JP2002532513A - Cyclic peptide antifungal agent having sugar substituent - Google Patents

Abstract

(57) Abstract: Described are compounds represented by structure (I) and pharmaceutically acceptable salts, esters, hydrates or solvates thereof, wherein R ⁸ represents a sugar moiety. These compounds have been shown to be useful as antifungal and antiparasitic agents, or as intermediates for such agents. Also described are methods of treatment and pharmaceutical formulations comprising the compounds represented by Structure (I). The present invention relates to antifungal / antiparasitic agents, particularly derivatives of Echinocandin compounds and their use in treating fungal and parasitic infections.

Description

DETAILED DESCRIPTION OF THE INVENTION

TECHNICAL FIELD The present invention relates to antifungal / antiparasitic agents, particularly derivatives of Echinocandin compounds and their use in treating fungal and parasitic infections.

BACKGROUND OF THE INVENTION Many naturally occurring cyclic peptides are known in the art, and Echinocandin B (A30912A), Aculeacin, Mu
Ludocandin, Sporiofugin, L-671, 329, and S31794 / F1. In general, these cyclic peptides can be structurally characterized as a cyclic hexapeptide core (or nucleus) having an acylated amino group on one core amino acid. The acyl group is typically a fatty acid moiety that forms a side chain away from the nucleus. For example, Echinocandin B has a linol oil side chain, while Aculeacin has a palmitoyl side chain.

[0003] These natural products have limited intrinsic antifungal and antiparasitic properties. These natural compounds can be structurally modified to enhance their properties or improve the stability and / or water solubility of the compound. Turner et al., Cur. Pharm. Des. 2: 209 (1996). For example, a fatty acid chain is removed from the cyclic peptide core to provide an amino nucleus, which can then be reacylated to provide a semi-synthetic compound.

SUMMARY OF THE INVENTION [0004] Provided are compounds represented by the following structure I and pharmaceutically acceptable salts, esters, hydrates or solvates thereof:

[0005]

Embedded image Wherein R is an alkyl, alkenyl, alkynyl, aryl, or heteroaryl group; R ¹ is independently —H, —OH, or —O—Pg; R ² is -H, -CH _3, -NH _2, or be a -NH-Pg,; R ³ is -
_{H, -CH 3, -CH 2 CONH} 2, -CH 2 CONH-Pg, -CH 2 CH 2 NH 2
Or —CH ₂ CH ₂ NH—Pg; R ⁴ is —H, —OH, or —O—
It is pg; R ⁵ is, -OH, an -OSO ₃ H, or -OPO ₂ HR ^a, where R ^a, 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 -H, -OH, or be a -OSO ₃ H,; R ⁷ is H or -CH _3; t is an 2-7 integer; R ⁸ has the following formula sugar Part

[0006]

Embedded image Here, R ⁹ is independently -H, -OH, -N ₃ , -O-Pg, -NH ₂ , -N
H-Pg, or a second saccharide moiety having 1 to 3 saccharide units selected from the group consisting of:

[0007]

Embedded imageWhere R^9aIs -H, -OH, -N_Three, -NH_Two, -O-Pg, or -NH-
Pg and R^9bIs -OPO_TwoR^a, -OSO_ThreeH, -H, -NH_Two, -OH,-
O-Pg or -NH-Pg;^9cIs -CH_Three, -CH_TwoOH, -CH _Two N_Three, -CH_TwoOSO_ThreeH, -CH_TwoNH-Pg, -CH_TwoO-Pg, -CO_TwoH,
Or -CO_Two-Pg, where R^aIs as defined above,
Then R is only one⁹But as long as it is represented by the second sugar moiety;
(I.e., -O-Pg is a hydroxy protecting group, -NH-Pg is
An amino group, -CH_TwoCONH-Pg is an amide protecting group and_Two -Pg is a carboxy protecting group).

[0008] The invention relates to one or more pharmaceutical carriers, diluents or excipients and structures I as described above.
And pharmaceutical formulations of the compounds represented by

The present invention further includes a method of inhibiting fungal and parasite activity by administering to a recipient in need thereof an effective amount of a compound represented by Structure I.

“Alkyl” means, unless otherwise stated, a general formula C _n containing from 1 to 30 carbon atoms.
Refers to a hydrocarbon group of H _{2n + 1} . An alkane group can be straight, branched, cyclic, or polycyclic. An alkane group may be substituted or unsubstituted.
Similarly, the alkoxy, alkylthio or alkyl portion of the alkanoate has the same definition as above.

“C ₁ -C ₁₂ alkyl” refers to a straight or branched saturated alkyl chain having 1 to 12 carbon atoms. C ₁ -C ₁₂ alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl,
sec-butyl, t-butyl, pentyl, 5-methylpentyl, hexyl, heptyl, 3,3-dimethylheptyl, octyl, 2-methyl-octyl, nonyl,
Decyl, undecyl and dodecyl. “C ₁ -C ₁₂ alkyl” includes “C ₁ -C ₆ alkyl”, “C ₁ -C ₄ alkyl”, “C ₃ -C ₁₂ cycloalkyl”.

“C ₃ -C ₁₂ cycloalkyl” refers to a cyclic saturated alkyl chain having 3 to 12 carbon atoms. Moreover, "C ₃ -C ₁₂ cycloalkyl", "C ₃ -C ₇ cycloalkyl", i.e., including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

“C ₁ -C ₁₂ alkoxy” refers to a C ₁ -C ₁₂ alkyl group attached through an oxygen atom. The C ₁ -C ₁₂ alkoxy groups include but are but not limited to: methoxy, ethoxy, propoxy, butoxy, sec- butoxy, n- pentoxy, 5-methyl - hexoxy, heptoxy, octyloxy, decyloxy and Dodecyloxy. “C ₁ -C ₁₂ alkoxy” includes “C ₁ -C ₆ alkoxy”, “C ₃ -C ₇ alkoxy”, and “C ₁ -C ₄ alkoxy”.

“C ₁ -C ₁₂ alkylthio” refers to C ₁ -C ₁₂ alkyl bonded through a sulfur atom.
Refers to an alkyl group. The C ₁ -C ₁₂ alkylthio group, but less is not limited to,: methylthio, ethylthio, propylthio, isopropylthio, butylthio, 3-methyl - heptylthio, octylthio, and 5,5-dimethyl - hexylthio. “C ₁ -C ₁₂ alkylthio” includes “C ₁ -C ₆ alkylthio” and “C ₁ -C ₄ alkylthio”.

“Alkenyl” refers to an acyclic hydrocarbon containing at least one carbon-carbon double bond. Alkene groups can be straight, branched, cyclic, or polycyclic. An alkene group can be substituted or unsubstituted.

“Alkynyl” refers to an acyclic hydrocarbon containing at least one carbon-carbon triple bond. An alkyne group can be straight or branched. An alkyne group can be substituted or unsubstituted.

