cold saturated aqueous sodium bicarbonate. The organic layer was dried over magnesium sulfate and filtered. The solvent was removed in vacuo and the product used without further purification.

The following compounds were prepared by the procedure of Preparation 8: OAc O ,C1 0Cl O ci 9" 'OAc 9 N ''OAc Ac OAc Ac OAc and Ac OAc Preparation 9 2,3,4-Tri-O-Acetyl-6-Deoxy-p-D-Glucopyranosyl Bromide: OAc 0 Br Ac OAcH In a 10 mL round bottom flask containing 10 mL of glacial acetic acid was placed 6-deoxyglucose (332.3 mg) and the reaction was cooled to 0°C. Hydrobromic acid in glacial acetic acid (5 mL of a 30 wt. solution) was added dropwise. The reaction was stirred for 4 hours. The reaction was diluted with 100 mL of dichloromethane and washed with 50 mL ice water and then 50 mL of cold saturated aqueous sodium bicarbonate. The organic layer was dried over magnesium sulfate and filtered. The solvent was removed in vacuo to yield the title compound as a yellow solid (636.5 mg, 85.4%) and the product was used without further purification. MS(FAB) calculated for C12H1707Br (M Br) 273.1, found 273.1.

The following compounds were prepared by the procedure of Preparation 9: WO 00/35944 PCT/US99/29914 N OAc 0 Br Me O Br OSO Br 9 'OAc 9 OAc 9"Y OAc Ac OAc Ac OAc and Ac N 3 Preparation 3,4,6-Tri-O-Acetyl-2-Azido-2-Deoxy- 1-D-Glucopyranosyl Bromide Ac 0 Br Ac OAc A 1 L flask containing 400 mL of acetonitrile was charged with sodium azide (7.75 g, 119.2 mmol) and ceric ammonium nitrate (120.7 g, 219.4 mmol). The resulting suspension was cooled to -30 0 C and a solution of tri-O-acetyl-D-glucal (20.75 g, 76.22 mmol) in 100 mL acetonitrile was added to it dropwise. The reaction mixture was stirred at -30 0 C for 20 hours and then warmed to room temperature, taken up in 800 mL of diethyl ether and washed with water (3 x 250 mL). The organics were dried over magnesium sulfate, filtered, and the solvent removed in vacuo to yield an oil. This oil was placed in a 1 L flask containing 400 mL of acetonitrile and lithium bromide (33.53 g, 386.1 mmol) and stirred at room temperature for at least 4 hours. The solvent was removed in vacuo and the resulting residue was taken up in 400 mL of dichloromethane.

The organic layer was washed with water (2 x 250 mL), dried over magnesium sulfate and filtered. The solvent was removed in vacuo to yield the title compound as a dark yellow oil which was used directly without further purification.

The following compounds were prepared by the procedure of Preparation Ac O0 Br Me, O Br 9Y N 3 9" N3 Ac OAc and Ac OAc WO 00/35944 PCT/US99/29914 Preparation 11 4-Acetoglucosyl-2-Butenol OAc 0 0 OH I, oAc Ac OAc A flask was charged with acetobromoglucose (10.05 g, 24.44 mmol), silver carbonate (13.64 g, 49.47 mmol) and 200 mL of 2-butene-1,4-diol. The reaction mixture was allowed to stir for 18 hours at room temperature. The crude reaction mixture was filtered over a celite pad to remove silver salts and washed several times with ethyl acetate. The organics were then washed several times with copious amounts of water to removed unreacted 2-butene-l,4-diol. The organic layer was then dried with magnesium sulfate and concentrated in vacuo to yield a yellow oil. Silica gel column chromatography of the oil eluting with 70% ethyl acetate in hexanes yielded 2.37 g of the title compound. The following compounds were prepared by the procedure of Preparation 11: Ac OAc 0 Ac O O OH Ac-OO,, O OH 9 OAc Ac-O O Ac Ac OAc and OAc OAc WO 00/35944 PCT/US99/29914 Preparation 12 Sn-pentyl OH OH M e N N o N

H

Me H N

Y

0 CH 3 HO NH N- OH r N u ""'OH

OH

The A-30912A nucleus (60.2 mmol) and the 2,4,5-trichlorophenol ester of pentyloxy)-l,1':4', "-terphenyl]-4-carboxylic acid (26.0 g, 48.2 mmol) were combined in 8.5 L of dimethylformamide. The resultant reaction mixture was stirred for approximately 48 hours at room temperature and then the solvent was removed in vacuo to provide a residue. This residue was slurried in ether, collected by filtration, washed with methylene chloride and then dissolved in methanol or a 1:1 acetonitrile/water mixture. The resultant solution is subjected to reverse phase HPLC (C18; eluent of 40% aqueous acetonitrile containing 0.5% monobasic ammonium phosphate mL/min.; 230 nm). After removing the unreacted A30912A nucleus, the desired product is eluted from the column using an eluent of aqueous acetonitrile. The fractions containing the desired product are combined and then concentrated in vacuo or lyophilized to provide 18 g of the title compound. MS(FAB): 1140.5103 WO 00/35944 PCT/US99/29914 Examples 1-14 Examples 1 14 have the following base structure: 0 n-pentyl R OH N O Me O o H 0 CH 3 HO NH N OH

