EP0881907A1 - Agents cycliques peptidiques antifongiques - Google Patents

Agents cycliques peptidiques antifongiques

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Publication number
EP0881907A1
EP0881907A1 EP97904148A EP97904148A EP0881907A1 EP 0881907 A1 EP0881907 A1 EP 0881907A1 EP 97904148 A EP97904148 A EP 97904148A EP 97904148 A EP97904148 A EP 97904148A EP 0881907 A1 EP0881907 A1 EP 0881907A1
Authority
EP
European Patent Office
Prior art keywords
compound
mmol
hydroxy
formula
subtitled compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP97904148A
Other languages
German (de)
English (en)
Other versions
EP0881907A4 (fr
Inventor
Stacy K. Henle
William W. Turner, Jr.
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Eli Lilly and Co
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Eli Lilly and Co
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Publication date
Priority claimed from GBGB9603151.3A external-priority patent/GB9603151D0/en
Application filed by Eli Lilly and Co filed Critical Eli Lilly and Co
Publication of EP0881907A1 publication Critical patent/EP0881907A1/fr
Publication of EP0881907A4 publication Critical patent/EP0881907A4/fr
Withdrawn legal-status Critical Current

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Classifications

    • 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

  • This invention relates to semi-synthetic cyclic peptide compounds which are useful as antifungal and antiparasitic agents and which have improved stability and water solubility.
  • it relates to derivatives of the echinocandin class of cyclic peptides, to methods for treating fungal and parasitic infections and to formulations useful in the methods.
  • the compounds provided by this invention are semi-synthetic compounds derived from cyclic peptides which are produced by cultunng various microorganisms.
  • number of cyc_ c peptides are known in the art including echinocandin B (A30912A) , aculeacm, mulundocandm, spo ⁇ ofungm, L-671,329, and S31794/F1.
  • these cyclic peptides may be characterized as a cyclic hexapeptide core (or nucleus) with an acylated ammo group on one of the core amino acids.
  • the ammo group is typically acylated with a fatty acid group forming a side chain off the nucleus.
  • echinocandin B has a lmoleoyl side chain while aculeacm has a palmitoyl side chain.
  • the fatty acid side chains may be removed from the cyclic peptide core to provide an ammo nucleus (for example, a compound of formula I, below, where F 2 is hydrogen) .
  • the ammo group may then be re-acylated to provide semi-synthetic compounds such as those claimed m the present application.
  • the echinocandin B nucleus has been re-acylated with certain non-naturally occurring side chain moieties to provide a number of antifungal agents (see, Debono, U.S. Pat. Ser. No. 4,293,489) .
  • cilofungm which is represented by a compound of formula IA where ?', R' and R"' are methyl, R xl , R x2 , R ⁇ 1 , RV 2 , Ri' 3 , RV4 and P° are each hydroxy and R 2 is p- (octyloxy)benzoyl .
  • the present invention provides a compound of formula I
  • R' is hydrogen, methyl, -CH2CH2NH2 or
  • R" and R'" are independently methyl or hydrogen;
  • R xl is hydrogen, hydroxy, -NH-R, or -O-R;
  • Ci-C ⁇ alkyl, or R zl and R z2 combine to form -CH (CH 2 ) e CH 2 -; R z3 and R z4 are independently hydroxy or Ci-Cg alkoxy; d is 1 or 2; e is 1, 2 or 3;
  • R x2 , RV 1 , RV 2 , RV 3 and R ⁇ 4 are independently hydroxy or hydrogen;
  • R° is hydroxy, -OP(O) (OH) 2 or a group of the formula:
  • R 1 is C 1 -C 6 alkyl, phenyl, p-halo-phenyl, p-nitrophenyl, benzyl, p-halo-benzyl or p-nitro-benzyl; R 2 is
  • A, B, and C are independently selected from the following groups:
  • X and Y are independently a bond or -C ⁇ C- ;
  • R 3 is C 1 -C1 2 alkyl, C 1 -C 12 alkoxy or -0-(CH 2 ) m -[0-(CH 2 ) n ]p-0-(Ci-C 12 alkyl); is 2, 3 or 4; n is 2, 3 or 4; and p is 0 or 1;
  • A, B, and C cannot all be O > — r ,* or a pharmaceutically acceptable salt thereof.
  • the present invention also provides a compound of formula II
  • R' is hydrogen, methyl or -CH2C(0)NH2
  • R" and R'" are independently methyl or hydrogen
  • R xl is hydrogen, hydroxy or -O-R
  • R z3 and R z4 are independently hydroxy or Ci-C ⁇ alkoxy; d is 1 or 2; e is 1, 2 or 3;
  • R 2 , RV 1 , R ⁇ 2 , RV 3 and R ⁇ 4 are independently hydroxy or hydrogen;
  • R° is hydroxy, -0P(0) (OH) 2 or a rroup of the formula:
  • R 1 is Ci-C ⁇ alkyl, phenyl, p-halo-phenyl, p-nitrophenyl, benzyl, p-halo-benzyl or p-nitro-benzyl;
  • R 2 is
  • A, B, and C are independently selected from the following groups:
  • X and Y are independently a bond or -C ⁇ C- ;
  • R 3 is C 1 -C 12 alkyl, C 1 -C 12 alkoxy or
  • compositions for inhibiting parasitic or fungal activity and methods of treating fungal or parasitic infections which employ the compounds of the invention.
  • the present invention also provides for the use of compounds of the invention for: inhibiting fungal activity, treating fungal infection, inhibiting parasitic activity, and treating or preventing the onset of Pneumocystis pneumonia in a host susceptible to Pneumocystis pneumonia.
  • C ⁇ -Ci 2 alkyl refers to a straight or branched alkyl chain having from one to twelve carbon atoms.
  • Typical C_-C ⁇ 2 alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, t- butyl, pentyl, 5-methylpentyl, hexyl, heptyl, 3,3- dimethylheptyl, octyl, 2-methyl-octyl, nonyl, decyl, undecyl, dodecyl and the like.
  • C 1 -C 12 alkyl includes within its definition the terms "Ci-C ⁇ alkyl" and C 1 -C 4 alkyl.
  • halo refers to chloro, fluoro, bro o or iodo.
  • C 1 -C 12 alkylthio refers to a straight or branched alkyl chain having from one to twelve carbon atoms attached to a sulfur atom.
  • Typical C 1 -C 12 alkylthio groups include methylthio, ethylthio, propylthio, isopropylthio, butylthio, 3-methyl-heptylthio, octylthio, 5, 5-dimethyl-hexylthio and the like.
  • C 1 -C 12 alkoxy refers to a straight or branched alkyl chain having from one to twelve carbon atoms attached to an oxygen atom.
  • Typical C 1 -C 12 alkoxy groups include methoxy, ethoxy, propoxy, butoxy, sec-butoxy, pentoxy, 5-methyl-hexoxy, heptoxy, octyloxy, decyloxy dodecyloxy and the like.