“C ₂ -C ₁₂ alkynyl” refers to a straight or branched monoalkynyl chain having 2 to 12 carbon atoms. The C ₂ -C ₁₂ alkynyl group include but are not limited to: ethynyl, 1-propyn-1-yl, 1-propyn-2-yl, 1-butyn-1-yl, 1-butyne -3-yl, 1-pentyn-3-yl, 4-pentyn-2-yl, 1-hexyn-3-yl, 3-hexyn-1-yl, 5-methyl-3-hexyn-1-yl, 5 -Octin-1-yl, 7-octin-1-yl, 4-decin-1-yl and 6-decyn-1-yl.

“Aryl” refers to an aromatic moiety having a single ring system (eg, phenyl) or a fused ring system (eg, naphthalene, anthracene, phenanthrene, etc.). An aryl group can be substituted or unsubstituted. A substituted aryl group comprises a chain of aromatic moieties (eg, biphenyl, terphenyl, phenylnaphthalyl, etc.).

“Heteroaryl” refers to an aromatic moiety that contains at least one heteroatom in the aromatic ring system (eg, pyrrole, pyridine, indole, thiophene, furan, benzofuran, imidazole, pyrimidine, purine, benz) Imidazole, quinoline, etc.). The aromatic moiety can be a single ring system or a fused ring system. Heteroaryl groups can be substituted or unsubstituted.

In the field of organic chemistry, and especially in the field of organic biochemistry, it is widely understood that significant substitution of compounds is acceptable or still useful. In the present invention, for example, the term alkyl group refers to a substituent that is a typical alkyl (eg, methyl, ethyl, propyl, n-butyl, i-butyl, t-butyl, hexyl, isooctyl, dodecyl, stearyl, etc.). To give permission. The term group refers to, in particular, substitutions on alkyls that are common in the art (eg, hydroxy, halogen, alkoxy, carbonyl, keto, ester, carbamat).
o) etc. are envisioned and permitted and include unsubstituted alkyl moieties. However, it is generally understood by those skilled in the art that substituents should be selected so as not to adversely affect the pharmacological properties of the compound or interfere with the use of the medicament. The same is true for each of the other groups (ie, aryl, alkynyl, alkenyl, heteroaryl). Suitable substituents for any of the above defined groups include alkyl, alkenyl, alkynyl, aryl, halo, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, mono- and di-alkylamino, quaternary Examples include ammonium salts, aminoalkoxy, hydroxyalkylamino, aminoalkylthio, carbamyl, carbonyl, carboxy, glycolyl, glycyl, hydrazino, guanyl, and combinations thereof.

“Halo” refers to chloro, fluoro, bromo and iodo.

“O—Pg” and “hydroxy protecting group” are commonly used hydroxy groups to block or protect a hydroxy function while a reaction is performed on another function in the compound. Means a substituent. The substituent, together with the oxygen to which it is attached, can be combined with an ether (eg, methyl, methoxymethyl, and benzyloxymethyl ether, silyl ether), ester (eg, acetoxy), or sulfonate moiety (eg, methane And p-toluenesulfonate). The actual genus and species of the hydroxy protecting group will be appropriate at the point where the derivatized hydroxy group is appropriate for the condition (s) of the subsequent reaction (s) and this protecting group will not disrupt the residues of the molecule. Not important as long as it can be removed. A preferred hydroxy protecting group is acetyl. Specific examples of hydroxy protecting groups are described in Greene, "Protective Groups in O."
rgnic Synthesis ", John Wiley and Son
s, New York, N.M. Y. (2nd edition, 1991), ("Greene")
It is described in Chapters 2 and 3 and the Preparations and Examples section that follows.

“NH _p -Pg” and “amino protecting group” are amino group substituents commonly used to block or protect amino functions during the reaction of other functional groups in a compound Say. When p is 0, the amino protecting group, when taken together with the nitrogen atom to which it is attached, forms a cyclic imide (eg, phthalimide and tetrachlorophthalimide). When p is 1, the protecting group, when taken together with the nitrogen atom to which it is attached, is a carbamate (eg, methyl, ethyl, and 9-fluorenylmethyl carbamate); or an amide (eg, N-
Formyl and N-acetylamide). The actual genus and species of amino protecting group used are such that the derivatized amino group is stable to the conditions of the subsequent reaction (s) at other positions of the intermediate molecule and that the protecting group is Is not critical, as long as it can be selectively removed at the appropriate point without disrupting the residues of the molecule, including any other amino protecting group (s). Preferred amino protecting groups are t-butoxycarbonyl (t-Boc), allyloxycarbonyl, phthalimide, and benzyloxycarbonyl (CbZ).
Further examples of groups referred to by the above terms are described in Chapter 7 of Greene.

“—CO ₂ —Pg” and “carboxy protecting group” are commonly used to block or protect a carboxy function while a reaction is performed on another function in the compound. Refers to a substituent of carbonyl. The substituents may be taken together with the carbonyl group to which it is attached, an ester (e.g., C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, substituted C ₂ -C ₆ Alkenyl, benzyl,
Substituted benzyl, benzhydryl, substituted benzhydryl, trityl, substituted trityl, and trialkylsilyl esters). The actual genus of carboxy protecting groups is that the derivatized hydroxy group is stable to the conditions of the subsequent reaction (s) and that the protecting group is suitable without disrupting the residues of the molecule. It doesn't matter as long as it can be eliminated at a certain point. Other examples of groups referred to by the above terms are described in Chapter 5 of Greene.

“C (O) NH—Pg” and “amide protecting group” refer to those amides commonly used to block or protect this amino moiety while reacting other functional groups on a compound. Refers to a substituent. The protecting group, when taken together with the nitrogen atom to which it is attached, can form an amide (eg, N-allyl, N-methoxymethyl, and N-benzyloxymethylamide). The actual species of amide protecting group used is such that the derivatized amide group is stable to the conditions of the subsequent reaction (s) at other positions of the intermediate molecule and that the protecting group is It is not important as long as it can be selectively removed at the appropriate point without disrupting the residues of the molecule, including any other amide protecting group (s). Other examples referred to by the above terms are described in Greene Chapter 7, page 397.

“Carbonyl activating group” refers to a carbonyl substituent that promotes a nucleophilic addition reaction at the carbonyl. Suitable activating substituents are those having a net electron withdrawing effect at the carbonyl. Such groups include, but are not limited to, alkoxy, aryloxy, nitrogen-containing aromatic heterocycles, or amino groups such as oxybenzotriazole, imidazolyl,
Nitrophenoxy, pentachlorophenoxy, N-oxysuccinimide, N,
N'-dicyclohexylisole-O-yl (N, N'-dicyclohexy)
acetate-, formate, sulfonate (eg, methanesulfonate, ethanesulfonate, benzenesulfonate, or p-tolylsulfonate); and halides (eg, chloride, bromide) Or iodine).