OH

R

4 Example 1 OAc o0 0 R c OAc R Ac OAc R4 The compound of Preparation 12 (269.8 mg, 0.237 mmol), the first compound of Preparation 11 (508.1 mg, 1.214 mmol), p-toluenesulfonic acid (100.8 mg, 0.530 mmol) and 15 mL of 1,4-dioxane were placed in a flask and stirred at room temperature for 4 hours. The crude reaction mixture was filtered and purified via HPLC eluting with water in acetonitrile at 60 mL/minute using a 3 x 40 x 100 mm Novapak C 18 column to afford 12.4 mg of the title compound. MS(FAB) 1562.7 (M+Na) Examples 2 7 were prepared by the procedure of Example 1.

Example 2 0O 0 O 9A OA

HO

"HoA c

R

8 Ac OAc R4 MS(FAB) 1563.5 (M+Na) WO 00/35944 WO 0035944PCT/US99/2 9914 Example 3 0OMe Ac OAc

R

8 ,R 4 Example4 OMe 0' i R 8 Ac QAc (nile): 1549.0 (M+Na) Example QAc r- 0 0 4 9 "OAc R 8 Ac QAc MS(FAB) (nile): 1562.7 (M+Na) Example6 OAc QV(Ac 0 R 8~ O cC MS(FAB) (nile): 1563.7 (M+Na) Example7 9 Q.Ac C- Ac 0 0 04 0 0 'Ac 9" /OA R 8 =Ac QAc R4Ac OAc MS(FAB) (nile): 1940.8 MS(FAB) (nile): 1964.0 (M+Na) 0 WO 00/35944 WO 0035944PCTIUS99/2991 4 Example 8 0OMe 9 0Ac 0 R8 Ac 0Ac

P

MS(FAB) (mle): 1935.2 MS(FAB) (mle): Example 9 0Me 0 Ac QAc 1935.1 (M+Na) QAc VAc 00 04( o 0 0' 9 QAc 9 0Ac R8 Ac QAc R 4 =Ac 0Ac MS(FAB) 1963.9 MS(FAB) 1963.9 (M+Na) Example R 8 =UC

UAC

Example I11 Ac Ac 0 0 Ac 0D OAc OAc Qc H0",& R HO0,,,

R

Example 12 0 v H0~

R

8 WO 00/35944 PCT/US99/29914 The compound of Example 1 (9.3 mg, 0.0060 mmol), potassium carbonate (5.3 mg, 0.0038 mmol), and 4 mL of a 50% mixture of methanol in water were combined and stirred for 30 minutes at room temperature. The crude reaction mixture was filtered and purified via HPLC eluting with 40% water in acetonitrile at 60 mL/minute using a 3 x x 100 mm Novapak C 18 column to afford 5.1 mg of the title compound. (62%) MS(FAB) 1373.7 Examples 13 22 were prepared by the procedure of Example 1.

Example 13 O Oo R4 Example 14 OMe HO 'OH R

OH

MS(FAB) 1427.5 (M+Na) Example OMe o O 0 0 HO'" '"OH

R

8

OH

Example 16 H HO OH

R

s

OH

MS(FAB) 1372 HOi H041 ,R

HO~~

WO 00/35944 WO 0035944PCT/US99/2 9914 Example 17 O 0 0 HO OH R 8

OH

MS(FAB) (nile): 1372 Example 18

OH

R

8 OHR4 Example 19

HO~~

OMe 00 Ir

IOH

Example 21

R

8 OMe 0 00 0 HO'o

'IIOH

OH

H

O 0 0 HO "OH

OH

O 0 o HO OH R8

OH

MS(FAB) (nile): 1605.8

SR

4 Example 21 HO O HO, 0 0 0 0 OH OH H, WO 00/35944 PCT/US99/29914 Example 22 HO

H

H 0 0 HO OH HO,,

R

8 OH OH R4= Representative examples of Compound I exhibit antifungal and antiparasitic activity. For example, Compound I inhibits growth of various infectious fungi including Candida spp. such as C. albicans, C. parapsilosis, C krusei, C. glabrata, or C. tropicalis, C. lusitaniae; Torulopus spp. such as T. glabrata; Aspergillus spp. such as A. fumigatus; Histoplasma spp. such as H. capsulatum; Cryptococcus spp. such as C. neoformans; Blastomyces spp. such as B. dermatitidis; Fusarium spp., Trichophyton spp., Pseudallescheria boydii, Coccidioides immitis, Sporothrix schenckii and the like.

