WO2000035945A1 - Agents antifongiques de peptide cyclique possedant un substituant sucre - Google Patents

Agents antifongiques de peptide cyclique possedant un substituant sucre Download PDF

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Publication number
WO2000035945A1
WO2000035945A1 PCT/US1999/029927 US9929927W WO0035945A1 WO 2000035945 A1 WO2000035945 A1 WO 2000035945A1 US 9929927 W US9929927 W US 9929927W WO 0035945 A1 WO0035945 A1 WO 0035945A1
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Prior art keywords
hydroxy
group
moiety
alkyl
oso
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PCT/US1999/029927
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WO2000035945A8 (fr
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John Michael Rodriguez
Michael John Nesler
Mark James Zweifel
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Eli Lilly And Company
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Priority to AU21895/00A priority Critical patent/AU2189500A/en
Priority to CA002354055A priority patent/CA2354055A1/fr
Priority to EP99966327A priority patent/EP1140992A1/fr
Priority to JP2000588202A priority patent/JP2002532513A/ja
Publication of WO2000035945A1 publication Critical patent/WO2000035945A1/fr
Publication of WO2000035945A8 publication Critical patent/WO2000035945A8/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/50—Cyclic peptides containing at least one abnormal peptide link
    • C07K7/54—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring
    • C07K7/56—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring the cyclisation not occurring through 2,4-diamino-butanoic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the invention relates to anti-fungal/anti-parasitic agents, in particular, derivatives of Echinocandin compounds and their use in treatment of fungal and parasitic infections.
  • cyclic peptides A number of naturally occurring cyclic peptides are known in the art including Echinocandin B (A30912A), Aculeacin, Mulundocandin, Sporiofungin, L-671,329, and S31794/Fl .
  • 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.
  • Echinocandin B has a linoleoyl side chain while Aculeacin has a palmitoyl side chain.
  • the natural compounds can be structurally modified to enhance these properties or improve the compound's stability and/or water solubility. Turner et al., Cur. Pharm. Des. 2:209 (1996).
  • the fatty acid side chain can be removed from the cyclic peptide core to provide an amino nucleus which can then be re-acylated to provide semi-synthetic compounds.
  • R is an alkyl group, an alkenyl group, an alkynyl group, an aryl group, or heteroaryl group;
  • R 1 is independently -H, -OH or -O-Pg;
  • R 2 is -H, -CH; violate -NH 2 , or - NH-Pg;
  • R 3 is -H, -CH 3 , -CH 2 CONH 2 , -CH 2 CONH-Pg, -CH 2 CH : NH 2 , or - CH 2 CH 2 NH-Pg;
  • R 4 is -H, -OH, or -O-Pg;
  • R 5 is -OH, -OSO 3 H.
  • R a is hydroxy, C ⁇ -C ⁇ alkyl, Ci -Cg alkoxy, phenyl, phenoxy, /j-halophenyl, p- halophenoxy, /j-nitrophenyl, -nitrophenoxy, benzyl, benzyloxy. j-halobenzyl, p- halobenzyloxy, -nitrobenzyl, or -nitrobenzyloxy;
  • R 6 is -H, -OH, or -OSO 3 H;
  • R 7 is H or -CH ;
  • t is an integer from 2-7;
  • R 8 is a sugar moiety of the formula
  • R is independently -H, -OH, -N 3 , -O-Pg, -NH 2 , -NH-Pg, or a second sugar moiety comprising one to three sugar units selected from the group consisting of
  • R 9a is -H, -OH, -N 3 , -NH 2 , -O-Pg, or -NH-Pg
  • R° b is -OPO 2 R ⁇ - OSO 3 H, -H, -NH 2 , -OH, -O-Pg, or -NH-Pg
  • R 9c 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 as defined above, and so long as no more than one R° is represented by said second sugar moiety
  • Pg is a protecting group ( i.e., -O-Pg is a hydroxy protecting group, -NH-Pg is an amino protecting group, -CH 2 CONH-Pg is an amido protecting group and -CO 2
  • the invention encompasses a pharmaceutical formulation of one or more pharmaceutical carriers, diluents or excipients and a compound represented by structure I described above.