“Pharmaceutical” or “pharmaceutically acceptable” means substantially non-toxic and substantially harmless to the recipient. "Pharmaceutical formulation" means that the carrier, solvent, excipients and salts are compatible with the active ingredient of the above formula (ie, Compound I).

“Pharmaceutical salt” or “pharmaceutically acceptable salt” refers to a salt of the compound represented by Structure I, which is substantially non-toxic to recipients at the dose administered. . Typical pharmaceutical salts include those prepared by reacting a compound of the present invention with an inorganic or organic acid or inorganic base. Such salts are known as acid addition and base addition salts. For further illustration, for example, Berg
e. Pharm. Sci. , 66: 1 (1997).

A “solvate” refers to a combination of one or more solvates (eg, a compound of Formula I) with one or more molecules of a pharmaceutical solvent, including, but not limited to, water and ethanol. Aggregates containing. A "suitable solvent" is any solvent or mixture thereof, which is inert to the ongoing reaction that solubilizes the reactants in the medium sufficiently to carry out the desired reaction. .

A “thermodynamic base” provides a reversible deprotonation of an acidic substrate or is a proton trap for protons produced as reaction by-products and significantly reduces any undesired reactions. A base that is sufficiently reactive to carry out the desired reaction without being carried out. Examples of thermodynamic bases include but are not limited to: acetate, acetate dihydrate, carbonate, bicarbonate, C ₁ -C ₄ alkoxide, and hydroxides (e.g., silver, lithium, sodium Or potassium acetate, acetate dihydrate,
Carbonate, bicarbonate, methoxide, or hydroxide), tri-
(C ₁ -C ₄ alkyl) amine, or an aromatic ring containing an aromatic nitrogen atom (for example,
Imidazole and pyridine).

“Inhibiting” refers to preventing, stopping, delaying, alleviating, improving, interrupting, limiting progress,
Slowing or reversing, or reducing the severity of growth or any additional features, symptoms and consequences resulting from the presence of parasites or fungi. These methods may be used where appropriate for medical therapeutic (acute) administration and / or prophylactic (
Prophylaxis) administration.

“Effective amount” refers to an amount of a compound of Formula I that can inhibit fungal and / or parasite activity.

“Recipient” includes mammals, preferably humans.

DETAILED DESCRIPTION OF THE INVENTION The compounds represented by structure I have now been found to be useful as antifungal and antiparasitic agents, or as intermediates thereof. I have. The most convenient means of producing a compound represented by structure I is by modification of a naturally occurring compound.

For illustrative purposes, Scheme I (below) describes a specific Echinocandi
Start with the n derivative. However, one could start with any natural product, semi-synthetic or synthetic Echinocandin-type compound that has a hemiaminal group.

The term “Echinocandin-type compound” refers to compounds having the following general structure, including any simple derivatives thereof, and pharmaceutically acceptable salts, esters, hydrates or solvates thereof. . :

[0037]

Embedded image Wherein R is an alkyl, alkenyl, alkynyl, aryl, or heteroaryl group; R ¹ is —H or —OH; R ² is —H, —NH ₂
Or be -CH _3; R ³ is _{-H, -CH 3, -CH 2 CONH} 2 or -CH ₂ C
It is H ₂ NH _2; R ⁴ is -H or -OH; R ⁵ is -OH, a -OSO ₃ H or -OPO ₂ HR ^a, where R ^a 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-
A nitro benzyloxy; R ⁶ is -H, -OH, or be a -OSO ₃ H;
R ⁷ is -H or -CH _3.

“Natural products” are these secondary metabolites, usually of a relatively complex structure, which is a more limited distribution of a particular source in nature and a more characteristic It is a target. Suitable natural product starting materials of the Echinocandin cyclopeptide family include Echinocandin B, Echinocand
din C, Aculeacin Aγ, Mulundocandin, Spo
riofugin A, Pneumocandin A ₀ , WF11899A,
And Pneumocandin B ₀ and the like.

The cyclic peptide used in the present invention can be produced by culturing various microorganisms. In general, the cyclic peptide can be characterized as a cyclic hexapeptide nucleus having an acylated amino group at one of the amino acids. Amino groups on naturally occurring cyclic peptides are typically acylated with fatty acid groups to form the core side chains. Examples of naturally occurring acyl groups include linoleoyl.
1) (Echinocandin B, C and D), palmitoyl (Acul
eacin Aγ and WF11899A), stearoyl, 12-methylmyristoyl (Mulundocandin), 10,12-dimethylmyristoyl (Sporiofungin A and Pneumocandin A ₀ ).

Semi-synthetic derivatives can generally be prepared by removing fatty acid side chains from the cyclic peptide nucleus to produce free amino acids (ie, without a pendant acyl group, -C (O) R). . The free amine is then reacylated with an appropriate acyl group. For example, the Echinocandin B nucleus is reacylated with certain non-naturally occurring side chain moieties to provide a number of antifungal agents. U.S. Pat. No. 4,293,489. The N-acyl side chain contains various side moieties known in the art. Suitable side chain moieties include substituted and unsubstituted alkyl, alkenyl, alkynyl, aryl, heteroaryl and combinations thereof. Preferably, the side chain contains both a linear rigid portion and a flexible alkyl portion to maximize antifungal efficacy. Representative examples of preferred acyl side chains include R groups having the following structure:

[0041]

Embedded image(Where A, B, C and D are independently hydrogen, C₁~ C₁₂Alkyl, C_Two~ C ₁₂ Alkynyl, C₁~ C₁₂Alkoxy, C₁~ C₁₂Alkylthio, halo, or-
O- (CH_Two)_m-[O- (CH_Two)_n]_p-O- (C₁~ C₁₂Alkyl) or -O
− (CH_Two)_qM 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, C₁~ C₁₂Alkyl, C_Three ~ C₁₂Cycloalkyl, benzyl or C_Three~ C₁₂Is cycloalkylmethyl
).

Scheme I illustrates the general semi-synthetic route described above, where the natural product (Compound II (a)) is modified to provide an intermediate (Compound II (d)), and then Further modifications are provided to provide representative examples of Compound I, as illustrated in II.

[0043]

Embedded image The cyclic peptide represented by structure II (a) can be prepared by fermentation of known microorganisms. For example, a cyclic peptide II (a) wherein R ¹ and R ⁴ are each hydroxy and R ² , R ³ and R ⁷ are each methyl (the cyclic nucleus is A-3091
2A) can be prepared using the procedures detailed in US Pat. No. 4,293,482. A cyclic peptide II (a) wherein R ¹ is hydroxy, R ² , R ³ and R ⁷ are each methyl and R ⁴ is hydrogen (the cyclic nucleus is A-309
12B) can be prepared using the procedure detailed in US Pat. No. 4,299,763. Aculeacin can be prepared using the procedure detailed in US Pat. No. 3,978,210. Cyclic peptide II (a) in which R ³ is CH ₂ C (O) NH ₂ , R ⁷ is methyl, R ² is hydrogen, and R ¹ and R ⁴ are hydroxyl is disclosed in US Pat. , 198,421.