  • C 1 -C 12 alkyl includes within its definition the terms "Ci-C ⁇ alkoxy” and C1-C 4 alkoxy.
  • hydroxy protecting group refers to a substituent of an 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.
  • hydroxy protecting groups include tetrahydropyranyl, 2-methoxyprop-2-yl, 1-ethoxyeth- 1-yi, methoxymethyl, ⁇ -methoxyethoxymethyl, methylthiomethyl, t-butyl, t-amyl, trityl, 4-methoxytrityl, 4 , 4'-d ⁇ methoxytr ⁇ tyl, 4, 4', 4"-t ⁇ methoxytr ⁇ tyl, benzyl, allyl, trimethylsilyl, trimethylsilylethyl, (t- butyl)dimethylsilyl, and 2,2 ,2-tr ⁇ chloroethoxycarbonyl and the like.
  • hydroxy protecting group is not critical so long as the derivatized hydroxy group is stable to the conditions of the subsequent reaction(s) and can be removed at the appropriate point without disrupting the remainder of the molecule.
  • a preferred hydroxy protecting group is trimethylsilylethyl.
  • Further examples of hydroxy protecting groups are described in T.W. Greene, "Protective Groups m Organic Synthesis, " John Wiley and Sons, New York, N.Y., (2nd ed. , 1991) chapters 2 and 3.
  • protected hydroxy refers to a hydroxy group bonded to one of the above hydroxy protecting groups.
  • amino protecting group refers to substituents of the ammo group commonly employed to block or protect the amino functionality while reacting other functional groups on the compound.
  • amino protecting groups include formyl, trityl, phthalimido, trichloroacetyl, chloroacetyl, bromoacetyl, lodoacetyl groups, or urethane-type blocking groups such as benzyloxycarbony1, 4- phenylbenzyloxycarbonyl, 2-methylbenzyloxycarbonyl, 4- methoxybenzyloxycarbonyl, 4-fluorobenzyloxycarbonyl, 4- chlorobenzyloxycarbonyl, 3-chlorobenzyloxycarbonyl, 2 - chlorobenzyloxycarbonyl, 2, -dichlorobenzyloxycarbonyl, 4- bromobenzyloxycarbonyl, 3-bromobenzyloxycarbonyl, 4- nitrobenzyloxycarbonyl, 4-
  • ammo protecting group employed is not critical so long as the derivatized ammo group is stable to the condition of subsequent reaction(s) on other positions of the intermediate molecule and can be selectively removed at the appropriate point without disrupting the remainder of the molecule including any other ammo protecting group(s) .
  • Preferred ammo protecting groups are t-butoxycarbonyl (t-Boc) , allyloxycarbonyl and benzyloxycarbonyl (CbZ) .
  • inhibiting i.e. a method of inhibiting parasitic or fungal activity, includes stopping, retarding or prophylactically hindering or preventing the growth or any attending characteristics and results from the existence of a parasite or fungus.
  • contacting i.e. contacting a compound of the invention with a parasite or fungus
  • contacting includes a union or junction, or apparent touching or mutual tangency of a compound of the invention with a parasite or fungus.
  • the term does not imply any further limitations to the process, such as by mechanism of inhibition, and the methods are defined to encompass the spirit of the invention, which is to inhibit parasitic and fungal activity by the action of the compounds and their inherent antiparasitic and antifungal properties, or in other words, the compounds, used in the claimed methods are the causative agent for such inhibition.
  • pharmaceutically acceptable salt refers to salts of the compounds of the above formula which are substantially non-toxic to living organisms.
  • Typical pharmaceutically acceptable salts include those salts prepared by reaction of the compounds of the present invention with a mineral or organic acid or an inorganic base. Such salts are known as acid addition and base addition salts.
  • Acids commonly employed to form acid addition salts are mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid and the like, and organic acids sucn as p-toluenesulfomc, ethanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succmic acid, citric acid, benzoic acid, acetic acid, and the like.
  • mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid and the like
  • organic acids sucn sucn as p-toluenesulfomc, ethanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succmic acid, citric acid, benzoic acid, acetic acid, and the like.
  • salts examples include the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, onohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, lsobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succmate, suberate, sebacate, fumarate, maleate, butyne-1, 4-d ⁇ oate, hexyne-1, 6-d ⁇ oate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, pheny
  • Preferred pharmaceutically acceptable acid addition salts are those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and those formed with organic acids such as maleic acid and methanesulfonic acid.
  • Base addition salts include those derived from inorganic bases, such as ammonium or alkali or alkaline earth metal hydroxides, carbonates, bicarbonates, and the like.
  • bases useful m preparing the salts of this invention thus include sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate, and the like.
  • the potassium and sodium salt forms are particularly preferred.
  • any salt of this invention is not of a critical nature, so long as the salt as a whole is pharmacologically acceptable and as long as the counterion does not contribute undesired qualities to the salt as a whole.
  • Preferred compounds of this invention are those compounds of formula I where:
  • R', R" and R"' are each methyl
  • R yl , RY 2 , RY 3 and R are each hydroxy;
  • R xl is hydrogen, hydroxy or -O-R;
  • R is methyl, benzyl, -CH 2 CHOHCH 2 OH, - (CH 2 ) b NR zl R z2 or - (CH 2 ) 2 P R z3 R z4 ;
  • R zl and P z2 are independently hydrogen or C 1 -C 4 alkyl
  • R z3 and R z4 are independently hydroxy or methoxy
  • R x2 is hydrogen or hydroxy
  • R° is hydroxy, -OP(O) (OH) 2 or a group of the formula:
  • R 1 is methyl; or a pharmaceutically acceptable salt thereof.
  • R l is hydrogen or hydroxy
  • R x2 is hydrogen or hydroxy
  • R° is hydroxy
  • R 3 is C1-C12 alkoxy or -O- (CH 2 ) 2 -0- (C1-C 12 alkyl); or a pharmaceutically acceptable salt thereof.
  • X and Y are a bond; R 3 is Ci-C ⁇ alkoxy; or a pharmaceutically acceptable salt thereof.
  • the compounds of formula I may be prepared according to Reaction Scheme I, as follows.
  • R n at i s a naturally occurring cyclic peptide sidechain and R', R", R'", R xl , R x2 , R ⁇ 1 , Y 2 , RY 3 , RY , R° and
  • R 2 are as defined above.
  • Reaction scheme I is accomplished by carrying out reactions A and B, above.
  • the intermediate compound may be isolated by procedures well-known in the art, for example, the compound may be crystallized or precipitated and then collected by filtration, or the reaction solvent may be removed by extraction, evaporation or decantation.
  • the intermediate compound may be further purified, if desired, by common techniques such as crystallization or precipitation or chromatography over solid supports such as silica gel, alumina and the like, before carrying out the next step of the reaction scheme.
  • reaction IA a naturally occurring cyclic peptide of the formula IA is deacylated using procedures known in the art to provide an amino nucleus of formula IB.