  • the invention further encompasses a method of inhibiting fungal and parasitic activity by administering an effective amount of a compound represented by structure I to a recipient in need of thereof.
  • Alkyl refers to a hydrocarbon radical of the general formula C n H 2n+1 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.
  • C1-C12 alkyl refers to a straight or branched saturated alkyl chain having from one to twelve carbon atoms.
  • C1- 2 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.
  • C1-C12 alkyl includes “Ci-C ⁇ alkyl”, “C1-C4 alkyl”, and “C3-C12 cycloalkyl.”
  • C3-C12 cycloalkyl refers to a cyclic saturated alkyl chain having from 3 to
  • C3-C12 cycloalkyl includes “C3-C7 cycloalkyl”, i.e., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
  • C1-C12 alkoxy refers to a C1-C12 alkyl group attached through an oxygen atom.
  • C1-C12 alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, sec-butoxy, n-pentoxy, 5-methyl-hexoxy, heptoxy, octyloxy, decyloxy and dodecyloxy.
  • C1-C12 alkoxy includes "C1-C6 alkoxy", “C3-C7 alkoxy", and "C1-C4 alkoxy".
  • C1-C12 alkylthio refers to 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 "C1-C6 alkylthio" and "C1-C4 alkylthio.”
  • Alkenyl refers to an acyclic hydrocarbon containing at least one carbon- carbon double bond. The alkene radical can be straight, branched, cyclic, or multi- cyclic. The alkene radical can be substituted or unsubstituted.
  • Alkynyl refers to an acyclic hydrocarbon containing at least one carbon- carbon triple bond.
  • the alkyne radical can be straight, or branched.
  • the alkyne radical can be substituted or unsubstituted.
  • C2-C12 alkynyl refers to 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, 1-propyn-l-yl, l-propyn-2-yl, 1-butyn-l-yl, l-butyn-3-yl, l-pentyn-3-yl, 4-pentyn-2-yl, l-hexyn-3-yl, 3-hexyn-l-yl, 5-methyl-3-hexyn-l-yl, 5-octyn-l-yl, 7- octyn-1-yl, 4-decyn-l-yl and 6-decyn-l-yl.
  • Aryl refers to aromatic moieties having single (e.g., phenyl) or fused ring systems (e.g., naphthalene, anthracene, phenanthrene, etc.).
  • the aryl groups can be substituted or unsubstituted.
  • Substituted aryl groups include a chain of aromatic moieties (e.g., biphenyl, terphenyl, phenylnaphthalyl, etc.).
  • Heteroaryl refers to aromatic moieties containing at least one heteratom within the aromatic ring system (e.g., pyrrole, pyridine, indole, thiophene, furan, benzofuran, imidazole, pyrimidine, purine, benzimidazole, quinoline, etc.).
  • the aromatic moiety can be a single or fused ring system.
  • the heteroaryl groups can be substituted or unsubstituted.
  • alkyl group allows for substituents which are a classic alkyl, such as methyl, ethyl, propyl, n-butyl, /-butyl, t-butyl, hexyl, isooctyl, dodecyl, stearyl, etc.
  • alkyls which are common in the art, such as hydroxy, halogen, alkoxy, carbonyl, keto, ester, carbamato, etc., as well as including the unsubstituted alkyl moiety.
  • substituents should be selected so as to not adversely affect the pharmacological characteristics of the compound or adversely interfere with the use of the medicament.
  • aryl, alkynyl, alkenyl, heteroaryl i.e., aryl, alkynyl, alkenyl, heteroaryl.
  • Suitable substituents for any of the groups defined above include alkyl, alkenyl, alkynyl, aryl, halo, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, mono- and di-alkyl amino, quaternary 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” refer to a substituent of a hydroxy group that is commonly employed to block or protect the hydroxy functionality while reactions are carried out on other functional groups on the compound.
  • This substituent when taken with the oxygen to which it is attached, can form an ether, e.g., methyl, methoxymethyl, and benzyloxymethyl ether, a silyl ether, an ester, e.g. acetoxy, or a sulfonate moiety, e.g. methane and p-toluenesulfonate.