Antifungal activity of a test compound is determined in vitro by obtaining the minimum inhibitory concentration (MIC) of the compound using a standard agar dilution test or a disc-diffusion test. The compound is then tested in vivo (in mice) to determine the effective dose of the test compound for controlling a systemic fungal infection.

Accordingly, representative compounds of the present invention were tested for, and displayed, antifungal activity against at least one of the following fungii: C. albicans, C. parapsilosis, C. neoformans, Histoplasma spp, and A. fumigatus.

The compounds of the invention also inhibit the growth of certain organisms primarily responsible for opportunistic infections in immunosuppressed individuals. For example, the compounds of the invention inhibit the growth ofPneumocystis carinii the causative organism ofpneumocystis pneumonia (PCP) in AIDS and other immunocompromised recipients. "Topley and Wilson's Microbiology and Microbial Infections," Vol. 5, Ch. 22, Oxford University Press, Inc., New York, 1998. Other protozoans that are inhibited by compounds of formula I include Plasmodium spp., Leishmania spp., Tr3panosoma spp., Cryptosporidium spp., Isospora spp., Cyclospora spp., Trichomonas spp., Microsporidiosis spp. and the like.

The dose of Compound I administered varies depending on such factors as the nature and severity of the infection, the age and general health of the recipient and the tolerance of the recipient to the active ingredient. The particular dose regimen likewise can vary according to such factors and can be given in a single daily dose or in multiple doses during the day. The regimen can last from about 2 3 days to about 2 3 weeks or longer. A typical daily dose (administered in single or divided doses) contains a dosage WO 00/35944 PCT/US99/29914 level of from about 0.01 mg/kg to about 100 mg/kg of body weight of the active compound of this invention. Preferred daily doses are generally from about 0.1 mg/kg to about 60 mg/kg, more preferably from about 2.5 mg/kg to about 40 mg/kg.

Compound I can be administered parenterally, for example using intramuscular, sub-cutaneous, or intra-peritoneal injection, nasal, or oral means. In addition to these methods of administration, Compound I can be applied topically for skin infections.

The present invention also provides pharmaceutical formulations useful for administering the compounds of the invention. The active ingredient in such formulations comprises from 0.1% to 99.9% by weight of the formulation, more generally from about 10% to about 30% by weight.

For parenteral administration, the formulation comprises Compound I and a physiologically acceptable diluent such as deionized water, physiological saline, dextrose and other commonly used diluents. The formulation can contain a solubilizing agent such as a polyethylene glycol or polypropylene glycol or other known solubilizing agent. Such formulations can be made up in sterile vials containing the active ingredient and one or more excipients in a dry powder or lyophilized powder form. Prior to use, a physiologically acceptable diluent is added and the solution withdrawn via syringe for administration to the recipient.

The present pharmaceutical formulations are prepared by known procedures using known and readily available ingredients. In making the compositions of the invention, the active ingredient will generally be admixed with a carrier, or diluted by a carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, paper or other container. When the carrier serves as a diluent, it can be a solid, semi-solid or liquid material which acts as a vehicle, excipient or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols, (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active ingredient, soft and hard gelatin capsules, suppositories, sterile injectable solutions, sterile packaged powders and the like.

For oral administration, the active ingredient is filled into gelatin capsules or formed into tablets. Such tablets can also contain a binding agent, a dispersant or other suitable excipients suitable for preparing a proper size tablet for the dosage and particular Compound represented by structure I. For pediatric or geriatric use the active ingredient can be formulated into a flavored liquid suspension, solution or emulsion. A preferred oral formulation is linoleic acid, cremophor RH-60 and water and preferably in the WO 00/35944 PCT/US99/29914 amount (by volume) of 8% linoleic acid, 5% cremophor RH-60, 87% sterile water and Compound I in an amount of from about 2.5 to about 40 mg/mL.

For topical use the active ingredient can be formulated with a dry powder for application to the skin surface or it can be formulated in a liquid formulation comprising a solubilizing aqueous liquid or non-aqueous liquid, an alcohol or glycol.

Formulations The following formulation examples are illustrative only and are not intended to limit the scope of the invention in any way. The term "active ingredient" refers to a compound of structure I or a pharmaceutically acceptable salt or solvate thereof.

0 Formulation Example 1 Hard gelatin capsules are prepared using the following ingredients: Quantity (mg/capsule) Active ingredient 250 Starch, dried Magnesium stearate 200 Total 460 mg Formulation Example 2 A tablet is prepared using the ingredients below.