  • This reaction is typically carried out using enzymatic deacylation by exposing the naturally occurring cyclic peptide to a deacylase enzyme.
  • the deacylase enzyme may be obtained from the microorganism Actinovlanes utahensis and used substantially as described in U.S. Patent Nos. 4,293,482 and 4,304,716, herein incorporated by reference.
  • the deacylase enzyme may also be obtained from the Pseudomonas species Deacylation may be accomplished using whole cells of Actmoplanes utahensis or Pseudomonas or the crude or purified enzyme thereof or using an immobilized form of the enzyme See European Patent Application No. 0 460 882 (December 11, 1991) .
  • Examples of naturally occurring cyclic peptides which may be used as starting materials include aculeacm (palmitoyl side chain) , tetrahydroechmocandm B (stearoyl side chain) , mulundocandin (branched C 15 side chain), L-671,329 (Ci 6 oranched side chain) , S 31794/Fl (tetradecanoyl side chain , sporiofung (C 15 branched side chain) , FR901379 (palmitoyl side chain) and the like.
  • a preferre ⁇ naturally occurring cyclic peptide is echinocandin B (a compound of formula IA where R', R" and R"' are each methyl, R xl , R x , RY 1 , RY 2 , RY 3 , RY 4 and R° are each hydroxy and R 2 is linoleoyl) .
  • the ammo nucleus of formula IB is then re-acylated using procedures known m the art to provide a compound of formula I where R° is hydroxy; R xl is hydroxy; and R 2 is an acyl group as defined hereinabove
  • the ammo nucleus may be acylated by reaction with an appropriately substituted acyl halide, preferably m the presence of an acid scavenger such as a tertiary amme, such as triethylamine.
  • the reaction is typically carried out at a temperature of from about -20°C to about 25°C.
  • Typical solvents for this reaction include polar aprotic solvents such as dioxane or dimethylformamide.
  • Solvent choice is not critical so long as the solvent employed is inert to the ongoing reaction and tne reactants are sufficiently solubilized to effect the desired reaction.
  • the ammo nucleus may also be acylated by reaction with an appropriately substituted carboxylic acid, in the presence of a coupling agent.
  • Typical coupling agents include dicyclohexylcarbodnmide (DCC) , N,N'-carDonyld ⁇ m ⁇ dazole, bis (2-oxo-3- oxazolid yDphosphmic chloride (BOP-Cl) , N-ethoxycarbonyl-2-ethoxy-l, 2-d ⁇ hydroqumolme (EEDQ) , benzotr ⁇ azol-1-yloxytr ⁇ pyrrol ⁇ dmophosphon ⁇ um hexafluorophosphate (PyBOP) and the like.
  • DCC dicyclohexylcarbodnmide
  • BOP-Cl bis (2-oxo-3- oxazolid yDphosphmic chloride
  • EEDQ 2-d ⁇ hydroqumolme
  • PyBOP benzotr ⁇ azol-1-yloxytr ⁇ pyrrol ⁇ dmophosphon ⁇ um hexafluorophosphate
  • ammo nucleus may be acylated with an activated ester of a carboxylic acid such as an ester of a carboxylic acid of the formula R 2 -COOH and p-nitrophenyl, 2 , 4, 5-tr ⁇ chlorophenyl, hydroxybenzotriazole hydrate (HOBT-H 2 0) , pentafluorophenol, N-hydroxysuccmimi ⁇ e and the like.
  • Preferred acylatmg moieties are the active esters of the carooxylic acid F 2 -COOH such as a benzot ⁇ azole ester.
  • the reaction is typically carried out for one to sixty five hours at a temperature from about 0°C to about 30°C in an aprotic solvent.
  • the reaction is generally complete after about twenty four to forty eight hours when carried out a temperature of from about 15°C to about 30°C.
  • Typical solvents for this reaction are tetrahydrofuran and dimethylformamide or a mixture of such solvents.
  • the amino nucleus is generally employed m equimolar proportions relative to the activated ester or with a slight excess of the ammo nucleus.
  • R xl is hydroxy
  • R xl is -O-R
  • the reaction is typically carried out in a polar aprotic solvent such as dioxane or dimethyisulfoxide at a temperature of from about 0°C to about 35°C, preferably at about room temperature.
  • Solvent choice is not critical so long as the solvent employed is inert to tne ongoing reaction and the reactants are sufficiently solubilized to effect the desired reaction.
  • Preferred acids include p-toluenesulfon_c acid, hydrochloric acid and camphorsulfonic acid.
  • R xl is - (CH 2 ) b NR zl z2 where R zl and R z2 are hydrogen
  • R xl is - (CH 2 ) b NR zl z2 where R zl and R z2 are hydrogen
  • Suitable catalysts clu ⁇ e N- me hylmorpholine N-oxide (NMO) and the like.
  • Typical solvents suitable for use in this reaction include dimethylformamide, tetrahydrofuran, acetone and dioxane.
  • Solvent choice is not critical so long as the solvent employed is inert to the ongoing reaction and the reactants are sufficiently solubilized to effect the desired reaction.
  • the reaction is preferably conducted at a temperature in the range of from about 20°C to about 30°C for about eighteen to twenty four hours .
  • the compounds of formula I where R° is hydroxy may be phosphorylated by reaction with an appropriately substituted alkyl or phenyl phosphate to provide a compound of formula I where R° is -O-PfOjOH-R 1 where R 1 is C ⁇ -C 6 alkoxy or phenoxy, or by reaction with an appropriately substituted alkyl or phenyl phosphonic acid to provide a compound of formula I where R° is -O-PfOjOH-R 1 where P 1 is Ci-C ⁇ alkyl, or an appropriately substituted phenyl or benzyl moiety, to provide a compound of formula I where P° is a group of tne formula -OPfOlOH-R 1 .
  • the phospnonic acid is typically used in an activated form, for example as a phosphonic halide, preferably a phosphonic chloride.
  • the reaction is carried out in the presence of a base such as lithium trimethylsilanolate (LiOTMS), lithium bis (trimethylsilyl) amide (LHMDS) , pyridine and the l ke.
  • a base such as lithium trimethylsilanolate (LiOTMS), lithium bis (trimethylsilyl) amide (LHMDS) , pyridine and the l ke.
  • the reaction is typically carried out for up to one hour at a temperature from about -30°C to about 0°C m an aprotic solvent such as tetrahydrofuran and dimethylformamide.
  • the reaction is generally complete about fifteen minutes when carried out under these conditions.
  • the phosphate or phosphonate reactant is generally employed in equimolar proportions to about a one mole excess relative to the ammo nucleus in the presence of an equimolar or slight excess of the base.
  • Phosphorylation of an ammo nucleus with unprotected ammal hydroxy groups is typically carried out at lower temperatures, for example from about -30°C to about -15°C.
  • the ammal hydroxy moieties on the compound of formula I are optionally protected with an hydroxy protecting group using procedures known in the art.