  • hydroxy protecting group is not critical so long as the derivatized hydroxy group is stable to the conditions of subsequent reaction(s) and the protecting group can be removed at the appropriate point without disrupting the remainder of the molecule.
  • a preferred hydroxy protecting group is acetyl. Specific examples of hydroxy protecting groups are described in Greene, "Protective Groups in Organic
  • amino protecting group refers to a substituent of the amino group commonly employed to block or protect the amino functionality while reacting other functional groups on the compound.
  • the amino protecting group when taken with the nitrogen to which it is attached, forms a cyclic imide, e.g., phthalimido and tetrachlorophthalimido.
  • the protecting group when taken with the nitrogen to which it is attached, can form a carbamate, e.g., methyl, ethyl, and 9-fluorenylmethylcarbamate; or an amide, e.g., N-formyl and N- acetylamide.
  • amino protecting group employed is not critical so long as the derivatized amino group is stable to the condition of subsequent reaction(s) on other positions of the intermediate molecule and the protecting group can be selectively removed at the appropriate point without disrupting the remainder of the molecule including any other amino protecting group(s).
  • Preferred amino protecting groups are t-butoxycarbonyl (t-Boc), allyloxycarbonyl, phthalimido, and benzyloxycarbonyl (CbZ). Further examples of groups referred to by the above terms are described in Greene at chapter 7.
  • -CO 2 -Pg and "carboxy protecting group” refer to a substituent of a carbonyl that is commonly employed to block or protect the carboxy functionality while reactions are carried out on other functional groups on the compound.
  • This substituent when taken with the carbonyl to which it is attached, can form an ester, e.g., Ci -Cg alkyl, substituted Ci -C ⁇ alkyl, C2-Cg alkenyl, substituted C2-Cg alkenyl, benzyl, substituted benzyl, benzhydryl, substituted benzhydryl. trityl, substituted trityl, and trialkylsilyl ester.
  • carboxy protecting group is not critical so long as the derivatized carboxy group is stable to the conditions of subsequent reaction(s) and the protecting group can be removed at the appropriate point without disrupting the remainder of the molecule.
  • groups referred to by the above terms are described in Greene, at chapter 5.
  • C(O)NH-Pg and “amido protecting group” refer to a substituent of an amide commonly employed to block or protect the amino portion while reacting other functional groups on the compound.
  • This protecting group when taken with the nitrogen to which it is attached, can form an amide, e.g. N-allyl, N-methoxymethyl, and N-benzyloxymethyl amide.
  • the exact species of amido protecting group employed is not critical so long as the derivatized amido group is stable to the condition of subsequent reaction(s) on other positions of the intermediate molecule and the protecting group can be selectively removed at the appropriate point without disrupting the remainder of the molecule including any other amido protecting group(s).
  • Other examples of groups referred to by the above terms are described in Greene, at chapter 7, pg. 397.
  • Carbonyl activating group refers to a substituent of a carbonyl that promotes nucleophilic addition reactions at that carbonyl. Suitable activating substituents are those which have a net electron withdrawing effect on the carbonyl.
  • 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'-dicyclohexylisoure-O-yl, N-hydroxy- N-methoxyamino; acetates, formates, sulfonates such as methanesulfonate, ethanesulfonate, benzenesulfonate, or p-tolylsulfonate; and halides such as chloride, bromide, or iodide.
  • “Pharmaceutical” or “pharmaceutically acceptable” means substantially non- toxic and substantially non-deleterious to the recipient.
  • “Pharmaceutical formulation” means that the carrier, solvent, excipients and salt are compatible with the active ingredient of the formulation (i.e., Compound I).
  • “Pharmaceutical salt” or “pharmaceutically acceptable salt” refers to salts of the compounds represented by structure I that are substantially non-toxic to the recipient at the doses administered.
  • Typical pharmaceutical salts include those prepared by reaction of the compounds of the invention with a mineral or organic acid or inorganic base. Such salts are known as acid addition and base addition salts.
  • Such salts are known as acid addition and base addition salts.
  • Solvate is an aggregate that comprises one or more molecules of the solute, such as a formula I compound, with one or more molecules of a pharmaceutical solvent, including, but not limited to, water and ethanol.