Active ingredient Cellulose, microcrystalline Silicon dioxide, fumed Quantity (mg/capsule) 250 400 Stearic acid Total 665 mg The components are blended and compressed to form tablets each weighing 665 mg.

Formulation Example 3 An aerosol solution is prepared containing the following components: Weight Active ingredient 0.25 Ethanol 25.75 Propellant 22 (Chlorodifluoromethane) 74.00 Total 100.00 The active compound is mixed with ethanol and the mixture added to a portion of the propellant 22, cooled to -30 0 C and transferred to a filling device. The required 31 WO 00/35944 PCT/US99/29914 amount is then fed to a stainless steel container and diluted with the remainder of the propellant. The valve units are then fitted to the container.

Formulation Example 4 Tablets, each containing 60 mg of active ingredient, are made as follows: Active ingredient 60 mg Starch 45 mg Microcrystalline cellulose 35 mg Polyvinylpyrrolidone (as 10% solution in water) 4 mg Sodium carboxymethyl starch 4.5 mg Magnesium stearate 0.5 mg Talc 1 mg Total 150 mg The active ingredient, starch and cellulose are passed through a No. 45 mesh U.S.

sieve and mixed thoroughly. The aqueous solution containing polyvinyl-pyrrolidone is mixed with the resultant powder, and the mixture then is passed through a No. 14 mesh U.S. sieve. The granules so produced are dried at 50 0 C and passed through a No. 18 mesh U.S. sieve. The sodium carboxymethyl starch, magnesium stearate and talc, previously passed through a No. 60 mesh U.S. sieve, are added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 150 mg.

Formulation Example Capsules, each containing 80 mg of active ingredient, are made as follows: Active ingredient 80 mg Starch 59 mg Microcrystalline cellulose 59 mg Magnesium stearate 2mg Total 200 mg The active ingredient, cellulose, starch and magnesium stearate are blended, passed through a No. 45 mesh U.S. sieve, and filled into hard gelatin capsules in 200 mg quantities.

Formulation Example 6 Suppositories, each containing 225 mg of active ingredient, are made as follows: Active ingredient 225 mg Saturated fatty acid glycerides 2,000 mg Total 2,225 mg The active ingredient is passed through a No. 60 mesh U.S. sieve and suspended in the saturated fatty acid glycerides previously melted using the minimum heat 32 WO 00/35944 PCT/US99/29914 necessary. The mixture is then poured into a suppository mold of nominal 2 g capacity and allowed to cool.

Formulation Example 7 Suspensions, each containing 50 mg of active ingredient per 5 mL dose, are made as follows: Active ingredient 50 mg Sodium carboxymethyl cellulose 50 mg Syrup 1.25 mL Benzoic acid solution 0.10 mL Flavor q.v.

Color q.v.

Purified water to total 5 mL The active ingredient is passed through a No. 45 mesh U.S. sieve and mixed with the sodium carboxymethyl cellulose and syrup to form a smooth paste. The benzoic acid solution, flavor and color are diluted with a portion of the water and added, with stirring.

Sufficient water is then added to produce the required volume.

Formulation Example 8 An intravenous formulation can be prepared as follows: Active ingredient 100 mg Isotonic saline 1,000 mL The solution of the above ingredients generally is administered intravenously to a subject at a rate of 1 mL per minute.

Throughout this specification the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps.

Any discussion of documents, acts, materials, devices, articles or the like which has been included in the present specification is solely for the purpose of providing a context for the present invention. It is not to be taken as an admission that any or all of these matters form part of the prior art base or were common general knowledge in the field relevant to the present invention as it existed before the priority date of each claim of this application.