  • the reaction is typically carried out by combining the compound of formula I with a suitable hydroxy protecting group in the presence of a catalyst at a temperature in the range of from about 0°C to about 40°C for about one to five hours in a mutually inert solvent.
  • the hydroxy protecting group is generally employed m an amount ranging from about equimolar proportions to about a 100 molar excess relative to the compound of formula I, preferably in a large molar excess.
  • Suitable catalysts include strong acids such as p-toluenesulfonic acid, ca phorsulfonic acid (CSA) , hydrochloric acid, sulfuric acid, trifiuoroacetic acid and the like.
  • Typical solvents suitable for use in this reaction include any organic solvent such as dioxane. Solvent choice is not critical so long as the solvent employed is inert to the ongoing reaction and the reactants are sufficiently solubilized to effect the desired reaction.
  • the reaction is preferably conducted at a temperature in the range of from about 20°C to about 30°C for about two to four hours.
  • the protected compound of formula I is then phosphorylated as described above.
  • the hydroxy protecting group(s) are then removed according to procedures known in the art to provide a phosphorylated compound of formula I.
  • the protecting groups can be removed by reaction with a Lewis acid in a mutual inert organic solvent such as methylene chloride.
  • Lewis acids examples include t ⁇ methylsilylbromide, boron trifluoride etherate and the like.
  • the reaction is typically carried out at a temperature of from about 0°C to about 40°C, preferably at a temperature of from about 20°C to about 30°C.
  • a preferred Lewis acid is boron trifluoride etherate.
  • the dideoxy compounds of formula I are prepared by removing the benzylic and ammal hydroxy groups (R x2 and R xl , respectively) .
  • the hydroxy groups may be removed by subjecting a non-dideoxy compound of formula I (where R 2 is hydrogen or acyl) to a strong acid and a reducing agent at a temperature of between -5°C and 70°C, m a suitable solven .
  • Typical strong acids include trichloroacetic acid, trifiuoroacetic acid or boron trifluoride etherate. A preferred strong acid is trifiuoroacetic acid.
  • Typical reducing agents include sodium cyanoborohydride or t ⁇ ethylsilane.
  • a preferred reducing agent is triethyls lane.
  • Suitable solvents include methylene chlori ⁇ e, chloroform or acetic acid, preferably methylene chloride.
  • the strong acid should be present in an amount of from 2 to 80 mol per mol of substrate, and the reducing agent snould be present in an amount of 2 to 80 mol per mol of substrate. This process affords selective removal of the ammal and benzylic hydroxy groups.
  • the cyclic peptides used to make the compounds of the present invention may be prepared by fermentation of known microorganisms.
  • the cyclic peptide of formula IB where R', R" and R"' are methyl, R xl , P x2 , R l , RY2, Y 3 , R y4 and R° are each hydroxy (cyclic nucleus corresponding to A-30912A) may be prepared using the procedure detailed in Abbott et al.. U.S. Pat. Ser. No. 4,293,482, which is herein incorporated by reference.
  • the cyclic peptide of formula IB where R', R" and R'" are methyl, R xl is hydroxy, R x2 is hydrogen, R vl , RY 2 , RY 3 , RY 4 and R° are each hydroxy (cyclic nucleus corresponding to A-30912B) may be prepared using the procedure detailed in Abbott et al. , U.S. Pat. Ser. No. 4,299,763, which is herein incorporated by reference.
  • Aculeacm may be prepared using the procedure detailed in Mizuno et al .. U.S. Pat. Ser. No. 3,978,210 which is herein incorporated by reference.
  • the cyclic peptide of formula IB where R' is -CH 2 C(0)NH , R" is methyl, R"' is hydrogen, R xl , R 2 , RY*, RY 2 , RY 3 , RY 4 and R° are each hydroxy may be prepared by deacylating the cyclic peptide prepared using the procedure detailed m Chen et al. , U.S. Pat. Ser. No 5,198,421, which is nerein incorporated by reference.
  • the R 2 -COOH precursor acids may be obtained commercially or prepared according to procedures known m the art.
  • an appropriately substituted aryl boronic acid or biaryl boronic acid reactant may be reacted with a haloaryl carboxylic acid reactant in the presence of a catalyst such as tetrakis (triphenylphosphme)palladium and an inorganic base such as potassium carbonate in a mutual inert organic solvent such as toluene at a temperature of from about 20°C to the reflux temperature of the reaction mixture to provide the corresponding biaryl carboxylic acids and teraryl carboxylic acids used to prepare the compounds of formula I.
  • a catalyst such as tetrakis (triphenylphosphme)palladium
  • an inorganic base such as potassium carbonate
  • a mutual inert organic solvent such as toluene
  • the reaction is typically carried out with equimolar proportions of the boronic acid reactant and the aryl carboxylic acid reactant, or a slight molar excess of the aryl carboxylic acid reactant relative to the boronic acid reactant, and a 1-2 molar excess of the inorganic base.
  • the reaction is generally complete after about four to about ten hours when carried out at reflux temperature in toluene.
  • the boronic acid reactant may be prepared by reacting an appropriately substituted haloaryl or halobiaryl reactant with two equivalents of tmsopropyl borate in the presence of an alkyl lithium, for example sec-butyl lithium, m a mutual inert solvent such as tetrahydrofuran.
  • the alkyl lithium is typically employed in a slight molar excess relative to the haloaryl or halobiaryl reactant.
  • the alkyl lithium is typically combined with the solvent by dropwise addition at reduced temperatures ( ⁇ -70°C) and allowed to stir for approximately thirty minutes before the addition of the t ⁇ isopropyl borate.
  • the reaction is typically carried out initially at a temperature of from about -100°C to about -50°C, preferably from about -75°C to about -85°C for thirty minutes to two hours and then warmed to room temperature and reacted for an additional one to three hours.
  • the reaction is generally complete m several minutes to aoout four hours.
  • a preferred acid is a l ⁇ hydrochloric acid solution.
  • R 2 -COOH precursor acids having an acetylene -moiety may be prepared by reacting an appropriately substituted acetylene reactant with an appropriately substituted aryl or biaryl reactant of the formula
  • acid scavengers include triethylamine and pyridine, preferably triethylamine.
  • a preferred catalyst is formed in si tu from palladium (II) chloride, triphenylphosphine and copper (I) iodide.
  • reaction is typically carried out for thirty minutes to twenty one hours at a temperature from about room temperature to the reflux temperature of reaction mixture.
  • the reaction is generally complete after about two to about six hours when carried out at reflux temperature.
  • a suitably substituted aryl reactant of the formula may be reacted with an appropriately substituted acetylene reactant as described , a compound of the formula
  • NHR or where R' is CH2CH2NH2 can be prepared by procedures and schemes disclosed herein in combination with procedures well known in the art. For example, such procedures are exemplifed by but not limited to the following publictions: WO94/25048; WO94/25050; WO 96/08266; and WO 96/08507.