The cyclic peptide II (a) is deacylated using procedures known in the art,
It may provide an amino nucleus represented by structure II (b). This reaction is typically performed enzymatically by exposing a naturally occurring cyclic peptide to a deacylase enzyme. This deacylase enzyme is based on the microorganism Actinoplanes utahe.
nsis and can be used substantially as described in U.S. Patent Nos. 4,293,482 and 4,304,716. The deacylase enzyme can also be obtained from Pseudomonas species. Deacylation is described in A. uta
hensis or Pseudomonas cells can be achieved using whole or purified enzymes thereof or using immobilized forms of the enzymes. See European Patent Application No. 0 460 882. Examples of naturally occurring cyclic peptides that can be used as starting materials include acleacin (palmitoyl side chain), tetrahydroechinocandin B (stearoyl side chain), mulundocandin (branched C ₁₅ side chain), L-671,32
9 (C ₁₆ branched side chain), S31794 / F1 (tetradecanoyl side chain), spo
riofungin (C ₁₅ branched side chain), FR901379 (palmitoyl side chain), but is not limited thereto. Preferred cyclic peptides are echi
nocandin B (compound II wherein R ¹ and R ⁴ are each hydroxy, R ² , R ³ and R ⁷ are each methyl, and R ^nat is linoleoyl
(A)).

The amino nucleus II (b) is disclosed in US Pat. Nos. 5,646,111 and 5,
Reacylated by the procedure taught in US Pat. No. 693,611 to provide compounds represented by structure II (c). See Preparation 12 below for an example of this conversion. For the preparation of an acyl group at R, see US Pat. No. 5,646,111
See also US Pat. No. 5,693,611. Cyclic peptides II (c) wherein R contains one or more heterocyclic rings can be prepared as taught in US Pat. No. 5,693,611.

Next, compound II (d) was prepared according to Antibiotics, 51: 239-
242 (1998) and US Pat. No. 5,652,213, and can be prepared by the selective etherification of compound II (c).

The compound represented by Structure I, as illustrated in Scheme II below,
Can be prepared from a compound of structure II (d), wherein R ¹⁰ is a carbonyl active group and t, R, R ¹ , R ² , R ³ , R ⁴ , R ⁷ and R ⁹ are defined above It was as done.

[0048]

Embedded image Compound I can be prepared by adding either compound III or IV to compound II (a) dissolved or suspended in a suitable solvent in the presence of a suitable thermodynamic base. A convenient and preferred solvent for this reaction is dimethylformamide, while a convenient and preferred base is triethylamine. The reaction can be carried out from 0 ° C. to the reflux temperature of the mixture, but is typically carried out at ambient temperature for about 24 hours. See Example 1 below for examples of specific reaction conditions.

Compounds represented by structures III and IV are known in the art and, if not commercially available, can be synthesized by techniques well known in the art of synthetic chemistry. Collins et al., "Monosaccharides: Their.
Chemistry and Their Roles in Natural
Products "John Wiley and Sons, New York
, NY, 1995; and "Methods in Carbohydrate."
Chemistry ", Volume 6, Academic Press, New Y
ork, N .; Y. , 1980.

Compounds III and IV where R ⁹ is hydroxy are known as carbohydrates or monosaccharides (sugars). These sugars can be modified by replacing one or more hydroxy groups with hydrogen, azide or amino, and include compounds III and IV, including disaccharides and polysaccharides, where R ⁹ is a second sugar moiety. ) Are provided. Such compounds can be prepared as illustrated in Scheme 3 below, where Lg is an activated hydroxy leaving group.

[0051]

Embedded image Commercially available compound VI may have hydroxyl group (s) activated for nucleophilic substitution by standard techniques known in the art. For example, the hydroxyl group may be methane-, benzene-, or p-toluene-sulfonyl chloride (
Or bromide) with Lg being OSO ₂ Me, OSO ₂ −
Compound VII is provided which is phenyl or OSO ₂ -p-toluenyl. At this point, the leaving group can be displaced by an azide ion, for example, from sodium or potassium azide. Alternatively, the leaving group may be replaced by an iodide ion, for example from sodium or potassium iodide.
The resulting compound VIII is reduced by catalytic hydrogenation or by using a reducing agent such as nickel chloride hexahydrate to obtain a compound IX wherein one or more of R ^9a or R ^9b is amino or hydrogen. Can be formed. The final product, compound I
In the above, when an amino group is desired, it is preferable that any azide group is converted to an amino group after coupling with the compound II (d).

Compound I wherein any R ⁹ is amino may be formed from compound I wherein R ⁹ is azide, as described by analogous procedures well known in the art. For example, La
rock, “Comprehensive Organic Transformer
nations ", p. 409, VCH Publishers, New York.
k, N. Y. , 1989.

Compound I wherein R ⁵ , R ⁹ , R ^9a , R ^9b , and / or R ^9c is a hydroxy group may be an appropriately substituted dichloro-phosphate or a compound of formula V

[0054]

Embedded imagePhosphorylation or phosphorylation by reaction with a phosphonic acid in the presence of a suitable base.
Which can be provided in a chlorinated form and then worked up with water to give R^Five, R⁹, R^9a, R ^9b And / or R^9cHas the formula:

[0055]

Embedded image To produce compound I. Suitable bases include lithium trimethylsilanolate (LiOTMS), and lithium bis (trimethylsilyl) amide (L
HMDS). Preferred solvents are aprotic solvents such as tetrahydrofuran and / or dimethylformamide. US Patent No. 5,693
611.

Alternatively, compounds represented by structure I, wherein R ^9b is hydroxy and / or R ^9c is hydroxymethyl, may be sulfated by reaction with a suitable sulfating agent. Guiseley et al. Org. Chem. , 26: 1248 (196
1). A protected compound of structure I may be removed from its protecting group to form deprotected compound I. Initial selection of protecting groups, and methods for their removal, are well-known in the art. See, for example, Greene.

Pharmaceutical salts are typically formed by reacting Compound I with an equimolar or excess amount of an acid or base. These reactants generally include diethyl ether, tetrahydrofuran, methanol, ethanol,
Mutual solvents such as isopropanol, benzene and the like, or, for base addition salts, water, alcohol or chlorinated solvents such as methylene chloride.
solvent). These salts precipitate from the solvent, usually within about 1 hour to about 10 days, and can be isolated by filtration or other conventional methods.

The acids generally used to form the acid addition salts include inorganic acids including, but not limited to, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and p-toluenesulfonic acid And organic acids such as methanesulfonic acid, ethanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, tartaric acid, benzoic acid and acetic acid.

Base addition salts include those derived from inorganic bases, including, but not limited to, ammonium or alkali or alkaline earth metal hydroxides, carbonates, bicarbonates. Useful bases for preparing the salts of the present invention include sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate, It is not limited to these.