o* a a

Claims

1. A compound represented by structure I S. S. S S 55 S S. S. S. wherein R is an alkyl group, an alkenyl group, an alkynyl. group, an aryl group, or heteroaryl group; R1 is independently -OH or -O-Pg; R2 is -CH 3 -NH 2 or -NH- Pg; R 3 is -CH 3 -CH 2 CONH 2 -CH 2 CONH-Pg, -CH 2 CH 2 NH 2 or- CH 2 CH 2 NH-Pg; R 5 is -OH, -050 3 H, or -OPO 2 HR a, where R a is hydroxy, C 1 -C 6 alkyl, CI-C 6 alkoxy, phenyl., phenoxy, p-halophenyl, p-halophenoxy, p-nitrophenyl, p-nitrophenoxy, benzyl, benzyloxy, p-halobenzyl, p-halobenzyloxy, p- nitrobenzyl, orp-nitrobenzyloxy; R 6is -OH, or -050 3 H; R 7 is -H or -CH 3 R 4 and R 8 are independently, hydrogen, or hydroxy and at least one of R 4 and R 8 is a sugar moiety of the formula S. *S S S S S S. S 55*5 5* S S SSS* 555555 S 0 0V 04< where R 9 is independently -OH, -N 3 -O-Pg, -NH 2 -NH-Pg, -OPO 2 Ra, GO 2 Pg, or a second sugar moiety consisting of one to three sugar units selected from the group consisting of R 9C R 9 b 0 0 Ra 0 R 9 a R 9 a R 9a 0 0 0- R 9 C 0 0Q R 9b R Ra 9a 9a 9 and mixtures thereof, wherein R 9 a is -OH, -N 3 -NH 2 -O-Pg, or -NH-Pg, R 9 is -OPO 2 Ra, -OSO 3 H, -NH 2 -OH, -O-Pg, or -NH-Pg, Rc is -CH 3 -CH 2 OH, -CH 2 N 3 -CH 2 OSO 3 H, -CH 2 NH-Pg, -CH 2 O-Pg, -CO 2 H, or -C0 2 -Pg, where R a is as defined above, and no more than one R 9 is represented by said second sugar moiety; and each Pg is independently a protecting group or a pharmaceutically acceptable salt, ester, hydrate, or solvate thereof. S S S S. S S. S S S We S *9 5 S* S.

2. The compound of claim 1 wherein R is S. S S S S *SS* *eSS S *5 S S. S S 9 Sor where A, B, C and D are independently hydrogen, CI-CI2 alkyl, C2-CI2, alkynyl, CI-CI2 alkoxy, CI-C2, alkylthio, halo, or -0-(CH2)-[O-(CH2),lp-O-(CI-CI2 alkyl) or E; m is 2, 3 or 4; n is 2, 3 or 4; p is 0 or 1; q is 2, 3 or 4; X is pyrrolidino, piperidino or piperazino; and E is hydrogen C-C2 alkyl, C3-CI2 cycloalkyl, benzyl or C3-CI2 cycloalkylmethyl.

3. The compound of claim 2 wherein R1 is hydroxy at each occurrence; R2, R 3, and R 7 are each methyl; R is a moiety of the formula or R 4 is hydroxy; R5 is -OP02!HR a, where R a is CI-C4 alkyl or CI-C4 alkoxy; R 8 is a sugar moiety of the formula 9 0 0, R 9 0 0 0, 0 R 9 R 9 or R or i' pharmaceutically acceptable salt or solvate thereof.

4. The compound of claim 3 wherein R 5 is hydroxy; R is a moiety of the formula where D is hydrogen or C 3 -C 7 alkoxy; R 8 is a moiety of the formula where R 9 is independently hydrogen, hydroxy, amino, or a moiety of the formula S. S S S S. *085 88 SS S 8 where R 9 b is -OPO 2 Ra, -OSO 3 H, -NH 2 -OH, -O-Pg, or -NH-Pg and n is 1, 2, or 3; or a pharmaceutically acceptable salt or solvate thereof. 10

5. The compound of claim 4 wherein D is n-pentoxy, and R 9 is independently hydroxy or amino; or a pharmaceutical salt or solvate thereof.

6. The compound of claim 5 wherein R 9 is hydroxy at each occurrence; or a pharmaceutical salt or solvate thereof.

7. A pharmaceutical formulation comprising one or more pharmaceutical carriers, diluents, or excipients and a compound of any one of the preceding claims. @8 05 8

8.8 8@88 8 8 8888 08 6 8. A method of inhibiting fungal activity comprising administering to a recipient in need of such inhibition an effective amount of a compound represented by structure 1: R8r 1 wherein R is an alkyl group, an alkenyl. group, an alkynyl group, an aryl group, or heteroaryl group; R1 is independently -OH or -O-Pg; R 2 is -CH 3 NH 2 or -NH-Pg; R 3 is -CH 3 -CH 2 CONH 2 -CH 2 CONH-Pg, -CH 2 CH 2 NH 2 or-CH 2 CH 2 NH-Pg; R 5 is -OH, -OSO 3 H, or -OPO 2 HRa, where R a is hydroxy, CI-C 6 alkyl, C 1 -C 6 alkoxy, phenyl, phenoxy, p-halophenyl, p-halophenoxy, p- nitrophenyl, p-nitrophenoxy, benzyl, benzyloxy, p-halobenzyl, p- halobenzyl1oxy, p-nitrobenzyl, or p-nitrobenzyloxy; R 6is -OH, or -OSO 3 H; R 7 is -H or -CH 3 R 4 and R 8 are independently, hydrogen, or hydroxy and at least one of R4~ and R 8 is a sugar moiety of the formula 06 0 S@ 6@ sOO OS 66 S 0 6 00 6 @8.060 0 06 6 @8 0. 060 060 660 where R 9 is independently -OH, -N 3 -O-Pg, -NH 2 -NH-Pg, -OPO 2 Ra, C0 2 Pg, or a second sugar moiety consisting of one to three sugar units selected from the group consisting of R 9b R 9 b and mixtures thereof, wherein R 9 is -OH, -N 3 -NH 2 -O-Pg, or -NH-Pg, R 9 b is -OPO 2 Ra, -OSO 3 H, -NH 2 -OH, -O-Pg, or -NH-Pg, R 9 c is -CH 3 -CH 2 N 3 -CH 2 OSO 3 H, -CH 2 NH-Pg, -CH 2 0-Pg, -CO 2 H, or -C0 2 -Pg, where Ra is as defined above, and no more than one R 9 is represented by said second sugar moiety; and each Pg is independently a protecting group for a pharmaceutically acceptable salt, ester, hydrate, or solvate thereof. o