  • the desired subtitled compound was prepared substantially m accordance with the procedure detailed in Preparation 2B, using 15.8 ml of a 1.3M. sec-butyllithium solution (20.54 mmol), 7 ml (30.33 mmol) of trnsopropyl borate, 125 ml of a 1U hydrochloric acid solution and 450 ml of anhydrous tetrahydrofuran. Yield: 4.0 g of an orange solid.
  • Prepa ation 3 A Prepa ation 3 A.
  • the desired compound was extracted from the resultant mixture using diethyl ether and the organic portions were then washed with water, dried over magnesium sulfate, filtered and concentrated :n vacuo to provide 35 g of an oil. Purification with column chromatography using silica gel (eluent of 10% ethyl acetate hexane) to provide a clear oil. Yield: 20.7 g (60%) .
  • the desired subtitled compound was prepared substantially in accordance with the procedure detailed in Preparation 2B, using 2.72 g (10 mmol) of the subtitled compound of Preparation 3A, 10 ml (16 mmol) of a 1.6M. solution of sec-butyllithium in hexane, 5.5 ml (24 mmol) of triisopropyl borate, 50 ml of a 1JJ hydrochloric acid solution and 60 ml of diethyl ether. Yield: 1.98 g of a white solid (83%) .
  • the desired subtitled compound was prepared substantially in accordance with the procedure detailed m Preparation 2B, using 0.48 g (1.38 mmol) of the subtitled compound of Preparation 4A, 1.4 ml of a 1.6M . solution of sec-butyllithium in hexane (2.2 mmol), 0.76 ml (3.3 mmol) of triisopropyl borate, an excess of a IN hydrochloric acid solution and 50 ml of diethyl ether. Yield: 0.439 g.
  • the desired subtitled compound was prepared substantially in accordance with the procedure detailed in Preparation 2B, using 2.77 g (10.1 mmol) of the subtitled compound of Preparation 6B, 12 ml of a 1.3M. solution of sec-butyllithium in hexane, 400 g or 21.3 mmol (15.6 mmol) of triisopropyl borate, 16 ml of a 1 hydrochloric acid solution. The resultant layers were separated and the organic layer was concentrated in vacuo to provide 2.83 g of a crude material which was used without further purification.
  • the desired subtitled compound was prepared substantially in accordance with the procedure detailed in Preparation 2A, using 51 g (0.29 moles) of 4-bromo-phenol, 49.4 g (0.44 moles) of 1-bromoheptane in 800 ml of tetrahydrofuran to provide 77 g of an oil which was used without further purification.
  • the desired subtitled compound was prepared substantially in accordance with the procedure detailed in Preparation 2B, using 2.72 g (10 mmol) of the subtitled compound of Preparation 7A, 10 ml (16 mmol) of a 1..6M. solution of sec-butyllithium in hexane, 5.5 ml (24 mmol) of triisopropyl borate, 50 ml of a IN hydrochloric acid solution and 60 ml of diethyl ether. Yield: 1.98 g of a white solid (83%).
  • the desired subtitled compound was prepared substantially in accordance with the procedure detailed in Preparation 2C, using 1.22 g (5.16 mmol) of the subtitled compound of Preparation 7B, 1.0 g (5.16 mmol) of the subtitled compound of Preparation 6A, 598.3 mg (0.516 mmol) of palladium tetrakis (triphenylphosphine) , 11.6 ml of a 2M. sodium carbonate solution (23 mmol) , 25 ml of toluene and 10 ml of methanol. Yield: 1.4520 g (92%) .
  • N-methanesulfonate benzotriazole To a cold (5°C) solution of 100 g (0.653 mol) of hydroxybenzotriazole (HOBT) in 750 ml of methylene chloride, was added 82.59 g (0.816 mol) of triethylamine while maintaining the temperature at 5-10°C followed by the addition of 82.28 g (0.718 mol) of methanesulfonyl chloride while maintaining the temperature at 4-10°C. The resultant reaction mixture was reacted for approximately one hour at 4°C.
  • HOBT hydroxybenzotriazole
  • reaction mixture was transferred to a separatory funnel and washed sequentially with water (three times) and a saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo to provide a solid. This solid was combined with a small amount of diethyl ether and the resultant mixture was filtered and dried in vacuo to provide a white solid. Yield: 126.2 g (91%) .
  • the desired subtitled compound was prepared substantially in accordance with the procedure detailed in Preparation 2C, using 1.99 g (6.98 mmol) of the subtitled compound of Preparation 2D, 1.25 g (7.28 mmol) of the titled compound of Preparation 1, 0.811 g (0.73 mmol) of palladium tetrakis (triphenylphosphine), 15.8 ml (31.6 mmol) of a 2££ sodium carbonate solution, 50 ml of toluene and 20 ml of methanol. Yield: 1.3381 g (51%) .
  • the desired subtitled compound was prepared substantially in accordance with the procedure detailed in Preparation 2C, using 2.00 g (7.01 mmol) of the subtitled compound of Preparation 2D, 2.02 g (7.71 mmol) of methyl-4- iodobenzoate, 830 mg (0.70 mmol) of palladium tetrakis (triphenylphosphine), 16 ml (31.5 mmol) of 2M. sodium carbonate, 50 ml of toluene and 20 ml of methanol to provide an off-white powder which was used without purification. Yield: 2.28 g (90%) .
  • the desired subtitled compound was prepared substantially in accordance with the procedure detailed in Example IB, using 2.28 g (6.3 mmol) of the subtitled compound of Example 2A, 16.6 ml of a 2N. sodium hydroxide solution (33.2 mmol), 500 ml of dioxane and 33.2 ml of a IH hydrochloric acid solution. Yield: 1.55 g (71%) .
  • the desired subtitled compound was prepared substantially in accordance with the procedure detailed in Example 1C, using 1.55 g (4.46 mmol) of the subtitled compound of Example 2B, 1.02 g (4.78 mmol) of the titled compound of Preparation 9, 0.67 ml (4.82 mmol) of triethylamine and 125 ml of dimethylformamide to provide 0.320 g of a tan powder.
  • D Preparation of the compound of formula T where ?'. P" and Ft'" are each methvl and RSl, R* 2 , RZI. RY , zl . H ⁇ n H R- Q . are each hvdroxv and F-2. 1S 0
  • Example 2C The desired subtitled compound was prepared substantially accordance with the procedure detailed in Example ID, using 0.320 g (0.668 mmol) of the subtitled compound of Example 2C, 486.4 mg (0.609 mmol) of the A-30912A nucleus in dimethylformamide. Yield: 0.2832 (41%)
  • the desired subtitled compound was prepared substantially in accordance with the procedure detailed in Example IB, using 0.797 g (1.9 mmol) of the subtitled compound of Example 3A, 5 ml of a 2E sodium hydroxide solution (10 mmol) , 200 ml of dioxane and 10 ml of a IH hydrochloric acid solution. Yield: 518 mg (70%) .