  • Suitable solvent is any solvent, or mixture thereof, inert to the ongoing reaction that sufficiently solubilizes the reactants to afford a medium within which to effect the desired reaction.
  • thermodynamic base is a base that provides a reversible deprotonation of an acidic substrate or is a proton trap for protons produced as reaction byproducts, and is reactive enough to effect the desired reaction without significantly effecting any undesired reactions.
  • thermodynamic bases include, but are not limited to, acetates, acetate dihydrates, carbonates, bicarbonates, C1-C4 alkoxides, and hydroxides (e.g. silver, lithium, sodium, or potassium acetate, acetate dihydrate, carbonate, bicarbonate, methoxide, or hydroxide), tri-(C ⁇ -C4 alkyl)amines, or aromatic nitrogen containing heterocycles (e.g. imidazole and pyridine).
  • “Inhibiting” includes prohibiting, stopping, retarding, alleviating, ameliorating, halting, restraining, slowing or reversing the progression, or reducing the severity of the growth or any attending characteristics, symptoms, and results from the existence of a parasite or fungus. These methods include both medical therapeutic (acute) and/or prophylactic (prevention) administration as appropriate.
  • Effective amount refers to an amount of a compound of formula I which is capable of inhibiting fungal and/or parasitic activity.
  • Recipient includes mammals, preferably, humans.
  • Echinocandin-type compounds refers to compounds having the following general structure including any simple derivatives thereof:
  • R is an alkyl group, an alkenyl group, an alkynyl group, an aryl group, or heteroaryl group;
  • R 1 is -H or -OH;
  • R 2 is -H, -NH 2 or -CH 3 ;
  • R 3 is -H, -CH 3 , -
  • R 4 is -H or -OH
  • R 5 is -OH, -OSO 3 H, or -OPO 2 HR a
  • R a is hydroxy, C1-C6 alkyl, Cj-Cg alkoxy, phenyl, phenoxy,/?-halophenyl,/>- halophenoxy, -nitrophenyl, /7-nitrophenoxy, benzyl, benzyloxy, p-halobenzyl, p- halobenzyloxy, jp-nitrobenzyl, or j9-nitrobenzyloxy;
  • R 6 is -H, -OH, or -OSO 3 H;
  • R 7 is - H or -CH 3 ; and pharmaceutically acceptable salts, esters, hydrates or solvates thereof.
  • Natural product is those secondary metabolites, usually of relatively complex structure, which are of more restricted distribution and more characteristic of a specific source in nature.
  • Suitable natural product starting materials of the Echinocandin cyclopeptide family include Echinocandin B, Echinocandin C, Aculeacin A ⁇ , Mulundocandm, Sporiofungin A, Pneumocandin A 0 , WFl 1899 A, and
  • the cyclic peptides used in the invention can be produced by culturing various microorganisms.
  • the cyclic peptides can be characterized as a cyclic hexapeptide nucleus with an acylated amino group on one of the amino acids.
  • the amino group on the naturally-occurring cyclic peptide is typically acylated with a fatty acid group forming a side chain off the nucleus.
  • acyl groups include, but are not limited to, linoleoyl ( Echinocandin B, C and D), palmitoyl (Aculeacin A ⁇ and WFl 1899A), stearoyl, 12-methylmyristoyl (Mulundocandm), 10,12-dimethylmyristoyl (Sporiofungin A and Pneumocandin Ao).
  • Semi-synthetic derivatives can be generally prepared by removing the fatty acid side chain from the cyclic peptide nucleus to produce a free amino group (i.e., no pendant acyl group -C(O)R). The free amine is then re-acylated with a suitable acyl group.
  • the echinocandin B nucleus has been re-acylated with certain nonnaturally occurring side chain moieties to provide a number of antifungal agents.
  • N-acyl side chain encompasses a variety of side chain moieties known in the art. Suitable side chain moieties include substituted and unsubstituted alkyl groups, alkenyl groups, alkynyl groups, aryl groups, heteroaryl groups and combinations thereof. Preferably, the side chain contains both a linearly rigid section and a flexible alkyl section to maximize antifungal potency.