9. The method of claim 8 wherein R is -4-CA C -ItO-C-G Sor 41 where A, B, C and D are independently hydrogen, C 1 -C 2 alkyl, C 2 -C 1 2 alkynyl, Ci-Cl2 alkoxy, Ci-C 2 alkylthio, halo, or -O-(CH 2 )m-[O-(CH 2 )n]p-O-(Ci-Ci 2 alkyl) or -O-(CH2)q m is 2, 3 or 4; n is 2, 3 or 4; p is 0 or 1; q is 2, 3 or 4; X is pyrrolidino, piperidmo or piperazino; and E is hydrogen, Ci-C 2 alkyl, C 3 -C 12 cycloalkyl, benzyl or C 3 -C 1 2 cycloalkylmethyl.

The method of claim 8 or claim 9 wherein the recipient is a human.

11. The method of claim 9 wherein R' is hydroxy at each occurrence; R 2 R 3 and R 7 are each methyl; R is a moiety of the formula D C or R 4 is hydroxy; R 5 is -OPO 2 HRa, where Ra is Ci-C 4 alkyl or CI-C 4 alkoxy; R 8 is a sugar moiety of the formula o o RR 0 R R or R or or a pharmaceutically acceptable salt or solvate thereof. s

12. The method of claim 10 wherein R 5 is hydroxy; R is a moiety of the formula where D is hydrogen or C 3 -C 7 alkoxy; R 8 is a moiety of the formula S S o R R RR 9 R R 9 where R 9 is independently hydrogen, hydroxy, amino, or a moiety of the formula 0 0- 9bI R R 9aR 9a R 9 a n where R 9 b is -OPO 2 Ra, -OSO 3 H, -NH 2 -OH, -O-Pg, or -NH-Pg and n is 1, 2, or 3; or a pharmaceutically acceptable salt or solvate thereof.

13. The method of claim 12 wherein D is n-pentoxy and R 9 is independently hydroxy or amino; or a pharmaceutical salt or solvate thereof.

14. The method of claim 13 wherein R 9 is hydroxy at each occurrence; or a pharmaceutical salt or solvate thereof.

The method according to claim 8 wherein the fungal activity arises from one or more fungi selected from the group consisting of Candida albicans, Aspergillus fumigatis, and Candida parapsilosis.

16. A method of inhibiting parasitic activity comprising administering to a recipient in need of such inhibition an effective amount of a compound represented by structure I: ee* *e *eeeo e*o R 8 R 1 R1 0 0 N OH 0 N R 7 R3 N 0 OH N 0- N R R 6 wherein R is an alkyl group, an alkenyl group, an alkynyl group, an aryl group, or heteroaryl group; R1 is independently -OH or -O-Pg; R 2 is -CH 3 NH 2 or -NH-Pg; R 3 is -CH 3 -CH 2 CONH 2 -CH 2 CONH-Pg, -CH 2 CH 2 NH 2 or-CH 2 CH 2 NH-Pg; R 5 is -OH, -OSO 3 H, or -OPO 2 HRa, where Ra is hydroxy, CI-C 6 alkyl, C 1 -C 6 alkoxy, phenyl, phenoxy, p-halophenyl, p-halophenoxy, p- nitrophenyl, p-nitrophenoxy, benzyl, benzyloxy, p-halobenzyl, p- halobenzylIoxy, p-nitrobenzyl, or p-nitrobenzyloxy; R 6is -OH, or -OSO 3 H; R 7 is -H or -CH 3 R 4 and R 8 are independently, hydrogen, or hydroxy and at .:least one of R4' and R 8 is a sugar moiety of the formula or where R 9 is independently -OH, -N 3 -O-Pg, -NH 2 -N-H-Pg, -~OPO 2 GO 2 Pg, or a second sugar moiety consisting of one to three sugar units selected from 0:0 the group consisting of o 000. .0.0 RU 0 0-0 R 9a R 9a R 9 a0- 0 0-R9 0 0- R 9b R aR9a R 9a RaR 9 a R 9 a and mixtures thereof, wherein R9 is -OH, -N 3 -NH 2 -O-Pg, or -NH-Pg, R 9 is 0OP0 2 R a, -OSO 3 H, -NH 2 -OH, -O-Pg, or -NH-Pg, R 9 is -CH 3 -CH 2 OH, -CH 2 N 3 -CH 2 OSO 3 H, -CH 2 NH-Pg, -CH 2 O-Pg, -CO 2 H, or -C0 2 -Pg, where R a is as defined above, and no more than one R 9 is represented by said second sugar moiety; and each Pg is independently a protecting group for a pharmaceutically acceptable salt, ester, hydrate, or solvate thereof.