  • the desired subtitled compound was prepared substantially in accordance with the procedure detailed in Example IB, using 0.458 g (1.13 mmol) of the subtitled compound of Example 4A, 5 ml of a 2 sodium hydroxide solution (10 mmol), 60 ml of dioxane and 10 ml of a
  • the desired subtitled compound was prepared substantially in accordance with the procedure detailed in Example 1C, using 0.51 g of the subtitled compound of Example 4B, 298 mg (1.4 mmol) of the titled compound of Preparation 9, 0.195 ml (1.4 mmol) of triethylamine and 50 ml of dimethylformamide to provide 234 mg of a white solid which was determined to be 98% pure using HPLC
  • R**-- 4 - and P- Q - are each hvdroxy and R 0
  • the desired subtitled compound was prepared substantially in accordance with the procedure detailed m Example 3A, using 131 mg (0.14 mmol) of Pd 2 dba 3 , 299 mg
  • the desired subtitled compound was prepared substantially in accordance with the procedure detailed m Example IB, using 200 mg (0.49 mmol) of the subtitled compound of Example 5A, 3 ml of a 2E sodium hydroxide solution (6 mmol), 15 ml of dioxane and 6 ml of a IN. hydrochloric acid solution to provide 153 mg of material which was used without further purification. Yield: 80%.
  • the desired subtitled compound was prepared substantially in accordance with the procedure detailed in Example 2C, using 2.00 g (7.03 mmol) of the subtitled compound of Preparation 5B, 1.51 g (8.80 mmol) of the titled compound of Preparation 1, 0.81 g (0.7 mmol) of palladium tetrakis (triphenylphosphine), 15.8 ml of a 2M solution of sodium carbonate (31.6 mmol), 50 ml of toluene and 20 ml of methanol to provide 0.8856 g of a solid. Yield: 30%.
  • the desired subtitled compound was prepared substantially in accordance with the procedure detailed in Example 1 B, using 0.8586 g (2.286 mmol) of the subtitled compound of Example 6A, 6 ml of a 2E sodium hydroxide solution (12 mmol), 228 ml of dioxane and 12 ml of a I hydrochloric acid solution to provide 0.65 g of material that was used without further purification. Yield: 78%.
  • the desired subtitled compound was prepared substantially in accordance with the procedure detailed in Example 1C, using 0.65 g (1.8 mmol) of the subtitled compound of Example 6B, 405 mg (1.90 mmol) of the titled compound of Preparation 9, 0.27 ml (1.94 mmol) of triethylamine and 60 ml of dimethylformamide. Yield: 624.4 mg (73%) .
  • the desired subtitled compound was prepared substantially in accordance with the procedure detailed in Example ID, using 587.7 mg (1.229 mmol) of the subtitled compound of Example 6C, 893 mg (1.119 mmol) of the A-30912A nucleus in 30 ml of dimethylformamide. Yield: 542.9 mg (38%) .
  • the desired subtitled compound was prepared substantially in accordance with the procedure detailed in Example 3A, using 1.415 g (5.95 mmol) of the subtitled compound of Preparation 6C, 2.75 g (7.63 mmol) of l-methoxycarbcnyl-4- (4'-trifluorosulfonate)phenyl, 863.3 mg
  • the desired subtitled compound was prepared substantially in accordance with the procedure detailed in Example IB, using 0.518 g (1.28 mmol) of the subtitled compound of Example 7A, 3.2 ml of a 2£J sodium hydroxide solution (6.4 mmol), dioxane and 6.4 ml of a IN. hydrochloric acid solution to provide 458.9 mg of material which was used without further purification.
  • the desired subtitled compound was prepared substantially in accordance with the procedure detailed in Example 1C, using 439.0 mg (1.12 mmol) of the subtitled compound of Example 7B, 251.5 mg (1.18 mmol) of the titled compound of Preparation 9, 0.165 ml (1.18 mmol) of triethylamine and 30 ml of dimethylformamide to provide 309 mg of a solid.
  • the desired subtitled compound was prepared substantially in accordance with the procedure detailed in Example IB, using 1.58 g (3.91 mmol) of the subtitled compound of Example 8A, 10.4 ml of a 2M sodium hydroxide solution (20.8 mmol), 250 ml of dioxane and 20.8 ml of a IE hydrochloric acid solution to provide 1.4133 g of material which was used without further purification.
  • MS(FD) 390.2.
  • the desired subtitled compound was prepared substantially in accordance with the procedure detailed m Example 1C, using 352.1 mg (0.902 mmol) of the subtitled compound of Example 8B, 202.2 mg (0.948 mmol) of the titled compound of Preparation 9, 0.13 ml (0.937 mmol) of triethylamine and 30 ml of dimethylformamide to provide 0.294 g of a solid which was used without further purification.
  • the desired subtitled compound was prepared substantially in accordance with the procedure detailed in Example ID, using 0.2881 g (0.5675 mmol) of the subtitled compound of Example 8C , 0.4116 g (0.516 mmol) of the A-30912A nucleus in 14 ml of dimethylformamide. Yield: 338.7 mg (51%) .
  • the desired subtitled compound was prepared substantially m accordance with the procedure detailed Example 2C, using 2.01 g (7.03 mmol) of the subtitled compound of Preparation 5B, 1.51 g (7.3 mmol) of the titled compound of Preparation 8, 816 mg of palladium tetrakis (triphenylphosphine) , 2E sodium carbonate, toluene and methanol. Yield: 1.9961 g (78%) .
  • the desired subtitled compound was prepared substantially in accordance with the procedure detailed in Example IB, using 1.996 g (5.47 mmol) of the subtitled compound of Example 9A, 13.7 ml of a 2N. sodium hydroxide solution (27.4 mmol) , 200 ml of dioxane and 13.7 ml of a I hydrochloric acid solution to provide 2.14 g of a solid. MS(FD) : 351.
  • the desired subtitled compound was prepared substantially in accordance with the procedure detailed in Example 1C, using 0.514 mg (1.47 mmol) of the subtitled compound of Example 9B, 0.393 g (1.84 mmol) of the titled compound of Preparation 9, 0.224 ml (1.61 mmol) of triethylamine in dimethylformamide. Yield: 0.377 g (55%) . MS(FD) : 467.
  • D Preparation of the compound of formula T where R'. R" and R-are each methyl and R*l, R*2, R-1, RY ⁇ . R ⁇ 3 .
  • R and R- Q - are each hvdroxy and R- 2 - is
  • the desired subtitled compound was prepared substantially in accordance with the procedure detailed in Example ID, using 355 mg (0.76 mmol) of the subtitled compound of Example 9C, 550.4 mg (0.69 mmol) of the A-30912A nucleus in 20 ml of dimethylformamide to provide 223.1 mg of a solid.