Certain counterions that form part of any of the salts of the present invention have no significant properties,
However, the salt as a whole is pharmaceutically acceptable, and the counterion does not contribute to the properties of the salt as a whole, which is undesirable. Preferred pharmaceutical acid addition salts are salts formed with mineral acids, such as hydrochloric acid and sulfuric acid, and salts formed with organic acids, such as maleic acid, tartaric acid, and methanesulfonic acid. Preferred pharmaceutical base addition salts are in the form of potassium and sodium salts.

[0061] Preferred compounds of the present invention is a compound or a pharmaceutically acceptable salt or solvate thereof represented by the structure I, wherein, R ¹ is is hydroxy at each occurrence; R ⁴ is R ² , R ³ , and R ⁷ are each methyl; R is of the formula:

[0062]

Embedded image And ^Ra is methyl or methoxy. More preferably, R ⁵ is hydroxy; R is of the formula:

[0063]

Embedded image R ⁸ is of the formula:

[0064]

Embedded image Be a part; D is hydrogen or C ₃ -C ₇ alkoxy; R ⁹ is independently hydrogen, hydroxy, amino, or a moiety of the formula:

[0065]

Embedded image (Where R ^9b is —OPO ₂ R ^a , —OSO ₃ H, —H, —NH ₂ , —OH, —O
-Pg, or -NH-Pg, wherein n is 1, 2, or 3), or a pharmaceutically acceptable salt or solvate thereof. Even more preferably, compounds wherein D is n-pentoxy; R ⁹ is independently hydroxy or amino, or a pharmaceutically acceptable salt or solvate thereof. Most preferred is a compound wherein R ⁹ is hydroxy at each occurrence; and t is 2 or a pharmaceutically acceptable salt or solvate thereof.

The optimal time to carry out the reactions of Schemes 1-3 can be determined by monitoring the progress of the reaction by conventional chromatographic techniques. The choice of reaction solvent is generally critical as long as the solvent used is inert to the ongoing reaction, sufficiently solubilizes the reactants and provides a medium that affects the desired reaction. is not. Unless otherwise indicated, all of the reactions described herein are preferably performed under an inert atmosphere. The preferred inert atmosphere is nitrogen. Once the reaction is complete,
The intermediate compound can be isolated by procedures well known in the art, for example, the compound can be crystallized or precipitated and then collected by filtration, or the reaction solvent can be extracted, evaporated, or decanted. Can be removed. This intermediate compound can, if desired, be prepared prior to performing the next step in the reaction scheme.
It can be further purified by conventional techniques, such as, for example, crystallization, precipitation, or chromatography on a solid support such as silica gel, alumina and the like.

The following examples are illustrative, but not limiting, of the present invention. All references cited herein are hereby incorporated by reference.

The following preparations and examples further describe the synthesis of the compounds. "High-speed atom bombardment mass spectrometry" and "High-performance liquid chromatography"
B) "and" HPLC ".

(Preparation 1)

[0070]

Embedded image A-30912A nucleus (60.2 mmol) and 2,4,5-trichlorophenol ester of [(4 "-pentyloxy) -1,1 ': 4', 1" -terphenyl] -4-carboxylic acid ( 26.0 g, 48.2 mmol) were combined in 8.5 L of dimethylformamide. The resulting reaction mixture was stirred at room temperature (RT) for about 48 hours, and the solvent was removed under vacuum to give a residue. The residue was slurried in ether, collected by filtration, washed with methylene chloride, and dissolved in methanol or a 1: 1 (v / v) acetonitrile / water mixture. The resulting solution is subjected to reverse phase HPLC (C18; elution of 20-40% aqueous acetonitrile containing 0.5% monobasic ammonium phosphate (w / v); 20 mL / min; 230 nm). After removing unreacted A30912A nucleus, the desired product is eluted from the column using aqueous acetonitrile elution. The fractions containing the desired product are combined and then concentrated under vacuum or lyophilized to give 18 mg of the title compound. MS (FAB): 1140
. 5103 (M ^{+ l} ).

(Preparation 2)

[0072]

Embedded image The compound of Preparation 1 (1.08 g, 0.9 mmol) and ethanolamine hydrochloride (185 mg, 1.9 mmol) were dissolved in about 20 mL of dimethyl sulfoxide. Hydrogen chloride is sprayed on the solution for about 5 seconds (blow o).
ver). The resulting mixture was stirred at room temperature under nitrogen for 28 hours. The reaction solution was subjected to reverse phase HPLC (elution of 60% acetonitrile in water containing 0.1% trifluoroacetic acid (v / v); 40 mL / min; 280 nm). Fractions containing the desired product were combined and concentrated under vacuum or lyophilized to give the title compound. MS (FAB): 1183.5577 (M + H). Examples 1 and 2 Examples 1 and 2 have the following basic structure:

[0073]

Embedded image (Example 1)

[0074]

Embedded image α-D-galacturonic acid (388 mg, 2.0 mmol) and N-hydroxysuccinimide (NHS) (230 mg, 2.0 mmol) were dissolved in anhydrous dimethylformamide. The mixture is cooled in an ice bath under nitrogen and dicyclohexylcarbodiimide (DCC) (412 mg, 2.0 mmol
) Was added. The ice bath was removed and the resulting mixture was stirred overnight,
The reaction solution was then filtered directly into a flask containing the compound of Preparation 2 (240 mg, 0.2 mmol). Then, triethylamine (0.030 mL,
0.2 mmol) is added and the resulting mixture is stirred at room temperature under nitrogen for 48 hours.
Stirred for hours. The resulting solution was subjected to reverse phase HPLC (C18; elution of 60% acetonitrile in water; 280 nm). Fractions containing the desired product were combined and then concentrated under vacuum or lyophilized to give the title compound. MS (FAB):
1381 (M ⁻ + Na).

(Example 2)

[0076]

Embedded image D-glucuronic acid (194 mg, 1.0 mmol) and the compound of Preparation 2 were converted to the title compound by the procedure of Example 1.

This compound represented by Structure I has been shown to exhibit various antifungal and antiparasitic activities to various degrees. For example, compounds of structure I can inhibit the growth of various infectious fungi, including: Candida spp
. (Eg, C. albicans, C. parapsilosis, C. kr)
use, C.I. glabrata, C.I. tropicalis or C.I. rus
itaniae), Torulopus spp. (For example, T. glabra
ta), Aspergillus spp. (For example, A. fumigatus
), Histoplasma spp. (Eg, H. capsulatum)
, Cryptococcus spp. (Eg, C. neoformans)
Blastomyces spp. (Eg, B. dermatitidis
), Fusarium spp. , Trichophyton spp. , Ps
eudalescheria boydii, Coccidioides i
mmitis, Sporothrix schenckii and the like.