17. The method of claim 16 wherein R is 4Q-Q-A ,or S. *D where A, B, C and D are independently hydrogen, CI-C 1 2 alkyl, C 2 -C 1 2 alkynyl, C1-C12 alkoxy, CI-C 2 alkylthio, halo, or -O-(CH 2 )m,[O-(CH 2 ),p-O-(Ci-CI 2 alkyl) or -O-(CH 2)q-X-E; m is 2, 3 or 4; n is 2, 3 or 4; p is 0 or 1; q is 2, 3 or 4; X is pyrrolidino, piperidino or piperazino; and E is hydrogen, Ci-C 2 alkyl, C 3 -Cl 2 cycloalkyl, benzyl or C 3 -C 2 cycloalkylmethyl.

18. The method of claim 16 wherein the recipient is a human.

19. The method of claim 17 wherein R' is hydroxy at each occurrence; R 2 R 3 and R 7 are each methyl; R is a moiety of the formula +C D +0 C R 4 is hydroxy; R 5 is -OPO 2 HRa, where Ra is CI-C 4 alkyl or CI-C 4 alkoxy; R 8 is a sugar moiety of the formula OO O R 0 0 0 R 9 R 9 oR .R 9 or a pharmaceutically acceptable salt or solvate thereof.

The method of claim 19 wherein R 5 is hydroxy; R is a moiety of the formula where D is hydrogen or C 3 -C alkoxy; R 8 is a moiety of the formula where D is hydrogen or C3-C7 alkoxy; R 8is a moiety of the formula where R 9 is independently hydrogen, hydroxy, amino, or a moiety of the formula -n where R 9 b is -OPO 2 Ra, -OSO 3 H, -NH 2 -OH, -O-Pg, or -NH-Pg and n is 1, 2, or 3; or a pharmaceutically acceptable salt or solvate thereof.

21. The method of claim 20 wherein D is n-pentoxy and R 9 is independently hydroxy or amino; or a pharmaceutical salt or solvate thereof. 47

22. The method of claim 21 wherein R 9 is hydroxy at each occurrence; or a pharmaceutical salt or solvate thereof.

23. The method according to any one of claims 16 to 22 wherein the parasitic activity arises from Pneumocystis carinii.

24. The compound of claim 1, wherein the Pg of -O-Pg is a hydroxy protecting group, the Pg of -NH-Pg is an amino protecting group, the Pg of CH 2 CONH-Pg is an amino protecting group and the Pg of-C0 2 -Pg is a carboxy protecting group.

The method of claim 8 or 16, wherein the Pg of -O-Pg is a hydroxy protecting group, the Pg of -NH-Pg is an amino protecting group, the Pg of CH 2 CONH-Pg is an amino protecting group and the Pg of-CO 2 -Pg is a carboxy protecting group.

26. The compound of claim 1 wherein both R 4 and R 8 are a sugar moiety of the formula ro 0 0Y r R 9 R9 9 R R where R 9 is independently -OH, -N 3 -O-Pg, -NH 2 -NH-Pg, -OPO 2 R a CO 2 Pg, or a second sugar moiety consisting of one to three sugar units selected from the group consisting of 9 9 48 R 9c R 9 b 0R 9a 0 R9a R a R9a 0 0- R 9 C 0 0- R 9b R9 R Ra Ra 9a 9 and mixtures thereof, wherein R 9 a is -OH, -N 3 -NH 2 -O-Pg, or NH-.Pg, R"b is -OPO 2 R a, -OSO 3 H, -NH 2 -OH, -O-Pg, or -NH-Pg, R 9 is -CH 3 -CH 2 OH, -CH 2 N 3 -CH 2 OSO 3 H, -CH 2 NH-Pg, -CH 2 O-Pg, -CO 2 H, or -CO 2 -Pg, where R a is R a is hydroxy, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, phenyl, phenoxy, p-halophenyl, p- halophenoxy, p-nitrophenyl, p-nitrophenoxy, benzyl, benzyloxy, p-halobenzyl, p-halobenzyloxy, p-nitrobenzyl, or p-nitrobenzyloxy; -R 6 is -OH, or OSO 3 H; R 7 is -H or -CH 3 and no more than one R 9 is represented by said second sugar moiety; and each Pg is independently a protecting group or a pharmaceutically acceptable salt, ester, hydrate, or solvate thereof.