  • acyl side chains include R groups having the following structures:
  • A, B, C and D are independently hydrogen, C,-C 12 alkyl.
  • Scheme I illustrates the general semi-synthetic route described above where a natural product (Compound 11(a)) is modified to provide an intermediate (Compound 11(d)) which is then further modified to provide a representative example of Compound I as illustrated in Scheme II.
  • Cyclic peptides represented by structure 11(a) can be prepared by fermentation of known microorganisms.
  • the cyclic peptide 11(a) where R 1 and R 4 are each hydroxy, R 2 , R 3 and R 7 are each methyl can be prepared using the procedure detailed in U.S. Patent No. 4,293,482.
  • Cyclic peptide 11(a) where R 1 is hydroxy, R 2 , R and R 7 are each methyl, and R 4 is hydrogen (cyclic nucleus corresponding to A-30912B) can be prepared using the procedure detailed in U.S. Patent No. 4,299,763.
  • Aculeacin can be prepared using the procedure detailed in U.S. Patent No. 3,978,210.
  • R 7 is methyl
  • R 2 is hydrogen
  • R 1 and R 4 are hydroxy
  • Cyclic peptide 11(a) can be deacylated using procedures known in the art to provide an amino nucleus represented by structure 11(b). This reaction is typically carried out enzymatically by exposing the naturally occurring cyclic peptide to a deacylase enzyme.
  • the deacylase enzyme can be obtained from the microorganism Actinoplanes utahensis and used substantially as described in U.S. Patent Nos. 4,293,482 and 4,304,716.
  • the deacylase enzyme can also be obtained from the Pseudomonas species. Deacylation can be accomplished using whole cells of A. utahensis or Pseudomonas or the crude or purified enzyme thereof or using an immobilized form of the enzyme.
  • cyclic peptides that can be used as starting materials include, but are not limited to, aculeacin (palmitoyl side chain), tetrahydroechinocandin B (stearoyl side chain), mulundocandm (branched C15 side chain), L-671,329 (Cj.6 branched side chain), S 31794/F1 (tetradecanoyl side chain), sporiofungin (C15 branched side chain), FR901379 (palmitoyl side chain).
  • a preferred cyclic peptide is echinocandin B (Compound 11(a) where R 1 and R 4 are each hydroxy, R 2 , R 3 and R 7 are each methyl, and R nal is linoleoyl).
  • amino nucleus H(b) can be re-acylated, by procedures taught in U.S. Patent Nos. 5,646, 111, and 5,693,611 to provide compounds represented by structure
  • Compound I can be prepared by adding either Compound III or IV to Compound 11(a) dissolved or suspended in a suitable solvent in the presence of a suitable thermodynamic base.
  • a convenient and preferred solvent for the reaction is dimethylformamide while a convenient and preferred base is triethylamine.
  • the reaction can be performed at from 0°C to the reflux temperature of the mixture but is typically performed at ambient temperatures for about 24 hours. See Example 1 below for an example of specific reaction conditions.
  • Compounds HI 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 to provide the other derivatives of Compounds III and IV including disaccharides and polysaccharides where R 9 is a second sugar moiety.
  • Such compounds can be prepared as illustrated in Scheme 3 below where Lg is an activated hydroxy leaving group.
  • a commercially available Compound VI can have its hydroxy group(s) activated for nucleophilic displacement by standard techniques known in the art.
  • the hydroxy group can be sulfonylated with methane-, benzene-, or p- toluene-sulfonyl chloride (or bromide) to provide a Compound VII where Lg is OSO2Me, OSO2-phenyl, or OSO2-p-toluenyl.
  • the leaving group can be displaced by azide ion, e.g., from sodium or potassium azide.
  • the leaving group can be displaced by iodide ion from, e.g., sodium or potassium iodide.
  • the resulting Compound VIII can be reduced to form a Compound IX where one or more of R 9a or R 9b is amino or hydrogen by catalytic hydrogenation or with a reducing agent such as nickel chloride hexahydrate. It is preferred that when an amino group is desired in the final product Compound I, that any azido groups are converted to amino groups after coupling to Compound 11(d).