  • the desired subtitled compound was prepared substantially in accordance with the procedure detailed in Preparation 2C, using 1.50 g (5.28 mmol) of the subtitled compound of Preparation 5B, 1.06 g (5.56 mmol) of
  • the desired subtitled compound was prepared substantially in accordance with the procedure detailed in Example IB, using 1.609 g (4.08 mmol) of the subtitled compound of Example 10A, 10.5 ml of a 2E sodium hydroxide solution (21 mmol), 100 ml of dioxane and 21 ml of a I hydrochloric acid solution to provide 1.4935 g of a white solid which was used without purification.
  • MS(FD) 366.
  • the desired subtitled compound was prepared substantially in accordance with the procedure detailed Example 1C, using 1.47 g (4.02 mmol) of the subtitled compound of Example 10B, 907 mg (4.25 mmol) of the titled compound of Preparation 9, 0.6 ml (4.37 mmol) of triethylamine in dimethylformamide to provide 1.0498 g of a yellow powder which was used without purification.
  • the desired subtitled compound was prepared substantially accordance with the procedure detailed m Example ID, using 1.043 g (2.15 mmol) of the subtitled compound of Example 10C, 1.56 g (1.96 mmol) of the A-30912A nucleus in dimethylformamide. Yield: 2.4611 g. MS (FAB) for C 56 H 70 N 7 O 16 S: Calcd: 1128.4600;
  • the desired subtitled compound was prepared substantially in accordance with the procedure detailed Preparation 2C, using 150.6 mg (0.64 mmol) of the subtitled compound of Preparation 7B, 194.6 mg (0.78 mmol) of the subitled compound of Preparation 11B, 73.4 mg (0.06 mmol) of palladium tetrakis (triphenylphosphine) , 1.5 ml of a 2M solution of sodium carbonate (3 mmol) , 5 ml of toluene, and 2 ml of methanol to provide 190 mg of a light-brown solid which was used without further purification.
  • the desired subtitled compound was prepared substantially in accordance with the procedure detailed in Example IB, using 190 mg (0.47 mmol) of the subtitled compound of Example 11A, 2.5 ml of a I . sodium hydroxide solution (2.5 mmol), 33 ml of dioxane, and 2.5 ml ol a l£I hydrochloride acid solution to provide 165.3 mg of crude material which was used without further purification.
  • MS (FD) 390.
  • the desired subtitled compound was prepared substantially in accordance with the procedure detailed in Example 1C, using 150.4 mg (0.305 mmol) of the subtitled compound of Example 11B, 86.7 mg (0.407 mmol) of the titled compound of Preparation 9, 57 ⁇ l (0.415 mmol) of triethylamine in dimethylformamide to provide 73.3 mg of a light-brown solid which was used without further purification.
  • D Preparation of the compound of formula I where R'. R" and R'" are each methyl and R ⁇ . R*- 2 -. RY-1. RY ⁇ . R l . PY-1 and R- Q - are each hvdroxv and R ⁇ is 0
  • the desired subtitled compound was prepared substantially in accordance wi* "1 -. the procedure detailed in
  • Example 3A using 1.04 g (3.6 mol) of the subtitled compound of Preparation 5B, C 3 (4.02 mmol) of the subtitled compound of P ⁇ epara. . 12D, 0.375 g (0.32 mmol) of palladium tetrakis (triphe .; ..nosphine) , 8 ml of a 2M . solution of sodium carbonate (16 mmol), 26 ml of toluene and
  • the desired subtitled compound was prepared substantially in accordance with the procedure detailed in Example IB, using 559.3 mg (1.432 mmol) of the subtitled compound of Example 12A, 7.2 ml of 2N. sodium hydroxide (7.2 mmol), 90 ml of dioxane and 1M hydrochloric acid. Yield: 167.1 mg (92%) . 97/27864
  • the desired subtitled compound was prepared substantially in accordance with the procedure detailed in Example 1C, using 154.5 mg (0.426 mol) of the subtitled compound of Example 12B, 97.6 mg (0.458 mmol) of the titled compound of Preparation 9, 0.06 ml (0.431 mmol) of triethylamine and 14 ml of dimethylformamide. Yield: 100 mg (49%) .
  • the desired subtitled compound was prepared substantially in accordance with the procedure detailed in Example ID, using 100 mg (0.208 mmol) of the subtitled compound of Example 12C, 158 mg (0.198 mmol) of the A-30912A nucleus in dimethylformamide to provide 11.8 mg of the desired compound.
  • the compounds of formula I exhibit antifungal and antiparasitic activity.
  • the compounds of formula I inhibit the growth of various infectious fungi including Candida spp . such as C. albicans, C. parapsilosis , C. krusei , C. glabrata , or C. tropicalis , C. lusi taniae; Torulopus spp. such as T. glabrata ;
  • Aspergillus spp . such as A . fumigatus; Histoplas a spp . such as H. capsulatum; Cryptococcus spp . such as
  • Antifungal activity of a test compound was determined in vi tro by obtaining the minimum inhibitory concentration (MIC) of the compound using a standard agar dilution test or a disc-diffusion test. The compound was then tested in vivo (in mice) to determine the effective dose of the test compound for controlling a systemic fungal infection. Accordingly, the following compounds were tested for antifungal activity against C. albi cans .
  • the compounds of the invention also inhibit the growth of certain organisms primarily responsible for opportunistic infections m immunosuppressed individuals.
  • the compounds of the invention inhibit the growth of Pneumocystis car ii the causative organism of pneumocystis pneumonia (PCP) in AIDS and other lmmunocompromised patients.
  • Other protozoans that are inhibited by compounds of formula I include Plasmodiu spp. , Leisnmania spp. , Trypanosoma spp. , Cryp ospori ⁇ ium spp. , Jsospora spp. , Cyclospora spp. , T ⁇ chomonas spp . , Microsporidiosis spp. and the like.
  • the compounds of formula I are active m vi tro and in vivo and are useful combating either systemic fungal infections or fungal skin infections. Accordingly, the present invention provides a method of inhibiting fungal activity comprising contacting a compound of formula I, or a pharmaceutically acceptable salt thereof, with a fungus. A preferred method includes inhibiting Candi da albi cans or Aspergillus fum gatis activity. The present invention arther provides a method of treating a fungal infection unich comprises administering an effective amount of a compound of rormula I, or a pharmaceutically acceptable salt thereof, to a host in need of such treatment. A preferred method includes treating a Candida albi cans or Aspergill us fumigatis infection.
  • the term "effective amount," means an amount of a compound of the present invention which is capable of inhibiting fungal activity.
  • the dose administered will vary depending on such factors as the nature and severity of the infection, the age and general health of the host and the tolerance of the host to the antifungal agent.
  • the particular dose regimen likewise may vary according to such factors and may be given in a single daily dose or m multiple doses during the ⁇ ay
  • the regimen may last from about 2-3 days to about 2-3 weeks or longer.
  • a typical daily dose (administered m single or divided doses) will contain a dosage level of from about 0.01 mg/kg to about 100 mg/kg of body weight of an active compound of this invention
  • Preferred daily doses generally will be from about 0.1 mg/kg to about 60mg/kg and ideally from about 2.5 mg/kg to about 40 mg/kg.