27. The compound of claim 2 wherein R' is hydroxy at each occurrence; R 2 R 3 and 7 R are each methyl; R is a moiety of the formula C or R 5is -OPO 2 HRa, where R a is CI-C 4 alkyl or C 1 -C 4 alkoxy; R 4 and R 8 are both a sugar moiety of the formula K- 0j R 9 0 6 R 9 R 9 9 9 R 9R9 or R 9 ;or a pharmaceutically acceptable salt or solvate thereof

28. The compound of claim 27 wherein R 5 is hydroxy; R is a moiety of the formula where D is hydrogen or C 3 -C 7 alkoxy; R 8 is a moiety of the formula OK *4 4 .4 44** .4 4 44 4 4 where R 9 is independently hydrogen, hydroxy, amino, or a moiety of the formula 0 0- R 9 b R 9a R 9a R 9 a In where R 9 b is -0P0 2 Ra, -OSO 3 H, -NH 2 -OH, -O-Pg, or -NH-Pg and n is 1, 2, or 3; or a pharmaceutically acceptable salt or solvate thereof. 44 4**4 44** 44@@ 4* 4. 4*4* 4 .4.4 4. 4@44 4 4 4

29. The method according to claim 8 or 16 wherein both R 4 and R 8 are a sugar moiety of the formula R 9 0 Y 0 0 VR' Ne'004 where R9 is independently -OH, -N 3 -O-Pg, -NH 2 -NH-Pg, -OPO 2 Ra, C0 2 -Pg, or a second sugar moiety consisting of one to three sugar units selected from the group consisting of R 9b FRa C 9 p. p. p. p p p p p. pp p p ppp~ pp p p p. R 9b-' 0 0- R9a R a R 9a R 9 c 0 0- V- R 9a R 9a R 9a 10 and mixtures thereof, wherein R 9 a is -OH, -N 3 -NH 2 -O-Pg, or -NH-Pg, R 9bis OPO 2 Ra, -OSO 3 H, -NH 2 -OH, -O-Pg, or -NH-Pg, R 9 c is -CH 3 -CH 2 OH, -GH 2 N 3 -CH 2 OSO 3 H, -CH 2 NH-Pg, -CH 2 O-Pg, -CO 2 H, or -C0 2 -Pg, where R a is Ra is hydroxy, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, phenyl, phenoxy, p-halophenyl, p-halophenoxy, p- nitrophenyl, p-nitrophenoxy, benzyl, benzyloxy, p-halobenzyl, p-halobenzyloxy, p- 15 nitrobenzyl, orp-nitrobenzyloxy; R 6is -OH, or -OSO 3 H; R 7is -H or -CH 3 and no more than one R 9 is represented by said second sugar moiety; and each Pg is independently a protecting group or a pharmaceutically acceptable salt, ester, hydrate, or solvate thereof.

The method according to claim 8 or 16 wherein R' is hydroxy at each occurrence; R 2 R 3 and R 7 are each methyl; R is a moiety of the formula tG- O-D C= R 5 is -OPO 2 HRa, where Ra is CI-C 4 alkyl or C 1 -C 4 alkoxy; R 4 and R 8 are both a sugar moiety of the formula (-7 .o 0$( .00j or a pharmaceutically acceptable salt or solvate thereof.

31. The method according to claim 30 wherein R 5 is hydroxy; R is a moiety of the formula S S *5 0 9S S S 5 where D is hydrogen or 3 7 alkoxy; R is a moiety of the formula where D is hydrogen or C3-C7 alkoxy; R8 is a moiety of the formula R 9 0 0 K R 9 R 9 S 0 0 where R 9 is independently hydrogen, hydroxy, amino, or a moiety of the formula 0 0 R 9 b R9a a R R 9 a n where R 9 b is -OPO 2 R a -OSO 3 H, -NH 2 -OH, -O-Pg, or -NH-Pg and n is 1, 2, or 3; or a pharmaceutically acceptable salt or solvate thereof.

32. A compound according to claim 1 substantially as herein before described with reference to any one of the Examples.

33. A method according to claim 8 or 16 substantially as herein before described with reference to any one of the Examples. Dated this twelfth day of September 2003 Eli Lilly and Company Patent Attorneys for the Applicant: F B RICE CO 6* go** *000 *S *04 06