The antifungal activity of a test compound is determined in vitro by obtaining a minimum inhibitory concentration (MIC) of the compound using a standard agar dilution test or a disk diffusion test. The compound is then tested in vivo (mouse) to determine an effective dose to control systemic fungal infection.

Accordingly, representative compounds of the present invention have been tested and presented for antifungal activity against at least one of the following fungi: albicans, C.I. par
apsilosis, C.I. neoformans, Histoplasmas
pp and A.I. fumigatus.

The compounds also inhibit the growth of certain organisms that are primarily responsible for opportunistic infections in immunosuppressed individuals. For example, this compound is a Pneumocystis
carinii, an organism responsible for Pneumocystis pneumonia (PCP) in AIDS and other immunocompromised recipients. "T
opley and Wilson's Microbiology and
Microbial Infections ", Volume 5, Chapter 22, Oxfor
d University Press, Inc. New York, N .; Y
. , 1998. Other protozoa inhibited by the compounds of formula I include: Plasmodium spp. , Leishmania spp
. , Trypanosoma spp. , Cryptosporium s
pp. , Isospora spp. , Cyclospora spp. , Tr
ichomonas spp. , Microsporidiosis spp.
Such.

The administered dose of the compound represented by structure I will vary depending on factors such 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. Let it. Similarly, the particular dosage regimen can be varied according to such factors and can be given in a single daily dose or in multiple doses during the day. This regimen can last from about 2-3 days to about 2-3 weeks or longer. A typical daily dose (single dose or divided dose) will contain a dosage level of about 0.01 mg to about 100 mg of active compound per kg of body weight. Preferred daily doses generally range from about 0.1 mg / kg to about 60 m.
g / kg, more preferably about 2.5 mg / kg to about 40 mg / kg.

Compound I can be administered parenterally, for example, using intramuscular, subcutaneous or intraperitoneal injection, nasal, or oral means. In addition to these modes of administration, Compound I
Can be applied topically for skin infections.

The present invention also provides useful pharmaceutical formulations for administering the compounds of the present invention. The active ingredient in such formulations comprises from 0.1% to 99.99% by weight of the formulation.
9%, and more usually from about 10% to about 30% by weight.

For parenteral administration, the formulation comprises Compound I and a physiologically acceptable diluent (eg, deionized water, saline, 5% dextrose, and other commonly used diluents). . The formulation may include a solubilizing agent, such as polyethylene glycol or polypropylene glycol or other known solubilizing agents. Such formulations may be made up in a sterile vial containing the active ingredient and one or more excipients, either in dry powder form or in lyophilized powder form. Prior to use, a physiologically acceptable diluent is added and the solution is drawn up with a syringe for administration to the recipient.

This pharmaceutical formulation is prepared by known procedures using known and readily available ingredients. To make the compositions of the present invention, the active ingredient will generally be mixed with or diluted with a carrier, or may be a carrier, such as a capsule, sachet, paper or other container. ). When the carrier acts 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 composition comprises tablets, pills,
Powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solids or in liquid media), ointments (for example containing up to 10% by weight of active ingredient), ointments It can be in the form of gelatin or 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. Tablets may also contain binders, dispersants or other excipients suitable for preparing tablets of a suitable size for administration, and certain compounds of formula I.
For pediatric or elderly use, the active ingredients may be formulated in flavored liquid suspensions, solutions or emulsions. Preferred oral formulations include linoleic acid, cr
emophor RH-60 and water, and preferably 8% linoleic acid, 5% cremophor RH-60, 87% sterile water, and about 2.5 to
In the amount (by volume) of the compound of formula I in an amount of about 40 mg / mL.

For topical use, the active ingredients are formulated with a dry powder for application to the skin, which is formulated in a liquid formulation, including solubilized or non-aqueous solutions (eg, alcohols or glycols). obtain.

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

Formulation Example 1 Hard gelatin capsules are prepared using the following ingredients: Amount (mg / capsule) Active ingredient 250 Starch (dry) 200 Magnesium stearate 10 Total 460 mg Formulation Example 2 Tablet Is prepared using the following ingredients: Amount (mg / capsule) Active ingredient 250 Cellulose (crystal) 400 Silicon dioxide (fumed) 10 Stearic acid 5 Total 665 mg Blend these ingredients, and Compress to form tablets of 665 mg each.

Formulation Example 3 An aerosol solution is prepared to contain the following ingredients: Weight Active Ingredient 0.25 Ethanol 25.75 Spray 22 (Chlorodifluoromethane) 74.00 Total 100.00.

The active compound is mixed with ethanol and the mixture is added to part of the propellant 22, cooled to −30 ° C. and transferred to a filling device. The required amount is then placed in a stainless steel container and diluted with the rest of the spray. Next, the valve unit is attached 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 (sodium) carboxymeth
yl star) 4.5 mg magnesium stearate 0.5 mg talc 1 mg 150 mg in total.

This active ingredient, starch and cellulose were 45 mesh U.S. S. Pass through sieve and mix thoroughly. An aqueous solution containing polyvinylpyrrolidone is mixed with the resulting powder, and the mixture is then 14 mesh U.S. S. Pass through sieve. The granules thus produced are dried at 50 ° C. and 18 mesh U.S. S. Pass through sieve. Then sodium carboxymethyl starch, magnesium stearate and talc (previously passed through a No. 60 mesh US sieve) were added to the granules, which were mixed and then mixed into a tablet machine.
Compress above to obtain tablets weighing 150 mg each.

Formulation Example 5 Capsules (each containing 80 mg of active ingredient) are made as follows: Active ingredient 80 mg Starch 59 mg Crystalline cellulose 59 mg Magnesium stearate 2 mg Total 200 mg.

The active ingredient, cellulose, starch and magnesium stearate are blended and 45 mesh U.S. S. Pass through a sieve and fill into hard gelatin in an amount of 200 mg.

Formulation Example 6 Suppositories (each containing 225 mg of active ingredient) are prepared as follows: active ingredient 225 mg saturated fatty acid glyceride 2,000 mg total 2,225 mg.

This active ingredient was designated as No. 60 mesh U.S. S. Pass through a sieve and suspend in saturated fatty acid glyceride (previously melted using minimal heat required). Then
The mixture is poured into a suppository mold of nominal 2 g capacity and allowed to cool.

Formulation Example 7 A suspension (each containing 50 mg of active ingredient per 5 mL dose) is made as follows: Active ingredient 50 mg Sodium carboxymethyl cellulose 50 mg Syrup 1.25 mL Benzoic acid solution 0.10 mL Flavoring agent q. v. Colorant q. v. Purified water (total) 5 mL.

This active ingredient was designated as No. 45 mesh U.S. S. Pass through sieve and mix with sodium carboxymethylcellulose and syrup to form a smooth paste. The benzoic acid solution, flavor, and color are diluted with some of the water and added, with stirring. Then enough water is added to create the required volume.

Formulation Example 8 An intravenous formulation may be prepared as follows: Active ingredient 100 mg Isotonic saline 1,000 mL.