  • Compound I where any of R ⁇ is amino can be formed from a Compound I where R ⁇ is azido as described by analogous procedures well known in the art. See, e.g., Larock, "Comprehensive Organic Transformations," pg. 409, VCH Publishers, New York, N.Y., 1989.
  • Compound I where R 5 , R 9 , R 9a , R 9b , and/or R 9c is a hydroxy group can be phosphorylated or phosphonylated by reaction with an appropriately substituted dichloro- phosphate or phosphonic acid of formula V
  • Suitable bases include lithium trimethylsilanolate (LiOTMS), and lithium bis(trimethylsilyl)amide (LHMDS).
  • a preferred solvent is an aprotic solvent such as tetrahydrofuran and/or dimethylformamide.
  • the compounds represented by structure I where R 9b is hydroxy and/or R 9c is hydroxymethyl can be sulfated by reaction with a suitable sulfation reagent.
  • the protected compound of structure I can have its protecting group(s) removed to form a deprotected Compound
  • Pharmaceutical salts are typically formed by reacting Compound I with an equimolar or excess amount of acid or base.
  • the reactants are generally combined in a mutual solvent such as diethylether, tetrahydrofuran, methanol. ethanol, isopropanol, benzene, and the like for acid addition salts, or water, an alcohol or a chlorinated solvent such as methylene chloride for base addition salts.
  • the salts normally precipitate out of solution within about one hour to about ten days and can be isolated by filtration or other conventional methods.
  • Acids commonly employed to form acid addition salts are inorganic acids including, but not limited to, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and organic acids such as ?-toluenesulfonic, methanesulfonic acid, ethanesulfonic acid, oxalic acid, -bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, tartaric acid, benzoic acid, 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.
  • Bases useful in preparing salts of this invention include, but are not limited to, sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide and calcium carbonate.
  • any salt of this invention is not of a critical nature, provided the salt as a whole is pharmacologically acceptable and the counterion does not contribute undesired qualities to the salt as a whole.
  • Preferred pharmaceutical acid addition salts are those formed with mineral acids such as hydrochloric acid and sulfuric acid, and those formed with organic acids such as maleic acid, tartaric acid, and methanesulfonic acid.
  • Preferred pharmaceutical base addition salts are the potassium and sodium salt forms.
  • Preferred compounds of the present invention are those compounds represented by structure I where R 1 is hydroxy at each occurrence; R 4 is hydroxy; R 2 ,
  • R 3 , and R 7 are each methyl; R is a moiety of the formula
  • R a is methyl or methoxy; 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
  • R 8 is a moiety of the formula:
  • D is hydrogen or C3-C7 alkoxy;
  • R 9 is independently hydrogen, hydroxy, amino, or a moiety of the formula: where 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; or a pharmaceutically acceptable salt or solvate thereof.
  • 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; or a pharmaceutically acceptable salt or solvate thereof.
  • Even more preferable are those compounds wherein D is n-pentoxy; R° is independently hydroxy or amino; or a pharmaceutically acceptable salt or solvate thereof.
  • Most preferred are those compounds wherein R 9 is hydroxy at each occurrence; and t is 2; or a pharmaceutically acceptable salt
  • the optimal time for performing the reactions of Schemes 1 - 3 can be determined by monitoring the progress of the reaction by conventional chromatographic techniques.
  • Choice of reaction solvent is generally not critical so long as the solvent employed is inert to the ongoing reaction and sufficiently solubilizes the reactants to afford a medium within which to effect the desired reaction.
  • all of the reactions described herein are preferably conducted under an inert atmosphere.
  • a preferred inert atmosphere is nitrogen.
  • the resultant solution is subjected to reverse phase HPLC (C18; eluent of 20-40% aqueous acetonitrile containing 0.5% monobasic ammonium phosphate (w/v); 20 mL/min.; 230 nm).
  • HPLC reverse phase HPLC
  • 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.
  • Examples 1 and 2 have the following base structure:
  • 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
  • the compounds represented by structure I have been shown to exhibit a variety of antifungal and antiparasitic activities to various degrees.