  • the present invention also provides pharmaceutical formulations useful for administering the antifungal compounds of the invention Accordingly, the present invention also provides a pharmaceutical formulation comprising one or more pnarmaceutically acceptable carriers, diluents or excipients and a compound of claim 1.
  • 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.
  • pharmaceutically acceptable it is meant that the carrier, diluent or exc pient is compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • a compound of formula I may be administered parenterally, for example using intramuscular, sub- cutaneous, or mtra-peritoneal injection, nasal, or oral means In addition to these methods of administration, a 7/27864
  • compound of formula I may be applied topically for skin infections.
  • the formulation comprises a compound of formula I and a physiologically acceptable diluent such as deionized water, physiological saline, 5% dextrose and other commonly used diluents.
  • a physiologically acceptable diluent such as deionized water, physiological saline, 5% dextrose and other commonly used diluents.
  • the formulation may contain a solubilizing agent such as a polyethylene glycol or polypropylene glycol or other known solubilizing agent.
  • Such formulations may be made up in sterile vials containing the antifungal and excipient in a dry powder or lyophilized powder form.
  • a physiologically acceptable diluent Prior to use, a physiologically acceptable diluent is added and the solution withdrawn via syringe for administration to the patient.
  • the present pharmaceutical formulations are prepared by known procedures using known and readily available ingredients.
  • the active ingredient will generally be admixed with a carrier, or diluted by a carrier, or enclosed within a carrier which may be in the form of a capsule, sachet, paper or other container.
  • a carrier which may be in the form of a capsule, sachet, paper or other container.
  • the carrier serves as a diluent, it may 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 compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, sterile packaged powders and the like.
  • the antifungal compound is filled into gelatin capsules or formed into tablets. Such tablets may also contain a binding agent, a dispersant or other suitable excipients suitable for preparing a proper size tablet for the dosage and particular antifungal compound of the formula I.
  • the antifungal compound may be formulated into a flavored liquid suspension, solution or emulsion.
  • a preferred oral formulation is linoleic acid, cremophor RH-60 and water ana preferably in the amount (by volume) of 8% linoleic acid, 5% cremophor RH-60, 87% sterile water and a compound of formula I m an amount of from about 2.5 to about 40 mg/ml.
  • the antifungal compound may be formulated with a dry powder for application to the skin surface or it may be formulated m a liquid formulation comprising a solubilizing aqueous liquid or non-aqueous liquid, e.g., an alcohol or glycol.
  • active ingredient means a compound according to formula I or a pharmaceutically acceptable salt thereof.
  • Hard gelatin capsules are prepared using the following ingredients:
  • Active ingredient 250 Starch, dried 200
  • the solution of the above ingredients generally is administered intravenously to a suoject at a rate of 1 ml per minute.
  • the present invention further provides a method for treating or preventing the onset of Pneumocystis pneumonia in a host susceptible to Pneumocystis pneumonia which comprises administering an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, to a host in need of such treatment.
  • the compounds of formula I can be used prophylactically to prevent the onset of the infection which is caused by the organism Pneumocystis carinii , or alternatively they can be used to treat a host that has been infected with P. carinii .
  • a compound of formula I may be administered parenterally, for example using intramuscular, intravenous or mtra-pe ⁇ toneal injection, orally or by inhaling directly into the airways of the lungs.
  • a preferred mode of administration is inhalation of an aerosol spray formulation of a compound of formula I.
  • the term "effective amount,” means an amount of a compound of the present invention which is capable of inhibiting parasitic activity.
  • An effective amount of the compound of formula I is from about 3 mg/kg of patient body weight to about 100 mg/kg.
  • the amount administered may be in a single daily dose or multiple doses of, for example, two, three or four times daily throughout the treatment regimen.
  • the amount of the individual doses, the route of delivery, the frequency of dosing and the term of therapy will vary according to such factors as the intensity and extent of infection, the age and general health of the patient, the response of the patient to therapy and how well the patient tolerates the drug.
  • Pneumocystis pneumonia infections in AIDS patients are highly refractory owing to the nature of the infection.
  • advanced infections the lumenal surface of the air passages becomes clogged with infectious matter and extensive parasite development occurs in lung tissue.
  • a patient with an advanced infection will accordingly require higher doses for longer periods of time.
  • immune deficient patients who are not severely infected and who are susceptible to Pneumocystis pneumonia can be treated with lower and less frequent prophylactic doses.

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Abstract

Composés peptidiques cycliques, utiles comme agents antifongiques et antiparasitaires, présentant une stabilité améliorée. L'invention porte en particulier sur des composés d'un dérivé cyclique d'échinocandine et des compositions pharmaceutiques issues de ces composés.
EP97904148A 1996-02-01 1997-01-29 Agents cycliques peptidiques antifongiques Withdrawn EP0881907A4 (fr)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US1094696P 1996-02-01 1996-02-01
US10946P 1996-02-01
GBGB9603151.3A GB9603151D0 (en) 1996-02-15 1996-02-15 Cyclic peptide antifungal agents
GB9603151 1996-02-15
PCT/US1997/001607 WO1997027864A1 (fr) 1996-02-01 1997-01-29 Agents cycliques peptidiques antifongiques

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EP0881907A1 true EP0881907A1 (fr) 1998-12-09
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US6323176B1 (en) 1998-02-25 2001-11-27 Eli Lilly And Company Cyclic peptide antifungal agents
EP1107981B1 (fr) 1998-08-20 2005-01-26 Eli Lilly & Company Synthese des analogues peptidiques cycliques a systeme cyclique modifie
PT1137663E (pt) 1998-12-09 2006-12-29 Lilly Co Eli Purificação de compostos ciclopéptidos equinocandina
WO2000052037A1 (fr) 1999-03-03 2000-09-08 Eli Lilly And Company Complexes d'echinocandine/glucide
CA2362482A1 (fr) 1999-03-03 2000-09-08 Eli Lilly And Company Procedes permettant de preparer des compositions et des formulations pharmaceutiques orales d'echinocandine b
CA2362481C (fr) 1999-03-03 2008-11-04 Eli Lilly And Company Formulations pharmaceutiques d'echinocandine contenant des tensioactifs formant des micelles
KR20020002476A (ko) * 1999-03-03 2002-01-09 피터 지. 스트링거 결정질 에키노칸딘 암모늄염의 형성 및 음이온 교환
WO2004035563A1 (fr) * 2002-10-17 2004-04-29 Syngenta Participations Ag Derives de 3-heterocyclylpyridine utilises comme herbicides

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Also Published As

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WO1997027864A1 (fr) 1997-08-07
AU1851797A (en) 1997-08-22
JP2001503015A (ja) 2001-03-06
EP0881907A4 (fr) 2000-05-10
CA2244238A1 (fr) 1997-08-07

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