A solution of the above components is generally administered to a subject intravenously at a rate of 1 mL per minute.

──────────────────────────────────────────────────続 き Continuation of front page (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE ), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SL, SZ, TZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CR, CU, CZ, DE, DK, DM, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID , IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, US, UZ, VN, YU, ZA, ZW (72) Inventor Zeifel , Mark James United States Indiana 46214, Indianapolis, Higdon Coat 7519 F term (reference) 4C084 AA02 AA07 BA01 BA08 BA17 BA24 BA34 CA59 MA13 MA21 MA35 MA37 MA55 MA60 MA63 MA66 NA14 ZB351 ZB352 4H045 AA10 BA30 BA30 BA

Claims (23)

[Claims] 1. A compound represented by the following structure I, and a pharmaceutically acceptable salt, ester, hydrate or solvate thereof: Wherein R is an alkyl, alkenyl, alkynyl, aryl, or heteroaryl group; R ¹ is independently —H, —OH, or —O—Pg; R ² is — H, -CH _3, be -NH ₂ or -NH-Pg,; R ³ _{is, -H, -CH 3, -CH 2} CONH 2, -CH 2 CONH-Pg, -CH 2 CH 2 NH 2, or be a _{-CH 2 CH 2 NH-Pg;} R 4 is, -H, it is -OH or -O-Pg,; R ⁵ is, -OH, be -OSO ₃ H, or -OPO ₂ HR ^a Where ^Ra is hydroxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, phenyl, phenoxy, p-halophenyl, p-halophenoxy, p-nitrophenyl, p-nitrophenoxy, benzyl, benzyl Oxy, p-halobenzyl, p-halove Jiruokishi, in there p- nitrobenzyl or p- nitrobenzyloxycarbonyl,; R ⁶ is, -H, -OH, or be a -OSO ₃ H; R ⁷ is, -H, or be -CH _3; t is Is an integer from 2 to 7; R ⁸ is a sugar moiety of the formula: Here, R ⁹ is independently -H, -OH, -N ₃ , -O-Pg, -NH ₂ , -NH
-Pg or a second saccharide moiety comprising 1 to 3 saccharide units selected from the group consisting of: Here, R ^9a is —H, —OH, —N ₃ , —NH ₂ , —O—Pg, or —NH
-Pg, and R ^9b is -OPO ₂ R ^a , -OSO ₃ H, -H, -NH ₂ , -OH, -O-Pg,
Or a -NH-Pg, P ^9c _{is, -CH 3, -CH 2 OH,} -CH 2 N 3, -CH 2 OSO 3 H, -CH 2 N
H-Pg, a _{-CH 2 O-Pg, -CO 2} H or -CO ₂ Pg,, wherein no more than one R ⁹ is, as long as represented by a sugar moiety of said 2, R ^a is As defined above, wherein Pg is a protecting group. 2. The compound according to claim 1, wherein R is: embedded imageHere, A, B, C and D independently represent hydrogen, C₁~ C₁₂Alkyl, C_Two~ C ₁₂ Alkynyl, C₁~ C₁₂Alkoxy, C₁~ C₁₂Alkylthio, halo, or-
O- (CH_Two)_m-[O- (CH_Two)_n]_p-O- (C₁~ C₁₂Alkyl) or-
O- (CH_Two)_qM is 2, 3 or 4; n is 2, 3 or 4; p is 0 or 1
And q is 2, 3 or 4; X is pyrrolidino, piperidino or piperazino; and E is hydrogen, C ₁ ~ C₁₂Alkyl, C_Three~ C₁₂Cycloalkyl, benzyl or C_Three~ C₁₂Cyclo
The compound, which is alkylmethyl. 3. A compound according to claim 2, or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is in each case hydroxy; R ⁴ is hydroxy There; R ⁵ is -OPO ₂ HR ^a, where R ^a is methyl or methoxy; R ^2, R ³ and R ⁷ are each methyl; and R is, portions of the following formula : A compound. 4. A compound according to claim 3, or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁵ is hydroxy; R is a moiety of the formula: Yes: Wherein C is hydrogen or C ₃ -C ₇ alkyl; R ⁸ is a moiety of the following formula: Wherein R ⁹ is independently hydrogen, hydroxy, amino or a moiety of the formula: And R ^9b is —OPO ₂ R ^a , —OSO ₃ H, —H, —NH ₂ , —OH, —O—
A compound wherein Pg, or -NH-Pg, and n is 1, 2 or 3. 5. A compound according to claim 4, or a pharmaceutically acceptable salt or solvate thereof, wherein C is n-pentoxy; R ⁹ is independently hydroxy. Or a compound that is amino. 6. A compound according to claim 5, or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁹ is in each case hydroxy; and t is 2 A compound. 7. A pharmaceutical formulation comprising one or more pharmaceutical carriers, diluents or excipients, and a compound according to claim 1. 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 Formula I and a pharmaceutically acceptable salt thereof. Comprising administering an ester, hydrate or solvate: Wherein R is an alkyl, alkenyl, alkynyl, aryl, or heteroaryl group; R ¹ is independently —H, —OH, or —O—Pg; R ² is — H, -CH _3, be -NH ₂ or -NH-Pg,; R ³ _{is, -H, -CH 3, -CH 2} CONH 2, -CH 2 CONH-Pg, -CH 2 CH 2 NH 2, or be a _{-CH 2 CH 2 NH-Pg;} R 4 is, -H, it is -OH or -O-Pg,; R ₅ is, -OH, be -OSO ₃ H, or -OPO ₂ HR ^a Where ^Ra is hydroxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, phenyl, phenoxy, p-halophenyl, p-halophenoxy, p-nitrophenyl, p-nitrophenoxy, benzyl, benzyl Oxy, p-halobenzyl, p-halove Jiruokishi, in there p- nitrobenzyl or p- nitrobenzyloxycarbonyl,; R ⁶ is, -H, -OH, or be a -OSO ₃ H; R ⁷ is, -H, or be -CH _3; t is Is an integer from 2 to 7; R ⁸ is a sugar moiety of the formula: Here, R ⁹ is independently -H, -OH, -N ₃ , -O-Pg, -NH ₂ , -NH
-Pg, or a second sugar moiety comprising 1 to 3 sugar units selected from the group consisting of: Here, R ^9a is —H, —OH, —N ₃ , —NH ₂ , —O—Pg, or —NH
-Pg, R ^9b is -OPO ₂ R ^a , -OSO ₃ H, -H, -NH ₂ , -OH, -O-Pg,
Or a -NH-Pg, P ^9c _{is, -CH 3, -CH 2 OH,} -CH 2 N 3, -CH 2 OSO 3 H, -CH 2 N
H-Pg, a _{-CH 2 O-Pg, -CO 2} H or -CO ₂ Pg,, wherein no more than one R ⁹ is, as long as represented by a sugar moiety of said 2, R ^a is As defined above, wherein Pg is a protecting group. 9. The method according to claim 8, wherein R is:Here, A, B, C and D independently represent hydrogen, C₁~ C₁₂Alkyl, C_Two~ C ₁₂ Alkynyl, C₁~ C₁₂Alkoxy, C₁~ C₁₂Alkylthio, halo, or-