  • the compounds of structure I can inhibit the growth of various infectious fungi including Candida spp. (e.g., C. albicans, C. parapsilosis, C. krusei, C. glabrata, C. tropicalis, or C. lusitaniae), Torulopus spp. (e.g., T. glabrata), Aspergillus spp. (e.g., A.fumigatus), Histoplasma spp. (e.g., H. capsulatum), Cryptococcus spp. (e.g.,
  • 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 for controlling a systemic fungal infection.
  • MIC minimum inhibitory concentration
  • 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 also inhibit growth of certain organisms primarily responsible for opportunistic infections in immunosuppressed individuals.
  • the compounds inhibit the growth of Pneumocystis carinii the causative organism of pneumocystis pneumonia (PCP) in AIDS and other imxnunocompromised recipients.
  • PCP pneumocystis pneumonia
  • Other protozoans that are inhibited by compounds of formula I include Plasmodium spp., Leishmania spp., Trypanosoma spp. , Cryptosporidium spp. , Isospora spp. , Cyclospora spp. ,
  • Trichomonas spp. Trichomonas spp., Microsporidiosis spp. and the like.
  • the dose of the compound represented by structure 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 level of from about 0.01 mg/kg to about 100 mg/kg of body weight of the active compound.
  • 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 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.
  • the formulation comprises Compound I and a physiologically acceptable diluent such as deionized water, physiological saline, 5% 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 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.
  • a carrier which can be in the form of a capsule, sachet, paper or other container.
  • 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.
  • 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.
  • the active ingredient is filled into gelatin capsules or formed into tablets. Tablets can also contain a binding agent, a dispersant or other excipients suitable for preparing a proper size tablet for the dosage and particular compound of the formula I.
  • 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 amount
  • the active ingredient can be formulated with a dry powder for application to the skin formulated in a liquid formulation comprising a solubilizing aqueous liquid or non-aqueous liquid, e.g., an alcohol or glycol.
  • a liquid formulation comprising a solubilizing aqueous liquid or non-aqueous liquid, e.g., an alcohol or glycol.
  • active ingredient refers to a compound represented by structure I or a pharmaceutically acceptable salt thereof.
  • Hard gelatin capsules are prepared using the following ingredients:
  • Active ingredient 250 Starch, dried 200
  • a tablet is prepared using the ingredients below: Quantity
  • the components are blended and compressed to form tablets of 665 mg each.
  • An aerosol solution is prepared containing the following components: Weight
  • 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°C and transferred to a filling device. The required 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
  • the active ingredient, starch and cellulose are passed through a No. 45 mesh U.S. sieve and mixed thoroughly.
  • the aqueous solution containing polyvinylpyrrolidone 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°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 then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 150 mg.
  • Capsules each containing 80 mg of active ingredient, are made as follows: Active ingredient 80 mg Starch 59 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
  • Formulation Example 6 Suppositories, each containing 225 mg of active ingredient, are made as follows: Active ingredient 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 necessary. The mixture is then poured into a suppository mold of nominal 2 g capacity and allowed to cool.
  • 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.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Biochemistry (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Genetics & Genomics (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)

Abstract

L'invention concerne des composés représentés par la formule (I), R8 représentant une fraction de sucre. Ces composés sont utiles comme agent antifongique et antiparasite ou comme intermédiaire de cet agent. L'invention concerne également des techniques de traitement et des formulations pharmaceutiques contenant les composés représentés par la formule (I).
PCT/US1999/029927 1998-12-16 1999-12-15 Agents antifongiques de peptide cyclique possedant un substituant sucre WO2000035945A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
AU21895/00A AU2189500A (en) 1998-12-16 1999-12-15 Cyclic peptide antifungal agents having a sugar substituent
CA002354055A CA2354055A1 (fr) 1998-12-16 1999-12-15 Agents antifongiques de peptide cyclique possedant un substituant sucre
EP99966327A EP1140992A1 (fr) 1998-12-16 1999-12-15 Agents antifongiques de peptide cyclique possedant un substituant sucre
JP2000588202A JP2002532513A (ja) 1998-12-16 1999-12-15 糖置換基を有する環式ペプチド抗真菌剤

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US11243398P 1998-12-16 1998-12-16
US60/112,433 1998-12-16

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WO2000035945A1 true WO2000035945A1 (fr) 2000-06-22
WO2000035945A8 WO2000035945A8 (fr) 2001-07-05

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AU (1) AU2189500A (fr)
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WO (1) WO2000035945A1 (fr)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6506726B1 (en) 1998-12-09 2003-01-14 Eli Lilly And Company Purification of Echinocandin cyclopeptide compounds
US6590073B2 (en) 1999-03-03 2003-07-08 Eli Lilly And Company Formation and anion-exchange of crystalline echinocandin ammonium salts
US6653281B1 (en) 1998-08-20 2003-11-25 Eli Lilly And Company Ring modified cyclic peptide analogs
US6821951B2 (en) 1999-03-03 2004-11-23 Eli Lilly And Company Processes for making pharmaceutical oral ECB formulations and compositions
US6960564B2 (en) 1999-03-03 2005-11-01 Eli Lilly And Company Echinocandin pharmaceutical formulations containing micelle-forming surfactants
US8022033B2 (en) 1999-03-03 2011-09-20 Eli Lilly And Company Echinocandin/carbohydrate complexes
US11548908B2 (en) 2017-12-29 2023-01-10 Glycomimetics, Inc. Heterobifunctional inhibitors of E-selectin and galectin-3
US11873317B2 (en) 2018-12-27 2024-01-16 Glycomimetics, Inc. Galectin-3 inhibiting c-glycosides

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020139962A1 (fr) 2018-12-27 2020-07-02 Glycomimetics, Inc. Inhibiteurs hétérobifonctionnels d'e-sélectine et de galectine-3

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0757058A1 (fr) * 1995-07-25 1997-02-05 Eli Lilly And Company Dérivées cyclopeptidiques et antifongiques
WO1997017365A1 (fr) * 1995-11-09 1997-05-15 Merck & Co., Inc. Compose de cyclohexapeptidyle bisamine, compositions contenant ce compose et procedes d'utilisation
WO1999043337A1 (fr) * 1998-02-25 1999-09-02 Eli Lilly And Company Agents antifongiques peptidiques cycliques

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0757058A1 (fr) * 1995-07-25 1997-02-05 Eli Lilly And Company Dérivées cyclopeptidiques et antifongiques
WO1997017365A1 (fr) * 1995-11-09 1997-05-15 Merck & Co., Inc. Compose de cyclohexapeptidyle bisamine, compositions contenant ce compose et procedes d'utilisation
WO1999043337A1 (fr) * 1998-02-25 1999-09-02 Eli Lilly And Company Agents antifongiques peptidiques cycliques

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6653281B1 (en) 1998-08-20 2003-11-25 Eli Lilly And Company Ring modified cyclic peptide analogs
US6939946B2 (en) 1998-08-20 2005-09-06 Eli Lilly And Company Ring modified cyclic peptide analogs
US6506726B1 (en) 1998-12-09 2003-01-14 Eli Lilly And Company Purification of Echinocandin cyclopeptide compounds
US6590073B2 (en) 1999-03-03 2003-07-08 Eli Lilly And Company Formation and anion-exchange of crystalline echinocandin ammonium salts
US6821951B2 (en) 1999-03-03 2004-11-23 Eli Lilly And Company Processes for making pharmaceutical oral ECB formulations and compositions
US6960564B2 (en) 1999-03-03 2005-11-01 Eli Lilly And Company Echinocandin pharmaceutical formulations containing micelle-forming surfactants
US8022033B2 (en) 1999-03-03 2011-09-20 Eli Lilly And Company Echinocandin/carbohydrate complexes
US11548908B2 (en) 2017-12-29 2023-01-10 Glycomimetics, Inc. Heterobifunctional inhibitors of E-selectin and galectin-3
US11873317B2 (en) 2018-12-27 2024-01-16 Glycomimetics, Inc. Galectin-3 inhibiting c-glycosides

Also Published As

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EP1140992A1 (fr) 2001-10-10
CA2354055A1 (fr) 2000-06-22
AU2189500A (en) 2000-07-03
WO2000035945A8 (fr) 2001-07-05
JP2002532513A (ja) 2002-10-02

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