O- (CH_Two)_m-[O- (CH_Two)_n]_p-O- (C₁~ C₁₂Alkyl) or-
O- (CH_Two)_qM is 2, 3 or 4; n is 2, 3 or 4; p is 0 or 1
And q is 2, 3 or 4; X is pyrrolidino, piperidino or piperazino; and E is hydrogen, C ₁ ~ C₁₂Alkyl, C_Three~ C₁₂Cycloalkyl, benzyl or C_Three~ C₁₂Cyclo
The method, which is an alkylmethyl. 10. The method of claim 8, wherein said recipient is a human. 11. The method of claim 9, wherein in the compound represented by structure I or a pharmaceutically acceptable salt or solvate thereof, R ¹ is in each case: is hydroxy; R ⁴ is is hydroxy; R ⁵ is -OPO ₂ HR ^a, where R ^a is methyl or methoxy; R ^2, R ³ and R ⁷ are each methyl And R is a moiety of the following formula: Is the way. 12. The method of claim 9, wherein in the compound represented by Structure I or a pharmaceutically acceptable salt or solvate thereof, R ⁵ is hydroxy; R is part of the following formula: Wherein C is hydrogen or C ₃ -C ₇ alkoxy; R ⁸ is a moiety of the following formula: Wherein R ⁹ is independently hydrogen, hydroxy, amino or a moiety of the formula: And R ^9b is —OPO ₂ R ^a , —OSO ₃ H, —H, —NH ₂ , —OH, —O—
Pg, or -NH-Pg, and n is 1, 2 or 3. 13. A method according to claim 12, in a compound or a pharmaceutically acceptable salt or solvate thereof represented by the structure I, C is an n- pentoxy; R ⁹ Is independently hydroxy or amino. 14. The method of claim 13, wherein in the compound represented by structure I or a pharmaceutically acceptable salt or solvate thereof, R ⁹ is in each case: And t is two. 15. The method of claim 8, wherein the fungal activity is Candida albicans, Aspergillus fumiga.
tis, and methods derived from one or more fungi selected from the group consisting of Candida parapsilosis. 16. A method of inhibiting parasite activity, said method comprising providing a recipient in need of such inhibition with an effective amount of a compound represented by Formula I, and a pharmaceutically acceptable salt thereof. Comprising administering a salt, ester, hydrate or solvate: Wherein R is an alkyl, alkenyl, alkynyl, aryl, or heteroaryl group; R ¹ is independently —H, —OH, or —O—Pg; R ² is — H, -CH _3, be -NH ₂ or -NH-Pg,; R ³ _{is, -H, -CH 3, -CH 2} CONH 2, -CH 2 CONH-Pg, -CH 2 CH 2 NH 2, or be a _{-CH 2 CH 2 NH-Pg;} R 4 is, -H, it is -OH or -O-Pg,; R ⁵ is, -OH, be -OSO ₃ H, or -OPO ₂ HR ^a Where ^Ra is hydroxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, phenyl, phenoxy, p-halophenyl, p-halophenoxy, p-nitrophenyl, p-nitrophenoxy, benzyl, benzyl Oxy, p-halobenzyl, p-halove Jiruokishi, in there p- nitrobenzyl or p- nitrobenzyloxycarbonyl,; R ⁶ is, -H, -OH, or be a -OSO ₃ H; R ⁷ is, -H, or be -CH _3; t is Is an integer from 2 to 7; R ⁸ is a sugar moiety of the formula: Here, R ⁹ is independently -H, -OH, -N ₃ , -O-Pg, -NH ₂ , -NH
-Pg or a second sugar moiety comprising 1 to 3 sugar units selected from the group consisting of: Here, R ^9a is —H, —OH, —N ₃ , —NH ₂ , —O—Pg, or —NH
-Pg, and R ^9b is -OPO ₂ R ^a , -OSO ₃ H, -H, -NH ₂ , -OH, -O-Pg,
Or a -NH-Pg, P ^9c _{is, -CH 3, -CH 2 OH,} -CH 2 N 3, -CH 2 OSO 3 H, -CH 2 N
H-Pg, a _{-CH 2 O-Pg, -CO 2} H or -CO ₂ Pg,, wherein no more than one R ⁹ is, as long as represented by a sugar moiety of said 2, R ^a is As defined above, wherein Pg is a protecting group. 17. The method according to claim 16, wherein R is:Here, A, B, C and D independently represent hydrogen, C₁~ C₁₂Alkyl, C_Two~ C ₁₂ Alkynyl, C₁~ C₁₂Alkoxy, C₁~ C₁₂Alkylthio, halo, or-
O- (CH_Two)_m-[O- (CH_Two)_n]_p-O- (C₁~ C₁₂Alkyl) or-
O- (CH_Two)_qM is 2, 3 or 4; n is 2, 3 or 4; p is 0 or 1
And q is 2, 3 or 4; X is pyrrolidino, piperidino or piperazino; and E is hydrogen, C ₁ ~ C₁₂Alkyl, C_Three~ C₁₂Cycloalkyl, benzyl or C_Three~ C₁₂Cyclo
The method, which is an alkylmethyl. 18. The method of claim 16, wherein said recipient is a human. 19. The method of claim 17, wherein in the compound represented by structure I or a pharmaceutically acceptable salt or solvate thereof, R ¹ is in each case: is hydroxy; R ⁴ is is hydroxy; R ⁵ is -OPO ₂ HR ^a, where R ^a is methyl or methoxy; R ^2, R ³ and R ⁷ are each methyl And R is a moiety of the following formula: Is the way. 20. The method of claim 17, wherein in the compound represented by structure I or a pharmaceutically acceptable salt or solvate thereof, R ⁵ is hydroxy; R is part of the following formula: Wherein C is hydrogen or C ₃ -C ₇ alkoxy; R ⁸ is a moiety of the formula: Wherein R ⁹ is independently hydrogen, hydroxy, amino or a moiety of the formula: And R ^9b is —OPO ₂ R ^a , —OSO ₃ H, —H, —NH ₂ , —OH, —O—
Pg, or -NH-Pg, and n is 1, 2 or 3. 21. The method of claim 20, wherein in the compound represented by Structure I or a pharmaceutically acceptable salt or solvate thereof, C is n-pentoxy. ; R ⁹ are independently hydroxy or amino, method. 22. The method of claim 21, wherein in the compound represented by structure I or a pharmaceutically acceptable salt or solvate thereof, R ⁹ is in each case: And t is two. 23. The method according to claim 23, wherein said parasite activity is Pneumocystis cari.
17. The method of claim 16, wherein the method results from nii.